PMID- 23012714 TI - [Commentary on the work of R. Kiesslich et al., pp. 767]. PMID- 23012715 TI - [Commentary on the work of V. Jairath et al., pp. 723]. PMID- 23012716 TI - [Commentary on the work of M.H. Larsen et al., pp. 759]. PMID- 23012717 TI - [Commentary on the work of K. Garborg et al., pp. 740]. PMID- 23012718 TI - [Commentary on the work of J. Sung et al., pp. 754]. PMID- 23012719 TI - [The minimal surgical access for appendectomy and complication of the acute appendicitis]. PMID- 23012720 TI - [The focal nodular hyperplasia of the liver]. PMID- 23012721 TI - [The miniinvasive colon decompression by the tumor obstruction]. PMID- 23012722 TI - Bile leaks after videolaparoscopic cholecystectomy: duct of Luschka. Endoscopic treatment in a single centre and brief literature review on current management. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) for gallstone disease is the most common surgical procedures performed in Western countries and bile leaks remain a significant cause of morbidity (0.2-2%). The bile ducts of Luschka (DL)are small ducts which originate from the right hepatic lobe, course along the gallbladder bed, and usually drain in the extrahepatic bile ducts. Injuries to these ducts are the second most frequent cause of bile leaks after cholecystectomy. Aim of our study is build a literature review starting from our experience. PERSONAL EXPERIENCE: Forty four patients with abdominal bile collections post cholecystectomy by suspected bile leak under-went endoscopic retrograde cholagio pancreatography (ERCP). A complete cholangiogram was obtained in 42 patients(95.5%). In according to the magnitude of bile leak daily, we subdivided the patients in two groups: a) < 180 ml/daily,and b) > 180 ml/daily. The most common site of the leak was the cystic duct stump (94.5%), followed by DL (2 patient = 5.5%). 10 Fr stent insertion after endoscopic sphincterotomy (ES) was the most common intervention. In 6 patients (14%) a 7 Fr naso-biliary drainage was inserted. On an intention-to-treat basis, endoscopic intervention at ERCP had 100% success rate for resolution of the leak. The median time for resolution of the leak was 8 and 12 days in the first and second group respectively. No mortality ERCP-related were recorded. Early minor complications occurred in 7/42 (16.5%) patients. METHODS: A literature search using MEDLINE's Medical Subject Heading terms was used to identify recent articles.Cross-references from these articles were also used. RESULTS: ERCP is the most common diagnostic and therapeutic method used in bile leaks post-cholecystectomy. Most patients with DL leaks are symptomatic, and most leaks are detected postoperatively during the first postoperative week. Reduction of intra-ductal pressure with ES and stent or naso-biliary tube insertion will lead to preferential flow of bile through the papilla, thus permitting DL injuries to heal. This is the most common treatment modality used. In a minority of patients,re-laparoscopy is performed. In such cases, the leaking DL is visualized directly and ligation usually is sufficient treatment.Simple drainage is adequate treatment for a small number of asymptomatic patients with low-volume leaks. CONCLUSIONS: DL leaks occur after cholecystectomy regardless of gallbladder pathology or urgency of operation. They have been encountered more frequently in the era of LC Intraoperative cholangiography does not detect all such leaks. ERCP with ES and stent placement are the most common effective diagnostic and therapeutic methods used. Intraoperative and perioperative adjunctive measures, such as fibrin glue instillation and pharmacologic relaxation of the sphincter of Oddi,can potentially be used in lowering the incidence and in the treatment of DL leaks. PMID- 23012724 TI - Using multiple sampling approaches to measure sexual risk-taking among young people in Haiti: programmatic implications. AB - No previous published research has examined the applicability of varying methods for identifying young people who are at high risk of experiencing unintended pregnancy and acquiring HIV infection. This study compares three surveys of young people aged 15-24 in Port-au-Prince, Haiti, in terms of their sociodemographic characteristics and sexual behaviors and the surveys'usefulness for identifying young people at high risk and for program planning. The surveys consist of responses from: a representative sample of young people in the 2005-06 Haiti Demographic and Health Survey (HDHS), a 2004 facility-based study, and a 2006-07 venue-based study that used the Priorities for Local AIDS Control Efforts (PLACE) method. The facility-based and PLACE studies included larger proportions of single, sexually experienced young people and people who knew someone with HIV/ AIDS than did the HDHS. More respondents in the PLACE sample had multiple sex partners in the past year and received money or gifts in return for sex, compared with respondents in the facility study. At first and last sex, more PLACE respondents used contraceptives, including condoms. Experience of pregnancy was most commonly reported in the data from the facility-based sample; however, more ever-pregnant PLACE respondents than others reported ever having terminated a pregnancy. Program managers seeking to implement prevention activities should consider using facility- or venue-based methods to identify and understand the behaviors of young people at high risk. PMID- 23012725 TI - The impact of the African Youth Alliance program on the sexual behavior of young people in Uganda. AB - This study evaluates the impact of the African Youth Alliance (AYA) program on the sexual behavior of young people aged 17-22 in Uganda. Between 2000 and 2005, the comprehensive multicomponent AYA program implemented behavior-change communication and youth-friendly clinical services, and it coordinated policy and advocacy. The program provided institutional capacity building and established coordination mechanisms between agencies that implemented programs for young people. The analysis of findings from both a self-reported exposure design and a static group comparison design indicated that AYA had a positive impact on sexual behavior among young females but not among young males. AYA-exposed girls were at least 13 percentage points more likely to report having used a condom at last sex, at least 10 percentage points more likely to report that they had consistently used condoms with their current partner, at least 10 percentage points more likely to have used contraceptives at last sex, and 13 percentage points more likely to have had fewer sex partners during the past 12 months, compared with girls who were not exposed to the AYA program. Scaling up the AYA program in Uganda could, therefore, be expected to improve significantly the sexual and reproductive health of young women. Effective strategies for promoting safer sexual behaviors among boys and young men must be identified, however. PMID- 23012726 TI - The effectiveness of a community-based education program on abandoning female genital mutilation/cutting in Senegal. AB - A pre- and post-test comparison-group design was used to evaluate the effect of a community education program on community members'willingness to abandon female genital mutilation/cutting (FGM/C) in rural areas of southern Senegal. Developed by TOSTAN (a Senegalese nongovernmental organization), the education program aimed to empower women through a broad range of educational and health-promoting activities. Our findings suggest that information from the program was diffused widely within the intervention villages, as indicated by improvements in knowledge about and critical attitudes toward FGM/C among women and men who had and had not participated in the program, without corresponding improvement in the comparison villages. The prevalence of FGM/C among daughters aged ten years and younger decreased significantly over time as reported by women who were directly and indirectly exposed to the program, but not among daughters in the comparison villages, suggesting that the program had an impact on family behaviors as well as attitudes. Findings from this study provide evidence-based information to program planners seeking to empower women and discourage a harmful traditional practice. PMID- 23012727 TI - Use of dual protection in Botswana. AB - High rates of unintended pregnancy and of HIV and other sexually transmitted infections prompt calls for use of "dual-protection" strategies, including consistent condom use or dual-method use. This study examines the use of dual protection strategies in a sample of 15-49-year-old men and women in Botswana in 2003. Half of sexually active respondents reported consistent condom use in the past year; 2.5 percent reported dual-method use. Multiple logistic regression analyses showed that urban residence, less than a ten-year age difference between partners, discussing HIV and contraception with one's partner, not intending to have a child in the next year, having no children, being in a relationship where one or both partners have additional concurrent partners, and supportive condom norms were associated with dual protection--that is, with consistent condom or dual-method use. In the context of high HIV prevalence, concerns about disease prevention likely influence contraception, and interventions should address childbearing desires and sexual risk simultaneously. PMID- 23012728 TI - Democratic Republic of Congo 2007: results from the Demographic and Health Survey. PMID- 23012729 TI - Indonesia 2007: results from the Demographic and Health Survey. PMID- 23012730 TI - [Can 'the unlike' and 'the rejected' become 'the regained'? From persecution to tolerance and perhaps acceptance--a discourse devoted to homosexual men]. AB - The author, a sexologist engaged since many years in research on various aspects of homosexuality, presents a discourse on the fate of homosexually-oriented men throughout the centuries from antiquity till modern times. The presentation of various social approaches to homosexual men reveals a wide spectrum of attitudes, from persecution and execution on one side to growing tolerance and perhaps acceptance on the other. This article also includes an analysis of the definition of homosexuality taking into account positive and pejorative connotations which reflect changing social attitudes. The question in the title addresses various models of 'The Unlike' and 'The Rejected', often 'The Alien', who may perhaps become 'The Regained' in the 21st century. PMID- 23012731 TI - Abstracts of the 37th ESMO (European Society for Medical Oncology) Congress. September 28-October 2, 2012. Vienna, Austria. PMID- 23012732 TI - Abstracts of the 59th Congress of the German Society of Gynecology and Obstetrics. October 9-13, 2012. Munich, Germany. PMID- 23012733 TI - Correcting an error. PMID- 23012734 TI - Abstracts of the 11th Biennial Meeting of the Asian-Pacific Society for Neurochemistry and the 55th Annual Meeting of the Japanese Society for Neurochemistry. September 29-October 2, 2012. Kobe, Japan. PMID- 23012735 TI - Apoptotic lymphocyte as a clue to infectious mononucleosis. PMID- 23012736 TI - Effective primary health care is essential for a high-quality, equitable, and cost-effective health care system. PMID- 23012737 TI - Life changes as polar regions thaw. PMID- 23012738 TI - Sir Andrew Huxley: 1917-2012. PMID- 23012739 TI - Andrea Musacchio. PMID- 23012740 TI - From epithelial cells to body function and disease. PMID- 23012741 TI - A remembrance of Professor TP FENG. PMID- 23012742 TI - In great memory of a great physiologist and my mentor Te-Pei FENG. PMID- 23012743 TI - Interview with Fiona Marshall. PMID- 23012744 TI - Bullying. PMID- 23012745 TI - Antenatal screening for group B streptococcus. PMID- 23012746 TI - The final push for polio. PMID- 23012747 TI - 15th International Congress on Infectious Diseases. PMID- 23012748 TI - First Hand: The surgeon and hepatitis C. PMID- 23012749 TI - Systematic training: from "master classes" to "science". PMID- 23012750 TI - Losing and finding myself in DNA repair. PMID- 23012751 TI - Payroll battlers dealt another blow: pay docking legislation attacks workers' rights. PMID- 23012752 TI - Unions form joint position on aged care funding package. PMID- 23012753 TI - Hands up for better health care: get ready to join the new nursing and midwifery campaign. PMID- 23012754 TI - Keep tabs on your CPD. PMID- 23012755 TI - The new world of Hospital and Health Services. PMID- 23012756 TI - Newman Government attacks state IR laws. PMID- 23012757 TI - Midwifery-led models: it's all about trusting the experts. PMID- 23012758 TI - Recognising first people in the Constitution. PMID- 23012759 TI - Hybrid ORs set the stage for cutting-edge care. PMID- 23012760 TI - Management connections: journal clubs can improve nurse involvement and patient care. PMID- 23012761 TI - Medical tourism presents opportunities and risks for patients. PMID- 23012762 TI - In focus: Electronic surgical safety checklists: can they improve surgical outcomes? PMID- 23012763 TI - Perioperative nursing at children's hospitals. PMID- 23012764 TI - [Human biomonitoring values for polychlorinated biphenyls in blood]. PMID- 23012765 TI - The Affordable Care Act's pre-existing condition insurance plan: enrollment, costs, and lessons for reform. AB - The Pre-Existing Condition Insurance Plan (PCIP) is the temporary, federal high risk pool created under the Affordable Care Act to provide coverage to uninsured individuals with preexisting conditions until 2014, when exchange coverage becomes avail-able to them. Nearly 78,000 people have enrolled since the program was implemented two years ago. This issue brief compares the PCIP with state based high-risk pools that existed prior to the Affordable Care Act and considers programmatic differences that may have resulted in lower-than-anticipated enrollment and higher-than-anticipated costs for the PCIP. PCIP coverage, like state high-risk pool coverage, likely remains unaffordable to most lower-income individuals with preexisting conditions, but provides much needed access to care for those able to afford it. Operational costs of these programs are also quite high, making them less than optimal as a means of broader coverage expansion. PMID- 23012766 TI - The effect of the medication coverage gap on seniors with co-occurring depression and heart failure. PMID- 23012767 TI - [Population coding of fear memory in the lateral amygdala]. PMID- 23012768 TI - [Hyperinsulinemia as a risk factor for peripheral nervous system disorders]. PMID- 23012769 TI - Energy return on investment for algal biofuel production coupled with wastewater treatment. AB - This study presents a second-order energy return on investment analysis to evaluate the mutual benefits of combining an advanced wastewater treatment plant (WWTP) (with biological nutrient removal) with algal biofuel production. With conventional, independently operated systems, algae production requires significant material inputs, which require energy directly and indirectly, and the WWTP requires significant energy inputs for treatment of the waste streams. The second-order energy return on investment values for independent operation of the WWTP and the algal biofuels production facility were determined to be 0.37 and 0.42, respectively. By combining the two, energy inputs can be reduced significantly. Consequently, the integrated system can outperform the isolated system, yielding a second-order energy return on investment of 1.44. Combining these systems transforms two energy sinks to a collective (second-order) energy source. However, these results do not include capital, labor, and other required expenses, suggesting that profitable deployment will be challenging. PMID- 23012770 TI - Completely stirred tank reactor behavior in an unmixed anaerobic digester: the induced bed reactor. AB - The induced bed reactor (IBR) was developed to apply high-rate anaerobic digestion techniques to high suspended solids substrates (6 to 12% total solids). This technology has been implemented at multiple full-scale installations in the United States and Canada. Residence time distribution studies for 58-L laboratory scale reactors operated at a 3.8-day hydraulic retention time were conducted at 35, 45, and 55 degrees C under control and active digestion conditions. Rhodamine WT and lithium ion were used as tracers. The results show that the IBR most closely approximated completely stirred tank reactor behavior when operated under the study conditions. Mixing was likely a result of a (1) combination of energy inputs from thermal gradients induced by heat flux through the reactors, and (2) shear induced by gas evolution in the sludge bed. PMID- 23012771 TI - Utilization of recycled polypropylene-acrylate grafted nonwoven for the removal of oil from water. AB - To solve water pollution caused by oil spillage, a new sorbent was prepared by radiation-induced graft polymerization. Acrylate monomer was introduced to polypropylene nonwoven and hydrophobic groups were introduced by the grafting method. The grafting degree of sorbent was determined as a function of monomer concentration and solvent solubility for monomer. Fourier transform-infrared spectra and static contact angle measurements were used to characterize the chemical changes of the polypropylene nonwoven surface. The grafted sorbent showed a fast sorption rate and a maximum sorption capacity of 13.56 g/g for diesel oil, while the original polypropylene nonwoven was only 7.48 g/g. In addition, retention measurement and the reusability test were conducted to evaluate the suitability of the polypropylene-acrylate grafted nonwoven for the treatment of oil spillage. PMID- 23012772 TI - An alternative process to treat boiler feed water for reuse. AB - A bench-scale process to treat boiler feed water for reuse in steam generation was developed. Industrial water samples from a steam-assisted gravity drainage plant in northern Alberta, Canada, were obtained and samples characterized. The technology, which consists of coagulation-settling to remove oil/grease and particulates followed by an advanced oxidative treatment, led to clean water samples with negligible organic carbon. Coagulation followed by settling removed most particulates and some insoluble organics. The advanced oxidative treatment removed any remaining color in the samples, decreased the organic content to near zero, and provided water ready for reuse. PMID- 23012773 TI - Adsorption of Cu(II) from aqueous solution by wine processing waste sludge. AB - Wine processing waste sludge (WPWS) has been shown to be an effective sorbent for sorption of nickel, lead, and chromium, but the sorption of copper (Cu) in aqueous solution by WPWS has not been conducted. The objective of this study was to explore the sorption mechanism of WPWS for copper. Infrared analysis revealed carboxyl was the major functional group in WPWS. The WPWS sorption isotherms of copper were only well described by Langmuir sorption isotherm. The maximum adsorption capacity (Qm) was 14.26 mg/g at 50 degrees C. A pseudo-second-order sorption kinetic model successfully described the kinetics of copper sorption onto WPWS. The Gibb free energies (deltaG0) ranged from -20.69 to -24.29 kJ mol( 1), and the deltaH0 and deltaS0 were 5.048 kJ mol(-1) and 91.05 J mol(-1) K(-1), respectively. The trend of the intra-particular diffusion rate is the opposite of the adsorption constant of the pseudo-second-order equation. PMID- 23012774 TI - Effects of shear and surface roughness on reducing the attachment of Oscillatoria sp. filaments on substrates. AB - The effects of surface roughness and shear on the attachment of Oscillatoria sp. algal filaments onto SS314 stainless steel coupons were investigated. Average surface roughness was used to systematically characterize the surface condition. An annular biofilm reactor with a spinning inner cylinder was used to create a uniform shear flow over the coupons. As far as the authors are able to establish, these systematic methods have yet to be used in the study of microalgae deposition. It was postulated that increasing average surface roughness would lead to an increase in the amount of algae deposited, whereas an increase in shear would lead to a decrease in algae deposition and reduce the algae lengths by way of fragmentation. The results indicate that an increasing surface roughness would increase the amount of algal strands that might deposit on the coupons, whereas shear was found to have the effect of reducing the amount of algae that might attach on the coupons. PMID- 23012775 TI - Removal of molybdate anions from water by adsorption on zeolite-supported magnetite. AB - Industrial wastewater may contain high molybdenum concentrations, making treatment before discharge necessary. In this paper, the removal of molybdate anions from water is presented, using clinoptilolite zeolite coated with magnetite nanoparticles. In batch experiments the influence of pH, ionic strength, possible interfering (oxy)anions, temperature and contact time is investigated. Besides determination of kinetic parameters and adsorption isotherms, thermodynamic modeling is performed to get better insight into the adsorption mechanism; molybdenum is assumed to be adsorbed as a FeOMoO2(OH).2H2O inner-sphere complex. At the optimum pH of 3, the adsorption capacity is around 18 mg molybdenum per gram adsorbent. The ionic strength of the solution has no influence on the adsorption capacity. Other anions, added to the molybdenum solution in at least a tenfold excess, only have a minor influence on the adsorption of molybdenum, with the exception of phosphate. Adsorption increases when temperature is increased. It is demonstrated that the adsorbent can be used to remove molybdenum from industrial wastewater streams, and that the limitations set by the World Health Organization (residual concentration of 70 microg/l Mo) can easily be met. PMID- 23012776 TI - [Licensing of activity of medical subunits of military forces and commands of the Armed Forces of the Russian Federation]. AB - The purpose of this article is a synthesis and analysis of laws and regulations on the licensing of medical activities, the study of the current state and problems of licensing of medical units and the development of recommendations for medical directors in conducting the work associated with the licensing of medical activities of medical units of military units and formations of the military districts. PMID- 23012777 TI - [Obstetric-gynecologic care for female soldiers: status and prospects]. AB - The article presents the analysis of primary gynecologic pathology in female soldiers for the last years. The basic disease groups are marked out. The information about the very medical help standard in different hospitals is given. This paper presents the perspective directions of development of the delivery of obstetrical and gynecological care for women due to level of military medical establishments of the Russian Federation Ministry of Defense. PMID- 23012778 TI - [Problems of delivery of health care for children of servicemen and educates of general educational institutions of the Ministry of Defence of the Russian Federation]. AB - On the basis of the legal, instructional-methodological data and evaluation of the organization of medical care for children and adolescents identified the main challenges of pediatric services for the optimization of the Russian Defense Ministry interagency medical personnel accompany the children and adolescents, pre-university students in military educational institutions, at the stage of military reform and optimize the structure of the military medical service. To provide medical assistance to children of servicemen and DVOU pupils in accordance with the standards of health required the integration of interagency efforts of the military-medical institutions and medical institutions of state and municipal health systems. PMID- 23012779 TI - [Development of activity of ophthalmological center of multi purpose hospital unit on the basis of IT]. AB - The article explores the potential information technologies have to intensify the diagnosis and treatment process in the ophthalmological centre of multipurpose military hospital unit and examines the present information analysis system that automates the ophthalmologist's workplace. The operation algorithm of the given system in ophthalmology is peculiar and distinct from the ones in other fields. PMID- 23012780 TI - [Evaluation of gynecologic morbidity in female cadets of military universities of St. Petersburg]. AB - In-depth medical examination carried out a comprehensive survey of the dynamic female cadets of higher military educational institutions of the city of St. Petersburg in order to analyze the health of the troops of the Russian Federation Ministry of Defense personnel in the learning process, their level of gynecological diseases, as a possible consequence of influence of combat training. Following the study, shape, volume and frequency of activities to assess the health of women students, as well as a set of measures for the prevention of gynecological morbidity and dispensary of the contingent were developed. PMID- 23012781 TI - [Therapeutic morbidity rate among female military personnel, with exposure to occupational hazards in the period of service in the Armed Forces its influence on the course of pregnancy and fetal development]. AB - The study was made into therapeutic incidence among female military personnel who had contact with various kinds of occupational hazards in the period of military service, its impact on pregnancy and fetal development. Special attention was also paid to long-term consequences of obstetric and therapeutic pathological comorbidity on the development of the child. It has been established, that in the spectrum of therapeutic morbidity among female military personnel chronic gastritis, pyelonephritis and autoimmune thyroiditis prevail and often have a chronic stress as a background for their development. Children born to mothers, who in the period of pregnancy showed the combination of chronic pyelonephritis, autoimmune thyroiditis and late gestosis are a group of high risk for the development of the intracranial hypertension in children and/or infectious diseases. PMID- 23012782 TI - [Experience of use of synthetic cellular implants for correction of genitals prolapse]. AB - The results of extraperitoneal pelvic floor reconstruction using synthetic prostheses implanted Prolift of 86 patients with genital prolapse III-IV(POP-Q; ICS, 1996) are presented. Analysis of treatment, intraoperative and postoperative complications, factors influencing the choice of a rational method of surgical intervention is performed. The results show the high efficiency of the method--no recurrence genital prolapse in 97.7% of patients in the observation period from 6 months to 6 years. However, in 27.9% of cases, surgery is accompanied by complications of varying severity, which requires a comprehensive assessment and balanced approach to the choice of method of surgical treatment. PMID- 23012783 TI - [Role of various risk factors in the development and diagnosis of recurrent pain in adolescents--students of cadet corps]. AB - Randomized single-blind case--control study is performed. In total, the cadet corp students with recurrent functional abdominal pain and headaches are examined. The paper shows the role of various risk factors in the occurrence of these states. Diagnostic validity is evaluated. Multifactorial genesis of the studied pathology is proved. The essential role in the formation of the psychological characteristics of personality, neurotic states and autonomic dysfunction is shown. Several constitutional characteristics of the organism were not diagnostically significant. PMID- 23012784 TI - [Expert assessment of commands of naval medical service, incorporated in Service for Disaster Medicine]. AB - Expert assessment of possibilities of naval medical service for delivery of assistance in emergency situations in deployment areas is performed. It is noted that the main menaces are radiation, chemical accidents, and explosiveness of objects. Inconsistency between supposed losses and possibilities of naval medical service is probable in case of emergency. This inconsistency requires improvement of interaction with medical services of other ministries, drill of coordinative actions of naval medical commands with other commands of other ministries in organizational frames of united Service for Disaster Medicine. PMID- 23012785 TI - [Formation and development of the military gynecology]. AB - Data about formation and development of the system of delivery health and obstetric-gynecologic care in the Russian army since 19th century is represented in this article. Special attention is paid to delivery of care during the conduct of operations. A lot of archival documents are published for the first time. Department of Obstetrics and Gynecology of the Military Medical Academy made an outstanding contribution to development of military gynecology. PMID- 23012786 TI - [Development of clinical radiology in the Military field therapy Department of the Military Medical Academy (the 90th anniversary of the birth of G. I. Alekseyev)]. AB - On August 18, 2012, 90 years have passed since the birth of the former head of the Military field therapy Department of The Military-Medical Academy named after S. M. Kirov--the main radiologist of the Ministry of Defence of Russian Federation, the corresponding member of the Soviet Union Academy of Medical Science and the Russian Academy of Medical Science, the major- general of a medical service G. I. Alekseyev, who had been working in the department since its foundation till the last day of his life. Being the head of the department for twelve years, G. I. Alekseyev made a considerable contribution to the formation and development of native military radiology, training of medical and scientific skilled specialists. Professor G. I. Alekseyev's scientific ideas and views in the sphere of radiology were realized and developed in further educational, research and medical work of the department. Nowadays the staff of the Military field therapy Department remembers G. I. Alekseyev with special gratitude and appreciation and successfully realizes his ideas and plans in work. PMID- 23012787 TI - [Current problems of medical supply of military echelon of Armed Forces of the Russian Federation]. PMID- 23012788 TI - [Transcriptional regulation of RAAS genes--in vivo analysis by artificial chromosome transgenic mouse]. PMID- 23012789 TI - [Research of RAAS: progress and perspective]. AB - Pharmacological inhibitions of the renin-angiotensin-aldosterone system (RAAS) are crowned with one of the greatest success in the current field of cardiovascular medicine. In addition to the systemic effects including elevation of blood pressure and retention of sodium and water, sustained and excessive RAAS activation has direct and deleterious effects on a wide variety of tissues. Recent studies have deciphered the regulatory mechanisms underlying tissue RAAS activation at cellular and molecular levels, and suggested pathogenic roles of RAAS activation in hitherto unanticipated disorders such as muscular dystrophy, osteoporosis, cancer, and aging itself. Novel drugs targeting RAAS are under research and development in search for further efficacy, specificity, and even multifunctionality. This review will discuss the current progress and future perspective of RAAS research. PMID- 23012790 TI - [Regulatory mechanisms for the renin-angiotensin-aldosterone system]. AB - While the circulating renin-angiotensin-aldosterone system(RAAS) plays an important role in the regulation of the sodium and extracellular fluid balance and blood pressure, the tissue RAAS has been reported to be involved in the pathophysiology of organ damage in patients with hypertension and diabetes. However, the regulation of the tissue RAAS, that is the production of angiotensin II and aldosterone within the tissue independently of the circulating RAAS, remains undetermined in detail. The purpose of this article is to review the recent advances in tissue RAAS research with a particular focus on the roles of (pro)renin receptor in the pathological conditions and its physiological function. PMID- 23012791 TI - [Systemic distribution of prorenin and its receptor]. AB - The (pro)renin receptor was first identified as a 350-amino acid protein with a single transmembrane domain. This receptor binds to prorenin to mediate its dual functions: activation of ERK1/2 independently from angiotensin II generation and induction of full enzymatic activity to initiate angiotensin II-dependent effects. (Pro) renin receptor has recently been shown to undergo intracellular processing, such that it exists in three different molecular forms. These include the full-length (pro)renin receptor, truncated amino-terminal soluble fragment, and carboxy-terminal fragment containing an accessory protein of the vacuolar type H(+)-ATPase. Their exact distributions and existing molecular forms remain to be determined. PMID- 23012792 TI - [The ACE2/Ang(1-7)/Mas receptor axis in cardiovascular and renal diseases]. AB - The renin-angiotensin-aldosterone system(RAAS) plays a crucial role in the regulation of physiological homeostasis and diseases such as hypertension, coronary artery disease and chronic renal failure. In this cascade, the ACE/Ang II/AT1 receptor axis induces pathological effects, such as vasoconstriction, cell proliferation and fibrosis. Recently the ACE2/Ang(1-7)/Mas receptor axis has been recognized as a negative regulator of the RAAS. ACE2 metabolizes Ang II into Ang(1-7), which has opposite properties of Ang II through Mas receptor activation. Both animal and human studies provide strong evidence that the ACE2/Ang(1-7)/Mas receptor axis is protective for end-organ damage. Therefore, the ACE2/Ang(1-7)/Mas receptor axis could be a therapeutic target for coronary artery disease and chronic renal failure. PMID- 23012793 TI - [Mechanisms underlying angiotensin II-independent activation of angiotensin II type 1 receptor]. AB - A growing body of evidence indicates that activation of angiotensin II (Ang II) type 1 (AT1) receptor, a seven -transmembrane G protein -coupled receptor, is critically involved in the development of various cardiovascular diseases. Inherently, AT1 receptor is structurally unstable, and shows spontaneous constitutive activity in an Ang II-independent manner. The constitutive activity of AT1 receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when AT1 receptor is up-regulated in the heart. Furthermore, mechanical stress can activate AT1 receptor by inducing conformational switch without the involvement of Ang II, and induce cardiac hypertrophy in vivo. These agonist-independent activities of AT1 receptor can be inhibited by inverse agonists, but not by neutral antagonists. Therefore, inverse agonism of AT1 receptor blockers provides therapeutic benefits in the prevention of cardiac remodeling, and thus has potential impact on long-term outcomes in patients with cardiovascular diseases. PMID- 23012794 TI - [Physiology of novel AT1 receptor-binding molecule, ATRAP]. AB - The AT1 receptor (AT1R)-associated protein (ATRAP) is a molecule specifically interacting with the carboxyl-terminal domain of AT1R. The results of in vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R. Accumulating evidence indicates that a tissue-specific regulatory balancing of ATRAP and AT1R expression may be involved in the modulation of AT1R signaling at local tissue sites and also in the pathophysiology of hypertension and its associated end-organ injury. Furthermore, the activation of ATRAP in transgenic-models inhibited inflammatory vascular remodeling and cardiac hypertrophy in response to Ang II stimulation. These results suggest the clinical potential benefit of an ATRAP activation strategy in the treatment of hypertension and related organ injury. PMID- 23012795 TI - [Mineralocorticoid receptor: an update]. AB - The aldosterone-mineralocorticoid receptor (MR) system is traditionally considered as a system involved in the homeostatic regulation of body fluid and blood pressure in our body. A landmark clinical trial RALES caused a paradigm shift: growing attention has been focused on its role as a mediator of target organ damage. Recent studies clarified novel aspects of MR action in the pathophysiology of cardiac injury, through the analyses of genetically-engineered mice. My group focused on the anti-proteinuric effects of MR antagonist, and examined the role of MR overactivation in the progression of chronic kidney disease, and mechanisms of ligand-independent MR activation. In this paper, I would like to review the recent progress in the field of MR research. PMID- 23012796 TI - [Molecular and cellular mechanisms of organ fibrosis]. AB - Extracellular matrix (ECM) is important component for the organ architecture and function, and dynamically regulated by fibroblasts in normal state. In pathological condition, abnormal ECM accumulation or fibrosis is induced by pathological stimulation and associated with organ dysfunction in liver, lung, kidney and heart. In the process of fibrosis, complex molecular mechanisms including renin-angiotensin-aldosterone system and transforming growth factor beta signaling play critical roles regulating fibroblast activation and ECM deposition. In addition to resident fibroblasts, it has been reported that other cell types originated from epithelial/endothelial mesenchymal transition, circulating fibrocytes, or pericytes also contribute to fibrosis. Detailed examination for molecular and cellular mechanisms of fibrosis can contribute to future therapy for organ failure. PMID- 23012797 TI - [Mechanisms of impairment of endothelial cell]. AB - Nitric oxide (NO) released from endothelial cell plays an important role in the regulation of vascular tone, the inhibition of platelet aggregation, and the suppression of smooth muscle cell proliferation. Activation of renin-angiotensin aldosterone system(RAAS) plays an important role in the pathogenesis, development, and maintenance of atherosclerosis through an impairment of endothelial function. Angiotensin II stimulates the production of reactive oxygen species by the activation of NADPH oxidase and increases Rho-associated kinase activity that decreases the stability of endothelial nitric oxide synthase (eNOS) mRNA and phosphorylation of eNOS, leading to inactivation of NO bioavailability. An imbalance of reduced production of NO or increased production of reactive oxygen species may promote endothelial cell dysfunction through angiotensin II induced various signal transduction cascades. PMID- 23012798 TI - [Activation of osteoclasts by RAAS and strategy of target therapy on bone metabolic diseases]. AB - Angiotensin II is a potent stimulator of vascular smooth mustle cells that increases blood pressure, and angiotensin type 1 receptors have been identified on osteoblasts; thus, the renin-angiotensin system has been suggested to be involved in bone metabolism. The authors reported that angiotensin II significantly increased TRAP-positive multinuclear osteoclasts with the up regulation of RANKL expression through extracellular kinase of osteoblast. These effects were abolished with co-treatment of angiotensin converting enzyme (ACE) inhibitors or angiotensin type 1 receptor blockers (ARB). Recently, RANK-RANKL OPG system is proved to be involved in vascular calcification and RAAS also might be involved in the development of the disease. Thus, target therapy for RAAS might bring additional beneficial effects on bone metabolic diseases such as osteoporosis, rheumatoid arthritis and vascular calcification other than blood pressure lowering effect. PMID- 23012799 TI - [Cancer and renin-angiotensin system]. AB - Besides the renin-angiotensin system (RAS) plays a critical role in the regulation of the cardiovascular system, there is accumulating molecular and in vivo evidence to demonstrate that the RAS is implicated in the development or invasion of several kinds of cancer tissue. Recent studies indicate that AT1 receptor blockers have the anti-tumor effect in various cancers by inhibiting angiogenesis. Furthermore, some angiotensin peptides including angiotensin 1-7 have been clarified to influence malignancy, and the insertion/deletion polymorphism in the angiotensin converting enzyme gene is likely to be associated with the risk of cancer. This article provides an overview of important aspects on the cutting edge of RAS in some kinds of cancer. PMID- 23012800 TI - [Renin-angiotensin-aldosterone system inhibitors and electrolyte disturbances]. AB - Recent numerous clinical studies have suggested that the renin-angiotensin aldosterone system (RAAS) inhibitors have beneficial effects on hypertension, cardiovascular and chronic kidney diseases (CKD). Electrolyte disorder, especially hyperkalemia, is observed after the administration of RAAS inhibitors. This review focuses on the prevalence and severity of hyperkalemia with the use of RAAS inhibitors. Clinical evidences suggest that hypertensive patients with heart failure and CKD, and patients with combination treatment of RAAS inhibition are at higher risk of hyperkalemia, and serum potassium levels should be carefully monitored. PMID- 23012801 TI - [RAAS and insulin resistance]. AB - The role of the renin-angiotensin-aldosterone system (RAAS) on the development of insulin resistance and type 2 diabetes (T2DM) is an area of growing interest. Most of the deleterious actions of the RAAS on insulin signals appear to be mediated through activation of the serine/threonine kinase, oxidative stress and tissue-inflammation in insulin-sensitive organs. Both experimental and clinical studies demonstrated that angiotensin II (Ang II) and aldosterone could play a role in the development of insulin resistance, diabetes and cardiovascular diseases. Large randomized clinical trials revealed that blockade of the RAAS with either angiotensin I converting enzyme inhibitors or AT1 receptor blockers results in decreased T2DM incidence, with a minor attenuation of markers for insulin resistance. This review focuses on the role of RAAS in the pathogenesis of insulin resistance, as well as on clinical relevance of RAAS blockade in the prevention and treatment of the metabolic syndrome and pre-diabetes. PMID- 23012802 TI - [Adipose tissue renin-angiotensin system in obese]. AB - Activation of the renin-angiotensin system (RAS) is commonly observed in patients with obesity. Adipose tissue expresses all components of RAS, implicating adipose renin-angiotensin system (A-RAS) in the pathophysiology of obesity. Angiotensin converting enzyme(ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers ameliorate obesity-related metabolic derangement. Of note, CASE-J trial demonstrated that a systemic blockade of RAS significantly reduced the incidence of newly occurring type 2 diabetes, notably in obese patients with hypertension. We reported that adipose tissue-derived AGT is substantially augmented in obesity and may contribute to hypertension in humans, thereby highlighting a pivotal role of A-RAS in systemic RAS activation and resultant metabolic derangement. PMID- 23012803 TI - [Pathophysiological role of tissue renin-angiotensin-aldosterone system (RAAS) in human atherosclerosis]. AB - Renin-angiotensin-aldosterone system (RAAS) has been demonstrated to play an important role in the pathogenesis of atherosclerosis development both in animal experiments and in clinical studies. Numerous clinical studies have shown that blockade of RAAS exerts beneficial effects to restore the impaired endothelial function and to reduce the mortality and morbidity of cardiovascular diseases beyond their blood pressure lowering effect. However, the underlying mechanisms of stabilizing vulnerable plaque and inhibiting plaque rupture associated with acute coronary syndrome have not yet been fully elucidated. Here, we summarized the characteristics of tissue RAAS expressions in human atherosclerotic lesions and assessed their therapeutic relevance in the prevention of atherosclerotic cardiovascular diseases. PMID- 23012804 TI - [Cardio-renal interactions]. AB - The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in pathophysiology of kidney and cardiovascular disease, and their interactions. Clinical studies have demonstrated that RAAS inhibition reduces cardiovascular and renal events, particularly in patients with renal dysfunction. It may be assumed that impairment of renal function induces various injurious substances such as inflammation and oxidative molecules, which may activate RAAS, and RAAS, in turn, enhances inflammations and oxidative stress. Studies have shown that indices of renal protection, such as reductions of albuminuria, are closely associated with cardiovascular protection. In addition, decrements of renal function are also associated with worse prognosis. Inhibitors of RAAS decrease urinary albumin excretion but also reduce GFR. From the clinical point of view, the most appropriate antihypertensive regime would be the one that reduces albuminuria but maintain GFR. PMID- 23012805 TI - [The clinical usefulness of RAAS inhibitors in hypertensive patients]. AB - Many kinds of antihypertensive drugs have been used recently. JSH2009 supported that we should prescribe one of these drugs [calcium channel blockers, angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, diuretics and beta-adrenergic blockers] for hypertensive patients at first. In this review, we provide a brief overview of the ARBs and ACE inhibitors and discuss the clinical evidence related to the use of ACE inhibitors and ARBs. In accordance with JSH2009, we summarize the clinical backgrounds which we should use ARB or ACE inhibitors for hypertensive patients with: left ventricular hypertrophy, heart failure, atrial fibrillation, old myocardial infarction, protein urea, renal disturbance, chronic cerebral stroke, diabetes mellitus, metabolic syndromes and the elderly. PMID- 23012806 TI - [Role of RAAS inhibitors for the treatment of heart failure]. AB - Heart failure (HF) is defined as an inability of the heart to supply sufficient blood flow to meet demand of the body. HF is characterized by an activation of various neurohumoral factors including the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS). Thus, medical treatments mainly consist of the blockade of the RAAS and/or SNS. In this chapter, the role of the RAAS inhibitors is discussed for the treatment of patients with HF. PMID- 23012807 TI - [Effect of RAAS inhibition on stroke prevention]. AB - Recently, molecular and experimental studies revealed that the brain possesses its own renin-angiotensin-aldosterone system(RAAS) and the brain angiotensin(Ang) II plays an important role on stroke protection, mediating its effects through stimulation of AT2 and possibly the AT4 receptors. Moreover, the novel ACE2/Ang (1-7)/Mas receptor axis was found to counterbalance the vasoconstrictive actions of the ACE/Ang II/AT1 receptor. Recent clinical trials indicate that blockade of RAAS has a potential role in stroke prevention, but was not conclusive. More carefully designed large clinical trial are needed to verify blood pressure independent stroke prevention effect by RAAS inhibition. PMID- 23012808 TI - [Salt-induced inappropriate augmentation of intrarenal RAAS and its treatment in patients with chronic kidney disease]. AB - Focus on the role of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of hypertension and renal damage has shifted recently to the role of the local RAAS in the kidneys. Inappropriate augmentation of intrarenal RAAS activity in patients with chronic kidney disease has suggested playing important roles in the development of hypertension and renal injury. In this article, I show the recent findings that salt-induced this augmentation may contribute to the development of salt-sensitive hypertension and play a key role in cardiorenal syndrome (CRS), and that blockade of intrarenal RAAS may be an important strategy for salt-sensitive hypertension and CRS. PMID- 23012809 TI - [Diabetes mellitus]. AB - Recently renin-angiotensin-aldosterone system (RAAS) including angiotensin converting enzyme (ACE) 2-angiotensin (Ang)-(1-7) system may concern both pancreatic insulin secretion and insulin resistance (IR). Actually, Ang II introduces pancreatic beta-cell apoptosis and suppresses insulin signal transduction by modulation of adipokines. Ang II also suppresses GLUT4 expression and AMP kinase activity. All of them introduce new onset diabetes mellitus and various kinds of diabetic complications. RAAS suppression by using not only ACE inhibitor, Ang II receptor blockade (ARB) but also aldosterone receptor blockade improved insulin secretion and IR. Clinically, ACE inhibitor and ARB suppress new onset diabetes mellitus and diabetic complications. In this review we will focus on the recent findings related RAAS and glucose metabolism and diabetic complications with special reference to ACE2-Ang-(1-7) system. PMID- 23012810 TI - [Alzheimer disease--contribution of renin-angiotensin system to Alzheimer disease progression]. AB - There is increasing evidence that certain components of the renin-angiotensin system (RAS) may have a crucial role in learning and memory processes. We have previously shown that brain-penetrating ACE inhibitors can reduce the incidence of Alzheimer diseases (AD) in elderly hypertensive patients and that hypertension treatment with brain penetrating ACE inhibitors slowed the rate of cognitive decline in mild-to-moderate AD patients with hypertension. We speculate that the favorable effects might be due to the direct effects of brain-penetrating ACE inhibitors on RAS in the brain, since no significant differences were found in the levels of blood pressure among the groups treated with several antihypertensive drugs. Brain penetrating ACE inhibitors might have benefits not only for the prevention but also for the treatment of mild to moderate AD with hypertension. PMID- 23012811 TI - [Renin-angiotensin system (RAS) as new molecular therapeutic targets in prostate cancer]. AB - Angiotensin II and AT1 receptor could be involved in the growth of androgen independent prostate cancer since we found the higher expression of AT1 receptor in prostate cancer tissue than in normal tissue. Angiotensin II directly and indirectly stimulates the growth of prostate cancer cells and stromal cells including angiogenic cells. ARBs experimentally inhibited the proliferation of cancer cells and angiogenesis. The administration of ARBs for castration resistant prostate cancer (CRPC) induced the decline of serum prostate specific antigen (PSA) and the improvement of performance status in cachexic CRPC patients. These results support the hypothesis that an intrinsic RAS exists in the prostate gland and it is likely that ARBs are useful molecular targeting agents for CRPC. PMID- 23012812 TI - [Azilsartan: a new angiotensin receptor blocker]. AB - Azilsartan is a new ARB with the specific and potent angiotensin II receptor binding-inhibitory effect and more continuous angiotensin II antagonistic and antihypertensive actions in pre-clinical studies compared with other ARBs. The controlled clinical study in Japanese hypertensive patients indicates that once daily azilsartan dose provides more potent 24-hour sustained antihypertensive effect than that of candesartan but with equivalent safety. Azilsartan was confirmed to improve more potently the insulin-resistance in SHR and type 2 diabetic mice and suppress more prominently the urinary albumin excretion in type 2 diabetic fatty rats than other ARBs. Thus, azilsartan is a unique antihypertensive agent with the profile of more beneficial pharmacological activity, and could provide higher rates of hypertension control over 24-hour following once daily administration. PMID- 23012813 TI - [Current topic of next generation of angiotensin II type 1 receptor blockers]. AB - Angiotensin receptor blockers(ARBs) are used as the first-choice anti hypertensives for prevention of multiple organ damage. Recently, the next generation ARBs have been expected to have more preventive effect for cardiovascular diseases. For example, metabosartans which have a partial agonistic effect of peroxisome proliferator-activated receptor gamma induce an improvement of metabolism compared with ordinary ARBs. Moreover, LCZ696, ARB with a neprilysin inhibitor which increases natriuretic peptides has a significant reduction in blood pressure compared with ARB. Furthermore, ARBs with nitric oxide donor or endothelin receptor blocker have been reported to have a benefit beyond ordinary ARBs. Dual action in the next multi-functional ARBs may be a strong therapeutic contributor for patients with multiple organ dysfunction. PMID- 23012814 TI - [Current status of vaccination therapy for hypertension]. AB - The renin-angiotensin system (RAS) plays a central role in the control of systemic blood pressure. Since the 1950s, both laboratory and clinical studies have been performed to test the efficacy of vaccines against the RAS for the management of hypertension. Although initial studies using renin vaccines and angiotensin I vaccines were unsuccessful, a recent phase IIa study has shown that vaccination against angiotensin II is effective for the treatment of patients with essential hypertension. Results from animal studies have also suggested that vaccination against the AT1 receptor may be effective not only for lowering blood pressure, but also for the prevention of hypertensive end-organ damage. In the future, the RAS may be an important target for the development of vaccines not only for the treatment, but also for the prevention of hypertension and hypertensive complications. PMID- 23012815 TI - [Regulation of immune responses by immune semaphorins]. AB - The semaphorin family are soluble and membrane-bound proteins originally identified as axon guidance factors which are involved in the development of the neuronal system. Moreover, Plexin family members are the most representative semaphorin receptors. Recently, accumulating evidence indicates that several semaphorins, so-called 'immune semaphorins' such as Sema3A, 3E, 4A, 4D, 6D, 7A are crucially involved in various phases of immune responses. Some semaphorins and their receptors regulate immune cell activation or differentiation, whereas others navigate the trafficking of immune cells. Here, we review the current knowledge of the function of semaphorins and their corresponding receptors in immune system, which is focused on dendritic cell, T cell, macrophage, and osteoclast. PMID- 23012816 TI - [High expectation for combination tablets for diabetes treatment]. AB - Recently, a combination therapy of several oral agents has been more common for antihyperglycemic therapy and four kinds of combination tablets are available in Japan. Any combination tablet is not allowed for the initial treatment but very useful for a numbers of patients who are already taking two-drug combinations and in stable condition to reduce the number of tablets. Additionally, a combination tablet is also beneficial for patients who are in inadequate glycemic control with a single agent to gain the better glucose lowing effectiveness with a single tablet of dual agents. For a favorable treatment outcome of chronic diseases, it is very important for physicians to enhance drug adherence rate of patients and utilize combination tablets more. PMID- 23012817 TI - [Experimental investigation of the effects of representations and perspectives for the comprehension of line graphs]. AB - The comprehension of graphs is achieved through interaction between bottom-up and top-down processing. This study experimentally investigated the interaction between the graph representations determining bottom-up processing and the reader's perspective relating to top-down processing. Different representations on graphs generated from an identical data set elicited different interpretations of the graphs. We call this the "representation effect" on graph comprehension. In Experiment 1, we confirmed the characteristic of the bottom-up process of graph comprehension by using a set of line graphs which were identical in perceptual characteristics. In Experiments 2A and 2B, the participants were given a perspective for reading the graphs, and then they interpreted the graphs. The results showed that this perspective affected their comprehension of the graphs. Previous studies have shown that top-down processing may not be compatible with bottom-up processing in graph comprehension. However, our result indicated that top-down processing controlled by a perspective for reading the graph was not inconsistent with bottom-up processing, and therefore does not violate bottom-up processing. PMID- 23012818 TI - [Historical connection between memory and testimony psychology by an experimental study of Seiichi Terada in Japan]. AB - In Japan, Seiichi Terada (1884-1922) was the first psychologist who applied psychological knowledge to the field of law, working in collaboration with the law professor Eiich Makino (1878-1970). Terada's work was mainly in the tradition of clinical psychology, although in his 1915 paper titled "How useful are testimonies?" he described a set of seven experiments concerned with the empirical relationship between eyewitness testimony and memory. This is probably the first experimental study of law and psychology carried out in Japan. This article introduces Terada's history as a psychologist, and his collaboration with Makino, followed by explanation of their experiments. Finally, we discuss perspectives on testimony research in consideration of Terada's approach. PMID- 23012819 TI - [The emergency exit sign can be made more effective with advance information on the evacuation route]. AB - Often after opening an emergency door, an evacuee may need to turn right or left or go further straight ahead to reach the emergency exit. This study examined whether the currently-adopted emergency exit sign could be made more effective with advance information on the evacuation route. The current sign was modified by adding a left-bent or right-bent arrow to its left-facing or right-facing version respectively. In a computer-simulated evacuation task, participants were required to decide as quickly as possible which direction to turn after going through the door under the current or the modified exit sign. The modified sign was shown to be effective in leading the participants to choose the direction consistent with its directional arrow, whereas the current sign, whether left facing or right-facing, showed no such effect. However, in a recognition memory test given immediately following the completion of the simulated evacuation task, many of those who had successfully chosen the direction suggested by the modified sign falsely selected the current left-facing sign as what they had seen. PMID- 23012820 TI - [The role of punctuation in implicit phonological processing during reading]. AB - This study explored the phonological role of punctuation in silent reading. Previous studies have suggested that commas trigger prosodic information, such as a pause, in implicit phonological processing during reading, which influences sentence processing considerably. In this study, 24 graduate and undergraduate students read, either silently or under articulatory suppression, syntactically ambiguous Japanese sentences with different types of semantic bias. Each sentence was presented with or without a comma that was either compatible or incompatible with each semantic bias. The results showed that in the silent reading condition, commas affect the duration of sentence reading and that even a comma that was incompatible with the semantic bias increased the interpretation that each comma favored. However, in the articulatory suppressed condition these effects of commas disappeared. We concluded that commas phonologically affect the processing of syntactically ambiguous sentences, which indicates that commas elicit prosodic information when constructing phonological representations in reading. PMID- 23012821 TI - [Effects of advance visual cue utilization on anticipation of ball direction]. AB - We examined skill-based differences in the anticipation of ball direction during the catching of a grounder in baseball. In Experiment 1, we used film stimuli which included a sequence of pitching and hitting action from the shortstop's customary perspective, and participants judged the ball's direction (left or right). Also, we used white-circle stimuli, and participants reported whether the circle was displaced to the left or to the right. Baseball players responded faster than non-players in the film task, but there was no significant difference between the two groups in the white-circle task. In Experiment 2, we used film stimuli which were cut off at four different temporal occlusion periods to examine the time of extraction of important visual cues. Accuracy exceeded the chance level prior to the bat-ball contact in both groups, but was earlier for players than for non-players. Our results suggest that players may extract anticipatory visual cues more effectively and earlier than non-players. PMID- 23012822 TI - [Reliability and validity of marital love scale in middle- aged and elderly couples]. AB - A marital love scale was created to study the marital quality of middle-aged and elderly couples, and the scale's reliability and validity were examined. In this study, 888 middle-aged and elderly married participants completed the marital love scale questionnaire as well as answering questions regarding marriage satisfaction and husband-wife communication. In all age groups, men scored higher than women on the marital love scale. The marital love score gradually increased from the middle-aged to the senior period, and like the marriage satisfaction score, the marital love score showed a U-shaped curve in the whole married life. The results also showed that the scale was highly correlated with marriage satisfaction and spousal self-disclosure. Thus, the validity and internal consistency of the marital love scale were confirmed. PMID- 23012823 TI - [Construction and evaluation of a facial expression database of children]. AB - This study constructed and evaluated a facial expression database of children age 11 to 13 years old. To construct the database, we took 535 facial images of 53 male and 54 female Japanese children. The children were requested to express one neutral and four other emotions (happiness, surprise, sadness, and anger). To evaluate the subjective strength of the facially-expressed emotions, we had 43 Japanese participants (mean age = 22.67 years old) rate the strength of the four emotions for the facial images using a seven-point scale. We found that (a) the participants appropriately recognized the emotions from all the facial images except those showing sadness, (b) the male faces were rated as expressing surprise, sadness, and anger more strongly than the female faces, and (c) the female faces were rated as expressing happiness more strongly than the male faces. These results suggest that there may be a gender difference in the production of facial expressions in children 11 to 13 years old. PMID- 23012824 TI - [Judgment of gaze direction related to social anxiety: facial expressions and interpretation biases]. AB - The present study investigated the effects of social anxiety on judgments about gaze direction. The participants (N = 123) were divided into two groups on the basis of social anxiety scores (social anxiety and control group). Participants who scored high on a social anxiety scale judged the direction of slightly averted gaze to be straight more often for angry faces than for neutral faces. This pattern was reversed for participants in control group. An angry face looking straight at a person may be seen as an overt threat. People suffering from social anxiety tend to interpret ambiguous situations as negative or threatening. This negativity bias may contribute to the increased judgments of straight-gaze responses for angry faces with slightly averted gazes. PMID- 23012825 TI - [The effect of cognitive load on the temporal focus of mind wandering]. AB - The present study investigated the effects of cognitive load on the temporal focus of mind wandering. Participants performed a cognitive-load task under three load conditions (0 back, 1 back, 2 back). During each condition, thought sampling was conducted to measure task-unrelated thoughts. When a thought probe was presented, participants responded what they were just thinking. The results showed that future-related thoughts were reduced with increasing cognitive-load. On the other hand, past-related thoughts were not reduced under moderate cognitive-load but were under high cognitive-load. This indicates that future related thoughts require additional resources. Furthermore, future-related thoughts were more prevalent than past-related thoughts under low cognitive-load. These findings may indicate that a future prospective bias is important for survival. PMID- 23012826 TI - [Self-awareness through words]. PMID- 23012827 TI - [Indication for emergency surgery--up-to-date knowledge--: preface and comments]. AB - Emergency surgery is performed whenever abnormal condition threatens the life or health of the patients. Anesthesia for emergency surgery is a challenge with increased risk of various perioperative complications. Prior to emergency anesthesia the anesthesiologist may have only a limited amount of time to prepare the patient. Anesthesiologists and surgeons must communicate to establish higher priority for emergency surgery patients in operating room because not all patients are appropriate for emergency surgery. This article shows up-to-date knowledge on the indication for emergency surgery which anesthesiologist should have to perform appropriate patient triage in the operating room. PMID- 23012828 TI - [Emergency cesarean section]. AB - There are abundant cases of obstetric emergencies demanding prompt intervention. Emergency cesarean sections are classified into stable, urgent and immediate surgeries, although there is significant overlap between three groups. Stable emergency cesarean sections are performed in patients with stable maternal and fetal physiology, but who need surgery before unstability occurs. Urgent cesarean sections refer to situations in which maternal and/or fetal physiology is unstable, whereas the immediate cesarean section is used for life-threatening condition such as sustained fetal bradycardia, maternal cardiopulmonary arrest. In most cases the key to proper management is the prompt communication between obstetricians and anesthesiologists. Anesthesiologists must have a clear understanding of certain obstetric emergencies. In the event of sustained fetal bradycardia caused by placental abruption, cord prolapse, uterine rupture etc, delivery by immediate cesarean section within 25 minutes improve long-term neonatal neurologic outcome. Although cardiopulmonary arrest in pregnancy is very uncommon, peripartum cesarean section should be considered within 5 minutes not only for maternal resuscitation but for neonatal survival. Only a well coordinated teamwork of all involved specialities will guarantee optimal prognosis of mother and fetus. PMID- 23012829 TI - [Diagnosis and treatment of acute appendicitis in children]. AB - In this review article, we discussed the pathogenesis, pathophysiology, diagnosis and treatment of acute appendicitis in children. Indications for early surgery, the operative methods of laparoscopic appendectomy and the treatment outcome are also presented. PMID- 23012830 TI - [Emergency coronary artery bypass grafting for acute coronary syndrome]. AB - Since the drug eluting stents appeared in Japan, the indication for percutaneous coronary intervention has become wide-spread for the treatment of coronary artery disease. In the past decade, 216 patients underwent emergency/urgent coronary artery bypass grafting (CABG) in our institution, while the annual numbers of both emergency and elective CABG cases have declined. On the contrary to the decreasing number, emergency CABG patients were significantly getting older with multiple co-morbidities. Thus, off-pump CABG is likely to be beneficial for preventing postoperative complications, leading to the decreased postoperative mortality. When emergency CABG patients developed refractory myocardial ischemia and unstable hemodynamics, a percutaneous cardiopulmonary support system was quickly applicable and useful for on-pump beating CABG achieving complete surgical revascularization. For keeping satisfactory hemodynamics during CABG, communication between cardiovascular surgeons, anesthesiologists, and perfusionists is most important. PMID- 23012831 TI - [Surgical treatment of acute cholecystitis]. AB - Fundamental treatment for acute cholecystitis is cholecystectomy. However, the adoption of a treatment is dependend on degree of a severity of acute cholecystitis in each patient because its degree is influenced by factors such as duration from the onset of symptoms to medical examination. Early laparoscopic cholecystectomy is the preferred procedure for mild acute cholecystitis. Early cholecystectomy is also performed for moderately acute cholecystitis. However, if patients have severe local inflammation (gangrenous and purulent cholecystitis) early gallbladder drainage or open cholecystectomy is indicated. Emergency operation under adequate medical treatment is indicated for a patient with severe local inflammation of the gallbladder, torsion of the gallbladder, emphysematous cholecystitis, gangrenous cholecystitis, and purulent cholecystitis. Pericholecystic abscess, necrosis of the gallbladder wall, and perforation of the gallbladder can be diagnosed accurately by use of imaging diagnosis. The optimal surgical treatment for acute cholecystitis according to grade of severity should be performed referring to imaging findings. PMID- 23012832 TI - [Acute cervical spinal cord injury]. AB - Cervical spinal cord injury is a tragic trauma causing immediate serious quadriplegia and respiratory paralysis. In unstable injuries with paralysis, emergency surgery must be performed immediately to achieve spinal cord decompression and spinal column stabilization. In the treatment of dislocation fractures, first priority should be given to reducing the dislocation, by which the spinal cord is decompressed. A successful attempt to reduce the dislocation using skeletal traction is followed by elective surgery for fixation. In the case of a failure in reducing the dislocation, surgery with a posterior approach is performed to reduce the dislocation and provide internal fixation. In patients with considerably affected anterior column stability and those with any anterior compression that must be eliminated, such as intervertebral disc herniation or a vertebral body fragment, anterior decompression and fixation surgery is indicated. PMID- 23012833 TI - [Management of aneurysmal subarachnoid hemorrhage]. AB - The annual incidence of aneurysmal subarachnoid hemorrhage (SAH) is approximately 20 per 100,000/ year in Japan, and it is suggested that approximately 40% of SAH patients have poor outcome. Rebleeding after SAH and delayed cerebral vasospasm are the most important causes of poor outcomes. Particularly, rebleeding significantly worsened the outcome, therefore, its prevention is of utmost importance. Preventive measures against rebleeding include open surgery and endovascular treatment without craniotomy. Selection of the measures to prevent rebleeding should be based on neurological assessment, location and shape of cerebral aneurysm, anticipated difficulties in the treatment, presence of complications, etc. At present, surgical clipping remains the method of choice in Japan. However, there has been growing acceptance that the efficacy of endovascular treatment is comparable to that of surgical treatment, suggesting endovascular treatment should be considered in suitable patients with ruptured cerebral aneurysms. In this report, we describe the proceedures for the standard management of SAH, in particular, treatment of ruptured cerebral aneurysm and selection of treatment measures, according to the Japanese guidelines for the management of aneurysmal subarachnoid hemorrhage. PMID- 23012834 TI - [Acute scrotal pain]. AB - The onset of the pain, tenderness and swelling in the scrotal content is a common complaint in the urological outpatient. A child with those symptoms should be looked on as an emergency sign requiring emergency surgical exploration as a testicular torsion. Testicular torsion represents a surgical emergency because the likelihood of testicular salvage diminishes with the duration of torsion. Therefore, we must act quickly to identify this condition in any patient who presents with an acute scrotum. The history, physical examination and patient age can provide important clues as to the exact cause of acute scrotal pain. Age is a key factor since many conditions responsible for acute scrotum commonly occur in certain age groups. Moreover, imaging is used more routinely to identify accurate diagnosis. PMID- 23012835 TI - [Medical accidents and defense activities against criminal investigation--the attorney's point of view]. AB - Even after the criminal investigation has begun on a medical accident, immediate defense activities can prevent false indictment. On appointing a lawyer, one has to be careful of "conflicts of interests". Defense lawyers try to reconstruct what happened on the scene with the records and the comments of the persons involved. Meanwhile, they try to nail down the medical standards in the particular case by scrutinizing medical bibliography. If they succeed in pointing out to the authorities the possibilities of not guilty verdict, arrest or indictment can be avoided. PMID- 23012836 TI - [Prophylactic effect of diphenhydramine on postoperative vomiting in children after laparoscopic surgery]. AB - BACKGROUND: Laparoscopic percutaneous extraperitoneal closure (LPEC), introduced as an alternative to a conventional open inguinal hernia repair in children, has shown a higher incidence of postoperative vomiting (POV). The aim of this study was to examine whether a prophylactic use of diphenhydramine can decrease the incidence of POV in children undergoing LPEC. METHODS: We studied 60 girls between 1 and 6 years of age with ASA physical status I or II undergoing LPEC. Patients were allocated to receive either diphenhydramine 1 mg x kg(-1) intravenously (n = 30) or placebo (n = 30) during the operation. Anesthesia was performed with air-oxygen-sevoflurane in combination with epidural anesthesia. Opioids were avoided throughout the perioperative period. The incidence of POV was recorded postoperatively. RESULTS: Demographic data were similar between the groups. The overall incidence of POV during the first 24 postoperative hours was significantly higher in the placebo group (56.7%) than in the diphenhydramine (6.7%) group (P < 0.01). The wake-up in the ward was significantly prolonged in the diphenhydramine group than control group. CONCLUSIONS: Prophylactic use of diphenhydramine substantially reduced the risk of postoperative vomiting, but was associated with prolonged sedation in pediatric patients undergoing LPEC. PMID- 23012837 TI - [Effect of the sacroiliac ligament block on intractable low back pain in elderly patients]. AB - BACKGROUND: Lumbar spine disease in the elderly people is complicated by a variety of pathophysiology in the spine and the cause of the pain is unclear. Diagnosis of pain may be difficult in patients with pain in the thigh and groin area. Sacroiliac joint is supporting the trunk and movable joint. We examined the effect of the sacroiliac joint block for intractable low back pain. METHODS: Retrospectively we examined the duration of disease in patients with hip and leg pain visiting the hospital for eight months, and we questioned the site of pain awareness. Newton test, Gaenslen test, Patrick test and Fadire test were carried out for sacroiliac joint pain in patients with at least one positive finding. When performing sacroiliac ligaments block local anesthetics was injected to check the position of the dorsal sacroiliac ligaments under ultrasonic echo whenever possible. The block is performed with the patients prone at a point one finger from the posterior superior iliac spine level at an angle of 30-45 degrees downward toward the outside. Injecting the drugs penetrating the ligament continued to give a feel slightly outward to avoid the iliac Cattelan 23 G needle. We confirmed pain assessment NRS at 11 (0-10), and the improvement of pain was assessed with the change of the NRS on the next return. RESULTS: NRS showed a significant decrease at all points in time before block, their pain decreased gradually. The patients showed NRS improvement of more than 50% of the first block in 15 of 24 patients. CONCLUSIONS: Block at the posterior sacroiliac ligament region significantly reduced pain for chronic intractable low back pain. The block was shown to be effective as a treatment and for diagnosis. PMID- 23012838 TI - [Pediatric central venous catheterization through the axillary veins using ultrasound guidance]. AB - BACKGROUND: Axillary veins (AXVs) are selected for the central venous catheterization (CVC) in adults using ultrasound echo but quite rarely in children. We evaluated the relationships between the widths and the depths of the pediatric AXVs. METHODS: The widths and the depths of the AXVs were measured using an ultrasound echo apparatus in fifty patients. RESULTS: The widths and depths of the AXVs were about 3.8 and 10.0 mm in patients of about 75.7 cm in height. In 35 children less than 80 cm in height, AXVs depth to width ratios (D/W) averaged 3.6, and the CVC through the AXVs seemed difficult, whereas in 7 children of more than 100 cm in height, D/W averaged 1.7, and it seemed easy. CONCLUSIONS: We should know the AXV characteristics to secure the pediatric CVC through the AXV. PMID- 23012839 TI - [Case of successful management with mirtazapine for prolonged pain after esophagectomy]. AB - This case report describes a successful outcome of mirtazapine treatment in a patient with difficult post-thoracotomy pain. A 63-year-old man received thoracotomy for the resection of esophageal tumor. The pain continued 2 years after the operation. Allodynia was present in the region of the intercostal nerves from the surgical wound. Remedies such as clonazepam, amitriptyline, gabapentin, and acetaminophen were not effective, and epidural block effect was only temporal. The patient experienced a reduction in shooting pain after taking pregabalin; however, he still suffered from persistent pain and, mirtazapine was additionally administrated. One month after this, shooting and persistent pain was reduced, and the patient's appetite was improved, which had been present since the thoracotomy. Since then, his weight slightly increased and the administration of mirtazapine was stopped in accordance with the patient's request. The pain became worse again. Therefore, mirtazapine, commonly used as an antidepressant agent, was considered to be beneficial for neuropathic pain as an analgesic adjuvant. PMID- 23012840 TI - [Anesthetic management using muscle relaxant in a patient with amyotrophic lateral sclerosis]. AB - A 31-year-old woman with amyotrophic lateral sclerosis (ALS) with respiratory muscle paralysis was scheduled for tracheotomy. After applying standard neuromuscular monitoring devices, general anesthesia was induced and maintained with propofol, remifentanil, rocuronium, and sevoflurane. Sugammadex is a potent agent for reversal of neuromuscular blockade by rocuronium. The patient emerged from general anesthesia smoothly using sugammadex; however, assisted respiration was continued for possible prolongation of the effect of muscle relaxant. The postoperative course was uneventful, and she was discharged without any discomfort. PMID- 23012841 TI - [Case of ulnar nerve palsy in a patient with a history of total elbow arthroplasty after abdominal surgery under general anesthesia]. AB - Ulnar nerve palsy is a well recognized complication of the general anesthesia. We experienced a case of ulnar nerve palsy after abdominal surgery under general anesthesia in a patient with a history of total elbow arthroplasty and ulnar nerve translocation. It appears that pressure on medial epicondyle caused the palsy and that the position of the ulnar nerve has to be carefully examined before surgery in a patient with a history of total elbow arthroplasty and ulnar nerve translocation. PMID- 23012842 TI - [Comparison of continuous cardiac output measurement methods: non-invasive estimated CCO using pulse wave transit time and CCO using thermodilution]. AB - BACKGROUND: esCCO (estimated continuous cardiac output, Nihon Kohden, esCCO) is a new cardiac output measurement system which uses pulse wave transit time to calculate cardiac output continuously and non-invasively. One of the most commonly used methods to monitor cardiac output is continuous cardiac output CCO (Edwards Lifesciences) which has an accuracy equivalent to that of thermodilution method. METHODS: We compared esCCO to CCO in 67 operating room patients and 128 intensive care unit patients. CCO and esCCO were measured simultaneously in patients with a pulmonary artery catheter inserted after admission to the operating room or intensive care unit. RESULTS: CCO and esCCO showed a high correlation with a correlation coefficient of 0.84 in 496 total data points, and 95% limits of agreement between these two methods were -2.49 to 2.35 l x min(-1). CONCLUSIONS: This result suggests that esCCO could be used to measure cardiac output accurately and non-invasively in different cases. PMID- 23012843 TI - [Influence of intraoperative fentanyl and remifentanil infusion on early postoperative oral intake after general anesthesia]. AB - BACKGROUND: There is no reports on influence of intraoperative fentanyl and remifentanil infusion on ability of oral intake after short stay surgery under general anesthesia. METHODS: Data were collected retrospectively on 497 patients undergoing short stay surgery under general anesthesia with intraoperative remifentanil infusion (R group, n = 273) or without intraoperative remifentanil infusion (NR group, n = 224). The amount of fentanyl used and percentage of patients unable to eat supper were compared. RESULTS: Amount of fentanyl used in patients unable to eat supper were significantly higher than in patients able to eat supper in both NR and R groups. There is no difference in the percentage of patients unable to take supper between group NR and R. Total amount of fentanyl used was significantly lower in group R than in group NR. CONCLUSIONS: With or without the use of remifentanil, greater the amount of fentanyl used, greater the percentage of patients unable to eat. Amount of fentanyl used in R group was significantly less than in group NR; however the difference in percentage of patients unable to eat supper was not observed. PMID- 23012844 TI - [Cuffed pediatric endotracheal tubes]. AB - BACKGROUND: The goal of this investigation was to evaluate the details of cuffed pediatric endotracheal tubes (PCETTs, I.D. 3.0-6.0 mm) available in Japan. METHODS: Following dimensions of all PCETTs were measured; the distance from the tube tip to the distal/proximal border of cuff, cuff length, cuff volume and cuff diameter at 20 cmH2O cuff pressure, outer diameter and length of tubes, the distance from tube tip to the distal border of depth markings, length and the number of depth markings, calculated cross sectional area of the Murphy eyes, and the number of the Murphy eyes. RESULTS: A total of 73 PCETTs, including 20 brands from 10 manufacturers, were investigated, in which 82.2% of PCETTs are larger than I. D. 5.0. There are significant differences in the distance from tube tip to the distal/proximal border of the cuff, and the cuff length at 20 cmH2O cuff pressure for a given I.D. Some tubes have no depth markings, others have multiple ones, and depth markings are positioned differently. Eighty-three point six % of PCETTs have one Murphy eye. CONCLUSIONS: There is no uniformity in the details of PCETTs available in Japan. The details of PCETTs including cuff design and depth marking should be updated. PMID- 23012845 TI - [Phagocytosis of Mycobacterium leprae down-regulates anti-microbial activity of murine macrophages against Mycobacterium intracellulare]. AB - Patients with highly bacillated lepromatous leprosy (LL) essentially lack T cell mediated immune responses specific to Mycobacterium leprae (ML) antigens, resulting in severely impaired host resistance to leprosy bacilli. Such type of immune unresponsiveness characteristic of LL patients is mainly attributable to markedly depressed T cell ability to activate/expand in response to ML antigens. In this study, we examined profiles of antimycobacterial activity of macrophages, which phagocytized leprosy bacilli, because there is another possibility that, in LL patients, host macrophages in the leprosy lesions are impaired in their antimicrobial activity due to their interaction with infected leprosy bacilli, particularly cellular events through binding with and/or internalization of the pathogens, thereby causing the reduction in host resistance to ML pathogens. The present study indicated the following. First, the anti-M. avium complex activity of murine peritoneal macrophages was significantly reduced when they had phagocytosed heat-killed leprosy bacilli. Second, infection of macrophages with leprosy bacilli did not affect macrophage-mediated suppressor activity against T cell proliferative response to Concanavalin A. These findings indicate that macrophage's intracellular signaling pathways that are up-regulated in response to phagocytosis of leprosy bacilli are linked to the signaling cascades participating in macrophage antimicrobial functions, but not cross-talk with those allowing the expression of macrophage's suppressor activity against T cell functions. PMID- 23012846 TI - [Buruli ulcer and the National Health Insurance Scheme in Ghana]. AB - The objectives of this paper are to grasp the current status of an endemic disease in the Republic of Ghana known as Buruli ulcer(BU) and to clarify relationships between the National Health Insurance Scheme(NHIS) and the health care system. As for the method of the study, I have adopted field investigations conducted in Ghana in March, 2009 and August, 2011. All the counter-measurements on BU taken either by the very government or international NGOs have been administered and controlled the disease in accordance with the National Buruli ulcer Control Programme(NBUCP) under the guidance of Global Buruli ulcer Initiative which was established in Geneva, Switzerland in 1998 as an advisory committee of the World Health Organization. BU patients can receive treatments free. The government sponsored NBUCP and direct and indirect donations from various NGOs provide the cost of medical treatments. The Ghanian NHIS of 2003 aimed to ease and improve the health situations of the people. Some of serious endemic diseases like BU, however, are excluded from the schemes. While the NHIS remains ineffective to the diseases like BU, the burden of treatment costs puts the strain on NBUCP. The field researches indicate that the budgets provided by the NBUCP often faile to cover the fundamental medical supplies like bandages. This causes to give an extra burden on the already constrained hospital budgets. Only reliefs the hospitals can rely on are the international aids which often determine the fate of the national disease control. The research reveals that the region's health system remains unsound. Ghana represents such realities of West Africa as a whole. PMID- 23012847 TI - Genotyping of Mycobacterium leprae in Myanmar and possible transmission modes. AB - The polymorphism of TTC repeats in Mycobacterium leprae was examined using bacilli from slit skin samples of leprosy patients attending at Central Special Skin Clinic, Yangon General Hospital and nasal swabs of their contacts to elucidate the possible mode of leprosy transmission. It was found that bacilli with different TTC genotypes were distributed among same household contacts and also harbored bacilli in patients were different TTC genotype from that harbored on the nasal mucus of the healthy contacts. Genotypes of TTC repeats were found to differ between husband under treatment and his wife and also mother under treatment and her sons living in same house. This study revealed that TTC genotype of bacilli harbored by household contacts was different with the TTC genotype by index cases. These results indicate that the family members get transmission from outside the dwellings rather than from commonly supposed their MB index cases. There might have been some infectious sources to which the populace had been commonly exposed outside the dwellings. PMID- 23012848 TI - [Enhanced activation of T lymphocytes by urease-deficient recombinant bacillus Calmette-Guerin producing heat shock protein 70-major membrane protein-II fusion protein]. AB - To activate naive T cells convincingly using Mycobacterium bovis BCG (BCG), rBCG (BCG-D70M) that was deficient in urease, expressed with gene encoding the fusion of BCG-derived heat shock protein (HSP) 70 and Mycobacterium leprae-derived major membrane protein (MMP)-II, one of the immunodominant Ags of M. leprae, was newly constructed. BCG-D70M was more potent in activation of both CD4+ and CD8+ subsets of naive T cells than rBCGs including urease-deficient BCG and BCG-70M secreting HSP70-MMP-II fusion protein. BCG-D70M efficiently activated dendritic cells (DC) to induce cytokine production and phenotypic changes, and activated CD4+ T cells even when macrophages were used as APCs. The activation of both subsets of T cells was MHC and CD86 dependent. Pre-treatment of DC with chloroquine inhibited both surface expression of MMP-II on DC and the activation of T cells by BCG-D70M infected APCs. The naive CD8+ T cell activation was inhibited by treatment of DC with brefeldin A and lactacystin so that the T cells was activated by TAP- and proteosome-dependent cytosolic cross-priming pathway. From naive CD8+ T cells, effector T cells producing perforin and memory T cells having migration markers, were produced by BCG-D70M stimulation. BCG-D70M primary infection in C57BL/6 mice produced T cells responsive to in vitro secondary stimulation with MMP-II and HSP70, and more efficiently inhibited the multiplication of subsequently challenged M. leprae than vector control BCG. These results indicate that the triple combination of HSP70, MMP-II and urease depletion may provide useful tool for inducing better activation of naive T cells. PMID- 23012849 TI - [Collaboration between Korea and Japan for basic research on leprosy]. AB - New case detection in Japan has been markedly decreased and same trends have been also shown in Korea. Despite of unfavorable circumstances, research activities are still continuing and we have the accumulation of knowledge on leprosy both in Japan and Korea. Following basic studies for leprosy on going in Japan were reviewed. 1. Analysis of drug resistance mechanism and its application for clinical samples. 2. Establishment of early diagnostic technique. 3. Clarification of mechanisms of neuropathy. 4. Analysis of in vivo growth mechanisms of Mycobacterium leprae. 5. Molecular epidemiology of leprosy. 6. Searching for new anti leprosy drugs. 7. Developing vaccine. 8. In vitro cultivation. Other subjects as follows was proposed as prospective studies. 1. Mechanisms of relapse. 2. Establishing diagnostic tool of reaction and preventive measures. 3. Clarification of immunological mechanisms of anergy in LL case. The possibility of future collaboration between Korea and Japan to solve remaining problems in the clinical field was discussed and a course of action for collaboration was deliberated. PMID- 23012850 TI - [Prof. Masao Ota was interested in Kaisyun Hospital of Kumamoto]. AB - From among the materials of Masao Ota, in the Library of Tokyo University, a letter (1931) was found from Isamu Miyake, prof. of Dermatology, Kumamoto Medical College. Its contents was some information on Kaisyun Hospital (The Kumamoto Hospital of the Resurrection of Hope, leprosy hospital), A calendar (the 1930s) of Kaisyun Hospital was also found in Riddell & Wright's Memorial Museum. This calendar was written in English, and it was to ask for the British and American sponsors to contribute. It includes a lot of articles related to leprosy like Riddell's article. Some new findings related to leprosy at that time were recognized from this calendar. PMID- 23012851 TI - [The difference between depression and melancholia: two distinct conditions that were combined into a single category in DSM-III]. AB - In DSM-III (1980), depressive states of neurosis and those of manic-depressive illness (melancholia or endogenous depression) were combined into the single category "major depression," which is the progenitor of "major depressive disorder" in DSM-IV-TR (2000). According to Hamilton, the word "depression" is used in three different ways. In common speech, it is used to describe the state of sadness that all persons experience when they lose something of importance to them. In psychiatry, the word is used to signify an abnormal mood, analogous to the sadness, unhappiness, and misery of everyday experiences. Moreover, the depression discussed in psychiatry often has another quality that makes it distinctive, and this quality appears to be related to an inability to experience any pleasure (anhedonia) regardless of experience. Accordingly, we classify these three uses of the term "depression" into sadness, depression, and melancholia in order of appearance within this paper. According to DSM-IV-TR criteria for major depressive disorder, depression corresponds closely to A1 "depressed mood", while melancholia is roughly compatible with A2 "markedly diminished interest or pleasure." Depression and melancholia differ in terms of origin, psychopathology, and therapy. Before DSM-III, depression had not been considered as a diagnosis, but was a ubiquitous symptom that was seen in such conditions as neurasthenia, psychasthenia, nervousness, and neurosis. Melancholia has a history that reaches back to Hippocratic times. Its modern meaning was established based on Kraepelin's manic-depressive illness. Depression is a deepened or prolonged sadness in everyday life, but melancholia has a distinct quality of mood that cannot be interpreted as severe depression. In modern times, depression has been treated with a diverse range of methods, including rest, talk therapy, amphetamines (1930s), meprobamate (1950s), and benzodiazepines (1970s). Melancholia has primarily been treated with somatic therapy, such as electroconvulsive therapy, and tricyclic antidepressants. When preparing diagnostic criteria for DSM-III, Spitzer referred not to DSM-II but to Feighner's (1972) criteria as a model because Feighner's operational criteria were considered to be effective in establishing inter-rater reliability. At the outset, Spitzer established Research Diagnostic Criteria (RDC, 1975), which he revised in 1978. In the first edition of RDC, Spitzer adopted most of the Feighner criteria, including essential criteria A "dysphoric mood" and eight optional criteria (B1-B8). However, he reduced the minimal morbid duration for diagnosis. Moreover, for the purpose of excluding neurosis from the diagnostic criteria, Spitzer eliminated the distinction between primary and secondary depression, which had been used to differentiate melancholia from depression. In the revised RDC, Spitzer upgraded optional criteria B5 "loss of pleasure or interest" to one of the essential criteria A with "dysphoric mood." This revision reflects the fact that "loss of pleasure or interest" has been designated as an essential feature of Klein's concept of "endogenomorphic depression" (1974), which is equivalent to melancholia or endogenous depression. At that time, depression and melancholia were completely amalgamated into a single category. DSM-III followed almost all of the revisions in the revised RDC and accepted the bipolar-unipolar dichotomy. However, Klein's endogenomorphic depression was downgraded to the specifier "with melancholia", which has been used only rarely. Thus, as depression and melancholia were fused into major depressive disorder, we have only limited evidence of the efficacy of pharmacotherapy and psychotherapy. DSM-IV divided major depression into major depressive disorder and bipolar II disorder. Consequently, some depression and some melancholia were moved from unipolar depression to bipolar disorder, although the bipolar-unipolar dichotomy was proposed for manic-depressive illness and recurrent unipolar melancholia, but not depression. Therefore, we suspect that we will not obtain strong therapeutic evidence for bipolar II disorder as well. Our proposals are as follows: give up the unitarian view of depression and melancholia and accept the binarian view; and restrict the bipolar-unipolar dichotomy to manic-depressive illness and unipolar melancholia. PMID- 23012852 TI - [Factitious disorder mixed with somatoform disorder in a patient treated with a psychotherapeutic approach: psychopathology and treatment]. AB - We encountered a case of somatoform disorder induced by bullying, and factitious disorder was revealed during treatment. This case was a 14-year-old female, who was admitted to a pediatric ward at first. However, she was transferred to a psychiatric ward after a serious suicidal attempt. She caused many problems, and demanded that medical staff treat her symptoms. We assumed that medical care promoted regression. We performed psychotherapeutic intervention based on consensus among medical staff, similar to behavioral therapy. During the patient's admission to the psychiatric ward, her mother was compulsorily hospitalized. After separation of the mother and child, medical staff could intervene, and this stabilized the mental state of her and her mother. PMID- 23012853 TI - [Pathology of social brain and social cognitive impairments in schizophrenia]. AB - Schizophrenia patients often have a difficulty in constructing appropriate relationships with others in social situations. This impairment of social cognition is also found in autism-spectrum disorder (ASD). To elucidate the neural basis of such commonality between these two disorders, we explored the association between Autism-Spectrum Quotient (AQ) and gray matter (GM) alterations measured by MRI in schizophrenia subjects. Schizophrenia patients showed significantly higher scores in total AQ compared with control subjects. In addition, the total AQ score in schizophrenia subjects showed significant negative correlation with GM volume in the cortical area surrounding the left superior temporal sulcus (STS). As STS is the area which has been reported to be pathological in ASD, our findings suggest a partial neuroanatomical commonality between ASD and schizophrenia. PMID- 23012854 TI - [Development and neural basis of social behavior]. AB - We have developed a multi variate analysis of social communication behavior which allows for discriminating the emotional state of an agent interacting with other agents (Bouquet method). Domestic chick or common marmoset was reared under socially isolated conditions, later tested for its development of communication behavior with peers by Bouquet, and compared with that of animals reared under grouping conditions. We found the existence of high sensitive period for social interaction, given less experience, developing less affiliated behavior. From chick model, a couple of neuronal difference was observed between two groups, amygdale core central cell size, MRI volumetric measure in mesolimbic area, and gene expression patter including brain type tryptophan hydroxylase in nucleus accumbens. The isolated chick behavior changed better to be socially affiliated by taking SSRI/SNRI or Ubiquinol (the reduced form of CoQ10) together with social interaction experience after the sensitive period. Finally, we could discriminate the behavior of Asperger syndrome children (n = 7) from that of the typically developed siblings (n = 6) during the clinical interview by applying Bouquet method. PMID- 23012855 TI - [Useful pharmacologic treatment in impaired social interaction in autism spectrum disorders]. AB - It is important to note that risperidone solution, intranasal administration of oxytocin, and dietary supplementation with large doses of arachidonic acid added to docosahexaenoic acid (DHA) have been reported to improve impaired social interaction. In addition, atypical antipsychotics aripiprazole and SSRI fluvoxamine were useful in treating some aspects of social relatedness or the core deficits of communication and socialization. The evaluation of treatments for ASD should be directed at neurobiological targets known to be important in the brain's response to abnormal developmental trajectories or toward enhancing plasticity during the highly sensitive period in gene-environment interaction (epigenetic mechanism). Recent epidemiological studies have indicated that at least one in every 100 people has some form of ASD. Environmental chemicals can affect the development of the brain. Further studies will be required to address the effect of environmental chemicals. PMID- 23012856 TI - [Disturbance in voluntary control of saccadic eye movements in disorders of social brain]. AB - Disorders of the social brain include Autism Spectrum Disorders (ASD), schizophrenia (SZ) and schizoid- and schizotypal-personality disorders. ASD is one of the developmental disorders with brain dysfunction, but the pathophysiology has not been clarified. In contrast, recent studies suggest that schizophrenia patients have pathologic findings mainly in the frontal and temporal cortices. The frontal eye movement related areas are involved in voluntary control of saccadic eye movements such as anti-saccades. We examined voluntary control of saccadic eye movements in 13 adult subjects aged 20-35 with ASD and compared the results with the performances of 13 controls. In the anti saccade task, ASD subjects showed error rates of 37.3 +/- 27.6 (mean +/- SD)%, significantly higher than controls (13.8 +/- 14.1%), although only 5 ASD subjects showed error rates higher than mean + 2SD of the controls. It has been shown that schizophrenia patients showed abnormalities in the antisaccade task including higher error rate and longer latencies. In our study about 70% of 99 schizophrenia patients showed abnormalities in the anti-saccade task. Difficulties in inhibiting reflexive saccades and initiating saccades without target based on working memory suggest dysfunction of the frontal eye movement areas such as the frontal eye field, supplementary eye field and prefrontal cortex. Although the number of ASD subjects examined was relatively small, the percentage of subjects who showed significantly higher error rates (mean 37.3%) was less compared to those of schizophrenics (mean 70%), suggesting less involvement of the frontal eye movement related areas in the ASD. PMID- 23012857 TI - [Developmental effects of perinatal hypothyroidism on cognitive functions: focused on attention]. AB - PURPOSE: Thyroid hormones are essential for the development of brain. Perinatal hypothyroidism induced by environmental endocrine disrupters is reported to cause cognitive dysfunctions such as attention and memory deficits. The purpose of this study is whether perinatal hypothyroidism causes deficits of shift attention and divided attention in offspring using a target detection task. METHODS: Pregnant rats were treated with the anti-thyroid drug methimazole [0.02% (w/v)] from gestational day 15 to postnatal day 21. The offspring received behavioral testing using shift attention and divided attention tasks. The testing of shift attention started with the presentation of one of two targets. A lever was inserted to the same side as the presented target (ipsilateral trial). However, a lever was inserted to the opposite side to the presented target with the probability of 20% (contralateral trial). Next, the testing of divided attention was introduced. The testing started with the presentation of one of the two targets (one-side trial). A lever was inserted to the same side as the presented target. However, both targets were presented (both-side trial) and one of the two levers was inserted with the probability of 20%. RESULTS AND DISCUSSION: On the contralateral trials in the shift attention task, the untreated rats responded frequently with reaction times of 1.4-1.6 s, whereas the treated rats responded sporadically with a wide range of reaction times of 1.2-7.2 s. This indicates that the treated rats were not able to shift their attention quickly toward the opposite side. When the both-side targets were presented in the divided attention task, the untreated rats responded frequently with the reaction times of 0.6-0.8 s and 1.4-1.6 s. The treated rats responded frequently with reaction times of 0.8-1.0 s and 1.0-6.4 s. Both the untreated and treated rats did not divide their attention toward the both-side targets but probably paid attention to one of the two targets. They responded with the shorter reaction times when the lever was inserted in the same side that they paid attention and responded with longer reaction times when the lever was inserted in the opposite side. We conclude that perinatal hypothyroidism affects shift attention in rats but further researches are necessary to examine whether hypothyroidism affects divided attention. CONCLUSION: Perinatal hypothyroidism causes the deficit of shift attention in rats but it was unclear whether hypothyroidism affects divided attention. PMID- 23012858 TI - [Are the new antiepileptic drugs a breakthrough for patients with epilepsy and for psychiatrists?]. AB - Advances in drug therapies for epilepsy have been remarkable, as well as surgical treatment including vagus nerve stimulation, the neuropsychological approach, and the new ketogenic diet. Over these past several years, four drugs (gabapentin, topiramate, lamotrigine, and levetiracetam) have been approved in Japan as new antiepileptic drugs and are expected to bring many benefits to patients. These new antiepileptic drugs have gained attention as leading candidates for "rational polytherapy". Furthermore, these drugs are very attractive to psychiatrists because of their effects on mood disorder, pain disorder, headaches, obesity, and other problems. Thus, the introduction of these new antiepileptic drugs is greatly welcomed in that the therapeutic options for patients are broadened. At this point, however, we should refrain from easy off-label drug use and should definitely comply with the recommended dosage regimens. In addition, several adverse effects require attention, such as severe rash or effects on cognitive function. Currently, the dominance in efficacy of these new drugs as compared with established antiepileptic drugs is not definite, and the issue of industry sponsorship bias should be taken into consideration. PMID- 23012859 TI - [Social resources for a patient with epilepsy]. AB - Epilepsy is a common episodic neurological disorder and is often accompanied by mental, psychiatric, and physical disorders; therefore, a comprehensive treatment, including seizure control, is needed to treat it. Epilepsy patients need frequent seizure preventive treatment, which is likely to induce medication dependence. This paper presents a report on the social resources involved in epilepsy treatment. "Services and Support for Persons with Disabilities Acts" is applicable to epilepsy patients and provides public compensation for psychiatric outpatient treatment, enabling disabled persons to apply for disability pension to support their living and medical expenditures. The Mental Health Welfare Notebook is issued to provide welfare services for the disabled, and it plays an important role in promoting employment of disabled persons. The welfare services for the disabled are diverse, ranging from home-based services to services aiding the disabled to step out of their homes, go to day care centers, or pay for house rent. The details of the welfare services for the disabled are available on the homepage of the website for the Ministry of Health, Labour and Welfare. The roles of physicians involve maximizing social resources in coordination with psychiatric social workers, aiming for normalization of disabled persons so that they are able to live comfortably in the community. PMID- 23012860 TI - [Recent pharmacology and molecular biology associated with epilepsy]. AB - In the past two decades, we have identified various mutant genes associated with idiopathic epilepsies. Many of these mutant genes encode several ion channel subunits or functionally related proteins, leading to the classification of epilepsy as channelopathy. Currently, after the onset of epilepsy, we prescribe the anticonvulsant medication; however, anticonvulsants inhibit epileptic seizure and probably prevent progression of secondary epileptogenesis which is induced by epileptic seizure. Despite these efforts, we have no effective medication to prevent primary epileptogenesis. Thus, to develop novel strategies for the treatment of epilepsy, including preventing onset and complete recovery, we should develop true antiepileptic drug via generation of the genetic animal models of epilepsy according to the validation criteria. PMID- 23012861 TI - [Understanding and treating self-injury]. AB - Recently self-injurious behavior including wrist-cutting among youth has been a serious problem in Japan. Self-injury is the act to injure oneself deliberately without a suicidal intent, by a nonfatal method, predicting a nonfatal consequence. It is frequently repeated to cope with distress, for instance, to reduce an intolerable and painful feeling. Self-injury is the act to be differentiated from suicide, and often cause a negative attitude in mental health professionals, although many previous studies reveal that individuals with self injury are more likely to death by suicide than those without, and that self injury may be one of the important risk factors predicting future suicide. In this paper, the author gives an outline of understanding and treating self injury, and indicates that to support and care self-injuring youth by mental health professionals may contribute to suicide prevention in adolescence. PMID- 23012862 TI - [Promote healthy self-esteem in your patients by your words and support for families with disabled children at home by improving the medical care system]. PMID- 23012863 TI - [An eight-month-old girl presenting with motor delay and hypotonia]. PMID- 23012864 TI - [Pediatric neurotransmitter disease in Japan]. AB - Pediatric neurotransmitter disease (PND) encompasses a range of rare genetic disorders that affect the metabolism of neurotransmitters in children. While these neurological disorders are often studied independently of each other, they all manifest central nervous system symptoms and require proper diagnosis and intervention at early stages. Since clinical symptoms of PND can be nonspecific, the conditions are often under-diagnosed, leaving patients without a chance to receive effective treatment. Envisioning PND as a whole, a comprehensive research effort is underway for a better understanding of pathophysiology and epidemiology in Japan, and toward the establishment of diagnostic criteria. The early diagnosis and development of new effective therapies are of urgent importance for these rare disorders that are not covered by newborn mass screening. For rarer forms of PND, at the same time, it is important to encourage recognition and understanding of the disease concept among healthcare professionals. PMID- 23012865 TI - [Effects of a rich emotionally-satisfying childbirth experience of mothers on their later parental attitudes and behavior in school-age children]. AB - This study examined the effects of a rich, emotionally-satisfying childbirth experience (CBE) of mothers on the behavior of school-age children using longitudinal data measured from immediately to 7 years and 6 months after birth. The results of structural equation modeling revealed the following: 1) giving birth in a midwifery center enhances emotional satisfaction with CBE, 2) a rich CBE of mothers was associated with parental warmth, 3) parental warmth during early childhood increased prosocial behavior and reduced behavioral problems in school-age children, and 4) temperamentally difficulty in early childhood were linked to later behavioral problems in school-age children. Thus, a rich CBE and parental warmth were suggested to be factors contributing to the good behavior of school-age children. PMID- 23012866 TI - [Evaluation of serum total carnitine values in persons with severe motor and intellectual disabilities with enteral (tube) feeding]. AB - OBJECTIVE: The nutritive evaluation and the serum carnitine values were measured for persons with severe motor and intellectual disabilities with enteral (tube) feeding. METHODS: In Shimada Rehabilitation Center, twenty one people who had serum albumin levels of 3.4 g/dl or less, and were taking nutrition with enteral (tube) feeding, were tested. Body weight, blood samples, and serum carnitine levels were measured. RESULTS: The total carnitine value was less than the standard value in 19 patients. The total carnitine value decreased in the group taking valporate sodium (VPA), compared to the values from the group non-taking VPA. CONCLUSIONS: From our evaluation, we think that daily carnitine supplements is essential for persons with sever motor and intellectual disabilities taking VPA to maintain carnitine levels in the blood, and regular urine test should be done for earlier detection secondary lack complications from the secondary lack of carnitine. PMID- 23012867 TI - [A study of reading disorder comorbid with pervasive developmental disorder or attention-deficit/hyperactivity disorder]. AB - OBJECTIVE: We investigated the frequency and characteristics of reading disorder comorbid with pervasive developmental disorder (PDD) or attention deficit/hyperactivity disorder (AD/HD). METHODS: Articulation times and reading errors were evaluated using four Japanese reading tasks (a monomoraic syllable reading task, a word reading task, a non-word reading task, and a short sentence reading task) in 31 children with PDD (22 boys and 9 girls) aged 6-14 years (average 9.5 years) and 39 children with AD/HD (33 boys and 6 girls) aged 6-12 years (average 9.6 years). Poor readers (PRs) were identified when articulation times were significantly longer than those of typically-developing children (> or = 2.0 SD) for two or more reading tasks, and non-PRs were identified when articulation times were within normal range (<2.0 SD) for all reading tasks. RESULTS: Eight children with PDD (25.8%) and 17 children with AD/HD (43.6%) were identified as PRs. For 13 of the 70 subjects, the chief complaints were difficulties in reading and writing words at their first visit to our hospital. All 13 of these subjects had AD/HD, and twelve of these were additionally identified as PRs. Among the remaining 26 children with AD/HD, five (19.2%) were identified as PRs. In AD/HD children, PRs made significantly more reading errors and had lower IQ scores than did non-PRs, but in PDDchildren, there were no significant differences between these two groups regarding IQ or reading errors. An analysis using the Clinical-Symptoms-Checklist for Reading and Writing Words revealed that PRs in our study showed difficulties in reading words in daily life. CONCLUSIONS: PRs in our study had reading disorders, which would, in turn, mean that reading disorder was often comorbid with PDD or AD/HD. These results strongly indicate the necessity of testing for the presence of reading disorder in children with PDD or AD/HD. PMID- 23012868 TI - [A case of spinal muscular atrophy type 0 in Japan]. AB - The patient was a 2-month-old female infant born at 41 weeks and 2 days of gestation presenting multiple arthrogryposis, severe muscle hypotonia and respiratory distress with difficulty in feeding. She suffered from repeated complications with aspiration pneumonia. On admission to our hospital, she exhibited fasciculation and absence of deep tendon reflexes. Examination of the motor nerve conduction velocity (MCV) revealed no muscle contraction. Deletions of the SMN and NAIP genes were noted. Based on severe clinical course and disease development in utero, she was given a diagnosis of spinal muscular atrophy (SMA) type 0 (very severe type). Arthrogryposis and disappearance of MCV are exclusion criteria for SMA. However, the clinical course of the infant was very severe and included such exclusion items. Consequently, when an infant presents muscle hypotonia and respiratory distress, SMA must be considered as one of the differential diagnoses, even though arthrogryposis is an exclusion criterion for SMA. We discuss this case in relation to the few extant reports on SMA type 0 in Japanese infants in the literature. PMID- 23012869 TI - [A case of DiGeorge syndrome with left internal carotid artery absence probably causing one-and-a-half syndrome]. AB - We experienced a case of DiGeorge syndrome with left internal carotid artery absence probably causing one-and-a-half syndrome. MR angiogram demonstrated the apparent absence of the left internal carotid artery and consequently abnormal blood supply to the left middle cerebral artery, which was derived from the basilar artery via the left posterior communicating artery. The patient alsoshowed both an extremely narrow carotid canal on the left side and a very fine vessel extending to the terminal of the left internal carotid artery. Therefore, we regarded this abnormality as severe hypoplasia of left internal carotid artery and supposed that this hypoplasia had originated in maldevelopment of the third aortic arch based on the coexisting lower bifurcation of the right common carotid artery. Since the lesion of one-and-a-half syndrome is restricted to the pontine tegmentum, we speculated that it had resulted from ischemia of the basilar artery area during the embryonic period associated with the absence of the internal carotid artery. To our knowledge, DiGeorge syndrome has never been reported as a complication of internal carotid artery absence. The patient did not demonstrate either chromosome 22q11.2 deletion or TBX1 gene mutation, which is considered the gene responsible for 22q11.2 deletion syndrome. Therefore, the etiology of DiGeorge syndrome in this case remains unclear. PMID- 23012870 TI - [Three pediatric cases of group A coxsackievirus-associated encephalitis/encephalopathy]. AB - We report three pediatric cases of group A coxsackievirus-associated encephalitis/encephalopathy. A 4-year-old girl with coxsackievirus A6 infection presented with an exanthem on her upper body on the fourth day of fever. The following day, she developed an episode of convulsions, and subsequently experienced sudden cardiopulmonary arrest. A head computed tomography scan revealed severe brain edema. Two patients with neurological sequelae had initially presented with status epilepticus that required intravenous barbiturate treatment. Both cases had high-signal-intensity lesions on their diffusion weighted brain magnetic resonance images. A 5-year-old girl with subcortical white matter lesions was diagnosed with acute encephalopathy with febrile convulsive status epilepticus, and a 2-year-old boy with bilateral hippocampal lesions was diagnosed with parainfectious limbic encephalitis. These findings indicate that group A coxsackievirus is a causative agent of pediatric encephalitis/encephalopathy; moreover, the prognosis may be poor in some cases. PMID- 23012871 TI - [Levetiracetam-induced aggravation to non-convulsive status epilepticus in a boy with Lennox-Gastaut syndrome]. PMID- 23012872 TI - [Cell-cell interaction networks during murine liver development]. PMID- 23012873 TI - [Characterization of hepatic stem/progenitor cells by molecular markers]. PMID- 23012874 TI - [Liver regeneration and sinusoidal endothelial cells]. PMID- 23012875 TI - [Mutual phenotypic plasticity between hepatocytes and bile ducts]. PMID- 23012876 TI - [Tissue morphogenesis of liver epithelial cells]. PMID- 23012877 TI - [microRNAs act as a fine-tuner of liver development, regeneration, and carcinogenesis]. PMID- 23012878 TI - [Identification of master regulators for induction of hepatocyte differentiation]. PMID- 23012879 TI - [Analysis of the regenerating murine liver by imaging mass spectrometry]. PMID- 23012880 TI - [Molecular mechanism of liver injury/regeneration--an analysis by bio-imaging]. PMID- 23012881 TI - [Platelets and liver regeneration]. PMID- 23012882 TI - [Chimeric mice with humanized liver: mechanism of hepatic hyperplasia induction]. PMID- 23012883 TI - [Autologous bone marrow cell infusion therapy to repair and regenerate liver]. PMID- 23012884 TI - [The history of CINP between 1958 and 2000]. AB - Collegium Internationale Neuropsychopharmacologicum (CINP) is an international society which was established to facilitate academic exchange of basic and clinical studies related to psychotropic drugs. The CINP has been devoted to the problems of methodology and to the analysis of the pharmacological and therapeutic results with psychotropic drugs under normal and pathological conditions as well to the medico-social implications of neuropsychopharmacology. The CINP was organized by Prof. Trabucchi (Milan) in collaboration with an international team of neuropsychopharmacologists from 15 countries. The first International CINP Congress was held on September of 1958 in Rome. Thereafter, CINP world congresses were held every two years until 2012. The number of Japanese neuropsycho-pharmacologists who are members has been increasing since the 1970s. The 17th CINP Congress was held in Kyoto in 1990, and the CINP Hiroshima regional meeting was held, combined the annual meeting of the Japanese Society of Neuropsychopharmacology and Korean Society of Psychopharmacology in 2001. The early history of CINP between 1958 and 2000 is briefly described with special reference to the participation of the Japanese Society of Neuropsychopharmacology. PMID- 23012885 TI - [Epigenetic regulation in depression]. AB - Recent research has raised the notion that epigenetic mechanisms (e.g., DNA methylation and histone modifications), which exert lasting control over gene expression without altering the genetic code, could mediate stable changes in brain function. However, the role of environmental factors along with genetic factors in the epigenetic regulation of the pathogenesis of depression is largely unknown. Two genetically distinct mice strains, BALB/c (BALB) and C57BL/6 (B6), exhibit different behavioral responses to chronic stress. With chronic stress, BALB mice showed depressive-like behaviors, but not B6 mice, and glial cell derived neurotrophic factor (GDNF) expression level was decreased in the ventral striatum of BALB mice but increased in B6 mice. In BALB mice, depressive-like behaviors and decreased GDNF expression were recovered by chronic antidepressant treatment. Therefore, we used these two mice strains to investigate how the epigenetic status of the GDNF gene in the ventral striatum modulates stress vulnerability. Both mice strains showed increased DNA methylation levels and MeCP2 recruitment in the GDNF promoter region. However, histone H3 acetylation level was decreased in BALB mice, but increased in B6 mice. Furthermore, BALB mice showed increased histone deacetylase2 (HDAC2) expression level and Re-ChIP assay revealed HDAC2-MeCP2 complex in BALB mice. Our results indicate the crucial role of histone modification by HDAC2 and MeCP2 complex for the control of GDNF expression and subsequent behavioral responses to chronic stress, in other words, the susceptibility to stress. In addition, we investigated the effect of antidepressants on the epigenetic regulation of GDNF expression. We found a reduced level of HDAC4 recruitment at the GDNF promoter region with antidepressants. Thus, our data suggest that antidepressants increase transcriptional activity of the GDNF gene through the modulation of histone acetylation by HDAC4. Finally, we examined the expressions of GDNF and epigenetic related molecules mRNAs with major depressive and bipolar disorder patients by using quantitative real-time PCR. We found the aberrant expression of GDNF and epigenetic-related genes including HDAC2 and HDAC4 in mood disorder patients. Thus, our data provide novel insights suggesting that epigenetic mechanisms of GDNF expression are involved in the pathogenesis or pathophysiology of depression. PMID- 23012886 TI - [Role of brain 5-HT7 receptors as a functional molecule involved in the development of stress adaptation]. AB - A growing body of evidence suggests that the brain serotonin (5-HT) nervous system is an important component related to the etiology as well as the treatment of stress-related psychiatric disorders. Molecular cloning studies have revealed the existence of 14 different genes, each encoding a distinct 5-HT receptor subtype. The 5-HT7 receptor is the most recently identified member of the 5-HT receptor subtypes, and the physiological role of this receptor is still unknown. Recently, either selective agonists or antagonists for 5-HT7 receptors, as well as 5-HT7 receptor knockout mice, have been developed, and these have recently been used as the experimental tools for determining the actual function of 5-HT7 receptors. The first half of the present article introduces the reports that have examined the role of the 5-HT7 receptor on emotional regulation. On the other hand, it has been indicated that the ability to adapt to stress is an important defensive function of a living body, and impairment of this ability may contribute to some stress-related disorders. Thus, the examination of brain mechanisms involved in stress adaptation could help to pave the way for new therapeutic strategies for stress-related psychiatric disorders. The second half of the present article introduces our recent studies focusing on the relationship between brain 5-HT7 receptors and the mechanisms of stress adaptation. PMID- 23012887 TI - [Novel therapeutic approach for the treatment of post-traumatic stress disorder (PTSD): facilitating fear extinction]. AB - Pharmacological agents enhancing fear extinction may be promising tools for the treatment of PTSD. Histone acetylation is involved in memory formation, and histone deacetylase (HDAC) inhibitors increase histone acetylation and subsequently enhance fear extinction. In this study, we examined whether vorinostat, an HDAC inhibitor, facilitated fear extinction, using a contextual fear conditioning (FC) paradigm. We found that vorinostat facilitated fear extinction. Next, the levels of global acetylated histone were measured by Western blotting. We also assessed the effect of vorinostat on the hippocampal levels of NMDA receptor mRNA by real-time quantitative PCR (RT-PCR). The levels of acetylated histone and NR2B mRNA, but not NR1 or NR2A mRNA, were elevated in the hippocampus 2 h after administration of vorinostat. We investigated the levels of acetylated histones and phospho-CREB (p-CREB) binding at the promoter of the NR2B gene using the chromatin immunoprecipitation (ChIP) assay followed by RT-PCR. The levels of acetylated histone and the binding of p-CREB to its binding site at the promoter of the NR2B gene were increased. These findings suggest that vorinostat in conjunction with exposure therapy can be a promising new avenue for the treatment of PTSD. PMID- 23012888 TI - [The hypothalamic-pituitary-adrenal axis and depressive disorder: recent progress]. AB - Depression is a stress-induced disorder and there is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in the disease. Chronic hyperactivity of the HPA axis and resultant excessive glucocorticoid (hypercortisolism) may be causal to depression. We demonstrated that the dexamethasone (DEX)/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities. Restoration from HPA axis abnormalities occurs with clinical responses to treatment. Brain-derived neurotrophic factor (BDNF) has also been implicated in depression. We found that glucocorticoid (DEX) suppresses BDNF-induced dendrite outgrowth and synaptic formation via blocking the MAPK pathway in early-developing cultured hippocampal neurons. Furthermore, we demonstrated that glucocorticoid receptor (GR) and TrkB (a specific receptor of BDNF) interact and that DEX acutely suppresses BDNF-induced glutamate release by affecting the PLC-gamma pathway in cultured cortical neurons, indicating a mechanism underlying the effect of excessive glucocorticoid on BDNF function and resultant damage in cortical neurons. In a macroscopic view using magnetic resonance imaging (MRI), we found that individuals with hypercortisolism detected by the DEX/CRH test demonstrated volume loss in gray matter and reduced neural network assessed with diffusion tensor imaging in several brain regions. Finally, we observed that individuals with hypocortisolism detected by the DEX/CRH test tend to present more distress symptoms, maladaptive coping styles, and schizotypal personality traits than their counterparts, which points to the important role of hypocortisolism as well as hypercortisolism in depression spectrum disorders. PMID- 23012889 TI - [A flow cytometric postmortem brain study for major depressive disorders: implication for oligodendroglial differentiation and functions]. AB - The neuropathology of psychiatric disorders has long been of interest in psychiatry. Several abnormalities in the prefrontal cortex have been demonstrated in major depressive disorders; however, only a small number of quantitative studies have been conducted, partly because the stereological techniques often used for such investigations are hampered by intrinsically low throughput, typically requiring long periods of time to complete. Recently, we developed a quantitative cell-counting method for frozen unfixed postmortem brains using a flow cytometer. Anisotropic frozen brain tissue was transformed into an isotropic suspension of nuclei; the numbers and fluorescent intensities of 7-AAD(+), a DNA marker, were quantified; and the nuclei were immunolabeled for the neuronal and oligodendroglial nuclear markers, NeuN and olig2, respectively. Using this method, the frontopolar and inferior temporal cortical gray matter of major depressive disorder patients, as well as that of normal controls, was analyzed. We found that the densities of 7-AAD(+) and olig2(+) nuclei in the gray matter tissue of the frontopolar cortex from major depressive disorder subjects were significantly reduced when compared to those from controls, but not in the inferior temporal cortex. Our findings suggest that the pathogenesis of major depressive disorders may involve some abnormalities in cortical myelination in the adult frontopolar cortex. PMID- 23012890 TI - [The potential of group II metabotropic glutamate receptor antagonists as a novel antidepressant]. AB - Recently, abnormalities of glutamatergic transmission have been implicated in the pathophysiology of depression. Moreover, both ketamine, an NMDA receptor antagonist, and riluzole, a modulator of glutamatergic, transmission have been reported to be effective for the treatment of patients with treatment-refractory depression. Based on these findings, extensive studies to develop agents acting on glutamatergic transmission have been conducted. Glutamate receptors are divided into two main subtypes, ionotropic glutamate receptors and metabotropic glutamate (mGlu) receptors, both of which have subtypes. Of these, much attention has been paid to mGlu2/3 receptors. mGlu2/3 receptor antagonists such as MGS0039 and LY341495 have been reported to exert antidepressant effects in animal models of depression including the forced swim test, tail suspension test, learned helplessness paradigm, olfactory bulmectomy model and isolation rearing model, and to enhance serotonin release in the prefrontal cortex and dopamine release in the nucleus accumbens. Moreover, activation of AMPA receptor and mTOR signaling have been suggested to be involved in the antidepressant effects of mGlu2/3 receptor antagonists, as demonstrated in the actions of ketamine. Thus, mGlu2/3 receptor antagonists may share some neural networks with ketamine in exerting their antidepressant effects. In addition, the potential of other agents targeting glutamatergic transmission for novel antidepressants is being investigated. PMID- 23012891 TI - [The association between beta-adrenergic receptor gene polymorphisms and personality traits]. AB - The relationship between the polymorphisms (SNPs) of the beta-adrenergic receptor (beta-AR) gene and personality assessed by TCI (Temperament and Character Inventory), was studied among 192 healthy Japanese subjects (121 male subjects and 71 female subjects). In this study, the statistical analyses were performed overall and separately for each sex. As a result, it was shown that there were significant relationships between SD (self-directedness) and 49Ser/Gly (rs1801252) in ADRB1, P (persistence) and 389Arg/Gly (rs1801253) in ADRB1, and ST (self-transcendence) and 27Gln/Glu (rs1042714) in ADRB2 overall. Among the male subjects, there were further significant relationships between ST and 49Ser/Gly in ADRB1, NS (novelty-seeking), HA (harm avoidance) and P and 389Arg/Gly in ADRB1, and P and 64Arg/Trp(rsrs4994) in ADRB3. Among the female subjects, there were also significant relationships between SD and 49Ser/Gly in ADRB1, and C (cooperativeness) and 389Arg/Gly in ADRB1. Thus it was shown that there were correlations between beta-AR gene polymorphisms and several subscales of TCI. PMID- 23012892 TI - [A long chain fatty acid receptor GPR40 as a novel pain control system]. AB - The important functional role of fatty acids in both onset and suppression of pain has become increasingly apparent in recent years. Recently, we have also demonstrated that the release of an endogenous opioid peptide, beta-endorphin, plays an important role in the induction of docosahexaenoic acid (DHA)-induced antinociception. It is well known that fatty acids affect intracellular and intercellular signaling as well as the membrane fluidity of neurons. In addition to intracellular actions, unbound free fatty acids (FFAs) can also carry out extracellular signaling by stimulating the G-protein-coupled receptor (GPCR). Among these receptors, GPR40 has been reported to be activated by long-chain fatty acids such as DHA, eicosapentaenoic acid (EPA) and arachidonic acid. In a peripheral area, GPR40 is preferentially expressed in pancreatic beta-cells and is known to be related to the secretion of hormone and peptides. On the other hand, even though this receptor is widely distributed in the central nervous system, reports studying the role and functions of GPR40 in the brain are not found. In this review, we summarize the findings of our recent study about the long-chain fatty acid receptor GPR40 as a novel pain regulatory system. PMID- 23012893 TI - Bioactive glass S53P4 in mastoid obliteration surgery for chronic otitis media and cerebrospinal fluid leakage. AB - OBJECTIVES: We evaluated the results of cases of chronic otitis media treated with mastoid obliteration surgery using bioactive glass S53P4. METHODS: Twenty five patients with chronic otitis media and 1 patient with cerebrospinal fluid leakage without chronic infection were treated with bioactive glass S53P4. Twenty patients had had previous surgery because of chronic otitis media with or without cholesteatoma. A mastoid obliteration was performed with bioactive glass S53P4 granules and a musculoperiosteal flap with or without bone pate. In 2 patients with a bony dehiscence at the middle cranial fossa, a bioactive glass plate was used to support the protruding dura. In addition, in 3 patients, occlusion of a dural fistula was needed The median follow-up period was 34.5 months (range, 1 to 182 months). RESULTS: Excluding the 2 patients with only 1 month of follow-up at our department, 96% of the patients had a dry, safe ear or only intermittent otorrhea. In 92% of the patients, the objective of achieving a smaller or nonexistent cavity was achieved. CONCLUSIONS: Bioactive glass S53P4 is a noteworthy material in mastoid obliteration surgery. PMID- 23012894 TI - Trade-off between survival and laryngeal preservation in advanced laryngeal cancer: the otorhinolaryngology patient's perspective. AB - OBJECTIVES: We performed a prospective study to evaluate, from the patient's perspective, the trade-off between speech and survival that individuals face when given a diagnosis of advanced-stage laryngeal cancer amenable to either total laryngectomy or a laryngeal preservation protocol using chemotherapy and radiotherapy. METHODS: Volunteers (309) consecutively seen at the otorhinolaryngology clinic of a university teaching hospital in France completed an anonymous questionnaire designed to determine their position if they faced the diagnosis of an advanced-stage laryngeal cancer. Univariate analysis was performed for potential statistical relationships with various variables. RESULTS: We found that 12.9% of patients were unable to determine their position regarding the two treatment options offered, and this group had a significant statistical relationship with four variables (age, education, professional status, and history of cancer among relatives). We found that 24.6% of patients made survival their main consideration and would not consider any trade-off. Among the 62.5% who considered the trade-off, the percentage of cure that patients were ready to lose in order to preserve their larynx varied from 5% to 100% (mean, 33%; SD, 23%). Aside from the undecided group, none of the variables analyzed was related either to the decision as to whether to consider a trade-off or to the percentage of c re that patients agreed to trade to preserve their larynx. CONCLUSIONS: In patients with advanced-stage laryngeal cancer, treatment should be initiated only after careful evaluation of the patient's attitude toward both laryngeal preservation and survival. PMID- 23012895 TI - Impact of endoscopic stapling of Zenker's diverticulum on patient health status as assessed by the Glasgow Benefit Inventory. AB - OBJECTIVES: The aim of this study was to measure the effect of endoscopic stapling of Zenker's diverticulum on the health status of patients. METHODS: We used the Glasgow Benefit Inventory (GBI) tool to ascertain patients' perceived experience. RESULTS: The study demonstrated a positive health impact following endoscopic stapling of the Zenker's diverticulum. The mean total GBI score was +18.9 (95% confidence interval, +/- 11.2). The impact of endoscopic stapling was positive for all three subsets of the GBI. The GBI scores were comparable to those obtained after other common otorhinolaryngological procedures such as tonsillectomy, rhinoplasty, and middle ear surgery. CONCLUSIONS: These data should improve our ability to counsel patients regarding important therapeutic decisions and expectations of surgical outcome. PMID- 23012896 TI - Etiology of nasal polyps in cystic fibrosis: not a unimodal disease. AB - OBJECTIVES: The objective was to determine whether the polyp subtypes observed in cystic fibrosis (CF)-related sinusitis were similar to those observed in non-CF related sinusitis. METHODS: Polyp and mucus samples were collected from CF patients who presented for sinus surgery. The polyps underwent histologic and cytochemical evaluation for the presence of lymphocyte cell populations and their respective cytokine markers. The mucus samples were evaluated for DNA content. RESULTS: Of the polyps, 42% had an eosinophilic infiltrate, of which 80% had an additional mixed neutrophilic infiltrate. Of the remaining polyp samples, 42% did not have a granulocytic infiltrate, consistent with non-eosinophilic polyps. All samples had CD138-positive plasma cells. The mucus samples from the patients with CF showed higher extracellular DNA concentrations than did the mucus samples from patients with non-CF sinus disease. CONCLUSIONS: Cystic fibrosis-related polyps demonstrated an eosinophil-based dichotomy similar to that of idiopathic non-CF related polyps. Many also demonstrated neutrophilic infiltrate, indicating that chronic mucus stasis and infection complicate the disease. Agents capable of reducing extracellular DNA may help manage sinusitis in CF patients. PMID- 23012897 TI - Safety and dosing of bevacizumab (avastin) for the treatment of recurrent respiratory papillomatosis. AB - OBJECTIVES: Increasing evidence supports the use of laryngeal injections of the antiangiogenic agent bevacizumab (Avastin) for the adjuvant treatment of recurrent respiratory papillomatosis (RRP). A recent prospective open-label investigation, approved by the US Food and Drug Administration, employing 12.5 mg of sublesional bevacizumab demonstrated single-site efficacy without complications; however, the safety of multiple-site injections and higher dosing has not yet been reported. The primary objective of this study was to report on the safety of increased doses of bevacizumab for the treatment of RRP. METHODS: Two cohorts of adult patients were evaluated. In the first group, a prospective analysis was performed on patients with a diagnosis of laryngeal RRP after t heir participation in th e initial clinical trial with a single-site lowerdose (7.5 to 12.5 mg). They received higher doses of sublesional laryngeal bevacizumab (15 to 50 mg total) with detailed physiologic, hematologic, and serum chemistry measurements performed before and after each bevacizumab injection. A second cohort of patients received sublesional laryngeal injections of bevacizumab (15 to 88 mg total) without physiologic measurements and underwent a retrospective analysis of reported complications. RESULTS: One hundred consecutive laryngeal injection sessions (office, 87; operating room, 13) with bevacizumab were performed in 43 patients, with a mean dose of 30 mg total per treatment (range, 15 to 88 mg). Sixty-three of the 100 sessions were accompanied by KTP laser photoangiolysis of the papilloma prior to bevacizumab injections. Eighteen patients (cohort 1) underwent detailed physiologic assessment, and no dysfunction was observed. There were no local or systemic complications of bevacizumab administration. The second group of 25 patients (cohort 2) also reported no significant local or systemic complications. Neither patient group was observed to have a local wound problem in the larynx. CONCLUSIONS: This investigation provides evidence that higher doses of bevacizumab are relatively safe in adult patients with laryngeal RRP. Further refinements in pharmacologic concentration and drug delivery will determine the optimal treatment regimens in the future. PMID- 23012898 TI - Free-flap reconstruction of large full-thickness lip and chin defects. AB - OBJECTIVES: We describe our experience in the reconstruction of large 3-layer lip defects using free revascularized lower-arm and fibula flaps. METHODS: Between 2005 and 2009, nine patients underwent free-flap reconstruction after oncological surgery involving the lip and chin with or without mandibular involvement. The flap techniques are described, and postoperative functional and aesthetic results were recorded. RESULTS: There were no flap failures. All patients showed intact oral function and good aesthetic results. Two patients died of distant metastases, 8 months and 17 months after surgery. CONCLUSIONS: Three-layer defects of the lip ideally require free-flap reconstruction, which has a high probability of achieving good functional and aesthetic results. PMID- 23012899 TI - Streptococcal tonsillitis and acute streptococcal myocarditis: an unusual combination assessed by cardiac magnetic resonance imaging and endomyocardial biopsy. AB - OBJECTIVES: Acute streptococcal tonsillitis is occasionally combined with myocarditis. Our aim was to examine patients with tonsillitis in whom myocarditis was suspected by using cardiac magnetic resonance imaging (MRI) and endomyocardial biopsy. METHODS: After prospective evaluation of 200 patients with tonsillitis, 17 men (median age, 23 years; age range, 18 to 29 years) were recruited for cardiac MRI because of a suspicion of myocarditis. Chest pain 3 to 5 days after tonsillitis was the main complaint in 15 patients, and atypical chest discomfort in 2 patients. We performed cardiac MRI including short TI inversion recovery T2-weighted scanning and T1-weighted scanning with early gadolinium enhancement (EGE) and late gadolinium enhancement (LGE). The left ventricular ejection fraction and the presence of myocarditis were evaluated by the standard protocol. A T2 ratio of greater than 2 and an EGE value of greater than 4 were considered abnormal. Heart biopsy was suggested for patients with a reduced left ventricular ejection fraction. RESULTS: Cardiac enzyme levels were increased in 8 of the 17 patients. Increased T2 ratio values (median, 2.8; range, 2.5 to 4.0) were documented in 16 patients. The EGE values were increased (median, 12; range, 8 to 19) in 16 patients. Positive LGE was identified in 13 patients. Endomyocardial biopsy in 4 patients revealed acute myocarditis, and polymerase chain reaction analysis identified streptococcal genomes. Re evaluation by cardiac MRI 3 months later showed normal results in 14 patients. CONCLUSIONS: Acute streptococcal tonsillitis can be occasionally complicated by myocarditis with either a typical or an atypical presentation. Cardiac MRI can facilitate the diagnosis in both forms and allow a noninvasive follow-up. PMID- 23012900 TI - Middle ear effusion and fungi. AB - OBJECTIVES: Bacteria and viruses are rarely isolated from the middle ear fluid in cases of otitis media with effusion (OME). However, since endotoxins are often detected in such effusions, it is suspected that patients with OME have a previous history of gram-negative infection. Recently, fungi have drawn attention as microorganisms that cause chronic sinusitis. We investigated the involvement of fungi in the formation of middle ear effusions of patients with OME and eosinophilic otitis media, in which patients have viscous middle ear effusions and a history of adult bronchial asthma indicating definite involvement of eosinophils. METHODS: Middle ear effusions and nasal secretions were collected from patients with eosinophilic otitis media (7 patients) or OME (12 patients), and smears were prepared for methenamine silver staining. The remaining specimens were embedded in Epon and stained with toluidine blue for observation under a light microscope, and ultrathin sections were prepared for examination under an electron microscope. RESULTS: Fungal hyphae were detected in the middle ear fluid in all of the patients with eosinophilic otitis media or OME. Charcot-Leyden crystals (CLCs) were observed in 6 of the 7 patients with eosinophilic otitis media. In regard to the findings in the nasal secretions, fungal hyphae were also detected in the nasal secretions of all patients, whereas CLCs were detected in only 1 patient with eosinophilic otitis media. CONCLUSIONS: It was clarified by use of the methenamine silver staining method that fungi were present in the middle ear fluid in 100% of the studied cases of eosinophilic otitis media or OME. Whether fungi are also present in the middle ear cavity of normal persons is unknown, but the possibility that they may contribute as a cause of both diseases cannot be excluded. Particularly in eosinophilic otitis media, the observation of numerous CLCs in the middle ear fluid suggests that many eosinophils have degenerated. The eosinophil granule proteins released from the degenerated eosinophils can cause epithelial injury of the middle ear. The possibility that fungi induce the eosinophils in the middle ear also cannot be excluded. PMID- 23012901 TI - Analysis of the roles of smoking and allergy in nasal polyposis. AB - OBJECTIVES: Recent studies on the etiopathogenesis of nasal polyps have shown that smoking and nonallergenic inhalants such as occupational dust exposure cause chronic inflammation of the nasal mucosa. These factors may be associated with nasal polyps. The aim of this study was to use laboratory tests to investigate the effects of smoking and allergens on the development of nasal polyps. METHODS: The study included 60 consecutive patients with a diagnosis of nasal polyposis who were treated with functional endoscopic sinus surgery at our clinic and 25 smoker and 25 nonsmoker participants who constituted a control group. RESULTS: In the patient and control groups, the mean absorbance value for cotinine in smokers was found to be statistically significantly lower than that in nonsmokers. There was a significant difference between the groups with respect to blood cotinine positivity. No significant difference was found between the groups in terms of allergy parameters. In the regression model, smoking was found to be the only significant risk factor for the development of nasal polyps, independent of smoking duration, absorbance value, or cotinine positivity. CONCLUSIONS: Smoking restriction and avoiding exposure to cigarette smoke by patients with nasal polyps may be an important strategy in the prevention and recurrence of nasal polyposis. No direct relationship was determined between allergy and nasal polyposis. PMID- 23012902 TI - Transcervical approach to benign parapharyngeal space tumors. AB - OBJECTIVES: We describe our experience with the postoperative sequelae, complications, and recurrences associated with resection of a series of parapharyngeal space (PPS) tumors via a transcervical approach without submandibular gland excision, parotidectomy, or mandibulotomy. METHODS: We performed a retrospective review of 51 cases, 40 of which were pleomorphic adenomas and 11 of which were lipomas or schwannomas. RESULTS: Of 30 fine-needle aspirations performed, 24 indicated pleomorphic adenoma before operation. Twenty eight of the 30 fine-needle aspirations yielded diagnoses that were consistent with the final pathologic diagnoses. The average hospital stay was 1.05 days. After operation, there were 9 cases of trismus, 4 cases of "first bite" pain, and 7 cases of transient marginal nerve weakness. There were no recurrences over an average follow-up of 115 months. CONCLUSIONS: The majority of PPS tumors are benign. It is important to use an approach that allows complete tumor excision but does not impart undue postoperative morbidity. We demonstrate that the transcervical approach without submandibular gland excision, parotidectomy, or mandibulotomy is ideal for benign PPS tumors. PMID- 23012903 TI - Experimental exploration of the soft tissue conduction pathway from skin stimulation site to inner ear. AB - OBJECTIVES: Auditory sensation can be elicited by air conduction (AC) and by bone conduction (BC). It is also possible to elicit such responses by applying the standard clinical bone vibrator to the skin over soft tissue sites on the head, neck, or thorax of humans and animals. This mode of auditory stimulation has been called soft tissue conduction (STC). This study was designed to investigate the pathway between soft tissue sites and the ear. METHODS: The air in the middle ear was replaced with saline solution in an animal with unique anatomy--the fat sand rat, in which about 70% of a thin-walled inner ear bulges into the middle ear bulla cavity--while we recorded the auditory brain stem responses (ABRs) to AC, BC, and STC stimulation. RESULTS: This replacement of air with saline solution led to a significant improvement in STC threshold. With AC stimulation, the ABR threshold was elevated and the latency of the first ABR wave was prolonged. Consistent changes were not seen with BC stimulation. CONCLUSIONS: When the air (which has a very low acoustic impedance) that normally surrounds most of the inner ear is replaced with saline solution (which has an acoustic impedance similar to that of soft tissues), the STC threshold is improved. This improvement may be due to improved transmission of acoustic energy from the soft tissues to the inner ear. PMID- 23012904 TI - IT takes a (big) village. Laying the IT foundations for population health. AB - With greater policy certainty assured by the Supreme Court's affirmation of the constitutionality of healthcare reform this summer, industry pioneers are beginning to shape the new healthcare, and moving forward on a broad range of population health-based concepts. The strategic challenges--and opportunities- for healthcare IT leaders can't be overstated. PMID- 23012905 TI - Asking population health's unanswered questions. AB - Pilots under the Query Health project are testing two standards: the HQMF standard that expresses an e-measure in machine-readable electronic format; and a query envelope for the secure exchange of queries. PMID- 23012906 TI - Devil in the Details. State health information exchange boards grapple with a dense thicket of policy questions. AB - The journey for statewide HIEs has been slow-going and fraught with challenges of governance, consent, security, auditing structure, and secondary data use. Executive directors of statewide health information exchanges speak about the policy hurdles they have encountered, and those that still lay ahead. PMID- 23012907 TI - Premier's Blair Childs sees healthcare payment's future. Interview by Mark Hagland. PMID- 23012908 TI - Getting a center for population health off the ground. Interview by Gabriel Perna. PMID- 23012909 TI - A dashboard for OR patient safety optimization. Interview by Mark Hagland. PMID- 23012910 TI - Telementoring at UPMC. Interview by Mark Hagland. PMID- 23012911 TI - The top 10 HIE pitfalls. PMID- 23012912 TI - Balancing business innovation and security. PMID- 23012913 TI - Implementation success hinges on business owner inclusion. PMID- 23012914 TI - Orchestrating revenue cycle management. Interview by Mark Hagland. PMID- 23012915 TI - A health plan helps lead provider-payer collaboration. Interview by Mark Hagland. PMID- 23012916 TI - Your finest hour. PMID- 23012917 TI - [Mid-term effectiveness of total hip arthroplasty with collum femoris preserving prosthesis]. AB - OBJECTIVE: To discuss the clinical application of total hip arthroplasty (THA) with collum femoris preserving (CFP) prosthesis and to analyze the mid-term effectiveness. METHODS: Between January 2004 and February 2007, 45 patients (48 hips) underwent THA with CFP prosthesis. There were 29 males (31 hips) and 16 females (17 hips) with an average age of 48.8 years (range, 38-60 years), including 20 left hips, 22 right hips, and 3 bilateral hips. The causes of hip replacement were osteoarthritis (20 cases), avascular necrosis of femoral head (13 cases), dysplasia (4 cases), rheumatoid arthritis (3 cases), posttraumatic osteoarthritis (2 cases), ankylosing spondylitis (2 cases), and Perths disease (1 case). The average disease duration was 6.1 years (range, 2-13 years). Harris scores, visual analogue scale (VAS) score, and the hip range of motion (ROM) were recorded at pre- and post-operation. The X-ray films were taken at pre- and post operation to observe the position, loosening of the prosthesis, and ectopic ossification. The gait of patients were also evaluated during follow-up. Short form 36 health survey scale (SF-36) was used to evaluate the life quality of patients. RESULTS: All 45 patients were followed up 5-8 years with an average of 6.4 years. All the incisions healed by first intention. No infection, hip dislocation, nerve injury, or deep vein thrombosis occurred. Six cleavage fractures (13.3%) of the lateral femoral diaphysis at the distal prosthesis occurred during operation, which healed at 8 months postoperatively without any treatment. Mild ectopic ossification occurred in 4 patients (8.9%) who had no discomfort. Five patients (11.1%) had bone mineral density loss in the region of the proximal femur. The survival rates of the cups and stems were all 100% at last follow-up. The results of Harris score, VAS score, and ROM of the hip joint at 1 year postoperatively and last follow-up were significantly better than preoperative ones (P < 0.05). No significant difference was found in VAS score and ROM of the hip joint between at 1 year postoperatively and at last follow-up (P > 0.05) except the Harris score (P < 0.05). According to Harris functional assessment at last follow-up, the results were excellent in 31 hips, good in 11 hips, and fair in 6 hips with an excellent and good rate of 87.5%. The physiological role, body pain, and total health scores were significantly lower than the reference value of urban men from Sichuan province (P < 0.05), but no significant difference was found in the other scores of the SF-36 when compared with the reference value (P > 0.05). CONCLUSION: THA with CFP prosthesis is a good option for the young patient with complete collum femoris and without osteoporosis, and can achieve good mid-term effectiveness. PMID- 23012918 TI - [Acetabulum reinforcement ring with allograft bone for reconstructing acetabular defects in hip revision]. AB - OBJECTIVE: To evaluate the effectiveness of acetabulum reinforcement ring (Cage) with allograft bone for reconstructing acetabular defects in hip revision. METHODS: Between February 2006 and August 2010, 14 patients (14 hips) with serious acetabular bone defects after total hip arthroplasty underwent acetabular reconstruction by using Cage with allograft bone. There were 6 males and 8 females with a mean age of 59.2 years (range, 45-76 years). The mean time between first replacement and revision was 7.2 years (range, 5-12 years). The revision causes included infection in 8 cases, osteolysis and aseptic loosening in 6 cases. The hip function Harris score was 37.7 +/- 5.3. According to America Association of Orthopedic Surgeon (AAOS) standard, the acetabular defect was classified as type III in 8 cases and as type IV in 6 cases. RESULTS: All incisions healed by first intention, and no complication occurred. The patients were followed up 14-62 months (mean, 44 months). The pain was relieved or disappeared. At last follow-up, the Harris score was 89.7 +/- 3.2, showing significant difference when compared with preoperative score (t = -44.40, P = 0.04). No loosening of the acetabular component or osteolysis was found in 14 hips. No absorption or collapse of the allograft was observed in all patients. CONCLUSION: Cage with allograft bone is a useful method of reconstructing acetabular bone defects in hip revision. Further follow-up is needed to assess the long-term effectiveness. PMID- 23012919 TI - [Comparison of proximal femoral nail antirotation and reconstruction nail for ipsilateral fractures of hip and femoral shaft]. AB - OBJECTIVE: To compare the effectiveness of proximal femoral nail antirotation (PFNA) and reconstruction nail with minimally invasive technique for ipsilateral femoral shaft and extracapsular hip fractures in young and middle-aged patients. METHODS: Sixty-nine young and middle-aged patients with ipsilateral femoral shaft and extracapsular hip fractures were treated between January 2000 and August 2010, and their data were analyzed retrospectively. Of them, fractures were fixed by reconstruction nail in 44 cases (reconstruction nail group) and by PFNA in 25 cases (PFNA group). There was no significant difference in gender, age, weight, injury cause, fracture type, or disease duration between 2 groups (P > 0.05). The operation time, blood loss, fracture healing time, complications, and functional outcomes were compared between 2 groups to evaluate the effectiveness. RESULTS: The operation time and blood loss in the PFNA group were significantly less than those in the reconstruction nail group (P < 0.05). The follow-up time was 12-38 months (mean, 20 months ) in the PFNA group and was 12-48 months (mean, 22 months) in the reconstruction nail group. No complication occurred as follows in 2 groups: wound infection, deep venous thrombosis, pulmonary embolism, breakage of the implants, avascular necrosis of the femoral head, or serious rotation and shortening deformity of lower limbs. In the PFNA group and the reconstruction nail group, 1 patient underwent technical difficulty in nail implant and 7 patients underwent technical difficulty in proximal locking screw, respectively; 3 patients and 6 patients had intra-operative iatrogenic fracture of femoral shaft, respectively; and delayed union of femoral shaft was observed in 1 patient and 2 patients, respectively. The complication rate was 20% (5/25) in the PFNA group and 34% (15/44) in the reconstruction nail group, showing no significant difference (chi2 = 1.538, P = 0.215). No significant difference was found in fracture healing time between 2 groups (P > 0.05). At last follow-up, there was no significant difference in Harris hip score and Evanich knee score between 2 groups (P > 0.05). CONCLUSION: PFNA or reconstruction nail with minimally invasive technique is a good method to treat ipsilateral femoral shaft and extracapsular hip fractures, but the PFNA is superior to the reconstruction nail because of simple operation. PMID- 23012920 TI - [Effectiveness comparison of improved anterolateral approach and lateral approach in treatment of senile intertrochanteric fracture]. AB - OBJECTIVE: To compare the effectiveness between improved anterolateral approach and lateral approach in the treatment of senile intertrochanteric fracture. METHODS: The clinical data were retrospectively analyzed, from 61 patients with senile intertrochanteric fracture treated between February 2008 and February 2010. Of 61 patients, 34 patients underwent improved anterolateral approach combined with fixation of dynamic hip screw (improved group), and 27 patients underwent conventional lateral approach combined with fixation of dynamic hip screw (conventional group). There was no significant difference in gender, age, injury cause, Evans classification, comorbidities, disease duration, or Harris hip scores between 2 groups (P > 0.05). RESULTS: The operation was successfully completed in all patients. The operation time, blood loss, perspective frequency during operation, drainage volume, hospitalization days, and out-of-bed time in the improved group were significantly less than those in the conventional group (P < 0.05). All patients were followed up 12-24 months (mean, 18.7 months). Bone union was achieved in both groups; the fracture healing time was (11.64 +/- 1.28) weeks in the improved group and was (12.29 +/- 1.12) weeks in the conventional group, showing no significant difference (t = 2.15, P = 0.15). Harris hip scores at 3, 6, and 12 months were significantly better than preoperative scores in 2 groups (P < 0.05), and significant differences were found among different time points after operation in 2 groups (P < 0.05), between 2 groups after operation (P < 0.05). There was no significant difference in the incidence of incision infection, limb shortening, coax vara, internal fixation loosening, main screw cutting-out from femoral head between 2 groups (P > 0.05), but the incidence of total complications in the improved group was significantly lower than that in the conventional group (P < 0.05). CONCLUSION: Compared with conventional lateral approach, improved anterolateral approach has the advantages of sufficient exposure, reducing muscle damage and surgical risk in treating intertrochanteric fracture. Operating treatment of improved anterolateral approach combined with early rehabilitation after surgery can recover hip joint function as quickly as possible. PMID- 23012921 TI - [Effectiveness of arthroscopic treatment for synovial chondromatosis]. AB - OBJECTIVE: To explore the technique of arthroscopic treatment of synovial chondromatosis of the hip and to evaluate its effectiveness. METHODS: Between July 2009 and June 2011, 15 patients with synovial chondromatosis of the hip underwent arthroscopic synovectomy and removal of loose bodier. Of 15 patients, 11 were male and 4 were female, aged from 21 to 45 years with an average of 33.1 years. The location was the left side in 6 cases and the right side in 9 cases. The disease duration was 12-43 months (mean, 23 months) Pain and functional motion limitation were the main clinical symptoms. The visual analogue scale (VAS) score was 5.8 +/- 1.1; the range of motion (ROM) of the hip was (149.8 +/- 27.5)degrees; the Harris hip score was 54.5 +/- 13.3. RESULTS: All incisions healed by first intention. All the patients were followed up 6 months to 2 years (mean, 17.4 months). At last follow-up, the VAS score was 2.0 +/- 1.2; the ROM of the hip was (258.3 +/- 35.4)degrees; the Harris hip score was 93.0 +/- 18.7; and the above indexes were significantly improved when compared with preoperative values (P < 0.05). No recurrence was found on postoperative MRI. CONCLUSION: Arthroscopic treatment of synovial chondromatosis of the hip has the advantages of minimal invasion, quick recovery, and best recovery of hip function and ROM. PMID- 23012922 TI - [Management of deep infection after total knee arthroplasty]. AB - OBJECTIVE: To evaluate the clinical treatment methods of deep infection after total knee arthroplasty (TKA) and its effectiveness. METHODS: Between January 2004 and January 2010, 32 cases (32 knees) of deep infection after TKA were treated, including 13 males and 19 females with an average age of 64.6 years (range, 52-79 years). The time from primary TKA to infection was 3 weeks to 10 years. The preoperative knee society score (KSS) was 104.6 +/- 9.1, and the visual analogue scale (VAS) score was 7.8 +/- 1.4. Open debridement and continuous irrigation were perfomed in 3 cases of acute infection, arthroscopic debridement and irrigation in 3 cases of acute haematogenous infection; in 26 cases of chronic deep infection, 9 cases underwent open debridement, 4 cases underwent antibiotics impregnated bone cement spacer, 12 cases received two-stage revision, and 1 case underwent conservative treatment by intravenous antibiotics. RESULTS: All cases of acute infection failed to control deep infection; 1 case of acute haematogenous infection failed to treat; 7 cases of chronic infection undergoing debridement and 1 case of conservative treatment failed to treat; and all the failure cases were cured after symptomatic treatment. Thirty-two cases were followed up 2-8 years (mean, 4.6 years). At last follow-up, the KSS score and VAS score were 158.4 +/- 8.3 and 4.1 +/- 0.8, respectively, all showing significant differences when compared with preoperative scores (P < 0.05). Re infection occurred in 3 patients who received two-stage revision during follow up. CONCLUSION: In patients with acute infection of methicillin-resistant Staphylococcus aureus after TKA, open debridement and liner change have low success rate; arthroscopic debridement can be performed to control acute haematogenous infection; and two-stage revision is an effective method to control chronic infection and restore the knee function, but two-stage revision has a potential risk of re-infection. PMID- 23012923 TI - [Surgical treatment of antero-medial rotatory instability of knee joint caused by motorcycle]. AB - OBJECTIVE: To discuss the effectiveness of operation technique for antero-medial rotatory instability (AMRI) of the knee joint caused by motorcycle. METHODS: Between June 2007 and December 2009, 32 cases of AMRI caused by motorcycle were treated. There were 28 males and 4 females with an average age of 35.5 years (range, 20-50 years). The interval between injury and surgery was 5-10 days (mean, 7 days). The anterior cruciate ligament (ACL) was injured at the attachment point of the condyles crest; the medial collateral ligament (MCL) was injured at central site in 19 cases, at medial condyles of femur in 10 cases, and at medial condyles of tibia in 3 cases, which were all closed injuries. The bone avulsion of condyles crest was fixed by steel wire and MCL was repaired. RESULTS: Red swelling and a little effusion occurred at the incision in 1 case, and the other incisions healed by first intention. Traumatic arthritis of the knee occured in 5 cases. Thirty-two cases were followed up 16-22 months (mean, 18.5 months). The X-ray examination showed that the fracture union time was 5-8 weeks (mean, 6 weeks) after operation. At last follow-up, the extension of knee joint was 0 degrees and the flexion of the knee joint was 110-170 degrees (mean, 155 degrees). According to the synthetic evaluating standard of International Knee Documentation Committee, 24 cases were rated as A level, 6 cases as B, 1 case as C, and 1 case as D at last follow-up. Lysholm knee score was 85.93 +/- 3.76 at last follow-up, which was significantly higher (t = 53.785, P = 0.000) than preoperative score 37.54 +/- 3.43. CONCLUSION: In patients with AMRI caused by motorcycle, steel wire is used to fix the bone avulsion of condyles crest and MCL should be repaired simultaneously as far as possible. And associating with the early postoperative functional exercise, the short-term effectiveness is satisfactory, but long-term effectiveness still need further follow-up observation. PMID- 23012924 TI - [Redintegration of articular surface and alignment with tibia type III Pilon fracture]. AB - OBJECTIVE: To explore an improved method of surgical operation for redintegration of the articular surface and alignment with type III Pilon fractures. METHODS: Between August 2005 and August 2010, 31 patiens with closed type III Pilon fracture (Ruedi-Allgower type III) were treated. There were 25 males and 6 females, aged 36.8 years on average (range, 16-60 years). The injury was caused by falling from height in 18 patients, by traffic accident in 10 patients, and by other reasons in 3 patients. The average time between injury and operation was 10 days (range, 6-14 days). Temporary external fixation was used for adjustment and maintenance of limb length and power lines; application of fibular flip combined with anteromedial approach was used for the repair of articular surface; and bone grafting and fixation were performed. RESULTS: No extensive necrosis or deep infection were observed. Superficial skin infection of incision and wound edge necrosis occurred in 2 cases respectively, and were cured after dressing change. All patients were followed up 26 months on average (range, 9-79 months). According to the Burwell et al. judging standards of radiology evaluating, the anatomical reduction was found in 25 cases (80.6%), satisfactory reduction in 4 cases (12.9%), and unsatisfactory reduction in 2 cases (6.5%). The X-ray films showed bony healing was achieved in all cases with an average fracture healing time of 16 weeks (range, 12-25 weeks). According to the Mazur et al. criterion for ankle joint function, excellent result was obtained in 11 cases, good in 13, fair in 5, and poor in 2; the excellent and good rate was 77.4%. CONCLUSION: Good exposure and fixation of articular surface or accurate adjustments and maintenance of the limb alignment are key factors of successful operation to treat type III Pilon fractures. PMID- 23012925 TI - [Biomechanical study on reconstructed anterior bundle of elbow medial collateral ligament]. AB - OBJECTIVE: To investigate the effect of complete anterior bundle of medial collateral ligament (MCL) on the valgus stability of the elbow after reconstruction and to assess the efficacy of artificial tendon and interference screw in reconstruction the anterior bundle of MCL. METHODS: The bone-tendon of the elbow were made in 12 adult upper limb specimens. There were 8 males and 4 females, left side and right side in half. Using biomechanic ways and pressure sensitive film, the valgus laxity, the stress area of the humeroulnar joint, and the intra-articular pressure were measured in integrated anterior bundle of MCL (control group, n = 12) and reconstructed anterior bundle of MCL with artificial tendon and interference screw (experimental group, n = 12) in elbow flexion of 0, 30, 60, and 90 degrees . RESULTS: There was no significant difference in the valgus laxity within group and between groups in different flexion degrees (P > 0.05). No significant difference was found in the intraarticular pressure in elbow flexion of 30, 60, and 90 degrees within group and between groups (P > 0.05) except in elbow flexion of 0 degrees (P < 0.05). The stress area of the humeroulnar joint in 0 degrees flexion was significantly larger than that in 30, 60, and 90 degrees flexion in the control group (P < 0.05), but no significant difference was found within group and between groups in the other flexion degrees (P > 0.05). CONCLUSION: The anterior bundle of MCL has important significance for maintaining the valgus stability of the elbow, after reconstructing the anterior bundle by using artificial tendon and interference screw, the medial stability of elbow can be recovered immediately. PMID- 23012926 TI - [In vivo degradable properties of a novel injectable calcium phosphate cement containing poly lactic-co-glycolic acid]. AB - OBJECTIVE: To investigate the in vivo degradable properties of new calcium phosphate cement (CPC) containing poly lactic-co-glycolic acid (PLGA) so as to lay a foundation for the future clinical application. METHODS: A novel CPC containing PLGA (CPC/PLGA) was prepared according to a ratio of 45% dicalcium phosphate anhydrous: 45% partially crystallized calcium phosphates: 10% PLGA. Thirty-two adult New Zealand rabbits (weighing 2.2-3.0 kg, male or female in half) were divided into the experimental group (n = 17) and the control group (n = 15). The bone defect models of the bilateral femoral condyles (4.5 mm in diameter and 1.5 cm in depth) were made by drilling hole. Defect at the right side was repaired with CPC/PLGA in the experimental group and with CPC in the control group, while defect at the left side was not treated as blank control. The general condition of rabbits was observed after operation; the histological observation and bone histomorphometric analysis were performed at 2, 4, 8, 16, and 24 weeks; and scanning electronic microscope (SEM) observation was performed at 8 and 16 weeks after operation. RESULTS: All rabbits survived to the end of experiment. The histological observation showed: CPC/PLGA degraded gradually, and the new-born bone trabecula ingrew; bone trabeculae became rough and strong; and CPC/ PLGA almost biodegraded at 24 weeks in the experimental group. The CPC degradation was much slower in the control group than in the experimental group. The total bone tissue percentage was 44.9% +/- 23.7% in the experimental group, and 25.7% +/- 10.9% in the control group, showing significant difference between 2 groups (t = 3.302, P = 0.001); and the bone tissue percentage showed significant difference between 2 groups at 8, 16, and 24 weeks (P < 0.05). The results of SEM observation showed that the pore size was 100-300 microm at 8 weeks after operation, new-born bone trabecula grew into the pores and combined strongly with residual cement in the experimental group. CONCLUSION: Novel CPC/PLGA has good in vivo degradable properties, and it can be an ideal bone substitute in future clinical application. PMID- 23012927 TI - [Application of facial tissue expander fibrous envelope for tension reduction]. AB - OBJECTIVE: To investigate the application of the fibrous envelope of tissue expanders for the tension reduction. METHODS: Between June 2005 and May 2011, 21 patients with facial scar were treated with skin soft tissue expansion. There were 6 males and 15 females, aged 19-33 years (mean, 24.5 years), including 19 cases of hypertrophic scar and 2 cases of atrophic scar with disease duration of 1-31 years. The scars ranged from 4 cm x 2 cm to 25 cm x 10 cm. The tissue expander was implanted under normal skin adjacent to lesions in the first stage. And the post-expanded skin flap was designed as advance flap or transpositional flap as supplement in the second stage. Fibrous envelope at the base was fixed to the periosteum or fascia nearby first, and then sutures were used between envelopes at the base and on the skin flap or to the dermis of the skin flap to keep the mouth and lower eyelid in proper position. It reduced the tension of incision and maintained the contour of the face and neck. RESULTS: After the first stage operation, 2 cases had replaced expanders because of infection and leakage. No complication of infection or hematoma occurred after the second stage operation. The patients were followed up 1-18 months (mean, 10.2 months); of them, 12 were followed up more than 1 year. No secondary deformity (deviation of mouth angle, eyebrows pulling, or eyelid ectropion) occurred. The flaps had good appearance and color. The satisfactory results were achieved. CONCLUSION: In skin soft tissue expansion of the face, the fibrous envelopes at the base could reduce the tension of the incision and prevent the deformity of the mouth and lower eyelids. PMID- 23012928 TI - [Improved pedicled superficial iliac circumflex artery flap for reconstruction of hand and forearm wounds]. AB - OBJECTIVE: To explore the effectiveness of the improved pedicled superficial iliac circumflex artery flap for repairing serious wound of the hand and forearm. METHODS: Between June 2008 and June 2011, 13 cases of serious wound of the hand and forearm were treated. There were 9 males and 4 females with a mean age of 41 years (range, 23-64 years). The disease causes included twist injury by machine in 2 cases, wire rope squeezed injury in 4 cases, traffic accident injury in 3 cases, crushing injury in 2 cases, high voltage electrical injury in 1 case, and snake bites in 1 case. There were 10 cases of fresh wounds and 3 cases of infection and necrosis wounds, and all had bone and tendon exposure. The skin and soft tissue defects ranged from 7 cm x 3 cm to 22 cm x 6 cm. The pedicled iliac artery flap was used in 8 cases, and pedicled iliac artery composite flap in 5 cases. The flap size ranged from 12 cm x 4 cm to 27 cm x 8 cm, with the flap pedicle of 2-4 cm wide strip and 3-5 cm wide fascia. RESULTS: The pedicle of flap was cut at 3 weeks in 12 patients, and at 4 weeks in 1 patient who had partial avulsion and hemorrhage at 1 week after operation. All flaps survived and incisions at donors and wounds healed by first intention. Eleven patients were followed up 6-36 months (mean, 20 months). The flap color and texture were good; 3 bulky flaps were observed, and satisfactory appearance was achieved after skin flap thinning. After 6 months, the protective sensation recovered in all cases; according to the Hand Surgery Society of Chinese Medical Association evaluation of upper extremity function trial standard for total active motion of the fingers, the results were excellent in 9 cases, good in 1 case, and poor in 1 case. CONCLUSION: Improved fascia pedicled superficial iliac circumflex artery skin flap can repair serious hand and forearm injury, which is easy-to-operate and less injury at donor site. PMID- 23012929 TI - [Reconstruction of postburn popliteal fossa contractures using popliteal fossa middle artery pedicled flaps in children]. AB - OBJECTIVE: To investigate the characteristics of blood supply of popliteal fossa middle artery pedicled flaps and the feasibility of reconstruction of postburn popliteal fossa contractures using the flaps in children. METHODS: Between January 2008 and October 2010, 6 cases of postburn popliteal fossa contractures were recontructed using popliteal fossa middle artery pedicled flaps. Of them, 2 were boys and 4 were girls, aged from 2 years and 2 months to 10 years. All burns were caused by hot water. The wound ranged from 5 cm x 4 cm to 10 cm x 8 cm after scar relaxation. The size of the flap ranged from 6 cm x 4 cm to 11 cm x 9 cm. Donor sites were covered with split-thickness skin graft in 5 cases, and sutured directly in 1 case. RESULTS: All the flaps and the skingraft survived; no vascular crisis or flap necrosis occurred. All incisions at donors and wounds healed by first intention. All patients were followed up 12-24 months. The color, texture, and appearance of the flaps were good. Hyperplastic scar was found at incision of popliteal fossa in 1 case at 6 months after operation; the range of motion (ROM) of the knee joint was 0-175 degrees, and no obvious change was observed at 15 months after operation. The others had no functional disturbance of the knee joints or claudication; the ROM of the knee joint was 0-180 degrees. CONCLUSION: The popliteal fossa middle artery pedicled flap has reliable blood supply, simple operative procedure, and good results in reconstruction of popliteal fossa contracture. PMID- 23012930 TI - [Soft tissue reconstruction after resection of musculoskeletal tumors]. AB - OBJECTIVE: To evaluate the effectiveness of soft tissue reconstruction after resection of musculoskeletal tumor and to discuss the strategy of soft tissue reconstruction. METHODS: Between June 2003 and December 2010, 90 patients with musculoskeletal tumor underwent tumor resection and soft tissue reconstruction. There were 59 males and 31 females with a median age of 37.2 years (range, 9-85 years), including 52 bone tumors and 38 soft tissue tumors. One stage reconstruction of soft tissue was performed after tumor resection in 75 cases; reconstruction of soft tissue was performed after debridement in 7 cases of wound dehiscence; and two stage reconstruction of soft tissue was performed after debridement and vacuum sealing drainage placement in 8 cases of infected wounds. The gastrocnemiums flap was used in 40 cases, the latissimus dorsi myocutaneous flap in 6 cases, rectus abdominis myocutaneous flap in 4 cases, gluteus maximus musculocutaneous flap in 1 case, pectoralis major muscle flap in 1 case, cross abdominal flap in 1 case, local transfer flap in 27 cases, pedicled flaps in 5 cases, and skin grafts in 5 cases. The size of the flap ranged from 6.5 cm x 4.5 cm to 21.0 cm x 9.0 cm. RESULTS: Eighty-seven flaps survived, and incisions healed by first intention in 81 cases. In 6 cases of healing by second intention, 2 had partial flap necrosis, which was cured by dressing change; 3 had delayed healing; 1 had mild infection, which was cured after conservative treatment. Wound of donor site healed primarily, and the grafted skin survived. Seventy three patients were followed up 10-102 months (mean, 36.1 months). Local tumor recurrence was observed in 6 patients, who received second resection at 2-27 months (mean, 8.2 months) after operation. Thirteen patients dead of primary disease at 6-34 months (mean, 19.2 months) after operation. CONCLUSION: The defects caused by resection of musculoskeletal tumor require soft tissue reconstructions. Optimal reconstruction can enhance wound closure, decrease incidence of wound complication, preserve limb function. PMID- 23012931 TI - [Clinical study on topical bismuth subgallate/borneol (Suile) dressing for treatment of diabetic foot ulcers]. AB - OBJECTIVE: To evaluate the efficacy and safety of Bismuth Subgallate/Borneol (Suile) (BSB) dressing in the treatment of diabetic foot ulcers. METHODS: A two center, randomized controlled parallel-group comparison study was conducted. Between September 2005 and November 2006, 35 patients with nonhealing diabetic foot ulcer (Wagner 2-3 grade) were recruited and divided randomly into the test group (BSB group, n = 25) and control group (IG group, n = 10). There was no significant difference in general data between 2 groups (P > 0.05). Based on the comprehensive therapy of diabetic foot, ulcers were topically treated by Suile dressing and Intrasite gel in the BSB group and IG group, respectively. The ulcer area was measured once a week. Ulcer bleeding was observed and acceptance of the dressing was inquired each week. RESULTS: Of the patients, 22 patients in the BSB group and 8 in the IG group completed the clinical trial. Intention to treat (ITT) analysis indicated that the results were excellent in 19 (76%) cases, good in 3 cases (12%), fair in 1 case (4%), and poor in 2 cases (8%) in the BSB group. In the IG group, the results were excellent in 8 cases (80%) cases, fair in 1 case (10%), and poor in 1 case (10%). Per-protocol (PP) analysis showed that the results were excellent in 19 cases (86%) and good in 3 cases (14%) in the BSB group, and were excellent in 8 cases (100%) in the IG group. The results of ITT and PP analysis all showed no significant difference between 2 groups (P > 0.05). The change trend of ulcer areas in the BSB group was similar to that in the IG group. There was no significant difference in the hemostatic effect between 2 groups (P > 0.05) and the patients were more likely to accept BSB dressings. CONCLUSION: BSB dressings is an effective, safe, and generally well-tolerated therapy dressing in the treatment of diabetic foot ulcers. PMID- 23012932 TI - [Effect of extracorporeal shock wave therapy on diabetic chronic wound healing and its histological features]. AB - OBJECTIVE: Extracorporeal shock wave (ESW) can promote angiogenesis and tissue repair. To investigate the influence of ESW therapy on the histological features of diabetic chronic wounds and wound healing. METHODS: Ninety-six male Sprague Dawley rats with weight (220 +/- 20) g were divided into 3 groups (n = 32): diabetic control group, ESW treatment group, and normal control group. The diabetic rats were prepared in diabetic control group and ESW treatment group by intraperitoneal injection of Streptozotocin (60 mg/kg). Then a circular full thickness skin wound of 1.8 cm in diameter was made at the back of diabetic rats to establish the diabetic chronic wound model, and the same wound was made in normal control group. In ESW treatment group, ESW (0.11 mJ/mm2, 1.5 Hz energy, and 500 pulses) was applied to treat the wound at 1 day after wounding; in two control groups, no ESW treatment was given. The wound healing and histological changes were observed by HE and Masson staining at 3, 7, and 14 days after treatment; and the cell proliferation, angiogenesis, and collagen deposition were observed by CD31 and proliferating cell nuclear antigen (PCNA) immunohistochemical staining. RESULTS: The wound closure rate in diabetic control group was lower, and the healing time was significantly longer than those in normal control group (P < 0.05); at 3, 7, and 14 days after treatment, the inflammatory cell infiltration in wound tissue was obvious, and the relative area density of collagen fibers, wound microvessel density (MVD), and the relative density of PCNA-positive cells were significantly lower than those in normal control group (P < 0.05). The wound healing time was significantly shorter and the wound closure rate was significantly higher in ESW treatment group than those in the diabetic control group (P < 0.05). At different time points in ESW treatment group, the inflammatory cells signficantly reduced, while the relative area density of collagen fibers, MVD, and relative density of PCNA-positive cells significantly increased when compared with those in diabetic control group (P < 0.05). No significant difference in MVD and relative density of PCNA-positive cells was found between ESW treatment group and normal control group (P > 0.05). CONCLUSION: Low-energy ESW treatment can inhibit the local inflammatory response, promote cell proliferation, increase angiogenesis and collagen deposition, and enhance granulation tissue formation, and so it can promote chronic wound healing in diabetic rats. PMID- 23012933 TI - [Effectiveness comparison between double Perclose ProGlide crossing suture and traditional suture for closure of puncture sites in endovascular aortic repair]. AB - OBJECTIVE: To compare the advantages and disadvantages between double Perclose ProGlide crossing suture and traditional suture for the closure of 20F or 22F access points so as to provide a basis for selecting appropriate approach to repair the puncture points in endovascular aortic repair. METHODS: Between June 2007 and May 2011, 103 patients (115 common femoral arteries) underwent endovascular aortic repair using sheaths of 20F or 22F (outer diameter); double Perclose ProGlide crossing suture was performed for closure of puncture sites in 57 cases (64 common femoral arteries) (double Perclose group) and traditional suture in 46 cases (51 common femoral arteries) (traditional group). There was no significant difference in age, gender, or disease duration between 2 groups (P > 0.05). RESULTS: The operation time, blood loss, and hospitalization days of double Perclose group were significantly better than those of traditional group (P < 0.05). Ecchymoma in inguinal region and lymphatic leakage occurred in 5 cases (5 common femoral arteries) and 2 cases (2 common femoral arteries) of double Perclose group respectively, in 2 cases (2 common femoral arteries) and 6 cases (8 common femoral arteries) of traditional group respectively; no significant difference was found in the rate of the early complication between double Perclose group and traditional group (7.8% vs. 15.7%, chi2 = 1.76, P = 0.19). The technique success rate of double Perclose group was 96.9% (62/64), and was 100% (51/51) in traditional group, showing no significant difference (chi2 = 0.31, P = 0.50). All patients were followed up, 2-19 months (mean, 15 months) in double Perclose group and 2-18 months (mean, 14 months) in traditional group. Pseudoaneurysm occurred in the puncture region at 3 months in 1 case (1 common femoral artery) of double Perclose group, and incision and suture therapy was performed; no arteriostenosis or pseudoaneurysm occurred in other cases; and the rate of mid-term complication was 1.6% (1/64) in double Perclose group and was 0 in traditional group, showing no significant difference (P = 1.000). CONCLUSION: Double Perclose ProGlide crossing suture has the same effectiveness to traditional surture in repairing the puncture point with 20F or 22F, but it is superior to traditional suture in reducing operation time, blood loss, and hospitalization days. PMID- 23012934 TI - [Short-term effectiveness of selective treatment of senile osteoporotic thoracolumbar burst fractures of Denis type B with kyphoplasty and Jack vertebral dilator]. AB - OBJECTIVE: To investigate the feasibility and effectiveness of selective treatment of senile osteoporotic thoracolumbar burst fractures of Denis type B with kyphoplasty and Jack vertebral dilator. METHODS: Between August 2007 and May 2011, 30 patients (32 vertebra) with osteoporotic thoracolumbar burst fractures of Denis type B were treated with kyphoplasty and Jack vertebral dilator. There were 7 males and 23 females, aged 57-85 years (mean, 76.9 years). The injured vertebrae included T11 in 2 vertebrae, T12 in 11 vertebrae, L1 in 7 vertebrae, L2 in 5 vertebrae, L3 in 3 vertebrae, and L4 in 4 vertebrae. The visual analogue scale (VAS) score, Oswestry disability index (ODI), the anterior and middle height of the vertebral body, and the Cobb angle were assessed before and after operation. RESULTS: The operation was completed smoothly in all cases; no cement leakage or intraoperative complication was found. Obvious back pain relief was achieved in all patients after operation. Thirty patients were followed up at 1 week and 6 months after operation. The VAS score was decreased from 8.2 +/- 1.3 before operation to 1.5 +/- 0.9 at 1 week after operation and 1.9 +/- 0.5 at 6 months after operation; the ODI was decreased from 82.4% +/- 15.0% to 17.8% +/- 9.5% and 23.0% +/- 8.6%; the anterior height of the vertebral body was increased from (19.5 +/- 3.2) mm to (24.8 +/- 3.0) mm and (24.0 +/- 2.6) mm; the middle height of the vertebral body was increased from (18.5 +/- 3.4) mm to (23.7 +/- 3.7) mm and (22.8 +/- 3.5) mm; the Cobb angle was decreased from (14.9 +/- 7.5)degrees to (7.6 +/- 6.0)degrees and (8.3 +/- 6.0)degrees; and there were significant differences in the VAS score, ODI, the anterior and middle height of the vertebral body, and the Cobb angle between at pre- and at post-operation (P < 0.05), but no significant difference between at 1 week and at 6 months after operation (P > 0.05). CONCLUSION: Kyphoplasty with Jack vertebral dilator for selective treatment of senile osteoporotic thoracolumbar burst fractures of Denis type B can restore the anterior and middle height of the vertebral body, correct the Cobb angle, and relieve pain, and it has good short-term effectiveness and safety. PMID- 23012935 TI - [An experimental study on effect of autologous platelet-rich plasma on treatment of early intervertebral disc degeneration]. AB - OBJECTIVE: Platelet-rich plasma (PRP) can stimulate intervertebral disc cell proliferation, promote extracellular matrix synthesis, and inhibit annulus fibrosus cell apoptosis. To investigate the effects of autologous PRP on the treatment of the early intervertebral disc degeneration (IDD) so as to provide the experimental basis for its clinical application. METHODS: Forty-five healthy New Zealand white rabbits (male or female, weighing 2.5-3.0 kg) were randomly divided into the experimental group (n = 15), the control group (n = 15), and the sham group (n = 15). PRP was prepared from the arterial blood of rabbit's ears of the experimental group with Landesberg's method. The platelet concentrations in both whole blood and PRP were detected. The rabbit model of early IDD was established by annulus fibrosus puncture (L4, 5, L5, 6) in both the experimental group and the control group; 100 microL autologous PRP and 100 microL PBS were injected into the degenerative intervertebral discs respectively after 2 weeks of models creation. In sham group, intervertebral discs were separated and exposed without treatment. The general conditions of the rabbits were observed after building models; at 2 weeks after degeneration, 1 and 2 weeks after intervention, 5 rabbits were selected randomly from each group respectively for MRI observation, histological observation by using HE staining and collagen type II immunohistochemical staining. The signal of lumbar MRI was assessed and the contents of collagen type II were detected. RESULTS: The platelet concentration of PRP was about 4.92 times as much as that of the whole blood. All the animals survived to the end of the experiment. At 2 weeks after degeneration, a lower T2 signal was observed in both the experimental group and the control group; the nucleus pulposus cells decreased and extracellular matrix degenerated; and the expression of collagen type II decreased in both the experimental group and control group. The degenerative grade of lumbar MRI in the experimental group and control group were significantly higher than that in the sham group (P < 0.05), and the content of collagen type II were significantly lower than that in the sham group (P < 0.05). At 1, 2 weeks after intervention, disc degeneration in the experimental group was significantly lower than that in control group (P < 0.05), and significant difference was found between experimental group and sham group (P < 0.05). The nucleus pulposus cells and chondroid matrix in the experimental group were more than those in the control group, showing slight stromal fibrosis; but the expression of collage type II was significantly higher than that in the control group (P < 0.05). CONCLUSION: The disc injection of autologous PRP may terminate or even reverse the progress of rabbit early IDD, which may be associated with the role of multiple growth factors of PRP in regulating cell function, improving the tissue microenvironment, and promoting tissue regeneration. PMID- 23012936 TI - [Effect of aminoguanidine on spinal cord edema of acute spinal cord injury in rats]. AB - OBJECTIVE: Aminoguanidine (AG) can reduce brain edema and increase the recovery of neuron functions in surgical brain injury and stroke. To investigate the effect of AG on spinal cord injury (SCI) in rats and its mechanism. METHODS: A total of 150 adult male Sprague Dawley rats (weighing, 230-255 g) were divided into control group (group A, 25 rats without treatment), the sham-operated group (group B, 25 rats undergoing laminectomy), SCI group (group C, 25 SCI rats with injection of 5% DMSO), SCI + AG groups (groups D, E, and F, 25 SCI rats and AG injection of 75, 150, and 300 mg/kg, respectively). The optimal dosage of AG was screened by dry-wet weight method with the percentage of water content at 0, 12, 24, and 48 hours after injury. The blood-spinal cord barriar permeability was further detected by Evans blue (EB) method, aquaporins 4 (AQP4) mRNA expression by RT-PCR, AQP4 protein expression by immunohistochemistry and Western blot. RESULTS: AG injection at dosage of 150 mg/kg can significantly reduce edema of spinal cords at 12, 24, and 48 hours after SCI (P < 0.05), so 150 mg/kg was the optimal dosage. The EB content in group E was significantly lower than that in group C at 12, 24, and 48 hours after SCI, and the permeability of blood-spinal cord barrier was significantly decreased compared with group C (P < 0.05). The AQP4 mRNA expressions in groups B and E were significantly lower than that in group C at 12, 24, and 48 hours after SCI (P < 0.05). AQP4 protein expressions in groups B and E were significantly lower than that in group C at 24 and 48 hours after SCI (P < 0.05) by Western blot. Immunohistochemical staining revealed that AQP4 protein expression in group C was significantly higher than that in groups B and E (P < 0.05) at 48 hours after SCI, but no significant difference was found between group B and group E (P > 0.05). CONCLUSION: AG injection at dosage of 150 mg/kg can induce spinal cord edema and injury in rats, which could be correlated with the down-regulation of AQP4 expression. PMID- 23012937 TI - [Preparation of basic fibroblast growth factor chitosan microsphere and its properties]. AB - OBJECTIVE: To study the release properties of basic fibroblast growth factor (bFGF) chitosan microspheres prepared by cross-linking-emulsion method using chitosan as a carrier material so as to lay a foundation for further study. METHODS: Using 0.6% sodium tripolyphosphate solution as a crosslinking agent and 1.5% solution of chitosan as a carrier material, bFGF chitosan microspheres were prepared by cross-linking-emulsion method. Laser particle size analyzer and Zeta electric potential analyzer were used to measure the particle diameter distribution, scanning electronic microscope to observe the morphology, and ELISA to determine the drug loading, the encapsulation rate, and the drug release properties. RESULTS: The particle size of bFGF chitosan microspheres ranged 20.312-24.152 microm. The microspheres were round with a smooth surface and uniform distribution, and it had no apparent porosity. The drug loading and encapsulation rate of microspheres were (7.57 +/- 0.34) mg/g and 95.14% +/- 1.58%, respectively. The bFGF chitosan microspheres could continuously release bFGF for 24 days; the bFGF level increased gradually with time and reached (820.45 +/- 21.34) ng/mL at 24 days; and the microspheres had a burst effect, and the burst rate was 18.08%, and the accumulative release rate of the microspheres reached 82.05% during 24 days. CONCLUSION: It is easy-to-operate to prepare the bFGF chitosan microspheres with the cross-linking-emulsion method. The bFGF chitosan microspheres have smooth surface, uniform distribution, and no apparent porosity. PMID- 23012938 TI - [Study on immune response after repair of nerve defect with acellular nerve xenograft laden with allogenic adipose-derived stem cells in rhesus monkey]. AB - OBJECTIVE: To observe the systemic and local immune response after repair of nerve defect with acellular nerve xenograft laden with allogenic adipose-derived stem cells (ADSCs) in rhesus monkey so as to evaluate the safety of the proposed material for nerve reconstruction. METHODS: Bilateral tibial nerves were taken from a healthy adult male landrace (weighing 48 kg) to prepare acellular nerve xenograft by chemical extraction. ADSCs were isolated from a healthy adult male rhesus monkey (weighing 4.5 kg), and were seeded into the acellular nerve grafts. The radial nerve defect models with 25 mm in length were established in 10 healthy adult female rhesus monkeys (weighing 3-5 kg), and they were divided into cell-laden group (n = 5) and non-cell-laden group (n = 5) randomly. Defect was repaired with acellular nerve xenograft laden with allogenic ADSCs in cell-laden group, with acellular nerve xenograft only in non-cell-laden group. The blood samples were taken from peripheral vein preoperatively and at 14, 60, and 90 days after operation for lymphocyte analysis; at 5 months after operation, the grafts were harvested to perform histological examination for local immune response and nerve regeneration. The nerve autograft in rhesus monkey was used as control. RESULTS: In cell-laden group and non-cell-laden group, no significant difference was found in the count of lymphocytes and T lymphocytes, the percentage ofT lymphocytes, CD8+ T lymphocytes, as well as the ratio of CD4+ T lymphocytes to CD8+ T lymphocytes between pre- and post-operation (P > 0.05); in cell-laden group, the percentage of CD4+ T lymphocytes at 14 days was significantly lower than that at 60 and 90 days postoperatively (P < 0.05). The percentage of CD4+ T lymphocytes in cell-laden group was significantly lower than that in non-cell laden group at 14 days (P < 0.05), but no significant difference was found in the other indexes at the other time between 2 groups (P > 0.05). At 5 months after operation, mild adhesion was found on the surface of nerve xenografts; the epineurium of nerve xenografts was thicker than that of nerve autografts; and neither necrosis nor fibrosis was found. CD3+, CD4+, CD8+, CD68+, and CD163+ T lymphocytes were scattered within the grafts, in which regenerative axons were revealed. CD3+, CD4+, CD8+, CD68+, and CD163+ T lymphocytes were comparable in cell-laden group, non-cell-laden group, and autograft group. CONCLUSION: Repair of nerve defect with acellular nerve xenograft elicits neither systemic nor local immune response in rhesus monkeys. Implantation of allogenic ADSCs might result in transient depression of CD4+ T lymphocytes proliferation early after surgery, no immune response can be found. PMID- 23012939 TI - [Preparation and biocompatibility of a novel biomimetic osteochondral scaffold: collagen-chitosan/nano-hydroxyapatite-collagen-polylactic acid]. AB - OBJECTIVE: To prepare collagen-chitosan/nano-hydroxyapatite-collagen-polylactic acid (Col-CS/nHAC-PLA) biomimetic scaffold and to examine its biocompatibility so as to lay the foundation for its application on the treatment of osteochondral defect. METHODS: PLA was dissolved in dioxane for getting final concentration of 8%, and the nHAC power was added at a weight ratio of nHAC to PLA, 1 : 1. The solution was poured into a mold and frozen. CS and Col were dissolved in 2% acetum for getting the final concentrations of 2% and 1% respectively, then compounded at a weight ratio of CS to Col, 20 : 1. The solution was poured into the frozen mold containing nHAC-PLA, and then biomimetic osteochondral scaffold of Col-CS/nHAC-PLA was prepared by freeze-drying. Acute systemic toxicity test, intracutaneous stimulation test, pyrogen test, hemolysis test, cytotoxicity test, and bone implant test were performed to evaluate its biocompatibility. RESULTS: Col-CS/nHAC-PLA had no acute systemic toxicity. Primary irritation index was 0, indicating that Col-CS/nHAC-PLA had very slight skin irritation. In pyrogen test, the increasing temperature of each rabbit was less than 0.6 degrees C, and the increasing temperature sum of 3 rabbits was less than 1.3 degrees C, which was consistent with the evaluation criteria. Hemolytic rate of Col-CS/nHAC-PLA was 1.38% (far less than 5%). The toxicity grade of Col-CS/nHAC-PLA was classified as grade I. Bone implant test showed that Col-CS/nHAC-PLA had good biocompatibility with the surrounding tissue. CONCLUSION: Col-CS/nHAC-PLA scaffold has good biocompatibility, which can be used as an alternative osteochondral scaffold. PMID- 23012940 TI - [Differentiation potential and application of stem cells from adipose tissue]. AB - OBJECTIVE: To introduce types and differentiation potentials of stem cells from adipose tissue, and its applications on regenerative medicine and advantages. METHODS: The literature of original experimental study and clinical research about bone marrow mesenchymal stem cells (BMSCs), adipose-derived stem cells (ADSCs), and dedifferentiated fat (DFAT) cells was extensively reviewed and analyzed. RESULTS: ADSCs can be isolated from stromal vascular fraction. As ADSCs have multi-lineage potentials, such as adipogenesis, osteogenesis, chondrogenesis, angiogenesis, myogenesis, and neurogenesis, they have already been successfully used in regenerative medicine areas. Dramatically, mature fat cells can be dedifferentiated and changed into fibroblast-like cells, named DFAT cells, via ceiling culture method. DFAT cells also had the same multi-lineage potentials as ADSCs, differentiating into adipocytes, osteocytes, chondrocytes, endothelial cells, muscle cells, and nerve cells. Compared with BMSCs which are commonly used as adult stem cells, ADSCs and DFAT cells have extensive sources and can be easily acquired. While compared with ADSCs, DFAT cells have good homogeneity and strong proliferation capacity. CONCLUSION: As a potential source of stem cells, adipose tissue will provide a new promising for regenerative medicine. PMID- 23012941 TI - [Progress in isolation and purification of porcine islets]. AB - OBJECTIVE: To review the common methods of isolation and purification of porcine islets and research progress. METHODS: Domestic and abroad literature concerning the isolation and purification of porcine islets was reviewed and analyzed thoroughly. RESULTS: The efficacy of the isolation and purification depends on the selection of donor, the procurement and cryopreservation of high-quality donor pancreas, and the selection and improvement of the operation. CONCLUSION: The shortage of transplanted islets could be resolved by the establishment of standardized and optimal process, which may also promote the development of porcine islet xenograft. PMID- 23012942 TI - [Changing trends of main endemic indicators of schistosomiasis in Dongting Lake area]. AB - OBJECTIVE: To analyze the main endemic indicators and their changing trend of schistosomiasis since the founding of new China for 60 years in Dongting Lake regions. METHODS: A variety of archival data on schistosomiasis epidemiology and control were collected, and several mathematical models were applied to estimate the main endemic indicators of schistosomiasis. RESULTS: Compared to those in 1950s, the infection rates of schistosomiasis among human and cattle in 2010 were declined by 89.3% and 94.7%, respectively; the number of schistosomiasis patients was reduced from 600 thousand to 88 thousand; the number of acute schistosomiasis patients dropped from 2 732 to 18; and that of advanced schistosomiasis patients decreased from 55 thousand to 5 632. CONCLUSIONS: The high priority by government authority, suitable control models according to local conditions and huge resources are the cornerstone of success on schistosomiasis control in Dongting Lake regions. PMID- 23012943 TI - [Cost-effectiveness evaluation and investigation of control measure changes in areas of schistosomiasis transmission control in hilly regions of mountain areas I epidemiological investigation and analysis of prevalence factors of schistosomiasis]. AB - OBJECTIVE: To investigate and analyze the schistosomiasis endemic status and influencing factors in areas of schistosomiasis transmission control in hilly regions of mountain areas, so as to provide the reference for establishing the strategy and measures to achieve the target of schistosomiasis transmission interrupted in the similar areas. METHODS: Dongpo District of Meishan City, Sichuan Province, which was appropriate to the standards of schistosomiasis transmission controlled by national evaluation in 2008, was selected as a study area. The data of schistosomiasis control from 2008 to 2010 were collected. A survey for epidemiological factors was carried out from April to November in 2011. The survey of Oncomelania snails was performed with the systematic sampling combined with environmental method. The schistosome infection status of residents was investigated by the seroimmunological test and fecal hatching examination. The schistosome infection status of cattle was investigated by the plastic cup with top tube hatching method. The infested water contact of residents was investigated with questionnaire. At the same time, in 2011, a simple random sampling combined with rapid field assessment method was used to investigate the distribution of outdoor feces, outdoor feces containing schistosome eggs, snails and infected snails in two spots of Jingyang District, Deyang City and Renshou County, Meishan City which had been appropriate to the standards of schistosomiasis transmission controlled in 2006 and 2007 respectively. RESULTS: From 2008 to 2010, 182.6 thousand-213.3 thousand local residents were examined in Dongpo District, the positive rate of sero-immunological tests of population was 6.30% - 6.81%, and the infection rate of population was 0.02% -0.07% by estimated calculation. Totally 2 835-7 260 heads of cattle were examined and no positive cases were found. The areas of snail habits were 190.00-232.00 hm2, the intensities of living snails were 0.02-0.19 snails/0.1 m2, and no infected snails were found. In 2011, totally 204.4 thousand residents were examined and the positive rate of sero-immunological tests of population was 4.98% but no positive cases were founded through the parasitological tests. A total of 1 735 heads of cattle were examined and no positive cases were found. The areas of snail habits were 99.00 hm2, the intensity of living snails was 0.18 snails/ 0.1 m2, and no infected snails were found. Questionnaire analyses of a total of 537 residents in 4 villages showed that ditch, channel, pond, and paddy field were the major environments of the infested water contact of the residents. In the ditches and paddy fields, the average annual median values of water contact of residents were 15 and 20 person-times respectively before the area was appropriate to the standards of schistosomiasis transmission controlled, and 20 and 30 person-times respectively after the area was appropriate to the standards of schistosomiasis transmission controlled, and there were no significant differences (chi(ditch2) = 1.61, chi(padd field2) = 0.03, both P > 0.05). Whereas, in the channels and ponds, the average annual median values of water contact were 15 and 30 person times respectively before the area was appropriate to the standards of schistosomiasis transmission controlled, but they were significantly reduced after the area was appropriate to the standards of schistosomiasis transmission controlled (chi(channel2) =10.35, chi(pond2) =18.69, both P < 0.01). In 2011, the rapid field investigation and assessment showed that the average appearance rates of snails through screening were 60.15% and 12.12% respectively in the 2 villages. The average densities of living snails were 1.19 snails/0.1m2 and 0.20 snails/0.1m2 respectively in the 2 villages, and there were no infected snails. A total of 78 outdoor feces of cattle and sheep were collected and the fecal hatching examinations showed that there were no positives. CONCLUSIONS: After the schistosomiasis endemic areas in hilly regions of mountain areas are appropriate to the standards of schistosomiasis transmission controll, the achievements have been consolidated. However, the potential schistosomiasis endemic factors still exist, such as the high positive rate of schistosome sero-immunological tests in population, frequently bovine flowing, and no obviously decrease of the snail area and density of living snails. Therefore, it is an urgent need to develop more suitable new technologies and measures to accelerate the process of schistosomiasis prevention and control. PMID- 23012944 TI - [Evolution of spatial-temporal pattern of schistosome infection rates in Nanchang County, Jiangxi Province]. AB - OBJECTIVE: To explore the evolution of spatial-temporal pattern of schistosome infection rates in Nanchang County, Jiangxi Province. METHODS: Based on the data of schistosome infection rates at unit of administrative villages during 2006 to 2009, the evolution of spatial-temporal pattern of schistosome infection rates was analyzed by means of global Moran's I, Getis-Ord General G, local Getis-Ord Gi and variogram. RESULTS: Since 2006, the global Moran's I index increased, and all the Getis-Ord General G index G (d) values were 0.02, all the Z(d) values were of statistic significance (all P values were < 0.01). The hotspots mainly distributed in the northeast and southeast of the county, while the cold spots and secondary cold spots mainly distributed in the southwest. The optimal fitted variograms of the 3 years were all Gaussian model, the Nugget coefficient decreased from 0.026 to 0.006. The spatial autocorrelation of schistosome infection rates got stronger, the ranges shrank by 9.04%. CONCLUSION: The schistosome infection rates in Nanchang County have a tendency of clustering towards the areas along the lake, and the impact of the structural factors is increasing, but the effect range of spatial correlation is decreasing. PMID- 23012945 TI - [Retrospective investigation of formation of large-scale Oncomelania snail-ridden area in Maogang Town, Songjiang District, Shanghai City]. AB - OBJECTIVE: To explore the influencing factors of the formation of large-scale Oncomelania snail situation in Maogang Town, so as to provide the scientific evidence for improving snail surveillance in Shanghai. METHODS: The data about the geography, construction and use of floodgate, and snail status of Maogang Town and its surrounding areas, as well as the meteorology and hydrology of Songjiang District were collected and reviewed, and the factors influencing the formation of snail status were analyzed. RESULTS: The condition of water, soil and temperature in Maogang Town was suitable for snail breeding. By 1993, 75% (18/24) of the mouths flowing to Huangpu River and its branches had been built. From 1991 to 2001, the average annual precipitation of Songjiang District was 7.44% higher than the usual condition. There were two basin-wide floods occurring in 1991 and 1999, respectively. The occurrence of tides reaching or exceeding the warning level (3.50 m) of Mishidu hydrology station was positively correlated with the rainfall in the flood season (between June and September, r = 0.903, P < 0.01). Snails were found in some adjacent areas surrounding Maogang Town, and the snail situation peak occurred in early 1990s. In 2002, a large scale area (26.67 hm2) of snail habitats was detected, which was mainly distributed in the west of Maogang Town in the upstream of the Huangpu River. CONCLUSIONS: The formation of large-scale snail-breeding area in Maogang Town probably is the result of the combined action of the construction and use of floodgates, increasing rainfall, floods, tides that frequently surpass warning level of Huangpu River and the snail status of upstream areas. It is necessary to pay more attention to the data collection, analysis and utilization about schistosomiasis-related natural and social factors. In addition, regular snail surveys are suggested in schistosomiasis non-endemic areas adjacent to snail-infested area. PMID- 23012946 TI - [Investigation on current status of advanced schistosomiasis in Sichuan Province, 2010]. AB - OBJECTIVE: To understand the current distribution and characteristics of patients with advanced schistosomiasis in Sichuan Province, so as to provide the scientific evidence for improving the management and treatment of advanced schistosomiasis. METHODS: The patients who had been diagnosed as advanced schistosomiasis or were supposed with advanced schistosomiasis were the objects of the investigation. The epidemiological survey and medical examination were used to investigate these persons one by one according to the national standard. RESULTS: There were 1 684 patients with confirmed diagnosis in 7 cities of Sichuan Province. There were 1 066 cases of splenomegaly including post-surgery (63.30%), 545 cases of ascites (32.36%), 44 cases of multiple granulomas in the colon (2.61%), and 29 cases of dwarf (1.72%). Most of the patients were old and 51.72% of them were more than 60 years old. A total of 1 331 patients (79.04%) needed treatment and assistance at present, and 36.44% of them who had ascites needed internal medicine treatment. CONCLUSION: There are also many patients with advanced schistosomiasis in Sichuan Province, and ascites and splenomegaly (post surgery) were the main types. The patients with ascites should be the important objects of the treatment and assistance in the future. PMID- 23012947 TI - [Investigation on prevalence of soil-transmitted nematode infections and influencing factors for children in southwest areas of China]. AB - OBJECTIVE: To understand the infection status and main risk factors of soil transmitted nematodes in southwest China so as to provide the evidence for making the control programs for soil-transmitted nematodiasis. METHODS: The prevalence of soil-transmitted nematode infections was determined by Kato-Katz technique and influencing factors were surveyed by using a standardized questionnaire, and in part of the children, the examination of Enterobius vermicularis eggs was performed by using the cellophane swab method. The relationship between soil transmitted nematode infections and influencing factors was analyzed by the multiple probit estimated method. RESULTS: A total of 1 707 children were examined, with a soil-transmitted nematode infection rate of 22.2%, the crowd infection rates ofAscaris lumbricoides, hookworm, and Trichuris trichiura were 16.0%, 3.8% and 6.6% respectively and 495 children were examined on Enterobius vermicularis eggs, with the infection rate of 5.1%. The results of probit estimated analysis suggested that the effects of 4 factors on soil-transmitted nematode infections were significant (all P values were less than 0.05), namely the number of sib, educational level of mother, drinking unboiled water and raising livestock and poultry. Among the factors above, the educational level of mother could reduce the probability of infection (ME = -0.074), while the number of sib, drinking unboiled water and raising livestock and poultry could increase the probability of the infections (with ME of 0.028, -0.112 and 0.080, respectively). CONCLUSIONS: Soil-transmitted nematode infection rates are still in a high level for children in southwest poor areas of China, with Ascaris lumbricoides as a priority. The changes of children's bad health habits, raising livestock and poultry habits, and implementing the health education about parasitic diseases in mothers would be of great significance for the prevention and control of soil-transmitted nematodiasis. PMID- 23012948 TI - [Report of analysis of National Technique Competition for Diagnosis of Parasitic Diseases in 2011--II Analysis of capabilities of Plasmodium detection]. AB - OBJECTIVE: To analyze the results of the National Technique Competition for Diagnosis of Parasitic Diseases in 2011, so as to understand the capability of detection on Plasmodium among professionals from institutes for disease control and prevention at different levels. METHODS: All the contestants were grouped by the gender, age, professional title, level of institution, epidemic degree of malaria of provinces, coverage status of the project of the global fund to fight malaria, and geographical location of the provinces, and their scores were statistically analyzed by SPSS 17.0 software. RESULTS: There were no significantly differences among the scores grouped by the different genders, ages, professional titles, and levels of institution (all P > 0.05). However, there were significantly differences among the scores grouped by the different epidemic degrees of malaria of the province, coverage statuses of the project of the global fund to fight malaria, and geographical locations of the province (all P < 0.05). For the contestants who came from the provinces with malaria epidemic counties of Class I and Class II types, provinces covered by the project of the global fund to fight malaria, and provinces located in the south, their scores of blood slides making and films reading under a microscope were significantly higher than those of the contestants from the provinces without epidemic counties of Class I and II types, not covered by the project of the global fund, and provinces located in the north, respectively. CONCLUSIONS: The overall level of the capabilities of detection on Plasmodium is imbalanced, and the capability of films reading under a microscope is especially low. It is urgent to promote the personnel training and strengthen the capability of pathogenic detection of parasitic diseases. PMID- 23012949 TI - [Screening and verification on characteristic differentially expressed genes of Schistosoma japonicum from three reservoir hosts]. AB - OBJECTIVE: To get the characteristic differentially expressed genes of Schistosoma japonicum from three important reservoir hosts: yellow cattle, water buffalo and goat, so as to find the genetic markers to identify the various sources of the parasite reservoir hosts. METHODS: The 49 d worms were collected from artificially infected animals, and the total RNA(s) of worms were extracted and reverse-transcripted to cDNA, and then hybridized with custom-built microarray to screen characteristic differentially expressed genes of every host, and the microarray results were validated by the real-time PCR method. RESULTS: From results of microarray, we got 3 characteristic differentially expressed genes of S. japonicum from yellow cattle, 4 from water buffalo and 7 from goat. We verified schistosome samples from three reservoir hosts in another experiment, the results showed that 2 in yellow cattle, 3 in water buffalo, and 5 in goat were verified to be consistent with microarray results. CONCLUSIONS: The ten characteristic differentially expressed genes of S. japonicum from three reservoir hosts screened by microarray might be used as genetic markers to identify the various sources of reservoir hosts for S. japonicum. PMID- 23012950 TI - [Observation on dynamic changes of SEA specific antibody in sera of BALB/c mice infected with Schistosoma japonicum]. AB - OBJECTIVE: To investigate the dynamic changes of SEA-induced specific IgG, IgM in sera of BALB/c mice infected with Schistosoma japonicum in 18 weeks. METHODS: After mice were infected with S. japonicum cercarial for 2 weeks, the sera were collected from 2 to 18 weeks post-infection. The serum levels of SEA-specific IgG and IgM antibodies were measured respectively by ELISA, and the different fractions of IgG and IgM antibodies were identified by the Western blotting method. RESULTS: The ELISA results showed that the serum levels of SEA-specific IgG increased 5, 6, 9, 11 week, after the infection, and SEA-specific IgM increased obviously 5, 9 weeks after the infection. The Western blotting results showed that 140, 180 kDa molecules were recognized by IgG antibodies in the mouse sera 4 weeks after the infection. The specific IgG antibodies of 43, 50 kDa antigens appeared 5 weeks after the infection. 60-130 kDa fractions were recognized by IgG in the sera 6 weeks post-infection, and 38, 73 kDa proteins were recognized by IgG in the sera 9 weeks post-infection. The IgG antibodies of 26, 32, 35, 80 kDa molecules appeared 11 weeks post-infection and reacted strongly 12 weeks post-infection. The IgM antibodies of 100, 140, 180 kDa molecules appeared 3 weeks after the infection, and 73 kDa protein was recognized by sera 6 weeks after the infection, but the reaction became strong 9 weeks after the infection. The 38, 43, 50 kDa proteins induced IgM antibodies in 9-week infection sera and the reaction became stronger 9 weeks after the infection. CONCLUSIONS: There is a dynamic change in the levels of specific IgG and IgM antibodies induced by S. japonica SEA and the appearance of the antibodies is related to different infection stages. The 43, 50, 10, 140, 180 kDa antigens might have the potential value of early immunodiagnosis. The 73 kDa antigen shows high diagnostic value in both acute and chronic schistosomiasis. The 28, 32, 35, 38, 80 kDa antigens are not only the diagnostic molecules for chronic schistosomiasis, but they may also have therapeutic effects, and in addition, they may be the candidate vaccines of the disease. PMID- 23012951 TI - [Expression and clinical significance of P-gp in colonic gland of chronic schistosomiasis patients]. AB - OBJECTIVE: To study the expression of P-glycoprotein (P-gp) in patients with chronic schistosomiasis and its relationship with gender and age, and to explore its clinical significance. METHODS: The colonic mucosa specimens of 50 chronic schistosomiasis patients and 4 persons who had a family history of colon cancer but their physical examinations were normal (as a control group) were selected and the expressions of P-gp in the colonic gland of these samples were detected with the immunohistochemical staining method. RESULTS: Compared with the control group, the mean gray value of the positive particles of P-gp of colonic epithelial cells of the chronic schistosomiasis group was significantly reduced (P < 0.05), but positive unit values were significantly increased (P < 0.05), which meant the P-gp expression in colonic gland of the patients with chronic schistosomiasis was significantly increased, but this increase had no relationship with sex and age. CONCLUSION: Chronic schistosomiasis may induce the increase of P-gp expression which may be a compensatory protection mechanism due to the stimulation of schistosome eggs to the colon tissues. PMID- 23012952 TI - [Cloning, expression and bioinformatics analysis of cyclophilin of Echinococcus granulosus]. AB - OBJECTIVE: To clone and express EgCyP gene of Echinococcus granulosas and analyze EgCyP using bioinformatics. METHODS: Total RNAS of adult E. granulosus was extracted and reversedly transcripted to cDNA. EgCyP gene was amplified from cDNA and inserted into vector pET28a. Recombinant plasmid pET28a-EgCyP was transformed into E. coli BL21 (DE3) for expression under the induction of IPTG. The expressed product was identified by SDS-PAGE and Western blotting. EgCyP was analyzed by the bioinformatics software. RESULTS: The EgCyP gene was successfully amplified from cDNA of adult E. granulosus and a fusion protein was expressed in E .coli BL21 (DE3). The molecular weight of the expressed protein was about 22 kDa. The Western blotting indicated that the antigenicity of the protein was specific. The bioinformatics analysis revealed that there were 7 antigen epitopes in EgCyP. CONCLUSION: EgCyP of E. granulosus is cloned and expressed in E. coli BL21 (DE3) successfully, which might be the foundation for the further study of its immunogenicity. PMID- 23012953 TI - [Field application of multiplex PCR to distinguish Plasmodium vivax and Plasmodium falciparum]. AB - OBJECTIVE: To explore the application value of multiplex PCR in the diagnosis of malaria in field. METHODS: The plasmodium genus-specific primer, Plasmodium vivax, P. falciparum species-specific primers were synthesis based on the specific target segments of small subunit of 18 S rRNA ribosomal. The multiplex PCR system was optimized, and a PCR diagnostic method of malaria was established based on the genomic specific DNA fragment of P. vivax, and P. falciparum was amplified in the same PCR reaction system. The sensitivity, specificity, and the value of field application of the multiplex PCR were investigated. RESULTS: The sizes of amplification products of multiplex PCR amplifying genomic DNA of P. vivax and P. falciparum were 833 bp and 1 451 bp, respectively, and the amplification did not take place with the samples DNA of P. berghei, P. cynomolgus and healthy human blood. The sensitivities of multiplex PCR to detect P. vivax and P.falciparum were 1.1 x 10(-6) and 5.6 x 10(-7) parasitemia, respectively. Compared with the microscopic examination, the positive rate of multiplex PCR to detect 119 cases of field samples was 54%, missed diagnosis rate was 0.8%, and the misdiagnosis rate was naught, while the positive rate of the microscopic examination was 53%, its misdiagnosis rate and missed diagnosis rate were 1.7% and 3.4%, respectively. The compliance rate between the multiplex PCR and microscopic examination was 94%. CONCLUSION: The multiplex PCR for detecting malaria is simple, rapid, specific, sensitive, etc., which is suitable for the differential diagnosis of suspected cases, and molecular epidemiology investigation. PMID- 23012954 TI - [Survey on Blastocystis hominis infection in HIV positive individuals in Fuyang City, Anhui Province]. AB - OBJECTIVE: To understand the epidemiological characteristics of co-infection of HIV and Blastocystis hominis and its risk factors. METHODS: A total of 309 people with HIV positive in the development zone of Fuyang City were recruited, and the face to face questionnaires were conducted to collect the information of behavioral characteristics and sociodemographic data of the participants. Meanwhile, the samples of stool and blood were collected to test B. hominis, cytokines and CD4+/CD8+ T-lymphocyte. The influencing factors of co-infection of HIV and Blastocystis hominis were analyzed by the single factor analysis and Logistic regression analysis. RESULTS: Among the 309 people involved, 302 accepted feces examinations, 286 accepted the questionnaire investigation, and 263 accepted both of them. The infection rate of B. hominis was 17.11%, that of the female was 21.90%, which was significantly higher than that of the male (11.90%) (P < 0.05). The results from the multivariate Logistic regression model showed that good nutrition was significantly associated with the co-infection of HIV and B. hominis (OR = 0.263, 95% CI: 0.073, 0.945). CONCLUSIONS: The infection rate of B. hominis is high in people with HIV positive, and the nutrition situation of individuals may be one of the important risk factors associated with co-infection. PMID- 23012955 TI - [Analysis of COX1 sequences of Taenia isolates from four areas of Guangxi]. AB - OBJECTIVE: To analyze the COX1 sequences of Taenia isolates from four areas of Guangxi Zhuang Autonomous Region, and to understand the distribution of Taenia asiatica in Guangxi. METHODS: Patients with taeniasis in Luzhai, Rongshui, Tiandong and Sanjiang in Guangxi were treated by deworming, and the Taenia isolates were collected. Cyclooxygenase-1 (COX1) sequences of these isolates were amplified by PCR, and the PCR products were sequenced by T-A clone sequencing. The homogeneities and genetic distances were calculated and analyzed, and the phylogenic trees were constructed by some softwares. Meanwhile, the COX1 sequences of the isolates from the 4 areas were compared separately with the sequences of Taenia species in GenBank. RESULTS: The COX1 sequence of the 5 Taenia isolates collected had the same length of 444 bp. There were 5 variable positions between the Luzhai isolate and Taenia asiatica, the homogeneity was 98.87% and their genetic distance was 0.011. The phylogenetic tree analysis revealed that the Luzhai isolate and Taenia asiatica locating at the same node had a close relationship. The homogeneity between Rongshui isolate A and Taenia solium was 100%, while the homogeneity of Rongshui isolate B with Taeniasis saginata and Taenia asiatica were 98.20% and 96.17%, respectively. The homogeneities of the Tiandong and Sanjiang isolates with Taenia solium were 99.55% and 96.40%, respectively, and the genetic distances were 0.005 and 0.037, respectively. The homogeneity between the Luzhai isolate and Taeniasis saginate was 96.40%. CONCLUSION: Taenia asiatica exists in Luzhai and Taenia solium and Taenia saginata coexist in Rongshui, Guangxi Zhuang Autonomous Region. PMID- 23012956 TI - [Preliminary study on serum proteomics in mice with acute toxoplasma gondii infection by using functionalized magnetic beads and MALDI-TOF-MS technique]. AB - OBJECTIVE: To detect and analyze the serum protein biomarkers in mice with acute Toxoplasma gondii infection. METHODS: The serum samples from 8 C57BL/6J mice with acute Toxoplasma gondii infection and 8 normal healthy paired mice were prepared with WCX magnetic beads, and then analyzed on PBS II -C mass spectrometer reader. The protein spectra of the serum samples were normalized by the Ciphergen Protein Chip software. The peak labeling was performed by the Biomarker Wizard software. The specific protein biomarkers were screened by the Biomarker Pattern software to construct a diagnostic model for acute Toxoplasma gondii infection. RESULTS: A total of 13 distinguished proteomic peaks were detected. Nine peaks were of up regulated expressions including m/z values of 1 932.76, 1 976.85, 2 090.53, 5 004.5, 5 776.01, 5 803.05, 5 847.99, 5 877.51 and 7 501.58, respectively; and four peaks were of down-regulated expressions including m/z values of 1 866.40,4 063.71, 8 120.31 and 8 203.83, respectively. CONCLUSION: The potential protein biomarkers for acute Toxoplasma gondii infection are discovered in mouse serum by MALDI-TOF-MS combined with WCX magnetic beads. PMID- 23012957 TI - [Influencing factors of changes of Oncomelania snail densities in Poyang Lake region, Nanchang City, 2011]. AB - OBJECTIVE: To explore the influencing factors of the significant decrease of snail densities in Poyang Lake region, Nanchang City, 2011. METHODS: According to the elevation of the environment, 5 grasslands where there were high snail densities and their elevations were from 14 to 17 m were selected as study areas. The data of snails in the past three years and the hydrological information in the past five years were collected and analyzed. The current snail status was surveyed and the fishermen were interviewed. RESULTS: The snail density of Poyang Lake region in Jinxian County decreased by 91.2% in 2011 compared with that in 2009 (P < 0.01). In 2010, the water levels were 13.90 m in April and 16.07 m in May respectively in Xingzi Station, and the rainfalls were 312 mm in April and 356 mm in May in Poyang Lake region; in 2011, the water levels were 8.73 m in April and 10.31 m in May respectively in Xingzi Station, and the rainfalls were 90 mm in April and 145 mm in May respectively in Poyang Lake region, which were lower than those during the past five years. There was no any other apparently unusual phenomenon. CONCLUSION: The significant decrease of snail densities in Poyang Lake region in 2011 may be related to the long soaking time of marshland in 2010 and low rainfall in the first half of 2011. PMID- 23012958 TI - [Cost-effectiveness of schistosomiasis monitoring in Rugao City from 2001 to 2010]. AB - OBJECTIVE: To understand the cost-effectiveness of schistosomiasis monitoring in Rugao City, a schistosomiasis transmission interrupted area, so as to provide the evidence for improving schistosomiasis control. METHODS: According to the national and Jiangsu provincial working scheme of schistosomiasis monitoring and consolidation, the data of schistosomiasis monitoring were collected and the cost effectiveness was analyzed in Rugao City from 2001 to 2010. RESULTS: During 10 years, the financial input for Oncomelania snail survey was 11.694 8 million Yuan, accounting for 92.9% of the total monitoring cost. In 6 years, a few remaining snails with low density and small area were detected, and per 100 m2 snail area spent 76 788 Yuan averagely. Totally 23 694 people were investigated with serological tests and 15 persons were positive, but no person was positive in feces tests, and the accumulative total cost was 410 350 Yuan. The average cost for detection of 1 person was 17.32 Yuan. Totally 454 heads of cattle were investigated but there was no positive, and the accumulative total cost was 18 716 Yuan and the average cost of detection of 1 case was 41.22 Yuan. The health education during the 10 years spent 172 500 Yuan, only accounting for 1.4% of the total monitoring funds. The awareness rate of schistosomiasis control knowledge and the health behavior formation rate increased year by year, and they were increased by 2.48 times and 2.71 times respectively from 2001 to 2010. CONCLUSIONS: In schistosomiasis transmission interrupted areas and areas with Oncomelania snails but without schistosomiasis, the monitoring index and monitoring method need to be studied and adjusted. Health education has a good cost-effectiveness. PMID- 23012959 TI - [Epidemiological analysis of malaria prevalence in Jiangsu Province in 2010]. AB - OBJECTIVE: To analyze malaria prevalence and epidemic characteristics in Jiangsu Province in 2010, so as to provide a theoretical basis for the development of effective malaria elimination strategies and measures. METHODS: The reported malaria cases from the Internet reporting system and epidemiological data of malaria in Jiangsu Province were analyzed statistically. RESULTS: A total of 386 malaria cases were reported in Jiangsu Province in 2010 with the incidence of 0.05/10 000 which was similar to that in 2009. There were 100 cases of local vivax malaria, which decreased by 47.92% compared to 192 cases in 2009. The majority (75/100) of local vivax malaria distributed in Xuzhou, Huai'an and Suqian cities which were all located along the Huai River. There were 286 imported cases including 207 imported falciparum malaria cases which increased by 104.95% comparing to 101 cases in 2009. The imported falciparum cases mainly distributed in Nantong, Taizhou, Yangzhou, Huai'an, Yancheng and Lianyungang cities which were located in central Jiangsu and coastal areas of northern Jiangsu. Among the 286 imported cases, 38 cases which were all vivax malaria were imported from other provinces of China, and 11 cases in these 38 imported vivax cases were relapse and with the significantly higher relapse rate than that of local patients. A total of 248 cases were imported from overseas and in which 207 cases were falciparum cases including 82 cases of recurrence after returning China. There were 23 relapse cases in 41 overseas imported vivax cases with the significantly higher relapse rate than those of both local cases and imported cases from other provinces of China. CONCLUSIONS: The local vivax malaria cases in Jiangsu Province decrease significantly, but the number of imported vivax cases are still high and the imported falciparum cases from overseas are increasing exponentially year by year. Therefore, to achieve the target of malaria elimination in Jiangsu Province on schedule, the malaria control in key areas should be strengthened to further reduce local infection incidence, also have to actively explore the radical cure approaches during no transmission season for vivax malaria cases among mobile population and reduce the relapse rate to reduce the impact of import- ed vivax cases to the control effects in Jiangsu Province. At the same time, the health education to the personnel of labor export should be further strengthened to improve their awareness of self protection, and actively carry out multi-sector collaboration and enhance the monitoring and management of returned labors from overseas to promote the work on imported falciparum malaria prevention and control. PMID- 23012960 TI - [Stabilities of two kinds of Plasmodium antigen substrate slides under different storage temperatures and time]. AB - OBJECTIVE: To observe and compare the inspection effects of antigen substrate slides of Plasmodium cynomolgi (P. c) and Plasmodium falciparum (P. f) on the malaria antibody titer under different storage temperatures and time. METHODS: The densities of Plasmodium of P. c and P. f antigen slides were counted through a microscope, and the average numbers of Plasmodium in each field of vision were calculated. The pooled serum of patients with tertian malaria and falciparum malaria were treated as antibody serum, and the dilutions were from 1:5 to 1:1 280. The two kinds of antibody slides were placed under the temperature of 4-6, 25-27, 33-35 degrees C, and two slides of each kind were selected at Day 3, 5, 7, 10 post-storage to detect the end point antibody titer of malaria by the indirect fluorescent antibody test. Meanwhile, the P. c and P. f antigen slides storing under -20 degrees C for 1 year and 2 years were placed under the aforementioned 3 temperature conditions for 3 d, and the changes of the antibody titers were compared. RESULTS: The densities of Plasmodium in blood cells of P. c and P. f antigen slides were 2.00 x 10(5)/microl and 1.89x 10(5)/microl, respectively, and the average numbers of Plasmodium in each field of vision were 157 +/- 13 and 142 +/- 9, respectively. The end point titers of antibody of P. c and P. f antigen slides placed under the temperatures of 4-6, 25-27, 33-35 degrees C were all on a downward trend after storing for 5 d. The average antibody titers of the two kinds of slides under temperature of 4-6 degrees C and above were 1:440 and 1:80, respectively, and there was a significantly statistic difference between them(t = 1.940, P < 0.05). When P. c and P. f antigen slides storing under -20 degrees C for 1 year were placed under 4-6 degrees C for 3 d, the end point antibody titers were both 1:640, while for those storing under -20 degrees C for 2 years, the end point antibody titers were 1:320 and 1:160, respectively, both the differences were statistically significant (t(P. c) =11.362, P(P. c) < 0.01; t(P. f) = 38.845, P(P. f) < 0.001). CONCLUSION: The end point antibody titers for malaria detection of P. c and P. f antigen slides decrease gradually with the raise of temperature and the prolonging of time for storage. PMID- 23012961 TI - [Analysis of seasonal variability of vivax malaria by circular distribution method in Jiangsu Province from 1961 to 2010]. AB - OBJECTIVE: To study the law of seasonal variability of vivax malaria in Jiangsu Province from 1961 to 2010, so as to provide the reference for improving malaria control. METHODS: The data of vivax malaria incidence from the epidemic reporting system of Jiangsu Province were collected and analyzed to understand the month morbidity, peak prevalence time and mean durations, and the peak incidence durations every 10 years with the circular distribution method. RESULTS: Vivax malaria appeared obvious seasonal variability (P < 0.01) with different peak time (P < 0.01). The average peak time occurred on August 9th. The morbidity duration was shortest (75 d) in 1963 and longest (123 d) in 2010 with a mean duration of 93 days, and the peak duration extended 146 days in 10 years from 2001-2010 compared with that from 1960-1970. CONCLUSION: The incidence of vivax malaria presents obvious seasonal peak in Jiangsu Province and its peak concentrates in mid-July to early August, and in nearly 10 years, the days of peak incidence of vivax malaria extended. PMID- 23012962 TI - [Investigation on anopheline species in Chayu County, Linzhi Prefecture of Tibet Autonomous Region]. AB - OBJECTIVE: To investigate Anopheline species in Chayu County of Linzhi Prefecture, Tibet. METHODS: Four natural villages in Chayu County were selected in this study in 2010. The methods of overnight/semi-overnight trapping indoor and outdoor human-bait, and overnight trapping with light traps were used, and all the Anopheline mosquitoes were confirmed by morphological characteristics. RESULTS: Totally 2 991 Anopheline mosquitoes were captured, with 76.36% (2 284/2 291) of An. peditaeniatus, 22.30% (667/2 291) of An. maculates group. The average densities of An. peditaeniatus by semi-overnight trapping were 56.2/per person indoor and 4/per person outdoor respectively, and the average densities of An. maculatus group by semi-overnight trapping were 17.8/per person indoor and 17.9/per person outdoor respectively. The man-biting rates of An. peditaeniatus by overnight trapping were 28.1/per person indoor and 2/per person outdoor respectively, and were both 8.9/per person to An. maculatus group. CONCLUSION: An. peditaeniatus and An. maculatus group are the possible transmission vectors of malaria in Chayu County. PMID- 23012963 TI - [Investigation on snails Achatina fulica and Pomacea canaliculata infected with Angiostrongylus cantonensis in Panyu region of Guangzhou City]. AB - OBJECTIVE: To understand the natural infection status of Angiostrongylus cantonensis in snails Achatina fulica and Pomacea canaliculata from Panyu region of Guangzhou City. METHODS: The snails Achatina fulica and Pomacea canaliculata captured from the field were digested with the artificial stomach fluid. The third-stage larvae of A. cantonensis were examined and counted under a microscope. The collected third-stage larvae were used to infect SD rats. RESULTS: A total of 367 Achatina fulica and 357 Pomacea canaliculata were examined. The infection rate of A. cantonensis in Achatina fulica was 22.62%, with a mean intensity of 57.00 larvae per positive snail. The infection rate of A. cantonensis in Pomacea canaliculata was 3.08%, with a mean intensity of 1.64 larvae per positive snail. The infection rates of A. cantonensis in Achatina fulica from Dagang, Shiqi, Hualong, and Lanhe towns and Nansha District, were 13.33%, 15.00%, 20.93%, 73.68% and 8.41%, respectively. Those in Pomacea canaliculata were 5.88%, 2.88%, 1.89%, 0% and 3.96%, respectively. CONCLUSIONS: A. cantonensis infection exists in Achatina fulica and Pomacea canaliculata from Panyu region of Guangzhou City, and the infection in Achatina fulica is more serious than that in Pomacea canaliculata. The infection rates of the snails among five sites are different. PMID- 23012964 TI - [Problems and improvements of water conservancy projects combined with schistosomiasis control in river beaches]. AB - Water conservancy projects combined with schistosomiasis prevention and control are crucial measures to change the habitats of Oncomelania hupensis and are helpful for schistosomiasis control. In this paper, the epidemic characteristics of O. hupensis in lake regions are elaborately analyzed. Also, the specialty problems and applications of the different projects in lake regions are exhaustively discussed. According to the above analysis, some measures and improvements are propounded to deal with these problems. PMID- 23012965 TI - [Risk assessment on laboratory biosafety of Leishmania]. AB - OBJECTIVE: To provide the evidence for improving the risk assessment and personal protective equipment and techniques to laboratory staff related to Leishmania. METHODS: The laboratory biosafety of Leishmania was preliminarily assessed based on the biological background information, potential hazards in experimental activities, the risk analyses of laboratory personnel and other relevant factors. RESULTS: The risk assessment on laboratory biosafety of Leishmania was helpful for the establishment of the laboratory standard operating procedure, and was helpful for protecting the staff from infection of Leishmania. CONCLUSION: The risk assessment on laboratory biosafety is important to the safety of laboratory activity related to Leishmania, and is of a great significance to protect the laboratory staff. PMID- 23012966 TI - [Progress of researches on diagnostic antigens of schistosomiasis japonica]. AB - The development of immunodiagnosis makes important contributions to the control of schistosomiasis. The most common way of diagnosis is to detect unknown antibodies through the known antigens, those are divided into soluble antigens, purified antigens and recombinant antigens. The diagnostic antigens which have high-sensitivity and high-specificity, and have the value of early diagnosis become the focus of researches, and are studied by many scholars. This article reviews the progress of the reaearches on diagnostic antigens of schistosomiasis japonica in recent years. PMID- 23012967 TI - [Progress of research on peroxiredoxin in invertebrates]. AB - Peroxiredoxin (Prx) belongs to a peroxidase family of antioxidant enzymes distributed ubiquitously in aerobic organisms such as yeast, fungi, parasites, mammals and humans. It plays an important role in the defense of reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by aerobic organisms. This article introduces the classification, mechanism of Prx and the progress of research on Prx in invertebrates. PMID- 23012968 TI - [Research progress in phosphoglycerate mutase]. AB - Phosphoglycerate mutase (PGAM) is one of glycolytic enzymes, concerning with the transport of carbohydrates, metabolism, catalytic activity and growth development. PGAM was discovered in yeast firstly, and with its amino acid sequence and crystal structure determined, this protein was found in varies organism, such as human, Escherichia coli, Schistosoma japonicum and Toxoplasma gondii. This article reviews the physico-chemical property and research progress of PGAM of vertebrate, invertebrate and protozoa. PMID- 23012969 TI - [Toll like receptors and malaria parasites invasion: progress and prospective]. AB - To deeply study the molecular mechanism of infection and reproduction of malaria parasites, this review began with co-relationship between toll like receptors (TLRs) and the parasites, further discussed how the parasites were recognized by TLRs and activated downstream inflammation reactions when the mechanical barrier of host was broken through. Some large molecules involved into the process had the potential to be novel drug targets. PMID- 23012970 TI - [Effect of health education on schistosomiasis control in heavy endemic areas]. AB - This paper described the evaluation on the effect of health education on schistosomiasis control in a pilot where a series of interventions were conducted, so as to provide the effective strategy of health education for improving schistosomiasis control. PMID- 23012971 TI - [Effects of reclaiming and cultivation in marshland on Oncomelania snail control]. AB - The changes of snail situation in the marshlands and the economic benefit of planting were investigated after planning sesame on marshlands above 16 meters' elevation in Poyang Lake at drought period in autumn and by comparing three groups, i.e. planting sesame alone, planting sesame plus fertilizing "Rong Bao" (a brand of one fertilizer), and no planting. Results showed that the yields in the groups of planting sesame alone and planting plus fertilizing were 15.5 kg and 19.5 kg per 667 m2, respectively, with the output increasing by 25.81% in the fertilizer group. The net incomes of the two groups of planting sesame were 56.5 Yuan and -36.0 Yuan per 667 m2, respectively. One year after the planting, the living snail densities of the three groups were decreased by 97.86%, 100% and 47.62%, respectively. It is suggested that planting sesame on marshlands with snails in Poyang Lake region has a preferable economic benefit and snail control effect. PMID- 23012972 TI - [Survey on historical Oncomelania snail environments in Changshu City]. AB - The historical Oncomelania snail environments discovered since 1976 were surveyed in Changshu City, Jiangsu Province. There were 425 foci of historical snail environments that were discovered in 16 towns, the snail area was 124 893 m2. The transformation rates of historical snail environments and of the snail area were 76.71% and 86.92%, respectively. The transformation rates of the ditches, the ponds and the land were 98.17%, 97.93%, and 95.04%, respectively, but the transformation rate of river channels was only 28.23%. We still need to strengthen the environmental transformation of historical snail river channels. PMID- 23012973 TI - [Effect of niclosamide spreading oil on killing schistosome cercariae]. AB - Dechlorinated water (100 ml, 30 degrees C) was put into a plate (diameter 15 cm), and 1% niclosamide spreading oil 5 microl was added, then a ring of Schistosoma japonicum cercariae were picked up to the plate. The time of killing all the cercariae was observed at three time points (immediately, 24, 48 h), and the dechlorinated water was used as control. The results showed that schistosome cercariae were all killed in three minutes by 1% niclosamide spreading oil at the three time points. The cercaria-killing effects of each time point were not significantly different (F = 0.062, P > 0.05). The cercariae were alive in the control in 48 h. PMID- 23012974 TI - [Analysis of malaria epidemic situation in Hainan Province, 2010]. AB - A total of 78 malaria cases were reported in 2010 and the incidence of malaria in this year was 9 per million in Hainan Province. The positive rate of blood tests in floating population was higher than that in local residents, and the antibody positive rate of residents was higher than that of students, and all the reported malaria patients received the correct treatment. The rate of the therapy for vivax malaria relapse was 96.56% and the rate of prevention medicine in the high risk groups was 94.15%. Totally 4 086 households were sprayed with insecticides and 26 843 persons were protected. Meanwhile, 153 116 LLINs were used and 250 851 persons were protected. In conclusion, the measures of malaria elimination is effective, however, we should strengthen malaria epidemic reports, case verification, treatment of epidemic foci, malaria prevention on floating population, malaria surveillance and so on. PMID- 23012975 TI - [Relationship between toxoplasma IgG and routine screening items of infectious diseases of blood donors]. AB - Among 745 blood donors whose routine screening items were unqualified, the positive rate of Toxoplasma IgG (TOX-IgG) was 21.9%, which was higher than that of the blood donors whose routine screening items were qualified, and there was a significant difference (P < 0.01). The positive rates of TOX-IgG were 22.8% (99/435), 13.7% (16/117), 12.2% (15/123), 10.0% (5/50), 31.0% (9/29), and 34.2% (13/38) in the blood donors with abnormal ALT, positive HBsAg, positive anti-HCV, and positive anti-HIV, respectively, and all the positive rates of TOX-IgG mentioned above were higher than those in the donors whose routine screening items were qualified (P < 0.05 or P < 0.01). In conclusion, there are correlations between the positive rate of TOX-IgG and the qualified situation of routine screening items of infectious diseases in blood donors. PMID- 23012976 TI - [Discovery and scientific investigation of a biological phenomenon]. AB - A brief discussion is devoted to the 55-year long history of interferons and the contribution of domestic researchers to the study of this problem. PMID- 23012977 TI - [Analysis of the polymorphism of the genome region of HIV-1 encoding the fusion protein]. AB - The prevalence of the mutations associated with HIV fusion inhibitor enfuvirtide resistance in Russia and CIS countries was studied. Enfuvirtide resistance mutations were not observed among studied viruses in Russia and CIS countries so far. It was found that high rate (35%) of natural polymorphism mutations were associated with enfuvirtide hypersusceptibility. It was also found that high frequency of accessory mutations N126K and E137K were observed in the HR2 region (27.5%). The accessory mutations in HR2 can contribute to increased resistance and improve viral fitness. Our data were compared with those obtained in similar previous studies. PMID- 23012978 TI - [Genotypes 4 and 5 of the tick-borne encephalitis virus: features of the genome structure and possible scenario for its formation]. AB - On the basis of the comparison of complete genome structures of 32 strains and gene E fragments (160 ndt) of 643 strains and RNA isolates of tick-borne encephalitis (TBE) virus, we confirmed our previously expressed assumption (Zlobin V.I. et al, 2001) of existence, along with the three major genotypes, of genotypes 4 (strain 178-79) and 5 (strain 886-84). "Mosaic" structure of the polyprotein in the two strains was established. It manifests itself in particular in the sequences of 14 positions (C-3, E-206, NS1-54, NS-285, NS2A-100, NS2A-127, NS2A-174, NS2A-175, NS2A-225, NS3-376, NS4B-28, NS4B-96, NS5-18, NS5-671) containing the amino acids strictly conserved for each of the three major genotypes and is consistent with a uniform pattern of distribution of nucleotide substitutions that are specific for genotypes 1, 2 and 3. Possible scenario of the origin of TBE genotypes 4 and 5 was suggested. PMID- 23012979 TI - [Reproduction of the metapneumovirus in different cell lines]. AB - The reproduction of the metapneumovirus was comparatively studied in 19 human and animal cell lines. The most sensitive transplanted cell lines were found to be human Chang Conjunctiva (clone 1-5C4) and animal cell lines of feline kidney CRFK. PMID- 23012980 TI - [Antiherpetic activity of netropsin derivatives as tested in experiments in laboratory animals]. AB - Two dimeric netropsin derivatives (Lys-bis-Nt 15Lys-bis-Nt) were comprehensively tested for antiviral and toxic activity in cell cultures and laboratory animals. The two compounds were found to provide effective and selective inhibition of reproduction of herpes simplex I both in cell culture Vero E6 and in brain of infected white mice, thereby increasing the survival rate and mean life expectation of treated animals as compared to control. PMID- 23012981 TI - [Dynamics of changes in the composition of leukocyte population of peripheral blood during the African swine fever]. AB - The comparison of the composition of leukocytes of peripheral blood of healthy and Infected swine revealed the quantitative alterations, as well as the appearance of new cells in leukocyte population during African swine fever. It was determined that African swine fever virus induced mass-scale mortality of cells of peripheral blood, especially lymphocytes and neutrophiles. The number of the dead cells reaches 60% of the initial number of all cells at the end of infection. It was also revealed that the appearance of atypical lymphocytes and lymphoblasts was observed during viral Infections. Most of these cells are characterized by the presence of additional nucleus. PMID- 23012982 TI - [Coordination of the changes in some sites of the hantaviral segments]. AB - Correlation in the changes of the nucleotide and amino acid sequences at the Hantaan virus occurring in different parts of S- and M-segments were studied. The correlation was analyzed using comparison of substitutions in aligned nucleic sequences of the segments. Correlations of the nucleotide substitutions between S and M-segments were observed. Probably, this coordination of the changes in both segments reflects features of the tertiary structure of RNA. PMID- 23012983 TI - [Detection of the nuclear polyhedrosis virus DNA in samples from eggs and caterpillars at different stages of the gypsy moth Lymantria dispar (L.) population dynamics]. AB - The nuclear polyhedrosis virus (NPV) DNA was detected in samples from eggs and caterpillars of the gypsy moth collected in natural populations of the Western Siberia and Ural by means of PCR with primers corresponding to the polyhedrin gene. According to censuring data, the gypsy moth populations of Western Siberia were at the depression stage. The NPV DNA detection frequencies in eggs (8.6 +/- 4.8% - 13.6 +/- 5.2%) and caterpillars (21.0 +/- 6.3% - 22.2 +/- 6.7%) were not significantly differed. In the Urals, collection of the insects was performed in their gradation focus at the phase of maximal abundance. The DNA detection rate in eggs (11.4 +/- 5.0%) was confidently (p < 0.001) lower than in caterpillars (59.8 +/- 5.6%). Consequently, variations of the NPV infection prevalence during ontogenesis of Lymantria dispar (L.) was associated with the gradation cycle of the insect population dynamics. PMID- 23012984 TI - [Comparative evaluation of two enzyme immunoassays for detection of immunoglobulin G antibodies to mumps virus]. AB - Two enzyme immunoassays (ELISA) for mumps antibody detection using the Enzygnost (Germany) and Parotit-screen (Russia) were comparatively assayed using sera of randomly assigned 70 healthy young adult volunteers. The neutralization test (NT) was performed for all sera using mumps viruses (MVs) of the relevant strains Enders and Leningrad-3. The proportion of positive results was significantly higher with the Parotit-screen than with the Enzygnost (80% versus 52.9%, p < 0.05). The proportion of the concordant results in both ELISAs was as 72.9% (50% for positive results and 22.9% for negative results). There was significantly better agreement between the NT with MV strain Enders and Enzygnost (98.6%, r = 0.9, p < 0.05) than between the NT with MV strain Leningrad-3 and Parotit-screen (77.1%, r = 0.6, p < 0.05). It was concluded that the Enzygnost was apparently more specific than the Parotit-screen. PMID- 23012985 TI - [Detection and antigenic characteristics of the recombinant nucleocapsid proteins of Lassa and Marburg viruses]. AB - Two plasmid vectors, which allow the recombinant polypeptides of Lassa and Marburg viruses to be expressed in prokaryotic cells E. coli strain BL21 (DE3), were produced. The two recombinant polypeptides are able to bind specific antibodies. This provides an opportunity to use them as antigenic components of immunoassay diagnostic test kits. PMID- 23012986 TI - [The problem of the so-called "change" of the tick-borne encephalitis virus genotype in the middle urals for the last 60 years]. AB - Although the history of the tick-borne encephalitis in Urals dates back to 75 years ago, the problem of the spread and evolution of the tick-borne encephalitis virus (TBEV) largely remains terra incognita. Any research in this area is of great basic and practical importance. A few years ago, a hypothesis about the change of the TBEV genotype in the Sverdlovsk region in the 50-60-year period was put forward. In other words, replacement of the Far-Eastern genotype by Siberian genotype was suggested. The goal of this work was to discuss this hypothesis and the fallacy of this view. Recent large-scale data show the long history of the formation of Siberian TBEV virus population in the Middle Urals, as well as a foreign nature of Far-Eastern genotype through their introduction in the past. The concept of the decisive role of anthropogenic factor in the spread of TBEV in the Urals is discussed as an alternative to the hypothesis of the genotype change. PMID- 23012987 TI - [Selective D1-receptor antagonist SCH23390 decreases maternal reactions in rats upon acute and chronic injections in postpartum period]. AB - The influence of the D1-receptor antagonist SCH23390 on the maternal behavior of female rats has been studied. It is established that a comparatively high dose of the drug (acute injections) significantly decreases both the locomotor activity and manifestations of the parental care. Lower dosages do not affect the locomotor activity, but still suppress the maternal behavior (after both acute and chronic injections of SCH23390). The obtained results are discussed in terms of the analysis of the maternal motivation mechanisms and the development of the D1-induced postpartum depression. PMID- 23012988 TI - [Neuroprotective effect of recombinant human erythropoietin-loaded poly(lactic-co glycolic) acid nanoparticles in rats with intracerebral posttraumatic hematoma]. AB - The neuroprotective activity of recombinant human erythropoietin (rhEPO) loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles has been observed in rats with model intracerebral post-traumatic hematoma (hemorrhagic stroke). It is established that rhEPO-loaded PLGA nanoparticles produce a neuroprotective effect in rats with hemorrhagic stroke, which is manifested by reduced number of lethal outcomes and animals with neurological disorders. Treatment with rhEPO-loaded PLGA prevented amnesia of passive avoidance reflex (PAR), which was produced by the hemorrhagic stroke, and reduced the area of brain damage caused by the intracerebral hematoma. These effects were recorded during one-week observation period. Native rhEPO exhibited a similar, but much less pronounced effect on the major disorders caused by the model hemorrhagic stroke in rats. PMID- 23012989 TI - [Peripheral mechanisms of action of oxatriazolium-5-olate derivative 3-(3-[1,2,4] triazolo)oxatriazolium-5-olate in spontaneously hypertensive rats]. AB - It is shown that 3-(3-[1,2,4]-triazolo)-oxatriazolium-5-olate (azasidnon-6) can act directly on the vascular wall of isolated segments of caudal ventral artery of SHR rats. Using heme-dependent soluble guanyl cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), it has been found that one of the possible mechanisms of azasidnon-6 vasodilatory action includes heme-dependent activation of a soluble form of guanylate cyclase. PMID- 23012990 TI - [Fullerene C60 exhibits immunomodulatory activity during adjuvant-induced arthritis in rats]. AB - The effect of fullerene C60 (FC60) on the immune processes during experimental adjuvant-induced arthritis (AA) in rats has been studied. The results indicate the inhibitory action of FN60 during AA on cellular splenocyte proliferation, neutrophil phagocytic and oxygen-stimulatory activities in the NBT test, and humoral immune mechanisms involved in the production of antinuclear antibodies, formation of circulating immune complexes, and restoration of morphological structure of spleen. Taken together, these results allow FC60 to be considered as a new potential pharmacological agent that can realize its effects mainly through anti-inflammatory and immunomodulatory activity. PMID- 23012991 TI - [Preclinical study of anxiolytic activity and safety of Racium phytomedicine]. AB - Results of a preclinical study of the anxiolytic activity and safety of original Racium phytomedicine are presented. The preparation possessed high anxiolytic activity, exhibits a wide range of therapeutic effects, produces no lethality in male and female rats and mice upon single intragastric and intraperitoneal introduction in doses up to 5 g/kg (VI class of toxicity according to OECD), induces no pathologic effects upon prolonged (120 days) administration in these rodents, and has no local irritant and/or allergen action. PMID- 23012992 TI - [Protective effects of metaprot and ethomerzol in carbophos intoxications]. AB - The mechanisms of protective action of thiobenzimidazole derivatives metaprot and ethomerzol (25 and 50 mg/kg) have been studied on a model of carbophos intoxication (256.0 +/- 8.7 mg/kg) in rats. Both compounds recovered the resistance to physical loads in forced swimming test, normalized the activity of aspartate and alanine transaminases, and reduced bilirubin, creatinine, and urea nitrogen levels in the blood serum. The intoxication was accompanied with increasing concentration of malonic dialdehyde and decreasing level of recovered glutation in the blood, as well as with the signs of endogenic intoxication. Metaprot and ethomerzol diminished disorders of both the lipid peroxidation and endogenic intoxication processes. Thus, the antihypoxic, antioxidant, actoprotective, energotropic, and reparative effects of metaprot and ethomerzol have been proved. Ethomerzol was more effective than metaprot in these tests. PMID- 23012993 TI - [Comparative evaluation of the hypnotic drugs under conditions of brain injury]. AB - The effect of hypnotic drugs on the brain stability with respect to complete ischemia posttraumatic convulsive reactions and hypoxia has been studied in animals with model brain injury. It is established that zopiclone exhibits pronounced hypnotic effect during the first and second week after brain injury, while nitrazepam, zolpidem, and melaxen are effective in the first week. The neuroprotective effects of zopiclone and zolpidem are more pronounced than those of melaxen and nitrazepam. PMID- 23012994 TI - [Clinical efficiency of reamberin - cycloferon combination in treatment of hepatic cirrhosis associated with chronic HCV infection]. AB - The clinical efficiency of a reamberin and cycloferon combination for the treatment of hepatic cirrhosis (HC) associated with chronic HCV infection has been studied. Immunological investigation of patients carried out before the treatment revealed a significant increase in the level of proinflammatory cytokines (CK) in serum, whereas the level of anti-inflammatory CK changed rather insignificantly. Use of the reamberin - cycloferon combination provided faster clinical-biochemical remission and, in respect of the pathogenetic state, ensured normalization of the CK profile in the blood. Based on these data, it can be considered as pathogenetically proved and clinically feasible and promising to use the reamberin - cycloferon combinations for a complex treatment of patients with HC associated with chronic HCV-infection. PMID- 23012995 TI - [Correction of bioenergetic processes in small intestine during experimental widespread purulent peritonitis]. AB - The functional activity of mitochondria of the muscular coat of small intestine (MCSI) has been studied in the normal state and under experimental widespread purulent peritonitis (WPP) conditions. The experiments have been carried out on a group of 55 male rabbits of chinchilla breed. It is established that, as a result of the WPP development, the functional activity of mitochondria in MCSI considerably decreases. The comparative analysis of the efficiency of metabolic drugs cytoflavin and neoton showed advantage of the citoflavin preparation, the administration of which allowed the indices of mitochondria in intact animals to be exceeded on the fifth day of postoperative period. The research results show expediency of a complex treatment of WPP using cytoflavin preparation for the normalization of biological oxidation processes and elimination of enteric insufficiency. PMID- 23012996 TI - [Analgesic properties of pineal hormone melatonin]. AB - Melatonin, the main hormone of the pineal gland, possesses analgesic properties, which were observed on various experimental models of pain and in the clinical practice. Such hormonal activity may be based on complex systemic and cellular mechanisms. Taking into account low toxicity of melatonin and its ability to enhance the effect of traditional analgesic agents, it is expedient to undertake broad investigation and testing of the potential of this hormonal preparation under clinical conditions. PMID- 23012997 TI - [The investigation of prevalence of genital inflammation in women of second generation of descendants whose ancestors were in the area of radiation exposure]. AB - There are the results of a comprehensive clinical examination of 112 women of childbearing age who are second generation descendants of those who were in the area of radiation exposure over 25 ED cSv. Incidence and factors leading to chronic inflammation of pelvic organs were studied. Immune status was evaluated by studying of subpopulation of immune cells in peripheral blood and levels of basic inflammatory cytokines. High incidence of the pelvic organs inflammatory diseases in women second-generation offspring due to disturbances in the complex chain of immunocompetent system was defined. PMID- 23012998 TI - [Endovascular treatment of ischemic heart disease in patients with multivessel coronary artery disease: immediate and long-term results]. AB - Immediate and long-term results of endovascular treatment of multivessel coronary artery disease by using different revascularization strategies were analyzed in 171 patients. Duration of follow up ranged from 12 to 18 months. Complete myocardium revascularization was performed in 63 patients, culprit vessel revascularization--in 86 pts and incomplete revascularization--in 22 pts. Results of this study showed that strategy of complete and culprit vessel revascularization in patients with multivessel coronary artery disease has comparable immediate and long-term results. Strategy of incomplete revascularization reduce immediate clinical success and lead to increased number of myocardial infarctions and needs of coronary artery bypass surgery in long term follow-up period. PMID- 23012999 TI - [Factors of intravascular hemolysis in cardiosurgical patients after cardiopulmonary bypass procedures]. AB - The study included patients with ischemic heart disease with moderate (52 patients) and apparent (23 patients) hemolysis after coronary bypass surgery in cardiopulmonary bypass (CB). The concentration of free hemoglobin in blood plasma, mechanical resistance and sorption capacity of red cells as well as the content of TBA-active products, cholesterol and phospholipids in red cells and reticulocytes levels in blood were studied before and after operation. It was shown that among patients with apparent post-perfusion hemolysis (in contrast to the patients with a moderate hemolysis) the sorption capacity of red cells and amount of reticulocytes in blood are increased before operation; level of TBA active products in erythrocytes is increasing after operation. Development of moderate hemolysis is associated with the decreased mechanical resistance of erythrocytes and increased cholesterol/phospholipid-ratio in membranes before operation. Thus, individually-specified apparent post-perfusion hemolysis is based on free-radical mechanism of erythrocytes damage and moderate hemoglobin level is referred to mechanical trauma of blood cells during CB. PMID- 23013000 TI - [Molecular mechanisms of development of cerebral tolerance to ischemia (Review. Part 2)]. AB - In the 2nd part the authors describe in details the main aspects of protective effect of preconditioning of the brain: inhibition of programmed cell death, weakening of phenomenon of excitotoxicity, activation of endogenous antioxidant systems, anti-inflammatory effects, modulation of glial cell function, changes in regional blood flow and vascular reactivity. In addition, data analysis on the impact of preconditioning on brain neurogenesis, the state of the blood-brain barrier, ion homeostasis and metabolism of neurons is presented. Review emphasizes the role of microRNAs in mechanisms of ischemic tolerance of brain. Profound understanding of molecular mechanisms of increased tolerance of brain to ischemic and reperfusion injury requires the implementation of this phenomenon in clinical practice. PMID- 23013001 TI - [Prenosological neuropsychiatric disorders among schoolchildren and their relationship to environmental factors]. AB - Environmental factor is one of the most accurate indicators of determining the health of the population, especially in childhood and adolescence. A significant increase in the amount of data on the status of school health and the environment are the most precise and correct, in view of causation, to evaluate an individual's health at prenosological level in the presence of a specialized database of automated systems. The aim of our study--the study of fundamental interactions and patterns of environmental factors in general and neuropsychiatric disease in schoolchildren of the city of Chelyabinsk. Revealed that among the multi-pollutant air Chelyabinsk first and second rank positions are occupied by selectively harmful to the central nervous system (lead, arsenic, manganese), or have complex adverse effects on the central nervous system, combined with damaging effects on the respiratory and cardio-vascular, urogenital system and blood forming organs, involving the immune mechanism (chromium compounds, lead, arsenic, carbon monoxide and manganese). PMID- 23013002 TI - [The ethiology structure of community-acquried pneumonia of young adults in closed communities]. AB - Despite of success in ethiology evaluation of community-acquired pneumonia (CAP) and instant improvement of diagnostic methods microbiological spectrum of CAP is still remaining underestimated and is still the problem for the routine clinical practice. In our study we estimated the role of fastidious bacteria which cause atypical CAP such as Chlamydophilla pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila. Furthermore we also defined the role of viral pathogens in ethiology of CAP. PMID- 23013003 TI - [Polymorphism of genes of the system of biotransformation of xenobiotics in patients with occupational allergic dermatoses]. AB - Evaluation of genes polymorphic system of xenobiotics biotransformation in patients with occupational allergodermatoses showed significantly higher percentage of incidence of polymorphic variants of genes CYP 1A1 *2C and EPHX1 AND-415G compared with population control. A combination of 3 or more adverse hetero--and homozygous gene alleles CYP 1A1, CYP3A4, EPHX1 and deletions of genes GSTM1 and GSTT1, is characterized by earlier (with the experience of work in harmful conditions up to 5 years) development, severe and unfavorable prognosis of occupational pathology of the skin. PMID- 23013004 TI - [The relation of heart rate variability and a dispersive electrocardiogram mapping indicators in human during fixed rate breathing test]. AB - Association of heart rate variability and dispersive electrocardiogram mapping indicators in women during fixed rate breathing test by the period of 10 s are observed. Disturbance of depolarization processes in auricles that show an increase in dispersive group G1 is associated with expressed vagal reserves deficiency. Intensity of control centralization level by heart rhythm and humoral metabolic influences both in a background and at active breathing can cause intensifying of high-speed microamplitude characteristics of initial front of ventricles depolarization that reflect an increase of dispersive group G9. PMID- 23013005 TI - [Endothelial protection drugs--a new class of pharmacological agents]. AB - This review considers issues dealing with the role of nitric oxide and endothelial function/dysfunction in providing a number of physiological and pathophysiological processes and various body systems functioning. It also covers in details the possible ways of pharmacological management of endothelial dysfunction (ED) using drugs of different pharmacological groups (classes). Diverse pharmacological effects which have various degree of intensity and presented at various stages of ED pathogenesis are discussed. The value and urgency of search and development of agents with endothelial protection potential are studied in available experimental and clinical works on the considerable role of endothelial system in cardiovascular diseases and lack of specific means for prevention and treatment of endothelial dysfunction. Integrated morphological functional approach to assessment of ED and endothelial protection of substances was developed and implemented in experimental practice in Cardiovascular Agents Laboratory of the Volgograd State Medical University Research Institute of Pharmacology. Various ED models were tested and most valid ones were selected. Endothelial protection of new compounds such as Salifen and Flavicin are considered and compared with cardiovascular drugs, antioxidants with metabolic effects, GABA derivatives. These drugs are assumed to belong to a new class of drugs--endothelial protection drugs. PMID- 23013006 TI - [Effect of mu- and kappa-opioid receptor antagonists on aggressiveness of male mice with repeated experience of aggression]. AB - Mu and kappa opioid receptors often show opposite actions in the regulation ofphysiological functions and behaviors including aggressive behavior. In the present study, effects ofmu antagonist CTAP (1 and 2 mg/kg, sc) and kappa antagonist nor-BNI (0.5 mg/kg, sc) on the manifestation of aggressive behavior of C57BL/6J male mice with a short (3 days) and a long (20 days) experience of victories in daily intermale confrontations were investigated. It was shown that the mice with a short experience of aggression are tolerant to blockade of both mu and kappa opioid receptors. In the mice with a long experience of aggression, CTAP increased latency of aggression in dose-dependent manner, but did not change the duration of attacks. Nor-BNI had no influence on the behavior of the male mice with a long experience of aggression in the intermale confrontation. The possible changes in opioid receptor sensitivity in C57BL/6J male mice under the influence ofa long experience of aggression are discussed. PMID- 23013007 TI - [Effects of buspirone on the behavior of female mice in a model of social discomfort]. AB - The influence of acute and chronic (14 days) buspirone administration (1 mg/kg, intraperitoneally) on the behavior of C57BL/6J female mice, being in social discomfort, were studied. The conditions of social discomfort include the permanent habitation of females in the cage with aggressive males through a perforated partition and daily presence during intermale confrontations. The dynamic changes of 5-HT1A-receptor sensitivity in the brain of female mice, estimated by the female behavior after 30 min ofbuspirone administration, were discovered. The sensitivity increased at the early stages of pathological behavior development (10 days) and decreased after 20-30 days. Females who had reduced of 5-HT1A receptor sensitivity after 30 day of maintenance in social discomfort conditions also showed a decreased sensitivity on chronic buspirone administration. PMID- 23013008 TI - [The positive effect of short-term haloperidol administration on the dysfunction of brain metabolism and neuronal activity]. AB - Chronic amphetamine injection increased spontaneous neuronal activity in sensomotor cortex and decreased spike activity in caudate nucleus. The neuronal ability to perform the conditioned reactions was greater in the cortex and smaller in the nucleus caudatus. By biochemical investigations it was showed the hyperactivity of dopaminergic system in the caudate nucleus compared to that in sensomotor cortex. During chronic amphetamine administration haloperidol caused effects similar to the ones caused by amphetamine on neuronal spike activity in sensomotor cortex and did not influence spike activity and neuronal conditioned reactions in the caudate nucleus. The short-term haloperidol action reduced the enzymes activity and particularly the biogenic amines level leading to the normalization of transmitter metabolism. PMID- 23013009 TI - [Influence of prenatal and postnatal illumination on male rat physiologycal parameters]. AB - Influence of different light conditions on some physiological parameters of 3 month old male rats was studied. It was established that influence of constant light on mothers during pregnancy or on their posterity from birth leads to one way changes of the antioxidant system, isoenzymatic spectrum of lactate dehydrogenase, blood indices and leucogram. However, the reaction is different and depends on moment of exposure. The results of testicular development of male rat indicate less sensitivity to light condition in the prenatal period compared to the postnatal ontogenesis. PMID- 23013010 TI - [Responses of peptide hydrolases of the small and large intestines in rats on the administration of antibiotics]. AB - Effects of antibiotics on the structure and functional state of the intestine are not clear. We investigated some structural parameters of the small and large intestine, and activities of two intestinal peptide hydrolases in rats after administration of ampicillin and metronidazole during 3 and 5 days. After 3 days of antibiotic administration a decrease in the weight of mucosa in the small intestine, accompanied with a reduction in the villous height and width in this part of the intestine, and in the weight ofmucosa in the colon occured. At the same time the number of goblet cells in the small intestinal epithelium was increased. Specific activities of aminopeptidase M, and glycyl-L-leucine dipeptidase (micromol/min per g) in the mucosa of the small intestine were increased, and the total activities (micromol/min calculated per a part of the intestine) of the same enzymes did not change. The administration of antibiotics for 5 days resulted in increase of specific activity ofaminopeptidase M in the mucosa of the proximal part of the small intestine. In the chyme of the small intestine and colon, activities of the same enzymes (micromol/min calculated per a part of the intestine) were increased on the third and fifth days of the antibiotic administration. Thus, the application ofampicillin and metronidazole within 3-5 days causes a disturbance of the structural and functional parameters in the small and large intestines, which is most pronounced on the third day of the drug administration. PMID- 23013011 TI - [Effect of pectin substances on activity of human pancreatic alpha-amylase in vitro]. AB - Pectin substances were extracted from food plants: sweet pepper Capsicum annuum L., carrot sowing Daucus sativus L., bulb onion Allium cepa L., white cabbage Brassica oleracea L. by two methods with acid solutions similar to gastric environment. The pectins that were extracted were characterized by Monosaccharide composition and quantitative contents of uronic acids, neutral monosaccharides, methoxy groups, protein. The inhibitory effect of all extracted pectin-protein complexes on activity of pharmaceutical drugs of human pancreatic alpha-amylase was detected. It was found that the inhibitory effect of isolated pectin substances was dependent upon the species of plant source, the manner of pectin substance extraction, the chemical composition and acting concentrations. The ability of pectin substances to suppress enzyme activity was found in a range of pectin concentrations from 0.5 up to 1.5 %. It was revealed that extracted pectin substances from bulb onion and white cabbage by acid solution with pepsin had a 2.4-3.4 times greater inhibiting effect on the human pancreatic alpha-amylase activity in comparison with pectin substances extracted by solution without pepsin from the same plant sources in high concentrations. PMID- 23013012 TI - [Effect of mild irritants on gastric outputs of bicarbonates and pepsinogen depends on the rate of acid secretion]. AB - The aggressive luminal content in the stomach activates gastroprotective processes affecting exocrine and endocrine secretion of gastric glands and permeability of the pre-epithelial mucus layer. The aim of the study was to investigate effects of chemical irritants similar to physiological characteristics of digestion (pH 2.0 and/or 500 mM NaCl) on outputs of bicarbonates and pepsinogen as well as assess the role of endogenous acid production in control ofnon-parietal secretion during irritation of the gastric mucosa. In experiments on conscious rats with chronic gastric fistula as well as on anesthetized animals it was demonstrated that luminal infusion of acidic hyperosmotic solution of NaCl enhances basal secretions of bicarbonates and pepsinogen that was fully blocked by indomethacin. Suppression of gastric acid secretion by omeprazole potentiates the stimulative effect of mild irritants likely due to the reduction of pH gradient on the surface of gastric mucosa which causes the growth of sensitivity of the epithelium to chemical stimuli and the increase of synthesis ofprostaglandins. Additionally, mild irritation enhances secretion of HCO3(-) and pepsinogen induced by stimulation of the vagus nerve; and this response does not depend on the action ofprostaglandins. The enhancing effect of irritation on the vagally induced bicarbonate output was eliminated after the treatment with omeprazole. PMID- 23013013 TI - [Hemodynamic mechanisms of the left atrial pressure changes after pressor and depressor vasoactive drug injection]. AB - In acute experiments in anesthetized cats the changes of the left atrial pressure, left ventricular myocardial contractility, its relaxation, venous return and cardiac output were studied after catecholamines or acetylcholine and histamine intravenous injection. When arterial pressure was elevated and venous return with cardiac output increased to the same level, the left atrial pressure decreased if the left ventricular myocardial contractility and its relaxation rate were increased equally. However, the left atrial pressure elevated, if left ventricular myocardial relaxation increased less than myocardial contractility. When arterial pressure was depressed, the left atrial pressure decreased if left ventricular myocardial contractility decreased less than myocardial relaxation diminished. If left ventricular myocardial contractility decreased significantly, the left atrial pressure increased. In the last case the value of cardiac output was more, than venous return one. The data suggest that after injection of the pressor and depressor vasoactive drugs, if the shifts of the venous return and cardiac output are equal, the changes of the nature and value of the left atrial pressure are dependent on the relation of the left ventricular myocardial contractility and its relaxation rate. PMID- 23013014 TI - [The influence of bulbus olfactorius at the reticular neurons of bulbar respiratory center in hypoxia]. AB - Under conditions of oxygen deficiency the influence of electrical stimulation of bulbus olfactorius on the impulse activity of reticular neurons of bulbar respiratory center was studied. Under conditions ofnormoxia both activation and inhibition of impulse activity of bulbar respiratory neurons are observed with a predominance of stimulating action. The changes in the dynamic of hypoxia had phase character. At the initial stage of oxygen deficiency (4000-5000 m altitude), during hypoxic activation, the stimulating action of bulbus olfactorius is less expressed than under the conditions ofnormoxia. At the second stage ofhypoxia (7500-8000 m altitude) the stimulating influence of this nucleus was significant. PMID- 23013015 TI - [Hyaluronidase activity of Wistar rat blood plasma: effect of dehydration and vasopressin]. AB - Effect of dehydration and arginine vasopressin treatment (Arg-VP Sigma, USA, 50 ng/100 g b.wt. ip.) on the blood plasma hyaluronidase activity in Wistar rats was studied. It was found that the pH optimum of the enzyme activity was in the range of 3.5-3.7 that is characteristic for the hyaluronidase type 1. Water deprivation for 1 day was followed by significant increase in the blood plasma hyaluronidase activity. The same response was observed under vasopressin treatment. The possible role of increased plasma hyaluronidase activity in the regulation of water balance is discussed. PMID- 23013016 TI - [The influence of neonatal interleukin-1beta increase on the formation of adult rats' spatial memory]. AB - Children's and adults' cognitive dysfunctions are frequently caused by various types of pathology such as birth injuries, hypoxias, and infections suffered in prenatal and early postnatal periods of ontogenesis. These abnormal conditions trigger high production of proinflammatory cytokines by the cells of nervous and immune systems. The role of interleukin-1 beta (IL-1beta), one of such proteins, in the formation of cognitive deficit in early ontogenesis is not sufficiently studied. In present research it was revealed that administration of IL-1beta during the third week of postnatal ontogenesis impaired the learning of adult rats in Morris Water Maze. The differences between rats of control and experimental groups were observed during the training of searching for hidden platform and during the alteration of formed reflex (when the platform was in a different place). Meanwhile the spatial extinction has not been disrupted. The nature of experimental rats' learning abnormalities allows us to assume that the mechanisms of long-term but not short-term spatial memory are damaged in this experimental situation. PMID- 23013017 TI - [Adaptation to hypoxia and hyperoxia improves physical endurance: the role of reactive oxygen species and redox-signaling]. AB - We have conducted theoretical foundation, experimental analysis and a pilot study of a new method of adaptation to hypoxia and hyperoxia in the prevention of hypoxic and stress-induced disorders and improving the body's tolerance to physical stress. It has been shown in the experimental part that a combination of physical exercise with adaptation to hypoxia-hyperoxia significantly increased tolerance to acute physical load (APL) and its active phase. Analysis of lipid peroxidation processes, antioxidant enzymes and HSPs showed that short-term training for physical exercise by itself compensates the stressor, but not the hypoxic component of the APL, the combination of training with adaptation to hypoxia-hyperoxia completely normalizes the stressor and hypoxic components of APL. The pilot study has been performed to evaluate the effectiveness of hypoxic hyperoxic training course in qualified young athletes with over-training syndrome. After completing the course of hypoxia-hyperoxia adaptation, 14 sessions, accompanied by light mode sports training, the athletes set the normalization of autonomic balance, increased resistance to acute hypoxia in hypoxic test, increased physical performance--increased PWC170, maximal oxygen consumption (VO2max) parameters, their relative values to body mass, diminished shift of rate pressure product in the load. Thus, we confirmed experimental findings that hypoxic-hyperoxic training optimizes hypoxic (increased athletes resistance to proper hypoxia) and stress (myocardium economy in acute physical stress testing) components in systemic adaptation and restoration of athletes' with over-training syndrome. PMID- 23013018 TI - [The high-pressure chemistry, barophysiological chemistry, comparative enzymology of cholinesterase the 100th anniversary from the birth of A. P. Brestkin]. AB - There are exposed the main landmarks of the scientific biography of Professor Aleksandr Pavlovich Brestkin, connected with his investigations in the field of chemistry of high pressures, physiological chemistry of caisson disease, kinetics of esterase catalysis, and in comparative enzymology of cholinesterases. PMID- 23013019 TI - [Evolution of intercellular comminication and structural brain organization]. AB - The review considers key problems connected with historical development of the nervous system, including intercellular contacts and brain neurotransmitter systems. A particular attention is paid to structural-functional organization of the central nervous system of the fresh-water pulmonary mollusc Lymnaea stagnalis. PMID- 23013020 TI - [Somatostatin receptors and signaling cascades coupled to them]. AB - The peptide hormone somatostatin controlling function of CNS and peripheral organs and tissues realizes its regulatory effects via five types of somatostatin receptors (SomR) coupled to heterotrimeric G-proteins. Targets of the hormone action are the enzymes generating second messengers (adenylyl cyclase, phospholipase C, phosphatidylinositol-3-kinase), phosphotyrosine phosphatases, ion channels. The review summarizes and analyzes literature data and results of our investigations dealing with molecular mechanisms of transduction of the somatostatin signal into the cell, selectivity of interaction of SomR with heterotrimeric G-proteins and intracellular effectors as well as of effect of the SomR oligomerization on their functional activity. PMID- 23013021 TI - [Substrate-inhibitory analysis of monoamine oxidase from hepatopancreas of the octopus Bathypolypus arcticus]. AB - Study of the substrate-inhibitory specificity of mitochondrial monoamine oxidase (MAO) of hepatopancreas of the octopus Bathypolypus arcticus revealed distinctive peculiarities of catalytic properties of this enzyme. The studied enzyme, on one hand, like the classic MAO of homoiothermal animals, is able to deaminate tyramine, serotonin, benzylamine, tryptamine, beta-phenylethylamine, while, on the other hand, deaminates histamine and does not deaminate putrescine--classic substrates of diamine oxidase (DAO). Results of the substrate-inhibitory analysis with use of chlorgiline and deprenyl are indirect proofs of the existence in the octopus hepatopancreas of one molecular MAO form. Semicarbazide and pyronine G turned out to be weak irreversible inhibitors, four derivatives of acridine- irreversible inhibitors of the intermediate effectiveness with respect to the octopus hepatopancreas MAO; specificity of action of inhibitors at deamination of different substrates was equal. PMID- 23013022 TI - [Cholinesterase activity in tissues of some crab species from the Japan Sea]. AB - The comparative study of the cholinesterase activity in some crab species was carried out for the first time with use of a set of thiocholine substrates. The substrate specificity was studied in stellar nerve, heart, and hemolymph of three crab species. The crab hemolymph was shown to be characterized by the highest enzyme activity. The enzyme from various crab organs has different structure o substrate specificity. Properties of crab enzymes was compared with acetylcholinesterase (AChE) of human blood erythrocytes, butyrylcholinesterase (BuChE) of horse blood serum, enzyme o squids and bivalve molluscs. The obtained data allow the conclusion to be made on differences in properties of enzymes both at the interspecies and at the tissue levels. PMID- 23013023 TI - [Age-related changes in activity of cerebellum Purkinje cells, shape of the complex spike, and locomotion of wistar rats under effect of ethanol]. AB - The work deals with study of peculiarities of effect of ethanol upon the Purkinje cell activity, shape of the complex spike, and locomotion of rats at different stages of ontogenesis, such as the stage of the morphofunstional maturation of the cerebellar cortex, the mature stage, and in the process of aging. The experiments were carried out on three age groups of Wistar rats: rat pups (2 weeks), adult rats (3-6 months), and senile animals (22-26 months). The administration of ethanol has been established to produce an increase in frequency of simple spikes, a decrease in frequency of complex spikes, a shortening of duration of depression of simple spikes, a decrease in the total duration of the complex spike, the number and frequency of its impulses as well as reduction of the motor activity of animals of all age groups. The change of the majority of the studied parameters occurred by the common temporal scheme. The earliest responding were the rat pups, later--the adult rats, and the last- the animals of the senior group. The stronger effect of ethanol was observed in adult rats. Their differences of all studied parameters, as compared with rat pups and senile animals, were characterized on the whole by the longer period of time and by the higher percent of changes relative to the initial values. Analysis of the obtained results has shown that the most pronounced changes in parameters of the cerebellum Purkinje cell activity and of the complex spike shape corresponded to the more significant decrease in the locomotion level, i. e., were recorded in adult rats. Thus, the work has demonstrated different sensitivity to administration of ethanol in the Wistar rats at different stages of ontogenetic development. PMID- 23013024 TI - [Effect of barium and ouabain on electrogenesis in various sites of intact and detubulated skeletal muscle fibers of the frog R. temporaria]. AB - In loose patch clamp experiments on intact sartorious muscle fibers of the frog Rana temporaria there were revealed two types of wave forms of the extracellularly recorded action potentials (AP). Responses of the first type (T1AP) consisted of the initial positive phase with subsequent phase of strong negativity. Responses of the second type (T2AP) had an additional positive phase concluding their waveform. In the detubulated fibers, only T1AP were recorded. Application Ba2+ (10 microM) to the muscle led to a significant increase in the amplitude of the third T2AP phase, whereas the T1AP characteristics of both intact and detubulated muscle preparations remained unchanged. After the higher applied Ba2+ concentration (50 microM), in some of the studied intact fibers the late positive signal phase was replaced by the late negative phase. The amplitude of the late negative phase was increased markedly by the high-frequency stimulation. At the combined action of ouabain and Ba2+ there was summation of effects. These results can tentatively be explained by that the locally recorded T1AP and T2AP represent responses of the muscle fiber surface and T-tubular membranes and that caracteristics of the late phase of T2AP are determined by activities of T-tubular potassium channels and of Na, K-ATPase. PMID- 23013025 TI - [Cardiac, respiratory, and motor activity in norm and after activation of catecholaminergic systems in newborn rat pups]. AB - Study of parameters of the cardiac, respiratory, and motor activity (MA) was carried out on newborn rat pups for the first day after birth (P0) and at the 14th day of postnatal development (P14) after change of the level of activity of catecholaminergic systems. The animals were administered with L-DOPA (25-100 mg/kg) and the indirect adrenomimetic isoamine (3 and 10 mg/kg). Additionally there were studied effects of L-DOPA and isoamine after blockade of D1 and D2 dopamine receptors (antagonists SCH-23390 and sulpiride). The L-DOPA administration produced a dose-dependent MA enhancement with its possible transition into the uninterrupted activity. In P0 the release of monoamines was accompanied by development of weak bradycardia. There was noted a tendency for acceleration of respiration at administration of the low dose both of L-DOPA and of isoamine and for its retardation at high doses. In P14 the L-DOPA administration was accompanied by retardation of the heart rate (HR) by 8 % and by acceleration of respiratory rate by 26%. The isoamine administration produced an insignificant decrease of HR and an increase of respiratory rate (RR) by 8% at the low dose and by 21% at the high dose of the agent. At the blockade of D1 receptors, RR remained close to the background values, while at the blockade of D2 - decreased insignificantly. Blockade of D1 and D2 receptors did not cause significant HR changes. Analysis of the HR variability has shown that both after L-DOPA administration and at blockade of dopamine receptors no unidirectional reaction was observed: in 80 % of rat pups the portion of nerve mechanisms of HR regulation increased, while in the rest--of sympathetic and humoral factors at a decrease of parasympathetic effects. In all rat pups the isoamine administration was accompanied by a shift of the specter power into the higher frequency area; in 60% of animals there were enhanced sympathetic influences. In P14 in rat pups after administration both of L-DOPA and of isoamine, the symphathetic nervous influences were predominant. Thus, in P0 both at release of endogenous catecholamines and at their excessive concentration in rat pups there occurs a qualitative change of character of the catecholaminergic influences on functional activity of excitable structures, especially of those connected with regulation of respiration. PMID- 23013026 TI - [Role of Bcl-2 in the regulation of creb activity and vasopressin expression in the hypothalamic neurons of rats]. AB - The antiapoptotic protein Bcl-2 has various functions besides its role in protecting cells from apoptosis. Previous studies have demonstrated that Bcl-2 recruits ERK1/2 and/or CREB to initiate different transcription program in the regulation of various neuronal activities as well as axonal growth. Recently we reported that Bcl-2 can participate in the regulation of synthesis and secretion of vasopressin of rat hypothalamic magnocellular nuclei. In thise study we have investigated the inhibition of Bcl-2 on vasopressin expression in magnocellular neurons of hypothalamic supraoptic nuclei. The experiments were done on short term incubated rat hypothalamic slices containing supraoptic nuclei. Our data demonstrated that in vitro inhibition of Bcl-2 by HA14-1 prevented CREB translocation into the cell nuclei and significantly decreased vasopressin mRNA level and enhanced contents of vasopressin protein in magnocellular neurons in supraoptic nucleus. Our results indicate that CREB-dependent vasopressin gene transcription in the hypothalamic magnocellular neurons can be regulated by Bcl 2. PMID- 23013027 TI - [Sequence of depolarization of atrial myocardium of the pig (Sus scrofa domesticus)]. AB - By the method of multichannel synchronous cardioelectropotography, sequence of depolarization of intramural atrial layers was studied in representatives of ungulate animals--pigs. In the pig atrial myocardium there is revealed a complex picture of spreading of activation fronts, connected with non-uniform anatomical structure and subendocardial (intramural) disposition of area of initial activation. The general character of sequence of depolarization of the pig atrial myocardium is comparable with carnivores (dog) and even-toed (sheep) animals. PMID- 23013028 TI - [Localization of cystathionine beta-synthase in digestive tract of the masu salmon Onchorhynchus masou (Teleostei)]. AB - By immunohistochemical method the hydrogen sulfide (H2S)-producing system was studied in digestive tract in fry and adult individuals of the masu salmon Onchorhynchus masou. The total and age-related peculiarities have been revealed in morphology, distribution, and the amount of enteral cystathionine beta synthase (CBS)-immunopositive neurons. They have been established to be present in fry only in esophagus a stomach, while in adult fish--along the entire length of the digestive tract, the number of marked cells in esophagus, stomach, and distal intestine exceeding that in the proximal and middle intestines. In fry and in adult fish the neurons and nerve fibers are located in branches of vagus, in intermuscular and submucosal nerve plexuses, in serosal and muscle layers. There are detected uni-, bi-, and much seldom the multipolar neurons surrounded by numerous poorly and undifferentiated nerve cells. Besides, the CBS-immunopositive netve fibers were present in the subepithelial area of the duct of swim bladder. PMID- 23013029 TI - [Complex neurons in dorsomedial nucleus of the inferior colliculus of the domestic mouse (Mus musculus)]. PMID- 23013030 TI - [Serotonin immunoreactivity in the optic nerve and in the eye of pulmonate gastropods]. PMID- 23013031 TI - [Disease from the point of view of evolution]. AB - In the process of evolution, such compensatory reactions as enhanced reabsorption of sodium chloride and an increase of arterial pressure could be formed only for compensation of acute pathological states (blood loss, dehydration). At present they remain similarly adequate in acute disturbances of blood circulation and of water-electrolyte balance. However, in severe chronic pathology of heart and kidney they often lose their compensatory function and even become dangerous. Evolution of human and of human society has created novel social conditions of adaptation. They are of humanitarian and technogenic character by promoting prevention and treatment of diseases. PMID- 23013032 TI - [K+/Na+ in the animal extracellular fluid at weathering of granitoids and problem of the origin of life]. AB - Leaching of granitoids of the paleoproterozoic age was performed from several seconds to 360 days in water solutions (pH < 6.0) in the oxygen or argon medium. Under these conditions the entrance of K+ into the solution has been shown to occur at the higher rate than that of Na+. The obtained data are considered as evidence in favor of a possibility of the existence at the earlier stages of the Earth geologic history of water reservoirs with predominance of K+ over Na+. The K+/Na+ ratio exceeding 1 has been shown in prokaryotes, in cells and tissues of the free living and parasitic species of invertebrate and vertebrate animals. At the same time in the extracellular fluid of the fresh water, marine, and terrestrial animals, in which the Na+ concentration varies from 13 to 482 mmol/l, the K+/Na+ ratio is preserved at the level of 0.034 +/- 0.001. These results are discussed in connection with the problem of origin of protocells and of concentration ratios of monovalent cations in water phases of multicellular organisms. PMID- 23013033 TI - A HaloTag-based small molecule microarray screening methodology with increased sensitivity and multiplex capabilities. AB - Small Molecule Microarrays (SMMs) represent a general platform for screening small molecule-protein interactions independent of functional inhibition of target proteins. In an effort to increase the scope and utility of SMMs, we have modified the SMM screening methodology to increase assay sensitivity and facilitate multiplex screening. Fusing target proteins to the HaloTag protein allows us to covalently prelabel fusion proteins with fluorophores, leading to increased assay sensitivity and an ability to conduct multiplex screens. We use the interaction between FKBP12 and two ligands, rapamycin and ARIAD's "bump" ligand, to show that the HaloTag-based SMM screening methodology significantly increases assay sensitivity. Additionally, using wild type FKBP12 and the FKBP12 F36V mutant, we show that prelabeling various protein isoforms with different fluorophores allows us to conduct multiplex screens and identify ligands to a specific isoform. Finally, we show this multiplex screening technique is capable of identifying ligands selective for a specific PTP1B isoform using a 20,000 compound screening deck. PMID- 23013034 TI - Classification of individual well-being scores for the determination of adverse health and productivity outcomes in employee populations. AB - Adverse health and productivity outcomes have imposed a considerable economic burden on employers. To facilitate optimal worksite intervention designs tailored to differing employee risk levels, the authors established cutoff points for an Individual Well-Being Score (IWBS) based on a global measure of well-being. Cross sectional associations between IWBS and adverse health and productivity outcomes, including high health care cost, emergency room visits, short-term disability days, absenteeism, presenteeism, low job performance ratings, and low intentions to stay with the employer, were studied in a sample of 11,702 employees from a large employer. Receiver operating characteristics curves were evaluated to detect a single optimal cutoff value of IWBS for predicting 2 or more adverse outcomes. More granular segmentation was achieved by computing relative risks of each adverse outcome from logistic regressions accounting for sociodemographic characteristics. Results showed strong and significant nonlinear associations between IWBS and health and productivity outcomes. An IWBS of 75 was found to be the optimal single cutoff point to discriminate 2 or more adverse outcomes. Logistic regression models found abrupt reductions of relative risk also clustered at IWBS cutoffs of 53, 66, and 88, in addition to 75, which segmented employees into high, high-medium, medium, low-medium, and low risk groups. To determine validity and generalizability, cutoff values were applied in a smaller employee population (N=1853) and confirmed significant differences between risk groups across health and productivity outcomes. The reported segmentation of IWBS into discrete cohorts based on risk of adverse health and productivity outcomes should facilitate well-being comparisons and worksite interventions. PMID- 23013035 TI - Sumatriptan succinate : pharmacokinetics of different formulations in clinical practice. AB - INTRODUCTION: Migraine is a common neurovascular disorder characterized by recurrent episodes of disabling headache, autonomic nervous system dysfunction, and in some patients, neurological aura symptoms. Triptans are frequently prescribed drugs for the treatment of the acute migraine attack, considering their capability to provide wide efficacy and tolerability. AREAS COVERED: This review discusses pharmacodynamics and pharmacokinetics of sumatriptan succinate, considering the clinical impact of new drug formulations in the treatment of acute migraine and cluster headache. The data were obtained by searching the following keywords in MEDLINE: sumatriptan succinate, pharmacokinetics, pharmacodynamics, triptans, migraine, new delivery systems, relative to the period 1989 - 2012. EXPERT OPINION: Subcutaneous sumatriptan has been considered as the most efficacious treatment in the acute phase of migraine both on pain alone as well as on associated autonomic symptoms. Pharmacologically, pharmacokinetic parameters, in particular bioavailability, T(max) and C(max) are responsible for the wide efficacy of the compound and the limited adverse effect (AE) profile. The new drug formulations that are the most similar to the pharmacokinetics parameters of the subcutaneous one are promising because they both improve pharmacokinetic bioavailability bypassing the first-pass metabolism and increase patient compliance. PMID- 23013036 TI - Rotational diffusion of nonpolar and ionic solutes in 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imides: is solute rotation always influenced by the length of the alkyl chain on the imidazolium cation? AB - In an attempt to find out whether the length of the alkyl chain on the imidazolium cation has a bearing on solute rotation, temperature-dependent fluorescence anisotropies of three structurally similar solutes have been measured in a series of 1-alkyl-3-methylimidazolium (alkyl = methyl, ethyl, propyl, butyl, and hexyl) bis(trifluoromethylsulfonyl)imides. Solute-solvent coupling constants obtained from the experimentally measured reorientation times with the aid of Stokes-Einstein-Debye hydrodynamic theory indicate that there is no influence of the length of the alkyl chain on the rotation of nonpolar, anionic, and cationic solutes 9-phenylanthracene (9-PA), fluorescein (FL), and rhodamine 110 (R110), respectively. It has also been noticed that the rotational diffusion of 9-PA is closer to the predictions of slip hydrodynamics, whereas the rotation of negatively charged FL and positively charged R110 is almost identical and follows stick hydrodynamics in these ionic liquids. Despite having similar shape and size, ionic solutes rotate slower by a factor of 3-4 compared to the nonpolar solute. Interplay of specific and electrostatic interactions between FL and the imidazolium cation of the ionic liquids, and between R110 and the bis(trifluoromethylsulfonyl)imide anion, appear to be responsible for the observed behavior. These results are an indication that the length of the alkyl chain on the imidazolium cation does not alter their physical properties in a manner that has an effect on solute rotation. PMID- 23013037 TI - Directed self-assembly of densely packed gold nanoparticles. AB - Directing the self-assembly of sub-10-nm nanoparticles has been challenging because of the simultaneous requirements to achieve a densely packed monolayer and rearrange nanoparticles to assemble within a template. We met both requirements by separating the processes into two steps by first forming a monolayer of gold nanoparticles on a suitable liquid subphase of anisole and then transferring it edgewise onto a silicon substrate with a prepatterned template comprising nanoposts and nanogratings. Doing so resulted in nanoparticles that assembled in commensuration with the template design while exhibiting appreciable template-induced strain. These dense arrays of nanostructures could either be directly applied or used as lithographic masks in applications for light collection, chemical sensing, and data storage. PMID- 23013038 TI - Dye regeneration kinetics in dye-sensitized solar cells. AB - The ideal driving force for dye regeneration is an important parameter for the design of efficient dye-sensitized solar cells. Here, nanosecond laser transient absorption spectroscopy was used to measure the rates of regeneration of six organic carbazole-based dyes by nine ferrocene derivatives whose redox potentials vary by 0.85 V, resulting in 54 different driving-force conditions. It was found that the reaction follows the behavior expected for the Marcus normal region for driving forces below 29 kJ mol(-1) (DeltaE = 0.30 V). Driving forces of 29-101 kJ mol(-1) (DeltaE = 0.30-1.05 V) resulted in similar reaction rates, indicating that dye regeneration is diffusion controlled. Quantitative dye regeneration (theoretical regeneration yield 99.9%) can be achieved with a driving force of 20 25 kJ mol(-1) (DeltaE ~ 0.20-0.25 V). PMID- 23013039 TI - Combined full-dose IV and endovascular thrombolysis in acute ischaemic stroke. AB - BACKGROUND: There is an increasing trend to treating proximal vessel occlusions with intravenous-inter-arterial (IV-IA) thrombolysis. The best dose of IV tissue plasminogen activator (tPA) remains undetermined. We compared the combination of full-dose IV recombinant tissue plasminogen activator (rtPA) and IA thrombolytic therapy to IA therapy. METHODS: Between 2002 and 2009, we reviewed our computed tomographic angiography database for patients who received full-dose intravenous rtPA and endovascular therapy or endovascular therapy alone for acute ischaemic stroke treatment. Details of demographics, risk factors, endovascular procedure, and symptomatic intracranial haemorrhage were noted. Modified Rankin Scale <=2 at three-months was used as good outcome. Recanalization was defined as Thrombolysis in Myocardial Ischaemia 2-3 flow on angiography. RESULTS: Among 157 patients, 104 patients received IV-IA treatment and 53 patients underwent direct IA therapy. There was a higher recanalization rate with IV-IA therapy compared with IA alone (71% vs. 60%, P < 0.21) which was driven by early recanalization after IV rtPA. Mortality and independent outcome were comparable between the two groups. Symptomatic intracranial haemorrhage occurred in 8% of patients (12% in the IA group, 7% in the IV-IA group) but was more frequent as the intensity of intervention increased from device alone to thrombolytic drug alone to device plus thrombolytic drug(s). Recanalization was a strong predictor of reduced mortality risk ratio (RR) 0.48 confidence interval95 0.27-0.84) and favourable outcome (RR 2.14 confidence interval95 1.3-3.5). CONCLUSIONS: Combined IV-IA therapy with full-dose intravenous rtPA was safe and results in good recanalization rates without excess symptomatic intracranial haemorrhage. Testing of full-dose IV tPA followed by endovascular treatment in the IMS3 trial is justified. PMID- 23013040 TI - Improving the accuracy of daily satellite-derived ground-level fine aerosol concentration estimates for North America. AB - We improve the accuracy of daily ground-level fine particulate matter concentrations (PM(2.5)) derived from satellite observations (MODIS and MISR) of aerosol optical depth (AOD) and chemical transport model (GEOS-Chem) calculations of the relationship between AOD and PM(2.5). This improvement is achieved by (1) applying climatological ground-based regional bias-correction factors based upon comparison with in situ PM(2.5), and (2) applying spatial smoothing to reduce random uncertainty and extend coverage. Initial daily 1-sigma mean uncertainties are reduced across the United States and southern Canada from +/- (1 MUg/m(3) + 67%) to +/- (1 MUg/m(3) + 54%) by applying the climatological ground-based regional scaling factors. Spatial interpolation increases the coverage of satellite-derived PM(2.5) estimates without increased uncertainty when in close proximity to direct AOD retrievals. Spatial smoothing further reduces the daily 1 sigma uncertainty to +/-(1 MUg/m(3) + 42%) by limiting the random component of uncertainty. We additionally find similar performance for climatological relationships of AOD to PM(2.5) as compared to day-specific relationships. PMID- 23013041 TI - The ACE2 gene: its potential as a functional candidate for cardiovascular disease. AB - The RAS (renin-angiotensin system) plays an important role in the pathophysiology of CVD (cardiovascular disease), and RAS blockade is an important therapeutic strategy in the management of CVD. A new counterbalancing arm of the RAS is now known to exist in which ACE (angiotensin-converting enzyme) 2 degrades Ang (angiotensin) II, the main effector of the classic RAS, and generates Ang-(1-7). Altered ACE2 expression is associated with cardiac and vascular disease in experimental models of CVD, and ACE2 is increased in failing human hearts and atherosclerotic vessels. In man, circulating ACE2 activity increases with coronary heart disease, as well as heart failure, and a large proportion of the variation in plasma ACE2 levels has been attributed to hereditary factors. The ACE2 gene maps to chromosome Xp22 and this paper reviews the evidence associating ACE2 gene variation with CVD and considers clues to potential functional ACE2 variants that may alter gene expression or transcriptional activity. Studies to date have investigated ACE2 gene associations in hypertension, left ventricular hypertrophy and coronary artery disease, but the results have been inconsistent. The discrepancies may reflect the sample size of the studies, the gender or ethnicity of subjects, the cardiovascular phenotype or the ACE2 SNP investigated. The frequent observation of apparent sex-dependence might be of special importance, if confirmed. As yet, there are no studies to concurrently assess ACE2 gene polymorphisms and circulating ACE2 activity. Large-scale carefully conducted clinical studies are urgently needed to clarify more precisely the potential role of ACE2 in the CVD continuum. PMID- 23013042 TI - Hepatitis B virus: from immunobiology to immunotherapy. AB - Owing to the major limitations of current antiviral therapies in HBV (hepatitis B virus) infection, there is a strong need for novel therapeutic approaches to this major health burden. Stimulation of the host's innate and adaptive immune responses in a way that results in the resolution of viral infection is a promising approach. A better understanding of the virus-host interaction in acute and chronic HBV infection revealed several possible novel targets for antiviral immunotherapy. In the present review, we will discuss the current state of the art in HBV immunology and illustrate how control of infection could be achieved by immunotherapeutic interventions. PMID- 23013043 TI - Circulating adipocyte fatty acid-binding protein levels are independently associated with heart failure. AB - A-FABP (adipocyte fatty acid-binding protein), one of the most abundant proteins in adipocytes, plays a key role in obesity-related insulin resistance, inflammation and atherosclerosis in animals. In the present study, we sought to investigate the association of A-FABP with HF (heart failure) in Chinese subjects. Serum A-FABP levels were measured in 252 HF patients and 261 age-, gender- and BMI (body mass index)-matched non-HF subjects. Echocardiography was performed on each patient. The severity of HF was determined by the NYHA (New York Heart Association) classification system. After adjustments for age, gender and BMI, serum A-FABP concentrations in patients with HF were significantly higher than in non-HF patients [11.17 (6.63-19.93) ng/ml compared with 5.67 (3.20 8.87) ng/ml; P<0.001] and significantly progressed with the NYHA class (P<0.001). In addition, NT-proBNP (N-terminal pro-brain natriuretic peptide) was independently and positively correlated with A-FABP (standardized beta=0.340, P<0.001) after adjusting for confounding factors. Each echocardiographic parameter, especially LVEF (left ventricular ejection fraction), was independently associated with A-FABP (all P<0.05). Multivariate logistic regression analysis demonstrated that A-FABP concentration was an independent risk factor for HF [odds ratio, 6.93 (95% confidence interval, 2.49-19.30); P<0.001]. Our results demonstrate that A-FABP is closely associated with HF, and raise the possibility that increased A-FABP may be causally related to the pathogenesis of heart dysfunction in humans. PMID- 23013044 TI - Validation of two ELISA kits for the screening of tylosin and streptomycin in honey according to the European decision 2002/657/EC. AB - Antibiotics are mixed with the food of bees to fight against diseases. No maximum residue limits have been set for honey. Recommended concentrations (RCs) have been published by European Union Reference Laboratories for tylosin and streptomycin. The objective of this project was to select and validate enzyme linked immunosorbent assay (ELISA) kits for the screening of tylosin and streptomycin/dihydrostreptomycin residues to be implemented in the French honey control plan. Four ELISA kits for tylosin and five ELISA kits for streptomycin were evaluated. At the end, one kit each was selected and validated for tylosin (TECNA AB620) and streptomycin (Europroxima). Both ELISA kits for tylosin and streptomycin are specific, robust, fast and easy-to-use tests. The detection capability CC beta of tylosin A was less than or equal to 10 ug kg(-1) (half the RC). The CC beta of desmycosin (the hydrolysed product of tylosin A in acidic conditions) is approximately 200 ug kg(-1), which is five times the RC for tylosin (20 ug kg(-1)). Thus, this kit is fit for the screening of tylosin A but is unsuitable to detect desmycosin. The detection capability CC beta of streptomycin was less than or equal to 10 ug kg(-1) (one fourth the RC). The cross-reactivity with dihydrostreptomycin was equal to 136%. Both ELISA kits were applicable to a wide variety of honey (single flower and multiflower, different floral origins, different geographic origins, different consistencies [liquid or solid] and different colours). PMID- 23013045 TI - Evaluation of the impact of writing exercises interventions on quality of life in patients with psoriasis undergoing systemic treatments. AB - BACKGROUND: Emotional writing is a short-term psychological intervention that has been successfully used in several controlled studies. OBJECTIVES: The overall objective of the study was to test the efficacy of Pennebaker's emotional writing intervention in patients with psoriasis treated with systemic therapy. METHODS: A randomized controlled trial was conducted in seven clinical centres in Italy, over a 2-year period. The main outcome measures were the psoriasis area and severity index and the Physician Global Assessment, as well as generic and dermatology-specific quality of life questionnaires. Such outcomes were measured at 4 weeks, and 6 and 12 months from baseline. The project recruitment time was 12 months, and the total follow-up time for each individual was also 12 months. RESULTS: In total, 202 patients were enrolled and assessed at baseline, 67 of whom completed all three follow-up visits. The writing exercise had little or no effect on patients with psoriasis who were undergoing systemic treatment. In the Generalized Estimating Equations models no statistically significant differences were observed in the Pennebaker intervention group vs. the control group. In subgroup analysis for health status, small effects in favour of patients assigned to the Pennebaker group were documented at the end of the study in women, in overweight individuals, in patients under treatment with biological drugs, and on the Physical Component Summary of the Short Form of the Medical Outcomes Study Questionnaire. CONCLUSIONS: The Pennebaker and control groups had similar changes over time for practically all the outcome variables, and also when considering all observations and adjusting for all the variables of interest. The longitudinal analysis confirmed that the intervention had little or no effect on the variables of interest. The implementation of writing exercises requires a careful and ad hoc organization, including dedicated spaces for the writing itself. PMID- 23013046 TI - Recommended Nordic paediatric reference intervals for 21 common biochemical properties. AB - Paediatric reference intervals based on samples from healthy children are difficult to establish and consequently data are often from hospitalized children. Furthermore, biases may present in published data due to differences in the analytical methods employed. Blood samples from 1429 healthy Danish children were collected for establishing reference intervals for 21 common biochemical properties (Alanine transaminase, Albumin, Alkaline phosphatase, Aspartate transaminase, Bilirubin, Calcium, Cholesterol, Creatinine, Creatine kinase, HDL Cholesterol, Iron, Lactate dehydrogenase, LDL- Cholesterol, Magnesium, Phosphate, Potassium, Protein, Sodium, Transferrin, Triglycerides and Urate). Samples were analyzed on a Roche-Modular-P/ISE-system. The NORIP reference material (NFKK Reference Serum X) was included in all the analytical runs. Reference values were recalculated according to the target values of X for the properties and statistical calculations carried out as performed in the NORIP study. Thus commutable (regarding analytical method) reference intervals for 20 properties were established and for LDL-Cholesterol reference intervals were reported for the specific analytical method employed. The data were compared to previous studies and to those obtained from the youngest age group in the NORIP study. Marked age differences were observed for most of the properties. Several properties also showed gender-related differences, mainly at the onset of puberty. Data are presented as suggested intervals for combined age groups, but can be accessed via the NORIP home page if more detailed division according to age or gender is desired. PMID- 23013047 TI - How about taking a low-cost, small, and wireless EEG for a walk? AB - To build a low-cost, small, and wireless electroencephalogram (EEG) system suitable for field recordings, we merged consumer EEG hardware with an EEG electrode cap. Auditory oddball data were obtained while participants walked outdoors on university campus. Single-trial P300 classification with linear discriminant analysis revealed high classification accuracies for both indoor (77%) and outdoor (69%) recording conditions. We conclude that good quality, single-trial EEG data suitable for mobile brain-computer interfaces can be obtained with affordable hardware. PMID- 23013048 TI - Evaluation of gustatory function in HIV-infected subjects with and without HAART. AB - BACKGROUND: Alteration in gustatory function among patients with human immunodeficiency virus (HIV) infection is sparsely studied and provides contradictory findings. The objectives of the study were to evaluate taste perversion in HIV-infected subjects and compare taste acuity between patients with and without Highly active antiretroviral therapy (HAART). MATERIALS AND METHODS: Fifty HIV-infected subjects aged 25-55 years were selected and divided into two subgroups: patients with HAART and patients without HAART. Control group included 50 healthy, age-, sex-, gender-, and socioeconomic status-matched individuals. Taste complaints were recorded on a structured questionnaire, and formal taste testing was carried out with triadic forced choice whole-mouth, above-threshold taste test for four tastants - sweet, salt, sour, and bitter. Taste identification, detection threshold, and intensity of tastant were recorded. RESULTS: Twenty-four (48%) among study group complained of taste perversion when compared to none among the control group (P < 0.001). During taste testing, identification and intensity scores were lower, while detection threshold scores for four tastants were higher in study group than in control group (P < 0.05). Among those patients with taste complaints, 16 were with HAART, while eight were without HAART (P = 0.043). Formal taste testing revealed greater taste perversion for sour and bitter tastants among patients with HAART medication. CONCLUSION: The results document significant taste losses in HIV infected subjects, and HAART contributes considerably to such taste perversion. PMID- 23013049 TI - Palladium-catalyzed annulation of arynes by o-halobenzamides: synthesis of phenanthridinones. AB - The palladium-catalyzed annulation of arynes by substituted o-halobenzamides produces N-substituted phenanthridinones in good yields. This methodology provides this important heterocyclic ring system in a single step by simultaneous C-C and C-N bond formation, under relatively mild reaction conditions, and tolerates a variety of functional groups. PMID- 23013050 TI - Patent Blue V dye anaphylaxis: experience of Australian and New Zealand surgeons. AB - BACKGROUND: Patent Blue V dye (PBVD) can cause severe anaphylaxis. For sentinel node biopsy (SNB) in breast cancer patients, controversy exists as to the utility of PBVD in addition to lymphoscintigraphy. This survey assessed Australian and New Zealand breast surgeons' experience of anaphylaxis with PBVD. METHODS: The survey was distributed to all 180 members of the BreastSurgANZ society in May 2011. Seventy-six (42%) current members responded. A retrospective analysis was performed on survey responses. RESULTS: Seventy-five members used PBVD on a median of 50 cases per year (0-250 cases per year) for a median of 10 years (4 months-15 years). Overall, 44 members (58.7%) experienced definite or possible allergic reaction to PBVD, but only 16 members (21%) witnessed severe anaphylaxis associated with a fall in blood pressure. Of the 34 members who experienced what they considered definite anaphylactic reactions with PBVD, only 18 members confirmed with allergy testing. The overall reported incidence of anaphylactic reactions of any severity was 0.15%. The median time to anaphylaxis was 20 min (0 90 min). Forty members (53.3%) reported routine discussion about PBVD risks as part of informed consent. Only seven members performed routine pre-op skin testing. Overall, 91% of the members accepted the rare but real risk of severe anaphylaxis and 76% did not question the additional value associated with its use. CONCLUSION: Australian and New Zealand breast surgeons' reported that the anaphylaxis rate from PBVD was 0.15%. The majority of surgeons continued to use PBVD to facilitate SNB. PMID- 23013051 TI - Unique device identification in the service of public health. PMID- 23013052 TI - Replacing Obamacare with real health care reform. PMID- 23013053 TI - Clinical decisions. Preexposure prophylaxis for HIV prevention--polling results. PMID- 23013054 TI - Securing the future of American health care. PMID- 23013055 TI - Unpredictable and difficult to control--the adolescence of West Nile virus. PMID- 23013057 TI - Insight, psychopathology, explanatory models and outcome of schizophrenia in India: a prospective 5-year cohort study. AB - BACKGROUND: The sole focus of models of insight on bio-medical perspectives to the complete exclusion of local, non-medical and cultural constructs mandates review. This study attempted to investigate the impact of insight, psychopathology, explanatory models of illness on outcome of first episode schizophrenia. METHOD: Patients diagnosed to have DSM IV schizophrenia (n = 131) were assessed prospectively for insight, psychopathology, explanatory models of illness at baseline, 6, 12 and 60 months using standard instruments. Multiple linear and logistic regression and generalized estimating equations (GEE) were employed to assess predictors of outcome. RESULTS: We could follow up 95 (72.5%) patients. Sixty-five of these patients (68.4%) achieved remission. There was a negative relationship between psychosis rating and insight scores. Urban residence, fluctuating course of the initial illness, and improvement in global functioning at 6 months and lower psychosis rating at 12 months were significantly related to remission at 5 years. Insight scores, number of non medical explanatory models and individual explanatory models held during the later course of the illness were significantly associated with outcome. Analysis of longitudinal data using GEE showed that women, rural residence, insight scores and number of non-medical explanatory models of illness held were significantly associated with BPRS scores during the study period. CONCLUSIONS: Insight, the disease model and the number of non-medical model positively correlated with improvement in psychosis arguing for a complex interaction between the culture, context and illness variables. These finding argue that insight and explanatory models are secondary to psychopathology, course and outcome of the illness. The awareness of mental illness is a narrative act in which people make personal sense of the many challenges they face. The course and outcome of the illness, cultural context, acceptable cultural explanations and the prevalent social stigma interact to produce a complex and multifaceted understanding of the issues. This complexity calls for a nuanced framing of insight. PMID- 23013058 TI - Secular trends in the fat and fat-free components of body mass index in children aged 8-18 years born 1958-1995. AB - BACKGROUND: It is unknown whether the secular trend in childhood BMI reflects increases in fat-free mass as well as fat mass. METHODS: This study decomposed BMI trends in 488 participants in the Fels Longitudinal Study born between 1958 1995 and aged 8-17.99 years into their fat and fat-free components. Generalized estimating equations estimated birth year cohort (1958-1970, 1971-1983, 1984 1995) effects on 2208 observations of BMI, fat mass index (FMI = fat mass (kg)/height (m)(2)) and fat-free mass index (FFMI = fat-free mass (kg)/height (m)(2)). RESULTS: BMI in boys increased across cohorts, with those born between 1984-1995 being 2 kg/m(2) larger than those born between 1958-1970 (p = 0.001) and increases in FMI were highly significant (p-values < 0.001). FFMI did not differ by cohort. In girls, there was a significant advantage in BMI (1.2 kg/m(2)) and FFMI (0.8 kg/m(2)) of the 1984-1995 cohort compared to the 1971-1983 cohort (p-values < 0.05). CONCLUSIONS: Because the long term trend in childhood BMI in boys appears to be driven by an increase in total body adiposity, evidence is provided to support current knowledge on the predicted deleterious long-term consequences of the childhood obesity epidemic in boys. Research is needed to confirm whether recent changes in BMI in girls are due to increases in fat-free mass resulting from changes in behaviour and lifestyle not yet manifest in boys. PMID- 23013059 TI - Use of nested flow models and interpolation techniques for science-based management of the Sheyenne National Grassland, North Dakota, USA. AB - Noxious weeds threaten the Sheyenne National Grassland (SNG) ecosystem and therefore herbicides have been used for control. To protect groundwater quality, the herbicide application is restricted to areas where the water table is less than 10 feet (3.05 m) below the ground surface in highly permeable soils, or less than 6 feet (1.83 m) below the ground surface in low permeable soils. A local MODFLOW model was extracted from a regional GFLOW analytic element model and used to develop depth-to-groundwater maps in the SNG that are representative for the particular time frame of herbicide applications. These maps are based on a modeled groundwater table and a digital elevation model (DEM). The accuracy of these depth-to-groundwater maps is enhanced by an artificial neural networks (ANNs) interpolation scheme that reduces residuals at 48 monitoring wells. The combination of groundwater modeling and ANN improved depth-to-groundwater maps, which in turn provided more informed decisions about where herbicides can or cannot be safely applied. PMID- 23013060 TI - Epidural blood patches are effective for postdural puncture headache in pediatrics--a 10-year experience. AB - BACKGROUND: Postdural puncture headache (PDPH) is a relatively common complication after lumbar punctures (LP). If conservative treatment is not sufficient within a few days and the symptoms are severe, an epidural blood patch (EBP) may be performed. AIM: A chart review to evaluate the need and effectiveness of EBPs in children and adolescents over a 10-year period at Kuopio University Hospital (KUH) and Satakunta Central Hospital (SCH). METHODS: The information system patient measures databases were reviewed to identify patients who had received an EBP. Then, the pediatric patients' medical records were compared to the characteristics of the PDPH and associated symptoms and were evaluated for the effectiveness of EBPs. RESULTS: Forty-two EBPs were performed in 41 patients (24 girls, 17 boys), 26 at KUH and 15 at SCH. Five patients, all at KUH, were children aged 3-12 years, and 36 patients were adolescents, aged 13 18 years. The indications for LPs were diagnostic (n = 26), spinal anesthesia/analgesia (n = 11), or introduction of chemotherapy (n = 2), and four patients developed PDPH after an inadvertent dural puncture with an epidural needle. The first EBP provided a complete relief of symptoms in 37 children, an initial success rate of 90%, and permanent relief in 85%. At KUH, the need for EBPs after spinal anesthesia/analgesia was <1/1000 in children and 2-3/1000 in adolescents, and that after chemotherapy 1-2/1000. No serious adverse effects related to EBPs were recorded. CONCLUSION: If PDPH symptoms are severe and are not relieved with conservative treatment, EBP is a highly effective procedure in pediatric patients. PMID- 23013061 TI - Oestrogen receptor beta and melanoma: a comparative study. AB - BACKGROUND: Oncological research has focused on evaluating oestrogen receptors (ERs) in oestrogen-related tumours, and understanding the potential role of ERs in the pathophysiology of cancer. OBJECTIVES: To investigate the significance of oestrogen receptor beta (ERbeta) in melanoma. METHODS: We prospectively evaluated ERbeta expression in malignant melanoma (MM) tissue and adjacent healthy skin by quantitative immunohistochemistry at the Department of Dermatology of the University of Florence, from 1998 to 2010. RESULTS: ERbeta was detected with varying staining intensity in the 66 malignant melanocytic lesions. After adjusting for age and sex, we found that ERbeta expression was significantly lower in melanoma tissue compared with adjacent healthy skin (P < 0.0001). We also found significantly lower ERbeta levels in thick melanoma tissue compared with thin melanoma tissue. In addition, there was a positive association between Breslow thickness and the difference of ERbeta expression between healthy tissue and melanoma tissue (P = 0.0004). Consistent with sex differences in melanoma survival, men showed significantly lower levels of ERbeta than women in both melanoma (P = 0.05) and healthy tissues (P = 0.02). CONCLUSIONS: ERbeta expression is inversely associated with Breslow thickness and is significantly influenced by sex in MM. PMID- 23013062 TI - Histological and hormonal testicular function in oligo/azoospermic infertile men. AB - We characterised and correlated the histological and hormonal aspects of a cohort of 261 azo/oligozoospermic men, applying a quantitative/qualitative evaluation of testicular tissue and serum and intratesticular hormonal measurements. One hundred and 93 azo/oligozoospermic patients were diagnosed as: complete sertoli cell only syndrome (cSCOS), n = 76; focal SCOS, n = 31; maturation arrest, n = 34; hypospermatogenesis, n = 17; mixed atrophy, n = 25; and severe atrophy, n = 10. Normal spermatogenesis was observed in 68 infertile men (controls). Patients with cSCOS, focal SCOS, mixed and severe atrophy had larger LC/clusters (11.5; 11.0; 10.7; 18.9 LC/cluster) than controls (6 LC/cluster; P < 0.001). cSCOS, focal SCOS, mixed and severe atrophy patients had higher FSH, LH and lower T/LH ratio serum levels than the other groups. Intratesticular testosterone concentrations were higher in tissues with complete or focal SCOS (45.6 ng mg(-1) protein) and mixed atrophy (79.0 ng mg(-1) protein) than normal tissues (20.3 ng mg(-1) protein; P = 0.03 and P = 0.007). Considering all subjects, significant correlations were found between T/LH ratio and Leydig cells/cluster (r = 0.510, P < 0.001), FSH levels (r = -0.692, P < 0.001) and with intratesticular testosterone (r = -0.354, P = 0.001); these correlations follow the pattern of severity of spermatogenic damage. By a thorough histological evaluation, we validate the concept that the severity of spermatogenic impairment is associated with major morphological and functional disturbance of the Leydig cell compartment. PMID- 23013063 TI - Comparative immunological evaluation of recombinant Salmonella Typhimurium strains expressing model antigens as live oral vaccines. AB - BACKGROUND: Despite the development of various systems to generate live recombinant Salmonella Typhimurium vaccine strains, little work has been performed to systematically evaluate and compare their relative immunogenicity. Such information would provide invaluable guidance for the future rational design of live recombinant Salmonella oral vaccines. RESULT: To compare vaccine strains encoded with different antigen delivery and expression strategies, a series of recombinant Salmonella Typhimurium strains were constructed that expressed either the enhanced green fluorescent protein (EGFP) or a fragment of the hemagglutinin (HA) protein from the H5N1 influenza virus, as model antigens. The antigens were expressed from the chromosome, from high or low-copy plasmids, or encoded on a eukaryotic expression plasmid. Antigens were targeted for expression in either the cytoplasm or the outer membrane. Combinations of strategies were employed to evaluate the efficacy of combined delivery/expression approaches. After investigating in vitro and in vivo antigen expression, growth and infection abilities; the immunogenicity of the constructed recombinant Salmonella strains was evaluated in mice. Using the soluble model antigen EGFP, our results indicated that vaccine strains with high and stable antigen expression exhibited high B cell responses, whilst eukaryotic expression or colonization with good construct stability was critical for T cell responses. For the insoluble model antigen HA, an outer membrane expression strategy induced better B cell and T cell responses than a cytoplasmic strategy. Most notably, the combination of two different expression strategies did not increase the immune response elicited. CONCLUSION: Through systematically evaluating and comparing the immunogenicity of the constructed recombinant Salmonella strains in mice, we identified their respective advantages and deleterious or synergistic effects. Different construction strategies were optimally-required for soluble versus insoluble forms of the protein antigens. If an antigen, such as EGFP, is soluble and expressed at high levels, a low-copy plasmid-cytoplasmic expression strategy is recommended; since it provokes the highest B cell responses and also induces good T cell responses. If a T cell response is preferred, a eukaryotic expression plasmid or a chromosome-based, cytoplasmic-expression strategy is more effective. For insoluble antigens such as HA, an outer membrane expression strategy is recommended. PMID- 23013064 TI - Education and cognitive change over 15 years: the atherosclerosis risk in communities study. AB - OBJECTIVES: To evaluate whether education level is associated with change in cognitive performance. DESIGN: Prospective cohort study. SETTING: The Atherosclerosis Risk in Communities (ARIC) Study, a community-based cohort. PARTICIPANTS: Nine thousand two hundred sixty-eight ARIC participants who underwent cognitive evaluation at least twice over a 15-year period. MEASUREMENTS: Education was evaluated as a predictor of change in word recall, the Digit Symbol Substitution Test (DSST), and word fluency. A random-effects linear regression model, and a time by educational level interaction was used. RESULTS: Educational level was highly associated with cognitive performance. The effect on performance of a less than high school education (vs more than high school) was equivalent to the effect of as much as 22 years of cognitive aging, but educational level was not associated with change in cognitive performance in whites or blacks, with the exception of the DSST for whites, in whom those with lower levels of education had less decline in scores. CONCLUSION: Educational level was not associated with change in cognitive performance, although the higher baseline cognitive performance of individuals with more education might explain lower rates of dementia in more-educated individuals, because more decline would have to take place between baseline higher performance and time at which dementia was diagnosed in more-educated individuals. PMID- 23013065 TI - Redesigning a graduate research course for evidence-based competencies. AB - Nursing research is critical to establish the science for the discipline and to provide a foundation for evidence-based practice. All nurses need to understand the research process and engage in research at the level for which they were prepared. The American Association of Colleges of Nursing has clearly outlined essential learning outcomes for each level of nursing education, including the competent application of research findings to clinical problems. This article describes the evolution of a graduate-level research course to provide master's level students with a sound foundational understanding of the research process, the innovation undertaken to address identified learning needs, and the important lessons learned. PMID- 23013066 TI - Using a human patient simulator to study the relationship between communication and nursing students' team performance. AB - This study examined the relationship between communication and nursing students' team performance by determining whether variations in team performance are related to differences in communication regarding five task-relevant functions: assessment, diagnosis, planning, implementation, and evaluation. The study results indicate a positive relationship between nursing students' team performance and comments focused on the implementation of treatment(s) and the evaluation of treatment options. A negative relationship between nursing students' team performance and miscellaneous comments made by team members was also observed. PMID- 23013067 TI - Characterization of three small supernumerary marker chromosomes (sSMC) in humans. AB - In the present study, three prenatally detected small supernumerary marker chromosomes (sSMC) were identified by banding cytogenetics and characterized in detail by molecular cytogenetics. In one case an sSMC(10) leading to a pericentric partial trisomy and in two cases heterochromatic sSMC derived from chromosome 22 were characterized. Outcomes were reportedly normal for two of the three cases for whom this information was known. PMID- 23013068 TI - Dynamic anthropometric changes in children as shown by longitudinal data for 2004 2009 from the city of Dalian, China. AB - BACKGROUND: The physical development of children and adolescents always attracts widespread attention in society. AIM: The goal of the present study was to systematically analyse the dynamic changes in some anthropometric characteristics among primary school age children. SUBJECTS AND METHODS: Using a longitudinal study design, this study monitored physical growth annually in 933 pupils of Dalian, China, from 2004-2009.Longitudinal multi-level modelling (mixed model) was used to analyse the trajectory of growth from ages 7-12 years by gender. Height, weight and BMI were transformed into Z-scores relative to the WHO 2007 references. RESULTS: Height, weight and BMI were all higher for boys than for girls. Due to the interaction of age and gender, boys and girls exhibited different growth models. Average heights and weights for children of 7-12 years old in Dalian were higher than the WHO 2007 references. BMI z-scores for boys were significantly greater than the WHO 2007 references. CONCLUSION: Height, weight and BMI z-scores among boys and girls of 7-12 years old in Dalian were generally greater than the WHO standards. The major reasons for the differences may be due to rapid socioeconomic development and improvements in nutrition and living conditions. PMID- 23013069 TI - Experience in treating congenital hypothyroidism: implications regarding free thyroxine and thyrotropin steady-state concentrations during optimal levothyroxine treatment. AB - BACKGROUND: A major problem in the treatment of patients with congenital hypothyroidism (CHT) is that the optimal individual target values of thyrotropin (TSH) and free thyroxine (fT(4)) are unknown. We investigated whether patients with CHT have during treatment considered optimal stable fT(4) and TSH steady state concentrations (SSCs) that can be used as target values, and whether TSH or fT(4) is more useful in guiding decisions regarding therapy. METHODS: From 60 early-treated patients with CHT, TSH and fT(4) follow-up samples within the age interval 1.5-132 months (postinitial period) and within TSH interval 0.5-10 mU/L were selected. TSH and fT(4) SSCs were estimated by taking the individual mean values of a series of determinations, under the most euthyroid conditions possible (n=1257), for the whole age and TSH intervals, as well as for the age intervals 1.5-24, 25-72, and 73-132 months, as well as, for fT(4), for the two split TSH intervals 0.5-4.49 and 4.5-10 mU/L. For all SSCs, the within-subject coefficient of variation (CV(w)) was determined. Further, fT(4) SSCs were assessed for the first 6 weeks after therapy initiation. RESULTS: For both TSH and fT(4), individual SSCs differed significantly (p<0.001). The 95% confidence interval for TSH SSCs was 1.1-5.7 mU/L and for fT(4) SSCs 16.6-28.7 pmol/L. Mean CV(w) values for TSH and fT(4) SSCs were 60.9% and 13.1%, respectively. Individual fT(4) and TSH SSCs were reproducible when assessed for the three age intervals, both slightly decreasing with age (p<=0.033), and fT(4) SSCs were reproducible for the two split TSH intervals, with a slight fT(4) difference (p<0.001). fT(4) SSCs were largely independent of the administered LT(4) dosage (range 2.4-6.1 MUg/kg). fT(4) SSCs of the initial period were comparable to those of postinitial period with a mean+/-SD difference of 1.0+/-3.5 pmol/L, p=0.07. CONCLUSIONS: Our study suggests that in CHT during therapy considered optimal, stable TSH and fT(4) SSCs can be found slightly decreasing with age and largely independent of the administered LT(4) dosage (range 2.4-6.1 MUg/kg). In clinical follow-up, fT(4) SSCs may be more valuable as individual target values than TSH SSCs. PMID- 23013070 TI - What's preventing us from preventing type 2 diabetes? PMID- 23013071 TI - Cutting family planning in Texas. PMID- 23013072 TI - Cure for the common cold. PMID- 23013073 TI - Use of reprogrammed cells to identify therapy for respiratory papillomatosis. AB - A patient with a 20-year history of recurrent respiratory papillomatosis had progressive, bilateral tumor invasion of the lung parenchyma. We used conditional reprogramming to generate cell cultures from the patient's normal and tumorous lung tissue. Analysis revealed that the laryngeal tumor cells contained a wild type 7.9-kb human papillomavirus virus type 11 (HPV-11) genome, whereas the pulmonary tumor cells contained a 10.4-kb genome. The increased size of the latter viral genome was due to duplication of the promoter and oncogene regions. Chemosensitivity testing identified vorinostat as a potential therapeutic agent. At 3 months after treatment initiation, tumor sizes had stabilized, with durable effects at 15 months. PMID- 23013074 TI - Physicians' warnings for unfit drivers and the risk of trauma from road crashes. AB - BACKGROUND: Physicians' warnings to patients who are potentially unfit to drive are a medical intervention intended to prevent trauma from motor vehicle crashes. We assessed the association between medical warnings and the risk of subsequent road crashes. METHODS: We identified consecutive patients who received a medical warning in Ontario, Canada, between April 1, 2006, and December 31, 2009, from a physician who judged them to be potentially unfit to drive. We excluded patients who were younger than 18 years of age, who were not residents of Ontario, or who lacked valid health-card numbers under universal health insurance. We analyzed emergency department visits for road crashes during a baseline interval before the warning and a subsequent interval after the warning. RESULTS: A total of 100,075 patients received a medical warning from a total of 6098 physicians. During the 3-year baseline interval, there were 1430 road crashes in which the patient was a driver and presented to the emergency department, as compared with 273 road crashes during the 1-year subsequent interval, representing a reduction of approximately 45% in the annual rate of crashes per 1000 patients after the warning (4.76 vs. 2.73, P<0.001). The lower rate was observed across patients with diverse characteristics. No significant change was observed in subsequent crashes in which patients were pedestrians or passengers. Medical warnings were associated with an increase in subsequent emergency department visits for depression and a decrease in return visits to the responsible physician. CONCLUSIONS: Physicians' warnings to patients who are potentially unfit to drive may contribute to a decrease in subsequent trauma from road crashes, yet they may also exacerbate mood disorders and compromise the doctor-patient relationship. (Funded by the Canada Research Chairs program and others.). PMID- 23013075 TI - Hepatitis E. PMID- 23013076 TI - Images in clinical medicine. X-chromosomal translocation and segmental hypopigmentation. PMID- 23013077 TI - Case records of the Massachusetts General Hospital. Case 30-2012. A 54-year-old woman with HIV infection, dyspnea, and chest pain. PMID- 23013078 TI - Enzalutamide--a major advance in the treatment of metastatic prostate cancer. PMID- 23013080 TI - Estimating glomerular filtration rate. PMID- 23013081 TI - Estimating glomerular filtration rate. PMID- 23013082 TI - Estimating glomerular filtration rate. PMID- 23013083 TI - Estimating glomerular filtration rate. PMID- 23013085 TI - Stroke and myocardial infarction with hormonal contraception. PMID- 23013086 TI - Stroke and myocardial infarction with hormonal contraception. PMID- 23013088 TI - Protocols, physiology, and trials of hydroxyethyl starch. PMID- 23013089 TI - Protocols, physiology, and trials of hydroxyethyl starch. PMID- 23013090 TI - Protocols, physiology, and trials of hydroxyethyl starch. PMID- 23013091 TI - Protocols, physiology, and trials of hydroxyethyl starch. PMID- 23013093 TI - Unruptured cerebral aneurysms in a Japanese cohort. PMID- 23013094 TI - Unruptured cerebral aneurysms in a Japanese cohort. PMID- 23013096 TI - Surgical margins in lumpectomy for breast cancer. PMID- 23013097 TI - Falsely low carboxyhemoglobin level after hydroxocobalamin therapy. PMID- 23013100 TI - Images in clinical medicine. A laryngeal fluke. PMID- 23013101 TI - Bortezomib inhibits the angiogenesis mediated by mesenchymal stem cells. AB - This study is to investigate the effects of bortezomib on the angiogenesis of mesenchymal stem cells (MSCs). We examined the effects of bortezomib on the cellular proliferation, migration, and capillary network formation of HUVECs cocultured with CMs of MSCs. We found that Bortezomib inhibited the cellular proliferation and tube formation of HUVECs cocultured with CMs in a dose dependent fashion. Bortezomib also prevented the migration of HUVECs cocultured with CMs. In addition, bortezomib dose-dependently inhibited the growth of MSCs and prevented the production of angiogenic factors including VEGF (vascular endothelial growth factor), HGF (hepatocyte growth factor), and bFGF (basic fibroblast growth factor) in MSCs. In conclusion, bortezomib prevented the angiogenesis mediated by MSCs. PMID- 23013102 TI - Self-assembled cationic micelles based on PEG-PLL-PLLeu hybrid polypeptides as highly effective gene vectors. AB - Developing safe and effective nonviral gene vector is highly crucial for successful gene therapy. In the present study, we designed a series of biodegradable micelles based on hybrid polypeptide copolymers of poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) for efficient gene delivery. A group of amphiphilic PEG-PLL-PLLeu hybrid polypeptide copolymers were synthesized by ring-opening polymerization of N-carboxyanhydride, and the chemical structure of each copolymer was characterized by (1)H NMR and FT-IR spectroscopy measurement. The PEG-PLL-PLLeu micelles were positively charged with tunable sizes ranging from 40 to 90 nm depending on the length of PLL and PLLeu segment. Compared with PEG-PLL copolymers, PEG-PLL-PLLeu micelles demonstrated significantly higher transfection efficiency and less cytotoxicity. Furthermore, the transfection efficiency and biocompatibility of the micelles can be simultaneously improved by tuning the length of PLL and PLLeu segments. The transfection efficiency of PEG-PLL-PLLeu micelles in vivo was two to three times higher than that of PEI(25k), which was attributable to their capability of promoting DNA condensation and cell internalization as well as successful lysosome escape. Hence well-defined PEG-PLL-PLLeu micelles would serve as highly effective nonviral vectors for in vivo gene delivery. PMID- 23013103 TI - Transport in supported polyelectrolyte brushes. AB - Functional polymers have a wide variety of applications ranging from energy storage to drug delivery. For energy storage applications, desirable material properties include low cost, high charge storage and/or mobility, and low rates of degradation. Isotropic thin films have been used for many of these types of applications, but research suggests that different structures such as polymer brushes can improve charge transport by an order of magnitude. Supported polymer brush structures produced by "grafting-from" polymerization methods offer a framework for a controlled study of these materials on the molecular scale. Using these materials, researchers can study the basis of hindered diffusion because they contain a relatively homogeneous polyelectrolyte membrane. In addition, researchers can use fluorescent molecular probes with different charges to examine steric and Coulombic contributions to transport near and within polymer brushes. In this Account, we discuss recent progress in using fluorescence correlation spectroscopy, single-molecule polarization-resolved spectroscopy, and a novel three-dimensional orientational technique to understand the transport of charged dye probes interacting with the strong polyanionic brush, poly(styrene sulfonate). Our preliminary experiments demonstrate that a cationic dye, Rhodamine 6G, probes the brush as a counterion, and diffusion is therefore dominated by Coulombic forces, which results in a 10,000-fold decrease in the diffusion coefficient in comparison with free diffusion. We also support our experimental results with molecular dynamics simulations. Further experiments show that, up to 50% of the time, Rhodamine 6G translates within the brush without significant rotational diffusion, which indicates a strong deviation from Fickian transport mechanisms (in which translational and rotational diffusion are related directly through parameters such as chemical potential, size, solution viscosity, and thermal properties). To understand this oriented transport, we discuss the development of an experimental technique that allows us to quantify the three-dimensional orientation on the time scale of intrabrush transport. This method allowed us to identify a unique orientational transport direction for Rhodamine 6G within the poly(styrene sulfonate) brush and to report preliminary evidence for orientational dye "hopping". PMID- 23013104 TI - Evaluation of teaching methods for students on hernias: an observational study. AB - BACKGROUND: Teaching may be delivered through different media in different settings. We aimed to evaluate four teaching modalities for medical students on a common surgical topic. We compared learning, student preferences and experiences as outcome measures. METHODS: This is a prospective observational study of all medical students undertaking their first attachment in surgery. Students were randomly allocated into four groups: lecture, handout, website and patient-based tutorial, all on the management of an inguinal hernia. Baseline knowledge was assessed prior to group allocations through a questionnaire. Students completed a 24-h post-intervention questionnaire and satisfaction survey. RESULTS: One hundred fifty-four students participated. There was no difference in the pre intervention knowledge scores between the groups. The post-intervention knowledge scores significantly improved in the lecture and website groups. However, the website was significantly less engaging and clinically relevant form of teaching compared with the lecture. Despite being engaging and relevant, the tutorial group failed to improve knowledge scores. The handout did not improve knowledge scores, nor was it considered engaging or relevant. CONCLUSION: Knowledge scores significantly improved with the lecture and website teaching methods. The lecture was more engaging, clinically relevant and instilled confidence. Students preferred the website/podcasts as additional information to facilitate their learning and increased their knowledge equivalent or superior to other standard media. However, despite being effective, the student experience was less positive than for non-reusable contact teaching. If student satisfaction is to be a factor in achievement of learning outcomes, a balance has to be struck between different media delivery. PMID- 23013105 TI - Controlling UV/vis absorption and Stokes shifts in highly fluorescent chromophores by molecular dynamics in targeted construction of dyads. AB - Perylenedicarboximides were interlinked in their free peri-position to form dyads where the UV/vis absorptivity was amplified by exciton effects and the strong fluorescence bathochromically shifted by molecular dynamics. Applications of this type of dye with such increased Stokes shifts were discussed. PMID- 23013106 TI - No association between COL3A1, COL6A1 or COL12A1 gene variants and range of motion. AB - Approximately 64-70% of the variability in joint range of motion (ROM) is heritable. A common variant within a type V collagen (COL5A1) gene is associated with joint range of motion. Like type V collagen, types III, VI and XII collagen are also involved in fibril assembly and/or diameter regulation. Mutations within the genes that encode these proteins, COL3A1, COL6A1 and COL12A1, also cause connective tissue hypermobility disorders and phenotypes. The aim of this study was to determine if variants within these genes are associated with measures of joint range of motion. Three hundred and fifty apparently healthy and physically active Caucasian participants were recruited. Anthropometric measurements were taken. Sit-and-reach (SR), straight leg raise (SLR) and total shoulder rotation (ShTR) range of motion were measured. All participants were genotyped for COL3A1 rs1800255, COL6A1 rs35796750 and COL12A1 rs970547. COL3A1 rs1800255, COL6A1 rs35796750 and COL12A1 rs970547 were not significantly associated with sit-and reach, straight leg raise or total shoulder rotation range of motion. Furthermore, no significant age-genotype interaction effects were identified between the variants and range of motion measurements. None of the variants investigated in this study were significantly associated with any of the measures of range of motion used. Further studies are required to identify additional intrinsic and extrinsic factors that may determine range of motion, including the genetic component. PMID- 23013107 TI - NeuroThera(r) Efficacy and Safety Trial-3 (NEST-3): a double-blind, randomized, sham-controlled, parallel group, multicenter, pivotal study to assess the safety and efficacy of transcranial laser therapy with the NeuroThera(r) Laser System for the treatment of acute ischemic stroke within 24 h of stroke onset. AB - RATIONALE: Transcranial laser therapy is undergoing clinical trials in patients with acute ischemic stroke. The NeuroThera(r) Efficacy and Safety Trial-1 was strongly positive for 90-day functional benefit with transcranial laser therapy, and post hoc analyses of the subsequent NeuroThera(r) Efficacy and Safety Trial-2 trial suggested a meaningful beneficial effect in patients with moderate to moderately severe ischemic stroke within 24 h of onset. These served as the basis for the NeuroThera(r) Efficacy and Safety Trial-3 randomized controlled trial. AIM: The purpose of this pivotal study was to demonstrate safety and efficacy of transcranial laser therapy with the NeuroThera(r) Laser System in the treatment of subjects diagnosed with acute ischemic stroke. DESIGN: NeuroThera(r) Efficacy and Safety Trial-3 is a double-blind, randomized, sham-controlled, parallel group, multicenter, pivotal study that will enroll 1000 subjects at up to 50 sites. All subjects will receive standard medical management based on the American Stroke Association and European Stroke Organization Guidelines. In addition to standard medical management, both groups will undergo the transcranial laser therapy procedure between 4.5 and 24 h of stroke onset. The study population will be randomized into two arms: the sham control group will receive a sham transcranial laser therapy procedure and the transcranial laser therapy group will receive an active transcranial laser therapy procedure. The randomization ratio will be 1:1 and will be stratified to ensure a balanced subject distribution between study arms. STUDY OUTCOMES: The primary efficacy end point is disability at 90 days (or the last rating), as assessed on the modified Rankin Scale, dichotomized as a success (a score of 0-2) or a failure (a score of 3 to 6). PMID- 23013108 TI - Thermodynamic investigations using molecular dynamics simulations with potential of mean force calculations for cardiotoxin protein adsorption on mixed self assembled monolayers. AB - Understanding protein adsorption onto solid surfaces is of critical importance in the field of bioengineering, especially for applications such as medical implants, diagnostic biosensors, drug delivery systems, and tissue engineering. This study proposed the use of molecular dynamics simulations with potential of mean force (PMF) calculations to identify and characterize the mechanisms of adsorption of a protein molecule on a designed surface. A set of model systems consisting of a cardiotoxin (CTX) protein and mixed self-assembled monolayer (SAM) surfaces were used as examples. The set of mixed SAM surfaces with varying topographies were created by mixing alkanethiol chains of different lengths. The results revealed that CTX proteins underwent similar conformal changes upon adsorption onto the various mixed SAMs but showed distinctive characteristics in free energy profiles. Enhancement of the adsorption affinity, i.e., the change in free energy of adsorption, for mixed SAMs was demonstrated by using atomic force microscopic measurements. A component analysis conducted to quantify the physical mechanisms that promoted CTX adsorption revealed contributions from both SAMs and the solvent. Further component analyses of thermodynamic properties, such as the free energy, enthalpy, and entropy, indicated that the contribution from SAMs was driven by enthalpy, and the contribution from the solvent was driven by entropy. The results indicated that CTX adsorption was an entropy-driven process, and the entropic component from the solvent, i.e., the hydrophobic interaction, was the major driving force for CTX adsorption onto SAMs. The study also concluded that the surfaces composed of mixtures of SAMs with different chain lengths promoted the adsorption of CTX protein. PMID- 23013109 TI - Respiratory distress syndrome after elective caesarean section in near term infants: a 5-year cohort study. AB - OBJECTIVE: to assess the incidence of respiratory distress syndrome (RDS) in late preterm (34(0/7)-36(6/7)) and just term (37(0/7)-37(6/7)) infants born via elective caesarean section (CS) in a tertiary care maternity facility. METHODS: retrospective cohort study between 2005 and 2009. Hundred and eighty-eight near term infants, divided in two groups: group A: 125 late preterm (34(0/7)-36(6/7)) and group B: 63 just term (37(0/7)-37(6/7)), from elective CS (except CS after pre-mature rupture of membranes and foetuses presenting congenital malformation) were included. RESULTS: In group A the overall incidence of RDS (RDS at or shortly after birth, requiring respiratory support or oxygen therapy) was 44% (n = 55) vs. 15.9% (n = 10) in group B (p < 0.01). The incidence of SRDS (requiring admission in the neonatal intensive care unit (NICU)) in group A was 13.6% (n = 17) and 3.2% (n = 2) group B (p < 0.01). The risk decreased significantly as gestational age (GA) increased: for RDS, 50.9% at 34 weeks of gestation (WG), 52.5% at 35 WG, 21.5% at 36 WG, and 15.9% at 37 WG; for admission, 30.2% at 34 WG, 25% at 35 WG, 9.4% at 36 WG, and 6.3% at 37 WG. Among late preterm infants with RDS, 30.9% (n = 17) developed severe RDS (SRDS). CONCLUSIONS: Late preterm infants born via elective CS are at high risk for RDS and NICU admission. The risk is influenced by each additional week spent in utero. As the incidence of CS is increasing within this population, new preventative strategies must be sought. PMID- 23013110 TI - Radiofrequency ablation of benign thyroid nodules does not affect thyroid function in patients with previous lobectomy. AB - BACKGROUND: Surgical management of symptomatic benign thyroid nodules in patients with previous lobectomy poses a dilemma for physicians. Radiofrequency (RF) ablation may provide a treatment option that avoids surgery and preserves thyroid function. We evaluated whether RF ablation of benign thyroid nodules affects thyroid function in patients with previous lobectomy. METHODS: A total of 11 patients with 14 thyroid nodules were enrolled using the following criteria: (i) having a predominantly solid nodule; (ii) reporting pressure symptoms or cosmetic problems; (iii) cytological confirmation of benignancy; (iv) no malignant features detected using ultrasound; (v) serum thyroid hormone and thyrotropin (TSH) levels within normal limits; and (vi) refusal of or ineligibility for surgery. Thyroid function, nodule volumes, and clinical concerns were evaluated before RF ablation and during follow-up after RF ablation. RESULTS: The mean follow-up duration after RF ablation was 43.7+/-30.7 months (range=7-92 months). The mean nodule volume was 9.7 mL (0.9-57.6 mL) before the procedure, and was significantly decreased at the last follow-up (p<0.001) with a mean volume reduction rate of 87.2%. The mean symptom score (p=0.003) and cosmetic score (p=0.003) were both significantly decreased at the last follow-up. Levels of TSH, free thyroxine, and triiodothyronine were not significantly different prior to treatment and at the last follow-up (p>0.05), and remained normal in all patients. CONCLUSIONS: In patients with previous lobectomy, RF ablation should be considered as a first-line treatment for symptomatic benign thyroid nodules to preserve thyroid function. PMID- 23013111 TI - Anti-PVC advocacy disguised as science (Response to Carlstedt et al., PVC flooring is related to human uptake of phthalates in infants). PMID- 23013112 TI - Incorporating local land use regression and satellite aerosol optical depth in a hybrid model of spatiotemporal PM2.5 exposures in the Mid-Atlantic states. AB - Satellite-derived aerosol optical depth (AOD) measurements have the potential to provide spatiotemporally resolved predictions of both long and short-term exposures, but previous studies have generally shown moderate predictive power and lacked detailed high spatio- temporal resolution predictions across large domains. We aimed at extending our previous work by validating our model in another region with different geographical and metrological characteristics, and incorporating fine scale land use regression and nonrandom missingness to better predict PM(2.5) concentrations for days with or without satellite AOD measures. We start by calibrating AOD data for 2000-2008 across the Mid-Atlantic. We used mixed models regressing PM(2.5) measurements against day-specific random intercepts, and fixed and random AOD and temperature slopes. We used inverse probability weighting to account for nonrandom missingness of AOD, nested regions within days to capture spatial variation in the daily calibration, and introduced a penalization method that reduces the dimensionality of the large number of spatial and temporal predictors without selecting different predictors in different locations. We then take advantage of the association between grid-cell specific AOD values and PM(2.5) monitoring data, together with associations between AOD values in neighboring grid cells to develop grid cell predictions when AOD is missing. Finally to get local predictions (at the resolution of 50 m), we regressed the residuals from the predictions for each monitor from these previous steps against the local land use variables specific for each monitor. "Out-of-sample" 10-fold cross-validation was used to quantify the accuracy of our predictions at each step. For all days without AOD values, model performance was excellent (mean "out-of-sample" R(2) = 0.81, year-to-year variation 0.79-0.84). Upon removal of outliers in the PM(2.5) monitoring data, the results of the cross validation procedure was even better (overall mean "out of sample"R(2) of 0.85). Further, cross validation results revealed no bias in the predicted concentrations (Slope of observed vs predicted = 0.97-1.01). Our model allows one to reliably assess short-term and long-term human exposures in order to investigate both the acute and effects of ambient particles, respectively. PMID- 23013113 TI - The effect of training set on the classification of honey bee gut microbiota using the Naive Bayesian Classifier. AB - BACKGROUND: Microbial ecologists now routinely utilize next-generation sequencing methods to assess microbial diversity in the environment. One tool heavily utilized by many groups is the Naive Bayesian Classifier developed by the Ribosomal Database Project (RDP-NBC). However, the consistency and confidence of classifications provided by the RDP-NBC is dependent on the training set utilized. RESULTS: We explored the stability of classification of honey bee gut microbiota sequences by the RDP-NBC utilizing three publically available ribosomal RNA sequence databases as training sets: ARB-SILVA, Greengenes and RDP. We found that the inclusion of previously published, high-quality, full-length sequences from 16S rRNA clone libraries improved the precision in classification of novel bee-associated sequences. Specifically, by including bee-specific 16S rRNA gene sequences a larger fraction of sequences were classified at a higher confidence by the RDP-NBC (based on bootstrap scores). CONCLUSIONS: Results from the analysis of these bee-associated sequences have ramifications for other environments represented by few sequences in the public databases or few bacterial isolates. We conclude that for the exploration of relatively novel habitats, the inclusion of high-quality, full-length 16S rRNA gene sequences allows for a more confident taxonomic classification. PMID- 23013114 TI - Meeting the needs of women who use drugs and alcohol in North-east India - a challenge for HIV prevention services. AB - BACKGROUND: The North-east Indian states of Manipur and Nagaland consistently report relatively high HIV prevalence. The targeted HIV prevention interventions in these two states are mostly delivered by non-government organizations (NGOs), and prevention of HIV transmission by injecting drug use is their main focus. Most injecting drug users (IDUs) are male, and the services are primarily tailored to meet their needs, which are not necessarily the same as those for women. This qualitative study describes the health service needs of women who use drugs and alcohol in Manipur and Nagaland, with the goal of identifying strategies and activities that can be implemented by NGOs wanting to improve their reach among vulnerable women. METHODS: In 2009-10, semi-structured in-depth interviews were conducted with 27 key informants and nine focus group discussions (FGDs) with women who use drugs and alcohol, and two FGDs with male IDUs. The thematic areas covered included: the context of female drug and alcohol use; drug and alcohol use patterns; HIV risk behaviours; barriers and facilitators of service use; perceived health needs; and expressed health service needs. The data were recorded, transcribed, translated and thematically analysed. RESULTS: The most problematic substance for women from Nagaland was alcohol, and for women from Manipur it was heroin. The most commonly identified health problems were primarily related to the women's drug and alcohol use, reproductive health and mental health. Other problems of major concern included social exclusion, violence, children's welfare, and financial difficulties. The expressed service needs of these women were women-only integrated health services, women-only detoxification and rehabilitation services, mental health services, desensitization of mainstream health workers, free access to medicines, assistance to meet basic needs, and a safe place for engaging in sex work. CONCLUSION: The expressed health and other service needs of women who use drugs and alcohol in Manipur and Nagaland do not match the services currently provided by HIV prevention NGOs, and this may, in part, account for the relatively poor uptake of these services by women. Strategies and activities that can be implemented by NGOs to strengthen their reach to vulnerable women are identified. However, many of these women's needs are beyond the scope of services typically offered by HIV prevention NGOs, and require a coordinated multi-sectoral response. PMID- 23013115 TI - Isotretinoin: dose, duration and relapse. What does 30 years of usage tell us? AB - With 30 years of clinical use, it is appropriate to review the use of isotretinoin. We now understand that retinoids influence cellular growth, differentiation, morphogenesis and apoptosis, inhibit tumour promotion and malignant cell growth, exert immuno-modulatory actions and alter cellular cohesiveness. This has expanded the indications of isotretinoin from just acne and rosacea to a wide range of inflammatory and malignant skin disorders. While the standard dose of 0.5 to 1 mg/kg per day for 4 months to a cumulative dose of 120-140 mg/kg per day has served us well in the management of acne vulgaris, there is emerging evidence that much lower dosages (as low as 5 mg/day) are just as effective but have significantly fewer adverse effects. Relapse of acne vulgaris continues to be a problem but we are beginning to recognise that this is related less to the cumulative dose and more to the length of sebaceous gland suppression. Other factors important for relapse include a macrocomedonal pattern of acne, smoking and age, both younger (under 14 years) and older (over 25 years). After 30 years of use, we now understand why isotretinoin is such an effective drug. Not only does it clear acne in almost all patients, long-term remission can be achieved in 70-80% of patients with a single course. Important changes in the use of isotretinoin include using a lower daily dose for a longer period of time. New indications continue to emerge, particularly as a potential treatment for both intrinsic and extrinsic (photo) aging. Teratogenicity however, remains a very significant concern. PMID- 23013116 TI - Luna B. Leopold--pioneer setting the stage for modern hydrology. PMID- 23013117 TI - Contribution of cardiac rehabilitation in the management of patients following acute myocardial infarction. PMID- 23013118 TI - The role of the built environment in shaping the health behaviors of physical activity and healthy eating for cardiovascular health. PMID- 23013119 TI - Cardiac computed tomography for the assessment of coronary perfusion: the way forward? PMID- 23013121 TI - Frontiers in cardiovascular biology: London 2012 - a scientific 'olympiad'. AB - Imperial College London (UK) was the showcase for the second in the 'Frontiers in Cardiovascular Biology' series, a biennial meeting of the European Society of Cardiology Council on basic cardiovascular sciences, held from 30 March to 1 April 2012. The aim of this series is to bring researchers together to learn the very latest findings in cardiac and vascular sciences, and to see state-of-the art and developing technologies that could impact cardiovascular research. Five keynote lectures, 25 scientific symposia and two translational lunchtime symposia were grouped around the central themes of bioimaging, degeneration and regeneration, and inflammation. PMID- 23013122 TI - High risk in atrial fibrillation following an ablation procedure: the wide usefulness of the CHADS(2) score. AB - Evaluation of: Chao TF, Ambrose K, Tsao HM et al. Relationship between the CHADS(2) score and risk of very late recurrences after catheter ablation of paroxysmal atrial fibrillation. Heart Rhythm 9(8), 1185-1191 (2012). Limited data are available on the predictors of adverse events and recurrences in patients with atrial fibrillation (AF) after catheter ablation. In a retrospective analysis of 238 patients with paroxysmal AF treated with catheter ablation, it was found that the congestive heart failure, hypertension, age >75 years, diabetes and previous stroke/transient ischemic attack (CHADS(2)) score was an independent predictor of AF recurrences. Moreover, among patients without recurrences at 2 years post-ablation, future recurrence rate during the subsequent follow-up was 64% in those with a CHADS(2) score of less than three, while it was only 3% in patients with a CHADS(2) score of zero. Patients with a higher CHADS(2) score have a different substrate, a more marked disease in the atrium and this may explain the higher rate of recurrence observed after AF ablation. Several more complex scores are available to separately identify the risk of different events in AF: stroke and embolic events, bleeding events, AF recurrences and progression to more sustained forms of AF. Whether it is a better strategy to use the simple CHADS(2) score to rapidly identify a global risk of all future events in AF more widely remains to be determined. PMID- 23013123 TI - The second law of thermodynamics and the heart. AB - The second law of thermodynamics explains the phenomenon of irreversibility and the increasing entropic trend of nature. Similar to human-made machines, living structures are subjected to entropy generation, becoming 'worn' and 'damaged' from use. However, they have the possibility of eluding or deferring these processes. According to nonequilibrium thermodynamics, the heart could be considered as an open dissipative system, since it has the potential to offset the body's increasing entropic burden by using energy to export entropy to the surroundings. By organizing the tissues' molecules in order to perform external work as a result of its ability to provide oxygen and nutrients and remove waste products, the heart maintains the organization of the living structure and acts as an open dissipative system. However, the increase in tissues' randomness and disorder as a result of a number of disease states may be responsible for the intervening cardiac damage and entropy generation. This effect is known as the 'Dorian Gray effect' of the heart. Technical advances, including MRI and 3D echocardiography, may provide a means to improve the understanding of thermodynamic aspects of cardiovascular physiology and heart disease. PMID- 23013124 TI - Should torsemide be the loop diuretic of choice in systolic heart failure? AB - Furosemide is the most widely prescribed loop diuretic in the setting of systolic heart failure (HF), yet torsemide has been shown to have less inter- and intra individual variation in bioavailability and a longer duration of action compared with furosemide. Thus, a systematic review and meta-analysis of randomized controlled trials comparing torsemide versus furosemide in patients with systolic HF using OVID MEDLINE, Excerpta Medica (Embase), Web of Science, PubMed and Google Scholar was performed. Extracted data included study design, sample characteristics, intervention, outcomes and control for potential confounding factors. A DerSimonian and Laird random-effects model was used to compute summary risk ratios for HF and cardiovascular (CV) readmission outcomes. Two randomized trials comparing furosemide with torsemide in 471 patients with systolic HF were identified. Compared to furosemide, torsemide significantly reduced total HF readmissions (relative risk [RR]: 0.41, 95% CI: 0.28-0.61, p < 0.0001) and HF readmissions (RR: 0.53, 95% CI: 0.33-0.84, p = 0.008) as well as CV readmissions (RR: 0.77, 95% CI: 0.60-0.98, p = 0.03) in patients with "at least 1 readmission." Moreover, compared with furosemide, torsemide caused a 14% reduction in all-cause mortality (RR: 0.86 [0.53-1.39], p = 0.54). Compared with furosemide, torsemide significantly reduces HF and CV-related hospital readmissions in systolic HF. Furthermore, torsemide is associated with a trend in reducing all-cause mortality. PMID- 23013125 TI - Exercise-based cardiac rehabilitation in patients with coronary heart disease: meta-analysis outcomes revisited. AB - Cardiac rehabilitation that includes either exercise training alone or exercise training in addition to psychosocial, risk factor management and/or educational interventions is considered a Class I indication [i.e., useful and effective] for patients with coronary heart disease. This overview of six independent cardiac rehabilitation meta-analyses published since 2000 includes a total of 71 randomized clinical trials (n = 13,824 patients) and clearly demonstrates significant clinical outcomes (reduced all-cause and cardiac mortality, nonfatal reinfarction and reduced hospitalization rates) and significant positive changes in modifiable risk factors (total cholesterol, triglycerides and systolic blood pressure). Despite the observation that the elderly, females, minority ethnic groups, low socioeconomic status patients and patients with comorbidities have not been well represented in the randomized clinical trials. Recent guidelines in the UK and USA have concluded with the recommendation that cardiac rehabilitation is reasonable and necessary and should be promoted by healthcare professionals, including senior medical staff. PMID- 23013126 TI - Mechanical bridging to orthotopic heart transplantation in children. AB - This article discusses the main methods currently used in clinical practice to support patients with end-stage heart failure and the research into new devices under development, particularly for young children. With an increasing demand on the supply of organs available for heart transplant, alternative strategies are being sought to maintain patients with end-stage cardiac failure for longer periods of time. Devices that support a failing heart, allowing cardiac recovery in some cases, or more commonly accommodate the time to source a suitable donor heart for transplantation, provide crucial therapeutic options. Extra-corporeal membrane oxygenation and ventricular assist devices are the mainstay of such bridging therapy. Although providing essential support to critically ill patients, they are not without their own significant associated risks. Therapeutic advances aim to reduce the risks associated with these bridging systems, and new artificial devices are being developed to improve this supportive care. PMID- 23013127 TI - Panoptic total cardiovascular risk prediction using all predictors versus optimized risk assessment using variable subsets. AB - Cardiovascular disease remains the primary cause of mortality and morbidity in the developed world. Risk scores can provide clinical risk stratification and many exist for use in cardiovascular disease prevention and treatment. Cardiovascular risk scores predict mortality, coronary heart disease and other vascular disease using risk predictors such as patient age, sex, BMI, smoking history, cholesterol level, blood pressure, glucose level or diabetes diagnosis, family history of cardiovascular disease and creatinine. While the risk scores in existence are excellent for risk stratification, actual use in a clinical environment is lagging behind the rate of new risk score creation. Future research should focus on how to utilize risk scores most effectively and efficiently in clinical practice. PMID- 23013128 TI - The once and future state of percutaneous mitral valve repair. AB - There has been a great deal of interest in percutaneous mitral valve repair techniques in recent years, with several devices undergoing animal testing and clinical trials. Percutaneous annuloplasty and leaflet repair devices are currently in development, and while safety rates have generally been equal or superior to conventional surgical techniques, efficacy has been suboptimal. Most current percutaneous mitral valve repair devices can only reduce regurgitant volumes by approximately 20-40%, but these reductions may be enough to treat high risk patients, including the elderly and those with comorbidities, who are otherwise ineligible for surgery. An analysis of how these devices alter the geometry and mechanics of the mitral valve apparatus can provide insight into long-term efficacy and durability and may lead to improvements in the reduction of mitral regurgitation. In the future, multiple percutaneous techniques may be utilized in combination to increase overall efficacy. In this article, we report on percutaneous mitral valve repair techniques with published clinical or animal data. PMID- 23013130 TI - Inhibition of extracellular signal-regulated kinase activity improves cognitive function in Tg2576 mice. AB - 1. Deposition of beta-amyloid (Abeta) peptide is a defining pathological hallmark of Alzheimer's disease (AD) and is involved in memory impairment. Evidence suggests that activation of an extracellular signal-regulated kinase (ERK) pathway is related to Abeta accumulation. Thus, the aim of the present study was to investigate the effects of an ERK inhibitor (U0126) on amyloidogenesis and cognitive function in Tg2576 mice. 2. Tg2576 mice were injected with U0126 (20 mg/kg, i.p.) or vehicle (1% dimethyl sulphoxide in sterile saline) once a day for 7 days and then cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, immunostaining, western blot analysis, ELISA and enzyme activity assays were used to examine the degree of Abeta deposition in the brains of Tg2576 mice. 3. Our results showed that U0126 attenuated memory impairment and inhibited Abeta deposition in the brains of Tg2576 mice. Further experiments revealed that the inhibition of Abeta deposition by U0126 was due to a reduction in beta-secretase and amyloid precursor protein expression in the brains of U0126-treated Tg2576 mice. 4. These results suggest that the ERK pathway is associated with Abeta accumulation and consequent memory dysfunction in Tg2576 mice and that inhibition of the ERK pathway may be an appropriate intervention in the treatment of AD. PMID- 23013132 TI - Matrix metalloproteinase-2 inhibition by temocapril and its important role in peritoneal transport. AB - 1. Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodelling during peritoneal injury caused by peritoneal dialysis (PD), but MMP-2 inhibitors have not yet been used clinically. Recently, it was reported that captopril, an angiotensin-converting enzyme inhibitor (ACEI), can inhibit MMP-2. 2. To investigate the potential usefulness of ACEI during PD, the molecular interaction between the MMP-2 active site and the active form of temocapril (temocaprilat) was investigated using molecular modelling. Furthermore, the effects of temocapril on MMP-2 activity in peritoneal effluents and the peritoneal solute transport rate of PD patients were determined. 3. Temocaprilat bound to the MMP-2 active centre and recognized two hydrophobic substrate-binding sites in the MMP-2 molecular model. Matrix metalloproteinase-2 activity in peritoneal effluents was directly inhibited by temocaprilat (IC(50) 0.47 MUmol/L). In one patient given temocapril, the peritoneal solute transport rate decreased gradually during PD. 4. Temocapril may prove to be an important candidate for development as a novel therapeutic agent for MMP-2 inhibition to prevent peritoneal injury caused by PD. PMID- 23013131 TI - Aldosterone induces p21-regulated apoptosis via increased synthesis and secretion of tumour necrosis factor-alpha in human proximal tubular cells. AB - 1. Aldosterone has been shown to mediate p21-dependent cellular senescence in rat kidney proximal tubules in vivo and in cultured human proximal tubular cells. The p21-induced senescent cells express higher levels of apoptotic cytokines, such as tumour necrosis factor (TNF)-alpha compared with non-senescent cells. The aim of the present study was to investigate the hypothesis that aldosterone increases proximal tubular apoptosis by increasing the secretion of apoptosis-inducing factors through a p21-dependent mechanism. 2. Human proximal tubular cells were incubated with aldosterone (10 nmol/L) and cell senescence was detected by senescence-associated beta-galactosidase staining and expression of p21. Apoptosis was analysed by terminal deoxyribonucleotidyl transferase-mediated dUTP digoxigenin nick end-labelling and annexin/propidium iodide staining, whereas p21 localization was determined by immunofluorescence. 3. Exposure of cells to aldosterone for 3 or 5 days increased senescence-associated beta-galactosidase staining, p21 and TNF-alpha mRNA expression and secretion of TNF-alpha into the culture medium. These changes were abolished by gene silencing of p21. Aldosterone failed to increase the number of apoptotic cells on day 3, but did increase them on day 5. A neutralizing antibody against TNF-alpha prevented the aldosterone-induced apoptotic changes. Aldosterone did not affect localization of p21. 4. These findings indicate that aldosterone increases TNF-alpha synthesis and secretion in proximal tubular cells via p21/senescence-dependent cell phenotypic changes and that the TNF-alpha secreted plays an important role as a paracrine factor in mediating cell apoptosis, indicating a possible involvement in aldosterone-induced renal damage. PMID- 23013133 TI - Adenosine A(2A) receptor antagonists are broad facilitators of antinicotinic neuromuscular blockade monitored either with 2 Hz train-of-four or 50 Hz tetanic stimuli. AB - 1. The 2 Hz train-of-four ratio (TOF(ratio)) is used to monitor the degree of patient curarization. Using a rat phrenic nerve-hemidiaphragm preparation, we showed that antinicotinic agents, such as hexamethonium, d-tubocurarine and pancuronium, but not cisatracurium, decreased contractions produced by physiological nerve activity patterns (50 Hz) more efficiently than those caused by 2 Hz trains. Uncertainty about the usefulness of the TOF(ratio) to control safe recovery from curarization prompted us to investigate the muscarinic and adenosine neuromodulation of tetanic (50 Hz) fade induced by antinicotinic agents at concentrations that cause a 25% reduction in the TOF(ratio) (TOF(fade)). 2. Tetanic fade caused by d-tubocurarine (1.1 MUmol/L), pancuronium (3 MUmol/L) and hexamethonium (5.47 mmol/L) was attenuated by blocking presynaptic inhibitory muscarinic M(2) and adenosine A(1) receptors with methoctramine (1 MUmol/L) and 1,3-dipropyl-8-cyclopentylxanthine (2.5 nmol/L), respectively. These compounds enhanced rather than decreased tetanic fade induced by cisatracurium (2.2 MUmol/L), but they consistently attenuated cisatracurium-induced TOF(fade). The effect of the M(1) receptor antagonist pirenzepine (10 nmol/L) on fade produced by antinicotinic agents at 50 Hz was opposite to that observed with TOF stimulation. Blockade of adenosine A(2A) receptors with ZM 241385 (10 nmol/L) attenuated TOF(fade) caused by all antinicotinic drugs tested, with the exception of the 'pure' presynaptic nicotinic antagonist hexamethonium. ZM 241385 was the only compound tested in this series that facilitated recovery from tetanic fade produced by cisatracurium. 3. The data suggest that distinct antinicotinic relaxants interfere with fine-tuning neuromuscular adaptations to motor nerve stimulation patterns via activation of presynaptic muscarinic and adenosine receptors. These results support the use of A(2A) receptor antagonists together with atropine to facilitate recovery from antinicotinic neuromuscular blockade. PMID- 23013134 TI - Technetium-99 conjugated with methylene diphosphonate inhibits receptor activator of nuclear factor-kappaB ligand-induced osteoclastogenesis. AB - 1. In the present study, we investigated the effects of technetium-99 conjugated with methylene diphosphonate ((99)Tc-MDP), an agent used in radionuclide therapy, on receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis and explored the underlying mechanisms. 2. The murine macrophage cell line RAW264.7 and bone marrow-derived-macrophages from C57BL/6 mice (BMM) were used as models for osteoclastogenesis in vitro. The expression of some key factors in RANKL (50 ng/mL)-induced osteoclastogenesis in RAW264.7 cells was investigated by flow cytometry and real-time reverse transcription-polymerase chain reaction (RT-PCR). To detect multinucleated osteoclast formation, RAW264.7 cells were induced with RANKL for 4 days, whereas BMM were induced by 50 ng/mL RANKL and 20 ng/mL macrophage colony-stimulating factor for 7 days, before being stained with tartrate-resistant acid phosphatase. 3. Osteoclastogenesis was evaluated using the osteoclast markers CD51, matrix metalloproteinase (MMP)-9 and cathepsin K. At 0.01 MUg/mL, (99)Tc-MDP significantly inhibited RANKL-induced osteoclastogenesis without any cytotoxicity. In addition, (99)Tc-MDP abolished the appearance of multinucleated osteoclasts. 4. Real-time RT-PCR analysis of transcription factor expression revealed that (99)Tc-MDP inhibited the expression of c-Fos and nuclear factor of activated T cells. In addition, (99)Tc-MDP inhibited the expression of the inflammatory factors interleukin (IL)-6, tumour necrosis factor-alpha and IL-1beta. Finally, (99)Tc-MDP inhibited the activation of mitogen-activated protein kinases in RAW264.7 cells following RANKL stimulation. 5. In conclusion, (99)Tc-MDP possesses anti-osteoclastogenic activity against RANKL-induced osteoclast formation. PMID- 23013135 TI - MiR-150 is associated with poor prognosis in esophageal squamous cell carcinoma via targeting the EMT inducer ZEB1. AB - The association of microRNAs (miRs) with cancer progression has been established in many cancers including esophageal squamous cell carcinoma (ESCC). A public microarray database showed that the expression of miR-150 was lower in ESCC than in normal esophageal mucosa. Here, we focused on ZEB1, epithelial-mesenchymal transition (EMT)-inducer, as a target gene of miR-150 based on in silico predictions. The purpose of this study was to clarify the clinicopathological significance of miR-150 in ESCC, and to investigate miR-150's EMT-regulatory ability. Quantitative RT-PCR was used to evaluate miR-150 expression in 108 curative resected ESCC samples to determine the clinicopathological significance. Moreover, we examined the in vitro and in vivo function of miR-150 via degradation of ZEB1. MiR-150 expression was significantly lower in cancer tissues compared to adjacent non-cancerous tissues (P < 0.001). Low expression of miR-150 in ESCC contributed to malignant potential, such as tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, clinical staging, and poor prognosis (P < 0.05). In vitro assays showed that EMT-inducer-ZEB1 is a new direct target of miR-150. Moreover, miR-150 induced MET-like changes in TE-8 cells through ZEB1 degradation (e.g., E-cadherin expression, vimentin repression, epithelial morphology, and suppression of migration ability), and significantly inhibited tumorigenicity and tumor growth in a mouse xenograft model. Analysis of the regulation of ZEB1 by miR-150 could provide new insights into preventing metastasis and also suggests novel targeted therapeutic strategies in ESCC. PMID- 23013136 TI - Formation and antifouling properties of amphiphilic coatings on polypropylene fibers. AB - We describe the formation of amphiphilic polymeric assemblies via a three-step functionalization process applied to polypropylene (PP) nonwovens and to reference hydrophobic self-assembled n-octadecyltrichlorosilane (ODTS) monolayer surfaces. In the first step, denatured proteins (lysozyme or fibrinogen) are adsorbed onto the hydrophobic PP or the ODTS surfaces, followed by cross-linking with glutaraldehyde in the presence of sodium borohydride (NaBH(4)). The hydroxyl and amine functional groups of the proteins permit the attachment of initiator molecules, from which poly (2-hydroxyethyl methacrylate) (PHEMA) polymer grafts are grown directly through "grafting from" atom transfer radical polymerization. The terminal hydroxyls of HEMA's pendent groups are modified with fluorinating moieties of different chain lengths, resulting in amphiphilic brushes. A palette of analytical tools, including ellipsometry, contact angle goniometry, Fourier transform infrared spectroscopy in the attenuated total reflection mode, and X ray photoelectron spectroscopy is employed to determine the changes in physicochemical properties of the functionalized surfaces after each modification step. Antifouling properties of the resultant amphiphilic coatings on PP are analyzed by following the adsorption of fluorescein isothiocyanate-labeled bovine serum albumin as a model fouling protein. Our results suggest that amphiphilic coatings suppress significantly adsorption of proteins as compared with PP fibers or PP surfaces coated with PHEMA brushes. The type of fluorinated chain grafted to PHEMA allows modulation of the surface composition of the topmost layer of the amphiphilic coating and its antifouling capability. PMID- 23013137 TI - HIV prevalence and incidence among women at higher risk of infection in Addis Ababa, Ethiopia. AB - This study aimed to estimate HIV incidence among women at higher HIV risk in Addis Ababa, Ethiopia using cross-sectional data. To refine the estimate, we sought to determine a local correction factor by estimating a false recent rate for the BED assay. The overall study had two parallel phases: cross-sectional incidence and BED false recent (BED FR). A total of 1856 women at higher HIV risk were enrolled into the cross-sectional phase. For the BED FR, 500 women and 70 men with known HIV infection of greater than 12 months were enrolled. Rapid HIV tests were used to assess participant HIV status. Samples from women with positive results on HIV rapid testing were then analyzed using the BED assay to determine incident HIV infections. The overall HIV prevalence was 11.3%, with women greater than 25 years old having a higher prevalence (26.5% vs. 7.9% for younger women). The overall unadjusted HIV incidence was 3.3%. The estimated HIV incidence was 2.6% when adjusted using the locally derived false recent rate of 3.5%. Similar incidence rates were found between the younger and older age groups. This is one of the first field-based studies of HIV incidence in Ethiopia; it demonstrates that there is sufficient incidence to warrant further HIV prevention efforts among women at higher risk of HIV infection. PMID- 23013139 TI - Hepatic resection for bilateral hepatolithiasis: a 20-year experience. AB - BACKGROUND: There is increasing evidence showing that hepatic resection is probably the best definitive treatment for unilateral hepatolithiasis. However, the role of hepatic resection for bilateral hepatolithiasis is rarely mentioned in the literature. METHODS: We retrospectively reviewed 197 patients who underwent hepatic resection for hepatolithiasis in Changhua Christian Hospital from December 1987 to December 2007. A total of 156 patients with unilateral hepatolithiasis were defined as the UNI group (control group), and 41 patients with bilateral hepatolithiasis were defined as the BI group (study group). The short- and long-term outcomes were measured. RESULTS: The BI group had longer operating time (200 min versus 173 min, P = 0.006), lower immediate stone clearance rate (56.1% versus 91.7%, P < 0.001), lower final stone clearance rate (75.6% versus 94.9%, P = 0.001), higher rate of stone recurrence (22.6% versus 6.1%, P = 0.009) and higher disease-related mortality (19.5% versus 5.1%, P = 0.006). Thirty patients with bilateral peripheral stones were indicated for bilateral hepatectomy, but only 20 (66.7%) of them actually underwent the proposed procedure. Of the patients who did not achieve immediate stone clearance, bilateral peripheral stones represented 88.9% (P = 0.044). Of the patients who had stone recurrence, patients less than 35 years old represented 42.9% (P = 0.007). CONCLUSION: Bilateral hepatolithiasis has worse outcomes than unilateral hepatolithiasis after being treated with hepatic resection. Regarding bilateral peripheral stones, there is often a discrepancy between the extent of stone-affected parenchyma and that of final liver resection, resulting in a lower immediate stone clearance rate. A higher stone recurrence rate was observed among younger population. PMID- 23013138 TI - Markers of circulating tumour cells in the peripheral blood of patients with melanoma correlate with disease recurrence and progression. AB - BACKGROUND: Multimarker quantitative real-time polymerase chain reaction (qRT PCR) represents an effective method for detecting circulating tumour cells in the peripheral blood of patients with melanoma. OBJECTIVES: To investigate whether the phenotype of circulating melanoma cells represents a useful indicator of disease stage, recurrence and treatment efficacy. METHODS: Peripheral blood was collected from 230 patients with melanoma and 152 healthy controls over a period of 3years and 9months. Clinical data and blood samples were collected from patients with primary melanoma (early stages, 0-II, n=154) and metastatic melanoma (late stages, III-IV, n=76). Each specimen was examined by qRT-PCR analysis for the expression of five markers: MLANA, ABCB5, TGFbeta2, PAX3d and MCAM. RESULTS: In total, 212 of the patients with melanoma (92%) expressed markers in their peripheral blood. Two markers, MLANA and ABCB5, had the greatest prognostic value, and were identified as statistically significant among patients who experienced disease recurrence within our study period, being expressed in 45% (MLANA) and 49% (ABCB5) of patients with recurrence (P=0.001 and P=0.031, respectively). For patients administered nonsurgical treatments, MCAM expression correlated with poor treatment outcome. CONCLUSIONS: Circulating tumour cells were detectable at all stages of disease and long after surgical treatment, even when patients were considered disease free. Specifically, expression of ABCB5 and MLANA had significant prognostic value in inferring disease recurrence, while MCAM expression was associated with poor patient outcome after treatment, confirming multimarker qRT-PCR as a potential technique for monitoring disease status. PMID- 23013140 TI - Colorectal cancer targeted Irinotecan-Assam Bora rice starch based microspheres: a mechanistic, pharmacokinetic and biochemical investigation. AB - The purpose of this investigation was to evaluate the colon-targeted Irinotecan Hydrochloride (ITC-HCl) loaded microspheres by pharmacokinetic and biochemical studies. The microspheres were prepared by double emulsion solvent evaporation method with natural polymer Assam Bora rice starch. The microspheres were characterized for their micromeritics properties, incorporation efficiency, in vitro and in vivo drug release studies. The release study confirmed the insignificant release of ITC-HCl in physiological condition of stomach and small intestine and major drug release in the caecal content. In vivo release study of the optimized microsphere was compared with immediate release (IR) ITC-HCl. ITC HCl was distributed predominantly in the upper GI tract from the IR, whereas ITC HCl was distributed primarily to the lower part of GI tract from the microspheres formulation. Enhanced levels of liver enzymes were found in animals given IR ITC HCl as well as augmented levels of serum albumin, creatinine, leucocytopenia and thrombocytopenia was also observed. In summary, Assam Bora rice starch microspheres exhibit slow and extended release of ITC-HCl over longer periods of time with reduced systemic side-effects. PMID- 23013142 TI - Rapid formation of secondary organic aerosol from the photolysis of 1 nitronaphthalene: role of naphthoxy radical self-reaction. AB - The chemical composition of secondary organic aerosol (SOA) formed from the photolysis of 1-nitronaphthalene in a series of simulation chamber experiments has been investigated using an aerosol time-of-flight mass spectrometer (ATOFMS). The resulting SOA is characterized by the presence of a dimer (286 Da) proposed to be formed through the self-reaction of naphthoxy radicals along with the expected product nitronaphthol. The molecular formulas of the SOA products were confirmed by collecting filter samples and analyzing the extracts using ultrahigh resolution mass spectrometry. Further evidence for the radical self-reaction mechanism was obtained by photolyzing 1-nitronaphthalene in the presence of excess nitrobenzene, where it was shown that the resulting SOA contained a product consistent with the cross-reaction of phenoxy and naphthoxy radicals. The naphthoxy dimer was formed from the photolysis of 1-nitronaphthalene under a variety of different experimental conditions including the presence of excess butyl ether as an OH scavenger and the presence of ambient air and particles. However, formation of the dimer was suppressed when 1-nitronaphthalene was photolyzed in the presence of excess NO and nitronaphthol was instead found to be the dominant particle-phase product indicating that the yield of the dimer is dependent upon the concentration of pre-existing NO(x). The results of this work suggest that photolysis of 1-nitronaphthalene represents a previously unidentified pathway to SOA formation in the troposphere. Analogous mechanisms may also be important for other nitrated polycyclic aromatic hydrocarbons. PMID- 23013141 TI - Web-based screening and brief intervention for poly-drug use among teenagers: study protocol of a multicentre two-arm randomized controlled trial. AB - BACKGROUND: Mid to late adolescence is characterised by a vulnerability to problematic substance use since the consumption of alcohol and illicit drugs is frequently initiated and increased in this life period. While the detrimental long- and short-term effects of problematic consumption patterns in adolescence pose a major public health concern, current prevention programs targeting alcohol and other substance-using adolescents are scarce. The study described in this protocol will test the effectiveness of a web-based brief intervention aimed at reducing problematic alcohol use and promoting abstinence from illegal drugs in adolescents with risky substance use aged 16 to 18 years old in four EU countries. METHODS/DESIGN: To determine the effectiveness of our web-BI, we apply a two-arm randomized controlled trial (RCT) study design, with baseline assessment at study entry and a three month follow-up assessment. Adolescents aged 16 to 18 years from Belgium, the Czech Republic, Germany, and Sweden will be randomly assigned to either the fully electronically delivered brief intervention group (N = 400) or an assessment only control group (N = 400) depending on their screening for risky substance use (using the CRAFFT). Recruitment, informed consent, randomization, intervention and follow-up will be implemented online. Primary outcomes are reductions in frequency and quantity of use of alcohol and drugs other than alcohol over a 30 day period, as well as consumption per typical occasion. Secondary outcomes concern changes in substance use related cognitions including the constructs of the Theory of Planned Behaviour, implementation intentions, and stages of change. Moreover the study addresses a number of moderator variables, including age of first use, general psychopathology and quality of parent-child relationship. DISCUSSION: The trial is expected to contribute to the growing literature on theory- and web-based brief interventions for adolescents. We will explore the potential of using web-based technologies as means of delivering preventive interventions. In doing so we are among the first to target the relevant group of young poly-drug users in Europe. TRIAL REGISTRATION: Current Controlled Trials ISRCTN95538913. PMID- 23013143 TI - The effect of hypoxia and exercise on heart rate variability, immune response, and orthostatic stress. AB - Hypoxia with exercise is commonly used to enhance physiological adaptation in athletes, but may prolong recovery between training bouts. To investigate this, heart rate variability (HRV), systemic immune response, and response to an orthostatic challenge were measured following exercise in hypoxia and air. Eleven trained men performed a 10-km cycling time trial breathing hypoxia (16.5 +/- 0.5% O(2)) or air. HRV and the heart rate response to an orthostatic challenge were measured for 3 days before and after each trial, while venous blood samples were collected pre-, 0, 2, and 24 h post-exercise. Hypoxia had no significant effect compared with air. Subgroup analysis of those who had a drop in oxyhemoglobin saturation (SpO(2)) > 10% between hypoxia and air compared with those who did not, demonstrated a significantly altered HRV response (?HFnu: -2.1 +/- 0.9 vs 8.6 +/- 9.3, ?LFnu: 2.1 +/- 1.0 vs -8.6 +/- 9.4) at 24 h post-exercise and increased circulating monocytes (1.3 +/- 0.2 vs 0.8 +/- 0.2 * 10(9) /L) immediately post-hypoxic exercise. Exercise and hypoxia did not change HRV or the systemic immune response to exercise. However, those who had a greater desaturation during hypoxic exercise had an attenuate recovery 24 h post-exercise and may be more susceptible to accumulating fatigue with subsequent training bouts. PMID- 23013144 TI - Copper bromide laser for facial telangiectasia: a dose response evaluation. AB - Facial telangiectases are small dilated vessels that are visible on the skin surface. They are a cosmetic disfigurement for millions of people, making their treatment one of the most frequently requested procedures in dermatology. Several treatment choices are available, including a variety of lasers. The purpose of this study was to evaluate the results, using a copper bromide laser, of variable energy levels related to vessel size and location, including side effects, and to survey patient assessment of benefit and tolerance. Two groups of 19 patients were treated at 23 J/cm(2) and 28 J/cm(2) , and 32 J/cm(2) and 38 J/cm(2) , respectively. Only facial telangiectasias were treated. Benefit was seen at all energy settings. Little additional benefit was noted with energy increase alone, but it was noted with a second treatment. This study showed that the copper bromide laser is a very effective, safe, and well tolerated treatment for facial telangiectasia at all four tested energy levels. PMID- 23013145 TI - Reaction-diffusion wave model for self-assembled network formation of poly(dA).poly(dT) DNA on mica and HOPG surfaces. AB - Deoxyribonucleic acid (DNA) is a vital molecule for life since it contains genetic information. However, DNA has recently been reported to have unique properties that make it suitable for bionanoelectronic applications, such as the possibility of electrical conductivity and self-organisation. Self-assembled DNA network structures have been observed on several substrates, but the detailed self-assembly mechanism has yet to be determined. The present study investigates self-assembled structures of DNA both theoretically and experimentally. We developed a reaction-diffusion model and used it to investigate pattern formations observed by atomic force microscopy. The computational results qualitatively replicate the network patterns of DNA molecules based on a quantitative agreement with the surface size and timescale. The model can account for the effect of the DNA concentration on pattern formation. Furthermore, peculiar geometric patterns are simulated for mica and highly oriented pyrolytic graphite surfaces. PMID- 23013147 TI - His encouragement of students and young scholars and his willingness and skill at collaborative work are renowned. Preface. PMID- 23013149 TI - Iridium-catalyzed alkylation of methylquinolines with alcohols. AB - Iridium-catalyzed alkylation of methylquinolines at the methyl substituent was achieved using alcohols as alkylating agents. The reaction proceeded through a transfer hydrogenation pathway from the alcohol to the Ir complex, affording an aldehyde and Ir-H species, followed by base-assisted aldol condensation and hydrogenation. This method provides an atom-economical and convenient route to alkylquinolines from easily accessible methylquinolines. PMID- 23013150 TI - Renal stone disease and obesity: what is important for urologists and nephrologists? AB - Currently, obesity has reached an epidemic stage and represents a challenge for health authorities across the globe. Certainly, with emergence of obesity epidemic, we started to see an increase in the prevalence of chronic kidney disease (CKD) and nephrolithiasis. Interestingly, epidemiologic studies have shown that the incident stone risk increases with body mass index (BMI), and no further increase in risk is noticed when the BMI > 30 kg/m(2). Furthermore, metabolic syndrome and diabetes are also associated with an increase in the incidence of renal stones disease. The shared links between these metabolic disorders are insulin resistance. Furthermore, insulin resistance is thought to alter renal acid-base metabolism, resulting in a lower urine pH and increased risk of uric acid stone disease. Obesity is also associated with excess nutritional intake of lithogenic substances such as refined sugars, low fluid intake, calcium, oxalate, and purine-rich foods. Obesity is also associated with an increase in incidence of urinary tract infection. Recent reports suggested that renal stone disease carries risk of myocardial infarction, progression of CKD, and diabetes. Alarmingly, orlistat (obesity medication) and bariatric surgery are associated with hyperoxaluria and associated stone formation and even oxalate nephropathy. Certainly, the many health risks of obesity, including nephrolithiasis, will add more burden on urologists and nephrologists. Shockwave lithotripsy, percutaneous nephrolithotomy, and ureteroscopy are all safe procedures in obese individuals. Further research is urgently needed to address the pathophysiology and management of obesity-induced renal stones disease. PMID- 23013151 TI - Early ischaemic diffusion lesion reduction in patients treated with intravenous tissue plasminogen activator: infrequent, but significantly associated with recanalization. AB - BACKGROUND AND PURPOSE: Recent studies have shown that thrombolysis could decrease or eliminate ischaemic diffusion-weighted imaging lesions. However, the features of such diffusion-weighted imaging lesion reduction are not well known. AIMS: To clarify, the frequency of and factors associated with lesion reduction were investigated. METHODS: Patients given intravenous tissue plasminogen activator therapy within three-hours of onset were prospectively enrolled. Magnetic resonance imaging including diffusion-weighted imaging and magnetic resonance angiography was performed four times: on admission, just after intravenous tissue plasminogen activator, 24 h from intravenous tissue plasminogen activator, and seven-days after intravenous tissue plasminogen activator. The diffusion-weighted imaging lesion volume was measured by manual trace using National Institutes of Health imaging software. All patients were divided into three groups according to the early diffusion-weighted imaging lesion volume change from admission to just after intravenous tissue plasminogen activator: the lesion reduction group (>20% decrease); the lesion growth group (>20% increase); and the lesion unchanged group. RESULTS: In total, 105 patients [56 males, median age 77 (interquartile range 70-83) years, and National Institutes of Health Stroke Scale score 16 (10-22)] were enrolled. Early diffusion-weighted imaging lesion reduction was observed in seven (7%) patients. The decreased lesion increased subsequently. On multivariate analysis, the glucose level on admission (odds ratio 0.95, 95% confidence interval 0.91 to 0.99, P = 0.045) and early recanalization (odds ratio 15.7, 95% confidence interval 1.61 to 153, P = 0.018) were independently related to early lesion reduction. CONCLUSION: Early diffusion-weighted imaging lesion reduction was observed in 7% of patients treated with intravenous tissue plasminogen activator. The decreased lesion increased subsequently. Initial glucose level and early recanalization were independently associated with early diffusion-weighted imaging lesion reduction. PMID- 23013153 TI - Diazo compounds and N-tosylhydrazones: novel cross-coupling partners in transition-metal-catalyzed reactions. AB - Transition-metal-catalyzed carbene transformations and cross-couplings represent two major reaction types in organometallic chemistry and organic synthesis. However, for a long period of time, these two important areas have evolved separately, with essentially no overlap or integration. Thus, an intriguing question has emerged: can cross-coupling and metal carbene transformations be merged into a single reaction cycle? Such a combination could facilitate the development of novel carbon-carbon bond-forming methodologies. Although this concept was first explored about 10 years ago, rapid developments inthis area have been achieved recently. Palladium catalysts can be used to couple diazo compounds with a wide variety of organic halides. Under oxidative coupling conditions, diazo compounds can also react with arylboronic acids and terminal alkynes. Both of these coupling reactions form carbon-carbon double bonds. As the key step in these catalytic processes, Pd carbene migratory insertion plays a vital role in merging the elementary steps of Pd intermediates, leading to novel carbon-carbon bond formations. Because the diazo substrates can be generated in situ from N-tosylhydrazones in the presence of base, the N-tosylhydrazones can be used as reaction partners, making this type of cross-coupling reaction practical in organic synthesis. N-Tosylhydrazones are easily derived from the corresponding aldehydes or ketones. The Pd-catalyzed cross-coupling of N-tosylhydrazones is considered a complementary reaction to the classic Shapiro reaction for converting carbonyl functionalities into carbon-carbon double bonds. It can also serve as an alternative approach for the Pd-catalyzed cross-coupling of carbonyl compounds, which is usually achieved via triflates. The combination of carbene formation and cross-coupling in a single catalytic cycle is not limited to Pd catalyzed reactions. Recent studies of Cu-, Rh-, Ni-, and Co-catalyzed cross coupling reactions with diazo compounds or N-tosylhydrazones show that these transformations also work with other transition metals, demonstrating the generality of the diazo compounds as new cross-coupling partners in transition metal-catalyzed coupling reactions. PMID- 23013152 TI - Light-triggered concomitant enhancement of magnetic resonance imaging contrast performance and drug release rate of functionalized amphiphilic diblock copolymer micelles. AB - Polymeric drug nanocarriers integrated with diagnostic and sensing functions are capable of in situ monitoring the biodistribution of chemotherapeutic drugs and imaging/contrasting agents, which enables the establishment of image-guided personalized cancer therapeutic protocols. Responsive multifunctional theranostic nanocarriers possessing external stimuli-tunable drug release rates and imaging signal intensities represent another promising direction in this field. In this work, we fabricated responsive amphiphilic diblock copolymer micelles exhibiting light-triggered hydrophobic-hydrophilic transition within micellar cores and the concomitant enhancement of magnetic resonance (MR) imaging contrast performance and release rate of physically encapsulated hydrophobic drugs. POEGMA-b-P(NIPAM co-NBA-co-Gd) diblock copolymer covalently labeled with Gd(3+) complex (Gd) in the light-responsive block was synthesized at first, where OEGMA, NIPAM, and NBA are oligo(ethylene glycol) monomethyl ether methacrylate, N-isopropylacrylamide, and o-nitrobenzyl acrylate, respectively. The amphiphilic diblock copolymer spontaneously self-assembles in aqueous solution into micellar nanoparticles possessing hydrophobic P(NIPAM-co-NBA-co-Gd) cores and hydrophilic POEGMA coronas, which can physically encapsulate doxorubicin (Dox) as a model chemotherapeutic drug. Upon UV irradiation, hydrophobic NBA moieties within micellar cores transform into hydrophilic carboxyl derivatives, triggering micelle microstructural changes and core swelling. During this process, the microenvironment surrounding Gd(3+) complexes was subjected to a transition from being hydrophobic to hydrophilic, leading to the enhancement of MR imaging contrast performance, that is, ~1.9-fold increase in longitudinal relaxivity (r(1)). In addition, the release rate of encapsulated Dox was also enhanced (~65% of Dox release in 12 h upon UV irradiation versus ~47% Dox release in 25 h for the control). The reported strategy of light-triggered coenhancement of MR imaging contrast performance and drug release profiles represents a general route to the construction of next generation smart polymeric theranostic nanocarriers. PMID- 23013154 TI - Characterization of a malignant T-cell line established from a rare case of CD8+ CD56+ Sezary syndrome. PMID- 23013155 TI - Factors affecting acceptability and usability of technological approaches to diabetes self-management: a case study. AB - PURPOSE: This study explored the impact of personal digital assistant (PDA) features, users' perceptions, and other factors that may have hindered PDA acceptability and usability as technology advances in e-health diabetes self management. STUDY DESIGN AND RESULTS: An ongoing study on PDA usage is set within the context of the advancements of Web 2.0 for type 2 diabetes mellitus (T2DM) self-management e-interventions. Advancements in technology as it relates to the future of T2DM mobile applications are discussed as possible deterrents of PDA acceptability and usability. CONCLUSIONS: This case study illustrates the importance of addressing factors that may impede the adoption of electronic devices intended for sustained health behavior change. Recognizing the importance of individual perception within the context of rapid technological advancements is imperative for designing future health interventions. Incorporating electronic devices that individuals are more inclined to utilize, such as smartphones, as the platform for health interventions is a promising strategy to improve acceptability and usability, allowing researchers to more accurately assess the health benefits of self-management programs. PMID- 23013156 TI - Protein diffusiophoresis and salt osmotic diffusion in aqueous solutions. AB - Diffusion of a solute can be induced by the concentration gradient of another solute in solution. This transport mechanism is known as cross-diffusion. We have investigated cross-diffusion in a ternary protein-salt-water system. Specifically, we measured the two cross-diffusion coefficients for the lysozyme NaCl-water system at 25 degrees C and pH 4.5 as a function of protein and salt concentrations by Rayleigh interferometry. One cross-diffusion coefficient characterizes salt osmotic diffusion induced by a protein concentration gradient, and is related to protein-salt thermodynamic interactions as described by the theories of Donnan membrane equilibrium and protein preferential hydration. The other cross-diffusion coefficient characterizes protein diffusiophoresis induced by a salt concentration gradient, and is described as the difference between a preferential-interaction coefficient and a transport parameter. We first relate our experimental results to the protein net charge and the thermodynamic excess of water near the protein surface. We then extract the Stefan-Maxwell diffusion coefficient describing protein-salt interactions in water. We find that the value of this coefficient is negative, contrary to the friction interpretation of Stefan-Maxwell equations. This result is explained by considering protein hydration. Finally, protein diffusiophoresis is quantitatively examined by considering electrophoretic and hydration effects on protein migration and utilized to accurately estimate lysozyme electrophoretic mobility. To our knowledge, this is the first time that protein diffusiophoresis has been experimentally characterized and a protein-salt Stefan-Maxwell diffusion coefficient reported. This work represents a significant contribution for understanding and modeling the effect of concentration gradients in protein-salt aqueous systems relevant to diffusion-based mass-transfer technologies and transport in living systems. PMID- 23013157 TI - Aerosols from fires: an examination of the effects on ozone photochemistry in the Western United States. AB - This study presents a first attempt to investigate the roles of fire aerosols in ozone (O(3)) photochemistry using an online coupled meteorology-chemistry model, the Weather Research and Foresting model with Chemistry (WRF-Chem). Four 1-month WRF-Chem simulations for August 2007, with and without fire emissions, were carried out to assess the sensitivity of O(3) predictions to the emissions and subsequent radiative feedbacks associated with large-scale fires in the Western United States (U.S.). Results show that decreases in planetary boundary layer height (PBLH) resulting from the radiative effects of fire aerosols and increases in emissions of nitrogen oxides (NO(x)) and volatile organic compounds (VOCs) from the fires tend to increase modeled O(3) concentrations near the source. Reductions in downward shortwave radiation reaching the surface and surface temperature due to fire aerosols cause decreases in biogenic isoprene emissions and J(NO(2)) photolysis rates, resulting in reductions in O(3) concentrations by as much as 15%. Thus, the results presented in this study imply that considering the radiative effects of fire aerosols may reduce O(3) overestimation by traditional photochemical models that do not consider fire-induced changes in meteorology; implementation of coupled meteorology-chemistry models are required to simulate the atmospheric chemistry impacted by large-scale fires. PMID- 23013158 TI - Decreasing stearoyl-CoA desaturase-1 expression inhibits beta-catenin signaling in breast cancer cells. AB - Stearoyl-CoA desaturase-1 (SCD1) is an endoplasmic reticulum anchored enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly palmytoleyl-CoA and oleyl-CoA. Recent studies have revealed a function for SCD1 in the modulation of signaling processes related to cell proliferation, survival and transformation to cancer. We used MCF7 and MDA-MB-231 cells to analyze the role of SCD1 in the metastatic acquisition of breast cancer cells. Silencing SCD1 expression in breast cancer cells has no effect on cell viability but the levels of cell proliferation, cell cycle genes' expressions and the phosphorylation state of ERK1/2 MAPK are significantly reduced. Decreasing SCD1 expression also reduces the level of GSK3 phosphorylation, indicating higher activity of the kinase. Using cells fractionation, immunofluorescence and a beta-catenin/TCF-responsive reporter construct, we demonstrate that lowering SCD1 expression leads to a decrease of beta-catenin amounts within the nucleus and to inhibition of its transactivation capacity. Moreover, MDA-MB-231 cells transfected with the SCD1 siRNA show a lower invasive potential than the control cells. Taken together, our data demonstrate that low SCD1 expression is associated with a decrease in the proliferation rate of breast cancer cells associated with a decrease in ERK1/2 activation. SCD1 silencing also inhibits GSK3 phosphorylation, lowering beta catenin translocation to the nucleus, and, subsequently, its transactivation capacity and the expression of its target genes. Finally, we show that silencing SCD1 impairs the epithelial to mesenchymal transition-like behavior of the cells, a characteristic of metastatic breast cancer. PMID- 23013159 TI - Improving the accuracy of a fluid transport method. AB - AIM: To compare the sealing ability of the same root fillings when measured by a conventional fluid transport method that uses water or by a modified fluid transport method that uses a wetting fluid as tracer. METHODOLOGY: The amount of fluid transport along the same root fillings (AH26, cold lateral compaction of gutta-percha) was measured in a cross-over design in fluid transport set-ups using either water or a wetting fluid as tracer. RESULTS: A Wilcoxon signed-rank test revealed a significant difference in the amount of fluid transport measured along the same root fillings by the two fluid transport methods (P = 0.013). The fluid transport method using wetting fluid detected a significantly higher percentage of root fillings with fluid transport (P = 0.021). CONCLUSIONS: Fluid transport using a wetting fluid as a tracer was more sensitive in the assessment of sealing ability of root fillings than the conventional fluid transport method using water. PMID- 23013146 TI - Changes in human gut flora with age: an Indian familial study. AB - BACKGROUND: The gut micro flora plays vital role in health status of the host. The majority of microbes residing in the gut have a profound influence on human physiology and nutrition. Different human ethnic groups vary in genetic makeup as well as the environmental conditions they live in. The gut flora changes with genetic makeup and environmental factors and hence it is necessary to understand the composition of gut flora of different ethnic groups. Indian population is different in physiology from western population (YY paradox) and thus the gut flora in Indian population is likely to differ from the extensively studied gut flora in western population. In this study we have investigated the gut flora of two Indian families, each with three individuals belonging to successive generations and living under the same roof. RESULTS: Denaturation gradient gel electrophoresis analysis showed age-dependant variation in gut microflora amongst the individuals within a family. Different bacterial genera were dominant in the individual of varying age in clone library analysis. Obligate anaerobes isolated from individuals within a family showed age related differences in isolation pattern, with 27% (6 out of 22) of the isolates being potential novel species based on 16S rRNA gene sequence. In qPCR a consistent decrease in Firmicutes number and increase in Bacteroidetes number with increasing age was observed in our subjects, this pattern of change in Firmicutes / Bacteroidetes ratio with age is different than previously reported in European population. CONCLUSION: There is change in gut flora with age amongst the individuals within a family. The isolation of high percent of novel bacterial species and the pattern of change in Firmicutes /Bacteroidetes ratio with age suggests that the composition of gut flora in Indian individuals may be different than the western population. Thus, further extensive study is needed to define the gut flora in Indian population. PMID- 23013160 TI - A serological survey of leptospiral antibodies in dogs in New Zealand. AB - AIM: To investigate the prevalence of titres to four endemic leptospiral serovars in dog sera from the lower half of the North Island, and the South Island of New Zealand submitted to diagnostic laboratories, and to explore the association between the prevalence of seropositive samples to leptospirosis and breed group, age group and sex. METHODS: Serum samples from 655 dogs residing in the central and lower North Island and from the South Island of New Zealand were sourced from the Massey University Veterinary Teaching Hospital and from submissions to New Zealand Veterinary Pathology in 2005. They were screened by the Microscopic Agglutination Test (MAT) against Leptospira interrogans serovars Copenhageni and Pomona and L. borgpetersenii serovars Hardjo and Ballum. Titres greater or equal to 96 were considered positive. Variables investigated for their association with the prevalence of seropositive samples to leptospirosis included serovar, breed, North vs. South Island, age and sex. RESULTS: Positive MAT titres to Leptospira interrogans serovar Copenhageni were found in 10.3 % of dogs (95% CI=8.1-12.9), and were more common than positive titres to other leptospiral serovars. Small breeds did not have a lower prevalence of Copenhageni titres than other breeds. Positive titres to Leptospira borgpetersenii serovar Hardjo were associated with breeds of dogs used as farm working dogs. There was no significant difference in the prevalence of positive leptospiral titres between dogs from the North or South Islands. Dogs greater than 12 years of age were less likely to have positive titres to Leptospira than younger dogs. No association was found between positive titres and sex. CONCLUSIONS: Breeds of dogs used as farm working were at greater risk of exposure to Leptospira borgpetersenii serovar Hardjo. Small breeds did not have a lower risk of seropositivity to Copenhageni than farm working breeds. Further study should be undertaken to confirm the prevalence of positive titres to leptospirosis in farm dogs and dogs resident in the South Island. CLINICAL RELEVANCE: The risk of dogs being exposed to Leptospira interrogans serovar Copenhageni, and requirement for vaccination against serovar Copenhageni, cannot be determined by geographical location or breed group. Vaccination against Leptospira borgpetersenii serovar Hardjo is likely to be beneficial in working dogs. PMID- 23013161 TI - Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B. AB - Mipomersen is a second generation antisense oligonucleotide that targets apolipoprotein B. It has been studied thoroughly in clinical trials (more than 800 subjects), including four randomized double-blind placebo controlled phase 3 studies involving 391 patients, and is in registration for the treatment of severe hypercholesterolaemia. The pharmacokinetic and pharmacodynamic properties of mipomersen are well characterized. Mipomersen is rapidly and extensively absorbed after subcutaneous administration and has an elimination half-life of approximately 30 days across species. It is cleared by nuclease metabolism and renal excretion of the metabolites. Mipomersen reduces all apolipoprotein B containing atherogenic particles and displays dose dependent reductions between 50-400 mg week-1 , both as a single agent and in the presence of maximal lipid lowering therapy. No drug-drug interactions have been identified. Mipomersen is a representative of second generation antisense drugs, all of which have similar properties, and is thus representative of the behaviour of the class of drugs. PMID- 23013162 TI - Effects of a one week multidisciplinary inpatient self-management programme for patients with fibromyalgia: a randomised controlled trial. AB - BACKGROUND: Self-management programmes (SMP) are recommended for patients with fibromyalgia. The purpose of this study was to evaluate effects of a one week multidisciplinary inpatient self-management programme on psychological distress, skills as a consumer of health services, self-efficacy, and functional and symptomatic consequences of fibromyalgia (FM). METHODS: A randomised controlled two-armed, assessor-blinded trial with three-week follow-up to evaluate SMP. Primary outcomes were the General Health Questionnaire (GHQ-20) and the Effective Musculoskeletal Consumer Scale (EC-17), while secondary outcomes included the Fibromyalgia Impact Questionnaire (FIQ) and Self-efficacy scales for pain, function and symptoms (ASES). RESULTS: 150 patients with FM were randomised to one week one SMP (n = 75) or to a waiting list control group (n = 75). Of these, 58 participants in the treatment group and 60 in the control group completed the study. At three weeks' follow up there was a significant difference in EC-17 (0 100) in favour of the treatment group (mean difference 4.26, 95 CI 0.8 to 7.7, p = 0.02). There were no differences between the groups for any of the other outcomes. CONCLUSION: This study shows that in patients with FM the SMP had no effect on psychological distress, functional and symptomatic consequences and self-efficacy, except for a small short-term effect on skills and behaviour that are important for managing and participating in health care (EC-17). Clinical Trials.gov Id: NCT01035125. TRIAL REGISTRATION: Clinical Trials.gov Id: NCT01035125. PMID- 23013163 TI - Prognostic significance of tumour markers in Chinese patients with gastric cancer. AB - BACKGROUND AND OBJECTIVES: The clinical value of preoperative tumour markers remains elusive in gastric cancer. The aim of this study was to investigate the prognostic value of alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen (CA)19-9, CA50 and CA72-4 in gastric cancer. METHODS: About 391 gastric cancer patients who underwent curative D2 gastrectomy between 2001 and 2006 were evaluated. The correlation between tumour markers and clinicopathologic characteristics and prognostic value of preoperative tumour markers was investigated. RESULTS: Correlation analysis showed that AFP was associated with tumour size (P = 0.040); CEA with lymphatic invasion (P = 0.023) and pathological stage (P = 0.018); CA19-9 with tumour size (P = 0.000), Borrmann type (P = 0.027), lymphatic invasion (P = 0.020) and pathological stage (P = 0.001); CA50 with lymphatic invasion (P = 0.004) and pathological stage (P = 0.004); CA72-4 with tumour size (P = 0.000), tumour size (P = 0.000) and Borrmann type (P = 0.008); lymphatic invasion (P = 0.000), nervous invasion (P = 0.028) and pathological stage (P = 0.000). Multivariate analysis showed that CEA, tumour site, Borrmann type and pathological stage were independent prognostic factors. CONCLUSIONS: Preoperative CEA might be a candidate for the staging system in addition to conventional factors. PMID- 23013164 TI - Stroke mortality variations in South-East Asia: empirical evidence from the field. AB - BACKGROUND: Stroke is a leading cause of death in Asia; however, many estimates of stroke mortality are based on epidemiological models rather than empirical data. Since 2005, initiatives have been undertaken in a number of Asian countries to strengthen and analyse vital registration data. This has increased the availability of empirical data on stroke mortality. AIMS: The aim of this paper is to present estimates of stroke mortality for Indonesia, Myanmar, Viet Nam, Thailand, and Malaysia, which have been derived using these empirical data. METHODS: Age-specific stroke mortality rates were calculated in each of the five countries, and adjusted for data completeness or misclassification where feasible. All data were age-standardized and the resulting rates were compared with World Health Organization estimates, which are largely based on epidemiological models. RESULTS: Using empirical data, stroke ranked as the leading cause of death in all countries except Malaysia, where it ranked as the second leading cause. Age-standardized rates for males ranged from 94 per 100,000 in Thailand, to over 300 per 100,000 in Indonesia. In all countries, rates were higher for males than for females, and those compiled from empirical data were generally higher than modelled estimates published by World Health Organization. CONCLUSIONS: This study highlights the extent of stroke mortality in selected Asian countries, and provides important baseline information to investigate the aetiology of stroke in Asia and design appropriate public health strategies to address the rapidly growing burden from stroke. PMID- 23013165 TI - Monascusazaphilones A-C, three new azaphilone analogues isolated from the fungus Monascus purpureus BCRC 38108. AB - Investigation of the 95% EtOH extract of red yeast rice fermented with the pink mutant of the fungus Monascus purpureus BCRC 38108 led to the isolation of three new azaphilone derivatives, namely monascusazaphilones A-C (1-3), together with two known compounds. Compounds 1-3 were isolated from this species for the first time. Their structures were elucidated by 1-D and 2-D nuclear magnetic resonance spectroscopy together with HR-ESI-MS analysis and comparison of the spectroscopic data with those reported in the literatures. All isolates were evaluated for their inhibitory effects on nitric oxide (NO) production by macrophages. Among the isolates, compound 1 demonstrated stronger inhibition on NO production. PMID- 23013166 TI - Colostrum-derived B and T cells as an extra-lymphoid compartment of effector cell populations in humans. AB - Colostrum contains cellular components that convey immunological protection to offspring. In the present study the main subsets of lymphocytes present in colostrum and in peripheral blood of healthy screened mothers were compared through the evaluation of >15 different flow cytometry markers. Colostrum and peripheral blood samples were collected within 3 days after full-term delivery. Flow cytometry assays and laboratory tests were performed soon after collection. Among B cells, percentages of CD19(+)CD5(+) cells, pertaining to natural immunity system, were significantly higher in colostrum than in peripheral blood (33 vs. 5%, p = 0.047). CD4(+) T cells, effector cells (CD45RA(+)/CD27(-)) and effector memory cells (CD45RA(-)/CD27(-)) were significantly higher in colostrum (p < 0.001) than in peripheral blood, as well as activated CD4(+) T cells (HLA( )DR(+)) (36% vs. 6% p = 0.0022) and CD4(+) terminally differentiated effector T cells (CD57(+)) (p < 0.001). With regards to CD8(+) T cells, a comparable significant increase in effector (p < 0.02) and effector memory cells (p < 0.001) was also observed. Moreover, an increased surface expression of HLA-DR and CD57 (p < 0.001) on CD8(+) T cells in colostrum was detected. Colostrum contains a different distribution of lymphocyte subsets with respect to peripheral blood from mothers, confirming the observation that lymphocytes probably migrate in milk in a selective way. Colostrum T and B lymphocytes appear to be enriched with subsets possessing effector functions or belonging to the innate immune system, what could transfer a prompt line of defence to offspring. PMID- 23013168 TI - Integrating genome annotation and QTL position to identify candidate genes for productivity, architecture and water-use efficiency in Populus spp. AB - BACKGROUND: Hybrid poplars species are candidates for biomass production but breeding efforts are needed to combine productivity and water use efficiency in improved cultivars. The understanding of the genetic architecture of growth in poplar by a Quantitative Trait Loci (QTL) approach can help us to elucidate the molecular basis of such integrative traits but identifying candidate genes underlying these QTLs remains difficult. Nevertheless, the increase of genomic information together with the accessibility to a reference genome sequence (Populus trichocarpa Nisqually-1) allow to bridge QTL information on genetic maps and physical location of candidate genes on the genome. The objective of the study is to identify QTLs controlling productivity, architecture and leaf traits in a P. deltoides x P. trichocarpa F1 progeny and to identify candidate genes underlying QTLs based on the anchoring of genetic maps on the genome and the gene ontology information linked to genome annotation. The strategy to explore genome annotation was to use Gene Ontology enrichment tools to test if some functional categories are statistically over-represented in QTL regions. RESULTS: Four leaf traits and 7 growth traits were measured on 330 F1 P. deltoides x P. trichocarpa progeny. A total of 77 QTLs controlling 11 traits were identified explaining from 1.8 to 17.2% of the variation of traits. For 58 QTLs, confidence intervals could be projected on the genome. An extended functional annotation was built based on data retrieved from the plant genome database Phytozome and from an inference of function using homology between Populus and the model plant Arabidopsis. Genes located within QTL confidence intervals were retrieved and enrichments in gene ontology (GO) terms were determined using different methods. Significant enrichments were found for all traits. Particularly relevant biological processes GO terms were identified for QTLs controlling number of sylleptic branches: intervals were enriched in GO terms of biological process like 'ripening' and 'adventitious roots development'. CONCLUSION: Beyond the simple identification of QTLs, this study is the first to use a global approach of GO terms enrichment analysis to fully explore gene function under QTLs confidence intervals in plants. This global approach may lead to identification of new candidate genes for traits of interest. PMID- 23013170 TI - Editorial: Measurements and perceptions in child psychology and psychiatry. PMID- 23013167 TI - Small-molecule structure correctors target abnormal protein structure and function: structure corrector rescue of apolipoprotein E4-associated neuropathology. AB - An attractive strategy to treat proteinopathies (diseases caused by malformed or misfolded proteins) is to restore protein function by inducing proper three dimensional structure. We hypothesized that this approach would be effective in reversing the detrimental effects of apolipoprotein (apo) E4, the major allele that significantly increases the risk of developing Alzheimer's disease and other neurodegenerative disorders. ApoE4's detrimental effects result from its altered protein conformation ("domain interaction"), making it highly susceptible to proteolytic cleavage and the generation of neurotoxic fragments. Here, we review apoE structure and function and how apoE4 causes neurotoxicity, and describe the identification of potent small-molecule-based "structure correctors" that induce proper apoE4 folding. SAR studies identified a series of small molecules that significantly reduced apoE4's neurotoxic effects in cultured neurons and a series that reduced apoE4 fragment levels in vivo, providing proof-of-concept for our approach. Structure-corrector-based therapies could prove to be highly effective for the treatment of many protein-misfolding diseases. PMID- 23013169 TI - Exophiala dermatitidis endocarditis on native aortic valve in a postrenal transplant patient and review of literature on E. dermatitidis infections. PMID- 23013171 TI - The adequacy of phosphorus binder prescriptions among American hemodialysis patients. AB - Because hemodialysis treatment has a limited ability to remove phosphorus, dialysis patients must restrict dietary phosphorus intake and use phosphorus binding medication. Among patients with restricted dietary phosphorus intake (1000 mg/d), phosphorus binders must bind about 250 mg of excess phosphorus per day and among patients with more typical phosphorus intake (1500 mg/d), binders must bind about 750 mg/d. To determine the phosphorus binding capacity of binder prescriptions among American hemodialysis patients, we undertook a cross sectional study of a random sample of in-center chronic hemodialysis patients. We obtained data for one randomly selected patient from 244 facilities nationwide. About one-third of the patients had hyperphosphatemia (serum phosphorus level > 5.5 mg/dL). Among the 224 patients prescribed binders, the mean phosphorus binding capacity was 256 mg/d [standard deviation (SD) 143]. A total of 59% of prescriptions had insufficient binding capacity for restricted dietary phosphorus intake, and 100% had insufficient binding capacity for typical dietary phosphorus intake. Patients using two binders had a higher binding capacity than patients using one binder (451 vs. 236 mg/d, p < 0.001). A majority of binder prescriptions have insufficient binding capacity to maintain phosphorus balance. Use of two binders results in higher binder capacity. Further work is needed to understand the impact of binder prescriptions on mineral balance and metabolism and to determine the value of substantially increasing binder prescriptions. PMID- 23013172 TI - Total synthesis of debromoflustramines B and E based on the intramolecular carbamoylketene-alkene [2 + 2] cycloaddition. AB - Total synthesis of debromoflustramines B and E has been accomplished by using a platinum-catalyzed addition reaction of o-aminophenylboronic acid with the allene and an intramolecular carbamoylketene-alkene [2 + 2] cycloaddition for the construction of the basic carbon framework of the target alkaloids as the key steps. PMID- 23013174 TI - Repeated anterior chamber fluorophotometric evaluation of the eyes of ophthalmologically normal dogs. AB - OBJECTIVE: To perform repeated anterior chamber fluorophotometry on both eyes of ophthalmologically normal dogs to measure fluorescein concentrations over a 5-day period and identify any change in the degree of anterior chamber fluorescence over time or difference between eyes. ANIMALS: 9 healthy adult dogs (18 eyes). PROCEDURES: Each dog received an IV injection of 10% fluorescein solution, and anterior chamber fluorophotometry was performed 1 hour later on both eyes. This procedure was repeated at the same time each day for 5 consecutive days. RESULTS: A significant increase in fluorescein concentration was evident in the anterior chamber on day 5 in the right eye and days 2, 3, 4, and 5 in the left eye. There was no significant difference in concentration between the left and the right eyes on any day. CONCLUSIONS AND CLINICAL RELEVANCE: The increase in ocular fluorescein concentration in the study dogs was unlikely to be of clinical importance and is only pertinent for subsequent research studies. This is a limitation that should be considered when reporting fluorophotometry data as fluorescein concentration or as change in fluorescein concentration from baseline. PMID- 23013175 TI - Assessments of thermal antinociceptive effects of butorphanol and human observer effect on quantitative evaluation of analgesia in green iguanas (Iguana iguana). AB - OBJECTIVE: To determine whether butorphanol induces thermal antinociception in green iguanas (Iguana iguana) and assess the human observer effect on quantitative evaluation of butorphanol-induced analgesia. ANIMALS: 6 juvenile green iguanas. PROCEDURES: Skin temperature was recorded, and then a direct increasing heat stimulus was applied to the lateral aspect of the tail base of each iguana. Temperature of the stimulus at which the iguana responded (thermal threshold) was measured before and for 8 hours after IM injection of either butorphanol tartrate (1.0 mg/kg) or an equal volume of saline (0.9% NaCl) solution. Six experiments (butorphanol [n = 3] and saline solution [3]) were conducted with the observer in the iguanas' field of vision, and 11 experiments (butorphanol [n = 5] and saline solution [6]) were conducted with the observer hidden from their view. The interval between treatments or tests was >= 1 month. RESULTS: Temperature difference between thermal threshold and skin temperature when iguanas were administered saline solution did not differ from temperature difference when iguanas were administered butorphanol regardless of whether the observer was or was not visible. Temperature difference between thermal threshold and skin temperature was significantly lower when iguanas were tested without the observer in visual range, compared with the findings obtained when iguanas were tested with an observer in view, at multiple times after either treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Intramuscular administration of 1.0 mg of butorphanol/kg did not induce thermal antinociception in juvenile green iguanas. The visible presence of an observer appeared to influence the results of noxious stimulus testing in this reptile species. PMID- 23013176 TI - Pharmacokinetics of a long-acting ceftiofur crystalline-free acid formulation in Asian elephants (Elephas maximus). AB - OBJECTIVE: To determine the pharmacokinetics of a long-acting formulation of ceftiofur, ceftiofur crystalline-free acid (CCFA), following SC injection to Asian elephants (Elephas maximus). ANIMALS: 11 adult Asian elephants. PROCEDURES: Each elephant received CCFA (6.6 mg/kg, SC) in the area caudoventral to the base of an ear. Blood samples were collected from an ear vein immediately prior to and at 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after CCFA administration. Plasma concentrations of desfuroylceftiofur acetamide (the acetamide derivative of ceftiofur) were measured via ultrahigh-pressure liquid chromatography-tandem mass spectrometry. Data were analyzed via a noncompartmental pharmacokinetics approach. RESULTS: The mean +/- SD maximum plasma concentration of desfuroylceftiofur acetamide was 1.36 +/- 0.74 MUg/mL and was detected at 4718 +/- 31.30 hours. The mean +/- SD area under the curve from time 0 to infinity was 2278 +/- 55.8 MUg*h/mL, and the mean residence time from time 0 to infinity was 158.2 +/- 90.2 hours. The terminal elimination half-life associated with the slope of the terminal phase had a harmonic mean +/- pseudo-SD of 83.36 +/- 30.01 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Elephants tolerated CCFA at a dose of 6.6 mg/kg, SC, well. Dosing recommendations will depend on the mean inhibitory concentration of ceftiofur for each bacterial pathogen. Desfuroylceftiofur acetamide concentrations remained > 0.25 MUg/mL for the entire 168-hour study period, which suggested CCFA would provide clinically relevant antimicrobial activity against certain pathogens for 7 to 10 days. PMID- 23013177 TI - Mechanical properties of isolated loops of nylon leader material, polyethylene cord, and polyethylene tape and mechanical properties of those materials secured to cadaveric canine femurs via lateral femoral fabellae, toggles placed through bone tunnels, or bone anchors. AB - OBJECTIVE: To determine mechanical properties of various prosthetic materials secured to cadaveric canine femurs via various methods and to compare results with those for isolated loops of prosthetic material. SAMPLE: 80 femurs obtained from cadavers of skeletally mature large-breed dogs. PROCEDURES: 10 femoral constructs in each of 8 groups (single circumfabellar loop of polyethylene cord, double loop of polyethylene tape secured via a bone anchor [BAPT], single or double circumfabellar loops of nylon leader material [CNL] or polyethylene tape [CPT], or single or double loops of polyethylene tape secured via a toggle placed through a bone tunnel [BTPT]) and 10 isolated loops of prosthetic material in each corresponding configuration were tested. Stress relaxation, creep, elongation, load at 3 mm of displacement, stiffness, and peak load at failure were determined. RESULTS: 5 single CNL constructs failed before completion of testing. Double CNL and single circumfabellar polyethylene cord constructs had the lowest loads at 3 mm of displacement. Single and double CPT constructs had the highest stiffness. Double BTPT and CPT constructs had the highest peak loads at failure. Double BTPT, double CPT, and BAPT constructs were mechanically superior on the basis of lower creep and stress relaxation and higher stiffness and load at 3 mm of displacement versus other constructs. Stiffness of femoral constructs was 28% to 69% that of corresponding isolated prosthetic loops. CONCLUSIONS AND CLINICAL RELEVANCE: Double BTPT, double CPT, and BAPT constructs were mechanically superior to other constucts. Mechanical properties and methods of anchorage and securing of free ends of prostheses contributed to mechanical properties of constructs. PMID- 23013178 TI - Concentration-dependent effects of tiludronate on equine articular cartilage explants incubated with and without interleukin-1beta. AB - OBJECTIVE: To determine concentration-dependent effects of tiludronate on cartilage explants incubated with or without recombinant equine interleukin-1beta (rEq IL-1). SAMPLE: Articular cartilage explants from the femorotibial joints of 3 young adult horses. PROCEDURES: Cartilage explants were incubated with 1 of 6 concentrations (0, 0.19, 1.9, 19, 190, or 1,900 mg/L) of tiludronate and with or without rEq IL-1 (0.01 ng/mL) for 96 hours. Prostaglandin E(2) (PGE(2)) concentrations in culture medium and explant digests were analyzed via PGE(2) enzyme immunoassay. Sulfated glycosaminoglycan (sGAG) concentrations in culture medium were quantified via 1,9-dimethylmethylene blue assay. Chondrocyte apoptosis in paraffin embedded explant sections was measured via terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. Relative gene expression of matrix metalloproteinases (MMPs), interleukin (IL)-6, and IL-8 was determined via the comparative cycle threshold method. RESULTS: rEq IL-1 increased PGE(2) concentration, sGAG release from explants, chondrocyte apoptosis, and MMP gene expression. Lower tiludronate concentrations reduced rEq IL-1-induced sGAG release and chondrocyte apoptosis, whereas the higher tiludronate concentrations increased sGAG release and chondrocyte apoptosis. At the highest tiludronate concentration evaluated, IL-8 gene expression was increased independent of whether rEq IL-1 was present. CONCLUSIONS AND CLINICAL RELEVANCE: Tiludronate had biphasic concentration-dependent effects on cartilage explants that were independent of PGE(2) secretion or MMP gene expression. Low tiludronate concentrations had some chondroprotective effects, whereas high tiludronate concentrations were detrimental to equine articular cartilage. Administration of tiludronate intra-articularly to horses may be detrimental, dependent on the dose used. In vivo studies are needed before intra-articular tiludronate administration to horses can be recommended. PMID- 23013179 TI - Evaluation of experimental impact injury for inducing post-traumatic osteoarthritis in the metacarpophalangeal joints of horses. AB - OBJECTIVE: To determine whether a single contusive impact injury to the palmar aspect of the metacarpus would progress to post-traumatic osteoarthritis or palmar osteochondral disease in horses. ANIMALS: 12 horses. PROCEDURES: In each horse, an impact injury was created on the palmar aspect of the medial metacarpal condyle of 1 randomly chosen limb with an impactor device under arthroscopic and fluoroscopic guidance. The opposite limb was sham operated as a control. A low to moderate amount of forced exercise was instituted, and horses were evaluated clinically via lameness examinations weekly for 5 months, then biweekly until endpoint, with synovial fluid analysis performed at 0, 1, 2, 3, 4, 6, 8, and 10 months and radiography at baseline and endpoint. Macroscopic examination, micro CT, and sample collection for cartilage viability and sulfated glycosaminoglycan content, histologic evaluation, immunohistochemical analysis, and fluorochrome analysis were performed following euthanasia at 1 (3 horses), 4 (4), and 8 to 10 (5) months after surgery. RESULTS: There was variability in impact lesion location, depth, and area on macroscopic inspection, but on histologic evaluation, cartilage defects were less variable. Mean sulfated glycosaminoglycan concentration from cartilage at the impact site was significantly lower than that at a similar site in control limbs. Higher concentrations of cartilage oligomeric matrix protein were observed in synovial fluid from impact-injured joints. CONCLUSIONS AND CLINICAL RELEVANCE: The impact injury method caused mild focal osteoarthritic lesions in the metacarpophalangeal joint, but did not progress to palmar osteochondral disease at this site. Repeated injury is probably required for the development of palmar osteochondral disease. PMID- 23013180 TI - Evaluation of the association between runt-related transcription factor 2 expression and intervertebral disk aging in dogs. AB - OBJECTIVE: To investigate the relationship between runt-related transcription factor 2 (RUNX2) expression in canine nucleus pulposus (NP) cells and intervertebral disk aging in chondrodystrophoid dogs. ANIMALS: 7 healthy Beagles (mean age, 35.6 months) and 11 Dachshunds with herniated disks (mean age, 61 months). PROCEDURES: All dogs underwent MRI examination of the thoracic and lumbar vertebral column immediately before sample collection under general anesthesia. The disk center-to-CSF T2-weighted signal intensity ratio was determined for healthy Beagles. Samples of NP were obtained from nonherniated disks in healthy Beagles and from herniated disks during surgical treatment of hospitalized Dachshunds. Samples were evaluated for RUNX2 and matrix metalloproteinase 13 transcript expression via reverse transcriptase PCR assay; RUNX2 protein expression was evaluated via immunohistochemical analysis, and correlation between these variables and age of dogs was evaluated. A 3' and 5' rapid amplification of cDNA ends method was used to identify the RUNX2 coding region. RESULTS: RUNX2 cDNA had > 97% conservation with the human cDNA sequence and approximately 95% conservation with the mouse cDNA sequence; RUNX2 and matrix metalloproteinase 13 mRNA expression and RUNX2 protein expression in NP cells were positively correlated with age. The disk center-to-CSF T2-weighted signal intensity ratio was negatively correlated with RUNX2 protein expression in the NP of healthy dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that RUNX2 mRNA and protein expression in the NP are enhanced in aging intervertebral disks in dogs. PMID- 23013181 TI - Comparison of transcoelomic, contrast transcoelomic, and transesophageal echocardiography in anesthetized red-tailed hawks (Buteo jamaicensis). AB - OBJECTIVE: To assess the agreement and reliability of cardiac measurements obtained with 3 echocardiographic techniques in anesthetized red-tailed hawks (Buteo jamaicensis). ANIMALS: 10 red-tailed hawks. PROCEDURES: Transcoelomic, contrast transcoelomic, and transesophageal echocardiographic evaluations of the hawks were performed, and cineloops of imaging planes were recorded. Three observers performed echocardiographic measurements of cardiac variables 3 times on 3 days. The order in which hawks were assessed and echocardiographic techniques were used was randomized. Results were analyzed with linear mixed modeling, agreement was assessed with intraclass correlation coefficients, and variation was estimated with coefficients of variation. RESULTS: Significant differences were evident among the 3 echocardiographic methods for most measurements, and the agreement among findings was generally low. Interobserver agreement was generally low to medium. Intraobserver agreement was generally medium to high. Overall, better agreement was achieved for the left ventricular measurements and for the transesophageal approach than for other measurements and techniques. CONCLUSIONS AND CLINICAL RELEVANCE: Echocardiographic measurements in hawks were not reliable, except when the left ventricle was measured by the same observer. Furthermore, cardiac morphometric measurements may not be clinically important. When measurements are required, one needs to consider that follow-up measurements should be performed by the same echocardiographer and should show at least a 20% difference from initial measurements to be confident that any difference is genuine. PMID- 23013182 TI - Effects of oral prednisone administration with or without ultralow-dose acetylsalicylic acid on coagulation parameters in healthy dogs. AB - OBJECTIVE: To determine the effects of oral prednisone administration with or without ultralow-dose acetylsalicylic acid on coagulation parameters in healthy dogs and to assess intraindividual variation in thromboelastography results. ANIMALS: 14 healthy research dogs and 10 healthy client-owned dogs. PROCEDURES: In a randomized controlled trial, research dogs underwent thromboelastography twice (3 days apart), and intraindividual variation in test results was calculated. Dogs were given prednisone (2 mg/kg/d, PO) plus acetylsalicylic acid (0.5 mg/kg/d, PO) or prednisone (2 mg/kg/d, PO) plus a placebo for 14 days, after which thromboelastography and other tests were repeated. Differences from preadministration (baseline) test results between and within groups were compared. In a separate trial, client-owned dogs also underwent thromboelastography twice 2 days apart to assess intraindividual variation in untreated dogs. RESULTS: Intraindividual variation in thromboelastography results for research dogs was <= 10% for maximum amplitude (MA) and alpha angle. In the research dogs, MA and fibrinogen values significantly increased from baseline, whereas percentage lysis 30 minutes after attainment of the MA as well as antithrombin activity significantly decreased within each group. In the dogs that received prednisone plus a placebo, percentage lysis 60 minutes after attainment of the MA was significantly lower than at baseline. For all parameters for research dogs, there was no difference between groups for change from baseline. Intraindividual variation in findings for client-owned dogs was similar to the variation for research dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Prednisone administration resulted in hypercoagulability in healthy dogs as indicated by an increase in MA and plasma fibrinogen concentration and a decrease in antithrombin activity. Concurrent ultralow-dose acetylsalicylic acid use had no effect on measured thromboelastography values. The high intraindividual variation in some thromboelastography parameters may preclude routine use of this technique in clinical practice. PMID- 23013183 TI - Viscoelastic pharmacodynamics after dalteparin administration to healthy dogs. AB - OBJECTIVE: To evaluate the pharmacodynamic effects of dalteparin in dogs by means of viscoelastic coagulation monitoring with a thromboelastograph and a dynamic viscoelastic coagulometer. ANIMALS: 6 healthy adult mixed-breed dogs. PROCEDURES: Dalteparin (175 U/kg, SC, q 12 h) was administered for 4 days (days 1 through 4). Viscoelastic coagulation monitoring was performed hourly on the first and last days of treatment and included intermittent measurement of anti-activated coagulation factor X activity (AXA). RESULTS: Dalteparin administration resulted in progressive hypocoagulability. On both day 1 and 4, activated clotting time and clot rate for the dynamic viscoelastic coagulometer differed significantly from baseline values, whereas the platelet function parameter did not change on day 1 but did on day 4. The R (reaction time), time from reaction time until the amplitude of the thromboelastography tracing is 20 mm, alpha-angle, and maximum amplitude differed from baseline values on days 1 and 4, although many thromboelastographic variables were not determined. The AXA was increased from baseline values at 3 and 6 hours after administration of the dalteparin injection on days 1 and 4, and all dogs had AXA values between 0.5 and 1.0 U/mL at 2 and 4 hours after administration. The AXA correlated well with activated clotting time (r = 0.761) and with R (r = 0.810), when values were available. Thromboelastography could not be used to distinguish AXA > 0.7 U/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Viscoelastic coagulation monitoring with strong coagulation activators may be used to monitor treatment with dalteparin in healthy dogs. PMID- 23013184 TI - Ultrasonographic evaluation of preprandial and postprandial gallbladder volume in healthy cats. AB - OBJECTIVE: To noninvasively assess the influence of ingestion of a standard meal on gallbladder volume (GBV) in healthy cats. ANIMALS: 10 healthy adult domestic shorthair cats (4 neutered females, 5 neutered males, and 1 sexually intact male). PROCEDURES: Nonsedated cats were positioned in dorsal and left lateral recumbency to obtain ultrasonographic measurements of the gallbladder via the subcostal and right intercostal acoustic windows, respectively. Gallbladder volume was calculated from linear measurements by use of an ellipsoid formula (volume [mL] = length [mm] * height [mm] * width [mm] * 0.52). Measurements were recorded after food was withheld for 12 hours (0 minutes) and at 5, 15, 30, 45, 60, and 120 minutes after cats were fed 50 g of a standard commercial diet (protein, 44.3%; fat, 30.3%; and carbohydrate, 15.6% [dry matter percentage]). RESULTS: Agreement between gallbladder linear measurements or GBV obtained from the subcostal and right intercostal windows was good. Feeding resulted in linear decreases in gallbladder linear measurements and GBV. Via the subcostal and intercostal windows, mean +/- SD GBV was 2.47 +/- 1.16 mL and 2.36 +/- 0.96 mL, respectively, at 0 minutes and 0.88 +/- 0.13 mL and 0.94 +/- 0.25 mL, respectively, at 120 minutes. Gallbladder width most closely reflected postprandial modification of GBV. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that ultrasonographic assessment (via the subcostal or right intercostal acoustic window) of postprandial changes in GBV can be used to evaluate gallbladder contractility in cats. These data may help identify cats with abnormal gallbladder emptying. PMID- 23013185 TI - Assessment of blood pool, soft tissue, and skeletal uptake of sodium fluoride F 18 with positron emission tomography-computed tomography in four clinically normal dogs. AB - OBJECTIVE: To determine the ideal interval to image acquisition after IV injection of sodium fluoride F 18 ((18)F-NaF) and evaluate biodistribution of the radiopharmaceutical in clinically normal skeletally immature dogs. ANIMALS: 4 female dogs. PROCEDURES: Each dog was anesthetized for evaluation with a commercial hybrid positron emission tomography (PET)-CT instrument. A low radiation dose, whole-body CT scan was acquired first. An IV injection of (18)F NaF (0.14 mCi/kg) was administered, and a dynamic PET scan centered over the heart and liver was acquired during a period of 120 minutes. Uptake of (18)F-NaF in the blood pool, soft tissues, and skeletal structures was evaluated via region of interest analysis to derive standardized uptake values and time-activity curves, which were used to determine the optimal postinjection time for skeletal image acquisition. Biodistribution was also assessed from a final whole-body PET CT scan acquired after the dynamic scan. RESULTS: Time-activity curves revealed a rapid decrease in the amount of radiopharmaceutical in the blood pool and soft tissues and a rapid increase in the amount of radiopharmaceutical in bones soon after injection. At 50 minutes after injection, the greatest difference in uptake between soft tissues and bones was detected, with continued subtle increase in uptake in the bones. Uptake of (18)F-NaF was slightly increased at growth plates and open ossification centers, compared with that at other parts of the bone. CONCLUSIONS AND CLINICAL RELEVANCE: At 50 minutes after IV injection of (18)F-NaF at the dose evaluated, PET-CT yielded excellent bone-to-background ratio images for evaluation of the skeletal system in dogs. PMID- 23013186 TI - Evaluation of a commercially available radioimmunoassay and species-specific ELISAs for measurement of high concentrations of insulin in equine serum. AB - OBJECTIVE: To evaluate a human radioimmunoassay (RIA) and equine and high-range porcine (hrp) species-specific ELISAs for the measurement of high serum insulin concentrations in ponies. SAMPLES: Serum samples from 12 healthy nonobese ponies (7 clinically normal and 5 laminitis prone; 13 to 26 years of age; 11 mares and 1 gelding) before and after glucose, insulin, and dexamethasone administration. PROCEDURES: Intra-and interassay repeatability, freeze-thaw stability, dilutional parallelism, and assay agreement were assessed. RESULTS: Assay detection limits were as follows: RIA, < 389 MUU/mL; equine ELISA, < 175 MUU/mL; and hrp ELISA, 293 to 8,775 MUU/mL. Mean +/- SD intra- and interassay repeatability were respectively as follows: RIA, 6.5 +/- 5.1 % and 74 +/- 3.4%; equine ELISA, 10.6 +/- 11.0% and 9.0 +/- 4.6%; and hrp ELISA, 19.9 +/- 172% and 173 +/- 16.6%. Freezing and thawing affected measured concentrations. Dilutional parallelism in the RIA was only evident when insulin-depleted equine serum was used as a diluent (percentage recovery, 95.7 +/- 274%); in the ELISAs, dilutional parallelism was observed when a zero calibrator was used. Agreement between RIA and equine ELISA results was good for samples containing concentrations < 175 MUU of insulin/mL (bias, -18.5 +/- 25.5 MUU/mL; higher in RIA). At higher concentrations, assay agreement was poor between RIA and equine ELISA results (bias, -185.3 +/- 98.7 MUU/mL) and between RIA and hrp ELISA results (bias, 25.3 +/- 183.0 MUU/mL). CONCLUSIONS AND CLINICAL RELEVANCE: Agreement among results of the 3 assays was variable, and dilutional parallelism was only evident with the RIA when insulin depleted equine serum was tested. Caution is recommended when evaluating high insulin concentrations measured with the RIA or ELISAs. PMID- 23013187 TI - Association of airborne concentration of virulent Rhodococcus equi with location (stall versus paddock) and month (January through June) on 30 horse breeding farms in central Kentucky. AB - OBJECTIVE: To determine whether the concentration of airborne virulent Rhodococcus equi varied by location (stall vs paddock) and month on horse farms. SAMPLE: Air samples from stalls and paddocks used to house mares and foals on 30 horse breeding farms in central Kentucky. PROCEDURES: Air samples from 1 stall and 1 paddock were obtained monthly from each farm from January through June 2009. Concentrations of airborne virulent R equi were determined via a modified colony immunoblot assay. Random-effects logistic regression was used to determine the association of the presence of airborne virulent R equi with location from which air samples were obtained and month during which samples were collected. RESULTS: Of 180 air samples, virulent R equi was identified in 49 (27%) and 13 (7%) obtained from stalls and paddocks, respectively. The OR of detecting virulent R equi in air samples from stalls versus paddocks was 5.2 (95% confidence interval, 2.1 to 13.1). Of 60 air samples, virulent R equi was identified in 25 (42%), 18 (30%), and 6 (10%) obtained from stalls during January and February, March and April, and May and June, respectively. The OR of detecting virulent R equi from stall air samples collected during May and June versus January and February was 0.22 (95% confidence interval, 0.08 to 0.63). CONCLUSIONS AND CLINICAL RELEVANCE: Foals were more likely to be exposed to airborne virulent R equi when housed in stalls versus paddocks and earlier (January and February) versus later (May and June) during the foaling season. PMID- 23013188 TI - Associations between yearling exercise and interruptions during race training in Thoroughbred racehorses. AB - OBJECTIVE: To investigate the effect of exercise during yearling sales preparation on the risk of interruptions during training in Thoroughbred racehorses. ANIMALS: 114 Thoroughbred racehorses. PROCEDURES: Information regarding the daily exercise of yearlings during sales preparation was obtained prospectively from a convenience sample of stud farms. Yearlings were followed to entry into race training, and subsequently, daily training information was recorded until the end of the racing season. Competing-risks survival analysis was used to model time from entry into race training to voluntary training interruption (no known condition or disease identified) and time from entry into race training to involuntary training interruption (due to presence of a condition or disease) occurring before the first trial (practice race for education). Total hand walking time and mechanical walker time accumulated during sales preparation were the main exposures of interest. RESULTS: 82 of 114 (71.9%) horses had an interruption before the first trial; 65 (79%) interruptions were voluntary, and 17 (21%) interruptions were involuntary. Increased total hand walking time was significantly associated with decreased risk of voluntary interruptions, whereas longer cumulative distances at a canter were significantly associated with decreased risk of involuntary interruptions. CONCLUSIONS AND CLINICAL RELEVANCE: Results identified an association between early exercise during sales preparation and decreased risk of voluntary interruption and increased risk of involuntary interruption during training of 2-year-old Thoroughbred racehorses. Further investigation into the effects of early exercise on racing performance is needed, but results have indicated that there may be an opportunity to modify early exercise programs. PMID- 23013189 TI - Surveillance for Mycobacterium bovis transmission from domestic cattle to wild ruminants in a Mexican wildlife-livestock interface area. AB - OBJECTIVE: To assess the prevalence of Mycobacterium bovis infection in cattle and wild ruminants (WRs) in a wildlife-livestock interface area (WLIA) of the Mexican highland plateau. ANIMALS: 24,400 cattle from 793 herds (including 17,351 commercially slaughtered cattle) and 142 WRs (110 white-tailed deer [Odocoileus virginianus], 20 red deer [Cervus elaphus], and 12 North American elk [Cervus canadensis]) harvested via controlled hunting. PROCEDURES: Cattle were serially tested for M bovis infection via caudal fold tuberculin and comparative cervical tuberculin tests during field surveillance. Carcasses of cattle and WRs were inspected for gross lesions; samples suggestive of tuberculosis were analyzed via histologic evaluation and mycobacterial culture (HMC). A PCR assay to detect Mycobacterium tuberculosis complex organisms was performed to confirm positive results of HMC. RESULTS: WRs had inflammatory lesions in lungs and lymph nodes, although HMC results did not indicate M bovis infection. Eight cattle had positive results for both tuberculin tests, and 31 had positive results for HMC of grossly detected lesions; all were from 7 herds, and >= 1 cow in each herd had positive PCR assay results. These 7 herds were depopulated; adjacent herds and herds related via commerce were quarantined. Calculated true prevalence of M bovis infection was 0.86% (95% confidence interval, 0.24% to 1.49%) in cattle; M bovis was not detected in any WRs. CONCLUSIONS AND CLINICAL RELEVANCE: M bovis infection was present in cattle. Although transmission to WRs in this WLIA was not detected, diagnosis and prevention activities should be implemented and consolidated to prevent potential M bovis transmission between cattle and WRs. PMID- 23013190 TI - Expression of microRNAs in urinary bladder samples obtained from dogs with grossly normal bladders, inflammatory bladder disease, or transitional cell carcinoma. AB - OBJECTIVE: To determine expression of microRNA (miRNA) in urinary bladder samples obtained from dogs with grossly normal urinary bladders, inflammatory bladder disease, or transitional cell carcinoma (TCC) and in cells of established canine TCC cell lines. SAMPLE: Samples of grossly normal bladders (n = 4) and bladders from dogs with inflammatory bladder disease (13) or TCC (18), and cells of 5 established canine TCC cell lines. PROCEDURES: Expression of 5 miRNAs (miR-34a, let-7c, miR-16, miR-103b, and miR-106b) that target p53, Rb, or Bcl-2 protein pathways was determined for bladder samples and cells via quantitative real-time PCR assay. Effects of cisplatin (5MUM) on proliferation and miRNA expression of cells were determined. RESULTS: Expression of miR-34a and miR-106b was significantly higher in TCC samples than it was in samples of grossly normal bladders. Expression of miR-34a, miR-16, miR-103b, and miR-106b was higher in TCC samples than it was in bladder samples from dogs with inflammatory bladder disease. Cells of established canine TCC cell lines that had the lowest growth after cisplatin treatment had increased miR-34a expression after such treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Findings of this study indicated results of miRNA expression assays can be used to distinguish between samples of grossly normal bladders and bladders of dogs with inflammatory bladder disease or TCC. This finding may have clinical relevance because currently available diagnostic tests cannot be used to differentiate these tissues, and inflammatory bladder disease and TCC are both prevalent in dogs. Validation of miRNA expression assays as diagnostic tests may be warranted. PMID- 23013191 TI - Pharmacokinetics and tissue elimination of tulathromycin following subcutaneous administration in meat goats. AB - OBJECTIVE: To determine the tissue depletion profile of tulathromycin and determine an appropriate slaughter withdrawal interval in meat goats after multiple SC injections of the drug. ANIMALS: 16 healthy Boer goats. PROCEDURES: All goats were administered tulathromycin (2.5 mg/kg, SC) twice, with a 7-day interval between doses. Blood samples were collected throughout the study, and goats were euthanized at 2, 5, 10, and 20 days after the second tulathromycin dose. Lung, liver, kidney, fat, and muscle tissues were collected. Concentrations of tulathromycin in plasma and the hydrolytic tulathromycin fragment CP-60,300 in tissue samples were determined with ultrahigh-pressure liquid chromatography tandem mass spectrometry. RESULTS: The plasma profile of tulathromycin was biphasic. Absorption was very rapid, with maximum drug concentrations (1.00 +/- 0.42 MUg/mL and 2.09 +/- 1.77 MUg/mL following the first and second doses, respectively) detected within approximately 1 hour after injection. Plasma terminal elimination half-life of tulathromycin was 61.4 +/- 14.1 hours after the second dose. Half-lives in tissue ranged from 2.4 days for muscle to 9.0 days for lung tissue; kidney tissue was used to determine the withdrawal interval for tulathromycin in goats because it is considered an edible tissue. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of the tissue tolerance limit in cattle of 5 ppm (MUg/g), the calculated withdrawal interval for tulathromycin would be 19 days following SC administration in goats. On the basis of the more stringent guidelines recommended by the FDA, the calculated meat withdrawal interval following tulathromycin administration in goats was 34 days. PMID- 23013192 TI - Evaluation of factors important in modeling plasma concentrations of tetracycline hydrochloride administered in water in swine. AB - OBJECTIVE: To model the plasma tetracycline concentrations in swine (Sus scrofa domestica) treated with medication administered in water and determine the factors that contribute to the most accurate predictions of measured plasma drug concentrations. SAMPLE: Plasma tetracycline concentrations measured in blood samples from 3 populations of swine. PROCEDURES: Data from previous studies provided plasma tetracycline concentrations that were measured in blood samples collected from 1 swine population at 0, 4, 8, 12, 24, 32, 48, 56, 72, 80, 96, and 104 hours and from 2 swine populations at 0, 12, 24, 48, and 72 hours hours during administration of tetracycline hydrochloride dissolved in water. A 1 compartment pharmacostatistical model was used to analyze 5 potential covariate schemes and determine factors most important in predicting the plasma concentrations of tetracycline in swine. RESULTS: 2 models most accurately predicted the tetracycline plasma concentrations in the 3 populations of swine. Factors of importance were body weight or age of pig, ambient temperature, concentration of tetracycline in water, and water use per unit of time. CONCLUSIONS AND CLINICAL RELEVANCE: The factors found to be of importance, combined with knowledge of the individual pharmacokinetic and chemical properties of medications currently approved for administration in water, may be useful in more prudent administration of approved medications administered to swine. Factors found to be important in pharmacostatistical models may allow prediction of plasma concentrations of tetracycline or other commonly used medications administered in water. The ability to predict in vivo concentrations of medication in a population of food animals can be combined with bacterial minimum inhibitory concentrations to decrease the risk of developing antimicrobial resistance. PMID- 23013193 TI - Pharmacokinetics and pharmacodynamics of zolpidem after oral administration of a single dose in dogs. AB - OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of zolpidem after oral administration of a single dose (0.15 or 0.50 mg/kg) and assess any associated antianxiety and sedative effects in dogs. ANIMALS: 8 clinically normal sexually intact male dogs of various breeds. PROCEDURES: Dogs were assigned to 2 groups (4 dogs/group) and administered zolpidem orally once at a dose of 0.15 or 0.50 mg/kg in a crossover study; each dog received the other treatment once after an interval of 1 week. Blood samples were collected before and at intervals during the 24-hour period following dose administration. For each time point, plasma zolpidem concentration was evaluated via a validated method of high performance liquid chromatography coupled with fluorescence detection, and pharmacodynamics were assessed via subjective assessments of sedation and level of agitation and selected clinical variables. RESULTS: The pharmacokinetic profile of zolpidem in dogs was dose dependent, and the plasma drug concentrations attained were lower than those for humans administered equivalent doses. The lower dose did not result in any clinical or adverse effects, but the higher dose generated paradoxical CNS stimulation of approximately 1 hour's duration and a subsequent short phase of mild sedation. This sedation phase was not considered to be of clinical relevance. The desired clinical effects were not evident at plasma zolpidem concentrations <= 30 ng/mL, and the minimal plasma concentration that induced adverse effects was 60 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that zolpidem is not a suitable drug for inducing sedation in dogs. PMID- 23013194 TI - Urodynamic and morphometric characteristics of the lower urogenital tracts of female Beagle littermates during the sexually immature period and first and second estrous cycles. AB - OBJECTIVE: To compare values of lower urogenital tract urodynamic and morphometric variables determined during the prepubertal (sexually immature) period and first and second estrous cycles in healthy female Beagle littermates to determine functional and anatomic changes of the lower urogenital tract during those periods. ANIMALS: 5 female Beagle littermates. PROCEDURES: Urethral pressure profilometry, diuresis cystometry, and vaginourethrography were performed when dogs were 3.5, 4.5, 5, 6, 7, 8, 8.5, and 9 months old and during proestrus; estrus; early, middle, and late diestrus; and early and late anestrus of the first and second estrous cycles. RESULTS: At the end of the prepubertal period, values of urodynamic and morphometric variables increased significantly, compared with values at earlier times. Maximum bladder capacity developed when dogs were 9 months old. In all dogs, the bladder was intermittently located in an intrapelvic position during the prepubertal period; the bladder was intra abdominal from the time dogs were 9 months old until the end of the study. Urethral pressure decreased significantly during estrus and early diestrus of the first and second estrous cycles. Bladder capacity increased significantly during diestrus of both estrous cycles. Urethral and vaginal lengths were significantly longer during proestrus and estrus than they were during anestrus. CONCLUSIONS AND CLINICAL RELEVANCE: Values of lower urogenital tract urodynamic and morphometric variables were influenced by age and phases of the estrous cycle of immature and young adult Beagles in this study. Age of dog and phase of estrous cycle should be considered when interpreting urodynamic and vaginourethrography data. PMID- 23013195 TI - Effects of sterilization with hydrogen peroxide gas plasma, ethylene oxide, and steam on bioadhesive properties of nylon and polyethylene lines used for stabilization of canine stifle joints. AB - OBJECTIVE: To compare effects of sterilization with hydrogen peroxide gas plasma (HPGP), ethylene oxide, and steam on bioadhesive properties of nylon and polyethylene lines used for stabilization of canine stifle joints. SAMPLE: Samples of a 36.3-kg test nylon leader line, 57.8-kg test nylon fishing line, and 2-mm ultrahigh-molecular weight polyethylene (UHMWPE) were used. PROCEDURES: In this in vitro study, samples of nylon leader line, fishing line, and UHMWPE sterilized by use of HPGP, ethylene oxide, and steam or unsterilized samples were used. Bacterial adherence on unsterilized and sterilized samples was tested with Staphylococcus epidermidis and Escherichia coli. Five samples were examined for each line type and sterilization condition, and final colony counts were obtained. RESULTS: Bacterial adherence was significantly affected by method of sterilization for all 3 line types. For most of the samples, bacterial adherence was similar or lower when HPGP sterilization was used, compared with results for sterilization via ethylene oxide and steam, respectively. Bacterial adherence was significantly higher for UHMWPE, compared with adherence for the nylon line, regardless of the sterilization method used. Bacterial adherence was higher for nylon fishing line than for nylon leader line for S epidermidis after ethylene oxide sterilization and for E coli after HPGP and ethylene oxide sterilization. CONCLUSIONS AND CLINICAL RELEVANCE: Effects of HPGP sterilization on bioadhesive properties of nylon and polyethylene lines compared favorably with those for ethylene oxide and steam sterilization. Also, nylon line may be a more suitable material than UHMWPE for suture prostheses on the basis of bacterial adherence properties. PMID- 23013196 TI - Randomized controlled field trial to assess efficacy of a Moraxella bovis pilin cytotoxin-Moraxella bovoculi cytotoxin subunit vaccine to prevent naturally occurring infectious bovine keratoconjunctivitis. AB - OBJECTIVE: To evaluate efficacy of a recombinant Moraxella bovis pilin-cytotoxin Moraxella bovoculi cytotoxin subunit vaccine to prevent naturally occurring infectious bovine keratoconjunctivitis (IBK). ANIMALS: 107 beef steers. PROCEDURES: 2 groups of calves were inoculated SC with an immunostimulating complex (ISCOM) matrix adjuvant (control group; n = 54) or a recombinant M bovis pilin-cytotoxin-M bovoculi cytotoxin subunit antigen with the ISCOM matrix adjuvant (vaccine group; 53); calves received booster injections 21 days later. Calves were examined once weekly for 16 weeks. Investigators and herd managers were not aware of the inoculum administered to each calf throughout the trial. Primary outcome of interest was the cumulative proportion of calves that developed IBK. Serum samples were obtained before inoculation (day 0) and on days 42 and 112. Serum hemolysin-neutralizing titers against native M bovis and M bovoculi cytotoxin were determined. RESULTS: No difference was detected between groups for the cumulative proportion of calves that developed IBK at weeks 8 and 16 after inoculation. Non-IBK-affected calves in the vaccine group had a significantly higher fold change in serum hemolysin-neutralizing titer against native M bovoculi cytotoxin from day 0 to 42 compared to control calves. CONCLUSIONS AND CLINICAL RELEVANCE: The M bovis pilin-cytotoxin-M bovoculi cytotoxin subunit vaccine with the ISCOM matrix adjuvant was not effective at preventing naturally occurring IBK. It is likely that the incorporation of additional protective antigens in a recombinant Moraxella spp subunit vaccine will be required to yield a product that can be used for effective immunization of cattle against IBK. PMID- 23013197 TI - Grover's disease secondarily infected with herpes simplex virus and Staphylococcus aureus: case report and review. AB - The case of a 73-year old man with herpes simplex and staphylococcus aureus infection complicating established Grover's disease is presented. This was treated successfully with valaciclovir. While reports of bacterial and herpetic infections complicating other acantholytic diseases, such as Darier's disease, have been published previously, only one publication to date shows herpes simplex infection in Grover's disease. PMID- 23013198 TI - Influence of hyperthermophilic protein Cren7 on the stability and conformation of DNA: insights from molecular dynamics simulation and free energy analysis. AB - Cren7, a novel chromatin protein highly conserved among crenarchaea, plays an important role in genome packaging and gene regulation. However, the detail dynamical structural characteristic of the Cren7-DNA complex and the detail study of the DNA in the complex have not been done. Focused on two specific Cren7-DNA complexes (PDB codes 3LWH and 3LWI ), we applied molecular dynamics (MD) simulations at four different temperatures (300, 350, 400, and 450 K) and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculation at 300 and 350 K to examine the role of Cren7 protein in enhancing the stability of DNA duplexes via protein-DNA interactions, and to study the structural transition in DNA. The simulation results indicate that Cren7 stabilizes DNA duplex in a certain temperature range in the binary complex compared with the unbound DNA molecules. At the same time, DNA molecules were found to undergo B-like to A-like form transitions with increased temperature. The results of statistical analyses of the H-bond and hydrophobic contacts show that some residues have significant influence on the structure of DNA molecules. Our work can give important information to understand the interactions of proteins with nucleic acids and other ligands. PMID- 23013199 TI - Challenges in applying diabetes technology to clinical care. PMID- 23013200 TI - Advanced meter features improve postprandial and paired self-monitoring of blood glucose in individuals with diabetes: results of the Actions with the CONTOUR Blood Glucose Meter and Behaviors in Frequent Testers (ACT) study. AB - BACKGROUND: This study evaluated whether education and use of the advanced meter features of the CONTOUR((r)) (Bayer HealthCare LLC, Diabetes Care, Tarrytown, NY) blood glucose monitoring system (BGMS) affect the frequency and pattern of blood glucose testing in insulin-using subjects with diabetes who routinely perform self-monitoring of blood glucose (SMBG). SUBJECTS AND METHODS: Insulin-using subjects with type 1 or type 2 diabetes were enrolled in this 6-month, multicenter, prospective study and randomized to one of two groups. The basic meter features group (BMF group) received basic instruction in the use of the BGMS, whereas the advanced meter features group (AMF group) also received training in the use of advanced features, including the meal marker and audible reminder, and were instructed to use these features. Both groups received education on the importance of postprandial testing. RESULTS: The AMF group (n=105) had significantly greater average weekly postprandial blood glucose testing than the BMF group (n=106) at each follow-up visit (P<0.001) and significantly increased the frequency of paired blood glucose testing (P<0.001) as well. In both groups, glycated hemoglobin decreased significantly as postprandial testing frequency increased (P<0.05). Subject reports indicated that use of advanced features made postmeal SMBG considerably easier to remember, helped them better understand how to make decisions on their own, and increased their confidence in meal choices. CONCLUSIONS: Study findings showed that advanced features of the CONTOUR BGMS increased structured testing as measured by postprandial and paired SMBG and were perceived as useful by patients. PMID- 23013201 TI - Use of continuous glucose monitoring as an outcome measure in clinical trials. AB - OBJECTIVE: Although developed to be a management tool for individuals with diabetes, continuous glucose monitoring (CGM) also has potential value for the assessment of outcomes in clinical studies. We evaluated using CGM as such an outcome measure. RESEARCH DESIGN AND METHODS: Data were analyzed from six previously completed inpatient studies in which both CGM (Freestyle NavigatorTM [Abbott Diabetes Care, Alameda, CA] or Guardian((r)) [Medtronic, Northridge, CA]) and reference glucose measurements were available. The analyses included 97 days of data from 93 participants with type 1 diabetes (age range, 5-57 years; mean, 18 +/- 12 years). RESULTS: Mean glucose levels per day were similar for the CGM and reference measurements (median, 148 mg/dL vs. 143 mg/dL, respectively; P = 0.92), and the correlation of the two was high (r = 0.89). Similarly, most glycemia metrics showed no significant differences comparing CGM and reference values, except that the nadir glucose tended to be slightly lower and peak glucose slightly higher with reference measurements than CGM measurements (respective median, 59 mg/dL vs. 66 mg/dL [P = 0.05] and 262 mg/dL vs. 257 mg/dL [P = 0.003]) and glucose variability as measured with the coefficient of variation was slightly lower with CGM than reference measurements (respective median, 31% vs. 35%; P<0.001). CONCLUSIONS: A reasonably high degree of concordance exists when comparing outcomes based on CGM measurements with outcomes based on reference blood glucose measurements. CGM inaccuracy and underestimation of the extremes of hyperglycemia and hypoglycemia can be accounted for in a clinical trial's study design. Thus, in appropriate settings, CGM can be a very meaningful and feasible outcome measure for clinical trials. PMID- 23013202 TI - Transdermal insulin application system with dissolving microneedles. AB - BACKGROUND: The aim of this report was to develop a dissolving microneedle (DM) application system, where 225-300 insulin-loaded DMs were formed on a chip. After the heat-sealed sheet is removed, the system covered with the press-through package layer is put on the skin. By pressing with the hand, insulin DMs were inserted into the skin. MATERIALS AND METHODS: Factors affecting the penetration depth of DM were studied using applicator in vitro and in vivo experiments. The penetration depth was determined for rat and human skin. Two-layered DM array chips were prepared to obtain complete absorption of insulin and administered to the rat abdominal skin. Plasma glucose levels were measured for 6 h. By comparing the hypoglycemic effect with that obtained after subcutaneous injection, relative pharmacological availability (RPA) was determined. RESULTS: The penetration depth increased from 21 +/- 3 MUm to 63 +/- 2 MUm in proportion to application speed to isolated rat skin, at 0.8-2.2 m/s. Human skin showed similar results in the penetration depth. The in vivo penetration depth was dependent on the force (0.5 2.5 N) and duration (1-10 min), as the secondary application force. The penetration depth was 211 +/- 3 MUm with a duration of 3 min in the in vivo rat experiment. DM array chips having an insulin-loaded space of 181.2 +/- 4.2 and 209 +/- 3.9 MUm were evaluated in the rat. RPA values of insulin from DMs were 98.1 +/- 0.8% and 98.1 +/- 3.1%, respectively. CONCLUSIONS: These results suggest the usefulness of the two-layered DM application system for the transdermal delivery of insulin. PMID- 23013204 TI - Hemoglobin A1c values and CGM. PMID- 23013206 TI - Chemically self-assembled antibody nanostructures as potential drug carriers. AB - Chemically self-assembled antibody nanorings (CSANs) displaying multiple copies of single-chain variable fragments can be prepared from dihydrofolate reductase (DHFR) fusion proteins and bis-methotrexate (bisMTX). We have designed and synthesized a bisMTX chemical dimerizer (bisMTX-NH(2)) that contains a third linker arm that can be conjugated to fluorophores, radiolabels, and drugs. Monovalent, divalent, and higher-order AntiCD3 CSANs were assembled with a fluorescein isothiocyanate (FITC)-labeled bis-methotrexate ligand (bisMTX-FITC) and found to undergo rapid internalization and trafficking by HPB-MLT, a CD3+ T leukemia cell line, to the early and late endosome and lysosome. Because the fluorescence of bisMTX-FITC when incorporated into CSANs was found to be significantly greater than that of the free ligand, the stability of the endocytosed AntiCD3 CSANs could be monitored. The internalized CSANs were found to be stable for several hours, while treatment with the nontoxic DHFR inhibitor trimethoprim resulted in a rapid loss (>80%) of cellular fluorescence within minutes, consistent with efficient intracellular disassembly of the nanorings. Over longer time periods (24 h), cellular fluorescence decreased by 75-90%, regardless of whether cells had been treated with DMSO or trimethoprim. Although bisMTX is a potent inhibitor of DHFR, it was found to be nontoxic (GI(50) > 20 MUM) to HPB-MLT cells. In contrast, AntiCD3 CSANs prepared with bisMTX were found to be at least 13-fold more cytotoxic (GI(50) = 0.5-1.5 MUM) than bisMTX at 72 h. Consistent with our findings from CSAN stability studies, no increase in cytotoxicity was observed upon treatment with trimethoprim. Taken together, our results suggest that cell receptor targeting CSANs prepared with trifunctional bisMTX could be used as potential tissue selective drug carriers. PMID- 23013207 TI - A 24-week randomized clinical trial investigating the efficacy and safety of two doses of etanercept in nail psoriasis. AB - BACKGROUND: Nail psoriasis is common in patients with psoriasis and can seriously affect their quality of life. Current treatments are limited and there is no standard course of therapy. OBJECTIVES: To assess the efficacy and safety of etanercept (ETN) on nail psoriasis in patients with moderate-to-severe psoriasis. METHODS: Patients with moderate-to-severe plaque psoriasis, who had previously failed at least one form of systemic therapy for nail psoriasis, were randomized to receive open-label ETN 50 mg twice weekly (BIW) for 12 weeks followed by once weekly (QW) for 12 weeks (BIW/QW group) or ETN 50 mg QW for 24 weeks (QW/QW group). The primary endpoint was the mean improvement in the Nail Psoriasis Severity Index (NAPSI; score range 0-8) over 24 weeks in the target fingernail with the most severe abnormalities. RESULTS: Seventy-two patients received one or more doses of ETN (38 BIW/QW; 34 QW/QW) and 69 patients were included in the modified intent-to-treat population. At baseline, mean (standard error) target fingernail NAPSI score was 6.0 (0.3) in the BIW/QW group and 5.8 (0.3) in the QW/QW group. At week 24, mean target fingernail NAPSI score had decreased significantly by -4.3 [95% confidence interval (CI) -4.9 to -3.7; P < 0.0001] in the BIW/QW group and by -4.4 (95% CI -5.0 to -3.7; P < 0.0001) in the QW/QW group. Improvement in NAPSI showed significant correlation with Psoriasis Area and Severity Index improvement. ETN was well tolerated with no unexpected safety findings. CONCLUSIONS: Both ETN regimens were effective at treating nail psoriasis in this patient population. PMID- 23013208 TI - Pharmacokinetics of 450 mg ropivacaine with and without epinephrine for combined femoral and sciatic nerve block in lower extremity surgery. A pilot study. AB - AIMS: No pharmacokinetic data exist on doses of ropivacaine larger than 300 mg for peripheral nerve block in man, although in clinical practice higher doses are frequently used. The purpose of the present study was to describe the pharmacokinetic profile in serum of 450 mg ropivacaine with and without epinephrine in patients undergoing anterior cruciate ligament reconstruction. METHODS: Twelve patients were randomly allocated to receive a single shot combined sciatic/femoral nerve block with 60 ml of either ropivacaine 0.75% alone (group R, n = 6) or ropivacaine 0.75% plus epinephrine 5 MUg ml(-1) (group RE, n = 6). Venous blood samples for total and free ropivacaine serum concentrations were obtained during 48 h following block placement. Pharmacokinetic parameters were calculated using a non-compartmental approach. RESULTS: Results are given as mean (SD) for group R vs. group RE (95% CI of the difference). Total Cmax was 2.81 (0.94) MUg ml(-1) vs. 2.16 (0.21) MUg ml(-1) (95% CI -0.23, 1.53). tmax was 1.17 (0.30) h vs. 1.67 (0.94) h (95% CI -1.40, 0.40). The highest free ropivacaine concentration per patient was 0.16 (0.08) MUg ml(-1) vs. 0.12 (0.04) MUg ml(-1) (95% CI -0.04, 0.12). t(1/2) was 6.82 (2.26) h vs. 5.48 (1.69) h (95% CI -1.23, 3.91). AUC was 28.35 (5.92) MUg ml(-1) h vs. 29.12 (7.34) MUg ml(-1) h (95% CI -9.35, 7.81). CONCLUSIONS: Free serum concentrations of ropivacaine with and without epinephrine remained well below the assumed threshold of 0.56 MUg ml(-1) for systemic toxicity. Changes in pharmacokinetics with epinephrine co administration did not reach statistical significance. PMID- 23013209 TI - Rates of change in liver copper concentration in cattle given a copper-deficient diet, with or without pre-treatment with tetrathiomolybdate, for evaluation of two parenteral copper supplements. AB - AIM: To minimise the impact of initial variation in liver copper (Cu) on assessments of Cu supplements for cattle in depletion/repletion experiments. METHODS: Efficacy of two Cu injections was assessed with 18 calves, weighing 200 250 kg, given a Cu-deficient barley diet, containing 4.1 mg Cu/kg dry matter (DM) and added molybdenum (3 mg/kg) and sulphur (3 g/kg). Initial liver biopsy Cu ranged from 3.15-14.17 mmol/kg DM and nine calves with the highest values were given three subcutaneous injections of 235 mg tetrathiomolybdate (TTM) after 42 46 days depletion to lower liver Cu. Untreated (L) and TTM-treated (H) calves were ranked separately for liver Cu after 50 days depletion and allocated to one of three treatments: 100 mg Cu given subcutaneously as CuCaEDTA in either a paraffin (CuP) or aqueous base (CuA) after 56 days depletion (Day 0) or no injection (O). Thereafter, plasma and liver biopsy Cu were measured every 2-4 weeks for 16 weeks. Responses in liver Cu to Cu injections were compared with and without loge transformation and by linear regression. RESULTS: Prior to Cu injection, the fractional decline in liver Cu concentration (FDLCu) after 50 days depletion was 0.64 (SE 0.066) and 0.80 (SE 0.090) in H and L calves, respectively (p=0.09) and mean liver Cu did not differ on Day -6 (6.65 (SE 0.516) and 4.91 (SE 0.681) mmol/kg DM, respectively). Mean plasma Cu was higher in H than L calves on Day 0 (16.6 (SE 0.52) and 13.3 (SE 0.49) MUmol/L, respectively (p<0.001)). Rates of decline in loge liver Cu between Days 0-84 in treatments L and H were: 0.0138 and 0.0071 for Groups O; 0.0033 and 0.0016 for Groups CuP; 0.0073 and 0.0049 for Groups CuA (pooled SE 0.0014) mmol/kg DM/day, respectively. Between Days 84-114, FDLCu was uniformly high across experiments and groups (0.59 (SE 0.042)). Cu injections did not affect plasma Cu, which remained 3.1 (SE 0.41) umol/L higher in Experiment H than in L (p=0.017). CONCLUSIONS: The use of rates of change in liver copper concentrations improved the assessment of efficacy for two parental copper supplements and that of pre-treatment with tetrathiomolybdate, which, contrary to expectation, slowed Cu turnover by mechanisms that remain unclear. PMID- 23013211 TI - Alopecia areata in a composite tissue (hand) allograft recipient following graft rejection. PMID- 23013210 TI - Percutaneous injuries amongst Greek endodontists: a national questionnaire survey. AB - AIM: To investigate amongst Greek endodontists the incidence of percutaneous injuries, the circumstances associated with them, the therapeutic measures taken after the injuries and their compliance with infection control measures. METHODOLOGY: One hundred and forty-seven endodontists met the inclusion criteria and were invited to participate in the survey. Personal and professional data, information on percutaneous injuries in the past 5 years and on infection control practices were gathered through interviews based on a questionnaire. Data were analysed using chi-square test, independent samples t-test, one-way anova and Pearson's correlation coefficient. The level of significance was set at P = 0.05. RESULTS: The response rate was 84%. The injury rate was estimated at 1.35 per endodontist per year. Endodontic files were associated with 37% of the injuries and fingers were injured in 75% of the most recent cases. Medical assistance was sought in 36% of the most recent injuries. Endodontists who always or usually practiced 4-handed endodontics (P = 0.007) as well as those not performing surgical endodontics (P = 0.007) reported significantly fewer injuries. In 91% of the participants, a complete hepatitis B virus vaccination was reported. Gloves, masks, rubber dam isolation and puncture-resistant containers for disposal of sharp instruments were always used by 98%, 94%, 100% and 81% of the respondents, respectively. CONCLUSIONS: The injury rate was low. The practice of four-handed endodontics was associated with a reduced number of percutaneous injuries; the performance of surgical endodontics increased their incidence. Greek endodontists showed a high level of compliance with infection control measures. PMID- 23013212 TI - Mental health nursing and the problematic of supervision as a confessional act. AB - Mental health nurses frequently draw on self-disclosure practices within their working relationships. These 'confessional' acts can in turn be predicated on traditional assumptions of moral authority exercised by more senior colleagues. More broadly, attention has been drawn to the increasing significance of 'technologies of the self' inside neo-liberal regimes of governance. Through various forms of self-disclosure people are obliged 'to speak the truth about themselves'. By publically declaring themselves as 'fit for purpose' nurses are required to be reflexive, self-monitoring individuals, capable of constructing their own identities and biographies, and guided by expert knowledges. In this way, risk becomes a form of governance, as the individuals continually find themselves balancing risks and opportunities. Foucault's insights into the importance of 'care of the self' and 'surveillance of the self' to systems of social order and governance, such as mental health services, are significant in identifying nursing as a potential form of confessional practice. 'Reflective practice' and 'clinical supervision' are therefore 'technologies', functioning as 'modes of surveillance', and as 'confessional practices'. So 'clinical supervision' may be understood as part of a process of 'governance' that does not necessarily empower nurses, but can act to guide, correct and modify ways in which they conduct themselves. PMID- 23013213 TI - Tunable ionic mobility filter for depletion zone isotachophoresis. AB - We present a novel concept of filtering based on depletion zone isotachophoresis (dzITP). In the micro/nanofluidic filter, compounds are separated according to isotachophoretic principles and simultaneously released selectively along a nanochannel-induced depletion zone. Thus, a tunable low-pass ionic mobility filter is realized. We demonstrate quantitative control of the release of fluorescent compounds through the filter using current and voltage actuation. Two modes of operation are presented. In continuous mode, supply, focusing, and separation are synchronized with continuous compound release, resulting in trapping of specific compounds. In pulsed mode, voltage pulses result in release of discrete zones. The dzITP filter was used to enhance detection of 6 carboxyfluorescein 4-fold over fluorescein, even though it had 250* lower starting concentration. Moreover, specific high-mobility analytes were extracted and enriched from diluted raw urine, using fluorescein as an ionic mobility cutoff marker and as a tracer for indirect detection. Tunable ionic filtering is a simple but essential addition to the capabilities of dzITP as a versatile toolkit for biochemical assays. PMID- 23013214 TI - Crystal structure of HutZ, a heme storage protein from Vibrio cholerae: A structural mismatch observed in the region of high sequence conservation. AB - BACKGROUND: HutZ is the sole heme storage protein identified in the pathogenic bacterium Vibrio cholerae and is required for optimal heme utilization. However, no heme oxygenase activity has been observed with this protein. Thus far, HutZ's structure and heme-binding mechanism are unknown. RESULTS: We report the first crystal structure of HutZ in a homodimer determined at 2.0 A resolution. The HutZ structure adopted a typical split-barrel fold. Through a docking study and site directed mutagenesis, a heme-binding model for the HutZ dimer is proposed. Very interestingly, structural superimposition of HutZ and its homologous protein HugZ, a heme oxygenase from Helicobacter pylori, exhibited a structural mismatch of one amino acid residue in beta6 of HutZ, although residues involved in this region are highly conserved in both proteins. Derived homologous models of different single point variants with model evaluations suggested that Pro140 of HutZ, corresponding to Phe215 of HugZ, might have been the main contributor to the structural mismatch. This mismatch initiates more divergent structural characteristics towards their C-terminal regions, which are essential features for the heme-binding of HugZ as a heme oxygenase. CONCLUSIONS: HutZ's deficiency in heme oxygenase activity might derive from its residue shift relative to the heme oxygenase HugZ. This residue shift also emphasized a limitation of the traditional template selection criterion for homology modeling. PMID- 23013215 TI - Linear and cyclic amides with a thiophene backbone: ultrasound-promoted synthesis and crystal structures. AB - A full synthetic study of linear and cyclic thiophene oligoamides has been carried out. The combination of an ultrasonic technique to diminish the intramolecular backfolding of longer oligoamide chains, therefore enhancing the accessibility of the carboxylic acid, and T3P as coupling reagent led to shorter reaction time and higher yields for both linear and cyclic oligoamides. By controlling the degree of dilution, macrocyclic amides with different sizes can selectively be prepared. Different crystal structures of cyclic thiophene oligoamides were also analyzed. PMID- 23013216 TI - Factors associated with delayed delivery of infant in Cesarean section. PMID- 23013218 TI - Characterising the impacts of emerging energy development on wildlife, with an eye towards mitigation. AB - Global demand for energy is projected to increase by 40% in the next 20 years, and largely will be met with alternative and unconventional sources. Development of these resources causes novel disturbances that strongly impact terrestrial ecosystems and wildlife. To effectively position ecologists to address this prevalent conservation challenge, we reviewed the literature on the ecological ramifications of this dominant driver of global land-use change, consolidated results for its mitigation and highlighted knowledge gaps. Impacts varied widely, underscoring the importance of area and species-specific studies. The most commonly reported impacts included behavioural responses and direct mortality. Examinations of mitigation were limited, but common easements included (1) reduction of the development footprint and human activity, (2) maintenance of undeveloped, 'refuge' habitat and (3) alteration of activity during sensitive periods. Problematically, the literature was primarily retrospective, focused on few species, countries, and ecoregions, and fraught with generalisations from weak inference. We advocate future studies take a comprehensive approach incorporating a mechanistic understanding of the interplay between development caused impacts and species ecology that will enable effective mitigation. Key areas for future research vital to securing a sustainable energy future in the face of development-related global change are outlined. PMID- 23013217 TI - Analysis of polymorphisms in interleukin-10, interleukin-6, and interleukin-1 receptor antagonist in Mexican-Mestizo women with pre-eclampsia. AB - Due to the fact that studies seeking associations of polymorphisms in regulatory regions of cytokine genes with pre-eclampsia (PE) have not always been consistent in different population analyses, the aim of this study was to investigate the possible association between rs1800896 of interleukin-10 (IL-10), rs1800795 of interleukin-6 (IL-6), and the variable number of tandem repeats (VNTR) in intron 2 of interleukin-1 receptor antagonist (IL-1Ra), as well as gene-gene interactions between these three polymorphisms with the presence of PE in Mexican Mestizo women and one Amerindian population from Mexico (Maya). A case-control study was performed where 411 pre-eclamptic cases and 613 controls were genotyped. For the rs1800896 of IL-10 and rs1800795 of IL-6, we used real-time polymerase chain reaction (PCR) allelic discrimination and for the VNTR of IL 1Ra, PCR. Allele frequency differences were assessed by Chi-squared test; logistic regression was used to test for associations; a gene-gene interaction was conducted. Genotypic and allelic distribution of the polymorphisms was similar in our population. The estimated of the gene-gene interaction between the polymorphisms did not differ significantly. However, we observed important differences in the distribution of the alleles and genotypes of the three polymorphisms analyzed between Mestiza-Mexicanas and Maya-Mestizo women. In conclusion, we did not find an association between polymorphisms in IL-10, IL-6, and IL-1Ra and PE in Mexican-Mestizo and Maya-Mestizo women. To our knowledge, this is the first time that these three polymorphisms were analyzed together with gene-gene interaction in women with PE. PMID- 23013219 TI - Angiogenic effect of endothelial progenitor cells transfected with telomerase reverse transcriptase on peritubular microvessel in five out of six subtotal nephrectomy rats. AB - Renal disease is caused by tubular interstitial injury and renal interstitial fibrosis. Previous studies have shown that transplantation of endothelial progenitor cells (EPCs) may provide an appropriate treatment for repair and reversing renal pathology. However, EPCs are typically low in abundance and have poor replication ability. Therefore, the this study investigated the use of EPCs transfected with the telomerase reverse transcriptase (TERT) in rats that had undergone five out of six subtotal nephrectomy. This study determined the effects of EPC transplantation on renal function, renal interstitial fibrosis, and peritubular capillary angiogenesis. Five groups of rats were investigated: sham group, model group (five out of six subtotal nephrectomy), EPCs-N group (transplantation with EPCs), pZ-TERT-EPCs-N group (transplantation with EPCs transfected with TERT), and pZ-EPCs-N group (transplantation with EPCs transfected with empty plasmid). At weeks 4, 8, and 12 after transplantation, renal function, renal interstitial fibrosis, and peritubular microvessel density (MVD) were investigated. EPCs transfected with TERT gene showed decreased in vitro senescence, apoptosis, and proliferative ability was significantly enhanced (p < 0.05). Furthermore, rat transplanted with EPCs transfected with TERT showed significantly reduced renal interstitial fibrosis and increased endogenous creatinine clearance rate and peritubular MVD (p < 0.05). The transplantation of EPCs expressing TERT into five out of six subtotal nephrectomy rats was shown to improve renal function, reduce loss of peritubular microvessel, and inhibit progression of renal interstitial fibrosis. These studies provide the basis for a potential treatment of renal disease using genetically modified EPCs. PMID- 23013220 TI - Triple valve endocarditis by mycobacterium tuberculosis: a case report. AB - BACKGROUND: Granulomas caused by Mycobacterium Tuberculosis have been observed at autopsy in the heart, pre-dominantly in the myocardium and endocardium, but rarely involving the coronary vessels and valvular structures. Mycobacterium tuberculosis valvular endocarditis is extremely rare, with most reports coming from autopsy series. CASE PRESENTATION: We report the case of a 17 year old immunocompetent girl who presented with history of fever, malaise, foot gangrene and a left sided hemiparesis. On investigation she was found to have infective endocarditis involving the aortic, mitral and tricuspid valves. She had developed a right middle cerebral artery stroke. She underwent dual valve replacement and tricuspid repair. The vegetations showed granulomatous inflammation but blood cultures and other biological specimen cultures were negative for any organisms. She was started on antituberculous treatment and anticoagulation. CONCLUSION: This is the first reported case of triple valve endocarditis by Mycobacterium Tuberculosis in an immunocompetent host. Especially important is the fact that the right heart is involved which has been historically described in the setting of intravenous drug abuse.This implies that Tuberculosis should be considered in cases of culture negative endocarditis in endemic areas like Pakistan even in immunocompetent hosts. PMID- 23013221 TI - Inhibition of uranium(VI) sorption on titanium dioxide by surface iron(III) species in ferric oxide/titanium dioxide systems. AB - Uranium (U(VI)) sorption in systems containing titanium dioxide (TiO(2)) and various Fe(III)-oxide phases was investigated in the acidic pH range (pH 2.5-6). Studies were conducted with physical mixtures of TiO(2) and ferrihydrite, TiO(2) with coprecipitated ferrihydrite, and with systems where Fe(III) was mostly present as crystalline Fe(III) oxides. The presence of ferrihydrite resulted in decreased U(VI) sorption relative to the pure TiO(2) systems, particularly below pH 4, an unexpected result given that the presence of another sorbent would be expected to increase U(VI) uptake. In mixtures of TiO(2) and crystalline Fe(III) oxide phases, U(VI) sorption was higher than for the analogous mixtures of TiO(2) with ferrihydrite, and was similar to U(VI) sorption on TiO(2) alone. X-ray absorption spectroscopy of the TiO(2) system with freshly precipitated Fe(III) oxides indicated the presence of an Fe(III) surface phase that inhibits U(VI) sorption-a reaction whereby Fe(III) precipitates as lepidocrocite and/or ferrihydrite effectively blocking surface sorption sites on the underlying TiO(2). Competition between dissolved Fe(III) and U(VI) for sorption sites may also contribute to the observed decrease in U(VI) sorption. The present study demonstrates the complexity of sorption in mixed systems, where the oxide phases do not necessarily behave in an additive manner, and has implications for U(VI) mobility in natural and impacted environments where Fe(III) (oxyhydr)oxides are usually assumed to increase the retention of U(VI). PMID- 23013222 TI - Haemorrhagic transformation of ischaemic stroke in young adults. AB - BACKGROUND: Frequency, factors associated with, and impact on outcome of haemorrhagic transformation in young adults with ischaemic stroke are unknown. METHODS: Consecutive young patients (age 15-49) with first-ever ischaemic stroke were included, having their first brain computed tomography/magnetic resonance imaging within seven-days of stroke onset, and second within seven-days from the first imaging. Haemorrhagic transformation in any imaging was classified as haemorrhagic infarct or parenchymal haemorrhage within or remote from the infarct. Symptomatic haemorrhagic transformation was defined according to the European Cooperative Acute Stroke Study II (ECASS II) criteria as any haemorrhage leading to a National Institutes of Health Stroke Scale score increase of >=4 points or death. Unfavourable three-month outcome was defined as a modified Rankin Scale 2-6. RESULTS: In 636 eligible patients, any haemorrhagic transformation occurred in 79 patients (12.4%; 10.0-15.2%): 66 (10.4%; 8.24 12.9%) had haemorrhagic infarct, and 13 (2.04%; 1.19-3.46%) had parenchymal haemorrhage. Symptomatic haemorrhagic transformation occurred in 16 patients (2.5%; 4.04-1.55%). In logistic regression analysis, independent factors associated with haemorrhagic transformation were large anterior (18.70; 6.72 52.04), large posterior (9.41; 3.13-28.25), medium-sized (odds ratio 3.30; 95% confidence interval 1.14-9.57) lesions, higher low-density lipoprotein level (1.44 per unit increment; 1.10-1.90), and lower platelet count (1.005 per unit decrement; 1.009-1.001). Haemorrhagic infarct (1.76; 0.76-4.11) or parenchymal haemorrhage (2.39; 0.23-24.76) were not associated with unfavourable functional outcome or death at three-months. CONCLUSIONS: In young adults, haemorrhagic transformation of ischaemic stroke occurred in comparable rates to haemorrhagic transformation in elderly patients. Although haemorrhagic transformation was more common in severe strokes, it was the lesion size and baseline stroke severity that were associated with three-month clinical outcome, not haemorrhagic transformation per se. PMID- 23013224 TI - Out of the frying pan and in to the fire? PMID- 23013226 TI - Comment on Nie et al. (2011), biometrics, early view. PMID- 23013227 TI - Remote epidural hemorrhage after unilateral decompressive hemicraniectomy in brain-injured patients. AB - Epidural hemorrhage (EDH) that develops remote from the decompressed hemisphere can be associated with devastating morbidity after hemicraniectomy for traumatic brain injury (TBI). In this study, we investigated the incidence, risk factors, and outcome influence of post-craniectomy remote EDH. For this retrospective study, we enrolled 139 patients undergoing unilateral hemicraniectomy for TBI. The patients were subdivided into two groups based on whether EDH remote from the site of bone decompression was present (n=11) or not (n=128). We identified the intergroup differences in clinical parameters and outcomes. Multivariate odds regression was used to adjust for independent risk factors of the development of EDH. The incidence of remote EDH following decompressive hemicraniectomy for TBI was 7.9%. There were two independent risk factors for remote EDH, including absence of contusional hemorrhage (odds ratio, 95% confidence interval=6.158, 1.090-34.802; p=0.040) and presence of remote skull fracture (odds ratio, 95% confidence interval=19.770, 2.194-178.152; p=0.008) in preoperative computed tomography scans. The mean Glasgow Outcome Scale did not differ between the patients with and without EDH. In conclusion, remote EDH in patients undergoing unilateral decompressive hemicraniectomy for TBI is not uncommon. The absence of contusional hemorrhage and presence of remote skull fracture are independent risk factors. Although postcraniectomy remote EDH is devastating, timely computed tomography scanning and immediate hematoma evacuation are efficient and crucial for patient outcomes. PMID- 23013228 TI - In situ unfolded lysozyme induces the lipid lateral redistribution of a mixed lipid model membrane. AB - Redistribution of charged lipids induced by polyelectrolytes is an intriguing phenomenon. Proteins, due to their nature as polyelectrolytes, should also have this capacity. But their highly ordered structures may bring about more complex mechanisms. We studied the interaction between positively charged lysozyme and liposomes consisting of neutral dipalmitoylphosphatidylcholine (DPPC) and negatively charged dioleoylphosphatidylglycerol (DOPG). Interestingly, the enrichment of DOPG cannot be induced by the native and ex situ unfolded (unfolded in the absence of liposomes) lysozyme, but requires that lysozyme undergo an in situ unfolding process (unfolding in the presence of liposomes). These observations suggest that, for proteins, the capacity to induce lipid redistribution relies on not only the net charges but also the spatial distribution of the charges. During the in situ unfolding process, lysozyme reorganizes its structure into a specially unfolded structure that is rich in flat beta-sheets and more "rigid" in the presence of lipid membrane. This special spatial structure changes the charge distribution and is advantageous to the protein-membrane electrostatic interaction and thus can induce lipid redistribution. PMID- 23013229 TI - Enantiomerically pure 1,3-dioxanes as highly selective NMDA and sigma1 receptor ligands. AB - We synthesized and investigated the NMDA and sigma1 receptor affinity of enantiomerically pure 2-(2-phenyl-1,3-dioxan-4-yl)ethanamines 17-26. The primary amines (R,R)-18-20 with an axially oriented phenyl moiety in position 2 interacted with high enantioselectivity (eudismic ratios 70-130) and high affinity (K(i)((R,R)-19) = 13 nM) with the PCP binding site of the NMDA receptor. Introduction of an N-benzyl moiety led to potent sigma1 ligands including compound (S,R)-22 (K(i) = 6 nM) with an equatorially oriented phenyl moiety in position 2. PMID- 23013230 TI - Taphonomy of hair--a study of postmortem root banding. AB - Although it has been generally accepted within the forensic hair community that decompositional changes in the form of an identifiable banding pattern can occur in the root area of hairs after death, little detailed information with regard to this phenomenon is known (e.g., rates at which this occurs and conditions that cause this banding). Hairs were collected daily from bodies placed in water, an air-conditioned environment, an enclosed vehicle, on the surface of the ground, and buried at the University of Tennessee Forensic Anthropology Center. The hairs were examined microscopically and the level of change documented for each environment. The onset of the banding was observed to have been delayed in water, air-conditioning, and cold weather and was hastened by warm weather and within the vehicle. This study provides validation that decomposition does produce varying effects on hair at the proximal portion of a hair root, including a dark band. PMID- 23013231 TI - Our authors focus on clinically relevant studies in this issue. PMID- 23013232 TI - A protective extracellular matrix-based gene delivery reservoir fabricated by electrostatic charge manipulation. AB - Gene therapy is a field that offers hope and promise for the treatment of diseases and traumas of a genetic nature and otherwise. However, progress toward the clinic has been delayed because of concerns over the safety of viral vectors and the efficacy of safer nonviral systems, which have low transfection efficacy and short transgene expression. This study describes the fabrication and characterization of a safe gene delivery reservoir system that has the potential to overcome issues associated with nonviral systems. Harnessing the electrostatic charges of collagen and polystyrene, microspheres were fabricated using a template-based method and characterized by microscopy techniques such as scanning electron microscopy, transmission electron microscopy, and atomic force microscopy, with the removal of the polystyrene template confirmed by Fourier transform infrared spectroscopy analysis. Loading and release of polyplexes confirmed the ability of the system to prolong polyplex delivery, with minimal cytotoxicity observed from viability studies on 3T3 fibroblasts. Finally, biological activity of released polyplexes was confirmed by reporter gene expression. Taken together, these properties indicate the potential of this system as a reservoir for gene delivery. PMID- 23013234 TI - Isolation and characterization of CD276+/HLA-E+ human subendocardial mesenchymal stem cells from chronic heart failure patients: analysis of differentiative potential and immunomodulatory markers expression. AB - Mesenchymal stem cells (MSCs) are virtually present in all postnatal organs as well as in perinatal tissues. MSCs can be differentiated toward several mature cytotypes and interestingly hold potentially relevant immunomodulatory features. Myocardial infarction results in severe tissue damage, cardiomyocyte loss, and eventually heart failure. Cellular cardiomyoplasty represents a promising approach for myocardial repair. Clinical trials using MSCs are underway for a number of heart diseases, even if their outcomes are hampered by low long-term improvements and the possible presence of complications related to cellular therapy administration. Therefore, elucidating the presence and role of MSCs that reside in the post-infarct human heart should provide essential alternatives for therapy. In the current article we show a novel method to reproducibly isolate and culture MSCs from the subendocardial zone of human left ventricle from patients undergoing heart transplant for post-infarct chronic heart failure (HSE MSCs, human subendocardial mesenchymal stem cells). By using both immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR), we demonstrated that these cells do express key MSCs markers and do express heart specific transcription factors in their undifferentiated state, while lacking strictly cardiomyocyte-specific proteins. Moreover, these cells do express immunomodulatory molecules that should disclose their further potential in immune modulation processes in the post-infarct microenvironment. Another novel datum of potentially relevant interest is the expression of cardiac myosin heavy chain at nucclear level in HSE-MSCs. Standard MSCs trilineage differentiation experiments were also performed. The present paper adds new data on the basic biological features of heart-resident MSCs that populate the organ following myocardial infarction. The use of heart-derived MSCs to promote in-organ repair or as a cellular source for cardiomyoplasty is a fascinating and challenging task, which deserves further research efforts. PMID- 23013235 TI - The prototype/willingness model, academic versus health-risk information, and risk cognitions associated with nonmedical prescription stimulant use among college students. AB - OBJECTIVES: Nonmedical prescription stimulant (NPS) use is an important problem among university students. The present studies applied the prototype-willingness model (Gibbons, Gerrard & Lane, 2003) to academic-based NPS use and examined the impact of academic versus health information on university students' NPS use cognitions. DESIGN AND METHODS: Study 1 used the prototype-willingness model to examine cognitions associated with academic-based willingness to use NPS. In Study 2, participants were randomly assigned to a control condition or to read information on the negative academic or negative health effects of NPS use. Beliefs, willingness, and expectation of engaging in future NPS use, prototypes of users, and perceived vulnerability were assessed. RESULTS: Students without a prescription for stimulants or a diagnosis of attention deficit hyperactivity disorder (ADHD) participated in each study (Ns = 555; 166). Twenty to thirty per cent reported NPS use, primarily for academic reasons. Controlling for past NPS, alcohol, and marijuana use: friends' NPS use, prototypes, perceived vulnerability, and negative health and positive academic beliefs were associated with willingness to use NPS in Study 1. Study 2 demonstrated that participants in the academic-information condition reported the lowest willingness and expectations as well as the least favourable prototypes of NPS users. Participants in the health-information condition reported the highest perceived vulnerability. CONCLUSIONS: These studies highlight: the utility of using a health model framework to examine NPS cognitions, the importance of examining beliefs about the behaviour, and the potential for academic and health information to reduce risky NPS use cognitions. PMID- 23013237 TI - The effect of fetal anemia on fetal cardiac troponin T in pregnancies complicated by RhD alloimmunization. AB - OBJECTIVE: To study the effect of fetal anemia on fetal cardiac troponin T (cTnT) in pregnancies complicated by RhD alloimmunization. METHOD: Twenty pregnant women complicated by RhD alloimmunization who underwent intrauterine transfusion (IUT) for treatment of fetal anemia were studied. Immediately before IUT, fetal blood was obtained for hemoglobin and cTnT measurements. RESULTS: Complete measurements of hemoglobin and cTnT before IUT were obtained in 49 procedures, of which 20 were first-time. The regression analysis between hemoglobin z-score and cTnT values in 49 procedures showed significant negative correlation (r = -0.43, p = 0.002, Regression equation Log(cTnT) = -1.5057 + -0.07563 Hb z-score). Cardiac TnT values before first IUT were significantly associated with perinatal death. In the group with elevated cTnT (n = 7), fetal or neonatal death was more frequent (2 IUD and 2 NND) when compared to normal cTnT group (n = 13, 1 IUD) (57.1 vs. 7.7%, p = 0.031, Fisher's exact test). CONCLUSION: Fetal blood concentration of cTnT before IUT was negatively correlated to hemoglobin z-score, and levels of cTnT help to manage the pregnancies complicated by RhD alloimmunization. PMID- 23013236 TI - Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers. AB - AIMS: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. METHODS: Two double blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). RESULTS: Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ~40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ~100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ~30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses >=5 mg and at 168 h postdose for >=10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ~80% maximal reduction. CONCLUSIONS: Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing. PMID- 23013238 TI - Social change in South Africa: a historical approach to relative deprivation. AB - Dramatic social change involves profound transformations that impact an entire group moving forward. Such is the reality for race relations in South Africa. Research has found that most people report a trajectory of group-based relative deprivation that appears to parallel actual historical events. However, a significant subset of respondents reported a trajectory in which the perceived status of their group remained stable despite dramatic social change. The first goal of our research was to assess whether both the historically 'assumed' and 'stable' group trajectories arise consistently among South Africans (N = 2,989). The second and more important goal was to identify the factors that might account for this dichotomy in perceived trajectory building on both traditional and recent advances in relative deprivation theory as well as on social identity theory. We hypothesized that higher levels of in-group identification would be associated with the historically assumed group trajectory. Results supported this hypothesis. The third goal was to link the different group trajectories with important psychological outcomes such as personal well-being, group self-esteem, and interracial attitudes. PMID- 23013239 TI - Online characterization of particles and gases with an ambient electrospray ionization source. AB - Methods for online characterization and quantification of gas- and particle-phase species greatly facilitate the study of aerosol particle formation and reaction mechanisms. An online method for aerosol analysis has been developed by altering a conventional electrospray ionization mass spectrometer to direct the aerosol flow through the nebulizing gas inlet. Interaction between the aerosol and electrospray droplets produces ions that are subsequently analyzed by MS or MS/MS with a quadrupole ion trap mass analyzer. Performance is assessed using both particle-phase (cesium iodide, glycine) and gas-phase (dimethylamine, dimethylnapthylamine) analytes as well as a secondary organic aerosol (SOA) produced by ozonolysis of alpha-pinene. Analyte signal intensity is strongly dependent on solubility in the electrospray solvent, suggesting that the predominant ionization mechanism involves extraction of the analyte into the electrospray droplets. For gas-phase analytes, gas-phase charge transfer also appears to play a minor role in ion formation. As currently configured, the source is capable of characterizing oligomers in a SOA at a mass loading of <30 MUg/m(3) and quantifying alkyl amine concentrations between approximately 8 ppb and 1 ppm. PMID- 23013240 TI - Antibacterial, anti-HIV-1 protease and cytotoxic activities of aqueous ethanolic extracts from Combretum adenogonium Steud. Ex A. Rich (Combretaceae). AB - BACKGROUND: Records have shown that Combretum adenogonium Steud. Ex A. Rich (Combretaceae) is used in traditional medicine systems of several tribes in Tanzania. This study focused on the investigation of antibacterial activity, anti HIV-1 protease activity, toxicity properties and classes of phytochemicals in extracts from C. adenogonium Steud. Ex A. Rich (Combretaceae) to evaluate potential of these extracts for development as herbal remedies. METHODS: Dried plant material were ground to fine powder and extracted using 80% aqueous ethanol to afford root, leaf and stem bark extracts. The extracts were assayed for anti HIV-1 protease activities, antibacterial activities using microdilution methods and cytotoxicity using brine shrimps lethality assay. Screening for major phytochemical classes was carried out using standard chemical tests. RESULTS: All extracts exhibited antibacterial activity to at least one of the test bacteria with MIC-values ranging from 0.31-5.0 mg/ml. Two extracts, namely, root and stem bark exhibited anti-HIV-1 PR activity with IC50 values of 24.7 and 26.5 MUg/ml, respectively. Stem bark and leaf extracts showed mild toxicity with LC50 values of 65.768 MUg/ml and 76.965 MUg/ml, respectively, whereas roots were relatively non-toxic (LC50 = 110.042 MUg/ml). Phytochemical screening of the extracts indicated presence of flavonoids, terpenoids, alkaloids, tannins, glycosides and saponins. CONCLUSION: These results provide promising baseline information for the potential development of C. adenogonium extracts in treatment of bacterial and HIV/AIDS-related opportunistic infections. PMID- 23013241 TI - Occupational exposure to aluminum and its biomonitoring in perspective. AB - Exposure to aluminum at work is widespread, and people are exposed to several species of aluminum, which differ markedly as to the kinetics and toxicity. Especially welding of aluminum is widely applied and continuously expanding. Inhalation of fine particles of sparsely soluble aluminum results in the retention of deposited particles in the lungs. From the lungs, aluminum is released to the blood and distributed to bones and the brain, and excreted to urine. Soluble aluminum compounds are not accumulated in the lungs. Neurotoxicity is the critical effect of exposure to sparsely soluble aluminum compounds. Studies on workers exposed to aluminum welding fumes have revealed disturbances of cognitive processes, memory and concentration, and changes in mood and EEG. Early pulmonary effects have been observed among aluminum powder-production workers using high-resolution computed tomography. The primary objective of aluminum biomonitoring (BM) is to help prevent the formation of aluminum burden in the lungs and thereby to prevent harmful accumulation of aluminum in target organs. BM of aluminum can be effectively used for this purpose in the production/use of aluminum powders, aluminum welding, as well as plasma cutting, grinding, polishing and thermal spraying of aluminum. BM of aluminum may also be similarly useful in the smelting of aluminum and probably in the production of corundum. BM can help identify exposed individuals and roughly quantitate transient exposure but cannot predict health effects in the production/use of soluble aluminum salts. For urinary aluminum (U-Al) we propose an action limit of 3 umol/L, corrected to a relative density of 1.021, in a sample collected preshift after two days without occupational exposure, and without use of aluminum-containing drugs. This value corresponds roughly to 2.3 umol/g creatinine. Compliance with this limit is expected to protect the worker against the critical effect of aluminum in exposure to sparsely soluble aluminum dusts, the cognitive function of the central nervous system. For serum aluminum (S-Al), we do not propose an action limit because S-Al is less sensitive as an indicator of aluminum load. PMID- 23013242 TI - Effects of predation on real-time host-parasite coevolutionary dynamics. AB - The impact of community complexity on pairwise coevolutionary dynamics is theoretically dependent on the extent to which species evolve generalised or specialised adaptations to the multiple species they interact with. Here, we show that the bacteria Pseudomonas fluorescens diversifies into defence specialists, when coevolved simultaneously with a virus and a predatory protist, as a result of fitness trade-offs between defences against the two enemies. Strong bacteria virus pairwise coevolution persisted, despite strong protist-imposed selection. However, the arms race dynamic (escalation of host resistance and parasite infectivity ranges) associated with bacteria-virus coevolution broke down to a greater extent in the presence of the protist, presumably through the elevated genetic and demographic costs of increased bacteria resistance ranges. These findings suggest that strong pairwise coevolution can persist even in complex communities, when conflicting selection leads to evolutionary diversification of different defence strategies. PMID- 23013243 TI - Maternal and offspring fasting glucose and type 2 diabetes-associated genetic variants and cognitive function at age 8: a Mendelian randomization study in the Avon Longitudinal Study of Parents and Children. AB - BACKGROUND: In observational epidemiological studies type 2 diabetes (T2D) and both low and high plasma concentrations of fasting glucose have been found to be associated with lower cognitive performance. These associations could be explained by confounding. METHODS: In this study we looked at the association between genetic variants, known to be robustly associated with fasting glucose and T2D risk, in the mother and her offspring to determine whether there is likely to be a causal link between early life exposure to glucose and child's intelligence quotient (IQ) scores in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We generated a fasting glucose (FGGRS) and a T2D (T2DGRS) genetic risk score and used them in a Mendelian randomization approach. RESULTS: We found a strong correlation between the FGGRS and fasting glucose plasma measurements that were available for a subset of children, but no association of either the maternal or the offspring FGGRS with child's IQ was observed. In contrast, the maternal T2DGRS was positively associated with offspring IQ. CONCLUSIONS: Maternal and offspring genetic variants which are associated with glucose levels are not associated with offspring IQ, suggesting that there is unlikely to be a causal link between glucose exposure in utero and IQ in childhood. Further exploration in even larger cohorts is required to exclude the possibility that our null findings were due to a lack of statistical power. PMID- 23013244 TI - Thermophysical characterization of the seeds of invasive Chinese tallow tree: importance for biofuel production. AB - The limited supply of traditional fossil based fuels, and increased concern about their environmental impact has driven the interest in the utilization of biomass based energy sources, including those that are underutilized or otherwise nuisance species such as Chinese tallow trees (Triadica sebifera [L.]). This species is a prolific seeds producer, and this paper shows that they contain more than 50% lipids by mass that are suitable for conversion into biodiesel. We present here, for the first time, the seeds' thermophysical properties important for biofuel production. The seeds were characterized using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and ultimate analysis; their thermal conductivity, thermal diffusivity, and specific heat were determined. The characterization results were correlated to fatty acid composition and lipid content for whole seeds and individual layers, as well as to the protein, hemicellulose, cellulose, and lignin content. The TGA analysis indicated the presence, in addition to lipids, of hemicellulose, cellulose, lignin, and proteins, depending on the layer analyzed. Thermal conductivity and specific heat were, respectively 0.14 +/- 0.007 W/mK and 3843.5 +/- 171.16 J/kgK for wax, 0.20 +/- 0.002 W/mK and 2018.7 +/- 5.18 J/kgK for shells, 0.13 +/- 0.0 W/mK and 1237 +/- 3.15 J/kgK for internal kernel, and 0.13 +/- 0.000 W/mK and 2833.9 +/- 104.11 J/kgK for whole seeds. These properties and characterization method can be further used in engineering analysis used to determine the most optimum processing method for production of biofuels from this feedstock. PMID- 23013245 TI - Involvement of WalK (VicK) phosphatase activity in setting WalR (VicR) response regulator phosphorylation level and limiting cross-talk in Streptococcus pneumoniae D39 cells. AB - WalRK (YycFG) two-component systems (TCSs) of low-GC Gram-positive bacteria play critical roles in regulating peptidogylcan hydrolase genes involved in cell division and wall stress responses. The WalRK (VicRK) TCSs of Streptococcus pneumoniae (pneumococcus) and other Streptococcus species show numerous differences with those of other low-GC species. Notably, the pneumococcal WalK sensor kinase is not essential for normal growth in culture, unlike its homologues in Bacillus and Staphylococcus species. The WalK sensor kinase possesses histidine autokinase activity and mediates dephosphorylation of phosphorylated WalR~P response regulator. To understand the contributions of these two WalK activities to pneumococcal growth, we constructed and characterized a set of walK kinase and phosphatase mutants in biochemical reactions and in cells. We identified an amino acid substitution in WalK that significantly reduces phosphatase activity, but not other activities. Comparisons were made between WalRK regulon expression levels and WalR~P amounts in cells determined by Phos-tag SDS-PAGE. Reduction of WalK phosphatase activity resulted in nearly 90% phosphorylation to WalR~P, consistent with the conclusion that WalK phosphatase is strongly active in exponentially growing cells. WalK phosphatase activity was also shown to depend on the WalK PAS domain and to limit cross-talk and the recovery of WalR~P from walK(+) cells. PMID- 23013246 TI - Syntheses of papyracillic acids: application of the tandem chain extension acylation reaction. AB - A synthetic approach to the papyracillic acid family of natural products has been developed. The spiroacetal core is rapidly assembled through an unprecedented zinc carbenoid-mediated tandem chain extension-acylation reaction. Subsequent functional group manipulation provided access to papyracillic acid B and 4-epi papyracillic acid C. The successful preparation of these molecules resulted in the clarification of structural assignments of members of this family of natural products. PMID- 23013247 TI - Ischemic bowel disease and risk of stroke: a one-year follow-up study. AB - BACKGROUND: Ischemic bowel disease and stroke have been noted to have shared pathomechanisms. However, data regarding the stroke occurrence following ischemic bowel disease are still lacking. AIM: The aim of this study is to explore the risk of stroke in patients with ischemic bowel disease during a one-year follow up period in Taiwan. METHODS: Data used in this study were retrieved from the 'Longitudinal Health Insurance Database 2000. Five hundred sixty-nine patients hospitalized with ischemic bowel disease were included as the study group, and 3414 subjects, matched by age and gender, were randomly extracted as a comparison group. Cox proportional hazards regression analysis was performed to test the relationship of ischemic bowel disease and subsequent stroke during the one-year follow-up period. RESULTS: The incidence rate of stroke among the sampled subjects during the 30-day, 90-day, and 365-day follow-up period was 1.24, 0.76, and 0.43 per 10 person-years. The adjusted hazard ratio for stroke for those patients with ischemic bowel disease within 30-, 90-, and 365-day follow-up periods was found to be 3.71 (95% confidence interval = 1.89-7.27), 2.11 (95% confidence interval = 1.22-3.66), and 1.70 (95% confidence interval = 1.14-2.52) times that of matched comparisons, respectively. The adjusted hazard ratio of ischemic stroke for patients with ischemic bowel disease was found to be 5.29 during the 30-day follow-up period than comparisons. CONCLUSIONS: We found ischemic bowel disease to be significantly associated with stroke occurrence. PMID- 23013248 TI - Comparative NMR-based metabonomic investigation of the metabolic phenotype associated with tienilic acid and tienilic acid isomer. AB - An NMR-based metabonomic approach was applied to study the systems level metabolic effects of two closely related thiophene compounds, tienilic acid (TA) and tienilic acid isomer (TAI). The metabonomic data were anchored with traditional clinical chemistry and histopathologic analyses. TA was removed from the market as a result of suspected immune-mediated hepatotoxicity, whereas TAI is an intrinsic hepatotoxin. Equimolar doses of TA and TAI were administered to Sprague-Dawley rats, and sampling was conducted at 2, 6, and 24 h post-treatment. Histopathologic analyses revealed development of a significant hepatic lesion 24 h post-TAI treatment with a parallel increase in plasma alanine aminotransferase (ALT) activity. In contrast, TA was not associated with the development of a hepatic lesion or an increase in plasma ALT activity. High-resolution NMR spectral metabolic profiles were generated for liver extracts, plasma, and urine at multiple time points. Multivariate statistical tools were applied to model the metabolic profiles and identify discriminatory metabolites that reflected both the adaptation to TA administration and the onset and progression of TAI-induced hepatotoxicity. TAI was shown to induce marked metabolic effects on the metabolome at all time points, with dramatic metabolic perturbations at 24 h post treatment correlating with the histopathologic and clinical chemistry evidence of a hepatic lesion. The TAI-induced metabolic perturbations provided evidence for the generation of electrophilic reactive metabolites and a significant impairment of bioenergetic metabolic pathways. TA induced early metabolic perturbations that were largely resolved by 24 h post-treatment, suggesting the reestablishment of metabolic homeostasis and the ability to adapt to the intervention, with hepatic hypotaurine potentially representing a means of assessment of hepatic adaptation. This comparative metabonomic approach enabled the discrimination of metabolic perturbations that were common to both treatments and were interpreted as nontoxic thiophene-induced perturbations. Importantly, this approach enabled the identification of temporal metabolic perturbations that were unique to TAI or TA treatment and hence were of relevance to the development of toxicity or the ability to adapt. This approach is applicable to the future study of pharmacologically and structurally similar compounds and represents a refined means of identification of biomarkers of toxicity. PMID- 23013249 TI - Semiparametric Bayesian survival analysis using models with log-linear median. AB - We present a novel semiparametric survival model with a log-linear median regression function. As a useful alternative to existing semiparametric models, our large model class has many important practical advantages, including interpretation of the regression parameters via the median and the ability to address heteroscedasticity. We demonstrate that our modeling technique facilitates the ease of prior elicitation and computation for both parametric and semiparametric Bayesian analysis of survival data. We illustrate the advantages of our modeling, as well as model diagnostics, via a reanalysis of a small-cell lung cancer study. Results of our simulation study provide further support for our model in practice. PMID- 23013250 TI - Absence of MYD88 L265P mutation in blastic plasmacytoid dendritic cell neoplasm. PMID- 23013251 TI - Allele-specific transcriptional activity of the variable number of tandem repeats in 5' region of the DRD4 gene is stimulus specific in human neuronal cells. AB - The dopamine receptor D4 (DRD4) gene includes several variable number of tandem repeat loci that have been suggested to modulate DRD4 gene expression patterns. Previous studies showed differential basal activity of the two most common variants of a tandem repeat (120 bp per repeat unit) located in the 5' region adjacent to the DRD4 promoter in human cell lines. In this communication, we further characterized the ability of this polymorphic repeat to elicit tissue-, allele- and stimuli-specific transcriptional activity in vitro. The short and long variants of the DRD4 5' tandem repeat were cloned into a luciferase reporter gene construct containing the SV40 promoter. The luciferase constructs were cotransfected with expression vectors of two ubiquitously expressed human transcription factors (TFs), CCCTC-binding factor (CTCF) and upstream stimulatory factor 2 (USF2), into human cell lines and primary cultures of neonate rat cortex and luciferase activity measured. Overexpression with these TFs resulted in differential cell- and allele-specific transcriptional activities of the luciferase constructs. The results of our experiments show that variants of this tandem repeat in the 5' promoter of the DRD4 gene will direct differential reporter gene transcriptional activity in a cell-type-specific manner dependent on the signal pathways activated. PMID- 23013252 TI - Evaluation procedure of electrostatic potential in 3D-RISM-SCF method and its application to hydrolyses of cis- and transplatin complexes. AB - In the three-dimensional reference interaction site model self-consistent field (3D-RISM-SCF) method, a switching function was introduced to evaluate the electrostatic potential (ESP) around the solute to smoothly connect the ESP directly calculated with the solute electronic wave function and that approximately calculated with solute point charges. Hydrolyses of cis- and transplatins, cis- and trans-PtCl(2)(NH(3))(2), were investigated with this method. Solute geometries were optimized at the DFT level with the M06-2X functional, and free energy changes were calculated at the CCSD(T) level. In the first hydrolysis, the calculated activation free energy is 20.8 kcal/mol for cisplatin and 20.3 kcal/mol for transplatin, which agrees with the experimental and recently reported theoretical results. A Cl anion, which is formed by the first hydrolysis, somehow favorably exists in the first solvation shell as a counteranion. The second hydrolysis occurs with a similar activation free energy (20.9 kcal/mol) for cisplatin but a somewhat larger energy (23.2 kcal/mol) for transplatin to afford cis- and trans-diaqua complexes. The Cl counteranion in the first solvation shell little influences the activation free energy but somewhat decreases the endothermicity in both cis- and transplatins. The present 3D-RISM SCF method clearly displays the microscopic solvation structure and its changes in the hydrolysis, which are discussed in detail. PMID- 23013253 TI - Identification of antischistosomal leads by evaluating bridged 1,2,4,5 tetraoxanes, alphaperoxides, and tricyclic monoperoxides. AB - Although antischistosomal properties of peroxides were studied in recent years, systematic structure-activity relationships have not been conducted. We evaluated the antischistosomal potential of 64 peroxides belonging to bridged 1,2,4,5 tetraoxanes, alphaperoxides, and tricyclic monoperoxides. Thirty-nine compounds presented IC50 values <15 MUM on newly transformed schistosomula. Active drugs featured phenyl-, adamantane-, or alkyl residues at the methylene bridge. Lower susceptibility was documented on adult schistosomes, with most hit compounds being tricyclic monoperoxides (IC50: 7.7-13.4 MUM). A bridged 1,2,4,5-tetraoxane characterized by an adamantane residue showed the highest activity (IC50: 0.3 MUM) on adult Schistosoma mansoni . Studies with hemin and heme supplemented medium indicated that antischistosomal activation of peroxides is not necessarily triggered by iron porphyrins. Two compounds (tricyclic monoperoxide; bridged 1,2,4,5-tetraoxane) revealed high worm burden reductions in the chronic (WBR: 75.4-82.8%) but only moderate activity in the juvenile (WBR: 18.9-43.1%) S. mansoni mouse model. Our results might serve as starting point for the preparation and evaluation of related derivatives. PMID- 23013254 TI - Implementation of an ICF-based project/program in a pediatric neuro-rehabiltation hospital: follow-up evaluation by stakeholders. AB - PURPOSE: We follow-up on the experience started 3 years ago with the introduction in a pediatric neurorehabilitation hospital of an ICF-CY based form for rehabilitation projecting/programming, by probing the impact that this process had on stakeholders to establish its long term cost/benefit ratio. METHODS: Two hundred and two rehabilitation projects/programs forms for children with various health conditions admitted for intensive rehabilitation were completed in 36 months. Assessment was carried out by (i) evaluating the compliance with the new process design, (ii) assessing the resource consumption and (iii) appraising the perceived change in terms of added quality. A structured questionnaire built by clustering statements about added quality determinants in rehabilitation expressed by team members and families, explored the perceived change in the rehabilitation process associated with the introduced form with a 0-5 Likert-type scaling. RESULTS: (i) Most projects/programs forms were filled appropriately, allowing the link of functional problems, objectives, rehabilitation activities, and outcome indicators. (ii) No additional resources were needed to implement the process. (iii) Questionnaire scores were 3.25 SD 0.2 for team members and 4.05 SD 0.2 for families, showing moderate to relevant appreciation in particular by families. CONCLUSIONS: The results confirmed the feasibility of ICF implementation in the clinical setting. ICF based project/program was appreciated by both team members and caregivers as adding quality to the rehabilitation process. These results further encourage the implementation of ICF based tools in the clinical sector. PMID- 23013255 TI - Epidemiology and antimicrobial sensitivities of 536 multi-drug-resistant gram negative bacilli isolated from patients treated on surgical wards. AB - BACKGROUND: In this era of increasing antimicrobial resistance, infections caused by multi-drug-resistant (MDR) gram-negative bacilli (GNB) are becoming more common and pose a challenge to all clinicians, including surgeons. METHODS: We evaluated the epidemiology and antimicrobial sensitivities of GNB isolated from patients treated on surgical wards at the University Hospital of Heraklion, Crete, Greece, from 2004 to 2009. The MDR isolates were defined according to an international expert proposal supported by the U.S. Centers for Disease Control and Prevention and the European Centre for Disease Prevention and Control. RESULTS: A total of 1,153 GNB were isolated; 536 (46.5%) were MDR. The most common isolates were Escherichia coli (312 [27.8%]; MDR rate 50.2%), Pseudomonas aeruginosa (298 [25.8%]; MDR rate 39.6%), Acinetobacter baumannii (137 [11.9%]; MDR rate 83.9%), and Klebsiella pneumoniae (112 [9.7%]; MDR rate 44.6%). Most pathogens were isolated from patients hospitalized in the Departments of Surgical Oncology (32.3%), Orthopedic and Trauma Surgery (31.8%), General Surgery (18.1%), and Pediatric Surgery (15.5%). The clinical specimens comprised pus (45.1%), normally sterile fluids (22.5%), urine (16.8%), blood (6.3%), and other body fluids. Most effective in vitro against all MDR pathogens were colistin (83%), meropenem (57%), and imipenem-cilastatin (56%). The MDR P. aeruginosa was susceptible most often to colistin (94%) and aminoglycosides (tobramycin 56%, amikacin 55%), MDR A. baumannii only to colistin (94%), and MDR K. pneumoniae to meropenem (92%) and aminoglycosides (amikacin 76%, gentamicin 74%). CONCLUSION: In a region with a high prevalence of antibiotic resistance, almost one-half of GNB isolated from surgical patients were MDR. Surgeons may consider these developments to guide empiric antibiotic therapy for infections caused by gram negative pathogens. PMID- 23013257 TI - Statistical validation for the profiling of heroin by associating simulated postcut samples with the corresponding precut sample. AB - Statistical validation is crucial for the clustering of unknown samples. This study aims to demonstrate how statistical techniques can be optimized using simulated heroin samples containing a range of analyte concentrations that are similar to those of the case samples. Eight simulated heroin distribution links consisting of 64 postcut samples were prepared by mixing one of two mixtures of paracetamol-caffeine-dextromethorphan at different proportions with eight precut samples. Analyte contents and compositional variation of the prepared samples were investigated. A number of data pretreatments were evaluated by associating the postcut samples with the corresponding precut samples using principal component analysis and discriminant analysis. Subsequently, combinations of seven linkage methods and five distance measures were explored using hierarchical cluster analysis. In this study, Ward-Manhattan showed better distinctions between unrelated links and was able to cluster all related samples in very close distance under the known links on a dendogram. A similar discriminative outcome was also achieved by 90 unknown case samples when clustered via Ward-Manhattan. PMID- 23013258 TI - Spatial emission profiles for flagging matrix interferences in axial-viewing inductively coupled plasma-atomic emission spectrometry: 1. Profile characteristics and flagging efficiency. AB - Spatially resolved measurements of analyte emission along the cross-sectional axis of an axially viewed inductively coupled plasma (ICP) are utilized to indicate the presence of any of the three major categories of matrix interferences (i.e., plasma-related, sample introduction-related, and spectral interferences). Barium at concentrations of 0.05 or 0.1 M was chosen as a prototype element for plasma-related matrix effects, whereas common mineral acids (nitric, hydrochloric, sulfuric, and phosphoric) at volumetric concentrations from 1% to 20% were used to simulate sample introduction-related matrix effects. Three spectrally interfering line pairs (As and Cd at 228.81 nm, Er and Co at 239.73 nm, and Er and Ce at 302.27 nm) were selected for the study of spectral interferences. Due to dependence on the nature of the interference, the analytical bias at the center of the cross-sectional profile varied between -40% and +50%. In all matrix-interference categories, because plasma characteristics and excitation conditions are heterogeneous along this cross-sectional axis, matrix-induced shifts in analyte emission vary accordingly. As a result, the concentrations determined for an analyte along the cross-sectional plasma axis are not constant but exhibit a position dependence that allows the interference to be flagged. With the exception of spectral interference from emission lines whose total excitation potentials (i.e., the sum of ionization and excitation energies of an ionic emission line) are very close, the spatially resolved concentrations provide an effective indicator for flagging any other matrix interference in axial-viewing ICP-emission spectrometry. The method can be employed under the plasma forward power and carrier-gas flow conditions that are common for robust plasma operation. PMID- 23013259 TI - ITGB4-associated non-Herlitz junctional epidermolysis bullosa: report of two new cases carrying two novel ITGB4 mutations. PMID- 23013260 TI - Characteristics of physicians receiving large payments from pharmaceutical companies and the accuracy of their disclosures in publications: an observational study. AB - BACKGROUND: Financial relationships between physicians and industry are extensive and public reporting of industry payments to physicians is now occurring. Our objectives were to describe physician recipients of large total payments from these seven companies, and to examine discrepancies between these payments and conflict of interest (COI) disclosures in authors' concurrent publications. METHODS: The investigative journalism organization, ProPublica, compiled the Dollars for Docs database of payments to individuals from publically available data from seven US pharmaceutical companies during the period 2009 to 2010. We examined the cohort of 373 physicians in this database who each received USD $100,000 or more in the reporting period 2009 to 2010. RESULTS: These physicians received a total of $52,600,624 during this period (mean payment per physician $141,020). The predominant specialties were internal medicine and psychiatry. 147 of these physicians authored a total of 134 publications in the first quarter of 2011 and 77% (103) of these publications provided a COI disclosure. 69% of the 103 publications did not contain disclosures of the payment listed in the Dollars for Docs database. CONCLUSIONS: With increased public reporting of industry payments to physicians, it is apparent that large sums are being paid for services such as consulting and peer education. In over two-thirds of publications where COI disclosures were provided, the disclosures by physician authors did not include industry payments that were documented in the Dollars for Docs database. PMID- 23013261 TI - Toxicology of dimethyl and monomethyl derivatives of acetamide and formamide: a second update. AB - Dimethylacetamide (DMAC) and dimethylformamide (DMF) continue to be important, widely used solvents involved in a wide variety of industrial applications. As liquids with relatively low vapor pressures, contact with both the integumentary and respiratory systems is the main source of human exposure. Although airborne control levels for the workplace have been established and industrial hygiene practices to limit dermal contact have been put in place, use of these chemicals has been associated with occupational illness, mainly in Asia where new and expanded uses have led to overexposures. Thus an update of the basic toxicology data including tables indicating the dose/exposure response characteristics of both DMAC and DMF is currently important. Both chemicals are similar from a toxicology perspective. Human experience has generally shown the materials to be without adverse effect except under conditions where airborne and dermal controls were not properly applied. The use of urinary metabolite monitoring has successfully been employed to measure integrated dermal and inhalation worker exposure. The chemicals are not particularly toxic following acute exposure but high doses can produce damage to the liver, the organ which is first affected by these two chemicals. Repeated dose/exposure studies have characterized both the targets of toxicity and the doses required to produce changes by various routes of exposure. Higher doses of these materials can produce changes in developing systems, infrequently in experiments at doses in which the maternal animal is unaffected, thus care needs to be taken when exposures are to women of child bearing age. The chemicals appear to be low in genetic activity and inhalation exposures have not shown the materials to produce tumors in rodents except with DMF in a situation in which aerosol formation was encountered. This presentation extends the two previous reviews and, like those, includes updated information on acetamide and formamide and their monomethyl derivatives as well as the commercially important DMAC and DMF. Since a large portion of the newer information deals with effects in humans and biomonitoring, these sections are presented at the start of this review. PMID- 23013262 TI - The influence of predation and competition on the survival of commensal and pathogenic fecal bacteria in aquatic habitats. AB - The role of fecal indicator bacteria (FIB) in water quality assessment is to provide a warning of the increased risk of pathogen presence. An effective surrogate for waterborne pathogens would have similar survival characteristics in aquatic environments. Although the effect of abiotic factors such as sunlight and salinity on the survival of FIB and pathogens are becoming better understood, the effect of the indigenous microbiota is not well characterized. The influence of biotic factors on the survival of non-pathogenic Escherichia coli, Enterococcus faecalis, and E. coli O157:H7 were compared in fresh (river) water and sediments over 5 days. Treatments were (i) disinfection (filtration of water and baking of sediments) to remove indigenous protozoa (predators) and bacteria (competitors), and (ii) kanamycin treatment to reduce competition from indigenous bacteria. The disinfection treatment significantly increased survival of E. coli, E. coli O157:H7 and Ent. faecalis in the water column. In sediments, survival of FIB but not that of E. coli O157:H7 increased in disinfected treatments, indicating that the pathogen's survival was unaffected by the natural microbiota. Location (water or sediment) influenced bacterial survival more than species/type in the disinfection experiment. In the competition experiments where only the natural bacterial flora was manipulated, the addition of kanamycin did not affect the survival of Ent. faecalis, but resulted in greater survival of E. coli in water and sediment. Species/type influenced survival more than the level of competition in this experiment. This study demonstrates the complexity of interactions of FIB and pathogens with indigenous microbiota and location in aquatic habitats, and argues against over-generalizing conclusions derived from experiments restricted to a particular organism or habitat. PMID- 23013263 TI - The role of cultural values and religion on views of body size and eating practices among adolescents from Fiji, Tonga, and Australia. AB - OBJECTIVES: This study investigated cultural values related to body image and eating practices in Western and non-Western societies. DESIGN AND METHODS: In total, 628 Fijian, 463 Indo-Fijian, 598 Tongan, and 534 Australian adolescents completed measures of cultural values and religious influences in relation to the ideal body and eating practices. RESULTS: Fijian and Tongan adolescents were more likely to value a large body. Religious influences were most strongly associated with eating practices for Fijians, Indo-Fijians, and Tongans. CONCLUSIONS: The findings support the role of religion in transmitting cultural values regarding eating practices in Pacific Island communities. STATEMENT OF CONTRIBUTION: What is already known on this subject? Previous research has demonstrated that sociocultural factors shape body image and eating behaviours. Most of this research has been conducted in Western countries. What does this study add? The current study identifies the role of cultural values and religious influences on body image and eating behaviours in a number of different cultural groups. This is the first study to use the same methodology to explore these relationships across Western and Pacific Island communities. PMID- 23013264 TI - Defensive dehumanization in the medical practice: a cross-sectional study from a health care worker's perspective. AB - Health care workers are often required to consider the emotions of their patients making their work susceptible for burnout. Extending recent developments in work on dehumanization, the present study tested whether or not considering a patient's suffering in terms of uniquely human compared to more basic emotions, would be linked with burnout especially for those health care workers that frequently encounter emotional demands through their contact with suffering patients. Professional health care workers were presented with the fictitious case of a terminal patient and asked to infer her emotional state in terms of uniquely human or basic, primary emotions. As expected, humanizing a patient's suffering positively predicted symptoms of burnout especially for those participants that had higher levels of direct contact with patients. PMID- 23013265 TI - Antenatal education and breastfeeding in a cohort of primiparas. AB - AIMS: To assess the association between attendance at antenatal education sessions and breastfeeding during the first year of life. BACKGROUND: Although there is evidence that antenatal education encourages breastfeeding, the size and duration of its effect remain unclear. DESIGN: A prospective cohort study. METHODS: The study was conducted in Bizkaia (North of Spain) between May 2005 June 2007 with a consecutive sample of 614 primiparas. Women were classified into three groups according to whether they had received antenatal education and, if so, how many classes (0, 1-4, or 5 or more). Telephone interviews at 1.5, 3, 6 and 12 months were used to estimate the risk of cessation of any breastfeeding and to compare the groups with Cox proportional hazards regression models adjusted for potential confounders. FINDINGS: Initially, 90% of women breastfed their infants, with no differences between the groups. During the first month, the risk of cessation of any breastfeeding was three times as high among non attendees and twice as high among women who attended 1-4 classes compared with those who attended 5 or more classes. The risk was, however, similar in the three groups from the end of first month onwards. CONCLUSION: The results suggest that though antenatal education may be associated with higher rates of breastfeeding in our setting this is only the case for the first month after the birth. Further research is necessary to optimize this beneficial effect to achieve long-term continuation of breastfeeding. PMID- 23013266 TI - Development of a disease-specific health-related quality of life questionnaire (THYCA-QoL) for thyroid cancer survivors. AB - BACKGROUND: To date, no valid instrument is available that focuses on specific health-related quality of life (HRQoL) issues that affect thyroid cancer survivors. The objective of this study was to develop and pretest a thyroid cancer specific HRQoL questionnaire that can be used in addition to the more general European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). MATERIAL AND METHODS: Potentially relevant issues were identified by a systematic literature review, a focus group meeting, and an issue list completed by six health care professionals (HCP) and 18 thyroid cancer survivors. Resultant issues were analyzed on importance and relevance (phase I). The issues were formulated into a long provisional list of questions (phase II). These questions were administered in combination with the EORTC QLQ C30 to 306 Dutch thyroid cancer survivors to pretest the hypothesized scale structure (phase III). Although the development of this questionnaire was not set up as an international study, phases I-III are in agreement with the methodology of the EORTC guidelines. RESULTS: The literature search, focus group and issue list completed by HCP and survivors resulted in 75 issues. These were reduced to create a 30 item provisional list. Pretesting led to a selection of 24 items with a good range of response. This resulted in the THYCA-QoL containing 24 items and seven conceptual scales. CONCLUSION: The THYCA-QoL in combination with the EORTC QLQ-C30 is ready for a large (international) scale validation study, and will assess HRQoL issues of most relevance and concern for thyroid cancer survivors. PMID- 23013267 TI - Early and persisting response to vismodegib in a patient with bone metastasizing medulloblastoma. PMID- 23013268 TI - Frequency of anxiety after stroke: a systematic review and meta-analysis of observational studies. AB - BACKGROUND AND PURPOSE: Negative psychological outcomes occur frequently after stroke; however, there is uncertainty regarding the occurrence of anxiety disorders and anxiety symptoms after stroke. A systematic review of observational studies was conducted that assessed the frequency of anxiety in stroke patients using a diagnostic or screening tool. SUMMARY OF REVIEW: Databases were searched up to March 2011. A random effects model was used to summarize the pooled estimate. Statistical heterogeneity was assessed using the I(2) statistic. Forty four published studies comprising 5760 stroke patients were included. The overall pooled estimate of anxiety disorders assessed by clinical interview was 18% (95%confidence interval 8-29%, I(2) = 97%) and was 25% (95% confidence interval 21-28%, I(2) = 90%) for anxiety assessed by rating scale. The Hospital Anxiety and Depression Scale-Anxiety subscale 'probable' and 'possible' cutoff scores were the most widely used assessment criteria. The combined rate of anxiety by time after stroke was: 20% (95% confidence interval 13-27%, I(2) = 96%) within one-month of stroke; 23% (95% confidence interval 19-27%, I(2) = 84%) one to five-months after stroke; and 24% (95% confidence interval 19-29%, I(2) = 89%) six-months or more after stroke. CONCLUSION: Anxiety after stroke occurs frequently although methodological limitations in the primary studies may limit generalizability. Given the association between prevalence rates and the Hospital Anxiety and Depression Scale-Anxiety cutoff used in studies, reported rates could in fact underrepresent the extent of the problem. Additionally, risk factors for anxiety, its impact on patient outcomes, and effects in tangent with depression remain unclear. PMID- 23013269 TI - Urinary and dietary sodium and potassium associated with blood pressure control in treated hypertensive kidney transplant recipients: an observational study. AB - BACKGROUND: In kidney transplant (Kt) recipients , hypertension is a major risk for cardiovascular complications but also for graft failure. Blood pressure (BP) control is therefore mandatory. Office BP (OBP) remains frequently used for clinical decisions, however home BP (HBP) have brought a significant improvement in the BP control. Sodium is a modifiable risk factor, many studies accounted for a decrease of BP with a sodium restricted diet. Increased potassium intake has been also recommended in hypertension management. Using an agreement between office and home BP, the present study investigated the relations between the BP control in Kt recipients and their urinary excretion and dietary consumption of sodium and potassium. METHODS: The BP control defined by OBP <140/90 mmHg and HBP <135/85 mmHg was tested in 70 Kt recipients (mean age 56 +/- 11.5 years; mean graft survival 7 +/- 6.6 years) treated with antihypertensive medications. OBP and HBP were measured with a validated oscillometric device (Omron M6(r)). The 24 hour urinary sodium (Na+) and potassium (K+) excretions as well as dietary intakes were compared between controlled and uncontrolled (in office and at home) recipients. Non parametric Wilcoxon Mann-Whitney Test was used for between groups comparisons and Fisher's exact test for frequencies comparisons. Pearson correlation coefficients and paired t-test were used when sample size was >30. RESULTS: Using an agreement between OBP and HBP, we identified controlled (21%) and uncontrolled recipients (49%). Major confounding effects susceptible to interfere with the BP regulation did not differ between groups, the amounts of sodium excretion were similar (154 +/- 93 vs 162 +/- 88 mmol/24 h) but uncontrolled patients excreted less potassium (68 +/- 14 vs 54 +/- 20 mmol/24 h; P = 0.029) and had significantly lower potassium intakes (3279 +/- 753 vs 2208 +/ 720 mg/24 h; P = 0.009), associated with a higher urinary Na+/K + ratio. Systolic HBP was inversely and significantly correlated to urinary potassium (r = -0.48; P = 0.002), a positive but non significant relation was observed with urinary sodium (r = 0,30;P = 0.074). CONCLUSIONS: Half of the treated hypertensive Kt recipients remained uncontrolled in office and at home. Restoring a well-balanced sodium/potassium ratio intakes could be a non pharmacological opportunity to improve blood pressure control. PMID- 23013270 TI - Hypoxia inducible factor-1alpha induces chemoresistance phenotype in non-Hodgkin lymphoma cell line via up-regulation of Bcl-xL. AB - Non-Hodgkin lymphoma (NHL) is one of the most common cancers in childhood. The development of chemoresistance in tumor cells is one of the principal causes of treatment failure. This resistance has been associated with different mechanisms, one being the overexpression of anti-apoptotic proteins such as Bcl-xL. It has been shown that this protein is regulated by the transcription factor hypoxia inducible factor-1alpha (HIF-1alpha), which is overexpressed in several tumors including NHL, and the overexpression of both proteins may result in resistance to chemotherapy. We investigated the role of HIF-1alpha in resistance to chemotherapy via the induction of Bcl-xL expression in NHL cell lines, using a pharmacological modulation of HIF-1alpha. Our data showed that treating Ramos cells with ethyl 3,4-dihydroxybenzoate, an inhibitor of prolyl hydroxylase, induces accumulation of HIF-1alpha and this correlates with an increase of Bcl-xL as well as resistance to apoptosis after exposure to chemotherapeutics drugs. In contrast, the treatment of Ramos cells with 2-methoxyestradiol, an inhibitor of HIF-1alpha activity, induced down-regulation of Bcl-xL expression, and this correlated with the sensitization of tumor cells to chemotherapeutic drugs. These data demonstrate that up-regulation of the anti-apoptotic protein Bcl-xL in NHL cells correlates with HIF-1alpha expression and activity, through which a phenotype of chemoresistance is induced. PMID- 23013271 TI - The moral status of extraterrestrial life. AB - If we eventually discover extraterrestrial life, do we have any moral obligations for how to treat the life-forms we find; does it matter whether they are intelligent, sentient, or just microbial-and does it matter that they are extraterrestrial? In this paper, I examine these questions by looking at two of the basic questions in moral philosophy: What does it take to be a moral object? and What has value of what kind? I will start with the first of these questions by looking at the most important attempts to answer this question on our own planet and by asking whether and how they could be applied to extraterrestrial life. The results range from a very strong protection of all extraterrestrial life and all extraterrestrial environments, whether inhabited or not, to total exclusion of extraterrestrial life. Subsequently, I also examine whether extraterrestrial life that lacks moral status can have value to human or alien life with moral status, and if that could generate any obligations for how to treat extraterrestrial life. Based on this analysis, I conclude that extraterrestrial life-forms can have both instrumental value and end value to moral objects, which has strong implications for how to treat them. PMID- 23013272 TI - The history of exoplanet detection. AB - I summarize the early developments of the more quantitative aspects of exoplanet detection. After a brief overview of the observational methods currently applied to exoplanet searches and a summary of the first true exoplanet detections resulting from these various techniques, the more relevant historical background is organized according to the observational techniques that are currently most relevant. PMID- 23013273 TI - Mass spectrometry-based proteomic analysis of cutaneous cryoglobulinaemia in formalin-fixed tissues. PMID- 23013274 TI - Determinants of substrate specificity and biochemical properties of the sn glycerol-3-phosphate ATP binding cassette transporter (UgpB-AEC2 ) of Escherichia coli. AB - Under phosphate starvation conditions, Escherichia coli can utilize sn-glycerol-3 phosphate (G3P) and G3P diesters as phosphate source when transported by an ATP binding cassette importer composed of the periplasmic binding protein, UgpB, the transmembrane subunits, UgpA and UgpE, and a homodimer of the nucleotide binding subunit, UgpC. The current knowledge on the Ugp transporter is solely based on genetic evidence and transport assays using intact cells. Thus, we set out to characterize its properties at the level of purified protein components. UgpB was demonstrated to bind G3P and glycerophosphocholine with dissociation constants of 0.68 +/- 0.02 MUM and 5.1 +/- 0.3 MUM, respectively, while glycerol-2-phosphate (G2P) is not a substrate. The crystal structure of UgpB in complex with G3P was solved at 1.8 A resolution and revealed the interaction with two tryptophan residues as key to the preferential binding of linear G3P in contrast to the branched G2P. Mutational analysis validated the crucial role of Trp-169 for G3P binding. The purified UgpAEC2 complex displayed UgpB/G3P-stimulated ATPase activity in proteoliposomes that was neither inhibited by phosphate nor by the signal transducing protein PhoU or the phosphodiesterase UgpQ. Furthermore, a hybrid transporter composed of MalFG-UgpC could be functionally reconstituted while a UgpAE-MalK complex was unstable. PMID- 23013275 TI - Mapping cancer risk in southwestern Ontario with changing census boundaries. AB - Mapping disease risk often involves working with data that have been spatially aggregated to census regions or postal regions, either for administrative reasons or confidentiality. When studying rare diseases, data must be collected over a long time period in order to accumulate a meaningful number of cases. These long time periods can result in spatial boundaries of the census regions changing over time, as is the case with the motivating example of exploring the spatial structure of mesothelioma lung cancer risk in Lambton County and Middlesex County of southwestern Ontario, Canada. This article presents a local-EM kernel smoothing algorithm that allows for the combining of data from different spatial maps, being capable of modeling risk for spatially aggregated data with time varying boundaries. Inference and uncertainty estimates are carried out with parametric bootstrap procedures, and cross-validation is used for bandwidth selection. Results for the lung cancer study are shown and discussed. PMID- 23013276 TI - Genetic dissection of memory for associative and non-associative learning in Caenorhabditis elegans. AB - The distinction between non-associative and associative forms of learning has historically been based on the behavioral training paradigm. Through discovering the molecular mechanisms that mediate learning, we can develop a deeper understanding of the relationships between different forms of learning. Here, we genetically dissect short- and long-term memory for a non-associative form of learning, habituation and an associative form of learning, context conditioning for habituation, in the nematode Caenorhabditis elegans. In short-term chemosensory context conditioning for habituation, worms trained and tested in the presence of either a taste (sodium acetate) or smell (diacetyl) context cue show greater retention of habituation to tap stimuli when compared with animals trained and tested without a salient cue. Long-term memory for olfactory context conditioning was observed 24 h after a training procedure that does not normally induce 24 h memory. Like long-term habituation, this long-term memory was dependent on the transcription factor cyclic AMP-response element-binding protein. Worms with mutations in glr-1 [a non-N-methyl-d-aspartate (NMDA)-type glutamate receptor subunit] showed short-term but not long-term habituation or short- or long-term context conditioning. Worms with mutations in nmr-1 (an NMDA receptor subunit) showed normal short- and long-term memory for habituation but did not show either short- or long-term context conditioning. Rescue of nmr-1 in the RIM interneurons rescued short- and long-term olfactory context conditioning leading to the hypothesis that these interneurons function to integrate information from chemosensory and mechanosensory systems for associative learning. PMID- 23013278 TI - 'Their type of drugs': perceptions of substance use, sex and social boundaries among young African American and Latino gay and bisexual men. AB - Studies of sexuality have increasingly shifted their attention towards understanding the social contexts that inform and organise sexual behaviour. Building on this work, we examine how substance use and sex are socially organised and meaningful activities for young African American and Latino gay and bisexual men who use substances with sex. Drawing on 30 qualitative interviews in Los Angeles and New York, we identify the ways in which social boundaries inform substance use among these young men. We find that many of them view the gay and racial/ethnic communities they belong to as differentiated by patterns of substance use. Further, they see these communities as actively constructing group boundaries through substance use, sanctioning the use of particular substances while simultaneously discouraging the use or discussion of others. For these young men, racial/ethnic and gay communities provide salient contexts in which the use of certain substances and not others is socially meaningful. Findings demonstrate the important and heretofore unrecognised ways that perceived social boundaries inform these young men's use of substances. As both protective and marginalising influences, perceptions of communities and social identities have real consequences for the sexual health of young African American and Latino gay and bisexual men. PMID- 23013277 TI - Alleviation of lung inflammatory responses by adeno-associated virus 2/9 vector carrying CC10 in OVA-sensitized mice. AB - Asthma is a chronic airway inflammatory disease characterized by eosinophilic infiltration and airway hyperresponsiveness. The over-activated Th2 and lung epithelium cells express many different cytokines, and chemokines mainly contribute to the severity of lung inflammation. Clara cell 10 kD protein (CC10) is highly expressed in airway epithelium cells and exhibits anti-inflammatory and immunomodulatory effects. Adeno-associated virus (AAV) 2/9 vector, composed of AAV2 rep and AAV9 cap genes, can efficiently and specifically target lung epithelium cells. Thus, AAV2/9 vector might carry therapeutic potential gene sequences for the treatment of asthma. This study tested whether AAV2/9 vector carrying CC10 could reduce inflammatory and asthmatic responses in OVA-induced asthmatic mouse model. The results showed that AAV2/9-CC10 vector virus significantly reduced airway hyperresponsiveness, CCL11, interleukin (IL)-4, IL 5, IL-6, IL-13, and eosinophilia in the lungs of sensitized mice. CC10 level in OVA-sensitized mice was rescued with the administration of AAV2/9-CC10 vector virus. Lung tissue remodeling, including collagen deposition and goblet cell hyperplasia, was also alleviated. However, serum levels of OVA-specific IgG1 and IgE as well as Th2 cytokine levels in OVA-stimulated splenocyte culture supernatants were at the comparable levels to the sensitized control group. The results demonstrate that AAV2/9-CC10 vector virus relieved local inflammatory and asthmatic responses in lung. Therefore, we propose that AAV2/9-CC10 vector virus guaranteed sufficient CC10 expression and had an anti-inflammatory effect in asthmatic mice. It might be applied as a novel therapeutic approach for asthma. PMID- 23013279 TI - Chemolithoautotrophic denitrification of epsilonproteobacteria in marine pelagic redox gradients. AB - Pelagic marine oxygen-depleted zones often exhibit a redox gradient, caused by oxygen depletion due to biological demand exceeding ventilation, and the accumulation of reduced chemical species, such as hydrogen sulfide. These redox gradients harbour a distinct assemblage of epsilonproteobacteria capable of fixing carbon dioxide autotrophically in the dark and potentially of utilizing hydrogen sulfide chemolithotrophically by oxidation with nitrate. Together, these two processes are referred to as chemolithoautotrophic denitrification. The focus of this study was the recently isolated and cultivated representative strain of pelagic epsilonproteobacteria, 'Sulfurimonas gotlandica' strain GD1, specifically dark carbon dioxide fixation and its substrate turnovers during chemolithotrophic denitrification. By connecting these processes stoichiometrically and comparing the results with those obtained for dark carbon dioxide fixation and nutrient concentrations measured in pelagic redox gradients of the Baltic Sea, we were able to estimate the role of chemolithoautotrophic denitrification in the environment. Evidence is provided for a defined zone where chemolithoautotrophic denitrification of these epsilonproteobacteria allows the complete removal of nitrate and hydrogen sulfide from the water column. This water layer is roughly equivalent in thickness to the average overlapping region of the two substrates, but slightly larger. Such a difference may be explained by a variety of reasons, including, e.g. utilization of substrates present at concentrations below the detection limit, alternative usage of other substrates as thiosulfate or nitrous oxide, or comparable activities of other microbes. However, the combined results of in vitro and in situ studies strongly suggest that epsilonproteobacteria are primarily responsible for hydrogen sulfide and nitrate removal from pelagic Baltic Sea redox gradients. PMID- 23013280 TI - Perceived recovery as a predictor of physical activity participation after mild stroke. AB - PURPOSE: The purpose of this study was to identify what acute care variables and/or perceived recovery factors could predict decreased participation in physical activities post-mild stroke. METHODS: Secondary analysis of persons with mild stroke. Participants were split into two groups based on the percentage of high-demand leisure (HDL) activities retained on the Activity Card Sort (ACS) at 6 months post-stroke. Demographic variables, measures from the acute care setting (National Institutes of Health Stroke Scale (NIHSS), premorbid Barthel Index, and Modified Rankin Scale), and a perceived recovery measure collected at 6 months post-stroke (Stroke Impact Scale (SIS)) were analyzed between groups using independent samples t-tests and logistic regression. RESULTS: There were no significant differences between groups on any of the demographic or acute care setting measures. Logistic regression indicated that only the overall perceived recovery (p = 0.05) and strength domain scores (p = 0.01) of the SIS were statistically significant factors for determining the percent of retained HDL activities following mild stroke. CONCLUSIONS: Clinicians must consider the clients' own perceived recovery level and other more subjective factors in determining what barriers are limiting their physical activity participation after stroke. PMID- 23013281 TI - Rat alpha-Fetoprotein binding affinities of a large set of structurally diverse chemicals elucidated the relationships between structures and binding affinities. AB - Endocrine disrupting chemicals interfere with the endocrine system in animals, including humans, to exert adverse effects. One of the mechanisms of endocrine disruption is through the binding of receptors such as the estrogen receptor (ER) in target cells. The concentration of any chemical in serum is important for its entry into the target cells to bind the receptors. alpha-Fetoprotein (AFP) is a major transport protein in rodent serum that can bind with estrogens and thus change a chemical's availability for entrance into the target cell. Sequestration of an estrogen in the serum can alter the chemical's potential for disrupting estrogen receptor-mediated responses. To better understand endocrine disruption, we developed a competitive binding assay using rat amniotic fluid, which contains very high levels of AFP, and measured the binding to the rat AFP for 125 structurally diverse chemicals, most of which are known to bind ER. Fifty-three chemicals were able to bind the rat AFP in the assay, while 72 chemicals were determined to be nonbinders. Observations from closely examining the relationship between the binding data and structures of the tested chemicals are rationally explained in a manner consistent with proposed binding regions of rat AFP in the literature. The data reported here represent the largest data set of structurally diverse chemicals tested for rat AFP binding. The data assist in elucidating binding interactions and mechanisms between chemicals and rat AFP and, in turn, assist in the evaluation of the endocrine disrupting potential of chemicals. PMID- 23013282 TI - Biotic ligand models for metals--a practical application in the revision of water quality standards in China. PMID- 23013283 TI - Plasmonic bowtie nanolaser arrays. AB - Plasmonic lasers exploit strong electromagnetic field confinement at dimensions well below the diffraction limit. However, lasing from an electromagnetic hot spot supported by discrete, coupled metal nanoparticles (NPs) has not been explicitly demonstrated to date. We present a new design for a room-temperature nanolaser based on three-dimensional (3D) Au bowtie NPs supported by an organic gain material. The extreme field compression, and thus ultrasmall mode volume, within the bowtie gaps produced laser oscillations at the localized plasmon resonance gap mode of the 3D bowties. Transient absorption measurements confirmed ultrafast resonant energy transfer between photoexcited dye molecules and gap plasmons on the picosecond time scale. These plasmonic nanolasers are anticipated to be readily integrated into Si-based photonic devices, all-optical circuits, and nanoscale biosensors. PMID- 23013284 TI - Economic burden of stroke in a large county in Sweden. AB - BACKGROUND: Stroke remains to be a major burden of disease, often causing death or physical impairment or disability. This paper estimates the economic burden of stroke in a large county of 1.5 million inhabitants in western Sweden. METHODS: The economic burden of stroke was estimated from a societal perspective with an incidence approach. Data were collected from clinical registries and 3,074 patients were included. In the cost calculations, both direct and indirect costs were estimated and were based on costs for 12 months after a first-ever stroke. RESULTS: The total excess costs in the first 12 months after the first-ever stroke for a population of 1.5 million was 629 million SEK (?69 million). Men consumed more acute care in hospitals, whereas women consumed more rehabilitation and long-term care provided by the municipalities. Younger patients brought a significantly higher burden on society compared with older patients due to the loss of productivity and the increased use of resources in health care. CONCLUSIONS: The results of this cost-of-illness study were based on an improved calculation process in a number of fields and are consistent with previous studies. In essence, 50% of costs for stroke care fall on acute care hospital, 40% on rehabilitation and long-time care and informal care and productivity loss explains 10% of total cost for the stroke disease. The result of this study can be used for further development of the methods for economic analyses as well as for analysis of improvements and investments in health care. PMID- 23013285 TI - Biochar carbon stability in a clayey soil as a function of feedstock and pyrolysis temperature. AB - The stability of biochar carbon (C) is the major determinant of its value for long-term C sequestration in soil. A long-term (5 year) laboratory experiment was conducted under controlled conditions using 11 biochars made from five C3 biomass feedstocks (Eucalyptus saligna wood and leaves, papermill sludge, poultry litter, cow manure) at 400 and/or 550 degrees C. The biochars were incubated in a vertisol containing organic C from a predominantly C4-vegetation source, and total CO(2)-C and associated delta(13)C were periodically measured. Between 0.5% and 8.9% of the biochar C was mineralized over 5 years. The C in manure-based biochars mineralized faster than that in plant-based biochars, and C in 400 degrees C biochars mineralized faster than that in corresponding 550 degrees C biochars. The estimated mean residence time (MRT) of C in biochars varied between 90 and 1600 years. These are conservative estimates because they represent MRT of relatively labile and intermediate-stability biochar C components. Furthermore, biochar C MRT is likely to be higher under field conditions of lower moisture, lower temperatures or nutrient availability constraints. Strong relationships of biochar C stability with the initial proportion of nonaromatic C and degree of aromatic C condensation in biochar support the use of these properties to predict biochar C stability in soil. PMID- 23013286 TI - Optimization of polymeric nano drug delivery system using 3(2) full factorial design. AB - This study investigated the utility of a 3(2) factorial design and optimization process for nanoparticle suspension prepared by two different polymers Eudragit((r)) RS 100 and Eudragit ((r)) RL 100 respectively. Total 18 formulations (9 formulations with each polymer) were prepared by solvent displacement technique. In these designs, two factors namely polymer weight (X1) and Aq. phase volume (X2) were evaluated each at three levels and experimental trials were performed at all nine possible combinations. Polymer weight (X1) and aqueous phase volume (X2) were selected as independent variables and particle size (Y1), % entrapment (Y2), drug release at 12(th) hrs. (Y3) are chosen as depended variables. In case of 3(2) factorial design, a full-model polynomial equation was established by subjecting the transformed values of independent variables to multiple regression analysis, and contour plots were drawn using the equation. The derived polynomial equations for particle size and % drug entrapment were verified by check point formulation. The result showed a wide variation in the responses for both of the polymer. For RS 100 polymer, particle size was 112-350 nm, entrapment: 26-72%, drug release was 42- 89% at 12(th) hrs. and for RL 100 polymer, particle size was 114-390 nm, entrapment: 30-72%, drug release was 50-90% at 12(th) hrs. The application of factorial design yielded a statistically systematic approach for the formulation and optimization of nanoparticles with desired particle size and high entrapment efficiency and release profile. The results of the optimized formulations showed particle size 225 nm, 63% drug entrapment and 83% drug release for RS 100 polymer and particle size was 148 nm, drug entrapment was 57%, drug release was 80% for RL 100 polymer. PMID- 23013287 TI - Commentary: How ethanol short-circuits the cerebellum-actions on Golgi cells in freely-moving animals. AB - This commentary discusses the important contributions of the article published in this journal by Huang and colleagues, titled, "Acute ethanol exposure increases firing and induces oscillations in cerebellar Golgi cells of freely moving rats." In this manuscript, Huang and colleagues present a number of interesting and important findings. While it has been shown previously that ethanol (EtOH) causes an increase in the firing of cerebellar Golgi cells in brain slice preparations and anesthetized animals, here the authors provide the first evidence that this action of EtOH occurs in vivo in freely moving, unanesthetized animals. These results also enhance our understanding of cerebellar functioning by describing the mechanism by which EtOH essentially de-afferentates (blocks specific inputs to) the cerebellum from the normal processing of sensory signals due to EtOH induced Golgi neuron excitation, resulting in inhibition of granule cells. Furthermore, the authors characterize the novel observation of EtOH-induced neuronal oscillations, which was not previously observed in other preparations. PMID- 23013288 TI - Positive experience, self-efficacy, and action control predict physical activity changes: a moderated mediation analysis. AB - OBJECTIVES: Experiencing positive consequences of one's physical activity is supposed to facilitate further activity. This motivational outcome might be generated by an increase in perceived self-efficacy. In addition to such a mediator effect, we examine whether this applies generally or only under conditions of volitional control. For this purpose, perceived action control was considered as a putative moderator. DESIGN AND METHOD: N = 193 students participated in a study with three measurement points in time. At baseline, positive experience with previous physical activity was measured as a predictor of physical activity. Two weeks later, self-efficacy and action control variables were assessed as putative mediator and moderator, respectively. After another 2 weeks, physical activity was measured as the outcome. A moderated mediation model was specified with baseline physical activity and sex as covariates. RESULTS: Self-efficacy was found to mediate between initial positive experience and later physical activity, and this mediation was moderated by action control. CONCLUSIONS: Participants' perceptions of positive experience were associated with their subsequent self-efficacy fostering physical activity. However, persons with low levels of action control did not translate positive experience into physical activity via self-efficacy. STATEMENT OF CONTRIBUTION: What is already known on this subject? Numerous studies have shown that exercise-specific self efficacy predicts subsequent physical activity. Prior positive experience with physical activity is suggested to be associated with exercise-specific self efficacy. Furthermore, action control was found to be beneficial for the maintenance of physical activity. What does this study add? This study unveils the mechanisms between these social-cognitive determinants: our longitudinal results suggest that the mediation of positive experience and subsequent physical activity via self-efficacy is moderated by action control. Persons with low levels of action control did not translate positive experience into physical activity via self-efficacy. PMID- 23013289 TI - Perceptions of the unregistered healthcare worker's role in pre-registration student nurses' clinical training. AB - AIM: To explore the unregistered healthcare worker's role and influence on student nurses' clinical learning experience. BACKGROUND: Across the developed world, the role of the unregistered worker is exceeding its traditional boundaries. Evidence suggests that this includes the day-to-day mentoring of pre registration student nurses. However, no research to date has explored reasons as to why this is occurring, what types of tasks are taught, and the consequence of this. DESIGN: A sequential exploratory mixed method research design was adopted. METHOD: Reporting on the final qualitative phase of a mixed method sequential research study, semi-structured interviews were undertaken with 59 unregistered healthcare workers across four hospitals in Northern Ireland. Transcriptions were analysed using a content analysis approach; all data were collected in 2010. RESULTS: Findings show the diversity of the unregistered healthcare workers' roles and confirm that they play a major part in the education of student nurses with regards to basic, clinical, and non-clinical tasks, with and without the approval of registered staff. However, their involvement did not reflect their levels of expertise as evidenced by certified training. Their participation was justified based on mentor unavailability, their closeness to the student and the patient. While some did raise concerns, they recommended that these workers be formally involved in nurse education. CONCLUSION: Mechanisms of workforce planning need to pay particular attention to the expanding role of unregistered healthcare workers as 'role drift' has the potential to alter patterns of work and affect current educational approaches impacting on the acquisition of clinical skills. Further research is recommended in this domain. PMID- 23013290 TI - Spatial distribution of lipid headgroups and water molecules at membrane/water interfaces visualized by three-dimensional scanning force microscopy. AB - At biological interfaces, flexible surface structures and mobile water interact with each other to present non-uniform three-dimensional (3D) distributions. In spite of their impact on biological functions, molecular-scale understanding of such phenomena has remained elusive. Here we show direct visualization of such interfacial structures with subnanometer-scale resolution by 3D scanning force microscopy (3D-SFM). We measured a 3D force distribution at an interface between a model biological membrane and buffer solution by scanning a sharp tip within the 3D interfacial space. We found that vertical cross sections of the 3D image taken along a specific lateral direction show characteristic molecular-scale contrasts tilted at 30 degrees to the membrane surface. Detailed analysis of the 3D image reveals that the tilted contrast corresponds to the time-averaged conformation of fluctuating lipid headgroups. On the basis of the obtained results, we discuss the relationships among the hydration structure, headgroup fluctuation, molecular fluidity, and mechanical strength of the membrane. The results demonstrate that 3D-SFM is capable of visualizing averaged 3D distribution of fluctuating surface structures as well as that of mobile water (i.e., hydration structure) at interfaces between biological systems and water. PMID- 23013291 TI - Microwave irradiation decreases ATP, increases free [Mg2+], and alters in vivo intracellular reactions in rat brain. AB - Rapid inactivation of metabolism is essential for accurately determining the concentrations of metabolic intermediates in the in vivo state. We compared a broad spectrum of energetic intermediate metabolites and neurotransmitters in brains obtained by microwave irradiation to those obtained by freeze blowing, the most rapid method of extracting and freezing rat brain. The concentrations of many intermediates, cytosolic free NAD(P)(+) /NAD(P)H ratios, as well as neurotransmitters were not affected by the microwave procedure. However, the brain concentrations of ATP were about 30% lower, whereas those of ADP, AMP, and GDP were higher in the microwave-irradiated compared with the freeze-blown brains. In addition, the hydrolysis of approximately 1 MUmol/g of ATP, a major in vivo Mg(2+) -binding site, was related to approximately five-fold increase in free [Mg(2+) ] (0.53 +/- 0.07 mM in freeze blown vs. 2.91 mM +/- 0.48 mM in microwaved brains), as determined from the ratio [citrate]/[isocitrate]. Consequently, many intracellular properties, such as the phosphorylation potential and the ?G' of ATP hydrolysis were significantly altered in microwaved tissue. The determinations of some glycolytic and TCA cycle metabolites, the phosphorylation potential, and the ?G' of ATP hydrolysis do not represent the in vivo state when using microwave-fixed brain tissue. PMID- 23013292 TI - Effect of phospholipid-based formulations of Boswellia serrata extract on the solubility, permeability, and absorption of the individual boswellic acid constituents present. AB - Boswellia serrata gum resin extracts are used widely for the treatment of inflammatory diseases. However, very low concentrations in the plasma and brain were observed for the boswellic acids (1-6, the active constituents of B. serrata). The present study investigated the effect of phospholipids alone and in combination with common co-surfactants (e.g., Tween 80, vitamin E-TPGS, pluronic f127) on the solubility of 1-6 in physiologically relevant media and on the permeability in the Caco-2 cell model. Because of the high lipophilicity of 1-6, the permeability experiments were adapted to physiological conditions using modified fasted state simulated intestinal fluid as apical (donor) medium and 4% bovine serum albumin in the basolateral (receiver) compartment. A formulation composed of extract/phospholipid/pluronic f127 (1:1:1 w/w/w) increased the solubility of 1-6 up to 54 times compared with the nonformulated extract and exhibited the highest mass net flux in the permeability tests. The oral administration of this formulation to rats (240 mg/kg) resulted in 26 and 14 times higher plasma levels for 11-keto-beta-boswellic acid (1) and acetyl-11-keto beta-boswellic acid (2), respectively. In the brain, five times higher levels for 2 compared to the nonformulated extract were determined 8 h after oral administration. PMID- 23013293 TI - New rules governing synaptic plasticity in core nucleus accumbens medium spiny neurons. AB - The nucleus accumbens is a forebrain region responsible for drug reward and goal directed behaviors. It has long been believed that drugs of abuse exert their addictive properties on behavior by altering the strength of synaptic communication over long periods of time. To date, attempts at understanding the relationship between drugs of abuse and synaptic plasticity have relied on the high-frequency long-term potentiation model of T.V. Bliss & T. Lomo [(1973) Journal of Physiology, 232, 331-356]. We examined synaptic plasticity using spike timing-dependent plasticity, a stimulation paradigm that reflects more closely the in vivo firing patterns of mouse core nucleus accumbens medium spiny neurons and their afferents. In contrast to other brain regions, the same stimulation paradigm evoked bidirectional long-term plasticity. The magnitude of spike-timing dependent long-term potentiation (tLTP) changed with the delay between action potentials and excitatory post-synaptic potentials, and frequency, whereas that of spike-timing-dependent long-term depression (tLTD) remained unchanged. We showed that tLTP depended on N-methyl-d-aspartate receptors, whereas tLTD relied on action potentials. Importantly, the intracellular calcium signaling pathways mobilised during tLTP and tLTD were different. Thus, calcium-induced calcium release underlies tLTD but not tLTP. Finally, we found that the firing pattern of a subset of medium spiny neurons was strongly inhibited by dopamine receptor agonists. Surprisingly, these neurons were exclusively associated with tLTP but not with tLTD. Taken together, these data point to the existence of two subgroups of medium spiny neurons with distinct properties, each displaying unique abilities to undergo synaptic plasticity. PMID- 23013294 TI - Audiological and radiological characteristics of a family with T961G mitochondrial mutation. AB - OBJECTIVE: The aim of this study was to describe audiological and radiological characteristics, and other secondary aspects, in a family carrying a T961G mutation in the 12S rRNA mitochondrial gene. DESIGN: Case report. STUDY SAMPLE: Six members of a family participated in an audiological evaluation that included pure-tone audiometry, immittance tests, auditory brainstem responses (ABR), and otoacoustic emissions (OAE). The radiological evaluation was conducted through temporal bone CT scans using a Toshiba 16 channels Aquilon Spirale. Neuropsychiatric evaluation was also administered. RESULTS: Three participants were diagnosed with severe sensorineural hearing loss of cochlear origin and cochlear malformations visible in CT scans. One participant had a mild mixed hearing loss and no cochlear malformations. Two participants had normal audiological and radiological findings. CONCLUSIONS: We believe our study can provide helpful insight on the clinical findings of a rare mutation, of which few data have been presented in literature. PMID- 23013295 TI - Low expression level of phosphatase and tensin homolog deleted on chromosome ten predicts poor prognosis in chronic lymphocytic leukemia. AB - Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is one of the best-studied tumor suppressor genes which can promote cell proliferation and contribute to tumorigenesis. This study aimed to investigate the PTEN mRNA (Pm) expression level in patients with chronic lymphocytic leukemia (CLL) and healthy controls, and its correlation with prognostic factors. Quantitative polymerase chain reaction (qPCR) was used to detect Pm expression. Compared to controls, patients with CLL presented a lower expression level of Pm (p < 0.001). In univariate analysis, the expression level of Pm was significantly decreased in patients with Binet C (p < 0.001) and higher level of beta2-microglobulin (beta2 MG) (p = 0.036), lactate dehydrogenase (LDH) (p = 0.019) and ZAP-70 (p = 0.008). Higher Pm expression level was found in favorable cytogenetic aberrations (p = 0.016) and the group without p53 aberration (p = 0.005). Multivariate analysis showed that advanced Binet stage (p = 0.027) and p53 aberration (p = 0.007) were associated with a low PTEN expression level. Survival analysis showed that low expression of PTEN was associated with shorter time to first treatment (TTFT) (p = 0.040). These results indicate that PTEN might be a new prognostic marker in patients with CLL. PMID- 23013296 TI - [UV-induced skin cancer as an occupational disease -- important decision of the Social Court Aachen]. PMID- 23013298 TI - Diagnostic PCR of dermatophytes--an overview. AB - The prevalence of onychomycosis is increasing steadily, sevenfold alone in the US within the last twenty years. An important aspect in this development is the demographic development of the human population of the industrial countries like Germany. A fast and accurate laboratory diagnosis is essential for successful treatment because 50% of the cases are misdiagnosed when relying on the clinical appearance only. The current diagnosis of dermatophytosis, based on direct microscopy and culture of the clinical specimen, is problematic given the lacking specificity of the former and the length of time needed for the latter. Molecular techniques can help to solve these problems. In recent years, a number of in house PCR assays have been developed to identify dermatophytes directly from clinical specimens. Based on the "Mikrobiologisch-infektiologischen Qualitatsstandards (MIQ) fur Nukleinsaure-Amplifikationstechniken" and the MIQE guideline (Minimum Information for Publication of Quantitative Real-Time PCR Experiments) 11 studies are reviewed which were published between 2007 and 2010. The present article evaluates the quality of the PCR assays regarding false positive and false negative results due to contamination, PCR format, statistical analysis, and diagnostic performance of the studies. It shows that we are only at the beginning of providing high quality PCR diagnosis of dermatophytes. PMID- 23013302 TI - In memoriam Anton Luger (1918-2012). PMID- 23013305 TI - Risk factors, radiological features, and infarct topography of craniocervical arterial dissection. AB - BACKGROUND: Craniocervical arterial dissection is a common cause of ischemic stroke in the young to middle-aged population. There have been a number of previous studies where radiological features have been described but few with detailed mapping of infarct topography and none where these features have been related to the reported risk factors. AIMS: The aims of this study were to describe the radiological characteristics of dissection patients <=55 years and relate these to reported risk factors. METHODS: Craniocervical arterial dissection cases <=55 years, and age- and gender-matched controls were identified from a medical records database between 1998 and 2009. Control cases had stroke from another cause than dissection. Records and radiology were reviewed. RESULTS: Thirty-six radiologically confirmed dissection cases [20 (56%) vertebral artery, 16 (44%) internal carotid], and 43 controls were identified. Dissections were extracranial with intracranial extension in 10 (28%) cases. Infarction was demonstrated in 22 (61%) dissection cases. The most common wall deficit identified was an intimal flap. Twenty-three (64%) dissection cases had a recent history of neck trauma (P > 0.000) and 13 (36%) had vascular variants (P = 0.013). CONCLUSION: Craniocervical arterial dissection cases, particularly vertebral artery, were more likely to have a history of neck trauma. Dissections were most commonly extracranial, in the upper cervical region, with intracranial extension in 28%. Dissection cases with trauma more commonly had a dissection flap and evidence of infarction in the lateral medulla, anterior or posterior inferior cerebellar artery territory. Close inspection of the V3 segment of the vertebral or skull base for internal carotid artery may be warranted with a history of neck trauma. PMID- 23013306 TI - Applicability of fibroblast growth factor 23 for evaluation of risk of vertebral fracture and chronic kidney disease-mineral bone disease in elderly chronic kidney disease patients. AB - BACKGROUND: Elderly patients with chronic kidney disease (CKD) are usually at a high risk of fractures due to both osteoporosis and CKD-mineral bone disease (MBD). A new marker is needed to prevent fractures and control CKD-MBD from the early to advanced stages of CKD. In the early stage of CKD, fibroblast growth factor 23 (FGF23) level increases before parathyroid hormone (PTH) and phosphate levels increase, and steadily increases with the progression of kidney disease. It has been reported that FGF23 is related to the overall fracture risk. We investigated the usefulness of FGF23 as a marker for evaluating the risk of vertebral fracture and CKD-MBD in elderly CKD patients. METHODS: One hundred and five elderly predialysis CKD patients who had never been treated for osteoporosis and had never used calcium supplements, vitamin D supplements, or phosphate binders were enrolled in this cross-sectional study in Tokyo, Japan. We investigated the prevalence of vertebral fracture and measured serum calcium, phosphate, 1,25(OH)2 vitamin D [1,25(OH)2D], intact PTH, FGF23, alkaline phosphatase, and urinary N-terminal telopeptide levels. Then, we examined the relationship between the level of FGF23 and those of bone-metabolism-related markers and identified markers associated with vertebral fractures in elderly CKD patients. RESULTS: The background features of the patients were as follows: female, 32.4%; diabetes mellitus, 39.0%; average age (standard deviation), 73.2 (7.7) years; and estimated glomerular filtration rate (eGFR), 45.7 (24.1) ml/min/1.73 m2. Adjusted multivariate regression analysis showed that the natural logarithm value of FGF23 level [ln(FGF23)] was positively associated with body mass index (p = 0.002), serum phosphate level (p = 0.0001), and negatively with eGFR (p = 0.0006). Multivariate logistic regression analysis showed that vertebral fracture was independently associated with ln(FGF23) (adjusted odds ratio, 4.44; 95% confidence interval, 1.13-17.46). A receiver-operating characteristic curve of ln(FGF23) showed that the optimal cutoff level of FGF23 indicative of vertebral fracture was 56.8 pg/ml (sensitivity, 0.82; specificity, 0.63). CONCLUSIONS: FGF23 level was independently associated with the levels of bone-metabolism-related markers and vertebral fracture. FGF23 is a new candidate marker for detecting abnormalities of bone metabolism and vertebral fracture in elderly CKD patients. PMID- 23013308 TI - EPR, resonance Raman, and DFT calculations on thiolate- and imidazole-bound iron(III) porphyrin complexes: role of the axial ligand in tuning the electronic structure. AB - Iron(III) porphyrin complexes bearing covalently attached imidazole and thiolate axial ligands are investigated using resonance Raman, electron paramagnetic resonance, and cyclic voltammetry. The thiolate ligand stabilizes a low-spin ground state in solvent-bound six-coordinate species, weakens the Fe-N(pyr) bonds, and shifts the Fe(III/II) potential more negative by ~500 mV relative to an imidazole-bound species. Density functional theory calculations reproduce the experimental observation and indicate that the covalent charge donation from thiolate to iron reduces the Z(eff) on the iron. This increases the Fe(3d) orbital energies, which changes the bonding interaction present in these complexes significantly. In particular, the increase of the Fe(3d) energies activates an iron-to-porphyrin pi*-back-bonding interaction not present in the imidazole-bound complex. PMID- 23013309 TI - Staphylococcus aureus and recurrent furunculosis: a growing hidden menace? PMID- 23013310 TI - Advance preparation of some patch test series should be avoided. PMID- 23013311 TI - Congenital erythropoietic porphyria: bringing evidence-based practice to a rare disease. PMID- 23013312 TI - Brodalumab and ixekizumab, anti-interleukin-17-receptor antibodies for psoriasis: a critical appraisal. AB - AIM: Papp et al. (N Engl J Med 2012; 366: 1181-9) and Leonardi et al. (N Engl J Med 2012; 366: 1190-9) respectively assessed the efficacy and safety of brodalumab (AMG 827), a human monoclonal antibody directed against interleukin (IL)-17RA, the receptor of IL-17A and ixekizumab (LY2439821), a humanized anti-IL 17 monoclonal antibody for the treatment of moderate-to-severe plaque psoriasis. SETTING AND DESIGN: In these phase II, multicentre, randomized, double-blind, placebo-controlled, dose-ranging studies, 198 patients with severe chronic plaque type psoriasis [Psoriasis Area and Severity Index (PASI) >= 12, body surface area (BSA) >= 10] were enrolled in Papp et al. between December 2009 and April 2010 and 142 patients in Leonardi et al. between April 2010 and March 2011. STUDY EXPOSURE: In Papp et al., patients with chronic plaque-type psoriasis were randomly assigned to receive placebo or brodalumab at a dose of 70, 140 or 210 mg, administered subcutaneously on day 1 and at weeks 1, 2, 4, 6, 8 and 10, or at a dose of 280 mg administered subcutaneously on day 1 and at weeks 4 and 8. In Leonardi et al., patients were randomly assigned to receive subcutaneous injections of placebo or 10, 25, 75 or 150 mg of ixekizumab at 0, 2, 4, 8, 12 and 16 weeks, followed by a 4-week follow-up period. OUTCOMES: In both studies the PASI, static Physician's Global Assessment (sPGA), Dermatology Life Quality Index (DLQI), adverse events, and routine haematological and laboratory values were analysed. Additionally in Papp et al. the BSA and Medical Outcomes Study 36-item short-form health survey, and in Leonardi et al. the joint pain visual analogue scale (VAS), itch severity VAS, Nail Psoriasis Severity Index (NAPSI) and the Psoriasis Scalp Severity Index (PSSI) were also measured. PRIMARY OUTCOME MEASURES: At week 12, in Papp et al. and Leonardi et al.: (A) The percentage improvement in PASI. In Leonardi et al. (and in Papp et al. as one of the secondary outcomes): (B) The percentage of patients who achieved a reduction in the PASI by at least 75% (PASI 75) over baseline. RESULTS: Primary endpoints: (A) At week 12 in Papp et al., the mean improvements in PASI were significantly greater in the 140, 210 and 280 mg brodalumab groups than in the 70 mg brodalumab group (85.9%, 86.3% and 76.0%, respectively, vs. 45.0%; P < 0.001); in addition, the mean improvement in PASI was significantly greater in each brodalumab group than in the placebo group (16.0%; P < 0.001). (At week 16 lower but still significant percentages compared with placebo were seen). In Leonardi et al., the mean improvements in PASI of the 10, 25, 75 and 150 mg ixekizumab groups are not reported. Significant differences between the two highest dose groups and the placebo group were seen as early as 1 week in PASI. (B) At week 12 in Papp et al., the percentages of patients with PASI 75 were 33% in the 70 mg, 77% in the 140 mg, 82% in the 210 mg and 67% in the 280 mg brodalumab group. The percentages of patients with a 50%, 75%, 90% or 100% improvement in PASI at week 12 were significantly higher among patients who received brodalumab (taking into account all doses) than among patients who received placebo. The authors do not give an explanation for the lower improvements at week 16. In Leonardi et al., the PASI 75 occurred in significantly more patients in the 25 mg (76.7%), 75 mg (82.8%) and 150 mg (82.1%) ixekizumab groups vs. placebo (7.7%; P < 0.001). No significant difference was seen for the 10 mg group. Significant differences between the 150 mg group and the placebo group were seen as early as 2 weeks in PASI 75. Differences were sustained through 20 weeks for all clinical measures in the ixekizumab study. Secondary endpoints: At week 12, in Papp et al., significant decreases of BSA, sPGA and DLQI were also seen. In Leonardi et al., significantly higher percentages of patients in the three highest ixekizumab dose groups had an sPGA score of 0 (clear of disease) or of 0 or 1 (minimal disease) for each dose and score group vs. placebo (P < 0.05). Significant reductions in the mean +/- SD DLQI scores were detected at 8 weeks in the 150 mg ixekizumab group (-7.8 +/- 5.7), the 75 mg ixekizumab group (-8.5 +/- 5.1) and the 25 mg ixekizumab group (-7.1 +/- 6.5) as compared with placebo (-2.4 +/- 4.4) for all comparisons (P < 0.001). In addition, at 16 weeks, significantly more patients had a DLQI score of 0 in the 150, 75 and 25 mg ixekizumab groups (39.3%, 37.9% and 31.0%, respectively) as compared with placebo (0%) for all comparisons (P < 0.05). In Leonardi et al., significant reductions were seen in the PSSI, in the NAPSI and in the itch severity (VAS scores). Significant reductions from baseline of the joint pain VAS were also observed in the 150 mg ixekizumab group at 12 weeks, and this reduction was sustained through 20 weeks. At week 16: with respect to the other secondary efficacy endpoints and patient-reported outcomes, significant improvements in scores were seen compared with placebo, but some of these differences were lower than observed at week 12. SAFETY: Papp et al. summarized that during the first 12 weeks of the trial, 68% of the patients in the 70 mg brodalumab group, 69% (140 mg), 82% (210 mg), 73% (280 mg) and 62% in the placebo group had at least one adverse event. Although the authors mentioned only three serious adverse events, four were reported during the study: renal colic (70 mg brodalumab group), two patients with grade 3 asymptomatic neutropenia (210 mg brodalumab group; Papp et al. clarified that only one of these episodes was a serious adverse event) and an ectopic pregnancy in one patient in the placebo group. Leonardi et al. reported that there were no serious adverse events in any group. The frequency of adverse events was similar between the combined ixekizumab groups and the placebo group. A few patients were withdrawn from the trial due to adverse events including hypertriglyceridaemia (placebo group), peripheral oedema (10 mg ixekizumab), hypersensitivity (10 mg ixekizumab) and urticaria (25 mg ixekizumab). CONCLUSIONS: Papp et al. and Leonardi et al. concluded that brodalumab and ixekizumab, respectively, significantly improved plaque psoriasis in 12-week, phase II studies. For difficult-to-treat areas such as the scalp and nails, significant differences from placebo were observed with ixekizumab treatment. These trials were not large enough or of long enough duration to ascertain uncommon adverse events or to assess the risk of infection or cardiovascular events. PMID- 23013314 TI - Commentary: Biologics for psoriasis: steps to heaven 17. PMID- 23013315 TI - Compound heterozygosity of the novel -186C>T mutation in the COL7A1 promoter and the recurrent c.497insA mutation leads to generalized dystrophic epidermolysis bullosa. PMID- 23013316 TI - Vertically resolved measurements of nighttime radical reservoirs in Los Angeles and their contribution to the urban radical budget. AB - Photolabile nighttime radical reservoirs, such as nitrous acid (HONO) and nitryl chloride (ClNO(2)), contribute to the oxidizing potential of the atmosphere, particularly in early morning. We present the first vertically resolved measurements of ClNO(2), together with vertically resolved measurements of HONO. These measurements were acquired during the California Nexus (CalNex) campaign in the Los Angeles basin in spring 2010. Average profiles of ClNO(2) exhibited no significant dependence on height within the boundary layer and residual layer, although individual vertical profiles did show variability. By contrast, nitrous acid was strongly enhanced near the ground surface with much smaller concentrations aloft. These observations are consistent with a ClNO(2) source from aerosol uptake of N(2)O(5) throughout the boundary layer and a HONO source from dry deposition of NO(2) to the ground surface and subsequent chemical conversion. At ground level, daytime radical formation calculated from nighttime accumulated HONO and ClNO(2) was approximately equal. Incorporating the different vertical distributions by integrating through the boundary and residual layers demonstrated that nighttime-accumulated ClNO(2) produced nine times as many radicals as nighttime-accumulated HONO. A comprehensive radical budget at ground level demonstrated that nighttime radical reservoirs accounted for 8% of total radicals formed and that they were the dominant radical source between sunrise and 09:00 Pacific daylight time (PDT). These data show that vertical gradients of radical precursors should be taken into account in radical budgets, particularly with respect to HONO. PMID- 23013317 TI - Immunity and autoimmunity to dsDNA and chromatin--the role of immunogenic DNA binding proteins and nuclease deficiencies. AB - Loss of immunological tolerance results in autoimmunity and may finally end in autoimmune disorders. For an autoimmune response against chromatin, autologous chromatin (nucleosomes) is assumed to activate both chromatin-specific B and T cells with a resulting anti-chromatin antibody response. As only fragmental elements of this process have been described, we do not have the full insight to justify this model in vivo. Early experimental immunization with methylated bovine serum albumin-DNA complexes elicited antibodies to various forms of synthetic ssDNA/dsDNA, but notably not to mammalian dsDNA. Thus, for a long time with intense research, the general result was that all forms of ssDNA and dsDNA, but mammalian B helical DNA, had an immunogenic potential. Summarizing these results, a preliminary conclusion was settled, saying that mammalian dsDNA was not immunogenic while other forms of DNA were really immunogenic in the situation where they were in complex with proteins. Recent studies have focused on nuclease deficiencies as a condition where chromatin may be presented to the immune system in an immunogenic form. However, although such deficiencies may provide information as to how chromatin may be exposed and targeted by relevant antibodies, data demonstrate that nuclease deficiencies is not in general correlated with autoimmunity to components of chromatin. This review discusses these topics, and provides information that may explain processes that account for anti-dsDNA antibody responses in vivo. PMID- 23013318 TI - Microbial interactions associated with secondary cucumber fermentation. AB - AIMS: To evaluate the interaction between selected yeasts and bacteria and associate their metabolic activity with secondary cucumber fermentation. METHODS AND RESULTS: Selected yeast and bacteria, isolated from cucumber secondary fermentations, were inoculated as single and mixed cultures in a cucumber juice model system. Our results confirmed that during storage of fermented cucumbers and in the presence of oxygen, spoilage yeasts are able to grow and utilize the lactic and acetic acids present in the medium, which results in increased brine pH and the chemical reduction in the environment. These conditions favour opportunistic bacteria that continue the degradation of lactic acid. Lactobacillus buchneri, Clostridium bifermentans and Enterobacter cloacae were able to produce acetic, butyric and propionic acids, respectively, when inoculated in the experimental medium at pH 4.6. Yeast and bacteria interactions favoured the survival of Cl. bifermentans and E. cloacae at the acidic pH typical of fermented cucumbers (3.2), but only E. cloacae was able to produce a secondary product. CONCLUSIONS: The methodology used in this study confirmed that a complex microbiota is responsible for the changes observed during fermented cucumber secondary fermentation and that certain microbial interactions may be essential for the production of propionic and butyric acids. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding the dynamics of the development of secondary cucumber fermentation aids in the identification of strategies to prevent its occurrence and economic losses for the pickling industry. PMID- 23013319 TI - Health improvement for disadvantaged people in Nepal - an evaluation. AB - BACKGROUND: An evaluation of progress with participatory approaches for improvement of health knowledge and health experiences of disadvantaged people in eight Districts of Eastern Nepal has been undertaken. METHODS: A random selection of Village Development Committees and households, within the eight Districts where participation and a Rights-based Approach had been promoted specifically by local NGOs were compared with similar villages and households in eight Districts where this approach had not been promoted. Information was sought by structured interview and observation by experienced enumerators from both groups of householders. Health knowledge and experiences were compared between the two sets of households. Adjustments were made for demographic confounders. RESULTS: Complete data sets were available for 628 of the 640 households. Health knowledge and experiences were low for both sets of households. However, health knowledge and experiences were greater in the participatory households compared with the non-participatory households. These differences remained after adjustment for confounders. CONCLUSIONS: The study was designed to evaluate progress with participatory processes delivered by non-governmental organisations over a five year period. Improvements in health knowledge and experiences of disadvantaged people were demonstrated in a consistent and robust manner where interventions had taken place. PMID- 23013320 TI - Production of alpha-cyclodextrin glycosyltransferase in Bacillus megaterium MS941 by systematic codon usage optimization. AB - alpha-Cyclodextrin glycosyltransferase is a key enzyme in the cyclodextrin industry. The Gram-positive bacterium Bacillus megaterium was chosen for production of recombinant alpha-CGTase for safety concerns. Successful production of heterologous alpha-CGTase was achieved by adapting the original alpha-cgt gene to the codon usage of B. megaterium by systematic codon optimization. This balanced the tRNA pool and reduced ribosomal traffic jams. Protein expression and secretion was ensured by using the strong inducible promoter P(xyl) and the signal peptide SP(LipA). The impact of culture medium composition and induction strategies on alpha-CGTase production was systematically analyzed. Production and secretion at 32 degrees C for 24 h using modified culture medium was optimal for alpha-CGTase yield. Batch- and simple fed-batch fermentation was applied to achieve a high yield of 48.9 U.mL(-1), which was the highest activity reported for a Bacillus species, making this production system a reasonable alternative to Escherichia coli. PMID- 23013321 TI - Electronic control over attachment and self-assembly of alkyne groups on gold. AB - Self-assembled monolayers are the basis for molecular nanodevices, flexible surface functionalization, and dip-pen nanolithography. Yet self-assembled monolayers are typically created by a rather inefficient process involving thermally driven attachment reactions of precursor molecules to a metal surface, followed by a slow and defect-prone molecular reorganization. Here we demonstrate a nonthermal, electron-induced approach to the self-assembly of phenylacetylene molecules on gold that allows for a previously unachievable attachment of the molecules to the surface through the alkyne group. While thermal excitation can only desorb the parent molecule due to prohibitively high activation barriers for attachment reactions, localized injection of hot electrons or holes not only overcomes this barrier but also enables an unprecedented control over the size and shape of the self-assembly, defect structures, and the reverse process of molecular disassembly from a single molecule to a mesoscopic length scale. Electron-induced excitation may therefore enable new and highly controlled approaches to molecular self-assembly on a surface. PMID- 23013322 TI - Asymmetric 1,2-reduction of enones with potassium borohydride catalyzed by chiral N,N'-dioxide-scandium(III) complexes. AB - The first catalytic enantioselective 1,2-reduction of enones with 0.45 mol equiv potassium borohydride solution catalyzed by a chiral N,N'-dioxide-Sc(III) complex catalyst was accomplished under mild reaction conditions. A number of optically active allylic alcohols were obtained in good to excellent enantioselectivities (up to 95% ee) with nearly quantitative yields. PMID- 23013323 TI - Combine and conquer: advantages and disadvantages of fixed-dose combination therapy. AB - The majority of patients with type 2 diabetes mellitus (T2DM) do not achieve the glycaemic goals recommended by leading diabetes organizations using monotherapy alone, and often require multiple antihyperglycaemic agents to achieve glycaemic control. Fixed-dose combination (FDC) therapies offer a means to simplify complex treatment regimens, and have several advantages that help patients reach their glycaemic goals. In this review, four key benefits are identified and discussed in support of FDCs for treatment of patients with T2DM: (i) Greater efficacy compared with higher dose monotherapy, (ii) Reduced risk of adverse reactions relative to higher dose monotherapy, (iii) Lower overall costs and (iv) Improved medication concordance. Given these advantages, the place of fixed combination therapy in the course of treatment is discussed. Establishing a therapeutic strategy that incorporates fixed combination therapy (including combinations with insulin) will simplify the treatment of diabetes, ideally resulting in improved medication concordance, clinical outcomes and quality of life for patients with T2DM. PMID- 23013324 TI - Fever, irritability, and ulcerations in an infant. AB - A young infant with fever and oral ulcerations is presented herein. Extensive infectious, nutritional, immunodeficiency and autoimmune work up was performed. Pertinent maternal history suggested the potential diagnosis of neonatal Behcet's, and treatment for this condition resulted in rapid and sustained clinical improvement. PMID- 23013326 TI - Increased risk of psoriasis following chronic rhinosinusitis without nasal polyps: a population-based matched-cohort study. AB - BACKGROUND: Although chronic rhinosinusitis without nasal polyps (CRSsNP) and psoriasis both share immunological disturbances as pathological factors, no prior study has investigated the risk for psoriasis among patients with CRSsNP. OBJECTIVES: To investigate the subsequent risk for psoriasis following a diagnosis of CRSsNP by utilizing a cohort study design and a population-based dataset in Taiwan. METHODS: In total, 13 242 subjects with CRSsNP were included in the study cohort and 39 726 subjects were randomly extracted for the comparison cohort. We individually tracked each individual in this study (n = 52 968) for a 5-year period following their index date to identify those subjects who received a subsequent diagnosis of psoriasis. Cox proportional hazards regression analysis was conducted to calculate the 5-year risk of subsequent psoriasis following a diagnosis of CRS among the sampled subjects. RESULTS: The incidence rate of psoriasis during the 5-year follow-up period was 1.41 [95% confidence interval (CI) 1.14-1.71] per 1000 person-years and 0.69 (95% CI 0.59 0.81) per 1000 person-years for the study and comparison cohort, respectively. Stratified Cox proportional hazards regression revealed that the hazard ratio for psoriasis during the 5-year follow-up period for subjects with CRSsNP compared with the control group was 2.01 (95% CI 1.54-2.62) after adjusting for monthly income, geographical region, hypertension, diabetes, coronary heart disease and hyperlipidaemia, and censoring the cases who died during the 5-year follow-up period. CONCLUSION: This study detected an increased risk for psoriasis among patients with CRSsNP. PMID- 23013325 TI - Fetal alcohol-related growth restriction from birth through young adulthood and moderating effects of maternal prepregnancy weight. AB - BACKGROUND: Fetal alcohol-related growth restriction persists through infancy, but its impact later in life is less clear. Animal studies have demonstrated important roles for maternal nutrition in fetal alcohol spectrum disorders, but the impact of prenatal maternal body composition has not been studied in humans. This study examined the effects of prenatal alcohol exposure on longitudinal growth from birth through young adulthood and the degree to which maternal weight and body mass index (BMI) moderate these effects. METHODS: Nearly 480 mothers were recruited at their first prenatal clinic visit to overrepresent moderate-to heavy use of alcohol during pregnancy, including a 5% random sample of low-level drinkers and abstainers. They were interviewed at every prenatal visit about their alcohol consumption using a timeline follow-back approach. Their children were examined for weight, length/height, and head circumference at birth, 6.5 and 13 months, and 7.5, 14, and 19 years. RESULTS: In multiple regression models with repeated measures (adjusted for confounders), prenatal alcohol exposure was associated with longitudinal reductions in weight, height, and weight-for length/BMI that were largely determined at birth. At low-to-moderate levels of exposure, these effects were more severe in infancy than in later childhood. By contrast, effects persisted among children whose mothers drank at least monthly and among those born to women with alcohol abuse and/or dependence who had consumed >= 4 drinks/occasion. In addition, effects on weight, height, and head circumference were markedly stronger among children born to mothers with lower prepregnancy weight. CONCLUSIONS: These findings confirm prior studies demonstrating alcohol-related reductions in weight, height, weight-for height/BMI, and head circumference that persist through young adulthood. Stronger effects were seen among children born to mothers with smaller prepregnancy weight, which may have been because of attainment of higher blood alcohol concentrations in smaller mothers for a given amount of alcohol intake or to increased vulnerability in infants born to women with poorer nutrition. PMID- 23013327 TI - Dietary nitrate and nitrite intake and risk of non-Hodgkin lymphoma. AB - Although established risk factors such as immunodeficiency and viral infections may be responsible for a portion of cases of non-Hodgkin lymphoma (NHL), the vast majority of cases of NHL remain unexplained. The role of dietary nitrate and nitrite in NHL risk is of interest since they are precursors of N-nitroso compounds, and nitrosoureas have been shown to induce B- and T-cell lymphomas in animal studies. However, few studies have evaluated the potential association between consumption of nitrate and nitrite and NHL by subtype or chromosomal translocation status, and the results of these studies have been inconsistent. We estimated the dietary intake of nitrate and nitrite using a food frequency questionnaire in a population-based, case-control study of 348 cases and 470 controls conducted in Nebraska in 1999-2002. A non-significant excess risk of NHL was found among women who reported an intake of nitrite in the highest quartile compared to the lowest quartile (odds ratio [OR] = 1.6; 95% confidence interval [CI]: 0.8-2.9), particularly nitrite from animal sources (OR = 1.9; 95% CI: 1.0 3.4). No significant associations were observed for nitrate or nitrite by NHL subtype. Although there were some increases in risk that support the N-nitroso hypothesis, they were not significant and do not confer strong evidence of an association. PMID- 23013328 TI - Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice. AB - Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or pro-depressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule stabilizing compounds. PMID- 23013329 TI - Simulations of shocked methane including self-consistent semiclassical quantum nuclear effects. AB - A methodology is described for atomistic simulations of shock-compressed materials that incorporates quantum nuclear effects on the fly. We introduce a modification of the multiscale shock technique (MSST) that couples to a quantum thermal bath described by a colored noise Langevin thermostat. The new approach, which we call QB-MSST, is of comparable computational cost to MSST and self consistently incorporates quantum heat capacities and Bose-Einstein harmonic vibrational distributions. As a first test, we study shock-compressed methane using the ReaxFF potential. The Hugoniot curves predicted from the new approach are found comparable with existing experimental data. We find that the self consistent nature of the method results in the onset of chemistry at 40% lower pressure on the shock Hugoniot than observed with classical molecular dynamics. The temperature shift associated with quantum heat capacity is determined to be the primary factor in this shift. PMID- 23013331 TI - A novel treatment strategy for sepsis and septic shock based on the interactions between prostanoids, nitric oxide, and 20-hydroxyeicosatetraenoic acid. AB - Sepsis is a systemic inflammatory response syndrome with a suspected or proven infection caused by any pathogen or a clinical syndrome associated with a high probability of infection. The definition of septic shock includes sepsis-induced hypotension despite adequate fluid resuscitation, along with the presence of organ perfusion abnormalities, and ultimately cell dysfunction. As the most common causes of morbidity and mortality in intensive care units worldwide, the societal and economic costs of sepsis and septic shock are staggering. The molecular pathophysiology of sepsis and septic shock and the complex roles played by cytokines, reactive oxygen and nitrogen species, and eicosanoids remain controversal despite decades of study. The lipid A part of lipopolysaccharide, also known as endotoxin, is the most potent microbial mediator of the pathogenesis of sepsis and septic shock. 20-Hydroxyeicosatetraenoic acid (20 HETE) is a vasoconstrictor omega-hydroxylation product of arachidonic acid that is produced by cytochrome P450 (CYP) enzymes, mainly by CYP4A and CYP4F isoforms. Studies from our laboratory and others have provided substantial evidence that administration of a synthetic analog of 20-HETE, N-[20-hydroxyeicosa-5(Z),14(Z) dienoyl]glycine, prevents endotox-ininduced vascular hyporeactivity, hypotension, and mortality associated with increased formation of inducible nitric oxide synthase-derived nitric oxide (NO) and cyclooxygenase-2-derived vasodilator prostanoids as well as decreased expression and activity of CYP4A1 and 20-HETE production in a rodent model of septic shock. CYP4A- and CYP4F-derived 20- HETE is also a proinflammatory mediator of endotoxin-induced acute systemic inflammation. In this review, we will present an overview of our current understanding of the interactions between prostanoids, NO, and 20-HETE in sepsis, and provide a rationale for the development of synthetic 20-HETE analogs for the treatment of sepsis and septic shock. PMID- 23013330 TI - Diagnostic value of urine sCD163 levels for sepsis and relevant acute kidney injury: a prospective study. AB - BACKGROUND: Sepsis is a common syndrome in critically ill patients and easily leads to the occurrence of acute kidney injury (AKI), with high mortality rates. This study aimed to investigate the diagnostic value of urine soluble CD163 (sCD163) for identification of sepsis, severity of sepsis, and for secondary AKI, and to assess the patients' prognosis. METHODS: We enrolled 20 cases with systemic inflammatory response syndrome (SIRS), 40 cases with sepsis (further divided into 17 sepsis cases and 23 severe sepsis cases) admitted to the intensive care unit (ICU), and 20 control cases. Results for urine sCD163 were recorded on the day of admission to the ICU, and AKI occurrence was noted. RESULTS: On the day of ICU admission, the sepsis group exhibited higher levels of urine sCD163 (74.8 ng/ml; range: 47.9-148.3 ng/ml) compared with those in the SIRS group (31.9 ng/ml; 16.8-48.0, P < 0.001). The area under the curve (AUC) was 0.83 (95% confidence interval [CI]: 0.72-0.94, P < 0.001) the sensitivity was 0.83, and the specificity was 0.75 (based on a cut-off point of 43.0 ng/ml). Moreover, the severe sepsis group appeared to have a higher level of sCD163 compared with that in the sepsis group (76.2; 47.2-167.5 ng/ml vs. 74.2; 46.2 131.6 ng/ml), but this was not significant. For 15 patients with AKI, urine sCD163 levels at AKI diagnosis were significantly higher than those of the remaining 35 sepsis patients upon ICU admission (121.0; 74.6-299.1 ng/ml vs. 61.8; 42.8-128.3 ng/ml, P = 0.049). The AUC for urine sCD163 was 0.688 (95% CI: 0.51-0.87, P = 0.049). Sepsis patients with a poor prognosis showed a higher urine sCD163 level at ICU admission (98.6; 50.3-275.6 ng/ml vs. 68.0; 44.8-114.5 ng/ml), but this was not significant. Patients with AKI with a poor prognosis had higher sCD163 levels than those in patients with a better prognosis (205.9; 38.6 766.0 ng/ml vs. 80.9; 74.9-141.0 ng/ml), but this was not significant. CONCLUSIONS: This study shows, for the first time, the potential value of urine sCD163 levels for identifying sepsis and diagnosing AKI, as well as for assessment of patients' prognosis. TRIAL REGISTRATION: ChiCTR-ONC-10000812. PMID- 23013332 TI - Editorial : PMID- 23013333 TI - Hydrogen peroxide-mediated growth of the root system occurs via auxin signaling modification and variations in the expression of cell-cycle genes in rice seedlings exposed to cadmium stress. AB - The link between root growth, H2O2, auxin signaling, and the cell cycle in cadmium (Cd)-stressed rice (Oryza sativa L. cv. Zhonghua No. 11) was analyzed in this study. Exposure to Cd induced a significant accumulation of Cd, but caused a decrease in zinc (Zn) content which resulted from the decreased expression of OsHMA9 and OsZIP. Analysis using a Cd-specific probe showed that Cd was mainly localized in the meristematic zone and vascular tissues. Formation and elongation of the root system were significantly promoted by 3-amino-1,2,4-triazole (AT), but were markedly inhibited by N,N'-dimethylthiourea (DMTU) under Cd stress. The effect of H2O2 on Cd-stressed root growth was further confirmed by examining a gain-of-function rice mutant (carrying catalase1 and glutathione-S-transferase) in the presence or absence of diphenylene iodonium. DR5-GUS staining revealed close associations between H2O2 and the concentration and distribution of auxin. H2O2 affected the expression of key genes, including OsYUCCA, OsPIN, OsARF, and OsIAA, in the auxin signaling pathway in Cd-treated plants. These results suggest that H2O2 functions upstream of the auxin signaling pathway. Furthermore, H2O2 modified the expression of cell-cycle genes in Cd-treated roots. The effects of H2O2 on root system growth are therefore linked to auxin signal modification and to variations in the expression of cell-cycle genes in Cd-stressed rice. A working model for the effects of H2O2 on Cd-stressed root system growth is thus proposed and discussed in this paper. PMID- 23013334 TI - In vivo bioluminescence imaging of cell differentiation in biomaterials: a platform for scaffold development. AB - In vivo testing is a mandatory last step in scaffold development. Agile longitudinal noninvasive real-time monitoring of stem cell behavior in biomaterials implanted in live animals should facilitate the development of scaffolds for tissue engineering. We report on a noninvasive bioluminescence imaging (BLI) procedure for simultaneous monitoring of changes in the expression of multiple genes to evaluate scaffold performance in vivo. Adipose tissue derived stromal mensenchymal cells were dually labeled with Renilla red fluorescent protein and firefly green fluorescent protein chimeric reporters regulated by cytomegalovirus and tissue-specific promoters, respectively. Labeled cells were induced to differentiate in vitro and in vivo, by seeding in demineralized bone matrices (DBMs) and monitored by BLI. Imaging results were validated by RT-polymerase chain reaction and histological procedures. The proposed approach improves molecular imaging and measurement of changes in gene expression of cells implanted in live animals. This procedure, applicable to the simultaneous analysis of multiple genes from cells seeded in DBMs, should facilitate engineering of scaffolds for tissue repair. PMID- 23013335 TI - The maladaptive personality traits of the Personality Inventory for DSM-5 (PID-5) in relation to the HEXACO personality factors and schizotypy/dissociation. AB - The Personality Inventory for DSM-5 (PID-5), a new measure of maladaptive personality traits, has recently been developed by the DSM-5 Personality and Personality Disorders Workgroup. The PID-5 variables were examined within the seven-factor space defined by the six HEXACO factors and the Schizotypy/Dissociation factor (Ashton & Lee, 2012) using participant samples from Canada (N = 378) and the Netherlands (N = 476). Extension analyses showed that several PID-5 facet-level scales represented each of the Honesty-Humility, Emotionality, Extraversion, Conscientiousness, and Schizotypy/Dissociation factors. In contrast, only one PID-5 scale loaded strongly on HEXACO Agreeableness, and no PID-5 scales loaded strongly on Openness to Experience. In addition, a joint factor analysis involving the PID-5 variables and facets of the Five-Factor Model was conducted in the Canadian sample and recovered a set of seven factors corresponding rather closely to the HEXACO factors plus Schizotypy/Dissociation. The authors discuss implications for the assessment and structure of normal and abnormal personality. PMID- 23013336 TI - Empathy and alexithymia in borderline personality disorder: clinical and laboratory measures. AB - The authors aimed to understand the role of alexithymia in borderline personality disorder (BPD). A total of 79 BPD patients, 76 healthy controls, and 39 patients with avoidant personality disorder (AVPD) were included. Alexithymia and its influence on interpersonal functioning were assessed. The authors explored group differences in empathy in relation to interpersonal function, and they measured responses to emotional pictures with a computer task in which subjects focused either on the experience of the individual in the picture or the subject's own imagined experience. Patients with BPD and AVPD had higher alexithymia than those in the control group. Patients with BPD had more difficulty identifying their own emotions than patients with AVPD. Patients with BPD reported poorer ability to take the perspective of others, but higher distress; they showed intact "empathic concern." Differences in computer task performance were clearest during self relevant responses to negatively valenced pictures. BPD patients are highly responsive to the feelings of others, but they are impaired in identifying/describing feelings and in taking the perspective of others. PMID- 23013337 TI - Alexithymia as a mediator between attachment and the development of borderline personality disorder in adolescence. AB - Insecure attachment and the inability to identify emotions have both been put forward as possible explanations for dysfunction of the emotional system in borderline personality disorder (BPD). This study aimed to test a model according to which the influence of attachment on the development of BPD in adolescence is mediated by alexithymia. Borderline severity was assessed by means of the Structured Interview for DSM-IV Personality Disorders. Attachment and alexithymia were measured respectively with the Relationship Styles Questionnaire and the Toronto Alexithymia Scale. Mediation analyses conducted on 105 participants (54 with BPD and 51 matched controls) suggest that the role of security and negative model of self (i.e., preoccupied and fearful attachment styles) in the development of BPD symptoms are mediated by alexithymia. PMID- 23013338 TI - Retention or deletion of personality disorder diagnoses for DSM-5: an expert consensus approach. AB - One of the official proposals for the fifth edition of the American Psychiatric Association's (APA) diagnostic manual (DSM-5) is to delete half of the existing personality disorders (i.e., dependent, histrionic, narcissistic, paranoid, and schizoid). Within the APA guidelines for DSM-5 decisions, it is stated that there should be expert consensus agreement for the deletion of a diagnostic category. Additionally, categories to be deleted should have low clinical utility and/or minimal evidence for validity. The current study surveyed members of two personality disorder associations (n = 146) with respect to the utility, validity, and status of each DSM-IV-TR personality disorder diagnosis. Findings indicated that the proposal to delete five of the personality disorders lacks consensus support within the personality disorder community. PMID- 23013339 TI - Core features of personality disorder: differentiating general personality dysfunctioning from personality traits. AB - The distinction between general personality dysfunctioning (GPD) and specific personality traits (SPT) is an important focus of attention in the proposed revisions of the DSM-5. The present study explores the distinction between GPD and SPT using the self-report questionnaires General Assessment of Personality Disorder (GAPD) and Severity Indices for Personality Problems (SIPP-118) to measure GPD, and the NEO-PI-R to measure SPT. The sample consisted of 424 psychiatric patients. Using principal component analysis, GPD and SPT appeared to be clearly distinct components of personality. Our GPD model consisted of three factors, i.e., Self-identity dysfunctioning, Relational dysfunctioning, and Prosocial functioning. This model remained by and large intact when combined with SFT factors. Our findings support the distinction between personality traits and personality dysfunction laid down in the recent proposal by the Personality and Personality Disorders Work Group of the DSM-5 Task Force. PMID- 23013340 TI - Viewing psychopathy from the perspective of the Personality Psychopathology Five model: implications for DSM-5. AB - The current study examined the association between domains from the Personality Psychopathology Five (PSY-5; Harkness & McNulty, 1994) model, which is a dimensional model of pathological personality that corresponds closely to the proposed domains of the DSM-5, and psychopathy as indexed by the Psychopathy Checklist-Screening Version (PCL-SV; Hart, Cox, & Hare, 1995). The sample comprised 99 individuals undergoing forensic psychological evaluations. The PSY-5 domain of Aggressiveness was strongly associated with the PCL-SV global measure of psychopathy, as well as both PCL-SV parts and the four facets. The PSY-5 domain Disconstraint was preferentially associated with the behavioral facets of psychopathy, whereas low Negative Emotionality was related to the affective characteristics of the construct. These findings have implications for the Antisocial/Psychopathic prototype proposed for the DSM-5. PMID- 23013341 TI - Relationships between childhood maltreatment, parenting style, and borderline personality disorder criteria. AB - This study examines the relationship of different types of childhood maltreatment and the perceived parenting style with borderline personality disorder (BPD) criteria. Kendall's Tau partial correlations were performed controlling for the effect of simultaneous adverse experiences and Axis I and II symptoms in a sample of 109 female patients (32 BPD, 43 other personality disorder, and 34 non personality disorder). BPD criteria were associated with higher scores on emotional and sexual abuse, whereas parenting style did not show a specific association with BPD. Findings of the present study help clarify the effects of overlapping environmental factors that are associated with BPD. PMID- 23013342 TI - Perinatal risk factors in offenders with severe personality disorder: a population-based investigation. AB - Although perinatal factors are associated with the development of several psychiatric disorders, it is unknown whether these factors are linked with personality disorder. Cases of personality disorder were drawn from a national registry of all forensic psychiatric evaluations (n = 150). Two control groups were used: (1) A sample of forensic evaluations without any psychiatric disorder (n = 97) allowing for a nested case-control investigation; and (2) A population based sample matched by age and gender with no history of psychiatric hospitalization (n = 1498). Prematurity (<37 weeks of completed gestation) was significantly associated with a diagnosis of personality disorder, both in the nested and the population-based case-control comparisons with adjusted odds ratios (OR) for this risk factor ranging from 2 to 4. Asphyxia (adjusted OR = 2.4, 95% CI: 1.4-4.1) and complicated delivery (adjusted OR = 1.5, 1.0-2.1) were associated with personality disorder in the population-based study, and the former remained significant in multivariate models. Overall, perinatal complications were found to be associated with a later diagnosis of personality disorder in this selected sample. As with other psychiatric disorders where such associations have been demonstrated, changes during the perinatal period may lead to abnormal brain development and function. PMID- 23013343 TI - Temporary separation from parents in early childhood and serious personality disorders in adult life. AB - We have previously shown that the temporary separation of Finnish children from both parents during World War II predicted any serious mental, substance use, and personality disorders in adulthood. Here we examine if parental separation is a specific vulnerability factor for any- and dramatic personality disorders relative to other mental disorders. We extracted information on separations from the Finnish National Archives and psychiatric diagnoses from the national Hospital Discharge and Causes of Death-Registers. Of the 12,734 Helsinki Birth Cohort Study participants, 1,717 were separated, 1,487 had any mental, 194 any personality, and 77 dramatic personality disorders. In those who were separated, the risk of any serious personality disorders was significantly higher also among individuals with any serious mental disorders. The increased risks of any serious and dramatic personality disorders were particularly characteristic of individuals separated before the age of five, and that of dramatic personality disorder of separated men. Parental separation may thus be a specific vulnerability factor for serious personality disorders. PMID- 23013344 TI - Personality disorder features through the life course. AB - Personality Disorders have proved to be more fluid through the life course than previously thought. However, because analyses have usually been undertaken at the level of diagnostic categories, relevant findings may be obscured. An examination at the criteria level could bypass arbitrary aggregations of heterogeneous traits and thus offer more accurate information. To this end, we administered the Personality Diagnostic Questionnaire-4+ (PDQ-4+) to 1,477 patients aged 15 to 82. Nine of 12 disorders declined to some extent over the lifespan, but the evolution of individual criteria diverged within categories. At this level, 45 of 93 criteria showed age-related decreases, whereas only seven presented increases. A clearer picture is offered of the PD traits that change and those that remain stable. Thus, pathological features are not only more fluid, but developmentally more heterogeneous than previously believed. PMID- 23013345 TI - Personality disorders, violence, and antisocial behavior: a systematic review and meta-regression analysis. AB - The risk of antisocial outcomes in individuals with personality disorder (PD) remains uncertain. The authors synthesize the current evidence on the risks of antisocial behavior, violence, and repeat offending in PD, and they explore sources of heterogeneity in risk estimates through a systematic review and meta regression analysis of observational studies comparing antisocial outcomes in personality disordered individuals with controls groups. Fourteen studies examined risk of antisocial and violent behavior in 10,007 individuals with PD, compared with over 12 million general population controls. There was a substantially increased risk of violent outcomes in studies with all PDs (random effects pooled odds ratio [OR] = 3.0, 95% CI = 2.6 to 3.5). Meta-regression revealed that antisocial PD and gender were associated with higher risks (p = .01 and .07, respectively). The odds of all antisocial outcomes were also elevated. Twenty-five studies reported the risk of repeat offending in PD compared with other offenders. The risk of a repeat offense was also increased (fixed-effects pooled OR = 2.4, 95% CI = 2.2 to 2.7) in offenders with PD. The authors conclude that although PD is associated with antisocial outcomes and repeat offending, the risk appears to differ by PD category, gender, and whether individuals are offenders or not. PMID- 23013346 TI - A comparison of latent class, latent trait, and factor mixture models of DSM-IV borderline personality disorder criteria in a community setting: implications for DSM-5. AB - With the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) scheduled for publication in 2013, researchers continue to debate the optimal classification of borderline personality disorder (BPD). Much of the discussion has focused on the relative merits of dimensional versus categorical classification schemes for BPD. Advances in statistical technologies have made it possible to adjudicate between continuous and categorical models of BPD using quantitative methods, yet no prior studies have attempted such a comparison. The current study directly compares the fit of dimensional, categorical, and hybrid models of BPD in a large community sample (N = 700) of young adults at risk for psychopathology due to elevated rates of maternal depression. BPD symptoms were assessed using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Latent class, latent trait, and factor mixture models of SCID-II symptoms were estimated, and a latent trait model provided superior fit to the data, supporting a dimensional conceptualization of borderline pathology. The nosological implications of these results are discussed with respect to a "hybrid" model of BPD diagnosis currently under consideration for DSM-5. PMID- 23013347 TI - The course of anxiety disorders other than PTSD in patients with borderline personality disorder and Axis II comparison subjects: a 10-year follow-up study. AB - The objectives of this study were to assess the rates of comorbid anxiety disorders other than PTSD in patients with borderline personality disorder (BPD) and Axis II comparison subjects over ten years of prospective follow-up and to determine time-to-remission, recurrence, and new onset of these disorders. The SCID I was administered to 290 borderline patients and 72 Axis II comparison subjects at baseline and at five contiguous 2-year follow-up waves. The rates of anxiety disorders for those in both groups declined significantly over time, although they remained significantly higher among borderline patients. By 10-year follow-up, the rates of remission for borderline patients who met criteria for these disorders at baseline were high, while the rates of recurrences and new onsets were moderate. These results suggest that anxiety disorders are very common over time among borderline patients. They also suggest that these disorders have an intermittent course among those with BPD. PMID- 23013348 TI - The contributions of neuroticism and childhood maltreatment to hyperbolic temperament. AB - Zanarini and colleagues have proposed that hyperbolic temperament, involving a preponderance of negative emotions and cognitions combined with a need for those dysphoric inner states to be validated and understood, underlies borderline symptomatology. This study examined neuroticism and childhood maltreatment as predictors of hyperbolic features measured 10 years later in a clinical sample. Neuroticism and childhood maltreatment were significant and independent predictors of prospective hyperbolic temperament. These findings expand upon the hyperbolic temperament model of borderline phenomenology by depicting its developmental antecedents. PMID- 23013349 TI - Perspective: celebrating the 25th anniversary of the International Society for the Study of Personality Disorders. PMID- 23013350 TI - A comparative study of neuroprotective effect of single and combined blockade of AT1 receptor and PARP-1 in focal cerebral ischaemia in rat. AB - BACKGROUND: Cerebral ischaemia results in enhanced expression of type 1 angiotensin receptor and oxidative stress. Free radicals due to oxidative stress lead to excessive DNA damage causing overactivation of poly (ADP-ribose) polymerase-1 resulting in neuronal death. Activation of both type 1 angiotensin receptors and poly (ADP-ribose) polymerase-1 following cerebral ischaemia takes place simultaneously, but until now, no study has explored the effect of combined blockade of both angiotensin type 1 angiotensin receptor and poly (ADP-ribose) polymerase-1 in cerebral ischaemia. AIM: Our purpose was to compare the effect of single and combined treatment with angiotensin type 1 angiotensin receptor blocker, candesartan, and the poly (ADP-ribose) polymerase-1 inhibitor, 1, 5 isoquinolinediol, on brain damage and oxidative stress in transient focal cerebral ischaemia in rats. METHOD: Transient focal cerebral ischaemia was induced in Sprague-Dawley rats by an intraluminal technique for two-hours following 48 h of reperfusion. Candesartan (0.05 mg/kg) was administered just after initiation of ischaemia followed by a repeat administration at 24 h while 1, 5 isoquinolinediol (0.1 mg/kg) was given one-hour after of ischaemia. After 24 h of reperfusion, neurological deficit was evaluated in the different treatment groups. After 48 h of reperfusion, the rats were sacrificed and the brain was isolated. Ischaemic brain damage by 2,3,5 triphenyl tetrazolium chloride staining, oxidative stress markers, and levels of reactive oxygen species were determined biochemically. RESULT: Single treatment with candesartan and 1, 5 isoquinolinediol significantly reduced neurological deficit, infarct, and oedema volume as compared to ischaemic control and different vehicle groups for each of the drugs. However, treatment with candesartan + 1, 5 isoquinolinediol offered greater reduction in neurological deficit, cerebral infarct volume, and oedema as compared to single-drug treatments. Furthermore, treatment with candesartan + 1, 5 isoquinolinediol significantly decreased oxidative stress as compared to single treatments with each drug. CONCLUSION: The study suggests that blockade of either type 1 angiotensin receptor or poly (ADP-ribose) polymerase-1 alone provides neuroprotection, but the better result was achieved when both type 1 angiotensin receptor and poly (ADP-ribose) polymerase-1 were blocked together by the combined use of their pharmacological inhibitor in transient cerebral ischaemia in rat. PMID- 23013351 TI - Photodynamic therapy with methyl aminolaevulinate for cervical and/or facial lesions of folliculotropic mycosis fungoides: interest and limits. PMID- 23013352 TI - Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. AB - BACKGROUND: Curcumin extracts of turmeric are proposed to produce health benefits. To date, human intervention studies have focused mainly on people with existing health problems given high doses of poorly absorbed curcumin. The purpose of the current study was to check whether in healthy people, a low dose of a lipidated curcumin extract could alter wellness-related measures. METHODS: The present study was conducted in healthy middle aged people (40-60 years old) with a low dose of curcumin (80 mg/day) in a lipidated form expected to have good absorption. Subjects were given either curcumin (N = 19) or placebo (N = 19) for 4 wk. Blood and saliva samples were taken before and after the 4 weeks and analyzed for a variety of blood and saliva measures relevant to health promotion. RESULTS: Curcumin, but not placebo, produced the following statistically significant changes: lowering of plasma triglyceride values, lowering of salivary amylase levels, raising of salivary radical scavenging capacities, raising of plasma catalase activities, lowering of plasma beta amyloid protein concentrations, lowering of plasma sICAM readings, increased plasma myeloperoxidase without increased c-reactive protein levels, increased plasma nitric oxide, and decreased plasma alanine amino transferase activities. CONCLUSION: Collectively, these results demonstrate that a low dose of a curcumin lipid preparation can produce a variety of potentially health promoting effects in healthy middle aged people. PMID- 23013353 TI - Topical cidofovir for refractory verrucae in children. AB - Warts are common and are a challenge to treat in some children, especially immunocompromised children and those who fail or cannot tolerate salicylic acid preparations and cryotherapy. Cidofovir, a nucleotide analogue with antiviral activity, has demonstrated promising results when compounded into a topical form to treat refractory warts. We present a retrospective institutional review of 12 children with refractory verrucae treated with 1% to 3% topical cidofovir compounded in an unscented moisturizing cream, applied every other day to daily. In our institutional series, only three patients (25%) demonstrated complete clearance of their verrucae. An additional four patients (33%) demonstrated partial clearance. Our experience using topical cidofovir has been less successful than previous institutional reviews, possibly because we used a lower concentration and less-frequent dosing. More studies are needed to better characterize the efficacy, safety, and dosing of topical cidofovir for the treatment of refractory warts. PMID- 23013355 TI - Absence of pathogenic gamma-secretase mutations in a South Wales cohort of familial and sporadic hidradenitis suppurativa (acne inversa). PMID- 23013354 TI - Glyphosate effects on plant mineral nutrition, crop rhizosphere microbiota, and plant disease in glyphosate-resistant crops. AB - Claims have been made recently that glyphosate-resistant (GR) crops sometimes have mineral deficiencies and increased plant disease. This review evaluates the literature that is germane to these claims. Our conclusions are: (1) although there is conflicting literature on the effects of glyphosate on mineral nutrition on GR crops, most of the literature indicates that mineral nutrition in GR crops is not affected by either the GR trait or by application of glyphosate; (2) most of the available data support the view that neither the GR transgenes nor glyphosate use in GR crops increases crop disease; and (3) yield data on GR crops do not support the hypotheses that there are substantive mineral nutrition or disease problems that are specific to GR crops. PMID- 23013356 TI - Elaiomycins D-F, antimicrobial and cytotoxic azoxides from Streptomyces sp. strain HKI0708. AB - Five new congeners of elaiomycin featuring the rare azoxy function were isolated from Streptomyces sp. strain HKI0708. Individual elaiomycins exhibit specific antimycobacterial, anti-Aspergillus, and cytotoxic activities, providing provisional data on structure-activity relationships. The co-occurrence of the azoxide variants indicates a biogenetic relationship that illustrates new diversification steps in elaiomycin biosynthesis. PMID- 23013357 TI - A direct comparison of the pharmacodynamic properties of insulin detemir and neutral protamine lispro insulin in patients with type 1 diabetes. AB - AIMS: To compare the pharmacodynamic properties of insulin detemir (detemir) and neutral protamine lispro (NPL) insulin using a euglycaemic glucose clamp. METHODS: In a double-blind, crossover study, 30 patients with C-peptide negative type 1 diabetes were randomly assigned to a single dose (0.4 U/kg) of detemir and NPL. Plasma glucose (PG) was normalized with a variable insulin infusion and then decreased stepwise, followed by a euglycaemic clamp at 5.5 mmol/l over 32 h. Duration of action was defined as time from dosing until PG exceeded 8.3 mmol/l for at least 30 min. RESULTS: Duration of action was similar for detemir [23.0 (range 2.25-32) h] and NPL [22.0 (9.5-32) h], p = 0.55. Using glucose infusion rate (GIR) parameters, detemir showed a flatter pharmacodynamic profile versus NPL: area under the curve, AUC(GIR) ((0-32)) = 1326 vs. 1841 mg/kg, p < 0.01 (detemir vs. NPL, respectively); AUC(GIR) ((0-12)) = 784 vs. 1392 mg/kg, p < 0.05; AUC(GIR) ((12-32)) = 455 vs. 274 mg/kg, p = 0.051; GIR(late) (12 32)/GIR(early) (0-12) ratio = 0.33 vs. 0.04, p < 0.001. Detemir also showed a lower and later peak of action than NPL [GIR(max) 2.0 vs. 3.2 mg/kg/min, p < 0.01; T(max) 9.1 (95% confidence interval: 3.0-14.7) vs. 7.0 h (1.8-15.2)]. CONCLUSIONS: Detemir and NPL had similar duration of action of approximately 24 h in patients with type 1 diabetes. Compared with NPL, detemir had a flatter profile with a more even distribution of metabolic effect over 24 h. PMID- 23013358 TI - Hematopoietic stem cells, progenitor cells and leukemic stem cells in adult myeloproliferative neoplasms. AB - The understanding of myeloproliferative neoplasms has changed dramatically since Dameshek proposed his classification over 50 years ago. Our knowledge of the types of cells which constitute the hematopoietic system and of how they are regulated has also appreciated significantly over this time. This review relates what is currently known about the acquired genetic mutations associated with adult myeloproliferative neoplasms to how they lead to the hematopoietic perturbations of myeloproliferative disease. There is a particular focus on how stem and progenitor cell compartments are affected by BCR-ABL1 and JAK2V617F mutations, and the particular issue of resistance of leukemic stem cells to conventional and targeted therapies. PMID- 23013359 TI - Modular synthesis of bipyridinium oligomers and corresponding donor-acceptor oligorotaxanes with crown ethers. AB - Donor-acceptor [4]- and [6]rotaxanes have been prepared from bipyridinium (BIPY(2+)) oligomers and 1,5-dinaphtho[38]crown-10 (DN38C10) by a threading followed-by-stoppering protocol employing click chemistry. An efficient, straightforward route to the BIPY(2+) oligomers has been developed that requires little to no chromatographic purification. Unlike most donor-acceptor oligorotaxanes that have been reported to date, 100% of the recognition sites on the dumbbells are occupied by rings. PMID- 23013360 TI - Ligand contributions to the electronic structures of the oxidized cobalt(II) salen complexes. AB - Square planar cobalt(II) complexes of salen ligands N,N'-bis(3-tert-butyl-5R salicylidene)-1,2-cyclohexanediamine), where R = OMe (1) and tert-butyl (2), were prepared. 1 and 2 were electrochemically reversibly oxidized into cations [1 H(2)O](+) and [2-H(2)O](+) in CH(2)Cl(2). The chemically generated [1 H(2)O](SbF(6)).0.68 H(2)O.0.82CH(2)Cl(2) and [2 H(2)O](SbF(6)).0.3H(2)O.0.85CH(2)Cl(2) were characterized by X-ray diffraction and NIR spectroscopy. Both complexes are paramagnetic species containing a square pyramidal cobalt ion coordinated at the apical position by an exogenous water molecule. They exhibit remarkable NIR bands at 1220 (7370 M(-1) cm(-1)) and 1060 nm (5560 M(-1) cm(-1)), respectively, assigned to a CT transition. DFT calculations and magnetic measurements confirm the paramagnetic (S = 1) ground spin state of the cations. They show that more than 70% of the total spin density in [1-H(2)O](+) and [2-H(2)O](+) is localized on the metal, the remaining spin density being distributed over the aromatic rings (30% phenoxyl character). In the presence of N-methylimidazole 1 and 2 are irreversibly oxidized by air into the genuine octahedral cobalt(III) bis(phenolate) complexes [1-im(2)](+) and [2 im(2)](+), the former being structurally characterized. Neither [1-im(2)](+) nor [2-im(2)](+) exhibits a NIR feature in its electronic spectrum. 1 and 2 were electrochemically two-electron oxidized into [1](2+) and [2](2+). The cations were identified as Co(III)-phenoxyl species by their characteristic absorption band at ca. 400 nm in the UV-vis spectrum. Coordination of the phenoxyl radical to the cobalt(III) metal ion is evidenced by the EPR signal centered at g = 2.00. PMID- 23013361 TI - Decreased levels of serum complement C3 and natural killer cells add to the predictive value of total immunoglobulin G for severe infection in heart transplant recipients. AB - BACKGROUND: Infection remains a source of mortality in heart recipients. We previously reported that post-transplant immunoglobulin G (IgG) quantification can help identify the risk for infection. We assessed whether other standardized parameters of humoral and cellular immunity could prove useful when identifying patients at risk of infection. METHODS: We prospectively studied 133 heart recipients over a 12-month period. Forty-eight patients had at least one episode of severe infection. An event was defined as an infection requiring intravenous antimicrobial therapy. RESULTS: Cox regression analysis revealed an association between the risk of developing infection and the following: lower IgG2 subclass levels (day 7: relative hazard [RH] 1.71; day 30: RH 1.76), lower IgA levels (day 7: RH 1.61; day 30: RH 1.91), lower complement C3 values (day 7: RH 1.25), lower CD3 absolute counts (day 30: RH 1.10), lower absolute natural killer [NK] cell count (day 7: RH 1.24), and lower IgG concentrations (day 7: RH 1.31; day 30: RH 1.36). Cox regression bivariate analysis revealed that lower day 7 C3 levels, IgG2 concentration, and absolute NK cell count remained significant after adjustment for total IgG levels. CONCLUSIONS: Data suggest that early immune monitoring including C3, IgG2, and NK cell testing in addition to IgG concentrations is useful when attempting to identify the risk of infection in heart transplant recipients. PMID- 23013362 TI - Chronic alcohol ingestion in rats decreases Kruppel-like factor 4 expression and intracellular zinc in the lung. AB - BACKGROUND: Chronic alcohol ingestion alters the dynamic balance between granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor beta1 (TGFbeta1) signaling within the alveolar space and, in parallel, impairs alveolar macrophage and epithelial cell function by inhibiting expression of the zinc importer ZIP4 and decreasing zinc bioavailability in the alveolar compartment. As the transcription factor Kruppel-like factor 4 (KLF4 ) binds to ZIP4 , we hypothesized that alcohol exposure and consequent perturbations in GM CSF and TGFbeta1 signaling could decrease cellular KLF4 expression and/or binding as a mechanism by which it inhibits ZIP4 expression and decreases cellular zinc levels. METHODS AND RESULTS: Alcohol exposure in vitro or chronic ingestion in vivo decreased KLF4 expression in alveolar macrophages and epithelial cells. Treatment with GM-CSF or TGFbeta1 showed an enhancing or dampening effect on KLF4 expression and binding, respectively. Further, treatment of a rat alveolar macrophage cell line with alcohol in vitro for 4 weeks decreased the expression of the zinc transporters ZIP4 and ZNT1, and of the zinc storage protein metallothionein 1. In parallel, treating these macrophages with KLF4 siRNA decreased ZIP4 expression and decreased cellular zinc and phagocytic capacity to levels equivalent to those following alcohol exposure. In epithelial monolayers, transepithelial electrical resistance (TER) was significantly decreased by alcohol ingestion as compared with control diets, and it was restored by in vitro GM-CSF treatment. In contrast, in vitro TGFbeta1 treatment of the epithelial monolayers from control-fed rats significantly decreased TER as compared with untreated control monolayers. CONCLUSIONS: Taken together, these results suggest that within the alveolar space, chronic alcohol exposure decreases KLF4 and ZIP4 expression and consequently decreases zinc transport into cells, which, in turn, impairs their function. Furthermore, the dynamic decrease in the relative influence of GM-CSF versus TGFbeta1 could mediate the zinc deficiency and consequent cellular dysfunction that characterize the "alcoholic lung" phenotype. PMID- 23013363 TI - Proinflammatory cytokine IL-1 beta polymorphisms in sudden sensorineural hearing loss. AB - The cause and pathogenesis of sudden sensorineural hearing loss (SSNHL) remain unknown. IL-1beta is one of the most powerful inflammatory cytokines. The aim of this study was to evaluate the relationships between interleukin-1 beta (IL 1beta) gene polymorphisms (-511 C/T and +3953 C/T) in patients with SSNHL. One hundred two patients affected by SSNHL and 595 controls were genotyped for IL 1beta gene polymorphisms. The polymorphisms were analyzed by polymerase chain reaction amplification and DNA fragment separation via electrophoresis. Compared to controls, the IL-1beta (+3953) T allele increased the relative risk of SSNHL in subjects with IL-1beta (-511) TT genotype (p = 0.022, OR = 9.111, 95% CI = 1.441-57.618). In this study, polymorphisms in the IL-1beta -511 and IL-1beta +3953 loci were assessed for evidence of association with SSNHL. From this assessment, a significant difference in carriage of both the IL-1beta -511 T allele and the IL-1beta +3953 T allele was observed between SSNHL and controls. This suggests that the IL-1beta -511 and +3953 loci may play an important role in the etiopathogenesis of SSNHL. PMID- 23013364 TI - Effects of capsaicin on testis ghrelin expression in mice. AB - Capsaicin (CAP), the active substance of red hot peppers, has been reported to stimulate development of the gonad. Ghrelin is an acylated polypeptide hormone that is secreted predominantly by endocrine cells of the stomach. There is evidence that ghrelin is involved in reproductive function. Ghrelin significantly inhibits testosterone secretion in a dose-dependent manner. We investigated the effect of CAP on ghrelin expression in testes of mice and on testosterone levels during pubertal and adult periods. We used a variety of morphometric, immunohistochemical and biochemical methods, and western blot analysis. The animals were divided into two age groups: puberty and adult. Control groups for both age groups were fed with standard diet and experimental groups were fed with a diet containing 0.02% CAP. Testes were collected quickly after sacrifice. After dehydration, the specimens were embedded in paraffin and 5 MUm sections were cut, and Crossman's triple staining and immunohistochemical staining for ghrelin were applied. Immunohistochemical staining with ghrelin antibody for both age groups demonstrated immunoreaction especially in Leydig and Sertoli cells, but no reaction was observed in spermatogenic cells. Ghrelin immunoreaction was less intense in the experimental groups. Serum testosterone levels were increased in both experimental groups, especially in adults. More spermatocytes were observed in the experimental group compared to the control group. In both pubertal and adult experimental groups, the seminiferous epithelium was thick. CAP appears to enhance testicular cell proliferation and can affect the release of ghrelin and testosterone directly or indirectly. PMID- 23013366 TI - The progress in the cholinesterase quantification methods. AB - INTRODUCTION: Determination of acetylcholinesterase and butyrylcholinesterase activity has become an important tool in drug design and discovery as well as in medicine and toxicology. There are a large number of compounds that are able to modulate cholinesterase activity. These compounds can be used for pharmacological management of various disorders (e.g., Alzheimer's disease, myasthenia Gravis). Moreover, organophosphate poisoning is frequently diagnosed via a cholinesterase activity assay. This broad variety of methods has been developed over the past decades for cholinesterase activity quantification. AREAS COVERED: This review provides a summary of the methods that are based on specific properties of cholinesterases and their interactions with native or artificial substrates. The authors also aim to provide an overview of different techniques used for the determination of quantitative cholinesterase activity. Specifically, the authors describe and discuss the manometric, potentiometric, titrimetric, photometric, fluorometric, and radioisotopic methods. EXPERT OPINION: Existing methods are able to cover most of the problems that arise during cholinesterase activity determination. Colorimetry according to Ellman has proved to be the most useful and versatile approach. It may be used in various protocols for the determination of pesticide or nerve agent exposure or for the development of new drugs. Its possible improvement lies in optimization of hemoglobin-rich samples. The progress of the most common methods (including Ellman) depends on miniaturization and modern physical platforms (e.g., optical fibers, chip methods, or nanotechnologies). PMID- 23013367 TI - The correct physical basis of protobranching stabilization. AB - The source of the extra stability of branched hydrocarbons over unbranched (hereafter referred to as protobraching stabilization) has been explained in several different self-consistent ways. Gronert, basing his arguments on well established properties of organic molecules, namely that geminal atoms strongly repel each other, formulated a model which accounted for this "protobranching" stability simply and very well. However, careful quantum computations were found to yield correct protobranching energies only if they properly took electron correlation into account. Such a source of stability would not have been needed in Gronert's model. The present article analyzes what is correct and what is uncertain about Gronert's atomic repulsion model, and concludes that the computations of Wiberg, Bader, Grimme, Schleyer, and their colleagues overturn Gronert's model and that bond-bond electron correlation energies provide the correct explanation of protobranching. PMID- 23013365 TI - Astrocyte activation and wound healing in intact-skull mouse after focal brain injury. AB - Localised brain tissue damage activates surrounding astrocytes, which significantly influences subsequent long-term pathological processes. Most existing focal brain injury models in rodents employ craniotomy to localise mechanical insults. However, the craniotomy procedure itself induces gliosis. To investigate perilesional astrocyte activation under conditions in which the skull is intact, we created focal brain injuries using light exposure through a cranial window made by thinning the skull without inducing gliosis. The lesion size was maximal at ~ 12 h and showed substantial recovery over the subsequent 30 days. Two distinct types of perilesional reactive astrocyte, identified by GFAP upregulation and hypertrophy, were found. In proximal regions the reactive astrocytes proliferated and expressed nestin, whereas in regions distal to the injury core the astrocytes showed increased GFAP expression but did not proliferate, lacked nestin expression, and displayed different morphology. Simply making the window did not induce any of these changes. There were also significant numbers of neurons in the recovering cortical tissue. In the recovery region, reactive astrocytes radially extended processes which appeared to influence the shapes of neuronal nuclei. The proximal reactive astrocytes also formed a cell layer which appeared to serve as a protective barrier, blocking the spread of IgG deposition and migration of microglia from the lesion core to surrounding tissue. The recovery was preceded by perilesional accumulation of leukocytes expressing vascular endothelial growth factor. These results suggest that, under intact skull conditions, focal brain injury is followed by perilesional reactive astrocyte activities that foster cortical tissue protection and recovery. PMID- 23013368 TI - Prevention of peritendinous adhesions with electrospun ibuprofen-loaded poly(L lactic acid)-polyethylene glycol fibrous membranes. AB - Physical barriers are commonly used to reduce peritendinous adhesion after injury. However, the inflammatory response to surgery cannot be prevented. This study was designed to evaluate the ability of ibuprofen-loaded poly(l-lactic acid)-polyethylene glycol (PELA) diblock copolymer fibrous membranes in preventing adhesion formation and reduce inflammation. Electrospun PELA fibrous membranes underwent mechanical testing and were characterized by morphology, surface wettability, drug release, and degradation. Results of an in vitro drug release study showed that a burst release was followed by sustained release from fibrous membranes with high initial ibuprofen content. Fewer L929 mouse fibroblasts adhered to and proliferated on the ibuprofen-loaded PELA fibrous membrane compared with tissue culture plates or PELA fibrous membrane without ibuprofen. In a chicken model of flexor digitorum profundus tendon surgery, the ibuprofen-loaded PELA fibrous membranes prevented tissue adhesion and significantly reduced inflammation. Taken together, these results demonstrate that ibuprofen-loaded PELA fibrous membranes prevent peritendinous adhesion formation better than membranes that do not contain ibuprofen, through anti adhesion and anti-inflammatory actions. PMID- 23013370 TI - Prevalence, incidence rates and persistence of contact allergy and allergic contact dermatitis in The Odense Adolescence Cohort Study: a 15-year follow-up. AB - BACKGROUND: A cohort of 1501 unselected 8th grade schoolchildren was established 15 years ago with the aim to follow the course of contact allergy and allergic contact dermatitis (ACD) from school age into adult life. To date no studies have evaluated incidence rates and persistence of contact allergy and ACD in an unselected population from adolescence to adulthood. OBJECTIVES: To estimate the incidence rates and persistence of contact allergy and ACD from adolescence to adulthood, and the point prevalence in adulthood. METHODS: In total, 1206 young adults from the cohort were contacted and asked to complete a questionnaire and participate in a clinical examination including patch testing with TRUE Test((r)) . The questionnaire was answered by 899 (74.6%), however, only 442 (36.7%) of those invited participated in patch testing. RESULTS: Over the 15-year period the incidence rates of contact allergy and ACD were 13.4% and 7.8%, respectively. The point prevalence of contact allergy was 20.1%, and present or past ACD was found in 12.9% of those followed. Nickel was the most common contact allergen (11.8%), followed by cobalt (2.3%), colophony (2.0%), thiomersal (1.4%) and p phenylenediamine (1.1%). Most nickel reactions were persistent, and a significant number of new nickel sensitizations were found. Fragrance mix I reactions from adolescence could not be reproduced. CONCLUSIONS: From adolescence to adulthood the incidence rates of contact allergy and ACD were high. Nickel was still the most common contact allergen, and new sensitizations occurred despite the European Union nickel regulation. Fragrance mix I was a poor marker for history of eczematous skin reaction to perfumed products. PMID- 23013369 TI - Studying the effectiveness of activated carbon R95 respirators in reducing the inhalation of combustion by-products in Hanoi, Vietnam: a demonstration study. AB - BACKGROUND: Urban air pollution is an increasing health problem, particularly in Asia, where the combustion of fossil fuels has increased rapidly as a result of industrialization and socio-economic development. The adverse health impacts of urban air pollution are well established, but less is known about effective intervention strategies. In this demonstration study we set out to establish methods to assess whether wearing an R95 activated carbon respirator could reduce intake of polycyclic aromatic hydrocarbons (PAH) in street workers in Hanoi, Vietnam. METHODS: In this demonstration study we performed a cross-over study in which non-smoking participants that worked at least 4 hours per day on the street in Hanoi were randomly allocated to specific respirator wearing sequences for a duration of 2 weeks. Urines were collected after each period, i.e., twice per week, at the end of the working day to measure hydroxy PAHs (OH-PAH) using gas chromatography/high resolution mass spectrometry. The primary endpoint was the urinary concentration of 1-hydroxypyrene (1-OHP). RESULTS: Forty-four participants (54.5% male, median age 40 years) were enrolled with the majority being motorbike taxi drivers (38.6%) or street vendors (34.1%). The baseline creatinine corrected urinary level for 1-OHP was much higher than other international comparisons: 1020 ng/g creatinine (IQR: 604-1551). Wearing a R95 mask had no significant effect on 1-OHP levels: estimated multiplicative effect 1.0 (95% CI: 0.92-1.09) or other OH-PAHs, except 1-hydroxynaphthalene (1-OHN): 0.86 (95% CI: 0.11-0.96). CONCLUSIONS: High levels of urine OH-PAHs were found in Hanoi street workers. No effect was seen on urine OH-PAH levels by wearing R95 particulate respirators in an area of high urban air pollution, except for 1-OHN. A lack of effect may be de to gaseous phase PAHs that were not filtered efficiently by the respirator. The high levels of urinary OH-PAHs found, urges for effective interventions. TRIAL REGISTRATION: ISRCTN74390617 (date of assignation: 04/08/2009). PMID- 23013371 TI - STAT1 expression and activation is increased in lesional psoriatic skin. AB - BACKGROUND: The JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling pathway is known to play an important role in many cellular processes including inflammation. The activation of STAT1 is dependent on tyrosine 701 and serine 727 phosphorylation, which leads to the formation of the STAT dimer and modulation of STAT1 activity, respectively. OBJECTIVE: To determine STAT1 expression and activation in psoriatic skin. METHODS: Biopsies were collected from patients with psoriasis. mRNA expression was evaluated by quantitative polymerase chain reaction, whereas the protein and phosphorylation level of STAT1 were evaluated by Western blotting. STAT1 localization was determined by immunofluorescence analysis and STAT1-induced transcriptional activity was analysed in cultured human keratinocytes using a reporter assay. RESULTS: The expression of STAT1 was demonstrated to be significantly increased at both mRNA and protein level in lesional psoriatic skin. In addition, the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) was significantly increased in lesional compared with nonlesional psoriatic skin. Luciferase assays showed a significant induction of the STAT1-induced transcriptional activity when cultured human keratinocytes were stimulated with either interferon (IFN)-alpha or IFN-gamma. STAT1(Ser727) phosphorylation induced by IFN-alpha, IFN-gamma or ultraviolet B was mediated by a protein kinase C (PKC)-delta- and p38 mitogen activated protein kinase-dependent mechanism in human keratinocytes, whereas IFN alpha-induced STAT1(Tyr701) phosphorylation was mediated by a PKC-delta-dependent mechanism. CONCLUSIONS: This study demonstrates for the first time that the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) is increased in lesional psoriatic skin. In addition, specific signalling pathways leading to this phosphorylation have been identified. Together, our data indicate an important role of STAT1 in the pathogenesis of psoriasis. PMID- 23013372 TI - Using a single hydrophobic-interaction chromatography to purify pharmaceutical grade supercoiled plasmid DNA from other isoforms. AB - CONTEXT: The recent developments in non-viral gene therapy and DNA vaccine have fostered the development of efficient plasmid DNA (pDNA) purification processes. OBJECTIVES: This work aimed to establish a cost-effective purification process for the large-scale production of plasmid DNA for gene therapy and DNA vaccine. MATERIALS AND METHODS: E. coli DH5alpha harboring pCDNA3.1-GFP (7200 base pairs) was used as a model plasmid. Hydrophobic-interaction chromatography (HIC) was employed to purify supercoiled plasmid DNA (sc pDNA). RESULTS: With this method, not only host contaminants, but also open circular plasmid DNA (oc pDNA) could be removed from sc pDNA. Anion-exchange HPLC analysis proved that the recovery of HIC could reach 75%. The plasmid DNA exhibited high purity with supercoiled percentage of 98 +/- 1.2% and undetectable residual endotoxins, genomic DNA, RNA and protein. The purity of pDNA had nothing to do with the flow rate in the range at least up to 400 cm/h. Liposomes transfection experiment prove that the purified pDNA in this article had higher transfection efficiency than the control pDNA. DISCUSSION AND CONCLUSION: In the present work, we confirmed the possibility of separation of sc pDNA from oc pDNA and other host contaminants using a single HIC chromatography. PMID- 23013373 TI - Comparison of stroke warning sign campaigns in Australia, England, and Canada. AB - BACKGROUND: Public awareness of the signs of stroke is essential to ensure that those affected by stroke arrive at the hospital in time for lifesaving therapies. It is unclear how well stroke awareness campaigns improve awareness of stroke signs and whether people translate this into action. METHODS: We evaluated stroke awareness campaigns conducted in England, Australia, and Canada using pre- and post-campaign surveys. We assessed the proportion of people who could name the main signs of stroke, and compared the proportion naming these correctly between locations. We also assessed whether people would call emergency services in the event of a stroke. Proportion responding correctly was compared using chi-square analysis. RESULTS: The amount spent on the campaigns was different in each country. The post-campaign survey was conducted among 400 people in Australia, 1921 in England, and 2703 in Canada. Sixty-eight per cent of people in Australia and 57% in Canada could name two or more signs of stroke (P < 0.001). After the campaign, knowledge of each of the elements of the campaign (face, arm, speech, time) was significantly greater in England than in Australia (P < 0.001 for each item). A high proportion of participants reported that they would call emergency services in the event of a stroke (97% in England, 90% in Australia, and 67% in Canada). CONCLUSION: Knowledge of stroke signs and the action to be taken can be improved with awareness campaigns. The effectiveness of these campaigns may be enhanced by spend on media, media mix, and key messages. It is critical to ensure that campaigns provide the clear and bold message that prompt action is an essential ingredient to reduce death and disability following stroke. PMID- 23013374 TI - Thermoresponsive micellization and micellar stability of poly(N isopropylacrylamide)-b-DNA diblock and miktoarm star polymers. AB - Linear and miktoarm star-shaped diblock copolymers consisting of single-stranded DNA and poly(N-isopropylacrylamide) (PNIPAAm) with various compositions were synthesized via atom transfer radical polymerization and click chemistry. The temperature-responsive phase transition behavior, micellization, was systematically examined using UV-vis spectrometry, high-sensitivity differential scanning calorimetry, dynamic light scattering, and small-angle X-ray scattering. The lower critical solution temperature (LCST) increased, and its enthalpy decreased with decreasing PNIPAAm content. The copolymers self-assembled into well-defined nanoparticles having a core composed of PNIPAAm and a coronal layer of DNA above LCST. The particle size and micellar aggregation number of copolymer chains depended on the macromolecular composition and chain architecture. On the other hand, regardless of their factors, the surface area occupied by one DNA strand was found to be almost unchanged. The hybridization of DNA on the nanoparticles with fully complementary one induced the aggregation of the particles in a non-cross-linking configuration. The nanoparticle composed of miktoarm star copolymer showed a quicker DNA-hybridization response in this non cross-linking aggregation compared with the case of a linear analogue. PMID- 23013375 TI - Acetylcholinesterase inhibitors from QSAR point of view: how close are we? AB - In view of the large libraries of acetylcholinesterase inhibitors (AChEIs) that are now being handled in organic synthesis, the identification of drug biological activity is advisable prior to synthesis and this can be achieved by employing predictive biological property methods. In this sense, Quantitative Structure Activity Relationships (QSAR) or docking approaches have emerged as promising tools. The intention of this review is to summarize the present knowledge concerning computational predictions of AChEIs and AChE. PMID- 23013376 TI - Continuing to learn. PMID- 23013377 TI - Centronuclear myopathy in a Border collie dog. AB - A two-year old, male entire Border collie was presented with a one-year history of exercise-induced collapsing on the pelvic limbs. Physical examination revealed generalised muscle atrophy. Neurological examination supported a generalised neuromuscular disorder. Electromyography revealed spontaneous electrical activity in almost all muscles. Unfixed and formaldehyde-fixed biopsy samples were collected from the triceps brachii, longissimus and vastus lateralis muscles. Histopathological, histochemical and ultrastructural examinations of biopsy specimens were consistent with either centronuclear or myotubular myopathy. The dog clinically improved with supportive treatment with L-carnitine, co-enzyme Q10 and vitamin B compound. To the authors' knowledge, this is the first report of centronuclear/myotubular myopathy in a Border collie. PMID- 23013378 TI - Cervicothoracic syringohydromyelia associated with a prosencephalic mass in a dog. AB - A five-year-old, female, neutered boxer, with neuroanatomical signs consistent with a C1-C5 myelopathy, was diagnosed with a prosencephalic mass and associated severe cervicothoracic syringohydromyelia. After treatment with corticosteroids and lomustine, neurological examination was normal. Imaging repeated three months later showed significant reduction in both the size of the mass and the syringohydromyelia. To the authors' knowledge, this is the first reported case of a dog with syringohydromyelia secondary to a rostral brain mass that had clinical signs on presentation solely due to the syrinx, and the first reported case in a dog of partial resolution of syringohydromyelia after treatment solely with chemotherapy. PMID- 23013379 TI - In vitro investigation of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone for glycemic control. AB - 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a compound isolated and purified from the dried flower buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae), was investigated for its glucose control benefits using in vitro methods. DMC showed strong noncompetitive (IC(50) of 43 MUM) inhibition of pancreatic alpha-amylase; it was, however, ineffective against intestinal alpha glucosidase. In addition, DMC exhibited remarkable glucose transport inhibition effects in both simulated fasting and fed states in Caco-2 cell monolayers (P < 0.05). Besides, exposure of MIN6 cells to 250 MUM H(2)O(2) for 1 h caused a significant viability loss and insulin secretion reduction. Pretreatment of MIN6 cells with DMC for 2 h protected against the H(2)O(2)-induced decrease in glucose stimulated insulin secretion in a dose-dependent manner and also enhanced the impaired basal insulin secretion. Such effects highlight the therapeutic potential of DMC in the management of hyperglycemia. PMID- 23013380 TI - Precise, biomimetic replication of the multiscale structure of intestinal basement membrane using chemical vapor deposition. AB - While it has been shown that cells respond to topographical cues, most studies of the influence of topography have been restricted to culture substrates with regular, single-scale features, such as grooves. In contrast, in vivo topography is highly complex, irregular, and multiscale. In this work, we demonstrate the use of chemical vapor deposition (CVD) on native tissue to fabricate a precise nonbiological replica of irregular macro-to-microscale biological topography. Specifically, the porcine intestinal basement membrane was decellularized and used as a template to create a silica replica from which tissue was removed to produce a free-standing topographically biomimetic silica film. Preservation of the crypt-villus structure (tens to hundreds of micrometers in scale), which is theorized to influence intestinal cell development and behavior, as well as the porosity of the native tissue membrane (1-5 MUM in scale), was demonstrated; however, submicrometer topography appeared to be masked by ball-like structures believed to be a result of the CVD process. CVD process parameters, including reactor pressure and deposition temperature, were explored in efforts to enhance structural and mechanical integrity of the silica replica. A rigid inorganic replica can be used as a template for casting of biocompatible polymeric membranes; thus, this is the first step in fabricating cell culture substrates that precisely mimic their in vivo counterparts in terms of irregular, multiscale topography. PMID- 23013381 TI - Sudden onset vision loss in an 8-year-old female with McCune-Albright syndrome. AB - We describe a case of an 8-year-old girl with large irregular cafe au lait macules on the right cheek and right lower extremity presenting with sudden onset vision loss and found to have polyostotic fibrous dysplasia on imaging. The classic triad of McCune-Albright syndrome is discussed along with the importance of recognition in patients with partial presentation. This case also highlights a rare and potentially devastating neurologic complication of McCune-Albright syndrome, as well as the need for early diagnosis and continual surveillance in these patients. PMID- 23013382 TI - Biomimetic total synthesis of (+/-)-garcibracteatone. AB - The polycyclic polyprenylated acylphloroglucinol natural product garcibracteatone has been synthesized in four steps from phloroglucinol, using a strategy based on biosynthetic speculation. The key biomimetic transformation is a cascade of 7 endo-trig and 5-exo-trig radical cyclizations followed by a terminating aromatic substitution reaction. PMID- 23013383 TI - Functional characterization of quinolone-resistant mechanisms in a lab-selected Salmonella enterica typhimurium mutant. AB - Correlation has been widely accepted between quinolone resistance and topoisomerase point mutations in quinolone resistance determination regions (QRDRs). Acquirement of point mutations in QRDRs usually increases the microbial resistance to both nalidixic acid and fluoroquinolones. The quinolone-resistant mechanisms accumulated in a lab-selected mutant were characterized through the construction of isogenic mutants using phage lambda Red recombinase system and phage P22. The function of a quinolone-resistant mechanism that increased resistance to fluoroquinolones, but decreased resistance to nalidixic acid was fully characterized. A previous reported point mutation in ParC (G78D) was identified in the lab-selected mutant LT2-128. Minimal inhibitory concentrations (MICs) of isogenic mutants showed that acquirement of this point mutation in the host with topoisomerase mutations in GyrA could increase 8- to 32-fold fluoroquinolones MICs, but decrease eight-fold nalidixic acid MICs. Multiple resistant mechanisms, such as the overexpressed effluxes, were accumulated besides the point mutations in QRDRs in LT2-128 during the mutant selection process. Through biological costs comparison among isogenic mutants, we found the biological cost in LT2-128 was not from the mutations in QRDRs, instead it was from other mutations accumulated during the mutant selection process, such as the mechanisms related to constitutively overexpressed effluxes. Mutation in ParC (G78D) was responsible for the increased resistance to fluoroquinolones, but decreased resistance to nalidixic acid. The existence of this mechanism demonstrated mutations in ParC could play different roles in nalidixic acid and ciprofloxacin resistance. PMID- 23013384 TI - Buprenorphine and buprenorphine/naloxone soluble-film for treatment of opioid dependence. AB - INTRODUCTION: Opioid dependence is a chronic relapsing disorder that shows excess mortality and comorbidity with somatic and psychiatric disorders. Methadone and buprenorphine/naloxone are widely accepted and are used as first-line maintenance treatments for opioid dependence. Fatal intoxications with these agents, risk of diversion, and accidental intoxications, especially in children, are apparent risks and are of increasing public concern. Buprenorphine/naloxone sublingual tablet is an established treatment for opioid dependence. A novel buprenorphine/naloxone film has been developed with improved pharmacokinetics and a hopefully lower risk of diversion and accidental intoxications. AREAS COVERED: This review evaluates the available preclinical and clinical data on the novel buprenorphine/naloxone film for the treatment of opioid dependence. Literature was identified though a comprehensive PubMed search and data sources included official FDA information. EXPERT OPINION: This is an interesting new formulation of a well-established medication in opioid dependence. However, few data have been published on its safety and efficacy. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal as expected. Results of an unpublished study made public by the FDA suggest a spectrum of adverse events similar to that of the conventional sublingual tablet. Some data show patients may prefer the novel film over the sublingual tablet. The estimated lower risk for diversion and especially for accidental poisoning in children cannot be assessed in clinical studies but requires data from emergency room visits. PMID- 23013385 TI - Prevalence of multidrug-resistant gram-negative bacilli producing extended spectrum beta-lactamases (ESBLs) and ESBL genes in solid organ transplant recipients. AB - BACKGROUND: Multidrug-resistant (MDR) gram-negative bacilli pose a serious and rapidly emerging threat to recipients of solid organ transplants (SOTs). However, extended-spectrum beta-lactamases (ESBLs), as one of the cardinal mechanisms of resistance to antimicrobial agents in SOT recipients, remain obscure. The aim of this study was to investigate the prevalence of strains producing ESBLs in SOT patients with MDR gram-negative bacilli infections and to identify the ESBL genes carried by them. MATERIALS AND METHODS: Isolates from various clinical specimens of SOT recipients were identified using the VITEK 2 system, and their antibiotic sensitivity was determined by the 2-fold agar dilution method. Isolates suspected of producing ESBL enzymes were tested by an ESBL phenotypic confirmatory method, and the ESBL genotypes were determined by the polymerase chain reaction and sequencing. RESULTS: A total of 80 MDR gram-negative strains were isolated from 350 SOT recipients. Among these strains, 42 (52.5%) had an ESBL-positive phenotype; 33 (42.3%) patients with ESBL-positive infection were found. Molecular analysis showed that most of the isolates harbored blaCTX-M-9 (78.6%), blaTEM (81.0%), and blaSHV (69.0%) genes. All the ESBL-producing strains were susceptible to carbapenems. CONCLUSIONS: MDR gram-negative isolates from SOT recipients are frequently ESBL producers. TEM and CTX-M9 were the predominant ESBL types. PMID- 23013386 TI - Fungal communities influence root exudation rates in pine seedlings. AB - Root exudates are hypothesized to play a central role in belowground food webs, nutrient turnover, and soil C dynamics in forests, but little is known about the extent to which root-associated microbial communities influence exudation rates in trees. We used a novel experimental technique to inoculate loblolly pine (Pinus taeda L.) seedlings with indigenous forest fungi to examine how diverse fungal communities influence exudation. Surface-sterilized seeds were sown in intact, unsieved soil cores for 14 weeks to promote root colonization by fungi. After 14 weeks, we transferred seedlings and root-associated fungi into cuvettes and measured exudate accumulation in trap solutions. Both the abundance and identity of root-associated fungi influenced exudation. Exudation rates were greatest in root systems least colonized by ectomycorrhizal (ECM) fungi and most colonized by putative pathogenic and saprotrophic fungi. However, the ECM community composition was not a strong determinant of exudation rates. These results suggest that environmental conditions that influence the degree to which tree roots are colonized by pathogenic and saprotrophic vs. mutualistic fungi are likely to mediate fluxes of labile C in forest soils, with consequences for soil biogeochemistry and ecosystem processes. PMID- 23013387 TI - A toxicological perspective on the use of spin column extraction to detect drugs and metabolites in biological matrices. PMID- 23013388 TI - Determination of drugs of abuse in hair. PMID- 23013389 TI - Quantitation by MS imaging: needs and challenges in pharmaceuticals. PMID- 23013390 TI - Novartis and University of Pennsylvania announce collaboration. PMID- 23013391 TI - Conference report: Bioanalysis highlights from the 2012 American Association of Pharmaceutical Scientists National Biotechnology Conference. AB - The American Association of Pharmaceutical Scientists (AAPS) is an international forum for the exchange of knowledge among scientists to enhance their contributions to drug development. The annual National Biotechnology Conference, organized by the AAPS on 21-23 May 2012 in San Diego, CA, USA, brings together experts from various disciplines representing private industry, academia and governing institutions dedicated toward advancing the scientific and technological progress related to discovery, development and manufacture of medical biotechnology products. Over 300 scientific poster presentations and approximately 50 oral presentation and discussion sessions examined a breadth of topics pertaining to biotechnology drug development, such as the advancement of vaccines and biosimilars, emerging and innovative technologies, nonclinical and clinical bioanalysis, and regulatory updates. This conference report highlights the existing challenges with ligand-binding assays, emerging challenges, innovative integration of various technology platforms and applicable regulatory considerations as they relate to immunogenicity and pharmacokinetic bioanalytical assessments. PMID- 23013392 TI - Conference report: 60th American Society for MS Conference on MS and Allied Topics. AB - The 60th American Society for Mass Spectrometry (ASMS) Conference on MS and Allied Topics was held in May 2012 at Vancouver in Canada. This international congress is the largest forum exclusively dedicated to MS through its diverse aspects: fundamental, method development and applications to biomolecules. This 4 day conference is also highly appreciated for discussion with the MS manufacturers presenting their latest instrumental developments. PMID- 23013393 TI - Protein quantification using LC-MS: can it make a difference? PMID- 23013395 TI - Utilizing design of experiments to characterize assay robustness. AB - BACKGROUND: Design of experiments (DOE) is a systematic approach to assess the effects of many factors on a response of an assay. This paper provides a case study whereby DOE was successfully utilized to evaluate robustness parameters for a ligand-binding assay (LBA). METHODOLOGY: A 24-run Plackett-Burman design was developed to investigate factors that may have caused a lack of robustness in this particular LBA. We modeled five main effects and their ten two-way interactions, using the standard curve signal as the response. RESULTS: By utilizing DOE, we were able to quickly identify the factors that affected our assay's performance. The lack of robustness was attributed to the handling of the coat reagent. Factors that had an adverse effect on the coat material were vortexing and freeze-thaw cycles. CONCLUSION: We recommend that a robustness DOE be conducted prior to the validation of an assay for early identification of critical factors that may impact assay performance. PMID- 23013394 TI - Recommendations on bioanalytical method stability implications of co-administered and co-formulated drugs by Global CRO Council for Bioanalysis (GCC). AB - An open letter written by the Global CRO Council for Bioanalysis (GCC) describing the GCC survey results on stability data from co-administered and co-formulated drugs was sent to multiple regulatory authorities on 14 December 2011. This letter and further discussions at different GCC meetings led to subsequent recommendations on this topic of widespread interest within the bioanalytical community over the past 2 years. PMID- 23013396 TI - Simultaneous quantification of davalintide, a novel amylin-mimetic peptide, and its active metabolite in beagle and rat plasma by online SPE and LC-MS/MS. AB - BACKGROUND: Davalintide, an investigational therapeutic peptide for the treatment of obesity, is rapidly metabolized by enzymatic cleavage of its N-terminal lysine residue to produce an active des-Lys metabolite in vivo. While a sensitive ELISA assay is available, it is unable to distinguish davalintide from its metabolite. Consequently, we developed an online SPE-LC-MS/MS method for simultaneous quantification of the drug and its active metabolite in beagle and rat plasma samples and compared the resulting pharmacokinetic profiles with those determined by ELISA. RESULTS: The total concentration of active drug measured by ELISA correlated well with the total concentration of davalintide and its metabolite using online SPE-LC-MS/MS. CONCLUSION: The technique is a viable alternative to immunochemistry-based methods for peptide quantitation in terms of sensitivity, reproducibility and specificity, and importantly, does not require developing antibody-based reagents. PMID- 23013397 TI - Choline-containing phospholipids in microdissected human Alzheimer's disease brain senile plaque versus neuropil. AB - BACKGROUND: Lipidomic studies related to Alzheimer's disease have been reported on either biological fluids or large human brain samples. For a better understanding of the role of lipids, especially during the amyloid-beta peptide aggregation, it is crucial to determine the composition of the senile plaque versus the surrounding tissue, that is, the neuropil. RESULTS: A laser microdissection step was added to the analysis by UPLC-MS/MS. Despite the very low amount of sample, two phosphatidylcholines that were significantly depleted in the senile plaque were identified. CONCLUSION: Changes in the phospholipid content have been shown between senile plaque versus neuropil. Nano HPLC, allowing a complete lipidomic profile, should further improve the results. PMID- 23013398 TI - Immunological screening and characterization of highly specific monoclonal antibodies against 20 kDa hGH. AB - BACKGROUND: hGH has been widely abused as a doping agent in sports for many years. There are some important approaches for the detection of hGH doping, and the ratio of 22:20 kDa GH was considered one of the most suitable detection indicators of GH abuse. Currently, effective anti-GH antibodies and related reagents are needed to develop a detection method, in particular, highly specific anti-20 kDa hGH monoclonal antibodies are a prerequisite. Herein we constructed the expression vector of 20 kDa hGH and prepared the corresponding antibodies by the immunization of the recombinant human 20 kDa into mice. Positive clones that can specifically recognize 20 kDa hGH were screened and characterized by enzyme immunoassay, Dot-ELISA and surface plasmon resonance. In total, 14 specific monoclonal cell lines were screened out. RESULTS: By a series of characterization, it was found that the 6C8, 44H3, 12G7 and 33Y19 clones were showing much higher specificity and affinity to 20 kDa hGH, and P3H9 could recognize both 20 and 22 kDa hGH isoforms. 6C8 and 44H3 matched well with P3H9 in the surface plasmon resonance testing. The 12G7 clone had the best surface properties with an association constant of 3.4 * 10(9) M(-1) and a dissociation constant of 2.95 * 10(10) M. CONCLUSION: Highly specific monoclonal antibodies against 20 kDa hGH were generated, and also two paired antibodies (P3H9 and 6C8 or P3H9 and 44H3) were characterized, which can serve as the potential components for 22:20 kDa detection kit. PMID- 23013399 TI - Challenges of developing and validating immunogenicity assays to support comparability studies for biosimilar drug development. AB - Imminent patent expiry for a number of biological products currently on the market (many of which are blockbusters) has created an increasing opportunity for the development of biosimilars in the biotechnology industry. The key for successful biosimilar development is to demonstrate biosimilarity to the originator drug. In addition to demonstrating the similarity of physical and chemical properties between biosimilar and originator compounds, regulatory agencies require that immunogenicity be evaluated in comparative studies between biosimilar and originator drugs. Immunogenicity assays are generally non quantitative (qualitative) and proving similarity/comparability based on qualitative assays can be very challenging. This review will discuss the challenges of developing and validating immunogenicity assays to support preclinical and clinical comparative studies for biosimilar drug development as well as the challenges in association with the interpretation of the data. PMID- 23013400 TI - Improved analytical methods for the detection and quantification of neutralizing antibodies to biopharmaceuticals. AB - Biopharmaceuticals are used extensively for the treatment of a number of chronic debilitating and fatal diseases such as cancer and inflammatory or autoimmune diseases. Although biopharmaceuticals are in general well tolerated, the development of anti-drug antibodies can impair their safety and efficacy. Assessment of immunogenicity is essential for a more effective and rational use of biopharmaceuticals, and is dependent upon the establishment of efficient standardized assays that allow direct comparison of immunogenicity data with clinical outcome. Although regulatory authorities recommend the use of cell-based assays that reflect the mechanism of action of the drug for the detection of neutralizing anti-drug antibodies, conventional cell-based assays are difficult to standardize and often give variable results. A number of strategies have been adopted to improve the performance of cell-based assays, including quantification of drug-induced proteins using either real-time RT-PCR or branched DNA to detect mRNA, or ELISAs to detect protein, bridging assays using immobilized cells and the use of reporter gene assays. The relative merits and limitations of each of these methods is reviewed herein. PMID- 23013401 TI - The transcription factor Sp1 is responsible for aging-dependent altered nucleocytoplasmic trafficking. AB - Hyporesponsiveness to external signals, such as growth factors and apoptotic stimuli, is a cardinal feature of cellular senescence. We previously reported that an aging-dependent marked reduction in nucleocytoplasmic trafficking (NCT) related genes could be responsible for this phenomenon. In searching for the mechanism, we identified the transcription factor, Sp1, as a common regulator of NCT genes, including various nucleoporins, importins, exportins, and Ran GTPase cycle-related genes. Sp1 knockdown led to a reduction of those genes in young human diploid fibroblast cells (HDF); Sp1 overexpression induced those genes in senescent cells. In addition, epidermal growth factor stimulation-induced p ERK1/2 nuclear translocation and Elk-1 phosphorylation were severely impaired by Sp1 depletion in young HDFs; Sp1 overexpression restored the nuclear translocation of p-ERK1/2 in senescent HDFs. Furthermore, we observed that Sp1 protein levels were decreased in senescent cells, and H(2) O(2) treatment decreased Sp1 levels in a proteasome-dependent manner. In addition, O GlcNAcylation of Sp1 was decreased in senescent cells as well as in H(2) O(2) treated cells. Taken together, these results suggest that Sp1 could be a key regulator in the control of NCT genes and that reactive oxygen species-mediated alteration in Sp1 stability may be responsible for the generalized repression of those genes, leading to formation of the senescence-dependent functional nuclear barrier, resulting in subsequent hyporesponsiveness to external signals. PMID- 23013402 TI - Sun behaviour after cutaneous malignant melanoma: a study based on ultraviolet radiation measurements and sun diary data. AB - BACKGROUND: It has been reported that patients with cutaneous malignant melanoma (CMM) can lower their risk of a second primary melanoma by limiting recreational sun exposure. Previous studies based on questionnaires and objective surrogate measurements indicate that before their diagnosis, patients with CMM are exposed to higher ultraviolet radiation (UVR) doses than controls, followed by a reduction after diagnosis. OBJECTIVES: In a prospective, observational case control study, we aimed to assess sun exposure after diagnosis of CMM by objective measurements to substantiate advice about sun behaviour. METHODS: The study population consisted of 24 patients recently diagnosed with CMM during the 7 months preceding the start of the study; 51 controls who matched these recently diagnosed patients in age, sex, occupation and constitutive skin type; and 29 patients diagnosed with CMM between 12 months and 6 years before the start of the study. During a summer season participants filled in sun exposure diaries daily and wore personal electronic UVR dosimeters in a wristwatch that continuously measured time-stamped UVR doses in standard erythema dose. RESULTS: The UVR dose of recently diagnosed patients on days with body exposure was one-third lower, and the number of days using sunscreen was double that of matched controls. However, in patients diagnosed more than 12 months earlier, the UVR dose on days with body exposure was one-third higher and the number of days using sunscreen was half that of recently diagnosed patients. CONCLUSIONS: Patients with CMM limited their UVR dose on days with body exposure, and by using sunscreen further reduced UVR reaching the skin, although only immediately after diagnosis. PMID- 23013403 TI - High creatinine clearance in critically ill patients with community-acquired acute infectious meningitis. AB - BACKGROUND: A high dose of anti-infective agents is recommended when treating infectious meningitis. High creatinine clearance (CrCl) may affect the pharmacokinetic / pharmacodynamic relationships of anti-infective drugs eliminated by the kidneys. We recorded the incidence of high CrCl in intensive care unit (ICU) patients admitted with meningitis and assessed the diagnostic accuracy of two common methods used to identify high CrCl. METHODS: Observational study performed in consecutive patients admitted with community-acquired acute infectious meningitis (defined by >7 white blood cells/mm3 in cerebral spinal fluid) between January 2006 and December 2009 to one medical ICU. During the first 7 days following ICU admission, CrCl was measured from 24-hr urine samples (24-hr-UV/P creatinine) and estimated according to Cockcroft-Gault formula and the simplified Modification of Diet in Renal Disease (MDRD) equation. High CrCl was defined as CrCl >140 ml/min/1.73 m2 by 24-hr-UV/P creatinine. Diagnostic accuracy was performed with ROC curves analysis. RESULTS: Thirty two patients were included. High CrCl was present in 8 patients (25%) on ICU admission and in 15 patients (47%) during the first 7 ICU days for a median duration of 3 (1-4) days. For the Cockcroft-Gault formula, the best threshold to predict high CrCl was 101 ml/min/1.73 m2 (sensitivity: 0.96, specificity: 0.75, AUC = 0.90 +/- 0.03) with a negative likelihood ratio of 0.06. For the simplified MDRD equation, the best threshold to predict high CrCl was 108 ml/min/1.73 m2 (sensitivity: 0.91, specificity: 0.80, AUC = 0.88 +/- 0.03) with a negative likelihood ratio of 0.11. There was no difference between the estimated methods in the diagnostic accuracy of identifying high CrCl (p = 0.30). CONCLUSIONS: High CrCl is frequently observed in ICU patients admitted with community-acquired acute infectious meningitis. The estimated methods of CrCl could be used as a screening tool to identify high CrCl. PMID- 23013405 TI - High-risk ALK negative anaplastic large-cell lymphoma presenting with hypereosinophilic syndrome in a 2.5-year-old child. AB - The hypereosinophilic syndromes (HES) are characterized by prolonged nonreactive peripheral blood hypereosinophilia with tissue damage. The lymphocytic HES variant can precede malignant clonal T-cell disease in adults but it is extremely rare to be the presenting feature of lymphomas in children. Here we present a 2.5 year-old boy with HES and mediastinal T-cell anaplastic lymphoma kinase (ALK) negative systemic anaplastic large-cell lymphoma. Mature and immature eosinophils without blasts were shown on bone marrow aspiration while biopsy revealed malignant infiltration. The patient responded well to initial corticosteroid therapy, but high-risk features make a challenge of finding the cure in this extremely rare case. PMID- 23013404 TI - A pilot randomized controlled trial of the feasibility of a self-directed coping skills intervention for couples facing prostate cancer: rationale and design. AB - BACKGROUND: Although it is known both patients' and partners' reactions to a prostate cancer diagnosis include fear, uncertainty, anxiety and depression with patients' partners' reactions mutually determining how they cope with and adjust to the illness, few psychosocial interventions target couples. Those that are available tend to be led by highly trained professionals, limiting their accessibility and long-term sustainability. In addition, it is recognised that patients who might benefit from conventional face-to-face psychosocial interventions do not access these, either by preference or because of geographical or mobility barriers. Self-directed interventions can overcome some of these limitations and have been shown to contribute to patient well-being. This study will examine the feasibility of a self-directed, coping skills intervention for couples affected by cancer, called Coping-Together, and begin to explore its potential impact on couples' illness adjustment. The pilot version of Coping-Together includes a series of four booklets, a DVD, and a relaxation audio CD. METHODS/DESIGN: In this double-blind, two-group, parallel, randomized controlled trial, 70 couples will be recruited within 4 months of a prostate cancer diagnosis through urology private practices and randomized to: 1) Coping Together or 2) a minimal ethical care condition. Minimal ethical care condition couples will be mailed information booklets available at the Cancer Council New South Wales and a brochure for the Cancer Council Helpline. The primary outcome (anxiety) and additional secondary outcomes (distress, depression, dyadic adjustment, quality of life, illness or caregiving appraisal, self-efficacy, and dyadic and individual coping) will be assessed at baseline (before receiving study material) and 2 months post-baseline. Intention-to-treat and per protocol analysis will be conducted. DISCUSSION: As partners' distress rates exceed not only population norms, but also those reported by patients themselves, it is imperative that coping skills interventions target the couple as a unit and enhance both partners' ability to overcome cancer challenges. This pilot study will examine the feasibility and potential efficacy of Coping-Together in optimising couples' illness adjustment. This is one of the first feasibility studies to test this innovative coping intervention, which in turn will contribute to the larger literature advocating for psychosocial care of couples affected by prostate cancer. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000438954. PMID- 23013406 TI - Genome-wide linkage scan for psoriasis susceptibility loci in multiplex Tunisian families. AB - BACKGROUND: Psoriasis is a relapsing chronic inflammatory skin disease affecting all population groups, with a peak prevalence of 3% in northern European and Scandinavian caucasians. Epidemiological studies have implicated a genetic component to psoriasis. In the past 12 years multiple genome-wide linkage analyses have identified putative susceptibility loci on several chromosomes, with a major locus in the major histocompatibility complex region. OBJECTIVES: To investigate the genetic basis of familial psoriasis in the Tunisian population using a genome-wide linkage scan in seven ultiplex psoriatic families from Tunisia. METHODS: Following single nucleotide polymorphism (SNP) genotyping on the Affymetrix 10K SNP array, we performed nonparametric linkage (NPL) multipoint analyses to identify genotypes and obtain evidence for linkage with psoriasis across the genome. RESULTS: No chromosomal region gave consistent evidence for linkage, providing evidence for genetic heterogeneity in Tunisian psoriasis families. Significant evidence for linkage of psoriasis to chromosome 2p12 was seen in one family. We also identified several regions of tentative psoriasis linkage on chromosomes 2q, 4q, 6p, 11q, 12q, 9q and 13q. One family exhibiting suggestive evidence for linkage to 17q25 (PSORS2) was identified and all affected members harboured a p.Gly117Ser mutation in CARD14 (caspase recruitment domain family, member 14), recently reported to lead to psoriasis in a large family from the U.S.A. CONCLUSIONS: Our results support the genetic heterogeneity of psoriasis in the Tunisian population, provide confirmatory evidence for a novel psoriasis locus at chromosome 2p12 and reveal a psoriasis family with a mutation at PSORS2. PMID- 23013407 TI - Intravenous alteplase versus rescue endovascular procedure in patients with proximal middle cerebral artery occlusion. AB - OBJECTIVES: To compare outcome of ischaemic stroke patients undergoing rescue endovascular procedure for proximal middle cerebral artery occlusion with matched patients without endovascular procedure after unsuccessful intravenous thrombolysis. METHODS: Endovascularly treated patients with middle cerebral artery occlusion (n = 41) were matched by propensity score with similar patients treated by intravenous thrombolysis and having a considerable post-thrombolysis neurological deficit (n = 82). We compared their three-month outcome (modified Rankin Scale) and frequency of symptomatic intracerebral haemorrhage. For the endovascular group, we report onset-to-puncture time, onset-to-recanalization time, and recanalization rates. RESULTS: In age, gender, time from onset, admission National Institutes of Health Stroke Scale, systolic and diastolic blood pressure, blood glucose, history of hypertension, diabetes mellitus, hyperlipidaemia, atrial fibrillation, and congestive heart failure, and in aetiology, the groups were similar. Endovascular group patients had a recanalization rate of 90%, and more often reached three-month modified Rankin Scale 0-2 (36.6% vs. 18.3%, P = 0.03). Mortality was equally common (19.5%) in both groups, and frequency of symptomatic intracerebral haemorrhage was 9.8% vs. 14.6% (P = 0.45). The endovascular group's median onset-to-puncture time was four hours and six-minutes and onset-to-recanalization time was five-hours and 12 min. The latter time was more than one-hour longer in patients treated under general anaesthesia compared with patients treated under conscious sedation (median four hours 50 min vs. five-hours 58 min; P < 0.01). CONCLUSIONS: Rescue endovascular approach increases likelihood of recanalization and may improve functional outcome in acute ischaemic stroke patients with proximal middle cerebral artery occlusion who did not respond to intravenous thrombolysis. PMID- 23013408 TI - Towards improved therapies using nanopharmaceuticals: recent patents on pharmaceutical nanoformulations. AB - Pharmaceutical formulations that contain nanosized drugs are perceived as "Nanopharmaceuticals" and offer significant benefit for the patient compared to the conventional formulated drugs. There are several advantages of nanoparticular drug formulations such as enhanced solubility and dissolution rate, enhanced oral bioavailability, improved dose proportionality, reduced food effects, suitability for administration by all routes and possibility of sterile filtration due to decreased particle size range. Several nanopharmaceuticals are successfully marketed. Different patented techniques are commercialized to prepare nanopharmaceuticals such as milling, homogenization and precipitation. The focus of the underlying review is to give an overview of those technologies for nanosizing active pharmaceutical ingredients and recently published patents in the field of nanosized pharmaceutics. PMID- 23013409 TI - Antimicrobial precious-metal nanoparticles and their use in novel materials. AB - Nanotechnology offers powerful new approaches to controlling unwanted microorganisms and other potential biohazards. Engineered nanoparticles with antifungal, antimicrobial, and antiviral properties are now being developed for a variety of applications, including manufacture and maintenance of sterile surfaces, prevention and control of biological contamination, food and water safety, and treatment of infectious diseases and cancer. The great potential of antimicrobial precious-metal nanoparticles is reflected by the high number of recent publications and patent applications, which is summarized, at least in part, in this paper. This review should provide an overview and offer guidance to the scientific community interested in nano(bio)technology, nanomedicine, and nanotoxicology, and may also be of interest to a broader scientific audience. Furthermore, this review covers specific topics in research and development addressing the effects of nanoparticles on microorganisms as well as novel nanotechnology-based approaches for controlling potentially pathogenic microorganisms. PMID- 23013410 TI - Patents on fiber spinning from starches. AB - Starch is a promising bio-based material to replace synthetics in a number of applications. The production of starch-based fibers has been actively pursued in the patent literature. This article reviews patents on starch fiber technology, including fiber spinning from amylose, thermoplastic starch compositions, and non thermoplastic starch compositions. Some new fiber spinning techniques, e.g. electrospinning and rotary jet spinning, employed for spinning starch fibers are also presented. PMID- 23013411 TI - Nanotechnologies in agriculture and food - an overview of different fields of application, risk assessment and public perception. AB - Nanomaterials in agriculture and food are key issues of public and regulatory interest. Over the past ten years, patents for nanotechnological applications in the field of food and agriculture have become abundant. Uncertainty prevails however regarding their current development status and presence in the consumer market. Thus, the discussion on nanotechnologies in the food sector with its specific public perception of benefits and risks and the patterns of communication are becoming similar to the debate on genetically modified organisms. The food industry's silence in communication increased mistrust of consumer organisations and policy makers. The article discusses the background of the current regulatory debates, starting with the EU recommendation for defining nanomaterials, provides an overview of possible fields of application in agriculture and food industries and discusses risk assessment and the public debate on benefits and risks. Communicative recommendations are directed at researchers, the food industry and regulators in order to increase trust both in stakeholders, risk management and regulatory processes. PMID- 23013412 TI - Extraction, structure and bioactivities of the polysaccharides from Fructus corni. AB - Plant-derived bioactive polysaccharides have a long history of application in traditional Chinese medicine (TCM). The polysaccharides of Fructus Corni, secondary metabolites from Cornus officinalis Sieb. Et Zucc, possess various pharmacological activities, including immune regulation, anti-oxidation, anti tumor, and anti-aging effects. The present review is trying to summarize the extraction process of polysaccharides of Fructus Corni, structural features and related patents. PMID- 23013413 TI - Hsp90 regulates Paracoccidioides brasiliensis proliferation and ROS levels under thermal stress and cooperates with calcineurin to control yeast to mycelium dimorphism. AB - Paracoccidioidomycosis is a systemic human mycosis in Latin America caused by Paracoccidioides brasiliensis, a dimorphic pathogenic fungus that lives as a mold in the environment and as yeast during infections of human lungs. In this work, we provide evidence that the inhibition of Hsp90 by geldanamycin (GDA) impairs the proliferation of the yeast, but has no effect on mycelial development. Treatment with cyclosporin A (CsA), an inhibitor of the Hsp90 client protein calcineurin, did not increase the effect of GDA. In contrast, GDA prevented mycelial to yeast differentiation through a mechanism partially dependent on calcineurin, whereas differentiation from yeast to mycelia occurred independent of GDA or CsA. A significant increase in reactive oxygen species (ROS) levels was detected in GDA-treated yeast at 42 degrees C. However, the levels of ROS remained unchanged in GDA-treated yeast or mycelia incubated at 37 degrees C, suggesting that Hsp90 plays different roles under normal and thermal stress conditions. We propose that Hsp90 strengthens the stress response of P. brasiliensis at 37 degrees C through a mechanism that does not involve ROS. Moreover, we suggest that Hsp90 has calcineurin-dependent functions in this organism. PMID- 23013414 TI - Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. AB - Melatonin exerts oncostatic effects on breast cancer by interfering with the estrogen-signaling pathways. Melatonin reduces estrogen biosynthesis in human breast cancer cells, surrounding fibroblasts and peritumoral endothelial cells by regulating cytokines that influence tumor microenvironment. This hormone also exerts antiangiogenic activity in tumoral tissue. In this work, our objective was to study the role of melatonin on the regulation of the vascular endothelial growth factor (VEGF) in breast cancer cells. To accomplish this, we cocultured human breast cancer cells (MCF-7) with human umbilical vein endothelial cells (HUVECs). VEGF added to the cultures stimulated the proliferation of HUVECs and melatonin (1 mM) counteracted this effect. Melatonin reduced VEGF production and VEGF mRNA expression in MCF-7 cells. MCF-7 cells cocultured with HUVECs stimulated the endothelial cells proliferation and increased VEGF levels in the culture media. Melatonin counteracted both stimulatory effects on HUVECs proliferation and on VEGF protein levels in the coculture media. Conditioned media from MCF-7 cells increased HUVECs proliferation, and this effect was significantly counteracted by anti-VEGF and 1 mM melatonin. All these findings suggest that melatonin may play a role in the paracrine interactions between malignant epithelial cells and proximal endothelial cells through a downregulatory action on VEGF expression in human breast cancer cells, which decrease the levels of VEGF around endothelial cells. Lower levels of VEGF could be important in reducing the number of estrogen-producing cells proximal to malignant cells as well as decreasing tumoral angiogenesis. PMID- 23013415 TI - Efficient control of pandemic 2009 H1N1 virus infection with intravenous zanamivir despite the lack of immune function. AB - A teenager who acquired 2009 H1N1 influenza A lower respiratory tract infection during total bone marrow and lymphoid aplasia, in the setting of human leukocyte antigen-haploidentical hematopoietic stem cell transplantation, was successfully treated with intravenous zanamivir. This case demonstrates efficient control of pandemic influenza infection by intravenous zanamivir in the absence of any functional immune system, thus suggesting profound antiviral activity. PMID- 23013416 TI - Characterization of pruritus in canine atopic dermatitis, flea bite hypersensitivity and flea infestation and its role in diagnosis. AB - BACKGROUND: In dogs, flea infestation (FI), flea bite hypersensitivity (FBH) and canine atopic dermatitis (CAD) have been mainly characterized by their lesions but never by their pruritus. In clinical practice, many of these dogs exhibit only pruritus. HYPOTHESIS/OBJECTIVES: The purpose of this study was to evaluate the characteristics of pruritus in these dermatoses and their potential usefulness for diagnosis. ANIMALS: Dogs included were selected from the Oniris clinical data. Cases were selected in which the dogs had only one of the three dermatoses diagnosed. The diagnosis of CAD was based on Prelaud's criteria and positive intradermal tests except flea; for FBH by compatible clinical signs and a response to an intradermal test with flea allergen; and for FI by the presence of fleas. Moreover, in each group, other primary pruritic skin diseases were excluded. METHODS: Location, behavioural manifestations, seasonality and quantification of the pruritus were evaluated. The statistical analysis used chi squared test with a P-value <0.05. RESULTS: Three hundred and forty-six dogs were analysed, 91 with CAD, 110 FI and 145 FBH. The period (season) of onset was not statistically different either for each dermatosis or among the three dermatoses. Some locations were highly specific for one dermatosis as follows: ventral abdomen/medial surface of thigh (chewing) and radius/carpus/tibia/tarsus (chewing) in FI; back/dorsolumbar area (chewing) and tail (chewing) in FBH; and paws (chewing/licking) and face/neck (rubbing) in CAD. CONCLUSIONS AND CLINICAL IMPORTANCE: Some features of pruritus could be suggestive of the causal disease, with possible diagnostic value in pruritic dogs. PMID- 23013417 TI - Absorption mechanism of ginsenoside compound K and its butyl and octyl ester prodrugs in Caco-2 cells. AB - Ginsenoside compound K (CK) is a bioactive compound with poor oral bioavailability due to its high polarity, while its novel ester prodrugs, the butyl and octyl ester (CK-B and CK-O), are more lipophilic than the original drug and have an excellent bioavailability. The aim of this study was to examine the transport mechanisms of CK, CK-B, and CK-O using human Caco-2 cells. Results showed that CK had a low permeability coefficient (8.65 * 10(-7) cm/s) for apical to-basolated (AP-BL) transport at 10-50 MUM, while the transport rate for AP to BL flux of CK-B (2.97 * 10(-6) cm/s) and CK-O (2.84 * 10(-6) cm/s) was significantly greater than that of CK. Furthermore, the major transport mechanism of CK was found as passive transcellular diffusion with active efflux mediated by P-glycoprotein (P-gp). In addition, it was found that CK-B and CK-O were not the substrate of efflux transporter since the selective inhibitors (verapamil and MK 571) of efflux transporter had little effects on the transport of CK-B and CK-O in the Caco-2 cells. These results suggest that improving the lipophilicity of CK by acylation can significantly improve the transport across Caco-2 cells. PMID- 23013418 TI - Swirl sign in intracerebral haemorrhage: definition, prevalence, reliability and prognostic value. AB - BACKGROUND: Swirl sign has previously been described in epidural hematomas as areas of low attenuation, radiolucency or irregular density. The aims of this study were to describe swirl sign in ICH, study its prevalence, study the reliability of the subjective evaluation on computed tomography (CT), and to explore its prognostic value. METHODS: CTs of 203 patients with ICH were retrospectively evaluated for the presence of swirl sign. Association between swirl sign and different clinical and radiological variables was studied. RESULTS: Inter- and intraobserver agreement with regard to the occurrence of swirl sign was substantial (K 0.80) and almost perfect (K 0.87), respectively. Swirl sign was found in 30% of the study population. 61% of patients with swirl sign were dead at one month compared with 21% of those with no swirl sign (p < 0.001). Only 19% of patients with swirl sign exhibited favorable outcome at three months compared with 53% of those with no swirl sign (p < 0.001). Patients with swirl sign exhibited larger ICHs with average ICH-volume 52 +/- 50 ml (median 42 ml) compared with 15 +/- 25 ml (median 6) in patients whose CT did not show swirl sign (p < 0.001). Swirl sign was independent predictor of death at one month (p = 0.03; adjusted odds ratio 2.6, 95% CI 1.1 - 6), and functional outcome at three months (p = 0.045; adjusted odds ratio 2.6, 95% CI 1.02 - 6.5). CONCLUSIONS: As swirl sign showed to be an ominous sign, we recommend identification of this sign in cases of ICHs. PMID- 23013419 TI - CD8+ Sezary syndrome with interleukin-22 production modulated by bacterial sepsis. PMID- 23013420 TI - Natural killer cells and B lymphocytes in peripheral blood of patients with psoriasis. PMID- 23013421 TI - Factors influencing quality of life in asthmatics--a case-control study. AB - INTRODUCTION: The quality of life (QOL) in persons with asthma is reduced and different factors such as demography, asthma severity and psychiatric comorbidity play an influential role. However, little is known about the interplay of these factors. OBJECTIVE: To describe QOL in relation to asthma and analyse for the relative impact of asthma severity, psychiatric comorbidity, lifestyle (smoking and obesity) and demographic determinants on QOL in persons with asthma. METHODS: One thousand one hundred sixty-one subjects from an earlier cohort with and without asthma were sent an asthma screening questionnaire and a generic QOL measuring instrument (15D). RESULTS: Seven hundred seventy-eight valid responses (67%). QOL was significantly reduced in persons with asthma compared with controls (P = 0.001), almost on all domains of 15D. In the adjusted regression model, asthma severity, depression, female gender and smoking were associated with reduced QOL, suggesting that these factors play an independent role on lowering QOL. Depression did not inflate the relationship between asthma severity and worse QOL, suggesting that asthma severity plays an independent role on everyday life regardless of psychological state. CONCLUSION: Asthma severity, psychiatric comorbidity, female gender and smoking were identified in this study to be major contributors to decreased QOL in asthmatics. Health professionals should be aware of this complex picture and take these factors into consideration when choosing the proper treatment of asthma patients. Asthma, asthma severity, epidemiology, psychiatric comorbidity, QOL. PMID- 23013422 TI - HDAC inhibitor trichostatin A promotes proliferation and odontoblast differentiation of human dental pulp stem cells. AB - Trichostatin A (TSA) is a potent histone deacetylase (HDAC) inhibitor with a broad spectrum of epigenetic activities known to regulate diverse cellular mechanisms, including differentiation of mesenchymal stem cells. In this study, we demonstrate that TSA promotes proliferation and odontoblast differentiation of human dental pulp stem cells (hDPSCs) in vitro and has the ability to enhance dentin formation and odontoblast differentiation in vivo during tooth development. We observed that TSA increased the expression of proliferating cell nuclear antigen and cyclin D1 in hDPSCs at a certain concentration and the activation of JNK/c-Jun pathway was essential for TSA-dependent hDPSC proliferation. Further, TSA accelerated mineral nodule formation in vitro and increased gene expression of dentin sialophosphoprotein, dentin matrix protein 1, bone sialoprotein, and osteocalcin. In addition, TSA significantly upregulated the levels of phospho-Smad2/3, Smad4, and nuclear factor I-C, while the specific inhibitor of Smad3 inhibits TSA enhancing mineralization differentiation of hDPSCs. HDAC3 is downregulated by TSA treatment, suggesting a possible mediator of TSA-dependent pathways among the members of HDAC family. Moreover, TSA injected embryos exhibited increased dentin thickness, larger dentin areas, and higher odontoblast numbers in their postnatal molars with stronger dentin sialoprotein expression in immunohistochemical staining. These findings indicate that TSA may serve a key role in proliferation and odontoblast differentiation of hDPSCs in dental developmental stages and can be used as an accelerator in dental hard tissue engineering. PMID- 23013423 TI - Effects of plant host species and plant community richness on streptomycete community structure. AB - We investigated soil streptomycete communities associated with four host plant species (two warm season C4 grasses: Andropogon gerardii, Schizachyrium scoparium and two legumes: Lespedeza capitata, Lupinus perennis), grown in plant communities varying in species richness. We used actinobacteria-selective PCR coupled with pyrosequencing to characterize streptomycete community composition and structure. The greatest pairwise distances between communities were observed in contrasts between monocultures of different plant species, indicating that plant species exert distinct selective effects on soil streptomycete populations. Increasing plant richness altered the composition and structure of streptomycete communities associated with each host plant species. Significant relationships between plant community characteristics, soil edaphic characteristics, and streptomycete community structure suggest that host plant effects on soil microbial communities may be mediated through changes to the soil environment. Co occurring streptomycete taxa also shared consistent relationships with soil edaphic properties, providing further indication of the importance of habitat preference for taxon occurrence. Physical distance between sampling points had a significant influence on streptomycete community similarity. This work provides a detailed characterization of soil streptomycete populations across a field scale and in relation to plant host identity and plant community richness. PMID- 23013424 TI - Hypertension. PMID- 23013425 TI - The prevalence and outcomes of thrombocytopenia in a neonatal intensive care unit: a three-year report. AB - Neonatal thrombocytopenia is one of the most common hematologic disorders in neonatal intensive care units (NICUs). The purpose of this study was to determine the prevalence of thrombocytopenia and whether thrombocytopenia has an effect on the occurrence of intraventricular hemorrhage (IVH) >= grade 2 and on mortality rate. This study was carried out retrospectively in neonates admitted to NICU of Cumhuriyet University in Sivas, Turkey, between 2009 and 2012. Among 2218 neonates evaluated, 208 (9.4%) developed thrombocytopenia. The prevalence of IVH >= grade 2 was more in infants with thrombocytopenia (7.2%) than in those without thrombocytopenia (4.4%), although this was not statistically significant (P = .08). In univariate analysis, IVH >= grade 2 was higher in cases with very severe thrombocytopenia (35.7%, n = 5) than in those with mild (2.1%, n = 2), moderate (4.7%, n = 3), and severe thrombocytopenia (15.2%, n = 5) (P = .04). Multivariate logistic regression analysis showed that birth weight <1500 g (OR 6.2, 95% CI 3.4 9.8; P = .0001), gram-negative sepsis (OR 2.5, 95% CI 1.8-4.2; P = .01), very severe thrombocytopenia (OR 1.3, 95% CI 1.1-2.1; P = .03), and platelet transfusion >=2 (OR 7.3, 95% CI 4.1-12.1; P = .001) were significant risk factors for mortality. The results of our study suggest that outcomes of neonates with thrombocytopenia depend not only on platelet count but also on decreased gestational age or birth weight, prenatal factors, and sepsis. PMID- 23013426 TI - The Anti-Clot Treatment Scale (ACTS) in clinical trials: cross-cultural validation in venous thromboembolism patients. AB - BACKGROUND: The Anti-Clot Treatment Scale (ACTS) is a 15-item patient-reported instrument of satisfaction with anticoagulant treatment. It includes a 12-item ACTS Burdens scale and a 3-item ACTS Benefits scale. Its role in clinical trials and other settings should be supported by evidence that it is both clinically meaningful and scientifically sound. The aim of the study was to evaluate the measurement performance of the ACTS (Dutch, Italian, French, German and English language versions) in patients with venous thromboembolism based on traditional psychometric methods. METHODS: ACTS Burdens and Benefits scale data from a large clinical trial (EINSTEIN DVT) involving 1336 people with venous thromboembolism were analysed at both the scale and item level. Five key psychometric properties were examined using traditional psychometric methods: acceptability, scaling assumptions, reliability (including internal consistency reliability, test-retest reproducibility); validity (including known groups and discriminant validity); and responsiveness. These methods of examination underpin the US Food and Drug Administration recommendations for patient-reported outcome instrument evaluation. RESULTS: Overall, the 12-item ACTS Burdens scale and 3-item ACTS Benefits scale met the psychometric criteria evaluated at both item and scale levels, with the exception of some relatively minor issues in the Dutch language version, which were just below reliability criteria (i.e. alpha = 0.72, test retest intraclass correlation = 0.79). A consistent finding from item-level evaluations of aggregate endorsement frequencies and skewness suggested that response scales may be improved by reducing the number of response options from five to four. CONCLUSIONS: Both the ACTS Burdens and ACTS Benefits scales consistently satisfied traditional reliability and validity criteria across multiple language datasets, supporting it as a clinically useful patient-reported instrument of satisfaction with anticoagulant treatment in clinical trials. TRIAL REGISTRATION NUMBER: NCT00440193. PMID- 23013427 TI - Healthcare costs associated with change in body mass index in patients with type 2 diabetes mellitus in Spain: the ECOBIM study. AB - BACKGROUND: Weight management is considered a key therapeutic strategy in type 2 diabetes mellitus. However, little is known about the impact of weight loss or body mass index (BMI) reduction on type 2 diabetes-related healthcare costs. OBJECTIVE: The aim of this study was to estimate the economic impact of change in BMI among patients with type 2 diabetes mellitus from the Spanish healthcare system perspective. METHODS: The ECOBIM study is an observational, non interventional study in which data on BMI change and costs incurred by patients with type 2 diabetes were collected cross-sectionally and retrospectively for a 12-month period. Generalized linear mixed models were applied to estimate the effects of (i) BMI change in general (one-slope model); (ii) BMI gain and no BMI gain (two-slope model); and (iii) BMI gain and no BMI gain among obese and non obese patients (four-slope model). RESULTS: We studied 738 patients with a mean (SD) age of 66 (11) years and BMI of 30.6 (5.2) kg/m2. During the 12-month study period, 41.2% of patients gained BMI (BMI gainers) and 58.8% experienced either loss (52.2%) or no change (6.6%) in BMI (non-BMI gainers). One-unit gain (or loss) in BMI was significantly (p < 0.001) associated with a 2.4% cost increase (or decrease) [one-slope model]. Every unit gain in BMI was associated with a 20.0% increase in costs among BMI gainers while losing one unit was associated with an 8.0% decrease in costs among non-BMI gainers (two-slope model, p < 0.01). The economic benefit associated with reducing one BMI unit was 9.4% cost decrease in obese and 2.7% in non-obese patients (4-slope model). CONCLUSION: An increase in BMI among patients with type 2 diabetes was associated with increased 1-year direct healthcare costs. A reduction in BMI was associated with appreciable short term economic benefits, especially in obese patients. PMID- 23013428 TI - Economic implications of rasburicase treatment in adult patients with tumour lysis syndrome. AB - BACKGROUND: Rasburicase is a recombinant urate-oxidase enzyme used to reduce high levels of plasma uric acid (PUA) resulting from tumour lysis syndrome (TLS). Rasburicase reduces PUA levels within 4 hours of administration, thereby minimizing the risk of serious complications from TLS. Treatment pattern analyses indicate rasburicase is often used in combination with allopurinol; however, no studies have evaluated the clinical and economic consequences of this pattern of care. The purpose of this study was to compare hospitalization costs, overall length of stay (LOS), and critical-care LOS in patients receiving rasburicase with or without allopurinol. METHODS: Hospital claims data from the Premier Perspective DatabaseTM were used to conduct this retrospective analysis. Patients in the Premier hospital database who were administered rasburicase or combination therapy (rasburicase + allopurinol) within 2 days of hospital admission were eligible for study inclusion. Patients were excluded if they were <18 years of age or received haemodialysis (or any other renal replacement therapy support) on admission. Rasburicase patients were propensity-score-matched to combination therapy patients based on gender, race, hospital type (urban/rural, teaching), provider type, payer type, admission source, use of electrolyte modification therapy, critical-care admission and presence of a cancer diagnosis. Differences in healthcare costs, overall LOS and critical-care LOS were assessed using gamma distributed generalized linear models with a log-link function. RESULTS: The study population comprised 66 patients receiving rasburicase monotherapy matched to 66 patients receiving combination therapy. Mean age was 62.9 years, and 29% were female. Patients initiated on combination therapy had a shorter mean duration of rasburicase administration than patients initiated on monotherapy (2.1 vs 2.7 days) [p = 0.0059]. Additionally, rasburicase monotherapy incurred an average total cost of $US35 843 per hospitalization, compared with $US46 672 for those receiving combination therapy (p = 0.0820). Rasburicase monotherapy patients also had a shorter mean overall LOS (10.0 days vs 15.4 days; p = 0.0067). The mean critical-care LOS was similar in both cohorts (2.4 days rasburicase vs 2.9 days combination therapy; p = 0.3389). CONCLUSION: Examination of claims data showed that combination therapy (rasburicase + allopurinol) trended toward higher total hospitalization costs than rasburicase monotherapy. In addition, combination therapy was associated with significantly longer overall LOS compared with upfront rasburicase monotherapy in patients at risk for developing TLS. PMID- 23013429 TI - Near infrared light triggered release of biomacromolecules from hydrogels loaded with upconversion nanoparticles. AB - Using a photosensitive hybrid hydrogel loaded with upconversion nanoparticles (UCNPs), we show that continuous-wave near-infrared (NIR) light (980 nm) can be used to induce the gel-sol transition and release large, inactive biomacromolecules (protein and enzyme) entrapped in the hydrogel into aqueous solution "on demand", where their bioactivity is recovered. This study is a new demonstration and development in harnessing the unique multiphoton effect of UCNPs for photosensitive materials of biomedical interest. PMID- 23013430 TI - Structure and catalytic mechanism of N(5),N(10)-methenyl-tetrahydromethanopterin cyclohydrolase. AB - Methenyltetrahydromethanopterin (methenyl-H(4)MPT(+)) cyclohydrolase (Mch) catalyzes the interconversion of methenyl-H(4)MPT(+) and formyl-H(4)MPT in the one-carbon energy metabolism of methanogenic, methanotrophic, and sulfate reducing archaea and of methylotrophic bacteria. To understand the catalytic mechanism of this reaction, we kinetically characterized site-specific variants of Mch from Archaeoglobus fulgidus (aMch) and determined the X-ray structures of the substrate-free aMch(E186Q), the aMch:H(4)MPT complex, and the aMch(E186Q):formyl-H(4)MPT complex. (Formyl-)H(4)MPT is embedded inside a largely preformed, interdomain pocket of the homotrimeric enzyme with the pterin and benzyl rings being oriented nearly perpendicular to each other. The active site is primarily built up by the segment 93:95, Arg183 and Glu186 that either interact with the catalytic water attacking methenyl-H(4)MPT(+) or with the formyl oxygen of formyl-H(4)MPT. The catalytic function of the strictly conserved Arg183 and Glu186 was substantiated by the low enzymatic activities of the E186A, E186D, E186N, E186Q, R183A, R183Q, R183E, R183K, and R183E-E186Q variants. Glu186 most likely acts as a general base. Arg183 decisively influences the pK(a) value of Glu186 and the proposed catalytic water mainly by its positive charge. In addition, Glu186 appears to be also responsible for product specificity by donating a proton to the directly neighbored N(10) tertiary amine of H(4)MPT. Thus, N(10) becomes a better leaving group than N(5) which implies the generation of N(5)-formyl-H(4)MPT. For comparison, methenyltetrahydrofolate (H(4)F) cyclohydrolase produces N(10)-formyl-H(4)F in an analogous reaction. An enzymatic mechanism of Mch is postulated and compared with that of other cyclohydrolases. PMID- 23013432 TI - Stimulated sweating as a therapy to reduce interdialytic weight gain and improve potassium balance in chronic hemodialysis patients: a pilot study. AB - Controlling the extracellular volume in hemodialysis patients is a difficult task. The aim of this study was to evaluate the capacity of different methods of stimulated sweating to reduce mean interdialytic weight gain (IWG), to improve blood pressure regulation, and potassium/urea balance. Two center, crossover pilot study. In Lausanne, hemodialysis patients took four hot-water baths a week, 30 minutes each, on nondialysis days during 1 month. In Sfax, patients visited the local Hammam Center four times a week. Hemodynamic parameters were recorded, and weekly laboratory analysis was performed. Results were compared with a preceding 1-month control period. In Lausanne, five patients (all men, median age 55 years) participated. Bathing temperature was (mean +/- standard deviation) 41.2 +/- 3 degrees C and sweating-induced weight loss 600 +/- 500 g. Mean IWG (control vs. intervention period) decreased from 2.3 +/- 0.9 to 1.8 +/- 1 kg (P = 0.004), Systolic blood pressure from 139 +/- 21 to 136 +/- 22 mmHg (P = 0.4), and diastolic blood pressure form 79 +/- 12 to 75 +/- 13 mmHg (P = 0.08); antihypertensive therapy could be reduced from 2.8 +/- 0.4 to 1.9 +/- 0.5 antihypertensive drugs per patient (P = 0.01). In Sfax (n = 9, median age 46 years), weight loss per Hammam session was 420 +/- 100 g. No differences were found in IWG or BP, but predialysis serum potassium level decreased from 5.9 +/- 0.8 to 5.5 +/- 0.9 mmol/L (P = 0.04) and urea from 26.9 +/- 6 to 23.1 +/- 6 mmol/L (P = 0.02). Hot-water baths appear to be a safe way to reduce IWG in selected hemodialysis patients. Hammam visits reduce serum potassium and urea levels, but not IWG. More data in larger patient groups are necessary before definite conclusion can be drawn. PMID- 23013433 TI - Oxygen regulates the band 3-ankyrin bridge in the human erythrocyte membrane. AB - The oxygenation state of erythrocytes is known to impact several cellular processes. As the only known O2-binding protein in red blood cells, haemoglobin has been implicated in the oxygenation-mediated control of cell pathways and properties. Band 3, an integral membrane protein linked to the spectrin/actin cytoskeleton, preferentially binds deoxygenated haemoglobin at its N-terminus, and has been postulated to participate in the mechanism by which oxygenation controls cellular processes. Because the ankyrin-binding site on band 3 is located near the deoxyHb (deoxygenated haemoglobin)-binding site, we hypothesized that deoxyHb might impact the association between band 3 and the underlying erythrocyte cytoskeleton, a link that is primarily established through band 3 ankyrin bridging. In the present paper we show that deoxygenation of human erythrocytes results in displacement of ankyrin from band 3, leading to release of the spectrin/actin cytoskeleton from the membrane. This weakening of membrane cytoskeletal interactions during brief periods of deoxygenation could prove beneficial to blood flow, but during episodes of prolonged deoxygenation, such as during sickle cell occlusive crises, could promote unwanted membrane vesiculation. PMID- 23013435 TI - From pioneers to team players: TGA transcription factors provide a molecular link between different stress pathways. AB - The plant immune system encompasses an arsenal of defense genes that is activated upon recognition of a pathogen. Appropriate adjustment of gene expression is mediated by multiple interconnected signal transduction cascades that finally control the activity of transcription factors. These sequence-specific DNA binding proteins act at the interface between the DNA and the regulatory protein network. In 1989, tobacco TGA1a was cloned as the first plant transcription factor. Since then, multiple studies have shown that members of the TGA family play important roles in defense responses against biotrophic and necrotrophic pathogens and against chemical stress. Here, we review 22 years of research on TGA factors which have yielded both consistent and conflicting results. PMID- 23013434 TI - mGluR antagonists and GABA agonists as novel pharmacological agents for the treatment of autism spectrum disorders. AB - INTRODUCTION: The CDC currently estimates the prevalence of autism spectrum disorders (ASD) at 1 in 88 children. Though the exact etiology of ASD is unknown, recent studies implicate synaptic maturation and plasticity in the pathogenesis of ASD leading to an imbalance of excitation and inhibition, and specifically a disproportionately high level of excitation. Pharmacological agents that modulate excitation and inhibition are currently in clinical trials for treatment of ASD and show promising preliminary results. AREAS COVERED: This paper reviews the literature implicating the role of glutamate and GABA pathways in the pathophysiology of ASD. It also provides a review of the current results from both animal models and human clinical trials of drugs aimed at normalizing the imbalance of excitation and inhibition through the use of metabotropic glutamate receptor (mGluR) antagonists and GABA agonists. EXPERT OPINION: Both mGluR antagonists and GABA agonists have promising preliminary data from animal model and small-scale Phase II human trials. They show significant efficacy in subpopulations and appear to have favorable side-effect profiles. Though preliminary data are extremely promising, results from ongoing larger, double blind, placebo-controlled studies will give a more complete understanding of the efficacy and side-effect profile related to these drugs. PMID- 23013436 TI - Development of tools for the biochemical characterization of the symbiotic receptor-like kinase DMI2. AB - The Medicago truncatula DMI2 gene encodes a leucine-rich repeat receptor-like kinase that is essential for symbiosis with nitrogen-fixing rhizobia. While phenotypic analyses have provided a description for the host's responses mediated by DMI2, a lack of tools for in vivo biochemical analysis has hampered efforts to elucidate the mechanisms by which DMI2 mediates symbiotic signal transduction. Here, we report stably transformed M. truncatula lines that express a genomic DMI2 construct that is fused to a dual-affinity tag containing three copies of the hemagglutinin epitope and a single StrepII tag (gDMI2:HAST). gDMI2: HAST complements the dmi2-1 mutation, and transgenic plants expressing this construct behave similarly to wild-type plants. We show that the expression patterns of gDMI2:HAST recapitulate those of endogenous DMI2 and that we can detect and purify DMI2:HAST from microsomal root and nodule extracts. Using this line, we show that DMI2 resides in a high-molecular weight complex, which is consistent with our observation that DMI2:GFP localizes to plasma membrane-associated puncta and cytoplasmic vesicles. We further demonstrate that Nod factor (NF) perception increases the abundance of DMI2 vesicles. These tools should be a valuable resource for the Medicago community to dissect the biochemical function of DMI2. PMID- 23013437 TI - The benyvirus RNA silencing suppressor is essential for long-distance movement, requires both zinc-finger and NoLS basic residues but not a nucleolar localization for its silencing-suppression activity. AB - The RNA silencing-suppression properties of Beet necrotic yellow vein virus (BNYVV) and Beet soil-borne mosaic virus (BSBMV) cysteine-rich p14 proteins have been investigated. Suppression of RNA silencing activities were made evident using viral infection of silenced Nicotiana benthamiana 16C, N. benthamiana agroinfiltrated with green fluorescent protein (GFP), and GF-FG hairpin triggers supplemented with viral suppressor of RNA silencing (VSR) constructs or using complementation of a silencing-suppressor-defective BNYVV virus in Chenopodium quinoa. Northern blot analyses of small-interfering RNAs (siRNAs) in agroinfiltration tests revealed reduced amounts of siRNA, especially secondary siRNA, suggesting that benyvirus VSR act downstream of the siRNA production. Using confocal laser-scanning microscopy imaging of infected protoplasts expressing functional p14 protein fused to an enhanced GFP reporter, we showed that benyvirus p14 accumulated in the nucleolus and the cytoplasm independently of other viral factors. Site-directed mutagenesis showed the importance of the nucleolar localization signal embedded in a C4 zinc-finger domain in the VSR function and intrinsic stability of the p14 protein. Conversely, RNA silencing suppression appeared independent of the nucleolar localization of the protein, and a correlation between BNYVV VSR expression and long-distance movement was established. PMID- 23013438 TI - Closely related poleroviruses depend on distinct translation initiation factors to infect Arabidopsis thaliana. AB - In addition to being essential for translation of eukaryotic mRNA, translation initiation factors are also key components of plant-virus interactions. In order to address the involvement of these factors in the infectious cycle of poleroviruses (aphid-transmitted, phloem-limited viruses), the accumulation of three poleroviruses was followed in Arabidopsis thaliana mutant lines impaired in the synthesis of translation initiation factors in the eIF4E and eIF4G families. We found that efficient accumulation of Turnip yellows virus (TuYV) in A. thaliana relies on the presence of eIF (iso)4G1, whereas Beet mild yellowing virus (BMYV) and Beet western yellows virus-USA (BWYV-USA) rely, instead, on eIF4E1. A role for these factors in the infectious processes of TuYV and BMYV was confirmed by direct interaction in yeast between these specific factors and the 5' viral genome-linked protein of the related virus. Although the underlying molecular mechanism is still unknown, this study reveals a totally unforeseen situation in which closely related viruses belonging to the same genus use different translation initiation factors for efficient infection of A. thaliana. PMID- 23013439 TI - Downregulation of miR-101 in gastric cancer correlates with cyclooxygenase-2 overexpression and tumor growth. AB - Cyclooxygenase-2 (COX-2) plays an important role in the carcinogenesis and progression of gastric cancer. It has been demonstrated that COX-2 overexpression depends on different cellular pathways, involving both transcriptional and post transcriptional regulation. MicroRNAs (miRNAs) are small, noncoding RNAs that function as post-transcriptional regulators. Here, we characterize miR-101 expression and its role in the regulation of COX-2 expression, which in turn, will provide us with additional insights into the potential therapeutic benefits of exogenous miR-101 for treatment of gastric cancer. Our results showed that miR 101 levels in gastric cancer tissues were significantly lower than those in the matched normal tissue (P < 0.01). Furthermore, lower levels of miR-101 were associated with increased tumor invasion and lymph node metastasis (P < 0.05). We also found an inverse correlation between miR-101 and COX-2 expression in both gastric cancer specimens and cell lines. Significant decreases in COX-2 mRNA and COX-2 levels were observed in the pre-miR-101-infected gastric cancer cells. One possible mechanism of interaction is that miR-101 inhibited COX-2 expression by directly binding to the 3'-UTR of COX-2 mRNA. Overexpression of miR-101 in gastric cancer cell lines also inhibited cell proliferation and induced apoptosis in vitro, as well as inhibiting tumor growth in vivo. These results collectively indicate that miR-101 may function as a tumor suppressor in gastric cancer, with COX-2 as a direct target. PMID- 23013440 TI - Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) causes several complications following cardiac transplantation including cardiac allograft vasculopathy. Previous studies suggested that immunosuppressive treatment based on everolimus might reduce CMV infection. Aiming to better characterize the action of everolimus on CMV and its interplay with patient/recipient serology and anti-CMV prophylaxis, we analyzed data from 3 large randomized studies comparing various everolimus regimens with azathioprine (AZA)- and mycophenolate mofetil (MMF)-based regimens. METHODS: CMV data were analyzed from 1009 patients in 3 trials of de novo cardiac transplant recipients who were randomized to everolimus 1.5 mg/day, everolimus 3 mg/day, or AZA 1-3 mg/kg/day, plus standard-dose (SD) cyclosporine (CsA; study B253, n = 634); everolimus 1.5 mg/day plus SD- or reduced-dose (RD)-CsA (study A2403, n = 199); and everolimus 1.5 mg/day plus RD-CsA or MMF plus SD-CsA (study A2411, n = 176). RESULTS: In study B253, patients allocated to everolimus experienced almost a 70% reduction in odds of experiencing CMV infection compared with AZA (P < 0.001). In study A2403, CMV infection was low in both everolimus arms, irrespective of CsA dosing, and in study A2411, patients allocated to everolimus experienced an 80% reduction in odds of experiencing CMV infection, compared with MMF (P < 0.001). CMV syndrome/disease was rare and less frequent in everolimus treated patients. Subgroup analyses showed that the benefit everolimus provides, in terms of CMV events, is retained in CMV-naive recipients and is independent of anti-CMV prophylaxis or preemptive approaches. CONCLUSIONS: Everolimus is associated with a lower incidence of CMV infection compared with AZA and MMF, which combined with its immunosuppressive efficacy and antiproliferative effects may positively impact long-term outcomes. PMID- 23013442 TI - Microtopography recreation benefits ecosystem restoration. PMID- 23013441 TI - RNA polymerase V targets transcriptional silencing components to promoters of protein-coding genes. AB - Transcriptional gene silencing controls transposons and other repetitive elements through RNA-directed DNA methylation (RdDM) and heterochromatin formation. A key component of the Arabidopsis RdDM pathway is ARGONAUTE4 (AGO4), which associates with siRNAs to mediate DNA methylation. Here, we show that AGO4 preferentially targets transposable elements embedded within promoters of protein-coding genes. This pattern of AGO4 binding cannot be simply explained by the sequences of AGO4 bound siRNAs; instead, AGO4 binding to specific gene promoters is also mediated by long non-coding RNAs (lncRNAs) produced by RNA polymerase V. lncRNA-mediated AGO4 binding to gene promoters directs asymmetric DNA methylation to these genomic regions and is involved in regulating the expression of targeted genes. Finally, AGO4 binding overlaps sites of DNA methylation affected by the biotic stress response. Based on these findings, we propose that the targets of AGO4 directed RdDM are regulatory units responsible for controlling gene expression under specific environmental conditions. PMID- 23013443 TI - Reflectance confocal microscopy allows in vivo real-time noninvasive assessment of the outcome of methyl aminolaevulinate photodynamic therapy of basal cell carcinoma. AB - BACKGROUND: Photodynamic therapy (PDT) with methyl aminolaevulinate (MAL) is an approved noninvasive treatment option for basal cell carcinoma (BCC). In vivo reflectance confocal microscopy (RCM) is a noninvasive imaging technique that has proved useful for in vivo real-time cytomorphological analysis of BCC cells infiltrating the epidermis. OBJECTIVES: To investigate the use of in vivo RCM to assess the persistence of BCC cells surviving MAL-PDT. METHODS: In vivo RCM images of 20 biopsy-proven BCCs were taken before patients underwent a treatment cycle with MAL-PDT. Follow-up after 3months was performed using clinical examination, RCM and conventional dermoscopy. Treated areas also underwent a targeted 3-mm punch biopsy for standard haematoxylin and eosin histology stain to establish the clinical and instrumental correlation of the treatment outcome. RESULTS: Three months after PDT, clinical examination established that two out of 20 BCCs were persistent; dermoscopy found three out of 20 residual BCCs, but RCM showed that one of these lesions was a false positive, and showed persistent BCC foci in five out of 20 lesions. Histological analysis of targeted biopsies confirmed these results. CONCLUSIONS: RCM provided noninvasive, early detection of incipient recurrences of BCC after MAL-PDT. RCM findings steered targeted biopsies and surgical removal, or a new MAL-PDT, of these subclinical recurrences with minimal invasiveness. PMID- 23013444 TI - Red cabbage ( Brassica oleracea ) as a new source of high-thermostable peroxidase. AB - Soluble and membrane-bound peroxidases (PODs) were extracted from red cabbage using Triton X-114. Optimum activity was obtained at pH 4.0 for both enzymes, and both were inactivated by sodium dodecyl sulfate (SDS). The K(M) and V(m) values for H(2)O(2) were found to be 0.98 mM and 8.1 MUM/min, respectively, for soluble POD and 0.82 mM and 6.1 MUM/min, respectively, for membrane-bound POD. When the 2,2'-azinobis(3-ethylbenzothiazolinesulfonic acid (ABTS) concentration was increased, maintaining a steady concentration of H(2)O(2), the activity was inhibited at the highest ABTS concentrations in soluble POD. Ascorbic acid was found to be the most active modulator of POD activity. The effect of cyclodextrins was also studied, and the complexation constant between ABTS and hydroxypropyl-beta-cyclodextrins (HP-beta-CDs) was calculated (K(c) = 312 M(-1)). Membrane-bound POD is more thermostable than soluble POD, losing >90% of relative activity after 5 min of incubation at 76.6 and 30.2 degrees C, respectively. PMID- 23013445 TI - Direct renin inhibitors in hypertension - approaching the moment of truth. PMID- 23013446 TI - Excess gestational weight gain: an exploration of midwives' views and practice. AB - BACKGROUND: Excess gestational weight gain (GWG) can affect the immediate and long term health outcomes of mother and infant. Understanding health providers' views, attitudes and practices around GWG is crucial to assist in the development of practical, time efficient and cost effective ways of supporting health providers to promote healthy GWGs. This study aimed to explore midwives' views, attitudes and approaches to the assessment, management and promotion of healthy GWG and to investigate their views on optimal interventions. METHODS: Midwives working in antenatal care were recruited from one rural and one urban Australian maternity hospital employing purposive sampling strategies to assess a range of practice areas. Face-to-face interviews were conducted with 15 experienced midwives using an interview guide and all interviews were digitally recorded, transcribed verbatim and analysed thematically. RESULTS: Midwives interviewed exhibited a range of views, attitudes and practices related to GWG. Three dominant themes emerged. Overall GWG was given low priority for midwives working in the antenatal care service in both hospitals. In addition, the midwives were deeply concerned for the physical and psychological health of pregnant women and worried about perceived negative impacts of discussion about weight and related interventions with women. Finally, the midwives saw themselves as central in providing lifestyle behaviour education to pregnant women and identified opportunities for support to promote healthy GWG. CONCLUSIONS: The findings indicate that planning and implementation of healthy GWG interventions are likely to be challenging because the factors impacting on midwives' engagement in the GWG arena are varied and complex. This study provides insights for guideline and intervention development for the promotion of healthy GWG. PMID- 23013447 TI - Acidobacterial community responses to agricultural management of soybean in Amazon forest soils. AB - This study focused on the impact of land-use changes and agricultural management of soybean in Amazon forest soils on the abundance and composition of the acidobacterial community. Quantitative real-time PCR (q-PCR) assays and pyrosequencing of 16S rRNA gene were applied to study the acidobacterial community in bulk soil samples from soybean croplands and adjacent native forests, and mesocosm soil samples from soybean rhizosphere. Based on qPCR measurements, Acidobacteria accounted for 23% in forest soils, 18% in cropland soils, and 14% in soybean rhizosphere of the total bacterial signals. From the 16S rRNA gene sequences of Bacteria domain, the phylum Acidobacteria represented 28% of the sequences from forest soils, 16% from cropland soils, and 17% from soybean rhizosphere. Acidobacteria subgroups 1-8, 10, 11, 13, 17, 18, 22, and 25 were detected with subgroup 1 as dominant among them. Subgroups 4, 6, and 7 were significantly higher in cropland soils than in forest soils, which subgroups responded to decrease in soil aluminum. Subgroups 6 and 7 responded to high content of soil Ca, Mg, Mn, and B. These results showed a differential response of the Acidobacteria subgroups to abiotic soil factors, and open the possibilities to explore acidobacterial subgroups as early-warning bioindicators of agricultural soil management effects in the Amazon area. PMID- 23013449 TI - Chitin-binding proteins of Artemia diapause cysts participate in formation of the embryonic cuticle layer of cyst shells. AB - The brine shrimp Artemia reproduces either ovoviviparously, producing free swimming nauplii, or oviparously, producing encysted embryos (diapause cysts) able to cope with harsh and complex habitats. When the cysts enter diapause they are encased in a complex external shell that protects them from certain extreme environments. The genomic comparison of oviparous and ovoviviparous ovisacs has been described previously. We isolated three significantly up-regulated genes in oviparous oocytes and identified them as Arp-CBP (Artemia parthenogenetica chitin binding protein) genes. Quantitative real-time PCR indicated that the expression of Arp-CBP genes gradually increases during diapause cyst formation and significant mRNA accumulation occurs during the ovisac stage of oviparous development. Moreover, in situ hybridization results demonstrated that Arp-CBP mRNAs are expressed in the embryo. Interestingly, the results of immune electron microscopy showed that all three Arp-CBPs are distributed throughout the cellular ECL (embryonic cuticle layer) of the cyst shell. Furthermore, knockdown of Arp CBP by RNA interference resulted in marked changes in the composition of the embryonic cuticular layer. The fibrous layer of the cyst shell adopted a loose conformation and the inner and outer cuticular membranes exhibited marked irregularities when Arp-CBP expression was suppressed. Finally, an in vitro recombinant protein-binding assay showed that all three Arp-CBPs have carbohydrate-binding activities. These findings provide significant insight into the mechanisms by which the ECL of Artemia cyst shell is formed, and demonstrate that Arp-CBPs are involved in construction of the fibrous lattice and are required for formation of the ECL of the cyst shell. PMID- 23013451 TI - An analysis of the genomic variability of the phytopathogenic mollicute Spiroplasma kunkelii. AB - Corn stunt disease has become a factor limiting maize production in some areas of the Americas in recent years. Although resistant maize genotypes have been developed in the past, this resistance has been unstable over time or in some geographical locations. To better understand disease components that could affect the stability of host resistance, we assessed the genome variability of the etiologic agent, Spiroplasma kunkelii. Isolates were obtained from a number of areas, and characterized molecularly by amplification of several regions of the spiroplasma chromosome and sequencing of specific gene fragments. The degree of polymorphism between isolates of different geographic origins was low, and the level of genomic variability was similar within isolates of different countries. Polymorphism among isolates was found in viral insertions and in the sequence of Skarp, a gene that encodes a membrane protein implicated in attachment to insect cells. The results suggest that the genome composition of this species is highly conserved among isolates. Hence, it is unlikely that the instability of maize resistance is due to generation of new pathotypes of S. kunkelii. Instead, other components of this complex pathosystem could account for the breakdown of resistance. PMID- 23013452 TI - Post-assembly derivatization of electrospun nanofibers via strain-promoted azide alkyne cycloaddition. AB - A primary amine-derivatized 4-dibenzocyclooctynol (DIBO) was used to initiate the ring-opening polymerization of poly(gamma-benzyl-L-glutamate) (DIBO-PBLG). This initiator yields well-defined PBLG polymers functionalized with DIBO at the chain termini. The DIBO end group further survives an electrospinning process that yields nanofibers that were then derivatized post-assembly with azide functionalized gold nanoparticles. The availability of DIBO on the surface of the fibers is substantiated by fluorescence, SEM, and TEM measurements. Post-assembly functionalization of nanofiber constructs with bioactive groups can be facilitated easily using this process. PMID- 23013450 TI - Three-dimensional-engineered matrix to study cancer stem cells and tumorsphere formation: effect of matrix modulus. AB - Maintenance of cancer stem cells (CSCs) is regulated by the tumor microenvironment. Synthetic hydrogels provide the flexibility to design three dimensional (3D) matrices to isolate and study individual factors in the tumor microenvironment. The objective of this work was to investigate the effect of matrix modulus on tumorsphere formation by breast cancer cells and maintenance of CSCs in an inert microenvironment without the interference of other factors. In that regard, 4T1 mouse breast cancer cells were encapsulated in inert polyethylene glycol diacrylate hydrogels and the effect of matrix modulus on tumorsphere formation and expression of CSC markers was investigated. The gel modulus had a strong effect on tumorsphere formation and the effect was bimodal. Tumorsphere formation and expression of CSC markers peaked after 8 days of culture. At day 8, as the matrix modulus was increased from 2.5 kPa to 5.3, 26.1, and 47.1 kPa, the average tumorsphere size changed from 37+/-6 MUm to 57+/-6, 20+/-4, and 12+/-2 MUm, respectively; cell number density in the gel changed from 0.8+/-0.1*105 cells/mL to 1.7+/-0.2*105, 0.4+/-0.1*105, and 0.2+/-0.1*105 cells/mL after initial encapsulation of 0.14*105 cells/mL; and the expression of CD44 breast CSC marker changed from 17+/-4-fold to 38+/-9-, 3+/-1-, and 2+/-1 fold increase compared with the initial level. Similar results were obtained with MCF7 human breast carcinoma cells. Mouse 4T1 and human MCF7 cells encapsulated in the gel with 5.3 kPa modulus formed the largest tumorspheres and highest density of tumorspheres, and had highest expression of breast CSC markers CD44 and ABCG2. The inert polyethylene glycol hydrogel can be used as a model-engineered 3D matrix to study the role of individual factors in the tumor microenvironment on tumorigenesis and maintenance of CSCs without the interference of other factors. PMID- 23013453 TI - Cardiac arrhythmias in adult patients with asthma. AB - OBJECTIVE: The pathogenesis of cardiac arrhythmias in asthma patients has not been fully elucidated. Adverse drug effects, particularly those of beta2 mimetics, may play a role. The aim of this study was to determine whether asthma is associated with the risk of cardiac arrhythmias and electrocardiographic characteristics of arrhythmogenicity (ECG) and to explore the role of beta2 mimetics. METHODS: A cross-sectional study was conducted among 158 adult patients with a diagnosis of asthma and 6303 participants without asthma from the cohort of the Utrecht Health Project-an ongoing, longitudinal, primary care-based study. All patients underwent extensive examinations, including resting 12-lead electrocardiogram (ECG) and pulmonary function tests. The primary outcome was "any arrhythmia on the ECG" (including tachycardia, bradycardia, premature ventricular contraction (PVC), and atrial fibrillation or flutter). Secondary outcomes were tachycardia, bradycardia, PVC, atrial fibrillation or flutter, mean heart rate, mean corrected QT (QTc) interval length, and prolonged QTc interval. RESULTS: Tachycardia and PVCs were more prevalent in patients with asthma (3% and 4%, respectively) than those without asthma (0.6%, p < .001; 2%, p = .03, respectively). The prevalence of QTc interval prolongation was similar in participants with (2%) and without asthma (3%, odds ratio [OR]: 0.6 and 95% confidence interval [95% CI]: 0.2-2.0). In 74 asthma patients, who received beta2 mimetics, tachycardia and PVCs were more common (OR: 12.4 [95% CI: 4.7-32.8] and 3.7 [95% CI: 1.3-10.5], respectively). CONCLUSIONS: The adult patients with asthma more commonly show tachycardia and PVCs on the ECG than those without asthma. The patients with asthma received beta2-mimetics; the risk of tachycardia and PVCs is even more pronounced. PMID- 23013455 TI - Structural requirement of fibrogenic laminin-derived peptide A119 (LSNIDYILIKAS) for amyloid-like fibril formation and cellular activity. AB - A119 peptide (LSNIDYILIKAS), derived from the mouse laminin alpha1 chain sequence (residues 1321-1332), promotes cell attachment, neurite outgrowth, and amyloid like fibril formation. In this study, we evaluated the structural requirements of A119 for biological activities and amyloid-like fibril formation. The attachment of the cell to A119 was inhibited by heparin, and using syndecan- and glypican overexpressed cells, it was determined that A119 specifically binds to syndecans. We also evaluated the critical residues for A119 activities using a set of alanine-substituted peptides. Cell attachment activity was significantly reduced in the Leu(1)-, Ser(2)-, Asn(3)-, Ile(4)-, Ile(7)-, Ile(9)-, and Lys(10) substituted alanine peptides. Residues Ile(4), Ile(7), Ile(9), and Lys(10) were important for neurite outgrowth activity. Congo red staining and electron microscopic examination revealed that the Ile(4), Ile(7), Ile(9), and Ser(12) residues of A119 were required for amyloid-like fibril formation. These data suggest that the Ile residues are critical for the amyloid-like fibril formation, cell attachment, and neurite outgrowth activity of A119. Furthermore, an enantiomer of A119 showed similar amyloid-like fibril formation and increased levels of cell attachment and FAK signal transduction. These findings shed light on the mechanism of amyloid-like fibril formation and demonstrate a relationship between the ability to form amyloid-like fibrils and cell behavior. PMID- 23013454 TI - Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells. AB - BACKGROUND: Arachidonic acid metabolite, generated by cyclooxygenase (COX), is implicated in the colorectal cancer (CRC) pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti inflammatory drugs inhibiting only COX have been conflicting. It has been postulated that this might result from the shunting of arachidonic acid metabolism to the 5-lipoxygenase (5-LOX) pathway. Cancer cell viability is promoted by 5-LOX through several mechanisms that are similar to those of cyclooxygenase-2 (COX-2). Expression of 5-LOX is upregulated in colorectal adenoma and cancer. The aim of this study was to investigate the shunting of arachidonic acid metabolism to the 5-LOX pathway by cyclooxygenase inhibition and to determine if this process antagonizes the anti-cancer effect in colorectal cancer cells. METHODS: Three colorectal cancer cell lines (HCA7, HT-29 & LoVo) expressing 5-LOX and different levels of COX-2 expression were used. The effects of aspirin (a non-selective COX inhibitor) and rofecoxib (COX-2 selective) on prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) secretion were quantified by ELISA. Proliferation and viability were studied by quantifying double-stranded DNA (dsDNA) content and metabolic activity. Apoptosis was determined by annexin V and propidium iodide staining using confocal microscopy, and caspase-3/7 activity by fluorescent substrate assay. RESULTS: COX inhibitors suppressed PGE2 production but enhanced LTB4 secretion in COX-2 expressing cell lines (P <0.001). The level of COX-2 expression in colorectal cancer cells did not significantly influence the anti-proliferative and pro-apoptotic effects of COX inhibitors due to the shunting mechanism. CONCLUSIONS: This study provides evidence of shunting between COX and 5-LOX pathways in the presence of unilateral inhibition, and may explain the conflicting anti-carcinogenic effects reported with use of COX inhibitors. PMID- 23013456 TI - Direct amidation of carboxylic acids catalyzed by ortho-iodo arylboronic acids: catalyst optimization, scope, and preliminary mechanistic study supporting a peculiar halogen acceleration effect. AB - The importance of amides as a component of biomolecules and synthetic products motivates the development of catalytic, direct amidation methods employing free carboxylic acids and amines that circumvent the need for stoichiometric activation or coupling reagents. ortho-Iodophenylboronic acid 4a has recently been shown to catalyze direct amidation reactions at room temperature in the presence of 4A molecular sieves as dehydrating agent. Herein, the arene core of ortho-iodoarylboronic acid catalysts has been optimized with regards to the electronic effects of ring substitution. Contrary to the expectation, it was found that electron-donating substituents are preferable, in particular, an alkoxy substituent positioned para to the iodide. The optimal new catalyst, 5 methoxy-2-iodophenylboronic acid (MIBA, 4f), was demonstrated to be kinetically more active than the parent des-methoxy catalyst 4a, providing higher yields of amide products in shorter reaction times under mild conditions at ambient temperature. Catalyst 4f is recyclable and promotes the formation of amides from aliphatic carboxylic acids and amines, and from heteroaromatic carboxylic acids and other functionalized substrates containing moieties like a free phenol, indole and pyridine. Mechanistic studies demonstrated the essential role of molecular sieves in this complex amidation process. The effect of substrate stoichiometry, concentration, and measurement of the catalyst order led to a possible catalytic cycle based on the presumed formation of an acylborate intermediate. The need for an electronically enriched ortho-iodo substituent in catalyst 4f supports a recent theoretical study (Marcelli, T. Angew. Chem. Int. Ed.2010, 49, 6840-6843) with a purported role for the iodide as a hydrogen-bond acceptor in the orthoaminal transition state. PMID- 23013457 TI - Phantom limb pain in daily practice--still a lot of work to do! AB - OBJECTIVES: Effective treatment of phantom limb pain (PLP, pain felt in the part of the body of an amputated limb) is still difficult to achieve, and improved treatment is needed. It is therefore of paramount interest to understand the current practice of PLP therapy outside pain centers. DESIGN: As a part of a nationwide survey, 537 amputees were asked 11 questions related to their treatment experiences and the pain relief. Furthermore, the patients' opinion about the quality of medical care was also asked. RESULTS: Five hundred thirty seven out of 1088 amputees returned the questionnaire (49.4%). Four hundred (74.5%) suffered from PLP. The patients rated their caregivers' knowledge about PLP lower than their own. Many (41.6%) of PLP patients had never been informed about the possibility of occurrence and mechanisms of PLP. The vast majority of the PLP patients did not try any treatment. Among those treated, more than 30% consulted more than three physicians for beneficial treatment. A >50% pain reduction was achieved in only 12.7% of PLP patients. The most successful treatments were opioids (67.4%) and anticonvulsants (51.7%). Surgery was performed in 46.4% of all PLP patients and in 29.7% due to a clinically suspected neuroma. After surgery, pain was worse or unchanged in 50% and improved in 41.6%, and 7.4% were pain-free. CONCLUSIONS: Our results suggest that there are primary needs for better information about PLP pathophysiology and treatment not only for patients but also for caregivers. Limited therapeutic success reveals a further need for increased research in PLP management. PMID- 23013458 TI - Pharmacoeconomic spotlight on rotavirus vaccine RIX4414 (RotarixTM) in the prevention of rotavirus gastroenteritis in developing countries. AB - This article provides an overview of the clinical profile of rotavirus vaccine RIX4414 (RotarixTM) in the prevention of rotavirus gastroenteritis (RVGE) in developing countries, followed by a review of pharmacoeconomic analyses with the vaccine in low- and middle-income countries. RVGE is associated with significant morbidity and mortality among children <5 years of age in developing countries. The protective efficacy of a two-dose oral series of rotavirus vaccine RIX4414 has been demonstrated in several well designed clinical trials conducted in developing countries, and the 'real-world' effectiveness of the vaccine has also been shown in naturalistic and case-control trials after the introduction of universal vaccination programs with RIX4414 in Latin American countries. The WHO recommends universal rotavirus vaccination programs for all countries. Numerous modelled cost-effectiveness analyses have been conducted with rotavirus vaccine RIX4414 across a wide range of low- and middle-income countries. Although data sources and assumptions varied across studies, results of the analyses consistently showed that the introduction of the vaccine as part of a national vaccination program would be very cost effective compared with no rotavirus vaccination program, according to widely used cost-effectiveness thresholds for developing countries. Vaccine price was not known at the time the analyses were conducted and had to be estimated. In sensitivity analyses, rotavirus vaccine RIX4414 generally remained cost effective at the highest of a range of possible vaccine prices considered. Despite these favorable results, decisions regarding the implementation of universal vaccination programs with RIX4414 may also be contingent on budgetary and other factors, underscoring the importance of subsidized vaccination programs for poor countries through the GAVI Alliance (formerly the Global Alliance for Vaccines and Immunization). PMID- 23013459 TI - When to start, what to start and other treatment controversies in pediatric HIV infection. AB - Over the last decade there have been dramatic changes in the management of pediatric HIV infection. Whilst observational studies and several randomized control trials (RCTs) have addressed some questions about when to start antiretroviral therapy (ART) in children and what antiretrovirals to start, many others remain unanswered. In infants, early initiation of ART greatly reduces mortality and disease progression. Treatment guidelines now recommend ART in all infants younger than 1 or 2 years of age depending on geographical setting. In children >1 year of age, US, European (Paediatric European Network for Treatment of AIDS; PENTA) and WHO guidelines differ and debate is ongoing. Recent data from an RCT in Thailand in children with moderate immune suppression indicate that it is safe to monitor asymptomatic children closely without initiating ART, although earlier treatment was associated with improved growth. Untreated HIV progression in children aged over 5 years is similar to that in adults, and traditionally adult treatment thresholds are applied. Recent adult observational and modeling studies showed a survival advantage and reduction of age-associated complications with early treatment. The current US guidelines have lowered CD4+ cell count thresholds for ART initiation for children aged >5 years to 500 cells/mm3. Co infections influence the choice of drugs and the timing of starting ART. Drug interactions, overlapping toxicities and adherence problems secondary to increased pill burden are important issues. Rapid changes in the pharmacokinetics of antiretrovirals in the first years of life, limited pharmacokinetic data in children and genetic variation in metabolism of many antiretrovirals make correct dosing difficult. Adherence should always be addressed prior to starting ART or switching regimens. The initial ART regimen depends on previous exposure, including perinatal administration for prevention of mother to child transmission (PMTCT), adherence, co-infections, drug availability and licensing. A European cohort study in infants indicated that treatment with four drugs produced superior virologic suppression and immune recovery. Protease inhibitor (PI)-based ART has the advantage of a high barrier to viral resistance. A recent RCT conducted in several African countries showed PI-based ART to be advantageous in children aged <3 years compared with nevirapine-based ART irrespective of previous nevirapine exposure. Another trial in older children from resource rich settings showed both regimens were equally effective. Treatment interruption remains a controversial issue in children, but one study in Europe demonstrated no short-term detrimental effects. ART in children is a rapidly evolving area with many new antiretrovirals being developed and undergoing trials. The aim of ART has shifted from avoiding mortality and morbidity to achieving a normal life expectancy and quality of life, minimizing toxicities and preventing early cancers and age-related illnesses. PMID- 23013461 TI - Cyclometalated iridium(III) complexes containing hydroxide/chloride ligands: isolation of heterobridged dinuclear iridium(III) compounds containing MU-OH and MU-pyrazole ligands. AB - The reaction of the cyclometalated chloro-bridged iridium(III) dimers [(ppy)(2) Ir(MU-Cl)](2) (ppyH = 2-phenyl pyridine) and [(tpy)(2)Ir(MU-Cl)](2) (tpyH = 2-p tolylpyridine) with 3,5-diphenylpyrazole (Ph(2)PzH) in the presence of sodium methoxide resulted in the formation of heterobridged dimers [(ppy)(2)Ir(MU-OH)(MU Ph(2)Pz)Ir(ppy)(2)] (1) and [(tpy)(2)Ir(MU-OH)(MU-Ph(2)Pz)Ir(tpy)(2)] (2). Interestingly, the reaction of [(ppy)(2)Ir(MU-Cl)](2) with 3(5)-methyl-5(3) phenylpyrazole (PhMePzH) afforded both a heterobridged dimer, [(ppy)(2)Ir(MU OH)(MU-PhMePz)Ir(ppy)(2)] (3), and the monomer [(ppy)(2)Ir(PhMePz)Cl] (4). The compound [(ppy)(2)Ir(PhMePz)OH] (5) containing a terminal OH was obtained in a hydrolysis reaction involving 4, sodium methoxide, and PhMePzH. Complexes 1-5 were characterized by X-ray crystallography and electrospray ionization high resolution mass spectrometry. All of the complexes are luminescent at room temperature in their dichloromethane solutions. The luminescence of the dinuclear complexes is characterized by a single structureless band centered at lambda(max) = 550 nm (1 and 3) and 546 nm (2). The emission spectra of the mononuclear complexes 4 and 5 display vibronic structures with their lambda(max) values at 497 nm (4) and 513 nm (5). In each case, the main emission bands are accompanied by shoulder bands at 526 (4) and 534 nm (5). The quantum yields, calculated with reference to [Ir(ppy)(2)(bpy)]PF(6) (Phi(CH(3)CN) = 0.0622), range from 0.11 to 0.17 for the dinuclear complexes and 0.045 to 0.048 for the mononuclear complexes. The lifetimes of the emission are in the microsecond region, suggesting the phosphorescent nature of the emission. Density functional theory (DFT) and time-dependent DFT calculations were performed on complexes 1 and 4 in the ground state to gain insight into the structural, electronic, and photophysical properties. Electrochemical studies on complexes 1-3 showed the presence of two consecutive one-electron-oxidation processes, assigned as the stepwise oxidation of the two Ir(III) centers, i.e., Ir(III)-Ir(III)/Ir(III) Ir(IV) and Ir(III)-Ir(IV)/Ir(IV)-Ir(IV) couples, respectively. The monomers displayed single-oxidation peaks. No reduction process was observed within the solvent cathodic potential limit. PMID- 23013460 TI - Apnea and oxygen desaturations in children treated with opioids after adenotonsillectomy for obstructive sleep apnea syndrome: a prospective pilot study. AB - BACKGROUND: Recent case reports have alerted the medical community of fatality in children receiving codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. OBJECTIVE: The objective of this study was to compare the rates of oxygen desaturation before and after adenotonsillectomy in children with obstructive sleep apnea syndrome (OSAS), and to examine the relationship between cytochrome P450 2D6 (CYP2D6) genotype and respiratory events. STUDY DESIGN: This was a prospective observational study. METHODS: Twenty six children with OSAS (mean age 78 months, range 1.8-17 years) who underwent adenotonsillectomy were studied. CYP2D6 genotype was characterized in 21 of these children. The primary endpoints of the study were the change in the rate of desaturation and in the nadir oxygen saturation values before and in the first 24 hours after surgery as measured by pulse oximetry. RESULTS: Twenty-two children received codeine and four were managed with hydrocodone. There was no post operative improvement in the mean rate of desaturation (1.84 +/- 1.45/hour pre operative vs 2.97 +/- 3.3/hour post-operative; p = 0.119; 95% CI -2.56, 0.313), or the post-operative nadir of oxygen saturation (85.2 +/- 5.8% pre-operative vs 84.0 +/- 6.8% post-operative; p = 0.632; 95% CI -3.00, 4.84) on the night after surgery. Prior to surgery, six children had an oxygen saturation nadir <80%, while post-surgery, the number increased to eight children. Ten children improved their parameters after surgery. CYP2D6 genotype by itself did not predict the changes in desaturation or nadir. CONCLUSION: Post-operative use of opioids following OSAS may not be safe for all children. It is conceivable that if the child is among the significant proportion that experiences increased oxygen desaturations, the CNS depressing effects of codeine or hydrocodone and their respectively potent morphine or hydromorphone metabolites can further compromise respiratory drive. Larger studies are needed to investigate the potential contribution of CYP2D6 genotype. PMID- 23013462 TI - Performances on Symbol Digit Modalities Test, Color Trails Test, and modified Stroop test in a healthy, elderly Danish sample. AB - This study presents Danish data for the Symbol Digit Modalities Test (SDMT), Color Trails Test (CTT), and a modified Stroop test from 100 subjects aged 60-87 years. Among the included demographic variables, age had the highest impact on test performances. Thus, the study presents separate data for different age groups. For SDMT and CTT1, Danish Adult Reading Test (DART) score also had a significant impact on test performances. The incongruent version of the modified Stroop test was significantly correlated to education. Moderate and significant correlations were found between the three tests. Even though the three tests are commonly used, few normative data for elderly exists. SDMT and CTT performances from this study were in the same range as previously published international norms, but the validity of the result from the modified Stroop test could not be investigated. PMID- 23013463 TI - Can skin temperature replace rectal temperature monitoring in babies undergoing therapeutic hypothermia in low-resource settings? PMID- 23013464 TI - Nuclear ubiquitin proteasome degradation affects WRKY45 function in the rice defense program. AB - The transcriptional activator WRKY45 plays a major role in the salicylic acid/benzothiadiazole-induced defense program in rice. Here, we show that the nuclear ubiquitin-proteasome system (UPS) plays a role in regulating the function of WRKY45. Proteasome inhibitors induced accumulation of polyubiquitinated WRKY45 and transient up-regulation of WRKY45 target genes in rice cells, suggesting that WRKY45 is constantly degraded by the UPS to suppress defense responses in the absence of defense signals. Mutational analysis of the nuclear localization signal indicated that UPS-dependent WRKY45 degradation occurs in the nuclei. Interestingly, the transcriptional activity of WRKY45 after salicylic acid treatment was impaired by proteasome inhibition. The same C-terminal region in WRKY45 was essential for both transcriptional activity and UPS-dependent degradation. These results suggest that UPS regulation also plays a role in the transcriptional activity of WRKY45. It has been reported that AtNPR1, the central regulator of the salicylic acid pathway in Arabidopsis, is regulated by the UPS. We found that OsNPR1/NH1, the rice counterpart of NPR1, was not stabilized by proteasome inhibition under uninfected conditions. We discuss the differences in post-translational regulation of salicylic acid pathway components between rice and Arabidopsis. PMID- 23013465 TI - Tivozanib: current status and future directions in the treatment of solid tumors. AB - INTRODUCTION: Tivozanib is a novel tyrosine kinase inhibitor (TKI) which inhibits vascular endothelial growth factor (VEGF) receptors-1, -2, and -3 at nanomolar concentrations. AREAS COVERED: A comprehensive MEDLINE and American Society of Clinical Oncology abstract search was performed to gather all relevant clinical and translational data related to tivozanib. We discuss pre-clinical studies associated with tivozanib, and the results of a Phase I assessment in advanced solid tumors. We highlight combination studies with tivozanib, including pairings of tivozanib with cytotoxic therapy in patients with colorectal cancer and breast cancer. A randomized discontinuation Phase II study and a randomized Phase III study assessing the activity of tivozanib in metastatic renal cell carcinoma (mRCC) are described in detail. EXPERT OPINION: Tivozanib will face the challenge of entering an already crowded therapeutic space in mRCC-emerging combination studies and biomarker assessments may distinguish this agent among other VEGF TKIs. The current review will outline the development pathway of tivozanib to date, and offer lessons learned and future opportunities. PMID- 23013466 TI - Carbon, land, and water footprint accounts for the European Union: consumption, production, and displacements through international trade. AB - A nation's consumption of goods and services causes various environmental pressures all over the world due to international trade. We use a multiregional input-output model to assess three kinds of environmental footprints for the member states of the European Union. Footprints are indicators that take the consumer responsibility approach to account for the total direct and indirect effects of a product or consumption activity. We quantify the total environmental pressures (greenhouse gas emissions: carbon footprint; appropriation of biologically productive land and water area: land footprint; and freshwater consumption: water footprint) caused by consumption in the EU. We find that the consumption activities by an average EU citizen in 2004 led to 13.3 tCO(2)e of induced greenhouse gas emissions, appropriation of 2.53 gha (hectares of land with global-average biological productivity), and consumption of 179 m(3) of blue water (ground and surface water). By comparison, the global averages were 5.7 tCO(2)e, 1.23 gha, and 163 m(3) blue water, respectively. Overall, the EU displaced all three types of environmental pressures to the rest of the world, through imports of products with embodied pressures. Looking at intra-EU displacements only, the UK was the most important displacer overall, while the largest net exporters of embodied environmental pressures were Poland (greenhouse gases), France (land), and Spain (freshwater). PMID- 23013467 TI - Size homeostasis can be intrinsic to growing cell populations and explained without size sensing or signalling. AB - The cell division cycle orchestrates cellular growth and division. The machinery underpinning the cell division cycle is well characterized, but the actual cue(s) driving the cell division cycle remains unknown. In rapidly growing and dividing yeast cells, this cue has been proposed to be cell size. Presumably, a mechanism communicating cell size acts as gatekeeper for the cell division cycle via the G(1) network, which triggers G(1) exit only when a critical size has been reached. Here, we evaluate this hypothesis with a minimal core model linking metabolism, growth and the cell division cycle. Using this model, we (a) present support for coordinated regulation of G(1)/S and G(2)/M transition in Saccharomyces cerevisiae in response to altered growth conditions, (b) illustrate the intrinsic antagonism between G(1) progression and cell size and (c) provide evidence that the coupling of growth and division is sufficient to allow for size homeostasis without directly communicating or measuring cell size. We show that even with a rudimentary version of the G(1) network consisting of a single unregulated cyclin, size homeostasis is maintained in populations during autocatalytic growth when the geometric constraint on nutrient supply is considered. Taken together, our results support the notion that cell size is a consequence rather than a regulator of growth and division. PMID- 23013468 TI - Is Mohs micrographic surgery more effective than wide local excision for treatment of dermatofibrosarcoma protuberans in reducing risk of local recurrence? A critically appraised topic. PMID- 23013469 TI - The simulation of meiosis in diploid and tetraploid organisms using various genetic models. AB - BACKGROUND: While the genetics of diploid inheritance are well studied and software for linkage mapping, haplotyping and QTL analysis are available, for tetraploids the available tools are limited. In order to develop such tools it would be helpful if simulated populations based on a variety of models of the tetraploid meiosis would be available. RESULTS: Here we present PedigreeSim, a software package that simulates meiosis in both diploid and tetraploid species and uses this to simulate pedigrees and cross populations. For tetraploids a variety of models can be used, including both bivalent and quadrivalent formation, varying degrees of preferential pairing of hom(oe)ologous chromosomes, different quadrivalent configurations and more. Simulation of quadrivalent meiosis results as expected in double reduction and recombination between more than two hom(oe)ologous chromosomes. The results are shown to match theoretical predictions. CONCLUSIONS: This is the first simulation software that implements all features of meiosis in tetraploids. It allows to generate data for tetraploid and diploid populations, and to investigate different models of tetraploid meiosis. The software and manual are available from http://www.plantbreeding.nl/UK/software_pedigreeSim.html and as Additional files 1, 2, 3 and 4 with this publication. PMID- 23013470 TI - Persistent Rhodococcus equi infection in a renal transplant patient: case report and review of the literature. AB - Rhodococcus equi is a pathogen that mainly causes infection in immunocompromised hosts. We report a case of relapsing R. equi pulmonary infection in a 57-year-old male renal transplant recipient who was treated with 12 months of antibiotics, adjunctive surgery, and a reduction in his immunosuppression. He suffered from relapsing disease, treatment-related complications, and ultimately died of Pneumocystis pneumonia. Case reports in the literature portray a good cure rate for transplant-related R. equi infections, with shorter durations of antibiotics. The case illustrates the difficulties in the management of R. equi infections. Forty cases from the literature were reviewed and compared in terms of epidemiology, location of infection, transplant type, immunosuppression used, treatment used, outcomes, and possible exposures. PMID- 23013471 TI - Targeting of CD34+CD38- cells using Gemtuzumab ozogamicin (Mylotarg) in combination with tipifarnib (Zarnestra) in Acute Myeloid Leukaemia. AB - BACKGROUND: The CD34+CD38- subset of AML cells is enriched for resistance to current chemotherapeutic agents and considered to contribute to disease progression and relapse in Acute Myeloid Leukaemia (AML) patients following initial treatment. METHODS: Chemosensitivity in phenotypically defined subsets from 34 primary AML samples was measured by flow cytometry following 48 hr in vitro treatment with gemtuzumab ozogamicin (GO, Mylotarg) and the farnesyltransferase inhibitor tipifarnib/zarnestra. The DNA damage response was measured using flow cytometry, immunofluorescence and immunohistochemistry. RESULTS: Using a previously validated in vitro minimal residual disease model, we now show that the combination of GO (10 ng/ml) and tipifarnib (5 MUM) targets the CD34+CD38- subset resulting in 65% median cell loss compared to 28% and 13% CD34+CD38- cell loss in GO-treated and tipifarnib-treated cells, respectively. Using phosphokinome profiling and immunofluorescence in the TF-1a cell line, we demonstrate that the drug combination is characterised by the activation of a DNA damage response (induction of gammaH2A.X and thr68 phosphorylation of chk2). Higher induction of gammaH2AX was found in CD34+CD38- than in CD34+CD38+ patient cells. In a model system, we show that dormancy impairs damage resolution, allowing accumulation of gammaH2AX foci. CONCLUSIONS: The chemosensitivity of the CD34+CD38- subset, combined with enhanced damage indicators, suggest that this subset is primed to favour programmed cell death as opposed to repairing damage. This interaction between tipifarnib and GO suggests a potential role in the treatment of AML. PMID- 23013472 TI - Expression of a glycosylphosphatidylinositol-anchored ligand, growth hormone, blocks receptor signalling. AB - We have investigated the interaction between GH (growth hormone) and GHR (GH receptor). We previously demonstrated that a truncated GHR that possesses a transmembrane domain but no cytoplasmic domain blocks receptor signalling. Based on this observation we investigated the impact of tethering the receptor's extracellular domain to the cell surface using a native lipid GPI (glycosylphosphatidylinositol) anchor. We also investigated the effect of tethering GH, the ligand itself, to the cell surface and demonstrated that tethering either the ecGHR (extracellular domain of GHR) or the ligand itself to the cell membrane via a GPI anchor greatly attenuates signalling. To elucidate the mechanism for this antagonist activity, we used confocal microscopy to examine the fluorescently modified ligand and receptor. GH-GPI was expressed on the cell surface and formed inactive receptor complexes that failed to internalize and blocked receptor activation. In conclusion, contrary to expectation, tethering an agonist to the cell surface can generate an inactive hormone receptor complex that fails to internalize. PMID- 23013473 TI - Seven years of the field epidemiology training programme (FETP) at Chennai, Tamil Nadu, India: an internal evaluation. AB - BACKGROUND: During 2001-2007, the National Institute of Epidemiology (NIE), Chennai, Tamil Nadu, India admitted 80 trainees in its two-year Field Epidemiology Training Programme (FETP). We evaluated the first seven years of the programme to identify strengths and weaknesses. METHODS: We identified core components of the programme and broke them down into input, process, output and outcome. We developed critical indicators to reflect the logic model. We reviewed documents including fieldwork reports, abstracts listed in proceedings and papers published in Medline-indexed journals. We conducted an anonymous online survey of the graduates to collect information on self-perceived competencies, learning activities, field assignments, supervision, curriculum, relevance to career goals, strengths and weaknesses. RESULTS: Of the 80 students recruited during 2001-2007, 69 (86%) acquired seven core competencies (epidemiology, surveillance, outbreaks, research, human subjects protection, communication and management) and graduated through completion of at least six field assignments. The faculty-to student ratio ranged between 0.4 and 0.12 (expected: 0.25). The curriculum was continuously adapted with all resources available on-line. Fieldwork led to the production of 158 scientific communications presented at international meetings and to 29 manuscripts accepted in indexed, peer-reviewed journals. The online survey showed that while most graduates acquired competencies, unmet needs persisted in laboratory sciences, data analysis tools and faculty-to-student ratio. CONCLUSIONS: NIE adapted the international FETP model to India. However, further efforts are required to scale up the programme and to develop career tracks for field epidemiologists in the country. PMID- 23013474 TI - Synthesis and characterization of antiapicophilic arsoranes and related compounds. AB - Utilizing bulky bidentate ligand systems with C(2)F(5) and n-C(3)F(7) groups, antiapicophilic arsoranes (5b and 5c, respectively) were synthesized. A kinetic study on the isomerization of these arsoranes to their more stable isomers showed that the barriers increased in the order of CF(3) < C(2)F(5) < n-C(3)F(7) in accord with their steric bulk. It was also revealed that the degree of freezing isomerization was larger for the change from CF(3) to C(2)F(5) than from C(2)F(5) to n-C(3)F(7), obvious from the differences in activation free energy at 363 K of 1.6 and 0.3 kcal mol(-1), respectively. X-ray structural analysis of several precursors of these two systems disclosed the unique structures of these compounds. PMID- 23013475 TI - Anti-inflammatory procyanidins and triterpenes in 109 apple varieties. AB - We evaluated the potential of apple to reduce inflammation. Phenolic compounds and triterpenes were analyzed in 109 apple cultivars. Total phenolics ranged from 29 to 7882 MUg g(-1) of fresh weight (FW) in the flesh and from 733 to 4868 MUg g(-1) FW in the skin, with flavanols including epicatechin and procyanidins as major components. Ursolic (44.7 to 3522 MUg g(-1) FW) and oleanolic (47.2 to 838 MUg g(-1) FW) acids dominated the skin triterpene profile. Five chemically contrasting cultivars were fractionated and their immune-modulating activity measured using two cell-based assays targeting key points in the inflammation process. Cultivars exhibiting high contents of procyanidins were the most potent at inhibiting NF-kappaB while triterpene-rich fractions reduced the promoter activity of the gene of TNFalpha. This study provides new insights into how apple genetic diversity could be used to alleviate inflammation. PMID- 23013476 TI - Mapping rainbow trout immune genes involved in inflammation reveals conserved blocks of immune genes in teleosts. AB - We report the genetic map location of 14 genes involved in the inflammatory response to salmonid bacterial and viral pathogens, which brings the total number of immune genes mapped in rainbow trout (RT, Oncorhynchus mykiss) to 61. These genes were mapped as candidate genes that may be involved in resistance to bacterial kidney disease, as well as candidates for known QTL for resistance to infectious hematopoietic necrosis virus, infectious pancreatic necrosis virus and Ceratomyxa shasta. These QTL map to one or more of the linkage groups containing immune genes. The combined analysis of these linkage results and those of previously mapped immune genes in RT shows that many immune genes are found in syntenic blocks of genes that have been retained in teleosts despite species divergence and genome duplication events. PMID- 23013477 TI - Minimal volume of local anesthetic required for an ultrasound-guided SGB. AB - BACKGROUND: Compared with the blind technique, ultrasound-guided stellate ganglion block (SGB) reduces the amount of local anesthetic needed for a successful block. The purpose of this study is to determine the minimal, optimal volume of local anesthetic required for successful ultrasound-guided SGB and to reduce its adverse effects. METHODS: Thirty-five patients with postherpetic neuralgia and complex regional pain syndrome of the upper extremity and the facial area were selected. For ultrasound-guided SGB by subfacial method, each patient was injected with 0.5% mepivacaine mixed with contrast media in 2 mL, 3 mL, and 4 mL doses at 2-week intervals. After the procedure, the spread of contrast media in the spine was checked by fluoroscopy. Ptosis and conjunctival flushing were rated and recorded. Adverse effects, such as hoarseness, foreign body sensation, swallowing difficulty, and upper arm weakness, were also recorded. RESULTS: Out of the 35 initial patients, the results for 33 patients who received all three SGBs were included in this study. The contrast media spread to 4.80 +/- 0.82, 4.94 +/- 0.86, and 5.09 +/- 0.97 total spinal segments in the 2 mL, 3 mL, and 4 mL groups, respectively. The cephalad spread of contrast media was 2.16 +/- 0.74, 2.23 +/- 0.85, and 2.30 +/- 0.78 spinal segments for the 2 mL, 3 mL, and 4 mL groups, respectively, and the caudad spread of contrast media was 2.64 +/- 0.51, 2.70 +/- 0.61, and 2.89 +/- 0.64 segments in the 2 mL, 3 mL, and 4 mL groups, respectively. There were no significant statistical differences in any segments for the three groups (P > 0.05). Review of the fluoroscopic images showed spread of the contrast media below the C7-T1 junction in all three groups. Ptosis developed in all three groups after the procedure. CONCLUSION: In conclusion, when performing an ultrasound-guided SGB, 2 mL dosage was sufficient for a successful block as the previous, conventional volume. Therefore, when performing an ultrasound-guided SGB, we recommend the 2 mL dosage of local anesthetics for a successful block. PMID- 23013479 TI - Sleep disorders in boys with Duchenne muscular dystrophy. AB - AIM: Determine the frequency and predictors of sleep disorders in boys with Duchenne Muscular Dystrophy (DMD). METHOD: Cross-sectional study by postal questionnaire. Sleep disturbances were assessed using the Sleep Disturbance Scale for Children (validated on 1157 healthy children). A total sleep score and six sleep disturbance factors representing the most common sleep disorders were computed. Potential associations between pathological scores and personal, medical and environmental factors were assessed. RESULTS: Sixteen of 63 boys (25.4%) had a pathological total sleep score compared with 3% in the general population. The most prevalent sleep disorders were disorders of initiating and maintaining sleep (DIMS) 29.7%, sleep-related breathing disorders 15.6% and sleep hyperhydrosis 14.3%. On multivariate analysis, pathological total sleep scores were associated with the need to be moved by a carer (OR = 9.4; 95%CI: 2.2-40.7; p = 0.003) and being the child of a single-parent family (OR =7.2; 95%CI: 1.5 35.1; p = 0.015) and DIMS with the need to be moved by a carer (OR = 18.0; 95%CI: 2.9-110.6; p = 0.002), steroid treatment (OR = 7.7; 95%CI: 1.4-44.0; p = 0.021) and being the child of a single-parent family (OR = 7.0; 95%CI: 1.3-38.4; p = 0.025). CONCLUSION: Sleep disturbances are frequent in boys with DMD and are strongly associated with immobility. Sleep should be systematically assessed in DMD to implement appropriate interventions. PMID- 23013478 TI - Catalytic effects of mutations of distant protein residues in human DNA polymerase beta: theory and experiment. AB - We carried out free-energy calculations and transient kinetic experiments for the insertion of the right (dC) and wrong (dA) nucleotides by wild-type (WT) and six mutant variants of human DNA polymerase beta (Pol beta). Since the mutated residues in the point mutants, I174S, I260Q, M282L, H285D, E288K, and K289M, were not located in the Pol beta catalytic site, we assumed that the WT and its point mutants share the same dianionic phosphorane transition-state structure of the triphosphate moiety of deoxyribonucleotide 5'-triphosphate (dNTP) substrate. On the basis of this assumption, we have formulated a thermodynamic cycle for calculating relative dNTP insertion efficiencies, Omega = (k(pol)/K(D))(mut)/(k(pol)/K(D))(WT) using free-energy perturbation (FEP) and linear interaction energy (LIE) methods. Kinetic studies on five of the mutants have been published previously using different experimental conditions, e.g., primer-template sequences. We have performed a presteady kinetic analysis for the six mutants for comparison with wild-type Pol beta using the same conditions, including the same primer/template DNA sequence proximal to the dNTP insertion site used for X-ray crystallographic studies. This consistent set of kinetic and structural data allowed us to eliminate the DNA sequence from the list of factors that can adversely affect calculated Omega values. The calculations using the FEP free energies scaled by 0.5 yielded 0.9 and 1.1 standard deviations from the experimental log Omega values for the insertion of the right and wrong dNTP, respectively. We examined a hybrid FEP/LIE method in which the FEP van der Waals term for the interaction of the mutated amino acid residue with its surrounding environment was replaced by the corresponding van der Waals term calculated using the LIE method, resulting in improved 0.4 and 1.0 standard deviations from the experimental log Omega values. These scaled FEP and FEP/LIE methods were also used to predict log Omega for R283A and R283L Pol beta mutants. PMID- 23013480 TI - Genistein inhibits cell invasion and motility by inducing cell differentiation in murine osteosarcoma cell line LM8. AB - BACKGROUND: One of the problems associated with osteosarcoma is the frequent formation of micrometastases in the lung prior to diagnosis because the development of metastatic lesions often causes a fatal outcome. Therefore, the prevention of pulmonary metastases during the early stage of tumor development is critical for the improvement of the prognosis of osteosarcoma patients. In Japan, soy is consumed in a wide variety of forms, such as miso soup and soy sauce. The purpose of this study is to investigate the effect of genistein, an isoflavone found in soy, on the invasive and motile potential of osteosarcoma cells. METHODS: LM8 cells were treated for 3 days with various concentrations of genistein. The effect of genistein on cell proliferation was determined by DNA measurement in the cultures and 5-bromo-2'-deoxyuridine (BrdU) incorporation study. The assays of cell invasion and motility were performed using the cell culture inserts with either matrigel-coated membranes or uncoated membranes in the invasion chambers. The expression and secretion of MMP-2 were determined by immunohistochemistry and gelatin zymography. The subcellular localization and cellular level of beta-catenin were determined by immunofluorescence and Western blot. For examining cell morphology, the ethanol-fixed cells were stained with hematoxylin-eosin (H&E). The expression of osteocalcin mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Genistein dose dependently inhibits cell proliferation. Genistein-treated cells were less invasive and less motile than untreated cells. The expression and secretion of MMP-2 were lower in the genistein-treated cultures than in the untreated cultures. beta-Catenin in untreated cells was located in the cytoplasm and/or nucleus, while in genistein-treated cells it was translocated near to the plasma membrane. The level of beta-catenin was higher in genistein-treated cells than in untreated cells. Treatment of LM8 cells with genistein induced morphological changes, markedly decreased the formation of multilayer masses of cells, and markedly increased the expression of osteocalcin mRNA. CONCLUSIONS: Genistein decreased invasive and motile potential by inducing cell differentiation in LM8 cells. Genistein may be useful as an anti-metastatic drug for osteosarcoma through its differentiation-inducing effects. PMID- 23013481 TI - Harvesting experiential expertise to support safe driving for people with diabetes mellitus: a qualitative study evaluated by peers in a survey. AB - BACKGROUND: Hypoglycemia is a frequent phenomenon in people being treated for diabetes mellitus, which can acutely disrupt driving performance. For the benefit of personal and public traffic safety, we decided to identify successful diabetes related (SDR) behaviors to support safe driving for people with diabetes, from the perspective of experiential experts with diabetes mellitus. Experiential experts are people who can manage their own illness and conditions by developing expertise relevant to maintaining health and countering illness, and who are able to use this expertise to the benefit of peers. OBJECTIVE: The aim of our study was to objectify and systematize experiential expertise in terms of SDR behaviors, based on reports by experiential experts, to support safe driving for people with type 1 and type 2 diabetes mellitus. The emphasis was on preventing hypoglycemia as a short-term complication during driving. METHODS: We performed a mixed-methods study involving (i) semi-structured in-depth interviews with 33 experiential experts with diabetes mellitus from the Dutch Diabetes Association (DVN; Diabetesvereniging Nederland), in order to identify SDR behaviors regarding safe driving, and (ii) a validation study by means of a survey among a panel of 98 experiential experts (peers) from the DVN, to determine the extent to which they agreed with the communicability, importance, and feasibility of these behaviors for drivers with diabetes mellitus. RESULTS: We identified a comprehensive set of 11 SDR behaviors, differentiated into seven general and four specific behaviors, to support safe driving. The general behaviors concern the following topics: (i) acquiring knowledge and information; (ii) acquiring and using self-measuring of blood glucose (SMBG) equipment; (iii) knowing one's physical response pattern; (iv) obtaining knowledge about the medication used; (v) preventing long-term eye complications; (vi) influencing factors that can affect blood glucose; and (vii) renewal procedure for driving license. The four specific behaviors refer to the following topics: (i) measures to be taken before driving; (ii) responding effectively to hypoglycemia while driving; (iii) informing and instructing passengers; and (iv) preventing hypoglycemia in drivers with type 2 diabetes mellitus not using SMBG equipment. Key factors for safe driving proved to be the ability of drivers to anticipate and respond effectively to hypoglycemia while driving and to inform and instruct fellow passengers. Participants of the validation survey agreed to a considerable degree with the communicability, importance, and feasibility of these behaviors to support safe driving for people with diabetes mellitus. CONCLUSIONS: This study resulted in the identification and description of SDR behaviors to support safe driving. It proved possible to operationalize experiential expertise in terms of such behaviors. The next step is to have these behaviors validated by professional care providers in the field of diabetes, followed by translation into recommendations in self-management programs. PMID- 23013482 TI - Disparities in melanoma incidence rates in Europe. PMID- 23013484 TI - Modulation of K(v)7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin 7(4H)-one compound QO-58. AB - BACKGROUND AND PURPOSE: Modulation of K(v)7/M channel function represents a relatively new strategy to treat neuronal excitability disorders such as epilepsy and neuropathic pain. We designed and synthesized a novel series of pyrazolo[1,5 a] pyrimidin-7(4H)-one compounds, which activate K(v)7 channels. Here, we characterized the effects of the lead compound, QO-58, on K(v)7 channels and investigated its mechanism of action. EXPERIMENTAL APPROACH: A perforated whole cell patch technique was used to record K(v)7 currents expressed in mammalian cell lines and M-type currents from rat dorsal root ganglion neurons. The effects of QO-58 in a rat model of neuropathic pain, chronic constriction injury (CCI) of the sciatic nerve, were also examined. KEY RESULTS: QO-58 increased the current amplitudes, shifted the voltage-dependent activation curve in a more negative direction and slowed the deactivation of K(v)7.2/K(v)7.3 currents. QO-58 activated K(v)7.1, K(v)7.2, K(v)7.4 and K(v)7.3/K(v)7.5 channels with a more selective effect on K(v)7.2 and K(v)7.4, but little effect on K(v)7.3. The mechanism of QO-58's activation of K(v)7 channels was clearly distinct from that used by retigabine. A chain of amino acids, Val(224)Val(225)Tyr(226), in K(v)7.2 was important for QO-58 activation of this channel. QO-58 enhanced native neuronal M currents, resulting in depression of evoked action potentials. QO-58 also elevated the pain threshold of neuropathic pain in the sciatic nerve CCI model. CONCLUSIONS AND IMPLICATIONS: The results indicate that QO-58 is a potent modulator of K(v)7 channels with a mechanism of action different from those of known K(v)7 openers. Hence, QO-58 shows potential as a treatment for diseases associated with neuronal hyperexcitability. PMID- 23013487 TI - Introducing the medical bioinformatics in Journal of Translational Medicine. PMID- 23013485 TI - Neuron-targeted copolymers with sheddable shielding blocks synthesized using a reducible, RAFT-ATRP double-head agent. AB - Adaptation of in vitro optimized polymeric gene delivery systems for in vivo use remains a significant challenge. Most in vivo applications require particles that are sterically stabilized, which significantly compromises transfection efficiency of materials shown to be effective in vitro. We present a multifunctional well-defined block copolymer that forms particles useful for cell targeting, reversible shielding, endosomal release, and DNA condensation. We show that targeted and stabilized particles retain transfection efficiencies comparable to the nonstabilized formulations. A novel, double-head agent that combines a reversible addition-fragmentation chain transfer agent and an atom transfer radical polymerization initiator through a disulfide linkage is used to synthesize a well-defined cationic block copolymer containing a hydrophilic oligoethyleneglycol and a tetraethylenepentamine-grafted polycation. This material effectively condenses plasmid DNA into salt-stable particles that deshield under intracellular reducing conditions. In vitro transfection studies show that the reversibly shielded polyplexes afford up to 10-fold higher transfection efficiencies than the analogous stably shielded polymer in four different mammalian cell lines. To compensate for reduced cell uptake caused by the hydrophilic particle shell, a neuron-targeting peptide is further conjugated to the terminus of the block copolymer. Transfection of neuron-like, differentiated PC-12 cells demonstrates that combining both targeting and deshielding in stabilized particles yields formulations that are suitable for in vivo delivery without compromising in vitro transfection efficiency and are thus promising carriers for in vivo gene delivery applications. PMID- 23013488 TI - Cobalt in a bis-beta-diketiminate environment. AB - The reaction of Co(2)(mesityl)(4) with acetonitrile leads to the formation of a planar, low spin, bis-beta-diketiminate cobalt(II) complex, (1-mesitylbutane-1,3 diimine)(2)Co (1). EPR spectroscopy, magnetic studies, and DFT calculations reveal the Co(II) ion to reside in a tetragonal ligand field with a (2)B(2)(d(yz))(1) ground state electronic configuration. Oxidation of 1 with ferrocenium hexafluorophosphate furnishes (1-mesitylbutane-1,3 diimine)(2)Co(THF)(2)PF(6) (2). The absence of significant changes in the metal ligand bond metrics of the X-ray crystal structures of 1 and 2 supports ligand participation in the oxidation event. Moreover, no significant changes in C-C or C-N bond lengths are observed by X-ray crystallography upon oxidation of a beta diketiminate ligand, in contrast to typical redox noninnocent ligand platforms. PMID- 23013489 TI - Can exercise ameliorate treatment toxicity during the initial phase of testosterone deprivation in prostate cancer patients? Is this more effective than delayed rehabilitation? AB - BACKGROUND: There has been substantial increase in use of androgen deprivation therapy as adjuvant management of prostate cancer. However, this leads to a range of musculoskeletal toxicities including reduced bone mass and increased skeletal fractures compounded with rapid metabolic alterations, including increased body fat, reduced lean mass, insulin resistance and negative lipoprotein profile, increased incidence of cardiovascular and metabolic morbidity, greater distress and reduced quality of life. Numerous research studies have demonstrated certain exercise prescriptions to be effective at preventing or even reversing these treatment toxicities. However, all interventions to date have been of rehabilitative intent being implemented after a minimum of 3 months since initiation of androgen deprivation, by which time considerable physical and psychological health problems have manifested. The pressing question is whether it is more efficacious to commence exercise therapy at the same time as initiating androgen deprivation, so treatment induced adverse effects can be immediately attenuated or indeed prevented. METHODS/DESIGN: We are proposing a multi-site randomized controlled trial with partial crossover to examine the effects of timing of exercise implementation (immediate or delayed) on preserving long-term skeletal health, reversing short- and long-term metabolic and cardiovascular risk factors, and supporting mental health in men receiving androgen deprivation therapy. 124 men who are about to initiate androgen deprivation for prostate cancer will be randomized to immediate or delayed groups. Immediate will commence a 6-month exercise program within 7-10 days of their first dose. Delayed will receive usual care for 6 months and then commence the exercise program for 6 months (partial cross-over). Immediate will be free to adopt the lifestyle of their choosing following the initial 6-month intervention. Measurements for primary and secondary endpoints will take place at baseline, 6 months and 12 months. DISCUSSION: This project is unique as it explores a fundamental question of when exercise implementation will be of most benefit and addresses both physical and psychological consequences of androgen deprivation initiation. The final outcome may be adjunct treatment which will reduce if not prevent the toxicities of androgen deprivation, ultimately resulting in reduced morbidity and mortality for men with prostate cancer. TRIAL REGISTRATION: ACTRN12612000097842. PMID- 23013491 TI - Accumulation of squalene is associated with the clustering of lipid droplets. AB - The isoprenoid squalene is an important precursor for the biosynthesis of sterols. The cellular storage of squalene and its impact on membrane properties have been the subject of recent investigations. In a screen for abnormal lipid droplet morphology and distribution in the yeast Saccharomyces cerevisiae, we found significant lipid droplet clustering (arbitrarily defined as an aggregation of six or more lipid droplets) in a number of mutants (e.g. erg1) that are defective in sterol biosynthesis. Interestingly, these mutants are also characterized by accumulation of large amounts of squalene. Reducing the level of squalene in these mutants restored normal lipid droplet distribution. Moreover, inhibition of squalene monooxygenase in two mammalian cell lines (CHO-K1 and 3T3 L1) by terbinafine also resulted in lipid droplet clustering. These results indicate that the level of squalene may affect the growth and distribution of lipid droplets. PMID- 23013490 TI - Epidemiology and clinical characteristics of pandemic (H1N1) 2009 influenza infection in pediatric hemato-oncology and hematopoietic stem cell transplantation patients. AB - BACKGROUND: For children with hemato-oncologic diseases, especially after hematopoietic stem cell transplantation (HSCT), the risk for developing complications related to pandemic influenza A (H1N1) 2009 (pH1N1) infection is largely unknown. METHODS: A retrospective chart study was performed of pH1N1 cases diagnosed between October 2009 to January 2010 in the hemato-oncologic unit of the University Children's Hospital of Dusseldorf, Germany. FINDINGS: In total, 21 children were diagnosed with laboratory-confirmed pH1N1; in 16 patients with malignancies (acute leukemia 7, lymphoma 4, solid tumors 2, others 3) and in 5 with benign hematologic disorders. Five patients had undergone prior HSCT, although 1 patient was diagnosed during conditioning therapy with high-dose chemotherapy in preparation for haploidentical HSCT. Most frequent symptoms were fever (>38.5 degrees C) and cough (in 100%), and rhinorrhea (57%). The 2 patients acquiring pH1N1 infection under high-dose or intensive chemotherapy did not require intensive care or mechanical ventilation, and both recovered under antiviral therapy. Oseltamivir was administered to 11 patients; in 1 patient, therapy was switched, on a compassionate-use basis, to intravenous zanamivir because of lack of clinical improvement after oseltamivir therapy. Complications were hospitalization (19%), demand of oxygen supplementation, delay/interruption of antineoplastic therapy, and prolonged administration of antibiotics and antipyretics. CONCLUSION: In the investigated patient population, pH1N1 was mild in most cases, but was associated with substantial morbidity in a proportion of patients and led to interruption and delay in anticancer treatment. PMID- 23013492 TI - Latent constructs of the autobiographical memory questionnaire: a recollection belief model of autobiographical experience. AB - Many researchers employ single-item scales of subjective experiences such as imagery and confidence to assess autobiographical memory. We tested the hypothesis that four latent constructs, recollection, belief, impact, and rehearsal, account for the variance in commonly used scales across four different types of autobiographical memory: earliest childhood memory, cue word memory of personal experience, highly vivid memory, and most stressful memory. Participants rated each memory on scales hypothesised to be indicators of one of four latent constructs. Multi-group confirmatory factor analyses and structural analyses confirmed the similarity of the latent constructs of recollection, belief, impact, and rehearsal, as well as the similarity of the structural relationships among those constructs across memory type. The observed pattern of mean differences between the varieties of autobiographical experiences was consistent with prior research and theory in the study of autobiographical memory. PMID- 23013483 TI - Is dispersal guided by the environment? A comparison of interspecific gene flow estimates among differentiated regions of a newt hybrid zone. AB - How frequently genes pass through a hybrid zone may be influenced by the environment. Accordingly, in long hybrid zones that span more than one environmental setting, different patterns may emerge. The varied conditions allow testing of hypotheses on dispersal as a function of the environment. We reconstruct the amount and direction of gene flow across a heterogeneous hybrid zone of two species of marbled newts (Triturus marmoratus and Triturus pygmaeus), in four widely separated areas of the Iberian Peninsula from one mitochondrial and three nuclear genes. The main variables associated with the position of the contact zone are precipitation, rivers, altitude and relief. In some sections of the contact zone, however, its position is not correlated with any environmental factor and is instead determined by the shortest geographical distance between fixed positions at either side (mountains in the East and river in the West). In areas where the position of the zone is stable, gene flow was bidirectional. External data show that T. pygmaeus has superseded T. marmoratus over a large area and here gene flow was unidirectional. The prediction that a major river would reduce gene flow was not confirmed. PMID- 23013493 TI - Model to investigate energy and greenhouse gas emissions implications of refining petroleum: impacts of crude quality and refinery configuration. AB - A petroleum refinery model, Petroleum Refinery Life-cycle Inventory Model (PRELIM), which quantifies energy use and greenhouse gas (GHG) emissions with the detail and transparency sufficient to inform policy analysis is developed. PRELIM improves on prior models by representing a more comprehensive range of crude oil quality and refinery configuration, using publicly available information, and supported by refinery operating data and experts' input. The potential use of PRELIM is demonstrated through a scenario analysis to explore the implications of processing crudes of different qualities, with a focus on oil sands products, in different refinery configurations. The variability in GHG emissions estimates resulting from all cases considered in the model application shows differences of up to 14 g CO2eq/MJ of crude, or up to 11 g CO2eq/MJ of gasoline and 19 g CO2eq/MJ of diesel (the margin of deviation in the emissions estimates is roughly 10%). This variability is comparable to the magnitude of upstream emissions and therefore has implications for both policy and mitigation of GHG emissions. PMID- 23013495 TI - Where to draw the line? PMID- 23013496 TI - AVMA policy on pregnant sow housing. PMID- 23013497 TI - The role of the colleges of veterinary medicine in realizing the research mission of land-grant institutions to promote animal, human, and environmental health. PMID- 23013498 TI - What is your diagnosis? Metastatic skeletal neoplasia. PMID- 23013499 TI - What is your diagnosis? Myelolipoma. PMID- 23013500 TI - Pathology in practice. Nasal and nasopharyngeal polyps. PMID- 23013501 TI - Employment, starting salaries, and educational indebtedness of year-2012 graduates of US veterinary medical colleges. PMID- 23013502 TI - Use of propofol for induction of anesthesia in dogs undergoing definitive radiation therapy: 31 cases (2006-2009). AB - OBJECTIVE: To evaluate changes in serial hemograms and serum biochemical profiles in tumor-bearing dogs undergoing daily anesthesia with propofol as an induction agent for radiation therapy. DESIGN: Retrospective case series. ANIMALS: 31 dogs with cutaneous or subcutaneous malignancies over the trunk or limbs. PROCEDURES: Radiation therapy consisted of 18 daily treatments administered Monday through Friday over a period of 24 days. Propofol was administered IV to effect for induction of anesthesia. Complete blood count and serum biochemical data were generated at the beginning, middle, and end of radiation therapy and compared to identify changes over time via either a repeated-measures ANOVA or Friedman test. RESULTS: Leukocyte and platelet parameters did not differ significantly over time. Calculated Hct, erythrocyte count, hemoglobin concentration, and mean corpuscular hemoglobin concentration decreased overtime, whereas mean corpuscular volume increased overtime. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs receiving propofol for induction of anesthesia and radiation therapy had a decrease in RBC count, although these changes were not determined to be of clinical importance in this patient population. The cause of these alterations was not immediately apparent. Propofol appeared to be a safe choice for induction of anesthesia in dogs during daily radiation therapy. PMID- 23013503 TI - Minimally invasive treatment of idiopathic chylothorax in dogs by thoracoscopic thoracic duct ligation and subphrenic pericardiectomy: 6 cases (2007-2010). AB - OBJECTIVE: To describe a technique and evaluate the outcome of thoracoscopic thoracic duct ligation (TDL) and subphrenic pericardiectomy (SPP) for treatment of idiopathic chylothorax (IC) in dogs. DESIGN: Retrospective case series. ANIMALS: 6 client-owned dogs. PROCEDURES: Medical records of dogs with a diagnosis of IC that were subsequently treated by thoracoscopic TDL and SPP and that had not undergone previous surgical treatment were reviewed. Thoracoscopic TDL was performed via a 3-portal technique with the patient in lateral recumbency. Subphrenic pericardiectomy was subsequently performed via a 3-portal technique with the patient in dorsal recumbency. If visualization during SPP was suboptimal, 1-lung ventilation was used to ensure that pericardial resection was close to the phrenic nerves bilaterally but without risk of iatrogenic nerve injury. RESULTS: All TDL and SPP procedures were completed successfully in a median surgical time of 177 minutes (range, 135 to 210 minutes). All 6 dogs showed resolution of clinical signs of chylothorax with no recurrence during a median follow-up period of 39 months (range, 19 to 60 months). Final postoperative thoracic radiographic evaluation was performed at a median of 14.5 months (range, 7 to 25 months). Complete resolution of pleural effusion occurred in all but 1 dog. In 1 dog, a small volume of pleural effusion was persistent at a 7-month postoperative radiographic follow-up but was not associated with clinical signs and did not require thoracocentesis at any time during the dog's 25-month follow-up period. CONCLUSIONS AND CLINICAL RELEVANCE: From this limited series of patients, results suggested that a minimally invasive TDL-SPP combined surgical technique for management of IC in dogs may be associated with a similarly successful outcome as has been reported for open surgical TDL-SPP. PMID- 23013504 TI - Aortic thrombosis in dogs: 31 cases (2000-2010). AB - OBJECTIVE: To describe clinical signs, treatment, and outcome of aortic thrombosis in dogs. DESIGN: Retrospective case series. ANIMALS: 31 dogs with aortic thrombosis. PROCEDURES: Records were retrospectively reviewed and data collected regarding signalment, historical signs, physical examination findings, laboratory testing, definitive diagnosis, and presence of concurrent disease. RESULTS: The records of 31 dogs with clinical or postmortem diagnosis of aortic thrombosis were reviewed. Onset of clinical signs was acute in 14 (45%) dogs, chronic in 15 (48%), and not documented in 2 (6%). Femoral pulses were subjectively weak in 6 (19%) dogs and absent in 17 (55%). Frequent laboratory abnormalities included high BUN concentration (n = 13), creatinine concentration (6), creatine kinase activity (10), and D-dimer concentration (10) and proteinuria with a urine protein-to-creatinine concentration ratio > 0.5 (12). Concurrent conditions included neoplasia (n = 6), recent administration of corticosteroids (6), and renal (8) or cardiac (6) disease. Median survival time was significantly longer for dogs with chronic onset of disease (30 days; range, 0 to 959 days) than for those with acute onset of clinical signs (1.5 days; range, 0 to 120 days). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that aortic thrombosis is a rare condition in dogs and accounted for only 0.0005% of hospital admissions during the study period. The clinical signs for dogs with aortic thrombosis differed from those seen in feline patients with aortic thromboembolism. Median survival time was significantly longer for dogs with chronic disease than for dogs with acute disease. Despite treatment, outcomes were typically poor, although protracted periods of survival were achieved in some dogs. PMID- 23013505 TI - Effect of antimicrobial-containing semen extender on risk of dissemination of contagious equine metritis. AB - OBJECTIVE: To determine the impact of antimicrobial-containing semen extender on the growth of Taylorella equigenitalis in semen culture-positive for contagious equine metritis (CEM) and the development of CEM after artificial insemination with CEM-positive semen extended with antimicrobial-containing semen extender. DESIGN: Prospective study. ANIMALS: 21 mature mares free of CEM, 1 mature stallion experimentally infected with CEM, and semen from a stallion naturally infected with CEM. PROCEDURES: CEM-positive semen was incubated in semen extender with and without antimicrobials (amikacin [final concentration, 1 g/L] and penicillin G potassium [0.63 g/L]) followed by determination of the number of colony-forming units of T equigenitalis. Mares were inseminated with raw, extended, or cryopreserved semen culture-positive for T equigenitalis and observed for clinical signs of CEM. Samples for bacterial culture were obtained from the uterus, clitoral sinuses, and clitoral fossa of mares 7, 14, and 21 days after artificial insemination. RESULTS: Antimicrobial-containing semen extender significantly reduced the number of colony-forming units of T equigenitalis in CEM-positive semen. Artificial insemination with raw CEM-positive semen resulted in clinical signs of CEM, whereas artificial insemination with extended or cryopreserved CEM-positive semen did not result in clinical signs of CEM. CONCLUSIONS AND CLINICAL RELEVANCE: Antimicrobial-containing semen extender significantly reduced the risk of dissemination of CEM. The inclusion of amikacin (1 g/L) and penicillin G potassium (0.63 g/L) in extended semen reduced the transmission of CEM from stallions to mares during artificial insemination, which may result in altered dissemination of the disease. PMID- 23013506 TI - Effect of the size of evacuated blood collection tubes on total carbon dioxide concentration in equine plasma. AB - OBJECTIVE: To determine whether plasma total CO(2) concentrations would vary with the size of the evacuated tube used to collect blood samples. DESIGN: Randomized crossover study. ANIMALS: Convenience sample of 20 healthy adult horses. PROCEDURES: Jugular venous blood was collected from horses in random order into 8 types of evacuated tubes: 2-mL glass, 2- or 3-mL plastic or plastic plasma separator, 4- or 6-mL plastic, and 10-mL glass or plastic. Total CO(2) concentrations in plasma were measured with a biochemistry analyzer. Data were analyzed via repeated-measures ANOVA and multivariate regression. RESULTS: The air volume-to-blood volume ratio was significantly higher and consequently, plasma total CO(2) concentration was significantly lower when blood was collected into 2-mL glass tubes and 2- or 3-mL plastic tubes than when the other 5 types of evacuated tubes were used. Concentrations in the other tube types were statistically equivalent. A linear relationship was detected between total CO(2) concentration and air volume-to-blood volume ratio. CONCLUSIONS AND CLINICAL RELEVANCE: Blood samples should be collected into evacuated tubes with a small air volume-to-blood volume ratio whenever an accurate estimate of plasma total CO(2) concentration is required. PMID- 23013507 TI - Survival rates of mares and foals and postoperative complications and fertility of mares after cesarean section: 95 cases (1986-2000). AB - OBJECTIVE: To assess survival-to-discharge rates of mares and foals and postoperative complications and fertility in mares following cesarean section (C section). DESIGN: Retrospective case series. ANIMALS: 95 mares. PROCEDURES: Medical and breeding records of mares that underwent C-section were reviewed; signalment, surgical technique, complications, survival-to-discharge rate, and pregnancy and foaling rates were recorded and evaluated. Foaling rates in the 3 years after C-section were compared with the cumulative foaling rate before C section. RESULTS: C-section was performed because of dystocia (n = 71) or concurrent maternal disease (20) or was elective (4). Overall survival-to discharge rate was 84% (80/95) for mares and 35% (28/80) for foals. Six of 15 mares that had partial fetotomies prior to C-section did not survive. Mares that had dystocia for < 90 minutes had the fewest complications. Cumulative foaling rate before C-section was 77% (394/509). Overall foaling rate for the 3 years after C-section was 52% (30/58) and 68% (13/19) when duration of dystocia was >= 90 minutes and < 90 minutes, respectively, and was 31 % (9/29) for mares >= 16 years old. Foaling rate was significantly lower for mares bred in the same year as C-section than for mares bred in later years. CONCLUSIONS AND CLINICAL RELEVANCE: Breeding in the same year as C-section, dystocia for >= 90 minutes before C-section, and mare age >= 16 years were associated with poor foaling rates. Prognosis for delivery of a live foal in years following C-section was good if duration of dystocia was < 90 minutes and the mare was < 16 years old at the time of surgery. PMID- 23013508 TI - Fatal musculoskeletal injuries of Quarter Horse racehorses: 314 cases (1990 2007). AB - OBJECTIVE: To determine major causes of death and the anatomic location of musculoskeletal injuries in Quarter Horse racehorses in California. DESIGN: Retrospective case series. ANIMALS: 314 Quarter Horse racehorses with musculoskeletal injuries that were necropsied through the California Horse Racing Board Postmortem Program from 1990 to 2007. PROCEDURES: Postmortem pathology reports were retrospectively reviewed. Musculoskeletal injuries were categorized by anatomic region and described. The number of Quarter Horse starts and starters for the same period of time were obtained from a commercial database for determination of fatal injury incidence. RESULTS: Musculoskeletal injuries accounted for 314 of the 443 (71 %) Quarter Horse racehorses that died during the 18-year study period. Fatal musculoskeletal injuries occurred at a rate of 2.0 deaths/1,000 race starts and 18.6 deaths/1,000 horses that started a race. Musculoskeletal injuries occurred predominantly during racing (84%) and in the forelimbs (81%). The most common fatal musculoskeletal injuries were metacarpophalangeal and metatarsophalangeal joint (fetlock) support injuries (40%) and carpal (24%), vertebral (10%), and scapular (8%) fractures. Proximal interphalangeal (pastern) joint luxations resulted in death of 3% of horses. Fracture configurations of some bones were consistent with those of Thoroughbred racehorses. Evidence of preexisting stress remodeling of bone was reported for some fractures. CONCLUSIONS AND CLINICAL RELEVANCE: Knowledge of common locations and types of fatal musculoskeletal injuries in racing Quarter Horses may enhance practitioners' ability to detect mild injuries early, rest horses, and help prevent catastrophic injuries. PMID- 23013509 TI - Evaluation of circulating eosinophil count and adrenal gland function in California sea lions naturally exposed to domoic acid. AB - OBJECTIVE: To determine the effect of natural exposure to domoic acid (DA) on eosinophil counts and adrenal gland function in California sea lions (Zalophus californianus). DESIGN: Cross-sectional prospective study. ANIMALS: 39 California sea lions. PROCEDURES: Adult female sea lions admitted to a rehabilitation hospital during 2009 were classified into 1 of 3 groups (acute DA toxicosis, chronic DA toxicosis, or no DA exposure) on the basis of clinical signs, DA concentration in urine or feces, and hippocampal morphology. Endoparasite burden, eosinophil count, and serum cortisol and plasma ACTH concentrations were determined for each sea lion. For a subset of 8 sea lions, fecal glucocorticoid concentration after IM administration of cosyntropin was determined. RESULTS: Sea lions exposed to DA (acute DA toxicosis, n = 11; chronic DA toxicosis, 19) had higher eosinophil counts and lower serum cortisol concentrations, compared with values for sea lions with no DA exposure (9). Eosinophil count was not associated with endoparasite burden. Serum cortisol concentration was associated with plasma ACTH concentrations in sea lions from the no DA exposure group but not in sea lions in the acute or chronic DA toxicosis groups. Following cosyntropin injection, fecal glucocorticoid concentrations increased in all sea lions evaluated except 1. CONCLUSIONS AND CLINICAL RELEVANCE: In adult sea lions, eosinophilia may be a cost-effective biomarker for DA exposure and may reflect alterations in hypothalamic, pituitary gland, or adrenal gland function. Domoic acid exposure may have subtle health effects on marine animals in addition to induction of neurologic signs. PMID- 23013510 TI - Two-dimensional gel electrophoresis analysis of mycelial cells treated with Tween 80: differentially expressed protein related to enhanced metabolite production. AB - Two-dimensional gel electrophoresis identified 40 differentially expressed proteins which explained the mechanisms underlying the stimulatory effect of Tween 80 for exopolysaccharide production in the mycelium of an edible mushroom Pleurotus tuber-regium. The up-regulation of fatty acid synthase alpha subunit FasA might promote the synthesis of long-chain fatty acids and their incorporation into the mycelial cell membranes, increasing the membrane permeability. A down-regulation of Phospholipase D1 and an up-regulation of Hypothetical protein PGUG_02954 might mediate signal transduction between the mycelial cells and the extracellular stimulus (Tween 80). The down-regulated ATP binding cassette transporter protein might function as pumps to extrude exopolysaccharide out of the cells that lead to a significant increase in its production. The present results explained how stimulatory agents like Tween 80 can increase mycelial cell membrane permeability to enhance the production of useful extracellular metabolites by submerged fermentation. PMID- 23013511 TI - Control of amyloid assembly by autoregulation. AB - The assembly of proteins into amyloid fibrils can be an element of both protein aggregation diseases and a functional unit in healthy biological pathways. In both cases, it must be kept under tight control to prevent undesired aggregation. In normophysiology, proteins can self-chaperone amyloidogenic segments by restricting their conformational flexibility in an overall stabilizing protein fold. However, some aggregation-prone segments cannot be controlled in this manner and require additional regulatory elements to limit fibrillation. The present review summarizes different molecular mechanisms that proteins use to control their own assembly into fibrils, such as the inclusion of a chaperoning domain or a blocking segment in the proform, the controlled release of an amyloidogenic region from the folded protein, or the adjustment of fibrillation propensity according to pH. Autoregulatory elements can control disease-related as well as functional fibrillar protein assemblies and distinguish a group of self-regulating amyloids across a wide range of biological functions and organisms. PMID- 23013512 TI - Controlled trial of morphine vs hydromorphone for patient-controlled analgesia in children with postoperative pain. PMID- 23013513 TI - Effects of simvastatin and ezetimibe on interleukin-6 and high-sensitivity C reactive protein. AB - OBJECTIVES: Statins decrease cardiovascular events mainly by lowering cholesterol but anti-inflammatory effects also play a role. The effects of the cholesterol absorption inhibitor ezetimibe on markers of inflammation remain unclear. We performed an exploratory post-hoc analysis whether these drugs influence the pro inflammatory markers interleukin-6 and high-sensitivity C-reactive protein in subjects with very-low cardiovascular risk. DESIGN: Single center, randomized, parallel 3-group study in 72 healthy men without apparent cardiovascular disease (age 32 +/- 9 years, BMI 25.7 +/- 3.2 kg/m(2)). Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. RESULTS: Baseline IL-6 and hsCRP concentrations in the total cohort were 0.72 +/- 0.57 ng/l and 0.40 +/- 0.65 mg/l, respectively, with no differences between the 3 groups. Median changes (interquartile range) in IL-6 and hsCRP concentrations were -22% (-43 to 0%) and -30% (-44 to +19%) after simvastatin, -5% (-36 to +30%) and +9% (-22 to +107%) after ezetimibe, and +15% ( 15 to +86%) and +1 (-30 to +49%) after the combination. Using a generalized linear model, the multivariable adjusted overall P-values for these changes were 0.008 (IL-6) and 0.1 (hsCRP). CONCLUSIONS: Simvastatin decreases the pro inflammatory markers IL-6 and almost significantly hsCRP while ezetimibe monotherapy or the combination with simvastatin has no effect. PMID- 23013514 TI - Treatment of prurigo nodularis with pregabalin. AB - WHAT IS KNOWN AND OBJECTIVE: Prurigo nodularis (PN) is a chronic skin condition that is difficult to treat. Pregabalin is one of the possible treatments for PN but its safety and efficacy are not well defined. We aimed to assess the efficacy of pregabalin in patients with PN. METHODS: Thirty patients (10 men, 20 women; mean age 51.6 +/- 9.39 years) were treated with pregabalin (75 mg/day) for 3 months. Efficacy was classified as (i) successful (disappearance of the pruritus and reduction of nodules); (ii) slight improvement/reduction of the nodules, that is, number and/or flattening, no disappearance of itching; or (iii) unsuccessful. RESULTS: Twenty-three patients (76%) responded successfully after 3 months of treatment. There was a statistically significant difference between visual analogue scale scores before and after 1 month treatment period (8.15 +/- 2.04 and 1.5 +/- 1.12, respectively; P < 0.0001). Pregabalin was generally well tolerated with only six (20%) patients reporting side effects. No patient showed any renal insufficiency. WHAT IS NEW AND CONCLUSION: In our study, pregabalin was effective for the treatment of PN. However, given the open and non-controlled study design used, a properly powered randomized controlled validation study is called for. PMID- 23013515 TI - Introducing the cardiovascular, metabolic and lipoprotein translation section of Journal of Translational Medicine. PMID- 23013516 TI - Is the C-terminal insertional signal in Gram-negative bacterial outer membrane proteins species-specific or not? AB - BACKGROUND: In Gram-negative bacteria, the outer membrane is composed of an asymmetric lipid bilayer of phopspholipids and lipopolysaccharides, and the transmembrane proteins that reside in this membrane are almost exclusively beta barrel proteins. These proteins are inserted into the membrane by a highly conserved and essential machinery, the BAM complex. It recognizes its substrates, unfolded outer membrane proteins (OMPs), through a C-terminal motif that has been speculated to be species-specific, based on theoretical and experimental results from only two species, Escherichia coli and Neisseria meningitidis, where it was shown on the basis of individual sequences and motifs that OMPs from the one cannot easily be over expressed in the other, unless the C-terminal motif was adapted. In order to determine whether this species specificity is a general phenomenon, we undertook a large-scale bioinformatics study on all predicted OMPs from 437 fully sequenced proteobacterial strains. RESULTS: We were able to verify the incompatibility reported between Escherichia coli and Neisseria meningitidis, using clustering techniques based on the pairwise Hellinger distance between sequence spaces for the C-terminal motifs of individual organisms. We noticed that the amino acid position reported to be responsible for this incompatibility between Escherichia coli and Neisseria meningitidis does not play a major role for determining species specificity of OMP recognition by the BAM complex. Instead, we found that the signal is more diffuse, and that for most organism pairs, the difference between the signals is hard to detect. Notable exceptions are the Neisseriales, and Helicobacter spp. For both of these organism groups, we describe the specific sequence requirements that are at the basis of the observed difference. CONCLUSIONS: Based on the finding that the differences between the recognition motifs of almost all organisms are small, we assume that heterologous overexpression of almost all OMPs should be feasible in E. coli and other Gram negative bacterial model organisms. This is relevant especially for biotechnology applications, where recombinant OMPs are used e.g. for the development of vaccines. For the species in which the motif is significantly different, we identify the residues mainly responsible for this difference that can now be changed in heterologous expression experiments to yield functional proteins. PMID- 23013518 TI - Our long-term results of Tenckhoff peritoneal dialysis catheters placement via laparoscopic preperitoneal tunneling technique. AB - Previously we described the technique to lessen complications of continuous ambulatory peritoneal dialysis (CAPD) and to achieve immediate use of the catheter. In this study we evaluated our long-term results of the technique. A total of 61 procedures were carried out in 58 patients from September 2003 to February 2009. All patients were followed in our hospital CAPD clinic. Demographic, medical, operative, postoperative, and other information regarding complications and continued patient management was obtained retrospectively from the patients' medical records and entered into a computerized database. There were 33 men and 25 women. The mean age was 58 years. In 29 of the 58 patients indication of catheter placement was end stage renal failure combined with diabetes mellitus. Mean follow-up time was 33.31 +/- 20.11 months. Catheter related complications were outflow obstruction (n=3, 5.2%) and peritonitis (n=2, 3.4%). Etiologies of catheter removal were out flow obstruction (n=2), recovery from renal disease (n=2), peritonitis (n=1), and pregnancy (n=1). The mean catheter survival time was found 5.57 +/- 0.17 years. Our long-term results showed that the method ensured accurate placement, preperitoneal fixation, and immediate use of the catheter for routine peritoneal dialysis. Preperitoneal fixation of the catheter decreased outflow obstruction over long-term follow-up. PMID- 23013519 TI - The rocky road to the top: why talent needs trauma. AB - The increasingly well funded and high-tech world of talent development (TD) represents an important investment for most sports. Reflecting traditional concepts of challenge and focus, the vast majority of such systems expend a great deal of effort maximizing support to the young athletes and trying to counter the impact of naturally occurring life stressors. In this article, we suggest that much of this effort is misdirected; that, in fact, talented potential can often benefit from, or even need, a variety of challenges to facilitate eventual adult performance. Our argument is built on evidence that such challenges are more common in athletes who reach the top, together with a critical consideration of the modus operandi and impact of psychological/character-focused interventions such as mental toughness and resilience. In conclusion, we explore some implications for the design and conduct of optimum academies and TD environments. PMID- 23013521 TI - Implications of stoichiometry-controlled structural changeover between heteroleptic trigonal [Cu(phenAr2)(py)]+ and tetragonal [Cu(phenAr2)(py)2]+ motifs for solution and solid-state supramolecular self-assembly. AB - A stoichiometric variant of the HETPYP concept (HETeroleptic PYridine and Phenanthroline metal complexes) opens the venue to heteroleptic metallosupramolecular HETPYP-I assemblies both in solution and the solid state, involving the trigonal [Cu(phenAr(2))(py)](+) coordination motif (phenAr(2) = 2,9 diarylphenanthroline; py = various oligopyridines). Combining the same building blocks at another stoichiometric ratio furnished metallosupramolecular HETPYP-II aggregates in the solid state, now based on the tetrahedral [Cu(phenAr(2))(py)(2)](+) coordination motif. Thus, a stoichiometry-controlled structural changeover based on the relative amounts of oligopyridines leads from a discrete assembly with trigonally coordinated copper(I) centers to a coordination polymer with tetrahedrally coordinated copper(I) ions, as shown by solid state studies. In solution, the analysis of both stoichiometric variants indicates that the HETPYP-I structure is congruent with that in the solid state, while the HETPYP-II assembly, as established through DOSY NMR and dynamic light scattering measurements, is only oligomeric at low temperature. At room temperature, i.e. due to entropic costs, the latter assembly prefers to keep "unsaturated" coordination sites that are in rapid exchange, making it an interesting system as a dynamic protecting group and for constitutional dynamic materials through the exchange and reshuffling of components. PMID- 23013520 TI - The use of nonsteroidal anti-inflammatory drugs for exercise-induced muscle damage: implications for skeletal muscle development. AB - Exercise-induced muscle damage (EIMD) is a common condition resulting from a bout of vigorous exercise, particularly if the individual is unaccustomed to performance of the given movement. Symptoms of EIMD include delayed-onset muscle soreness (DOMS) and a loss of physical function. Nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely prescribed post-exercise to alleviate these symptoms and restore normal physical function. Of potential concern for those who use NSAIDs to treat EIMD is the possibility that they may impair the adaptive response to exercise. Specifically, there is emerging evidence that the action of cyclo-oxygenase (COX) enzymes, and COX-2 in particular, are important and even necessary to achieve maximal skeletal muscle hypertrophy in response to functional overload. Given that NSAIDs exert their actions by blocking COX and thus suppressing prostaglandin production, a theoretical rationale exists whereby these drugs may have detrimental effects on muscle regeneration and supercompensation. Therefore, the purpose of this article is to extensively review the literature and evaluate the effects of NSAIDs on muscle growth and development. Based on current evidence, there is little reason to believe that the occasional use of NSAIDs will negatively affect muscle growth, although the efficacy for their use in alleviating inflammatory symptoms remains questionable. Evidence on the hypertrophic effects of the chronic use of NSAIDs is less clear. In those who are untrained, it does not appear that regular NSAID use will impede growth in the short term, and at least one study indicates that it may in fact have a positive impact. Given their reported impairment of satellite cell activity, however, longer-term NSAID use may well be detrimental, particularly in those who possess greater growth potential. PMID- 23013522 TI - Asexual reproduction in introduced and native populations of the ant Cerapachys biroi. AB - Asexual reproduction is particularly common among introduced species, probably because it helps to overcome the negative effects associated with low population densities during colonization. The ant Cerapachys biroi has been introduced to tropical and subtropical islands around the world since the beginning of the last century. In this species, workers can reproduce via thelytokous parthenogenesis. Here, we use genetic markers to reconstruct the history of anthropogenic introductions of C. biroi, and to address the prevalence of female parthenogenesis in introduced and native populations. We show that at least four genetically distinct lineages have been introduced from continental Asia and have led to the species' circumtropical establishment. Our analyses demonstrate that asexual reproduction dominates in the introduced range and is also common in the native range. Given that C. biroi is the only dorylomorph ant that has successfully become established outside of its native range, this unusual mode of reproduction probably facilitated the species' worldwide spread. On the other hand, the rare occurrence of haploid males and at least one clear case of sexual recombination in the introduced range show that C. biroi has not lost the potential for sex. Finally, we show that thelytoky in C. biroi probably has a genetic rather than an infectious origin, and that automixis with central fusion is the most likely underlying cytological mechanism. This is in accordance with what is known for other thelytokous eusocial Hymenoptera. PMID- 23013523 TI - Effects of parental depressive symptoms on child adjustment moderated by hypothalamic pituitary adrenal activity: within- and between-family risk. AB - Child hypothalamic pituitary adrenal (HPA) activity was investigated as a moderator of parental depressive symptom effects on child behavior in an adoption sample (n = 210 families). Adoptive parents' depressive symptoms and child internalizing and externalizing were assessed at 18, 27, and 54 months, and child morning and evening HPA activity measured through salivary cortisol at 54 months. Children's daily cortisol levels and day-to-day variability were tested as moderators of longitudinal associations between parent and child symptoms at within- and between-family levels. Mothers' symptoms related directly to child internalizing, but child evening cortisol moderated effects of fathers' symptoms on internalizing, and of both parents' symptoms on externalizing. Different paths of within-family risk dynamics versus between-family risk synergy were found for internalizing versus externalizing outcomes. PMID- 23013525 TI - Is Mohs micrographic surgery more effective than wide local excision for treatment of dermatofibrosarcoma protuberans in reducing risk of local recurrence? Reply from authors. PMID- 23013524 TI - Guiding the design of synthetic DNA-binding molecules with massively parallel sequencing. AB - Genomic applications of DNA-binding molecules require an unbiased knowledge of their high affinity sites. We report the high-throughput analysis of pyrrole imidazole polyamide DNA-binding specificity in a 10(12)-member DNA sequence library using affinity purification coupled with massively parallel sequencing. We find that even within this broad context, the canonical pairing rules are remarkably predictive of polyamide DNA-binding specificity. However, this approach also allows identification of unanticipated high affinity DNA-binding sites in the reverse orientation for polyamides containing beta/Im pairs. These insights allow the redesign of hairpin polyamides with different turn units capable of distinguishing 5'-WCGCGW-3' from 5'-WGCGCW-3'. Overall, this study displays the power of high-throughput methods to aid the optimal targeting of sequence-specific minor groove binding molecules, an essential underpinning for biological and nanotechnological applications. PMID- 23013527 TI - Functional predictions from inference and observation in sequence-based inflammatory bowel disease research. AB - Meta-omics approaches such as metagenomics, metatranscriptomics and metaproteogenomics have the potential to improve our understanding of how the human microbiome affects digestive health and disease. PMID- 23013526 TI - Antioxidant vitamins C, E and coenzyme Q10 vs dexamethasone: comparisons of their effects in pulmonary contusion model. AB - BACKGROUND: The goal of our study is to evaluate the effects of antioxidant vitamins (vitamin C and E), Coenzyme Q10 (CoQ10) and dexamethasone (Dxm) in experimental rat models with pulmonary contusion (PC). METHODS: Rats were randomly divided into six groups. Except for the control, all subgroups had a moderate pulmonary contusion. Animals in the group I and group II received intraperitoneal saline, group III received 10mg.kg-1 CoQ10 group IV received 100mg.kg-1 vitamin C, group V received 150 mg.kg-1 vitamin E, and group VI received 10mg.kg-1 Dxm. Blood gas analysis, serum nitric oxide (NO) and malondialdehyde (MDA) levels as well as superoxide dismutase (SOD) activity assays, bronchoalveolar lavage (BAL) fluid and histopathological examination were performed. RESULTS: Administration of CoQ10 resulted in a significant increase in PaO2 values compared with the group I (p = 0.004). Levels of plasma MDA in group II were significantly higher than those in the group I (p = 0.01). Early administration of vitamin C, CoQ10, and Dxm significantly decreased the levels of MDA (p = 0.01). Lung contusion due to blunt trauma significantly decreased SOD activities in rat lung tissue compared with group I (p = 0.01). SOD levels were significantly elevated in animals treated with CoQ10, Vitamin E, or Dxm compared with group II (p = 0.01). CONCLUSIONS: In our study, CoQ10, vitamin C, vitamin E and Dxm had a protective effect on the biochemical and histopathological outcome of PC after experimental blunt thorax trauma. PMID- 23013528 TI - Dysregulation of the type I interferon system in adult-onset clinically amyopathic dermatomyositis has a potential contribution to the development of interstitial lung disease. AB - BACKGROUND: It has been speculated that viral infection might be one of the potential aetiologies for adult-onset clinically amyopathic dermatomyositis (CADM). The molecular pathogenesis remains largely unknown. OBJECTIVES: To explore whether dysregulation of the type I interferon (IFN) system is involved in the pathogenesis of CADM. METHODS: We studied 16 patients with CADM and compared them with healthy control subjects (n = 20) and patients with classic dermatomyositis (DM, n = 16) and polymyositis (PM, n = 16). Expressions of mRNA for serial toll-like receptor genes (TLR2, TLR3, TLR4, TLR7, TLR8 and TLR9) and type I IFN-regulated genes (IRF7, ISG15 and MxA) in peripheral blood leucocytes (PBL) were detected by real-time polymerase chain reaction analysis. The level of IFN-alpha in blood was tested by enzyme-linked immunosorbent assay. RESULTS: The mRNA expressions of TLR7, TLR9 and IRF7 were greatly elevated in the PBL from patients with CADM compared with controls. Upregulation of the ISG15 and MxA genes was detected in the PBL from patients with CADM, as well as from patients with classic DM. Among the four study groups, the overproduction of IFN-alpha in blood was most significant in the CADM group. Especially, IFN-alpha level was obviously high in the clinical interstitial lung disease (ILD) subgroup of patients with CADM. Positive correlations were found between IFN-alpha concentration and other unfavourable prognostic factors of CADM-associated ILD. CONCLUSIONS: Our data suggest that the dysregulation of the type I IFN system may be implicated in CADM pathogenesis. IFN-alpha may be a useful biomarker for assessing the disease severity of CADM-associated ILD. PMID- 23013529 TI - Extra-pancreatic manifestations of IgG4-related systemic disease: a single-centre experience of treatment with combined immunosuppression. AB - BACKGROUND/AIM: IgG4-related systemic disease (IgG4-RSD) is a systemic inflammatory disease distinguished by tissue infiltrates of IgG4(+) plasma cells and elevated serum IgG4 levels. While IgG4-RSD often involves the pancreas, extra pancreatic organs are also frequently affected. Here, we review the presentation and management of patients with extra-pancreatic IgG4-RSD. METHODS: A retrospective analysis was performed on patients diagnosed with extra-pancreatic IgG4-RSD identified from a single centre. RESULTS: Six patients with extra pancreatic IgG4-RSD were identified. The median age of the patients was 64 years. The range of involved organs included lymph nodes (three patients), ocular adnexa, lung, kidneys, meninges and exocrine glands. The median delay in diagnosis was 13.5 months (4-60 months). Four patients had elevated serum IgG4 levels at diagnosis. Five symptomatic patients were commenced on combination immunosuppression, which included corticosteroids. Maintenance therapy with azathioprine was used in one patient, methotrexate and mycophenolate were each used in two patients, and cyclophosphamide in one patient. Four treated patients went into remission, while two patients had persistent radiological disease. One patient experienced two relapses. CONCLUSION: IgG4-RSD can manifest in a variety of organs. Lack of awareness regarding this entity may delay diagnosis. Combination treatment of corticosteroids and conventional immunosuppression is effective. PMID- 23013531 TI - Influence of methylsulfonylmethane on markers of exercise recovery and performance in healthy men: a pilot study. AB - BACKGROUND: Methylsulfonylmethane (MSM) has been reported to provide anti inflammatory and antioxidant effects in both animal and man. Strenuous resistance exercise has the potential to induce both inflammation and oxidative stress. Using a pilot (proof of concept) study design, we determined the influence of MSM on markers of exercise recovery and performance in healthy men. METHODS: Eight, healthy men (27.1 +/- 6.9 yrs old) who were considered to be moderately exercise trained (exercising <150 minutes per week) were randomly assigned to ingest MSM at either 1.5 grams per day or 3.0 grams per day for 30 days (28 days before and 2 days following exercise). Before and after the 28 day intervention period, subjects performed 18 sets of knee extension exercise in an attempt to induce muscle damage (and to be used partly as a measure of exercise performance). Sets 1-15 were performed at a predetermined weight for 10 repetitions each, while sets 16-18 were performed to muscular failure. Muscle soreness (using a 5-point Likert scale), fatigue (using the fatigue-inertia subset of the Profile of Mood States), blood antioxidant status (glutathione and Trolox Equivalent Antioxidant Capacity [TEAC]), and blood homocysteine were measured before and after exercise, pre and post intervention. Exercise performance (total work performed during sets 16-18 of knee extension testing) was also measured pre and post intervention. RESULTS: Muscle soreness increased following exercise and a trend was noted for a reduction in muscle soreness with 3.0 grams versus 1.5 grams of MSM (p = 0.080), with a 1.0 point difference between dosages. Fatigue was slightly reduced with MSM (p = 0.073 with 3.0 grams; p = 0.087 for both dosages combined). TEAC increased significantly following exercise with 3.0 grams of MSM (p = 0.035), while homocysteine decreased following exercise for both dosages combined (p = 0.007). No significant effects were noted for glutathione or total work performed during knee extension testing (p > 0.05). CONCLUSION: MSM, especially when provided at 3.0 grams per day, may favorably influence selected markers of exercise recovery. More work is needed to extend these findings, in particular using a larger sample of subjects and the inclusion of additional markers of exercise recovery and performance. PMID- 23013530 TI - Interactions of the CpxA sensor kinase and cognate CpxR response regulator from Yersinia pseudotuberculosis. AB - BACKGROUND: The CpxA sensor kinase-CpxR response regulator two-component regulatory system is a sentinel of bacterial envelope integrity. Integrating diverse signals, it can alter the expression of a wide array of components that serve to shield the envelope from damage and to promote bacterial survival. In bacterial pathogens such as Yersinia pseudotuberculosis, this also extends to pathogenesis. CpxR is thought to dimerize upon phosphorylation by the sensor kinase CpxA. This phosphorylation enables CpxR binding to specific DNA sequences where it acts on gene transcription. As Cpx pathway activation is dependent on protein-protein interactions, we performed an interaction analysis of CpxR and CpxA from Y. pseudotuberculosis. RESULTS: CpxR full-length and truncated versions that either contained or lacked a putative internal linker were all assessed for their ability to homodimerize and interact with CpxA. Using an adenylate cyclase based bacterial two hybrid approach, full-length CpxR readily engaged with CpxA. The CpxR N-terminus could also homodimerize with itself and with a full-length CpxR. A second homodimerization assay based upon the lambdacI repressor also demonstrated that the CpxR C-terminus could homodimerize. While the linker was not specifically required, it enhanced CpxR homodimerization. Mutagenesis of cpxR identified the aspartate at residue 51, putative N-terminal coiled-coil and C terminal winged-helix-turn-helix domains as mediators of CpxR homodimerization. Scrutiny of CpxA full-length and truncated versions revealed that dimerization involved the N-terminus and an internal dimerization and histidine phosphotransfer domain. CONCLUSIONS: This interaction analysis mapped regions of CpxR and CpxA that were responsible for interactions with self or with each other. When combined with other physiological and biochemical tests both hybrid based assays can be useful in dissecting molecular contacts that may underpin Cpx pathway activation and repression. PMID- 23013532 TI - Pharmacogenetics and personalized medicine. PMID- 23013533 TI - Synthesis of aminocyanopyrazoles via a multi-component reaction and anti-carbonic anhydrase inhibitory activity of their sulfamide derivatives against cytosolic and transmembrane isoforms. AB - A convenient protocol for the multicomponent reaction (MCRs) between malononitrile with an orthoester and hydrazine derivatives, under acid catalyst is described. A series of aminocyanopyrazoles 4 was prepared, isolated and characterized. These pyrazoles reacted with sodium nitrite followed by secondary amine reagent and with formic acid to lead pyrazolotriazines 6 and pyrazolopyrimidinones 7. Some of the aminopyrazoles were converted to the corresponding sulfamides by reaction with sulfamoyl chloride. The aminopyrazoles incorporating phenyl and tosyl moieties were tested as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII. Many of them showed low micromolar or submicromolar inhibition of these enzymes. The corresponding sulfamides were low nanomolar CA inhibitors. PMID- 23013534 TI - Oxamflatin improves developmental competence of porcine somatic cell nuclear transfer embryos. AB - Abstract Aberrant epigenetic nuclear reprogramming of somatic nuclei is a major cause of low success in cloning. It has been demonstrated that treatment of histone deacetylase inhibitors (HDACi) enhances developmental potential of somatic cell nuclear transfer (SCNT) embryos by alteration of epigenetic status. The aim of the present study was to investigate the effect of oxamflatin, a novel HDACi, on the developmental competence of porcine SCNT embryos. Treatment with 1 MUM oxamflatin for 9 h after activation of SCNT embryos increased both in vitro and in vivo developmental competence. Treatment of SCNT embryos with 1 MUM oxamflatin significantly increased blastocyst rate and total cell number in blastocysts (33.3+/-6.0 and 73.1+/-1.6, respectively) than that of controls (10.3+/-3.7 and 54.1+/-3.5, respectively) or scriptaid (16.4+/-4.6 and 64.4+/ 2.1, respectively). Moreover, oxamflatin showed significant higher overall cloning efficiency from 0.9% to 3.2%, whereas scriptaid demonstrated 0% to 1.8%. In conclusion, these results indicate that oxamflatin treatment improves the developmental competence of porcine SCNT embryos. PMID- 23013536 TI - Platelet activation, function, and reactivity in atherosclerotic carotid artery stenosis: a systematic review of the literature. AB - An important proportion of transient ischemic attack or ischemic stroke is attributable to moderate or severe (50-99%) atherosclerotic carotid stenosis or occlusion. Platelet biomarkers have the potential to improve our understanding of the pathogenesis of vascular events in this patient population. A detailed systematic review was performed to collate all available data on ex vivo platelet activation and platelet function/reactivity in patients with carotid stenosis. Two hundred thirteen potentially relevant articles were initially identified; 26 manuscripts met criteria for inclusion in this systematic review. There was no consistent evidence of clinically informative data from urinary or soluble blood markers of platelet activation in patients with symptomatic moderate or severe carotid stenosis who might be considered suitable for carotid intervention. Data from flow cytometry studies revealed evidence of excessive platelet activation in patients in the early, sub-acute, or late phases after transient ischemic attack or stroke in association with moderate or severe carotid stenosis and in asymptomatic moderate or severe carotid stenosis compared with controls. Furthermore, pilot data suggest that platelet activation may be increased in recently symptomatic than in asymptomatic severe carotid stenosis. Excessive platelet activation and platelet hyperreactivity may play a role in the pathogenesis of first or subsequent transient ischemic attack or stroke in patients with moderate or severe carotid stenosis. Larger longitudinal studies assessing platelet activation status with flow cytometry and platelet function/reactivity in symptomatic vs. asymptomatic carotid stenosis are warranted to improve our understanding of the mechanisms responsible for transient ischemic attack or stroke. PMID- 23013535 TI - Genetic polymorphisms in CYP1A1, GSTM1, GSTP1 and GSTT1 metabolic genes and risk of lung cancer in Asturias. AB - BACKGROUND: Metabolic genes have been associated with the function of metabolizing and detoxifying environmental carcinogens. Polymorphisms present in these genes could lead to changes in their metabolizing and detoxifying ability and thus may contribute to individual susceptibility to different types of cancer. We investigated if the individual and/or combined modifying effects of the CYP1A1 MspI T6235C, GSTM1 present/null, GSTT1 present/null and GSTP1 Ile105Val polymorphisms are related to the risk of developing lung cancer in relation to tobacco consumption and occupation in Asturias, Northern Spain. METHODS: A hospital-based case-control study (CAPUA Study) was designed including 789 lung cancer patients and 789 control subjects matched in ethnicity, age, sex, and hospital. Genotypes were determined by PCR or PCR-RFLP. Individual and combination effects were analysed using an unconditional logistic regression adjusting for age, pack-years, family history of any cancer and occupation. RESULTS: No statistically significant main effects were observed for the carcinogen metabolism genes in relation to lung cancer risk. In addition, the analysis did not reveal any significant gene-gene, gene-tobacco smoking or gene occupational exposure interactions relative to lung cancer susceptibility. Lastly, no significant gene-gene combination effects were observed. CONCLUSIONS: These results suggest that genetic polymorphisms in the CYP1A1, GSTM1, GSTT1 and GSTP1 metabolic genes were not significantly associated with lung cancer risk in the current study. The results of the analysis of gene-gene interactions of CYP1A1 MspI T6235C, GSTM1 present/null, GSTT1 present/null and GSTP1 Ile105Val polymorphisms in lung cancer risk indicate that these genes do not interact in lung cancer development. PMID- 23013538 TI - Physical activity, fitness and the metabolic syndrome in rural youths from Mozambique. AB - BACKGROUND: Except for North America and Europe, few studies have reported the association among physical activity (PA), cardiorespiratory fitness (CRF) and metabolic syndrome (MetS) in youths, especially for rural African youth. AIM: The aims of this study were to determine the prevalence of PA levels, CRF, MetS and its indicators, and examine the association between these variables in a school aged sample of youth from rural Mozambique. SUBJECTS AND METHODS: The sample included 209 children and adolescents aged 7-15 years old from Calanga, a rural community in Mozambique. PA was estimated with a culturally-specific questionnaire. CRF was determined by 1-mile run test. Indicators of the MetS included fasting glucose, triglycerides, total cholesterol, blood pressure and body mass index. A continuous metabolic risk score was computed. RESULTS: Results showed high levels of PA and CRF and a low prevalence of MetS ( < 2%) among children and adolescents from Calanga. However, there was a moderately high prevalence of elevated blood pressure (81.8%) and triglycerides (18.7%), respectively. There were no significant associations between PA, CRF and MetS. CONCLUSION: Youths from Calanga are physically active and possess high CRF and their lifestyle may be a protective effect against MetS. PMID- 23013537 TI - Nitric oxide-releasing dendrimers as antibacterial agents. AB - The antibacterial activity of a series of nitric oxide (NO)-releasing poly(propylene imine) (PPI) dendrimers was evaluated against both Gram-positive and Gram-negative pathogenic bacteria, including methicillin-resistant Staphylococcus aureus . A direct comparison of the bactericidal efficacy between NO-releasing and control PPI dendrimers (i.e., non-NO-releasing) revealed both enhanced biocidal action of NO-releasing dendrimers and reduced toxicity against mammalian fibroblast cells. Antibacterial activity for the NO donor functionalized PPI dendrimers was shown to be a function of both dendrimer size (molecular weight) and exterior functionality. In addition to minimal toxicity against fibroblasts, NO-releasing PPI dendrimers modified with styrene oxide exhibited the greatest biocidal activity (>=99.999% killing) against all bacterial strains tested. The N-diazeniumdiolate NO donor-functionalized PPI dendrimers presented in this study hold promise as effective NO-based therapeutics for combating bacterial infections. PMID- 23013539 TI - Co-release of hexabromocyclododecane (HBCD) and Nano- and microparticles from thermal cutting of polystyrene foams. AB - Polystyrene foam is a very important insulation material, and hexabromocyclododecane (HBCD) is frequently used as its flame retardant. HBCD is persistent, bioaccumulative, and toxic, and therefore workplace exposure and environmental emission should be avoided. In this study, we investigated the co release of HBCD and aerosol particles during the thermal cutting of expanded polystyrene foam (EPS) and extruded polystyrene foam (XPS). The generated particles were simultaneously measured by a fast mobility particle sizer (FMPS) and collected by a cascade impactor (NanoMoudi). In the breathing zone of a cutting worker, the number concentration of aerosol particles was above 1 * 10(12) particles m(-3), and the air concentration of HBCD was more than 50 MUg m( 3). Most of the released HBCD was partitioned into particles with an aerodynamic diameter at the nanometer scale. The average concentrations of HBCD in these submicrometer particles generated from the thermal cutting of EPS and XPS were 13 times and 15 times higher than the concentrations in raw foams, respectively. An occupational exposure assessment indicated that more than 60% of HBCD and 70% of particles deposited in the lung of cutting worker would be allocated to the alveolar region. The potential subchronic (or chronic) toxicity jointly caused by the particles and HBCD calls for future studies. PMID- 23013540 TI - Manipulation of interfacial amine density in epoxy-amine systems as studied by near-edge X-ray absorption fine structure (NEXAFS). AB - In this work, we investigate the ability to tune the quantity of surface amine functional groups in the interfacial region of epoxy-diamine composites using NEXAFS, a technique that is extremely sensitive to surface composition. Thereby, we employ a model surface (silicon wafer with the native oxide present) and, after deposition of an epoxy functionalized silane, we immersed the wafers in various diamines, followed by reaction with a diepoxy acting as a molecular probe. These results show that the number of available surface amines depends on the diamine chosen, wherein smaller molecular weight diamines provide more reaction sites. Subsequent experiments with mixtures of diamines undergoing competitive adsorption show that the amine quantity can be tailored by choice of the diamine mixture. Further experiments of diamine treated 3-(glycidoxypropyl) trimethoxysilane layers in a reacting epoxy/diamine showed that the surface reaction site density differences observed for adsorption experiments persisted in the reacting epoxy, implying that the surface reaction rate (and by extension, the surface amine concentration) dictate interfacial cross-link density up to the point of gelation. PMID- 23013541 TI - Pisiferdiol restores the growth of a mutant yeast suffering from hyperactivated Ca2+ signalling through calcineurin inhibition. AB - In the course of our screening program for a new inhibitor of the Ca(2+) signalling pathway using mutant yeast [Saccharomyces cerevisiae (zds1Delta erg3Delta pdr1Delta pdr3Delta)], a mouse PP2Calpha activator, pisiferdiol, isolated from Chamaecyparis pisifera, was found to alleviate the Ca(2+) signal mediated growth inhibition. Pisiferdiol showed growth inhibition activity against the mpk1Delta strain compared with the cnb1Delta strain and induced Li(+) sensitivity to the wild-type strain, indicating that it suppresses the calcineurin pathway in the yeast. However, the Li(+) sensitivity to ptc1Delta strain by pisiferdiol was diminished. Pisiferdiol showed growth restored activity in the zds1Delta strain without immunophilins Fkb1p or Cph1p, and in the pmc1Delta strain. It inhibited calcineurin-induced expression in the reporter gene assay and decreased the protein expression (Western blots) of calcineurin (Cnb1p) in addition to a decrease of Swe1p and phosphorylation of Cdc28p in the mutant yeast. These results showed that pisiferdiol could suppress indirectly the action of calcineurin and restored the growth inhibition of the mutant yeast through Ptc1p activation. PMID- 23013542 TI - Trifluoropropynyl as a surrogate for the cyano ligand and intense, room temperature, metal-centered emission from its Rh(III) complex. AB - The trifluoropropynyl ligand -C=CCF(3) was studied as a possible surrogate for the cyano ligand. Complexes of the type trans-[M(cyclam)(C=CCF(3))(2)]OTf (where M = Cr(3+), Co(3+), and Rh(3+); OTf = trifluoromethanesulfonate) were prepared and then characterized by electronic spectroscopy and by cyclic voltammetry for the Co(3+) complex. The UV-vis spectra for all three bear a remarkable similarity to that of the trans-M(cyclam)(CN)(2)(+) cations. The trifluoropropynyl complex of Co(3+) shows electrochemical behavior nearly identical with that of its dicyano analogue. Metal-centered phosphorescence from the Rh(III) complex in room temperature aqueous solution has a quantum yield of 0.12 and a lifetime of 73 MUs, nearly 10 times higher than those of its dicyano analogue. PMID- 23013543 TI - Digital microfluidic magnetic separation for particle-based immunoassays. AB - We introduce a new format for particle-based immunoassays relying on digital microfluidics (DMF) and magnetic forces to separate and resuspend antibody-coated paramagnetic particles. In DMF, fluids are electrostatically controlled as discrete droplets (picoliters to microliters) on an array of insulated electrodes. By applying appropriate sequences of potentials to these electrodes, multiple droplets can be manipulated simultaneously and various droplet operations can be achieved using the same device design. This flexibility makes DMF well-suited for applications that require complex, multistep protocols such as immunoassays. Here, we report the first particle-based immunoassay on DMF without the aid of oil carrier fluid to enable droplet movement (i.e., droplets are surrounded by air instead of oil). This new format allowed the realization of a novel on-chip particle separation and resuspension method capable of removing greater than 90% of unbound reagents in one step. Using this technique, we developed methods for noncompetitive and competitive immunoassays, using thyroid stimulating hormone (TSH) and 17beta-estradiol (E2) as model analytes, respectively. We show that, compared to conventional methods, the new DMF approach reported here reduced reagent volumes and analysis time by 100-fold and 10-fold, respectively, while retaining a level of analytical performance required for clinical screening. Thus, we propose that the new technique has great potential for eventual use in a fast, low-waste, and inexpensive instrument for the quantitative analysis of proteins and small molecules in low sample volumes. PMID- 23013544 TI - Evolution of extrafloral nectaries: adaptive process and selective regime changes from forest to savanna. AB - Much effort has been devoted to understanding the function of extrafloral nectaries (EFNs) for ant-plant-herbivore interactions. However, the pattern of evolution of such structures throughout the history of plant lineages remains unexplored. In this study, we used empirical knowledge on plant defences mediated by ants as a theoretical framework to test specific hypotheses about the adaptive role of EFNs during plant evolution. Emphasis was given to different processes (neutral or adaptive) and factors (habitat change and trade-offs with new trichomes) that may have affected the evolution of ant-plant associations. We measured seven EFN quantitative traits in all 105 species included in a well supported phylogeny of the tribe Bignonieae (Bignoniaceae) and collected field data on ant-EFN interactions in 32 species. We identified a positive association between ant visitation (a surrogate of ant guarding) and the abundance of EFNs in vegetative plant parts and rejected the hypothesis of phylogenetic conservatism of EFNs, with most traits presenting K-values < 1. Modelling the evolution of EFN traits using maximum likelihood approaches further suggested adaptive evolution, with static-optimum models showing a better fit than purely drift models. In addition, the abundance of EFNs was associated with habitat shifts (with a decrease in the abundance of EFNs from forest to savannas), and a potential trade off was detected between the abundance of EFNs and estipitate glandular trichomes (i.e. trichomes with sticky secretion). These evolutionary associations suggest divergent selection between species as well as explains K-values < 1. Experimental studies with multiple lineages of forest and savanna taxa may improve our understanding of the role of nectaries in plants. Overall, our results suggest that the evolution of EFNs was likely associated with the adaptive process which probably played an important role in the diversification of this plant group. PMID- 23013545 TI - Salvage of a totally occluded peritoneal dialysis catheter by laparoscopic milking. AB - Mechanical problems of the Peritoneal Dialysis (PD) catheter remain a significant cause of temporary or even permanent transfer to hemodialysis. Until recently, the most popular approach was to remove the problematic PD catheter than to try to salvage it. We report a case of severe (two-way) PD catheter obstruction that appeared after spontaneous hemoperitoneum and did not resolve with multiple conservative measures. However, it was successfully salvaged by laparoscopic surgery and milking of a big intraluminal clot. PMID- 23013546 TI - QSAR classification model for antibacterial compounds and its use in virtual screening. AB - As novel and drug-resistant bacterial strains continue to present an emerging health threat, the development of new antibacterial agents is critical. This includes making improvements to existing antibacterial scaffolds as well as identifying novel ones. The aim of this study is to apply a Bayesian classification QSAR approach to rapidly screen chemical libraries for compounds predicted to have antibacterial activity. Toward this end we assembled a data set of 317 known antibacterial compounds as well as a second data set of diverse, well-validated, non-antibacterial compounds from 215 PubChem Bioassays against various bacterial species. We constructed a Bayesian classification model using structural fingerprints and physicochemical property descriptors and achieved an accuracy of 84% and precision of 86% on an independent test set in identifying antibacterial compounds. To demonstrate the practical applicability of the model in virtual screening, we screened an independent data set of ~200k compounds. The results show that the model can screen top hits of PubChem Bioassay actives with accuracy up to ~76%, representing a 1.5-2-fold enrichment. The top screened hits represented a mixture of both known antibacterial scaffolds as well as novel scaffolds. Our study suggests that a well-validated Bayesian classification QSAR approach could compliment other screening approaches in identifying novel and promising hits. The data sets used in constructing and validating this model have been made publicly available. PMID- 23013547 TI - Understanding carbon dioxide adsorption on univalent cation forms of the flexible zeolite Rho at conditions relevant to carbon capture from flue gases. AB - A series of univalent cation forms of zeolite Rho (M(9.8)Al(9.8)Si(38.2)O(96), M = H, Li, Na, K, NH(4), Cs) and ultrastabilized zeolite Rho (US-Rho) have been prepared. Their CO(2) adsorption behavior has been measured at 298 K and up to 1 bar and related to the structures of the dehydrated forms determined by Rietveld refinement and, for H-Rho and US-Rho, by solid state NMR. Additionally, CO(2) adsorption properties of the H-form of the silicoalumino-phosphate with the RHO topology and univalent cation forms of the zeolite ZK-5 were measured for comparison. The highest uptakes at 0.1 bar, 298 K for both Rho and ZK-5 were obtained on the Li-forms (Li-Rho, 3.4 mmol g(-1); Li-ZK-5, 4.7 mmol g(-1)). H- and US-Rho had relatively low uptakes under these conditions: extra-framework Al species do not interact strongly with CO(2). Forms of zeolite Rho in which cations occupy window sites between alpha-cages show hysteresis in their CO(2) isotherms, the magnitude of which (Na(+),NH(4)(+) < K(+) < Cs(+)) correlates with the tendency for cations to occupy double eight-membered ring sites rather than single eight-membered ring sites. Hysteresis is not observed for zeolites where cations do not occupy the intercage windows. In situ synchrotron X-ray diffraction of the CO(2) adsorption on Na-Rho at 298 K identifies the adsorption sites. The framework structure of Na-Rho "breathes" as CO(2) is adsorbed and desorbed and its desorption kinetics from Na-Rho at 308 K have been quantified by the Zero Length Column chromatographic technique. Na-Rho shows much higher CO(2)/C(2)H(6) selectivity than Na-ZK-5, as determined by single component adsorption, indicating that whereas CO(2) can diffuse readily through windows containing Na(+) cations, ethane cannot. PMID- 23013548 TI - Ventricular assist device outflow graft in congenitally corrected transposition of great arteries - a surgical challenge. AB - Congenitally corrected transposition of the great arteries is a complex congenital cardiac anomaly with a wide spectrum of morphologic features and clinical profiles. Most patients are diagnosed late in their life, undergoes surgical repairs, eventually leading to systemic ventricular failure needing heart transplant or mechanical circulatory assistance. As, aorta is located anterior to and left of the PA (Transposition of great arteries), the outflow graft of ventricular assist device traverse across pulmonary artery to reach aorta which poses challenge during further surgical explorations. PMID- 23013549 TI - Why science and synchronized swimming should not be Olympic sports. PMID- 23013550 TI - Double-donor complex in vertically coupled quantum dots in a threading magnetic field. AB - We consider a model of hydrogen-like artificial molecule formed by two vertically coupled quantum dots in the shape of axially symmetrical thin layers with on-axis single donor impurity in each of them and with the magnetic field directed along the symmetry axis. We present numerical results for energies of some low-lying levels as functions of the magnetic field applied along the symmetry axis for different quantum dot heights, radii, and separations between them. The evolution of the Aharonov-Bohm oscillations of the energy levels with the increase of the separation between dots is analyzed. PMID- 23013551 TI - Characterization of malaria transmission by vector populations for improved interventions during the dry season in the Kpone-on-Sea area of coastal Ghana. AB - BACKGROUND: Malaria is a major public health problem in Ghana. We present a site specific entomological study of malaria vectors and transmission indices as part of an effort to develop a site for the testing of improved control strategies including possible vaccine trials. METHODS: Pyrethrum spray catches (PSC), and indoor and outdoor human landing collections of adult female anopheline mosquitoes were carried out over a six-month period (November 2005 - April 2006) at Kpone-on-Sea, a fishing village in southern Ghana. These were morphologically identified to species level and sibling species of the Anopheles gambiae complex further characterized by the polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay was used to detect Plasmodium falciparum mosquito infectivity and host blood meal sources. Parity rate was examined based on dilatation of ovarian tracheoles following dissection. RESULTS: Of the 1233 Anopheles mosquitoes collected, An. gambiae s.l. was predominant (99.5%), followed by An. funestus (0.4%) and An. pharoensis (0.1%). All An. gambiae s.l. examined (480) were identified as An. gambiae s.s. with a majority of M molecular form (98.2%) and only 1.8% S form with no record of M/S hybrid. A significantly higher proportion of anophelines were observed outdoors relative to indoors (chi2 = 159.34, df = 1, p < 0.0000). Only An. gambiae M molecular form contributed to transmission with a high degree of anthropophily, parity rate and an estimated entomological inoculation rate (EIR) of 62.1 infective bites/person/year. The Majority of the infective bites occurred outdoors after 09.00 pm reaching peaks between 12.00-01.00 am and 03.00-04.00 am. CONCLUSION: Anopheles gambiae M molecular form is responsible for maintaining the status quo of malaria in the surveyed site during the study period. The findings provide a baseline for evidence-based planning and implementation of improved malaria interventions. The plasticity observed in biting patterns especially the combined outdoor and early biting behavior of the vector may undermine the success of insecticide-based strategies using insecticide treated nets (ITN) and indoor residual spray (IRS). As such, novel or improved vector interventions should be informed by the local malaria epidemiology data as it relates to vector behavior. PMID- 23013552 TI - Safe introduction of a new surgical technique: remote telementoring for posterior retroperitoneoscopic adrenalectomy. AB - BACKGROUND: Posterior retroperitoneoscopic adrenalectomy (PRA) is a safe and effective approach to adrenalectomy, offering less pain and faster recovery than open or laparoscopic surgery. Although the popularity of PRA is increasing, few surgical centres have extensive experience with the procedure. The ideal approach to achieve proficiency with any new technique involves on-site observation of an experienced surgeon-mentor, followed by mentored hands-on experience of the surgeon-learner. However, it is not always feasible for a surgeon-mentor to offer on-site supervision to the surgeon-learner in his or her home institution. Advances in Internet applications have made remote telementoring a viable alternative to on-site mentoring in selected situations. METHODS: We describe our experience in safely introducing PRA to Melbourne, Australia, where no highly experienced surgeon-mentors were available. A surgeon with experience of 12 PRA procedures attended from interstate, along with live telementoring via Skype video link by an overseas surgeon who had performed more than 200 PRA procedures, to mentor the surgeon-learner performing her first three cases. RESULTS: The operating surgeon's first three PRA procedures proceeded uneventfully, with no complications, relatively short operative times and one-night hospital stays for all three patients. Twenty-two more have been performed since, without complications. CONCLUSION: Remote telementoring is a safe and feasible way to assist surgeons in safely introducing new techniques. This strategy is particularly applicable in centres where no surgeon-mentor is locally available. It is important that the surgeon-learner has the skills and experience to complete the procedure using alternative techniques in the case of complications or technical failure. PMID- 23013553 TI - Antiangiogenic effects of axitinib, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, on laser-induced choroidal neovascularization in mice. AB - PURPOSE: To investigate the effects of axitinib, an inhibitor of vascular endothelial growth factor receptors, on choroidal neovascularization (CNV) in an animal model of neovascular age-related macular degeneration (AMD). METHODS: Experimental CNV lesions were induced in C57BL/6 mice by laser photocoagulation. Beginning 1 day after CNV induction, mice were treated with axitinib (5 mg/kg/day) or vehicle for 2 weeks. In other groups of mice, axitinib or vehicle treatment was started 7 days after the laser application to determine the effect of the drug on established CNV. Untreated mice were used as a baseline group. Two weeks after laser injury, the extent of CNV was assessed from choroidal flat mounts perfused with fluorescein-labeled dextran. Immunofluorescence staining with isolectin IB4 was also used to quantify the CNV lesions. RESULTS: Orally administered axitinib inhibited CNV growth in the laser-induced CNV model. Axitinib caused a 70.1% inhibition of CNV lesions compared to vehicle-treatment (p < 0.001). Axitinib also caused a significant regression of established CNV, reducing the area by 71.1% compared to vehicle treatment (p < 0.001). Moreover, immunofluorescence staining showed that the area of isolectin IB4 labeled vessels was smaller in the axitinib-treated group compared to the vehicle-treated group (p < 0.001). CONCLUSIONS: Axitinib effectively inhibits the progression of CNV in an experimental animal model. These results suggest that axitinib could constitute a therapeutic alternative for the treatment of neovascular AMD. PMID- 23013554 TI - Hippocampal volume as marker of daily life stress sensitivity in psychosis. AB - BACKGROUND: Reduced hippocampal size and increased stress sensitivity are associated with psychotic disorder and familial risk for psychosis. However, to what degree the hippocampus is implicated in daily life stress reactivity has not yet been examined. The current study investigated (i) whether familial risk (the contrast between controls, patients and siblings of patients) moderated the relationship between hippocampal volume (HV) and emotional daily stress reactivity and (ii) whether familial risk (the contrast between controls and siblings of patients) moderated the relationship between HV and cortisol daily stress reactivity. Method T1-weighted magnetic resonance imaging (MRI) scans were acquired from 20 patients with schizophrenia, 37 healthy siblings with familial risk for schizophrenia and 32 controls. Freesurfer 5.0.0 was used to measure HV. The experience sampling method (ESM), a structured momentary assessment technique, was used to assess emotional stress reactivity, that is the effect of momentary stress on momentary negative affect (NA). In addition, in the control and sibling groups, cortisol stress reactivity was assessed using momentary cortisol levels extracted from saliva. RESULTS: Multilevel linear regression analyses revealed a significant three-way interaction between group, HV and momentary stress in both the model of NA and the model of cortisol. Increased emotional stress reactivity was associated with smaller left HV in patients and larger total HV in controls. In line with the results in patients, siblings with small HV demonstrated increased emotional and cortisol stress reactivity compared to those with large HV. CONCLUSIONS: HV may index risk and possibly disease related mechanisms underlying daily life stress reactivity in psychotic disorder. PMID- 23013555 TI - Synthesis, self-assembly, and high performance in gas sensing of X-shaped iron oxide crystals. AB - X-shaped goethite iron oxide crystals were synthesized by a surfactant-free mild hydrothermal synthesis method with the aid of fluorine ions. The X-shaped goethite crystals could readily self-assemble into microscopic hollow spheres through an oil-water interface induced self-assembly method. X-shaped hematite crystals were obtained by phase topotactic transformation of the goethite precursors. The gas sensor properties of X-shaped hematite iron oxide were investigated, and the mechanism for excellent sensor properties was discussed. PMID- 23013557 TI - Synergistic effect of follicle-stimulating hormone receptor and androgen receptor gene variants on semen quality. AB - Follicle-stimulating hormone (FSH), interacting with its receptor (FSHR), participates in the production of spermatozoa and androgens. Androgens exert their effects on male sex determination, development and sperm production by binding to androgen receptor (AR). In the present study, we sought to explore the potential synergistic effects of FSHR and AR gene variants on sperm quality. 200 oligozoospermic and 250 normozoospermic men were examined. DNA was extracted from spermatozoa, and the FSHR 307 (T/A), FSHR 680 (N/S) and AR (CAG)n polymorphisms were genotyped. Their parallel analysis revealed six combined genotypes. A gradual reduction of sperm motility, from long AR allele-Thr307Thr/Asn680Asn carriers to long AR allele-Ala307Ala/Ser680Ser carriers and from short AR allele Thr307Thr/Asn680Asn carriers to short AR allele-Ala307Ala/Ser680Ser carriers was revealed in normozoospermic men (P < 0.001). Similar associations were observed in oligozoospermic men (P < 0.001). In our series, the synergism of the long AR alleles with the FSHRThr307/Asn680 allelic variant was associated with increased sperm motility, while the synergism of the short AR alleles with the FSHRAla307/Ser680 allelic variant was associated with decreased motility, supporting the significance of these genes in semen quality. PMID- 23013556 TI - Stroke radiology and distinguishing characteristics of intracranial atherosclerotic disease in native South Asian Pakistanis. AB - BACKGROUND: There are no descriptions of stroke mechanisms from intracranial atherosclerotic disease in native South Asian Pakistanis. METHODS: Men and women aged >= 18 years with acute stroke presenting to four tertiary care hospitals in Karachi, Pakistan were screened using magnetic resonance angiography/transcranial Doppler scans. Trial of ORG 10172 in Acute Stroke Treatment criteria were applied to identify strokes from intracranial atherosclerotic disease. RESULTS: We studied 245 patients with acute stroke due to intracranial atherosclerotic disease. Two hundred thirty scans were reviewed. Also, 206/230 (89.0%) showed acute ischaemia. The most frequent presentation was with cortically based strokes in 42.2% (87/206) followed by border-zone infarcts (52/206, 25.2%). Increasing degrees of stenosis correlated with the development of both cortical and border zone strokes (P = 0.002). Important associated findings were frequent atrophy (166/230, 72.2%), silent brain infarcts (66/230, 28%) and a marked lack of severe leukoaraiosis identified in only 68/230 (29.6%). A total of 1870 arteries were studied individually. Middle cerebral artery was the symptomatic stroke vessel in half, presenting with complete occlusion in 66%. Evidence of biological disease, symptomatic or asymptomatic was identified in 753 (40.2%) vessels of which 543 (72%) were significantly (>50%) stenosed at presentation. CONCLUSION: Intracranial atherosclerotic disease is a diffuse process in Pakistani south Asians, with involvement of multiple vessels in addition to the symptomatic vessel. The middle cerebral artery is the most frequent symptomatic vessel presenting with cortical embolic infarcts. There is a relative lack of leukoaraiosis. Concomitant atrophy, silent brain infarcts and recent ischaemia in the symptomatic territory are all frequently associated findings. PMID- 23013558 TI - Plasma concentrations of soluble cytokine receptors in euthymic bipolar patients with and without subsyndromal symptoms. AB - BACKGROUND: Current evidence suggests that high concentrations of pro inflammatory markers are associated with bipolar disorder characterized by severe impairment during inter-episodic periods, reduced treatment response and persistent subsyndromal symptoms. We tested whether persistent subsyndromal symptoms in euthymic bipolar patients were associated with markers of an ongoing chronic pro-inflammatory process. METHODS: Forty-five euthymic bipolar patients (22 with subsyndromal symptoms (BD+) and 23 without subsyndromal symptoms (BD-) and 23 well controls (WC) were recruited for assessment of soluble tumor necrosis factor receptor-1 (sTNF-R1), soluble interleukin-6 receptor (sIL-6R) and soluble interleukin-2 receptor (sIL-2R) concentrations. Soluble cytokine receptor concentrations were assessed using enzyme-linked immunosorbent assay. RESULTS: In comparison to WC, sTNF-R1 concentration was higher in both BD- and BD+ (age and sex adjusted standardized beta, respectively: beta = 0.34, p = 0.012 and beta = 0.41, p = 0.003). Similarly, compared to WC, sIL-6R concentration was higher in both BD- and BD+ (age and sex adjusted standardized beta, respectively: beta = 0.44, p = 0.001 and beta = 0.37, p = 0.008). There was no difference between BD- and BD+ in the concentration of either sTNF-R1 or sIL-6R; plasma concentration of sIL-2R was not analyzed as 75% percent of the samples were non-detectable. CONCLUSIONS: Although bipolar patients present with a pro-inflammatory shift compared to well controls, subsyndromal symptoms are not associated with additive increasing effects. Longitudinal studies with larger samples are required to clarify the relationship between illness course and inflammatory markers in bipolar disorder. PMID- 23013596 TI - A model of magnetic and relaxation properties of the mononuclear [Pc2Tb](-)TBA+ complex. AB - The present work is aimed at the elaboration of the model of magnetic properties and magnetic relaxation in the mononuclear [Pc(2)Tb](-)TBA(+) complex that displays single-molecule magnet properties. We calculate the Stark structure of the ground (7)F(6) term of the Tb(3+) ion in the exchange charge model of the crystal field, taking account for covalence effects. The ground Stark level of the complex possesses the maximum value of the total angular momentum projection, while the energies of the excited Stark levels increase with decreasing |M(J)| values, thus giving rise to a barrier for the reversal of magnetization. The one phonon transitions between the Stark levels of the Tb(3+) ion induced by electron vibrational interaction are shown to lead to magnetization relaxation in the [Pc(2)Tb](-)TBA(+) complex. The rates of all possible transitions between the low lying Stark levels are calculated in the temperature range 14 K10%) of most of these markers exist in the gas phase under typical atmospheric conditions. Therefore, these species should be considered semivolatile. Predictions from a chemical kinetics model indicate that gas-particle partitioning has important effects on the atmospheric lifetime of these species. The atmospheric decay of semivolatile compounds proceeds much more rapidly than nonvolatile compounds because gas-phase oxidation induces evaporation of particle-phase material. Therefore, both gas-particle partitioning and chemical reactions need to be accounted for when semivolatile molecular markers are used for source apportionment studies. PMID- 23013601 TI - Association of kidney disease measures with poor outcomes. PMID- 23013604 TI - Rollover cyclometalation pathway in rhodium catalysis: dramatic NHC effects in the C-H bond functionalization. AB - Organometallic chelates are readily obtained upon coordination of metal species to multidentate ligands. Because of the robust structural nature, chelation frequently serves as a driving force in the molecular assembly and chemical architecture, and they are used also as an efficient catalyst in numerous reactions. Described herein is the development of a Rh(NHC) catalytic system for the hydroarylation of alkenes and alkynes with 2,2'-bipyridines (bipy) and 2,2' biquinolines; the most representative chelating molecules. Initially generated (bipy)Rh(NHC) chelates become labile because of the strong trans-effect of N heterocyclic carbenes, thus weakening a rhodium-pyridyl bond, which is trans to the bound NHC. Subsequent rollover cyclometalation leads to the C-H bond activation, eventually giving rise to double functionalization of chelate molecules. Density functional calculations are in good agreement with our mechanistic proposal based on the experimental data. The present study elucidated for the first time the dramatic NHC effects on the rollover cyclometalation pathway enabling highly efficient and selective bisfunctionalization of 2,2' bipyridines and 2,2'-biquinolines. PMID- 23013605 TI - Trion X+ in vertically coupled type II quantum dots in threading magnetic field. AB - We analyze the energy spectrum of a positively charged exciton confined in a semiconductor heterostructure formed by two vertically coupled, axially symmetrical type II quantum dots located close to each other. The electron in the structure is mainly located inside the dots, while the holes generally move in the exterior region close to the symmetry axis. The solutions of the Schrodinger equation are obtained by a variational separation of variables in the adiabatic limit. Numerical results are shown for bonding and anti-bonding lowest-lying of the trion states corresponding to the different quantum dots morphologies, dimensions, separation between them, thicknesses of the wetting layers, and the magnetic field strength. PMID- 23013600 TI - Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis. AB - BACKGROUND: Hypertension is the most prevalent comorbidity in individuals with chronic kidney disease. However, whether the association of the kidney disease measures, estimated glomerular filtration rate (eGFR) and albuminuria, with mortality or end-stage renal disease (ESRD) differs by hypertensive status is unknown. METHODS: We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and ESRD associated with eGFR and albuminuria in individuals with and without hypertension. FINDINGS: We analysed data for 45 cohorts (25 general population, seven high-risk, and 13 chronic kidney disease) with 1,127,656 participants, 364,344 of whom had hypertension. Low eGFR and high albuminuria were associated with mortality irrespective of hypertensive status in the general population and high-risk cohorts. All-cause mortality risk was 1.1-1.2 times higher in individuals with hypertension than in those without hypertension at preserved eGFR. A steeper relative risk gradient in individuals without hypertension than in those with hypertension at eGFR range 45 75 mL/min per 1.73 m(2) led to much the same mortality risk at lower eGFR. With a reference eGFR of 95 mL/min per 1.73 m(2) in each group to explicitly assess interaction, adjusted HR for all-cause mortality at eGFR 45 mL/min per 1.73 m(2) was 1.77 (95% CI 1.57-1.99) in individuals without hypertension versus 1.24 (1.11 1.39) in those with hypertension (p for overall interaction=0.0003). Similarly, for albumin-creatinine ratio of 300 mg/g (vs 5 mg/g), HR was 2.30 (1.98-2.68) in individuals without hypertension versus 2.08 (1.84-2.35) in those with hypertension (p for overall interaction=0.019). We recorded much the same results for cardiovascular mortality. The associations of eGFR and albuminuria with ESRD, however, did not differ by hypertensive status. Results for chronic kidney disease cohorts were similar to those for general and high-risk population cohorts. INTERPRETATION: Chronic kidney disease should be regarded as at least an equally relevant risk factor for mortality and ESRD in individuals without hypertension as it is in those with hypertension. FUNDING: US National Kidney Foundation. PMID- 23013607 TI - Surface modification of siliceous materials using maleimidation and various functional polymers synthesized by reversible addition-fragmentation chain transfer polymerization. AB - A novel surface modification method was investigated. The surface of siliceous materials was modified using polystyrene, poly(acrylic acid), poly(N isopropylacrylamide), and poly(p-acrylamidophenyl-alpha-mannoside) synthesized by reversible addition-fragmentation chain transfer polymerization. Thiol-terminated polymers were obtained by reduction of the thiocarbonate group using sodium borohydride. The polymers were immobilized on the surface via the thiol-ene click reaction, known as the Michael addition reaction. Immobilization of the polymers on the maleimidated surface was confirmed by X-ray photoelectron spectroscopy, infrared spectroscopy, and contact angle measurements. The polymer-immobilized surfaces were observed by atomic force microscopy, and the thickness of the polymer layers was determined by ellipsometry. The thickness of the polymer immobilized by the maleimide-thiol reaction was less than that formed by spin coating, except for polystyrene. Moreover, the polymer-immobilized surfaces were relatively smooth with a roughness of less than 1 nm. The amounts of amine, maleimide, and polymer immobilized on the surface were determined by quartz crystal microbalance measurements. The area occupied by the amine-containing silane coupling reagent was significantly less than the theoretical value, suggesting that a multilayer of the silane coupling reagent was formed on the surface. The polymer with low molecular weight had the tendency to efficiently immobilize on the maleimidated surface. When poly(p-acrylamidophenyl-alpha mannoside)-immobilized surfaces were used as a platform for protein microarrays, strong interactions were detected with the mannose-binding lectin concanavalin A. The specificity of poly(p-acrylamidophenyl-alpha-mannoside)-immobilized surfaces for concanavalin A was compared with poly-l-lysine-coated surfaces. The poly-l lysine-coated surfaces nonspecifically adsorbed both concanavalin A and bovine serum albumin, while the poly(p-acrylamidophenyl-alpha-mannoside)-immobilized surface preferentially adsorbed concanavalin A. Moreover, the poly(p acrylamidophenyl-alpha-mannoside)-immobilized surface was applied to micropatterning with photolithography. When the micropattern was formed on the poly(p-acrylamidophenyl-alpha-mannoside)-spin-coated surface by irradiation with ultraviolet light, the pattern of the masking design was not observed on the surface adsorbed with fluorophore-labeled concanavalin A using a fluorescent microscope because of elution of poly(p-acrylamidophenyl-alpha-mannoside) from the surface. In contrast, fluorophore-labeled concanavalin A was only adsorbed on the shaded region of the poly(p-acrylamidophenyl-alpha-mannoside)-immobilized surface, resulting in a distinctive fluorescent pattern. The surface modification method using maleimidation and reversible addition-fragmentation chain transfer polymerization can be used for preparing platforms for microarrays and micropatterning of proteins. PMID- 23013608 TI - Age-related changes in electrogustometry thresholds, tongue tip vascularization, density, and form of the fungiform papillae in humans. AB - The aim of the study was to investigate age-related changes in electrogustometry (EGM) thresholds, in morphology and density of the fungiform papillae (fPap) and in vessels' shape and density at the tip of the human tongue.In 156 nonsmokers (74 males, 82 females; age range: 10-80 years), divided in age groups, EGM thresholds at the chorda tympani area, at the soft palate area, and at the area of the vallate papillae were recorded bilaterally. Morphology and density of the fPap and blood vessels' density and morphology at the tip of the tongue were examined using contact endoscopy (CE). EGM thresholds at the chorda tympani area were significantly higher in both men and women <-60 years of age than in younger individuals. At the soft-palatine area, EGM thresholds were significantly higher in men aged 20-29 years and <-60 years compared with men of other age groups. In women older than 50 years, thresholds at all 3 areas were significantly higher than in the younger age groups. No significant differences in EGM thresholds between the two sexes at all locations tested were detected. The density of fPap decreased significantly in men aged >50 years and in women aged >60 years compared with younger individuals. Vascular density decreased significantly and vascular morphology worsened at the tip of the tongue in subjects older than 60 years of age compared with younger subjects. The study showed statistically significant differences in EGM thresholds between the right and the left side of the tongue and between the two sexes. Aging is associated with a progressive increase in EGM thresholds. Density of fPap plays an important role for taste acuity in females aged >60 years and males aged <-50 years. Morphology of fPap and vessels' density and morphology at the tip of the tongue, as tested by CE, emerge as factors influencing taste function in subjects of both sexes aged >60 years. PMID- 23013609 TI - Environmental influence on the single-molecule magnet behavior of [Mn(III)6Cr(III)]3+: molecular symmetry versus solid-state effects. AB - The structural, spectroscopic, and magnetic properties of a series of [Mn(III)(6)Cr(III)](3+) (= [{(talen(t-Bu(2)))Mn(III)(3)}(2){Cr(III)(CN)(6)}](3+)) compounds have been investigated by single-crystal X-ray diffraction (XRD), Fourier transform infrared (FT-IR) and electronic absorption spectroscopy, elemental analysis, electro spray ionization-mass spectrometry (ESI-MS) and matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS), cyclic voltammetry, AC and DC magnetic measurements, as well as theoretical analysis. The crystal structures obtained with [Cr(III)(CN)(6)](3-) as a counterion exhibit (quasi-)one-dimensional (1D) chains formed by hydrogen-bonded (1) or covalently linked (2) trications and trianions. The rod-shaped anion lactate enforces a rod packing of the [Mn(III)(6)Cr(III)](3+) complexes in the highly symmetric space group R3[overline] (3) with a collinear arrangement of the molecular S(6) axes. Incorporation of the spherical anion BPh(4)(-) leads to less-symmetric crystal structures (4-6) with noncollinear orientations of the [Mn(III)(6)Cr(III)](3+) complexes, as evidenced by the angle between the approximate molecular C(3) axes taking no specific values in the range of 2 degrees -69 degrees . AC magnetic measurements on freshly isolated crystals (1a and 3a-6a), air-dried crystals (3b 6b), and vacuum-dried powder samples (3c-6c) indicate single-molecule magnet (SMM) behavior for all samples with U(eff) values up to 28 K. The DC magnetic data are analyzed by a full-matrix diagonalization of the appropriate spin Hamiltonian including isotropic exchange, zero-field splitting, and Zeeman interaction, taking into account the relative orientation of the D-tensors. Simulations for 3a-6a and 3c-6c indicate a weak antiferromagnetic exchange between the Mn(III) ions in the trinuclear subunits (J(Mn-Mn) = -0.70 to -0.85 cm(-1), H(ex) = -2?(i96 wt% clay, are >95% transparent, and, because of their nanobrick wall structure, exhibit super gas barrier behavior at thicknesses of <165 nm. When coupled with flexibility, the optical clarity and super barrier that these coatings can impart make them superb candidates for a variety of packaging applications. PMID- 23013615 TI - Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. AB - BACKGROUND: The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status. RESULTS: Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways. CONCLUSIONS: This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis. PMID- 23013621 TI - Five-year changes in biologic risk factors and risk of type 2 diabetes: are attained but not initial risk factor levels of importance? AB - Independent effects of changes in biologic risk factors on type 2 diabetes incidence remain unclear. The authors examined whether associations between changes in biologic risk factors and diabetes risk are driven by initial or attained risk factor levels. Biologic risk factors were measured at baseline and at each 5-year interval follow-up (rounds 2, 3, and 4) among 4,204 initially healthy men and women, aged 20-59 years, participating in the Dutch Doetinchem Cohort Study (1987-2007). Time-dependent Cox regression analyses were used to analyze associations between changes in waist circumference, blood pressure, and high density lipoprotein cholesterol (HDL cholesterol) and incident diabetes, adjusted for initial or attained levels; 130 diabetes cases occurred during 9 years of follow-up. Five-year increases in waist circumference and blood pressure and decreases in HDL cholesterol were positively associated with risk of diabetes after adjustment for initial levels but no longer after adjustment for attained levels: waist circumference (hazard ratio (HR) = 0.86, 95% confidence interval (CI): 0.69, 1.07), systolic blood pressure (HR = 0.96, 95% CI: 0.84, 1.10), diastolic blood pressure (HR = 0.96, 95% CI: 0.87, 1.06), and HDL cholesterol (HR = 0.91, 95% CI: 0.81, 1.01). In conclusion, the associations between changes in biologic risk factors and risk of diabetes are mainly driven by the attained levels. Hence, not the prior changes, but the attained levels seem to be of importance with regard to diabetes risk. PMID- 23013620 TI - Validity and reliability of self-reported diabetes in the Atherosclerosis Risk in Communities Study. AB - The objective of this study was to assess the validity of prevalent and incident self-reported diabetes compared with multiple reference definitions and to assess the reliability (repeatability) of a self-reported diagnosis of diabetes. Data from 10,321 participants in the Atherosclerosis Risk in Communities (ARIC) Study who attended visit 4 (1996-1998) were analyzed. Prevalent self-reported diabetes was compared with reference definitions defined by fasting glucose and medication use obtained at visit 4. Incident self-reported diabetes was assessed during annual follow-up telephone calls and was compared with reference definitions defined by fasting glucose, hemoglobin A1c, and medication use obtained during an in-person visit attended by a subsample of participants (n = 1,738) in 2004-2005. The sensitivity of prevalent self-reported diabetes ranged from 58.5% to 70.8%, and specificity ranged from 95.6% to 96.8%, depending on the reference definition. Similarly, the sensitivity of incident self-reported diabetes ranged from 55.9% to 80.4%, and specificity ranged from 84.5% to 90.6%. Percent positive agreement of self-reported diabetes during 9 years of repeat assessments ranged from 92.7% to 95.4%. Both prevalent self-reported diabetes and incident self reported diabetes were 84%-97% specific and 55%-80% sensitive as compared with reference definitions using glucose and medication criteria. Self-reported diabetes was >92% reliable over time. PMID- 23013623 TI - Lower gastrointestinal bleeding: incidence, etiology, and outcomes in a population-based setting. AB - OBJECTIVES: To investigate the incidence and outcomes of acute lower gastrointestinal bleeding (ALGIB) in a population-based setting and examine the role of drugs potentially associated with GIB. METHODS: The study was prospective and population based. The cohort included all patients who underwent colonoscopy during the year 2010 at the National University Hospital of Iceland. Indications for endoscopies and drug history were recorded in a systematic manner. The inclusion criteria were overt bleeding leading to hospitalization or occurring in hospitalized patients. The use of NSAIDs, low-dose aspirin, warfarin, selective serotonin receptor inhibitors, and bisphosphonates before GIB was also checked in a Pharmaceutical Database covering all drug prescriptions in the country. A control group included patients who underwent colonoscopy during the study period and did not have GIB. RESULTS: Altogether, 1134 patients underwent 1275 colonoscopies. Overall, 163 patients had ALGIB. The crude incidence for ALGIB was 87/100 000 inhabitants/year. The most common findings were diverticulosis (23%) and ischemic colitis (16%). A total of 7.4% of individuals had endoscopic therapy and none had undergone surgery. Two (1.2%) patients died because of ALGIB, both with severe comorbidities. Overall, 19% with ALGIB were on NSAIDs versus 9% in nonbleeders (P=0.0096); 37% with ALGIB were on low-dose aspirin versus 25% in nonbleeders (P=0.0222). CONCLUSION: The incidence for ALGIB is the highest reported to date. The most common reasons for ALGIB were diverticulosis and ischemic colitis. Mortality during hospitalization was very low. NSAIDs and low dose aspirin seem to increase the risk for ALGIB. PMID- 23013619 TI - Modulating antiangiogenic resistance by inhibiting the signal transducer and activator of transcription 3 pathway in glioblastoma. AB - Determining the mechanism of treatment failure of VEGF signaling inhibitors for malignant glioma patients would provide insight into approaches to overcome therapeutic resistance. In this study, we demonstrate that human glioblastoma tumors failing bevacizumab have an increase in the mean percentage of p-STAT3 expressing cells compared to samples taken from patients failing non antiangiogenic therapy containing regimens. Likewise, in murine xenograft models of glioblastoma, the mean percentage of p-STAT3-expressing cells in the gliomas resistant to antiangiogenic therapy was markedly elevated relative to controls. Administration of the JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib reduced tumor hypoxia and the infiltration of VEGF inhibitor-induced p STAT3 macrophages. Thus, the combination of AZD1480 with cediranib markedly reduced tumor volume, and microvascular density, indicating that up regulation of the STAT3 pathway can mediate resistance to antiangiogenic therapy and combinational approaches may delay or overcome resistance. PMID- 23013624 TI - Association between Helicobacter pylori and liver-to-spleen ratio: a randomized controlled single-blind study. AB - BACKGROUND AND AIM: Helicobacter pylori infection is reported to be associated with some extragastrointestinal manifestations, such as hematological diseases (thrombocytopenia, anemia), obesity, and fatty liver disease. The length or the volume ratio of liver to spleen was suggested to be changed in some hematological and hepatobiliary disorders. We hypothesized that the liver-to-spleen ratio may be affected in H. pylori-positive patients. In this respect, we aimed to evaluate the effect of H. pylori infection on the liver-to-spleen ratio and platelet indices. METHOD: A total of 174 patients with functional dyspepsia were included in the study. Patients were divided into group 1 (H. pylori-positive gastritis) (n=95) and group 2 (H. pylori negative, control group) (n=79). Liver, spleen length measurement, and liver steatosis scores were performed by ultrasonography by the same physicians who were blinded to the H. pylori results. Blood count values including the platelet count and the mean platelet volume (MPV) were compared between the two groups. BMI was also evaluated as a potential confounding factor for fatty liver. RESULTS: The liver-to-spleen ratio, platelet to-spleen ratio, MPV-to-spleen ratio, and the MPV-to-liver ratio were significantly lower in the H. pylori-positive group compared with the H. pylori negative group (P<0.001, <0.001, <0.001, and 0.038, respectively). Fatty liver was significantly more frequent in H. pylori-positive patients. CONCLUSION: Liver to-spleen ratio and the MPV-to-spleen ratio are important indices in the pathogenesis of H. pylori-linked liver and spleen manifestations, and thrombocytopenia. PMID- 23013625 TI - Posttraumatic stress disorder (PTSD): a tailor-made diagnosis for an age of disenchantment and disillusionment? PMID- 23013626 TI - Posttraumatic stress disorders (PTSD) between fallacy and facts: what we know and what we don't know? AB - BACKGROUND: PTSD been recognized as a major problem in public health and has attracted an ever-growing scientific, epistemological and clinical interest. On the other side, PTSD is one of the most controversial diagnosis in psychiatry as well as in medicine in general. METHOD: We have made an overview of available literature on PTSD to identify what is our real knowledge about PTSD with all dilemmas, controversies and challenges. RESULTS: We have various options as to how to evaluate, explain and describe PTSD and other trauma-related mental and somatic disorders. In this paper we compiled an extensive set of facts and meta facts in order to to understand the real nature of traumatic stress, negative life events and PTSD. CONCLUSION: Conflict between various concepts of PTSD and our current knowledge will probably bring with itself a new scientific paradigm with new diagnostic phenotypes and refining the old ones. PMID- 23013627 TI - Posttraumatic stress disorders (PTSD) from different perspectives: a transdisciplinary integrative approach. AB - BACKGROUND: Psychotraumatization continues to be a pervasive aspect of life in the 21st century all over the world so we should better understand psychological trauma and PTSD for the sake of prevention and healing. METHOD: We have made an overview of available literature on PTSD to identify explanatory models, hypotheses and theories. RESULTS: In this paper we describe our transdisciplinary multiperspective integrative model of PTSD based on the seven perspective explanatory approach, on the fifth discipline, the art and practice of the learning organization as well as on the method of multiple working hypotheses.Trauma vulnerability, strengths, resilience and posttraumatic growth are key concepts that enable an integration of the distinct perspectives into a coherent transdisciplinary multiperspective explanatory and treatment model of PTSD. CONCLUSION: PTSD is a complex highly disabling and suffering disorder where the past is always present in people haunted by the dread frozen in memory of the traumatic events. However, PTSD also represents an oportunity for psychological and spiritual growth due to the human ability to adapt and thrive despite experiencing adversity and tough times. PMID- 23013628 TI - The role of personality traits in posttraumatic stress disorder (PTSD). AB - BACKGROUND: A number of studies have shown that although exposure to potentially traumatic events is common, development of PTSD is relatively rare, which is one of the reasons PTSD still remains a controversial psychiatric entity. The aim of this article was to provide an overview of the research on the role of personality traits in the vulnerability, resilience, posttraumatic growth and expressions associated with PTSD. Personality based approach represents a dimensional aspect of the transdisciplinary integrative model of PTSD. METHODS: We conducted a systematic search on PubMed, PsycINFO, and Academic Search Complete from 1980 (the year PTSD was first included in the DSM) and 2012 (the year the literature search was performed). Manual examination of secondary sources such as the reference sections of selected articles and book chapters were also conducted. RESULTS: Most of the reviewed studies dealing with personality traits as vulnerability and protective factors for PTSD examined the relationship between basic personality dimensions and severity of symptoms of PTSD. These studies have applied three types of methodological designs: cross sectional, post-trauma and pre-trauma longitudinal studies, with latter being the least common option. CONCLUSION: Finding that appears relatively consistent is that PTSD is positively related to negative emotionality, neuroticism, harm avoidance, novelty-seeking and self-transcendence, as well as to trait hostility/anger and trait anxiety. On the other hand, PTSD symptoms are negatively associated with extraversion, conscientiousness, self-directedness, the combination of high positive and low negative emotionality, as well as with hardiness and optimism, while posttraumatic growth shows inverse relation to most of these traits. Furthermore, a number of studies have confirmed the existence of three distinct personality-based subtypes of PTSD: internalizing, externalizing and low pathology PTSD. These findings may help in further uncovering etiological mechanisms and in building new strategies for prevention, identification and reduction of health risks among this trauma population, as well as facilitating potential posttraumatic growth. However, focusing on just a single dimensional perspective will unable us to generate comprehensive knowledge of the etiology, course and treatment of PTSD. PMID- 23013629 TI - Patho-genetics of posttraumatic stress disorder. AB - Clinical genetic studies propose a moderate genetic contribution to the pathogenesis of PTSD with a heritability of about 30-35%. The present brief review will give an overview of molecular genetic research in PTSD yielding support for specific vulnerability genes. Additionally, evidence for gene environment (GxE) interactions between susceptibility genes of PTSD and traumatic experiences will be reported. Recent studies suggest a pivotal role of epigenetic mechanisms such as DNA methylation in mediating the impact of trauma in the pathogenesis of PTSD. Future approaches to further unravel the genetic underpinnings of PTSD might comprise genome-wide association studies (GWAS), the investigation of the genetic influence on intermediate phenotypes of PTSD (e.g., imaging genetics) as well as pharmaco- and psychotherapy-genetic studies. Genetic research in PTSD will be discussed with respect to its potential benefit regarding innovative and individually tailored therapeutic approaches in PTSD. PMID- 23013630 TI - Comment on 'patho-genetics of posttraumatic stress disorder'. PMID- 23013631 TI - Invited commentary on patho-genetics of posttraumatic stress disorder. PMID- 23013632 TI - Genetic influences on posttraumatic stress disorder (PTSD): inspirations from a memory-centered approach. PMID- 23013633 TI - Psychiatric and health impact of primary and secondary traumatization in wives of veterans with posttraumatic stress disorder. AB - BACKGROUND: Along with primary traumatization, wives of PTSD-diagnosed war veterans often become victims of the altered and dysfunctional state of their partners, which adds to the severity of symptoms of primary traumatization and furthers the development of other mental disorders. The aim of this study was to compare the effects of primary and secondary traumatization in wives of PTSD diagnosed war veterans and wives of war veterans without PTSD. SUBJECTS AND METHODS: The experimental group consisted of 154 wives whose veteran husbands had been treated in Mostar Clinical Hospital for psychotrauma-induced PTSD. The control group was formed of 77 wives of war veterans who do not suffer from PTSD. The research used a general demographic questionnaire, the Harvard Trauma Questionnaire (HTQ) and the MINI International Neuropsychiatric Interview. RESULTS: Wives of veterans with chronic PTSD experienced a significantly greater number of traumatic events (t=2.66; p=0.008) and had higher scores of PTSD symptoms (t=8.93; p<0.001). A significantly larger number of these women reported chronic somatic diseases (chi2=4.553; p=0.033). Furthermore, wives of PTSD affected veterans significantly more frequently met criteria for current depression episode (chi2=20.65; p<0.001), past depression episode (chi2=24.40; p<0.001), depression with melancholic features (chi2=19.20; p<0.001), dysthymia (chi2=7.15; p=0.007), panic disorder with agoraphobia (chi2=5.28; p=0.022), PTSD (chi2=18.39; ss=1; p<0.001) and generalized anxiety disorder (chi2=19.58; p<0.001). This group also showed a higher level of suicidality (chi2=8.95; p=0.003). CONCLUSION: The findings of this research show how mental difficulties experienced by wives of PTSD-diagnosed war veterans affect the interrelationship of their primary and secondary traumatization. PMID- 23013634 TI - Psychiatrists' empathy, beliefs and attitudes towards veterans suffering from combat-related posttraumatic stress disorder. AB - BACKGROUND: Empathy is a powerful and necessary skill for understanding another person's subjective experience. In this study we wanted to explore psychiatrists' attitudes towards PTSD, general empathy, possible differences related to age, sex and regional location in Croatia. SUBJECTS AND METHODS: 205 psychiatrists from different Croatian regions participated in this study. To define psychiatrists' attitudes towards PTSD patients a questionnaire was devised. It contained 14 items related to psychiatrists' ability to live through emotional and social conditions of PTSD patients. BarOn Emotional Quotient-Inventory Empathy Subscale was used to measure the empathy among the subjects. RESULTS: This study has found statistically significant differences regarding gender in measured variables of the designed questionnaire. Male participants believed they were able to understand war veterans' feeling's and relate to traumatic experience while female participants stated that they had the ability to understand the trivial triggers for suicidal intentions. Regional differences were found in the understanding of war traumatic experience and social deviations occurring in PTSD. Older psychiatrists stated their incomprehension of the social difficulties the PTSD patients were facing. The years of experience in the psychiatric field were associated with inability to understand the patients' feelings'. Differences in empathy among the subjects were not found. CONCLUSION: The understanding of the empathic process in the therapeutic approach towards PTSD explored in this study was associated with basic variables such as gender and age but the construct of empathy itself is more complex and related with variables not assessed in this study, so our findings are preliminary and further research is needed. PMID- 23013635 TI - Hopelessness, suicidality and religious coping in Croatian war veterans with PTSD. AB - BACKGROUND: Hopelessness is a strong predictor of suicide which is closely associated with PTSD in war veterans. Previous studies showed that if religious faith in war veterans was weakened it contributed to more extensive current use of mental health services. War trauma experience can weaken religious faith as well as strengthen it. It partly depends on religious coping which can be positive or negative. SUBJECTS AND METHODS: In our work we present correlation between hopelessness (measured with Beck Hopelessness Scale) and style of religious coping (positive or negative, measured with R-COPE) in 111 Croatian war veterans with PTSD and 39 healthy volunteers. RESULTS: Veterans with PTSD were more hopeless than healthy volunteers, and had greater usage of negative religious coping. In PTSD group, less hopeless veterans showed greater extent in use of positive religious coping strategies. CONCLUSION: These findings suggest that experts treating male combat veterans with PTSD should inquire about religious coping of the individual. Positive religious coping should be encouraged while negative religious coping should be addressed appropriately. PMID- 23013636 TI - Family relationships and post-traumatic growth in breast cancer patients. AB - BACKGROUND: Post-traumatic growth (PTG) refers to the process of attributing meaning to traumatic events and positive changes in life after facing trauma. A number of studies have already demonstrated that demographic- and coping approaches related variables predict PTG, yet little is known about whether PTG may be predicted by family processes such as flexibility, cohesion, communication and satisfaction. The main purpose of the study therefore was to determine whether family-related factors predict PTG above and beyond demographic variables and coping related processes. SUBJECTS AND METHODS: The study included 190 women, breast-cancer patients, aged 31 to 83 years. Their educational level was representative of the educational level in the population of this age range. The Participants were members of the Oncology Patients Society. Post traumatic growth index, FACES-IV - family relationships scale, coping response inventory, demographic, and illness-related questionnaires were administered after informed consent was obtained. The PTG index was used as an outcome measure. RESULTS: Congruent with previous findings, analyses yielded weak correlations between demographic- and illness-related variables, and PTG. Also congruent with previous findings, approach related coping strategies were found to predict PTG, R squared =0.16, p<0.001. In addition to previous findings, family related factors predicted unique proportion of variance on PTG, p<0.05, with communication having positive and satisfaction negative load on PTG. CONCLUSIONS: Results showed that family related factors predicted PTG above and beyond coping-related strategies and demographics. Communication, however, seems to mediate the association between satisfaction and PTG. Theoretical concerns and practical implications are discussed. PMID- 23013637 TI - The prevalence of cardiometabolic risk factors and the ten-year risk of fatal cardiovascular events in patients with schizophrenia and related psychotic disorders. AB - BACKGROUND: People suffering from schizophrenia have a significantly shorter lifespan compared to the general population. The majority of deaths are caused by physical diseases, including cardiovascular events. The aim of this cross sectional study was to predict the risk of premature cardiovascular mortality and assess the prevalence of cardiometabolic risk factors in a sample of Czech patients with schizophrenia and related psychoses. SUBJECTS AND METHODS: We reviewed data from 129 subjects treated in an outpatient clinic that specialised in psychoses. The main collected variables included basic physical parameters (height, weight, waist circumference, blood pressure), smoking habits, laboratory data (glucose level, serum lipid level) and an electrocardiograph (ECG). We calculated the ten-year risk of fatal cardiovascular events using the Systematic Coronary Risk Evaluation (SCORE) chart. RESULTS: The most prevalent risk factors were being overweight (70% of patients had a BMI over 25), dyslipidaemia (70% of patients) and smoking (43% of patients). According to the SCORE diagram, there was a high risk of fatal cardiovascular events over a ten-year period in 10% of the study group. The percentage was even higher (24%) when the latest European guidelines for cardiovascular disease prevention were used to calculate the risk. CONCLUSIONS: Our outcomes indicate even higher cardiometabolic morbidity rates in patients with psychoses than those referenced in the literature. PMID- 23013638 TI - The prevalence of metabolic syndrome and Framingham cardiovascular risk scores in adult inpatients taking antipsychotics - a retrospective medical records review. AB - BACKGROUND: The objective of this retrospective records review was to evaluate the prevalence of metabolic syndrome (MetS) and Framingham cardiovascular risk scores in adult inpatients taking antipsychotics. SUBJECTS AND METHODS: Hospital records of 62 patients (27 women and 35 men) taking antipsychotics were retrospectively reviewed for: body height and weight, waist circumference, cigarette smoking, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides (TGA), fasting plasma glucose (FPG), blood pressure, concomitant use of antidiabetic, antihypertensive and antihyperlipidemic medications. RESULTS: MetS was diagnosed in 29.0% (ATPIII), 35.5% (ATPIII A) and 41.9% (IDF) of patients. The prevalence of MetS components was: central obesity 50.0% (ATPIII and ATPIII A), 75.8% (IDF); hypertension 40.3% (ATPIII, ATPIII A and IDF); reduced HDL cholesterol 51.6% (ATPIII, ATPIII A and IDF); raised TGA 38.7% (ATPIII and ATPIII A), 41.9% (IDF); raised FPG 11.3% (ATPIII), 24.2% (ATPIII A) and 24.2% (IDF). Most of cardiovascular risk scores were higher in subjects with MetS. Mean BMI (28.4 kg/m2) and waist circumference (97.8 cm) were above cut points for overweight and IDF-defined abdominal obesity. Mean total cholesterol (203.2 mg/dL) and TGA (159.1 mg/dL) levels were above upper limit of normal ranges. Overweight or obesity and abdominal obesity (more frequent in women: 88.9% vs. 65.7%; P=0.035) were found in 69.4% and 75.8% of the patients, respectively. Over 60% of subjects with hyperlipidemia (77.4% of the whole group) had no hypolipidemic therapy on discharge. CONCLUSIONS: The prevalence of MetS in subjects taking antipsychotics exceeds the prevalence in general population. Its presence increases the risk of cardiovascular events. Increased body weight and metabolic abnormalities were frequent in our group of patients (particularly in women) taking antipsychotics. Most patients with hyperlipidemia had no antihyperlipidemic introduced. PMID- 23013639 TI - Early intervention program for psychotic disorders at the psychiatric hospital "Sveti Ivan". AB - The Early intervention program for the first episodes of psychotic disorders (RIPEPP) at the Psychiatric Hospital "Sveti Ivan" in Zagreb encompasses patients hospitalized due to various psychoses (acute psychotic disorder, schizophrenia, schizoaffective and delusional disorder, bipolar affective disorder with psychotic symptoms) in the "critical period" of illness, i.e. within five years after the occurrence of the first symptoms. The RIPEPP Program consists of an in- and out-patient part, and includes psychotherapeutic and psychoeducative components as well as the administration of antipsychotics. The Psychotherapeutic part, conducted by psychotherapists - group analysts, comprises psychodynamic group psychotherapy for patients and for family members. The Psychoeducative part, led by cognitive-behavioral therapists, is carried out through educative interactive workshops for both patients and their family members. The paper describes the theoretical framework, as well as the professional, personnel, educative and organizational basis of the Program, the principles of evaluation and some experiences after five years of implementation. PMID- 23013640 TI - Family survived the sinking of "Costa Concordia". PMID- 23013641 TI - Three polymorphisms in the IL-10 gene and the risk of HCV infection: a meta analysis plus a Chinese Association Study involving 1140 subjects. AB - The influence of an immunosuppressive cytokine, interleukin-10 (IL-10), on the outcome of hepatitis C virus (HCV) infection has been increasingly reported recently. A number of polymorphisms appear to control the level of IL-10 production. Among them, -592C/A, -819C/T and -1082G/A in the IL-10 gene are three most studied single nucleotide polymorphisms. To provide a more definitive conclusion about their association with the risk of HCV infection, a meta analysis was performed by combining and summarizing a total of 17 studies. A biological justification for the choice of genetic model was provided. The results indicated no significant association between these IL-10 polymorphisms and the susceptibility to HCV infection [-592C/A: odds ratio (OR) 0.99, 95% confidence interval (CI) 0.78-1.25; -819C/T: OR 0.90, 95% CI 0.69-1.18; -1082G/A: OR 1.34, 95% CI 0.90-2.00]. However, this analysis did not account for the possible risk modifications by other factors, such as ethnicity and virus persistence. Therefore, the effects of ethnicity and virus persistence were investigated using Bayesian meta-regression and subgroup analysis. Finally, an extended case-control association study was conducted in a Chinese population involving 1140 subjects. Both serum level and genotype data of IL-10 -1082G/A were determined. As a result, a low prevalence of G allele was observed. Significantly higher IL-10 production was observed in HCV patients, especially patients with the GG genotype. PMID- 23013642 TI - Cyclotron resonance in HgTe/CdTe-based heterostructures in high magnetic fields. AB - : Cyclotron resonance study of HgTe/CdTe-based quantum wells with both inverted and normal band structures in quantizing magnetic fields was performed. In semimetallic HgTe quantum wells with inverted band structure, a hole cyclotron resonance line was observed for the first time. In the samples with normal band structure, interband transitions were observed with wide line width due to quantum well width fluctuations. In all samples, impurity-related magnetoabsorption lines were revealed. The obtained results were interpreted within the Kane 8.8 model, the valence band offset of CdTe and HgTe, and the Kane parameter EP being adjusted. PMID- 23013643 TI - The early anti-inflammatory effect of Kefir in experimental corrosive esophagitis. AB - AIM: Corrosive esophageal burns are still an important problem. The aim of this study was to evaluate the effect of kefir in an experimental corrosive esophagitis model. MATERIAL AND METHOD: Twenty-four male wistar albino rats were used in this experimental study. The rats were randomized into three groups according to the procedure and treatment type (each group has eight rats). Group I: (Control group), Group II: (Induction of corrosive esophagitis with 5 % NaOH without any treatment) and Group III: (Corrosive esophagitis treated with kefir). The rats were sacrificed on the first and seventh days. Mediastinum and abdominal cavity of rats were explorated. Approximately 1.5 cm of esophagus was removed for histopathological examination. Inflammation, injury in the muscularis mucosa and collagen deposition were evaluated. RESULTS: Histopathological results on the first day after caustic injury; inflammation was detected in three rats in Group II and there were no inflammation in rats in Group III. This difference was statistically significant (p<0.05). Injury in muscularis mucosa was detected in three rats in Group II and in one rat in Group III. Histopathological results on the seventh days after caustic injury; Inflammation was positive in four rats in Group II and three rats in Group III. Injury in muscularis mucosa was equal in two groups (three rats each). Collagen deposition with high grade (Grade 2) was detected in two rats in Group II and in four rats in Group III (p<0.05). CONCLUSION: Kefir has anti-inflammatory effect specially in early phase of caustic injury. It has also some beneficial effect in wound healing. PMID- 23013644 TI - Aptamer-based protein detection using a bioluminescent fusion protein. AB - An aptamer-based sandwich-type immunoassay is presented to detect human thrombin using a bioluminescent fusion protein, SSB-fLuc. Escherichia coli single-stranded DNA binding protein (SSB) is used as a linker between the aptamer and firefly luciferase (fLuc). For proof-of-principle, thrombin was used as the test analyte and thrombin aptamer as the sensing probe. In this fusion protein, both the SSB and the fLuc parts retained their biological activities after expression and purification. The SSB fragment of the fusion protein also had the thrombin aptamer binding ability either alone or in combination with thrombin as a triplex, which was confirmed by gel mobility shift assay using native polyacrylamide gels. The fusion protein can be used to detect thrombin in the nanomolar range. The present study thus demonstrates an aptamer-based bioluminescent assay that is simple and cost effective, and at the same time eliminates the need for labeling of either analytes or aptamers. This biomolecular detection scheme can be extended to the detection of a wide range of analytes. PMID- 23013645 TI - Annotate-it: a Swiss-knife approach to annotation, analysis and interpretation of single nucleotide variation in human disease. AB - The increasing size and complexity of exome/genome sequencing data requires new tools for clinical geneticists to discover disease-causing variants. Bottlenecks in identifying the causative variation include poor cross-sample querying, constantly changing functional annotation and not considering existing knowledge concerning the phenotype. We describe a methodology that facilitates exploration of patient sequencing data towards identification of causal variants under different genetic hypotheses. Annotate-it facilitates handling, analysis and interpretation of high-throughput single nucleotide variant data. We demonstrate our strategy using three case studies. Annotate-it is freely available and test data are accessible to all users at http://www.annotate-it.org. PMID- 23013646 TI - Immune-modulating gut symbionts are not "Candidatus Arthromitus". PMID- 23013648 TI - Systems biology approaches in biological and biomedical research: opportunities and challenges. PMID- 23013647 TI - Outcomes in cardiac surgery in 500 consecutive Jehovah's Witness patients: 21 year experience. AB - BACKGROUND: Refusal of heterogenic blood products can be for religious reasons as in Jehovah's Witnesses or otherwise or as requested by an increasing number of patients. Furthermore blood reserves are under continuous demand with increasing costs. Therefore, transfusion avoidance strategies are desirable. We describe a historic comparison and current results of blood saving protocols in Jehovah's Witnesses patients. METHODS: Data on 250 Jehovah's Witness patients operated upon between 1991 and 2003 (group A) were reviewed and compared with a second population of 250 patients treated from 2003 to 2012 (group B). RESULTS: In group A, mean age was 51 years of age compared to 68 years in group B. An iterative procedure was performed in 13% of patients in group B. Thirty days mortality was 3% in group A and 1% in group B despite greater operative risk factors, with more redo, and lower ejection fraction in group B. Several factors contributed to the low morbidity-mortality in group B, namely: preoperative erythropoietin to attain a minimal hemoglobin value of 14 g/dl, warm blood cardioplegia, the implementation of the Cornell University protocol and fast track extubation. CONCLUSIONS: Cardiac surgery without transfusion in high-risk patients such as Jehovah Witnesses can be carried out with results equivalent to those of low risk patients. Recent advances in surgical techniques and blood conservation protocols are main contributing factors. PMID- 23013649 TI - Network-based approaches for extending the Wnt signalling pathway and identifying context-specific sub-networks. AB - Wnt signalling is a critically important signalling pathway regulating embryogenesis and differentiation, and is broadly conserved amongst multicellular animals. In addition, dysregulation of Wnt signalling contributes to the pathogenesis of many human cancers, in particular colorectal cancer. Core members of the Wnt signalling pathway are quite well defined, although it has become apparent that a much broader network of interacting proteins regulates Wnt signalling activity. The goal of this paper is first to identify novel members of the Wnt regulatory network; and second, to identify sub-networks of the larger Wnt signalling network that are active in different biological contexts. We address these two questions using complementary computational approaches and show how these approaches may identify potentially novel Wnt signalling proteins as well as defining Wnt sub-networks active in different stages of colorectal cancer. PMID- 23013650 TI - Identification of disease-related nsSNPs via the integration of protein sequence features and domain-domain interaction data. AB - Recent studies have suggested the common disease-rare variant (CD-RV) hypothesis in the mapping of disease-related genetic variants and have proposed a number of statistical methods to detect associations between rare variants and human inherited diseases. However, most of these methods take the selection of functional variants as a preliminary step in order to maximise the power of statistical tests. To meet this end, we put forward a filtration approach to identify genetic variants that are potentially associated with a query disease of interest from the perspective of one-class novelty learning. We propose to prioritise candidate non-synonymous single nucleotide polymorphisms (nsSNPs) relying on the integrated use of two sequence conservation properties of amino acids calculated from multiple sequence alignment of protein sequences and one functional similarity measure derived from domain-domain interaction data. We show the power of this approach in the detection of disease-related nsSNP via large-scale leave-one-out cross-validation experiments. PMID- 23013651 TI - Functional identification in correlation networks using gene ontology edge annotation. AB - Correlation networks identify mechanisms behind observed change in temporal data sets; however, it is often difficult to discriminate between causative versus coincidental structures in such networks. We propose a method to enhance causative relationships based on annotations derived from the Gene Ontology (GO). Enriching correlation networks with biological relationships is likely to conserve relevant signals while reducing the network size. The obtained results are structures enriched in GO functions, despite reduction in network size. Our proposed method annotates edges according to the shortest path between elements and the position of the deepest common parent in the GO tree. Our results show that such enrichment brings functional relationships to the forefront which allows for the identification of clusters with significant biological relevance. Further, this method impacts the identification of essential genes within a network model. This approach for uncovering true function of relationships provides annotation beyond traditional statistical analysis. PMID- 23013652 TI - Functional classification of genes using semantic distance and fuzzy clustering approach: evaluation with reference sets and overlap analysis. AB - Functional classification aims at grouping genes according to their molecular function or the biological process they participate in. Evaluating the validity of such unsupervised gene classification remains a challenge given the variety of distance measures and classification algorithms that can be used. We evaluate here functional classification of genes with the help of reference sets: KEGG (Kyoto Encyclopaedia of Genes and Genomes) pathways and Pfam clans. These sets represent ground truth for any distance based on GO (Gene Ontology) biological process and molecular function annotations respectively. Overlaps between clusters and reference sets are estimated by the F-score method. We test our previously described IntelliGO semantic distance with hierarchical and fuzzy C means clustering and we compare results with the state-of-the-art DAVID (Database for Annotation Visualisation and Integrated Discovery) functional classification method. Finally, study of best matching clusters to reference sets leads us to propose a set-difference method for discovering missing information. PMID- 23013653 TI - Associating functional groups to multiple clinical types using combined t-test scores and contingency-based measures: a study on breast cancer genes. AB - Stemming from the need to score relations between functional groups of genes and multiple clinical types associated with a tumour, this study proposes to use contingency-based measures to quantify such relations. It aims at reflecting a relative measure of association within a specific set of functional groups, and a specific set of clinical statuses. The proposed methodology is based on extracting features (scores) from expression sets that relate genes to multiple cancer subtypes (clinical statuses), and use those features (scores) to associate cancer subtypes with functional groups. It proposes combining t-test scores at several levels of cancer statuses' differentiation to calculate such gene features. It also proposes using contingency based measures as Jaccard and F measure to associate gene functional groups to multiple cancer subtypes/statuses. Variations from the original Jaccard measure are proposed to reflect scores of genes' relations to classes/groups rather than using binary relations. The core objective of the experimental study is to identify the functional categories of genes that mark the change in lymph node status under each of oestrogen receptor positive and negative statuses in breast cancer expression sets. PMID- 23013654 TI - A linear-time algorithm for finding a maximum-length ORF in a splice graph. AB - We present a linear-time, deterministic algorithm for finding a longest Open Reading Frame (ORF) in an alternatively spliced gene represented by a splice graph. Finding protein-encoding regions is a fundamental problem in genomic and transcriptomic analysis, and in some circumstances long ORFs can provide good predictions of such regions. Splice graphs are a common way of compactly representing what may be exponentially many alternative splicings of a sequence. The efficiency of our algorithm is achieved by pruning the search space so as to bound the number of reading frames considered at any vertex of the splice graph. The algorithm guarantees that the unpruned reading frames contain at least one longest ORF of the gene. We are therefore able to find a longest ORF among all splice variants in time linear in the size of the splice graph, even though the number of potential transcripts may be much larger. PMID- 23013655 TI - Integrating image analysis algorithms in a web interface for the quantification of microtubule dynamics. AB - We present improvements to a web interface and an integrated computational tracking algorithm for quantitative analysis of microtubule dynamics in live-cell microscopy images. Based on a previously implemented system, more new functionalities have been added to the interface. The system also integrates a computational tracking algorithm to aid the analysis. The analysis workflow of the proposed interface is made similar to the current manual analysis workflow in order to make the interface intuitive to use. We show the workflow of the computer analysis algorithm and how it is used to aid the existing analysis workflow. We also demonstrate how to re-evaluate existing data in a case study using real imaging data. Lastly, we show the added functionalities of the interface including how to share image data and analysis results. PMID- 23013656 TI - Identification of two post-translational modifications via tandem mass spectrometry. AB - Post-Translational Modifications (PTMs) play most important roles in the accomplishment of biological processes and molecular functions. It is challenging to identify two PTMs for a tandem mass spectrum. In this paper, we proposed a new algorithm to detect two PTMs with unknown types. First, we constructed a Pair of Peak Set (PPS) which is composed of pairs of peaks that have the highest sum of intensities. Second, we revealed the relationship between PPS and the whole experimental spectrum. Third, a series of logic conditions was proposed to detect PTMs from a MS/MS spectrum. Finally, we used a scoring function to rank the candidate hits. We applied the method to a large MS/MS data set and the experimental results demonstrated that the proposed method achieved better performance of identifying any types of PTMs in a blind mode than current existing methods. PMID- 23013657 TI - Peptide sequence tag generation for tandem mass spectra containing post translational modifications. AB - Tandem mass spectrometry is a popular tool for the identification of peptide sequences. In this paper, we present a method for a rapid generation of short peptide sequences via tandem mass spectrometry based on a graph search method. The approach takes advantage of several pairs of peaks that have high intensities. We proposed a Pair Peak value Set (PPS) and used the pair peak values of highest intensities as the root of a tree. The other nodes are viewed as the reference nodes to search the most promising path. We aimed to determine the peptide sequences for MS/MS spectra that have low signal-to-noise ratios. Our experiment on 2420 experimental MS/MS spectra with two PTMs shows that our algorithm achieves better accuracy than the PepNovo approach with higher efficiency. PMID- 23013658 TI - Fourth generation detour matrix-based topological indices for QSAR/QSPR - part-1: development and evaluation. AB - In the present study, four detour matrix-based Topological Indices (TIs) termed as augmented path eccentric connectivity indices 1-4 (denoted by (AP)xi(1)(C), (AP)xi(2)(C), (AP)xi(3)(C) and (AP)xi(4)(C)) as well as their topochemical versions (denoted by (AP)xi(1c)(C), (AP)xi(2c)(C), (AP)xi(3c)(C) and (AP)xi(4c)(C)) have been conceptualised. A modified detour matrix termed as chemical detour matrix (Delta(c)) has also been proposed so as to facilitate computation of index values of topochemical versions of the said TIs. Values of the proposed TIs were computed for all the possible structures containing three, four and five vertices using an in-house computer program. The said TIs exhibited exceptionally high discriminating power and high sensitivity towards branching/relative position of substituent(s) in cyclic structures amalgamated with negligible degeneracy. Due care was taken during the development of TIs so as to ensure that reduction in index values of complex chemical structures to be within reasonable limits without compromising discriminating power. The mathematical properties of one of the proposed TIs have also been studied. With exceptionally high discriminating power, high sensitivity towards branching as well as relative position(s) of substituents in cyclic structures and negligible degeneracy, the proposed indices offer a vast potential for use in characterisation of structures, similarity/dissimilarity studies, lead identification and optimisation, combinatorial library design and quantitative structure-activity/property/toxicity/pharmacokinetic relationship studies. PMID- 23013660 TI - Single-step route to diamond-nanotube composite. AB - Candle wax was used as a precursor for the production of a diamond-nanotube composite in a single step. The composite films were fabricated by sulfur assisted hot-filament chemical vapor deposition technique. The morphology of the composite films was analyzed by scanning electron microscopy and transmission electron microscopy. Raman spectra of the films show characteristic diamond band at 1,332 cm-1, D-band around 1,342 cm-1, and graphitic G-band around 1,582 cm-1. The electron energy-loss spectroscopy recorded at the carbon K-edge region shows signature features of diamond and carbon nanotube in the fabricated material. The ability to synthesize diamond-nanotube composites at relatively low temperatures by a single-step process opens up new possibilities for the fabrication of nanoelectronic devices. PMID- 23013659 TI - Community incidence of pathogen-specific gastroenteritis: reconstructing the surveillance pyramid for seven pathogens in seven European Union member states. AB - By building reconstruction models for a case of gastroenteritis in the general population moving through different steps of the surveillance pyramid we estimated that millions of illnesses occur annually in the European population, leading to thousands of hospitalizations. We used data on the healthcare system in seven European Union member states in relation to pathogen characteristics that influence healthcare seeking. Data on healthcare usage were obtained by harmonized cross-sectional surveys. The degree of under-diagnosis and underreporting varied by pathogen and country. Overall, underreporting and under diagnosis were estimated to be lowest for Germany and Sweden, followed by Denmark, The Netherlands, UK, Italy and Poland. Across all countries, the incidence rate was highest for Campylobacter spp. and Salmonella spp. Incidence estimates resulting from the pyramid reconstruction approach are adjusted for biases due to different surveillance systems and are therefore a better basis for international comparisons than reported data. PMID- 23013661 TI - Molecular imaging for prostate cancer diagnosing and for guiding tailored therapies. PMID- 23013662 TI - Clinical and diagnostic assessment for therapeutic decisions in prostate cancer. AB - Due to the heterogeneity of prostate cancer (PCa) outcomes, there is a need for individualized treatment plans based on clinical and cancer characteristics. Recent advances in sophisticated imaging modalities have improved the ability to stratify patients according to their risk of PCa diagnosis and progression. This, in turn, has positively influenced the clinical decision making process. However, there is also an overuse of diagnostic imaging in the evaluation of PCa patients. Baseline diagnostic and re-staging evaluations need to be indeed personalized, in order to maximize the results and reduce unnecessary, lengthy and costly procedures. The aim of this review was to critically evaluate current international guidelines in order to identify clinical and diagnostic markers that might help clinicians in the selection of the most appropriate imaging approach. For this aim, different imaging modalities were analyzed in patients with newly diagnosed PCa, focusing on local, nodal and distant staging. Every step of staging was taken into consideration based on patient individualized risk, as defined by routinely available clinical variables. Second, different imaging techniques were also reviewed in the context of relapse after primary treatment, highlighting their utility and impact in the clinical decision making process. This review focuses mainly on conventional established imaging techniques, with an eye also to novel approaches that still need to be validated on large patient series. PMID- 23013663 TI - Conventional imaging and multiparametric magnetic resonance (MRI, MRS, DWI, MRP) in the diagnosis of prostate cancer. AB - The evaluation and management of prostate cancer (PCa) are based mainly on parameters such as the serum prostate-specific antigen level, clinical stage, and pathologic findings at biopsy or after surgery. The aim of this paper was to review the current roles of conventional imaging and multiparametric magnetic resonance imaging (mpMRI) techniques in the diagnosis of PCa. A non systematic literature search using the Medline and Cochrane Library databases was performed up to January 2012. Bibliographies of retrieved articles and review articles were also examined. Only those articles reporting complete data with clinical relevance for the present review (i.e., diagnosis, staging) were selected. The advent of a high performance (1.5T) and higher fields strength (3T), and thus, higher spatial resolution, increased the potentiality and the diffusion of MR examinations. Intense research has focused on the use of complementary techniques to improve the detection, characterization, and staging of PCa by MRI. This review article is divided into two major parts: the first one considers the technical aspects of mpMRI; the second part is intended to provide the impact of this technique on patients with PCa. Published data indicate an emerging role for MRI (particularly mpMRI combining T2 weighted imaging, diffusion weighted imaging, contrast enhanced MR, and spectroscopy) as the most sensitive and specific tool available for imaging PCa. MpMRI can provide metabolic information, characterize tissue and tumor vascularity, as well as tissue cellularity and correlate with tumor aggressiveness. PMID- 23013664 TI - PET/CT and choline: diagnosis and staging. AB - As prostate cancer is the most prevalent form of cancer in men and constitutes the third most common cause of cancer associated deaths, early diagnosis of primary prostate cancer and accurate staging influencing the appropriate choice of therapy is crucial. PET and PET/CT using [11C]- and [18F]-labelled choline derivates are increasingly being used for imaging primary and recurrent prostate cancer. The value of [11C]- and [18F]choline PET and PET/CT in patients with biochemical recurrence of prostate cancer has been evaluated in many studies and shows an increasing importance. Morphological imaging techniques such as TRUS, CT and MRI (including functional imaging tools) have shown only limited accuracy for the diagnosis of primary prostate cancer. Molecular imaging techniques such as PET and PET/CT may improve the detection rate and localization of primary prostate cancer. The potential of PET/CT using [11C]- and [18F]-labelled choline derivates for the diagnosis of primary prostate cancer has been assessed in a lot of studies with partly controversial results. [11C]- and [18F]choline PET and PET/CT demonstrated moderate sensitivity for the detection of primary prostate cancer, which depends on the tumour configuration. Furthermore the detection rate is limited by a considerable number of microcarcinomas that can often not be visualized due to partial volume effects. Therefore small and in part rind-like tumours can often not be detected. Additionally, specificity of [11C]- and [18F]choline PET and PET/CT is limited as differentiation between benign prostatic changes like prostatitis, prostatic hyperplasia and high-grade intraepithelial neoplasia (HGPIN) is not always possible. At the present time, the routine use of PET/CT with [11C]- and [18F]-labelled choline derivates can not be recommended as a first-line screening procedure for primary prostate cancer in men at risk. However, choline PET and PET/CT may be useful in preparation of a focused re-biopsy in patients suffering from clinically suspected prostate cancer with repeatedly negative prostate biopsies. In the future [11C]- and [18F]choline PET and PET/CT may also be helpful in patient stratification with respect to primary surgery and radiation therapy. PMID- 23013665 TI - Restaging prostate cancer patients with biochemical failure with PET/CT and radiolabeled choline. AB - PET/CT with either [11C]choline or [18F]fluorocholine represents a powerful technique for restaging prostate cancer (PCa) patients with biochemical failure. The availability of dedicated PET/CT scanners allows fusioning of morphological and functional images, which enables accurate localization of sites of pathological tracer uptake and ease the differentiation between malignant and benign findings. A noteworthy advantage of this whole-body technique is that it provides information on multiple anatomic sites at a single time. As such, the technique has the capability of distinguishing between local relapse and distant metastases, and therefore has the potential to guide the medical treatment. The positive detection rate of [11C]choline PET/CT varies substantially in relation to the inclusion criteria. Studies which included unselected consecutive patients reported a positive detection rate ranging between 40% and 70%. Serum PSA level represents the single, most important factor affecting the rate of positive scans. Other positive predicitive factors include fast PSA kinetics (PSA velocity, PSA doubling time), advanced pathological state at initial staging, previous biochemical failure, hormone resistance and older age. Recent studies indicate that [11C]choline PET/CT has the potential to early restaging PCa patients for PSA levels lower than 1-1.5 ng/mL. However, more studies are necessary to better define the potential of this technique for low PSA levels. The previously cited risk factors can be used to identify patients that are at greater risk and that might best benefit from PET/CT scans. Patients that develop biochemical failure during androgen deprivation therapy (hormone resistance) have a higher likelihood for a positive [11C]choline PET/CT scan in comparison to patients that are drug naive (hormone sensitive) and are not required to withdraw the anti-androgenic treatment before PET/CT. PMID- 23013666 TI - PET/CT in prostate cancer: non-choline radiopharmaceuticals. AB - In this brief review, the major potential clinical applications of 18F-FDG, 11C acetate, 18F-FDHT, 18F-FLT, 18F-FMAU, and anti-18F-FACBC in the imaging evaluation of men with prostate cancer are discussed. 18F-FDG has a limited role in primary diagnosis and staging but it may be able to reflect tumour aggressiveness, detect sites of recurrence in some men with high serum PSA after biochemical failure and assess response to chemo- and hormonal treatment in metastatic disease. 11C-acetate has been investigated for intra-prostatic primary tumour detection and staging as well as for re-staging in case of biochemical relapse with results that are overall similar to those with 18F- and 11C-labeled choline. 18F-FDHT targets the androgen receptor and may be particularly useful in the assessment of the pharmacodynamics of the androgen signalling pathway. PET in conjunction with 18F-FLT or 18F-FMAU that track the thymidine salvage pathway of DNA synthesis has also been investigated for imaging cellular proliferation in prostate cancer. Initial experience with the radiolabeled synthetic amino acid, anti-18F-FACBC, which displays slow urinary excretion has been encouraging but further studies will be needed to decipher its exact role in the imaging management of men with prostate cancer. PMID- 23013667 TI - Comparison of 18F-FDG positron emission tomography/computed tomography and computed tomography in patients with already-treated breast cancer: diagnostic and prognostic implications. AB - AIM: The purpose of the study was to assess the comparison of 18F-FDG PET/CT and CT in patients with breast cancer (BC) already treated with primary therapy, in evaluating the diagnostic and prognostic values. METHODS: We retrospectively studied 190 patients (187 women and 3 men, mean age 61+/-11 years) with previous BC (all stages) after surgery and other primary treatments. They underwent within three months CT and 18F-FDG PET/CT examinations for the evaluation of disease status. Disease relapse was confirmed by clinical evaluation and/or radiological findings. Survival curves of disease-free survival (DFS) and overall survival (OS) were computed using Kaplan-Meier method. Cox analysis regression was used to determine predictive factors of DFS and OS. RESULTS: Of the overall 190 patients, 82 (43%) had evidence of clinical and/or imaging disease relapse, while 108 (57%) did not. Sensitivity, specificity, negative predictive and positive predictive values for disease relapse or progression were of 89% vs. 77%, 73% vs. 53%, 90% vs. 75% and 72% vs. 55%, respectively for PET/CT and CT. DFS curves were significantly different in patients with both negative and positive PET/CT and CT (log-rank test 33.6; P<0.0001 and 12.7; P=0.003, respectively). OS curves were similar in patients with positive/negative PET/CT and CT (P=NS). By both univariate and multivariate Cox regression analysis positive PET/CT was found to be related to the disease recurrence (HR 0.18 and 0.20, both P<0.0001, respectively). CONCLUSION: PET/CT is more accurate than CT in identification of disease relapse in a large population of BC patients. In women at high-risk of recurrence, PET/CT imaging can provide the early detection of BC metastases, tailoring a proper treatment. PMID- 23013668 TI - Molybdenum-99 production from reactor irradiation of molybdenum targets: a viable strategy for enhanced availability of technetium-99m. AB - Fission-produced 99Mo (F 99Mo) is traditionally used for fabrication of 99Mo/99mTc alumina-based column generators. In this paper, several emerging strategies are discussed which are being pursued or have been suggested to overcome the continuing shortages of F 99Mo. In addition to the hopeful eventual success of these proposed new 99Mo and 99mTc production technologies, an additional attractive strategy is the alternative production and use of low specific activity (LSA) 99Mo. This strategy avoids fission and is accomplished by direct activation of molybdenum targets in nuclear reactors, which would preclude sole continued reliance on F 99Mo. The principal focus of this paper is a detailed discussion on the advantages and strategies for enhanced production of LSA 99Mo using an international network of research reactors. Several effective strategies are discussed to obtain 99mTc from LSA 99Mo as well as more efficient use of the alumina-based generator system. The delayed time period between 99Mo production and traditional 99Mo/99mTc alumina column generator manufacture and distribution to user sites results in the loss of more than 50% of 99Mo activity. Another strategy is a paradigm shift in the use of 99Mo by recovering clinical grade 99mTc from 99Mo solution as an alternative to use of 99Mo/99mTc column generators, thereby avoiding substantial decreased availability of 99Mo from radioactive decay. Implementation of the suggested strategies would be expected to increase availability of 99mTc to the clinical user community by several fold. Additional important advantages for the use of LSA 99Mo include eliminating the need for fission product waste management and precluding proliferation concerns by phasing out the need for high (HEU)- and low (LEU)-enriched uranium targets required for F 99Mo production. PMID- 23013670 TI - Difficulties for cardiovascular retrospective diagnosis on mummified foetal remains. PMID- 23013669 TI - Development and testing of a new disposable sterile device for labelling white blood cells. AB - AIM: White blood cell (WBC) labelling requires isolation of cells from patient's blood under sterile conditions using sterile materials, buffers and disposables under good manufacturing practice (GMP) conditions. Till now, this limited the use of white blood cell scintigraphy (WBC-S) only to well equipped laboratories with trained personnel. We invented, developed and tested a disposable, sterile, closed device for blood manipulation, WBC purification and radionuclide labelling without exposing patient's blood and the operator to contamination risks. This device prototype and a final industrialized device (Leukokit(r)) were tested for WBC labelling and compared to standard procedure. Leukokit(r) was also tested in an international multi-centre study for easiness of WBC purification and labelling. METHODS: On the device prototype we tested in parallel, with blood samples from 7 volunteers, the labelling procedure compared to the standard procedure of the International Society of Radiolabeled Blood Elements (ISORBE) consensus protocol with respect to cell recovery, labelling efficiency (LE), cell viability (Trypan Blue test) and sterility (haemoculture). On the final Leukokit(r) we tested the biocompatibility of all components, and again the LE, erythro-sedimentation rate, cell viability, sterility and apyrogenicity. ACD-A, HES and PBS provided by Leukokit(r) were also compared to Heparin, Dextran and autologous plasma, respectively. In 4 samples, we tested the chemotactic activity of purified WBC against 1 mg/ml of lipopolysaccharide (LPS) and chemotaxis of 99mTc-HMPAO-labelled WBC (925 MBq) was compared to that of unlabelled cells. For the multi-centre study, 70 labellings were performed with the Leukokit(r) by 9 expert operators and 3 beginners from five centers using blood from both patients and volunteers. Finally, Media-Fill tests were performed by 3 operators on two different days (11 procedures) by replacing blood and kit reagents with bacterial culture media (Tryptic Soy Broth) and testing sterility of aliquots of the medium at the end of procedure. RESULTS: Tests performed with the prototype showed no significant differences with the standard procedure but a faster and safer approach. Tests performed with the final Leukokit(r) confirmed full biocompatibility, sterility and apyrogenicity of all reagents and plastic ware. Average WBC recovery with Leukokit(r) was comparable to that of the ISORBE protocol (117x106+/-24x106 vs. 132x106+/-29x106 cells, P=not significant). No differences in red blood cells and platelet content were observed. LE was 82% +/- 3% for Leukokit(r) and 65+/-5% for control (P=0.0003) being PBS vs autologous plasma the main reason of such difference. Cell viability was always >99.9% in both conditions. Chemotactic tests showed no differences between all Leukokit(r) samples and controls. Haemocultures and Media-Fill tests were always sterile. The procedure was well accepted by expert operators and beginners, with a very fast learning curve (confidence after 2+/-2 labellings). CONCLUSION: The invented device offers high level of protection to operators and patients. The derived Leukokit(r) is safe and easy to use, and gives a high LE of WBC without affecting cell viability and function. Being a registered closed, sterile medical device, it may allow easier and faster WBC labelling that is not limited to only well equipped laboratories. Also simultaneously labelling of multiple patients is possible. PMID- 23013671 TI - Complete resection of undifferentiated cardiac sarcoma and reconstruction of the atria and the superior vena cava: case report. AB - Primary cardiac tumors are rare with an incidence ranging from 0.001% to 0.03% in autopsy series. The prognosis of cardiac sarcomas remains poor because it proliferates rapidly and distant metastases are often found at diagnosis. A 47 year-old male complained of persistent cough. The chest roentgenogram was normal. Subsequent computed tomography revealed a mass in the right atrium. Echocardiography and magnetic resonance imaging confirmed also a right atrial mass (34 x 35 mm) infiltrating the atrial septum. The tumor was completely resected en bloc, including the anterior and lateral right atrial walls, the left atrial dome, and a large segment of the superior vena cava, and reconstructed the atria and superior vena cava with bovine pericardium. The tumor was histologically and immunohistochemically diagnosed as undifferentiated pleomorphic sarcoma. This type of cardiac sarcoma is very rare and usually found in the left atrium. Twenty-seven months after surgery, the patient is doing well without metastasis or local tumor recurrence. PMID- 23013673 TI - The future of deciphering personal genomes? The flies (and yeast and worms) still have it. AB - A report on the 13th International Conference on Systems Biology, held in Toronto, Ontario, Canada, 19-23 August 2012. PMID- 23013672 TI - Optimizing muscle power after stroke: a cross-sectional study. AB - BACKGROUND: Stroke remains a leading cause of disability worldwide and results in muscle performance deficits and limitations in activity performance. Rehabilitation aims to address muscle dysfunction in an effort to improve activity and participation. While muscle strength has an impact on activity performance, muscle power has recently been acknowledged as contributing significantly to activity performance in this population. Therefore, rehabilitation efforts should include training of muscle power. However, little is known about what training parameters, or load, optimize muscle power performance in people with stroke. The purpose of this study was to investigate lower limb muscle power performance at differing loads in people with and without stroke. METHODS: A cross-sectional study design investigated muscle power performance in 58 hemiplegic and age matched control participants. Lower limb muscle power was measured using a modified leg press machine at 30, 50 and 70% of one repetition maximum (1-RM) strength. RESULTS: There were significant differences in peak power between involved and uninvolved limbs of stroke participants and between uninvolved and control limbs. Peak power was greatest when pushing against a load of 30% of 1RM for involved, uninvolved and control limbs. Involved limb peak power irrespective of load (Mean:220 +/- SD:134 W) was significantly lower (p < 0.05) than the uninvolved limb (Mean:466 +/- SD:220 W). Both the involved and uninvolved limbs generated significantly lower peak power (p < 0.05) than the control limb (Mean:708 +/- SD:289 W). CONCLUSIONS: Significant power deficits were seen in both the involved and uninvolved limbs after stroke. Maximal muscle power was produced when pushing against lighter loads. Further intervention studies are needed to determine whether training of both limbs at lighter loads (and higher velocities) are preferable to improve both power and activity performance after stroke. PMID- 23013674 TI - Fragment screening of GPCRs using biophysical methods: identification of ligands of the adenosine A(2A) receptor with novel biological activity. AB - Fragment-based drug discovery (FBDD) has proven a powerful method to develop novel drugs with excellent oral bioavailability against challenging pharmaceutical targets such as protein-protein interaction targets. Very recently the underlying biophysical techniques have begun to be successfully applied to membrane proteins. Here we show that novel, ligand efficient small molecules with a variety of biological activities can be found by screening a small fragment library using thermostabilized (StaR) G protein-coupled receptors (GPCRs) and target immobilized NMR screening (TINS). Detergent-solubilized StaR adenosine A(2A) receptor was immobilized with retention of functionality, and a screen of 531 fragments was performed. Hits from the screen were thoroughly characterized for biochemical activity using the wild-type receptor. Both orthosteric and allosteric modulatory activity has been demonstrated in biochemical validation assays. Allosteric activity was confirmed in cell-based functional assays. The validated fragment hits make excellent starting points for a subsequent hit-to lead elaboration program. PMID- 23013675 TI - Look beyond the rhetoric. PMID- 23013676 TI - Partnering with families. AB - Those who know the patient best can help bridge the gap between hospital and home. PMID- 23013679 TI - Knowing the patient's name. PMID- 23013680 TI - Nurse experts. PMID- 23013681 TI - Patient satisfaction and student nurses. PMID- 23013682 TI - Want fries with that? AB - Drive-through flu vaccination is proving convenient and safe. PMID- 23013683 TI - Diabetes nurse specialists deliver care comparable to physicians' at lower cost. AB - Cost-effectiveness is important in the current world economy. PMID- 23013684 TI - Severe blood conservation doesn't increase risk in cardiac surgery patients. AB - Strategies used to treat Jehovah's Witnesses could benefit other patients. PMID- 23013686 TI - Sports and 'active commuting' mitigate adolescent obesity. AB - As sports programs are being cut, active commuting might fill the gap. PMID- 23013687 TI - Nursing's image on YouTube. AB - If a picture is worth a thousand words, what's a YouTube video worth? PMID- 23013690 TI - Will health care reform increase access for the homeless? AB - Some communities say 'yes,' but more needs to be done, and nurses can help. PMID- 23013693 TI - The 2012 Republican and Democratic health care platforms. AB - Here's what you need to know as the fall elections approach. PMID- 23013699 TI - It takes a team. AB - Challenging the belief that each patient should be cared for by just one nurse. PMID- 23013700 TI - Common misconceptions about professional licensure. AB - Although most health care professionals know that licensing boards can take disciplinary action against them for professional misconduct or gross negligence in clinical practice, nurses may not appreciate the true extent of authority the nursing boards maintain or the issues they address. This three-part series will discuss nursing disciplinary actions and provide tips for maintaining one's license in good standing. Part 1 discusses misconceptions nurses commonly have about licensure. Part 2 will discuss common reasons boards of nursing conduct investigations and take disciplinary action. Part 3 will be a discussion of strategies for protecting your license. PMID- 23013703 TI - Crisis standards of care: a framework for responding to catastrophic disasters. PMID- 23013704 TI - Fecal immunochemical tests for colorectal cancer screening. AB - New fecal occult blood tests have a higher sensitivity and specificity for detection of adenomas and cancer than guaiac-based tests. PMID- 23013705 TI - A good nurse? PMID- 23013707 TI - Chronic obstructive pulmonary disease. PMID- 23013706 TI - Correlation between single nucleotide polymorphisms in CYP4F2 and warfarin dosing in Chinese valve replacement patients. AB - BACKGROUND: Individuals with implanted mechanical valve prostheses require lifelong anticoagulation therapy with warfarin. The narrow therapeutic index of warfarin makes it difficult to dose and maintain proper anticoagulation. A number of single nucleotide polymorphisms (SNPs) affecting vitamin K or warfarin metabolism have been shown to affect warfarin dosing. Our aim was to study the effect of the CYP4F2 rs2108622-1347 (C > T) variant on warfarin dosing in Chinese patients. METHODS: We studied 352 patients after heart valve replacement surgery. Warfarin dosing for patients was adjusted to achieve 1.8 <= INR <= 2.5. We determined the presence of SNPs in CYP4F2 in these patients and investigated their association with warfarin dosing. RESULTS: We found the frequency of the CYP4F2 rs2108622 C allele was 79.5% and T-allele frequency was 20.5%. The warfarin dose requirement for CC individuals was significantly lower than that for CT or TT individuals (P < 0.05). TT-homozygous individuals required a 0.56 mg/day higher dose of warfarin than their CC counterparts. CONCLUSIONS: This study demonstrates that CYP4F2 rs2108622 significantly affects the warfarin dose requirement to achieve adequate anticoagulant activity in Chinese individuals. Genotyping of this SNP may allow clinicians to determine the initiation dose for patients following valve-replacement surgery in China. PMID- 23013708 TI - Nutrition: The vitamin D complex. PMID- 23013709 TI - Devices: Artificial inspiration. PMID- 23013710 TI - Perspective: Clues, not conclusions. PMID- 23013711 TI - Therapeutics: Strength in numbers. PMID- 23013712 TI - Public health: Where there's smoke. PMID- 23013713 TI - Health impact: Breathless. PMID- 23013714 TI - Biochemistry: A radical treatment. PMID- 23013715 TI - Perspective: How can genetics help? PMID- 23013716 TI - Diagnosis: To catch a killer. PMID- 23013718 TI - Correlations in health status between estimates of families of people with amyotrophic lateral sclerosis and estimates of staff. AB - OBJECTIVE: The aim of this study was to compare self-estimates of the physical, psychological, and general well-being of patients with amyotrophic lateral sclerosis (ALS) and their next of kin with the assessment of the nurses and physician of these participants. METHOD: The well-being of 35 pairs of patients and their next of kin was rated by themselves, and by a physician and nurses. The well-being was examined over time, using a visual analogue scale (VAS). Patients' physical function was estimated at the same time with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and the Norris scale. RESULTS: The correlations between the staff's estimates of the well-being of patients and next of kin were similar to their own estimates, even though staff to a higher degree estimated a decrease in well-being over time among the patients. The estimates by the nurses correlated better to that of the patients and next of kin in psychological and general well-being than the physicians' estimates did. SIGNIFICANCE OF RESULTS: Even though the staff's estimates of participants were roughly equivalent to their self-estimates, there were some differences. This result calls attention to the importance of working in teams in which different professional roles are combined and integrated, making it possible to form a holistic view of the situation of each family. A concern overlooked by one member of staff might be covered by another, and different focuses on the family may give a better composite picture of their life situation, which could lead to better support to the family. PMID- 23013720 TI - Influenza vaccination coverage among health-care personnel: 2011-12 influenza season, United States. AB - Influenza vaccination of health-care personnel (HCP) is recommended by the Advisory Committee on Immunization Practices (ACIP). Vaccination of HCP can reduce morbidity and mortality from influenza and its potentially serious consequences among HCP, their family members, and their patients. To provide timely estimates of influenza vaccination coverage and related data among HCP for the 2011-12 influenza season, CDC conducted an Internet panel survey with 2,348 HCP during April 2-20, 2012. This report summarizes the results of that survey, which found that, overall, 66.9% of HCP reported having had an influenza vaccination for the 2011-12 season. By occupation, vaccination coverage was 85.6% among physicians, 77.9% among nurses, and 62.8% among all other HCP participating in the survey. Vaccination coverage was 76.9% among HCP working in hospitals, 67.7% among those in physician offices, and 52.4% among those in long-term care facilities (LTCFs). Among HCP working in hospitals that required influenza vaccination, coverage was 95.2%; among HCP in hospitals not requiring vaccination, coverage was 68.2%. Widespread implementation of comprehensive HCP influenza vaccination strategies is needed, particularly among those who are not physicians or nurses and who work in LTCFs, to increase HCP vaccination coverage and minimize the risk for medical-care-acquired influenza illnesses. PMID- 23013719 TI - Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception. AB - BACKGROUND: The Transient Receptor Potential (TRP) ion channel TRPA1 is a key player in pain pathways. Irritant chemicals activate ion channel TRPA1 via covalent modification of N-terminal cysteines. We and others have shown that 15 Deoxy-Delta12, 14-prostaglandin J2 (15d-PGJ2) similarly activates TRPA1 and causes channel-dependent nociception. Paradoxically, 15d-PGJ2 can also be anti nociceptive in several pain models. Here we hypothesized that activation and subsequent desensitization of TRPA1 in dorsal root ganglion (DRG) neurons underlies the anti-nociceptive property of 15d-PGJ2. To investigate this, we utilized a battery of behavioral assays and intracellular Ca2+ imaging in DRG neurons to test if pre-treatment with 15d-PGJ2 inhibited TRPA1 to subsequent stimulation. RESULTS: Intraplantar pre-injection of 15d-PGJ2, in contrast to mustard oil (AITC), attenuated acute nocifensive responses to subsequent injections of 15d-PGJ2 and AITC, but not capsaicin (CAP). Intraplantar 15d-PGJ2 administered after the induction of inflammation-reduced mechanical hypersensitivity in the Complete Freund's Adjuvant (CFA) model for up to 2 h post injection. The 15d-PGJ2-mediated reduction in mechanical hypersensitivity is dependent on TRPA1, as this effect was absent in TRPA1 knockout mice. Ca2+ imaging studies of DRG neurons demonstrated that 15d-PGJ2 pre-exposure reduced the magnitude and number of neuronal responses to AITC, but not CAP. AITC responses were not reduced when neurons were pre-exposed to 15d-PGJ2 combined with HC-030031 (TRPA1 antagonist), demonstrating that inhibitory effects of 15d PGJ2 depend on TRPA1 activation. Single daily doses of 15d-PGJ2, administered during the course of 4 days in the CFA model, effectively reversed mechanical hypersensitivity without apparent tolerance or toxicity. CONCLUSIONS: Taken together, our data support the hypothesis that 15d-PGJ2 induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons in vitro and in vivo. Moreover, we demonstrate novel evidence that 15d-PGJ2 is analgesic in mouse models of pain via a TRPA1-dependent mechanism. Collectively, our studies support that TRPA1 agonists may be useful as pain therapeutics. PMID- 23013721 TI - Influenza vaccination coverage among pregnant women: 2011-12 influenza season, United States. AB - Pregnant women and their newborns are at elevated risk for influenza-associated hospitalization and death. The Advisory Committee on Immunization Practices (ACIP) and the American College of Obstetricians and Gynecologists (ACOG) have recommended influenza vaccination for all women who are or will be pregnant during the influenza season, regardless of trimester. To estimate influenza vaccination coverage among pregnant women for the 2011-12 influenza season, CDC analyzed data from an Internet panel survey conducted April 3-17, 2012, among women pregnant at any time during the 4-month period October 2011-January 2012. Among 1,660 survey respondents, 47.0% reported they had received influenza vaccination; 9.9% were vaccinated before pregnancy, 36.5% during pregnancy, and <1.0% after pregnancy. Overall, 43.7% of women reported receipt of both a health care provider recommendation and offer of influenza vaccination; these women had higher vaccination coverage (73.6%) than women who received only a recommendation but no offer of vaccination (47.9%) and women who received neither a recommendation nor an offer (11.1%). Continued efforts are needed to encourage providers of medical care to routinely recommend and offer influenza vaccination to women who are pregnant or who might become pregnant. PMID- 23013722 TI - Influenza A (H3N2) variant virus-related hospitalizations: Ohio, 2012. AB - Since July 2012, 305 cases of infection with influenza A (H3N2) variant (H3N2v) virus containing the influenza A (H1N1)pdm09 M gene have occurred in multiple U.S. states, primarily associated with swine exposure at agricultural fairs. In Ohio, from July 28 to September 25, 2012, a total of 106 confirmed H3N2v cases were identified through enhanced surveillance. Whereas most H3N2v patients experienced mild, self-limited influenza-like illness (ILI), 11 of the Ohio patients were hospitalized, representing 69% of all H3N2v hospitalizations in the United States. Of these hospitalized H3N2v patients, six were at increased risk for influenza complications because of age or underlying medical conditions, including the only H3N2v-associated fatality reported in the United States to date. This report summarizes the epidemiology and clinical features of the 11 hospitalized H3N2v patients in Ohio. These findings reinforce the recommendation for persons at high risk for influenza complications to avoid swine exposure at agricultural fairs this fall. In addition, persons not at high risk for influenza complications who wish to reduce their risk for infection with influenza viruses circulating among pigs also should avoid swine and swine barns at agricultural fairs this fall. PMID- 23013723 TI - Postvaccination serologic testing results for infants aged <=24 months exposed to hepatitis B virus at birth: United States, 2008-2011. AB - An estimated 25,000 infants are born to hepatitis B surface antigen (HBsAg) positive women annually in the United States. With no intervention, 40%-90% of these infants will acquire hepatitis B virus (HBV) infection. Approximately 90% of infected infants develop chronic HBV infection, with a 15%-25% risk for premature death from cirrhosis or cancer of the liver. To prevent perinatal HBV transmission, the Advisory Committee on Immunization Practices (ACIP) recommends that infants born to HBsAg-positive women receive postexposure prophylaxis with hepatitis B vaccine (HepB) and hepatitis B immune globulin (HBIG) within 12 hours of birth, and complete the 3-dose HepB series. To determine infant outcomes after postexposure prophylaxis, ACIP recommends postvaccination serologic testing (PVST) at age 9-18 months. To evaluate the implementation of these recommendations, CDC assessed outcomes at age 24 months (through 2011) among infants born to HBsAg-positive women enrolled during 2008-2009 in Enhanced Perinatal Hepatitis B Case Management Projects (EPHBP). Of 4,214 EPHBP-managed infants who completed >=3 HepB doses, 63.7% had reported PVST results, 13.3% had reported PVST results but infant age was unknown, and 23.0% had no reported PVST results. Of 2,683 infants with PVST results by age 24 months, 93.3% were protected, 1.2% were infected, 3.2% remained susceptible, and 2.3% had indeterminate results. ACIP-recommended postexposure prophylaxis was highly effective among infants who completed vaccination and received PVST. PVST is critical for guiding medical management of infants born to HBsAg-positive women, identifying infants with HBV infection and in need of further care, and monitoring progress toward the elimination of perinatal HBV transmission. PMID- 23013724 TI - Application of different chemometric strategies to voltammetric and UV-vis spectroscopic data to obtain a complexation model: study of the Cu(II) binding with the phytohormone 6-benzylaminopurine. AB - The complexation processes of Cu(II) by the phytohormone and the possible antitumoral agent 6-benzylaminopurine (BAP) were studied by Differential Pulse Polarography (DPP) and ultraviolet-visible spectroscopy (UV-vis) in combination with chemometric programs such as Multivariate Curve Resolution by Alternating Least-Squares (MCR-ALS) and Gaussian Peak Adjustment (GPA). All data confirm the formation of the predominant 1 : 1 and 1 : 2 Cu(2+) : BAP complexes. The corroboration of the presented stoichiometries was performed by ElectroSpray Ionization-Mass Spectrometric (ESI-MS) experiments of the Cu(II)-BAP system at different ratios. PMID- 23013725 TI - Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcgammaR-mediated CD14 macrophage activation. AB - BACKGROUND: Chronic inflammation characterised by IgG-producing plasma cell infiltration of colonic mucosa is a histological hallmark of ulcerative colitis (UC); however, whether its function is pathogenic or protective remains unclear. OBJECTIVE: To explore the contribution of intestinal IgG plasma cells to UC pathogenesis. METHODS: We isolated lamina propria mononuclear cells (LPMCs) from intestinal mucosa of UC patients and analysed the characteristics of intestinal plasma cells (expression profiles of differentiation molecules and chemokine receptors). We investigated the involvement of IgG-immune complex (IC)-Fc gamma receptor (FcgammaR) signalling in intestinal inflammation by examining the cytokine production by LPMCs in response to IgG-IC stimulation. RESULTS: IgG plasma cells that were markedly increased in number in the inflamed mucosa of UC patients showed a distinct expression profile (CD19(+)CD27(low), CCR10(low)CXCR4(high)) compared with IgA plasma cells (CD19(+/-)CD27(high), CCR10(high)CXCR4(-/low)). In vitro IgG-IC stimulation activated intestinal CD14 macrophages that were increased in number in the inflamed mucosa of UC patients via FcgammaRI and FcgammaRII, and induced the extensive production of pro inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1beta (IL-1beta), comparable to the effect of commensal bacteria stimulation. Co stimulation with IgG-IC and commensal bacteria increased TNF and IL-1beta production more than stimulation with the latter alone. Furthermore, IgG-IC notably up-regulated the expression of TL1A, whereas commensal bacteria specifically induced IL-23. CONCLUSIONS: Collectively, these results demonstrate a novel aspect of UC pathogenesis in which unique IgG plasma cells infiltrate the inflamed mucosa via CXCR4, and critically influence UC pathogenesis by exacerbating mucosal inflammation through the activation of 'pathogenic' intestinal CD14 macrophages via IgG-IC-FcgammaR signalling. PMID- 23013726 TI - A meta-analysis for percutaneous tumour ablation in patients with small hepatocellular carcinoma: highlighting combined strategy in the future. PMID- 23013727 TI - Spontaneous intramural hematoma of rectum in a patient on anticoagulant therapy: case report and review of literature. AB - AIM: Gastrointestinal spontaneous hematomas (GSHs) represent 5-10% of patients with acute abdomen. Conservative treatment is the most common approach but the bowel perforation can be a fatal complication. In patients with spontaneous rectal wall hematoma, high comorbidity and abdominal signs of acute abdomen but without radiological signs of intestinal perforation, an early exploratory laparotomy should be considered. CASE PRESENTATION: A 70-year-old man with severe dilatative cardiomyopathy and chronic obstructive pulmonary disease (COPD) on anticoagulant therapy was admitted with acute abdominal pain and anemia. An abdominal CT scan showed a perihepatic, perisplenic and parietocolic effusion associated with a retro-rectal hematoma measuring 6 * 6 * 14 cm without signs of active bleeding. Because of sudden onset of signs of peritonitis, a laparotomy was performed which showed an ischemic perforation of the sigmoid-rectal junction. We performed a recto-sigmoid resection (Hartmann operation) but the patient died twelve days later for septic shock. DISCUSSION: In patients with GSH the main problem is represented by the choice between conservative and surgical treatment. In case of complications, such as active and persistent intra abdominal bleeding, wall ischemia with or without bowel perforation and peritonitis, surgical treatment is mandatory. The absence of radiological signs of perforation can cause a delay of surgical treatment with unfavourable outcome especially in patient with rectal hematoma and severe comorbidity. CONCLUSIONS: GSHs of rectum are uncommon but a strict clinical monitoring is crucial because the extraperitoneal position make it possible a late clinical or radiological identification of perforation and a late laparotomy. PMID- 23013728 TI - Letter from editor October 2012. PMID- 23013729 TI - Prevalence of HPV genotypes in cervical cancer in Thailand. PMID- 23013730 TI - Fibrillar type I collagen matrices enhance metastasis/invasion of ovarian epithelial cancer via beta1 integrin and PTEN signals. AB - OBJECTIVE: This study investigated the involvement of fibrillar collagen in remodeling extracellular matrices (ECM) and its significant impact on the metastasis/invasion of epithelial ovarian cancer cells via beta1 integrin/phosphatase and tensin homolog (PTEN) signaling. MATERIALS/METHODS: Normal ovarian surface epithelium tissues (n = 13), ovarian cancer tissues (n = 28), ovarian cancer cell lines, and a 3-dimensional model of fibrillar type I collagen that mimicked pathological ECM in vivo were used in the study. We explored the specific mechanisms behind ECM remodeling and the cellular signals that affected the invasion of ovarian cancer cells. RESULTS: The data showed that increased beta1 integrin expression in ovarian cancer cells led to enhance migration/invasion of ovarian cancer cells via regulation of PTEN/protein kinase B (Akt) signal in response to fibrillar type I collagen matrices. Low PTEN activity corresponded to the following: (1) increased PTEN degradation and (2) phosphorylation of PTEN. Decreased protein phosphatase 2A activity was detected in ovarian cancer. Protein phosphatase 2A might play a role in enhancing the progression of ovarian cancer through regulating PTEN/Akt signal. CONCLUSION: These findings indicate that fibrillar type I collagen, by modulating integrin PTEN/PI3K/Akt signaling pathway in remodeling ECM, is very important in affecting the invasion of aggressive ovarian cancer cells. Moreover, these data provide direct evidence for pathological ECM remodeling and cell signaling networks involved in the invasion of ovarian cancer cells. PMID- 23013731 TI - Racial differences in oncogene mutations detected in early-stage low-grade endometrial cancers. AB - OBJECTIVE: To describe the pattern and frequency of oncogene mutations in white and African American women with endometrial cancer and to determine if racial differences in oncogene mutations exist among women with pathologically similar tumors. METHODS: Patients with endometrial cancer from a large urban hospital were identified through medical records, and representative formalin-fixed paraffin-embedded tumor blocks were retrieved. The study sample included 150 patients (84 African Americans) who underwent total abdominal hysterectomy for endometrial cancer. The Sequenom MassARRAY system and the OncoCarta Assay version 1.0 (Sequenom) were used to test for 238 mutations in 19 common oncogenes. The chi(2) test and the Fisher exact test were used to assess differences in distribution of variables by race and oncogene mutation status. RESULTS: There were 20 mutations identified in 2 oncogenes (PIK3CA and KRAS) in tumors from 19 women (12.7%). Most of the mutations were found in PIK3CA (16/20). Thirteen percent of endometrioid tumors harbored mutations (11 PIK3CA and 2 KRAS) as did 29% of the malignant mixed Mullerian tumors (3 PIK3CA and 1 KRAS). There were no observed mutations in serous, clear cell, or mucinous tumor types. Among low grade endometrioid cancers, tumors from African American patients were significantly associated with harboring either a KRAS or PIK3CA mutation (P = 0.04), with 7 PIK3CA mutations and all 4 KRAS mutations identified in African American women. CONCLUSIONS: This study provides preliminary evidence that oncogene mutation frequency of some subtypes of histologically similar endometrial carcinoma differ by race. Additional studies are needed to further explore this phenomenon in patients with endometrial carcinoma. PMID- 23013733 TI - Ovarian cancer: prevention, detection, and treatment of the disease and its recurrence. Molecular mechanisms and personalized medicine meeting report. AB - OBJECTIVE: To review the current understanding of the underlying molecular, biologic, and genetic mechanisms involved in ovarian cancer development and how these mechanisms can be targets for prevention, detection, and treatment of the disease and its recurrence. METHODS: In May 2012, we convened a meeting of researchers, clinicians, and consumer advocates to review the state of current knowledge on molecular mechanisms and identify fruitful areas for further investigations. RESULTS: The meeting consisted of 7 scientific sessions ranging from Epidemiology, Early Detection, and Biology to Therapeutics and Quality of Life. Sessions consisted of talks and panel discussions by international leaders in ovarian cancer research. A special career development session by the Congressionally Directed Medical Research Program Department of Defense Ovarian Cancer Academy as well as an oral abstract and poster session showcased promising new research by junior scientists. CONCLUSIONS: Technological advances in the last decade have increased our knowledge of the molecular mechanisms involved in a host of biological activities related to ovarian cancer. Understanding the role these mechanisms play in cancer initiation and progression will help lead to the development of prevention and treatment modalities that can be personalized to each patient, thereby helping to overcome this highly fatal malignancy. PMID- 23013732 TI - Human papillomavirus (HPV) and HPV 16-variant distribution in vulvar squamous cell carcinoma in Sweden. AB - OBJECTIVE: To investigate the human papillomavirus (HPV) and HPV type 16-variant distribution in a series of vulvar squamous cell carcinomas (VSCC) and to evaluate the impact of HPV and HPV 16-variant on prognosis. METHODS: A series of 133 patients who had a diagnosis of VSCC (1983-2008) was selected for the study. Detection of 11 high-risk HPV types (16, 18, 31, 33, 39, 45, 51, 52, 56, 58, and 59) and 2 low-risk HPV types (6 and 11) was performed with real-time polymerase chain reaction. Samples positive for HPV 16 were further analyzed for variant determination of 7 positions in the E6 gene with polymerase chain reaction and pyrosequencing. RESULTS: Forty (30.8%) of 130 tumors were found to be HPV positive. Human papillomavirus type 16 was found in 31 cases, HPV 18 was found in 2 cases, HPV 33 was found in 5 cases, and HPV 56 and HPV 59 were found in one case each. All but one tumor harboring HPV 16 were of European linage, and the 3 most common variants were E-p (n = 13), E-G350 (n = 7), and E-G131 (n = 5). HPV positivity was associated with the basaloid tumor type and occurred in significantly younger patients. Overall and recurrence-free survival rates were better in HPV-positive cases, but after correction for age and tumor size, HPV status was no longer an independent and significant prognostic factor. The survival rates of the various HPV 16 variants were not significantly different, but there was a trend of worse outcome for the E-G131-variant group. CONCLUSIONS: Human papillomavirus positivity of 30.8% is similar to other reports on VSCC. To our knowledge, this first variant determination of HPV 16 in vulvar carcinoma in a Swedish cohort indicated that the variant E-G131 may have an increased oncogenic potential in patients with VSCC. PMID- 23013742 TI - Sharing experiences in a support group: men's talk during the radiotherapy period for prostate cancer. AB - OBJECTIVE: Prostate cancer, one of the most common cancers in men, is often treated with radiotherapy, which strains both physical and mental health. This study aimed to describe the experiences of men living with prostate cancer shared within conversational support groups during a course of radiotherapy. METHOD: Nine men participated in one of two groups that met six or seven times, led by a professional nurse. Qualitative content analysis was used to identify themes and subthemes in the recorded group conversations. RESULTS: The analysis resulted in six themes: living with a changing body, being in the hands of others, learning to live with the disease, the importance of knowledge, everyday life support, and meeting in the support group. The men discussed a wide variety of bodily experiences and described support from healthcare professionals, relatives, friends, and the support group as crucial to their recovery. SIGNIFICANCE OF RESULTS: Meeting men in a similar situation, sharing experiences of living with the disease, and feeling allied to each other were important to the men in our study. The conversational support group provided the patient with prostate cancer a forum where sharing was made possible. PMID- 23013745 TI - Surface properties of beached plastic pellets. AB - The presence of pollutants on plastic debris is an emerging environmental hot topic. Understanding the surface alteration of plastics while in the marine environment increases our understanding of the pollutant-plastic debris interaction. Plastic pellets are widely distributed throughout the world oceans. Eroded and virgin polyethylene (PE) and polypropylene (PP) pellets were studied for their surface properties to better understand the interaction between plastic and compounds in marine environment. Surface properties such as point of zero charge, surface area and pore volume, surface topography, functional groups and acid-base behavior are important factors which affect sorption. Virgin plastic pellets had homogeneous smooth surfaces that do not have any acid-base behavior. Eroded PE demonstrates an altered surface that at seawater pH acquires a negative charge due to ketone groups. The uneven surface and possible functional groups could have been formed from the erosion processes while floating at the sea surface and might explain the interaction of eroded plastics with microbes and metals. PMID- 23013755 TI - "Tumor and Host" by R.E. Kavetsky (1962): implications for the past, present and future. PMID- 23013746 TI - Effect of enzyme therapy and prognostic factors in 69 adults with Pompe disease: an open-label single-center study. AB - BACKGROUND: Enzyme replacement therapy (ERT) in adults with Pompe disease, a progressive neuromuscular disorder, is of promising but variable efficacy. We investigated whether it alters the course of disease, and also identified potential prognostic factors. METHODS: Patients in this open-label single-center study were treated biweekly with 20 mg/kg alglucosidase alfa. Muscle strength, muscle function, and pulmonary function were assessed every 3-6 months and analyzed using repeated-measures ANOVA. RESULTS: Sixty-nine patients (median age 52.1 years) were followed for a median of 23 months. Muscle strength increased after start of ERT (manual muscle testing 1.4 percentage points per year (pp/y); hand-held dynamometry 4.0 pp/y; both p < 0.001). Forced vital capacity (FVC) remained stable when measured in upright, but declined in supine position (-1.1 pp/y; p = 0.03). Muscle function did not improve in all patients (quick motor function test 0.7 pp/y; p = 0.14), but increased significantly in wheelchair independent patients and those with mild and moderate muscle weakness.Relative to the pre-treatment period (49 patients with 14 months pre-ERT and 22 months ERT median follow-up), ERT affected muscle strength positively (manual muscle testing +3.3 pp/y, p < 0.001 and hand-held dynamometry +7.9 pp/y, p < 0.001). Its effect on upright FVC was +1.8 pp/y (p = 0.08) and on supine FVC +0.8 (p = 0.38). Favorable prognostic factors were female gender for muscle strength, and younger age and better clinical status for supine FVC. CONCLUSIONS: We conclude that ERT positively alters the natural course of Pompe disease in adult patients; muscle strength increased and upright FVC stabilized. Functional outcome is probably best when ERT intervention is timely. PMID- 23013756 TI - R.E. Kavetsky "Tumour and Host". - Kiev, 1962. - 301 p. PMID- 23013757 TI - Extracellular acidity as favouring factor of tumor progression and metastatic dissemination. AB - The bidirectional interactions between tumor cells and the so-called "host reactive stroma" play a critical role in most of the events characterizing tumor progression and distant organ colonization. This review discusses critical components of tumor environment involved in tumor cell dissemination. More specifically, it addresses some of the experimental evidences providing that acidity of tumor environment facilitates local invasiveness and metastasis formation, independently from hypoxia, with which acidity may be associated. Besides, acidity renders tumor cells resistant to radiation therapy and chemotherapeutic drugs. Therefore, this review examines the strategies for raising the low extracellular pH of tumors that might have considerable potential in cancer therapy. PMID- 23013758 TI - Effects of IL-6, IL-10 and TGF-beta on the expression of survivin and apoptosis in nasopharyngeal carcinoma TW01 cells. AB - The aim of this study is to investigate whether IL-6, IL-10 and TGF-beta are able to confer resistance to apoptosis in nasopharyngeal carcinoma cells by upregulating the expression of survivin. METHODS: The human nasopharyngeal carcinoma cell line TW01 (WHO NPC Type I) was cultured in DMEM-F12 Ham medium containing 10% FBS in a humidified atmosphere of 5% CO(2) and 37 degrees C and treated with different concentrations of IL-6, IL-10 and TGF-beta. Survivin mRNA expression was measured by real-time quantitative PCR and Western blot. Apoptosis was determined based on the assay for caspase-3 activity. RESULTS: Of all the cytokines tested, only TGF-beta (10 pg/mL) induced the over-expression of survivin at a significant level and this correlated with resistance to apoptosis (p <= 0.05). To confirm if survivin is responsible for resistance to apoptosis, YM155 which is a survivin inhibitor was used and the results showed that YM155 abrogated the protective effect of TGF-beta. Interestingly, IL-10 did not significantly alter the expression of survivin. CONCLUSIONS: We conclude that TGF beta up-regulates the expression of survivin leading to the resistance to apoptosis in NPC TW01 cells. PMID- 23013759 TI - 17-AAG mediated targeting of Hsp90 limits tert activity in peritoneal sarcoma related malignant ascites by downregulating cyclin D1 during cell cycle entry. AB - AIM: Peritoneal or retro-peritoneal sarcomatosis related malignant ascites formation is a rare but serious consequence of the locoregional metastatic event. The present work aimed to study the effect of the Hsp90 inhibitor (17-AAG), an ansamycin analog, on cell cycle and DNA replication specific chaperone-clients interaction in the event of peritoneal sarcoma related malignant ascites formation in mouse model at the late stage of malignant growth. METHODS: We administered 17-AAG, an Hsp90 inhibitor, divided doses (330 MUg/kg b.w./day for first five days then next ten days with166 MUg/kg b.w./day) through intra peritoneal route of inbred Swiss albino mice bearing full grown peritoneal malignant ascites of sarcoma-180. Our study was evaluated by peripheral blood hemogram analysis, malignant ascitic cytology, cell viability test, survival time and mitotic indexing. Furthermore, flowcytometric HSP90, TERT, CyclinD1, PCNA and GM-CSF expression analysis has been considered for special objective of the study. RESULTS: Our experimental efforts reduced the aggressive proliferation of malignant ascites by drastic downregulation of TERT and cyclin D1 on the verge of cell cycle entry along with DNA replication processivity factor PCNA by directly modulating their folding machinery - heat shock protein 90. Consequently, we observed that malignant ascitic cells became error prone during the event of karyokinesis and produced micronucleus containing malignant cells with low viability. Peripheral neutrophilia due to over-expression of GM-CSF by the peritoneal malignant ascites were also controlled by the treatment with 17-AAG and overall, the treatment modality improved the median survival time. CONCLUSION: Finally we can conclude that 17AAG administration might serve as a prospective pharmacological agent for the management of peritoneal sarcoma related malignant ascites and throws light towards prolonged survival of the patients concerned. PMID- 23013760 TI - The lipid content of cisplatin- and doxorubicin-resistant MCF-7 human breast cancer cells. AB - AIM: To perform the comparative study both of qualitative and quantitative content of lipids in parental and drug resistant breast cancer cells. MATERIALS AND METHODS: Parental (MCF-7/S) and resistant to cisplatin (MCF-7/CP) and doxorubicin (MCF-7/Dox) human breast cancer cells were used in the study. Cholesterol, total lipids and phospholipids content were determined by means of thin-layer chromatography. RESULTS: It was found that cholesterol as well as cholesterol ethers content are significantly higher but diacylglycerols, triacyl glycerols content are significantly lower in resistant cell strains than in parental (sensitive) cells. Moreover the analysis of individual phospholipids showed the increase of sphingomyelin, phosphatidylserine, cardiolipin, phosphatidic acid and the decrease of phosphatidy-lethanolamine, phosphatidylcholine in MCF-7/CP and MCF-7/Dox cells. CONCLUSION: Obtained results allow to suggest that the lipid profile changes can mediate the modulation of membrane fluidity in drug resistant MCF-7 breast cancer cells. PMID- 23013761 TI - Comparative study of dye-loaded liposome accumulation in sensitive and resistant human breast cancer cells. AB - The aim of this research is to study the dynamics and efficiency of liposome accumulation in sensitive and resistant human breast cancer cells. METHODS: Methods of fluorescence microscopy, fluorescence microspectroscopy and MTT-test have been used. RESULTS: The liposome-to-cell interaction and dye cellular uptake in sensitive, cisplatin-resistant and doxorubicin-resistant MCF-7 human breast cancer cells have been analyzed using time changes in both fluorescence resonance energy transfer signal from the donor probe DiO to the acceptor one DiI preloaded in liposomes and cell image brightness. CONCLUSION: Obtained results show that resistant cells accumulate dye-loaded liposomes more effectively and reveal more effective dye molecule cellular uptake. PMID- 23013762 TI - Antitumor and adjuvant effects of phagelysates of E.coli in mice with Ehrlich carcinoma. AB - AIM: To augment anti-tumor host response and overcome the tumor-induced immunosuppression is of paramount importance especially when patient is subjected to radio-/chemotherapy and immune system suffers significantly. Various immunological methods have been employed as supplemental antitumor therapies. We were aimed to investigate the antitumor potential of phagelysates of gram negative bacteria and their adjuvant effects for conventional chemotherapy in experiment. METHODS: Bacterial phagelysates of E.coli and purified suspensions of corresponding Un bacteriophage were obtained by standard methods of phage research. Experiments were carried out on BL57C/6J mice bearing transplanted Ehrlich carcinoma. Different regimens of phagelysate administration (0,5 ml E. coli phagelysate, 3/8 times with 5 day intervals) and conventional chemotherapy (combination of Doxorubicin 60 mg/m2, Cyclophosphan 800 mg/m(2), Ftoruracil 600 mg/m(2), 3 times with 21 day intervals) were tested. Treatment efficacy was evaluated by tumor growth inhibition percent, index of malignant growth, lifespan and survival percent. RESULTS: Experiments have shown that application of optimal doses of E. coli phagelysate can be well tolerated in mice. No stimulation or support of malignant growth was observed. E. coli phagelysate exhibited significant anticancer effect and adjuvant efficacy. Cancer development was delayed in 65% of inoculated animals in the test group. E. coli phagelysate inhibited tumor growth by 80-90% without apparent side effects. The mice survival was prolonged twice and more. On 65th-69th days of tumor growth in 13% animals complete regression of neoplasms was registered. Application of phagelysates in combination with chemotherapy significantly increased antitumor efficacy of conventional chemotherapeutic drugs. CONCLUSION: Application of bacterial phagelysates can be considered as promising novel strategy in cancer therapeutics. PMID- 23013763 TI - Abnormalities of apoptosis of the thyroid gland cells from extratumoral microfollicular tissue. AB - AIM: The aim of this study was to evaluate the frequency of existence of thyroid extratumoral normo- and microfollicular tissue in patients with thyroid carcinoma and peculiarities of apoptosis in mentioned tissue. MATERIALS AND METHODS: Using samples of normo- and microfollicular thyroid tissue it was determined the content of fragmented DNA and intensity of stimulated internucleosomal DNA fragmentation; activities of caspase-3 and cysteine lysosomal cathepsins. RESULTS: It was found that normofollicular tissue is observed more often in patients with nodal euthyroid goiter but microfollicular tissue is more common for patients with carcinoma. Extratumoral microfollicular tissue was found in the thyroid of patients above 50 years old mostly, and more rarely in young ones. The fragmented DNA concentration in microfollicular tissue was lower by a factor of 3.5 and intensity of stimulated internucleosomal DNA fragmentation was also decreased. Activity both of cathepsin B in lisosomes and caspase-3 in lysates of such tissue was also decreased. CONCLUSIONS: The decrease of intensity of spontaneous apoptosis and the absence of its modulation/induction following proapoptotic factors in extratumoral microfollicular thyroid tissue may be considered as a respond of the thyroid gland tissue to an existence of carcinoma. PMID- 23013764 TI - Cancer incidence and nuclear facilities in Ukraine: a community-based study. AB - The study goal was to investigate malignant tumors incidence in 5 Ukrainian cities with nuclear hazardous enterprises: extractive, processing enterprises of uranium ore (Zhovti Wody and Dniprodzerzhynsk of Dnipropetrovsk region) and nuclear power stations (Energodar of Zaporizhska region, Pivdennoukrainsk of Mykolayivska region, Netishyn of Khmelnytska region). MATERIALS AND METHODS: average annual population of the cities under study in 2003-2008 was 439 600 persons. Total and specific cancer incidence was investigated. Site specific incidence was analyzed for malignancies proved to be radiosensitive in previous studies: trachea, bronchus and lung, breast, kidney, thyroid cancer and leukemia. Data on cancer cases were received in National Cancer Registry of Ukraine (National Cancer Institute). There was used the data of the State Statistics Committee of Ukraine on the size of the studied population by gender - age groups. Standardized incidence ratio of cancer at a whole and for each of five specific forms of malignancies were calculated for the population of each city and group of cities depending on the nature of industrial activity. RESULTS: During the observed period there were registered 9 381 cancer cases in inhabitants of Ukrainian cities with radiation hazardous facilities. There was stated that cancer incidence rate in population of 5 cities significantly exceeded national and regional levels. Among specific forms of malignancy there were observed excess of lung, trachea, bronchus, breast, kidney cancer and leukemia in population of extractive, processing uranium ore cities. No excess of thyroid cancer was identified. In cities with nuclear power station there were registered excess of kidney cancer. CONCLUSION: Results of the study suggest the necessity to explore the role of various factors in forming the identified cancer incidence features in the Ukrainian population living near the nuclear power facilities. PMID- 23013765 TI - Chromosomal radiosensitivity in Ukrainian breast cancer patients and healthy individuals. AB - AIM: Recent studies showed that increased chromosomal damage induced by ionizing radiation is observed among patients with different tumor types. The aim of the study was evaluation of chromosomal radiosensitivity in breast cancer (BC) patients (n = 37) and healthy women (n = 44). METHODS: Chromosomal radiosensitivity was assessed with G0 and G2 assay. For G0 assay lymphocytes were exposed in vitro to 1,5 Gy of X-rays before culture setting. For G2 assay lymphocytes were irradiated with 0,5 Gy of X-rays after 47 h of incubation. RESULTS: Significant differences in mean scores both of G0 and G2 assay between breast cancer patients and controls were observed indicating the increased chromosomal radiosensitivity of lymphocytes of cancer patients. 11% of healthy women and 38% of BC patients were determined to be radiosensitive with G2 assay. CONCLUSION: Obtained results support the concept of association between elevated individual G2 chromosomal radiosensitivity and predisposition to BC. PMID- 23013766 TI - Initial experience with using frameless image-guided radiosurgery for the treatment of brain metastases. AB - AIM: Recent technologic advances have led to the development of frameless radiosurgery. We report our initial results using frameless image-guided radiosurgery for the management of brain metastases. METHODS: Over a 2-year period, 16 patients harboring 28 lesions were treated in our institution. 12 of 16 patients were treated in a single fraction, but 4 patients were treated using fractioned stereotactic radiotherapy in 3-5 fractions. The maximum target diameter, as determined by T1 - weighted contrast - enhanced magnetic resonance imaging were < 4 cm in all patients. 8 patients (50%) received WBRT (3 Gy in 10 fractions to a total dose of 30 Gy) prior to stereotactic radiosurgery, and were treated with SRS for either lesion progression or new lesions. The total treatment volume for each patient was the sum of the treatment volumes for all treated metastases. The median total treatment volume was 18.63 cm(3) (range 1,85 47.03 cm3). RESULTS: Median overall survival time of entire group were 10 months (95% confidence interval 7.470-12.530 months). Of the 3 (11.11%) lesions that showed complete response, all were associated with breast cancer. Partial response was seen in 8 (29.62%) cases. Stable disease was seen in 13 (48.14%) cases, but 3 (11.11%) cases showed progression of disease. CONCLUSION: Further studies are needed to to match the treatment results with other available modalities to optimize and individualize care of patients with brain metastases. PMID- 23013767 TI - Thyroid metastases from a breast cancer diagnosed by fine-needle aspiration biopsy. Case report and overview of the literature. AB - AIM: Intrathyroid metastases are uncommon in cytology practice. We report a case of metastatic lesion in the thyroid from breast carcinoma which was recognized in a fine-needle aspiration (FNA) biopsy and confirmed by immunohistopathology. In addition, we provide an overview of the literature describing similar cases. STUDY DESIGN: The patient was a 54-year old woman with a large, multinodular goiter and bilaterally enlarged lymph nodes in the supraclavicular areas. Fourteen years earlier she had undergone radical mastectomy followed by chemio- and radiotherapy due to a breast carcinoma. RESULTS: FNA of the thyroid nodules showed a metastatic breast carcinoma and was followed by total strumectomy and lymphadenectomy. Histological reassessment of the surgical thyroid specimens as well as the neck lymph nodes revealed multiple breast metastases. This was strongly confirmed by immunohistochemical examinations, which revealed a positive staining for: CKMNF 116, CK7, CEA as well as for ER, PgR and HER2, and a negative staining for: CK20, thyroglobulin, TTF1, calcitonin, and chromogranin. CONCLUSION: Every new aggregate in the thyroid in patients with even a long-term history of cancer should be considered as potentially metastatic until proved otherwise. FNA could be helpful in the diagnosis of thyroid metastatic lesion, but it should be confirmed by immunohistopathology. PMID- 23013768 TI - Primary extranodal non-Hodgkin's lymphoma presenting as painful gingival swelling. AB - Primary extra-nodal non-Hodgkin's lymphomas (NHL) constitute 25-40% of NHL but less than 1% arises in oral cavity. Here in 53-year-old man with stage IE gingival diffuse large B cell lymphoma who was treated successfully with chemotherapy and radiotherapy was presented. PMID- 23013769 TI - Development of an improved single-drop microextraction method and its application for the analysis of carbamate and organophosphorus pesticides in water samples. AB - An improved single-drop microextraction (SDME) method combined with high performance liquid chromatography has been developed for the detection of trace carbamate and organophosphorus pesticides in water samples. The most fascinating feature of the proposed method is the use of an oval-shaped polychloroprene rubber (PCR) tube to load the extraction solvent, which efficiently loads more solvent and improves the stability of extraction microdrop. Furthermore, this device provides a larger contact surface between the extraction solvent and the inner surface of the oval-shaped PCR tube than that between the extraction solvent and the tip of a microsyringe needle in the conventional SDME. It thereby avoids the problem of the drop floating upwards or dislodging from the tip of the microsyringe needle as observed in the traditional SDME. This method is significant for the great improvement it can offer in extraction efficiency. A series of extraction parameters were investigated systematically using carbamate and organophosphorus as the model analytes. Under the optimal conditions, the enrichment factors for analysis were between 117 and 177, and the limits of detection were ?0.63 MUg L(-1) (S/N = 3). The repeatability study was carried out by extracting the spiked water samples. Here the relative standard deviations varied between 4.0 and 5.8% (n = 5). Additionally, the proposed method was successfully applied to the determination of pesticides in real water samples, and good recoveries were obtained from 79% to 112%. The proposed method was demonstrated to hold advantages of low cost, simplicity of operation, and successful application to in real water samples. PMID- 23013770 TI - Comparative genomic analysis of the DUF71/COG2102 family predicts roles in diphthamide biosynthesis and B12 salvage. AB - BACKGROUND: The availability of over 3000 published genome sequences has enabled the use of comparative genomic approaches to drive the biological function discovery process. Classically, one used to link gene with function by genetic or biochemical approaches, a lengthy process that often took years. Phylogenetic distribution profiles, physical clustering, gene fusion, co-expression profiles, structural information and other genomic or post-genomic derived associations can be now used to make very strong functional hypotheses. Here, we illustrate this shift with the analysis of the DUF71/COG2102 family, a subgroup of the PP-loop ATPase family. RESULTS: The DUF71 family contains at least two subfamilies, one of which was predicted to be the missing diphthine-ammonia ligase (EC 6.3.1.14), Dph6. This enzyme catalyzes the last ATP-dependent step in the synthesis of diphthamide, a complex modification of Elongation Factor 2 that can be ADP ribosylated by bacterial toxins. Dph6 orthologs are found in nearly all sequenced Archaea and Eucarya, as expected from the distribution of the diphthamide modification. The DUF71 family appears to have originated in the Archaea/Eucarya ancestor and to have been subsequently horizontally transferred to Bacteria. Bacterial DUF71 members likely acquired a different function because the diphthamide modification is absent in this Domain of Life. In-depth investigations suggest that some archaeal and bacterial DUF71 proteins participate in B12 salvage. CONCLUSIONS: This detailed analysis of the DUF71 family members provides an example of the power of integrated data-miming for solving important "missing genes" or "missing function" cases and illustrates the danger of functional annotation of protein families by homology alone. PMID- 23013780 TI - No evidence for relevant QT interval prolongation in mitotane-treated patients with adrenocortical carcinoma. AB - OBJECTIVE: We designed a single-center retrospective study to assess the QT interval duration and to describe cardio vascular events among patients treated with mitotane for a adrenocortical carcinoma (ACC). DESIGN: We selected 14 patients (6 males and 8 females) that met the following criteria: ACC treated with mitotane, for whom an electrocardiogram (ECG) at baseline (before mitotane initiation) was available and for whom at least one ECG was available during the course of mitotane therapy together with a concomitant mitotane plasma level determination. RESULTS: Mean mitotane plasma level at baseline and after treatment showed a significant increase (mean level increased from 0 to 14.9+/-2 mg/l). At baseline and before mitotane was initiated all QTc intervals were <450 msec for men and <460 msec for women. During the treatment phase with mitotane, no QTc>470 msec was found in any patients respectively for men and women. In addition, no patient showed any significant QTc prolongation (>5% or >10 msec) at any time during mitotane treatment. During a mean follow-up of 15.9+/-3.5 months (range 2-45 months). No cardiovascular deaths or hospitalization for cardiovascular events was documented. No torsades de pointes were documented on ECG. No syncope, dizziness, heart failure were observed during follow up. Six out of 14 patients died during the follow-up, in five cases due to the progression of the disease, one patient died suddenly at home during followup. CONCLUSION: This short and retrospective series shows no evidence that mitotane induce any QT prolongation, even when plasma levels are well above the therapeutic window. PMID- 23013781 TI - Heroin dependence duration influences the metabolic parameters: mechanisms and consequences of impaired insulin sensitivity in hepatitis C virus seronegative heroin dependents. AB - OBJECTIVE: Carbohydrate metabolism disorder in heroin dependence is an issue with long history and contradicting results. The aim of the study was to evaluate basal insulin sensitivity in hepatitis C virus seronegative heroin dependents with normal body mass index, taking into consideration the duration of heroin dependence. METHOD: 78 heroin dependents and 32 healthy controls were enrolled in the cross-sectional, prospective study. The dependents were observed in 2 groups: group 1 with dependence duration less than or equal to 3 years and group 2 with more than 3 years. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) and beta-cell function (HOMA-B%) were used to define basal glucose-insulin homeostasis. RESULTS: The group with longer dependence duration had HOMA-IR (2.23 +/- 3.15) significantly higher compared with the control group (1.23 +/- 0.53, P = 0.016) but lower compared with the group with the shorter dependence duration (2.65 +/- 2.66, P = 0.024), after adjustment for HOMA-B%, waist circumference, and aspartate aminotransferase. The decrease in HOMA-IR during prolonged heroin addiction was significantly associated with the reduced beta-cell function (P < 0.001) and waist circumference (P = 0.004). CONCLUSIONS: Heroin dependence is associated with increased insulin resistance in hepatitis C virus seronegative heroin dependents. Prolonged heroin use is associated with reduction of basal beta-cell pancreatic function with decreased insulin resistance controlled for waist circumference, but still inducing significantly decreased basal insulin sensitivity. PMID- 23013788 TI - My final thoughts. PMID- 23013789 TI - Sequence-based identification and characterization of nosocomial influenza A(H1N1)pdm09 virus infections. AB - BACKGROUND: Highly transmissible viruses such as influenza are a potential source of nosocomial infections and thereby cause increased patient morbidity and mortality. AIM: To assess whether influenza virus sequence data can be used to link nosocomial influenza transmission between individuals. METHODS: Dutch A(H1N1)pdm09-positive specimens from one hospital (N = 107) were compared with samples from community cases (N = 685). Gene fragments of haemagglutinin, neuraminidase and PB2 were sequenced and subsequently clustered to detect patients infected with identical influenza viruses. The probability of detecting a second patient was calculated for each hospital cluster against the background diversity observed in hospital and community strains. All clusters were further analysed for possible links between patients. FINDINGS: Seventeen A(H1N1)pdm09 hospital clusters were detected of which eight had a low probability of occurrence compared with background diversity (P < 0.01). Epidemiological analysis confirmed a total of eight nosocomial infections in four of these eight clusters, and a mother-child combination in a fifth cluster. The nine clusters with a high probability of occurrence involved community cases of influenza without a known epidemiological link. CONCLUSION: If a background sequence dataset is available, the detection of hospital sequence clusters that differ from dominant community strains can be used to select clusters requiring further investigation by hospital hygienists before a nosocomial influenza outbreak is epidemiologically suspected. PMID- 23013779 TI - The clinical benefits of antiretroviral therapy in severely immunocompromised HIV 1-infected patients with and without complete viral suppression. AB - BACKGROUND: The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression. METHODS: A total of 3,780 patients from the EuroSIDA study under follow-up after 2001 with a current CD4(+) T-cell count <=200 cells/mm(3) were stratified into five groups: group 1, viral load (VL)<50 copies/ml on cART; group 2, VL 50-99,999 copies/ml on cART; group 3, VL 50-99,999 copies/ml off cART; group 4, VL>=100,000 copies/ml on cART; and group 5, VL>=100,000 copies/ml off cART. Poisson regression was used to identify the risk of (non-fatal or fatal) AIDS- and non-AIDS-related events considered together (AIDS/non-AIDS) or separately as AIDS or non-AIDS events within each group. RESULTS: There were 428 AIDS/non-AIDS events during 3,780 person-years of follow-up. Compared with group 1, those in group 2 had a similar incidence of AIDS/non-AIDS events (incidence rate ratio [IRR] 1.04; 95% CI 0.79 1.36). Groups 3, 4 and 5 had significantly higher incidence rates of AIDS/non AIDS events compared with group 1; incidence rates increased from group 3 (IRR 1.78; 95% CI 1.25-2.55) to group 5 (IRR 2.36; 95% CI 1.66-3.40), demonstrating the increased incidence of AIDS/non-AIDS events associated with increasing viraemia. After adjustment, the use of cART was associated with a 40% reduction in the incidence of AIDS/non-AIDS events in patients with VL 50-99,999 copies/ml (IRR 0.59; 95% CI 0.41-0.85) and in those with a VL>100,000 copies/ml (IRR 0.66; 95% CI 0.44-1.00). Similar relationships were seen for non-AIDS events and AIDS events when considered separately. CONCLUSIONS: In patients with ongoing severe immunosuppression, cART was associated with significant clinical benefits in patients with suboptimal virological control or virological failure. PMID- 23013790 TI - Paying for the Orphan Drug System: break or bend? Is it time for a new evaluation system for payers in Europe to take account of new rare disease treatments? AB - Since its enactment in 2000, the European Orphan Medicinal Products Regulation has allowed the review and approval of approaching 70 treatments for some 55 different conditions in Europe. Success does not come without a price, however. Many of these so-called "orphan drugs" have higher price points than treatments for more common diseases. This has been raising debate as to whether the treatments are worth it, which, in turn risks blocking patient access to treatment. To date, orphan drugs have only accounted for a small percentage of the overall drug budget. It would appear that, with increasing numbers of orphan drugs, governments are concerned about the future budget impact and their cost effectiveness in comparison with other healthcare interventions. Orphan drugs are under the spotlight, something that is likely to continue as the economic crisis in Europe takes hold and governments respond with austerity measures that include cuts to healthcare expenditures. Formally and informally, governments are looking at how they are going to handle orphan drugs in the future. Collaborative proposals between EU governments to better understand the value of orphan drugs are under consideration. In recent years there has been increasing criticism of behaviours in the orphan drug field, mainly centring on two key perceptions of the system: the high prices of orphan drugs and their inability to meet standard cost-effectiveness thresholds; and the construct of the system itself, which allows companies to gain the benefits that accrue from being badged as an orphan drug. The authors hypothesise that, by examining these criticisms individually, one might be able to turn these different "behaviours" into criteria for the creation of a system to evaluate new orphan drugs coming onto the market. It has been acknowledged that standard methodologies for Health Technology Assessments (HTA) will need to be tailored to take into account the specificities of orphan drugs given that the higher price-points claimed by orphan drugs are unlikely to meet current cost-effectiveness thresholds. The authors propose the development of a new assessment system based on several evaluation criteria, which would serve as a tool for Member State governments to evaluate each new orphan drug at the time of pricing and reimbursement. These should include rarity, disease severity, the availability of other alternatives (level of unmet medical need), the level of impact on the condition that the new treatment offers, whether the product can be used in one or more indications, the level of research undertaken by the developer, together with other factors, such as manufacturing complexity and follow-up measures required by regulatory or other authorities. This will allow governments to value an orphan drug that fulfilled all the criteria very differently from one that only met some of them. An individual country could determine the (monetary) value that it places on each of the different criteria, according to societal preferences, the national healthcare system and the resources at its disposal - each individual government deciding on the weighting attributed to each of the criteria in question, based on what each individual society values most. Such a systematic and transparent system will help frame a more structured dialogue between manufacturers and payers, with the involvement of the treating physicians and the patients; and foster a more certain environment to stimulate continued investment in the field. A new approach could also offer pricing and reimbursement decision-makers a tool to handle the different characteristics amongst new orphan drugs and to redistribute the national budgets in accordance with the outcome of a differentiated assessment. The authors believe that this could, therefore, facilitate the approach for all stakeholders. PMID- 23013791 TI - TP53 PIN3 and PEX4 polymorphisms and infertility associated with endometriosis or with post-in vitro fertilization implantation failure. AB - p53 has a crucial role in human fertility by regulating the expression of leukemia inhibitory factor (LIF), a secreted cytokine critical for blastocyst implantation. To examine whether TP53 polymorphisms may be involved with in vitro fertilization (IVF) failure and endometriosis (END), we have assessed the associations between TP53 polymorphism in intron 2 (PIN2; G/C, intron 2), PIN3 (one (N, non-duplicated) or two (D, duplicated) repeats of a 16-bp motif, intron 3) and polymorphism in exon 4 (PEX4; C/G, p.P72R, exon 4) in 98 women with END and 115 women with post-IVF failure. In addition, 134 fertile women and 300 women unselected with respect to fertility-related features were assessed. TP53 polymorphisms and haplotypes were identified by amplification refractory mutation system polymerase chain reaction. TP53 PIN3 and PEX4 were associated with both END (P=0.042 and P=0.007, respectively) and IVF (P=0.004 and P=0.009, respectively) when compared with women both selected and unselected for fertility related features. Haplotypes D-C and N-C were related to higher risk for END (P=0.002, P=0.001, respectively) and failure of IVF (P=0.018 and P=0.002, respectively) when compared with the Fertile group. These results support that specific TP53 haplotypes are associated with an increased risk of END-associated infertility and with post-IVF failure. PMID- 23013801 TI - Applications of reversible covalent chemistry in analytical sample preparation. AB - Reversible covalent chemistry (RCC) adds another dimension to commonly used sample preparation techniques like solid-phase extraction (SPE), solid-phase microextraction (SPME), molecular imprinted polymers (MIPs) or immuno-affinity cleanup (IAC): chemical selectivity. By selecting analytes according to their covalent reactivity, sample complexity can be reduced significantly, resulting in enhanced analytical performance for low-abundance target analytes. This review gives a comprehensive overview of the applications of RCC in analytical sample preparation. The major reactions covered include reversible boronic ester formation, thiol-disulfide exchange and reversible hydrazone formation, targeting analyte groups like diols (sugars, glycoproteins and glycopeptides, catechols), thiols (cysteinyl-proteins and cysteinyl-peptides) and carbonyls (carbonylated proteins, mycotoxins). Their applications range from low abundance proteomics to reversible protein/peptide labelling to antibody chromatography to quantitative and qualitative food analysis. In discussing the potential of RCC, a special focus is on the conditions and restrictions of the utilized reaction chemistry. PMID- 23013792 TI - Regulation of the tumor suppressor PTEN by SUMO. AB - The crucial function of the PTEN tumor suppressor in multiple cellular processes suggests that its activity must be tightly controlled. Both, membrane association and a variety of post-translational modifications, such as acetylation, phosphorylation, and mono- and polyubiquitination, have been reported to regulate PTEN activity. Here, we demonstrated that PTEN is also post-translationally modified by the small ubiquitin-like proteins, small ubiquitin-related modifier 1 (SUMO1) and SUMO2. We identified lysine residue 266 and the major monoubiquitination site 289, both located within the C2 domain required for PTEN membrane association, as SUMO acceptors in PTEN. We demonstrated the existence of a crosstalk between PTEN SUMOylation and ubiquitination, with PTEN-SUMO1 showing a reduced capacity to form covalent interactions with monoubiquitin and accumulation of PTEN-SUMO2 conjugates after inhibition of the proteasome. Moreover, we found that virus infection induces PTEN SUMOylation and favors PTEN localization at the cell membrane. Finally, we demonstrated that SUMOylation contributes to the control of virus infection by PTEN. PMID- 23013803 TI - Lymph node transfer and perinodal lymphatic growth factor treatment for lymphedema. AB - OBJECTIVE: Our objective was to define the optimal growth factor treatment to be used in combination with lymph node transfer to normalize lymphatic vascular anatomy. BACKGROUND: In the lymph node transfer method, lymphatic anastomoses are expected to form spontaneously. However, lymphangiogenic growth factor therapies have shown promising results in preclinical models of lymphedema. METHODS: The inguinal lymphatic vasculature of pigs was surgically destroyed around the inguinal lymph node. To enhance the regrowth of the lymphatic network in the defected area, adenoviral vascular endothelial growth factor C (VEGF-C) was administered intranodally or perinodally. Control animals received injections of saline or control vector. The lymphangiogenic effect of the growth factor therapy and any potential adverse effects associated with the 2 alternative delivery routes were examined 2 months postoperatively. RESULTS: Both routes of growth factor administration induced robust growth of lymphatic vessels and helped to preserve the structure of the transferred lymph nodes in comparison with the controls. The lymph nodes of the control treated animals regressed in size and their nodal structure was partly replaced by fibro-fatty scar tissue. Intranodally injected adenoviral VEGF-C and adenoviral vector encoding control gene LacZ induced macrophage accumulation inside the node, whereas perinodal administration of VEGF-C did not have this adverse effect. CONCLUSIONS: Lymphangiogenic growth factors improve lymphatic vessel regeneration and lymph node function after lymph node transfer. The perinodal route of delivery provides a basis for future clinical trials in lymphedema patients. PMID- 23013802 TI - Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial. AB - BACKGROUND: Severe TBI, defined as a Glasgow Coma Scale <= 8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI. METHODS/DESIGN: The DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1 mg intravenously every 6 h for 7 days) and clonidine (0.1 mg per tube every 12 h for 7 days), and the other group, double placebo, within 48 h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12 months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications. DISCUSSION: The DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI. TRIAL REGISTRATION: ClinicalTrials.gov NCT01322048. PMID- 23013804 TI - Adhesiolysis-related morbidity in abdominal surgery. AB - OBJECTIVE: To determine the incidence of bowel injury in operations requiring adhesiolysis and to assess the impact of adhesiolysis on the incidence of surgical complications, postoperative morbidity, and costs. BACKGROUND: Morbidity of adhesiolysis during abdominal surgery seems an important health care problem, but the direct impact of adhesiolysis on inadvertent organ damage, morbidity, and costs is unknown. METHODS: In a prospective cohort study, detailed data on adhesiolysis were gathered by direct observation during elective abdominal surgery. Comparison was made between surgical procedures with and without adhesiolysis on the incidence of inadvertent bowel defects. Secondary outcomes were the effect of adhesiolysis and bowel injury on surgical complications, other morbidity, and costs. RESULTS: A total of 755 (out of 844) surgeries in 715 patients were included. Adhesiolysis was required in 475 (62.9%) of operations. Median adhesiolysis time was 20 minutes (range: 1-177). Fifty patients (10.5%) undergoing adhesiolysis inadvertently incurred bowel defect, compared with 0 (0%) without adhesiolysis (P < 0.001). In univariate and multivariate analyses, adhesiolysis was associated with an increase of sepsis incidence [odds ratio (OR): 5.12; 95% confidence interval (CI): 1.06-24.71], intra-abdominal complications (OR: 3.46; 95% CI: 1.49-8.05) and wound infection (OR: 2.45; 95% CI: 1.01-5.94), longer hospital stay (2.06 +/- 1.06 days), and higher hospital costs [$18,579 (15,204-21,954) vs $14,063 (12,471-15,655)]. Mortality after adhesiolysis complicated by a bowel defect was 4 out of 50 (8%), compared with 7 out of 425 (1.6%) after uncomplicated adhesiolysis (OR: 5.19; 95% CI: 1.47 18.41). CONCLUSIONS: Adhesiolysis and inadvertent bowel injury have a large negative effect on the convalescence after abdominal surgery. The awareness of adhesion-related morbidity during reoperation and the prevention of postsurgical adhesion deserve priority in research and clinical practice. PMID- 23013805 TI - Role of preoperative biliary drainage in jaundiced patients who are candidates for pancreatoduodenectomy or hepatic resection: highlights and drawbacks. AB - INTRODUCTION: In this review of the literature, we analyze the indications for preoperative drainage in jaundiced patients who are candidates for pancreaticoduodenectomy (PD) or major hepatectomy due to periampullary or proximal bile duct neoplasms. OBJECTIVE: The aim of this study is to review the literature and to report on the current management of jaundiced patients with periampullary or proximal bile duct neoplasms who are candidates for PD or major liver resection. BACKGROUND: Jaundiced patients represent a major challenge for surgeons. Alterations and functional impairment caused by jaundice increase the risk of surgery; therefore, preoperative biliary decompression has been suggested. METHODS: A literature review was performed in the MEDLINE database to identify studies on the management of jaundice in patients undergoing PD or liver resection. Papers considering palliative drainage in jaundiced patients were excluded. RESULTS: The first group of papers considered patients affected by middle-distal obstruction from periampullary neoplasms, in which preoperative drainage was applied selectively. The second group of papers evaluated patients with biliary obstructions from proximal biliary neoplasms. In these cases, Asian authors and a few European authors considered it mandatory to drain the future liver remnant (FLR) in all patients, while American and most European authors indicated preoperative drainage only in selected cases (in malnourished patients and in those with hypoalbuminemia, cholangitis or long-term jaundice; with an FLR < 30% or 40%) given the high risk of complications of drainage (choleperitoneum, cholangitis, bleeding, and seeding). The optimal type of biliary drainage is still a matter of debate; recent studies have indicated that endoscopy is preferable to percutaneous drainage. Although the type of endoscopic biliary drainage has not been clearly established, the choice is made between plastic stents and short, covered, metallic stents, while other authors suggest the use of nasobiliary drainage. CONCLUSIONS: : A multidisciplinary evaluation (made by a surgeon, biliary endoscopist, gastroenterologist, and radiologist) of jaundiced neoplastic patients should be performed before deciding to perform biliary drainage. Middle-distal obstruction in patients who are candidates for PD does not usually require routine biliary drainage. Proximal obstruction in patients who are candidates for major hepatic resection in the majority of cases requires a drain; however, the type, site, number, and approach must be defined and tailored according to the planned hepatic resection. Recently, the use of preoperative biliary drainage limited to the FLR has been a suggested strategy. However, multicenter, randomized, controlled trials should be conducted to clarify this issue. PMID- 23013806 TI - Validation of a structured training and assessment curriculum for technical skill acquisition in minimally invasive surgery: a randomized controlled trial. AB - OBJECTIVE: : To develop and validate an ex vivo comprehensive curriculum for a basic laparoscopic procedure. BACKGROUND: : Although simulators have been well validated as tools to teach technical skills, their integration into comprehensive curricula is lacking. Moreover, neither the effect of ex vivo training on learning curves in the operating room (OR), nor the effect on nontechnical proficiency has been investigated. METHODS: : This randomized single blinded prospective trial allocated 20 surgical trainees to a structured training and assessment curriculum (STAC) group or conventional residency training. The STAC consisted of case-based learning, proficiency-based virtual reality training, laparoscopic box training, and OR participation. After completion of the intervention, all participants performed 5 sequential laparoscopic cholecystectomies in the OR. The primary outcome measure was the difference in technical performance between the 2 groups during the first laparoscopic cholecystectomy. Secondary outcome measures included differences with respect to learning curves in the OR, technical proficiency of each sequential laparoscopic cholecystectomy, and nontechnical skills. RESULTS: : Residents in the STAC group outperformed residents in the conventional group in the first (P = 0.004), second (P = 0.036), third (P = 0.021), and fourth (P = 0.023) laparoscopic cholecystectomies. The conventional group demonstrated a significant learning curve in the OR (P = 0.015) in contrast to the STAC group (P = 0.032). Residents in the STAC group also had significantly higher nontechnical skills (P = 0.027). CONCLUSIONS: : Participating in the STAC shifted the learning curve for a basic laparoscopic procedure from the operating room into the simulation laboratory. STAC-trained residents had superior technical proficiency in the OR and nontechnical skills compared with conventionally trained residents. (The study registration ID is NCT01560494.). PMID- 23013807 TI - Association between average daily gain, faecal dry matter content and concentration of Lawsonia intracellularis in faeces. AB - BACKGROUND: The objective of this study was to investigate the association between average daily gain and the number of Lawsonia intracellularis bacteria in faeces of growing pigs with different levels of diarrhoea. METHODS: A longitudinal field study (n = 150 pigs) was performed in a Danish herd from day 29 to 47 post weaning. Every third day all pigs were weighed, subjected to a clinical examination and faecal samples were obtained. Faecal samples were subjected to dry matter determination and absolute quantification by PCR for L. intracellularis and porcine circovirus type 2 (PCV2). Association between average daily gain, faecal dry matter content, numbers of L. intracellularis bacteria and PCV2 genome copies in faeces was investigated in a multilevel mixed-effects linear model. RESULTS: Increasing numbers of L. intracellularis log10 bacteria/g faeces were significantly associated with decreasing average daily gain (P < 0.001). The association was decreasing with increasing faecal dry matter content (P < 0.01). The number of PCV2 log10 copies/g faeces was not significantly associated with average daily gain of the pigs (P > 0.5). CONCLUSION: The results suggest a potential application of a PCR quantifying L. intracellularis in growing pigs. Faecal dry matter content must be taken into consideration in interpretation of such test results. PMID- 23013827 TI - Bioluminescent imaging of Trypanosoma cruzi infection in Rhodnius prolixus. AB - BACKGROUND: Usually the analysis of the various developmental stages of Trypanosoma cruzi in the experimentally infected vertebrate and invertebrate hosts is based on the morphological observations of tissue fragments from animals and insects. The development of techniques that allow the imaging of animals infected with parasites expressing luciferase open up possibilities to follow the fate of bioluminescent parasites in infected vectors. METHODS: D-luciferin (60 MUg) was injected into the hemocoel of the whole insect before bioluminescence acquisition. In dissected insects, the whole gut was incubated with D-luciferin in PBS (300 MUg/ml) for ex vivo bioluminescence acquisition in the IVIS(r) Imaging System, Xenogen. RESULTS: Herein, we describe the results obtained with the luciferase gene integrated into the genome of the Dm28c clone of T. cruzi, and the use of these parasites to follow, in real time, the infection of the insect vector Rhodnius prolixus, by a non- invasive method. The insects were evaluated by in vivo bioluminescent imaging on the feeding day, and on the 7 th, 14 th, 21 st and 28 th days after feeding. To corroborate the bioluminescent imaging made in vivo, and investigate the digestive tract region, the insects were dissected. The bioluminescence emitted was proportional to the number of protozoans in regions of the gut. The same digestive tracts were also macerated to count the parasites in distinct morphological stages with an optical microscope, and for bioluminescence acquisition in a microplate using the IVIS(r) Imaging System. A positive correlation of parasite numbers and bioluminescence in the microplate was obtained. CONCLUSIONS: This is the first report of bioluminescent imaging in Rhodnius prolixus infected with trypomastigotes of the Dm28c-luc stable strain, expressing firefly luciferase. In spite of the distribution limitations of the substrate (D-luciferin) in the insect body, longitudinal evaluation of infected insects by bioluminescent imaging is a valuable tool. Bioluminescent imaging of the digestive tract infected with Dm28c luc is highly sensitive and accurate method to track the fate of the parasite in the vector, in the crop, intestine and rectum. This methodology is useful to gain a better understanding of the parasite - insect vector interactions. PMID- 23013835 TI - Do the hospitalized patients with osteoporotic fractures require endocrinologists' help? AB - AIM: Osteoporotic fractures are a crucial cause of morbidity and mortality in patients with fragility fractures and impose huge economic burden on health care services. Orthopedic surgeons are often the only clinicians seen by the patients with osteoporotic fractures. The improvement in osteoporosis management is an urgent require; therefore, the aim of this study was to determine the efficacy of consultation with an endocrinologist in osteoporosis management of patients with a fragility fracture. METHODS: This survey was undertaken in three phases that focused on patients with osteoporotic fractures who were admitted to five tertiary care, level-I, trauma hospital. Patients were evaluated through a questionnaire which was designed to determine whether physicians manage underlying osteoporosis. RESULTS: The number of patients who underwent a bone mineral density test increased from a rate of 3.6% to 91% after the intervention, as calcium and vitamin D supplementation from 18% to 92%, bisphosphonate prescription from 0.5% to 83%. Also, the overall medication usage increased from 9% to 87%. A small number of patients (3%) were followed up in contrast to a rate of 73% in the third phase. CONCLUSION: Orthopedic surgeons are not completely engaged in osteoporosis care for patients with a fragility fracture; therefore, a consultation with an endocrinologist is required to enable orhopedic surgeons to provide an effective osteoporosis care for their patients with an osteoporotic fracture. PMID- 23013828 TI - Early retinoic acid deprivation in developing zebrafish results in microphthalmia. AB - Vitamin A deficiency causes impaired vision and blindness in millions of children around the world. Previous studies in zebrafish have demonstrated that retinoic acid (RA), the acid form of vitamin A, plays a vital role in early eye development. The objective of this study was to describe the effects of early RA deficiency by treating zebrafish with diethylaminobenzaldehyde (DEAB), a potent inhibitor of the enzyme retinaldehyde dehydrogenase (RALDH) that converts retinal to RA. Zebrafish embryos were treated for 2 h beginning at 9 h postfertilization. Gross morphology and retinal development were examined at regular intervals for 5 days after treatment. The optokinetic reflex (OKR) test, visual background adaptation (VBA) test, and the electroretinogram (ERG) were performed to assess visual function and behavior. Early treatment of zebrafish embryos with 100 MUM DEAB (9 h) resulted in reduced eye size, and this microphthalmia persisted through larval development. Retinal histology revealed that DEAB eyes had significant developmental abnormalities but had relatively normal retinal lamination by 5.5 days postfertilization. However, the fish showed neither an OKR nor a VBA response. Further, the retina did not respond to light as measured by the ERG. We conclude that early deficiency of RA during eye development causes microphthalmia as well as other visual defects, and that timing of the RA deficiency is critical to the developmental outcome. PMID- 23013837 TI - Blunted responses to heart failure symptoms in adults with mild cognitive dysfunction. AB - INTRODUCTION: Mild cognitive dysfunction is common among adults with heart failure (HF). We hypothesized that mild cognitive dysfunction would be associated with poor HF self-care behaviors, particularly patients' ability to respond to symptoms. METHODS: We analyzed data on 148 participants in an observational study of symptoms in adults with moderate-to-advanced HF. Mild cognitive dysfunction was measured with the Montreal Cognitive Assessment (MoCA; range, 0-30), using cutoff scores for the general population (26) and for adults with cardiovascular disease (24). Heart failure self-care management (evaluation and response to HF symptoms) was measured with the Self-care of HF Index, and consulting behaviors (calling a provider when symptoms occur) were measured using the European HF Self care Behavior Scale-9. Generalized linear modeling and hierarchical linear modeling were used to quantify the relationship between MoCA cutoff scores and indices of HF self-care. RESULTS: The mean age of the sample was 57 +/- 12 years, 61.5% were men, and 58.8% had class III/IV HF; the mean left ventricular ejection fraction was 28% +/- 12%. Using MoCA scores of 26 and 24, respectively, 33.1% and 14.2% of the sample had mild cognitive dysfunction. Controlling for common confounders, participants with MoCA scores lower than 26 reported self-care comparable with that of participants with MoCA scores of 26 or higher. Participants with MoCA scores lower than 24, however, reported 21.5% worse self care management (P = 0.014) and 51% worse consulting behaviors (P < 0.001) compared with participants with MoCA scores of 24 or higher. CONCLUSIONS: A disease-specific cutoff for mild cognitive dysfunction reveals marked differences patients' ability to recognize and respond to HF symptoms when they occur. Adults with HF and mild cognitive dysfunction are a vulnerable patient group in great need of interventions that complement HF self-care. PMID- 23013836 TI - Highly acetylated tubulin permits enhanced interactions with and trafficking of plasmids along microtubules. AB - Microtubule-based transport is required for plasmid translocation to the nucleus during transfections, and having stable structures could enhance this movement. In previous studies, in which the cytoskeleton was disrupted, we found that populations of microtubules remain that are stable and highly acetylated. By increasing the levels of acetylated tubulin through inhibition of the tubulin deacetylase HDAC6, we observe more rapid plasmid nuclear localization of transfected plasmids and greater levels of gene transfer. In this study, we sought to understand plasmid movement in cells with enhanced tubulin acetylation. Using variations of a microtubule spin-down assay, we found that plasmids bound to hyper-acetylated microtubules to a greater degree than they did to unmodified microtubules. To determine whether microtubule acetylation also affects cytoplasmic trafficking, plasmid movement was evaluated in real time by particle tracking in cells with varying levels of acetylated microtubules. We found that plasmids display greater net rates of movement, spend more time in productive motion and display longer runs of continuous motion in cells with highly acetylated microtubules compared with those with fewer modifications. These results all suggest that plasmid movement is enhanced along highly acetylated microtubules, reducing the time spent in the cytoplasm before nuclear import. Taken together, these findings provide a foundation for determining how modulation of microtubule acetylation can be used as a means to increase intracellular trafficking of plasmids and enhance gene therapy. PMID- 23013838 TI - Simultaneous testing of multiclass organic contaminants in food and environment by liquid chromatography/dielectric barrier discharge ionization-mass spectrometry. AB - A Dielectric Barrier Discharge Ionization (DBDI) LC/MS interface is based on the use of a low-temperature helium plasma, which features the possibility of simultaneous ionization of species with a wide variety of physicochemical properties. In this work, the performance of LC/DBDI-MS for trace analysis of highly relevant species in food and environment has been examined. Over 75 relevant species including multiclass priority organic contaminants and residues such as pesticides, polycyclic aromatic hydrocarbons, organochlorine species, pharmaceuticals, personal care products, and drugs of abuse were tested. LC/DBDI MS performance for this application was assessed and compared with standard LC/MS sources (electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI)). The used benchtop Orbitrap mass spectrometer features a 10 Hz polarity switching mode, so that both positive and negative ion mode acquisitions are possible with acquisition cycles matching the requirements of fast liquid chromatography. Both polar and nonpolar species (including those typically analyzed by GC/electron ionization-MS) can be tested in a single run using polarity switching mode. The methodology was found to be effective in detecting a wide array of organic compounds at concentration levels in the low ng L(-1) to MUg kg(-1) range in wastewater and food matrices, respectively. The linearity was evaluated in an olive oil extract, obtaining good correlation coefficients in the studied range. Additionally, minor matrix effects (<=15% of signal suppression or enhancement) were observed for most of the studied analytes in this complex fatty matrix. The results obtained were compared with data from both ESI and APCI sources, obtaining a merged coverage between ESI and APCI in terms of analyte ionization and higher overall sensitivity for the proposed ion source based on the DBD principle. The use of this approach further extends the coverage of current LC/MS methods towards an even larger variety of chemical species including both polar and nonpolar (non-ESI amenable) species and may find several applications in fields such as food and environment testing or metabolomics where GC/MS and LC/MS are combined to cover as many different species as possible. PMID- 23013841 TI - Dogma disputed: postdialysis increase of aminotransferase values cannot be attributed to an inhibitor removal by hemodialysis. AB - The objective of this study was to assess changes of aspartate aminotransferase (AST [serum glutamic oxalacetic transaminase]) and alanine aminotransferase (ALT [serum glutamic pyruvic transaminase]) values after a hemodialysis (HD) session. Aspartate aminotransferase and ALT serum values were measured before and after a 4 h HD session in 37 stable patients (group A), before and after a 3.5 h isovolemic HD (IVHD, with a zero ultrafiltration rate) session in eight patients (group B), as well as before and after a session of "isolated ultrafiltration" (IUF) in eight more patients (group C). In group A, mean predialysis AST and ALT serum values that were 16.4 +/- 4.3 and 16.0 +/- 5.5 IU/L, increased to 20.1 +/- 5.4 and 17.7 +/- 6.2 IU/L, respectively (p < 0.0001, comparing pre- to postdialysis values, for both). When the postdialysis values were corrected for hemoconcentration induced by ultrafiltration, no differences were found in ALT values. However, postdialysis-corrected AST values (mean 17.7 +/- 4.4 IU/l) remained higher compared with predialysis values (p < 0.001). The AST/ALT ratio was 1.13 +/- 0.4 for predialysis values and 1.26 +/- 0.5 for postdialysis values (p < 0.0001). Predialysis mean serum AST and ALT values did not show any difference after the 3.5 h IVHD sessions (group B), but increased significantly (p < 0.02) after the removal of 1.7 +/- 0.2 L of fluid by IUF (group C). In chronic HD patients, postdialysis serum AST and ALT values increased significantly compared with predialysis values. This increment is mainly due to hemoconcentration induced by ultrafiltration and cannot be attributed to the removal of an aminotransferase inhibitor by HD. PMID- 23013842 TI - Influence of LVAD cannula outflow tract location on hemodynamics in the ascending aorta: a patient-specific computational fluid dynamics approach. AB - To develop a better understanding of the hemodynamic alterations in the ascending aorta, induced by variation of the cannula outflow position of the left ventricular assist device (LVAD) device based on patient-specific geometries, transient computational fluid dynamics (CFD) simulations using the realizable k epsilon turbulent model were conducted for two of the most common LVAD outflow geometries. Thoracic aortic flow patterns, pressures, wall shear stresses (WSSs), turbulent dissipation, and energy were quantified in the ascending aorta at the location of the cannula outflow. Streamlines for the lateral geometry showed a large region of disturbed flow surrounding the LVAD outflow with an impingement zone at the contralateral wall exhibiting increased WSSs and pressures. Flow disturbance was reduced for the anterior geometries with clearly reduced pressures and WSSs. Turbulent dissipation was higher for the lateral geometry and turbulent energy was lower. Variation in the position of the cannula outflow clearly affects hemodynamics in the ascending aorta favoring an anterior geometry for a more ordered flow pattern. The new patient-specific approach used in this study for LVAD patients emphasizes the potential use of CFD as a truly translational technique. PMID- 23013843 TI - DiAlert: a prevention program for overweight first degree relatives of type 2 diabetes patients: results of a pilot study to test feasibility and acceptability. AB - BACKGROUND: Prevalence of type 2 diabetes mellitus is increasing due to lifestyle changes, particularly affecting those genetically at risk. We developed DiAlert as a targeted group-based intervention aimed to promote intrinsic motivation and action planning for lifestyle changes and weight loss in first degree relatives of patients with type 2 diabetes mellitus.The main objective of the pilot of the DiAlert intervention was to assess fidelity, feasibility and acceptability prior to starting the randomized controlled trial. METHODS: Individuals with a family history of type 2 diabetes mellitus were self-identified and screened for eligibility. DiAlert consists of two group sessions. Feasibility, fidelity, acceptability and self-reported perceptions and behavioral determinants were evaluated in a pre-post study using questionnaires and observations. Determinants of behavior change were analyzed using paired-samples t tests and Wilcoxon signed rank tests. RESULTS: DiAlert was delivered to two groups of first degree relatives of patients with type 2 diabetes mellitus (N = 9 and N = 12). Feasibility and fidelity were confirmed. Overall, the DiAlert group sessions were positively evaluated (8.0 on a scale of 1 to 10) by participants. The intervention did not impact perceived susceptibility or worry about personal diabetes risk. Action planning with regard to changing diet and physical activity increased. CONCLUSIONS: DiAlert proved feasible and was well-accepted by participants. Positive trends in action planning indicate increased likelihood of actual behavior change following DiAlert. Testing the effectiveness in a randomized controlled trial is imperative. TRIAL REGISTRATION: Netherlands National Trial Register (NTR): NTR2036. PMID- 23013844 TI - Synthesis and interfacing of biocompatible iron oxide nanoparticles through the ferroxidase activity of Helicobacter Pylori ferritin. AB - Ferritin is an iron storage protein that is often used to coat metallic nanoparticles, such as iron oxide nanoparticles (IONPs). However, the synthesis and biocompatibility of ferritin-coated IONPs remain unclear. Therefore, this study reports the synthesis of a ferritin gene cloned and expressed from Helicobacter pylori (HPFn). The ferroxidase activity of the synthase HPFn was used for the de novo synthesis of HPFn-coated IONPs under mild conditions. Gel filtration chromatography and transmission electron microscopy analyses demonstrated that the core-shell structure of both the 5.0 nm IONP nanocore and the 12.4 nm HPFn shell were correctly assembled. The cellular uptake of mouse macrophage cells (RAW 264.7 cells) has shown that only a few HPFn-coated IONPs (3%) were taken up after 24 h of incubation. This study compares the biocompatibility of HPFn-coated IONPs, superparamagnetic iron oxide nanoparticles (SPIOs) and ferric salt (ferric ammonium citrate) in respect to cell growth inhibition, reactive oxygen species generation and pro-inflammatory cytokine TNF alpha release. Assessment results showed that the responses elicited by HPFn coated IONPs were similar to those elicited by SPIO treatment but milder than those elicited by ferric salt treatment. This accounts for the notion that ferritin-coated IONPs are biocompatible iron agents. These findings show that the ferroxidase activity of ferritin can be used to synthesize biocompatible IONPs. The favorable properties of HPFn-coated IONPs suggest that they can be used as a non-macrophage contrast agent through further surface conjugation. PMID- 23013845 TI - Percutaneous evacuation of diffuse pulmonary interstitial emphysema by lung puncture in a baby with extremely low birth weight: a case report. AB - INTRODUCTION: Pulmonary interstitial emphysema is a serious complication of mechanical ventilation and can become life-threatening if progression occurs. Therapeutic lung puncture is a treatment option for severe pulmonary interstitial emphysema but has a limited use in babies with extremely low birth weight. We present a case of pulmonary interstitial emphysema in a Japanese baby (1-day-old) boy with extremely low birth weight. The emphysema was successfully decompressed by therapeutic lung puncture performed with a trocar catheter. CASE PRESENTATION: The baby was born with a weight of 420g, which, to the best of our knowledge, is the lowest reported birth weight among babies with pulmonary interstitial emphysema. A chest X-ray on postnatal day 2 revealed pulmonary interstitial emphysema, which gradually progressed to diffuse pseudocystic changes. His condition became life-threatening despite the use of high-frequency oscillatory ventilation and lateral decubitus positioning. We evacuated the pulmonary interstitial emphysema by lung puncture with a trocar catheter to avoid respiratory and cardiovascular collapse. This resulted in adequate evacuation of the emphysema and a dramatic improvement in his clinical condition. CONCLUSIONS: Therapeutic lung puncture performed with a trocar catheter is beneficial in babies with extremely low birth weight and diffuse pulmonary interstitial emphysema. This treatment option may be broadly applicable, especially in an emergency situation. PMID- 23013846 TI - Subacromial bursitis with giant rice bodies as initial presentation of rheumatoid arthritis. AB - Rice body formation is a nonspecific response to chronic synovial inflammation associated with tuberculous arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative inflammatory arthritis, and even osteoarthritis. Such bodies were termed rice bodies because of their close resemblance to grains of polished white rice. We present a case report of a middle-aged woman with right shoulder subacromial/subdeltoid bursitis with giant rice body formation as her initial presentation of rheumatoid arthritis. Her right shoulder symptoms resolved after subacromial and subdeltoid bursectomy and removal of the rice bodies. She subsequently developed inflammatory arthritis of other joints, met the criteria for rheumatoid arthritis, and has been treated medically. PMID- 23013847 TI - Unfavorable prognosis in a patient with neglected juvenile idiopathic arthritis. PMID- 23013848 TI - Occurrence of rheumatoid arthritis requiring oral and/or biological disease modifying antirheumatic drug therapy following a diagnosis of primary Sjogren syndrome. AB - We report 6 patients with an established diagnosis of primary Sjogren syndrome who developed severe rheumatoid arthritis (RA) requiring oral disease-modifying antirheumatic drug with or without biologic therapy. Rheumatoid arthritis was diagnosed between 14 months and 17 years following initial sicca symptoms. Five patients were female. Two thirds were seropositive for Sjogren antibody, and 5 of 6 were either rheumatoid factor or anti-cyclic citrullinated peptide positive at the time of RA diagnosis. All had either hand or wrist involvement; one third had nodules. Although none demonstrated erosion on x-ray, all required methotrexate or leflunomide, and 4 required a biologic agent for the treatment of their arthritis. Primary Sjogren patients may develop RA after a long course of stable Sjogren. PMID- 23013849 TI - Wait times for rheumatology consultation: is rheumatoid arthritis prioritized? AB - OBJECTIVES: Patients with rheumatoid arthritis (RA) should be seen by a rheumatologist promptly; however, there are no recommendations for patients with osteoarthritis (OA). Our goal was to describe wait times from referral by the primary care provider to rheumatology consultation and to explore whether wait times are associated with type of arthritis diagnosis, geographic area, or type of rheumatology office. METHODS: Appointments were requested by telephone using case scenarios that were created by a group of experts and included (1) presumed RA, (2) possible RA, and (3) presumed OA. Wait times were evaluated as the time between the initial request and the appointment date provided. We used descriptive statistics, bivariate analysis, and logistic regression in the analysis. RESULTS: For all scenarios combined, 34% were given an appointment with a rheumatologist within 3 months of referral, 32% waited longer than 3 months, and 34% were told that the rheumatologist was not accepting new referrals at the time the request was made. Patients with presumed RA were much more likely to be seen within 3 months of referral compared with those with presumed OA (odds ratio, 13; 95% confidence interval, 1.70-99.38). CONCLUSIONS: Rheumatoid arthritis is prioritized over OA for rheumatology appointments. However, most patients with RA are still not receiving an appointment to a rheumatologist in a timely manner. Effective triage tools to decrease these delays should be instituted. PMID- 23013850 TI - Systemic lupus erythematosus with lung, brain, liver, and spleen tuberculosis. PMID- 23013851 TI - Hypopyon uveitis in ankylosing spondylitis. PMID- 23013852 TI - B12 deficiency myelopathy in a patient with long-standing rheumatoid arthritis. PMID- 23013853 TI - Great artists with rheumatoid arthritis: what did their disease and coping teach? Part I. Pierre-Auguste Renoir and Alexej von Jawlensky. AB - The famous artists Pierre-Auguste Renoir (1841-1919) and Alexej von Jawlensky (1864-1941) had rheumatoid arthritis (RA). Both represent an outstanding example of successful coping with RA in former times when treatment was very limited, and these individuals took advantage of creative disease management. The most popular French impressionist painter Renoir used his creativity to develop his own exercises and assistive equipments for painting despite his disability. Thus, Renoir exemplifies an artistic life altered by RA over more than 25 years that he dedicated entirely to his art and the depiction of beauty and happiness testified by his own words: "The pain passes, but the beauty remains." Jawlensky, a Russian from origin, was one of the most important expressionist painter active in Germany and the first painter in the 20th century who created extensive series of paintings especially of human faces. From Jawlensky, we learned that his rapidly progressing, late-onset RA induced depression, disability, financial pressure, and social retreat. But the resulting artistic sublimation contributed to the change in his paintings, which we owe the more than 1000 series of the very unique, small-format "Meditations."For those interested in art, new insight will be opened into the life and work of the artists and increase the appreciation for their contribution to modern art. PMID- 23013882 TI - Prevalence of Dio2(T92A) polymorphism and its association with thyroid autoimmunity. AB - The 3,5,3'-L-triiodothyronine (T3) partly derives by the deiodination of the prohormone 3,5,3',5'-L-tetraiodothyronine (T4) by the type 2 iodothyronine deiodinase (D2). The single-nucleotide polymorphism in the D2 gene at position 92 (Dio(2T92A)), generates an enzyme with a reduced T4 to T3 conversion velocity. Because thyroid hormones can modulate the immune response, we hypothesized a pathophysiological role for Dio(2T92A) polymorphism in autoimmunity. The objective of this study was to investigate the Dio(2T92A) polymorphism in relation to thyroid autoimmunity (TA). We compared the prevalence of Dio(2T92A) polymorphism and serum thyroid hormone levels in healthy subjects and subjects with TA. A total of 110 subjects with TA and 106 controls were genotypized for Dio(2T92A) polymorphism. Free T3 (FT3), free T4 (FT4) and TSH were measured and compared with the Dio(2T92A) polymorphism. Dio(292T/A), Dio(292A/A), and Dio(292T/T) healthy subjects were 40.9%, 46.4%, and 12.7%, respectively. These prevalences were similar to those of some European countries whilst significantly different from that of Brazil. In the two groups of healthy subjects and TA subjects, Dio(2T92A) polymorphism had a similar distribution with non-significant differences. Similarly, no significant differences were observed in the serum concentration of FT3, FT4, and TSH between subjects with different Dio(2T92A) polymorphism. The FT4/FT3, and TSH/FT3 ratios were higher in Dio(292T/T) than in Dio(292T/A) and Dio(292A/A) subjects in both TA and healthy groups, but these differences were not significant. In conclusion, the distribution of Dio(2T92A) polymorphism may reflect geographical and ethnic differences, and it is not associated with TA. PMID- 23013868 TI - Distinct mechanisms of axonal globule formation in mice expressing human wild type alpha-synuclein or dementia with Lewy bodies-linked P123H beta-synuclein. AB - BACKGROUND: Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB linked P123H beta-synuclein (P123H betaS) were characterized by P123H betaS immunoreactive axonal swellings (P123H betaS-globules). Therefore, the objectives of this study were to evaluate alpha-synuclein (alphaS)-immunoreactive axonal swellings (alphaS-globules) in the brains of tg mice expressing human wild-type alphaS and to compare them with the globules in P123H betaS tg mice. RESULTS: In alphaS tg mice, alphaS-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H betaS-globules in P123H betaS tg mice. In the alphaS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated alphaS and 4 hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H betaS-globules, staining of nitrated alphaS and 4-HNE in these globules was weaker than that for alphaS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in alphaS-globules, suggesting a specific role of this molecule in these globules. CONCLUSIONS: Lysosomal pathology was similarly observed for both alphaS- and P123H betaS-globules, while oxidative stress was associated with the alphaS-globules, and to a lesser extent with the P123H betaS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for alphaS-globules. Collectively, both alphaS- and P123H betaS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies. PMID- 23013883 TI - An intramolecular charge transfer (ICT) based chemosensor for silver ion using 4 methoxy-N-((thiophen-2-yl)methyl)benzenamine. AB - 4-Methoxy-N-((thiophen-2-yl)methyl)benzenamine was found to be a highly selective chemosensor for Ag(+) ion in methanol-water (1 : 1 v/v) mixture over other metal ions such as Na(+), K(+), Li(+), Cu(+), Ba(2+), Cd(2+), Co(2+), Cu(2+), Fe(2+), Hg(2+), Mn(2+), Ni(2+), Pb(2+) and Zn(2+) with a limit of detection (LOD) is 5.0 * 10(-6) mol L(-1). Upon binding to Ag(+) ion, a strong fluorescent enhancement is observed which is attributed to an increase in intramolecular charge transfer (ICT). The proposed mechanism is strongly supported by TD-DFT calculations. PMID- 23013884 TI - Impact of visit-to-visit variability of blood pressure on deterioration of renal function in patients with non-diabetic chronic kidney disease. AB - An association between visit-to-visit variability (VVV) of blood pressure (BP) and renal damage was recently reported in a cross-sectional study. We aimed to clarify the longitudinal effect of VVV of BP on deterioration of renal function in patients with non-diabetic chronic kidney disease (CKD). We retrospectively studied 56 patients with non-diabetic CKD (stage 3 or 4) who visited our nephrology clinic between September 1994 and May 2011. VVV of BP was defined as the standard deviation and coefficient of variation (CV) of office BP measured at 12 consecutive visits. Main outcomes were the annual decline in the estimated glomerular filtration rate (eGFR) and the composite renal end point defined as a doubling of serum creatinine or the need for dialysis. The median observation period was 83 months. Standard deviation and CV of office systolic BP (SBP) were significantly associated with the slope of the eGFR after adjustments for confounders. The adjusted risk for composite renal end points more than doubled for each increment of 1-standard deviation of the standard deviation of office SBP (hazard ratio (HR) 2.20, P=0.001), and for each increment of 1-standard deviation of the CV of office SBP (HR 2.12, P=0.002). The present study demonstrated that the visit-to-visit variability of BP is an independent determinant of deterioration of renal function in patients with non-diabetic CKD. PMID- 23013885 TI - Right and left ventricles: as inseparable as the twin brothers 'Castor and Pollux'. PMID- 23013886 TI - Regional wall motion abnormalities in patients with pheochromocytoma. PMID- 23013887 TI - Intake of high sucrose during pregnancy altered large-conductance Ca2+-activated K+ channels and vessel tone in offspring's mesenteric arteries. AB - Antenatal malnutrition could be linked to hypertension and vascular diseases in fetal origins. This study determined the influence of maternal intake of high sucrose (HS) during pregnancy on vessel tone, intracellular Ca(2+) ([Ca(2+)](i)), K(+) channels, especially large-conductance Ca(2+)-activated K(+) channels (BK), in mesenteric arteries in the offspring rats exposed to prenatal HS. Vessel tension and [Ca(2+)](i) induced by angiotensin II were higher in the small mesenteric arteries of the HS offspring. In the vascular smooth muscle cells (VSMCs) from the HS offspring, electrophysiological studies showed depressed BK current density and depolarized membrane. Western blot showed altered expressions of BK alpha-subunits, AT1 and AT2 receptors in mesenteric arteries. The results suggest that decreased BK channel activity and depolarized membrane potential in the VSMCs partly contributed to the increased vessel tone and [Ca(2+)](i) in the HS offspring, adding new information for understanding mechanisms in vascular malfunctions in fetal origins, and novel insights for early prevention and treatments against such vascular diseases. PMID- 23013888 TI - Comparison of effects of angiotensin II receptor blocker on morning home blood pressure and cardiorenal protection between morning administration and evening administration in hypertensive patients: the COMPATIBLE study. AB - Whether the time of administering the angiotensin receptor antagonist olmesartan influences antihypertensive and renoprotective effectiveness remains unclear. This study compared the effects of olmesartan on morning home blood pressure (MHBP), office BP (OBP) and renoprotective parameters between morning and evening administration. A total of 218 patients with primary hypertension were randomly assigned to receive olmesartan once daily in the morning (morning-dose group) or evening (evening-dose group), and 188 completed the study protocol (morning-dose group, n=95; evening-dose group, n=93). In both groups, morning home systolic BP, morning home diastolic BP, office systolic BP and office diastolic BP decreased significantly. There was no significant difference between the groups in MHBP or OBP after 6 months of treatment. The urinary albumin-to-creatinine ratio (UACR) decreased from 13.9 to 6.9 mg g(-1) (geometric means, P<0.001) in the morning dose group and from 14.4 to 9.1 mg g(-1) (P<0.001) in the evening-dose group. The changes in UACR after treatment did not differ significantly between the groups. SV1+RV5 decreased significantly from baseline to 6 months in the morning-dose group (P<0.001) and the evening-dose group (P<0.01), and did not differ significantly between the groups. In conclusion, olmesartan effectively decreased MHBP, OBP, SV1+RV5 and UACR regardless of whether the drug was administered in the morning or in the evening. Our results suggest that olmesartan can be prescribed once daily, either in the morning or in the evening. PMID- 23013889 TI - Revascularization for atherosclerotic renal artery stenosis: another flawed son of the ASTRAL Study. PMID- 23013896 TI - Determination of seven phenolic compounds in Rhizoma Sparganii by RP-HPLC. AB - A reversed-phase high-performance liquid chromatographic method was developed for the simultaneous quantification of seven phenolic compounds from Rhizoma Sparganii. The samples were separated on a Waters SunFire C18 column with a temperature of 30 degrees C. Gradient elution was applied, using 0.8% acetic acid (solvent A) and methanol (solvent B) with a flow rate of 1.0 mL/min, and detection wavelength was 280 nm. The validation of the method included linearity, precision, repeatability, stability and recovery. The calibration curves showed good linear regression (R(2) > 0.9996) within the test range. The developed method indicated good precision and accuracy, with the overall intra-day and inter-day variation at less than 3%. The range of recoveries for the seven analytes was 95.34-100.06% with relative standard deviation < 3.08 %. The established method was successfully applied for the determination of seven phenolic compounds in 12 batches of Rhizoma Sparganii. The study may be useful in the quality evaluation of Rhizoma Sparganii, and can provide technical support for pharmacological and clinical research of related drugs. PMID- 23013897 TI - Polarimetric detection in HPLC of R(-)-naproxen: features and intrinsic weakness. AB - Polarimetric detection in high-performance liquid chromatography (HPLC) might seem like a matter of course, especially in areas such as control of the optical purity of drugs or fingerprinting of herbal extracts. However, there are well founded reasons for the relatively low popularity of polarimetric detection in HPLC. Such reasons include, for example, the insufficient sensitivity of this type of detector when compared with photodiode array detection or evaporative light-scattering detection, or the economic factors. This paper, regarding an example of R(-)-naproxen, discusses physical phenomena (i.e., gelation of organic solvents by small organic molecules, the effect of molecular rotors and oscillatory interconversion of chiral analytes) that might obstruct the quantification of profen drugs (more generally, of chiral low molecular carboxylic acids) with the use of HPLC with polarimetric detection. The discussed (or analogous) phenomena are even more general, which hamper the widespread application of polarimetric detection in HPLC. PMID- 23013898 TI - Evidence-based assessments in the ventilator discontinuation process. AB - The ventilator discontinuation process is an essential component of overall ventilator management. Undue delay leads to excess stay, iatrogenic lung injury, unnecessary sedation, and even higher mortality. On the other hand, premature withdrawal can lead to muscle fatigue, dangerous gas exchange impairment, loss of airway protection, and also a higher mortality. An evidence-based task force has recommended a daily discontinuation assessment and management process for most ICU patients requiring at least 24 hours of mechanical ventilator support. This process focuses on assessments on the causes for ventilator dependence, assessments for evidence of disease stability/reversal, use of regular spontaneous breathing trials (SBTs) as the primary assessment tool for ventilator discontinuation potential, use of separate assessments to evaluate the need for an artificial airway in patients tolerating the SBT, and the use of comfortable, interactive ventilator modes (that do not need to be "weaned") in between regular SBTs. More recent developments have focused on the utility of computer decision support to guide these processes and the importance of linking sedation reduction protocols to ventilator discontinuation protocols. These guidelines are standing the test of time, and practice patterns are evolving in accordance with them. Nevertheless, there is still room for improvement and need for further clinical studies, especially in the patient requiring prolonged mechanical ventilation. PMID- 23013899 TI - The role of noninvasive ventilation in the ventilator discontinuation process. AB - In recent years, there has been increasing interest in the use of noninvasive ventilation (NIV) in the post-extubation period to shorten the length of invasive ventilation, to prevent extubation failure, and to rescue a failed extubation. The purpose of this review is to summarize the evidence related to the use of NIV in these settings. NIV can be used to allow earlier extubation in selected patients who do not successfully complete a spontaneous breathing trial (SBT). Its use in this setting should be restricted to patients who are intubated during an exacerbation of COPD or patients with neuromuscular disease. This category of patients should be good candidates for NIV and should be extubated directly to NIV. In patients who successfully complete an SBT, but are at risk for extubation failure, NIV can be used to prevent extubation failure. These patients should also be good candidates for NIV and should be extubated directly to NIV. NIV should be used cautiously in patients who successfully complete an SBT, but develop respiratory failure within 48 hours post-extubation. In this setting, NIV is indicated only in patients with hypercapnic respiratory failure. Reintubation should not be delayed if NIV is not immediately successful in reversing the post extubation respiratory failure. Evidence does not support routine use of NIV post extubation. PMID- 23013900 TI - The ventilator liberation process: update on technique, timing, and termination of tracheostomy. AB - Tracheostomy is one of the most commonly performed procedures in the ICU. Despite the frequency of the procedure, there remains controversy regarding selection of patients who should undergo tracheostomy, the optimal technique, timing of placement and decannulation, as well as impact on outcome associated with the procedure. A growing body of literature demonstrates that percutaneous tracheostomy performed in the ICU is a safe procedure, even in high risk patients. Advances in techniques, together with adjuncts to improve visualization, seem promising and likely to further improve the safety of the technique. Although there was initial enthusiasm in support of early tracheostomy to improve patient outcomes, repeated studies have been unable to produce robust benefits. The question of optimal timing and location of decannulation has not been answered, but there is some reassurance that in aggregate, across a variety of ICUs, patients do not appear to be harmed by transfer to ward with tracheostomy. Future research into techniques, timing, and termination of tracheostomy is warranted. PMID- 23013901 TI - Modes to facilitate ventilator weaning. AB - Weaning comprises 40 percent of the duration of mechanical ventilation. Protocols to reduce weaning time and to identify candidates at the earliest possible moment have been introduced to reduce complications and costs. Increased demand for mechanical ventilation, an increase in the number of patients requiring prolonged ventilation, and resource/staffing issues have created an environment where automated weaning may play a role. A number of closed loop techniques have been introduced since the early 1990s, with increasing sophistication. Preliminary research has demonstrated mixed results. Current systems continue to be evaluated in different patient populations and environments. Automated weaning is part of the ICU armamentarium, and identification of the patient populations most likely to benefit needs to be further defined. PMID- 23013902 TI - Ventilator discontinuation protocols. AB - Mechanical ventilation is a life-saving supportive therapy, but it can also cause lung injury, diaphragmatic dysfunction, and lung infection. Ventilator liberation should be attempted as soon as clinically indicated, to minimize morbidity and mortality. The most effective method of liberation follows a systematic approach that includes a daily assessment of weaning readiness, in conjunction with interruption of sedation infusions and spontaneous breathing trials. Protocols and checklists are decision support tools that help ensure consistent application of key elements of evidence-based practice. A majority of studies of weaning protocols applied by non-physician healthcare providers suggest faster weaning and shorter duration of ventilation and ICU stay, and some suggest reduced failed extubation and ventilator-associated pneumonia rates. Checklists can be used to reinforce application of the protocol, or possibly in lieu of one, particularly in environments where the caregiver-to-patient ratio is high and clinicians are well versed in and dedicated to applying evidence-based care. There is support for integrating best-evidence rules for weaning into the mechanical ventilator so that a substantial portion of the weaning process can be automated, which may be most effective in environments with low caregiver-to-patient ratios or those in which it is challenging to consistently apply evidence-based care. This paper reviews evidence for ventilator liberation protocols and discusses issues of implementation and ongoing monitoring. PMID- 23013903 TI - Early physical rehabilitation in the ICU and ventilator liberation. AB - Critically ill patients requiring mechanical ventilation are frequently subjected to long periods of physical inactivity, leading to skeletal muscle atrophy and muscle weakness. Disuse muscle atrophy is the result of complex mechanisms, including altered protein turnover and disturbed redox signaling. These ICU acquired complications are associated with longer duration of mechanical ventilation, prolonged ICU and hospital stays, and poorer functional status at hospital discharge. Similarly, there is growing evidence that continuous mandatory ventilation alters diaphragmatic structure and contractile function and promotes oxidative injury, resulting in a rapid-onset diaphragmatic atrophy and weakness, which most likely delays discontinuing mechanical ventilation. Physical rehabilitation, when started at the onset of mechanical ventilation, has been associated with shorter periods of mechanical ventilation, decreased ICU and hospital stay, and improved physical function at hospital discharge. This review summarizes the impact of both physical inactivity and mechanical ventilation on skeletal and diaphragmatic muscles structure and function. Also reviewed is the growing evidence demonstrating the feasibility and safety of early physical rehabilitation interventions for mechanically ventilated patients, as well as their benefit on patient outcomes. PMID- 23013904 TI - RSBI and NIV: who is failing: patient or machine? PMID- 23013905 TI - Tracheal reintubation: caused by "too much of a good thing"? PMID- 23013906 TI - Spirometry: how should we order this bedrock of diagnosis and management for Asthma and COPD? PMID- 23013907 TI - High-flow nasal cannula oxygen therapy during hypoxemic respiratory failure. PMID- 23013890 TI - Bronchial asthma and COPD due to irritants in the workplace - an evidence-based approach. AB - BACKGROUND: Respiratory irritants represent a major cause of occupational obstructive airway diseases. We provide an overview of the evidence related to irritative agents causing occupational asthma or occupational COPD. METHODS: We searched MEDLINE via PubMed. Reference lists of relevant reviews were also screened. The SIGN grading system was used to rate the quality of each study. The modified RCGP three-star system was used to grade the body of evidence for each irritant agent regarding its causative role in either occupational asthma or occupational COPD. RESULTS: A total of 474 relevant papers were identified, covering 188 individual agents, professions or work-sites. The focus of most of the studies and the predominant diagnosis was occupational asthma, whereas occupational COPD arose only incidentally.The highest level assigned using the SIGN grading was 2+ (well-conducted systematic review, cohort or case-control study with a low risk of confounding or bias). According to the modified RCGP three-star grading, the strongest evidence of association with an individual agent, profession or work-site ("**") was found for 17 agents or work-sites, including benzene-1,2,4-tricarboxylicacid-1,2-anhydride, chlorine, platinum salt, isocyanates, cement dust, grain dust, animal farming, environmental tobacco smoke, welding fumes or construction work. Phthalic anhydride, glutaraldehyde, sulphur dioxide, cotton dust, cleaning agents, potrooms, farming (various), foundries were found to be moderately associated with occupational asthma or occupational COPD ("*[+]"). CONCLUSION: This study let us assume that irritant induced occupational asthma and especially occupational COPD are considerably underreported. Defining the evidence of the many additional occupational irritants for causing airway disorders will be the subject of continued studies with implications for diagnostics and preventive measures. PMID- 23013908 TI - Acute hypoxemic respiratory failure in acquired immune deficiency syndrome: effects of noninvasive ventilation: the highest PEEP may not be best. PMID- 23013909 TI - Neonatal and infant pulmonary thromboembolism: a literature review. AB - Pulmonary thromboembolism (PTE) is rare in neonates and infants; however evidence suggests it is underdiagnosed. The primary objective is to conduct a scientific review to determine if the presentation, diagnosis, treatment and outcomes of neonates and infants with PTE are consistent across studies. Secondly, to develop an algorithm to establish the diagnosis and management of the condition based on current information. Two authors searched the literature independently using existing databases and verified that identical articles were assembled. Infants aged less than 1 year with PTE were included and further categorized into neonates 28 days or less and infants 29 days to 1 year or less. Forty-five articles with 157 cases (121 neonates; 36 infants) were identified with PTE. All of the reports were descriptive and neither randomized controlled trials nor prospective or case-control studies were identified. The reports are sub classified into cases of pulmonary air embolism (PAE) with a higher mortality rate and patients with PTE. Diagnostic and treatment strategies varied widely and were individually case-based, dependent on clinical findings, which influenced patient outcomes. Scientific data to guide an evidence-based, diagnostic and treatment approach to PTE is limited because of the absence of rigorous clinical trials. Large scale, multicenter collaborative studies are required to firmly establish the management of PTE in this population. PMID- 23013912 TI - Unusual cardiac outcomes of bacteremia due to Staphylococcus aureus infection: a case report. AB - INTRODUCTION: Patients on hemodialysis, particularly those with temporary non tunneled dialysis access, constitute a high-risk population for bloodstream infections associated with significant morbidity and mortality rates. This population also has a high prevalence of cardiovascular diseases with poor prognosis. CASE PRESENTATION: We report the case of a 62-year-old Caucasian man with end-stage renal disease undergoing hemodialysis, who presented with an eventually lethal case of staphylococcal septicemia with an unusual involvement of the heart, including bacterial coronary arteritis, myocardial abscesses and papillary muscle infarction and rupture, along with complications involving other organs. CONCLUSIONS: It is important to try to minimize invasive procedures in patients who are hemodialysis dependent. The strict control of heart function is indicated considering the large spectrum of unusual cardiac complications. PMID- 23013910 TI - Rising incidence of type 1 diabetes in Belgrade children aged 0-14 years in the period from 1982 to 2005. AB - BACKGROUND: Type 1 diabetes (T1DM) is an autoimmune disease in which both genetic and environmental factors play a role in the etiology. AIM: The aim of this study was to analyze the incidence of T1DM. METHODS: A retrospective technique was used to register all newly diagnosed cases of T1DM in Belgrade (Serbia) children at the age of 0- 14 yr between 1982 and 2005. The incidence was adjusted directly by age using the Segi's world population as the standard. A total of 702 cases was identified from the two sources: patients' records from two pediatric hospitals in Belgrade referent for the disease, and from the population based register. RESULTS: The average annual age adjusted incidence rate of T1DM for Belgrade was 10.4/100,000 [95% confidence interval (95% CI)=3.8-15.4]. It was slightly higher in boys than in girls. The age-specific annual incidence rates (per 100,000) for the age groups 0-4, 5-9, and 10-14 were 5.5 (95% CI=4.5-6.7), 11.9 (95% CI=10.5 13.5), and 15.4 (95% CI=13.8-17.1), respectively. Over the 24 yr incidence rates significantly increased by 8.5% for boys and 3.0% for girls. The highest increase of incidence rate was in the 5-9 age group. DISCUSSION: The results obtained are in line with data from other studies showing that the incidence of T1DM has been increasing in almost all populations worldwide. PMID- 23013913 TI - Long work hours and adiposity among police officers in a US northeast city. AB - OBJECTIVE: To investigate the associations between long work hours and adiposity measures in police officers. METHODS: Participants included 408 officers from the Buffalo Cardio-Metabolic Occupational Police Stress study who were examined between 2004 and 2009. Total work hours were abstracted from payroll records and questionnaires. Analysis of variance and covariance models were used. RESULTS: Among male officers who worked the midnight shift, mean values of waist circumference and body mass index increased with longer work hours after adjustment for age, physical activity, energy intake, sleep duration, smoking status, police rank, activities after work (eg, child/family care, sports), and household income. Adiposity measures were not associated with work hours among women on any shift. CONCLUSION: Working longer hours was significantly associated with larger waist circumferences and higher body mass index among male police officers working the midnight shift. PMID- 23013914 TI - Gel-cast glass-ceramic tissue scaffolds of controlled architecture produced via stereolithography of moulds. AB - Two glass-ceramic scaffolds with a simple cubic structure of 500 um square ligaments and square channels of width 400 or 600 um have been fabricated by gel casting into moulds produced by stereolithography, followed by mould removal, polymer burnout and sintering. The scaffolds have crushing strengths of 41 +/- 14 and 17 +/- 5 Mpa, respectively. Using a method of assembling discrete slices of scaffold, we are able to study cell behaviour within a scaffold by disassembly. Both scaffold structures were seeded with primary human osteoblasts and these penetrate, adhere, spread and proliferate on the scaffold structure. The larger channel diameter scaffold shows a greater cell population (despite its smaller surface area) and more pronounced production of ECM components (collagen and mineralization) with increased time in culture. Studies of sectioned scaffolds show that cell density and ECM production decrease with depth and that the difference between the two scaffold architectures is maintained. PMID- 23013916 TI - Colorimetric detection of copper ions in sub-micromolar concentrations using a triarylamine-linked resin bead. AB - The triarylamine derivative ETPA reacts with Cu(2+) to give deeply colored, stable radical cations in acetonitrile solution. ETPA was immobilized on to a tentagel resin bead which was then used for the fabrication of a simple device capable of the colorimetric detection of submicromolar concentrations of Cu(2+) ions in water. The naked eye detection limit reported here for Cu(2+) is one of the lowest ever reported for small molecule sensors. PMID- 23013925 TI - Effect of pH, substrate and free nitrous acid concentrations on ammonium oxidation rate. AB - Respirometric techniques have been used to determine the effect of pH, free nitrous acid (FNA) and substrate concentration on the activity of the ammonium oxidizing bacteria (AOB) present in an activated sludge reactor. With this aim, bacterial activity has been measured at different pH values (ranging from 6.2 to 9.7), total ammonium nitrogen concentrations (ranging from 0.1 to 10 mg TAN L( 1)) and total nitrite concentrations (ranging from 3 to 43 mg NO(2)-NL(-1)). According to the results obtained, the most appropriate kinetic expression for the growth of AOB in activated sludge reactors has been established. Substrate half saturation constant and FNA and pH inhibition constants have been obtained by adjusting model predictions to experimental results. Different kinetic parameter values and different Monod terms should be used to model the growth of AOB in activated sludge processes and SHARON reactors due to the different AOB species that predominate in both systems. PMID- 23013926 TI - Prognostic impact of red blood cell transfusion in patients undergoing primary angioplasty for ST elevation myocardial infarction. AB - OBJECTIVES: We aimed to examine in-hospital and long-term outcomes of red blood cell (RBC) transfusions in patients undergoing a primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). METHODS: Overall, 2537 consecutive STEMI patients (mean age 56.2 +/- 11.7 years, 2111 men, 426 women) undergoing primary angioplasty were enrolled retrospectively into the present study. Patients were categorized according to whether they received RBC transfusions during hospitalization. Clinical characteristics, and in-hospital and long-term outcomes of the primary PCI were analyzed. RESULTS: Of the consecutive 2537 patients, 88 (3.4%) received RBC transfusions during the index hospitalization. The transfused patients were older than nontransfused patients (mean age 63.6 +/- 12.1 vs. 56.2 +/- 11.8, P<0.001). Compared with nontransfused patients, female sex and hypertension were more prevalent in transfused patients (45.4 vs. 15.8%, P<0.001; 52.3 vs. 40.7%, P=0.04, respectively). Baseline values of hematocrit and hemoglobin were lower in patients receiving transfusion (33 +/- 6.2 vs. 40.2 +/- 4.7%, P<0.001; 11.1 +/- 2.3 vs. 13.7 +/- 1.6 mg/dl, P<0.001, respectively). The transfused patients had significantly higher in-hospital and long-term mortality (for in-hospital mortality: 10.2 vs. 2.7%, P<0.001; for long-term mortality: 14.1 vs. 5.1%, P=0.001). By multivariate Cox regression analysis, in all 2537 patients, RBC transfusion was found to be a powerful independent predictor of in-hospital cardiovascular mortality (odds ratio 8.31, P<0.001). CONCLUSION: These results show that RBC transfusion is associated with increased in-hospital and long-term mortality in patients with STEMI undergoing a primary PCI. PMID- 23013927 TI - Medicinal use of fauna by a traditional community in the Brazilian Amazonia. AB - BACKGROUND: Zootherapy inventories are important as they contribute to the world documentation of the prevalence, importance and diversity of the medicinal use of animals in traditional human communities. The present study aims to contribute with a more valuable example of the zootherapy practices of a traditional community in the Brazilian Amazonia - the "Riozinho do Anfrisio" Extractive Reserve, in Northern Brazil. METHODS: We used the methods of participant observation and semi-structured interviews, applied to 25 informants. We employed the combined properties of two indices to measure the medicinal importance of each cited species to the studied community, as well as their versatility in the treatment of diseases: the well known Use Value (UV) and the Medicinal Applications Value (MAV) that we developed. RESULTS: We recorded 31 species of medicinal animals from six taxonomic categories, seven of which are new to science. The species are used for the treatment of 28 diseases and one species is used as an amulet against snakebites. The five species with the highest UV indices are the most popular and valued by the studied community. Their contrasting MAV indices indicate that they have different therapeutic properties: specific (used for the treatment of few diseases; low versatility) and all purpose (several diseases; high versatility). Similarly, the most cited diseases were also those that could be treated with a larger number of animal species. Ten species are listed in the CITES appendices and 21 are present in the IUCN Red List. The knowledge about the medicinal use of the local fauna is distributed evenly among the different age groups of the informants. CONCLUSIONS: This study shows that the local fauna represents an important medicinal resource for the inhabitants of the protected area. The combined use of the UV and MAV indices allowed identifying the species with the highest therapeutic potential. This type of information about a species may be of interest to pharmacological research, and is crucial to its conservation, since it helps signaling the species that may undergo higher hunting pressures. Data on zootherapy can also be of interesting to ecologists by contributing to indicators of local biodiversity richness. PMID- 23013930 TI - Laxative treatment with polyethylene glycol does not affect lipid absorption in rats. AB - OBJECTIVES: Polyethylene glycol (PEG) is a frequently used laxative agent. It is unknown, however, whether PEG affects the absorptive capacity of the intestine. Reduced lipid (dietary fat and cholesterol) absorption induced by long-term PEG treatment could negatively affect growth in children. We tested whether PEG accelerates gastrointestinal transit and alters lipid absorption and plasma lipid levels. METHODS: Wistar rats were administered drinking water with or without PEG (7%) for 2 weeks. We studied whole gut transit time by recording the first appearance of red feces after intragastric carmine red administration. We measured plasma concentrations of cholesterol and triglycerides, dietary fat absorption by 48-hour fat balance and by plasma appearance of intragastrically administered stable-isotope labeled fats, and cholesterol absorption with a dual stable isotope technique. RESULTS: PEG decreased whole gut transit time by 20% (P=0.028) without causing diarrhea. PEG treatment did neither affects overall dietary fat balance nor fat uptake kinetics, cholesterol absorption, or plasma lipid concentrations. CONCLUSIONS: PEG does not affect lipid absorption nor steady-state plasma lipid levels in rats, although it accelerates the gastrointestinal transit. PMID- 23013933 TI - Optimisation of pharmacokinetic properties in a neutral series of 11beta-HSD1 inhibitors. AB - 11beta-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11beta-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl pyrimidines was circumvented by a switch from sulfur to carbon substitution. PMID- 23013934 TI - Acremomannolipin A, the potential calcium signal modulator with a characteristic glycolipid structure from the filamentous fungus Acremonium strictum. AB - By the newly developed assay method, the glycolipid Acremomannolipin A (1) was isolated from a filamentous fungus Acremonium strictum as a potential calcium signal modulator. The structure of 1 elucidated on the basis of intensive spectroscopic analyses as well as its degradation studies is quite unique: the d mannopyranose is connected to d-mannitol through a beta-glycoside linkage; all the hydroxyls in the mannose are highly masked as peresters with aliphatic acids, and this moiety is made hydrophobic, whereas the mannitol part exhibits a highly hydrophilic property. The compound (1) showed the characteristic bioactivity property, enabling calcineurin deletion cells to grow in the presence of Cl(-), which would be caused by calcium signal modulating. The activity was so potent as to exert the effect at a concentration of 200 nM. PMID- 23013935 TI - Chronic abdominal pain, appendiceal mucinous neoplasm, and concurrent intestinal endometriosis: a case report. AB - INTRODUCTION: Although both appendiceal tumor and intestinal endometriosis have been reported as rare causes of abdominal pain, the coexistence of appendiceal mucinous neoplasm and ileal endometriosis has not previously been reported. CASE PRESENTATION: A 41-year-old Japanese woman presented with a positive fecal occult blood test and a 3-year history of menstruation-related lower abdominal pain. A colonoscopy demonstrated extrinsic compression of the cecum, suggesting a mass arising from the appendix or adjacent structures. Abdominal imaging showed a 6-cm cystic mass with intraluminal thick fluids originating from the appendix. At ileocecal resection for an appendiceal tumor, a 2-cm mass in the terminal ileum was incidentally found, which was included in the surgical specimen. Microscopic examination confirmed a diagnosis of a mucinous neoplasm of the appendix with endometriosis of the terminal ileum. CONCLUSIONS: To avoid urgent surgery for subsequent serious events associated with disease progression, appendiceal tumor and intestinal endometriosis should be ruled out in patients with chronic abdominal pain. PMID- 23013936 TI - Expression of TRAF6 and ubiquitin mRNA in skeletal muscle of gastric cancer patients. AB - OBJECTIVE: To investigate the prognostic significance of tumor necrosis factor receptor (TNFR),-associated factor 6 (TRAF6),-and ubiquitin in gastric cancer patients. METHODS: Biopsies of the rectus abdominis muscle were obtained intra operatively from 102 gastric cancer patients and 29 subjects undergoing surgery for benign abdominal diseases, and muscle TRAF6 and ubiquitin mRNA expression and proteasome proteolytic activities were assessed. RESULTS: TRAF6 was significantly upregulated in muscle of gastric cancer compared with the control muscles. TRAF6 was upregulated in 67.65% (69/102) muscle of gastric cancer. Over expression of TRAF6 in muscles of gastric cancer were associated with TNM stage, level of serum albumin and percent of weight loss. Ubiquitin was significantly upregulated in muscle of gastric cancer compared with the control muscles. Ubiquitin was upregulated in 58.82% (60/102) muscles of gastric cancer. Over expression of ubiquitin in muscles of gastric cancer were associated with TNM (Tumor-Node Metastasis) stage and weight loss. There was significant relation between TRAF6 and ubiquitin expression. CONCLUSIONS: We found a positive correlation between TRAF6 and ubiquitin expression, suggesting that TRAF6 may up regulates ubiquitin activity in cancer cachexia. While more investigations are required to understand its mechanisms of TRAF6 and ubiquitin in skeletal muscle. Correct the catabolic anabolic imbalance is essential for the effective treatment of cancer cachexia. PMID- 23013937 TI - Seasonal variations of plasma gonadotropin, prolactin, and testosterone levels in primary and secondary hypogonadism: evidence for an independent testicular role. AB - BACKGROUND: Seasonal hormonal rhythmicity of the hypothalamic-pituitary-gonadal axis may influence reproductive and sexual activity in mammals. AIM: To investigate whether pituitary-gonadal axis secretion seasonality occurs in men with primary and secondary hypogonadism and whether a hierarchical machinery regulates these variations. SUBJECTS AND METHODS: Six adult males with Klinefelter's syndrome (KS), eight with idiopathic normosmic hypogonadotropic hypogonadism (HH) and ten sex- and age-matched healthy controls were studied longitudinally for one year. Every three months, three plasma samples for assay of testosterone, LH, FSH, and prolactin were drawn and the mean value was used for statistical analysis. RESULTS: Healthy males showed a significant seasonality in LH (zenith in spring) and testosterone (zenith in autumn) but not in FSH and prolactin concentrations. Patients with KS and those with HH showed a seasonal rhythmicity only of testosterone values, even if with small amplitude, with the zenith in spring and summer respectively. CONCLUSION: The lack of dependence of testosterone on gonadotropin variations in normal men and the persistence of seasonal testosterone but not gonadotropin variations both in primary and secondary hypogonadism seem to indicate a possible independent testicular regulation of this seasonality. The shift of testosterone peak in hypogonadal men with respect to controls suggests that LH variations could play a synchronizing, rather than pace-making, role in seasonal testosterone variations. Since hormonal seasonality may also influence gonadal activity in humans, replacement therapy in hypogonadism should be aimed also at restoring a normal seasonal rhythmicity of pituitary-gonadal hormone concentrations. PMID- 23013938 TI - A ratiometric fluorescence recognition of guanosine triphosphate on the basis of Zn(II) complex of 1,4-bis(imidazol-1-ylmethyl) benzene. AB - As one vital member among the family of phosphates, guanosine triphosphate (GTP) not only plays a very important role in many critical biological processes but also closely associates with definite pathological states. Based on the ratiometric fluorescence response of the zinc complex of 1,4-bis(imidazol-1 ylmethyl) benzene (bix) in this contribution, a highly selective recognition of GTP has been successfully developed. The fluorescence of bix-Zn(II) at 289 nm decreased in the presence of GTP with the appearance of one new emission band at 341 nm, resulting in ratiometric fluorescence changes with the concentration of GTP. With that, ratiometric fluorescence recognition for GTP could be effectively established, and so GTP could be successfully discriminated from other structurally similar anions, including ATP and PPi. Furthermore, bix-Zn(II) also has a ratiometric fluorescence response to DNA sequences containing guanine. PMID- 23013939 TI - Horizontal transfers of Mariner transposons between mammals and insects. AB - BACKGROUND: Active transposable elements (TEs) can be passed between genomes of different species by horizontal transfer (HT). This may help them to avoid vertical extinction due to elimination by natural selection or silencing. HT is relatively frequent within eukaryotic taxa, but rare between distant species. FINDINGS: Closely related Mariner-type DNA transposon families, collectively named as Mariner-1_Tbel families, are present in the genomes of two ants and two mammalian genomes. Consensus sequences of the four families show pairwise identities greater than 95%. In addition, mammalian Mariner1_BT family shows a close evolutionary relationship with some insect Mariner families. Mammalian Mariner1_BT type sequences are present only in species from three groups including ruminants, tooth whales (Odontoceti), and New World leaf-nosed bats (Phyllostomidae). CONCLUSIONS: Horizontal transfer accounts for the presence of Mariner_Tbel and Mariner1_BT families in mammals. Mariner_Tbel family was introduced into hedgehog and tree shrew genomes approximately 100 to 69 million years ago (MYA). Most likely, these TE families were transferred from insects to mammals, but details of the transfer remain unknown. PMID- 23013940 TI - Renal sympathetic denervation: a new treatment strategy in the management of refractory arterial hypertension. PMID- 23013941 TI - Biological markers of nephrotic syndrome: a few steps forward in the long way. AB - One of the major challenges modern nephrology should face is the identification of biomarkers that are associated with histopathological patterns or defined pathogenic mechanisms that might aid in the non-invasive diagnosis of the causes of nephrotic syndrome, or in establishing prognosis sub-groups based on each type of disease, thus predicting response to treatment and/or recurrence. Advancements in the understanding of the pathogenesis of the different diseases that cause nephrotic syndrome, along with the progressive development and standardisation of plasma and urine proteomics techniques, have facilitated the identification of a growing number of molecules that might be useful for these objectives. Currently, the available information for many of the possible candidates identified to date, above all those discovered using proteomics, are still very preliminary. In this review, we summarise the available evidence for the different molecules that have been best assessed using clinical studies. PMID- 23013942 TI - Transplantectomy following renal graft failure. AB - Approximately 4%-10% of incident patients on dialysis have a non-functioning kidney graft, and according to series, as many as 32% require transplantectomy for a variety of reasons. Mortality in these patients is significantly higher than in those with a functioning graft or on renal replacement therapy without having received a graft. Graft intolerance syndrome, early graft loss, severe proteinuria, recurring pyelonephritis or neoplasia, and chronic inflammation syndrome have all been proposed as indications for transplantectomy. Chronic inflammation syndrome occurs in patients with high levels of inflammatory markers (C-reactive protein), anaemia resistant to treatment with erythropoiesis stimulators, and malnutrition markers. This inflammatory state is provoked by the graft, and reverts when a transplantectomy is performed, as several studies have shown. We have reviewed the medical literature published on this topic, the indications for transplantectomy and embolectomy, their advantages and disadvantages, the incidence of graft intolerance syndrome, and the pathophysiology of chronic inflammation syndrome, as well as the currently proposed therapeutic management algorithm. PMID- 23013943 TI - Dialysate calcium individualisation: a pending issue. AB - Calcium is one of the key elements to consider in patients on dialysis due to its relationship with cardiovascular risk. The introduction of non-calcium-based phosphate binders and calcimimetics has changed the setting for pre-dialysis serum calcium in recent years from 9.5-10.5mg/dl to 8.5-9.5mg/dl. To assess more accurately the changes in calcium (Ca) during haemodialysis sessions and to individualise prescriptions, the aim of this study was to assess the intradialytic changes of two different dialysate Ca concentrations before and after hemodialysis and their implications in controlling calcium-phosphate metabolism. PATIENTS AND METHOD: We analysed 98 patients with a mean age of 59.3 +/- 15 years, 68 of which were men and 30 women. Each patient received two HD sessions with two different dialysate Ca concentrations: 2.5 mEq/l (Ca25 group) or 3.0 mEq/l (Ca30 group). Pre- and post-dialysis Ca, phosphorus (P) and PTH were determined, and associated medications were recorded. For a more individualised analysis, patients were divided into four subgroups of Ca<8.5mg/dl, 8.5-9.0mg/dl, 9.0-9.5mg/dl, and >9.5mg/dl, according to pre-dialysis serum calcium levels. RESULTS: There were no differences in pre-dialysis values of Ca: 8.81 +/- 0.65 (CA25) and 8.88 +/- 0.61 (CA30), P: 4.01 +/- 1.3 (CA25) and 4.19 +/- 1.2 (CA30), or PTH: 352 +/- 288 (CA25) and 369 +/- 310 (CA30). Post-dialysis Ca and PTH did not change significantly with CA25 dialysate, although there was a significant post-dialysis Ca increase to 10.2 +/- 0.6 (P<.001) accompanied by a decrease in post-dialysis PTH (181 +/- 227, P<.001) with CA30. However, with CA25 dialysate, when different subgroups of pre-dialysis Ca were analysed: <8.5mg/dl (30.6%), 8.5 9.0mg/dl (31.6%), 9.1-9.5mg/dl (23.5%) and >9.5mg/dl (14.3%) we observed a Ca increase during the session in the <8.5 (P<.001) and 8.5-9.0 (P<.01) subgroups. Ca was unchanged in the 9.1-9.5 group and Ca decreased when the initial Ca values were >9.5mg/dL (P<.01). A Ca increase (P<.001) and a decrease in PTH (P<.01) were observed in all subgroups with CA30 dialysate. A total of 42% of patients were taking calcimimetics, 47% paricalcitol, and 32% calcium-based phosphate binders, although these drugs were not linked with pre- or post-dialysis Ca levels in or dialysate treatment. CONCLUSION: We concluded that the prescription of Ca dialysate needs to be individualised based on pre- and post-dialysis Ca values and the need for an increase, decrease, or no changes in post-dialysis calcium in relation to the clinical condition of the patient's phosphorous-calcium metabolism. PMID- 23013944 TI - Achieving better results for peritoneal dialysis in recent years. AB - INTRODUCTION: Survival rates between haemodialysis (HD) and peritoneal dialysis (PD) are the same but the associated comorbidity factors have a great impact on mortality. In the most recent studies the prognosis for PD has improved more than that for HD, although this has not meant an increase in the use of this treatment. OBJECTIVES: To determine whether the PD has improved over time with respect to its outcomes in our community, and determine the influence of comorbidity and treatment characteristics on the final results. METHODS: Incident patients undergoing DP in Andalusia between 1999 and 2010. The cohort was divided into two groups: before and after 2004. STATISTICS: mean +/- standard deviation, frequency, chi-square test, Student's t-test, risk determination (95% confidence interval), Kaplan-Meyer, log-rank and multivariate Cox proportional hazards models. RESULTS: 1464 incident patients undergoing DP, 537 before 2004 and 927 after 2004. The baseline characteristics of both groups (age, diabetes) were similar, although the first group had more severe cardiovascular disease and higher Charlson comorbidity index. In the second period, more automatic PD and solutions of bicarbonate and icodextrin were used. The overall survival rate for patients was 55 months median and 65 mean. Within all subgroups (age, diabetes, cardiovascular disease, technique type) there was a greater tendency towards survival in the second period (the technique type, age and diabetes were found to be statistically significant variables). Age, cardiovascular disease, diabetes mellitus and incident cases before 2004 were all independent risk factors. This latter variable lost significance as bicarbonate or icodextrin-based solutions were introduced, which were independent risk factors. Technique survival showed a median of 68 months and a mean of 73 months. Dialysis solutions and the period when the DP was initiated were independent risk factors for the technique. CONCLUSIONS: DP has shown improved results in recent years; probably the new solutions are having a positive influence. As such PD should be implemented applying the criteria of effectiveness, free choice, efficiency and PD units should be fully developed within Nephrology Departments. PMID- 23013945 TI - Incidence of acute myocardial infarction in the evolution of dialysis patients. AB - BACKGROUND: Although the estimated frequency of coronary artery disease (CAD) in patients on dialysis is very high, there is considerable variation in the studies published to date regarding the rate of acute myocardial infarction (AMI) in these patients. OBJECTIVE: To establish the incidence of AMI and to analyse the characteristics and consequences of this entity on the clinical progression of incident dialysis patients. METHODS: We recorded AMI in the patients treated in our dialysis unit between 01/01/1999 and 31/12/07. The variables assessed were: prior diagnosis of diabetes, hypertension, CAD (AMI or lesions observed in coronary angiography), ischaemic cerebrovascular accident, advanced peripheral artery disease (PAD), atrial fibrillation and tobacco use. Biochemical analyses included: urea, creatinine, haematocrit, calcium, phosphorous, iPTH, lipids and albumin. Follow-up lasted until transplant, death, loss to follow-up or study end in Dec. 2010. RESULTS: Of the 576 patients recruited (aged 64.6 +/- 16 years), 24.7% had diabetes, 82.3% were on haemodialysis (17.7% on peritoneal dialysis), and 34 (5.9%) had a previous diagnosis of CAD. In a follow-up lasting a mean of 40.2 +/- 32 months (1931.5 patient-years), 40 patients (6.9%) suffered an AMI. The incidence was 2.13/100 patient-years. The patients without CAD had an incidence of 1.84/100 patient-years and those with a previous diagnosis of CAD had an incidence of 7.53/100 patient-years. In 22.5% of patients, AMI happened in the first 3 months of dialysis, and 37.5% in the 1st year. Of the 40 AMI, 15 were with ST-segment elevation (incidence: 0.79/100 patient-years) and 25 were non ST segment elevation (incidence: 1.33/100 patient-years). The factors that predicted the occurrence of AMI in dialysis were older age (OR: 1.037; 95% CI: 1.009-1.067; P=.011), previous CAD (OR: 3.35; 95% CI: 1.48-7.16; P=.004), and diabetes as a cause of nephropathy (OR: 2.96; 95% CI: 1.49-5.86; P=.002). In-hospital mortality was 30%, with 72.5% of deaths occurring in the 1st year and 82.5% in the 2nd; 80% of the patients who underwent a coronary angiography had multi-vessel disease. CONCLUSIONS: The incidence of AMI in incident dialysis patients is high. In previous coronary disease patients, the incidence is 3-fold higher. Post infarction mortality is very high and multi-vessel disease is very frequent. PMID- 23013946 TI - Evaluation of coagulation and anti-Xa factor when using a heparin-coated AN69ST(r) dialyser. AB - BACKGROUND: Hemodialysis systems are potentially thrombogenic, so it is routinely used anticoagulation. Its prescription is with risks though which the recommendations regarding the scheduled dose are still based on very different criteria. METHODS: We performed a randomized, crossover pilot study. Six patients underwent six sessions of post-dilution hemodiafiltration with polysulfone HF80(r) dialyzer and standard anticoagulation with nadroparin, and six sessions with heparin-coated poliacrylonitrile AN69ST(r) membrane without using systemic anticoagulation. Dialyser and the extracorporeal circuit clotting grade was evaluated through visual scale every hour and coagulation parameters like anti-Xa factor. Our endpoint was to assess anti-Xa activity without differences in the rate of massive clotting between the two groups. RESULTS: No complete or grade 4 dialyzer clotting occurred in any of 36 sessions with each dialyzer. A partial lower 25% (grade 1-2) dialyzer clotting was in 32 (89.7%) AN69ST(r) sessions and 35 (97.2%) with the usual dialyzer and upper 25% (grade 3-4) in 4 (11.1%) AN69ST(r) sessions and 1 (2.8%) dialysis session with heparin. Arterial chamber blood coagulation was not greater than 25% (grade 3 and 4) in any of the studied sessions and the venous chamber in only 1 (2.8%) session with the usual dialyzer and 3 (8.4%) with no differences AN69ST(r) between the two dialyzers. The activated partial thromboplastin time at two hours showed differences between techniques related to administration of low molecular weight heparin (33.3 +/- 2.7s with polysulfone and 27.5 +/- 2.3s in AN69ST(r); P < 0.05) which remained significant at the end of the session (29.8 +/- 2.1s with polysulfone and 27.2 +/ 1.8s with AN69ST(r); P < 0.05). Anti-Xa factor activity was maximal two hours after administration of nadroparin, with differences between the two dialyzers (0.46 +/- 0.13 IU / ml in dialysis with polysulfone and 0.04 +/- 0.04 IU / ml with AN69ST(r)p<0.005) and went down after 4 hours (0.17 +/- 0.12 IU / ml in dialysis with polysulfone and 0.02 +/- 0.03 IU / ml in AN69ST(r); p<0.05). One patient in dialysis AN69ST(r); had an adverse reaction characterized by generalized pruritus and was excluded from the study, by withdrawing the consent in the first session. CONCLUSION: We demonstrate the low thrombogenicity of the AN69ST(r); dialyzer that allows post-dilution hemodiafiltration sessions without systemic anticoagulation, and without increasing the frequency of severe clotting events compared to HF80(r); dialyzer with nadroparin and with less risk of bleeding by not modifying the anti-Xa factor activity. PMID- 23013947 TI - Level of dependence in patients on haemodialysis in Catalonia and evolution of mortality rates. AB - INTRODUCTION: Age and the comorbidities associated with ESRD impair the functional autonomy of patients on haemodialysis (HD). Our objectives were to assess the level of dependence in patients on HD and their mortality rates after three years of treatment. To do so, we followed the criteria established by the "Ley de Promocion de la Autonomia Personal y Atencion a las Personas en situacion de dependencia", the Spanish Law of Dependence (LD). METHODS: We carried out a cross-sectional descriptive study between October 2007 and January 2008. From 3702 patients in 40 dialysis units in Catalonia, 806 were selected as potential dependent individuals according to the criteria of their healthcare providers. Variables studied included: level of dependence according to the LD criteria, age, time on HD, associated pathology, treatment characteristics, family circumstances, and survival from 2009 to 2011. RESULTS: According to the LD, 137 were not dependent, 350 had a grade 1 dependence level, 237 grade 2, and 82 grade 3. In addition, 121 were living in an institution. The mean age was 74.9 +/- 18.2 years and the median time on HD was 36 months. The prevalence of common pathologies was: diabetes (35.7%) and cardiovascular disease (29.1%). Musculoskeletal alterations (87%) and neurological disorders (38%) were the main causes of dependence. 64.2% of patients had a catheter as a vascular access. 34.9% of patients survived after three years, and these had a lower level of dependence when compared to those patients who had died, with no statistically significant differences within those three years. CONCLUSIONS: According to the LD, the prevalence of dependent patients in Catalonia is substantial (18.07%). These patients have a high mortality rate after three years. PMID- 23013948 TI - Psychosocial predictors of the quality of life of chronic renal failure patients undergoing haemodialysis. AB - OBJECTIVES: To assess health-related quality of life (HRQOL) of chronic renal failure patients undergoing dialysis replacement therapy, and to evaluate the predictive power of psychosocial variables (social support, self-efficacy, optimistic outlook, depression, anxiety and coping strategies) on the different levels of HRQOL. METHODS: We evaluated the HRQOL of 39 haemodialysis patients using the SF-36 instrument. The predictive ability of the evaluated variables was analysed using bivariate correlations and multiple regression analysis. RESULTS: Patients showed lower levels of HRQOL than the reference values for the instrument. Depression is the main predictor of HRQOL, associated negatively with all of its components. The degree of concern and the use of passive coping strategies for stress such as helplessness-hopelessness, and fatalism are also associated with lower levels of HRQOL. By contrast, self-efficacy, optimism, social support, and fighting spirit were associated with higher levels of HRQOL. CONCLUSIONS: These results have clear clinical implications regarding the ways in which psychological interventions should be aimed at improving HRQOL in renal patients. PMID- 23013949 TI - mTOR inhibitor monotherapy. A good treatment choice in renal transplantation? AB - Calcineurin inhibitors have reduced acute rejection rates and improved short-term graft survival, but without any improvement in long-term outcomes, since calcineurin inhibitors cause nephrotoxicity and death with a functioning graft. mTOR inhibitors have antiproliferative and anti-angiogenic effects with no nephrotoxicity. These properties could improve patient and graft long-term survival rates in select transplant recipients. In addition, monotherapy always diminishes the rate of non-compliance in chronic patients. We examined the evolution of 47 low immunological risk kidney transplant recipients with mTOR inhibitor monotherapy. The mean age was 45 +/- 10 years (range: 18-69 years), with 25 males y 22 females. We performed an immunological evaluation before and at 3 and 12 months after starting monotherapy by detection of donor-specific antibodies by microsphere cytometry and the determination of lymphocyte activity with production of ATP by CD4+ T-lymphocytes activated by PHA mitogen. We considered patients to be of low immunological risk when the patient had an ATP production less than 520 ng/dl and no history of acute rejection episode or donor specific antibodies. Initially, 5 patients received immunosuppression induction without calcineurin inhibitors (mycophenolate, prednisone, mTOR inhibitors and anti-CD25), and 42 were converted to mTOR inhibitors due to secondary effects of calcineurin inhibitors or malignancies. A total of 34 recipients had received sirolimus and 13 everolimus. Eighteen out 47 patients (38.2%) received prednisone and 29 (61.7%) mycophenolate with mTor before starting monotherapy. The mean follow-up period after starting monotherapy was 46.9 months (95% CI: 38.8-55.0 months). At the end of the follow-up, 7 out of 47 recipients (11.5%) had to change immunosuppression without losing their grafts after 1 year, due to heavy proteinuria in 2 cases, pulmonary infection in 1, acute rejection in 1, hepatotoxicity in 1, vasculitis in 1 and a temporary inclusion on dialysis after acute pyelonephritis in 1. Four out of 47 patients (8.5%) lost their grafts, as a result of chronic rejection in 3 cases, and as a result of death with a functioning graft in 1. The rate of acute rejection was 2.1%, one episode, which was solved with steroid pulses and switching from mTOR inhibitors to tacrolimus and mycophenolate. No patients developed donor-specific antibodies, and all of them maintained an ATP production less than 520 ng/dl. The rates of graft and recipient survival were both 100% at 1 year, and 88.7% and 95.7% at 5 years. The percentages of patients on monotherapy were 97.9% and 70.5 % at 1 and 5 years, respectively. At the end of the follow-up, 36 out of 47 recipients remained on mTOR inhibitor monotherapy. Serum creatinine and glomerular filtration rates improved significantly, from 2.16 +/- 1.05 mg/dl to 1.49 +/- 0.56 mg/dl (P=.001) and from 39.23 +/- 25.23 ml/min to 52.23 +/- 23.20 ml/min (P=.001), respectively. Proteinuria increased but not significantly, from 306.6 +/- 400 mg/24h to 418.1 +/- 514.1mg/24h (P=.17). The patients treated with mTOR inhibitors received significantly more erythropoietin and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers than before starting mTOR, but there was no change in the treatment with statins or hypotensive agents. Body weight and the percentage of diabetic recipients were similar during the study. No cases of non-compliance were observed during the follow-up. The present study supports the safety and efficacy of monotherapy with mTOR inhibitors in select kidney transplant recipients. PMID- 23013950 TI - Perinatal complications in women with kidney transplant. AB - BACKGROUND: Pregnancy in patients with kidney grafts is considered high-risk. OBJECTIVES: Determine perinatal complications in women with kidney transplants treated by our hospital and compare them with complications reported in national and international literature. MATERIAL AND METHOD: We studied perinatal complications in 18 patients with renal transplantation who delivered 19 newborns and were treated between 1 January 2009 and 31 December 2010. Results were compared with previous reports. RESULTS: Maternal age: 28.27 +/- 4.70 years old, parity: 2, interval from transplant to conception: 7.52 +/- 6.20 years, first prenatal visit 14.35 +/- 6.74 weeks, prenatal care: 18.88 +/- 9.18 weeks, 6 prenatal visits, gestational age at birth: 33.11 +/- 8.72 weeks. Maternal complications: cesarean section: 88.88%, blood transfusion: 38.88%, anaemia: 33.33%, premature rupture of membranes: 22.22%, preterm delivery: 22.22%, urinary tract infection: 16.66%, preeclampsia: 11.11%, uncontrolled hypertension: 11.11%, miscarriage: 11.11%, uterine antony: 5.55%, gestational diabetes: 0%, and mortality: 0%. Foetal complications: premature birth: 52.63%, mortality: 21.05%, intensive care: 21.05%, and low birth weight due to growth restriction: 10.52%. Transplantation complications: filtration impairment without need for dialysis: 5.55%, graft rejection: 0%, and graft loss: 0%. CONCLUSIONS: The frequency of perinatal complications was high. Pregnancy had no adverse effect on renal function and patient survival. Stable renal grafts in women of childbearing age is not necessarily a contraindication for pregnancy. PMID- 23013951 TI - Fibroblast growth factor 23 (FGF 23) and phosphocalcic metabolism in chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: The ample information available in relation to FGF 23, calcium, phosphorus, PTH, and 25/1,25 vitamin D has allowed us to define consistent values for each variable in each stage of chronic kidney disease (CKD). These values can define early stages, prognostic issues, and new treatment targets. We describe a cross-sectional study of these parameters in patients with different stages of CKD. METHOD: We measured FGF 23 by ELISA (intact molecule, Kainos Laboratory, Japan), calcium, phosphorus, PTH and vit D by standard methods. RESULTS: We examined 251 patients, 146 of which were men, with a mean age of 62.5 (11.5) years and 43% prevalence of type II DM. Levels of FGF 23 rose progressively, in a very significant manner, in correlation with the evolution of CKD, especially in stage 4 as compared to stage 1 (110.61 ng/L vs 31.32 ng/L). The same happened with iPTH values. Additionally, levels of 1,25 vitamin D decreased in a similar manner. Calcium values did not change. 25 vit D3 levels were low at all times and showed no tendency for a steady decline. Phosphorus rose in stage 4 CKD. Levels of FGF 23 were negatively correlated with renal function indicators and positively correlated with PTH and P. CONCLUSIONS: During the evolution of CKD, changes of FGF 23 and PTH would be the earliest markers. Calcium and 25 vit D3 do not vary with changes in the progression of CKD. Values of FGF 23 show an important correlation with PTH, 1,25 vit D3, P and estimated glomerular filtration rate. PMID- 23013952 TI - Hypercalcemia as a side effect of potassium binding agents. AB - Hypercalcemia is a potential adverse effect of calcium-containing ion exchange resins, often used in the treatment and prevention of hyperkalemia in chronic kidney disease (CKD). We describe a series of seven outpatients with moderate CKD (mean glomerular filtration rate estimated with the CKD-EPI formula 41.29 +/- 10.83 mL/min/1.73 m(2)), presenting mild hypercalcemia in relation to the treatment with calcium polystyrene sulfonate. Serum calcium increased a mean of 0.91 +/- 0.46 mg/dL, with a mean concomitant decrease of serum intact parathormone (iPTH) of 52.24 +/- 49.29 ng/dL. After treatment withdrawal or dose reduction, we observed a recovery of serum calcium and iPTH values. Treatment with calcic potassium binders should be included in the differential diagnosis of hypercalcemia in patients with moderate CKD. PMID- 23013953 TI - Outcomes weighting for comprehensive haemodialysis centre assessment. AB - BACKGROUND: At present, there is no adequate system available for evaluating dialysis centres. OBJECTIVES: To construct an overall haemodialysis results weighting system, acceptable to the different stakeholders involved which allows the comparison of centres using a compound marker. METHOD: The Quality Management Work Group of the Spanish Society of Nephrology (WG) established a set of preselected indicators. A Focus Group, independent of the WG, was established. It was made up of nine individuals: three patients, three clinicians and three clinical managers, who assessed these indicators using an approved methodology and established the selected indicators. Finally, the indicators were weighted through three weighting stages, each separated by two debate periods, which involved the distribution of 100 points between each variable, according to the personal assessment and the debate sustained. RESULTS: The clinical results included: haemodialysis doses, anaemia, plasma calcium and phosphorus, type of vascular access, and hospitalisation days. The weighting given to each variable following the third weighting process, expressed as an average of all the factors, was as follows: clinical results 38.9; annual mortality 25.0; satisfaction with the centre 12.2; health-related quality of life 15.6; and cost 8.3 (total 100). CONCLUSIONS: The weighting structure covers relevant and overall results and includes the opinion of all stakeholders involved; all of which will increase its acceptability and widespread use and contribute to the analysis of the value produced by the centres and the improvement of the results. PMID- 23013955 TI - Role of renal sympathetic denervation in a refractory arterial hypertension patient. AB - Despite advances in the pharmacological treatment of arterial hypertension (AHT) and the use of multiple antihypertensive drugs, a small but significant percentage of true severe refractory arterial hypertension patients are still not reaching their target blood pressure. In these cases, renal sympathetic denervation (RSD) seems to be a safe and effective method for severe hypertensive patients who are resistant to multiple drug treatment. We present the case of a 52-year-old patient diagnosed with essential hypertension, resistant to treatment with seven antihypertensive drugs. After 10 hospitalisations without achieving adequate blood pressure control, we decided to propose renal sympathetic denervation as an addition to medical treatment. The procedure was performed without complications in the short to medium-long term, achieving a significant improvement in blood pressure with the intention of reducing overall vascular risk. PMID- 23013954 TI - The importance of early haemodiafiltration in the treatment of lactic acidosis associated with the administration of metformin. AB - Metformin is a drug widely used in type 2 diabetic patients. Metformin-associated lactic acidosis (MALA) in diabetic patients is rare but can be serious. However, the relationship between metformin and lactic acidosis is under debate. We present seven cases of patients with MALA who came to our centre over a period of one year and who were treated early with haemodiafiltration. There are some risk factors that appear to predispose patients to this pathology, such as: acute renal failure, situations of hypoxemia and sepsis, cardiac or respiratory failure, previous history of lactic acidosis, liver disease and dehydration. As such, the use of metformin is discouraged in patients with GFR below 30 ml/min/1.73 m(2). All patients in our study were treated early with haemodiafiltration. The mortality in our study was 16.6%. We believe that MALA is a serious condition that requires prompt diagnosis and early treatment. Renal replacement therapy is not the solution for all patients, but can improve prognosis in more severe cases if started early. We should limit the use of metformin in diabetic patients with impaired renal function, although there is still controversy in the medical literature. PMID- 23013956 TI - NPHS2 gene mutation in an Iranian family with familial steroid-resistant nephrotic syndrome. PMID- 23013957 TI - Catheterography: a simple technique for the diagnosis of poor peritoneal dialysis catheter functioning. PMID- 23013958 TI - Immunosuppressive treatment of lupus nephritis in severe renal impairment. About the ALMS study. PMID- 23013959 TI - Dialysis hypotension and vasopressin. PMID- 23013960 TI - On-Line haemodialfiltration versus high flux haemodialysis. PMID- 23013961 TI - Chronic renal failure and peripheral arterial disease. PMID- 23013962 TI - Disseminated histoplasmosis and haemophagocytic syndrome in two kidney transplant patients. PMID- 23013963 TI - Dress syndrome and acute tubulointerstitial nephritis after treatment with vancomycin and beta-lactams. Case report and literature review. PMID- 23013964 TI - Endovascular rescue of a prosthetic arteriovenous fistula with multiple pseudoaneurysms in a patient with no other vascular access options. PMID- 23013965 TI - Senile adult with acute post-infectious glomerulonephritis. PMID- 23013966 TI - Massive hypercalcaemia in rhabdomyolysis associated with acute renal failure. PMID- 23013967 TI - Minimal change nephropathy in a patient with polymyalgia rheumatica. PMID- 23013968 TI - Kidney post-transplantectomy ruptured iliac pseudoaneurysm: emergency endovascular repair. PMID- 23013969 TI - Mono-bacterial peritonitis caused by Bacteroides thetaiotaomicron in a patient on peritoneal dialysis. PMID- 23013970 TI - Cutaneous cryptococcosis in a patient on chronic haemodialysis. PMID- 23013971 TI - Renal AA amyloidosis in a Castleman's disease patient. PMID- 23014062 TI - Hydronephrosis and renal failure following inadequate management of neuropathic bladder in a patient with spinal cord injury: Case report of a preventable complication. AB - BACKGROUND: Condom catheters are indicated in spinal cord injury patients in whom intravesical pressures during storage and voiding are safe. Unmonitored use of penile sheath drainage can lead to serious complications. CASE REPORT: A 32 year old, male person, sustained complete paraplegia at T-11 level in 1985. He had been using condom catheter. Eleven years after sustaining spinal injury, intravenous urography showed no radio-opaque calculus, normal appearances of kidneys, ureters and bladder. Blood urea and Creatinine were within reference range. A year later, urodynamics revealed detrusor pressure of 100 cm water when detrusor contraction was initiated by suprapubic tapping. This patient was advised intermittent catheterisation and take anti-cholinergic drug orally; but, he wished to continue penile sheath drainage. Nine years later, this patient developed bilateral hydronephrosis and renal failure. Indwelling urethral catheter drainage was established. Five months later, ultrasound examination of urinary tract revealed normal kidneys with no evidence of hydronephrosis. CONCLUSION: Spinal cord injury patients with high intravesical pressure should not have penile sheath drainage as these patients are at risk for developing hydronephrosis and renal failure. Intermittent catheterisation along with antimuscarinic drug should be the preferred option for managing neuropathic bladder. PMID- 23014060 TI - Genetic diversity and antimicrobial resistance among isolates of Escherichia coli O157: H7 from feces and hides of super-shedders and low-shedding pen-mates in two commercial beef feedlots. AB - BACKGROUND: Cattle shedding at least 104 CFU Escherichia coli O157:H7/g feces are described as super-shedders and have been shown to increase transmission of E. coli O157:H7 to other cattle in feedlots. This study investigated relationships among fecal isolates from super-shedders (n = 162), perineal hide swab isolates (PS) from super-shedders (n = 137) and fecal isolates from low-shedder (< 104 CFU/g feces) pen-mates (n = 496) using pulsed-field gel electrophoresis (PFGE). A subsample of these fecal isolates (n = 474) was tested for antimicrobial resistance. Isolates of E. coli O157:H7 were obtained from cattle in pens (avg. 181 head) at 2 commercial feedlots in southern Alberta with each steer sampled at entry to the feedlot and prior to slaughter. RESULTS: Only 1 steer maintained super-shedder status at both samplings, although approximately 30% of super shedders in sampling 1 had low-shedder status at sampling 2. A total of 85 restriction endonuclease digestion clusters (REPC; 90% or greater similarity) and 86 unique isolates (< 90% similarity) were detected, with the predominant REPC (30% of isolates) being isolated from cattle in all feedlot pens, although it was not associated with shedding status (super- or low-shedder; P = 0.94). Only 2/21 super-shedders had fecal isolates in the same REPC at both samplings. Fecal and PS isolates from individual super-shedders generally belonged to different REPCs, although fecal isolates of E. coli O157:H7 from super- and low-shedders showed greater similarity (P < 0.001) than those from PS. For 77% of super-shedders, PFGE profiles of super-shedder fecal and PS isolates were distinct from all low shedder fecal isolates collected in the same pen. A low level of antimicrobial resistance (3.7%) was detected and prevalence of antimicrobial resistance did not differ among super- and low-shedder isolates (P = 0.69), although all super shedder isolates with antimicrobial resistance (n = 3) were resistant to multiple antimicrobials. CONCLUSIONS: Super-shedders did not have increased antimicrobial resistance compared to low-shedder pen mates. Our data demonstrated that PFGE profiles of individual super-shedders varied over time and that only 1/162 steers remained a super-shedder at 2 samplings. In these two commercial feedlots, PFGE subtypes of E. coli O157:H7 from fecal isolates of super- and low-shedders were frequently different as were subtypes of fecal and perineal hide isolates from super-shedders. PMID- 23014065 TI - Mid-term results after ultrasound-monitored treatment of developmental dysplasia of the hips: to what extent can a physiological development be expected? AB - The purpose of this study was to evaluate the radiological outcome after ultrasound-monitored treatment of developmental dysplasia of the hip at the age of 3 years. We retrospectively reviewed the findings of the second radiographic follow-up of 72 consecutive infants (mean age 31.3 months) with residual developmental dysplasia of the hip. Statistical analysis showed significant regression of acetabular index. Nevertheless, nine hips in seven children showed substantial residual dysplasia. Although remodelling of the acetabulum can be expected, there remains a risk of residual dysplasia. For this reason, radiographic follow-up of every once treated hip as well as the initially physiological contralateral hip is necessary. PMID- 23014066 TI - Foreword. PMID- 23014067 TI - New and old knowledge on differentiated thyroid cancer epidemiology and risk factors. AB - Differentiated thyroid cancer (DTC) represents 1-2% of all human malignancies. The annual incidence varies among countries and it is estimated that 1.2-2.6 men and 2.0-3.8 women/100,000 individuals are affected worldwide. This incidence has been increasing in the last decades, likely due to an "over-diagnosis" of small cancers that would have remained occult and that have been likely revealed because of an increased diagnostic scrutiny rather than a real increase of incidence. The annual mortality rate for DTC is 0.5/100,000 both in men and women. DTC is 2-4 times more frequent in females than in males. The mean age at diagnosis is 40-45 yr for papillary tumors (PTC) and 50-55 yr for follicular tumors (FTC). They are very rare in children. Ninety percent of DTC are represented by PTC hystotype, mainly follicular and classical variants. In the last years it has been observed an important change in the oncogenic pattern of PTC with a significant reduction of RET/PTC rearrangements and an increase of BRAFV600E mutation suggesting a change in pathogenic events. The unique well demonstrated risk factor of DTC is the exposure to external radiation which is also correlated with the presence of RET/PTC rearrangements. Recently, other environmental factors (i.e. living in a volcanic area or in a iodine- either deficient or rich area) or some eating habits leading to obesity have been considered as potential DTC risk factors. However, at present, the favorite hypothesis is that a complex interaction between genetic and environmental factors is required to develop DTC. PMID- 23014068 TI - Primary surgery for differentiated thyroid cancer in the new millennium. AB - Differentiated thyroid cancers (DTC) are malignancies of follicular cell derivation. Histopathologically and oncologically, DTC fall into two broad tumor categories: papillary (PTC) and follicular thyroid cancer (FTC). These major tumor categories, based on clinical manifestation and biological behavior, are further subdivided into low-risk [papillary microcarcinoma (mPTC); minimally invasive follicular cancer (MIFTC)] and high-risk DTC [PTC>1 cm or metastatic; MIFTC with histopathological angioinvasion; widely invasive FTC (WIFTC)]. Recently, a surgical approach has been adopted that differentiates between low risk and high-risk DTC. The rationale behind this new concept is to better balance oncologic risk (high vs low) with the surgical morbidity attendant to the procedure (recurrent laryngeal nerve palsy and hypoparathyroidism). This surgical risk is larger with routine total thyroidectomy (TT) and central node dissection (CND) than with less than TT or TT without CND.Whereas TT with CND remains the treatment of choice for high-risk DTC with metastases, the extent of thyroid resection and lymph node dissection can be reduced in low-risk PTC and FTC without demonstrable loss of oncological benefit. In the new millennium, the surgical approach to DTC, especially low-risk PTC and FTC, has undergone considerable change, resulting in less extensive procedures. This risk-adapted strategy relies not only on the skillful histopathologic detection of multifocality in PTC and vascular invasion in MIFTC, but likewise necessitates diligent follow-up to spot and adequately treat local recurrences and distant metastases as they become clinically apparent. PMID- 23014069 TI - Radioiodine post-surgical remnant ablation in patients with differentiated thyroid cancer: news from the last 10 years. AB - Due to the growing incidence of differentiated thyroid carcinoma (DTC) and in particular of small papillary thyroid cancer observed in the last few decades, the indications, the activity of radioiodine (131I) to be administered, and the efficacy of post surgical thyroid 131I remnant ablation (RRA) have been widely discussed. In the last 10 years, the use of recombinant human TSH (rhTSH) or thyroid hormone withdrawal (THW) to stimulate the 131I remnant uptake has also interested many authors. The general agreement is that small (<=1 cm) intrathyroidal unifocal DTC with a favorable histology and no node metastases should not be submitted to RRA because of the low risk of relapse and cancer specific mortality. Conversely, RRA is indicated in patients with a higher risk level since it seems to reduce recurrence rates and mortality. The recent demonstration that the RRA preparation with rhTSH is as effective as THW using either high (100 mCi) or low (30 mCi) 131I activities suggests that rhTSH preparation and low activity of 131I should be considered as the standard of care for both low- and intermediate-risk DTC patients in the near future. Moreover, the use of low 131I activities and rhTSH reduces whole body radiation exposure and improves the quality of life which are very important advantages for DTC patients. PMID- 23014070 TI - Radioiodine therapy of metastatic lesions of differentiated thyroid cancer. AB - Seventy years after the first successful radioiodine treatment of metastatic differentiated thyroid cancer (DTC), radioiodine (131I) therapy for this type of tumor is still without alternative. During the last decade, some key issues such as individual dosimetry, and preparation of 131I therapy by recombinant human TSH have been addressed, but this has not yet lead to conclusive results; furthermore a number of questions related to indication, preparation, and treatment protocol of 131I therapy still remain unanswered. In this review, we will address the literature pertaining to the latest developments in the field of 131I therapy of advanced DTC and we will give an overview of the state of the art regarding patient preparation, dosimetry, and therapy. PMID- 23014071 TI - Recombinant human thyrotropin: safety and quality of life evaluation. AB - Recombinant human TSH (rhTSH) (thyrotropin alfa, Genzyme Co.) has been developed to improve the management of patients with differentiated thyroid cancer, who need radioiodine (131I) for treatment or follow-up diagnosis. Data available from published series involving approximately 500 patients prove that rhTSH is safe and that mostly unspecific non-severe side effects may occur (e.g. nausea, vomiting, headache or fatigue and dizziness). Tumor swelling which has been occasionally observed after rhTSH injection is a phenomenon well known from the past attributed to endogenous TSH stimulation after thyroid hormone withdrawal (THW) and can be prevented or alleviated by concomitant administration of glucocorticoids. The absorbed dose to the tumor after preparation of 131I therapy with rhTSH as compared to THW is not statistically different. The radiation dose to the blood and the remainder, however, is significantly lower if rhTSH is used instead of THW which is a strong argument in favor of rhTSH. Most importantly, the quality of life (QOL) after rhTSH is preserved as compared to THW where symptoms of hypothyroidism significantly impair QOL. Last but not least, more convenient scheduling of patients and shorter duration of time to be spent in the radioprotective ward are further arguments in favor of rhTSH. PMID- 23014072 TI - New insight in the follow-up strategies of differentiated thyroid cancer. AB - Differentiated thyroid carcinoma (DTC), either papillary or follicular, has usually a very good prognosis with an overall mortality of less than 10%. In recent decades, the clinical presentation of DTC has been changing from advanced cases requiring intense treatment and surveillance to cancer detected by fortuitous neck ultrasonography requiring less aggressive treatment and follow up. Given the changing presentation of DTC in the last years, the aim of DTC follow-up is to ensure the most effective and less invasive follow-up for a disease that nowadays is mostly cured just with surgery and is rarely fatal. The concept of "Ongoing Risk Stratification" or "Delayed Risk Stratification" which better define the patient risk based on the results of the initial treatment, can maximize the beneficial effects of aggressive therapy in patients with DTC who are likely to benefit from it, while minimizing potential complications and side effects in low-risk patients who will achieve complete remission. PMID- 23014073 TI - Target therapies for radioiodine refractory advanced thyroid tumors. AB - A small but not irrelevant percentage of differentiated thyroid cancers become refractory to radioiodine treatment either because they lose the ability of taking up iodine over the time or because, despite a persistent uptaking ability, the effect of the radioiodine is lost in terms of tumor burden reduction. These patients receive only few and transient benefits from other conventional therapies and particularly from chemotherapy. In the last decade, several new drugs have been discovered as potentially useful and tested in clinical trials. They are mainly represented by protein kinase inhibitor molecules that should be proposed to advanced and progressive 131I refractory thyroid cancer patients by enrolling them in clinical trials or by the "off label" use of the drug. PMID- 23014075 TI - Commentary: A cohort study of patients with anemia on admission and fatality after acute ischemic stroke. PMID- 23014074 TI - Optic disc and visual test findings in patients with migraine. AB - This study was conducted to determine whether the optic disc appearance and the visual field parameters of patients with migraine vary from those of age-matched controls. Twenty-two patients with migraine and 20 control participants were enrolled in the study. The automated visual field tests by Humphrey Field Analyzer(r) and optic disc images by Topcon(r) fundus camera were obtained from each participant. Horizontal and vertical cup-to-disc ratios were calculated by a manual, planimetric technique performed by two independent observers. The visual field indices including mean deviation (MD) and pattern standard deviations (PSD) were documented. No difference was found in the average cup-to-disc ratio between patients with migraine and control participants. However, MD and PSD of the groups were different. The average MD in the migraine group was -0.86+1.21, and in the control group was 0.10+1.03 (p=0.009). The average PSD in the migraine group was 2.11+0.68 and in the control group was 1.68+0.44 (p=0.024). In conclusion, this study demonstrated that patients with migraine had decreased sensitivity in their visual fields compared to the control participants. PMID- 23014076 TI - Physical child abuse: perception, diagnosis, and management by Southern Brazilian pediatric dentists. AB - PURPOSE: This study evaluated the perception, diagnosis, and attitudes of child abuse among Brazilian pediatric dentists. METHODS: Data, collected through a survey sent to 212 pediatric dentists in Curitiba, Brazil, included perceived knowledge about signs of child abuse, whether they had seen and reported it, and knowledge of their obligation to report, how, and to whom. RESULTS: The response rate was ~33%. The youngest group was significantly more likely to report cases than the group with more than 18 years since graduation. Fifty-five percent of the professionals thought they are able to identify child abuse, 36% thought they were unable, and 9% did not know. Although 73% knew that reporting incidents of abuse is compulsory, only 48% responded that they would report cases of abuse to the relevant authorities. Although 36% of the pediatric dentists reported to have seen suspected cases of abuse, only approximately 12% reported such cases to authorities. Signs of abuse most frequently mentioned were hematoma throughout the body (61%) and behavioral changes (53%). Lesions on the face, mouth, and teeth were cited by only 17% of the professionals. CONCLUSION: More information is needed in undergraduate dental schools and among pediatric dentists to recognize and report child abuse. PMID- 23014077 TI - The comparative morbidities of acute dental pain and acute asthma on quality of life in children. AB - PURPOSE: The purpose of this prospective cross-section survey study was to examine the comparative burden of acute exacerbations of the two most common chronic illnesses of childhood: acute dental pain and acute asthma. METHODS: All patients came from one of three distinct clinics within Nationwide Children's Hospital, Columbus, Ohio: (1) outpatient dental clinic; (2) urgent medical care unit; or (3) emergency department. Caregivers were asked information about their child's condition and the impact on their daily function. RESULTS: A total of 112 parent-child dyads were included in this study. Children were significantly more likely to be under the care of a physician for asthma than a dentist for caries (P<.001). More caregivers worried about their child's overall health due to dental caries than asthma-related symptoms (P<.001). Two thirds of children had pain due to dental caries, which kept them from sleeping; 45% were prevented from playing; 45% were prevented from going to school; and 68% from eating in the preceding week. CONCLUSION: Acute dental disease had a comparative and, in some aspects, greater impact on a child's quality of life than acute asthma. PMID- 23014078 TI - Permeability and smear layer removal: effects of different chemical agents on the primary root dentin. AB - PURPOSE: The purpose of this study was to evaluate the effects of chemical agents on the permeability and removal of the smear layer in the primary root dentin. METHODS: Fifty roots were distributed into 6 groups: (1) 5.25% sodium hypochlorite (SH); (2) 5.25% SH+17% ethylenedia-minetetraacetic acid (SHE); (3) 2% chlorhexidine (CHX); (4) 2% CHX+17% ethylenediaminetetraacetic acid (CHXE); (5) 17% EDTA (E); and (6) saline solution (SS). The canals were instrumented and irrigated. The roots were dyed, washed, and sectioned, and the permeability index was measured. The amount of smear layer was scored. Data were submitted to analysis of variance, Kruskal-Wallis, Student-Newman-Keuls and t tests (P<.05). RESULTS: Significant differences were observed in the cervical and apical thirds for the CHX (P=.03), CHXE (P=.027), SS (P=.038), and SH (P<.001) groups. The SS group showed a heavy smear layer in all thirds. Root canals treated with SHE showed great cleaning in the cervical, middle, and apical thirds. CONCLUSION: Sodium hypochlorite associated with ethylenediaminetetraacetic acid produces the best root canal cleaning and the highest permeability in all thirds. PMID- 23014079 TI - Factors related to maternal transmission of mutans streptococci in high-risk children-pilot study. AB - PURPOSE: The purpose of this study was to investigate virulence factors associated with maternal transmission of mutans streptococci (MS). METHODS: Saliva samples were collected from 10 mothers with active caries and their 2- to 5-year-old children. Ten MS colonies were isolated from each subject. Transmission of MS was identified by arbitrarily primed polymerase chain reactions. Biofilm formation and mutacin production of the isolates against Streptococcus gordonii 10558, Streptococcus sanguinis 10557, Streptococcus mutans 25175, and Streptococcus sobrinus 6715 were analyzed. RESULTS: All mothers and children had MS colonization. Only 7 of the 36 maternal genotypes (33 Streptococcus mutans genotypes and 3 Streptococcus sobrinus genotypes) were transmitted. Maternal transmission was found in 4 mother-child pairs, whereas 9 children had nonmaternal genotypes. There was no difference in biofilm formation between transmitted and nontransmitted genotypes (P>.05). Transmitted genotypes, however, produced more mutacin against Streptococcus sobrinus 6715 than nontransmitted genotypes. CONCLUSIONS: This pilot study showed that there may be nonmaternal as well as maternal mutans streptococci transmission. PMID- 23014080 TI - Effects of laser-assisted fluoride therapy with a CO2 laser and Er, Cr:YSGG laser on enamel demineralization. AB - PURPOSE: The purpose of this in vitro study was to evaluate the irradiation efficacy of the CO(2) laser and the Er, Cr:YSGG laser-either unassisted or assisted by acidulated phosphate fluoride (APF) treatment-on enamel's acid resistance. METHODS: One hundred twenty enamel samples, obtained from 20 extracted human molars, were randomly assigned to 6 groups as follows: (1) control (C); (2) exposed to acidulated phosphate fluoride (APF) gel (F); (3) Er, Cr:YSGG laser (EL); (4) irradiated with Er, Cr:YSGG laser through APF gel (EL/F); (5) CO(2) laser (CL); and (6) irradiated with CO(2) laser through APF gel (CL/F). The specimens were individually demineralized in an acidified hydroxyethylcellulose system, and the acid resistance was evaluated by determining the calcium ion using atomic absorption spectrometry. RESULTS: The average concentration of the calcium ion determined in groups C, F, EL, EL/F, CL, and CL/F was, respectively, 3.36, 2.63, 2.26, 2.32, 2.24, and 1.51 ppm. The results showed that demineralization in the: CL/F group was significantly less than the other groups; and the control group was significantly more than the other groups (P<.001). CONCLUSION: The effect of CO(2) laser irradiation, used with acidulated phosphate fluoride, in decreasing the enamel demineralization was more than all the other groups. PMID- 23014081 TI - Evaluation of survival of 3 different fixed space maintainers. AB - PURPOSE: The purpose of this study was to provide a comparative evaluation of the survival times and failure rates of different types of fixed space maintainers (SMs). METHODS: A total of 30 4- to 10-year-olds were selected for the study. Children were divided into 3 groups, according to type of SM, namely: band and loop (B&L), direct bonded (DB), and fiber-reinforced composite (FRC). Patients were recalled once every 3 months for clinical evaluation for 1 year or until failure. The survival times of SMs were estimated by means of the Kaplan-Meier method, and confounding factors were investigated using Cox regression analysis. RESULTS: Mean survival time was highest for B&L SMs (11.20 months), followed by DB SMs (9.20 months) and FRC SMs (6.70 months). There were statistically significant differences noted between types of SMs (log rank=11.99; P=.002). The Cox proportional hazards model revealed that age, sex, dental arch, and side of the jaw were not significantly correlated with "success of SMs" (P>.05). CONCLUSIONS: Band and loop fixed space maintainers showed superior performance in terms of both survival time and success rates versus direct bonded and fiber reinforced composite space maintainers. PMID- 23014083 TI - So what can I do? PMID- 23014082 TI - Green teeth are a late complication of prolonged conjugated hyperbilirubinemia in extremely low birth weight infants. AB - Eruption of green, discolored teeth affecting the primary dentition has been described in association with congenital viral infection, sepsis, hemolytic jaundice, and cholestasis. The purpose of this paper was to present the cases of 3 extremely low birth weight preterm infants who were noted to have green teeth at the corrected ages of 10 to 12 months. All had a history of prolonged conjugated hyperbilirubinemia during their time in neonatal intensive care. For infants with prolonged conjugated hyperbilirubinemia, extreme preterm birth and/or extremely low birth weight may be additional risk factors predisposing to the eruption of green teeth in later infancy. PMID- 23014084 TI - Effect of ozone application on the immediate shear bond strength and microleakage of dental sealants. AB - PURPOSE: The purpose of this study was to evaluate whether gaseous ozone application affects the immediate enamel bond strength or microleakage of 2 dental sealants. METHODS: Sixty bovine incisors were randomly divided into 4 groups, and sealants were applied to the enamel surfaces as follows: ozone + Concise; Concise (control); ozone + UltraSeal XT Plus; and UltraSeal XT Plus (control). Ozone application was performed for 80 seconds, and shear bond strength was measured. Additionally, 60 human molars were randomly divided into 4 groups, as aforementioned, and sealants were applied onto occlusal surfaces. Dye penetration (microleakage) was assessed. RESULTS: No significant differences were found between the 2 sealants. Ozone application did not result in a significant reduction in enamel bond strength or an increase in microleakage. CONCLUSIONS: Ozone gas did not compromise the adhesion of tested materials; therefore, one can disinfect the enamel surface before placing a dental sealant without impairing the material's clinical performance. PMID- 23014085 TI - Waiting for the pain to get worse: characteristics of a pediatric population with acute dental pain. AB - PURPOSE: The purpose of this study was to examine how acute dental pain in children is managed. METHODS: A prospective 18-item cross-sectional survey was administered to 300 parent-child dyads seeking care at a large urban tertiary care hospital emergency walk-in dental clinic. RESULTS: The children's mean age was 8 years, 6 months (+/-3 years, 2 months). The mean duration of pain was 17.7 days. Seventy-six percent of children had been treated with at least 1 dose of over-the-counter pain medication. Acetaminophen was most commonly used (40%), followed by ibuprofen (37%). Regression analysis revealed child age to be significantly correlated with over 40% of pain management behaviors. Younger children were less likely to have received over-the-counter analgesia for dental pain (P<.05). CONCLUSION: Parents delayed seeking dental care for over 2 weeks. Acute dental pain was most commonly managed with acetaminophen. Seeking dental care was delayed more often for older children. PMID- 23014086 TI - Parental perception vs. professional assessment of speech changes following premature loss of maxillary primary incisors. AB - PURPOSE: This study's purpose was to compare parental perceptions of children's speech changes with a professional speech assessment following premature extractions of maxillary primary incisors (PEMPI). METHODS: Healthy 5- to 6-year olds, with no cognitive and speech delay and who received PEMPI between the ages of 2 and 4 years old at a university-based clinic, were recruited for the study. First, their parents took part in a telephone interview regarding their perceptions of speech changes following the extractions. The children were then invited to undergo individual speech evaluations by a certified speech and language pathologist. RESULTS: Of 204 patients identified from the database, 57 parental interviews were completed. Sixty percent (34) felt their children sounded different following extractions, and 65% (37) reported difficulty with pronunciation of the "s" sound. For children who were perceived by their parents to sound different, 46% had problems pronouncing words with the letters s and z. For parents who did not perceive speech changes, none of the children had problems with s and z as determined by the professionally conduced speech evaluations (Fisher exact test P=.02). CONCLUSIONS: Children who undergo premature extractions of maxillary primary incisors show problems articulating words containing s and z, and there is an agreement between parental perceptions and actual disarticulations detected from a professional assessment. PMID- 23014087 TI - Impact of traumatic dental injury on quality of life among Brazilian preschool children and their families. AB - PURPOSE: The purpose of this study was to assess the impact of traumatic dental injury (TDI) on the quality of life of preschool children and their families. METHODS: This cross-sectional study was carried out with 388 60- to 71-month-old children. Data on oral health-related quality of life (OHRQoL) were collected using the Brazilian version of the Early Childhood Oral Health Impact Scale (ECOHIS). Oral examinations of the children were performed to determine the prevalence of TDI. Data analysis involved the chi-square test and multiple Poisson regression analysis. RESULTS: The prevalence of OHRQoL of the children and their families was approximately 49% and 35%, respectively. The adjusted Poisson regression model revealed that the OHRQoL of the children and their families was significantly related to parents'/caregivers' report of the occurrence of TDI (PR =1.54, 95% confidence interval=1.22-1.93; and PR=1.63, 95% CI=1.21-2.19, respectively). The nonadjusted Poisson regression analysis, the OHRQofL of the children and their families was not related to TDI, as determined by the clinical examination (PR=1.15, 95% CI=0.92-1.42; and PR=1.28, 95% CI=0.95 1.71, respectively). CONCLUSIONS: The families and children who had traumatic dental injury, perceived by the parents/caregivers, had a greater chance of reporting an impact on quality of life. PMID- 23014088 TI - An association of premature loss of primary maxillary incisors with speech production of bilingual children. AB - PURPOSE: Early childhood caries is prevalent in the United States, especially among Hispanic children. One consequence may be premature loss of primary teeth, raising concern about developmental challenges. This study examined speech sound articulation errors association with premature loss of the primary maxillary incisors of bilingual children (Spanish/English). METHODS: Hispanic children were assessed with a speech sound articulation test at 7 to 10 years of age against their history of primary maxillary anterior incisor loss. The exposed group (N =25) experienced premature extraction of these incisors, and the unexposed group (N =8) had normal dental exfoliation. RESULTS: The groups were similar regarding: age at speech assessment; gender; language spoken at home; socioeconomic status; caries prevalence; mean number of decayed, missing, filled and sealed teeth. Higher values for the dental articulation errors (P=.04) were revealed among exposed vs unexposed. Exposed boys had more total speech articulation errors (P=.03), dental-related errors (P=.048), and other errors (P=.04) than the unexposed boys, although of small sample size. DISCUSSION: Bilingual children who experienced early primary tooth loss exhibited differences in speech sound production vs those who did not. Further research is warranted to determine the extent early tooth loss in bilingual children predicts speech problems. PMID- 23014089 TI - In vitro estrogenicity of dental resin sealants. AB - PURPOSE: This investigation assessed the estrogenic action of various types of sealants. METHODS: Three light-cured sealants (Denton Clear, Delton Opaque, Ultraseal XT Plus) were applied in polyethylene molds (O:10mm, h:2mm, n:8) and photopolymerized (40 seconds, halogen bulb unit, standard mode 650 mW/cm 2 intensity). All specimens were immersed in normal saline for 1 week at 37 degrees C. Samples of eluents at concentrations of 5% and 10% (volume per volume) were tested for estrogenicity by measuring their effect on the proliferation of the estrogen responsive MCF-7 breast cancer cells. In addition, an estrogen insensitive cell line was used as a control (MDA-MB-231) to exclude a possible cytostatic effect of the tested materials. All assays were repeated 4 times, and results analyzed with a 2-way analysis of variance and Tukey's test at the 0.05 level. RESULTS: Eluents of the sealants tested at concentrations of 5% and 10% did not possess estrogenicity, except for the eluent of one sealant (Delton Opaque) at concentration 10%, which caused an induction of the proliferation rate of the MCF-7 cells. CONCLUSIONS: Eluents of sealants tested at a concentration of 5% had no estrogenic activity. The eluent of Delton Opaque at a concentration of 10% possessed some estrogenic activity. PMID- 23014090 TI - Effectiveness of 2 chemomechanical caries removal methods on residual bacteria in dentin of primary teeth. AB - PURPOSE: The purpose of this study was to evaluate the effectiveness of 2 chemomechanical caries removal methods-Carisolv and Papacarie-on the residual cariogenic bacteria in the dentin of primary teeth vs traditional hand excavation. METHODS: Forty-five primary teeth were divided into 3 groups, according to the caries removal method used. Carious dentin samples were taken, then all softened dentin was removed, and a second sample was taken when the cavities were clinically caries-free, All teeth were filled with composite resins. All dentin samples were serially diluted and cultured anaerobically on different agar plates: blood agar, Mitis salivarius agar, and Rogosa agar plates. Colony forming units were determined for total bacterial, mutans streptococci, and lactobacilli counts. RESULTS: The 3 caries removal methods significantly reduced the residual cariogenic bacteria for the total bacterial, mutans streptococci, and lactobacilli counts. There was a statistically significant difference between Papacarie and both Carisolv and hand excavation methods, with Papacarie being more effective in caries removal and causing more reduction in bacterial count. CONCLUSION: Papacarie is significantly more efficient in reducing the residual cariogenic bacteria in the dentin of primary teeth vs both Carisolv and the hand excavation method. PMID- 23014091 TI - Assessment of parental tooth-brushing following instruction with single-headed and triple-headed toothbrushes. AB - PURPOSE: The purpose of this study was to evaluate the effect of toothbrush design on the ability of parents to effectively brush their children's teeth. METHODS: Parents of children (mean age=5.1+/-0.75 years old) from 4 kindergarten schools were randomly assigned to receive instruction in brushing their children's teeth using a manual single-headed toothbrush (2 schools) or a triple headed toothbrush (2 schools). The parents' ability to brush their children's teeth was evaluated according to a novel toothbrush performing skill index (Ashkenazi Index), based on 2 criteria: (1) placement of the toothbrush on each tooth segment to be brushed ("reach"); and (2) completion of enough strokes on each segment ("stay"). One month after instruction, tooth-brushing ability was re evaluated and plaque index of the children's teeth was assessed. RESULTS: One month after instruction, parents using the triple-headed toothbrush received significantly higher scores on the tooth-brushing performance index (~86%), than did those in the single-headed group (~61%; P=.001). The plaque index was significantly higher in the single-headed group (0.97+/-0.38) vs the triple headed group (0.72+/-0.29; P<.01). The tooth-brushing performance index correlated negatively with the plaque index (P<.01). CONCLUSIONS: A triple-headed toothbrush promotes more consistent tooth-brushing by parents than does a single headed toothbrush. PMID- 23014092 TI - Misdiagnosis of erythema multiforme: a literature review and case report. AB - Erythema multiforme is primarily considered a disease of the skin. Diagnosis tends to be centered on dermatologic lesions of the extremities, with mouth ulcers regarded as a secondary finding. The purpose of this paper was to report a case of an 8-year-old male diagnosed with erythema multiforme limited to the oral cavity. The patient was referred to Texas A&M Health Science Center's Baylor College of Dentistry for biopsy of recurrent mouth ulcers following an outbreak of a fever blister. Previous hospitalization occurred twice due to severe mouth ulcers causing dehydration and loss of nutrition. He was treated with 10 mg of prednisone twice daily and was able to eat and drink without pain within 48 hours. Nearly all lesions healed within 5 days of therapy. Although rare, erythema multiforme should always be considered in the differential diagnosis in the event of acute onset stomatitis. PMID- 23014093 TI - Ocular complications following an inferior alveolar nerve block on a child patient: a review of the literature and report of a case. AB - A 7-year-old male patient developed palpebral ptosis and paralysis of the extraocular muscles following local anesthetic administration for a major operative procedure on the permanent mandibular left first molar. Complete resolution occurred within approximately 30 minutes. The purpose of this case report was to detail an iatrogenic paresis of the third cranial nerve following local anesthetic delivery on a child patient. PMID- 23014094 TI - A single-institution study of stereotactic body radiotherapy for patients with unresectable visceral pulmonary or hepatic oligometastases. AB - PURPOSE: The purpose of this study is to evaluate the feasibility, efficacy and toxicity of SBRT for treatment of unresectable hepatic or lung metastases regardless of their primary tumor site for patients who received prior systemic chemotherapy. METHODS AND MATERIALS: Between July 2007 and June 2010, 90 patients were treated with the CyberKnife(r) SBRT system for hepatic or pulmonary metastatic lesions. Medical records were retrospectively reviewed. The endpoints of this study were local control, overall survival (OS), disease-free survival (DFS), local relapse free-survival (LRFS), and treatment toxicity. RESULTS: A total of 113 liver and 26 lung metastatic lesions in 52 men (58%) and 38 women (42%) were treated. Median follow-up was 17 months. Median age at treatment was 65 years (range, 23-84 years). Primary cancers were 63 GI, three lung, eight breast, four melanoma, three neuro-endocrine tumors, and three sarcomas. Median diameter of the lesions was 28 mm (range, 7-110 mm) for liver and 12.5 mm (range, 5-63.5 mm) for lung. Local control rates at 1 and 2 years were 84.5% and 66.1%, respectively. Two-year overall survival rate was 70% (95% CI: 55-81%). The 1 and 2-year disease-free survival rates were 27% (95% CI: 18-37%) and 10% (95% CI: 4 20%), respectively. Median duration of disease-free survival was 6.7 months (95% CI: 5.1-9.5 months). Observed toxicities included grade 1-3 acute toxicities. One grade 3 and no grade 4 toxicity were reported. CONCLUSION: High-dose SBRT for metastatic lesions is both feasible and effective with high local control rates. Overall survival is comparable with other available techniques. Treatment is well tolerated with low toxicity rates. It could represent an interesting treatment option for oligometastatic patients not amenable to surgery, even when patients had been pre-treated with chemotherapy. SUMMARY: Stereotactic body radiotherapy (SBRT) has previously been successfully used in the treatment of metastatic lesions. It could be considered as a curative option for oligometastatic patients. This retrospective study involved 90 patients, designed to test potential effectiveness of SBRT in the treatment of oligometastases irrespective of primary. Results suggest SBRT could be an effective treatment extending patients' life span. This treatment appears to be more effective when used prior to multiple systemic treatment regimens. PMID- 23014095 TI - Predicting the difficulty of pure, strict, epistatic models: metrics for simulated model selection. AB - BACKGROUND: Algorithms designed to detect complex genetic disease associations are initially evaluated using simulated datasets. Typical evaluations vary constraints that influence the correct detection of underlying models (i.e. number of loci, heritability, and minor allele frequency). Such studies neglect to account for model architecture (i.e. the unique specification and arrangement of penetrance values comprising the genetic model), which alone can influence the detectability of a model. In order to design a simulation study which efficiently takes architecture into account, a reliable metric is needed for model selection. RESULTS: We evaluate three metrics as predictors of relative model detection difficulty derived from previous works: (1) Penetrance table variance (PTV), (2) customized odds ratio (COR), and (3) our own Ease of Detection Measure (EDM), calculated from the penetrance values and respective genotype frequencies of each simulated genetic model. We evaluate the reliability of these metrics across three very different data search algorithms, each with the capacity to detect epistatic interactions. We find that a model's EDM and COR are each stronger predictors of model detection success than heritability. CONCLUSIONS: This study formally identifies and evaluates metrics which quantify model detection difficulty. We utilize these metrics to intelligently select models from a population of potential architectures. This allows for an improved simulation study design which accounts for differences in detection difficulty attributed to model architecture. We implement the calculation and utilization of EDM and COR into GAMETES, an algorithm which rapidly and precisely generates pure, strict, n locus epistatic models. PMID- 23014101 TI - Transient heat generation in a quantum dot under a step-like pulse bias. AB - We study the transient heat generation in a quantum dot system driven by a step like or a square-shaped pulse bias. We find that a periodically oscillating heat generation arises after adding the sudden bias. One particularly surprising result is that there exists a heat absorption from the zero-temperature phonon subsystem. Thus the phonon population in non-equilibrium can be less than that of the equilibrium electron-phonon system. In addition, we also ascertain the optimal conditions for the operation of a quantum dot with the minimum heat generation. PMID- 23014102 TI - Non-fatal injuries among pediatric patients seeking care in an urban Ghanaian emergency department. AB - BACKGROUND: According to the World Health Organization (WHO), injuries represent the largest cause of death among people ages 140 -and contribute to a large burden of disease worldwide. The aims of this study were to characterize the prevalence and relative mechanism of injury among children seeking emergency care and describe the demographics at time of presentation among these children to inform further research in Ghana and sub-Saharan Africa. METHODS: A prospective cross-sectional survey of pediatric patients (n = 176) was conducted between 13 July 2009 and 30 July 2009 in the Accident and Emergency Center at Komfo Anoche Teaching Hospital (KATH) in Kumasi, Ghana. Participants were asked questions regarding demographics, insurance status, overall health, and chief complaint. RESULTS: Of the 176 patients surveyed, 66% (n = 116) presented for injuries. The mean age was 4.7 years (range 1.5 months to 17 years), and 68% (n = 120) were male. Of those presenting with injury, 43% (n = 50) had road traffic injuries (RTI). Of the RTIs, 58% (n = 29) were due to being an occupant in a car crash, 26% (n = 13) were pedestrian injuries, and 14% (n = 7) were from motorcycles. There was no significant difference in demographics, health status or indicators of socioeconomic status between injured and non-injured patients. CONCLUSIONS: Among pediatric patients presenting for acute care at KATH during the study time frame, the majority (n = 116, 66%) presented for injuries. To date, there are no studies that characterize pediatric patients that present for acute care in Ghana. Identifying injury patterns and collecting epidemiologic data are important to guide future research and educational initiatives for Emergency Medicine. PMID- 23014114 TI - Phosphorescent chemosensor for Hg2+ and acetonitrile based on iridium(III) complex. AB - A new phosphorescent chemosensor for Hg(2+) and acetonitrile (MeCN) based on iridium(III) complex Ir(dpp)(2)(dtc) (Ir1, dppH = 4,6-diphenylpyrimidine, dtcH = diethyl dithiocarbamic acid) was realized. Upon addition of a tetrahydrofuran (THF) solution of Hg(2+), the dichloromethane (DCM) solution of Ir1 gave a visual color change and significant fluorescent quenching. When MeCN was added, a new fluorescent emission emerged, which constituted a selective MeCN phosphorescent chemosensor. Complex Ir1 has been developed as an AND logic gate with Hg(2+) and MeCN as inputs. PMID- 23014115 TI - Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms: 211G>A (G71R) mutation becomes a risk factor under inadequate feeding. AB - Breastfeeding jaundice is a well-known phenomenon, but its pathogenesis is still unclear. Increased production of bilirubin, impaired hepatic uptake and metabolism of bilirubin, and increased enterohepatic circulation of bilirubin account for most cases of pathological neonatal hyperbilirubinemia. We previously reported that 211G>A (G71R) mutation of the UGT1A1 gene is prevalent in East Asians and is associated with the development of neonatal hyperbilirubinemia. Recently, significant association of G71R mutation with hyperbilirubinemia in breast-fed neonates was reported. We enrolled 401 full-term Japanese infants, who were exclusively breast-fed without supplementation of formula before developing hyperbilirubinemia, and classified them into two groups based on the degree of maximal body weight loss during the neonatal period. We analyzed the sex, gestational age, delivery mode, body weight at birth, maximal body weight loss and genotypes of G71R and (TA)(7) polymorphic mutations of UGT1A1. Statistical analysis revealed that maximal body weight loss during the neonatal period is the only independent risk factor for the development of neonatal hyperbilirubinemia. The effect of G71R mutation on neonatal hyperbilirubinemia is significant in neonates with 5% or greater maximal body weight loss and its influence increases in parallel with the degree of maximal body weight loss. Our study indicates that G71R mutation is a risk factor for neonatal hyperbilirubinemia only in infants with inadequate breastfeeding and suggests that adequate breastfeeding may overcome the genetic predisposing factor, G71R mutation, for the development of neonatal hyperbilirubinemia. PMID- 23014117 TI - Pilot study of a sensory room in an acute inpatient psychiatric unit. AB - OBJECTIVE: The use of sensory rooms (also known as comfort rooms) to reduce seclusion rates has generated a great deal of interest. This study examined the outcomes associated with the introduction of a sensory room in an acute inpatient psychiatric unit. METHOD: Consumers rated distress and staff rated a variety of disturbed behaviours before and after each use of the room. Items used during each episode were recorded. RESULTS: Use of the room was associated with significant reductions in distress and improvements in a range of disturbed behaviours. Those individuals who used the weighted blanket reported significantly greater reductions in distress and clinician-rated anxiety than those who did not. No changes were noted in rates of seclusion or aggression. CONCLUSIONS: The sensory room was an effective intervention to ameliorate distress and disturbed behaviour, although this did not translate into reductions in overall rates of seclusion or aggression. Weighted blankets appear to be particularly useful. PMID- 23014118 TI - Diagnostic processes in mental health: GPs and psychiatrists reading from the same book but on a different page. AB - OBJECTIVE: To explore the clinical reasoning processes underpinning diagnostic and management decision-making in treating patients presenting with psychological distress in general practice. METHOD: Practising GPs were invited to attend small group workshops in which two case histories were presented. Discussion was GP facilitated and recorded for thematic analysis. GPs provided demographic data, completed personality and attitudinal questionnaires, and answered a series of multiple-choice questions embedded in the cases. RESULTS: GPs recognize the possibility of psychiatric disorders early in the clinical reasoning process, but are cautious about applying definitive diagnoses. GPs perceive that patients may be resistant to a psychiatric diagnosis and instead emphasize the need to build rapport and explore and exclude physical comorbidities. GPs see patients with a broad spectrum of distress, illness and impairment, in whom the initial presentation of psychological symptoms is often poorly differentiated and somatically focused, requiring elucidation over time. GPs therefore adopt a longitudinal strategy for diagnosis rather than investing heavily in cross sectional assessment. CONCLUSION: GPs appear cognizant of possible psychiatric disorders and management strategies, but employ diagnostic strategies and decision-making processes that, in addition to experience and expertise, likely reflect key differences between the primary care and specialist practice settings. PMID- 23014119 TI - Use of ultra-brief pulse electroconvulsive therapy to treat severe postnatal mood disorder. AB - OBJECTIVE: To describe the use of ultra-brief electroconvulsive therapy (ECT) in three postnatal women with severe, treatment resistant depression. The indications and evidence for the use of ECT in the treatment of postnatal depression are discussed. METHOD: We present a case series and review relevant literature. RESULTS: Three patients with severe episodes of depression postnatally, not responding to medication, presented to a private mother-baby inpatient unit. All three patients had significant suicidal ideation and two underwent involuntary treatment in public hospitals during the course of their presenting illnesses. They were treated with right unilateral ultra-brief ECT and a range of medications. All women began to respond within 3-6 treatments and no significant cognitive side effects were observed. CONCLUSIONS: Our findings suggest that right unilateral ultra-brief ECT is a useful treatment modality for severe and treatment resistant depression in the postnatal period. ECT is a useful option in women who have experienced significant medication side effects, or for those whose severity of illness necessitates rapid symptom resolution. Ultra-brief ECT caused minimal clinically observable side effects, which may assist mothers to resume care of their infants more rapidly. PMID- 23014120 TI - Behavioural treatment of chronic, severe self-loathing in people with borderline personality disorder. Part 1: interrupting the self-loathing cycle. AB - OBJECTIVE: The purpose of this article is to briefly outline difficulties in the standard behavioural treatment of severe chronic self-loathing in people with borderline personality disorder, and to follow with a fuller discussion on interrupting the self-loathing cycle. This is the first of a series of two articles on this topic. The second article focuses on the specific intervention of self-compassion and briefly mentions a range of other behavioural interventions. CONCLUSIONS: Treating severe chronic self-loathing in people with borderline personality disorder can be challenging for client and clinician alike, with standard approaches often being ineffective. Assessment of reinforcers of the locked-in downward spiral of self-loathing will guide interventions for clients to interrupt this vicious cycle. PMID- 23014121 TI - Perceived body weight, eating and exercise problems of different groups of women. AB - OBJECTIVE: To compare prevalence of problems with body weight, eating and exercise (past or present) of female psychiatric inpatients with routine care, gynaecological and obstetric female outpatients, and eating disorder inpatients. METHOD: One thousand and thirty-eight females aged 18-55 years from routine care (n=99), gynaecological (n=263) and obstetric (n=271) outpatient clinics, and eating disorder (n=223) and general psychiatric units (n=182) participated. Participants self-reported past or current problems with weight, eating and exercise using a short survey. A sub-sample of women completed the Eating and Exercise Examination (EEE) which includes the Quality of Life for Eating Disorders (QOL ED). RESULTS: The prevalence of self-reported problems controlling weight (52%), disordered eating and eating disorders (43%) for the psychiatric patients was significantly greater than for the routine care and gynaecological and obstetrics outpatients. The psychiatric group had a significantly higher mean body mass index (BMI) of 27.3 kg/m(2) (standard deviation (SD)=6.7) and prevalence of self-reported obesity (28%) than the other groups. CONCLUSION: Treatment of women with psychiatric problems should include assessment and concurrent attention to body weight, eating disorder and exercise problems in association with appropriate medical, psychiatric, psychological and medication treatment of their presenting disorder. PMID- 23014122 TI - Witchcraft and Huntington's disease: a salutary history of societal and medical stigmatisation. AB - OBJECTIVE: This paper examines the notions that psychiatry can be greatly influenced by what society considers as 'normal', and that psychiatric thoughts and beliefs ebb and flow according to history and the social and cultural values of the time. CONCLUSIONS: As part of the medical profession, psychiatrists have much power in determining treatment and outcomes for patients. Unfortunately, this also means psychiatry has also been involved with the darker aspects of humanity, such as during the Nazi regime, and the abuse of patients' human rights. Huntington's disease (HD) is a neuropsychiatric illness from which observation and little knowledge reported by the medical profession spanned decades of incorrect and sensationalised documentation, that was also influenced by the values of the time. Such was the atmosphere of society during this period that the ideas and notions regarding HD disseminated by the respected medical profession were believed and accepted as fact by the general population and other professions, who would have been ignorant of any other contrary information. We need to be aware of social and cultural values as these can influence our understanding of diagnoses and treatments of our patients. PMID- 23014123 TI - An exploration of the ability of routine outcome measurement to represent clinically meaningful information regarding individual consumers. AB - OBJECTIVE: Evidence that feedback on outcome measures can improve consumer outcomes is building but clinician engagement remains inconsistent. Clinicians can interpret and utilize familiar measures but have difficulty in relating to routine outcome measures like the Health of the Nation Outcomes Scales (HoNOS). This paper aims to explore and illustrate how these measures can represent clinically meaningful information regarding individual consumers. METHOD: Exploration of the aspects of individual clinical states and scenarios that can be represented using the HoNOS and Kessler-10 (K-10) will be used to illustrate their utility in clinical practice. RESULTS: Routine outcome measures have the capacity to represent aspects of consumer symptoms, individual functioning and the need for support relevant to clinical care. These measures may be considered using pattern recognition and reflective practice to answer the following questions. Have we adequately assessed the consumer? Is there agreement between the consumer and clinician? Has anything changed? CONCLUSIONS: While it may be difficult to relate to the total scores on outcome measures, information from within such measures, individual items and subscales can be presented in a manner that is clinically meaningful. Where clinicians are familiar with the measures, this ability is already being used. The challenge is to make it 'routine'. PMID- 23014124 TI - Potentiating patient participation: the 'Homeward Bound' psychoeducation programme for depression in old age. AB - OBJECTIVES: The aims of this paper are to briefly describe the need for psychoeducation for older adults with depression, the nature of the existing resources, the need for an alternative resource and the development and context of the St. Vincent's Hospital Psychogeriatrics Mental Health Service (SVHMHS) 'Homeward Bound' psychoeducation programme using an education-workbook for older adults with depression and their carers. CONCLUSIONS: 'Homeward Bound' is a psychoeducation programme designed for older adults with depression and their carers to actively engage in a collaborative process that will improve patient adherence, hasten recovery, maximize carer support and enhance patient outcomes and satisfaction. We believe this can be achieved by utilizing the education workbook designed by the SVHMHS multidisciplinary team. PMID- 23014125 TI - Dialectical behavioral therapy informed treatment with deaf mental health consumers: an Australian pilot program. AB - OBJECTIVE: This paper outlines the process of implementation of a dialectical behavioral therapy (DBT) informed treatment for Australian Deaf mental health consumers. METHOD: The pilot project team members adapted DBT materials for the Australian Deaf population. Feedback was obtained from the pilot participants and modifications made during the pilot. Participant progress and therapeutic alliance were monitored using culturally valid tools. RESULTS: The DBT informed therapy approach was well received by this target group, with the observation and self report of improved interpersonal skills and emotional regulation. CONCLUSIONS: While labor intensive, the process of developing a DBT informed treatment program for Australian Deaf mental health consumers appears to be beneficial for this group. Culturally valid, objective measures of skill attainment need to be developed and further studies comparing different adapted therapeutic approaches would be useful. PMID- 23014126 TI - Prevalence of parents within an adult mental health service: census results 2008 2011. AB - OBJECTIVE: The objective of this article is to determine the prevalence of parents of children (aged 0-17 years) within a mental health service system and gather contextual data regarding this population. METHOD: The study uses a census approach. The Census is conducted annually across Central Coast Adult Mental Health Services, NSW, Australia. All five community mental health teams and four acute inpatient units within the service participate, with each team completing Census forms for active clients identified as parents on Census day. The Census form collects data on parents and children including demographic data, parental diagnosis, parental contact and risk factors. RESULTS: Consecutive data shows 25 28% of active clients are parents. Annually, at least 400 children are identified; approximately 60% reside permanently with their parent with a mental illness. CONCLUSIONS: The Census is a valuable tool to determine the prevalence of parenthood. Moreover, it collects contextual data on this population. Data show an emerging relationship between parental diagnosis and parental contact. A picture of level of risk across the system has also been highlighted. Results add to the evidence regarding parental mental illness and circumstances of these families. The data clearly articulate a large need for interventions for children of parents with a mental illness (COPMI) within this population, given the high proportion of children who permanently reside with their parent with a mental illness. PMID- 23014127 TI - 'Theory of mind' III: the unbearable idea of other minds. AB - OBJECTIVE: In order to give an alternative explanation for the phenomena described by 'theory of mind', this topic is approached firstly by an examination of literary productions and then by reference to psychoanalysis. CONCLUSIONS: In literature there are many references to the apprehension of the other in terms of a mirror image of the self. The difficulty of grasping the other is described in a passage by the author Ian McEwan as 'the unbearable idea of other minds'. The notion that this difficulty can in part be overcome through both spoken and written language is also salient in the novels examined here. The concept of an entrapment within one's image of oneself was elaborated by Freud in his notion of narcissism. Lacan further developed this notion as foundational in one's relation to the other, but clarified that such mirroring relations to others are always imbued with jealousy and rivalry. Lacan's notion of "paranoid knowledge", an imagined knowledge of what the other is thinking, is precisely a 'theory of mind' that is able to account for the way one subject attempts, and ultimately fails, to read the mind of another. PMID- 23014128 TI - Clinical Practice Improvement Payments: incentives for delivery of quality care. AB - OBJECTIVE: In 2008, Queensland Health mental health services participated in a quality incentive payment scheme referred to as the Clinical Practice Improvement Payment. Services across the state engaged in local improvement projects with the collective aim of improving the number of consumers, diagnosed with schizophrenia, followed up within seven days post discharge. This paper describes the application of this approach over two and a half years. METHOD: Sixteen mental health services across Queensland participated and were provided with the opportunity to receive incentive payments during the period between January 2009 and June 2011. Data collection was conducted using information available on existing Queensland Health databases. Services were provided with regular updates on their progress through a secure intranet site, state-wide forums and individual service presentations, enabling them to compare their individual service data with peer and state data. RESULTS: State-wide results showed steady and continual improvement in the indicator over the reporting period. CONCLUSIONS: The results suggest that the implementation of incentive payments for routine clinical work in mental health can assist with state-wide service improvement. The impact of target setting and supporting activities remains unclear and improvements appeared to be robust to administrative challenges and unexpected external events. PMID- 23014129 TI - Psychiatry versus general physicians: who is better at differentiating epileptic from psychogenic non-epileptic seizures? AB - OBJECTIVE: To determine how accurately psychiatry and general medical doctors can differentiate epileptic and psychogenic non-epileptic seizures based on videotaped events (closest proxy to witnessed events). This study aims to establish how confidently this distinction can be made, the reasons why a particular diagnosis is reached, and inter-rater agreement. METHODS: 18 videos of patients demonstrating a heterogeneous mixture of epileptic and psychogenic non epileptic seizures were collected and ordered in a random mix. These videos were shown to groups of general physicians, medical registrars and residents (n=19) as well as to psychiatrists and psychiatry registrars (n=8) who were provided with a questionnaire. RESULTS: A total of 27 doctors participated in the study. The overall percentage of correct diagnoses was 55.4%. There were no significant differences in correct diagnosis rates between psychiatry and general medical doctors. There was poor inter-rater agreement (Kappa = 0.159). Neither group was particularly confident in reaching a diagnosis, and diverse reasons underpinned the diagnoses given. CONCLUSION: Among the participants, merely observing an epileptic or non-epileptic event is insufficient to establish a definitive diagnosis. The results indicate poor diagnostic accuracy and agreement among psychiatry and general medical doctors. This may have important implications for both education and clinical practice. PMID- 23014130 TI - Irregular rhythm adversely influences calcium handling in ventricular myocardium: implications for the interaction between heart failure and atrial fibrillation. AB - BACKGROUND: Despite adequate rate control, the combination of atrial fibrillation with heart failure (HF) has been shown, in a number of studies, to hasten HF progression. In this context, we aimed to test the hypothesis that an irregular ventricular rhythm causes an alteration in ventricular cardiomyocyte excitation contraction coupling which contributes to the progression of HF. METHODS AND RESULTS: We investigated the effects of electrical field stimulation (average frequency 2 Hz) in an irregular versus regular drive train pattern on the expression of calcium-handling genes and proteins in rat ventricular myocytes. The effect of rhythm on intracellular calcium transients was examined using Fura 2AM fluorescence spectroscopy. In conjunction, calcium-handling protein expression was examined in left ventricular samples obtained from end-stage HF patients, in patients with either persistent atrial fibrillation or sinus rhythm. Compared with regularly paced ventricular cardiomyocytes, in cells paced irregularly for 24 hours, there was a significant reduction in the expression of sarcoplasmic reticulum calcium (Ca(2+)) ATPase together with reduced serine-16 phosphorylation of phospholamban. These findings were accompanied by a 59% reduction (P<0.01) in the peak Ca2+ transient in irregulary paced myocytes compared with those with regular pacing. Consistent with these observations, we observed a 54% (P<0.05) decrease in sarcoplasmic reticulum Ca(2+)ATPase protein expression and an 85% (P<0.01) reduction in the extent of phosphorylation of phospholamban in the left ventricular myocardium of HF patients in atrial fibrillation compared with those in sinus rhythm. CONCLUSIONS: Together, these data demonstrate that ventricular rhythmicity contributes significantly to excitation-contraction coupling by altering the expression and activity of key calcium-handling proteins. These data suggest that control of rhythm may be of benefit in patients with HF. PMID- 23014131 TI - Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling. AB - BACKGROUND: Hypertension (HTN) causes concentric left ventricular remodeling, defined as an increased relative wall thickness or overt left ventricular hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction. It is not known whether the myofilament contributes to diastolic dysfunction in patients with concentric remodeling. METHODS AND RESULTS: Intraoperative myocardial biopsies were obtained in 15 male patients undergoing coronary bypass grafting, all with normal left ventricular ejection fraction and wall motion. Eight patients had a history of HTN and concentric remodeling. Seven without HTN or remodeling served as controls. Myocardial strips were dissected and demembranated with detergent. Isometric tension was measured and sinusoidal length perturbation analysis performed at sarcomere length 2.2 MUm and pCa 8 to 4.5. Sinusoidal analysis provides estimates of cross-bridge dynamics, including rate constants of attachment and detachment and cross-bridge attachment time. The normalized isometric tension-pCa relation was similar in HTN and controls. However, cross-bridge attachment time was significantly prolonged at submaximal [Ca(2+)] (pCa >=6.5) in HTN patients. Analysis of protein phosphorylation revealed ~25% reduction in phosphorylation of troponin I in HTN patients (P<0.05). CONCLUSIONS: Compared with controls, patients with HTN and concentric remodeling display prolonged cross-bridge attachment time at submaximal [Ca(2+)] without a change in the tension-pCa relation. Prolonged cross-bridge attachment time implicates altered cross-bridge dynamics as a cause of slowed relaxation in these patients. This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism. PMID- 23014133 TI - Thyroglobulin autoantibodies of patients with subacute thyroiditis are restricted to a major B cell epitope. AB - BACKGROUND: Thyroglobulin autoantibodies (TgAb) can develop in patients with subacute thyroiditis (SAT). AIM: Comparison of the epitope pattern of TgAb of patients with SAT, Hashimoto's thyroiditis (HT) [autoimmune thyroid disease (AITD)] and non-toxic multinodular goiter (NTMG) (non-AITD). SUBJECTS AND METHODS: Serum TgAb from 10 patients with SAT, 45 with HT, and 19 with NTMG were evaluated. Serum TgAb binding to Tg was inhibited by 4 recombinant human TgAb Fab, recognizing Tg epitope regions A, B, C, and D. The ability of single TgAb Fab to inhibit the binding of serum TgAb to Tg was evaluated in enzymelinked immunosorbent assay. RESULTS: Levels of inhibition were different for all TgAb Fab in the 3 groups of patients. Inhibition by region A TgAb-Fab in SAT [50.5 (30.3-62.5)%] (median and 25th to 75th percentiles) was similar to HT [49.0 (38.0 69.5)%] and significantly higher than in NTMG [25.0 (14.0-37.0)%]; by region B TgAb-Fab in SAT [0.0 (0.0-12.5)%] was significantly lower than in HT [28.0 (9.5 48.0)%] and similar to NTMG [9.0 (4.8-20.5)%]; by region C TgAb-Fab in SAT [9.5 (0.0-25.8)%] were similar to HT [23.0 (9.5-41)%] and NTMG [6.5 (1.7-21.5)%]; and by region D TgAb-Fab in SAT [0.0 (0.0-8.0)%] were lower than in HT [12.0 (1.0 28.5)%] and similar to NTMG [1.0 (0.0-5.0)%]. CONCLUSIONS: The epitope pattern of TgAb of SAT is restricted to the A region that is immunodominant in AITD and non AITD. In the majority of patients with SAT, the autoimmune phenomena represent a non-specific and transient response to the release of thyroid antigens, rather than the expression of thyroid autoimmunity. PMID- 23014135 TI - Endocrinology and Art. Goitrous countrymen - Andrea Fantoni (1659-1734). PMID- 23014136 TI - D-fending the cardiovascular benefits of vitamin D. PMID- 23014137 TI - Cardiovascular risk and early menopause: cause or consequence? PMID- 23014134 TI - Growth hormone, prolactin, and sexuality. AB - GH and PRL, although not considered as 'classical' sexual hormones, could play a role in the endocrine control of sexual function both in men and women. Physiologically, PRL seems to be involved in the central control of sexual behavior and activity, by modulating mainly the effects of dopaminergic and serotoninergic systems on sexual function. Indeed, circulating PRL levels increase after orgasm and may potentially play a role in the acute regulation of further sexual arousal following orgasm both in men and women. On the other hand, either short-term or long-term PRL increase can modulate central nervous system areas involved in the control of sexual function and, peripherally, can directly influence mechanisms of penile erection in men, and presently only as an hypothesis, mechanisms related to the sexual response of genitalia in women. Furthermore, chronic hyperprolactinemia is classically associated with hypogonadotropic hypogonadism and sexual dysfunction in both sexes. Successful treatment of chronic hyperprolactinemia generally restores normal sexual function both in men and women although this effect is not only related to relapse of gonadal function. Hypoprolactinemia is recently recognised as a possible risk factor of arteriogenic erectile dysfunction while a possible role on female sexual function is not known. The physiological role of GH on sexual function is not fully elucidated. GH is an important regulator of hypothalamuspituitary- gonadal axis and seems to participate in the regulation of the sexual response of genitalia in men, and potentially also in women. Sexual function in men and women with GH deficiency (GHD) and GH excess, particularly in acromegaly, is scantily studied and GH- or IGF-I-dependent effects are difficult to quantify. Nevertheless, a decrease of desire and arousability both in men and women, together with an impairment of erectile function in men, have been described both in patients with GHD and acromegaly, although it is not clear whether they are dependent directly on the hormone defect or excess or they are consequence of the hypogonadism or the different clinical complications or the physical disfigurement and psychological imbalance, which are associated with the diseases, and are potentially affecting sexual function. Data on beneficial effects of GH replacement therapy and specific surgical or pharmacological approach for acromegaly are far to be fully elucidated although restoring normal GH/IGF-I levels have been associated to improvement of sexual function. PMID- 23014138 TI - Focused teaching in menopause: the time is now. PMID- 23014139 TI - Soy germ isoflavones improve menopausal symptoms. PMID- 23014140 TI - Managed care is here to stay: implications for obstetrics and gynecology practice. AB - PURPOSE OF REVIEW: This article provides an overview of types and trends in managed care, as well as insights into how obstetrician/gynecologists can work with managed care plans to improve process and outcomes for patients. RECENT FINDINGS: Although studies of managed care between 1990 and 2005 generally did not show clear positive impact on cost or outcomes of care for women, more recent literature indicates the emergence of new models of care with greater success. Promising practices often focus on quality assurance and improvement. SUMMARY: Managed care is the predominant form of healthcare delivery in the United States, including millions of women with public or private health coverage. PMID- 23014141 TI - Review of nonsurgical/minimally invasive treatments for uterine fibroids. AB - PURPOSE OF REVIEW: Many nonsurgical and minimally invasive therapies for symptomatic uterine fibroids have been introduced. The purpose of this review is to summarize the recent evidence on these techniques, and their effect on fibroid volume, menorrhagia, health related quality of life (HRQOL), fertility and their risk of complications. RECENT FINDINGS: Laparoscopic or hysteroscopic myomectomy and uterine artery embolization (UAE) have been the most widely studied and all show significantly beneficial effects on menorrhagia and HRQOL, with a low incidence of complications. Magnetic resonance-guided high-intensity focused ultrasound (MRgFUS), myolysis/radiofrequency ablation (RFA) and laparoscopic or vaginal occlusion of uterine vessels (L/V-OUA) are newer interventions, with a smaller body of evidence.For women wishing to retain their childbearing possibilities, myomectomy is the best-studied intervention. Hysteroscopic myomectomy is specifically indicated in submucosal fibroids with subsequently beneficial effects on fertility. The use of UAE in fertile women has not been studied extensively, but evidence points toward an increase in adverse pregnancy outcomes after UAE compared with myomectomy. For MRgFUS, myolysis/RFA and L/V-OUA more evidence is needed. SUMMARY: Laparoscopic/hysteroscopic myomectomy and UAE are evidence-based beneficial alternative therapies for symptomatic uterine fibroids. Until more evidence is available, myomectomy stays the option of choice for women who wish to conceive in the future. PMID- 23014142 TI - Physical exercise during pregnancy: a systematic review. AB - PURPOSE OF REVIEW: This review aims to provide an update on the recent evidence concerning exercise during pregnancy including effects for mother and fetus and the types, frequency, intensity, duration and rate of progression of exercise performed. RECENT FINDINGS: Exercises during pregnancy are associated with higher cardiorespiratory fitness, prevention of urinary incontinence and low back pain, reduced symptoms of depression, gestational weight gain control, and for cases of gestational diabetes, reduced number of women who required insulin. There is no association with reduction in birth weight or preterm birth rate. The type of exercise shows no difference on results, and its intensity should be mild or moderate for previous sedentary women and moderate to high for active women. The exercise recommendations still are based on the current guidelines on moderate intensity, low-impact, aerobic exercise at least three times a week. Yet, new guidelines propose increasing weekly physical-activity expenditure while incorporating vigorous exercise and adding light strength training to the exercise routine of healthy pregnant women. In the case of other chronic diseases like hypertension, there are still few data, and therefore more studies should be performed to assess the safety of the intervention. SUMMARY: Physical exercise is beneficial for women during pregnancy and also in the postpartum period; it is not associated with risks for the newborn and can lead to changes in lifestyle that imply long-term benefits. PMID- 23014147 TI - Thermoelectric properties of HfN/ScN metal/semiconductor superlattices: a first principles study. AB - Nitride-based metal/semiconductor superlattices are promising candidates for high temperature thermoelectric applications. Motivated by recent experimental studies, we perform first-principles density functional theory based analysis of electronic structure, vibrational spectra and transport properties of HfN/ScN metal/semiconductor superlattices for their potential applications in thermoelectric and thermionic energy conversion devices. Our results suggest (a) an asymmetric linearly increasing density of states and (b) flattening of conduction bands along the cross-plane Gamma-Z direction near the Fermi energy of these superlattices, as is desirable for a large power factor. The n-type Schottky barrier height of 0.13 eV at the metal/semiconductor interface is estimated by the microscopic averaging technique of the electrostatic potential. Vibrational spectra of these superlattices show softening of transverse acoustic phonon modes and localization of ScN phonons in the vibrational energy gap between the HfN (metal) and ScN (semiconductor) states. Our estimates of lattice thermal conductivity within the Boltzmann transport theory suggests up to two orders of magnitude reduction in the cross-plane lattice thermal conductivity of these superlattices compared to their individual bulk components. PMID- 23014143 TI - Automating the analysis of EEG recordings from prematurely-born infants: a Bayesian approach. AB - OBJECTIVE: To implement an automated analysis of EEG recordings from prematurely born infants and thus provide objective, reproducible results. METHODS: Bayesian probability theory is employed to compute the posterior probability for developmental features of interest in EEG recordings. Currently, these features include smooth delta waves (0.5-1.5Hz, >100MUV), delta brushes (delta portion: 0.5-1.5Hz, >100MUV; "brush" portion: 8-22Hz, <75MUV), and interburst intervals (<10MUV), though the approach taken can be generalized to identify other EEG features of interest. RESULTS: When compared with experienced electroencephalographers, the algorithm had a true positive rate between 72% and 79% for the identification of delta waves (smooth or "brush") and interburst intervals, which is comparable to the inter-rater reliability. When distinguishing between smooth delta waves and delta brushes, the algorithm's true positive rate was between 53% and 88%, which is slightly less than the inter rater reliability. CONCLUSION: Bayesian probability theory can be employed to consistently identify features of EEG recordings from premature infants. SIGNIFICANCE: The identification of features in EEG recordings provides a first step towards the automated analysis of EEG recordings from premature infants. PMID- 23014149 TI - Systems thinking for strengthening health systems in LMICs: need for a paradigm shift. PMID- 23014150 TI - When 'solutions of yesterday become problems of today': crisis-ridden decision making in a complex adaptive system (CAS)--the Additional Duty Hours Allowance in Ghana. AB - Implementation of policies (decisions) in the health sector is sometimes defeated by the system's response to the policy itself. This can lead to counter intuitive, unanticipated, or more modest effects than expected by those who designed the policy. The health sector fits the characteristics of complex adaptive systems (CAS) and complexity is at the heart of this phenomenon. Anticipating both positive and negative effects of policy decisions, understanding the interests, power and interaction between multiple actors; and planning for the delayed and distal impact of policy decisions are essential for effective decision making in CAS. Failure to appreciate these elements often leads to a series of reductionist approach interventions or 'fixes'. This in turn can initiate a series of negative feedback loops that further complicates the situation over time. In this paper we use a case study of the Additional Duty Hours Allowance (ADHA) policy in Ghana to illustrate these points. Using causal loop diagrams, we unpack the intended and unintended effects of the policy and how these effects evolved over time. The overall goal is to advance our understanding of decision making in complex adaptive systems; and through this process identify some essential elements in formulating, updating and implementing health policy that can help to improve attainment of desired outcomes and minimize negative unintended effects. PMID- 23014152 TI - Health systems, systems thinking and innovation. PMID- 23014151 TI - Introducing vouchers for malaria prevention in Ghana and Tanzania: context and adoption of innovation in health systems. AB - There are striking similarities in health system and other contexts between Tanzania and Ghana that are relevant to the scaling up of continuous delivery of insecticide treated nets (ITNs) for malaria prevention. However, specific contextual factors of relevance to ITN delivery have led implementation down very different pathways in the two countries. Both countries have made major efforts and investments to address this intervention through integrating consumer discount vouchers into the health system. Discount vouchers require arrangements among the public, private and non-governmental sectors and constitute a complex intervention in both health systems and business systems. In Tanzania, vouchers have moved beyond the planning agenda, had policies and programmes formulated, been sustained in implementation at national scale for many years and have become as of 2012 the main and only publicly supported continuous delivery system for ITNs. In Ghana national-scale implementation of vouchers never progressed beyond consideration on the agenda and piloting towards formulation of policy; and the approach was replaced by mass distribution campaigns with less dependency on or integration with the health system. By 2011, Ghana entered a phase with no publicly supported continuous delivery system for ITNs. To understand the different outcomes, we compared the voucher programme timelines, phases, processes and contexts in both countries in reference to the main health system building blocks (governance, human resources, financing, informatics, technologies and service delivery). Contextual factors which provided an enabling environment for the voucher scheme in Tanzania did not do so in Ghana. The voucher scheme was never seen as an appropriate national strategy, other delivery systems were not complementary and the private sector was under-developed. The extensive time devoted to engagement and consensus building among all stakeholders in Tanzania was an important and clearly enabling difference, as was public sector support of the private sector. This contributed to the alignment of partner action behind a single co-ordinated strategy at service delivery level which in turn gave confidence to the business sector and avoided the 'interference' of competing delivery systems that occurred in Ghana. Principles of systems thinking for intervention design correctly emphasize the importance of enabling contexts and stakeholder management. PMID- 23014153 TI - Expecting the unexpected: applying the Develop-Distort Dilemma to maximize positive market impacts in health. AB - Although health interventions start with good intentions to develop services for disadvantaged populations, they often distort the health market, making the delivery or financing of services difficult once the intervention is over: a condition called the 'Develop-Distort Dilemma' (DDD). In this paper, we describe how to examine whether a proposed intervention may develop or distort the health market. Our goal is to produce a tool that facilitates meaningful and systematic dialogue for practitioners and researchers to ensure that well-intentioned health interventions lead to productive health systems while reducing the undesirable distortions of such efforts. We apply the DDD tool to plan for development rather than distortions in health markets, using intervention research being conducted under the Future Health Systems consortium in Bangladesh, China and Uganda. Through a review of research proposals and interviews with principal investigators, we use the DDD tool to systematically understand how a project fits within the broader health market system, and to identify gaps in planning for sustainability. We found that while current stakeholders and funding sources for activities were easily identified, future ones were not. The implication is that the projects could raise community expectations that future services will be available and paid for, despite this actually being uncertain. Each project addressed the 'rules' of the health market system differently. The China research assesses changes in the formal financing rules, whereas Bangladesh and Uganda's projects involve influencing community level providers, where informal rules are more important. In each case, we recognize the importance of building trust between providers, communities and government officials. Each project could both develop and distort local health markets. Anyone intervening in the health market must recognize the main market perturbations, whether positive or negative, and manage them so as to maximize the benefits to the health system and population health. PMID- 23014154 TI - Rethinking health systems strengthening: key systems thinking tools and strategies for transformational change. AB - While reaching consensus on future plans to address current global health challenges is far from easy, there is broad agreement that reductionist approaches that suggest a limited set of targeted interventions to improve health around the world are inadequate. We argue that a comprehensive systems perspective should guide health practice, education, research and policy. We propose key 'systems thinking' tools and strategies that have the potential for transformational change in health systems. Three overarching themes span these tools and strategies: collaboration across disciplines, sectors and organizations; ongoing, iterative learning; and transformational leadership. The proposed tools and strategies in this paper can be applied, in varying degrees, to every organization within health systems, from families and communities to national ministries of health. While our categorization is necessarily incomplete, this initial effort will provide a valuable contribution to the health systems strengthening debate, as the need for a more systemic, rigorous perspective in health has never been greater. PMID- 23014155 TI - Strengthening health systems through networks: the need for measurement and feedback. PMID- 23014156 TI - Evaluating health systems strengthening interventions in low-income and middle income countries: are we asking the right questions? AB - In recent years, there have been several calls for rigorous health policy and systems research to inform efforts to strengthen health systems (HS) in low- and middle-income countries (LMICs), including the use of systems thinking concepts in designing and evaluating HS strengthening interventions. The objectives of this paper are to assess recent evaluations of HS strengthening interventions to examine the extent to which they ask a broader set of questions, and provide an appropriately comprehensive assessment of the effects of these interventions across the health system. A review of evaluations conducted in 2009-10 was performed to answer these questions. Out of 106 evaluations, less than half (43%) asked broad research questions to allow for a comprehensive assessment of the intervention's effects across multiple HS building blocks. Only half of the evaluations referred to a conceptual framework to guide their impact assessment. Overall, 24% and 9% conducted process and context evaluations, respectively, to answer the question of whether the intervention worked as intended, and if so, for whom, and under what circumstances. Almost half of the evaluations considered HS impact on one building block, while most interventions were complex targeting two or more building blocks. None incorporated evaluation designs that took into account the characteristics of complex adaptive systems such as non-linearity of effects or interactions between the HS building blocks. While we do not argue that all evaluations should be comprehensive, there is a need for more comprehensive evaluations of the wider range of the intervention's effects, when appropriate. Our findings suggest that the full range of barriers to more comprehensive evaluations need to be examined and, where appropriate, addressed. Possible barriers may include limited capacity, lack of funding, inadequate time frames, lack of demand from both researchers and research funders, or difficulties in undertaking this type of evaluation. PMID- 23014157 TI - Characteristics and in-hospital outcomes of patients with acute coronary syndromes and heart failure in the United Arab Emirates. AB - BACKGROUND: Heart failure (HF) is a serious complication of acute coronary syndromes (ACS), and is associated with high in-hospital mortality and poor long term survival. The aims of this study were to describe the clinical characteristics, management and in-hospital outcomes of coronary syndrome (ACS) patients with HF in the United Arab Emirates. FINDINGS: The study was selected from the Gulf Registry of Acute Coronary Events (Gulf RACE), a prospective multi national, multicenter registry of patients hospitalized with ACS in six Middle East countries. The present analysis was focused on participants admitted to various hospitals in the UAE with a diagnosis of ACS in 2007 and were analyzed in terms of HF (Killip class II/III and IV) on admission. Of 1691 patients (mean age: 52.6 +/- 11.7 years; 210 Females, 1481 Males) with ACS, 356 (21%) had an admission diagnosis of HF (Killip class II/III and IV). HF patients were less frequently males (19.2% vs. 34.3%; P < 0.001). HF was more frequently associated with hypertension (64.3% vs. 43.9%; P < 0.001), hyperlipidemia (49.4% vs. 31.8%; P < 0.001) and diabetes mellitus (DM) (51.1% vs. 36.2%; P < 0.001). HF was significantly associated with in-hospital mortality (OR = 11.821; 95% CI: 5.385 25.948; P < 0.001). In multivariate logistic regression, age, hyperlipidemia, heart rate and DM were associated with higher in-hospital HF. CONCLUSIONS: HF is observed in about 1 in 5 patients with ACS in the UAE and is associated with a significant increase in in-hospital mortality and other adverse outcomes. PMID- 23014158 TI - A turn-on and reversible fluorescence sensor for Al3+ ion. AB - A simple 2-hydroxy-1-naphthaldehyde (receptor 1) serves as a selective chemosensor for Al(3+) based on chelation-enhanced fluorescence (CHEF). The receptor 1 exhibited a high association constant with micromolar detection for Al(3+) in EtOH-H(2)O solution. PMID- 23014173 TI - Latent autoimmune diabetes of adulthood: a case presentation. PMID- 23014171 TI - Social and monetary reward processing in autism spectrum disorders. AB - BACKGROUND: Social motivation theory suggests that deficits in social reward processing underlie social impairments in autism spectrum disorders (ASD). However, the extent to which abnormalities in reward processing generalize to other classes of stimuli remains unresolved. The aim of the current study was to examine if reward processing abnormalities in ASD are specific to social stimuli or can be generalized to other classes of reward. Additionally, we sought to examine the results in the light of behavioral impairments in ASD. METHODS: Participants performed adapted versions of the social and monetary incentive delay tasks. Data from 21 unmedicated right-handed male participants with ASD and 21 age- and IQ-matched controls were analyzed using a factorial design to examine the blood-oxygen-level-dependent (BOLD) response during the anticipation and receipt of both reward types. RESULTS: Behaviorally, the ASD group showed less of a reduction in reaction time (RT) for rewarded compared to unrewarded trials than the control group. In terms of the fMRI results, there were no significant group differences in reward circuitry during reward anticipation. During the receipt of rewards, there was a significant interaction between group and reward type in the left dorsal striatum (DS). The ASD group showed reduced activity in the DS compared to controls for social rewards but not monetary rewards and decreased activation for social rewards compared to monetary rewards. Controls showed no significant difference between the two reward types. Increased activation in the DS during social reward processing was associated with faster response times for rewarded trials, compared to unrewarded trials, in both groups. This is in line with behavioral results indicating that the ASD group showed less of a reduction in RT for rewarded compared to unrewarded trials. Additionally, de-activation to social rewards was associated with increased repetitive behavior in ASD. CONCLUSIONS: In line with social motivation theory, the ASD group showed reduced activation, compared to controls, during the receipt of social rewards in the DS. Groups did not differ significantly during the processing of monetary rewards. BOLD activation in the DS, during social reward processing, was associated with behavioral impairments in ASD. PMID- 23014174 TI - Computed tomography angiography and pulmonary embolism. PMID- 23014177 TI - What NPs need to know about anticoagulation therapy. AB - Venous thromboembolism (VTE) refers to pulmonary embolism and deep venous thrombosis. Anticoagulation is the cornerstone of management for patients with VTE. This review will discuss current anticoagulation guidelines. PMID- 23014178 TI - Recognizing anxiety disorders. AB - The majority of patients with anxiety disorders present in primary care settings, and many are undiagnosed or undertreated-each disorder has defining characteristics. Anxiety disorders are debilitating, and proper treatment can improve quality of life. Preferred treatments are cognitive-behavior therapy and pharmacotherapy with selective serotonin reuptake inhibitors. PMID- 23014179 TI - The pediatric medical home: will it become the norm? AB - This review will discuss policies that influenced medical home establishment and involvement of nurse practitioners, the background of the pediatric medical home, challenges, successful programs, and recommendations. PMID- 23014180 TI - When a broken heart is real: Takotsubo cardiomyopathy. AB - Takosubo cardiomyopathy is a rare but reversible type of cardiomyopathy that often mimics symptoms of acute coronary syndromes. It is essential that NPs differentiate the causes because treatment strategies vary. PMID- 23014183 TI - Detoxification and anti-nutrients reduction of Jatropha curcas seed cake by Bacillus fermentation. AB - Jatropha curcas seed cake is a by-product generated from oil extraction of J. curcas seed. Although it contains a high amount of protein, it has phorbol esters and anti-nutritional factors such as phytate, trypsin inhibitor, lectin and saponin. It cannot be applied directly in the food or animal feed industries. This investigation was aimed at detoxifying the toxic and anti-nutritional compounds in J. curcas seed cake by fermentation with Bacillus spp. Two GRAS (generally recognized as safe) Bacillus strains used in the study were Bacillus subtilis and Bacillus licheniformis with solid-state and submerged fermentations. Solid-state fermentation was done on 10 g of seed cake with a moisture content of 70% for 7 days, while submerged fermentation was carried out on 10 g of seed cake in 100 ml distilled water for 5 days. The fermentations were incubated at the optimum condition of each strain. After fermentation, bacterial growth, pH, toxic and anti-nutritional compounds were determined. Results showed that B. licheniformis with submerged fermentation were the most effective method to degrade toxic and anti-nutritional compounds in the seed cake. After fermentation, phorbol esters, phytate and trypsin inhibitor were reduced by 62%, 42% and 75%, respectively, while lectin could not be eliminated. The reduction of phorbol esters, phytate and trypsin inhibitor was related to esterase, phytase and protease activities, respectively. J. curcas seed cake could be mainly detoxified by bacterial fermentation and the high-protein fermented seed cake could be potentially applied to animal feed. PMID- 23014186 TI - Dual human epidermal growth factor receptor 2 blockade: another step forward in treating patients with human epidermal growth factor receptor 2-positive breast cancer. AB - PURPOSE OF REVIEW: Many antihuman epidermal growth factor receptor (anti-HER2) targeted agents, covering a broad spectrum of mechanisms of action, have been recently developed. The concept of dual anti-HER2 blockade has been preclinically and clinically assessed with positive results. In this article, the authors review the biologic rationale for dual HER2 blockade, along with the clinical findings. RECENT FINDINGS: Dual anti-HER2 blockade has been assessed in the metastatic setting, including with chemotherapy-free regimens, leading to impressive responses, even in heavily pretreated patients. In the neoadjuvant setting, dual anti-HER2 blockade combinations and chemotherapy have almost doubled the rates of pathologic complete response compared to single anti-HER2 therapy. Similar strategies are now actively being pursued in the adjuvant setting and, it is hoped, will improve the outcome of many patients with HER2 positive breast cancer. SUMMARY: Combining different anti-HER2-targeted agents represents a promising therapeutic strategy, now reaching clinical practice. There are major clinical challenges yet to be resolved, rising from the increasing number of potential combinations and their mechanisms of resistance. Smartly designed clinical trials are required to address these challenges and perhaps to define a subset of patients that can be spared chemotherapy. PMID- 23014187 TI - Current treatment of acute myeloid leukemia. AB - PURPOSE OF REVIEW: The objectives of this review are to discuss standard and investigational nontransplant treatment strategies for acute myeloid leukemia (AML), excluding acute promyelocytic leukemia. RECENT FINDINGS: Most adults with AML die from their disease. The standard treatment paradigm for AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or allogeneic stem cell transplantation, depending on the patient's ability to tolerate intensive treatment and the likelihood of cure with chemotherapy alone. Although this approach has changed little in the last three decades, increased understanding of the pathogenesis of AML and improvements in molecular genomic technologies are leading to novel drug targets and the development of personalized, risk-adapted treatment strategies. Recent findings related to prognostically relevant and potentially 'druggable' molecular targets are reviewed. SUMMARY: At the present time, AML remains a devastating and mostly incurable disease, but the combination of optimized chemotherapeutics and molecularly targeted agents holds significant promise for the future. PMID- 23014188 TI - Venous thromboembolism in the hematologic malignancies. AB - PURPOSE OF REVIEW: This review summarizes the current knowledge of the epidemiology, prophylaxis, and treatment of venous thromboembolism (VTE) in patients with lymphoma, multiple myeloma or acute leukemia. RECENT FINDINGS: Hematologic malignancies are associated with a high risk of thrombotic complications. The incidence of these events is greatly variable and is influenced by many factors, including the type and the stage of disease, antitumor therapies, and the use of central venous device (CVD). Epidemiological data allow an estimate of the incidence of VTE in acute leukemia, lymphomas, and multiple myeloma. The effect of chemotherapy on the incidence of thrombosis is particularly evident in acute leukemia as it causes the exacerbation of the clotting/bleeding syndrome typical of this disease. The role of chemotherapy is also relevant in lymphoma, and in multiple myeloma, in which the use of immunomodulating agents, in combination with chemotherapy and steroids significantly increases the risk of VTE. SUMMARY: Thrombotic complications have a significant impact on morbidity and mortality of hematological cancer patients, therefore, in this setting, the issue of thromboprophylaxis to prevent VTE is important. However, no clear recommendation in these conditions is available, with the exception of multiple myeloma. Large prospective randomized clinical trials are needed to establish the best practice for prevention and treatment of VTE in these types of malignant diseases. PMID- 23014189 TI - Next-generation sequencing in breast cancer: first take home messages. AB - PURPOSE OF REVIEW: We are currently on the threshold of a revolution in breast cancer research, thanks to the emergence of novel technologies based on next generation sequencing (NGS). In this review, we will describe the different sequencing technologies and platforms, and summarize the main findings from the latest sequencing articles in breast cancer. RECENT FINDINGS: Firstly, the sequencing of a few hundreds of breast tumors has revealed new cancer genes. Although these were not frequently mutated, mutated genes from different patients could be grouped into the deregulation of similar pathways. Secondly, NGS allowed further exploration of intratumor heterogeneity and revealed that although subclonal mutations were present in all tumors, there was always a dominant clone, which comprised at least 50% of the tumor cells. Finally, tumor-specific DNA rearrangements could be detected in the patient's plasma, suggesting that NGS could be used to personalize the monitoring of the disease. SUMMARY: The application of NGS to breast cancer has been associated with tremendous advances and promises for increasing the understanding of the disease. However, there still remain many unanswered questions, such as the role of structural changes of tumor genomes in cancer progression and treatment response/resistance. PMID- 23014190 TI - Analysis of protein expression in developmental toxicity induced by MeHg in zebrafish. AB - Mercury toxicity and its implications in development are a major concern, due to the major threat to ecosystems and human health that this compound represents. Although some of the effects of methylmercury (MeHg) exposure have been extensively studied, the molecular mechanisms of interaction between this compound and developing organisms are still not completely understood. To provide further insights into these mechanisms, we carried out a quantitative proteomic study (iTRAQ) using zebrafish larvae exposed to 5 MUg L(-1) and 25 MUg L(-1) MeHg as a model. In this study, a multidimensional approach combining isoelectric focusing (IEF) and strong cation exchange (SCX) followed by reversed phase liquid chromatography prior to MALDI TOF/TOF analysis was employed, which resulted in a substantial increase in proteome coverage. Among the proteins identified, 71 were found de-regulated by more than 1.5-fold, and implicated in embryonic development, protein synthesis, calcium homeostasis and energy production. Furthermore, morphological and histological analysis of exposed larvae was carried out, reflecting changes such as smaller swim bladder, remaining yolk, bent body axis and accumulation of blood in the heart, among others. PMID- 23014191 TI - Intraoperative 3-D mapping of parathyroid adenoma using freehand SPECT. AB - BACKGROUND: Freehand single photon emission computed tomography (fSPECT) is a three-dimensional (3-D) tomographic imaging modality based on data acquisition with a handheld detector that is moved freely, in contrast to conventional, gantry-mounted gamma camera systems. In this pilot study, we evaluated the feasibility of fSPECT for intraoperative 3-D mapping in patients with parathyroid adenomas. METHODS: Three patients (range 30 to 45 years) diagnosed with hyperparathyroidism (one primary and two tertiary) underwent parathyroid scintigraphy with technetium-99m sestamibi (99mTc-MIBI) to localize parathyroid adenomas. Two patients were referred with persistent hyperparathyroidism after conventional parathyroidectomy. In all three patients, a planar scintigraphy of the neck was performed 10 min after injection (p.i.) followed by SPECT/CT (Symbia T2, Siemens Healthcare) and a correlative ultrasound 2 h p.i. 99mTc-MIBI scan was performed the day before surgery in two patients and at the same day in one patient. fSPECT images were acquired intraoperatively using declipse SPECT (SurgicEyeTM). RESULTS: A total of five parathyroid adenomas were successfully located with SPECT/CT. fSPECT allowed intraoperative detection of all adenomas, and successful parathyroidectomy was accomplished. Parathyroid hormone level decreased intraoperatively in all three patients, on average, by 79% (range 72% to 91%). CONCLUSION: In this preliminary study, we could demonstrate that intraoperative localization of parathyroid adenomas is feasible using the freehand SPECT technology, thus allowing an image-guided parathyroidectomy. PMID- 23014243 TI - The delocalized nature of holes in (Ga, N) cluster-doped ZnO. AB - A spin-polarized density-functional theory study is presented here, revealing that a single hole state created by (Ga, N) cluster doping in ZnO contains the contributions from all of the N atoms in the cluster. This is in contrast to the situation where N atoms alone are doped into ZnO, and have a highly localized hole state centered around the dopant N atoms. Hence, this study shows that an enhanced delocalized hole state can be obtained if an appropriate electronic environment is provided. PMID- 23014244 TI - 18F-Fluorodeoxyglucose: the Trojan horse of PET/CT. PMID- 23014245 TI - An unusual presentation of May-Thurner syndrome in a pediatric patient with a pelvic kidney. AB - We report a case of an adolescent who presented with a deep vein thrombosis (DVT) and clinical findings consistent with May-Thurner Syndrome. Specific imaging demonstrated direct compression of the left common iliac vein by an overlying pelvic kidney. The patient's history and clinical presentation is detailed. The discussion focuses on the potential implications for care and management of a patient with an ectopic left pelvic kidney. PMID- 23014246 TI - Translation.........please!! PMID- 23014247 TI - The reliability of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP/ATP III) and the International Diabetes Federation (IDF) definitions in diagnosing metabolic syndrome (MetS) among Gaza Strip Palestinians. AB - OBJECTIVES: Metabolic syndrome (MetS) which is a multifaceted syndrome, has been demonstrated as a common precursor for developing cardiovascular diseases and/or type 2 diabetes mellitus. Different diagnostic definitions for MetS have been proposed and recommended. We set up to evaluate the reliabilities of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP/ATP III) and the International Diabetes Federation (IDF) definitions in diagnosing MetS among Gaza Strip Palestinians. MATERIALS AND METHODS: This cross sectional study involved a randomly selected two hundred and thirty apparently healthy adults from the Gaza Strip. Anthropometric measurements, blood pressure, fasting plasma glucose, lipid profile, and questionnaire interviews were performed. RESULTS: The overall prevalence of MetS in our Gaza Strip cohort was 23.0% and 39.5% according to NCEP/ATP III and IDF definitions respectively (p<0.001). No significant differences were seen in the number of MetS components in individuals having MetS by either definition (mean 3.42 +/- 0.63 vs 3.52 +/- 0.69 respectively, p=0.865). Both IDF and NCEP/ATP III showed an increased prevalence of MetS with age, and body mass index (BMI), however they revealed different prevalence trends with sex. Except for BMI, there were no significant differences in the general and metabolic related characteristics between subjects with MetS of IDF and NCEP/ATP III definitions. CONCLUSIONS: Independently of the definition used, MetS is highly prevalent in Gaza Strip population, with a steady increase in MetS prevalence through age and BMI. The IDF definition tends to give higher values for MetS prevalence, and therefore could be more appropriate for diagnosing MetS in Gaza Strip cohort. PMID- 23014248 TI - Serum high sensitivity C-reactive protein, nitric oxide metabolites, plasma fibrinogen, and lipid parameters in Indian type 2 diabetic males. AB - AIMS: Inflammation is postulated to play a role in diabetogenesis and its further vascular complications. The aim was to assess the inflammatory and lipid parameters in patients of type 2 diabetic mellitus with or without complication. MATERIAL AND METHODS: Serum high sensitivity C-reactive protein (hs-CRP), nitric oxide metabolite (NO(X)), fibrinogen, and lipid parameters were measured in eighty type 2 diabetic males (40-65 years) without (n=40, group B) and with complication (16 retinopathy, group C; 24 hypertension, group D); and compared with 40 healthy, age and sex matched nondiabetic males (group A) from the general population. RESULT: The mean age of subjects and fasting plasma glucose among groups A, B, and C+D were 51.0 +/- 7.1 vs. 48.7 +/- 5.7 vs. 50.2 +/- 6.1 years (p>0.05); and 96.7 +/- 10.4 vs. 134.3 +/- 27.8 vs. 136.4 +/- 29.8 mg/dl (p<0.001) respectively. Patients with retinopathy were older, with longer duration of diabetes, and high fasting plasma glucose (p<0.001). The mean hs-CRP, NO(X), fibrinogen, TC, TG, and LDL(C) varied significantly (p<0.001) between control and diabetics. hs-CRP, NO(X), and fibrinogen were found to be highest in retinopathy group whereas no significant (p>0.05) difference was noted between groups B and D in relation to hs-CRP and NO(X). TC and LDL(C) were significantly (p<0.001) high among group B patients. Significant positive correlation was observed between all three inflammatory markers in all categories of patients; between FPG, hs-CRP, and fibrinogen among patients with hypertension; between FPG, hs-CRP, and NO(X) in patients with retinopathy. However, none of the lipid parameters showed any significant correlation with any of the inflammatory markers in any group of patients studied. CONCLUSION: Low grade systemic inflammation, in association with dyslipidemia, plays a role in diabetogenesis and its complications. PMID- 23014249 TI - References of anthropometric indices of central obesity and metabolic syndrome in Jordanian men and women. AB - AIMS: To set references and evaluate the associations between the predictive powers of the anthropometric indices of obesity, particularly central obesity, including body mass index (BMI), waist circumference (WC), waist to hip ratio (WHpR) and waist to height ratio (WHtR), and the risk factor accumulations of >= 2 of the components of the metabolic syndrome (MS) in a group of Jordanian men and women. METHODS: Five hundreds subjects were randomly selected from among the visitors attending several family clinics in Amman. Obesity was assessed using BMI, WC, WHpR and WHtR anthropometric indices. MS risk factors as defined by the International Diabetes Federation were determined. Receiver operating characteristic curve (ROC) analysis was used to determine the predictive powers and the cut off points of each index associated with increased MS risk. RESULTS: There were 212 men and 288 women with age ranged 20-85 years. Optimal cut off points of BMI, WC, WHpR for MS diagnosis in men were 28.4 kg/m(2), 97.8 cm and 0.89, respectively. In women, these were 30.3 kg/m(2), 95.6 cm and 0.84, respectively. WHtR was 0.61 in both genders. Area under the curve (AUC) of ROC analysis for identifying of MS (>= 2 risk factors) was the highest for WHpR (AUC=0.71), followed by WHtR (AUC=0.67), WC (AUC=0.64) and BMI (AUC=0.59) in men; whereas in women WHpR, WHtR and WC were almost equal (AUC=0.76, 0.75 and 0.74, respectively), followed by BMI (AUC=0.67). Correlation coefficients (r) between WHpR and MS risk factors were the strongest among the other obesity indices, followed by WC and WHtR. WHpR correlated significantly with FBG (r=0.27, p<0.01), systolic blood pressure (r=0.20, p<0.01), TGs (r=0.24, p<0.01) and HDL-C (r= 0.39, p<0.01). The respective r-values between WC and WHtR and each MS risk factors were: FBG (r=0.15, p<0.001 or r=0.13, p<0.01), systolic blood pressure (r=0.16, p<0.01 or r=0.11, p<0.05), TGs (r=0.20, p<0.01 or r=0.14, p<0.01) and HDL-C (r=-0.25, p<0.01 or r=-0.11, p<0.01). CONCLUSION: This study showed that BMI tended to be the weakest index for identifying MS risk factors in both sexes. WHpR exhibited the best predictive index for MS, particularly in men. Almost similar predictive powers of WHtR, WHpR and WC for identifying MS risk factors were seen in women. WHtR had the highest sensitivity for MS diagnosis among obesity indices in men and its boundary value was the same for both men and women. These cut off values of obesity particularly waist circumference should be advocated and used in Arab Jordanians until larger cross sectional studies shows different results. PMID- 23014250 TI - Hematological parameters and metabolic syndrome: findings from an occupational cohort in Ethiopia. AB - AIMS: To examine associations between hematological parameters (i.e., hemoglobin, hematocrit, platelet counts, red blood cell (RBC), and white blood cell (WBC) counts) and components of metabolic syndrome (MetS) among working adults in Addis Ababa, Ethiopia. MATERIALS AND METHODS: Participants were 1868 (1131 men and 737 women) working Ethiopian adults. MetS was classified according to the International Diabetes Federation criterion. Odds ratios (ORs) and 95% confidence intervals (95% CIs) of MetS were calculated using logistic regression procedures. RESULTS: Hematologic parameters (hemoglobin, hematocrit, and RBC) were positively associated with MetS components (P(trend)<0.05). In both men and women, white blood cell (WBC) counts were positively associated with BMI and waist circumference (P<0.05). RBC counts were associated with diastolic blood pressure in men (P<0.05) and women (P<0.001). Men in the third quartile of hemoglobin concentrations had 2-fold increased odds (OR=1.99; 95% CI) of MetS compared with the lowest reference quartile (P(trend)=0.031) while women in the fourth hemoglobin quartile had 2.37-fold increased odds of having MetS compared with the reference group (P(trend)=0.003). Both men and women in the fourth quartiles of RBC counts had 2.26-fold and 3.44-fold increased odds of MetS (P=0.002 in men, P<0.001 in women). Among women, those in the fourth quartiles of hematocrit and platelet counts had 2.53-fold and 2.01-fold increased odds of MetS as compared with those in the reference group (P(trend)=0.004 and 0.065 respectively). CONCLUSION: Our study findings provide evidence in support of using hematological markers for early detection of individuals at risk for cardiovascular disease. PMID- 23014251 TI - Is vitamin D status a predictor glycaemic regulation and cardiac complication in type 2 diabetes mellitus patients? AB - OBJECTIVE: To evaluate vitamin D as a predictor of glycaemic regulation in type 2 diabetes mellitus patients. RESEARCH DESIGN AND METHODS: In observational study 171 type 2 diabetic patients who are followed for median (range) of 10.15 (3-18) years. Mean +/- SD age was 56 +/- 10. Plasma 25-hydroxyvitamin D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry on baseline samples. Vitamin D deficiency was defined as a 25-OHD level of less than 20 ng/ml. Vitamin D levels between 20 and 30 ng/ml are termed 'insufficient'. Vitamin D levels greater than 30 ng/ml are termed 'optimal'. RESULTS: 125 patients have vitamin D deficiency, 14 patients have insufficient and the others have optimal. Vitamin D levels were not associated with sex, age, BMI, HDL, LDL, kreatinin, hypertension and smoking. But vitamin D deficiency patients had more longer duration (p=0.011), more higher uric acid (p=0.021), fasting glucose (p=0.037), postprandial glucose (p=0.001) and HbA1c (p=0.026). CONCLUSIONS: In our study type 2 diabetic patients have 73% of vitamin D deficiency. Vitamin D deficiency predicts higher fasting and postprandial blood glucose and diabetes disregulation. Type 2 DM patients and low 25-OH vitamin D levels could increased cardiovascular disease directly or indirectly (low HDL and high uric acid in 25 OH vitamin D <20 ng/ml). Whether vitamin D substitution improves prognosis remains to be investigated. PMID- 23014252 TI - Blood urea level and diabetes duration are independently associated with ankle brachial index in type 2 diabetic patients. AB - AIM: The purpose of the study was to determine factors of ankle-brachial index (ABI) in a population of patients with type 2 diabetes and coronary artery disease. MATERIAL AND METHODS: 370 patients (mean age 60.3 +/- 8.3 years and diabetes duration 8.6 +/- 6.2 years) with type 2 diabetes and coronary artery disease were enrolled in a cross sectional study during 2006-2007. Multivariable linear regression analysis was conducted to determine the factors of ABI, considering systolic and diastolic blood pressure, weight, body mass index, waist circumference, glycemia, urea, creatinin, triglycerides, total cholesterol, LDL- and HDL-cholesterol. RESULTS: Peripheral arterial disease was detected in 82.35% (280 pts). Mean ABI value of 0.97 +/- 0.33, and its minimal value of 0.95 +/- 0.38 was detected in this study population. Regression analysis demonstrated that mean and minimal values of ABI were independently associated with diabetes duration (beta 0.120, 95% CI -0.014, -0.001) and blood urea level (beta -0.126, 95% CI -0.020, -0.002). CONCLUSION: Results might have clinical implications for patients with type 2 diabetes and coronary artery disease in defining those with a long diabetes duration and a higher blood urea level to have greater probability of detecting pathological ankle-brachial index. PMID- 23014253 TI - Prevalence of hypertension and diabetes among Ethiopian adults. AB - OBJECTIVE: To determine the prevalence of hypertension and diabetes among members of an Ethiopian occupational cohort; and to examine the proportion of adults who were aware of their conditions. METHODS: A total of 2153 of subjects were included in this cross-sectional study. The World Health Organization STEPwise approach for non-communicable diseases was used to collect socio-demographic data, blood pressure measures and blood samples from participants. Prevalence estimates for hypertension and diabetes were determined separately. The 95% confidence intervals for prevalence estimates were also determined. RESULTS: The overall prevalence of hypertension was 19.1% (95%CI: 17.1-20.8) and 22% (95%CI: 20.2-23.8) and 14.9% (95%CI: 13.4-16.4) among men and women respectively. The overall prevalence of diabetes was 6.5% (95%CI: 5.4-7.6) and 6.4% (95%CI: 5.0 7.8) and 6.6% (95%CI: 4.8-8.4) among men and women correspondingly. Notably, 15% of hypertensives reported never having had their blood pressure checked prior to the present study examination. Approximately 45% of participants who had their blood pressure checked were never diagnosed with hypertension, but were found to be hypertensive in our study. Approximately 27% of newly diagnosed diabetics (during this study) reported never having a previous blood glucose test. Among those who had their blood glucose assessed prior to this study, 17.4% were found to have diabetes but were never diagnosed. CONCLUSION: The high prevalence of hypertension and diabetes reported in our study confirms findings from other Sub Saharan Africa countries, and extends the literature to urban dwelling Ethiopians where non-communicable diseases are emerging as a major public health concern. PMID- 23014254 TI - Descriptive analysis of resistance exercise and metabolic syndrome. AB - BACKGROUND: Resistance exercise (RE) is an important mode of physical activity in the management of metabolic syndrome (MetS). However, little is known about the patterns of RE participation among U.S. adults with and without MetS. METHODS: Utilizing data from 1999-2006 National Health and Nutrition Examination Survey, we examined the association(s) between MetS and RE in a representative sample (n=7432) of the U.S. adult population. RESULTS: U.S. adults with MetS were found to be approximately 50% less likely to report engaging in RE compared to U.S. adults without MetS. Across all demographic categories those who did not meet the criteria for MetS reported engaging in significantly greater levels of RE compared to their counterparts with MetS. Furthermore, a potential inverse dose response relationship was seen for engaging in RE and the prevalence of MetS. CONCLUSIONS: In a diverse representative sample, significantly fewer U.S. adults with MetS report engaging in RE compared to adults without MetS. Engaging in two or more days per week of RE may attenuate MetS prevalence and risk estimates in U.S. adults. PMID- 23014256 TI - Genetics of type 2 diabetes mellitus and other specific types of diabetes; its role in treatment modalities. AB - Type 2 diabetes mellitus (T2DM) is among the most challenging health issues of the 21st century and is associated with an alarming rise in the incidence. The pathophysiological processes that lead to development of T2DM are still unclear, however impairment in insulin secretion and/or action is clearly indicated. Type 2 diabetes is a polygenic disorder with multiple genes located on different chromosomes contributing to its susceptibility. Analysis of the genetic factors is further complicated by the fact that numerous environmental factors interact with genes to produce the disorder. Only a minority of cases of type 2 diabetes are caused by single gene defects and one example is maturity onset diabetes of the young (MODY). Previous studies indicated that variants in genes encoding the pancreatic beta-cell K+ATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) are associated with neonatal diabetes. Six different types of maturity onset diabetes of young (MODY) have been identified based on characteristic gene defect. The common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma (PPAR-gamma) gene was confirmed in several studies to be associated with type 2 diabetes as well. More recently, studies reported variants within a novel gene, TCF7L2, as a putative susceptibility gene for type 2 diabetes across many ethnic backgrounds around the world. MODY patients respond better to sulphonylureas and metformin, while neonatal diabetes patients with genetic mutations can be changed from insulin to oral drugs. We hereby provide a comprehensive review on the role of genetics in type 2 diabetes mellitus. PMID- 23014255 TI - Relationship of transcription factor 7 like 2 gene rs7903146 variation with type 2 diabetes and obesity related parameters. AB - AIMS: The allele frequencies of transcription factor 7 like 2 (TCF7L2) gene rs7903146 polymorphism in type 2 diabetes mellitus (T2DM) and non-T2DM controls were determined. METHODS: TCF7L2 rs7903146 genotypes were determined with qPCR. RESULTS: The TCF7L2 gene rs7903146 genotype frequencies for homozygous wild type (C/C), heterozygous (C/T) and homozygous polymorphic (T/T) for T2DM patients were determined, respectively, as 71.4%, 14.3%, 14.3% and 72.5%, 11.8%, 15.7% for controls. The weight, length and lean body mass were higher in C/T+T/T compared to C/C carriers. Glucose, insulin, insulin resistance and homeostatic model assessment (HOMA) were nonsignificantly higher in rs7903146C/T+T/T in comparison to C/C. TCF7L2 gene rs7903146 genotypes were not found to interact with drugs. The absence of any difference between genotype frequencies among study groups indicates that no association persists with TCF7L2 gene rs7903146 polymorphism and T2DM. CONCLUSIONS: The effects of rs7903146 variation over some obesity variables suggest that this variation may effect T2DM development via obesity. PMID- 23014257 TI - HbA1c in pregnancy. AB - During pregnancy, the glucose levels vary according to the hormonal changes and the metabolic needs necessary to maintain fetal nutrition but strict glycemic control is essential to minimize the maternal and fetal morbidity and mortality of pregnancies complicated by diabetes. Although considered the "gold standard" for diagnosis, measurement of glucose in the blood is subject to several limitations, many of which are not widely appreciated. Measurement of A1c for diagnosis is appealing as with one number, a total, integrated view of glycemia over time is derived though it has some inherent limitations. Thus, supplementation with HbA1c, as is common outside pregnancy, seems appropriate. Before pregnancy, the target for metabolic control in women with diabetes is HbA1c values near the normal range. However, the upper normal range of HbA1c during normal pregnancy is only sparsely investigated with different methods though recently a number of papers have been published regarding the determination of reference ranges for HbA1c in pregnancy. These changes may have clinical implications for the assessment and management of glycemic control in diabetic pregnancy and calls for establishment of separate reference limits of HbA1c levels in different trimesters as compared to general population. PMID- 23014259 TI - Updated meta-analysis of non-melanoma skin cancer rates reported from prospective observational studies in patients treated with tumour necrosis factor inhibitors. PMID- 23014260 TI - Reply to: subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRE Study. PMID- 23014258 TI - Development and qualitative evaluation of an adapted return to work guideline for the sick-listed unemployed and temporary agency workers with minor psychological problems. AB - BACKGROUND: Among the working population, unemployed and temporary agency workers with psychological problems are a particularly vulnerable group, at risk for sickness absence and prolonged work disability. There is a need for the development of a new protocol for this group, because the existing return to work (RTW) interventions, including practice guidelines, do not address the situation when there is no workplace to return to. The purpose of this study was to (1) describe the adaptations needed in the practice guideline for employed workers to enable its use by insurance physicians (IPs) for counselling of sick-listed unemployed and temporary agency workers with minor psychological problems; and (2) evaluate the experiences of IPs when using the new guidance document for minor psychological problems (MPP guidance document). METHODS: The MPP guidance document for unemployed and temporary agency workers was developed through discussions with nine IPs and with the help of an expert. Semi-structured interviews with five IPs were then held to evaluate the IPs' field experience using the MPP guidance document, in terms of (a) feasibility and (b) perceived usefulness of the MPP guidance document. RESULTS: The main adaptation introduced in the guideline is that interaction with the workplace, which is absent in this population, needed to be established in an alternative way, i.e., through the involvement of vocational rehabilitation agencies and labour experts. Overall, the guideline required minimal changes. In total, nineteen sick-listed workers were counselled using the MPP guidance document. The overall experience of the IPs was that the MPP guidance document was feasible and useful for the IP, while they had mixed responses on its usefulness for the sick-listed worker, in part due to the follow-up period of this study. CONCLUSIONS: An existing practice guideline for employed workers was adapted for use as a guidance document for unemployed and temporary agency workers with minor psychological problems. IPs were positive about applying the MPP guidance document. The guidance document provides opportunities for RTW counselling for unemployed and temporary agency workers with minor psychological problems. PMID- 23014261 TI - Planning in Dutch health promotion practice: a comprehensive view. AB - Health promotion has a strong tradition of using planning models based on an a priori set of goals and processes defined by professionals. Those rational models only partly fit with today's view and practice of health promotion, where programmes can be considered as processes because they are guided by principles such as community participation and intersectoral collaboration. The aim of this paper is to provide a comprehensive view on approaches to planning in health promotion practice. To investigate these, Whittington's typology has been used. Whittington identifies four approaches to planning, i.e. classical, evolutionary, processual and systemic. In a retrospective multiple case study, we describe actual planning processes used in the development and implementation of a healthy ageing programme in three Dutch municipalities. These processes were described using data gathered by: interviews, participant observation and document analysis, and external auditing. Characteristics of the four planning approaches were used to interpret the data. The results show that, in practice, all forms of planning approaches were used, depending on the degree of complexity and dynamics of the context, the phase of the health promotion programme, and the time available. Our findings suggest that in the emergent practice of health promotion different approaches to planning are used. To make those planning approaches explicit and manageable for practice and science, discussion and reflection between stakeholders are essential. PMID- 23014263 TI - Cooperativity between hydrogen bonds and beryllium bonds in (H2O)(n)BeX2 (n = 1 3, X = H, F) complexes. A new perspective. AB - The interaction of BeX(2) (X = H, F) with water molecules has been analyzed at the B3LYP/6-311+G(3df,2p)//B3LYP/6-311+G(d,p) level of theory. The formation of strong beryllium bonds between water molecules and the BeX(2) derivative triggers significant electron density redistribution within the whole system, resulting in significant changes in the proton donor and proton acceptor capacity of the water molecules involved. Hence, significant cooperative and anti-cooperative effects are present, explaining why there is no case in which the global minimum corresponds to a tetracoordinated beryllium atom. In fact, the most stable clusters can be viewed as the result of the attachment of BeX(2) to the water trimer and the water dimer, respectively, and not as the result of the solvation of the BeX(2) molecule. We have also shown that the decomposition of the interaction energy into atomic components is a reliable quantitative tool to describe all the closed-shell interactions present in the clusters investigated herein, namely hydrogen bonds, beryllium bonds and dihydrogen bonds. Indeed, we have shown that the changes in the atomic energy components are correlated with the changes in the strength of these interactions, and they provide a quantitative measure of cooperative effects directly in terms of energies. PMID- 23014264 TI - Management of optic neuritis as a clinically first event of multiple sclerosis. AB - PURPOSE OF REVIEW: This article aims to provide a review of demyelinating optic neuritis as a presenting symptom of multiple sclerosis, clinical features, management options, and recent literature. RECENT FINDINGS: To date, several questions remain to be unsolved relating to the presentation, treatment, and implications of optic neuritis. Although some authors recommend high-dose corticosteroids for the treatment of acute demyelinating optic neuritis, there is still no consensus relating to corticosteroids treatment including the dosage and length of treatment. Studies have shown that the risk of developing clinically definite multiple sclerosis (MS) after presenting with a clinically isolated syndrome including optic neuritis is increased in patients with an abnormal brain MRI. Better diagnostic tools are needed to precisely predict the conversion to MS and the factors influencing disease severity to determine the most appropriate therapeutic paradigm and avoid unnecessary treatment. SUMMARY: Management of optic neuritis presenting as a demyelinating first event still remains inconclusive relating to the acute management and long-term treatment. But recent literature suggests high-dose corticosteroids for acute treatment and disease modifying treatments may be a valuable option for long-term treatment. However, decision is very individualized and is based on the clinical and imaging findings of the patient. PMID- 23014265 TI - Neuro-ophthalmology of movement disorders. AB - PURPOSE OF REVIEW: Movement disorders commonly present with ocular features. The purpose of this review is to outline neuro-ophthalmologic findings that can help in diagnosis, treatment and determining prognosis in patients with movement disorders. RECENT FINDINGS: Common movement disorders with ophthalmic symptoms include extrapyramidal disorders such as Parkinson disease-associated dry eye, decreased blink rate, and vergence dysfunction, and progressive supranuclear palsy-related lid retraction, frequent square-wave jerks and supranuclear gaze palsy. Multisystem atrophy can present with gaze-evoked horizontal or positional downbeat nystagmus and impaired vestibulo-ocular reflex suppression. Genetic disorders such as Huntington disease produce increased saccadic latencies and impaired suppression of saccades to presented stimulus, whereas Wilson disease is associated with saccadic pursuits, increased antisaccade latencies and decreased pursuit gain. Whipple's disease can present with supranuclear gaze palsy and characteristic oculomasticatory myorrhythmia. SUMMARY: Movement disorders commonly present with ocular features. Knowledge of these ocular symptoms can assist the ophthalmologist in diagnosis and treatment of movement disorders. PMID- 23014266 TI - Medical treatment of acquired nystagmus. AB - PURPOSE OF REVIEW: This article synthesises recent findings and addresses relevant anatomy, pathophysiologic considerations, and current treatment options for common forms of acquired nystagmus including vestibular and gaze holding dysfunction. RECENT FINDINGS: Some forms of nystagmus have relatively specific treatments, such as baclofen for periodic alternating nystagmus, and repositioning for benign paroxysmal positional vertigo. Recent studies have brought changes to many of the treatments of nystagmus variants. Additionally, other recent advances in nystagmus treatment, like the usage of 4-aminopyridine, have added potent medications to the physician's armamentarium. SUMMARY: Nystagmus is a commonly encountered entity in clinical practice. However, evidence supported treatments are scarce. Medical treatment of nystagmus is difficult, with often limited and variable response to pharmacologic therapies. This mandates a continued re-evaluation of patients and creation of an individualized approach to this common clinical problem. PMID- 23014267 TI - Different ophthalmologic manifestations of sarcoidosis. AB - PURPOSE OF REVIEW: Sarcoidosis can manifest with different ocular findings. Three different cases have been presented, each of which showed different ocular problems. The literature has also been reviewed as to find out other eye signs and treatment strategies of the disease. The diagnosis may be difficult and the treatment may include combination of different immunosuppressors. RECENT FINDINGS: Recent findings include a genetic basis, and certain human leukocyte antigens may affect the course of the disease. Sarcoidosis can influence the eye and the optic nerves in the beginning, and biopsy of the involved tissue may be necessary for the diagnosis. Laboratory investigation may be unyielding. Once the diagnosis is made, steroids are generally started. Other than the classical corticosteroid treatment, other immunosuppressive agents show promise in the atypical cases. SUMMARY: Our cases show different manifestations of the disease like bilateral optic neuropathy, Horner's syndrome, pars planitis, and anterior and posterior uveitis. Patients recovered with steroid treatment, but especially in young patients other agents like methotrexate were needed because of the sideeffects of steroids. PMID- 23014271 TI - C9orf72 immunohistochemistry in Alzheimer's disease. AB - Mutation in chromosome 9 open reading frame 72 (C9orf72) is a major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), referred to as C9FTD/ALS. The function of the protein is currently unknown, and the pathomechanism of C9FTD/ALS remains to be elucidated. The study by Satoh and colleagues in the previous issue of Alzheimer's Research & Therapy presents important new findings on C9orf72 protein expression in neurodegenerative disorders along with characterization of C9orf72 antibodies. PMID- 23014272 TI - The Jeff = 1/2 insulator Sr3Ir2O7 studied by means of angle-resolved photoemission spectroscopy. AB - The low-energy electronic structure of the J(eff) = 1/2 spin-orbit insulator Sr3Ir2O7 has been studied by means of angle-resolved photoemission spectroscopy. A comparison of the results for bilayer Sr3Ir2O7 with available literature data for the related single-layer compound Sr2IrO4 reveals qualitative similarities and similar J(eff) = 1/2 bandwidths for the two materials, but also pronounced differences in the distribution of the spectral weight. In particular, photoemission from J(eff) = 1/2 the states appears to be suppressed. Yet, it is found that the Sr3Ir2O7 data are in overall better agreement with band-structure calculations than the data for Sr2IrO4. PMID- 23014273 TI - National Ski Patrol leads in outdoor rescue. PMID- 23014278 TI - Then and now: updating clinical nurse advancement programs. PMID- 23014279 TI - Striving for...imperfection? PMID- 23014282 TI - Patient education series. Nosebleeds. PMID- 23014284 TI - Caring for body and soul during addiction and recovery. PMID- 23014285 TI - A nurse's guide to electroconvulsive therapy. PMID- 23014286 TI - Learning the language of finance. PMID- 23014287 TI - Assess patients for depression for a safer discharge. PMID- 23014288 TI - Animal-assisted therapy: using animals to promote healing. PMID- 23014289 TI - Palliative care: are you asking the right questions? PMID- 23014290 TI - Contraindications to nasopharyngeal airway insertion. PMID- 23014291 TI - Managing acute hyperkalemia. PMID- 23014293 TI - Malignant hyperthermia. PMID- 23014294 TI - One-step immobilization of Ru(bpy)3(2+) in a silica matrix for the construction of a solid-state electrochemiluminescent sensor with high performance. AB - An electrochemically induced sol-gel process has been used to efficiently immobilize Ru(bpy)(3)(2+) in a 3D porous silica film matrix deposited on a glassy carbon electrode (GCE), forming a solid state electro-chemiluminescence (ECL) sensor. In this approach, electrolysis of the GCE at cathodic voltages from a solution of ammonium fluorosilicate containing Ru(bpy)(3)(2+) results in the reduction of water to hydroxyl ions and hydrogen bubbles. The former product catalyzes the hydrolysis of ammonium fluorosilicate to form a silica film; while the hydrogen bubbles act as a dynamic template in forming a porous silica matrix. Therefore, a large quantity of Ru(bpy)(3)(2+) ions can be efficiently encapsulated in the porous silica matrix, and the formed porous structure offers a good mass transport path. The fabricated [Ru(bpy)(3)](2+) solid-state ECL sensor shows high sensitivity and stability towards the determination of tripropylamine (TPA). The electrochemically generated luminescence signal shows a good linear relationship to TPA concentration ranging from 3.46 * 10(-10) to 3.70 * 10(-6) M and 3.70 * 10(-6) to 3.60 * 10(-4) M, with an extremely low detection limit of 17 pM (S/N = 3). The present approach is effective for encapsulation of various molecules and could find wide application in the construction of various sensors. PMID- 23014334 TI - Endogenous retinoids in the pathogenesis of alopecia areata. AB - Alopecia areata (AA) is an autoimmune disease that attacks anagen hair follicles. Gene array in graft-induced C3H/HeJ mice revealed that genes involved in retinoic acid (RA) synthesis were increased, whereas RA degradation genes were decreased in AA compared with sham controls. This was confirmed by immunohistochemistry in biopsies from patients with AA and both mouse and rat AA models. RA levels were also increased in C3H/HeJ mice with AA. C3H/HeJ mice were fed a purified diet containing one of the four levels of dietary vitamin A or an unpurified diet 2 weeks before grafting and disease progression followed. High vitamin A accelerated AA, whereas mice that were not fed vitamin A had more severe disease by the end of the study. More hair follicles were in anagen in mice fed high vitamin A. Both the number and localization of granzyme B-positive cells were altered by vitamin A. IFNgamma was also the lowest and IL13 highest in mice fed high vitamin A. Other cytokines were reduced and chemokines increased as the disease progressed, but no additional effects of vitamin A were seen. Combined, these results suggest that vitamin A regulates both the hair cycle and immune response to alter the progression of AA. PMID- 23014336 TI - High anti-staphylococcal antibody titers in patients with epidermolysis bullosa relate to long-term colonization with alternating types of Staphylococcus aureus. PMID- 23014335 TI - Local delivery of gene-modifying triplex-forming molecules to the epidermis. AB - Epidermal keratinocytes are particularly suitable candidates for in situ gene correction. Intraperitoneal administration of a triplex-forming oligonucleotide (TFO) was previously shown to introduce DNA base changes in a reporter gene in skin, without identifying which cells had been targeted. We extend those previous experiments using two triplex-forming molecules, a peptide nucleic acid antennapedia (PNA-Antp), and a TFO (AG30), as well as two lines of transgenic mice that have the chromosomally integrated lambdasupFG1 shuttle-reporter transgene. Successful in vivo genomic modification occurs in the epidermis and dermis in CD1 transgenic mice following either intraperitoneal or intradermal delivery of the PNA-Antp conjugate. FITC-PNA-Antp accumulates in nuclei of keratinocytes, and, after intradermal delivery of the PNA-Antp, chromosomally modified, keratin 5-positive basal keratinocytes persist for at least 10 days. In hairless (SKH1) mice with the lambdasupFG1 transgene, intradermal delivery of the TFO, AG30, introduces gene modifications in both tail and back skin, and these chromosomal modifications persist in basal keratinocytes for 10 days. Hairless mice should facilitate comparison of various targeting agents and methods of delivery. Gene targeting by repeated local administration of oligonucleotides may prove clinically useful for judiciously selected disease-causing genes in the epidermis. PMID- 23014337 TI - A method for intravital monitoring of human cells using a far-red luminescent probe in graft-versus-host disease model mice. PMID- 23014338 TI - Global epidemiology of psoriasis: a systematic review of incidence and prevalence. AB - The worldwide incidence and prevalence of psoriasis is poorly understood. To better understand this, we performed a systematic review of published population based studies on the incidence and prevalence of psoriasis. Three electronic databases were searched from their inception dates to July 2011. A total of 385 papers were critically appraised; 53 studies reported on the prevalence and incidence of psoriasis in the general population. The prevalence in children ranged from 0% (Taiwan) to 2.1% (Italy), and in adults it varied from 0.91% (United States) to 8.5% (Norway). In children, the incidence estimate reported (United States) was 40.8/100,000 person-years. In adults, it varied from 78.9/100,000 person-years (United States) to 230/100,000 person-years (Italy). The data indicated that the occurrence of psoriasis varied according to age and geographic region, being more frequent in countries more distant from the equator. Prevalence estimates also varied in relation to demographic characteristics in that studies confined to adults reported higher estimates of psoriasis compared with those involving all age groups. Studies on the prevalence and incidence of psoriasis have contributed to a better understanding of the burden of the disease. However, further research is required to fill existing gaps in understanding the epidemiology of psoriasis and trends in incidence over time. PMID- 23014340 TI - Caspase-14-deficient mice are more prone to the development of parakeratosis. AB - Caspase-14 is an important protease in the proper formation of a fully functional skin barrier. Newborn mice that are deficient in caspase-14 exhibit increased transepidermal water loss and are highly sensitive to UVB-induced photodamage. Decreased caspase-14 expression and incomplete caspase-14 processing in lesional psoriatic parakeratotic stratum corneum has been reported previously. In this study, we show that caspase-14-deficient skin frequently displays incompletely cornified cells in the transitional zone between the granular and the cornified layers, pointing to a delay in cornification. We also demonstrate that after challenge of epidermal permeability barrier function by repetitive acetone treatment, a higher incidence of large parakeratotic plaques was observed in caspase-14-deficient skin. Furthermore, caspase-14-deficient mice are more prone than control mice to the development of parakeratosis upon induction of psoriasis like dermatitis by imiquimod treatment. These results show that lack of caspase 14 expression predisposes to the development of parakeratosis and that caspase-14 has an important role in keratinocyte terminal differentiation and the maintenance of normal stratum corneum, especially in conditions causing epidermal hyperproliferation. PMID- 23014339 TI - Topical antihistamines display potent anti-inflammatory activity linked in part to enhanced permeability barrier function. AB - Systemic antagonists of the histamine type 1 and 2 receptors (H1/2r) are widely used as anti-pruritics and central sedatives, but demonstrate only modest anti inflammatory activity. Because many inflammatory dermatoses result from defects in cutaneous barrier function, and because keratinocytes express both Hr1 and Hr2, we hypothesized that H1/2r antagonists might be more effective if they were used topically to treat inflammatory dermatoses. Topical H1/2r antagonists additively enhanced permeability barrier homeostasis in normal mouse skin by the following mechanisms: (i) stimulation of epidermal differentiation, leading to thickened cornified envelopes; and (ii) enhanced epidermal lipid synthesis and secretion. As barrier homeostasis was enhanced to a comparable extent in mast cell-deficient mice, with no further improvement following application of topical H1/2r antagonists, H1/2r antagonists likely oppose mast cell-derived histamines. In four immunologically diverse, murine disease models, characterized by either inflammation alone (acute irritant contact dermatitis, acute allergic contact dermatitis) or by prominent barrier abnormalities (subacute allergic contact dermatitis, atopic dermatitis), topical H1/2r agonists aggravated, whereas H1/2r antagonists improved, inflammation and/or barrier function. The apparent ability of topical H1r/2r antagonists to target epidermal H1/2r could translate into increased efficacy in the treatment of inflammatory dermatoses, likely due to decreased inflammation and enhanced barrier function. These results could shift current paradigms of antihistamine utilization from a predominantly systemic to a topical approach. PMID- 23014341 TI - Opening of chloride channels by 1alpha,25-dihydroxyvitamin D3 contributes to photoprotection against UVR-induced thymine dimers in keratinocytes. AB - UVR produces vitamin D in skin, which is hydroxylated locally to 1alpha,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). 1,25(OH)(2)D(3) protects skin cells against UVR-induced DNA damage, including thymine dimers, but the mechanism is unknown. As DNA repair is inhibited by nitric oxide (NO) products but facilitated by p53, we examined whether 1,25(OH)(2)D(3) altered the expression of nitrotyrosine, a product of NO, or p53 after UVR in human keratinocytes. 1,25(OH)(2)D(3) and the nongenomic agonist 1alpha,25-dihydroxylumisterol(3) reduced nitrotyrosine 16 hours after UVR, detected by a sensitive whole-cell ELISA. p53 was enhanced after UVR, and this was further augmented in the presence of 1,25(OH)(2)D(3). DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid), a chloride channel blocker previously shown to prevent 1,25(OH)(2)D(3)-induced chloride currents in osteoblasts, had no effect on thymine dimers on its own but prevented the 1,25(OH)(2)D(3)-induced protection against thymine dimers. Independent treatment with DIDS, at concentrations that had no effect on thymine dimers, blocked UVR-induced upregulation of p53. In contrast, reduction of nitrotyrosine remained in keratinocytes treated with 1,25(OH)(2)D(3) and DIDS at concentrations shown to block decreases in post-UVR thymine dimers. These results suggest that 1,25(OH)(2)D(3)-induced chloride currents help protect from UVR induced thymine dimers, but further increases in p53 or reductions of nitrotyrosine by 1,25(OH)(2)D(3) are unlikely to contribute substantially to this protection. PMID- 23014342 TI - Genetic profiling of BRAF inhibitor-induced keratoacanthomas reveals no induction of MAP kinase pathway expression. PMID- 23014343 TI - A single-nucleotide polymorphism in the Abcc6 gene associates with connective tissue mineralization in mice similar to targeted models for pseudoxanthoma elasticum. PMID- 23014344 TI - Parakeratotic corneocytes play a unique role in human skin wound healing. PMID- 23014345 TI - Methods to improve adoptive T-cell therapy for melanoma: IFN-gamma enhances anticancer responses of cell products for infusion. AB - Further development of adoptive T-cell therapy (ACT) with autologous tumor infiltrating lymphocytes (TILs) has the potential to markedly change the long term prognosis of patients with metastatic melanoma, and modifications of the original protocol that can improve its clinical efficacy are highly desirable. In this study, we demonstrated that a high in vitro tumor reactivity of infusion products was associated with clinical responses upon adoptive transfer. In addition, we systematically characterized the responses of a series of TIL products to relevant autologous short term-cultured melanoma cell lines from 12 patients. We provide evidence that antitumor reactivity of both CD8(+) and CD4(+) T cells could be enhanced in most TIL products by autologous melanoma sensitization by pretreatment with low-dose IFN-gamma. IFN-gamma selectively enhanced responses to tumor-associated antigens other than melanoma differentiation antigens. In addition, IFN-gamma treatment was invariably associated with restored/increased cancer immunogenicity as demonstrated by upregulation of major histocompatibility complex molecules. These findings suggest a potential synergism between IFN-gamma and ACT, and have important implications for clinical development of combination strategies for the treatment of metastatic melanoma. PMID- 23014346 TI - BRAF mutations and KIT aberrations and their clinicopathological correlation in 202 Korean melanomas. PMID- 23014353 TI - Size-dependent fluorescence properties of [n]cycloparaphenylenes (n = 8-13), hoop shaped pi-conjugated molecules. AB - Hoop-shaped pi-conjugated molecules such as cycloparaphenylene (CPP) have attracted the attention of many chemists because they exhibit interesting properties due to the distorted pi-electron system. To gain a systematic understanding of the properties that result from distorted pi-electron systems, it is important to know precisely how these properties depend on the hoop size. In the present study, we have investigated the size dependence of the fluorescence properties of CPPs. The fluorescence spectra of smaller CPPs showed red-shifted fluorescence peaks, smaller fluorescence quantum yields, and longer lifetimes, when compared to those of larger ones. One of the important factors that gave rise to these fluorescence properties of smaller CPPs was greater structural relaxation from the Franck-Condon state, which is a postulation supported by theoretical calculations. The structural relaxation in the picosecond domain was experimentally detected by the fluorescence upconversion method. The present results are an important example that confirms steric factors strongly governing the fluorescence properties of a molecule. PMID- 23014354 TI - The L-arginine/asymmetric dimethylarginine ratio is improved by anti-tumor necrosis factor-alpha therapy in inflammatory arthropathies. Associations with aortic stiffness. AB - BACKGROUND: Anti-Tumor Necrosis Factor (TNF)-alpha therapy improves vascular pathology in inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. The l-arginine/ADMA ratio is important for modulation of the nitric oxide synthase activity. We examined the effect of TNF alpha antagonists on ADMA and l-arginine/ADMA, and associations between ADMA, L arginine/ADMA, aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies. METHODS: Forty-eight patients who started with anti-TNF-alpha therapy were compared with a non-treated group of 32 patients. Plasma ADMA and L-arginine were assessed at baseline, 3 and 12 months. In a subgroup of 55 patients, aortic pulse wave velocity (aPWV) was measured at baseline, 3 and 12 moths, and CIMT was examined at baseline and 12 months. RESULTS: Anti-TNF-alpha therapy increased the L-arginine/ADMA ratio (mean [SD]) in the treatment group compared to the control group after 3 months (12 [29] vs. 13 [20], P < 0.001) and 12 months (7 [27] vs. -8 [19], P = 0.008), but did not affect ADMA (3 months: 0.00 [0.09] MUmol/L vs. 0.02 [0.07] MUmol/L, P = 0.42, 12 months: 0.01 [0.08] MUmol/L vs. 0.01 [0.09] MUmol/L, P = 0.88). Baseline aPWV was associated with ADMA (P = 0.02) and L-arginine/ADMA (P = 0.02) in multiple regression analyses, and the L-arginine/ADMA ratio was continuously associated with aPWV after initiation of anti-TNF-alpha therapy (P = 0.03). ADMA and L arginine/ADMA were not correlated with CIMT. CONCLUSION: Anti-TNF-alpha therapy improved the L-arginine/ADMA ratio in patients with inflammatory arthropathies. ADMA and the L-arginine/ADMA ratio were associated with aPWV, and might have a mechanistic role in the aortic stiffening observed in these patients. PMID- 23014355 TI - Presumed hydrogen sulfide-mediated neurotoxicity after streptococcus anginosus group meningitis. AB - Hydrogen sulfide is an environmental toxicant and gaseous neurotransmitter. It is produced enterically by sulfur-reducing bacteria and invasive pathogens including Streptococcus anginosus group, Salmonella and Citrobacter. We describe putative focal hydrogen sulfide neurotoxicity after Streptococcus constellatus meningitis, treated with adjunctive sodium nitrite and hyperbaric oxygen therapy. PMID- 23014356 TI - Effectiveness of an incomplete RotaTeq (RV5) vaccination regimen in preventing rotavirus gastroenteritis in the United States. AB - BACKGROUND: Effectiveness of the pentavalent rotavirus vaccine (RV5) after administration of the complete (3 dose) regimen has been demonstrated in a real world setting. This study assessed the effectiveness of RV5 following partial completion of the 3-dose regimen. METHODS: Using a large national health insurance claims database, 2 cohorts of infants (those who received RV5 and a concurrent group who received diphtheria-tetanus-acellular pertussis, but not RV5) were followed through the 2007 and 2008 rotavirus seasons (January 1 to May 31) to identify cases of rotavirus gastroenteritis and all-cause gastroenteritis resulting in medical care encounters. Vaccine effectiveness following the first and the second RV5 doses was estimated by quantifying reductions in hospitalizations, emergency department (ED) and physician office visits. RESULTS: A first RV5 dose was received by 42,306 infants whereas 28,417 infants in the concurrent comparison group received a first diphtheria-tetanus-acellular pertussis dose; 43,704 infants received a second RV5 dose, and 31,810 infants received a second diphtheria-tetanus-acellular pertussis dose. One dose of RV5 was associated with 88% effectiveness against rotavirus gastroenteritis hospitalizations and ED visits and 44% effectiveness against all-cause gastroenteritis hospitalizations and ED visits. A 2-dose regimen of RV5 was associated with 94% effectiveness against rotavirus gastroenteritis hospitalizations and ED visits and 40% effectiveness against all-cause gastroenteritis hospitalizations and ED visits. CONCLUSION: The RV5 vaccine exhibits effectiveness against rotavirus gastroenteritis even before completing the full 3-dose regimen. These results are of particular relevance when considering the benefits of a partially completed rotavirus vaccine series. PMID- 23014357 TI - Carriage-associated Streptocccus pneumoniae serotype 1 in Brussels, Belgium. AB - Streptococcus pneumoniae serotype 1 presents a high invasiveness index and is seldom isolated from its niche, the nasopharynx. We report an unusual serotype 1 carriage in a healthy pediatric population at the time of the heptavalent pneumococcal vaccine adoption in Belgium. Our sampling period coincides with an epidemic wave of serotype 1 invasive pneumococcal infections. Invasive and colonizing isolates were characterized by both antibiotic resistance profile and multilocus sequence typing and were shown to share the same backbone (ST306 and ST350). PMID- 23014358 TI - Outbreak of human Salmonella Typhimurium infections linked to contact with baby poultry from a single agricultural feed store chain and mail-order hatchery, 2009. AB - BACKGROUND: Over 30 outbreaks of human salmonellosis linked to contact with live poultry from mail-order hatcheries were reported to Centers for Disease Control and Prevention between 1990 and 2010. In May 2009, we investigated an outbreak of human Salmonella Typhimurium infections, primarily affecting children. METHODS: A case was defined as a person with the outbreak strain of Salmonella Typhimurium, as determined by pulsed-field gel electrophoresis and multiple-locus variable number tandem repeat analysis, in a Pennsylvania or New York resident with illness onset between May 1 and September 1, 2009. We conducted a case-control study to examine the relationship between illness and live poultry contact. Controls were age-matched and geographically-matched. Traceback and environmental investigations were conducted. RESULTS: We identified 36 case-patients in Pennsylvania and New York; 36% were children aged <=5 years. Case-patients were more likely than controls to report live baby poultry contact (matched odds ratio [mOR]: 17.0; 95% confidence interval [CI]: 2.7-710.5), contact with chicks (mOR: 14.0; 95% CI: 2.1-592.0), ducklings (mOR: 8.0; 95% CI: 1.1-355.0) and visiting agricultural feed stores (mOR: 6.0; 95% CI: 1.3-55.2). Most (83%) visited agricultural Feed Store Chain Y, a national agricultural feed store chain, which received poultry from Hatchery C, which is supplied by multiple egg sources. Salmonella Typhimurium was isolated from a source duck flock, but had a different pulsed-field gel electrophoresis pattern than the outbreak strain. CONCLUSIONS: Live baby poultry remain an important source of human salmonellosis, particularly among children. Preventing these infections requires comprehensive interventions at hatcheries and agricultural feed stores; pediatricians should inform patients of risks associated with live poultry contact. PMID- 23014360 TI - Prevalence of pharyngeal carriage of Kingella kingae in young children and risk factors for colonization. AB - The carriage rate of Kingella kingae among Jewish and Bedouin children living in southern Israel paralleled the age-related incidence of invasive infections. Age 6-29 months was a significant risk factor for K. kingae colonization in both ethnic groups; day-care attendance was a risk factor in Jewish children, whereas living in a shanty town was negatively associated with carriage in Bedouins. PMID- 23014359 TI - Interleukin-1 receptor antagonist gene polymorphism increases susceptibility to septic shock in children with acute lymphoblastic leukemia. AB - BACKGROUND: Interleukin-1 receptor antagonist polymorphism (ILRN) 2 (ILRN*2) has been associated with a poor outcome in septic patients because of an elevated production of anti-inflammatory cytokines. In >70% of patients, morbidity and mortality in childhood acute lymphoblastic leukemia is caused by infections. The aim of this study was to determine the association between this polymorphism and the frequency of septic shock from the time of diagnosis until completion of treatment. METHODS: This cohort study was conducted in 57 consecutive children with acute lymphoblastic leukemia. At the end of follow-up, children were stratified according to their IL1RN polymorphism (ILRN*1/ILRN*2), evaluating the impact of genotype on the severity of febrile neutropenic events during their treatment. RESULTS: Overall survival was 80% at 55 months after treatment. The average number of febrile neutropenic events in this cohort was 2.82 per patient. Genotype distribution was 50.9% for homozygote IL-1RN*1, 38.6% for heterozygote ILRN*1/ILRN*2 and 10.5% for homozygote IL-1RN*2. The risk of presenting septic shock for homozygote IL1RN*2/IL1RN*2 and heterozygote ILRN*1/ILRN*2 patients was significantly greater (odds ratio, 45; P = 0.001) adjusted for age, gender, risk of leukemia and presence of pathogenic bacteria. Genotype IL-1RN*2 is associated with the risk of development of septic shock in children with acute lymphoblastic leukemia. Further research in larger population-based studies is needed to replicate these findings. CONCLUSIONS: This information would allow us to identify more predictive factors in this group of acute lymphoblastic leukemia patients in whom this information is lacking to establish an earlier and more aggressive approach. PMID- 23014361 TI - Inflammatory gene expression profiles in Crohn's disease and ulcerative colitis: a comparative analysis using a reverse transcriptase multiplex ligation-dependent probe amplification protocol. AB - BACKGROUND AND AIMS: Cytokines and their receptors play a critical role in the pathogenesis of the inflammatory bowel disease (IBD). The aim of this study was to investigate the expression profiles of inflammatory genes in inflamed and non inflamed colonic tissue samples in patients with Crohn's disease (CD) and ulcerative colitis (UC), and to identify molecular signatures for different IBD phenotypes. METHODS: Seventy-one patients diagnosed with IBD (38 CD, 33 UC) and 15 non-IBD controls have been included in the study. For each patient, biopsy samples were obtained during colonoscopy from inflamed (L) and healthy (N) mucosa. We investigated by commercially available reverse-transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) kit the mRNA expression of a set of 40 genes involved in inflammation: cytokines, chemokines, receptors, signal transduction molecules and transcription factors. RESULTS: In L biopsies from patients with CD, higher expression levels were found for IL-4 (p=0.009) and IL 12p35 (p=0.0005), whereas in L biopsy samples from patients with UC higher expression levels were found for IL-8 (p=0.03), chemokines SCYA3 (p=0.05), SCYA4 (p=0.01) and glutathione S-transferase P1 (p=0.01). In N biopsies of patients with CD higher expression levels were found for IL-1R (p=0.01) and IL-12p35 (p=0.007), whereas in N biopsies of patients with UC higher expression levels were found for IL-15 (p=0.009) and SCYA8 (p=0.001). The logistic regression analysis has indicated that low expression levels of IL-2 and IL-10, together with higher ASCA IgG titers were independently associated with penetrating/stricturing CD. CONCLUSIONS: RT-MLPA is a sensitive and effective method for the evaluation of the profiles of inflammatory genes in IBD, with potential future applications for diagnosis, phenotypic stratification and targeted therapy. PMID- 23014375 TI - Layer-by-layer self-assembled graphene oxide/silica microsphere composites as stationary phase for high performance liquid chromatography. AB - Graphene oxide (GO) has been layer-by-layer assembled onto silica microspheres to form a GO/SiO(2) composite stationary phase. All the characterizations of GO/SiO(2) by elemental analysis, Raman spectroscopy and Fourier transformed infrared spectrometry confirmed that with the increase of the assembled layer, GO gradually increases on the silica surface. The chromatographic properties of bare SiO(2) and GO/SiO(2) with different GO assembled layers show that the amount of GO plays an important role in the separation of analytes. Only the appropriate amount of GO on SiO(2) can perform a good chromatographic separation. The comparison between chromatographic performances of bare SiO(2) column, GO/SiO(2) 2 column and C18 commercial column clearly show that GO/SiO(2)-2 and C18 columns obtained a better separation; GO/SiO(2)-2 exhibits a large pi-electron system and C18 exhibits hydrophobicity. The eluting order, peak width and resolution of analyte on GO/SiO(2)-2 column was highly dependent on the size of its pi-electron system, while on the C18 column the decisive factor is its hydrophobic property. PMID- 23014377 TI - Electronic correlations and crystal structure distortions in BaBiO3. AB - BaBiO3 is a material where Bi4+ ions with half-filled 6s-states form an alternating set of Bi3+ and Bi5+ ions resulting in a charge ordered insulator. The charge ordering is accompanied by breathing distortion of the BiO6 octahedra (extension and contraction of the Bi-O bond lengths). Standard density functional theory (DFT) calculations fail to obtain the crystal structure instability caused by the pure breathing distortions. Combining effects of the breathing distortions and tilting of the BiO6 octahedra allows DFT to reproduce qualitatively an experimentally observed insulator with monoclinic crystal structure but strongly underestimates the breathing distortion parameter and energy gap values. In the present work we reexamine the BaBiO3 problem within the GGA + U method using a Wannier function basis set for the Bi 6s-band. Due to the high oxidation state of bismuth in this material, the Bi 6s-symmetry Wannier function is predominantly extended spatially on surrounding oxygen ions and hence differs strongly from a pure atomic 6s-orbital. That is in sharp contrast to transition metal oxides (with exclusion of high oxidation state compounds) where the major part of the d band Wannier function is concentrated on the metal ion and a pure atomic d orbital can serve as a good approximation. The GGA + U calculation results agree well with experimental data, in particular with experimental crystal structure parameters and energy gap values. Moreover, the GGA + U method allows one to reproduce the crystal structure instability due to the pure breathing distortions without octahedra tilting. PMID- 23014383 TI - Ethics of emerging technologies and their transition to accepted practice: intestinal transplant for short bowel syndrome. AB - Parental counseling becomes complex when considering the use of emerging technologies, especially if it is unclear whether the level of evidence is sufficient to transform the proposed therapy into accepted practice. This paper addresses ethical issues underlying medical decision-making and counseling in the setting of emerging treatments, when long-term outcomes are still in the process of being fully validated. We argue that the ethical transition of emerging technologies, ideally from ethically impermissible to permissible, to obligatory, depends primarily on two factors: outcome data (or prognosis) and treatment feasibility. To illustrate these points, we will use intestinal transplant for short bowel syndrome (SBS) as a specific example. After reviewing the data, this paper will identify the ethical justifications for both comfort care only and intestinal transplant in patients with ultra SBS, and argue that both are ethically permissible, but neither is obligatory. The approach outlined will not only be valuable as ultra SBS outcomes data continue to change, but will also be applicable to other novel therapies as they emerge in perinatal medicine. PMID- 23014385 TI - Cutaneous melanoma arising from a cesarean delivery skin scar. AB - A 41-year-old pregnant African-American woman noticed rapid growth of her cesarean delivery skin scar beginning at 14-week gestation. Skin biopsy, which was performed at 31 weeks, revealed poorly differentiated cutaneous melanoma. At 34 weeks, she underwent repeat cesarean delivery with tumor excision, pelvic lymphadenectomy and abdominal wall reconstruction. Locally advanced disease and anatomical limitations prevented attainment of negative surgical margins. Despite adjuvant chemotherapy and radiation, she died 1 year after diagnosis. Deferring biopsy of a suspicious skin lesion during pregnancy may have delayed the diagnosis of melanoma in this case and possibly affected the long-term outcome. PMID- 23014384 TI - Newborn ventilatory response to maternal chronic hypercapnia. AB - This is a case of a neonate born with a respiratory acidosis with a compensatory metabolic alkalosis. This case demonstrates placental physiology of gas exchange as well as the blunted ventilatory response in the neonate from chronic hypercapnia. PMID- 23014386 TI - Neonatal presentation of lethal neuromuscular glycogen storage disease type IV. AB - A total of 11 types of glycogen storage disorders have been recognized with variable clinical presentations. Type IV, also known as Andersen disease, represents a rare subtype that can induce severe clinical findings early in life. We report on a patient with early fetal onset of symptoms with severe neuromuscular findings at birth. The pregnancy was further complicated by polyhydramnios and depressed fetal movement. At birth severe hypotonia was noticed requiring active resuscitation and then mechanical ventilation. His lack of expected course for hypoxic ischemic encephalopathy prompted genetic testing, including a muscle biopsy, which confirmed the diagnosis of glycogen storage disease IV (GSD IV). Mutation analysis of the glycogen branching enzyme 1 gene demonstrated a previously unrecognized mutation. We review recent information on early presentation of GSD IV with particular interest in the presentation of the neonatal lethal neuromuscular form of this rare disorder. PMID- 23014387 TI - Anopthalmia/microphthlamia-esophageal atresia association with additional features imperforate anus, choanal atresia, cyanotic heart disease. PMID- 23014388 TI - [1] Automated sample injection in amino acid analyzers. PMID- 23014389 TI - [2] Determination of d- and l-amino acids by ion-exchange chromatography. PMID- 23014390 TI - [3] Gas-liquid chromatography (GLC) of amino acid derivatives. PMID- 23014391 TI - [4] Determination of tryptophan. PMID- 23014392 TI - [5] Determination of cystine and cysteine as S-sulfocysteine. PMID- 23014393 TI - [6] Thin-layer chromatography of amino acids and derivatives. PMID- 23014394 TI - [7] Use of cyanate for determining NH(2)-terminal residues in protein. PMID- 23014395 TI - [8] End-group analysis using dansyl chloride. PMID- 23014396 TI - [9] hydrazinolysis. PMID- 23014397 TI - [10] Enzymatic hydrolysis with carboxypeptidases. PMID- 23014398 TI - [11] Significance of interactions in electrophoretic and chromatographic methods. PMID- 23014399 TI - [12] The applicability of acrylamide gel electrophoresis to determination of protein purity. PMID- 23014400 TI - [13] Reduction of disulfide bonds in proteins with dithiothreitol. PMID- 23014401 TI - [14] Maleylation of amino groups. PMID- 23014402 TI - [15] Separation of peptides by chromatography on columns of Dowex 50 with volatile developers. PMID- 23014403 TI - [16] Separation of peptides by chromatography on columns of Dowex 1 with volatile developers. PMID- 23014404 TI - [17] Chromatography of proteins and peptides on diethylaminoethyl cellulose. PMID- 23014405 TI - [18] Terminal pyrrolidonecarboxylic acid: Cleavage with enzymes. PMID- 23014406 TI - [19] Gas-liquid chromatographic analysis of constituent carbohydrates in glycoproteins. PMID- 23014407 TI - [20] Leucine aminopeptidase in sequence determination of peptides. PMID- 23014408 TI - [21] carboxypeptidases a and B. PMID- 23014409 TI - [22] Preparation and specificity of dipeptidyl aminopeptidase I. PMID- 23014410 TI - [23] Sequencing of peptides with dipeptidyl aminopeptidase I. PMID- 23014411 TI - [24] Degradation of peptides by the Edman method with direct identification of the phenylthiohydantoin-amino acid. PMID- 23014412 TI - [25] Mass spectroscopy of methylthiohydantoin amino acids: Identification, quantitation, and the analysis of mixtures. PMID- 23014413 TI - [26] Subtractive Edman degradation. PMID- 23014414 TI - [26a] Sequence analysis with dansyl chloride. PMID- 23014415 TI - [27] Automatic solid-phase Edman degradation. PMID- 23014416 TI - [28] Subtractive Edman degradation with an insoluble reagent. PMID- 23014417 TI - [29] Sequential degradation of peptides and proteins from their COOH termini with ammonium thiocyanate and acetic anhydride. PMID- 23014418 TI - [30] Reduction and reoxidation at disulfide bonds. PMID- 23014419 TI - [31] Oxidation with hydrogen peroxide. PMID- 23014420 TI - [32] Dye-sensitized photooxidation. PMID- 23014421 TI - [33] Specific modification of NH(2)-terminal residues by transamination. PMID- 23014422 TI - [34] Modification of tryptophan with BNPS-skatole (2-(2-nitrophenylsulfenyl)-3 methyl-3-bromoindolenine). PMID- 23014423 TI - [34a] carboxymethylation. PMID- 23014424 TI - [35] Iodination-Isolation of peptides from the active site. PMID- 23014425 TI - [36] Reactions with N-ethylmaleimide and p-mercuribenzoate. PMID- 23014426 TI - [37] Reaction of protein sulfhydryl groups with Ellman's reagent. PMID- 23014427 TI - [38] The rapid determination of amino groups with TNBS. PMID- 23014428 TI - [39] Modification of proteins with active benzyl halides. PMID- 23014429 TI - [40] Sulfenyl halides as modifying reagents for polypeptides and proteins. PMID- 23014430 TI - [41] acetylation. PMID- 23014431 TI - [42] o-acetyltyrosine. PMID- 23014432 TI - [43] cyanuration. PMID- 23014433 TI - [44] Nitration with tetranitromethane. PMID- 23014434 TI - [45] Diazonium salts as specific reagents and probes of protein conformation. PMID- 23014435 TI - [46] Acylation with dicarboxylic acid anhydrides. PMID- 23014436 TI - [47] Hybridization of chemically modified proteins. PMID- 23014437 TI - [48] thiolation. PMID- 23014438 TI - [49] Reaction of proteins with citraconic anhydride. PMID- 23014439 TI - [50] Reaction with N-carboxy-alpha-amino acid anhydrides. PMID- 23014440 TI - [51] Guanidination of proteins. PMID- 23014441 TI - [52] Modification of arginine by diketones. PMID- 23014442 TI - [53] Modification of proteins with cyanate. PMID- 23014443 TI - [54] amidination. PMID- 23014444 TI - [55] esterification. PMID- 23014445 TI - [56] Carbodiimide modification of proteins. AB - A carbodiimide-nucleophile procedure for modifying carboxyl groups in proteins can be utilized under mild conditions for the quantitative determination of all carboxyl groups or for the modification of selected residues in activity studies. The method allows numerous variations both in the activating carbodiimide and in the nature of the nucleophile. Side reactions do occur but can be corrected for. PMID- 23014446 TI - [57] Bifunctional reagents. PMID- 23014447 TI - [58] Site-specific reagents for chymotrypsin, trypsin, and other serine proteases. PMID- 23014449 TI - Preface. PMID- 23014448 TI - [59] Site-specific reagents for triose phosphate isomerase and their potential applicability to aldolase and glycerol phosphate dehydrogenase. PMID- 23014450 TI - Raman spectra of titanium dioxide (anatase, rutile) with identified oxygen isotopes (16, 17, 18). AB - Six representative isotope-labeled samples of titanium dioxide were synthesized: Ti(16)O(2), Ti(17)O(2) and Ti(18)O(2), each in anatase and rutile forms. Their Raman scattering was analyzed at temperatures down to 5 K. Spectral assignment was supported by numerical simulation using DFT calculations. The combination of experimental and theoretical Raman frequencies with the corresponding isotopic shifts allowed us to address various still-open questions about the second-order Raman scattering in rutile, and the analysis of overlapping features in the anatase spectrum. PMID- 23014451 TI - Study on the distribution of binary mixed counterions in surfactant adsorbed films by total reflection XAFS measurements. AB - The total reflection X-ray absorption fine structure (TR-XAFS) technique was applied to adsorbed films at the surface of aqueous solutions of surfactant mixtures composed of dodecyltrimethylammonium bromide (DTAB) and dodecyltrimethylammonium tetrafluoroborate (DTABF(4)). The obtained XAFS spectra were expressed as linear combinations of two specific spectra corresponding to fully hydrated bromide ions (free-Br) and partially dehydrated bromide ions adsorbed to the hydrophilic groups of surfactant ions (bound-Br) at the surface. The ratio of free- and bound-Br ions was determined as a function of surface tension and surface composition of the surfactants. Taking also the results in our previous studies on the DTAB - dodecyltrimethylammonium chloride (DTAC) and 1 hexyl-3-methylimidazolium bromide (HMIMBr) - 1-hexyl-3-methylimidazolium tetrafluoroborate (HMIMBF(4)) mixed systems into consideration, the relation between counterion distribution and miscibility of counterions at the solution surface was deduced for the surfactant mixtures having common surfactant ions but different counterions. PMID- 23014457 TI - Shorter length dialysis sessions are associated with increased mortality, independent of body weight. AB - Hemodialysis patients have high rates of mortality that may be related to aspects of the dialytic procedure. In prior studies, shorter length dialysis sessions have been associated with decreased survival, but these studies may have been confounded by body size differences. Here we tested whether in-center three-times weekly hemodialysis patients with adequate urea clearances but shorter dialysis session length is associated with mortality independent of body size. Data were taken from a large national cohort of patients from a large dialysis organization undergoing three-times-weekly in-center hemodialysis. In the primary analysis, patients with prescribed dialysis sessions greater and less than 240 min were pair-matched on post-dialysis weight as well as on age, gender, and vascular access type. Compared to prescribed longer dialysis sessions, session lengths less than 240 min were significantly associated with increased all-cause mortality (adjusted hazard ratio 1.26). The association was consistent across strata of age, gender, and dialysis post-weight. Secondary analyses found a dose response between prescribed session length and survival. Thus, among patients with adequate urea clearance, shorter dialysis session lengths are associated with increased mortality independent of body weight. PMID- 23014458 TI - Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury. AB - Acute kidney injury (AKI) has been recognized as a risk factor for the development of chronic kidney disease (CKD). Aldosterone has a critical role in promoting renal injury induced by ischemia. Here, we evaluated whether spironolactone administered before or after AKI caused by ischemia protects against CKD. In the first set of experiments, Wistar rats underwent a sham operation without or with prior spironolactone treatment, or underwent 45 minutes of bilateral renal ischemia without or with spironolactone treatment before ischemia and assessed over 270 days. The second set of rats received low (20 mg/kg) or high (80 mg/kg) doses of spironolactone at three different times after the sham operation or bilateral renal ischemia and were assessed after 90 days. Untreated animals developed CKD following ischemia-induced AKI as characterized by a progressive increase in proteinuria, renal dysfunction, podocyte injury, glomerular hypertrophy, and focal sclerosis. This was associated with increased oxidative stress, an upregulation of tumor growth factor (TGF)-beta, followed by upregulation of the TGF-beta downstream effectors phospho-Smad3, collagen I, fibronectin, and proinflammatory cytokines. Treatment with spironolactone either before or after ischemia prevented subsequent CKD by avoiding the activation of fibrotic and inflammatory pathways. Thus, spironolactone may be a promising treatment for the prevention of AKI-induced CKD. PMID- 23014459 TI - Chronic kidney disease may be differentially diagnosed from preeclampsia by serum biomarkers. AB - Preeclampsia, affecting 5-8% of pregnancies, is the main cause of fetal-maternal mortality and morbidity. The differential diagnosis with chronic kidney disease (CKD) is a challenge owing to the overlapping clinical features. No biomarker has been found to discriminate between the two conditions. Here, we tested whether maternal serum levels of placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1), markers of preeclampsia, could be used to discriminate between 34 patients with preeclampsia, 23 patients with CKD during pregnancy, and 38 healthy pregnant women. Serum levels of PlGF and sFlt-1 were determined during the third trimester by commercially available immunoassays. In preeclampsia, sFlt-1 levels were significantly increased in comparison with that in CKD and in the control women. Serum levels of PlGF in preeclampsia were significantly decreased relative to both controls and patients with CKD. The sFlt 1 to PlGF ratio was significantly increased in preeclampsia (median 436) compared with controls (median 9.4) and CKD (median 4.0). No differences were found between controls and patients with CKD. Thus, our study suggests that it is possible to discriminate between preeclampsia and CKD during pregnancy by determining maternal serum levels of sFlt-1 and PlGF and their ratio. PMID- 23014460 TI - Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis. AB - Mutations in the inverted formin 2 gene (INF2) have recently been identified as the most common cause of autosomal dominant focal and segmental glomerulosclerosis (FSGS). To quantify the contribution of various genes contributing to FSGS, we sequenced INF2 where all mutations have previously been described (exons 2 to 5) in a total of 215 probands and 281 sporadic individuals with FSGS, along with other known genes accounting for autosomal dominant FSGS (ACTN4, TRPC6, and CD2AP) in 213 probands. Variants were classified as disease causing if they altered the amino acid sequence and if they were not found in control samples and in families segregated with disease. Mutations in INF2 were found in a total of 20 of the 215 families (including those previously reported) in our cohort of autosomal dominant familial nephrotic syndrome or FSGS, thereby explaining disease in 9%. INF2 mutations were found in 2 of 281 individuals with sporadic FSGS. In contrast, ACTN4- and TRPC6-related diseases accounted for 3 and 2% of our familial cohort, respectively. INF2-related disease showed variable penetrance, with onset of disease ranging widely from childhood to adulthood, and commonly leading to end-stage renal disease in the third and fourth decade of life. Thus, mutations in INF2 are a more common, although still a minor, monogenic cause of familial FSGS when compared with other known autosomal dominant genes associated with FSGS. PMID- 23014463 TI - Modulation of amyloid-beta 1-42 structure and toxicity by proline-rich whey peptides. AB - A proline-rich peptide product prepared from bovine whey protein that was enriched in several hydrophobic amino acids including proline (whey proline-rich peptide, wPRP) was shown to modulate the folding pathway of human amyloid beta peptide 1-42 (Abeta42) into oligomers. Concentration-dependent changes in ThT binding to Ab42 by wPRP indicated suppression of oligomerisation, that was supported by Transmission Electron Microscopy. Suppression of beta-sheet and specifically, anti-parallel beta-sheet structures by wPRP was demonstrated by ATR FTIR spectroscopy, where evidence for capacity of wPRP to dissociate pre-existing beta-sheet structures in Abeta42 was also apparent. Suppression of anti-parallel beta-sheets of oligomeric Abeta42 was associated with rescue of yeast and SH-SY5Y neuronal cells providing important evidence for the association between anti parallel beta-sheet structure and oligomer toxicity. It was proposed that the interaction of wPRP with Abeta42 interfered with the anti-parallel folding pathway of oligomeric Abeta42 and ultimately produced 'off-pathway' structures of lowered total beta-sheet content, with attenuated cellular toxicity. PMID- 23014464 TI - Ultrafast insulator-metal phase transition in vanadium dioxide studied using optical pump-terahertz probe spectroscopy. AB - We studied the ultrafast dynamic behavior of the photoinduced insulator-metal phase transition in VO2 thin film using optical pump-terahertz probe spectroscopy with different excitation fluences and at different temperatures. We observed two processes in the insulator-metal phase transition in VO2: a fast process and a slow process. The fast process is a nonthermal process, which is ascribed to the nucleation of the metal phase, while the slow process is strongly affected by temperature and is ascribed to the thermally driven growth and coalescence of metal domains in VO2. The transient complex conductivity spectra at different delay times are also investigated. PMID- 23014479 TI - Harboring oil-degrading bacteria: a potential mechanism of adaptation and survival in corals inhabiting oil-contaminated reefs. AB - Certain coral reef systems north of the Arabian Gulf are characterized by corals with a unique ability to thrive and flourish despite the presence of crude oil continuously seeping from natural cracks in the seabed. Harboring oil-degrading bacteria as a part of the holobiont has been investigated as a potential mechanism of adaptation and survival for corals in such systems. The use of conventional and molecular techniques verified a predominance of bacteria affiliated with Gammaproteobacteria, Actinobacteria and Firmicutes in the mucus and tissues of Acropora clathrata and Porites compressa. These bacteria were capable of degrading a wide range of aliphatic (C9-C28) aromatic hydrocarbons (Phenanthrene, Biphenyl, Naphthalene) and crude oil. In addition, microcosms supplied with coral samples and various concentrations of crude oil shifted their bacterial population toward the more advantageous types of oil degraders as oil concentrations increased. PMID- 23014480 TI - Prevalence, predictors and clinical impact of unique and multiple chronic total occlusion in non-infarct-related artery in patients presenting with ST-elevation myocardial infarction. AB - OBJECTIVES: To investigate the predictors and impact on long-term survival of one chronic total occlusion (CTO) or multiple CTOs in patients presenting with ST elevation myocardial infarction (STEMI). DESIGN: Single-centre retrospective observational study. SETTING: University-based tertiary referral centre. PATIENTS: Between 2006 and 2011, a total of 2020 consecutive patients referred with STEMI were categorised into single vessel disease, multivessel disease (MVD) without CTO, with one CTO or with multiple CTOs. INTERVENTION: Primary percutaneous coronary intervention. MAIN OUTCOME MEASURE: The primary end-point was the 1-year mortality. RESULTS: The prevalence of single vessel disease, MVD without CTO, with one CTO or with multiple CTOs was 70%, 22%, 7.2% and 0.8%, respectively. Independent clinical predictors for the presence of CTO were cardiogenic shock (OR 5.05; 95% CI 3.29 to 7.64), prior myocardial infarction (OR 2.06; 95% CI 1.35 to 3.09), age >65 years (OR 1.94; 95% CI 1.40 to 2.71) and history of angina (OR 1.94; 95% CI 1.29 to 2.87). Mortality was worse in patients with multiple CTOs (76.5%) compared with those with one CTO (28.1%) or without CTO (7.3%) (p<0.0001). After adjustment for left ventricular ejection fraction and renal function, MVD was an independent predictor for 1-year mortality (HR: 1.81; 95% CI 1.18 to 2.77, p=0.007), but CTO was not (HR: 1.07; 95% CI 0.66 to 1.73, p=0.78). CONCLUSIONS: Simple clinical factors are associated with the presence of CTO in non-infarct-related artery in patients presenting with STEMI. In these patients, long-term survival was independently associated with MVD, left ventricular ejection fraction and renal function, but not with CTO per se. PMID- 23014481 TI - Mortality risk of triglyceride levels in patients with coronary artery disease. AB - OBJECTIVE: The association between triglyceride level and the risk of coronary artery disease (CAD) remains controversial. In particular, the prognostic significance of triglyceride levels in established CAD is unclear. We aimed to assess the relationship between triglyceride levels and long-term (>10 years) prognosis in a cohort of patients after complete coronary revascularisation. DESIGN: Observational cohort study. SETTING: Departments of cardiology and cardiovascular surgery in a university hospital. PATIENTS: Consecutive patients who had undergone complete revascularisation between 1984 and 1992. All patients were categorised according to the quintiles of fasting triglyceride levels at baseline. MAIN OUTCOME MEASURES: The risk of fasting triglyceride levels for all cause and cardiac mortality was assessed by multivariable Cox proportional hazards regression analyses. RESULTS: Data from 1836 eligible patients were assessed. There were 412 (22.4%) all-cause deaths and 131 (7.2%) cardiac deaths during a median follow-up of 10.5 years. Multivariable analyses including total and high-density lipoprotein cholesterol and other covariates revealed no significant differences in linear trends for all-cause mortality according to the quintiles of triglyceride (p for trend=0.711). However, the HR increased with the triglyceride levels in a significant and dose-dependent manner for cardiac mortality (p for trend=0.031). Multivariable analysis therefore showed a significant relationship between triglyceride levels, when treated as a natural logarithm-transformed continuous variable, and increased cardiac mortality (HR 1.51, p=0.044). CONCLUSIONS: Elevated fasting triglyceride level is associated with increased risk of cardiac death after complete coronary revascularisation. PMID- 23014483 TI - Multijunction organic photovoltaics with a broad spectral response. AB - We demonstrate series-integrated multijunction organic photovoltaics fabricated monolithically by vapor-deposition in a transposed subcell order with the near infrared-absorbing subcell in front of the green-absorbing subcell. This transposed subcell order is enabled by the highly complementary absorption spectra of a near-infrared-absorbing visibly-transparent subcell and a visible absorbing subcell and motivated by the non-spatially-uniform optical intensity in nanoscale photovoltaics. The subcell order and thicknesses are optimized via transfer-matrix formalism and short-circuit current simulations. An efficient charge recombination zone consisting of layers of BCP/Ag/MoOx leads to negligible voltage and series-resistance losses. Under 1-sun illumination the multijunction solar cells exhibit a power conversion efficiency of 5.5 +/- 0.2% with an FF of 0.685 +/- 0.002 and a V(OC) of 1.65 +/- 0.02 V, corresponding to the sum of the V(OC) of the component subcells. These devices exhibit a broad spectral response (in the wavelength range of 350 nm to 850 nm) but are limited by subcell external quantum efficiencies between 20% and 30% over the photoactive spectrum. PMID- 23014482 TI - In vivo measurement of plaque neovascularisation and thermal heterogeneity in intermediate lesions of human carotid arteries. AB - OBJECTIVES: Both neoangiogenesis and inflammation contribute in atherosclerosis progression. Contrast-enhanced ultrasound (CEUS) provides visualisation of plaque neovascularisation. Microwave radiometry (MR) allows in vivo non-invasive measurement of temperature of tissues, reflecting inflammatory activation. We assessed the association of carotid plaque temperature, measured by MR, with plaque neovascularisation assessed by CEUS in intermediate lesions. METHODS: Consecutive patients with coronary artery disease and carotid atherosclerosis underwent carotid ultrasound imaging, CEUS and MR. Plaque texture, plaque surface and plaque echogenicity were analysed. Contrast enhancement (CE) by CEUS was defined as the % percentage of signal intensity difference, prior and post contrast infusion. Thermal heterogeneity (DeltaT) was assigned as maximal temperature along the carotid artery minus minimum. RESULTS: Eighty-six carotid arteries of 48 patients were included. Fatty plaques had higher CE% and DeltaT compared with mixed and calcified (p<0.01 for all comparisons). Heterogeneous plaques had higher CE% and DeltaT compared with homogenous (p<0.01 for all comparisons). Plaques with irregular surface had higher CE% and DeltaT compared with plaques with regular (p<0.01 for all comparisons). There was a good correlation between DeltaT and CE (R=0.60, p<0.001). CONCLUSIONS: Carotid plaque neovascularisation on CEUS examination is associated with increased thermal heterogeneity and ultrasound characteristics of plaque vulnerability in intermediate lesions. PMID- 23014485 TI - The New Zealand PUFA semiquantitative food frequency questionnaire is a valid and reliable tool to assess PUFA intakes in healthy New Zealand adults. AB - The health benefits of PUFA are well established. There is no valid tool or complete fatty acid database to assess PUFA intake in New Zealand (NZ). This study aimed to develop, validate, and test the reproducibility of a NZ-specific PUFA FFQ. A semiquantitative NZ PUFA FFQ was developed based on a validated Australian PUFA FFQ. The Australian fatty acid database was adapted to include NZ specific data for major PUFA sources. Healthy participants from Auckland, NZ (n = 48) provided fasting blood samples for erythrocyte PUFA analysis, completed the NZ PUFA FFQ and a 3-d weighed food record (WFR), and repeated the NZ PUFA FFQ 3 mo later (n = 42). Relative validity was evaluated by assessing the triangular relationship among the NZ PUFA FFQ, WFR, and erythrocyte PUFA using the methods of triads [EPA, DHA, total omega-3 (n-3) long-chain (LC) PUFA only] and by comparing, correlating, cross-classifying into quintiles and assessing agreement using Bland-Altman plots of intakes between the NZ PUFA FFQ and WFR. Reproducibility was assessed by comparing and correlating intakes between repeat administrations of the NZ PUFA FFQ. The NZ PUFA FFQ effectively estimated EPA [rho(QT) = 0.72 (95% CI: 0.49, 0.89)], DHA [rho(QT) = 0.72 (95% CI: 0.53, 0.95)], and total (n-3) LCPUFA [rho(QT) = 0.68 (95% CI: 0.47, 0.89)] intakes and was comparable with the WFR for other PUFA except docosapentaenoic acid. Repeated implementation of the NZ PUFA FFQ showed agreement for PUFA intakes. The NZ PUFA FFQ is a valid and reliable tool to measure PUFA intake in healthy NZ adults. PMID- 23014486 TI - Opuntia ficus indica (nopal) attenuates hepatic steatosis and oxidative stress in obese Zucker (fa/fa) rats. AB - Nonalcoholic fatty liver disease (NAFLD) is associated with multiple factors such as obesity, insulin resistance, and oxidative stress. Nopal, a cactus plant widely consumed in the Mexican diet, is considered a functional food because of its antioxidant activity and ability to improve biomarkers of metabolic syndrome. The aim of this study was to assess the effect of nopal consumption on the development of hepatic steatosis and hepatic oxidative stress and on the regulation of genes involved in hepatic lipid metabolism. Obese Zucker (fa/fa) rats were fed a control diet or a diet containing 4% nopal for 7 wk. Rats fed the nopal-containing diet had ~50% lower hepatic TG than the control group as well as a reduction in hepatomegaly and biomarkers of hepatocyte injury such as alanine and aspartate aminotransferases. Attenuation of hepatic steatosis by nopal consumption was accompanied by a higher serum concentration of adiponectin and a greater abundance of mRNA for genes involved in lipid oxidation and lipid export and production of carnitine palmitoyltransferase-1 and microsomal TG transfer proteins in liver. Hepatic reactive oxygen species and lipid peroxidation biomarkers were significantly lower in rats fed nopal compared with the control rats. Furthermore, rats fed the nopal diet had a lower postprandial serum insulin concentration and a greater liver phosphorylated protein kinase B (pAKT):AKT ratio in the postprandial state. This study suggests that nopal consumption attenuates hepatic steatosis by increasing fatty acid oxidation and VLDL synthesis, decreasing oxidative stress, and improving liver insulin signaling in obese Zucker (fa/fa) rats. PMID- 23014487 TI - Iron fortification of whole wheat flour reduces iron deficiency and iron deficiency anemia and increases body iron stores in Indian school-aged children. AB - Wheat is the primary staple food for nearly one-third of the world's population. NaFeEDTA is the only iron (Fe) compound suitable for fortifying high extraction flours. We tested the hypothesis that NaFeEDTA-fortified, whole wheat flour reduces Fe deficiency (ID) and improves body Fe stores (BIS) and cognitive performance in Indian children. In a randomized, double-blind, controlled, school feeding trial, 6- to 15-y-old, Fe-depleted children (n = 401) were randomly assigned to either a daily wheat-based lunch meal fortified with 6 mg of Fe as NaFeEDTA or an otherwise identical unfortified control meal. Hemoglobin (Hb) and Fe status were measured at baseline, 3.5 mo, and 7 mo. Cognitive performance was evaluated at baseline and 7 mo in children (n = 170) at one of the study sites. After 7 mo, the prevalence of ID and ID anemia in the treatment group significantly decreased from 62 to 21% and 18 to 9%, respectively. There was a time x treatment interaction for Hb, serum ferritin, transferrin receptor, zinc protoporphyrin, and BIS (all P < 0.0001). Changes in BIS differed between the groups; it increased in the treatment group (0.04 +/- 0.04 mmol/kg body weight) and decreased in the control group (-0.02 +/- 0.04 mmol/kg body weight) (P < 0.0001). In sensory tests, NaFeEDTA-fortified flour could not be differentiated from unfortified flour. There were no significant differences in cognitive performance tests between the groups. NaFeEDTA-fortified wheat flour markedly improved BIS and reduced ID in Fe-depleted children. It may be recommended for wider use in national school feeding programs. PMID- 23014488 TI - Early life iron deficiency impairs spatial cognition in neonatal piglets. AB - Iron deficiency is common throughout the world and has been linked to cognitive impairments. Using neonatal piglets to model human infants, we assessed the impact of iron deficiency on spatial learning and memory. Artificially reared piglets were fed 1 of 3 liquid diets with varying concentrations of iron: control (CON), mildly deficient (MID), or severely deficient (SID; 100, 25.0, or 10.0 mg iron/kg milk solids, respectively) for 4 wk. Relative to CON, SID and MID piglets had reduced hemoglobin (P < 0.05) as well as magenta skin color (P < 0.001), which correlated with hematocrit (R(2) = 0.76; P < 0.001). SID and MID hemoglobin differed at wk 3 and 4 (P < 0.05). In a hippocampal-dependent, spatial, T-maze task, SID piglets were unable to acquire the task (post hoc contrast: first vs. last day of acquisition), while MID piglets demonstrated deficits in reversal learning (P = 0.032). Iron concentrations in the liver (P < 0.001), serum (P = 0.003), and hippocampus (P = 0.004), but not prefrontal cortex, were lower in MID and SID compared with CON piglets. The level of the transferrin receptor mRNA (TFR) was greater in the prefrontal cortex of CON piglets than in MID and SID piglets (P = 0.001) but not the hippocampus. Gene expression of several neurotrophic factors and proinflammatory cytokines, as well as whole-brain and hippocampal volume, were not affected by dietary treatment. In conclusion, neonatal iron deficiency leads to cognitive impairment, which may be due in part to a reduced iron concentration in the hippocampus. PMID- 23014489 TI - Fecal lactic acid bacteria increased in adolescents randomized to whole-grain but not refined-grain foods, whereas inflammatory cytokine production decreased equally with both interventions. AB - The intake of whole-grain (WG) foods by adolescents is reported to be approximately one-third the recommended intake of 48 g/d. This 6-wk randomized interventional study determined the effect of replacing grains within the diet with refined-grain (RG; n = 42) or WG (n = 41) foods/d on gastrointestinal and immune health in adolescents (aged 12.7 +/- 0.1 y). A variety of grain-based foods were delivered weekly to participants and their families. Participants were encouraged to eat 3 different kinds of study foods (e.g., bread, cereals, snacks)/d with goals of 0 g/d (RG) and 80 g/d (WG). Stool samples were obtained during the prebaseline and final weeks to measure bifidobacteria and lactic acid bacteria (LAB) using qPCR. Stool frequency was recorded daily. Blood was drawn at baseline and at final visits for immune markers. Across groups, total-grain intake increased by one serving. The intake of WG was similar at baseline (18 +/- 3 g) between groups but increased to 60 +/- 5 g in the WG group and decreased to 4 +/- 1 g in the RG group. Fecal bifidobacteria increased from baseline with both interventions, but LAB increased (P < 0.05) from baseline [2.4 +/- 0.2 log(10) genome equivalents (eq)] to wk 6 (3.0 +/- 0.2 log(10) genome eq) in the WG group but not in the RG group (baseline: 2.9 +/- 0.2 log(10) genome eq; wk 6: 3.0 +/- 0.1 log(10) genome eq). There was no difference in stool frequency, serum antioxidant potential, or in vitro LPS-stimulated mononuclear cell production of inflammatory cytokines between groups. However, across both groups the number of daily stools tended to increase (P = 0.08) by 0.0034 stools/g WG or by 0.2 stools with 60 g WG, mean antioxidant potential increased by 58%, and mean production of TNF-alpha, IL-1beta, and IL-6 decreased by 24, 22, and 42%, respectively, between baseline and wk 6. Overall, incorporating either WG or RG foods increased serum antioxidant concentrations and decreased inflammatory cytokine production; however, WG study foods had more of an effect on aspects of gastrointestinal health. PMID- 23014490 TI - A hydrogen gas-water equilibration method produces accurate and precise stable hydrogen isotope ratio measurements in nutrition studies. AB - Stable hydrogen isotope methodology is used in nutrition studies to measure growth, breast milk intake, and energy requirement. Isotope ratio MS is the best instrumentation to measure the stable hydrogen isotope ratios in physiological fluids. Conventional methods to convert physiological fluids to hydrogen gas (H(2)) for mass spectrometric analysis are labor intensive, require special reagent, and involve memory effect and potential isotope fractionation. The objective of this study was to determine the accuracy and precision of a platinum catalyzed H(2)-water equilibration method for stable hydrogen isotope ratio measurements. Time to reach isotopic equilibrium, day-to-day and week-to-week reproducibility, accuracy, and precision of stable hydrogen isotope ratio measurements by the H(2)-water equilibration method were assessed using a Thermo DELTA V Advantage continuous-flow isotope ratio mass spectrometer. It took 3 h to reach isotopic equilibrium. The day-to-day and week-to-week measurements on water and urine samples with natural abundance and enriched levels of deuterium were highly reproducible. The method was accurate to within 2.8 (o)/oo and reproducible to within 4.0 (o)/oo based on analysis of international references. All the outcome variables, whether in urine samples collected in 10 doubly labeled water studies or plasma samples collected in 26 body water studies, did not differ from those obtained using the reference zinc reduction method. The method produced highly accurate estimation on ad libitum energy intakes, body composition, and water turnover rates. The method greatly reduces the analytical cost and could easily be adopted by laboratories equipped with a continuous-flow isotope ratio mass spectrometer. PMID- 23014491 TI - Dietary selenium deficiency partially rescues type 2 diabetes-like phenotypes of glutathione peroxidase-1-overexpressing male mice. AB - This study was conducted to determine whether dietary Se deficiency precluded overproduction of glutathione peroxidase-1 (GPX1) activity in mice overexpressing (OE) this gene and thus rescued their type 2 diabetes-like phenotypes. A total of 20 male OE and wild-type (WT) mice were fed an Se-deficient (<0.02 mg/kg) diet or an Se-supplemented (0.3 mg/kg as sodium selenite) diet from 1 to 5 mo of age. Dietary Se deficiency eliminated or attenuated (P < 0.05) genotype differences in concentrations of blood glucose, plasma insulin, and/or hepatic lipids, insulin sensitivity, and glucose-stimulated insulin secretion at the end of the study. Dietary Se deficiency decreased (P < 0.05) OE islet mRNA levels of 2 key transcriptional activators (Beta2 and Foxa2) and removed genotype differences in islet mRNA levels of 7 genes (Beta2, Cfos, Foxa2, Pregluc, Ins1, p53, and Sur1) related to insulin synthesis and secretion. Compared with those of the Se adequate OE mice, the Se-deficient OE mice had lower (P < 0.05) hepatic mRNA levels of 2 key rate-limiting enzymes for lipogenesis (Acc1) and glycolysis (Gk1), along with lower (P < 0.05) activities of hepatic glucokinase and muscle phosphoenolpyruvate carboxykinase. Dietary Se deficiency also decreased (P < 0.05) blood glucose and hepatic lipid concentrations in the WT mice. In conclusion, dietary Se deficiency precluded the overproduction of GPX1 in full fed OE mice and partially rescued their metabolic syndromes. This alleviation resulted from modulating the expression and/or function of proinsulin genes, lipogenesis rate-limiting enzyme genes, and key glycolysis and gluconeogenesis enzymes in islets, liver, and muscle. PMID- 23014492 TI - Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake. AB - Elevated homocysteine (Hcy) concentrations are associated with increased risk of several chronic diseases. Hcy can be removed by methylating it to form methionine via either the betaine homocysteine S-methyltransferase (BHMT) or the methionine synthase (MS) pathway. BHMT uses betaine as the methyl donor, whereas MS uses 5 methyltetrahydrofolate. We previously found that mice with the gene encoding Bhmt deleted (Bhmt(-/-)) had altered Hcy metabolites in tissues. This study aimed to determine whether folate supplementation of Bhmt(-/-) mice reverses, and folate deficiency exacerbates, these metabolic changes. Bhmt(-/-) mice and their littermates (Bhmt(+/+) mice) were fed a folate-deficient (FD; 0 mg/kg diet), a folate control (FC; 2 mg/kg diet), or a folate-supplemented (FS; 20 mg/kg diet) diet for 4 wk. Bhmt(-/-) mice had higher plasma Hcy and hepatic S adenosylhomocysteine (AdoHcy) concentrations and had lower hepatic S adenosylmethionine (AdoMet) concentrations compared with Bhmt(+/+) mice for all diets. Although the FD diet increased plasma Hcy (P < 0.05) and hepatic AdoHcy (P < 0.001) concentrations in Bhmt(+/+) mice compared with FC and FS mice, the FD diet had no effect on the metabolites measured in Bhmt(-/-) mice. The FS diet did not ameliorate elevated plasma Hcy and elevated hepatic AdoHcy concentrations but did increase hepatic AdoMet concentrations in Bhmt(-/-) mice (P < 0.001) compared with FD and FC mice. We conclude that the BHMT pathway is a major route for the elimination of Hcy in mice and that the MS pathway has little excess capacity to methylate the Hcy that accumulates when the BHMT pathway is blocked. PMID- 23014493 TI - Maternal serum ferritin concentration is positively associated with newborn iron stores in women with low ferritin status in late pregnancy. AB - Iron deficiency (ID) is common in pregnant women and infants, particularly in developing countries. The relation between maternal and neonatal iron status remains unclear. This study considered the issue in a large sample of mother newborn pairs in rural southeastern China. Hemoglobin (Hb) and serum ferritin (SF) were measured in 3702 pregnant women at >=37 wk gestation and in cord blood of their infants born at term (37-42 wk gestation). Maternal anemia (Hb <110 g/L) was present in 27.5% and associated with maternal SF <20 MUg/L in 86.9%. Only 5.6% of neonates were anemic (Hb <130 g/L) and 9.5% had cord-blood SF <75 MUg/L. There were low-order correlations between maternal and newborn iron measures (r = 0.07-0.10 for both Hb and SF; P <= 0.0001 due to the large number). We excluded 430 neonates with suggestion of inflammation [cord SF >370 MUg/L, n = 208 and/or C-reactive protein (CRP) >5 mg/L, n = 233]. Piecewise linear regression analyses identified a threshold for maternal SF at which cord-blood SF was affected. For maternal SF below the threshold of 13.6 MUg/L (beta = 2.4; P = 0.001), cord SF was 0.17 SD lower than in neonates whose mothers had SF above the threshold (167 +/- 75 vs. 179 +/- 80 MUg/L). The study confirmed that ID anemia remains common during pregnancy in rural southeastern China. Despite widespread maternal ID, however, iron nutrition seemed to meet fetal needs except when mothers were very iron deficient. The impact of somewhat lower cord SF on iron status later in infancy warrants further study. PMID- 23014494 TI - High prevalence of vitamin A deficiency is detected by the modified relative dose response test in six-month-old Senegalese breast-fed infants. AB - To alleviate vitamin A (VA) deficiency (VAD) in Senegal, understanding the relationship between VA status of lactating women and their 6-mo-old infants is important. This study measured 6-mo-old infants' VA intake from human milk and assessed the VA status of mothers and infants. A comprehensive study was undertaken in 34 mother-infant pairs. Nonpregnant lactating women and their infants were included. None of the infants had received a VA supplement. Mothers were grouped as supplemented with 2 doses of 200,000 iu (60,000 MUg; 210 MUmol) retinol as retinyl palmitate (n = 13) or nonsupplemented (n = 19) after delivery. Breast milk intake was measured by the deuterium dilution technique. Plasma and breast milk retinol concentrations were measured by HPLC. Infants' VA liver stores were assessed by the modified relative dose-response (MRDR) test. Plasma retinol detected 15% VAD among infants and the MRDR test (>=0.06) indicated 73.5% with low VA liver stores. Infants' milk VA intakes were close to estimated requirements (375 MUg/d). No correlation was found between infants' plasma retinol and MRDR value. Infants' MRDR value was lower in the group from supplemented mothers (0.055 +/- 0.017 vs. 0.073 +/- 0.017; P = 0.009), but no difference was observed between plasma retinol concentrations of both groups of mothers; 8.8% of mothers were VA deficient based on plasma retinol (<=0.7 MUmol/L). Low VA liver stores were prevalent among Senegalese infants at the beginning of the complementary feeding period. Postpartum VA-supplemented mothers significantly enhanced their infants' VA liver stores. PMID- 23014495 TI - Fish oil enhances intestinal integrity and inhibits TLR4 and NOD2 signaling pathways in weaned pigs after LPS challenge. AB - Long-chain (n-3) PUFA exert beneficial effects on inflammatory bowel diseases in animal models and clinical trials. In addition, pattern recognition receptors such as toll-like receptors (TLR) and nucleotide-binding oligomerization domain proteins (NOD) play a critical role in intestinal inflammation. We hypothesized that fish oil could alleviate Escherichia coli LPS-induced intestinal injury via modulation of TLR4 and NOD signaling pathways. Twenty-four weaned piglets were used in a 2 * 2 factorial design and the main factors included a dietary treatment (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline). After feeding fish oil or corn oil diets for 21 d, pigs were injected with LPS or saline. At 4 h postinjection, blood samples were collected and pigs were killed. EPA, DHA, and total (n-3) PUFA were enriched in intestinal mucosa through fish supplementation. Fish oil improved intestinal morphology, indicated by greater villus height and villus height:crypt depth ratio, and intestinal barrier function, indicated by decreased plasma diamine oxidase (DAO) activity and increased mucosal DAO activity as well as enhanced protein expression of intestinal tight junction proteins including occludin and claudin-1. Moreover, fish oil decreased intestinal TNFalpha and PGE(2) concentrations and caspase-3 and heat shock protein 70 protein expression. Finally, fish oil downregulated the mRNA expression of intestinal TLR4 and its downstream signals myeloid differentiation factor 88, IL-1 receptor-associated kinase 1, TNFalpha receptor associated factor 6, and NOD2, and its adaptor molecule, receptor-interacting serine/threonine-protein kinase 2. Fish oil decreased the protein expression of intestinal NFkappaB p65. These results indicate that fish oil supplementation is associated with inhibition of TLR4 and NOD2 signaling pathways and concomitant improvement of intestinal integrity under an inflammatory condition. PMID- 23014498 TI - Recent updates in redox regulation and free radical scavenging effects by herbal products in experimental models of Parkinson's disease. AB - Parkinson's disease (PD) is a complex multifactorial disease marked by extensive neuropathology in the brain with selective yet prominent and progressive loss of mid-brain dopaminergic neurons. The etiological factors involved in the development of PD are still elusive, but oxidative stress arising when reactive oxygen species (ROS) exceed amounts required for normal redox signaling is considered one of the major factors. ROS cause oxidative damage to proteins, lipids, and DNA and are one of the most prominent factors related to neurodegeneration. Pre-clinical and clinical studies clearly demonstrate the effectiveness of oxidative stress in the pathogenesis of PD. Therefore, regulation of redox signaling and inhibiting excess ROS would contribute greatly not only to extend longevity but also to ameliorate the progression of dopaminergic cell death seen in patients with PD. Several herbal products are beneficial for maintaining nerve cell function and for treating various neurodegenerative disorders by reducing oxidative stress. Here, we summarize the recent knowledge concerning promising herbs that have shown significant beneficial effects based on regulation of redox status and ROS inhibition in toxin-induced PD models. PMID- 23014496 TI - Maternal PUFA status but not prenatal methylmercury exposure is associated with children's language functions at age five years in the Seychelles. AB - Evidence from the Seychelles Child Development Nutrition Study suggests that maternal nutritional status can modulate the relationship between prenatal methylmercury (MeHg) exposure and developmental outcomes in children. The aim of this study was to investigate whether maternal PUFA status was a confounding factor in any possible associations between prenatal MeHg exposure and developmental outcomes at 5 y of age in the Republic of Seychelles. Maternal status of (n-3) and (n-6) PUFA were measured in serum collected at 28 wk gestation and delivery. Prenatal MeHg exposure was determined in maternal hair collected at delivery. At 5 y of age, the children completed a comprehensive range of sensitive developmental assessments. Complete data from 225 mothers and their children were available for analysis. Multiple linear regression analyses revealed Preschool Language Scale scores of the children improved with increasing maternal serum DHA [22:6(n-3)] concentrations and decreased with increasing arachidonic acid [20:4(n-6)] concentrations, albeit verbal intelligence improved with increasing (n-6) PUFA concentrations in maternal serum. There were no adverse associations between MeHg exposure and developmental outcomes. These findings suggest that higher fish consumption, resulting in higher maternal (n-3) PUFA status, during pregnancy is associated with beneficial developmental effects rather than detrimental effects resulting from the higher concomitant exposures of the fetus to MeHg. The association of maternal (n-3) PUFA status with improved child language development may partially explain the authors' previous finding of improving language scores, as prenatal MeHg exposure increased in an earlier mother-child cohort in the Seychelles where maternal PUFA status was not measured. PMID- 23014499 TI - Effects of cultivar and process variables on dynamic-mechanical and sensorial behavior of value-added grape-based smoothies. AB - The effects of either cooking temperature (45, 80, and 100 degrees C) or inclusion of seed particles on the dynamic-mechanical and sensorial properties of value-added Crimson seedless, Black Pearl, or Baresana grape-based smoothies were studied. The inclusion of seed particles resulted in significant increases of the phenolic content, both in Black Pearl and Baresana, but it did not affect in a negative way the sensorial characteristics of smoothies whereas it caused an increase of the viscoelastic behavior of Black Pearl and a slight decrease in Baresana grape-based smoothies. In particular, the investigated rheological parameters were the loss and storage modulus. Moreover, the loss tangent value (the ratio between loss and storage modulus) remained unchanged, indicating a pseudoplastic behavior of all samples, independent on the process conditions. The smoothies produced from Crimson grapes at the intermediate temperature (80 degrees C) showed sensorial and rheological characteristics similar to those manufactured at 45 degrees C and better than those manufactured at 100 degrees C. PMID- 23014500 TI - Recombinant VAA-I from Viscum album induces apoptotic cell death of hepatocellular carcinoma SMMC7721 cells. AB - Researchers have proposed that VAA-I, a specific plant lectin found in Viscum album, has therapeutic effects on cancer and autoimmune diseases. VAA-I has shown some promising treatment results in some types of tumor cell lines, especially SMMC-7721 cells (human hepatocellular carcinoma cells). However, few details are known about the mechanism and process of cell death induced by VAA-I in tumor cells. In this study, the cell morphology results showed that SMMC-7721 cells treated with VAA-I exhibited several features typical of apoptotic cell death, which was confirmed by the Caspase inhibition assay. Fluo-3-acetoxymethyl ester (AM) fluorescence imaging techniques showed that rVAA-I significantly elevated the intracellular calcium level ([Ca2+]i) in SMMC-7721 cells. These findings suggest that apoptosis may play the most important role in SMMC-7721 cell death induced by rVAA-I. Finally, in the SMMC-7721 cells treated with rVAA-I, a series of genes in the p38 mitogen-activated protein kinase (MAPK) signaling pathway were expressed differentially, and further found that PI 3-kinase pathway is involved in rVAA-I signal transduction in SMMC-7721 cells. PMID- 23014502 TI - Long-term stability and risk assessment of lead in mill waste treated by soluble phosphate. AB - In an effort to address public concerns of the long-term stability and ecological risk reduction of phosphate (P)-stabilized lead (Pb) in mine wastes, mill tailings located at the Jasper County Superfund Site of southwest Missouri, containing ~4000 mg Pb kg(-1), were treated in situ by phosphoric acid at three rates: 0; 7.5; and 10.0 g P kg(-1) soil. Field experiment consisted of 2- by 4-m plots arranged in a randomized complete block design with four replicates of each P level. Soil and plant samples were collected at a 3-month interval during five to six (5-6) years post treatments and analyzed for Pb bioaccessibility and leachability, microbial toxicity, Pb chemical fraction, and elemental composition of Pb solids, and Pb concentration in plant tissue. Results indicated that the P treatments significantly reduced bioaccessible and leachable Pb in the mill waste, and the reductions were maintained during the sampling period. Lead concentration in plant tissue was positively related to the Pb bioaccessibility. There was no significant toxicological effect of the treatments on soil microbial community. The treatment using 10 g P kg(-1) appeared to be most effective for overall risk reduction. The Pb stabilization and risk reduction by the P treatments were accomplished by the induced transformation of labile Pb species to relatively insoluble forms, probably pyromorphite-like minerals. This study illustrated that in situ Pb stabilization by soluble phosphate would be long-term and ecologically-safe, which could safeguard human health and ecosystem from Pb contamination in mining areas. PMID- 23014503 TI - Spin-splitting calculation for zincblende semiconductors using an atomic bond orbital model. AB - We develop a 16-band atomic bond-orbital model (16ABOM) to compute the spin splitting induced by bulk inversion asymmetry in zincblende materials. This model is derived from the linear combination of atomic-orbital (LCAO) scheme such that the characteristics of the real atomic orbitals can be preserved to calculate the spin splitting. The Hamiltonian of 16ABOM is based on a similarity transformation performed on the nearest-neighbor LCAO Hamiltonian with a second-order Taylor expansion k at the Gamma point. The spin-splitting energies in bulk zincblende semiconductors, GaAs and InSb, are calculated, and the results agree with the LCAO and first-principles calculations. However, we find that the spin-orbit coupling between bonding and antibonding p-like states, evaluated by the 16ABOM, dominates the spin splitting of the lowest conduction bands in the zincblende materials. PMID- 23014515 TI - Mesoporous nanomagnet supercaptors for selective heme-proteins from human cells. AB - Nanomagnet-selective supercaptors of heme-proteins (iron-porphyrin prosthetic group) based on mesoporous NiO and Fe(3)O(4) NPs were fabricated. PMID- 23014505 TI - Gastroprotective effect and structure of a rhamnogalacturonan from Acmella oleracea. AB - The plant Acmella oleracea (L.) R.K.Jansen (Asteraceae), locally known as jambu, is widely used in Legal Amazon in local dishes and in folk medicine. A polysaccharide (SC) was isolated from this plant, following aqueous extraction, which contained uronic acid, galactose, arabinose, rhamnose, and glucose in a 15:2:1:1:0.5 molar ratio and had a M(w) 226,000 g/mol. Methylation analysis and NMR spectroscopy indicated that SC is a rhamnogalacturonan composed of a long chain of ->4)-6-OMe-alpha-D-GalpA-(1->, interspersed with some alpha-L-Rhap residues, partly substituted by side-chains of type II arabinogalactans. SC significantly inhibited ethanol-induced gastric ulcers in rats with an ED50 of 1.5 mg/kg, indicating that SC acts as gastroprotective agent. PMID- 23014516 TI - Antiretroviral therapy, labor productivity, and sex: a longitudinal cohort study of tea pluckers in Kenya. AB - OBJECTIVE: To estimate the impact of antiretroviral therapy (ART) on labor productivity and income using detailed employment data from two large tea plantations in western Kenya for HIV-infected tea pluckers who initiated ART. DESIGN: Longitudinal study using primary data on key employment outcomes for a group of HIV-infected workers receiving antiretroviral therapy (ART) and workers in the general workforce. METHODS: We used nearest-neighbor matching methods to estimate the impacts of HIV/AIDS and ART among 237 HIV-positive pluckers on ART (index group) over a 4-year period (2 years pre-ART and post-ART) on 4 monthly employment outcomes - days plucking tea, total kilograms (kgs) harvested, total days working, and total labor income. Outcomes for the index group were compared with those for a matched reference group from the general workforce. RESULTS: We observed a rapid deterioration in all four outcomes for HIV-infected individuals in the period before ART initiation and then a rapid improvement after treatment initiation. By 18-24 months after treatment initiation, the index group harvested 8% (men) and 19% (women) less tea than reference individuals. The index group earned 6% (men) and 9% (women) less income from labor than reference individuals. Women's income would have dropped further if they had not been able to offset their decline in tea plucking by spending more time on nonplucking assignments. CONCLUSION: HIV-infected workers experienced long-term income reductions before and after initiating ART. The implications of such long-term impacts in low income countries have not been adequately addressed. PMID- 23014517 TI - Cost and outcomes of paediatric antiretroviral treatment in South Africa. AB - OBJECTIVE: Little is known about the cost of paediatric antiretroviral treatment (ART) in low-income and middle-income countries. We analysed the average cost of providing paediatric ART in South Africa during the first 2 years after ART initiation, stratified by patient outcomes. METHODS: We collected data on outpatient resource use and treatment outcomes of 288 children in two Johannesburg public clinics, Empilweni Services and Research Unit (ESRU) and Harriet Shezi Children's Clinic (HSCC) from 2005 to 2009. Patient-level resource use was estimated from patient records. Unit cost data came from site accounts and public-sector sources. Patient outcomes at month 12 and 24 after initiation were defined based on patients' weight CD4 cell counts/percentages, viral loads, and the presence of new WHO stage 3/4 conditions. RESULTS: Median age/CD4 percentage at initiation was 4.03 years/12.40% in ESRU and 5.84 years/14.05% in HSCC, respectively. Sixty-two and 91% of patients remained in care and responding to treatment at month 12 in ESRU and HSCC, respectively, and 68 and 80% at month 24. The average cost per patient in care and responding was US$ 830 in year 1 and US$ 717 in year 2 in ESRU and US$ 678 and US$ 782 in HSCC. Antiretroviral drugs comprised 33-52% of total cost, clinic visits 23-31%, lab tests 12-16%, and fixed costs 8-18%. CONCLUSIONS: Costs varied between the two clinics but were comparable with those of adult ART. Few very young children accessed ART in either clinic and those who did were already very ill, emphasizing the importance of early infant treatment. PMID- 23014518 TI - No impact of rifamycin selection on tuberculosis treatment outcome in HIV coinfected patients. AB - Rifabutin has been substituted for rifampicin when treating tuberculosis (TB)/HIV coinfection. However, despite reports of anti-TB treatment failure and acquired rifamycin resistance, long-term clinical outcome data are lacking. Observational analyses performed in a UK TB/HIV cohort demonstrated no difference in severe adverse events, anti-TB treatment completion, relapse frequency or subsequent rifamycin resistance when rifampicin and rifabutin were compared, using different combinations of antiretroviral therapy. Our data support the wider use of rifabutin in TB/HIV coinfection. PMID- 23014520 TI - Non-AIDS-defining hematological malignancies in HIV-infected patients: an epidemiological study in Japan. AB - OBJECTIVE: To clarify the incidence and clinical outcomes of non-AIDS-defining hematological malignancies (NADHMs), excluding non-Hodgkin's lymphomas, in HIV infected patients. DESIGN: A nationwide epidemiological study was conducted to evaluate the incidence and clinical outcomes of NADHMs. METHODS: Questionnaires were sent to 429 regional AIDS centers and 497 educational hospitals certified by the Japanese Society of Hematology. Data from 511 institutes were obtained. RESULTS: From 1991 to 2010, 47 patients with NADHMs were detected (median age, 42.0 years; male, 93.6%). The median CD4-positive T-cell count was 255/MUl, and the median duration from the diagnosis of HIV infection to development of hematological malignancy was 28.0 months. Most patients with acute leukemia were treated with standard induction chemotherapy. Complete remission rates and median overall survival periods for acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL) were 70.0 and 85.7% and 13 and 16 months, respectively. Three of four patients with chronic-phase chronic myeloid leukemia (CML-CP) were well controlled with imatinib. Five patients (2 AML, 1 ALL, 1 accelerated-phase CML, and 1 myeloma) were treated with autologous or allogeneic stem-cell transplantation. Comparison of patients over the two periods (1991-2000 and 2001-2009) revealed a 4.5-fold increase in the incidence of hematological malignancies. CONCLUSION: The incidence of NADHMs has increased in the past decade. The prognosis of these patients was similar to that of HIV-negative patients; therefore, standard chemotherapy may be a feasible treatment option for HIV-infected patients with hematological malignancies. PMID- 23014519 TI - Modelling the global competing risks of a potential interaction between injectable hormonal contraception and HIV risk. AB - BACKGROUND: Some, but not all, observational studies have suggested an increase in the risk of HIV acquisition for women using injectable hormonal contraception (IHC). METHODS: We used country-level data to explore the effects of reducing IHC use on the number of HIV infections, the number of live births and the resulting net consequences on AIDS deaths and maternal mortality for each country. RESULTS: High IHC use coincides with high HIV incidence primarily in southern and eastern Africa. If IHC increases the risk of HIV acquisition, this could generate 27 000 130 000 infections per year globally, 87-88% of which occur in this region. Reducing IHC use could result in fewer HIV infections but also a substantial increase in live births and maternal mortality in countries with high IHC use, high birth rates and high maternal mortality: mainly southern and eastern Africa, South-East Asia, and Central and South America. For most countries, the net impact of reducing IHC use on maternal and AIDS-related deaths is dependent on the magnitude of the assumed IHC-HIV interaction. CONCLUSIONS: If IHC use increases HIV acquisition risk, reducing IHC could reduce new HIV infections; however, this must be balanced against other important consequences, including unintended pregnancy, which impacts maternal and infant mortality. Unless the true effect size approaches a relative risk of 2.19, it is unlikely that reductions in IHC could result in public health benefit, with the possible exception of those countries in southern Africa with the largest HIV epidemics. PMID- 23014521 TI - Concurrent measures of total and integrated HIV DNA monitor reservoirs and ongoing replication in eradication trials. AB - OBJECTIVES: Interest in targeting HIV reservoirs is fueling trials that may decrease reservoir size and/or induce viral replication. Therefore, we aimed to develop strategies to sensitively measure changes in these parameters in patients on and off antiretroviral therapy (ART). Achieving these goals may help evaluate the effects of future clinical trials. DESIGN: To determine the relationship between measurements of total and integrated HIV DNA and their role as markers of reservoir size and ongoing replication, these parameters were measured during the first year of ART, during long-term effective ART, and during a clinical trial aimed at targeting reservoirs. METHODS: Total and integrated HIV DNA were measured in patient samples using quantitative PCR techniques. CD4(+)T cell counts and plasma viremia were also monitored. RESULTS: Unintegrated HIV DNA became undetectable during the first year of ART. Total and integrated HIV DNA levels were generally equal in well controlled patients on ART, and low-level plasma viremia correlated best with integration measures. Finally, patients who controlled plasma viremia (<400 copies/ml) during interferon-alpha monotherapy exhibited a decrease in the level of integrated but not total HIV DNA and a rise in the ratio of total to integrated HIV DNA over time. CONCLUSION: Our findings suggest that appearance of unintegrated HIV DNA reflects residual HIV expression and de-novo reverse transcription, providing insight into the mechanism by which interferon-alpha reduces the HIV reservoir. We conclude that concurrent measurements of total and integrated HIV DNA provide information regarding reservoir size and ongoing replication in trials targeting HIV. PMID- 23014522 TI - Solution-processed vanadium oxide as a hole collection layer on an ITO electrode for high-performance polymer solar cells. AB - A solution-processed vanadium oxide (s-VO(x)) anode buffer layer on an indium-tin oxide (ITO) electrode was used instead of PEDOT:PSS for improving the stability and photovoltaic performance of the polymer solar cells (PSCs). The s-VO(x) layer was prepared by spin-coating a vanadyl acetylacetonate (VO(acac)(2)) isopropyl alcohol solution on the ITO electrode and then thermal annealing at 150 degrees C for 10 min. The s-VO(x) oxide layer is highly transparent in the visible range and shows effective hole collection property. The photovoltaic performance of the s-VO(x) buffer layer was studied by fabricating the PSCs based on poly(3 hexylthiophene) (P3HT) as an electron donor and four soluble fullerene derivatives, [6,6]-phenyl-C(61)-butyric acid methyl ester (PC(60)BM), [6,6] phenyl-C(71)-butyric acid methyl ester (PC(70)BM), indene-C(60) bisadduct (IC(60)BA), and indene-C(70) bisadduct (IC(70)BA), as electron acceptors. The PSCs with the s-VO(x) buffer layer show improved performance in comparison with the traditional devices with the PEDOT:PSS buffer layer on ITO, no matter which fullerene derivative was used as an acceptor. The power conversion efficiency of the PSC based on P3HT:IC(70)BA (1 : 1, w/w) with the s-VO(x) anode buffer layer reached 6.35% under the illumination of AM1.5G 100 mW cm(-2). PMID- 23014523 TI - Loss of heterozygosity at tumor suppressor genes detectable on fractionated circulating cell-free tumor DNA as indicator of breast cancer progression. AB - PURPOSE: LOH on circulating DNA may provide tumor-specific information on breast cancer. As identification of LOH on cell-free DNA is impeded by the prevalence of wild type DNA in blood of cancer patients, we fractionated plasma DNA, and determined the diagnostic and prognostic value of both fractions. EXPERIMENTAL DESIGN: Our cohort of 388 patients with primary breast cancer before chemotherapy was selected from a multicenter study (SUCCESS). Postoperative plasma was fractionated in low- and high-molecular weight DNA by two different column systems. In both fractions, LOH was determined by a PCR-based microsatellite analysis using a panel of 8 polymorphic markers. Circulating tumor DNA in plasma from 30 patients after chemotherapy was additionally analyzed. The significance levels were adjusted for multiple comparisons. RESULTS: More patients (38%) had LOH at all markers in the fraction containing short DNA fragments than in the fraction containing the long DNA molecules (28%, P = 0.0001). In both fractions 32.85% of LOH were concordant. LOH at the markers D3S1605, D10S1765, D12S1725, D13S218, and D17S855 significantly correlated with tumor stage, tumor size, and lymph node metastasis, positive progesterone, and HER2 receptor status. Most importantly, LOH at D12S1725 mapping to cyclin D2 correlated with shorter overall survival (P = 0.004). CONCLUSIONS: The improved detection of LOH on cell-free DNA provides important information on DNA losses of tumor suppressor genes TIG1, PTEN, cyclin D2, RB1, and BRCA1 in breast cancer. In particular, loss of the cyclin D2 gene might become an important prognostic marker easily detectable in the peripheral blood. PMID- 23014524 TI - Challenges in the enumeration and phenotyping of CTC. AB - PURPOSE: Presence of circulating tumor cells (CTC) in metastatic carcinoma is associated with poor survival. Phenotyping and genotyping of CTC may permit "real time" treatment decisions, provided CTCs are available for examination. Here, we investigate what is needed to detect CTC in all patients. EXPERIMENTAL DESIGN: CTCs enumerated in 7.5 mL of blood together with survival from 836 patients with metastatic breast, colorectal, and prostate cancer were used to predict the CTC concentration in the 42% of these patients in whom no CTCs were found and to establish the relation of concentration of CTCs with survival. Influence of different CTC definitions were investigated by automated cell recognition and a flow cytometric assay without an enrichment or permeabilization step. RESULTS: A log-logistic regression of the log of CTC yielded a good fit to the CTC frequency distribution. Extrapolation of the blood volume to 5 L predicted that 99% of patients had at least one CTC before therapy initiation. Survival of patients with EpCAM+, cytokeratin+, CD45- nucleated CTCs is reduced by 6.6 months for each 10-fold CTC increase. Using flow cytometry, the potential three-fold recovery improvement is not sufficient to detect CTC in all patients in 7.5 mL of blood. CONCLUSIONS: EpCAM+, cytokeratin+, CD45- nucleated CTCs are present in all patients with metastatic breast, prostate, and colorectal cancer and their frequency is proportional to survival. To serve as a liquid biopsy for the majority of patients, a substantial improvement of CTC yield is needed, which can only be achieved by a dramatic increase in sample volume. PMID- 23014525 TI - Decreased NK cells in patients with head and neck cancer determined in archival DNA. AB - PURPOSE: Natural killer (NK) cells are a key element of the innate immune system implicated in human cancer. To examine NK cell levels in archived bloods from a study of human head and neck squamous cell carcinoma (HNSCC), a new DNA-based quantification method was developed. EXPERIMENTAL DESIGN: NK cell-specific DNA methylation was identified by analyzing DNA methylation and mRNA array data from purified blood leukocyte subtypes (NK, T, B, monocytes, granulocytes), and confirmed via pyrosequencing and quantitative methylation specific PCR (qMSP). NK cell levels in archived whole blood DNA from 122 HNSCC patients and 122 controls were assessed by qMSP. RESULTS: Pyrosequencing and qMSP confirmed that a demethylated DNA region in NKp46 distinguishes NK cells from other leukocytes, and serves as a quantitative NK cell marker. Demethylation of NKp46 was significantly lower in HNSCC patient bloods compared with controls (P < 0.001). Individuals in the lowest NK tertile had over 5-fold risk of being a HNSCC case, controlling for age, gender, HPV16 status, cigarette smoking, alcohol consumption, and BMI (OR = 5.6, 95% CI, 2.0 to 17.4). Cases did not show differences in NKp46 demethylation based on tumor site or stage. CONCLUSIONS: The results of this study indicate a significant depression in NK cells in HNSCC patients that is unrelated to exposures associated with the disease. DNA methylation biomarkers of NK cells represent an alternative to conventional flow cytometry that can be applied in a wide variety of clinical and epidemiologic settings including archival blood specimens. PMID- 23014526 TI - Measurement of tumor VEGF-A levels with 89Zr-bevacizumab PET as an early biomarker for the antiangiogenic effect of everolimus treatment in an ovarian cancer xenograft model. AB - PURPOSE: The mTOR pathway is frequently activated in ovarian cancers. mTOR inhibitors, such as everolimus, can reduce VEGF-A production by cancer cells. We investigated whether early everolimus treatment effects could be monitored by positron emission tomography (PET) with (89)Zr-bevacizumab. EXPERIMENTAL DESIGN: The effect of everolimus on VEGF-A secretion was determined in a panel of human ovarian cancer cell lines and in A2780(luc+) ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily 10 mg/kg everolimus intraperitoneally (i.p.) for 14 days. PET scans with the tracer (89)Zr-labeled bevacizumab were conducted before and after treatment. Ex vivo (89)Zr-bevacizumab biodistribution and correlative tissue analyses were conducted. Tumor VEGF-A levels were measured with ELISA and mean vascular density (MVD) was determined with immunohistochemistry. RESULTS: Everolimus treatment reduced VEGF-A levels in the supernatant of all cell lines. Everolimus lowered (89)Zr-bevacizumab tumor uptake by 21.7% +/- 4.0% [mean standardized uptake value (SUV(mean)) 2.3 +/- 0.2 vs. 2.9 +/- 0.2, P < 0.01]. Ex vivo biodistribution also showed lower tracer uptake in the tumors of treated as compared with control animals (7.8 +/- 0.8%ID/g vs. 14.0 +/- 1.7%ID/g, P < 0.01), whereas no differences were observed for other tissues. This coincided with lower VEGF-A protein levels in tumor lysates in treated versus untreated tumors (P = 0.04) and reduced MVD (P < 0.01). CONCLUSION: Tumor VEGF-A levels are decreased by everolimus. (89)Zr-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy. PMID- 23014527 TI - Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. AB - PURPOSE: The molecular epidemiology of most EGFR and KRAS mutations in lung cancer remains unclear. EXPERIMENTAL DESIGN: We genotyped 3,026 lung adenocarcinomas for the major EGFR (exon 19 deletions and L858R) and KRAS (G12, G13) mutations and examined correlations with demographic, clinical, and smoking history data. RESULTS: EGFR mutations were found in 43% of never smokers and in 11% of smokers. KRAS mutations occurred in 34% of smokers and in 6% of never smokers. In patients with smoking histories up to 10 pack-years, EGFR predominated over KRAS. Among former smokers with lung cancer, multivariate analysis showed that, independent of pack-years, increasing smoking-free years raise the likelihood of EGFR mutation. Never smokers were more likely than smokers to have KRAS G > A transition mutation (mostly G12D; 58% vs. 20%, P = 0.0001). KRAS G12C, the most common G > T transversion mutation in smokers, was more frequent in women (P = 0.007) and these women were younger than men with the same mutation (median 65 vs. 69, P = 0.0008) and had smoked less. CONCLUSIONS: The distinct types of KRAS mutations in smokers versus never smokers suggest that most KRAS-mutant lung cancers in never smokers are not due to second-hand smoke exposure. The higher frequency of KRAS G12C in women, their younger age, and lesser smoking history together support a heightened susceptibility to tobacco carcinogens. PMID- 23014528 TI - Using pharmacokinetic and pharmacodynamic data in early decision making regarding drug development: a phase I clinical trial evaluating tyrosine kinase inhibitor, AEE788. AB - PURPOSE: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and VEGFR-2, a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients. EXPERIMENTAL DESIGN: Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues. RESULTS: Overall, 111 patients were treated (25 to 550 mg/day). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC(50)) for EGFR in skin (0.033 MUmol/L) and tumor (0.0125 MUmol/L) were similar to IC(50) in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at <= MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses <= MTD. A total of 16 of 96 evaluable patients showed a >10% shrinkage of tumor size; one partial response was observed. CONCLUSION: Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development. PMID- 23014529 TI - TRAIL and Noxa are selectively upregulated in prostate cancer cells downstream of the RIG-I/MAVS signaling pathway by nonreplicating Sendai virus particles. AB - PURPOSE: The treatment of cancer with oncolytic viruses primarily depends on the selective viral replication in cancer cells. However, a replication-incompetent hemagglutinating virus of Japan (HVJ; Sendai virus) envelope (HVJ-E) suppresses the growth of human cancer cells as effectively as replication-competent live HVJ without producing toxic effects in nonmalignant cells. Here, we analyze the molecular mechanism of the oncolytic activity of HVJ-E. EXPERIMENTAL DESIGN: The molecules responsible for HVJ-E-induced cancer cell death were elucidated in prostate cancer cell lines, and the effect of HVJ-E on orthotopic prostate cancers was evaluated in nonobese diabetic-severe combined immunodeficient (NOD SCID) mice. RESULTS: The liposome-mediated transfer of viral RNA genome fragments from HVJ-E suppressed the viability of prostate cancer cells but not the viability of the noncancerous prostate epithelium. Knockdown experiments using siRNAs showed that the cancer cell-selective killing induced by HVJ-E was mediated by retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). Downstream of the RIG-I/MAVS pathway, both TNF-related apoptosis-inducing ligand (TRAIL) and Noxa were upregulated by HVJ-E in the castration-resistant prostate cancer cell line PC3 but not in the noncancerous prostate epithelial cell line PNT2. TRAIL siRNA but not Noxa siRNA significantly inhibited HVJ-E-induced cell death in PC3 cells. However, Noxa siRNA effectively suppressed HVJ-E-induced cell death in DU145 cells, another castration-resistant prostate cancer cell line, in which Noxa but not TRAIL was upregulated by HVJ-E. Furthermore, the orthotopic prostate cancers were dramatically eradicated in immunodeficient mice injected with HVJ-E. CONCLUSION: The RIG-I/MAVS signaling pathway represents an attractive target for cancer therapy. PMID- 23014530 TI - Outcomes of phase II clinical trials with single-agent therapies in advanced/metastatic non-small cell lung cancer published between 2000 and 2009. AB - PURPOSE: We analyzed the outcomes of single-agent phase II clinical trials in non small cell lung cancer (NSCLC) to determine trial parameters that predicted clinical activity. EXPERIMENTAL DESIGN: Data on response rate (RR), progression free survival (PFS), and overall survival (OS) from all English language, single agent phase II trials in advanced/metastatic NSCLC indexed by PubMed (January 2000 through December 2009) were abstracted. RESULTS: A total of 143 single-agent phase II trials (7,701 patients) were identified. The median RR was 10%, PFS 2.8 months, and OS 7.6 months. RR and PFS correlated with OS (r = 0.46, P < 0.001, r = 0.52, P < 0.001, respectively) and RR correlated with PFS (r = 0.61, P < 0.001). Treatment arms enriched for patients with molecular targets had a higher median RR (48.8% vs. 9.7%, P = 0.005), longer median PFS (6 vs. 2.8 months, P = 0.005), and OS (11.3 vs. 7.5 months, P = 0.05) as compared with those of unselected patients. In multivariate analysis, only studies enriched for patients with molecular targets or including drugs that eventually gained FDA/EMA approval were associated with a higher RR, and longer PFS/OS. CONCLUSIONS: In phase II trials in NSCLC, RR and PFS correlated with OS. Studies enriched for patients with putative molecular drug targets were associated with higher therapeutic benefit as compared with those of unselected populations. PMID- 23014531 TI - Antibody-dependent cell-mediated cytotoxicity overcomes NK cell resistance in MLL rearranged leukemia expressing inhibitory KIR ligands but not activating ligands. AB - PURPOSE: Leukemias with MLL gene rearrangement are associated with a poor prognosis. Natural killer (NK) cell therapy is a potential treatment, but leukemia cells may be resistant. Here, we sought to determine the susceptibility of MLL-rearranged leukemia cells to NK cell lysis and to develop a novel immunotherapeutic approach to optimize NK cell therapy, including the use of an antibody against leukemia-associated antigen and the elimination of killer-cell immunoglobulin-like receptor (KIR)-mediated inhibition. EXPERIMENTAL DESIGN: Three MLL-rearranged leukemia cell lines (RS4;11, SEM, and MV4-11) and primary leukemia blasts were assessed for surface phenotype and susceptibility to NK cell lysis with or without antibodies against CD19 (XmAb5574), CD33 (lintuzumab), or KIR ligands. RESULTS: All three cell lines were resistant to NK cell lysis, had some inhibitory KIR ligands and protease inhibitor-9, and expressed low levels of NKG2D activating ligands and adhesion molecules. After treatment with XmAb5574 or lintuzumab, MLL-rearranged leukemia cells were efficiently killed by NK cells. The addition of pan-major histocompatibility complex class I antibody, which blocked inhibitory KIR-HLA interaction, further augmented degranulation in all three KIR2DL1, KIR2DL2/3, and KIR3DL1 subsets of NK cells based on the rule of missing-self recognition. A mouse model showed a decreased rate of leukemia progression in vivo as monitored by bioluminescence imaging and longer survival after antibody treatment. CONCLUSION: Our data support the use of a triple immunotherapy approach, including an antibody directed against tumor-associated antigen, KIR-mismatched NK cell transplantation, and inhibitory KIR blockade, for the treatment of NK cell-resistant MLL-rearranged leukemias. PMID- 23014532 TI - Inhibition of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells by quorum sensing autoinducer-mimics. AB - Pseudomonas aeruginosa is a notorious human pathogen associated with a range of life-threatening nosocomial infections. There is an increasing problem of antibiotic resistance in P. aeruginosa, highlighted by the emergence of multi drug resistant strains. Thus the exploration of new strategies for the treatment of P. aeruginosa infections is clearly warranted. P. aeruginosa is known to produce a range of virulence factors that enhance its ability to damage the host tissue and cause disease. One of the most important virulence factors is pyocyanin. P. aeruginosa regulates pyocyanin production using an intercellular communication mechanism called quorum sensing, which is mediated by small signalling molecules termed autoinducers. One native autoinducer is N-(3 oxododecanoyl)-L-homoserine lactone (OdDHL). Herein we report the synthesis of a collection of abiotic OdDHL-mimics. A number of novel compounds capable of competing with the endogenous OdDHL and consequently, inhibiting the production of pyocyanin in cultures of wild type P. aeruginosa were identified. We present evidence suggesting that compounds of this general structural type act as direct antagonists of quorum sensing in P. aeruginosa and as such may find value as molecular tools for the study and manipulation of this signalling pathway. A direct quantitative comparison of the pyocyanin suppressive activities of the most active OdDHL-mimics with some previously-reported inhibitors (based around different general structural frameworks) of quorum sensing from the literature, was also made. PMID- 23014564 TI - A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia. AB - Gain-of-function mutations in fibroblast growth factor receptor-3 (FGFR3) lead to several types of human skeletal dysplasia syndromes including achondroplasia, hypochondroplasia and thanatophoric dysplasia (TD). Currently, there are no effective treatments for these skeletal dysplasia diseases. In this study, we screened, using FGFR3 as a bait, a random 12-peptide phage library and obtained 23 positive clones that share identical amino acid sequences (VSPPLTLGQLLS), named as peptide P3. This peptide had high binding specificity to the extracellular domain of FGFR3. P3 inhibited tyrosine kinase activity of FGFR3 and its typical downstream molecules, extracellular signal-regulated kinase/mitogen activated protein kinase. P3 also promoted proliferation and chondrogenic differentiation of cultured ATDC5 chondrogenic cells. In addition, P3 alleviated the bone growth retardation in bone rudiments from mice mimicking human thanatophoric dysplasia type II (TDII). Finally, P3 reversed the neonatal lethality of TDII mice. Thus, this study identifies a novel inhibitory peptide for FGFR3 signaling, which may serve as a potential therapeutic agent for the treatment of FGFR3-related skeletal dysplasia. PMID- 23014565 TI - Optimized removal of dissolved organic carbon and trace organic contaminants during combined ozonation and artificial groundwater recharge. AB - Pilot scale experiments using an 8 g/h ozonation unit and a 1.4 m(2) slow sand filter have demonstrated that the combination of ozonation and artificial groundwater recharge is suitable for efficient reduction of bulk and trace organics. The biodegradation of dissolved organic carbon (DOC) in the slow sand filter was enhanced from 22% without pre-treatment to 34% by pre-ozonation. In addition, realistic surface water concentrations of most investigated trace organic compounds (TrOCs) including carbamazepine, sulfamethoxazole, phenazone and metoprolol were reduced below the limits of quantification. Only a few TrOCs, e.g. primidone and benzotriazole, were not efficiently removed in both treatment steps and could be detected regularly in the filter effluent. For these compounds, enhanced treatment, such as advanced oxidation processes, needs to be considered. Testing for genotoxicity and cytotoxicity did not reveal any systematic adverse effects for human health. The formation of the by-product bromate from bromide was below the limit of the German drinking water directive of 10 MUg/L. No removal of bromate was observed in the aerobic slow sand filter. Additional experiments with sand columns showed that operating a preceding bank filtration step to reduce DOC can reduce oxidant demand by approximately 20%. PMID- 23014566 TI - Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. AB - To improve the efficacy of risk-adapted melphalan (MEL) in patients with amyloidosis (AL), we conducted a phase II trial using bortezomib and dexamethasone (BD) as consolidation. Forty untreated patients with renal (70%), cardiac (65%), liver/gastrointestinal (15%) or nervous system (13%) AL were assigned MEL 100, 140 or 200 mg/m(2) based on age, renal function and cardiac involvement. Hematological response was assessed at 3 months post stem cell transplant (SCT); patients with less than complete hematological response (CR) received BD consolidation. Four patients with advanced cardiac AL died within 100 days of SCT (10% treatment-related mortality). Survival at 12 and 24 months post treatment start was 88 and 82% overall and was 81 and 72% in patients with cardiac AL. At 3 months post SCT, 45% had >= partial response (PR) including 27% CR. Twenty-three patients received consolidation and in 86% response improved; all patients responded in one cycle. At 12 and 24 months, 79 and 60% had >= PR, 58 and 40% CR. Organ responses occurred in 55 and 70% at 12 and 24 months. Eight patients relapsed/progressed. One patient with serologic progression had organ impairment at time of progression. In newly diagnosed AL, BD following SCT rapidly and effectively improves responses resulting in high CR rates and maintained organ improvement. PMID- 23014567 TI - Uncovering early, lineage-dependent effects of TPMT genotype in adult acute lymphoblastic leukemia by minimal residual disease. PMID- 23014568 TI - Perception of dimethyl sulfide (DMS) by loggerhead sea turtles: a possible mechanism for locating high-productivity oceanic regions for foraging. AB - During their long-distance migrations, sea turtles of several species feed on jellyfish and other invertebrates that are particularly abundant in ocean regions characterized by high productivity. An ability to distinguish productive oceanic regions from other areas, and to concentrate foraging activities in locations where prey density is highest, might therefore be adaptive. The volatile compound dimethyl sulfide (DMS) accumulates in the air above productive ocean areas such as upwelling and frontal zones. In principle, DMS might therefore serve as an indicator of high prey density for turtles. To determine whether turtles perceive DMS, juvenile loggerhead sea turtles (Caretta caretta) were placed into a water filled arena in which DMS and other odorants could be introduced to the air above the water surface. Turtles exposed to air that had passed over a cup containing 10 nmol l(-1) DMS spent more time at the surface with their noses out of the water than control turtles, which were exposed to air that had passed over a cup containing distilled water. Odors that do not occur in the sea (cinnamon, jasmine and lemon) did not elicit increased surface time, implying that the response to DMS is unlikely to reflect a generalized response to any novel odor. The results demonstrate for the first time that sea turtles can detect DMS, an ability that might enable the identification of favorable foraging areas. PMID- 23014569 TI - A flavonol present in cocoa [(-)epicatechin] enhances snail memory. AB - Dietary consumption of flavonoids (plant phytochemicals) may improve memory and neuro-cognitive performance, though the mechanism is poorly understood. Previous work has assessed cognitive effects in vertebrates; here we assess the suitability of Lymnaea stagnalis as an invertebrate model to elucidate the effects of flavonoids on cognition. (-)Epicatechin (epi) is a flavonoid present in cocoa, green tea and red wine. We studied its effects on basic snail behaviours (aerial respiration and locomotion), long-term memory (LTM) formation and memory extinction of operantly conditioned aerial respiratory behaviour. We found no significant effect of epi exposure (15 mg l(-1)) on either locomotion or aerial respiration. However, when snails were operantly conditioned in epi for a single 0.5 h training session, which typically results in memory lasting ~3 h, they formed LTM lasting at least 24 h. Snails exposed to epi also showed significantly increased resistance to extinction, consistent with the hypothesis that epi induces a more persistent LTM. Thus training in epi facilitates LTM formation and results in a more persistent and stronger memory. Previous work has indicated that memory-enhancing stressors (predator kairomones and KCl) act via sensory input from the osphradium and are dependent on a serotonergic (5-HT) signalling pathway. Here we found that the effects of epi on LTM were independent of osphradial input and 5-HT, demonstrating that an alternative mechanism of memory enhancement exists in L. stagnalis. Our data are consistent with the notion that dietary sources of epi can improve cognitive abilities, and that L. stagnalis is a suitable model with which to elucidate neuronal mechanisms. PMID- 23014570 TI - Backward flight in hummingbirds employs unique kinematic adjustments and entails low metabolic cost. AB - Backward flight is a frequently used transient flight behavior among members of the species-rich hummingbird family (Trochilidae) when retreating from flowers, and is known from a variety of other avian and hexapod taxa, but the biomechanics of this intriguing locomotor mode have not been described. We measured rates of oxygen uptake (V(O2)) and flight kinematics of Anna's hummingbirds, Calypte anna (Lesson), within a wind tunnel using mask respirometry and high-speed videography, respectively, during backward, forward and hovering flight. We unexpectedly found that in sustained backward flight is similar to that in forward flight at equivalent airspeed, and is about 20% lower than hovering V(O2). For a bird that was measured throughout a range of backward airspeeds up to a speed of 4.5 m s(-1), the power curve resembled that of forward flight at equivalent airspeeds. Backward flight was facilitated by steep body angles coupled with substantial head flexion, and was also characterized by a higher wingbeat frequency, a flat stroke plane angle relative to horizontal, a high stroke plane angle relative to the longitudinal body axis, a high ratio of maximum:minimum wing positional angle, and a high upstroke:downstroke duration ratio. Because of the convergent evolution of hummingbird and some hexapod flight styles, flying insects may employ similar kinematics while engaged in backward flight, for example during station keeping or load lifting. We propose that backward flight behavior in retreat from flowers, together with other anatomical, physiological, morphological and behavioral adaptations, enables hummingbirds to maintain strictly aerial nectarivory. PMID- 23014571 TI - Sink fast and swim harder! Round-trip cost-of-transport for buoyant divers. AB - Efficient locomotion between prey resources at depth and oxygen at the surface is crucial for breath-hold divers to maximize time spent in the foraging layer, and thereby net energy intake rates. The body density of divers, which changes with body condition, determines the apparent weight (buoyancy) of divers, which may affect round-trip cost-of-transport (COT) between the surface and depth. We evaluated alternative predictions from external-work and actuator-disc theory of how non-neutral buoyancy affects round-trip COT to depth, and the minimum COT speed for steady-state vertical transit. Not surprisingly, the models predict that one-way COT decreases (increases) when buoyancy aids (hinders) one-way transit. At extreme deviations from neutral buoyancy, gliding at terminal velocity is the minimum COT strategy in the direction aided by buoyancy. In the transit direction hindered by buoyancy, the external-work model predicted that minimum COT speeds would not change at greater deviations from neutral buoyancy, but minimum COT speeds were predicted to increase under the actuator disc model. As previously documented for grey seals, we found that vertical transit rates of 36 elephant seals increased in both directions as body density deviated from neutral buoyancy, indicating that actuator disc theory may more closely predict the power requirements of divers affected by gravity than an external work model. For both models, minor deviations from neutral buoyancy did not affect minimum COT speed or round-trip COT itself. However, at body-density extremes, both models predict that savings in the aided direction do not fully offset the increased COT imposed by the greater thrusting required in the hindered direction. PMID- 23014572 TI - Achilles tendon stiffness is unchanged one hour after a marathon. AB - Overuse-induced injuries have been proposed as a predisposing factor for Achilles tendon (AT) ruptures. If tendons can be overloaded, their mechanical properties should change during exercise. Because there data are lacking on the effects of a single bout of long-lasting exercise on AT mechanical properties, the present study measured AT stiffness before and after a marathon. AT stiffness was determined as the slope of the force-elongation curve between 10 and 80% of maximum voluntary force. AT force-elongation characteristics were measured in an ankle dynamometer using simultaneous motion-capture-assisted ultrasonography. Oxygen consumption and ankle kinematics were also measured on a treadmill at the marathon pace. All measurements were performed before and after the marathon. AT stiffness did not change significantly from the pre-race value of 197+/-62 N mm( 1) (mean +/- s.d.) to the post-race value of 206+/-59 N mm(-1) (N=12, P=0.312). Oxygen consumption increased after the race by 7+/-10% (P<0.05) and ankle kinematic data revealed that in nine out of 12 subjects, the marathon induced a change in their foot strike technique. The AT of the physically active individuals seems to be able to resist mechanical changes under physiological stress. We therefore suggest that natural loading, like in running, may not overstress the AT or predispose it to injury. In addition, decreased running economy, as well as altered foot strike technique, was probably attributable to muscle fatigue. PMID- 23014573 TI - Left-sided IVC in left renal cell carcinoma. AB - AIM: Congenital anomalies of the inferior vena cava (IVC) are very rare and extremely diverse, reflecting the complexity of the embryological development of these structures. The variants must be differentiated from pathology, particularly lymphadenopathy, on imaging studies as their presence can affect surgical and interventional procedures in retroperitoneum. We describe two patients with renal cell carcinoma of left kidney and left IVC. CASE REPORT: First patient was taken up for left radical nephroureterectomy. During surgery the existence of a transposed left IVC was demonstrated. The second case is a fifty-four-year-old man; abdomen and pelvic CT-scan with coronal maximum intensity projection reconstruction showed a 7 cm heterogeneously enhancing neoformation involving the left kidney with intraparenchymal hematoma and a transposed left IVC. CONCLUSIONS: Preoperative detection of congenital IVC anomalies can prevent morbidity. Once diagnosed, appropriate care must be taken during the operation to expose and define the anatomic anomaly and protect it from injury. PMID- 23014580 TI - Contribution of the NH2-terminal EGF-domain of factor IXa to the specificity of intrinsic tenase. AB - Factor IXa (FIXa) is a vitamin K-dependent coagulation serine protease which binds to factor VIIIa (FVIIIa) on negatively charged phospholipid vesicles (PCPS) to catalyse the activation of factor X (FX) to factor Xa (FXa) in the intrinsic pathway. Fluorescence resonance energy transfer (FRET) studies have indicated that the Gla-domain-dependent interaction of FIXa and FX with PCPS in the presence of FVIIIa positions the active-site of the protease at an appropriate height above the membrane surface to optimise the catalytic reaction. In this study, we investigated the contribution of the NH2-terminal EGF-domain (EGF1) of FIXa to the recognition specificity of intrinsic tenase by constructing an EGF1 deletion mutant of FIXa (FIXa-desEGF1) and characterising the properties of the mutant in kinetic, direct binding and FRET assays. The results of direct binding and kinetic studies demonstrated that the binding affinity of the mutant for interaction with FVIIIa on PCPS has been impaired greater than 10-fold and the catalytic efficiency of the mutant protease-FVIIIa-PCPS complex in the activation of FX has been decreased ~100-fold. By contrast, the mutant protease exhibited a normal activity toward FX in the absence of the protein cofactor. FRET measurements revealed that the distance of the active-site of the mutant FIXa relative to PCPS vesicles has been decreased 10 A from 75 +/- 2 A for FIXa to 65 +/- 2 A for FIXa-desEGF1 independent of FVIIIa. These results suggest that the NH2-terminal EGF-domain of FIXa provides a binding-site for FVIIIa and plays an essential spacer function in the intrinsic tenase complex. PMID- 23014581 TI - Will mass drug administration eliminate lymphatic filariasis? Evidence from northern coastal Tanzania. AB - This article documents understandings and responses to mass drug administration (MDA) for the treatment and prevention of lymphatic filariasis among adults and children in northern coastal Tanzania from 2004 to 2011. Assessment of village level distribution registers, combined with self-reported drug uptake surveys of adults, participant observation and interviews, revealed that at study sites in Pangani and Muheza districts the uptake of drugs was persistently low. The majority of people living at these highly endemic locations either did not receive or actively rejected free treatment. A combination of social, economic and political reasons explain the low uptake of drugs. These include a fear of treatment (attributable, in part, to a lack of trust in international aid and a questioning of the motives behind the distribution); divergence between biomedical and local understandings of lymphatic filariasis; and limited and ineffective communication about the rationale for mass treatment. Other contributory factors are the reliance upon volunteers for distribution within villages and, in some locations, strained relationships between different groups of people within villages as well as between local leaders and government officials. The article also highlights a disjuncture between self-reported uptake of drugs by adults at a village level and the higher uptake of drugs recorded in official reports. The latter informs claims that elimination will be a possibility by 2020. This gives voice to a broader problem: there is considerable pressure for those implementing MDA to report positive results. The very real challenges of making MDA work are pushed to one side - adding to a rhetoric of success at the expense of engaging with local realities. It is vital to address the kind of issues raised in this article if current attempts to eliminate lymphatic filariasis in mainland coastal Tanzania are to achieve their goal. PMID- 23014586 TI - Prophylactic therapy in children with hereditary angioedema. PMID- 23014585 TI - The Thr715Pro variant impairs terminal glycosylation of P-selectin. AB - P-selectin variant 715Pro is associated with lower concentrations of plasma P selectin and reduced risk for thrombosis. We examined the influence of 715Pro on P-selectin synthesis, post-translational processing, surface expression and function using HEK293 cells, which do not express endogenous P-selectin. Mass spectrometry revealed that HEK293 cells produced recombinant P-selectin which has a glycosylation pattern comparable to platelet P-selectin. Compared to wild-type transfectants, 715Pro transfectants have ~50% less terminally glycosylated P selectin and accumulate more immature P-selectin in Golgi. Following Brefeldin A treatment, the majority of 715Pro P-selectin is not modified by Golgi enzymes, while wild-type P-selectin undergoes complete modification. Flow cytometry revealed that 715Pro transfectants have ~20% less P-selectin on the cell surface compared to wild-type transfectants. Secretion of P-selectin by 715Pro transfectants was about 38% lower compared to wild-type transfectants. Binding of HL-60 cells to 715Pro transfectants was ~29% lower than to wild-type transfectants. This observation was confirmed by the presence of fewer platelet monocyte aggregates (PMA) in the blood of healthy individuals and patients with angiographically proven atherosclerosis, carrying 715Pro P-selectin compared to individuals with wild-type P-selectin. We conclude that the 715Pro variant impairs terminal glycosylation of P-selectin in Golgi, leading to reduced amounts of mature P-selectin and subsequently less surface expression and secretion of P selectin. The reduced surface expression of 715Pro P-selectin contributes to inefficient adhesion to HL-60 cells or monocytes. PMID- 23014587 TI - First reported case of Omenn syndrome in a patient with reticular dysgenesis. PMID- 23014589 TI - DNA damage as a result of psychological stress: implications for breast cancer. AB - Accumulating evidence indicates that psychological stress can have deleterious influences on cancer development and progression, but the mechanisms responsible remain unclear. One possible mechanism is suggested by emerging evidence that DNA damage is increased by exposure to stress and stress hormones (for example, cortisol, catecholamines). Possible molecular mechanisms for such effects were the subject of a recent paper by Hara and colleagues, which suggests that chronic stress, through beta-adrenergic stimulation, can induce two synergistic pathways that result in accumulation of DNA damage. Herein, we discuss the potential implications of these findings for breast cancer etiology, progression, and treatment response. PMID- 23014592 TI - Work injury risk by time of day in two population-based data sources. AB - OBJECTIVE: To estimate the rate of work injury over the 24 h clock in Ontario workers over 5 years (2004-2008). METHODS: A cross-sectional, observational study of work-related injury and illness was conducted for a population of occupationally active adults using two independent data sources (lost-time compensation claims and emergency department encounter records). Hours worked annually by the Ontario labour force by time of day, age, gender and occupation were estimated from population-based surveys. RESULTS: There was an approximately 40% higher incidence of emergency department visits for work-related conditions than of lost-time workers' compensation claims (707 933 emergency department records and 457 141 lost-time claims). For men and women and across all age groups, there was an elevated risk of work-related injury or illness in the evening, night and early morning periods in both administrative data sources. This elevated risk was consistently observed across manual, mixed and non-manual occupational groups. The fraction of lost-time compensation claims that can be attributed to elevated risk of work injury in evening or night work schedules is 12.5% for women and 5.8% for men. CONCLUSIONS: Despite the high prevalence of employment in non-daytime work schedules in developed economies, the work injury hazards associated with evening and night schedules remain relatively invisible. This study has demonstrated the feasibility of using administrative data sources to enhance capacity to conduct surveillance of work injury risk by time of day. More sophisticated aetiological research is needed to understand the specific mechanisms of hazards associated with non-regular work hours. PMID- 23014593 TI - Chronic workplace stress and insufficient physical activity: a cohort study. AB - OBJECTIVES: To examine whether exposure to workplace stressors predicts changes in physical activity and the risk of insufficient physical activity. METHODS: Prospective data from the Finnish Public Sector Study. Repeated exposure to low job control, high job demands, low effort, low rewards and compositions of these (job strain and effort-reward imbalance) were assessed at Time 1 (2000-2002) and Time 2 (2004). Insufficient physical activity (<14 metabolic equivalent task hours per week) was measured at Time 1 and Time 3 (2008). The effect of change in workplace stressors on change in physical activity was examined using fixed effects (within-subject) logistic regression models (N=6665). In addition, logistic regression analysis was applied to examine the associations between repeated exposure to workplace stressors and insufficient physical activity (N=13 976). In these analyses, coworker assessed workplace stressor scores were used in addition to individual level scores. RESULTS: The proportion of participants with insufficient physical activity was 24% at baseline and 26% at follow-up. 19% of the participants who were sufficiently active at baseline became insufficiently active at follow-up. In the fixed-effect analysis, an increase in workplace stress was weakly related to an increase in physical inactivity within an individual. In between-subjects analysis, employees with repeated exposure to low job control and low rewards were more likely to be insufficiently active at follow-up than those with no reports of these stressors; fully adjusted ORs ranged from 1.11 (95% CI 1.00 to 1.24) to 1.21 (95% CI 1.05 to 1.39). CONCLUSIONS: Workplace stress is associated with a slightly increased risk of physical inactivity. PMID- 23014594 TI - Cross-shift and longitudinal changes in FEV1 among wood dust exposed workers. AB - OBJECTIVES: Acute lung function (LF) changes might predict an accelerated decline in LF. In this study, we investigated the association between cross-shift and longitudinal changes in forced expiratory volume in 1 s (FEV(1)) among woodworkers in a 6-year follow-up study. METHODS: 817 woodworkers and 136 controls participated with cross-shift changes of FEV(1) at baseline and FEV(1) and forced vital capacity at follow-up. Height and weight were measured and questionnaire information on respiratory symptoms, employment and smoking habits was collected. Wood dust exposure was assessed from 3572 personal dust measurements at baseline and follow-up. Cumulative wood dust exposure was assessed by a study-specific job exposure matrix and exposure time. RESULTS: The median (range) of inhalable dust at baseline and cumulative wood dust exposure was 1.0 (0.2-9.8) mg/m(3) and 3.8 (0-7.1) mg year/m(3), respectively. Mean (SD) for %DeltaFEV(1)/workday and DeltaFEV(1)/year was 0.2 (6.0)%, and -29.1 (41.8) ml. Linear regression models adjusting for smoking, age, height and weight change showed no association between cross-shift and annual change in FEV(1) among woodworkers or controls. Including different exposure estimates, atopy or cross shift change dichotomised or as quartiles did not change the results. CONCLUSIONS: This study among workers exposed to low levels of wood dust does not support an association between acute LF changes and accelerated LF decline. PMID- 23014595 TI - Longitudinal decline in lung function in former asbestos exposed workers. AB - BACKGROUND: This study was designed to assess the effect of asbestos exposure on longitudinal lung function decline. METHODS: A group of 502 former asbestos cement workers with at least two spirometry tests 4 years apart. Repeated evaluations included respiratory symptoms questionnaire, spirometry and chest imaging. Asbestos exposure was ascertained as years of exposure, an index of cumulative exposure and latency time. The mixed effects model was used to evaluate the effect of exposure on the level and rate of change in forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC). RESULTS: Mean age at entry was 51 (SD 9.9) years, mean latency time 25.6 (SD 10.0) years, mean follow-up time 9.1 (SD 2.8) years and mean number of spirometry tests 3.5. The FEV(1) level was significantly related to pack-years of smoking at entry and during the follow-up, the index of cumulative asbestos exposure at entry, and the presence of asbestosis at follow-up. The FVC level was significantly related to pack-years of smoking during the follow-up, cumulative asbestos exposure at entry, asbestosis and pleural thickening at follow-up, and body mass index at entry. Asbestos exposure was not associated with increasing rates of FEV(1) and FVC decline. However, FEV(1) regression slopes with age, estimated by terciles of cumulative exposure, showed significant differences. Combined effects of smoking and exposure conferred further acceleration in lung function decline. CONCLUSIONS: Occupational exposure in asbestos-cement industry was a risk factor for increased lung function decline. The effect seems to be mostly concentrated during the working period. Smoking and exposure had synergic effects. PMID- 23014597 TI - The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition. AB - Coagulation and complement regulators belong to two interactive systems constituting emerging mechanisms of diabetic nephropathy. Thrombomodulin (TM) regulates both coagulation and complement activation, in part through discrete domains. TM's lectin like domain dampens complement activation, while its EGF like domains independently enhance activation of the anti-coagulant and cytoprotective serine protease protein C (PC). A protective effect of activated PC in diabetic nephropathy is established. We hypothesised that TM controls diabetic nephropathy independent of PC through its lectin-like domain by regulating complement. Diabetic nephropathy was analysed in mice lacking TM's lectin-like domain (TMLeD/LeD) and controls (TMwt/wt). Albuminuria (290 MUg/mg vs. 166 MUg/mg, p=0.03) and other indices of experimental diabetic nephropathy were aggravated in diabetic TMLeD/LeD mice. Complement deposition (C3 and C5b-9) was markedly increased in glomeruli of diabetic TMLeD/LeD mice. Complement inhibition with enoxaparin ameliorated diabetic nephropathy in TMLeD/LeD mice (e.g. albuminuria 85 MUg/mg vs. 290 MUg/mg, p<0.001). In vitro TM's lectin-like domain cell-autonomously prevented glucose-induced complement activation on endothelial cells and - notably - on podocytes. Podocyte injury, which was enhanced in diabetic TMLeD/LeD mice, was reduced following complement inhibition with enoxaparin. The current study identifies a novel mechanism regulating complement activation in diabetic nephropathy. TM's lectin-like domain constrains glucose-induced complement activation on endothelial cells and podocytes and ameliorates albuminuria and glomerular damage in mice. PMID- 23014600 TI - Quantitative PCR analysis of DNA, RNAs, and proteins in the same single cell. AB - BACKGROUND: The single cell represents the basic unit of all organisms. Most investigations have been performed on large cell populations, but understanding cell dynamics and heterogeneity requires single-cell analysis. Current methods for single-cell analysis generally can detect only one class of analytes. METHODS: Reverse transcription and the proximity ligation assay were coupled with quantitative PCR and used to quantify any combination of DNA, mRNAs, microRNAs (miRNAs), noncoding RNAs (ncRNAs), and proteins from the same single cell. The method was used on transiently transfected human cells to determine the intracellular concentrations of plasmids, their transcribed mRNAs, translated proteins, and downstream RNA targets. RESULTS: We developed a whole-cell lysis buffer to release unfractionated DNA, RNA, and proteins that would not degrade any detectable analyte or inhibit the assay. The dynamic range, analytical sensitivity, and specificity for quantifying DNA, mRNAs, miRNAs, ncRNAs, and proteins were shown to be accurate down to the single-cell level. Correlation studies revealed that the intracellular concentrations of plasmids and their transcribed mRNAs were correlated only moderately with translated protein concentrations (Spearman correlation coefficient, 0.37 and 0.31, respectively; P < 0.01). In addition, an ectopically expressed gene affected the correlations between analytes and this gene, which is related to gene regulation. CONCLUSIONS: This method is compatible with most cell-sampling approaches, and generates output for the same parameter for all measured analytes, a feature facilitating comparative data analysis. This approach should open up new avenues in molecular diagnostics for detailed correlation studies of multiple and different classes of analytes at the single-cell level. PMID- 23014609 TI - Guest editorial: special section on medical near-infrared spectroscopy. AB - This Special Section Guest Editorial provides an overview of the topical area and an introduction to the articles featured in the special section. PMID- 23014601 TI - Circulating tumor cells: liquid biopsy of cancer. AB - BACKGROUND: The detection and molecular characterization of circulating tumor cells (CTCs) are one of the most active areas of translational cancer research, with >400 clinical studies having included CTCs as a biomarker. The aims of research on CTCs include (a) estimation of the risk for metastatic relapse or metastatic progression (prognostic information), (b) stratification and real-time monitoring of therapies, (c) identification of therapeutic targets and resistance mechanisms, and (d) understanding metastasis development in cancer patients. CONTENT: This review focuses on the technologies used for the enrichment and detection of CTCs. We outline and discuss the current technologies that are based on exploiting the physical and biological properties of CTCs. A number of innovative technologies to improve methods for CTC detection have recently been developed, including CTC microchips, filtration devices, quantitative reverse transcription PCR assays, and automated microscopy systems. Molecular characterization studies have indicated, however, that CTCs are very heterogeneous, a finding that underscores the need for multiplex approaches to capture all of the relevant CTC subsets. We therefore emphasize the current challenges of increasing the yield and detection of CTCs that have undergone an epithelial-mesenchymal transition. Increasing assay analytical sensitivity may lead, however, to a decrease in analytical specificity (e.g., through the detection of circulating normal epithelial cells). SUMMARY: A considerable number of promising CTC-detection techniques have been developed in recent years. The analytical specificity and clinical utility of these methods must be demonstrated in large prospective multicenter studies to reach the high level of evidence required for their introduction into clinical practice. PMID- 23014610 TI - Discovery of the near-infrared window into the body and the early development of near-infrared spectroscopy. AB - Extension of optical monitoring of intact tissues from the visible and ultraviolet to the near-infrared (NIR) range (700-1300 nm) was first undertaken in 1977 for the purpose of monitoring the redox behavior of Cytochrome c oxidase (cyt c ox) in vivo. Soon it became evident that the much greater NIR translucency of skin and bone made it possible to reach brain and muscle tissue without surgical intervention. The presence of hemoglobin absorption led to complications forcing the construction of algorithms to separate the signals of the two molecular entities. It was also realized, however, that the hemoglobin signals provide information regarding the source of oxygen in the tissue, while the cyt c ox signals indicate the intracellular availability of oxygen for oxidative phosphorylation. This ability of recognizing the source/sink relationship greatly enhances the value of NIR spectrophotometry (NIRS) for research and clinical purposes. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014611 TI - Biochemical and physiological basis of medical near-infrared spectroscopy. AB - Near infrared spectroscopy (NIRS) can monitor both the redox status of Cytochrome c oxidase located in the mitochondria within the cell and the oxygenation of the blood in the tissue being monitored. Since the enzyme catalyzes more than 90% of oxygen utilization, it is the sink for the oxygen while the hemoglobin in the capillaries is the oxygen source. In order to evaluate the oxidative metabolic status of a tissue the optical data obtained from both molecules are commonly interpreted on the basis of test tube experiments with purified preparations. We are concerned that the validity of this practice may not have been tested sufficiently and raise four basic questions that have not yet been answered. Citing some examples of in vitro versus in vivo differences we conclude that more effort should be expended on the in vivo testing of the range of the signals, their natural variability, and the physiological and pathological meaning of their deviations from norm. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014612 TI - Higher-order brain function analysis by trans-cranial dynamic near-infrared spectroscopy imaging. AB - Near-infrared spectroscopy is discussed from the viewpoint of human higher-order brain function analysis. Pioneering work in this field is reviewed; then we describe our concept of noninvasive trans-cranial dynamic optical topography and its instrumentation. Also, the validity of its functional images is assessed from both physical and physiological viewpoints. After confirming the validity of this method, we have applied it to a wide variety of fields such as clinical medicine, cognitive science, and linguistics in collaboration with researchers at several other institutes. Further application possibilities and the future of trans cranial dynamic optical topography are also discussed. (c) 1999 Society of Photo Optical Instrumentation Engineers. PMID- 23014613 TI - Measurement system for noninvasive dynamic optical topography. AB - We have developed a 24-channel simultaneous measurement system for optical topography that noninvasively obtains dynamic images of brain activity using near infrared light. To evaluate the system performance, we utilized a dynamic phantom containing a rotating absorber in a cylindrical scattering medium. In this system, eight incident and eight detecting optical fibers are arranged alternately at square lattice points on the phantom. The phantom is illuminated with light of two wavelengths (780 and 830 nm) from each incident fiber. Reflected light is received by the detecting fibers, each of which is connected to an avalanche photodiode. Multiple light intensity modulation and lock-in detection are used to enable highly sensitive measurement with negligible cross talk for multichannel measurement. In the phantom measurement, we obtained topographic dynamic images of the absorber rotating in the medium with a temporal resolution of 0.5 s over a measurement area of 90 mm*90 mm. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014614 TI - Correlation between cerebral oxygen metabolism and cerebral blood flow simultaneously measured before and after acetazolamide administration. AB - The cerebral circulation and metabolism of ten preoperative cardiac surgery patients were assessed. Alterations in regional cerebral blood flow (rCBF), measured by 123I-N-isopropyl-p-iodo-amphetamine single-photon emission computed tomography, and in cerebral oxygen metabolism, simultaneously detected by near infrared spectroscopy (NIRS) before and after acetazolamide administration, were investigated. The rCBF (ml/min/100 g) increased significantly from 40.21+/-7.65 to 56.24+/-13.69(p<0.001), and a significant increase in oxyhemoglobin (Oxy-Hb) of 13.9% (p=0.0022) and total hemoglobin (Total-Hb) of 5.7% (0.0047) along with a significant decrease in deoxyhemoglobin (Deoxy-Hb) of 8.9% (p=0.0414) were observed concomitantly. Thus, the Oxy-Hb/Total-Hb ratio (%Oxy-Hb) rose significantly from 67.26+/-9.82% to 72.98+/-8.09%(p=0.0022). Examination of the relationships between individual parameters showed that the percentage changes in rCBF and Oxy-Hb were significantly correlated (r=0.758,p=0.011). The percentage changes in rCBF and %Oxy-Hb were also correlated significantly (r=0.740,p=0.014). In conclusion, this evidence suggested that NIRS is able to detect relative changes in cerebral hemodynamics and reflect luxury perfusion induced by acetazolamide. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014615 TI - Optical analysis of cirrhotic liver by near infrared time-resolved spectroscopy. AB - The severity of liver cirrhosis was related with the optical properties of liver tissue. Various grades of liver cirrhosis were produced in rats by intraperitoneal injection of thioacetamide (TAA) for different periods: 4 weeks, 8 weeks, 12 weeks, and 16 weeks. Optical properties of the liver, absorption coefficient (MUa) and scattering coefficient (MUs'), were measured by near infrared time-resolved spectroscopy. Histological examination confirmed cirrhotic changes in the liver, which were more severe in rats with TAA administration for longer periods. The MUa increased in 4- and 8-week rats, and then decreased in 12 and 16-week rats. The MUa of blood-free liver decreased as liver cirrhosis progressed. The hemoglobin content in the liver calculated from the MUa values increased in 4- and 8-week rats and decreased in 12- and 16-week rats. The MUs' decreased in the cirrhotic liver, probably reflecting the decrease in the mitochondria content. It was shown that MUa and MUs' determination is useful to assess the severity of liver cirrhosis. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014616 TI - Modulation sensing of fluorophores in tissue: a new approach to drug compliance monitoring. AB - We describe a method to detect the presence of fluorophores in scattering media, including intralipid suspensions and chicken muscle covered with skin. The fluorophores were rhodamine 800 (Rh800) and indocyanine green (IcG), both of which can be excited at long wavelengths where there is minimal absorption by tissues. These fluorophores were dissolved in intralipid or in chicken muscle under skin. A method to approximate the fluorophore concentration in such samples was developed using a long lifetime reference fluorophore in a polymer film placed immediately on the illuminated surface of the sample. Because of the long lifetime of the reference film, the modulation of its emission at low frequencies near 2 MHz is near zero. Since the lifetime of Rh800 and IcG are below 2 ns the modulation of the combined emission is a measure of the intensity of the fluorophore (Rh800 or IcG) relative to the long lifetime reference. Using this method we were able to measure the concentration-dependent intensities of Rh800 and IcG in an intralipid suspension. Additionally, micromolar concentrations of these probes could be detected in chicken muscles, even when the muscle was covered with a layer of chicken skin. The presence of an India ink absorber in the intralipid had only a moderate effect on the modulation values. We suggest the use of this transdermal detection of long-wavelength fluorophores as a noninvasive method to monitor patient compliance when taking medicines used for treatment of chronic diseases such as AIDS or tuberculosis. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014617 TI - Polarization-based sensing of glucose using an oriented reference film. AB - We describe a new approach to glucose sensing using polarization measurements in the presence of a stretch-oriented reference film. The method relies on measurement of the polarized emission from the reference film and of a fluorophore which changes intensity in response to glucose. A glucose-sensitive fluorescent signal was provided by the glucose/galactose binding protein from E. coli. This protein was labeled with an environmentally sensitive fluorophore at a single genetically inserted cysteine residue, and displayed decreased fluorescence upon glucose binding. Using the protein and the reference film we observed glucose-sensitive polarization values for micromolar glucose concentrations. This method of polarization-based sensing is generic and can be used for any sensing fluorophore which displays a change in intensity. In principle, one can construct simple and economical devices for this type of glucose measurement. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014618 TI - Comparison of optical coherence tomography imaging of cataracts with histopathology. AB - This paper presents a comparison of in vivo optical coherence tomography (OCT) captured cataract images to subsequent histopathological examination of the lenticular opacities. OCT imaging was performed on anesthetized Rhesus monkeys, known as the delayed effects colony (DEC), with documented cataracts. These monkeys were exposed to several types of radiation during the mid and late 1960s. The radiation and age related cataracts in these animals were closely monitored using a unique grading system developed specifically for the DEC. In addition to this system, a modified version of a common cataract grading scheme for use in humans was applied. Of the original 18 monkeys imaged, lenses were collected at necropsy from seven of these animals, processed, and compared to OCT images. Results showed a direct correlation between the vertical OCT images and the cataractous lesions seen on corresponding histopathologic sections of the lenses. Based on the images obtained and their corresponding documented comparison to histopathology, OCT showed tremendous potential to aid identification and characterization of cataracts. There can be artifactual problems with the images related to movement and shadows produced by opacities. However, with the advent of increased speed in imaging and multiplanar imaging, these disadvantages may easily be overcome. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014619 TI - Compact laser Doppler choroidal flowmeter. AB - A compact instrument is described that allows the measurement of the laser Doppler flow parameters, i.e., the velocity, the volume, and flow of blood in the foveal region of the human choroidal vascular system. This new device uses the optical principle of confocality for the delivery of the laser light to the site of measurement and heterodyne detection of the Doppler frequency shifted scattered light. Power of the incident light (785 nm) at the cornea is 90 MUW. Measurements were obtained in both eyes of a group of 21 normal volunteers without pupil dilatation. We determined the intrasubject reproducibility and the minimum statistically significant detectable changes in the flow parameters for a group of 21 eyes (one in each subject). Linear correlations were also established between the flow parameters in the right and left eyes. (c) 1999 Society of Photo Optical Instrumentation Engineers. PMID- 23014620 TI - Minimizing Thermal Damage in Corneal Ablation with Short Pulse Mid-infrared Lasers. AB - Photospallation is proposed as the primary mechanism behind our recent animal studies involving corneal ablation by nanosecond-pulse mid-IR laser beams. Following a brief summary of earlier work directed to refractive procedures in the mid-IR, a preliminary analysis is presented, based on simple one-dimensional models of thermoelastic expansion developed previously. The results of the analysis indicate that front surface spallation is consistent with the striking tissue ablation characteristics observed in our recent in vivo work with short pulse beams, including very small ablation rates and submicron thermal damage zones. This is attributed to the fact that spallation is a mechanical-rather than a thermal-mechanism, which allows tissue to be removed in small layers at fluences far lower than those used in the earlier corneal studies with mid-IR beams, typically under 200 mJ/cm2, resulting in minimal heating of tissue. Unlike prior work in the area of photospallation, we also suggest that the existing theoretical basis supports the use of nanosecond pulses as an effective approach to achieving controlled ablation in the presence of very high absorption. We further suggest that such domain of operation may be preferred over shorter pulses, both from a practical standpoint and to mitigate against potential damage from shock waves. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014621 TI - Visible-near infrared multispectral imaging of the rat dorsal skin flap. AB - Visible-near infrared multispectral reflectance image sets were acquired from the dorsal surface of rats both before and after elevation of reversed McFarlane skin flaps. Raw images were dominated by uneven surface illumination and shadowing along with the variation associated with instrument response. These interfering features obscured variation associated with a change in tissue reflectance, which is related to the degree of flap perfusion. Logarithmic residual preprocessing followed by principal component analysis of multispectral images could clearly detect a difference in the optical properties between the base and distal section of the flap. The difference in the reflectance properties correlates with the varying degree of tissue perfusion. Principal component analysis detected this optical difference between the well-perfused base of the skin flap and the compromised distal section of the flap immediately following surgery. The first visual signs of compromised tissue perfusion appeared only 6 or more hours after surgery. The results from this study indicate that the application of principal component analysis to discrete wavelength near infrared multispectral reflectance images of skin flaps can effectively distinguish reflectance changes related to the degree of tissue perfusion immediately following surgical elevation of the reversed McFarlane skin flap. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014622 TI - Characterizing the Coherence of Broadband Sources using Optical Phase Space Contours. AB - Advances in optical coherence tomography (OCT) rely on the availability of broadband light that is spatially coherent. We present a technique to characterize coherence properties of broadband light using optical phase-space contours in transverse momentum and position. We demonstrate that these contour plots can be directly measured by a simple heterodyne imaging scheme possessing high dynamic range (130 dB) and 0.1 fW sensitivity (for mW input beams). These phase space distributions are shown to yield quantitative information on the longitudinal and transverse coherence and the wavefront curvature of the light beam. We apply this technique to characterize the light emitted by a novel high power extended-bandwidth superluminescent diode (SLD) recently developed at the David Sarnoff Research Center. Its performance is compared to that of standard commercially available SLDs. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014623 TI - Inverse problems of spectroturbidimetry of biological disperse systems: an overview. AB - The obtainment of stable solutions of inverse problems for studying the disperse composition of suspensions using effects of elastic light scattering was discussed. Versions of a regularization of solving the inverse problems of the spectroturbidimetric method were considered, taking into account unavoidable restrictions on the scope of the necessary prior data for particles and on the width of the spectral interval for real biological disperse systems. Possibilities for increasing the number of particle parameters determined in a single optical experiment were analyzed. They were shown to be provided by the use of effects of the orientation ordering of a system on combination of capabilities of the methods of spectroturbidimetry and electro-optics, using bacterial cell suspensions as an example. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23014624 TI - Plasmonic gold and luminescent silicon nanoplatforms for multimode imaging of cancer cells. AB - The development of multimodal nanoparticle platforms is desirable for cancer nanotechnology applications. Creating single nanoplatforms with both plasmonic and photoluminescent optical properties has remained a challenge, because combining discrete entities each having one of these unique properties typically results in the attenuation of one of the desirable properties. Here, we overcome challenges associated with combining plasmonic gold with luminescent silicon nanocrystals for biological imaging applications by incorporating multiple silicon quantum dots into the core of a micelle and then depositing gold on the surface of the nanostructure. Within the newly developed nanoconstruct, the gold shell exhibits plasmonic light scattering properties useful for dark field imaging, while the silicon nanocrystals maintain their photoluminescence. The result is a nanoplatform with both plasmonic and luminescent properties in a useful form. Multimodal imaging of pancreatic cancer cells demonstrates overlap of luminescence from the silicon quantum dots with light scattering from the gold shell. This approach can be tailored to other formulations and address the challenge of fluorescence attenuation that is typically observed when quantum dots are combined with plasmonic materials. The usefulness of these particles may eventually extend beyond multimodal imaging to include photothermal treatment. PMID- 23014625 TI - Multiple sclerosis and co-morbid autoimmune disease: the final nail in the coffin? PMID- 23014626 TI - Rehabilitation therapy in MS; a short-term, expensive, placebo. PMID- 23014627 TI - Rehabilitation therapy in MS; a short-term, expensive, placebo. PMID- 23014628 TI - Rehabilitation therapy in MS: a short-term, expensive, placebo: commentary. PMID- 23014629 TI - Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF. AB - STUDY QUESTION: In women undergoing IVF, are urinary bisphenol A (BPA) concentrations associated with ovarian response and early reproductive outcomes, including oocyte maturation and fertilization, Day 3 embryo quality and blastocyst formation? SUMMARY ANSWER: Higher urinary BPA concentrations were found to be associated with decreased ovarian response, number of fertilized oocytes and decreased blastocyst formation. WHAT IS KNOWN ALREADY: Experimental animal and in vitro studies have reported associations between BPA exposure and adverse reproductive outcomes. We previously reported an association between urinary BPA and decreased ovarian response [peak serum estradiol (E(2)) and oocyte count at the time of retrieval] in women undergoing IVF; however, there are limited human data on reproductive health outcomes, such as fertilization and embryo development. STUDY DESIGN, SIZE AND DURATION: Prospective preconception cohort study. One hundred and seventy-four women aged 18-45 years and undergoing 237 IVF cycles were recruited at the Massachusetts General Hospital Fertility Center, Boston, MA, USA, between November 2004 and August 2010. These women were followed until they either had a live birth or discontinued treatment. Cryothaw and donor egg cycles were not included in the analysis. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Urinary BPA concentrations were measured by online solid phase extraction-high-performance liquid chromatography-isotope dilution-tandem mass spectrometry. Mixed effect models, poisson regression and multivariate logistic regression models were used wherever appropriate to evaluate the association between cycle-specific urinary BPA concentrations and measures of ovarian response, oocyte maturation (metaphase II), fertilization, embryo quality and cleavage rate. We accounted for correlation among multiple IVF cycles in the same woman using generalized estimating equations. MAIN RESULTS AND THE ROLE OF CHANCE: The geometric mean (SD) for urinary BPA concentrations was 1.50 (2.22) ug/l. After adjustment for age and other potential confounders (Day 3 serum FSH, smoking, BMI), there was a significant linear dose-response association between increased urinary BPA concentrations and decreased number of oocytes (overall and mature), decreased number of normally fertilized oocytes and decreased E(2) levels (mean decreases of 40, 253 and 471 pg/ml for urinary BPA quartiles 2, 3 and 4, when compared with the lowest quartile, respectively; P-value for trend = 0.001). The mean number of oocytes and normally fertilized oocytes decreased by 24 and 27%, respectively, for the highest versus the lowest quartile of urinary BPA (trend test P < 0.001 and 0.002, respectively). Women with urinary BPA above the lowest quartile had decreased blastocyst formation (trend test P-value = 0.08). LIMITATIONS AND REASONS FOR CAUTION: Potential limitations include exposure misclassification due to the very short half-life of BPA and its high variability over time; uncertainty about the generalizability of the results to the general population of women conceiving naturally and limited sample. WIDER IMPLICATIONS OF THE FINDINGS: The results from this extended study, using IVF as a model to study early reproductive health outcomes in humans, indicate a negative dose-response association between urinary BPA concentrations and serum peak E(2) and oocyte yield, confirming our previous findings. In addition, we found significantly decreased metaphase II oocyte count and number of normally fertilizing oocytes and a suggestive association between BPA urinary concentrations and decreased blastocyst formation, thus indicating that BPA may alter reproductive function in susceptible women undergoing IVF. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants ES009718 and ES000002 from the National Institute of Environmental Health Sciences and grant OH008578 from the National Institute for Occupational Safety and Health. None of the authors has actual or potential competing financial interests. DISCLAIMER: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. PMID- 23014630 TI - integIRTy: a method to identify genes altered in cancer by accounting for multiple mechanisms of regulation using item response theory. AB - MOTIVATION: Identifying genes altered in cancer plays a crucial role in both understanding the mechanism of carcinogenesis and developing novel therapeutics. It is known that there are various mechanisms of regulation that can lead to gene dysfunction, including copy number change, methylation, abnormal expression, mutation and so on. Nowadays, all these types of alterations can be simultaneously interrogated by different types of assays. Although many methods have been proposed to identify altered genes from a single assay, there is no method that can deal with multiple assays accounting for different alteration types systematically. RESULTS: In this article, we propose a novel method, integration using item response theory (integIRTy), to identify altered genes by using item response theory that allows integrated analysis of multiple high throughput assays. When applied to a single assay, the proposed method is more robust and reliable than conventional methods such as Student's t-test or the Wilcoxon rank-sum test. When used to integrate multiple assays, integIRTy can identify novel-altered genes that cannot be found by looking at individual assay separately. We applied integIRTy to three public cancer datasets (ovarian carcinoma, breast cancer, glioblastoma) for cross-assay type integration which all show encouraging results. AVAILABILITY AND IMPLEMENTATION: The R package integIRTy is available at the web site http://bioinformatics.mdanderson.org/main/OOMPA:Overview. CONTACT: kcoombes@mdanderson.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23014631 TI - SGNS2: a compartmentalized stochastic chemical kinetics simulator for dynamic cell populations. AB - MOTIVATION: Cell growth and division affect the kinetics of internal cellular processes and the phenotype diversity of cell populations. Since the effects are complex, e.g. different cellular components are partitioned differently in cell division, to account for them in silico, one needs to simulate these processes in great detail. RESULTS: We present SGNS2, a simulator of chemical reaction systems according to the Stochastic Simulation Algorithm with multi-delayed reactions within hierarchical, interlinked compartments which can be created, destroyed and divided at runtime. In division, molecules are randomly segregated into the daughter cells following a specified distribution corresponding to one of several partitioning schemes, applicable on a per-molecule-type basis. We exemplify its use with six models including a stochastic model of the disposal mechanism of unwanted protein aggregates in Escherichia coli, a model of phenotypic diversity in populations with different levels of synchrony, a model of a bacteriophage's infection of a cell population and a model of prokaryotic gene expression at the nucleotide and codon levels. AVAILABILITY: SGNS2, instructions and examples available at www.cs.tut.fi/~lloydpri/sgns2/ (open source under New BSD license). CONTACT: jason.lloyd-price@tut.fi. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23014632 TI - SpolPred: rapid and accurate prediction of Mycobacterium tuberculosis spoligotypes from short genomic sequences. AB - SUMMARY: Spoligotyping is a well-established genotyping technique based on the presence of unique DNA sequences in Mycobacterium tuberculosis (Mtb), the causal agent of tuberculosis disease (TB). Although advances in sequencing technologies are leading to whole-genome bacterial characterization, tens of thousands of isolates have been spoligotyped, giving a global view of Mtb strain diversity. To bridge the gap, we have developed SpolPred, a software to predict the spoligotype from raw sequence reads. Our approach is compared with experimentally and de novo assembly determined strain types in a set of 44 Mtb isolates. In silico and experimental results are identical for almost all isolates (39/44). However, SpolPred detected five experimentally false spoligotypes and was more accurate and faster than the assembling strategy. Application of SpolPred to an additional seven isolates with no laboratory data led to types that clustered with identical experimental types in a phylogenetic analysis using single-nucleotide polymorphisms. Our results demonstrate the usefulness of the tool and its role in revealing experimental limitations. AVAILABILITY AND IMPLEMENTATION: SpolPred is written in C and is available from www.pathogenseq.org/spolpred. CONTACT: francesc.coll@lshtm.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Online. PMID- 23014633 TI - Evaluation of a self-administrated pediatric bleeding questionnaire measuring bleeding severity in children. PMID- 23014634 TI - Distribution and persistence of tricyaclazole in agricultural field soils. AB - Soil is the major sink for majority of pesticides applied on agricultural crops and its fate depends on variety of factors. There is little research on fate of pesticide in field soil under different climatic conditions and there is a need of study on the influence of climate on pesticide degradation and persistence in soil. In the present study, the persistence and distribution of tricyclazole was investigated in rice field soil under the influence of cold winter condition. Field experiment was carried at 35 different field sites from 6 provinces in Republic of Korea. Limit of detection and limit of quantification of tricyclazole were found to be 0.005 and 0.0165 mg/kg, respectively. The concentrations of tricyclazole in soil samples ranged from 0.387 mg/kg in sites in Gyeongsangbuk-do areas and lowest 0.021 mg/kg in sites from Chuncheongnam-do areas. In natural environmental conditions, tricyclazole persisted longer than 11 months post application in agricultural field soils. Our result indicates the influence of cold climatic condition on the persistence of tricyclazole. PMID- 23014635 TI - Sandhopper Talitrus saltator (Montagu) as a bioindicator of contamination by polycyclic aromatic hydrocarbons. AB - This study evaluates the use of the sandhopper Talitrus saltator as a bioindicator of PAHs contamination of the supralittoral zone of sandy beaches. Adult amphipods were collected at eight localities on the Tuscany shore in summer. Concentrations of 16 PAHs indicated as priority pollutants by the Environmental Protection Agency were determined. T. saltator is able to accumulate PAHs (total PAHs ranging from 0.75 to 62.1 ng g(-1)), with concentrations generally greater than in the sand (total PAHs ranging from 0.04 to 38 ng g(-1)). In particular, it accumulates Phe, Cry, and BbF. Preliminary laboratory tests indicate food as a possible route of PAHs intake by sandhoppers. Despite the need of further studies to clarify the variability of the PAH concentrations found in the substrata and in sandhoppers, T. saltator could be used as a bioindicator of PAHs contamination of the supralittoral zone of sandy shores. PMID- 23014636 TI - Detecting meaningful changes in trials of headache treatments: which outcome measure is best? PMID- 23014640 TI - Editorial: a letter from the editor. PMID- 23014637 TI - The association between migraine and obesity: empty calories? PMID- 23014641 TI - Time-resolved transillumination and optical tomography. PMID- 23014642 TI - Quantitative thermal imaging using liquid crystals. PMID- 23014643 TI - Recent developments in laser cardiac surgery. PMID- 23014644 TI - Raman spectroscopy for the detection of cancers and precancers. PMID- 23014645 TI - Three-photon excitation in fluorescence microscopy. PMID- 23014646 TI - Scanning near-field optical microscopy with a tetrahedral tip at a resolution of 6 nm. PMID- 23014648 TI - Computer-aided retinal photocoagulation system. PMID- 23014647 TI - Microarterial anastomoses using the diode laser: long term morphological results. PMID- 23014649 TI - Noncontact determination of thermal diffusivity in biomaterials using infrared imaging radiometry. PMID- 23014650 TI - Photophysical properties of fluorescence probes I: dialkylamino stilbazolium dyes. PMID- 23014651 TI - Optical properties of scattering and absorbing materials used in the development of optical phantoms at 1064 nm. PMID- 23014652 TI - Optical properties of brain tissue. PMID- 23014653 TI - Directly modulated diode laser frequency doubled in a KTP waveguide as an excitation source for CO2 and O2 phase fluorometric sensors. PMID- 23014654 TI - Performance enhancement of fluorescence energy transfer-based biosensors by site directed mutagenesis of the transducer. PMID- 23014659 TI - Fludarabine with cytarabine followed by reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with poor-risk chronic lymphocytic leukemia. AB - Allogeneic stem cell transplantation (SCT) is a treatment option for patients with poor-risk chronic lymphocytic leukemia (CLL). Sequential use of chemotherapy and reduced-intensity conditioning has been proposed to improve the treatment outcomes. Fludarabine (30 mg/m(2)/day) and cytarabine (2 g/m(2)/day) for 4 days (combination of fludarabine with cytarabine; FAraC) were used for cytoreduction. After 3 days of rest, reduced intensity conditioning (RIC) was carried out consisting of 4 Gy total body irradiation, 10-20 mg/kg/day antithymocyte globulin for 3 days, and 40-60 mg/kg/day cyclophosphamide for 2 days. The median time of neutrophil engraftment was 16 days. The most frequent toxicities were grades III/IV infections in 12 of 15 cases and gastrointestinal toxicities in 8 of 15 cases. Remission (complete remission + partial remission) was achieved in 14 of 15 patients (93 %), minimal residual disease negativity according to flowcytometric analysis was observed in 10 patients. Nonrelapse mortality after 1 and 2 years was 7 and 13 %, respectively. After the median follow-up from SCT of 30 months, 80 % of patients were alive (12/15), three patients have died, and three relapses occurred. The FAraC-RIC protocol seems to be a promising approach to the treatment of poor-risk CLL with a high response rate of 93 % and favorable progression-free survival and overall survival of 70 and 85 % at 2 years after SCT, respectively. Other prospective clinical trials are needed to confirm the results of this novel therapeutic strategy. PMID- 23014660 TI - Zoledronic acid effectiveness against breast cancer metastases - a role for estrogen in the microenvironment? AB - Zoledronic acid (ZA) is an imidazole-containing bisphosphonate that has been extensively studied as an osteoclast inhibitor. ZA decreases bone turnover and has been effective in limiting osteolysis in metastatic cancers, including breast cancer. Recent clinical trials that demonstrated enhancement of disease-free survival by bisphosphonates have prompted interest in bisphosphonates as anti cancer agents. ZA, for example, increased disease-free survival in postmenopausal and in premenopausal, hormone-suppressed breast cancer patients. Intriguingly, however, there was a lack of an anti-cancer effect of ZA in premenopausal women without ovarian suppression. These observations have prompted the conjecture that anti-cancer effects of ZA are limited to estrogen-poor environments. This review explores possible mechanisms compatible with differences in ZA activity in premenopausal women compared with postmenopausal (or hormone-suppressed) women. PMID- 23014669 TI - Characterisation of exposure versus response of edoxaban in patients undergoing total hip replacement surgery. AB - Edoxaban is an oral direct factor Xa inhibitor approved for the prevention of venous thromboembolism (VTE) in Japan. The objectives of this analysis were to characterise the population pharmacokinetics (PK) of edoxaban and the relationships between edoxaban exposure and clinical outcomes in a phase IIb study of surgical patients following total hip replacement (THR). A total of 1,795 subjects from a phase IIb study, 10 phase I studies, and three phase IIa studies were included in the PK analysis. The exposure-response analysis included data from surgical patients assigned to edoxaban in the phase IIb study. Edoxaban disposition in healthy and post-surgical patients was well-described with a linear, two-compartment model. Creatinine clearance was significantly correlated with edoxaban clearance and the rate of oral absorption was affected by surgery. The probability of a post-operative VTE was significantly correlated with steady state metrics of edoxaban exposure estimated for each subject by Bayesian post hoc methods with age and gender being the significant and expected covariates. The incidence of bleeding was low in these studies and hence no exposure-response relationship could be identified. These analyses suggest that edoxaban has a predictable anticoagulant effect in this patient population leading to dose proportional reduction in incidence of VTE with low incidence of bleeding. PMID- 23014668 TI - Interpretation of endpoints in a network meta-analysis of new oral anticoagulants following total hip or total knee replacement surgery. AB - New oral anticoagulant (NOAC) regimens [dabigatran 150 mg (D150) and 220 mg (D220), rivaroxaban 10 mg (R20), and apixaban 2.5 mg bid (A5)] were effective and safe compared to enoxaparin for the prevention of venous thromboembolism (VTE) following elective total knee (TKR) or hip replacement (THR) surgery. First a cluster analysis was used to identify homogeneous studies for the trial programs of each NOAC. Second, only studies reporting VTE and VTE-related death, major bleeding, and mortality were included. The odds ratio (OR) and 95% confidence interval (CI) were calculated for each NOAC regimen versus the comparator. Third, these data were used for the indirect comparison between NOACs. Cluster analysis identified duration of treatment (10 +/- 5 and 34 +/- 5 days) as the only homogeneous parameter across all NOAC programs (p>0.05) except for A5 and VTE over 10 +/- 5 days (analysis not performed). The results of the calculated OR and 95% CI of the four NOAC regimens over 10 +/- 5 and 34 +/- 5 days showed inferiority of D150 and D220 compared to R10 for VTE (p<0.01, p<0.001). Comparisons of major bleeding and mortality were not different for all indirect comparisons. Despite the lack of standard definitions for VTE and bleeding outcomes, cluster analysis seems to be an appropriate tool to identify homogeneity across trial programs and to perform an indirect comparison for NOACs for prevention of VTE following TKR and THR surgery. PMID- 23014670 TI - Synthesis of lithium corrole and its use as a reagent for the preparation of cyclopentadienyl zirconium and titanium corrole complexes. AB - The lithium corrole complex (Mes(2)(p-OMePh)corrole)Li(3).6THF (1.6THF), prepared via deprotonation of the free-base corrole with lithium amide, acts as precursor for the preparation of cyclopentadienyl zirconium(iv) corrole (2) and pentamethylcyclopentadienyl titanium(IV) corrole (3). PMID- 23014671 TI - Magnetic resonance spectroscopy of the brain. AB - Proton magnetic resonance (MR) spectroscopy of the brain is a non-invasive, in vivo technique that allows investigation into regional chemical environments. Its complementary use with MR imaging sequences provides valuable insights into brain tumour characteristics, progression and response to treatment. Additionally, its sensitivity to brain dysfunction in the presence of apparently normal structural imaging has galvanised interest in its use as a biomarker of neurodegenerative disorders such as Alzheimer's disease. Accordingly, its integration into clinical imaging protocols within many neuroscience centres throughout the world is increasing. This growing attention is encouraging but if the potential of MR spectroscopy is to be realised, fundamental questions need to be addressed, such as reproducibility of the technique and the biochemistry that underpins the neurometabolites measured. Failure to resolve these issues will continue to hinder the extent and accuracy of conclusions that can be drawn from its data. In this review we discuss the issues regarding MR spectroscopy in the brain with particular attention paid to its technique. Key examples of current clinical applications are provided and future directions are discussed. PMID- 23014672 TI - Development of siRNA-probes for studying intracellular trafficking of siRNA nanoparticles. AB - One important barrier facing the delivery of short interfering RNAs (siRNAs) via synthetic nanoparticles is the rate of nanoparticle disassembly. However, our ability to optimize the release kinetics of siRNAs from nanoparticles for maximum efficacy is limited by the lack of methods to track their intracellular disassembly. Towards this end, we describe the design of two different siRNA based fluorescent probes whose fluorescence emission changes in response to the assembly state of the nanoparticle. The first probe design involves a redox sensitive fluorescence-quenched probe that fluoresces only when the nanoparticle is disassembled in a reductive environment. The second probe design is based on a FRET-labeled siRNA pair that fluoresces due to the proximity of the siRNA pair when the nanoparticle is intact. In both approaches, the delivery vehicle need not be labeled. The utility of these probes was investigated with a lipidoid nanoparticle (LNP) as proof-of-concept in both extracellular and intracellular environments. Fluorescence kinetic data from both probes were fit to a two-phase release and decay curve and subsequently quantified to give intracellular disassembly rate constants. Quantitative analysis revealed that the rate constant of siRNA release measured via the fluorescence-quenched probe was almost identical to the rate constant for nanoparticle disassembly measured via the FRET labeled probes. Furthermore, these probes were utilized to determine subcellular localization of LNPs with the use of automated high-resolution microscopy as they undergo dissociation. Interestingly, this work shows that large amounts of siRNA remain inside vesicular compartments. Altogether, we have developed new siRNA probes that can be utilized with multiple nanocarriers for quantitative and qualitative analysis of nanoparticle dissociation that may serve as a design tool for future delivery systems. PMID- 23014673 TI - Deciphering the importance of host and environmental factors that influence the genesis of asthma during childhood. PMID- 23014679 TI - Topical timolol maleate 0.5% for infantile capillary haemangioma of the eyelid. PMID- 23014680 TI - Editorial: a letter from the editor. PMID- 23014674 TI - Comparison of the etiology of viral respiratory illnesses in inner-city and suburban infants. AB - BACKGROUND: The risk of developing childhood asthma has been linked to the severity and etiology of viral respiratory illnesses in early childhood. Since inner-city infants have unique environmental exposures, we hypothesized that patterns of respiratory viral infections would also be distinct. METHODS: We compared the viral etiology of respiratory illnesses in 2 groups: a cohort of 515 infants from 4 inner-city areas and a cohort of 285 infants from mainly suburban Madison, Wisconsin. Nasal secretions were sampled during periods of respiratory illness and at 1 year of age and were analyzed for viral pathogens by multiplex polymerase chain reaction. RESULTS: Overall, inner-city infants had lower rates of viral detection. Considering specific viruses, sick urban infants had lower rates of detectable rhinovirus or respiratory syncytial virus infection and higher rates of adenovirus infection. Every urban site had a higher proportion of adenovirus-positive samples associated with illnesses (10%-21%), compared with Madison (6%). CONCLUSIONS: These findings provide evidence that inner-city babies have different patterns of viral respiratory illnesses than babies who grow up in a more suburban location. These findings raise important questions about the etiology of virus-negative illnesses in urban infants and the possibility of long term consequences of early life infections with adenovirus in this population. PMID- 23014681 TI - Aging changes in the optical elements of the eye. PMID- 23014682 TI - Optical coherence tomography. PMID- 23014683 TI - Laser speckle contrast analysis (LASCA): a nonscanning, full-field technique for monitoring capillary blood flow. PMID- 23014684 TI - Optical coherence propagation and imaging in a multiple scattering medium. PMID- 23014685 TI - Elastic scattering spectroscopy as a diagnostic tool for differentiating pathologies in the gastrointestinal tract: preliminary testing. PMID- 23014686 TI - Dependence of tissue optical properties on solute-induced changes in refractive index and osmolarity. PMID- 23014687 TI - Group refractive index measurement of dry and hydrated type I collagen films using optical low-coherence reflectometry. PMID- 23014688 TI - Cell damage by UVA radiation of a mercury microscopy lamp probed by autofluorescence modifications, cloning assay, and comet assay. PMID- 23014689 TI - Low-frequency variability in the blood volume and in the blood volume pulse measured by photoplethysmography. PMID- 23014690 TI - Holmium:YAG laser: effects of various treatments on root surface topography and acid resistance. PMID- 23014691 TI - The use of practice guidelines by the American Society of Anesthesiologists for the identification of surgical patients at high risk of sleep apnea. AB - American Society of Anesthesiologists (ASA) has introduced a simple tool to assess the perioperative risk of surgery/anesthesia in patients with obstructive sleep apnea (OSA). We compared the surgical outcomes in patients at high risk of OSA with the matched controls. This was a case-control study conducted on 3593 surgical patients receiving a general anesthesia at a single institution. On the basis of a preoperative OSA scoring system using the ASA checklist, patients were classified as high-risk OSA (HR-OSA) or low-risk OSA (LR-OSA) groups. Apnea/hypopnea index of >5 h(-1) during a formal preoperative sleep study was used to confirm or rule out the diagnosis of OSA. Receiver operating characteristic curves were plotted to determine the predictive values as well as sensitivity and specificity of the ASA tool in predicting HR-OSA. The HR-OSA group was matched with the patients in LR-OSA using the propensity scoring and logistic regression. Patients were analyzed for premorbid conditions, intraoperative course and postoperative events using cross tabulation, logistic regression model and paired t test. The development of a composite respiratory complication in the postoperative period was considered as the primary end point. The ASA risk tool was found to have 95.1% sensitivity and 52.2% specificity. At a prevalence of 10%, the negative predictive value was 98.5%. Of the 3593 patients, 306 were identified as HR-OSA. The HR-OSA group was found to have a higher incidence of hypertension and diabetes preoperatively when compared with LR-OSA. Postoperatively, the HR-OSA group had higher incidence of hypoxia, reintubation, postoperative use of continuous positive airway pressure and a longer stay in the recovery room. The ASA checklist offers a highly sensitive tool to identify the patients at a higher risk of OSA during the perioperative period. Patients at HR OSA have a higher incidence of adverse events in the postoperative period when compared with those with LR-OSA. PMID- 23014692 TI - Neurological symptoms following exposure to ozone. PMID- 23014694 TI - Acute vision loss revealing central nervous system aggressive myelomatosis. PMID- 23014693 TI - Cognitive and affective theory of mind in patients with essential tremor. AB - The theory of mind (ToM) is the ability to attribute mental states to oneself and others and to understand that others have beliefs, desires and intentions different from one's own. The aim of the present study was to explore the neuropsychological correlates of cognitive and affective ToM in patients affected by essential tremor (ET). Thirty consecutive ET outpatients and 30 healthy age-, sex- and education-matched control subjects underwent tasks assessing short-term memory, verbal learning and executive functions, as well as tasks assessing "cognitive" and "affective" ToM; questionnaires evaluating behavioral disorders and quality of life were also administered. Although the two groups did not differ on demographic variables, ET patients scored worse on memory tasks, and showed more apathy and worse quality of life than controls. After covarying for mnestic, behavioral and quality of life scores, ET patients achieved significantly lower scores than controls on task assessing cognitive ToM, whereas no difference was found between the two groups on task assessing affective ToM. In ET, "Cognitive" ToM was significantly associated with frontal tasks, whereas "Affective" ToM was not correlated with cognitive, behavioral or quality of life scales. Our results indicate that cognitive aspects of ToM may be selectively impaired in ET. Possible underlying neural mechanisms of the deficits are discussed. PMID- 23014695 TI - Molecular anatomy of tunicate senescence: reversible function of mitochondrial and nuclear genes associated with budding cycles. AB - Zooids of the asexual strain of Polyandrocarpa misakiensis have a lifespan of 4-5 months; before dying, they produce many buds, enabling continuation of the strain. This study was designed to investigate the nature of gene inactivation and reactivation during this continuous process of senescence and budding. During senescence, the zooidal epidermis showed acid beta-galactosidase activity, lost proliferating cell nuclear antigen immunoreactivity and became ultrastructurally worn, indicating that the epidermis is a major tissue affected by the ageing process. Semi-quantitative PCR analysis showed that the genes encoding mitochondrial respiratory chains (MRCs) engaged in decreased transcriptional activity in senescent adults compared with younger adults. The results of in situ hybridization showed that the epidermis dramatically attenuates MRC expression during ageing but restores gene activity when budding commences. During budding and ageing, the nuclear gene Eed (a polycomb group component) was activated and inactivated in a pattern similar to that observed in MRCs. In buds, RNA interference (RNAi) of Eed attenuated Eed transcripts but did not affect the gene expression of pre-activated MRCs. A tunicate humoral factor, TC14-3, could induce Eed, accompanying the reactivation of MRC in adult zooids. When RNAi of Eed and Eed induction were performed simultaneously, zooidal cells and tissues failed to engage in MRC reactivation, indicating the involvement of Eed in MRC activation. Results of this study provide evidence that the mitochondrial gene activities of Polyandrocarpa can be reversed during senescence and budding, suggesting that they are regulated by nuclear polycomb group genes. PMID- 23014697 TI - Imatinib mesylate treatment for a Chinese patient with metastatic and recurrent dermatofibrosarcoma protuberans: is sustained partial remission possible? PMID- 23014698 TI - Breast and stomach cancer incidence and survival in migrants in the Netherlands, 1996-2006: retraction. PMID- 23014696 TI - Temporal deletion of Arl13b reveals that a mispatterned neural tube corrects cell fate over time. AB - Cilia are necessary for sonic hedgehog (Shh) signaling, which is required to pattern the neural tube. We know that ventral neural cell fates are defined by a specific cohort of transcription factors that are induced by distinct thresholds of Shh activity mediated by opposing gradients of Gli activator (GliA) and Gli repressor (GliR). Despite this understanding, the role of Shh as an instructive morphogen is viewed as increasingly complex, with current models integrating positive inputs in terms of ligand concentration and time, along with negative feedback via the downstream gene regulatory network. To investigate the relative contributions of the positive and negative inputs from Shh signaling in neural patterning, we took advantage of a protein that uncouples the regulation of GliA and GliR: the cilia protein ADP-ribosylation factor-like 13b (Arl13b). By deleting Arl13b in mouse, we induced low-level constitutive GliA function at specific developmental stages and defined a crucial period prior to E10.5 when shifts in the level of GliA cause cells to change their fate. Strikingly, we found that improperly patterned cells in these mice converted to the wild-type pattern by E12.5. We further showed that the recovery of patterning did not occur when we also deleted Gli3, the primary GliR in the neural tube, revealing a crucial role of Gli3 in the maintenance of neural patterning. PMID- 23014701 TI - Sight restoration comes into focus: versions of visual prostheses. AB - The first visual prosthetic is on the commercial stage now, and a variety of new retinal and cortical implants are in the wings. When it won the European stamp of approval last year, the Argus II became the first commercially available visual prosthesis. Now Second Sight Medical Products Inc. of Sylmar, California, the company behind the Argus II, hopes to receive approval to sell the device in the United States by late 2012. As the excitement over the Argus II continues at a fever pitch, other research groups are developing their own versions of visual prostheses, working to create the potential for restoring sight. PMID- 23014702 TI - Role of the hippocampus in memory formation: restorative encoding memory integration neural device as a cognitive neural prosthesis. AB - Remind, which stands for "restorative encoding memory integration neural device," is a Defense Advanced Research Projects Agency (DARPA)-sponsored program to construct the first-ever cognitive prosthesis to replace lost memory function and enhance the existing memory capacity in animals and, ultimately, in humans. Reaching this goal involves understanding something fundamental about the brain that has not been understood previously: how the brain internally codes memories. In developing a hippocampal prosthesis for the rat, we have been able to demonstrate a multiple-input, multiple- output (MIMO) nonlinear model that predicts in real time the spatiotemporal codes for specific memories required for correct performance on a standard learning/memory task, i.e., delayed-nonmatch-to sample (DNMS) memory. The MIMO model has been tested successfully in a number of contexts; most notably, in animals with a pharmacologically disabled hippocampus, we were able to reinstate long-term memories necessary for correct DNMS behavior by substituting a MIMO model-predicted code, delivered by electrical stimulation to the hippocampus through an array of electrodes, resulting in spatiotemporal hippocampal activity that is normally generated endogenously. We also have shown that delivering the same model-predicted code to electrode-implanted control animals with a normally functioning hippocampus substantially enhances animals memory capacity above control levels. These results in rodents have formed the basis for extending the MIMO model to nonhuman primates; this is now underway as the last step of the REMIND program before developing a MIMO-based cognitive prosthesis for humans. PMID- 23014703 TI - A digital health solution for using and managing medications: wirelessly observed therapy. AB - Taking oral medication on a prescribed schedule can be a nuisance, especially for elderly individuals and busy people with lots of things on their minds. Nonetheless, taking medication as prescribed is important for maintaining health and well-being. In cases where medication use is part of a clinical trial, taking prescribed medication is important to the entire investigation and outcome of the study, including the determination of whether a drug is effective and safe. PMID- 23014704 TI - Realities of biomedical product liability suits and the role of junk science: from breast implants to TASER weapons. AB - In the summer of 2006, manufacturers of a simple respirator mask costing US$1 told the U.S. Congress that Americans would find a shortage of these masks if there was another flu pandemic. The reason for this was that suing the makers of these dust masks became a major business for trial lawyers. By 2006, there had been more than 326,000 lawsuits filed. It has been reported in many cases that the law firms worked with cooperative physicians and contracted with X-ray labs to screen individuals for lung problems. If an individual had an abnormal lung X ray and claimed that they had used a certain brand of respirator and the manufacturer was still in business and had economic resourcesa lawsuit was filed. Some manufacturers went out of business while others simply stopped making the masks. PMID- 23014705 TI - Supporting clinical engineering in Italy: results of a survey conducted by the AIIC. AB - This article presents the outcomes of a survey developed and conducted by the Italian Association of Clinical Engineers (AIIC) in 2010 [1]. The AIIC, affiliated with the International Federation for Medical and Biological Engineering (IFMBE) since 2003, conducted this in-depth survey to investigate the educational profile of clinical engineers (CEs) as well as the activities and organization of clinical engineering departments (CEDs) in Italy. The survey consisted of a six-section questionnaire designed by the AIIC Board, which was based on other previous international surveys of CEDs. The questionnaire was sent to the AIIC members and to the most important Italian health-care organizations. PMID- 23014706 TI - Standards in capstone design courses and the engineering curriculum. AB - In 1990, I was the group leader of Research and Development for Surgitek, a urological device manufacturer in Racine, Wisconsin, which was the market leader in ureteral stents. I recognized the need for an industry standard for ureteral stents, felt that taking a leadership role in the development of a new standard would be a good professional development activity, and volunteered to serve as the chair of the American Society for Testing and Materials (ASTM, now known as ASTM International) Task Group on Ureteral Stents. After several years, the standard was approved, and I continue to serve as the chair of the ASTM Subcommittee on Urological Materials and Devices. This experience helped me understand the value of industry standards, expanded my professional network and visibility within the medical device industry, and helped develop my leadership skills. PMID- 23014707 TI - Ludwig: the physiologist. AB - The thought reproduced in the above epigraph is taken from an article by Thurau et al. [1], who attribute it to Arthur Schopenhauer (17881860), an outstanding philosopher and author of the far-reaching piece Die Welt als Wille und Vorstellung (The World as Will and Representation). In German, it would perhaps read as etwas denken, das niemand vorher gedacht hat, wahrend etwas sehen, was jeder sieht. We could not assert whether Schopenhauer really said that, but it should not be at all surprising if it were, because it sounds simple, perhaps even naive, and very deep, indeed. It fits perfectly to Carl Friedrich Wilhelm Ludwigs personality (18161895), whom we will look at as physiologist in this second note. Yes, second note-because in the first one [2], we looked at him as bioengineer. A third and last Retrospectroscope column completing this series will deal with his wonderful and always humble and generous activities as teacher. PMID- 23014708 TI - The effect of hyperthyroidism on procoagulant, anticoagulant and fibrinolytic factors: a systematic review and meta-analysis. AB - Several coagulation and fibrinolytic parameters appear to be affected by thyroid hormone excess; however, the net effect on the haemostatic system remains unclear. We aimed to update our previous review and systematically summarise and meta-analyse the data by assessing the effects of thyrotoxicosis on the coagulation and fibrinolytic system in vivo . Data sources included MEDLINE (2006-2012), EMBASE (2006-2012), and reference lists. The sources were combined with our previous search containing studies from 1980-2006. Eligible studies were all observational or experimental studies. Two investigators independently extracted data and rated study quality. Weighted mean proportion and 95% confidence intervals were calculated and pooled using a fixed and a random effects model. A total of 29 articles consisting of 51 studies were included, as in several articles more than one study was described. We included four intervention (before and after treatment in hyperthyroid patients), five cross sectional (hyperthyroid subjects and euthyroid controls), and four experimental (before and after use of thyroid hormone in euthyroid subjects) medium/high quality studies for meta-analysis. We found that thyrotoxicosis shifts the haemostatic balance towards a hypercoagulable and hypofibrinolytic state with a rise in factors VIII and IX, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1. This was observed in endogenous and exogenous thyrotoxicosis, and in subclinical as well as overt hyperthyroidism. We conclude that both subclinical and overt hyperthyroidism induce a prothrombotic state, which is therefore likely to be a risk factor for venous thrombosis. PMID- 23014710 TI - Bench to bedside review: Extracorporeal carbon dioxide removal, past present and future. AB - Acute respiratory distress syndrome (ARDS) has a substantial mortality rate and annually affects more than 140,000 people in the USA alone. Standard management includes lung protective ventilation but this impairs carbon dioxide clearance and may lead to right heart dysfunction or increased intracranial pressure. Extracorporeal carbon dioxide removal has the potential to optimize lung protective ventilation by uncoupling oxygenation and carbon dioxide clearance. The aim of this article is to review the carbon dioxide removal strategies that are likely to be widely available in the near future. Relevant published literature was identified using PubMed and Medline searches. Queries were performed by using the search terms ECCOR, AVCO2R, VVCO2R, respiratory dialysis, and by combining carbon dioxide removal and ARDS. The only search limitation imposed was English language. Additional articles were identified from reference lists in the studies that were reviewed. Several novel strategies to achieve carbon dioxide removal were identified, some of which are already commercially available whereas others are in advanced stages of development. PMID- 23014712 TI - Automatic segmentation of the pulmonary lobes from chest CT scans based on fissures, vessels, and bronchi. AB - Segmentation of the pulmonary lobes is relevant in clinical practice and particularly challenging for cases with severe diseases or incomplete fissures. In this work, an automated segmentation approach is presented that performs a marker-based watershed transformation on computed tomography (CT) scans to subdivide the lungs into lobes. A cost image for the watershed transformation is computed by combining information from fissures, bronchi, and pulmonary vessels. The lobar markers are calculated by an analysis of the automatically labeled bronchial tree. By integration of information from several anatomical structures the segmentation is made robust against incomplete fissures. For evaluation the method was compared to a recently published method on 20 CT scans with no or mild disease. The average distances to the reference segmentation were 0.69, 0.67, and 1.21 mm for the left major, right major, and right minor fissure, respectively. In addition the results were submitted to LOLA11, an international lung lobe segmentation challenge with publically available data including cases with severe diseases. The average distances to the reference for the 55 CT scans provided by LOLA11 were 0.98, 3.97, and 3.09 mm for the left major, right major, and right minor fissure. Moreover, an analysis of the relation between segmentation quality and fissure completeness showed that the method is robust against incomplete fissures. PMID- 23014713 TI - Hemodynamic analysis for transjugular intrahepatic portosystemic shunt (TIPS) in the liver based on a CT-image. AB - In this paper, we apply a 3-D flow model and a 1-D circulation model to the hemodynamic analysis of transjugular intrahepatic portosystemic shunt (TIPS), the therapy for treating acute portal hypertension (PH) induced diseases. Using the 3 D model we are able to simulate the blood flow within a patient-specific TIPS system which was reconstructed from a computed tomography image, and quantify such hemodynamic data as the wall shear stress and flow velocity. The 1-D model is used for the investigation of generic TIPS-induced hepatic circulation phenomena. By incorporating physiological data into the 1-D model we can reproduce some complex flow patterns such as the increased arterial flow after TIPS implantation, the formation of retrograde flow in the portal vein, etc. In particular, our model gives a quantitative analysis of the interplay between TIPS and hepatic flows. In conclusion, the presented computational model can be used for the theoretical analysis of TIPS, in which clinical decisions are often made based on contradictory considerations to balance the procedure-induced complications and the urgency of relieving acute PH symptoms. PMID- 23014711 TI - Efficacy and safety of prophylaxis with once-weekly BAY 79-4980 compared with thrice-weekly rFVIII-FS in haemophilia A patients. A randomised, active controlled, double-blind study. AB - The benefits of prophylaxis of haemophilia A patients regarding joint health and quality-of-life are well established. However, adherence to an up to every-other day infusion regimen is a barrier to widespread adoption of prophylaxis. BAY 79 4980 is an investigational drug consisting of rFVIII-FS (sucrose-formulated recombinant FVIII) reconstituted with liposome solvent. Previous clinical studies showed extended protection from bleeding after a single injection of BAY 79-4980 (13.3 +/- 6.2 days) compared with rFVIII-FS (7.2 +/- 1.7 days). The effect of once-a-week prophylaxis with BAY 79-4980 (35 IU/kg) compared with three times-per week rFVIII-FS (25 IU/kg) in previously treated, severe haemophilia A patients was evaluated in a 52-week, double-blind, two-arm, randomised, controlled study. The primary and secondary endpoints were protection from total bleeds and joint bleeds, respectively. Short- and long-term safety and tolerability of BAY 79-4980 including effects on lipid levels were assessed. A total of 139 and 131 subjects were evaluable for safety and efficacy analyses, respectively. A large difference in efficacy between treatment groups was observed with 72.1% (49/68) in the rFVIII-FS control group demonstrating <9 bleeds/year compared with 38.1% (24/63) of BAY 79-4980-treated subjects. A similar difference was seen in annualised joint bleeds, with 43 subjects (63.2%) in the control group demonstrating <5 joint bleeds/year compared with 24 subjects (38.1%) treated with BAY 79-4980. The distribution of bleeds seven days post-prophylactic treatment with BAY 79-4980 showed that 61% of bleeds occurred after day 4 post dosing. There were no safety concerns identified. The investigational treatment arm was prematurely discontinued due to failure to achieve the primary endpoint. PMID- 23014715 TI - A virtual imaging platform for multi-modality medical image simulation. AB - This paper presents the Virtual Imaging Platform (VIP), a platform accessible at http://vip.creatis.insa-lyon.fr to facilitate the sharing of object models and medical image simulators, and to provide access to distributed computing and storage resources. A complete overview is presented, describing the ontologies designed to share models in a common repository, the workflow template used to integrate simulators, and the tools and strategies used to exploit computing and storage resources. Simulation results obtained in four image modalities and with different models show that VIP is versatile and robust enough to support large simulations. The platform currently has 200 registered users who consumed 33 years of CPU time in 2011. PMID- 23014714 TI - Combining boundary-based methods with tensor-based morphometry in the measurement of longitudinal brain change. AB - Tensor-based morphometry is a powerful tool for automatically computing longitudinal change in brain structure. Because of bias in images and in the algorithm itself, however, a penalty term and inverse consistency are needed to control the over-reporting of nonbiological change. These may force a tradeoff between the intrinsic sensitivity and specificity, potentially leading to an under-reporting of authentic biological change with time. We propose a new method incorporating prior information about tissue boundaries (where biological change is likely to exist) that aims to keep the robustness and specificity contributed by the penalty term and inverse consistency while maintaining localization and sensitivity. Results indicate that this method has improved sensitivity without increased noise. Thus it will have enhanced power to detect differences within normal aging and along the spectrum of cognitive impairment. PMID- 23014717 TI - Completion of a truncated attenuation image from the attenuated PET emission data. AB - Positron emission tomographs (PETs) are currently almost exclusively designed as hybrid systems. The current standard is the PET/CT combination, while prototype PET/MRI systems are being studied by several research groups. One problem in these systems is that the transaxial field-of-view of the second system is smaller than that of the PET camera and does not provide complete attenuation data. Because this second system provides the image for PET attenuation and scatter correction, the smaller FOV causes truncation of the attenuation map, producing bias in the attenuation corrected activity image. In this paper, we propose a maximum-a-posteriori algorithm for estimating the missing part of the attenuation map from the PET emission data. The method is evaluated on five artificially truncated 18F-FDGPET/CT studies, where it reduced the error on the reconstructed PET activities from 20% to less than 7%. The results on a PET/MRI patient study with 18F-FDG are presented as well. PMID- 23014716 TI - Generation of synthetic but visually realistic time series of cardiac images combining a biophysical model and clinical images. AB - We propose a new approach for the generation of synthetic but visually realistic time series of cardiac images based on an electromechanical model of the heart and real clinical 4-D image sequences. This is achieved by combining three steps. The first step is the simulation of a cardiac motion using an electromechanical model of the heart and the segmentation of the end diastolic image of a cardiac sequence. We use biophysical parameters related to the desired condition of the simulated subject. The second step extracts the cardiac motion from the real sequence using nonrigid image registration. Finally, a synthetic time series of cardiac images corresponding to the simulated motion is generated in the third step by combining the motion estimated by image registration and the simulated one. With this approach, image processing algorithms can be evaluated as we know the ground-truth motion underlying the image sequence. Moreover, databases of visually realistic images of controls and patients can be generated for which the underlying cardiac motion and some biophysical parameters are known. Such databases can open new avenues for machine learning approaches. PMID- 23014718 TI - Conversion of OXA-66 into OXA-82 in clinical Acinetobacter baumannii isolates and association with altered carbapenem susceptibility. AB - OBJECTIVES: Three clinical Acinetobacter baumannii isolates (A-C) were isolated from three separate patients during an outbreak in a hospital in Krakow, Poland. Isolate A was recovered first and was susceptible to carbapenems, whereas isolates B and C were resistant. The aim of this study was to investigate the differences in carbapenem susceptibility in these outbreak-related isolates. METHODS: Clonal relatedness was determined using rep-PCR-based DiversiLab. The bla(OXA-51-like) genes and their upstream regions were sequenced. Expression of the genes encoding OXA-51-like and the three major porins CarO, OprD-like and 33 36 kDa Omp were investigated by semi-quantitative RT-PCR. Comparison of outer membrane protein (OMP) profiles was performed using SDS-PAGE. ISAba1-bla(OXA-82) was cloned into the shuttle vector pWH1266 and transferred into A. baumannii ATCC 17978. RESULTS: The isolates were identical by rep-PCR and clustered with international clonal lineage 2. Sequencing of bla(OXA-51-like) revealed a conversion of OXA-66 (isolate A) into OXA-82 (isolates B and C). bla(OXA-82) was also associated with ISAba1. Expression analysis revealed overexpression of bla(OXA-82). There was no difference in OMP expression between the isolates. ISAba1-bla(OXA-82) conferred carbapenem resistance in ATCC 17978. CONCLUSIONS: Carbapenem resistance in outbreak-related isolates was mediated by conversion of OXA-66 into OXA-82 and its subsequent overexpression. This further highlights the genome plasticity of A. baumannii, leading to carbapenem resistance. PMID- 23014719 TI - Nosocomial dissemination of Providencia stuartii isolates carrying bla OXA-48, bla PER-1, bla CMY-4 and qnrA6 in a Tunisian hospital. AB - OBJECTIVES: To report an outbreak due to Providencia stuartii isolates carrying bla(OXA-48), bla(PER-1), bla(CMY-4) and qnrA6 in a Tunisian hospital in 2011. METHODS: Eight intensive care unit (ICU) patients infected/colonized by extended spectrum beta-lactamase (ESBL)-producing P. stuartii between March and May 2011 were included. Molecular epidemiology was studied by PFGE. Antibiotic resistance genes were analysed by PCR and sequencing and the plasmid incompatibility group by a PCR-based replicon typing scheme. RESULTS: Eight patients were colonized with ESBL-producing P. stuartii isolates. All these isolates were clonally related and found to carry bla(OXA-48), bla(PER-1), bla(CMY-4), qnrA6 and aac-6' Ib genes on the same self-conjugative IncA/C plasmid. The same strain was also cultured from environmental samples in the ICU. All these isolates were susceptible to carbapenems. Only one colonized patient developed P. stuartii pleurisy and was effectively treated with imipenem alone. CONCLUSIONS: This is the first report of an outbreak due to P. stuartii isolates carrying bla(OXA-48) in Tunisia. The simultaneous expression of various resistance genes (bla(OXA-48), bla(CMY-4), bla(PER-1), qnrA and aac-6'-Ib) by P. stuartii isolates is alarming. PMID- 23014720 TI - European Antibiotic Awareness Day 2012: general practitioners encouraged to TARGET antibiotics through guidance, education and tools. AB - On 18 November 2012, the UK will once again support the annual European Antibiotic Awareness Day (EAAD). In particular, hospitals will be asked to promote the Start Smart-Then Focus guidance for hospitals launched in 2011, while the Royal College of General Practitioners will publish the TARGET Antibiotics toolkit on their web site. TARGET (Treat Antibiotics Responsibly, Guidance, Education, Tools) emphasizes the need for both primary care staff and the public to use antibiotics responsibly, and provides guidance, education and tools. The web site has been developed by a multiprofessional group and hosts national antibiotic guidance, an antibiotic app, leaflets designed to be shared by patients during consultations, a presentation for clinicians, an interactive self assessment tool, audit tools, posters and videos for the waiting room and links to other materials. The EAAD is still very relevant and worth promoting enthusiastically through all clinical professionals in an effort to encourage responsible use of antibiotics and thereby control antibiotic resistance. PMID- 23014721 TI - Guest editorial: special section on light scatter and fluorescence of the eye lens. AB - This Special Section Guest Editorial provides an overview of the topical area and an introduction to the articles featured in the special section. PMID- 23014722 TI - Summary of studies on the blue-green autofluorescence and light transmission of the ocular lens. PMID- 23014723 TI - Age and human lenticular fluorescence. PMID- 23014724 TI - Visual efficiency of scattering and fluorescence in the human eye lens. PMID- 23014725 TI - Refractive index changes in the ocular lens result from increased light scatter. PMID- 23014726 TI - Dimethyl sulfoxide cataract: a model for optical anisotropy fluctuations. PMID- 23014728 TI - Optical tomography of the in vivo human lens: three-dimensional visualization of cataracts. PMID- 23014727 TI - Development of a noninvasive diabetes screening device using the ratio of fluorescence to Rayleigh scattered light. PMID- 23014729 TI - Two-photon excitation in functional biological imaging. PMID- 23014731 TI - Error assessment of a wavelength tunable frequency domain system for noninvasive tissue spectroscopy. PMID- 23014730 TI - Detection limit in localizing objects hidden in a turbid medium using an optically scanned phased array. PMID- 23014732 TI - Numerical verification of time-domain moment method in ultrasound tomography. PMID- 23014733 TI - Quantitative measurement of optical parameters in normal breasts using time resolved spectroscopy: in vivo results of 30 Japanese women. PMID- 23014734 TI - Ultraviolet laser-induced autofluorescence distinction between malignant and normal urothelial cells and tissues. PMID- 23014735 TI - Optical properties of normal and diseased breast tissues: prognosis for optical mammography. PMID- 23014736 TI - Fragmentation of DNA in a sub-microliter microfluidic sonication device. AB - Fragmentation of DNA is an essential step for many biological applications including the preparation of next-generation sequencing (NGS) libraries. As sequencing technologies push the limits towards single cell and single molecule resolution, it is of great interest to reduce the scale of this upstream fragmentation step. Here we describe a miniaturized DNA shearing device capable of processing sub-microliter samples based on acoustic shearing within a microfluidic chip. A strong acoustic field was generated by a Langevin-type piezo transducer and coupled into the microfluidic channel via the flexural lamb wave mode. Purified genomic DNA, as well as covalently cross-linked chromatin were sheared into various fragment sizes ranging from ~180 bp to 4 kb. With the use of standard PDMS soft lithography, our approach should facilitate the integration of additional microfluidic modules and ultimately allow miniaturized NGS workflows. PMID- 23014738 TI - 6-gingerol ameliorated doxorubicin-induced cardiotoxicity: role of nuclear factor kappa B and protein glycation. AB - PURPOSE: Doxorubicin is a widely used antitumour drug. Cardiotoxicity is considered a major limitation for its clinical use. The present study was designed to assess the possible antioxidant and antiapoptotic effects of 6 gingerol in attenuating doxorubicin-induced cardiac damage. METHOD: Male albino rats were treated with either intraperitoneal doxorubicin (18 mg/kg divided into six equal doses for 2 weeks) and/or oral 6-gingerol (10 mg/kg starting 5 days before and continued till the end of the experiment). RESULTS: 6-gingerol significantly ameliorated the doxorubicin-induced elevation in the cardiac enzymes. The stimulation of oxidative stress by doxorubicin was evidenced by the significant decrease in the serum soluble receptor for advanced glycation endproduct allowing unopposed serum advanced glycation endproduct availability. Moreover, doxorubicin activated nuclear factor kappa B (NF-kappaB) which was indicated by an increase in its immunohistochemical staining in the nucleus. In addition, doxorubicin-induced cardiotoxicity was accompanied by elevation of cardiac caspase-3. Notably, pretreatment with 6-gingerol significantly ameliorated the changes in sRAGE, NF-kappaB and cardiac caspase-3. Cardiac enzymes showed significant positive correlation with NF-kappaB and caspase-3 but negative with serum sRAGE, suggesting their role in doxorubicin-induced cardiac injury. These findings were confirmed by cardiac tissue histopathology. CONCLUSION: 6-gingerol, a known single compound from ginger with anticancer activity, was shown to have a promising role in cardioprotection against doxorubicin-induced cardiotoxicity. This study suggested a novel mechanism for 6 gingerol cardioprotection, which might be mediated through its antioxidative effect and modulation of NF-kappaB as well as apoptosis. PMID- 23014737 TI - A Phase I clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy. AB - PURPOSE: Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors. METHODS: Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed. RESULTS: Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1-4, 8-11, 15-18, and 22-25, and 100 mg/m(2) paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7-28 weeks). CONCLUSIONS: This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease specific Phase II trials is warranted. PMID- 23014739 TI - Elevated IL-1beta and IL-6 levels in lumbar herniated discs in patients with sciatic pain. AB - PURPOSE: Previous experimental models have shown that proinflammatory cytokines modulate peripheral and central nociception. However, the direct correlation between inflammation and pain in patients remains unclear. Our aim is to correlate the levels of inflammation in the spine with pre- and postoperative pain scores after discectomy. METHODS: Paravertebral muscle, annulus fibrosus (AF) and nucleus pulposus (NP) biopsies were intraoperatively collected from ten lumbar disc hernia (LDH) patients suffering from chronic sciatic pain and, as painless controls, five scoliosis patients. IL-1beta and IL-6 expressions in these biopsies were assessed by qPCR and western blot. The amount of pain, indicated on a 0-10 point visual analogue scale (VAS), was assessed 1 day before surgery and 6 weeks and 1 year after surgery. For analysis purposes, LDH patients were grouped into painful (VAS >= 3.5) and non-painful (VAS < 3.5). LDH painful patient group showed a onefold increased mRNA expression of IL-1beta in the NP, and IL-6 in the AF and NP (p < 0.05 vs. controls). RESULTS: By western blot analysis, both cytokines were clearly visible in all LDH biopsies, but not in controls. However, cytokine expression of the painful patient group did not differ from those of the non-painful patient group. In addition, there was no correlation between VAS scores and either marker. CONCLUSIONS: These findings support the idea that LDH is accompanied by a local inflammatory process. Yet, the lack of correlation between IL-1beta or IL-6 expression and the severity pain suggests that these cytokines may not play a leading role in maintaining a pain generating network. PMID- 23014740 TI - Posterior spinal cord herniation: a novel occurrence following surgery for an intramedullary cyst at the thoracolumbar junction. AB - BACKGROUND: Dorsal herniation of the spinal cord through the dura is an uncommon phenomenon and this is only the fifth reported case in the thoracolumbar spine, the first following surgery at the thoracolumbar junction. CASE: A 57-year-old male underwent marsupialisation of a benign intramedullary cyst at the T12-L1 level and subsequently returned with symptoms of dorsal column compromise. He was found to have a posterior herniation of the cord into a pseudomeningocele at the level of the previous surgery. CONCLUSION: The hernia was reduced surgically and the defect closed directly without the need for a dural patch leading to a full recovery. Posterior cord herniation, its possible aetiologies and management strategies are discussed. PMID- 23014741 TI - Intradural lumbar disc herniation: report of five cases with literature review. AB - INTRODUCTION: Intradural lumbar disc herniations are uncommon presentations of a relatively frequent pathology, representing less than 1% of all lumbar disc hernias. They show specific features concerning their clinical diagnosis, with a higher incidence of cauda equina syndrome, and their surgical treatment requires a transdural approach. METHODS: In this article, we describe five cases of this pathology and review the literature as well as some considerations about the difficulties in the preoperative diagnostic issues and the surgical technique. CONCLUSION: We concluded that for intradural disc herniations the diagnosis is mainly intraoperative, and the surgical technique has some special aspects. PMID- 23014744 TI - Sparse representation with kernels. AB - Recent research has shown the initial success of sparse coding (Sc) in solving many computer vision tasks. Motivated by the fact that kernel trick can capture the nonlinear similarity of features, which helps in finding a sparse representation of nonlinear features, we propose kernel sparse representation (KSR). Essentially, KSR is a sparse coding technique in a high dimensional feature space mapped by an implicit mapping function. We apply KSR to feature coding in image classification, face recognition, and kernel matrix approximation. More specifically, by incorporating KSR into spatial pyramid matching (SPM), we develop KSRSPM, which achieves a good performance for image classification. Moreover, KSR-based feature coding can be shown as a generalization of efficient match kernel and an extension of Sc-based SPM. We further show that our proposed KSR using a histogram intersection kernel (HIK) can be considered a soft assignment extension of HIK-based feature quantization in the feature coding process. Besides feature coding, comparing with sparse coding, KSR can learn more discriminative sparse codes and achieve higher accuracy for face recognition. Moreover, KSR can also be applied to kernel matrix approximation in large scale learning tasks, and it demonstrates its robustness to kernel matrix approximation, especially when a small fraction of the data is used. Extensive experimental results demonstrate promising results of KSR in image classification, face recognition, and kernel matrix approximation. All these applications prove the effectiveness of KSR in computer vision and machine learning tasks. PMID- 23014745 TI - Nonlocal regularization of inverse problems: a unified variational framework. AB - We introduce a unifying energy minimization framework for nonlocal regularization of inverse problems. In contrast to the weighted sum of square differences between image pixels used by current schemes, the proposed functional is an unweighted sum of inter-patch distances. We use robust distance metrics that promote the averaging of similar patches, while discouraging the averaging of dissimilar patches. We show that the first iteration of a majorize-minimize algorithm to minimize the proposed cost function is similar to current nonlocal methods. The reformulation thus provides a theoretical justification for the heuristic approach of iterating nonlocal schemes, which re-estimate the weights from the current image estimate. Thanks to the reformulation, we now understand that the widely reported alias amplification associated with iterative nonlocal methods are caused by the convergence to local minimum of the nonconvex penalty. We introduce an efficient continuation strategy to overcome this problem. The similarity of the proposed criterion to widely used nonquadratic penalties (e.g., total variation and lp semi-norms) opens the door to the adaptation of fast algorithms developed in the context of compressive sensing; we introduce several novel algorithms to solve the proposed nonlocal optimization problem. Thanks to the unifying framework, these fast algorithms are readily applicable for a large class of distance metrics. PMID- 23014746 TI - Robust image analysis with sparse representation on quantized visual features. AB - Recent techniques based on sparse representation (SR) have demonstrated promising performance in high-level visual recognition, exemplified by the highly accurate face recognition under occlusion and other sparse corruptions. Most research in this area has focused on classification algorithms using raw image pixels, and very few have been proposed to utilize the quantized visual features, such as the popular bag-of-words feature abstraction. In such cases, besides the inherent quantization errors, ambiguity associated with visual word assignment and misdetection of feature points, due to factors such as visual occlusions and noises, constitutes the major cause of dense corruptions of the quantized representation. The dense corruptions can jeopardize the decision process by distorting the patterns of the sparse reconstruction coefficients. In this paper, we aim to eliminate the corruptions and achieve robust image analysis with SR. Toward this goal, we introduce two transfer processes (ambiguity transfer and mis detection transfer) to account for the two major sources of corruption as discussed. By reasonably assuming the rarity of the two kinds of distortion processes, we augment the original SR-based reconstruction objective with l(0) norm regularization on the transfer terms to encourage sparsity and, hence, discourage dense distortion/transfer. Computationally, we relax the nonconvex l(0) norm optimization into a convex l(1) norm optimization problem, and employ the accelerated proximal gradient method to optimize the convergence provable updating procedure. Extensive experiments on four benchmark datasets, Caltech 101, Caltech-256, Corel-5k, and CMU pose, illumination, and expression, manifest the necessity of removing the quantization corruptions and the various advantages of the proposed framework. PMID- 23014747 TI - Rate-distortion optimized rate control for depth map-based 3-D video coding. AB - In this paper, a novel rate control scheme with optimized bits allocation for the 3-D video coding is proposed. First, we investigate the R-D characteristics of the texture and depth map of the coded view, as well as the quality dependency between the virtual view and the coded view. Second, an optimal bit allocation scheme is developed to allocate target bits for both the texture and depth maps of different views. Meanwhile, a simplified model parameter estimation scheme is adopted to speed up the coding process. Finally, the experimental results on various 3-D video sequences demonstrate that the proposed algorithm achieves excellent R-D efficiency and bit rate accuracy compared to benchmark algorithms. PMID- 23014748 TI - Modified gradient search for level set based image segmentation. AB - Level set methods are a popular way to solve the image segmentation problem. The solution contour is found by solving an optimization problem where a cost functional is minimized. Gradient descent methods are often used to solve this optimization problem since they are very easy to implement and applicable to general nonconvex functionals. They are, however, sensitive to local minima and often display slow convergence. Traditionally, cost functionals have been modified to avoid these problems. In this paper, we instead propose using two modified gradient descent methods, one using a momentum term and one based on resilient propagation. These methods are commonly used in the machine learning community. In a series of 2-D/3-D-experiments using real and synthetic data with ground truth, the modifications are shown to reduce the sensitivity for local optima and to increase the convergence rate. The parameter sensitivity is also investigated. The proposed methods are very simple modifications of the basic method, and are directly compatible with any type of level set implementation. Downloadable reference code with examples is available online. PMID- 23014749 TI - Image enhancement using the hypothesis selection filter: theory and application to JPEG decoding. AB - We introduce the hypothesis selection filter (HSF) as a new approach for image quality enhancement. We assume that a set of filters has been selected a priori to improve the quality of a distorted image containing regions with different characteristics. At each pixel, HSF uses a locally computed feature vector to predict the relative performance of the filters in estimating the corresponding pixel intensity in the original undistorted image. The prediction result then determines the proportion of each filter used to obtain the final processed output. In this way, the HSF serves as a framework for combining the outputs of a number of different user selected filters, each best suited for a different region of an image. We formulate our scheme in a probabilistic framework where the HSF output is obtained as the Bayesian minimum mean square error estimate of the original image. Maximum likelihood estimates of the model parameters are determined from an offline fully unsupervised training procedure that is derived from the expectation-maximization algorithm. To illustrate how to apply the HSF and to demonstrate its potential, we apply our scheme as a post-processing step to improve the decoding quality of JPEG-encoded document images. The scheme consistently improves the quality of the decoded image over a variety of image content with different characteristics. We show that our scheme results in quantitative improvements over several other state-of-the-art JPEG decoding methods. PMID- 23014750 TI - Wavelet Bayesian network image denoising. AB - From the perspective of the Bayesian approach, the denoising problem is essentially a prior probability modeling and estimation task. In this paper, we propose an approach that exploits a hidden Bayesian network, constructed from wavelet coefficients, to model the prior probability of the original image. Then, we use the belief propagation (BP) algorithm, which estimates a coefficient based on all the coefficients of an image, as the maximum-a-posterior (MAP) estimator to derive the denoised wavelet coefficients. We show that if the network is a spanning tree, the standard BP algorithm can perform MAP estimation efficiently. Our experiment results demonstrate that, in terms of the peak-signal-to-noise ratio and perceptual quality, the proposed approach outperforms state-of-the-art algorithms on several images, particularly in the textured regions, with various amounts of white Gaussian noise. PMID- 23014751 TI - Maximum Margin Correlation Filter: a new approach for localization and classification. AB - Support vector machine (SVM) classifiers are popular in many computer vision tasks. In most of them, the SVM classifier assumes that the object to be classified is centered in the query image, which might not always be valid, e.g., when locating and classifying a particular class of vehicles in a large scene. In this paper, we introduce a new classifier called Maximum Margin Correlation Filter (MMCF), which, while exhibiting the good generalization capabilities of SVM classifiers, is also capable of localizing objects of interest, thereby avoiding the need for image centering as is usually required in SVM classifiers. In other words, MMCF can simultaneously localize and classify objects of interest. We test the efficacy of the proposed classifier on three different tasks: vehicle recognition, eye localization, and face classification. We demonstrate that MMCF outperforms SVM classifiers as well as well known correlation filters. PMID- 23014752 TI - Missing texture reconstruction method based on error reduction algorithm using Fourier transform magnitude estimation scheme. AB - A missing texture reconstruction method based on an error reduction (ER) algorithm, including a novel estimation scheme of Fourier transform magnitudes is presented in this brief. In our method, Fourier transform magnitude is estimated for a target patch including missing areas, and the missing intensities are estimated by retrieving its phase based on the ER algorithm. Specifically, by monitoring errors converged in the ER algorithm, known patches whose Fourier transform magnitudes are similar to that of the target patch are selected from the target image. In the second approach, the Fourier transform magnitude of the target patch is estimated from those of the selected known patches and their corresponding errors. Consequently, by using the ER algorithm, we can estimate both the Fourier transform magnitudes and phases to reconstruct the missing areas. PMID- 23014753 TI - Adaptive fingerprint image enhancement with emphasis on preprocessing of data. AB - This article proposes several improvements to an adaptive fingerprint enhancement method that is based on contextual filtering. The term adaptive implies that parameters of the method are automatically adjusted based on the input fingerprint image. Five processing blocks comprise the adaptive fingerprint enhancement method, where four of these blocks are updated in our proposed system. Hence, the proposed overall system is novel. The four updated processing blocks are: 1) preprocessing; 2) global analysis; 3) local analysis; and 4) matched filtering. In the preprocessing and local analysis blocks, a nonlinear dynamic range adjustment method is used. In the global analysis and matched filtering blocks, different forms of order statistical filters are applied. These processing blocks yield an improved and new adaptive fingerprint image processing method. The performance of the updated processing blocks is presented in the evaluation part of this paper. The algorithm is evaluated toward the NIST developed NBIS software for fingerprint recognition on FVC databases. PMID- 23014757 TI - An Efficient Approach to Integrating Radius Information into Multiple Kernel Learning. AB - Integrating radius information has been demonstrated by recent work on multiple kernel learning (MKL) as a promising way to improve kernel learning performance. Directly integrating the radius of the minimum enclosing ball (MEB) into MKL as it is, however, not only incurs significant computational overhead but also possibly adversely affects the kernel learning performance due to the notorious sensitivity of this radius to outliers. Inspired by the relationship between the radius of the MEB and the trace of total data scattering matrix, this paper proposes to incorporate the latter into MKL to improve the situation. In particular, in order to well justify the incorporation of radius information, we strictly comply with the radius-margin bound of support vector machines (SVMs) and thus focus on the l2-norm soft-margin SVM classifier. Detailed theoretical analysis is conducted to show how the proposed approach effectively preserves the merits of incorporating the radius of the MEB and how the resulting optimization is efficiently solved. Moreover, the proposed approach achieves the following advantages over its counterparts: 1) more robust in the presence of outliers or noisy training samples; 2) more computationally efficient by avoiding the quadratic optimization for computing the radius at each iteration; and 3) readily solvable by the existing off-the-shelf MKL packages. Comprehensive experiments are conducted on University of California, Irvine, protein subcellular localization, and Caltech-101 data sets, and the results well demonstrate the effectiveness and efficiency of our approach. PMID- 23014758 TI - Gaussian Bare-Bones Differential Evolution. AB - Differential evolution (DE) is a well-known algorithm for global optimization over continuous search spaces. However, choosing the optimal control parameters is a challenging task because they are problem oriented. In order to minimize the effects of the control parameters, a Gaussian bare-bones DE (GBDE) and its modified version (MGBDE) are proposed which are almost parameter free. To verify the performance of our approaches, 30 benchmark functions and two real-world problems are utilized. Conducted experiments indicate that the MGBDE performs significantly better than, or at least comparable to, several state-of-the-art DE variants and some existing bare-bones algorithms. PMID- 23014754 TI - Association between blood levels of PCDDs/PCDFs/dioxin-like PCBs and history of allergic and other diseases in the Japanese population. AB - BACKGROUND: Previous studies reported that exposure to dioxins was associated with an increased risk of various diseases in general populations. OBJECTIVES: The aim of this study was to examine the association between levels of dioxins in blood and allergic and other diseases. METHODS: We conducted a cross-sectional study on 1,063 men and 1,201 women (aged 15-76 years), who were living throughout Japan and not occupationally exposed to dioxins, during 2002-2010. In fasting blood samples, polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs (DL-PCBs) were analyzed by isotope dilution high-resolution gas chromatography/mass spectrometry. We obtained information on life style and self-reported history of diseases using a questionnaire. Blood pressure, blood levels of hemoglobin A1c, and serum lipids were also measured. Multiple logistic regression models were used to analyze the association between dioxin levels in blood and various diseases. RESULTS: Toxic equivalents of PCDDs/PCDFs and total dioxins showed significant inverse dose response relationships with atopic dermatitis, after adjustments for potential confounders. The highest quartile for total dioxins had an adjusted odds ratio of 0.26 (95 % confidence interval 0.08-0.70) compared to the reference group (first quartile). The odds ratios for hypertension, diabetes mellitus, hyperlipidemia, gout in men, and gynecologic diseases in women significantly increased with increasing toxic equivalents of PCDDs/PCDFs, DL-PCBs, and total dioxins in blood. CONCLUSIONS: The present findings suggest that background exposure to dioxins was associated with reduced risk of atopic dermatitis. The results also support the idea that low-level exposure to dioxins is associated with an increased risk of diabetes, hypertension, and hyperlipidemia. PMID- 23014759 TI - A New Surrogate-Assisted Interactive Genetic Algorithm With Weighted Semisupervised Learning. AB - Surrogate-assisted interactive genetic algorithms (IGAs) are found to be very effective in reducing human fatigue. Different from models used in most surrogate assisted evolutionary algorithms, surrogates in IGA must be able to handle the inherent uncertainties in fitness assignment by human users, where, e.g., interval-based fitness values are assigned to individuals. This poses another challenge to using surrogates for fitness approximation in evolutionary optimization, in addition to the lack of training data. In this paper, a new surrogate-assisted IGA has been proposed, where the uncertainty in subjective fitness evaluations is exploited both in training the surrogates and in managing surrogates. To enhance the approximation accuracy of the surrogates, an improved cotraining algorithm for semisupervised learning has been suggested, where the uncertainty in interval-based fitness values is taken into account in training and weighting the two cotrained models. Moreover, uncertainty in the interval based fitness values is also considered in model management so that not only the best individuals but also the most uncertain individuals will be chosen to be re evaluated by the human user. The effectiveness of the proposed algorithm is verified on two test problems as well as in fashion design, a typical application of IGA. Our results indicate that the new surrogate-assisted IGA can effectively alleviate user fatigue and is more likely to find acceptable solutions in solving complex design problems. PMID- 23014760 TI - A Bayesian framework for active artificial perception. AB - In this paper, we present a Bayesian framework for the active multimodal perception of 3-D structure and motion. The design of this framework finds its inspiration in the role of the dorsal perceptual pathway of the human brain. Its composing models build upon a common egocentric spatial configuration that is naturally fitting for the integration of readings from multiple sensors using a Bayesian approach. In the process, we will contribute with efficient and robust probabilistic solutions for cyclopean geometry-based stereovision and auditory perception based only on binaural cues, modeled using a consistent formalization that allows their hierarchical use as building blocks for the multimodal sensor fusion framework. We will explicitly or implicitly address the most important challenges of sensor fusion using this framework, for vision, audition, and vestibular sensing. Moreover, interaction and navigation require maximal awareness of spatial surroundings, which, in turn, is obtained through active attentional and behavioral exploration of the environment. The computational models described in this paper will support the construction of a simultaneously flexible and powerful robotic implementation of multimodal active perception to be used in real-world applications, such as human-machine interaction or mobile robot navigation. PMID- 23014761 TI - Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. AB - Despite aggressive treatment with radiation and chemotherapy, recurrence of glioblastoma multiforme (GBM) is inevitable. The objective of this study was to show that the blood-brain barrier (BBB), through a combination of tight junctions and active efflux transporters in the brain microvasculature, can significantly restrict delivery of molecularly targeted agents to invasive glioma cells. Transgenic mice lacking P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) were used to study efflux of erlotinib at the BBB. A U87 rat xenograft model of GBM was used to investigate the regional distribution of erlotinib to the tumor, and brain regions surrounding the tumor. The effect of concurrent administration of elacridar on regional tumor distribution of erlotinib was evaluated. We show that erlotinib transport across an intact BBB is significantly restricted due to P-gp- and Bcrp-mediated efflux transport. We then show that the BBB is sufficiently intact in areas of brain adjacent to the tumor core to significantly restrict erlotinib delivery. Inhibition of P-gp and Bcrp by the dual inhibitor elacridar dramatically increased erlotinib delivery to the tumor core, rim, and normal brain. These results provide conclusive evidence of the impact that active efflux at the BBB has on the delivery of molecularly targeted therapy to different tumor regions in glioma. These data also support the possibility that the repeated failure of clinical trials of new drugs for gliomas may be in part due to a failure to achieve effective concentrations in invasive tumor cells that reside behind an intact BBB. PMID- 23014762 TI - Mediator MED15 modulates transforming growth factor beta (TGFbeta)/Smad signaling and breast cancer cell metastasis. PMID- 23014763 TI - Position recognition to support bedsores prevention. AB - In this paper, a feasibility study where small wireless devices are used to classify some typical users positions in the bed is presented. Wearable wireless low-cost commercial transceivers operating at 2.4 GHz are supposed to be widely deployed in indoor settings and on peoples bodies in tomorrows pervasive computing environments. The key idea of this work is to leverage their presence by collecting the received signal strength (RSS) measured among fixed devices, deployed in the environment, and the wearable one. The RSS measurements are used to classify a set of users positions in the bed, monitoring the activities of patients unable to make the desirable bodily movements. The collected data are classified using both support vector machine and K-nearest neighbour methods, in order to recognize the different users position, and thus supporting the bedsores issue. PMID- 23014764 TI - A novel D235Y mutation in the GP1BA gene enhances platelet interaction with von Willebrand factor in an Iranian family with platelet-type von Willebrand disease. AB - Platelet-type von Willebrand disease (PT-VWD) is a rare bleeding disorder with an intrinsic defect in platelets rather than von Willebrand factor (VWF), but has clinical and laboratory features similar to the more common type 2B VWD. The intriguing nature of the pathophysiology and molecular genetics of PT-VWD has created lengthy debate in literature regarding its discrimination from type 2B VWD, and essentially confirming DNA analysis as the gold standard in diagnosis and revealing pathologic mutations. In this report we identify a novel Asp235Tyrmutation in the GP1BA gene of two Iranian patients showing the PT-VWD phenotype who were originally misdiagnosed as type 2B VWD. By structural modelling of the mutant by introducing Tyr235 into the available crystal structure of the glycoprotein (GP)Ibalpha N-terminal domain, we observed the mutant Tyr235 generates a hydrophobic tip to the extended beta-switch loop of GPIbalpha. Further modelling of the resulting complex with VWFA1 indicates this could result in an enhanced interface compared to wild-type Asp235. This data provides an update to the present knowledge about this rare disorder, and confirms the necessity of genetic testing for accurate diagnosis, and the importance of studying natural mutations to better understand molecular aspects of GPIbalpha-VWFA1 interaction. PMID- 23014765 TI - Does sleep deprivation impair orthopaedic surgeons' cognitive and psychomotor performance? AB - BACKGROUND: Sleep deprivation may slow reaction time, cloud judgment, and impair the ability to think. Our purpose was to study the cognitive and psychomotor performances of orthopaedic trauma surgeons on the basis of the amount of sleep that they obtained. METHODS: We prospectively studied the performances of thirty two orthopaedic trauma surgeons (residents, fellows, and attending surgeons) over two four-week periods at an urban academic trauma center. Testing sessions used handheld computers to administer validated cognitive and psychomotor function tests. We conducted a multivariate analysis to examine the independent association between test performance and multiple covariates, including the amount of sleep the night before testing. RESULTS: Our analysis demonstrated that orthopaedic surgeons who had slept four hours or less the night before the test had 1.43 times the odds (95% confidence interval, 1.04 to 1.95; p = 0.03) of committing at least one error on an individual test compared with orthopaedic surgeons who had slept more than four hours the previous night. The Running Memory test, which assesses sustained attention, concentration, and working memory, was most sensitive to deterioration in performance in participants who had had four hours of sleep or less; when controlling for other covariates, the test demonstrated a 72% increase in the odds of making at least one error (odds ratio, 1.72 [95% confidence interval, 1.02 to 2.90]; p = 0.04). No significant decrease in performance with sleep deprivation was shown with the other three tests. CONCLUSIONS: Orthopaedic trauma surgeons showed deterioration in performance on a validated cognitive task when they had slept four hours or less the previous night. It is unknown how performance on this test relates to surgical performance. PMID- 23014767 TI - A qualitative model for aggregation and diffusion of beta-amyloid in Alzheimer's disease. AB - In this paper we present a mathematical model for the aggregation and diffusion of Abeta amyloid in the brain affected by Alzheimer's disease, at the early stage of the disease. The model is based on a classical discrete Smoluchowski aggregation equation modified to take diffusion into account. We also describe a numerical scheme and discuss the results of the simulations in the light of the recent biomedical literature. PMID- 23014768 TI - Biomarkers of platelet activation in acute coronary syndromes. AB - The most convincing evidence for the participation of platelets in arterial thrombosis in humans comes from studies of platelet activation in patients with acute coronary syndromes (ACS) and from trials of antiplatelet drugs. Both strongly support the concept that repeated episodes of platelet activation over the thrombogenic surface of a vulnerable plaque may contribute to the risk of death from coronary causes. However, the relation of in vivo platelet activation and adverse clinical events to results of platelet function tests remains largely unknown. A valuable marker of in vivo platelet activation should be specific, unaltered by pre-analytical artefacts and reproducibly measured by easily performed methods. This article describes current biomarkers of platelet activation in ACS, reviews their advantages and disadvantages, discusses their potential pitfalls, and demonstrates emerging data supporting the positive clinical implications of monitoring in vivo platelet activation in the setting of ACS. PMID- 23014771 TI - Synthetic lethality for linking the mycophenolate mofetil mode of action with molecular disease and drug profiles. AB - Systematic study of the effect of mycophenolate mofetil (MMF) on the molecular level in the context of other drugs and molecular disease profiles became possible due to the availability of large scale molecular profiles on both disease characterization and drug mode of action. Such analysis is of particular value in elucidating alternative drug use for addressing clinically unmet needs, and the concept of synthetic lethality provides an alternative tool for such repositioning strategies. Resting on consolidation of transcriptomics data and literature mining, a MMF molecular footprint became available including a set of 170 genes specifically affected by the drug. Analysis of this profile on a molecular pathway level reveals a set of 14 pathways as affected. Next to assignment of molecular pathways and associated diseases synergistic drug combinations are proposed by utilizing the synthetic lethal interaction network. Of particular interest is the combination of MMF with adenosine deaminase inhibitors, sulfasalazine, and other selected drugs interfering with calcium based regulatory pathways and metabolism. Indeed analysis of drugs in clinical trials positively identifies combinations with MMF in the context of synthetic lethality and affected pathways, particularly in diseases such as multiple sclerosis, vasculitis, GVHD and lupus nephritis. Importantly, the synthetic lethal interaction of the drug mode of action is an interesting basis for rational repositioning strategies by suggesting combinations which exhibit a synergistic rather than a mere additive effect, as for example is evident for the combination of tacrolimus and MMF. Inherent is also the assessment of possible adverse effects of drug combinations. PMID- 23014769 TI - Clinical review: Biomarkers of acute kidney injury: where are we now? AB - The recognition that acute kidney injury (AKI) is a significant independent risk factor for morbidity and mortality has resulted in a substantial number of publications over the past 5 years or more. In no small part these have, to a degree, highlighted the inadequacy of conventional markers of renal insufficiency in the acute setting. Much effort has been invested in the identification of early, specific AKI markers in order to aid early diagnosis of AKI and hopefully improve outcome. The search for a 'biomarker' of AKI has seen early promise replaced by a degree of pessimism due to the lack of a clear candidate molecule and variability of results. We outline the major studies described to date as well as discuss potential reasons for the discrepancies observed and suggest that evolution of the field may result in success with ultimately an improvement in patient outcomes. PMID- 23014772 TI - A validated spectrofluorimetric method for the determination of citalopram in bulk and pharmaceutical preparations based on the measurement of the silver nanoparticles-enhanced fluorescence of citalopram/terbium complexes. AB - A simple, sensitive, and accurate spectrofluorimetric method was developed for the determination of citalopram in bulk and pharmaceutical preparations. The method is based on the enhancement of the weak fluorescence signal (FL) of the Tb (III)-citalopram system in the presence of silver nanoparticles. Fluorescence intensities were measured at 555 nm after excitation at 281 nm. Prepared silver nanoparticles (AgNPs) were characterized by UV-Visible spectra and transmission electron microscopy (TEM). Various factors affecting the formation of citalopram Tb (III)-AgNPs complexes were studied and optimized. The fluorescence intensity versus concentration plot was linear over the range 0.02-14 MUg mL(-1), with an excellent correlation coefficient of 0.9978. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 7.15 * 10(-6) MUg mL(-1) and 2.38 * 10(-5) MUg mL(-1) respectively. The proposed method was found to have good reproducibility with a relative standard deviation of 3.66% (n = 6). The interference effects of common excipients found in pharmaceutical preparations were studied. The developed method was validated statistically by performing recoveries studies and successfully applied for the assay of citalopram in bulk powder and pharmaceutical preparations. Percent recoveries were found to range from 98.98% to 100.97% for bulk powder and from 96.57% to 101.77% for pharmaceutical preparations. PMID- 23014774 TI - Regulatory considerations in production of a cell therapy medicinal product in Europe to clinical research. AB - The development of new drugs using stem cells has become a clinic alternative for the treatment of different diseases such as Alzheimer's, diabetes and myocardial infarction. Similar to conventional medicines, stem cells as new medicinal products for cell therapy are subjected to current legislation concerning their manufacture process. Besides, their legality is determined by the Regulatory Agencies belonging to the Member State of the European Union in which they are being registered. With the evolution of therapy that uses cells as medicines, there is a need to develop the appropriate legislative and regulatory framework capable of ensuring their safety and effectiveness. However, few works have been published regarding the regulations that these products must comply through production and commercialization processes. The present work is focused on the description of key events during clinical development and cell production of stem cells as drugs. Such as the regulations, requirements and directives involved in the production of cell therapy medicinal products, from the clinical design stage to its commercialization in Europe. PMID- 23014775 TI - Total femoral and tibial osteochondral allograft for remobilizing a knee after arthrodesis. AB - PURPOSE: Knee arthrodesis is a scarcely tolerated procedure with a strong negative impact on the quality of life of the patient. The use of a fresh osteochondral allograft represents a fascinating option for a biological joint reconstruction. Aim of this report is to describe a case of total femoral and tibial osteochondral allograft used for reversing a non-tolerated knee fusion in a young patient and to report the clinical and radiographic results obtained at a 4-year follow-up. METHODS: A 22-year-old man with right knee arthrodesis received a reversion of the arthrodesis with a total femoral and tibial osteochondral allograft. Clinical and radiographical evaluations were carried out periodically up to 48 months. RESULTS: At 48 months of follow-up, the patient had full integration of the allograft with a range of motion from 0 degrees to 80 degrees . Clinical scores improved from preoperative to final follow-up (IKDC from 25 to 65, KOOS from 32 to 65 and WOMAC from 30 to 74). Radiographic arthritis occurrence of the transplanted surfaces was evident at follow-up. CONCLUSIONS: Despite the good clinical results achieved in the case described, a wider applicability of total femoral and tibial osteochondral allograft requires further studies on long-term larger allograft survival. Arthritis recurrence of the transplanted surfaces is cause of concern. Causes and possible solutions need to be more deeply investigated. PMID- 23014778 TI - Guest editorial: special section on near infrared spectroscopy and imaging of tissues. AB - This Special Section Guest Editorial provides an overview of the topical area and an introduction to the articles featured in the special section. PMID- 23014777 TI - Fractalkine is an independent predictor of mortality in patients with advanced heart failure. AB - Immunological processes are implicated in the multifactorial pathophysiology of heart failure (HF). The multifunctional chemokine fractalkine (CX3CL1) promotes the extravasation of cytotoxic lymphocytes into tissues. We aimed to assess the prognostic value of fractalkine in HF. Fractalkine plasma levels were determined in 349 patients with advanced systolic HF (median 75 years, 66% male). During a median follow-up of 4.9 years (interquartile range: 4.6-5.2), 55.9% of patients died. Fractalkine was a significant predictor of all-cause mortality (p<0.001) with a hazard ratio of 2.78 (95% confidence interval: 1.95-3.95) for the third compared to the first tertile. This association remained significant after multivariable adjustment for demographics, clinical predictive variables and N terminal pro-B-type natriuretic peptide (NT-proBNP, p=0.008). The predictive value of fractalkine did not significantly differ between patients with ischaemic and non-ischaemic HF aetiology (p=0.79). The predictive value of fractalkine tertiles was not significantly modified by tertiles of NT-proBNP (p=0.18) but was more pronounced in the first and third tertile of NT-proBNP. Fractalkine was also an independent predictor of cardiovascular mortality (p=0.015). Fractalkine levels were significantly lower in patients on angiotensin-converting enzyme inhibitor therapy (p<0.001). In conclusion, circulating fractalkine with its pro inflammatory and immunomodulatory effects is an independent predictor of mortality in advanced HF patients. Fractalkine improves risk prediction beyond NT proBNP and might therefore help to identify high risk patients who need special care. Our data indicate the implication of immune modulation in HF pathology. PMID- 23014776 TI - BODIPY dyes in photodynamic therapy. AB - BODIPY dyes tend to be highly fluorescent, but their emissions can be attenuated by adding substituents with appropriate oxidation potentials. Substituents like these have electrons to feed into photoexcited BODIPYs, quenching their fluorescence, thereby generating relatively long-lived triplet states. Singlet oxygen is formed when these triplet states interact with (3)O(2). In tissues, this causes cell damage in regions that are illuminated, and this is the basis of photodynamic therapy (PDT). The PDT agents that are currently approved for clinical use do not feature BODIPYs, but there are many reasons to believe that this situation will change. This review summarizes the attributes of BODIPY dyes for PDT, and in some related areas. PMID- 23014779 TI - Use of near infrared spectroscopy for the clinical monitoring of adult brain. PMID- 23014780 TI - Cerebral oxygenation and hemodynamic changes during infant cardiac surgery: measurements by near infrared spectroscopy. PMID- 23014781 TI - Noninvasive near infrared optical imaging of human brain function with subsecond temporal resolution. PMID- 23014782 TI - Cerebral blood oxygenation changes induced by visual stimulation in humans. PMID- 23014783 TI - Intraoperative monitoring during carotid cross-clamping with near-infrared spectroscopy: a preliminary study. PMID- 23014784 TI - Retinopathy of prematurity and induced changes in arterial oxygen saturation with near infrared spectrophotometry: a retrospective cohort study. PMID- 23014785 TI - Influence of adipose tissue thickness on near infrared spectroscopic signal in the measurement of human muscle. PMID- 23014786 TI - Characterization of female breasts in vivo by time-resolved and spectroscopic measurements in the near infrared spectroscopy. PMID- 23014787 TI - Detection of point mutations in DNA by fluorescence energy transfer. PMID- 23014788 TI - Laser action in condensed disordered media of active dye-stained animal tissues and sandy colloidal scattering walls. PMID- 23014789 TI - Treatment of skin melanoma with pulsed radiation from a neodymium laser. PMID- 23014790 TI - Infrared radiometry of dental enamel during Er:YAG and Er:YSGG laser irradiation. PMID- 23014791 TI - Comparative bactericidal activities of lasers operating at seven different wavelengths. PMID- 23014792 TI - Three-photon excitation of 2,5-bis(4-biphenyl)oxazole: steady-state and time resolved intensities and anisotropies. PMID- 23014794 TI - A hard pill to swallow: medication, empathy, and the value of collaborative recovery. AB - Recovery from mental illness is a complex journey that is greatly facilitated when client and professional helper collaborate in the decision making process. It is further aided when the latter has an empathetic awareness of the client's experience, especially with regard to the impact of pharmacological treatment. The following article describes one psychologist's experience of being prescribed medication during a period of acute illness. Analysis of this experience is via a narrative, phenomenological approach. Results suggest that even when taken as directed, a medication can augment one's subjective feeling of illness. It further shows how challenging it can be for the ailing individual to assert his or her needs for something other than hospitalization. Although only one case is analyzed, it points to the impact that medication may have on the life of a person with mental illness, reinforcing the importance of collaboration and empathetic understanding of the other's experience. PMID- 23014793 TI - Exposure of rats to environmental tobacco smoke during cerebellar development alters behavior and perturbs mitochondrial energetics. AB - BACKGROUND: Environmental tobacco smoke (ETS) exposure is linked to developmental deficits and disorders with known cerebellar involvement. However, direct biological effects and underlying neurochemical mechanisms remain unclear. OBJECTIVES: We sought to identify and evaluate underlying neurochemical change in the rat cerebellum with ETS exposure during critical period development. METHODS: We exposed rats to daily ETS (300, 100, and 0 ug/m3 total suspended particulate) from postnatal day 8 (PD8) to PD23 and then assayed the response at the behavioral, neuroproteomic, and cellular levels. RESULTS: Postnatal ETS exposure induced heightened locomotor response in a novel environment on par initially with amphetamine stimulation. The cerebellar mitochondrial subproteome was significantly perturbed in the ETS-exposed rats. Findings revealed a dose dependent up-regulation of aerobic processes through the modification and increased translocation of Hk1 to the mitochondrion with corresponding heightened ATP synthase expression. ETS exposure also induced a dose-dependent increase in total Dnm1l mitochondrial fission factor; although more active membrane-bound Dnm1l was found at the lower dose. Dnm1l activation was associated with greater mitochondrial staining, particularly in the molecular layer, which was independent of stress-induced Bcl-2 family dynamics. Further, electron microscopy associated Dnm1l-mediated mitochondrial fission with increased biogenesis, rather than fragmentation. CONCLUSIONS: The critical postnatal period of cerebellar development is vulnerable to the effects of ETS exposure, resulting in altered behavior. The biological effect of ETS is underlain in part by a Dnm1l-mediated mitochondrial energetic response at a time of normally tight control. These findings represent a novel mechanism by which environmental exposure can impact neurodevelopment and function. PMID- 23014795 TI - Diagnostic performance of radiographs and computed tomography for displacement and instability of acute scaphoid waist fractures. AB - BACKGROUND: Fracture displacement is the most important factor associated with nonunion of a scaphoid waist fracture.We evaluated the performance characteristics of radiographs and computed tomography (CT) in the diagnosis of intraoperative displacement and instability of scaphoid waist fractures using wrist arthroscopy as the reference standard. METHODS: During a six-year period (2004 to 2010) at two institutions, forty-four adult patients with a scaphoid waist fracture underwent arthroscopy-assisted operative fracture treatment at a mean of nine days (range, two to twenty-two days) after injury. Subjects included all of those with a displaced scaphoid fracture seen on radiographs and a selection of patients with a nondisplaced scaphoid fracture. All patients had preoperative radiographs and CT. Arthroscopy with up to 5 kg of traction was the reference standard for fracture displacement and instability. RESULTS: The reference standard (arthroscopy) led to a diagnosis of twenty-two displaced fractures (all unstable) and twenty-two nondisplaced fractures (seven unstable). Displacement was diagnosed in eleven patients (25%) with the use of radiographs and in twenty (45%) with CT. The sensitivity, specificity, and accuracy for diagnosing intraoperative displacement were 45%, 95%, and 70%, respectively, with the use of radiographs and 77%, 86%, and 82%, respectively, with CT. The sensitivity, specificity, and accuracy for diagnosing intraoperative instability were 34%, 93%, and 55%, respectively,with the use of radiographs and 62%, 87%, and 70%, respectively, with CT. Assuming a 10% prevalence of fracture displacement and instability among all scaphoid waist fractures, the positive and negative predictive values for displacement were 53% and 94%, respectively, with the use of radiographs and 39% and 97% with CT whereas the positive and negative predictive values for instability were 36% and 93%, respectively, with radiographs and 34% and 95% with CT. CONCLUSIONS: Radiographs and CT scans cannot be relied on to accurately diagnose intraoperative scaphoid fracture displacement or instability compared with arthroscopic examination. The influence, with regard to the risk of nonunion, of intraoperative instability of a scaphoid fracture that is seen to be nondisplaced on radiographs or CT is currently unknown. LEVEL OF EVIDENCE: Diagnostic Level III. PMID- 23014796 TI - Blood flow restriction does not result in prolonged decrements in torque. AB - We sought to determine if blood flow restriction (BFR) by itself or in combination with exercise would result in prolonged decrements in torque when using restriction pressures relative to the participants' limb size. Sixteen participants were randomized into Experiment A (n = 9) or Experiment B (n = 7). Experiment A participants performed unilateral knee extensions at 30 % of their one repetition maximum (1RM) with moderate blood flow restriction on one leg (BFR + Exercise) and exercised the other leg without BFR (CON + Exercise). Experiment B participants rested for 4 min with BFR applied to one leg and rested for 4 min without any treatment on the other leg (CON). Maximal voluntary isometric torque (MVC) was measured before and immediately after the exercise or 4 min of rest, 1 h post, and 24 h post. Ratings of perceived exertion (RPE) and discomfort were taken before and after each set. MVC was significantly reduced following both exercise conditions with BFR + Exercise having the largest reduction in torque. However, torque quickly recovered by 1 h post exercise and was back to baseline by 24 h. No changes in torque were observed in Experiment B. RPE and discomfort were rated consistently higher for those in the BFR + Exercise and BFR conditions compared to control. In conclusion, BFR + Exercise does not result in prolonged decrements in torque. The acute changes in torque are due to fatigue and quickly recover back to baseline within 24 h of exercise. In addition, BFR in the absence of exercise has no effect on torque at any time point. PMID- 23014799 TI - Measuring glomerular filtration rate in acute kidney injury: yes, but not yet. AB - Acute kidney injury has become a major focus for nephrologists and critical care physicians. The development of structural biomarkers is proceeding, but the results to date have been disappointing. The use of a shortened creatinine clearance as a functional acute kidney injury biomarker is not new but has not been compared with that of other diagnostic approaches. A rapid, repeatable, and accurate measured glomerular filtration rate would be the gold standard for a functional biomarker and is not far off. PMID- 23014797 TI - MRI-based biodistribution assessment of holmium-166 poly(L-lactic acid) microspheres after radioembolisation. AB - OBJECTIVES: To demonstrate the feasibility of MRI-based assessment of the intrahepatic Ho-PLLA-MS biodistribution after radioembolisation in order to estimate the absorbed radiation dose. METHODS: Fifteen patients were treated with holmium-166 ((166)Ho) poly(L-lactic acid)-loaded microspheres (Ho-PLLA-MS, mean 484 mg; range 408-593 mg) in a phase I study. Multi-echo gradient-echo MR images were acquired from which R (2) maps were constructed. The amount of Ho-PLLA-MS in the liver was determined by using the relaxivity r (2) of the Ho-PLLA-MS and compared with the administered amount. Quantitative single photon emission computed tomography (SPECT) was used for comparison with MRI regarding the whole liver absorbed radiation dose. RESULTS: R (2) maps visualised the deposition of Ho-PLLA-MS with great detail. The mean total amount of Ho-PLLA-MS detected in the liver based on MRI was 431 mg (range 236-666 mg) or 89 +/- 19 % of the delivered amount (correlation coefficient r = 0.7; P < 0.01). A good correlation was found between the whole liver mean absorbed radiation dose as assessed by MRI and SPECT (correlation coefficient r = 0.927; P < 0.001). CONCLUSION: MRI-based dosimetry for holmium-166 radioembolisation is feasible. Biodistribution is visualised with great detail and quantitative measurements are possible. PMID- 23014800 TI - Knowledge and attitudes about AIDS/HIV in a semi-nomadic population in Somaliland. AB - This study aimed to evaluate the level of knowledge concerning HIV transmission and the attitudes towards AIDS among a rural semi-nomadic community in Somaliland. Cross-sectional survey. Questionnaire-based interviews were conducted via a household survey in Sharmake, a village in the Hargeisa district, Somaliland. 141 adults living within 7 km of the village center were asked to complete the survey. Questions about HIV transmission as well as attitudes towards those afflicted were included. The majority of respondents (91 %) had heard of AIDS. Most respondents demonstrated a low to moderate understanding of HIV transmission. Less than half of the respondents (n = 61; 43.6 %) were able to identify 4 means of transmission correctly out of 6 possibilities. Degree of knowledge was unrelated to age or gender. There was a significant positive correlation between an accepting attitude of HIV and knowledge concerning HIV transmission. Stigma against HIV was found among the participants. More than half (58 %) of respondents expressed a desire to be tested, most of whom were deemed to have a high level of knowledge. Knowledge is a significant factor in the prevention of HIV infection. Therefore, information about AIDS and its prevention needs to be disseminated among the rural population immediately. Radio campaigns should focus on increasing public knowledge concerning HIV transmission and reducing stigma against HIV. It is also vital that HIV tests be made available to the remote population. PMID- 23014801 TI - Improvements in health behaviors and health status among newly insured members of an innovative health access plan. AB - The Healthy Howard Health Plan (HHHP) is an innovative health access plan providing healthcare and health coaching to previously uninsured adults in Howard County, Maryland. HHHP members who enrolled in HHHP between January 2009 to June 2010 are followed over time using a variety of self-reported data collection tools including a health risk assessment (HRA), the SF-12, a measure of health status, and the PAM, patient activation measure. We describe their unmet health needs, demographics, health status and behaviors at baseline and we describe changes in health-related behaviors over time. Demographic and baseline HRA results for 700 individuals who enrolled over the first 18 months reveal HHHP members generally were racially diverse (white: 37 %; African American: 23 %, and Asian: 30 %), married (50 %) females (59 %). Most (62 %) have a family income between 121 and 200 % of the federal poverty level, and were without health insurance for more than 1 year (56 %). Self-reported health and behaviors for 163 plan members who completed initial and follow up HRAs revealed increases in physical activity, fruit and vegetable consumption, and health status. Statistically significant differences were found in patient activation from baseline to follow up (44 vs 58 %, p value 0.0005). Patient demographics, health status, and health behaviors of these newly insured Americans may help policy makers and care providers prepare to meet their needs. We noted improvements in certain self-reported health behaviors and health status, suggesting participation in the Plan is associated with positive health impacts for some Plan members. PMID- 23014807 TI - Neighbor communities in drug combination networks characterize synergistic effect. AB - Combination therapies are urgently needed for optimal clinical benefit, but an efficient strategy for rational discovery of drug combinations, especially combinations of experimental drugs, is still lacking. Consequently, we proposed here a network-based computational method to identify novel synergistic drug combinations. A large-scale drug combination network (DCN), which provides an alternative way to study the underlying mechanisms of drug combinations, was constructed by integrating 345 drug combination relationships, 1293 drug-target interactions and 15134 target-protein interactions. It was illustrated that synergistic drugs seldom have identical or directly connected targets, while most targets in DCN can be reached from every other by 2 to 4 edges (interactions). Accordingly, the concept 'neighbor community' was introduced to characterize the relationships between synergistic drugs by specifying the interactions between drug targets and their neighbor proteins in the context of DCN. A subsequent study revealed that the integrated topological and functional properties of neighbor communities can be employed to successfully predict drug combinations. It was shown that this method can achieve 88% prediction accuracy and 0.95 AUC (Area Under ROC Curve), demonstrating its good performance in specificity and sensitivity. Moreover, ten predicted synergistic drug combinations unknown to the method were confirmed by recent literature, and three predicted new combinations of experimental drug BI-2536 were validated by in vitro assays. The results suggested that this method provides a means to explore promising drug combinations at an earlier stage of the drug development process. PMID- 23014811 TI - Medium and high oxidation state metal/non-metal fluoride and oxide-fluoride complexes with neutral donor ligands. AB - While most high and medium oxidation state (O.S. >= 3) metal and non-metal fluorides and oxide fluorides are strong Lewis acids, exploration of their coordination chemistry with neutral ligands has been limited and mostly non systematic. This is despite the very different properties conferred on the acceptor centre by the small electronegative fluoride ligands compared to the heavier halides. This article sets out these key differences, discusses possible synthetic routes, the key characterisation techniques, and appropriate bonding models. Current knowledge of the coordination chemistry of d, f and p-block fluorides and oxide fluorides with neutral ligands (with donor atoms drawn from Groups 15 and 16 and including N-heterocyclic carbenes) is then presented and discussed, and the differences in properties compared to complexes containing the heavier halides are illustrated. The emphasis is on work published post 1990, but earlier work is also included as essential background and where no more recent information exists. Attention is drawn to unexplored areas meriting investigation and to possible applications of these complexes. PMID- 23014814 TI - Stroke prevention in patients with atrial fibrillation: disease burden and unmet medical needs. AB - The incidence of atrial fibrillation (AF), as well as the related morbidity and mortality, is increasing in step with the aging of the US population. Frequently, AF leads to untoward outcomes, including a 5-fold increased risk of stroke, hospitalization, impaired quality of life, and decreased work productivity. Therapeutic decision making for patients with AF at risk for stroke is a process that varies from one physician to the next. This lack of consistency in care is compounded by disrupted communication among caregivers coupled with barriers to health care resources. Improved application of evidence-based treatment guidelines for the diagnosis, staging, and tracking of AF-associated stroke is needed, especially because patients with AF are at high risk. In addition to affecting practice guidelines, the latest anticoagulants are poised to change the standard of care for preventing stroke in patients with AF. These novel agents, with their greater safety and ease of administration, have the potential to improve treatment outcomes. PMID- 23014813 TI - Mycoheterotrophic growth of Cephalanthera falcata (Orchidaceae) in tripartite symbioses with Thelephoraceae fungi and Quercus serrata (Fagaceae) in pot culture condition. AB - Mixotrophy, obtaining carbon by mycoheterotrophy and photosynthesis, has been suggested in Cephalanthera species (Orchidaceae) by analyses on stable isotopes of carbon. In this study, we examined the growth of Cephalanthera falcata in pot cultured tripartite symbioses with Thelephoraceae fungi and Quercus serrata. Mycorrhizal fungi were isolated from roots of C. falcata in natural habitats. Two fungal isolates identified as Thelephoraceae were cultured and inoculated to fine roots of non-mycorrhizal seedlings of Q. serrata (Fagaceae). After the ectomycorrhizal formation, non-mycorrhizal seedlings of C. falcata were co planted. The pots with tripartite symbioses were cultured in greenhouse for 30 months, and growth of C. falcata seedlings was examined. Fresh weight of C. falcata seedlings was significantly increased by the tripartite symbioses even in those with no shoot, thus providing further evidence for the mycoheterotrophic nature of this orchid. The achievement of seedling culture in tripartite symbioses would be valuable for conserving many forest orchids and for conducting experiments to understand their physiology and ecology. PMID- 23014815 TI - A new era of anticoagulation treatment: optimizing outcomes for atrial fibrillation. AB - Atrial fibrillation is a common condition that is associated with a high risk of stroke. In the present article, which is based on a roundtable discussion held on February 8, 2012, the faculty discuss various aspects of caring for patients with atrial fibrillation. These topics include the burden of the disease, stroke risk assessment, use of stroke prophylaxis, and improvement of outcomes. PMID- 23014817 TI - Neonatal intensive care: an obvious, yet difficult area for cerebral near infrared spectroscopy. PMID- 23014818 TI - Recent advances in fetal near infrared spectroscopy. PMID- 23014819 TI - Application of near infrared spectroscopy to the evaluation of exercise performance and limitations in patients with heart failure. PMID- 23014816 TI - Management consensus guidance for the use of rivaroxaban--an oral, direct factor Xa inhibitor. AB - A number of novel oral anticoagulants that directly target factor Xa or thrombin have been developed in recent years. Rivaroxaban and apixaban (direct factor Xa inhibitors) and dabigatran etexilate (a direct thrombin inhibitor) have shown considerable promise in large-scale, randomised clinical studies for the management of thromboembolic disorders, and have been approved for clinical use in specific indications. Rivaroxaban is licensed for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery, the treatment of deep-vein thrombosis and prevention of recurrent venous thromboembolism, and for stroke prevention in patients with non-valvular atrial fibrillation. Based on the clinical trial data for rivaroxaban, feedback on its use in clinical practice and the authors' experience with the use of rivaroxaban, practical guidance for the use of rivaroxaban in special patient populations and specific clinical situations is provided. Although most recommendations are in line with the European summary of product characteristics for the approved indications, additional and, in several areas, different recommendations are given based on review of the literature and the authors' clinical experience. PMID- 23014821 TI - Lasers in digestive endoscopy. PMID- 23014820 TI - Use of near infrared spectroscopy to identify traumatic intracranial hemotomas. PMID- 23014822 TI - Fluorescence spectroscopy of dermal wounds in rats. PMID- 23014824 TI - Patterned planar array immunosensor for multianalyte detection. PMID- 23014823 TI - Evaluation of optical methods of detecting dental pulp vitality. PMID- 23014825 TI - Wavelength-selective light quenching of biochemical fluorophores. PMID- 23014826 TI - Artificial eye for in vitro experiments of laser light interaction with aqueous media. PMID- 23014827 TI - Local thermal coagulation due to laser-tissue interaction as irreversible phase transition. PMID- 23014828 TI - New method for reshaping the cornea. PMID- 23014829 TI - Laser microdissection of metaphase chromosomes and characterization by atomic force microscopy. PMID- 23014830 TI - Characterization of the effects of postextraction treatments on human dentin resin interface by micro-Raman spectroscopy. PMID- 23014831 TI - DNA-binding and fluorescence properties of the DNA bis-intercalating purple oxazole dimer POPO-1. PMID- 23014832 TI - Study on the absorption properties of sulphonated aluminum phthalocyanine in vivo and ex vivo in murine tumor models. PMID- 23014833 TI - Synchronous double cancers of primary hepatic adenosquamous carcinoma and hepatocellular carcinoma: report of a case. AB - A 76-year-old male was referred for the treatment of liver tumors detected by abdominal computed tomography (CT). Dynamic CT revealed a low-density tumor with an irregularly enhanced rim in the left lateral sector, and a highly enhanced, well-circumscribed tumor in the caudate lobe, accompanied by dilation of the intrahepatic biliary ducts in the left lobe. Preoperative imaging studies led to the diagnosis of double cancers consisting of intrahepatic cholangiocarcinoma and hepatocellular carcinoma (HCC). Left hemihepatectomy with caudate lobectomy was performed. The postoperative course was uneventful. Microscopic evaluation revealed that the tumor in the left lateral sector was adenosquamous carcinoma (ASC), whereas that in the caudate lobe was HCC. This report presents the first case describing the resection of synchronous double cancers of primary hepatic ASC and HCC. PMID- 23014835 TI - Total hip replacement versus open reduction and internal fixation of displaced femoral neck fractures: a randomized long-term follow-up study. AB - BACKGROUND: Clinical trials with short and intermediate-term follow-up have demonstrated superior results for total hip replacement as compared with internal fixation with regard to hip function and the need for secondary surgery in elderly patients with a displaced intracapsular femoral neck fracture. The aim of the present study was to compare the results of total hip replacement with those of internal fixation over a long-term follow-up period of seventeen years. METHODS: We enrolled 100 patients who had sustained a femoral neck fracture in a single-center, randomized controlled trial;all patients had had a healthy hip before the injury. The study group included seventy-nine women and twenty-one men with a mean age of seventy-eight years (range, sixty-five to ninety years). The subjects were randomly assigned to either total hip replacement (the arthroplasty group) (n = 43) or internal fixation (the control group) (n = 57). The primary end point was hip function, evaluated with use of the Harris hip score. Secondary end points included mortality, reoperations, gait speed, and activities of daily life. Follow-up evaluations were performed at three months and at one, two, four, eleven, and seventeen years. RESULTS: The Harris hip score was higher in the total hip arthroplasty group, with a mean difference of 14.7 points (95%confidence interval, 9.2 to 20.1 points; p < 0.001 [analysis of covariance]) during the study period. We found no difference in mortality between the two groups. Four patients (9%) in the total hip replacement group and twenty-two patients (39%) in the internal fixation group had undergone a major reoperation (relative risk, 0.24; 95% confidence interval, 0.09 to 0.64).The overall reoperation rate was 23% (ten of forty-three) in the total hip replacement group and 53% (thirty of fifty-seven) in the internal fixation group (relative risk, 0.44; 95% confidence interval, 0.24 to 0.80). The results related to gait speed and activities of daily living favored the arthroplasty group during the first year. CONCLUSIONS: Over a period of seventeen years in a group of healthy, elderly patients with a displaced femoral neck fracture, total hip replacement provided better hip function and significantly fewer reoperations compared with internal fixation without increasing mortality. LEVEL OF EVIDENCE: Therapeutic Level I. PMID- 23014834 TI - Fast-track surgery: procedure-specific aspects and future direction. AB - INTRODUCTION: Fast-track (FT) surgery can be defined as a coordinated perioperative approach aimed at reducing surgical stress and facilitating postoperative recovery. The objective of this review was to examine the literature on the procedure-specific application of FT surgery. DISCUSSION: The concept of FT rehabilitation has been applied mainly in colorectal surgery, but positive data have appeared also in other areas such as orthopedic, hepatopancreaticobiliary, urological, upper gastrointestinal, gynecological, thoracic, vascular, endocrine, breast, and pediatric surgeries. There is very little experience with comprehensive FT programs in cardiac surgery or trauma. Quantitative analysis from randomized trials and cohort studies suggest that FT is effective in reducing hospital stay without increased adverse events. Other benefits of the FT approach include a reduction in complications, ileus, fatigue, pain, and hospital expenses. However, despite clear benefits of FT care, implementation in daily practice has been slow. Further efforts must be undertaken to secure implementation in routine clinical practice. Standardized FT protocols should be provided on a procedure-specific basis. PMID- 23014836 TI - Results and outcomes after endoscopic treatment of upper urinary tract carcinoma: the Austrian experience. AB - INTRODUCTION: Through evolution in technology, endoscopic treatment has gained popularity for the treatment of upper tract urothelial carcinoma (ENDO-UTUC). METHODS: A total of 20 patients with ENDO-UTUC were compared to 178 treated by radical nephroureterectomy (RNU) for a pTa-1 UTUC, and a systematic review was performed. RESULTS: Mean age for ENDO-UTUC was 71.9 +/- 16.0 years, and tumor features were favorable (90 % papillary, 14 low grade, 11 pTa). All ENDO-UTUC were performed ureteroscopically. Mean follow-up was 20.4 +/- 30 months. The 5 year overall survival (OS) rate was 45 %. Local (LR) and bladder recurrence (BR) was 25 and 15 %. Time to definitive treatment was longer, ASA higher, LR rates higher, OS lower for ENDO-UTUC (all p < 0.001), but no difference was recorded for BR (p = 0.056) and cancer-specific survival (CSS) (p = 0.364). Postoperative kidney function (KF) was better in the ENDO-UTUC (p = 0.048), though preoperative KF showed no difference. The maximal level of evidence was 3b, patients were highly selected, numbers of patients were low, and ASA scores high. OS was rather low and CSS high. LR rate was high (61 %) and BR rate moderate (39 %) for ureteroscopic and 36 and 28 %, respectively, for percutaneous approach. CONCLUSIONS: LR for ENDO-UTUC is high. In high-grade UTUC, oncological outcome is worse. RNU is associated with a significant loss of KF, but LR is rare. ENDO-UTUC is reserved for selected cases if elective. In imperative cases, it has to be balanced between KF, morbidity of the procedure, risk of operation and tumor control. ENDO-UTUC is not necessarily underused in Austria, because of lack in evidence, but 41 % of all RNU were performed in pTa/pTis/pT1 lesions. PMID- 23014837 TI - Urothelial carcinomas of the upper urinary tract are now recognised as a true and distinct entity from bladder cancer and belong fully to the broad spectrum of onco-urologic neoplasms. PMID- 23014838 TI - Functions of transmembrane domain 3 of human melanocortin-4 receptor. AB - The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor critical for maintaining energy homeostasis. Transmembrane domain 3 (TM3) of MC4R contains residues that were suggested to be essential in ligand binding and signaling. Several MC4R mutations in TM3 are associated with human obesity. To gain a better understanding of the functions of TM3, we analyzed the functions of 26 residues in TM3 using alanine-scanning mutagenesis. We showed that all mutants had normal cell-surface expression. Four mutants were defective in ligand binding and signaling and six mutants had normal ligand binding but impaired cAMP production. L140A had increased basal cAMP level. To further characterize the function of L140, we generated 17 additional L140 mutants. Fifteen L140 mutants had significantly decreased cell-surface expression, with L140R and L140V expressed normally. Ten L140 mutants had increased basal cAMP activities. Four L140 mutants were defective in ligand-stimulated cAMP generation. Interestingly, with the ERK1/2 pathway, we showed that nine constitutively active mutants had similar levels of basal pERK1/2 as that of WT, and two signaling defective mutants had similar levels of pERK1/2 as that of WT upon agonist stimulation, different from their cAMP signaling properties, suggesting biased signaling in these mutant receptors. In summary, we identified 13 residues in TM3 that were essential for ligand binding and/or signaling. Moreover, L140 was critical for locking MC4R in inactive conformation and several mutants showed biased signaling in cAMP and ERK1/2 signaling pathways. PMID- 23014839 TI - Pleiotropic functions of the transmembrane domain 6 of human melanocortin-4 receptor. AB - The melanocortin-4 receptor (MC4R) is a critical regulator of energy homeostasis and has emerged as a premier target for obesity treatment. Numerous mutations in transmembrane domain 6 (TM6) of MC4R resulting in functional alterations have been identified in obese patients. Several mutagenesis studies also provided some data suggesting the importance of this domain in receptor function. To gain a better understanding of the structure-function relationship of the receptor, we performed alanine-scanning mutagenesis in TM6 to determine the functions of side chains. Of the 31 residues, two were important for cell surface expression, five were indispensable for alpha-melanocyte-stimulating hormone (alpha-MSH) and beta MSH binding, and six were important for signaling in the Gs-cAMP-PKA pathway. H264A, targeted normally to the plasma membrane, was undetectable by competitive binding assay and severely defective in basal and stimulated cAMP production and ERK1/2 phosphorylation. Nine mutants had decreased basal cAMP signaling. Seven mutants were constitutively active in cAMP signaling and their basal activities could be inhibited by two MC4R inverse agonists, Ipsen 5i and ML00253764. Five mutants were also constitutively active in the MAPK pathway with enhanced basal ERK1/2 phosphorylation. In summary, our study provided comprehensive data on the structure-function relationship of the TM6 of MC4R. We identified residues that are important for cell surface expression, ligand binding, cAMP generation, and residues for maintaining the WT receptor in active conformation. We also reported constitutive activation of the MAPK pathway and biased signaling. These data will be useful for rationally designing MC4R agonists and antagonists for treatment of eating disorders. PMID- 23014840 TI - The ligand-mediated nuclear mobility and interaction with estrogen-responsive elements of estrogen receptors are subtype specific. AB - 17beta-Estradiol (E(2)) plays important roles in functions of many tissues. E(2) effects are mediated by estrogen receptor (ER) alpha and beta. ERs regulate transcriptions through estrogen-responsive element (ERE)-dependent and ERE independent modes of action. ER binding to ERE constitutes the basis of the ERE dependent pathway. Direct/indirect ER interactions with transcription complexes define ERE-independent signaling. ERs share functional features. Ligand-bound ERs nevertheless induce distinct transcription profiles. Live cell imaging indicates a dynamic nature of gene expressions by highly mobile ERs. However, the relative contribution of ER mobility at the ERE-independent pathway to the overall kinetics of ER mobility remains undefined. We used fluorescent recovery after a photo-bleaching approach to assess the ligand-mediated mobilities of ERE binding defective ERs, ER(EBD). The decrease in ERalpha mobility with E(2) or the selective ER modulator 4-hydroxyl-tamoxifen (4HT) was largely due to the interaction of the receptor with ERE. Thus, ERalpha bound to E(2) or 4HT mediates transcriptions from the ERE-independent pathway with remarkably fast kinetics that contributes fractionally to the overall motility of the receptor. The antagonist Imperial Chemical Industries 182 780 immobilized ERalphas. The mobilities of ERbeta and ERbeta(EBD) in the presence of ligands were indistinguishable kinetically. Thus, ERbeta mobility is independent of the nature of ligands and the mode of interaction with target sites. Chimeric ERs indicated that the carboxyl-termini are critical regions for subtype-specific mobility. Therefore, while ERs are highly mobile molecules interacting with target sites with fast kinetics, an indication of the hit-and-run model of transcription, they differ mechanistically to modulate transcriptions. PMID- 23014841 TI - Endophytic bacteria isolated from orchid and their potential to promote plant growth. AB - Twelve endophytic bacteria were isolated from the meristem of in vitro Cymbidium eburneum orchid, and screened according to indole yield quantified by colorimetric assay, in vitro phosphate solubilization, and potential for plant growth promotion under greenhouse conditions. Eight strains with positive results were classified into the genus Paenibacillus by FAME profile, and evaluated for their ability to increase survival and promote the growth of in vitro germinated Cattleya loddigesii seedlings during the acclimatization process. The obtained results showed that all strains produced detectable indole levels and did not exhibit potential for solubilizing inorganic phosphate. Particularly, an increase of the total biomass and number of leaves was observed. Two strains of Paenibacillus macerans promoted plant growth under greenhouse conditions. None of the treatments had a deleterious effect on growth of inoculated plants. These results suggest that these bacterial effects could be potentially useful to promote plant growth during seedling acclimatization in orchid species other than the species of origin. PMID- 23014842 TI - Heterologous expression of beta-xylosidase gene from Paecilomyces thermophila in Pichia pastoris. AB - beta-xylosidase from thermophilic fungi Paecilomyces thermophila was functionally expressed in Pichia pastoris with a his tag in the C-terminal under the alcohol oxidase 1 (AOX1) promoter and secreted into the medium at 0.22 mg l(-1). Its molecular mass was estimated to be 52.3 kDa based on the SDS-PAGE analysis, which is 1.3 times higher than the predicted 39.31 kDa from its amino acid compositions, although no potential N- or O- glycosylation sites were predicted from its amino acid sequence. This is presumed to be caused by some unpredictable posttranslational modifications based on mass spectrum analysis of the recombinant protein. The enzyme was most active at 60 degrees C and pH 7. It showed not only a beta-xylosidase activity with a K(m) of 8 mM and a V(max) of 54 MUmol min(-1) mg(-1) for hydrolysis of p-nitrophenyl beta-D-xylopyranoside but also an arabinofuranosidase activity (6.2 U mg(-1)) on p-nitrophenyl arabinofuranoside. PMID- 23014843 TI - Influence of metal ions on bioremediation activity of protocatechuate 3,4 dioxygenase from Stenotrophomonas maltophilia KB2. AB - The aim of this paper was to describe the effect of various metal ions on the activity of protocatechuate 3,4-dioxygenase from Stenotrophomonas maltophilia KB2. We also compared activity of different dioxygenases isolated from this strain, in the presence of metal ions, after induction by various aromatic compounds. S. maltophilia KB2 degraded 13 mM 3,4-dihydroxybenzoate, 10 mM benzoic acid and 12 mM phenol within 24 h of incubation. In the presence of dihydroxybenzoate and benzoate, the activity of protocatechuate 3,4-dioxygenase and catechol 1,2-dioxygenase was observed. Although Fe(3+), Cu(2+), Zn(2+), Co(2+), Al(3+), Cd(2+), Ni(2+) and Mn(2+) ions caused 20-80 % inhibition of protocatechuate 3,4-dioxygenase activity, the above-mentioned metal ions (with the exception of Ni(2+)) inhibited catechol 1,2-dioxygenase to a lesser extent or even activate the enzyme. Retaining activity of at least one of three dioxygenases from strain KB2 in the presence of metal ions makes it an ideal bacterium for bioremediation of contaminated areas. PMID- 23014844 TI - Comparative effectiveness of anti-TNF agents for Crohn's disease in a tertiary referral IBD practice. AB - BACKGROUND: The three Food and Drug Administration (FDA)-approved anti-tumor necrosis factor drugs (anti-TNFs) for Crohn's disease (CD) have not been directly compared. AIM: To compare the efficacy of the three anti-TNFs for CD in clinical practice. METHODS: Retrospective review of patients initiated on anti-TNF between 2004 and 2008. Disease activity, quality of life, and remission rates were compared between groups over 1 year. RESULTS: Sixty patients with CD were initiated on anti-TNF from 2004 to 2008: 31 on infliximab (IFX) and 29 on adalimumab (ADA) or certolizumab pegol (CTZ). More patients in the ADA/CTZ scores group had prior exposure to anti-TNF (76 versus 10%, p < 0.01). Mean Harvey Bradshaw Index (HBI) scores in the IFX group were lower than in the ADA/CTZ group at 12 months (2.72 +/- 3.34 versus 5.63 +/- 5.33, p = 0.03). At 12 months, more IFX patients were in remission compared with those on ADA/CTZ (88 versus 53%, p <= 0.01). Mean short inflammatory bowel disease questionnaire (SIBDQ) scores were not different between the IFX and ADA/CTZ groups at 12 months. Stratified analyses and logistic regression based on prior anti-TNF use did not show differences in remission rates at any time point post-baseline between groups. CONCLUSIONS: After adjustment for prior anti-TNF there was no difference in remission rates between the IFX and ADA/CTZ groups at any time point post baseline. This suggests that differences between groups were accounted for by a higher rate of prior anti-TNF in the ADA/CTZ group. Our results should be reviewed with caution given the small sample size. PMID- 23014845 TI - Early diagnosis of hepatocellular carcinoma by microRNAs: shining a light from the genome's "dark matter". PMID- 23014846 TI - Modulation of function of sodium-dependent vitamin C transporter 1 (SVCT1) by Rab8a in intestinal epithelial cells: studies utilizing Caco-2 cells and Rab8a knockout mice. AB - BACKGROUND: Ascorbic acid (AA) is required for normal human health and development. Human intestine expresses two sodium-dependent vitamin C transporters (hSVCT-1 and -2) that mediate cellular AA transport, with hSVCT1 targeting to the apical membrane of polarized epithelia. Studies have shown a role for the Rab8a in the apical membrane targeting of transporters in intestinal cells. AIMS: The purpose of this study was to determine whether Rab8a impacts the function and/or targeting of hSVCT1, and intestinal AA uptake. METHODS: We used human intestinal cells and cells from a Rab8a knockout mouse. (14)C-AA uptake was performed to determine functionality. PCR and western blotting were performed to determine RNA and protein expression, respectively. Confocal imaging was performed to determine co-localization. RESULTS: We show that hSVCT1 co-localized with Rab8a in intestinal cells. Knockdown of Rab8a lead to a significant inhibition in AA uptake and cell surface biotinylation studies revealed a lower cell surface expression of hSVCT1 in Rab8a siRNA-treated cells. Similarly, in the small intestine of a Rab8a knockout mouse, AA uptake was significantly inhibited. This effect again resulted from a decreased expression level of mSVCT1 protein, even though mRNA expression of SVCT1 was similar in intestinal cells from Rab8a knockout and wild-type litter-mates. The latter data are suggestive of enhanced lysosomal degradation of hSVCT1 protein in Rab8a-deficient cells; indeed, confocal imaging of Rab8a siRNA-treated intestinal cells revealed a strong overlap between hSVCT1-YFP and LAMP1-RFP. CONCLUSIONS: These findings show a role for Rab8a in the physiological function of hSVCT1 in intestinal epithelia. PMID- 23014848 TI - Association between nutritional status, food habits and physical activity level in schoolchildren. AB - OBJECTIVES: To analyze the relation between nutritional status, food habits and physical activity level in schoolchildren. METHODS: A cross-sectional study was carried out with 661 schoolchildren, from 6 to 14 years old, enrolled in public and private schools located in the urban area of Ouro Preto, state of Minas Gerais, Brazil. A semi-structured questionnaire was applied to collect data on demographic, socio-economic, anthropometric and level of physical activity variables. Schoolchildren were classified according to criteria for body mass index by age, body fat percentage and physical activity level, respectively. Dietary data were collected through a validated food frequency questionnaire specific for children and adolescents. Food consumption was evaluated according to an adaptation of the Recommended Foods Score, whose objective is the assessment of overall diet quality with a focus on healthy food consumption. RESULTS: We observed high frequency of overweight according to body mass index per age (20.1%) and body fat percentage (22.8%), as well as physical inactivity (80.3%) among schoolchildren. We also found low scores on the Recommended Foods Score in 77.2% of students. There was no significant relation between overweight and physical inactivity or food consumption (p > 0.05). CONCLUSION: Schoolchildren had a high frequency of overweight, which, alone, was not associated with the high physical inactivity and the low quality diet observed. Therefore, more studies should be performed to identify other factors besides those already described, which may be influencing overweight in this population. PMID- 23014849 TI - Combination of metallomics and proteomics to study the effects of the metallodrug RAPTA-T on human cancer cells. AB - An approach to characterize the interactions of RAPTA-T, a novel ruthenium-based anticancer drug candidate with intriguing antimetastatic properties, with human ovarian cancer cells in vitro is described. The distribution profile of the metallodrug within the cancer cells was determined by (size exclusion chromatography)-inductively coupled mass spectrometry combined with subcellular fractionation procedures (metallomics). Multidimensional protein identification technology (MudPIT) was then used to obtain insight into the alteration of the cellular proteome upon RAPTA-T treatment. The metallomics approach reveals striking differences in the intracellular behavior of the drug between cisplatin sensitive and resistant cell lines and provides clues on possible mechanisms of action as well as detoxification, quantitative proteomics based on spectral counting sheds light on cellular response mechanisms to metallodrug treatment. PMID- 23014850 TI - P=P bond photophysics in an Ar-P=P-Ar diphosphene. AB - The details of the photophysics of a diphosphene DmpP=PDmp (Dmp: 2,6 Mes(2)C(6)H(3)) have been examined experimentally and computationally. Femtosecond transient absorption spectroscopy has been used to probe the dynamics of the S(1) and S(2) excited states of DmpP=PDmp, through excitation at 480 and 400 nm, respectively. The molecule returns to S(0) on sub-nanosecond timescales; no irreversible photochemistry is observed. The S(2) state is observed in the transient spectra with an absorption feature at the red end of the visible spectrum. Its lifetime was measured to be 275 fs. The S(1) state does not absorb appreciably in the probe wavelength range. Excitation into either of these states leads to transient absorption signals in the 400-600 nm region that exhibit a rise time longer than the measured instrument response function, indicating that they do not arise from the initially excited state. These bands decay biexponentially, with lifetimes of ~20 ps and of a few hundred ps. Calculations at the CASSCF(8,6)/6-31G** and CASPT2(8,6)/6-31G**//CASSCF(8,6)/6-31G** levels support these assignments, and underpin an initial working model that involves participation of phenyl torsional twisting motions and the possibility of rapid intersystem crossing to the low-lying triplet manifold. PMID- 23014847 TI - Rodent thyroid, liver, and fetal testis toxicity of the monoester metabolite of bis-(2-ethylhexyl) tetrabromophthalate (tbph), a novel brominated flame retardant present in indoor dust. AB - BACKGROUND: Bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a replacement for polybrominated diphenyl ethers (PBDEs) in commercial flame retardant mixtures such as Firemaster 550. It is also used in a commercial mixture called DP 45. Mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) is a potentially toxic metabolite. OBJECTIVES: We used in vitro and rodent in vivo models to evaluate human exposure and the potential metabolism and toxicity of TBPH. METHODS: Dust collected from homes, offices, and cars was measured for TBPH by gas chromatography followed by mass spectrometry. Pregnant rats were gavaged with TBMEHP (200 or 500 mg/kg) or corn oil on gestational days 18 and 19, and dams and fetuses were evaluated histologically for toxicity. We also assessed TBMEHP for deiodinase inhibition using rat liver microsomes and for peroxisome proliferator-activated receptor (PPAR) alpha and gamma activation using murine FAO cells and NIH 3T3 L1 cells. RESULTS: TBPH concentrations in dust from office buildings (median, 410 ng/g) were higher than in main living areas in homes (median, 150 ng/g). TBPH was metabolized by purified porcine esterases to TBMEHP. Two days of TBMEHP exposure in the rat produced maternal hypothyroidism with markedly decreased serum T3 (3,3',5-triiodo-l-thyronine), maternal hepatotoxicity, and increased multinucleated germ cells (MNGs) in fetal testes without antiandrogenic effects. In vitro, TBMEHP inhibited deiodinase activity, induced adipocyte differentiation in NIH 3T3 L1 cells, and activated PPARalpha- and PPARgamma-mediated gene transcription in NIH 3T3 L1 cells and FAO cells, respectively. CONCLUSIONS: TBPH a) is present in dust from indoor environments (implying human exposure) and b) can be metabolized by porcine esterases to TBMEHP, which c) elicited maternal thyrotoxic and hepatotoxic effects and d) induced MNGs in the fetal testes in a rat model. In mouse NIH 3T3 L1 preadipocyte cells, TBMEHP inhibited rat hepatic microsome deiodinase activity and was an agonist for PPARs in murine FAO and NIH 3T3 L1 cells. PMID- 23014851 TI - The reasons behind early adolescents' responses to peer victimization. AB - Victims of school-based peer harassment face a range of risks including psycho social, physical, and academic harm. The aim of the present study was to examine the behavioral coping responses used by early adolescents when they face peer victimization. To meet this aim, 216 sixth grade students (55 % girls) from two urban middle schools and 254 students (50 % girls) from one suburban middle school completed structured open-ended questions about a recent peer victimization experience. In both school settings, the results supported both previously- and newly-identified coping responses that fit within the approach avoidance coping framework, reasoning that maps on to social information processing models, and systematic associations between reasoning and the coping responses adopted by the adolescents. In both school settings, approach responses were associated with having the goal of defending oneself against the victimization whereas avoidance responses were associated with wanting to prevent the escalation of the peer victimization event. The discussion argues that knowledge about the link between reasoning and coping responses can be informative to understanding what coping responses are effective for victims. PMID- 23014855 TI - Microencapsulation of conjugated linolenic acid-rich pomegranate seed oil by an emulsion method. AB - Controlled release of food ingredients and their protection from oxidation are the key functionality provided by microencapsulation. In the present study, pomegranate seed oil, rich in conjugated linolenic acid, was microencapsulated. As encapsulating agent, sodium alginate or trehalose was used. Calcium caseinate was used as the emulsifier. Performances of the two encapsulants were compared in respect of the rate of release of core material from the microcapsules and stability of microcapsules against harsh conditions. Microencapsulation was carried out by preparation of an emulsion containing calcium caseinate as the emulsion stabilizer and a water-soluble carbohydrate (either sodium alginate or trehalose) as the encapsulant. An oil-in-water emulsion was prepared with pomegranate seed oil as the inner core material. The emulsion was thereby freeze dried and the dried product pulverized. External morphology of the microcapsules was studied under scanning electron microscope. Micrographs showed that both types of microcapsules had uneven surface morphology. Release rate of the microcapsules was studied using UV-spectrophotometer. Trehalose-based microcapsules showed higher release rate. On subjecting the microcapsules at 110 degrees C for specific time periods, it was observed that sodium alginate microcapsules retained their original properties. Hence, we can say that sodium alginate microcapsules are more heat resistant than trehalose microcapsules. PMID- 23014856 TI - Bioactive compounds and phenolic-linked functionality of powdered tropical fruit residues. AB - Tropical fruit residues consisting of seeds, peels and residual pulp generated as by-products of fruit processing industry were investigated for bioactive compounds, the in vitro antioxidant capacity as well as alpha-glucosidase and alpha-amylase inhibitory activities. Cyanidin, quercetin, ellagic acid (EA) and proanthocyanidins were found in acerola, jambolan, pitanga and caja-umbu residue powders. Acerola powder had the highest phenolic content (8839.33 mg catechin equivalents (CE)/100 g) and also high-ascorbic acid (AA) concentration (2748.03 mg/100 g), followed by jambolan and pitanga. The greatest 1,1-Diphenyl-2 picrylhydrazyl (DPPH) inhibition was observed for jambolan (436.76 mmol Trolox eq/g) followed by pitanga (206.68 mmol Trolox eq/g) and acerola (192.60 mmol Trolox eq/g), while acerola had the highest ferric reducing antioxidant power (FRAP) assay result (7.87 mmol Trolox eq/g). All fruit powders exhibited enzymatic inhibition against alpha-amylase (IC50 ranging from 3.40 to 49.5 mg CE/mL) and alpha-glucosidase (IC50 ranging from 1.15 to 2.37 mg CE/mL). Therefore, acerola, jambolan and pitanga dried residues are promising natural ingredients for food and nutraceutical manufacturers, due to their rich bioactive compound content. PMID- 23014857 TI - Effects of optimized mixtures containing phenolic compounds on the oxidative stability of sausages. AB - Phenolic compounds were applied in a sausage formulation as a substitute for artificial sodium erythorbate used as antioxidant. Five assays were prepared in which sodium erythorbate control at 0.05 g/100 g was replaced with a hydrosoluble mixture containing caffeic acid + carnosic acid (47% + 53%) and a liposoluble mixture containing quercetin + rutin (67% + 33%) in two final concentrations (0.05 g/100 g and 0.08 g/100 g). Physico-chemical, color, texture, and sensory parameters were measured on the first day and after 45 days of storage at 4 degrees C. All phenolic compound mixtures were able to maintain oxidative stability in the sausages when measured by the malondialdehyde concentration, which was expressed as TBARS. The mixture containing quercetin + rutin at 0.05 g/100 g showed lower malondialdehyde formation after 45 days of storage, and no sensory differences from the sausage adopted as control. PMID- 23014858 TI - Structural and electronic characterization of self-assembled molecular nanoarchitectures by X-ray photoelectron spectroscopy. AB - Molecular monolayers and similar nanoarchitectures are indicative of the promising future of nanotechnology. Therefore, many scientists recently devoted their efforts to the synthesis, characterization, and properties of mono- and multilayer-based systems. In this context, X-ray photoelectron spectroscopy is an important technique for the in-depth chemical and structural characterization of nanoscopic systems. In fact, it is a surface technique suitable for probing thicknesses of the same order of the photoelectron inelastic mean free paths (a few tens of angstroms) and allows one to immediately obtain qualitative and quantitative data, film thickness, surface coverage, molecule footprint, oxidation states, and presence of functional groups. Nevertheless, other techniques are important in obtaining a complete spectroscopic characterization of the investigated systems. Therefore, in the present review we report on X-ray photoelectron spectroscopy of self-assembled molecular mono- and multilayer materials including some examples on which other characterization techniques produced important results. PMID- 23014859 TI - The influence of climate change on the global distribution and fate processes of anthropogenic persistent organic pollutants. AB - The effect of climate change on the global distribution and fate of persistent organic pollutants (POPs) is of growing interest to both scientists and policy makers alike. The impact of warmer temperatures and the resulting changes to earth system processes on chemical fate are, however, unclear, although there are a growing number of studies that are beginning to examine these impacts and changes in a quantitative way. In this review, we examine broad areas where changes are occurring or are likely to occur with regard to the environmental cycling and fate of chemical contaminants. For this purpose we are examining scientific information from long-term monitoring data with particular emphasis on the Arctic, to show apparent changes in chemical patterns and behaviour. In addition, we examine evidence of changing chemical processes for a number of environmental compartments and indirect effects of climate change on contaminant emissions and behaviour. We also recommend areas of research to address knowledge gaps. In general, our findings indicate that the indirect consequences of climate change (i.e. shifts in agriculture, resource exploitation opportunities, etc.) will have a more marked impact on contaminants distribution and fate than direct climate change. PMID- 23014860 TI - Determination of heart rate variability with an electronic stethoscope. AB - INTRODUCTION: Heart rate variability (HRV) is widely used to characterize cardiac autonomic function by measuring beat-to-beat alterations in heart rate. Decreased HRV has been found predictive of worse cardiovascular (CV) outcomes. HRV is determined from time intervals between QRS complexes recorded by electrocardiography (ECG) for several minutes to 24 h. Although cardiac auscultation with a stethoscope is performed routinely on patients, the human ear cannot detect heart sound time intervals. The electronic stethoscope digitally processes heart sounds, from which cardiac time intervals can be obtained. METHODS: Accordingly, the objective of this study was to determine the feasibility of obtaining HRV from electronically recorded heart sounds. We prospectively studied 50 subjects with and without CV risk factors/disease and simultaneously recorded single lead ECG and heart sounds for 2 min. RESULTS: Time and frequency measures of HRV were calculated from R-R and S1-S1 intervals and were compared using intra-class correlation coefficients (ICC). CONCLUSION: The majority of the indices were strongly correlated (ICC 0.73-1.0), while the remaining indices were moderately correlated (ICC 0.56-0.63). In conclusion, we found HRV measures determined from S1-S1 are in agreement with those determined by single lead ECG, and we demonstrate and discuss differences in the measures in detail. In addition to characterizing cardiac murmurs and time intervals, the electronic stethoscope holds promise as a convenient low-cost tool to determine HRV in the hospital and outpatient settings as a practical extension of the physical examination. PMID- 23014861 TI - Reduction of cAMP and cGMP inhibitory effects in human platelets by MRP4-mediated transport. AB - Cyclic nucleotide-dependent inhibition of platelets represents the most important physiological way to limit thrombus formation. cAMP and cGMP increase in platelets as a consequence of prostacyclin and nitric oxide production by endothelial cells and act through PKA and PKG, respectively. The cytosolic concentration of cyclic nucleotides in platelets is regulated by AC- and GC dependent synthesis and PDE-dependent degradation. In some cells cyclic nucleotides are eliminated also through MRP4/5/8-dependent efflux. As only MRP4 is expressed in platelets, at high levels in dense granules, we determined its role in the elimination of cyclic nucleotides from platelet cytosol. We studied the effects of MRP4 inhibition on cAMP/cGMP effects in platelets. Cyclic nucleotide inhibitory effects triggered by cAMP and cGMP-elevating agents on platelet aggregation are strongly enhanced by MRP4 inhibition and so is cyclic nucleotide-dependent phosphorylation of the common substrate VASP. MRP4 inhibition decreases cAMP concentration in platelet granules and both cAMP and cGMP compete with an established substrate of MRP4 (fluo-cAMP) for entrance in granules. Here we provide the first evidence of the transport of cyclic nucleotides mediated by MRP4 as part of their physiological mechanism of elimination in human platelets, which might represent a novel target to increase cyclic nucleotide-dependent inhibition. PMID- 23014862 TI - Getting the right diagnosis: ST-elevation myocardial infarction in situs inversus. PMID- 23014863 TI - Epicardial management of myocarditis-related ventricular tachycardia. PMID- 23014864 TI - Optical coherence tomography findings in renal denervation. PMID- 23014865 TI - Mitral annular caseous necrosis: insights from multimodality imaging. PMID- 23014867 TI - Quantitative spectroscopic determination of hemoglobin concentration and saturation in a turbid medium: analysis of the effect of water absorption. PMID- 23014868 TI - Study of an algorithm based on model experiments and diffusion theory for a portable tissue oximeter. PMID- 23014869 TI - Age dependency of cerebral oxygenation assessed with near infrared spectroscopy. PMID- 23014866 TI - Contrasting theories of interaction in epidemiology and toxicology. AB - BACKGROUND: Epidemiologists and toxicologists face similar problems when assessing interactions between exposures, yet they approach the question very differently. The epidemiologic definition of "interaction" leads to the additivity of risk differences (RDA) as the fundamental criterion for causal inference about biological interactions. Toxicologists define "interaction" as departure from a model based on mode of action: concentration addition (CA; for similarly acting compounds) or independent action (IA; for compounds that act differently). OBJECTIVES: We compared and contrasted theoretical frameworks for interaction in the two fields. METHODS: The same simple thought experiment has been used in both both epidemiology and toxicology to develop the definition of "noninteraction," with nearly opposite interpretations. In epidemiology, the "sham combination" leads to a requirement that noninteractive dose-response curves be linear, whereas in toxicology, it results in the model of CA. We applied epidemiologic tools to mathematical models of concentration-additive combinations to evaluate their utility. RESULTS: RDA is equivalent to CA only for linear dose-response curves. Simple models demonstrate that concentration additive combinations can result in strong synergy or antagonism in the epidemiologic framework at even the lowest exposure levels. For combinations acting through nonsimilar pathways, RDA approximates IA at low effect levels. CONCLUSIONS: Epidemiologists have argued for a single logically consistent definition of interaction, but the toxicologic perspective would consider this approach less biologically informative than a comparison with CA or IA. We suggest methods for analysis of concentration-additive epidemiologic data. The two fields can learn a great deal about interaction from each other. PMID- 23014870 TI - Comparison of two methods of measuring forearm oxygen consumption (VO2) by near infrared spectroscopy. PMID- 23014871 TI - Optoelectronic moire projector for real-time shape and deformation studies of the tympanic membrane. PMID- 23014872 TI - 2',7'-bis-(Carboxyethyl)-5-(6')-Caroboxyfluorescein (BCECF) as a probe for intracellular fluorescence polarization measurements. PMID- 23014873 TI - Hybrid approach to retinal tracking and laser aiming for photocoagulation. PMID- 23014874 TI - Photoablation with the free-electron laser between 10 and 15 um in biological soft tissue (cornea). PMID- 23014875 TI - Automatic threshold selection using histogram quantization. PMID- 23014876 TI - Indocyanine green videoangiography using cooled charge-coupled devices in central serous choroidopathy. PMID- 23014877 TI - Optical low-coherence reflectometry to enhance monte Carlo modeling of skin. PMID- 23014878 TI - Scattering and beam profile measurements of plastic, silica, and metal radiation waveguides. PMID- 23014879 TI - Molecular systems for light driven hydrogen production. AB - Recent work towards the production of hydrogen via reduction of protons is described. Most of the systems examined in this perspective use a molecular chromophore for harvesting visible light, a catalyst, which is reduced by the excited (or reduced) chromophore, and finally a sacrificial electron source to oxidatively or reductively quench the chromophore. The reduced catalyst is then responsible for the reduction of protons resulting in hydrogen evolution. Relevant mechanistic work on this topic is also discussed. PMID- 23014882 TI - Evaluating the impact of interdisciplinary networking in environmental geochemistry and health: reviewing SEGH conferences and workshops. AB - The Society for Environmental Geochemistry and Health (SEGH) is a forum for multidisciplinary interaction relating the geochemical environment to health. With national funding, SEGH identified collaborative opportunities through the MULTITUDE series of workshops (2007-2011). We reviewed the meetings by electronic questionnaire (39 % response). Smaller meetings saw most returning delegates, suggesting networking and personal interaction is a key positive feature of SEGH; 31 % of practitioners and 25 % of academics participated in more than one meeting. Collaboration between SEGH participants resulted in joint funding (13 academics, 4 practitioners, 1 other) and joint papers (19, 5, 3). Evidence of behavioural change was seen in comments in five themes regarding the impacts of the conferences: support for current direction; impact on education practice (academics); new approaches; networking; multidisciplinary work. Multidisciplinary meetings and resulting networking were seen as having real value by many respondents, who encouraged further active pursuit of these activities. SEGH is eager to continue these activities which transform research, education and practice, resulting in a better understanding of the structure and processes comprising the broad geochemical environment on health. Comments showed the value and strength of small, well-organised conferences, bringing together a mixed group of disciplines, both research and applied, in a relaxed atmosphere. The absence of serious negative critique along with clear, positive comments suggests that there is a substantial level of support for, and even pleasure in, SEGH multidisciplinary conferences and workshops over the past years. It is encouraging that annual European conferences are viewed as such a positive achievement. PMID- 23014880 TI - Airway smooth muscle STIM1 and Orai1 are upregulated in asthmatic mice and mediate PDGF-activated SOCE, CRAC currents, proliferation, and migration. AB - Airway smooth muscle cell (ASMC) remodeling contributes to the structural changes in the airways that are central to the clinical manifestations of asthma. Ca(2+) signals play an important role in ASMC remodeling through control of ASMC migration and hypertrophy/proliferation. Upregulation of STIM1 and Orai1 proteins, the molecular components of the store-operated Ca(2+) entry (SOCE) pathway, has recently emerged as an important mediator of vascular remodeling. However, the potential upregulation of STIM1 and Orai1 in asthmatic airways remains unknown. An important smooth muscle migratory agonist with major contributions to ASMC remodeling is the platelet-derived growth factor (PDGF). Nevertheless, the Ca(2+) entry route activated by PDGF in ASMC remains elusive. Here, we show that STIM1 and Orai1 protein levels are greatly upregulated in ASMC isolated from ovalbumin-challenged asthmatic mice, compared to control mice. Furthermore, we show that PDGF activates a Ca(2+) entry pathway in rat primary ASMC that is pharmacologically reminiscent of SOCE. Molecular knockdown of STIM1 and Orai1 proteins inhibited PDGF-activated Ca(2+) entry in these cells. Whole cell patch clamp recordings revealed the activation of Ca(2+) release-activated Ca(2+) (CRAC) current by PDGF in ASMC. These CRAC currents were abrogated upon either STIM1 or Orai1 knockdown. We show that either STIM1 or Orai1 knockdown significantly inhibited ASMC proliferation and chemotactic migration in response to PDGF. These results implicate STIM1 and Orai1 in PDGF-induced ASMC proliferation and migration and suggest the potential use of STIM1 and Orai1 as targets for ASMC remodeling during asthma. PMID- 23014881 TI - The limitations of renal epithelial cell line HK-2 as a model of drug transporter expression and function in the proximal tubule. AB - Acquiring a mechanistic understanding of the processes underlying the renal clearance of drug molecules in man has been hampered by a lack of robust in vitro models of human proximal tubules. Several human renal epithelial cell lines derived from the renal cortex are available, but few have been characterised in detail in terms of transporter expression. This includes the HK-2 proximal tubule cell line, which has been used extensively as a model of nephrotoxicity. The aim of this study was to investigate the expression and function of drug transporters in HK-2 cells and their suitability as an in vitro model of the human proximal tubule. qPCR showed no mRNA expression of the SLC22 transporter family (OAT1, OAT3, OCT2) in HK-2 cells compared to renal cortex samples. In contrast, SLC16A1 (MCT1), which is important in the uptake of monocarboxylates, and SLCO4C1 (OATP4C1) were expressed in HK-2 cells. The functional expression of these transporters was confirmed by uptake studies using radiolabelled prototypic substrates DL-lactate and digoxin, respectively. The mRNA expression of apical membrane efflux transporters ABCB1 (MDR1) and several members of the ABCC family (multidrug resistance proteins, MRPs) was shown by qPCR. ABCG1 (BCRP) was not detected. The efflux of Hoechst 33342, a substrate for MDR1, was blocked by MDR1 inhibitor cyclosporin A, suggesting the functional expression of this transporter. Similarly, the efflux of the MRP-specific fluorescent dye glutathione methylfluorescein was inhibited by the MRP inhibitor MK571. Taken together, the results of this study suggest that HK-2 cells are of limited value as an in vitro model of drug transporter expression in the human proximal tubule. PMID- 23014883 TI - Measurement of indoor radon concentration and assessment of doses in different districts of Alexandria city, Egypt. AB - The main objective of this study is to assess the health hazard due to the indoor radon. Measurement studies have been carried out in 56 dwellings belonging to 14 residential areas in Alexandria city, Egypt. Results are obtained using the LR 115 (Type II) alpha track detector in "closed-can" geometry. The dosimeters were installed in bedroom, living room, and the kitchens of each house. For intercomparison purpose, dosimeters are installed in basements, ground floor, and first floor. Measured indoor radon concentrations were found to vary from 15 to 132 Bq m(-3). The average radon concentrations in living room, bedrooms, and kitchen in basements were found to vary from to be 39 +/- 10, 63 +/- 15 and 81 +/ 25 Bq m(-3), respectively. In living room, bedrooms, and kitchen, on ground floor, the average radon concentrations were found to be 35 +/- 9, 44 +/- 6 and 56 +/- 10 Bq m(-3), whereas on first floor, the average values are 29 +/- 8, 34 +/- 7 and 45 +/- 8 Bq m(-3), respectively. The overall mean radon concentration in all surveyed districts has been found to be 44 +/- 16 Bq m(-3). The mean annual estimated effective dose received by the residents of the studied area is estimated to be 0.75 mSv. The obtained results are compared with the indoor radon levels prescribed by the International Commission on Radiation Protection and are found to be less than the action level recommended. PMID- 23014884 TI - Dermal exposure to immunostimulants induces changes in activity and proliferation of coelomocytes of Eisenia andrei. AB - Due to the specific habitat conditions in which they live, earthworms are constantly exposed to pathogens. Consequently, they have evolved various immuno defense mechanisms, including cellular (coelomocytes) and humoral responses, which may help to eliminate deleterious micro-organisms but also repair and/or protect host cells and tissues. Similar to mammalian phagocytes, coelomocytes can kill ingested pathogens with reactive oxygen species (ROS) and nitric oxide. In the present work, we studied the effects of the dermal exposure of Eisenia andrei earthworms to different immuno-stimulants: phorbol-12-myristate-13-acetate (PMA), lipopolysaccharide (LPS) or concanavalin A (ConA). After 3 days of treatment with all immuno-stimulants, decreased numbers and changed composition of the coelomocytes were observed. The immuno-stimulants also induced numerous changes in bactericidal activity, including ROS production. Furthermore, all stimulants increased cell proliferation while only LPS-treatment significantly elevated apoptosis of coelomocytes. These results demonstrate that in vivo treatment of earthworms with immuno-stimulants induces various changes in their coelomocyte response. PMID- 23014885 TI - The isotopic composition and insect content of diet predict tissue isotopic values in a South American passerine assemblage. AB - We analyzed the carbon and nitrogen isotopic values of the muscle, liver, and crop contents ("diet") of 132 individuals of 16 species of Chilean birds. The nitrogen content of diet was tightly correlated with the fraction of gut contents represented by insects relative to plant material. The carbon and nitrogen isotopic values of diet, liver, and muscle were all linearly correlated, implying high temporal consistency in the isotopic value of the diet of these birds. However, delta(15)N was not significantly related with the percentage of insects in diet. These results cast doubt on the applicability of the use of (15)N enrichment to diagnose trophic level in, at least some, terrestrial ecosystems. However, the residuals of the relationship relating the isotopic value of bird tissues with those of their diet were weakly negatively correlated with insect intake. We hypothesize that this negative correlation stems from the higher quality of protein found in insects relative to that of plant materials. Finally, our data corroborated a perplexing and controversial negative relationship between tissue to diet isotopic discrimination and the isotopic value of diet. We suggest that this relationship is an example of the commonly observed regression to the mean effect that plagues many scientific studies. PMID- 23014886 TI - Melanoma tumor inhibition by tetrachlorido(O,O'-dibutyl-ethylenediamine-N,N'-di-3 propionate)platinum(IV) complex: in vitro and in vivo investigations. AB - Tetrachlorido(O,O'-dibutyl-ethylenediamine-N,N'-di-3-propionate)platinum(iv) complex, [PtCl(4)(n-Bu(2)eddp)], was previously found to be effective against fibrosarcoma and glioma cell lines. Here we presented that [PtCl(4)(n-Bu(2)eddp)] strongly reduced the growth of B16 melanoma cells in vitro. Inhibition of cell viability was accompanied with induction of both necrotic and apoptotic cell death. In addition, [PtCl(4)(n-Bu(2)eddp)] concealed the expansion of tumors induced in syngeneic C57Bl/6 mice without visible signs of nephrotoxicity. PMID- 23014887 TI - P2X7 receptor activation induces reactive oxygen species formation in erythroid cells. AB - The presence of P2X7 on erythroid cells is well established, but its physiological role remains unclear. The current study aimed to determine if P2X7 activation induces reactive oxygen species (ROS) formation in murine erythroleukaemia (MEL) cells, a commonly used erythroid cell line. ATP induced ROS formation in a time- and concentration-dependent fashion. The most potent P2X7 agonist, 2'(3')-O-(4-benzoylbenzoyl)ATP, but not UTP or ADP, also induced ROS formation. The P2X7 antagonist, A-438079, impaired ATP-induced ROS formation. The ROS scavenger, N-acetyl-L-cysteine, and the ROS inhibitor, diphenyleneiodonium, also impaired P2X7-induced ROS formation, but use of enzyme specific ROS inhibitors failed to identify the intracellular source of P2X7 induced ROS formation. P2X7-induced ROS formation was impaired partly by physiological concentrations of Ca(2+) and Mg(2+) and almost completely in cells in N-methyl-D-glucamine chloride medium. The p38 MAPK inhibitors SB202190 and SB203580, and the caspase inhibitor Z-VAD-FMK, but not N-acetyl-L-cysteine, impaired P2X7-induced MEL cell apoptosis. ATP also stimulated p38 MAPK and caspase activation, both of which could be impaired by A-438079. In conclusion, these findings indicate that P2X7 activation induces ROS formation in MEL cells and that this process may be involved in events downstream of P2X7 activation, other than apoptosis, in erythroid cells. PMID- 23014889 TI - Evaluation of ricinine, a ricin biomarker, from a non-lethal castor bean ingestion. AB - A case is presented of the attempted suicide of a 58-year-old man using castor beans. The patient came to the emergency room complaining of nausea, vomiting and diarrhea for nine hours following the ingestion of six castor beans. Urine samples were taken throughout the hospital stay and submitted to the Centers for Disease Control and Prevention for analysis of ricinine, a castor bean component. The samples were found to be positive for ricinine, with a maximum concentration of 674 ug/g-creatinine excreted approximately 23 h post-exposure. Subsequent samples demonstrated lower ricinine concentrations, with the final sample taken at 62 h post-exposure at a concentration of 135 ug/g-creatinine of ricinine. The estimated urinary excretion half-life was approximately 15 h and the recovery of ricinine in the urine over the three days was estimated to be less than 10%. The patient fully recovered with supportive care and was discharged from the hospital six days after admission. PMID- 23014891 TI - Increasing the elution of vancomycin from high-dose antibiotic-loaded bone cement: a novel preparation technique. AB - BACKGROUND: Antibiotic bone cement is commonly used in staged revision arthroplasty as well as the treatment of open fractures. Multiple factors affect antibiotic elution from bone cement. This study was performed to investigate the effect of two variables, the quantity of liquid monomer and the timing of antibiotic addition, on the ultimate elution of antibiotic from bone cement. METHODS: Vancomycin-loaded Simplex P and SmartSet MV bone cement was prepared with three different methods: a common surgical technique, a mixing technique that doubled the amount of liquid monomer, and a novel technique that delayed antibiotic addition until after thirty seconds of polymerization. Cylinders of a standardized size were created from each preparation. The elution profiles of five cylinders from each preparation were measured over six weeks with use of high-performance liquid chromatography. Cylinders were tested in compression to quantify strength. RESULTS: Delayed antibiotic addition resulted in significantly greater cumulative elution over six weeks (p < 0.0001), with minimal reduction in strength, compared with the other groups. Doubling the liquid monomer significantly reduced cumulative elution over six weeks compared with either of the other techniques (p < 0.0001). Vancomycin elution from Simplex P was 52%greater and vancomycin elution from SmartSet MV was 25% greater in the delayed antibiotic-addition groups than it was in the corresponding standard surgical technique groups. The majority of the antibiotic was released over the first week in all groups. : High-dose-antibiotic bone cement prepared with delayed antibiotic addition increased vancomycin elution compared with the standard surgical preparation. Incorporating additional liquid monomer decreased vancomycin elution from high-dose-antibiotic cement. We recommend preparing high dose-antibiotic bone cement with the delayed-antibiotic addition technique and not incorporating additional liquid monomer. CLINICAL RELEVANCE: Both the relative volume of liquid monomer and the timing of antibiotic addition have substantial effects on the elution of antibiotic from bone cement. PMID- 23014890 TI - Trends in health insurance status of US children and their parents, 1998-2008. AB - In the United States (US), a parent's health insurance status affects their children's access to health care making it critically important to examine trends in coverage for both children and parents. To gain a better understanding of these health insurance trends, we assessed the coverage status for both children and their parents over an 11-year time period (1998-2008). We conducted secondary analysis of data from the nationally-representative Medical Expenditure Panel Survey. We examined frequency distributions for full-year child/parent insurance coverage status by family income, conducted Chi-square tests of association to assess significant differences over time, and explored factors associated with full-year insurance coverage status in 1998 and in 2008 using logistic regression. When considering all income groups together, the group with both child and parent insured decreased from 72.4 % in 1998 to 67.2 % in 2008. When stratified by income, the percentage of families with an insured child, but an uninsured parent increased for low-income families from 12.4 to 25.1 % and from 3.8 to 7.1 % for middle-income families when comparing 1998-2008. In regression analyses, family income remained the strongest characteristic associated with a lack of full-year health insurance. As future policy reforms take shape, it will be important to look beyond children's coverage patterns to assess whether gains have been made in overall family coverage. PMID- 23014892 TI - Taking control: Complementary and alternative medicine in diabetes and cardiovascular disease management. AB - The chronicity of chronic disease, and its associated uncertainties and fluctuations in health status, pain and/or discomfort, often leaves those so diagnosed feeling that they have lost control. Treatment can exacerbate this sense of loss of control, as people surrender to the expertise of their biomedical providers and interventions. In principle, self-management aims to return control to the individual, but its promotion is as much motivated by cost containment as patient autonomy, and is advocated in an environment largely shaped by policy makers and biomedical providers. In this article, we examine how Australians with type 2 diabetes and/or cardiovascular disease supplement medical with complementary and alternative medical (CAM) care. Drawing on in-depth interviews with 69 participants collected in 2009-2010, we illustrate how people rely on medical providers and pharmaceuticals to manage their diabetes, but concurrently consulted with CAM practitioners and used non-biomedical therapies to enhance well-being. In explaining this, participants framed CAM use in the context of reclaiming relative personal and bodily control. PMID- 23014893 TI - Combined use of percutaneous cryoablation and vertebroplasty with 3D rotational angiograph in treatment of single vertebral metastasis: comparison with vertebroplasty. AB - INTRODUCTION: This study aims to assess the effectiveness of combined procedure of cryoablation and vertebroplasty (CVT) for reduction of pain and improvement of the quality of life in patients with single painful metastatic vertebral fractures. METHODS: We retrospectively analyzed data from 23 patients with single vertebral metastasis treated with combined procedure of CVT, compared with those obtained in 23 patients treated by vertebroplasty. Pain intensity was evaluated by a visual analog scale (VAS) score administered before and 1 day, 1 week, and 1, 3, and 6 months after procedure. Quality of life was evaluated by an Oswestry Disability Index (ODI) score administered before and at 3 and 6 months after procedure. RESULTS: Procedural success was achieved in all patients without any complications. The VAS and ODI scores showed a reduction in both groups during follow-up (VAS score, p < 0.05 and p < 0.001, respectively; ODI score, p < 0.0001). No difference of the VAS and ODI scores were observed before treatment (p = 0.33 and 0.78, respectively). VAS score showed a difference at 1 week and 1, 3, and 6 months after treatment (p < 0.001). ODI score showed a difference at 3 and 6 months after treatment (p < 0.001). CONCLUSION: Our findings suggested that combined procedure of CVT is safe and effective for pain relief in single metastatic vertebral fractures, especially when other standard palliative treatments have failed, and improves disability. Careful needle positioning and accurate fluoroscopic and CT guidance are mandatory for a complication-free treatment. PMID- 23014894 TI - Phenprocoumon and acenocoumarol treatment in paediatric patients. PMID- 23014895 TI - Isolation and characterization of a novel Rhodococcus strain with switchable carbonyl reductase and para-acetylphenol hydroxylase activities. AB - In the search for an effective biocatalyst for the reduction of acetophenones with unprotected hydroxy group on the benzene ring, a microorganism, which reduced para-acetylphenol to S-(-)-1-(para-hydroxyphenyl)ethanol under anaerobic conditions, was isolated from soil samples and the 16S rDNA study showed that it was phylogenetically affiliated with species of the genus Rhodococcus and was most similar to Rhodococcus pyridinivorans. Unexpectedly, this strain also hydroxylated para-acetylphenol to give 4-acetylcatechol in presence of oxygen, possessing para-acetylphenol hydroxylase activity. While the reduction of para acetylphenol had an optimal reaction pH at 7 and a broad optimal temperature range (35-45 degrees C), the hydroxylation reached the maximum conversion at the pH range of 7-8 and 35 degrees C. This study identified for the first time a Rhodococcus strain with para-acetylphenol hydroxylase activity, which also contains highly enantioselective carbonyl reductase activity with potential applications for the asymmetric reduction of these less-explored but important ketones such as alpha-aminoacetophenone, 3'-hydroxyacetophenone and 4' hydroxyacetophenone. The para-acetylphenol hydroxylase and carbonyl reductase activity are switchable by the reaction conditions. PMID- 23014897 TI - Visualizing clinical predictors of febrile neutropenia in Asian cancer patients receiving myelosuppressive chemotherapy. AB - PURPOSE: Febrile neutropenia is a serious complication among cancer patients receiving myelosuppressive chemotherapy. Patient-specific risk factors, chemotherapy-related and disease-related characteristics can affect the clinical outcome and management of febrile neutropenia. Although many factors have been identified, they vary among different patient populations. We identified clinically-relevant febrile neutropenia predictors in Asian cancer patients through visualization of these factors. METHODS: A single-centered, retrospective study was conducted from May to July 2011 at a local cancer center. Demographics and risk factor data were collated from electronic health records and four cancer registries. Data were summarized using descriptive statistics. Additionally, potential febrile neutropenia predictors were identified using categorical principal component and multiple correspondence analyses. RESULTS: A total of 583 patients were analyzed. Majority was females (79%), Chinese (75%) and diagnosed with breast cancers (60%). Six risk factors were identified as potential predictors: types of cancer (16.9-19.8% of variance), chemotherapy regimen (anthracycline-based 11.8-12.9%, taxane-based 8.1%), liver function tests (alanine transaminase 8.6%, alkaline phosphatase 4.0%), renal function tests (serum creatinine 3.1%), prior granulocyte colony stimulating factor use (5.6%) and diabetes mellitus (6.6-6.9%). In terms of cancer types, lymphomas were more predictive than breast cancers. CONCLUSION: From our knowledge, this is the first study that has identified clinically-relevant febrile neutropenia predictors in Asian cancer patients through visualization of their risk factors. The use of these predictors to identify patients at risk for adverse reactions, such as FN, can allow clinicians to optimize prophylactic granulocyte colony stimulating factor usage in these patients. PMID- 23014896 TI - Structural and component characterization of meristem cells in Araucaria angustifolia (Bert.) O. Kuntze zygotic embryo. AB - Araucaria angustifolia, the Brazilian pine, is an endangered native conifer with economic and ecological importance. The female cone develops seeds containing the zygotic embryo, which, at cotyledonary stage, shows well-developed meristems. Little is known about the structure of gymnosperm meristems. In the present work, the composition and morphological organization of Araucaria angustifolia shoot and root apical meristems were studied during embryo development, using histochemical and microscope analyses. Histochemical evaluation revealed the presence of cellulose within the cell wall, cells with the presence of total proteins that react with Coomassie Brilliant Blue, starch grains, and large nuclei with evident nucleoli in the cytoplasm. Scanning electron microscopy showed apical meristem surface morphology, and both scanning and transmission microscopy revealed a thin and irregular cell wall with plasmodesmata and within the cells, mitochondria, many vacuoles, lipid bodies, Golgi bodies, and many amyloplasts with endoplasmic reticulum surrounding them and large nuclei. Similar to angiosperm cells, A. angustifolia meristem cells exhibit pluripotent characteristics, such as apparatus for intercellular communication and differentiation. PMID- 23014898 TI - Selective ophthalmic intra-arterial melphalan therapy for advanced retinoblastoma: implementation and outcomes of a new chemotherapy protocol. AB - Retinoblastoma is a relatively uncommon childhood tumor. If untreated, RB grows to fill the eye and destroys the ocular globe's internal architecture. Metastatic spread usually begins after the first 6 months, and death occurs within a matter of years. When treated, overall survival rounds 97%, the alkylating drug melphalan being the most extensively used chemotherapeutic agent in localized treatment. In our hospital, pediatric oncologists asked the Pharmacy Department for assessment in order to implement a new chemotherapy protocol for the treatment of advanced intraocular elegible retinoblastoma cases using melphalan administered directly through the ophthalmic artery. In this paper, we describe the protocol implementation carried out by our collaborative interdisciplinary team as well as the clinical outcomes of five cases treated with ophthalmic intra arterial melphalan therapy. Oncology pharmacists can contribute with their knowledge to the implementation process of new collaborative practice protocols recommending doses, predicting possible adverse effects and assessing about drug stability and elaboration, packaging and administration methods. PMID- 23014899 TI - A quantitative and qualitative method to control chemotherapeutic preparations by Fourier transform infrared-ultraviolet spectrophotometry. AB - Chemotherapy products in hospitals include a reconstitution step of manufactured drugs providing an adapted dosage to each patient. The administration of highly iatrogenic drugs raises the question of patients' safety and treatment efficiency. In order to reduce administration errors due to faulty preparations, we introduced a new qualitative and quantitative routine control based on Fourier Transform Infrared (FTIR) and UV-Visible spectrophotometry. This automated method enabled fast and specific control for 14 anticancer drugs. A 1.2 mL sample was used to assay and identify each preparation in less than 90 sec. Over a two-year period, 9370 controlled infusion bags showed a 1.49% nonconformity rate, under 15% tolerance from the theoretical concentration and 96% minimum identification matching factor. This study evaluated the reliability of the control process, as well as its accordance to chemotherapy deliverance requirements. Thus, corrective measures were defined to improve the control process. PMID- 23014900 TI - Five-year follow-up of the ABSORB bioresorbable everolimus-eluting vascular scaffold system: multimodality imaging assessment. PMID- 23014901 TI - Weight faltering and failure to thrive in infancy and early childhood. PMID- 23014903 TI - Hypoglycaemia linked to excess deaths in critically ill adults. PMID- 23014902 TI - A swollen leg in the middle of the night. PMID- 23014904 TI - Electronic cigarettes: medical device or consumer product? PMID- 23014905 TI - Susceptibilities. PMID- 23014906 TI - Randomised trials link sugary drinks to weight gain in children. PMID- 23014908 TI - UK cancer death rates are predicted to fall 17% by 2030. PMID- 23014907 TI - The key to longevity. PMID- 23014909 TI - A fifth of children with epilepsy miss out on specialist input, UK audit shows. PMID- 23014910 TI - The role of bridging ligand in hydrogen generation by photocatalytic Ru/Pd assemblies. AB - The synthesis and characterisation of two terpyridine based ruthenium/palladium heteronuclear compounds are presented. The photocatalytic behaviour of the Ru/Pd complex containing the linear 2,2':5',2''-terpyridine bridge (1a) and its analogue the non-linear 2,2':6',2''-terpyridine bridge (2a) are compared together with the respective mononuclear complexes 1 and 2. Irradiation of 1a with visible light (e.g., 470 nm) results in the photocatalytic generation of dihydrogen gas. Photocatalysis was not observed with complex 2a by contrast. A comparison with the photocatalytic behaviour of the precursors 1 and 2 indicates, that while for 1a the photocatalysis is an intramolecular process, for the mononuclear precursors it is intermolecular. The photophysical and electrochemical properties of the mono- and heterobinuclear compounds are compared. Raman spectroscopy and DFT calculations indicate that there are substantial differences in the nature of the lowest energy (3)MLCT states of 1a and 2a, from which the contrasting photocatalytic activities of the complexes can be understood. PMID- 23014911 TI - Limitations in measurement of subsurface temperatures using pulsed photothermal radiometry. PMID- 23014912 TI - Finite-difference time-domain simulation of light scattering from single cells. PMID- 23014914 TI - Noninvasive polarimetric measurement of glucose in cell culture media. PMID- 23014913 TI - Visualization and quantification of dentin structure using confocal laser scanning microscopy. PMID- 23014916 TI - Temperature distribution in Escherichia coli liquid suspensions during irradiation by a high-power Nd:YAG laser for sterilization applications. PMID- 23014915 TI - Integral equation solution to the scattering of electromagnetic radiation by a system of two interacting triaxial dielectric ellipsoids: the case of a two red blood cell Rouleau. PMID- 23014917 TI - Novel approach to laser Doppler measurement of pulpal blood flow. PMID- 23014919 TI - Monte Carlo modeling studies of the effect of physiological factors andother analytes on the determination of glucose concentration in vivoby near infrared optical absorption and scattering measurements. PMID- 23014918 TI - Light scattering by pathological and deformed erythrocytes: an integral equation model. PMID- 23014921 TI - Optical tweezers based on near infrared diode laser. PMID- 23014920 TI - Thermal lens detector system for capillary electrophoresis. PMID- 23014922 TI - Metal contamination in water, sediment and biota from a semi-enclosed coastal area. AB - This study identifies and quantifies the spatial variations of metal contamination in water, sediment and biota: the common cockle (Cerastoderma edule) and the Mermaid's glove sponge (Haliclona oculata), within a heavily anthropogenically impacted semi-enclosed estuarine-coastal area with a low ability to disperse and flush contaminants (Poole Harbour, UK). The results showed that metal contamination was detected in all environmental compartments. Water was polluted with As, and Hg sediment metals were mostly within "the possible effect range" in which adverse effects occasionally occurs. Cockles had considerable concentrations of Ni, Ag and Hg in areas close to pollution sources, and sponges accumulate Cu and Zn with very high magnitude. A systematic monitoring approach that includes biological monitoring techniques, which covers all embayments, is needed, and an integrated management of the semi-enclosed coastal zones should be based on the overall hydrological characteristics of these sensitive areas and their ability to self-restore which is different than open coastal zones. PMID- 23014923 TI - Metals in water, sediments, and biota of an offshore oil exploration area in the Potiguar Basin, Northeastern Brazil. AB - Metal concentrations were evaluated in water, bottom sediments, and biota in four field campaigns from 2002 to 2004 in the Potiguar Basin, northeastern Brazil, where offshore oil exploration occurs. Analyses were performed by inductively coupled plasma mass spectrometry and inductively coupled plasma optical emission spectrometry. Total metal concentrations in water (dissolved + particulate) and sediments were in the range expected for coastal and oceanic areas. Abnormally high concentrations in waters were only found for Ba (80 MUg l(-1)) and Mn (12 MUg l(-1)) at the releasing point of one of the outfalls, and for the other metals, concentrations in water were found in stations closer to shore, suggesting continental inputs. In bottom sediments, only Fe and Mn showed abnormal concentrations closer to the effluent releasing point. Metal spatial distribution in shelf sediments showed the influence of the silt-clay fraction distribution, with deeper stations at the edge of the continental shelf, which are much richer in silt-clay fraction showing higher concentrations than shallower sediments typically dominated by carbonates. Metal concentrations in estuarine (mollusks and crustaceans) and marine (fish) organisms showed highest concentrations in oysters (Crassostrea rhizophorae). Fish tissues metal concentrations were similar between the continental shelf influenced by the oil exploration area and a control site. The results were within the range of concentrations reported for pristine environments without metals contamination. The global results suggest small, if any, alteration in metal concentrations due to the oil exploration activity in the Potiguar Basin. For monitoring purposes, the continental inputs and the distribution of the clay-silt fraction need to be taken into consideration for interpreting environmental monitoring results. PMID- 23014925 TI - A geographical approach to tracking Escherichia coli and other water quality constituents in a Texas coastal plains watershed. AB - Diffuse sources of surface water pathogens and nutrients can be difficult to isolate in larger river basins. This study used a geographical or nested approach to isolate diffuse sources of Escherichia coli and other water quality constituents in a 145.7-km(2) river basin in south central Texas, USA. Average numbers of E. coli ranged from 49 to 64,000 colony forming units (CFU) per 100 mL depending upon season and stream flow over the 1-year sampling period. Nitrate-N concentrations ranged from 48 to 14,041 MUg L(-1) and orthophosphate-P from 27 to 2,721 MUg L(-1). High concentrations of nitrate-N, dissolved organic nitrogen, and orthophosphate-P were observed downstream of waste water treatment plants but E. coli values were higher in a watershed draining an older part of the city. Total urban land use explained between 56 and 72 % of the variance in mean annual E. coli values (p < 0.05) in nine hydrologically disconnected creeks. Of the types of urban land use, commercial land use explained most of the variance in E. coli values in the fall and winter. Surface water sodium, alkalinity, and potassium concentrations in surface water were best described by the proportion of commercial land use in the watershed. Based on our nested approach in examining surface water, city officials are able to direct funding to specific areas of the basin in order to mitigate high surface water E. coli numbers and nutrient concentrations. PMID- 23014924 TI - Associations between self-reported odour annoyance and volatile organic compounds in 'Chemical Valley', Sarnia, Ontario. AB - Annoyance produced by air pollution has been suggested as a useful proxy for determining ambient air pollution exposure. However, most of the studies, to date, have focused on nitrogen dioxide and sulphur dioxide, with no work done on volatile organic compounds (VOC). This study is aimed at examining the associations between odour annoyance and VOC in 'Chemical Valley', Sarnia, Ontario, Canada. Annoyance scores were extracted from a community health survey (N = 774), and exposures to VOC were estimated from respondents' six-digit alphanumeric postal codes using land use regression models. Univariate analyses were used to explore the relationships between odour annoyance and modelled pollutants, whilst multivariate ordinal logistic regression was utilized to examine the determinants of odour annoyance. The results indicate that odour annoyance is significantly associated with modelled benzene, toluene, ethylbenzene, o-xylene and (m + p) xylene (BTEX) pollutants. The findings also show that the determinants of odour annoyance in the context of VOC include gender, number of relatives in the community, perception of air pollution, community satisfaction, medical checkups, ability to cope with daily life demands and general symptoms. When compared, the analysis indicates that Sarnia residents respond to considerably lower BTEX concentrations than the allowable 'safe' levels in the province of Ontario. In general, the results exhibit a dose response gradient with annoyance score increasing with rising modelled pollutant concentrations. The observed relationships suggest that odour annoyance might be a function of true exposure and may serve as a proxy for air quality and ambient air pollution monitoring. However, questionnaire-based odour annoyance scores need to be longitudinally validated across different geographical scales and pollutants if they are to be adopted at the national level. PMID- 23014926 TI - Natural stilbenoids: distribution in the plant kingdom and chemotaxonomic interest in Vitaceae. AB - Stilbenoids, a family of polyphenols known for the complexity of their structure and for their diverse biological activities, occur with a limited but heterogeneous distribution in the plant kingdom. The most prominent stilbene containing plant family, the Vitaceae, represented by the famous wine producing grape vines Vitis vinifera L., is one of the richest sources of novel stilbenes currently known, together with other families, such as Dipterocarpaceae, Gnetaceae and Fabaceae. This review focuses on the distribution of stilbenes and 2-arylbenzofuran derivatives in the plant kingdom, the chemical structure of stilbenes in the Vitaceae family and their taxonomic implication. PMID- 23014927 TI - Effects of intravenous atrial natriuretic peptide and nitroglycerin on coronary vasodilation and flow velocity determined using 3 T magnetic resonance imaging in patients with nonischemic heart failure. AB - Although atrial natriuretic peptide (ANP) is widely used in patients with congestive heart failure (CHF), little is known about its effect on epicardial coronary arteries. Magnetic resonance imaging (MRI) enables precise measurement of coronary vasodilation and flow velocity. In this study, we examined the changes in epicardial coronary artery size and flow velocity in response to intravenous infusion of ANP or nitroglycerin (NTG) by using 3 T MRI in patients with CHF. The study cohort contained a total of 14 subjects: 8 patients with CHF and 6 healthy volunteers as controls, randomly divided into two groups: the ANP group (0.03 MUg/kg/min) and the NTG group (0.3 MUg/kg/min). Cross-sectional MR angiography and phase-contrast flow velocity of the right coronary artery in the same in-plane slice were obtained at the baseline, during drug infusion, and at two subsequent time points after stopping drug infusion. A significant increase was observed in the coronary cross-sectional area at 15 min after drug infusion in both groups compared with that at baseline; however, a late peak was observed at 15 min after stopping infusion in the ANP group. No significant differences were detected in the flow velocity in both groups. Furthermore, although NTG increased the heart rate, this change was not found in the ANP group. Coronary vasodilation and flow velocity can be measured simultaneously using 3 T MRI. Using this method, we showed that the effects of ANP on the coronary artery vasodilation and flow velocity were not inferior to those of NTG, with no significant alteration in heart rate. PMID- 23014928 TI - Dehydrin, alcohol dehydrogenase, and central metabolite levels are associated with cold tolerance in diploid strawberry (Fragaria spp.). AB - The use of artificial freezing tests, identification of biomarkers linked to or directly involved in the low-temperature tolerance processes, could prove useful in applied strawberry breeding. This study was conducted to identify genotypes of diploid strawberry that differ in their tolerance to low-temperature stress and to investigate whether a set of candidate proteins and metabolites correlate with the level of tolerance. 17 Fragaria vesca, 2 F. nilgerrensis, 2 F. nubicola, and 1 F. pentaphylla genotypes were evaluated for low-temperature tolerance. Estimates of temperatures where 50 % of the plants survived (LT50) ranged from 4.7 to -12.0 degrees C between the genotypes. Among the F. vesca genotypes, the LT50 varied from -7.7 degrees C to -12.0 degrees C. Among the most tolerant were three F. vesca ssp. bracteata genotypes (FDP821, NCGR424, and NCGR502), while a F. vesca ssp. californica genotype (FDP817) was the least tolerant (LT50) -7.7 degrees C). Alcohol dehydrogenase (ADH), total dehydrin expression, and content of central metabolism constituents were assayed in select plants acclimated at 2 degrees C. The LT50 estimates and the expression of ADH and total dehydrins were highly correlated (r(adh) = -0.87, r (dehyd) = -0.82). Compounds related to the citric acid cycle were quantified in the leaves during acclimation. While several sugars and acids were significantly correlated to the LT50 estimates early in the acclimation period, only galactinol proved to be a good LT50 predictor after 28 days of acclimation (r(galact) = 0.79). It is concluded that ADH, dehydrins, and galactinol show great potential to serve as biomarkers for cold tolerance in diploid strawberry. PMID- 23014930 TI - Aspects of acute care in Sleep Medicine. PMID- 23014931 TI - Total hip replacement is preferred for displaced femoral neck fracture in selected elderly patients: commentary on an article by Ghazi Khalil Chammout, MD, et al.: "total hip replacement versus open reduction and internal fixation of displaced femoral neck fractures. A randomized long-term follow-up study". PMID- 23014932 TI - Comparative analysis of classical and molecular microbiology methods for the detection of Escherichia coli and Enterococcus spp. in well water. AB - The microbiological quality of 165 1 litre well water samples collected in the Quebec City region was assessed by culture-based methods (mFC agar, Chromocult coliform agar, Colilert((r)), MI agar, Chromocult enterococci, EnterolertTM, and mEI agar) and by a molecular microbiology strategy, dubbed CRENAME-rtPCR, developed for the detection of Escherichia coli, Enterococcus spp., Enterococcus faecalis/faecium, and Bacillus atrophaeus subsp. globigii. In these drinking water samples, approved culture-based methods detected E. coli at rates varying from 1.8 to 3.6% and Enterococcus spp. at rates varying from 3.0 to 11.5%, while the molecular microbiology approach for E. coli was found to be as efficient, detecting contamination in 3.0% of samples. In contrast, CRENAME-rtPCR detected Enterococcus spp. in 27.9% of samples while the E. faecalis/faecium molecular assay did not uncover a single contaminated sample, thereby revealing a discrepancy in the coverage of waterborne enterococcal species detected by classical and molecular microbiology methods. The validation of the CRENAME-E. coli rtPCR test as a new tool to assess the quality of drinking water will require larger scale studies elaborated to demonstrate its equivalence to approved methods. PMID- 23014933 TI - Protective effect of gallic acid isolated from Peltiphyllum peltatum against sodium fluoride-induced oxidative stress in rat's kidney. AB - In the present study, the nephroprotective effect of gallic acid isolated from Peltiphyllum peltatum was examined in sodium fluoride (NaF) treated rats. Nephrotoxicity was induced by 1-week intoxication of NaF at 600 ppm through drinking water. The levels of thiobarbituric acid reactive substances, reduced glutathione as well as activities of superoxide dismutase and catalase in renal tissues homogenates were determined. The serum biochemical markers of renal injuries including creatinine, serum urea, blood urea nitrogen, uric acid levels as well as the levels of phosphate and calcium were also assessed. Intoxication with NaF caused a significant increase in the levels of thiobarbituric acid reactive substances (46 % versus to control) and reduced the glutathione concentration (47 %) and the activities of superoxide dismutase (46 %) and catalase (41 %) in renal tissues homogenates. NaF intoxication also induced significant alterations in the kidney biochemical markers increasing the levels of urea, uric acid, blood urea nitrogen, creatinine, and phosphate and decreasing the levels of calcium. Daily administration of gallic acid (20 mg/kg) for 1 week before NaF intoxication brought the antioxidant-oxidant balance similar to the NaF-untreated group. Silymarin, used a standard antioxidant agent, also showed a nephroprotective activity. We concluded that NaF caused nephrotoxicity and oxidative stress in renal tissues and daily administration of gallic acid for 1 week prior to intoxication inhibited toxicity and oxidative stress. PMID- 23014934 TI - Time course analysis of cardiac pacing-induced gene expression changes in the canine heart. AB - Rapid right ventricular pacing in anesthetized dogs results in marked protection against ischemia and reperfusion-induced ventricular arrhythmias, 24 h later. We have previous evidence that this protection associates with altered expression of genes, encoding proteins involved in the delayed cardioprotection. However, the sequence of transcriptional changes occurring between the pacing stimulus and the test ischemia has not yet been elucidated. Thus, we designed studies in which the expression of 29 genes was examined by real-time PCR at various time intervals, i.e., immediately (0 h), 6, 12, and 24 h after short periods (4 times 5 min) of rapid (240 beats min(-1)) right ventricular pacing in the canine. Sham-operated dogs (the pacing electrode was introduced but the dogs were not paced) served as controls. Compared with these dogs, pacing induced an early up-regulation of genes which encode, for example, HSP90, MnSOD, ERK1, PKCepsilon, Bcl2, and sGC; all these somehow relate to the early phase of the protection. These genes remained either up-regulated or, after a transient lower expression (around 6 h), were up-regulated again, suggesting their involvement in the delayed protection. There were also some genes which down-regulated soon after the pacing stimulus (e.g., Bax, Casp3, Casp9, MMP9, GSK3beta), and showed also low expression 24 h later. Genes encoding eNOS and iNOS, as well as Cx43 were only up-regulated 12 h after pacing. We conclude that cardiac pacing induces time-dependent changes in gene expression, and the sequence of these changes is important in the development of the delayed protection. PMID- 23014935 TI - Dose-dependent effects of the herbicide mesotrione on soil cyanobacterial communities. AB - This study aimed to investigate the dose-response effects of an herbicide on soil photosynthetic microbial communities, particularly cyanobacteria, using a microcosm approach. Pure mesotrione (active ingredient), and Callisto (a commercial formulation of this triketone herbicide), were spread at different rates on soil microcosm surfaces. Soil Chlorophyll concentrations were quantified to assess the photosynthetic biomass, and the genetic structure and diversity of the cyanobacterial community were investigated by a group-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis. Dose dependent responses were evidenced for both functional and structural parameters. No effect was detected in soils treated with 1 * AR (1-fold recommended application rate) irrespective of the herbicide formulation. At 10 * AR (10-fold recommended application rate), only Callisto treatment induced significant decreases of photosynthetic biomass, whereas structural parameters were less affected. At the 100 * AR (100-fold recommended application rate), both pure mesotrione and Callisto had strong negative impacts on soil chlorophyll concentrations and cyanobacterial genetic structure and diversity. At both the 10 * AR and 100 * AR treatments, Callisto induced significant stronger effects than pure mesotrione. In addition, indicators of photosynthetic biomass, compared with structural parameters of cyanobacterial communities (within 14 days), responded (within 7 days) more quickly to herbicide stress. The results of this study underscore the relevance of soil photosynthetic microbial communities to develop indicators for herbicide risk assessment. PMID- 23014936 TI - Fractionation and potential toxic risk of metals from superficial sediment in Itaipu Lake--boundary between Brazil and Paraguay. AB - The objective of this study was to evaluate fractions of metals (labile and pseudo-total) extracted from sediment samples collected in Itaipu Lake (boundary between Brazil and Paraguay) and to assess the dynamics and mobility of these fractions by identifying the same bioavailability and ecological risk to metals in the aquatic environment. The concentrations of metal ions were determined by flame atomic absorption spectrometry. There was a correlation between the metal ions, both in the labile and the pseudo-total, with regard to particle size. To assess metals concentrations in sediment, numerical sediment-quality guidelines were applied. The concentrations of aluminum, cadmium, iron, manganese, lead, and zinc in all sediment samples are lower than the proposed probable effects level (PEL), thus possibly indicating that there are no harmful effects from these metals. In contrast, concentrations of copper, chromium, and nickel exceeded the PEL in some samples, thus indicating that these stations are at potential risk. The level of contamination in sediments of Itaipu Lake for all metals was evaluated using contamination factor, degree of contamination, and sum-of-metals toxic unit. PMID- 23014937 TI - Late-onset offending: fact or fiction. AB - This research focuses on a detailed exploration of late-onset offending. Using the National Youth Survey, this work seeks to answer three questions. First, is late-onset offending a real phenomenon? Second, if late onset does exist, is the evidence for it conditioned by how we define crime and delinquency? Finally, is late-onset offending an artifact of measurement methodology? Most literature evidencing late onset relies on official police contact and arrest data. Propensity or control theories in general posit that late onset should not exist. Propensity, namely self-control, should be instilled early in life and if absent, results in early initiation into crime and delinquency. Research in developmental psychology seems to support this notion. The findings from this study indicate that late-onset offending is almost nonexistent when self-reported measures are used leading one to conclude that contemporary evidence for late-onset is heavily conditioned by how we measure crime and delinquency. A comprehensive discussion includes future directions for research, and implications for theory development and methodology. PMID- 23014938 TI - Republished: Glaucoma: a systemic condition? PMID- 23014940 TI - Republished: Daily consultant gastroenterologist ward rounds: reduced length of stay and improved inpatient mortality. AB - BACKGROUND: For gastroenterology, The Royal College of Physicians reiterates the common practice of two to three consultant ward rounds per week. The Royal Bolton Hospital NHS Foundation Trust operated a 26-bed gastroenterology ward, covered by two consultants at any one time. A traditional system of two ward rounds per consultant per week operated, but as is commonplace, discharges peaked on ward round days. OBJECTIVE: To determine whether daily consultant ward rounds would improve patient care, shorten length of stay and reduce inpatient mortality. METHODS: A new way of working was implemented in December 2009 with a single consultant taking responsibility for all ward inpatients. Freed from all other direct clinical care commitments for their 2 weeks of ward cover, they conducted ward rounds each morning. A multidisciplinary team (MDT) meeting followed immediately. The afternoon was allocated to gastroenterology referrals and reviewing patients on the medical admissions unit. RESULTS: The changes had an immediate and dramatic effect on average length of stay, which was reduced from 11.5 to 8.9 days. The number of patients treated over 12 months increased by 37% from 739 to 1010. Moreover, the number of deaths decreased from 88 to 62, a reduction in percentage mortality from 11.2% to 6%. However, these major quality outcomes involved a reduction in consultant-delivered outpatient and endoscopy activity. CONCLUSION: This new method of working has both advantages and disadvantages. However, it has had a major impact on inpatient care and provides a compelling case for consultant gastroenterology expansion in the UK. PMID- 23014939 TI - Republished: Defining impact of a rapid response team: qualitative study with nurses, physicians and hospital administrators. AB - OBJECTIVE: The objective of this study was to qualitatively describe the impact of a Rapid Response Team (RRT) at a 944-bed, university-affiliated hospital. METHODS: We analysed 49 open-ended interviews with administrators, primary team attending physicians, trainees, RRT attending hospitalists, staff nurses, nurses and respiratory technicians. RESULTS: Themes elicited were categorised into the domains of (1) morale and teamwork, (2) education, (3) workload, (4) patient care, and (5) hospital administration. Positive implications beyond improved care for acutely ill patients were: increased morale and empowerment among nurses, real-time redistribution of workload for nurses (reducing neglect of non-acutely ill patients during emergencies), and immediate access to expert help. Negative implications were: increased tensions between nurses and physician teams, a burden on hospitalist RRT members, and reduced autonomy for trainees. CONCLUSIONS: The RRT provides advantages that extend well beyond a reduction in rates of transfers to intensive care units or codes but are balanced by certain disadvantages. The potential impact from these multiple sources should be evaluated to understand the utility of any RRT programme. PMID- 23014941 TI - Improving outcome in severe trauma: trauma systems and initial management: intubation, ventilation and resuscitation. AB - Severe trauma is an increasing global problem mainly affecting fit and healthy younger adults. Improvements in the entire pathway of trauma care have led to improvements in outcome. Development of a regional trauma system based around a trauma centre is associated with a 15-50% reduction in mortality. Trauma teams led by senior doctors provide better care. Although intuitively advantageous, the involvement of doctors in the pre-hospital care of trauma patients currently lacks clear evidence of benefit. Poor airway management is consistently identified as a cause of avoidable morbidity and mortality. Rapid sequence induction/intubation is frequently indicated but the ideal drugs have yet to be identified. The benefits of cricoid pressure are not clear cut. Dogmas in the management of pneumothoraces have been challenged: chest x-ray has a role in the diagnosis of tension pneumothoraces, needle aspiration may be ineffective, and small pneumothoraces can be managed conservatively. Identification of significant haemorrhage can be difficult and specific early resuscitation goals are not easily definable. A hypotensive approach may limit further bleeding but could worsen significant brain injury. The ideal initial resuscitation fluid remains controversial. In appropriately selected patients early aggressive blood product resuscitation is beneficial. Hypothermia can exacerbate bleeding and the benefit in traumatic brain injury is not adequately studied for firm recommendations. PMID- 23014942 TI - Brief encounter. PMID- 23014943 TI - Inhibition of endothelial nitric oxyde synthase increases capillary formation via Rac1-dependent induction of hypoxia-inducible factor-1alpha and plasminogen activator inhibitor-1. AB - Disruption of endothelial homeostasis results in endothelial dysfunction, characterised by a dysbalance between nitric oxide (NO) and reactive oxygen species (ROS) levels often accompanied by a prothrombotic and proproliferative state. The serine protease thrombin not only is instrumental in formation of the fibrin clot, but also exerts direct effects on the vessel wall by activating proliferative and angiogenic responses. In endothelial cells, thrombin can induce NO as well as ROS levels. However, the relative contribution of these reactive species to the angiogenic response towards thrombin is not completely clear. Since plasminogen activator inhibitor-1 (PAI-1), a direct target of the proangiogenic transcription factors hypoxia-inducible factors (HIFs), exerts prothrombotic and proangiogenic activities we investigated the role of ROS and NO in the regulation of HIF-1alpha, PAI-1 and capillary formation in response to thrombin. Thrombin enhanced the formation of NO as well as ROS generation involving the GTPase Rac1 in endothelial cells. Rac1-dependent ROS formation promoted induction of HIF-1alpha, PAI-1 and capillary formation by thrombin, while NO reduced ROS bioavailability and subsequently limited induction of HIF 1alpha, PAI-1 and the angiogenic response. Importantly, thrombin activation of Rac1 was diminished by NO, but enhanced by ROS. Thus, our findings show that capillary formation induced by thrombin via Rac1-dependent activation of HIF-1 and PAI-1 is limited by the concomitant release of NO which reduced ROS bioavailability. Rac1 activity is sensitive to ROS and NO, thereby playing an essential role in fine tuning the endothelial response to thrombin. PMID- 23014944 TI - Dynamic MR imaging of a minipig's knee using a high-density multi-channel receive array and a movement device. AB - OBJECT: To construct an optimised, high-density receive array and a movement device to achieve dynamic imaging of the knee in orthopedic large animal models (e.g., minipigs) at 1.5 T. MATERIALS AND METHODS: A 13-channel RF receive array was constructed, and the crucial choice of the array element size (based on considerations like region of interest, geometry of the minipig's knee, achievable signal-to-noise ratio, applicability of parallel imaging, etc.) was determined using the Q factors of loops with different sizes. A special movement device was constructed to guide and produce a reproducible motion of the minipig's knee during acquisition. RESULTS: The constructed array was electrically characterised and the reproducibility of the cyclic motion was validated. Snapshots of dynamic in vivo images taken at a temporal resolution (308 ms) are presented. Some of the fine internal structures within the minipig's knee, like cruciate ligaments, are traced in the snapshots. CONCLUSION: This study is a step towards making dynamic imaging which can give additional information about joint injuries when static MRI is not able to give sufficient information, a routine clinical application. There, the combination of a high density receive array and a movement device will be highly helpful in the diagnosis and therapy monitoring of knee injuries in the future. PMID- 23014946 TI - Anion binding induced conformational changes exploited for recognition, sensing and pseudorotaxane disassembly. AB - Investigations to exploit the anion binding induced conformational changes displayed by a new class of acyclic receptor for anion recognition, fluorescence sensing and pseudorotaxane disassembly are described. A series of imidazolium appended bis-amide-pyridine, pyridine N-oxide and pyridinium containing receptors are synthesised and their anion binding properties elucidated using (1)H NMR spectroscopy. Upon anion recognition, the receptors exhibit a substantial conformational change from an 'open' to a more 'closed' intramolecular geometry. The fluorescence anion sensing ability of a bis-pyrene-functionalised analogue is investigated, with anion-induced responses arising from excimer signalling mechanisms. A pseudorotaxane assembly formed between the pyridine N-oxide receptor acting as a threading component and an isophthalamide macrocycle is demonstrated to undergo disassembly resulting from the conformational behaviour exhibited by the thread upon chloride binding. PMID- 23014945 TI - Unprotected left main stenting in the real world: five-year outcomes of the French Left Main Taxus registry. AB - AIMS: Limited long-term data are available to support drug-eluting stent (DES) unprotected left main (LM) intervention. We sought to evaluate long-term outcomes of LM intervention with paclitaxel-eluting stents. METHODS AND RESULTS: In this prospective multicentre registry, 291 patients with unprotected LM stenosis underwent percutaneous revascularisation with the TAXUS(r) Express(r) stent, using a consistent technical approach for both ostial/shaft and bifurcation lesions (provisional side branch stenting). At five years (n=263), the cumulative incidence of major adverse cardiac events (MACE) and cardiac death were 23.6% and 12.5%, respectively. Myocardial infarction (MI) occurred in 16 patients (6.1%), definite stent thrombosis in 0.4%, and target lesion revascularisation (TLR) was required in 10.3%. Patients with distal LM lesions requiring two-stent procedures had increased MACE compared with those with single-stent interventions (34.1% vs. 17.8%, p=0.009). This was primarily driven by an increased incidence of cardiac death (18.2% vs. 8.5%, p=0.05). Diabetes was associated with increased TLR and was an independent predictor of MACE at five years (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.10-3.99, p=0.02). CONCLUSIONS: This study confirms the long-term safety and efficacy of the TAXUS(r) DES in unprotected LM stenting. Diabetes and the need for a second stent in distal LM interventions were associated with an increased risk of adverse outcomes. PMID- 23014947 TI - Catalysts to withdrawal from familial ovarian cancer screening for surgery and reactions to discontinued screening: a qualitative study. AB - Women at high risk of familial ovarian cancer face a potentially difficult risk management choice between unproven ovarian cancer screening (OCS) and bilateral salpingo-oophorectomy (BSO). It is not fully understood why women who initially opt for OCS may later undergo BSO, nor what the impact of this may be. This study explored the catalysts for surgery and reactions to discontinuing OCS. Semi structured interviews were completed with 21 women who had undergone surgery having initially chosen OCS to explore their screening experiences, reasons for and feelings about surgery, and reactions to discontinuing OCS. The invasive nature and frequency of OCS were not by themselves a catalyst for surgery. A number of catalysts, including abnormal OCS test results, and secondary considerations, such as age-related factors, were found to prompt surgery. The emotional impact of discontinuing OCS following BSO varied between relief, acceptance, and loss of reassurance. OCS appears to be an acceptable risk management strategy under certain circumstances, but varying factors can prompt the decision to opt instead for BSO. The complexity of this management change decision should not be underestimated and needs to be taken into account by clinicians assisting women making choices. These findings highlight the importance of the timing of decision-making about BSO and that risk management options need routine reconsideration, through clinical discussions, information and support. PMID- 23014948 TI - Binding of cerium monoxide to annulenes and buckybowls. AB - The structural, electronic, bonding and magnetotropic properties of inclusion compounds formed upon interaction of cerium monoxide, CeO, with buckybowls (quadrannulene, C(31)H(16), corannulene, C(20)H(10) and sumanene, C(21)H(12)) have been investigated by DFT calculations. For the sake of comparison the structural, electronic, bonding and magnetotropic spectroscopic properties of related annulenes (cyclobutadiene, C(4)H(4), benzene, C(6)H(6) and cyclooctatetraene, C(8)H(8)) have also been investigated at the same level of theory. The metal-ligand bonding was characterized by Natural Bond Orbital (NBO) analysis. Despite the weak covalent interactions involving pi...pi*, delta...pi* and phi...pi* interactions in some adducts the larger part of the interaction energy is due to electrostatic and dispersion forces. The effect of the adduct formation on the structural and magnetotropic properties of the coordinated buckybowls and annulenes has also been explored by employing electronic structure computational techniques. PMID- 23014949 TI - Routine sectioning of the C2 nerve root and ganglion for C1 lateral mass screw placement in children: surgical and functional outcomes. AB - PURPOSE: Adult studies have shown that sectioning the C2 nerve root and ganglion may facilitate placement of C1 lateral mass screws and lead to decreased operative time and blood loss. We report the functional outcomes and complications following routine sectioning of the C2 nerve root and ganglion, which have not been reported in pediatric patients. METHODS: Fifteen consecutive pediatric patients underwent C1 lateral mass screw insertion and bilateral C2 nerve root and ganglion sectioning. Clinical and radiographic assessments were performed at follow-up. Numbness in the C2 distribution and/or occipital neuralgia, operative times, estimated blood loss (EBL), length of stay (LOS), and complications were recorded. RESULTS: Average follow-up time was 35.7 months. Overall mean operative time was 250.5 min, LOS was 8.46 days, and EBL was 337 cc. When considering only atlantoaxial fusions, mean operative time was 180.7 min and EBL was 97.1 cc. There were no intraoperative complications, and no patient reported new onset occipital neuralgia or numbness in the C2 distribution that would interfere with daily living. Of the patients, 93 % achieved Lenke fusion grade A; one achieved Lenke fusion grade B. CONCLUSIONS: Routine C2 nerve root sectioning and ganglionectomy enhanced surgical exposure of the C1 lateral mass and C1-2 facet joint, potentially maximizing fusion rate and minimizing intraoperative complications. This technique may yield favorable operative times, EBL, and LOS in children undergoing C1 lateral mass screw insertion without negatively affecting functional outcome. PMID- 23014951 TI - Preoperative embolization of choroid plexus papilloma with Onyx via the anterior choroidal artery: technical note. AB - INTRODUCTION: Total surgical resection is the treatment of choice for choroid plexus tumors. However, the hypervascular nature of such lesions imposes challenges to the surgical treatment. Preoperative embolization for intracranial tumors has been widely used in an attempt to reduce blood loss, but rarely with choroid plexus tumors. CASE REPORT: We describe the first case of preoperative embolization of choroid plexus papilloma with Onyx via the anterior choroidal artery. The procedure underwent without any complications and surgical treatment was possible with minimal blood loss. DISCUSSION: Embolization of choroid plexus tumors via anterior choroidal artery is potentially dangerous, but following a meticulous technique, it can be used as a safe and effective preoperative procedure. PMID- 23014950 TI - Management of ruptured dissecting intracranial aneurysms in infants: report of four cases and review of the literature. AB - BACKGROUND: Intracranial cerebral aneurysms in the pediatric population are infrequent, and those occurring in infants less than 1 year old are extremely rare. Of intracranial aneurysms in children, dissecting aneurysms are the most common type seen. While spontaneous dissecting aneurysms usually present with ischemia, hemorrhage can also occur. METHODS: A retrospective review of our patients revealed that from July 1, 2007 to June 30, 2012, four infants were treated for ruptured distal dissecting intracranial aneurysms at Texas Children's Hospital. Mycotic aneurysms and collagen vascular disorder were excluded in all four cases. All patients presented in our series presented with subarachnoid hemorrhage, and three had intraventricular hemorrhage. All patients underwent conventional catheter angiography for diagnosis. All patients in this series were managed in the acute or subacute period with surgical or endovascular trapping without distal bypass procedures. All four patients tolerated sacrifice of the parent vessels feeding these distal aneurysms well. CASE REPORT AND REVIEW OF LITERATURE: We describe the presentation and management of these rare cases and then review the current literature on the management of these dissecting aneurysms in infants. PMID- 23014952 TI - Antibiotic bone cement: are timing and dosing important variables for vancomycin elution? Commentary on an article by Tanay J. Amin, MD, et al.:" increasing the elution of vancomycin from high-dose antibiotic-loaded bone cement: a novel preparation technique". PMID- 23014954 TI - Organochlorinated pesticides, PCBs, dioxins, and PBDEs in grey mullets (Liza ramada) and allis shads (Alosa alosa) from the Vilaine estuary (France). AB - This study aimed to compare the contamination levels of various organohalogenated compounds in two migratory fish species in the Vilaine River in western France. Organochlorinated pesticides, polychlorinated biphenyls (PCBs), dioxins (polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDDs/Fs)), and polybrominated diphenyl ethers (PBDEs) were analyzed in two diadromous species from the Vilaine estuary, the grey mullet (Liza ramada)-an amphihaline species, and the allis shad (Alosa alosa)-an anadromous species. Fish were collected in spring 2004 and spring 2005, upstream and downstream of the Arzal Dam. PCB contamination varied from 27 to 200 ng g(-1) dry weight (d.w.). PCDDs/Fs, expressed in toxicity equivalent quantity (TEQ) varied from 0.4 to 2.8 pg g(-1) d.w. Dioxins and dioxin like PCBs expressed in total TEQ varied from 1.4 to 18.8 pg g(-1) d.w. PBDE47 was present at around 2-10 ng g(-1) d.w. and concentrations of the insecticide dichlorodiphenyltrichloroethane breakdown product p,p' dichlorodiphenylchloroethylene varied from 1 to 14 ng g(-1) d.w. For both species, specimens collected upstream were more contaminated. The grey mullet specimens were less contaminated than the allis shad when taken downstream of the dam but were more contaminated upstream. The allis shads presented intermediate contaminant concentrations with a less pronounced difference between upstream and downstream specimens. However, it is thought that shads do not feed when they spawn in the upstream parts of rivers, which should modify the contaminant concentrations. However, measurements in upstream shad samples show an unexpected increase of the contamination, which remains unexplained. PMID- 23014955 TI - Organ transplantation and meaning of life: the quest for self fulfilment. AB - Today, the frequency and the rate of success resulting from advances in medicine have made organ transplantations an everyday occurrence. Still, organ transplantations and donations modify the subjective experience of human beings as regards the image they have of themselves, of body, of life and of death. If the concern of the quality of life and the survival of the patients is a completely human phenomenon, the fact remains that the possibility of organ transplantation and its justification depend a great deal on the culture in which we live. The exploration of the philosophical tradition allows for a reconsideration of organ transplantation. If we listen to people who have experienced the decline of one of their organs and their own rebirth through the organ of someone else, we arrive at the conclusion that they went through an extreme experience in which nothing appeared as before. All those experiences intensify philosophical questionings on the meaning of life with respect to self fulfilment. The concept of nature as the experience of others can be an authentic source from which to nourish our thoughts about organ transplantation. However, and this is our hypothesis, we need something more if we are to decide something about our own life. We need a hermeneutical stance in relation to ourselves and to our world. Philosophical counselling, as a long established tradition originating with Pythagoras and later reframed by the German philosopher Achenbach could be useful in inspiring a reflection on the good life, chiefly as it takes the form of a Socratic dialogue. PMID- 23014953 TI - In vivo exposure of Mytilus edulis to living enteric bacteria: a threat for immune competency? AB - Mussels are widespread in coastal environments and experience various physical, chemical, and bacteriological conditions. Owing to the increase of coastal urbanization, mussels are now commonly exposed not only to indigenous bacteria, but also to enteric bacteria originating from pulsed and chronic sewage discharges into coastal environments. Due to its broad resilience to environmental variations, the blue mussel Mytilus edulis is commonly used as an indicator of environmental quality in bio-monitoring programs. However, since mussel immune system capabilities may be affected by the presence of exogenous fecal bacteria in coastal seawater subjected to sewage discharges, we aimed to determine the effect of in vivo bacterial challenges on mussels' immune competency by using two exogenous enteric bacterial strains, Escherichia coli and Enterococcus faecalis, and an indigenous bacterial strain Vibrio splendidus (as control). Bacterial strains were tested individually, by injection into the posterior adductor muscle at three different cell densities (10(2), 10(3), and 10(4) cells). Unlike classic in vitro experiments using higher bacterial concentrations, neither the enteric bacteria nor the indigenous strain induced significant increase or decrease of either cell-mediated (phagocytosis, reactive oxygen species, and NO(x) production) or humoral components (prophenoloxidase like, acid phosphatase, and L-leucine-aminopeptidase production) of the immune system. This study demonstrates that, at low concentrations, E. coli and E. faecalis do not represent an additional threat that could impair M. edulis immune competency and, as a consequence, its potential of survival in coastal areas subjected to sewage discharges. PMID- 23014957 TI - Laser, the physician, and the vessels. PMID- 23014958 TI - Grating couplers for dual-channel thin-film waveguide sensors produced by transmission photolithography. PMID- 23014956 TI - Arsenobetaine formation in plankton: a review of studies at the base of the aquatic food chain. AB - Arsenobetaine is one of the major organoarsenic compounds found in aquatic organisms, including seafood and fish meant for human consumption. It has been widely studied over the last 50 years because of its non-toxic properties, and its origin is postulated to be at bottom of the aquatic food chains. The present review focuses on arsenobetaine formation in marine and freshwater plankton, comparing the arsenic compounds found in the different plankton organisms, and the methods used to assess arsenic speciation. The main findings indicate that in the marine environment, phytoplankton and micro-algae contain arsenosugars, with the first traces of arsenobetaine appearing in herbivorous zooplankton, and becoming a major arsenic compound in carnivorous zooplankton. Freshwater plankton contains less arsenobetaine than their marine relatives, with arsenosugars dominating. The possible role and formation pathways of arsenobetaine in plankton organisms are reviewed and the literature suggests that arsenobetaine in zooplankton comes from the degradation of ingested arsenosugars, and is selectively accumulated by the organism to serve as osmolyte. Several arsenic compounds such as arsenocholine, dimethylarsinoylacetate or dimethylarsinoylethanol that are intermediates of this pathway have been detected in plankton. The gaps in research on arsenobetaine in aquatic environments are also addressed: primarily most of the conclusions are drawn on culture-based experiments, and few data are present from the natural environment, especially for freshwater ecosystems. Moreover, more data on arsenic in different zooplankton species would be helpful to confirm the trends observed between herbivorous and carnivorous organisms. PMID- 23014959 TI - Higher order moment processing of laser Doppler perfusion signals. PMID- 23014960 TI - Ratio-based decisions and the quantitative analysis of cDNA microarray images. PMID- 23014961 TI - Image quality in pseudophakic eyes with two different types of intraocular lenses ranging in the degree of high myopia. PMID- 23014962 TI - Noninvasive detection of cardiovascular pulsations by optical Doppler techniques. PMID- 23014963 TI - Sensing and reference pads for integrated optical immunosensors. PMID- 23014964 TI - Light propagation in tissues with controlled optical properties. PMID- 23014965 TI - Imaging spectroscopy of the human ocular fundus in vivo. PMID- 23014966 TI - Diffuse optical tomography based on a WKB approximation. PMID- 23014967 TI - Rapid observation of unfixed, unstained human skin biopsy specimens with confocal microscopy and visualization. PMID- 23014968 TI - Ascending aorta thrombosis in a HeartWare(r) left ventricular assist device recipient. PMID- 23014969 TI - Long-term survival from 801 adjunctive coronary endarterectomies in diffuse coronary artery disease. AB - OBJECTIVES: The role of coronary endarterectomy (CE) in modern cardiac surgery has been an extant debate as coronary artery bypass grafting (CABG) has advanced. However, as cardiac surgeons are being referred ever more complex coronary disease for surgical correction, adjunctive strategies may need re-evaluation. The long-term results of CE are largely unknown. We present the longest cohort follow-up in a single institution looking at our 20-year experience of CEs employed as an adjunct to CABG in diffuse coronary artery disease. METHODS: We performed retrospective analysis of data collected prospectively on 801 patients undergoing CEs between February 1988 and September 2010 by a single surgeon using a standard open hydrodissection technique. We looked at patient demographics, characteristics of the vessels subjected to endarterectomy and predictors of long term survival within this surgical group using Cox's regression analysis. RESULTS: The mean age was 63.2 (+/-9.6) years. The mean number of coronary arteries undergoing endarterectomy was 1.16 (+/-0.4) per patient. Of these, 63.7% were performed on the right coronary artery (n = 558) and 32.3% on the left anterior descending artery (n = 283). The operative mortality was 2.62% (n = 21). The median survival time was 16.67 years (95% confidence interval 15.14-18.19 years). The significant predictors of survival (P < 0.05) were a lower age at surgery, a lower EuroSCORE I, the absence of peripheral vascular disease and shorter bypass times. CONCLUSION: This significant long-term survival demonstrates that CE can be an attractive adjunct to CABG in otherwise inoperable coronary artery disease. PMID- 23014971 TI - Rupture of the NovaFlex balloon during transcatheter aortic valve implantation and subsequent dissection of the right iliac arteries. AB - We report a case with a very rare complication of transcatheter aortic valve implantation. Rupture of the NovaFlex balloon (Edwards transfemoral balloon catheter) occurred during the inflation of the Edwards SAPIEN valve, resulting in dissection of the right common and external iliac arteries during withdrawal of the balloon catheter. The NovaFlex balloon is a part of the Edwards NovaFlex XT transfemoral delivery system. PMID- 23014970 TI - Validation of the lung cancer staging system revisions using a large prospective clinical trial database (ACOSOG Z0030). AB - OBJECTIVES: A new revision of the international lung cancer staging system has been recently introduced. The revisions are largely focussed on the T descriptor. We sought to test the validity of this new system on a separate prospectively collected cohort of patients from a recent multicentre trial of early-stage lung cancer. METHODS: We reviewed the prospectively collected data from 1012 patients undergoing pulmonary resection for early-stage lung cancer in the ACOSOG Z0030 trial. TNM descriptors and overall staging were assessed using both the sixth and seventh editions of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer (AJCC/UICC) lung cancer staging system. Survival results were analysed according to both staging allocations. RESULTS: Using the proposed criteria, the number of patients by stage in the sixth and seventh edition allocations, respectively, were as follows: IA (432, 431); IB (402, 303); IIA (39, 167); IIB (94, 70); IIIA (26, 40); IIIB (19,0); there were no stage IV patients by either version. Overall, 180 (18%) patients had a change in the stage group from the sixth to seventh edition versions with 76 (8%) being downstaged and 104 (10%) being upstaged. In the sixth edition staging system based on pathological stages, median survivals in years were as follows: IA, NA; IB, 7.7; IIA, 4.0; IIB, 3.6; IIIA, 2.6 and IIIB, 2.4. Five-year survivals were: IA, 76.4%; IB, 62.0%; IIA, 47.8%; IIB, 40.4%; IIIA, 31.3% and IIIB, 44.4%. In the new system, median survivals in years were as follows: IA, NA; IB, 8.2; IIA, 4.4; IIB, 3.6 and IIIA, 1.8. Five-year survivals were: IA, 76.9%; IB, 65.0%; IIA, 48.5%; IIB, 42.9% and IIIA, 30.6%. Survival analysis and Kaplan-Meier survival curves showed more monotonic progression, distinction and homogeneity within groups in the seventh edition. CONCLUSIONS: This study provides an external validation of the recently revised lung cancer staging system using a large multicentre database. The seventh edition of the AJCC/UICC lung cancer staging system appears to be an improvement over the preceding system. PMID- 23014972 TI - A novel flow cytometry single tube bead assay for quantitation of von Willebrand factor antigen and collagen-binding. AB - Deficiency of or defects in the plasma protein von Willebrand factor (VWF) lead to bleeding and von Willebrand disease (VWD), which may be congenital or acquired. VWD is considered the most common inherited bleeding disorder and laboratory testing for VWF level and activity is critical for appropriate diagnosis and management. We have designed and established a novel Flow Cytometry (FC) based method for measuring VWF antigen (VWF:Ag) and collagen binding (VWF:CB), together in the same tube and at the same time. The results of the novel FC method have been compared against existing reference methods using a range of normal and pathological material. Methods correlated well (VWF:Ag, r=0.866; VWF:CB, r=0.888) and generally permitted similar discrimination of quantitative versus qualitative VWD types (e.g. type 1 vs type 2A or 2B VWD). The novel procedure is expected to permit future streamlined performance of VWD screening, either using stand-alone FC systems or potentially incorporated into FC-capable automated blood cell and particle counters to allow for improved, automated and faster identification or exclusion of VWD. PMID- 23014973 TI - Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes. AB - Evidence indicates that the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells (MSCs) is regulated by several hormones, growth factors, and their downstream signaling cascades. Previous studies suggest that retinoic acid (RA) plays a role in osteoblastogenesis and adipogenesis. However, it is unknown whether RA regulates commitment of MSCs into osteoblasts and adipocytes. In this study, we investigated the role of RA in differentiation of MSCs using the C3H10T1/2 cell line. RA stimulated activity and expression of alkaline phosphatase (ALP) and upregulated activity of the ALP gene promoter. The effects of RA were further enhanced by bone morphogenetic protein 2 (BMP2) and resultant Smad signaling. Furthermore, overexpression of Runx2 and Msx2, critical transcription factors for bone formation and BMP2-dependent osteoblastogenesis, enhanced RA-dependent ALP activity. In view of these findings, RA likely stimulates osteoblast differentiation through the BMP2-Smad-Runx2/Msx2 pathway. In contrast, RA markedly inhibited BMP2-induced adipocyte differentiation, suppressing expression of peroxisome proliferator-activated receptor-gamma (PPARgamma), CCAAT/enhancer-binding protein (C/EBP)alpha and C/EBPdelta, and inhibiting adipogenic function of C/EBPbeta, C/EBPdelta, and PPARgamma. In conclusion, our data suggest that RA regulates commitment of MSCs into osteoblasts and adipocytes by controlling transcriptional regulators. PMID- 23014974 TI - Changes in CLIP3 expression after sciatic nerve injury in adult rats. AB - CLIP3 (cytoplasmic linker protein 3) is a 547 amino acid residue cytoplasmic protein that localises to Golgi stacks and tubulovesicular elements juxtaposed to Golgi cisternae. Composed of three Ank (ankyrin) repeats and two CAP-Gly (cytoskeleton-associated protein-glycine) domains, CLIP3 may function as a cytoplasmic linker protein that is involved in TGN-endosome dynamics. To define the expression and role of CLIP3 during peripheral nervous system degeneration and regeneration, we created an acute sciatic nerve injury (SNI) model in adult rats. Western blot analyses revealed prominent up-regulation of CLIP3 and PCNA (proliferating cell nuclear antigen) protein levels at 3 days after SNI. Immunohistochemistry displayed that the expression of CLIP3 was noticeably increased in the injured nerve. Immunofluorescence further revealed that the CLIP3 and PCNA proteins colocalised respectively with S100 in the cytoplasm of Schwann cells. The expression profile of the SC/neuron co-cultures demonstrated that CLIP3 and PCNA protein levels were markedly expressed during the early stage of myelination. These results suggest that CLIP3 is likely associated with the myelination of proliferating Schwann cells, and nerve tissue regeneration after peripheral nerve injury. CLIP3 and PCNA expression during early myelination may be related to the direct uptake and transport of lipids and cholesterol, which were derived from the degenerating myelin, by Schwann cells to prepare for the formation of myelin sheath-like structures around regenerated axons after SNI. PMID- 23014975 TI - Comparison of intracorporeal single-stapled and double-stapled anastomosis in laparoscopic low anterior resection for rectal cancer: a case-control study. AB - PURPOSE: Recently, a single-stapled technique (SST) was performed instead of the conventional double-stapled technique (DST) in laparoscopic low anterior resection for anastomosis, by placement of intracorporeal purse-string sutures on the distal rectum with transanal specimen extraction. This study aimed to compare the short-term outcomes between the two anastomotic techniques. METHODS: Between July 2007 and April 2010, 60 patients underwent SST by laparoscopic or robotic procedure. These patients were matched 1:2 by age, gender, date of surgery, and tumor stage with 120 patients who underwent conventional DST in laparoscopic low anterior resection. RESULTS: The robotic-assisted operative approach was used more frequently in the SST group than in the DST group (61.7 % vs. 3.3 %, p < 0.001). The mean operative time was 203.9 (range, 120-400) min for the SST group and 167.6 (range, 90-300) min for the DST group (p < 0.001). For specimen removal, the transanal approach was used in the SST group, while the transabdominal approach was used for the DST group. The pain score (visual analogue scale) of the SST group was lower (4.5 vs. 5.6, p < 0.001), although postoperative recovery was similar. Pathological examination revealed that the distal resection margin was significantly longer in the SST group (3.1 vs. 2.5 cm, p = 0.018). Postoperative morbidity including anastomotic leakage was similar in both groups. CONCLUSIONS: SST yielded equivalent short-term outcomes when compared to conventional DST and provided the advantages of minimal access and a longer distal resection margin. Therefore, SST in lower anterior resection may be a useful alternative to conventional DST. PMID- 23014976 TI - i-Scan high-definition white light endoscopy and colorectal polyps: prediction of histology, interobserver and intraobserver agreement. AB - PURPOSE: Aim of the study was the evaluation of high-definition white light (HDWL) i-Scan endoscopy for diagnostic prediction of histology, inter- and intraobserver agreement for colorectal polyps. METHODS: In this prospective single-center cohort study, a skilled endoscopist, with HDWL i-Scan, predicted on real-time the histology of 150 polyps from 78 patients undergoing colonoscopy. Subsequently, four endoscopists, not involved in the collection of cases, predicted the polyps' histology (neoplastic vs nonneoplastic) and repeated the assessment after 6 months. RESULTS: Real-time assessment of the lesions predicted a correct histology in 138/150 cases with a sensitivity, specificity, and accuracy of 95, 82, and 92 %, respectively. Sensitivity, specificity, and accuracy of post-acquisition evaluation were 87.7, 61.7, and 82.2 %, respectively. The kappa values of inter- and intraobserver agreement of prediction of histology were 0.462 (0.373-0.537) and 0.657 (0.523-0.917). Among the subset of polyps (n = 82) with good/excellent quality image, sensitivity and accuracy of HDWL i-Scan improved (97 %, p = 0.003 and 94 %, p = 0.002, respectively) as well as kappa value of interobserver agreement (0.699). CONCLUSIONS: HDWL i-Scan technology helps for characterization of polyps of the colon with good accuracy even if it cannot replace, at the moment, the histopathological examination. Reproducibility among operators is supported by a moderate substantial interobserver and intraobserver agreement. PMID- 23014977 TI - Risk factors for anastomotic leakage following anterior resection for colorectal cancer: the effect of epidural analgesia on occurrence. AB - PURPOSE: The effect of thoracic epidural analgesia (TEA) on anastomotic leakage (AL) after anterior resection for colorectal cancer is controversial. The aim of this study was to evaluate the risk factors including TEA for the occurrence of AL after anterior resection for colorectal cancer. METHODS: This retrospective study included 1,312 patients with colorectal cancer who underwent anterior resection between 2000 and 2011 at the Cancer Center, Sun Yat-sen University. Univariate and multivariate logistics analyses were performed to determine the risk factors, including TEA, for AL. Additionally, we evaluated the effect of TEA on outcome parameters. RESULTS: AL occurred in 118 (9 %) of the 1,312 patients. In univariate analysis, the American Society of Anesthesiologists (ASA) score, history of hypertension, episodes of hypotension, anastomosis technique, tumor localization, anesthesia duration, and perioperative blood transfusion were significant risk factors for AL. Multivariate analysis showed that ASA (P = 0.001), perioperative blood transfusion (P < 0.001), anastomosis technique (P = 0.019), anesthesia duration (P = 0.033), and tumor localization (P = 0.009) were independent factors affecting AL. TEA had no effect on the occurrence of AL (P = 0.451) in multivariate analysis. However, the length of hospital stay was shortened by the use of TEA (P < 0.001). CONCLUSIONS: The results of this retrospective study suggest that TEA has no effect on the occurrence of AL. However, TEA may be recommended to shorten the length of hospital stay. PMID- 23014978 TI - Enteral nutrition to suppress postoperative Crohn's disease recurrence: a five year prospective cohort study. AB - PURPOSE: The aim of this study was to investigate the long-term effect of enteral nutrition (EN) as a maintenance therapy in Crohn's disease (CD) patients following surgery. METHODS: This study was an extension of our previous study to prolong the duration of intervention and follow-up from 1 to 5 years. Forty consecutive patients who underwent resection for ileal or ileocolic CD were included. Following surgery, 20 patients received continuous elemental diet infusion during the nighttime plus a low-fat diet during the daytime (EN group). Another 20 patients received neither nutritional therapy nor food restriction (control group). All patients were followed for 5 years after operation. No patient received corticosteroid, immunosuppressants, or infliximab except patients who developed recurrence. The end point of this study was recurrence requiring biologic therapy or reoperation. Recurrence rates were analyzed on an intention-to-treat basis. RESULTS: In the EN group, four patients could not continue tube intubation for elemental diet intake. Two patients (10 %) in the EN group and nine patients (45 %) in the control group developed recurrence requiring infliximab therapy (P = 0.03). The cumulative recurrence incidence rate requiring infliximab was significantly lower in the EN group vs the control group (P = 0.02). One patient (5 %) in the EN group and five patients (25 %) in the control group required reoperation for recurrence (P = 0.18). The cumulative incidence of reoperation was lower in the EN group vs the control group, the difference not being significant (P = 0.08). CONCLUSION: The outcomes of this study suggest that EN therapy reduces the incidence of postoperative CD recurrence. PMID- 23014979 TI - Functional group chemistry at intramolecular frustrated Lewis pairs: substituent exchange at the Lewis acid site with 9-BBN. AB - The vicinal frustrated P/B Lewis pair (FLP) Mes(2)PCH(2)CH(2)B(C(6)F(5))(2) reacts with 9-borabicyclo[3.3.1]nonane (9-BBN) by C(6)F(5)vs. H exchange at boron to give the new [B]-H functionalized FLP Mes(2)PCH(2)CH(2)B(H)(C(6)F(5)) (4) and 9-C(6)F(5)-BBN. The latter was characterized as an isonitrile adduct by X-ray diffraction. The new FLP 4 forms an adduct with pyridine and it undergoes clean hydroboration reactions with 1-pentyne or added styrene or dimesitylvinylphosphane. The products formed stable adducts with pyridine; two such examples were also characterized by X-ray crystal structure analysis. A similar alkyl vs. hydrogen exchange was observed upon treatment of an Al/N based Lewis pair, iBu(2)Al-(Me(3)Si)C=C(H)-N(CH(2)CH(2))(2)NMe (14), with 9-BBN. PMID- 23014985 TI - Very long-term outcomes after percutaneous coronary intervention with bare metal stents for unprotected left main coronary artery disease. AB - AIMS: The aim of this study was to evaluate very long-term clinical outcomes and potential predictors after percutaneous coronary intervention (PCI) with bare metal stents (BMS) for unprotected left main coronary artery disease (ULMCAD). METHODS AND RESULTS: From March 1991 to August 2001, 151 patients who underwent PCI with BMS for ULMCAD were investigated retrospectively. The patient-oriented major adverse cardiac events (MACE) were defined as the occurrence of all-cause death, any MI, and any coronary revascularisation. The median follow-up duration was 10.5 years. The mean age was 69.9+/-11.5 years, and 106 patients (70.2%) were male. At 10 years, the incidences of cardiac death (CD), target lesion revascularisation (TLR) and patient-oriented MACE were 11.1%, 25.2% and 81.9%, respectively. In multivariate analysis, the pre-reference diameter of the left main trunk (LMT) was significantly associated with TLR (adjusted hazard ratio [HR] [95% confidence interval (CI)], 0.28 [0.14-0.54], p<0.001) and the SYNTAX score remained an independent predictor of patient-oriented MACE (adjusted HR [95% CI], 1.03 [1.007-1.05], p=0.009). CONCLUSIONS: The pre-reference diameter of LMT was significantly associated with TLR, and the SYNTAX score significantly predicted the risk of patient-oriented MACE at 10 years. BMS implantation for larger size of ULMCAD with a lower SYNTAX score was feasible for up to 10 years. PMID- 23014986 TI - Physical origin of hydrophobicity studied in terms of cold denaturation of proteins: comparison between water and simple fluids. AB - A clue to the physical origin of the hydrophobicity is in the experimental observations, which show that it is weakened at low temperatures. By considering a solvophobic model protein immersed in water and three species of simple solvents, we analyze the temperature dependence of the changes in free energy, energy, and entropy of the solvent upon protein unfolding. The angle-dependent and radial-symmetric integral equation theories and the morphometric approach are employed in the analysis. Each of the changes is decomposed into two terms, which depend on the excluded volume and on the area and curvature of the solvent accessible surface, respectively. The excluded-volume term of the entropy change is further decomposed into two components representing the protein-solvent pair correlation and the protein-solvent-solvent triplet and higher-order correlation, respectively. We show that water crowding in the system becomes more serious upon protein unfolding but this effect becomes weaker as the temperature is lowered. If the hydrophobicity originated from the water structuring near a nonpolar solute, it would be strengthened upon lowering of the temperature. Among the three species of simple solvents, considerable weakening of the solvophobicity at low temperatures is observed only for the solvent where the particles interact through a strong attractive potential and the particle size is as small as that of water. Even in the case of this solvent, however, cold denaturation of a protein cannot be reproduced. It would be reproducible if the attractive potential was substantially enhanced, but such enhancement causes the appearance of the metastability limit for a single liquid phase. PMID- 23014987 TI - Effects of strength training and detraining on knee extensor strength, muscle volume and muscle quality in elderly women. AB - Strength training seems to be an interesting approach to counteract decreases that affect knee extensor strength, muscle mass and muscle quality (force per unit of muscle mass) associated with ageing. However, there is no consensus regarding the changes in muscle mass and their contribution to strength during periods of training and detraining in the elderly. Therefore, this study aimed at verifying the behaviour of knee extensor muscle strength, muscle volume and muscle quality in elderly women in response to a 12-week strength training programme followed by a similar period of detraining. Statistical analysis showed no effect of time on muscle quality. However, strength and muscle volume increased from baseline to post-training (33 and 26 %, respectively). After detraining, the knee extensor strength remained 12 % superior to the baseline values, while the gains in muscle mass were almost completely lost. In conclusion, strength gains and losses due to strength training and detraining, respectively, could not be exclusively associated with muscle mass increases. Training-induced strength gains were partially maintained after 3 months of detraining in elderly subjects. PMID- 23014988 TI - A copper-responsive global repressor regulates expression of diverse membrane associated transporters and bacterial drug resistance in mycobacteria. AB - Sequencing of entire bacterial genomes has led to the identification of many membrane-associated transporters, including several multidrug resistance transport proteins, in recent years. However, the regulators and signaling pathways involved in the expression of these genes remain largely unknown. In this study, we have identified Ms2173, a GntR/FadR family transcription factor, as a novel global regulator in Mycobacterium smegmatis. Ms2173 was found to specifically recognize a 15-bp palindromic motif and to broadly regulate expression of 292 genes, including 37 genes that encode membrane-associated transport proteins. Copper ions induced Ms2173 to form inactive proteins lacking DNA-binding activity. Ms2173 was shown to function as a repressor of its target genes. Interestingly, we found that the function of Ms2173 was linked to mycobacterial drug resistance. Compared with the substantially enhanced drug resistance in the Ms2173-deleted mutant strain, the strains overexpressing Ms2173 were more sensitive to anti-tuberculosis drugs than the wild-type strain. Additionally, copper ions could partially counteract the in vivo function of Ms2173. We have thus characterized the first mycobacterial GntR/Fad-like transcription factor that functions as a copper ion-responsive global repressor that we have renamed GfcR. These findings further enhance our understanding of membrane-associated transporter regulation and drug resistance in mycobacteria. PMID- 23014989 TI - Acetylation of histone deacetylase 1 regulates NuRD corepressor complex activity. AB - BACKGROUND: HDAC1-containing NuRD complex is required for GATA-1-mediated repression and activation. RESULTS: GATA-1 associated with acetylated HDAC1 containing NuRD complex, which has no deacetylase activity, for gene activation. CONCLUSION: Acetylated HDAC1 converts NuRD complex from a repressor to an activator during GATA-1-directed erythroid differentiation program. SIGNIFICANCE: HDAC1 acetylation may function as a master regulator for the activity of HDAC1 containing complexes. Histone deacetylases (HDACs) play important roles in regulating cell proliferation and differentiation. The HDAC1-containing NuRD complex is generally considered as a corepressor complex and is required for GATA 1-mediated repression. However, recent studies also show that the NuRD complex is involved in GATA-1-mediated gene activation. We tested whether the GATA-1 associated NuRD complex loses its deacetylase activity and commits the GATA-1 complex to become an activator during erythropoiesis. We found that GATA-1 associated deacetylase activity gradually decreased upon induction of erythroid differentiation. GATA-1-associated HDAC1 is increasingly acetylated after differentiation. It has been demonstrated earlier that acetylated HDAC1 has no deacetylase activity. Indeed, overexpression of an HDAC1 mutant, which mimics acetylated HDAC1, promotes GATA-1-mediated transcription and erythroid differentiation. Furthermore, during erythroid differentiation, acetylated HDAC1 recruitment is increased at GATA-1-activated genes, whereas it is significantly decreased at GATA-1-repressed genes. Interestingly, deacetylase activity is not required for Mi2 remodeling activity, suggesting that remodeling activity may be required for both activation and repression. Thus, our data suggest that NuRD can function as a coactivator or repressor and that acetylated HDAC1 converts the NuRD complex from a repressor to an activator during GATA-1-directed erythroid differentiation. PMID- 23014990 TI - ELMO domains, evolutionary and functional characterization of a novel GTPase activating protein (GAP) domain for Arf protein family GTPases. AB - The human family of ELMO domain-containing proteins (ELMODs) consists of six members and is defined by the presence of the ELMO domain. Within this family are two subclassifications of proteins, based on primary sequence conservation, protein size, and domain architecture, deemed ELMOD and ELMO. In this study, we used homology searching and phylogenetics to identify ELMOD family homologs in genomes from across eukaryotic diversity. This demonstrated not only that the protein family is ancient but also that ELMOs are potentially restricted to the supergroup Opisthokonta (Metazoa and Fungi), whereas proteins with the ELMOD organization are found in diverse eukaryotes and thus were likely the form present in the last eukaryotic common ancestor. The segregation of the ELMO clade from the larger ELMOD group is consistent with their contrasting functions as unconventional Rac1 guanine nucleotide exchange factors and the Arf family GTPase activating proteins, respectively. We used unbiased, phylogenetic sorting and sequence alignments to identify the most highly conserved residues within the ELMO domain to identify a putative GAP domain within the ELMODs. Three independent but complementary assays were used to provide an initial characterization of this domain. We identified a highly conserved arginine residue critical for both the biochemical and cellular GAP activity of ELMODs. We also provide initial evidence of the function of human ELMOD1 as an Arf family GAP at the Golgi. These findings provide the basis for the future study of the ELMOD family of proteins and a new avenue for the study of Arf family GTPases. PMID- 23014991 TI - Mechanical stimulation of polycystin-1 induces human osteoblastic gene expression via potentiation of the calcineurin/NFAT signaling axis. AB - Mechanical forces trigger biological responses in bone cells that ultimately control osteoblastogenesis and bone program. Although several mechanosensors have been postulated, the precise mechanotransduction pathway remains obscure as the initial mechanosensing event has not yet been identified. Studies in kidney cells have shown that polycystin-1 (PC1), via its extracellular N-terminal part, may function as an "antenna-like" protein providing a linkage between environmental cues and their conversion into biochemical responses that regulate various cellular processes via the calcineurin/NFAT pathway. Here we explored the involvement of PC1 in mechanical load (stretching)-induced signaling cascades that control osteoblastogenesis/bone formation. FACS and TransAM Transcription Factor ELISA analyses employing extracts from primary human osteoblast-like, PC1 expressing cells subjected to mechanical stretching (0-6 h) revealed that unphosphorylated/DNA-binding competent NFATc1 increased at 0.5-1 h and returned to normal at 6 h. In accordance with the activation mechanism of NFATc1, stretching of cultured cells pre-treated with cyclosporin A (CsA, a specific inhibitor of the calcineurin/NFAT pathway) abrogated the observed decrease in the abundance of the cytoplasmic pNFATc1 (phosphorylated/inactive) species. Furthermore, stretching of osteoblastic cells pre-treated with an antibody against the mechanosensing N-terminal part of PC1 also abrogated the observed decrease in the cytoplasmic levels of the inactive pNFATc1 species. Importantly, under similar conditions (pre-incubation of stretched cells with the inhibitory anti-PC1 antibody), the expression of the key osteoblastic, NFATc1-target gene runx2 decreased compared to untreated cells. Therefore, PC1 acts as chief mechanosensing molecule that modulates osteoblastic gene transcription and hence bone-cell differentiation through the calcineurin/NFAT signaling cascade. PMID- 23014993 TI - Study of the association between glutathione S-transferase (GSTM1, GSTT1, GSTP1) polymorphisms with type II diabetes mellitus in southern of Iran. AB - Diabetes Mellitus is characterized by chronic hyperglycemia and associated with an increased production of reactive oxygen species (ROS). Oxidative stress is the result of accumulation of free radicals in tissues which specially affects beta cells in pancreas. Glutathione S-transferases (GSTs) are a family of antioxidant enzymes that include several classes of GSTs. These enzymes have important roles in decreasing of ROS species and act as a kind of antioxidant defense. To investigate the association between GSTs polymorphism with type 2 diabetes mellitus (T2DM), we investigated the frequency of GSTM1, T1 and P1 genotypes in patients with T2DM and controls. The genotypes of GSTT1, M1 and P1 were determined in 171 clinically documented T2DM patients and 169 normal cases (as controls) by multiplex polymerase chain reaction and PCR-RFLP. In diabetic patients, the frequency of GSTM1-null genotype was significantly (OR = 1.74; 95 % CI = 1.13-2.69, P = 0.016) higher than that in control. However, the frequency of GSTT1 (OR = 1.29; 95 % CI = 0.07-2.14, P = 0.367) and GSTP1 (OR = 0.83; 95 % CI = 0.53-1.30, P = 0.389) genotypes were not significantly different comparing both groups. Also, the frequency of both GSTT1-null and GSTM1-null genotypes in patients (19.88 %) was significantly higher compared to controls with the same genotypes (11.83 %, P = 0.022). Our results indicated that GSTM1 and GSTT1 genotypes might be involved in the pathogenesis of T2DM in south Iranian population. PMID- 23014994 TI - DGGE analysis of buffalo manure eubacteria for hydrogen production: effect of pH, temperature and pretreatments. AB - Buffalo dung is a low-cost substrate with plenty of carbohydrates, an optimal carbon/nitrogen ratio, and a rich microbial flora, and could become a valuable source of biogas. Therefore, in the present study we compared the type and amount of specific eubacteria to the different configurations of pH, temperature and thermal pretreatment after fermentation in batch reactors in order to understand the suitability of buffalo manure for hydrogen production. The phylogenetic structure of the microbial community in fermentation samples was studied using denaturing gradient gel electrophoresis to generate fingerprints of 16S rRNA genes. The sequences analysis revealed abundance of the phyla Bacteroidetes and Firmicutes, and in particular of the order Clostridiales. Very active hydrogen producing bacteria belonging to Clostridium cellulosi species were identified demonstrating the suitability of this substrate to produce hydrogen. Moreover, a large fraction of 16S-rDNA amplicons could not be assigned to lower taxonomic ranks, demonstrating that numerous microorganisms involved in anaerobic fermentation in digesters or bioreactors are still unclassified or unknown. PMID- 23014995 TI - Consequences of evolution: is rhinosinusitis, like otitis media, a unique disease of humans? AB - We hypothesize that if otitis media is most likely primarily a human disease due to consequences of evolution, rhinosinusitis may also be limited to humans for similar reasons. If otitis media, with its associated hearing loss, occurred in animals in the wild, they probably would have been culled out by predation. Similarly, if rhinosinusitis occurred regularly in animals, they likely would have suffered from severely decreased olfactory abilities, crucial for predator avoidance, and presumably would likewise have been selected against evolutionarily. Thus, both otitis media and rhinosinusitis-common conditions particularly in infants and young children-appear to be essentially human conditions. Their manifestation in our species is likely due to our unique evolutionary trajectory and may be a consequence of adaptations, including adaptations to bipedalism and speech, loss of prognathism, and immunologic and environmental factors. PMID- 23014992 TI - Neuroprotection against hypoxia/ischemia: delta-opioid receptor-mediated cellular/molecular events. AB - Hypoxic/ischemic injury remains the most dreaded cause of neurological disability and mortality. Despite the humbling experiences due to lack of promising therapy, our understanding of the complex cascades underlying the neuronal insult has led to advances in basic science research. One of the most noteworthy has been the effect of opioid receptors, especially the delta-opioid receptor (DOR), on hypoxic/ischemic neurons. Our recent studies, and those of others worldwide, present strong evidence that sheds light on DOR-mediated neuroprotection in the brain, especially in the cortex. The mechanisms of DOR neuroprotection are broadly categorized as: (1) stabilization of the ionic homeostasis, (2) inhibition of excitatory transmitter release, (3) attenuation of disrupted neuronal transmission, (4) increase in antioxidant capacity, (5) regulation of intracellular pathways-inhibition of apoptotic signals and activation of pro survival signaling, (6) regulation of specific gene and protein expression, and (7) up-regulation of endogenous opioid release and/or DOR expression. Depending upon the severity and duration of hypoxic/ischemic insult, the release of endogenous opioids and DOR expression are regulated in response to the stress, and DOR signaling acts at multiple levels to confer neuronal tolerance to harmful insult. The phenomenon of DOR neuroprotection offers a potential clue for a promising target that may have significant clinical implications in our quest for neurotherapeutics. PMID- 23014996 TI - Submucosal lingualplasty for adult obstructive sleep apnea. AB - OBJECTIVE: To measure quality-of-life outcomes, polysomnographic outcomes, and adverse effects for a new technique of tongue reduction in obstructive sleep apnea. STUDY DESIGN: Case series. SETTING: Tertiary hospital. SUBJECTS AND METHODS: Consecutively treated adult patients (N = 27) with obstructive sleep apnea having submucosal lingualplasty in 2007 were studied. All had concurrent or previous uvulopalatoplasty +/- palatal advancement. Full polysomnography preoperatively and 3.7 +/- 0.4 months postoperatively, scored using the American Academy of Sleep Medicine 2007 criteria, was recorded. Snoring severity score, Epworth Sleepiness Scale, and complication data were collected at a 2.61 +/- 0.08 year follow-up via questionnaire. RESULTS: Mean snoring severity score fell from 7.1 +/- 0.4 to 2.3 +/- 0.6 (P < .05). Epworth Sleepiness Scale score fell from 8.3 +/- 1.1 to 5.8 +/- 1.0 (P < .05). The apnea-hypopnea index (AHI) fell from 44.0 +/- 4.3 to 12.5 +/- 2.3 (P < .05). Success, defined as achieving an AHI <15 postoperatively, was observed in 74% (20/27), with each of these patients achieving a reduction in AHI >50%. Lowest oxygen saturation improved from 84 +/- 1 to 88 +/- 1 (P < .05). Pain was mild to moderate. Short-term postoperative complications included bleeding (3.7%) and infection (14.8%). Some minor long term (6 months) alteration in tongue function was reported with regard to speech (47%), swallow (33%), and taste (33%). CONCLUSION: Submucosal lingualplasty with concurrent palatal surgery is a promising treatment option in adult patients with obstructive sleep apnea with macroglossia. PMID- 23014997 TI - A systematic review of simulators in otolaryngology. AB - OBJECTIVE: To conduct a systematic review of published articles that describe simulators that could be used in otolaryngology for education, skill acquisition, and/or skill improvement. Data Sources Ovid and Embase databases searched July 14, 2011. REVIEW METHODS: Three hundred fifty-three abstracts were independently reviewed by both authors, then 154 eligible articles were reviewed by both authors, and 95 articles were categorized by organ system (eg, otologic); type of simulator (eg, physical, virtual); whether the simulator was a prototype, could be purchased, or was constructed; validation; and level of learning assessment. Discrepancies were resolved by re-review and discussion. RESULTS: In addition to 11 overview articles, 28 articles described 16 otology simulators, most of which are virtual and prototypes. Ninteen articles described 10 sinus/rhinology simulators; most are virtual surgery simulators and prototypes. Eight articles described 8 oral cavity simulators, and 8 articles described neck simulators. Seventeen articles described 13 bronchoscopy simulators; several are full-body high-technology manikins adapted from other purposes. Five articles described eclectic simulators, including some for learning nontechnical and teamwork skills. Half of the simulators have been validated. Learning levels were often not assessed or assessment was limited to the learners' perceptions. CONCLUSION: A wide variety of simulators are available or under development. Lack of unified validation concepts and limited descriptions restricted our ability to assess model characteristics, availability, and validation. Simulators are emerging as powerful tools to facilitate learning; this review may provide a platform for discussion and refinement of the information reported and analyzed in evaluating simulators. PMID- 23014998 TI - Transnasal endoscopic repair of posterior table fractures. AB - OBJECTIVES/HYPOTHESIS: Conventional treatment of frontal sinus posterior table fractures has included osteoplastic flap or cranialization procedures despite considerable advances in endoscopic technique and experience. The objective of the current study was to evaluate outcomes of frontal sinus fractures involving the posterior table managed using endoscopic approaches. STUDY DESIGN: Prospective cohort. SETTING: Tertiary care, academic university hospital. METHODS: Prospective evaluation of patients with posterior table fractures was performed. Data were collected regarding demographics, etiology, technique, operative site, length involving the posterior table, size of the skull base defect, complications, and clinical follow-up. RESULTS: Thirteen patients (average age 37 years) with posterior table fractures were treated using endoscopic techniques from 2008 to 2012. Mean follow-up time was 68 weeks (range, 2-206 weeks). Patients were primarily managed using Draf IIb frontal sinusotomies with 1 individual requiring a concomitant trephine. A Draf III procedure was performed in 1 patient. Average fracture defect (length vs width) was 13 * 4.5 mm, and average length involving the posterior table was 9.7 mm (1-30 mm). Skull base defects were covered with a septal flap and/or free tissue grafts. Although 1 individual required a revision frontal sinusotomy and follow-up was short in several patients, all sinuses remained patent on last clinical examination. CONCLUSION: Management of frontal sinus posterior table fractures using minimally invasive endoscopic techniques provides excellent outcomes in selected cases. Fractures of up to 30 mm in length were adequately managed in this series and indicate this approach can be a viable alternative in the treatment of these fractures. PMID- 23014999 TI - Guest editorial: special section on interferometry in biomedicine, part I. AB - This Special Section Guest Editorial provides an overview of the topical area and an introduction to the articles featured in the special section. PMID- 23015000 TI - Simultaneous measurement of dispersion, spectrum, and distance with a fourier transform spectrometer. AB - A Fourier transform spectrometer is used to simultaneously measure distance, dispersion and spectrum. It is shown that short coherence interferometry has the potential to measure the three-dimensional distribution of the spatial structure of a sample with a resolution determined by the coherence length of the light source, absorption spectrum with a resolution of 1 cm-1 and a dispersion with a resolution of up to 10-5. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015001 TI - Transversal and longitudinal images from the retina of the living eye using low coherence reflectometry. AB - An optical coherence tomography (OCT) system to produce both longitudinal and transversal images of the in vivo human eye is presented. For the first time, OCT transversal images collected from the living eye at 50-MUm depth steps show details unobtainable with the state-of-the-art scanning laser ophthalmoscope. Images of up to 3*3 mm are produced from the retina in less than a second. For images larger than 1.6*1.6 mm, a path modulation is introduced by the galvanometric scanning mirror and is used as an effective phase modulation method.(c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015002 TI - "Coherence radar" and "spectral radar"-new tools for dermatological diagnosis. AB - "Coherence radar," an optical 3-D sensor based on short coherence interferometry, is used to measure skin surface topology. This method is called optical coherence profilometry (OCP) and it may be a useful tool for medical diagnosis in dermatology because different medical conditions show distinct alterations of the skin surface. The measuring uncertainty is less than 2 MUm. The measuring time is about 4 s. in vivo 3-D mapping of naked skin was performed without preparation. For clinical application, a fiber optical implementation was introduced. Spectral radar is an optical sensor for the acquisition of skin morphology based on OCT techniques. The scattering amplitude a(z) along one vertical axis from the surface into the bulk can be measured within one exposure. No reference arm scanning is necessary. The theory of the sensor, including the dynamic range, is discussed and in vivo measurements of human skin by a fiber optical implementation of the sensor are demonstrated. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015003 TI - Analysis of shearing interferograms of tear film using fast fourier transforms. AB - A new method for evaluating tear film stability on the human eye is reported. The tear film distribution on the cornea is measured by the lateral shearing interference technique. The eye is kept open during approximately a 2-min recording, when blinking has to be prevented. Continuous recording and viewing of interferograms allows the changes in disturbances of the interference fringes to be registered during elapsed time. The changes in fringes are caused by the evaporation of tears from the ocular surface and appearance of the breakups. For precise and repetitive assessment of the tear film breakup time, a fast fourier transform (FFT) is applied to consecutive interferograms. Larger fringe disturbances result in wider Fourier spectra. The tear breakup time can be evaluated noninvasively by comparing the value of the second momentum of Fourier spectra calculated from the consecutive interferograms. (c) 1998 Society of Photo Optical Instrumentation Engineers. PMID- 23015004 TI - Optical in-fiber bragg grating sensor systems for medical applications. AB - Two in-fiber Bragg grating (FBG) temperature sensor systems for medical applications are demonstrated: (1) an FBG flow-directed thermodilution catheter based on interferometric detection of wavelength shift that is used for cardiac monitoring; and (2) an FBG sensor system with a tunable Fabry-Perot filter for in vivo temperature profiling in nuclear magnetic resonance (NMR) machines. Preliminary results show that the FBG sensor is in good agreement with electrical sensors that are widely used in practice. A field test shows that the FBG sensor system is suitable for in situ temperature profiling in NMR machines for medical applications. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015005 TI - Signal and resolution enhancements in dual beam optical coherence tomography of the human eye. AB - In the past 10 years, a dual beam version of partial coherence interferometry has been developed for measuring intraocular distances in vivo with a precision on the order of 0.3 to 3 MUm. Two improvements of this technology are described. A special diffractive optical element allows matching of the wavefronts of the divergent beam reflected at the cornea and the parallel beam reflected at the retina and collimated by the optic system of the eye. In this way, the power of the light oscillations of the interfering beams incident on the photodetector is increased and the signal-to-noise ratio of in vivo measurements to the human retina is improved by 20 to 25 dB. By using a synthesized light source consisting of two spectrally displaced superluminescent diodes with an effective bandwidth of 50 nm, and by compensating for the dispersive effects of the ocular media, it was possible to record the first optical coherence tomogram of the retina of a human eye in vivo with an axial resolution of ~6 to 7 MUm. This is a twofold improvement over the current technology. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015006 TI - Dual beam optical coherence tomography: signal identification for ophthalmologic diagnosis. AB - The dual beam version of optical coherence topography can be used for noninvasive, high-resolution imaging of the human eye fundus, enabling in vivo visualization of retinal morphology as well as accurate quantification of the thickness profiles of its layers. Interferometric fundus signals-optical A-scans and retinal tomograms of patients with glaucoma, diabetic retinopathy, and age related macular degeneration are compared with those of healthy, normal subjects to elucidate the origin of the signal peaks detected and to investigate and interpret the retinal microstructures contained in the cross-sectional images. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015007 TI - Restoration of Optical Coherence Images of Living Tissue Using the CLEAN Algorithm. AB - CLEAN, an iterative point-deconvolution algorithm developed originally for use in radio astronomy, was investigated as a means of restoring optical coherence tomography (OCT) images of biological tissue. The CLEAN deconvolution kernel was derived from the theoretical point-spread function of an OCT scanner, which depends on the properties of the imaging system as well as the characteristics of the scattering properties of the medium. The kernel incorporates a modification based on an inverse Wiener filter that is designed to reduce ripple artifacts in images of densely packed scatterers. Evaluation of the performance of the CLEAN algorithm was carried out on a set of images acquired with a prototype scanner with built-in speckle-reduction hardware. The results show the ability of the algorithm to improve the resolution of features in coherence images of scattering phantoms and living tissue. In many cases, the restored images reveal tissue morphology not evident in the unprocessed images. CLEAN tolerates speckle noise well and its performance degrades gracefully as the number of unresolvable scatterers causing mutual interference increases. Ways of coping with the long processing time required for the restorations are outlined, along with possible improvements that would permit CLEAN to take advantage of both amplitude and phase information in partially coherent interference signals. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015008 TI - Optical Coherence Tomographic Imaging of Human Tissue at 1.55 MUm and 1.81 MUm Using Er- and Tm-Doped Fiber Sources. AB - We demonstrate two short-coherence-length, rare-earth-doped fiber optical sources for performing optical coherence tomography (OCT) in human tissue. The first source is a stretched-pulse, mode-locked Er-doped fiber laser with a center wavelength of 1.55 MUm, a power of 100 mW, and a bandwidth of 80 nm. The second is a Tm-doped silica fiber fluorescent source emitting up to 7 mW of power at 1.81 MUm with a bandwidth of 80 nm. The OCT imaging depth of penetration in in vitro human aorta is compared using these sources and conventional 1.3-MUm sources. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015009 TI - Ultraviolet-visible acousto-optic tunable spectroscopic imager for medical diagnosis. AB - An ultraviolet to visible acousto-optic tunable filter was used to measure native fluorescence images from in vitro breast tissues at different wavelengths. Pseudocolor maps based on fluorescence images at two wavelengths were used to separate normal and abnormal regions in human breast tissues in vitro, providing diagnostic information. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015010 TI - Fundamental Studies of Fiber-Guided Soft Tissue Cutting by Means of Pulsed Midinfrared Lasers and their Application in Ureterotomy. AB - Fiber-guided ablation of soft tissue with pulsed holmium and thulium lasers was investigated for intraluminal incisions. A bare fiber/tissue-contact application system with a nearly tangential irradiation geometry was first used in vitro on porcine ureter tissue. The efficiency and precision of the method was analyzed for different laser and application parameters. The ablation dynamics in water and tissue was investigated by fast flash photography. Uniform cuts could be achieved with 200- and 318-MUm fibers using a free-running holmium laser with a pulse repetition rate of 10 Hz and an average power of up to 4 W. The depth of the cuts could be increased by using a thulium laser with the same laser parameters. By reducing the pulse duration by one order of magnitude, the quality of the incisions was made more irregular, the zone of thermomechanical damage increased, and the cuts became deeper owing to the growing influence of cavitation on shorter laser pulse durations. In a first clinical trial, 20 patients underwent holmium laser therapy to reopen ureteral strictures. Neither bleeding nor other adverse effects due to the laser treatment occurred, showing IR laser ureterotomy to be a suitable and promising minimally invasive technique. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015011 TI - Experimental and computational laser tissue welding using a protein patch. AB - An in vitro study of laser tissue welding mediated with a dye-enhanced protein patch was conducted. Fresh sections of porcine aorta were used for the experiments. Arteriotomies were treated using an indocyanine green dye-enhanced collagen patch activated by an 805-nm continuous-wave fiber-delivered diode laser. Temperature histories of the surface of the weld site were obtained using a hollow glass optical fiber-based two-color infrared thermometer. The experimental effort was complemented by simulations with the LATIS (LAser-TISsue) computer code, which uses coupled Monte Carlo, thermal transport, and mass transport models. Comparison of simulated and experimental thermal data indicated that evaporative cooling clamped the surface temperature of the weld site below 100 degrees C. For fluences of approximately 200 J/cm2, peak surface temperatures averaged 74 degrees C and acute burst strengths consistently exceeded 0.14*106 dyn/cm (hoop tension). The combination of experimental and simulation results showed that the inclusion of water transport and evaporative losses in the computer code has a significant impact on the thermal distributions and hydration levels throughout the tissue volume. The solid-matrix protein patch provided a means of controllable energy delivery and yielded consistently strong welds. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015012 TI - Effective interface dynamics of laser-induced heat diffusion-limited thermal coagulation. AB - The general problems of describing local thermal coagulation dynamics leading to the growth of necrosis that is limited by heat diffusion to surrounding live tissue is considered. It is demonstrated that in this case the typically used distributed model for thermal coagulation is based on a self-inconsistent approach, and a more rigorously justified free boundary model is derived. This free boundary model takes into account only the general properties of thermal coagulation and so provides a self-consistent description. It is shown that the two models, nevertheless, predict practically the same dynamics of necrosis growth because this growth is insensitive to the particular properties of heat transfer in the thin layer of partially damaged tissue. Necrosis growth is also simulated numerically under various physical conditions to verify the assumptions adopted. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015013 TI - Side-Firing Fiber Device for Underwater Tissue Ablation with Ho:YAG and Er:YAG Laser Radiation. AB - A side-firing fiber device for arthroscopic Ho:YAG (lambda=2.12 MUm) and Er:YAG (lambda=2.94 MUm) laser applications was designed and constructed. The fiber delivery instrument consisted of a zirconium fluoride (ZrF4) fiber equipped with a coaxially mounted short end-piece of low OH- quartz fiber polished at an angle of 30 deg. The dynamics and depth of the vapor channel in water and the amplitude of pressure transients associated with the collapse of the vapor channel were measured for pulse energies up to 1 J (Ho:YAG) and 200 mJ for the Er:YAG laser (pulse duration tau=400 MUs), respectively. To assess the feasibility of the side firing fiber delivery instrument, the ablation efficiency and laser-induced damage in poly(acylamide) and meniscal tissue were determined after Ho:YAG and Er:YAG laser ablation. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015014 TI - Bacterial versus archaeal origin of extracellular enzymatic activity in the Northeast Atlantic deep waters. AB - We determined the total and dissolved extracellular enzymatic activity (EEA) of alpha-glucosidase and beta-glucosidase (AGase and BGase), alkaline phosphatase (APase) and leucine aminopeptidase (LAPase) activities in the epi-, meso- and bathypelagic waters of the subtropical Northeast Atlantic. EEA was also determined in treatments in which bacterial EEA was inhibited by erythromycin. Additionally, EEA decay experiments were performed with surface and deep waters to determine EEA lifetimes in both water masses. The proportion of dissolved to total EEA (66-89 %, 44-88 %, 57-82 % and 86-100 % for AGase, BGase, APase and LAPase, respectively) was generally higher than the cell-associated (i.e., particulate) EEA. The percentage of dissolved to total EEA was inversely proportional to the percentage of erythromycin-inhibited to total EEA. Since erythromycin-inhibited plus dissolved EEA equaled total EEA, this tentatively suggests that cell-associated EEA in the open oceanic water column is almost exclusively of bacterial origin. The decay constants of dissolved EEA were in the range of 0.002-0.048 h(-1) depending on the type of extracellular enzyme, temperature and depth in the water column. Although dissolved EEA can have different origins, the major contribution of Bacteria to cell-associated EEA and the long life-time of dissolved EEA suggest that Bacteria-and not mesophilic Archaea-are essentially the main producers of EEA in the open subtropical Northeast Atlantic down to bathypelagic layers. PMID- 23015015 TI - The risk of delayed atrioventricular and intraventricular conduction block following ablation of bundle branch reentry. AB - BACKGROUND: The aim of the study was to determine the long-term reliability of atrioventricular and intraventricular conduction and the implications for cardiac resynchronization therapy (CRT-D) following catheter ablation of bundle branch reentry tachycardia (BBRT) and interfascicular tachycardia. METHODS AND RESULTS: Fourteen patients with recurrent monomorphic ventricular tachycardia (VT) (n = 11) and incessant VT (n = 3) underwent catheter ablation of BBRT (n = 7), interfascicular tachycardia (n = 5) or both arrhythmias (n = 2). Successful ablation was achieved in all patients without intraprocedural atrioventricular (AV) block. Within 2 months after ablation, three patients with BBRT and pre existing prolonged QRS developed a delayed third-degree AV block. During the follow-up of 2 years, two patients with interfascicular tachycardia developed a new left bundle branch block (LBBB) associated with worsening of heart failure. Three patients underwent upgrading of implantable cardioverter defibrillator therapy to CRT-D early after ablation which improved heart failure during the 6 months follow-up. During the long-term follow-up of 39 +/- 13 months, VT storm recurred in one patient. Four of the 14 patients died of deterioration of heart failure and one had to undergo heart transplantation. CONCLUSIONS: Catheter ablation for BBRT in patients with prolonged QRS is associated with a high risk of delayed third-degree AV block. Ablation of interfascicular tachycardia can be associated with delayed LBBB. After ablation of bundle branch reentry, patients with prolonged QRS are candidates for cardiac resynchronization therapy but the mortality remains high. PMID- 23015016 TI - Analysis of compound weighing precision in drug discovery. AB - Early drug discovery laboratories often call for the precise weighing of 1- to 5 mg solids into 4- to 5-g glass vials. For the balance used in this study (Mettler Toledo XP205), the manufacturer rates its accuracy at +/-0.01 mg over the working range of 1 mg to 220 g and its precision or repeatability at 0.015 mg for 10-g weights. The manufacturer ratings were confirmed using standard steel weights, but these calibrators do not well represent the weighing precision of drug compound. For example, when pre-taring a 4- to 5-g vial on the balance and then weighing 1- to 5-mg calibration weights, although no bias was observed, precision dropped appreciably. When measuring solid sample in the range of 1 to 5 mg, deviation of the measured weight from the actual (true) weight was even worse, in the range of +/-20% to 50%. Balance settings and environmental factors exert a strong influence on weighing precision. Although most environmental factors, such as air draughts, temperature, vibrations, and levelness, can be optimized to the extent practical in laboratory settings, problems due to static electricity are often overlooked. By controlling static electricity, we demonstrate how we optimized the process to where measurements were within +/-10% of actual weight when weighing solid sample in the range of 2 to 5 mg and +/-20% when weighing 1 mg into a 4- to 5-g vial. Our weighing process and method to calculate actual weight are given in detail. PMID- 23015017 TI - A continuous, fluorescence-based assay of MU-opioid receptor activation in AtT-20 cells. AB - Opioids are widely prescribed analgesics, but their use is limited due to development of tolerance and addiction, as well as high variability in individual response. The development of improved opioid analgesics requires high-throughput functional assays to assess large numbers of potential opioid ligands. In this study, we assessed the ability of a proprietary "no-wash" fluorescent membrane potential dye to act as a reporter of u-opioid receptor (MOR) activation and desensitization via activation of G-protein-coupled inwardly rectifying potassium channels. AtT-20 cells stably expressing mouse MOR were assayed in 96-well plates using the Molecular Devices FLIPR membrane potential dye. Dye emission intensity decreased upon membrane hyperpolarization. Fluorescence decreased in a concentration-dependent manner upon application of a range of opioid ligands to the cells, with high-efficacy agonists producing a decrease of 35% to 40% in total fluorescence. The maximum effect of morphine faded in the continued presence of agonist, reflecting receptor desensitization. The effects of opioids were prevented by prior treatment with pertussis toxin and blocked by naloxone. We have demonstrated this assay to be an effective method for assessing ligand signaling at MOR, which may potentially be scaled up as an additional high throughput screening technique for characterizing novel opioid ligands. PMID- 23015018 TI - A high-throughput-compatible fluorescence anisotropy-based assay for competitive inhibitors of Escherichia coli UDP-N-acetylglucosamine acyltransferase (LpxA). AB - LpxA, the first enzyme in the biosynthetic pathway for the Lipid A component of the outer membrane lipopolysaccharide in Gram-negative bacteria, is a potential target for novel antibacterial drug discovery. A fluorescence polarization assay was developed to facilitate high-throughput screening for competitive inhibitors of LpxA. The assay detects displacement of a fluorescently labeled peptide inhibitor, based on the previously reported inhibitor peptide 920, by active site ligands. The affinity of the fluorescent ligand was increased ~10-fold by acyl carrier protein (ACP). Competition with peptide binding was observed with UDP-N acetylglucosamine (IC(50) ~6 mM), UDP-3-O-(R-3-hydroxymyristoyl)-N acetylglucosamine (IC(50) ~200 nM), and DL-3-hydroxymyristic acid (IC(50) ~50 uM) and peptide 920 (IC(50) ~600 nM). The IC(50)s were not significantly affected by the presence of ACP. PMID- 23015019 TI - Inhibitors of Streptococcus pneumoniae surface endonuclease EndA discovered by high-throughput screening using a PicoGreen fluorescence assay. AB - The human commensal pathogen Streptococcus pneumoniae expresses a number of virulence factors that promote serious pneumococcal diseases, resulting in significant morbidity and mortality worldwide. These virulence factors may give S. pneumoniae the capacity to escape immune defenses, resist antimicrobial agents, or a combination of both. Virulence factors also present possible points of therapeutic intervention. The activities of the surface endonuclease, EndA, allow S. pneumoniae to establish invasive pneumococcal infection. EndA's role in DNA uptake during transformation contributes to gene transfer and genetic diversification. Moreover, EndA's nuclease activity degrades the DNA backbone of neutrophil extracellular traps (NETs), allowing pneumococcus to escape host immune responses. Given its potential impact on pneumococcal pathogenicity, EndA is an attractive target for novel antimicrobial therapy. Herein, we describe the development of a high-throughput screening assay for the discovery of nuclease inhibitors. Nuclease-mediated digestion of double-stranded DNA was assessed using fluorescence changes of the DNA dye ligand, PicoGreen. Under optimized conditions, the assay provided robust and reproducible activity data (Z'= 0.87) and was used to screen 4727 small molecules against an imidazole-rescued variant of EndA. In total, six small molecules were confirmed as novel EndA inhibitors, some of which may have utility as research tools for understanding pneumococcal pathogenesis and for drug discovery. PMID- 23015020 TI - Collagen cross-linking for resistant corneal ulcer. AB - Corneal ulcer is a devastating corneal disease which is potentially sight threatening and conventionally is treated by topical antibiotics and in some cases with more invasive procedures such as keratoplasty. The aim of this study is to evaluate the efficacy of corneal collagen cross-linking in resistant corneal ulcers. Ten patients with resistant infectious corneal ulcers who had not responded properly to maximal treatment with topical and subconjunctival antibiotics were enrolled in the study and underwent classic corneal collagen cross-linking with riboflavin and UV-A under sterile conditions in the operating room and were followed up regularly. The result was healing and scar formation with improvement of vision in all patients except for two who underwent enucleation and tectonic penetrating keratoplasty. Corneal collagen cross-linking is a viable therapeutic option for treatment of corneal ulcers and can be used as an adjuvant for conventional treatment in resistant cases. PMID- 23015021 TI - Corneal perforation during Nd:YAG laser capsulotomy: a case report. AB - We report a case where corneal perforation developed during Nd:YAG laser capsulotomy. We present a 20-year-old male with the complaint of impaired vision in the right eye. Leukoma consistent with the incision line in the cornea and opacity in the posterior capsule were observed. PMID- 23015022 TI - Topiramate maculopathy. AB - The purpose of this study is to present the first case of a pure 'topiramate maculopathy' without acute glaucoma and/or myopia, which form the classical syndrome. DESIGN: Interventional/observational case report. SETTING: Institutional University Teaching Hospital. PATIENT: A 22-year-old American female, after taking 100 mg of topiramate (Topamax(r)) a day for 6 days because of a migraine attack, complained of severe visual acuity deterioration of sudden onset in both eyes, regardless of distance (far or near), during the span of 1 day. A complete ocular examination was carried out. Best-corrected visual acuity (BCVA) in the right eye was hand motion and in the left eye was counting fingers. Cycloplegic refraction and pinhole did not improve the visual acuity of patient's eyes. The anterior chamber depth was normal in both eyes. Tonometry was 14 mmHg in both eyes. Fundus biomicroscopy disclosed a maculopathy with macular striae and a cellophane-like reflex. Optical coherence tomography (OCT) showed an undulating profile with congruent retinal folds and choroidal layers plicae. INTERVENTIONAL/OBSERVATION PROCEDURE: Immediate discontinuation of Topamax and steroid therapy. MAIN OUTCOME MEASURES: BCVA, cycloplegic refraction, tonometry, fundus photography, and OCT. Three days after suspension of Topomax and steroid therapy the patient's BCVA was 6/6 in both eyes. Tonometry was 14 mmHg in both eyes. Fundus appearance and OCT features were nearly normal. After 2 years of follow-up, the patient's BCVA, tonometry, macula, and OCT are stable in both eyes. In conclusion, an isolated (unassociated with glaucoma and/or induced myopia) acute maculopathy, previously known as being part of a rare syndrome, has been identified, described, and documented. PMID- 23015023 TI - Peripapillary choroidal neovascularisation in the context of ocular syphilis is sensitive to combination antibiotic and corticosteroid treatment. AB - Peripapillary choroidal neovascularisation (CNV) in the context of ocular syphilis is exceptional and little is known about its natural history and optimal therapeutic management. We report here a case of right eye peripapillary CNV with subretinal fluid encroaching on the fovea in a patient with mild bilateral ocular inflammation and cystoid macular oedema (CMO) in his contralateral eye. Extensive investigations revealed positive serology for active syphilitic infection. The patient received treatment with intravenous benzylpenicillin according to the algorithm for neurosyphilis complemented with oral corticosteroids as prophylaxis against Jarisch-Herxsheimer reaction for a period of 17 days. On the 15th day, receding of subretinal fluid in his right eye to a small pocket around the optic disc was identified as well as resolution of left eye CMO. We suggest that a course of antibiotic treatment for neurosyphilis with the addition of oral corticosteroids may be an effective therapeutic option for CNV in the context of ocular syphilis and thus more invasive treatment approaches are not warranted. PMID- 23015025 TI - Functional dental status and oral health-related quality of life in an over 40 years old Chinese population. AB - OBJECTIVES: This study aimed to assess oral health-related quality of life (OHRQoL) related to dental status. MATERIAL AND METHODS: One thousand four hundred sixty-two Chinese subjects over 40 years, dentate in both jaws, were categorized in a hierarchical functional classification system with and without tooth replacements. OHIP-14CN scores were used to assess OHRQoL and analyzed using multivariable logistic regression including five dental conditions ('>=10 teeth in each jaw'; 'complete anterior regions'; 'sufficient premolar regions' (>=3 posterior occluding pairs (POPs)); 'sufficient molar regions' (bilaterally >=1 POP); and tooth replacement) after adjustment for five background variables. Likelihood ratios for impaired OHRQoL (OHIP total score >=5) were assessed at each level of the classification system. RESULTS: In the hierarchical scheme, OHIP-14CN total scores were highest in branch '<10 teeth in each jaw' (8.5 +/- 9.5 to 12.3 +/- 13.2). In branch '>=10 teeth' scores ranged from 6.2 +/- 7.7 to 8.3 +/- 9.3. The most important dental condition discriminating for impact on OHRQoL was '>=10 teeth in each jaw' (Likelihood ratio 1.59). In this branch subsequent levels were discriminative for impaired OHRQoL (Likelihoods 1.29 1.69), in the branch '<10 teeth in each jaw' they were not (Likelihoods 0.99 1.04). Tooth replacements were perceived poorer as their natural counterparts (odd ratios, 1.30 for fixed and 1.47 for removable appliances). CONCLUSIONS: OHRQoL was strongly associated with the presence of at least 10 teeth in each jaw. The hierarchical classification system predicted approximately 60 % of subjects correctly with respect to impaired OHRQoL. CLINICAL RELEVANCE: From an OHRQoL perspective, natural teeth were preferred over artificial teeth. PMID- 23015027 TI - Design, synthesis, magnetic properties of a pi-radical ligand with photo-excited high-spin state and its Fe(II) complex. The first stage of a new strategy for LIESST materials. AB - A pi-radical ligand (9-[4-(6-oxo-1,5-dimethylverdazyl)phenyl]-10-[5-(2,2' bipyridyl)ethynyl]anthracene, L1) with a photo-excited high-spin quartet state (S = 3/2) and its iron(II) complex [Fe(L1){H(2)B(Pz)(2)}(2)] (1) {H(2)B(Pz)(2)(-) = dihydrobis(1-pyrazolyl)borate} were synthesized as a candidate for a new strategy for spin-crossover compounds exhibiting light-induced excited spin state trapping (LIESST), which is via the photo-excited high-spin state of the pi-conjugated aromatic system. Control compounds, ligand L2 and [Fe(L2){H(2)B(Pz)(2)}(2)] (2), in which the verdazyl radical moiety in L1 was removed, were also synthesized. The photo-excited quartet state of the pi-radical ligand L1 was confirmed by the time-resolved ESR technique. Temperature dependence of the magnetic behaviors of 1 and 2 were investigated from 5 K to 350 K, showing spin-crossover transition at T(c) = 222 K and at T(c) = 162 K for complexes 1 and 2, respectively. The transition enthalpies and entropies were determined to be DeltaH = 8.09 kJ mol( 1) and DeltaS = 36.4 J K(-1) mol(-1) for 1 and to be DeltaH = 22.39 kJ mol(-1) and DeltaS = 138 J K(-1) mol(-1) for 2. LIESST phenomena were also observed below ca. 50 K for both complexes. The effects of the attachment of radical moiety are discussed based on the results. PMID- 23015028 TI - Enhanced overcharge performance of nano-LiCoO2 by novel Li3VO4 surface coatings. AB - LiCoO(2) nanoparticles were coated with 3.4 and 5.5 wt% of lithium vanadate (Li(3)VO(4)) by a wet-chemical and sintering method. When the electrode containing 5.5-wt% Li(3)VO(4)-coated LiCoO(2) was overcharged to 4.5 V at a current of 30 mA g(-1) (~0.2 C), ~85% of the initial discharge capacity after 100 charge-discharge cycles was maintained, compared to only ~67% for the electrode with bare LiCoO(2) nanoparticles. The electrode with 5.5 wt% coating can also deliver 115 mA h g(-1) discharge capacity at a current of 1200 mA g(-1) (~8 C) and a discharge-charge voltage of 4.5 V, which is twice the capacity of the bare LiCoO(2) sample. The improvement of overcharge cyclability and high-rate capability was believed to be due to the structurally protective Li(3)VO(4) surface coating with good Li-ion conductivity. PMID- 23015026 TI - Photodynamic therapy in dentistry: a literature review. AB - OBJECTIVES: The purpose of this review was to summarize recent developments regarding photodynamic therapy (PDT) in the field of dentistry. MATERIALS AND METHODS: A review of pertinent literature was carried out in PubMED to determine the current position of PDT applications in dentistry. One hundred thirteen relevant articles were retrieved from PubMED by inserting the keywords "photodynamic therapy", "dentistry", "periodontology", "oral surgery", and "endodontics". It is anticipated that this overview will create a specific picture in the practitioner's mind regarding the current status and use of PDT. RESULTS: In spite of different results and suggestions brought about by different researchers, PDT can be considered as a promising and less invasive technique in dentistry. CONCLUSION: PDT seems to be an effective tool in the treatment of localized and superficial infections. Within the limitations of the present review, it can be concluded that although PDT cannot replace antimicrobial therapy at its current stage, it may be used as an adjunctive tool for facilitating the treatment of oral infections. CLINICAL RELEVANCE: Oral infections (such as mucosal and endodontic infections, periodontal diseases, caries, and peri-implantitis) are among the specific targets where PDT can be applied. Further long-term clinical studies are necessary in establishing a more specific place of the technique in the field of dentistry. PMID- 23015029 TI - Do tumor grade and location affect survival in esophageal squamous cell carcinoma? Survival analysis of 302 cases of pT3N0M0 esophageal squamous cell carcinoma. AB - BACKGROUND: The 7th edition of the American Joint Committee on Cancer (AJCC) cancer staging manual incorporates tumor grade and location for staging pT2-3N0M0 esophageal squamous cell carcinoma. Patients with pT3N0M0, classified as stage IIa according to the 6th edition of the AJCC cancer staging manual, can now be classified as stage Ib, IIa, or IIb. We aimed to discuss whether these changes affect survival and determine other potential prognostic factors. METHODS: We retrospectively analyzed 302 patients with postoperative pathologic stage T3N0M0 who underwent esophagectomy between 1990 and 2005 at Sun Yat-sen University Cancer Center. We performed univariate and multivariate analyses to identify prognostic factors for survival and used the Kaplan-Meier method to compare survival difference in each prognostic factor, including tumor grade and location. RESULTS: The 5-year overall survival rate was 46 %, with a median survival of 1,244.5 days. Gender, age, alcohol consumption, forced expiratory volume in 1 s (FEV1), and number of removed lymph nodes were independent prognostic factors in both univariate and multivariate analyses. Smoking was also a prognostic factor in survival analysis by the Kaplan-Meier method. However, histologic tumor grade and location had no significant influence on patient survival. CONCLUSIONS: Age, gender, alcohol consumption, FEV1, number of removed lymph nodes, and cigarette smoking are independent prognostic factors in patients with pT3N0M0 esophageal squamous cell carcinoma. However, tumor grade and location may not be as strong predictors in these patients as indicated in the 7th edition of the AJCC cancer staging manual. PMID- 23015030 TI - Differential haemostatic risk factors for pregnancy-related deep-vein thrombosis and pulmonary embolism: a population-based case-control study. AB - Limited data exist on thrombophilia and the risk of venous thrombosis (VT) during pregnancy and postpartum. The objectives of the present study were to investigate the role of haemostatic risk factors for pregnancy-related VT and their phenotypic expression in deep-vein thrombosis (DVT) and pulmonary embolism (PE). Total 313 cases with objectively verified first time VT and 353 controls were selected from a source population of 377,155 women with 613,232 pregnancies. The adjusted odds ratio (aOR) for pregnancy-related VT was 1.7 (95% confidence interval [CI] 1.1-2.8) for women with factor VIII >90th percentile. The aOR for VT for endogenous thrombin potential and D-dimer values >90th percentiles were 1.8 (95% CI 1.1-3.0) and 2.1 (95% CI 1.3-3.3), respectively. Factor IX >90th percentile or free protein S <=the 5th percentile increased the risk for PE, and the aORs were 2.4 (95% CI 1.1-5.0) and 3.1 (95% CI 1.3-7.2), respectively. Women carrying the factor V Leiden (F5 rs6025) polymorphism, or who had reduced sensitivity to activated protein C (aPC) in the absence of F5 rs6025, had increased risk for DVT, with unadjusted ORs 7.7 (95% CI 4.7-12.7) and 3.5 (95% CI 2.2-5.4), respectively. Women with a history of pregnancy-related VT showed activation of coagulation and had elevated factor VIII. Furthermore, high levels of factor IX and low levels of free protein S were associated with increased risk for PE, whereas aPC resistance and F5 rs6025 were risk factors for DVT and not PE. PMID- 23015031 TI - Hybrid treatment of a giant coronary artery fistula between the left circumflex coronary artery and the coronary sinus. PMID- 23015033 TI - Obesity in children and adolescents. PMID- 23015032 TI - Cardiovascular disease risk in healthy children and its association with body mass index: systematic review and meta-analysis. AB - OBJECTIVES: To describe the association and its magnitude between body mass index category, sex, and cardiovascular disease risk parameters in school aged children in highly developed countries. DESIGN: Systematic review and meta-analysis. Quality of included studies assessed by an adapted version of the Cochrane Collaboration's risk of bias assessment tool. Results of included studies in meta analysis were pooled and analysed by Review Manager version 5.1. DATA SOURCES: Embase, PubMed, EBSCOHost's cumulative index to nursing and allied health literature, and the Web of Science databases for papers published between January 2000 and December 2011. REVIEW METHODS: Healthy children aged 5 to 15 in highly developed countries enrolled in studies done after 1990 and using prospective or retrospective cohort, cross sectional, case-control, or randomised clinical trial designs in school, outpatient, or community settings. Included studies had to report an objective measure of weight and at least one prespecified risk parameter for cardiovascular disease. RESULTS: We included 63 studies of 49 220 children. Studies reported a worsening of risk parameters for cardiovascular disease in overweight and obese participants. Compared with normal weight children, systolic blood pressure was higher by 4.54 mm Hg (99% confidence interval 2.44 to 6.64; n=12 169, eight studies) in overweight children, and by 7.49 mm Hg (3.36 to 11.62; n=8074, 15 studies) in obese children. We found similar associations between groups in diastolic and 24 h ambulatory systolic blood pressure. Obesity adversely affected concentrations of all blood lipids; total cholesterol and triglycerides were 0.15 mmol/L (0.04 to 0.25, n=5072) and 0.26 mmol/L (0.13 to 0.39, n=5138) higher in obese children, respectively. Fasting insulin and insulin resistance were significantly higher in obese participants but not in overweight participants. Obese children had a significant increase in left ventricular mass of 19.12 g (12.66 to 25.59, n=223), compared with normal weight children. CONCLUSION: Having a body mass index outside the normal range significantly worsens risk parameters for cardiovascular disease in school aged children. This effect, already substantial in overweight children, increases in obesity and could be larger than previously thought. There is a need to establish whether acceptable parameter cut-off levels not considering weight are a valid measure of risk in modern children and whether methods used in their study and reporting should be standardised. PMID- 23015035 TI - Does celebrity involvement in public health campaigns deliver long term benefit? No. PMID- 23015034 TI - Clinicians' gut feeling about serious infections in children: observational study. AB - OBJECTIVE: To investigate the basis and added value of clinicians' "gut feeling" that infections in children are more serious than suggested by clinical assessment. DESIGN: Observational study. SETTING: Primary care setting, Flanders, Belgium. PARTICIPANTS: Consecutive series of 3890 children and young people aged 0-16 years presenting in primary care. MAIN OUTCOME MEASURES: Presenting features, clinical assessment, doctors' intuitive response at first contact with children in primary care, and any subsequent diagnosis of serious infection determined from hospital records. RESULTS: Of the 3369 children and young people assessed clinically as having a non-severe illness, six (0.2%) were subsequently admitted to hospital with a serious infection. Intuition that something was wrong despite the clinical assessment of non-severe illness substantially increased the risk of serious illness (likelihood ratio 25.5, 95% confidence interval 7.9 to 82.0) and acting on this gut feeling had the potential to prevent two of the six cases being missed (33%, 95% confidence interval 4.0% to 100%) at a cost of 44 false alarms (1.3%, 95% confidence interval 0.95% to 1.75%). The clinical features most strongly associated with gut feeling were the children's overall response (drowsiness, no laughing), abnormal breathing, weight loss, and convulsions. The strongest contextual factor was the parents' concern that the illness was different from their previous experience (odds ratio 36.3, 95% confidence interval 12.3 to 107). CONCLUSIONS: A gut feeling about the seriousness of illness in children is an instinctive response by clinicians to the concerns of the parents and the appearance of the children. It should trigger action such as seeking a second opinion or further investigations. The observed association between intuition and clinical markers of serious infection means that by reflecting on the genesis of their gut feeling, clinicians should be able to hone their clinical skills. PMID- 23015036 TI - Does celebrity involvement in public health campaigns deliver long term benefit? Yes. PMID- 23015037 TI - Medical screening of older drivers is not evidence based. PMID- 23015038 TI - A computational investigation of ring-shift isomerization of sym octahydrophenanthrene to sym-octahydroanthracene catalyzed by acidic zeolites. AB - The ring-shift isomerization of sym-octahydrophenanthrene (sym-OHP) to sym octahydroanthracene (sym-OHA) catalyzed by acidic zeolites (Mordenite (MOR) and Faujasite (FAU)) was investigated by the ONIOM(DFT:UFF) and DFT approaches. A "five-membered ring" mechanism through carbocation rearrangement via 1-2 migration was proved to be kinetically favored over a "six-membered ring" mechanism through Friedel-Crafts reactions. Computational studies based on the "five-membered ring" mechanism demonstrate that a decreasing Bronsted acid site strength from Al-H-MOR to Ga-H-MOR to B-H-MOR reduces the catalytic activity. The catalyst acid site strength would thereby impact the yield of sym-OHA. The isomerization barrier increases when using an Al-H-FAU catalyst that has a similar Bronsted acid site strength as Al-H-MOR but considerably bigger cages, indicating that apart from the desired density and strength of acid sites, optimal zeolite catalysts should have a pore size that better fits the intermediates and transition states. DFT calculations on Gibbs free energy were performed to evaluate the equilibrium ratios of sym-OHA to sym-OHP at specific reaction temperatures from 175 to 325 degrees C. The results indicate that reaction temperature has a moderate impact on the equilibrium yield of sym-OHA, whose formation is relatively favorable at a lower temperature under experimental conditions. PMID- 23015039 TI - Transcatheter aortic valve replacement and vascular complications definitions. AB - AIMS: Transcatheter aortic valve replacement (TAVR) requires large calibre catheters and is therefore associated with increased vascular complications. The aim of this study was to illustrate the impact of the different definitions of major vascular complications on their incidence and to underscore the importance of uniform reporting. METHODS AND RESULTS: We pooled dedicated databases of consecutive patients undergoing TAVR from two tertiary care facilities and looked for the incidence of major vascular complications using various previously reported definitions. The level of agreement (Kappa statistic) between the respective definitions and the Valve Academic Research Consortium (VARC) consensus definition of vascular complications was assessed. A total of 345 consecutive patients underwent transfemoral TAVR and were included in this analysis. A completely percutaneous access and closure technique was applied in 96% of cases. Arterial sheath size ranged between 18 and 24 Fr, the majority being 18 Fr (60%). Procedural success was reached in 94.5%. Depending on the definition used, major vascular complications occurred in 5.2-15.9% of patients. According to the VARC definitions, the rate of major and minor vascular complications was 9.0% and 9.6%, respectively. Major vascular complications according to VARC criteria demonstrated at least a substantial level of agreement with the SOURCE registry (k 0.80), the UK registry (k 0.82) the Italian registry (k 0.72) and "FRANCE" registry (k 0.70) definitions, compared to a moderate level of agreement with the definitions used in the German registry ( 0.47) and the 18 Fr Safety and Efficacy study (k 0.42). Minor complications according to VARC demonstrated a moderate agreement only with vascular complications using the German registry definition (k 0.54). CONCLUSIONS: Non-uniformity in how vascular complications are defined precludes any reliable comparison between previously reported TAVR registries. The VARC consensus document offers standardised endpoint definitions and should be universally adopted to obtain better insights into global TAVR experience. PMID- 23015040 TI - Tareciliosides N-S: further cycloartane saponins from the leaves of Tarenna gracilipes, and cytotoxicity of saponins and triterpenes. AB - Six cycloartane glycosides, named tareciliosides N-S, and a known iridoid glucoside, ixoroside, were isolated in further extensive studies on the 1-BuOH soluble fraction of a MeOH extract of the leaves of Tarenna gracilipes. From the EtOAc-soluble fraction, three known triterpenes were isolated. Their toxicities toward A549 and Leishmania major trypanosome protozoa were assayed. Triterpenes were selectively active in the two organisms. PMID- 23015041 TI - Waist circumference percentiles among Turkish children under the age of 6 years. AB - Waist circumference, a proxy measure of abdominal obesity, is associated with cardio-metabolic risk factors in childhood and adolescence. Although there are numerous studies about waist circumference percentiles in children, only a few studies cover preschool children. The aim of this study was to develop age- and gender-specific waist circumference smoothed reference curves in Turkish preschool children to determine abdominal obesity prevalence and to compare them with reference curves obtained from different countries. The design of the study was cross-sectional. A total of 2,947 children (1,471 boys and 1,476 girls) aged 0-6 years were included in the study. The subjects were divided according to their gender. Waist circumference was measured by using a standardized procedure. The age- and gender-specific waist circumference reference curves were constructed and smoothed with LMS method. The reference values of waist circumference, including 3rd, 10th 25th, 50th, 75th, 90th, and 97th percentiles, and standard deviations were given for preschool children. Waist circumference values increased with age, and there were differences between genders. The prevalence of abdominal obesity was calculated as 10.1 % for boys and 10.7 % for girls. Having compared our data with two other countries' data, we found that our waist circumference data were significantly lower. This is the first cross sectional study for age- and gender-specific references of 0- to 6-year-old Turkish children. The gender- and age-specific waist circumference percentiles can be used to determine the risk of central obesity. PMID- 23015042 TI - Clinical practice: Helicobacter pylori infection in childhood. AB - Helicobacter pylori infection is recognised as a cause of gastritis and peptic ulcer disease (PUD) and usually acquired during the first years of life. While there is a decline in the prevalence of H. pylori infection in northern and western European countries, the infection is still common in southern and eastern parts of Europe and Asia. Symptoms of H. pylori-related PUD are nonspecific in children and may include epigastric pain, nausea and/or vomiting, anorexia, iron deficiency anaemia and hematemesis. Besides, only a small proportion of children develop symptoms and clinically relevant gastrointestinal disease. H. pylori infection can be diagnosed either by invasive tests requiring endoscopy and biopsy or non-invasive tests including the (13)C-urea breath test, detection of H. pylori antigen in stool and detection of antibodies in serum, urine and saliva. The aim of treatment is at least 90 % eradication rate of the bacteria, and a combination of two antibiotics plus a proton pump inhibitor has been recommended as first-line treatment. However, frequent use of antibiotics during childhood is associated with a decline in eradication rates and the search for new treatment strategies as well. This is an overview of the latest knowledge and evidence-based guidelines regarding clinical presentation, diagnosis and treatment of H. pylori infection in childhood. PMID- 23015043 TI - Impact of home oxygen therapy on hospital stay for infants with acute bronchiolitis. AB - Acute bronchiolitis has been associated with an increasing hospitalization rate over the past decades. The aim of this paper was to estimate the impact of home oxygen therapy (HOT) on hospital stay for infants with acute bronchiolitis. A retrospective cohort study was done including all children aged <= 12 months discharged from a pediatric tertiary-care center with a diagnosis of bronchiolitis, between November 2007 and March 2008. Oxygen was administered according to a standardized protocol. We assumed children with the following criteria could have been sent home with O(2), instead of being kept in hospital: age >= 2 months, distance between home and hospital <50 km, in-hospital observation >= 24 h, O(2) requirement <= 1.0 L/min, stable clinical condition, no enteral tube feeding, and intravenous fluids <50 mL/kg/day. Children with significant underlying disease were excluded. A total of 177 children were included. Median age was 2.0 months (range 0-11), and median length of stay was 3.0 days (range 0-18). Forty-eight percent of patients (85/177) received oxygen during their hospital stay. Criteria for discharge with HOT were met in 7.1 % of patients, a mean of 1.8 days (SD 1.8) prior to real discharge. The number of patient-days of hospitalization which would have been saved had HOT been available was 21, representing 3.0 % of total patient-days of hospitalization for bronchiolitis over the study period (21/701). CONCLUSIONS: In this study setting, few children were eligible for an early discharge with HOT. Home oxygen therapy would not significantly decrease the overall burden of hospitalization for bronchiolitis. PMID- 23015045 TI - Choroid plexus papilloma in an infant: ultrasound diagnosis. AB - A 6-month-old baby with enlarged head circumference was found on ultrasound to have a choroid plexus papilloma with striking sonographic appearance. This entity has received relatively little attention in the literature and may be encountered on ultrasound as the first imaging study. PMID- 23015044 TI - Management of unstable pediatric hemato-oncology patient: results of a Web-based survey to pediatric oncologists in Spain. AB - The current management and monitoring of unstable pediatric hemato-oncology patient (UPHOP) in the oncology ward is not well defined. To evaluate this concept, an anonymous Web-based survey was sent to the 150 Spanish pediatric oncologists registered in the Spanish Society of Pediatric Hemato-Oncology. The response rate was 57 %, with the following main results: Pediatric intensive consulting was available for 97 %, and it was made in case of UPHOP by 37 % of oncologists, up to 65 % if hemodynamic instability. In case of inotropic support initiation, 32 % of respondents never consulted the intensivist. Dopamine is first chosen inotropic; 28 % of surveyed considered there is no limit in its dosage or it is superior to 20 MUg/kg/min before an intensivist consulting. Pediatric intensive care admission was considered necessary in case of fever with hemodynamic instability by 15 % of respondents. Respiratory monitoring was mainly done by clinical signs (67 %). In case of respiratory insufficiency, the noninvasive respiratory support by high-flow ventilation with nasal cannula was applied by 57 % in the oncology ward. In case of acute kidney injury, diuretics were generally the initial therapy. The anticonvulsive drugs most frequently applied were valproic acid (93 %), diazepam (88 %), and phenytoin (81 %). CONCLUSION: A consensus should be achieved among oncologists and intensivists. The creation and training of rapid response teams could be useful to improve the UPHOP management. PMID- 23015046 TI - Association of adipokines with cardiovascular risk factors in low birth weight children: a case-control study. AB - Our aim was to investigate plasma levels of adiponectin, monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) in low birth weight (LBW) children and to determine correlations among these adipokines and birth weight and cardiovascular disease risk factors. In a case-control study, the concentrations of adiponectin, MCP-1 and PAI-1 were measured in 180 schoolchildren (ages 6-11 years). MCP-1 and PAI-1 levels were significantly elevated in LBW children. Conversely, adiponectin concentration was significantly reduced in these children. Similar findings were observed after adjustment for current age, gender and abdominal circumference. Because the children with LBW had altered adipokine levels, as well as higher abdominal circumference, HOMA-IR and systolic blood pressure (SBP), we evaluated the correlation among these variables. These analyses showed that adiponectin levels were inversely correlated with systolic blood pressure (SBP) (r = -0.501; P < 0.001), HOMA-IR (r = -0.293; P = 0.023) and waist circumference (r = -0.317; P = 0.014). The proinflammatory markers were positively correlated with HOMA-IR (PAI-1: r = 0.358; P = 0.005) and waist circumference (PAI-1: r = 0.571; P < 0.001 and MCP-1: r = 0.267; P = 0.039). CONCLUSION: Adipokines levels were correlated with cardiovascular risk factors in LBW children, and these compounds could be involved in the mechanism that links birth weight to the development of cardiovascular diseases in adulthood. PMID- 23015047 TI - Neurologic manifestations of Fusobacterium infections in children. AB - Fusobacterium necrophorum causes various clinical syndromes, ranging from otitis media to life-threatening Lemierre's syndrome. The purpose of this study was to review our experience with pediatric Fusobacterium infections. The medical records of all children aged 0 to 18 years who were diagnosed between 1999 and 2011 with Fusobacterium infection were reviewed. Fusobacterium was isolated from clinical samples of 27 children: blood cultures (n = 16), abscesses (n = 8), joint fluids (n = 2), and cerebrospinal fluid (n = 1). The median age at admission was 3.5 years (range, 7 months to 17 years). Eight children (30 %) had seizures at presentation. Ten children (37 %) underwent lumbar puncture. Fifteen children (56 %) underwent brain imaging, and in seven of these children, a thrombus was identified either in a sinus vein or in an internal jugular vein. The most common source of infection was otogenic in 19 (70 %) of the children. Six of the children presented in 2011. All patients recovered. CONCLUSIONS: Neurologic manifestations are common at presentation of children with Fusobacterium infections. In young children, the most common source of infection is otogenic. Thrombotic complications are common, and imaging should be considered in all children with Fusobacterium infections arising from the head or neck region. There was a recent increase in the isolation of this bacterium, either because of better culturing techniques and increased awareness to this entity or a true increase in infections due to this organism. PMID- 23015049 TI - Contrast features of breast cancer in frequency-domain laser scanning mammography. AB - Frequency-domain optical mammography has been advocated to improve contrast and thus cancer detectability in breast transillumination. To the best of our knowledge, this report provides the first systematic clinical results of a frequency-domain laser scanning mammograph (FLM). The instrument provides monochromatic light at 690 and 810 nm, whose intensity is modulated at 110.0010 and 110.0008 MHz, respectively. The breast is scanned by stepwise positioning of source and detector, and amplitude and phase for both wavelengths are measured by a photomultiplier tube using heterodyne detection. Images are formed representing amplitude or phase data on linear gray scales. Furthermore, various algorithms carrying on more than one signal (amplitude ratio, phase difference, MUa,MUs',N) were essayed. Twenty visible cancers out of 25 cancers in the first 59 investigations were analyzed for their quantitative contrast with respect to the whole breast or to defined reference areas. Contrast definitions refer to the signal itself (definition 1), to the signal noise (definition 2), or were based on nonparametric comparison (definition 3). The amplitude signal provides better contrast than the phase signal. Ratio images between red and infrared amplitudes gave variable results; in some cases the tumor contrast was canceled. The algorithms to determine MUa and MUs' from amplitude and phase data did not significantly improve upon objective contrast. The N algorithm, using the phase signal to flatten the amplitude signal did significantly improve upon contrast according to contrast definitions 1 and 2, however, did not improve upon nonparametric contrast. Thus, with the current instrumentation, the phase signal is helpful to correct for the complex and variable geometry of the breast. However, an independent informational content for tumor differentiation could not be determined. The flat field algorithm did greatly enhance optical contrast in comparison with amplitude or amplitude ratio images. Further evaluation of FLM will have to be based on the N-algorithm images. (c) 1998 Society of Photo Optical Instrumentation Engineers. PMID- 23015050 TI - Dependence of image quality on image operator and noise for optical diffusion tomography. AB - By applying linear perturbation theory to the radiation transport equation, the inverse problem of optical diffusion tomography can be reduced to a set of linear equations, WMU=R, where W is the weight function, MU are the cross-section perturbations to be imaged, and R is the detector readings perturbations. We have studied the dependence of image quality on added systematic error and/or random noise in W and R. Tomographic data were collected from cylindrical phantoms, with and without added inclusions, using Monte Carlo methods. Image reconstruction was accomplished using a constrained conjugate gradient descent method. Results show that accurate images containing few artifacts are obtained when W is derived from a reference state whose optical thickness matches that of the unknown test medium. Comparable image quality was also obtained for unmatched W, but the location of the target becomes more inaccurate as the mismatch increases. Results of the noise study show that image quality is much more sensitive to noise in W than in R, and the impact of noise increases with the number of iterations. Images reconstructed after pure noise was substituted for R consistently contain large peaks clustered about the cylinder axis, which was an initially unexpected structure. In other words, random input produces a nonrandom output. This finding suggests that algorithms sensitive to the evolution of this feature could be developed to suppress noise effects. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015048 TI - Adults with autism: outcomes, family effects, and the multi-family group psychoeducation model. AB - Although an increasing number of individuals with autism spectrum disorders are entering adulthood, currently there are few evidence-based programs for individuals later in the life course. In this paper we present an overview of recent research on outcomes for adolescents and adults with ASD and highlight the role of the family for individuals with ASD during the transition to adulthood. We also discuss multi-family group psychoeducation as a promising model for use with individuals with ASD who are transitioning to adulthood. PMID- 23015051 TI - Imaging and quantitation of a tissue-selective lanthanide chelate using an endoscopic fluorometer. AB - Tissue spectroscopy and endoscopy are combined with a tissue site-selective fluorescent probe molecule to demonstrate in vitro, spatial, remote, quantitative imaging of the rat small intestine. The probe molecule employed, Tb-3,6,9 tris(methylene phosphonic acid n-butyl ester)-3,6,9,15-tetraaza bicyclo[9.3.1]pentadeca-1(15),11,13-triene (Tb-PCTMB), is shown to bind with the small intestine and provide improved image contrast. High sensitivity is possible due to the absorption-emission Stokes's shift exhibited by the Tb-PTCMB complex. Excitation is centered near 270 nm and multifeatured emission is observed at 490, 550, 590, and 625 nm. Sprague-Dawley rats were dosed with the Tb-PTCMB complex, which shows biodistribution, leading to preferential binding to the inner surface of the small intestine. It is shown that the fluorescent image, taken at 550 nm, can be used to quantify the amount of Tb-PCTMB present in an excised tissue sample. The 3sigma detection limits are found to be in the femtomole range. An optical mass balance for Tb-PCTMB-dosed small intestine is performed and along with radiotracer biodistribution, demonstrates that approximately 40% of the marker probe resides in the endothelial tissue of the small intestine inner lumen. This result is of particular interest since most adult colon cancers develop in this region. These results demonstrate the ability to perform spatial, quantitative, in vitro, endoscopic imaging of a complex biological sample using a probe marker. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015052 TI - Fret imaging of pit-1 protein interactions in living cells. AB - The combined use of fluorescence resonance energy transfer (FRET) microscopy and expression of genetic vectors encoding protein fusions with green fluorescent protein (GFP) and blue fluorescent protein (BFP) provides an exceptionally sensitive method for detecting the interaction of protein partners in living cells. The acquisition of FRET signals from GFP- and BFP-fusion proteins expressed in living cells was demonstrated using an optimized imaging system and high sensitivity charge coupled device camera. This imaging system was used to detect energy transfer signals from a fusion protein containing GFP physically linked to BFP expressed in living HeLa cells. In contrast, the co-localization of noninteracting GFP- and BFP-fusion proteins was not sufficient for energy transfer. The FRET imaging system was then used to demonstrate dimerization of the pituitary-specific transcription factor Pit-1 within the living cell nucleus. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015053 TI - Surface scanning: an application to mammary surgery. AB - The possibility of mathematically describing the body surface represents a useful tool for several medical sectors, such as prosthetics or plastic surgery, and could improve diagnosis and objective evaluation of deformities and the follow-up of progressive diseases. The approach presented is based on the acquisition of a surface scanned by a laser beam. The 3-D coordinates of the spot generated on the surface by the laser beam are computed by an automatic image analyzer (ELITE system). Using at least two different views of the subject, the 3-D coordinates are obtained by stereophotogrammetry. A software package for graphic representation and extraction of linear superficial and volumetric features from the acquired surface has been developed and some preliminary results with mammary reconstruction are presented. A good mammary reconstruction after mastectomy must achieve two results. First, the reconstruction should follow the patients' wishes and second, the reconstructed breast should be as similar as possible to the contralateral one (symmetry is the most important aesthetic parameter to be considered). To achieve these goals, a knowledge of breast volume, area, and shape features are essential for the surgeon. In such a context, this system could be a valuable tool in improving breast reconstructive surgery. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015054 TI - Correction of the internal absorption effect in fluorescence emission and excitation spectra from absorbing and highly scattering media: theory and experiment. AB - Fluorescence spectra measured from biological samples, such as tissues or cell suspensions, are usually distorted due to the light absorption by intrinsic chromophores. These distortions are aggravated by strong scattering of light inside the samples. A new method is described for a fast correction of these spectral distortions, using only steady-state spectroscopic measurements. The method is based on the formulas derived from a simplified photon diffusion model, in the isotropic one-dimensional approximation applied to a semi-infinite, highly scattering, and moderately absorbing medium with a refractive-index-matched boundary. The formulas describe the spectral distortions of the fluorescence emission and excitation spectra, together with the diffuse reflectance spectrum, as the functions of one spectral characteristic of the medium, the darkness, which is the ratio of absorption coefficient and reduced scattering coefficient. The algorithm does not involve any iterative procedures, and offers a direct, simple, and fast method for real-time spectral correction. The true fluorescence emission or excitation spectrum is directly calculated from a pair of experimental spectra: the fluorescence emission or excitation spectrum and the diffuse reflectance spectrum, measured from the same position on a sample. The correction produces the profile of the true fluorescence spectrum, the same as the one measured from the corresponding sample with an infinitely low absorption and no scattering. The restoration of the spectral profiles of true fluorescence emission and excitation spectra was tested experimentally, using highly scattering phantoms with a fluorescent dye and a deliberately added nonfluorescent dye producing strong inner-filter distortions. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015055 TI - Feasibility of picosecond laser-Doppler flowmetry provides basis for time resolved Doppler tomography of biological tissues. AB - A detectable signal is obtained from a laser Doppler flowmeter operating in the heterodyne mode with nano- and pico-second pulse laser sources. The ultrashort pulse probing may be useful for depth-dependent time-resolved laser Doppler velocity measurements of blood perfusion in biological tissues. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015056 TI - Myocardial oxygenation in dogs during reactive hyperemia. AB - The mechanisms of myocardial oxygenation during reactive hyperemia were studied in the beating heart using continuous near infrared (NIR) spectroscopy. In open chest dogs, NIR spectroscopy was used to monitor brief occlusions of the left anterior descending artery. These occlusions produced a precipitous drop in tissue oxygen stores (tHbO2+MbO2), tissue blood volume, and the oxidation level of mitochondrial cytochrome a,a3. Reperfusion produced a rapid increase in the NIR signals to supranormal levels, followed by gradual return to baseline. When the duration of occlusion was increased from 20 to 120 s, an essentially linear increase was produced in the overshoot areas defined by the NIR signals. Near infrared spectroscopy (NIRS) separated reactive hyperemia into two phases according to the tissue level of deoxyhemoglobin and deoxymyoglobin (tHb+Mb): (1) an early phase during which the tHb+Mb level was supranormal, reflecting enhanced O2 extraction; and (2) a late phase during which the tHb+Mb level was below baseline, reflecting decreased O2 extraction and increased tissue O2 availability. During reactive hyperemia, when O2 availability was maximal by NIR spectroscopy, O2 consumption was elevated but submaximal, indicating that MVO2 was not limited by O2 availability. Cytochrome a,a3 oxidation state also was restored fully. Thus, myocardial oxygenation is highly regulated during reactive hyperemia. Cellular O2 supply and mitochondrial oxidation state are restored early during reactive hyperemia by increased O2 delivery, increases in tissue blood volume and enhanced O2 extraction. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015057 TI - In vivo fluorescence spectroscopy of the human skin: experiments and models. AB - The results of the experimental investigation of autofluorescence spectra of human skin in vivo caused by the UV radiation of the skin and by the external mechanical pressure applied to the skin are presented. These results are compared with results of Monte Carlo modeling of the autofluorescence of the skin with variable blood content. The proposed simple model of the skin gives the possibility of evaluation of changes of the blood and melanin content within the skin. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015058 TI - Light scattering multipole solution for a cell. AB - We derive a multipole scattering solution for a system resembling a simple cell. In the model, a spherical cytoplasm is surrounded by a concentric cell membrane. Contained within the cytoplasm is a nonconcentric spherical nucleus. Because of the nature of the (multipole expansion) solution, numerical results can be acquired quite rapidly. We show that the resulting scatter is very sensitive to the system geometry and optical properties. Such a solution may also be used to calculate the scatter from fluorescing molecules located within the cell. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015059 TI - Magnetic resonance imaging of cranial nerves at 7 Tesla. AB - PURPOSE: The aim of this study was to demonstrate the feasibility of cranial nerve (CN II-XII) imaging with 7 Tesla magnetic resonance imaging (MRI). METHODS: In this study four sequences were evaluated in three healthy volunteers using magnetization preparation rapid gradient echo (MPRAGE), constructive interference in steady state (CISS), true fast imaging with steady state precession (TrueFISP) and proton density (PD) T2-weighted turbo spin echo (TSE) sequences. RESULTS: It was found that MPRAGE did not always provide sufficient contrast to delineate in particular small CNs but displayed an overall good identification rate. The T2 sequence was not able to adequately differentiate the small CNs but showed a very good contrast between nerves and cerebrospinal fluid (CSF). As at lower magnetic fields steady state sequences displayed a high identification rate of all CNs in the axial plane but CISS suffered from susceptibility and pulsation artifacts, furthermore it was limited as no parallel imaging could be performed. The TrueFISP technique was reliable in identifying most CNs although suffering from banding artifacts. CONCLUSIONS: The TrueFISP sequence showed superior spatial resolution and contrast in comparison to the other sequences for imaging of CNs at 7 T. PMID- 23015060 TI - Phosphoinositide 5-phosphatases: How do they affect tumourigenesis? AB - The activity of biological molecules is often affected by their phosphorylation state. Regulatory phosphorylation operates as a binary switch and is usually controlled by counteracting kinases and phosphatases. However, phosphatidylinositol (PtdIns) has three phosphorylation sites on its inositol ring. The phosphorylation status of PtdIns is controlled by multiple kinases and phosphatases with distinct substrate specificities, serving as a 'lipid code' or 'phosphoinositide code'. Class I phosphoinositide 3-kinase (PI3K) converts PtdIns(4,5)P2 to PtdIns(3,4,5)P3, which plays a pivotal role in signals controlling glucose uptake, cytoskeletal reorganization, cell proliferation and apoptosis. PI3K is pro-oncogenic, whereas phosphoinositide phosphatases that degrade PtdIns(3,4,5)P3 are not always anti-oncogenic. Recent studies have revealed the unique characteristics of phosphoinositide 5-phosphatases. PMID- 23015062 TI - Scattering techniques in biology--Marking the contributions to the field from Peter Laggner on the occasion of his 68th birthday. PMID- 23015061 TI - Calcitriol [1, 25[OH]2 D3] pre- and post-treatment suppresses inflammatory response to influenza A (H1N1) infection in human lung A549 epithelial cells. AB - PURPOSE: Influenza viruses infect airway epithelial cells, causing respiratory distress. Immune defense is maintained by chemokine/cytokine secretions from airway epithelial cells. While moderate inflammatory response protects from ill effects, hyper-inflammatory response promotes the pathogenesis. High circulating levels of vitamin D are known to mitigate effects of infectious diseases, including respiratory infectious diseases. The question whether and how vitamin D treatment pre-/post-viral exposure modulates inflammatory response is not clear. The present study was undertaken to understand autophagy/apoptosis balance and chemokine/cytokine response to influenza A (H1N1) infection by pre- and post-1, 25-dihydroxyvitamin D3 (1,25[OH]2 D3)[calcitriol] treatment of human lung A549 epithelial cells. METHODS: Influenza A (H1N1) virus was propagated in A549 cell line, titrated using hemagglutination assay, and was used to assess effect of calcitriol. After confirming that 100 nM of calcitriol fails to clear virus, A549 cells were either pre-treated (16 h) with 100 nM or post-treated with 30 nM of 1,25[OH]2 D3 of virus inoculation (1 h). Cells after incubation at 37 degrees C under 5 % CO2 for 48 h were collected and subjected to RNA and protein extraction. Measurements of viability, influenza M protein, and molecular parameters of cell death and inflammatory response were performed. RESULTS: We report that treatment of these cells with 100/30 nM of 1,25[OH]2 D3 prior to/or post-H1N1 exposure does not affect viral clearance but significantly reduces autophagy and restores increased apoptosis seen on H1N1 infection back to its constitutive level. However, it significantly decreases the levels of H1N1 induced TNF-alpha (tumor necrosis factor-alpha), IFN-beta (interferon-beta), and IFN-stimulated gene-15 (ISG15). 1,25[OH]2 D3 treatment prior to/or post-H1N1 infection significantly down-regulates IL-8 as well as IL-6 RNA levels. These results demonstrate that calcitriol treatment suppresses the H1N1-induced transcription of the chemokines RANTES and IL-8 in epithelial cells. CONCLUSION: The findings provide support for the initiation of vitamin D supplementation program to VDD populations in reducing the severity of influenza. PMID- 23015063 TI - kappa-Casein terminates casein micelle build-up by its "soft" secondary structure. AB - In our previous paper (Nagy et al. in J Biol Chem 285:38811-38817, 2010) by using a multilayered model system, we showed that, from alpha-casein, aggregates (similar to natural casein micelles) can be built up step by step if Ca-phosphate nanocluster incorporation is ensured between the protein adsorption steps. It remained, however, an open question whether the growth of the aggregates can be terminated, similarly to in nature with casein micelles. Here, we show that, in the presence of Ca-phosphate nanoclusters, upon adsorbing onto earlier alpha casein surfaces, the secondary structure of alpha-casein remains practically unaffected, but kappa-casein exhibits considerable changes in its secondary structure as manifested by a shift toward having more beta-structures. In the absence of Ca-phosphate, only kappa-casein can still adsorb onto the underlying casein surface; this kappa-casein also expresses considerable shift toward beta structures. In addition, this kappa-casein cover terminates casein aggregation; no further adsorption of either alpha- or kappa-casein can be achieved. These results, while obtained on a model system, may show that the Ca-insensitive kappa casein can, indeed, be the outer layer of the casein micelles, not only because of its "hairy" extrusion into the water phase, but because of its "softer" secondary structure, which can "occlude" the interacting motifs serving casein aggregation. We think that the revealed nature of the molecular interactions, and the growth mechanism found here, might be useful to understand the aggregation process of casein micelles also in vivo. PMID- 23015065 TI - Nano-branched transparent conducting oxides: beyond the brittleness limit for flexible electrode applications. AB - Although the performance of transparent conducting oxides based on bixbyite In(2)O(3) (Sn doped In(2)O(3): ITO) and wurtzite ZnO (Al, In, and Ga doped ZnO) is sufficient in conventional optoelectronic devices, their flexibility remains insufficient for demands in mobile and foldable electronics generation. A lot of alternative materials such as metallic nanowires and carbon based nano-structures have been tried for transparent flexible electrodes, but poor thermal stability of metal nanowires and limits in conductivity of carbon based nano-structures are still waiting for permanent solutions. Here, we show that the cross-linked ITO nano-branches have superior mechanical flexibility compared to ITO bulk film without any cracks even with a bending radius of 0.1 cm. Moreover, for equivalent sheet resistivity, the ITO nano-branches exhibit optical transmittance comparable to that of commercial metallic nanowires (such as Ag and Cu in the visible spectrum) but show far superior thermal stability in conductivity without any degradation even at a temperature of 200 degrees C and a humidity of 90%. PMID- 23015066 TI - Anatomy of the temporomandibular joint in the cat: a study by microdissection, cryosection and vascular injection. AB - The minute anatomy of the temporomandibular joint (TMJ) is of great clinical relevance in cats owing to a high number of lesions involving this articulation. However, the precise anatomy is poorly documented in textbooks and scientific articles. The aim of this study was to describe, in detail, the TMJ anatomy and its relationship with other adjacent anatomical structures in the cat. Different anatomical preparations, including vascular and articular injection, microdissection, cryosection and plastination, were performed in 12 cadaveric cats. All TMJ anatomical structures were identified and described in detail. A thorough understanding of the TMJ anatomy is essential to understand the clinical signs associated with TMJ disorders, to locate lesions precisely and to accurately interpret the results in all diagnostic imaging techniques. PMID- 23015064 TI - Translational recoding in archaea. AB - Translational recoding includes a group of events occurring during gene translation, namely stop codon readthrough, programmed +/-1 frameshifting, and ribosome bypassing, which have been found in organisms from all domains of life. They serve to regulate protein expression at translational level and represent a relatively less known exception to the traditional central 'dogma' of biology that information flows as DNA->RNA->protein and that it is stored in a co-linear way between the 5'->3' of nucleic acids and N->C-terminal of polypeptides. In archaea, in which translational recoding regulates the decoding of the 21st and the 22nd amino acids selenocysteine and pyrrolysine, respectively, only one case of programmed -1 frameshifting has been reported so far and further examples, although promising, have not been confirmed yet. We here summarize the current state-of-the-art of this field that, especially in archaea, has relevant implications for the physiology of life in extreme environments and for the origin of life. PMID- 23015067 TI - A musculoskeletal modeling approach for estimating anterior cruciate ligament strains and knee anterior-posterior shear forces in stop-jumps performed by young recreational female athletes. AB - The central goal of this study was to contribute to the advancements being made in determining the underlying causes of anterior cruciate ligament (ACL) injuries. ACL injuries are frequently incurred by recreational and professional young female athletes during non-contact impact activities in sports like volleyball and basketball. This musculoskeletal-neuromuscular study investigated stop-jumps and factors related to ACL injury like knee valgus and internal external moment loads, knee anterior-posterior (AP) shear forces, ACL strains and internal forces. Motion capture data was obtained from the landing phase of stop jumps performed by eleven young recreational female athletes and electromyography (EMG) data collected from quadriceps, hamstring and gastrocnimius muscles which were then compared to numerically estimated activations. Numerical simulation tools used were Inverse Kinematics, Computed Muscle Control and Forward Dynamics and the knee modeled as a six degree of freedom joint. Results showed averaged peak strains of 12.2 +/- 4.1% in the right and 11.9 +/- 3.0% in the left ACL. Averaged peak knee AP shear forces were 482.3 +/- 65.7 N for the right and 430.0 +/- 52.4 N for the left knees, approximately equal to 0.7-0.8 times body weight across both knees. A lack of symmetry was observed between the knees for valgus angles (p < 0.04), valgus moments (p < 0.001) and muscle activations (p < 0.001), all of which can be detrimental to ACL stability during impact activities. Comparisons between recorded EMG data and estimated muscle activations show the relation between electrical signal and muscle depolarization. In summary, this study outlines a musculoskeletal simulation approach that provides numerical estimations for a number of variables associated with ACL injuries in female athletes performing stop-jumps. PMID- 23015068 TI - Synthesis of iridium and ruthenium complexes with (N,N), (N,O) and (O,O) coordinating bidentate ligands as potential anti-cancer agents. AB - Several Ru-arene and Ir-Cp* complexes have been prepared incorporating (N,N), (N,O) and (O,O) coordinating bidentate ligands and have been found to be active against both HT-29 and MCF-7 cell lines. By incorporating a biologically active ligand into a metal complex the anti-cancer activity is increased. PMID- 23015069 TI - Estimation of the warfarin dose with a pharmacogenetic refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation. AB - Pharmacogenetic (PG) dosing algorithms have been confirmed to predict warfarin therapeutic dose more accurately; however, most of them are based on standard intensity of warfarin anticoagulation, and their utility outside this range is limited. This study was designed to develop and validate a PG refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation. Consented Chinese-Han patients (n=310) under stable warfarin treatment were randomly divided into a derivation (n=207) and a validation cohort (n=103), with 83% and 80% of the patients under low-intensity anticoagulation, respectively. In the derivation cohort, a PG algorithm was constructed on the basis of genotypes (CYP2C9*3 and VKORC1-1639A/G) and clinical data. After integrating additional covariates of international normalised ratio (INR) values (INR on day 4 of therapy and target INR) and genotype of CYP4F2 (rs2108622), a PG refinement algorithm was established and explained 54% of warfarin dose variability. In the validation cohort, warfarin dose prediction was more accurate (p < 0.01) with the PG refinement algorithm than with the PG algorithm and the fixed dose approach (3 mg/day). In the entire cohort, the PG refinement algorithm could accurately identify larger proportions of patients with lower dose requirement (<=2 mg/day) and higher dose requirement (>=4 mg/day) than did the PG algorithm. In conclusion, PG refinement algorithm integrating early INR response and three genotypes (CYP2C9*3, VKORC1-1639A/G, CYP4F2 rs2108622) improves the accuracy of warfarin dose prediction in Chinese patients mainly under low intensity anticoagulation. PMID- 23015070 TI - Sequential energy and charge transfer processes in mixed host-guest complexes of subphthalocyanine, porphyrin and phthalocyanine chromophores. AB - Porphyrins, phthalocyanines and subphthalocyanines are three attractive classes of chromophores with intriguing properties making them suitable for the design of artificial photosynthetic systems. The assembly of these components by a supramolecular approach is of particular interest as it provides a facile means to build multi-chromophoric arrays with various architectures and tuneable photophysical properties. In this paper, we show the formation of mixed host guest supramolecular complexes that consist of a beta-cyclodextrin-conjugated subphthalocyanine, a tetrasulfonated porphyrin and a series of silicon(IV) phthalocyanines substituted axially with two beta-cyclodextrins via different spacers. We found that the three components form supramolecular complexes held by host-guest interactions in aqueous solution. Upon excitation of the subphthalocyanine part of the complex, the excitation energy is delivered to the phthalocyanine unit via excitation energy transfer and the porphyrin chromophore acts as an energy transfer bridge enabling this process. It was shown that photo induced charge transfer also takes place. A sequential electron transfer process from the porphyrin unit to the phthalocyanine moiety and subsequently from the subphthalocyanine moiety to the porphyrin unit takes place, and the probability of this process is controlled by the linker between beta-cyclodextrin and phthalocyanine. The lifetime of the charge-separated state was found to be 1.7 ns by transient absorption spectroscopy. PMID- 23015071 TI - Prosthetic valve endocarditis after transcatheter aortic valve implantation: the incidence in a single-centre cohort and reflections on clinical, echocardiographic and prognostic features. AB - AIMS: Transcatheter aortic valve implantation (TAVI) has recently developed into an accepted alternative to conventional surgery in high-risk patients. According to current data, post-TAVI prosthetic valve endocarditis (PVE) seems to occur very rarely. METHODS AND RESULTS: We followed the first 180 consecutive patients who underwent TAVI at our institution to assess safety and efficacy of the procedure. During follow-up (median, 319 days), PVE was seen more frequently than expected. By applying modified Duke criteria five cases could be confirmed (four early-onset and one late-onset PVE, four cases with "definite diagnosis" and one with "possible diagnosis") representing an estimated PVE incidence of 3.4% at one year. Two patients died subsequently. Clinical summaries of all cases are reported and compared to previously published case reports. CONCLUSIONS: According to our hypothesis, PVE might be particularly difficult to diagnose after TAVI, whereas TAVI-specific elderly patients might be exceptionally vulnerable. There exists little experience of TEE interpretation in post-TAVI endocarditis which should possess unique characteristics regarding, e.g., valve dehiscence or abscess formation. Therefore, echocardiography as a diagnostic tool often remains initially inconclusive. Because of incongruence between prosthetic device and calcified native aortic valve, some degree of paravalvular leak is common after TAVI. These paravalvular leaks as a nidus for infection, advanced age and abundant comorbidities might predispose TAVI patients for infective endocarditis. PMID- 23015074 TI - Guest Editorial: Special Section on Interferometry in Biomedicine, Part II. AB - This Special Section Guest Editorial provides an overview of the topical area and an introduction to the articles featured in the special section. PMID- 23015072 TI - KRAS p.G13D mutations are associated with sensitivity to anti-EGFR antibody treatment in colorectal cancer cell lines. AB - PURPOSE: Targeted therapies using the anti-EGFR antibodies panitumumab (Pmab) or cetuximab (Cmab) are currently restricted to patients with metastatic colorectal adenocarcinoma whose tumours do not show a mutation in KRAS. However, recent retrospective studies indicated that patients with tumours mutated in codon 13 of KRAS may benefit from treatment with Cmab in contrast to patients with tumours mutated in KRAS codon 12. METHODS: To study the functional impact of the subtype of KRAS mutations on the efficiency of EGFR-targeted therapies, we correlated the KRAS mutation status of 15 colorectal carcinoma cell lines with the in vitro sensitivity of these cells to Cmab/Pmab. Mutations in the potential predictive biomarkers BRAF and PIK3CA as well as protein expression of EGFR and PTEN were also determined. RESULTS: Four out of seven KRAS-mutated cell lines were characterised by the p.G13D mutation. Treatment of these cells using Cmab/Pmab induced a significant growth inhibition in contrast to cell lines showing a KRAS mutation at codon 12 or 61. Out of the eight KRAS wild-type cell lines, five were insensitive to Cmab/Pmab. These cell lines were characterised either by BRAF mutation or by absence of EGFR or PTEN protein expression. CONCLUSIONS: Since KRAS p.G13D-mutated tumour cells may respond to EGFR-targeted therapy, we suggest including subtype analysis of KRAS mutations in prospective clinical trials. In KRAS wild-type tumour cells, BRAF mutations and loss of EGFR or PTEN expression may lead to resistance to EGFR-targeted therapy and should be considered as additional negative predictive biomarkers. PMID- 23015075 TI - Compensation of eye movements in retinal speckle flowmetry using flexible correlation analysis based on the specific variance. AB - Bio-speckle flowmetry using the photon correlation technique is useful for measuring the retinal blood flow velocity. In practical situations, however, it often suffers from eye-movement artifacts and other external moving factors. To solve this problem, we studied in this paper a flexible correlation analysis, by which the blood flow information can be effectively extracted from erroneous data influenced by displacement of the measuring point. The signal-analyzing system including the photon correlator directly stores the sequential counts of photoelectron pulses into a memory. After measurements, the stored data are read out and used to calculate the first-order statistics of time-integrated bio speckles and the autocorrelation function with an arbitrary delay-time unit for an arbitrary period. These results are used to specify and to eliminate the erroneous parts of data due to the displacement of the measuring point. The usefulness of this technique was verified for a glass capillary model and human retinal vessels. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015076 TI - Speckled speckle statistics with a small number of scatterers: implication for blood flow measurement. AB - Formulas relating to diffraction of the focused Gaussian beam from a narrow blood microvessel have been derived. A native vessel has been considered as a set of moving random screens. The correlation function of intensity fluctuations of statistically inhomogeneous speckled speckles has been studied with applications to flow measurement. Dependencies of statistical characteristics of biospeckles with a small number of scatterers on the number of scattering screens have been analyzed. It has been shown that the value of Doppler shift in the scattered light essentially depends on the spatial velocity distribution in the blood flow. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015073 TI - Office evaluation of male patients with lower urinary tract symptoms. AB - Lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH) are one of the most common urologic disorders in men. Accurate history-taking and focused physical examination allows us to diagnose the majority of cases. A better understanding of risk factors helps us tailor our treatment and predict outcomes more accurately. Population studies are crucial in our understanding of LUTS/BPH natural history. Temporary prostatic urethral stents that are used for the management of urinary retention may also be used for evaluation of patients with detrusor hypo-contractility. The use of ultrasound to measure intravesical prostatic protrusion (IPP) and the Doppler study for prostate capsular artery resistive index are promising. Near-infrared spectroscopy (NIRS) examines the tissue oxygenation that may be affected by bladder outlet obstruction. The mathematical algorithm needs some fine-tuning, and its reproducibility is debatable. Serum and urinary biomarkers may help us to diagnose the disorder, and more effectively monitor patients' response to therapy. Among all, IPP is clinically more applicable at this time. PMID- 23015077 TI - Laser interferometric investigations of pulsatile choroidal blood flow: review and new results on the validity of the technique. AB - A short overview of currently available ocular blood flow techniques is given. We have recently introduced a laser interferometric technique for the measurement of ocular fundus pulsation. The eye is illuminated by a single mode laser beam which is reflected at the anterior corneal surface and the fundus. The two re-emitted waves produce interference fringes from which distance changes between cornea and retina during the cardiac cycle can be calculated. These rhythmic changes in corneo-retinal distance are caused by the arterial pulsatile inflow of blood, which increases the ocular volume. The fundus pulsation amplitude (FPA) is the maximum distance change between cornea and retina during the cardiac cycle and is taken as a relative measure of pulsatile choroidal blood flow. The high reproducibility and the high sensitivity of the method are discussed. In addition, the present article reviews comparative measurement with other techniques for the assessment of choroidal blood flow, which validates the method. Furthermore, we present new data on a comparison of color Doppler imaging in the posterior ciliary arteries and laser interferometric measurement of FPA. Applications of laser interferometric measurement of FPA to study the physiology, the pharmacology, and the pathophysiology of the choroidal circulation are reviewed. In conclusion, FPA can be taken as a relative measure of pulsatile choroidal blood flow. The technique is particularly suitable for pharmacodynamic studies. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015078 TI - Rapid and precise in vivo measurement of human corneal thickness with optical low coherence reflectometry in normal human eyes. AB - An optical low-coherence reflectometer is used for rapid noncontact measurements of the human corneal thickness in vivo. Thickness measurements on ten volunteers show a standard deviation of 3.4 MUm. The experiments reveal that the optical reflectometer benefits from a 2.5 fold enhancement of the measurement precision and a 2.8 fold reduction in measurement time compared to a standard clinical ultrasonic pachometer. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015079 TI - Chirp optical coherence tomography of layered scattering media. AB - A new noninvasive technique that reveals cross sectional images of scattering media is presented. It is based on a continuous wave frequency modulated radar, but uses a tunable laser in the near infrared. As the full width at half maximum resolution of 16 MUm is demonstrated with an external cavity laser, the chirp optical coherence tomography becomes an alternative to conventional short coherence tomography with the advantage of a simplified optical setup. The analysis of two-layer solid phantoms shows that the backscattered light gets stronger with decreasing anisotropic factor and increasing scattering coefficient, as predicted by Monte Carlo simulations. By introducing a two-phase chirp sequence, the combination of lateral resolved perfusion and depth resolved structure is shown. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015080 TI - Band analysis of hydrated human skin stratum corneum attenuated total reflectance fourier transform infrared spectra in vivo. AB - Water content is an important factor for skin condition. The determination of the hydration state of the skin is necessary to obtain basic knowledge about the penetration and loss of water in the skin stratum corneum. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy is used to measure hydration of the stratum corneum. In this study we apply direct band fitting of the water bending, combination, and OH stretch bands over the 4000-650 cm-1 wave number range. Measurements are performed on the volar aspect of the forearm using a Nicolet 800 FTIR spectrometer equipped with an ATR unit with a ZnSe crystal. Hydration of the skin is obtained by occlusion keeping the forearm pressed onto the crystal. Spectra are recorded before and after occlusion up to 30 min. The spectra are fitted with a nonlinear least-squares algorithm with Gaussian bands. Separate band fits of water, normal stratum corneum, and occluded hydrated stratum corneum spectra are obtained yielding band parameters of the individual water contributions in the bending mode at 1640 cm-1, the combination band at 2125 cm-1, and the OH stretches in the hydrated skin stratum corneum spectra. A scaling factor representing the contribution of the water spectrum into the skin stratum corneum spectrum is determined during the occlusion process. In comparison to the dependence of the infrared absorbance ratio in time used by Potts, our scaling factor shows a more distinct transition from enhanced signal due to increased contact area to extra signal due to water content at maximum contact area. Band fit analysis of hydrated skin stratum corneum ATR-FTIR spectra offers the possibility for quantitative determination of individual water band parameters. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015081 TI - Noncontact MMG Sensor Based on the Optical Feedback Effect in a Laser Diode. AB - An optical interferometric MMG sensor is presented. It uses the feedback effect in a laser diode to measure the vibration generated by the MMG at the skin surface. Its key features are noncontact measurement, high sensitivity, and extended bandwidth toward low frequencies (~1 Hz). Furthermore, as it is able to recover with a good accuracy the shape of vibrations ranging from 1 MUm peak-to peak, the MMG is expressed in the physiological unit (micrometer) rather than the sensor dependent unit. The MMG measurement conditions are reviewed through a clinical protocol, including the perturbation causes. This probe is compared with a classical microphone based sensor, and thereby the influence of the coupling between the muscle and a contact sensor is demonstrated. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015082 TI - Evaluation of the silicon phthalocyanine pc 4 for photodynamic bone marrow purging. AB - The silicon phthalocyanine Pc 4 was tested as a photosensitizer for the selective photoinactivation of malignant cells in bone marrow transplantation samples. Using a murine model system, incubation of 1.5*107 cells/mL with 15 nM Pc 4 followed by exposure to red light (lambda>600 nm, fluence of 18 J/cm2) was shown to result in a greater than 6 log10 reduction of the clonogenic growth for the murine cell lines ABE-8.1/2, BC3A and L1210. The clonogenic growth of WEHI-3 and P815 cells was reduced by more than 5 log10 and more than 3 log10, respectively. Late murine hematopoietic progenitor cells were less sensitive than cancer cells; the surviving fractions were 0.084 for the colony forming unit, megakaryocyte (CFU-Mk); 0.038 for the colony forming unit, granulocyte macrophage (CFU-GM); 0.0018 for the colony forming unit, mix (CFU-mix) and <0.003 for burst forming units, erythroid (BFU-E). Early hematopoietic progenitor cells, assayed by the in vitro cobble stone area forming cell assay, were not affected by the photodynamic treatment. Likewise, in vivo assays of early hematopoietic progenitor cells showed no reduction of their ability to repopulate the bone marrow. Irradiation of the samples following incubation of 1.5*106 cells/mL with Pc 4 resulted in increased photosensitivity of all cell types, including the early and late hematopoietic progenitor cells. Flow cytometric analysis of Pc 4 uptake by the cells revealed that the increased photosensitivity could be traced to increased Pc 4 uptake; however, Pc 4 uptake among cell types did not correlate with photosensitivity. When mixed with bone marrow (BM) cells, Pc 4 uptake in the cell lines increased as the fraction of BM increased from 0.5 to 0.95. These observations suggest that Pc 4 may be a suitable photosensitizer for bone marrow purging. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015083 TI - Oxygen Saturation Measurements of Blood in Retinal Vessels during Blood Loss. AB - We describe a noninvasive technique and instrumentation for measuring the oxygen saturation of blood in retinal arteries and veins. The measurements are made by shining low-power lasers into the eye, and scanning the beams across a retinal blood vessel. The light reflected and scattered back out of the eye is collected and measured. The oxygen saturation of blood within the vessel is determined by analyzing the vessel absorption profiles at two wavelengths. A complete saturation measurement can be made in less than 1 s, allowing real-time measurement during physiologic changes. The sensitivity of this measurement technique to changes in retinal saturation has been demonstrated through a series of pilot studies in anesthetized swine. We present data indicating that retinal venous oxygen saturation decreases during ongoing blood loss, demonstrating a potential application of an eye oximeter to noninvasively monitor blood loss. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015084 TI - Computer-assisted intra-operative magnetic resonance imaging monitoring of interstitial laser therapy in the brain: a case report. AB - Hardware and software for a customized system to use magnetic resonance imaging (MRI) to noninvasively monitor laser-induced interstitial thermal therapy of brain tumors are reported. An open-configuration interventional MRI unit was used to guide optical fiber placement and monitor the deposition of laser energy into the targeted lesion. T1-weighted fast spin echo and gradient echo images were used to monitor the laser tissue interaction. The images were transferred from the MRI scanner to a customized research workstation and were processed intraoperatively. Newly developed software enabled rapid (27-221 ms) availability of calculated images. A case report is given showing images which reveal the laser-tissue interaction. The system design is feasible for on-line monitoring of interstitial laser therapy. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015085 TI - Prelytic stimulation of target and effector cells following conjugation as measured by intracellular fluorescein fluorescence polarization. AB - The aim of the present study was to detect prelytic intracellular changes induced in target and effector cells following their conjugation at room temperature. Changes in the cytoplasmic matrix were measured by means of intracellular fluorescein fluorescence polarization (IFFP) using the Cellscan apparatus. Both natural killer and lymphocyte activated killer cells were used as effector cells, while K562 and Daudi cell lines were used as targets. The results show that following their conjugation, both the effector and the target cells show significant reductions (>10%) in IFFP values. Changes in IFFP were induced by specific interaction and only between viable cells. No evidence of fluorescein transfer from a stained cell to its nonstained counterpart was found. To the best of our knowledge, this is the first time that effector-target interaction is monitored on an individual cell basis within a population, by means of IFFP measurements. In addition, in order to explain the physical phenomena, measurements of physical parameters which might affect the IFFP, such as changes in osmolality and pH, were performed and discussed. (c) 1998 Society of Photo Optical Instrumentation Engineers. PMID- 23015086 TI - Articular Cartilage Optical Properties in the Spectral Range 300-850 nm. AB - Measurements of absolute total reflectance were recorded from weight-bearing (n=9) and nonweight-bearing (n=9) equine articular cartilage specimens from 300 to 850 nm using a spectrophotometer with integrating sphere attachment. Following correction of measured spectra for interfacial reflections and edge losses, Kubelka-Munk theory was applied to estimate absorption and scattering coefficient, one-dimensional light intensity distribution, and light penetration depth. Kubelka-Munk absorption coefficients ranged from ~7 cm-1 at 330 nm to ~1 cm-1 at 850 nm. A localized absorption peak was noted at ~340 nm. Above 510 nm, weight-bearing cartilage demonstrated significantly higher absorption coefficients than nonweight-bearing tissue (paired t-test, p<0.05). Kubelka-Munk scattering coefficients ranged from ~40 cm-1 at 360 nm to ~6 cm-1 at 850 nm. No statistical differences in scattering coefficient were noted between weight bearing and nonweight-bearing tissue. Penetration depths predicted by Kubelka Munk theory ranged from 0.6 mm at 350 nm to over 3 mm at 850 nm. Stronger absorption in weight-bearing cartilage compared to nonweight-bearing tissue resulted in lower light penetration depths in weight-bearing cartilage at all wavelengths longer than 510 nm. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015087 TI - Single fiber laser-Doppler flowmetry-dependence on wavelength and tip optics. AB - Single fiber, laser-Doppler flowmetry can be used for blood flow measurement in deeply located tissue structures by the insertion of optical fibers into the tissue. The geometry of the monitored volume has been estimated at two different wavelengths and when using two types of fiber tips, one of which has been modified with a lens formed at the fiber end surface. Physical models as well as intramuscular measurements have been used in the experiments. The scattering image was studied in latex solutions of three different scatterer concentrations. The wavelengths 632.8 and 750 nm were used. At higher concentrations of scatterers, the near infrared (NIR) wavelength gave a larger scattering area. At the lower concentration, the difference between the areas was smaller or nonexistent. The NIR wavelength also showed an increased monitoring depth than that of the He-Ne laser in an experimental model study. The properties of the tip optics were evaluated in a flow-through model where the distance between the fiber tips and the flow channel was varied. The flat tip fiber has a sensitivity maximum close to its end surface, whereas the modified fiber ("pear" tip) showed a sensitivity maximum 1.5 mm from the end surface. This property may decrease the influence caused by the insertion trauma in intramuscular measurements. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015088 TI - Noninvasive fluorescence detection of hepatic and renal function. AB - A noninvasive in vivo fluorescence detection scheme was employed to continuously monitor exogenous dye clearance from the vasculature. Differentiation between normal and impaired physiological function in a rat model was demonstrated for both liver and kidney. A fiber optic transmitted light from source to ear; a second fiber optic positioned near the ear transmitted the fluorescent light to a detector system. Two model dye systems were employed in this initial study. Indocyanine green, known to be exclusively cleared from the blood stream by the liver, was excited in vivo with laser light at 780 nm. The fluorescence signal was detected at 830 nm. A characteristic clearance curve of normal hepatic function was obtained. After a partial hepatectomy of the liver, the clearance curve was extended in time, as would be expected from reduced hepatic function. In addition, fluorescein labeled poly-D-lysine, a small polymer predominantly cleared from the blood stream by the kidney, was excited in vivo with laser light at 488 nm. The fluorescence signal was detected at 518 nm. A characteristic clearance curve of normal renal function was obtained. After a bilateral ligation of the kidneys, the clearance curve remained elevated and constant, indicating little if any clearance. Thus, the feasibility of a new noninvasive method for physiological function assessment was established. (c) 1998 Society of Photo Optical Instrumentation Engineers. PMID- 23015089 TI - Metal Ion Quenching Kinetics of DTDCI in Viscous Solution and Nafion Membranes: Model System for Near Infrared Fluorescence Sensing. AB - Forster type energy transfer offers opportunities as a sensitive and frequently selective method of monitoring the concentration of analytes in medical sensing applications. However, the fluorescence quenching kinetics observed in microheterogeneous media such as tissue are likely to be less than ideal. In the present article, the quenching kinetics of the carbocyanine dye DTDCI by transition metal ions in solutions and in the microheterogeneous polymer Nafion (a registered trademark of Dupont Corporation) are reported and compared with a view to understanding the complex fluorescence kinetics likely to be encountered in biological media. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015090 TI - Diabetic retinopathy assessed by dynamic light scattering and corneal autofluorescence. AB - Autofluorescence of the cornea within specific wavelength region and dynamic light scattering measurements of ocular tissue have both been used for early stage detection of the presence of diabetic retinopathy. In the present study, autofluorescence of the cornea and dynamic light scattering in the cornea and vitreous have been measured and compared using two innovative research instruments in twenty-two insulin-dependent diabetes mellitus patients, for the diagnosis of diabetic retinopathy. Corneal autofluorescence mean values in each diabetic retinopathy grade significantly correlated with dynamic light scattering measurements in the vitreous, and in the cornea, thus confirming that changes in the natural fluorescence is strictly correlated with molecular changes of ocular tissues. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015091 TI - Scattering of light by a red blood cell. AB - The optical parameters of a red blood cell suspended in the blood plasma and, namely, the scattering and absorption cross sections and the scattering phase function describing the small-angle distribution of the scattered light are calculated. Dependence of the optical parameters on all possible values of size, shapes, orientations, hemoglobin concentration, and oxygenation degree is considered. The data are calculated with the so-called straight-ray approximation. The accuracy of the approximation is estimated by comparison with the Mie theory. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015092 TI - Color correction of the video image obtained by angioscope. AB - In this article, a simple color correction method for the color reproduction of image obtained by angioscope is reported. We present the method to obtain the matrices theoretically and experimentally, respectively. For the angioscope system, we suggest two matrices: an average color correction matrix A and a blood vessel color correction matrix A'. Using the two matrices, the images of several color samples captured by an angioscope are processed, and their reproduced colors are evaluated. With this method, the discrimination ability of the angioscope will be improved dramatically. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015093 TI - Internal fixation of fractures of the proximal humerus with the MultiLoc nail. AB - OBJECTIVE: Anatomical reduction of two- to four-part fractures of the proximal humerus using indirect reduction techniques. Intramedullary fixation with a short humerus nail. Restoration of a stable bone-implant construct that enables early functional after-treatment. INDICATIONS: Displaced and unstable two- to four-part fractures of the proximal humerus. Fractures of the proximal humerus extending in the humeral diaphysis (use a long nail). Ipsilateral combined lesions of the proximal humerus and the humeral diaphysis (use a long nail). CONTRAINDICATIONS: Poor physical and/or mental status. Critical soft tissue conditions in the area near the surgical site. Local soft tissue infection. Pre-existing severe osteoarthritis of the shoulder joint; severe shoulder stiffness. Head-split fractures of the humerus head that cannot be reduced. SURGICAL TECHNIQUE: Exposure of the fracture using an anterior acromial approach and determination of the correct nail entrance point. Anatomic fracture reduction using indirect reduction techniques. Stable fixation using an intramedullary MultiLoc(r) nail. Determination of the proximal locking configuration depending on the fracture morphology. Distal locking with angle-stable option. POST-OPERATIVE TREATMENT: Post-operative radiographs for documentation of the surgical result and implant position. Use of an arm sling for 7-10 days. Active and passive exercises of the shoulder joint starting on day 1. Shoulder abduction limited to 60 degrees for 2 weeks. Subsequent abduction to 90 degrees until the 4th week. Subsequent active mobilisation without restrictions. Weight bearing and sporting activities after 3 months. Radiological evaluation after 2, 6 and 12 weeks. RESULTS: During a 6 month period, 160 patients were documented in a prospective clinical multicentre study. According to the AO classification, there were 36% A-type fractures, 41% B and 23% C-type injuries. A 6-month follow-up was available for 17 patients. The mean age of these patients was 67 years. One patient had an A-type fracture. There were ten B- and six C-type fractures. At the time of follow-up, the mean Constant score was 66 points. Radiographically, all fractures had healed. Intra articular screw penetration and loss of reduction were both observed once. PMID- 23015094 TI - [Minimally invasive osteosynthesis of pilon fractures]. AB - OBJECTIVE: The primary aim of minimally invasive osteosynthesis (MIO) is the anatomical reconstruction of the distal tibial articular surface, with preservation of the soft tissue to allow early functional postoperative management. This should lead to a normal bone healing and recovery without arthrosis. INDICATIONS: Fractures type Ruedi I + II or AO 43-B1, -B2, AO 43-C1, C2, rare and relative indications are fractures of type AO 43-B3 and -C3 fractures without IIb and III degrees soft tissue injuries. It may also be used as an additional technique for osteosynthesis with external fixators. CONTRAINDICATIONS: Severe comminuted fractures of the pilon with closed or open II and III degrees soft tissue damage. Severe soft tissue damage (III degrees ). SURGICAL TECHNIQUE: An intensive preoperative analysis of conventional X-rays and CT images is necessary to support the indication for MIO of pilon fractures. The first step is reduction of the fracture with axial traction, in some cases with a distractor or external fixator. The definitive reduction is performed with K-wire joysticks or reduction clamps. The key step is the intraoperative X-ray control of the reduction in various planes, if possible with 3D reconstruction. An alternative is also arthroscopic control of the articular reduction. All manipulations are performed via small incisions. After incision of the skin, all layers of soft tissue are smoothly divided with scissors allowing the soft tissue including vessels and nerves to be moved out of the working channel. All instruments and implants (e.g., K-wires, drill sleeve, screws) are introduced between the opened scissor branches. After lag screw osteosynthesis with 3.5 or 4.5 mm conventional screws, the articular block is reduced to the diaphysis and fixed with a minimally invasively inserted plate. Under X-ray control in two planes, the plate is adjusted into position and preliminarily fixed with K-wires. The screws are inserted using the minimally invasive technique. POSTOPERATIVE MANAGEMENT: Immediate mobilization starting on day 1 with partial weight bearing (sole contact or 12-15 kg) for 4-6 weeks, postoperative protection with orthesis or split cast for 2-5 days depending on degree of swelling, early functional physiotherapy, thrombosis prophylaxis with heparin until complete mobilization. Full weight-bearing depending on fracture type after 6-8 weeks. RESULTS: Advantages of minimally invasive osteosynthesis of pilon fractures compared to conventional open reduction and osteosynthesis, include protection of the soft tissue and no further disturbances of circulation-ideal prerequisites for undisturbed bone healing. In 129 patients after osteosynthesis of pilon fracture, no reoperations were necessary when using MIO, but reoperation was necessary with other techniques in 17.6% of all patients. In addition, no infections were observed with MIO vs. 13.4% of patients with other techniques. The average Olerud/Molander Score was 95 points for the MIO group vs. 58.91 points for all patients treated, while MIO plus an external fixator received a score of 50 points. The average Ankle Hindfoot Score was 64.9 points, for MIO 87.5 points, and for operations consisting of MIO plus an external fixator 58 points. PMID- 23015095 TI - The prognostic value of IDH mutations and MGMT promoter status in secondary high grade gliomas. AB - Reports about the prognostic value of IDH mutations and the promoter region of the O6-Methyl-guanyl-methyl-transferase gene in secondary high-grade gliomas (sHGG) are few in number. We investigated the prognostic value of IDH mutations and methylation of the promoter region of the MGMT gene in 99 patients with sHGG and analyzed the clinical course of those tumors. Patients with sHGG were screened for IDH mutations by direct sequencing, and, for promoter status of MGMT gene, by the methylation-specific polymerase chain reaction. A total of 48 of 99 patients (48.5 %) had secondary anaplastic gliomas (Group 1), while 51 patients had secondary glioblastomas (Group 2). The median survival time after malignant progression of all patients with sHGG and with an IDH mutation was 4 years, which is significantly longer than in patients with wild-type IDH (1.2 years, p = 0.009). Patients' survival was not significantly influenced by the tumors' MGMT promoter status, both in Group 1- 9.7 years vs. 6.1 years, methylated vs. unmethylated promoter (p = 0.330)-as well as in Group 2-1.5 years vs. 1.6 years, methylated versus unmethylated promoter (p = 0.829). In our population, the IDH mutation status was not associated with increased PFS or median survival time in sGBM patients. However, patients with secondary anaplastic glioma and IDH mutation had a significantly improved outcome. In addition, IDH mutations are a more powerful prognostic marker concerning both PFS and MS than the MGMT promoter status in those patients. PMID- 23015096 TI - Somatic mosaicism in TPM2-related myopathy with nemaline rods and cap structures. PMID- 23015097 TI - Managing the after effects of serious patient safety incidents in the NHS: an online survey study. AB - OBJECTIVE: To examine the current state of practice in English NHS Trusts in relation to the communication of serious patient safety incidents to patients and families and support for all parties involved. DESIGN: Cross-sectional design using online surveys. PARTICIPANTS: 209 patient safety managers, responsible for the 'Being Open' policy (54% response rate). SETTING: English NHS Trusts. RESULTS: 98% of the participants reported that they are familiar with the National Patient Safety Agency Being Open guidance and 82% that they implement it more than half the time when incidents occur. However, provision of timely information was not reported as routine, with two-thirds of the discussions taking place 3-6 months [corrected] after the investigation. The frequency of taking responsibility for harm was low for incidents of different severity levels but significantly lower for less serious ones (p<0.001). Follow-ups of patients in the long term and ex gratia payments were provided less than half the time. The most highly rated barriers to being open were clinical staff's fear of negative reactions from patients or their families and anxiety about litigation. Support practices for staff, such as debriefing and training on being open, were acknowledged as highly important but not always available. CONCLUSIONS: Awareness of the importance of being open is high among patient safety managers in English NHS Trusts, but there is still considerable scope for improvement in the management of the after effects of patient safety incidents. More research is needed on patients' and healthcare professionals' preferences for support after patient safety incidents. PMID- 23015098 TI - Method for developing national quality indicators based on manual data extraction from medical records. AB - Developing quality indicators (QI) for national purposes (eg, public disclosure, paying-for-performance) highlights the need to find accessible and reliable data sources for collecting standardised data. The most accurate and reliable data source for collecting clinical and organisational information still remains the medical record. Data collection from electronic medical records (EMR) would be far less burdensome than from paper medical records (PMR). However, the development of EMRs is costly and has suffered from low rates of adoption and barriers of usability even in developed countries. Currently, methods for producing national QIs based on the medical record rely on manual extraction from PMRs. We propose and illustrate such a method. These QIs display feasibility, reliability and discriminative power, and can be used to compare hospitals. They have been implemented nationwide in France since 2006. The method used to develop these QIs could be adapted for use in large-scale programmes of hospital regulation in other, including developing, countries. PMID- 23015099 TI - Improving polyhydroxyalkanoate production by knocking out the genes involved in exopolysaccharide biosynthesis in Haloferax mediterranei. AB - Haloferax mediterranei is capable of producing large amounts of poly(3 hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) from many kinds of carbon sources, with exopolysaccharide (EPS) as a by-product. In this study, we identified a gene cluster involved in EPS biosynthesis in H. mediterranei. Knocking out the genes in this cluster encoding the putative UDP-N-acetylglucosamine 6-dehydrogenase (HFX_2145), glycosyltransferases (HFX_2146 and HFX_2147) and polysaccharide transporter (HFX_2148) eliminated EPS synthesis. The deficiency in EPS biosynthesis in the mutant strain remarkably decreased the viscosity of culture broth, and hence increased the dissolved oxygen content and decreased the foaming propensity. Compared with the wild-type (WT) strain, the PHBV production of the EPS-mutant strain was significantly enhanced (approximately 20%), whereas the cell growth rate remained similar under the same culture conditions. These results indicated that the carbon sources used for synthesizing EPS were shifted to PHBV production. Thus, a novel engineered H. mediterranei strain was developed, which would be favorable for future industrial production of PHBV. PMID- 23015100 TI - Use of uridine auxotrophy (ura3) for markerless transformation of the mycoinsecticide Beauveria bassiana. AB - Genetic engineering offers a practical route for enhancing the insect biological control potential of entomopathogenic fungi such as Beauveria bassiana. To date, however, such efforts have relied upon transformation protocols that utilize antibiotic or herbicidal resistance markers as selection agents for the introduction of genes into the fungus. In order to avoid the use of such markers for the development of field-usable fungal strains, a markerless transformation system based upon complementation of uridine auxotrophy was developed. A targeted gene deletion knockout of orotidine 5'-phosphate decarboxylase (ura3) was isolated using a positive screening protocol with 5'-fluoro-orotate. Although growth was restored when the mutant, DeltaBbura3, was grown in the presence of exogenous uridine, conidiation remained impaired and conidial yield was reduced. Insect bioassays revealed that the DeltaBbura3 strain was essentially avirulent using both topical and intrahemocoel injection assays, indicating that the deletion mutant was unable to scavenge uridine from the host during infection. A series of plasmid constructs were developed for complementation of the ura3 mutant, and complemented strains were restored to wild-type growth and virulence. These data indicate that the ura3 mutant and corresponding complementation vectors can be used to construct markerless strains for the bioengineering of desired traits in B. bassiana. PMID- 23015102 TI - Discovery of potent inhibitors for interleukin-2-inducible T-cell kinase: structure-based virtual screening and molecular dynamics simulation approaches. AB - In our study, a structure-based virtual screening study was conducted to identify potent ITK inhibitors, as ITK is considered to play an important role in the treatment of inflammatory diseases. We developed a structure-based pharmacophore model using the crystal structure (PDB ID: 3MJ2) of ITK complexed with BMS-50944. The most predictive model, SB-Hypo1, consisted of six features: three hydrogen bond acceptors (HBA), one hydrogen-bond donor (HBD), one ring aromatic (RA), and one hydrophobic (HY). The statistical significance of SB-Hypo1 was validated using wide range of test set molecules and a decoy set. The resulting well validated model could then be confidently used as a 3D query to screen for drug like molecules in a database, in order to retrieve new chemical scaffolds that may be potent ITK inhibitors. The hits retrieved from this search were filtered based on the maximum fit value, drug-likeness, and ADMET properties, and the hits that were retained were used in a molecular docking study to find the binding mode and molecular interactions with crucial residues at the active site of the protein. These hits were then fed into a molecular dynamics simulation to study the flexibility of the activation loop of ITK upon ligand binding. This combination of methodologies is a valuable tool for identifying structurally diverse molecules with desired biological activities, and for designing new classes of selective ITK inhibitors. PMID- 23015104 TI - BMA consults GMC about cash incentives to GPs to cut patient care. PMID- 23015103 TI - Quantum chemistry studies of the catalysis mechanism differences between the two isoforms of glutamic acid decarboxylase. AB - The production of gamma-aminobutyric acid (GABA) is catalyzed by two isoforms of glutamic acid decarboxylase (GAD), using pyridoxal 5'-phosphate (PLP) as the cofactor. Between the two enzymes, GAD67 accounts for normal GABA requirement, while GAD65 stays inactive until emergent demand for GABA. Recent crystal structure findings revealed that the distinct conformation of a common catalytic loop of the enzymes may account for their different functions (Fenalti et al Nat Struct Mol Biol, 14:280-286, 2007). Enlightened by their inferences, we studied the underlying reaction mechanism of the two GAD isoforms using density functional theory (DFT). A rather complete reaction pathway is identified, including nine transition state (TS) structures and 14 intermediate (IM) structures. The rate limiting step occurs early during the reaction and involves a proton transfer. In the late stage, there are two pathways that involve C(4') and C(alpha) protonation by Tyr or Lys. Our calculations show that the reaction barriers corroborate the conjecture made by Fenalti et al. PMID- 23015105 TI - Paediatric cardiologist is found guilty of sexually motivated behaviour towards boys. PMID- 23015107 TI - Inversion of selectivity in anion recognition with conformationally blocked calix[4]pyrroles. AB - Two calixpyrrole derivatives were synthesised. A p-dimethylaminobenzoyl group was electronically attached to a pyrrole ring, establishing an intramolecular hydrogen bond in a 1,3-alternate conformation. The formation of the H-bond was corroborated by IR, NMR, and X-ray measurements. NMR titration studies reveal that the H-bond is strong enough to block the conversion to a cone conformation, allowing them to only acquire a partial cone conformation. Affinity constants for several anions were calculated, and a noticeable increase was observed for tridentate tetrahedral anions, while the K(a) of spheric or bidentate anions decreased. In the presence of several acids, the synthesised compounds can act as chemosensors by a double process: protonation of the amino group and coordination of the generated anion. In addition, a displacement approach gives rise to a proof of concept for sulphonate recognition. PMID- 23015108 TI - Intravenous infusion of hyperosmotic NaCl solution induces acute cor pulmonale in anesthetized rats. AB - Intravenous hyperosmotic NaCl infusion is an effective treatment for circulatory shock. However, a fast infusion rate (2 mL/kg at the rate of 1 mL/s) induces transient hypotension. This response has been reported to be due to decreased total peripheral resistance and/or decreased cardiac performance. Although the hypotension is transient and recovers within 2 min without detrimental consequences, it is important to understand the associated hemodynamics and mechanisms. We found that the hypotensive effect was larger with intravenous NaCl infusion than with intra-aortic infusion, indicating that change in cardiac performance played a more significant role than change in peripheral resistance. NaCl infusion induced an increase in pulmonary vascular resistance and central venous pressure and a decrease in right ventricular dP/dt max, suggesting acute cor pulmonale. Diastolic ventricular crosstalk-induced left ventricular failure was also observed. Hyperosmotic NaCl-induced hypotension was therefore mainly due to a combination of acute cor pulmonale and left ventricular failure. PMID- 23015109 TI - Emotion recognition and visual-scan paths in Fragile X syndrome. AB - This study investigated emotion recognition abilities and visual scanning of emotional faces in 16 Fragile X syndrome (FXS) individuals compared to 16 chronological-age and 16 mental-age matched controls. The relationships between emotion recognition, visual scan-paths and symptoms of social anxiety, schizotypy and autism were also explored. Results indicated that, compared to both control groups, the FXS group displayed specific emotion recognition deficits for angry and neutral (but not happy or fearful) facial expressions. Despite these evident emotion recognition deficits, the visual scanning of emotional faces was found to be at developmentally appropriate levels in the FXS group. Significant relationships were also observed between visual scan-paths, emotion recognition performance and symptomology in the FXS group. PMID- 23015110 TI - A comparison of social cognitive profiles in children with autism spectrum disorders and attention-deficit/hyperactivity disorder: a matter of quantitative but not qualitative difference? AB - The aim of this study was to compare social cognitive profiles of children and adolescents with Autism Spectrum Disorders (ASD) and ADHD. Participants diagnosed with an ASD (n = 137) were compared to participants with ADHD (n = 436) on tests of facial and vocal affect recognition, social judgment and problem-solving, and parent- and teacher-report of social functioning. Both groups performed significantly worse than the normative sample on all measures. Although the ASD group had more severe deficits, the pattern of deficits was surprisingly similar between groups, suggesting that social cognitive deficit patterns may be more similar in ASD and ADHD than previously thought. Thus, like those with ASDs, individuals with ADHD may also need to be routinely considered for treatments targeting social skills. PMID- 23015111 TI - The French version of the autism-spectrum quotient in adolescents: a cross cultural validation study. AB - We assessed the accuracy of the French version of the Autism Spectrum Quotient (AQ) in adolescents with Asperger syndrome (AS) and high-functioning autism (HFA) compared to healthy controls and adolescents with psychiatric disorders (PDs). Three groups of adolescents, aged 11-18, were assessed: 116 with AS/HFA (93 with IQ >= 85 and 20 with 70 <= IQ < 85), 39 with other PDs, and 199 healthy controls. The AS/HFA group scored significantly higher than the healthy control and PD groups. A cut-off score of 26 was used to differentiate the autism group from healthy controls with 0.89 sensitivity and 0.98 specificity. Scores did not vary by age or sex. PMID- 23015112 TI - Brief report: altered social behavior in isolation-reared Fmr1 knockout mice. AB - Social behavior abnormalities in Fragile X syndrome (FXS) are characterized by social withdrawal, anxiety, and deficits in social cognition. To assess these deficits, a model of FXS, the Fmr1 knockout mouse (Fmr1 KO), has been utilized. This mouse model has a null mutation in the fragile X mental retardation 1 gene (Fmr1) and displays physical and behavioral characteristics similar to humans with FXS. Several studies have investigated the social behavior of this model, but the results on the behavioral phenotype have not been consistent. In order to further characterize the social behavior in the knockout, isolation-reared Fmr1 KO were evaluated to determine if they differ in their social behavior compared to wild-type littermate controls. Differences by genotype were not observed in social approach behavior; however, the knockout mice showed a significantly reduced preference for social novelty and decreased sniff time in the sociability phase. These findings add to the growing body of knowledge on the subtle differences in social behavior shown by the Fmr1 knockout mice, and that differences occur when the subjects are isolation-reared. Validity of the model and possible changes to methodology are discussed. PMID- 23015113 TI - Thrombus and antiplatelet therapy in type 2 diabetes mellitus. A prospective study after non-ST elevation acute coronary syndrome and a randomised, blinded, placebo-controlled study in stable angina. AB - Type 2 diabetes mellitus (T2DM) is associated with higher rates of thrombotic complications in patients with coronary artery disease (CAD) despite optimal medical therapy. Thrombus area was measured in T2DM and non-diabetic patients receiving aspirin and clopidogrel 7-10 days after troponin positive Non ST elevation acute coronary syndrome (NSTE-ACS). Secondly, we assessed response to clopidogrel in naive patients with T2DM and stable CAD in a randomised controlled trial. Thrombus area was measured by Badimon chamber and platelet reactivity by VerifyNow(r). In T2DM patients presenting with NSTE-ACS, thrombus area was greater compared to non-diabetic patients (mean +/- SD, 20,512 +/- 12,567 [n=40] vs. 14,769 +/- 8,531 [n=40] MUm2/mm, p=0.02) Clopidogrel decreased thrombus area among stable CAD patients with T2DM (mean +/- SD, Clopidogrel [n=45]: 13,978 +/- 5,502 to 11,192 +/- 3,764 MUm2/mm vs. placebo [n=45]: 13,959 +/- 7,038 to 14,201 +/- 6,780 MUm2/mm, p<0.001, delta values: clopidogrel vs. placebo, mean +/- SD, 2,786 +/- 4,561 vs. -249 +/- 2,478, p<0.0005). Only 44% of patients with CAD and T2DM responded to clopidogrel as per VerifyNow(r) (cut-off PRUz value of >= 240). Importantly, no correlation was observed between thrombus area and VerifyNow(r) values (rho 0.08, p=0.49). Thrombus area values were similar among hypo responders and good responders to clopidogrel (mean thrombus area +/- SD: 12,186 +/- 4,294 vs. 10,438 +/- 3,401; p=0.17). Type 2 diabetes mellitus is associated with an increased blood thrombogenicity among NSTE-ACS patients on currently recommended medical therapy. Thrombus area was significantly reduced in all stable CAD patients independently of their response to clopidogrel therapy. PMID- 23015114 TI - Applicability of the CATCH, CHALICE and PECARN paediatric head injury clinical decision rules: pilot data from a single Australian centre. AB - BACKGROUND: Clinical decision rules (CDRs) for paediatric head injury (HI) exist to identify children at risk of traumatic brain injury. Those of the highest quality are the Canadian assessment of tomography for childhood head injury (CATCH), Children's head injury algorithm for the prediction of important clinical events (CHALICE) and Pediatric Emergency Care Applied Research Network (PECARN) CDRs. They target different cohorts of children with HI and have not been compared in the same setting. We set out to quantify the proportion of children with HI to which each CDR was applicable. METHODS: Consecutive children presenting to an Australian paediatric Emergency Department with HIs were enrolled. Published inclusion/exclusion criteria and predictor variables from the CDRs were collected prospectively. Using these we determined the frequency with which each CDR was applicable. RESULTS: 1012 patients (69.9%) were enrolled with 949 available for analysis. Mean age was 6.8 years (21% <2 years). 95% had initial Glasgow Coma Scale 15. CT rate was 12.8% and neurosurgery rate was 0.7%. No CDR was applicable to all patients. CHALICE was applicable to the most (97%, 95% CI 96% to 98%) and CATCH to the fewest (26%, 95% CI 24% to 29%). PECARN was applicable to 76% (95% CI 70% to 82%) aged <2 years, and 74% (95% CI 71% to 77%) aged 2-<18 years. CONCLUSIONS: Each CDR is applicable to a different proportion of children with HI. This makes a direct comparison of the CDRs difficult. Prior to selection of any for implementation they should undergo validation outside the derivation setting coupled with an analysis of their performance accuracy, usability and cost effectiveness. PMID- 23015115 TI - Hyponatraemia in patients with crush syndrome during the Wenchuan earthquake. AB - BACKGROUND: Although sodium disturbances are common in hospitalised patients, no study has specifically investigated the epidemiology of hyponatraemia in patients with crush syndrome. OBJECTIVES: To describe the incidence of hyponatraemia and assess its effect on outcome in patients with crush syndrome during the Wenchuan earthquake. METHODS: A retrospective study was conducted in 17 reference hospitals during the Wenchuan earthquake. We excluded patients younger than 15 years and those with missing sodium values within 3 days after being rescued from the ruins. RESULTS: Hyponatraemia (serum sodium concentration <135 mmol/l) was seen in 91/180 (50.6%) patients on admission. Compared with patients with normonatraemia, those with hyponatraemia were younger, had more severe traumatic injury and renal failure, underwent more fasciotomies, received more blood transfusion and renal replacement therapy. In the multivariable-adjusted model, the number of extremity injuries (OR=1.59, 95% CI 1.08 to 2.33) and serum creatinine (OR=1.30, 95% CI 1.07 to 1.59) were independently associated with the occurrence of hyponatraemia. Covariate adjusted multiple logistic regression analysis showed an independent mortality risk rising with hyponatraemia (OR=5.74, 95% CI 1.18 to 28.00). CONCLUSIONS: Hyponatraemia was common in the patients with crush syndrome during the Wenchuan earthquake and associated with poor prognosis. Water, commercial drinks and hypotonic intravenous fluids should be supplied carefully to patients with crush syndrome. PMID- 23015116 TI - Residents' experiences in dealing with abuse in emergency department: a survey in Iran hospitals. AB - BACKGROUND: Abuse in Emergency Department (ED) as a widespread phenomenon, has negative effects on ED residents. This issue pertains to Western as well as Asian countries. OBJECTIVE: The purpose of this study was to assess how Iranian ED residents deal with abuse. Awareness, educational programmes, reports, causes of abuse and ways to reduce this were considered in this survey. METHOD: In 2011, a cross-section survey was conducted at seven ED residencies of central hospitals in Tehran, Mashhad, Ahwaz and Tabriz. ED residents were asked about their age, sex, abuse time, awareness of abuse, educational programmes, reporting abuse, causes of reluctance to report, and how to reduce abuse. The data were analysed by SPSS V.20. RESULTS: A total of 215 questionnaires were completed. Abuse was reported to have occurred most frequently during night shifts (n=89, 41.4%), and most of the residents were abused by men rather than women (n=132, 61% vs n=22, 10%, p<0.05). About half the residents (n=107, 49.8%) were not aware of any abuse. Only 22% (n=46) had formal or informal education in abuse, and 74% (n=158) of them had not gone through any learning programmes. Most residents (n=175, 81%) did not know how to report abuse, and among respondents, most of the residents did not report the abuse (n=86, 40%), and the cause was mostly the uncertainty towards officials being able to solve the problem of abuse (n=67, 38%). Residents most often reported not to admit patients more than the hospital's capacity as the main solution to reduce abuse (n=61, 32%). CONCLUSIONS: Being abused during residency is a universal problem, and there is a lack of awareness and the knowledge of how to deal with abuse, and reporting it among ED residents in Iranian hospitals. PMID- 23015117 TI - [Delays in the diagnosis and treatment of lung cancer for patients treated with radiation therapy]. AB - OBJECTIVE: To describe delays in diagnosis and treatment of lung cancer in patients treated by radiotherapy from the first abnormal imaging to the first day of treatment. PATIENTS AND METHODS: Our retrospective single-center study included all patients treated for primary lung cancer in our center receiving radiotherapy alone or in association to chemotherapy or surgery, between 1st May and 15th September 2011. RESULTS: We included 40 patients. Mean age was 65.3 years and sex ratio was 4 (32 males). In 72.5% (n = 29) of the cases, the objective of the treatment was palliative. Median delay between the first abnormal imaging to the first day of treatment was 75.5 days (CI 95% [63.6 134.4]). Median diagnostic delay to obtain a pathological proof was 38 days (CI 95% [27.9-100]). Median therapeutic delay to start treatment was 31 days (CI 95% [24.6-38.5]). When considering radiotherapy, median delay between multidisciplinary staff decision and first radiotherapy session was 26 days (CI 95% [22.4-33.3]). CONCLUSION: The study of the delays in diagnosis and treatment is the first step to reduce them. Detailed analysis helps to propose some measures to improve these delays. PMID- 23015118 TI - Langmuir polymer films: recent results and new perspectives. AB - Langmuir polymer films (LPFs) are very interesting systems to probe quasi-two dimensional dynamics. Although adsorbed on water, the substrate is fluid enough to avoid irreversible pinning at adsorption sites, as with solid substrates. LPFs in dense states can exhibit a high degree of metastability, however reproducible measurements can be performed on films which have not been previously compressed. The shear rheology is one of the most active fields of research, especially because it allows investigation of flow behaviour in LPFs, thus of possible reptation motion in semidilute films under good solvent conditions. It also allows probing glassy behaviour in dense films under poor solvent conditions. In this perspective article, we review the recent literature and discuss unpublished results on the dynamics of the glass transition, recently observed in these quasi 2D systems at low temperatures. We conclude by listing new problems and open questions emerging from this research area. PMID- 23015119 TI - Report of breakout session: Coxa profunda/protrusio management. PMID- 23015122 TI - Increased COMT expression in pancreatic cancer and correlation with clinicopathologic parameters. AB - Catechol-O-methyl transferase (COMT) is an enzyme involved in estrogen metabolism. Proteomic and immunoproteomic screens suggested COMT might be an immunogenic membrane antigen in human pancreatic cancer. The aim of this study was to investigate the dynamic expression of COMT in pancreatic ductal adenocarcinoma (PDAC) and noncancerous pancreatic tissue, and to determine the relationship between COMT expression and clinicopathologic parameters. COMT expression was analyzed by reverse transcription-polymerase chain reaction (RT PCR) and western blot in five pancreatic cell lines and five pairs of PDAC and noncancerous pancreatic tissue. Immunohistochemistry was used to evaluate COMT expression in tissue microarrays and 20 cases of paraffin-embedded clinical specimens. The results indicated that COMT expression was detected in AsPC-1, BxPC-3, MIA PaCa-2, Capan-1 and SW1990 pancreatic cell lines, and in five pairs of PDAC and noncancerous pancreatic tissue, at the mRNA and protein levels. Immunohistochemistry analysis revealed that COMT expression was significantly higher in PDAC than in nonmalignant pancreatic tissue. High expression of COMT significantly correlated to early T stages. Therefore, we conclude that COMT might serve as a potential biomarker for applied clinical pathology in PDAC. PMID- 23015123 TI - Ion channels/transporters as epigenetic regulators? -a microRNA perspective. AB - MicroRNA (miRNA) alterations in response to changes in an extracellular microenvironment have been observed and considered as one of the major mechanisms for epigenetic modifications of the cell. While enormous efforts have been made in the understanding of the role of miRNAs in regulating cellular responses to the microenvironment, the mechanistic insight into how extracellular signals can be transduced into miRNA alterations in cells is still lacking. Interestingly, recent studies have shown that ion channels/transporters, which are known to conduct or transport ions across the cell membrane, also exhibit changes in levels of expression and activities in response to changes of extracellular microenvironment. More importantly, alterations in expression and function of ion channels/transporters have been shown to result in changes in miRNAs that are known to change in response to alteration of the microenvironment. In this review, we aim to summarize the recent data demonstrating the ability of ion channels/transporters to transduce extracellular signals into miRNA changes and propose a potential link between cells and their microenvironment through ion channels/transporters. At the same time, we hope to provide new insights into epigenetic regulatory mechanisms underlying a number of physiological and pathological processes, including embryo development and cancer metastasis. PMID- 23015121 TI - Changing distributions of ticks: causes and consequences. AB - Today, we are witnessing changes in the spatial distribution and abundance of many species, including ticks and their associated pathogens. Evidence that these changes are primarily due to climate change, habitat modifications, and the globalisation of human activities are accumulating. Changes in the distribution of ticks and their invasion into new regions can have numerous consequences including modifications in their ecological characteristics and those of endemic species, impacts on the dynamics of local host populations and the emergence of human and livestock disease. Here, we review the principal causes for distributional shifts in tick populations and their consequences in terms of the ecological attributes of the species in question (i.e. phenotypic and genetic responses), pathogen transmission and disease epidemiology. We also describe different methodological approaches currently used to assess and predict such changes and their consequences. We finish with a discussion of new research avenues to develop in order to improve our understanding of these host-vector pathogen interactions in the context of a changing world. PMID- 23015124 TI - Cyprinid phylogeny based on Bayesian and maximum likelihood analyses of partitioned data: implications for Cyprinidae systematics. AB - Cyprinidae is the biggest family of freshwater fish, but the phylogenetic relationships among its higher-level taxa are not yet fully resolved. In this study, we used the nuclear recombination activating gene 2 and the mitochondrial 16S ribosomal RNA and cytochrome b genes to reconstruct cyprinid phylogeny. Our aims were to (i) demonstrate the effects of partitioned phylogenetic analyses on phylogeny reconstruction of cyprinid fishes; (ii) provide new insights into the phylogeny of cyprinids. Our study indicated that unpartitioned strategy was optimal for our analyses; partitioned analyses did not provide better-resolved or -supported estimates of cyprinid phylogeny. Bayesian analyses support the following relationships among the major monophyletic groups within Cyprinidae: (Cyprininae, Labeoninae), ((Acheilognathinae, ((Leuciscinae, Tincinae), Gobioninae)), Xenocyprininae). The placement of Danioninae was poorly resolved. Estimates of divergence dates within the family showed that radiation of the major cyprinid groups occurred during the Late Oligocene through the Late Miocene. Our phylogenetic analyses improved our understanding of the evolutionary history of this important fish family. PMID- 23015125 TI - Total body irradiation of donors can alter the course of tolerance and induce acute rejection in a spontaneous tolerance rat liver transplantation model. AB - Liver transplantation is an established therapy for end-stage liver diseases. Graft rejection occurs unless the recipient receives immunosuppression after transplantation. This study aimed to explore the mechanism of acute rejection of liver allografts in rats pre-treated with total body irradiation to eliminate passenger lymphocytes and to define the role of CD4(+)CD25(+) regulatory T cells in the induction of immunotolerance in the recipient. Male Lewis rats were used as donors and male DA rats were recipients. Rats were randomly assigned to the following four groups: control group, homogeneity liver transplantation group, idio-immunotolerance group and acute rejection group. After transplantation, the survival time of each group, serum alanine aminotransferase, total bilirubin levels, number of Foxp3(+)CD4(+)CD25(+) regulatory T cells, expression of glucocorticoid-induced tumor necrosis factor receptor on T cell subgroups, histopathology of the hepatic graft and spleen cytotoxic T lymphocyte lytic activity were measured. In the acute rejection group, where donors were preconditioned with total body irradiation before liver transplantation, all recipients died between day 17 and day 21. On day 14, serum alanine aminotransferase increased significantly to (459.2+/-76.9) U L(-1), total bilirubin increased to (124.1+/-33.7) MUmol L(-1) (P<0.05) and the ratio of Foxp3(+)CD4(+)CD25(+) regulatory T cells decreased significantly to 1.50%+/-0.50% (P<0.05) compared with the other groups. Analysis of the T cell subpopulations in the acute rejection group varied from the other groups. Histological analysis showed typical changes of acute rejection in the acute rejection group only. Preconditioning of the donors with total body irradiation eliminated passenger lymphocytes of the liver graft, and thus affected the course of tolerance and induced acute rejection after liver transplantation. PMID- 23015126 TI - An in vivo study with an MRI tracer method reveals the biophysical properties of interstitial fluid in the rat brain. AB - The nature of brain interstitial fluid (ISF) has long been a subject of controversy. Most of the previous studies on brain ISF were carried out in vitro. In the present study, a novel method was developed to characterize ISF in the living rat brain by magnetic resonance (MR) imaging using gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) as a tracer. Sprague Dawley rats (n=8) were subjected to MR scanning before and after the introduction of Gd-DTPA into the caudate nucleus. A one-way drainage of brain ISF was demonstrated on the dynamic MR images. According to the traditional diffusion model, the diffusion and clearance rate constants of the tracer within brain extracellular space (ECS) were derived as (3.38+-1.07)*10(-4) mm(2) s(-1) and (7.60+/-4.18)*10(-5) s(-1). Both diffusion and bulk flow contributed to the drainage of ISF from the caudate nucleus, which demonstrated an ISF-cerebrospinal fluid confluence in the subarachnoid space at the lateral and ventral surface of the brain cortex at 3 h after the injection. By using this newly developed method, the brain ECS and ISF can be quantitatively measured simultaneously in the living brain, which will enhance the understanding of ISF and improve the efficiency of drug therapy via the brain interstitium. PMID- 23015127 TI - Evolution of quasispecies diversity for porcine reproductive and respiratory syndrome virus under antibody selective pressure. AB - To study the quasispecies diversity of porcine reproductive and respiratory syndrome virus (PRRSV), open reading frame 5 (ORF5) of strain SD0612 was amplified and cloned. Sixty clones of ORF5 were sequenced and analyzed with DNAStar software. Nucleic acid sequence homology was 97.7%-100%, with 78 mutations observed. Among these 60 clones, the sequences of 17 clones were identical and recognized as the dominant quasispecies of strain SD0612. Evolution of SD0612 quasispecies diversity under antibody selective pressure was also studied. SD0612 was passed continuously in the Marc-145 cell line over 40 passages in 6 independent lineages. SD0612 antiserum was not added to lineage A, B, and C cultures; however, antiserum was added to culture medium for lineages D, E, and F. PRRSV ORF5 was then amplified, cloned, and sequenced from each of the 6 lineages, designated as A40-F40. F40 was further passed in Marc-145 cells using 6 independent lineages with or without F40 antiserum for another 40 passages. ORF5 from the 6 newly-derived virus lineages, which we designated as a40-f40, were amplified, cloned and sequenced. The proportion of dominant quasispecies increased with passage number in cell cultures supplemented with antibodies, but decreased when antibodies were lacking. Our work has demonstrated a diversity of quasispecies for ORF5 in PRRSV SD0612. Antibody selective pressure was able to significantly influence quasispecies diversity and promote a dominant quasispecies that was able to evade immune reactions. PMID- 23015128 TI - Effects of cadmium stress on seed germination and seedling growth of Elymus dahuricus infected with the Neotyphodium endophyte. AB - Various cadmium (Cd) concentrations (0, 50, 100, 200 and 300 MUmol L(-1)) affected Elymus dahuricus seed germination, seedling growth, antioxidative enzymes activities (AEA), and amounts of malondialdehyde (MDA) and proline present. These influences were determined for separate E. dahuricus cohorts known to be either infected (E+) or non-infected (E-) by a Neotyphodium endophyte. Under high Cd concentrations (100, 200 and 300 MUmol L(-1)), E+ specimens showed a significantly (P<0.05) higher germination rate and index, as well as higher values for shoot length, root length and dry biomass. However, the germination rate and index, root length and dry weight did not show a significant (P<0.05) difference under the low Cd concentrations (0 and 50 MUmol L(-1)). AEA and proline content increased, as did MDA content, in the E+ (vs. E-) specimens under high Cd concentrations. There was no significant (P>0.05) difference under low Cd concentrations. Endophyte infection was concluded to be of benefit to E. dahuricus exposed to high Cd concentrations. PMID- 23015129 TI - Immunotherapy using IL-2 and GM-CSF is a potential treatment for multidrug resistant Mycobacterium tuberculosis. AB - This study investigated the therapeutic effects of interleukin (IL)-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) co-administrated with antibacterial agents isoniazid (INH) and rifampin (RIF) to treat a mouse model of tuberculosis (TB) infection. A drug-susceptible TB strain, H37Rv was used to infect mice and the effectiveness of IL-2 and GM-CSF was initially evaluated based on survival rate, bacterial counts in lungs and spleens and the pathological condition of the lungs. Next, the therapeutic effect of the immunotherapy regimen was assessed in multidrug-resistant strain OB35-infected mice. In the H37Rv infection model, IL-2 and GM-CSF monotherapies reduced bacterial numbers in the lungs by 0.82 (P<0.01) and 0.58 (P<0.05) lg colony forming units (CFU), respectively, and in the spleens by 1.42 (P<0.01) and 1.22 (P<0.01) lg CFU, respectively, compared with the untreated group. Mice receiving immunotherapy developed fewer lesions in the lungs compared with mice receiving antibacterial therapy alone. In the OB35 infection model, immunotherapy with either cytokine resulted in a significant reduction of bacterial load in the lungs and spleens and less severe lesions in the lungs compared with the untreated or antibacterial therapy treated mice. Notably, mice receiving immunotherapy with both cytokines had a 30% survival rate which was higher than that in other treated groups, and had significantly less CFUs in the lungs and spleens (1.02 and 1.34 lg CFU) compared with antibacterial therapy alone (P<0.01). This study demonstrated that immunotherapy with both IL-2 and GM-CSF may be useful to treat multidrug resistant tuberculosis (MDR-TB). PMID- 23015130 TI - Computational prediction and experimental verification of miRNAs in Panicum miliaceum L. AB - MicroRNAs (miRNAs) are a class of non-coding RNAs that play critical roles in post-transcriptional regulation. Their target genes are involved in a variety of biological processes such as development, metabolism, and stress response. Panicum miliaceum L. (Panicum) is an important grain crop, but, until now, no miRNAs have been identified in this plant. Using a homology search based on expressed sequence tag (EST) analysis and miRNA precursor secondary structure, a total of 43 new miRNAs were identified. The miRNAs were found to be unevenly distributed among 11 miRNA families. Target analysis using the plant small RNA target analysis server psRNATarget showed that the newly identified miRNAs can potentially regulate 68 target genes. Ten of the 11 miRNA families were annotated as involved in RNA regulation, suggesting they may play an essential role in post transcriptional regulation in Panicum. Selected miRNAs representing eight of the families were verified by northern blotting, indicating that the prediction method that we used to identify the miRNAs was effective. PMID- 23015131 TI - Peptide binding specificities of HLA-B*5701 and B*5801. AB - Recently, genome wide association studies showed that there is a strong association between abacavir-induced serious, idiosyncratic, adverse drug reactions (ADRs) and human leukocyte antigen-B*5701 (HLA-B*5701). Studies also found that abacavir-induced ADRs were seldom observed in patients carrying the HLA-B*5801 subtype. HLA-B*5801 of the same serotype (B17) as B*5701 differs by only 4 amino acids from B*5701. It is believed that because of these sequence differences, HLA-B*5801 cannot bind the specific peptides which are required for HLA-B*5701 to stimulate the T cell immune response. Thus, the difference in peptide binding profiles between HLA-B*5701 and B*5801 is an important clue for exploring the mechanisms of abacavir-induced ADRs. VHSE (principal component score vector of hydrophobic, steric, and electronic properties), a set of amino acid structural descriptors, was employed to establish QSAR models of peptide binding affinities of HLA-B*5701 and B*5801. Optimal linear SVM (support vector machine) models with high predictive capabilities were obtained for both B*5701 and B*5801. The R(2) (coefficient of determination), Q(2) (cross-validated R(2)), and R(PRE)(2) (R(2) of test set) of two optimal models were 0.7530, 0.7037, 0.6153 (B*5701) and 0.6074, 0.5966, 0.5762 (B*5801), respectively. For B*5701 and B*5801, the mutations in positions 45 (MET-THR) and 46 (ALA-GLU) have little influence on the selection specificity of the P2 position of the bound peptide. However, the mutation in position 97 (VAL-ARG) greatly influences the selection specificity of the P7 position. HLA-B*5701 prefers the bulky and positively charged amino acids at the P7 position. In contrast, HLA-B*5801 prefers the non polar hydrophobic amino acids at the P7 position while positively charged amino acids are unfavored. PMID- 23015132 TI - A glimpse of enzymology within the idea of systems. PMID- 23015133 TI - Translational medicine in China. PMID- 23015134 TI - Opportunity and challenge: ten years of proteomics in China. PMID- 23015136 TI - Unresolved instrumentation problems following clinical trials using near infrared spectroscopy. AB - Near infrared spectroscopy (NIRS) clinical trials conducted over a seven year period have identified instrument engineering problems related to fiber optic failure, electromagnetic interference, chromophore algorithms, and computational software. These problems have caused confusion amongst clinicians at the bedside, rejection of large volumes of data, repeated reanalysis of data, and a significant diversion of project resources away from clinical studies and into engineering solutions. This article summarizes previously published studies and presents new data which, together, emphasize the need for improvements in NIRS technology. Instrument designers need to be aware of the need for these improvements if NIRS is to serve clinicians better during research designed to rationally define clinical management protocols. (c) 1998 Society of Photo Optical Instrumentation Engineers. PMID- 23015137 TI - Infrared imaging of in vivo microvasculature following pulsed laser irradiation. AB - Infrared emission images of the chick chorioallantoic membrane (CAM) microvasculature following pulsed laser irradiation were recorded using a high speed infrared focal plane array camera. A three-dimensional tomographic reconstruction algorithm was applied to compute the initial space-dependent temperature increase in discrete CAM blood vessels caused by light absorption. The proposed method may provide consistent estimates of the physical dimensions of subsurface blood vessels and may be useful in understanding a variety of biomedical engineering problems involving laser-tissue interaction. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015138 TI - A new laser Doppler system for examining optic nerve head circulation. AB - A new laser Doppler system for the noninvasive examination of the human optic nerve head microcirculation is described. The electro-optical component of the system consists of a retinal camera modified with laser input optics and a fiber optic light detection system for collection of the Doppler-shifted scattered light. Data acquisition is carried out in real time under computer control. Automated analysis of the data provides a quantitative measure of the speed of blood cells flowing through the capillaries of the optic nerve head. Unlike previous systems, this system provides results within a few minutes following data acquisition. It is thus appropriate for use in a clinical setting. Analysis of multiple measurements on a patient shows a coefficient of variation of 8.9%. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015139 TI - Dye-assisted laser skin closure with pulsed radiation: an in vitro study of weld strength and thermal damage. AB - Previous laser skin welding studies have used continuous wave delivery of radiation. However, heat diffusion during irradiation prevents strong welds from being achieved without creating large zones of thermal damage. Previously published results indicate that a thermal damage zone in skin greater than 200 MUm may prevent normal wound healing. We propose that both strong welds and minimal thermal damage can be achieved by introducing a dye and delivering the radiation in a series of sufficiently short pulses. Two-cm-long incisions were made in guinea pig skin, in vitro. India ink and egg white (albumin) were applied to the wound edges to enhance radiation absorption and to close the wound, respectively. Continuous wave (cw), 1.06 MUm, Nd:yttrium-aluminum-garnet laser radiation was scanned over the weld producing ~100 ms pulses. The cooling time between scans and the number of scans was varied. The thermal damage zone at the weld edges was measured using a transmission polarizing light microscope. The tensile strength of the welds was measured using a tensiometer. For pulsed welding and long cooling times between pulses (8 s), weld strengths of 2.4+/-0.9 kg/cm2 were measured, and lateral thermal damage at the epidermis was limited to 500+/-150 MUm. With cw welding, comparable weld strengths produced 2700+/-300 MUm of lateral thermal damage. The cw weld strengths were only 0.6+/-0.3 kg/cm2 for thermal damage zones comparable to pulsed welding. (c) 1998 Society of Photo Optical Instrumentation Engineers. PMID- 23015140 TI - Stress Relaxation of Porcine Septal Cartilage During Nd:YAG (lambda=1.32 MUm) Laser Irradiation: Mechanical, Optical, and Thermal Responses. AB - Laser-assisted cartilage reshaping is mediated by thermally induced stress relaxation, and may be used to alter cartilage morphology for reconstructive surgical procedures in the upper airway and face without carving, morselizing, or suturing. Internal stress sigma(t), integrated backscattered light intensity I(t) from a He-Ne probe laser (lambda=632.8 nm), and radiometric surface temperature Sc(t) were measured during the reshaping of porcine nasal septal cartilage using a pulsed Nd:YAG laser (lambda=1.32 MUm). Internal stress and integrated backscattered light intensity were observed to increase, plateau, and then decrease in similar ways during laser irradiation. The plateau region occurred when the cartilage front surface temperature approached 65 degrees C. I(t) was utilized in a feedback control procedure to reshape cartilage specimens from a flat to a curved geometry. Immediately following laser irradiation, the tissues were rehydrated in normal saline for 15 min while wrapped around a small dowel. A stable shape change was retained for 21 days while the specimens were stored in normal saline at 5 degrees C. The backscattered light intensity signal mirrors underlying changes in internal stress, and further rate of change or slope of I(t) is nearly zero when the surface temperature reaches about 65 degrees C. Measurements of I(t) (or, equivalently, the fractional change in integrated backscattered light intensity DeltaI(t)/I0) may be used to control the process of laser-assisted cartilage reshaping and minimize nonspecific thermal injury due to uncontrolled heating. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015141 TI - Laser based instruments for ocular blood flow assessment. AB - Assessment of ocular blood flow using laser based instruments is a rapidly emerging area of ophthalmic diagnosis. In this article, six specific laser based instruments are described and compared in terms of appropriate target vasculature and measured hemodynamic parameters. Described are retinal laser Doppler instruments, laser Doppler instruments for assessment of the optic nerve head microcirculation, and laser speckle instruments. (c) 1998 Society of Photo Optical Instrumentation Engineers. PMID- 23015142 TI - Biocompatibility of Laser-deposited Hydroxyapatite Coatings on Titanium and Polymer Implant Materials. AB - We have investigated the biocompatibility of calcium phosphate coatings deposited by pulsed laser ablation from hydroxyapatite (HA) targets onto polyethylene and Teflon substrates. It was found that the cell density, attachment, and morphology of primary rat calvaria osteoblasts were influenced by both the original polymer and by the nature of the apatite coatings. HA coatings on Teflon were found to have higher biocompatibility in terms of cell adhesion and spreading. In vivo studies of bone response to coatings deposited by KrF excimer and CO2 lasers on commercial Ti6A14V alloy implants show that both deposition techniques suppress fibrous tissue formation and promote osteogenesis. (c) 1998 Society of Photo Optical Instrumentation Engineers. PMID- 23015143 TI - Near real time confocal microscopy of cultured amelanotic cells: sources of signal, contrast agents and limits of contrast. AB - The use of high resolution, in vivo confocal imaging for noninvasive assessment of tissue pathology may offer a clinically important adjunct to standard histopathological techniques. To augment the present understanding of both the capabilities and limitations of in vivo confocal imaging, we investigated cellular sources of image contrast in amelanotic tissues, how contrast can be enhanced with external agents and how contrast is degraded by the scattering of overlying cells. A high-resolution reflected light confocal microscope was constructed and used to obtain images of various types of unstained amelanotic cells in suspension in real time before and after the addition of contrast agents. Reflectance images were compared to phase contrast images and electron micrographs to identify morphology visible with real time reflected light confocal microscopy. Mechanisms which decrease image contrast, including interference effects and scattering in overlying layers of cells, were considered. In amelanotic epithelial cells, fluctuations in the nuclear index of refraction provide signal which can be imaged even under several overlying cell layers. Acetic acid is an external contrast agent which can enhance this nuclear backscattering. Image contrast is degraded by the presence of multiple scattering in overlying cell layers. The degradation of image contrast by cell scattering depends on the scattering phase function; in vitro models which use polystyrene microspheres to approximate tissue underestimate the actual degradation caused by cell scattering. The loss in contrast can be explained using a finite difference time domain model of cellular scattering. We conclude that near real time reflected light confocal microscopy can be used to study cell morphology in vivo. Contrast degradation due to overlying tissue is a concern and cannot adequately be modeled using conventional tissue phantoms; however, acetic acid may be used to substantially increase intrinsic contrast, allowing imaging at significant depths despite distortion from overlying layers. (c) 1998 Society of Photo Optical Instrumentation Engineers. PMID- 23015144 TI - Computational and in vivo investigation of optical reflectance from human brain to assist neurosurgery. AB - Parkinson's disease (PD) is a chronic, progressive disease involving the globus pallidus (GP), which is a gray matter mass, surrounded by white matter deep within the brain. During a neurosurgery procedure, a thin probe is inserted into the GP to create a lesion that often relieves the cardinal symptoms of PD. The goal of this study is to develop an optical method to accurately locate the GP border. In theory, Monte Carlo simulations were performed to predict the optical reflectance from brain tissue. In experiment, a portable, real-time display spectrometer with a fiber optic reflectance probe was developed and used during human surgery. Optical reflectance values were recorded at 1 mm intervals to obtain a spatial profile of the tissue as the probe passed through regions of gray and white matter. The simulation and in vivo studies of the reflectance from the brain are in good agreement with one another. The clinical data show that the reflectance from gray matter is approximately 50% or less than that from white matter between 650 and 800 nm. A slope algorithm is developed to distinguish gray and white matter in vivo. This study provides previously unknown optical reflectance of the human brain. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015145 TI - Noninvasive imaging of living human skin with dual-wavelength optical coherence tomography in two and three dimensions. AB - We demonstrate the potential of optical coherence-domain tomography (OCT) for noninvasive imaging of living skin simultaneously at two wavelengths in the near infrared range (830 and 1285 nm). The technical details of a prototype monomode fiber-optic coherence tomographic scanner providing rapid two-dimensional (2D) and three-dimensional (3D) imaging of biological tissues are described. The effects of both instrumentation parameters and the dynamic characteristics of living tissue on image contrast and resolution and on speckle reduction are discussed. The impact of imaging speed on OCT image quality is studied by a comparison between a single scan and the corresponding frame-averaged OCT images, with the latter resulting in decreased speckle noise as well as loss of some subtle structures. Both theoretical predictions and experimental results in human skin imaging show that longer wavelength can minimize the influence of multiple scattering on image contrast and resolution and thus increase the effective penetration depth of OCT imaging to about 2 mm. Some high-resolution 2D and 3D images of microscopic anatomic structures of living human skin are presented and analyzed, illustrating the unique capability of OCT for in depth, noninvasive visualization of living skin microscopic morphology in vivo. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015146 TI - Laser assisted soldering: effects of hydration on solder-tissue adhesion. AB - Wound stabilization is critical in early wound healing. Other than superficial skin wounds, most tissue repair is exposed to a hydrated environment postoperatively. To simulate the stability of laser-soldered tissue in a wet environment, we studied the effects of hydration on laser soldered rat dermis and baboon articular cartilage. In this in vitro study, we used a solder composed of human serum albumin, sodium hyaluronate, and Indocyanine Green. A 2 MUL solder droplet was deposited on each tissue specimen and then the solder was irradiated with a scanning laser beam (808 nm and 27 W/cm2). After photocoagulation, each tissue specimen was cut into two halves dividing the solder. One half was reserved as control while the other half was soaked in saline for a designated period before fixation (1 h, 1, 2, and 7 days). All tissue specimens were prepared for scanning electron microscopy (SEM). SEM examinations revealed nonuniform coagulation across the solder thickness for most of the specimens, likely a result of the temperature gradient generated by laser heating. Closer to the laser beam, the uppermost region of the solder formed a dense coagulum. The solder aggregated into small globules in the region anterior to the solder-tissue interface. All cartilage specimens soaked in saline suffered coagulum detachment from tissue surface. We noted a high concentration of the protein globules in the detached coagulum. These globules were likely responsible for solder detachment from the cartilage surface. Solder adhered better to the dermis than to cartilage. The dermal layer of the skin, composed of collagen matrix, provided a better entrapment of the solder than the smooth surface of articular cartilage. Insufficient laser heating of solder formed protein globules. Unstable solder tissue fusion was likely a result of these globules being detached from tissue substrate when the specimen was submerged in a hydrated environment. The solder tissue bonding was compromised as a result of this phenomenon. (c) 1998 Society of Photo-Optical Instrumentation Engineers. PMID- 23015147 TI - The calcineurin-NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury. AB - Circulating and podocyte-bound urokinase receptor (uPAR) is a mediator of podocyte injury, proteinuria, and focal segmental glomerulosclerosis (FSGS) allowing pathological activation of the uPAR-beta3 integrin signaling axis. Clinically, calcineurin inhibitors (e.g., cyclosporine A, CsA) are known to suppress T cells, yet are also being used to reduce proteinuria in FSGS, suggesting the possibility of signal cross talk between uPAR and calcineurin. Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT). Accordingly, in vivo conditional NFATc1 activation in podocytes leads to proteinuria in mice, yet the downstream targets of NFAT remain unclear. Here, we show that inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays. Pathological uPAR signals in podocytes are independent of T cells and affect cell motility via activation, but not expression, changes of the beta3 integrin and can be blocked by CsA, NFAT-siRNA, or the cell-permeable NFAT inhibitor (11R VIVIT) using rodent models of glomerular disease (LPS; 5/6 nephrectomized rats). Taken together, these findings identify podocyte uPAR as a downstream target of NFAT and provide further insights into the pathogenesis of FSGS. PMID- 23015148 TI - Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism. AB - In Chuvash polycythemia, a homozygous 598C>T mutation in the von Hippel-Lindau gene (VHL) leads to an R200W substitution in VHL protein, impaired degradation of alpha-subunits of hypoxia-inducible factor (HIF)-1 and HIF-2, and augmented hypoxic responses during normoxia. Chronic hypoxia of high altitude is associated with decreased serum glucose and insulin concentrations. Other investigators reported that HIF-1 promotes cellular glucose uptake by increased expression of GLUT1 and increased glycolysis by increased expression of enzymes such as PDK. On the other hand, inactivation of Vhl in murine liver leads to hypoglycemia associated with a HIF-2-related decrease in the expression of the gluconeogenic enzyme genes Pepck, G6pc, and Glut2. We therefore hypothesized that glucose concentrations are decreased in individuals with Chuvash polycythemia. We found that 88 Chuvash VHL ( R200W ) homozygotes had lower random glucose and glycosylated hemoglobin A1c levels than 52 Chuvash subjects with wild-type VHL alleles. Serum metabolomics revealed higher glycerol and citrate levels in the VHL ( R200W ) homozygotes. We expanded these observations in VHL ( R200W ) homozygote mice and found that they had lower fasting glucose values and lower glucose excursions than wild-type control mice but no change in fasting insulin concentrations. Hepatic expression of Glut2 and G6pc, but not Pdk2, was decreased, and skeletal muscle expression of Glut1, Pdk1, and Pdk4 was increased. These results suggest that both decreased hepatic gluconeogenesis and increased skeletal uptake and glycolysis contribute to the decreased glucose concentrations. Further study is needed to determine whether pharmacologically manipulating HIF expression might be beneficial for treatment of diabetic patients. PMID- 23015149 TI - Role of vascular endothelial growth factor as a tumour marker in osteosarcoma: a prospective study. AB - PURPOSE: A prospective study was undertaken to evaluate the diagnostic and prognostic significance of serum levels of vascular endothelial growth factor (VEGF) in patients with primary localised osteosarcoma. METHODS: Serum VEGF levels were measured by an enzyme-linked immunosorbent assay (ELISA) in blood samples collected prechemotherapy, postchemotherapy, and postsurgery in 40 patients with histologically proven primary osteosarcoma. Comparison was made between serum VEGF level of healthy controls (n = 10) and prechemotherapy patient sera to evaluate its diagnostic potential. Serum VEGF levels of patients with and without metastasis were compared. Immunohistochemical staining was done to establish the correlation between serum and tissue VEGF expression. The Kaplan Meier curve was used for survival analysis RESULTS: No significant relationship was observed between serum VEGF levels and age, gender, tumour size, local recurrence or histopathological subtypes of osteosarcoma. We observed significantly raised mean serum VEGF in patient sera compared with healthy controls (p = 0.001). Significant fall in mean serum VEGF level was observed following chemotherapy (p = 0.001). Patients who developed metastases had significantly higher serum VEGF levels compared with the nonmetastatic group (P = 0.001). Serum VEGF levels correlated well with VEGF expression in tissues. CONCLUSION: Serum VEGF levels might prove to be of diagnostic, predictive and prognostic value in patients with primary osteosarcoma, although further studies with larger sample size and longer follow-up is needed to support the hypothesis. PMID- 23015150 TI - Audit of domperidone use as a galactogogue at an Australian tertiary teaching hospital. AB - BACKGROUND: Domperidone is often used to promote lactation among women who have difficulty breastfeeding. OBJECTIVE: To examine prescribing and dispensing practices of domperidone at the Women's and Children's Hospital (WCH), Adelaide. METHODS: A retrospective audit of domperidone dispensing among women with singleton pregnancies who delivered at the WCH between January 2000 and July 2010 was undertaken. Women dispensed domperidone were identified using WCH pharmacy dispensing records. Maternal and infant clinical data were obtained from the WCH Perinatal Statistics Collection. An audit of paper-based medical records was undertaken for a random sample of 261 mother-child pairs to collect prescribing and additional clinical data. RESULTS: From 2000 to 2010, 1605 women were dispensed domperidone. There was a steady increase in the percentage of women dispensed domperidone, from < 0.5% in 2000 to > 5% of total WCH pregnancies in 2010. Among women dispensed domperidone, the percentage of women who received > 1 dispensing remained consistent (20%) over time, as did the median number of days (12) from delivery to first dispensing. Multiparous women were more likely to receive domperidone within 3 days following delivery compared to primiparous women (8% vs 4%; P < .01). Most women (80%) received directions to take domperidone according to a standard tapering dosing regimen over 12 days. Notably, 60% of women had no documentation of being assessed by a lactation consultant. CONCLUSION: From 2000 to 2010, there was a considerable increase in domperidone dispensing. With a lack of clinical evidence to guide use, current practice appears to be based on anecdotal evidence. PMID- 23015152 TI - Aerobic vaginitis and mixed infections: comparison of clinical and laboratory findings. AB - PURPOSE: To investigate the clinical features of aerobic vaginitis (AV) and mixed infections with AV to achieve efficient diagnosis. METHODS: From April 2008 to August 2009, 657 consecutive outpatients with vaginal symptoms in gynecology clinic in the General Hospital of Tianjin Medical University were investigated. Samples were taken for examination of vaginal discharge and fresh wet mount microscopy. AV, bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and trichomonal vaginitis (TV) were diagnosed according to standardized definitions. Sixty patients with single AV were randomly selected over the same period. Each patient accepted moxifloxacin therapy. Two kinds of treatment course (400 mg qd, 6 days or 400 mg qd, 12 days) were given. Clinical features and laboratory test results in the first visit and follow-ups were recorded and statistically analyzed. RESULT: Among the 657 cases, AV was found in 23.74 % of the cases (156/657). AV mixed infections were diagnosed in 53.85 % (84/156): the mixed infections included VVC (32/84, 38.10 %), BV (31/84, 36.90 %), and TV (21/84, 25.00 %). Common symptoms of AV were a change in the characteristics of the discharge (44/72, 61.11 %) and increased discharge (30/72, 41.67 %). Vaginal pH was usually higher than 4.5 (63/72, 87.50 %). Enterococcus faecalis, Streptococcus viridans, Escherichia coli, and Staphylococcus epidermidis were frequently isolated. There is no statistically significant difference between two moxifloxacin treatment groups (p > 0.05). Cure rate was 89.7 % in 6-day group, and 71.4 % in 12-day group. CONCLUSIONS: AV is a common vaginal infection, and it is often mixed with other infections, especially VVC, BV and TV. The symptoms and signs of AV mixed infections are atypical. If a patient has vaginal complaints, it is necessary to determine whether AV or mixed infections are present. Oral moxifloxacin is effective in treating AV, and an appropriate course should be selected taking the severity of AV into consideration. PMID- 23015154 TI - ICJP and research and publication integrity. PMID- 23015155 TI - Influence of initial acute myocardial infarction presentation on the outcome of surgical procedures after coronary stent implantation: a report from the CREDO Kyoto PCI/CABG Registry Cohort-2. AB - Several previous publications have consistently reported that surgical procedures performed early after coronary stenting were associated with significantly higher risk for ischemic events than those performed late. In the current post hoc analysis of the Coronary REvascularization Demonstrating Outcome Study in Kyoto PCI/coronary artery bypass grafting Registry Cohort-2, we compared the outcomes of early (within 42 days) versus late surgery (beyond 42 days) after coronary stenting stratified by the initial clinical presentations [acute myocardial infarction (AMI) [early N = 153, and late N = 586] and non-AMI (early N = 202, and late N = 1457)]. Cumulative incidence of death/myocardial infarction/stent thrombosis at 30 days after surgery was significantly higher in the early group than in the late group in the AMI stratum [18.4 vs. 2.6 %, P < 0.0001, and adjusted HR 5.65 (95 % CI 2.42-13.5), P < 0.0001], but not in the non-AMI stratum [3.0 vs. 1.8 %, P = 0.3, and adjusted HR 1.52 (95 % CI 0.47-4.17), P = 0.5]. There was a significant interaction for the risk of ischemic events between the clinical presentation and the timing of surgery (P interaction = 0.03). Deaths in patients with early surgery in the AMI stratum were mostly related to preoperative complications of AMI (76 %), but not related to perioperative stent related complications (4.0 %). In conclusion, significantly higher risk of early versus late surgery for perioperative ischemic events was seen only in patients with initial AMI presentation, but not in patients with non-AMI presentation. Previous observations suggesting higher risk in early surgery might not be related to the timing after stent implantation per se, but related to more morbid preoperative conditions in patients who underwent early surgery. PMID- 23015156 TI - Ultrasound-guided ilioinguinal/iliohypogastric nerve blocks for chronic pain after inguinal hernia repair. AB - PURPOSE: The aim of this study was to evaluate the outcome of ilioinguinal and iliohypogastric nerve blocks in patients with chronic pain after herniorrhaphy, by comparing nerve stimulator and ultrasound guidance to administer the block. METHODS: A total of 43 patients who received nerve blocks for chronic inguinal post-herniorrhaphy pain received standardized questionnaires. Nerve stimulator guided blocks were performed prior to January 2009, and thereafter, ultrasound guided blocks were performed using a local anaesthetic solution and a corticosteroid. RESULTS: The questionnaire was completed by 38 patients (88 %). The inguinal hernia repair was performed for a median 16 months (range 3-219) ahead of the nerve blocks. A median of 2 pain treatments (range 1-7) was calculated. Median follow-up was 21 months (range 3-68). According to the DN4, 21 patients (55.3 %) no longer reported neuropathic pain. Subjectively, 32 % no longer reported moderate-to-severe pain. After ultrasound-guided blocks, a higher VAS score (at rest and during activities), a higher proportion of daily pain and more anxiety and depression are reported compared to blocks performed after nerve stimulator guidance. CONCLUSIONS: Ilioinguinal/iliohypogastric nerve blocks can be effective to treat chronic inguinal pain following surgery of the groin. The use of ultrasound was not superior to nerve stimulator-guided blocks. These blocks could be considered prior to more invasive procedures such as neurectomy. PMID- 23015157 TI - Magnesium intake mediates the association between bone mineral density and lean soft tissue in elite swimmers. AB - Magnesium (Mg) deficiency has been associated with bone disorders. Physical activity is also crucial for bone mineralization. Bone mass loss has been observed to be accelerated in subjects with low Mg intake. We aim to understand if Mg intake mediates the association between bone mineral density (BMD) and lean soft tissue (LST) in elite swimmers. Seventeen elite swimmers (eight males; nine females) were evaluated. Bone mineral content, BMD, LST, and fat mass were assessed using dual energy X-ray absorptiometry. Energy and nutrient intake were assessed during a seven-day period and analyzed with Food Processor SQL. Males presented lower values than the normative data for BMD. Mg, phosphorus (P) and vitamin D intake were significantly lower than the recommended daily allowance. A linear regression model demonstrated a significant association between LST and BMD. When Mg intake was included, we observed that this was a significant, independent predictor of BMD, with a significant increase of 24% in the R(2) of the initial predictive model. When adjusted for energy, vitamin D, calcium, and P intake, Mg remained a significant predictor of BMD. In conclusion, young athletes engaged in low impact sports, should pay special attention to Mg intake, given its potential role in bone mineral mass acquisition during growth. PMID- 23015159 TI - Preimplantation diagnosis for beta-thalassemia combined with HLA matching: first "savior sibling" is born after embryo selection in Brazil. PMID- 23015158 TI - Kisspeptins in human reproduction-future therapeutic potential. AB - OBJECTIVE: Kisspeptins (Kps), were first found to regulate the hypothalamopituitary-gonadal axis (HPG) axis in 2003, when two groups demonstrated that mutations of GPR54 causes idiopathic hypogonadotropic hypogonadism (IHH) characterized by delayed puberty. Objective of this review is to highlight both animal and human discoveries in KISS1/GPR54 system in last decade and extrapolate the therapeutic potential in humans from till date human studies. DESIGN: A systematic review of international scientific literature by a search of PUBMED and the authors files was done for Kp in reproduction, metabolic control & signal transduction. SETTING: None Patient(s): In human studies--normal subjects patients with HH, or HA. MAIN OUTCOME MEASURES: Effects of Kp on puberty, brain sexual maturation, regulation of GnRH secretion, metabolic control of GnRH Neurons (N). RESULTS: Kps/GPR54 are critical for brain sexual maturation, puberty and regulation of reproduction. Kps have been implicated in mediating signals to GnRH N--positive and negative feedback, metabolic input. Ability of Kp neurons to coordinate signals impinging on the HPG axis makes it one of most important regulators of reproductive axis since GnRH N's lack many receptors, with Kp neurons serving as upstream modulators. CONCLUSIONS: Kps have proven as pivotal regulators of the reproduction, with the ability to integrate signals from both internal and external sources. Knowledge about signaling mechanisms involved in Kp stimulation of GnRH and with human studies has made it possible that therapeutically available Kp agonists/antagonists may be used for treatment of delayed puberty/HH, Hypothalamic amenorrhea and in prevention of spread of malignant ovarian/gonadal malignancies along with uses in some eating disorders. PMID- 23015162 TI - Guest editorial: special section on biomedical applications of vibrational spectroscopic imaging. AB - This Special Section Guest Editorial provides an overview of the topical area and an introduction to the articles featured in the special section. PMID- 23015161 TI - Randomised comparison of a simple warfarin dosing algorithm versus a computerised anticoagulation management system for control of warfarin maintenance therapy. AB - Excellent control of the international normalised ratio (INR) is associated with improved clinical outcomes in patients receiving warfarin, and can be achieved by anticoagulation clinics but is difficult in general practice. Anticoagulation clinics have often used validated commercial computer systems to manage the INR, but these are not usually available to general practitioners. It was the objective of this study to perform a randomised trial of a simple one-step warfarin dosing algorithm against a widely used computerised dosing system. During the period of introduction of a commercial computerised warfarin dosing system (DAWN AC) to an anticoagulation clinic, patients were randomised to have warfarin dose adjustment done according to recommendations of the existing warfarin dosing algorithm or to those of the computerised system. The study tested if the computerised system was non-inferior to the existing algorithm for the primary outcome of time in therapeutic INR range of 2.0-3.0 (TTR), with a one sided non-inferiority margin of 4.5%. There were 541 patients randomised to commercial computerised system and 527 to the algorithm. Median follow-up was 159 days. A dose recommendation was provided and followed in 91% of occasions for the computerised system and in 90% for the algorithm (p=0.03). The mean TTR was 71.0% (standard deviation [SD] 23.2) for the computerised system and 71.9% (SD 22.9) for the algorithm (difference 0.9% [95% confidence interval: -1.4% to 4.1%]; p value for non-inferiority=0.002; p-value for superiority=0.34). In conclusion, similar maintenance control of the INR was achieved with a simple one-step dosing algorithm and a commercial computerised management system. PMID- 23015160 TI - Targeted imaging of breast tumor progression and therapeutic response in a human uMUC-1 expressing transgenic mouse model. AB - The ability to monitor breast cancer initiation and progression on the molecular level would provide an effective tool for early diagnosis and therapy. In the present study, we focused on the underglycosylated MUC-1 tumor antigen (uMUC-1), which is directly linked to tumor progression from pre-malignancy to advanced malignancy in breast cancer and has been identified as the independent predictor of local recurrence and tumor response to chemotherapy. We investigated whether changes in uMUC-1 expression during tumor development and therapeutic intervention could be monitored non-invasively using molecular imaging approach with the uMUC-1-specific contrast agent (MN-EPPT) detectable by magnetic resonance and fluorescence optical imaging. This was done in mice that express human uMUC-1 tumor antigen (MMT mice) and develop spontaneous mammary carcinoma in a stage-wise fashion. After the injection of MN-EPPT there was a significant reduction in average T2 relaxation times of the mammary fat pad between pre malignancy and cancer. In addition, T2 relaxation times were already altered at pre-malignant state in these mice compared to non-tumor bearing mice. This indicated that targeting uMUC-1 could be useful for detecting pre-malignant transformation in the mammary fat pad. We also probed changes in uMUC-1 expression with MN-EPPT during therapy with doxorubicin (Dox). We observed that tumor delta-T2s were significantly reduced by treatment with Dox indicating lower accumulation of MN-EPPT. This correlated with a lower level of MUC-1 expression in the Dox-treated tumors, as confirmed by immunoblotting. Our study could provide a very sensitive molecular imaging approach for monitoring tumor progression and therapeutic response. PMID- 23015163 TI - Infrared Spectroscopic Imaging of the Biochemical Modifications Induced in the Cerebellum of the Niemann-Pick type C Mouse. AB - We have applied Fourier transform infrared (IR) spectroscopic imaging to the investigation of the neuropathologic effects of a genetic lipid storage disease, Niemann-Pick type C (NPC). Tissue sections both from the cerebella of a strain of BALB/c mice that demonstrated morphology and pathology of the human disease and from control animals were used. These samples were analyzed by standard histopathological procedures as well as this new IR imaging approach. The IR absorbance images exhibit contrast based on biochemical variations and allow for the identification of the cellular layers within the tissue samples. Furthermore, these images provide a qualitative description of the localized biochemical differences existing between the diseased and control tissue in the absence of histological staining. Statistical analyses of the IR spectra extracted from individual cell layers of the imaging data sets provide concise quantitative descriptions of these biochemical changes. The results indicate that lipid is depleted specifically in the white matter of the NPC mouse in comparison to the control samples. Minor differences were noted for the granular layers, but no significant differences were observed in the molecular layers of the cerebellar tissue. These changes are consistent with significant demyelination within the cerebellum of the NPC mouse. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015164 TI - Infrared spectroscopy, microscopy, and microscopic imaging of mineralizing tissues: spectra-structure correlations from human iliac crest biopsies. AB - Infrared microscopic images of the cortical region of human iliac crest biopsies have been obtained at ~7 MUm spatial resolution and 8 cm-1 spectral resolution with a 64*64 mercury-cadmium-telluride focal plane array detector coupled to a Fourier transform infrared microscope and a step scanning interferometer. Images of several spectral parameters provide information about the spatial distribution of the mineral (apatite) and protein (mostly collagen) components of the tissue. In addition, the image of a parameter known to reflect the crystallinity/perfection of the mineral phase, namely, the intensity ratio of bands at 1030 and 1020 cm-1 within the phosphate nu1,nu3 contour, revealed a progressive increase in the apatite crystal size/perfection from the osteonal center to the periphery. Finally, a detailed comparison of the spatial distribution of the I(1020)/I(1030) ratio for the same osteon obtained by array detection and by conventional point-by-point microspectroscopy revealed statistically identical behavior, thereby providing a validation of infrared imaging for structural analysis of apatite forming tissues. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015165 TI - Spectroscopic and morphologic characterization of the dentin/ adhesive interface. AB - The potential environmental risks associated with mercury release have forced many European countries to ban the use of dental amalgam. Alternative materials such as composite resins do not provide the clinical function for the length of time characteristically associated with dental amalgam. The weak link in the composite restoration is the dentin/adhesive bond. The purpose of this study was to correlate morphologic characterization of the dentin/adhesive bond with chemical analyses using micro-Fourier transform infrared and micro-Raman spectroscopy. A commercial dental adhesive was placed on dentin substrates cut from extracted, unerupted human third molars. Sections of the dentin/adhesive interface were investigated using infrared radiation produced at the Aladdin synchrotron source; visible radiation from a Kr+ laser was used for the micro Raman spectroscopy. Sections of the dentin/adhesive interface, differentially stained to identify protein, mineral, and adhesive, were examined using light microscopy. Due to its limited spatial resolution and the unknown sample thickness the infrared results cannot be used quantitatively in determining the extent of diffusion. The results from the micro-Raman spectroscopy and light microscopy indicate exposed protein at the dentin/adhesive interface. Using a laser that reduces background fluorescence, the micro-Raman spectroscopy provides quantitative chemical and morphologic information on the dentin/adhesive interface. The staining procedure is sensitive to sites of pure protein and thus, complements the Raman results. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015166 TI - Spatial distribution of phosphate species in mature and newly generated Mammalian bone by hyperspectral Raman imaging. AB - Hyperspectral Raman images of mineral components of trabecular and cortical bone at 3 MUm spatial resolution are presented. Contrast is generated from Raman spectra acquired over the 600-1400 cm-1 Raman shift range. Factor analysis on the ensemble of Raman spectra is used to generate descriptors of mineral components. In trabecular bone independent phosphate (PO4-3) and monohydrogen phosphate (HPO4 2) factors are observed. Phosphate and monohydrogen phosphate gradients extend from trabecular packets into the interior of a rod. The gradients are sharply defined in newly regenerated bone. There, HPO4-2 content maximizes near a trabecular packet and decreases to a minimum value over as little as a 20 MUm distance. Incomplete mineralization is clearly visible. In cortical bone, factor analysis yields only a single mineral factor containing both PO4-3 and HPO4-2 signatures and this implies uniform distribution of these ions in the region imaged. Uniform PO4-3 and HPO4-2 distribution is verified by spectral band integration. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015167 TI - Guest editorial: special section on optical diagnostics of biological fluids. AB - This Special Section Guest Editorial provides an overview of the topical area and an introduction to the articles featured in the special section. PMID- 23015168 TI - Optical Properties of Circulating Human Blood in the Wavelength Range 400-2500 nm. AB - Knowledge about the optical properties MUa,MUs, and g of human blood plays an important role for many diagnostic and therapeutic applications in laser medicine and medical diagnostics. They strongly depend on physiological parameters such as oxygen saturation, osmolarity, flow conditions, haematocrit, etc. The integrating sphere technique and inverse Monte Carlo simulations were applied to measure MUa,MUs, and g of circulating human blood. At 633 nm the optical properties of human blood with a haematocrit of 10% and an oxygen saturation of 98% were found to be 0.210+/-0.002 mm-1 for MUa,77.3+/-0.5 mm-1 for MUs, and 0.994+/-0.001 for the g factor. An increase of the haematocrit up to 50% lead to a linear increase of absorption and reduced scattering. Variations in osmolarity and wall shear rate led to changes of all three parameters while variations in the oxygen saturation only led to a significant change of the absorption coefficient. A spectrum of all three parameters was measured in the wavelength range 400-2500 nm for oxygenated and deoxygenated blood, showing that blood absorption followed the absorption behavior of haemoglobin and water. The scattering coefficient decreased for wavelengths above 500 nm with approximately lambda-1.7; the g factor was higher than 0.9 over the whole wavelength range. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015169 TI - Influence of the scattering phase function approximation on the optical properties of blood determined from the integrating sphere measurements. AB - We investigated the impact of the scattering phase function approximation on the optical properties of whole human blood determined from integrating sphere measurements using an inverse Monte Carlo technique. The diffuse reflectance Rd and the total transmittance Tt(lambda=633 nm) of whole blood samples (Hct=38%) were measured with double-integrating sphere equipment. The scattering phase functions of highly diluted blood samples (Hct=0.1%) were measured using a goniophotometer. We approximated the experimentally determined scattering phase functions with either Henyey-Greenstein (HGPF), Gegenbauer kernel (GKPF), or Mie (MPF) phase functions to preset the anisotropy factor MU- for the inverse problem. We have employed HGPF, GKPF, and MPF approximations in the inverse Monte Carlo procedure to derive the absorption coefficient MUa and the scattering coefficient MUs. To evaluate the obtained data, we calculated the angular distributions of scattered light for optically thick samples and compared the results with goniophotometric measurements. The data presented in this study demonstrate that the employed approximation of the scattering phase function can have a substantial impact on the derived values of MUs and MU-, while MUa and the reduced scattering coefficient MUs' are much less sensitive to the exact form of the scattering phase function. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015170 TI - Low-level chemiluminescent analysis of nondiluted human blood reveals its dynamic system properties. AB - Lucigenin- and luminol-dependent chemiluminescence [(LC-CL) and (LM-CL)] in nondiluted human blood was studied. LM-CL was low in fresh blood and disappeared after its storage for 3 h, though the respiratory burst (RB) stimulation in blood was followed by high intensity and long-lasting LM-CL. LC-CL was high in fresh blood and was steadily increasing with blood storage. Blood dilution with saline resulted in LC-CL attenuation and LM-CL elevation. LC-CL did not depend on air supply to blood, while LM-CL elevation during RB needed constant blood aeration. The results suggest that besides a well-known mechanism of reactive oxygen species production by neutrophils during RB, another process of electron excited state generation reflected by LC-CL operates in blood. It needs blood integrity for its manifestation and uses oxygen supplied by erythrocytes. Dynamic system properties of blood were revealed also in experiments with blood transfer from one sample to another in the course of RB. Highly nonlinear changes of CL intensity both in a "donor" and in a "recipient" sample resulted in strong differences in CL levels in two samples, one of which was prepared by blood subtraction, and another by blood addition. We suggest that CL data from measurements on nondiluted blood may be informative of integrative properties of blood tissue in addition to its being a measure of some sort of oxidative metabolism in it. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015171 TI - Coherent optical techniques for diagnostics of retinal blood flow. AB - Up to now, a variety of coherent optical techniques have been proposed and extensively studied for diagnostics of the retinal blood flow. These techniques are mainly based on dynamic laser light-scattering phenomena such as the laser Doppler effect and the laser speckle fluctuation. This paper reviews, first, spectral reflectance properties of the ocular fundus tissue layers and, then, principles of the techniques with the comparison of the Doppler and the speckle methods. Some physical phenomena are also discussed in the origin of the techniques such as heterodyne and homodyne beatings, and time-varying speckles. Developing processes of each technique are briefly outlined. Peculiarities of blood flow measurements at the retina are finally examined from the methodological point of view. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015172 TI - Aggregation and disaggregation of erythrocytes in whole blood: study by backscattering technique. AB - The aggregation phenomenon is of great importance for the evaluation of performance of the microcirculation system because of its influence on the blood viscosity at low shear stresses. Some important features and consequences of this phenomenon in vivo can be predicted in the in vitro experiments using optical methods. These methods are considered to be the most informative and applicable not only for the basic study of the aggregation phenomenon, but also for the diagnosis of a number of diseases and for the monitoring of therapeutic treatment in clinics. Results presented in this paper prove that the backscattering technique allows one to detect different changes of aggregational ability and deformability of erythrocytes and to get reliable and reproducible results distinguishing normal blood and blood with different pathologies. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015173 TI - Optical Diagnostics of Mechanical Properties of Red Blood Cells based on the Deformation by High Frequency Electric Field. AB - Erythrocyte placed in a low-conductivity isotonic medium can be elongated by a high frequency electric field. The elongation can be registered optically, finally enabling the determination or monitoring of elastic moduli and viscous properties of erythrocytes. However, an unambiguous evaluation of mechanical parameters from the optical data is complicated. It requires an adequate theory of dielectro deformation which takes into account the influence of the cell's mechanical, electric, and transient shape parameters on field-induced deformations. The present work is aimed at the development of a comprehensive and experimentally verified theoretical basis for the dielectro-deformational investigation of erythrocytes. The previous concept of the dielectro-deformation process, supported solely by the shear deformation of erythrocyte membrane, is revised completely. It is shown that in the practical relevant range of dielectro deformation, it is mainly supported by bending deformation of the membrane, with a gradual development of shear deformation as the cell becomes more elongated. This new bending-shear theory of dielectro deformation is developed here. The theory is shown to describe unambiguously both observational and quantitative data on the static and dynamic dielectro deformation of erythrocytes. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015174 TI - Guest editorial: special section on coherence domain optical methods in biomedical science and clinics. AB - This Special Section Guest Editorial provides an overview of the topical area and an introduction to the articles featured in the special section. PMID- 23015175 TI - Speckle in optical coherence tomography. AB - Speckle arises as a natural consequence of the limited spatial-frequency bandwidth of the interference signals measured in optical coherence tomography (OCT). In images of highly scattering biological tissues, speckle has a dual role as a source of noise and as a carrier of information about tissue microstructure. The first half of this paper provides an overview of the origin, statistical properties, and classification of speckle in OCT. The concepts of signal-carrying and signal-degrading speckle are defined in terms of the phase and amplitude disturbances of the sample beam. In the remaining half of the paper, four speckle reduction methods-polarization diversity, spatial compounding, frequency compounding, and digital signal processing-are discussed and the potential effectiveness of each method is analyzed briefly with the aid of examples. Finally, remaining problems that merit further research are suggested. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015176 TI - Coherent optical techniques for the analysis of tissue structure and dynamics. AB - This paper summarizes the description of the speckle-correlation, speckle interferometric, and polarimetric methods and instruments designed for various tissue structure imaging and their optical and dynamical parameter monitoring. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015177 TI - Phase-domain processing of optical coherence tomography images. AB - In optical coherence tomography (OCT), images are usually formed from the envelope of the measured interference signal. Computation of the absolute magnitude of the signal for measurement of the envelope is a nonlinear process that destroys phase information. This study explores the idea of recording and processing the phase of the OCT interference signal before calculation of the magnitudes for display. Processing the partially coherent OCT signals in the complex domain provides the opportunity to correct phase aberrations responsible for speckle noise in OCT images. We describe an OCT system that incorporates a quadrature-demodulation scheme for accurate recording of the phase and amplitude of OCT signals from single or multiple detectors. A speckle-reduction technique that works in the complex domain, called the zero-adjustment procedure (ZAP), is investigated as an example of complex-domain processing. After demonstrating its speckle-correction properties mathematically and in numerical simulations, we apply ZAP to OCT images of living skin. The results show that ZAP reduces speckle contrast in regions where scatterer density is high and expands the range of gray values in the image. However, as presently implemented, ZAP tends to blur sharp boundaries between image features. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015178 TI - In situ Monitoring of Laser Modification Process in Human Cataractous Lens and Porcine Cornea Using Coherence Tomography. AB - We demonstrate that optical coherence tomography (OCT) is a convenient diagnostic tool to monitor pulse-to-pulse kinetics in laser interactions with biological tissue. In experiments on laser modification and ablation of the cataractous human lens and the porcine cornea we have applied this technique in situ to investigate different modes of preablation tissue swelling, crater formation and thermally affected zone development. The cataractous lens is an example of highly scattering media whereas the cornea is initially low scattering. The radiation with different wavelengths has been employed including that of a YAG:Er laser (lambda=2.94 MUm), a glass:Er laser (lambda=1.54 MUm), YAG:Nd lasers (lambda=1.32 MUm and lambda=1.44 MUm), as well as of the fifth harmonic of a Nd:YAP laser (lambda=0.216 MUm). Pulse-to-pulse OCT monitoring has been accompanied by the probe beam shielding diagnostics to provide the time-resolved observation of the interaction dynamics. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015179 TI - Dispersion effects in partial coherence interferometry: implications for intraocular ranging. AB - In nondispersive media, the minimum distance that can be resolved by partial coherence interferometry (PCI) and optical coherence tomography (OCT) is inversely proportional to the source spectral bandwidth. Dispersion tends to increase the signal width and to degrade the resolution. We analyze the situation for PCI ranging and OCT imaging of ocular structures. It can be shown that for each ocular segment an optimum source bandwidth yielding optimum resolution exists. If the resolution is to be improved beyond this point, the group dispersion of the ocular media has to be compensated. With the use of a dispersion compensating element, and employing a broadband superluminescent diode, we demonstrate a resolution of 5 MUm in the retina of both a model eye and a human eye in vivo. This is an improvement by a factor of 2-3 as compared to currently used instruments. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015180 TI - Precision and Reproducibility of Measurements of Human Corneal Thickness with Rapid Optical Low-Coherence Reflectometry (OLCR). AB - This study investigates the precision and intraindividual variability of a clinical optical pachometer based on low-coherence reflectometry, which was used to measure the central thickness of a human cornea in vivo. The instrument, attached to a slit lamp, is a single mode fiber optic based Michelson interferometer with a high repetition rate as previously described. The same operator performed ten sets of measurements on the same subject, each consisting of 20 consecutive scans, on each day for three consecutive days. By computing the means from every scan series, the thickness of the central cornea with optical pachometry was found to be 519.6+/-1.2 (range 518-521) MUm on day 1, 519.9+/-0.9 (range 519-521) MUm on day 2, and 523.8+/-0.6 (range 523-525) MUm on day 3. The thickness values on day 3, where the subject suffered from a cold without clinical ocular involvement, were different from the two previous days (p<0.001, one way analysis of variance). Optical low-coherence reflectometry measurements of corneal thickness can be performed with high precision of about 1 MUm and a high intra- and intersession reproducibility. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015181 TI - Characteristic scales of optical field depolarization and decorrelation for multiple scattering media and tissues. AB - Decorrelation and depolarization properties of multiply scattering media and tissues in the case of propagation of coherent probe beams are analyzed in terms of photon path distribution. A specific correlation time determining the relationship between correlation and polarization states of scattered optical fields is introduced. Results of correlation and polarization experiments with phantom scatterers (such as water suspensions of polystyrene spheres) and tissues with controlled optical properties (such as the human sclera) are presented. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015182 TI - Capillary Blood Flow Monitoring Using Laser Speckle Contrast Analysis (LASCA). AB - Coherent light scattered from an ensemble of moving scatterers produces a time varying speckle pattern. The intensity fluctuations observed in a single speckle can be regarded either as a time-varying interference effect or as a Doppler beating effect. Techniques based on each of these approaches have been developed to analyze the fluctuations in an attempt to measure the velocities of the scatterers. Most of these methods measure the temporal statistics of the intensity fluctuations in a single speckle, i.e., at a single point. If a map of the velocity distribution is required, some form of scanning must be introduced. One way of avoiding the need to scan is to make use of the spatial statistics of time-integrated speckle. This is the basis of a technique, already described in the literature, called laser speckle contrast analysis (LASCA). In this article, we present a brief review of the theory linking the intensity fluctuations to the velocity and of the various techniques that have been proposed to measure them. We then describe the present configuration of our LASCA technique and describe some recent developments in our search for a real-time, noninvasive, full-field technique for visualizing capillary blood flow. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015183 TI - Application of twyman-green interferometer for evaluation of in vivo breakup characteristic of the human tear film. AB - The paper presents an interferometric method of assessing the in vivo stability of the precorneal tear film. To observe dynamic effects on a human cornea the Twyman-Green interferometer with television frame speed digital registration synchronized with a laser flash was used. The instrument was applied to the human cornea in vivo. The results of the experiment, both tear film distribution and its dynamics, are presented. The proposed interferometric setup can be used to evaluate the breakup characteristics of the tear film, its distribution, and to examine its dynamic changes. The breakup profiles and their cross sections calculated from the interferogram analysis are presented. The depth of recorded breakup, calculated on the basis of interferogram analysis, amounts to about 1.5 MUm. The proposed method has the advantage of being noncontact and applies only a low-energy laser beam to the eye. This provides noninvasive viewing of human cornea in vivo and makes it possible to observe the kinetics of its tear film deterioration. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015184 TI - Time integrated spectroscopy of turbid media based on the microscopic beer lambert law: application to small-size phantoms having different boundary conditions. AB - Continued work on time-integrated spectroscopy (TIS) is presented to quantify absorber concentrations in turbid media. We investigated the applicability of the TIS method to small-size media that have different boundary conditions by measuring two 20*20*50 mm3 cuboid liquid tissue-like phantoms at various absorption levels (absorption coefficients of the phantom from 2.5*10-3 to 4.4*10 2 mm-1 at 782 nm and from 3.1*10-3 to 2.7*10-2 mm-1 at 831 nm). The scattering and absorbing solution was filled into ordinary and black-anodized aluminum containers to provide different boundary conditions. By means of a single equation, the absorber concentrations have been recovered within errors of a few percent in both cases. This demonstrates that the TIS method can quantify absorbers in small-size media having different boundary conditions. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015190 TI - In vitro biomineralization and bulk characterization of chitosan/hydroxyapatite composite microparticles prepared by emulsification cross-linking method: orthopedic use. AB - Chitosan/hydroxyapatite composite microparticles were prepared by a solid-in water-in-oil emulsification cross-linking method. The characteristics and activity in presence of simulated body fluid for 14 and 21 days were investigated. The size distribution, surface morphology, and microstructure of these biomaterials were evaluated. The scanning electron microscopy revealed an aggregate of microparticles with a particle size, ranged from 4 to 10 MUm. The deposited calcium phosphate was studied using X-ray diffraction analysis, Fourier transform infrared spectroscopy, and inductively coupled plasma/atomic emission spectroscopy analysis of phosphorus. These results show that the mineral, formed on microparticles, was a mixture of carbonated hydroxyapatite and calcite. Scanning electron microscopy revealed that calcium phosphate crystals growth was in form of rods organized as concentric triangular packets interconnected to each other by junctions. Interaction between chitosan and growing carbonated hydroxyapatite and calcite crystals are responsible for a composite growth into triangular and spherical shapes. The results demonstrated that these microparticles were potential materials for bone repair. PMID- 23015189 TI - Characterization of CCDC28B reveals its role in ciliogenesis and provides insight to understand its modifier effect on Bardet-Biedl syndrome. AB - Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder that is generally inherited in an autosomal recessive fashion. However, in some families, trans mutant alleles interact with the primary causal locus to modulate the penetrance and/or the expressivity of the phenotype. CCDC28B (MGC1203) was identified as a second site modifier of BBS encoding a protein of unknown function. Here we report the first functional characterization of this protein and show it affects ciliogenesis both in cultured cells and in vivo in zebrafish. Consistent with this biological role, our in silico analysis shows that the presence of CCDC28B homologous sequences is restricted to ciliated metazoa. Depletion of Ccdc28b in zebrafish results in defective ciliogenesis and consequently causes a number of phenotypes that are characteristic of BBS and other ciliopathy mutants including hydrocephalus, left-right axis determination defects and renal function impairment. Thus, this work reports CCDC28B as a novel protein involved in the process of ciliogenesis whilst providing functional insight into the cellular basis of its modifier effect in BBS patients. PMID- 23015191 TI - Characterization of a glycoside hydrolase family 1 beta-galactosidase from hot spring metagenome with transglycosylation activity. AB - A novel, thermostable, alkalophilic beta-D-galactosidase (Mbgl) was isolated from a metagenome of geothermal springs in northern Himalayan region of India. Mbgl was 447 amino acids in size and had conserved catalytic residues E170 and E358, indicating that it belonged to family 1 of glycosyl hydrolases showing maximum homology (89 %) with uncharacterized beta-galactosidase of Eubacterium, Meiothermus ruber DSM1279. Temperature and pH optima of Mbgl were 65 degrees C and 8.0 respectively, and it retained 80 % activity even at pH 10.0. Mbgl was active as a homotetramer, recognized beta-(1,4)-D-galactoside as the preferred glycosidic bond, and preferentially hydrolyzed pNPgal with K(m) 3.33 mM and k(cat) 2,000 s(-1). It displayed high transglycosylation activity with wide acceptor specificity including hexoses and pentoses leading to the formation of prebiotic galacto-oligosaccharides whereas its lactose hydrolysis potential was low. PMID- 23015192 TI - Can land managers control Japanese knotweed? Lessons from control tests in Belgium. AB - Japanese knotweed Fallopia japonica is an extremely abundant invasive plant in Belgium and surrounding countries. To date, no eradication method is available for land managers facing the invasion of this rhizomatous plant. We tested different chemical herbicides with two application methods (spraying and stem injection), as well as mechanical treatments, on knotweed clones throughout southern Belgium. The tested control methods were selected to be potentially usable by managers, e.g., using legally accepted rates for herbicides. Stem volume, height and density reduction were assessed after one or two years, depending on the control method. Labor estimations were made for each control method. No tested control method completely eradicated the clones. Stem injection with glyphosate-based herbicide (3.6 kg ha(-1) of acid equivalent glyphosate) caused the most damage, i.e., no sprouting shoots were observed the year following the injection. The following year, though, stunted shoots appeared. Among the mechanical control methods, repeated cuts combined with native tree transplanting most appreciably reduced knotweed development. The most efficient methods we tested could curb knotweed invasion, but are not likely to be effective in eradicating the species. As such, they should be included in a more integrated restoration strategy, together with prevention and public awareness campaigns. PMID- 23015193 TI - [EU-funded treatment study: WAKE-UP: a randomized, placebo-controlled MRI-based trial of thrombolysis in wake-up stroke]. AB - Patients waking up with stroke symptoms are generally excluded from intravenous thrombolysis. It was shown that magnetic resonance imaging (MRI) can identify patients within the time window for thrombolysis (<= 4.5 h from symptom onset) by a mismatch between the acute ischemic lesion visible on diffusion-weighted imaging (DWI) but not visible on fluid-attenuated inversion recovery (FLAIR) imaging. The WAKE-UP trial is an investigator initiated, European, randomized, double-blind, placebo-controlled trial designed to test efficacy and safety of MRI-based thrombolysis with alteplase (tPA) in stroke patients with unknown time of symptom onset, e.g. due to symptom recognition on awakening. A total of 800 patients showing MRI findings of a DWI-FLAIR-mismatch will be randomized to either tPA or placebo. The primary efficacy endpoint will be favourable outcome defined by a modified Rankin scale score 0-1 at day 90. The primary safety outcome measures will be mortality and death or dependency defined by modified Rankin scale score 4-6 at 90 days. If positive the WAKE-UP trial is expected to change clinical practice and to make effective and safe treatment available for a large group of acute stroke patients currently excluded from specific acute treatment. PMID- 23015194 TI - [Experimental therapy approaches for ischemic stroke]. AB - In Germany, as in most other industrialized countries, ischemic stroke is the leading cause of disability and the third leading cause of death. As the incidence of ischemic stroke increases with age it is expected that this problem will become even more urgent in an aging society. Despite significant research efforts on the clinical as well as on the experimental level, treatment of ischemic stroke is still based on general intensive care measures and on reperfusion therapy with recombinant tissue plasminogen activator (rtPA); however, rtPA is not suitable for a wide range of patients and is restricted to a therapeutic window of 4.5 h due to an increasing risk of bleeding. Accordingly, novel therapeutic options for ischemic stroke are urgently need. The current review discusses novel experimental therapeutic principles for ischemic stroke which may have clinical potential. The main topics are neuroprotection and strategies addressing the immune system. PMID- 23015195 TI - [Focal neuropathy]. AB - The differential diagnosis of focal neuropathy continues to be one of the main tasks in peripheral neurology and clinical neurophysiology. In this respect a detailed medical history a topologically oriented clinical examination based on profound anatomical knowledge and a targeted neurophysiological examination are the cornerstones of successful diagnosis. Refined imaging techniques, such as sonography and magnetic resonance imaging provide - additional and valuable morphological information especially in atypical or unresolved cases. The aim of this overview is therefore to summarize the spectrum of focal neuropathy and diagnostic approaches, particularly in terms of a well-founded differential diagnosis. PMID- 23015197 TI - Phase I clinical study of vascular targeting fluorescent cationic liposomes in head and neck cancer. AB - The aim of this first-time-in-human non-randomized dose-escalating prospective phase I clinical trial was to analyze safety of two doses of fluorescent rhodamine-labeled cationic liposomes (LDF01) in head and neck squamous cell carcinoma (HNSCC). Patients had resectable UICC stadium I-IV A HNSCCs. LDF01 was administered before tumor resection under general anesthesia as an intravenous infusion with effective lipid doses of 0.5 or 2 mg/kg b.w., respectively. In addition to clinical monitoring for safety assessment, tumor biopsies were taken during the surgical procedure for fluorescence histological analysis. Eight patients were assigned to the two dose groups. During safety follow-up no clinically relevant adverse events occurred. Fluorescence histology revealed some evidence of favorable selectivity of LDF01 for tumor microvessels in the high dose group. LDF01 is safe applied as infusion at both tested dose levels. Furthermore, LDF01 can be detected in the vicinity of tumor cells and could be assigned to the microvessel target in individual HNSSC cases. Detailed analysis of targeting properties of LDF01 has to be performed in upcoming clinical phase II trials. PMID- 23015198 TI - Endoscopic or external approach revision surgery for pharyngeal pouch following primary endoscopic stapling: which is the favoured approach? AB - This study aimed to assess outcomes of revision endoscopic stapling and external excision of pharyngeal pouch. A 5-year prospective study was performed on all patients requiring revision pouch surgery following primary endoscopic stapling. Data were collected retrospectively. Eighteen patients underwent revision pouch surgery. In seven patients, pouch size was down-graded from 3 to 2, and these were stapled endoscopically. Two leaks resulted. Eleven patients with grade 1 or 3 pouches underwent external excision of pouch, with no post-operative complications. As per results external excision of pouch is safe for grade 1 and 3 pouches. It avoids risking redundant mucosa and recurrence of symptoms which can complicate stapling and enables a myotomy to be performed to reduce cricopharyngeal hypertonicity. The highest predictable success is with grade 2 pouches, whose size is amenable to adequate endoscopic stapling. However, the "staple over staple" effect of revision stapling leads to unpredictable fibrosis, which can contribute to risk of perforation. PMID- 23015199 TI - Sulfate influx on band 3 protein of equine erythrocyte membrane (Equus caballus) using different experimental temperatures and buffer solutions. AB - The aim of this study was to assess the anion transport in equine erythrocytes through the measurement of the sulfate uptake operating from band 3 using different experimental temperatures and buffer solutions. Blood samples of six clinically healthy horses were collected via jugular vein puncture, and an emochrome-citometric examination was performed. The blood was divided into four aliquots and by centrifugation and aspiration the plasma and buffy coat were carefully discarded. The red blood cells were washed with an isosmotic medium and centrifuged. The obtained cell suspensions were incubated with two different experimental buffer solutions (buffer A: 115 mM Na2SO4, 10 mM NaCl, 20 mM ethylenediaminetetraacetic acid, 30 mM glucose; and buffer B: 115 mM Na2SO4, 10 mM NaCl, 20 mM ethylenediaminetetraacetic acid, 30 mM MgCl2) in a water bath for 1 h at 25 degrees C and 37 degrees C. Normal erythrocytes, suspended at 3% hematocrit, were used to measure the SO4= influx by absorption spectrophotometry at 425 nm wavelength. Unpaired Student's t-test showed a statistically significant decrease (P < 0.01) of rate constants in equine erythrocytes at 25 degrees C versus 37 degrees C using both experimental buffer solutions. Comparing the buffer A with buffer B unpaired Student's t-test showed statistically lower values (P < 0.0001) for A solution versus B solution both at 25 degrees C and at 37 degrees C. The greater inhibition of SO4 (=) influx measured in equine erythrocytes indicates the increased formation of the sulfydryl bonds in band 3 and the modulation of the sulfydryl groups, culminating in the conformational changes in band 3. PMID- 23015196 TI - Wnt signaling in vertebrate neural development and function. AB - Members of the Wnt family of secreted signaling proteins influence many aspects of neural development and function. Wnts are required from neural induction and axis formation to axon guidance and synapse development, and even help modulate synapse activity. Wnt proteins activate a variety of downstream signaling pathways and can induce a similar variety of cellular responses, including gene transcription changes and cytoskeletal rearrangements. This review provides an introduction to Wnt signaling pathways and discusses current research on their roles in vertebrate neural development and function. PMID- 23015200 TI - Bosentan improved persistent pulmonary hypertension in a case after implantation of a left ventricular assist device. AB - No medical treatment has been established to ameliorate pulmonary hypertension (PH) due to left heart disease. Heart transplantation (HTx) is thus far the definitive therapy for stage D heart failure, but concomitant PH is one of the major risk factors for death after HTx. Recently, implantation of a left ventricular assist device (LVAD) has been reported to improve PH and has become a major bridge tool for HTx. We experienced a rare case with persistent PH even after the implantation of a continuous-flow LVAD. The administration of an endothelin receptor antagonist, bosentan, significantly decreased pulmonary vascular resistance. Combination therapy with LVAD implantation and anti-PH medication may be useful for patients with stage D heart failure complicated with severe PH. PMID- 23015201 TI - [ThorAKUSTIK - a computer-based method to determine the oronasal respiratory flow]. AB - BACKGROUND: Respiratory flow detection with the aim of detecting sleep-related breathing disorders plays a major role in polysomnography. Due to the fact that pneumotachographs are too bulky and not suitable for measurements during sleep, the ThorAKUSTIK system has been developed. By attaching a noise sensor right next to larynx, it determines the respiratory flow in an acoustic way. METHODS: The ThorAKUSTIK system as well as a pneumotachograph were applied simultaneously. The correlation between those two methods has been calculated. PATIENTS: We investigated twenty male subjects. All of them were non-smokers. RESULTS: The ThorAKUSTIK-System showed a highly positive correlation (r = 0.89 to 0.91; p < 0.01) and was able to measure the respiratory flow in a reliable way. CONCLUSIONS: The ThorAKUSTIK-System allows a long-term live monitoring and has the potential to be used in several clinical departments. Larger studies are necessary to verify the application in the clinical routine. PMID- 23015202 TI - Down-regulation of hepatic phosphoenolpyruvate carboxykinase expression in magnesium-deficient rats. AB - Many epidemiological studies have reported the link between magnesium deficiency and metabolic syndrome. We examined whether magnesium deficiency in rats induces changes in glucocorticoid metabolism. Twelve-week-old, female Wistar rats were weaned onto a very low-magnesium diet or a control diet for two weeks. Quantitative real-time PCR was used to assess mRNA for 11beta hydroxysteroid dehydrogenase-1 (11beta-HSD1), 11beta-HSD2, phosphoenolpyruvate carboxykinase (PEPCK), peroxisome proliferator-activated receptor alpha (PPARalpha), and glucocorticoid receptor in the liver. Concentrations of adiponectin, leptin, corticosterone, insulin and asymmetric dimethylarginine (ADMA) in fasting serum were determined using a rat-specific enzyme-linked immunosorbent assay. After two weeks, no differences in serum glucose, leptin, corticosterone, or adiponectin levels were observed between the groups. Magnesium-deficient rats showed higher HOMA-IR, insulin, ionized calcium, ADMA levels and diastolic blood pressure. There were no significant differences in hepatic mRNA expression levels of GR, 11beta-HSD1, 11beta-HSD2, or PPARalpha between the groups. We observed lower expression of hepatic PEPCK mRNA, in the magnesium-deficient rats, thus suggesting a possible compensatory mechanism to diminish glycogenesis. A low magnesium diet alters glucocorticoid metabolism, which leads to endothelial damage. Higher ADMA induces hypertension and insulin resistance. Hyperinsulinemia induces hepatic down-regulation of PEPCK, and is possibly a key mechanism inducing the metabolic complications of magnesium deficiency. PMID- 23015204 TI - A letter from the editor. PMID- 23015205 TI - Panoramic optical imaging of electrical propagation in isolated heart. AB - Optical imaging of cardiac transmembrane potential in dye-stained tissue is an emerging technique in cardiac electrophysiology. Despite its widespread application to studies of isolated hearts, it has been applied traditionally to recording only a single view that presents the potential distribution of a fraction of the cardiac surface. This poses a significant limitation in studying whole heart electrophysiology, particularly when large-scale phenomena such as fibrillation and defibrillation are of interest. We have developed a panoramic imaging system based on a high-speed charge-coupled device camera with a maximum imaging speed of 335 frames/s at 128*64 pixels/frame. Our system provides one front view and two back mirror views of isolated hearts, thus extending optical imaging capabilities to record from the entire three dimensional heart surface with only one camera. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015203 TI - Cloning and comparative analysis of carotenoid beta-hydroxylase genes provides new insights into carotenoid metabolism in tetraploid (Triticum turgidum ssp. durum) and hexaploid (Triticum aestivum) wheat grains. AB - Carotenoid beta-hydroxylases attach hydroxyl groups to the beta-ionone rings (beta-rings) of carotenoid substrates, resulting in modified structures and functions of carotenoid molecules. We cloned and characterized two genes (each with three homeologs), HYD1 and HYD2, which encode beta-hydroxylases in wheat. The results from bioinformatic and nested degenerate PCR analyses collectively suggest that HYD1 and HYD2 may represent the entire complement of non-heme di iron beta-hydroxylases in wheat. The homeologs of wheat HYDs exhibited major beta ring and minor epsilon-ring hydroxylation activities in carotenoid-accumulating E. coli strains. Distinct expression patterns were observed for different HYD genes and homeologs in vegetative tissues and developing grains of tetraploid and hexaploid wheat, suggesting their functional divergence and differential regulatory control in tissue-, grain development-, and ploidy-specific manners. An intriguing observation was that the expression of HYD1, particularly HYD-B1, reached highest levels at the last stage of tetraploid and hexaploid grain development, suggesting that carotenoids (at least xanthophylls) were still actively synthesized in mature grains. This result challenges the common perception that carotenoids are simply being turned over during wheat grain development after their initial biosynthesis at the early grain development stages. Overall, this improved understanding of carotenoid biosynthetic gene expression and carotenoid metabolism in wheat grains will contribute to the improvement of the nutritional value of wheat grains for human consumption. PMID- 23015206 TI - Assessment of spatially resolved spectroscopy during cardiopulmonary bypass. AB - Controversy remains about which tissue is primarily responsible for light attenuation of near infrared spectroscopy (NIRS) in the adult, the spatial resolution provided and the preferred algorithm for quantification. Until recently, changes in NIRS have not been fully quantified and have been difficult to interpret without sophisticated computation. A new development by Hamamatsu Photonics, the spatially resolved spectrometer (SRS), may be able to give a quantitative measure of oxygen saturation. We have incorporated the SRS into a multimodality monitoring system for the purpose of direct validation against jugular bulb oxygen saturation (SjO2) in patients undergoing routine cardiopulmonary bypass (CPB). The importance of this investigation is in the development of the SRS machine which shows potential as a useful clinical tool. The results demonstrated good correlation between SRS and SjO2 in 12 out of the 24 patients studied. Although these results are encouraging, this study suggests that the SRS, in its present form, is not a reliable clinical monitor of cerebral oxygen saturation during CPB. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015207 TI - Custom designed acoustic pulses. AB - We have used a tunable, infrared, free-electron laser with a Pockels cell controlled pulse duration to generate photoacoustic pulses with separate variable rise times (from 15 to 100 ns), durations (100-400 ns), and amplitudes (0.005-0.1 MPa). The tunability of the free-electron laser across water absorption bands allows the rise time of the thermal-elastically generated acoustical pulsed to be varied, while a Pockels cell controls the duration and cross polarizers control the pressure amplitude. The mechanical effects of pressure transients on biological tissue can have dramatic consequences. In addition to cell necrosis, carefully controlled pressure transients can also be used for therapeutic applications, such as drug delivery and gene therapy. This technique permits systemic probing of how biological tissue is affected by stress transients. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015208 TI - Fiber optic sensor for the measurement of respiratory chest circumference changes. AB - A fiber optic sensor for the measurement of the respiratory depth has been developed. The sensor is composed of a bent optic fiber which is connected to an elastic section of a chest belt so that its radius of curvature changes during respiration due to respiratory chest circumference changes (RCCC). The measurement of light transmission through the bent fiber provides information on its changes in curvature since a higher fraction of light escapes through the core-cladding surface of a fiber bent to a lower radius of curvature. The sensor can quantitatively measure the RCCC, although in relative terms, and it is sensitive enough to detect changes of the chest circumference due to the heart beat. Measurements of the RCCC were simultaneously performed with photoplethysmography (PPG)-the measurement by light absorption of the cardiac induced blood volume changes in the tissue-and a significant correlation was found between the RCCC and some parameters of the PPG signal. The fiber optic respiratory depth sensor enables a quantitative assessment of the respiratory induced changes in the cardiovascular parameters. (c) 1999 Society of Photo Optical Instrumentation Engineers. PMID- 23015209 TI - Correlation properties of light backscattered multiply from fractal aggregates of particles under brownian motion. AB - Studies on the phenomena of light scattered multiply from strongly absorbent media have been of benefit to metrology in biophysics, chemistry, and other areas. In this article, a temporal autocorrelation function of time-varying light backscattered multiply from a fractal aggregate of particles under Brownian motion suspended in an absorbent medium is investigated by means of Monte Carlo simulation. Temporal statistics of the backscattered light in time regions longer and shorter than the relaxation time depend on the fractal dimension and agree with the case of the homogeneously random media, respectively. The angular dependence of light backscattered multiply from fractal media varies dramatically depending on the fractal dimension in comparison with that from homogeneously random media. The influence of absorption generates the time shift in the temporal autocorrelation function in such a way that they vary approximately in accordance with a square root of the absorption coefficient but are independent of the fractal dimension. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015210 TI - Early development of optical low-coherence reflectometry and some recent biomedical applications. AB - This paper explains the term low-coherence interferometry, reviews the early development of optical low-coherence reflectometry, and shows some of the paths that led to the field of biomedical optics. This paper demonstrates that early technical developments in the telecommunications industry resulted in a myriad of technical implementations and applications in biology, medicine, and the explosion of the field in noninvasive biomedical optical techniques. Recent examples of innovative applications of this proliferating technology into the fields of ophthalmology, developmental biology, and endoscopy are described. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015211 TI - Effect of blood vessel discreteness on necrosis formation during laser induced thermal coagulation limited by heat diffusion. AB - When heated, living tissue exhibits random nonuniformities in temperature that are due to the discreteness of vessel arrangement. Because of the strong temperature dependence of the thermal coagulation rate these nonuniformities should substantially affect the necrosis growth induced by local heating. In the present work we study the effect of vessel discreteness on the form of a necrosis domain when its growth is limited by heat diffusion into the surrounding tissue. Namely, we analyze the characteristics of the necrosis boundary that are due to vessel discreteness. In particular, we find the mean amplitude deltaGamma and the correlation length lGamma of the necrosis boundary perturbations depending on the main tissue parameters. In addition, it is shown that there are universal relations between the mean size R of the necrosis domain and the characteristics deltaGamma,lGamma of the boundary perturbations, which are due to the fractal structure of the vascular network. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015212 TI - Cell Viability and DNA Denaturation Measurements by Two-Photon Fluorescence Excitation in CW Al:GaAs Diode Laser Optical Traps. AB - Cell viability and DNA denaturation are measured through two-photon fluorescence excitation using a single diode laser beam as the trapping and exciting source simultaneously. Two-photon fluorescence emission spectra are presented for CHO cells and T lymphocytes loaded with various fluorescent probes. This single beam method is demonstrated to be a safe tool to monitor the viability of optically trapped cells, even under intense 809 nm diode laser illumination (~106 W/cm2). The dynamics of cellular necrosis is monitored by adding ethanol to the cell suspension during trapping. Thermal damage to heat-treated samples is assessed by recording shifts in the emission spectra from trapped cells loaded with the nucleic acid probe, acridine orange. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015213 TI - Salt leaching leads to drier soils in disturbed semiarid woodlands of central Argentina. AB - Disturbances in semiarid environments have revealed a strong connection between water, salt and vegetation dynamics highlighting how the alteration of water fluxes can drive salt redistribution process and long-term environmental degradation. Here, we explore to what extent the reciprocal effect, that of salt redistribution on water fluxes, may play a role in dictating environmental changes following disturbance in dry woodlands. We assessed salt and water dynamics comparing soil-solution electrical conductivity, chloride concentration, soil water content (SWC) and soil matric and osmotic water potential (Psim, Psios) between disturbed and undisturbed areas. A large pool of salts and chlorides present in undisturbed areas was absent in disturbed plots, suggesting deep leaching. Unexpectedly, this was associated with slight but consistently lower SWC in disturbed versus undisturbed situations during two growing seasons. The apparent paradox of increased leaching but diminishing SWC after disturbance can be explained by the effect of native salt lowering Psios enough to prevent full soil drying. Under disturbed conditions, the onset of deep drainage and salt leaching would raise Psios allowing a decline of Psim and SWC. Soil water storage seems to be modulated by the presence (under natural conditions) and partial leaching (following selective shrub disturbance) of large salt pools. This counterintuitive effect of disturbances may be important in semiarid regions where deep soil salt accumulation is a common feature. Our results highlight the importance of water-salt-vegetation coupling for the understanding and management of these systems. PMID- 23015214 TI - Synthesis, characterization and anti-diabetic therapeutic potential of a new benzyl acid-derivatized kojic acid vanadyl complex. AB - Vanadium complexes are potent hypoglycemic agents and of great potential for therapeutical treatment of diabetes. In the present work, a novel vanadium compound, bis ((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl benzoatato) oxovanadium (IV) (BBOV) has been synthesized. Treatment of STZ-induced diabetic rats with BBOV restored the blood glucose to normal level and ameliorated glucose tolerance. The hypoglycemic effect of BBOV is similar to that of bis (maltolato) oxovanadium but is less toxic in median lethal dose. Overall, the present work will provide useful information for further development of new anti-diabetic vanadium compounds. PMID- 23015215 TI - Improvement happens: a commercial IT solution for reviving primary care? An interview with Hello Health CEO Nathanial Findlay and colleagues by Richard L. Kravitz. PMID- 23015217 TI - Large-scale parentage analysis in an extended set of grapevine cultivars (Vitis vinifera L.). AB - Inheritance of nuclear microsatellite markers (nSSR) has been proved to be a powerful tool to verify or uncover the parentage of grapevine cultivars. The aim of the present study was to undertake an extended parentage analysis using a large sample of Vitis vinifera cultivars held in the INRA "Domaine de Vassal" Grape Germplasm Repository (France). A dataset of 2,344 unique genotypes (i.e. cultivars without synonyms, clones or mutants) identified using 20 nSSR was analysed with FAMOZ software. Parentages showing a logarithm of odds score higher than 18 were validated in relation to the historical data available. The analysis first revealed the full parentage of 828 cultivars resulting in: (1) 315 original full parentages uncovered for traditional cultivars, (2) 100 full parentages confirming results established with molecular markers in prior papers and 32 full parentages that invalidated prior results, (3) 255 full parentages confirming pedigrees as disclosed by the breeders and (4) 126 full parentages that invalidated breeders' data. Second, incomplete parentages were determined in 1,087 cultivars due to the absence of complementary parents in our cultivar sample. Last, a group of 276 genotypes showed no direct relationship with any other cultivar in the collection. Compiling these results from the largest set of parentage data published so far both enlarges and clarifies our knowledge of the genetic constitution of cultivated V. vinifera germplasm. It also allows the identification of the main genitors involved in varietal assortment evolution and grapevine breeding. PMID- 23015216 TI - Differences in intraprocedural ACTs with standardized heparin dosing during catheter ablation for atrial fibrillation in patients treated with dabigatran vs. patients on uninterrupted warfarin. AB - PURPOSE: Effective intraprocedural anticoagulation for catheter ablation for atrial fibrillation is critical to minimize the risk of cerebral thromboembolism. The effect of dabigatran on anticoagulation with heparin during the procedure is unknown. This study compares heparin anticoagulation in patients treated with dabigatran vs. patients on uninterrupted warfarin. METHODS: Seventy-six consecutive patients (24 dabigatran and 52 warfarin) subjected to a standard intraprocedural heparin protocol were included. Heparin administration and rapidity and degree of anticoagulation were compared between the groups. RESULTS: Despite greater administration of heparin (52.5 +/- 22.0 vs. 33.2 +/- 10.1 units kg(-1) h(-1); p < 0.001), the mean (320.3 +/- 19.5 s) and peak (358.8 +/- 28.6 s) activated clotting time (ACT) for the dabigatran group were significantly lower than for the warfarin group (mean, 362.9 +/- 35.9 and peak, 410.4 +/- 49.7; p < 0.001). The time from initial heparin bolus to first ACT of >=300 s in the dabigatran group was more than twice that observed in the warfarin group (45.0 +/ 30.4 vs. 20.9 +/- 14.5 min; p < 0.001). The time to first ACT of >=350 s was similarly prolonged (109.1 +/- 60.0 vs. 55.2 +/- 51.1 min; p < 0.001) in the dabigatran group, with eight patients (33 %) failing to reach this target. Outcome differences persisted following analysis using linear models and Cox proportional hazard regression with adjustment for propensity scores. CONCLUSION: A standard intraprocedural heparin protocol results in delayed and lower levels of anticoagulation as measured by the ACT for patients treated with dabigatran compared with those on uninterrupted warfarin. PMID- 23015218 TI - Molecular mapping of vernalization requirement and fertility restoration genes in carrot. AB - Carrot (Daucus carota L.) is a cool-season vegetable normally classified as a biennial species, requiring vernalization to induce flowering. Nevertheless, some cultivars adapted to warmer climates require less vernalization and can be classified as annual. Most modern carrot cultivars are hybrids which rely upon cytoplasmic male-sterility for commercial production. One major gene controlling floral initiation and several genes restoring male fertility have been reported but none have been mapped. The objective of the present work was to develop the first linkage map of carrot locating the genomic regions that control vernalization response and fertility restoration. Using an F(2) progeny, derived from the intercross between the annual cultivar 'Criolla INTA' and a petaloid male sterile biennial carrot evaluated over 2 years, both early flowering habit, which we name Vrn1, and restoration of petaloid cytoplasmic male sterility, which we name Rf1, were found to be dominant traits conditioned by single genes. On a map of 355 markers covering all 9 chromosomes with a total map length of 669 cM and an average marker-to-marker distance of 1.88 cM, Vrn1 mapped to chromosome 2 with flanking markers at 0.70 and 0.46 cM, and Rf1 mapped to chromosome 9 with flanking markers at 4.38 and 1.12 cM. These are the first two reproductive traits mapped in the carrot genome, and their map location and flanking markers provide valuable tools for studying traits important for carrot domestication and reproductive biology, as well as facilitating carrot breeding. PMID- 23015219 TI - Thoughts on one thousand chronic cough patients. AB - Cough is the most common complaint for which patients seek medical attention. Although most cases of acute cough, due to viral upper respiratory tract infection, are transient and self-limited, chronic cough often poses a diagnostic and therapeutic challenge. A subgroup of patients suffering from chronic cough will elude a diagnosis despite appropriate evaluation, and will prove refractory to all therapeutic intervention. Having personally evaluated 1000 individuals presenting to a specialty cough center, the author shares insights regarding the demographic composition of this unique group of patients, as well as clinical observations and opinions on currently unmet needs requiring further research. PMID- 23015221 TI - Effects of vehicle size on pedestrian injury pattern and severity: prospective study. AB - BACKGROUND: The type of injuries caused by sport utility vehicles may be different from those caused by small passenger cars. We studied prospectively the effects of the offending vehicle type and design on severity and pattern of pedestrian injuries. METHODS: All injured pedestrians admitted to the two major trauma centers of Al-Ain city were studied prospectively during the period of April 2006 to October 2007. Patients were classified into two groups according to the offending vehicle type: small vehicle and sport utility vehicle. These two groups were compared regarding the distribution of injury and its severity. RESULTS: The anatomical distribution of injury in a descending order were the lower extremities (56.3, 67 %), head (53.8, 57.1 %), face (37.5, 57.1 %), and upper extremities (32.5, 28.6 %) in small vehicle and sport utility vehicle groups, respectively. No significant statistical difference has been found between the two groups regarding the anatomical distribution and severity. CONCLUSIONS: The vehicle size and design did not affect the anatomical injury distribution and severity in our setting. High-impact speed may overcome the vehicle type when it comes to injury severity and pattern of distribution. PMID- 23015222 TI - Does obesity affect outcomes in patients undergoing esophagectomy for cancer? Comments on a meta-analysis. PMID- 23015223 TI - Use of amylase and alanine transaminase to predict acute gallstone pancreatitis in a population with high HIV prevalence. AB - BACKGROUND: The etiology of acute pancreatitis can be difficult to determine early in the course of the disease. The aim of the present study was to determine the relationship between biochemical parameters and the cause of acute pancreatitis. METHODS: A prospectively collected database of patients admitted with acute pancreatitis between 2001 and 2008 was analyzed. The relationships between etiology and age, sex, admission serum amylase level, and admission alanine transaminase (ALT) level were evaluated. RESULTS: Acute pancreatitis was diagnosed in 464 patients. The disease was related to alcohol in 275 cases, gallstones in 81 cases, HIV in 49 cases, dyslipidemia in 42 cases, and it was idiopathic in 17 cases. Alcoholic pancreatitis was more common in men, whereas the other identifiable causes were more common in women (P < 0.001). Mean age at presentation was 39 years with no difference in age in relation to etiology (P = 0.057). When compared to patients with non-biliary causes of pancreatitis, patients with gallstone pancreatitis had greater median (range) serum amylase activity [1,423 U/l (153-7,500 U/l) versus 589 U/l (58-11,144 U/l); P < 0.001] and ALT activity [153 U/l (8-13,233 U/l) versus 31 U/l (6-421 U/l); P < 0.001]. No significant differences in amylase or ALT activity were found between non biliary etiologies (P > 0.05). Alanine transaminase was the only factor independent of sex to predict gallstone etiology, with activity >150 U/l having a specificity of 97 %. CONCLUSIONS: In patients with acute gallstone pancreatitis, the serum amylase and ALT activities were more than double those of other etiologies. An ALT level of >150 U/l was highly predictive of gallstone etiology independent of gender. Neither amylase nor ALT could differentiate non-biliary etiologies. The combination of amylase and ALT offered no improvement in predicting etiology over each alone. PMID- 23015224 TI - Preoperative assessment of tumor location and station-specific lymph node status in patients with adenocarcinoma of the gastroesophageal junction. AB - BACKGROUND: In esophageal cancer patients preoperative staging will determine the type of surgical procedure and use of neoadjuvant therapy. Tumor location and lymph node status play a pivotal role in this tailored strategy. The aim of the present study was to prospectively evaluate the accuracy of preoperative assessment of tumor location according to the Siewert classification and lymph node status per station with endoscopy/endoscopic ultrasound (EUS) and computed tomography (CT). METHODS: In 50 esophagectomy patients with adenocarcinoma of the gastroesophageal junction (GEJ), tumor location according to Siewert and N-stage per nodal station as determined preoperatively by endoscopy/EUS and CT were compared with the histopathologic findings in the resection specimen. RESULTS: Overall accuracy in predicting tumor location according to the Siewert classification was 70 % for endoscopy/EUS and 72 % for CT. Preoperative data could not be compared with the pathologic assessment in 11 patients (22 %), as large tumors obscured the landmark of the gastric folds. The overall accuracy for predicting the N-stage in 250 lymph node stations was 66 % for EUS and 68 % for CT. The accuracy was good for those stations located high in the thorax, but poor for celiac trunk nodes. CONCLUSIONS: Given the frequent discrepancy between the endoscopic and pathologic location of the GEJ and the common problem of advanced tumors obscuring the landmarks used in the assessment of the Siewert classification, its usefulness is limited. The overall accuracy for EUS and CT in predicting the N-stage per station was moderate. PMID- 23015227 TI - Perifosine induces cell apoptosis in human osteosarcoma cells: new implication for osteosarcoma therapy? AB - Despite the advances of adjuvant chemotherapy and significant improvement of survival, the prognosis for patients with osteosarcoma is generally poor. The search for more effective anti-osteosarcoma agents is necessary and urgent. Here we report that perifosine induces cell apoptosis and growth inhibition in cultured human osteosarcoma cells. Perifosine blocks Akt/mTOR complex 1 (mTORC1) signaling, while promoting caspase-3, c-Jun N-terminal kinases (JNK), and p53 activation. Further, perifosine inhibits survivin expression probably by disrupting its association with heat shock protein-90 (HSP-90). These signaling changes together were responsible for a marked increase of osteosarcoma cell apoptosis and growth inhibition. Finally, we found that a low dose of perifosine enhanced etoposide- or doxorubicin-induced anti-OS cells activity. The results together suggest that perifosine might be used as a novel and effective anti osteosarcoma agent. PMID- 23015228 TI - Patients with well-established ankylosing spondylitis show limited deterioration in a ten-year prospective cohort study. AB - This study aims to describe the deterioration of well-established ankylosing spondylitis (AS) over a 10-year period. Patients with well-established AS under secondary care review were assessed at baseline and re-assessed after a 10-year period. Data on patient characteristics, spinal mobility and self-reported health status (AS Quality of Life, Bath AS Disease Activity Index, EuroQoL, Revised Leeds Disability Questionnaire and Short Form-12) were compared between the two time points. One hundred fifty-nine patients took part in the initial assessment. After 10 years, 69/117 patients still under secondary care follow-up attended a second assessment. At the second assessment, this cohort was predominately male (92.8 %), mean age of 48.7 years (SD 9.7) and mean disease and symptom duration of 14.9 (SD 9.0) and 21.9 years (SD 13.3), respectively. Amongst the physical and patient-reported measures, only tragus to wall (p < 0.001), cervical rotation (p = 0.001) and disability (p = 0.02) had significantly deteriorated over time. The percentage of patients who had withdrawn from the workforce before normal retirement age increased from 37 to 53 % over the 10-year period. Many of the measures used in the assessment of AS do not generally deteriorate over time in those with well-established disease. This suggests that deterioration may plateau in established disease. However, AS has a long-term social impact with levels of employment in this cohort 30 % lower than the general population. Interventions directed at preventing deterioration may be more effective earlier in their disease course, before this plateau is reached. PMID- 23015229 TI - Reflections of caretakers on the process of implementation of life space crisis intervention at a therapeutic centre for youngsters with emotional and behavioural disorders. AB - Life space crisis intervention (LSCI) is a therapeutic and verbal strategy used to intervene when children are in crisis. It has its roots in the work of Aichorn, Redl, Wineman and Bettelheim, and is part of the milieu-therapeutic tradition. In 2000, LSCI was introduced at the Orthopedagogical Observation and Treatment Centre, a school and day unit for 60 children with emotional and behavioural disorders affiliated with the Department of Orthopedagogy at Ghent University (Belgium). The particular position of orientation towards 'therapeutic environments' in the department's history has encouraged the integration of LSCI in the daily activities of the departments' school (Broekaert et al., Int J Ther Communities 30(2):122-145, 2009). In 2003, LSCI was implemented and studied in several Flemish Institutes. Positive effects were found on school results, attendance in the classroom and number of conflicts. In this article, the reflections of the caretakers are taken into account. Analyses of these reflections resulted in 4 major themes: content of job and tasks, the youth in the centre, working with the youth in the centre, and cooperation with colleagues and other teams. The results of this analysis will be discussed. PMID- 23015230 TI - [Cognitive-behavioral specialized units in Alzheimer disease treatment: a necessity]. PMID- 23015231 TI - [Arterial stiffness a new risk factor to measure]. AB - We revue the epidemiology of cardiovascular disease in the elderly, their relationship to arterial stiffness. The measurement of arterial stiffness is of considerable increasing interest in this early 21 century. This paper is focusing on modeling, in different measurement methods. Several measurement techniques are presented. A review of the bibliography that explain the link between cardiovascular risk factors and arterial stiffness is summarized, as are the relationships between the various risk factors and arterial stiffness. The current role of these measurement methods seems to be time consuming although the European consensus recommends the measure once a year in the management of vascular patients. New techniques for the assessment of the arterial stiffness, more reproducible and easy to use, could ultimately trivialize this measurement, contributing in medical practice to the assessment and the management of the vascular risk. PMID- 23015232 TI - [Healing gardens: recommendations and criteria for design]. AB - The French Alzheimer plan anticipates new specialized structures for cognitive rehabilitation and psycho-behavioural therapy of Alzheimer's patients: the cognitive-behavioural units as follow-care units, the units of reinforced hospitalization inside the long term care units and the adapted activities units. this plan indicates the need to make healing gardens integral parts of these units. The benefits of green space in urban environments has been demonstrated with regards to physical, psychological and sociological effects and similarly studies in hospitals have revealed objective and measurable improvements of patients well being. Although green spaces and gardens are available in many French care units, they are rarely specifically adapted to the needs of Alzheimer's patients. For the garden "art, memory and life" a specific concept guided by a neuropsychological approach was developed, complemented by an artistic vision based on cultural invariants. It is already used in the frame of non-pharmacological therapies to improve symptoms such as deambulation, sleep disorders, apathy and aggressive behaviors. Based on the literature, and our experience and research, recommendations for the design of such gardens dedicated to Alzheimer's patients can be proposed. Beyond taking into account obvious aspects relating to security, allowing for free access, a careful design of walk ways and a conscious choice of plants is needed. A systematic analysis of the existing green spaces or garden must be conducted in order to pinpoint the weakness of the space and identify the potential for developing it into a real healing garden. Evaluation of adapted questionnaires for users and professionals allow to establish a list of requirements combining both user requests and therapeutic needs as basis for the design of the garden as well as to evaluate during the course of the project, whether the needs of the various stakeholders have been met or if adjustments are necessary. PMID- 23015233 TI - [A same deficit of cognitive inhibition in early and late-onset depression in elderly women: a pilot study]. AB - OBJECTIVE: Late-life depression has been associated with frontostriatal abnormalities that are thought to lead to deficits of cognitive inhibition. However, it remains unclear, whether age-of-onset identifies subgroups of depression. The objective of this study was to compare cognitive inhibition in depressed women aged 60 and older, according to age of the first onset depression (before or after 60 years old). METHODS: We compared 10 currently depressed women (HDRS-17>=18) with a late-onset depression to 10 depressed women with an early onset depression, and to 10 healthy controls. We examined cognitive inhibition (Stroop, Hayling, Go/No-Go), shifting (TMT), updating in working memory (WAIS) and executive functions (BREF). All groups were matched for age, education level, and MMSE score (MMSE>=24). RESULTS: Depressed elderly women with a late and an early-onset depression had a greater impairment in executive functions and cognitive inhibition compared with healthy controls (p<0,001), but without significant differences according to the age of the first onset depression. Futhermore, late-onset depression in women was significantly correlated with a deficit of cognitive inhibition (rs=0.55; p=0.012). CONCLUSION: Cognitive inhibition should be assessed in late-life depression. Interventions may be developed to specifically target cognitive impairment in the prevention of late life depression, to identify those who are the most vulnerable to relapse. PMID- 23015234 TI - [Place and characteristics of patients older than 85 managed by mobile palliative care team; a retrospective study]. AB - The objectives of this study was to specify the place of the patients older than 85 in the activity of the Mobile health unit of the Hospital of Metz-Thionville, to determine their characteristics and to show possible care differences as compared with younger patients. This is a retrospective study concerning all the patients seen by the Mobile health unit in 2006 and 2007. The patients older than 85 represent 11% of the 652 patients followed by the Unit and 7.8% of the 2.436 consultations on the study period. The older patients have a WHO mean score significantly higher and a Karnofsky mean score significantly lower than the younger subjects. Their survival rate tends to be lower but not significantly. Cancers are less frequent in older patients and they have fewer consultations than younger ones. The older patients present fewer communication problems and less often pain than the younger patients. The prescriptions of non-opioid and opioid analgesics, steroids or antiepileptic drugs (used as analgesics) are less frequent in the older patients. The results of this study showed some specificities of palliative care in the older patients: we observed a great variety of pathologies and a lower frequency of cancers than in younger patients, various places of care, difficulties to evaluate the symptoms or to treat them due to communication problems especially. If these specificities are real, they do not seem to have important repercussions on following since the group of the patients older than 85 and the one of the younger patients differ only little in terms of survival rate or mean number of consultations. PMID- 23015235 TI - [Cognitive-behavioral specialized units: predictive factors of readmissions within three months]. AB - BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are frequent and belong to the natural evolution of the disease. Specialized cognitive behavioral units (Unites cognitivo-comportementales) were created, in France (plan Alzheimer 2008-2012), to cope with this problem. Despite a stay in such a unit, some patients have to be rehospitalized. The main aim of the current study was to highlight the predictive factors of readmissions. METHOD: Descriptive, retrospective study of demented patients >=75 years, hospitalized between January 2010 and April 2011. We compared patients that had to be rehospitalized within 3 months (group 1), with the patients that did not need to be rehospitalized or after 3 months of time (group 2). Patients characteristics included: basic daily living activities (French GIR score), MMSE score, neuropsychiatric inventory score, type of BPSD, length of stay and antipsychotropic drugs. RESULTS: Two hundred thirty-five patients were included including, 147 women (62.5%), with mean age of 82.74+/-7.13 years. SPCD was the main reason for hospitalization. Thirty patients (12.77%) belonged to group 1. The mean number of psychotropic treatments increased during the stay (p=0.02), particularly in group 2 (p=0.01). The NPI score decreased during the hospitalization in both groups. Linear regression analysis showed that behavioral type of symptoms (OR: 3.18; 95% CI 1.32-7.65) and association of antidepressant and antipsychotic drugs (OR: 4.77; 95% CI 1.35-16.83) were significantly predictive of an early readmission. The risk of readmission also significantly decreased as the length of stay increased. CONCLUSION: This work confirms the specificity and the need for such units. The results will help improving the outcome of demented patients with BPSD and treated with different antipsychotropic drugs. PMID- 23015236 TI - [Evaluation of adherence to recommendations within 3 months after comprehensive geriatric assessment by an inpatient geriatric consultation team]. AB - BACKGROUND: Frail elderly patients during their hospitalization can benefit of a comprehensive geriatric assessment (CGA) by an inpatient geriatric consultation team (IGCT). This assessment yields recommendations aiming to improve medical and social management during the patient's hospital stay and after discharge. OBJECTIVES: This study examines the socio-demographic profile of patients assessed by the IGCT and describes the type of recommendations, their adherence rate at 3 months and their impact in terms of mortality, rehospitalization, and institutionalization. METHODS: Retrospective, single center study including all patients assessed by the IGCT during the 4 first months of 2009. These 151 patients fulfilled criteria of either medical and/or social frailty or had been submitted to an inappropriate in-hospital trajectory. Hospital records and telephone follow-up (with informal and/or professional caregivers as well as primary care physicians) were used to monitor the implementation of recommendations up to three months after hospital discharge. RESULTS: Mean age of the 151 patients was 85.6 years, 63% were women. 94% of patients lived at home, 70% had a non-supportive environment, 85% were frail and 11% had dementia. On admission, 64% of them had an acute functional loss. 93% of patients were admitted via the emergency room where 67% benefited from CGA. The median hospital duration stay was 14 days. At discharge, 76% of patients went back home, 12% were institutionalized and 12% had died. Three months after discharge, 18% of the 134 patients surviving hospitalization had been readmitted, 26% institutionalized and 12% had died. The CGA yielded an average of 7 recommendations (median value). The mean adherence rate was 78%. The majority of medical recommendations concerned ancillary care and standard medical management, showing high adherence rates (95%). Recommendations concerning the management of cognitive problems were less frequent and overall poorly adhered to (62%). CONCLUSION: Mean adherence rate was maximal (97%) when the number of recommendations was limited to 4 and it dropped under 80% with more than 5 recommendations. The recommendations concerning management at home were generally followed (60-77%). Regarding to social outcomes, the main recommendation was to mobilize home assistance and its financial support. There was no significant difference between adherence rate in the hospital and in the community. The extent of adherence rate did not correlate with mortality or readmission at 3 months. PMID- 23015237 TI - [Editorial]. PMID- 23015238 TI - [Stigmatization in Alzheimer's disease, a review]. AB - Stigma against chronic disease or mental illness is a well-known phenomenon and results in devastating consequences for individuals who suffer from these diseases and their families. However, few studies have evaluated the stigma and its various processes associated with Alzheimer's disease (AD). The aim of the present review is to discuss the concepts that underlie stigma and its different forms, and then to explain its causes and consequences. Indeed, if the stigma primarily affects individuals with a diagnosis of AD, recent studies have shown that the caregivers of the patients as well as their relatives are also exposed to stigma by association. Moreover, past and current studies on other chronic diseases highlight the importance of using methods issued from experimental social psychology to assess the explicit representations but also the implicit stigma associated with the disease. Finally, several researches and possible interventions are proposed to reduce the stigma associated with AD and related concepts such as MCI. PMID- 23015239 TI - [Identification and memorisation of emotions in Alzheimer's disease: a critical review of litterature]. AB - Although the first signs of Alzheimer's disease (AD) mainly affect episodic memory and executive functions, emotional disturbances also have a considerable impact on the mental and relational capacities of AD patients. In AD, the early impairment of amygdala structures, whose central role in the recognition and memorisation of emotions has previously been demonstrated, has led researchers to focus on the possible implications of such impairment in generating cognitive disturbances or behavioural troubles in these subjects. Several studies have shown that emotional processes are altered in AD, and can contribute to varying degrees to deficits in terms of social cognition, and to the generation of behavioural troubles. This review will detail the main avenues of research into the capacity to identify and memorise emotions in AD, and summarise the often conflicting results that have, to date, prevented the emergence of a general consensus concerning the emotional processes. It seems thereby legitimate to question about different elements that can explain these conflicting results, such as the existence of various theories, divergences about the definition of emotions and important methodological differences. PMID- 23015240 TI - [Addictive behaviors in the aged]. AB - This review is devoted to alcoholism but also to other substance-dependences (tobacco, medication, illicit drugs) and behavioral addictions (gambling) in the aged. Compared to younger subjects, addictions in older people are marked by the high frequency of somatic comorbidities, physiological changes related to age, increased severity due to atypical presentations. Moreover, usual screening tests and diagnostic questionnaires are often not suited for the aged. Psychopathology of addictions in the aged points out vulnerabilities not resolved with the advance in age, in connection with separation, narcissism, oral regression, alexithymia and other pathological dimensions of personality. The weight of the environment, dominated by a certain agism, remains a brake to the global care that must be based, as in younger adults, on motivational approach and specific treatments with special pharmacological vigilance. PMID- 23015241 TI - [Paquid 2012: illustration and overview]. AB - Paquid (personnes agees quid) is a population-based cohort specifically designed to study the epidemiology of brain aging and dependency in activities of daily living in elderly people. At baseline screening, 3.777 subjects older than 65 were randomly selected in 75 different parishes from Gironde and Dordogne, and two administrative districts around Bordeaux in South-Western France. The participation rate was 68%. Subjects were followed up every two to three years with repeated measures of cognition, instrumental and basic activities of daily living collected by a trained psychologist, and a systematic detection of incident cases of dementia. The participation rate of each follow-up screening was around 75%. The detection of dementia was conducted with a two-stage design, with a first stage conducted by the psychologist and the confirmation of the diagnosis made at home by a physician, specialist in Alzheimer disease and related disorders (ADRD). Over 20 years of follow-up more than 800 subjects developed incident dementia and more than 2.500 died. Paquid remains the only representative cohort of elderly people living at home in France, giving estimations of prevalence, incidence and duration of ADRD and dependency. Thirty six risk factors of dementia and/or AD have been studied. On the basis of the Paquid data, we have shown that the prodromal phase of AD was longer than ten years and that dementia represented the major cause of dependency in the elderly. PMID- 23015242 TI - [Is ageism a relevant concept for health care practice in the elderly?]. AB - With the demographic aging, the older adults' needs for assistance and care will inevitably increase. Therefore, it is important to explore the beliefs and attitudes of the health care professionals toward the elderly. This paper discusses the notion of ageism and its paradoxes in health care practices for the elderly. First, the concept of ageism is defined through its cognitive, affective and behavioral components. Second, on the basis of the literature review, different "age biases" induced by ageism are described, which can influence the assessment of health condition of the elderly, the treatment decisions, but also the attitudes of the health care workers with out-patients as with institutionalized subjects. Third, the potential negative effects of ageist stereotypes on the health status and psychological well-being of the elderly are examined. Finally, some propositions are made to oppose ageism in health care practices for the elderly, including continuing education, better knowledge of the diversity of aging processes, reflexion on professionals' own prejudices, values and beliefs, promotion of relational attitudes which sustain autonomy. PMID- 23015243 TI - [Caring for young patients with Alzheimer's disease or associated disorders in day care centers of the Rhone-Alpes region]. AB - CONTEXT: The prevalence of Alzheimer's disease and associated disorders (ADAD) increases with aging but patients younger than 65 years may also be concerned. OBJECTIVE: To assess how ADAD young patients (less than 65 years old) were managed in day care centers in the Rhone-Alpes Region (France). METHOD: A questionnaire was sent to the day care centers to specify the number and the profile of young patients they took in care, and to assess their aptitude for accepting or not such patients. RESULTS: Forty-four day care centers had fulfilled the questionnaire (45%). The young patients displayed heterogeneous clinical presentations and types of coping. Only 29.5% of the day care centers received young ADAD patients. However most of them (78.6%) claimed to be ready to accept these patients even if they reported limitations for their activity. CONCLUSION: This study gives a fair idea of the present taking in care for young ADAD patients by day units in Rhone-Alpes region and provides some indications to improve their management. PMID- 23015244 TI - [Psychiatric outpatient consultation-liaison services--how do they work and what are their effects: results of a pilot study?]. AB - OBJECTIVES: Many patients benefit from interventions performed by the psychiatric liaison service. METHODS: Prospective longitudinal study of community dwelling elderly patients supplemented by a questionnaire answered by family members, as well as expert interviews with the members of the consultation-liaison team and semi-structured interviews with family members. RESULTS: The majority of patients had some benefit from the liaison psychiatric interventions, access to care was improved and lack of specialist support was reduced. In addition there was some cost offset due to prevention of admissions to nursing homes and inpatient hospital treatment. DISCUSSION: With regard to demographic developments gerontopsychiatric liaison services should be integrated into the present system of health care. This should be supported by adjusting judicial obstacles that hamper such strategies. PMID- 23015246 TI - A letter from the editor. PMID- 23015245 TI - [Implementation of joint-crisis plans--a study of health care users and professionals]. AB - OBJECTIVE: To study effects of the implementation of joint-crisis plans (JCP) on health-care users and professionals. METHODS: The first 3 years of the implementation of JCP were followed with structured interviews with health-care users and professionals. Legal and administrative complications were documented. RESULTS: 36 of 44 subjects with JCP were assessed. Most of them had learned of JCP through other users or self-help. 55 % had prior experience with compulsory treatment. Better communication and self-determination were main goals of JCP. A relevant change in hospital treatment through JCP was not observed. Only few professionals had made direct experience with JCP. They valued JCP mildly positive. No legal and administrative complications were documented. CONCLUSIONS: Only a small minority of users signed JCP. JCP were easily employed and improved communication and self-determination. PMID- 23015247 TI - Photodynamic treatment of epithelial tissue derived from patients with endometrial cancer: a contribution to the role of laminin and epidermal growth factor receptor in photodynamic therapy. AB - Photodynamic therapy (PDT) was used to treat endometrial G1 cancer tissue derived from patients who had undergone a total hysterectomy and bilateral salpingo oophorectomy. After surgical treatment the cancerous tissue was kept in a medium containing Dulbecco solution, fetal calf serum, and antibiotics. The tissue was then exposed to hematoporphyrin derivative (0.1 mg/l) and 24 h later exposed to light (total light dose-18 J/sq cm). Necrosis depth was evaluated 24 h later using a light microscope. In order to assess the possible role of the basal membrane component laminin, as well as epidermal growth factor receptor susceptibility to PDT, immunohistochemical studies were carried out. Additionally, nucleolar organizer regions evaluation was performed. Our experiment confirmed that PDT results in the necrosis in the treated endometrial cancer, while not affecting the laminin in the cancerous tissue. In contrast, PDT strongly affects the epidermal growth factor receptor and nucleolar organizer regions in cancer cells. We suggest that laminin may contribute to the prevention of cancer dissemination in the cases where PDT has to be repeated, and that after PDT the cells become less susceptible to a mitogen, like, e.g., epidermal growth factor. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015248 TI - Naphthalocyanine complexes as potential photosensitizers for photodynamic therapy of tumors. AB - In the present paper information about the synthesis and results on the pharmacokinetic and experimental photodynamic therapy (PDT) of naphthalocyanines are given. The photodynamic activity of differently substituted zinc(II)- and silicon(IV)-naphthalocyanines using liposomes or Cremophor EL as drug-delivery systems is shown on different tumor models. For the evaluation of the phototherapeutic effect different assessment criteria were used, including light and electron microscopy observations. The main conclusions which can be arrived at on the basis of our findings are the following: silicon(IV)-naphthalocyanine seems to be not a very effective tumor sensitizer, especially in the treatment of pigmented melanoma, while zinc(II)-naphthalocyanines appear to be very promising for PDT of tumors. Their selective targeting and slow clearance from tumor tissue, fast clearance from skin and pronounced phototherapeutic effect on different tumor models and especially at melanotic tumors, even after application of low drug doses, make this group of photosensitizers very attractive for successful PDT of cancer. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015249 TI - Topical versus Systemic 5-Aminolevulinic Acid Administration for Photodynamic Therapy of the Colon in B10.RBP Mice. AB - 5-aminolevulinic acid (5-ALA) is an interesting photosensitizing substance for photodynamic therapy (PDT), successfully applied topically for urological malignancy. In gastroenetrology it has proven efficacy for treatment of some GI neoplasms after systemic administration. This study was aimed at investigating the possibility of topical 5-ALA administration also for the PDT of gut cancer in a mice model. 5-ALA solution at different concentrations (5%, 1.5%, and 0.5%) was instilled in the colon of mice, which was later removed and examined by fluorescence microscopy. The results of fluorescence studies were compared with those obtained in a control group treated with 5-ALA given systemically. Satisfactory epithelial fluorescence levels and good selectivity between gut layers was obtained after intracolonic 5-ALA instillation. However, mean fluorescence intensity was higher after systemic drug application. Our results suggest that 5-ALA may probably be used topically for the PDT of some gut neoplasms. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015250 TI - Photochemical decontamination of red cell concentrates with the silicon phthalocyanine pc 4 and red light. AB - Virus inactivation in red blood cell concentrates (RBCC) is being studied in order to increase the safety of the blood supply. For this purpose we have been studying the silicon phthalocyanine (Pc 4), a photosensitizer activated with red light. Two approaches were used to achieve enhanced selectivity of Pc 4 for virus inactivation. One was formulation of Pc 4 in liposomes that reduce its binding to red cells. The other was the use of a light emitting diode (LED) array emitting at 700 nm. Vesicular stomatitis virus (VSV) infectivity served as an endpoint for virus kill in treated RBCC. Red cell hemolysis and circulatory survival in rabbits served as measures for red cell damage. Treatment of small aliquots of human RBCC with 2 MUM Pc 4 in liposomes and 10 J/cm2 of 700 nm LED light in the presence of the quenchers of reactive oxygen species glutathione and trolox resulted in 6 log10 inactivation of VSV. Under these conditions hemolysis of treated red cells stored at 4 degrees C for 21 days was only slightly above that of control cells. Rabbit RBCC similarly treated circulated with a half life of 7.5 days compared with 10.5 days of control. It is concluded that Pc 4 used as described here may be useful for viral decontamination of RBCC, pending toxicological and clinical studies. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015251 TI - Tetrapyrrolic Glycosylated Macrocycles for an Application in PDT. AB - The synthesis and characterization of amphiphilic glycoconjugated porphyrins, benzochlorin, and azaporphyrins were reported. Among these molecules, several were found to be efficient photosensitizers in an in vitro assay using the human tumoral cell line HT29. Moreover, glycosylated benzochlorin and azaporphyrins, whose absorption bands in the red region of the visible spectrum are substantially increased as compared to porphyrins, display a good photocytotoxicity on tumor cells after irradiation with wavelength above 590 nm. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015252 TI - Spectral analysis of the porphyrins incorporation into human blood. AB - The porphyrins seem to be the most effective photosensitizers in photodynamic therapy of cancer. Monomers and dimers of sulfonated and nonsulfonated porphyrins [5,10,15,20-tetra-phenyl-porphyrin, 5,10,15,20-tetra-naphtyl-porphyrin (TNP), 5,10,15,20-tetra-p-sulfonato-phenyl-porphyrin (TS4PP) and 5,10,15,20-tetra-p sulfonato-naphtyl-porphyrin], are studied in this paper by means of different spectral methods (UV-vis, fluorescence and polarization fluorescence). The porphyrins as TNP seem to be the most effective photosensitizer especially in a DMSO:water binary mixture of solvent. Monomer-dimer and J-aggregation equilibria and the temperature dependence of TS4PP spectra are also studied in this paper. The incorporation of the forms of these porphyrins into blood cells is studied by means of the cytofluorimetric method. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015253 TI - Controlled temperature photothermal tissue welding. AB - Photothermal tissue welding has been investigated as an alternative surgical tool to improve bonding of a variety of severed tissues. Yet, after almost two decades of research, inconsistencies in interpretation of experimental reports and, consequently, mechanism of this photothermal process as well as control of dosimetry remain an enigma. Widespread clinical use may greatly depend on full automation of light dosimetry to perform durable and reproducible welds with minimal thermal damage to surrounding and/or underlying tissues. Recognizing photothermal damage as a rate process, radiometrically measured tissue surface temperature has been studied as an indirect marker of tissue status during laser irradiation. Dosimetry control systems and surgical devices were developed to perform controlled temperature tissue welding using surface temperature feedback from the site of laser impact. Nevertheless, end points that mark the completion of a durable and stable weld have not been precisely identified, and subsequently, not incorporated into dosimetry control algorithms. This manuscript reviews thermal dosimetry control systems of the 1990s in an attempt to systematically indicate the difficulties encountered so far and to elaborate on major issues for photothermal tissue welding to become a clinical reality in the new millennium. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015254 TI - Comparative study of laser damage threshold energies in the artificial retina. AB - Laser damage threshold energies produced from ultrashort (i.e., ?1 ns) laser pulses are investigated as a function of both pulse width and spot size for an artificial retina. A piece of film acts as the absorbing layer and is positioned at the focus of a variant on the Cain artificial eye [C. Cain, G. D. Noojin, D. X. Hammer, R. J. Thomas, and B. A. Rockwell, "Artificial eye for in vitro experiments of laser light interaction with aqueous media," J. Biomed. Opt.2, 88 94 (1997)]. Experiments were performed at the focal point and at two and ten Rayleigh ranges (RR) in front of the focus with the damage end point being the presence of a bubble imaged at the film plane. Pulse energy thresholds were determined for wavelengths of 1064, 580, and 532 nm with pulse durations ranging from the nanosecond (ns) to the femtosecond (fs) regime. For the at-focus data in the visible regime, the threshold dropped from 0.25 MUJ for a 532 nm, 5 ns pulse to 0.11 MUJ for a 580 nm, 100 fs pulse. The near-infrared (NIR) threshold changed from 5.5 MUJ for a 5 ns pulse to 0.9 MUJ for a 130 fs pulse at a distance two RR in front of the focus. The experiment was repeated using the same pulse widths and wavelengths, except the water path was removed to determine the impact of nonlinear self-focusing in water. A vertical microscope imaging system was employed in order to observe the threshold event. The NIR fluence threshold of 0.5 J/cm2 remained constant within an experimental uncertainty for all pulse widths, which corresponds to values in the literature [C. P. Lin and M. W. Kelly, "Ultrafast time-resolved imaging of stress transient and cavitation from short pulsed laser irradiated melanin particles," SPIE Laser-Tissue Interactions VI, Proc. SPIE2391, 294-299 (1995)]. The visible data also demonstrated a nearly constant fluence of 0.07 J/cm2. The disparity in thresholds between the two techniques arises from nonlinear optical phenomena related to propagation differences in the ocular fluid. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015255 TI - Activated rate processes and a specific biochemical mechanism for explaining delayed laser induced thermal damage to the retina. AB - Laser induced thermal damage to the retina is investigated. The one step Arrhenius type thermal damage integral of Henriques is analyzed for its strengths and weaknesses. The zero-order activated rate process is shown to well represent the data for pulse durations greater than 10 MUs. A zero-order biochemical damage mechanism involving free radical formation and thermal disruption of the melanosome's protein coat is proposed as the initial molecular process that leads to cellular damage which appears after a delay. Data are presented that show the photoactivation of melanin granule oxidative reactivity. This in vitro data is evidence for an important step in our hypothesized damage pathway. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015256 TI - Comparison of fluence rate distributions made by side-firing fibers in an optical phantom. AB - Side-firing fibers are used to provide coagulative therapy to the urologic tract. These fibers use different optical technologies to deflect the beam transverse to the fibers' optical axis. This produces emitted beams which differ in both beam direction and divergence angles. The relative optical performance of 13 fibers was studied in an optical phantom suspension. The fluence rate distribution created by each side-firing fiber was determined. The fluence rate distribution accounts for both the direct and spurious beams emitted from side-firing fibers as well as the light scattering produced by the target tissue. Based upon limited clinical dosimetry studies, the relative fluence rate distribution appears to indicate general exposure conditions for the evaluated fibers. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015257 TI - Effect of pulse shape on the efficiency of multiphoton processes: implications for biological microscopy. AB - The effects of spectral shape on two photon fluorescence excitation are investigated experimentally using an acousto-optic pulse shaper to modify femtosecond pulses from a Ti:sapphire laser. By using different spectral window shapes, we find that the measured two photon efficiency can vary by a factor of 2 for differently shaped spectra with the same full width at half maximum. We find that these effects are described well by a simple model assuming transform limited pulses. The fact that even small changes in the spectral wings can significantly affect the efficiency of nonlinear processes has implications for biological multiphoton imaging, where it may be desirable to minimize sample exposure to radiation and maximize fluorescence or harmonic efficiency. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015258 TI - Detection of breast lesions by holographic interferometry. AB - The holographic interferometry (HI) technique commonly used for nondestructive testing of laminate materials was applied to create fringe contour distortion near the site of indwelling breast lesions. For this medical imaging application, the HI technique was successful in demonstrating abnormal mechanical properties of living tissue. Adequate density and contrast of fringes, crucial factors necessary for analysis of surface deformation of an object, can be made only with an appropriate stressing method. We have applied vibration and mild pressure to the surface of female breasts for the purpose of detecting localized densities and mass alterations of the tissue, which may be indicative of an abnormality of that tissue. Even though each stressing method had both positive and negative aspects, pneumatic pressure was adopted for the present study because it was more suitable for a noninvasive and noncontact breast examination. We also developed a computer based holographic imaging system to precisely control the stressing phase for the pressure and laser triggering so the resultant holograms had manageable fringe density and repeatability. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015259 TI - Lymphocyte Nucleus Reconstruction via Wavelet Tomography. AB - A wavelet tomographic algorithm is presented for statistical reconstruction of a lymphocyte nucleus. The investigation is concerned with lymphocyte nuclei of peripheral blood from two groups of patients: those who live in the area affected by the Chernobyl accident and the control group. The purpose of reconstruction is to find the probability density function of radial distribution of condensed chromatin. The difference between the two test groups is seen from considering the results of reconstruction and the wavelet energy spectra. The Radon transform is treated here as a singular wavelet transform, which allows us to reconstruct the essential scales from projection and to denoise them simultaneously. The algorithm of reconstruction involves back projecting and continuous wavelet synthesis with denoising. The use of a special local filter insures the stability of reconstruction. (c) 1999 Society of Photo-Optical Instrumentation Engineers. PMID- 23015260 TI - HbA(1c) and birthweight in women with pre-conception type 1 and type 2 diabetes: a population-based cohort study. AB - AIMS/HYPOTHESIS: To investigate clinical and sociodemographic predictors of birthweight in singletons born to women with type 1 or type 2 diabetes. METHODS: Normally formed singleton live births and intrapartum stillbirths, born to women with pre-conception diabetes during 1996-2008, were identified from the population-based Northern Diabetes in Pregnancy Survey (n = 1,505). Associations between potential predictors and birthweight were analysed by multiple regression. RESULTS: Potentially modifiable independent predictors of increase in birthweight were pre-pregnancy care (adjusted regression coefficient [b] = 87.1 g; 95% CI 12.9, 161.3), increasing third-trimester HbA(1c) <=7% (53 mmol/mol) (b = 310.5 g per 1% [11 mmol/mol]; 95% CI 246.3, 374.7) and increasing maternal BMI (b = 9.5 g per 1 kg/m(2); 95% CI 3.5, 15.5). Smoking during pregnancy (b = -145.1 g; 95% CI -231.4, -58.8), later gestation at first antenatal visit (b = -15.0 g; 95% CI -26.9, -3.0) and higher peri-conception HbA(1c) (b = -48.2 g; 95% CI 68.8, -27.6) were independently associated with birthweight reduction. Pre pregnancy nephropathy (b = -282.7 g; 95% CI -461.8, -103.6) and retinopathy (b = 175.5 g; 95% CI -269.9, -81.0) were independent non-modifiable predictors of reduced birthweight, while greater maternal height was a non-modifiable predictor of increasing birthweight (b = 17.8 g; 95% CI 12.3, 23.2). Other predictors of birthweight increase were male sex, multiparity and increasing gestational age at delivery. Type or duration of diabetes, socioeconomic status and ethnicity were not associated with continuous birthweight. CONCLUSIONS/INTERPRETATION: Poor glycaemic control before and throughout pregnancy is associated with abnormal fetal growth, with increasing peri-conception HbA(1c) predicting weight reduction and increasing third-trimester HbA(1c) predicting increased birthweight. Women with microvascular complications of diabetes may require increased surveillance to detect fetal growth restriction. PMID- 23015262 TI - How flow changes polymer depletion in a slit. AB - A theoretical model is developed for predicting dynamic polymer depletion under the influence of fluid flow. The results are established by combining the two fluid model and the self-consistent field theory. We consider a uniform fluid flow across a slit containing a solution with polymer chains. The two parallel and infinitely long walls are permeable to solvent only and the polymers do not adsorb to these walls. For a weak flow and a narrow slit, an analytic expression is derived to describe the steady-state polymer concentration profiles in a Theta solvent. In both Theta- and good-solvents, we compute the time evolution of the concentration profiles for various flow rates characterized by the Peclet number. The model reveals the interplay of depletion, solvent condition, slit width, and the relative strength of the fluid flow. PMID- 23015261 TI - Elevated nuclear expression of the SMRT corepressor in breast cancer is associated with earlier tumor recurrence. AB - Silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), also known as nuclear corepressor 2 (NCOR2) is a transcriptional corepressor for multiple members of the nuclear receptor superfamily of transcription factors, including estrogen receptor-alpha (ERalpha). In the classical model of corepressor action, SMRT binds to antiestrogen-bound ERalpha at target promoters and represses ERalpha transcriptional activity and gene expression. Herein SMRT mRNA and protein expression was examined in a panel of 30 breast cancer cell lines. Expression of both parameters was found to vary considerably amongst lines and the correlation between protein and mRNA expression was very poor (R (2) = 0.0775). Therefore, SMRT protein levels were examined by immunohistochemical staining of a tissue microarray of 866 patients with stage I-II breast cancer. Nuclear and cytoplasmic SMRT were scored separately according to the Allred score. The majority of tumors (67 %) were negative for cytoplasmic SMRT, which when detected was found at very low levels. In contrast, nuclear SMRT was broadly detected. There was no significant difference in time to recurrence (TTR) according to SMRT expression levels in the ERalpha-positive tamoxifen-treated patients (P = 0.297) but the difference was significant in the untreated patients (P = 0.01). In multivariate analysis, ERalpha-positive tamoxifen-untreated patients with high nuclear SMRT expression (SMRT 5-8, i.e., 2nd to 4th quartile) had a shorter TTR (HR = 1.94, 95 % CI, 1.24-3.04; P = 0.004) while there was no association with SMRT expression for ERalpha-positive tamoxifen-treated patients. There was no association between SMRT expression and overall survival for patients, regardless of whether they received tamoxifen. Thus while SMRT protein expression was not predictive of outcome after antiestrogen therapy, it may have value in predicting tumor recurrence in patients not receiving adjuvant tamoxifen therapy. PMID- 23015263 TI - Preparation and evaluation of biocomposites as wound dressing material. AB - Collagen was isolated from the chrome containing leather waste (CCLW) which is a major solid waste in leather industry. Composite films were made using sago starch (SG), soya protein (SY), and collagen (C) and were cross linked with glutaraldehyde (G).The films prepared were characterized for their physico chemical properties like tensile strength, infrared spectra, thermogravimetric analysis, surface morphology, and water absorption studies. Better mechanical properties and surface morphology were observed for SG-SY-G-C films compared to other films prepared using collagen. The composite films prepared were used as wound dressing material on the experimental wounds of rats and healing pattern was evaluated using planimetric, biochemical, and histopathological studies. These studies have revealed better wound healing capacity of SG-SY-G-C film and utilization of CCLW in the preparation of value added product like wound dressing material. PMID- 23015264 TI - Feasibility, safety and pharmacokinetic study of hepatic administration of drug eluting beads loaded with irinotecan (DEBIRI) followed by intravenous administration of irinotecan in a porcine model. AB - Irinotecan eluting embolization beads (DEBIRI) are currently being evaluated in the clinic for the treatment of colorectal cancer metastases to the liver. The aim of this study was to determine the safety and pharmacokinetics associated with two cycles of hepatic embolization using DEBIRI followed by intravenous administration of irinotecan. Pigs were embolized with DEBIRI (100-300 MUm, 100 mg dose, n = 6) and blood samples taken over 24 h to determine plasma levels of irinotecan and SN-38 metabolite and for haematology and biochemistry. At 24 h an IV infusion of 250 mg/m(2) of irinotecan was administered and the plasma levels taken again. This cycle was repeated 3 weeks later. A single animal was subjected to a more aggressive regimen of embolization with 200 mg bead dose and IV of 350 mg/m(2) for two cycles. Three animals were sacrificed at 6 weeks and the remaining four (n = 3 standard dose, n = 1 high dose) animals at 12 weeks and detailed histopathology performed. All animals tolerated the treatments well, with only minor changes in haematological and biochemical parameters. There was no overlap in drug plasma levels observed from the bead and IV treatments when given 24 h apart and no difference between the pharmacokinetic profiles of the two cycles separated by 3 weeks. Irinotecan plasma AUC values were similar in both the embolization and IV arms of the study. C(max) values obtained during the IV arms of the study are approximately double that of the embolization arms whilst T(max) times are shorter in the IV arms, supporting extended release of drug from the beads. Bioavailability for bead-based delivery was double that for IV administration, which was attributed to reduced clearance of the drug when delivered by this route. No additive toxicity was observed as a consequence of the combined treatments. The combination of irinotecan delivery via drug eluting bead and IV was well-tolerated with no significant clinical effects. Pharmacokinetic analyses suggest the bioavailability from bead-based delivery of drug is double that of IV infusion, attributable to reduced drug clearance for the former. PMID- 23015265 TI - In vitro characterization and ex vivo surgical evaluation of human hair keratin films in ocular surface reconstruction after sterilization processing. AB - The disadvantages of human amniotic membrane (hAM), used for ocular surface reconstruction, necessitate the development of standardized alternatives. Keratin derived-films (KF) have been indicated as transferable substrate for cell cultivation and tissue engineering. The impact of different sterilization procedures on KF and surgical feasibility were investigated. Human hair KF were prepared and sterilized; optical, biomechanical properties, in vitro cell seeding efficiency and proliferation of human corneal epithelial cells were studied and compared with hAM. Surgical feasibility was tested on enucleated porcine eye. Sterilized KF showed higher light transmission and significantly higher E-modulus than hAM; cell-seeding-efficiency and proliferation rate were not affected. Although KF could be surgically handled, suture placement was more difficult compared to hAM. Plasma treatment seems the best sterilization method for KF; it does not affect cell biology or optical and biomechanical properties. However material modifications are requested before KF may represent a feasible alternative for ocular surface reconstruction. PMID- 23015266 TI - Measuring the impact of cataract surgery on generic and vision-specific quality of life. AB - PURPOSE: Cataracts are the leading cause of blindness worldwide and cause visual impairment for millions of adults in the United States. We compared the sensitivity of a vision-specific health-related quality of life (HRQOL) measure to that of multiple generic measures of HRQOL before and at 2 time points after cataract surgery. METHODS: Participants completed 1 vision-specific and 5 generic quality of life measures before cataract surgery, and again 1 and 6 months after surgery. Random effects modeling was used to measure changes over the three assessment points. RESULTS: The NEI-VFQ25 total score and all 11 subscales showed significant improvements during the first interval (baseline and 1 month). During the second interval (1-6 months post-surgery), significant improvements were observed on the total score and 5 of 11 NEI-VFQ25 subscales. There were significant increases in HRQOL during the first interval on some preference-based generic HRQOL measures, though changes during the second interval were mostly non significant. None of the SF-36v2TM or SF6D scales changed significantly between any of the assessment periods. CONCLUSIONS: The NEI-VFQ25 was sensitive to changes in vision-specific domains of QOL. Some preference-based generic HRQOL measures were also sensitive to change and showed convergence with the NEI-VFQ25, but the effects were small. The SF-36v2TM and SF-6D did not change in a similar manner, possibly reflecting a lack of vision-related content. Studies seeking to document both the vision-specific and generic HRQOL improvements of cataract surgery should consider these results when selecting measures. PMID- 23015267 TI - Induced transcription results in local changes in chromatin structure, replication timing, and DNA polytenization in a site of intercalary heterochromatin. AB - In salivary gland polytene chromosomes of Drosophila melanogaster, the regions of intercalary heterochromatin are characterized by late replication, under replication, and genetic silencing. Using Gal4/UAS system, we induced transcription of sequences adjacent to transgene insertions in the band 11A6-9. This activation resulted in a loss of "silent" and appearance of "active" epigenetic marks, recruitment of RNA polymerase II, and formation of a puff. The activated region is now early replicating and shows increased level of DNA polytenization. Notably, all these changes are restricted to the area around the inserts, whereas the rest of the band remains inactive and late replicating. Although only a short area near the insertion site is transcribed, it results in an "open" chromatin conformation in a much broader region. We conclude that regions of intercalary heterochromatin do not form stand-alone units of late replication and under-replication. Every part of such regions can be activated and polytenized independently of other parts. PMID- 23015268 TI - Secondary hyperparathyroidism, vitamin D sufficiency, and serum calcium 5 years after gastric bypass and duodenal switch. AB - BACKGROUND: The prevalence of secondary hyperparathyroidism (SHPT) is high after bariatric surgery. Vitamin D is supplied to counteract SHPT and bone disease, and we studied vitamin D associations with SHPT. METHODS: We measured serum levels of 25-OH vitamin D and parathyroid hormone (PTH) 5 years after gastric bypass and duodenal switch. One hundred twenty-five patients were included, of whom 114 (91 %) had undergone gastric bypass and 11 (9 %) had undergone duodenal switch. SHPT was defined as PTH > 7.0 pmol/l in the absence of hypercalcemia. 25-OH vitamin D levels were divided into three categories: <50, 50-74, and >=75 nmol/l. Serum ionized calcium, magnesium, phosphate, and creatinine were divided into tertiles. RESULTS: Mean age +/- SD was 44 +/- 9 years at 5 years follow-up. Ninety out of 125 (72 %) patients were women. SHPT was present in 45 out of 114 (40 %) gastric bypass patients and in 11 out of 11 (100 %) duodenal switch patients. The prevalence was high in all vitamin D categories studied. An inverse association between ionized calcium and PTH was found. For the gastric bypass patients, the odds ratio for SHPT in the upper two tertiles of ionized calcium was 0.35; 95 % CI, 0.15-0.79; p = 0.011, compared with the lowest tertile. Supplements of vitamin D and calcium were not associated with a lower prevalence of SHPT at 5 years follow-up. CONCLUSIONS: The prevalence of SHPT was high 5 years after gastric bypass and duodenal switch. SHPT was inversely associated with serum ionized calcium, but not with vitamin D. The supplementation used was insufficient to compensate for the impaired calcium absorption after surgery. PMID- 23015269 TI - Bariatric surgery: severity, level of control, and time required for preoperative asthma control. AB - BACKGROUND: There is an increased prevalence of asthmatic, obese patients undergoing bariatric surgery. The objective of our study is to evaluate the severity, level of control, respiratory medication use, and time required for prebariatric surgery asthma control. METHODS: This is a prospective study in which 88 obese asthmatics were evaluated by a pulmonologist in two steps, prebariatric surgery. In the first step, patients were evaluated for severity, level of control, and respiratory medication in use, categorized as bronchodilators and corticosteroids. In the second step, the time required for asthma control between steps and appropriate respiratory medication was determined. RESULTS: Thirty-eight obese patients (43.2%) had intermittent asthma, 22 had mildly persistent (25.0%), 24 moderately persistent (27.3%), and 4 severely persistent (4.5%). There were 43 patients with controlled asthma (48.9%), 31 partly controlled (35.2%), and 14 uncontrolled (15.9%). The study sample showed a significant increase in bronchodilators in the first step and corticosteroids in the second step (p <= 0.0001). Comparisons between steps showed significant differences with a reduction of bronchodilators and increase in corticosteroids in the second step (p <= 0.0001). The mean time (days) required for asthma control between steps was 28.98 +/- 33.40 days, with significant differences between groups (p <= 0.001). CONCLUSIONS: In prebariatric surgery, there was a higher proportion of intermittent asthma and uncontrolled asthma, with asthma severity influencing the achievement of asthma control and the time required for surgical release. PMID- 23015270 TI - Stable isotope analysis in primatology: a critical review. AB - Stable isotope analysis has become an important tool in ecology over the last 25 years. A wealth of ecological information is stored in animal tissues in the relative abundances of the stable isotopes of several elements, particularly carbon and nitrogen, because these isotopes navigate through ecological processes in predictable ways. Stable carbon and nitrogen isotopes have been measured in most primate taxonomic groups and have yielded information about dietary content, dietary variability, and habitat use. Stable isotopes have recently proven useful for addressing more fine-grained questions about niche dynamics and anthropogenic effects on feeding ecology. Here, we discuss stable carbon and nitrogen isotope systematics and critically review the published stable carbon and nitrogen isotope data for modern primates with a focus on the problems and prospects for future stable isotope applications in primatology. PMID- 23015271 TI - Reversible and efficient inhibition of UDP-galactopyranose mutase by electrophilic, constrained and unsaturated UDP-galactitol analogues. AB - A series of UDP-galactitols were designed as analogues of high-energy intermediates of the UDP-galactopyranose mutase (UGM) catalyzed furanose/pyranose interconversion, an essential step of Mycobacterium tuberculosis cell wall biosynthesis. The final compounds structurally share the UDP and the galactitol substructures that were connected by four distinct electrophilic connections (epoxide, lactone and Michael acceptors). All molecules were synthesized from a common perbenzylated acyclic galactose precursor that was derivatized by alkenylation, alkynylation and cyclopropanation. The inhibition study against UGM could clearly show that slight changes in the relative orientation of the UDP and the galactitol moieties resulted in dramatic variations of binding properties. Compared to known inhibitors, the epoxide derivative displayed a very tight, reversible, inhibition profile. Moreover, a time-dependent inactivation study showed that none of these electrophilic structures could react with UGM, or its FAD cofactor, the catalytic nucleophile of this still intriguing reaction. PMID- 23015272 TI - Synthesis and application of nanostructured calcium phosphate ceramics for bone regeneration. AB - In the past two decades, nanotechnology has entered the field of regenerative medicine, resulting in the development of a novel generation of instructive, nanostructured biomaterials that are able to orchestrate cellular behavior by presenting specific morphological and biological cues. Using nanotechnology, materials containing nanosized features (e.g., pores, patterns, textures, grain sizes) can be obtained that exhibit properties that are considerably altered compared with micron-structured materials. Inspired by the hierarchical nanostructure of bone, the application of nanostructured materials for bone regeneration is gaining increasing interest in the field of biomaterials research. Because crystallographic and chemical studies have shown that synthetic hydroxyapatite closely resembles the inorganic phase found in bone and teeth, synthesis and applications of nanostructured calcium phosphate ceramics have been reviewed. Synthesis techniques for the preparation of calcium phosphate nanoparticles include precipitation, sol-gel, and hydrothermal processes, whereas four main biomedical applications of nanostructured calcium phosphate ceramics in bone regeneration have been addressed in more detail, that is, (1) polymer/calcium phosphate nanocomposites, (2) nanostructured monophasic calcium phosphate bone fillers, (3) nanostructured precursor phases for calcium phosphate cements, and (4) nanostructured calcium phosphate coatings. PMID- 23015274 TI - Treatment abandonment is a major hurdle to improving survival in childhood cancer in the developing world. PMID- 23015273 TI - Vitamin D status and incident cardiovascular disease and all-cause mortality: a general population study. AB - Low vitamin D status has been associated with cardiovascular disease (CVD) and mortality primarily in selected groups, smaller studies, or with self-reported vitamin D intake. We investigated the association of serum vitamin D status with the incidence of a registry-based diagnosis of ischemic heart disease (IHD), stroke, and all-cause mortality in a large sample of the general population. A total of 9,146 individuals from the two population-based studies, Monica10 and Inter99, were included. Measurements of serum 25-hydroxyvitamin D at baseline were carried out using the IDS ISYS immunoassay system in Monica10 and High performance liquid chromatography in Inter99. Information on CVDs and causes of death was obtained from Danish registries until 31 December 2008. There were 478 cases of IHD, 316 cases of stroke, and 633 deaths during follow-up (mean follow up 10 years). Cox regression analyses with age as underlying time axis showed a significant association between vitamin D status and all-cause mortality with a HR = 0.95 (P = 0.005) per 10 nmol/l higher vitamin D level. We found no association between vitamin D status and incidence of IHD or stroke (HR = 1.01, P = 0.442 and HR = 1.00, P = 0.920, respectively). In this large general population study, the observed inverse association between serum vitamin D status and all cause mortality was not explained by a similar inverse association with IHD or stroke. PMID- 23015275 TI - Making the decision to stop pain: Probability and magnitude effects of expected pain relief on the choice of analgesics. AB - BACKGROUND: Pain is a major ailment that motivates individuals to look for treatment. Despite its enormous clinical relevance, very little is known about the factors that influence our preference of an analgesic (or pain-relieving treatment). The current study investigated the influence of the information regarding the probability and the magnitude of the expected analgesic effect on preference of analgesic options. METHODS: Twenty-four healthy volunteers were instructed to imagine pain across different scenarios and choose between two hypothetical analgesics that differed in their probabilities to successfully relieve pain and the magnitude of their expected analgesic effects. The conservative analgesic was more reliable but less potent than the radical analgesic, whereas the radical analgesic was less reliable but more potent than the conservative analgesic. RESULTS: Consistent with the predictions of prospect theory, a larger proportion of the participants chose the radical analgesic when the overall probability of both analgesics decreased, and when the potency of the radical analgesic was expected to be stronger relative to the conservative analgesic. At the individual level, individuals' relative imagined pain relief (radical analgesic/conservative analgesic) predicted their preference for the radical analgesic. CONCLUSIONS: Our findings revealed that preference of analgesic options is mediated by the overall probability of analgesic effect and the relative potency of analgesics. The expected relief one imagines to obtain from analgesics would guide preference. The findings highlight the importance for clinicians to understand how patients subjectively frame the probability and magnitude factors related to decision making in medical context. PMID- 23015276 TI - Rupture of multiple receptor-ligand bonds: bimodal distribution of bond rupture force. AB - Monte Carlo simulation of the rupture of multiple receptor-ligand bonds between two PMN cells suspended in a Newtonian fluid is performed. In the presence of a hydrodynamic drag force acting on two PMN cells the interplay of multiple receptor-ligand bonds between these cells leads to a bimodal distribution of the bond rupture force at certain loading rates. Specifically, it is found that the interplay of multiple bonds between two PMN cells in the presence of hydrodynamic drag force acting on these cells modifies the bond energy landscape in such a way as to lead to a bimodal distribution of the bond rupture force where a low force peak switches to a high force peak as the loading rate is increased progressively, characteristics of two-state systems. PMID- 23015277 TI - Strictly two-dimensional self-avoiding walks: thermodynamic properties revisited. AB - The density crossover scaling of various thermodynamic properties of solutions and melts of self-avoiding and highly flexible polymer chains without chain intersections confined to strictly two dimensions is investigated by means of molecular dynamics and Monte Carlo simulations of a standard coarse-grained bead spring model. In the semidilute regime we confirm over an order of magnitude of the monomer density rho the expected power law scaling for the interaction energy between different chains e(int) ~ rho(21/8), the total pressure P ~ rho(3) and the dimensionless compressibility g(T) = lim(q->0)S(q) ~ 1/rho(2). Various elastic contributions associated to the affine and non-affine response to an infinitesimal strain are analyzed as functions of density and sampling time. We show how the size xi(rho) of the semidilute blob may be determined experimentally from the total monomer structure factor S(q) characterizing the compressibility of the solution at a given wave vector q. We comment briefly on finite persistence length effects. PMID- 23015278 TI - Single centre experience with prolonged waiting time on transplant list with "high-urgency" status. AB - INTRODUCTION: The waiting list for heart transplantation (HTx) in Eurotransplant area has grown to a record size of nearly 1,300 patients, whereas only around 600 hearts were transplanted last year. The prolonged time for patients awaiting HTx on the high-urgency (HU) status leads mostly to serious medical complications. OBJECTIVE: The aim of this study was to study the trend of changes in the frequency of ventricular assist device (VAD) implantation in patients on the HU status. METHODS: A total of 22 adult patients awaiting transplantation on the HU status at our hospital between January 2011 and December 2011 were analyzed, assessing risk profile, blood group, and complication rates in terms of VAD implantation or death. Results were compared with 16 consecutive patients who were on transplant list with the HU status between January 2010 and December 2010 at our institution. RESULTS: Mean age was 49.5 +/- 12.1 (2010 group) years and 51.4 +/- 10.7 years (2011 group; p = 0.62). Mean logEuroSCORES raised not significantly from 9.1 +/- 6.3% (2010 group) to 10.7 +/- 14.7% (2011 group; p = 0.68). Six patients died on the HU status and seven patients had to be supplied with a VAD in 2011. In comparison with the preceding year, only two patients died in 2010 and none of our patients on the HU status had to be provided with mechanical circulatory support. CONCLUSION: Because of the prolonged waiting time on the HU list, the earlier-mentioned data demonstrate a negative trend in transplant medicine. Especially when taking into consideration that five of seven patients who needed a VAD implantation during the HU waiting period had blood group O. Furthermore, the data derived from Eurotransplant show that the waiting period for patients with blood group O was considerably longer when compared with patients of the same average body height and weight but with other blood groups. PMID- 23015279 TI - Quantification of morbidity associated with congenital heart surgery. AB - OBJECTIVE: The objective of this study was to estimate the morbidity according to observed complications after congenital heart surgery over 1-year period. METHODS: The previously established list of conditions prone to affect patients' well-being or increase cost of in-hospital stays was used systematically to score the severity of postoperative complications from 1 to 4 points. The morbidity score was calculated by adding the scores of observed complications. When the sum amounted to more than 5 points, a morbidity score of only 5 points was attributed. If no complication was detected, a score of 0.5 points was assigned. The resulting morbidity scores were correlated with the length of stay in the intensive care unit (ICU) and in the hospital, the duration of mechanical ventilation, and Aristotle complexity scores. RESULTS: A total of 542 primary procedures performed in the year 2011 were studied. Aristotle basic and comprehensive scores amounted to 7.78 +/- 2.65 and 10.15 +/- 3.83, respectively. Mortality was 1.85% (10/542). The standardized ratio of surgical performance reached 103.10%. Total cavopulmonary connection with extracardiac fenestrated conduit constituted the most frequent operation (n = 34). No complication was observed following 183 (33.8%) procedures. More than two complications were observed in 114 cases (21%). The three most frequent unfavorable conditions were "mechanical ventilation 25 to 95 hours" (n = 150), low cardiac output syndrome (n = 56), and cardiac arrhythmia requiring medication (n = 50). The estimated mean morbidity score amounted to 2.26 +/- 1.80 points. Scores ranged from 0.68 +/- 0.50 for primary closure of atrial septal defect to 4.50 +/- 0.79 for the Norwood procedure. They were perfectly related to the length of ICU stay and to the duration of mechanical ventilation (Spearman coefficient r = 1). Correlation was high with the length of hospital stay (r = 0.83), Aristotle basic score (r = 0.89) (r = 0.96), and comprehensive score (r = 0.94) (C-index = 0.97). The observed mean morbidity score was statistically not different from the expected mean morbidity score according to the basic Aristotle complexity: p = 0.73. CONCLUSION: Quantification of morbidity indicates the length of ICU stay and the duration of mechanical ventilation as the best surrogates for morbidity. Such benchmarking and scoring of observed postoperative complications paves the way for an accurate assessment and improvement of quality care in congenital heart surgery. PMID- 23015280 TI - Comparison of initial warfarin response in obese patients versus non-obese patients. AB - Achieving therapeutic anticoagulation with warfarin is complicated by substantial inter-patient and intra-patient variability with numerous factors known to influence dose requirements. Obesity is one factor for which there remains no study to date investigating its initial effect on warfarin response assessed by INR, stratified by BMI category in hospitalized patients. To compare initial warfarin response between obese and non-obese patients by evaluating average daily dose (ADD), time required to attain therapeutic INR, and mean discharge dose (MDD), stratified by BMI category. A retrospective review was conducted to evaluate initial warfarin response in hospitalized patients of different BMI categories initiated on warfarin with >=4 consecutive days of therapy and managed by pharmacy dosing service. 211 patients were included (10 underweight, 45 normal weight, 48 overweight, 71 obese, 37 morbidly obese). Across BMI categories, the percentage of patients attaining therapeutic INR prior to discharge differed (p = 0.0004) with 71.1 % of normal weight therapeutic compared to 42.3 % of obese and 38 % of morbidly obese. Within BMI categories, when comparing ADD between patients therapeutic and subtherapeutic at discharge, no differences were observed, except among overweight patients (5.6 +/- 0.3 vs. 7 +/- 0.4 mg, p = 0.0143). Compared to normal weight, obese and morbidly obese required a significantly longer median time to achieve therapeutic INR (8 and 10 days vs. 6 days) and a higher ADD (6.6 +/- 0.3 and 7.6 +/- 0.5 vs. 5 +/- 0.3 mg) and MDD (6.7 +/- 0.5 and 6.7 +/- 0.7 vs. 4.4 +/- 0.5 mg). Compared to normal weight, obese and morbidly obese patients had a decreased initial response to warfarin. PMID- 23015281 TI - An improved reconstruction of May-June precipitation using tree-ring data from western Turkey and its links to volcanic eruptions. AB - We developed a high quality reconstruction of May-June precipitation for the interior region of southwestern Turkey using regional tree-ring data calibrated with meteorological data from Burdur. In this study, three new climate sensitive black pine chronologies were built. In addition to new chronologies, four previously published black pine chronologies were used for the reconstruction. Two separate reconstructions were developed. The first reconstruction used all site chronologies over the common interval AD 1813-2004. The second reconstruction used four of the chronologies with a common interval AD 1692-2004. R2 values of the reconstructions were 0.64 and 0.51 with RE values of 0.63 and 0.51, respectively. During the period AD 1692-1938, 41 dry and 48 wet events were found. Very dry years occurred in AD 1725, 1814, 1851, 1887, 1916, and 1923, while very wet years occurred in AD 1736, 1780, 1788, 1803, and 1892. The longest dry period was 16 years long between 1860 and 1875. We then explored relationships between the reconstructed rainfall patterns and major volcanic eruptions, and discovered that wetter than normal years occurred during or immediately after the years with the largest volcanic eruptions. PMID- 23015282 TI - CD43 in the nucleus and cytoplasm of lung cancer is a potential therapeutic target. AB - CD43 is a transmembrane sialoglycoprotein. Normally the molecule is only produced by white blood cells where it regulates functions such as intercellular adhesion, intracellular signaling, apoptosis, migration and proliferation. Two CD43 antibodies were used to interrogate 66 cases of non-small cell lung cancer (NSCLC) and 24 cases of small cell lung cancer (SCLC). In addition, we engineered the CD43-positive lung cancer cell line A549 to stably express either non targeted or CD43-targeted small-interfering RNA (siRNA). These lines were then subjected to in vitro assays of apoptosis, natural killer (NK) cell cytotoxicity, intercellular adhesion and transendothelial migration. A xenograft mouse model evaluated the ability of the lines to grow primary tumors in vivo. CD43 was found to be expressed in the majority of both SCLC and NSCLC. Inclusive of CD43 negative tumors, differential patterns of nuclear and cytoplasmic expression of CD43 define four molecular subcategories of lung cancer. Targeting CD43 in A549 lung cancer cells, increased homotypic adhesion, decreased heterotypic adhesion and transendothelial migration, increased susceptibility to apoptosis and increased vulnerability to lysis by NK cells. Furthermore, targeting inhibited the growth of primary tumors in nude mice. PMID- 23015283 TI - Correlates of health-related quality of life, psychological well-being, and eating self-regulation after successful weight loss maintenance. AB - The purpose of this study was to evaluate health-related quality of life and other psychosocial characteristics, including eating self-regulation and body image, in a group of successful long-term weight loss maintainers. Women enrolled in the Portuguese Weight Control Registry (n = 107) were matched and compared to women at the end of a behavior weight loss treatment program (n = 107), and also with women in the community who were not trying to lose weight (n = 107). Successful maintainers displayed higher quality of life and a more positive profile in selected eating and exercise markers of self-regulation compared to similarly-weighed women not attempting weight loss, but not when compared to the 'weight loss treatment' group. However, results also suggest that concerns with body shape and size may persist after weight loss and that some aspects of well being and eating self-regulation can be more successfully targeted in specific weight loss programs. PMID- 23015284 TI - Disseminated intravascular coagulation: a review for the internist. AB - Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to widespread deposition of fibrin in the circulation. Recent knowledge on important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with DIC. The diagnosis of DIC can be made by sensitive laboratory tests; however, most of these tests are not readily available in a clinical setting. A reliable diagnosis can also be made on the basis of a small series of laboratory tests that can be combined in a scoring algorithm. The cornerstone of the management of DIC is the specific and vigorous treatment of the underlying disorder. Strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways. PMID- 23015285 TI - Surface modification of Thai silk fibroin scaffolds with gelatin and chitooligosaccharide for enhanced osteogenic differentiation of bone marrow derived mesenchymal stem cells. AB - In this study, the surface modification of silk fibroin (SF) scaffolds with gelatin/chitooligosaccharide (G/COS) blends using the reaction of glutaraldehyde (GA) was established. The effects of G/COS mixing ratio (100/0, 90/10, 80/20, and 70/30) and GA crosslinking concentration (0.05, 0.10, 0.15, and 0.20 vol %) on the properties of scaffolds were investigated. At 0.10-0.20 vol % GA, all G/COS blends could be successfully conjugated on the SF scaffolds, as confirmed by the percentage of weight increased and the presence of functional groups indicating SF, G, and COS from FTIR spectra. Pore size of SF scaffolds was around 570 MUm with 92% porosity, however, the G/COS-conjugated SF scaffolds showed thickened pore's wall, smaller pore size (~184-275 MUm) and less porosity (~81%), but increased density. This modified structure subsequently improved the compressive modulus of the G/COS-conjugated SF scaffolds. In terms of biological properties, the gelatin-conjugated SF scaffolds promoted the attachment and proliferation of bone marrow-derived mesenchymal stem cells (MSC) rather than the other scaffolds. However, the G/COS-conjugated SF scaffolds, particularly at the ratio of 70/30, promoted the osteogenic differentiation of MSC comparing to the SF scaffold, as confirmed by the production of alkaline phosphatase (ALP) activity and calcium (Ca), and the deposition of calcium phosphate (CaP). It was concluded that the G/COS-conjugated SF scaffolds showed great mechanical properties due to the beta structure of silk fibroin, as well as the enhanced biological properties due to the G/COS blends. PMID- 23015287 TI - Reproductive ecology of female chimpanzees. AB - An important adaptive problem for mammals in general, and primates in particular, is how females can manage the high costs of reproduction in the face of fluctuating energetic supplies. For many species, the best solution is to breed seasonally such that high costs are temporally coincident with predictable periods of resource abundance. This is an unreliable strategy for some primates, such as chimpanzees (Pan troglodytes), for which large body size forces an increase in dietary complexity and prolonged reproductive efforts. Here, I review data on reproductive function in chimpanzees, a species that demonstrates a risk averse reproductive strategy wherein reproductive investment is allocated in accordance with maternal condition. Life history parameters for chimpanzees indicate that most females produce very few surviving offspring. However, comparisons between captive and wild populations and within wild populations illustrate that variation in resource access leads to highly variable reproductive success. Focused hormonal studies have demonstrated these effects at a proximate level, with energetic influences on female dispersal, receptivity, cycle quality, conception success, and lactational amenorrhea. Downstream of these effects, female reproductive function affects sexual attractiveness, and by virtue of males' own optimal reproductive strategies, can lead to coercive aggression and decreased foraging efficiency. Because of their extreme reproductive costs, female chimpanzees utilize a highly conservative reproductive strategy, one that minimizes the costs of ecological variation but makes them vulnerable to sexual conflict and costs of sociality. PMID- 23015286 TI - Obesity and survival in population-based patients with pancreatic cancer in the San Francisco Bay Area. AB - BACKGROUND: Obesity has been consistently associated with increased risk of pancreatic cancer incidence and mortality. However, studies of obesity and overall survival in patients with pancreatic cancer are notably lacking, especially in population-based studies. METHODS: Active and passive follow-up were used to determine vital status and survival for 510 pancreatic cancer patients diagnosed from 1995 to 1999 in a large population-based case-control study in the San Francisco Bay Area. Survival rates were computed using Kaplan Meier methods. Hazard ratios (HR) and 95 % confidence intervals (CI) were estimated in multivariable Cox proportional hazards models as measures of the association between pre-diagnostic obesity and pancreatic cancer survival. RESULTS: An elevated hazard ratio of 1.3 (95 % CI, 0.91-1.81) was observed for obese [body mass index (BMI) >= 30] compared with normal range BMI (<25) patients. Associations between BMI and overall survival did not statistically significantly vary by known prognostic and risk factors (all p-interaction >=0.18), yet elevated HRs consistently were observed for obese compared with normal BMI patients [localized disease at diagnosis (HR, 3.1), surgical resection (HR, 1.6), ever smokers (HR, 1.6), diabetics (HR, 3.3)]. Poor survival was observed among men, older patients, more recent and current smokers, whereas improved survival was observed for Asian/Pacific Islanders. CONCLUSIONS: Our results in general provide limited support for an association between pre diagnostic obesity and decreased survival in patients with pancreatic cancer. Patterns of reduced survival associated with obesity in some patient subgroups could be due to chance and require assessment in larger pooled studies. PMID- 23015288 TI - Copper-catalyzed three-component borylstannylation of alkynes. AB - Regio- and stereoselective installation of boryl and stannyl moieties into a carbon-carbon triple bond of various alkynes has been achieved based on a three component coupling reaction by using a diboron and a tin alkoxide with the aid of a copper(II) acetate-tricyclohexylphosphine complex, giving diverse vic borylstannylalkenes in a straightforward manner. Carbon-tin and carbon-boron bonds of the resulting borylstannylation product are successively transformed into carbon-carbon bonds by a Migita-Kosugi-Stille and a Suzuki-Miyaura coupling, leading to the formation of (Z)-tamoxifen with anti-breast cancer activity. PMID- 23015289 TI - The significance of tibial and common peroneal nerves in nerve blocks. AB - PURPOSE: The aim of this study was to elucidate the anatomical location of tibial nerve (TN) and common peroneal nerve (CPN) in the popliteal crease for specific nerve block. METHODS: Fifty fresh specimens from 27 adult Korean cadavers (16 males and 11 females, age 35-87 years) were investigated. Five of the 27 cadavers were used to determine the depths of nerves in cross-section. RESULTS: Tibial nerve was located 50 % from the most lateral point of the popliteal crease and 1.4-cm deep to the surface. In 20 % of the 50 specimens, the medial sural cutaneous nerve branched out below or at the popliteal crease, whereas the CPN was located at 26 % from the most lateral point of the popliteal crease and 0.7 cm deep from the surface. Furthermore, in 6 % of specimens the lateral sural cutaneous nerve branched out below or at the popliteal crease. CONCLUSION: The results concerning the location of the TN and CPN at the popliteal crease offer a good guide to optimal nerve block. PMID- 23015290 TI - Monitoring the initial delivery of an oncolytic measles virus encoding the human sodium iodide symporter to solid tumors using contrast-enhanced computed tomography. AB - BACKGROUND: We aimed to determine the feasibility of monitoring viral delivery and initial distribution to solid tumors using iodinated contrast agent and micro computed tomography (CT). METHODS: Human BxPC-3 pancreatic tumor xenografts were established in nude mice. An oncolytic measles virus with an additional transcriptional unit encoding the sodium iodide symporter (NIS), as a reporter for viral infection, was mixed with a 1:10 dilution of Omnipaque 300 (GE Healthcare, Milwaukee, WI, USA) contrast agent and injected directly into tumors. Mice were imaged with micro-CT immediately before and after injection to determine the location of contrast agent/virus mixture. Mice were imaged again on day 3 after injection with micro-single-photon emission CT/CT to determine the location of NIS-mediated (99m) TcO(4) transport. RESULTS: A 1:10 dilution of Omnipaque had no effect on viral infectivity or cell viability in vitro and was more than adequate for CT imaging of the intratumoral injectate distribution. The volume of tumor coverage with initial CT contrast agent and the 3-day postinfection measurement of virally infected tumor volume were significantly correlated. Additionally, regions of the tumor that did not receive contrast agent from the initial injection were largely devoid of viral infection at early time points. CONCLUSIONS: Contrast-enhanced viral delivery enables a rapid and accurate prediction of the initial viral distribution within a solid tumor. This technique should enable real-time monitoring of viral propagation from initially infected tumor regions to adjacent tumor regions. PMID- 23015291 TI - Kisspeptin and the hypothalamic control of reproduction: lessons from the human. AB - The hypothalamic hormone GnRH is a central driver of pituitary gonadotropin secretion, controlling pulsatile gonadotropin secretion, modulating gonadal steroid feedback, and bringing about full fertility in the adult. Thus, understanding GnRH neuronal regulation is essential to understanding the neurohumoral control of human reproduction. Genetic tools were used in patients with GnRH deficiency (i.e. idiopathic hypogonadotropic hypogonadism), a clinical syndrome that results from the failure of a normal pattern of pulsatile GnRH, to discover upstream modulators of GnRH secretion (1). In 2003, homozygosity mapping of two consanguineous pedigrees led to the identification of loss of function mutations in KISS1R (a G protein coupled receptor) by two groups (2, 3). In parallel, the Kiss1r(-/-) mouse was shown to be a phenocopy of the human GnRH deficient state, demonstrating that the function of KISS1R/Kiss1r is conserved across mammalian species (4). Just before these human genetic discoveries, the ligand for kisspeptin-1 receptor [KISS1R; also known as G protein coupled receptor 54 (GPR54)], was discovered to be kisspeptin. Soon thereafter a large array of experimental studies began assembling genetic, expression, physiologic, transgenic, knockdown, and electrophysiological data to characterize the physiology of kisspeptin and its seminal role in modulating GnRH release. PMID- 23015292 TI - Discovery of a novel glucagon-like peptide (GCGL) and its receptor (GCGLR) in chickens: evidence for the existence of GCGL and GCGLR genes in nonmammalian vertebrates. AB - Glucagon (GCG), glucagon-related peptides, and their receptors have been reported to play important roles including the regulation of glucose homeostasis, gastrointestinal activity, and food intake in vertebrates. In this study, we identified genes encoding a novel glucagon-like peptide (named GCGL) and its receptor (GCGLR) from adult chicken brain using RACE and/or RT-PCR. GCGL was predicted to encode a peptide of 29 amino acids (cGCGL(1-29)), which shares high amino acid sequence identity with mammalian and chicken GCG (62-66%). GCGLR is a receptor of 430 amino acids and shares relatively high amino acid sequence identity (53-55%) with the vertebrate GCG receptor (GCGR). Using a pGL3-CRE luciferase reporter system, we demonstrated that synthetic cGCGL(1-29), but not its structurally related peptides, i.e. exendin-4 and GCG, could potently activate GCGLR (EC(50): 0.10 nm) expressed in Chinese hamster ovary cells, indicating that GCGLR can function as a GCGL-specific receptor. RT-PCR assay revealed that GCGL expression is mainly restricted to several tissues including various brain regions, spinal cord, and testes, whereas GCGLR mRNA is widely expressed in adult chicken tissues with abundant expression noted in the pituitary, spinal cord, and various brain regions. Using synteny analysis, GCGL and GCGLR genes were also identified in the genomes of fugu, tetraodon, tilapia, medaka, coelacanth, and Xenopus tropicalis. As a whole, the discovery of GCGL and GCGLR genes in chickens and other nonmammalian vertebrates clearly indicates a previously unidentified role of GCGL-GCGLR in nonmammalian vertebrates and provides important clues to the evolutionary history of GCG and GCGL genes in vertebrates. PMID- 23015293 TI - Examination of ERalpha signaling pathways in bone of mutant mouse models reveals the importance of ERE-dependent signaling. AB - The mechanisms of estrogen receptor (ER)-alpha activity can be categorized into those involving direct (classical) or indirect (nonclassical) DNA binding. Although various mouse models have demonstrated the importance of ERalpha in bone, the specific gene expression patterns affected by these modes of ERalpha action are unknown. In this report, the gene expression patterns of ERalpha deficient (ERKO) mice and nonclassical ER knock-in (NERKI) mice, which can function only by nonclassical means, were analyzed. Three-month-old mice were ovariectomized and implanted with estrogen pellets for 1 month to normalize estrogen levels. Microarray analysis of flushed cortical bone revealed 28% (210 of 763) of the genes differentially expressed in ERKO mice were altered in NERKI mice, suggesting estrogen response element-dependent regulation of these genes in bone. Pathway analysis revealed alterations in genes involved in focal adhesion and extracellular matrix interactions. However, the majority of genes regulated in ERKO mice (72%) were unique (i.e. not altered in NERKI mice), suggesting these are regulated by nonclassical mechanisms. To further explore the pathways affected in ERKO mice, we performed focused quantitative PCR arrays for genes involved in various aspects of bone physiology. Genes involved in bone formation, senescence, apoptosis, and autophagy were significantly regulated. Overall, the majority of the genes regulated by ERalpha in bone are via nonclassical pathways. However, because NERKI mice display an osteoporotic phenotype, it can be deduced that the minority of the estrogen response element-dependent genes/pathways play critical roles in the regulation of bone physiology. These data demonstrate the importance of classical ERalpha signaling in regulating bone metabolism. PMID- 23015294 TI - MicroRNAs regulated by adiponectin as novel targets for controlling adipose tissue inflammation. AB - A low-grade proinflammatory state contributes to the metabolic syndrome (MS). Adiponectin (ApN), which is reduced in the MS, has emerged as a master regulator of inflammation/immunity. We wanted to identify whether microRNAs (miRNAs) may mediate the antiinflammatory action of ApN on adipose tissue (AT). miRNA expression profiling was performed in mice overexpressing ApN specifically in AT and in wild-type controls. The role of specific miRNAs was analyzed by gain- or loss-of function approaches in 3T3-F442A (pre)-adipocytes and in de novo AT formed from engineered 3T3-F442A preadipocytes transplanted in nude mice. miRNA expression was compared in the omental AT of lean and obese subjects. The expression of miR532-5p and miR1983 was down-regulated, whereas that of miR883b 5p and miR1934 was up-regulated in AT of mice overexpressing ApN specifically in AT. We focused on miR883b-5p identified by computational analysis as being involved in inflammatory pathways. miR883b-5p overexpression down-regulated the lipopolysaccharide-binding protein (LBP) in 3T3-F442A cells, whereas miR883b-5p blockade had reverse effects. LBP aids in lipopolysaccharide binding to Toll-like receptor-4. miR883b-5p blockade also abolished the protective effects of ApN on proinflammatory adipokine induction. These data were recapitulated in the de novo AT in which miR883b-5p silencing induced LBP production and tissue inflammation. Eventually miR883b-5p expression was down-regulated in AT of obese subjects. We identified several novel miRNAs that are regulated by ApN in AT in vivo. miR883b 5p, which is up-regulated by ApN represses LBP and Toll-like receptor-4 signaling, acting therefore as a major mediator of the antiinflammatory action of ApN. These novel miRNAs may open new therapeutic perspectives for the MS. PMID- 23015296 TI - Solid variant of aneurysmal bone cyst of the left parietal bone without preceding trauma. AB - INTRODUCTION: We report the case of a 17-year-old girl with an indolent, smooth swelling of the left cranial vault that had been developing for 2 months. Complete surgical excision was performed and the defect was closed using artificial bone cement. The integrity of the dura mater was conserved and the patient recovered without neurological deficit. Magnetic resonance imaging (MRI) controls 6 and 18 months after the operation did not find signs of recurrence. RESULTS: The lesion consisted of an elastic bone shell containing bony trabeculae with soft brown-greyish tissue and posthemorrhagic dark fluid. Histological assessment found CD68 positive multinucleated giant cells in a highly cellular fibroblastic matrix surrounding bony lamellar structures, without signs of inflammation or malignancy. Hyperparathyroidism was ruled out by normal serum values for parathyroid hormone, calcium, phosphate, and alkaline phosphatase. Histologically, first diagnosis was giant cell reparative granuloma and reference pathology disclosed aneurysmal bone cyst. CONCLUSIONS: The solid variant of aneurysmal bone cyst and the giant cell reparative granuloma can be histologically indistinguishable. Both lesions are only rarely encountered in cranial bones and most published cases affected the cranial base or the jaw, mainly in children or young adults. From a clinical point of view, classification into "outward" lesions (osteolysis of external parts of the vault with preservation of internal tabula) and "inward" lesions (intracranial multicystic lesions with raise of intracranial pressure) has been proposed. Three phases of development can be identified, and spontaneous involution has been described. Both entities are benign, but because in several cases an underlying malignant disease has been found, complete resection and regular follow-up by MRI are recommended. PMID- 23015295 TI - Whole exome sequencing of pediatric gastric adenocarcinoma reveals an atypical presentation of Li-Fraumeni syndrome. AB - BACKGROUND: Gastric adenocarcinoma is a rare diagnosis in childhood. A 14-year old male patient presented with metastatic gastric adenocarcinoma, and a strong family history of colon cancer. Clinical sequencing of CDH1 and APC were negative. Whole exome sequencing was therefore applied to capture the majority of protein-coding regions for the identification of single-nucleotide variants, small insertion/deletions, and copy number abnormalities in the patient's germline as well as primary tumor. MATERIALS AND METHODS: DNA was extracted from the patient's blood, primary tumor, and the unaffected mother's blood. DNA libraries were constructed and sequenced on Illumina HiSeq2000. Data were post processed using Picard and Samtools, then analyzed with the Genome Analysis Toolkit. Variants were annotated using an in-house Ensembl-based program. Copy number was assessed using ExomeCNV. RESULTS: Each sample was sequenced to a mean depth of coverage of greater than 120*. A rare non-synonymous coding single nucleotide variant (SNV) in TP53 was identified in the germline. There were 10 somatic cancer protein-damaging variants that were not observed in the unaffected mother genome. ExomeCNV comparing tumor to the patient's germline, identified abnormal copy number, spanning 6,946 genes. CONCLUSION: We present an unusual case of Li-Fraumeni detected by whole exome sequencing. There were also likely driver somatic mutations in the gastric adenocarcinoma. These results highlight the need for more thorough and broad scale germline and cancer analyses to accurately inform patients of inherited risk to cancer and to identify somatic mutations. PMID- 23015297 TI - Ictal epileptic headache: an old story with courses and appeals. AB - The term "ictal epileptic headache" has been recently proposed to classify the clinical picture in which headache is the isolated ictal symptom of a seizure. There is emerging evidence from both basic and clinical neurosciences that cortical spreading depression and an epileptic focus may facilitate each other, although with a different degree of efficiency. This review address the long history which lead to the 'migralepsy' concept to the new emerging pathophysiological aspects, and clinical and electroencephalography evidences of ictal epileptic headache. Here, we review and discuss the common physiopathology mechanisms and the historical aspects underlying the link between headache and epilepsy. Either experimental or clinical measures are required to better understand this latter relationship: the development of animal models, molecular studies defining more precise genotype/phenotype correlations as well as multicenter clinical studies with revision of clinical criteria for headache /epilepsy-related disorders represent the start of future research. Therefore, the definition of ictal epileptic headache should be used to classify the rare events in which headache is the only manifestation of a seizure. Finally, using our recently published criteria, we will be able to clarify if ictal epileptic headache represents an underestimated phenomenon or not. PMID- 23015298 TI - Evaluation of six SNPs of MicroRNA machinery genes and risk of schizophrenia. AB - MicroRNAs (miRNAs) are small regulatory RNAs that modulate the expression of approximately half of all human genes. Small changes in miRNA expression have been associated with several psychiatric and neurological disorders, but whether the polymorphisms in genes involved in the processing of miRNAs into maturity influence the susceptibility of a person to schizophrenia (SZ) has not yet been elucidated. In this study, we investigated the association between SZ risk and single-nucleotide polymorphisms (SNPs) in microRNA machinery genes. We assessed the associations between SZ as a risk and six potentially functional SNPs from five miRNA processing genes (DROSHA, DGCR8, DICER, AGO1, and GEMIN4) in a case control study of 256 Chinese SZ patients and 252 frequency-matched (age, gender, and ethnicity) controls. All the SNPs (rs10719, rs3757, rs3742330, rs636832, rs7813, and rs3744741) were genotyped by high resolution melting method. We found that two SNPs in the DGCR8 and DICER gene were significantly associated with the altered SZ risk. The genotype or allele frequency of rs3742330 in DICER was significantly different in patients and controls. Moreover, the recessive model of rs3757 in DGCR8 (AA vs. GA/GG) exhibited a significantly increased risk with an odds ratio (OR) of 3.73 [95 % confidence interval (CI), 1.03-13.52, P = 0.032]; the dominant model of rs3742330 in DICER (AA vs. AG/GG) exhibited a significantly increased risk with OR of 1.49 (95 % CI, 1.04-2.13; P = 0.028). Other SNPs and the haplotype of GEMIN4 (rs3744741 and rs7813) did not show any association with SZ. Our results suggested that the specific genetic variants in microRNA machinery genes may affect SZ susceptibility. PMID- 23015299 TI - Postoperative use of non-steroidal anti-inflammatory drugs in patients with anastomotic leakage requiring reoperation after colorectal resection: cohort study based on prospective data. AB - OBJECTIVES: To evaluate the effect of postoperative use of non-steroidal anti inflammatory drugs (NSAIDs) on anastomotic leakage requiring reoperation after colorectal resection. DESIGN: Cohort study based on data from a prospective clinical database and electronically registered medical records. SETTING: Six major colorectal centres in eastern Denmark. PARTICIPANTS: 2766 patients (1441 (52%) men) undergoing elective operation for colorectal cancer with colonic or rectal resection and primary anastomosis between 1 January 2006 and 31 December 2009. Median age was 70 years (interquartile range 62-77). INTERVENTION: Postoperative use of NSAID (defined as at least two days of NSAID treatment in the first seven days after surgery). MAIN OUTCOME MEASURES: Frequency of clinical anastomotic leakage verified at reoperation; mortality at 30 days. RESULTS: Of 2756 patients with available data and included in the final analysis, 1871 (68%) did not receive postoperative NSAID treatment (controls) and 885 (32%) did. In the NSAID group, 655 (74%) patients received ibuprofen and 226 (26%) received diclofenac. Anastomotic leakage verified at reoperation was significantly increased among patients receiving diclofenac and ibuprofen treatment, compared with controls (12.8% and 8.2% v 5.1%; P<0.001). After unadjusted analyses and when compared with controls, more patients had anastomotic leakage after treatment with diclofenac (7.8% (95% confidence interval 3.9% to 12.8%)) and ibuprofen (3.2% (1.0% to 5.7%)). But after multivariate logistic regression analysis, only diclofenac treatment was a risk factor for leakage (odds ratio 7.2 (95% confidence interval 3.8 to 13.4), P<0.001; ibuprofen 1.5 (0.8 to 2.9), P=0.18). Other risk factors for anastomotic leakage were male sex, rectal (v colonic) anastomosis, and blood transfusion. 30 day mortality was comparable in the three groups (diclofenac 1.8% v ibuprofen 4.1% v controls 3.2%; P=0.20). CONCLUSIONS: Diclofenac treatment could result in an increased proportion of patients with anastomotic leakage after colorectal surgery. Cyclo-oxygenase-2 selective NSAIDs should be used with caution after colorectal resections with primary anastomosis. Large scale, randomised controlled trials are urgently needed. PMID- 23015300 TI - Hip pain in an adolescent after injury while playing football. PMID- 23015301 TI - Change peripheral intravenous catheters only when necessary. PMID- 23015302 TI - European audit reports higher than expected mortality after surgery. PMID- 23015303 TI - What happened to caring? PMID- 23015304 TI - Activation of GABA(A) receptors suppresses ethanol-induced upregulation of type 1 IP(3) receptors. AB - Although Type 1 inositol 1,4,5-trisphosphate receptors (IP(3) Rs-1) are one of the major calcium channels to regulate intracellular Ca(2+) concentration, there have been few available data how their expression is modified by long-term exposure to ethanol. The present study attempted to clarify mechanisms of modification of IP(3) R-1 expression during long-term ethanol exposure by gamma aminobutyric acid (GABA)A receptors using mouse cerebral cortical neurons. Long term exposure to ethanol induced IP(3) R-1 protein upregulation following increased expression of its mRNA. Pretreatment with muscimol, a selective GABA(A) receptor agonist, significantly suppressed the ethanol-induced upregulation of IP(3) R-1 protein and its mRNA, which was significantly abolished by bicuculline, a selective GABA(A) receptor antagonist. These results indicate that GABA(A) receptors negatively regulate the ethanol-induced upregulation of IP(3) R-1 protein expression via the suppression of gene transcription. PMID- 23015305 TI - Overexpression of galectin-3 enhances migration of colon cancer cells related to activation of the K-Ras-Raf-Erk1/2 pathway. AB - BACKGROUND: Galectin-3 has been independently correlated with malignant behavior in human colon cancer. The involvement of galectin-3 in the invasiveness of colon cancer cells remains to be determined. We investigated whether galectin-3 was involved in the colon cancer cell migration mediated by certain kinase pathways. METHODS: We studied 2 colon cancer cell lines (DLD-1 and Caco2) and clinical samples. Immunostaining and Western blotting were used to analyze the expression of galectin-3 in vitro and in the clinical samples. Short hairpin RNA and overexpression of galectin-3 were used to study loss- and gain-of-function in a wound-healing assay and a Transwell migration assay, and Western blotting was used to study the Ras-Raf signaling pathway. RESULTS: Galectin-3 was expressed at lower levels in DLD-1 than in Caco2 cells. The lower galectin-3 level in DLD-1 cells was associated with decreased cell migration, in comparison with that of Caco2 cells. Overexpression of galectin-3 increased the migration rate of DLD-1, while knockdown of galectin-3 decreased the migration. Overexpression of galectin 3 was correlated with increased lamellipodia formation and distal lung localization in a mouse model. The galectin-3 enhancement of DLD-1 cell migration was mediated by K-Ras, Raf and Erk1/2 pathway activation, but not the H-Ras, p38, or JNK activation. CONCLUSIONS: Galectin-3 plays an important role in regulating colon cancer cell migration and potential distal localization. The galectin-3 enhancement of cell migration is mediated through the K-Ras-Raf-Erk1/2 pathway. Specific targeting of the K-Ras-Raf-Erk1/2 pathway may be useful for treating colon cancers associated with increased galectin-3 expression. PMID- 23015307 TI - Light-governed capillary flow in microfluidic systems. AB - Light-based flow systems for point-of-care devices are of interest because, in principle, sunlight could be used to operate them, potentially allowing for high functionality with minimal device complexity and expense. A light-operated method to drive flow using poly(N-isopropylacrylamide), a 'smart' polymer that changes wettability as a function of temperature, is introduced. It is grafted onto a carbon black-polydimethylsiloxane surface, which converts light into a thermal pattern that valves flow at user-defined locations. Flow rates are demonstrated ranging from 4 MUL min(-1) at 25 degrees C to 0.1 MUL min(-1) at 40 degrees C. The valving dynamics are also characterised, and a response time of less than 4 s is shown. Light-operated flow could provide the simple architecture and advanced functionality needed in low-resource point-of-care devices. PMID- 23015306 TI - In vitro analysis of the functional effects of an NLRP3 G809S variant with the co existence of MEFV haplotype variants in atypical autoinflammatory syndrome. AB - PURPOSE: Hereditary periodic fever syndromes have been considered monogenic diseases. However, some recent reports have described patients with co-existence of recurrent fever responsible genes. This study assessed whether a rare variant, found in Japanese children showing atypical autoinflammatory syndrome, located in the leucine-rich repeat domain of Nod-like receptor family, pyrin domain containing 3 (NLRP3) with co-existence of Mediterranean fever (MEFV) haplotype variants may contribute to a proinflammatory phenotype using a systematic approach. METHODS: Cytokine production in serum or from peripheral blood monocytes was measured by ELISA. DNA sequence analysis of genes including NLRP3, MEFV, mevalonate kinase (MVK), and tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) were performed on patient samples. In vitro functional assays determined the effects of the NLRP3 variants and pyrin using NF-kappaB activation and speck formation assays. RESULTS: A heterozygous genetic variant of NLRP3, G809S, was found in samples from both patients. Additionally the previously reported heterozygous MEFV variants (P369S-R408Q or E148Q-P369S-R408Q) were also detected in both patients. Serum IL-1ra and sTNFR1 levels increased in the attack phase of the disease in both patients. The production levels of IL 1beta from monocytes isolated from both cases were elevated following LPS and IFN gamma stimulation. The NLRP3 G809S variant demonstrated no increase of NF-kappaB activity following monosodium urate stimulation, whereas it significantly increased speck formation by interacting with apoptosis-associated speck-like protein with caspase recruitment domain. CONCLUSIONS: The phenotype of atypical autoinflammatory disease in patients could be modified by a synergistic effect with two other variants of autoinflammatory-associated genes. PMID- 23015309 TI - Human papillomavirus type 52 polymorphism and high-grade lesions of the uterine cervix. AB - The association between polymorphism of human papillomavirus type 52 (HPV52) and high-grade cervical intraepithelial neoplasia (CIN2,3) was investigated in Canadian women. HPV-52-positive endocervical specimens collected from 216 women selected from a total of 3,614 participants recruited in two case-control and two cohort studies conducted in Canada, were further analyzed by PCR-sequencing of the LCR and E6 gene. Overall, the HPV52 LCR prototype was detected more frequently in Caucasian women (69 of 132, 52.3%, 95% confidence interval (CI): 43.8%-60.6%) than in non-Caucasian women (15 of 48, 31.3%, 95% CI 19.9%-45.4%). In two cohort studies, HPV52 prototype was detected in seven of 15 (46.7%, 95% CI 24.8-69.9) HPV52 persistent infections and 14 of 35 (40.0%, 95% CI 25.5-56.5) transient infections (p = 0.76). In two case-control studies, 30 participants did not have CIN, 18 had low-grade CIN (CIN1), 64 had CIN2,3, seven had cervical cancer and the diagnosis was undefined for 27 women. Variant MTL-52-LCR-02 was detected more frequently in women with cancer (28.6%, 95% CI 7.6%-64.8%) than in women without cancer or CIN2,3 (0%, 95% CI 0.0%-9.2%; p = 0.015). CIN2,3 risk was significantly associated with a deletion at nucleotide position 7695 in the LCR (OR 4.9, 95% CI 1.2-20.8), the T7744C variation in the LCR (OR 5.7, 95% CI 1.1 32.0), and the K93R variation in E6 (OR 6.9, 95% CI 1.3-36.8), after adjusting for age, detection of HPV16 or 18 and study site. These findings indicate that HPV52 polymorphism influences risk of CIN-2,3 and possibly invasive cancer. PMID- 23015308 TI - Association between conventional risk factors and different ultrasound-based markers of atherosclerosis at carotid and femoral levels in a middle-aged population. AB - Ultrasound detection of sub-clinical atherosclerosis (ATS) may help identify individuals at high cardiovascular risk. Most studies evaluated intima-media thickness (IMT) at carotid level. We compared the relationships between main cardiovascular risk factors (CVRF) and five indicators of ATS (IMT, mean and maximal plaque thickness, mean and maximal plaque area) at both carotid and femoral levels. Ultrasound was performed on 496 participants aged 45-64 years randomly selected from the general population of the Republic of Seychelles. 73.4 % participants had >= 1 plaque (IMT thickening >= 1.2 mm) at carotid level and 67.5 % at femoral level. Variance (adjusted R2) contributed by age, sex and CVRF (smoking, LDL-cholesterol, HDL-cholesterol, blood pressure, diabetes) in predicting any of the ATS markers was larger at femoral than carotid level. At both carotid and femoral levels, the association between CVRF and ATS was stronger based on plaque-based markers than IMT. Our findings show that the associations between CVRF and ATS markers were stronger at femoral than carotid level, and with plaque-based markers rather than IMT. Pending comparison of these markers using harder cardiovascular endpoints, our findings suggest that markers based on plaque morphology assessed at femoral artery level might be useful cardiovascular risk predictors. PMID- 23015310 TI - Chiral benzamidinate ligands in rare-earth-metal coordination chemistry. AB - The treatment of the recently reported potassium salt (S)-N,N'-bis-(1 phenylethyl)benzamidinate ((S)-KPEBA) and its racemic isomer (rac-KPEBA) with anhydrous lanthanide trichlorides (Ln = Sm, Er, Yb, Lu) afforded mostly chiral complexes. The tris(amidinate) complex [{(S)-PEBA}(3)Sm], bis(amidinate) complexes [{Ln(PEBA)(2)(MU-Cl)}(2)] (Ln = Sm, Er, Yb, Lu), and mono(amidinate) compounds [Ln(PEBA)(Cl)(2)(thf)(n)] (Ln = Sm, Yb, Lu) were isolated and structurally characterized. As a result of steric effects, the homoleptic 3:1 complexes of the smaller lanthanide atoms Yb and Lu were not accessible. Furthermore, chiral bis(amidinate)-amido complexes [{(S) PEBA}(2)Ln{N(SiMe(3))(2)}] (Ln = Y, Lu) were synthesized by an amine-elimination reaction and salt metathesis. All of these chiral bis- and tris(amidinate) complexes had additional axial chirality and they all crystallized as diastereomerically pure compounds. By using rac-PEBA as a ligand, an achiral meso arrangement of the ligands was observed. The catalytic activities and enantioselectivities of [{(S)-PEBA}(2)Ln{N(SiMe(3))(2)}] (Ln = Y, Lu) were investigated in hydroamination/cyclization reactions. A clear dependence of the rate of reaction and enantioselectivity on the ionic radius was observed, which showed higher reaction rates but poorer enantioselectivities for the yttrium compound. PMID- 23015311 TI - Facile fabrication of SERS arrays through galvanic replacement of silver onto electrochemically deposited copper micropatterns. AB - Scatter me: A fast and cost-effective approach for the fabrication of surface enhanced Raman scattering (SERS) arrays is developed. The method applied combines microcontact printing, electrodeposition, and galvanic replacement without the need for expensive instruments and intricate processing. The as-prepared arrays show excellent SERS activity and high reproducibility for Rhodamine 6G. PMID- 23015312 TI - Fast transmethylation of serum lipids using microwave irradiation. AB - Microwave irradiation as the energy source for one-step direct transesterification of fatty acids in human serum lipids was examined in a solvent system of methanol: hexane: acetyl chloride based on a Lepage & Roy assay. Innovative and explosion proof single-mode or multimode microwave accelerated reaction system was employed. Recoveries were calculated as the percentage of fatty acid concentrations measured by microwave assay to those by the reference method of the Lepage & Roy assay that utilized conductive heating at 100 degrees C for 60 min. Under conditions of 100 degrees C for 1 min in Single-mode (S4-100 * 1), or 125 degrees C for 5 min in Multimode (M5-125 * 5), the recoveries were 100-103 % for the total fatty acids and 96-106 % for each categorized fatty acid, including saturates, monounsaturates, n-6 PUFA, and n-3 PUFA. For individual PUFA, the mean recoveries were 102-105 % for 18:2n-6 and 18:3n-3; 99, 109, and 95 % for 20:4n-6, 20:5n-3, and 22:6n-3, respectively. Thus, fatty acid concentrations determined by microwave fatty acid assay were accurate to those results by the reference method, when the microwave conditions were optimal. In summary, the microwave irradiation could replace conductive heating in one-step direct transesterification, and reduce the duration from 60 min to 5 min or less. This methodology may be applied in both the absolute and relative quantification of serum total fatty acids. PMID- 23015314 TI - Feeding disorders of early childhood: an empirical study of diagnostic subtypes. AB - OBJECTIVE: The aim of this study was to examine the differences among three subtypes of feeding disorders (FD), defined through the criteria of the DC:0-3R: "Infantile Anorexia" (IA), "Feeding Disorder Associated with Insults to the Gastrointestinal Tract" (FDIGT), and "Sensory Food Aversions" (SFA), by exploring mother-child interactions during feeding, children's temperament and emotional adaptive functioning, and mothers' psychological profile and eating attitudes. METHOD: The sample consisted of 146 Italian mother-child pairs, of which 51 children with IA, 47 children with FDIGT, and 48 mothers and their children with SFA. All dyads were videotaped during feeding; mothers completed questionnaires assessing their psychological profiles and eating attitudes, as well as their children's temperament and emotional/behavioral functioning. RESULTS: Analyses revealed significant differences between the diagnostic groups of FD in relation to mother-child interactions during feeding, children's temperament and emotional adaptive functioning, and mothers' psychological profile and eating attitudes. DISCUSSION: Both interactional and individual variables may contribute differently to specific FD and outcomes during childhood. Definitions by FD subtypes, using operational diagnostic criteria, and the assessment of mother child interactions are relevant to target interventions strategies to treat specific disorders. PMID- 23015313 TI - Fish oil supplementation reduces cachexia and tumor growth while improving renal function in tumor-bearing rats. AB - The objective of the present work was to study the renal function of healthy and tumor-bearing rats chronically supplemented with fish oil (FO), a source of n-3 polyunsaturated fatty acids. Weanling male rats were divided in two groups, one control (C) and another orally supplemented for 70 days with FO (1 g/kg body weight). After this time, half the animals of each group were injected in the right flank with a suspension of Walker 256 tumor cells (W and WFO). The W group had less proteinemia reflecting cachectic proteolysis, FO reversed this fact. Tumor weight gain was also reduced in WFO. Glomerular filtration rate (GFR) was not different in FO or W compared to C, but was higher in WFO. Renal plasma flow (RPF) was higher in the FO supplemented groups. The W group had lower plasma osmolality than the C group, but FO supplementation resulted in normalization of this parameter. Fractional sodium excretion (FE(Na+)) of FO rats was similar to C. Proximal Na(+) reabsorption, evaluated by lithium clearance, was similar among the groups. Urinary thromboxane B(2) (TXB(2)) excretion was lower in the supplemented groups. The number of macrophages in renal tissue was higher in W compared to C rats, but was lower in WFO rats compared to W rats. In conclusion, FO supplementation resulted in less tumor growth and cachexia, and appeared to be renoprotective, as suggested by higher RPF and GFR. PMID- 23015315 TI - Traditional and modern medicine: morbidity of paediatric forearm fractures in Sierra Leone. PMID- 23015317 TI - Overexpression of LSD1 in hepatocellular carcinoma: a latent target for the diagnosis and therapy of hepatoma. AB - The aim of this study was to investigate the expression of LSD1 in human hepatocellular carcinoma (HCC) cell lines and HCC samples. In this study, we examined LSD1 expression in 60 paired liver cancer tissues and adjacent noncancerous tissues by Western blot. In addition, we analyzed LSD1 expression in 198 HCC samples by immunohistochemistry. The relationship between LSD1 expression and clinicopathological features was investigated. The HCC cell line SMMC-7721 was transfected with LSD1 siRNA expressing plasmids. We subsequently examined in vitro cell growth using the MTT assay and anchorage-independent growth through a soft-agar colony-formation assay. In addition, the expression levels of Bcl-2 and c-Myc were also examined. Immunohistochemistry and Western blotting consistently confirmed LSD1 overexpression in HCC tissues compared with adjacent non neoplastic tissues (P < 0.01). Additionally, immunostaining showed more LSD1 positive cells in the higher tumor stage (T3-4) and tumor grade (G3) than in the lower tumor stage (T1-2, P < 0.001) and tumor grade (G1-2, P < 0.001). Knockdown of LSD1 expression in HCC cells led to decreased cell proliferation. The expression of Bcl-2 and c-Myc were down-regulated after transfection of LSD1 siRNA into HCC cell line SMMC-7721. In conclusion, because LSD1 was overexpressed in HCC and has an important role in the development of HCC, LSD1 could be a latent target in the diagnosis and therapy of HCC. PMID- 23015319 TI - Amyloid beta-protein suppressed nicotinic acetylcholine receptor-mediated currents in acutely isolated rat hippocampal CA1 pyramidal neurons. AB - Amyloid beta protein (Abeta) is responsible for the deficits of learning and memory in Alzheimer's disease (AD). The high affinity between Abeta and nicotinic acetylcholine receptors (nAChRs) suggests that the impairment of cognitive function in AD might be involved in the Abeta-induced damage of nAChRs. This study investigated the effects of Abeta fragments on nAChR-mediated membrane currents in acutely isolated rat hippocampal pyramidal neurons by using whole cell patch clamp technique. The results showed that: (1) nonspecific nAChR agonist nicotine, selective alpha7 nAChR agonist choline, and alpha4beta2 nAChR agonist epibatidine all effectively evoked inward currents in CA1 neurons at normal resting membrane potential, with different desensitization characteristics; (2) acute application of different concentrations (pM-MUM) of Abeta25-35, Abeta31-35, or Abeta35-31 alone did not trigger any membrane current, but pretreatment with 1 MUM Abeta25-35 and Abeta31-35 similarly and reversibly suppressed the nicotine-induced currents; (3) further, choline- and epibatidine induced currents were also reversibly suppressed by the Abeta pretreatment, but more prominent for the choline-induced response. These results demonstrate that the functional activity of both alpha7 and alpha4beta2 nAChRs in the membrane of acutely isolated hippocampal neurons was significantly downregulated by Abeta treatment, suggesting that nAChRs, especially alpha7 nAChRs, in the brain may be the important biological targets of neurotoxic Abeta in AD. In addition, the similar suppression of nAChR currents by Abeta25-35 and Abeta31-35 suggests that the sequence 31-35 in Abeta molecule may be a shorter active center responsible for the neurotoxicity of Abeta in AD. PMID- 23015320 TI - Using gene-environment interaction analyses to clarify the role of well-done meat and heterocyclic amine exposure in the etiology of colorectal polyps. AB - BACKGROUND: The role of well-done meat intake and meat-derived mutagen heterocyclic amine (HCA) exposure in the risk of colorectal neoplasm has been suggested but not yet established. OBJECTIVE: With the use of gene-environment interaction analyses, we sought to clarify the association of HCA exposure with colorectal polyp risk. DESIGN: In a case-control study including 2057 colorectal polyp patients and 3329 controls, we evaluated 16 functional genetic variants to construct an HCA-metabolizing score. To derive dietary HCA-exposure amount, data were collected regarding dietary intake of meat by cooking method and degree of doneness. RESULTS: A 2-fold elevated risk associated with high red meat intake was found for colorectal polyps or adenomas in subjects with a high HCA metabolizing risk score, whereas the risk was 1.3- to 1.4-fold among those with a low risk score (P-interaction <= 0.05). The interaction was stronger for the risk of advanced or multiple adenomas, in which an OR of 2.8 (95% CI: 1.8, 4.6) was observed for those with both a high HCA-risk score and high red meat intake (P interaction = 0.01). No statistically significant interaction was found in analyses that used specific HCA exposure derived from dietary data. CONCLUSION: High red meat intake is associated with an elevated risk of colorectal polyps, and this association may be synergistically modified by genetic factors involved in HCA metabolism. PMID- 23015321 TI - Associations of erythrocyte palmitoleic acid with adipokines, inflammatory markers, and the metabolic syndrome in middle-aged and older Chinese. AB - BACKGROUND: Palmitoleic acid has been shown to regulate adipokine expression and systemic metabolic homeostasis in animal studies. However, its association with human metabolic diseases remains controversial. OBJECTIVE: We aimed to investigate associations of erythrocyte palmitoleic acid with adipokines, inflammatory markers, and metabolic syndrome (MetS) in a Chinese population. DESIGN: Erythrocyte fatty acids were measured in a population-based sample of 3107 men and women aged 50-70 y, for whom plasma glucose, insulin, lipid profile, adiponectin, retinol binding protein 4 (RBP-4), plasminogen activator inhibitor type 1, and high-sensitivity C-reactive protein (hsCRP) were measured. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. RESULTS: The mean (+/-SD) erythrocyte palmitoleic acid value was 0.41 +/- 0.20% of total fatty acids. Palmitoleic acid was positively correlated with RBP-4 (r = 0.14, P < 0.001) and inversely correlated with adiponectin (r = -0.15, P < 0.001). After multivariable adjustment, palmitoleic acid was strongly associated with MetS and its components. ORs (95% CIs) for comparisons of extreme quartiles of palmitoleic acid were 3.50 (2.66, 4.59) for MetS, 7.88 (5.90, 10.52) for hypertriglyceridemia, 2.13 (1.66, 2.72) for reduced HDL cholesterol, 1.99 (1.60, 2.48) for central obesity, and 1.86 (1.41, 2.44) for elevated blood pressure (all P < 0.001). Further control for adipokines and hsCRP abolished the association of palmitoleic acid with central obesity but not with other MetS components. CONCLUSION: Erythrocyte palmitoleic acid is associated with an adverse profile of adipokines and inflammatory markers and an increased risk of MetS in this Chinese population. PMID- 23015322 TI - Vitamin D and the racial difference in the genotype 1 chronic hepatitis C treatment response. AB - BACKGROUND: African Americans with genotype 1 chronic hepatitis C attain a sustained virologic response (SVR) at only approximately one-half the rate of whites after peginterferon and ribavirin treatment. The serum concentration of 25 hydroxyvitamin D [25(OH)D] has recently been established as a predictor of treatment response. Therefore, the low serum concentrations of 25(OH)D found among African Americans may contribute to the low response rate; however, to our knowledge, none of the studies of vitamin D in chronic hepatitis C treatment have included a significant number of black patients. OBJECTIVE: The objective was to compare the relation between the 25(OH)D concentration and genotype 1 chronic hepatitis C treatment response in African Americans with that in whites. DESIGN: This cross-sectional analysis included 106 African American and 65 white patients with genotype 1 chronic hepatitis C. RESULTS: Consistent with previous studies, we found that the SVR rate in the white patients increased significantly with an increasing serum concentration of 25(OH)D [SVR rates were 20%, 46%, and 70% for 25(OH)D serum concentrations <20, 20-35, and >35 ng/mL, respectively; P-trend = 0.008]; however, there was no relation between the SVR rate and 25(OH)D serum concentration in the African American patients [SVR rates were 32%, 28%, and 33% for 25(OH)D serum concentrations <20, 20-35, and >35 ng/mL, respectively; P-trend = 0.832]. We also found an analogous racial difference in the relation between the extent of liver fibrosis and the 25(OH)D concentration. CONCLUSION: Racial differences in vitamin D physiology or race-specific factors that modify the effects of vitamin D may affect the immune response to genotype 1 hepatitis C virus. PMID- 23015323 TI - Development of oligoclonal nanobodies for targeting the tumor-associated glycoprotein 72 antigen. AB - The tumor-associated glycoprotein 72 (TAG-72) is a membrane mucin whose over expression is correlated with advanced tumor stage and increased invasion and metastasis. In this study, we identified a panel of four nanobodies, single variable domains of dromedary heavy-chain antibodies that specifically recognize the TAG-72 antigen. All selected nanobodies were shown to selectively bind to this cancer-related molecule with low-nanomolar affinities and do not cross-react with other antigens, such as MUC1 or HER2. Furthermore, they can detect TAG-72 in concentrations as low as 5 U/ml which is valuable in sensitive detection of this molecule in cancerous patients. Cell ELISA experiments proved their ability for binding to the native target antigen on TAG-72 expressing cells while not showing any reactivity to HT-29 cells, a TAG-72-negative cell line. Using competition studies, we found that each nanobody recognizes a distinct epitope on the TAG-72 antigen that is different from the one recognized by the mouse anti-TAG-72 antibody, CC49. Considering their high specificity, reduced immunogenicity and multi-targeting behavior, these oligoclonal nanobodies represent a promising tool to target TAG-72 over-expressing tumor cells. PMID- 23015325 TI - Bars to jars: bamboo value chains in Cameroon. AB - Bamboo is a well know and versatile material, which is a common sight across Cameroon's diverse ecosystems, from dry to humid tropical and Afromontane forests. Its numerous uses range from storage jars to decorating restaurant-bars, beehives to knives, fences, fodder, and fuel. Responding to the paucity of data on species and uses, the value chain for bamboo in Cameroon was analyzed. Based on 171 interviews and field observations, two African indigenous species (alpine Yushania alpina and savannah Oxytenanthera abyssinica) and exotic (Bambusa vulgaris spp.) bamboos were identified as most utilized. They were tracked from major production zones to final consumers. The ecological, socio-economic, institutional, and governance contexts and impacts are described and analyzed. Issues for research, conservation, and development are highlighted. These include the ambiguous regulatory status, the relationship between tenure and management, threats and conservation of African species and options to increase the sustainable livelihoods for stakeholders dependent upon bamboo. PMID- 23015324 TI - Tired of diabetes genetics? Circadian rhythms and diabetes: the MTNR1B story? AB - Circadian rhythms are ubiquitous in biological systems and regulate metabolic processes throughout the body. Misalliance of these circadian rhythms and the systems they regulate has a profound impact on hormone levels and increases risk of developing metabolic diseases. Melatonin, a hormone secreted by the pineal gland, is one of the major signaling molecules used by the master circadian oscillator to entrain downstream circadian rhythms. Several recent genetic studies have pointed out that a common variant in the gene that encodes the melatonin receptor 2 (MTNR1B) is associated with impaired glucose homeostasis, reduced insulin secretion, and an increased risk of developing type 2 diabetes. Here, we try to review the role of this receptor and its signaling pathways in respect to glucose homeostasis and development of the disease. PMID- 23015326 TI - Mitigating global warming potentials of methane and nitrous oxide gases from rice paddies under different irrigation regimes. AB - A field experiment was conducted in Bangladesh Agricultural University Farm to investigate the mitigating effects of soil amendments such as calcium carbide, calcium silicate, phosphogypsum, and biochar with urea fertilizer on global warming potentials (GWPs) of methane (CH4) and nitrous oxide (N2O) gases during rice cultivation under continuous and intermittent irrigations. Among the amendments phosphogypsum and silicate fertilizer, being potential source of electron acceptors, decreased maximum level of seasonal CH4 flux by 25-27 % and 32-38 % in continuous and intermittent irrigations, respectively. Biochar and calcium carbide amendments, acting as nitrification inhibitors, decreased N2O emissions by 36-40 % and 26-30 % under continuous and intermittent irrigations, respectively. The total GWP of CH4 and N2O gases were decreased by 7-27 % and 6 34 % with calcium carbide, phosphogypsum, and silicate fertilizer amendments under continuous and intermittent irrigations, respectively. However, biochar amendments increased overall GWP of CH4 and N2O gases. PMID- 23015327 TI - Early brain injury following aneurysmal subarachnoid hemorrhage: emphasis on cellular apoptosis. AB - Subarachnoid hemorrhage (SAH) due to intracranial aneurysm rupture is a complex clinical disease with high mortality and morbidity. Recent studies suggest that early brain injury (EBI) rather than vasospasm might be responsible for morbidity and mortality within 24-72 hours after SAH. The rise in intracranial pressure following SAH causes a significant drop in cerebral perfusion pressure that leads to global cerebral ischemia and initiates the acute injury cascade. Various molecular mechanisms have been shown to involve in the pathophysiology of EBI including cellular apoptosis. In this review, we summarize apoptotic molecular mechanisms involved in the etiology of EBI and its potential as a target for future therapeutic intervention. PMID- 23015328 TI - Surgical results of degenerative spondylolisthesis patients over 70 years old: a single-center experience and clinical outcomes. AB - AIM: The aim of this study is to evaluate results of surgery in Degenerative Spondylolisthesis (DS) patients over 70 years old. MATERIAL AND METHODS: This is a non-randomized retrospective analysis of the clinical outcome of 34 patients older than 70 years who underwent surgery. At the end of two-year follow-up period, preoperative and postoperative courses were assessed by Oswestry Disability Index (ODI) and Visual Analog Scales (VAS). RESULTS: The mean age was 75 years (range 70-86 years). The mean duration of symptoms was 13.5 years (range 2-30 years). All patients underwent physiotherapy and also 15 (11 female, 4 male) patients used brace. L4-L5 was the most commonly affected level (n=26), Preoperative ODI and VAS scores were mean 71,63 (range 34-100) and 6,77 (range 2-9) (p < 0,05). Postoperative ODI and VAS scores were mean 22,73 (range 0-100) and 2,13 (range 0-10) (p < 0,05). Patients were asked if they had known the outcome, would they accept surgical treatment or not. 86.6% (n=26) of the patients answered the question positively. CONCLUSION: A conventional decompressive laminectomy with foraminotomy and posterolateral fusion in situ with transpedicular instrumentation is necessary and reduces pain and recovers functional disability in elderly patients over 70 years old with DS. PMID- 23015329 TI - Morphometric evaluation of parasagittal venous anatomy for intracranial approaches: a cadaveric study. AB - AIM: Obstruction of superior sagittal sinus (SSS) and collateral bridging veins is a well-known reason of postoperative brain edema and brain infarct, however, morphometric anatomic studies done in the light of surgical landmarks aren't sufficient in number. Object of this study is to describe venous structures related to SSS with silicon injected cadaveric models. MATERIAL AND METHODS: This study was on 6 silicon injected cadaveric heads at Anatomy Department. Duramater was removed and veins on parasagittal area were examined. SSS morphology, veins draining into SSS, their size, number and distance were evaluated. RESULTS: Mean vein number draining into SSS is 2.9+/-1.5 at anterior to coronal suture (CS), between CS and vertex is 3.2+/-0.8, between vertex and lambdoid suture (LS) is 2.3+/-0.9, between LS and confluens sinuum 0.3+/-0.5. There was no statically difference between right and left sides (p=0.140, p > 0.05). Diameter of veins was 2.4+/-1.0 mm at anterior to CS, 3.0+/-1.2 mm at between CS and vertex, 2.4+/ 0.7 mm at between vertex and LS, and 2.2+/-0.5 mm at between LS and confluens sinuum. CONCLUSION: Knowing details of anatomic structures of SSS and venous structures draining into it may protect the patients from many surgical complications. SSS and related structures with surgical landmarks are valuable for neurosurgeons. PMID- 23015330 TI - Large medial sphenoid wing meningiomas: long-term outcome and correlation with tumor size after microsurgical treatment in 127 consecutive cases. AB - AIM: We present the long-term outcomes as well as their correlation with tumor size in 127 consecutive patients harboring large MSWM after microsurgical treatment. MATERIAL AND METHODS: The retrospective analysis of clinical data and follow-up data of 127 microsurgical treated patients with MSWM was performed. The mean maximum diameter of tumors was 5.2cm (ranged 1.5-10.0cm). RESULTS: 104 cases (81.9%) achieved gross total resection. There was no operative mortality. Detailed follow-up data was available in 120 cases for a mean duration of 81.6 months (12-216 months). The permanent morbidity was 14.2%. The mean KPS score 1 year after surgery was 90.6 (ranged 60-100). Among 74 patients of preoperative visual acuity (VA) impairment, postoperative VA improved in 42 cases (56.8%), unchanged in 30 (40.5%), and deteriorated in 2 (2.7%). MR images revealed tumor recurrence after total resection in 10 cases (10.2%) and tumor progression after subtotal resection in 10 cases (45.5%). CONCLUSION: Tumor recurrence was the major risk in the long run, thus the initial surgery was extremely important and hence should be aggressive. The size of tumor affected the extent of tumor removal determining clinical outcomes including VA improvement and KPS score immediately after surgery; however, it was not correlated with long-term overall outcomes. PMID- 23015331 TI - Preoperative assessment using multimodal functional magnetic resonance imaging techniques in patients with brain gliomas. AB - AIM: To evaluate the value of magnetic resonance spectroscopy (MRS), blood oxygen level-dependent imaging (BOLD) and diffusion tensor imaging (DTI) for preoperative assessment in patients with brain gliomas. MATERIAL AND METHODS: Twenty-three consecutive glioma patients underwent MRS, BOLD and DTI before operation. The characteristics of images were analysed according to histopathological results. RESULTS: There is significant elevation of the choline (Cho) /creatine (Cr) ratio, Cho peak and depression of the N acetylaspartate (NAA) peak in gliomas. Elevation of the Cho/Cr, Cho/NAA ratio and the presence of a lipids peak, were consistent with high-grade malignancy. A motor activation scan was achieved by using a motor task paradigm in 20 patients. Deformation and displacement of the motor activations was found in 5 cases. The margin of tumor and peritumoural white matter tracts were identified using apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps. Three patterns of white matter tracts alteration were identified: displacement, infiltration, and disruption. In all 23 patients, the tumors were completely resected in 6 patients, subtotal resected in 8 patients, partial resected in 9 patients. No secondary neurological deficit was occurred in all patients after operation. CONCLUSION: The combination of MRS, BOLD, and DTI techniques allows appropriate presurgical planning of brain gliomas. PMID- 23015332 TI - Malign transformation in the low grade astrocytomas and related factors. AB - AIM: Retrospective investigation of prognostic factors in low-grade astrocytomas. MATERIAL AND METHODS: In the study, prognostic factors were prospectively identified and assumed to be effective on prognosis, which were reviewed in 67 cases diagnosed as low-grade astrocytoma with craniotomy between May 1998 to December 2005 at Erciyes University Neurosurgery Department. Assessment of demographic, neurologic, radiological, surgical and clinical features of cases and adjuvant therapies and their relationship with prognosis were evaluated. Post-operative cumulative survival of the cases was estimated by using the Kaplan-Meier method. The Log Rank test was used to compare the survival curve of the sub-groups. Multivariate analysis of survival was analyzed by using the Cox regression method. RESULTS: It was seen that malign transformation occurred in 9 patients of subtotal resection group. The difference was statistically significant (p < 0.01). malign transformation was detected in one female (3.2%) and 8 male patients (22.2%). Difference in favor of men was statistically significant (p < 0.05). Malignant transformation was detected in 7 of the patients given post-operative radiotherapy, only 2 patients displayed malign transformation in the group which received no radiotherapy. Comparison of groups revealed a significant difference (p=0.01). CONCLUSION: Detection of higher malign transformation rate in cases underwent radiotherapy than those did not and the statistical significance in this meaning mandates to revise treatment plan regarding radiotherapy. PMID- 23015333 TI - Effect of prenatal stress on expression of glutathione system in neonatal rat brain. AB - AIM: Prenatal stress is known to adversely affect the fetal brain development and also neuronal loss. The mechanism(s) associated with prenatal stress induced developmental neurotoxicity remains obscure. Few studies point to the glutathione (GSH) antioxidant system which is an important molecular target for this toxicant. Hence the present study investigates the effect of prenatal stress on glutathione system in neonatal rat brain. MATERIAL AND METHODS: Three to four months old pregnant Wistar rats were subjected to restraint stress during early or late gestational period. The offspring were sacrificed on 40th day and their brain homogenate was subjected to antioxidant studies. The serum corticosterone and adrenal ascorbic acid levels were also estimated from offspring. RESULTS: The prenatal stress has resulted in an increase in the serum corticosterone and reduced adrenal ascorbic acid levels in neonatal pups. Prenatal stress during early or late gestation life showed reduced glutathione, glutathione reductase (GSSG-Rd) and superoxide dismutase (SOD) activity in offspring brain homogenate. CONCLUSION: These data suggest that stress during early or late gestation period affect glutathione system in developing neonatal rat brain, which is associated with elevated serum corticosterone and reduced adrenal ascorbic acid levels. PMID- 23015334 TI - Clinical results of surgical management in type II odontoid fracture: a preliminary report. AB - AIM: This study was conducted to evaluate the therapeutic effectiveness of surgical approaches in type II odontoid fracture. MATERIAL AND METHODS: In a retrospective study in Mashhad university, 15 patients with anterior screw fixation technique (ASF) and 31 patients with posterior approaches (PA) were reviewed. Patient demographics, clinical presentation, length of hospital stay, operation time, injury severity score (ISS), Preinjury Charlson comorbidity index, fusion rate and surgical complications were analyzed in these two groups. RESULTS: Neck pain was the most common clinical presentation in these two groups (89.7%). There were no significant differences in ISS and mean length of hospital stay and Comorbidity index between the two groups. The operation time was different between these two groups (65 minutes in ASF versus118 minutes in PA, P < 0.05). Bone union was documented in 13 patients (87%) with ASF and 28 patients (90%) with PA. CONCLUSION: The outcome of surgery with anterior or posterior approach in the patients are potential candidates for surgery is good. In our patients, the operation time is different in the two groups but differences in fusion rate, length of hospital stay, comorbidity index and postsurgical complications are not considerable. PMID- 23015335 TI - Duration of intra-operative stimulation as a predictor of success of spinal cord stimulation for chronic pain syndromes. AB - AIM: Electrical stimulation of the dorsal column of the spinal cord stands out as a major method of neuromodulation. Its popularity stems from the long lasting support to the "gate theory" in which electrical stimulation of the gate prevents passage of nociceptive impulses and reduces pain sensation. There is little known about the effect of the duration of intraoperative stimulation (IOS) trial on the success of the spinal cord stimulation trial. MATERIAL and METHODS: We present our result on 58 patients with spinal cord stimulation implantation and their IOS trials and short-term follow up. RESULTS: The major finding of this study is that the longer the IOS trial, the higher the chances for failure of SCS. Our study also suggests that tripolar spinal cord stimulation leads present a more reliable option for long-term success of the spinal cord stimulation (SCS). CONCLUSION: The duration of IOS seems to influence the result of the initial trial of SCS. IOS should be between 30-60 minutes to optimize the placement of the lead for better correlation with the SCS trial. PMID- 23015336 TI - Surgical management strategies of intracranial arachnoid cysts: a single institution experience of 75 cases. AB - AIM: Arachnoid cysts are benign intra-arachnoid cystic lesions filled with cerebrospinal fluid. With advent of modern treatment techniques, debate continues regarding which surgical treatment is most effective. MATERIAL and METHODS: A consecutive series of 75 patients with arachnoid cysts that were surgically treated between January 1992 and December 2009 are reported. Included in the study were 54 male and 21 female patients, ranging in age from 2 months to 45 years (mean age 20.02 years) at the time of surgery. Symptoms at presentation, location on the cysts, and treatment modalities were evaluated. RESULTS: Headache was controlled in 92.5% of adult cases. Hydrocephalus, cognitive decline weakness and gait disturbances were controlled 100% after overall treatment methods. Follow-up CT scans showed significant reduction in cyst size in supratentorial arachnoid cysts. No significant changes in cyst size were found in infratentorial cysts but symptomatic improvements were noted. CONCLUSION: Patients with symptomatic arachnoid cysts regardless of age and cyst location should be treated. We think that avoiding shunt dependence should be one of the principle treatment goals. Proper patient selection results in good outcomes. PMID- 23015337 TI - Microscopic supraciliary approach for terminal laminotomy for treatment of hydrocephalus: a preliminary report of eight cases. AB - AIM: Shunting and endoscopic third ventriculostomy for treatment of hydrocephalus have their own complications which make the management of such patients more difficult. We have examined the subfrontal route to fenestrate lamina terminalis in order to achieve relief of hydrocephalus in eight consecutive patients. MATERIAL AND METHODS: Eight patients with the diagnosis of hydrocephalus were chosen. A supraciliary approach to the central skull base was used to fenestrate the lamina terminalis to allow cerebrospinal fluid egress from the third ventricle to the basal cisterns. RESULTS: Clinical and/or radiological remission of hydrocephalus symptoms were observed in all patients. No complications were encountered in this small series of patients. CONCLUSION: Microsurgical third ventriculo-cisternostomy through a supraciliary might be a reasonable alternative to endoscopic third ventriculostomy. However, a more sample size with controlled subjects is required to draw conclusions and comparisons with other techniques of treatment of hydrocephalus. PMID- 23015338 TI - Anxiety caused by traumatic brain injury correlates to decreased prefrontal cortex VEGF immunoreactivity and neuron density in immature rats. AB - AIM: Traumatic brain injury (TBI) may cause neuropsychiatric disorders such as anxiety disorder which has negative effects on cognitive functions and behavior. The aim of this study is to investigate the effects of TBI on anxiety and vascular endothelial growth factor (VEGF) immunoreactivity on the prefrontal cortex of immature rats, which is one of the anxiety-related regions of the brain in 7-day-old immature rats subjected to contusion injury. MATERIAL and METHODS: Rats were divided into three groups: Control (n=7), Sham (n=7) and TBI (n=7). Anxiety levels were assessed with open field activity and elevated plus maze in postnatal 27 days. Prefrontal cortex damage related to TBI was examined by cresyl violet staining and VEGF immunostaining. Prefrontal cortex neuronal density was calculated. Serum corticosterone levels were determined. RESULTS: The anxiety level in the TBI group was significantly greater than the control and sham groups. The prefrontal cortex VEGF immunostaining score and neuron density were decreased in the TBI group compared to control and sham group. Serum corticosterone levels were significantly increased in the TBI group. CONCLUSION: These results indicate that TBI decreases VEGF immunoreactivity in prefrontal cortex neurons and increases the anxiety levels of immature rats. PMID- 23015339 TI - Outcome evaluation of a zero-profile implant for anterior cervical diskectomy with fusion. AB - AIM: Supplementing anterior cervical diskectomy and fusion (ACDF) with plates enhances stabilization, increases fusion and reduces failure rates. Zero-P implant for stand-alone anterior interbody fusion procedures of the cervical spine was recently developed to avoid complications associated with anterior cervical plates. We evaluate the outcome of its use in our patients undergoing ACDF. MATERIAL AND METHODS: 84 patients were selected to undergo ACDF with Zero-P implant of whom 75 (52 male and 23 female) were followed up for 12 to 16 months (mean 14.2 months) with a total of 94 operated levels (54 single, 21 double level). Patients underwent pre- and postoperative clinical evaluation with full neurological examination, visual analogue scale (VAS), Neck Pain and Disability Scale (NPAD) and Bazaz-Yoo dysphagia index for postoperative dysphagia. Postoperative plain X-ray evaluation of fusion and implant-associated complications was done. REAULTS: All patients had significant reduction in arm and neck pain and NPAD maintained over 12 months, no implant-associated complications during follow-up, and radiological fusion by 3 months. None had dysphagia after 3 months postoperatively. CONCLUSION: The Zero-P implant is a valid alternative to anterior cervical plating after ACDF with a very low incidence of postoperative dysphagia and no implant-related complications. PMID- 23015340 TI - Does the sphenoid angle effect the operation strategy? Anatomical and radiological investigation. AB - AIM: The aim of our study is to suggest the sphenoid wing-lesser wing angulation (SWA) importance during surgeries directed to this region. MATERIAL AND METHODS: SWA on 40 skulls were measured bilaterally (n=80). The depth of the middle cranial fossa (DMCF) at the level of the SWA was determined. The same measurements were done on 40 randomly selected computerized tomography (CT) scans bilaterally (n=80). RESULTS: The specimens were classified into 3 groups according the degree of SWA; Group-A, SWA was more than 130 degrees (27%), Group-B, SWA was 110-130 degrees (43%) and Group-C, SWA was less than 110 degrees (28%). MCF was measured (mean) as 10.1 mm in Group-A, 6.4 mm in Group-B and 4.6 mm in Group-C. MCF was increasing with the increase in SWA. CT scans were classified into same procedure. Group-A was 26%, Group-B was 42% and Group-C was 31% fitting in the relevant groups. The superior orbital fissure (SOF) was evaluated according to the Sharma's classification. CONCLUSION: We suggest that by the preoperative evaluation of CT scans measurements the SWA, it is possible to estimate the MCF and the type of SOF. This knowledge may be important for all surgeries requiring removal of the sphenoid wing and these region pathologies. PMID- 23015341 TI - Computed tomographic evaluation of the distance between the medial border of longus colli muscle and foramen transversarium in ventral approaches to the subaxial cervical spine. AB - AIM: Iatrogenic vertebral artery (VA) injury during ventral approaches to the subaxial cervical spine ranges from 0.22% to 2.77%. Evaluation of the extent of safe lateral working distance before the V2 segment of the VA is reached can be helpful to avoid this complication. MATERIAL AND METHODS: In 100 patients (48 males and 52 females) axial computed tomographic scanning was used to measure the distance from the medial border of longus colli muscle (LCM) to the medial border of the foramen transversarium along the anterior border of the vertebral body at each level from C3-4 down to C6-7. The arithmetic mean of the 2 measurements at the upper and lower end-plates of the corresponding level was considered representative of the safe lateral working distance at this level. Statistical significance was set as P value < 0.001. RESULTS: No statistically significant difference was found between the measurements in the whole study population at various levels or between subgroups. A gradual increase in the distances was noticed from C3-4 down to C6-7 level in all subgroups except for spondylotic males. CONCLUSION: This study offers useful morphometric data that can help the surgeon avoid VA injury during anterior procedures to the subaxial cervical spine. PMID- 23015342 TI - Do translaminar facet screws have the same stability as pedicle screws in two level anterior lumbar interbody fusion? A biomechanical study. AB - AIM: To determine whether translaminar facet screws can provide stability equivalent to pedicle screws in two-level anterior lumbar interbody fusion. MATERIAL AND METHODS: We performed a biomechanical study using 12 fresh human lumbar spines and tested intact spine, stand-alone two-level ALIF and anterior fusion augmented with pedicle screws or translaminar facet screws under 400N compressive preloads and 7.5Nm moments in flexion, extension, axial rotation and lateral bending, and measured the range of motion and the stiffness of operative level. RESULTS: We found two-level ALIF had significantly reduced range of motion, greater stiffness at operative segments in flexion, axial rotation and lateral bending (p < 0.05), but decreased stiffness and increased range of motion in extension (p < 0.05), when compared to intact spine. The two augmented ALIF constructs have significantly reduced range of motion (p < 0.05) and increased stiffness at operative level (p < 0.05), when compared to intact spine or stand-alone two-level ALIF. There is no significant difference of range of motion and stiffness at operative level between the two augmented constructs in all loading directions (p > 0.05). CONCLUSION: Translaminar facet screws can provide stability equivalent to pedicle screws, and we recommend translaminar facet screws as perfect alternatives to pedicle screws in two-level ALIF. PMID- 23015343 TI - Prevention of epidural fibrosis in rats by local or systemic administration of citicoline. AB - AIM: The objective of this study was to investigate the effect of citicoline administration on epidural fibrosis which is a frequent complication of lumbar disc surgery with no effective treatment or preventive surgical technique. MATERIAL AND METHODS: Sixty Sprague-Dawley female rats undergoing L4-5 right hemilaminotomy and annular fenestration were arranged in three groups: rats in Group 1 (control group) and Group 2 (topical citicoline group) were applied 0,9% saline and 100 MUM citicoline on surgical area, respectively, while rats in Group 3 (systemic citicoline group) received 600 MUmol/kg citicoline intraperitoneally. Rats were sacrificed four weeks later and their vertebral colons were removed en bloc. Groups were evaluated according to histological criteria and results were compared using statistical tools. RESULTS: Compared with control group, significantly less epidural fibrosis, dural adhesion, fibroblast cell density, foreign body reaction, and medulla spinalis retraction were observed in groups treated with topical and systemic citicoline (groups 2 and 3) (p < 0,001). No significant difference was found with regard to measured parameters between two treatment groups (p > 0,05). CONCLUSION: Our study demonstrates for the first time in the literature that citicoline may be effective for preventing postoperative epidural fibrosis. However, its mechanism of action and clinical effectiveness must be further investigated. PMID- 23015344 TI - The importance and efficacy of posterior only instrumentation and fusion for severe idiopathic scoliosis. AB - AIM: In mild and moderate idiopathic scoliosis (IS), posterior only instrumentation and fusion can provide satisfactory reduction. However in severe and rigid curvatures, combined anterior and posterior fusion is generally required. In this study we have aimed to evaluate the efficacy of posterior only instrumentation in severe thoracolumbar scoliosis clinically and radiologically and compare these results with the literature. MATERIAL AND METHODS: In this retrospective study, 29 consecutive patients with severe idiopathic scoliosis who underwent posterior only instrumentation and fusion between March 2003 and February 2011 were included the study. Radiological evaluation was performed with preoperative, postoperative and folllow up standing AP and lateral x-rays. Clinical evaluation was made with shoulder balance and trunk shift. REAULTS: Major curve magnitude decreased to 24,1 degrees and compensatory curve magnitude decreased to 12.20 degrees at postoperative period. There was no significant difference in sagittal plane angles. Major curve correction rate was %68,65 in screw only instrumentation and % 65 in hybrid instrumentation. CONCLUSION: Transpedicular screw instrumentation in severe IS is a safe and effective method in proper hands when flexibility of the curve evaluated accurately in preoperative period. PMID- 23015346 TI - Incidence and management of late postsurgical seizures in clinical practice. AB - AIM: Seizures are a frequent complication in patients who undergo neurosurgery, and can complicate the post-operative course and deteriorate patients' quality of life. Evidence on the prophylactic anticonvulsant therapy after craniotomy is still lacking. MATERIAL AND METHODS: We undertook an observational longitudinal study following neurosurgical supratentorial interventions, to evaluate seizures onset or persistence, and differences in effectiveness between conventional and newer AEDs. RESULTS: A total of 100 consecutive subjects were enrolled. Each patient underwent a neurosurgical treatment by craniotomy. Pre-operative seizures occurred in 33% patients, early seizures in 13%. Late seizures occurred in 46 patients. At baseline (1 month after surgery) and during follow up the main therapeutic regimen was monotherapy. At last follow up adjustment of antiepileptic regimen or AED dosage had rendered 27 subjects seizure free. People taking newer AEDs at baseline maintain the same antiepileptic regimen more often than patients taking conventional AEDs; late seizures tended to have a higher incidence in the latter group. Adverse events from baseline AEDs were reported by 17% of patients. CONCLUSION: In this study population late postsurgical seizures had a remarkable occurrence. Newer AEDs were continued more often than conventional AEDs, with a better tolerability but no significant differences in late seizures incidence. PMID- 23015345 TI - Improvement in remission rates of the first operation in acromegalic patients. AB - AIM: The aim of the study was to determine the remission rates of the first operation with respect to the number of surgeons and the parameters important for the prediction of the success. MATERIAL AND METHODS: The study cohort consisted of 180 acromegalic patients who presented over a 29 year. All the patients had undergone transnasal transsphenoidal adenomectomy and then octreotide treatment and/or radiotherapy were applied to the patients who were not cured. Remission criteria was accepted as nadir GH < 1 MUg/L with oral glucose tolerance test (OGTT) and normal IGF-1 with respect to age and gender. RESULTS: The postoperative median follow up period was 84 months (range 6-372 months). The remission rate of the first operation before 2003 was 20%, but this rate increased to 51% after 2003 (p=0.018). The most impressive improvement was due to the single experienced surgeon (49% vs. 5.3%) (p < 0.001). The success of the first operation was determined by the tumor size, microadenomas were more successfully treated than macroadenomas (p=0.014). The prevalence of discordance between GH and IGF-1 was 24% in patients cured after first surgery. CONCLUSION: The clinical recognition of acromegaly and outcomes of single experienced surgeons in specialized centers have significantly improved over the last years. PMID- 23015347 TI - Hyponatremic seizure due to huge abdominal cerebrospinal fluid pseudocsyt in a child with ventriculoperitoneal shunt: a case report. AB - Placement of ventriculoperitoneal(VP) shunt is a worldwide accepted procedure for treatment of hydrocephalus. This procedure have various intra-abdominal complications, of which pseudocyst formation is a rare one. Common presentations of this complication are abdominal mass, abdominal pain, intestinal obstruction, and shunt dysfunction. In this paper, we report a case of 3 year old boy with cerebrospinal fluid (CSF) pseudocyst of the VP shunt presenting with hyponatremic seizure. To the best of our knowledge, hyponatremic seizure has not been previously reported as a presentation of abdominal CSF pseudocyst in the literature. Our case has also the largest CSF pseudocyst with respect to body surface area of the child in the literature. PMID- 23015348 TI - Epidermoid cyst inside anterior sacral meningocele in an adult patient of Currarino syndrome manifesting with meningitis. AB - The Currarino triad, also known as the "Currarino Syndrome", is a rare complex of congenital caudal anomalies including three main features; a sacral bony deformity, anorectal malformations, and a presacral mass. We present an extremely uncommon case of Currarino syndrome in adulthood presenting with repeated episodes of meningitis. Magnetic resonance imaging of spine was suggestive of caudal regression. Cord was low lying, conus ending at L3 level with evidence of tethering at that level. A large cyst was noted in the sacral canal extending forwards in the pelvis through the widened sacral foramina on right side. She was operated through a posterior approach, via sacral laminectomy. Dura was opened in the midline, large silvery white epidermoid tumor was found completely occupying the anterior sacral meningocele. The case and relevant literature is discussed. PMID- 23015349 TI - Endoscopic transphenoidal approach for fibrous dysplasia of clivus, tuberculum sellae and sphenoid sinus; report of three cases. AB - AIM: Fibrous dysplasia is a benign disease in which medullary bone is replaced by fibro-osseous tissue, and causes distortion and overgrowth of the involved bone and represents about 3% of all bone tumors. There is variability in the manifestation of Fibrous Dysplasia lesions with imaging techniques due to their proportional variations of fibrous to osseous tissue. Radiological differential diagnoses include meningioma, chordoma on MRI and Paget disease on CT imagings. MATERIAL AND METHODS: We report three cases of monostotic fibrous dysplasia, affecting clivus, tuberculum sellae, and sphenoid sinus through the pterygopalatine fossa. We performed pure endoscopic transphenoidal approach for those three cases with the guide of neuronavigation. Extended approach was used via binostril for fibrous dysplasia of clivus and Tuberculum sellae. RESULTS: Radiologic report revealed chordoma and meningioma for the two cases and fibrous dysplasia for the last case. Total resection of tuberculum sellae, subtotal resection of clivus and partial resection of sphenoid sinus lesions were performed. Pathology diagnosis were fibrous dysplasia in all three patients. CONCLUSION: Histopathological sampling provided by surgical approach should be obtained to establish the final diagnosis. Endoscopic approaches are convenient for skull base lesions even for biopsy or curative resections providing panoramic view and avoid brain retraction. PMID- 23015350 TI - Cervical intradural glass fragment: a rare cause of neuropathic pain. AB - Intradural foreign bodies after penetrating injuries are seen very rarely. Limited number of cases of glass fragments in the spinal canal were reported previously. Migration of foreign bodies and delayed onset of neurological symptoms due to foreign bodies were also reported. In this report a 33-year-old male patient was presented, who had penetration of glass fragments through oropharyngeal mucosa in to the spinal canal after crashing into a glass door. Glass fragment, which migrated through an unusual route, and reached cervical spinal intradural space, caused neuropathic pain with radicular symptoms, 21 years after the initial injury. This case report emphasize that after penetrating injuries of spine, foreign bodies may remain silent until the patient became symptomatic years after the initial injury and these foreign bodies may migrate to extreme distant and unexpected locations in the central nervous system. PMID- 23015351 TI - Synthesis, cytotoxicity, induction of apoptosis, and interaction with DNA of dinuclear platinum(II) complexes. AB - Six dicarboxylato-bridged dinuclear platinum(II) complexes S1-S6, with a newly designed chiral ligand, 2-{[(1R,2R)-2-aminocyclohexyl]amino}propanoic acid (HL), were prepared and spectrally characterized. The in vitro cytotoxicity of all resulting platinum(II) complexes was evaluated against human HCT-116, MCF-7, and HepG-2 tumor cell lines. The results show that all compounds exhibit positive biological activity toward HCT-116 and MCF-7 cell lines, of which complexes S3, S4, and S5, with succinate and its derivatives as bridges, showing better activity than the positive controls. Moreover, double-dyeing flow cytometric resection experiments indicate that the target compounds inhibit tumor cell growth by inducing apoptosis; gel electrophoresis experiments demonstrate the compounds' ability to prompt pET22b plasmid DNA degradation in almost the same way as oxaliplatin. PMID- 23015353 TI - Isolated cutaneous Langerhans cell histiocytosis in a premature baby: what is the optimal approach? PMID- 23015352 TI - Eating patterns in youth with and without loss of control eating. AB - OBJECTIVE: To compare the characteristic meal patterns of adolescents with and without loss of control (LOC) eating episodes. METHOD: The Eating Disorder Examination was administered to assess self-reported LOC and frequency of meals consumed in an aggregated sample of 574 youths (12-17 years; 66.6% female; 51.2% Caucasian; BMI-z: 1.38 +/- 1.11), among whom 227 (39.6%) reported LOC eating. RESULTS: Compared to those without LOC, youth with LOC were less likely to consume lunch and evening meals (p's < .05), but more likely to consume morning, afternoon, and nocturnal snacks (p's <= .05), accounting for age, sex, race, socio-economic status, BMI-z, and treatment-seeking status. DISCUSSION: Adolescents with reported LOC eating appear to engage in different meal patterns compared to youth without LOC, and adults with binge eating. Further research is needed to determine whether the meal patterns that characterize adolescents with LOC play a role in worsening disordered eating and/or excessive weight gain. PMID- 23015354 TI - Anthelmintic utilisation practices and prevalence of gastrointestinal helminth infections in sheep kept in the urban and peri-urban areas of Bishoftu Town. AB - Assessment of the anthelmintic (AH) utilisation practices and estimation of the prevalence of gastrointestinal helminth infections in sheep were carried out from November 2010 to April 2011 in urban and peri-urban areas of Bishoftu Town, central Ethiopia. A structured questionnaire was employed to assess the AH utilisation practices in sheep of 310 owners/households, while floatation and sedimentation techniques were used to study the prevalence of helminth infections. Faecal examinations revealed that 53.9 % of sheep harboured gastrointestinal helminth infections with a high frequency due to strongyles (77.3 %). The questionnaire survey revealed that sources of AH for sheep were government and private veterinary clinics for 98.5 % of urban and 65.4 % peri urban respondents. In peri-urban areas, AH were also purchased from open markets and illegal dealers. Albendazole was the most common (75.5 %) drug used in sheep followed by ivermectin (18.7 %) and tetramisole (5.8 %). The criteria for selecting AH were: prescription by veterinarians (51.6 %), efficacy (31.9 %), price (12.3 %) and arbitrary reasons (4.2 %). Treatment frequency was minimal with 51.3, 32.3 and 15.8 % of the owners treating their sheep once, twice and less than once per year, respectively. Treatments mainly depended on manifestations of general (45.8 %) and digestive (23.3 %) symptoms. Irrespective of the body weight of the sheep, albendazole was the only drug reported to be given at half bolus/sheep (14.1 %). Owing to this practice, albendazole faces the risk of reduced efficacy or AH resistance due to its wide spread utilisation, handling by untrained personnel and suspected underdosage, which altogether support the perception of sheep owners on its lower effect on the performance of treated sheep. PMID- 23015355 TI - Characterization of non-O157 shiga toxin-producing Escherichia coli isolates from healthy fat-tailed sheep in southeastern of Iran. AB - The objectives of this study were to determine the presence and prevalence of non O157 shiga toxin-producing Escherichia coli (STEC) isolates from faeces of healthy fat-tailed sheep and detection of phylogenetic background and antibiotic resistance profile of isolates. One hundred ninety-two E. coli isolates were recovered from obtained rectal swabs and were confirmed by biochemical tests. Antibiotic resistance profiles of isolates were detected and phylogenetic background of isolates was determined according to the presence of the chuA, yjaA and TspE4.C2 genetic markers. The isolates were examined to determine stx (1), stx (2) and eae genes. Non-O157 STEC isolates were identified by using O157 specific antiserum. Forty-three isolates (22.40 %) were positive for one of the stx (1), stx (2) and eae genes, whereas 10.42 % were positive for stx (1), 19.38 % for eae and 2.60 % for stx (2) gene. None of the positive isolates belonged to O157 serogroup. Twenty isolates possessed stx ( 1 ) were distributed in A (six isolates), B1 (13) and D (one) phylogroups, whereas stx (2) positive isolates fell into A (three isolates) and B1 (two) phylogenetic groups. Eighteen isolates contained eae gene belonged to A (five isolates), B1 (seven) and D (six) phylogroups. The maximum and minimum resistance rates were recorded against to penicillin and co-trimoxazole respectively. The positive isolates for stx (1), stx (2) and eae genes showed several antibiotic resistance patterns, whereas belonged to A, B1 and D phylogroups. In conclusion, faeces of healthy sheep could be considered as the important sources of non-O157 STEC and also multidrug resistant E. coli isolates. PMID- 23015356 TI - Antinociceptive effects of eugenol evaluated in a monoiodoacetate-induced osteoarthritis rat model. AB - The aim of the present study was to evaluate whether eugenol, the main constituent of clove oil, has the capacity to provide analgesia in the monoiodoacetate-induced rat model of osteoarthritis. Animals (n = 6/group) received either eugenol (20 or 40 mg/kg) or a vehicle by gavage. Daily administrations were initiated 2 days post osteoarthritis induction and continued for the duration of the study (4 weeks). Gait analysis was performed using the CatWalk method and secondary mechanical allodynia was assessed with von Frey filaments. Selected spinal cord peptides (substance P, calcitonin gene-related peptide and dynorphin) were quantified by mass spectrometry. Significant changes were identified in dynamic gait parameters (swing speed, swing phase duration and duty cycle) of the affected limb following 40 mg/kg eugenol treatment compared with the vehicle (p < 0.05). Von Frey results revealed significant differences between the 40 mg/kg treatment and the vehicle group during the first and the third week of the study (p < 0.02). Spinal pain-related peptide analysis revealed a decreased content of substance P and CGRP accompanied by an increase of dynorphin in animals treated with 40 mg/kg eugenol. These results suggest a therapeutic potential of eugenol to alleviate osteoarthritis-related pain. PMID- 23015358 TI - Advanced glycated albumin isolated from poorly controlled type 1 diabetes mellitus patients alters macrophage gene expression impairing ABCA-1-mediated reverse cholesterol transport. AB - BACKGROUND: We evaluated the effects of albumin isolated from control individuals and from patients with poorly controlled type 1 diabetes mellitus on macrophage gene expression and on reverse cholesterol transport. METHODS: Serum albumin was purified from control subjects (n = 12) and from patients with poorly controlled type 1 diabetes mellitus (n = 13). (14)C-cholesterol-labelled J774 macrophages treated with albumin were employed to measure cholesterol efflux mediated by apo A-I, HDL(3) or HDL(2), the intracellular lipid accumulation and the cellular ABCA 1 protein content. Agilent arrays (44000 probes) were used to analyse gene expression. Several differentially expressed genes were validated by real-time reverse transcription-PCR using TaqMan Two Step RT-PCR. RESULTS: Levels of glycation-modified and (carboxymethyl)lysine-modified albumin were higher in diabetic patients than in control subjects. Apo A-I-mediated and HDL(2)-mediated cellular cholesterol efflux were impaired in macrophages treated with albumin from diabetic patients in comparison with control albumin-treated cells, which was attributed to the reduction in ABCA-1 protein content. Even in the presence of cholesterol acceptors, a higher level of intracellular lipid was observed in macrophages exposed to albumin from diabetic individuals in comparison with the control. The reduction in ABCA-1 content was associated with enhanced expression of stearoyl CoA desaturase 1 and decreased expression of janus kinase 2, which were induced by albumin from patients with type 1 diabetes mellitus. CONCLUSIONS: (Carboxymethyl)lysine-modified albumin isolated from poorly controlled type 1 diabetic patients impairs ABCA-1-mediated reverse cholesterol transport and elicits intracellular lipid accumulation, possibly contributing to atherosclerosis. PMID- 23015357 TI - Menstrual and reproductive factors in women, genetic variation in CYP17A1, and pancreatic cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort. AB - Menstrual and reproductive factors and exogenous hormone use have been investigated as pancreatic cancer risk factors in case-control and cohort studies, but results have been inconsistent. We conducted a prospective examination of menstrual and reproductive factors, exogenous hormone use and pancreatic cancer risk (based on 304 cases) in 328,610 women from the EPIC cohort. Then, in a case-control study nested within the EPIC cohort, we examined 12 single nucleotide polymorphisms (SNPs) in CYP17A1 (an essential gene in sex steroid metabolism) for association with pancreatic cancer in women and men (324 cases and 353 controls). Of all factors analyzed, only younger age at menarche (<12 vs. 13 years) was moderately associated with an increased risk of pancreatic cancer in the full cohort; however, this result was marginally significant (HR = 1.44; 95% CI = 0.99-2.10). CYP17A1 rs619824 was associated with HRT use (p value = 0.037) in control women; however, none of the SNPs alone, in combination, or as haplotypes were associated with pancreatic cancer risk. In conclusion, with the possible exception of an early age of menarche, none of the menstrual and reproductive factors, and none of the 12 common genetic variants we evaluated at the CYP17A1 locus makes a substantial contribution to pancreatic cancer susceptibility in the EPIC cohort. PMID- 23015359 TI - NHS is unlikely to meet Nicholson challenge to deliver L20bn in efficiency savings, says King's Fund. PMID- 23015361 TI - Common clinical problems in children living with HIV/AIDS: systemic approach. AB - Clinical manifestations in children living with HIV/ AIDS differ from those in adults due to poorly developed immunity that allows greater dissemination throughout various organs. In developing countries, HIV-infected children have an increased frequency of malnutrition and common childhood infections such as ear infections, pneumonias, gastroenteritis and tuberculosis. The symptoms common to many treatable conditions, such as recurrent fever, diarrhea and generalized dermatitis, tend to be more persistent and severe and often do not respond as well to treatment. The use of Anti Retroviral Therapy (ART) has greatly increased the long term survival of perinatally infected children so that AIDS is becoming a manageable chronic illness. As the immunity is maintained, the incidence of infectious complications is declining while noninfectious complications of HIV are more frequently encountered. Regular clinical monitoring with immunological and virological monitoring and the introduction of genotypic and phenotypic resistance testing where resources are available have allowed for dramatically better clinical outcomes. However, these growing children are left facing the challenges of lifelong adherence with complex treatment regimens, compounded by complex psycho-social, mental and neuro-cognitive issues. These unique challenges must be recognized and understood in order to provide appropriate medical management. PMID- 23015360 TI - Dysplasia has A differential diagnosis: distinguishing genuine myelodysplastic syndromes (MDS) from mimics, imitators, copycats and impostors. AB - Just as a pawnshop owner who is unable to distinguish a genuine RolexTM watch from a cheap knockoff courts financial ruin, the physician who fails to discriminate between authentic myelodysplastic syndromes (MDS) and conditions resembling MDS risks misinforming or harming patients. This review summarizes minimal criteria for diagnosing MDS and discusses common diagnostic challenges. MDS needs to be separated from numerous neoplastic and non-clonal hematologic disorders that can mimic MDS, including other myeloid neoplasms, nutritional deficiencies, toxin exposures, aplastic anemia, and inherited disorders (e.g., congenital sideroblastic anemia). Some distinctions are more critical therapeutically than others; e.g., recognizing B12 deficiency is more important than parsing high-risk MDS from erythroleukemia. Diagnostically ambiguous cases may be assigned holding-pattern terms, "idiopathic cytopenia(s) of undetermined significance" (ICUS) or "idiopathic dysplasia of undetermined significance" (IDUS), while awaiting clarifying information or further clinical developments. In the future, advances in molecular pathology will improve diagnostic accuracy, especially in morphologically non-descript cases. PMID- 23015362 TI - Dose-response analysis of bromate-induced DNA damage and mutagenicity is consistent with low-dose linear, nonthreshold processes. AB - Mutagenic agents have long been inferred to act through low-dose linear, nonthreshold processes. However, there is debate about this assumption, with various studies interpreting datasets as showing thresholds for DNA damage and mutation. We have applied rigorous statistical analyses to investigate the shape of dose-response relationships for a series of in vitro and in vivo genotoxicity studies using potassium bromate (KBrO(3) ), a water ozonation byproduct that is bioactivated to a reactive species causing oxidative damage to DNA. We analyzed studies of KBrO(3) genotoxicity where no-effect/threshold levels were reported as well as other representative datasets. In all cases, the data were consistent with low-dose linear models. In the majority of cases, the data were fit either by a linear (straight line) model or a model which was linear at low doses and showed a saturation-like downward curvature at high doses. Other datasets with apparent upward curvature were still adequately represented by models that were linear at low dose. Sensitivity analysis of datasets showing upward curvature revealed that both low-dose linear and nonlinear models provide adequate fits. Additionally, a simple biochemical model of selected key processes in bromate induced DNA damage was developed and illustrated a situation where response for early primary events suggested an apparent threshold while downstream events were linear. Overall, the statistical analyses of DNA damage and mutations induced by KBrO(3) are consistent with a low-dose linear response and do not provide convincing evidence for the presence of a threshold. PMID- 23015363 TI - Use of Joint Commission International standards to evaluate and improve pediatric oncology nursing care in Guatemala. AB - BACKGROUND: Inadequate nursing care is a major impediment to development of effective programs for treatment of childhood cancer in low-income countries. When the International Outreach Program at St. Jude Children's Research Hospital established partner sites in low-income countries, few nurses had pediatric oncology skills or experience. A comprehensive nursing program was developed to promote the provision of quality nursing care, and in this manuscript we describe the program's impact on 20 selected Joint Commission International (JCI) quality standards at the National Pediatric Oncology Unit in Guatemala. We utilized JCI standards to focus the nursing evaluation and implementation of improvements. These standards were developed to assess public hospitals in low-income countries and are recognized as the gold standard of international quality evaluation. METHODS: We compared the number of JCI standards met before and after the nursing program was implemented using direct observation of nursing care; review of medical records, policies, procedures, and job descriptions; and interviews with staff. RESULTS: In 2006, only 1 of the 20 standards was met fully, 2 partially, and 17 not met. In 2009, 16 were met fully, 1 partially, and 3 not met. Several factors contributed to the improvement. The pre-program quality evaluation provided objective and credible findings and an organizational framework for implementing change. The medical, administrative, and nursing staff worked together to improve nursing standards. CONCLUSION: A systematic approach and involvement of all hospital disciplines led to significant improvement in nursing care that was reflected by fully meeting 16 of 20 standards. PMID- 23015364 TI - Empirical assessment of methods for risk identification in healthcare data: results from the experiments of the Observational Medical Outcomes Partnership. AB - BACKGROUND: Expanded availability of observational healthcare data (both administrative claims and electronic health records) has prompted the development of statistical methods for identifying adverse events associated with medical products, but the operating characteristics of these methods when applied to the real-world data are unknown. METHODS: We studied the performance of eight analytic methods for estimating of the strength of association-relative risk (RR) and associated standard error of 53 drug-adverse event outcome pairs, both positive and negative controls. The methods were applied to a network of ten observational healthcare databases, comprising over 130 million lives. Performance measures included sensitivity, specificity, and positive predictive value of methods at RR thresholds achieving statistical significance of p < 0.05 or p < 0.001 and with absolute threshold RR > 1.5, as well as threshold-free measures such as area under receiver operating characteristic curve (AUC). RESULTS: Although no specific method demonstrated superior performance, the aggregate results provide a benchmark and baseline expectation for risk identification method performance. At traditional levels of statistical significance (RR > 1, p < 0.05), all methods have a false positive rate >18%, with positive predictive value <38%. The best predictive model, high-dimensional propensity score, achieved an AUC = 0.77. At 50% sensitivity, false positive rate ranged from 16% to 30%. At 10% false positive rate, sensitivity of the methods ranged from 9% to 33%. CONCLUSIONS: Systematic processes for risk identification can provide useful information to supplement an overall safety assessment, but assessment of methods performance suggests a substantial chance of identifying false positive associations. PMID- 23015365 TI - NAVA enhances tidal volume and diaphragmatic electro-myographic activity matching: a Range90 analysis of supply and demand. AB - Neurally adjusted ventilatory assist (NAVA) is a ventilation assist mode that delivers pressure in proportionality to electrical activity of the diaphragm (Eadi). Compared to pressure support ventilation (PS), it improves patient ventilator synchrony and should allow a better expression of patient's intrinsic respiratory variability. We hypothesize that NAVA provides better matching in ventilator tidal volume (Vt) to patients inspiratory demand. 22 patients with acute respiratory failure, ventilated with PS were included in the study. A comparative study was carried out between PS and NAVA, with NAVA gain ensuring the same peak airway pressure as PS. Robust coefficients of variation (CVR) for Eadi and Vt were compared for each mode. The integral of Eadi (?Eadi) was used to represent patient's inspiratory demand. To evaluate tidal volume and patient's demand matching, Range90 = 5-95 % range of the Vt/?Eadi ratio was calculated, to normalize and compare differences in demand within and between patients and modes. In this study, peak Eadi and ?Eadi are correlated with median correlation of coefficients, R > 0.95. Median ?Eadi, Vt, neural inspiratory time (Ti_ ( Neural )), inspiratory time (Ti) and peak inspiratory pressure (PIP) were similar in PS and NAVA. However, it was found that individual patients have higher or smaller ?Eadi, Vt, Ti_ ( Neural ), Ti and PIP. CVR analysis showed greater Vt variability for NAVA (p < 0.005). Range90 was lower for NAVA than PS for 21 of 22 patients. NAVA provided better matching of Vt to ?Eadi for 21 of 22 patients, and provided greater variability Vt. These results were achieved regardless of differences in ventilatory demand (Eadi) between patients and modes. PMID- 23015367 TI - The influence of neural cell adhesion molecule isoform 140 on the metastasis of thyroid carcinoma. AB - We previously showed that the preservation of neural adhesion molecule (NCAM) in differentiated thyroid carcinoma is an important indicator for a higher risk of distant metastasis. In the present study, we further demonstrated that forced NCAM-140 isoform expression in human thyroid cancer cells could lead to aggressive growth by enhancing migration and anchorage-independent growth, and exhibiting partial features of epithelial mesenchymal transition. More extensive distant metastasis was also noted in an animal xenograft model when NCAM expressing thyroid cancer cells were introduced into mice intravascularly. Bioinformatic analysis of NCAM-associated expression profiles predicted a highly interactive protein network, which further implies potential molecular mechanisms underlying the metastatic processes of thyroid cancer. PMID- 23015366 TI - Muscle relaxant use during intraoperative neurophysiologic monitoring. AB - Neuromuscular blocking agents have generally been avoided during intraoperative neurophysiological monitoring (IOM) where muscle responses to nerve stimulation or transcranial stimulation are monitored. However, a variety of studies and clinical experience indicate partial neuromuscular blockade is compatible with monitoring in some patients. This review presents these experiences after reviewing the currently used agents and the methods used to assess the blockade. A review was conducted of the published literature regarding neuromuscular blockade during IOM. A variety of articles have been published that give insight into the use of partial pharmacological paralysis during monitoring. Responses have been recorded from facial muscles, vocalis muscles, and peripheral nerve muscles from transcranial or neural stimulation with neuromuscular blockade measured in the muscle tested or in the thenar muscles from ulnar nerve stimulation. Preconditioning of the nervous system with tetanic or sensory stimulation has been used. In patients without neuromuscular pathology intraoperative monitoring using peripheral muscle responses from neural stimulation is possible with partial neuromuscular blockade. Monitoring of muscle responses from cranial nerve stimulation may require a higher degree of stimulation and less neuromuscular blockade. The role of tetanic or sensory conditioning of the nervous system is not fully characterized. The impact of neuromuscular pathology or the effect of partial blockade on monitoring muscle responses from spontaneous neural activity or mechanical nerve stimulation has not been described. PMID- 23015368 TI - Synthesis and structure-activity relationship of vicenistatin, a cytotoxic 20 membered macrolactam glycoside. AB - We have developed two syntheses of vicenistatin and its analogues. Our first generation strategy included the rapid and sequential assembly of the macrocyclic lactam by using an intermolecular Horner-Wadsworth-Emmons reaction between the C3 C13 fragment and the C1-C2, C14-C19 fragment, followed by an intramolecular Stille coupling reaction. The second-generation strategy utilized a ring-closing metathesis of a hexaene intermediate to generate the desired 20-membered macrolactam. This second-generation strategy made it possible to prepare synthetic analogues of vicenistatin, including the C20- and/or C23-demethyl analogues. Evaluation of the cytotoxic effect of these analogues indicated the importance of the fixed conformation of aglycon for determining the biological activity of the vicenistatins. PMID- 23015369 TI - Balloon aortic valvuloplasty for severe aortic stenosis as a bridge to transcatheter/surgical aortic valve replacement. AB - OBJECTIVES: This study aimed to determine success- and complication rates after balloon aortic valvuloplasty (BAV) and the outcome of BAV as a standalone therapy versus BAV as a bridge to transcatheter/surgical aortic valve replacement (T/SAVR). BACKGROUND: The introduction of transcatheter aortic valve replacement (TAVR) has led to a revival in BAV as treatment for patients with severe aortic stenosis. METHODS: A cohort of 472 patients underwent 538 BAV procedures. The cohort was divided into two groups: BAV alone 387 (81.9%) and BAV as a bridge 85 (18.1%) to (n = 65, TAVR; n = 20, surgery). Clinical, hemodynamic, and follow-up mortality data were collected. RESULTS: There was no significant difference between the two groups in mean age (81.7 +/- 8.3 vs. 83.2 +/- 10.9 years, P = 0.18), society of thoracic surgeons score (13.1 +/- 6.2 and 12.4 +/- 6.4, P = 0.4), logistic EuroSCORE (45.4 +/- 22.3 vs. 46.9 +/- 21.8, P = 0.43), and other comorbidities. The mean increase in aortic valve area was 0.39 +/- 0.25 in the BAV alone group and 0.42 +/- 0.26 in the BAV as a bridge group, P = 0.33. The decrease in mean gradient was 24.1 +/- 13.1 in the BAV alone group vs. 27.1 +/- 13.8 in the BAV as a bridge group, P = 0.06. During a median follow up of 183 days [54-409], the mortality rate was 55.2% (n = 214) in the BAV alone group vs. 22.3% (n = 19) in the BAV as a bridge group during a median follow-up of 378 days [177-690], P < 0.001. CONCLUSION: In high-risk patients with aortic stenosis and temporary contraindications to SAVR/TAVR, BAV may be used as a bridge to intervention with good mid-term outcomes. PMID- 23015370 TI - Strategies for the development of gadolinium-based 'q'-activatable MRI contrast agents. AB - The emergence and rapid development of activatable contrast agents (CAs), whose relaxivity changes in response to the variation of a specific marker in the surrounding physiological microenvironment, have expanded the scope of MRI beyond anatomical and functional imaging to also convey information at the cellular and molecular level. The essence of an activatable MRI CA is the difference in relaxivity before and after a change in a physiological variable: the larger the difference, the better the CA. In this review, strategies for the design of activatable gadolinium CAs, with a switching mechanism based on the modulation of hydration (q), sensitive to common variables in the physiological microenvironment, such as pH, light, redox and metal ions, are illustrated and discussed. PMID- 23015371 TI - Recent advances in the imaging of frontotemporal dementia. AB - Neuroimaging has played an important role in the characterization of the frontotemporal dementia (FTD) syndromes, demonstrating neurodegenerative signatures that can aid in the differentiation of FTD from other neurodegenerative disorders. Recent advances have been driven largely by the refinement of the clinical syndromes that underlie FTD, and by the discovery of new genetic and pathological features associated with FTD. Many new imaging techniques and modalities are also now available that allow the assessment of other aspects of brain structure and function, such as diffusion tensor imaging and resting-state functional MRI. Studies have used these recent techniques, as well as traditional volumetric MRI, to provide further insight into disease progression across the many clinical, genetic, and pathological variants of FTD. Importantly, neuroimaging signatures have been identified that will improve the clinician's ability to predict underlying genetic and pathological features, and hence ultimately improve patient diagnosis. PMID- 23015372 TI - Preparation and characterization of shape memory polymer scaffolds via solvent casting/particulate leaching. AB - PURPOSE: Porous Shape Memory Polymers (SMPs) are ideal candidates for the fabrication of defect fillers, able to support tissue regeneration via minimally invasive approaches. In this regard, control of pore size, shape and interconnection is required to achieve adequate nutrient transport and cell ingrowth. Here, we assessed the feasibility of the preparation of SMP porous structures and characterized their chemico-physical properties and in vitro cell response. METHODS: SMP scaffolds were obtained via solvent casting/particulate leaching of gelatin microspheres, prepared via oil/water emulsion. A solution of commercial polyether-urethane (MM-4520, Mitsubishi Heavy Industries) was cast on compacted microspheres and leached-off after polymer solvent evaporation. The obtained structures were characterized in terms of morphology (SEM and micro-CT), thermo-mechanical properties (DMTA), shape recovery behavior in compression mode, and in vitro cytocompatibility (MG63 Osteoblast-like cell line). RESULTS: The fabrication process enabled easy control of scaffold morphology, pore size, and pore shape by varying the gelatin microsphere morphology. Homogeneous spherical and interconnected pores have been achieved together with the preservation of shape memory ability, with recovery rate up to 90%. Regardless of pore dimensions, MG63 cells were observed adhering and spreading onto the inner surface of the scaffolds obtained for up to seven days of static in vitro tests. CONCLUSIONS: A new class of SMP porous structures has been obtained and tested in vitro: according to these preliminary results reported, SMP scaffolds can be further exploited in the design of a new class of implantable devices. PMID- 23015373 TI - A new method for shape and texture classification of orthopedic wear nanoparticles. AB - PURPOSE: Detailed morphologic analysis of particles produced during wear of orthopedic implants is important in determining a correlation among material, wear, and biological effects. However, the use of simple shape descriptors is insufficient to categorize the data and to compare the nature of wear particles generated by different implants. An approach based on Discrete Fourier Transform (DFT) is presented for describing particle shape and surface texture. METHOD: Four metal-on-metal bearing couples were tested in an orbital wear simulator under standard and adverse (steep-angled cups) wear simulator conditions. Digitized Scanning Electron Microscope (SEM) images of the wear particles were imported into MATLAB to carry out Fourier descriptor calculations via a specifically developed algorithm. The descriptors were then used for studying particle characteristics (shape and texture) as well as for cluster classification. RESULTS AND CONCLUSIONS: Analysis of the particles demonstrated the validity of the proposed model by showing that steep-angle Co-Cr wear particles were more asymmetric, compressed, extended, triangular, square, and roughened at 3 Mc than after 0.25 Mc. In contrast, particles from standard angle samples were only more compressed and extended after 3 Mc compared to 0.25 Mc. Cluster analysis revealed that the 0.25 Mc steep-angle particle distribution was a subset of the 3 Mc distribution. PMID- 23015374 TI - Improving indoor air quality by using the new generation of corrugated cardboard based filters. AB - PURPOSE: Indoor Air Quality (IAQ) is strictly affected by the concentration of total suspended particulate matter (TSP). Air filtration is by far the most feasible suggestion to improve IAQ. Unfortunately, highly effective HEPA filters also have a few major weaknesses that have hindered their widespread use. There is therefore a renewed interest in developing novel, cost-effective filtration systems. We have recently reported the development of cardboard-based filters for bacterial removal that were further implemented and tested herein. METHODS: A parallelepiped filter manufactured by aligning strips of corrugated cardboard and surrounded by a cardboard frame was specifically designed with an internal pocket holding a partially cut antistatic pleated fabric (HP). This filter, together with its parent version (CTRL) and a commercially sourced specimen (CAF), were assessed comparatively in a long-time test to assess their effectiveness on TSP removal. RESULTS: We found that the TSP abatement efficiency (E%) of the HP filter was relatively high and invariable over the 93 days of test and the pressure drop (PD%) decrease because of filter clogging was moderate. Most important, the HP filter was the most effective if assessed in terms of overall yield (Y%) and its performance was quite constant over the entire period considered. CONCLUSIONS: This work disclosed this novel class of corrugated cardboard-based filters as promising tools to ameliorate IAQ in light of their good TSP removal properties that endure over time. Moreover, cardboard is a lightweight, inexpensive, and eco-friendly material and corrugated cardboard based air filters are very easy to shape and mount on and/or replace in existing ventilation systems. PMID- 23015375 TI - We still have a long way to go to effectively deliver genes! AB - Gene therapy is emerging as a revolutionary alternative to conventional therapeutic approaches. However, its clinical application is still hampered by the lack of safe and effective gene delivery techniques. Among the plethora of diverse approaches used to ferry nucleic acids into target cells, non-viral vectors represent promising and safer alternatives to viruses and physical techniques. Both cationic lipids and polymers spontaneously wrap and shrink the genetic material in complexes named lipoplexes and polyplexes, respectively, thereby protecting it and shielding its negative charges. The development of non viral vectors commenced more than two decades ago. Since then, some major classes of interesting molecules have been identified and modified to optimize their properties. However, the way towards the final goal of gene delivery, i.e. protein expression or gene silencing, is filled with obstacles and current non viral carriers still have concerns about their overall efficiency. We strongly believe that the future of non-viral gene delivery relies on the development of multifunctional vectors specifically tailored with diverse functionalities that act more like viruses. Although these vectors are still a long way from clinical practice they are the ideal platform to effectively shuttle the genetic material to target cells in a safe and controlled way. In this review, after briefly introducing the basis of gene delivery and therapeutic applications we discuss the main polymeric and lipidic vectors utilized for gene delivery, focusing on the strategies adopted to overcome the major weaknesses inherent to their still limited activity, on the way towards ideal multifunctional vectors. PMID- 23015376 TI - A host-guest supramolecular complex with photoregulated delivery of nitric oxide and fluorescence imaging capacity in cancer cells. AB - Herein we report the design, preparation, and properties of a supramolecular system based on a tailored nitric oxide (NO) photodonor and a rhodamine-labeled beta-cyclodextrin conjugate. The combination of spectroscopic and photochemical experiments shows the absence of significant interchromophoric interactions between the host and the guest in the excited states. As a result, the complex is able to release NO under the exclusive control of visible light, as unambiguously demonstrated by direct detection of this transient species through an amperometric technique, and exhibits the typical red fluorescence of the rhodamine appendage. The supramolecular complex effectively internalizes in HeLa cancer cells as proven by fluorescence microscopy, shows a satisfactory biocompatibility in the dark, and induces about 50% of cell mortality upon irradiation with visible light. The convergence of all these properties in one single complex makes the present host-guest ensemble an appealing candidate for further delevopment of photoactivatable nanoscaled systems addressed to photostimulated NO-based therapy. PMID- 23015377 TI - Overcoming autopsy barriers in pediatric cancer research. AB - BACKGROUND: More than 13,000 children annually in the United States and Canada under the age of 20 will be diagnosed with cancer at a mortality approaching 20% 1,2. Tumor samples obtained by autopsy provide an innovative way to study tumor progression, potentially aiding in the discovery of new treatments and increased survival rates. The purpose of this study was to identify barriers to autopsies and develop guidelines for requesting autopsies for research purposes. PROCEDURE: Families of children treated for childhood cancer were referred by patient advocacy groups and surveyed about attitudes and experiences with research autopsies. From 60 interviews, barriers to autopsy and tumor banking were identified. An additional 14 interviews were conducted with medical and scientific experts. RESULTS: Ninety-three percent of parents of deceased children did or would have consented to a research autopsy if presented with the option; however, only half of these families were given the opportunity to donate autopsy tissue for research. The most significant barriers were the physicians' reluctance to ask a grieving family and lack of awareness about research opportunities. CONCLUSIONS: The value of donating tumor samples to research via an autopsy should be promoted to all groups managing pediatric cancer patients. Not only does autopsy tumor banking offer a potentially important medical and scientific impact, but the opportunity to contribute this Legacy Gift of autopsy tumor tissue also creates a positive outlet for the grieving family. Taking these findings into account, our multidisciplinary team has developed a curriculum addressing key barriers. PMID- 23015378 TI - Factors associated with false-positive results from fingerstick OraQuick ADVANCE rapid HIV 1/2 antibody test. AB - OBJECTIVE: Identify factors associated with false-positive rapid HIV antibody tests. DESIGN: This retrospective cohort study with nested case-controls involved patients tested for HIV by Boston Medical Center (BMC) affiliates. METHODS: Cases had a reactive fingerstick OraQuick ADVANCE rapid HIV 1/2 antibody test and a negative Western blot. Controls had nonreactive rapid tests. We compared the prevalence of HIV risk factors between cases and the total nonreactive population and the prevalence of other clinical factors between cases and controls. RESULTS: Of the 15 094 tests, 14 937 (98.9%) were negative and 11 (0.07%) were false positives (specificity of 99.9%). Cases were more likely to have had an HIV infected sex partner and to be tested at certain sites compared to true negatives. More cases than controls had O-negative blood type. CONCLUSION: O negative blood type and sex with an HIV-infected person may increase false positive HIV fingerstick results. More targeted studies should examine these risk factors. PMID- 23015379 TI - Cryptococcal antigen screening and preemptive therapy in patients initiating antiretroviral therapy in resource-limited settings: a proposed algorithm for clinical implementation. AB - HIV-associated cryptococcal meningitis (CM) is estimated to cause over half a million deaths annually in Africa. Many of these deaths are preventable. Screening patients for subclinical cryptococcal infection at the time of entry into antiretroviral therapy programs using cryptococcal antigen (CRAG) immunoassays is highly effective in identifying patients at risk of developing CM, allowing these patients to then be targeted with "preemptive" therapy to prevent the development of severe disease. Such CRAG screening programs are currently being implemented in a number of countries; however, a strong evidence base and clear guidance on how to manage patients with subclinical cryptococcal infection identified by screening are lacking. We review the available evidence and propose a treatment algorithm for the management of patients with asymptomatic cryptococcal antigenemia. PMID- 23015380 TI - Use of the exercise treadmill test for the assessment of cardiac risk markers in adults infected with HIV. AB - BACKGROUND: Despite the association between HIV and coronary artery disease (CAD), there are no specific recommendations for the cardiovascular evaluation of the HIV-infected population. Besides being a tool for the evaluation of CAD, the exercise treadmill test (ETT) provides insights into functional capacity and autonomic function, which have been frequently affected in HIV infection, and thus may be useful in this setting. METHODS: Forty-nine HIV-infected individuals without known CAD underwent ETT. Peak oxygen consumption during exercise (VO2 peak), functional capacity (in metabolic equivalents [METs]), exercise-induced ischemia, chronotropic incompetence (CI) and abnormal heart rate recovery (HRR) after exercise were studied. RESULTS: VO2 peak was 31.4+/-4.8 mL/kg/min and functional capacity was 9.2+/-1.6 MET. CI was observed in 30.6%, and 10.2% had abnormal HRR. VO2 peak was lower in women and inversely correlated with age and body mass index. None of the patients displayed ischemic changes. CONCLUSION: Although functional capacity was good, risk markers such as CI and abnormal HRR were not infrequent. This study identifies a subgroup of HIV-infected patients the older, overweight, or obese-who may have higher risk and deserve cardiovascular screening with the ETT. PMID- 23015381 TI - Synthesis and positive inotropic evaluation of (E)-2-(4-cinnamylpiperazin-1-yl)-N (1-substituted-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides. AB - A series of (E)-2-(4-cinnamylpiperazin-1-yl)-N-(1-substituted-4,5-dihydro [1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume on isolated rabbit heart preparations. This class of compounds presented favorable in vitro activity compared with the standard drug, milrinone, among which N-(1-(3 chlorophenyl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(4 cinnamylpiperazin-1-yl)acetamide 5e was found to be the most potent with 16.58 +/ 0.11% increased stroke volume (milrinone: 2.46 +/- 0.07%) at a concentration of 3 * 10(-5) M. The chronotropic effects of the compounds having inotropic effects were also evaluated. PMID- 23015382 TI - Effects of Brazilian green propolis on double-stranded RNA-mediated induction of interferon-inducible gene and inhibition of recruitment of polymorphonuclear cells. AB - BACKGROUND: Propolis is a bee product with various biological properties, including an antiviral activity when taken orally. However, its mechanisms at the cellular and molecular level are not well understood. RESULTS: We investigated the effect of propolis on antiviral signaling in A549 cells transfected with double-stranded RNA (dsRNA), a model for viral infection. Pretreatment of the cells with propolis inhibited poly I:C (synthetic dsRNA)-induced interferon (IFN) beta expression. Propolis had no effect on the dsRNA-induced expression of RIG-I like receptors (RLRs), which are known as intracellular viral RNA sensors. As to the effect on antiviral executor genes, propolis enhanced myxovirus resistance 1 (MX1) expression, whereas interferon-inducible gene 6-16 (G1P3) and 2'-5' oligoadenylate synthetase (OAS) were unaffected. All of these genes belong to the IFN-inducible genes, suggesting that the effect of propolis on antiviral signaling is not necessarily mediated by the autocrine regulation by IFN-beta. Propolis pretreatment inhibited dsRNA-induced interleukin-8 (IL8) and CCL5 expression, and consequently lowered polymorphonuclear leukocyte (PMN) chemotactic activity in the cell-conditioned medium. CONCLUSION: Taken together, these results suggest that propolis may suppress excess inflammatory responses without affecting the innate immunity during viral infection. PMID- 23015383 TI - Can training support free movement of forensic psychiatrists between nations? PMID- 23015385 TI - What about forensic psychiatry as a career? Undergraduate and early post-graduate medical perspectives. AB - BACKGROUND: Medical students in the UK are encouraged to plan their career earlier than ever before. What do they need to do that? AIM: To explore the roles of the undergraduate curriculum and the foundation programme from the perspective of a foundation trainee looking towards a career in forensic psychiatry, and to conduct a pilot survey of undergraduates and early trainees about their knowledge and wishes with respect to forensic psychiatry. FINDINGS: A fifth of those given a questionnaire responded. Among 36 responders, 14 were considering a career in forensic psychiatry. Some of the remainder did not know about the option at all; no one felt that they had sufficient information about this career option. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This was a pilot study with a low response rate, and confined to Wales, so the findings must be regarded with caution. Nevertheless, it does appear that a concerted effort by medical schools and relevant professional bodies to provide more information and encouragement to trainees at an early stage would be likely to support recruitment to the specialty of forensic psychiatry. PMID- 23015384 TI - Teaching forensic psychiatry in Europe. AB - BACKGROUND: Forensic psychiatry was long regarded as sufficiently defined by the laws of a country to be restricted by national boundaries in all but a few areas. European Union (EU) employment rights and travel facilities have changed that within the EU. AIMS: The goal of this research is to explore the role and development of a network of teachers and trainees in forensic psychiatry. INFORMATION AND DISCUSSION: European Union countries differ widely in the extent to which they recognise forensic psychiatry as a specialty and thus also in the amount of training clinicians receive before they present themselves as expert witnesses in court, or develop or run services, or manage and treat individual offender patients. Nevertheless, a summer seminar for practicing clinicians, who also present evidence to court and for bodies considering discharge of potentially dangerous patients, has proved a useful forum for joint 'European learning'. Participants have left with a sense of improved understanding of their own law and practices as well as new perspectives on what works for offenders with mental disorder. PMID- 23015386 TI - Specialist training in forensic psychiatry: the UK experience. AB - BACKGROUND: Training pathways and structures in forensic psychiatry differ between European Union countries, and perspective may differ between trainees and trainers. AIM: To describe the context of forensic psychiatry training in the UK, with a particular emphasis on England and Wales, as well as some details of core psychiatry and specialist forensic training. INFORMATION AND DISCUSSION: Forensic psychiatry in the UK takes place in the context of general medical training guidance and regulation. In the last decade, it has changed to be in line with the European working directive and to take account of opinions from outside medicine. The specialist component is typically during the last 3 years of post graduate training and is based on an apprenticeship/competency model. PMID- 23015387 TI - Training in forensic psychiatry when no nationally recognised scheme exists. AB - BACKGROUND: In some European countries, forensic psychiatric training is formalised within a psychiatric framework. In others, the approach is radically different, but the end result may be a practitioner who is qualified to practise forensic psychiatry in all European jusrisdictions. AIM: The aim of this study is to describe the context of training to work with offender-patients in Spain. INFORMATION AND DISCUSSION: There is no nationally recognised training scheme in forensic psychiatry in Spain but rather a dichotomy between legal doctors, trained to assess offenders and provide reports for the courts but not necessarily in psychiatry, and psychiatrists, trained in clinical management and treatment but not necessarily in relation to offender patients. This dichotomy arose as training pathways diverged historically, legal medicine being the older discipline. In this system, the courts are always assured of an independent medical opinion, although treating psychiatrists would generally advise on release decisions. Almost all offender-patient treatment is in prisons. The system is heavily dependent on the goodwill and drive of practitioners who seek to provide themselves with dual skills in the absence of national guidance and support for such training. PMID- 23015388 TI - Selling forensic psychiatry: recruiting for the future, establishing services. AB - BACKGROUND AND AIM: The Ghent Group - a group of European forensic psychiatrists has discussed ways of informing fellow professionals and the wider public about their difficult and frequently misunderstood discipline, agreeing that the specialty may have to be 'sold' to those who pay for it and use it. Our aim was to consider the areas where this commonly occurs and the strengths and pitfalls of such promotion. DISCUSSION: Forensic psychiatrists need to be effective, accurate communicators. For court work, they need special training. High standards of work are the best selling technique. Outside court, the greatest challenge for forensic psychiatry is to reduce its stigma - it can easily be construed, wrongly, as excusing serious anti-social behaviour. Special attention should be given to writing for a wider audience, not just the inner circle of practitioners. Electronic social media should also be deployed for this task. Those who provide funds for academic work should be specifically but differently targeted. They need to be persuaded of the scientific merit of the subject. ETHICS: Temptation to claim more for the discipline than can be justified have to be resisted. An English case that led to a miscarriage of justice illustrates this. The limitations of science here have to be understood. Philosophical questions relating to responsibility and culpability cannot be resolved by physical science alone. Misuse neuroimaging in court, for example, can lead to miscarriages of justice. CONCLUSION: Selling forensic psychiatry to public and professionals is difficult but essential to counter anti-forensic psychiatry movements that have emerged. The discipline needs to persuade others of its unique skills and embrace good science, compassion, public duty and ethical practice. It needs to treat with politicians and funders as well as the medical, psychological and legal professions. PMID- 23015389 TI - The treating psychiatrist as expert in the courts: is it necessary or possible to separate the roles of physician and expert? AB - BACKGROUND: Certified medical specialists, including forensic psychiatrists, from the 27 member states of the European Union (EU) may practise in each other's countries, but there are professional and legal differences between them. One may lie in whether a patient's treating doctor/clinician may give expert evidence about that person in court. AIMS: To examine similarities and differences between EU jurisdictions in law and practice in combining or separating such roles and to review the evidence in support of either position. METHODS: A psychiatrist with court experience was contacted in each EU country about law, practice and guidance on division of clinician-expert roles. Published literature was searched for an evidence base for practice in the field. Additional material is from discussion at a residential meeting of practising forensic psychiatrists from Austria, Belgium, Denmark, Germany, Hungary, the Netherlands, Switzerland and the UK. RESULTS: All acknowledge that a treating clinician can never be an independent expert in that case, but the 22 (of 27) EU countries responding vary in law and practice on whether the dual role may be assumed. There has been almost no research interest in factors relevant to separation of roles. International discussion revealed that ethical and practice issues are not straightforward. CONCLUSIONS: On current evidence, either separation or combination of clinical and expert roles in a particular case may be acceptable. Insofar as there are national legal or professional guidelines on this issue, anyone practising in that country must follow them and may safely do so, regardless of practice in their native country. The most important ethical issue lies in clarity for all parties on the nature and extent of roles in the case. This paper has additional material online. PMID- 23015390 TI - Mapping offender-patient pathways in the different jurisdictions of the European Union. PMID- 23015391 TI - Researchers find no link between XMRV and chronic fatigue syndrome. PMID- 23015392 TI - Promoting health and improving survival into very old age. PMID- 23015393 TI - Nonkeratinizing undifferentiated nasopharyngeal carcinoma. PMID- 23015394 TI - Understanding safety and performance in the cardiac operating room: from 'sharp end' to 'blunt end'. PMID- 23015395 TI - Tuning the electrical and optical properties of diketopyrrolopyrrole complexes for panchromatic dye-sensitized solar cells. AB - A series of metal-free organic dyes that were bridged by a diketopyrrolopyrrole moiety and were composed of indoline and triphenylamine as donor groups and furan and benzene as conjugated spacer groups were designed and synthesized for use in dye-sensitized solar cells (DSCs). The photophysical properties, electrochemical properties, and performance of the DSCs were related to the structure of their corresponding dyes. Their absorption spectra broadened upon the introduction of the indoline and heterocyclic furan moieties through fine-tuning of their molecular configuration. The overall conversion efficiencies of DSCs that were based on these dyes ranged from 5.14-6.53%. Among the four dyes that were tested, indoline-based ID01 and ID02 showed higher efficiencies (6.35% and 6.53%) as a result of their improved light-harvesting efficiency and larger electron driving force. The ID01 dye, which contained an indoline moiety as an electron donor and a furan group as a pi-conjugated linker, showed an excellent monochromatic incident-photon-to-current-conversion efficiency (IPCE) spectrum (350-650 nm) with a maximum value of 78% in the high plateau region and an onset value close to 800 nm. Intensity-modulated photovoltage spectroscopy (IMVS) and impedance spectroscopy (IS) revealed that dyes that contained benzene conjugation spacers suppressed the charge-recombination rate more efficiently than dyes that contained furan spacers, thereby resulting in improved photovoltage. PMID- 23015396 TI - Bone formation and resorption markers as diagnostic tools for bone metastases evaluation. AB - Bone metastases are a frequent complication of several types of cancers. Since bone metastases are difficult to diagnose with the current available approaches, there is a demand for new methods for assessing bone response. In this context, biochemical markers of bone remodeling may provide useful information on bone turnover that, in turn, may reflect disease activity in bone. In this study we tested a panel of bone remodeling markers (distinguishing between bone formation and bone resorption ones) in different groups of cancer patients, so as to evaluate the potential clinical role of the examined bone remodeling markers in the early diagnosis of metastases formation and progression. Among the bone resorption markers, tartrate resistant acid phosphatase 5b (TRAP5b) resulted the most specific for the metastatic tumor stage. Both the bone formation markers we analyzed displayed a direct correlation (positive for bone-specific alkaline phosphatase [BAP] and negative for osteocalcin [OC]) with tumor disease progression, ranging from healthy controls to primary tumor and, ultimately, to the metastatic stage. Taken together our results suggest that these markers can be valuable tools to be used, in parallel with traditional methods of metastases diagnosis, in order to monitor more in detail the pathological effect of metastases progression in bone tissue. PMID- 23015397 TI - Evaluation of an ELISA method for the measurement of chromogranin A and comparison with an immunoradiometric method. PMID- 23015398 TI - Circulating tumor cells as predictors of response and failure in breast cancer patients treated with preoperative chemotherapy. AB - AIM: To explore the significance of circulating tumor cells (CTCs) detection in the course of preoperative chemotherapy (PC) and their effect on the outcomes.? METHODS: Fifty-five patients with stage II/III invasive breast cancer were enrolled into a preoperative clinical trial. Patients were given PC with sequential single-agent doxorubicin and paclitaxel vs paclitaxel followed by doxorubicin. Blood samples (8 mL) were collected from patients before PC, after each phase, and at 6 months intervals during follow-up. Peripheral blood mononuclear cells were isolated and enriched for epithelial cells. Quantitative RT-PCR was used to determine the presence of cytokeratin 19 (CK19) mRNA. Samples were considered positive when the PCR curve crossed the standard threshold curve.? RESULTS: After the first phase of chemotherapy, there was a 59% overall reduction in the median tumor volume. The percentage of volume reduction did not differ between patients who presented with detectable CTCs at baseline and those who did not (p=0.89). After the second phase of chemotherapy, there was a further decrease in the median tumor volume to 93% from baseline. There was no correlation between the lack of response and the presence of CTCs either after the first (p=0.36) or second (p=0.5391) phases of PC. The presence of CTCs was a predictor of local or distant relapse (p=0.0411). The detection of CTCs did not affect overall survival (p=0.2569).? CONCLUSION: CTCs can be used as predictors of relapse after definitive treatment of locally advanced breast cancer; however, CTCs detection in peripheral blood during the course of PC does not implicate a particular pattern of response to treatment. PMID- 23015399 TI - Endothelial nitric oxide synthase Glu298Asp polymorphism as a risk factor for prostate cancer. AB - BACKGROUND: The endothelial form of nitric oxide synthases (eNOS) seems to have an important role in vascular development, maintenance of the vascular tone and tumor growth in human prostate cancer (PC). The purpose of this study was to investigate the association between grade and stage of disease, age of diagnosis, vascular or perineural invasion, pre-diagnostic plasma prostate-specific antigen (PSA) levels, prostate cancer risk and Glu298Asp polymorphism of the eNOS gene.? METHODS: Ninety-five prostate cancer patients and 111 benign prostate hyperplasia subjects were included. The Glu298Asp polymorphism of the eNOS gene was determined by polymerase chain reaction and restriction fragment length polymorphism ? RESULTS: The odds ratio (OR) between the GT and GG polymorphism was 0.76, indicating that the presence of the GT polymorphism decreased the risk of prostate cancer of more than 20% compared to the GG polymorphism. This difference, however, was not statistically significant. The GT polymorphism had an inverse association with cancer grade compared to the reference group (OR=0.47, p value=0.2).? CONCLUSIONS: These results suggest that prostate cancer development is not associated with the Glu298Asp polymorphism of the endothelial nitric oxide synthase gene in our population. Further studies in larger samples are needed to confirm our results and characterize the molecular mechanisms by which eNOS is involved in the susceptibility to prostate cancer. PMID- 23015400 TI - E-Selectin S128R gene polymorphism in gastric cancer. AB - BACKGROUND: E-selectin is an adhesion molecule expressed on activated endothelial cells. E-selectin plays an important role in the process of inflammation and is also involved in the mechanism of cancer metastasis regulating the adhesion of circulating cancer cells to the blood vessels. The aim of our study was to determine whether an association exists between its most common gene polymorphism, S128R, and gastric cancer (GC).? METHODS: We performed a case control study of 88 GC cases and 480 controls to analyze the association between E-selectin S128R gene polymorphism and GC susceptibility. The genotyping analysis was done by PCR-restriction fragment length polymorphism method. ? RESULTS: The E selectin S128R C allele, CA and CC genotypes were over-represented among the GC cases. No statistically significant association was observed between E-selectin S128R polymorphisms and tumor characteristics. However, carrying the C allele was associated with poor survival. ? CONCLUSIONS: The E-selectin S128R C allele may confer an increased susceptibility to gastric cancer development and correlate with a poor prognosis. PMID- 23015401 TI - p63 Expression is a prognostic factor in colorectal cancer. AB - p63 is highly expressed in some malignant tumors and is associated with tumorigenesis, invasion and metastasis. The aim of our study was to evaluate the clinical significance of p63 in colorectal cancer (CRC). p63 expression was detected by immunohistochemistry in 66 CRC patients. Correlations between p63 expression and clinicopathological factors, progression-free survival (PFS) and overall survival (OS) were analyzed. Among the 66 CRC cases, 31 cases (47%) exhibited a high score of p63 expression, while 35 cases (53%) were marked with a low score. The p63 level correlated with peritumoral deposits (p=0.021). The 5 year OS rates in the low p63 score and high p63 score groups were, respectively, 49% and 74% (p<0.001). The 5-year PFS rates in the low p63 score and high p63 score groups were, respectively, 44% and 71% (p<0.001). Univariate analysis revealed that p63 expression was correlated with OS and PFS. Multivariate analysis suggested that p63 expression was an independent prognostic factor for OS (p=0.035). In conclusion, p63 was negatively correlated with peritumoral deposits and positively associated with OS and PFS in CRC. The data suggest that p63 is a potential prognostic factor for CRC. PMID- 23015402 TI - Thymidylate synthase expression and prognosis in colorectal cancer: a meta analysis of colorectal cancer survival data. AB - BACKGROUND: Although many studies have investigated the prognostic effect of thymidylate synthase (TS) in colorectal cancer, no consensus has been reached. The aim of this meta-analysis was to obtain a more precise estimate of the prognostic significance of TS expression in localized cancers treated by curative resection and adjuvant chemotherapy. MATERIALS AND METHOD: Seventeen eligible studies reporting survival in 2,893 patients stratified by TS expression were pooled using a fixed- or random-effects model. The main outcome measure was hazard ratio (HR). RESULTS: The overall HR for overall survival was 1.01 (95% CI 0.74-1.39, p=0.947), with an I2 of 64.4%. The total HR for disease-free survival was 1.36 (95% CI 0.97-1.89, p=0.072), with an I2 of 75.8%. In the TS protein tested subgroup, the total HR for disease-free survival was 1.72 (95% CI 1.02 2.89, p=0.042), with an I2 of 81.3%. CONCLUSION: Our meta-analysis showed that, in the adjuvant setting, TS expression does not predict a poorer disease-free survival or a worse overall survival. Therefore, we believe that it is inappropriate to regard TS expression as a prognostic factor for patients with stage II and stage III colorectal cancer treated by surgery and adjuvant chemotherapy. PMID- 23015403 TI - Microsatellite polymorphisms in the EGFR, NOTCH4 and E2F4 genes and their association with breast cancer risk. AB - BACKGROUND: The sequences of many human genes that encode proteins involved in cancer contain polymorphic microsatellites. Variations in microsatellite length may constitute risk factors in several human diseases, a possibility that has been little explored in breast cancer. Among the genes that contain polymorphic microsatellites are EGFR, NOTCH4 and E2F4. The length of some of these microsatellites has been associated with breast cancer risk. PURPOSE AND METHODS: To determine whether the length of the microsatellites (CA)n in EGFR, (CTG)n in NOTCH4 and (AGC)n in E2F4 was associated with breast cancer risk, we genotyped these 3 microsatellites in 212 women with breast cancer and a control group of 308 women from the general population who did not have this disease. RESULTS AND CONCLUSIONS: The allelic distribution observed for the 3 microsatellites matched that found in other white populations, with the exception of some (AGC)n alleles in E2F4, which have not been described previously. The length of (CA)n in EGFR and (CTG)n in NOTCH4 was not associated with breast cancer (OR=0.99; 95% CI 0.59 1.37; p=0.619 and OR=1.08; 95% CI 0.71-1.65; p=0.725, respectively). Short alleles (<13 repeats) of (AGC)n in E2F4 were less frequent in women with cancer than in the control sample. PMID- 23015404 TI - SIOP PODC: clinical guidelines for the management of children with Wilms tumour in a low income setting. AB - Wilms tumour is a relatively common and curable paediatric tumour. Known challenges to cure in low income countries are late presentation with advanced disease, malnutrition, failure to complete treatment and limited facilities. In this article, management recommendations are given for a low income setting where only the minimal requirements for treatment with curative intent are available (setting 1). These include general management, supportive care, social support and registration of patients. Recommendations specific for Wilms tumour care include diagnostic procedures with emphasis on the role of ultrasonography, preoperative chemotherapy with a reduced dosage for malnourished children and postoperative chemotherapy based on surgical staging. PMID- 23015405 TI - Photoinduced electron transfer in an amine-corrole-perylene bisimide assembly: charge separation over terminal components favoured by solvent polarity. AB - An assembly has been synthesised that consists of four units: a meso-substituted corrole (C3), perylene bisimide (PI), and two electron-rich triphenylamine (DPA) units. PI is connected through a 1,4-phenylene bridge to C3, whereas the two DPA units are linked to C3 through a diphenyl ether linkage, which is used for the first time to connect the various moieties. Various synthetic strategies were elaborated, and the chosen one afforded the final system in six steps in an overall yield of 6 %. The resulting assembly, made of three different units, was named a "triad". Excitation of the corrole (C3) or perylene bisimide (PI) units led to the charge-separated state DPA-C3(+)-PI(-) with a rate k>10(11) s(-1) in benzonitrile and dichloromethane (CH(2) Cl(2) ) or with k of the order of 10(10) s(-1) in toluene. The latter charge-separated state decayed to the ground state with a rate k=1.8*10(9) s(-1) in toluene. In the polar solvents benzonitrile and dichloromethane, recombination to the ground state competes with a charge shift to form the distal charge-separated state, DPA(+)-C3-PI(-), the formation of which occurs with a yield of 50 %. Recombination to the ground state of DPA(+)-C3 PI(-) occurs with a rate k=5*10(7) s(-1) in CH(2)Cl(2) and k=2*10(7) s(-1) in benzonitrile. PMID- 23015406 TI - Synthesis of alpha-hydroxyphosphonates and their antioxidant properties. AB - A series of alpha-hydroxyphosphonates were synthesized from the reaction of aldehyde (1) with triethylphosphite (2) in the presence of oxone and evaluated for their antioxidant properties against lipid peroxidation, reduced glutathione, superoxide dismutase, and catalase. The majority of the compounds showed promising antioxidant activity. Diethyl anthracen-9-yl (hydroxy) methylphosphonate (3n) is the most potent and biologically active compound against free radicals. PMID- 23015407 TI - Side-chain hydrophobicity and the stability of Abeta16-22 aggregates. AB - Recent mutagenesis studies using the hydrophobic segment of Abeta suggest that aromatic pi-stacking interactions may not be critical for fibril formation. We have tested this conjecture by probing the effect of Leu, Ile, and Ala mutation of the aromatic Phe residues at positions 19 and 20, on the double-layer hexametric chains of Abeta fragment Abeta16-22 using explicit solvent all-atom molecular dynamics. As these simulations rely on the accuracy of the utilized force fields, we first evaluated the dynamic and stability dependence on various force fields of small amyloid aggregates. These initial investigations led us to choose AMBER99SB-ILDN as force field in multiple long molecular dynamics simulations of 100 ns that probe the stability of the wild-type and mutants oligomers. Single-point and double-point mutants confirm that size and hydrophobicity are key for the aggregation and stability of the hydrophobic core region (Abeta16-22). This suggests as a venue for designing Abeta aggregation inhibitors the substitution of residues (especially, Phe 19 and 20) in the hydrophobic region (Abeta16-22) with natural and non-natural amino acids of similar size and hydrophobicity. PMID- 23015408 TI - Angiotensin I-converting enzyme inhibitory peptides derived from bovine casein and identified by MALDI-TOF-MS/MS. AB - BACKGROUND: Hypertension is a major and common threat to the health of individuals around the world. Although agents such as captopril have been shown to regulate high blood pressure effectively, they bring unfavourable side effects such as dry cough and angioedema. If angiotensin I-converting enzyme (ACE) inhibitors derived from natural substances such as milk proteins can be shown to be safe and efficient at managing hypertension, such inhibitors will be a valuable auxiliary to agents such as captopril. RESULTS: Low-molecular-weight casein-derived peptides hydrolysed by cell envelope proteinase of Lactobacillus casei subsp. casei (ATCC 15008) showed quite high ACE-inhibitory activity. The peptide fraction from alpha-casein with molecular weight between 5 and 10 kDa showed the highest ACE-inhibitory activity of 82.35%, with a 50% inhibition concentration (IC50 ) of 2.36 mg mL(-1). Peptides from beta-casein exhibited lower ACE-inhibitory activity (56.67%, IC50 4.00 mg mL(-1)). Three distinct peptide sequences derived from alpha-casein (alpha(s1) -cn f95-105, f106-115 and f148-166) were identified using two-dimensional gel electrophoresis coupled with matrix-assisted laser desorption/ionisation time-of-flight tandem mass spectrometry. CONCLUSION: This work investigated the ACE-inhibitory properties of casein-derived peptides. Three distinct peptide sequences derived from alpha casein were identified. Characterisation of such peptides furthers the investigation of casein-derived ACE-inhibitory peptides from fermented dairy products. PMID- 23015409 TI - Design rationale for customized TKA: a new idea or revisiting the past? AB - Today's most basic and important total knee replacement design concepts arose out of an earlier era in which 2 distinct approaches emerged, functional and anatomic. Functional approaches simplified knee kinetics, were easier to implant, and gained widespread popularity, in part, from their inventory control. Anatomic approaches were an attempt to recreate normal knee motion with low prosthetic contact stress. Historically, however, they became impractical to produce because of the cost of maintaining a wide variety of anatomic knee implants. New customized designs may return the anatomic design to favor due to several key features that borrow anatomic principles developed in the past, and improved with new ideas. PMID- 23015410 TI - A way to probe the microenvironment of free sulfhydryls in intact proteins with a series of monofunctional organic mercurials. AB - Monofunctional organic mercurials (MFOHgs) of different sizes and electronic properties were used to evaluate the accessibility of SH groups in intact proteins. The change in conformation of proteins, such as BLG and OVA, when treated with MFOHgs of increasing size was used as a measure of the accessibility of SH groups contained within these proteins. PMID- 23015411 TI - Fullerene-catalyzed reduction of azo derivatives in water under UV irradiation. AB - Metal-free fullerene (C(60)) was found to be an effective catalyst for the reduction of azo groups in basic aqueous solution under UV irradiation in the presence of NaBH(4). Use of NaBH(4) by itself is not sufficient to reduce the azo dyes without the assistance of a metal catalyst such as Pd and Ag. Experimental and theoretical results suggest that C(60) catalyzes this reaction by using its vacant orbital to accept the electron in the bonding orbital of azo dyes, which leads to the activation of the N=N bond. UV irradiation increases the ability of C(60) to interact with electron-donor moieties in azo dyes. PMID- 23015413 TI - A mixed method approach to describe the out-of-pocket expenses incurred by families of children with cancer. AB - BACKGROUND: Families of children with cancer are confronted with a broad range of direct costs (out-of-pocket expenses), but the nature of these costs is poorly understood. This study aimed to disaggregate and describe these costs. PROCEDURE: A prospective, mixed method, cost-of-illness design was utilized. Starting in the fourth week following their child's diagnosis, parents recorded resources consumed, and costs incurred for 1 week per month for 3 consecutive months. Any additional costs not captured in this typical 1 week period were added for the remainder of the month. Parents also discussed their costs in an audio-taped interview at the end of the 3 months. Descriptive statistics and qualitative content analyses were performed to disaggregate and describe families' costs. RESULTS: In total, 99 families reported utilizing 16 cost categories and 74 cost items. Nearly three quarters of these costs were attributed to travel (56%) and food (18%). Costly items included acquisition of a car ($CAD35,000), relocation of a family ($CAD6,000), and purchase of a wheelchair ($CAD6,800). Parents described facing significant out-of-pocket expenses to ensure that their children had access to cancer treatment, to cope with the clinical treatment side effects of treatment, and to maintain the family household. CONCLUSION: Families of children with cancer experience a wide range of costs. Our understanding of the nature of their costs and resource use may formulate the basis for future cost assessments and provide insight into practice and policy changes aimed at lessening the economic impact of this burden. PMID- 23015412 TI - The impact of influenza hemagglutinin fusion peptide length and viral subtype on its structure and dynamics. AB - A peptide comprising no fewer than the first 20 residues of the influenza hemagglutinin HA2 subunit suffices to induce lipid mixing between the membranes of different unilamellar vesicles. This 20-residue peptide was previously reported to adopt an open "boomerang" structure that differs significantly from the closed helical-hairpin structure of a fusion peptide consisting of the first 23 residues of the HA2 sequence. This study investigates the structural and dynamic features of fusion peptides of different length and subtype. Lacking key interactions that stabilize the closed, helical-hairpin structure, the 20-residue peptide is in a dynamic equilibrium between closed and open states, adopting a ca. 11% population of the former when solubilized by DPC micelles. Peptides shorter than 20 residues would have even fewer interactions to stabilize a helical hairpin fold, resulting in a vanishing hairpin population. Considering the conserved nature of hairpin-stabilizing interactions across all serotypes, and the minimum of 20 residues needed for fusion, we postulate that the closed state plays an essential role in the fusion process. However, opening of this hairpin structure may be essential to the formation of a membrane pore at the final stage of the fusion process. PMID- 23015414 TI - Women who kill their mates. AB - Spousal homicide perpetrators are much more likely to be men than women. Accordingly, little research has focused on delineating characteristics of women who have committed spousal homicide. A retrospective clinical review of coroners' files containing all cases of spousal homicide occurring in Quebec over a 20-year period was carried out. A total of 276 spousal homicides occurred between 1991 and 2010, with 42 homicides by female spouses and 234 homicides by male spouses. Differences between homicides committed by female offenders and male offenders are discussed, and findings on spousal homicide committed by women are compared with those of previous studies. Findings regarding offenses perpetrated by females in the context of mental illness, domestic violence, and homicide-suicide are explored. The finding that only 28% of the female offenders in the Quebec sample had previously been subjected to violence by their victim is in contrast to the popular belief and reports that indicate that most female-perpetrated spousal homicide occurs in self-defense or in reaction to long-term abuse. In fact, women rarely gave a warning before killing their mates. Most did not suffer from a mental illness, although one-fifth were acutely intoxicated at the time of the killing. In the vast majority of cases of women who killed their mates, there were very few indicators that might have signaled the risk and helped predict the violent lethal behavior. PMID- 23015415 TI - Dietary diversity score is a useful indicator of vitamin A status of adult women in Northern Kenya. AB - OBJECTIVES: Diets consisting of diverse food items provide a wide range of nutrients that can enhance nutritional quality of the diet. Few studies have, however, assessed dietary diversity and its effects on micronutrient health in rural populations in field settings. This study assesses how well Dietary Diversity Score (DDS), an indicator of dietary diversity based on a simple count of food groups consumed, predicts the micronutrient status, focusing on serum vitamin A concentration. METHODS: We used cross-sectional data from women in food insecure northern Kenya where dietary diversity is likely critical for micronutrient health yet under-studied. A linear regression model was applied to examine the relationships between DDS and serum retinol concentration. A logistic regression model was used to test DDS as a predictor of vitamin A insufficiency (serum retinol < 1.05 MUmol/l). RESULTS: DDS had a significant positive effect on serum retinol concentration (t = 2.01, P = 0.045) after adjusting for age, wealth, acute phase reaction, hemoglobin, vitamin A intake and vitamin A supplementation. A one unit increase in DDS by adding an extra food group in one's diet was significantly less likely to have vitamin A insufficiency (OR = 0.64, P = 0.026) after adjusting for the covariates. CONCLUSIONS: Our results indicate that diversified diets enhance vitamin A status relative to narrower diets with equivalent vitamin A content. DDS shows a potential as a low-cost, field-friendly method for exploratory assessments of vitamin A status, and a potential as a research tool for human biologists and anthropologists interested in dietary quality and micronutrient health. PMID- 23015416 TI - Effects of season, browse species and polyethylene glycol addition on gas production kinetics of forages in the subhumid subtropical savannah, South Africa. AB - BACKGROUND: This study was conducted to investigate the effects of season, species and polyethylene glycol addition on gas production (GP) and GP kinetic parameters by in vitro incubation (72 h) of five plant species from the subhumid subtropical savannah, South Africa. Plant species used were Acacia natalitia, Acacia nilotica, Dichrostachys cinerea, Scutia myrtina and Chromolaena odorata, leaves of which were harvested during the dry (June/July), early wet (November/December) and late wet (February/March) seasons. An automated in vitro gas production technique was used in two experiments carried out with nine replicates. The first experiment was to test the effect of season and species, while the second experiment tested the effect of tannins using polyethylene glycol 4000 (PEG). The PEG treatment was applied to samples in the early wet and late wet seasons. RESULTS: There were wide variations among seasons and species in crude protein (CP), neutral detergent fibre (NDF), acid detergent fibre (ADF) and condensed tannin (CT). Season and species affected the maximum GP and GP kinetic parameters. During the three seasons, C. odorata had the highest CP (186 226 g kg(-1) dry matter (DM)) and GP (87-104 mL g(-1) DM) and S. myrtina had the lowest CP (105-129 g kg(-1) DM), while A. nilotica, A. natalitia, D. cinerea and S. myrtina had similar and low GP (23-50 mL g(-1) DM). The maximum GP, its degradation rate and GP from the soluble fraction were positively correlated with CP both without and with PEG. With PEG, GP from the soluble fraction was negatively correlated with NDF, ADL and CT; without PEG, it was negatively correlated with CT. CONCLUSION: Both season and species affected the GP parameters. The addition of PEG emphasises that the inhibitory effect of tannins on rumen microbes was greater for all but C. odorata, confirming that these browse species can be used as feed supplements. PMID- 23015418 TI - Guest editorial: Epigenetics of hematopoiesis and hematological malignancies. PMID- 23015419 TI - Crystal growth, structure, and magnetic properties of a two-dimensional triangular lattice magnet, Cu2(OH)3HCO2. AB - We prepared single crystals of basic copper formate Cu(2)(OH)(3)HCO(2) (1) by hydrolysis of formate anions in an aqueous solution of copper formate. X-ray structure analysis showed that this material has a two-dimensional triangular lattice network with S = 1/2. The temperature dependence of magnetic susceptibility revealed antiferromagnetic ordering at 5.4 K. A spin-flop transition was observed at about 20 kOe at 2 K, thereby indicating metamagnetic like behavior. The saturation magnetization was almost one-half of the theoretical value at 2 K under 70 kOe. The magnetic behaviors of 1 were also discussed with regard to its crystal structure. The preparation method presented herein is convenient and available for single crystal growth of metal hydroxide derivatives with various anions. PMID- 23015417 TI - Epigenetic alterations in hematopoietic malignancies. AB - Gene discovery efforts in patients with hematopoietic malignancies have brought to the forefront a series of mutations in genes thought to be involved in the epigenetic regulation of gene transcription. These mutations occur in genes known, or suspected, to play a role in modifying cytosine nucleotides on DNA and/or altering the state of histone modifications. Genes such as ASXL1, DNMT3A, EZH2, IDH1/2, MLL1, and TET2 all have been shown to be mutated and/or translocated in patients with myeloid malignancies. Intriguingly, many of the alterations affecting DNA cytosine modifications in myeloid malignancies (mutations in DNMT3A, IDH1/2, and TET2) have also been found in patients with T cell lymphomas, and EZH2 mutations appear to be critical in T-cell acute lymphoblastic leukemia development as well. In addition, the discovery of frequent mutations in CREBBP, EP300, EZH2, and MLL2 in B-cell lymphomas suggests that epigenetic alterations play a critical role in lymphomagenesis. The purpose of this review is to present functional evidence of how alterations in these epigenetic modifiers promote hematopoietic transformation. The conclusions drawn from these data are valuable in understanding biological mechanisms and potential therapeutic targets. PMID- 23015420 TI - Coassembly of metal and titanium dioxide nanocrystals directed by monolayered block copolymer inverse micelles for enhanced photocatalytic performance. AB - Functional nanostructures of self-assembled block copolymers (BCPs) incorporated with various inorganic nanomaterials have received considerable attention on account of their many potential applications. Here we demonstrate the two dimensional self-assembly of anisotropic titanium dioxide (TiO(2)) nanocrystals (NCs) and metal nanoparticles (NPs) directed by monolayered poly(styrene)-block poly(4-vinylpyridine) (PS-b-P4VP) copolymer inverse micelles. The independent position-selective assembly of TiO(2) NCs and silver nanoparticles (AgNPs) preferentially in the intermicelle corona regions and the core of micelles, respectively, for instance, was accomplished by spin-coating a mixture solution of PS-b-P4VP and ex situ synthesized TiO(2) NCs, followed by the reduction of Ag salts coordinated in the cores of micelles into AgNPs. Hydrophobic TiO(2) NCs with a diameter and length of approximately 3 nm and 20-30 nm, respectively, were preferentially sequestered in the intermicelle nonpolar PS corona regions energetically favorable with the minimum entropic packing penalty. Subsequent high-temperature annealing at 550 degrees C not only effectively removed the block copolymer but also transformed the TiO(2) NCs into connected nanoparticles, thus leading to a two-dimensionally ordered TiO(2) network in which AgNPs were also self-organized. The enhanced photocatalytic activity of the AgNP-decorated TiO(2) networks by approximately 27 and 44 % over that of Ag-free TiO(2) networks and randomly deposited TiO(2) nanoparticles, respectively, was confirmed by the UV degradation property of methylene blue. PMID- 23015421 TI - Cortical mechanisms for pitch representation. PMID- 23015422 TI - Pitch perception. AB - Pitch is one of the primary auditory sensations and plays a defining role in music, speech, and auditory scene analysis. Although the main physical correlate of pitch is acoustic periodicity, or repetition rate, there are many interactions that complicate the relationship between the physical stimulus and the perception of pitch. In particular, the effects of other acoustic parameters on pitch judgments, and the complex interactions between perceptual organization and pitch, have uncovered interesting perceptual phenomena that should help to reveal the underlying neural mechanisms. PMID- 23015423 TI - Neural mechanisms for the abstraction and use of pitch information in auditory cortex. AB - Experiments in animals have provided an important complement to human studies of pitch perception by revealing how the activity of individual neurons represents harmonic complex and periodic sounds. Such studies have shown that the acoustical parameters associated with pitch are represented by the spiking responses of neurons in A1 (primary auditory cortex) and various higher auditory cortical fields. The responses of these neurons are also modulated by the timbre of sounds. In marmosets, a distinct region on the low-frequency border of primary and non-primary auditory cortex may provide pitch tuning that generalizes across timbre classes. PMID- 23015424 TI - Mapping pitch representation in neural ensembles with fMRI. AB - Functional magnetic resonance imaging (fMRI) in humans and macaques allows a test of the hypothesis that there is a specialized neural ensemble for pitch within auditory cortex: a pitch center. fMRI measures the blood oxygenation level dependent (BOLD) response related to regional synaptic activity (Logothetis et al., 2001). The distinction between synaptic activity and spike firing, and species differences encourage caution when comparing BOLD activity in humans and macaques to recordings from single neurons in ferret and marmoset in the previous mini-review. The BOLD data provide support for the pitch-center concept, with ongoing debate about its location. PMID- 23015425 TI - Mapping human pitch representation in a distributed system using depth-electrode recordings and modeling. AB - Depth-electrode recordings from the auditory cortex of humans undergoing presurgical evaluation for epilepsy allow the recording of ensemble responses to pitch in the form of local field potentials. These recordings allow another test of the hypothesis that there is a specialized neural ensemble for pitch within auditory cortex. Moreover, the technique allows recordings from multiple sites with millisecond temporal resolution to allow modeling of the effective connectivity between these sites. Here we argue that this takes the form of a hierarchical network of pitch-sensitive regions. Activity can be understood as reflecting predictive coding, in which perceptual predictions and error messages are continuously exchanged between a higher pitch center and lower-level auditory cortex. PMID- 23015426 TI - Neural mechanisms of attentional reorienting in three-dimensional space. AB - How the human brain reconstructs the three-dimensional (3D) world from two dimensional (2D) retinal images has received a great deal of interest as has how we shift attention in 2D space. In contrast, it remains poorly understood how visuospatial attention is shifted in depth. In this fMRI study, by constructing a virtual 3D environment in the MR scanner and by presenting targets either close to or far from the participants in an adapted version of the Posner spatial cueing paradigm, we investigated the behavioral and neural mechanisms underlying visuospatial orienting/reorienting in depth. At the behavioral level, although covering the same spatial distance, attentional reorienting to objects unexpectedly appearing closer to the observer and in the unattended hemispace was faster than reorienting to unexpected objects farther away. At the neural level, we found that in addition to the classical attentional reorienting system in the right temporoparietal junction, two additional brain networks were differentially involved in aspects of attentional reorienting in depth. First, bilateral premotor cortex reoriented visuospatial attention specifically along the third dimension of visual space (i.e., from close to far or vice versa), compared with attentional reorienting within the same depth plane. Second, a network of areas reminiscent of the human "default-mode network," including posterior cingulate cortex, orbital prefrontal cortex, and left angular gyrus, was involved in the neural interaction between depth and attentional orienting, by boosting attentional reorienting to unexpected objects appearing both closer to the observer and in the unattended hemispace. PMID- 23015427 TI - Distinct functional organizations for processing different motion signals in V1, V2, and V4 of macaque. AB - Motion perception is qualitatively invariant across different objects and forms, namely, the same motion information can be conveyed by many different physical carriers, and it requires the processing of motion signals consisting of direction, speed, and axis or trajectory of motion defined by a moving object. Compared with the representation of orientation, the cortical processing of these different motion signals within the early ventral visual pathway of the primate remains poorly understood. Using drifting full-field noise stimuli and intrinsic optical imaging, along with cytochrome-oxidase staining, we found that the orientation domains in macaque V1, V2, and V4 that processed orientation signals also served to process motion signals associated with the axis and speed of motion. In contrast, direction domains within the thick stripes of V2 demonstrated preferences that were independent of motion speed. The population responses encoding the orientation and motion axis could be precisely reproduced by a spatiotemporal energy model. Thus, our observation of orientation domains with dual functions in V1, V2, and V4 directly support the notion that the linear representation of the temporal series of retinotopic activations may serve as another motion processing strategy in primate ventral visual pathway, contributing directly to fine form and motion analysis. Our findings further reveal that different types of motion information are differentially processed in parallel and segregated compartments within primate early visual cortices, before these motion features are fully combined in high-tier visual areas. PMID- 23015428 TI - Ionic current correlations underlie the global tuning of large numbers of neuronal activity attributes. AB - Ionic conductances in identified neurons are highly variable. This poses the crucial question of how such neurons can produce stable activity. Coexpression of ionic currents has been observed in an increasing number of neurons in different systems, suggesting that the coregulation of ionic channel expression, by thus linking their variability, may enable neurons to maintain relatively constant neuronal activity as suggested by a number of recent theoretical studies. We examine this hypothesis experimentally using the voltage- and dynamic-clamp techniques to first measure and then modify the ionic conductance levels of three currents in identified neurons of the crab pyloric network. We quantify activity by measuring 10 different attributes (oscillation period, spiking frequency, etc.), and find linear, positive and negative relationships between conductance pairs and triplets that can enable pyloric neurons to maintain activity attributes invariant. Consistent with experimental observations, some of the features most tightly regulated appear to be phase relationships of bursting activity. We conclude that covariation (and probably a tightly controlled coregulation) of ionic conductances can help neurons maintain certain attributes of neuronal activity invariant while at the same time allowing conductances to change over wide ranges in response to internal or environmental inputs and perturbations. Our results also show that neurons can tune neuronal activity globally via coordinate expression of ion currents. PMID- 23015429 TI - Repetition suppression and expectation suppression are dissociable in time in early auditory evoked fields. AB - Repetition of a stimulus, as well as valid expectation that a stimulus will occur, both attenuate the neural response to it. These effects, repetition suppression and expectation suppression, are typically confounded in paradigms in which the nonrepeated stimulus is also relatively rare (e.g., in oddball blocks of mismatch negativity paradigms, or in repetition suppression paradigms with multiple repetitions before an alternation). However, recent hierarchical models of sensory processing inspire the hypothesis that the two might be separable in time, with repetition suppression occurring earlier, as a consequence of local transition probabilities, and suppression by expectation occurring later, as a consequence of learnt statistical regularities. Here we test this hypothesis in an auditory experiment by orthogonally manipulating stimulus repetition and stimulus expectation and, using magnetoencephalography, measuring the neural response over time in human subjects. We found that stimulus repetition (but not stimulus expectation) attenuates the early auditory response (40-60 ms), while stimulus expectation (but not stimulus repetition) attenuates the subsequent, intermediate stage of auditory processing (100-200 ms). These findings are well in line with hierarchical predictive coding models, which posit sequential stages of prediction error resolution, contingent on the level at which the hypothesis is generated. PMID- 23015430 TI - A role for the subthalamic nucleus in response inhibition during conflict. AB - The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN. We intended to determine whether cognitive psychological phenomena such as the Stroop effect can be explained via mechanisms of response inhibition involving the STN, or whether higher cognitive centers are alone responsible. We show stimulus-driven desychronization in the beta band (15-35 Hz) that lasts throughout the verbal response, in keeping with the idea that beta-band synchrony decreases to allow motor output to occur. During incongruent trials--in which response times were elongated due to the Stroop effect--a resynchronization was seen in the beta band before response. Crucially, in the incongruent trials during which the participant was unable to withhold the prepotent response, this resynchronization occurred after response onset. We suggest that this beta-band resynchronization pauses the motor system until conflict can be resolved. PMID- 23015431 TI - Nothing is irrelevant in a noisy world: sensory illusions reveal obligatory within-and across-modality integration. AB - In the "flash-beep illusion," a single light flash is perceived as multiple flashes when presented in close temporal proximity to multiple auditory beeps. Accounts of this illusion argue that temporal auditory information interferes with visual information because temporal acuity is better in audition than vision. However, it may also be that whenever there are multiple sensory inputs, the interference caused by a to-be-ignored stimulus on an attended stimulus depends on the likelihood that the stimuli are perceived as coming from a single distal source. Here we explore, in human observers, perceptual interactions between competing auditory and visual inputs while varying spatial proximity, which affects object formation. When two spatially separated streams are presented in the same (visual or auditory) modality, temporal judgments about a target stream from one direction are biased by the content of the competing distractor stream. Cross-modally, auditory streams from both target and distractor directions bias the perceived number of events in a target visual stream; however, importantly, the auditory stream from the target direction influences visual judgments more than does the auditory stream from the opposite hemifield. As in the original flash-beep illusion, visual streams weakly influence auditory judgments, regardless of spatial proximity. We also find that perceptual interference in the flash-beep illusion is similar to within-modality interference from a competing same-modality stream. Results reveal imperfect and obligatory within- and across-modality integration of information, and hint that the strength of these interactions depends on object binding. PMID- 23015432 TI - Antidepressant suppression of non-REM sleep spindles and REM sleep impairs hippocampus-dependent learning while augmenting striatum-dependent learning. AB - Rapid eye movement (REM) sleep enhances hippocampus-dependent associative memory, but REM deprivation has little impact on striatum-dependent procedural learning. Antidepressant medications are known to inhibit REM sleep, but it is not well understood if antidepressant treatments impact learning and memory. We explored antidepressant REM suppression effects on learning by training animals daily on a spatial task under familiar and novel conditions, followed by training on a procedural memory task. Daily treatment with the antidepressant and norepinephrine reuptake inhibitor desipramine (DMI) strongly suppressed REM sleep in rats for several hours, as has been described in humans. We also found that DMI treatment reduced the spindle-rich transition-to-REM sleep state (TR), which has not been previously reported. DMI REM suppression gradually weakened performance on a once familiar hippocampus-dependent maze (reconsolidation error). DMI also impaired learning of the novel maze (consolidation error). Unexpectedly, learning of novel reward positions and memory of familiar positions were equally and oppositely correlated with amounts of TR sleep. Conversely, DMI treatment enhanced performance on a separate striatum-dependent, procedural T maze task that was positively correlated with the amounts of slow-wave sleep (SWS). Our results suggest that learning strategy switches in patients taking REM sleep-suppressing antidepressants might serve to offset sleep-dependent hippocampal impairments to partially preserve performance. State-performance correlations support a model wherein reconsolidation of hippocampus-dependent familiar memories occurs during REM sleep, novel information is incorporated and consolidated during TR, and dorsal striatum-dependent procedural learning is augmented during SWS. PMID- 23015433 TI - Striatal indirect pathway contributes to selection accuracy of learned motor actions. AB - The dorsal striatum, which contains the dorsolateral striatum (DLS) and dorsomedial striatum (DMS), integrates the acquisition and implementation of instrumental learning in cooperation with the nucleus accumbens (NAc). The dorsal striatum regulates the basal ganglia circuitry through direct and indirect pathways. The mechanism by which these pathways mediate the learning processes of instrumental actions remains unclear. We investigated how the striatal indirect (striatopallidal) pathway arising from the DLS contributes to the performance of conditional discrimination. Immunotoxin targeting of the striatal neuronal type containing dopamine D(2) receptor in the DLS of transgenic rats resulted in selective, efficient elimination of the striatopallidal pathway. This elimination impaired the accuracy of response selection in a two-choice reaction time task dependent on different auditory stimuli. The impaired response selection was elicited early in the test sessions and was gradually restored as the sessions continued. The restoration from the deficits in auditory discrimination was prevented by excitotoxic lesion of the NAc but not by that of the DMS. In addition, lesion of the DLS mimicked the behavioral consequence of the striatopallidal removal at the early stage of test sessions of discriminative performance. Our results demonstrate that the DLS-derived striatopallidal pathway plays an essential role in the execution of conditional discrimination, showing its contribution to the control of selection accuracy of learned motor responses. The results also suggest the presence of a mechanism that compensates for the learning deficits during the repetitive sessions, at least partly, demanding accumbal function. PMID- 23015434 TI - Frequency-selective exocytosis by ribbon synapses of hair cells in the bullfrog's amphibian papilla. AB - The activity of auditory afferent fibers depends strongly on the frequency of stimulation. Although the bullfrog's amphibian papilla lacks the flexible basilar membrane that effects tuning in mammals, its afferents display comparable frequency selectivity. Seeking additional mechanisms of tuning in this organ, we monitored the synaptic output of hair cells by measuring changes in their membrane capacitance during sinusoidal electrical stimulation at various frequencies. Using perforated-patch recordings, we found that individual hair cells displayed frequency selectivity in synaptic exocytosis within the frequency range sensed by the amphibian papilla. Moreover, each cell's tuning varied in accordance with its tonotopic position. Using confocal imaging, we observed a tonotopic gradient in the concentration of proteinaceous Ca(2+) buffers. A model for synaptic release suggests that this gradient maintains the sharpness of tuning. We conclude that hair cells of the amphibian papilla use synaptic tuning as an additional mechanism for sharpening their frequency selectivity. PMID- 23015435 TI - Spatially coordinated kinase signaling regulates local axon degeneration. AB - In addition to being a hallmark of neurodegenerative disease, axon degeneration is used during development of the nervous system to prune unwanted connections. In development, axon degeneration is tightly regulated both temporally and spatially. Here, we provide evidence that degeneration cues are transduced through various kinase pathways functioning in spatially distinct compartments to regulate axon degeneration. Intriguingly, glycogen synthase kinase-3 (GSK3) acts centrally, likely modulating gene expression in the cell body to regulate distally restricted axon degeneration. Through a combination of genetic and pharmacological manipulations, including the generation of an analog-sensitive kinase allele mutant mouse for GSK3beta, we show that the beta isoform of GSK3, not the alpha isoform, is essential for developmental axon pruning in vitro and in vivo. Additionally, we identify the dleu2/mir15a/16-1 cluster, previously characterized as a regulator of B-cell proliferation, and the transcription factor tbx6, as likely downstream effectors of GSK3beta in axon degeneration. PMID- 23015437 TI - Capsaicin induces theta-band synchronization between gustatory and autonomic insular cortices. AB - In the insular cortex, the primary gustatory area caudally adjoins the primary autonomic area that is involved in visceral sensory-motor integration. However, it has not been addressed whether neural activity in the gustatory insula (Gu-I) is coordinated with that in the autonomic insula (Au-I). We have demonstrated that TRPV1 activation in Gu-I induces theta-band synchronization between Gu-I and Au-I in rat slice preparations. Electron-microscopic immunohistochemistry revealed that TRPV1 immunoreactivity was much higher in Gu-I than in Au-I, and was mostly detected in dendritic spines receiving asymmetrical synapses. Whole cell voltage-clamp recordings revealed that, in Gu-I, capsaicin-induced currents in layer 3 (L3) pyramidal cells (PCs) displayed no apparent desensitization, while those in layer 5 (L5) PCs displayed Ca(2+)-dependent desensitization, suggesting that L3 and L5 PCs respond differentially to TRPV1 activation. Voltage sensitive dye imaging demonstrated that TRPV1 activation in Gu-I can alter an optical response with a monophasic and columnar temporospatial pattern evoked within Gu-I into an oscillatory one extending over Gu-I and Au-I. Power and cross power spectral analyses of optical responses revealed theta-band synchronization between Gu-I and Au-I. Whole-cell current-clamp recordings demonstrated that such theta-band waves were mediated by sustained rhythmic firings at 4 and 8 Hz in L3 and L5 PCs, respectively. These results strongly suggested that theta-band oscillatory neural coordination between Gu-I and Au-I was induced by two distinct TRPV1-mediated theta-rhythm firings in L3 and L5 PCs in Gu-I. This network coordination induced by TRPV1 activation could be responsible for autonomic responses to tasting and ingesting spicy foods. PMID- 23015436 TI - Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. AB - Abnormal deposition and intercellular propagation of alpha-synuclein plays a central role in the pathogenesis of disorders such as Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). Previous studies demonstrated that immunization against alpha-synuclein resulted in reduced alpha-synuclein accumulation and synaptic loss in a transgenic (tg) mouse model, highlighting the potential for immunotherapy. However, the mechanism by which immunization prevents synucleinopathy-associated deficits remains unknown. Here, we show that antibodies against alpha-synuclein specifically target and aid in clearance of extracellular alpha-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Antibody-assisted clearance occurs mainly in microglia through the Fcgamma receptor, and not in neuronal cells or astrocytes. Stereotaxic administration of antibody into the brains of alpha-synuclein tg mice prevented neuron-to-astroglia transmission of alpha-synuclein and led to increased localization of alpha-synuclein and the antibody in microglia. Furthermore, passive immunization with alpha-synuclein antibody reduced neuronal and glial accumulation of alpha-synuclein and ameliorated neurodegeneration and behavioral deficits associated with alpha-synuclein overexpression. These findings provide an underlying mechanistic basis for immunotherapy for PD/DLB and suggest extracellular forms of alpha-synuclein as potential therapeutic targets. PMID- 23015439 TI - Spatial localization of auditory stimuli in human auditory cortex is based on both head-independent and head-centered coordinate systems. AB - In humans, whose ears are fixed on the head, auditory stimuli are initially registered in space relative to the head. Eventually, locations of sound sources need to be encoded also relative to the body, or in absolute allocentric space, to allow orientation toward the sounds sources and consequent action. We can therefore distinguish between two spatial representation systems: a basic head centered coordinate system and a more complex head-independent system. In an ERP experiment, we attempted to reveal which of these two coordinate systems is represented in the human auditory cortex. We dissociated the two systems using the mismatch negativity (MMN), a well studied EEG effect evoked by acoustic deviations. Contrary to previous findings suggesting that only primary head related information is present at this early stage of processing, we observed significant MMN effects for both head-independent and head-centered deviant stimuli. Our findings thus reveal that both primary head-related and secondary body- or world-related reference frames are represented at this stage of auditory processing. PMID- 23015438 TI - The conserved dopaminergic diencephalospinal tract mediates vertebrate locomotor development in zebrafish larvae. AB - The most conserved part of the vertebrate dopaminergic system is the orthopedia (otp)-expressing diencephalic neuronal population that constitutes the dopaminergic diencephalospinal tract (DDT). Although studies in the neonatal murine spinal cord in vitro suggest an early locomotor role of the DDT, the function of the DDT in developing vertebrates in vivo remains unknown. Here, we investigated the role of the DDT in the locomotor development of zebrafish larvae. To assess the development of the behavioral and neural locomotor pattern, we used high-throughput video tracking in combination with peripheral nerve recordings. We found a behavioral and neural correspondence in the developmental switch from an immature to mature locomotor pattern. Blocking endogenous dopamine receptor 4 (D(4)R) signaling in vivo either before or after the developmental switch prevented or reversed the switch, respectively. Spinal transections of post-switch larvae reestablished the immature locomotor pattern, which was rescued to a mature-like pattern via spinal D(4)R agonism. Selective chemogenetic ablation of otp b (otpb) neurons that contribute to the DDT perpetuated the immature locomotor pattern in vivo. This phenotype was recapitulated by diencephalic transections that removed the dopaminergic otpb population and was rescued to a mature-like locomotor pattern by D(4)R agonism. We conclude that the dopaminergic otpb population, via the DDT, is responsible for spinal D(4)R signaling to mediate the developmental switch to the mature locomotor pattern of zebrafish. These results, integrated with the mammalian literature, suggest that the DDT represents an evolutionarily conserved neuromodulatory system that is necessary for normal vertebrate locomotor development. PMID- 23015440 TI - Optogenetic analysis of neuronal excitability during global ischemia reveals selective deficits in sensory processing following reperfusion in mouse cortex. AB - We have developed an approach to directly probe neuronal excitability during the period beginning with induction of global ischemia and extending after reperfusion using transgenic mice expressing channelrhodopsin-2 (ChR2) to activate deep layer cortical neurons independent of synaptic or sensory stimulation. Spontaneous, ChR2, or forepaw stimulation-evoked electroencephalogram (EEG) or local field potential (LFP) records were collected from the somatosensory cortex. Within 20 s of ischemia, a >90% depression of spontaneous 0.3-3 Hz EEG and LFP power was detected. Ischemic depolarization followed EEG depression with a ~2 min delay. Surprisingly, neuronal excitability, as assessed by the ChR2-mediated EEG response, was intact during the period of strong spontaneous EEG suppression and actually increased before ischemic depolarization. In contrast, a decrease in the somatosensory-evoked potential (forepaw-evoked potential, reflecting cortical synaptic transmission) was coincident with the EEG suppression. After 5 min of ischemia, the animal was reperfused, and the ChR2-mediated response mostly recovered within 30 min (>80% of preischemia value). However, the recovery of the somatosensory-evoked potential was significantly delayed compared with the ChR2-mediated response (<40% of preischemia value at 60 min). By assessing intrinsic optical signals in combination with EEG, we found that neuronal excitability approached minimal values when the spreading ischemic depolarization wave propagated to the ChR2 stimulated cortex. Our results indicate that the ChR2-mediated EEG/LFP response recovers much faster than sensory-evoked EEG/LFP activity in vivo following ischemia and reperfusion, defining a period where excitable but synaptically silent neurons are present. PMID- 23015441 TI - Species differences in somatodendritic dopamine transmission determine D2 autoreceptor-mediated inhibition of ventral tegmental area neuron firing. AB - The somatodendritic release of dopamine within the ventral tegmental area (VTA) and substantia nigra pars compacta activates inhibitory postsynaptic D2-receptors on dopaminergic neurons. The proposed mechanisms that regulate this form of transmission differ between electrochemical studies using rats and guinea pigs and electrophysiological studies using mice. This study examines the release and resulting dopamine D2-autoreceptor-mediated IPSCs (D2-IPSCs) in the VTA of mouse, rat, and guinea pig. Robust D2-IPSCs were observed in all recordings from neurons in slices taken from mouse, whereas D2-IPSCs in rat and guinea pig were observed less frequently and were significantly smaller in amplitude. In slices taken from guinea pig, dopamine release was more persistent under conditions of reduced extracellular calcium. The decline in the concentration of dopamine was also prolonged and not as sensitive to inhibition of reuptake by cocaine. This resulted in an increased duration of D2-IPSCs in the guinea pig. Therefore, unlike the mouse or the rat, the time course of dopamine in the extracellular space of the guinea pig determined the duration the D2-IPSC. Functionally, differences in D2-IPSCs resulted in inhibition of dopamine neuron firing only in slices from mouse. The results suggest that the mechanisms and functional consequences of somatodendritic dopamine transmission in the VTA vary among species. This highlights the complexity that underlies dopamine-dependent transmission in one brain area. Differences in somatodendritic transmission would be expected in vivo to affect the downstream activity of the mesocorticolimbic dopamine system and subsequent terminal release. PMID- 23015442 TI - A critical and cell-autonomous role for MeCP2 in synaptic scaling up. AB - Rett syndrome (Rett) is the leading genetic cause of mental retardation in females. Most cases of Rett are caused by loss-of-function mutations in the gene coding for the transcriptional regulator methyl-CpG binding protein 2 (MeCP2), but despite much effort, it remains unclear how a loss of MeCP2 function generates the neurological deficits of Rett. Here we show that MeCP2 plays an essential and cell-autonomous role in homeostatic synaptic scaling up in response to reduced firing or reduced sensory drive in rat visual cortical pyramidal neurons. We found that acute RNAi knockdown of MeCP2 blocked synaptic scaling within targeted neocortical pyramidal neurons. Furthermore, MeCP2 knockdown decreased excitatory synapse number without affecting basal mEPSC amplitude or AMPAR accumulation at spared synapses, demonstrating that MeCP2 acts cell autonomously to maintain both excitatory synapse number and synaptic scaling in individual neocortical neurons. Finally, we used a mouse model of Rett to show that MeCP2 loss prevents homeostatic synaptic scaling up in response to visual deprivation in vivo, demonstrating for the first time that MeCP2 loss disrupts homeostatic plasticity within the intact developing neocortex. Our results establish MeCP2 as a critical mediator of synaptic scaling and raise the possibility that some of the neurological defects of Rett arise from a disruption of homeostatic plasticity. PMID- 23015443 TI - Vestibular labyrinth contributions to human whole-body motion discrimination. AB - To assess the contributions of the vestibular system to whole-body motion discrimination in the dark, we measured direction recognition thresholds as a function of frequency for yaw rotation, superior-inferior translation ("z translation"), interaural translation ("y-translation"), and roll tilt for 14 normal subjects and for 3 patients following total bilateral vestibular ablation. The patients had significantly higher average threshold measurements than normal (p < 0.01) for yaw rotation (depending upon frequency, 5.4* to 15.7* greater), z translation (8.3* to 56.8* greater), y-translation (1.7* to 4.5* greater), and roll tilt (1.3* to 3.0* greater)--establishing the predominant contributions of the vestibular system for these motions in the dark. PMID- 23015444 TI - Cognitive regulation during decision making shifts behavioral control between ventromedial and dorsolateral prefrontal value systems. AB - Cognitive regulation is often used to influence behavioral outcomes. However, the computational and neurobiological mechanisms by which it affects behavior remain unknown. We studied this issue using an fMRI task in which human participants used cognitive regulation to upregulate and downregulate their cravings for foods at the time of choice. We found that activity in both ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) correlated with value. We also found evidence that two distinct regulatory mechanisms were at work: value modulation, which operates by changing the values assigned to foods in vmPFC and dlPFC at the time of choice, and behavioral control modulation, which operates by changing the relative influence of the vmPFC and dlPFC value signals on the action selection process used to make choices. In particular, during downregulation, activation decreased in the value-sensitive region of dlPFC (indicating value modulation) but not in vmPFC, and the relative contribution of the two value signals to behavior shifted toward the dlPFC (indicating behavioral control modulation). The opposite pattern was observed during upregulation: activation increased in vmPFC but not dlPFC, and the relative contribution to behavior shifted toward the vmPFC. Finally, ventrolateral PFC and posterior parietal cortex were more active during both upregulation and downregulation, and were functionally connected with vmPFC and dlPFC during cognitive regulation, which suggests that they help to implement the changes to the decision-making circuitry generated by cognitive regulation. PMID- 23015445 TI - Quantitative regional and ultrastructural localization of the Ca(v)2.3 subunit of R-type calcium channel in mouse brain. AB - R-type calcium channels (RTCCs) are well known for their role in synaptic plasticity, but little is known about their subcellular distribution across various neuronal compartments. Using subtype-specific antibodies, we characterized the regional and subcellular localization of Ca(v)2.3 in mice and rats at both light and electron microscopic levels. Ca(v)2.3 immunogold particles were found to be predominantly presynaptic in the interpeduncular nucleus, but postsynaptic in other brain regions. Serial section analysis of electron microscopic images from the hippocampal CA1 revealed a higher density of immunogold particles in the dendritic shaft plasma membrane compared with the pyramidal cell somata. However, the labeling densities were not significantly different among the apical, oblique, or basal dendrites. Immunogold particles were also observed over the plasma membrane of dendritic spines, including both synaptic and extrasynaptic sites. Individual spine heads contained <20 immunogold particles, with an average density of ~260 immunoparticles per MUm(3) spine head volume, in accordance with the density of RTCCs estimated using calcium imaging (Sabatini and Svoboda, 2000). The Ca(v)2.3 density was variable among similar sized spine heads and did not correlate with the density in the parent dendrite, implying that spines are individual calcium compartments operating autonomously from their parent dendrites. PMID- 23015446 TI - Time-dependent cross talk between spinal serotonin 5-HT2A receptor and mGluR1 subserves spinal hyperexcitability and neuropathic pain after nerve injury. AB - Emerging evidence implicates serotonergic descending facilitatory pathways from the brainstem to the spinal cord in the maintenance of pathologic pain. Upregulation of the serotonin receptor 2A (5-HT(2A)R) in dorsal horn neurons promotes spinal hyperexcitation and impairs spinal MU-opioid mechanisms during neuropathic pain. We investigated the involvement of spinal glutamate receptors, including metabotropic receptors (mGluRs) and NMDA, in 5-HT(2A)R-induced hyperexcitability after spinal nerve ligation (SNL) in rat. High-affinity 5 HT(2A)R agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2) enhanced C-fiber-evoked dorsal horn potentials after SNL, which was prevented by mGluR1 antagonist AIDA [(RS)-1-aminoindan-1,5-dicarboxylic acid] but not by group II mGluR antagonist LY 341495 [(2S)-2-amino-2-[(1S,2S)-2 carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid] or NMDA antagonist d-AP5 [D (-)-2-amino-5-phosphonopentanoic acid]. 5-HT(2A)R and mGluR1 were found to be coexpressed in postsynaptic densities in dorsal horn neurons. In the absence of SNL, pharmacological stimulation of 5-HT(2A)R with TCB-2 both induced rapid bilateral upregulation of mGluR1 expression in cytoplasmic and synaptic fractions of spinal cord homogenates, which was attenuated by PKC inhibitor chelerythrine, and enhanced evoked potentials during costimulation of mGluR1 with 3,5-DHPG [(RS) 3,5-dihydroxyphenylglycine]. SNL was followed by bilateral upregulation of mGluR1 in 5-HT(2A)R-containing postsynaptic densities. Upregulation of mGluR1 in synaptic compartments was partially prevented by chronic administration of selective 5-HT(2A)R antagonist M100907 [(R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2 (4-fluorophenyl)ethyl]-4-pipidinemethanol], confirming 5-HT(2A)R-mediated control of mGluR1 upregulation triggered by SNL. Changes in thermal and mechanical pain thresholds following SNL were increasingly reversed over the days after injury by chronic 5-HT(2A)R blockade. These results emphasize a role for 5-HT(2A)R in hyperexcitation and pain after nerve injury and support mGluR1 upregulation as a novel feedforward activation mechanism contributing to 5-HT(2A)R-mediated facilitation. PMID- 23015447 TI - L-type voltage-gated calcium channels in the basolateral amygdala are necessary for fear extinction. AB - L-type voltage-gated calcium channels (L-VGCCs) in the basolateral nucleus of the amygdala (BLA) are necessary for long-term memory of fear conditioning, where they are thought to drive the activation of protein kinases and to initiate gene transcription. However, their role in fear extinction learning is unclear given that systemic injections of VGCC antagonists induce a protracted stress response. Here we tested the effects of local infusions of the L-VGCC antagonists verapamil and nifedipine on both within-session extinction and fear extinction consolidation. Intra-BLA infusions of verapamil or nifedipine did not affect the expression of fear conditioning or the amount of within-session extinction but impaired extinction memory when rats were tested 24 h later drug-free. L-VGCC antagonists also prevented the increase in phosphorylated mitogen-activated protein kinase (MAPK) normally seen in the BLA following extinction learning. These results suggest that activation of L-VGCCs in the BLA at the time of fear extinction learning is necessary for the long-term retention of fear extinction via the MAPK pathway. PMID- 23015448 TI - Bcl-x pre-mRNA splicing regulates brain injury after neonatal hypoxia-ischemia. AB - The bcl-x gene appears to play a critical role in regulating apoptosis in the developing and mature CNS and following CNS injury. Two isoforms of Bcl-x are produced as a result of alternative pre-mRNA splicing: Bcl-x(L) (the long form) is anti-apoptotic, while Bcl-x(S) (short form) is pro-apoptotic. Despite the antagonistic activities of these two isoforms, little is known about how regulation of alternative splicing of bcl-x may mediate neural cell apoptosis. Here, we report that apoptotic stimuli (staurosporine or C2-ceramide) reciprocally altered Bcl-x splicing in neural cells, decreasing Bcl-x(L) while increasing Bcl-x(S). Specific knockdown of Bcl-x(S) attenuated apoptosis. To further define regulatory elements that influenced Bcl-x splicing, a Bcl-x minigene was constructed. Deletional analysis revealed several consensus sequences within intron 2 that altered splicing. We found that the splicing factor, CUG-binding-protein-1 (CUGBP1), bound to a consensus sequence close to the Bcl-x(L) 5' splice site, altering the Bcl-x(L)/Bcl-x(S) ratio and influencing cell death. In vivo, neonatal hypoxia-ischemia reciprocally altered Bcl-x pre mRNA splicing, similar to the in vitro studies. Manipulation of the splice isoforms using viral gene transfer of Bcl-x(S) shRNA into the hippocampus of rats before neonatal hypoxia-ischemia decreased vulnerability to injury. Moreover, alterations in nuclear CUGBP1 preceded Bcl-x splicing changes. These results suggest that alternative pre-mRNA splicing may be an important regulatory mechanism for cell death after acute neurological injury and may potentially provide novel targets for intervention. PMID- 23015449 TI - Tonic and transient endocannabinoid regulation of AMPAergic miniature postsynaptic currents and homeostatic plasticity in embryonic motor networks. AB - Endocannabinoid signaling has been shown to mediate synaptic plasticity by retrogradely inhibiting presynaptic transmitter release in several systems. We found that endocannabinoids act tonically to regulate AMPA miniature postsynaptic current (mPSC) frequency in embryonic motor circuits of the chick spinal cord. Further, strong postsynaptic depolarizations also induced a short-lived endocannabinoid-mediated suppression of mEPSC frequency. Unlike many previous studies, endocannabinoid signaling was not found to influence evoked transmitter release. The results suggest a special role for spontaneous glutamatergic mPSCs and their control by endocannabinoids in the developing spinal cord. We determined that blocking endocannabinoid signaling, which increases spontaneous glutamatergic release, increased spontaneous network activity in vitro and in vivo. Previous work in spinal motoneurons had shown that reducing spontaneous network activity (SNA) chronically in vivo led to homeostatic increases in AMPA and GABA mPSC amplitude (homeostatic synaptic plasticity). Blocking endocannabinoid signaling in vivo, and thus increasing SNA, triggered compensatory decreases of both AMPA and GABA mPSC amplitudes. These findings, combined with previous results, are consistent with the idea that this form of homeostatic synaptic plasticity is a bidirectional process in the living embryo. Together, our results suggest a role for tonic signaling of endocannabinoids as a potential mechanism to regulate the level of SNA, which is known to be critical for synaptic maturation in the embryonic spinal cord. PMID- 23015450 TI - Form and function of the M4 cell, an intrinsically photosensitive retinal ganglion cell type contributing to geniculocortical vision. AB - The photopigment melanopsin confers photosensitivity upon a minority of retinal output neurons. These intrinsically photosensitive retinal ganglion cells (ipRGCs) are more diverse than once believed, comprising five morphologically distinct types, M1 through M5. Here, in mouse retina, we provide the first in depth characterization of M4 cells, including their structure, function, and central projections. M4 cells apparently correspond to ON alpha cells of earlier reports, and are easily distinguished from other ipRGCs by their very large somata. Their dendritic arbors are more radiate and highly branched than those of M1, M2, or M3 cells. The melanopsin-based intrinsic photocurrents of M4 cells are smaller than those of M1 and M2 cells, presumably because melanopsin is more weakly expressed; we can detect it immunohistochemically only with strong amplification. Like M2 cells, M4 cells exhibit robust, sustained, synaptically driven ON responses and dendritic stratification in the ON sublamina of the inner plexiform layer. However, their stratification patterns are subtly different, with M4 dendrites positioned just distal to those of M2 cells and just proximal to the ON cholinergic band. M4 receptive fields are large, with an ON center, antagonistic OFF surround and nonlinear spatial summation. Their synaptically driven photoresponses lack direction selectivity and show higher ultraviolet sensitivity in the ventral retina than in the dorsal retina, echoing the topographic gradient in S- and M-cone opsin expression. M4 cells are readily labeled by retrograde transport from the dorsal lateral geniculate nucleus and thus likely contribute to the pattern vision that persists in mice lacking functional rods and cones. PMID- 23015451 TI - Perceptual learning reconfigures the effects of visual adaptation. AB - Our sensory experiences over a range of different timescales shape our perception of the environment. Two particularly striking short-term forms of plasticity with manifestly different time courses and perceptual consequences are those caused by visual adaptation and perceptual learning. Although conventionally treated as distinct forms of experience-dependent plasticity, their neural mechanisms and perceptual consequences have become increasingly blurred, raising the possibility that they might interact. To optimize our chances of finding a functionally meaningful interaction between learning and adaptation, we examined in humans the perceptual consequences of learning a fine discrimination task while adapting the neurons that carry most information for performing this task. Learning improved discriminative accuracy to a level that ultimately surpassed that in an unadapted state. This remarkable improvement came at a price: adapting directions that before learning had little effect elevated discrimination thresholds afterward. The improvements in discriminative accuracy grew quickly and surpassed unadapted levels within the first few training sessions, whereas the deterioration in discriminative accuracy had a different time course. This learned reconfiguration of adapted discriminative accuracy occurred without a concomitant change to the characteristic perceptual biases induced by adaptation, suggesting that the system was still in an adapted state. Our results point to a functionally meaningful push-pull interaction between learning and adaptation in which a gain in sensitivity in one adapted state is balanced by a loss of sensitivity in other adapted states. PMID- 23015453 TI - Substitution with doxorubicin for daunorubicin during induction for high risk pediatric acute lymphoblastic leukemia results in increased toxicity. PMID- 23015452 TI - NKCC1 knockdown decreases neuron production through GABA(A)-regulated neural progenitor proliferation and delays dendrite development. AB - Signaling through GABA(A) receptors controls neural progenitor cell (NPC) development in vitro and is altered in schizophrenic and autistic individuals. However, the in vivo function of GABA(A) signaling on neural stem cell proliferation, and ultimately neurogenesis, remains unknown. To examine GABA(A) function in vivo, we electroporated plasmids encoding short-hairpin (sh) RNA against the Na-K-2Cl cotransporter NKCC1 (shNKCC1) in NPCs of the neonatal subventricular zone in mice to reduce GABA(A)-induced depolarization. Reduced GABA(A) depolarization identified by a loss of GABA(A)-induced calcium responses in most electroporated NPCs led to a 70% decrease in the number of proliferative Ki67(+) NPCs and a 60% reduction in newborn neuron density. Premature loss of GABA(A) depolarization in newborn neurons resulted in truncated dendritic arborization at the time of synaptic integration. However, by 6 weeks the dendritic tree had partially recovered and displayed a small, albeit significant, decrease in dendritic complexity but not total dendritic length. To further examine GABA(A) function on NPCs, we treated animals with a GABA(A) allosteric agonist, pentobarbital. Enhancement of GABA(A) activity in NPCs increased the number of proliferative NPCs by 60%. Combining shNKCC1 and pentobarbital prevented the shNKCC1 and the pentobarbital effects on NPC proliferation, suggesting that these manipulations affected NPCs through GABA(A) receptors. Thus, dysregulation in GABA(A) depolarizing activity delayed dendritic development and reduced NPC proliferation resulting in decreased neuronal density. PMID- 23015454 TI - Two new triterpenoid saponins from Pittosporum senacia Putterlick (Pittosporaceae). AB - From the branches of Pittosporum senacia Putterlick (Pittosporaceae), two new triterpenoid saponins, senaciapittosides A and B (1, 2), were isolated. Their structures were elucidated by extensive analysis of one- and two-dimensional nuclear magnetic resonance spectroscopy, high-resolution electrospray ionization mass spectrometry (HR-ESIMS) and chemical evidence as 3-O-[beta-D-glucopyranosyl (1 -> 2)]-[alpha-L-arabinopyranosyl-(1 -> 3)]-[alpha-L-arabinofuranosyl-(1 -> 4)] beta-D-glucuronopyranosyl oleanolic acid 28-O-beta-D-glucopyranosyl ester (1) and 3-O-[beta-D-glucopyranosyl-(1 -> 2)]-[alpha-L-arabinopyranosyl-(1 -> 3)]-[alpha-L arabinofuranosyl-(1 -> 4)]-beta-D-glucuronopyranosyl-22-O-alpha-L arabinopyranosyl-21-acetoxy R1-barrigenol (2). Compound 2 presents an unusual glycosylation at C-22 of its aglycone. PMID- 23015455 TI - Congruent responses to weather variability in high arctic herbivores. AB - Assessing the role of weather in the dynamics of wildlife populations is a pressing task in the face of rapid environmental change. Rodents and ruminants are abundant herbivore species in most Arctic ecosystems, many of which are experiencing particularly rapid climate change. Their different life-history characteristics, with the exception of their trophic position, suggest that they should show different responses to environmental variation. Here we show that the only mammalian herbivores on the Arctic islands of Svalbard, reindeer (Rangifer tarandus) and sibling voles (Microtus levis), exhibit strong synchrony in population parameters. This synchrony is due to rain-on-snow events that cause ground ice and demonstrates that climate impacts can be similarly integrated and expressed in species with highly contrasting life histories. The finding suggests that responses of wildlife populations to climate variability and change might be more consistent in Polar regions than elsewhere owing to the strength of the climate impact and the simplicity of the ecosystem. PMID- 23015456 TI - Experimental evolution of multicellularity using microbial pseudo-organisms. AB - In a major evolutionary transition to a new level of organization, internal conflicts must be controlled before the transition can truly be successful. One such transition is that from single cells to multicellularity. Conflicts among cells in multicellular organisms can be greatly reduced if they consist of genetically identical clones. However, mutations to cheaters that experience one round of within-individual selection could still be a problem, particularly for certain life cycles. We propose an experimental evolution method to investigate this issue, using micro-organisms to construct multicellular pseudo-organisms, which can be evolved under different artificial life cycles. These experiments can be used to test the importance of various life cycle features in maintaining cooperation. They include structured reproduction, in which small propagule size reduces within-individual genetic variation. They also include structured growth, which increases local relatedness within individual bodies. Our method provides a novel way to test how different life cycles favour cooperation, even for life cycles that do not exist. PMID- 23015457 TI - Reproductive effects on skeletal health in Shuar women of Amazonian Ecuador: a life history perspective. AB - OBJECTIVE: Clinical and epidemiological research suggest that bone mineral density (BMD) in women is shaped by various reproductive factors such as parity and lactation patterns. However, the extent of these effects on BMD remains unclear because of contradictory findings and a focus on industrialized populations. Because fertility patterns in these groups are vastly different than those of women from non-Western, subsistence populations, our current understanding of the reproductive effects on skeletal health is incomplete. Using a life history perspective, this study examines the relationship between reproductive factors and bone density among women from the Indigenous Shuar population, an Amazonian Ecuadorian forager-horticulturalist group. METHODS: This preliminary, cross-sectional study included 130 premenopausal and postmenopausal women (14-86 years old) from the Morona-Santiago region of Ecuador. Anthropometrics were recorded, as was estimated BMD using a calcaneal ultrasonometer. A reproductive history questionnaire was administered that included questions regarding menarche, parity, lactation patterns, and menopause. RESULTS: Among postmenopausal women, early menarche and greater stature were significantly associated with higher bone density values. Among premenopausal women, few significant relationships between bone values and reproductive variables were documented; effects of lactation appeared to be transient and restored following weaning. CONCLUSIONS: Although preliminary and not based on longitudinal data, these findings suggest that the effects of reproduction are transient as the system of calcium homeostasis in premenopausal women efficiently restores the bone loss that results from metabolically active reproductive states. Further, this research suggests that the timing of early life history events may canalize bone density phenotype. PMID- 23015458 TI - Ribosomal protein S6 phosphorylation is associated with epithelial dysplasia and squamous cell carcinoma of the oral cavity. AB - Ribosomal protein S6 (RPS6), a downstream effector of the mammalian target of rapamycin pathway (mTOR), is activated in many cancers including oral squamous cell carcinoma (OSCC). However, the role of RPS6 in the progression of potentially malignant disorders (or premalignant lesions) to OSCC is unknown. The purpose of this study was to examine the expression of RPS6 in epithelial dysplasia and OSCC to determine the association of RPS6 in tumor progression. In our study, an immunohistochemical analysis of RPS6 was performed on tissue microarrays containing 30 control samples, 15 epithelial dysplasia cases, and 53 OSCC cases. Correlations between the clinicopathologic features of OSCC and RPS6 expression were analyzed using the Chi-square test. We found RPS6 phosphorylation (p-RPS6) in 15/30 (50 %) control normal oral mucosa samples, 15/15 (100 %) epithelial dysplasia cases, and 47/53 (88.68 %) OSCC cases. The frequency of p RPS6 in epithelial dysplasia or OSCC showed a statistically significant difference compared to control (P < 0.001). However, there were no significant correlations between p-RPS6 and the clinicopathologic features of OSCC. Our findings suggest that RPS6 activation is associated with the early events of tumor progression, suggesting p-RPS6 as a potential marker for early detection of oral cancer. PMID- 23015459 TI - Multielectron-transfer templates via consecutive two-electron transformations: iron-sulfur complexes relevant to biological enzymes. AB - [FeFe] hydrogenase mimics: two polynuclear iron-sulfur complexes (1 and 2) were prepared and structurally characterized. They are potentially effective and stable multielectron-transfer relays for mediating four- and six-electron transformations via a cascade of reversible two-electron redox steps with relatively narrow potential spans. PMID- 23015460 TI - The Korean version of the Connor-Davidson Resilience Scale: an extended validation. AB - The Connor-Davidson Resilience Scale (CD-RISC) is a brief self-rating questionnaire for measuring resilience. The aims of the present study were to describe the development of a Korean version of the CD-RISC (K-CD-RISC) and to more firmly establish its psychometric properties in terms of reliability and validity. The participants consisted of a general population sample (n=194) and psychiatric outpatients (n=127) with non-psychotic mood or anxiety disorders. The K-CD-RISC score means (standard deviation) were 65.9 (13.6) in the general population and 50.4 (20.5) in the psychiatric outpatients. The mean score of the general population was significantly higher than that of the psychiatric outpatients. Exploratory factor analysis revealed five factors, and the obtained factor structure was verified through confirmatory factor analysis. In the general population, the Cronbach's alpha coefficient of the K-CD-RISC was found to be 0.92. Greater resilience was found to be associated with less perceived stress, anxiety and depression and with higher levels of positive affect and purpose in life. Taken together, our findings suggest that the K-CD-RISC has good psychometric properties and is a valid and reliable tool for assessing resilience. PMID- 23015461 TI - Acute onset of ovarian dysfunction in young females after start of cancer treatment. AB - BACKGROUND: Female childhood cancer survivors are at risk of ovarian failure and premature ovarian insufficiency. We hereby present an interim analysis of a prospective observational study of ovarian function during cancer treatment of young females in relation to clinical factors. PROCEDURE: Thirty-four consecutive female cancer patients aged 0-18 year were included after informed consent. Serum/Plasma levels of anti-Mullerian hormone (AMH), inhibin B, FSH, LH, and oestradiol (E2) were measured at diagnosis and every 3-4 months during and after treatment. RESULTS: All patients had detectable AMH levels at diagnosis. Eleven patients had reached menarche (mean age 141/2 years) and the remaining patients had a mean age of 61/2 years. They all showed a rapid decline in AMH after 3 months of treatment, regardless of AMH at diagnosis, age, menarche, or treatment given. Those given radiotherapy below the diaphragm and/or stem cell transplantation (SCT) (n = 9) had no ovarian recovery during or 11/2-year after treatment. However, recovery was observed in those given standard treatment for acute lymphatic leukemia (n = 7) already during maintenance chemotherapy. For the remaining patients, longer follow-up is required for analysis of ovarian recovery after treatment. CONCLUSIONS: Rapid ovarian dysfunction is observed in all females after initiation of cancer treatment as measured by AMH and inhibin B. Our data regarding those who require abdominal radiotherapy and/or SCT confirms the recommendations in the Nordic countries where these patients are eligible for cryopreservation of ovarian cortical tissue before start of cancer treatment. PMID- 23015463 TI - Headspace-single drop microextraction with a commercial capillary electrophoresis instrument. AB - Automated coupling of headspace-single drop microextraction (HS-SDME) and CE has been demonstrated using a commercial CE instrument. When a drop hanging at the inlet tip of a capillary for CE is used as the acceptor phase, HS-SDME becomes a simple but powerful sample pretreatment technique for CE before injection to facilitate sample cleanup and enrichment. By combining HS-SDME with an on-line sample preconcentration technique, large volume sample stacking using an electroosmotic flow pump, the sensitivity can be improved further. The overall enrichment factors for phenolic compounds were from 1900 to 3400. HS-SDME large volume sample stacking using an electroosmotic flow pump was successfully applied to a red wine sample to obtain an LOD of 4 nM (0.8 ppb) for 2,4,6-trichlorophenol which is a precursor for 2,4,6-trichloroanisole causing the foul odor in wine called cork taint. PMID- 23015464 TI - Small-vessel disease in patients with Parkinson's disease: a clinicopathological study. AB - Few studies have examined the relationship between cerebrovascular disease, vascular risk factors, and Parkinson's disease (PD), although 1 study found small vessel disease (SVD) to be the main subtype of cerebrovascular disease. In this study we compared the extent and topography of SVD and assessed associated vascular risk factors in autopsy-proven PD cases and community-dwelling controls. Seventy-seven PD and 32 control brains from the Sydney Brain Bank were assessed microscopically by a single examiner blinded to the diagnosis. SVD was assessed by grading perivascular pallor, gliosis, hyaline thickening, and enlargement of perivascular spaces in the white matter underlying the superior frontal and primary motor cortices, basal ganglia, and white matter tracts. A history of vascular risk factors (hypertension, heart disease, diabetes, and cigarette smoking) was obtained. Groups were compared using stepwise multiple regression analysis. There was significantly greater frontal pallor (P = .004) and widening of perivascular spaces in the globus pallidus interna (P = .007) in controls compared with PD. Hyaline thickening and widening of perivascular spaces in the frontal white matter, hyaline thickening in the motor white matter, and widening of perivascular spaces in the caudate nucleus were more common in the control group, but did not reach significance. The prevalence of vascular risk factors and SVD pathology was significantly lower in autopsy-proven PD compared with controls (P = .03) living in the same community. The results of this study support the need for further research in this area. PMID- 23015465 TI - Preparation of graphene by using an intense cavitation field in a pressurized ultrasonic reactor. AB - A new and efficient method to produce a large quantity of high-quality and non oxidized graphene flakes from powdered natural graphite by using a high-intensity cavitation field in a pressurized ultrasonic reactor is demonstrated. TEM and selected-area electron diffraction (SAED) confirmed the ordered graphite crystal structure of graphene. Atomic force microscopy (AFM) was used to examine the thickness of the graphene sheets. The delamination (exfoliation) of natural graphite in the liquid phase depends on the physical effects of ultrasound, which break down the 3D graphite structure into a 2D graphene structure. The prepared graphene is of high purity and without defects because no strongly oxidizing chemicals are used and no toxic products result. TEM shows that graphene nanosheets were produced with sizes in the range of tens to hundreds of square nanometers; these nanosheets were smooth and without any ripples and corrugations. High-resolution TEM (HRTEM) and SAED analysis confirmed that the products were graphene nanosheets. PMID- 23015466 TI - Work-family conflict and job satisfaction: emotional intelligence as a moderator. AB - The negative impact of work-family conflict (WFC) on employees' well-being and job-related outcomes has attracted much research attention recently. A major gap in the literature is which factors could potentially buffer its negative effect on employees. The present study examined the moderating effect of emotional intelligence on the relationship between WFC and job satisfaction in a sample of 212 Chinese high school teachers. On the basis of conservation of resource theory, we hypothesized that emotional intelligence would weaken the negative effect of family-to-work and work-to-family interference on job satisfaction. Results suggested that WFC (work-to-family interference and family-to-work interference) was negatively related to job satisfaction and that emotional intelligence weakened the effect of WFC on job satisfaction. These findings provide implications for theories on WFC and emotional intelligence, such as conservation of resource theory. The current study also provides a test of these theories in Chinese culture to support the generalizability of theories developed in previous research. Practical implications for reducing the negative influence of WFC on employees' job satisfaction are also provided, such as the potential value of emotional intelligence for the training and development of employees in teaching professions. PMID- 23015467 TI - Relations frequency hypermatrices in mutual, conditional and joint entropy-based information indices. AB - Graph-theoretic matrix representations constitute the most popular and significant source of topological molecular descriptors (MDs). Recently, we have introduced a novel matrix representation, named the duplex relations frequency matrix, F, derived from the generalization of an incidence matrix whose row entries are connected subgraphs of a given molecular graph G. Using this matrix, a series of information indices (IFIs) were proposed. In this report, an extension of F is presented, introducing for the first time the concept of a hypermatrix in graph-theoretic chemistry. The hypermatrix representation explores the n-tuple participation frequencies of vertices in a set of connected subgraphs of G. In this study we, however, focus on triple and quadruple participation frequencies, generating triple and quadruple relations frequency matrices, respectively. The introduction of hypermatrices allows us to redefine the recently proposed MDs, that is, the mutual, conditional, and joint entropy-based IFIs, in a generalized way. These IFIs are implemented in GT-STAF (acronym for Graph Theoretical Thermodynamic STAte Functions), a new module of the TOMOCOMD CARDD program. Information theoretic-based variability analysis of the proposed IFIs suggests that the use of hypermatrices enhances the entropy and, hence, the variability of the previously proposed IFIs, especially the conditional and mutual entropy based IFIs. The predictive capacity of the proposed IFIs was evaluated by the analysis of the regression models, obtained for physico-chemical properties the partition coefficient (Log P) and the specific rate constant (Log K) of 34 derivatives of 2-furylethylene. The statistical parameters, for the best models obtained for these properties, were compared to those reported in the literature depicting better performance. This result suggests that the use of the hypermatrix-based approach, in the redefinition of the previously proposed IFIs, avails yet other valuable tools beneficial in QSPR studies and diversity analysis. PMID- 23015462 TI - Cardiac intercellular communication: are myocytes and fibroblasts fair-weather friends? AB - The cardiac fibroblast (CF) has historically been thought of as a quiescent cell of the heart, passively maintaining the extracellular environment for the cardiomyocytes (CM), the functional cardiac cell type. The increasingly appreciated role of the CF, however, extends well beyond matrix production, governing many aspects of cardiac function including cardiac electrophysiology and contractility. Importantly, its contributions to cardiac pathophysiology and pathologic remodeling have created a shift in the field's focus from the CM to the CF as a therapeutic target in the treatment of cardiac diseases. In response to cardiac injury, the CF undergoes a pathologic phenotypic transition into a myofibroblast, characterized by contractile smooth muscle proteins and upregulation of collagens, matrix proteins, and adhesion molecules. Further, the myofibroblast upregulates expression and secretion of a variety of pro inflammatory, profibrotic mediators, including cytokines, chemokines, and growth factors. These mediators act in both an autocrine fashion to further activate CFs, as well as in a paracrine manner on both CMs and circulating inflammatory cells to induce myocyte dysfunction and chronic inflammation, respectively. Together, cell-specific cytokine-induced effects exacerbate pathologic remodeling and progression to HF. A better understanding of this dynamic intercellular communication will lead to novel targets for the attenuation of cardiac remodeling. Current strategies aimed at targeting cytokines have been largely unsuccessful in clinical trials, lending insights into ways that such intercellular cross talk can be more effectively attenuated. This review will summarize the current knowledge regarding CF functions in the heart and will discuss the regulation and signaling behind CF-mediated cytokine production and function. We will then highlight clinical trials that have exploited cytokine cross talk in the treatment of heart failure and provide novel strategies currently under investigation that may more effectively target pathologic CF-CM communication for the treatment of cardiac disease. This review explores novel mechanisms to directly attenuate heart failure progression through inhibition of signaling downstream of pro-inflammatory cytokines that are elevated after cardiac injury. PMID- 23015469 TI - Author's reply: Chemotherapy during first trimester of pregnancy. PMID- 23015468 TI - How well does the body adiposity index capture adiposity change in midlife women?: The SWAN fat patterning study. AB - OBJECTIVES: The body adiposity index (BAI) is a proposed alternative to the body mass index (BMI) that has shown good cross-sectional agreement with percent body fat (%BF) in validation studies. The objective of this study was to examine the ability of BAI to track adiposity change over time in a biracial sample of midlife women. METHODS: African-American (n = 159) and Caucasian (n = 206) women, aged 42-60 years, at the Chicago site of the Study of Women's Health Across the Nation were followed from 2002 to 2008. BAI and BMI were calculated from measurements taken at annual assessments. %BF was quantified using whole-body dual-energy X-ray absorptiometry. Difference scores (BAI(Delta) , BMI(Delta) , and %BF(Delta) ) quantified adiposity change over a mean of 1.6 (SD = 0.7) years. Lin's concordance correlation (rho(c) ) and Bland-Altman limits-of-agreement assessed agreement between BAI and %BF. RESULTS: In examining adiposity change, BAI(Delta) showed poor agreement with %BF(Delta) in the overall sample (rho(c) = 0.41), African-American women (rho(c) = 0.36), and Caucasian women (rho(c) = 0.43). BAI(Delta) estimated %BF(Delta) with minimal bias (+0.4%) but low precision (+/-6.3%BF limits-of-agreement). %BF(Delta) had weaker correlations with BAI(Delta) (rs = 0.38-0.48) than with BMI(Delta) (rs = 0.48-0.59). BAI and BMI showed similar cross-sectional associations with %BF in the overall sample and within each race (rs > 0.74). CONCLUSIONS: We conclude that BAI is less accurate than BMI in tracking adiposity change in midlife women, and would not be a suitable replacement for BMI in most research applications involving adiposity change. PMID- 23015470 TI - Parental informed consent in pediatric cancer trials: a population-based survey in Germany. AB - BACKGROUND: Ensuring adequate parental consent is a key issue of ethical practice in pediatric oncology. In Germany, however, knowledge about parental comprehension and satisfaction with the informed consent procedure is limited, and representative data on parents' perspectives are still missing. Based on data collected by means of a population-based survey, we evaluated the parental recall of the informed consent process for pediatric clinical trials, and how they rated the consent process retrospectively. PROCEDURE: A standardized survey was carried out among 1,465 parents whose children were first diagnosed in 2005 with a disease defined by ICCC-3 in the German Childhood Cancer Registry (response: 55.1%). The survey's primary objective was to assess how well parents were able to recall of the informed consent process. To evaluate the results, we set up a second survey among 581 parents who had given consent recently for their child's participation in a clinical trial (response: 53.5%). RESULTS: Approximately 81% of the parents in the population-based survey correctly remembered whether or not their child had been enrolled in a clinical trial or treated off-trial. The ability to recall accurately is significantly lower if the parents have a migration background or if their child was not a trial participant. However, parents who recalled the child's trial participation status incorrectly felt as adequately informed as parents who recalled it correctly. CONCLUSIONS: Our results identified weak points and vulnerable subgroups in the parental consent process in pediatric oncology in Germany. PMID- 23015472 TI - Validation of a treatment algorithm for major depression in an older Brazilian sample. AB - OBJECTIVE: The aim of this study was to investigate the effectiveness of a modified version of the Duke Somatic Algorithm Treatment for Geriatric Depression (STAGED) in a Brazilian sample of older patients with major depression. Besides, we aimed to investigate possible baseline predictive factors for remission in this sample. METHODS: Sixty-seven depressed individuals were treated according to STAGED over 24 weeks in a prospective cohort design with follow-up. All patients had criteria for major depression and were at least 60 years of age at baseline enrollment. RESULTS: During this follow-up, 56 patients could be classified in remitted or not remitted group, 42.85% reached remission, and 57.14% did not reach remission. These results are even better than those found in the original study, probably due to the lower baseline depression severity of our sample. When baseline characteristics were compared between remitted and not remitted groups, scores of Mini Mental State Examination and Cambridge Cognitive Examination (CAMCOG) were the only variables with statistical significant difference (p < 0.05) between groups. Logistic regression analysis was carried out to try to predict remission and statistical significance (p < 0.05) was found only for baseline MMSE scores. It may mean that patients with mixed cognitive disorders and mood disorders have a worse course of depression. CONCLUSIONS: This version of STAGED seems to be a useful strategy for treatment of depression in late life. Baseline general cognitive performance might be useful to predict remission of depression in older patients with mild to moderate depression. Further research with different population characteristics should be conducted in order to evaluate its usefulness and feasibility in different settings. PMID- 23015471 TI - Personal factors associated with smoking among marginalized and disadvantaged youth in Japan. A strong relationship between smoking and convenience store use. AB - BACKGROUND: A national survey in Japan reported that the prevalence of smoking among high school students has sharply decreased in recent years. However, the survey only considered students who attended regular high schools (RHSs), and Japan offers part-time high schools (PHSs) that are often attended by academically and socioeconomically disadvantaged youth. PURPOSE: Therefore, we examined the smoking prevalence and smoking-related factors among PHS students. METHOD: A self-administered questionnaire-based survey was conducted at six PHSs. The subjects included 540 enrolled students aged 15 to 18 years. The questionnaire included items on smoking status, smokers in the family, frequency of convenience store use, lifestyle behaviors, and health awareness. Logistic regression analysis was used to identify factors that were significantly associated with smoking. RESULTS: A total of 45.6 % of students had smoking experience, and 29.3 % were smokers. For males and females, the smoking prevalence was about 3 and 7-12 times higher, respectively, than that reported in the national survey. The factors found to be significantly associated with smoking included having a smoker in the family, experience with drinking alcohol, and using convenience store daily (odds ratio [OR] = 12.5) or sometimes (OR = 3.63). There was a significant dose-response relationship between smoking and convenience store use. CONCLUSION: The smoking prevalence among PHS students was remarkably higher than that among RHS students. These findings suggest that marginalized and disadvantaged youth should be targeted for tobacco control, and intervention is needed to protect youth from tobacco sales and advertising at convenience stores. PMID- 23015473 TI - Nitric oxide donor-based platinum complexes as potential anticancer agents. AB - Joining forces: Platinum complexes containing organic nitrate ligands were investigated as anticancer agents. The complexes, which were stable in aqueous solution, showed cytotoxicity that was superior to that of the corresponding parent compound (carboplatin), thus suggesting an interesting synergy between the ability of the nitrate-based ligands to release nitric oxide and the ability of the platinum moiety to inhibit DNA synthesis (see scheme). PMID- 23015474 TI - Exploring the energy landscapes of flexible molecular loops using higher dimensional continuation. AB - The conformational space of a flexible molecular loop includes the set of conformations fulfilling the geometric loop-closure constraints and its energy landscape can be seen as a scalar field defined on this implicit set. Higher dimensional continuation tools, recently developed in dynamical systems and also applied to robotics, provide efficient algorithms to trace out implicitly defined sets. This article describes these tools and applies them to obtain full descriptions of the energy landscapes of short molecular loops that, otherwise, can only be partially explored, mainly via sampling. Moreover, to deal with larger loops, this article exploits the higher-dimensional continuation tools to find local minima and minimum energy transition paths between them, without deviating from the loop-closure constraints. The proposed techniques are applied to previously studied molecules revealing the intricate structure of their energy landscapes. PMID- 23015475 TI - Transoral resection of pharyngeal cancer: summary of a National Cancer Institute Head and Neck Cancer Steering Committee Clinical Trials Planning Meeting, November 6-7, 2011, Arlington, Virginia. AB - Recent advances now permit resection of many pharyngeal tumors through the open mouth, an approach that can greatly reduce the morbidity of surgical exposure. These transoral techniques are being rapidly adopted by the surgical community and hold considerable promise. On November 6-7, 2011, the National Cancer Institute sponsored a Clinical Trials Planning Meeting to address how to further investigate the use of transoral surgery, both in the good prognosis human papillomavirus (HPV)-initiated oropharyngeal cancers, and in those with HPV unrelated disease. The proceedings of this meeting are summarized. PMID- 23015476 TI - Synthesis of biologically active and photostable rigid poly(vinyl chloride). AB - N,N-Dimethyl-N'-(6-oxo-2-thioxo-1H-pyrimidine-4-yl)formamidine has been synthesized and introduced as a substituent in poly(vinyl chloride) (PVC) chains via a chemical reaction. Both the dimethyl derivative and the modified PVC have been characterized via spectroscopic analyses and their biological activities have been evaluated. Both IR and (1) H NMR spectral data confirm the incorporation of the newly prepared bioactive dimethyl pyrimidine derivative in the polymeric chains. The dimethyl pyrimidine derivative has exhibited good antibacterial and antifungal activities. The modified PVC shows higher antibacterial effects than that of the blank one. Photostabilizing efficiency of the modified PVC is determined by measuring the changes that occurred in the molecular weights of modified PVC samples after UV irradiation using the gel permeation chromatography technique. The extent of discoloration of the photodegraded modified PVC samples has also been measured. The results have been compared with that of the blank PVC and that of the PVC stabilized with phenyl salicylate as a reference UV absorber. The lower decrease in the values of weight average molecular weight, M(w) , at the first stages of UV irradiation and the absence of crosslinking at the latter stages of irradiation confirms the photostability of the modified PVC. The extent of discoloration of the modified sample is also decreased when compared with the blank and stabilized PVC samples. PMID- 23015477 TI - Development of a relational database to capture and merge clinical history with the quantitative results of radionuclide renography. AB - Our objective was to design and implement a clinical history database capable of linking to our database of quantitative results from (99m)Tc mercaptoacetyltriglycine (MAG3) renal scans and export a data summary for physicians or our software decision support system. METHODS: For database development, we used a commercial program. Additional software was developed in Interactive Data Language. MAG3 studies were processed using an in-house enhancement of a commercial program. The relational database has 3 parts: a list of all renal scans (the RENAL database), a set of patients with quantitative processing results (the Q2 database), and a subset of patients from Q2 containing clinical data manually transcribed from the hospital information system (the CLINICAL database). To test interobserver variability, a second physician transcriber reviewed 50 randomly selected patients in the hospital information system and tabulated 2 clinical data items: hydronephrosis and presence of a current stent. The CLINICAL database was developed in stages and contains 342 fields comprising demographic information, clinical history, and findings from up to 11 radiologic procedures. A scripted algorithm is used to reliably match records present in both Q2 and CLINICAL. An Interactive Data Language program then combines data from the 2 databases into an XML (extensible markup language) file for use by the decision support system. A text file is constructed and saved for review by physicians. RESULTS: RENAL contains 2,222 records, Q2 contains 456 records, and CLINICAL contains 152 records. The interobserver variability testing found a 95% match between the 2 observers for presence or absence of ureteral stent (kappa = 0.52), a 75% match for hydronephrosis based on narrative summaries of hospitalizations and clinical visits (kappa = 0.41), and a 92% match for hydronephrosis based on the imaging report (kappa = 0.84). CONCLUSION: We have developed a relational database system to integrate the quantitative results of MAG3 image processing with clinical records obtained from the hospital information system. We also have developed a methodology for formatting clinical history for review by physicians and export to a decision support system. We identified several pitfalls, including the fact that important textual information extracted from the hospital information system by knowledgeable transcribers can show substantial interobserver variation, particularly when record retrieval is based on the narrative clinical records. PMID- 23015478 TI - Sarcoidlike reaction of neoplasia causing hypermetabolic thoracic adenopathy in setting of extrathoracic malignancy: report of two cases and a review of the differential diagnostic considerations. AB - The development of noncaseating granulomas in a patient with underlying malignancy and no symptoms or signs suggestive of systemic sarcoid is often referred to as a sarcoidlike reaction and is estimated to occur in a small but significant portion of cancer patients. The pathogenesis is poorly understood, but the entity is hypothesized to be an immune phenomenon representing a host defense mechanism against the spread of tumor cells. Sarcoidlike reactions can occur at any time from the time of diagnosis to several years afterward and may occur in lymph nodes draining a malignant tumor, in the tumor itself, and even in nonregional tissues. Like sarcoid, sarcoidlike reactions of neoplasia can demonstrate hypermetabolic lymph nodes on (18)F-FDG PET imaging and thus be readily confused with metastatic disease. We describe 2 cases of a sarcoidlike reaction of neoplasia presenting as hypermetabolic thoracic lymph nodes on (18)F FDG PET/CT obtained for follow-up of extrathoracic malignancies: one a 73-y-old woman with a history of stage III head and neck squamous cell carcinoma and the other a 34-y-old woman with recurrent giant cell tumor of the sacrum. In both instances, the differential diagnosis for the finding of hypermetabolic thoracic lymph nodes included the possibility of a sarcoidlike reaction, though tissue sampling was pursued to exclude the more worrisome presence of metastatic disease or, less likely, a new primary malignancy. We review the topic of sarcoidlike reactions of neoplasia as well as the analytic approach to hypermetabolic mediastinal and hilar lymph nodes encountered on (18)F-FDG PET/CT. PMID- 23015479 TI - A new futility test approach in clinical interim data monitoring. AB - Sequential monitoring of efficacy and safety data has become a vital component of modern clinical trials. It affords companies the opportunity to stop studies early in cases when it appears as if the primary objective will not be achieved or when there is clear evidence that the primary objective has already been met. This paper introduces a new concept of the backward conditional hypothesis test (BCHT) to evaluate clinical trial success. Unlike the regular conditional power approach that relies on the probability that the final study result will be statistically significant based on the current interim look, the BCHT was constructed based on the hypothesis test framework. The framework comprises a significant test level as opposed to the arbitrary fixed futility index utilized in the conditional power method. Additionally, the BCHT has proven to be a uniformly most powerful test. Noteworthy features of the BCHT method compared with the conditional power method will be presented. PMID- 23015481 TI - A generalized procedure for calibrated MRI incorporating hyperoxia and hypercapnia. AB - Calibrated MRI techniques use the changes in cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) signal evoked by a respiratory manipulation to extrapolate the total BOLD signal attributable to deoxyhemoglobin at rest (M). This parameter can then be used to estimate changes in the cerebral metabolic rate of oxygen consumption (CMRO(2)) based on task-induced BOLD and CBF signals. Different approaches have been described previously, including addition of inspired CO(2) (hypercapnia) or supplemental O(2) (hyperoxia). We present here a generalized BOLD signal model that reduces under appropriate conditions to previous models derived for hypercapnia or hyperoxia alone, and is suitable for use during hybrid breathing manipulations including simultaneous hypercapnia and hyperoxia. This new approach yields robust and accurate M maps, in turn allowing more reliable estimation of CMRO(2) changes evoked during a visual task. The generalized model is valid for arbitrary flow changes during hyperoxia, thus benefiting from the larger total oxygenation changes produced by increased blood O(2) content from hyperoxia combined with increases in flow from hypercapnia. This in turn reduces the degree of extrapolation required to estimate M. The new procedure yielded M estimates that were generally higher (7.6 +/- 2.6) than those obtained through hypercapnia (5.6 +/- 1.8) or hyperoxia alone (4.5 +/- 1.5) in visual areas. These M values and their spatial distribution represent a more accurate and robust depiction of the underlying distribution of tissue deoxyhemoglobin at rest, resulting in more accurate estimates of evoked CMRO(2) changes. PMID- 23015480 TI - A stringent preemptive protocol reduces cytomegalovirus disease in the first 6 months after kidney transplantation. AB - BACKGROUND: The optimal strategy to prevent cytomegalovirus (CMV) disease after kidney transplantation continues to be open to debate. The preemptive approach requires regular determination of CMV viremia and prompt initiation of therapy. METHODS: We retrospectively compared the incidence of CMV disease during two periods at our center: A first phase (P1, n = 84 kidney recipients), during which time the intensity of surveillance was determined by the responsible physician, was compared to a second phase (P2, n = 74), when a stringent protocol of CMV surveillance was required for all patients. The preemptive approach was applied for all CMV risk groups; prophylaxis was optional in the case of treatment for rejection or delayed graft function in the intermediate- and high-risk group. Follow-up was truncated at 6 months after transplant surgery. CMV syndrome was differentiated from asymptomatic replication by the presence of at least one systemic symptom, while diagnosis of CMV end-organ disease required histological confirmation. RESULTS: Immunosuppression was similar in the two periods. CMV prophylaxis was used equally (26 %) in both periods. The probability for asymptomatic viremia episodes was not different for patients in P1 and P2 regardless of the prevention strategy. For patients following the preemptive strategy, the probability for CMV disease was increased during P1 (p = 0.016), despite fewer PCR assays being performed in phase 2. Protocol violations were only observed during P1. CONCLUSIONS: The probability of CMV disease episodes (CMV syndrome and CMV end-organ disease) was substantially reduced using a very stringent protocol. This study highlights the crucial importance of a stringent protocol with optimal adherence by all caregivers if the preemptive strategy is to be successful. PMID- 23015482 TI - Core-shell designed scaffolds of alginate/alpha-tricalcium phosphate for the loading and delivery of biological proteins. AB - Development of scaffolds to load and deliver therapeutic molecules like growth factors greatly enhances tissue regenerative capacity. Here, we report the core shell design of fibrous scaffolds made of alginate and alpha-tricalcium phosphate (Alg/alpha-TCP) for in situ protein loading and controllable delivery. Direct deposition of Alg/alpha-TCP solution through designed coconcentric nozzle in CaCl(2) bath allowed the generation of fibrous scaffolds. Through the process, in situ protein loading was possible and the core and shell composition was controlled. Feasibility of the designed scaffolds in loading and release of biological model protein cytochrome C (cyt C) was investigated. Scaffolding formed in CaCl(2) led to a considerable loss of cyt C in a crosslinking time dependent manner, and the change in hardening conditions (Alg concentration, CaCl(2) concentration, and Alg/alpha-TCP ratio) was not as effective in reducing the protein loss. Subsequent release of cyt C from Alg scaffolds displayed a marked initial burst depending on crosslinking conditions, and shortening crosslinking time and decreasing CaCl(2) concentration lowered the initial burst. The alpha-TCP addition (up to 75%) resulted in more continual and sustainable release patterns. Composition change (alpha-TCP content) in core or shell significantly altered the release profiles, suggesting the possible designing core-shell configuration for target release patterns, such as dual-protein delivery. Additionally, the alpha-TCP incorporation significantly increased the mechanical stiffness to values much closer to those of hard tissues. Results indicate that coaxial deposited alpha-TCP/Alg fibrous scaffolds may be useful for designing proper growth factor delivery systems in hard tissue engineering. PMID- 23015483 TI - Theoretical description of dihydrogen/hydride and trihydride molybdocene complexes: an insight from static and molecular dynamics simulations. AB - In this study ab initio Car-Parrinello molecular dynamics simulations, extended transition state (ETS)-natural orbitals for chemical valence (NOCV) and QTAIM bonding analyses, were performed to characterize the ansa-bridged molybdocene complexes [(C(5)H(4))(2)XMe(2)MoH(3)](+) for X = C, Si, Ge, Sn, Pb, and nonbridged Cp(2)MoH(3)(+) system. The results have shown that the [(C(5)H(4))(2)CMe(2)MoH(H(2))](+) complex exhibits nonclassical dihydrogen/hydride (H(2)/H) conformation (97.6% of time of simulation), contrary to trihydride (H(3)) structure noted for nonbridged Cp(2)MoH(3)(+) (86.9%) and ansa-bridged [(C(5)H(4))(2)SnMe(2)MoH(3)](+) (84.8%), [(C(5) H(4))(2)PbMe(2)MoH(3)](+) (84.9%) systems. Further, [(C(5)H(4))(2)SiMe(2)MoH(3)](+) and [(C(5)H(4))(2)GeMe(2)MoH(3)](+) complexes, appeared to exist in both conformations (H(2)/H--55.4%, H(3)--44.6% for Si-based system and H(2)/H--36.2%, H(3)--63.8 % for germanium congener). It has been proven that the "steric availability" of the metal center, measured by the changes in the Cp-Mo-Cp angle (alpha), determines the existence of a given conformation--namely, the smaller value of the angle (molybdenum is sterically more accessible) the larger preference for the formation of dihydrogen/hydride structure. ETS-NOCV method allowed to conclude that increase in the Cp-Mo-Cp angle (from alpha ca. 120 degrees to alpha ca. 150 degrees ) leads to the enhancement of donation from H(2) and back-donation from Mo to the sigma*(H-H), what consequently leads to breaking of the H-H bond and formation of the trihydride structure. Systematical increase in the charge depletion from the sigma-bonding orbital of H(2) can be related to the reduction of the energy gap between the major orbitals involved in this contribution, namely highest occupied molecular orbital (HOMO) of H(2) with lowest unoccupied molecular orbital (LUMO) of [MoHL](+); DeltaE = 0.0868 a.u. [for L =(C(5)H(4))(2)C], DeltaE = 0.0827a.u. [for L = (C(5)H(4))(2)Si] DeltaE = 0.0638 a.u. [for L = Cp(2)]. Further, the relatively low energetic barrier to hydrogen exchange (DeltaE(#) = 3.3 kcal/mol) for carbon-bridged complex, [(C(5)H(4))(2)CMe(2)MoH(c)(H(a)H(b))](+) -> [(C(5)H(4)) (2)CMe(2)MoH(a)(H(b)H(c))](+), is related to strengthening of the Mo H bonds when going from the substrate to the transition state (TS). Notably higher barrier to hydrogen rotation (DeltaE(#) = 10.1 kcal/mol) in [(C(5)H(4))(2) CMe(2)MoH(H(2))](+) is due to lowering in the electrostatic stabilization as well as weakening of the donation (H(2) -> Mo charge transfer) and practically lack-of back-donation (Mo -> H(2)) in the rotated TS. PMID- 23015484 TI - Helicobacter species methods and protocols. Introduction. AB - Helicobacter infection is a chronic persistent condition which is responsible for the majority of cases of gastric and duodenal ulcers, and gastric cancer. The study of the bacteria, the interaction of the bacteria with the host, and the host immune response has greatly benefited from standardization of culture techniques and animal models. The following chapters will describe the clinical aspects of infection and touch on the important techniques for optimal investigation of this infection. PMID- 23015485 TI - Helicobacter pylori: an overview. AB - Infection with Helicobacter pylori is directly responsible for substantial morbidity and mortality worldwide. This ubiquitous organism causes disease through the interaction of multiple factors including bacterial factors, host immune responses, and environmental factors. The following chapters address the bacterial specific contributions to disease. PMID- 23015486 TI - Perspectives on methodology for in vitro culture of Helicobacter pylori. AB - Over the past 25 years, a variety of methods have been developed for culture of Helicobacter pylori in vitro. H. pylori is a capnophilic and microaerophilic organism that is typically cultured using complex culture media. Analysis of H. pylori growth in chemically defined media has provided insight into the nutritional requirements, physiology, and metabolic capacities of this organism. PMID- 23015487 TI - Successful culture techniques for Helicobacter species: general culture techniques for Helicobacter pylori. AB - Half of the world's population is persistently infected with Helicobacter pylori. The chronicity of this infection ultimately elicits clinical manifestations ranging from gastritis and peptic ulcers to adenocarcinoma and MALT lymphoma. Laboratory research following the initial observations of Helicobacter species was greatly hindered by an inability to isolate and culture the bacteria. Thus, the ability to culture bacterial species from this genus is an extremely important step in expanding clinical knowledge and development of therapies. This chapter describes successful techniques for culturing H. pylori on selective horse blood agar media and in Brucella broth liquid media. Additionally, the specific growth requirements of other Helicobacter species are noted. PMID- 23015488 TI - Successful culture techniques for Helicobacter species: establishing H. pylori cultures from infected rodents. AB - This chapter describes protocols for establishing H. pylori cultures from infected rodents. PMID- 23015489 TI - Successful culture techniques for Helicobacter species: verification of Helicobacter identity using 16S rRNA gene sequence analysis. AB - This chapter describes protocols for the verification of putative Helicobacter species' identities using 16S rRNA gene sequence analysis. PMID- 23015491 TI - Genetic manipulation of a naturally competent bacterium, Helicobacter pylori. AB - Genetic manipulation of Helicobacter pylori facilitates characterization and functional analysis of individual H. pylori genes. This chapter discusses the methods involved in H. pylori chromosomal DNA isolation, mutagenesis of individual genes, and natural transformation. PMID- 23015490 TI - The Helicobacter pylori cag Pathogenicity Island. AB - The cag pathogenicity island is a well-characterized virulence determinant. It is composed of 32 genes that encode a type IV bacterial secretion system and is linked with a more severe clinical outcome. The following chapters will explore the manipulation of bacterial factors in order to understand their role in gastric mucosal disease. PMID- 23015492 TI - A method for short-term culture of human gastric epithelial cells to study the effects of Helicobacter pylori. AB - In vitro studies of Helicobacter pylori pathogenesis mostly rely on the use of tumor-derived cell lines. Although invaluable, tumor cell lines are not representative of the normal cell physiology. Thus, the use of primary gastric epithelial cell cultures provides an important tool for investigating the mechanisms underlying H. pylori infection, as well as for validating the in vitro findings obtained with tumor-derived cell line models. Here we describe a method for isolation and short-term culture of human primary gastric epithelial cells obtained from gastric biopsy specimens, and the use of these cells to evaluate the effect of H. pylori on the junctional adhesion molecule-A protein. PMID- 23015493 TI - Cell culture-based assays to test for bacterial adherence and internalization. AB - Adherence and internalization of Helicobacter pylori into epithelial cells is a recently recognized event in the pathogen's life cycle. PMID- 23015494 TI - Cell culture assays to evaluate bacterial toxicity and virulence. AB - Helicobacter pylori CagA and VacA are two critical virulence factors that modulate disease severity in the infected host. The following chapter outlines methods employed to study the effects of these virulence factors on several key signaling pathways in epithelial cells. PMID- 23015496 TI - Bacterial culture and inoculation of mice (simple infection). AB - Standardization of bacterial culture is crucial for in vivo experiments addressing Helicobacter/host -interaction. Here we present methods for bacteria culture and infection of mice. PMID- 23015495 TI - Rodent models of Helicobacter infection, inflammation, and disease. AB - Animal models are essential for in vivo analysis of Helicobacter-related diseases. Transgenic mice and Mongolian gerbil models have been the corner stone of present research focusing on both bacterial virulence factors and host response to infection. Establishing a reproducible rodent model of persistent Helicobacter pylori infection that resembles the H. pylori-associated gastritis observed in humans was a considerable challenge until Lee et al. (Gastroenterology 112:1386-1397, 1997) successfully adapted a clinical Cag A- and Vac A-expressing strain for the mouse stomach. This so-called SS1 (Sydney) strain has since been extensively used for H. pylori research; other rodent-adapted Helicobacter strains have subsequently been developed and utilized in wild-type and genetically engineered rodent models. These bacteria include both H. pylori and the larger but related species H. felis (originally isolated from cats). In this chapter we focus mainly on these two Helicobacter strains and review the rodent models that have been employed to investigate how Helicobacter species induce gastric inflammation and disease. PMID- 23015497 TI - Adoptive transfer of splenocytes to immunocompromised mice. AB - Analysis of the immune response of mice to Helicobacter infection has been greatly aided by the use of various deficient mouse strains. Here we present protocols for reconstitution of immune-deficient mice with wild-type immune cells and protocols for analysis of the outcome. PMID- 23015498 TI - Isolation of gastric lamina propria leukocytes. AB - Immune cells recruited to the infected gastric mucosa can be isolated and used for a variety of purposes. Here we describe methods for the isolation and characterization of gastric lamina propria leukocytes. PMID- 23015499 TI - Delayed-type hypersensitivity determination. AB - Delayed-type hypersensitivity responses in the skin (in the case of mice, in the foot pad) is used to assess cell-mediated immunity (CMI) in vivo. In the case of CMI to Helicobacter infection, the mice are given an injection of cultured Helicobacter organisms into the hind footpad, and induration is measured at the site of inoculation 24 h after inoculation. Here we describe the methods for assessing delayed-type hypersensitivity in the mouse. PMID- 23015500 TI - Necropsy, blood, tissue collection, and mRNA isolation for detection of host cytokine gene expression. AB - Processing of tissue and blood must be done in a systematic and controlled fashion in order to optimize results and allow comparison of samples between experiments and between laboratories. Here we present our protocols for blood and tissue processing. PMID- 23015501 TI - Animal models of Helicobacter-induced disease: methods to successfully infect the mouse. AB - Animal models of microbial diseases in humans are an essential component for determining fulfillment of Koch's postulates and determining how the organism causes disease, host response(s), disease prevention, and treatment. In the case of Helicobacter pylori, establishing an animal model to fulfill Koch's postulates initially proved so challenging that out of frustration a human volunteer undertook an experiment to become infected with H. pylori and to monitor disease progression in order to determine if it did cause gastritis. For the discovery of the organism and his fulfillment of Koch's postulates he and a colleague were awarded the Nobel Prize in Medicine. After H. pylori was established as a gastric pathogen, it took several years before a model was developed in mice, opening the study of the organism and its pathogenicity to the general scientific community. However, while the model is widely utilized, there are a number of difficulties that can arise and need to be overcome. The purpose of this chapter is to raise awareness regarding the problems, and to offer reliable protocols for successfully establishing the H. pylori mouse model. PMID- 23015503 TI - Mouse models of Helicobacter-induced gastric cancer: use of cocarcinogens. AB - The human pathogen Helicobacter pylori causes inflammation in the stomach of infected hosts, leading in some cases to the development of gastric cancer. Several mouse models have been developed to study Helicobacter-induced carcinogenesis with similarities to gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma (MALToma) in humans. These models require chronic infection of animals with mouse-colonizing isolates of H. pylori or with related gastric Helicobacter spp., such as the canine/feline species Helicobacter felis. Furthermore, consistent with the known influence of host and environmental factors in human gastric cancer, it is possible to manipulate the type and severity of gastric lesions in mouse Helicobacter infection models through the use of different mouse genetic backgrounds and/or by the administration of known cocarcinogens, such as alkylating agents (e.g., N-nitroso-N-methylurea), or even elevated quantities of dietary salt. Here, we describe protocols for the inoculation of mice with gastric Helicobacter spp. and the administration of these cocarcinogens. Furthermore, we will describe the various methodologies used to study gastric inflammation and carcinogenesis in Helicobacter-infected animals. PMID- 23015502 TI - Verifying and quantifying Helicobacter pylori infection status of research mice. AB - Mice used to model helicobacter gastritis should be screened by PCR prior to experimental dosing to confirm the absence of enterohepatic Helicobacter species (EHS) that colonize the cecum and colon of mice. Natural infections with EHS are common and impact of concurrent EHS infection on Helicobacter pylori-induced gastric pathology has been demonstrated.PCR of DNA isolated from gastric tissue is the most sensitive and efficient technique to confirm the H. pylori infection status of research mice after experimental dosing. To determine the level of colonization, quantitative PCR to estimate the equivalent colony-forming units of H. pylori per MUg of mouse DNA is less labor-intensive than limiting dilution culture methods. Culture recovery of H. pylori is a less sensitive technique due to its fastidious in vitro culture requirements; however, recovery of viable organisms confirms persistent colonization and allows for further molecular characterization of wild-type or mutant H. pylori strains. ELISA is useful to confirm PCR and culture results and to correlate pro- and anti-inflammatory host immune responses with lesion severity and cytokine gene or protein expression. Histologic assessment with a silver stain has a role in identifying gastric bacteria with spiral morphology consistent with H. pylori but is a relatively insensitive technique and lacks specificity. A variety of spiral bacteria colonizing the lower bowel of mice can be observed in the stomach, particularly if gastric atrophy develops, and these species are not morphologically distinct at the level of light microscopy either in the stomach or lower bowel. Other less commonly used techniques to localize H. pylori in tissues include immunohistochemistry using labeled polyclonal antisera or in situ hybridization for H. pylori rRNA. In this chapter, we will summarize strategies to allow initiation of experiments with helicobacter-free mice and then focus on PCR and ELISA techniques to verify and quantify H. pylori infection of research mice. PMID- 23015504 TI - Gastric Helicobacter spp. in animal models: pathogenesis and modulation by extragastric coinfections. AB - Animal models are used to study complex host, microbial, and environmental influences associated with gastric Helicobacter infection. Evidence that gastric helicobacters are pathogenic in animals first came from ferrets. Felids, nonhuman primates, and many other species also harbor stomach helicobacters. Today, mice are preferred by most researchers for scientific investigation because of cost efficiencies, rapid reproduction, choice of laboratory reagents, and availability of genetically engineered models. Infection with Helicobacter felis or H. pylori Sydney strain-1 in appropriate mouse strains produces disease with remarkable similarities to H. pylori in humans. Due to recent advances in genetic engineering, in vivo imaging, and system-wide genomics and proteomics, these models will become even more widespread in the future. Recently, it has been shown that extragastric infections can dramatically affect the severity of disease induced by gastric Helicobacter spp. through heterologous immunity. These models provide proof-of-principle for the "African enigma" wherein gastric cancer is underrepresented in low-lying tropical countries with concurrently high H. pylori and internal parasite prevalence. Helicobacter gastritis and carcinogenesis in mouse models may be augmented or ameliorated by other infectious agents depending on the character of the invoked immune response. Knowledge gained from the Human Microbiome Project and other investigations is certain to shed new light on the influence of extragastric bacterial, viral, fungal, and parasitic coinfections on H. pylori-associated peptic ulcer disease and gastric adenocarcinoma. PMID- 23015506 TI - Innate immune responses to Helicobacter pylori infection: an overview. AB - Innate immune receptors detect Helicobacter pylori infection and trigger downstream signaling events that result in the production of cytokines and interferon-beta. This chapter gives an overview of the receptors and their roles in responding to H. pylori infection and details the downstream signaling events. The tools that have been developed to study the innate immune response to H. pylori are also discussed. Understanding the immune response to H. pylori is critical to develop better treatments for H. pylori-induced disease states including gastric malignancies and cancer. PMID- 23015505 TI - Histologic scoring of gastritis and gastric cancer in mouse models. AB - Histopathology is a defining endpoint in mouse models of experimental gastritis and gastric adenocarcinoma. Presented here is an overview of the histology of gastritis and gastric cancer in mice experimentally infected with Helicobacter pylori or H. felis. A modular histopathologic scoring scheme is provided that incorporates relevant disease-associated changes. Whereas the guide uses Helicobacter infection as the prototype challenge, features may be applied to chemical and genetically engineered mouse models of stomach cancer as well. Specific criteria included in the combined gastric histologic activity index (HAI) include inflammation, epithelial defects, oxyntic atrophy, hyperplasia, pseudopyloric metaplasia, and dysplasia or neoplasia. Representative photomicrographs accompany descriptions for each lesion grade. Differentiation of genuine tumor invasion from pseudoinvasion is highlighted. A brief comparison of normal rodent versus human stomach anatomy and physiology is accompanied by an introduction to mouse-specific lesions including mucous metaplasia and eosinophilic droplets (hyalinosis). In conjunction with qualified pathology support, this guide is intended to assist research scientists, postdoctoral fellows, graduate students, and medical professionals from affiliated disciplines in the interpretation and histologic grading of chronic gastritis and gastric carcinoma in mouse models. PMID- 23015507 TI - Methods for in vivo and in vitro analysis of innate immune responses to Helicobacter pylori infection. AB - It is estimated that half of the world's population is infected by Helicobacter pylori (H. pylori) (Polk and Peek, Nat Rev Cancer 10:403-414, 2010; Peek et al., Physiol Rev 90:831-858, 2010). Following infection, H. pylori induces a chronic innate immune response that is thought to contribute to gastric complications. Due to the widespread prevalence of H. pylori, it is important to study the innate immune responses that result from the infection. A variety of in vitro and in vivo techniques have been developed by our laboratory to study this immune response (Fox et al., Am J Pathol 171:1520-1528, 2007; Kurt-Jones et al., Infect Immun 75:471-480, 2007; Kurt-Jones et al., J Endotoxin Res 10:419-424, 2004). These methods are described here. PMID- 23015508 TI - Techniques for following labeled cells in vivo: use of X/Y FISH, techniques to optimize fluorescent detection, and beta-galactosidase detection. AB - The redistribution and trafficking patterns of cells to different anatomic sites throughout the body is important during cancer development and metastasis. Interest in the origin and fate of gastric cancer stem cells has recently arisen, as it may explain the underlying mechanism of cancer development. The ability to monitor the migration patterns of cancer stem cells is imperative to understanding the functional changes associated with the migration and proliferation of these cells. Here we detail a collection of techniques that include fluorescent in vivo imaging, X/Y FISH, and beta-galactosidase detection that are used for following labeled cells in vivo after adoptive transfer or transplant of donor cells for identifying the migration and engraftment of donor cells within the recipient. PMID- 23015509 TI - In vivo measurement of Helicobacter pylori infection. AB - Helicobacter pylori is a well-recognized gastroduodenal pathogen (National Institute of Health Consensus Conference, JAMA 272:65-9, 1994) and a class I carcinogen (International Agency for Research on Cancer, IARC Monograph on the Evaluation of Carcinogenic Risk to Humans 61:177-240, 1994) which successfully colonizes the harsh acidic environment of the stomach. H. pylori is the causative factor for peptic ulcer disease (PUD) and an independent risk factor for gastric adenocarcinoma development. Therefore, accurate detection of infection is crucial for devising proper eradication regimens and preventing the more severe GI complications.Detection of H. pylori in the gastric mucosa can be performed via (1) direct detection of the bacterium; culture, histology and polymerase chain reaction (PCR) or (2) indirect detection of its enzymatic products particularly urease as well as serum H. pylori-specific antibody responses, which can be detected by rapid urease test (RUT) and serology, respectively.The accuracy of these diagnostic tests is reported as follows: 98.1% for bacterial culture, 98.1% for histology, 94.3% for PCR, 96.2% for RUT, and 84.9% for serology (Ni et al, J Pediatr 136(6):823-7, 2000). PMID- 23015510 TI - Public perception of birth defects terminology. AB - BACKGROUND: 'Birth defect' is a common phrase, yet concerns have been expressed that the word 'defect' carries a negative connotation. Our objective was to examine public perceptions of terms used to refer to birth defects. METHODS: Four questions about terminology of birth defects were included in the U.S. nationally representative 2007 HealthStyles survey. Respondents answered questions about whether they or a family member were affected by birth defects (condition status), and which terms used to refer to birth defects they found preferable and which offensive. We further examined whether condition status, race/ethnicity, gender, income, geographical region, and education level impacted respondents' term selection. Chi-square tests and multinomial logistic regression were performed using SAS 9.1. RESULTS: 'Birth defects' was most frequently selected as the first choice preferred term (35.4%), followed by 21.9% who selected 'children with special needs. ' For respondents who said they themselves or a family member were affected by birth defects (11.5%), their responses differed statistically (p <= 0.0001) from nonaffected respondents, but the leading choices were still 'birth defects' (28.5%) and 'children with special needs' (27.2%). Condition status, race/ethnicity, gender, income, and education level were all significant predictors of the respondents' choice of a preferred term. When asked which phrases might be offensive, the top choices were 'none of the phrases listed' (37.0%), 'adverse pregnancy outcomes' (23.1%), and 'birth defects' (21.4%). CONCLUSIONS: 'Birth defect' was the preferred term; however, survey participants affected by birth defects responded less positively to the term. Continued dialogue about accepted and appropriate terminology is necessary. PMID- 23015511 TI - Metal-free arylation of oxygen nucleophiles with diaryliodonium salts. AB - Phenols and carboxylic acids are efficiently arylated with diaryliodonium salts. The reaction conditions are mild, metal free, and avoid the use of halogenated solvents, additives, and excess reagents. The products are obtained in good-to excellent yields after short reaction times. Steric hindrance is very well tolerated, both in the nucleophile and diaryliodonium salt. The scope includes ortho- and halo-substituted products, which are difficult to obtain by metal catalyzed protocols. Many functional groups are tolerated, including carbonyl groups, heteroatoms, and alkenes. Unsymmetric salts can be chemoselectively utilized to obtain products with hitherto unreported levels of steric congestion. The arylation has been extended to sulfonic acids, which can be converted to sulfonate esters by two different approaches. With recent advances in efficient synthetic procedures for diaryliodonium salts the reagents are now inexpensive and readily available. The iodoarene byproduct formed from the iodonium reagent can be recovered quantitatively and used to regenerate the diaryliodonium salt, which improves the atom economy. PMID- 23015513 TI - Increasing prevalence of comorbidity in patients with colorectal cancer in the South of the Netherlands 1995-2010. AB - Comorbidity has large impact on colorectal cancer (CRC) treatment and outcomes and may increase as the population ages. We aimed to evaluate the prevalence and time trends of comorbid diseases in patients with CRC from 1995 to 2010. The Eindhoven Cancer Registry registers comorbidity in all patients with primary CRC in the South of the Netherlands. We analyzed the prevalence of serious comorbid diseases in four time frames from 1995 to 2010. Thereby, we addressed its association with age, gender and socio-economic status (SES). The prevalence of comorbidity was registered in 27,339 patients with primary CRC. During the study period, the prevalence of comorbidity increased from 47% to 62%, multimorbidity increased from 20% to 37%. Hypertension and cardiovascular diseases were most prevalent and increased largely over time (respectively 16-29% and 12-24%). Pulmonary diseases increased in women, but remained stable in men. Average age at diagnosis increased from 68.3 to 69.5 years (p = 0.004). A low SES and male gender were associated with a higher risk of comorbidity (not changing over time). This study indicates that comorbidity among patients with CRC is common, especially in males and patients with a low SES. The prevalence of comorbidity increased from 1995 to 2010, in particular in presumably nutritional diseases. Ageing, increased life expectancy and life style changes may contribute to more comorbid diseases. Also, improved awareness among health care providers on the importance of comorbidity may have resulted in better registration. The increasing burden of comorbidity in patients with CRC emphasizes the need for more focus on individualized medicine. PMID- 23015514 TI - Copolymer cell/scaffold constructs for bone tissue engineering: co-culture of low ratios of human endothelial and osteoblast-like cells in a dynamic culture system. AB - The aim of this study was to compare the effect of different ratios of human umbilical vein endothelial cells (HUVECs) on osteogenic activity of human osteoblast-like cells (HOB) and capillary-like structure (CLS), seeded into copolymer scaffolds in a dynamic culture system. HOB and HUVEC were co-cultured into poly(L-lactide)-co-(1,5-dioxepan-2-one) [poly(LLA-co-DXO)] scaffolds at ratios of 5:1 (5:1 group) and 2:1 (2:1 group). Samples were collected after 5, 15, and 25 days. Cross-sections were processed and the CLS from HUVEC was disclosed in both groups. Cell viability was determined by dsDNA assay. Cells seeded at the ratio of 5:1 had good viability. Total RNA was isolated and the reverse transcription reaction was performed. The influences on the expression of several osteogenic genes were various with regarding to different ratios of HUVEC demonstrated by the PCR array. The RT-PCR results was in consistent with the PCR array results that several osteogenesis related genes had higher expression in the 5:1 group than in the 2:1 group, especially at day 25, such as alkaline phosphatase, insulin-like growth factor 1 (IGF1), and so forth. ELISA showed that the production of IGF1 after 25 days of incubation were higher in cells co cultured at the 5:1 ratio than at the 2:1 ratio. The results show that under dynamic culture conditions, co-culture of HOB with a low ratio of HUVEC in copolymer scaffolds results in CLS formation and significantly influenced the expression of osteogenic markers. PMID- 23015515 TI - Electric field assisted oxygen removal from the basal plane of the graphitic material. AB - We provide a novel strategy to eliminate the epoxy group from the basal plane of graphene platelets. Given that the current reduction methods are unsatisfactory to clean the epoxides or sometimes cause undesirable structure deformations, the proposed strategy restores the original hexagonal carbon network without creating other new defects. To the best of our knowledge, the electric field mediated graphene oxide (GO) reduction has not yet been systematically investigated. The capability would permit the improvement of existing GO reduction methods and assist in the fabrication of high-quality graphitic materials. PMID- 23015512 TI - Reduced fMRI activity predicts relapse in patients recovering from stimulant dependence. AB - Relapse presents a significant problem for patients recovering from stimulant dependence. Here we examined the hypothesis that patterns of brain function obtained at an early stage of abstinence differentiates patients who later relapse versus those who remain abstinent. Forty-five recently abstinent stimulant-dependent patients were tested using a randomized event-related functional MRI (ER-fMRI) design that was developed in order to replicate a previous ERP study of relapse using a selective attention task, and were then monitored until 6 months of verified abstinence or stimulant use occurred. SPM revealed smaller absolute blood oxygen level-dependent (BOLD) response amplitude in bilateral ventral posterior cingulate and right insular cortex in 23 patients positive for relapse to stimulant use compared with 22 who remained abstinent. ER fMRI, psychiatric, neuropsychological, demographic, personal and family history of drug use were compared in order to form predictive models. ER-fMRI was found to predict abstinence with higher accuracy than any other single measure obtained in this study. Logistic regression using fMRI amplitude in right posterior cingulate and insular cortex predicted abstinence with 77.8% accuracy, which increased to 89.9% accuracy when history of mania was included. Using 10-fold cross-validation, Bayesian logistic regression and multilayer perceptron algorithms provided the highest accuracy of 84.4%. These results, combined with previous studies, suggest that the functional organization of paralimbic brain regions including ventral anterior and posterior cingulate and right insula are related to patients' ability to maintain abstinence. Novel therapies designed to target these paralimbic regions identified using ER-fMRI may improve treatment outcome. PMID- 23015516 TI - A fully automated system for measuring cellular mechanical properties. AB - As a novel effective label-free biomarker, the mechanical properties of cells have become increasingly important. However, the current methods of mapping cellular mechanical properties are mostly carried out manually, resulting in measurements that are time-consuming with low efficiency. In this article, a fully automated system of measuring the mechanical properties of cells based on atomic force microscopy (AFM) is proposed. In this system, the cells are recognized using an image-processing method and the relative position of the cell, and the AFM tip is accurately calibrated by the local scan method, meaning that the mechanical properties of cells can be measured sequentially without performing the step of AFM imaging. In addition, with the implementation of the automation, the high-throughput measurement of cellular mechanical properties can be performed rapidly. The capability of our system is validated on Raji cells, and the results indicate that the measurement rate of our system is 26 times faster than that of the traditional manual method, providing the technology for high-throughput measurement of cellular mechanical properties. PMID- 23015517 TI - Cellular-level surgery using nano robots. AB - The atomic force microscope (AFM) is a popular instrument for studying the nano world. AFM is naturally suitable for imaging living samples and measuring mechanical properties. In this article, we propose a new concept of an AFM-based nano robot that can be applied for cellular-level surgery on living samples. The nano robot has multiple functions of imaging, manipulation, characterizing mechanical properties, and tracking. In addition, the technique of tip functionalization allows the nano robot the ability for precisely delivering a drug locally. Therefore, the nano robot can be used for conducting complicated nano surgery on living samples, such as cells and bacteria. Moreover, to provide a user-friendly interface, the software in this nano robot provides a "videolized" visual feedback for monitoring the dynamic changes on the sample surface. Both the operation of nano surgery and observation of the surgery results can be simultaneously achieved. This nano robot can be easily integrated with extra modules that have the potential applications of characterizing other properties of samples such as local conductance and capacitance. PMID- 23015518 TI - Silicon nanosensor for diagnosis of cardiovascular proteomic markers. AB - A silicon nanosensor technology based on electrical impedance measurements has been developed for the detection of proteins. The nanosensor miniaturizes the high-density, low-volume multiwell plate concept. The scientific core of this technology lies in integrating nanoporous membranes with microfabricated chip platforms. This results in the conversion of individual pores into nanowells of picoliter volume. Monoclonal antibodies were localized and isolated into individual wells. Detection of two cardiac proteomic biomarkers has been demonstrated with this technology. The two proteins, C-reactive protein and NT pro-brain natriuretic peptide (BNP), are associated with adverse cardiac outcomes in clinical samples when detected in the pg/mL concentration. The formation of the antibody-antigen binding complex occurs in individual wells. The membrane allows for robust separation among individual wells. This technology has the capability to achieve near real-time detection with improved sensitivity at 1 ag/mL for BNP and 1 fg/mL for CRP from human serum. PMID- 23015519 TI - Automated operation of immiscible filtration assisted by surface tension (IFAST) arrays for streamlined analyte isolation. AB - The purification of analytes is an important prerequisite for many analytical processes. Although automated infrastructure has dramatically increased throughput for many of these processes, the upstream analyte purification throughput has lagged behind, partially due to the complexity of conventional isolation processes. Here, we demonstrate automated operation of arrays of a new sample preparation technology--immiscible filtration assisted by surface tension (IFAST). IFAST uses surface tension to position an immiscible liquid barrier between a biological sample and downstream buffer. Paramagnetic particles are used to capture analytes of interest and draw them across the immiscible barrier, thus resulting in purification in a single step. Furthermore, the planarity of the IFAST design enables facile and simultaneous operation of multiple IFAST devices. To demonstrate the application of automation to IFAST, we successfully perform an array of 48 IFAST-based assays to detect the presence of a specific antibody. This assay array uses only a commercial automated liquid handler to load the devices and a custom-built magnet actuator to operate the assays. Automated operation of the IFAST devices resulted in more repeatable results relative to manual operation. PMID- 23015520 TI - The MainSTREAM component platform: a holistic approach to microfluidic system design. AB - A microfluidic component library for building systems driving parallel or serial microfluidic-based assays is presented. The components are a miniaturized eight channel peristaltic pump, an eight-channel valve, sample-to-waste liquid management, and interconnections. The library of components was tested by constructing various systems supporting perfusion cell culture, automated DNA hybridizations, and in situ hybridizations. The results showed that the MainSTREAM components provided (1) a rapid, robust, and simple method to establish numerous fluidic inputs and outputs to various types of reaction chips; (2) highly parallel pumping and routing/valving capability; (3) methods to interface pumps and chip-to-liquid management systems; (4) means to construct a portable system; (5) reconfigurability/flexibility in system design; (6) means to interface to microscopes; and (7) compatibility with tested biological methods. It was found that LEGO Mindstorms motors, controllers, and software were robust, inexpensive, and an accessible choice as compared with corresponding custom-made actuators. MainSTREAM systems could operate continuously for weeks without leaks, contamination, or system failures. In conclusion, the MainSTREAM components described here meet many of the demands on components for constructing and using microfluidics systems. PMID- 23015521 TI - Automated production of plant-based vaccines and pharmaceuticals. AB - A fully automated "factory" was developed that uses tobacco plants to produce large quantities of vaccines and other therapeutic biologics within weeks. This first-of-a-kind factory takes advantage of a plant viral vector technology to produce specific proteins within the leaves of rapidly growing plant biomass. The factory's custom-designed robotic machines plant seeds, nurture the growing plants, introduce a viral vector that directs the plant to produce a target protein, and harvest the biomass once the target protein has accumulated in the plants-all in compliance with Food and Drug Administration (FDA) guidelines (e.g., current Good Manufacturing Practices). The factory was designed to be time, cost, and space efficient. The plants are grown in custom multiplant trays. Robots ride up and down a track, servicing the plants and delivering the trays from the lighted, irrigated growth modules to each processing station as needed. Using preprogrammed robots and processing equipment eliminates the need for human contact, preventing potential contamination of the process and economizing the operation. To quickly produce large quantities of protein-based medicines, we transformed a laboratory-based biological process and scaled it into an industrial process. This enables quick, safe, and cost-effective vaccine production that would be required in case of a pandemic. PMID- 23015522 TI - Biological versus electronic adaptive coloration: how can one inform the other? AB - Adaptive reflective surfaces have been a challenge for both electronic paper (e paper) and biological organisms. Multiple colours, contrast, polarization, reflectance, diffusivity and texture must all be controlled simultaneously without optical losses in order to fully replicate the appearance of natural surfaces and vividly communicate information. This review merges the frontiers of knowledge for both biological adaptive coloration, with a focus on cephalopods, and synthetic reflective e-paper within a consistent framework of scientific metrics. Currently, the highest performance approach for both nature and technology uses colourant transposition. Three outcomes are envisioned from this review: reflective display engineers may gain new insights from millions of years of natural selection and evolution; biologists will benefit from understanding the types of mechanisms, characterization and metrics used in synthetic reflective e-paper; all scientists will gain a clearer picture of the long-term prospects for capabilities such as adaptive concealment and signaling. PMID- 23015523 TI - Interaction intimacy organizes networks of antagonistic interactions in different ways. AB - Interaction intimacy, the degree of biological integration between interacting individuals, shapes the ecology and evolution of species interactions. A major question in ecology is whether interaction intimacy also shapes the way interactions are organized within communities. We combined analyses of network structure and food web models to test the role of interaction intimacy in determining patterns of antagonistic interactions, such as host-parasite, predator-prey and plant-herbivore interactions. Networks describing interactions with low intimacy were more connected, more nested and less modular than high intimacy networks. Moreover, the performance of the models differed across networks with different levels of intimacy. All models reproduced well low intimacy networks, whereas the more elaborate models were also capable of reproducing networks depicting interactions with higher levels of intimacy. Our results indicate the key role of interaction intimacy in organizing antagonisms, suggesting that greater interaction intimacy might be associated with greater complexity in the assembly rules shaping ecological networks. PMID- 23015524 TI - DNA-based species detection capabilities using laser transmission spectroscopy. AB - Early detection of invasive species is critical for effective biocontrol to mitigate potential ecological and economic damage. Laser transmission spectroscopy (LTS) is a powerful solution offering real-time, DNA-based species detection in the field. LTS can measure the size, shape and number of nanoparticles in a solution and was used here to detect size shifts resulting from hybridization of the polymerase chain reaction product to nanoparticles functionalized with species-specific oligonucleotide probes or with the species specific oligonucleotide probes alone. We carried out a series of DNA detection experiments using the invasive freshwater quagga mussel (Dreissena bugensis) to evaluate the capability of the LTS platform for invasive species detection. Specifically, we tested LTS sensitivity to (i) DNA concentrations of a single target species, (ii) the presence of a target species within a mixed sample of other closely related species, (iii) species-specific functionalized nanoparticles versus species-specific oligonucleotide probes alone, and (iv) amplified DNA fragments versus unamplified genomic DNA. We demonstrate that LTS is a highly sensitive technique for rapid target species detection, with detection limits in the picomolar range, capable of successful identification in multispecies samples containing target and non-target species DNA. These results indicate that the LTS DNA detection platform will be useful for field application of target species. Additionally, we find that LTS detection is effective with species-specific oligonucleotide tags alone or when they are attached to polystyrene nanobeads and with both amplified and unamplified DNA, indicating that the technique may also have versatility for broader applications. PMID- 23015525 TI - Impact factor trends for general medical journals: non-English-language journals are lacking behind. AB - BACKGROUND: The impact factor (IF) is a common citation metric used for evaluating and comparing scientific journals within a certain field. Previous studies have shown that IFs are increasing. However, rates may depend on journal publication language. The aim of this study was to determine IF values and trends for general medical journals, comparing non-English-language with English language journals. METHODS: For all journals categorised as "medicine, general and internal" (n = 150) in the Journal Citation Reports (JCR), publication language, country of origin and IFs for the last 10 years were recorded (2001 2010). Data were classified, analysed descriptively and compared using non parametric tests. RESULTS: From 2001 to 2010, IFs increased for English-language and non-English-language journals (p <0.001). During the 10-year study period, IFs were higher for English-language than for non-English-language journals (p <0.001). The proportion of non-English-language journals included in the JCR was 12.2% in 2001 and 18.0% in 2010 (p = 0.28). INTERPRETATION: From 2001 to 2010, IFs increased significantly for English-language and non-English-language journals. When comparing IF values year-by-year (2001-2010), IFs were significantly higher for English-language than for non-English-language journals. In an international scientific community with English as the universal language of science, non-English-language journals should consider changing publication language, and adopt either a bi- or a monolingual approach. Publishing in English will increase citation counts and thus IFs, but, more importantly, scientific findings will be accessible to a much wider audience. PMID- 23015526 TI - Fast synthesis of PbS nanocrystals in aqueous solution with shape evolution from cubic to octahedral structures and their assembled structures. AB - In this study, we have developed for the first time a fast and energy-efficient method for the synthesis of PbS nanocrystals with systematic shape evolution from cubic to truncated cubic, cuboctahedral, truncated octahedral, and octahedral structures. The method involves the addition of a small volume of preheated lead acetate and thioacetamide (TAA) mixture to an aqueous growth solution of lead acetate, thioacetamide, cetyltrimethylammonium bromide, and nitric acid. By varying the amount of thioacetamide added to the growth solution, PbS nanocrystals with different morphologies were generated in 2 h at 90 degrees C. Slight experimental modifications were adopted to generate truncated octahedra. The nanocrystals have very uniform dimensions with average sizes of 32-47 nm. Their structures have been extensively examined by electron microscopy. Nanocube sizes can also be tuned within a range. UV/Vis absorption spectra of PbS cubes, cuboctahedra, and octahedra all show decreasing but continuous absorption from 300 nm to beyond 1000 nm. By monitoring the speed of darkening of solution color, particle growth rate was found to be fastest for nanocubes, followed by truncated cubes, cuboctahedra, and octahedra. These monodisperse nanocrystals can readily form self-assembled structures. Truncated cubes and octahedra that form monolayer and multilayer packing arrangements have also been studied. This green approach to the synthesis of PbS nanocrystals with fine size and shape control should allow for investigations of their facet-dependent properties and the fabrication of novel heterostructures. PMID- 23015527 TI - Anatomical correlates for category-specific naming of objects and actions: a brain stimulation mapping study. AB - The production of object and action words can be dissociated in aphasics, yet their anatomical correlates have been difficult to distinguish in functional imaging studies. To investigate the extent to which the cortical neural networks underlying object- and action-naming processing overlap, we performed electrostimulation mapping (ESM), which is a neurosurgical mapping technique routinely used to examine language function during brain-tumor resections. Forty one right-handed patients who had surgery for a brain tumor were asked to perform overt naming of object and action pictures under stimulation. Overall, 73 out of the 633 stimulated cortical sites (11.5%) were associated with stimulation induced language interferences. These interference sites were very much localized (<1 cm(2) ), and showed substantial variability across individuals in their exact localization. Stimulation interfered with both object and action naming over 44 sites, whereas it specifically interfered with object naming over 19 sites and with action naming over 10 sites. Specific object-naming sites were mainly identified in Broca's area (Brodmann area 44/45) and the temporal cortex, whereas action-naming specific sites were mainly identified in the posterior midfrontal gyrus (Brodmann area 6/9) and Broca's area (P = 0.003 by the Fisher's exact test). The anatomical loci we emphasized are in line with a cortical distinction between objects and actions based on conceptual/semantic features, so the prefrontal/premotor cortex would preferentially support sensorimotor contingencies associated with actions, whereas the temporal cortex would preferentially underpin (functional) properties of objects. PMID- 23015528 TI - Prenatal detection of del(10)(q11.2) mosaicism in chorionic villus specimens likely caused by a common chromosomal fragile site FRA10G is associated with a normal phenotype. AB - OBJECTIVE: To summarize the pregnancy outcomes of cases with mosaicism for chromosome 10q11.2 deletion detected by chorionic villus sampling (CVS) and determine whether extensive cytogenetic work-up and follow-up amniocentesis are necessary in such cases. METHODS: CVS was performed at 10-12 weeks of gestation. Chromosome analysis of chorionic villi was performed by standard G-banding techniques. RESULTS: Mosaicism of chromosome 10q11.2 deletion was observed in 24 out of 6063 CVS cases (0.39%). A common fragile site, FRA10G is located at the breakpoint region. The level of mosaicism ranged from 4% to 25%. No evidence of mosaic 10q11.2 deletion was found in follow-up amniocentesis, maternal peripheral blood cells, or from cytogenetic studies of other pregnancies from the same group of patients. All these cases resulted in the live birth of normal healthy infants. CONCLUSION: The presence of del(10)(q11.2) mosaicism in chorionic villus specimens most likely represents an in vitro culture artifact due to FRA10G fragile site in this region without any clinical consequences. If ultrasound results are normal, it is not necessary to perform follow-up amniocenteses and additional laboratory work-up for such cases. PMID- 23015529 TI - Understanding small biomolecule-biomaterial interactions: a review of fundamental theoretical and experimental approaches for biomolecule interactions with inorganic surfaces. AB - Interactions between biomolecules and inorganic surfaces play an important role in natural environments and in industry, including a wide variety of conditions: marine environment, ship hulls (fouling), water treatment, heat exchange, membrane separation, soils, mineral particles at the earth's surface, hospitals (hygiene), art and buildings (degradation and biocorrosion), paper industry (fouling) and more. To better control the first steps leading to adsorption of a biomolecule on an inorganic surface, it is mandatory to understand the adsorption mechanisms of biomolecules of several sizes at the atomic scale, that is, the nature of the chemical interaction between the biomolecule and the surface and the resulting biomolecule conformations once adsorbed at the surface. This remains a challenging and unsolved problem. Here, we review the state of art in experimental and theoretical approaches. We focus on metallic biomaterial surfaces such as TiO(2) and stainless steel, mentioning some remarkable results on hydroxyapatite. Experimental techniques include atomic force microscopy, surface plasmon resonance, quartz crystal microbalance, X-ray photoelectron spectroscopy, fluorescence microscopy, polarization modulation infrared reflection absorption spectroscopy, sum frequency generation and time of flight secondary ion mass spectroscopy. Theoretical models range from detailed quantum mechanical representations to classical forcefield-based approaches. PMID- 23015530 TI - Improvement in function after spinal cord injury: the black-box entitled rehabilitation. AB - Rehabilitation can be referred to as a "black box" because little is known about what specific interventions comprise the rehabilitation process, including patients with spinal cord injury (SCI). Despite that rehabilitation professionals can "see" daily what rehabilitation looks like, the contribution of each intervention to the final outcome of rehabilitation remains unclear. Moreover, there is only limited evidence supporting the efficacy of those interventions. To determine the efficacy of these interventions with respect to the outcome of rehabilitation and general functional improvement, we need appropriate outcome measurements and we need to know how profiles of functional improvement look in patients with SCI. It is sometimes forgotten, but obviously profiles of recovery depend to a large extent on the assessment tool applied. International efforts have been made to select and recommend a number of assessments with good psychometric properties and some of these assessments have been applied to hundreds of patients with SCI providing us with patterns of functional improvement. Currently, information about the efficacy of specific interventions is still lacking. For the coming years, one focus of rehabilitation research should be to determine the contribution of each specific intervention to the overall outcome of the rehabilitation process. Only by applying well-controlled randomised trials or large-scale observational studies, the most effective interventions can be selected, improving the efficacy of rehabilitation and turning the black-box into a more translucent one. PMID- 23015532 TI - Femtogram detection of explosive nitroaromatics: fluoranthene-based fluorescent chemosensors. AB - Herein we report a novel fluoranthene-based fluorescent fluorophore 7,10-bis(4 bromophenyl)-8,9-bis[4-(hexyloxy)phenyl]fluoranthene (S(3)) and its remarkable properties in applications of explosive detection. The sensitivity towards the detection of nitroaromatics (NACs) was evaluated through fluorescence quenching in solution, vapor, and contact mode approaches. The contact mode approach using thin-layer silica chromatographic plates exhibited a femtogram (1.15 fg cm(-2)) detection limit for trinitrotoluene (TNT) and picric acid (PA), whereas the solution-phase quenching showed PA detection at the 2-20 ppb level. Fluorescence lifetime measurements revealed that the quenching is static in nature and the quenching process is fully reversible. Binding energies between model binding sites of the S(3) and analyte compounds reveal that analyte molecules enter into the cavity created by substituted phenyl rings of fluoranthene and are stabilized by strong intermolecular interactions with alkyl chains. It is anticipated that the sensor S(3) could be a promising material for the construction of portable optical devices for the detection of onsite explosive nitroaromatics. PMID- 23015531 TI - The influence of individual motor imagery ability on cerebral recruitment during gait imagery. AB - Motor imagery (MI) is often used in combination with neuroimaging techniques to study the cognitive control of gait. However, imagery ability (IA) varies widely across individuals, potentially influencing the pattern of cerebral recruitment during MI. The aim of the current study was to investigate this effect of IA on the neural correlates of gait control using functional magnetic resonance imaging (fMRI). Twenty healthy young subjects were subdivided into a good and bad imagers group, on the basis of their performance on two mental chronometry tests. For the whole group, MI activated a bilateral network of areas highly consistent with previous studies, encompassing primary motor cortex (BA 4), supplementary motor area, and other frontal and parietal areas, anterior insula, and cerebellum. Compared to bad imagers, good imagers showed higher activation in the right BA 4, left prefrontal cortex (BA 10), right thalamus, and bilateral cerebellum. Good imagers thus appear better able to recruit motor areas during MI, but also activate a prefrontal executive area (BA 10), which integrates information from the body and the environment and participates in higher-order gait control. These differences were found even though the two groups did not differ in other imagery abilities according to a standard questionnaire for vividness of motor and visual imagery. Future studies on MI should take into account these effects, and control for IA when comparing different populations, using appropriate measures. A better understanding of the neural mechanisms that underlie MI ability is crucial to accurately evaluate locomotor skills in clinical measures and neurorehabilitation techniques. PMID- 23015533 TI - Cancer incidence and mortality in Indigenous Australian children, 1997-2008. AB - We report cancer incidence and mortality among Indigenous children in Australia and compare the results with corresponding data for non-Indigenous children. This information is important in understanding the overall burden of cancer in this population, and where disparities exist, to plan what action is required. Age standardized rates, and indirectly standardized incidence and mortality ratios (SIRs and SMRs) were calculated for the years 1997-2008. There were 224 cancers identified among Indigenous children (99.5 per million per year) and 52 Indigenous children died from cancer during the study period (22.9 per million per year). The SIR for all cancers was 0.64 (95% CI = 0.56-0.73; P < 0.001) while the SMR was 0.81 (95% CI = 0.61-1.07). These results provide a baseline with which to monitor cancer among Indigenous children over time. PMID- 23015534 TI - Development of silver nanoparticle loaded antibacterial polymer mesh using plasma polymerization process. AB - Plasma polymerized polyacrylic acid (PPAA) was deposited on a polymer substrate, namely polyethylene terephthalate (PET) mesh, for entrapment of silver nanoparticle (Ag-NP) in order to achieve antibacterial property to the material. Carboxylic groups of PPAA act as anchor as well as capping and stabilizing agents for Ag-NPs synthesized by chemical reduction method using NaBH(4) as a reducing agent. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy (XPS), and water contact angle analysis were used to characterize the PPAA coatings. The Ag-NPs loaded polymer samples were characterized by UV-visible spectroscopy, field emission scanning electron microscopy, energy dispersive X ray, and XPS techniques. XPS analysis showed ~1.0 at.% loading of Ag-NPs on to the PPAA-PET-mesh, which was composed of 79% zero-valent (Ag degrees ) and 21% oxidized nano-Ag (Ag(+) ). The plasma processed PET meshes samples were tested for antibacterial activity against two bacterial strains, namely Staphylococcus aureus (Gram positive) and Escherichia coli (Gram negative). Qualitative and quantitative tests showed that silver containing PPAA-PET meshes exhibit excellent antibacterial property against the tested bacteria with percent reduction of bacterial concentration >99%, compared to the untreated PET mesh. PMID- 23015535 TI - A review of the most economically important poisonous plants to the livestock industry on temperate grasslands of China. AB - The majority of the literature on poisonous plant species in China is published in Chinese and not available to the majority of interested researchers and grassland managers in other countries. Therefore, a review of the Chinese literature was conducted to summarize the occurrence of poisonous plant species on temperate grasslands in China. We reviewed the literature to obtain general information on poisonous species but focus on locoweeds (Astragalus and Oxytropis spp.), drunken horse grass [Achnatherum inebrians (Hance) Keng ex Tzvelev] and langdu (Stellera chamaejasme L.) for information on their toxins, distribution and ecology, control methods and alternate uses. Of the almost 1300 poisonous species found on grasslands in China, these species are responsible for an estimated 80% of all livestock losses. This includes loss of performance as well as mortality. The locoweeds are a complex made up of Oxytropis and Astragalus species. The toxic principle in this complex, as well as in drunken horse grass, is the result of an endophyte fungus whereas in langdu it is produced by the plant. All these species are native to the grasslands, which suggest they have been a problem ever since herding began. Over that period of at least several millennia, herders would have learned and adapted to the presence of poisonous species. Strategies were developed and therapies employed to allow the animals to cope before and after poisoning. Nevertheless, grazing management could still be refined that would allow the use of the toxic legumes, while preventing poisonous symptoms, as has been tested elsewhere. PMID- 23015536 TI - Exploring the use of the Swiss medical tariffication codes (TARMED) in the establishment of the frequency of radiodiagnostic examinations. AB - In population surveys of the exposure to medical X-rays both the frequency of examinations and the effective dose per examination are required. The use of the Swiss medical tariffication system (TARMED) for establishing the frequency of X ray medical examinations was explored. The method was tested for radiography examinations performed in 2008 at the Lausanne University Hospital. The annual numbers of radiographies determined from the "TARMED" database are in good agreement with the figures extracted from the local RIS (Radiology Information System). The "TARMED" is a reliable and fast method for establishing the frequency of radiography examination, if we respect the context in which the "TARMED" code is used. In addition, this billing context provides most valuable information on the average number of radiographs per examination as well as the age and sex distributions. Radiographies represent the major part of X-ray examinations and are performed by about 4,000 practices and hospitals in Switzerland. Therefore this method has the potential to drastically simplify the organisation of nationwide surveys. There are still some difficulties to overcome if the method is to be used to assess the frequency of computed tomography or fluoroscopy examinations; procedures that deliver most of the radiation dose to the population. This is due to the poor specificity of "TARMED" codes concerning these modalities. However, the use of CT and fluoroscopy installations is easier to monitor using conventional survey methods since there are fewer centres. Ways to overcome the "TARMED" limitations for these two modalities are still being explored. PMID- 23015537 TI - A randomized clinical trial of an identity intervention programme for women with eating disorders. AB - OBJECTIVE: Findings of a randomized trial of an identity intervention programme (IIP) designed to build new positive self-schemas that are separate from other conceptions of the self in memory as the means to promote improved health in women diagnosed with eating disorders are reported. METHOD: After baseline data collection, women with anorexia nervosa or bulimia nervosa were randomly assigned to IIP (n = 34) or supportive psychotherapy (SPI) (n = 35) and followed at 1, 6, and 12 months post-intervention. RESULTS: The IIP and supportive psychotherapy were equally effective in reducing eating disorder symptoms at 1 month post intervention, and changes were stable through the 12-month follow-up period. The IIP tended to be more effective in fostering development of positive self schemas, and the increase was stable over time. Regardless of baseline level, an increase in the number of positive self-schemas between pre-intervention and 1 month post-intervention predicted a decrease in desire for thinness and an increase in psychological well-being and functional health over the same period. DISCUSSION: A cognitive behavioural intervention that focuses on increasing the number of positive self-schemas may be central to improving emotional health in women with anorexia nervosa and bulimia nervosa. PMID- 23015538 TI - Low dose of carbon monoxide intraperitoneal injection provides potent protection against GalN/LPS-induced acute liver injury in mice. AB - Carbon monoxide (CO) is an important effector-signaling molecule involved in various pathophysiological processes. Here we investigated the protective effects of exogenous CO in a murine model of acute liver damage induced by d galactosamine (GalN) and lipopolysaccharide (LPS). Exogenous CO gas was administered to mice via intraperitoneal injection (first at a dose of 15 ml kg( 1) and then, 6 h later, 8 ml kg(-1)), which caused a significant elevation of blood carboxyhemoglobin levels of up to 12-14% for more than 12 h. GalN/LPS were given to induce acute liver damage in mice 30 min prior to CO exposure. This showed that GalN/LPS induced severe liver injury in mice, whereas CO injection remarkably improved the survival rate of mice and led to attenuated hepatocellular damage. CO exhibited anti-oxidative capabilities by inhibiting hepatic malondialdehyde contents and restoring superoxide dismutase and glutathione, as well as by reducing inducible NOS/NO production. The anti apoptotic and anti-inflammatory effects of CO were substantial, characterized by a notable inhibition of hepatocyte apoptosis and a reduction of pro-inflammatory cytokines in mice. Our findings thus supported the hypothesis that exogenous CO provides protective effects against acute liver damage in mice, mainly dependent on its anti-oxidative, anti-inflammatory and anti-apoptotic properties. PMID- 23015539 TI - Nucleic acid driven DNA machineries synthesizing Mg2+-dependent DNAzymes: an interplay between DNA sensing and logic-gate operations. AB - Polymerase/nicking enzymes and nucleic-acid scaffolds are implemented as DNA machines for the development of amplified DNA-detection schemes, and for the design of logic gates. The analyte nucleic acid target acts, also, as input for the logic gates. In the presence of two DNA targets, acting as inputs, and appropriate DNA scaffolds, the polymerase-induced replication of the scaffolds, followed by the nicking of the replication products, are activated, leading to the autonomous synthesis of the Mg(2+)-dependent DNAzyme or the Mg(2+)-dependent DNAzyme subunits. These biocatalysts cleave a fluorophore/quencher-functionalized nucleic-acid substrate, thus providing fluorescence signals for the sensing events or outputs for the logic gates. The systems are used to develop OR, AND, and Controlled-AND gates, and the DNA-analyte targets represent two nucleic acid sequences of the smallpox viral genome. PMID- 23015541 TI - Caffeine, extraversion and working memory. AB - Research has shown that extraverts performing a working memory task benefit more from caffeine than do introverts. The present study aimed to replicate this and extend our knowledge by using a lower dose of caffeine (65 mg) and a range of tasks related to different components of working memory. In addition, tasks assessing psychomotor speed and the encoding of new information were included to determine whether caffeine-extraversion interactions were restricted to working memory tasks. A double-blind design was used, with 128 participants being randomly assigned to caffeinated or de-caffeinated coffee conditions. The results showed that caffeine interacted with extraversion in the predicted direction for serial recall and running memory tasks. Caffeine improved simple reaction time and the speed of encoding of new information, effects which were not modified by extraversion. These results suggest possible biological mechanisms underlying effects of caffeine on cognitive performance. PMID- 23015540 TI - 3D bioprinting of heterogeneous aortic valve conduits with alginate/gelatin hydrogels. AB - Heart valve disease is a serious and growing public health problem for which prosthetic replacement is most commonly indicated. Current prosthetic devices are inadequate for younger adults and growing children. Tissue engineered living aortic valve conduits have potential for remodeling, regeneration, and growth, but fabricating natural anatomical complexity with cellular heterogeneity remain challenging. In the current study, we implement 3D bioprinting to fabricate living alginate/gelatin hydrogel valve conduits with anatomical architecture and direct incorporation of dual cell types in a regionally constrained manner. Encapsulated aortic root sinus smooth muscle cells (SMC) and aortic valve leaflet interstitial cells (VIC) were viable within alginate/gelatin hydrogel discs over 7 days in culture. Acellular 3D printed hydrogels exhibited reduced modulus, ultimate strength, and peak strain reducing slightly over 7-day culture, while the tensile biomechanics of cell-laden hydrogels were maintained. Aortic valve conduits were successfully bioprinted with direct encapsulation of SMC in the valve root and VIC in the leaflets. Both cell types were viable (81.4 +/- 3.4% for SMC and 83.2 +/- 4.0% for VIC) within 3D printed tissues. Encapsulated SMC expressed elevated alpha-smooth muscle actin, while VIC expressed elevated vimentin. These results demonstrate that anatomically complex, heterogeneously encapsulated aortic valve hydrogel conduits can be fabricated with 3D bioprinting. PMID- 23015542 TI - Behavioural, neurochemical and neuroendocrine effects of the endogenous beta carboline harmane in fear-conditioned rats. AB - The putative endogenous imidazoline binding site ligand harmane enhances neuronal activation in response to psychological stress and alters behaviour in animal models of anxiety and antidepressant efficacy. However, the neurobiological mechanisms underlying harmane's psychotropic effects are poorly understood. We investigated the effects of intraperitoneal injection of harmane (2.5 and 10 mg/kg) on fear-conditioned behaviour, hypothalamo-pituitary-adrenal axis activity, and monoaminergic activity within specific fear-associated areas of the rat brain. Harmane had no significant effect on the duration of contextually induced freezing or 22 kHz ultrasonic vocalisations and did not alter the contextually induced suppression of motor activity, including rearing. Harmane reduced the duration of rearing and tended to increase freezing in non-fear conditioned controls, suggesting potential sedative effects. Harmane increased plasma ACTH and corticosterone concentrations, and serotonin (in hypothalamus, amygdaloid cortex, prefrontal cortex and hippocampus) and noradrenaline (prefrontal cortex) content, irrespective of fear-conditioning. Furthermore, harmane reduced dopamine and serotonin turnover in the PFC and hypothalamus, and serotonin turnover in the amygdaloid cortex in both fear-conditioned and non-fear conditioned rats. In contrast, harmane increased dopamine and noradrenaline content and reduced dopamine turnover in the amygdala of fear-conditioned rats only, suggesting differential effects on catecholaminergic transmission in the presence and absence of fear. The precise mechanism(s) mediating these effects of harmane remain to be determined but may involve its inhibitory action on monoamine oxidases. These findings support a role for harmane as a neuromodulator, altering behaviour, brain neurochemistry and neuroendocrine function. PMID- 23015543 TI - Incensole acetate reduces depressive-like behavior and modulates hippocampal BDNF and CRF expression of submissive animals. AB - Incensole acetate (IA), a constituent of Boswellia resin ('frankincense'), was previously demonstrated to exhibit an antidepressive-like effect in the Forced Swim Test (FST) in mice following single dose administration (50 mg/kg). Here, we show that acute administration of considerably lower dose (10 mg/kg) IA to selectively bred mice, showing prominent submissive behavior, exerted significant antidepressant-like effects in the FST. Furthermore, chronic administration of 1 or 5 mg/kg per day of IA for three consecutive weeks dose- and time-dependently reduced the submissiveness of the mice in the Dominant-Submissive Relationship test, developed to screen the chronic effect of antidepressants. This behavioral effect was concomitant to reduced serum corticosterone levels, dose-dependent down-regulation of corticotropin releasing factor and up-regulation of brain derived neurotrophic factor transcripts IV and VI expression in the hippocampus. These data suggest that IA modulates the hypothalamic-pituitary-adrenal (HPA) axis and influences hippocampal gene expression, leading to beneficial behavioral effects supporting its potential as a novel treatment of depressive-like disorders. PMID- 23015544 TI - A tale of two collagen receptors, integrin beta1 and discoidin domain receptor 1, in epithelial cell differentiation. AB - As increase in collagen deposition is no longer taken as simply a consequence but, rather, an inducer of disease progression; therefore, the understanding of collagen signal transduction is fundamentally important. Cells contain at least two types of collagen receptors: integrins and discoidin domain receptors (DDRs). The integrin heterodimers alpha(1)beta(1), alpha(2)beta(1), alpha(10)beta(1), and alpha(11)beta(1) are recognized as the non-tyrosine kinase collagen receptors. DDR1 and 2, the tyrosine kinase receptors of collagen, are specifically expressed in epithelium and mesenchyme, respectively. While integrin beta(1) and DDR1 are both required for cell adhesion on collagen, their roles in epithelial cell differentiation during development and disease progression seem to counteract each other, with integrin beta(1) favoring epithelium mesenchyme transition (EMT) and DDR1 inducing epithelial cell differentiation. The in vitro evidence shows that the integrin beta(1) and DDR1 exert opposing actions in regulation of membrane stability of E-cadherin, which itself is a critical regulator of epithelial cell differentiation. Here, we review the functional roles of integrin beta(1) and DDR1 in regulation of epithelial cell differentiation during development and disease progression, and explore the underlining mechanisms regarding to the regulation of membrane stability of E-cadherin. PMID- 23015546 TI - Single fiber analyses of glycogen-related proteins reveal their differential association with glycogen in rat skeletal muscle. AB - To understand how glycogen affects skeletal muscle physiology, we examined enzymes essential for muscle glycogen synthesis and degradation using single fibers from quiescent and stimulated rat skeletal muscle. Presenting a shift in paradigm, we show these proteins are differentially associated with glycogen granules. Protein diffusibility and/or abundance of glycogenin, glycogen branching enzyme (GBE), debranching enzyme (GDE), phosphorylase (GP), and synthase (GS) were examined in fibers isolated from rat fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscle. GDE and GP proteins were more abundant (~10- to 100-fold) in fibers from EDL compared with SOL muscle. GS and glycogenin proteins were similar between muscles while GBE had an approximately fourfold greater abundance in SOL muscle. Mechanically skinned fibers exposed to physiological buffer for 10 min showed ~70% total pools of GBE and GP were diffusible (nonbound), whereas GDE and GS were considerably less diffusible. Intense in vitro stimulation, sufficient to elicit a ~50% decrease in intracellular glycogen, increased diffusibility of GDE, GP, and GS (~15-60%) and decreased GBE diffusibility (~20%). Amylase treatment, which breaks alpha-1,4 linkages of glycogen, indicated differential diffusibilities and hence glycogen associations of GDE and GS. Membrane solubilization (1% Triton-X-100) allowed a small additional amount of GDE and GS to diffuse from fibers, suggesting the majority of nonglycogen-associated GDE/GS is associated with myofibrillar/contractile network of muscle rather than membranes. Given differences in enzymes required for glycogen metabolism, the current findings suggest glycogen particles have fiber-type-dependent structures. The greater catabolic potential of glycogen breakdown in fast-twitch fibers may account for different contraction induced rates of glycogen utilization. PMID- 23015545 TI - Basolateral targeting and microtubule-dependent transcytosis of the aquaporin-2 water channel. AB - The aquaporin-2 (AQP2) water channel relocates mainly to the apical plasma membrane of collecting duct principal cells after vasopressin (VP) stimulation. AQP2 transport to this membrane domain is assumed to be a direct route involving recycling of intracellular vesicles. However, basolateral plasma membrane expression of AQP2 is observed in vivo in principal cells. Here, we asked whether there is a transcytotic pathway of AQP2 trafficking between apical and basolateral membranes. We used MDCK cells in which AQP2 normally accumulates apically after VP exposure. In contrast, both site-specific biotinylation and immunofluorescence showed that AQP2 is strongly accumulated in the basolateral membrane, along with the endocytic protein clathrin, after a brief cold shock (4 degrees C). This suggests that AQP2 may be constitutively targeted to basolateral membranes and then retrieved by clathrin-mediated endocytosis at physiological temperatures. Rab11 does not accumulate in basolateral membranes after cold shock, suggesting that the AQP2 in this location is not associated with Rab11 positive vesicles. After rewarming (37 degrees C), basolateral AQP2 staining is diminished and it subsequently accumulates at the apical membrane in the presence of VP/forskolin, suggesting that transcytosis can be followed by apical insertion of AQP2. This process is inhibited by treatment with colchicine. Our data suggest that the cold shock procedure reveals the presence of microtubule-dependent AQP2 transcytosis, which represents an indirect pathway of apical AQP2 delivery in these cells. Furthermore, our data indicate that protein polarity data obtained from biotinylation assays, which require cells to be cooled to 4 degrees C during the labeling procedure, should be interpreted with caution. PMID- 23015547 TI - Keeping the beat. Focus on "enrichment of neonatal rat cardiomyocytes in primary culture facilitates long-term maintenance of contractility in vitro". PMID- 23015548 TI - Serum- and glucocorticoid-inducible kinase SGK1 regulates reorganization of actin cytoskeleton in mast cells upon degranulation. AB - Aggregation of the high-affinity IgE receptor (FcepsilonRI) on mast cells (MCs) causes MC degranulation, a process that involves cortical F-actin disassembly. Actin depolymerization may be triggered by increase of cytosolic Ca(2+). Entry of Ca(2+) through the Ca(2+) release-activated Ca(2+) (CRAC) channels is under powerful regulation by the serum- and glucocorticoid-inducible kinase SGK1. Moreover, FcepsilonRI-dependent degranulation is decreased in SGK1-deficient (sgk1(-/-)) MCs. The present study addressed whether SGK1 is required for actin cytoskeleton rearrangement in MCs and whether modulation of actin architecture could underlie decreased degranulation of sgk1(-/-) MCs. Confirming previous results, release of beta-hexosaminidase reflecting FcepsilonRI-dependent degranulation was impaired in sgk1(-/-) MCs compared with sgk1(+/+) MCs. When CRAC channels were inhibited by 2-aminoethoxydiphenyl borate (2-APB; 50 MUM), MC degranulation was strongly decreased in both sgk1(+/+) and sgk1(-/-) MCs and the difference between genotypes was abolished. Moreover, degranulation was impaired by actin-stabilizing (phallacidin) and enhanced by actin-disrupting (cytochalasin B) agents to a similar extent in sgk1(+/+) MCs and sgk1(-/-) MCs, implying a regulatory role of actin reorganization in this event. In line with this, measurements of monomeric (G) and filamentous (F) actin content by FACS analysis and Western blotting of detergent-soluble and -insoluble cell fractions indicated an increase of the G/F-actin ratio in sgk1(+/+) MCs but not in sgk1(-/-) MCs upon FcepsilonRI ligation, an observation reflecting actin depolymerization. In sgk1(+/+) MCs, FcepsilonRI-induced actin depolymerization was abolished by 2-APB. The observed actin reorganization was confirmed by confocal laser microscopic analysis. Our observations uncover SGK1-dependent Ca(2+) entry in mast cells as a novel mechanism regulating actin cytoskeleton. PMID- 23015549 TI - Plasticity-related gene-1 inhibits lysophosphatidic acid-induced vascular smooth muscle cell migration and proliferation and prevents neointima formation. AB - Plasticity-related gene-1 (PRG-1) protects neuronal cells from lysophosphatidic acid (LPA) effects. In vascular smooth muscle cells (VSMCs), LPA was shown to induce phenotypic modulation in vitro and vascular remodeling in vivo. Thus we explored the role of PRG-1 in modulating VSMC response to LPA. PCR, Western blot, and immunofluorescence experiments showed that PRG-1 is expressed in rat and human vascular media. PRG-1 expression was strongly inhibited in proliferating compared with quiescent VSMCs both in vitro and in vivo (medial vs. neointimal VSMCs), suggesting that PRG-1 expression is dependent on the cell phenotype. In vitro, adenovirus-mediated overexpression of PRG-1 specifically inhibited LPA induced rat VSMC proliferation and migration but not platelet-derived growth factor-induced proliferation. This effect was abolished by mutation of a conserved histidine in the lipid phosphate phosphatase family that is essential for interaction with lipid phosphates. In vivo, balloon-induced neointimal formation in rat carotid was significantly decreased in vessels infected with PRG 1 adenovirus compared with beta-galactosidase adenovirus (-71%; P < 0.05). PRG-1 overexpression abolished the activation of the p42/p44 signaling pathway in LPA stimulated rat VSMCs in culture and in balloon-injured rat carotids. Taken together, these findings provide the first evidence of a protective role of PRG-1 in the vascular media under pathophysiological conditions. PMID- 23015550 TI - Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology. AB - Cultured primary epithelial cells are used to examine inflammation in cystic fibrosis (CF). We describe a new human model system using cultured nasal brushings. Nasal brushings were obtained from 16 F508del homozygous patients and 11 healthy controls. Cells were resuspended in airway epithelial growth medium and seeded onto collagen-coated flasks and membranes for use in patch-clamp, ion transport, and mediator release assays. Viable cultures were obtained with a 75% success rate from subjects with CF and 100% from control subjects. Amiloride sensitive epithelial Na channel current of similar size was present in both cell types while forskolin-activated CF transmembrane conductance regulator current was lacking in CF cells. In Ussing chambers, cells from CF patients responded to UTP but not to forskolin. Spontaneous and cytomix-stimulated IL-8 release was similar (stimulated 29,448 +/- 9,025 pg/ml; control 16,336 +/- 3,308 pg/ml CF; means +/- SE). Thus nasal epithelial cells from patients with CF can be grown from nasal brushings and used in electrophysiological and mediator release studies in CF research. PMID- 23015552 TI - The pathogenesis of degeneration of the intervertebral disc and emerging therapies in the management of back pain. AB - This article reviews the current knowledge of the intervertebral disc (IVD) and its association with low back pain (LBP). The normal IVD is a largely avascular and aneural structure with a high water content, its nutrients mainly diffusing through the end plates. IVD degeneration occurs when its cells die or become dysfunctional, notably in an acidic environment. In the process of degeneration, the IVD becomes dehydrated and vascularised, and there is an ingrowth of nerves. Although not universally the case, the altered physiology of the IVD is believed to precede or be associated with many clinical symptoms or conditions including low back and/or lower limb pain, paraesthesia, spinal stenosis and disc herniation. New treatment options have been developed in recent years. These include biological therapies and novel surgical techniques (such as total disc replacement), although many of these are still in their experimental phase. Central to developing further methods of treatment is the need for effective ways in which to assess patients and measure their outcomes. However, significant difficulties remain and it is therefore an appropriate time to be further investigating the scientific basis of and treatment of LBP. PMID- 23015553 TI - Proximal interphalangeal joint replacement in patients with arthritis of the hand: a meta-analysis. AB - We systematically reviewed all the evidence published in the English language on proximal interphalangeal joint (PIPJ) replacement, to determine its effectiveness on the function of the hand and the associated post-operative complications. Original studies were selected if they reported clinical outcome with a minimum of one year's follow-up. Quality was assessed using the Cowley systematic review criteria modified for finger-joint replacements. Of 319 articles identified, only five were adequately reported according to our quality criteria; there were no randomised controlled trials. PIPJ replacements had a substantial effect size on hand pain of -23.2 (95% confidence interval (CI) -27.3 to -19.1) and grip strength 1.2 (95% CI -10.7 to 13.1), and a small effect on range of movement 0.2 (95% CI -0.4 to 0.8). A dorsal approach was most successful. Post-operative loosening occurred in 10% (95% CI 3 to 30) of ceramic and 12.5% (95% CI 7 to 21) of pyrocarbon replacements. Post-operative complications occurred in 27.8% (95% CI 20 to 37). We conclude that the effectiveness of PIPJ replacement has not been established. Small observational case studies and short-term follow-up, together with insufficient reporting of patient data, functional outcomes and complications, limit the value of current evidence. We recommend that a defined core set of patients, surgical and outcome data for this intervention be routinely and systematically collected within the framework of a joint registry. PMID- 23015554 TI - FRAX and the assessment of the risk of developing a fragility fracture. AB - Osteoporosis is common and the health and financial cost of fragility fractures is considerable. The burden of cardiovascular disease has been reduced dramatically by identifying and targeting those most at risk. A similar approach is potentially possible in the context of fragility fractures. The World Health Organization created and endorsed the use of FRAX, a fracture risk assessment tool, which uses selected risk factors to calculate a quantitative, patient-specific, ten-year risk of sustaining a fragility fracture. Treatment can thus be based on this as well as on measured bone mineral density. It may also be used to determine at-risk individuals, who should undergo bone densitometry. FRAX has been incorporated into the national osteoporosis guidelines of countries in the Americas, Europe, the Far East and Australasia. The United Kingdom National Institute for Health and Clinical Excellence also advocates its use in their guidance on the assessment of the risk of fragility fracture, and it may become an important tool to combat the health challenges posed by fragility fractures. PMID- 23015555 TI - The radiological assessment of total and unicompartmental knee replacements. AB - Radiological assessment of total and unicompartmental knee replacement remains an essential part of routine care and follow-up. Appreciation of the various measurements that can be identified radiologically is important. It is likely that routine plain radiographs will continue to be used, although there has been a trend towards using newer technologies such as CT, especially in a failing knee, where it provides more detailed information, albeit with a higher radiation exposure. The purpose of this paper is to outline the radiological parameters used to evaluate knee replacements, describe how these are measured or classified, and review the current literature to determine their efficacy where possible. PMID- 23015556 TI - Risk factors associated with surgical site infection in 30,491 primary total hip replacements. AB - We examined patient and surgical factors associated with deep surgical site infection (SSI) following total hip replacement (THR) in a large integrated healthcare system. A retrospective review of a cohort of primary THRs performed between 2001 and 2009 was conducted. Patient characteristics, surgical details, surgeon and hospital volumes, and SSIs were identified using the Kaiser Permanente Total Joint Replacement Registry (TJRR). Proportional-hazard regression models were used to assess risk factors for SSI. The study cohort consisted of 30,491 THRs, of which 17,474 (57%) were performed on women. The mean age of the patients in the whole series was 65.5 years (13 to 97; SD 11.8) and the mean body mass index was 29.3 kg/m(2) (15 to 67; SD 5.9). The incidence of SSI was 0.51% (155 of 30,491). Patient factors associated with SSI included female gender, obesity, and American Society of Anesthesiologists (ASA) score >= 3. Age, diagnosis, diabetes and race were not associated with SSI. The only surgical factor associated with SSI was a bilateral procedure. Surgeon and hospital volumes, use of antibiotic-laden cement, fixation method, laminar flow, body exhaust suits, surgical approach and fellowship training were not associated with risk of SSI. A comprehensive infection surveillance system, combined with a TJRR, identified patient and surgical factors associated with SSI. Obesity and chronic medical conditions should be addressed prior to THR. The finding of increased SSI risk with bilateral THR requires further investigation. PMID- 23015557 TI - The removal of acetabular bone in hip resurfacing and cementless total hip replacement: a comparison using the ratio of the size of the acetabular component to the diameter of the native femoral head. AB - The purpose of this study was to compare the amount of acetabular bone removed during hip resurfacing (HR) and cementless total hip replacement (THR), after controlling for the diameter of the patient's native femoral head. Based on a power analysis, 64 consecutive patients (68 hips) undergoing HR or THR were prospectively enrolled in the study. The following data were recorded intra operatively: the diameter of the native femoral head, the largest reamer used, the final size of the acetabular component, the size of the prosthetic femoral head and whether a decision was made to increase the size of the acetabular component in order to accommodate a larger prosthetic femoral head. Results were compared using two-sided, independent samples Student's t-tests. A statistically significant difference was seen in the mean ratio of the size of the acetabular component to the diameter of the native femoral head (HR: 1.05 (SD 0.04) versus THR: 1.09 (SD 0.05); p < 0.001) and largest acetabular reamer used to the diameter of the native femoral head (HR: 1.03 (SD 0.04) versus THR: 1.09 (SD 0.05); p < 0.001). The ratios varied minimally when the groups were subdivided by gender, age and obesity. The decision to increase the size of the acetabular component to accommodate a larger femoral head occurred more often in the THR group (27% versus 9%). Despite the emphasis on avoiding damage to the femoral neck during HR, the ratio of the size of the acetabular component to the diameter of the native femoral head was larger in cementless THR than in HR. PMID- 23015558 TI - Early micromovement of the Articular Surface Replacement (ASR) femoral component: two-year radiostereometry results. AB - Radiostereometric analysis (RSA) can detect early micromovement in unstable implant designs which are likely subsequently to have a high failure rate. In 2010, the Articular Surface Replacement (ASR) was withdrawn because of a high failure rate. In 19 ASR femoral components, the mean micromovement over the first two years after implantation was 0.107 mm (SD 0.513) laterally, 0.055 mm (SD 0.204) distally and 0.150 mm (SD 0.413) anteriorly. The mean backward tilt around the x-axis was -0.08 degrees (SD 1.088), mean internal rotation was 0.165 degrees (SD 0.924) and mean varus tilt 0.238 degrees (SD 0.420). The baseline to two-year varus tilt was statistically significant from zero movement, but there was no significant movement from one year onwards. We conclude that the ASR femoral component achieves initial stability and that early migration is not the mode of failure for this resurfacing arthroplasty. PMID- 23015559 TI - Does obesity influence clinical outcome at nine years following total knee replacement? AB - A total of 445 consecutive primary total knee replacements (TKRs) were followed up prospectively at six and 18 months and three, six and nine years. Patients were divided into two groups: non-obese (body mass index (BMI) < 30 kg/m(2)) and obese (BMI >= 30 kg/m(2)). The obese group was subdivided into mildly obese (BMI 30 to 35 kg/m(2)) and highly obese (BMI >= 35 kg/m(2)) in order to determine the effects of increasing obesity on outcome. The clinical data analysed included the Knee Society score, peri-operative complications and implant survival. There was no difference in the overall complication rates or implant survival between the two groups. Obesity appears to have a small but significant adverse effect on clinical outcome, with highly obese patients showing lower function scores than non-obese patients. However, significant improvements in outcome are sustained in all groups nine years after TKR. Given the substantial, sustainable relief of symptoms after TKR and the low peri operative complication and revision rates in these two groups, we have found no reason to limit access to TKR in obese patients. PMID- 23015560 TI - Mobile-bearing lateral unicompartmental knee replacement with the Oxford domed tibial component: an independent series. AB - The Oxford mobile-bearing unicompartmental knee replacement (UKR) is an effective and safe treatment for osteoarthritis of the medial compartment. The results in the lateral compartment have been disappointing due to a high early rate of dislocation of the bearing. A series using a newly designed domed tibial component is reported. The first 50 consecutive domed lateral Oxford UKRs in 50 patients with a mean follow-up of three years (2.0 to 4.3) were included. Clinical scores were obtained prospectively and Kaplan-Meier survival analysis was performed for different endpoints. Radiological variables related to the position and alignment of the components were measured. One patient died and none was lost to follow-up. The cumulative incidence of dislocation was 6.2% (95% confidence interval (CI) 2.0 to 17.9) at three years. Survival using revision for any reason and aseptic revision was 94% (95% CI 82 to 98) and 96% (95% CI 85 to 99) at three years, respectively. Outcome scores, visual analogue scale for pain and maximum knee flexion showed a significant improvement (p < 0.001). The mean Oxford knee score was 43 (SD 5.3), the mean Objective American Knee Society score was 91 (SD 13.9) and the mean Functional American Knee Society score was 90 (SD 17.5). The mean maximum flexion was 127 degrees (90 degrees to 145 degrees ). Significant elevation of the lateral joint line as measured by the proximal tibial varus angle (p = 0.04) was evident in the dislocation group when compared with the non-dislocation group. Clinical results are excellent and short-term survival has improved when compared with earlier series. The risk of dislocation remains higher using a mobile-bearing UKR in the lateral compartment when compared with the medial compartment. Patients should be informed about this complication. To avoid dislocations, care must be taken not to elevate the lateral joint line. PMID- 23015561 TI - Evaluation of the relationship between anteroposterior translation of a posterior cruciate ligament-retaining total knee replacement and functional outcome. AB - The success of total knee replacement (TKR) depends on optimal soft-tissue balancing, among many other factors. The objective of this study is to correlate post-operative anteroposterior (AP) translation of a posterior cruciate ligament-retaining TKR with clinical outcome at two years. In total 100 patients were divided into three groups based on their AP translation as measured by the KT-1000 arthrometer. Group 1 patients had AP translation < 5 mm, Group 2 had AP translation from 5 mm to 10 mm, and Group 3 had AP translation > 10 mm. Outcome assessment included range of movement of the knee, the presence of flexion contractures, hyperextension, knee mechanical axes and functional outcome using the Knee Society score, Oxford knee score and the Short-Form 36 questionnaire. At two years, patients in Group 2 reported significantly better Oxford knee scores than the other groups (p = 0.045). A positive correlation between range of movement and AP translation was noted, with patients in group 3 having the greatest range of movement (mean flexion: 117.9 degrees (106 degrees to 130 degrees )) (p < 0.001). However, significantly more patients in Group 3 developed hyperextension > 10 degrees (p = 0.01). In this study, the best outcome for cruciate-ligament retaining TKR was achieved in patients with an AP translation of 5 mm to 10 mm. PMID- 23015562 TI - Differences in long-term fixation between mobile-bearing and fixed-bearing knee prostheses at ten to 12 years' follow-up: a single-blinded randomised controlled radiostereometric trial. AB - This single-blinded randomised controlled trial investigated whether one design of mobile-bearing (MB) total knee replacement (TKR) has any advantage over a fixed-bearing (FB) design on long-term fixation as measured by radiostereometry. The amount of wear underneath the mobile bearing was also evaluated. A series of 42 knees was randomised to MB or FB tibial components with appropriate polyethylene inserts and followed for between ten and 12 years, or until the death of the patient. The polyethylene in the MB group was superior in that it was gamma-irradiated in inert gas and was calcium-stearate free; the polyethylene in the FB group was gamma-irradiated in air and contained calcium stearate. In theory this should be advantageous to the wear rate of the MB group. At final follow-up the overall mean migration was 0.75 mm (SD 0.76) in the MB group and 0.66 mm (SD 0.4) in the FB group, with the FB group demonstrating more posterior tilt and the MB group more internal rotation. In the FB group there was one revision for aseptic loosening, but none in the MB group. There were no significant differences in clinical or radiological scores. For the MB group, the mean linear wear rate on the under-surface was 0.026 mm/year (SD 0.014). This was significantly smaller than the wear rate of 0.11 mm/year (SD 0.06) in the MB between femur and polyethylene (p < 0.001). Nevertheless, even in a best-case setting the mobile bearings of this TKR design had no apparent advantage in terms of fixation over the FB knee prosthesis at ten to 12 years. The wear underneath the mobile bearing was small and is unlikely to be clinically relevant. PMID- 23015563 TI - Does the posterolateral bundle influence rotational movement more than the anteromedial bundle in anterior cruciate ligament reconstruction?: a clinical study. AB - The biomechanical function of the anteromedial (AM) and posterolateral (PL) bundles of the anterior cruciate ligament (ACL) remains controversial. Some studies report that the AM bundle stabilises the knee joint in anteroposterior (AP) translation and rotational movement (both internal and external) to the same extent as the PL bundle. Others conclude that the PL bundle is more important than the AM in controlling rotational movement. The objective of this randomised cohort study involving 60 patients (39 men and 21 women) with a mean age of 32.9 years (18 to 53) was to evaluate the function of the AM and the PL bundles of the ACL in both AP and rotational movements of the knee joint after single-bundle and double-bundle ACL reconstruction using a computer navigation system. In the double-bundle group the patients were also randomised to have the AM or the PL bundle tensioned first, with knee laxity measured after each stage of reconstruction. All patients had isolated complete ACL tears, and the presence of a meniscal injury was the only supplementary pathology permitted for inclusion in the trial. The KT-1000 arthrometer was used to apply a constant load to evaluate the AP translation and the rolimeter was used to apply a constant rotational force. For the single-bundle group deviation was measured before and after ACL reconstruction. In the double-bundle group deviation was measured for the ACL-deficient, AM- or PL-reconstructed first conditions and for the total reconstruction. We found that the AM bundle in the double-bundle group controlled rotation as much as the single-bundle technique, and to a greater extent than the PL bundle in the double-bundle technique. The double-bundle technique increases AP translation and rotational stability in internal rotation more than the single-bundle technique. PMID- 23015564 TI - The adverse effect of elevated body mass index on outcome after autologous chondrocyte implantation. AB - We analysed whether a high body mass index (BMI) had a deleterious effect on outcome following autologous chondrocyte implantation (ACI) or matrix-carried autologous chondrocyte implantation (MACI) for the treatment of full-thickness chondral defects of the knee from a subset of patients enrolled in the ACI vs MACI trial at The Royal National Orthopaedic Hospital. The mean Modified Cincinnati scores (MCS) were significantly higher (p < 0.001) post-operatively in patients who had an ideal body weight (n = 53; 20 to 24.9 kg/m(2)) than in overweight (n = 63; 25 to 30 kg/m(2)) and obese patients (n = 22; > 30 kg/m(2)). At a follow-up of two years, obese patients demonstrated no sustained improvement in the MCS. Patients with an ideal weight experienced significant improvements as early as six months after surgery (p = 0.007). In total, 82% of patients (31 of 38) in the ideal group had a good or excellent result, compared with 49% (22 of 45) of the overweight and 5.5% (one of 18) in the obese group (p < 0.001). There was a significant negative relationship between BMI and the MCS 24 months after surgery (r = -0.4, p = 0.001). This study demonstrates that obese patients have worse knee function before surgery and experience no sustained benefit from ACI or MACI at two years after surgery. There was a correlation between increasing BMI and a lower MCS according to a linear regression analysis. On the basis of our findings patient selection can be more appropriately targeted. PMID- 23015565 TI - Management of peri-prosthetic fracture of the humerus with severe bone loss and loosening of the humeral component after total shoulder replacement. AB - There is little information about the management of peri-prosthetic fracture of the humerus after total shoulder replacement (TSR). This is a retrospective review of 22 patients who underwent a revision of their original shoulder replacement for peri-prosthetic fracture of the humerus with bone loss and/or loose components. There were 20 women and two men with a mean age of 75 years (61 to 90) and a mean follow-up 42 months (12 to 91): 16 of these had undergone a previous revision TSR. Of the 22 patients, 12 were treated with a long-stemmed humeral component that bypassed the fracture. All their fractures united after a mean of 27 weeks (13 to 94). Eight patients underwent resection of the proximal humerus with endoprosthetic replacement to the level of the fracture. Two patients were managed with a clam-shell prosthesis that retained the original components. The mean Oxford shoulder score (OSS) of the original TSRs before peri-prosthetic fracture was 33 (14 to 48). The mean OSS after revision for fracture was 25 (9 to 31). Kaplan-Meier survival using re intervention for any reason as the endpoint was 91% (95% confidence interval (CI) 68 to 98) and 60% (95% CI 30 to 80) at one and five years, respectively. There were two revisions for dislocation of the humeral head, one open reduction for modular humeral component dissociation, one internal fixation for nonunion, one trimming of a prominent screw and one re-cementation for aseptic loosening complicated by infection, ultimately requiring excision arthroplasty. Two patients sustained nerve palsies. Revision TSR after a peri-prosthetic humeral fracture associated with bone loss and/or loose components is a salvage procedure that can provide a stable platform for elbow and hand function. Good rates of union can be achieved using a stem that bypasses the fracture. There is a high rate of complications and function is not as good as with the original replacement. PMID- 23015566 TI - Collagenase for Dupuytren's disease of the thumb. AB - Injectable collagenase is an alternative to surgical treatment for Dupuytren's disease. Previous studies have reported on the effectiveness of collagenase in finger contractures. This prospective study reports on the short-term safety and efficacy of collagenase treatment in five thumb and first web space Dupuytren's contractures. The thumb and first web space contractures were treated with injectable collagenase in four consecutive patients (five hands) with experience of previous surgical digital fasciectomy. The thumb contracture was measured by angle and span in two planes of thumb extension and abduction before injection and after manipulation. Collagenase treatment resulted in release of the contracture with a mean increase in thumb to index angle from 23 degrees (10 degrees to 35 degrees ) to 56 degrees (45 degrees to 60 degrees ) in extension and from 30 degrees (10 degrees to 50 degrees ) to 58 degrees (50 degrees to 65 degrees ) in abduction and a mean increase in span from 1.9 cm (1 to 3.5) to 3.9 cm (3 to 5) in extension and from 2.4 cm (1.5 to 3.5) to 3.9 cm (3 to 4.5) in abduction. All patients reported an increased range of movement and function and described collagenase therapy as preferable to surgery. In the short-term collagenase is an effective, well-tolerated and safe alternative to surgery for Dupuytren's disease of the thumb. PMID- 23015567 TI - Hybrid versus total pedicle screw instrumentation in patients undergoing surgery for neuromuscular scoliosis: a comparative study with matched cohorts. AB - We compared the clinical, radiological and quality-of-life outcomes between hybrid and total pedicle screw instrumentation in patients undergoing surgery for neuromuscular scoliosis. A matched comparison using prospectively collected data was undertaken. A total of 66 patients underwent posterior or anteroposterior correction and fusion with hybrid (n = 33, mean age at surgery 15.8 years (9.10 to 19.6)) or total pedicle screw instrumentation (n = 33, mean age 14.7 years (7.0 to 20.7)) with a minimum follow-up of two years. The major curve pre operatively was a mean of 87 degrees (SD 29, 25 degrees to 141 degrees ) and 81 degrees (SD 18, 47 degrees to 116 degrees ) in the hybrid and total pedicle screw groups, respectively (p = 0.29) and at a minimum of two years it was 33 degrees (SD 20; 2 degrees to 87 degrees ) and 20 degrees (SD 12; 1 degrees to 55 degrees ), respectively (p = 0.0016). The mean correction of the major curve was 59% (41% to 88%) in the hybrid and 75% (43% to 99%) in the total pedicle screw groups at two-year follow-up (p = 0.0011). The mean operating time was 7.45 hours (SD 2.18) and 6.04 hours (SD 1.71) in the hybrid and total pedicle screw groups, respectively (p = 0.001), and the mean intra-operative blood loss was 3760 ml (SD 2790) and 1785 ml (SD 1110), respectively (p = 0.001). Total pedicle screw instrumentation provided shorter operating times, less blood loss and better correction of the major curve compared with hybrid constructs in patients undergoing surgery for neuromuscular scoliosis. PMID- 23015568 TI - Spondylodiscitis in infancy: a potentially fatal condition that can lead to major spinal complications. AB - An eight-week-old boy developed severe thoracic spondylodiscitis following pneumonia and septicaemia. A delay in diagnosis resulted in complete destruction of the T4 and T5 vertebral bodies and adjacent discs, with a paraspinal abscess extending into the mediastinum and epidural space. Antibiotic treatment controlled the infection and the abscess was aspirated. At the age of six months, he underwent posterior spinal fusion in situ to stabilise the spine and prevent progressive kyphosis. At the age of 13 months, repeat imaging showed lack of anterior vertebral body re-growth and he underwent anterior spinal fusion from T3 to T6 and augmentation of the posterior fusion. At the age of five years, he had no symptoms and radiographs showed bony fusion across the affected levels. Spondylodiscitis should be included in the differential diagnosis of infants who present with severe illness and atypical symptoms. Delayed diagnosis can result in major spinal complications with a potentially fatal outcome. PMID- 23015569 TI - The clinical and radiological outcome of pulsed electromagnetic field treatment for acute scaphoid fractures: a randomised double-blind placebo-controlled multicentre trial. AB - The use of pulsed electromagnetic fields (PEMF) to stimulate bone growth has been recommended as an alternative to the surgical treatment of ununited scaphoid fractures, but has never been examined in acute fractures. We hypothesised that the use of PEMF in acute scaphoid fractures would accelerate the time to union by 30% in a randomised, double-blind, placebo-controlled, multicentre trial. A total of 53 patients in three different medical centres with a unilateral undisplaced acute scaphoid fracture were randomly assigned to receive either treatment with PEMF (n = 24) or a placebo (n = 29). The clinical and radiological outcomes were assessed at four, six, nine, 12, 24 and 52 weeks. A log-rank analysis showed that neither time to clinical and radiological union nor the functional outcome differed significantly between the groups. The clinical assessment of union indicated that at six weeks tenderness in the anatomic snuffbox (p = 0.03) as well as tenderness on longitudinal compression of the scaphoid (p = 0.008) differed significantly in favour of the placebo group. We conclude that stimulation of bone growth by PEMF has no additional value in the conservative treatment of acute scaphoid fractures. PMID- 23015570 TI - Modification of the Resch procedure: a new technique and its results in managing three- and four-part proximal humeral fractures. AB - Controversy surrounds the management of displaced three- and four-part fractures of the proximal humerus. The percutaneous Resch technique of stabilisation involves minimal soft-tissue dissection and a reduced risk of stiffness and avascular necrosis. However, it requires a second operation to remove Kirschner wires and the humeral block. We describe a modification of this technique that dispenses with the need for this second operation and relies on a sequential pattern of screw placement. We report the outcome of 32 three- or four-part fractures of the proximal humerus treated in this way at a mean follow-up of 3.8 years (2 to 8)). There were 14 men and 18 women with a mean age of 56 years (28 to 83). At final follow-up the mean Oxford shoulder scores were 38 (31 to 44) and 39 (31 to 42), and the mean Constant scores were 79 (65 to 92) and 72 (70 to 80) for three- and four-part fractures, respectively. We further analysed the results in patients aged < 60 years with high-energy fractures and those aged >= 60 years with osteoporotic fractures. There were no cases of nonunion or avascular necrosis. The results were good and comparable to those previously reported for the Resch technique and other means of fixation for proximal humeral fractures. We would recommend this modification of the technique for the treatment of displaced three-part and four-part fractures in patients both younger and older than 60 years of age. PMID- 23015571 TI - The outcomes of navigation-assisted bone tumour surgery: minimum three-year follow-up. AB - We evaluated the oncological and functional outcome of 18 patients, whose malignant bone tumours were excised with the assistance of navigation, and who were followed up for more than three years. There were 11 men and seven women, with a mean age of 31.8 years (10 to 57). There were ten operations on the pelvic ring and eight joint-preserving limb salvage procedures. The resection margins were free of tumour in all specimens. The tumours, which were stage IIB in all patients, included osteosarcoma, high-grade chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma of bone, and adamantinoma. The overall three-year survival rate of the 18 patients was 88.9% (95% confidence interval (CI) 75.4 to 100). The three-year survival rate of the patients with pelvic malignancy was 80.0% (95% CI 55.3 to 100), and of the patients with metaphyseal malignancy was 100%. The event-free survival was 66.7% (95% CI 44.9 to 88.5). Local recurrence occurred in two patients, both of whom had a pelvic malignancy. The mean Musculoskeletal Tumor Society functional score was 26.9 points at a mean follow-up of 48.2 months (22 to 79). We suggest that navigation can be helpful during surgery for musculoskeletal tumours; it can maximise the accuracy of resection and minimise the unnecessary sacrifice of normal tissue by providing precise intra-operative three-dimensional radiological information. PMID- 23015572 TI - Somatosensory evoked potential monitoring of peripheral nerves during external fixation for limb lengthening and correction of deformity in children. AB - We undertook a retrospective analysis of 306 procedures on 233 patients, with a mean age of 12 years (1 to 21), in order to evaluate the use of somatosensory evoked potential (SSEP) monitoring for the early detection of nerve compromise during external fixation procedures for limb lengthening and correction of deformity. Significant SSEP changes were identified during 58 procedures (19%). In 32 instances (10.5%) the changes were transient, and resolved once the surgical cause had been removed. The remaining 26 (8.5%) were analysed in two groups, depending on whether or not corrective action had been performed in response to critical changes in the SSEP recordings. In 16 cases in which no corrective action was taken, 13 (81.2%, 4.2% overall) developed a post operative neurological deficit, six of which were permanent and seven temporary, persisting for five to 18 months. In the ten procedures in which corrective action was taken, four patients (40%, 1.3% overall) had a temporary (one to eight months) post-operative neuropathy and six had no deficit. After appropriate intervention in response to SSEP changes, the incidence and severity of neurological deficits were significantly reduced, with no cases of permanent neuropathy. SSEP monitoring showed 100% sensitivity and 91% specificity for the detection of nerve injury during external fixation. It is an excellent diagnostic technique for identifying nerve lesions when they are still highly reversible. PMID- 23015573 TI - Smoking affects mRNA expression of bone morphogenetic proteins in human periosteum. AB - Periosteum is important for bone homoeostasis through the release of bone morphogenetic proteins (BMPs) and their effect on osteoprogenitor cells. Smoking has an adverse effect on fracture healing and bone regeneration. The aim of this study was to evaluate the effect of smoking on the expression of the BMPs of human periosteum. Real-time polymerase chain reaction was performed for BMP-2,-4,-6,-7 gene expression in periosteal samples obtained from 45 fractured bones (19 smokers, 26 non-smokers) and 60 non-fractured bones (21 smokers, 39 non-smokers). A hierarchical model of BMP gene expression (BMP-2 > BMP-6 > BMP-4 > BMP-7) was demonstrated in all samples. When smokers and non smokers were compared, a remarkable reduction in the gene expression of BMP-2, 4 and -6 was noticed in smokers. The comparison of fracture and non-fracture groups demonstrated a higher gene expression of BMP-2, -4 and -7 in the non fracture samples. Within the subgroups (fracture and non-fracture), BMP gene expression in smokers was either lower but without statistical significance in the majority of BMPs, or similar to that in non-smokers with regard to BMP-4 in fracture and BMP-7 in non-fracture samples. In smokers, BMP gene expression of human periosteum was reduced, demonstrating the effect of smoking at the molecular level by reduction of mRNA transcription of periosteal BMPs. Among the BMPs studied, BMP-2 gene expression was significantly higher, highlighting its role in bone homoeostasis. PMID- 23015574 TI - The role of the sensory nerve response in ultrasound accelerated fracture repair. AB - This study was designed to test the hypothesis that the sensory innervation of bone might play an important role in sensing and responding to low-intensity pulsed ultrasound and explain its effect in promoting fracture healing. In 112 rats a standardised mid-shaft tibial fracture was created, supported with an intramedullary needle and divided into four groups of 28. These either had a sciatic neurectomy or a patellar tendon resection as control, and received the ultrasound or not as a sham treatment. Fracture union, callus mineralisation and remodelling were assessed using plain radiography, peripheral quantitative computed tomography and histomorphology. Daily ultrasound treatment significantly increased the rate of union and the volumetric bone mineral density in the fracture callus in the neurally intact rats (p = 0.025), but this stimulating effect was absent in the rats with sciatic neurectomy. Histomorphology demonstrated faster maturation of the callus in the group treated with ultrasound when compared with the control group. The results supported the hypothesis that intact innervation plays an important role in allowing low-intensity pulsed ultrasound to promote fracture healing. PMID- 23015576 TI - Review of VA/DOD Clinical Practice Guideline on management of acute stress and interventions to prevent posttraumatic stress disorder. AB - This article summarizes the recommendations of the Department of Veterans Affairs (VA)/Department of Defense (DOD) VA/DOD Clinical Practice Guideline for Management of Post-Traumatic Stress that pertain to acute stress and the prevention of posttraumatic stress disorder, including screening and early interventions for acute stress states in various settings. Recommended interventions during the first 4 days after a potentially traumatic event include attending to safety and basic needs and providing access to physical, emotional, and social resources. Psychological first aid is recommended for management of acute stress, while psychological debriefing is discouraged. Further medical and psychiatric assessment and provision of brief, trauma-focused cognitive behavioral therapy are warranted if clinically significant distress or functional impairment persists or worsens after 2 days or if the criteria for a diagnosis of acute stress disorder are met. Follow-up monitoring and rescreening are endorsed for at least 6 months for everyone who experiences significant acute posttraumatic stress. Four interventions that illustrate early intervention principles contained in the VA/DOD Clinical Practice Guideline are described. PMID- 23015577 TI - Assessment of posttraumatic stress disorder-related functional impairment: a review. AB - In 2010, the Department of Veterans Affairs (VA) and Department of Defense (DOD) jointly published the revised VA/DOD Clinical Practice Guideline for Management of Posttraumatic Stress. The Clinical Practice Guideline (CPG) provides evidence based recommendations for diagnosing and treating a spectrum of stress-related disorders. Included in the CPG were recommendations for assessing posttraumatic stress disorder (PTSD) and other stress disorder-related functional impairment. This article complements those CPG recommendations by providing information that may further guide clinicians in the assessment of functional impairment related to PTSD and other stress-related disorders. We briefly review some of the empirical literature on the association between PTSD and functional impairment and some of the more frequently used methods and measures for assessing functional impairment and introduce a new measure currently being developed by our group. We suggest that information obtained via patient self-report and/or clinician rating be supplemented whenever possible with collateral data from friends, family members, coworkers, or supervisors to provide a complete picture of current and premorbid functional status. Finally, we explore several important issues that we encourage clinicians to keep in mind when assessing functional impairment among Veterans and Active Duty servicemembers. PMID- 23015578 TI - Dissemination and experience with cognitive processing therapy. AB - Clinical practice guidelines suggest that cognitive behavioral therapies are recommended for the treatment of posttraumatic stress disorder (PTSD). One of these treatments, cognitive processing therapy (CPT), is an evidence-based treatment that has been shown to be effective at treating combat, assault, and interpersonal violence trauma in randomized controlled trials. The Department of Veterans Affairs (VA) Office of Mental Health Services has implemented an initiative to disseminate CPT as part of a broad effort to make evidence-based psychotherapies widely available throughout the VA healthcare system. This article provides an overview of CPT and reviews the efficacy and program evaluation data supporting its use in a variety of settings. In addition, we report on survey data from individuals who have participated in the VA initiative and on outcome data from patients treated by rollout-trained therapists. Our data suggest that many clinicians trained in the rollout show good adoption of the CPT model and demonstrate solid improvements in their patients' PTSD and depressive symptomotology. Finally, we offer recommendations for using CPT in clinical settings. PMID- 23015579 TI - Review of exposure therapy: a gold standard for PTSD treatment. AB - Prolonged exposure (PE) is an effective first-line treatment for posttraumatic stress disorder (PTSD), regardless of the type of trauma, for Veterans and military personnel. Extensive research and clinical practice guidelines from various organizations support this conclusion. PE is effective in reducing PTSD symptoms and has also demonstrated efficacy in reducing comorbid issues such as anger, guilt, negative health perceptions, and depression. PE has demonstrated efficacy in diagnostically complex populations and survivors of single- and multiple-incident traumas. The PE protocol includes four main therapeutic components (i.e., psychoeducation, in vivo exposure, imaginal exposure, and emotional processing). In light of PE's efficacy, the Veterans Health Administration designed and supported a PE training program for mental health professionals that has trained over 1,300 providers. Research examining the mechanisms involved in PE and working to improve its acceptability, efficacy, and efficiency is underway with promising results. PMID- 23015580 TI - Review of group treatment for PTSD. AB - The purpose of this article is to provide a brief review of group treatment for posttraumatic stress disorder (PTSD). This review includes a description of group based treatments for PTSD and the available data on the efficacy of group treatment for PTSD. The literature review indicates that group treatment for PTSD is efficacious compared with no treatment. However, specific types of group treatment are not efficacious when compared with a nonspecific group treatment, such as psychoeducation or supportive counseling. Recommendations for practice and research are made in light of the available literature. PMID- 23015581 TI - Pharmacotherapy for posttraumatic stress disorder: review with clinical applications. AB - Posttraumatic stress disorder (PTSD) is a prevalent psychiatric diagnosis among veterans and has high comorbidity with other medical and psychiatric conditions. This article reviews the pharmacotherapy recommendations from the 2010 revised Department of Veterans Affairs/Department of Defense Clinical Practice Guideline (CPG) for PTSD and provides practical PTSD treatment recommendations for clinicians. While evidence-based, trauma-focused psychotherapy is the preferred treatment for PTSD, pharmacotherapy is also an important treatment option. First line pharmacotherapy agents include selective serotonin reuptake inhibitors and the selective serotonin-norepinephrine reuptake inhibitor venlafaxine. Second line agents have less evidence for their usefulness in PTSD and carry a potentially greater side effect burden. They include nefazodone, mirtazapine, tricyclic antidepressants, and monoamine oxidase inhibitors. Prazosin is beneficial for nightmares. Benzodiazepines and antipsychotics, either as monotherapy or used adjunctively, are not recommended in the treatment of PTSD. Treating co-occurring disorders, such as major depressive disorder, substance use disorders, and traumatic brain injury, is essential in maximizing treatment outcomes in PTSD. The CPG provides evidence-based treatment recommendations for treating PTSD with and without such co-occurring disorders. PMID- 23015582 TI - Couple/family therapy for posttraumatic stress disorder: review to facilitate interpretation of VA/DOD Clinical Practice Guideline. AB - A well-documented association exists among Veterans' posttraumatic stress disorder (PTSD) symptoms, family relationship problems, and mental health problems in partners and children of Veterans. This article reviews the recommendations regarding couple/family therapy offered in the newest version of the Department of Veterans Affairs (VA)/Department of Defense (DOD) VA/DOD Clinical Practice Guideline for Management of Post-Traumatic Stress. We then provide a heuristic for clinicians, researchers, and policy makers to consider when incorporating couple/family interventions into Veterans' mental health services. The range of research that has been conducted on couple/family therapy for Veterans with PTSD is reviewed using this heuristic, and suggestions for clinical practice are offered. PMID- 23015583 TI - Treatment of sleep disturbances in posttraumatic stress disorder: a review. AB - Sleep disturbances are among the most commonly reported posttraumatic stress disorder (PTSD) symptoms. It is essential to conduct a careful assessment of the presenting sleep disturbance to select the optimal available treatment. Cognitive behavioral therapies (CBTs) are at least as effective as pharmacologic treatment in the short-term and more enduring in their beneficial effects. Cognitive behavioral treatment for insomnia and imagery rehearsal therapy have been developed to specifically treat insomnia and nightmares and offer promise for more effective relief of these very distressing symptoms. Pharmacotherapy continues to be an important treatment choice for PTSD sleep disturbances as an adjunct to CBT, when CBT is ineffective or not available, or when the patient declines CBT. Great need exists for more investigation into the effectiveness of specific pharmacologic agents for PTSD sleep disturbances and the dissemination of the findings to prescribers. The studies of prazosin and the findings of its effectiveness for PTSD sleep disturbance are examples of studies of pharmacologic agents needed in this area. Despite the progress made in developing more specific treatments for sleep disturbances in PTSD, insomnia and nightmares may not fully resolve. PMID- 23015584 TI - Review of posttraumatic stress disorder and chronic pain: the path to integrated care. AB - With the large number of Veterans experiencing posttraumatic stress disorder (PTSD) and chronic pain, the purpose of this article is to review the prevalence of PTSD and chronic pain, the theoretical models that explain the maintenance of both conditions, and the challenges faced by providers and families who care for these patients. The Department of Veterans Affairs (VA)/Department of Defense (DOD) VA/DOD Clinical Practice Guideline for Management of Post-Traumatic Stress with special attention to chronic pain is presented. Limited scientific evidence supports specific care and treatment of PTSD and chronic pain, and this challenges providers to investigate and research potential treatment options. Integrated care models designed for working with these patients are reviewed, including a focus on the techniques and strategies to address not only PTSD and chronic pain, but other conditions, including substance dependence and depression. A specific focus on headaches, back pain, and neuropathic pain follows, including treatment recommendations such as pharmacological, psychotherapeutic, and complementary approaches, given the high rates of these pain complaints for Veterans in PTSD clinical programs. Integrated care is presented as a viable solution and approach that challenges clinicians and researchers to develop innovative, scientifically based therapeutics and treatments to enhance the recovery and quality of life for Veterans with PTSD and chronic pain. PMID- 23015585 TI - Assessment and treatment of posttraumatic anger and aggression: a review. AB - The Department of Veterans Affairs (VA) and Department of Defense's (DOD) recently published and updated Department of Veterans Affairs/Department of Defense VA/ DOD Clinical Practice Guideline for Management of PostTraumatic Stress includes irritability, severe agitation, and anger as specific symptoms that frequently co-occur with PTSD. For the first time, the guideline includes nine specific recommendations for the assessment and treatment of PTSD-related anger, irritability, and agitation. This article will review the literature on PTSD and its association with anger and aggression. We highlight explanatory models for these associations, factors that contribute to the occurrence of anger and aggression in PTSD, assessment of anger and aggression, and effective anger management interventions and strategies. PMID- 23015586 TI - Review: managing posttraumatic stress disorder in combat veterans with comorbid traumatic brain injury. AB - Military deployments to Afghanistan and Iraq have been associated with elevated prevalence of both posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) among combat veterans. The diagnosis and management of PTSD when a comorbid TBI may also exist presents a challenge to interdisciplinary care teams at Department of Veterans Affairs (VA) and civilian medical facilities, particularly when the patient reports a history of blast exposure. Treatment recommendations from VA and Department of Defense's (DOD) recently updated VA/DOD Clinical Practice Guideline for Management of Post-Traumatic Stress are considered from the perspective of simultaneously managing comorbid TBI. PMID- 23015587 TI - Treatment for PTSD: clinical practice guidelines and steps toward further knowledge. PMID- 23015588 TI - 2010 VA/DOD Clinical Practice Guideline for Management of Post-Traumatic Stress: how busy clinicians can best adopt updated recommendations. PMID- 23015589 TI - Bridging the gap in delivery of psychological treatments for posttraumatic stress disorder. PMID- 23015590 TI - The VA/DOD Clinical Practice Guideline for Management of Post-Traumatic Stress (update 2010): development and methodology. PMID- 23015591 TI - Ctip2 is a dynamic regulator of epidermal proliferation and differentiation by integrating EGFR and Notch signaling. AB - Epidermal morphogenesis results from a delicate balance between keratinocyte proliferation and differentiation, and this balance is perturbed upon deletion of transcription factor Ctip2. Here we demonstrate that Ctip2, in a cell autonomous manner, controls keratinocyte proliferation and cytoskeletal organization, and regulates the onset and maintenance of differentiation in keratinocytes in culture. Ctip2 integrates keratinocyte proliferation and the switch to differentiation by directly and positively regulating EGFR transcription in proliferating cells and Notch1 transcription in differentiating cells. In proliferative cells, the EGFR promoter is occupied by Ctip2, whereas Ctip2 is only recruited to the Notch1 promoter under differentiating conditions. Activation of EGFR signaling downregulates Ctip2 at the transcript level, whereas high calcium signaling triggers SUMOylation, ubiquitination and proteasomal degradation of Ctip2 at the protein level. Together, our findings demonstrate a novel mechanism(s) of Ctip2-mediated, coordinated control of epidermal proliferation and terminal differentiation, and identify a pathway of negative feedback regulation of Ctip2 during epidermal development. PMID- 23015592 TI - Interactions between ICAM-5 and beta1 integrins regulate neuronal synapse formation. AB - Intercellular adhesion molecule-5 (ICAM-5) is a dendrite-specific adhesion molecule, which functions in both the immune and nervous systems. ICAM-5 is the only negative regulator that has been identified for maturation of dendritic spines so far. Shedding of the ICAM-5 ectodomain promotes spine maturation and enhances synaptic activity. However, the mechanism by which ICAM-5 regulates spine development remains poorly understood. In this study, we found that ablation of ICAM5 expression resulted in a significant increase in the formation of synaptic contacts and the frequency of miniature excitatory post-synaptic currents, an indicator of pre-synaptic release probability. Antibodies against ICAM-5 and beta1 integrins altered spine maturation. Furthermore, we found that beta1 integrins serve as binding partners for ICAM-5. beta1 integrins were immunoprecipitated with ICAM-5 from mouse brain and the binding region in ICAM-5 was localized to the two first Ig domains. beta1 integrins were juxtaposed to filopodia tips at the early stage of synaptic formation, but as synapses matured, beta1 integrins covered the mushroom spines. Loss of beta1 integrins from the pre synaptic sites affected the morphology of the post-synaptic structures. ICAM-5 ectodomain cleavage decreased or increased when the interaction between ICAM-5 and beta1 integrins was potentiated or weakened, respectively, using antibodies. These results suggest that the interaction between ICAM-5 and beta1 integrins is important in formation of functional synapses. PMID- 23015593 TI - Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM dependent G2/M arrest and aneuploidy through DNA replication stress. AB - Mitochondrial fission and fusion cycles are integrated with cell cycle progression. In this paper, we demonstrate that the inhibition of mitochondrial fission protein Drp1 causes an unexpected delay in G2/M cell cycle progression and aneuploidy. In investigating the underlying molecular mechanism, we revealed that inhibiting Drp1 triggers replication stress, which is mediated by a hyperfused mitochondrial structure and unscheduled expression of cyclin E in the G2 phase. This persistent replication stress then induces an ATM-dependent activation of the G2 to M transition cell cycle checkpoint. Knockdown of ATR, an essential kinase in preventing replication stress, significantly enhanced DNA damage and cell death of Drp1-deficienct cells. Persistent mitochondrial hyperfusion also induces centrosomal overamplification and chromosomal instability, which are causes of aneuploidy. Analysis using cells depleted of mitochondrial DNA revealed that these events are not mediated by the defects in mitochondrial ATP production and reactive oxygen species (ROS) generation. Thus dysfunctional mitochondrial fission directly induces genome instability by replication stress, which then initiates the DNA damage response. Our findings provide a novel mechanism that contributes to the cellular dysfunction and diseases associated with altered mitochondrial dynamics. PMID- 23015594 TI - Poc1A and Poc1B act together in human cells to ensure centriole integrity. AB - Proteomic studies in unicellular eukaryotes identified a set of centriolar proteins that included proteome of centriole 1 (Poc1). Functional studies in these organisms implicated Poc1 in centriole duplication and length control, as well as ciliogenesis. Using isoform-specific antibodies and RNAi depletion, we have examined the function of the two related human proteins, Poc1A and Poc1B. We find that Poc1A and Poc1B each localize to centrioles and spindle poles, but do so independently and with different dynamics. However, although loss of one or other Poc1 protein does not obviously disrupt mitosis, depletion of both proteins leads to defects in spindle organization with the generation of unequal or monopolar spindles. Our data indicate that, once incorporated, a fraction of Poc1A and Poc1B remains stably associated with parental centrioles, but that depletion prevents incorporation into nascent centrioles. Nascent centrioles lacking both Poc1A and Poc1B exhibit loss of integrity and maturation, and fail to undergo duplication. Thus, when Poc1A and Poc1B are co-depleted, new centrosomes capable of maturation cannot assemble and unequal spindles result. Interestingly, Poc1B, but not Poc1A, is phosphorylated in mitosis, and depletion of Poc1B alone was sufficient to perturb cell proliferation. Hence, Poc1A and Poc1B play redundant, but essential, roles in generation of stable centrioles, but Poc1B may have additional independent functions during cell cycle progression. PMID- 23015595 TI - Electron tomography of the microtubule cytoskeleton in multinucleated hyphae of Ashbya gossypii. AB - We report the mechanistic basis guiding the migration pattern of multiple nuclei in hyphae of Ashbya gossypii. Using electron tomography, we reconstructed the cytoplasmic microtubule (cMT) cytoskeleton in three tip regions with a total of 13 nuclei and also the spindle microtubules of four mitotic nuclei. Each spindle pole body (SPB) nucleates three cMTs and most cMTs above a certain length grow according to their plus-end structure. Long cMTs closely align for several microns along the cortex, presumably marking regions where dynein generates pulling forces on nuclei. Close proximity between cMTs emanating from adjacent nuclei was not observed. The majority of nuclei carry duplicated side-by-side SPBs, which together emanate an average of six cMTs, in most cases in opposite orientation with respect to the hyphal growth axis. Such cMT arrays explain why many nuclei undergo short-range back and forth movements. Only occasionally do all six cMTs orient in one direction, a precondition for long-range nuclear bypassing. Following mitosis, daughter nuclei carry a single SPB with three cMTs. The increased probability that all three cMTs orient in one direction explains the high rate of nuclear bypassing observed in these nuclei. The A. gossypii mitotic spindle was found to be structurally similar to that of Saccharomyces cerevisiae in terms of nuclear microtubule (nMT) number, length distribution and three-dimensional organization even though the two organisms differ significantly in chromosome number. Our results suggest that two nMTs attach to each kinetochore in A. gossypii and not only one nMT like in S. cerevisiae. PMID- 23015596 TI - Clathrin is not required for SNX-BAR-retromer-mediated carrier formation. AB - Clathrin has been implicated in retromer-mediated trafficking, but its precise function remains elusive. Given the importance of retromers for efficient endosomal sorting, we have sought to clarify the relationship between clathrin and the SNX-BAR retromer. We find that the retromer SNX-BARs do not interact directly or indirectly with clathrin. In addition, we observe that SNX-BAR retromer tubules and carriers are not clathrin coated. Furthermore, perturbing clathrin function, by overexpressing a dominant-negative clathrin or through suppression of clathrin expression, has no detectable effect on the frequency of SNX-BAR-retromer tubulation. We propose that SNX-BAR-retromer-mediated membrane deformation and carrier formation does not require clathrin, and hence the role of clathrin in SNX-BAR-retromer function would appear to lie in pre-SNX-BAR retromer cargo sorting. PMID- 23015597 TI - Mental health effects from urban bed bug infestation (Cimex lectularius L.): a cross-sectional study. AB - OBJECTIVE: To assess whether bed bug infestation was linked to sleep disturbances and symptoms of anxiety and depression. DESIGN: Exploratory cross-sectional study. SETTING: Convenience sample of tenants recruited in apartment complexes from Montreal, Canada. PARTICIPANTS: 39 bed bug-exposed tenants were compared with 52 unexposed tenants. MAIN OUTCOME MEASURES: The effect of bed bug-exposed tenants on sleep disturbances, anxiety and depression symptoms measured using the Pittsburgh Sleep Quality Index, 5th subscale, Generalised Anxiety Disorder 7-item scale and Patient Health Questionnaire, 9-item, respectively. RESULTS: In adjusted models, bed bug infestation was strongly associated with measured anxiety symptoms (OR (95% CI)=4.8 (1.5 to 14.7)) and sleep disturbance (OR (95% CI)=5.0 (1.3-18.8)). There was a trend to report more symptoms of depression in the bed bug-infested group, although this finding was not statistically significant ((OR (95% CI)=2.5(0.8 to 7.3)). CONCLUSIONS: These results suggest that individuals exposed to bed bug infestations are at risk of experiencing sleep disturbance and of developing symptoms of anxiety and possibly depression. Greater clinical awareness of this problem is needed in order for patients to receive appropriate mental healthcare. These findings highlight the need for undertaking of deeper inquiry, as well as greater collaboration between medical professionals, public health and community stakeholders. PMID- 23015598 TI - Staff's perception of abuse in healthcare: a Swedish qualitative study. AB - OBJECTIVE: The study aim was to apprehend staff's perception of abuse in healthcare (AHC) after an intervention based on 'Forum Play', and make comparisons to preintervention interviews and interviews with male and female patients. AHC can be described as a failing encounter from the patient's perspective. DESIGN: Qualitative interview follow-up study. SETTING: A Swedish Women's Clinic. PARTICIPANTS: In a preintervention study 21 staff members were interviewed. Eligible for the follow-up study were 14 informants who had participated in the intervention. Four declined participation leaving ten informants for this study. INTERVENTION: During January 2008-January 2009, all staff members (N=136) were invited to participate in Forum Play workshops. Seventy-four participants took part in at least 1 of the 17 half-day workshops. PRIMARY OUTCOME MEASURES: Staffs perception of AHC. RESULTS: The core category, 'a summoning stone in the shoe', was constructed of five categories: 'Dehumanising the patient', 'Unacceptable: you are bound to act!', 'Ubiquitous', 'Unintentional' and 'Relative'. Forum Play had demonstrated possibilities to act even in seemingly 'impossible' situations, and that the taboo status of AHC was altered at the clinic. When our results were compared to those in the preintervention study, we found an increased awareness about AHC, more concrete examples of AHC, a stronger empathy for patients, and fewer explanations, justifications and trivialisations of AHC. CONCLUSION: In this follow-up study staff's perception of AHC was closer to the patient's perspective. Compared to the preintervention interviews staff showed a greater willingness not only to acknowledge AHC, but also to take on a responsibility to act in order to stop or prevent AHC. Explanations for this stance could be that Forum Play had showed staff that there were possibilities to act, and that the taboo status of AHC had been broken at the clinic. PMID- 23015599 TI - Effectiveness of telemedicine and distance learning applications for patients with chronic heart failure. A protocol for prospective parallel group non randomised open label study. AB - INTRODUCTION: Chronic heart failure in Baltic Sea Region is responsible for more hospitalisations than all forms of cancer combined and is one of the leading causes of hospitalisations in elderly patients. Frequent hospitalisations, along with other direct and indirect costs, place financial burden on healthcare systems. We aim to test the hypothesis that telemedicine and distance learning applications is superior to the current standard of home care. METHODS AND ANALYSIS: Prospective parallel group non-randomised open label study in patients with New York Heart Association (NYHA) II-III chronic heart failure will be carried out in six Baltic Sea Region countries. The study is organised into two 6 month follow-up periods. The first 6-month period is based on active implementation of tele-education and/or telemedicine for patients in two groups (active run period) and one standard care group (passive run period). The second 6-month period of observation will be based on standard care model (passive run period) to all three groups. Our proposed practice change is based on translational research with empirically supported interventions brought to practice and aims to find the home care model that is most effective to patient needs. ETHICS AND DISSEMINATION: This study has been approved by National Bioethics Committee (2011-03-07; Registration No: BE-2-11). TRIAL REGISTRATION: This study has been registered in Australian New Zealand Clinical Trials Registry (ANZCTR) with registration number ACTRN12611000834954. PMID- 23015600 TI - Review of quality assessment tools for the evaluation of pharmacoepidemiological safety studies. AB - OBJECTIVES: Pharmacoepidemiological studies are an important hypothesis-testing tool in the evaluation of postmarketing drug safety. Despite the potential to produce robust value-added data, interpretation of findings can be hindered due to well-recognised methodological limitations of these studies. Therefore, assessment of their quality is essential to evaluating their credibility. The objective of this review was to evaluate the suitability and relevance of available tools for the assessment of pharmacoepidemiological safety studies. DESIGN: We created an a priori assessment framework consisting of reporting elements (REs) and quality assessment attributes (QAAs). A comprehensive literature search identified distinct assessment tools and the prespecified elements and attributes were evaluated. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the percentage representation of each domain, RE and QAA for the quality assessment tools. RESULTS: A total of 61 tools were reviewed. Most tools were not designed to evaluate pharmacoepidemiological safety studies. More than 50% of the reviewed tools considered REs under the research aims, analytical approach, outcome definition and ascertainment, study population and exposure definition and ascertainment domains. REs under the discussion and interpretation, results and study team domains were considered in less than 40% of the tools. Except for the data source domain, quality attributes were considered in less than 50% of the tools. CONCLUSIONS: Many tools failed to include critical assessment elements relevant to observational pharmacoepidemiological safety studies and did not distinguish between REs and QAAs. Further, there is a lack of considerations on the relative weights of different domains and elements. The development of a quality assessment tool would facilitate consistent, objective and evidence-based assessments of pharmacoepidemiological safety studies. PMID- 23015601 TI - A national cross-sectional study on effects of fluoride-safe water supply on the prevalence of fluorosis in China. AB - OBJECTIVE: To assess the effects of provided fluoride-safe drinking-water for the prevention and control of endemic fluorosis in China. DESIGN: A national cross sectional study in China. SETTING: In 1985, randomly selected villages in 27 provinces (or cities and municipalities) in 5 geographic areas all over China. PARTICIPANTS: Involved 81 786 children aged from 8 to 12 and 594 698 adults aged over 16. MAIN OUTCOME MEASURE: The prevalence of dental fluorosis and clinical skeletal fluorosis, the fluoride concentrations in the drinking-water in study villages and in the urine of subjects. RESULTS: The study showed that in the villages where the drinking-water fluoride concentrations were higher than the government standard of 1.2 mg/l, but no fluoride-safe drinking-water supply scheme was provided (FNB areas), the prevalence rate and index of dental fluorosis in children, and prevalence rate of clinical skeletal fluorosis in adults were all significantly higher than those in the historical endemic fluorosis villages after the fluoride-safe drinking-water were provided (FSB areas). Additionally, the prevalence rate of dental fluorosis as well as clinical skeletal fluorosis, and the concentration of fluoride in urine were found increased with the increase of fluoride concentration in drinking-water, with significant positive correlations in the FNB areas. While, the prevalence rate of dental fluorosis and clinical skeletal fluorosis in different age groups and their degrees of prevalence were significantly lower in the FSB areas than those in the FNB areas. CONCLUSIONS: The provision of fluoride-safe drinking-water supply schemes had significant effects on the prevention and control of dental fluorosis and skeletal fluorosis. The study also indicated that the dental and skeletal fluorosis is still prevailing in the high-fluoride drinking-water areas in China. PMID- 23015602 TI - Is admission blood glucose concentration a more powerful predictor of mortality after myocardial infarction than diabetes diagnosis? A retrospective cohort study. AB - OBJECTIVE: To explore the relative association of admission blood glucose levels and antecedent diabetes on early and long-term survival in a contemporary UK population of patients with ST elevation myocardial infarction (STEMI) and non STEMI (NSTEMI). DESIGN: Retrospective cohort study based on the Myocardial Ischaemia National Audit Project dataset. SETTING: Tertiary care centre. PARTICIPANTS: 4111 (20.3% known diabetes) consecutive patients admitted with acute myocardial infarction (58.3% STEMI) between October 2002 and September 2008. PRIMARY AND SECONDARY OUTCOME MEASURES: All-cause mortality at 30 days and 1 year. The relative association of admission blood glucose and of antecedent diabetes with mortality was assessed using multivariate Cox regression analysis. Furthermore, we compared these relationships in patients with STEMI to those with NSTEMI. RESULTS: By 30 days and 1 year, 409 (9.9%) and 677 (16.5%) of patients died. After adjusting for covariates, diabetes did not show independent association with mortality at any time point, in the entire cohort (HR 30 days 0.93 (95% CI 0.63 to 1.38); 1 year 1.00 (0.77 to 1.30)) or in subgroups of STEMI (HR 30 days 1.03 (0.65 to 1.64); 1 year 1.08 (0.77 to 1.51)) and NSTEMI (HR 30 days 0.62 (0.26 to 1.50); 1 year 0.87 (0.56 to 1.36)). In contrast, after adjusting for covariates, admission glucose showed robust and independent association with mortality in the entire cohort (HR: 30 days 1.07 (1.04 to 1.10); 1 year 1.05 (1.03 to 1.08)), and in the subgroup of STEMI (30 days 1.07 (1.03 to 1.10); 1 year 1.07 (1.04 to 1.10)), and NSTEMI (HR 30 days 1.07 (1.00 to 1.14); 1 year 1.02 (0.97 to 1.06)). CONCLUSIONS: Admission glucose is strongly associated with mortality in all presentations of acute myocardial infarction (AMI), irrespective of established diabetes diagnosis. The increased risk is maintained up to 1 year. Future studies are required to assess the impact of active management of elevated blood glucose in improving mortality in individuals admitted with AMI. PMID- 23015603 TI - Iron intake, haemoglobin and risk of gestational diabetes: a prospective cohort study. AB - OBJECTIVE: To investigate the possible association between total daily iron intake during pregnancy, haemoglobin in early pregnancy and the risk of gestational diabetes mellitus (GDM) in women at increased risk of GDM. DESIGN: A prospective cohort study (based on a cluster-randomised controlled trial, where the intervention and the usual care groups were combined). SETTING: Primary healthcare maternity clinics in 14 municipalities in south-western Finland. PARTICIPANTS: 399 Pregnant women who were at increased risk of GDM participated in a GDM prevention trial and were followed throughout pregnancy. MAIN OUTCOME MEASUREMENTS: The main outcome was GDM diagnosed with oral glucose tolerance test at 26-28 weeks' gestation or based on a diagnosis recorded in the Finnish Medical Birth registry. Data on iron intake was collected using a 181-item food frequency questionnaire and separate questions for supplement use at 26-28 weeks' gestation. RESULTS: GDM was diagnosed in 72 women (18.1%) in the study population. The OR for total iron intake as a continuous variable was 1.006 (95% CI 1.000 to 1.011; p=0.038) after adjustment for body mass index, age, diabetes in first-degree or second-degree relatives, GDM or macrosomia in earlier pregnancy, total energy intake, dietary fibre, saturated fatty acids and total gestational weight gain. Women in the highest fifth of total daily iron intake had an adjusted OR of 1.66 (95% CI 0.84 to 3.30; p=0.15) for GDM. After excluding participants with low haemoglobin levels (<=120 g/l) already in early pregnancy the adjusted OR was 2.35 (95% CI 1.13 to 4.92; p=0.023). CONCLUSIONS: Our results suggest that high iron intake during pregnancy increases the risk of GDM especially in women who are not anaemic in early pregnancy and who are at increased risk of GDM. These findings suggest that routine iron supplementation should be reconsidered in this risk group of women. PMID- 23015604 TI - Elevated HIV prevalence and risk behaviours among men who have sex with men (MSM) in Vietnam: a systematic review. AB - OBJECTIVES: To review and analyse original studies on HIV prevalence and risk behaviours among men who have sex with men (MSM) in Vietnam. DESIGN: Systematic literature review. Comprehensive identification of material was conducted by systematic electronic searches of selected databases. Inclusion criteria included studies conducted from 2002 onwards, following a systematic review concluding in 2001 conducted by Colby, Nghia Huu and Doussantousse. Data analysis was undertaken through the application of both the Cochrane Collaboration and ePPI Centre approaches to the synthesis of qualitative and quantitative studies. SETTING: Vietnam. RESULTS: Sixteen studies, undertaken during 2005-2011, were identified that met the inclusion criteria. The analysis showed that HIV prevalence among MSM in Vietnam has increased significantly (eg, from 9.4% in 2006 to 20% in 2010 in Hanoi) and that protective behaviours, such as condom use and HIV testing and counselling, continue at inadequately low levels. CONCLUSIONS: Increasing HIV prevalence and the lack of effective protective behaviours such as consistent condom use during anal sex among MSM in Vietnam indicate a potential for a more severe HIV epidemic in the future unless targeted and segmented comprehensive HIV prevention strategies for MSM in Vietnam are designed and programmes implemented. PMID- 23015605 TI - Effects of nicotine mouth spray on urges to smoke, a randomised clinical trial. AB - OBJECTIVE: A new nicotine mouth spray was shown to be an effective stop-smoking treatment. This study was set up to examine the speed with which it relieves urges to smoke, and how it compares with nicotine lozenge in this respect. DESIGN: Randomised, cross-over trial that compared nicotine mouth spray 2 mg versus nicotine lozenge 2 or 4 mg. SETTING: Clinical pharmacology research unit. PARTICIPANTS: 200 Volunteer smokers who smoked their first cigarette of the day within 30 min of waking. INTERVENTIONS: Subjects abstained from smoking the night before the morning they attended the laboratory. Treatment was administered following 5 h of witnessed abstinence. PRIMARY AND SECONDARY OUTCOME MEASURES: Urge to smoke was rated before and at 1, 3, 5, 10, 15, 25, 30, 45 min and 1, 1.5, and 2 h after treatment administration. The primary outcome concerned change during the first 1, 3 and 5 min after treatment administration. RESULTS: Nicotine mouth spray achieved greater reductions in craving than either lozenge during the first 1, 3 and 5 min postadministration. After using mouth spray, half of the users experienced 50% reduction in craving within 3.40 min, while the same treatment effect was achieved within 9.92 and 9.20 min for the 2 and 4 mg lozenge, respectively. Adverse events with both mouth spray and lozenge were mostly mild. Hiccups, local irritation, nausea and dyspepsia were more frequent with spray than lozenge. CONCLUSIONS: Nicotine mouth spray provides a faster relief of cravings than nicotine lozenge. PMID- 23015606 TI - Perceptions of school nurses in the care of students with disabilities. AB - Many children are surviving prematurity and serious childhood illnesses due to advances in technology and medical care. As a result, more children are entering public school systems with complex health care needs and intellectual and developmental disabilities. School nurses are responsible for caring for these children; however, many nurses feel unprepared due to a lack education on disability studies in nursing school, difficulty with effective communication, and a lack of experience. A qualitative study was conducted to explore the perceptions and challenges of school nurses who worked with students with intellectual and developmental disabilities. Participants included eight nurses who worked in a public school setting, and data were collected through personal interviews, observations, and field notes. Results were analyzed categorically, and data showed that school nurses identified that they lacked education in disability studies and encountered challenges with communication, conducting health assessments, and screenings in students with intellectual and developmental disabilities. PMID- 23015607 TI - [Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma]. AB - Targeted therapies such as sunitinib, pazopanib, bevacizumab, sorafenib and everolimus have become established as new therapeutic standards in the treatment of metastatic renal cell carcinoma. New substances are going to complement these treatment options. Therefore, cytokines as long-term standard therapy are being more and more replaced. The achievements raise a lot of questions in clinical daily routine: Which criteria influence the decision for therapy? How can a remission be assessed when antiangiogenetic agents are administered? And last but not least, the optimal sequence remains a controversially discussed topic. Based on the current study situation, an interdisciplinary expert meeting was held to debate these aspects. Results from the 2010 conference provided the basis for the 2011 meeting. The results of the 2011 conference are presented as short theses. PMID- 23015608 TI - Modelling the cost-effectiveness of alcohol screening and brief interventions in primary care in England. AB - AIMS: To estimate the cost-effectiveness and resourcing implications of universal alcohol screening and brief intervention (SBI) programmes in primary care in England. METHODS: This was a health economic model, combining evidence of the effectiveness and health care resource requirements of SBI activities with existing epidemiological modelling of the relationship between alcohol consumption and health harms. RESULTS: Screening patients on registration with a family doctor would steadily capture ~40% of the population over a 10-year programme; screening patients at next primary care consultation would capture 96% of the population over the same period, but with high resourcing needs in the first year. The registration approach, delivered by a practice nurse, provides modest cost savings to the health care system of L120 m over 30 years. Health gains over the same period amount to 32,000 quality-adjusted life years (QALYs). This SBI programme still appears cost-effective (at L6900 per QALY gained) compared with no programme, under pessimistic effectiveness assumptions. Switching to a consultation approach, delivered by a doctor, would incur an incremental net cost of L108 m, with incremental health gains equivalent to 92,000 QALYs, giving an incremental cost-effectiveness ratio of L1175 per QALY gained compared with current practice. CONCLUSION: A universal programme of alcohol SBI in primary care is estimated to be cost-effective, under all but the most pessimistic assumptions for programme costs and effectiveness. Policymakers should ensure that SBI programmes are routinely evaluated and followed up, given the substantial uncertainty over the effects of many of the implementation details. PMID- 23015609 TI - Hair ethyl glucuronide is highly sensitive and specific for detecting moderate-to heavy drinking in patients with liver disease. AB - AIMS: Hair ethyl glucuronide (EtG) is a promising biomarker of moderate-to-heavy alcohol consumption and may have utility in detecting and monitoring alcohol use in clinical populations where alcohol use is of particular importance. This study evaluated the relationship between hair EtG and drinking in patients with liver disease. METHODS: The subjects (n = 200) were patients with liver disease who presented for care at a university medical center. Alcohol use during the 3 months preceding participation in the study was assessed, and a sample of hair was obtained for EtG testing. Classification of drinking status (any drinking or averaging at least 28 g per day) by hair EtG was evaluated, as well as the effects of liver disease severity and demographic and hair care factors. RESULTS: The area under the receiver operating characteristic curve for detecting an average of 28 g or more per day during the prior 90 days was 0.93. The corresponding sensitivity and specificity of hair EtG >=8 pg/mg for averaging at least 28 g of ethanol per day were 92 and 87%, respectively. Cirrhosis and gender may have a modest influence on the relationship between drinking and hair EtG. CONCLUSION: Hair EtG was highly accurate in differentiating subjects with liver disease averaging at least 28 g of ethanol per day from abstainers and lighter drinkers. PMID- 23015610 TI - Mechanisms involved in the p62-73 idiopeptide-modulated delay of lupus nephritis in SNF(1) mice. AB - The F(1) progeny of the (SWR * NZB) cross develop a lupus-like disease with high serum titers of autoantibodies, and increased frequency and severity of immune complex-mediated glomerulonephritis in females. In previous work, we found that an idiotypic peptide corresponding to aa62-73 (p62-73) of the heavy chain variable region of autoantibody 540 (Id(LN)F(1)) induced the proliferation of p62 73 idiotype-reactive T cell clones. Further, monthly immunization of pre nephritic SNF(1) female mice with p62-73 resulted in decreased nephritis and prolonged life spans. Here we show that this treatment modulated proliferative responses to Id(LN)F(1) antigen, including a reduction in the population of idiopeptide-presenting antigen-presenting cells (APCs), as early as two weeks after immunization (10 weeks of age). Th1-type cytokine production was increased at 12 weeks of age. The incidence and severity of nephritis was reduced by 14 weeks compared to controls. Clinical indicators of nephritis, specifically histological evidence of glomerulonephritis and urine protein levels, were reduced by 20 weeks. Together these data suggest that events involved in the mechanism(s) whereby p62-73 immunization delayed nephritis occurred early after immunization, and involved modulation of APCs, B and T cell populations. PMID- 23015611 TI - The alpha2-adrenoceptor antagonist yohimbine normalizes increased islet blood flow in GK rats: a model of type 2 diabetes. AB - Overexpression of alpha2A-adrenoceptors contributes to type 2 diabetes in GK rats. We aimed to investigate if alpha2-adrenoceptor inhibition affected islet blood flow in these rats. Anesthetized GK and Wistar-F rats were given the alpha2 adrenoceptor inhibitor yohimbine (2.5 mg/kg BW) intravenously. The GK rats had higher blood glucose and serum insulin concentrations than WF rats. Yohimbine affected neither of these values in WF rats, but decreased blood glucose and increased serum insulin concentrations in GK rats. Total pancreatic and islet blood flows, measured with microspheres, were increased in GK when compared to WF rats. Yohimbine affected none of the blood flow values in WF rats, whereas islet blood flow in GK rats was reduced to values similar to those seen in WF rats. Overexpression of alpha2-adrenoceptors may contribute to the increased islet blood flow seen in GK rats, and may be eligible for pharmacologic intervention. PMID- 23015612 TI - Activated glucose-6-phosphate dehydrogenase is associated with insulin resistance by upregulating pentose and pentosidine in diet-induced obesity of rats. AB - Recent studies have shown that glucose-6-phosphate dehydrogenase (G6PD), the rate limiting enzyme for the pentose phosphate pathway, was involved in insulin resistance via reduced nicotinamide adenine dinucleotide phosphate, while the roles of pentose were not examined. In the present study, the association of G6PD, pentose, and pentosidine with insulin resistance was investigated in diet induced obesity of rats. Male Wistar rats were fed a high-fat diet for 6 weeks to generate obesity-prone (OP, n=14) and obesity-resistant (OR, n=14) rats. The levels of G6PD, pentose, and pentosidine, and oxidative stress were analyzed in serum and tissues. The OP rats, compared to the OR and control rats, had a significant increase in body weight (16.2% and 12.8%), serum triglyceride (43.4% and 12.3), and free fatty acids (49.5% and 23.6%), and developed marked insulin resistance. G6PD activities were increased in the pancreas and liver with upregulated pentose levels in serum, pancreas, and liver of OP rats. Pentosidine levels were increased only under the condition of high pentose levels and oxidative stress status in serum and pancreas of OP rats. G6PD activities in pancreas and liver, pentose levels in serum, pancreas, and liver, and pentosidine levels in serum and pancreas were positively correlated with homeostasis model of assessment-insulin resistance. Our results suggest that the upregulation of G6PD causes an increase in the accumulation of pentose and pentosidine, which might be associated with insulin resistance in the condition of obesity. PMID- 23015613 TI - Basal and T3-induced ROS production in lymphocyte mitochondria is increased in type 2 diabetic patients. AB - Mitochondrial function, including production of reactive oxygen species (ROS), is important in the pathogenesis of diabetes and its complications. Thyroid hormones are major regulator of these processes. Hence, the aim of this study was to examine the thyroid hormone regulation of ROS production in human lymphocytes in patients with diabetes mellitus type 2 (T2DM). Lymphocytes from 10 controls and 10 persons with T2DM were examined. Mitochondrial membrane potential (MMP) was examined by flow cytometry after staining with MitoTracker Green (MTG). Similarly ROS was measured following staining with carboxy-H2DCFDA. MMP was increased in T2DM patients and T3 stimulation increased MMP in controls [1398 a.u. (979-4094) vs. 2156 a.u. (1611-15189), p=0.04, median and quartiles] as well as in T2DM patients [9167 a.u. (7387-11746) vs. 20274 a.u. (17183-27839 p=0.004, median and quartiles]. Basal ROS concentration was increased in lymphocytes from T2DM and T3 significantly stimulated ROS concentration in controls [3691 a.u. (2584-6396) vs. 5650 a.u. (3001-7802) p=0.013, median and quartiles] and in T2DM patients [19271 a.u. (6288-25282) vs. 23178 a.u. (10004-28857) p=0.013, median and quartiles]. The ratio of ROS production related to MMP was significantly higher in T2DM, unstimulated as well as T3-stimulated in T2DM. Unstimulated and T3 stimulated ROS production and MMP were higher in lymphocytes from diabetic patients. An altered balance between ROS production and MMP, favoring ROS production in T2DM patients, was found suggesting that an increased mitochondrial sensitivity for T3 may be a significant factor responsible for increased ROS activity in diabetic patients. PMID- 23015617 TI - Systemic metoclopramide to prevent postoperative nausea and vomiting: a meta analysis without Fujii's studies. AB - Previous evidence suggested that 10 mg systemic metoclopramide is not effective to prevent postoperative nausea and/or vomiting (PONV) in patients receiving general anaesthesia. However, the evidence included data with questioned validity by the author Yoshitaka Fujii. The objective of the current study was to examine the effect of a systemic dose of 10 mg metoclopramide to prevent PONV. This quantitative systematic review was performed according to the PRISMA guidelines. A wide search was performed to identify randomized clinical trials that evaluated systemic 10 mg metoclopramide as a prophylactic agent to reduce PONV. Meta analysis was performed using a random-effect model. Thirty trials evaluating the effect of 10 mg systemic metoclopramide in 3328 subjects on PONV outcomes were included. Metoclopramide reduced the incidence of 24 h PONV compared with control, odds ratio (OR) [95% confidence interval (CI)] of 0.58 (0.43-0.78), number needed to treat (NNT)=7.8. When evaluated as separate outcomes, metoclopramide also decreased the incidence of nausea over 24 h, OR (95% CI) of 0.51 (0.38-0.68), NNT=7.1, and vomiting over 24 h, OR (95% CI) of 0.51 (0.40 0.66), NNT=8.3. A post hoc analysis examining three studies with questioned validity performed by the author Yoshitaka Fujii that would meet criteria for inclusion in the current study did not demonstrate a significant benefit of metoclopramide compared with control on the incidence of 24 h PONV. Our findings suggest that metoclopramide 10 mg i.v. is effective to prevent PONV in patients having surgical procedures under general anaesthesia. Metoclopramide seems to be a reasonable agent to prevent PONV. PMID- 23015618 TI - Randomized comparison of closed-loop feedback computer-controlled with manual controlled infusion of phenylephrine for maintaining arterial pressure during spinal anaesthesia for caesarean delivery. AB - BACKGROUND: Closed-loop feedback computer-controlled infusion has not been described for administering phenylephrine to maintain arterial pressure (AP) during spinal anaesthesia for caesarean delivery. We aimed to compare AP control using this automated system with a previously described manual infusion system. METHODS: We randomly allocated 222 healthy subjects having spinal anaesthesia for scheduled caesarean delivery to have systolic AP maintained near baseline with phenylephrine (100 ug ml(-1)) by computer-controlled infusion utilizing a proportional algorithm or manual-controlled infusion utilizing an on-off algorithm. AP control was assessed by comparing the proportion of systolic AP measurements within +/-20% of baseline and by performance error (PE) calculations. RESULTS: A total of 212 subjects finished the study. In the computer-control group, 97% of systolic AP recordings fell within +/-20% of baseline compared with 95% in the manual-control group (P=0.0004). For computer control compared with manual-control, wobble was smaller [median 3.5 (inter quartile range 2.5-4.8)% vs 4.2 (3.3-5.9)%, P=0.003], but there was no difference in the median PE [2.9 (0.3-4.7)% vs 1.9 (0-4.2)%], median absolute PE [4.7 (3.5 5.6)% vs 4.7 (3.8-6.7)%], or divergence [-0.01 (-0.03-0)% vs -0.06 (-0.26 0.08)%]. Fewer interventions per subject for controlling AP were required in the computer-control group [2 (2-2) vs 10 (8-13), P<0.001]. There were no differences in measured clinical outcomes. CONCLUSIONS: Within the constraints of the studied algorithms, closed-loop feedback computer-controlled phenylephrine infusion provided better AP control with fewer interventions required compared with manual controlled infusion. PMID- 23015619 TI - Magnetic resonance imaging study of the in vivo position of the extraglottic airway devices i-gelTM and LMA-SupremeTM in anaesthetized human volunteers. AB - BACKGROUND: Exact information on the anatomical in situ position of extraglottic airway (EGA) devices is lacking. We used magnetic resonance imaging (MRI) to visualize the positions of the i-gelTM and the LMA-SupremeTM (LMA-S) relative to skeletal and soft-tissue structures. METHODS: Twelve volunteers participated in this randomized, prospective, cross-over study. Native MRI scans were performed before induction of anaesthesia. Anaesthesia was induced, and the two EGAs were inserted in a randomized sequence. Their positions were assessed functionally, optically by fibrescope, and with MRI scans of the head and neck. RESULTS: The LMA-S protruded deeper into the upper oesophageal sphincter than the i-gelTM (P<0.001). Both devices reduced the area of the glottic aperture (P<0.001), and the LMA-S had the largest effect (P=0.049). The i-gelTM significantly compressed the tongue (P<0.001). Both devices displaced the hyoid bone ventrally (P<0.001); the i-gelTM to a greater degree (P=0.029). The fibreoptically determined position of the bowl of the devices was identical. CONCLUSIONS: The LMA-S and i-gelTM differ significantly with regard to in situ position and spatial relationship with adjacent structures assessed by MRI, despite similar clinical and fibreoptical findings. This could be relevant with regard to risk of aspiration, glottic narrowing, and airway resistance and soft-tissue morbidity. PMID- 23015620 TI - Pharmacokinetics of intravenous emulsified isoflurane in beagle dogs. AB - BACKGROUND: We previously demonstrated that i.v. emulsified isoflurane induces general anaesthesia in animals. In this study, we compared the pharmacokinetics of emulsified isoflurane given as i.v. bolus and as infusion in beagle dogs. METHODS: Sixteen beagle dogs were assigned randomly to a bolus group comprising three subgroups and an infusion group. The three bolus subgroups received 120, 150, or 180 mg kg(-1) of isoflurane and the infusion group received isoflurane at 12 mg kg(-1) min(-1) for 150 min. Isoflurane concentrations were determined by gas chromatography. The parameters involved in the pharmacokinetic model were calculated using the DAS ver1.0 software. RESULTS: A two-compartment model best described the data in both bolus and infusion groups. The half-lives of distribution [t(1/2alpha): 1.77 (0.57) min] and elimination [t(1/2beta): 17.66 (5.56) min] in the bolus group were shorter than those in the infusion group [14.12 (4.04) min, 58.21 (11.39) min, P<0.01]. The apparent volume of the central compartment [V(1), 0.377 (0.138) litre kg(-1)] in the bolus group was less than that in the infusion group [0.809 (0.077) litre kg(-1), P<0.01]. The total body clearance [Cl, 0.043 (0.032) litre kg(-1) min(-1)] in the bolus group was greater than that in the infusion group [0.028 (0.008) litre kg(-1) min(-1)]. CONCLUSIONS: A two-compartment model adequately describes the pharmacokinetics of emulsified isoflurane for both bolus and infusion. The resulting kinetic parameters differ mainly because of the increasing blood/gas partition coefficient and the sustained nature of the isoflurane partial pressure during infusion. PMID- 23015621 TI - The riddle of Tasmanian languages. AB - Recent work which combines methods from linguistics and evolutionary biology has been fruitful in discovering the history of major language families because of similarities in evolutionary processes. Such work opens up new possibilities for language research on previously unsolvable problems, especially in areas where information from other sources may be lacking. I use phylogenetic methods to investigate Tasmanian languages. Existing materials are so fragmentary that scholars have been unable to discover how many languages are represented in the sources. Using a clustering algorithm which identifies admixture, source materials representing more than one language are identified. Using the Neighbor Net algorithm, 12 languages are identified in five clusters. Bayesian phylogenetic methods reveal that the families are not demonstrably related; an important result, given the importance of Tasmanian Aborigines for information about how societies have responded to population collapse in prehistory. This work provides insight into the societies of prehistoric Tasmania and illustrates a new utility of phylogenetics in reconstructing linguistic history. PMID- 23015622 TI - Footprints in time: comparative quantitative trait loci mapping of the pitcher plant mosquito, Wyeomyia smithii. AB - Identifying regions of the genome contributing to phenotypic evolution often involves genetic mapping of quantitative traits. The focus then turns to identifying regions of 'major' effect, overlooking the observation that traits of ecological or evolutionary relevance usually involve many genes whose individual effects are small but whose cumulative effect is large. Herein, we use the power of fully interfertile natural populations of a single species of mosquito to develop three quantitative trait loci (QTL) maps: one between two post-glacially diverged populations and two between a more ancient and a post-glacial population. All demonstrate that photoperiodic response is genetically a highly complex trait. Furthermore, we show that marker regressions identify apparently 'non-significant' regions of the genome not identified by composite interval mapping, that the perception of the genetic basis of adaptive evolution is crucially dependent upon genetic background and that the genetic basis for adaptive evolution of photoperiodic response is highly variable within contemporary populations as well as between anciently diverged populations. PMID- 23015623 TI - Changing spatial epidemiology of pertussis in continental USA. AB - Prediction and control of the geographical spread of emerging pathogens has become a central public health issue. Because these infectious diseases are by definition novel, there are few data to characterize their dynamics. One possible solution to this problem is to apply lessons learnt from analyses of historical data on familiar and epidemiologically similar pathogens. However, the portability of the spatial ecology of an infectious disease in a different epoch to other infections remains unexamined. Here, we study this issue by taking advantage of the recent re-emergence of pertussis in the United States to compare its spatial transmission dynamics throughout the 1950s with the past decade. We report 4-year waves, sweeping across the continent in the 1950s. These waves are shown to emanate from highly synchronous foci in the northwest and northeast coasts. In contrast, the recent resurgence of the disease is characterized by 5.5 year epidemics with no particular spatial structure. We interpret this to be the result of dramatic changes in patterns of human movement over the second half of the last century, together with changing age distribution of pertussis. We conclude that extrapolation regarding the spatial spread of contemporaneous pathogens based on analyses of historical incidence may be potentially very misleading. PMID- 23015624 TI - A test of maternal human chorionic gonadotropin during pregnancy as an adaptive filter of human gestations. AB - The risk of abnormalities and morbidity among live births increases with advanced maternal age. Explanations for this elevated morbidity invoke several maternal mechanisms. The relaxed filter stringency (RFS) hypothesis asserts that mothers, nearing the end of their reproductive lifespan, reduce the stringency of a screen of offspring quality in utero based on life-history traits of parity and interbirth interval (IBI). A separate line of research implicates human chorionic gonadotropin (hCG) during pregnancy as a signal of offspring quality. We test the RFS hypothesis directly by examining whether the difference in gestational hCG across consecutive live births varies positively with the mother's number of previous live births but inversely with her most recent IBI. We applied multivariable regression methods to a unique dataset of gestational hCG for over 500 000 live births from 2002 to 2007. The difference in gestational hCG across mothers' consecutive live births varies positively with both mothers' parity and IBI. These associations remain similar among older mothers (35+ years). Findings support the RFS hypothesis for the parity expectation but not for the IBI expectation. Further evidence for the RFS hypothesis among contemporary human gestations would have to invoke screening mechanisms other than hCG. PMID- 23015625 TI - Sex-ratio adjustment in response to local mate competition is achieved through an alteration of egg size in a haplodiploid spider mite. AB - Sex-ratio adjustments are commonly observed in haplodiploid species. However, the underlying proximate mechanisms remain elusive. We investigated these mechanisms in Tetranychus urticae, a haplodiploid spider mite known to adjust sex ratio in response to the level of local mate competition (LMC). In this species, egg size determines fertilization probability, with larger eggs being more likely to be fertilized, and thus become female. We explored the hypothesis that sex-ratio adjustment is achieved through adjustment of egg size. By using spider mites from a large population, we found that females produced not only a higher proportion of daughters under high levels of LMC, but also larger eggs. Moreover, in populations experimentally evolving under varying levels of LMC, both the proportion of females and the egg size increased with LMC intensity. These results suggest that sex-ratio adjustment in spider mites is mediated by egg size, although the causal relationship remains to be tested. PMID- 23015627 TI - Vampire squid: detritivores in the oxygen minimum zone. AB - Vampire squid (Vampyroteuthis infernalis) are considered phylogenetic relics with cephalopod features of both octopods and squids. They lack feeding tentacles, but in addition to their eight arms, they have two retractile filaments, the exact functions of which have puzzled scientists for years. We present the results of investigations on the feeding ecology and behaviour of Vampyroteuthis, which include extensive in situ, deep-sea video recordings from MBARI's remotely operated vehicles (ROVs), laboratory feeding experiments, diet studies and morphological examinations of the retractile filaments, the arm suckers and cirri. Vampire squid were found to feed on detrital matter of various sizes, from small particles to larger marine aggregates. Ingested items included the remains of gelatinous zooplankton, discarded larvacean houses, crustacean remains, diatoms and faecal pellets. Both ROV observations and laboratory experiments led to the conclusion that vampire squid use their retractile filaments for the capture of food, supporting the hypothesis that the filaments are homologous to cephalopod arms. Vampyroteuthis' feeding behaviour is unlike any other cephalopod, and reveals a unique adaptation that allows these animals to spend most of their life at depths where oxygen concentrations are very low, but where predators are few and typical cephalopod food is scarce. PMID- 23015626 TI - Virulence, drug sensitivity and transmission success in the rodent malaria, Plasmodium chabaudi. AB - Here, we test the hypothesis that virulent malaria parasites are less susceptible to drug treatment than less virulent parasites. If true, drug treatment might promote the evolution of more virulent parasites (defined here as those doing more harm to hosts). Drug-resistance mechanisms that protect parasites through interactions with drug molecules at the sub-cellular level are well known. However, parasite phenotypes associated with virulence might also help parasites survive in the presence of drugs. For example, rapidly replicating parasites might be better able to recover in the host if drug treatment fails to eliminate parasites. We quantified the effects of drug treatment on the in-host survival and between-host transmission of rodent malaria (Plasmodium chabaudi) parasites which differed in virulence and had never been previously exposed to drugs. In all our treatment regimens and in single- and mixed-genotype infections, virulent parasites were less sensitive to pyrimethamine and artemisinin, the two antimalarial drugs we tested. Virulent parasites also achieved disproportionately greater transmission when exposed to pyrimethamine. Overall, our data suggest that drug treatment can select for more virulent parasites. Drugs targeting transmission stages (such as artemisinin) may minimize the evolutionary advantage of virulence in drug-treated infections. PMID- 23015629 TI - Dramatic intraspecific differences in migratory routes, stopover sites and wintering areas, revealed using light-level geolocators. AB - Migratory divides are contact zones between breeding populations that use divergent migratory routes and have been described in a variety of species. These divides are of major importance to evolution, ecology and conservation but have been identified using limited band recovery data and/or indirect methods. Data from band recoveries and mitochondrial haplotypes suggested that inland and coastal Swainson's thrushes (Catharus ustulatus) form a migratory divide in western North America. We attached light-level geolocators to birds at the edges of this contact zone to provide, to our knowledge, the first direct test of a putative divide using data from individual birds over the entire annual cycle. Coastal thrushes migrated along the west coast to Mexico, Guatemala and Honduras. Some of these birds used multiple wintering sites. Inland thrushes migrated across the Rocky Mountains, through central North America to Columbia and Venezuela. These birds migrated longer distances than coastal birds and performed a loop migration, navigating over the Gulf of Mexico in autumn and around this barrier in spring. These findings support the suggestion that divergent migratory behaviour could contribute to reproductive isolation between migrants, advance our understanding of their non-breeding ecology, and are integral to development of detailed conservation strategies for this group. PMID- 23015628 TI - Environmental extremes versus ecological extremes: impact of a massive iceberg on the population dynamics of a high-level Antarctic marine predator. AB - Extreme events have been suggested to play a disproportionate role in shaping ecological processes, but our understanding of the types of environmental conditions that elicit extreme consequences in natural ecosystems is limited. Here, we investigated the impact of a massive iceberg on the dynamics of a population of Weddell seals. Reproductive rates of females were reduced, but survival appeared unaffected. We also found suggestive evidence for a prolonged shift towards higher variability in reproductive rates. The annual number of females attending colonies showed unusual swings during the iceberg period, a pattern that was apparently the consequence of changes in sea-ice conditions. In contrast to the dramatic effects that were recorded in nearby populations of emperor penguins, our results suggest that this unusual environmental event did not have an extreme impact on the population of seals in the short-term, as they managed to avoid survival costs and were able to rapidly re-achieve high levels of reproduction by the end of the perturbation. Nevertheless, population projections suggest that even this modest impact on reproductive rates could negatively affect the population in the long run if such events were to occur more frequently, as is predicted by models of climate change. PMID- 23015630 TI - Jack-of-all-trades: phenotypic plasticity facilitates the invasion of an alien slug species. AB - Invasive alien species might benefit from phenotypic plasticity by being able to (i) maintain fitness in stressful environments ('robust'), (ii) increase fitness in favourable environments ('opportunistic'), or (iii) combine both abilities ('robust and opportunistic'). Here, we applied this framework, for the first time, to an animal, the invasive slug, Arion lusitanicus, and tested (i) whether it has a more adaptive phenotypic plasticity compared with a congeneric native slug, Arion fuscus, and (ii) whether it is robust, opportunistic or both. During one year, we exposed specimens of both species to a range of temperatures along an altitudinal gradient (700-2400 m a.s.l.) and to high and low food levels, and we compared the responsiveness of two fitness traits: survival and egg production. During summer, the invasive species had a more adaptive phenotypic plasticity, and at high temperatures and low food levels, it survived better and produced more eggs than A. fuscus, representing the robust phenotype. During winter, A. lusitanicus displayed a less adaptive phenotype than A. fuscus. We show that the framework developed for plants is also very useful for a better mechanistic understanding of animal invasions. Warmer summers and milder winters might lead to an expansion of this invasive species to higher altitudes and enhance its spread in the lowlands, supporting the concern that global climate change will increase biological invasions. PMID- 23015631 TI - Fluctuations in food supply drive recruitment variation in a marine fish. AB - Reproductive rates and survival of young in animal populations figure centrally in generating management and conservation strategies. Model systems suggest that food supply can drive these often highly variable properties, yet for many wild species, quantifying such effects and assessing their implications have been challenging. We used spatially explicit time series of a well-studied marine reef fish (black surfperch Embiotoca jacksoni) and its known prey resources to evaluate the extent to which fluctuations in food supply influenced production of young by adults and survival of young to subadulthood. Our analyses reveal: (i) variable food available to both adults and to their offspring directly produced an order of magnitude variation in the number of young-of-year (YOY) produced per adult and (ii) food available to YOY produced a similar magnitude of variation in their subsequent survival. We also show that such large natural variation in vital rates can significantly alter decision thresholds (biological reference points) important for precautionary management. These findings reveal how knowledge of food resources can improve understanding of population dynamics and reduce risk of overharvest by more accurately identifying periods of low recruitment. PMID- 23015632 TI - Simultaneous multi-electrode high-density map using NavX system visualized the mechanism of unusual atrial tachycardia after pulmonary vein isolation. PMID- 23015633 TI - Conservative management of infected pacemaker and implantable defibrillator sites with a closed antimicrobial irrigation system. AB - AIMS: Current guidelines recommend that patients with infected cardiac rhythm management device (CRMD) sites undergo removal of all system components (pulse generator and leads). However, lead removal may not be an option for patients who lack access to state-of-the-art technology, lack the necessary financial resources, or are at very high risk because of age or concomitant disease. In this case series, we report our successful experience with conservative treatment of five such patients, who had CRMD infections localized to the device pocket. METHODS AND RESULTS: The device pocket and remaining hardware were completely sterilized to successfully eradicate the infection. First, all non-viable tissue, chronically inflamed tissue, granulation tissue, and scar tissue were completely removed, with special attention to complete haemostasis. Secondly, all non essential foreign materials, including old sutures and plastic suture anchoring sleeves, were removed, and the remaining hardware was completely sterilized. To achieve this goal, we used mechanical means (scrubbing and pulsed lavage), as well as a closed antimicrobial irrigation system. In all five cases, the pulse generator site was saved, lead removal was avoided, and the patients were free of local or systemic infection for a minimum of 1 year after treatment. CONCLUSION: Our conservative approach to the management of infected CRMD sites is feasible and beneficial in selected patients who are at very high risk for lead removal or who lack access to the technology necessary for safe performance of this procedure, provided that the infection is limited to the implant site. PMID- 23015634 TI - Complications of catheter ablation for atrial fibrillation in a high-volume centre with the use of intracardiac echocardiography. AB - AIMS: Catheter ablation (CA) for atrial fibrillation (AF) is a complex procedure that is associated with higher risk of complications. This study aimed at exploring the complication rate and corresponding risk factors in a high-volume centre with routine use of intracardiac echocardiography (ICE). METHODS AND RESULTS: In total 1192 consecutive AF ablation procedures (100% ICE-guided; 96.4% 3D-navigated; point-by-point radiofrequency ablation with open-irrigated tip catheter; 22.4% robotic navigation; 25.4% repeated ablation) were performed in 959 patients (aged 58 +/- 9 years; 70.8% males; 35.9% persistent AF) between March 2006 and December 2010. Ablation endpoint in paroxysmal AF was complete electrical pulmonary vein isolation (PVI). Complex ablation was defined as PVI plus stepwise strategy for left atrial substrate ablation (43.5%) in persistent AF. Forty major complications (3.3%) during the procedure or within the 3 month follow-up were observed. No death or atrioesophageal fistula occurred. Three patients (0.25%) had cardiac tamponade/hemopericardium and five patients (0.42%) had cerebrovascular embolic event. Vascular injury was the most frequent (2.3%) complication. Low body weight was the only significant risk factor with 0.8% increase of complication rate per 10 kg of body weight decrease (P = 0.013). A trend for increase in complication rate was also observed for advanced age, female gender, and complex procedure. CONCLUSION: Atrial fibrillation ablation procedures guided by ICE in a high-volume centre are associated with low rate of serious complications. The composite risk score consisting of body weight, age, gender, and complexity of procedure predicted complications. PMID- 23015635 TI - Average. PMID- 23015636 TI - The double-half bilobe flap: an alternative for midline defects of the tip and supratip region. PMID- 23015637 TI - Fiddling with the pacemaker: Twiddler's syndrome in a Parkinsonian patient. AB - We describe the case report of an 86-year-old Afro-Caribbean Parkinsonian gentleman with intermittent Mobitz II heart block and syncope who received a DDD pacemaker. Due to Parkinson's syndrome, the patient rotated the atrial lead around the pacemaker, causing the famous "Twiddler's syndrome", a rare clinical issue which can easily be diagnosed with a simple chest X-ray. PMID- 23015638 TI - Safety of training and assessment in operating theatres--a systematic review and meta-analysis. AB - OBJECTIVE: Procedural outcomes can be used to assess the performance of specialists and trainees. This article establishes a systematic evidence base for the safety of training in the operating theatre. It also explores the possibility of using early, intermediate and late procedural outcomes of cardiac surgical operations to evaluate the performance of the clinicians and the healthcare system. METHODS: Medline, EMBASE and PsycINFO databases were searched. Comparative studies evaluating quality indicators of cardiac surgical procedures (coronary artery bypass grafting (CABG) and valve surgery) were included. guidelines from the preferred reporting items for systematic reviews and meta analyses (PRISMA) were used. RESULTS: Fourteen studies met the inclusion criteria. For CABG, meta-analysis of outcomes did not show any significant differences between the technical and non-technical skills of trainees versus specialists apart from bypass time (less for specialists) and intensive care unit (ICU) length of stay (less for trainees). Studies reporting outcomes on valve surgery also did not report any statistically significant differences amongst the outcomes. CONCLUSION: This systematic review did not discern any significant differences between the procedural outcomes of trainees and specialists, which indicates that trainees are safe to operate under senior supervision. In addition, this article recommends that various procedural outcomes can be used to evaluate the performance of clinicians and healthcare systems. Prospective studies need to be performed, taking into account the specific contribution of trainees and specialists during the procedure. This will give a clearer indication of safety and performance of trainees and specialists in the operating theatre. PMID- 23015639 TI - Association of DJ-1/PTEN/AKT- and ASK1/p38-mediated cell signalling with ischaemic cardiomyopathy. AB - AIMS: Dilated cardiomyopathies from chronic ischaemia (ISCM) or idiopathic (IDCM) pathological mechanisms are accompanied by similar clinical symptoms but may differ in protein expression, cell metabolism, and signalling processes at the cellular level. Using a combination of proteomic and metabolomic profiling, we sought to decipher the relationships between the metabolism and cellular signalling pathways in human heart tissues collected from patients with ISCM, IDCM, and those without heart disease and dilation. METHODS AND RESULTS: The comparative analysis suggested a decrease in glycolysis, Krebs cycle, and malate aspartate shuttle activities in both types of cardiomyopathies and an increase in ketone body oxidation only in ISCM. Chronic ischaemic injury was associated with increased DJ-1 and decreased phosphatase and tensin homolog (PTEN) protein expression. The reduced PTEN expression was accompanied by increased phosphorylation of cell-protective AKT. Phosphorylation at T845 of apoptosis signal-regulating kinase 1 and p38 mitogen-activated protein kinase proteins, with no change in the phosphorylation of extracellular signal-regulated kinases, was also observed. The downregulation of peptidyl-prolyl cis/trans isomerase and NF-kappaB essential modulator potentially inhibits NF-kappaB-initiated processes. CONCLUSION: The present study characterized differences in the molecular mechanisms, metabolism, and pathological cell signalling associated with ISCM and IDCM, which may provide novel targets for intervention at the cellular level. PMID- 23015641 TI - A comparison of levels and predictors of emotional problems among preadolescent Ethiopians in Addis Ababa, Ethiopia, and Toronto, Canada. AB - According to a literature of theory and advocacy, immigration and resettlement jeopardize the mental health of children and youth, largely because of factors such as intergenerational tensions arising from conflicts about the retention of traditional values, and experiences of prejudice and discrimination. The current study examines the specificity of these putative mental health risks to the immigration experience. The level and predictors of emotional problems among preadolescent Ethiopians living in immigrant families in Toronto, Canada, were compared with a matched sample of Ethiopian youngsters in Addis Ababa, Ethiopia. Data came from structured interviews with the person most knowledgeable about the family (usually a parent), as well as from the children themselves. Youth reported higher levels of emotional problems (EP) than their parents. Predictors differed for parent and child ratings. In both the Toronto and Addis Ababa samples, parental mental health predicted parent-rated, but not self-rated EP. Contrary to immigration stress theory, parental perceptions of prejudice predicted EP in Addis Ababa, but not Toronto, and parent-child discordance regarding ethnic adherence were predictors of self-rated emotional problems in Ethiopia, but not in Canada. Perceived discrimination was a significant predictor of self-rated emotional problems in both settings. Implications for theory and further research are discussed. PMID- 23015640 TI - Importance of endothelial NF-kappaB signalling in vascular remodelling and aortic aneurysm formation. AB - AIMS: Vascular remodelling and aortic aneurysm formation are induced mainly by inflammatory responses in the adventitia and media. However, relatively little is known about the mechanistic significance of endothelium in the pathogenesis of these vascular disorders. The transcription factor nuclear factor-kappa B (NF kappaB) regulates the expressions of numerous genes, including those related to pro-inflammatory responses. Therefore, to investigate the roles of endothelial pro-inflammatory responses, we examined the impact of blocking endothelial NF kappaB signalling on intimal hyperplasia and aneurysm formation. METHODS AND RESULTS: To block endothelial NF-kappaB signalling, we used transgenic mice expressing dominant-negative IkappaBalpha selectively in endothelial cells (E DNIkappaB mice). E-DNIkappaB mice were protected from the development of cuff injury-induced neointimal formation, in association with suppressed arterial expressions of cellular adhesion molecules, a macrophage marker, and inflammatory factors. In addition, the blockade of endothelial NF-kappaB signalling prevented abdominal aortic aneurysm formation in an experimental model, hypercholesterolaemic apolipoprotein E-deficient mice with angiotensin II infusion. In this aneurysm model as well, aortic expressions of an adhesion molecule, a macrophage marker, and inflammatory factors were suppressed with the inhibited expression and activity of matrix metalloproteinases in the aorta. CONCLUSION: Endothelial NF-kappaB activation up-regulates adhesion molecule expression, which may trigger macrophage infiltration and inflammation in the adventitia and media. Thus, the endothelium plays important roles in vascular remodelling and aneurysm formation through its intracellular NF-kappaB signalling. PMID- 23015642 TI - Gender-, strain-, and inheritance-dependent variation in aldosterone secretion in mice. AB - Arterial hypertension represents one of the most common diseases in developed countries and the rennin-angiotensin-aldosterone system is among the major factors in the regulation of blood pressure and sodium balance. With the exception of rare monogenetic diseases, however, inheritance of aldosterone secretion is widely unknown. In this study, we investigated the aldosterone levels in male and female mice of two inbred strains, C3HeB/FeJ and C57BL/6J, as well as their offspring of the F1 and F2 generation. In all cases, female animals displayed lower aldosterone levels than males. Furthermore, C57BL/6J animals had significantly higher aldosterone levels than C3HeB/FeJ mice of the same age and gender. Depending on the paternal origin of the animal, the F1 offspring showed a tendency toward higher aldosterone values when the paternal side was from the C57BL/6J strain. This observation was confirmed in the F2 generation and over repeated measurements over three consecutive years. Quantification of the aldosterone to renin ratio in the different mouse groups did not show any significant differences, and, similarly, the determination of plasma potassium and kidney parameters did not provide any differences. On the molecular level, investigation of the expression of the enzymes involved in steroidogenesis displayed the same trend as for the aldosterone values, with animals hosting C57BL/6J background in their paternal origin having also the highest expression levels for StAR, cyp11a1, and cyp11b2 enzymes. Taken together, we could demonstrate that the genetic background of the animals plays a significant role modulating their plasma aldosterone levels without clear interference of other parameters in the renin-angiotensin-aldosterone system. PMID- 23015643 TI - Inhibition of Rho-kinase attenuates endothelial-leukocyte interaction during ischemia-reperfusion injury. AB - Resuscitation from hemorrhagic shock induces endothelial dysfunction and activates inflammatory cascades leading to organ damage. Following restoration of blood flow to ischemic vascular beds, leukocyte-endothelium interactions leading to leukocyte infiltration into the vascular wall occur very early due, in part, to the loss of endothelium-derived nitric oxide (NO). The mechanism by which ischemia-reperfusion injury impairs endothelium-derived NO is not completely understood. We hypothesized that inhibition of Rho-kinase could exert beneficial effects following hemorrhagic shock by preserving endothelial function and attenuating leukocyte trafficking in the microcirculation. Using intravital microscopy, we found that resuscitation from hemorrhage acutely increased the number of rolling and adherent leukocytes in the mouse splanchnic microcirculation. Treatment of mice with the Rho-kinase inhibitor fasudil, markedly attenuated leukocyte-endothelium interaction in response to hemorrhage/reinfusion. The beneficial effect of fasudil was not observed in endothelial nitric oxide synthase (eNOS)(-/-) mice. In conclusion, inhibition of Rho-kinase prevents inflammatory leukocyte trafficking in the microcirculation via an eNOS-dependent mechanism. Our data support a role for Rho-kinase inhibitors in the treatment of ischemia-reperfusion injury. PMID- 23015644 TI - Evaluation of the liaison automated testing system for diagnosis of congenital toxoplasmosis. AB - Congenital toxoplasmosis is a worldwide health problem, and different screening strategies exist. Testing of toxoplasma-specific antibodies in infants identifies congenital toxoplasmosis during the first year of life. However, experience with commercial available immunoassays is limited. The aim of this study was to evaluate both the performance and analytical characteristics of the Liaison diagnostic system in infants. In a retrospective study, serum Toxoplasma gondii antibodies were measured in samples from 333 infants, including 212 noninfected infants and 121 infants with congenital toxoplasmosis. A total of 1,157 umbilical cord blood and peripheral serum samples were analyzed. Liaison toxoplasma specific IgG and IgM antibodies and the IgG avidity index were compared to the infection status of the infant, determined by the Sabin-Feldman dye test and immunosorbent agglutination assay--IgM. All noninfected infants were seronegative by Liaison IgG within the first year of life. The Liaison system showed a sensitivity of 81.8%, a specificity of 100.0%, a positive predictive value of 100.0%, a negative predictive value of 90.6%, and overall agreement of 84.4% by comparison with the dye test. Overall agreement of both IgM test systems was 96.0%. In this study cohort, avidity did not show a potential diagnostic benefit for the detection of congenital infection. In conclusion, the Liaison system is a valuable tool to monitor the serologic course of infants at risk. A final serologic confirmatory test is recommended to improve the rate of detection of congenital toxoplasmosis at 1 year of life. Protocols of routine follow-up testing in infants and accurate diagnostic tools after acute gestational infections are needed to improve medical care. PMID- 23015645 TI - Evaluation and characterization of Fasciola hepatica tegument protein extract for serodiagnosis of human fascioliasis. AB - Tegument protein extract from Fasciola hepatica adult flukes (FhTA) was obtained and assessed for its potential as a diagnostic agent for the serological detection of human fascioliasis using an indirect enzyme-linked immunosorbent assay (ELISA). In an analysis of sera from 45 patients infected with F. hepatica, sera from 41 patients with other parasitic infections, and sera from 33 healthy controls, the FhTA-ELISA showed sensitivity, specificity, and accuracy of 91.1%, 97.3%, and 95%, respectively. Specific IgG1 and IgG4 were the antibody isotypes mainly detected in sera from patients with fascioliasis. Polypeptides of 52, 38, 24 to 26, and 12 to 14 kDa were identified by Western blotting as the most immunoreactive components of the FhTA. A proteomic approach led us to identify enolase, aldolase, glutathione S-transferase, and fatty acid binding protein as the major immunoreactive components of the FhTA. PMID- 23015646 TI - Fluorometric high-throughput assay for measuring chlamydial neutralizing antibody. AB - Chlamydia trachomatis is an obligate intracellular mucosotropic pathogen that causes human infections of global importance. C. trachomatis causes trachoma, the leading cause of preventable blindness worldwide, and is the most common cause of bacterial sexually transmitted disease. Although oculogenital infections are treatable with antibiotics, a vaccine is needed to control C. trachomatis infection. Ideally, a vaccine would provide coverage against most, if not all, naturally occurring antigenically distinct serovariants. The development of a subunit vaccine to prevent oculogenital disease could be advanced by identifying chlamydial antigens that elicit pan-neutralizing antibodies, particularly among infected human populations of known risk factors. There is currently no objective high-throughput in vitro assay to screen human sera for neutralization to aid in identification of these antigens. This report describes an objective, high throughput in vitro assay that measures C. trachomatis-neutralizing antibodies. Antibody-mediated neutralization of chlamydial infection was performed in a 96 well microtiter format, and neutralization was quantified by immunostaining fixed cells followed by automated fluorometric analysis. This report shows that fluorometric analysis of C. trachomatis infection directly correlates to labor intensive manual inclusion counts. Furthermore, this report shows that fluorometry can be used to identify C. trachomatis serovar- and serocomplex specific neutralization. This objective, high-throughput analysis of serum neutralization is amenable to epidemiological studies of human chlamydial infection, human clinical vaccine trials, and preclinical animal model experiments of Chlamydia infection. PMID- 23015647 TI - Analysis of immune responses against a wide range of Mycobacterium tuberculosis antigens in patients with active pulmonary tuberculosis. AB - Characterizing host immune responses to molecular targets of Mycobacterium tuberculosis is essential to develop effective immunodiagnostics and better vaccines. We investigated the immune response against a large series of M. tuberculosis antigens, including 5 classical and 64 nonclassical (39 DosR regulon encoded, 4 resuscitation-promoting factor [RPF], and 21 reactivation-associated) antigens in active-pulmonary-tuberculosis (TB) patients. Whole blood from TB patients (n = 34) was stimulated in vitro with M. tuberculosis antigens. Gamma interferon (IFN-gamma) was measured after 7 days of stimulation, using an enzyme linked immunosorbent assay (ELISA). The majority of the study participants responded to the classical M. tuberculosis antigens TB10.4 (84.8%), early secreted antigenic target-6 kDa (ESAT-6)/CFP-10 (70.6%), and purified protein derivative (PPD) (55.9%). However, only 26.5% and 24.2% responded to HSP65 and Ag85A/B, respectively. Of the 64 nonclassical antigens, 23 (33.3%) were immunogenic (IFN-gamma levels, >62 pg/ml) and 8 were strong inducers of IFN-gamma (IFN-gamma levels, >=100 pg/ml). The RPF antigens were the most immunogenic. In addition, we observed distinct cytokine expression profiles in response to several M. tuberculosis antigens by multiplex immunoassay. Tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10), and IL-6 were commonly detected at high levels after stimulation with 4/15 latency antigens (Rv0081, Rv2006, Rv2629, and Rv1733c) and were found especially in supernatants of the three strong IFN gamma inducers (Rv2629, Rv1009, and Rv2389c). IL-8, IL-6, and IL-17 were exclusively detected after stimulation with Rv0574c, Rv2630, Rv1998, Rv054c, and Rv2028c. In conclusion, in active-pulmonary-TB patients, we identified 23 new immunogenic M. tuberculosis antigens. The distinct expression levels of IFN gamma, TNF-alpha, IL-6, and IL-10 in response to specific subsets of M. tuberculosis antigens may be promising for the development of immunodiagnostics. PMID- 23015648 TI - Protective efficacy of a Toxoplasma gondii rhoptry protein 13 plasmid DNA vaccine in mice. AB - Toxoplasma gondii is an obligate intracellular parasite infecting humans and other warm-blooded animals, resulting in serious public health problems and economic losses worldwide. Rhoptries are involved in T. gondii invasion and host cell interaction and have been implicated as important virulence factors. In the present study, a DNA vaccine expressing rhoptry protein 13 (ROP13) of T. gondii inserted into eukaryotic expression vector pVAX I was constructed, and the immune protection it induced in Kunming mice was evaluated. Kunming mice were immunized intramuscularly with pVAX-ROP13 and/or with interleukin-18 (IL-18). Then, we evaluated the immune response using a lymphoproliferative assay, cytokine and antibody measurements, and the survival times of mice challenged with the virulent T. gondii RH strain (type I) and the cyst-forming PRU strain (type II). The results showed that pVAX-ROP13 alone or with pVAX/IL-18 induced a high level of specific anti-T. gondii antibodies and specific lymphocyte proliferative responses. Coinjection of pVAX/IL-18 significantly increased the production of gamma interferon (IFN-gamma), IL-2, IL-4, and IL-10. Further, challenge experiments showed that coimmunization of pVAX-ROP13 with pVAX/IL-18 significantly (P < 0.05) increased survival time (32.3 +/- 2.7 days) compared with pVAX-ROP13 alone (24.9 +/- 2.3 days). Immunized mice challenged with T. gondii cysts (strain PRU) had a significant reduction in the number of brain cysts, suggesting that ROP13 could trigger a strong humoral and cellular response against T. gondii cyst infection and that it is a potential vaccine candidate against toxoplasmosis, which provided the foundation for further development of effective vaccines against T. gondii. PMID- 23015650 TI - A new dawn of anticoagulation for patients with antiphospholipid syndrome? PMID- 23015649 TI - T-cell responses before and after the fifth consecutive acellular pertussis vaccination in 4-year-old Dutch children. AB - Immunization with acellular pertussis vaccine (aP) induces higher specific antibody levels and fewer adverse reactions than does immunization with the whole cell vaccine (wP). However, antibody levels in infants induced by both types of pertussis vaccines wane already after 1 year. Therefore, long-term T-cell responses upon vaccination might play a role in protection against pertussis. In a cross-sectional study (ISRCTN65428640), we investigated T-helper (Th) cell immune responses in wP- or aP-vaccinated children before and after an aP low-dose or high-dose preschool booster at 4 years of age in The Netherlands. T cells were stimulated with pertussis vaccine antigens. The numbers of gamma interferon producing cells and Th1, Th2, Th17, and interleukin-10 (IL-10) cytokine concentrations were determined. In addition, pertussis-specific IgE levels were measured in plasma. Children being vaccinated with aP vaccinations at 2, 3, 4, and 11 months of age still showed higher pertussis-specific T-cell responses at 4 years of age than did wP-vaccinated children. These T-cell responses failed to show a typical increase in cytokine production after a fifth aP vaccination but remained high after a low-dose booster and seemed to decline even after a high dose booster. Importantly, elevated IgE levels were induced after this booster vaccination. In contrast, wP-vaccinated children had only low prebooster T-cell responses, and these children showed a clear postbooster T-cell memory response even after a low-dose booster vaccine. Four high-dose aP vaccinations in infancy induce high T-cell responses still present even 3 years after vaccination and enhanced IgE responses after preschool booster vaccination. Therefore, studies of changes in vaccine dosage, timing of pertussis (booster) vaccinations, and the possible association with local side effects are necessary. PMID- 23015651 TI - Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. AB - CONTEXT: Maternal thyroid dysfunction, especially in early pregnancy, may lead to pregnancy complications and adverse birth outcomes. Few population-based prospective studies have evaluated these effects and results are discrepant. OBJECTIVE: We examined the association of thyroid function and autoimmunity in early pregnancy with adverse pregnancy and birth outcomes. SETTING AND PARTICIPANTS: The study used data from the prospective mother-child cohort "Rhea" study in Crete, Greece. A total of 1170 women with singleton pregnancies participated in this analysis. Maternal serum samples in the first trimester of pregnancy were tested for thyroid hormones (TSH, free T(4), and free T(3)) and thyroid antibodies (thyroid peroxidase antibody and thyroglobulin antibody). Multivariable log-Poisson regression models were used adjusting for confounders. MAIN OUTCOME MEASURES: Outcomes included gestational diabetes, gestational hypertension/preeclampsia, cesarean section, preterm delivery, low birth weight, and small-for-gestational-age neonates. RESULTS: The combination of high TSH and thyroid autoimmunity in early pregnancy was associated with a 4-fold increased risk for gestational diabetes [relative risk (RR) 4.3, 95% confidence interval (CI) 2.1-8.9)] and a 3-fold increased risk for low birth weight neonates (RR 3.1, 95% CI 1.2-8.0) after adjustment for several confounders. Women positive for thyroid antibodies without elevated TSH levels in early pregnancy were at high risk for spontaneous preterm delivery (RR 1.7, 95% CI 1.1-2.8), whereas the combined effect of high TSH and positive thyroid antibodies did not show an association with preterm birth. CONCLUSIONS: High TSH levels and thyroid autoimmunity in early pregnancy may detrimentally affect pregnancy and birth outcomes. PMID- 23015652 TI - Boys with undescended testes: endocrine, volumetric and morphometric studies on testicular function before and after orchidopexy at nine months or three years of age. AB - CONTEXT: A randomized controlled study was conducted comparing the outcome of surgery for congenital cryptorchidism at 9 months or 3 yr of age. OBJECTIVE: The aim of the study was to investigate whether surgery at 9 months is more beneficial than at 3 yr and to identify early endocrine markers of importance for testicular development. PATIENTS AND METHODS: A total of 213 biopsies were taken at orchidopexy, and the number of germ and Sertoli cells per 100 seminiferous cord cross-sections and the surface area of seminiferous tubules and interstitial tissue were analyzed. Inhibin B, FSH, LH, and testosterone were determined. Testicular volume was assessed by ultrasonography and by a ruler. RESULTS: The number of germ and Sertoli cells and testicular volume at 9 months were significantly larger than at 3 yr. The intraabdominal testes showed the largest germ cell depletion at 3 yr. At both ages, testicular volume correlated to the number of germ and Sertoli cells. None of the hormones measured during the first 6 months of life (LH, FSH, testosterone, and inhibin B) could predict the number of germ or Sertoli cells at either 9 or 36 months of age, nor could hormone levels predict whether spontaneous descent would occur or not. CONCLUSION: Morphometric and volumetric data show that orchidopexy at 9 months is more beneficial for testicular development than an operation at 3 yr of age. Testicular volume was furthermore shown to reflect germ cell numbers in early childhood, whereas endocrine parameters could not predict cellular structure of the testis or its spontaneous descent. PMID- 23015653 TI - Negative fetal FSH/LH regulation in late pregnancy is associated with declined kisspeptin/KISS1R expression in the tuberal hypothalamus. AB - OBJECTIVE: Kisspeptins were recently identified as hypothalamic neuropeptides that control GnRH release at pubertal onset and in adults via the activation of KISS-1 receptor (KISS1R). Here, we have tested whether the fetal activation of the gonadotropic axis is related to the hypothalamic expression of kisspeptins and KISS1R. DESIGN AND METHODS: LH and FSH levels were measured in fetal blood from the 15th week of gestation (WG) to birth. Immunohistochemistry was performed on the hypothalamus and pituitary at different developmental stages. RESULTS: Immunostaining for kisspeptins and KISS1R appeared for both proteins in the hypothalamus as early as 15 WG and subsequently increased until 30-31 WG. In the meantime, serum LH and FSH levels decreased from postmenopausal levels in females or adult levels in males to very low levels. At full term, kisspeptin and KISS1R staining was still observed in the paraventricular, supraoptic, and ventromedial hypothalamic nuclei but not in the arcuate nucleus or median eminence. Hypothalamic GnRH staining was observed at 15 WG and did not vary after the first trimester. In an arhinencephalic fetus of 23 WG, very few GnRH neurons were observed in the hypothalamus, but serum FSH and LH levels were postmenopausal. CONCLUSION: Serum LH and FSH levels are independent from GnRH and kisspeptins at midgestation, and then GnRH progressively controls LH and FSH release. A shift from kisspeptin-independent to kisspeptin-dependent GnRH-induced LH and FSH release seems to occur after 30-31 WG. In addition to their function in adults, kisspeptins are also the master regulators of the gonadotropic axis activation in the fetus. PMID- 23015654 TI - Insulin-like growth factor-I and insulin-like growth factor binding protein-3 in Alzheimer's disease. AB - CONTEXT: Few large studies have been conducted to assess the relationship between circulating IGF and late-life cognition. OBJECTIVE: The aim of the study was to assess the relationship between IGF-I and IGF binding protein-3 (IGFBP-3) serum levels and cognitive impairment, including Alzheimer's disease (AD). METHODS: In this multicentric cross-sectional study, 694 elderly subjects (218 men, 476 women; 78.6 +/- 6.7 yr old) were included; 481 had memory complaints and were diagnosed, after comprehensive cognitive assessment, with AD (n = 224) or mild cognitive impairment (MCI) (n = 257). The control group was comprised of 213 subjects without memory complaint and with normal cognition (recruited among patients' caregivers). IGF-I and IGFBP-3 serum levels were determined by ELISA. RESULTS: IGF-I and IGFBP-3 serum levels were significantly associated with cognitive status in men (IGF-I, 137 +/- 69 ng/ml for AD vs. 178 +/- 88 ng/ml for MCI and 172 +/- 91 ng/ml for controls, P = 0.01; IGFBP-3, 3675 +/- 1542 ng/ml for AD vs. 4143 +/- 1828 ng/ml for MCI and 4488 +/- 1893 ng/ml for controls, P = 0.04). In women, IGFBP-3 was significantly associated with cognitive status (3781 +/- 1351 ng/ml for AD vs. 4190 +/- 1408 ng/ml for MCI and 4390 +/- 1552 ng/ml for controls; P < 0.001), but no significant differences between groups for IGF-I occurred. After adjustment for confounding variables (age, educational level, body mass index, diabetes, apolipoprotein E epsilon4 status), logistic regression indicated that IGF-I [odds ratio (95% confidence interval) = 0.48 (0.26-0.88)] and IGFBP-3 [odds ratio (95% confidence interval) = 0.71 (0.52-0.97)] serum levels were independently associated with AD in men, but not in women. CONCLUSIONS: We report a significant association between low IGF-I and IGFBP-3 serum levels and AD in men, but not in women. PMID- 23015656 TI - High hepatic SCD1 activity is associated with low liver fat content in healthy subjects under a lipogenic diet. AB - CONTEXT: Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar is implicated in the pathophysiology of fatty liver. Saturated fatty acids are the product of DNL and exert lipotoxic effects that promote liver fat accumulation. Desaturation of fatty acids by stearoyl-CoA desaturase 1 (SCD1) can prevent these deleterious effects. Here we investigated whether DNL and SCD1 are activated in parallel by dietary sugar and influence liver fat accumulation. METHODS: In 20 healthy subjects (eight females and 12 males, aged 30.5 +/- 2.0 yr, body mass index 25.9 +/- 0.5 kg/m(2)) who received a 4-wk lipogenic diet supplemented with 150 g/d of monosaccharides, hepatic SCD1 activity and DNL were determined using validated fatty acid ratios (16:1n-7/16:0; 16:0/18:2n-6) in very low-density lipoprotein triglycerides. Liver fat content was measured by localized (1)H-magnetic resonance spectroscopy. RESULTS: At baseline, liver fat content was positively associated with the DNL (r = 0.54, P = 0.01) but not the SCD1 activity index (r = 0.16, P = 0.49). Dietary sugar supplementation increased liver fat content and DNL and SCD1 activity indices (+33, +19, and +8%, respectively). The increase of the DNL index was strongly related to the changes in liver fat content during the sugar supplementation (r = 0.75, P = 0.0001) but showed no association with changes in the SCD1 activity (P > 0.35). After the monosaccharide supplementation, the DNL index was still positively associated with liver fat content (r = 0.52, P = 0.02), whereas SCD1 activity showed a strong negative correlation with liver fat content (r = -0.63, P = 0.002). CONCLUSIONS: DNL is closely linked with hepatic steatosis under dietary conditions rich in monosaccharides. Our data suggest that the individual hepatic SCD1 activity is a determinant of liver fat accumulation under lipogenic dietary conditions. PMID- 23015655 TI - Metabolic effects of a growth hormone-releasing factor in obese subjects with reduced growth hormone secretion: a randomized controlled trial. AB - CONTEXT: Obesity is associated with reduced GH secretion and increased cardiovascular disease risk. OBJECTIVE: We performed this study to determine the effects of augmenting endogenous GH secretion on body composition and cardiovascular disease risk indices in obese subjects with reduced GH secretion. DESIGN, PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled study was performed involving 60 abdominally obese subjects with reduced GH secretion. Subjects received tesamorelin, a GHRH(1-44) analog, 2 mg once daily, or placebo for 12 months. Abdominal visceral adipose tissue (VAT) was assessed by abdominal computed tomography scan, and carotid intima-media thickness (cIMT) was assessed by ultrasound. Treatment effect was determined by longitudinal linear mixed-effects modeling. RESULTS: VAT [-16 +/- 9 vs.19 +/- 9 cm(2), tesamorelin vs. placebo; treatment effect (95% confidence interval): -35 (-58, -12) cm(2); P = 0.003], cIMT (-0.03 +/- 0.01 vs. 0.01 +/- 0.01 mm; -0.04 (-0.07, -0.01) mm; P = 0.02), log C-reactive protein (-0.17 +/- 0.04 vs. -0.03 +/- 0.05 mg/liter; -0.15 (-0.30, -0.01) mg/liter, P = 0.04), and triglycerides (-26 +/- 16 vs. 12 +/- 8 mg/dl; -37 (-67, -7) mg/dl; P = 0.02) improved significantly in the tesamorelin group vs. placebo. No significant effects on abdominal sc adipose tissue (-6 +/- 6 vs. 3 +/- 11 cm(2); -10 (-32, +13) cm(2); P = 0.40) were seen. IGF-I increased (86 +/- 21 vs. -6 +/- 8 MUg/liter; 92 (+52, +132) MUg/liter; P < 0.0001). No changes in fasting, 2-h glucose, or glycated hemoglobin were seen. There were no serious adverse events or differences in adverse events between the groups. CONCLUSION: Among obese subjects with relative reductions in GH, tesamorelin selectively reduces VAT without significant effects on sc adipose tissue and improves triglycerides, C-reactive protein, and cIMT, without aggravating glucose. PMID- 23015658 TI - Both low and high serum IGF-I levels associate with cancer mortality in older men. AB - BACKGROUND: Although recent population-based studies suggest a U-shaped relationship between serum IGF-I concentration and all-cause mortality, the distribution of death causes underlying this association remains unclear. We hypothesized that high IGF-I levels associate with increased cancer mortality, whereas low IGF-I levels associate with increased cardiovascular disease (CVD) mortality. METHODS: Serum IGF-I levels were measured in 2901 elderly men (mean age 75.4, range 69-81 yr) included in the prospective population-based Osteoporotic Fractures in Men Study (Sweden) study. Mortality data were obtained from central registers with no loss of follow-up. The statistical analyses included Cox proportional hazards regressions with or without a spline approach. RESULTS: During the follow-up (mean 6.0 yr), 586 of the participants died (cancer deaths, n = 211; CVD deaths, n = 214). As expected, our data revealed a U-shaped association between serum IGF-I levels and all-cause mortality. Low as well as high serum IGF-I (quintile 1 or 5 vs. quintiles 2-4) associated with increased cancer mortality [hazard ratio (HR) = 1.86, 95% confidence interval (CI) = 1.34 2.58; and HR = 1.90, 95% CI = 1.37-2.65, respectively]. Only low serum IGF-I associated with increased CVD mortality (quintile 1 vs. quintiles 2-4, HR = 1.48, 95% CI = 1.08-2.04). These associations remained after adjustment for multiple covariates and exclusion of men who died during the first 2 yr of follow-up. CONCLUSIONS: Our findings demonstrate that both low and high serum IGF-I levels are risk markers for increased cancer mortality in older men. Moreover, low IGF-I levels associate with increased CVD mortality. PMID- 23015657 TI - Patients with an HbA1c in the prediabetic and diabetic range have higher numbers of circulating cells with osteogenic and endothelial progenitor cell markers. AB - CONTEXT: Vascular calcification, an important feature of diabetic vasculopathy, is an active process potentially mediated by endothelial progenitor cells (EPCs) coexpressing the osteoblastic marker osteocalcin (OCN). OBJECTIVE: In this study we tested the hypothesis that cells expressing these markers are associated with the presence of elevated glycated hemoglobin (HbA1c). DESIGN, SETTING, AND PATIENTS: This was a cross-sectional comparison. Patients (n = 133, aged 57.4 +/- 15.7 yr) were divided into two groups according to the presence of an HbA1c in a (pre-)diabetic (>5.6) or normal range at the time of blood sampling. METHODS: Using flow cytometry of peripheral blood mononuclear cells (MNCs), cells positive for OCN, the EPC markers (CD34/KDR and CD133(+)/CD34(-)/KDR(+)) and OCN(+) EPCs were counted. RESULTS: Patients with elevated HbA1c compared with those with normal HbA1c had a significantly higher percentage of circulating OCN(+) MNCs [4.6 (interquartile range 2.68-7.81%) vs. 3.12 (0.99-7.81%), P = 0.035], higher numbers of OCN(+)/CD133(+)/CD34(-)/KDR(+) cells [20 (9-74) vs. 8 (0-19) counts per 100,000 gated events, P < 0.001] and a higher fraction of CD133(+)/CD34( )/KDR(+) and CD34/KDR cells coexpressing OCN (23.7 +/- 24.3 vs. 40.5 +/- 34.6%, P = 0.002 and 37.1 +/- 39.5 vs. 59.7 +/- 37.7%, P = 0.002, respectively). The association between circulating OCN(+)/CD133(+)/CD34(-)/KDR(+) cells and an HbA1c in the (pre-) diabetic range remained strong, even after adjusting for differences in obesity and cardiovascular risk factors, disease, and medications in a multivariate model [odds ratio 1.72 (1.21-2.61), P =0.002]. CONCLUSION: This study demonstrated that patients with HbA1c in the (pre-)diabetic range have a significant increase in OCN(+) MNCs, and OCN(+)/CD133(+)/CD34(-)/KDR(+) cells, in particular. Whether these cells increase vascular calcification in (pre-)diabetes warrants further studies. PMID- 23015659 TI - Managing demand for laboratory tests: a laboratory toolkit. AB - Healthcare budgets worldwide are facing increasing pressure to reduce costs and improve efficiency, while maintaining quality. Laboratory testing has not escaped this pressure, particularly since pathology investigations cost the National Health Service L2.5 billion per year. Indeed, the Carter Review, a UK Department of Health-commissioned review of pathology services in England, estimated that 20% of this could be saved by improving pathology services, despite an average annual increase of 8%-10% in workload. One area of increasing importance is managing the demands for pathology tests and reducing inappropriate requesting. The Carter Review estimated that 25% of pathology tests were unnecessary, representing a huge potential waste. Certainly, the large variability in levels of requesting between general practitioners suggests that inappropriate requesting is widespread. Unlocking the key to this variation and implementing measures to reduce inappropriate requesting would have major implications for patients and healthcare resources alike. This article reviews the approaches to demand management. Specifically, it aims to (a) define demand management and inappropriate requesting, (b) assess the drivers for demand management, (c) examine the various approaches used, illustrating the potential of electronic requesting and (d) provide a wider context. It will cover issues, such as educational approaches, information technology opportunities and challenges, vetting, duplicate request identification and management, the role of key performance indicators, profile composition and assessment of downstream impact of inappropriate requesting. Currently, many laboratories are exploring demand management using a plethora of disparate approaches. Hence, this review seeks to provide a 'toolkit' with the view to allowing laboratories to develop a standardised demand management strategy. PMID- 23015660 TI - Utilisation of fluorescent multiplex PCR and laser-induced capillary electrophoresis for the diagnosis of Ewing family of tumours in formalin-fixed paraffin-embedded tissues. AB - AIMS: The localisation of the translocation breakpoint of the Ewing sarcoma family of tumours shows significant variability on relatively large regions of fusion partner genes. As a consequence, many alternative forms of EWSR1-ETS translocation exist which make the RNA-based molecular diagnostics of Ewing sarcoma family of tumours complicated. In addition to the heterogeneity of fusion transcripts, the degradation of RNA also presents a significant difficulty in the molecular analysis of formalin-fixed paraffin-embedded (FFPE) tissues. Our aim was to establish a sensitive method which is able to identify all combinatorially possible EWSR1-FLI1 and EWSR1-ERG translocation transcripts in FFPE tissue samples despite significant RNA-degradation. METHODS: The combination of fluorescent multiplex PCR with laser-induced capillary electrophoresis was used to detect and identify EWSR1-FLI1 and EWSR1-ERG chimeric transcripts on the basis of amplicon size, and forward primers labelled by distinct fluorophores. RESULTS: Using this method, we processed 60 FFPE samples of Ewing sarcoma family of tumours, and identified six types EWSR1-FLI1 and one type EWSR1-ERG chimeric transcripts acceptable for RT-PCR analysis in 27 out of 45 samples. This result shows 60% sensitivity for detecting the most frequent Ewing family of tumour (EFT)-related fusion transcripts. CONCLUSIONS: The utilisation of fluorescent multiplex PCR and laser-induced fluorescent capillary electrophoresis is effective for the diagnosis of EFT in FFPE tissue, and after the defined modifications it can offer a sensitive method to overcome the diagnostic difficulties connected with heterogeneity of the variant translocations in EFT. PMID- 23015661 TI - Biomass waste: the way ahead. PMID- 23015663 TI - Single nucleotide polymorphisms (SNPs) in non-small cell lung cancer (NSCLC) patients. PMID- 23015662 TI - Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. AB - BACKGROUND: The Avastin Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community-based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration. METHODS: The ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan-Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors. RESULTS: In total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX-bevacizumab (n = 968) or FOLFIRI-bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX-bevacizumab and FOLFIRI-bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88-1.21) and OS (HR, 0.95; 95% CI, 0.78-1.16) outcome as with FOLFOX bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies. CONCLUSIONS: In first-line mCRC patients, the FOLFOX-bevacizumab and FOLFIRI-bevacizumab regimens were associated with similar treatment patterns and clinical outcomes. PMID- 23015665 TI - Variable expression of O:61 in Salmonella group C2. AB - According to the Kauffmann-White scheme, 39 pairs of serovars in Salmonella serogroup C2 differ only by the minor antigen O:6(1). We characterized strains from 10 serovars representing five Salmonella serogroup C2 pairs. All strains demonstrated variable expression of O:6(1). These results indicate that these pairs are not distinct serovars. PMID- 23015664 TI - Novel two-round phenotypic assay for protease inhibitor susceptibility testing of recombinant and primary HIV-1 isolates. AB - Antiretroviral drug susceptibility tests facilitate therapeutic management of HIV 1-infected patients. Although genotyping systems are affordable, inaccuracy in the interpretation of complex mutational patterns may limit their usefulness. Currently available HIV-1 phenotypic assays are based on the generation of recombinant viruses in which the specific viral gene of interest, derived from a patient plasma sample, is cloned into a susceptible genetic viral backbone prior to in vitro drug susceptibility evaluation. Nevertheless, in the case of protease inhibitors, not only are mutations in the HIV-1 protease-coding region involved in resistance, but the role of Gag in drug susceptibility has also recently been reported. In order to avoid the inherent limitations resulting from partial cloning of the viral genome, we designed and evaluated a new experimental strategy to test the in vitro susceptibility of primary viral isolates to protease inhibitors. Our protocol, which is based on a two-round infection protocol using the reporter TZM-bl cell line, showed a good correlation with genotypic resistance prediction and with the Antivirogram phenotypic assay, in both protease-recombinant viruses and primary viral isolates. The protocol is suitable for any HIV-1 subtype and enables rapid in-house measurement of protease inhibitor susceptibility, thus making it possible to evaluate the concomitant effects of both patient-derived gag and protease-coding regions. PMID- 23015666 TI - Identification of and screening for human Helicobacter cinaedi infections and carriers via nested PCR. AB - Helicobacter cinaedi is the most frequently reported enterohepatic Helicobacter species isolated from humans. Earlier research suggested that certain patients with H. cinaedi infection may remain undiagnosed or incorrectly diagnosed because of difficulties in detecting the bacteria by conventional culture methods. Here, we report a nested PCR assay that rapidly detects the cytolethal distending toxin gene (cdt) of H. cinaedi with high specificity and sensitivity. Specificity of the assay was validated by using different species of Helicobacter and Campylobacter, as well as known H. cinaedi-positive and -negative samples. The sensitivity of detection for the cdt gene in the assay was 10(2) CFU/ml urine or 10(2) CFU/10(5) infected RAW 264.7 cells. In an H. cinaedi-infected mouse model, the cdt gene of H. cinaedi was effectively detected via the assay with urine (6/7), stool (2/3), and blood (2/6) samples. Importantly, it detected H. cinaedi in blood, urine, and stool samples from one patient with a suspected H. cinaedi infection and three patients with known infections. The assay was further used clinically to follow up two H. cinaedi-infected patients after antibiotic treatment. Stool samples from these two patients evaluated by nested PCR after antibiotic therapy showed clearance of bacterial DNA. Finally, analysis of stool specimens from healthy volunteers showed occasional positive reactions (4/30) to H. cinaedi DNA, which suggests intestinal colonization by H. cinaedi in healthy subjects. In conclusion, this nested PCR assay may be useful for the rapid diagnosis, antimicrobial treatment evaluation, and epidemiological study of H. cinaedi infection. PMID- 23015667 TI - Multicenter clinical evaluation of the portrait toxigenic C. difficile assay for detection of toxigenic Clostridium difficile strains in clinical stool specimens. AB - We compared the Portrait Toxigenic C. difficile Assay, a new semiautomated sample to-result molecular test, to a toxigenic bacterial culture/cell cytotoxin neutralization assay (TBC/CCNA) for the detection of toxigenic Clostridium difficile in 549 stool specimens. Stool specimens were also tested by one of three alternative FDA-cleared molecular tests for toxigenic C. difficile (Xpert C. difficile, Illumigene C. difficile, or GeneOhm Cdiff). The sensitivities and specificities of the molecular tests compared to TBC/CCNA were as follows: 98.2% and 92.8% for the Portrait assay, 100% and 91.7% for the Xpert assay, 93.3% and 95.1% for the Illumigene assay, and 97.4% and 98.5% for the GeneOhm assay, respectively. The majority of Portrait false-positive results (20/31; 64.5%) were also positive for C. difficile by an alternative molecular test, suggesting an increased sensitivity compared to the culture-based "gold standard" method. The Portrait test detected an assay input of 30 CFU in 100% of spiked samples and detected an input of 10 CFU in 96.7% of samples tested. PMID- 23015668 TI - Pseudo-outbreak of Lecanicillium and Acremonium species in orthopedic surgery patients. AB - Acremonium species cause a variety of human infections, while Lecanicillium species have not been reported as human pathogens. We describe a pseudo-outbreak involving both organisms, highlighting the role and limitations of molecular methods in the characterization of rare fungal isolates. Repeated isolation of these fungi from patient tissue samples raises concerns about exogenous contamination in the hospital environment. PMID- 23015669 TI - Prospective multicenter study of Pneumocystis jirovecii colonization among cystic fibrosis patients in France. AB - Pneumocystis carriage was detected in 12.5% of 104 cystic fibrosis (CF) patients during a prospective multicenter French study, with a prevalence of genotype 85C/248C and geographic variations. It was significantly associated with the absence of Pseudomonas aeruginosa colonization and a greater forced expiratory volume in 1 s. Results are discussed considering the natural history of CF. PMID- 23015670 TI - The rise of Tropheryma whipplei: a 12-year retrospective study of PCR diagnoses in our reference center. AB - Tropheryma whipplei is the causative agent of classic Whipple's disease (WD) and other clinical entities, such as localized infection. Asymptomatic carriers have also been reported, mainly based on the testing of fecal samples. Our objective was to undertake a retrospective analysis of molecular biology usage for the diagnosis of WD over a 12-year period in our reference center. We tested 27,923 samples from 15,473 patients. The number of patients tested and the number of patients with a positive PCR result for T. whipplei have increased significantly over the last 12 years (P < 0.0001). Overall, T. whipplei was more frequently recovered from stools (43%), saliva (15%), duodenal biopsy samples (12.5%), blood (5%), and cerebrospinal fluid (CSF) (6%) and less commonly from cardiac valves (3%), urine (0.5%), skin biopsy samples (1%), lymph nodes (2.5%), aqueous humor (0.5%), and intra-articular fluid (1%). Among all the positive samples, we observed that stool samples and skin biopsy samples exhibited a higher prevalence of positivity by real-time quantitative PCR (qPCR) at 10.07% and 15.4%, respectively. The number of patients with a positive PCR result for T. whipplei has increased significantly over the last 12 years, although the positive ratio has not changed. Improvements in diagnostic tools have contributed greatly toward greater knowledge of WD and, consequently, the interest of physicians in this condition. In addition, we propose here an update of the diagnostic strategy for WD when qPCR is being used. PMID- 23015671 TI - Post-prostate biopsy infection with Escherichia coli ST131 leading to epididymo orchitis and meningitis caused by Gram-negative bacilli. AB - A 57-year-old man who had recently undergone a transrectal prostate biopsy for a rising prostate-specific antigen level developed postbiopsy necrotizing epididymo orchitis (requiring orchiectomy) and then Gram-negative meningitis, despite fluoroquinolone administration for periprocedural prophylaxis and subsequent therapy. The causative organism proved to be a fluoroquinolone-resistant Escherichia coli strain from sequence type ST131. PMID- 23015672 TI - Human parechovirus in respiratory specimens from children in Kansas City, Missouri. AB - We detected a 3% prevalence rate for human parechovirus (HPeV) in 720 respiratory specimens collected from 637 children seen in our hospital in 2009. Fifteen of 20 were HPeV-3 and two were HPeV-1. Only nonspecific, modest respiratory symptoms were evident in patients with detectable HPeV in respiratory specimens. Seven patients had concurrent respiratory and central nervous system (CNS) HPeV-3 infection, suggesting a possible respiratory route of acquisition. PMID- 23015673 TI - Female epidemiology of transcription-mediated amplification-based Trichomonas vaginalis detection in a metropolitan setting with a high prevalence of sexually transmitted infection. AB - Recent literature has reported increased accuracy of Trichomonas vaginalis transcription-mediated amplification (TMA)-based analyte-specific reagent (ASR) testing in female populations. A retrospective investigation assessed 7,277 female first-void urine, cervical, or vaginal specimens submitted from a high prevalence sexually transmitted infection (STI) community to characterize prevalence of disease etiologies. The most common STI phenotype reflected detection of solely T. vaginalis (54.2% of all health care encounters that resulted in STI detection). In females with detectable T. vaginalis, codetection of Chlamydia trachomatis and Neisseria gonorrhoeae occurred in 7.8% and 2.7% of health care encounters, respectively. The mean age of women with detectable T. vaginalis (30.6) was significantly higher than those for women with C. trachomatis or N. gonorrhoeae (22.3 and 21.6, respectively; P < 0.0001). T. vaginalis was the predominant sexually transmitted agent in women over the age of 20 (P < 0.0002). C. trachomatis was the most commonly detected agent in females under the age of 21, particularly from cervical specimens. However, first-void urine detection rates for T. vaginalis and C. trachomatis within this age demographic demonstrated no difference (P = 0.92). While overall and cervical specimen-derived detection of T. vaginalis within African American majority geographical locales outweighed that within majority Caucasian geographical regions (P <= 0.004), this difference was not noted with first-void urine screening (P = 0.54). Health care professionals can consider TMA-based T. vaginalis screening for a wide age range of patients; incorporation of first-void urine specimens into screening algorithms can potentiate novel insight into the epidemiology of trichomoniasis. PMID- 23015674 TI - Culture-dependent and -independent investigations of microbial diversity on urinary catheters. AB - Catheter-associated urinary tract infection is caused by bacteria, which ascend the catheter along its external or internal surface to the bladder and subsequently develop into biofilms on the catheter and uroepithelium. Antibiotic treated bacteria and bacteria residing in biofilm can be difficult to culture. In this study we used culture-based and 16S rRNA gene-based culture-independent methods (fingerprinting, cloning, and pyrosequencing) to determine the microbial diversity of biofilms on 24 urinary catheters. Most of the patients were catheterized for <30 days and had undergone recent antibiotic treatment. In addition, the corresponding urine samples for 16 patients were cultured. We found that gene analyses of the catheters were consistent with cultures of the corresponding urine samples for the presence of bacteria but sometimes discordant for the identity of the species. Cultures of catheter tips detected bacteria more frequently than urine cultures and gene analyses; coagulase-negative staphylococci were, in particular, cultured much more often from catheter tips, indicating potential contamination of the catheter tips during sampling. The external and internal surfaces of 19 catheters were separately analyzed by molecular methods, and discordant results were found in six catheters, suggesting that bacterial colonization intra- and extraluminally may be different. Molecular analyses showed that most of the species identified in this study were known uropathogens, and infected catheters were generally colonized by one to two species, probably due to antibiotic usage and short-term catheterization. In conclusion, our data showed that culture-independent molecular methods did not detect bacteria from urinary catheters more frequently than culture-based methods. PMID- 23015675 TI - Two techniques for simultaneous identification of Plasmodium ovale curtisi and Plasmodium ovale wallikeri by use of the small-subunit rRNA gene. AB - The primers traditionally used to detect Plasmodium ovale infections are known for not binding all P. ovale parasites within the small-subunit rRNA gene when used alone. We describe a simple, cost- and time-efficient multiplex nested PCR and a nested PCR using a novel set of primers for the simultaneous detection of P. ovale curtisi and P. ovale wallikeri. PMID- 23015676 TI - Comparison of three statistical methods for establishing tentative wild-type population and epidemiological cutoff values for echinocandins, amphotericin B, flucytosine, and six Candida species as determined by the colorimetric Sensititre YeastOne method. AB - The Sensititre YeastOne (SYO) method is a widely used method to determine the susceptibility of Candida spp. to antifungal agents. CLSI clinical breakpoints (CBP) have been reported for antifungals, but not using this method. In the absence of CBP, epidemiological cutoff values (ECVs) are useful to separate wild type (WT) isolates (those without mechanisms of resistance) from non-WT isolates (those that can harbor some resistance mechanisms), which is the goal of any susceptibility test. The ECVs for five agents, obtained using the MIC distributions determined by the SYO test, were calculated and contrasted with those for three statistical methods and the MIC(50) and modal MIC, both plus 2 fold dilutions. The median ECVs (in mg/liter) (% of isolates inhibited by MICs equal to or less than the ECV; number of isolates tested) of the five methods for anidulafungin, micafungin, caspofungin, amphotericin B, and flucytosine, respectively, were as follows: 0.25 (98.5%; 656), 0.06 (95.1%; 659), 0.25 (98.7%; 747), 2 (100%; 923), and 1 (98.5%; 915) for Candida albicans; 8 (100%; 352), 4 (99.2%; 392), 2 (99.2%; 480), 1 (99.8%; 603), and 0.5 (97.9%; 635) for C. parapsilosis; 1 (99.2%; 123), 0.12 (99.2%; 121), 0.25 (99.2%; 138), 2 (100%; 171), and 0.5 (97.2%; 175) for C. tropicalis; 0.12 (96.6%; 174), 0.06 (96%; 176), 0.25 (98.4%; 188), 2 (100%; 209), and 0.25 (97.6%; 208) for C. glabrata; 0.25 (97%; 33), 0.5 (93.9%; 33), 1 (91.9%; 37), 4 (100%; 51), and 32 (100%; 53) for C. krusei; and 4 (100%; 33), 2 (100%; 33), 2 (100%; 54), 1 (100%; 90), and 0.25 (93.4%; 91) for C. orthopsilosis. The three statistical methods gave similar ECVs (within one dilution) and included >= 95% of isolates. These tentative ECVs would be useful for monitoring the emergence of isolates with reduced susceptibility by use of the SYO method. PMID- 23015678 TI - Optimizing the management of prostate cancer in senior adults: call to action. PMID- 23015677 TI - Dry storage and transport of a cervicovaginal self-sample by use of the Evalyn Brush, providing reliable human papillomavirus detection combined with comfort for women. AB - Primary screening using high-risk human papillomavirus (hrHPV) detection has been suggested as a way of improving cervical cancer prevention. Women currently not attending screening (nonresponders) are more likely to participate when given the opportunity of self-sampling for hrHPV testing. The Evalyn Brush is a new cervicovaginal self-sampling device, developed specifically to meet women's demands, which is user-friendly and easy to use. The aims of this study were to investigate agreement of hrHPV detection by two PCR methods between the Evalyn Brush and physician-obtained samples and to study women's acceptance of this self sampling device. Each of 134 women visiting the gynecology outpatient clinic collected a self-obtained sample (self-sample) and completed a questionnaire. The brush was stored dry. After self-sampling, a trained physician obtained a conventional cervical cytology specimen in ThinPrep medium. HrHPV detection was performed using the SPF(10)-DEIA-LiPA(25) and GP5+/6+-LQ-test. The overall agreement for hrHPV detection using SPF(10)-DEIA-LiPA(25) between the self-sample and the physician-taken sample was 85.8% (kappa value, 0.715; 95% confidence interval [CI], 0.597 to 0.843; P = 1.000). The overall agreement for hrHPV detection using GP5+/6+-LQ between the self-sample and the physician-taken sample was 86.6% (kappa value, 0.725; 95% CI, 0.607 to 0.843; P = 0.815). Ninety-eight percent of the women rated their experience as good to excellent. Moreover, 95% of women preferred self-sampling to physician sampling. Self-sampling using the dry Evalyn Brush system is as good as a physician-taken sample for hrHPV detection and is highly acceptable to women. To validate this self-sampling device for clinical use, a large screening cohort should be studied. PMID- 23015679 TI - Is radical prostatectomy a useful therapeutic option for high-risk prostate cancer in older men? AB - Prostate cancer affects a high proportion of men over 70 years of age, who are likely to have high-risk disease and a substantial risk of prostate-cancer specific death. With life expectancy increasing worldwide, the burden of prostate cancer is also expected to rise. Thus, effective management of this high-risk senior patient group is increasingly important. Radical prostatectomy can increase survival and decrease the risk of metastatic progression. Postsurgery complications are affected more by comorbidity than by age. In patients without comorbidities, surgery is associated with a low risk of mortality. Advanced age may increase the likelihood of incontinence following radical prostatectomy, but patients with higher risk disease are no more likely to experience this complication compared with lower risk groups. Treatment decisions should be made after considering the health status and life expectancy of the individual patient. If eligible, the patient should be offered radical prostatectomy as a potentially curative treatment, without a rigid restriction to a certain chronological age. PMID- 23015680 TI - Radical radiotherapy for high-risk prostate cancer in older men. AB - Historical data for older men with high-risk nonmetastatic prostate cancer treated with radiotherapy alone have demonstrated a 10-year prostate-cancer specific mortality of around 30%. The development of dose escalation, using techniques such as intensity-modulated radiotherapy, has enabled more targeted delivery of treatment with improved efficacy and a reduction in the risk of toxicity compared with conventional radiotherapy. The combination of radiotherapy and androgen-deprivation therapy (ADT) has been shown to improve overall survival compared with radiotherapy or ADT alone without a significant increase in toxicity in patients with minimal comorbidities. There is evidence that patient age has only a marginal effect on genitourinary and gastrointestinal toxicities following radiotherapy. Further research has shown that although age does have an effect on the likelihood of sexual dysfunction after radiation therapy, there is no significant difference in the proportion of men aged >= 75 years who feel that sexual dysfunction is a moderate or serious problem before or 24 months after diagnosis. Radical radiotherapy is effective and well tolerated in senior men with high-risk prostate cancer and should be offered in combination with long term ADT to patients with minimal comorbidities. In case of significant comorbid conditions, shorter durations of ADT may be considered. PMID- 23015681 TI - Management of advanced prostate cancer in senior adults: the new landscape. AB - The landscape of treatment for advanced prostate cancer is continually evolving as new therapies are developed and guidelines are constantly updated. However, the management of older men with advanced disease is not optimal. Many men are denied chemotherapy based on their chronological age, not their health status. Androgen-deprivation therapy (ADT) remains the mainstay of first-line treatment of advanced disease. Once the disease becomes resistant to castration, docetaxel based chemotherapy is the regulatory-approved standard of care, irrespective of age. The place of weekly docetaxel in patients with poor performance status and signs of frailty has to be further evaluated in clinical studies. New treatments are now available, or on the horizon, for disease that progresses during or after docetaxel therapy. Cabazitaxel and abiraterone have been shown to prolong survival, irrespective of age, and are already in clinical use having received regulatory approval. The optimal sequence for these two agents is still unknown, although there is some indication that in patients predicted to be poor responders to abiraterone (high Gleason score, progression during docetaxel therapy, rapid progression to castrate-resistant prostate cancer with ADT) cabazitaxel should be the preferred choice. Further advances are being investigated, with promising data reported from phase III trials. PMID- 23015682 TI - The importance of supportive care in optimizing treatment outcomes of patients with advanced prostate cancer. AB - Optimal oncologic care of older men with prostate cancer, including effective prevention and management of the disease and treatment side effects (so-called best supportive care measures) can prolong survival, improve quality of life, and reduce depressive symptoms. In addition, the proportion of treatment discontinuations can be reduced through early reporting and management of side effects. Pharmacologic care may be offered to manage the side effects of androgen deprivation therapy and chemotherapy, which may include hot flashes, febrile neutropenia, fatigue, and diarrhea. Nonpharmacologic care (e.g., physical exercise, acupuncture, relaxation) has also been shown to benefit patients. At the Georges Pompidou European Hospital, the Program of Optimization of Chemotherapy Administration has demonstrated that improved outpatient follow-up by supportive care measures can reduce the occurrence of chemotherapy-related side effects, reduce cancellations and modifications of treatment, reduce chemotherapy wastage, and reduce the length of stay in the outpatient unit. The importance of supportive care measures to optimize management and outcomes of older men with advanced prostate cancer should not be overlooked. PMID- 23015683 TI - A comment on the International Society of Geriatric Oncology guidelines: evidence based advice for the clinical setting. AB - Largely a disease of older men, prostate cancer is likely to become a growing burden in the developed world as the population ages and overall life expectancy increases. Furthermore, prostate cancer management in older men is not optimal, reflecting the lack of training dedicated to senior adults in fellowship programs and the lack of specific guidelines to manage senior adults. The International Society of Geriatric Oncology (SIOG) convened a multidisciplinary Prostate Cancer Working Group to review the evidence base and provide advice on the management of the disease in senior age groups. The Working Group reported that advancing age, by itself, is not a reliable guide to treatment decision making for men with either localized or advanced prostate cancer. Instead, the SIOG guidelines advise health care teams to assess the patient's underlying health status, which is largely dictated by associated comorbid conditions, but also by dependency in activities of daily living and nutritional status, and to use the findings to categorize the individual into one of four groups: healthy, vulnerable, frail, or terminally ill. The guidelines recommend that a patient categorized as healthy or vulnerable (i.e., with reversible problems following geriatric intervention) should receive the same approach to treatment as a younger patient. Frail patients should be managed using adapted treatment strategies, and the terminally ill should receive symptomatic/palliative care only. The guidelines may have ongoing relevance as the treatment options for prostate cancer expand. PMID- 23015684 TI - Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset. AB - BACKGROUND: Eosinophilic inflammation is implicated in asthma. Eotaxin 1-3 regulate eosinophil trafficking into the airways along with other chemotactic factors. However, the epithelial and bronchoalveolar lavage (BAL) cell expression of these chemokines in relation to asthma severity and eosinophilic phenotypes has not been addressed. OBJECTIVE: To measure the expression of the three eotaxin isoforms in bronchoscopically obtained samples and compare them with clinically relevant parameters between normal subjects and patients with asthma. METHODS: Normal subjects and patients with asthma of varying severity recruited through the Severe Asthma Research Program underwent clinical assessment and bronchoscopy with airway brushing and BAL. Eotaxin 1-3 mRNA/protein were measured in epithelial and BAL cells and compared with asthma severity, control and eosinophilic inflammation. RESULTS: Eotaxin-2 and eotaxin-3 mRNA and eotaxin-2 protein were increased in airway epithelial brushings from patients with asthma and were highest in cases of severe asthma (p values 0.0155, 0.0033 and 0.0006, respectively), with eotaxin-2 protein increased with age at onset. BAL cells normally expressed high levels of eotaxin-2 mRNA/protein but BAL fluid levels of eotaxin-2 were lowest in severe asthma. Epithelial eotaxin-2 and eotaxin-3 mRNA/protein was associated with sputum eosinophilia, lower forced expiratory volume in 1 s and more asthma exacerbations. Airway epithelial cell eotaxin-2 protein differed by asthma severity only in those with late onset disease, and tended to be highest in those with late onset eosinophilic asthma. CONCLUSIONS: Epithelial eotaxin-2 and 3 are increased in asthma and severe asthma. Their expression may contribute to luminal migration of eosinophils, especially in later onset disease, asthma control and severity. PMID- 23015685 TI - Meta-analysis of the association of urbanicity with schizophrenia. AB - The association between urbanicity and risk of schizophrenia is well established. The incidence of schizophrenia has been observed to increase in line with rising levels of urbanicity, as measured in terms of population size or density. This association is expressed as Incidence Rate Ratio (IRR), and the results are usually presented by comparing the most urban with the most rural environment. In this study, we undertook to express the effect of urbanicity on the risk of schizophrenia in a linear form and to perform a meta-analysis of all available evidence. We first employed a simple regression analysis of log (IRR) as given in each study on the urbanicity category, assuming a uniform distribution and a linear association. In order to obtain more accurate estimates, we developed a more sophisticated method that generates individual data points with simulation from the summary data presented in the original studies, and then fits a logistic regression model. The estimates from each study were combined with meta-analysis. Despite the challenges that arise from differences between studies as regards to the number and relative size of urbanicity levels, a linear association was observed between the logarithm of the odds of risk for schizophrenia and urbanicity. The risk for schizophrenia at the most urban environment was estimated to be 2.37 times higher than in the most rural environment. The same effect was found when studies measuring the risk for nonaffective psychosis were included. PMID- 23015686 TI - Schizophrenia in translation: dissecting motivation in schizophrenia and rodents. AB - The negative symptoms of schizophrenia include deficits in motivation, for which there is currently no treatment available. Animal models provide a powerful tool for identifying the potential pathophysiological mechanisms underlying the motivation deficits of schizophrenia with the aim of discovering novel treatment targets. The success of such an approach critically depends on meticulously detailed analysis of motivational phenotypes in patients and in animal models. Here, we review the results of recent human behavioral and imaging studies of motivation, and we relate those findings to the results from animal studies, including a mouse model of striatal dopamine D2 receptor hyperfunction. The motivational deficit in patients with schizophrenia is not due to an inability to experience pleasure in the moment as hedonic reaction appears intact in patients. Instead, the motivation deficit represents a reduced capacity for anticipating future pleasure resulting from goal-directed action. The diminished anticipation appears to be a consequence of an inability to accurately represent the expected reward values of actions. A strikingly similar phenotype in incentive motivation has also been described in mice with striatal dopamine D2 receptor hyperfunction. These convergent findings identify potential pathophysiological mechanisms that underlie the deficit in anticipatory motivation, and importantly, the mouse model provides a tool for investigating novel treatment strategies, which we discuss here. PMID- 23015688 TI - An inexpensive particle monitor for smoker behaviour modification in homes. AB - OBJECTIVE: To compare the response of a new particle counting instrument (Dylos DC1700) with that produced by a device (TSI Sidepak Personal Aerosol Monitor AM510) commonly used to measure PM2.5 in settings where secondhand smoke (SHS) is encountered. METHODS: Controlled chamber experiments with different SHS concentrations were generated by burning a cigarette for varying time periods and running both devices simultaneously. RESULTS: The Dylos and Sidepak devices produced similar responses to changes in SHS concentrations up to 1000 MUg/m(3). Using 591 min of contemporaneous measurements from 13 chamber experiments, an equation was developed to allow conversion of particle number concentration data from the Dylos to estimated mass concentration data for SHS aerosol. CONCLUSIONS: The Dylos DC1700 can provide real-time data that may be converted to an estimate of SHS levels in smoky environments. Given the low cost, low noise and simplicity of use, this device is likely to be a useful tool for interventions to provide feedback of SHS concentrations to help motivate changes in smoking behaviour at home. PMID- 23015687 TI - Structural brain alterations associated with schizophrenia preceded by conduct disorder: a common and distinct subtype of schizophrenia? AB - Conduct disorder (CD) prior to age 15 is a precursor of schizophrenia in a minority of cases and is associated with violent behavior through adulthood, after taking account of substance misuse. The present study used structural magnetic imaging to examine gray matter (GM) volumes among 27 men with schizophrenia preceded by CD (SZ+CD), 23 men with schizophrenia but without CD (SZ-CD), 27 men with CD only (CD), and 25 healthy (H) men. The groups with schizophrenia were similar in terms of age of onset and duration of illness, levels of psychotic symptoms, and medication. The 2 groups with CD were similar as to number of CD symptoms, lifelong aggressive behavior, and number of criminal convictions. Men with SZ+CD, relative to those with SZ-CD, displayed (1) increased GM volumes in the hypothalamus, the left putamen, the right cuneus/precuneus, and the right inferior parietal cortex after controlling for age, alcohol, and drug misuse and (2) decreased GM volumes in the inferior frontal region. Men with SZ+CD (relative to the SZ-CD group) and CD (relative to the H group) displayed increased GM volumes of the hypothalamus and the inferior and superior parietal lobes, which were not associated with substance misuse. Aggressive behavior, both prior to age 15 and lifetime tendency, was positively correlated with the GM volume of the hypothalamus. Thus, among males, SZ+CD represents a distinct subtype of schizophrenia. Although differences in behavior emerge in childhood and remain stable through adulthood, further research is needed to determine whether the differences in GM volumes result from abnormal neural development distinct from that of other males developing schizophrenia. PMID- 23015689 TI - Who would use PrEP? Factors associated with intention to use among MSM in London: a community survey. AB - OBJECTIVE: To assess current and intended future use of pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) and characterise those attending sexual health clinics, the anticipated PrEP delivery setting. DESIGN: Cross sectional study. METHODS: Self-administered survey of 842 HIV negative MSM recruited from social venues in London in 2011. RESULTS: One in 10 (10.2%, 83/814, 95% CI 8.2% to 12.5%) and one in 50 (2.1%, 17/809, 95% CI 1.2% to 3.3%) reported having ever used post-exposure prophylaxis (PEP) and PrEP respectively. Half reported they would be likely to use PrEP if it became available as a daily pill (50.3%, 386/786, 95% CI 46.7% to 53.9%). MSM were more likely to consider future PrEP use if they were <35 years (adjusted OR (AOR) 1.57, 95% CI 1.16 to 2.14), had unprotected anal intercourse with casual partners (AOR 1.70, 95% CI 1.13 to 2.56), and had previously used PEP (AOR 1.94, 95% CI 1.17 to 3.24). Over half of MSM (54.8% 457/834 95% CI 51.3 to 58.2) attended a sexual health clinic the previous year. Independent factors associated with attendance were age <35 (AOR 2.29, 95% CI 1.68 to 3.13), and >= 10 anal sex partners in the last year (AOR 2.49, 95% CI 1.77 to 3.52). CONCLUSIONS: The concept of PrEP for HIV prevention in the form of a daily pill is acceptable to half of sexually active MSM in London. MSM reporting higher risk behaviours attend sexual health clinics suggesting this is a suitable setting for PrEP delivery. PMID- 23015690 TI - Atrial fibrillation ablation techniques. AB - We performed a survey on current atrial fibrillation (AF) ablation techniques used for catheter ablation of AF among the European Heart Rhythm Association Research Network. The focus of this questionnaire is on the ablation strategy, such as the use of different lesion sets or sites of ablation in the various forms of AF, and on the technical aspects of catheter ablation with respect to energy sources and imaging modalities. PMID- 23015691 TI - Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the Baikal seal (Pusa sibirica) and the mouse. AB - The constitutive androstane receptor (CAR) not only displays a high basal transcriptional activity but also acts as a ligand-dependent transcriptional factor. It is known that CAR exhibits different ligand profiles across species. However, the mechanisms underlying CAR activation by chemicals and the species specific responses are not fully understood. The objectives of this study are to establish a high-throughput tool to screen CAR ligands and to clarify how CAR proteins from the Baikal seal (bsCAR) and the mouse (mCAR) interact with chemicals and steroid receptor coactivator 1 (SRC1). We developed the surface plasmon resonance (SPR) system to assess quantitatively the interaction of CAR with potential ligands and SRC1. The ligand-binding domain (LBD) of bsCAR and mCAR was synthesized in a wheat germ cell-free system. The purified CAR LBD was then immobilized on the sensor chip for the SPR assay, and the kinetics of direct interaction of CARs with ligand candidates was measured. Androstanol and androstenol, estrone, 17beta-estradiol, TCPOBOP, and CITCO showed compound specific but similar affinities for both CARs. The CAR-SRC1 interaction was ligand dependent but exhibited a different ligand profile between the seal and the mouse. The results of SRC1 interaction assay accounted for those of our previous in vitro CAR-mediated transactivation assay. In silico analyses also supported the results of CAR-SRC1 interaction; there is little structural difference in the ligand-binding pocket of bsCAR and mCAR, but there is a distinct discrimination in the helix 11 and 12 of these receptors, suggesting that the interaction of ligand-bound CAR and SRC1 is critical for determining species-specific and ligand-dependent transactivation over the basal activity. The SPR assays demonstrated a potential as a high-throughput screening tool of CAR ligands. PMID- 23015692 TI - Body image dysmorphic disorder in persons who undergo aesthetic medical treatments. AB - This article reviews the literature on body dysmorphic disorder (BDD) in patients who seek aesthetic surgery and other appearance-enhancing medical treatments such as dermatologic treatment. It begins with a discussion of the growing popularity of aesthetic medical treatments. The literature investigating the psychological characteristics of individuals interested in these treatments is highlighted. Studies suggest that 5% to 15% of individuals who seek these aesthetic medical treatments suffer from BDD. Retrospective reports suggest that persons with BDD rarely experience improvement in their symptoms following these treatments, leading some to suggest that BDD is a contraindication to treatment. The article ends with a discussion of the clinical management of patients with BDD who present for an aesthetic change in their appearance. PMID- 23015693 TI - Functional analysis of a crustacean microRNA in host-virus interactions. AB - Growing evidence from mammals suggests that host microRNAs (miRNAs) play important roles in the antiviral immune response. However, the roles of invertebrate miRNAs in response to virus infection remain to be investigated. Based on our previous studies, the shrimp miR-7 was found to be upregulated in response to white spot syndrome virus (WSSV) infection. In this study, the results showed that shrimp miR-7 could target the 3'-untranslated region (3'UTR) of the WSSV early gene wsv477, implying that miR-7 was involved in viral DNA replication. In insect High Five cells, the synthesized miR-7 significantly decreased the expression level of the fluorescent construct bearing the 3'UTR of wsv477 compared with the expression of the control constructs. When the activity of transfected miR-7 was blocked by locked-nucleic-acid (LNA)-modified anti-miR-7 oligonucleotide (AMO-miR-7), the repression of luciferase gene expression by miR 7 was relieved. In vivo, when the synthesized miR-7 was injected into shrimp, the numbers of WSSV genome copies/mg gills were 1,000-fold lower than those of WSSV only at 72 and 96 h postinfection. The results indicated that the blocking of endogenous miR-7 by AMO-miR-7 led to about a 10-fold increase of WSSV genome copies/mg gills in WSSV-infected shrimp compared with the control WSSV only. Further, it was revealed that the host Dicer1 was an important component for the biogenesis of miR-7, which had a large effect on virus infection. Therefore, our study revealed a novel regulatory function for an invertebrate miRNA in host virus interactions by targeting the viral early gene. PMID- 23015694 TI - In vitro assembly of an empty picornavirus capsid follows a dodecahedral path. AB - The Picornaviridae are a large family of small, spherical RNA viruses that includes numerous pathogens. The picornavirus structural proteins VP0, VP1, and VP3 are believed to first form protomers, which then form 14S particles and subsequently assemble to form empty and RNA-filled particles. 14S particles have long been presumed to be pentamers. However, the structure of the 14S particles, their mechanism of assembly, and the role of empty particles during infection are all unknown. We established an in vitro assembly system for bovine enterovirus (BEV) by using purified baculovirus-expressed proteins. By Rayleigh scattering, we determined that 14S particles are 488 kDa, confirming they are pentamers. Image reconstructions based on negative-stain electron microscopy showed that 14S particles have 5-fold symmetry, and their structures correlate extremely well with the corresponding pentamer from crystal structures of mature BEV. Purified 14S particles readily assemble in response to increasing ionic strength or temperature to form 5.8-MDa 12-pentamer particles, indistinguishable from native empty particles. Surprisingly, empty particles were sufficiently stable that, under physiological conditions, dissociation is unlikely to be a biologically relevant reaction. This suggests that empty particles are not a storage form of 14S particles, at least for bovine enterovirus, but are either a dead-end product or direct precursor into which viral RNA is packaged by as-yet-unidentified machinery. PMID- 23015695 TI - Vaccine-elicited CD8+ T cells protect against respiratory syncytial virus strain A2-line19F-induced pathogenesis in BALB/c mice. AB - CD8(+) T cells may contribute to vaccines for respiratory syncytial virus (RSV). Compared to CD8(+) T cells responding to RSV infection, vaccine-elicited anti-RSV CD8(+) T cells are less well defined. We used a peptide vaccine to test the hypothesis that vaccine-elicited RSV-specific CD8(+) T cells are protective against RSV pathogenesis. BALB/c mice were treated with a mixture (previously termed TriVax) of an M2(82-90) peptide representing an immunodominant CD8 epitope, the Toll-like receptor (TLR) agonist poly(I.C), and a costimulatory anti CD40 antibody. TriVax vaccination induced potent effector anti-RSV CD8(+) cytotoxic T lymphocytes (CTL). Mice were challenged with RSV strain A2-line19F, a model of RSV pathogenesis leading to airway mucin expression. Mice were protected against RSV infection and against RSV-induced airway mucin expression and cellular lung inflammation when challenged 6 days after vaccination. Compared to A2-line19F infection alone, TriVax vaccination followed by challenge resulted in effector CD8(+) T cells with greater cytokine expression and the more rapid appearance of RSV-specific CD8(+) T cells in the lung. When challenged 42 days after TriVax vaccination, memory CD8(+) T cells were elicited with RSV-specific tetramer responses equivalent to TriVax-induced effector CD8(+) T cells. These memory CD8(+) T cells had lower cytokine expression than effector CD8(+) T cells, and protection against A2-line19F was partial during the memory phase. We found that vaccine-elicited effector anti-RSV CD8(+) T cells protected mice against RSV infection and pathogenesis, and waning protection correlated with reduced CD8(+) T cell cytokine expression. PMID- 23015696 TI - In vitro and in vivo analysis of the interaction between RNA helicase A and HIV-1 RNA. AB - RNA helicase A (RHA) promotes multiple steps of HIV-1 RNA metabolism during viral replication, including transcription, translation, and the annealing of primer tRNA(3)(Lys) to the viral RNA. RHA is a member of the DExH subclass of RNA helicases that uniquely contains two double-stranded RNA binding domains (dsRBDs) at its N terminus. Here, we performed a genome-wide analysis of the interaction of RHA with HIV-1 RNA both in vitro, using fluorescence polarization, and during viral replication, using an RNA-protein coprecipitation assay. In vitro, RHA binds to all the isolated regions of the HIV-1 RNA genome tested, with K(d) (equilibrium dissociation constant) values ranging from 44 to 178 nM. In contrast, during viral replication, RNA-protein coprecipitation assays detected only a major interaction of RHA with the 5'-untranslated region (5'-UTR) and a minor interaction with the Rev response element (RRE) of HIV-1 RNA. Since RHA does not associate well with all the highly structured regions of HIV-1 RNA tested in vivo, the results suggest that other viral or cellular factors not present in vitro may modulate the direct interaction of RHA with HIV-1 RNA during virus replication. Nevertheless, a role for duplex RNA as a target for RHA binding in vivo is suggested by the fact that the deletion of either one or both dsRBDs eliminates the in vivo interaction of RHA with HIV-1 RNA. Furthermore, these mutant RHAs do not promote the in vivo annealing of tRNA(3)(Lys) to viral RNA, nor are they packaged into virions, demonstrating that the dsRBDs are essential for the role of RHA in HIV-1 replication. PMID- 23015698 TI - Properties of the adeno-associated virus assembly-activating protein. AB - Adeno-associated virus (AAV) capsid assembly requires expression of the assembly activating protein (AAP) together with capsid proteins VP1, VP2, and VP3. AAP is encoded by an alternative open reading frame of the cap gene. Sequence analysis and site-directed mutagenesis revealed that AAP contains two hydrophobic domains in the N-terminal part of the molecule that are essential for its assembly promoting activity. Mutation of these sequences reduced the interaction of AAP with the capsid proteins. Deletions and a point mutation in the capsid protein C terminus also abolished capsid assembly and strongly reduced the interaction with AAP. Interpretation of these observations on a structural basis suggests an interaction of AAP with the VP C terminus, which forms the capsid protein interface at the 2-fold symmetry axis. This interpretation is supported by a decrease in the interaction of monoclonal antibody B1 with VP3 under nondenaturing conditions in the presence of AAP, indicative of steric hindrance of B1 binding to its C-terminal epitope by AAP. In addition, AAP forms high molecular-weight oligomers and changes the conformation of nonassembled VP molecules as detected by conformation-sensitive monoclonal antibodies A20 and C37. Combined, these observations suggest a possible scaffolding activity of AAP in the AAV capsid assembly reaction. PMID- 23015697 TI - Human metapneumovirus M2-2 protein inhibits innate cellular signaling by targeting MAVS. AB - Human metapneumovirus (hMPV) is a leading cause of respiratory infections in pediatric populations globally, with no prophylactic or therapeutic measures. Recently, a recombinant hMPV lacking the M2-2 protein (rhMPV-DeltaM2-2) demonstrated reduced replication in the respiratory tract of animal models, making it a promising live vaccine candidate. However, the exact nature of the interaction between the M2-2 protein and host cells that regulates viral infection/propagation is largely unknown. By taking advantage of the available reverse genetics system and ectopic expression system for viral protein, we found that M2-2 not only promotes viral gene transcription and replication but subverts host innate immunity, therefore identifying M2-2 as a novel virulence factor, in addition to the previously described hMPV G protein. Since we have shown that the RIG-I/MAVS pathway plays an important role in hMPV-induced signaling in airway epithelial cells, we investigated whether M2-2 antagonizes the host cellular responses by targeting this pathway. Reporter gene assays and coimmunoprecipitation studies indicated that M2-2 targets MAVS, an inhibitory mechanism different from what we previously reported for hMPV G, which affects RIG-I- but not MAVS-dependent gene transcription. In addition, we found that the domains of M2-2 responsible for the regulation of viral gene transcription and antiviral signaling are different. Our findings collectively demonstrate that M2 2 contributes to hMPV immune evasion through the inhibition of MAVS-dependent cellular responses. PMID- 23015699 TI - Genome-wide analyses of Zta binding to the Epstein-Barr virus genome reveals interactions in both early and late lytic cycles and an epigenetic switch leading to an altered binding profile. AB - The Epstein-Barr virus (EBV) genome sustains substantial epigenetic modification involving chromatin remodelling and DNA methylation during lytic replication. Zta (ZEBRA, BZLF1), a key regulator of the EBV lytic cycle, is a transcription and replication factor, binding to Zta response elements (ZREs) in target promoters and EBV lytic origins of replication. In vitro, Zta binding is modulated by DNA methylation; a subset of CpG-containing Zta binding sites (CpG ZREs) is bound only in a DNA methylation-dependent manner. The question of how the dynamic epigenetic environment impacts Zta interaction during the EBV lytic cycle is unknown. To address this, we used chromatin immunoprecipitation coupled with next generation sequencing (ChIP-Seq) to identify Zta binding sites across the EBV genome before and after viral DNA replication. Replication did not alter the association of Zta across many regions of the EBV genome, but a striking reduction in Zta binding occurred at some loci that contain CpG ZREs. Separating Zta-bound DNA into methylated and nonmethylated fractions, we found that promoters that contain CpG ZREs were enriched in the methylated fraction but that Zta binding to promoters lacking CpG ZREs was not reduced. We hypothesize that the loss of DNA methylation on the EBV genome during the lytic cycle causes the reduced binding to CpG ZREs; this may act as a lytic cycle epigenetic switch. However, the epigenetic changes associated with the replicated EBV genome do not affect the interaction of Zta with many loci that are rich in non-CpG ZREs; this leads to sustained binding at these regions. PMID- 23015700 TI - Cytosolic phospholipase A2 gamma is involved in hepatitis C virus replication and assembly. AB - Similar to other positive-sense, single-stranded RNA viruses, hepatitis C virus (HCV) replicates its genome in a remodeled intracellular membranous structure known as the membranous web (MW). To date, the process of MW formation remains unclear. It is generally acknowledged that HCV nonstructural protein 4B (NS4B) can induce MW formation through interaction with the cytosolic endoplasmic reticulum (ER) membrane. Many host proteins, such as phosphatidylinositol 4 kinase IIIalpha (PI4KIIIalpha), have been identified as critical factors required for this process. We now report a new factor, the cytosolic phospholipase A2 gamma (PLA2G4C), which contributes to MW formation, HCV replication, and assembly. The PLA2G4C gene was identified as a host gene with upregulated expression upon HCV infection. Knockdown of PLA2G4C in HCV-infected cells or HCV replicon-containing cells by small interfering RNA (siRNA) significantly suppressed HCV replication and assembly. In addition, the chemical inhibitor methyl arachidonyl fluorophosphonate (MAFP), which specifically inhibits PLA2, reduced HCV replication and assembly. Electron microscopy demonstrated that MW structure formation was defective after PLA2G4C knockdown in HCV replicon containing cells. Further analysis by immunostaining and immunoprecipitation assays indicated that PLA2G4C colocalized with the HCV proteins NS4B and NS5A in cells infected with JFH-1 and interacted with NS4B. In addition, PLA2G4C was able to transport the HCV nonstructural proteins from replication sites to lipid droplets, the site for HCV assembly. These data suggest that PLA2G4C plays an important role in the HCV life cycle and might represent a potential target for anti-HCV therapy. PMID- 23015701 TI - Amplification of JNK signaling is necessary to complete the murine gammaherpesvirus 68 lytic replication cycle. AB - Several studies have previously defined host-derived signaling events capable of driving lytic gammaherpesvirus replication or enhancing immediate-early viral gene expression. Yet signaling pathways that regulate later stages of the productive gammaherpesvirus replication cycle are still poorly defined. In this study, we utilized a mass spectrometric approach to identify c-Jun as an abundant cellular phosphoprotein present in late stages of lytic murine gammaherpesvirus 68 (MHV68) infection. Kinetically, c-Jun phosphorylation was enhanced as infection progressed, and this correlated with enhanced phosphorylation of the c Jun amino-terminal kinases JNK1 and JNK2 and activation of AP-1 transcription. These events were dependent on progression beyond viral immediate-early gene expression, but not dependent on viral DNA replication. Both pharmacologic and dominant-negative blockade of JNK1/2 activity inhibited viral replication, and this correlated with inhibition of viral DNA synthesis and reduced viral gene expression. These data suggest a model in which MHV68 by necessity amplifies and usurps JNK/c-Jun signaling as infection progresses in order to facilitate late stages of the MHV68 lytic infection cycle. PMID- 23015702 TI - Longitudinal analysis of the human antibody response to Chikungunya virus infection: implications for serodiagnosis and vaccine development. AB - Chikungunya virus (CHIKV) is an alphavirus which causes chronic and incapacitating arthralgia in humans. Although previous studies have shown that antibodies against the virus are produced during and after infection, the fine specificity of the antibody response against CHIKV is not known. Here, using plasma from patients at different times postinfection, we characterized the antibody response against various proteins of the virus. We have shown that the E2 and E3 glycoproteins and the capsid and nsP3 proteins are targets of the anti CHIKV antibody response. Moreover, we have identified the different regions in these proteins which contain the linear epitopes recognized by the anti-CHIKV antibodies and determined their structural localization. Data also illustrated the effect of a single K(252)Q amino acid change at the E2 glycoprotein that was able to influence antibody binding and interaction between the antibodies and epitope because of the changes of epitope-antibody binding capacity. This study provides important knowledge that will not only aid in the understanding of the immune response to CHIKV infection but also provide new knowledge in the design of modern vaccine development. Furthermore, these pathogen-specific epitopes could be used for future seroepidemiological studies that will unravel the molecular mechanisms of human immunity and protection from CHIKV disease. PMID- 23015703 TI - Intrinsic temperature sensitivity of influenza C virus hemagglutinin-esterase fusion protein. AB - Influenza C virus replicates more efficiently at 33 degrees C than at 37 degrees C. To determine whether hemagglutinin-esterase-fusion protein (HEF), a surface glycoprotein of influenza C virus, is a restricting factor for this temperature sensitivity, we analyzed the biological and biochemical properties of HEF at 33 degrees C and 37 degrees C. We found that HEF exhibits intrinsic temperature sensitivities for surface expression and fusion activity. PMID- 23015704 TI - Mouse mammary tumor virus suppresses apoptosis of mammary epithelial cells through ITAM-mediated signaling. AB - Many receptors in hematopoietic cells use a common signaling pathway that relies on a highly conserved immunoreceptor tyrosine-based activation motif (ITAM), which signals through Src family tyrosine kinases. ITAM-bearing proteins are also found in many oncogenic viruses, including the mouse mammary tumor virus (MMTV) envelope (Env). We previously showed that MMTV Env expression transformed normal mammary epithelial cells and that Src kinases were important mediators in this transformation. To study how ITAM signaling affects mammary cell transformation, we utilized mammary cell lines expressing two different ITAM-containing proteins, one encoding a MMTV provirus and the other a B cell receptor fusion protein. ITAM expressing cells were resistant to both serum starvation- and chemotherapeutic drug-induced apoptosis, whereas cells transduced with these molecules bearing ITAM mutations were indistinguishable from untransduced cells in their sensitivity to these treatments. We also found that Src kinase was activated in the MMTV-expressing cells and that MMTV-induced apoptosis resistance was completely restored by the Src inhibitor PP2. In vivo, MMTV infection delayed involution-induced apoptosis in the mouse mammary gland. Our results show that MMTV suppresses apoptosis through ITAM-mediated Src tyrosine kinase signaling. These studies could lead to the development of effective treatment of nonhematopoietic cell cancers in which ITAM-mediated signaling plays a role. PMID- 23015705 TI - Activating KIR copy number variation is associated with granzyme B release by NK cells during primary simian immunodeficiency virus infection in rhesus monkeys. AB - Here we show that the number of activating killer cell immunoglobulin-like receptor (KIR) copies in rhesus monkeys is associated with the extent of release of cytotoxic granules by cytolytic NK cells during primary simian immunodeficiency virus SIVmac251 infection. These findings suggest that NK cells expressing high levels of activating KIRs efficiently kill SIVmac251-infected cells, and this efficient killing contributes to the NK cell-mediated control of replication of this virus during early infection. PMID- 23015706 TI - Comprehensive analysis of host cellular interactions with human papillomavirus E6 proteins identifies new E6 binding partners and reflects viral diversity. AB - We have begun to define the human papillomavirus (HPV)-associated proteome for a subset of the more than 120 HPV types that have been identified to date. Our approach uses a mass spectrometry-based platform for the systematic identification of interactions between human papillomavirus and host cellular proteins, and here we report a proteomic analysis of the E6 proteins from 16 different HPV types. The viruses included represent high-risk, low-risk, and non cancer-associated types from genus alpha as well as viruses from four different species in genus beta. The E6 interaction data set consists of 153 cellular proteins, including several previously reported HPV E6 interactors such as p53, E6AP, MAML1, and p300/CBP and proteins containing PDZ domains. We report the genus-specific binding of E6s to either E6AP or MAML1, define the specific HPV E6s that bind to p300, and demonstrate several new features of interactions involving beta HPV E6s. In particular, we report that several beta HPV E6s bind to proteins containing PDZ domains and that at least two beta HPV E6s bind to p53. Finally, we report the newly discovered interaction of proteins of E6 of beta genus, species 2, with the Ccr4-Not complex, the first report of a viral protein binding to this complex. This data set represents a comprehensive survey of E6 binding partners that provides a resource for the HPV field and will allow continued studies on the diverse biology of the human papillomaviruses. PMID- 23015707 TI - Conserved region 3 of human papillomavirus 16 E7 contributes to deregulation of the retinoblastoma tumor suppressor. AB - The human papillomavirus (HPV) E7 oncoprotein binds cellular factors, preventing or retargeting their function and thereby making the infected cell conducive for viral replication. A key target of E7 is the product of the retinoblastoma susceptibility locus (pRb). This interaction results in the release of E2F transcription factors and drives the host cell into the S phase of the cell cycle. E7 binds pRb via a high-affinity binding site in conserved region 2 (CR2) and also targets a portion of cellular pRb for degradation via the proteasome. Evidence suggests that a secondary binding site exists in CR3, and that this interaction influences pRb deregulation. Additionally, evidence suggests that CR3 also participates in the degradation of pRb. We have systematically analyzed the molecular mechanisms by which CR3 contributes to deregulation of the pRb pathway by utilizing a comprehensive series of mutations in residues predicted to be exposed on the surface of HPV16 E7 CR3. Despite differences in the ability to interact with cullin 2, all CR3 mutants degrade pRb comparably to wild-type E7. We identified two specific patches of residues on the surface of CR3 that contribute to pRb binding independently of the high-affinity CR2 binding site. Mutants within CR3 that affect pRb binding are less effective than the wild-type E7 in overcoming pRb-induced cell cycle arrest. This demonstrates that the interaction between HPV16 E7 CR3 and pRb is functionally important for alteration of the cell cycle. PMID- 23015708 TI - Differential activation of cellular DNA damage responses by replication-defective and replication-competent adenovirus mutants. AB - Adenovirus (Ad) mutants that lack early region 4 (E4) activate the phosphorylation of cellular DNA damage response proteins. In wild-type Ad type 5 (Ad5) infections, E1b and E4 proteins target the cellular DNA repair protein Mre11 for redistribution and degradation, thereby interfering with its ability to activate phosphorylation cascades important during DNA repair. The characteristics of Ad infection that activate cellular DNA repair processes are not yet well understood. We investigated the activation of DNA damage responses by a replication-defective Ad vector (AdRSVbetagal) that lacks E1 and fails to produce the immediate-early E1a protein. E1a is important for activating early gene expression from the other viral early transcription units, including E4. AdRSVbetagal can deliver its genome to the cell, but it is subsequently deficient for viral early gene expression and DNA replication. We studied the ability of AdRSVbetagal-infected cells to induce cellular DNA damage responses. AdRSVbetagal infection does activate formation of foci containing the Mdc1 protein. However, AdRSVbetagal fails to activate phosphorylation of the damage response proteins Nbs1 and Chk1. We found that viral DNA replication is important for Nbs1 phosphorylation, suggesting that this step in the viral life cycle may provide an important trigger for activating at least some DNA repair proteins. PMID- 23015709 TI - Implication of Bemisia tabaci heat shock protein 70 in Begomovirus-whitefly interactions. AB - The whitefly Bemisia tabaci (Gennadius) is a major cosmopolitan pest capable of feeding on hundreds of plant species and transmits several major plant viruses. The most important and widespread viruses vectored by B. tabaci are in the genus Begomovirus, an unusual group of plant viruses owing to their small, single stranded DNA genome and geminate particle morphology. B. tabaci transmits begomoviruses in a persistent circulative nonpropagative manner. Evidence suggests that the whitefly vector encounters deleterious effects following Tomato yellow leaf curl virus (TYLCV) ingestion and retention. However, little is known about the molecular and cellular basis underlying these coevolved begomovirus whitefly interactions. To elucidate these interactions, we undertook a study using B. tabaci microarrays to specifically describe the responses of the transcriptomes of whole insects and dissected midguts following TYLCV acquisition and retention. Microarray, real-time PCR, and Western blot analyses indicated that B. tabaci heat shock protein 70 (HSP70) specifically responded to the presence of the monopartite TYLCV and the bipartite Squash leaf curl virus. Immunocapture PCR, protein coimmunoprecipitation, and virus overlay protein binding assays showed in vitro interaction between TYLCV and HSP70. Fluorescence in situ hybridization and immunolocalization showed colocalization of TYLCV and the bipartite Watermelon chlorotic stunt virus virions and HSP70 within midgut epithelial cells. Finally, membrane feeding of whiteflies with anti-HSP70 antibodies and TYLCV virions showed an increase in TYLCV transmission, suggesting an inhibitory role for HSP70 in virus transmission, a role that might be related to protection against begomoviruses while translocating in the whitefly. PMID- 23015710 TI - Induction of alternatively activated macrophages enhances pathogenesis during severe acute respiratory syndrome coronavirus infection. AB - Infection with severe acute respiratory syndrome coronavirus (SARS-CoV) causes acute lung injury (ALI) that often leads to severe lung disease. A mouse model of acute SARS-CoV infection has been helpful in understanding the host response to infection; however, there are still unanswered questions concerning SARS-CoV pathogenesis. We have shown that STAT1 plays an important role in the severity of SARS-CoV pathogenesis and that it is independent of the role of STAT1 in interferon signaling. Mice lacking STAT1 have greater weight loss, severe lung pathology with pre-pulmonary-fibrosis-like lesions, and an altered immune response following infection with SARS-CoV. We hypothesized that STAT1 plays a role in the polarization of the immune response, specifically in macrophages, resulting in a worsened outcome. To test this, we created bone marrow chimeras and cell-type-specific knockouts of STAT1 to identify which cell type(s) is critical to protection from severe lung disease after SARS-CoV infection. Bone marrow chimera experiments demonstrated that hematopoietic cells are responsible for the pathogenesis in STAT1(-/-) mice, and because of an induction of alternatively activated (AA) macrophages after infection, we hypothesized that the AA macrophages were critical for disease severity. Mice with STAT1 in either monocytes and macrophages (LysM/STAT1) or ciliated lung epithelial cells (FoxJ1/STAT1) deleted were created. Following infection, LysM/STAT1 mice display severe lung pathology, while FoxJ1/STAT1 mice display normal lung pathology. We hypothesized that AA macrophages were responsible for this STAT1-dependent pathology and therefore created STAT1/STAT6(-/-) double-knockout mice. STAT6 is essential for the development of AA macrophages. Infection of the double-knockout mice displayed a lack of lung disease and prefibrotic lesions, suggesting that AA macrophage production may be the cause of STAT1-dependent lung disease. We propose that the control of AA macrophages by STAT1 is critical to regulating immune pathologies and for protection from long-term progression to fibrotic lung disease in a mouse model of SARS-CoV infection. PMID- 23015711 TI - Cell-specific regulation of nucleic acid sensor cascades: a controlling interest in the antiviral response. AB - In this study, we examined the capacities of non-antigen-presenting cell types to propagate antiviral signals following infection with recombinant adenovirus or by direct nucleic acid transfection. Three murine cell lines (RAW264.7 macrophages as a positive control, FL83B hepatocytes, and MS1 endothelial cells) were assessed following exposure to adenovirus, DNA, or RNA ligands. Based on primary (interferon response factor 3 [IRF3] phosphorylation) and secondary (STAT1/2 phosphorylation) response markers, we found each cell line presented a unique response profile: RAW cells were highly responsive, MS1 cells were modified in their response, and FL83B cells were essentially nonresponsive. Comparative reverse transcription-quantitative PCR (RT-qPCR) of nucleic acid sensing components revealed major differences between the three cell types. A prominent difference was at the level of adaptor molecules; TRIF, MyD88, MAVS, and STING. TRIF was absent in MS1 and FL83B cells, whereas MyD88 levels were diminished in FL83B hepatocytes. These differences resulted in compromised TLR-mediated activation. While the cytosolic adaptor MAVS was well represented in all cell lines, the DNA adaptor STING was deficient in FL83B hepatocytes (down by nearly 3 log units). The absence of STING provides an explanation for the lack of DNA responsiveness in these cells. This hypothesis was confirmed by acquisition of IRF3 activation in Flag-STING FL83B cells following DNA transfection. To consolidate the central role of adaptors in MS1 endothelial cells, short hairpin RNA (shRNA) knockdown of STING and MAVS resulted in a ligand-specific loss of IRF3 responsiveness. In contrast to the requirement for specific adaptor proteins, a requirement for a specific DNA sensor (AIM2, DDx41, or p204) in the IRF3 activation response was not detected by shRNA knockdown in MS1 cells. The data reveal that cell-specific regulation of nucleic acid sensing cascade components influences antiviral recognition responses, that controlling levels of adaptor molecules is a recurring strategy in regulating antiviral recognition response functions, and that comparative RT-qPCR has predictive value for antiviral/innate response functions in these cells. PMID- 23015712 TI - Two closely related novel picornaviruses in cattle and sheep in Hungary from 2008 to 2009, proposed as members of a new genus in the family Picornaviridae. AB - Two novel picornaviruses were serendipitously identified in apparently healthy young domestic animals-cattle (Bos taurus) and, subsequently, sheep (Ovis aries) in Hungary during 2008 and 2009. Complete genome sequencing and comparative analysis showed that the two viruses are related to each other and have identical genome organizations, VPg + 5' UTR(IRES-II)[L/1A-1B-1C-1D-2A(NPG?P)/2B-2C/3A 3B(VPg)-3C(pro)-3D(pol)] 3' UTR-poly(A). We suggest that they form two novel viral genotypes/serotypes, bovine hungarovirus 1 (BHuV-1; GenBank accession number JQ941880) and ovine hungarovirus 1 (OHuV-1; GenBank accession number HM153767), which may belong to a potential novel picornavirus genus in the family Picornaviridae. The genome lengths of BHuV-1 and OHuV-1 are 7,583 and 7,588 nucleotides, each comprising a single open reading frame encoding 2,243 and 2,252 amino acids, respectively. In the 5' untranslated regions (5' UTRs), both hungaroviruses are predicted to have a type II internal ribosome entry site (IRES). The nucleotide sequence and the secondary RNA structure of the hungarovirus IRES core domains H-I-J-K-L are highly similar to that of human parechovirus (HPeV) (genus Parechovirus), especially HPeV-3. However, in the polyprotein coding region, the amino acid sequences are more closely related to those of porcine teschoviruses (genus Teschovirus). Hungaroviruses were detected in 15% (4/26) and 25% (4/16) of the fecal samples from cattle and sheep, respectively. This report describes the discovery of two novel picornaviruses in farm animals, cattle and sheep. The mosaic genetic pattern raises the possibility that hungaroviruses, human parechoviruses, and porcine teschoviruses may be linked to each other by modular recombination of functional noncoding RNA elements. PMID- 23015713 TI - Genomic and phylogenetic characterization of Brazilian yellow fever virus strains. AB - Globally, yellow fever virus infects nearly 200,000 people, leading to 30,000 deaths annually. Although the virus is endemic to Latin America, only a single genome from this region has been sequenced. Here, we report 12 Brazilian yellow fever virus complete genomes, their genetic traits, phylogenetic characterization, and phylogeographic dynamics. Variable 3' noncoding region (3'NCR) patterns and specific mutations throughout the open reading frame altered predicted secondary structures. Our findings suggest that whereas the introduction of yellow fever virus in Brazil led to genotype I-predominant dispersal throughout South and Central Americas, genotype II remained confined to Bolivia, Peru, and the western Brazilian Amazon. PMID- 23015714 TI - Genetic characterization of simian foamy viruses infecting humans. AB - Simian foamy viruses (SFVs) are retroviruses that are widespread among nonhuman primates (NHPs). SFVs actively replicate in their oral cavity and can be transmitted to humans after NHP bites, giving rise to a persistent infection even decades after primary infection. Very few data on the genetic structure of such SFVs found in humans are available. In the framework of ongoing studies searching for SFV-infected humans in south Cameroon rainforest villages, we studied 38 SFV infected hunters whose times of infection had presumably been determined. By long term cocultures of peripheral blood mononuclear cells with BHK-21 cells, we isolated five new SFV strains and obtained complete genomes of SFV strains from chimpanzee (Pan troglodytes troglodytes; strains BAD327 and AG15), monkey (Cercopithecus nictitans; strain AG16), and gorilla (Gorilla gorilla; strains BAK74 and BAD468). These zoonotic strains share a very high degree of similarity with their NHP counterparts and have a high degree of conservation of the genetic elements important for viral replication. Interestingly, analysis of FV DNA sequences obtained before cultivation revealed variants with deletions in both the U3 region and tas that may correlate with in vivo chronicity in humans. Genomic changes in bet (a premature stop codon) and gag were also observed. To determine if such changes were specific to zoonotic strains, we studied local SFV infected chimpanzees and found the same genomic changes. Our study reveals that natural polymorphism of SFV strains does exist at both the intersubspecies level (gag, bet) and the intrasubspecies (U3, tas) levels but does not seem to reflect a viral adaptation specific to zoonotic SFV strains. PMID- 23015715 TI - Role of human immunodeficiency virus type 1 envelope structure in the induction of broadly neutralizing antibodies. AB - Very soon after the discovery of neutralizing antibodies (NAbs) toward human immunodeficiency virus type 1 (HIV-1) infection, it became apparent that characterization of these NAbs would be an important step in finding a cure for or a vaccine to eradicate HIV-1. Since the initial description of broadly cross clade NAbs naturally produced in HIV-1 patients, numerous studies have described new viral targets for these antibodies. More recently, studies concerning new groups of patients able to control their viremia, such as long-term nonprogressors (LTNPs) or elite controllers, have described the generation of numerous envelope-targeted NAbs. Recent studies have marked a new stage in research on NAbs with the description of antibodies obtained from a worldwide screening of HIV-positive patients. These studies have permitted the discovery of NAb families with great potential for both neutralization and neutralization breadth, such as PG, PGT, CH, and highly active agonistic anti-CD4 binding site antibodies (HAADs), of which VRC01 and its variants are members. These antibodies are able to neutralize more than 80% of circulating strains without any autoreactivity and can be rapidly integrated into clinical trials in order to test their protective potential. In this review, we will focus on new insights into HIV-1 envelope structure and their implications for the generation of potent NAbs. PMID- 23015716 TI - Cross-allele cytotoxic T lymphocyte responses against 2009 pandemic H1N1 influenza A virus among HLA-A24 and HLA-A3 supertype-positive individuals. AB - Lack of a universal vaccine against all serotypes of influenza A viruses and recent progress on T cell-related vaccines against influenza A virus illuminate the important role of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes (CTLs) in anti-influenza virus immunity. However, the diverse HLA alleles among humans complicate virus-specific cellular immunity research, and elucidation of cross-HLA allele T cell responses to influenza virus specificity requires further detailed work. An ideal CTL epitope-based vaccine would cover a broad spectrum of epitope antigens presented by most, if not all, of the HLAs. Here, we evaluated the 2009 pandemic influenza A (H1N1) virus-specific T cell responses among the HLA-A24(+) population using a rationally designed peptide pool during the 2009 pandemic. Unexpectedly, cross-HLA allele T cell responses against the influenza A virus peptides were detected among both HLA-A11(+) and HLA-A24(+) donors. Furthermore, we found cross-responses in the entire HLA-A3 supertype population (including HLA-A11, -A31, -A33, and -A30). The cross-allele antigenic peptides within the peptide pool were identified and characterized, and the crystal structures of the major histocompatibility complex (MHC)-peptide complexes were determined. The subsequent HLA-A24-defined cross-allele peptides recognized by the HLA-A11(+) population were shown to mildly bind to the HLA A*1101 molecule. Together with the structural models, these results partially explain the cross-allele responses. Our findings elucidate the promiscuity of the cross-allele T cell responses against influenza A viruses and are beneficial for the development of a T cell epitope-based vaccine applied in a broader population. PMID- 23015718 TI - Influenza virus neuraminidases with reduced enzymatic activity that avidly bind sialic Acid receptors. AB - Influenza virus neuraminidase (NA) cleaves off sialic acid from cellular receptors of hemagglutinin (HA) to enable progeny escape from infected cells. However, NA variants (D151G) of recent human H3N2 viruses have also been reported to bind receptors on red blood cells, but the nature of these receptors and the effect of the mutation on NA activity were not established. Here, we compare the functional and structural properties of a human H3N2 NA from A/Tanzania/205/2010 and its D151G mutant, which supports HA-independent receptor binding. While the wild-type NA efficiently cleaves sialic acid from both alpha2-6- and alpha2-3 linked glycans, the mutant exhibits much reduced enzymatic activity toward both types of sialosides. Conversely, while wild-type NA shows no detectable binding to sialosides, the D151G NA exhibits avid binding with broad specificity toward alpha2-3 sialosides. D151G NA binds the 3' sialyllactosamine (3'-SLN) and 6'-SLN sialosides with equilibrium dissociation constant (K(D)) values of 30.0 MUM and 645 MUM, respectively, which correspond to much higher affinities than the corresponding affinities (low mM) of HA to these glycans. Crystal structures of wild-type and mutant NAs reveal the structural basis for glycan binding in the active site by exclusively impairing the glycosidic bond hydrolysis step. The general significance of D151 among influenza virus NAs was further explored by introducing the D151G mutation into three N1 NAs and one N2 NA, which all exhibited reduced enzymatic activity and preferential binding to alpha2-3 sialosides. Since the enzymatic and binding activities of NAs are not routinely assessed, the potential for NA receptor binding to contribute to influenza virus biology may be underappreciated. PMID- 23015717 TI - The cellular ataxia telangiectasia-mutated kinase promotes epstein-barr virus lytic reactivation in response to multiple different types of lytic reactivation inducing stimuli. AB - The Epstein-Barr virus (EBV) latent-to-lytic switch is mediated by the viral proteins BZLF1 (Z), BRLF1 (R), and BRRF1 (Na). Since we previously showed that DNA-damaging agents (including chemotherapy and irradiation) can induce EBV lytic reactivation and recently demonstrated that wild-type p53 contributes to lytic reactivation, we investigated the role of the ATM kinase during EBV reactivation. ATM phosphorylates and activates p53, as well as numerous other substrates involved in the cellular DNA damage response. Using an ATM inhibitor (KU55933), we found that ATM activity is required for efficient induction of EBV lytic gene expression by a variety of different stimuli, including a histone deacetylase (HDAC) inhibitor, the transforming growth factor beta (TGF-beta) cytokine, a demethylating agent (5-azacytidine), B cell receptor engagement with anti-IgG antibody, hydrogen peroxide, and the proteosome inhibitor bortezomib. In EBV infected AGS (gastric) cells, knockdown of ATM, or p53, expression inhibits EBV reactivation. Conversely, treatment of these cells with nutlin-3 (which activates p53 and ATM) robustly induces lytic reactivation in a p53- and ATM-dependent manner. The ability of the EBV R and Na proteins to induce lytic reactivation in EBV-infected AGS cells is ATM dependent. However, overexpression of Z induces lytic gene expression in the presence or absence of ATM activity. Our results suggest that ATM enhances Z promoter activity in the context of the intact EBV genome and that p53 contributes to the ATM effect. Nevertheless, since we found that ATM inhibitors also reduce lytic reactivation in Burkitt lymphoma cells that have no p53, additional ATM substrates must also contribute to the ATM effect. PMID- 23015719 TI - Pseudotyped influenza A virus as a vaccine for the induction of heterotypic immunity. AB - There is a need for vaccines that can protect broadly across all influenza A strains. We have produced a pseudotyped influenza virus based on suppression of the A/PR/8/34 hemagglutinin signal sequence (S-FLU) that can infect cells and express the viral core proteins and neuraminidase but cannot replicate. We show that when given by inhalation to mice, S-FLU is nonpathogenic but generates a vigorous T cell response in the lung associated with markedly reduced viral titers and weight loss after challenge with H1 and H3 influenza viruses. These properties of S-FLU suggest that it may have potential as a broadly protective A virus vaccine, particularly in the setting of a threatened pandemic before matched subunit vaccines become available. PMID- 23015720 TI - Japanese encephalitis virus enters rat neuroblastoma cells via a pH-dependent, dynamin and caveola-mediated endocytosis pathway. AB - Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus and one of the most common agents of viral encephalitis. The infectious entry process of JEV into host cells remains largely unknown. Here, we present a systemic study concerning the cellular entry mechanism of JEV to B104 rat neuroblastoma cells. It was observed that JEV internalization was inhibited by chloroquine and ammonium chloride, both of which can elevate the pH of acidic organelles. However, JEV entry was not affected by chlorpromazine, overexpression of a dominant-negative form of EPS 15 protein, or silencing of the clathrin heavy chain by small interfering RNA (siRNA). These results suggested that JEV entry depended on the acidic intracellular pH but was independent of clathrin. We found that endocytosis of JEV was dependent on membrane cholesterol and was inhibited by inactivation of caveolin-1 with siRNA or dominant-negative mutants. It was also shown, by using the inhibitor dynasore, the K44A mutant, and specific siRNA, that dynamin was required for JEV entry. Phagocytosis or macropinocytosis did not play a role in JEV internalization. In addition, we showed that JEV entry into the neuroblastoma cells is not virus strain specific by assessing the effect of the pharmacological inhibitors on the internalization of JEV belonging to different genotypes. Taken together, our results demonstrate that JEV enters B104 cells through a dynamin-dependent caveola-mediated uptake with a pH-dependent step, which is distinct from the clathrin-mediated endocytosis used by most flaviviruses. PMID- 23015722 TI - Design of Escherichia coli-expressed stalk domain immunogens of H1N1 hemagglutinin that protect mice from lethal challenge. AB - The hemagglutinin protein (HA) on the surface of influenza virus is essential for viral entry into the host cells. The HA1 subunit of HA is also the primary target for neutralizing antibodies. The HA2 subunit is less exposed on the virion surface and more conserved than HA1. We have previously designed an HA2-based immunogen derived from the sequence of the H3N2 A/HK/68 virus. In the present study, we report the design of an HA2-based immunogen from the H1N1 subtype (PR/8/34). This immunogen (H1HA0HA6) and its circular permutant (H1HA6) were well folded and provided complete protection against homologous viral challenge. Antisera of immunized mice showed cross-reactivity with HA proteins of different strains and subtypes. Although no neutralization was observable in a conventional neutralization assay, sera of immunized guinea pigs competed with a broadly neutralizing antibody, CR6261, for binding to recombinant Viet/04 HA protein, suggesting that CR6261-like antibodies were elicited by the immunogens. Stem domain immunogens from a seasonal H1N1 strain (A/NC/20/99) and a recent pandemic strain (A/Cal/07/09) provided cross-protection against A/PR/8/34 viral challenge. HA2-containing stem domain immunogens therefore have the potential to provide subtype-specific protection. PMID- 23015721 TI - Intersubtype differences in the effect of a rare p24 gag mutation on HIV-1 replicative fitness. AB - Certain immune-driven mutations in HIV-1, such as those arising in p24(Gag), decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24(Gag) M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (P = 0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (P < 0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24(Gag) codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness. PMID- 23015723 TI - Loss of the protease dimerization inhibition activity of tipranavir (TPV) and its association with the acquisition of resistance to TPV by HIV-1. AB - Tipranavir (TPV), a protease inhibitor (PI) inhibiting the enzymatic activity and dimerization of HIV-1 protease, exerts potent activity against multi-PI-resistant HIV-1 isolates. When a mixture of 11 multi-PI-resistant (but TPV-sensitive) clinical isolates (HIV(11MIX)), which included HIV(B) and HIV(C), was selected against TPV, HIV(11MIX) rapidly (by 10 passages [HIV(11MIX)(P10)]) acquired high level TPV resistance and replicated at high concentrations of TPV. HIV(11MIX)(P10) contained various amino acid substitutions, including I54V and V82T. The intermolecular FRET-based HIV-1 expression assay revealed that TPV's dimerization inhibition activity against cloned HIV(B) (cHIV(B)) was substantially compromised. The introduction of I54V/V82T into wild-type cHIV(NL4 3) (cHIV(NL4-3(I54V/V82T))) did not block TPV's dimerization inhibition or confer TPV resistance. However, the introduction of I54V/V82T into cHIV(B) (cHIV(B)(I54V/V82T)) compromised TPV's dimerization inhibition and cHIV(B)(I54V/V82T) proved to be significantly TPV resistant. L24M was responsible for TPV resistance with the cHIV(C) genetic background. The introduction of L24M into cHIV(NL4-3) (cHIV(NL4-3(L24M))) interfered with TPV's dimerization inhibition, while L24M increased HIV-1's susceptibility to TPV with the HIV(NL4 3) genetic background. When selected with TPV, cHIV(NL4-3(I54V/V82T)) most readily developed TPV resistance and acquired E34D, which compromised TPV's dimerization inhibition with the HIV(NL4-3) genetic background. The present data demonstrate that certain amino acid substitutions compromise TPV's dimerization inhibition and confer TPV resistance, although the loss of TPV's dimerization inhibition is not always associated with significantly increased TPV resistance. The findings that TPV's dimerization inhibition is compromised with one or two amino acid substitutions may explain at least in part why the genetic barrier of TPV against HIV-1's development of TPV resistance is relatively low compared to that of darunavir. PMID- 23015724 TI - Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly. AB - Mx1 is a GTPase that is part of the antiviral response induced by type I and type III interferons in the infected host. It inhibits influenza virus infection by blocking viral transcription and replication, but the molecular mechanism is not known. Polymerase basic protein 2 (PB2) and nucleoprotein (NP) were suggested to be the possible target of Mx1, but a direct interaction between Mx1 and any of the viral proteins has not been reported. We investigated the interplay between Mx1, NP, and PB2 to identify the mechanism of Mx1's antiviral activity. We found that Mx1 inhibits the PB2-NP interaction, and the strength of this inhibition correlated with a decrease in viral polymerase activity. Inhibition of the PB2-NP interaction is an active process requiring enzymatically active Mx1. We also demonstrate that Mx1 interacts with the viral proteins NP and PB2, which indicates that Mx1 protein has a direct effect on the viral ribonucleoprotein complex. In a minireplicon system, avian-like NP from swine virus isolates was more sensitive to inhibition by murine Mx1 than NP from human influenza A virus isolates. Likewise, murine Mx1 displaced avian NP from the viral ribonucleoprotein complex more easily than human NP. The stronger resistance of the A/H1N1 pandemic 2009 virus against Mx1 also correlated with reduced inhibition of the PB2-NP interaction. Our findings support a model in which Mx1 interacts with the influenza ribonucleoprotein complex and interferes with its assembly by disturbing the PB2-NP interaction. PMID- 23015725 TI - Heparan sulfate facilitates Rift Valley fever virus entry into the cell. AB - Rift Valley fever virus (RVFV), an emerging arthropod-borne pathogen, has a broad host and cell tropism. Here we report that the glycosaminoglycan heparan sulfate, abundantly present on the surface of most animal cells, is required for efficient entry of RVFV. Entry was significantly reduced by preincubating the virus inoculum with highly sulfated heparin, by enzymatic removal of heparan sulfate from cells and in cells genetically deficient in heparan sulfate synthesis. PMID- 23015726 TI - Evaluation of methods for measuring coverage and representativeness of an early warning disease surveillance system. AB - Early-warning surveillance provides an essential component of the evidence required to protect animal health. Assessing the proportion of the population included in surveillance systems (coverage) provides a measure of the effectiveness of early-warning surveillance, and contributes to ensuring that these systems are efficient. This paper describes an investigation of methods used for assessing the coverage and representativeness of the 'FarmFile' early warning surveillance system. This system uses information collected with samples submitted to diagnostic laboratories by private veterinary practitioners in England and Wales. Available data on pig holdings and veterinary practices in four English counties, selected to represent a range of diverse population characteristics, were supplemented using surveys of veterinary practices. Coverage assessments were based on submissions made to FarmFile in 2009. The proportion of holdings covered varied from 5-62 per cent in Devon and Cumbria, and 16-97 per cent in Norfolk and East Riding of Yorkshire. The results suggest that while the proportion of individual pigs covered by the current early-warning surveillance system is high, small and breeding-only holdings in some regions may be poorly covered. Coverage assessments vary depending on the methods used for their assessment, and multiple assessment methods can provide a 'range' within which coverage lies. PMID- 23015727 TI - Care and Justice orientations to moral decision making in veterinary students. AB - An adapted version of the Moral Justification Scale was used to assess moral decision-making orientation in veterinary students, comparing sex and year of study. The Scale consists of vignettes and related statements, each of which was classified as Justice, Care for People or Care for Animals. The importance of each statement in the decision-making process was rated by 204 students on a 10 point Likert Scale. An average score of importance for Justice, Care for People and Care for Animals related statements were calculated for each individual. General inclination scores were calculated by subtracting an individual's average Care score from their average Justice score. Inclination scores suggested that two-thirds of students have a balanced approach, using Justice and Care almost equally in approaching ethical dilemmas. The majority of students, however, show an overall Justice orientation. The attitude towards the importance of Justice did not vary between students of different years or sexes. Students' attitudes towards the importance of Care for People in their decision making were, however, significantly lower for final-year students. Reasons hypothesised include the start of placements. Care for Animals scores were affected by sex, whereby females give more importance to such statements than males. PMID- 23015728 TI - Acute lung injury and acute respiratory distress syndrome requiring tracheal intubation and mechanical ventilation in the intensive care unit: impact on managing uncertainty for patient-centered communication. AB - A case of acute lung injury (ALI) progressing to acute respiratory distress syndrome (ARDS) requiring tracheal intubation and mechanical ventilation (ETMV) is presented. The palliative medicine service was asked to address concerns expressed by the patient's spouse reflecting uncertainty regarding outcome expectations. Acknowledging and confronting the uncertainties of a critical illness is an essential component of patient-centered communication. Addressing and managing uncertainty for the case scenario requires consideration of both short- and long-term outcomes including mortality, ventilator independence, and adverse effects on quality of life for survivors. In this paper, ALI/ARDS requiring ETMV in the ICU was used as a focal point for preparing a prognostic assessment incorporating these issues. This assessment was based on a review of recently published literature regarding mortality and ventilator independence of survivors for adult patients receiving ETMV for ALI/ARDS in the ICU. In the studies reviewed, long-term survival reported at 60 days to 1 year was 50-73% with greater than 84% of the survivors in each study breathing independently. Selected articles discussing outcomes other than mortality or recovery of respiratory function, particularly quality of life implications for ALI/ARDS survivors, were also reviewed. A case of of ALI/ARDS requiring ETMV in the ICU is used to illustrate the situation of an incapacitated critically ill patient where the outcome is uncertain. Patient-centered communication should acknowledge and address this uncertainty. Managing uncertainty consists of effectively expressing a carefully formulated prognostic assessment and using sound communication principles to alleviate the distress associated with the uncertain outcome probabilities. PMID- 23015729 TI - Medicare as insurance innovator: the case of hospice. AB - The stylized fact is that while private insurance has tended to innovate on the benefit design side of the insurance contract, Medicare has lead innovation on the payment side. Traditional or Fee-For-Service Medicare has produced many innovations in the payment for health care services, such as Prospective Payment for hospitals, Diagnostic-Related Groups to categorize care, and the Resource Based Relative Value System used by the program to pay physicians, while private insurance has produced a series of benefit design innovations. This story misses one important example of Medicare benefit innovation: the creation of the Medicare hospice benefit. A key question is whether Medicare can again lead a system-wide benefit design effort to improve upon current hospice and palliative care policy. PMID- 23015730 TI - Leg pain and gynecologic malignancy. AB - Gynecologic malignancies affect more than 83 000 women in the United States, each year. Because the disease involves the pelvis, many patients have side effects distal to this area in their lower extremities. The differential diagnosis of leg pain can be divided into vascular, neurologic, and musculoskeletal causes. In this review article, we address numerous etiologies of leg pain, reviewing the prevalence of disease, physical examination findings, diagnostic as well as treatment modalities. PMID- 23015731 TI - The development of a validated checklist for thoracentesis: preliminary results. AB - Thoracentesis is an invasive procedure known to result in complications. Procedure skills should be taught and evaluated more effectively to improve health care quality. Validated checklists are central to teaching and assessing procedural skills. The results of the first step of the validation of a thoracentesis checklist are described. A comprehensive literature review of articles published on thoracentesis did not yield a validated checklist. A modified Delphi technique, involving a panel of 8 interdisciplinary, interinstitutional experts, was used to develop a thoracentesis checklist. The internal consistency coefficient using Cronbach's alpha was .94. Developing the 23-item thoracentesis checklist for teaching and assessing thoracentesis is the first step in the validation process. For this checklist to become further validated, it should be implemented and studied in the simulation and clinical environments. PMID- 23015732 TI - Measurement of muscle sympathetic nerve activity reveals true sympathetic changes in chronic pain. PMID- 23015733 TI - 'Sympathovagal balance from heart rate variability: an obituary', but what is sympathovagal balance? PMID- 23015734 TI - Sympathovagal balance from heart rate variability: time for a second round? PMID- 23015735 TI - Cryptococcal genotype influences immunologic response and human clinical outcome after meningitis. AB - In sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was used to characterize genotypes, yielding 15 sequence types and 4 clonal clusters. The largest clonal cluster consisted of 74 isolates. The results of Burst and phylogenetic analysis suggested that the C. neoformans var. grubii strains could be separated into three nonredundant evolutionary groups (Burst group 1 to group 3). Patient mortality was differentially associated with the different evolutionary groups (P = 0.04), with the highest mortality observed among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 3 strains, Burst group 1 strains were associated with higher mortality (P = 0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more pronounced Th(2) response during ex vivo cytokine release assays with strain-specific capsule stimulation (P = 0.02). The results of these analyses suggest that cryptococcal strain variation can be an important determinant of human immune responses and mortality. IMPORTANCE: Cryptococcus neoformans is a common life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis in HIV-infected patients annually. Virulence factors that are important in human disease have been identified, yet the impacts of the fungal strain genotype on virulence and outcomes of human infection remain poorly understood. Using an analysis of strain variation based on in vitro assays and clinical data from Ugandans living with AIDS and cryptococcal infection, we report that strain genotype predicts the type of immune response and mortality risk. These studies suggest that knowledge of the strain genotype during human infections could be used to predict disease outcomes and lead to improved treatment approaches aimed at targeting the specific combination of pathogen virulence and host response. PMID- 23015736 TI - High levels of genetic recombination during nasopharyngeal carriage and biofilm formation in Streptococcus pneumoniae. AB - Transformation of genetic material between bacteria was first observed in the 1920s using Streptococcus pneumoniae as a model organism. Since then, the mechanism of competence induction and transformation has been well characterized, mainly using planktonic bacteria or septic infection models. However, epidemiological evidence suggests that genetic exchange occurs primarily during pneumococcal nasopharyngeal carriage, which we have recently shown is associated with biofilm growth, and is associated with cocolonization with multiple strains. However, no studies to date have comprehensively investigated genetic exchange during cocolonization in vitro and in vivo or the role of the nasopharyngeal environment in these processes. In this study, we show that genetic exchange during dual-strain carriage in vivo is extremely efficient (10(-2)) and approximately 10,000,000-fold higher than that measured during septic infection (10(-9)). This high transformation efficiency was associated with environmental conditions exclusive to the nasopharynx, including the lower temperature of the nasopharynx (32 to 34 degrees C), limited nutrient availability, and interactions with epithelial cells, which were modeled in a novel biofilm model in vitro that showed similarly high transformation efficiencies. The nasopharyngeal environmental factors, combined, were critical for biofilm formation and induced constitutive upregulation of competence genes and downregulation of capsule that promoted transformation. In addition, we show that dual-strain carriage in vivo and biofilms formed in vitro can be transformed during colonization to increase their pneumococcal fitness and also, importantly, that bacteria with lower colonization ability can be protected by strains with higher colonization efficiency, a process unrelated to genetic exchange. IMPORTANCE: Although genetic exchange between pneumococcal strains is known to occur primarily during colonization of the nasopharynx and colonization is associated with biofilm growth, this is the first study to comprehensively investigate transformation in this environment and to analyze the role of environmental and bacterial factors in this process. We show that transformation efficiency during cocolonization by multiple strains is very high (around 10(-2)). Furthermore, we provide novel evidence that specific aspects of the nasopharyngeal environment, including lower temperature, limited nutrient availability, and epithelial cell interaction, are critical for optimal biofilm formation and transformation efficiency and result in bacterial protein expression changes that promote transformation and fitness of colonization-deficient strains. The results suggest that cocolonization in biofilm communities may have important clinical consequences by facilitating the spread of antibiotic resistance and enabling serotype switching and vaccine escape as well as protecting and retaining poorly colonizing strains in the pneumococcal strain pool. PMID- 23015737 TI - MetR-regulated Vibrio cholerae metabolism is required for virulence. AB - LysR-type transcriptional regulators (LTTRs) are the largest, most diverse family of prokaryotic transcription factors, with regulatory roles spanning metabolism, cell growth and division, and pathogenesis. Using a sequence-defined transposon mutant library, we screened a panel of V. cholerae El Tor mutants to identify LTTRs required for host intestinal colonization. Surprisingly, out of 38 LTTRs, only one severely affected intestinal colonization in the suckling mouse model of cholera: the methionine metabolism regulator, MetR. Genetic analysis of genes influenced by MetR revealed that glyA1 and metJ were also required for intestinal colonization. Chromatin immunoprecipitation of MetR and quantitative reverse transcription-PCR (qRT-PCR) confirmed interaction with and regulation of glyA1, indicating that misregulation of glyA1 is likely responsible for the colonization defect observed in the metR mutant. The glyA1 mutant was auxotrophic for glycine but exhibited wild-type trimethoprim sensitivity, making folate deficiency an unlikely cause of its colonization defect. MetJ regulatory mutants are not auxotrophic but are likely altered in the regulation of amino acid-biosynthetic pathways, including those for methionine, glycine, and serine, and this misregulation likely explains its colonization defect. However, mutants defective in methionine, serine, and cysteine biosynthesis exhibited wild-type virulence, suggesting that these amino acids can be scavenged in vivo. Taken together, our results suggest that glycine biosynthesis may be required to alleviate an in vivo nutritional restriction in the mouse intestine; however, additional roles for glycine may exist. Irrespective of the precise nature of this requirement, this study illustrates the importance of pathogen metabolism, and the regulation thereof, as a virulence factor. IMPORTANCE: Vibrio cholerae continues to be a severe cause of morbidity and mortality in developing countries. Identification of V. cholerae factors critical to disease progression offers the potential to develop or improve upon therapeutics and prevention strategies. To increase the efficiency of virulence factor discovery, we employed a regulator-centric approach to multiplex our in vivo screening capabilities and allow whole regulons in V. cholerae to be interrogated for pathogenic potential. We identified MetR as a new virulence regulator and serine hydroxymethyltransferase GlyA1 as a new MetR regulated virulence factor, both required by V. cholerae to colonize the infant mouse intestine. Bacterial metabolism is a prerequisite to virulence, and current knowledge of in vivo metabolism of pathogens is limited. Here, we expand the known role of amino acid metabolism and regulation in virulence and offer new insights into the in vivo metabolic requirements of V. cholerae within the mouse intestine. PMID- 23015738 TI - Increased nasopharyngeal bacterial titers and local inflammation facilitate transmission of Streptococcus pneumoniae. AB - The transmission of the bacterium Streptococcus pneumoniae (the pneumococcus) marks the first step toward disease development. To date, our ability to prevent pneumococcal transmission has been limited by our lack of understanding regarding the factors which influence the spread of this pathogen. We have previously developed an infant mouse model of pneumococcal transmission which was strictly dependent on influenza A virus (IAV) coinfection of both the experimentally colonized "index mice" and the naive cohoused "contact mice." Here, we sought to use this model to further elucidate the factors which facilitate S. pneumoniae transmission. In the present report, we demonstrate that increasing the nasopharyngeal load of S. pneumoniae in the colonized index mice (via the depletion of neutrophils) and inducing a proinflammatory response in the naive cohoused contact mice (as demonstrated by cytokine production) facilitates S. pneumoniae transmission. Thus, these data provide the first insights into the factors that help mediate the spread of S. pneumoniae throughout the community. IMPORTANCE: Streptococcus pneumoniae (the pneumococcus) is a major cause of worldwide morbidity and mortality and is a leading cause of death among children under the age of five years. Transmission of S. pneumoniae marks the first step toward disease development. Therefore, understanding the factors that influence the spread of pneumococci throughout the community plays an essential role in preventing pneumococcal disease. We previously developed the first reproducible infant mouse model for pneumococcal transmission and showed that coinfection with influenza virus facilitates the spread of S. pneumoniae. Here, we show that increasing the bacterial load in the nasal cavity of colonized individuals as well as inducing an inflammatory response in naive "contact cases" facilitates the spread of pneumococci. Therefore, this study helps to identify the factors which must be inhibited in order to successfully prevent pneumococcal disease. PMID- 23015739 TI - beta-1,3-glucan, which can be targeted by drugs, forms a trabecular scaffold in the oocyst walls of Toxoplasma and Eimeria. AB - The walls of infectious pathogens, which are essential for transmission, pathogenesis, and diagnosis, contain sugar polymers that are defining structural features, e.g., beta-1,3-glucan and chitin in fungi, chitin in Entamoeba cysts, beta-1,3-GalNAc in Giardia cysts, and peptidoglycans in bacteria. The goal here was to determine in which of three walled forms of Toxoplasma gondii (oocyst, sporocyst, or tissue cyst) is beta-1,3-glucan, the product of glucan synthases and glucan hydrolases predicted by whole-genome sequences of the parasite. The three most important discoveries were as follows. (i) beta-1,3-glucan is present in oocyst walls of Toxoplasma and Eimeria (a chicken parasite that is a model for intestinal stages of Toxoplasma) but is absent from sporocyst and tissue cyst walls. (ii) Fibrils of beta-1,3-glucan are part of a trabecular scaffold in the inner layer of the oocyst wall, which also includes a glucan hydrolase that has a novel glucan-binding domain. (iii) Echinocandins, which target the glucan synthase and kill fungi, arrest development of the Eimeria oocyst wall and prevent release of the parasites into the intestinal lumen. In summary, beta-1,3 glucan, which can be targeted by drugs, is an important component of oocyst walls of Toxoplasma but is not a component of sporocyst and tissue cyst walls. IMPORTANCE: We show here that walls of Toxoplasma oocysts, the infectious stage shed by cats, contain beta-1,3-glucan, a sugar polymer that is a major component of fungal walls. In contrast to fungi, beta-1,3-glucan is part of a trabecular scaffold in the inner layer of the oocyst wall that is independent of the permeability barrier formed by the outer layer of the wall. While glucan synthase inhibitors kill fungi, these inhibitors arrest the development of the oocyst walls of Eimeria (an important chicken pathogen that is a surrogate for Toxoplasma) and block release of oocysts into the intestinal lumen. The absence of beta-1,3-glucan in tissue cysts of Toxoplasma suggests that drugs targeted at the glucan synthase might be used to treat Eimeria in chickens but not to treat Toxoplasma in people. PMID- 23015741 TI - Tropism, compartmentalization and retention of banana bunchy top virus (Nanoviridae) in the aphid vector Pentalonia nigronervosa. AB - Plant viruses of the families Luteoviridae and Geminiviridae rely on hemipteran vectors for the infection of their hosts. Several lines of evidence have revealed that these viruses are transmitted by competent vectors in a circulative manner, involving entry into the vector's body and the crossing of epithelial tissues forming the alimentary tract and the salivary glands. Similar to luteovirids and geminiviruses, a third family of plant viruses, the family Nanoviridae, have also been reported to be transmitted by aphids in a circulative manner. However, there is limited direct evidence of a possible path of translocation through the aphid vectors. Here, we used time-course experiments and transmission assays coupled with real-time PCR and immunofluorescence assays on dissected tissues to examine the translocation, compartmentalization and retention of banana bunchy top virus (BBTV) into the aphid vector Pentalonia nigronervosa. Our results indicate that BBTV translocates rapidly through the aphid vector; it is internalized into the anterior midgut in which it accumulates and is retained at concentrations higher than either the haemolymph or the principal salivary glands. Despite the large increase in viral concentration, we have failed to detect BBTV transcripts with RT-PCR. When tissues were not permeabilized, BBTV localized as distinct puncta in the proximity of the basal surface of the cells forming the anterior midgut and principal salivary glands, suggesting an on-going process of virion escape and internalization, respectively. Interestingly, we document that those organs can have direct contact within the aphid body, suggesting a possible haemolymph independent translocation path. PMID- 23015740 TI - Propionibacterium acnes bacteriophages display limited genetic diversity and broad killing activity against bacterial skin isolates. AB - Investigation of the human microbiome has revealed diverse and complex microbial communities at distinct anatomic sites. The microbiome of the human sebaceous follicle provides a tractable model in which to study its dominant bacterial inhabitant, Propionibacterium acnes, which is thought to contribute to the pathogenesis of the human disease acne. To explore the diversity of the bacteriophages that infect P. acnes, 11 P. acnes phages were isolated from the sebaceous follicles of donors with healthy skin or acne and their genomes were sequenced. Comparative genomic analysis of the P. acnes phage population, which spans a 30-year temporal period and a broad geographic range, reveals striking similarity in terms of genome length, percent GC content, nucleotide identity (>85%), and gene content. This was unexpected, given the far-ranging diversity observed in virtually all other phage populations. Although the P. acnes phages display a broad host range against clinical isolates of P. acnes, two bacterial isolates were resistant to many of these phages. Moreover, the patterns of phage resistance correlate closely with the presence of clustered regularly interspaced short palindromic repeat elements in the bacteria that target a specific subset of phages, conferring a system of prokaryotic innate immunity. The limited diversity of the P. acnes bacteriophages, which may relate to the unique evolutionary constraints imposed by the lipid-rich anaerobic environment in which their bacterial hosts reside, points to the potential utility of phage-based antimicrobial therapy for acne. IMPORTANCE: Propionibacterium acnes is a dominant member of the skin microflora and has also been implicated in the pathogenesis of acne; however, little is known about the bacteriophages that coexist with and infect this bacterium. Here we present the novel genome sequences of 11 P. acnes phages, thereby substantially increasing the amount of available genomic information about this phage population. Surprisingly, we find that, unlike other well-studied bacteriophages, P. acnes phages are highly homogeneous and show a striking lack of genetic diversity, which is perhaps related to their unique and restricted habitat. They also share a broad ability to kill clinical isolates of P. acnes; phage resistance is not prevalent, but when detected, it appears to be conferred by chromosomally encoded immunity elements within the host genome. We believe that these phages display numerous features that would make them ideal candidates for the development of a phage-based therapy for acne. PMID- 23015742 TI - Reduction of polyhedrin mRNA and protein expression levels in Sf9 and Hi5 cell lines, but not in Sf21 cells, infected with Autographa californica multiple nucleopolyhedrovirus fp25k mutants. AB - During cell infection, the fp25k gene of baculoviruses frequently mutates, producing the few polyhedra (FP) per cell phenotype with reduced polyhedrin (polh) expression levels compared with wild-type baculoviruses. Here we report that the fp25k gene of the model baculovirus, Autographa californica multiple nucleopolyhedrovirus (AcMNPV), contains two hypermutable seven-adenine (A7) mononucleotide repeats (MNRs) that were mutated to A8 MNRs and a TTAA site that had host DNA insertions, producing fp25k mutants during Sf21 cell infection. The FP phenotype in Sf9 and Hi5 cells was more pronounced than in Sf21 cells. AcMNPV fp25k mutants produced similar levels of polyhedra or enhanced GFP, which were both under the control of the AcMNPV polh promoter for expression, in Sf21 cells but lower levels in Sf9 and Hi5 cells compared with AcMNPV with an intact fp25k gene. This correlated with the polh mRNA levels detected in each cell line. The majority of Sf21 cells infected with fp25 mutants showed high polh promoter mediated GFP expression levels. Two cell lines subcloned from Sf21 cells that were infected with fp25k mutants showed different GFP expression levels. Furthermore, a small proportion of Hi5 cells infected with fp25k mutants showed higher production of polyhedra and GFP expression than the rest, and the latter was not correlated with increased m.o.i. Therefore, these data suggest that AcMNPV polh promoter-mediated gene expression activities differ in the three cell lines and are influenced by different cells within the cell line. PMID- 23015743 TI - Molecular characterization of two evolutionarily distinct endornaviruses co infecting common bean (Phaseolus vulgaris). AB - Two high-molecular-mass dsRNAs of approximately 14 and 15 kbp were isolated from the common bean (Phaseolus vulgaris) cultivar Black Turtle Soup. These dsRNAs did not appear to cause obvious disease symptoms, and were transmitted through seeds at nearly 100% efficiency. Sequence information indicates that they are the genomes of distinct endornavirus species, for which the names Phaseolus vulgaris endornavirus 1 (PvEV-1) and Phaseolus vulgaris endornavirus 2 (PvEV-2) are proposed. The PvEV-1 genome consists of 13,908 bp and potentially encodes a single polyprotein of 4496 aa, while that of PvEV-2 consists of 14 820 bp and potentially encodes a single ORF of 4851 aa. PvEV-1 is more similar to Oryza sativa endornavirus, while PvEV-2 is more similar to bell pepper endornavirus. Both viruses have a site-specific nick near the 5' region of the coding strand, which is a common property of the endornaviruses. Their polyproteins contain domains of RNA helicase, UDP-glycosyltransferase and RNA-dependent RNA polymerase, which are conserved in other endornaviruses. However, a viral methyltransferase domain was found in the N-terminal region of PvEV-2, but was absent in PvEV-1. Results of cell-fractionation studies suggested that their subcellular localizations were different. Most endornavirus-infected bean cultivars tested were co-infected with both viruses. PMID- 23015744 TI - Human immunodeficiency virus type 1 gp120 envelope characteristics associated with disease progression differ in family members infected with genetically similar viruses. AB - The human immunodeficiency virus type 1 (HIV-1) envelope protein provides the primary contact between the virus and host, and is the main target of the adaptive humoral immune response. The length of gp120 variable loops and the number of N-linked glycosylation events are key determinants for virus infectivity and immune escape, while the V3 loop overall positive charge is known to affect co-receptor tropism. We selected two families in which both parents and two children had been infected with HIV-1 for nearly 10 years, but who demonstrated variable parameters of disease progression. We analysed the gp120 envelope sequence and compared individuals that progressed to those that did not in order to decipher evolutionary alterations that are associated with disease progression when individuals are infected with genetically related virus strains. The analysis of the V3-positive charge demonstrated an association between higher V3-positive charges with disease progression. The ratio between the amino acid length and the number of potential N-linked glycosylation sites was also shown to be associated with disease progression with the healthier family members having a lower ratio. In conclusion in individuals initially infected with genetically linked virus strains the V3-positive charges and N-linked glycosylation are associated with HIV-1 disease progression and follow varied evolutionary paths for individuals with varied disease progression. PMID- 23015745 TI - Eight novel hepatitis C virus genomes reveal the changing taxonomic structure of genotype 6. AB - Analysis of partial hepatitis C virus sequences has revealed many novel genotype 6 variants that cannot be unambiguously classified, which obscure the distinctiveness of pre-existing subtypes. To explore this uncertainty, we obtained genomes of 98.0-98.8% full-length for eight such variants (KM35, QC273, TV257, TV476, TV533, L349, QC271 and DH027) and characterized them using phylogenetic analyses and per cent nucleotide similarities. The former four are closely related phylogenetically to subtype 6k, TV533 and L349 to subtype 6l, QC271 to subtypes 6i and 6j, and DH027 to subtypes 6m and 6n. The former six defined a high-level grouping that comprised subtypes 6k and 6l, plus related strains. The threshold between intra- and inter-subtype diversity in this group was indistinct. We propose that similar results would be seen elsewhere if more intermediate variants like QC271 and DH027 were sampled. PMID- 23015746 TI - Genetic and antigenic characteristics of H4 subtype avian influenza viruses in Korea and their pathogenicity in quails, domestic ducks and mice. AB - In Korea, a nationwide surveillance programme was implemented in 2003 to identify highly pathogenic avian influenza viruses (AIVs). AIVs belonging to one of the most common haemagglutinin subtypes, H4, were isolated from two domestic ducks and 52 wild birds between 2004 and 2010. These H4 AIVs could be further classified into three neuraminidase subtypes: H4N6 (94.4%), H4N2 (3.7%) and H4N3 (1.9%). Phylogenetic analysis revealed that the H4 AIVs had a variety of genetic constellations, with at least nine different genotypes represented. The pathogenicity of these H4 viruses was assessed in quails, domestic ducks and mice. None of the H4 AIVs induced clinical signs in quails or domestic ducks. Viral shedding in quails was relatively high, and virus was recovered up to 5-7 days post-inoculation (p.i.) in oropharyngeal swabs, but the viruses replicated poorly in domestic ducks. Quails may act as an intermediate host in which AIVs are amplified and transmitted to other species. In mice, all of the AIVs were recovered efficiently at relatively high titres from the lungs up to 7 days p.i., demonstrating the potential for AIVs to infect mice directly without prior adaptation. None of the AIVs induced clinical signs nor was any lethal to infected mice. However, there was significant loss of body weight in mice infected with viruses of duck origin. It is suggested that the active surveillance of influenza viruses needs to be enhanced in domestic poultry as well as in wild birds, and that it should include assessment of pathogenicity in animal models. PMID- 23015747 TI - Ethics and eplerenone. AB - The use of a placebo arm in clinical trials is unethical if there is an active comparator that is acceptably safe and effective. We argue that reasonable evidence of effectiveness and safety of an inexpensive alternative to an expensive therapy is sufficient to require that the inexpensive therapy be included as a comparator when the expensive therapy is tested, and that use of an inactive placebo comparator only is not ethical. For example, studies of the expensive drug eplerenone for congestive heart failure have not included a spironolactone arm, although there is reasonable evidence that spironolactone would be safe and effective, and spironolactone is inexpensive. The requirement to study inexpensive therapies is based on avoidance of unnecessary cost in medical care as an example of non-maleficence. Several ethical actors in the design, conduct, and publication of clinical trials and their results bear responsibility for the appropriate conduct of clinical trials. That responsibility includes protecting study subjects from being asked to participate in clinical trials that serve primarily to promote the use of new and expensive therapies. PMID- 23015748 TI - Cumulative morbidity and prognostic staging of illness in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). AB - OBJECTIVE: Staging models may provide heuristic utility for intervention selection in psychiatry. Although a few proposals have been put forth, there is a need for empirical validation if they are to be adopted. Using data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), we tested a previously elaborated hypothesis on the utility of using the number of previous episodes as a relevant prognostic variable for staging in bipolar disorder. METHODS: This report utilizes data from the multisite, prospective, open-label study 'Standard Care Pathways' and the subset of patients with acute depressive episodes who participated in the randomized trial of adjunctive antidepressant treatment. Outpatients meeting DSM-IV diagnostic criteria for bipolar disorder (n = 3345) were included. For the randomized pathway, patients met criteria for an acute depressive episode (n = 376). The number of previous episodes was categorized as less than 5, 5-10 and more than 10. We used disability at baseline, number of days well in the first year and longitudinal scores of depressive and manic symptoms, quality of life and functioning as validators of models constructed a priori. RESULTS: Patients with multiple previous episodes had consistently poorer cross-sectional and prospective outcomes. Functioning and quality of life were worse, disability more common, and symptoms more chronic and severe. There was no significant effect for staging with regard to antidepressant response in the randomized trial. CONCLUSIONS: These findings confirm that bipolar disorder can be staged with prognostic validity. Stages can be used to stratify subjects in clinical trials and develop specific treatments. PMID- 23015749 TI - Do early intervention for psychosis services really save money? PMID- 23015750 TI - Randomised controlled trial of group cognitive behaviour therapy versus brief intervention for depression in cardiac patients. AB - OBJECTIVE: To determine whether a six-session group cognitive behaviour therapy (CBT) programme results in a greater reduction in depression symptoms than a brief intervention alone in cardiac patients with clinically significant symptoms of depression. METHOD: Fifty-seven community dwelling cardiac patients scoring >13 on the Beck Depression Inventory-II (BDI-II) received a single-session brief intervention. They were then block randomised to either six sessions of group CBT (n = 25) or no further intervention (BI; n = 32). All were re-assessed at 2, 6 and 12 months. Differences between treatment groups in the primary (BDI-II) and secondary [rates of depression; anxiety symptoms, as measured by the Hospital Anxiety and Depression Scale-Anxiety (HADS-A)] outcomes were examined using generalised linear mixed models with a random intercept term for the individual. RESULTS: Significant improvements were seen for the total group from baseline to 12 months on BDI-II and HADS-A scores. However, no differences were found between the CBT and BI conditions on change in BDI-II score, rates of major depressive episode or HADS-A score. Post hoc analysis on the total group found 12-month symptom non-remission was associated with higher baseline BDI-II score (p = 0.03), more visits to health professionals 12 months prior to baseline (p = 0.05) and a greater likelihood of either drinking alcohol over recommended levels or smoking at baseline (p = 0.01). CONCLUSIONS: Group CBT of up to six sessions did not result in greater reductions in depression or anxiety symptoms compared with a single-session brief intervention. Further work should focus on the efficacy and role of brief interventions, and addressing smoking and alcohol misuse in cardiac patients with depression. PMID- 23015751 TI - Neuropsychiatric presentation of Lyme disease in Australia. PMID- 23015752 TI - Maternal high-fat diet modulates the fetal thyroid axis and thyroid gene expression in a nonhuman primate model. AB - Thyroid hormone (TH) is an essential regulator of both fetal development and energy homeostasis. Although the association between subclinical hypothyroidism and obesity has been well studied, a causal relationship has yet to be established. Using our well-characterized nonhuman primate model of excess nutrition, we sought to investigate whether maternal high-fat diet (HFD)-induced changes in TH homeostasis may underlie later in life development of metabolic disorders and obesity. Here, we show that in utero exposure to a maternal HFD is associated with alterations of the fetal thyroid axis. At the beginning of the third trimester, fetal free T(4) levels are significantly decreased with HFD exposure compared with those of control diet-exposed offspring. Furthermore, transcription of the deiodinase, iodothyronine (DIO) genes, which help maintain thyroid homeostasis, are significantly (P < 0.05) disrupted in the fetal liver, thyroid, and hypothalamus. Genes involved in TH production are decreased (TRH, TSHR, TG, TPO, and SLC5A5) in hypothalamus and thyroid gland. In experiments designed to investigate the molecular underpinnings of these observations, we observe that the TH nuclear receptors and their downstream regulators are disrupted with maternal HFD exposure. In fetal liver, the expression of TH receptor beta (THRB) is increased 1.9-fold (P = 0.012). Thorough analysis of the THRB promoter reveals a maternal diet-induced alteration in the fetal THRB histone code, alongside differential promoter occupancy of corepressors and coactivators. We speculate that maternal HFD exposure in utero may set the stage for later in life obesity through epigenomic modifications to the histone code, which modulates the fetal thyroid axis. PMID- 23015753 TI - Communication between the calcium and cAMP pathways regulate the expression of the TSH receptor: TRPC2 in the center of action. AB - Transient receptor potential (TRP) cation channels are widely expressed and function in many physiologically important processes. Perturbations in the expression or mutations of the channels have implications for diseases. Many thyroid disorders, as excessive growth or disturbed thyroid hormone production, can be a result of dysregulated TSH signaling. In the present study, we found that of TRP canonicals (TRPCs), only TRPC2 was expressed in Fischer rat thyroid low-serum 5% cells (FRTL-5 cells). To investigate the physiological importance of the channel, we developed stable TRPC2 knockdown cells using short hairpin RNA (shTRPC2 cells). In these cells, the ATP-evoked entry of calcium was significantly decreased. This led to increased cAMP production, because inhibitory signals from calcium to adenylate cyclase 5/6 were decreased. Enhanced cAMP signaling projected to Ras-related protein 1-MAPK kinase 1 (MAPK/ERK kinase 1) pathway leading to phosphorylation of ERK1/2. The activated ERK1/2 pathway increased the expression of the TSH receptor. In contrast, secretion of thyroglobulin was decreased in shTRPC2 cells, due to improper folding and glycosylation of the protein. We show here a novel role for TRPC2 in regulating thyroid cell function. PMID- 23015754 TI - Retinal horizontal cells lacking Rb1 sustain persistent DNA damage and survive as polyploid giant cells. AB - The retinoblastoma tumor susceptibility gene, Rb1, is a key regulator of the cell cycle, and mutations in this gene have been found in many human cancers. Prior studies showed that retina-specific knockout of Rb1 in the mouse results in the formation of abnormally large horizontal cells, but the development, fate, and genomic status of these cells remain unknown. In this study, we conditionally inactivate Rb1 in early retinal progenitors and show that the loss of Rb1 leads to the rapid degeneration of most retinal cells except horizontal cells, which persist as giant cells with aberrant centrosome content, DNA damage, and polyploidy/aneuploidy. We observed inappropriate cell cycle entry of Rb1 deficient horizontal cells during the first postnatal weeks, which dropped off abruptly by P30. Despite extensive DNA damage in Rb1-deficient horizontal cells, these cells can still enter mitosis. Adult Rb1-deficient horizontal cells display elevated DNA content (5N-34N) that varied continuously, suggesting the presence of aneuploidy. We also found evidence of supernumerary and disoriented centrosomes in a rare population of mitotic cells in the mutant retinas. Overall our data demonstrate that horizontal cells are a remarkably robust cell type and can survive for months despite extensive DNA damage and elevated genome content. PMID- 23015755 TI - The nuclear membrane leukotriene synthetic complex is a signal integrator and transducer. AB - Leukotrienes (LTs) are lipid-signaling molecules derived from arachidonic acid (AA) that initiate and amplify inflammation. To initiate LT formation, the 5 lipoxygenase (5-LO) enzyme translocates to nuclear membranes, where it associates with its scaffold protein, 5-lipoxygenase-activating protein (FLAP), to form the core of the multiprotein LT synthetic complex. FLAP is considered to function by binding free AA and facilitating its use as a substrate by 5-LO to form the initial LT, LTA(4). We used a combination of fluorescence lifetime imaging microscopy, cell biology, and biochemistry to identify discrete AA-dependent and AA-independent steps that occur on nuclear membranes to control the assembly of the LT synthetic complex in polymorphonuclear leukocytes. The association of AA with FLAP changes the configuration of the scaffold protein, enhances recruitment of membrane-associated 5-LO to form complexes with FLAP, and controls the closeness of this association. Granulocyte monocyte colony-stimulating factor provides a second AA-independent signal that controls the closeness of 5-LO and FLAP within complexes but not the number of complexes that are assembled. Our results demonstrate that the LT synthetic complex is a signal integrator that transduces extracellular signals to modulate the interaction of 5-LO and FLAP. PMID- 23015756 TI - MITD1 is recruited to midbodies by ESCRT-III and participates in cytokinesis. AB - Diverse cellular processes, including multivesicular body formation, cytokinesis, and viral budding, require the sequential functions of endosomal sorting complexes required for transport (ESCRTs) 0 to III. Of these multiprotein complexes, ESCRT-III in particular plays a key role in mediating membrane fission events by forming large, ring-like helical arrays. A number of proteins playing key effector roles, most notably the ATPase associated with diverse cellular activities protein VPS4, harbor present in microtubule-interacting and trafficking molecules (MIT) domains comprising asymmetric three-helical bundles, which interact with helical MIT-interacting motifs in ESCRT-III subunits. Here we assess comprehensively the ESCRT-III interactions of the MIT-domain family member MITD1 and identify strong interactions with charged multivesicular body protein 1B (CHMP1B), CHMP2A, and increased sodium tolerance-1 (IST1). We show that these ESCRT-III subunits are important for the recruitment of MITD1 to the midbody and that MITD1 participates in the abscission phase of cytokinesis. MITD1 also dimerizes through its C-terminal domain. Both types of interactions appear important for the role of MITD1 in negatively regulating the interaction of IST1 with VPS4. Because IST1 binding in turn regulates VPS4, MITD1 may function through downstream effects on the activity of VPS4, which plays a critical role in the processing and remodeling of ESCRT filaments in abscission. PMID- 23015757 TI - Displacement of basolateral Bazooka/PAR-3 by regulated transport and dispersion during epithelial polarization in Drosophila. AB - Polarity landmarks guide epithelial development. In the early Drosophila ectoderm, the scaffold protein Bazooka (Drosophila PAR-3) forms apicolateral landmarks to direct adherens junction assembly. However, it is unclear how Bazooka becomes polarized. We report two mechanisms acting in concert to displace Bazooka from the basolateral membrane. As cells form during cellularization, basally localized Bazooka undergoes basal-to-apical transport. Bazooka requires its three postsynaptic density 95, discs large, zonula occludens-1 (PDZ) domains to engage the transport mechanism, but with the PDZ domains deleted, basolateral displacement still occurs by gastrulation. Basolateral PAR-1 activity appears to act redundantly with the transport mechanism. Knockdown of PAR-1 sporadically destabilizes cellularization furrows, but basolateral displacement of Bazooka still occurs by gastrulation. In contrast, basolateral Bazooka displacement is blocked with disruption of both the transport mechanism and phosphorylation by PAR-1. Thus Bazooka is polarized through a combination of transport and PAR-1 induced dispersion from basolateral membranes. Our work complements recent findings in Caenorhabditis elegans and thus suggests the coupling of transport and dispersion is a common protein polarization strategy. PMID- 23015758 TI - The complex interactions of Chs5p, the ChAPs, and the cargo Chs3p. AB - The exomer complex is a putative vesicle coat required for the direct transport of a subset of cargoes from the trans-Golgi network (TGN) to the plasma membrane. Exomer comprises Chs5p and the ChAPs family of proteins (Chs6p, Bud7p, Bch1p, and Bch2p), which are believed to act as cargo receptors. In particular, Chs6p is required for the transport of the chitin synthase Chs3p to the bud neck. However, how the ChAPs associate with Chs5p and recognize cargo is not well understood. Using domain-switch chimeras of Chs6p and Bch2p, we show that four tetratricopeptide repeats (TPRs) are involved in interaction with Chs5p. Because these roles are conserved among the ChAPs, the TPRs are interchangeable among different ChAP proteins. In contrast, the N-terminal and the central parts of the ChAPs contribute to cargo specificity. Although the entire N-terminal domain of Chs6p is required for Chs3p export at all cell cycle stages, the central part seems to predominantly favor Chs3p export in small-budded cells. The cargo Chs3p probably also uses a complex motif for the interaction with Chs6, as the C terminus of Chs3p interacts with Chs6p and is necessary, but not sufficient, for TGN export. PMID- 23015759 TI - CTTNBP2, but not CTTNBP2NL, regulates dendritic spinogenesis and synaptic distribution of the striatin-PP2A complex. AB - Cortactin-binding protein 2 (CTTNBP2) interacts with cortactin to regulate cortactin mobility and control dendritic spine formation. CTTNBP2 has also been associated with autistic spectrum disorder. The regulation of dendritic spinogenesis could explain the association of CTTNBP2 with autism. Sequence comparison has indicated that CTTNBP2 N-terminal-like protein (CTTNBP2NL) is a CTTNBP2 homologue. To confirm the specific effect of CTTNBP2 on dendritic spinogenesis, here we investigate whether CTTNBP2NL has a similar function to CTTNBP2. Although both CTTNBP2 and CTTNBP2NL interact with cortactin, CTTNBP2NL is associated with stress fibers, whereas CTTNBP2 is distributed to the cortex and intracellular puncta. We also provide evidence that CTTNBP2, but not CTTNBP2NL, is predominantly expressed in the brain. CTTNBP2NL does not show any activity in the regulation of dendritic spinogenesis. In addition to spine morphology, CTTNBP2 is also found to regulate the synaptic distribution of striatin and zinedin (the regulatory B subunits of protein phosphatase 2A [PP2A]), which interact with CTTNBP2NL in HEK293 cells. The association between CTTNBP2 and striatin/zinedin suggests that CTTNBP2 targets the PP2A complex to dendritic spines. Thus we propose that the interactions of CTTNBP2 and cortactin and the PP2A complex regulate spine morphogenesis and synaptic signaling. PMID- 23015761 TI - Molecular and physiological analysis of growth-limiting drought stress in Brachypodium distachyon leaves. AB - The drought-tolerant grass Brachypodium distachyon is an emerging model species for temperate grasses and cereal crops. To explore the usefulness of this species for drought studies, a reproducible in vivo drought assay was developed. Spontaneous soil drying led to a 45% reduction in leaf size, and this was mostly due to a decrease in cell expansion, whereas cell division remained largely unaffected by drought. To investigate the molecular basis of the observed leaf growth reduction, the third Brachypodium leaf was dissected in three zones, namely proliferation, expansion, and mature zones, and subjected to transcriptome analysis, based on a whole-genome tiling array. This approach allowed us to highlight that transcriptome profiles of different developmental leaf zones respond differently to drought. Several genes and functional processes involved in drought tolerance were identified. The transcriptome data suggest an increased energy availability in the proliferation zones, along with an up-regulation of sterol synthesis that may influence membrane fluidity. This information may be used to improve the tolerance of temperate cereals to drought, which is undoubtedly one of the major environmental challenges faced by agriculture today and in the near future. PMID- 23015762 TI - Mothers' Repartnering after a Nonmarital Birth. AB - This paper examines the prevalence, predictors and outcomes of unmarried mothers' repartnering patterns following a nonmarital birth. Results indicate that, within five years after a birth, approximately two-thirds of unmarried mothers ended their relationship with the focal child's biological father, and over half of these mothers entered new partnerships. Among those who repartnered, 60 percent of mothers formed unions with men with higher economic capabilities than their former partners, 20 percent formed unions with men with similar capabilities, and 20 percent formed unions with men with lower capabilities. This pattern holds for both nonresidential and coresidential unions. Our findings are consistent with marriage market, learning, and evolutionary biology theories about union formation, and they provide support for qualitative evidence that unmarried mothers have high standards for new partners. While many mothers are able to successfully find new partners with better economic capabilities, many other mothers remain unpartnered, likely due (at least in part) to the limited pool of potential partners with relatively high levels of economic capabilities. PMID- 23015763 TI - BIFURCATING DISTRIBUTIVE SYSTEM USING MONTE CARLO METHOD. AB - A new method to generate a bifurcating distributive system is presented. The method utilizes random points inside a given area and is sensitive to the global and local concentrations of the points. The algorithm is highly efficient compared to the current area-halving algorithms. PMID- 23015760 TI - The Salmonella Typhimurium effector SteC inhibits Cdc42-mediated signaling through binding to the exchange factor Cdc24 in Saccharomyces cerevisiae. AB - Intracellular survival of Salmonella relies on the activity of proteins translocated into the host cell by type III secretion systems (T3SS). The protein kinase activity of the T3SS effector SteC is required for F-actin remodeling in host cells, although no SteC target has been identified so far. Here we show that expression of the N-terminal non-kinase domain of SteC down-regulates the mating and HOG pathways in Saccharomyces cerevisiae. Epistasis analyses using constitutively active components of these pathways indicate that SteC inhibits signaling at the level of the GTPase Cdc42. We demonstrate that SteC interacts through its N-terminal domain with the catalytic domain of Cdc24, the sole S. cerevisiae Cdc42 guanine nucleotide exchange factor (GEF). SteC also binds to the human Cdc24-like GEF protein Vav1. Moreover, expression of human Cdc42 suppresses growth inhibition caused by SteC. Of interest, the N-terminal SteC domain alters Cdc24 cellular localization, preventing its nuclear accumulation. These data reveal a novel functional domain within SteC, raising the possibility that this effector could also target GTPase function in mammalian cells. Our results also highlight the key role of the Cdc42 switch in yeast mating and HOG pathways and provide a new tool to study the functional consequences of Cdc24 localization. PMID- 23015764 TI - Photoreactive elastin-like proteins for use as versatile bioactive materials and surface coatings. AB - Photocrosslinkable, protein-engineered biomaterials combine a rapid, controllable, cytocompatible crosslinking method with a modular design strategy to create a new family of bioactive materials. These materials have a wide range of biomedical applications, including the development of bioactive implant coatings, drug delivery vehicles, and tissue engineering scaffolds. We present the successful functionalization of a bioactive elastin-like protein with photoreactive diazirine moieties. Scalable synthesis is achieved using a standard recombinant protein expression host followed by site-specific modification of lysine residues with a heterobifunctional N-hydroxysuccinimide ester-diazirine crosslinker. The resulting biomaterial is demonstrated to be processable by spin coating, drop casting, soft lithographic patterning, and mold casting to fabricate a variety of two- and three-dimensional photocrosslinked biomaterials with length scales spanning the nanometer to millimeter range. Protein thin films proved to be highly stable over a three-week period. Cell-adhesive functional domains incorporated into the engineered protein materials were shown to remain active post-photo-processing. Human adipose-derived stem cells achieved faster rates of cell adhesion and larger spread areas on thin films of the engineered protein compared to control substrates. The ease and scalability of material production, processing versatility, and modular bioactive functionality make this recombinantly engineered protein an ideal candidate for the development of novel biomaterial coatings, films, and scaffolds. PMID- 23015765 TI - A great barrier reef Sinularia sp. yields two new cytotoxic diterpenes. AB - The methanol extract of a Sinularia sp., collected from Bowden Reef, Queensland, Australia, yielded ten natural products. These included the new nitrogenous diterpene (4R*,5R*,9S*,10R*,11Z)-4-methoxy-9-((dimethylamino)-methyl)-12,15-epoxy 11(13)-en-decahydronaphthalen-16-ol (1), and the new lobane, (1R*,2R*,4S*,15E) loba-8,10,13(14),15(16)-tetraen-17,18-diol-17-acetate (2). Also isolated were two known cembranes, sarcophytol-B and (1E,3E,7E)-11,12-epoxycembratrien-15-ol, and six known lobanes, loba-8,10,13(15)-triene-16,17,18-triol, 14,18-epoxyloba 8,10,13(15)-trien-17-ol, lobatrientriol, lobatrienolide, 14,17-epoxyloba 8,10,13(15)-trien-18-ol-18-acetate and (17R)-loba-8,10,13(15)-trien-17,18-diol. Structures of the new compounds were elucidated through interpretation of spectra obtained after extensive NMR and MS investigations and comparison with literature values. The tumour cell growth inhibition potential of 1 and 2 along with loba 8,10,13(15)-triene-16,17,18-triol, 14,17-epoxyloba-8,10,13(15)-trien-18-ol-18 acetate, lobatrienolide, (1E,3E,7E)-11,12-epoxycembratrien-15-ol and sarcophytol B were assessed against three human tumour cell lines (SF-268, MCF-7 and H460). The lobanes and cembranes tested demonstrated 50% growth inhibition in the range 6.8-18.5 uM, with no selectivity, whilst 1 was less active (GI50 70-175 uM). PMID- 23015766 TI - Trypanocidal action of (-)-elatol involves an oxidative stress triggered by mitochondria dysfunction. AB - Natural compounds have shown good potential for the discovery of new chemotherapeutics for the treatment of Chagas' disease. Recently, our group reported the effective trypanocidal activity of (-)-elatol, extracted from the red macroalgae Laurencia dendroidea present in the Brazilian coast against Trypanosoma cruzi. However, the mechanism of action of this compound has remained unclear. There are only hypotheses concerning its action on mitochondrial function. Here, we further investigated the mechanisms of action of (-)-elatol on trypomastigotes of T. cruzi. For this, we evaluated some biochemical alterations in trypomastigotes treated with (-)-elatol. Our results show that (-)-elatol induced depolarization of the mitochondrial membrane, an increase in the formation of mitochondrial superoxide anion and loss of cell membrane and DNA integrity. Additionally, (-)-elatol induced formation of autophagic vacuoles and a decrease in cell volume. All together, these results suggest that the trypanocidal action of (-)-elatol involves multiple events and mitochondria might be the initial target organelle. Our hypothesis is that the mitochondrial dysfunction leads to an increase of ROS production through the electron transport chain, which affects cell membrane and DNA integrity leading to different types of parasite death. PMID- 23015767 TI - Preparation and characterization of O-acylated fucosylated chondroitin sulfate from sea cucumber. AB - Fucosylated chondroitin sulfate (FuCS), a kind of complex glycosaminoglycan from sea cucumber, has potent anticoagulant activity. In order to understand the relationship between structures and activity, the depolymerized FuCS (dFuCS) was chosen to prepare its derivates by selective substitution at OH groups. Its O acylation was carried out in a homogeneous way using carboxylic acid anhydrides. The structures of O-acylated derivatives were characterized by NMR. The results indicated that the 4-O-sulfated fucose residues may be easier to be acylated than the other ones in the sulfated fucose branches. But the O-acylation was always accompanied by the beta-elimination, and the degree of elimination was higher as that of acylation was higher. The results of clotting assay indicated that the effect of partial O-acylation of the dFuCS on their anticoagulant potency was not significant and the O-acylation of 2-OH groups of 4-O-sulfated fucose units did not affect the anticoagulant activity. PMID- 23015768 TI - Briareolate esters from the gorgonian Briareum asbestinum. AB - Two new briarane diterpenoids briareolate esters J (1) and K (2) were isolated from the methanolic extract of the octocoral Briareum asbestinum collected off the coast of Boca Raton, Florida. The structures of briaranes 1 and 2 were elucidated by interpretation of spectroscopic data. Briareolate ester K (2) showed weak growth inhibition activity against human embryonic stem cells (BG02). PMID- 23015769 TI - Glycosides from marine sponges (Porifera, Demospongiae): structures, taxonomical distribution, biological activities and biological roles. AB - Literature data about glycosides from sponges (Porifera, Demospongiae) are reviewed. Structural diversity, biological activities, taxonomic distribution and biological functions of these natural products are discussed. PMID- 23015770 TI - Evaluation of pseudopteroxazole and pseudopterosin derivatives against Mycobacterium tuberculosis and other pathogens. AB - Pseudopterosins and pseudopteroxazole are intriguing marine natural products that possess notable antimicrobial activity with a commensurate lack of cytotoxicity. New semi-synthetic pseudopteroxazoles, pseudopteroquinoxalines and pseudopterosin congeners along with simple synthetic mimics of the terpene skeleton were synthesized. In order to build structure-activity relationships, a set of 29 new and previously reported compounds was assessed for in vitro antimicrobial and cytotoxic activities. A number of congeners exhibited antimicrobial activity against a range of Gram-positive bacteria including Mycobacterium tuberculosis H37Rv, with four displaying notable antitubercular activity against both replicating and non-replicating persistent forms of M. tuberculosis. One new semi synthetic compound, 21-((1H-imidazol-5-yl)methyl)-pseudopteroxazole (7a), was more potent than the natural products pseudopterosin and pseudopteroxazole and exhibited equipotent activity against both replicating and non-replicating persistent forms of M.tuberculosis with a near absence of in vitro cytotoxicity. Pseudopteroxazole also exhibited activity against strains of M. tuberculosis H37Rv resistant to six clinically used antibiotics. PMID- 23015771 TI - Gene sequence based clustering assists in dereplication of Pseudoalteromonas luteoviolacea strains with identical inhibitory activity and antibiotic production. AB - Some microbial species are chemically homogenous, and the same secondary metabolites are found in all strains. In contrast, we previously found that five strains of P. luteoviolacea were closely related by 16S rRNA gene sequence but produced two different antibiotic profiles. The purpose of the present study was to determine whether such bioactivity differences could be linked to genotypes allowing methods from phylogenetic analysis to aid in selection of strains for biodiscovery. Thirteen P. luteoviolacea strains divided into three chemotypes based on production of known antibiotics and four antibacterial profiles based on inhibition assays against Vibrio anguillarum and Staphylococcus aureus. To determine whether chemotype and inhibition profile are reflected by phylogenetic clustering we sequenced 16S rRNA, gyrB and recA genes. Clustering based on 16S rRNA gene sequences alone showed little correlation to chemotypes and inhibition profiles, while clustering based on concatenated 16S rRNA, gyrB, and recA gene sequences resulted in three clusters, two of which uniformly consisted of strains of identical chemotype and inhibition profile. A major time sink in natural products discovery is the effort spent rediscovering known compounds, and this study indicates that phylogeny clustering of bioactive species has the potential to be a useful dereplication tool in biodiscovery efforts. PMID- 23015772 TI - Natural products from Antarctic colonial ascidians of the genera Aplidium and Synoicum: variability and defensive role. AB - Ascidians have developed multiple defensive strategies mostly related to physical, nutritional or chemical properties of the tunic. One of such is chemical defense based on secondary metabolites. We analyzed a series of colonial Antarctic ascidians from deep-water collections belonging to the genera Aplidium and Synoicum to evaluate the incidence of organic deterrents and their variability. The ether fractions from 15 samples including specimens of the species A. falklandicum, A. fuegiense, A. meridianum, A. millari and S. adareanum were subjected to feeding assays towards two relevant sympatric predators: the starfish Odontaster validus, and the amphipod Cheirimedon femoratus. All samples revealed repellency. Nonetheless, some colonies concentrated defensive chemicals in internal body-regions rather than in the tunic. Four ascidian-derived meroterpenoids, rossinones B and the three derivatives 2,3-epoxy-rossinone B, 3 epi-rossinone B, 5,6-epoxy-rossinone B, and the indole alkaloids meridianins A-G, along with other minoritary meridianin compounds were isolated from several samples. Some purified metabolites were tested in feeding assays exhibiting potent unpalatabilities, thus revealing their role in predation avoidance. Ascidian extracts and purified compound-fractions were further assessed in antibacterial tests against a marine Antarctic bacterium. Only the meridianins showed inhibition activity, demonstrating a multifunctional defensive role. According to their occurrence in nature and within our colonial specimens, the possible origin of both types of metabolites is discussed. PMID- 23015773 TI - The transcriptome of Bathymodiolus azoricus gill reveals expression of genes from endosymbionts and free-living deep-sea bacteria. AB - Deep-sea environments are largely unexplored habitats where a surprising number of species may be found in large communities, thriving regardless of the darkness, extreme cold, and high pressure. Their unique geochemical features result in reducing environments rich in methane and sulfides, sustaining complex chemosynthetic ecosystems that represent one of the most surprising findings in oceans in the last 40 years. The deep-sea Lucky Strike hydrothermal vent field, located in the Mid Atlantic Ridge, is home to large vent mussel communities where Bathymodiolus azoricus represents the dominant faunal biomass, owing its survival to symbiotic associations with methylotrophic or methanotrophic and thiotrophic bacteria. The recent transcriptome sequencing and analysis of gill tissues from B. azoricus revealed a number of genes of bacterial origin, hereby analyzed to provide a functional insight into the gill microbial community. The transcripts supported a metabolically active microbiome and a variety of mechanisms and pathways, evidencing also the sulfur and methane metabolisms. Taxonomic affiliation of transcripts and 16S rRNA community profiling revealed a microbial community dominated by thiotrophic and methanotrophic endosymbionts of B. azoricus and the presence of a Sulfurovum-like epsilonbacterium. PMID- 23015774 TI - Scavenging capacity of marine carotenoids against reactive oxygen and nitrogen species in a membrane-mimicking system. AB - Carotenoid intake has been associated with the decrease of the incidence of some chronic diseases by minimizing the in vivo oxidative damages induced by reactive oxygen (ROS) and nitrogen species (RNS). The carotenoids are well-known singlet oxygen quenchers; however, their capacity to scavenge other reactive species, such as peroxyl radical (ROO*, hydroxyl radical (HO*), hypochlorous acid (HOCl) and anion peroxynitrite (ONOO-), still needs to be more extensively studied, especially using membrane-mimicking systems, such as liposomes. Moreover, the identification of carotenoids possessing high antioxidant capacity can lead to new alternatives of drugs or nutritional supplements for prophylaxis or therapy of pathological conditions related to oxidative damages, such as cardiovascular diseases. The capacity to scavenge ROO*, HO*, HOCl and ONOO- of seven carotenoids found in marine organisms was determined in liposomes based on the fluorescence loss of a fluorescent lipid (C11-BODIPY581/591) due to its oxidation by these reactive species. The carotenoid-bearing hydroxyl groups were generally more potent ROS scavengers than the carotenes, whilst beta-carotene was the most efficient ONOO- scavenger. The role of astaxanthin as an antioxidant should be highlighted, since it was a more potent scavenger of ROO*, HOCl and ONOO- than alpha-tocopherol. PMID- 23015775 TI - Chemistry of the nudibranch Aldisa andersoni: structure and biological activity of phorbazole metabolites. AB - The first chemical study of the Indo-Pacific dorid nudibranch Aldisa andersoni resulted in the isolation of five chlorinated phenyl-pyrrolyloxazoles belonging to the phorbazole series. Two new molecules, 9-chloro-phorbazole D and N1-methyl phorbazole A, co-occurring with known phorbazoles A, B and D, have been characterized. Phorbazoles were found to be present mainly in the external part of the mollusc. The structures of the new compounds were determined by interpretation of spectroscopic data, mainly NMR and mass spectrometry and by comparison with the literature data. Evaluation of feeding-deterrence activity as well as in vitro growth inhibitory properties in human cancer cells was also carried out. PMID- 23015777 TI - Pardaxin, a fish antimicrobial peptide, exhibits antitumor activity toward murine fibrosarcoma in vitro and in vivo. AB - The antitumor activity of pardaxin, a fish antimicrobial peptide, has not been previously examined in in vitro and in vivo systems for treating murine fibrosarcoma. In this study, the antitumor activity of synthetic pardaxin was tested using murine MN-11 tumor cells as the study model. We show that pardaxin inhibits the proliferation of MN-11 cells and reduces colony formation in a soft agar assay. Transmission electron microscopy (TEM) showed that pardaxin altered the membrane structure similar to what a lytic peptide does, and also produced apoptotic features, such as hollow mitochondria, nuclear condensation, and disrupted cell membranes. A qRT-PCR and ELISA showed that pardaxin induced apoptosis, activated caspase-7 and interleukin (IL)-7r, and downregulated caspase 9, ATF 3, SOCS3, STAT3, cathelicidin, p65, and interferon (IFN)-gamma suggesting that pardaxin induces apoptosis through the death receptor/nuclear factor (NF) kappaB signaling pathway after 14 days of treatment in tumor-bearing mice. An antitumor effect was observed when pardaxin (25 mg/kg; 0.5 mg/day) was used to treat mice for 14 days, which caused significant inhibition of MN-11 cell growth in mice. Overall, these results indicate that pardaxin has the potential to be a novel therapeutic agent to treat fibrosarcomas. PMID- 23015776 TI - Sea anemone (Cnidaria, Anthozoa, Actiniaria) toxins: an overview. AB - The Cnidaria phylum includes organisms that are among the most venomous animals. The Anthozoa class includes sea anemones, hard corals, soft corals and sea pens. The composition of cnidarian venoms is not known in detail, but they appear to contain a variety of compounds. Currently around 250 of those compounds have been identified (peptides, proteins, enzymes and proteinase inhibitors) and non proteinaceous substances (purines, quaternary ammonium compounds, biogenic amines and betaines), but very few genes encoding toxins were described and only a few related protein three-dimensional structures are available. Toxins are used for prey acquisition, but also to deter potential predators (with neurotoxicity and cardiotoxicity effects) and even to fight territorial disputes. Cnidaria toxins have been identified on the nematocysts located on the tentacles, acrorhagi and acontia, and in the mucous coat that covers the animal body. Sea anemone toxins comprise mainly proteins and peptides that are cytolytic or neurotoxic with its potency varying with the structure and site of action and are efficient in targeting different animals, such as insects, crustaceans and vertebrates. Sea anemones toxins include voltage-gated Na+ and K+ channels toxins, acid-sensing ion channel toxins, Cytolysins, toxins with Kunitz-type protease inhibitors activity and toxins with Phospholipase A2 activity. In this review we assessed the phylogentic relationships of sea anemone toxins, characterized such toxins, the genes encoding them and the toxins three-dimensional structures, further providing a state-of-the-art description of the procedures involved in the isolation and purification of bioactive toxins. PMID- 23015778 TI - Metabolomic analyses of blood plasma after oral administration of D-glucosamine hydrochloride to dogs. AB - D-Glucosamine hydrochloride (GlcN?HCl) is an endogenous amino monosaccharide synthesized from glucose that is useful in the treatment of joint diseases in both humans and animals. The aim of this study was to examine amino acid metabolism in dogs after oral administration of GlcN?HCl. Accelerated fumarate respiration and elevated plasma levels of lactic acid and alanine were observed after administration. These results suggest that oral administration of GlcN?HCl induces anaerobic respiration and starvation in cells, and we hypothesize that these conditions promote cartilage regeneration. Further studies are required to evaluate the expression of transforming growth factor-beta (TGF-beta). PMID- 23015779 TI - Induction of apoptosis by 11-dehydrosinulariolide via mitochondrial dysregulation and ER stress pathways in human melanoma cells. AB - In this study the isolated compound 11-dehydrosinulariolide from soft coral Sinularia leptoclados possessed anti-proliferative, anti-migratory and apoptosis inducing activities against A2058 melanoma cells. Anti-tumor effects of 11 dehydrosinulariolide were determined by MTT assay, cell migration assay and flow cytometry. Growth and migration of melanoma cells were dose-dependently inhibited by 2-8 MUg/mL 11-dehydrosinulariolide. Flow cytometric data indicated that 11 dehydrosinulariolide induces both early and late apoptosis in melanoma cells. It was found that the apoptosis induced by 11-dehydrosinulariolide is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by loss of mitochondrial membrane potential (?Psim), release of cytochrome C, activation of caspase-3/-9 and Bax as well as suppression of Bcl-2/Bcl-xL. The cleavage of PARP-1 suggested partial involvement of caspase-independent pathways. Immunoblotting data displayed up-regulations of PERK/eIF2alpha/ATF4/CHOP and ATF6/CHOP coupling with elevation of ER stress chaperones GRP78, GRP94, calnexin, calreticulin and PDI, implicating the involvement of these factors in ER stress mediated apoptosis induced by 11-dehydrosinulariolide. The abolishment of apoptotic events after pre-treatment with salubrinal indicated that ER stress mediated apoptosis is also induced by 11-dehydrosinulariolide against melanoma cells. The data in this study suggest that 11-dehydrosinulariolide potentially induces apoptosis against melanoma cells via mitochondrial dysregulation and ER stress pathways. PMID- 23015781 TI - Functional adaptation of cortical interneurons to attenuated activity is subtype specific. AB - Functional neuronal homeostasis has been studied in a variety of model systems and contexts. Many studies have shown that there are a number of changes that can be activated within individual cells or networks in order to compensate for perturbations or changes in levels of activity. Dissociating the cell autonomous from the network-mediated events has been complicated due to the difficulty of sparsely targeting specific populations of neurons in vivo. Here, we make use of a recent in vivo approach we developed that allows for the sparse labeling and manipulation of activity within superficial caudal ganglionic eminence (CGE) derived GABAergic interneurons. Expression of the inward rectifying potassium channel Kir2.1 cell-autonomously reduced neuronal activity and lead to specific developmental changes in their intrinsic electrophysiological properties and the synaptic input they received. In contrast to previous studies on homeostatic scaling of pyramidal cells, we did not detect any of the typically observed compensatory mechanisms in these interneurons. Rather, we instead saw a specific alteration of the kinetics of excitatory synaptic events within the reelin expressing subpopulation of interneurons. These results provide the first in vivo observations for the capacity of interneurons to cell-autonomously regulate their excitability. PMID- 23015780 TI - Multiple embryonic origins of nitric oxide synthase-expressing GABAergic neurons of the neocortex. AB - CORTICAL GABAERGIC INTERNEURONS IN RODENTS ORIGINATE IN THREE SUBCORTICAL REGIONS: the medial ganglionic eminence (MGE), the lateral/caudal ganglionic eminence (LGE/CGE), and the preoptic area (POA). Each of these neuroepithelial precursor domains contributes different interneuron subtypes to the cortex. Neuronal NOS (nNOS)-expressing neurons represent a heterogenous population of cortical interneurons. We examined the development of these cells in the mouse embryonic cortex and their abundance and distribution in adult animals. Using genetic lineage tracing in transgenic mice we find that nNOS type I cells originate only in the MGE whereas type II cells have a triple origin in the MGE, LGE/CGE, and POA. The two populations are born at different times during development, occupy different layers in the adult cortex and have distinct neurochemical profiles. nNOS neurons are more numerous in the adult cortex than previously reported and constitute a significant proportion of the cortical interneuron population. Our data suggest that the heterogeneity of nNOS neurons in the cortex can be attributed to their multiple embryonic origins which likely impose distinct genetic specification programs. PMID- 23015782 TI - Evaluation of pattern recognition and feature extraction methods in ADHD prediction. AB - Attention Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder, being one of the most prevalent psychiatric disorders in childhood. The neural substrates associated with this condition, both from structural and functional perspectives, are not yet well established. Recent studies have highlighted the relevance of neuroimaging not only to provide a more solid understanding about the disorder but also for possible clinical support. The ADHD-200 Consortium organized the ADHD-200 global competition making publicly available, hundreds of structural magnetic resonance imaging (MRI) and functional MRI (fMRI) datasets of both ADHD patients and typically developing (TD) controls for research use. In the current study, we evaluate the predictive power of a set of three different feature extraction methods and 10 different pattern recognition methods. The features tested were regional homogeneity (ReHo), amplitude of low frequency fluctuations (ALFF), and independent components analysis maps (resting state networks; RSN). Our findings suggest that the combination ALFF+ReHo maps contain relevant information to discriminate ADHD patients from TD controls, but with limited accuracy. All classifiers provided almost the same performance in this case. In addition, the combination ALFF+ReHo+RSN was relevant in combined vs. inattentive ADHD classification, achieving a score accuracy of 67%. In this latter case, the performances of the classifiers were not equivalent and L2 regularized logistic regression (both in primal and dual space) provided the most accurate predictions. The analysis of brain regions containing most discriminative information suggested that in both classifications (ADHD vs. TD controls and combined vs. inattentive), the relevant information is not confined only to a small set of regions but it is spatially distributed across the whole brain. PMID- 23015783 TI - A quantitative philology of introspection. AB - The cultural evolution of introspective thought has been recognized to undergo a drastic change during the middle of the first millennium BC. This period, known as the "Axial Age," saw the birth of religions and philosophies still alive in modern culture, as well as the transition from orality to literacy-which led to the hypothesis of a link between introspection and literacy. Here we set out to examine the evolution of introspection in the Axial Age, studying the cultural record of the Greco-Roman and Judeo-Christian literary traditions. Using a statistical measure of semantic similarity, we identify a single "arrow of time" in the Old and New Testaments of the Bible, and a more complex non-monotonic dynamics in the Greco-Roman tradition reflecting the rise and fall of the respective societies. A comparable analysis of the twentieth century cultural record shows a steady increase in the incidence of introspective topics, punctuated by abrupt declines during and preceding the First and Second World Wars. Our results show that (a) it is possible to devise a consistent metric to quantify the history of a high-level concept such as introspection, cementing the path for a new quantitative philology and (b) to the extent that it is captured in the cultural record, the increased ability of human thought for self reflection that the Axial Age brought about is still heavily determined by societal contingencies beyond the orality-literacy nexus. PMID- 23015784 TI - Brain regions associated with the acquisition of conditioned place preference for cocaine vs. social interaction. AB - Positive social interaction could play an essential role in switching the preference of the substance dependent individual away from drug related activities. We have previously shown that conditioned place preference (CPP) for cocaine at the dose of 15 mg/kg and CPP for four 15-min episodes of social interaction were equally strong when rats were concurrently conditioned for place preference by pairing cocaine with one compartment and social interaction with the other. The aim of the present study was to investigate the differential activation of brain regions related to the reward circuitry after acquisition/expression of cocaine CPP or social interaction CPP. Our findings indicate that cocaine CPP and social interaction CPP activated almost the same brain regions. However, the granular insular cortex and the dorsal part of the agranular insular cortex were more activated after cocaine CPP, whereas the prelimbic cortex and the core subregion of the nucleus accumbens were more activated after social interaction CPP. These results suggest that the insular cortex appears to be potently activated after drug conditioning learning while activation of the prelimbic cortex-nucleus accumbens core projection seems to be preferentially involved in the conditioning to non-drug stimuli such as social interaction. PMID- 23015785 TI - Learning on Jupiter, learning on the Moon: the dark side of the G-force. Effects of gravity changes on neurovascular unit and modulation of learning and memory. AB - On earth, gravity vector conditions the development of all living beings by physically imposing an axis along which to build their organism. Thus, during their whole life, they have to fight against this force not only to maintain their architectural organization but also to coordinate the communication between organs and keep their physiology in a balanced steady-state. In space, astronauts show physiological, psychological, and cognitive deregulations, ranging from bone decalcification or decrease of musculature, to depressive-like disorders, and spatial disorientation. Nonetheless, they are confronted to a great amount of physical changes in their environment such as solar radiations, loss of light dark cycle, lack of spatial landmarks, confinement, and obviously a dramatic decrease of gravity force. It is thus very hard to selectively discriminate the strict role of gravity level alterations on physiological, and particularly cerebral, dysfunction. To this purpose, it is important to design autonomous models and apparatuses for behavioral phenotyping utilizable under modified gravity environments. Our team actually aims at working on this area of research. PMID- 23015787 TI - Socio-economic factors related to moral reasoning in childhood and adolescence: the missing link between brain and behavior. AB - Neuroscientific and psychological research on moral development has until now developed independently, referring to distinct theoretical models, contents, and methods. In particular, the influence of socio-economic and cultural factors on morality has been broadly investigated by psychologists but as yet has not been investigated by neuroscientists. The value of bridging these two areas both theoretically and methodologically has, however, been suggested. This study aims at providing a first connection between neuroscientific and psychological literature on morality by investigating whether socio-economic dimensions, i.e., living socio-geographic/economic area, immigrant status and socio-economic status (SES), affect moral reasoning as operationalized in moral domain theory (a seminal approach in psychological studies on morality) and in Greene et al. (2001) perspective (one of the main approaches in neuroethics research). Participants were 81 primary school (M = 8.98 years; SD = 0.39), 72 middle school (M = 12.14 years; SD = 0.61), and 73 high school (M = 15.10 years; SD = 0.38) students from rural and urban areas. Participants' immigrant status (native vs. immigrant) and family SES level were recorded. Moral reasoning was assessed by means of a series of personal and impersonal dilemmas based on Greene et al. (2001) neuroimaging experiment and a series of moral and socio-conventional rule dilemmas based on the moral domain theory. Living socio-geographic/economic area, immigrant status and SES mainly affected evaluations of moral and, to a higher extent, socio-conventional dilemmas, but had no impact on judgment of personal and impersonal dilemmas. Results are mainly discussed from the angle of possible theoretical links and suggestions emerging for studies on moral reasoning in the frameworks of neuroscience and psychology. PMID- 23015788 TI - Event-related potential alterations in fragile X syndrome. AB - Fragile X Syndrome (FXS) is the most common form of X-linked intellectual disability (ID), associated with a wide range of cognitive and behavioral impairments. FXS is caused by a trinucleotide repeat expansion in the FMR1 gene located on the X-chromosome. FMR1 is expected to prevent the expression of the "fragile X mental retardation protein (FMRP)", which results in altered structural and functional development of the synapse, including a loss of synaptic plasticity. This review aims to unveil the contribution of electrophysiological signal studies for the understanding of the information processing impairments in FXS patients. We discuss relevant event-related potential (ERP) studies conducted with full mutation FXS patients and clinical populations sharing symptoms with FXS in a developmental perspective. Specific deviances found in FXS ERP profiles are described. Alterations are reported in N1, P2, Mismatch Negativity (MMN), N2, and P3 components in FXS compared to healthy controls. Particularly, deviances in N1 and P2 amplitude seem to be specific to FXS. The presented results suggest a cascade of impaired information processes that are in line with symptoms and anatomical findings in FXS. PMID- 23015789 TI - Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias. AB - Cardiac arrhythmias are a major cause of morbidity and mortality. In younger patients, the majority of sudden cardiac deaths have an underlying Mendelian genetic cause. Over the last 15 years, enormous progress has been made in identifying the distinct clinical phenotypes and in studying the basic cellular and genetic mechanisms associated with the primary Mendelian (monogenic) arrhythmia syndromes. Investigation of the electrophysiological consequences of an ion channel mutation is ideally done in the native cardiomyocyte (CM) environment. However, the majority of such studies so far have relied on heterologous expression systems in which single ion channel genes are expressed in non-cardiac cells. In some cases, transgenic mouse models have been generated, but these also have significant shortcomings, primarily related to species differences. The discovery that somatic cells can be reprogrammed to pluripotency as induced pluripotent stem cells (iPSC) has generated much interest since it presents an opportunity to generate patient- and disease-specific cell lines from which normal and diseased human CMs can be obtained These genetically diverse human model systems can be studied in vitro and used to decipher mechanisms of disease and identify strategies and reagents for new therapies. Here, we review the present state of the art with respect to cardiac disease models already generated using IPSC technology and which have been (partially) characterized. Human iPSC (hiPSC) models have been described for the cardiac arrhythmia syndromes, including LQT1, LQT2, LQT3-Brugada Syndrome, LQT8/Timothy syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). In most cases, the hiPSC-derived cardiomyoctes recapitulate the disease phenotype and have already provided opportunities for novel insight into cardiac pathophysiology. It is expected that the lines will be useful in the development of pharmacological agents for the management of these disorders. PMID- 23015790 TI - Impact of new electrocardiographic criteria in arrhythmogenic cardiomyopathy. AB - Arrhythmogenic cardiomyopathy (AC) has originally been described as a disorder characterized by fibrofatty replacement of the myocardium, primarily of the right ventricle (RV), and ventricular tachyarrhythmias, sudden death, and at a late stage progressive heart failure. Arrhythmogenic right ventricular dysplasia or cardiomyopathy (ARVD/C) was the previous name of the disease. However, similar histopathologic changes are also found in the left ventricle (LV). AC is also considered a hereditary disease. Recent molecular genetic studies provide accumulating evidence that fibrofatty replacement is preceded by mutation-related desmosomal changes. Desmosomal dysfunction may lead to mechanical and thereafter electrical uncoupling, ultimately resulting in conduction delay. This activation delay and conduction block, provide a substrate for re-entrant mechanisms and thereby ventricular tachycardia (VT). The gold standard for AC diagnosis is demonstration of transmural fibrofatty replacement in cardiac tissue obtained by autopsy or surgery. To facilitate diagnosis in clinical practice, an international Task Force defined in 1994 a set of criteria (TFC) based on electrocardiographic, functional and morphologic features, and family history. These criteria have recently been revised. Routine 12-lead electrocardiography is one of the most important tools for AC diagnosis in all stages of the disease. Even in the absence of other markers in the early concealed stage of the disease, in line with early slow conduction and electrical uncoupling ECG analysis may contribute to early diagnosis. Activation delay and site of origin of VT are reflected in various characteristics of the surface 12-lead electrocardiogram. Since the ECG is easy to obtain, this technique is particularly useful, for both diagnosis and follow up of disease progression. PMID- 23015786 TI - The extended fronto-striatal model of obsessive compulsive disorder: convergence from event-related potentials, neuropsychology and neuroimaging. AB - In this work, we explored convergent evidence supporting the fronto-striatal model of obsessive-compulsive disorder (FSMOCD) and the contribution of event related potential (ERP) studies to this model. First, we considered minor modifications to the FSMOCD model based on neuroimaging and neuropsychological data. We noted the brain areas most affected in this disorder -anterior cingulate cortex (ACC), basal ganglia (BG), and orbito-frontal cortex (OFC) and their related cognitive functions, such as monitoring and inhibition. Then, we assessed the ERPs that are directly related to the FSMOCD, including the error-related negativity (ERN), N200, and P600. Several OCD studies present enhanced ERN and N2 responses during conflict tasks as well as an enhanced P600 during working memory (WM) tasks. Evidence from ERP studies (especially regarding ERN and N200 amplitude enhancement), neuroimaging and neuropsychological findings suggests abnormal activity in the OFC, ACC, and BG in OCD patients. Moreover, additional findings from these analyses suggest dorsolateral prefrontal and parietal cortex involvement, which might be related to executive function (EF) deficits. Thus, these convergent results suggest the existence of a self-monitoring imbalance involving inhibitory deficits and executive dysfunctions. OCD patients present an impaired ability to monitor, control, and inhibit intrusive thoughts, urges, feelings, and behaviors. In the current model, this imbalance is triggered by an excitatory role of the BG (associated with cognitive or motor actions without volitional control) and inhibitory activity of the OFC as well as excessive monitoring of the ACC to block excitatory impulses. This imbalance would interact with the reduced activation of the parietal-DLPC network, leading to executive dysfunction. ERP research may provide further insight regarding the temporal dynamics of action monitoring and executive functioning in OCD. PMID- 23015793 TI - How Noisy is Lexical Decision? AB - Lexical decision is one of the most frequently used tasks in word recognition research. Theoretical conclusions are typically derived from a linear model on the reaction times (RTs) of correct word trials only (e.g., linear regression and ANOVA). Although these models estimate random measurement error for RTs, considering only correct trials implicitly assumes that word/non-word categorizations are without noise: words receive a yes-response because they have been recognized, and they receive a no-response when they are not known. Hence, when participants are presented with the same stimuli on two separate occasions, they are expected to give the same response. We demonstrate that this not true and that responses in a lexical decision task suffer from inconsistency in participants' response choice, meaning that RTs of "correct" word responses include RTs of trials on which participants did not recognize the stimulus. We obtained estimates of this internal noise using established methods from sensory psychophysics (Burgess and Colborne, 1988). The results show similar noise values as in typical psychophysical signal detection experiments when sensitivity and response bias are taken into account (Neri, 2010). These estimates imply that, with an optimal choice model, only 83-91% of the response choices can be explained (i.e., can be used to derive theoretical conclusions). For word responses, word frequencies below 10 per million yield alarmingly low percentages of consistent responses (near 50%). The same analysis can be applied to RTs, yielding noise estimates about three times higher. Correspondingly, the estimated amount of consistent trial-level variance in RTs is only 8%. These figures are especially relevant given the recent popularity of trial-level lexical decision models using the linear mixed-effects approach (e.g., Baayen et al., 2008). PMID- 23015791 TI - Polyunsaturated Fatty acids in atrial fibrillation: looking for the proper candidates. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice with growing prevalence in developed countries. Several medical and interventional therapies, such as atrial specific drugs and pulmonary vein isolation, have demonstrated prevention of recurrences. However, their suboptimal long-term success and significant rate of secondary effects have led to intensive research in the last decade focused on novel alternative and supplemental therapies. One such candidate is polyunsaturated fatty acids (PUFAs). Because of their biological properties, safety, simplicity, and relatively cheap cost, there is a special clinical interest in omega-3 PUFAs as a possible antiarrhythmic agent. Obtained from diets rich in fish, they represent one of the current supplemental therapies. At the cellular level, an increasing body of evidence has shown that n-3 PUFAs exert a variety of effects on cardiac ion channels, membrane dynamic properties, inflammatory cascade, and other targets related to AF prevention. In this article, we review the current basic and clinical evidence pertinent to n-3 PUFAs in AF treatment and prevention. We also discuss controversial outcomes among clinical studies and propose specific subsets of AF patients who will benefit most from n-3 PUFAs. PMID- 23015794 TI - Framing attention in Japanese and american comics: cross-cultural differences in attentional structure. AB - Research on visual attention has shown that Americans tend to focus more on focal objects of a scene while Asians attend to the surrounding environment. The panels of comic books - the narrative frames in sequential images - highlight aspects of a scene comparably to how attention becomes focused on parts of a spatial array. Thus, we compared panels from American and Japanese comics to explore cross cultural cognition beyond behavioral experimentation by looking at the expressive mediums produced by individuals from these cultures. This study compared the panels of two genres of American comics (Independent and Mainstream comics) with mainstream Japanese "manga" to examine how different cultures and genres direct attention through the framing of figures and scenes in comic panels. Both genres of American comics focused on whole scenes as much as individual characters, while Japanese manga individuated characters and parts of scenes. We argue that this framing of space from American and Japanese comic books simulate a viewer's integration of a visual scene, and is consistent with the research showing cross cultural differences in the direction of attention. PMID- 23015792 TI - Finite-Element Model Predicts Current Density Distribution for Clinical Applications of tDCS and tACS. AB - Transcranial direct current stimulation (tDCS) has been applied in numerous scientific studies over the past decade. However, the possibility to apply tDCS in therapy of neuropsychiatric disorders is still debated. While transcranial magnetic stimulation (TMS) has been approved for treatment of major depression in the United States by the Food and Drug Administration (FDA), tDCS is not as widely accepted. One of the criticisms against tDCS is the lack of spatial specificity. Focality is limited by the electrode size (35 cm(2) are commonly used) and the bipolar arrangement. However, a current flow through the head directly from anode to cathode is an outdated view. Finite-element (FE) models have recently been used to predict the exact current flow during tDCS. These simulations have demonstrated that the current flow depends on tissue shape and conductivity. To face the challenge to predict the location, magnitude, and direction of the current flow induced by tDCS and transcranial alternating current stimulation (tACS), we used a refined realistic FE modeling approach. With respect to the literature on clinical tDCS and tACS, we analyzed two common setups for the location of the stimulation electrodes which target the frontal lobe and the occipital lobe, respectively. We compared lateral and medial electrode configuration with regard to their usability. We were able to demonstrate that the lateral configurations yielded more focused stimulation areas as well as higher current intensities in the target areas. The high resolution of our simulation allows one to combine the modeled current flow with the knowledge of neuronal orientation to predict the consequences of tDCS and tACS. Our results not only offer a basis for a deeper understanding of the stimulation sites currently in use for clinical applications but also offer a better interpretation of observed effects. PMID- 23015795 TI - Model-based analysis of context-specific cognitive control. AB - Interference resolution is improved for stimuli presented in contexts (e.g., locations) associated with frequent conflict. This phenomenon, the context specific proportion congruent (CSPC) effect, has challenged the traditional juxtaposition of "automatic" and "controlled" processing because it suggests that contextual cues can prime top-down control settings in a bottom-up manner. We recently obtained support for this "priming of control" hypothesis with functional magnetic resonance imaging by showing that CSPC effects are mediated by contextually cued adjustments in processing selectivity. However, an equally plausible explanation is that CSPC effects reflect adjustments in response caution triggered by expectancy violations (i.e., prediction errors) when encountering rare events as compared to common ones (e.g., incongruent trials in a task context associated with infrequent conflict). Here, we applied a quantitative model of choice, the linear ballistic accumulator (LBA), to distil the reaction time and accuracy data from four independent samples that performed a modified flanker task into latent variables representing the psychological processes underlying task-related decision making. We contrasted models which differentially accounted for CSPC effects as arising either from contextually cued shifts in the rate of sensory evidence accumulation ("drift" models) or in the amount of evidence required to reach a decision ("threshold" models). For the majority of the participants, the LBA ascribed CSPC effects to increases in response threshold for contextually infrequent trial types (e.g., congruent trials in the frequent conflict context), suggesting that the phenomenon may reflect more a prediction error-triggered shift in decision criterion rather than enhanced sensory evidence accumulation under conditions of frequent conflict. PMID- 23015796 TI - Intracerebral hemorrhage in the oldest old: a population-based study (vantaa 85+). AB - AIMS: Very elderly subjects represent the fastest growing population in the world. Most of the recent studies on intracerebral hemorrhage (ICH) have been carried out on younger patients and/or preferably using novel radiological techniques. We investigated the prevalence, risk factors, and histopathological characteristics of the ICH in the oldest old. MATERIALS AND METHODS: The brains of 300 autopsied individuals (248 females, 52 males, mean age at death 92.4 +/- 3.7 years) were investigated as part of the prospective population-based Vantaa 85+ study. After macroscopic investigation, the presence and extent of microscopic brain hemorrhages (MH) were analyzed by counting the number of iron containing macrophages (siderophages) by Prussian blue staining. Deposits with >5 siderophages were defined as MH+, forming a subgroup of MH. Genotyping of apolipoprotein E (APOE) and the analysis of microscopic (MI) or larger infarctions and cerebral amyloid angiopathy (CAA) were performed using standardized methods. Regression analysis was used to predict the presence of ICH, with and without co-localized CAA, and was adjusted for age at death and gender. RESULTS: The prevalence of macroscopic ICH was 2.3% in total; consisting of 1% large lobar hemorrhage (LH), 1% deep hemorrhage (DH), and 0.3% of subarachnoid hemorrhage (SAH). 62% had MH and 15.3% MH+. All MH+ lesions were found to be >2 mm wide. 55.9% of subjects with MH and 81.2% of those with MH+ showed MH/MH+ and CAA in the same brain region (MHCAA and MH+CAA, respectively). MH was associated with none of the neuropathological or clinical conditions, nor with the APOE carrier status. The subjects with MH+, MHCAA or MH+CAA carried the APOE epsilon4 allele more frequently than controls (OR 3.681, 3.291, 7.522, respectively). Siderophages in MH+CAA co-localized with CAA and with two-thirds of the MI in the tissue sections. CONCLUSION: Macroscopic ICH was rare in the very elderly. MH was frequent and clinically insignificant. MH+ was rare but closely related with the APOE epsilon4 genotype and the presence of severe CAA and infarction. PMID- 23015797 TI - Galvanic vestibular stimulation produces sensations of rotation consistent with activation of semicircular canal afferents. PMID- 23015799 TI - Modified Pediatric ASPECTS Correlates with Infarct Volume in Childhood Arterial Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Larger infarct volume as a percent of supratentorial brain volume (SBV) predicts poor outcome and hemorrhagic transformation in childhood arterial ischemic stroke (AIS). In perinatal AIS, higher scores on a modified pediatric version of the Alberta Stroke Program Early CT Score using acute MRI (modASPECTS) predict later seizure occurrence. The objectives were to establish the relationship of modASPECTS to infarct volume in perinatal and childhood AIS and to establish the interrater reliability of the score. METHODS: We performed a cross sectional study of 31 neonates and 40 children identified from a tertiary care center stroke registry with supratentorial AIS and acute MRI with diffusion weighted imaging (DWI) and T2 axial sequences. Infarct volume was expressed as a percent of SBV using computer-assisted manual segmentation tracings. ModASPECTS was performed on DWI by three independent raters. The modASPECTS were compared among raters and to infarct volume as a percent of SBV. RESULTS: ModASPECTS correlated well with infarct volume. Spearman rank correlation coefficients (rho) for the perinatal and childhood groups were 0.76, p < 0.001 and 0.69, p < 0.001, respectively. Excluding one perinatal and two childhood subjects with multifocal punctate ischemia without large or medium sized vessel stroke, rho for the perinatal and childhood groups were 0.87, p < 0.001 and 0.80, p < 0.001, respectively. The intraclass correlation coefficients for the three raters for the neonates and children were 0.93 [95% confidence interval (CI) 0.89-0.97, p < 0.001] and 0.94 (95% CI 0.91-0.97, p < 0.001), respectively. CONCLUSION: The modified pediatric ASPECTS on acute MRI can be used to estimate infarct volume as a percent of SBV with a high degree of validity and interrater reliability. PMID- 23015800 TI - Benefits of hemicraniectomy seen many years after malignant stroke in a young patient. AB - The benefits of hemicraniectomy for malignant middle cerebral artery (MCA) stroke may not be apparent in the 3- to 6-months in which final outcomes are assessed in research studies. We present the case of a 15-year-old who underwent hemicraniectomy for malignant MCA stroke and was significantly disabled 3 and 6 months after event. Over the long-term she was able to graduate from university, play tennis, and live an independent life. Although functional independence with only minor disability is relatively rare in adult hemicraniectomy patients, this outcome may be more easily achieved in children during a longer period of follow up. PMID- 23015798 TI - Neuropathological sequelae of developmental exposure to antiepileptic and anesthetic drugs. AB - Glutamate (Glu) and gamma-aminobutyric acid (GABA) are major neurotransmitters in the mammalian brain which regulate brain development at molecular, cellular, and systems level. Sedative, anesthetic, and antiepileptic drugs (AEDs) interact with glutamate and GABA receptors to produce their desired effects. The question is posed whether such interference with glutamatergic and GABAergic neurotransmission may exert undesired, and perhaps even detrimental effects on human brain development. Preclinical research in rodents and non-human primates has provided extensive evidence that sedative, anesthetic, and AEDs can trigger suicide of neurons and oligodendroglia, suppress neurogenesis, and inhibit normal synapse development and sculpting. Behavioral correlates in rodents and non-human primates consist of long-lasting cognitive impairment. Retrospective clinical studies in humans exposed to anesthetics or AEDs in utero, during infancy or early childhood have delivered conflicting but concerning results in terms of a correlation between drug exposure and impaired neurodevelopmental outcomes. Prospective studies are currently ongoing. This review provides a short overview of the current state of knowledge on this topic. PMID- 23015801 TI - A Locus Identified on Chromosome18P11.31 is Associated with Hippocampal Abnormalities in a Family with Mesial Temporal Lobe Epilepsy. AB - We aimed to identify the region harboring a putative candidate gene associated with hippocampal abnormalities (HAb) in a family with mesial temporal lobe epilepsy (MTLE). Genome-wide scan was performed in one large kindred with MTLE using a total of 332 microsatellite markers at ~12 cM intervals. An additional 13 markers were genotyped in the candidate region. Phenotypic classes were defined according to the presence of hippocampal atrophy and/or hyperintense hippocampal T2 signal detected on magnetic resonance imaging. We identified a significant positive LOD score on chromosome 18p11.31 with a Z(max) of 3.12 at D18S452. Multipoint LOD scores and haplotype analyses localized the candidate locus within a 6-cM interval flanked by D18S976 and D18S967. We present here evidence that HAb, which were previously related mainly to environmental risk factors, may be influenced by genetic predisposition. This finding may have major impact in the study of the mechanisms underlying abnormalities in mesial temporal lobe structures and their relationship with MTLE. PMID- 23015802 TI - Cognitive functions in ataxia with oculomotor apraxia type 2. AB - BACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by cerebellar atrophy, peripheral neuropathy, oculomotor apraxia, and elevated serum alpha-fetoprotein (AFP) levels. The disease is caused by a recessive mutation in the senataxin gene. Since it is a very rare cerebellar disorder, no detailed examination of cognitive functions in AOA2 has been published to date. The aim of the present study was to investigate the neuropsychological profile of a 54-year old patient with AOA2. METHODS: A broad range of neuropsychological examination protocol was administered including the following domains: short-term, working- and episodic-memories, executive functions, implicit sequence learning, and the temporal parameters of speech. RESULTS: The performance on the Listening Span, Letter Fluency, Serial Reaction Time Task, and pause ratio in speech was 2 or more standard deviations (SD) lower compared to controls, and 1 SD lower on Backward Digit Span, Semantic Fluency, articulation rate, and speech tempo. CONCLUSION: These findings indicate that the pathogenesis of the cerebrocerebellar circuit in AOA2 is responsible for the weaker coordination of complex cognitive functions such as working memory, executive functions, speech, and sequence learning. PMID- 23015804 TI - Evidence that Memantine Reduces Chronic Tinnitus Caused by Acoustic Trauma in Rats. AB - Subjective tinnitus is a chronic neurological disorder in which phantom sounds are perceived. Increasing evidence suggests that tinnitus is caused by neuronal hyperactivity in auditory brain regions, either due to a decrease in synaptic inhibition or an increase in synaptic excitation. One drug investigated for the treatment of tinnitus has been the uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, memantine, although the evidence relating to it has been unconvincing to date. We re-investigated the effects of memantine on the behavioral manifestations of tinnitus induced by acoustic trauma (a 16-kHz, 110 dB pure tone presented unilaterally for 1 h) in rats. We used a conditioned lick suppression model in which lick suppression was associated with the perception of high frequency sound resembling tinnitus and a suppression ratio (SR) was calculated by comparing the number of licks in the 15-s period preceding the stimulus presentation (A) and the 15-s period during the stimulus presentation (B), i.e., SR = B/(A + B). Acoustic trauma resulted in a significant increase in the auditory brainstem-evoked response (ABR) threshold in the affected ear (P <= 0.0001) and a decrease in the SR compared to sham controls in response to 32 kHz tones in five out of eight acoustic trauma-exposed animals. A 5-mg/kg dose of memantine significantly reduced the proportion of these animals which exhibited tinnitus-like behavior (2/5 compared to 5/5; P <= 0.006), suggesting that the drug reduced tinnitus. These results suggest that memantine may reduce tinnitus caused by acoustic trauma. PMID- 23015803 TI - Obstructive sleep apnea and type 2 diabetes: is there a link? AB - Type 2 diabetes is a chronic illness that is increasing in epidemic proportions worldwide. Major factors contributing to the development of type 2 diabetes include obesity and poor lifestyle habits (e.g., excess dietary intake and limited physical activity). Despite the proven efficacy of lifestyle interventions and the use of multiple pharmacological agents, the economic and public health burden of type 2 diabetes remains substantial. Obstructive sleep apnea (OSA) is a treatable sleep disorder that is pervasive among overweight and obese adults, who represent about two thirds of the U.S. population today. An ever-growing number of studies have shown that OSA is associated with insulin resistance, glucose intolerance and type 2 diabetes, independent of obesity. Evidence from animal and human models that mimic OSA provides potential mechanisms for how OSA may alter glucose metabolism. Up to 83% of patients with type 2 diabetes suffer from unrecognized OSA and increasing severity of OSA is associated with worsening glucose control. However, it is still unclear whether OSA may lead to the development of diabetes over time. More data from large-scale longitudinal studies with rigorous assessments of diabetes and OSA are needed. In addition, there is still controversy whether continuous positive airway pressure (CPAP) treatment of OSA improves glucose metabolism. Large-scale randomized controlled trials of CPAP treatment of OSA with well-validated assessments of insulin sensitivity and glucose tolerance are needed. These studies may reveal that OSA represents a novel, modifiable risk factor for the development of prediabetes and type 2 diabetes. PMID- 23015805 TI - Variability in the Perception of Informed Consent for IV-tPA during Telestroke Consultation. AB - OBJECTIVE: To study the perception of informed consent among various raters for thrombolysis in acute ischemic stroke patients receiving intravenous tissue plasminogen activator (IV-tPA). METHODS: Twenty randomly selected videotaped telestroke consultations of acute stroke patients administered IV-tPA were retrospectively reviewed. Adequacy of informed consent was reviewed by five raters: a neurologist and emergency physician who routinely treat stroke, a medical risk management paralegal, a bioethicist, and a lay person. Raters assessed the quality of the informed consent presentation by the treating physician and the degree of understanding demonstrated by the patient/family authorizing consent. Factors associated with adequacy of consent were analyzed. RESULTS: Consent was rated as adequately understood by the patient-family in 78.6% cases. Agreement between all five raters with regard to the patient-family understanding of consent was poor and also between the subgroups of non-physician and physician (all k < 0.20). Similarly, the quality of the physician consent process was poor for agreement between all five raters (k = 0.07) or between the subgroup of the three non-physician raters (k = -0.06) and fair between the two physician raters (k = 0.24). The legal reviewer and the bioethicist rated the physician consent process as being of lower quality than did the two physicians and the layperson. CONCLUSION: Despite high variability in the perception of informed consent among raters in this time-sensitive clinical situation, almost 80% of patients were rated by all reviewers as having adequate understanding of risks and benefits of tPA. This suggests the need for a standardized but brief tPA consent process that includes patient/family demonstration of understanding. PMID- 23015806 TI - Cerebral microbleeds on magnetic resonance imaging and anticoagulant-associated intracerebral hemorrhage risk. AB - The increasing use of antithrombotic drugs in an aging population [including anticoagulants to prevent future ischemic stroke in individuals with atrial fibrillation (AF)] has been associated with a dramatic increase in the incidence of intracerebral hemorrhage (ICH) in users of antithrombotic drugs. Several lines of evidence suggest that cerebral small vessel disease (particularly sporadic cerebral amyloid angiopathy) is a risk factor for this rare but devastating complication of these commonly used treatments. Cerebral microbleeds (CMBs) have emerged as a key MRI marker of small vessel disease and a potentially powerful marker of future ICH risk, but adequately powered, high quality prospective studies of CMBs and ICH risk on anticoagulation are not available. Further data are urgently needed to determine how neuroimaging and other biomarkers may contribute to individualized risk prediction to make anticoagulation as safe and effective as possible. In this review we discuss the available evidence on cerebral small vessel disease and CMBs in the context of antithrombotic treatments, especially regarding their role as a predictor of future ICH risk after ischemic stroke, where risk-benefit judgments can be a major challenge for physicians. We will focus on patients with AF because these are frequently treated with anticoagulation. We briefly describe the rationale and design of a new prospective observational inception cohort study (Clinical Relevance of Microbleeds in Stroke; CROMIS-2) which investigates the value of MRI markers of small vessel disease (including CMBs) and genetic factors in assessing the risk of oral anticoagulation-associated ICH. PMID- 23015807 TI - Challenges in O-glycan engineering of plants. AB - Plants are attractive alternative expression hosts for the production of recombinant proteins. Many therapeutic proteins are glycosylated with N- and O glycosylation being the most prevalent forms of protein glycosylation. While N glycans have already been modified in plants toward the formation of homogenous mammalian-type glycoforms with equal or improved biological function compared to mammalian-cell culture produced glycoproteins little attention has been paid to the modification of O-linked glycans. Recently, the first step of mammalian O glycan biosynthesis has been accomplished in plants. However, as outlined in this short review there are important issues that have to be addressed in the future. These include: (i) elimination of potentially immunogenic or allergenic carbohydrate epitopes containing arabinosides or arabinogalactans, (ii) a detailed investigation of the interplay between engineered N- and O-glycosylation pathways to avoid competition for common metabolites like UDP-GlcNAc, and (iii) a deeper understanding of signals and mechanisms for distribution of glycan processing enzymes, which is a prerequisite for complete and homogenous glycosylation of recombinant proteins. PMID- 23015808 TI - Evolution of the Arabidopsis telomerase RNA. AB - The telomerase reverse transcriptase promotes genome integrity by continually synthesizing a short telomere repeat sequence on chromosome ends. Telomerase is a ribonucleoprotein complex whose integral RNA subunit TER contains a template domain with a sequence complementary to the telomere repeat that is reiteratively copied by the catalytic subunit. Although TER harbors well-conserved secondary structure elements, its nucleotide sequence is highly divergent, even among closely related organisms. Thus, it has been extremely challenging to identify TER orthologs by bioinformatics strategies. Recently, TER was reported in the flowering plant, Arabidopsis thaliana. In contrast to other model organisms, A. thaliana encodes two TER subunits, only one of which is required to maintain telomere tracts in vivo. Here we investigate the evolution of the loci that encode TER in Arabidopsis by comparison to the same locus in its close relatives. We employ a combination of PCR and bioinformatics approaches to identify putative TER loci based on syntenic regions flanking the TER1 and TER2 loci of A. thaliana. Unexpectedly, we discovered that the genomic regions encoding the two A. thaliana TERs occur as a single locus in other Brassicaceae. Moreover, we find striking sequence divergence within the telomere template domain of putative TERs from Brassicaceae, including some orthologous loci that completely lack a template domain. Finally, evolution of the locus is characterized by lineage specific events rather than changes shared among closely related species. We conclude that the Arabidopsis TER duplication occurred very recently, and further that changes at this locus in other Brassicaceae indicate the process of TER evolution may be different in plants compared with vertebrates and yeast. PMID- 23015809 TI - Highly specific label-free molecular imaging with spectrally tailored excitation stimulated Raman scattering (STE-SRS) microscopy. AB - Label-free microscopy with chemical contrast and high acquisition speed up to video-rate has recently been made possible by stimulated Raman scattering (SRS) microscopy. While SRS imaging offers superb sensitivity, the spectral specificity of the original narrowband implementation is limited, making distinguishing chemical species with overlapping Raman bands difficult. Here we present a highly specific imaging method that allows mapping of a particular chemical species in the presence of interfering species based on tailored multiplex excitation of its vibrational spectrum. This is done by spectral modulation of a broadband pump beam at a high-frequency (>1MHz), allowing detection of the stimulated Raman gain signal of the narrowband Stokes beam with high sensitivity. Using the scheme, we demonstrate quantification of cholesterol in the presence of lipids, and real time three-dimensional spectral imaging of protein, stearic acid and oleic acid in live C.elegans. PMID- 23015810 TI - Alkoxide-induced ring opening of bicyclic 2-vinylcyclobutanones: A convenient synthesis of 2-vinyl-substituted 3-cycloalkene-1-carboxylic acid esters. AB - The fused 2-vinyl or 2-phenyl substituted cyclobutanones 4 undergo stereoselective ring openings by the action of alkoxide ions (t-BuO(-) or MeO(-)) to produce novel vicinally disubstituted cycloalkene derivatives 5 and 6 in moderate to high yields. The ring cleavage usually occurs with complete regioselectivity. The accessibility of gamma,delta-unsaturated ester or acid derivatives makes this transformation a good supplementary method for the well established Johnson-Claisen rearrangement. PMID- 23015811 TI - Facile isomerization of silyl enol ethers catalyzed by triflic imide and its application to one-pot isomerization-(2 + 2) cycloaddition. AB - A triflic imide (Tf(2)NH) catalyzed isomerization of kinetically favourable silyl enol ethers into thermodynamically stable ones was developed. We also demonstrated a one-pot catalytic reaction consisting of (2 + 2) cycloaddition and isomerization. In the reaction sequence, Tf(2)NH catalyzes both of the reactions. PMID- 23015812 TI - Carbohydrate-auxiliary assisted preparation of enantiopure 1,2-oxazine derivatives and aminopolyols. AB - An approach to enantiopure hydroxylated 2H-1,2-oxazine derivatives is presented utilizing the [3 + 3] cyclisation of lithiated alkoxyallenes and an L-erythrose derived N-glycosyl nitrone as precursors. This key step proceeded only with moderate diastereoselectivity, but allowed entry into both enantiomeric series of the resulting 3,6-dihydro-2H-1,2-oxazines. Their enol ether double bond was then subjected to a hydroboration followed by an oxidative work-up, and finally the auxiliary was removed. The described three-step procedure enabled the synthesis of enantiopure hydroxylated 1,2-oxazines. Typical examples were treated with samarium diiodide leading to enantiopure acyclic aminopolyols. We also report on our attempts to convert these compounds into enantiopure hydroxylated pyrrolidine derivatives. PMID- 23015813 TI - Sonogashira-Hagihara reactions of halogenated glycals. AB - Herein, we report on our findings of the Sonogashira-Hagihara reaction with 1 iodinated and 2-brominated glycals using several aromatic and aliphatic alkynes. This Pd-catalyzed cross-coupling reaction presents a facile access to alkynyl C glycosides and sets the stage for a reductive/oxidative refunctionalization of the enyne moiety to regenerate either C-glycosidic structures or pyran derivatives with a substituent in position 2. PMID- 23015814 TI - Thiophene-based donor-acceptor co-oligomers by copper-catalyzed 1,3-dipolar cycloaddition. AB - Herein we present a three-component one-pot procedure to synthesize co-oligomers of a donor-acceptor-donor type, in which thiophene moieties work as donor and 1,2,3-triazoles as acceptor units. In this respect, terminally ethynylated (oligo)thiophenes were coupled to halogenated (oligo)thiophenes in the presence of sodium azide and a copper catalyst. Optoelectronic properties of various thiophene-1,2,3-triazole co-oligomers were investigated by UV-vis spectroscopy and cyclic voltammetry. Several co-oligomers were electropolymerized to the corresponding conjugated polymers. PMID- 23015815 TI - Synthesis of 2,6-disubstituted tetrahydroazulene derivatives. AB - Synthesis of hydroazulene derivatives has been carried out through a ring enlargement route by using carbene adduct intermediates. The protocol can be applied for the construction of functionalized hydroazulene skeletons as key components of many natural products as well as the core system of novel liquid crystalline materials. PMID- 23015816 TI - Enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes catalyzed by binaphthyl-derived organocatalysts. AB - The highly enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes, promoted by binaphthyl-modified chiral bifunctional organocatalysts is described. This reaction afforded the chiral functionalized naphthoquinones in high yields (81-95%) and excellent enantioselectivities (91-98% ee) under low catalyst loading (1 mol %). PMID- 23015817 TI - Synthesis and antiviral activities of spacer-linked 1-thioglucuronide analogues of glycyrrhizin. AB - The influenza virus infection remains a significant threat to public health and the increase of antiviral resistance to available drugs generates an urgent need for new antiviral compounds. Starting from the natural, antivirally active compound glycyrrhizin, spacer-bridged derivatives were generated with improved antiviral activity against the influenza A virus infection. Simplified analogues of the triterpene saponin glycyrrhizin containing 1-thio-beta-D-glucuronic acid residues have been prepared in good yields by alkylation of 3-amino and 3-thio derivatives of glycyrrhetinic acid with a 2-iodoethyl 1-thio-beta-D glucopyranosiduronate derivative. The spacer-connected 3-amino derivatives were further transformed into N-acetylated and N-succinylated derivatives. The deprotected compounds containing these carboxylic acid appendices mimic the glycon part of glycyrrhizin as well as the hemisuccinate derivative of glycyrrhetinic acid, carbenoxolone. Antiviral activities of the compounds were determined in a biological test based on influenza A virus-infected cells, wherein the 3-(2-thioethyl)-N-acetylamino- and 3-(2-thioethyl)-thio-linked glucuronide derivatives were effective inhibitors with IC(50) values as low as 54 uM. PMID- 23015818 TI - Chemo-enzymatic modification of poly-N-acetyllactosamine (LacNAc) oligomers and N,N-diacetyllactosamine (LacDiNAc) based on galactose oxidase treatment. AB - The importance of glycans in biological systems is highlighted by their various functions in physiological and pathological processes. Many glycan epitopes on glycoproteins and glycolipids are based on N-acetyllactosamine units (LacNAc; Galbeta1,4GlcNAc) and often present on extended poly-LacNAc glycans ([Galbeta1,4GlcNAc](n)). Poly-LacNAc itself has been identified as a binding motif of galectins, an important class of lectins with functions in immune response and tumorigenesis. Therefore, the synthesis of natural and modified poly LacNAc glycans is of specific interest for binding studies with galectins as well as for studies of their possible therapeutic applications. We present the oxidation by galactose oxidase and subsequent chemical or enzymatic modification of terminal galactose and N-acetylgalactosamine residues of poly-N acetyllactosamine (poly-LacNAc) oligomers and N,N-diacetyllactosamine (LacDiNAc) by galactose oxidase. Product formation starting from different poly-LacNAc oligomers was characterised and optimised regarding formation of the C6-aldo product. Further modification of the aldehyde containing glycans, either by chemical conversion or enzymatic elongation, was established. Base-catalysed beta elimination, coupling of biotin-hydrazide with subsequent reduction to the corresponding hydrazine linkage, and coupling by reductive amination to an amino functionalised poly-LacNAc oligomer were performed and the products characterised by LC-MS and NMR analysis. Remarkably, elongation of terminally oxidised poly LacNAc glycans by beta3GlcNAc- and beta4Gal-transferase was also successful. In this way, a set of novel, modified poly-LacNAc oligomers containing terminally and/or internally modified galactose residues were obtained, which can be used for binding studies and various other applications. PMID- 23015819 TI - Synthesis of axially chiral oxazoline-carbene ligands with an N-naphthyl framework and a study of their coordination with AuCl.SMe(2). AB - Axially chiral oxazoline-carbene ligands with an N-naphthyl framework were successfully prepared, and their coordination behavior with AuCl.SMe(2) was also investigated, affording the corresponding Au(I) complexes in moderate to high yields. PMID- 23015820 TI - Synthesis and antifungal properties of papulacandin derivatives. AB - Derivatives of an antifungal agent that targets the beta-(1,3)-D-glucan synthase, papulacandin D, were synthesized and tested for activity. The papulacandin D structure contains a challenging benzannulated spiroketal unit, which is introduced in a palladium-catalyzed cross-coupling reaction of a glycal silanolate and an aryl iodide followed by an oxidative spiroketalization. Four different variants were made, differing in the nature of the acyl side chain with respect to the length, and in the number and stereochemistry of the double bonds. Moderate biological activity was observed for the derivatives with a side chain based on palmitic acid and linoleic acid. PMID- 23015821 TI - Synthesis of functionalized macrocyclic derivatives of trioxabicyclo[3.3.0]nonadiene. AB - C(72)-Macrocyclic systems functionalized with nitroaryl and arylamino groups were synthesized from the bisdioxine diacid dichloride 1,3,5,7-tetra-tert-butyl-2,6,9 trioxabicyclo[3.3.1]nona-3,7-diene-4,8-dicarbonyl dichloride (3). PMID- 23015822 TI - Regioselective chlorination and bromination of unprotected anilines under mild conditions using copper halides in ionic liquids. AB - By using ionic liquids as solvents, the chlorination or bromination of unprotected anilines at the para-position can be achieved in high yields with copper halides under mild conditions, without the need for potentially hazardous operations such as supplementing oxygen or gaseous HCl. PMID- 23015823 TI - Identification and isolation of insecticidal oxazoles from Pseudomonas spp. AB - Two new and five known oxazoles were identified from two different Pseudomonas strains in addition to the known pyrones pseudopyronine A and B. Labeling experiments confirmed their structures and gave initial evidence for a novel biosynthesis pathway of these natural oxazoles. In order to confirm their structure, they were synthesized, which also allowed tests of their bioactivity. Additionally, the bioactivities of the synthesis intermediates were also investigated revealing interesting biological activities for several compounds despite their overall simple structures. PMID- 23015824 TI - Formation of carbohydrate-functionalised polystyrene and glass slides and their analysis by MALDI-TOF MS. AB - Glycans functionalised with hydrophobic trityl groups were synthesised and adsorbed onto polystyrene and glass slides in an array format. The adsorbed glycans could be analysed directly on these minimally conducting surfaces by MALDI-TOF mass spectrometry analysis after aluminium tape was attached to the underside of the slides. Furthermore, the trityl group appeared to act as an internal matrix and no additional matrix was necessary for the MS analysis. Thus, trityl groups can be used as simple hydrophobic, noncovalently linked anchors for ligands on surfaces and at the same time facilitate the in situ mass spectrometric analysis of such ligands. PMID- 23015825 TI - Triterpenoid saponins from the roots of Acanthophyllum gypsophiloides Regel. AB - Two new triterpenoid saponins 1 and 2 were isolated from the methanol extract of the roots of Acanthophyllum gypsophiloides Regel. These saponins have quillaic acid or gypsogenin moieties as an aglycon, and both bear similar sets of two oligosaccharide chains, which are 3-O-linked to the triterpenoid part trisaccharide alpha-L-Arap-(1->3)-[alpha-D-Galp-(1->2)]-beta-D-GlcpA and pentasaccharide beta-D-Xylp-(1->3)-beta-D-Xylp-(1->3)-alpha-L-Rhap-(1->2)-[beta-D Quip-(1->4)]-beta-D-Fucp connected through an ester linkage to C-28. The structures of the obtained saponins were elucidated by a combination of mass spectrometry and 2D NMR spectroscopy. A study of acute toxicity, hemolytic, anti inflammatory, immunoadjuvant and antifungal activity was carried out. Both saponins 1 and 2 were shown to exhibit immunoadjuvant properties within the vaccine composition with keyhole limpet hemocyanin-based immunogen. The availability of saponins 1 and 2 as individual pure compounds from the extract of the roots of A. gypsophiloides makes it a prospective source of immunoactive agents. PMID- 23015826 TI - Synthesis and characterization of a novel carboxyl group containing (co)polyimide with sulfur in the polymer backbone. AB - Soluble functional (co)polyimides are of great interest in the area of separation processes or optical applications, due to their excellent mechanical-, thermal- and optical properties, their superior processability and the ability to adapt their properties to a wide range of special applications. Therefore, two series of novel (co)polyimides containing fluorinated sulfur- and carboxylic acid groups consisting of 4,4'-(hexafluoroisopropylidene)di(phthalic anhydride) (6FDA), 3,5 diaminobenzoic acid (DABA), 4,4'-diaminodiphenylsulfide (4,4'-SDA) and 3,3' diaminodiphenylsulfone (3,3'-DDS) were synthesized in a two-step polycondensation reaction. The synthesized copolymers were characterized by using NMR, FTIR, GPC, and DSC. Furthermore, with regard to processing and potential applications, the thermal stability, solubility in common organic solvents, moisture uptake, and transparency were investigated. Compared to commercially available transparent polymers, i.e., polymethylmethacrylate and cycloolefin polymers, the sulfur (co)polyimides containing carboxyl groups showed much higher glass-transition temperatures, comparably low moisture uptake and high transmission at the sodium D-line. Furthermore, good solubility in commonly used organic solvents makes them very attractive as high-performance coating materials. PMID- 23015827 TI - An easily accessible sulfated saccharide mimetic inhibits in vitro human tumor cell adhesion and angiogenesis of vascular endothelial cells. AB - Oligosaccharides aberrantly expressed on tumor cells influence processes such as cell adhesion and modulation of the cell's microenvironment resulting in an increased malignancy. Schmidt's imidate strategy offers an effective method to synthesize libraries of various oligosaccharide mimetics. With the aim to perturb interactions of tumor cells with extracellular matrix proteins and host cells, molecules with 3,4-bis(hydroxymethyl)furan as core structure were synthesized and screened in biological assays for their abilities to interfere in cell adhesion and other steps of the metastatic cascade, such as tumor-induced angiogenesis.The most active compound, (4-{[(beta-D-galactopyranosyl)oxy]methyl}furan-3-yl)methyl hydrogen sulfate (GSF), inhibited the activation of matrix-metalloproteinase-2 (MMP-2) as well as migration of the human melanoma cells of the lines WM-115 and WM-266-4 in a two-dimensional migration assay. GSF inhibited completely the adhesion of WM-115 cells to the extracellular matrix (ECM) proteins, fibrinogen and fibronectin.In an in vitro angiogenesis assay with human endothelial cells, GSF very effectively inhibited endothelial tubule formation and sprouting of blood vessels, as well as the adhesion of endothelial cells to ECM proteins. GSF was not cytotoxic at biologically active concentrations; neither were 3,4 bis{[(beta-D-galactopyranosyl)oxy]methyl}furan (BGF) nor methyl beta-D galactopyranoside nor 3,4-bis(hydroxymethyl)furan, which were used as controls, eliciting comparable biological activity. In silico modeling experiments, in which binding of GSF to the extracellular domain of the integrin alpha(v)beta(3) was determined, revealed specific docking of GSF to the same binding site as the natural peptidic ligands of this integrin. The sulfate in the molecule coordinated with one manganese ion in the binding site.These studies show that this chemically easily accessible molecule GSF, synthesized in three steps from 3,4-bis(hydroxymethyl)furan and benzoylated galactose imidate, is nontoxic and antagonizes cell physiological processes in vitro that are important for the dissemination and growth of tumor cells in vivo. PMID- 23015829 TI - High-affinity multivalent wheat germ agglutinin ligands by one-pot click reaction. AB - A series of six mono-, di-, and trivalent N,N'-diacetylchitobiose derivatives was conveniently prepared by employing a one-pot procedure for Cu(II)-catalyzed diazo transfer and Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) starting from commercially available amines. These glycoclusters were probed for their binding potencies to the plant lectin wheat germ agglutinin (WGA) from Triticum vulgaris by an enzyme-linked lectin assay (ELLA) employing covalently immobilized N acetylglucosamine (GlcNAc) as a reference ligand. IC(50) values were in the low micromolar/high nanomolar range, depending on the linker between the two disaccharides. Binding enhancements beta up to 1000 for the divalent ligands and 2800 for a trivalent WGA ligand, compared to N,N'-diacetylchitobiose as the corresponding monovalent ligand, were observed. Molecular modeling studies, in which the chitobiose moieties were fitted into crystallographically determined binding sites of WGA, correlate the binding enhancements of the multivalent ligands with their ability to bind to the protein in a chelating mode. The best WGA ligand is a trivalent cluster with an IC(50) value of 220 nM. Calculated per mol of contained chitobiose, this is the best WGA ligand known so far. PMID- 23015830 TI - Recent developments in chemical diversity. PMID- 23015828 TI - Synthetic glycopeptides and glycoproteins with applications in biological research. AB - Over the past few years, synthetic methods for the preparation of complex glycopeptides have been drastically improved. The need for homogenous glycopeptides and glycoproteins with defined chemical structures to study diverse biological phenomena further enhances the development of methodologies. Selected recent advances in synthesis and applications, in which glycopeptides or glycoproteins serve as tools for biological studies, are reviewed. The importance of specific antibodies directed to the glycan part, as well as the peptide backbone has been realized during the development of synthetic glycopeptide-based anti-tumor vaccines. The fine-tuning of native chemical ligation (NCL), expressed protein ligation (EPL), and chemoenzymatic glycosylation techniques have all together enabled the synthesis of functional glycoproteins. The synthesis of structurally defined, complex glycopeptides or glyco-clusters presented on natural peptide backbones, or mimics thereof, offer further possibilities to study protein-binding events. PMID- 23015831 TI - An intramolecular inverse electron demand Diels-Alder approach to annulated alpha carbolines. AB - Intramolecular inverse electron demand cycloadditions of isatin-derived 1,2,4 triazines with acetylenic dienophiles tethered by amidations or transesterifications proceed in excellent yields to produce lactam- or lactone fused alpha-carbolines. Beginning with various isatins and alkynyl dienophiles, a pilot-scale library of eighty-eight alpha-carbolines was prepared by using this robust methodology for biological evaluation. PMID- 23015832 TI - Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors. AB - Sant-75 is a newly identified potent inhibitor of the hedgehog pathway. We designed a diversity-oriented synthesis program, and synthesized a series of Sant 75 analogues, which lays the foundation for further investigation of the structure-activity relationship of this important class of hedgehog-pathway inhibitors. PMID- 23015833 TI - Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds. AB - Two-directional synthesis represents an ideal strategy for the rapid elaboration of simple starting materials and their subsequent transformation into complex molecular architectures. As such, it is becoming recognised as an enabling technology for diversity-oriented synthesis. Herein, we provide a thorough account of our work combining two-directional synthesis with diversity-oriented synthesis, with particular reference to the synthesis of polycyclic alkaloid scaffolds. PMID- 23015834 TI - Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations. AB - We describe the unprecedented formation of six ansamitocin derivatives that are deoxygenated at C-7 of the ansamitocin core, obtained during fermentation experiments by employing a variety of Actinosynnema pretiosum mutants and mutasynthetic approaches. We suggest that the formation of these derivatives is based on elimination at C-7/C-8 followed by reduction(s) of the intermediate enone. In bioactivity tests, only ansamitocin derivatives bearing an ester side chain at C-3 showed strong antiproliferative activity. PMID- 23015835 TI - Molecular switches and cages. PMID- 23015836 TI - The importance of the rotor in hydrazone-based molecular switches. AB - The pH-activated E/Z isomerization of a series of hydrazone-based systems having different functional groups as part of the rotor (R = COMe, CN, Me, H), was studied. The switching efficiency of these systems was compared to that of a hydrazone-based molecular switch (R = COOEt) whose E/Z isomerization is fully reversible. It was found that the nature of the R group is critical for efficient switching to occur; the R group should be a moderate H-bond acceptor in order to (i) provide enough driving force for the rotor to move upon protonation, and (ii) stabilize the obtained Z configuration, to achieve full conversion. PMID- 23015837 TI - meta-Oligoazobiphenyls - synthesis via site-selective Mills reaction and photochemical properties. AB - The investigation of multi-photochromic compounds constitutes a great challenge, not only from a synthetic point of view, but also with respect to the analysis of the photochemical properties. In this context we designed a novel strategy to access meta-oligoazobiphenyls via site-selective Mills reaction and Suzuki cross coupling in a highly efficient iterative way. Photochemical examination of the resulting monomeric and oligomeric azo compounds revealed that the overall degree of switching was independent of the connected azo-units. However, one of the azobonds in the bis-azobiphenyl is isomerized preferentially despite the high structural similarity. PMID- 23015838 TI - Intramolecular bridges formed by photoswitchable click amino acids. AB - Photoswitchable click amino acids (PSCaa) are amino acids bearing a side chain consisting of a photoswitchable unit elongated with a functional group that allows for a specific click reaction, such as an alkene that can react with the thiol group of a cysteine residue. An intramolecular click reaction results in the formation of a photoswitchable bridge, which can be used for controlling conformational domains in peptides and proteins. The ability to control conformations as well as the efficiency of the intramolecular bridging depends on the length of the PSCaa side chain and the distance to the cysteine residue to be clicked with. On comparing i,i+4 and i,i+7 spacings of PSCaa and cysteine in a model peptide without a preferred conformation, it was seen that the thiol-ene click reaction takes place efficiently in both cases. Upon induction of an alpha helical structure by the addition of trifluoroethanol, the thiol click reaction occurs preferentially with the i,i+4 spacing. Even in the presence of glutathione as an additional thiol the click reaction of the PSCaa occurs intramolecularly with the cysteine rather than with the glutathione, indicating that the click reaction may be used even under reducing conditions occurring in living cells. PMID- 23015839 TI - Building photoswitchable 3,4'-AMPB peptides: Probing chemical ligation methods with reducible azobenzene thioesters. AB - Photoswitchable peptides were synthesized by using cysteine- and auxiliary-based native chemical ligation reactions. For this purpose, the two regioisomeric azobenzene building blocks 3,4'-AMPB thioester 1b and 4,4'-AMPB thioester 2b were employed in the ligation reactions. While 4,4'-AMPB requires the 4,5,6-trimethoxy 2-mercaptobenzyl auxiliary to minimize reduction of the diazene unit, 3,4'-AMPB can be used in combination with the 4,5,6-trimethoxy-2-mercaptobenzyl auxiliary as well as the N(alpha)-2-mercaptoethyl auxiliary. Thus, 3,4'-AMPB derivatives/peptides proved to be significantly less prone to reduction by aliphatic and aromatic thiols than were the 4,4'-AMPB compounds. PMID- 23015840 TI - Multistep organic synthesis of modular photosystems. AB - Quite extensive synthetic achievements vanish in the online supporting information of publications on functional systems. Underappreciated, their value is recognized by experts only. As an example, we here focus in on the recent synthesis of multicomponent photosystems with antiparallel charge-transfer cascades in co-axial hole- and electron-transporting channels. The synthetic steps are described one-by-one, starting with commercial starting materials and moving on to key intermediates, such as asparagusic acid, an intriguing natural product, as well as diphosphonate "feet", and panchromatic naphthalenediimides (NDIs), to finally reach the target molecules. These products are initiators and propagators for self-organizing surface-initiated polymerization (SOSIP), a new method introduced to secure facile access to complex architectures. Chemoorthogonal to the ring-opening disulfide exchange used for SOSIP, hydrazone exchange is then introduced to achieve stack exchange, which is a "switching" technology invented to drill giant holes into SOSIP architectures and fill them with functional pi-stacks of free choice. PMID- 23015841 TI - Diarylethene-modified nucleotides for switching optical properties in DNA. AB - Diarylethenes were attached to the 5-position of 2'-deoxyuridine in order to yield three different photochromic nucleosides. All nucleosides were characterized with respect to their absorption and photochromic properties. Based on these results, the most promising photochromic DNA base modification was incorporated into representative oligonucleotides by using automated phosphoramidite chemistry. The switching of optical properties in DNA can be achieved selectively at 310 nm (forward) and 450 nm (backward); both wavelengths are outside the normal nucleic acid absorption range. Moreover, this nucleoside was proven to be photochemically stable and allows switching back and forth several times. These results open the way for the use of diarylethenes as photochromic compounds in DNA-based architectures. PMID- 23015843 TI - Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization. AB - By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure-activity relationship (SAR) studies were also undertaken. PMID- 23015842 TI - The use of glycoinformatics in glycochemistry. AB - Glycoinformatics is a small but growing branch of bioinformatics and chemoinformatics. Various resources are now available that can be of use to glycobiologists, but also to chemists who work on the synthesis or analysis of carbohydrates. This article gives an overview of existing glyco-specific databases and tools, with a focus on their application to glycochemistry: Databases can provide information on candidate glycan structures for synthesis, or on glyco-enzymes that can be used to synthesize carbohydrates. Statistical analyses of glycan databases help to plan glycan synthesis experiments. 3D Structural data of protein-carbohydrate complexes are used in targeted drug design, and tools to support glycan structure analysis aid with quality control. Specific problems of glycoinformatics compared to bioinformatics for genomics or proteomics, especially concerning integration and long-term maintenance of the existing glycan databases, are also discussed. PMID- 23015844 TI - Algicidal lactones from the marine Roseobacter clade bacterium Ruegeria pomeroyi. AB - Volatiles released by the marine Roseobacter clade bacterium Rugeria pomeroyi were collected by use of a closed-loop stripping headspace apparatus (CLSA) and analysed by GC-MS. Several lactones were found for which structural proposals were derived from their mass spectra and unambiguously verified by the synthesis of reference compounds. An enantioselective synthesis of two exemplary lactones was performed to establish the enantiomeric compositions of the natural products by enantioselective GC-MS analyses. The lactones were subjected to biotests to investigate their activity against several bacteria, fungi, and algae. A specific algicidal activity was observed that may be important in the interaction between the bacteria and their algal hosts in fading algal blooms. PMID- 23015845 TI - Low-generation dendrimers with a calixarene core and based on a chiral C(2) symmetric pyrrolidine as iminosugar mimics. AB - The preparation of low-generation dendrimers based on a simple calix[4]arene scaffold by insertion of the iminosugar-analogue C(2)-symmetric 3,4 dihydroxypyrrolidine is described. This methodology allows a rapid incorporation of a considerable number of iminosugar-like moieties in a reduced volume and in a well-defined geometry. The inclusion of alkali-metal ions (sodium and potassium) in the polar cavity defined by the acetamide moieties at the lower rim of the calixarene was demonstrated, which allows also the rigidification of the dendrimer structure and the iminosugar presentation in the clusters. The combination of the supramolecular properties of calixarenes with the advantage of a dendrimeric presentation of repetitive units opens up the possibility of generating well-defined multivalent and multifaceted systems with more complex and/or biologically relevant iminosugars. PMID- 23015846 TI - On the bromination of the dihydroazulene/vinylheptafulvene photo-/thermoswitch. AB - BACKGROUND: The dihydroazulene (DHA)/vinylheptafulvene (VHF) system (with two cyano groups at C1) functions as a photo-/thermoswitch. Direct ionic bromination of DHA has previously furnished a regioselective route to a 7,8-dibromide, which by elimination was converted to a 7-bromo-substituted DHA. This compound has served as a central building block for functionalization of the DHA by palladium catalyzed cross-coupling reactions. The current work explores another bromination protocol for achieving the isomeric 3-bromo-DHA and also explores the outcome of additional bromination of this compound as well as of the known 7-bromo-DHA. RESULTS: Radical bromination on two different VHFs by using N bromosuccinimide/benzoyl peroxide and light, followed by a ring-closure reaction generated the corresponding 3-bromo-DHAs, as confirmed in one case by X-ray crystallography. According to a (1)H NMR spectroscopic study, the ring closure of the brominated VHF seemed to occur readily under the reaction conditions. A subsequent bromination-elimination protocol provided a 3,7-dibromo-DHA. In contrast, treating the known 7-bromo-DHA with bromine generated a very labile species that was converted to a new 3,7-dibromoazulene, i.e., the fully unsaturated species. Azulenes were also found to form from brominated compounds when left standing for a long time in the solid state. Kinetics measurements reveal that the 3-bromo substituent enhances the rate of the thermal conversion of the VHF to DHA, which is opposite to the effect exerted by a bromo substituent in the seven-membered ring. CONCLUSION: Two general procedures for functionalizing the DHA core with a bromo substituent (at positions 3 and 7, respectively) are now available with the DHA as starting material. PMID- 23015847 TI - Synthesis and anion recognition properties of shape-persistent binaphthyl containing chiral macrocyclic amides. AB - We report on the synthesis and characterization of novel shape-persistent, optically active arylamide macrocycles, which can be obtained using a one-pot methodology. Resolved, axially chiral binol scaffolds, which incorporate either methoxy or acetoxy functionalities in the 2,2' positions and carboxylic functionalities in the external 3,3' positions, were used as the source of chirality. Two of these binaphthyls are joined through amidation reactions using rigid diaryl amines of differing shapes, to give homochiral tetraamidic macrocycles. The recognition properties of these supramolecular receptors have been analyzed, and the results indicate a modulation of binding affinities towards dicarboxylate anions, with a drastic change of binding mode depending on the steric and electronic features of the functional groups in the 2,2' positions. PMID- 23015849 TI - Welcome to sports health! PMID- 23015848 TI - Toward unidirectional switches: 2-(2-Hydroxyphenyl)pyridine and 2-(2 methoxyphenyl)pyridine derivatives as pH-triggered pivots. AB - The pH-induced switching process of 2-(2-hydroxyphenyl)pyridine and 2-(2 methoxyphenyl)pyridine derivatives was investigated with the help of UV spectroscopy. Quantum chemical calculations at the B3LYP/6-31G* level of theory were performed to show that in the case of 2-(2-methoxyphenyl)-3-methylpyridine and 2-(2-hydroxyphenyl)-3-methylpyridine the rotation during the switching process proceeds unidirectionally at the molecular level. If a 2-(2 methoxyphenyl)pyridine derivative is fixed to a chiral cyclopeptidic scaffold, a unidirectional progress of the rotation is achieved macroscopically. PMID- 23015850 TI - The role of automated external defibrillators in athletics. AB - CONTEXT: Sudden cardiac arrest is the leading cause of death in young athletes. The purpose of this review is to summarize the role of automated external defibrillators and emergency planning for sudden cardiac arrest in the athletic setting. EVIDENCE ACQUISITION: Relevant studies on automated external defibrillators, early defibrillation, and public-access defibrillation programs were reviewed. Recommendations from consensus guidelines and position statements applicable to automated external defibrillators in athletics were also considered. RESULTS: Early defibrillation programs involving access to automated external defibrillators by targeted local responders have demonstrated a survival benefit for sudden cardiac arrest in many public and athletic settings. CONCLUSION: Schools and organizations sponsoring athletic programs should implement automated external defibrillators as part of a comprehensive emergency action plan for sudden cardiac arrest. In a collapsed and unresponsive athlete, sudden cardiac arrest should be suspected and an automated external defibrillator applied as soon as possible, as decreasing the time interval to defibrillation is the most important priority to improve survival in sudden cardiac arrest. PMID- 23015851 TI - Evaluation of lipid profiles and the use of omega-3 essential Fatty Acid in professional football players. AB - BACKGROUND: Recent research showed 82% of 233 retired National Football League players under age 50 had abnormal narrowing and blockages in arteries compared to the general population of the same age. It has been suggested that early screening and intervention in this at-risk population be a priority. HYPOTHESIS: Omega-3 essential fatty acid has been shown to improve cardiovascular lipid risk factors and should improve lipid profiles in professional football players to help reduce their recently shown accelerated risk of developing cardiovascular disease. METHODS: A total of 36 active national football players were randomly assigned to 2 groups: the first group (n = 20) was provided fish oil capsules (2200 mg of mixed docosahexaenoic acid and eicosapentaenoic acid and 360 mg of other omega-3s), and the second group (n = 16) served as controls during a 60-day trial. Vertical Auto Profile cholesterol tests directly measuring serum low density lipoprotein, high-density lipoprotein, and other subfractions were performed. Compliance, side effects, and seafood consumption data were also collected. Baseline, midpoint, and poststudy blood work measured plasma docosahexaenoic acid and eicosapentaenoic acid. RESULTS: Treatment increased high density lipoprotein (average percent change: +25.96, control +14.16), decreased triglycerides treatment (-8.06, control +43.98), very low-density lipoprotein treatment (-13.98, control +23.18), intermediate density lipoprotein (-27.58, control +12.07), remnant lipoproteins (-23.86, control +8.33), and very low density lipoprotein-3 (-17.10, control +7.77). An average increase of 106.67% for docosahexaenoic acid and 365.82% for eicosapentaenoic acid compared to control was also shown. CONCLUSION: Omega-3 supplementation significantly improved the lipid profile of active players randomized to treatment. These results suggest that fish oil supplementation is an effective way to increase eicosapentaenoic acid and docosahexaenoic acid levels in plasma and should be considered as a method to improve modifiable cardiovascular risk lipid factors in professional football players. CLINICAL RELEVANCE: A prospective study examining the effects of 60 days of a highly purified fish oil supplementation in professional football players. PMID- 23015852 TI - The use of eccentrically biased resistance exercise to mitigate muscle impairments following anterior cruciate ligament reconstruction: a short review. AB - BACKGROUND: Novel interventions that can safely and effectively overload muscle early following anterior cruciate ligament reconstruction are needed to minimize atrophy and weakness that often becomes longstanding. EVIDENCE ACQUISITION: Eccentrically induced forces can be safely applied during the early stages of rehabilitation following surgery and serve as a potent stimulus for increasing muscle size and strength. RESULTS: Compared to a standard rehabilitation program, adding an early 12-week eccentric resistance-training program 3 weeks after anterior cruciate ligament reconstruction induces improvement in quadriceps and gluteus maximus volume at 15 weeks and at 1 year after surgery. Likewise, those who performed an eccentrically biased rehabilitation program also achieved greater improvements in quadriceps strength and hopping ability measured at 15 weeks and at 1 year after surgery. CLINICAL RELEVANCE: There is potential to safely and feasibly perform eccentric contractions as part of a formal rehabilitation program following anterior cruciate ligament reconstruction. PMID- 23015853 TI - Management of the athlete with acute anterior cruciate ligament deficiency. AB - BACKGROUND: Identification of highly active individuals early after acute anterior cruciate ligament deficiency who are good candidates for nonoperative management is a clinical challenge. The University of Delaware has developed and validated a treatment algorithm and screening examination to distinguish between nonoperative and surgical candidates. STUDY DESIGN: Review. EVIDENCE ACQUISITION: A description of the decision-making rules and rehabilitation protocol for highly active individuals with anterior cruciate ligament deficiency is provided. Results from clinical trials, outcome studies, and biomechanical investigations conducted using the treatment algorithm and screening examination are also reviewed. RESULTS: Patients identified as nonoperative rehabilitation candidates using these clinical guidelines have a far greater success rate than what has been reported when patients self-select nonoperative management. Furthermore, nonoperative outcomes are improved when patients participate in a perturbation enhanced rehabilitation protocol. Divergent lower extremity movement patterns are consistent with the different functional abilities of the dichotomous patient groups identified with the screening examination. CONCLUSION: Given the differential patient response to anterior cruciate ligament injury, implementation of the decision-making guidelines discussed in this review offers clinicians the opportunity to provide individualized patient care rather than continuing with a blanket surgical treatment strategy. PMID- 23015854 TI - Factors associated with function after anterior cruciate ligament reconstruction. AB - BACKGROUND: Many individuals do not resume unrestricted, preinjury sports participation after anterior cruciate ligament reconstruction, thus a better understanding of factors associated with function is needed. The purpose of this study was to investigate the association of knee impairment and psychological variables with function in subjects with anterior cruciate ligament reconstruction. HYPOTHESIS: After controlling for demographic variables, knee impairment and psychological variables contribute to function in subjects with anterior cruciate ligament reconstruction. STUDY DESIGN: Cross-sectional study; Level of evidence, 4a. METHODS: Fifty-eight subjects with a unilateral anterior cruciate ligament reconstruction completed a standardized testing battery for knee impairments (range of motion, effusion, quadriceps strength, anterior knee joint laxity, and pain intensity), kinesiophobia (shortened Tampa Scale for Kinesiophobia), and function (International Knee Documentation Committee subjective form and single-legged hop test). Separate 2-step regression analyses were conducted with International Knee Documentation Committee subjective form score and single-legged hop index as dependent variables. Demographic variables were entered into the model first, followed by knee impairment measures and Tampa Scale for Kinesiophobia score. RESULTS: A combination of pain intensity, quadriceps index, Tampa Scale for Kinesiophobia score, and flexion motion deficit contributed to the International Knee Documentation Committee subjective form score (adjusted r(2) = 0.67; P < .001). Only effusion contributed to the single legged hop index (adjusted r(2) = 0.346; P = .002). CONCLUSION: Knee impairment and psychological variables in this study were associated with self-report of function, not a performance test. CLINICAL RELEVANCE: The results support focusing anterior cruciate ligament reconstruction rehabilitation on pain, knee motion deficits, and quadriceps strength, as well as indicate that kinesiophobia should be addressed. Further research is needed to reveal which clinical tests are associated with performance testing. PMID- 23015855 TI - Association between Previous Concussion History and Symptom Endorsement during Preseason Baseline Testing in High School and Collegiate Athletes. AB - BACKGROUND: A graded symptom checklist is a commonly used concussion evaluation measure. Little is known about preseason baseline symptomatology of high school and college athletes with and without a previous concussion history. HYPOTHESIS: The primary hypothesis investigated was that those individuals with a concussion history would report more symptoms at baseline testing. The effects of sex and age on symptoms were also examined. STUDY DESIGN: Cross-sectional study. METHODS: Subjects included 8930 high school and collegiate athletes (height, 177.79 +/- 9.97 cm; mass, 75.20 +/- 19.21 kg; age, 16.60 +/- 1.64 years). Subjects completed a self-report graded symptom checklist and concussion history questionnaire during a preseason clinical testing session. Symptoms reported (yes or no) on the 18-item graded symptom checklist served as the dependent variables. RESULTS: A significant association was observed between symptoms on the graded symptom checklist and previous concussion history (P <= .001). No differences were observed between high school and college athletes regarding symptom endorsement (t(8928) = 0.620; P = .535). A statistical but not clinically meaningful difference was observed between the means for males and females symptom endorsement (t(8928) = -3.03; P = .002): men endorsed 1.88 +/- 2.81 symptoms, and women endorsed 2.09 +/- 2.90 symptoms. Headache, sleeping more than usual, difficulty concentrating, drowsiness, difficulty remembering, fatigue, difficulty sleeping, and irritability were reported by more than 10% of athletes. CONCLUSION: High school and college athletes with a history of multiple concussions may be at risk for experiencing concussion-linked symptoms well beyond the acute stage of injury. Clinicians should be mindful of previous concussion history in athletes with increased presence of base-rate symptoms as they may be predisposed to future injury. PMID- 23015857 TI - Transepiphyseal anterior cruciate ligament reconstruction in pediatric patients: surgical technique. PMID- 23015856 TI - The function of the human anterior cruciate ligament and analysis of single- and double-bundle graft reconstructions. AB - CONTEXT: There exists controversy on the ability of a single or double anterior cruciate ligament graft technique to restore anterior cruciate ligament function. This article examines the published experimental and clinical data supporting these surgical procedures in the ability to restore knee stability. EVIDENCE ACQUISITION: An analysis of anterior cruciate ligament function and single- and double-graft reconstructions defined by selected biomechanical, robotic, kinematic, anatomical, and clinical studies. RESULTS: The anterior cruciate ligament resists the combined motions of anterior tibial translation and internal tibial rotation, which defines the concept of rotational stability. This function prevents anterior tibial subluxation of the lateral and medial tibiofemoral compartments that accounts for the pivot-shift phenomena. The placement of single anterior cruciate ligament grafts high and proximal at the femoral attachment and posterior at the tibial attachment results in a vertical graft orientation. This graft placement results in a limited ability to provide rotational stability and is inferior when compared to a double-bundle graft procedure. Studies show that a more oblique single-graft orientation, in the sagittal and coronal plane, achieved from a central anatomic femoral and tibial location provides rotational stability similar to a double-bundle anterior cruciate ligament graft. CONCLUSION: There exists insufficient experimental and clinical data to recommend the more complex double-bundle anterior cruciate ligament graft technique over a well-placed central anatomic single graft in terms of restoring knee rotational stability. Meticulous surgical technique for anterior cruciate ligament graft placement is necessary to avoid failure. PMID- 23015858 TI - Sports medicine imaging update. PMID- 23015859 TI - Legal liability in covering athletic events. PMID- 23015860 TI - Let's Play Ball. PMID- 23015862 TI - Os acromiale as a cause for shoulder pain in a competitive swimmer: a case report. PMID- 23015863 TI - Rotator Cuff Repair Rehabilitation: A Level I and II Systematic Review. AB - BACKGROUND: There is no consensus for the optimal postoperative rehabilitation protocol after rotator cuff repairs. OBJECTIVE: To determine if there is sufficient level I or II evidence available in the literature for establishment of a uniform, optimal rotator cuff rehabilitation protocol. DATA SOURCES: A systematic review of level I and II English-language, prospective, randomized controlled trials published between 1966 and 2008 was performed. MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and secondary references were appraised for studies that met the inclusion criteria. Search terms included rotator cuff, supraspinatus, infraspinatus, subscapularis, teres minor, rehab, rehabilitation, physical therapy, and physiotherapy. STUDY SELECTION: Inclusion criteria were English-language level I or level II studies, including randomized clinical trials involving the rehabilitation of rotator cuff repairs. Exclusion criteria were non-English language, level IV or V studies, or studies involving shoulder rehabilitation of diagnoses other than rotator cuff repairs. Three independent reviewers arrived at a consensus for including 4 studies in this review out of 12 studies identified by the literature search. DATA EXTRACTION: Included studies underwent worksheet quality appraisal independently by each of the 3 authors identifying strengths, weaknesses, and biases. The quality appraisal was then discussed among the authors and consensus reached regarding the strengths, weaknesses, and value of the included studies. RESULTS: Two studies examined the use of continuous passive motion for rotator cuff rehabilitation, and 2 studies compared an unsupervised, standardized rehabilitation program to a supervised, individualized rehabilitation program. These studies did not support the use of continuous passive motion in rotator cuff rehabilitation, and no advantage was shown with a supervised, individualized rehabilitation protocol compared to an unsupervised, standardized home program. Each investigation had weaknesses in study design that decreased the validity of its findings. CONCLUSION: There is not enough high-level evidence to develop an evidence-based medicine approach to rotator cuff rehabilitation. There is a need for well-designed level I and level II trials to elucidate the optimal rotator cuff repair rehabilitation protocol. PMID- 23015861 TI - Shoulder pain in the overhead throwing athlete. AB - Treatment of the overhead throwing athlete is among the more challenging aspects of orthopaedic sports medicine. Awareness and understanding of the throwing motion and the supraphysiologic forces to which the structures of the shoulder are subjected are essential to diagnosis and treatment. Pain and dysfunction in the throwing shoulder may be attributed to numerous etiologies, including scapular dysfunction, intrinsic glenohumeral pathology (capsulolabral structures), extrinsic musculature (rotator cuff), or neurovascular structures. Attention to throwing mechanics and appropriate stretching, strength, and conditioning programs may reduce the risk of injury in this highly demanding activity. Early discovery of symptoms, followed by conservative management with rest and rehabilitation with special attention to retraining mechanics may mitigate the need for surgical intervention. Prevention of injury is always more beneficial to the long-term health of the thrower than is surgical repair. An anatomic approach is used in this report, focusing on common etiologies of pain in the overhead thrower and emphasizing the clinical presentation and treatment. PMID- 23015864 TI - Glenohumeral internal rotation measurements differ depending on stabilization techniques. AB - BACKGROUND: The loss of glenohumeral internal rotation range of motion in overhead athletes has been well documented in the literature. Several different methods of assessing this measurement have been described, making comparison between the results of studies difficult. HYPOTHESIS: Significant differences in the amount of internal rotation range of motion exist when using different methods of stabilization. STUDY DESIGN: Descriptive laboratory study. METHODS: THREE TECHNIQUES WERE USED BILATERALLY IN RANDOM FASHION TO MEASURE GLENOHUMERAL INTERNAL ROTATION RANGE OF MOTION: stabilization of the humeral head, stabilization of the scapula, and visual inspection without stabilization. An initial study on 20 asymptomatic participants was performed to determine the intrarater and interrater reliability for each measurement technique. Once complete, measurements were performed on 39 asymptomatic professional baseball players to determine if a difference existed in measurement techniques and if there was a significant side-to-side difference. A 2-way repeated-measures analysis of variance was used. RESULTS: While interrater reliability was fair between all 3 methods, scapular stabilization provided the best intrarater reliability. A statistically significant difference was observed between all 3 methods (P < .001). Internal rotation was significantly less in the dominant shoulder than in the nondominant shoulder (P < .001). CONCLUSION: Differences in internal rotation range of motion measurements exist when using different methods. The scapula stabilization method displayed the highest intrarater reproducibility and should be considered when evaluating internal rotation passive range of motion of the glenohumeral joint. CLINICAL RELEVANCE: A standardized method of measuring internal rotation range of motion is required to accurately compare physical examinations of patients. The authors recommend the use of the scapula stabilization method to assess internal rotation range of motion by allowing normal glenohumeral arthrokinematics while stabilizing the scapulothoracic articulation. PMID- 23015865 TI - Focused extracorporeal shock wave therapy in calcifying tendinitis of the shoulder: a meta-analysis. AB - BACKGROUND: The objective of this study is to assess the effectiveness of extracorporeal shock wave therapy in the management of calcifying tendinitis of the shoulder. Furthermore, a dose-response relationship was sought as a secondary confirmation of effectiveness. HYPOTHESIS: Focused extracorporeal shock wave therapy has a high, dose-responsive effectiveness in the management of calcifying tendinitis of the shoulder. STUDY DESIGN: Meta-analysis. METHODS: Studies were identified from online databases (MEDLINE, EMBASE, and Cochrane Controlled Trials Register), manual searches, and personal communication with experts in the field. After assessment of heterogeneity, a random effects model was generated. The primary end points were identified as pain and function by using the visual analog scale and the Constant-Murley Score, respectively. These end points were pooled and the weighted mean differences and 95% confidence intervals were estimated. Odds ratios of the secondary end point deposit resorption were pooled. RESULTS: In 14 studies, shock wave therapy led to a significantly higher reduction of pain (weighted mean difference, -2.8 points; 95% confidence interval, -4.2 to -1.5 points) and improvement of function (weighted mean difference, 19.8 points; 95% confidence interval, 13.4-26.3 points), compared to other treatments and placebo. High-energy treatment produced significantly better results than low-energy treatment for pain reduction (weighted mean difference, 1.7 points; 95% confidence interval, 0.7-2.6 points) and improvement of function (weighted mean difference, 10.7 points; 95% confidence interval, 7.2-14.1 points). These results are consistent with a dose-response relationship supporting the effectiveness of shock wave therapy. CONCLUSION: Shock wave therapy for calcifying tendinitis of the shoulder is effective in pain relief, function restoration, and deposit resorption; however, these conclusions are susceptible to bias arising from the limitations of the included studies. PMID- 23015866 TI - Data-based interval throwing programs for baseball players. AB - CONTEXT: Baseball throwing injuries are common. Emphasis on injury prevention and rehabilitation is made in an attempt to keep athletes on the field of competition. Interval throwing programs are an integral part of training, conditioning, and returning an injured baseball player to the game. EVIDENCE ACQUISITION: Development of data-driven programs was based on the number, type, distance, and intensity of throws during games, across the spectrum of ages and positions for baseball athletes at all levels of play. Statistical analysis by age, position, and level of play determined the need for separate throwing programs. Means, the high range, game rules, and practical considerations were used to develop each data-based interval throwing program. RESULTS: Data-based age and level-of-play interval throwing programs for pitchers, catchers, infielders, and outfielders have been developed, tested, and implemented for more than 10 years. Progression is based on type and location of injury, symptoms in response to throwing, and preinjury performance profile. Although the throwing programs are highly structured, there is ample opportunity to modify them to meet the needs of individual athletes. CONCLUSION: Data-based interval throwing programs for baseball athletes are an integral training and conditioning element for both injured and uninjured athletes who are preparing for sports participation. Medical team members should equip themselves with an understanding of how to use the programs for safe training, conditioning, and return to play. PMID- 23015867 TI - An evidence-based approach to hamstring strain injury: a systematic review of the literature. AB - BACKGROUND: Hamstring strain injury is a common problem within sport. Despite research interest, knowledge of risks for and management of hamstring strain is limited, as evidenced by high injury rates. OBJECTIVE: To present the current best evidence for hamstring strain injury risk factors and the management of hamstring strain injury. METHODS: MEDLINE, AMED, SportDiscus, and AUSPORT databases were searched (key terms "hamstring" and "strain," "injury," "pull," or "tear") to identify relevant literature published between 1982 and 2007 in the English language. Studies of adult athlete populations (older than 18 years) pertaining to hamstring strain incidence, prevalence, and/or intervening management of hamstring strain injury were included. Articles were limited to full-text randomized, controlled studies or cohort studies. Twenty-four articles were included. Articles were critically appraised using the McMaster Quantitative Review Guidelines instrument. Data pertaining to injury rates and return to sport outcomes were extracted. Each author undertook independent appraisal of a random selection of articles after establishing inter-rater agreement of appraisal. RESULTS: Previous strain, older age, and ethnicity were consistently reported as significant risks for injury, as was competing in higher levels of competition. Associations with strength and flexibility were conflicting. Functional rehabilitation interventions had preventive effects and resulted in significantly earlier return to sport. Additionally, weak evidence existed for other interventions. CONCLUSION: Current evidence is inconclusive regarding most interventions for hamstring strain injury, while the effect of potentially modifiable risks is unclear. Further high-quality prospective studies into potential risks and management are required to provide a better framework within which to target interventions. PMID- 23015868 TI - Sagittal Plane Knee Biomechanics and Vertical Ground Reaction Forces Are Modified Following ACL Injury Prevention Programs: A Systematic Review. AB - CONTEXT: Injuries to the anterior cruciate ligament (ACL) occur because of excessive loading on the knee. ACL injury prevention programs can influence sagittal plane ACL loading factors and vertical ground reaction force (VGRF). OBJECTIVE: To determine the influence of ACL injury prevention programs on sagittal plane knee biomechanics (anterior tibial shear force, knee flexion angle/moments) and VGRF. DATA SOURCES: The PubMed database was searched for studies published between January 1988 and June 2008. Reference lists of selected articles were also reviewed. STUDY SELECTION: Studies were included that evaluated healthy participants for knee flexion angle, sagittal plane knee kinetics, or VGRF after performing a multisession training program. Two individuals reviewed all articles and determined which articles met the selection criteria. Approximately 4% of the articles fulfilled the selection criteria. DATA EXTRACTION: Data were extracted regarding each program's duration, frequency, exercise type, population, supervision, and testing procedures. Means and variability measures were recorded to calculate effect sizes. One reviewer extracted all data and assessed study quality using PEDro (Physiotherapy Evidence Database). A second reviewer (blinded) verified all information. RESULTS: There is moderate evidence to indicate that knee flexion angle, external knee flexion moment, and VGRF can be successfully modified by an ACL injury prevention program. Programs utilizing multiple exercises (ie, integrated training) appear to produce the most improvement, in comparison to that of single-exercise programs. Knee flexion angle was improved following integrated training (combined balance and strength exercises or combined plyometric and strength exercises). Similarly, external knee flexion moment was improved following integrated training consisting of balance, plyometric, and strength exercises. VGRF was improved when incorporating supervision with instruction and feedback on proper technique. CONCLUSION: ACL injury prevention programs that are aimed at modifying sagittal plane knee biomechanics and VGRF should use an integrated training approach that incorporates instruction and feedback on proper movement technique. PMID- 23015869 TI - Commotio cordis. AB - CONTENT: Commotio cordis is blunt, nonpenetrating trauma to the chest resulting in irregular heart rhythm and often leading to sudden death. This article presents the epidemiology, variables leading to commotio cordis, theories on predisposing factors, diagnosis, treatment, treatment outcomes, and return-to play recommendations. EVIDENCE ACQUISITION: A PubMed (MEDLINE) search for commotio cordis was conducted on July 1, 2008, and it yielded 106 results, of which 26 were used for this review, including experimental models, simulation studies, case analysis studies, case reports, general recommendation, review articles, and editorials. RESULTS: There are more than 190 reported cases of commotio cordis in the United States. Forty-seven percent of reported cases occurred during athletic participation. Commotio cordis is the second-most common cause of sudden cardiac death in athletes. Occurrence of commotio cordis is related to time of impact during the cardiac cycle, direct impact over the heart, the hardness and speed of the projectile, and the ineffectiveness of chest barriers. As a result, the US Consumer Product Safety Commission recommends that softer "safety" baseballs be used for youth baseball. Resuscitation using defibrillation was effective in only 15% of cases. Resuscitation within 3 minutes resulted in a survival rate of 25% (17 of 68 cases). Survival drops to 3% when resuscitation is delayed beyond 3 minutes. Survival of commotio cordis has risen from 10% to 15% since 2001. Reduced ventricular ejection fraction has been identified in some commotio cordis survivors. CONCLUSION: Preventive measures, such as using soft "safety" balls and making automated external defibrillators available at sporting venues, can reduce commotio cordis morbidity and mortality. Chest protector designs can be improved to enhance protection. Return to play is best left to clinical judgment given that data are lacking with regard to susceptibility for reoccurrence. PMID- 23015871 TI - They're Not Just Little Adults. PMID- 23015870 TI - MRI challenge. PMID- 23015872 TI - Anterior cruciate ligament insertion site and knee flexion angle. PMID- 23015874 TI - Low back pain in young athletes. AB - CONTEXT: Low back pain in young athletes is a common complaint and should be taken seriously. It frequently results from a structural injury that requires a high degree of suspicion to diagnose and treat appropriately. EVIDENCE ACQUISITION: A Medline search was conducted from 1996 to May 2008 using the search terms "low back pain in children" and "low back pain in athletes." Known texts on injuries in young athletes were also reviewed. References in retrieved articles were additionally searched for relevant articles. Sources were included if they contained information regarding diagnosis and treatment of causes of low back pain in children. RESULTS: Low back pain is associated with sports involving repetitive extension, flexion, and rotation, such as gymnastics, dance, and soccer. Both acute and overuse injuries occur, although overuse injuries are more common. Young athletes who present with low back pain have a high incidence of structural injuries such as spondylolysis and other injuries to the posterior elements of the spine. Disc-related pathology is much less common. Simple muscle strains are much less likely in this population and should be a diagnosis of exclusion only. CONCLUSION: Young athletes who present with low back pain are more likely to have structural injuries and therefore should be investigated fully. Muscle strain should be a diagnosis of exclusion. Treatment should address flexibility and muscle imbalances. Injuries can be prevented by recognizing and addressing risk factors. Return to sport should be a gradual process once the pain has resolved and the athlete has regained full strength. PMID- 23015873 TI - Peri-epiphyseal and Overuse Injuries in Adolescent Athletes. AB - CONTEXT: Overuse injuries of the musculoskeletal system in immature athletes are commonly seen in medical practice. EVIDENCE ACQUISITION: An analysis of published clinical, outcome, and biomechanical studies of adolescent epiphyseal and overuse injuries was performed through 2008 to increase recognition and provide treatment recommendations. RESULTS: Adolescent athletes can sustain physeal and bony stress injuries. Recovery and return to play occur more swiftly if such injuries are diagnosed early and immobilized until the patient is pain-free, typically about 4 weeks for apophyseal and epiphyseal overuse injuries. Certain epiphyseal injuries have prolonged symptoms with delayed treatment, including those involving the bones in the hand, elbow, and foot. If such injuries are missed, prolonged healing and significant restrictions in athletic pursuits may occur. CONCLUSION: Some of these injuries are common to all weightbearing sports and are therefore widely recognized. Several are common in gymnastics but are rarely seen in other athletes. Early recognition and treatment of these conditions lead to quicker recovery and so may prevent season-ending, even career-ending, events from occurring. PMID- 23015875 TI - Strength training in children and adolescents: raising the bar for young athletes? AB - CONTEXT: Strength training in children, in combination with plyometric and/or agility training, has become an increasingly popular tactic for athletes to gain a competitive edge during the off-season. The present review clarifies some common myths associated with strength training in children, and it outlines the most current recommendations. EVIDENCE ACQUISITION: Relevant studies on strength training in children and adolescents were reviewed (search results included studies indexed in PubMed and MEDLINE from 1980 through 2008). Also reviewed were recommendations from consensus guidelines and position statements applicable to strength training in youth. RESULTS: Children can improve strength by 30% to 50% after just 8 to 12 weeks of a well-designed strength training program. Youth need to continue to train at least 2 times per week to maintain strength. The case reports of injuries related to strength training, including epiphyseal plate fractures and lower back injuries, are primarily attributed to the misuse of equipment, inappropriate weight, improper technique, or lack of qualified adult supervision. CONCLUSION: Youth-athletes and nonathletes alike-can successfully and safely improve their strength and overall health by participating in a well supervised program. Trained fitness professionals play an essential role in ensuring proper technique, form, progression of exercises, and safety in this age group. PMID- 23015876 TI - Weight management in amateur wrestling. AB - CONTEXT: Unhealthy weight loss practices continue to plague amateur wrestling. The National Collegiate Athletic Association weight loss guidelines are beneficial but have not solved the problem. EVIDENCE ACQUISITION: All relevant databases through 2008 were searched using PubMed. The references of relevant articles were then searched for additional publications. STUDY TYPE: Clinical review. RESULTS: New rules approved by the National Collegiate Athletic Association have been implemented in an attempt to prevent drastic weight loss practices in wrestlers. Although some are effective, such as establishing a minimum wrestling weight and decreasing the period between weigh-ins and actual wrestling, unsafe weight loss practices still occur. CONCLUSION: The attempts made by the National Collegiate Athletic Association to prevent drastic weight loss in wrestling have been effective to some degree. The mind-set of athletes, coaches, and clinicians needs to change if further improvements are to be made. PMID- 23015877 TI - Risk factors for medical withdrawals in United States tennis association junior national tennis tournaments: a descriptive epidemiologic study. AB - BACKGROUND: There have been no large-scale epidemiologic studies designed to determine the risk factors related to medical withdrawal in United States Tennis Association junior national tennis tournaments. HYPOTHESIS: Risk of medical withdrawal will increase on the basis of cumulative match volume within a tournament. METHODS: A retrospective, cross-sectional analysis was performed of data collected for every match of all 4 United States Tennis Association supernational tournaments (spring, summer, fall, winter) for the boys and girls divisions and for all age divisions (12, 14, 16, 18) during a single year (2005). Logistic regression analysis was performed to determine relative risk of all risk factors. Additional analysis was performed to determine the threshold (ie, match number) at which a player would substantially increase his or her risk of medical withdrawal. RESULTS: A total of 28336 match exposures were analyzed, with an even distribution with respect to sex and age. The total medical withdrawal rate was 15.6 per 1000 match exposures. Every factor of interest was highly significant in predicting a higher rate of medical withdrawal per 1000 match exposures. The medical withdrawal rate was significantly higher in the fifth match or greater (26.3/1000) versus the first 4 matches (12.7/1000; P < .0001), even when analyzing main draw and singles matches. CONCLUSION: In United States Tennis Association national junior tennis tournaments, there is a significant increase in risk of medical withdrawals directly related to older age divisions, boys, singles matches, and main draw matches. Specifically, there is a significant increase in medical withdrawal rate beyond the fourth match in the tournament regardless of whether it is a main draw, consolation, or singles match. CLINICAL RELEVANCE: Recommendations can be made to exercise caution in tournaments that involve boys, older age divisions, and singles. In addition, there may be sufficient evidence to suggest intervention within a tournament when players play beyond their fourth match. PMID- 23015878 TI - Return to basketball and soccer after anterior cruciate ligament reconstruction in competitive school-aged athletes. AB - BACKGROUND: Little is known about the return to sports after anterior cruciate ligament reconstruction and whether sex differences exist regarding the level and timing at which athletes return. HYPOTHESES: Compared to school-aged girls, boys return to full sports earlier and at a higher frequency after surgery (1). Athletes who return to sports earlier will not have a higher incidence of subsequent injury to either knee after surgery (2). STUDY DESIGN: Cohort. METHODS: The patient population comprised 413 consecutive school-aged athletes who were injured while competing in basketball or soccer. Patients were enrolled prospectively, and activity levels were obtained through follow-up visits, surveys, phone calls, and e-mail. RESULTS: Follow-up was obtained for 402 patients (basketball: 58 boys, 242 girls; soccer: 25 boys, 77 girls). Eighty seven percent of girls and boys returned to high school basketball after surgery: the mean time to return to full participation in basketball was 5.2 +/- 2.1 months for girls and 5.3 +/- 2.2 months for boys (P = .92). Similarly, 93% of girls and 80% of boys returned to compete in high school soccer after surgery (P = .13); the mean time to return to full participation in soccer was 5.1 +/- 1.9 months for girls and 5.1 +/- 2.0 for boys (P = 1.00). About 20% of athletes went on to compete in their sport in college. The time of return to sports was not a statistically significant factor for the incidence of subsequent anterior cruciate ligament injury. CONCLUSION: Of 402 athletes competing in basketball and soccer, women and men returned at the same rate and same level of sport after surgery. Athletes who returned to sports at earlier times after surgery did not have a higher incidence of subsequent anterior cruciate ligament injury than patients who returned at later times. PMID- 23015879 TI - Suspected mechanisms in the cause of overuse running injuries: a clinical review. AB - CONTEXT: Various epidemiological studies have estimated that up to 70% of runners sustain an overuse running injury each year. Although few overuse running injuries have an established cause, more than 80% of running-related injuries occur at or below the knee, which suggests that some common mechanisms may be at work. The question then becomes, are there common mechanisms related to overuse running injuries? EVIDENCE ACQUISITION: RESEARCH STUDIES WERE IDENTIFIED VIA THE FOLLOWING ELECTRONIC DATABASES: MEDLINE, EMBASE PsycInfo, and CINAHL (1980-July 2008). Inclusion was based on evaluation of risk factors for overuse running injuries. RESULTS: A majority of the risk factors that have been researched over the past few years can be generally categorized into 2 groups: atypical foot pronation mechanics and inadequate hip muscle stabilization. CONCLUSION: Based on the review of literature, there is no definitive link between atypical foot mechanics and running injury mechanisms. The lack of normative data and a definition of typical foot structure has hampered progress. In contrast, a large and growing body of literature suggests that weakness of hip-stabilizing muscles leads to atypical lower extremity mechanics and increased forces within the lower extremity while running. PMID- 23015880 TI - Cervical spine alignment during on-field management of potential catastrophic spine injuries. AB - CONTEXT: When cervical spine injuries are suspected, the cervical spine should be immobilized in a neutral position and neck motion controlled in preparation for transport to an emergency facility. Protocols for emergency transport utilizing common devices (cervical collars) and methods (transfer techniques) during these procedures are not entirely evidence based. EVIDENCE ACQUISITION: The medical literature search covered the time period of January 1966 to June 2008 using the following keywords, either alone or in combination: extrication collars, cervical collars, spine orthoses, spinal immobilization, spine board, spinal board, transfer techniques, and back board. Biomedical databases searched included Medline, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL [1982 to 2008]). The reference lists of all trials identified were also searched for additional trials. METHODS: Only trials that directly compared the efficacy or safety of transfer methods and/or immobilization devices were included. Studies that measured voluntary head movement after the fitting of the cervical orthoses and those that did not evaluate motion across individual spinal segments were not included. RESULTS: A lift-and-slide transfer method with a full body immobilization device creates less motion than a log-roll maneuver. Extrication-type cervical immobilization collars are limited in their ability to control neck motion in the injured cadaveric model. CONCLUSION: Allied health professionals responsible for the management of the cervical spine-injured patient should become familiar with and employ a lift-and-slide transfer technique in appropriate situations and should not rely exclusively on extrication-type collars to immobilize the neck. PMID- 23015882 TI - Proximal hamstring avulsion injuries: a technique note on surgical repairs. AB - Proximal hamstring avulsions from the ischium are becoming more frequently recognized, secondary to their disability when treated nonoperatively. The acute repair of these injuries is becoming prevalent given the improved outcomes reported in the literature. Anatomic studies have recently been conducted on the proximal hamstring origin; however, there are few reports on surgical techniques for repair in the setting of injury. The present article describes the technique for proximal hamstring avulsion repair, as performed by the senior author. More than 30 cases have been performed based on this technique, with excellent results. PMID- 23015881 TI - Bone health: part 1, nutrition. AB - Nutrition, in sufficient amount and substance, is crucial for healthy growth and development of the skeleton and surrounding tissues, especially in physically active populations. Inadequate nutrition has been linked to maladies such as the female athlete triad, as well as poor training or competitive performance and increased risk of injury. Dietary choices favoring items high in quality protein of animal or plant origin, polyunsaturated fatty acids, fruits and vegetables high in potassium and fiber, and dairy products or other beverages fortified with calcium and vitamin D are essential to athletes to ensure adequate vitamin and mineral availability to the skeleton, which in turn can affect peak physical performance. PMID- 23015883 TI - Pelvic fractures in professional cyclists: a report of 3 cases. AB - BACKGROUND: Professional riders demonstrate increased risk factors for such injuries including both extensive time on the bike in addition to a possible underlying osteopenia secondary to the nonimpact nature of the sport. HYPOTHESIS: Nonoperative management of stable, nondisplaced pelvic fractures in professional cyclists offers excellent results. STUDY DESIGN: Case series. METHODS: Three cases of professional cyclists with pelvic fractures were reviewed. RESULTS: All 3 cyclists were able to return to professional competition and remain symptom free. CONCLUSION: Accurate early diagnosis of pelvic fractures, with the aid of computed tomography, is crucial. Early nonweightbearing with a progression to weightbearing as tolerated and early return to stationary training are appropriate. Accurate diagnosis and careful nonoperative management of stable, nondisplaced pelvic fractures in professional cyclists offers excellent results. CLINICAL RELEVANCE: Accurate diagnosis of pelvic fractures in high-demand athletes with few complaints and no obvious findings on plain film radiographs. Control of weightbearing and competitive status to prevent injury progression. Gauged return to competition at professional level. PMID- 23015884 TI - The spirit of "the bird". PMID- 23015886 TI - Imaging of tendons. AB - Both magnetic resonance imaging (MRI) and sonography are well suited to tendon imaging. A normal tendon on MRI demonstrates low signal intensity and on sonography, an echogenic fibrillar pattern. MRI is considered the imaging gold standard, providing an anatomic overview and excellent soft tissue contrast. Sonography is a more rapidly performed examination; it has greater resolution than that of MRI; it allows dynamic evaluation of tendons and muscles; and it can guide percutaneous therapeutic procedures. Moreover, the advent of sonographic extended-field-of-view imaging allows the demonstration of the entire length of a tendon, matching MRI's ability to display a large anatomic region. Sonography should best be considered a focused examination, concentrating on the area of pain and clinical suspicion of pathology, whereas MRI can provide a global assessment of the region of concern. Both modalities demonstrate high accuracy for abnormalities of various tendons. This article reviews normal tendon anatomy and its imaging appearance, as well as the imaging appearances of tendon degeneration and tear. PMID- 23015887 TI - Current concepts in rehabilitation following ulnar collateral ligament reconstruction. AB - Injuries to the ulnar collateral ligament (UCL) in throwing athletes frequently occurs from the repetitive valgus loading of the elbow during the throwing motion, which often results in surgical reconstruction of the UCL requiring a structured postoperative rehabilitation program. Several methods are currently used and recommended for UCL reconstruction using autogenous grafts in an attempt to reproduce the stabilizing function of the native UCL. Rehabilitation following surgical reconstruction of the UCL begins with range of motion and initial protection of the surgical reconstruction, along with resistive exercise for the entire upper extremity kinetic chain. Progressions for resistive exercise are followed that attempt to fully restore strength and local muscular endurance in the rotator cuff and scapular stabilizers, in addition to the distal upper extremity musculature, to allow for a return to throwing and overhead functional activities. Rehabilitation following UCL reconstruction has produced favorable outcomes, allowing for a return to throwing in competitive environments. PMID- 23015885 TI - Tendinosis: pathophysiology and nonoperative treatment. AB - Tendinosis is a troublesome clinical entity affecting many active people. Its treatment remains a challenge to sports medicine clinicians. The etiopathophysiology of tendinosis has not been well delineated. The known pathophysiology and the recent advances in the understanding of the etiologic process of tendinosis are discussed here, including new concepts in mechanotransduction and the biochemical alterations that occur during tendon overload. The optimal, nonoperative treatment of tendinosis is not clear. This article reviews recent evidence of the clinical efficacy of the following interventions: eccentric exercise, extracorporal shock wave treatment, corticosteroid and nonsteroidal anti-inflammatory medications, sclerosing injections, nitric oxide, platelet-rich plasma injections, and matrix metalloproteinase inhibitors. Eccentric exercise has strongest evidence of efficacy. Extracorporal shock wave treatment has mixed evidence and needs further study of energy and application protocols. Sclerosing agents show promising early results but require long-term studies. Corticosteroid and nonsteroidal anti inflammatory medications have not been shown to be effective, and many basic science studies raise possible concerns with their use. Nitric oxide has been shown in several basic science studies to be promising, but clinical efficacy has not been well established. More clinical trials are needed to assess dosing, indications, and clinical efficacy of nitric oxide. Platelet-rich plasma injections have offered encouraging short-term results. Larger and longer-term clinical trials are needed to assess this promising modality. Matrix metalloproteinase inhibitors have had few clinical studies, and their role in the treatment of tendinosis is still in the early phase of investigation. PMID- 23015888 TI - Baseball pitching biomechanics in relation to injury risk and performance. AB - CONTEXT: Baseball pitching kinematics, kinetics, ball velocity, and injuries at the shoulder and elbow are related. EVIDENCE ACQUISITION: PubMed and Sport Discus were searched for original studies published between 1994 and 2008. Relevant references in these studies were retrieved. Inferential studies that tested relationships between kinematics and kinetics were included, as were studies that tested relationships between kinematics and ball velocity. Descriptive studies that simply quantified kinematics and/or kinetics were excluded. RESULTS: SEVERAL KINEMATIC PARAMETERS AT THE INSTANT OF FOOT CONTACT WERE ASSOCIATED WITH INCREASED UPPER EXTREMITY KINETICS: front foot position, front foot orientation, shoulder abduction, and shoulder horizontal adduction. The timing of shoulder external rotation, pelvis rotation, and upper trunk rotation was associated with increased kinetics and decreased ball velocity. Low braking force of the lead leg and a short stride were associated with decreased ball velocity. Decreased maximum shoulder external rotation, shoulder abduction, knee extension, and trunk tilt were also associated with decreased ball velocity. As pitchers develop, kinematic values remain similar, their variability reduces, and kinetic values gradually increase. Slight kinematic variations were seen among pitch types, although the kinetics of fastballs and curveballs were relatively the same; changeup kinetics were the lowest. As pitchers fatigued, kinetic values remained constant, but increases in arm pain were reported. CONCLUSIONS: Several kinematic parameters were related to joint kinetics and ball velocity. To enhance performance and reduce injury risk, pitchers need to learn proper fastball mechanics at an early age. A changeup is recommended as a safe secondary pitch to complement the fastball; the curveball can be added after fastball and changeup mechanics are mastered. Avoiding overuse and pitching while fatigued is necessary to minimize the risk of arm injury. PMID- 23015889 TI - The effect of grip size on the hitting force during a soft tennis forehand stroke. AB - BACKGROUND: Grip size of a tennis racquet has been reported to influence performance, but clear evidence of a correlation has yet to be established. HYPOTHESIS: Hitting force during a soft tennis forehand stroke correlates with grip size. STUDY DESIGN: Controlled clinical study. METHODS: A total of 40 healthy volunteers (20 men and 20 women) with a mean age of 21.9 years were enrolled. Of the 40 participants, 20 were experienced soft tennis players (10 men and 10 women) and 20 were nonexperienced soft tennis players (10 men and 10 women). Based on racquets with 5 different grip sizes, the hitting force during a soft tennis forehand stroke was measured with a handheld dynamometer. Correlations between 4 factors (sex, experience, grip and pinch strengths, and middle finger length) and hitting force were evaluated with each grip size. Measurements for each factor were repeated, and a 2-way analysis of variance was performed on the obtained data. RESULTS: The hitting force was greater for male players than for female players and greater for experienced players than for nonexperienced players (P < .01). Men with large grip and pinch strengths demonstrated an increased hitting force with an increase in grip size. Men who had a long middle finger also demonstrated increased hitting force when grip size increased (P < .05). CONCLUSION: The hypothesis proved accurate for experienced men who had a large grip strength, a large pinch strength, and a long middle finger. CLINICAL RELEVANCE: Large-grip-sized racquets may result in better forehand stroke performance when used by experienced male soft tennis players with a large grip strength, a large pinch strength, and a long middle finger. PMID- 23015890 TI - Surgical treatment options for osteochondritis dissecans of the knee. AB - Osteochondritis dissecans of the knee is identified with increasing frequency in the young adult patient. Left untreated, osteochondritis dissecans can lead to the development of osteoarthritis at an early age, resulting in progressive pain and disability. Treatment of osteochondritis dissecans may include nonoperative or operative intervention. Surgical treatment is indicated mainly by lesion stability, physeal closure, and clinical symptoms. Reestablishing the joint surface, maximizing the osteochondral biologic environment, achieving rigid fixation, and ensuring early motion are paramount to fragment preservation. In cases where the fragment is not amenable to preservation, the treatment may include complex reconstruction procedures, such as marrow stimulation, osteochondral autograft, fresh osteochondral allograft, and autologous chondrocyte implantation. Treatment goals include pain relief, restoration of function, and the prevention of secondary osteoarthritis. PMID- 23015891 TI - Ultraviolet light and skin cancer in athletes. AB - The incidence of melanoma and nonmelanoma skin cancers is increasing worldwide. Ultraviolet light exposure is the most important risk factor for cutaneous melanoma and nonmelanoma skin cancers. Nonmelanoma skin cancer includes basal cell carcinoma and squamous cell carcinoma. Constitutive skin color and genetic factors, as well as immunological factors, play a role in the development of skin cancer. Ultraviolet light also causes sunburn and photoaging damage to the skin. PMID- 23015893 TI - Keeping them on the field. PMID- 23015892 TI - Bone health: part 2, physical activity. AB - Mechanical loading is a crucial factor for maintaining skeletal health. Physical activities, exercise, and sports provide a wealth and variety of mechanical loads to bones, through muscle forces, ground reaction forces, and other contact or impact forces. Weightbearing activities can be effective exercises to enhance bone health-particularly, those that involve jumping and impact loads (with greater strain magnitudes, rates, and frequencies). Physical activity appears to be acutely beneficial for enhancing bone health in the early pubertal period and in older age, such as in postmenopausal women. In preparing this article, PubMed, Web of Science, and relevant edited books (English language) were reviewed from 1961 to present. PMID- 23015894 TI - Concussion in sports: the sideline assessment. AB - CONTEXT: The vast differences between individual athletes makes identifying and evaluating sports-related concussion one of the most complex and perplexing injuries faced by medical personnel. EVIDENCE ACQUISITION: This review summarizes the existing literature supporting the use of a multifaceted approach to concussion evaluation on the sideline of the athletic field. Information was drawn from a PubMed search (MEDLINE) for the terms sport concussion for the most recent and relevant literature. CONCLUSIONS: By using a standardized clinical examination that is supported by objective measures of concussion-related symptoms, mental status, and postural control, the medical professional becomes well equipped to make an informed diagnosis. PMID- 23015895 TI - Rehabilitation considerations of a brachial plexus injury with complete avulsion of c5 and c6 nerve roots in a college football player: a case study. AB - Severe brachial plexus injuries are rare in sports, but they have catastrophic results with a significant loss of function in the involved upper extremity. Nerve root avulsions must be timely managed with prompt evaluation, accurate diagnosis, and surgical treatment to optimize the potential for a functional outcome. This case report describes the mechanism of injury, diagnostic evolution, surgical management, and rehabilitation of a college football player who sustained a traumatic complete nerve root avulsion of C5 and C6 (upper trunk of the brachial plexus). Diagnostics included clinical evaluation, magnetic resonance imaging, computed tomography myelogram, and electromyogram. Surgical planning included nerve grafting and neurotization (nerve transfer). Rehabilitation goals were to bring the hand to the face (active biceps function), to stabilize the shoulder for abduction and flexion, and to reduce neuropathic pain. Direct current stimulation, bracing, therapeutic exercise, and biofeedback were used to maximize the use of the athlete's upper extremity. Although the athlete could not return to sport or normal function by most standards, his results were satisfactory in that he regained an ability to perform many activities of daily living. PMID- 23015896 TI - Cervical spine injuries and the return to football. AB - BACKGROUND: The literature dealing with the diagnosis and treatment of cervical spine injuries is considerable. Absent, however, are comprehensive criteria or guidelines for permitting or prohibiting return to collusion activities such as tackle football. OBJECTIVE: The purpose of this report is to describe developmental and posttraumatic conditions of the cervical spine as presenting (1) no contraindication, (2) relative contraindication, or (3) an absolute contraindication to continued participation in tackle football and other contact activities. STUDY DESIGN: Systematic review. METHODS: Analysis of data compiled from more than 1200 cervical spine injuries documented by the National Football Head and Neck Registry, in addition to a review of the limited published literature, plus an understanding of the recognized axial load injury mechanism and extensive anecdotal experience. CONCLUSION: The one overriding principle regarding the return to football or, for that matter, any collusion activity is that the individual be asymptomatic, pain-free, and neurologically intact and have full strength and full range of cervical motion. PMID- 23015897 TI - Imaging of cervical spine injuries in athletes. AB - Trauma of the cervical spine is one of the most harrowing injuries seen in athletics. Although such injuries are not common, their impact can be devastating. Based on a thorough review of the literature, this article explains the identification of cervical spine trauma and the importance of stability therein. Multiple examples are given highlighting these findings and the way that multiple modalities can be used to asses such injuries. The article concludes with a brief review of the current recommendations as they relate to imaging in the initial assessment of cervical spine trauma. PMID- 23015898 TI - Recovery from injury in sport: considerations in the transition from medical care to performance care. AB - Return from athletic injury can be a lengthy and difficult process. The injured athlete commonly receives care from several providers during rehabilitation. As their condition improves, injured athletes resume strength and conditioning programs and sport-specific activities in preparation for return to play. Until full medical clearance is provided to return to sport and the athlete is psychologically ready to return to play, the injured athlete remains a patient regardless of who is developing and supervising each component of the recovery process. An understanding of and commitment to the plan of care for each athlete, as well as communication among health care providers, strength and conditioning specialists, coaches, and the athletes, are essential to the safest and most efficient recovery from injury. PMID- 23015900 TI - Community-Associated Methicillin-Resistant Staphylococcus aureus Infections in the Athlete. AB - CONTEXT: Community-associated methicillin-resistant Staphlococcus aureus (CA MRSA) has become of increasing concern in the athletic setting. Appropriate recognition, treatment, and prevention measures are all paramount to protect individual athletes and teamwide outbreaks. EVIDENCE ACQUISITION: Relevant electronic databases (Medline or PubMed) through 2008 were searched. Articles and studies relevant to this topic were reviewed for pertinent clinical information. STUDY TYPE: Clinical review. RESULTS: CA-MRSA is an increasing problem both in the community at large and in the athletic population. CONCLUSION: Early infections based on methicillin-resistant Staphlococcus aureus are often misidentified, leading to delay in appropriate treatment. A high level of suspicion, prompt recognition, and appropriate treatment can minimize morbidity associated with CA-MRSA. Careful selection of antibiotics in suspected cases is important, with more severe infections requiring hospitalization and intravenous antibiotics. Eradication of bacteria in colonized patients has not yet proven to be effective. Prevention of infections is multifaceted, and it includes education, proper personal hygiene, routine cleaning of equipment, and proper wound care. PMID- 23015899 TI - Soft tissue injections in the athlete. AB - BACKGROUND: Injections into or adjacent to soft tissue structures, including muscle, tendon, bursa, and fascia, for pain relief and an earlier return to play have become common in the field of sports medicine. STUDY DESIGN: Clinical review. RESULTS: Corticosteroids, local anesthetics, and ketorolac tromethamine (Toradol) are the most commonly used injectable agents in athletes. The use of these injectable agents have proven efficacy in some disorders, whereas the clinical benefit for others remain questionable. All soft tissue injections performed for pain control and/or an anti-inflammatory effect have potentially serious side effects, which must be considered, especially in the pregame setting. CONCLUSIONS: The primary concern regarding corticosteroid and local anesthetic injections is an increased risk of tendon rupture associated with the direct injection into the tendon. Intramuscular Toradol injections provide significant analgesia, as well as an anti-inflammatory effect via its inhibitory effect on the cyclooxygenase pathway. The risk of bleeding associated with Toradol use is recognized but not accurately quantified. PMID- 23015901 TI - Protective athletic mouthguards: do they cause harm? AB - BACKGROUND: Protective athletic mouthguards (PAMs) have been worn in competitive sports for more than 100 years. Today, participants in contact and noncontact sports wear PAMs. HYPOTHESIS: Wearing a PAM produces oral injury. STUDY TYPE: Case series. STUDY DESIGN AND METHODS: Sixty-two Division I football players voluntarily participated in the study. Before the beginning of the season, each player underwent a thorough oral examination, and all abnormal oral findings were photographed (hyperkeratosis, erythema, ulceration, and combinations thereof). At midseason, 14 players were given complete oral examinations, with all abnormal oral findings documented. At season end, all remaining players (n = 53) had complete oral examinations and photographs taken of abnormal oral findings. RESULTS: The preseason examination of 62 players found a total of 85 lesions (1.4 lesions per player) on the gingiva (n = 17), buccal mucosa (n = 60), and palate (n = 8). The 14 midseason players had 28 lesions (2.0 lesions per player) on gingiva (n = 8), buccal mucosa (n = 16), and tongue (n = 4). At season end, the 53 remaining players had 198 lesions (3.7 per player) on the gingiva (n = 96), buccal mucosa (n = 79), tongue (n = 18), and palate (n = 5). In addition, the lesion intensity scores progressively increased over the season. Because the palate did not come into direct contact with the PAM, it was used as an internal control. CONCLUSION: The wearing of a PAM may increase the number and intensity of oral mucosal injuries, which may cause localized soft tissue reactions such as hyperkeratosis, erythema, and ulceration. CLINICAL RELEVANCE: Because the PAM reduces tooth injury but may cause oral lesions, it should be sanitized daily and changed regularly and replaced whenever it becomes sharp and jagged or when the athlete develops an irritation in the mouth. PMID- 23015902 TI - Unloader braces for medial compartment knee osteoarthritis: implications on mediating progression. AB - BACKGROUND: For persons with unicompartment knee osteoarthritis (OA), off unloader braces are a mechanical intervention designed to reduce pain, improve physical function, and possibly slow disease progression. Pain relief is thought to be mediated by distracting the involved compartment via external varus or valgus forces applied to the knee. In so doing, tibiofemoral alignment is improved, and load is shifted off the degenerative compartment, where exposure to potentially damaging and provocative mechanical stresses are reduced. OBJECTIVES: To provide a synopsis of the evidence documented in the scientific literature concerning the efficacy of off-loader knee braces for improving symptomatology associated with painful disabling medial compartment knee OA. SEARCH STRATEGY: Relevant peer-reviewed publications were retrieved from a MEDLINE search using the terms with the reference terms osteoarthritis, knee, and braces (per Medical Subject Headings), plus a manual search of bibliographies from original and review articles and appropriate Internet resources. RESULTS: For persons with combined unicompartment knee OA and mild to moderate instability, the strength of recommendation reported by the Osteoarthritis Research Society International in the ability of off-loader knee braces to reduce pain, improve stability, and diminish the risk of falling was 76% (95% confidence interval, 69%-83%). The more evidence the treatment is effective, the higher the percentage. CONCLUSIONS: Given the encouraging evidence that off-loader braces are effective in mediating pain relief in conjunction with knee OA and malalignment, bracing should be fully used before joint realignment or replacement surgery is considered. With the number of patients with varus deformities and knee pain predicted to increase as the population ages, a reduction of patient morbidity for this widespread chronic condition in combination with this treatment modality could have a positive impact on health care costs and the economic productivity and quality of life of the affected individuals. PMID- 23015904 TI - Partial tendon release for treatment of a symptomatic snapping biceps femoris tendon: a case report. AB - Snapping of the biceps femoris tendon over the fibular head is an uncommon condition. Reported causes include an anomalous insertion of the tendon, trauma at the insertion site of the tendon, and an abnormality of the fibular head. This article reports a case of a painful snapping biceps femoris tendon in a patient without an anomalous tendon insertion or an abnormality of the fibular head. Partial release of the superior aspect of the tendon resulted in resolution of symptoms. PMID- 23015903 TI - Heel pain in the athlete. AB - CONTEXT: Heel pain, a relatively common problem in the athlete, can present a diagnostic and therapeutic dilemma. The purpose of this article is to review treatment techniques for common causes of heel pain in the athlete. EVIDENCE ACQUISITION: Articles in the English literature through August 2008 were selected and reviewed in the context of the management of heel pain in the athlete. Clinical and surgical photographs are presented as an illustration of preferred techniques and pertinent pathologic findings. RESULTS: Although nonoperative treatment remains the mainstay for most painful heel pathologies, a number of surgical interventions have shown encouraging results in carefully selected patients. CONCLUSIONS: The management of heel pain in the athlete requires diagnostic skill, appropriate imaging evaluation, and a careful, initially conservative approach to treatment. Surgical treatment can be successful in carefully selected patients. PMID- 23015905 TI - All-inside meniscal repair. AB - All-inside meniscal repair has gained widespread popularity over recent years. The devices and techniques have rapidly evolved, resulting in increased ease of use and reduced surgical times and risk to the neurovascular structures. Despite these advances, inside-out suture repairs remain the current gold standard, with proven long-term results. All-inside techniques must continue to be compared to inside-out meniscal repair. PMID- 23015906 TI - Big hits. PMID- 23015908 TI - Sports-related wrist injuries in adults. AB - BACKGROUND: Wrist injuries are common in sports. Those who are involved in the care of athletes should be familiar with hand and wrist anatomy, common wrist injuries, and clinical examination; they should also know how to recognize emergent problems. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 23015907 TI - The basic science of articular cartilage: structure, composition, and function. PMID- 23015909 TI - Operative treatment of a complete rupture of the origination of the rectus femoris. AB - A 23-year-old male athlete reported both feeling and hearing a pop in his anterior thigh while sprinting. This was followed by immediate pain and an inability to walk. He had swelling and tenderness in his inguinal region. Radiographs were normal. An magnetic resonance imaging revealed a complete avulsion of the rectus femoris from its origin on the anterior inferior iliac spine. Following discussions of his treatment options, the patient chose to undergo operative management of the injury. A surgical repair was performed of the tendon of the direct head to the anterior inferior iliac spine through bone tunnels. He had a full recovery over the next 6 months and subsequently returned to unrestricted active military duty. PMID- 23015910 TI - Instrumentation-specific infection after anterior cruciate ligament reconstruction. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is uncommonly complicated by postoperative infections, the causes of which are rarely identified. HYPOTHESIS/PURPOSE: The goal of this study was to characterize the relationship between methodological sterilization failure and ACL reconstruction infection at an army medical center. STUDY DESIGN: Case series. METHODS: Demographic, clinical, and laboratory data were collected on 5 postoperative infections during a 14-week period in 2003. All ACL reconstructions completed within the past 6 years at the institution were reviewed to establish a baseline infection rate. RESULTS: There was a 14-week period in which 5 cases of infection occurred postoperatively, an infection rate of 12.2%. Previous and subsequent to the identified period, the established rate of infection after ACL reconstruction was 0.3%. There were no violations of sterile technique noted in any of the identified cases. All cases utilized hamstring autograft. All cases also used the DePuy Mitek Intrafix system for tibial fixation of the graft. Two of these cases had positive cultures. CONCLUSIONS: An isolated series of increased infection rate led to an investigation into the sterile technique. This revealed gross biomaterial remaining inside instrumentation common to all the cases, the DePuy Mitek Intrafix system. The modular cannulated hex driver, made to fit over a small caliber wire, had no wire brushes of a small-enough diameter for the cleaning and sterilization procedure. After recognition of infection, all patients were treated with surgical irrigation and debridement of the affected knee, as well as individualized antibiotic therapy. Patients were followed postoperatively and no patients required revision ACL reconstruction or radical debridement of the graft. PMID- 23015911 TI - Myths concerning alpine skiing injuries. AB - There are many commonly discussed myths about ski safety that are propagated by industry, physicians, and skiers. Through a review of the literature concerning 12 such topics, this article demonstrates that the following are untrue: (1) Broken legs have been traded for blown-out knees. (2) If you know your DIN (a slang term for release indicator value), you can adjust your own bindings. (3) Toe and heel piece settings must be the same to function properly. (4) Formal ski instruction will make you safer. (5) Very short skis do not need release bindings. (6) Spending a lot of money on children's equipment is not worth the cost. (7) Children need plenty of room in ski boots for their growing feet. (8) If you think you are going to fall, just relax. (9) Exercise can prevent skiing injuries. (10) Lower release settings can reduce the risk of anterior cruciate ligament injury. (11) Buying new ski equipment is safer than renting. (12) Skiing is among the most dangerous of activities. It is important for the skiing public, physicians, and all those interested in improving skiing safety to verify the measures they advocate. The statements analyzed here are simply untrue and have the potential to cause harm if taken as fact by those exposed to these unsupported opinions. PMID- 23015912 TI - Effort thrombosis presenting as pulmonary embolism in a professional baseball pitcher. AB - CONTEXT: Effort thrombosis, or Paget-Schroetter's syndrome, is a rare subset of thoracic outlet syndrome in which deep venous thrombosis of the upper extremity occurs as the result of repetitive overhead motion. It is occasionally associated with pulmonary embolism. This case of effort thrombosis and pulmonary embolus was in a 25-year-old major league professional baseball pitcher, in which the only presenting complaints involved dizziness and shortness of breath without complaints involving the upper extremity-usually, a hallmark of most cases of this condition. The patient successfully returned to play for 5 subsequent seasons at the major league level after multimodal treatment that included surgery for thoracic outlet syndrome. OBJECTIVE: Though rare, effort thrombosis should be included in the differential diagnosis of throwing athletes with traditional extremity-focused symptoms and in cases involving pulmonary or thoracic complaints. Rapid diagnosis is a critical component of successful treatment. PMID- 23015913 TI - Cardiovascular health, part 1: preparticipation cardiovascular screening. AB - CONTEXT: Identification of potentially fatal cardiac conditions in otherwise healthy athletes presents a major challenge to the sports medicine community. The requirements for preparticipation screening vary among countries and even from state to state within the United States. The mandated use of an electrocardiogram as a screening implement has provoked international controversy. EVIDENCE ACQUISITION: Part 1 of this review highlights the current guidelines and controversies surrounding cardiovascular screening, with a focus on the diagnostic challenges associated with identifying athletes with inheritable cardiomyopathies. Data sources were limited to peer-reviewed publications from 1984 to the present. RESULTS: Preparticipation screening should include at least a history and a physical examination for all athletes, whereas use of an electrocardiogram is still controversial. Diagnosis of inherited cardiomyopathies presents unique challenges, particularly in hypertrophic cardiomyopathy, where many features can mimic those found in the "athlete's heart." CONCLUSIONS: Recognizing cardiac conditions in athletes that can predispose them to sudden cardiac death or other adverse outcomes is of vital importance, as is the appropriate exclusion of these athletes from competition. Further studies are needed to determine the most efficient and cost-effective means of screening and to increase the sensitivity and specificity of diagnostic testing for inheritable cardiovascular diseases. PMID- 23015914 TI - Participation in high-impact sports predicts bone mineral density in senior olympic athletes. AB - BACKGROUND: Loss of bone mineral density (BMD) and resultant fractures increase with age in both sexes. Participation in resistance or high-impact sports is a known contributor to bone health in young athletes; however, little is known about the effect of participation in impact sports on bone density as people age. HYPOTHESIS: To test the hypothesis that high-impact sport participation will predict BMD in senior athletes, this study evaluated 560 athletes during the 2005 National Senior Games (the Senior Olympics). STUDY DESIGN: Cross-sectional methods. The athletes completed a detailed health history questionnaire and underwent calcaneal quantitative ultrasound to measure BMD. Athletes were classified as participating in high impact sports (basketball, road race [running], track and field, triathalon, and volleyball) or non-high-impact sports. Stepwise linear regression was used to determine the influence of high impact sports on BMD. RESULTS: On average, participants were 65.9 years old (range, 50 to 93). There were 298 women (53.2%) and 289 men (51.6%) who participated in high-impact sports. Average body mass index was 25.6 +/- 3.9. The quantitative ultrasound-generated T scores, a quantitative measure of BMD, averaged 0.4 +/- 1.3 and -0.1 +/- 1.4 for the high-impact and non-high-impact groups, respectively. After age, sex, obesity, and use of osteoporosis medication were controlled, participation in high-impact sports was a significant predictor of BMD (R(2) change 3.2%, P < .001). CONCLUSIONS: This study represents the largest sample of BMD data in senior athletes to date. Senior participation in high-impact sports positively influenced bone health, even in the oldest athletes. CLINICAL RELEVANCE: These data imply that high-impact exercise is a vital tool to maintain healthy BMD with active aging. PMID- 23015915 TI - Prevention of overuse injuries in young baseball pitchers. AB - With millions of athletes participating in baseball in the United States annually, overuse injuries are common occurrences. Epidemiological studies, including surveys of orthopaedic surgeons, coaches, and athletes, indicate that injuries such as those to the ulnar collateral ligament are increasing in incidence. Many risk factors for throwing injuries have been proposed-including the immature skeleton, throwing mechanics, glenohumeral internal rotation deficit, pitch type, velocity, and counts-but little evidence is available to support the majority of these factors. Recent studies have shown that pitch volume and overuse are central factors that lead to shoulder and elbow injuries in the young throwing athlete. Pitching while fatigued and in spite of arm pain has also been implicated. PMID- 23015916 TI - Grip lock injury in male gymnasts. AB - BACKGROUND: Grip lock is a high bar injury in male gymnastics and occurs while the gymnast is rotating around the high bar. Its mechanism and treatment have been poorly documented. STUDY DESIGN: Case reports. RESULTS: One gymnast sustained an extensor tendon injury and ulnar styloid fracture and was treated nonoperatively. The second gymnast sustained open fracture of the radius and ulna with extensor tendon ruptures and was surgically treated. Both gymnasts healed and were able to return to collegiate gymnastics despite residual finger extensor lag. CONCLUSIONS: Grip lock is a physically and psychologically devastating injury on the men's high bar that can cause forearm fractures and extensor tendon injuries at the wrist (Zone 8), which may result in residual extensor tendon lag. Injuries may be prevented with proper grip fit, appropriate maintenance of grips, and limited duration of use, as well as education of athletes, athletic trainers, and coaches. PMID- 23015918 TI - Dying to run. PMID- 23015919 TI - Characteristics of drug and dietary supplement inquiries by college athletes. AB - BACKGROUND: In the United States, the National Center for Drug Free Sport manages the drug-testing programs for athletes of the National Collegiate Athletic Association (NCAA). Through its Resource Exchange Center (REC), Drug Free Sport supports athletic staff and athletes with information regarding drugs and dietary supplements. PURPOSE: To characterize the types of drug-related and dietary supplement-related inquiries submitted to Drug Free Sport through the REC. STUDY DESIGN: Cross-sectional study. METHODS: All inquiries submitted to the REC for the period of September 1, 2005, through June 30, 2006, were reviewed. The data were categorized by the method of inquiry submission; the name of the substance in question; the sex, sport, and NCAA division of the athlete involved; the nature of the inquiry; and the response provided by the REC regarding the NCAA's status of the substance in question. RESULTS: Pseudoephedrine, acetaminophen/hydrocodone, and albuterol were the most commonly self-searched medications; stimulants accounted for the majority of banned medications. Dietary supplements accounted for 80% of all inquiries submitted to the REC via the Banned Drug Inquiry Form. Among all dietary supplements, creatine was the most commonly inquired. Banned substances accounted for 29% of all inquiries. CONCLUSIONS: There were more than 10 000 inquiries regarding the status of medications, dietary supplements, and other substances for NCAA athletes during the 2005-2006 academic year. It is helpful for athletes to have resources that help them navigate banned-substance lists and so avoid the inadvertent use of banned substances. CLINICAL RELEVANCE: Educating athletes regarding the stimulant content of various dietary supplements and addressing the lack of clinical trials to support stated claims and safety appear critical. PMID- 23015917 TI - Data-based interval hitting program for female college volleyball players. AB - CONTEXT: Interval sports programs are a critical rehabilitation element when preparing the injured athlete for a return to preinjury activities. There is currently no published interval hitting program to guide a return to unrestricted play for the volleyball athlete. Therefore, data-based, position-specific overhead hitting programs that control for intensity, time, and number of ball strikes were developed for female college volleyball players. EVIDENCE ACQUISITION: Records from a single Division I varsity women's volleyball team were examined for all matches during 7 consecutive years of team play. Data were collected for number of hitting and service attempts per game for each position and the number of games per match. RESULTS: Per game, middle hitters averaged 4.51 attacks and 2.77 service attempts; right-side hitters, 3.58 attacks and 1.26 service attempts; outside hitters, 6.37 attacks and 3.44 service attempts; and setters and defensive specialists, 0.17 attacks and 1.78 service attempts. CONCLUSION: The interval hitting program can provide rehabilitation specialists with a data-based approach that may facilitate a return to play and minimize the risk of reinjury for volleyball athletes. PMID- 23015920 TI - Cardiovascular health, part 2: sports participation in athletes with cardiovascular conditions. AB - CONTEXT: An athlete's health may be endangered if he or she continues to compete after diagnosis of certain cardiovascular conditions. The most worrisome risk is sudden cardiac death; the annual rate in US athletes is 1 in 50 000 to 200 000. EVIDENCE ACQUISITION: Part 2 of this review highlights the current guidelines and controversies surrounding compatibility of participation with a variety of cardiac conditions in competitive and recreational athletics. Data sources were limited to peer-reviewed publications from 1984 to the April 2009. RESULTS: The guidelines published by the American College of Cardiology and the European Society of Cardiology provide a framework for safe competitive and recreational sports participation in athletes with a broad spectrum of inherited and acquired cardiovascular disorders. These guidelines are necessarily conservative because it is not currently possible to individualize risk prediction. Few data are available in many areas, particularly in the noncompetitive arena or in older athletes. CONCLUSIONS: Published national guidelines are currently the foundation governing return-to-play decisions in athletes with cardiovascular conditions. Further studies are needed to refine risk stratification algorithms to allow athletes with cardiovascular conditions to reap the health benefits of regular exercise and sports participation without undue risk. PMID- 23015921 TI - Diabetes in sports. AB - CONTEXT: Exercise is recommended for individuals with diabetes mellitus, and several facets of the disease must be considered when managing the diabetic athlete. The purpose of this article is to review diabetes care in the context of sports participation. EVIDENCE ACQUISITION: Relevant studies were identified through a literature search of MEDLINE and the Cochrane database, as well as manual review of reference lists of identified sources. RESULTS: Diabetics should be evaluated for complications of long-standing disease before beginning an exercise program, and exercise should be modified appropriately if complications are present. Athletes who use insulin or oral insulin secretogogues are at risk for exercise-induced immediate or delayed hypoglycemia. Diabetics are advised to engage in a combination of regular aerobic and resistance exercise. Insulin dependent diabetics should supplement carbohydrate before and after exercise, as well as during exercise for events lasting longer than 1 hour. Adjustment of insulin dosing based on planned exercise intensity is another strategy to prevent hypoglycemia. Insulin-dependent athletes should monitor blood sugar closely before, during, and after exercise. Significant hyperglycemia before exercise should preclude exercise because the stress of exercise can paradoxically exacerbate hyperglycemia and lead to ketoacidosis. Athletes should be aware of hypoglycemia symptoms and have rapidly absorbable glucose available in case of hypoglycemia. CONCLUSION: Exercise is an important component of diabetes treatment, and most people with diabetes can safely participate in sports at recreational and elite levels with attention to appropriate precautions. PMID- 23015922 TI - Current concepts in the evaluation and treatment of the shoulder in overhead throwing athletes, part 1: physical characteristics and clinical examination. AB - The overhead-throwing athlete is a challenging sports medicine patient. The repetitive microtraumatic stresses imposed on the athlete's shoulder joint complex during the throwing motion constantly places the athlete at risk for injury. These stresses may effect several adaptations to normal shoulder range of motion, strength, and scapula position. The clinician should therefore appreciate the unique physical characteristics of the overhead-throwing athlete to accurately evaluate and treat throwing-related injuries. PMID- 23015923 TI - Massive rotator cuff tear in an adolescent athlete: a case report. AB - Full-thickness rotator cuff tears in the young athlete are a rare injury. These injuries typically result from an acute traumatic event in a contact athlete, as opposed to overuse injuries more commonly seen in throwing athletes. Acute tears may be initially overlooked, with the symptoms attributed to other, more common causes, such as cuff contusion or brachial plexus neuropraxia ("stinger" or "burner"). If undiagnosed, the tear may progress to an irreparable state at the time of eventual diagnosis. Therefore, rotator cuff tear must be included in the differential for acute shoulder injuries in the young athlete. This article presents a case of an adolescent athlete with a traumatic, massive rotator cuff tear that was diagnosed and managed promptly with excellent outcome. PMID- 23015924 TI - Clinical outcomes after anterior cruciate ligament reconstruction: a meta analysis of autograft versus allograft tissue. AB - BACKGROUND: Clinical outcomes of autograft and allograft anterior cruciate ligament (ACL) reconstructions are mixed, with some reports of excellent to good outcomes and other reports of early graft failure or significant donor site morbidity. OBJECTIVE: To determine if there is a difference in functional outcomes, failure rates, and stability between autograft and allograft ACL reconstructions. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials (Evidence Based Medicine Reviews Collection), Cochrane Database of Systematic Reviews, Web of Science, CINAHL, and SPORTDiscus were searched for articles on ACL reconstruction. Abstracts from annual meetings of the American Academy of Orthopaedic Surgeons, American Orthopaedic Society for Sports Medicine, and Arthroscopy Association of North America were searched for relevant studies. STUDY SELECTION: INCLUSION CRITERIA FOR STUDIES WERE AS FOLLOWS: primary unilateral ACL injuries, mean patient age less than 41 years, and follow-up for at least 24 months postreconstruction. Exclusion criteria for studies included the following: skeletally immature patients, multiligament injuries, and publication dates before 1990. DATA EXTRACTION: Joint stability measures included Lachman test, pivot-shift test, KT-1000 arthrometer assessment, and frequency of graft failures. Functional outcome measures included Tegner activity scores, Cincinnati knee scores, Lysholm scores, and IKDC (International Knee Documentation Committee) total scores. RESULTS: More than 5000 studies were identified. After full text review of 576 studies, 56 were included, of which only 1 directly compared autograft and allograft reconstruction. Allograft ACL reconstructions were more lax when assessed by the KT-1000 arthrometer. For all other outcome measures, there was no statistically significant difference between autograft and allograft ACL reconstruction. For all outcome measures, there was strong evidence of statistical heterogeneity between studies. The sample size necessary for a randomized clinical trial to detect a difference between autograft and allograft reconstruction varied, depending on the outcome. CONCLUSIONS: With the current literature, only KT-1000 arthrometer assessment demonstrated more laxity with allograft reconstruction. A randomized clinical trial directly comparing allograft to autograft ACL reconstruction is warranted, but a multicenter study would be required to obtain an adequate sample size. PMID- 23015925 TI - Psychological rehabilitation from anterior cruciate ligament-medial collateral ligament reconstructive surgery: a case study. AB - BACKGROUND: Research has shown that some of the more common psychological responses to injury (ie, depression, anger, anxiety) are amplified in cases of traumatic injury. HYPOTHESIS/PURPOSE: An 18-year-old male scholarship soccer player who, owing to a perceived deliberate injurious tackle by an opposition player, tore the medial collateral ligament and anterior cruciate ligament of his right knee. A psychological case perspective is presented. STUDY DESIGN: Retrospective case report. RESULTS: Various personal and situational factors can compound negative psychological response to injury. A number of extreme responses are explored, including posttraumatic stress, depression, and fear of reinjury. CONCLUSIONS: Practitioners should be willing and able to facilitate referral in the instance of more extreme psychological response to anterior cruciate ligament injury. PMID- 23015926 TI - New Year's Resolutions. PMID- 23015927 TI - A randomized controlled single-blinded comparison of stretching versus stretching and joint mobilization for posterior shoulder tightness measured by internal rotation motion loss. AB - BACKGROUND: Posterior shoulder tightness, as demonstrated by limited internal rotation range of motion, is a suggested factor in many shoulder pathologies. Methods to increase posterior shoulder mobility may be beneficial. HYPOTHESIS: Shoulder internal rotation range of motion will not change with either of 2 interventions: cross-body stretch alone and cross-body stretch plus posterior capsule joint mobilization. STUDY DESIGN: Randomized controlled single-blinded clinical trial. METHODS: The study comprised 39 college-age asymptomatic participants (7 men, 32 women) who were randomly assigned to 1 of 2 groups: stretching only (n, 20) and stretching plus posterior joint mobilizations (n, 19). All had a between-shoulder difference of internal rotation of 10 degrees or more. Shoulder internal and external rotation was measured before and after a 4 week intervention period and 4 weeks postintervention. Participants in the stretching-only group performed the cross-body stretch on the limited side. Those in the other group (cross-body stretch plus joint mobilization) were treated with posterior joint mobilization techniques on the limited side. RESULTS: Overall means for internal rotation of the treated shoulders significantly increased over baseline at the end of the intervention period and at 4 weeks postintervention. External rotation in all shoulders remained unchanged. By the end of intervention, total motion increased significantly from baseline but decreased significantly from the end of intervention to 4 weeks postintervention. Although not statistically significant, the second group (cross-body stretch plus joint mobilization) had greater increases in internal rotation. At 4 weeks postintervention, the second group had maintained its internal rotation gains to a greater degree than those of the stretching-only group. CONCLUSION: Internal rotation increased in both groups. Inclusion of joint mobilization in a rehabilitation program created trends toward increased shoulder internal rotation mobility. CLINICAL RELEVANCE: Both methods-cross-body stretch and cross-body stretch plus joint mobilization-may be beneficial for those with limited internal rotation range of motion. PMID- 23015929 TI - Ulnar shaft stress fracture in a high school softball pitcher. AB - This article presents a case of a 17-year-old softball pitcher with insidious onset of right forearm pain. On presentation, the patient had tenderness on palpation of the midshaft of the ulna, pain with resisted pronation, and pain with fulcrum-type stressing of the forearm. A bone scan revealed increased uptake in the right ulna, and a subsequent magnetic resonance imaging revealed bone marrow edema and numerous small ulnar stress fractures. She was treated with bone stimulation and complete rest and is in the process of returning to pitching. PMID- 23015928 TI - Current concepts in the evaluation and treatment of the shoulder in overhead throwing athletes, part 2: injury prevention and treatment. AB - The overhead throwing athlete is an extremely challenging patient in sports medicine. The repetitive microtraumatic stresses imposed on the athlete's shoulder joint complex during the throwing motion constantly place the athlete at risk for injury. Treatment of the overhead athlete requires the understanding of several principles based on the unique physical characteristics of the overhead athlete and the demands endured during the act of throwing. These principles are described and incorporated in a multiphase progressive rehabilitation program designed to prevent injuries and rehabilitate the injured athlete, both nonoperatively and postoperatively. PMID- 23015930 TI - A shoulder health survey: correlating behaviors and comorbidities with shoulder problems. AB - Shoulder pain and loss of shoulder function are common complaints reported by a variety of patients. This article suggests that shoulder pain and loss of function are directly proportional to lifestyle choices, including smoking and obesity. To investigate possible relationships between lifestyle choices and shoulder health, the authors conducted an online survey combining the Oxford Shoulder Questionnaire, the Shoulder Rating Questionnaire, and the Subjective Shoulder Rating System. Data were collected from 166 respondents. Statistical significance was set at P < .05. The data show a statistically significant correlation between decreased shoulder function and cigarette smoking and a similar correlation between decreased shoulder function, elevated cholesterol, and obesity. PMID- 23015931 TI - The kinetic chain in overhand pitching: its potential role for performance enhancement and injury prevention. AB - The overhead throwing motion is a coordinated effort of muscle units from the entire body, culminating with explosive motion of the upper extremity. The throwing motion occurs at a rapid pace, making analysis difficult in real time. Electromyographic studies and high-speed video recordings have provided invaluable details regarding the involved musculature, the sequence of muscle involvement, and associated kinematic variables. The goal of the present article is to provide an overview of the kinetic chain-that is, a detailed description of the muscular coordination during each phase of pitching-and to describe specific types of pitches. An enhanced understanding of the components of the kinetic chain and the phases of the throwing motion can provide important information for rehabilitation, performance enhancement, and injury prevention. PMID- 23015932 TI - Clinical management of scapulothoracic bursitis and the snapping scapula. AB - CONTEXT: Symptomatic scapulothoracic bursitis and crepitus are disorders of the scapulothoracic articulation that are often poorly understood. They can be a source of persistent pain and dysfunction in the active overhead throwing athlete. It is important to distinguish between scapulothoracic bursitis and scapulothoracic crepitus. Scapulothoracic bursitis refers to inflammation of the bursae secondary to trauma or overuse owing to sports activities or work. Scapulothoracic crepitus is defined by a grinding, popping, or thumping sound or sensation secondary to abnormal scapulothoracic motion. EVIDENCE ACQUISITION: This article presents the causes, diagnosis, and management of these shoulder conditions in a manner that is relevant to clinicians, athletic trainers, and physical therapists, and it reviews relevant studies to determine the consensus on nonoperative treatment, as well as open and arthroscopic surgical treatment. RESULTS: The causes of scapulothoracic bursitis and crepitus include direct or indirect trauma, overuse syndromes, glenohumeral joint dysfunction, osseous abnormalities, muscle atrophy or fibrosis, and idiopathic causes. Scapulothoracic bursitis and crepitus remain primarily clinical diagnoses; however, imaging studies or local injections may also be helpful. The initial treatment of scapulothoracic bursitis and scapulothoracic crepitus should be nonoperative. Surgical treatment options include partial scapulectomy or resection of the superomedial angle of the scapula, open bursal resection, and arthroscopic bursectomy. Despite the lack of agreement among orthopaedic surgeons concerning which procedure is best for treating symptomatic scapulothoracic bursitis and crepitus, most reports have demonstrated good to excellent outcomes in a significantly high percentage of patients. CONCLUSION: Clearly, the best initial approach to these conditions is a nonoperative treatment plan that combines scapular strengthening, postural reeducation, and core strength endurance. The addition of local modalities, nonsteroidal anti- inflammatory drugs, and localized injections may also be helpful. If an appropriate trial of nonoperative management proves unsuccessful, surgical correction can produce good results. PMID- 23015934 TI - Sports health orthopaedic magnetic resonance challenge. PMID- 23015933 TI - Systematic review of rehabilitation versus operative stabilization for the treatment of first-time anterior shoulder dislocations. AB - CONTEXT: Primary anterior shoulder dislocation is a frequent injury in young active patients. Traditionally, conservative nonoperative primary treatment has been advocated for a majority of first-time dislocators, whereas operative stabilization has been reserved for recurrent dislocators or those involved in strenuous physical activity. Currently, no consensus exists on whether to treat a first-time anterior shoulder dislocation surgically. OBJECTIVE: (1) To provide clinical recommendations regarding the therapeutic intervention for first-time anterior shoulder dislocators and (2) to determine if there is sufficient Level 1 or 2 evidence available for the establishment of a uniform, optimal treatment protocol. DATA SOURCES: A systematic review of prospective randomized controlled trials with human participants was performed. PubMed, the Cochrane Database of Systematic Reviews, and secondary references were appraised for studies published between 1994 and 2009. STUDY SELECTION: Inclusion criteria were English-language Level 1 or 2 studies involving the treatment of primary anterior shoulder dislocation. Exclusion criteria included non-English-language articles; Level 3, 4, or 5 studies; and studies examining treatment of recurrent/posterior shoulder dislocation or diagnoses other than primary anterior shoulder dislocations. DATA EXTRACTION: Each author conducted an independent quality appraisal of the included studies, identifying strengths, weaknesses, and biases, then reached consensus regarding their values. RESULTS: Five randomized controlled trials were included, and they supported the use of operative management in a focused population. No long-term follow-up data were available describing the effects of surgical intervention or the development of osteoarthritis. Each study design had weaknesses that decreased the validity of the findings. CONCLUSIONS: While limited, the available evidence from randomized controlled trials supports operative stabilization as a reasonable alternative to nonoperative treatment for primary acute shoulder dislocation in young, active adults participating in highly demanding physical activities. Recommendations on the optimal surgical intervention cannot be provided. There is no conclusive evidence available to determine whether operative stabilization or conservative rehabilitation is superior for other patient or injury types. PMID- 23015935 TI - Sports injury prevention failure. PMID- 23015936 TI - Extra-articular Snapping Hip: A Literature Review. AB - CONTEXT: Snapping hip, or coxa saltans, is a vague term used to describe palpable or auditory snapping with hip movements. As increasing attention is paid to intra articular hip pathologies such as acetabular labral tears, it is important to be able to identify and understand the extra-articular causes of snapping hip. EVIDENCE ACQUISITION: The search terms snapping hip and coxa sultans were used in PubMed to locate suitable studies of any publication date (ending date, November 2008). RESULTS: Extra-articular snapping may be caused laterally by the iliotibial band or anteriorly by the iliopsoas tendon. Snapping of the iliopsoas tendon usually requires contraction of the hip flexors and may be difficult to differentiate from intra-articular causes of snapping. Dynamic ultrasound can help detect abrupt tendon translation during movement, noninvasively supporting the diagnosis of extra-articular snapping hip. The majority of cases of snapping hip resolve with conservative treatment, which includes avoidance of aggravating activities, stretching, and anti-inflammatory medication. In recalcitrant cases, surgery to lengthen the iliotibial band or the iliopsoas tendon has produced symptom relief but may result in prolonged weakness. CONCLUSIONS: In treating active patients with snapping soft tissues around the hip, clinicians should recognize that the majority of cases resolve without surgical intervention, while being mindful of the potential for concomitant intra-articular and internal snapping hips. PMID- 23015937 TI - Lateral hip pain in an athletic population: differential diagnosis and treatment options. AB - CONTEXT: Historically, the term greater trochanteric pain syndrome has been used to describe a spectrum of conditions that cause lateral-sided hip pain, including greater trochanteric bursitis, snapping iliotibial band, and/or strains or tendinopathy of the abductor mechanism. Diagnosis of these conditions may be difficult because clinical presentations are variable and sometimes inconclusive. Especially difficult is differentiating intrinsic pain from pain referred to the greater trochanteric region. The purposes of this article are to review the relevant anatomy and pathophysiology of the lateral hip. EVIDENCE ACQUISITION: Data were collected through a thorough review of the literature conducted through a MEDLINE search of all relevant papers between 1980 and January 2010. RESULTS: Recent advances in imaging and an improved understanding of pathomechanics have helped to guide the evaluation, diagnosis, and appropriate treatment for patients presenting with lateral hip pain. CONCLUSION: Various diagnostic tools and treatment modalities can be used to effectively manage the athletic patient presenting with lateral hip pain. PMID- 23015938 TI - Management of the complicated sports concussion patient. AB - CONTEXT: Whereas the majority of sports concussions are isolated self-limited events, some patients have more complicated presentations and management needs. This review presents a framework for the management of these complicated concussion patients. EVIDENCE ACQUISITION: A MEDLINE search for the years 1990 to 2009 was performed using the search terms concussion and athletic injuries. Secondary search terms included symptom, incidence, treatment, and risk factor. The Strength of Recommendation Taxonomy grading system was used for all clinical recommendations. RESULTS: Patterns of complicated sports concussion presentations were identified from literature review, anecdote, and personal experience of the author and colleagues. All clinical recommendations carry a grade of C, unless otherwise noted. CONCLUSION: The sports medicine provider should be aware of certain patterns of complicated sports concussion presentations in order to use a patient-focused approach to management. PMID- 23015939 TI - Platelet-rich plasma: where are we now and where are we going? AB - CONTEXT: Platelet-rich plasma (PRP) may affect soft tissue healing via growth factors released after platelet degranulation. Because of this potential benefit, clinicians have begun to inject PRP for the treatment of tendon, ligament, muscle, and cartilage injuries and early osteoarthritis. EVIDENCE ACQUISITION: A PubMed search was performed for studies relating to PRP, growth factors, and soft tissue injuries from 1990 to 2010. Relevant references from these studies were also retrieved. RESULTS: Soft tissue injury is a major source of disability that may often be complicated by prolonged and incomplete recovery. Numerous growth factors may potentiate the healing and regeneration of tendons and ligaments. The potential benefits of biologically enhanced healing processes have led to a recent interest in the use of PRP in orthopaedic sports medicine. There has been widespread anecdotal use of PRP for muscle strains, tendinopathy, and ligament injuries and as a surgical adjuvant to rotator cuff repair, anterior cruciate ligament reconstruction, and meniscal or labral repairs. Although the fascination with this emerging technology has led to a dramatic increase in its use, scientific data supporting this use are still in their infancy. CONCLUSIONS: The literature is replete with studies on the basic science of growth factors and their relation to the maintenance, proliferation, and regeneration of various tissues and tissue-derived cells. Despite the promising results of several animal studies, well-controlled human studies are lacking. PMID- 23015940 TI - A minimally disruptive surgical technique for the treatment of osteitis pubis in athletes. AB - BACKGROUND: MULTIPLE SURGICAL PROCEDURES EXIST FOR THE TREATMENT OF OSTEITIS PUBIS: curettage of the symphysis joint, wedge resection, complete resection of the joint, placement of extraperitoneal retropubic synthetic mesh, and arthrodesis of the joint. However, a paucity of literature has reported long-term successful outcomes with the aforementioned approaches. Patients treated operatively have reported recalcitrant pain resulting from iatrogenic instability. The article presents the results of a conservative operative technique that avoids disruption of adjacent ligaments. HYPOTHESIS: Preserving the adjacent ligamentous structures will allow competitive athletes to return to competition and activities of daily living free of iatrogenic pelvic instability and pain. STUDY DESIGN: Case series. METHODS: Four competitive athletes (2 professional and 2 collegiate football players) diagnosed with osteitis pubis were treated conservatively for a minimum of 6 months. Patients underwent surgical intervention upon failure to respond to nonoperative management. The degenerative tissue was resected, allowing only bleeding cancellous bone to remain while preserving the adjacent ligaments. An arthroscope was used to assist in curettage, allowing the debridement to be performed through a small incision in the anterior capsule. RESULTS: The symptoms of all 4 patients resolved, and they returned to competitive athletics. This ligament-sparing technique provided a solid, stable repair and pain relief. CONCLUSION: This surgical technique preserves the adjacent ligamentous structures and allows competitive athletes to return to competition and activities of daily living free of pain and void of pelvic instability. CLINICAL RELEVANCE: This technique is a surgical treatment option for athletes with osteitis pubis who fail conservative treatment. PMID- 23015941 TI - Sportsmen's Groin-Diagnostic Approach and Treatment With the Minimal Repair Technique: A Single-Center Uncontrolled Clinical Review. AB - CONTEXT: Sportsmen's groin, also called sports hernia and Gilmore groin, is one of the most frequent sports injuries in athletes and may place an athletic career at risk. It presents with acute or chronic groin pain exacerbated with physical activity. So far, there is little consensus regarding pathogenesis, diagnostic criteria, or treatment. There have been various attempts to explain the cause of the groin pain. The assumption is that a circumscribed weakness in the posterior wall of the inguinal canal, which leads to a localized bulge, induces a compression of the genital branch of the genitofemoral nerve, considered responsible for the symptoms. METHODS: The authors developed an innovative open suture repair-the Minimal Repair technique-to fit the needs of professional athletes. With this technique, the circumscribed weakness of the posterior wall of the inguinal canal is repaired by an elastic suture; the compression on the nerve is abolished, and the cause of the pain is removed. In contrast with that of common open suture repairs, the defect of the posterior wall is not enlarged, the suture is nearly tension free, and the patient can return to full training and athletic activity within a shorter time. The outcome of patients undergoing operations with the Minimal Repair technique was compared with that of commonly used surgical procedures. RESULTS: THE FOLLOWING ADVANTAGES OF THE MINIMAL REPAIR TECHNIQUE WERE FOUND: no insertion of prosthetic mesh, no general anesthesia required, less traumatization, and lower risk of severe complications with equal or even faster convalescence. In 2009, a prospective cohort of 129 patients resumed training in 7 days and experienced complete pain relief in an average of 14 days. Professional athletes (67%) returned to full activity in 14 days (median). CONCLUSION: The Minimal Repair technique is an effective and safe way to treat sportsmen's groin. PMID- 23015942 TI - Postoperative rehabilitation guidelines for hip arthroscopy in an active population. AB - CONTEXT: With the evolution of hip arthroscopy has come an increased recognition of intra-articular hip pathologies and improved techniques for their management. Whereas mechanical problems can often be corrected through surgery, functional deficits must be corrected through the rehabilitation process. Therefore, the evolution of hip arthroscopy has necessitated a progression in hip rehabilitation to ensure optimal postsurgical results. EVIDENCE ACQUISITION: Literature review was conducted with PubMed, EMBASE, and PEDro (1992 to 2009) with the terms hip, rehabilitation, and physical therapy. RESULTS: Although it is generally accepted that rehabilitation after hip arthroscopy is important, there is limited evidence based research to support the rehabilitative guidelines. CONCLUSION: The common goal of hip rehabilitation should remain focused on the return to pain-free function of the hip joint. Outcome data indicate that this goal is being met; however, further data are required to completely validate the long-term success of hip rehabilitation after arthroscopy. PMID- 23015943 TI - Groin injuries in sports medicine. AB - CONTEXT: An in-season groin injury may be debilitating for the athlete. Proper diagnosis and identification of the pathology are paramount in providing appropriate intervention. Furthermore, an adductor strain that is treated improperly can become chronic and career threatening. Any one of the 6 muscles of the adductor muscle group can be involved. The degree of injury can range from a minor strain (grade 1), where minimal playing time is lost, to a severe strain (grade 3), in which there is complete loss of muscle function. Persistent groin pain and muscle imbalance may lead to athletic pubalgia. EVIDENCE ACQUISITION: Relevant studies were identified through a literature search of MEDLINE and the Cochrane database from 1990 to 2009, as well as a manual review of reference lists of identified sources. RESULTS: Ice hockey and soccer players seem particularly susceptible to adductor muscle strains. In professional ice hockey and soccer players throughout the world, approximately 10% to 11% of all injuries are groin strains. These injuries have been linked to hip muscle weakness, a previous injury to that area, preseason practice sessions, and level of experience. This injury may be prevented if these risk factors are addressed before each season. CONCLUSION: Despite the identification of risk factors and strengthening intervention for athletes, adductor strains continue to occur throughout sport. If groin pain persists, the possibility of athletic pubalgia needs to be explored, because of weakening or tears in the abdominal wall muscles. A diagnosis is confirmed by exclusion of other pathology. PMID- 23015944 TI - Posterior hip pain in an athletic population: differential diagnosis and treatment options. AB - CONTEXT: Posterior hip pain is a relatively uncommon but increasingly recognized complaint in the orthopaedic community. Patient complaints and presentations are often vague or nonspecific, making diagnosis and subsequent treatment decisions difficult. The purposes of this article are to review the anatomy and pathophysiology related to posterior hip pain in the athletic patient population. EVIDENCE ACQUISITION: Data were collected through a thorough review of the literature via a MEDLINE search of all relevant articles between 1980 and 2010. RESULTS: Many patients who complain of posterior hip pain actually have pain referred from another part of the body-notably, the lumbar spine or sacroiliac joint. Treatment options for posterior hip pain are typically nonoperative; however, surgery is warranted in some cases. CONCLUSIONS: Recent advancements in the understanding of hip anatomy, pathophysiology, and treatment options have enabled physicians to better diagnosis athletic hip injuries and select patients for appropriate treatment. PMID- 23015945 TI - Orthopaedic magnetic resonance imaging challenge: apophyseal avulsions at the pelvis. AB - Apophyseal avulsion injuries of the hip and pelvis are frequent athletic injuries in children and adolescents, most commonly associated with explosive movement or sprinting. This article details typically encountered apophyseal injuries and their appearance on magnetic resonance imaging. PMID- 23015947 TI - STOP Sports Injuries. PMID- 23015946 TI - Imaging of sports-related hip and groin injuries. AB - A normally functioning hip joint is imperative for athletes who use their lower extremities with running, jumping, or kicking activities. Sports-related injuries of the hip and groin are far less frequent than injuries to the more distal aspect of the extremity, accounting for less than 10% of lower extremity injuries. Despite the lower incidence, hip and groin injuries can lead to significant clinical and diagnostic challenges related to the complex anatomy and biomechanical considerations of this region. Loads up to 8 times normal body weight have been documented in the joint in common daily activities, such as jogging, with significantly greater force expected during competitive athletics. Additionally, treatment for hip and groin injuries can obviate the participation of medical and surgical specialties, with a multidisciplinary approach frequently required. Delay in diagnosis and triage of these injuries may cause loss of time from competition and, potentially, early onset of degenerative changes. Magnetic resonance imaging (MRI) of the hip has proven to be the gold standard for the diagnosis of sports-related hip and groin injuries in the setting of negative radiographs. With its exquisite soft tissue contrast, multiplanar capabilities, and lack of ionizing radiation, MRI is unmatched in the noninvasive diagnosis of intra-articular and extra-articular pathology, as well as intraosseous processes. This review focuses on MRI of common athletic injuries of the hip and groin, including acetabular labral tears, femoral acetabular impingement syndrome, muscle injuries around the hip and groin (including athletic pubalgia), and athletic osseous injuries. PMID- 23015948 TI - Exercise-associated muscle cramps: causes, treatment, and prevention. AB - CONTEXT: Exercise-associated muscle cramps (EAMC) are a common condition experienced by recreational and competitive athletes. Despite their commonality and prevalence, their cause remains unknown. Theories for the cause of EAMC are primarily based on anecdotal and observational studies rather than sound experimental evidence. Without a clear cause, treatments and prevention strategies for EAMC are often unsuccessful. EVIDENCE ACQUISITION: A search of Medline (EBSCO), SPORTDiscus, and Silverplatter (CINHAL) was undertaken for journal articles written in English between the years 1955 and 2008. Additional references were collected by a careful analysis of the citations of others' research and textbooks. RESULTS: Dehydration/electrolyte and neuromuscular causes are the most widely discussed theories for the cause of EAMC; however, strong experimental evidence for either theory is lacking. CONCLUSIONS: EAMC are likely due to several factors coalescing to cause EAMC. The variety of treatments and prevention strategies for EAMC are evidence of the uncertainty in their cause. Acute EAMC treatment should focus on moderate static stretching of the affected muscle followed by a proper medical history to determine any predisposing conditions that may have triggered the onset of EAMC. Based on physical findings, prevention programs should be implemented to include fluid and electrolyte balance strategies and/or neuromuscular training. PMID- 23015949 TI - Injury in the national basketball association: a 17-year overview. AB - BACKGROUND: Injury patterns in elite athletes over long periods continue to evolve. The goal of this study was to review of the injuries and medical conditions afflicting athletes competing in the National Basketball Association (NBA) over a 17-year period. DESIGN: Descriptive epidemiological study. METHODS: Injuries and player demographic information were reported by each team's athletic trainer. Criteria for reportable injuries were those that resulted in (1) physician referral, (2) a practice or game being missed, or (3) emergency care. The demographics, frequency of injury, time lost, and game exposures were tabulated, and game-related injury rates and 95% confidence intervals were calculated. RESULTS: A total of 1094 players appeared in the database 3843 times (3.3 +/- 2.6 seasons). Lateral ankle sprains were the most frequent orthopaedic injury (n, 1658; 13.2%), followed by patellofemoral inflammation (n, 1493; 11.9%), lumbar strains (n, 999; 7.9%), and hamstring strains (n, 413; 3.3%). The most games missed were related to patellofemoral inflammation (n, 10 370; 17.5%), lateral ankle sprains (n, 5223; 8.8%), knee sprains (n, 4369; 7.4%), and lumbar strains (n, 3933; 6.6%). No correlations were found between injury rate and player demographics, including age, height, weight, and NBA experience. CONCLUSION: Professional athletes in the NBA experience a high rate of game related injuries. Patellofemoral inflammation is the most significant problem in terms of days lost in competition, whereas ankle sprains are the most common injury. True ligamentous injuries of the knee were surprisingly rare. Importantly, player demographics were not correlated with injury rates. Further investigation is necessary regarding the consequences and sport-specific treatment of various injuries in NBA players. CLINICAL RELEVANCE: Knowledge of these injury patterns can help to guide treatments and provide more accurate guidelines for an athlete to return to play. PMID- 23015950 TI - Return to activity at altitude after high-altitude illness. AB - CONTEXT: Sports and other activities at high altitude are popular, yet they pose the unique risk for high-altitude illness (HAI). Once those who have suffered from a HAI recover, they commonly desire or need to perform the same activity at altitude in the immediate or distant future. EVIDENCE ACQUISITION: As based on key text references and peer-reviewed journal articles from a Medline search, this article reviews the pathophysiology and general treatment principles of HAI. RESULTS: In addition to the type of HAI experienced and the current level of recovery, factors needing consideration in the return-to-play plan include physical activity requirements, flexibility of the activity schedule, and available medical equipment and facilities. Most important, adherence to prudent acclimatization protocols and gradual ascent recommendations (when above 3000 m, no more than 600-m net elevation gain per day, and 1 rest day every 1 to 2 ascent days) is powerful in its preventive value and thus strongly recommended. When these are not practical, prophylactic medications (acetazolamide, dexamethasone, salmeterol, nifedipine, or phosphodiesterase inhibitors, depending on the type of prior HAI) may be prescribed and can reduce the risk of illness. Athletes with HAI should be counseled that physical and mental performance may be adversely affected if activity at altitude continues before recovery is complete and that there is a risk of progression to a more serious HAI. CONCLUSION: With a thoughtful plan, most recurrent HAI in athletes can be prevented. PMID- 23015952 TI - Isolated unilateral brachial neuritis of the phrenic nerve (parsonage-turner syndrome) in a marathon runner with exertional dyspnea. AB - Parsonage-Turner syndrome, or acute brachial neuritis/plexitis, is a rare condition that should be included in the differential diagnosis of any athlete who presents with antecedent flulike symptoms, with progression to significant neuropathic pain, followed by profound weakness in the affected upper extremity. In rare cases, the main presenting symptom of this condition may be dyspnea on exertion secondary to an isolated unilateral brachial neuritis of the phrenic nerve. PMID- 23015951 TI - Cardiac risks associated with marathon running. AB - CONTEXT: A recent cluster of sudden cardiac deaths in marathon runners has attracted considerable media attention and evoked concern over the safety of long distance running and competition. This review discusses the acute and potential long-term risks associated with marathon running and puts these into perspective with the many health benefits afforded by habitual vigorous exercise. EVIDENCE ACQUISITION: Data sources included peer-reviewed publications from 1979 to January 2010 as identified via PubMed and popular media. RESULTS: Marathon running is associated with a transient and low risk of sudden cardiac death. This risk appears to be even lower in women and is independent of marathon experience or the presence of previously reported symptoms. Most deaths are due to underlying coronary artery disease. The value of preparticipation screening is limited by its insensitivity and impracticality of widespread implementation. Appropriate preparation and deployment of trained medical personnel and availability of automatic external defibrillators are expected to have a major impact on survival from cardiac arrests during marathons. Cardiac biochemical and functional abnormalities are commonly observed transiently following completion of a marathon, although their clinical significance is unknown. CONCLUSIONS: Sudden cardiac deaths associated with marathon running are exceedingly rare events. Prevention should focus on recognition and investigation of prodromal symptoms, if present, and access to rapid defibrillation and trained medical personnel. The robust association of endurance running with improved quality of life and longevity underscores the importance of putting risks into perspective with other well-established health benefits of regular vigorous exercise. PMID- 23015953 TI - Exercise-induced bronchospasm. AB - CONTEXT: Exercise-induced bronchospasm (EIB) is a phenomenon of airway narrowing that occurs during or after exercise or physical exertion. This condition has been reported in a range of sporting activities but is most common in participants of cold-weather sports (eg, Nordic skiing) and indoor sports (eg, ice-skating and swimming). Traditionally, the terms exercise induced-asthma (EIA) and EIB have been used interchangeably; however, more recent evidence suggests that these entities are separate and should be described as such, given that their treatments differ. EVIDENCE ACQUISITION: Literature from 2000 to 2010 was obtained through searches of PubMed, Medline, and Google, with the keywords exercise-induced asthma, exercise-induced bronchospasm, asthma and athlete, and asthma and sport and with an emphasis on the current literature (last 3 to 4 years). RESULTS: Although the current literature suggests a differentiation between EIA and EIB, this differentiation is not always clear, and the terms are still often used interchangeably. This lack of distinction makes it difficult to draw conclusions on optimal diagnosis and treatment of EIB. CONCLUSION: EIB is prevalent in elite-level athletes, with certain groups being at increased risk. Diagnostic testing should be used when possible, given that recent studies suggest poor correlation between symptoms and testing. The mainstay of treatment remains the use of short-acting beta-adrenergic agonists. PMID- 23015954 TI - Medial knee pain in a runner: a case report. AB - A 41-year-old female runner presented to the sports medicine clinic for evaluation of bilateral medial knee pain, left greater than right. Physical examination demonstrated tenderness to palpation over the central aspect of the medial collateral ligament. Anteroposterior and lateral standing knee films were unremarkable. The patient received a corticosteroid injection over the tibial collateral ligament bursa with resolution of symptoms within 2 weeks. There have been few documented case reports of this type of injury in patients with knee pain. Prompt diagnosis and appropriate definitive treatment are important to establish to provide maximum recovery and minimize long-term disability, which may include chronic refractory pain during aggravating activities. PMID- 23015955 TI - Femoroacetabular impingement in athletes, part 1: cause and assessment. AB - CONTEXT: Femoroacetabular impingement (FAI) is a common cause of intra-articular hip pathology and secondary osteoarthritis. It affects athletes at a young age as they push their bodies beyond the diminished physiologic limits imposed by the altered joint morphology. Understanding the cause of this condition and its assessment in athletes is important. EVIDENCE ACQUISITION: The scientific literature was reviewed to reflect the current understanding of hip joint pathology among athletic individuals. Focus is given to the literature since 2003, when FAI was first reported as a cause of joint damage in the native hip. RESULTS: There are 3 types of FAI: pincer, cam, and combined. The pathomechanics and pattern of secondary intra-articular pathology are different among the types. History and examination usually reflect findings of joint damage among athletes, and radiographs can reveal the presence of underlying FAI. Other imaging studies may variably aid in detecting the pathology. CONCLUSIONS: FAI is a common cause of hip problems in athletes. Early recognition is an important first step in order to avoid the severe secondary damage that can occur. PMID- 23015956 TI - The prevalence of medial epicondylitis among patients with c6 and c7 radiculopathy. AB - BACKGROUND: Medial epicondylitis, or golfer's/pitcher's elbow, develops as a result of medial stress overload on the flexor muscles at the elbow and presents as pain at the medial epicondyle. Cervical radiculopathy has been associated with lateral epicondylitis, but few associations between the cervical spine and medial epicondylitis have been made. Researchers propose that there is an association, suggesting that the weakness and imbalance in the elbow flexor and extensor muscles from C6 and C7 radiculopathy allow for easy onset of medial epicondylitis. HYPOTHESIS: Medial epicondylitis will present in over half the patients diagnosed with C6 and C7 radiculopathy. METHODOLOGY: A total of 102 patients initially presenting with upper extremity or neck symptoms were diagnosed with cervical radiculopathy. They were then examined for medial epicondylitis. Data were collected by referring to patient charts from February 2008 until June 2009. RESULTS: Fifty-five patients were diagnosed with medial epicondylitis. Of these, 44 had C6 and C7 radiculopathy whereas 11 presented with just C6 radiculopathy. CONCLUSION: Medial epicondylitis presented with cervical radiculopathy in slightly more than half the patients. Weakening of the flexor carpi radialis and pronator teres and imbalance of the flexor and extensor muscles from the C6 and C7 radiculopathy allow for easy onset of medial epicondylitis. Patients with medial epicondylitis should be examined for C6 and C7 radiculopathy to ensure proper treatment. Physicians dealing with golfers, pitchers, or other patients with medial epicondylitis should be aware of the association between these 2 diagnoses to optimize care. PMID- 23015957 TI - Minimizing injuries and enhancing performance in golf through training programs. AB - CONTEXT: Golf is a popular sport, particularly in older populations. Regardless of age and skill level, golfers risk injury to the back, shoulder, wrist and hand, elbow, and knee. Because of the unique compressive, shear, rotational, and lateral bending forces created in the lumbar region during the golf swing, the primary sport-related malady experienced by amateurs and professionals is low back pain. Extrinsic and intrinsic injury risk factors have been reported in the literature. A growing body of evidence supports the prescription of strength training routines to enhance performance and reduce the risk of injury. EVIDENCE ACQUISITION: Relevant studies were reviewed on golf injuries, swing mechanics, training routines, and general training program design. The following electronic databases were used to identify research relevant to this report: MEDLINE (from 1950-November 2009), CINAHL (1982-November 2009), and SPORTDiscus (1830-November 2009). RESULTS: Injuries may be associated with lack of warm-up, poor trunk flexibility and strength, faulty swing technique, and overuse. CONCLUSIONS: Implementing a training program that includes flexibility, strength, and power training with correction of faulty swing mechanics will help the golfer reduce the likelihood of injury and improve overall performance. PMID- 23015958 TI - Elbow joint active replication in college pitchers following simulated game throwing: an exploratory study. AB - BACKGROUND: Elbow injuries are common in college baseball players. Pitching creates stress and fatigue in and around the elbow. Lack of joint proprioception can contribute to nonphysiological joint loading and injury. HYPOTHESIS: There will be no difference in elbow joint active reproduction sense following a simulated 3-inning pitching sequence. STUDY DESIGN: Cross-sectional study. METHODS: Seventeen collegiate pitchers participated. Each pitcher was bilaterally tested for active elbow range of motion using goniometric technique. Percentages of motion determined positions for further study of elbow joint active replication sense (20%, 35%, 50%, 80%). The elbow was passively taken to a position and held for 10 seconds, then returned to full extension. Pitchers were asked to actively reproduce the angle. The opposite elbow was tested in the same manner. One week later, prethrowing joint position reproduction was tested; then a simulated 3-inning game was thrown. Immediately afterward, elbow joint active replication testing was performed. A repeated-measures analysis of variance analyzed differences. RESULTS: No change in active joint reproduction occurred in the nondominant elbow at any angle tested. Dominant elbows demonstrated significant losses of active joint reproduction following throwing. Significant differences occurred at the 35% and 80% angles (P < .05). CONCLUSION: Active elbow joint replication sense may be compromised following 3 innings of throwing. Because joint proprioception is thought to be an important component of joint stabilization, an alteration in joint position sense may increase the risk of elbow injury during throwing. CLINICAL RELEVANCE: Pitching may cause a loss of active elbow joint replication. PMID- 23015960 TI - Real professionals. PMID- 23015959 TI - Orthopaedic magnetic resonance imaging challenge. PMID- 23015961 TI - Upper limb biomechanics during the volleyball serve and spike. AB - BACKGROUND: The shoulder is the third-most commonly injured body part in volleyball, with the majority of shoulder problems resulting from chronic overuse. HYPOTHESIS: Significant kinetic differences exist among specific types of volleyball serves and spikes. STUDY DESIGN: Controlled laboratory study. METHODS: Fourteen healthy female collegiate volleyball players performed 5 successful trials of 4 skills: 2 directional spikes, an off-speed roll shot, and the float serve. Volunteers who were competent in jump serves (n, 5) performed 5 trials of that skill. A 240-Hz 3-dimensional automatic digitizing system captured each trial. Multivariate analysis of variance and post hoc paired t tests were used to compare kinetic parameters for the shoulder and elbow across all the skills (except the jump serve). A similar statistical analysis was performed for upper extremity kinematics. RESULTS: Forces, torques, and angular velocities at the shoulder and elbow were lowest for the roll shot and second-lowest for the float serve. No differences were detected between the cross-body and straight ahead spikes. Although there was an insufficient number of participants to statistically analyze the jump serve, the data for it appear similar to those of the cross-body and straight-ahead spikes. Shoulder abduction at the instant of ball contact was approximately 130 degrees for all skills, which is substantially greater than that previously reported for female athletes performing tennis serves or baseball pitches. CONCLUSION: Because shoulder kinetics were greatest during spiking, the volleyball player with symptoms of shoulder overuse may wish to reduce the number of repetitions performed during practice. Limiting the number of jump serves may also reduce the athlete's risk of overuse-related shoulder dysfunction. CLINICAL RELEVANCE: Volleyball-specific overhead skills, such as the spike and serve, produce considerable upper extremity force and torque, which may contribute to the risk of shoulder injury. PMID- 23015962 TI - The effectiveness of prophylactic knee bracing in american football: a systematic review. AB - CONTEXT: Knee injuries, particularly of the medial collateral ligament (MCL), are the most common injury sustained in American football. In 1979, Anderson et al described a knee brace that could protect uninjured knees from MCL injuries resulting from lateral impact. Since then, a number of light and free-moving bracing devices have been developed. However, the efficacy of prophylactic knee bracing remains in question. OBJECTIVE: A systematic review of the efficacy of prophylactic knee bracing in preventing MCL injuries in football players. DATA SOURCES: Based on MedSearch and PubMed, articles from 1985 to November 2009 were identified with the following keywords and their combinations: prophylactic, prevent injury, knee brace, prevention, medial collateral ligament, MCL, football, and bracing. STUDY SELECTION: One randomized controlled trial (level 1 study) and 5 prospective cohort studies (level 2 studies) were selected. RESULTS: The results of the studies were inconsistent; only 1 study showed that prophylactic knee bracing significantly reduced MCL injuries (P < .05). In contrast, 2 studies found that knee bracing was associated with an increase in knee injuries. CONCLUSIONS: Prophylactic bracing in American football has not consistently reduced MCL injuries. There remains a lack of evidence to support the routine use of prophylactic knee bracing in uninjured knees. There is limited high-level evidence, bias in the available literature, and confounding variables that limit the current literature. PMID- 23015963 TI - Semimembranosus tendinopathy: one cause of chronic posteromedial knee pain. AB - CONTEXT: Semimembranosus tendinopathy (SMT) is an uncommon cause of chronic knee pain that is rarely described in the medical literature and may be underdiagnosed or inadequately treated owing to a lack of understanding of the condition. EVIDENCE ACQUISITION: A search of the entire PubMed (MEDLINE) database using the terms knee pain semimembranosus and knee tendinitis semimembranosus, returned only 5 references about SMT-4 case series and 1 case report-and several relevant anatomical or imaging references. RESULTS: The incidence of SMT is unknown in the athletic population and is probably more common in older patients. The usual presentation for SMT is aching posteromedial knee pain. Physical examination can usually localize the area of tenderness to the distal semimembranosus tendon or its insertion on the medial proximal tibia. In unclear cases, bone scan, magnetic resonance imaging, or ultrasound may distinguish SMT from other causes of posteromedial knee pain. Treatment should begin with relative rest, ice, nonsteroidal anti-inflammatory drugs, and rehabilitative exercise. In the minority of cases that persist greater than 3 months, a corticosteroid injection at the tendon insertion site may be effective. Surgery to reroute and reattach the tendon is rarely needed but may be effective. CONCLUSION: SMT is an uncommon cause of knee pain, but timely diagnosis can lead to effective treatments. PMID- 23015964 TI - Use of knee magnetic resonance imaging by primary care physicians in patients aged 40 years and older. AB - BACKGROUND: Criteria are needed for primary care providers such that they can evaluate age-related knee pain in a cost-effective manner. This study examined (1) in what percentage of patients are appropriate radiographic views of the knee ordered before magnetic resonance imaging (MRI) for knee pain, (2) specialists' retrospective evaluation for appropriate utilization of MRI in knee pain, and (3) in what manner would the MRIs have altered diagnosis and management of knee disorders. HYPOTHESIS: Primary care providers underuse appropriate radiographs especially, flexion weightbearing posteroanterior films-and overuse MRIs when evaluating older patients with knee pain. STUDY DESIGN: Case control. METHODS: The authors performed a retrospective analysis of 100 patients older than 40 years with knee MRIs. Patient encounters with primary care physicians were reviewed. Given available information, specialists then formulated a pre- and post-MRI diagnosis and treatment plan and indicated whether the MRI would have altered their treatment. RESULTS: Only 12 of 100 MRIs would have been ordered by an orthopaedist given the documented data. No MRIs would have been ordered in the 19 patients aged 60 years or older. Among 44 radiographs ordered, only 7 were flexion weightbearing. The most common pre-MRI diagnoses made by primary care providers were joint pain (22%) and meniscus injury (24%); the most common post MRI diagnoses were osteoarthritis (40%) and degenerative meniscus injury (23%). In contrast, the 2 most common pre- and post-MRI diagnoses by specialists were osteoarthritis (28% and 37%, respectively) and degenerative meniscus injury (23% and 24%, respectively). Also, referrals to specialists increased from 9% pre-MRI to 76% post-MRI. CONCLUSION: Primary care providers may be overusing knee MRIs and underusing flexion weightbearing posteroanterior radiographs in patients older than 40 years with knee pain. CLINICAL RELEVANCE: Primary care providers should strongly consider not ordering knee MRI in patients with radiographic evidence of degenerative changes. PMID- 23015965 TI - Cerebral microhemorrhages in a collegiate football player: clinical implications in the management of sports concussion. AB - Most concussions in sports medicine are managed without advanced neurological imaging. However, computed tomography and magnetic resonance imaging are sometimes used in the management of complex sports concussions to identify acute/delayed intracranial bleeding or other associated pathology. Advances in imaging techniques have led to greater resolution and the identification of pathology of uncertain clinical significance. This report describes the presence of persistent cerebral microhemorrhages identified on magnetic resonance imaging in a collegiate football player who suffered a concussion. The associated risks and clinical significance of cerebral microhemorrhages have not been determined in the young athletic population. This case highlights provocative issues in the management of sports concussions as related to findings on modern neurological imaging and their potential implication on to return-to-play considerations. PMID- 23015966 TI - Cryptogenic stroke associated with patent foramen ovale in a collegiate volleyball athlete: a case report. AB - Cryptogenic stroke is a form of cerebral vascular accident that has an unknown origin and is rarely associated with patent foramen ovale (PFO) and migraine headaches. This is an uncommon occurrence in young, healthy, active adults, and it is increasingly rare for the episode to occur during an athletic competition. Stroke is easily recognizable with its distinct signs and symptoms, but it is also easily confused with many of its differential diagnoses, such as seizures or head trauma, if the episode occurs during an athletic competition. This case report describes the stroke episode, incidence of migraine headaches, diagnostic testing, and surgical management of a college female volleyball athlete who suffered a cryptogenic stroke associated with PFO during an athletic competition. Diagnostic testing included magnetic resonance imaging with contrast, electroencephalograph, lower extremity Doppler testing, and a transesophageal echocardiograph with agitated saline study. Surgical correction of the PFO included a cardiac catheterization percutaneous procedure based on fluoroscopic and echocardiograph imaging. After release from physicians, the athlete returned to full participation in the sport of volleyball, where she competed for the next 2 years without complications. The patient has reported no symptoms from stroke or PFO closure procedure in 3 years, and migraine headaches have decreased in severity, frequency, and duration. PMID- 23015967 TI - Traumatic Bone Bruises in the Athlete's Knee. AB - CONTEXT: Mobile water within the bone marrow is a physiological phenomenon that is identifiable on magnetic resonance (MR) imaging, and signal changes can result from blood pooling, reactive hyperemia, edema, and microfracture. When these MR lesions are associated with an acute traumatic event, the findings are referred to as bone bruises and so represent a unique manifestation of injury. This review discusses bone bruises in anterior cruciate ligament (ACL) tears, patella dislocations, occult fractures, and contusions. METHODS: A PubMed search of the literature from 1982 to December 2009 was conducted with the terms knee and bone bruise. RESULTS: Bone bruises are associated with ACL tears, patella dislocations, occult fractures, and contusions. For each injury, a unique pattern of bone bruising is found on MR imaging, which results from the acute trauma. When acute trauma produces a subchondral lesion with low T1-weighted and high T2 weighted signal intensity, the resulting bony contusion is best described as a bone bruise. CONCLUSIONS: Bone marrow edema is identified using MR imaging and may result from traumatic or atraumatic causes. Bone bruises can be characterized by their pattern at presentation, by the mechanism of injury, and by their associated injuries. This type of bone edema can accompany contact and noncontact ACL ruptures as well as patella dislocations. Although increased marrow edema can be associated with an occult fracture, the long-term significance of these lesions is unclear. PMID- 23015968 TI - Femoroacetabular Impingement in Athletes, Part II: Treatment and Outcomes. AB - CONTEXT: Femoroacetabular impingement (FAI) is a common cause of hip pathology and secondary dysfunction among athletes. Much information has been gained regarding the cause and pathomechanics of this disorder. Now, efforts are focusing on treatment to restore the joint and reduce the secondary damage that causes painful dysfunction. EVIDENCE ACQUISITION: This article reviews the scientific literature in reference to treatment of FAI in athletes. RESULTS: Several studies reported reasonably successful outcomes in the arthroscopic management of FAI in athletes, and 1 study reported on open surgical correction of this disorder. Few major complications have been described. CONCLUSIONS: When the diagnosis is given early, some athletes may benefit from a rehabilitation strategy that includes training modifications to protect the at-risk hip. When indicated, arthroscopic surgery can address the joint damage and correct the underlying impingement. Although the joint may not be normal, successful results with return to sports can often be expected. PMID- 23015969 TI - The effect of an exercise program in conjunction with short-period patellar taping on pain, electromyogram activity, and muscle strength in patellofemoral pain syndrome. AB - BACKGROUND: McConnell recommended that patellar tape be kept on all day, until patients learn how to activate their vastus medialis obliquus (VMO) during an exercise program. This application may pose problems because prolonged taping may be inadvisable for some patients or even contraindicated owing to skin discomfort, irritation, or allergic reaction. HYPOTHESIS: Wearing patellofemoral tape for a shorter duration during an exercise program would be just as beneficial as a prolonged taping application. STUDY DESIGN: Prospective cohort. METHODS: Twelve patients and 16 healthy people participated. Patients underwent short-period patellar taping plus an exercise program for 3 months. Numeric pain rating, muscle strength of the knee extensors, and electromyogram activity of the vastus lateralis and VMO were evaluated. RESULTS: There were significant differences in electromyogram activity (P = .04) and knee extensor muscle strength (P = .03) between involved and uninvolved sides before treatment. After treatment, pain scores decreased, and there were no significant differences between involved and uninvolved sides in electromyogram activity (P = .68) and knee extensor strength (P = .62). Before treatment, mean VMO activation started significantly later than that of vastus lateralis, as compared with the matched healthy control group (P = .01). After treatment, these differences were nonsignificant (P = .08). CONCLUSION: Short-period patellar taping plus an exercise program improves VMO and vastus lateralis activation. CLINICAL RELEVANCE: A shorter period of taping for the exercise program may be as beneficial as a prolonged taping application. PMID- 23015970 TI - Perioperative rehabilitation using a knee extension device and arthroscopic debridement in the treatment of arthrofibrosis. AB - BACKGROUND: Arthrofibrosis is a postoperative complication of intra-articular knee surgery that can be difficult to treat. Evidence suggests that maximizing knee range of motion may improve outcomes in patients with arthrofibrosis who undergo arthroscopic debridement. HYPOTHESIS: Patients who achieve greater knee range of motion will have better subjective scores. STUDY DESIGN: Retrospective case series analysis. METHODS: A review of records was performed for 33 patients with arthrofibrosis who underwent knee arthroscopy and scar resection coupled with perioperative rehabilitation to maximize knee range of motion. Patient demographics and preoperative and postoperative range of motion measurements were extracted from the records. The International Knee Documentation Committee (IKDC) Subjective Knee Form was administered to assess pain, activity, and knee function. Patients performed a preoperative and postoperative rehabilitation program utilizing a knee extension device to maximize knee extension. RESULTS: According to the IKDC range of motion criteria, 27 of 33 patients achieved normal knee extension, and 14 of 33 achieved normal knee flexion at a mean of 8.6 months after surgery. Patients with normal knee motion had a mean IKDC Subjective Knee Form score of 72.6 +/- 13.6, which was significantly higher than patients who did not achieve normal motion (P = .04). Overall, mean IKDC Subjective Knee Form scores improved from 45.3 +/- 16.7 preoperatively to 67.1 +/- 18.0 postoperatively (P < .01) at a mean of 14.7 months after surgery. CONCLUSIONS: Perioperative rehabilitation that emphasizes restoration of normal knee range of motion appears to improve outcomes in patients with arthrofibrosis who undergo arthroscopic scar resection. In support of our hypothesis, patients who achieved greater knee range of motion had better subjective knee scores. PMID- 23015971 TI - An electromyographic evaluation of subdividing active-assistive shoulder elevation exercises. AB - BACKGROUND: Active-assistive range of motion exercises to gain shoulder elevation have been subdivided into gravity-minimized and upright-assisted exercises, yet no study has evaluated differences in muscular demands. HYPOTHESIS: Compared with gravity-minimized exercises, upright-assisted exercises will generate larger electromyographic (EMG) activity. Compared with all active-assistive exercises, upright active forward elevation will generate more EMG activity. STUDY DESIGN: Controlled laboratory study. METHODS: Fifteen healthy individuals participated in this study. The supraspinatus, infraspinatus, and anterior deltoid were evaluated. The independent variables were 11 exercises performed in random order. The dependent variable was the maximum EMG amplitude of each muscle that was normalized to a maximal voluntary isometric contraction (MVIC). RESULTS: Each muscle demonstrated significant differences between exercises (P < .001), with upright active forward elevation producing the greatest EMG for all muscles (95% confidence interval [CI], 12% to 50% MVIC). The orders of exercise varied by muscle, but the 5 gravity-minimized exercises always generated the lowest EMG activity. The upright-assisted exercises (95% CI, 23% to 42% MVIC) for the anterior deltoid generated more EMG activity than did the gravity-minimized exercises (95% CI, 9% to 21% MVIC) (P < .05). The infraspinatus and supraspinatus demonstrated increasing trends in EMG activity from gravity minimized to upright assisted (P > .05). CONCLUSION: The results suggest a clear distinction between gravity-minimized exercises and upright-assisted exercises for the anterior deltoid but not for the supraspinatus and infraspinatus. Between the 2 types of assisted exercises, the results also suggest a clear distinction in terms of active elevation of the arm for the supraspinatus and anterior deltoid but not for the infraspinatus. CLINICAL RELEVANCE: Muscle activation levels increase as support is removed, but subdivision of active-assistive range of motion to protect the supraspinatus and infraspinatus may not be necessary. PMID- 23015972 TI - Superficial precooling on a 4-week static stretching regimen: a randomized trial. AB - BACKGROUND: The influence of superficial precooling on range of motion (ROM) as part of a stretching program has not been extensively studied. It is not clear if the analgesic effect can benefit a stretching program. HYPOTHESES: Superficial precooling will result in greater gains in ROM as part of a stretching program, compared with stretching without a precooling intervention. Superficial precooling will also result in greater retention in ROM gains following cessation of stretching, compared with stretching without a precooling intervention. STUDY DESIGN: Prospective randomized single-blind test-retest design. METHODS: Twenty nine participants were randomly assigned to 1 of 2 static stretching protocols: a standard protocol (n, 14; age, 24.6 +/- 5.4 years) or a precool protocol (n, 15; age, 25.1 +/- 7.3 years). These samples allowed for 80% power for statistical significance testing. Both groups performed static hamstring stretching daily for 4 weeks. The precool group applied ice to the hamstring for 10 minutes before stretching. Both groups stretched for 4 weeks and then stopped stretching for the last 4 weeks. Hip ROM measures were obtained each week for 8 weeks. RESULTS: For the standard group, mean hip ROM increased from 71.4 degrees +/- 18.5 degrees to 90.6 degrees +/- 20.5 degrees and for the precool group, 71.5 degrees +/- 22.3 degrees to 91.8 degrees +/- 20.9 degrees . For the standard group, mean hip ROM decreased from 90.6 degrees +/- 20.5 degrees to 83.9 degrees +/- 20.3 degrees and for the precool group, 91.8 degrees +/- 20.9 to 85.0 degrees +/- 19.4 degrees . There were no differences between groups at any time in the study (P > .05). CONCLUSIONS: Precooling had no beneficial effects on ROM or on retention of ROM. CLINICAL RELEVANCE: Cold application, before stretching, does not provide any benefit to a stretching program. PMID- 23015973 TI - Segond fractures: not necessarily pathognemonic of anterior cruciate ligament injury in the pediatric population. AB - Initially described following cadaveric studies in the late 19th century by Dr. Paul Segond, the Segond fracture is now widely accepted as a pathognemonic radiographic marker of anterior cruciate ligament injury. This fracture in a skeletally immature 16-year-old was not seen with an anterior cruciate ligament injury, but with a Salter-Harris type IV fracture of the tibial plateau. A nonweightbearing knee immobilizer with the leg in full extension was used for 6 weeks. Recovery was uncomplicated, and range of motion and weightbearing began at 6 weeks. PMID- 23015974 TI - Banging heads. PMID- 23015975 TI - Mechanical joint laxity associated with chronic ankle instability: a systematic review. AB - CONTEXT: Lateral ankle sprains can manifest into chronic mechanical joint laxity when not treated effectively. Joint laxity is often measured through the use of manual stress tests, stress radiography, and instrumented ankle arthrometers. PURPOSE: To systematically review the literature to establish the influence of chronic ankle instability (CAI) on sagittal and frontal plane mechanical joint laxity. DATA SOURCES: Articles were searched with MEDLINE (1966 to October 2008), CINAHL (1982 to October 2008), and the Cochrane Database of Systematic Reviews (to October 2008) using the key words chronic ankle instability and joint laxity, functional ankle instability and joint laxity, and lateral ankle sprains and joint laxity. STUDY SELECTION: To be included, studies had to employ a case control design; mechanical joint laxity had to be measured via a stress roentogram, an instrumented ankle arthrometer, or ankle/foot stress-testing device; anteroposterior inversion or eversion ankle-subtalar joint complex laxity had to be measured; and means and standard deviations of CAI and control groups had to be provided. DATA EXTRACTION: One investigator assessed each study based on the criteria to ensure its suitability for analysis. The initial search yielded 1378 potentially relevant articles, from which 8 were used in the final analysis. Once the study was accepted for inclusion, its quality was assessed with the PEDro scale. DATA SYNTHESIS: Twenty-one standardized effect sizes and their 95% confidence intervals were computed for each group and dependent variable. CAI produced the largest effect on inversion joint laxity; 45% of the effects ranged from 0.84 to 2.61. Anterior joint laxity measures were influenced second most by CAI (effects, 0.32 to 1.82). CAI had similar but less influence on posterior joint laxity (effects, -0.06 to 0.68) and eversion joint laxity (effects, 0.03 to 0.69). CONCLUSION: CAI has the largest effect with the most variability on anterior and inversion joint laxity measurements, consistent with the primary mechanism of initial injury. PMID- 23015977 TI - Twelve years of national football league concussion data. AB - BACKGROUND: Concussion in the National Football League (NFL) remains an important issue. An initial description of the injury epidemiology involved 6 years from 1996 to 2001. HYPOTHESIS: The increased attention to concussions may have resulted in team physicians being more conservative in treating players in recent years. STUDY DESIGN: Two consecutive 6-year periods (1996-2001 and 2002-2007) were compared to determine changes in the circumstances associated with the injury, the patterns of signs and symptoms, and the players' time loss from participation in the NFL. METHODS: During 2002-2007, concussions were recorded by NFL team physicians and athletic trainers using the same standardized reporting form used from 1996 to 2001. Player position, type of play, concussion signs and symptoms, loss of consciousness, and medical action taken were recorded. RESULTS: There were 0.38 documented concussions per NFL game in 2002-2007-7.6% lower than the 0.42 in the earlier period (1996-2001). The injury rate was lower in quarterbacks and wide receivers but significantly higher in tight ends during the second 6 years. The most frequent symptoms were headaches and dizziness; the most common signs were problems with information processing and immediate recall. During 2002-2007, a significantly lower fraction of concussed players returned to the same game, and more were removed from play. Most concussed players (83.5%) returned to play in < 7 days; the percentage decreased to 57.4% with loss of consciousness. The number of players returning in < 7 days was 8% lower during 2002-2007 and 25% lower for those with loss of consciousness. CONCLUSION: The most recent 6 years of NFL concussion data show a remarkable similarity to the earlier period. However, there was a significant decrease in the percentage of players returning to the same game, and players were held out of play longer. CLINICAL RELEVANCE: There was a more conservative management of concussion in NFL players from 2002 to 2007 even though the clinical signs and symptoms remained similar to the earlier 6-year period. PMID- 23015976 TI - Rehabilitation of syndesmotic (high) ankle sprains. AB - CONTEXT: High ankle sprains are common in athletes who play contact sports. Most high ankle sprains are treated nonsurgically with a rehabilitation program. EVIDENCE ACQUISITION: All years of PUBMED, Cochrane Database of Systematic Reviews, CINAHL PLUS, SPORTDiscuss, Google Scholar, and Web of Science were searched to August 2010, cross-referencing existing publications. Keywords included syndesmosis ankle sprain or high ankle sprain and the following terms: rehabilitation, treatment, cryotherapy, braces, orthosis, therapeutic modalities, joint mobilization, massage, pain, pain medications, TENS (ie, transcutaneous electric nerve stimulation), acupuncture, aquatic therapy, strength, neuromuscular training, perturbation training, and outcomes. RESULTS: Level of evidence, 5. A 3-phase rehabilitation program is described. The acute phase is directed at protecting the joint while minimizing pain, inflammation, muscle weakness, and loss of motion. Most patients are treated with some form of immobilization and have weightbearing restrictions. A range of therapeutic modalities are used to minimize pain and inflammation. Gentle mobilization and resistance exercises are used to gain mobility and maintain muscle size and strength. The subacute phase is directed at normalizing range of motion, strength, and function in activities of daily living. Progressive mobilization and strengthening are hallmarks of this phase. Neuromuscular training is begun and becomes the central component of rehabilitation. The advanced training phase focuses on preparing the patient for return to sports participation. Perturbation of support surfaces, agility drills, plyometrics, and sport-specific training are central components of this phase. CONCLUSION: The rehabilitation guidelines discussed may assist clinicians in managing syndesmotic ankle sprains. PMID- 23015978 TI - Median nerve compression from a nondisplaced fracture of the coronoid process of the ulna: a case report. AB - Median nerve neuropathy following an elbow injury is uncommon. When it occurs, understanding the median nerve distribution and anatomy is crucial for identifying the cause and for distinguishing cases that can be managed with observation as opposed to intervention. The consequences of misdiagnosis can result in permanent disability. Understanding the mechanisms of nerve injury will help the clinician anticipate prognosis and guide treatment. Stretch, transection, and compression of nerves may present similarly, but isolating the mechanism and the extent of injury can guide the treatment modalities and help predict the overall recovery. The case is a report of median nerve compression in a woman after a nondisplaced fracture of the coronoid process of the ulna. Despite the unique nature of the patient's symptoms, the neuropathy resolved with "watchful waiting." The location of the injury was a key component in identifying the cause of the neuropathy. It highlights the importance of identifying a cause; some cases will resolve without intervention. Clinicians should consider median nerve compression when presented with a patient experiencing neurologic symptoms following such a fracture. PMID- 23015979 TI - Turf toe: anatomy, diagnosis, and treatment. AB - CONTEXT: Despite an increasing awareness of turf toe injury, confusion still exists regarding the anatomy, mechanism, diagnosis, and treatment of this hyperextension injury to the hallux metatarsophalangeal (MTP) joint. EVIDENCE ACQUISITION: This article reviews the anatomy, diagnosis, and treatment algorithm for turf toe injury by reviewing relevant studies and presenting information useful to clinicians, therapists, and athletic trainers. A literature search was performed by a review of PubMed and OVID articles published from 1976 to July 2010. RESULTS: Grade I injury is a sprain or attenuation of the plantar capsular ligamentous complex of the hallux MTP joint; athletes are typically able to return to play as tolerated. Grade II injury is a partial rupture of the plantar soft tissue structures of the hallux MTP joint, typically requiring about 2 weeks to recover. Grade III injury is a complete rupture of the plantar structures of the hallux MTP joint, requiring at least 10 to 16 weeks to recover. Some complete ruptures require surgical repair. CONCLUSION: With accurate diagnosis, athletes can have an appropriate treatment plan, and their expectations can be tempered to the degree of injury. Careful management may allow successful return to play at a preinjury level of participation. PMID- 23015980 TI - Medial impingement of the ankle in athletes. AB - CONTEXT: Medial impingement syndrome of the ankle is common in the athletic population. A marginal osteophyte on the leading edge of the medial talar facet and a corresponding "kissing" osteophyte on the tibia, in front of the medial malleolus, may abut and cause pain and limited dorsiflexion. BACKGROUND: Palpation of the talar osteophyte and standard imaging-especially, the oblique view of the foot-are useful in making the diagnosis. Surgical removal of the osteophyte may be necessary. CONCLUSIONS: Ankle impingement is commonly seen in running and jumping sports, especially if the athlete has a subtle cavus foot. It may be associated with ankle instability, osteochondritis dissecans of the talus, and stress fractures of the foot. PMID- 23015981 TI - Early Results of Concurrent Arthroscopic Repair of Rotator Cuff and Type II Superior Labral Anterior Posterior Tears. AB - BACKGROUND: Recent reports on concurrent arthroscopic rotator cuff and type II superior labral anterior posterior (SLAP) repair have raised concerns over postoperative stiffness and patient satisfaction. However, it is unclear if the observed stiffness relates to the repair of degenerative SLAP tears in older adults, the surgical technique, the postoperative rehabilitation, or to a combination of these factors. PURPOSE: The purpose of this study was to evaluate the outcome and repair integrity of concurrent arthroscopic rotator cuff and type II SLAP repair. STUDY DESIGN: Case series. METHODS: Of 11 patients identified, 7 had a full-thickness rotator cuff tear and 4 had a high-grade partial thickness tear that was completed. A cannula placed through the rotator cuff tear improved the trajectory for posterior suture anchor placement during SLAP repair. Postoperative rehabilitation employed continuous passive motion to prevent stiffness. RESULTS: At minimum of 1-year follow-up, mean yes responses on the Simple Shoulder Test improved from 5.4 to 10.7 (out of 12; P < .01), and mean American Shoulder and Elbow Surgeons scores improved from 40 to 87 (out of 100; P < .01). Mean forward elevation improved from 148 degrees to 161 degrees (P < .01) and external rotation from 58 degrees to 67 degrees (P < .01). Magnetic resonance imaging, obtained at most recent follow-up in 10 patients, demonstrated a healed SLAP tear in all patients and a persistent rotator cuff defect in 1 patient. CONCLUSIONS: Arthroscopic rotator cuff repair can be successfully combined with type II SLAP repair in relatively young patients who have sustained traumatic injury to their shoulders. Allowing early passive motion may help prevent postoperative stiffness without compromising rotator cuff healing. PMID- 23015982 TI - Periodization: current review and suggested implementation for athletic rehabilitation. AB - BACKGROUND: Clinicians are constantly faced with the challenge of designing training programs for injured and noninjured athletes that maximize healing and optimize performance. Periodization is a concept of systematic progression-that is, resistance training programs that follow predictable patterns of change in training variables. The strength training literature is abundant with studies comparing periodization schemes on uninjured, trained, and untrained athletes. The rehabilitation literature, however, is scarce with information about how to optimally design resistance training programs based on periodization principles for injured athletes. The purpose of this review is to discuss relevant training variables and methods of periodization, as well as periodization program outcomes. A secondary purpose is to provide an anecdotal framework regarding implementation of periodization principles into rehabilitation programs. EVIDENCE ACQUISITION: A Medline search from 1979 to 2009 was implemented with the keywords periodization, strength training, rehabilitation, endurance, power, hypertrophy, and resistance training with the Boolean term AND in all possible combinations in the English language. Each author also undertook independent hand searching of article references used in this review. RESULTS: Based on the studies researched, periodized strength training regimens demonstrate improved outcomes as compared to nonperiodized programs. CONCLUSIONS: Despite the evidence in the strength training literature supporting periodization programs, there is a considerable lack of data in the rehabilitation literature about program design and successful implementation of periodization into rehabilitation programs. PMID- 23015983 TI - Biomechanical Considerations in the Competitive Swimmer's Shoulder. AB - CONTEXT: Competitive swimming has become an increasingly popular sport in the United States. In 2007, more than 250 000 competitive swimmers were registered with USA Swimming, the national governing body. The average competitive swimmer swims approximately 60 000 to 80 000 m per week. With a typical count of 8 to 10 strokes per 25-m lap, each shoulder performs 30 000 rotations each week. This places tremendous stress on the shoulder girdle musculature and glenohumeral joint, and it is why shoulder pain is the most frequent musculoskeletal complaint among competitive swimmers. EVIDENCE ACQUISITION: Articles were obtained through a variety of medical search sources, including Medline, Google Scholar, and review articles from 1980 through January 2010. RESULTS: The most common cause of shoulder pain in swimmers is supraspinatus tendinopathy. Glenohumeral instability and labral tears have also been reported, but a paucity of information remains regarding prevalence and treatment in swimmers. CONCLUSION: Because of the great number of stroke repetitions and force generated through the upper extremity, the shoulder is uniquely vulnerable to injury in the competitive swimmer. Comprehensive evaluation should include the entire kinetic chain, including trunk strength and core stability. PMID- 23015984 TI - Sports health magnetic resonance imaging challenge. AB - Injuries to the Lisfranc ligament complex are often suspected, particularly in the setting of midfoot pain without radiographic abnormality. Knowledge of the anatomy and magnetic resonance imaging findings of injuries to this region is helpful for the diagnosing and treating physicians. PMID- 23015985 TI - Hurray for sports medicine. PMID- 23015986 TI - Repeat concussions in the national football league. AB - BACKGROUND: Repeat concussion is an important issue in the National Football League (NFL). An initial description of repeat injuries was published for 6 years (1996-2001). HYPOTHESIS: The characteristics and frequency of repeat concussion in the NFL have not changed in the subsequent 6 years (2002-2007). STUDY DESIGN: Case control. METHODS: From 1996 to 2007, concussions were reported using a standardized form documenting signs and symptoms, loss of consciousness and medical action taken. Data on repeat concussions were analyzed for the 12 years and compared between the 2 periods. RESULTS: In 2002-2007, 152 players had repeat concussions (vs 160 in 1996-2001); 44 had 3+ head injuries (vs 52). The positions most often associated with repeat concussion in 2002-2007 were the defensive secondary, kick unit, running back, and linebacker. The odds for repeat concussion were elevated for wide receivers, tight ends, and linebackers but lower than in the earlier period. During 2002-2007, over half of players with repeat concussion were removed from play, and fewer immediately returned (vs 1996 2001). The average duration between concussions was 1.25 years for 2002-2007 and 1.65 years for the 12-year period. Over 12 years, 7.6% of all repeat concussions occurred within 2 weeks of the prior concussion. CONCLUSIONS: The defensive secondary, kick unit, running back, and linebacker have the highest incidence of repeat concussion. During 2002-2007, more than half of players with repeat concussion were removed from play, and only a fraction immediately returned. Although concussion was managed more conservatively by team physicians in the recent 6 years, repeat concussions occurred at similar rates during both periods. PMID- 23015987 TI - National collegiate athletic association division I athletes' use of nonprescription medication. AB - BACKGROUND: Athletes are known to use over-the-counter pain medication. However, the frequency of such use among National Collegiate Athletic Association (NCAA) Division I-A football athletes is unknown. HYPOTHESIS: NCAA Division I-A football athletes who use nonprescription analgesics for pain misuse these medications. STUDY DESIGN: Cross-sectional study. METHODS: The football players (N, 144) who met the criteria and agreed to participate were from 8 NCAA Division I-A schools. The participants were administered the Over the Counter Drug Screen for Athletes, which measures attitudes toward the use of a spectrum of substances. RESULTS: Among football athletes surveyed who took nonprescription analgesics for football related pain, 37% reported taking more than the recommended dose. This was slightly higher than the 28% of players who stated they have not taken nonprescription analgesics for football-related pain. Thirty-four percent of all athletes reported using more than the recommended dose of nonprescription analgesics. Athletes who purchased their own nonprescription analgesics communicated poorly regarding nonprescription analgesics use. Those lacking knowledge about nonprescription analgesics and those using nonprescription analgesics in anticipation of pain or to avoid missing a practice or game were most likely to misuse nonprescription analgesics. CONCLUSION: NCAA Division I-A football athletes who use nonprescription analgesics for athletic competition do not misuse nonprescription analgesics. PMID- 23015988 TI - Indirect catastrophic injuries in olympic styles of wrestling in iran. AB - BACKGROUND: Data on indirect catastrophic injuries in wrestling are scarce. OBJECTIVES: To develop a profile of indirect catastrophic injuries in international styles of wrestling and to describe possible risk factors. STUDY DESIGN: Retrospective case series; Level of evidence, 3. METHODS: Indirect catastrophic injuries that occurred in wrestling clubs in Iran from July 1998 to June 2005 were identified by contacting several sources. The cases were retrospectively reviewed. RESULTS: The injuries included 9 indirect catastrophic injuries. The injury rate was 0.62 injuries per 100 000 wrestlers per year. The majority of indirect injuries were cardiovascular events in veteran groups of wrestlers. CONCLUSIONS: Indirect catastrophic wrestling injuries are rare and present most commonly in older athletes. Coronary artery disease was the main cause. PMID- 23015989 TI - Abscess after a laparoscopic appendectomy presenting as low back pain in a professional athlete. AB - A professional baseball player presented to the orthopaedic clinic for a preseason assessment because of continued lumbar spine and flank pain. He had a laparoscopic appendectomy for a perforated appendix 8 months before his presentation. He was able to finish the previous season with only mild limitation. He presented with back pain that limited his activity. His examination was nonlocalizing, but subsequent computed tomography revealed a hepatic abscess. The abscess was drained; he was treated with intravenous antibiotics; and his symptoms resolved. PMID- 23015990 TI - Pathophysiology of sports-related concussion: an update on basic science and translational research. AB - CONTEXT: Concussions that occur during participation in athletic events affect millions of individuals each year. Although our understanding of the pathophysiology of concussion has grown considerably in recent years, much remains to be elucidated. This article reviews basic science and relevant translational clinical research regarding several aspects of concussion. EVIDENCE ACQUISITION: A literature search was conducted using PubMed from 1966 to 2010, with an emphasis on work published within the past 10 years. Additional articles were identified from the bibliography of recent reviews. RESULTS: Basic science and clinical data both indicate that there is a period of increased vulnerability to repeated injury following a concussion and that its duration is variable. Growing evidence indicates that postinjury activity is likely to affect recovery from brain injury. Data suggest that long-term sequelae may result from prior concussion-particularly, repeated injuries. The unique aspects of cerebral development may account for differences in the effects of concussion in children and adolescents when compared with adults. CONCLUSIONS: The available pathophysiologic data from basic science and clinical studies have increased the evidence base for concussion management strategies-the approaches to which may differ between young athletes and adults. PMID- 23015991 TI - Arthroscopic posterior cruciate ligament tibial inlay reconstruction: a surgical technique that may influence rehabilitation. AB - CONTEXT: The reconstruction of isolated complete posterior cruciate ligament (PCL) injuries remains a controversial topic. Proponents for reconstruction cite the premature development of arthritis in the medial and patellofemoral compartments as a compelling reason to offer reconstruction. Currently, no consensus exists about which technique should be used to reconstruct the PCL. TYPE OF STUDY: Surgical technique. EVIDENCE ACQUISITION: A MEDLINE and PUBMED search was performed using the following combination of keywords for the years 1985-2009: PCL, posterior cruciate ligament, and rehabilitation. The reviewed articles were those that addressed rehabilitation of the PCL after reconstruction and were written in the English language. RESULTS: This PCL reconstruction technique may be more inherently stable and allow a more progressive rehabilitation program. CONCLUSION: There are unique features of all arthroscopic, double-bundle, allograft reconstruction of the PCL that allow a more aggressive approach in PCL reconstruction rehabilitation. The stability afforded by the anatomic press-fit tibial plug and the augmented tibial and augmented femoral fixation are a plus. The anatomic position of the tibial insertion avoids the "killer turn" of the transtibial approach, limiting concerns for graft abrasion with range of motion and resultant elongation. The outside-in method for the femoral tunnels also minimizes the abrasion that can occur at the "critical corner." PMID- 23015992 TI - Is there a role for high tibial osteotomies in the athlete? AB - CONTEXT: The use of high tibial osteotomies (HTOs) in elite and professional athletes has been slow to gain acceptance by both the athlete and the surgeon because it is generally thought that return to competitive sports will be unlikely. Conversely, HTOs have been used extensively and effectively in managing degenerative knee arthrosis in the less active recreational patient with varus deformity who wishes to maintain activity and delay the need for knee arthroplasty. Unfortunately, situations arise where elite athletes develop debilitating pain secondary to malalignment that prevents them from participation, at which time corrective osteotomy may be indicated. Return to sport is not necessarily the goal of osteotomy surgery, but success with correction may allow the athlete to return to high-level activity. Return to elite competition is not the singular goal of HTO in the athlete; however, if the surgery is successful, then consideration can be given to return to play. EVIDENCE ACQUISITION: Despite an extensive literature on return to elite competition after many orthopaedic procedures, there are relatively few data following osteotomies. RESULTS: With expanded indications, osteotomies have become increasingly popular in young patients with malalignment and arthrosis. In addition to addressing malalignment and degenerative processes, HTO can be used in elite athletes in combination with knee reconstructive procedures to address articular defects, meniscal deficiency, and instability, thereby optimizing knee function. CONCLUSION: When performed with the proper indications in competitive athletes, HTO can result in unloading of joint resurfacing procedures, pain reduction, increased functional stability, and restored joint mechanics. Furthermore, as performed in select elite athletes, HTO realignment may not only result in return to play but also improve function and possibly prolong competition at a high level. PMID- 23015993 TI - Lumbo-pelvic-hip complex pain in a competitive basketball player: a case study. AB - Establishing the cause of lumbo-pelvic-hip complex pain is a challenge for many clinicians. This case report describes the mechanism of injury, diagnostic process, surgical management, and rehabilitation of a female high school basketball athlete who sustained an injury when falling on her right side. Diagnostics included clinical examination, radiography of the spine and hip joint, magnetic resonance imaging arthrogram, 3-dimensional computed tomography scan, and computed tomography of the hip joint. A systematic multidisciplinary clinical approach resulted in the patient's return to previous functional levels. PMID- 23015994 TI - Allograft Versus Autograft Anterior Cruciate Ligament Reconstruction: Predictors of Failure From a MOON Prospective Longitudinal Cohort. AB - BACKGROUND: Tearing an anterior cruciate ligament (ACL) graft is a devastating occurrence after ACL reconstruction (ACLR). Identifying and understanding the independent predictors of ACLR graft failure is important for surgical planning, patient counseling, and efforts to decrease the risk of graft failure. HYPOTHESIS: Patient and surgical variables will predict graft failure after ACLR. STUDY DESIGN: Prospective cohort study. METHODS: A multicenter group initiated a cohort study in 2002 to identify predictors of ACLR outcomes, including graft failure. First, to control for confounders, a single surgeon's data (n = 281 ACLRs) were used to develop a multivariable regression model for ACLR graft failure. Evaluated variables were graft type (autograft vs allograft), sex, age, body mass index, activity at index injury, presence of a meniscus tear, and primary versus revision reconstruction. Second, the model was validated with the rest of the multicenter study's data (n = 645 ACLRs) to evaluate the generalizability of the model. RESULTS: Patient age and ACL graft type were significant predictors of graft failure for all study surgeons. Patients in the age group of 10 to 19 years had the highest percentage of graft failures. The odds of graft rupture with an allograft reconstruction are 4 times higher than those of autograft reconstructions. For each 10-year decrease in age, the odds of graft rupture increase 2.3 times. CONCLUSION: There is an increased risk of ACL graft rupture in patients who have undergone allograft reconstruction. Younger patients also have an increased risk of ACL graft failure. CLINICAL RELEVANCE: Given these risks for ACL graft rupture, allograft ACLRs should be performed with caution in the younger patient population. PMID- 23015995 TI - Extra-articular Mimickers of Lateral Meniscal Tears. AB - CONTEXT: Lateral meniscus tears are a common entity seen in sports medicine. Although lateral-side knee pain is often the result of a meniscus injury, several extra-articular pathologies share signs and symptoms with a meniscus tear. It is critical for the clinician to be able to identify and understand extra-articular pathologies that can present similar to a lateral meniscus tear. EVIDENCE ACQUISITION: Data were collected through a thorough review of the literature conducted through a MEDLINE search for all relevant articles between 1980 and February 2010. STUDY TYPE: Clinical review. RESULTS: Common extra-articular pathologies that can mimic lateral meniscal tears include iliotibial band syndrome, proximal tibiofibular joint instability, snapping biceps femoris or popliteus tendons, and peroneal nerve compression syndrome or neuritis. The patient history, physical examination features, and radiographic findings can be used to separate these entities from the more common intra-articular knee pathologies. CONCLUSIONS: In treating patients who present with lateral-sided knee pain, clinicians should be able to recognize and treat extra-articular pathologies that can present in a similar fashion as lateral meniscus tears. PMID- 23015996 TI - Lower body stiffness and muscle activity differences between female dancers and basketball players during drop jumps. AB - BACKGROUND: Anterior cruciate ligament (ACL) injuries often occur during landing, with female athletes at higher injury risk than male athletes. Interestingly, female dancers have lower ACL injury rates than do female athletes in general. HYPOTHESIS: Female dancers will have earlier and greater lower extremity muscle activity and higher sagittal knee joint and leg stiffness than will female basketball players. STUDY DESIGN: Cross-sectional group comparison. METHODS: Fifty-five healthy female athletes (35 dancers, 20 basketball players) performed 5 double-leg drop jumps from a 45-cm box. Surface electromyography (onsets and amplitudes; prelanding and postlanding) was recorded from the lateral gastrocnemius, medial and lateral hamstrings, lateral quadriceps muscles with a 3 dimensional electromagnetic tracking system, and forceplates recording biomechanics (leg spring stiffness and knee joint stiffness). RESULTS: Compared with basketball players, dancers had greater leg spring stiffness (P = 0.047) but similar knee joint stiffness (P = 0.44). Although no significant differences were observed in overall muscle onset times (P = 0.22) or activation amplitudes (prelanding, P = 0.60; postlanding, P = 0.78), small to moderate effect sizes (ESs) suggest trends in dancers toward earlier (ES = 0.53) and higher medial hamstrings activation pre- (ES = 0.55) and post- (ES = 0.41) landing and lower lateral quadriceps (ES = 0.30) and higher gastrocnemius (ES = 0.33) postlanding muscle activation. CONCLUSIONS: In dancers, the higher leg spring stiffness and trends toward higher hamstrings prelanding and postlanding, as well as lower quadriceps and higher gastrocnemius activation postlanding with similar knee joint stiffness, indicate lower extremity neuromechanical differences across other joints. CLINICAL RELEVANCE: Female dancers may have lower extremity neuromechanics that are different from those of basketball players during drop jumps. If dancers use ACL-protective strategies during activity, then their training routines should be further investigated to improve ACL injury prevention programs. PMID- 23015997 TI - Glenohumeral range of motion in major league pitchers: changes over the playing season. AB - BACKGROUND: Although overhead throwing athletes may develop unique glenohumeral range of motion characteristics, to our knowledge these characteristics have not been studied longitudinally in major league pitchers. HYPOTHESIS: Major league pitchers (starters and relievers) experience an increase in glenohumeral external rotation and a decrease in internal rotation and total range of motion. Glenohumeral internal rotation deficit worsens over a regular playing season. STUDY DESIGN: Retrospective cohort study. METHODS: In 21 major league baseball pitchers (29 individual playing seasons), glenohumeral range of motion was measured in external and internal rotation for the throwing and nonthrowing shoulders before and at the conclusion of the regular season. The total range of motion (the sum of external rotation and internal rotation) and the glenohumeral internal rotation deficit were calculated (the difference between internal rotation of the nonthrowing shoulder minus that of the throwing shoulder), and data were compared between starting and relief pitchers. RESULTS: The overall mean changes in external rotation (+1.5 degrees ), internal rotation (+2.7 degrees ), and total range of motion (+3.3 degrees ) were not statistically significant. However, starting pitchers showed statistically significant increases in internal rotation (+6.5 degrees , P = 0.01) and total range of motion (+7.9 degrees , P = 0.04), whereas relief pitchers had significant worsening of glenohumeral internal rotation deficit (+5.3 degrees , P = 0.04). CONCLUSIONS: The characteristics of glenohumeral range of motion in major league pitchers did not differ significantly from the beginning to the end of a season, but significant changes did occur between starting and relief pitchers. CLINICAL RELEVANCE: Adaptations to the daily routines of starter and reliever pitchers may be warranted on the basis of these findings. PMID- 23015999 TI - Medical Economics (and Politics). PMID- 23015998 TI - Return to sports for professional baseball players after surgery of the shoulder or elbow. AB - BACKGROUND: The purpose of this study was to assess major and minor league baseball players' return to professional baseball at a preinjury level or higher after surgery of the shoulder or elbow. HYPOTHESIS: The majority of athletes will be able to return to their preinjury level after surgery. STUDY DESIGN: Case series. METHODS: Over a 4-season period, prospective injury and surgery records were reviewed for one professional baseball club. Forty-four players underwent 51 procedures (28 shoulder and 23 elbow) by multiple experienced surgeons; 7 players underwent more than 1 procedure. RESULTS: Twenty-eight shoulder surgeries were performed on 27 players: 19 pitchers and 8 position players. The majority of the procedures were labral repairs (n = 21). Nine players returned to their preoperative level; 2 advanced to a higher level; 5 returned to a lower level; and 11 retired from professional baseball. Only 2 of the 12 players at the high professional level (Major League Baseball, triple-A, double-A) returned to the same level. Twenty-three elbow surgeries were performed on 21 players (20 pitchers). The majority of the procedures were ulnar collateral ligament reconstructions (n = 12). Seven players returned to their preoperative level; 4 advanced to a higher level; 4 returned to a lower level; and 6 retired from professional baseball. Of the 12 players at the high professional level, 3 returned to the same or higher level. CONCLUSION: Following surgery, 21 of 44 players (48%) returned to the same or higher level of professional baseball. For those players performing at a high professional level, 5 of 22 (23%) returned to the same or higher level. Return to the same or higher level was more likely with elbow surgery than with shoulder surgery. CLINICAL RELEVANCE: Elite throwing athletes may not return to the same level at a high rate following shoulder or elbow surgery. PMID- 23016000 TI - Concussions involving 7 or more days out in the national football league. AB - BACKGROUND: Positions, signs, symptoms, and medical management of National Football League players with concussions involving 7 or more days out (7+) from play were compared for two 6-year study periods (2002-2007 vs 1996-2001). HYPOTHESIS: More players were held out 7+ days in the 2002-2007 period without significant difference in concussion signs and symptoms. STUDY DESIGN: Cohort. METHODS: From 1996 through 2007, National Football League team physicians reported concussion signs and symptoms, medical action taken, and follow-up management. RESULTS: During the 2002-2007 period, 143 (16.7%) and 33 (3.86%) concussed players were out 7+ days and 21+ days, respectively, compared with 73 (8.2%) and 7 (0.79%) in the 1996-2001 period, a significant difference (z = 5.39, P < .01). The positions with the highest fraction of 7+ days out were the quarterback (24.5% vs 16.1%), linebacker (19.7% vs 4.6%), and wide receiver (19.5% vs 8.2%) in the later versus earlier period. The player positions with the highest odds for being out 7+ days were quarterback (odds ratio = 1.80 vs 4.02), linebacker (odds ratio = 1.28 vs 0.65), and wide receiver (odds ratio = 1.25 vs 1.15). The highest incidence of 7+ days out occurred after passing plays (32.2% vs 37.0%), followed by kickoffs (18.9% vs 21.9%). The majority of players with 7+ days out were removed from the game on the day of injury (74.8% vs 72.6%); a smaller fraction were returned to play on the day of injury in the later 6 years (3.5% vs 6.8%). CONCLUSIONS: The positions with the highest odds for being out 7+ days with concussion were quarterbacks, linebackers, and wide receivers. In the more recent 6-year period, more players were managed conservatively by being held out 7+ days, even though the signs and symptoms of their concussions were similar to those in the earlier period. PMID- 23016001 TI - Prevalence of hyponatremia, renal dysfunction, and other electrolyte abnormalities among runners before and after completing a marathon or half marathon. AB - BACKGROUND: Prior reports on metabolic derangements observed in distance running frequently have small sample sizes, lack prerace laboratory measures, and report sodium as the sole measure. HYPOTHESIS: Metabolic abnormalities-hyponatremia, hypokalemia, renal dysfunction, hemoconcentration-are frequent after completing a full or half marathon. Clinically significant changes occur in these laboratory values after race completion. STUDY DESIGN: Observational, cross-sectional study. METHODS: Consenting marathon and half marathon racers completed a survey as well as finger stick blood sampling on race day of the National Marathon to Fight Breast Cancer (Jacksonville, Florida, February 2008). Parallel blood measures were obtained before and after race completion (prerace, n = 161; postrace, n = 195). RESULTS: The prevalence of prerace and postrace hyponatremia was 8 of 161 (5.0%) and 16 of 195 (8.2%), respectively. Hypokalemia was not present prerace but was present in 1 runner postrace (1 of 195). Renal dysfunction occurred prerace in 14 of 161 (8.7%) and postrace in 83 of 195 (42.6%). Among those with postrace renal dysfunction, 45.8% (38 of 83) were classified as moderate or severe. Hemoconcentration was present in 2 of 161 (1.2%) prerace and 6 of 195 (3.1%) postrace. The mean changes in laboratory values were (postrace minus prerace): sodium, 1.6 mmol/L; potassium, -0.2 mmol/L; blood urea nitrogen, 2.8 mg/dL; creatinine, 0.2 mg/dL; and hemoglobin, 0.3 g/dL for 149 pairs (except blood urea nitrogen, n = 147 pairs). Changes were significant for all comparisons (P < 0.01) except potassium (P = 0.08) and hemoglobin (P = 0.01). CONCLUSIONS: Metabolic abnormalities are common among endurance racers, and they may be present prerace, including hyponatremia. The clinical significance of these findings is unknown. CLINICAL RELEVANCE: It is unclear which runners are at risk for developing clinically important metabolic derangements. Participating in prolonged endurance exercise appears to be safe in the majority of racers. PMID- 23016002 TI - Effect of patterned electrical neuromuscular stimulation on vertical jump in collegiate athletes. AB - BACKGROUND: Patterned electrical neuromuscular stimulation (PENS) uses the electrical stimulation of sensory and motor nerves to achieve a skeletal muscle contraction using an electromyogram-derived functional pattern. PENS is used extensively for neuromuscular reeducation and treatment of muscle disuse atrophy. PURPOSE: To explore the effectiveness of PENS as applied to the quadriceps muscles on the vertical jump of an athletic population. STUDY DESIGN: Experimental with control and repeated measures over time. METHODS: Healthy college athletes (54 women, 75 men) were divided into 3 groups (control, n = 30; jump, n = 33; and jump with PENS, n = 63). There was no difference among groups' height and weight. Athletes performed a baseline standing vertical jump using a vertical jump system. The control group continued its normal daily activities with no jumping tasks included. The jump groups performed 3 sets of 12 repetitions with a 2-minute rest between sets at a frequency of 3 times per week. The PENS group did the jumping with the coordination of an electrical stimulation system. Vertical jump was retested after 6 weeks of intervention and 2 weeks after cessation. RESULTS: A 3-way repeated measures analysis of variance for time (control, jump alone, jump with PENS) revealed a significant difference (P < 0.05) for time and an interaction between time and treatment, as well as a significant difference for the PENS group from baseline to posttest and for the jump group from posttest to follow-up jump. There was no significant difference between groups for the baseline vertical jump. CONCLUSIONS: This study demonstrated that 6 weeks of vertical jump training coordinated with PENS resulted in a greater increase than jumping only or control. This pattern of stimulation with PENS in combination with jump training may positively affect jumping. PMID- 23016003 TI - Patellofemoral disorders: role of computed tomography and magnetic resonance imaging in defining abnormal rotational lower limb alignment. AB - BACKGROUND: The contribution of lower limb rotational malalignment to patellofemoral pain and instability has been well recognized. The purpose of the present study is to review the role of computed tomography (CT) and magnetic resonance imaging (MRI) in assessment of abnormal rotational alignment of lower limb. EVIDENCE ACQUISITION: An analysis of all available literature in the English language through 2010 was performed to provide data on a comparison between MRI and CT-specifically, the techniques and normative values used to determine abnormal lower limb alignment. RESULTS: CT and MRI are highly accurate in defining abnormal alignment of the lower limb. Determination of axis of femoral anteversion in proximal femur has been the subject of debate in the literature. The determination of distal femoral condylar axis, proximal tibial axis and distal tibial axis are less controversial. CONCLUSIONS: CT and MRI are both used for assessing the rotational abnormalities of the femur and tibia during evaluation for patellofemoral disorders. MRI has an advantage over CT because femoral anteversion measurements are more accurate and ionizing radiation is avoided. A standardized protocol defining the level and axes for measurement of femoral and tibial alignment indices should be used to maintain consistency in measurements. PMID- 23016004 TI - A treatment algorithm for primary patellar dislocations. AB - CONTEXT: Primary patellar dislocation continues to be a common problem facing clinicians today. These injuries are associated with significant morbidity and a substantial recurrence rate. Myriad operative and nonoperative options have been described to treat these injuries, although the evidence-based literature is sparse. EVIDENCE ACQUISITION: PubMed was searched from 1970-2010 to identify publications on patellar dislocations, including clinical presentation, natural history, radiographic workup, and treatment. RESULTS: The initial workup of a patella dislocation includes a history, physical examination, and radiographs. If there is evidence of a displaced osteochondral fragment or hemarthrosis, then magnetic resonance imaging should be obtained. The treatment of first-time patella dislocators has been controversial, and no study has demonstrated a clear benefit to early operative intervention. CONCLUSION: First-time patellar dislocations should be treated conservatively unless there is evidence of a displaced osteochondral fragment. PMID- 23016005 TI - Partial triceps disruption: a case report. AB - Partial triceps tendon disruptions are a rare injury that can lead to debilitating outcomes if misdiagnosed or managed inappropriately. The clinician should have a high index of suspicion when the mechanism involves a fall onto an outstretched arm and there is resultant elbow extension weakness along with pain and swelling. The most common location of rupture is at the tendon-osseous junction. This case report illustrates a partial triceps tendon disruption with involvement of, primarily, the medial head and the superficial expansion. Physical examination displayed weakness with resisted elbow extension in a flexed position over 90 degrees . Radiographs revealed a tiny fleck of bone proximal to the olecranon, but this drastically underestimated the extent of injury upon surgical exploration. Magnetic resonance imaging is essential to ascertain the percentage involvement of the tendon; it can be used for patient education and subsequently to determine treatment recommendations. Although excellent at finding associated pathology, it may misjudge the size of the tear. As such, physicians must consider associated comorbidities and patient characteristics when formulating treatment plans. PMID- 23016006 TI - Treatment of a symptomatic forearm muscle herniation with a mesh graft. AB - Symptomatic muscle herniations are an unusual cause of upper extremity pain in the athlete that is rarely reported in the literature. Out of 18 reported cases of upper extremity herniations, only 3 were caused by strenuous exertion. This article describes a successful repair of a 21-year-old rock climber's ventral forearm herniation with polypropylene mesh. PMID- 23016007 TI - Effect of therapeutic modalities on patients with patellofemoral pain syndrome: a systematic review. AB - CONTEXT: Patellofemoral pain syndrome (PFPS) is a common orthopaedic condition for which operative and nonoperative treatments have been used. Therapeutic modalities have been recommended for the treatment of patients with PFPS including cold, ultrasound, phonophoresis, iontophoresis, neuromuscular electrical stimulation, electrical stimulation for pain control, electromyographic biofeedback, and laser. OBJECTIVE: To determine the effectiveness of therapeutic modalities for the treatment of patients with PFPS. DATA SOURCES: In May and August 2010, Medline was searched using the following databases: PubMed, CINAHL, Web of Science Citation Index, Science Direct, ProQuest Nursing & Allied Health, and Your Journals@OVID. STUDY SELECTION: Selected studies were randomized controlled trials that used a therapeutic modality to treat patients with PFPS. The review included articles with all outcome measures relevant for the PFPS patient: knee extension and flexion strength (isokinetic and isometric), patellofemoral pain assessment during activities of daily life, functional tests (eg, squats), Kujala patellofemoral score, and electromyographic recording from knee flexors and extensors and quadriceps femoris cross-sectional areas. DATA EXTRACTION: Authors conducted independent quality appraisals of studies using the PEDro Scale and a system designed for analysis of studies on interventions for patellofemoral pain. RESULTS: TWELVE STUDIES MET CRITERIA: 1 on the effects of cold and ultrasound together, ice alone, iontophoresis, and phonophoresis; 3, neuromuscular electrical stimulation; 4, electromyographic biofeedback; 3, electrical stimulation for control of pain; and 1, laser. DISCUSSION: Most studies were of low to moderate quality. Some reported that therapeutic modalities, when combined with other treatments, may be of some benefit for pain management or other symptoms. There was no consistent evidence of any beneficial effect when a therapeutic modality was used alone. Studies did not consistently provide added benefit to conventional physical therapy in the treatment of PFPS. CONCLUSIONS: None of the therapeutic modalities reviewed has sound scientific justification for the treatment of PFPS when used alone. PMID- 23016008 TI - Effectiveness of elastic resistance in rehabilitation of patients with patellofemoral pain syndrome: what is the evidence? AB - CONTEXT: Patellofemoral pain syndrome (PFPS) is associated with muscle imbalance at the knee and hip. Therapeutic exercise is effective at reducing pain associated with PFPS. OBJECTIVE: To identify and analyze clinical trials of elastic resistance in patients with PFPS to determine its efficacy. DATA SOURCES: PubMed, CINAHL, and PEDro databases were searched for terms relevant to PFPS rehabilitation in patients aged 12 to 40 years. STUDY SELECTION: Only peer reviewed clinical trials lasting at least 4 weeks and specifying the use of elastic resistance in their protocols were included. DATA EXTRACTION: Eight eligible studies were analyzed for design, sample, intervention, outcomes, and clinical application. RESULTS: The studies included in this review lacked high quality design, often using exercise as a "quasi-control" condition. Most studies did not provide specific exercise prescription or progression. Although participants in each study reported significant improvements in pain, deficiencies in scientific design limit the conclusion. CONCLUSION: Elastic resistance exercise may reduce pain and improve function and strength in patients with PFPS. PMID- 23016009 TI - Radiologic assessment of patellofemoral pain in the athlete. AB - CONTEXT: Although disorders of the patellofemoral joint are common in the athlete, their management can be challenging and require a thorough physical examination and radiologic evaluation, including advanced magnetic resonance imaging techniques. EVIDENCE ACQUISITION: Relevant articles were searched under OVID and MEDLINE (1968 to 2010) using the keywords patellofemoral joint, patellofemoral pain or patella and radiography, imaging, or magnetic resonance imaging, and the referenced sources were reviewed for additional articles. The quality and validity of the studies were assessed on the basis of careful analysis of the materials and methods before their inclusion in this article. RESULTS: Physical examination and imaging evaluation including standard radiographs are crucial in identifying evidence of malalignment or instability. Magnetic resonance imaging provides valuable information about concomitant soft tissue injuries to the medial stabilizers as well as injuries to the articular cartilage, including chondral shears and osteochondral fractures. Quantitative magnetic resonance imaging assessing the ultrastructure of cartilage has shown high correlation with histology and may be useful for timing surgery. CONCLUSIONS: Evaluation of patellofemoral disorders is complex and requires a comprehensive assessment. Recent advancements in imaging have made possible a more precise evaluation of the individual anatomy of the patient, addressing issues of malalignment, instability, and underlying cartilage damage. PMID- 23016010 TI - Internet medicine. PMID- 23016011 TI - Letter to the editor. PMID- 23016012 TI - Issues encountered by physicians during international travel with youth national soccer teams. AB - BACKGROUND: Little information is available to guide the selection, preparation, and support of a traveling team physician. PURPOSE: To determine the types of injuries and medical problems, as well as general team health and performance issues, encountered by physicians traveling internationally with youth national soccer teams. STUDY DESIGN: Descriptive epidemiology. METHODS: Physicians assigned to travel abroad with the under-17 men's and women's US national soccer teams during a 2-year period documented all encounters with team and staff members. Physicians also documented consultations related to team health and performance issues. RESULTS: The 108 cases (5.71 per 10 days) were evenly divided between injuries (n = 54) and noninjuries (n = 54). Players sought care at a higher rate than did staff (2.28 vs 1.09 per 100 person days). Mean severity for all player cases was 5.19 days missed (injuries, 10.48; noninjuries, 0.23). Nearly 69% of injuries involved the lower extremities: strains, sprains, and contusions accounted for 74.1% of injuries. Gastrointestinal, dermatologic, and otolaryngologic complaints accounted for 77.8% of noninjuries. Medications were administered in 71% of cases, with analgesics, cough and cold remedies, antibiotics, and gastrointestinal agents accounting for the majority. The leading team health and performance concerns were nutrition/hydration, conditioning, prevention, and doping control. CONCLUSION: Physicians traveling internationally with youth soccer teams manage an equal proportion of musculoskeletal and medical problems using simple medications. PMID- 23016013 TI - Microbiota found in protective athletic mouthguards. AB - BACKGROUND: Protective athletic mouthguards (PAM) produce oral mucosal injuries and may be associated with other systemic conditions. HYPOTHESIS: With wear, PAM become contaminated by a range of microorganisms. The number of microorganisms in PAM can be reduced by daily use of an antimicrobial solution. STUDY TYPE: Case series. STUDY DESIGN AND METHODS: Sixty-two division I football player volunteers were divided into 4 groups, using PAM for varying lengths of time before surrendering them for microbial analysis. One group had their PAM soaked in an antimicrobial solution between uses. The PAM were analyzed qualitatively and quantitatively for bacteria, yeasts, and fungi, using previously accepted methods. RESULTS: The 62 football players surrendered a total of 81 PAM for microbial analysis. The PAM yielded 154 gram-positive cocci, 150 gram-positive bacilli, 21 gram-negative cocci, 31 gram-negative bacilli, 22 yeasts, and 107 molds. The most common species of gram-positive cocci were Staphylococcus spp. and Micrococcus spp. Only 3 PAM (4%) were positive for Staphylococcus aureus. The most common species of gram-positive bacilli were Brevibacterium spp. and Cellulomonas spp. The most common species of yeasts were Candida parapsilosis and Rhodotorula mucilaginosa, while the most common species of mold were Cochliobolus spp. and Penicillium chrysogenum. Soaking the PAM in an antimicrobial solution between uses substantially reduced the numbers of microorganisms. CONCLUSIONS: Substantial microbial contamination of PAM occurs with use. The microbial load can be reduced by soaking in an antimicrobial solution between uses. CLINICAL RELEVANCE: PAM are contaminated by microorganisms that have the potential to produce oral and systemic diseases. They should be sanitized daily and changed when they become sharp and/or jagged. PMID- 23016014 TI - Body mass index and percentage of body fat as indicators for obesity in an adolescent athletic population. AB - BACKGROUND: Body mass index (BMI) is widely accepted in determining obesity. Skinfold thickness measurements have been commonly used to determine percentage of body fat. HYPOTHESIS: The authors hypothesize that because BMI does not measure fat directly but relies on body weight alone, a large percentage of athletic adolescents will be misclassified as obese by BMI. DESIGN: Cross sectional study. METHODS: To compare BMI and skinfold measurements as indicators for obesity in the adolescent athletic population, anthropometric data (height, weight, percentage body fat, age, and sex) were recorded from 33 896 student athletes (average age, 15 years; range, 11-19 years) during preparticipation physical examinations from 1985 to 2003. BMI was calculated from height and weight. Percentage of body fat was determined by measuring skinfold thickness. RESULTS: According to their BMI percentile, 13.31% of adolescent athletes were obese. Using the skinfold method, only 5.95% were obese. Of those classified as obese by the BMI, 62% were considered false positives by the skinfold method. In contrast, there was a 99% probability that the nonobese by BMI would not be obese by the skinfold method (negative predictive value = 0.99). CONCLUSIONS: BMI is a measurement of relative body weight, not body composition. Because lean mass weighs far more than fat, many adolescent athletes are incorrectly classified as obese based on BMI. Skinfold testing provides a more accurate body assessment than BMI in adolescent athletes. CLINICAL RELEVANCE: Correct body composition data can help to provide better diet and activity guidelines and prevent the psychological problems associated with being labeled as obese. PMID- 23016016 TI - Predicting chronic stinger syndrome using the mean subaxial space available for the cord index. AB - A 21-year-old division I collegiate football player who had a history of several stingers presented with 5 days of persistent left neck and shoulder pain associated with paresthesias and upper extremity weakness. His symptoms began immediately during a game when he was struck on the right side of his helmet, which induced a compression-extension mechanism of injury to his neck. Clinical and electrodiagnostic evaluation was consistent with a left C5 radiculopathy, but magnetic resonance imaging of the cervical spine yielded normal results. The mean subaxial cervical space available for the cord (MSCSAC) index is a novel tool to predict chronic stinger syndrome. It is calculated by subtracting the sagittal diameter of the spinal cord from the disc-level sagittal diameter of the spinal canal at levels C3 through C6 and then averaging these values. A cutoff of < 4.3 mm has been shown to predict a greater-than-13-fold increase in risk of developing chronic stinger syndrome. This patient had a MSCSAC index of 3.2 mm, which correlated with his history of multiple stingers. The MSCSAC index may be a useful tool to help counsel athletes on the risk of developing future stingers, although more extensive research on this measurement tool is indicated. PMID- 23016015 TI - Evaluation and management of posterior shoulder instability. AB - CONTEXT: Posterior shoulder instability is a commonly misdiagnosed disorder in many competitive athletes. TYPE OF STUDY: Clinical review. EVIDENCE ACQUISITION: Relevant studies on posterior shoulder instability from 1950 to 2010 in PubMed and Cochrane databases were reviewed. RESULTS: A total of 107 studies were reviewed. CONCLUSION: Patients who have undergone at least 6 months of physical therapy and still experience instability symptoms should be considered for surgical stabilization directed at their underlying pathology. PMID- 23016017 TI - Meta-analysis of Clinical and Radiographic Outcomes After Arthroscopic Single-Row Versus Double-Row Rotator Cuff Repair. AB - CONTEXT: Double-row rotator cuff repair methods have improved biomechanical performance when compared with single-row repairs. OBJECTIVE: To review clinical outcomes of single-row versus double-row rotator cuff repair with the hypothesis that double-row rotator cuff repair will result in better clinical and radiographic outcomes. DATA SOURCES: Published literature from January 1980 to April 2010. Key terms included rotator cuff, prospective studies, outcomes, and suture techniques. STUDY SELECTION: The literature was systematically searched, and 5 level I and II studies were found comparing clinical outcomes of single-row and double-row rotator cuff repair. Coleman methodology scores were calculated for each article. DATA EXTRACTION: Meta-analysis was performed, with treatment effect between single row and double row for clinical outcomes and with odds ratios for radiographic results. The sample size necessary to detect a given difference in clinical outcome between the 2 methods was calculated. RESULTS: Three level I studies had Coleman scores of 80, 74, and 81, and two level II studies had scores of 78 and 73. There were 156 patients with single-row repairs and 147 patients with double-row repairs, both with an average follow-up of 23 months (range, 12-40 months). Double-row repairs resulted in a greater treatment effect for each validated outcome measure in 4 studies, but the differences were not clinically or statistically significant (range, 0.4-2.2 points; 95% confidence interval, -0.19, 4.68 points). Double-row repairs had better radiographic results, but the differences were also not statistically significant (P = 0.13). Two studies had adequate power to detect a 10-point difference between repair methods using the Constant score, and 1 study had power to detect a 5-point difference using the UCLA (University of California, Los Angeles) score. CONCLUSIONS: Double-row rotator cuff repair does not show a statistically significant improvement in clinical outcome or radiographic healing with short term follow-up. PMID- 23016018 TI - Activity profile of members of an online health community after articular cartilage repair of the knee. AB - BACKGROUND: Articular cartilage repair (ACR) procedures aim to alleviate pain and restore function for individuals with chondral defects. Rehabilitation is lengthy, and there are limited data on return to sports and exercise activities after ACR in non-elite-athlete populations. The Internet is a growing source of health-related information for patients, and it has resulted in the emergence of online health communities. PURPOSE: To establish a postoperative activity profile of users of an online health community who have undergone ACR of the knee and to compare this profile with those from the same community who have undergone initial anterior cruciate ligament reconstruction (ACLR). STUDY DESIGN: Cross sectional. METHODS: Tegner Activity Scale ratings were collected via a self reported online questionnaire from 201 participants of an online health community who had undergone tibiofemoral and/or patellofemoral ACR (n = 75) or ACLR (n = 126). RESULTS: A higher Tegner activity level was significantly correlated to time from surgery for ACR (P < 0.005) and ACLR (P < 0.01). At a minimum of 24 months' follow-up, the ACR group had a median postoperative Tegner score of 3, compared with 6 for the ACLR group. Tegner score was significantly negatively correlated with age at time of surgery for ACLR (P < 0.05) but not for ACR. Men demonstrated significantly higher Tegner activity levels than did women for both ACLR and ACR (P < 0.05). CONCLUSIONS: Activity levels after ACR in this population increased with postoperative time but remained lower than expected when compared with current published clinical and normative data. CLINICAL RELEVANCE: Engagement with an online health community may influence expectations regarding return to sports and exercise activities. Reporting of activity-level data within clinical studies should be differentiated on the basis of sex. Further research is needed to elucidate factors that determine return to sports and exercise activities after ACR. PMID- 23016019 TI - Subscapularis strain from swinging a baseball bat in an adolescent with closed physis. AB - A healthy 16-year-old female baseball player was referred by her pediatrician for evaluation of pain in her right, dominant shoulder. The pain had begun insidiously 4 weeks previously after several sessions of batting practice and had worsened until she could not participate in baseball, even with low doses of ibuprofen. She was not participating in any other sports or weight lifting and had had no previous incidents of shoulder pain, but she did have a history of being able to voluntarily subluxate the right shoulder since she was a child. Her voluntary shoulder subluxation and reduction did not reproduce or worsen her pain. Results from her physical examination and radiographs were normal. Magnetic resonance imaging showed edema in the subscapularis muscle consistent with acute muscle strain. She was treated with 6 weeks of rest, ice, and anti-inflammatory medication as needed. She returned to baseball and hitting during the following 6 weeks with no limitations. PMID- 23016020 TI - Systematic review of the balance error scoring system. AB - CONTEXT: The Balance Error Scoring System (BESS) is commonly used by researchers and clinicians to evaluate balance.A growing number of studies are using the BESS as an outcome measure beyond the scope of its original purpose. OBJECTIVE: To provide an objective systematic review of the reliability and validity of the BESS. DATA SOURCES: PubMed and CINHAL were searched using Balance Error Scoring System from January 1999 through December 2010. STUDY SELECTION: Selection was based on establishment of the reliability and validity of the BESS. Research articles were selected if they established reliability or validity (criterion related or construct) of the BESS, were written in English, and used the BESS as an outcome measure. Abstracts were not considered. RESULTS: Reliability of the total BESS score and individual stances ranged from poor to moderate to good, depending on the type of reliability assessed. The BESS has criterion-related validity with force plate measures; more difficult stances have higher agreement than do easier ones. The BESS is valid to detect balance deficits where large differences exist (concussion or fatigue). It may not be valid when differences are more subtle. CONCLUSIONS: Overall, the BESS has moderate to good reliability to assess static balance. Low levels of reliability have been reported by some authors. The BESS correlates with other measures of balance using testing devices. The BESS can detect balance deficits in participants with concussion and fatigue. BESS scores increase with age and with ankle instability and external ankle bracing. BESS scores improve after training. PMID- 23016021 TI - Infrapatellar Straps Decrease Patellar Tendon Strain at the Site of the Jumper's Knee Lesion: A Computational Analysis Based on Radiographic Measurements. AB - BACKGROUND: The impetus for the use of patellar straps in the treatment of patellar tendinopathy has largely been based on empirical evidence and not on any mechanistic rationale. A computational model suggests that patellar tendinopathy may be a result of high localized tendon strains that occur at smaller patella patellar tendon angles (PPTAs). HYPOTHESIS: Infrapatellar straps will decrease the mean localized computational strain in the area of the patellar tendon commonly involved in jumper's knee by increasing the PPTA. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty adult males had lateral weightbearing and nonweightbearing radiographs of their knees taken with and without 1 of 2 infrapatellar straps at 60 degrees of knee flexion. Morphologic measurements of PPTA and patellar tendon length with and without the straps were used as input data into a previously described computational model to calculate average and maximum strain at the common location of the jumper's knee lesion during a simulated jump landing. RESULTS: The infrapatellar bands decreased the predicted localized strain (average and maximum) in the majority of participants by increasing PPTA and/or decreasing patellar tendon length. When both PPTA and patellar tendon length were altered by the straps, there was a strong and significant correlation with the change in predicted average localized strain with both straps. CONCLUSION: Infrapatellar straps may limit excessive patella tendon strain at the site of the jumper's knee lesion by increasing PPTA and decreasing patellar tendon length rather than by correcting some inherent anatomic or functional abnormality in the extensor apparatus. CLINICAL RELEVANCE: The use of infrapatellar straps may help prevent excessive localized tendon strains at the site of the jumper's knee lesion during a jump landing. PMID- 23016022 TI - Impact forces of plyometric exercises performed on land and in water. AB - BACKGROUND: Aquatic plyometric programs are becoming increasingly popular because they provide a less stressful alternative to land-based programs. Buoyancy reduces the impact forces experienced in water. PURPOSE: To quantify the landing kinetics during a range of typical lower limb plyometric exercises performed on land and in water. STUDY DESIGN: Crossover design. METHODS: Eighteen male participants performed ankle hops, tuck jumps, a countermovement jump, a single leg vertical jump, and a drop jump from 30 cm in a biomechanics laboratory and in a swimming pool. Land and underwater force plates (Kistler) were used to obtain peak impact force, impulse, rate of force development, and time to reach peak force for the landing phase of each jump. RESULTS: Significant reductions were observed in peak impact forces (33%-54%), impulse (19%-54%), and rate of force development (33%-62%) in water compared with land for the majority of exercises in this study (P < 0.05). CONCLUSIONS: The level of force reduction varies with landing technique, water depth, and participant height and body composition. CLINICAL RELEVANCE: This information can be used to reintroduce athletes to the demands of plyometric exercises after injury. PMID- 23016023 TI - The 2011 sports health sisk awards. PMID- 23016024 TI - Letter to the editor. PMID- 23016025 TI - The Epidemiology of Pediatric Basketball Injuries Presenting to US Emergency Departments: 2000-2006. AB - BACKGROUND: There is limited published research on the epidemiology of basketball injuries treated in US emergency departments (EDs). HYPOTHESIS: Age and sex patterns exist for the most common pediatric basketball injuries treated in EDs. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data from the National Electronic Injury Surveillance System and the National Sporting Goods Association were used to calculate national injury incidence rates and 95% confidence intervals of pediatric basketball injuries. RESULTS: An estimated 325 465 annual visits were made to US EDs for pediatric basketball-related injuries from 2000 to 2006. The 5 most common injuries were ankle sprains (21.7%), finger sprains (8.0%), finger fractures (7.8%), knee sprains (3.9%), and facial lacerations (3.9%). Among persons aged 12 to 17 years, girls had a higher rate of knee sprains than boys (P < 0.001), but this association did not exist among those aged 7 to 11 years (P = 0.27). Boys had a higher rate of facial lacerations than girls (P < 0.01). Among persons aged 12 to 17 years, girls had a higher rate of finger sprains (P < 0.01). For both boys and girls, the rate of the 5 most common basketball injuries was higher among those aged 12 to 17 years compared with those aged 7 to 11 years (P < 0.01). CONCLUSIONS: The annual number of basketball related pediatric ED visits approaches a third of a million and demonstrates the extent of the public health problem that injuries in this sport pose. Distinct sex and age patterns were observed. CLINICAL RELEVANCE: The study findings provide important information on basketball injury rates that may be used for targeting prevention interventions by sex and age group. PMID- 23016026 TI - Evaluation of low back pain in athletes. AB - CONTEXT: Low back pain is a common complaint in athletes. Athletes differ from the general population physiologically, making it unclear if the evaluation of low back pain should differ between these 2 groups. EVIDENCE ACQUISITION: A literature search (PubMed, Ovid) was performed for the years 1995 through 2010. Keywords used were lumbar back pain, athletes, and adolescence. RESULTS: Athletes with low back pain represent a very diverse group. The evaluation depends on the athlete's age and the presence of "red flags." The most common causes of low back pain in the preadolescent population are infection, tumor, and trauma. In the adolescent population, trauma spondylolysis/spondylolisthesis and hyperlordosis are commonly seen. Leading causes in the adult population are mechanics and osteoarthritis. The elderly frequently present with osteoarthritis, spinal stenosis, and internal medical etiologies. CONCLUSION: Athletes with back pain should have a diagnostic workup guided by their age, history, and physical examination. Although this work up is similar in nonathletes, the demands of the athlete must be taken into account in a treatment plan. PMID- 23016027 TI - Absorption of hydrocortisone acetate in human connective tissue using phonophoresis. AB - BACKGROUND: Therapeutic ultrasound to drive medication (phonophoresis) has been a mainstay in physical therapy. The most common drug used in phonophoresis is hydrocortisone acetate (HA). A number of studies have been done examining phonophoresis in the delivery of HA through the skin to underlying tissues; however, a study has never been done examining the absorption of HA using phonophoresis on human connective tissue. HYPOTHESIS: Phonophoresis will facilitate the transmission of HA in human connective tissue. STUDY DESIGN: Randomized controlled study. METHODS: Twenty-one patients undergoing anterior cruciate ligament reconstruction surgery were randomly assigned to either a sham or true phonophoresis treatment group. The latter group received 6 minutes of 10% HA ultrasound at a point consistent with the gastrocnemius slip of the semitendinosis tendon (treatment site). The sham group received 6 minutes of 10% HA ultrasound to the same area, but the ultrasound was not turned on. The slip and a sample of the distal attachment of the tendon (control) were removed. Samples were analyzed for HA levels. RESULTS: Although the mean and median levels of HA found at the treatment site were greater than those of the control site (means, 34.1 vs 22.9 parts per billion; medians, 7 vs 0 parts per billion), the levels of HA found at the treatment site were not significantly greater than those at the control site (P = 0.15). There were no statistically significant differences between the true and sham phonophoresis groups in HA levels (P = 0.80) nor in age, sex, or skin thickness. CONCLUSION: Phonophoresis does not appear to facilitate the absorption of HA in connective tissue when compared with simple absorption (sham). CLINICAL RELEVANCE: Phonophoresis does not appear to enhance the transmission of HA in human connective tissue; therefore, use of phonophoresis should be reconsidered in inflammatory conditions. PMID- 23016028 TI - Pilates: what is it? Should it be used in rehabilitation? AB - CONTEXT: The interest and popularity of Pilates is increasing worldwide. In addition to being used in fitness programs, it is being used in some rehabilitation programs. EVIDENCE ACQUISITION: This review summarizes level III evidence from 1995 to 2009 obtained from PubMed (MEDLINE), CINAHL, and the Internet. Meta-analyses, systematic reviews, randomized controlled trials, and controlled trials published in peer-reviewed journals were retrieved for appraisal. The keywords searched were Pilates and core stabilization. RESULTS: Ninety articles were identified in MEDLINE and CINAHL; 9 articles satisfied the inclusion criteria for level III evidence. CONCLUSION: There is a scientific basis for the effectiveness of Pilates exercise, with limited evidence to support it as a rehabilitative intervention. PMID- 23016029 TI - A treatment-based classification approach to examination and intervention of lumbar disorders. AB - CONTEXT: Low back injuries are a common occurrence in athletes and often result in missed competition and practice time. The examination of athletes with low back pain commonly involves diagnostic imaging, which rarely guides the clinician in selecting the appropriate interventions. DATA ACQUISITION: All years of PubMed, CINAHL, PEDro, and SPORTDiscus were searched in December 2010. Keywords included treatment based classification and lumbar with the following terms: rehabilitation, treatment, athlete, low back pain, sports, and outcomes. RESULTS: A treatment-based classification approach is preferred for the management of the athlete with low back pain. The treatment-based classification approach involves 3 steps. First is to screen the patient for potentially serious conditions that are not appropriate for conservative management. Second is staging the athlete (based on current disability ratings and ability to perform functional activities). Finally, treatment interventions are selected on the basis of the athlete's signs and symptoms. CONCLUSION: The treatment-based classification scheme provides the clinician with a reliable algorithm for matching an athlete's symptom presentation to the optimal intervention, potentially reducing participation loss. Managing individuals with low back pain using a treatment based classification approach significantly reduces disability and pain compared with current clinical practice guideline standards. PMID- 23016030 TI - Sex differences in knee abduction during landing: a systematic review. AB - BACKGROUND: Females suffer injuries to the anterior cruciate ligament at rates significantly higher than males. Frontal plane knee motion and load have been identified as major risk factors for anterior cruciate ligament injury and in turn have been examined extensively. METHODS: A systematic review of MEDLINE, CINHAL, and SportDISCUS was performed (1982-June 2010). Criteria for inclusion were the use of 3-dimensional analyses of frontal plane knee motion and moments during landing between males and females. RESULTS: Twenty-seven studies met the inclusion criteria and were reviewed. Sixty-three percent of included studies identified sex differences in knee abduction when landing across a variety of landing conditions. CONCLUSIONS: Females appear to land with increased knee abduction motion compared with males in most biomechanics studies. PMID- 23016031 TI - Humeral retrotorsion in collegiate baseball pitchers with throwing-related upper extremity injury history. AB - BACKGROUND: Collegiate baseball pitchers, as well as position players, exhibit increased humeral retrotorsion compared with individuals with no history of overhead sport participation. Whether the humeral retrotorsion plays a role in the development of throwing-related injuries that are prevalent in collegiate baseball pitchers is unknown. HYPOTHESES: Humeral retrotorsion will be significantly different in collegiate pitchers with throwing-related shoulder or elbow injury history compared with pitchers with no injury history. Humeral retrotorsion can also discriminate participants with and without shoulder or elbow injury. STUDY DESIGN: Cross-sectional study. METHODS: Comparisons of ultrasonographically-obtained humeral retrotorsion were made between 40 collegiate pitchers with and without history of throwing-related shoulder or elbow injury. The ability of humeral retrotorsion to discriminate injury history was determined from the receiver operating characteristic area under the curve. RESULTS: Participants with an elbow injury history demonstrated a greater humeral retrotorsion limb difference (mean difference = 7.2 degrees , P = 0.027) than participants with no history of upper extremity injury. Participants with shoulder injury history showed no differences in humeral torsion compared with participants with no history of injury. Humeral retrotorsion limb difference exhibited a fair ability (receiver operating characteristic area under the curve = 0.74) to discriminate elbow injury history. CONCLUSIONS: Collegiate pitchers with a history of elbow injury exhibited a greater limb difference in humeral retrotorsion compared with pitchers with no history of injury. No differences in humeral retrotorsion variables were present in participants with and without shoulder injury history. CLINICAL RELEVANCE: Baseball players with a history of elbow injury demonstrated increased humeral retrotorsion, suggesting that the amount of retrotorsion and the development of elbow injury may be associated. PMID- 23016032 TI - Magnetic resonance imaging double popliteus tendon sign: a case report. AB - The double popliteus tendon sign is seen on sagittal magnetic resonance imaging (MRI) of the knee as a low-signal-intensity band parallel to the popliteus tendon at the level of the popliteus hiatus. It is the result of a displaced complex flap tear of the lateral meniscus. This type of displaced meniscal tear can be easily missed on MRI, unless the clinician is aware of its existence and significance and is familiar with its MRI appearance. PMID- 23016033 TI - Symptomatic ganglion cyst of the popliteus tendon treated with ultrasound-guided aspiration and steroid injection: a case report. AB - Ultrasound-guided aspiration of symptomatic ganglion cysts about peripheral joints is a valuable and routinely performed therapeutic modality. Intratendinous and peritendinous ganglia involving the popliteus tendon are rare, with only 3 cases previously reported. These ganglion cysts are usually small and can easily be mistaken for normal anatomy on magnetic resonance imaging (ie, small periarticular vessel or fluid within the popliteus tendon sheath), leading to delayed patient diagnosis and appropriate treatment. PMID- 23016035 TI - A need for change. PMID- 23016034 TI - Systematic review of arthroscopic versus open repair for recurrent anterior shoulder dislocations. AB - CONTEXT: It remains unknown if arthroscopic repair of recurrent anterior shoulder instability is as effective as open repair. OBJECTIVE: The purpose of this study is to analyze the literature to provide clinical recommendations regarding the most appropriate therapeutic intervention for recurrent anterior shoulder instability. STUDY DESIGN: Systematic review of level I and II studies. DATA SOURCES: PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and secondary references from 1967 to March 2010 were appraised for studies that met the inclusion criteria. STUDY SELECTION: Inclusion criteria were English-language level I or level II trials involving the treatment of recurrent anterior shoulder instability. Exclusion criteria included non-English-language studies; level III, IV, or V studies; and trials examining treatment of first-time shoulder dislocation, posterior shoulder dislocation, or diagnoses other than recurrent anterior shoulder dislocations. DATA EXTRACTION: Included studies underwent quality appraisal independently by each author identifying strengths, weaknesses, and biases. RESULTS: Four randomized controlled trials compared the use of arthroscopic and open repair for recurrent anterior shoulder dislocations. These studies show no statistically significant difference between the 2 operative approaches. No long-term follow-up data describing the effects of either surgical approach are available at this time. Each investigation had weaknesses in study design that decreased the validity of its findings. CONCLUSIONS: While limited, the available evidence from randomized controlled trials does not show a statistically significant difference in redislocation rates, return to activity, and functional outcomes between the arthroscopic and open repair groups. Range of motion is marginally better following arthroscopic treatment when compared with open repair. Recommendations on the optimal surgical intervention cannot be provided. PMID- 23016036 TI - Body mass index and percentage of body fat as indicators for obesity in an adolescent athletic population: why the jackson-pollock formula? PMID- 23016037 TI - Letter to the editor. PMID- 23016038 TI - Hamstring injuries in professional football players: magnetic resonance imaging correlation with return to play. AB - BACKGROUND: Magnetic resonance imaging (MRI) allows for detailed evaluation of hamstring injuries; however, there is no classification that allows prediction of return to play. PURPOSE: To correlate time for return to play in professional football players with MRI findings after acute hamstring strains and to create an MRI scoring scale predictive of return to sports. STUDY DESIGN: Descriptive epidemiologic study. METHODS: Thirty-eight professional football players (43 cases) sustained acute hamstring strains with MRI evaluation. Records were retrospectively reviewed, and MRIs were evaluated by 2 musculoskeletal radiologists, graded with a traditional radiologic grade, and scored with a new MRI score. Results were correlated with games missed. RESULTS: Players missed 2.6 +/- 3.1 games. Based on MRI, the hamstring injury involved the biceps femoris long head in 34 cases and the proximal and distal hamstrings in 25 and 22 cases, respectively. When < 50% of the muscle was involved, the average number of games missed was 1.8; if > 75%, then 3.2. Ten players had retraction, missing 5.5 games. By MRI, grade I injuries yielded an average of 1.1 missed games; grade II, 1.7; and grade III, 6.4. Players who missed 0 or 1 game had an MRI score of 8.2; 2 or 3 games, 11.1; and 4 or more games, 13.9. CONCLUSIONS: Rapid return to play (< 1 week) occurred with isolated long head of biceps femoris injures with < 50% of involvement and minimal perimuscular edema, correlating to grade I radiologic strain (MRI score < 10). Prolonged recovery (missing > 2 or 3 games) occurs with multiple muscle injury, injuries distal to musculotendinous junction, short head of biceps injury, > 75% involvement, retraction, circumferential edema, and grade III radiologic strain (MRI score > 15). CLINICAL RELEVANCE: MRI grade and this new MRI score are useful in determining severity of injury and games missed-and, ideally, predicting time missed from sports. PMID- 23016039 TI - Tattoo-induced skin "burn" during magnetic resonance imaging in a professional football player: a case report. AB - The authors present the case of a professional football player with an immediate and sustained cutaneous reaction ("burn") at the site of lower extremity tattoos that occurred during magnetic resonance imaging of the pelvis. The burn was attributed to an electromagnetic reaction due to the ferromagnetic metallic compounds found in tattoo pigments, especially iron oxide-a reaction that has the potential to distort the field of image. These compounds can theoretically create an electric current that increases the local skin temperature, enough to cause a cutaneous burn. "At risk" tattoos are those with black pigment or any other pigments containing iron oxide, as well as those with a design that displays loops, large circular objects, or multiple adjacent points. Patients who develop this reaction may be treated prophylactically or symptomatically with a cold compress to assist with completion of the examination. Alternatively, a towel or cloth may be placed between the cutaneous body parts in those patients who experience the typical reaction resulting from an electrical arc between 2 separate cutaneous tattoos. This is likely an underreported issue that merits mention in the sports medicine literature given the frequent occurrence of cosmetic tattoos in athletes requiring magnetic resonance imaging to diagnose a musculoskeletal injury. As in the present patient, no permanent sequelae have been noted in the literature. Therefore, patients who develop this reaction should be reassured that the reaction is only temporary. PMID- 23016040 TI - The importance of the recognition and treatment of glenoid bone loss in an athletic population. AB - CONTEXT: Osseous injury to the glenoid is increasingly being recognized as one of the most important aspects in the successful management of recurrent shoulder instability. Proper early recognition of glenoid bone injury in the setting of recurrent instability will lead to successful nonoperative and operative decision making, particularly in the athletic patient. EVIDENCE ACQUISITION: We conducted a MEDLINE search on shoulder instability from 2000 to 2010. The emphasis was placed on patient-oriented Level 1 literature from 2000 to 2010. RESULTS: After a traumatic anterior dislocation of the shoulder, the most common structural injury is an avulsion of the anteroinferior capsulolabrum, which is also known as a Bankart lesion. If this specific injury is accompanied by an associated fracture in the glenoid rim, the term bony Bankart lesion is more applicable. With diminished articular constraints, the glenohumeral joint is subject to recurrent instability, thereby potentiating the bony injury cycle. Additionally, patients with osseous defects usually complain of instability within the midranges of motion, or they recall a progression of instability. If glenoid bone loss is present, the humeral head often easily subluxates over the glenoid in the midranges of abduction (30 degrees -90 degrees ) and lower levels of external rotation. Imaging workup should begin with plain radiographs, but advanced imaging should be obtained if there is any suspicion of bone loss. Treatment includes both nonoperative and operative interventions. CONCLUSIONS: Estimation of the amount of glenoid bone loss and the failure of nonoperative care is essential for guiding management, patient expectations, and surgical decision making. PMID- 23016041 TI - Physical activity after total joint arthroplasty. AB - CONTEXT: Total joint arthroplasty (TJA) is a common surgical option to treat painful degenerative joint disease. However, there is currently no consensus on the appropriate intensity of physical activity after TJA or how physical activity level affects the rate of revision surgery. MATERIALS AND METHODS: A systematic review of the literature regarding physical or athletic activity after TJA was performed to determine current clinical opinion and recommendations regarding appropriate activity levels after TJA, as well as variables affecting successful surgery and improved outcomes. RESULTS: Many studies in the literature regarding athletic activity after TJA focus on total hip arthroplasty and total knee arthroplasty. The literature reports contradictory results regarding rates of physical activity after TJA as well as the relationship between physical activity and rates of revision surgery. The current trend in expert opinion shows more liberal recommendations for patients to engage in athletic activity after TJA. CONCLUSIONS: Individual characteristics, lifestyle, and patient preferences must be taken into account when one considers appropriate recommendations for athletic activity after TJA. Current trends in clinical opinion favor a higher level of athletic activity after TJA, but clinicians should caution patients not to participate in contact sports or sports that create high joint loads in the replaced joint. PMID- 23016042 TI - Lack of awareness of fluid needs among participants at a midwest marathon. AB - BACKGROUND: Marathon running has become popular, particularly among inexperienced runners. HYPOTHESIS: Many marathoners are inexperienced and lack concern for potential complications of marathon running. STUDY DESIGN: Cross-sectional survey. METHODS: In sum, 419 runners completed a survey on a variety of topics regarding training for a marathon and hydration strategies. RESULTS: Overall, 211 females (38.3 +/- 9.1 years old) and 208 males (41.6 +/- 11.0 years old) participated. They trained for 6.8 +/- 4.3 months and had run for 9.8 +/- 9.1 years; 33.5% had no marathon experience and 16.9% had run 1 marathon. Of the injuries reported, 77.6% and 72.9% were minor musculoskeletal injuries during the current and previous running seasons, respectively. Of the 278 runners who had run a marathon, 54 (19.0%) had been treated in the medical tent, 31.5% of whom for dehydration. Furthermore, 54.9% and 64.3% of the survey participants were "not at all" concerned with musculoskeletal injury and hyponatremia, respectively. Also, 88.7% did not know their sweat rate; 67.8% did not weigh themselves; and 81.3% had no other method of hydration assessment. No significant correlations were found between concern for hyponatremia and age, sex, or experience. CONCLUSIONS: Most participants were inexperienced, lacked concern for injury or hyponatremia, and were not using methods of hydration assessment. PMID- 23016043 TI - Influence of the hip on patients with patellofemoral pain syndrome: a systematic review. AB - CONTEXT: Patellofemoral pain syndrome (PFPS) is one of the most common conditions limiting athletes. There is a growing body of evidence suggesting that dysfunction at the hip may be a contributing factor in PFPS. DATA SOURCES: MEDLINE (1950-September 2010), CINAHL (1982-September 2010), and SPORTDiscus (1830-September 2010) were searched to identify relevant research to this report. STUDY SELECTION: Studies were included assessing hip strength, lower extremity kinematics, or both in relation to PFPS were included. DATA EXTRACTION: Studies included randomized controlled trials, quasi-experimental designs, prospective epidemiology, case-control epidemiology, and cross-sectional descriptive epidemiology in a scientific peer-reviewed journal. RESULTS: PFPS is associated with decreased hip strength, specifically at the abductors and external rotators. There is a correlation between PFPS and faulty hip mechanics (adduction and internal rotation). CONCLUSIONS: There is a link between the strength and position of the hip and PFPS. These patients have a common deficit once symptomatic. Hip strengthening and a coordination program may be useful in a conservative treatment plan for PFPS. PMID- 23016044 TI - Dynamic Balance Differences as Measured by the Star Excursion Balance Test Between Adult-aged and Middle-aged Women. AB - BACKGROUND: Middle-aged women have less postural control than younger women. The Star Excursion Balance Test is a functional and inexpensive postural control measurement tool that is sensitive to age-related changes in balance. HYPOTHESIS: The middle-aged females will experience lower excursion scores compared with the younger women. METHODOLOGY: Fifty-three healthy, recreationally active women were divided into 2 groups: adult-aged (n = 29; age range, 23-39 years) and middle aged (n = 24; age range, 40-54 years). Each participant performed 3 reaches for 3 trials (anteromedial, medial, posteromedial) in a randomized order. The 3 reach trials were converted to a normalized value (percentage of participant's height) and assessed as an overall mean for the 1-way analysis of variance. Intraclass correlation coefficients and 95% confidence intervals were calculated. RESULTS: No differences were found for body mass index and height; however, age was different between groups (P < 0.01). Intraclass correlation coefficient(2,3) values for the 3 directions ranged from 0.72 to 0.97. The adult-aged women were able to reach farther in all 3 directions when tested with the Star Excursion Balance Test (6.8-7.6 cm, P < 0.05). CONCLUSION: Lower postural control scores based on the Star Excursion Balance Test were found for the older women. The younger women were able to reach approximately 7 cm farther during the anterior, anteromedial, and posteromedial excursions. PMID- 23016046 TI - Sports Science vs "Boutique Medicine". PMID- 23016045 TI - Performance enhancement in the terminal phases of rehabilitation. AB - CONTEXT: There is a dearth of literature on the performance enhancement in the recovering athlete in the terminal phases of rehabilitation. There are established training methods that target strength, power, speed, endurance, and metabolic capacity that all lead to performance enhancement. EVIDENCE ACQUISITION: A PubMed search from 1980 to 2010 was undertaken for articles in English. Additional references were accrued from reference lists of research articles. RESULTS: Multiple options are available to improve strength, power, speed, endurance, and metabolic capacity during rehabilitation. CONCLUSION: Sports clinicians have several components to address in the rehabilitation of a recovering athlete in addition to performance enhancement. Sports clinicians should focus their efforts on increasing power, a product of maximum force and speed of performance. PMID- 23016047 TI - Letter to the editor response. PMID- 23016048 TI - Letter to the editor response. PMID- 23016049 TI - Eccentric strengthening for chronic lateral epicondylosis: a prospective randomized study. AB - BACKGROUND: Effective treatments for chronic lateral epicondylosis have not been studied adequately. Eccentric overload exercises have been used with success for other chronic tendinopathy, mainly Achilles and patellar. HYPOTHESIS/PURPOSE: To compare a wrist extensor eccentric strengthening exercise program with a wrist extensor stretching/modality program for the treatment of chronic lateral epicondylosis. The authors hypothesized that the eccentric strengthening program would produce more favorable results than a stretching/modality program. STUDY DESIGN: Prospective randomized controlled trial. METHODS: Twenty-eight adults with lateral epicondylosis of greater than 4 weeks' duration were randomized to an eccentric strengthening group or a stretching group. Exercises were taught by a physical therapist, and participants performed most of the exercises on their own at home. Pain scores with visual analog scale from 0 to 100 were obtained at baseline and then at 4, 8, 12, 16, and 20 weeks after the start of the exercise program. RESULTS: Both groups improved their pain scores from baseline to the 4 week time point, followed by nonsignificant further decreases in pain scores thereafter. No statistically significant differences were found between the eccentric strengthening group and stretching groups at any follow-up time point. CONCLUSIONS: Despite previous reports documenting favorable results with eccentric exercises for other tendinopathy, the authors were unable to show any statistical advantage to eccentric exercises for lateral epicondylosis during these periods compared with local modalities and stretching exercises. PMID- 23016050 TI - An 8-stage model for evaluating the tennis serve: implications for performance enhancement and injury prevention. AB - BACKGROUND: The tennis serve is a complex stroke characterized by a series of segmental rotations involving the entire kinetic chain. Many overhead athletes use a basic 6-stage throwing model; however, the tennis serve does provide some differences. EVIDENCE ACQUISITION: To support the present 8-stage descriptive model, data were gathered from PubMed and SPORTDiscus databases using keywords tennis and serve for publications between 1980 and 2010. RESULTS: An 8-stage model of analysis for the tennis serve that includes 3 distinct phases preparation, acceleration, and follow-through-provides a more tennis-specific analysis than that previously presented in the clinical tennis literature. When a serve is evaluated, the total body perspective is just as important as the individual segments alone. CONCLUSION: The 8-stage model provides a more in-depth analysis that should be utilized in all tennis players to help better understand areas of weakness, potential areas of injury, as well as components that can be improved for greater performance. PMID- 23016051 TI - Examination and treatment of cuboid syndrome: a literature review. AB - CONTEXT: Cuboid syndrome is thought to be a common source of lateral midfoot pain in athletes. EVIDENCE ACQUISITION: A Medline search was performed via PubMed (through June 2010) using the search terms cuboid, syndrome, subluxed, locked, fault, dropped, peroneal, lateral, plantar, and neuritis with the Boolean term AND in all possible combinations. Retrieved articles were hand searched for additional relevant references. RESULTS: Cuboid syndrome is thought to arise from subtle disruption of the arthrokinematics or structural congruity of the calcaneocuboid joint, although the precise pathomechanic mechanism has not been elucidated. Fibroadipose synovial folds (or labra) within the calcaneocuboid joint may play a role in the cause of cuboid syndrome, but this is highly speculative. The symptoms of cuboid syndrome resemble those of a ligament sprain. Currently, there are no definitive diagnostic tests for this condition. Case reports suggest that cuboid syndrome often responds favorably to manipulation and/or external support. CONCLUSIONS: Evidence-based guidelines regarding cuboid syndrome are lacking. Consequently, the diagnosis of cuboid syndrome is often based on a constellation of signs and symptoms and a high index of suspicion. Unless contraindicated, manipulation of the cuboid should be considered as an initial treatment. PMID- 23016052 TI - Factors that influence the efficacy of stretching programs for patients with hypomobility. AB - CONTEXT: Passive stretching exercise protocols, as part of outpatient treatment or home exercise programs, are used to improve hypomobility. Despite the cosmopolitan use of stretching exercises, little is known about the forces being applied to the joint during these routine treatments. TYPE OF STUDY: Clinical review. EVIDENCE ACQUISITION: Articles were identified using MEDLINE and Google Scholar databases, with searches initially limited to those articles published after 1995. Seminal articles that were referenced were also included. RESULTS: Many factors contribute to the clinical success of a stretching program, including the frequency, intensity, and duration of the stretching exercises, as well as patient- and joint-specific factors. CONCLUSIONS: The goal of a stretching protocol is to maximize total end-range time both in the clinic and at home. Higher intensity, prolonged, and frequent stretching (10- to 15-minute bouts, 3 to 6 times per day) used as an adjunct to high-grade mobilizations may be beneficial for certain hypomobility conditions. PMID- 23016053 TI - Static balance in patients with patellofemoral pain syndrome. AB - BACKGROUND: The relationship between one-leg static standing balance (OLSSB) and patellofemoral pain syndrome (PFPS) is unknown. HYPOTHESIS: OLSSB decreases in patients with PFPS. DESIGN: Prospective case series. METHODS: Fifty-two women with unilateral PFPS were enrolled in this study. OLSSB was evaluated with a stabilometer. Q angle was measured with a lengthened-arm universal goniometer. Lower extremity alignment was analyzed with full-length standing anteroposterior teleroentgenograms. Quadriceps and hamstring strength was measured on an isokinetic dynamometer. RESULTS: There were significant differences in OLSSB, Q angle, and strength of quadriceps and hamstring between the symptomatic and asymptomatic sides. There was a correlation between the strength of the quadriceps and hamstring and OLSSB, while there was no correlation between OLSSB and the severity of pain, lower extremity alignment, and Q angle on the symptomatic side. CONCLUSIONS: OLSSB and quadriceps and hamstring strength decreased and Q angle increased on the symptomatic side in PFPS patients. A relationship between OLSSB and pain, Q angle, and lower extremity alignment was not detected, while there was a correlation between the strength of the quadriceps and hamstring and OLSSB. CLINICAL RELEVANCE: A quadriceps and hamstring strengthening may be beneficial to improve OLSSB in patients with PFPS. PMID- 23016054 TI - Outcome of Grade I and II Hamstring Injuries in Intercollegiate Athletes: A Novel Rehabilitation Protocol. AB - BACKGROUND: Hamstring muscle strains represent a common and disabling athletic injury with variable recurrence rates and prolonged recovery times. OBJECTIVES: To present the outcomes of a novel rehabilitation protocol for the treatment of proximal hamstring strains in an intercollegiate sporting population and to determine any significant differences in the rate of reinjury and time to return to sport based on patient and injury characteristics. STUDY DESIGN: Retrospective case series. METHODS: A retrospective review was performed of 48 consecutive hamstring strains in intercollegiate athletes. The rehabilitation protocol consisted of early mobilization, with flexible progression through supervised drills. Athletes were allowed to return to sport after return of symmetrical strength and range of motion with no pain during sprinting. Primary outcomes included time to return to sport and reinjury rates. RESULTS: All patients returned to their sports, and 3 sustained repeat hamstring strains (6.2% reinjury rate) after a minimum follow-up of 6 months. The average number of days missed from sport was 11.9 (range, 5-23 days). There was no statistically significant difference for time to return to sport between first-time and recurrent injuries and between first- and second-degree injuries (P > 0.05). CONCLUSIONS: Grade I and II hamstring strains may be aggressively treated with a protocol of brief immobilization followed by early initiation of running and isokinetic exercises with an average expected return to sport of approximately 2 weeks and with a relatively low reinjury rate regardless of injury grade (I or II), injury characteristics (including first-time and recurrent injuries), or athlete characteristics. PMID- 23016056 TI - Electromyographic analysis of the triceps surae muscle complex during achilles tendon rehabilitation program exercises. AB - BACKGROUND: Specific guidelines for therapeutic exercises following an Achilles tendon repair are lacking. HYPOTHESIS: A hierarchical progression of triceps surae exercises can be determined on the basis of electromyographic (EMG) activity. STUDY DESIGN: Randomized laboratory trial. METHODS: Bipolar surface electrodes were applied over the medial and lateral heads of the gastrocnemius as well as the soleus on 20 healthy lower extremities (10 participants, 27 +/- 5 years old). Muscle activity was recorded during 8 therapeutic exercises commonly used following an Achilles repair. Maximal voluntary isometric contractions (MVICs) were also performed on an isokinetic device. The effect of exercise on EMG activity (% MVIC) was assessed using repeated measures analysis of variance with Bonferroni corrections for planned pairwise comparisons. RESULTS: Seated toe raises (11% MVIC) had the least amount of activity compared with all other exercises (P < 0.01), followed by single-leg balance on wobble board (25% MVIC), prone ankle pumps (38% MVIC), supine plantarflexion with red elastic resistance (45% MVIC), normal gait (47% MVIC), lateral step-ups (60% MVIC), single-leg heel raises (112% MVIC), and single-leg jumping (129% MVIC). CONCLUSION: There is an increasing progression of EMG activity for exercises that target the triceps surae muscle complex during common exercises prescribed in an Achilles tendon rehabilitation program. Seated toe raises offer relatively low EMG activity and can be utilized as an early rehabilitative exercise. In contrast, the single-leg heel raise and single-leg jumping should be utilized only during later-stage rehabilitation. CLINICAL RELEVANCE: EMG activity in the triceps surae is variable with common rehab exercises. PMID- 23016055 TI - Subgrouping patients with low back pain: a treatment-based approach to classification. AB - CONTEXT: Low back pain (LBP) is a prevalent condition imposing a large socioeconomic burden. Despite intensive research aimed at the efficacy of various therapies for patients with LBP, most evidence has failed to identify a superior treatment approach. One proposed solution to this dilemma is to identify subgroups of patients with LBP and match them with targeted therapies. Among the subgrouping approaches, the system of treatment-based classification (TBC) is promoted as a means of increasing the effectiveness of conservative interventions for patients with LBP. EVIDENCE ACQUISITION: MEDLINE and PubMed databases were searched from 1985 through 2010, along with the references of selected articles. RESULTS: TBC uses a standardized approach to categorize patients into 1 of 4 subgroups: spinal manipulation, stabilization exercise, end-range loading exercise, and traction. Although the TBC subgroups are in various stages of development, recent research lends support to the effectiveness of this approach. CONCLUSIONS: While additional research is required to better elucidate this method, the TBC approach enhances clinical decision making, as evidenced by the improved clinical outcomes experienced by patients with LBP. PMID- 23016057 TI - First-rib stress fracture in a high-school lacrosse player: a case report and short clinical review. AB - A 14-year-old right-hand dominant female lacrosse player presented with a complaint of right shoulder and upper posterior thorax pain of 8 days' duration. She had been playing lacrosse at the attack wing and midfielder positions and experienced insidious pain after a game. She had no history of trauma to that shoulder during that game and had not experienced an injury in the past. Six days after the pain developed, she woke up one night with a sudden increase in the pain, which brought her to tears and caused slight difficulty with breathing. The pain was located anteriorly just lateral to the right sternoclavicular joint and posteriorly in the paraspinal muscles in the upper thoracic region. Physical examination suggested a first-rib stress fracture, which was subsequently confirmed by chest and shoulder radiographs. PMID- 23016059 TI - Intra-articular Lidocaine Injection for Shoulder Reductions: A Clinical Review. AB - CONTEXT: The shoulder is the most commonly dislocated joint, and shoulder dislocations are very common in sports. Many of these dislocations present to the office or training room for evaluation. Usual practice is an attempt at manual reduction without analgesia and then transfer to the emergency department if unsuccessful. The clinical efficacy of intra-articular lidocaine for reduction of anterior shoulder dislocations in the outpatient setting was examined. EVIDENCE ACQUISITION: An OVID MEDLINE search (1966-present) was performed using the keywords shoulder, reduction, and analgesia as well as shoulder, intra-articular, and lidocaine. Search limits included articles in the English language. Bibliographic references from these articles were also examined to identify pertinent literature. RESULTS: Six randomized controlled clinical trials were identified that directly addressed this clinical technique. Although the reduction techniques used in these studies were not controlled, there was no statistically significant difference in success rates between groups. The complication rate, length of stay, and costs were significantly less in the intra articular lidocaine group when compared with the intravenous sedation group. CONCLUSIONS: According to current evidence, the use of intra-articular lidocaine injection for reduction of anterior shoulder dislocations is not harmful and is likely advantageous in the outpatient clinical setting. PMID- 23016058 TI - Treatment options for low back pain in athletes. AB - CONTEXT: Low back pain is one of the most common medical presentations in the general population. It is a common source of pain in athletes, leading to significant time missed and disability. The general categories of treatment for low back pain are medications and therapies. EVIDENCE ACQUISITION: Relevant studies were identified through a literature search of MEDLINE and the Cochrane Database from 1990 to 2010. A manual review of reference lists of identified sources was also performed. RESULTS: It is not clear whether athletes experience low back pain more often than the general public. Because of a aucity of trials with athlete-specific populations, recommendations on treatments must be made from reviews of treatments for the general population. Several large systemic reviews and Cochrane reviews have compiled evidence on different modalities for low back pain. Superficial heat, spinal manipulation, nonsteroidal anti inflammatory medications, and skeletal muscle relaxants have the strongest evidence of benefit. CONCLUSIONS: Despite the high prevalence of low back pain and the significant burden to the athletes, there are few clearly superior treatment modalities. Superficial heat and spinal manipulation therapy are the most strongly supported evidence-based therapies. Nonsteroidal anti-inflammatory medications and skeletal muscle relaxants have benefit in the initial management of low back pain; however, both have considerable side effects that must be considered. Athletes can return to play once they have recovered full range of motion and have the strength to prevent further injury. PMID- 23016060 TI - Isolated anterior compartment syndrome after a bimalleolar-equivalent ankle fracture in a collegiate football player. AB - Compartment syndrome after an ankle fracture is an extremely rare and potentially devastating event. The authors report a case of an isolated anterior compartment syndrome in a college student athlete who suffered a bimalle olar ankle fracture dislocation. A review of the literature highlights the importance of vigilance when the sports medicine physician and the community orthopaedist are treating these seemingly basic orthopaedic injuries. PMID- 23016061 TI - The ACL Dilemma. PMID- 23016062 TI - Letter to the editor: other interventions in approach to lumbar disorders. PMID- 23016063 TI - Letter to the editor: response. PMID- 23016064 TI - Clinical Outcomes and Return-to-Sports Participation of 50 Soccer Players After Anterior Cruciate Ligament Reconstruction Through a Sport-Specific Rehabilitation Protocol. AB - BACKGROUND: Rehabilitation of soccer players after anterior cruciate ligament reconstruction is usually performed without sport-specific guidelines, and the final phases are often left to the team coaches. The possibility of changing this approach has not yet been investigated. STUDY DESIGN: Case series. HYPOTHESIS: A specific rehabilitation protocol for soccer players, with direct control of the last on-field rehabilitation phases, may lead to complete functional recovery. METHODS: Fifty competitive soccer players who followed a sport-specific rehabilitation protocol for soccer were evaluated during the recovery period until their return to competition. The assessment of the functional outcomes was performed using the Knee Outcome Survey-Sports Activity Scale and isokinetic and aerobic fitness tests. RESULTS: The average start of on-field rehabilitation was 90 +/- 26 days after surgery; the average time to return to the competitions was 185 +/- 52 days. The improvement in the Knee Outcome Survey-Sports Activity Scale during on-field rehabilitation was significant (P < 0.01; from 79 +/- 15% to 96 +/- 7%). The isokinetic and aerobic fitness tests showed a significant improvement of muscle strength (knee extensors, +55%, P < 0.01; knee flexors, +86%, P < 0.01) and aerobic threshold (+23%, P < 0.01) from the beginning to the end of on-field rehabilitation. CONCLUSIONS: Adding on-field rehabilitation to the traditional protocols after anterior cruciate ligament reconstruction may safely lead to complete functional recovery in soccer players. PMID- 23016065 TI - Glenohumeral range of motion and lower extremity flexibility in collegiate-level baseball players. AB - BACKGROUND: The throwing motion results in unilateral increases in dominant arm external rotation (ER) range of motion (ROM). Trunk forward tilt at ball release is related to ball velocity. The relationship between lower quarter flexibility and dominant arm ROM is not known. HYPOTHESIS: There is a relationship between lower extremity flexibility and dominant arm ER ROM and total rotation ROM. STUDY DESIGN: Prospective cohort study. METHODS: Forty-two collegiate baseball pitchers were studied. Demographics, dominant arm, and bilateral glenohumeral ER and internal rotation (IR) ROM were measured. Lower quarter flexibility was assessed via sit-and-reach test. Total rotation motion (TRM) was calculated as ER + IR = TRM. Paired t tests examined differences between the dominant and nondominant arms for ER, IR, and TRM; Pearson product-moment correlation coefficients, shoulder ROM and lower extremity flexibility variables (alpha = 0.05). RESULTS: ER mean value was significantly greater, and IR mean value significantly less, in the dominant arm. TRM mean values were not significantly different bilaterally. Sit-and-reach results were strongly correlated with TRM and ER of the dominant arm. CONCLUSIONS: There was a significant shift in TRM toward ER in collegiate baseball players. Lower quarter flexibility was strongly correlated with dominant arm ER and total rotation ROM but not in the nondominant arm. CLINICAL RELEVANCE: The sit-and-reach test may be useful to identify a pitcher's potential to achieve an appropriate amount of trunk forward tilt. This may maximize the lag effect necessary to achieve maximum ER of the dominant arm and increased ball velocity. PMID- 23016066 TI - A theoretical framework for understanding neuromuscular response to lower extremity joint injury. AB - BACKGROUND: Neuromuscular alterations are common following lower extremity joint injury and often lead to decreased function and disability. These neuromuscular alterations manifest in inhibition or abnormal facilitation of the uninjured musculature surrounding an injured joint. Unfortunately, these neural alterations are poorly understood, which may affect clinical recognition and treatment of these injuries. Understanding how these neural alterations affect physical function may be important for proper clinical management of lower extremity joint injuries. METHODS: Pertinent articles focusing on neuromuscular consequences and treatment of knee and ankle injuries were collected from peer-reviewed sources available on the Web of Science and Medline databases from 1975 through 2010. A theoretical model to illustrate potential relationships between neural alterations and clinical impairments was constructed from the current literature. RESULTS: Lower extremity joint injury affects upstream cortical and spinal reflexive excitability pathways as well as downstream muscle function and overall physical performance. Treatment targeting the central nervous system provides an alternate means of treating joint injury that may be effective for patients with neuromuscular alterations. CONCLUSIONS: Disability is common following joint injury. There is mounting evidence that alterations in the central nervous system may relate to clinical changes in biomechanics that may predispose patients to further injury, and novel clinical interventions that target neural alterations may improve therapeutic outcomes. PMID- 23016067 TI - Anterior cruciate ligament injury prevention training in female athletes: a systematic review of injury reduction and results of athletic performance tests. AB - CONTEXT: Many anterior cruciate ligament (ACL) injury prevention training programs have been published, but few have assessed the effects of training on both ACL injury rates and athletic performance tests. OBJECTIVE: To determine if ACL injury prevention programs have a positive influence on both injury rates and athletic performance tests in female athletes. DATA SOURCES: In August 2011, a search was conducted (1995-August 2011) of the PubMed, Science Direct, and CINAHL databases. STUDY SELECTION: Selected studies determined the effect of ACL intervention training programs on ACL incidence rates (determined by athlete exposures) and athletic performance tests, such as isokinetic strength, vertical jump height, speed, agility, and dynamic balance. Because no single article contained both criteria, investigations were cross-referenced to obtain data on both factors from the same training programs. DATA EXTRACTION: The authors reviewed the selected studies for cohort population numbers, age, sports, duration of study, program components, duration of training, number of athlete exposures, ACL injury incidence rates, and results of athletic performance tests. RESULTS: Initially, 57 studies were identified that described 42 ACL injury prevention training programs. Of these, 17 studies that investigated 5 programs met the inclusion criteria. Two programs significantly reduced ACL injury rates and improved athletic performance tests: Sportsmetrics and the Prevent Injury and Enhance Performance program (PEP). Sportsmetrics produced significant increases in lower extremity and abdominal strength, vertical jump height, estimated maximal aerobic power, speed, and agility. Prevent Injury and Enhance Performance significantly improved isokinetic knee flexion strength but did not improve vertical jump height, speed, or agility. The other 3 programs (Myklebust, the "11," and Knee Ligament Injury Prevention) did not improve both ACL injury rates and athletic performance tests. CONCLUSIONS: Only the Sportsmetrics and PEP ACL intervention training programs had a positive influence on injury reduction and athletic performance tests. PMID- 23016068 TI - Joint line fullness and meniscal pathology. AB - BACKGROUND: Meniscal tears have been associated with meniscal cysts and fullness of the knee joint line on physical examination. HYPOTHESIS: Joint line fullness is an accurate, sensitive, and specific test to detect meniscal tears. STUDY DESIGN: Prospective cohort study. METHODS: One hundred consecutive patients undergoing knee arthroscopy were included. All had physical examinations documenting the presence of joint line fullness, joint line tenderness, and the McMurray sign. Arthroscopy was the gold standard for tears. Accuracy, sensitivity, and specificity were calculated and correlated with type of tear. Sixty-one patients had a magnetic resonance imaging preoperatively (the gold standard for determining the presence of a cyst). RESULTS: Meniscal tears were found in 67 patients at arthroscopy. The accuracy, sensitivity, and specificity of joint line fullness were, respectively, 73%, 70%, and 82% in detecting meniscal tears; 68%, 87%, and 30% for joint line tenderness; and 47%, 32%, and 78% for the McMurray sign. The highest positive predictive value for detecting a tear was 88% for joint line fullness, compared with 77% for joint line tenderness and 76% for the McMurray sign. However, joint line fullness did not correlate well with the presence of a cyst, with a low positive predictive value (29%). Of those patients with joint line fullness on physical examination, 89% had a horizontal cleavage component of their tear at arthroscopy. CONCLUSION: Joint line fullness is an accurate, sensitive, and specific test to detect meniscal tears. CLINICAL RELEVANCE: The findings support the routine use of joint line fullness during physical examination along with other common tests to improve the accuracy of clinically diagnosing meniscal tears. PMID- 23016069 TI - Isolated hyoid bone fractures in collegiate football players: a case series and review of the literature. AB - Hyoid fractures in athletes are rare injuries that can be difficult to diagnose. Typically resulting from a direct blow to the anterior neck, hyoid fractures can lead to subcutaneous edema and subsequent airway compromise. The treatment of this fracture depends largely on the severity of the presenting symptoms. Generally, these fractures do not require surgical intervention but warrant close observation for delayed onset of airway obstruction. To raise awareness of this potentially dangerous fracture, the authors present 2 cases of isolated hyoid fractures in collegiate football players at our institution. PMID- 23016070 TI - Acute exertional rhabdomyolysis and triceps compartment syndrome during a high school football cAMP. AB - BACKGROUND: Acute exertional rhabdomyolysis has been infrequently reported among adolescents. In August 2010, several high school football players from one team developed rhabdomyolysis and triceps compartment syndrome following an upper arm exercise held in a non-air-conditioned wrestling room. PURPOSE: To confirm the diagnoses, characterize the spectrum of illnesses, and determine the factors contributing to rhabdomyolysis and triceps compartment syndromes. STUDY DESIGN: Descriptive epidemiology study. METHODS: The authors reviewed hospital medical records and interviewed players, coaches, school administrators, and hospital staff, using a standardized questionnaire that assessed symptoms, exposures, and activities. RESULTS: Among 43 players, 22 (51%) experienced rhabdomyolysis (peak creatine kinase range, 2434-42 000 U/L): 22 patients had upper arm myalgia; 12 were hospitalized; 3 experienced triceps compartment syndrome; none experienced renal failure. Illnesses started 1 to 3 days after the triceps exercise. Forty players (93%) completed questionnaires. Among 19 players receiving at least 1 vote from a teammate as 1 of the 3 hardest working players, 13 (68%) experienced rhabdomyolysis versus 7 (33%) of 21 not considered hardest working (relative risk, 2.1; 95% confidence interval, 1.04-4.0). Of 40 players, 10 (25%) reported creatine supplement use, which was not associated with rhabdomyolysis. No player acknowledged use of alcohol, illicit drugs, or performance-enhancing drugs; results of performance-enhancing drug tests on the 4 players tested were negative. Environmental investigation did not identify additional factors contributing to illness. CONCLUSIONS: The upper arm exercise, possibly exacerbated by heat, led to rhabdomyolysis and compartment syndrome. Greater awareness of specific exercise hazards and prevention strategies can minimize risk for clinically significant muscle injury. PMID- 23016071 TI - Anterior cruciate ligament graft choices. AB - CONTEXT: Reconstruction of the anterior cruciate ligament (ACL) is a common surgical procedure; however, there is no consensus to what the best graft option is to replace the injured ACL. The main options available consist of allografts and autografts, which include patellar tendon, hamstring tendon, and quadriceps tendon autografts. EVIDENCE ACQUISITION: The PubMed database was searched in August 2010 for English-language articles pertaining to ACL grafts. RESULTS: Postoperative outcome variables were analyzed to determine similarities and differences among the different graft options. These variables include stability, strength, function, return to sports, patient satisfaction, complications, and cost. CONCLUSIONS: Both allografts and the 3 main options for autografts can provide excellent results in ACL reconstruction and lead to a high percentage of satisfied patients. However, differences exist among the graft choices. Both the similarities and the differences are important to discuss with a patient who will be undergoing ACL reconstruction so that he or she has the best information available when making a choice of graft. PMID- 23016072 TI - Risk factors for anterior cruciate ligament injury: a review of the literature - part 1: neuromuscular and anatomic risk. AB - CONTEXT: Injuries to the anterior cruciate ligament (ACL) of the knee are immediately debilitating and can cause long-term consequences, including the early onset of osteoarthritis. It is important to have a comprehensive understanding of all possible risk factors for ACL injury to identify individuals who are at risk for future injuries and to provide an appropriate level of counseling and programs for prevention. OBJECTIVE: This review, part 1 of a 2 part series, highlights what is known and still unknown regarding anatomic and neuromuscular risk factors for injury to the ACL from the current peer-reviewed literature. DATA SOURCES: Studies were identified from MEDLINE (1951-March 2011) using the MeSH terms anterior cruciate ligament, knee injury, and risk factors. The bibliographies of relevant articles and reviews were cross-referenced to complete the search. STUDY SELECTION: Prognostic studies that utilized the case control and prospective cohort study designs to evaluate risk factors for ACL injury were included in this review. RESULTS: A total of 50 case-control and prospective cohort articles were included in the review, and 30 of these studies focused on neuromuscular and anatomic risk factors. CONCLUSIONS: Several anatomic and neuromuscular risk factors are associated with increased risk of suffering ACL injury-such as female sex and specific measures of bony geometry of the knee joint, including decreased intercondylar femoral notch size, decreased depth of concavity of the medial tibial plateau, increased slope of the tibial plateaus, and increased anterior-posterior knee laxity. These risk factors most likely act in combination to influence the risk of ACL injury; however, multivariate risk models that consider all the aforementioned risk factors in combination have not been established to explore this interaction. PMID- 23016073 TI - Osteoarthritis after anterior cruciate ligament reconstruction: the importance of regaining and maintaining full range of motion. AB - CONTEXT: Several factors have been associated with the development of osteoarthritis after anterior cruciate ligament (ACL) reconstruction, yet little attention has been given to the association between range of motion (ROM) and osteoarthritis after ACL reconstruction. Several studies have shown a link between ROM loss and a higher incidence of osteoarthritis. EVIDENCE ACQUISITION: A search was performed with PubMed (MEDLINE) for English-language level I-IV studies involving the long-term evaluation of ROM and osteoarthritis after ACL reconstruction. Keywords were osteoarthritis, anterior cruciate ligament, and range of motion. RESULTS: SIX STUDIES CONSIDERED WHETHER ROM WAS A FACTOR IN ASSOCIATION WITH OSTEOARTHRITIS AFTER ACL RECONSTRUCTION: In 3 of these studies, an association was found between loss of knee motion and the development of osteoarthritis, while the other 3 studies failed to identify a significant association. Two studies identified an association between ROM loss and decreased subjective outcomes after ACL reconstruction. CONCLUSIONS: Previous studies have shown an association between loss of knee ROM and osteoarthritic changes on radiographs in the long term after ACL reconstruction. Loss of ROM and osteoarthritis are also associated with lower subjective scores. Other factors related to osteoarthritis, such as meniscal and articular cartilage status, cannot be modified, but through implementation of a directed rehabilitation program before and after ACL surgery, the achievement of full symmetric ROM can be promoted. More emphasis needs to be placed on careful and precise examination of knee ROM, as well as rehabilitation to achieve and maintain full symmetric ROM in the long term after ACL reconstruction. PMID- 23016074 TI - The PRP Question. PMID- 23016075 TI - Torque measures of common therapies for the treatment of loss of knee flexion. AB - BACKGROUND: Conservative treatment protocols to effectively treat knee flexion motion restrictions are dependent in part on the torque applied to the joint. HYPOTHESES: Clinicians apply greater torque with the test leg in a simulated prone position than in a seated position. Clinicians also apply greater torque than a dynamic splint or a static progressive stretch brace. Finally, clinicians apply a torque equal to the high-intensity stretch device. STUDY DESIGN: bservational study. METHODS: An instrumented test leg was used to record peak torque applied by 14 licensed clinicians (7 women, 7 men; age, 44.3 +/- 10.2 years; height, 172.9 +/- 13.2 cm; weight, 72.6 +/- 13.0 kg) during knee flexion mobilizations and 3 types of mechanical therapy (dynamic splint, static progressive stretch, and high-intensity stretch). RESULTS: The dynamic splint applied 5.1 +/- 0.1 N.m, while the static progressive stretch brace applied 20.8 +/- 2.2 N.m. Clinicians applied 49.5 +/- 22.4 N.m with the test leg in a seated position and 55.8 +/- 22.0 N.m with the leg in a prone position. The high intensity stretch device applied up to 214.7 +/- 29.2 N.m. All comparisons were statistically significant (P <= 0.02) with the exception of the 2 testing positions (P = 0.94). CONCLUSIONS: The results demonstrate that the torques applied to the knee differ between passive stretching therapies. Clinicians should be cognizant of these torque differences when constructing treatment protocols for patients with limited knee flexion range of motion. PMID- 23016076 TI - Examination and treatment of hamstring related injuries. AB - CONTEXT: There is a wide spectrum of hamstring-related injuries that can occur in the athlete. Accurate diagnosis is imperative to prevent delayed return to sport, injury recurrence, and accurate clinical decision making regarding the most efficacious treatment. EVIDENCE ACQUISITION: This review highlights current evidence related to the diagnosis and treatment of hamstring-related injuries in athletes. Data sources were limited to peer-reviewed publications indexed in MEDLINE from 1988 through May 2011. RESULTS: An accurate diagnostic process for athletes with posterior thigh-related complaints should include a detailed and discriminative history, followed by a thorough clinical examination. Diagnostic imaging should be utilized when considering hamstring avulsion or ischial apophyseal avulsion. Diagnostic imaging may also be needed to further define the cause of referred posterior thigh pain. CONCLUSIONS: Differentiating acute hamstring strains, hamstring tendon avulsions, ischial apophyseal avulsions, proximal hamstring tendinopathies, and referred posterior thigh pain is critical in determining the most appropriate treatment and expediting safe return to play. PMID- 23016077 TI - Prospective Predictors of Patellofemoral Pain Syndrome: A Systematic Review With Meta-analysis. AB - CONTEXT: Patellofemoral pain syndrome (PFPS) is one of the most common overuse injuries. OBJECTIVE: To assess the collective evidence of predisposing factors to PFPS. DATA SOURCES: MEDLINE (1960-June 2010), EMBASE (1980-June 2010), and CINAHL (1982-June 2010). STUDY SELECTION: Studies were included if patients were asymptomatic at baseline testing (free of PFPS) and were prospectively followed for the development of the disorder. Only studies that assessed at least 1 variable that can be measured at a typical clinic were included. After duplicates were removed, 973 studies were assessed from their titles or abstracts, 20 from the full text, and from these, 7 met the inclusion criteria. DATA EXTRACTION: Data were extracted for age, weight, height, sample size, patient type (military vs civilian), follow-up periods, diagnostic methods, and diagnostic criteria. Means and standard deviations were extracted for all outcome variables. RESULTS: Meta-analyses were performed for height, weight, leanness, Q angle, number of sit ups, knee extension strength, and peak knee valgus angle during landing. Lower knee extension strength was the only variable that was predictive of PFPS (P < 0.01). Other variables that were identified as predictive of PFPS by single studies were vertical jump, push-ups, knee flexion and hip abduction strength, thumb-to-forearm flexibility, quadriceps and gastrocnemius flexibility, genu varum, navicular drop, knee valgus moment at initial contact during landing, social support, and palliative reaction. CONCLUSIONS: It appears that anthropometric variables are not associated with PFPS, while knee extension strength deficits appear to be predictors of PFPS. PMID- 23016078 TI - Chronic lower leg pain in athletes: a guide for the differential diagnosis, evaluation, and treatment. AB - CONTEXT: Chronic lower leg pain in athletes can be a frustrating problem for patients and a difficult diagnosis for clinicians. Myriad approaches have been suggested to evaluate these conditions. With the continued evolution of diagnostic studies, evidence-based guidance for a standard approach is unfortunately sparse. EVIDENCE ACQUISITION: PubMed was searched from January 1980 to May 2011 to identify publications regarding chronic lower leg pain in athletes (excluding conditions related to the foot), including differential diagnosis, clinical presentation, physical examination, history, diagnostic workup, and treatment. RESULTS: Leg pain in athletes can be caused by many conditions, with the most frequent being medial tibial stress syndrome; chronic exertional compartment syndrome, stress fracture, nerve entrapment, and popliteal artery entrapment syndrome are also considerations. Conservative management is the mainstay of care for the majority of causes of chronic lower leg pain; however, surgical intervention may be necessary. CONCLUSION: Chronic lower extremity pain in athletes includes a wide differential and can pose diagnostic dilemmas for clinicians. PMID- 23016079 TI - Overtraining syndrome: a practical guide. AB - CONTEXT: Fatigue and underperformance are common in athletes. Understanding overtraining syndrome (OTS) is helpful in the evaluation, management, and education of athletes. EVIDENCE ACQUISITION: Relevant articles in English were searched with OVID (1948-2011) and PubMed using the following keywords: overtraining syndrome, overtraining, overreaching, unexplained underperformance, staleness, pathophysiology, management, treatment, evaluation. Bibliographies were reviewed for additional resources. RESULTS: OTS appears to be a maladapted response to excessive exercise without adequate rest, resulting in perturbations of multiple body systems (neurologic, endocrinologic, immunologic) coupled with mood changes. Many hypotheses of OTS pathogenesis are reviewed, and a clinical approach to athletes with possible OTS (including history, testing, and prevention) is presented. CONCLUSIONS: OTS remains a clinical diagnosis with arbitrary definitions per the European College of Sports Science's position statement. History and, in most situations, limited serologies are helpful. However, much remains to be learned given that most past research has been on athletes with overreaching rather than OTS. PMID- 23016080 TI - Central diabetes insipidus following a sports-related concussion: a case report. AB - A 24-year-old female swimmer presented to a sports medicine clinic with complaints of frequent urination and increased thirst. The patient admitted to progressive worsening of her symptoms over a 4-year period since suffering a concussion. A water deprivation test, antidiuretic hormone level, and diamino-8-D arginine vasopressin challenge were completed, and the patient was diagnosed with persistent central diabetes insipidus. As concussion awareness increases, health care professionals will be faced with treatment of post-concussive patients more often. The aim of this case report is to increase awareness of possible pituitary dysfunction-specifically, central diabetes insipidus-following a concussion. PMID- 23016081 TI - Emerging supplements in sports. AB - CONTEXT: Nutritional supplements advertised as ergogenic are commonly used by athletes at all levels. Health care professionals have an opportunity and responsibility to counsel athletes concerning the safety and efficacy of supplements on the market. EVIDENCE ACQUISITION: An Internet search of common fitness and bodybuilding sites was performed to identify supplement promotions. A search of MEDLINE (2000-August, 2011) was performed using the most commonly identified supplements, including glutamine, choline, methoxyisoflavone, quercetin, zinc/magnesium aspartate, and nitric oxide. The search terms supplement, ergogenic aid, and performance were also used. RESULTS: Six common and newer supplements were identified, including glutamine, choline, methoxyisoflavone, quercetin, zinc/magnesium aspartate, and nitric oxide. CONCLUSIONS: Controlled studies have not determined the effects of these supplements on performance in athletes. Scientific evidence is not available to support the use of these supplements for performance enhancement. PMID- 23016083 TI - Risk factors for anterior cruciate ligament injury: a review of the literature part 2: hormonal, genetic, cognitive function, previous injury, and extrinsic risk factors. AB - CONTEXT: Injuries to the anterior cruciate ligament (ACL) are immediately disabling and are associated with long-term consequences, such as posttraumatic osteoarthritis. It is important to have a comprehensive understanding of all possible risk factors for ACL injury to identify individuals who are at risk for future injuries and to provide an appropriate level of counseling and programs for prevention. OBJECTIVE: This review, part 2 of a 2-part series, highlights what is known and still unknown regarding hormonal, genetic, cognitive function, previous injury, and extrinsic risk factors for ACL injury. DATA SOURCES: Studies were identified from MEDLINE (1951-March 2011) using the MeSH terms anterior cruciate ligament, knee injury, and risk factors. The bibliographies of relevant articles and reviews were cross-referenced to complete the search. STUDY SELECTION: Prognostic case-control and prospective cohort study designs to evaluate risk factors for ACL injury were included in this review. RESULTS: A total of 50 case-control and prospective cohort articles were included in parts 1 and 2. Twenty-one focused on hormonal, genetic, cognitive function, previous injury, and extrinsic risk factors. CONCLUSIONS: Several risk factors are associated with increased risk of suffering ACL injury-such as female sex, prior reconstruction of the ACL, and familial predisposition. These risk factors most likely act in combination with the anatomic factors reviewed in part 1 of this series to influence the risk of suffering ACL injury. PMID- 23016082 TI - Rehabilitation of Concussion and Post-concussion Syndrome. AB - CONTEXT: Prolonged symptoms after concussion are called post-concussion syndrome (PCS), which is a controversial disorder with a wide differential diagnosis. EVIDENCE ACQUISITION: MEDLINE and PubMed searches were conducted for the years 1966 to 2011 using the search terms brain concussion/complications OR brain concussion/diagnosis OR brain concussion/therapy AND sports OR athletic injuries. Secondary search terms included post-concussion syndrome, trauma, symptoms, metabolic, sports medicine, cognitive behavioral therapy, treatment and rehabilitation. Additional articles were identified from the bibliographies of recent reviews. RESULTS: Of 564 studies that fulfilled preliminary search criteria, 119 focused on the diagnosis, pathophysiology, and treatment/rehabilitation of concussion and PCS and formed the basis of this review. Rest is the primary treatment for the acute symptoms of concussion. Ongoing symptoms are either a prolonged version of the concussion pathophysiology or a manifestation of other processes, such as cervical injury, migraine headaches, depression, chronic pain, vestibular dysfunction, visual dysfunction, or some combination of conditions. The pathophysiology of ongoing symptoms from the original concussion injury may reflect multiple causes: anatomic, neurometabolic, and physiologic. CONCLUSIONS: Treatment approaches depend on the clinician's ability to differentiate among the various conditions associated with PCS. Early education, cognitive behavioral therapy, and aerobic exercise therapy have shown efficacy in certain patients but have limitations of study design. An algorithm is presented to aid clinicians in the evaluation and treatment of concussion and PCS and in the return-to-activity decision. PMID- 23016084 TI - Platelet-rich plasma treatment in symptomatic patients with knee osteoarthritis: preliminary results in a group of active patients. AB - BACKGROUND: With increasing frequency, platelet-rich plasma (PRP) preparations have been used to treat cartilage lesions to regenerate tissue homeostasis and retard the progression of knee osteoarthritis (OA). PURPOSE: To determine the effectiveness of intra-articular PRP injections in active patients with knee OA and to evaluate clinical outcomes in patients with and without previous surgical treatment for cartilage lesions. STUDY DESIGN: Case series. MATERIALS AND METHODS: Fifty patients with knee OA were followed for a minimum of 12 months. All were treated with 2 intra-articular injections of autologous PRP. Twenty-five patients had undergone a previous operative intervention for cartilage lesions, whereas 25 had not. Operated patients had undergone either cartilage shaving or microfracture. Multiple evaluative scores were collected at pretreatment and at 6 and 12 months posttreatment. The required sample of patients was determined beforehand by using statistical power analysis; International Knee Documentation Committee (subjective) score was defined as the primary parameter. A P value of less than 0.05 was considered statistically significant. General linear model repeated measure test evaluated within-time improvement for each variable for all patients. Post hoc test with Bonferroni adjustment for multiple comparisons was performed to investigate the significance in improvement within time evaluations for each variable for the total sample. The differences in improvement between operated and nonoperated patients were also investigated, as were those between sexes. RESULTS: All patients showed significant improvement in all scores at 6 and 12 months (P < 0.01) and returned to previous activities. No significant difference in improvement was found between the evaluated subgroups (P < 0.01). CONCLUSIONS: The PRP treatment showed positive effects in patients with knee OA. Operated and nonoperated patients showed significant improvement by means of diminishing pain and improved symptoms and quality of life. CLINICAL RELEVANCE: There are only a few studies of PRP treatment for cartilage on osteoarthritic knees. Different PRP products might be more or less appropriate to treat different types of tissues and pathologies. The clinical efficacy of PRP remains under debate, and a standardized protocol has not yet been established. PMID- 23016085 TI - Rising star. PMID- 23016087 TI - Knowledge of and compliance with pitch count recommendations: a survey of youth baseball coaches. AB - BACKGROUND: Pain and injuries suffered by youth pitchers are ongoing concerns that have been addressed through the institution of rules and recommendations regarding pitch counts and rest periods. The aim of our study was to see if coaches of youth baseball pitchers in our region were aware of the recommended guidelines and if they followed them. METHODS: An Internet-based survey consisting of 18 items including demographic information and questions concerning the USA Baseball Medical and Safety Advisory Committee pitching guidelines was sent to coaches affiliated with a local youth league to assess their knowledge of and reported compliance with these recommendations. RESULTS: Ninety-five of 228 coaches (41.4%) participated in the survey. On average, coaches answered 43% of questions regarding pitch count and rest periods correctly; 73% reported that they followed the recommendations, while only 53% felt that other coaches in the league abided by the recommendations. Thirty-five percent of coaches stated that their pitchers reported shoulder or elbow pain during the season, and 19% reported that one of their pitchers pitched a game with a sore or fatigued arm during the season. No coaches reported any pitching-related injuries among their players requiring surgery. Fewer than 10% of coaches reported that their players pitched in multiple leagues or participated in showcases, while 91% reported that pitchers attended camps or received specific instruction to improve their pitching form. CONCLUSIONS: This study shows that this subset of youth baseball coaches is deficient with regard to knowledge of the USA Baseball Medical and Safety Advisory Committee pitching guidelines. This situation may put youth pitchers at increased risk for upper extremity pain and injuries. PMID- 23016088 TI - The effects of exercise on decreasing pain and increasing function in patients with patellofemoral pain syndrome: a systematic review. AB - CONTEXT: Exercise or rest is commonly prescribed as treatment for patellofemoral pain syndrome. STUDY SELECTION: This study is based on Level I or II research studies examining the effects of exercise and rest on decreasing pain (visual analog scale) and increasing function (Kujala Scoring Questionnaire) using human participants. Articles were limited to those printed in English from PubMed (1966 September 2010), CINAHL (1982-September 2010), and SPORTDiscus (1972-September 2010). DATA EXTRACTION: Weighted aggregate effect sizes and 95% confidence intervals were calculated from means and standard deviations extracted from 10 studies, resulting in an analysis of 433 patients. RESULTS: A very large effect for exercise was found for patient-reported functional outcomes (d = 2.19) and perceived pain (d = -1.24) in treated patients, which were larger than functional outcomes (d = 0.77) and pain (d = -0.14) in controls. Short-term follow-up of 191 patients from 4 data sets in 2 studies revealed a large effect for functional outcomes (d = 1.04) and pain (d = -0.82) in patients who performed an exercise intervention. One study reported moderate effect sizes for functional outcomes (d = 0.59) and pain (d = -0.35) at 3 months postintervention. CONCLUSIONS: Exercise is the more effective treatment for immediate decrease in pain and increase in function although these differences appear to be less distinguishable over time. PMID- 23016086 TI - Tendinopathy in sport. AB - CONTEXT: Tendinopathy is increasing in prevalence and accounts for a substantial part of all sports injuries and occupational disorders. Despite the magnitude of the disorder, high-quality scientific data on etiology and available treatments have been limited. EVIDENCE ACQUISITION: The authors conducted a MEDLINE search on tendinopathy, or "tendonitis" or "tendinosis" or "epicondylitis" or "jumpers knee" from 1980 to 2011. The emphasis was placed on updates on epidemiology, etiology, and recent patient-oriented Level 1 literature. RESULTS: Repetitive exposure in combination with recently discovered intrinsic factors, such as genetic variants of matrix proteins, and metabolic disorders is a risk factor for the development of tendinopathy. Recent findings demonstrate that tendinosis is characterized by a fibrotic, failed healing response associated with pathological vessel and sensory nerve ingrowth. This aberrant sensory nerve sprouting may partly explain increased pain signaling and partly, by release of neuronal mediators, contribute to the fibrotic alterations observed in tendinopathy. The initial nonoperative treatment should involve eccentric exercise, which should be the cornerstone (basis) of treatment of tendinopathy. Eccentric training combined with extracorporeal shockwave treatment has in some reports shown higher success rates compared to any therapies alone. Injection therapies (cortisone, sclerosing agents, blood products including platelet-rich plasma) may have short-term effects but have no proven long-term treatment effects or meta-analyses to support them. For epicondylitis, cortisone injections have demonstrated poorer long-time results than conservative physiotherapy. Today surgery is less indicated because of successful conservative therapies. New minioperative procedures that, via the endoscope, remove pathologic tissue or abnormal neoinnervation demonstrate promising results but need confirmation by Level 1 studies. CONCLUSIONS: Novel targeted therapies are emerging, but multicenter trials are needed to confirm the results of exercise and mini-invasive treatments. PMID- 23016089 TI - Jet lag in athletes. AB - CONTEXT: Prolonged transmeridian air travel can impart a physical and emotional burden on athletes in jet lag and travel fatigue. Jet lag may negatively affect the performance of athletes. STUDY TYPE: Descriptive review. EVIDENCE ACQUISITION: A Medline search for articles relating to jet lag was performed (1990-present), as was a search relating to jet lag and athletes (1983-January, 2012). The results were reviewed for relevance. Eighty-nine sources were included in this descriptive review. RESULTS: Behavioral strategies are recommended over pharmacological strategies when traveling with athletes; pharmacological aides may be used on an individual basis. Strategic sleeping, timed exposure to bright light, and the use of melatonin are encouraged. CONCLUSIONS: There is strong evidence that mood and cognition are adversely affected by jet lag. Some measures of individual and team performance are adversely affected as well. PMID- 23016090 TI - Incidence, nature, and causes of fractures and dislocations in olympic styles of wrestling in iran: a 1-year prospective study. AB - BACKGROUND: Several studies have evaluated the incidence of and risk factors for injuries among wrestlers, but there are limited data in this population. Understanding the incidence and risk factors could provide important information for educational and preventive efforts at the national and international levels. PURPOSE: To assess the incidence of and risk factors for fractures and dislocations among Greco-Roman and freestyle wrestlers in Iran. STUDY DESIGN: Prospective cohort study. METHODS: Members of 8 randomly selected wrestling clubs in Kermanshah, Iran, were followed for 12 months. Details of their training and the occurrence of fractures and dislocations were recorded. Related data on fractures and dislocations include site of injury, previous history of injury, coach supervision, and wresting technique that led to the injury. RESULTS: A total of 495 male wrestlers were included in the study. Seven fractures and 8 dislocations were reported. The incidence of fractures and dislocations was 1.1 per 10 000 athlete exposures, with a fracture rate of 0.5 and a dislocation rate of 0.6. Of the 15 fractures and dislocations, 11 occurred among freestyle wrestlers (0.8 per 10 000 athlete exposures) and 4 occurred among Greco-Roman wrestlers (0.3 per 10 000 athlete exposures). There was a positive correlation between the incidence of wrestlers' fractures and dislocations and their age (P < 0.01), years of wrestling experience (P < 0.01), previous history of fracture or dislocation (P < 0.01), and age of starting to wrestle (P = 0.03). CONCLUSION: The incidence of fractures and dislocations in this study was lower than that seen in previous studies. The risk of fracture and dislocation was heightened by a wrestler's increased age and years of experience, history of previous fracture or dislocation, and younger age of starting to wrestle. PMID- 23016091 TI - Accuracy of magnetic resonance imaging of the knee in the community setting. AB - BACKGROUND: Magnetic resonance imaging (MRI) is routinely used in the diagnosis of sports-related knee injuries. PURPOSE: To determine the accuracy, sensitivity, and specificity of MRI compared with clinical evaluation in the diagnosis of meniscal pathology when the MRI facility and the radiologist are not preselected. METHODS: A total of 288 knee arthroscopies were retrospectively compared. Patients were divided into 3 groups: those who had MRI performed and interpreted at a single institution, MRI performed and interpreted at community facilities, or a clinical evaluation by a senior orthopaedic surgeon. RESULTS: The sensitivity, specificity, and accuracy of the diagnosis of medial meniscal pathology at a single institution were 90%, 59%, 76%; in community facilities, 73%, 68%, 70%; and by a clinical evaluation, 93%, 55%, 73%, respectively. For lateral meniscal pathology, the results were as follows: single institution, 75%, 76%, 81%; community facilities, 60%, 88%, 79%; and clinical evaluation, 45%, 90%, 79%, respectively. Sensitivity for medial meniscus was greater than for lateral meniscus, but specificity of diagnosis was better for lateral meniscus by MRI and clinical evaluation. While not statistically significant, there was increased sensitivity in the diagnosis of medial meniscus and lateral meniscus at SIs, but they have less specificity than at community facilities. The number of false positive diagnoses (ie, no intra-articular pathology) that resulted in surgery was 4 of 288 (1.39%). The overall accuracy for medial meniscus by MRI was 73% vs 73% for clinical evaluation. The overall accuracy for MRI for lateral meniscus was 78% vs 79% for clinical evaluation. CONCLUSION: Routine MRI may not be more beneficial than clinical evaluation when there is no preselection of MRI facility and interpreting radiologist. CLINICAL RELEVANCE: The use of MRI for diagnosing meniscal pathology should be reserved for those cases where the orthopaedic clinical examination is ambiguous. PMID- 23016092 TI - Splenic lacerations and return to play: case report of 2 professional hockey players. AB - BACKGROUND: Several sports medicine reviews have highlighted a 3- to 6-month time frame for return to play after splenic lacerations. These reviews are based on several well-defined grading scales for splenic injury based on computed tomography (CT). None of the articles suggest that serial CT scanning is necessary for follow-up; some even indicate that it has no role in the management of these injuries. HYPOTHESIS: With proper follow-up and possibly the use of serial CT scanning or other imaging modalities, it may be possible for athletes to safely return to play sooner than what current guidelines recommend. STUDY DESIGN: The authors present 2 cases of professional hockey players who both suffered grade III splenic lacerations while playing. METHODS: Both players were treated conservatively and monitored with serial CT scanning until radiographic and clinical findings suggested complete healing. RESULTS: Both players were able to return to full-contact professional hockey within 2 months after suffering grade III splenic lacerations. Neither athlete suffered any complications after his return. CONCLUSIONS: With CT scanning, 2 athletes were able to return to play earlier (2 months) than previously recommended (3-6 months) without compromising their safety. CLINICAL RELEVANCE: Additional cases must be examined before outlining more definitive recommendations regarding splenic lacerations in sports, but it is possible that elite athletes may return to play sooner than what the current literature recommends. PMID- 23016093 TI - Rowing injuries. AB - CONTEXT: Rowing is one of the original modern Olympic sports and was one of the most popular spectator sports in the United States. Its popularity has been increasing since the enactment of Title IX. The injury patterns in this sport are unique because of the stress applied during the rowing stroke. EVIDENCE ACQUISITION: This review summarizes the existing literature describing the biomechanics of the rowing stroke and rowing-related injury patterns. Data were obtained from previously published peer-reviewed literature through a search of the entire PubMed database (up to December, 2011) as well as from textbook chapters and rowing coaching manuals. RESULTS: Rowing injuries are primarily overuse related. The knee, lumbar spine, and ribs are most commonly affected. The injury incidence is directly related to the volume of training and technique. CONCLUSION: Familiarity of the injury patterns and the biomechanical forces affecting the rowing athlete will aid in prompt diagnosis and appropriate management. PMID- 23016094 TI - Epidemiology of injuries and prevention strategies in competitive swimmers. AB - CONTEXT: Competitive swimmers are predisposed to musculoskeletal injuries of the upper limb, knee, and spine. This review discusses the epidemiology of these injuries, in addition to prevention strategies that may assist the physician in formulating rehabilitation programs for the swimmer following an injury. EVIDENCE ACQUISITION: A literature search was performed by a review of Google Scholar, OVID, and PubMed articles published from 1972 to 2011. RESULTS: This study highlights the epidemiology of injuries common to competitive swimmers and provides prevention strategies for the sports health professional. CONCLUSIONS: An understanding of swimming biomechanics and typical injuries in swimming aids in early recognition of injury, initiation of treatment, and design of optimal prevention and rehabilitation strategies. PMID- 23016096 TI - Emergency department usage and medical care needs of adolescent participants in a high-intensity wrestling cAMP. AB - BACKGROUND: Thousands of children and adolescents attend high-intensity athletic camps each year; the rate and type of injuries sustained are unknown. HYPOTHESIS: Participants in a high-intensity athletic camp would have significant, identifiable health care needs associated with injuries and illnesses. STUDY DESIGN: Retrospective, observational study. METHODS: Acute medical care for camp participants was primarily provided in an academic medical center emergency department (ED). All participants treated in the ED or by a volunteer camp physician were included in the study. Medical and camp records for camp participants were reviewed and described. RESULTS: In sum, 263 participants attended the high-intensity wrestling camp in 2009. Seventy-eight (30%) were treated in the ED; median age was 15.8 years. Sixteen were seen more than once, totaling 96 visits. Thirty-four percent of visits included x-ray and 25% laboratory studies. Forty-four percent were skin complaints. One patient had methicillin-resistant Staphylococcus aureus infection; none had positive viral skin cultures. Musculoskeletal or facial trauma occurred in 37%, with 5 fractures. Injury rate was 1.9 per 1000 athlete exposures. Overall, 47% of campers sought medical care during camp; 11 (4.2%) left camp early because of illness or injury. Few wrestlers received follow-up care. CONCLUSIONS: Illnesses and injuries requiring medical attention were common in this high-intensity sports camp. While many ED patients could have been treated in a clinic, 50% required ED medical resources for diagnosis or care. PMID- 23016095 TI - Mesenchymal stem cell therapy in the sports knee: where are we in 2011? AB - BACKGROUND: The relationship between biological tissue healing following knee injury or surgery and long-term clinical outcome has come to the forefront of sports medicine practice. This has led many knee surgeons to incorporate biologically mediated healing factors into the management of knee injuries. In particular, the clinical use of mesenchymal stem cells has opened new horizons. EVIDENCE ACQUISITION: Relevant studies were identified through a search of PubMed from January 2000 to April 2011, combining the term mesenchymal stem cells with articular cartilage, anterior cruciate ligament, and meniscus. Relevant citations from the reference lists of selected studies were also reviewed. RESULTS: Knee injury treatment with mesenchymal stem cells shows potential. Most reports represent animal model studies; few advances have been translated to human clinical applications. CONCLUSION: Mesenchymal stem cell use to promote healing following knee injury is likely to increase. There are scientific methodological concerns and ethical and legal issues regarding mesenchymal stem cell use for treating knee injuries. PMID- 23016098 TI - 40 years ago. PMID- 23016097 TI - Sports health orthopaedic magnetic resonance imaging challenge: shoulder pain from a fall while surfing. PMID- 23016099 TI - Muscle impairments in patients with knee osteoarthritis. AB - CONTEXT: Muscle impairments associated with knee osteoarthritis (OA) are the primary underlying cause of functional limitations. Understanding the extent of muscle impairments, its relationship with physical function and disease progression, and the evidence behind exercise therapy that targets muscle impairments is crucial. EVIDENCE ACQUISITION: An electronic search for relevant articles using MEDLINE and CINHAL databases up to September 2011 was performed. In addition to the electronic search, retrieved articles were searched manually for relevant studies. RESULTS: Quadriceps, hamstrings, and hip muscles are significantly impaired in subjects with knee OA compared with age-matched controls. Muscle strength, especially quadriceps, is a major determinant of both performance-based and self-reported physical function. Whether stronger quadriceps is protective against knee OA onset and progression is not clear. Exercise therapy, including global and targeted resistance training, is effective in reducing pain and improving function in subjects with knee OA. CONCLUSIONS: Subjects with knee OA have significant muscle impairments. These muscle impairments affect physical function and should be targeted in therapy. Further research is needed to explore the relationship between quadriceps strength and knee OA initiation and progression and to determine the optimal exercise prescription that augments outcomes in this patient population. PMID- 23016100 TI - Therapeutic exercise for athletes with nonspecific neck pain: a current concepts review. AB - CONTEXT: Benign neck pain is common in athletes and is usually the result of minor sprains, strains, or contusions. Athletes with neck pain may have deficits in cervical and/or upper thoracic mobility, muscle recruitment, strength and endurance, repositioning acuity, postural stability, and oculomotor control. EVIDENCE ACQUISITION: A Medline search was performed via PubMed to locate articles of any publication date through December 2011 using the search terms cervical pain, neck pain, athlete, athletic, therapeutic exercise, and rehabilitation. Reference lists of retrieved articles were searched for additional relevant references. RESULTS: Therapeutic exercise has promise as an intervention for individuals with neck pain, although reports on isolated athletic populations are lacking. To date, recommendations for specific therapeutic exercises have been derived largely from anecdotal or uncontrolled level IV or V evidence. CONCLUSION: Clinicians should consider deficits, functional limitations, irritability level, and the sport's cervical spine stress profile when selecting exercises for athletes with neck pain. PMID- 23016102 TI - Collagen gene variants previously associated with anterior cruciate ligament injury risk are also associated with joint laxity. AB - BACKGROUND: Genetic association studies demonstrate a relationship between several collagen gene variants and anterior cruciate ligament (ACL) injury, yet the mechanism of these relationships is still unclear. Joint laxity is a heritable trait; increased magnitudes of anterior knee laxity (AKL), genu recurvatum (GR), and general joint laxity (GJL) have been consistently associated with a greater risk of ACL injury. Joint laxity may constitute an important intermediate phenotype for the genetic association with ACL injury that can be measured clinically. HYPOTHESIS: To determine if genetic variants within the COL1A1, COL5A1, and COL12A1 genes, previously associated with ACL injury, were also associated with greater magnitudes of AKL, GR, and GJL. STUDY DESIGN: Descriptive laboratory study. METHODS: Blood samples and measures of AKL, GR, and GJL were obtained from 124 (50 male, 74 female) healthy, recreationally active subjects. Genomic DNA was extracted from the blood samples and genotyped for single-nucleotide polymorphisms previously examined relative to ACL injury. Univariate analyses of variance compared the magnitude of each laxity variable across the 3 genotypes for each single-nucleotide polymorphism in both sex combined and sex-specific models. RESULTS: Specific genotypes were associated with greater GR in all subjects. Some genotypes were associated with greater magnitudes of GR, AKL, and GJL in females only. CONCLUSIONS: Gene variants previously associated with ACL injury risk were in large part also associated with joint laxity. Sex-specific genetic associations with joint laxity were consistent with those previously reported for ACL injury. CLINICAL RELEVANCE: These data provide insight into potential pathways through which genotypic variants in collagen genes have the potential to alter ligament structure and behavior and, thus, ACL injury risk. PMID- 23016101 TI - The female athlete triad. AB - CONTEXT: The female athlete triad (the triad) is an interrelationship of menstrual dysfunction, low energy availability (with or without an eating disorder), and decreased bone mineral density; it is relatively common among young women participating in sports. Diagnosis and treatment of this potentially serious condition is complicated and often requires an interdisciplinary team. EVIDENCE ACQUISITION: Articles from 1981 to present found on PubMed were selected for review of major components of the female athlete triad as well as strategies for diagnosis and treatment of the conditions. RESULTS: The main goal in treatment of young female athletes with the triad is a natural return of menses as well as enhancement of bone mineral density. While no specific drug intervention has been shown to consistently improve bone mineral density in this patient population, maximizing energy availability and optimizing vitamin D and calcium intake are recommended. CONCLUSIONS: Treatment requires a multidisciplinary approach involving health care professionals as well as coaches and family members. Prevention of this condition is important to minimize complications of the female athlete triad. PMID- 23016103 TI - Intramuscular ketorolac injections in the athlete. AB - BACKGROUND: Pain control is a factor in the sideline treatment of competitive athletes. Ketorolac injections by team physicians as a pain control measure are seemingly becoming more mainstream, although there have been very little data published on its use. HYPOTHESIS: Intramuscular ketorolac injections are being used regularly by orthopaedic surgeons and primary care sports medicine physicians in their care of athletes. STUDY DESIGN: Descriptive epidemiology study. METHODS: A 19-question survey was generated online for physician members of the American Orthopaedic Society for Sports Medicine, the Arthroscopy Association of North America, and the American Medical Society for Sports Medicine. The survey link was e-mailed, with reminders sent every 1 to 2 weeks, and results were collected from April to June 2011. RESULTS: The survey was e mailed to 6950 physicians, with 1100 respondents completing it (60% orthopaedic surgeons, 40% nonsurgical sports medicine physicians). Approximately 49% use intramuscular ketorolac in the treatment of athletes, primarily at the collegiate and professional levels; 95.8% reported effective pain control after administration; 2.9% reported bleeding complications; and 1.9% reported kidney complications from its use. CONCLUSION: Intramuscular ketorolac injections are used by approximately half of all team physicians in their sideline treatment of competitive athletes. PMID- 23016104 TI - Anterior cruciate ligament injuries in wakeboarding: prevalence and observations on injury mechanism. AB - BACKGROUND: Wakeboarding is an increasingly popular sport that involves aggressive stunts with high risk for lower extremity injury, including anterior cruciate ligament (ACL) rupture. Little has been reported on prevalence or mechanism of ACL injury while wakeboarding. HYPOTHESIS: The prevalence of ACL injury in wakeboarding approaches that of other high-risk sports. Analyzing the mechanism of ACL injury may aid in future efforts of prevention. STUDY DESIGN: Descriptive epidemiology study. METHODS: In sum, 1580 surveys were sent internationally to professional and amateur wakeboarders. The survey questioned the participants on their history of an ACL tear while wakeboarding and asked them to describe the mechanism of injury and treatment. RESULTS: A total of 123 surveys were returned. Of this group, 52 (42.3%) acknowledged having had an ACL tear while wakeboarding. The majority described feeling a pop or buckle after attempting to land a high jump. Only 5 participants (13.5%) described a rotational mechanism created by catching the board edge in the water. Thirty seven participants (71.15%) said that the injury ruined their ability to wakeboard before reconstruction, and 41 (78.85%) had the injury repaired surgically. CONCLUSION: The prevalence of ACL tears in this data set, 42.3%, is the highest reported in the literature for wakeboarding and one of the highest for any sport. The main mechanism of injury appears to involve axial compression while one lands in a provocative position; it is not related to a rotational force created by fixed bindings. The injury should be surgically repaired to effectively continue the sport. Further study is needed to determine if wakeboarding represents a high-risk sport for ACL injury. CLINICAL SIGNIFICANCE: Wakeboarding may be a high-risk sport for ACL injury. Noncontact axial compression appears to be the main mechanism of injury. PMID- 23016105 TI - Intravenous fluid use in athletes. AB - CONTEXT: Time allowing, euhydration can be achieved in the vast majority of individuals by drinking and eating normal beverages and meals. Important to the competitive athlete is prevention and treatment of dehydration and exercise associated muscle cramps, as they are linked to a decline in athletic performance. Intravenous (IV) prehydration and rehydration has been proposed as an ergogenic aid to achieve euhydration more effectively and efficiently. EVIDENCE ACQUISITION: PubMed database was searched in November 2011 for all English-language articles related to IV utilization in sport using the keywords intravenous, fluid requirements, rehydration, hydration, athlete, sport, exercise, volume expansion, and performance. RESULTS: Limited evidence exists for prehydration with IV fluids. Although anecdotal evidence does exist, at this time there are no high-level studies confirming that IV prehydration prevents dehydration or the onset of exercise-associated muscle cramps. Currently, there are no published studies describing IV fluid use during the course of an event, at intermission, or after the event as an ergogenic aid. CONCLUSION: The use of IV fluid may be beneficial for a subset of fluid-sensitive athletes; this should be reserved for high-level athletes with strong histories of symptoms in well monitored settings. Volume expanders may also be beneficial for some athletes. IV fluids and plasma binders are not allowed in World Anti-Doping Agency-governed competitions. Routine IV therapy cannot be recommended as best practice for the majority of athletes. PMID- 23016107 TI - A displaced femoral neck stress fracture in an amenorrheic adolescent female runner. AB - This case demonstrates the potential serious consequences of the female athlete triad and its effects on bone. Displaced femoral neck stress fractures cause significant morbidity, and this case highlights the preventable nature of this injury. The treatment was focused on improving low energy availability, and, although challenging, improvements were made. This injury could have been prevented if the signs and symptoms of her injury had been addressed and there had been better knowledge of her risk factors. This case highlights the need for further education in the sports and health communities. PMID- 23016108 TI - Movement in the right direction. PMID- 23016106 TI - The basic science of human knee menisci: structure, composition, and function. AB - CONTEXT: Information regarding the structure, composition, and function of the knee menisci has been scattered across multiple sources and fields. This review contains a concise, detailed description of the knee menisci-including anatomy, etymology, phylogeny, ultrastructure and biochemistry, vascular anatomy and neuroanatomy, biomechanical function, maturation and aging, and imaging modalities. EVIDENCE ACQUISITION: A literature search was performed by a review of PubMed and OVID articles published from 1858 to 2011. RESULTS: This study highlights the structural, compositional, and functional characteristics of the menisci, which may be relevant to clinical presentations, diagnosis, and surgical repairs. CONCLUSIONS: An understanding of the normal anatomy and biomechanics of the menisci is a necessary prerequisite to understanding the pathogenesis of disorders involving the knee. PMID- 23016109 TI - I wish I knew then what I know now. PMID- 23016110 TI - Recommendations of the national football league physician society task force on the use of toradol((r)) ketorolac in the national football league. AB - Ketorolac tromethamine (Toradol((r))) is a non-steroidal anti-inflammatory drug that has potent analgesic and anti-inflammatory properties. It can be administered orally, intravenously, intramuscularly, or via a nasal route. Ketorolac injections have been used for several years in the National Football League (NFL), in both the oral and injectable forms, to treat musculoskeletal injuries and to prevent post-game soreness. In an attempt to determine the appropriate use of this medication in NFL players, the NFL Team Physician Society appointed a Task Force to consider the best available evidence as to how ketorolac should be used for pain management in professional football players. These treatment recommendations were established based on the available medical literature taking into consideration the pharmacokinetic properties of ketorolac, its accepted indications and contraindications, and the unique clinical challenges of the NFL. The Task Force recommended that 1) ketorolac should only be administered under the direct supervision and order of a team physician; 2) ketorolac should not be used prophylactically as a means of reducing anticipated pain either during or after participation in NFL games or practices and should be limited to those players diagnosed with an injury or condition and listed on the teams' injury report; 3) ketorolac should be given in the lowest effective therapeutic dose and should not be used in any form for more than 5 days; 4) ketorolac should be given in its oral preparation under typical circumstances; 5) ketorolac should not be taken concurrently with other NSAIDs or by those players with a history of allergic reaction to ketorolac, other NSAIDs or aspirin; and 6) ketorolac should not be used by a player with a history of significant gastrointestinal bleeding, renal compromise, or a past history of complications related to NSAIDs. PMID- 23016111 TI - Evaluation and management of elbow tendinopathy. AB - CONTEXT: Elbow tendinopathy is a common cause of pain and disability among patients presenting to orthopaedic surgeons, primary care physicians, physical therapists, and athletic trainers. Prompt and accurate diagnosis of these conditions facilitates a directed treatment regimen. A thorough understanding of the natural history of these injuries and treatment outcomes will enable the appropriate management of patients and their expectations. EVIDENCE ACQUISITIONS: The PubMed database was searched in December 2011 for English-language articles pertaining to elbow tendinopathy. RESULTS: Epidemiologic data as well as multiple subjective and objective outcome measures were investigated to elucidate the incidence of medial epicondylitis, lateral epicondylitis, distal biceps and triceps ruptures, and the efficacy of various treatments. CONCLUSIONS: Medial and lateral epicondylitis are overuse injuries that respond well to nonoperative management. Their etiology is degenerative and related to repetitive overuse and underlying tendinopathy. Nonsteroidal anti-inflammatory drugs and localized corticosteroid injections yield moderate symptomatic relief in short term but do not demonstrate benefit on long-term follow-up. Platelet-rich plasma injections may be advantageous in cases of chronic lateral epicondylitis. If 6 to 12 months of nonoperative treatment fails, then surgical intervention can be undertaken. Distal biceps and triceps tendon ruptures, in contrast, have an acute traumatic etiology that may be superimposed on underlying tendinopathy. Prompt diagnosis and treatment improve outcomes. While partial ruptures confirmed with magnetic resonance imaging can be treated nonoperatively with immobilization, complete ruptures should be addressed with primary repair within 3 to 4 weeks of injury. PMID- 23016112 TI - Ehlers-danlos syndrome in orthopaedics: etiology, diagnosis, and treatment implications. AB - Ehlers-Danlos syndrome is a heterogeneous connective tissue condition characterized by varying degrees of skin hyperextensibility, joint hypermobility, and vascular fragility. Joint dislocations, musculoskeletal pain, atrophic scars, easy bleeding, vessel/viscera rupture, severe scoliosis, and obstetric complications may occur. These manifestations are secondary to abnormal collagen, with specific molecular defects in types I, III, and V collagen; they may also be related to tenascin-X, which has been identified in some patients. Ehlers-Danlos syndrome has been classified into 6 types, with variable degrees of joint instability, skin hyperextensibility, wound healing difficulty, and vascular fragility. Diagnosis begins with recognition of the signs and symptoms of global hypermobility and referring appropriate patients for genetic consultation. It is important to accurately identify patients with Ehlers-Danlos syndrome to initiate appropriate musculoskeletal treatment, optimize anesthetic and postoperative management, perform appropriate vascular screening, and help families address their concerns with other families and advocacy groups. PMID- 23016114 TI - Pitch velocity is a predictor of medial elbow distraction forces in the uninjured high school-aged baseball pitcher. AB - BACKGROUND: Medial elbow injuries are common among baseball pitchers. Easily accessed methods to assess medial elbow stress may be useful in identifying individuals with increased injury risk. HYPOTHESIS: Pitch velocity (PV) is positively associated with higher medial elbow adduction moments. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Participants included 26 uninjured high school pitchers, 15 to 18 years in age. Three-dimensional data and PV were collected as athletes threw 10 fastballs for strikes to a regulation-distance target. Variables of interest were the normalized peak internal elbow adduction moment and peak PV. Linear regression was performed to evaluate the influence of PV on the adduction moment. RESULTS: For the group, mean PV was 71 mph (range, 58 81 mph), and the adduction moment was 0.558 Nm/Ht * mass (range, 0.378-0.723). PV was positively associated with the adduction moment (P < 0.01, R(2)= 0.373). CONCLUSIONS: Talented young pitchers may be more susceptible to elbow injuries as a consequence of a biomechanical coupling between PV and upper extremity joint moments. CLINICAL RELEVANCE: PV may be measured easily and serve as an indicator of medial elbow stress. PMID- 23016113 TI - Rehabilitation of the Overhead Athlete's Elbow. AB - The activities required during overhead sports, particularly during baseball pitching, produce large forces at the elbow joint. Injuries to the elbow joint frequently occur in the overhead athlete because of the large amount of forces observed during the act of throwing, playing tennis, or playing golf. Injuries may result because of repetitive overuse, leading to tissue failure. Rehabilitation following injury or surgery to the throwing elbow is vital to fully restore normal function and return the athlete to competition as quickly and safely as possible. Rehabilitation of the elbow, whether following injury or postsurgical, must follow a progressive and sequential order, building on the previous phase, to ensure that healing tissues are not compromised. Emphasis is placed on restoring full motion, muscular strength, and neuromuscular control while gradually applying loads to healing tissue. In addition, when one is creating a rehabilitation plan for athletes, it is imperative to treat the entire upper extremity, core, and legs to create and dissipate the forces generated at each joint. PMID- 23016115 TI - Prevention of elbow injuries in youth baseball pitchers. AB - CONTEXT: Although baseball is a relatively safe sport, numerous reports suggest a rapid rise in elbow injury rate among youth baseball pitchers. EVIDENCE ACQUISITION: PUBMED WAS SEARCHED FOR EPIDEMIOLOGIC, BIOMECHANICAL, AND CLINICAL STUDIES OF ELBOW INJURIES IN BASEBALL (KEYWORDS: "youth OR adolescent" AND baseball AND pitching AND "ulnar collateral ligament OR elbow"; published January 2000 - April 2012). Studies with relevance to youth baseball pitchers were reviewed. Relevant references from these articles were also retrieved and reviewed. Original data, insight, and recommendations were added. RESULTS: The majority of baseball elbow injuries are noncontact injuries to the dominant arm resulting from repetitive pitching. Five percent of youth pitchers suffer a serious elbow or shoulder injury (requiring surgery or retirement from baseball) within 10 years. The risk factor with the strongest correlation to injury is amount of pitching. Specifically, increased pitches per game, innings pitched per season, and months pitched per year are all associated with increased risk of elbow injury. Pitching while fatigued and pitching for concurrent teams are also associated with increased risk. Pitchers who also play catcher have an increased injury risk, perhaps due to the quantity of throws playing catcher adds to the athlete's arm. Another risk factor is poor pitching biomechanics. Improper biomechanics may increase the torque and force produced about the elbow during each pitch. Although throwing breaking pitches at a young age has been suggested as a risk factor, existing clinical, epidemiologic, and biomechanical data do not support this claim. CONCLUSIONS: Some elbow injuries to youth baseball pitchers can be prevented with safety rules, recommendations, education, and common sense. Scientific and medical organizations have published safety rules and recommendations, with emphasis on prevention of overuse and pitching while fatigued. STRENGTH-OF-RECOMMENDATION TAXONOMY (SORT): A. PMID- 23016116 TI - Surgical treatment for osteochondritis dissecans of the capitellum. AB - CONTEXT: Osteochondritis dissecans (OCD) of the capitellum is most often seen in adolescents who participate in sports that involve repetitive loading of the elbow. Unstable defects typically require surgical intervention that involves fragment fixation, debridement, or reconstruction with an osteochondral autograft transfer. Optimum surgical management of unstable defects remains controversial. TYPE OF STUDY: Clinical review. EVIDENCE ACQUISITION: Relevant articles published after 1992 were identified using MEDLINE, the EMBASE database, and the Cochrane Library. RESULTS: Both debridement and osteochondral autograft transfer for treatment of capitellar OCD lesions result in good short- and midterm outcomes with a high rate of return to sports. Larger defects involving more than 50% of the articular surface or involving the lateral margin of the capitellum may have worse outcomes after debridement and may be better treated with fragment fixation or osteochondral autograft transfer. CONCLUSIONS: High-level evidence is lacking to determine the superiority of debridement or osteochondral autograft transfer for the treatment of capitellar OCD lesions. A prospective longitudinal multicenter study, using validated outcome measures, that enrolls a large number of patients is needed to establish optimal treatment for unstable capitellar OCD lesions. PMID- 23016117 TI - Ulnar collateral ligament reconstruction revisited: the procedure I use and why. AB - CONTEXT: Ulnar collateral ligament (UCL) insufficiency of the elbow can be a debilitating injury that often prevents athletes from competing effectively. The overhead athlete is particularly susceptible to this injury because the anterior bundle of the UCL is the primary restraint to the valgus stress that is created during the throwing motion. Repetitive trauma from constant overhead or throwing activity can ultimately render the ligament incompetent and cause recurrent pain and instability. RESULTS: The authors currently use a "docking" technique that provides excellent graft fixation and reduces ulnar nerve related complications. CONCLUSIONS: This article details the assessment of the throwing athlete with valgus instability secondary to UCL insufficiency and highlights the technical aspects for reconstruction. The majority of athletes who undergo UCL reconstruction of the elbow can successfully return to their preinjury function. STRENGTH-OF-RECOMMENDATION TAXONOMY (SORT): A. PMID- 23016118 TI - The ulnar collateral ligament procedure revisited: the procedure we use. AB - CONTEXT: The ulnar collateral ligament of the elbow (UCL) is frequently injured in throwing athletes, most commonly baseball pitchers. The ligament is reconstructed through bone tunnels using palmaris longus or gracilis autograft. RESULTS: This study highlights the following technique for UCL reconstruction in over 2000 athletes.(2) CONCLUSION: When conservative management fails, ligament reconstruction can allow the athlete to return to their sport.(1). PMID- 23016119 TI - A segmental approach to imaging of sports-related injuries of the pediatric elbow. AB - CONTEXT: The imaging of pediatric sports injuries of the elbow requires an understanding of the interaction between biomechanical forces common in sports and the developing skeleton. EVIDENCE ACQUISITION: A PubMed search was performed using the terms elbow, radiology, and sports with the search limited to children up to 18 years of age. No limits were set on the range of years searched. Articles were reviewed for relevance with an emphasis of the changing nature of sports injuries about the pediatric elbow. RESULTS: A clear progression of injuries about the elbow can be identified as the skeleton matures. Sports most commonly associated with injuries in the pediatric age group were baseball and gymnastics. CONCLUSIONS: Most pediatric sports injuries result from overhand throwing, especially in baseball or gymnastics. The manifestation of the injuries shifts as the physes progress toward closure. PMID- 23016120 TI - The relationship between zinc intake and serum/plasma zinc concentration in children: a systematic review and dose-response meta-analysis. AB - Recommendations for zinc intake during childhood vary widely across Europe. The EURRECA project attempts to consolidate the basis for the definition of micronutrient requirements, taking into account relationships among intake, status and health outcomes, in order to harmonise these recommendations. Data on zinc intake and biomarkers of zinc status reported in randomised controlled trials (RCTs) can provide estimates of dose-response relationships which may be used for underpinning zinc reference values. This systematic review included all RCTs of apparently healthy children aged 1-17 years published by February 2010 which provided data on zinc intake and biomarkers of zinc status. An intake status regression coefficient (beta) was calculated for each individual study and calculated the overall pooled and SE (beta) using random effects meta-analysis on a double log scale. The pooled dose-response relationship between zinc intake and zinc status indicated that a doubling of the zinc intake increased the serum/plasma zinc status by 9%. This evidence can be utilised, together with currently used balance studies and repletion/depletion studies, when setting zinc recommendations as a basis for nutrition policies. PMID- 23016121 TI - Infant nutrition and later health: a review of current evidence. AB - There is a growing recognition of the need for a lifecourse approach to understanding the aetiology of adult disease, and there is now significant evidence that links patterns of infant feeding to differences in health outcomes, both in the short and longer term. Breastfeeding is associated with lower rates of infection in infancy; in high-income populations, it is associated with reductions in blood pressure and total blood cholesterol, and lower risks of obesity and diabetes in adult life. Breastfeeding rates are suboptimal in many countries, and strategies to promote breastfeeding could therefore confer important benefits for health at a population level. However, there are particular challenges in defining nutritional exposures in infancy, including marked social gradients in initiation and duration of breastfeeding. In recent studies of low and middle-income populations of children and young adults, where the influences on infant feeding practice differ, beneficial effects of breastfeeding on blood pressure, BMI and risk of diabetes have not been confirmed, and further information is needed. Little is currently known about the long-term consequences of differences in the timing and nature of the weaning diet. Future progress will depend on new studies that provide detailed prospective data on duration and exclusivity of breastfeeding together with appropriate characterisation of the weaning diet. PMID- 23016123 TI - Steroidal compounds in commercial parenteral lipid emulsions. AB - Parenteral nutrition lipid emulsions made from various plant oils contain steroidal compounds, called phytosterols. During parenteral administration of lipid emulsions, phytosterols can reach levels in the blood that are many fold higher than during enteral administration. The elevated phytosterol levels have been associated with the development of liver dysfunction and the rare development of liver failure. There is limited information available in the literature related to phytosterol concentrations in lipid emulsions. The objective of the current study was to validate an assay for steroidal compounds found in lipid emulsions and to compare their concentrations in the most commonly used parenteral nutrition lipid emulsions: Liposyn((r)) II, Liposyn((r)) III, Lipofundin((r)) MCT, Lipofundin((r)) N, Structolipid((r)), Intralipid((r)), Ivelip((r)) and ClinOleic((r)). Our data demonstrates that concentrations of the various steroidal compounds varied greatly between the eight lipid emulsions, with the olive oil-based lipid emulsion containing the lowest levels of phytosterols and cholesterol, and the highest concentration of squalene. The clinical impression of greater incidences of liver dysfunction with soybean versus MCT/LCT and olive/soy lipid emulsions may be reflective of the levels of phytosterols in these emulsions. This information may help guide future studies and clinical care of patients with lipid emulsion-associated liver dysfunction. PMID- 23016124 TI - Effect of diets supplemented with different sources of astaxanthin on the gonad of the sea urchin Anthocidaris crassispina. AB - The effect of the microalgae Haematococcus pluvialis and Chorella zofingiensis, and synthetic astaxanthin on the gonad of the sea urchin Anthocidaris crassispina was studied. The basal diet was supplemented with H. pluvialis, C. zofingiensis, or synthetic astaxanthin, at two levels of astaxanthin (approximately 400 mg/kg and 100 mg/kg), to obtain the experimental diets HP1, HP2, CZ1, CZ2, AST1, and AST2, respectively, for two months of feeding experiment. The results showed that the concentrations of astaxanthin in the gonads of the sea urchins fed these experimental diets ranged from 0.15 to 3.01 mg/kg dry gonad weight. The higher astaxanthin levels (>2.90 mg/kg) were found in the gonads of the sea urchins fed the diets HP1 (containing 380 mg/kg of astaxanthins, mostly mono- and diesters) and AST1 (containing 385 mg/kg of synthetic astaxanthin). The lowest astaxanthin level (0.15 mg/kg) was detected in the gonads of the sea urchins fed the diet CZ2 (containing 98 mg/kg of astaxanthins, mostly diesters). Furthermore, the highest canthaxanthin level (7.48 mg/kg) was found in the gonads of the sea urchins fed the diet CZ1 (containing 387 mg/kg of astaxanthins and 142 mg/kg of canthaxanthin), suggesting that astaxanthins, especially astaxanthin esters, might not be assimilated as easily as canthaxanthin by the sea urchins. Our results show that sea urchins fed diets containing astaxanthin pigments show higher incorporation of these known antioxidant constituents, with the resultant seafood products therefore being of potential higher nutritive value. PMID- 23016122 TI - Cellular mechanisms of zinc dysregulation: a perspective on zinc homeostasis as an etiological factor in the development and progression of breast cancer. AB - Worldwide, breast cancer is the most commonly diagnosed cancer among women and is the leading cause of female cancer deaths. Zinc (Zn) functions as an antioxidant and plays a role in maintaining genomic stability. Zn deficiency results in oxidative DNA damage and increased cancer risk. Studies suggest an inverse association between dietary and plasma Zn levels and the risk for developing breast cancer. In contrast, breast tumor biopsies display significantly higher Zn levels compared with normal tissue. Zn accumulation in tumor tissue also correlates with increased levels of Zn importing proteins. Further, aberrant expression of Zn transporters in tumors correlates with malignancy, suggesting that altered metal homeostasis in the breast could contribute to malignant transformation and the severity of cancer. However, studies have yet to link dysregulated Zn transport and abnormal Zn-dependent functions in breast cancer development. Herein, we summarize studies that address the multi-modal role of Zn dyshomeostasis in breast cancer with respect to the role of Zn in modulating oxidative stress, DNA damage response/repair pathways and cell proliferation/apoptosis, and the relationship to aberrant regulation of Zn transporters. We also compare Zn dysregulation in breast tissue to that of prostate, pancreatic and ovarian cancer where possible. PMID- 23016125 TI - Dietary patterns of infants and toddlers are associated with nutrient intakes. AB - Dietary patterns are a useful summary measure of diet. Few studies have examined the nutrient profiles underpinning the dietary patterns of young children. The study aim is to determine whether dietary patterns at 6 and 15 months of age are associated with nutrient intakes at 8 and 18 months, respectively. Participants were children from the Avon Longitudinal Study of Parents and Children who had complete dietary pattern and nutrient intake data (n = 725 at 6-8 months, n = 535 at 15-18 months). The association between tertiles of dietary pattern scores and nutrient intake was examined using a non-parametric test for trend. Scores on the home-made traditional pattern (6-8 months) were positively associated with median energy intake. Each dietary pattern had different associations with energy adjusted intakes of macro- and micro-nutrients. At both times, the discretionary pattern was positively and the ready-prepared baby foods pattern was negatively associated with sodium intake. At 6-8 months, calcium and iron intakes decreased across scores on the home-made traditional and breastfeeding patterns, but increased across the ready-prepared baby food patterns. These findings highlight that dietary patterns in infants and toddlers vary in their underlying energy and nutrient composition. PMID- 23016126 TI - Pre-exercise hyperhydration-induced bodyweight gain does not alter prolonged treadmill running time-trial performance in warm ambient conditions. AB - This study compared the effect of pre-exercise hyperhydration (PEH) and pre exercise euhydration (PEE) upon treadmill running time-trial (TT) performance in the heat. Six highly trained runners or triathletes underwent two 18 km TT runs (~28 degrees C, 25%-30% RH) on a motorized treadmill, in a randomized, crossover fashion, while being euhydrated or after hyperhydration with 26 mL/kg bodyweight (BW) of a 130 mmol/L sodium solution. Subjects then ran four successive 4.5 km blocks alternating between 2.5 km at 1% and 2 km at 6% gradient, while drinking a total of 7 mL/kg BW of a 6% sports drink solution (Gatorade, USA). PEH increased BW by 1.00 +/- 0.34 kg (P < 0.01) and, compared with PEE, reduced BW loss from 3.1% +/- 0.3% (EUH) to 1.4% +/- 0.4% (HYP) (P < 0.01) during exercise. Running TT time did not differ between groups (PEH: 85.6 +/- 11.6 min; PEE: 85.3 +/- 9.6 min, P = 0.82). Heart rate (5 +/- 1 beats/min) and rectal (0.3 +/- 0.1 degrees C) and body (0.2 +/- 0.1 degrees C) temperatures of PEE were higher than those of PEH (P < 0.05). There was no significant difference in abdominal discomfort and perceived exertion or heat stress between groups. Our results suggest that pre-exercise sodium-induced hyperhydration of a magnitude of 1 L does not alter 80-90 min running TT performance under warm conditions in highly-trained runners drinking ~500 mL sports drink during exercise. PMID- 23016128 TI - Breastfeeding promotion, support and protection: review of six country programmes. AB - Reviews of programmes in Bangladesh, Benin, the Philippines, Sri Lanka, Uganda, and Uzbekistan sought to identify health policy and programmatic factors that influenced breastfeeding practices during a 10 to 15 year period. Exclusive breastfeeding rates and trends were analysed in six countries in general and from an equity perspective in two of them. Success factors and challenges were identified in countries with improved and stagnated rates respectively. The disaggregated data analysis showed that progress may be unequal in population subgroups, but if appropriately designed and implemented, a programme can become a "health equalizer" and eliminate discrepancies among different subgroups. Success requires commitment, supportive policies, and comprehensiveness of programmes for breastfeeding promotion, protection and support. Community-based promotion and support was identified as a particularly important component. Although health workers' training on infant feeding support and counselling was prioritized, further improvement of interpersonal counselling and problem solving skills is needed. More attention is advised for pre-service education, including a stronger focus on clinical practice, to ensure knowledge and skills among all health workers. Large-scale communication activities played a significant role, but essential steps were often underemphasized, including identifying social norms and influencing factors, ensuring community participation, and testing of approaches and messages. PMID- 23016129 TI - Dietary cholesterol affects plasma lipid levels, the intravascular processing of lipoproteins and reverse cholesterol transport without increasing the risk for heart disease. AB - The associations between dietary cholesterol and heart disease are highly controversial. While epidemiological studies and clinical interventions have shown the lack of correlation between cholesterol intake and cardiovascular disease (CVD) risk, there is still concern among health practitioners and the general population regarding dietary cholesterol. In this review, several clinical studies utilizing cholesterol challenges are analyzed in terms of changes that occur in lipoprotein metabolism resulting from excess consumption of cholesterol. Dietary cholesterol has been shown to increase both LDL and HDL in those individuals who respond to a cholesterol challenge without altering the LDL cholesterol/HDL cholesterol ratio, a key marker of CVD risk. Further, dietary cholesterol has been shown to increase only HDL with no changes in LDL with average cholesterol consumption and during weight loss interventions. Ingestion of cholesterol has also been shown to increase the size of both LDL and HDL particles with the associated implications of a less atherogenic LDL particle as well as more functional HDL in reverse cholesterol transport. Other changes observed in lipoprotein metabolism are a greater number of large LDL and decreases in small LDL subfractions. All this information put together points to specific roles of dietary cholesterol in substantially altering intravascular processing of lipoproteins as well as reverse cholesterol transport. PMID- 23016127 TI - The role of ghrelin, salivary secretions, and dental care in eating disorders. AB - Eating disorders, including anorexia and bulimia nervosa, are potentially life threatening syndromes characterized by severe disturbances in eating behavior. An effective treatment strategy for these conditions remains to be established, as patients with eating disorders tend to suffer from multiple relapses. Because ghrelin was originally discovered in the stomach mucosa, it has been widely studied over the past decade in an effort to uncover its potential roles; these studies have shed light on the mechanism by which ghrelin regulates food intake. Thus, studying ghrelin in the context of eating disorders could improve our understanding of the pathogenesis of eating disorders, possibly resulting in a promising new pharmacological treatment strategy for these patients. In addition, early detection and treatment of eating disorders are critical for ensuring recovery of young patients. Oral symptoms, including mucosal, dental, and saliva abnormalities, are typically observed in the early stages of eating disorders. Although oral care is not directly related to the treatment of eating disorders, knowledge of the oral manifestations of eating disorder patients may aid in early detection, resulting in earlier treatment; thus, oral care might contribute to overall patient management and prognosis. Moreover, ghrelin has also been found in saliva, which may be responsible for oral hygiene and digestion-related functions. This review discusses the pharmacological potential of ghrelin in regulating food-intake and the role of saliva and oral care in young patients with eating disorders. PMID- 23016130 TI - Association between polymorphisms in the fatty acid desaturase gene cluster and the plasma triacylglycerol response to an n-3 PUFA supplementation. AB - Eicosapentaenoic and docosahexaenoic acids have been reported to have a variety of beneficial effects on cardiovascular disease risk factors. However, a large inter-individual variability in the plasma lipid response to an omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation is observed in different studies. Genetic variations may influence plasma lipid responsiveness. The aim of the present study was to examine the effects of a supplementation with n-3 PUFA on the plasma lipid profile in relation to the presence of single-nucleotide polymorphisms (SNPs) in the fatty acid desaturase (FADS) gene cluster. A total of 208 subjects from Quebec City area were supplemented with 3 g/day of n-3 PUFA, during six weeks. In a statistical model including the effect of the genotype, the supplementation and the genotype by supplementation interaction, SNP rs174546 was significantly associated (p = 0.02) with plasma triglyceride (TG) levels, pre and post-supplementation. The n-3 supplementation had an independent effect on plasma TG levels and no significant genotype by supplementation interaction effects were observed. In summary, our data support the notion that the FADS gene cluster is a major determinant of plasma TG levels. SNP rs174546 may be an important SNP associated with plasma TG levels and FADS1 gene expression independently of a nutritional intervention with n-3 PUFA. PMID- 23016131 TI - Experimental alcohol-related peripheral neuropathy: role of insulin/IGF resistance. AB - The mechanisms of alcohol-related peripheral neuropathy (ALPN) are poorly understood. We hypothesize that, like alcohol-related liver and brain degeneration, ALPN may be mediated by combined effects of insulin/IGF resistance and oxidative stress. Adult male Long Evans rats were chronically pair-fed with diets containing 0% or 37% ethanol (caloric), and subjected to nerve conduction studies. Chronic ethanol feeding slowed nerve conduction in the tibial (p = 0.0021) motor nerve, and not plantar sensory nerve, but it did not affect amplitude. Histological studies of the sciatic nerve revealed reduced nerve fiber diameters with increased regenerative sprouts, and denervation myopathy in ethanol-fed rats. qRT-PCR analysis demonstrated reduced mRNA levels of insulin, IGF-1, and IGF-2 polypeptides, IGF-1 receptor, and IRS2, and ELISAs revealed reduced immunoreactivity for insulin and IGF-1 receptors, IRS-1, IRS-4, myelin associated glycoprotein, and tau in sciatic nerves of ethanol-fed rats (all p < 0.05 or better). The findings suggest that ALPN is characterized by (1) slowed conduction velocity with demyelination, and a small component of axonal degeneration; (2) impaired trophic factor signaling due to insulin and IGF resistance; and (3) degeneration of myelin and axonal cytoskeletal proteins. Therefore, ALPN is likely mediated by molecular and signal transduction abnormalities similar to those identified in alcoholic liver and brain degeneration. PMID- 23016132 TI - Impaired insulin/IGF signaling in experimental alcohol-related myopathy. AB - Alcohol-related myopathy (Alc-M) is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8) or 35.5% (N = 13) ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3beta. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration. PMID- 23016133 TI - Vitamin D and calcium status in South African adolescents with alcohol use disorders. AB - Adequate vitamin D and calcium are essential for optimal adolescent skeletal development. Adolescent vitamin D insufficiency/deficiency and poor calcium intake have been reported worldwide. Heavy alcohol use impacts negatively on skeletal health, which is concerning since heavy adolescent drinking is a rising public health problem. This study aimed to examine biochemical vitamin D status and dietary intakes of calcium and vitamin D in 12-16 year-old adolescents with alcohol use disorders (AUD), but without co-morbid substance use disorders, compared to adolescents without AUD. Substance use, serum 25-hydroxyvitamin D (s 25(OH)D) concentrations, energy, calcium and vitamin D intakes were assessed in heavy drinkers (meeting DSM-IV criteria for AUD) (n = 81) and in light/non drinkers without AUD (non-AUD) (n = 81), matched for age, gender, language, socio economic status and education. Lifetime alcohol dose was orders of magnitude higher in AUD adolescents compared to non-AUD adolescents. AUD adolescents had a binge drinking pattern and "weekends-only" style of alcohol consumption. Significantly lower (p = 0.038) s-25(OH)D (adjusted for gender, smoking, vitamin D intake) were evident in AUD adolescents compared to non-AUD adolescents. High levels of vitamin D insufficiency/deficiency (s-25(OH)D < 29.9 ng/mL) were prevalent in both groups, but was significantly higher (p = 0.013) in the AUD group (90%) compared to the non-AUD group (70%). All participants were at risk of inadequate calcium and vitamin D intakes (Estimated Average Requirement cut-point method). Both groups were at risk of inadequate calcium intake and had poor biochemical vitamin D status, with binge drinking potentially increasing the risk of the latter. This may have negative implications for peak bone mass accrual and future osteoporosis risk, particularly with protracted binge drinking. PMID- 23016135 TI - Plant calcium content: ready to remodel. AB - By identifying the relationship between calcium location in the plant cell and nutrient bioavailability, the plant characteristics leading to maximal calcium absorption by humans can be identified. Knowledge of plant cellular and molecular targets controlling calcium location in plants is emerging. These insights should allow for better strategies for increasing the nutritional content of foods. In particular, the use of preparation-free elemental imaging technologies such as synchrotron X-ray fluorescence (SXRF) microscopy in plant biology may allow researchers to understand the relationship between subcellular location and nutrient bioavailability. These approaches may lead to better strategies for altering the location of calcium within the plant to maximize its absorption from fruits and vegetables. These modified foods could be part of a diet for children and adults identified as at-risk for low calcium intake or absorption with the ultimate goal of decreasing the incidence and severity of inadequate bone mineralization. PMID- 23016137 TI - X-ray absorption spectroscopy by full-field X-ray microscopy of a thin graphite flake: Imaging and electronic structure via the carbon K-edge. AB - We demonstrate that near-edge X-ray-absorption fine-structure spectra combined with full-field transmission X-ray microscopy can be used to study the electronic structure of graphite flakes consisting of a few graphene layers. The flake was produced by exfoliation using sodium cholate and then isolated by means of density-gradient ultracentrifugation. An image sequence around the carbon K-edge, analyzed by using reference spectra for the in-plane and out-of-plane regions of the sample, is used to map and spectrally characterize the flat and folded regions of the flake. Additional spectral features in both pi and sigma regions are observed, which may be related to the presence of topological defects. Doping by metal impurities that were present in the original exfoliated graphite is indicated by the presence of a pre-edge signal at 284.2 eV. PMID- 23016138 TI - Nanostructures for sensors, electronics, energy and environment. PMID- 23016136 TI - Fructose rich diet-induced high plasminogen activator inhibitor-1 (PAI-1) production in the adult female rat: protective effect of progesterone. AB - The effect of progesterone (P4) on fructose rich diet (FRD) intake-induced metabolic, endocrine and parametrial adipose tissue (PMAT) dysfunctions was studied in the adult female rat. Sixty day-old rats were i.m. treated with oil alone (control, CT) or containing P4 (12 mg/kg). Rats ate Purina chow-diet ad libitum throughout the entire experiment and, between 100 and 120 days of age drank ad libitum tap water alone (normal diet; CT-ND and P4-ND) or containing fructose (10% w/v; CT-FRD and P4-FRD). At age 120 days, animals were subjected to a glucose tolerance test or decapitated. Plasma concentrations of various biomarkers and PMAT gene abundance were monitored. P4-ND (vs. CT-ND) rats showed elevated circulating levels of lipids. CT-FRD rats displayed high (vs. CT-ND) plasma concentrations of lipids, leptin, adiponectin and plasminogen activator inhibitor-1 (PAI-1). Lipidemia and adiponectinemia were high (vs. P4-ND) in P4 FRD rats. Although P4 failed to prevent FRD-induced hyperleptinemia, it was fully protective on FRD-enhanced plasma PAI-1 levels. PMAT leptin and adiponectin mRNAs were high in CT-FRD and P4-FRD rats. While FRD enhanced PMAT PAI-1 mRNA abundance in CT rats, this effect was absent in P4 rats. Our study supports that a preceding P4-enriched milieu prevented the enhanced prothrombotic risk induced by FRD-elicited high PAI-1 production. PMID- 23016134 TI - Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. AB - The gastrointestinal (GI) microbiota is the collection of microbes which reside in the GI tract and represents the largest source of non-self antigens in the human body. The GI tract functions as a major immunological organ as it must maintain tolerance to commensal and dietary antigens while remaining responsive to pathogenic stimuli. If this balance is disrupted, inappropriate inflammatory processes can result, leading to host cell damage and/or autoimmunity. Evidence suggests that the composition of the intestinal microbiota can influence susceptibility to chronic disease of the intestinal tract including ulcerative colitis, Crohn's disease, celiac disease and irritable bowel syndrome, as well as more systemic diseases such as obesity, type 1 diabetes and type 2 diabetes. Interestingly, a considerable shift in diet has coincided with increased incidence of many of these inflammatory diseases. It was originally believed that the composition of the intestinal microbiota was relatively stable from early childhood; however, recent evidence suggests that diet can cause dysbiosis, an alteration in the composition of the microbiota, which could lead to aberrant immune responses. The role of the microbiota and the potential for diet-induced dysbiosis in inflammatory conditions of the GI tract and systemic diseases will be discussed. PMID- 23016139 TI - Ultraviolet photodetection of flexible ZnO nanowire sheets in polydimethylsiloxane polymer. AB - ZnO nanowires are normally exposed to an oxygen atmosphere to achieve high performance in UV photodetection. In this work we present results on a UV photodetector fabricated using a flexible ZnO nanowire sheet embedded in polydimethylsiloxane (PDMS), a gas-permeable polymer, showing reproducible UV photoresponse and enhanced photoconduction. PDMS coating results in a reduced response speed compared to that of a ZnO nanowire film in air. The rising speed is slightly reduced, while the decay time is prolonged by about a factor of four. We conclude that oxygen molecules diffusing in PDMS are responsible for the UV photoresponse. PMID- 23016140 TI - Structural, electronic and photovoltaic characterization of multiwalled carbon nanotubes grown directly on stainless steel. AB - We have taken advantage of the native surface roughness and the iron content of AISI-316 stainless steel to grow multiwalled carbon nanotubes (MWCNTs) by chemical vapour deposition without the addition of an external catalyst. The structural and electronic properties of the synthesized carbon nanostructures have been investigated by a range of electron microscopy and spectroscopy techniques. The results show the good quality and the high graphitization degree of the synthesized MWCNTs. Through energy-loss spectroscopy we found that the electronic properties of these nanostructures are markedly different from those of highly oriented pyrolytic graphite (HOPG). Notably, a broadening of the pi plasmon peak in the case of MWCNTs is evident. In addition, a photocurrent was measured when MWCNTs were airbrushed onto a silicon substrate. External quantum efficiency (EQE) and photocurrent values were reported both in planar and in top down geometry of the device. Marked differences in the line shapes and intensities were found for the two configurations, suggesting that two different mechanisms of photocurrent generation and charge collection are in operation. From this comparison, we are able to conclude that the silicon substrate plays an important role in the production of electron-hole pairs. PMID- 23016141 TI - Functionalised zinc oxide nanowire gas sensors: Enhanced NO(2) gas sensor response by chemical modification of nanowire surfaces. AB - Surface coating with an organic self-assembled monolayer (SAM) can enhance surface reactions or the absorption of specific gases and hence improve the response of a metal oxide (MOx) sensor toward particular target gases in the environment. In this study the effect of an adsorbed organic layer on the dynamic response of zinc oxide nanowire gas sensors was investigated. The effect of ZnO surface functionalisation by two different organic molecules, tris(hydroxymethyl)aminomethane (THMA) and dodecanethiol (DT), was studied. The response towards ammonia, nitrous oxide and nitrogen dioxide was investigated for three sensor configurations, namely pure ZnO nanowires, organic-coated ZnO nanowires and ZnO nanowires covered with a sparse layer of organic-coated ZnO nanoparticles. Exposure of the nanowire sensors to the oxidising gas NO(2) produced a significant and reproducible response. ZnO and THMA-coated ZnO nanowire sensors both readily detected NO(2) down to a concentration in the very low ppm range. Notably, the THMA-coated nanowires consistently displayed a small, enhanced response to NO(2) compared to uncoated ZnO nanowire sensors. At the lower concentration levels tested, ZnO nanowire sensors that were coated with THMA-capped ZnO nanoparticles were found to exhibit the greatest enhanced response. DeltaR/R was two times greater than that for the as-prepared ZnO nanowire sensors. It is proposed that the DeltaR/R enhancement in this case originates from the changes induced in the depletion-layer width of the ZnO nanoparticles that bridge ZnO nanowires resulting from THMA ligand binding to the surface of the particle coating. The heightened response and selectivity to the NO(2) target are positive results arising from the coating of these ZnO nanowire sensors with organic-SAM-functionalised ZnO nanoparticles. PMID- 23016142 TI - Reduced electron recombination of dye-sensitized solar cells based on TiO(2) spheres consisting of ultrathin nanosheets with [001] facet exposed. AB - An anatase TiO(2) material with hierarchically structured spheres consisting of ultrathin nanosheets with 100% of the [001] facet exposed was employed to fabricate dye-sensitized solar cells (DSCs). Investigation of the electron transport and back reaction of the DSCs by electrochemical impedance spectroscopy showed that the spheres had a threefold lower electron recombination rate compared to the conventional TiO(2) nanoparticles. In contrast, the effective electron diffusion coefficient, D(n), was not sensitive to the variation of the TiO(2) morphology. The TiO(2) spheres showed the same D(n) as that of the nanoparticles. The influence of TiCl(4) post-treatment on the conduction band of the TiO(2) spheres and on the kinetics of electron transport and back reactions was also investigated. It was found that the TiCl(4) post-treatment caused a downward shift of the TiO(2) conduction band edge by 30 meV. Meanwhile, a fourfold increase of the effective electron lifetime of the DSC was also observed after TiCl(4) treatment. The synergistic effect of the variation of the TiO(2) conduction band and the electron recombination determined the open-circuit voltage of the DSC. PMID- 23016143 TI - Glassy carbon electrodes modified with multiwalled carbon nanotubes for the determination of ascorbic acid by square-wave voltammetry. AB - Multiwalled carbon nanotubes were used to modify the surface of a glassy carbon electrode to enhance its electroactivity. Nafion served to immobilise the carbon nanotubes on the electrode surface. The modified electrode was used to develop an analytical method for the analysis of ascorbic acid (AA) by square-wave voltammetry (SWV). The oxidation of ascorbic acid at the modified glassy carbon electrode showed a peak potential at 315 mV, about 80 mV lower than that observed at the bare (unmodified) electrode. The peak current was about threefold higher than the response at the bare electrode. Replicate measurements of peak currents showed good precision (3% rsd). Peak currents increased with increasing ascorbic acid concentration (dynamic range = 0.0047-5.0 mmol/L) and displayed good linearity (R(2) = 0.994). The limit of detection was 1.4 MUmol/L AA, while the limit of quantitation was 4.7 MUmol/L AA. The modified electrode was applied to the determination of the amount of ascorbic acid in four brands of commercial orange-juice products. The measured content agreed well (96-104%) with the product label claim for all brands tested. Recovery tests on spiked samples of orange juice showed good recovery (99-104%). The reliability of the SWV method was validated by conducting parallel experiments based on high-performance liquid chromatography (HPLC) with absorbance detection. The observed mean AA contents of the commercial orange juice samples obtained by the two methods were compared statistically and were found to have no significant difference (P = 0.05). PMID- 23016144 TI - Colloidal lithography for fabricating patterned polymer-brush microstructures. AB - We exploit a series of robust, but simple and convenient colloidal lithography (CL) approaches, using a microsphere array as a mask or as a guiding template, and combine this with surface-initiated atom-transfer radical polymerization (SI ATRP) to fabricate patterned polymer-brush microstructures. The advantages of the CL technique over other lithographic approaches for the fabrication of patterned polymer brushes are (i) that it can be carried out with commercially available colloidal particles at a relatively low cost, (ii) that no complex equipment is required to create the patterned templates with micro- and nanoscale features, and (iii) that polymer brush features are controlled simply by changing the size or chemical functionality of the microspheres or the substrate. PMID- 23016145 TI - The morphology of silver nanoparticles prepared by enzyme-induced reduction. AB - Silver nanoparticles were synthesized by an enzyme-induced growth process on solid substrates. In order to customize the enzymatically grown nanoparticles (EGNP) for analytical applications in biomolecular research, a detailed study was carried out concerning the time evolution of the formation of the silver nanoparticles, their morphology, and their chemical composition. Therefore, silver-nanoparticle films of different densities were investigated by using scanning as well as transmission electron microscopy to examine their structure. Cross sections of silver nanoparticles, prepared for analysis by transmission electron microscopy were additionally studied by energy-dispersive X-ray spectroscopy in order to probe their chemical composition. The surface coverage of substrates with silver nanoparticles and the maximum particle height were determined by Rutherford backscattering spectroscopy. Variations in the silver nanoparticle films depending on the conditions during synthesis were observed. After an initial growth state the silver nanoparticles exhibit the so-called desert-rose or nanoflower-like structure. This complex nanoparticle structure is in clear contrast to the auto-catalytically grown spherical particles, which maintain their overall geometrical appearance while increasing their diameter. It is shown, that the desert-rose-like silver nanoparticles consist of single crystalline plates of pure silver. The surface-enhanced Raman spectroscopic (SERS) activity of the EGNP structures is promising due to the exceptionally rough surface structure of the silver nanoparticles. SERS measurements of the vitamin riboflavin incubated on the silver nanoparticles are shown as an exemplary application for quantitative analysis. PMID- 23016146 TI - Conducting composite materials from the biopolymer kappa-carrageenan and carbon nanotubes. AB - Conducting composite films containing carbon nanotubes (CNTs) were prepared by using the biopolymer kappa-carrageenan (KC) as a dispersant. Rheological studies indicated that 0.5% w/v was the appropriate KC concentration for dispersing CNTs. Our results showed that multiwalled nanotubes (MWNTs) required less sonic energy than single-walled nanotubes (SWNTs) for the dispersion process to be complete. Films prepared by vacuum filtration exhibited higher conductivity and improved mechanical characteristics compared to those prepared by evaporative casting. All composite films displayed sensitivity to water vapour, but MWNT films were more sensitive than SWNT films. PMID- 23016147 TI - Distribution of functional groups in periodic mesoporous organosilica materials studied by small-angle neutron scattering with in situ adsorption of nitrogen. AB - Periodic mesoporous materials of the type (R'O)(3)Si-R-Si(OR')(3) with benzene as an organic bridge and a crystal-like periodicity within the pore walls were functionalized with SO(3)H or SO(3) (-) groups and investigated by small-angle neutron scattering (SANS) with in situ nitrogen adsorption at 77 K. If N(2) is adsorbed in the pores the SANS measurements show a complete matching of all of the diffraction signals that are caused by the long-range ordering of the mesopores in the benzene-PMO, due to the fact that the benzene-PMO walls possess a neutron scattering length density (SLD) similar to that of nitrogen in the condensed state. However, signals at higher q-values (>1 1/A) are not affected with respect to their SANS intensity, even after complete pore filling, confirming the assumption of a crystal-like periodicity within the PMO material walls due to pi-pi interactions between the organic bridges. The SLD of pristine benzene-PMO was altered by functionalizing the surface with different amounts of SO(3)H-groups, using the grafting method. For a low degree of functionalization (0.81 mmol SO(3)H.g(-1)) and/or an inhomogeneous distribution of the SO(3)H groups, the SLD changes only negligibly, and thus, complete contrast matching is still found. However, for higher amounts of SO(3)H-groups (1.65 mmol SO(3)H.g( 1)) being present in the mesopores, complete matching of the neutron diffraction signals is no longer observed proving that homogeneously distributed SO(3)H groups on the inner pore walls of the benzene-PMO alter the SLD in a way that it no longer fits to the SLD of the condensed N(2). PMID- 23016148 TI - Effect of deposition temperature on the structural and optical properties of chemically prepared nanocrystalline lead selenide thin films. AB - Nanocrystalline lead selenide (PbSe) thin films were prepared on glass substrates by a chemical bath deposition method, using sodium selenosulfate (Na(2)SeSO(3)) as a source of Se(2-) ions, and lead acetate as a source of Pb(2+) ions. Trisodium citrate (TSC) was used as a complexing agent. PbSe films were prepared at various deposition temperatures while the pH value was kept fixed at 11, and the effect on the resulting film properties was studied by X-ray diffraction (XRD), X-ray fluorescence (XRF), scanning electron microscopy (SEM) and optical absorption studies. The structural parameters, such as the lattice constant (a), crystallite size (D), dislocation density (rho) and microstrain (epsilon) were evaluated from the XRD spectra. It was found that average crystallite size, as calculated from Scherrer's formula, increased from 23 to 33 nm as the deposition temperature was varied from 303 to 343 K. The dislocation density and microstrain were found to vary inversely with the crystallite size, whereas the lattice constant was found to increase with an increase in crystallite size. The optical absorption spectra of the nanocrystalline PbSe films showed a blue shift, and the optical band gap (E(g)) was found to increase from 1.96 to 2.10 eV with the decrease in crystallite size. PMID- 23016149 TI - Magnetic-Fe/Fe(3)O(4)-nanoparticle-bound SN38 as carboxylesterase-cleavable prodrug for the delivery to tumors within monocytes/macrophages. AB - The targeted delivery of therapeutics to the tumor site is highly desirable in cancer treatment, because it is capable of minimizing collateral damage. Herein, we report the synthesis of a nanoplatform, which is composed of a 15 +/- 1 nm diameter core/shell Fe/Fe(3)O(4) magnetic nanoparticles (MNPs) and the topoisomerase I blocker SN38 bound to the surface of the MNPs via a carboxylesterase cleavable linker. This nanoplatform demonstrated high heating ability (SAR = 522 +/- 40 W/g) in an AC-magnetic field. For the purpose of targeted delivery, this nanoplatform was loaded into tumor-homing double-stable RAW264.7 cells (mouse monocyte/macrophage-like cells (Mo/Ma)), which have been engineered to express intracellular carboxylesterase (InCE) upon addition of doxycycline by a Tet-On Advanced system. The nanoplatform was taken up efficiently by these tumor-homing cells. They showed low toxicity even at high nanoplatform concentration. SN38 was released successfully by switching on the Tet-On Advanced system. We have demonstrated that this nanoplatform can be potentially used for thermochemotherapy. We will be able to achieve the following goals: (1) Specifically deliver the SN38 prodrug and magnetic nanoparticles to the cancer site as the payload of tumor-homing double-stable RAW264.7 cells; (2) Release of chemotherapeutic SN38 at the cancer site by means of the self containing Tet-On Advanced system; (3) Provide localized magnetic hyperthermia to enhance the cancer treatment, both by killing cancer cells through magnetic heating and by activating the immune system. PMID- 23016150 TI - Repulsive bimodal atomic force microscopy on polymers. AB - Bimodal atomic force microscopy can provide high-resolution images of polymers. In the bimodal operation mode, two eigenmodes of the cantilever are driven simultaneously. When examining polymers, an effective mechanical contact is often required between the tip and the sample to obtain compositional contrast, so particular emphasis was placed on the repulsive regime of dynamic force microscopy. We thus investigated bimodal imaging on a polystyrene-block polybutadiene diblock copolymer surface and on polystyrene. The attractive operation regime was only stable when the amplitude of the second eigenmode was kept small compared to the amplitude of the fundamental mode. To clarify the influence of the higher eigenmode oscillation on the image quality, the amplitude ratio of both modes was systematically varied. Fourier analysis of the time series recorded during imaging showed frequency mixing. However, these spurious signals were at least two orders of magnitude smaller than the first two fundamental eigenmodes. Thus, repulsive bimodal imaging of polymer surfaces yields a good signal quality for amplitude ratios smaller than A(01)/A(02) = 10:1 without affecting the topography feedback. PMID- 23016151 TI - Real time measurement of myocardial oxygen dynamics during cardiac ischemia reperfusion of rats. AB - Because oxygen plays a critical role in the pathophysiology of myocardial injury during subsequent reperfusion, as well as ischemia, the accurate measurement of myocardial oxygen tension is crucial for the assessment of myocardial viability by ischemia-reperfusion (IR) injury. Therefore, we utilized a sol-gel derived electrochemical oxygen microsensor to monitor changes in oxygen tension during myocardial ischemia-reperfusion. We also analyzed differences in oxygen tension recovery in post-ischemic myocardium depending on ischemic time to investigate the correlation between recovery parameters for oxygen tension and the severity of IR injury. An oxygen sensor was built using a xerogel-modified platinum microsensor and a coiled Ag/AgCl reference electrode. Rat hearts were randomly divided into 5 groups: control (0 min ischemia), I-10 (10 min ischemia), I-20 (20 min ischemia), I-30 (30 min ischemia), and I-40 (40 min ischemia) groups (n = 3 per group, respectively). After the induction of ischemia, reperfusion was performed for 60 min. As soon as the ischemia was initiated, oxygen tension rapidly declined to near zero levels. When reperfusion was initiated, the changes in oxygen tension depended on ischemic time. The normalized peak level of oxygen tension during the reperfusion episode was 188 +/- 27 in group I-10, 120 +/- 24 in group I-20, 12.5 +/- 10.6 in group I-30, and 1.24 +/- 1.09 in group I-40 (p < 0.001, n = 3, respectively). After 60 min of reperfusion, the normalized restoration level was 129 +/- 30 in group I-10, 88 +/- 4 in group I-20, 3.40 +/- 4.82 in group I-30, and 0.99 +/- 0.94 in group I-40 (p < 0.001, n = 3, respectively). The maximum and restoration values of oxygen tension in groups I 30 and I-40 after reperfusion were lower than pre-ischemic values. In particular, oxygen tension in the I-40 group was not recovered at all. These results were also demonstrated by TTC staining. We suggest that these recovery parameters could be utilized as an index of tissue injury and severity of ischemia. Therefore, quantitative measurements of oxygen tension dynamics in the myocardium would be helpful for evaluation of the cardioprotective effects of therapeutic treatments such as drug administration. PMID- 23016152 TI - Colorimetric determination of resorcinol based on localized surface plasmon resonance of silver nanoparticles. AB - In this paper, we have developed a simple colorimetric method for detection of resorcinol (RE); the method is based on the reaction of RE with silver ions (oxidizing agent) in the presence of starch as a stabilizer and formation of silver nanoparticles (AgNPs). At nanometer dimensions the electron cloud can oscillate on the particle surfaces when dispersed in liquid media so these nanoparticles exhibit a strong UV-Vis extinction band. A UV-Vis spectrophotometer is used to monitor the changes of the localized surface plasmon resonance (LSPR) of AgNPs at a wavelength of 430 nm. There is a linear relationship between absorbance intensity of AgNPs and the concentration of RE over the range of 4 * 10(-6) to 1.1 * 10(-5) mol L(-1) at 430 nm. The detection limit was 1.2 * 10(-6) mol L(-1). The proposed method has been successfully applied for the determination of RE in anti-acne solution and spiked shampoo samples. PMID- 23016153 TI - Novel core etching technique of gold nanoparticles for colorimetric dopamine detection. AB - This study develops a novel and high performance colorimetric probe for dopamine (DA) detection. Aqueous-phase gold nanoparticles (AuNPs) extracted with 4 (dimethylamino)pyridine (DMAP) from toluene solvent are used as the reaction probes. The original AuNPs of diameter around 13 nm separate into 2-5 nm sizes when dopamine (DA) is added, resulting in the color change of the AuNP solution from red to blackish green. Transmission electron microscopy (TEM) observations and dynamic light scattering (DLS) tests show that the AuNPs break into their smaller sizes right after addition of DA. The results confirm that the DMAP capped AuNPs are etched by the DA molecules due to the strong affinity between DA and AuNPs, thus causing a blue shift in the absorption spectrum. The concentration of DA is quantitatively monitored by using a UV-Vis spectrometer with a limit of detection (LOD) as low as 5 nM. In addition, the results also show that the methods developed appear to have no significant problems in detecting DA in the sample even with the presence of (10 mM) common interferents such as ascorbic acid (AA), homovanillic acid (HVA), catechol (CA) and glutathione (GSH). The developed AuNP etching protocol for dopamine detection provides a novel and versatile approach for rapid biosensing applications. PMID- 23016155 TI - Retraction notice to "Redox regulation of resveratrol-mediated switching of death signal into survival signal" [FRB 44 (2009) 82-90]. PMID- 23016154 TI - Retraction notice to "Expression of the longevity proteins by both red and white wines and their cardioprotective components, resveratrol, tyrosol, and hydroxytyrosol" FRB 46 (2009) 573-578. PMID- 23016156 TI - Obesity, reproductive health, and bariatric surgery in adolescents and young adults. PMID- 23016157 TI - Exploring knowledge and healthseeking behaviour related to sexually transmitted infections among the tribal population of Madhya Pradesh, central India. AB - This community-based cross-sectional study was carried out in the tribal population of randomly selected villages of Jabalpur district, Madhya Pradesh, central India. A total of 200 married men and women aged 15-49 years were interviewed to explore their knowledge, experience and health-seeking behaviour related to sexually transmitted infections (STIs). Though 91% of respondents were aware of STIs, the sexual route was mentioned by only 19%as the route of transmission. Around 18% reported a need for social isolation from persons with STIs. Though 88% of the respondents felt modern medicine was the best remedy for STIs, only a few of them used medical treatment while suffering from an STI. Twenty-seven per cent of respondents resorted to traditional healers, and 30% utilized home remedies for STI treatment. The study highlights a need for generating STI awareness amongst the tribal population of the region through a needs-based behaviour change communication (BCC)strategy. PMID- 23016158 TI - Female genital cutting and other intra-vaginal practices: implications for TwoDay Method use. AB - This report examines the implications of female genital cutting and other intra vaginal practices for offering the TwoDay Method(r) of family planning.This fertility awareness-based method relies on the identification of cervicovaginal secretions to identify the fertile window. Female genital cutting and traditional vaginal practices, such as the use of desiccants, may affect the presence or absence of secretions and therefore the woman's perception of her fertility. These issues and their implications for service delivery of the method are discussed. PMID- 23016159 TI - Spotlight on cardioprotection against ischemia-reperfusion injury. PMID- 23016169 TI - Regular exercise helps maintain heart's elasticity as you age. Research also shows that consistent exercise reduces your risk of coronary artery disease. PMID- 23016170 TI - Know how to respond to overnight strokes. Study shows one in seven strokes occur during sleep. PMID- 23016171 TI - Research raises questions about calcium supplements. Know your risks for osteoporosis before you start taking high doses of calcium. PMID- 23016172 TI - Breast calcifications and breast radiation linked to heart disease. Research confirms that calcium deposits in breast arteries, which can be detected in a mammogram, raise your risk of coronary artery disease. PMID- 23016173 TI - Know what to eat after heart surgery. Even if you have no appetite, your body is hungry for protein. PMID- 23016174 TI - Sophisticated device for heart failure works best in women. Research indicates cardiac synchronization therapy with defibrillation may actually reverse heart muscle damage caused by the condition. PMID- 23016175 TI - Your mother's history of stroke increases your heart attack risk. It's not too late to take preventive measures and control other risk factors. PMID- 23016176 TI - I have a 20-plus year history of arrhythmias, which I manage without medications. My cardiologist said I shouldn't worry, because my mother also had this problem, and she is now 91. Recently, I have been experiencing "pushes" in the center of my chest lasting only a few seconds. I also get breathless when climbing stairs or walking briskly. I am 63, exercise regularly and eat a healthy diet. Should I be tested for coronary artery disease, and if so, what kind of test should I have? PMID- 23016177 TI - Ever since my mother (age 90) had a heart attack and stents, she has had no appetite. She is taking about eight medications. Do you think one of these medications is responsible? She is losing a lot of weight and getting very frail. PMID- 23016178 TI - Three years ago I received a drug-coated stent and was put on aspirin and Plavix. My cardiologist recently retired, and my new cardiologist told me to stop taking Plavix. It scares me to death. I read the story you released in February about the dangers of the first 90 days off Plavix extending out for a year and being unknown after 18 months. Is there something I should do or take to prevent Plavix withdrawal problems? PMID- 23016179 TI - I am a 37-year-old woman and was diagnosed with coronary artery spasms two years ago. I am taking Plavix, verapamil and Imdur for my condition. What other things can I do to help my heart? PMID- 23016180 TI - How do you manage female patients who have migraine with aura? I understand there is a connection with heart disease. I had a whopper of a headache before my heart attack? PMID- 23016181 TI - Should I take plant sterol supplements along with cholesterol-lowering medications for high cholesterol? PMID- 23016182 TI - I have chronic venous insufficiency in my legs. Could impairment in blood returning to my heart cause my blood pressure to rise or my heart to enlarge? PMID- 23016183 TI - Improve the quality and duration of sleep to lower heart risk. Research indicates a substantial increase in cardiovascular risk if you sleep less than seven hours and have frequently interrupted sleep. PMID- 23016184 TI - Exercise benefits people with fatty liver disease and pre-diabetes. Cleveland Clinic study finds that treadmill walking slows the progression of non-alcoholic fatty liver disease and improves your fat-burning ability. PMID- 23016185 TI - Cardiac rehabilitation remains underprescribed treatment plan. With its life saving benefits verified, the question is "why"? PMID- 23016186 TI - I"m 62 and have mitral valve prolapse that is considered severe. I have 40 percent regurgitation and it's worsening, causing ever increasing shortness of breath. My doctor wants to replace the valve soon, but I don't want open heart surgery. Is transcatheter mitral valve replacement approved in the U.S., as it is overseas? If not, should I consider going abroad for the surgery? PMID- 23016187 TI - I just read that the time of day or night you take certain blood pressure medications can have a lot to do with how effective they are. In particular, I noticed that ACE inhibitors, which I take, are much more effective if taken before bed. My doctor never told me that. Is this true and what difference does the time of day make? PMID- 23016188 TI - Removal of 30-day residency requirement for per diem payments. Direct final rule. AB - The Department of Veterans Affairs (VA) is taking direct final action to amend its regulations concerning per diem payments to State homes for the provision of nursing home care to veterans. Specifically, this rule removes the requirement that a veteran must have resided in a State home for 30 consecutive days before VA will pay per diem for that veteran when there is no overnight stay. The intended effect of this direct final rule is to permit per diem payments to State homes for veterans who do not stay overnight, regardless of how long the veterans have resided at the State homes, so that the State homes will hold the veterans' beds until the veterans return. PMID- 23016190 TI - [Zeitschrift fur Psychosomatische Medizin und Psychotherapie goes international]. PMID- 23016191 TI - Removal notice to: A challenging injury interpretation: could this be a stab wound? [J Forensic Legal Med (2012) 179-181]. PMID- 23016192 TI - Multisociety sedation curriculum for gastrointestinal endoscopy. PMID- 23016193 TI - [Q & A. Enteritis causing diarrhea and mucous and blood stool]. PMID- 23016194 TI - Think globally, act locally. PMID- 23016195 TI - International patients in a Turkish hospital: a quantitative study on cross border health care at the intersection of Eastern Europe, Asia and the Middle East. AB - This is the first attempt, to our knowledge, that aims to empirically quantify and characterize international patient flows to Turkey. A cross-sectional retrospective study was performed on consecutive patients seen at the International Services Department of a 209-bed private hospital in urban Turkey. Over six months, international patients represented 4 percent and 6 percent of all consultations and surgical procedures, respectively. Six hundred and fifty unique international patients received health care and represented 44 different countries. Among these 650 unique encounters, most patients originated from Bulgaria (37%), Romania (35%), Azerbaijan (6%), Iraq (3%) and Georgia (3%). International patients commonly required oncological (54%), surgical (13%) and neurological (7%) services. Although quantitative data on medical travel to Turkey is limited, significant patient flows exist from neighboring countries to Turkey. PMID- 23016196 TI - World Trade Organization activity for health services. AB - Since the establishment of a multilateral trading system and the increasing mobility of professionals and consumers of health services, it seems strongly necessary that the World Trade Organization (WTO) undertakes negotiations within the General Agreement on Trade in Services (GATS), and that WTO's members attempt to reach commitments for health-related trade in services. How important is the GATS for health policy and how does the GATS refer to health services? What are the current negotiations and member's commitments? PMID- 23016197 TI - Integration of hospitals: is it time for similar changes in Georgia? AB - Health care is the most difficult and dynamic industry where the expenditure has grown almost four times during the past 20 years. Constantly, there are demands for expenditure cuts, for effectiveness, for quality improvement and evaluation of economic risks. All the precise and sophisticated strategic decisions taken by hospitals are to guarantee maximum profits from scarce resources and good service from an organization in unstable environmental conditions. From the different development alternatives, hospitals might prefer a horizontal and vertical integration. The integration of stationary hospitals into a network is convenient from a financial and economic point of view. Benefits are also expected in other areas, such as economies of scale, the improvement of human resources organization as well as the management and service offering. Consequently, expenses will be reduced and incomes will grow. However, there are some important questions about integration to be discussed in this research, including: Is Georgia's health care sector ready for reform, are the qualitative and quantitative improvements achievable, and what is the main motivation? PMID- 23016198 TI - Information technology orientation for young hospital administrators. AB - Information technology has evolved over the years and taken its place in every sector, including health care. Every health care professional uses a computer almost every day. Information technology is expected to provide the staff with reliable information for decision making, reducing medical errors and processing time and improving communication. As the health care market grows increasingly competitive and complex, hospitals are relying more and more on information technology as a primary tool to help them compete. Every postgraduate should take a basic course on computers and IT applications. Many universities and colleges offer a masters program in health administration, and with enormous numbers of new post graduates, well grounded in IT, are offering their services to hospitals and allied health care divisions. Their experiences are reflected in the various job codes, which illustrate the need for planning, careful investment, and educational training to put information technology to work in today's sophisticated advanced health care setting. Information technology cannot reach its full potential without a properly trained staff working together as a team. PMID- 23016199 TI - Using a contribution margin system to manage medical centers in Berlin. AB - After German reunification, the Charite-Universitatsmedizin Berlin was restructured from three existing Berlin university hospitals. More than a too departments were reorganized into 17 centers. Professional management was necessary to improve the overall balance. A contribution margin-orientated management system was introduced in 2008 by using German benchmarks. All sectors help to improve the results continuously. In 2011, and for the first time, the balance showed a profit of 8.2 million Euros. PMID- 23016200 TI - Stress, health and satisfaction of Australian and German doctors--a comparative study. AB - BACKGROUND: Currently no study exists focusing on international differences in perception of stress, working conditions and satisfaction of hospital staff. Therefore the present study aimed to examine and compare the work and privacy situation of Australian and German physicians. METHODS: The present study was designed as a cross-sectional comparison using questionnaire data. The population consisted of representative samples of 310 German and 256 Australian hospital doctors who received mailed questionnaires. The questionnaires contained items on demography, perception of stress, working conditions, job satisfaction and Life satisfaction. RESULTS: According to the comparison, German physicians perceived higher values of work stress. They work significantly longer hours than Australian doctors. In general, work intensity and demands are highly rated in both countries. In terms of job and life satisfaction, Australian doctors responded more positively than German doctors. CONCLUSION: This is the first comparative study illustrating a subjective evaluation of physicians' perception of stress, their work and privacy situation in two different countries. Based on these results health policy decisions can be developed. PMID- 23016201 TI - Improved use of allied health professionals in the health care system: the case of the advanced practice physiotherapist in orthopedic care. AB - This article provides an overview of work done in Canada involving the use of physiotherapists in models of collaborative care to enhance orthopedic care and practice. Valuable lessons learned and an important model of collaborative care are summarized. The research around these models of care has also contributed to important scope of practice changes for the profession of physiotherapy. PMID- 23016202 TI - A five-year prevalence study of burn injury in a Nigerian teaching hospital. AB - Burn injury has been observed as a worldwide problem. The knowledge of the epidemiology is important for planning of management and preventive programmes. This is a retrospective review of burn patients who presented with acute burn injuries between January 2006 and December 2010. Admission registers and patients' folders were the sources of information. The information obtained includes: age, gender, number of patients who died, sources of burn injury and outcome of management. A total of 407 patients with acute burn injuries were studied. Males numbered 274 (67.3%), females 133 (32.7%). A majority, 98 (24%) of burn injuries occurred in the year 2010 and mortality in the series increased progressively except for 2006 which is explainable by the strike due to industrial disputes between and among various health disciplines over the period. Mortality was highest in 2010 (30%). The prevalence was higher among males than females throughout the 5-year period. The incidence, prevalence and mortality of burn injury have remained high in this environment. We suggest a well-targeted prevention campaign program to reduce this high incidence and high mortality in burn injury in Nigeria. PMID- 23016203 TI - [The rights of patients, the rights of children]. PMID- 23016204 TI - [Breast feeding and return to work, a societal challenge]. PMID- 23016205 TI - [Improving vaccination coverage in France]. PMID- 23016207 TI - [Feeding newborns, on-demand or scheduled?]. PMID- 23016208 TI - [The well-being of adolescents]. PMID- 23016206 TI - [Living better at school is important to us all!]. PMID- 23016209 TI - [Breast feeding support of the hospitalized newborn. A public health approach]. PMID- 23016210 TI - [Issues surrounding the breastfeeding of hospitalized newborns]. AB - The nutritional and physiological qualities of breast milk make it the best food for newborns, favouring their wellbeing and growth. The implementation of a programme encouraging the breastfeeding of hospitalised newborns in care departments requires specific methods of organisation, as well as constant and adapted support from health professionals. PMID- 23016211 TI - [Management of oral feeding problems in neonatology]. PMID- 23016212 TI - [The direct donation of human milk in neonatology]. AB - The superiority of human milk over its substitutes is no longer questioned, especially for the feeding of premature babies or newborns hospitalised in neonatology. Milk banks organise the collection, conservation, treatement and distribution of human milk. The objective is however to encourage the direct donation of raw milk, avoiding the need for freezing and pasteurisation, in order to preserve its properties as best as possible. PMID- 23016213 TI - [A taskforce to support breastfeeding in neonatal intensive care units]. AB - In neonatal intensive care, the choice of breastfeeding and its success are dependent notably on the information and support given to mothers by the team. In order to provide high quality support, a multi-professional task force has looked into the actions which need to be carried out with mothers, babies and professionals. PMID- 23016214 TI - [The role of hospital care partners in supporting breastfeeding]. AB - Mothers who breastfeed their babies hospitalised in neonatology or neonatal intensive care units need to be supported to enable them to fulfill the mission which is so important to them. The support of a multi-disciplinary team comprising in particular a dietician, a speech therapist and a lactation consultant is an advantage not only for the mothers but also for the nursing staff. PMID- 23016215 TI - [Breastfeeding support, an account of two mothers]. PMID- 23016216 TI - [The promotion of breastfeeding in Gabon]. AB - Breastfeeding is beneficial for all newborns, but even more so in Gabon where the neonatal mortality rate is still high. The neonatal intensive care and neonatology department of Libreville hospital has set up a support scheme for mothers in order to promote the breastfeeding of hospitalised newborns. PMID- 23016217 TI - [Breast feeding support of the hospitalized newborn. Bibliography]. PMID- 23016218 TI - [Pain in children, using the right words]. AB - Verbal communication is an essential element in the prevention and treatment of pain in children and adolescents. It is essential to take into account existing knowledge and recommendations relating to verbal communication in the caregiver's relationship with a child in pain. Developing the nurse's ability to adapt to diverse situations and carrying out research concerning the effects of speech on the child are priorities. PMID- 23016219 TI - [Allowing parents to enter the recovery room]. AB - At Necker-Enfants malades hospital, the presence of the parents alongside the child during the immediate postoperative period has been allowed and encouraged for a number of years. In order to standardise the practices in terms of allowing parents to enter post-anaesthetic recovery rooms, nurses have drawn up a procedure to follow. In parallel, a study and a satisfaction survey have been carried out in order to measure the benefits of this approach for parents and for the child undergoing the operation. PMID- 23016220 TI - [The psychological processes in play in the complete remission of pediatric cancer]. AB - The experience of cancer represents an upsetting ordeal, in particular for adolescents. After treatment, the patient has to undergo an agonising transition period until the announcement of a recovery: complete remission.The disappearance of the signs of the disease does not exclude the risk of the cancer returning, which makes it difficult for the patient to resume a normal life. PMID- 23016221 TI - [Curtailment of religious freedom]. PMID- 23016222 TI - [Treatment of asphyxia with hypothermia]. PMID- 23016223 TI - [Bonding. A foundation for life]. PMID- 23016224 TI - [Arranging visiting hours on the postnatal floor]. PMID- 23016225 TI - [Circumcision of children in dispute]. PMID- 23016226 TI - ["Intensive care" section: which topics are essential for you?]. PMID- 23016228 TI - [Herpes zoster ("shingles")]. PMID- 23016229 TI - [Exercise despite rheumatism]. PMID- 23016230 TI - [The long way to an emotionally closed off girl]. PMID- 23016231 TI - [Constantly staying indoors and reading increases risk of myopia]. PMID- 23016232 TI - [Fewer tumors in children since folic acid supplementation: value of the B vitamin is possibly greater than expected]. PMID- 23016233 TI - [Time to take responsibility]. PMID- 23016234 TI - [Healthy lifestyle protects the cardiovascular system. We know it!]. PMID- 23016235 TI - [Pay for disease or invest in health?]. PMID- 23016236 TI - [Mediterranean diet and statins against cardiovascular disease]. PMID- 23016237 TI - [Hypertension is a clinical problem ... even though we have tools to solve it]. PMID- 23016238 TI - [Glucose control is a strategy for cardiovascular prevention]. PMID- 23016239 TI - [Vasterbotten focus on large-scale cardiovascular prevention]. PMID- 23016240 TI - [Organizational new thinking for children with cognitive disabilities]. PMID- 23016241 TI - [Bed rest during risk for premature birth may do more harm than good]. PMID- 23016242 TI - [Response to criticism on guidelines for prehospital care in head injury: Guidelines exist--and they are followed]. PMID- 23016243 TI - [New quality system for internship education in the United States--an inspiration also for us?]. PMID- 23016244 TI - [Legal standards built on extrajudicial rules. How science and proven experience became the beacon of medicine]. PMID- 23016245 TI - The role of case management in an era of healthcare reform--Part 3. AB - It is CMS's contention that this efficiency measure will positively impact on both cost and length of stay. It will do this by accomplishing all the goals listed above. Length of stay should be decreased as patients are treated more rapidly. Faster treatment means improved quality of care and less opportunity for adverse events to occur such as falls, medication errors or infections. In addition, if pre-admission and post-discharge costs and interventions are taken into consideration as part of a "package of services," compartmentalization of services is less likely to occur and patients will be less likely to be exposed to unnecessary tests, treatments and procedures. This shift in reimbursement, like other shifts before it, will hopefully result in a system that considers patient events regardless of where they happen across the health care continuum. PMID- 23016246 TI - An example to us all. PMID- 23016247 TI - Apixaban. After hip or knee replacement: LMWH remains the standard treatment. AB - The standard anticoagulant for prevention of venous thromboembolism in patients undergoing hip or knee replacement surgery is a low-molecular-weight heparin (LMWH) such as subcutaneous enoxaparin. Apixaban is the second oral factor Xa inhibitor, after rivaroxaban, to be approved in the European Union for use in these two situations. Three double-blind randomised trials versus enoxaparin in a total of nearly 12 000 patients failed to show that apixaban was more effective in terms of relevant endpoints: mortality, and the incidence of pulmonary embolism and symptomatic deep vein thrombosis. The incidence of bleeding did not differ between the apixaban and enoxaparin groups under the conditions of these trials. Apixaban is mainly metabolised by cytochrome P450 isoenzymes CYP 3A4 and 3A5 and also binds to P-glycoprotein, resulting in a high potential for pharmacokinetic interactions. Renal failure is a risk factor for overdose. Pharmacodynamic interactions are also likely. There is no known antidote for apixaban. In practice, LMWH remains the standard treatment. PMID- 23016248 TI - Apixaban in other situations? PMID- 23016249 TI - Denosumab and bone metastases. No better than a bisphosphonate. AB - The standard treatment used to prevent clinical repercussions of bone metastases from solid tumours consists of an intravenous bisphosphonate such as pamidronic acid. Denosumab,a monoclonal antibody injected subcutaneously, has been licensed in the European Union for use in this setting. Three double-blind randomised trials including a total of about 6000 patients showed no tangible difference between denosumab and zoledronic acid in terms of mortality, disease progression, quality of life, or pain. The authors resorted to a composite endpoint in order to demonstrate a statistically significant difference in favour of denosumab. Overall, toxicity was similar with denosumab and zoledronic acid in the 3 trials. Adverse effects that were more frequent with denosumab than with zoledronic acid included jaw osteonecrosis (1.8% versus 1.3%) and hypocalcaemia (9.3% versus 4.7%). However, renal failure was less frequent (2.6% versus 3.7%). Denosumab is administered subcutaneously and zoledronic acid by intravenous infusion. It is not known whether local and systemic reactions to administration are different. In practice, there is no tangible reason to choose denosumab rather than a bisphosphonate. PMID- 23016250 TI - Ranibizumab and retinal vein occlusion. Too many outstanding questions. AB - A loss of visual acuity due to macular oedema is a complication of retinal vein occlusion. Vision improves spontaneously within 3 to 6 months in about 50% of cases. There are no drugs with proven benefits in this setting. In addition to its indications in the treatment of age-related macular degeneration (AMD) and diabetic macular oedema, ranibizumab, an anti-VEGF antibody, has now been approved in the European Union for the treatment of visual impairment associated with macular oedema due to retinal vein occlusion. In this setting, clinical evaluation of ranibizumab (Lucentis, Novartis) is based on two double-blind randomised trials comparing ranibizumab (0.3 mg or 0.5 mg) versus placebo in a total of 795 patients. Compared with placebo, about 30% more patients receiving ranibizumab (0.3 mg or 0.5 mg) experienced a tangible improvement in their visual acuity (gain of at least 15 letters on the ETDRS scale) after 6 months of treatment. Efficacy was similar in patients with central retinal vein occlusion and those with occlusion of a peripheral branch. All patients received ranibizumab after the initial 6-month period; the lack of a placebo group means that the long-term effects of ranibizumab cannot be distinguished from spontaneous improvement. There were too few cases of ischaemic occlusion to assess the efficacy of ranibizumab in this subgroup of patients, who are most in need of treatment. The adverse effects of ranibizumab were the same as those observed in other clinical situations. They mainly consisted of ocular adverse reactions, such as haemorrhage, pain, and elevated intraocular pressure. Uncertainties persist as to the long-term risk of recurrent occlusion or progression to retinal ischaemia. The frequency of systemic adverse events was similar in the ranibizumab and placebo groups. The incidence of heart failure and transient ischaemic attacks was higher during the second year of ranibizumab therapy than during the first year of treatment. The packaging (bottles) available in early 2012 creates a risk of handling errors, and improvements are needed to prevent these errors. Monthly ranibizumab administration is expensive. In practice, the decision to grant marketing authorisation for ranibizumab in macular oedema due to retinal vein occlusion was premature. Ranibizumab is one option that should be assessed in clinical trials. Patients should be informed of the potential adverse effects and uncertainties and be reminded that this condition improves spontaneously in about 50% of cases. PMID- 23016251 TI - HPV 6, 11, 16, 18 vaccine in men. Inadequate assessment. AB - In a trial including 4065 men aged 16 to 26 years, HPV 6, 11, 16, 18 vaccination reduced the incidence of anogenital warts, but the preventive effect on cancer remains to be demonstrated. PMID- 23016252 TI - Phentermine: an appetite-suppressant amphetamine classified as a narcotic in France. Is a combination with topiramate on the horizon? AB - In France, extra restrictions have been placed on this appetite-suppressant drug. Phentermine is widely used in many countries despite its multiple adverse effects and lack of proven efficacy in preventing complications of obesity. PMID- 23016253 TI - Proton pump inhibitors: bacterial pneumonia. AB - After two decades of widespread use, proton pump inhibitors are considered to have a very well-documented and acceptable adverse effect profile in the short term. Yet adverse effects continue to emerge. In particular, epidemiological studies conducted over the past 10-12 years showed an increased incidence of fractures. New data now point to an increased risk of bacterial pneumonia. A Korean meta-analysis published in 2011 showed a statistically significant increase in the risk of bacterial pneumonia in patients taking proton pump inhibitors, with an odds ratio of 1.27 (95% confidence interval (95% CI): 1.11 to 1.46). The increase in community-acquired pneumonia was also statistically significant, with an odds ratio of 1.34 (95% CI: 1.14 to 1.57). This is consistent with the results of a meta-analysis published in 2010, which gave an odds ratio of 1.36 (95% CI: 1.12 to 1.65). The increase in the frequency of bacterial pneumonia was highest during the first week of treatment, with an odds ratio of 3.95 (95% CI: 2.86 to 5.45). Subsequent studies have provided conflicting results. Possible mechanisms include bacterial passage into the lungs after colonisation of the upper gastrointestinal tract resulting from the reduction in gastric acidity; bacterial overgrowth in the lungs due to a change in the pH of respiratory secretions; and impaired neutrophil phagocytic function. The available data suggest that proton pump inhibitors play a role in the increased frequency of bacterial pneumonia in treated patients. Similar data implicating H2 receptor antagonists and the proposed mechanism (acid suppression) imply that there are no alternative acid-suppressive medications. This risk of pneumonia is yet another reason not to trivialise the use of proton pump inhibitors. These drugs should only be used when the likely benefits clearly outweigh the potential harms. PMID- 23016254 TI - Intestinal alpha-glucosidase inhibitors: abdominal gas cysts. AB - Detailed imaging studies of gas cysts in the intestinal mucosa (pneumatosis cystoides intestinalis) have been reported in around 20 patients taking acarbose, miglitolor voglibose, i.e. intestinal alpha-glucosidase inhibitors used as hypoglycaemic agents. Almost all the patients had nonspecific abdominal symptoms such as abdominal pain, abdominal distension, rectal bleeding or loss of appetite. They underwent multiple diagnostic tests before a role of the drug was raised. The disorders resolved completely when the drugs were withdrawn. In practice, as acarbose and miglitol have no proven impact on morbidity or mortality, and as they have multiple adverse effects, including gas cysts, they should not be used to treat diabetic patients. PMID- 23016255 TI - Doripenem: excess mortality. PMID- 23016256 TI - Ursodeoxycholic acid: increased mortality. PMID- 23016257 TI - Cosmetic silicone injections: respiratory failure. PMID- 23016258 TI - Bortezomib: 3 deaths following intrathecal injection. PMID- 23016259 TI - PSA-based screening for prostate cancer. Too many adverse effects. AB - Has the evaluation of PSA screening for prostate cancer progressed since 2009? We examined the recent literature on the value of this test, using the standard Prescrire methodology. Five randomised trials have yielded conflicting results. One trial was too flawed to be conclusive. In two trials, the Erspc and Gothenburg studies, PSA-based screening appeared to prevent about 1 death from prostate cancer per 300 to 1400 men screened. However, two other trials, including the PLCO study that enrolled 77 000 men, showed no statistically significant benefit from screening. Two meta-analyses showed that PSA screening did not reduce mortality from prostate cancer among 340 000 and 390 000 men followed for 9 to 15 years. About 70% of men with PSA levels above 4 ng/l do not have prostate cancer. These false-positive results unnecessarily expose patients to the adverse effects of prostate biopsy, which include haematuria, pain, infections and septicaemia. Between 30% and 80% of cancers diagnosed by screening would never have compromised patients' health if they had remained undetected. This over-diagnosis unnecessarily exposes patients to the adverse effects of treatment, which include urinary incontinence, erectile dysfunction, and psychological effects. In early 2012, the clinical utility of PSA-based screening for prostate cancer has not been demonstrated. Patients should be informed of the natural history of localised prostate cancer and the adverse effects of screening. PMID- 23016260 TI - Yaws, a non-venereal treponemal infection. Still endemic in some parts of the world. AB - Yaws is an infection that mainly affects the poorest populations living in humid tropical areas. We reviewed the literature on yaws, the most common non-venereal treponemal infection, using the standard Prescrire methodology. Yaws is often transmitted directly from person to person. It starts as a single lesion, later leading to multiple contagious lesions. Yaws mainly affects children. The infection remains asymptomatic for several years. In about 10% of cases, late reactivation leads to bone lesions, deformities and disability. Diagnosis of yaws is based on the clinical and epidemiological context. Serological tests cannot distinguish between yaws and syphilis or other non-venereal treponematoses. Curative treatment consists of a single injection of benzathine benzylpenicillin. The results of a randomised trial suggest that a single oral dose of azithromycin is as effective as penicillin. In India, yaws was successfully eradicated through a programme based on providing information to the population at risk, screening and treatment. PMID- 23016261 TI - Management of serious adverse drug reactions: proposals from a victims' organisation. AB - Amalyste is a French patient-advocacy group for victims of two very serious adverse drug reactions: Lyell and Stevens-Johnson syndromes. The aims of this organisation are to represent the interests of patients who have experienced these syndromes; to better inform the public about these syndromes; to provide analyses of drug-related risks; and to demand collective compensation for victims of serious adverse drug reactions. The following text is our translation of an Amalyste position statement on drug-related risks. It provides valuable food for thought, both for healthcare professionals and for drug regulatory agencies, and has the potential to improve practice (a). PMID- 23016263 TI - The access series: dental care in America. PMID- 23016262 TI - Medical devices: marketing authorisations are needed. PMID- 23016264 TI - Causes of abutment screw loosening and crestal bone resorption. Year loading: a case report. PMID- 23016265 TI - Antithrombin activity, platelet count, hemoglobin concentration and hematocrit value determined immediately before vaginal delivery among healthy women. AB - AIMS: To determine the normal reference values for antithrombin (AT) activity, platelet count (Plt), hemoglobin concentration (Hb), and hematocrit value (Ht) immediately before vaginal delivery among healthy pregnant women with singleton pregnancies and to determine association of these blood parameters with fetal growth. METHODS: A complete blood count was performed and the AT activity was examined in 300 consecutive women admitted to hospital at > or = gestational week 36 for labor pains and/or the rupture of fetal membranes. All the women were normotensive and had singleton pregnancies, and none of the women had proteinuria, a weekly weight gain > or = 0.5 kg, or other specific complications upon admission. All the women attempted a vaginal delivery. RESULTS: The medians (5th-95th percentile) were 90% (71-110%) for AT activity, 234x10(9)/L (150 337x10(9)/L) for Plt, 11.0 g/dL (9.5-12.8 g/dL) for Hb, and 34.0% (30.4-38.6%) for Ht. Women with an Hb value of > or = the median (11.0 g/dL) gave birth to significantly smaller infants than their counterparts. CONCLUSIONS: A considerable number of healthy women exhibit a reduced AT activity and/or platelet count immediately before delivery. Hemoconcentration evidenced by a raised Hb value adversely effects on infant growth. Our data may be helpful when considering the normal ranges of these blood parameters for healthy parturient women. PMID- 23016266 TI - [A novel adherent culture method of glioblastoma cells expressing CD133 using collagen-1-coated plates]. AB - BACKGROUND AND AIMS: Glioblastoma is one of the most malignant brain tumors, causing death within two years despite maximal tumor resection and concurrent radio-chemotherapy. Tumor stem cells are thought to be closely related to tumor progression and recurrence and are attractive therapeutic targets. It is common to culture cell lines in serum-free medium with growth factors to stimulate spheres of enriched tumor stem cells. To avoid spontaneous differentiation and cell death in the sphere environment, Pollard et al. formulated an adherent culture method using laminin-coated plates. We here evaluated collagen-1-coated plates, which are superior to laminin-coated plates in handling and cost, as an alternative adherent culture method of CD133 expressing glioblastoma cells. MATERIALS AND METHODS: We cultured the human glioblastoma cell line, U87MG, under serum contained medium (SCM) or serum free medium with EGF, FGF2, LIF, B27 and N2 supplements (SFM) in non-coated, laminin or collagen-1-coated plates. The growth morphology in various cultures was evaluated, and the number of living cells in each plate on day 5 after cell seeding was calculated. The RNA expression level of CD133 as a stem cell marker in each plate was examined. Semi-quantitative measurement of CD133 positive cells by immunocytochemistry was performed. RESULTS: In collagen-1-coated plates with SFM, cell lines were cultured in an adherent monolayer. Cell proliferation was statistically encouraged in collagen-1 coated plates. Both laminin-coated plates and collagen-1-coated plates with SFM enhanced the RNA expression of CD133 compared to non-coated plates with SCM. Immunocytochemistry showed a statistically significant increase of CD133 positive cells in collagen-1-coated plates with SFM. CONCLUSION: Collagen-1-coated plates with SFM was used for cell morphology and cell proliferation of CD133 expression in the U87MG malignant glioma cell line. PMID- 23016267 TI - Raising future forensic pathologists (first report): results of a preliminary questionnaire survey. AB - The shortage of future forensic pathologists is a serious problem both in Japan and overseas. In Japan, however, factors such as government budget cuts and increasing the autopsy rates, make the condition even worse. In an attempt to improve this situation, we implemented a questionnaire survey to investigate the particular features necessary when selecting a career in forensic medicine. As a preliminary study, we sent the questionnaire along with an anonymous answer sheet to all forensic pathologists with a degree in medicine M.D., who were affiliated with universities in Hokkaido and the Tohoku district of Japan as of August 2011. Thirteen physicians in nine universities (response rate 77.8%) returned the answer sheet. Characteristics of participants are listed below: years of experience, board specialty and number of years as board certified specialists, percentage of work effort spent on autopsy practice, the time when they decided to work as a forensic pathologist, the time when to best recommend forensic pathologist as a career, and crucial factors in choosing the specialty of forensic medicine. As a result of this research, we've revealed the importance of undergraduate medical education or the effect on the role models. Furthermore, we've also extracted miscellaneous comments, such as standardization of minimum requirements. In our study, we' ve found some clues to increase future candidates in the field forensic medicine. However, we must collect further samples for our questionnaire survey to validate the study, and, as a future project, we must also address this problem at the congress of forensic medicine. PMID- 23016268 TI - Raising future forensic pathologists (second report): results of a preliminary interview survey. AB - Fostering the specialists of forensic pathology has become a worldwide problem. In Japan, factors such as government budget cuts, the introduction of initial postgraduate clinical training system, as well as national policy on increasing autopsy rates, may deter young graduates from entering this specialty. The aim of this study was to look for clues to promote the training of young forensic pathologists. We selected and interviewed five forensic pathologists, with each interview lasting approximately 60 minutes, and picked up common views among them. The interviews topic, based on a prior survey, was: "What do you believe forensic pathologists require to promote the training of their successors." We selected common views on the three themes listed below; 1) standardization of minimum requirements to be independent forensic pathologists, 2) balancing forensic pathologists' time among autopsy practice, research, and education, and 3) preparing positions for younger forensic pathologists. These opinions were the same as those of previous studies conducted overseas and must be discussed at academic conferences in the future, where both junior and senior forensic pathologists participate. PMID- 23016269 TI - [Statistical analysis of 32 patients with nasopharyngeal carcinoma]. AB - In order to assess the clinical outcome and prognostic factors of patients with nasopharyngeal carcinoma (NPC) who were initially treated in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine between 1997 and 2006, statistical analyses were performed based on the patient medical records. Cause-specific survival (CSS) and disease-free survival (DFS) in all cases (stage I to IV, n = 32) and advanced cases (stage III and IV, n = 22) were estimated using the Kaplan-Meier method. The independent prognostic values of the clinical and therapeutic factors were determined using multivariate Cox proportional hazards models. RESULTS: The 5-year CSS/DFS were 43.4%/34.8% in all cases and 34.5%/29.8% in advanced cases. Multivariate analysis revealed that, in all cases, the independent prognostic factors for CSS were age (> or = 61 vs. < or = 60, risk ratio (RR) = 5.717, p = 0.006), T-stage (3/4 vs. 1/2, RR = 6.957, p = 0.004), and the use of platinum agents (unused vs. used, RR = 3.911, p = 0.012), whereas those for DFS were T-stage (3/4 vs. 1/2, RR = 3.499, p = 0.019) and the use of platinum agents (unused vs. used, RR = 2.947, p = 0.028). In advanced cases, the use of platinum agents alone was significant for both CSS (RR = 4.503, p = 0.023) and DFS (RR = 4.218, p = 0.014). The patients who received neoadjuvant chemotherapy (NAC) showed better CSS and DFS than the patients who did not (p = 0.066 and p = 0.025, respectively) in a univariate analysis (Log rank test), although no significant difference was seen between these groups in the multivariate analysis. CONCLUSION: The advantage of the administration of platinum agents in the treatment of NPC was statistically corroborated even in our study with its small sample size. As agents combined with chemoradiotherapy, the efficacy of docetaxel alone did not seem comparable to that of platinum agents. The docetaxel-CDDP-5-FU regimen applied as NAC was suggested to be possibly beneficial for advanced cases of NPC. PMID- 23016270 TI - [Solitary hyoid bone metastasis from hepatocellular carcinoma treated with surgery]. AB - The incidence of bone metastasis in patients with hepatocellular carcinoma (HCC) has reportedly been increasing. The hyoid bone is rarely a target of metastatic HCC. We present a unique case of HCC which showed a single distant metastasis to the hyoid bone. An 81-year-old Japanese man was referred to us from the Department of Gastroenterology complaining of a 1-month history of a painful left neck mass when swallowing. He had a serial history of non-surgical treatments for HCC in the previous six years. Ultrasonography-guided fine needle aspiration cytology yielded a diagnosis of poorly differentiated carcinoma. PET-CT demonstrated a mass (SUV 3.8) which had destroyed the left side of the hyoid body. Based on these cytological and radiological findings of the mass in addition to his medical history of having recurrent HCC, we strongly suspected that the mass was a solitary metastatic HCC of the hyoid bone. The mass was completely resected combined with the hyoid bone under general anesthesia. Postoperative pathologic findings were consistent with metastatic HCC. The patient was relieved from pain in swallowing just after surgery. Minimally invasive surgery can be an effective treatment modality for pain relief even in patients with bone metastasis from HCC. PMID- 23016271 TI - [Three cases of suspected re-infection of mumps virus]. AB - A 32-year-old woman, 5-year-old girl, and 33-year-old man visited our otorhinolaryngology outpatient clinic with tumentia of the unilateral parotid gland. A high titer of serum IgG antibodies against the mumps virus was detected. Around the same time, other members of their families had the same parotid tumentia, and they were diagnosed as having their first mumps infection. Therefore, the diagnosis of the three cases was strongly suspected to be re infection with mumps. In Japan, it was classically believed that the mumps virus infection occurs only once in patients and reinfection doesn't occur. However, some pediatricians in Japan have reported that re-infection with mumps is strongly suspected when high titers of serum IgG antibodies against the mumps virus are found at the initial visit. It is now believed many more examples of mumps re-infection cases have existed than we previously believed. When high titers of serum IgG antibodies against the mumps virus are detected at an initial visit in patients who have had mumps previously, re-infection should be strongly suspected. And to make it certain, we suggest that the mumps IgG antibodies should be checked twice to confirm the diagnosis. If elevation of the IgG antibodies persist, the diagnosis will be much more certain. PMID- 23016272 TI - [Thiel's method of embalming and its usefulness in surgical assessments]. AB - When we assess anatomical problems and the safety and effectiveness for performing a difficult surgical procedure or planning novel surgical approaches, preoperative human dissections are very helpful. However, embalming with the conventional formaldehyde method makes the soft tissue of the cadaver harder than that of a living body. Therefore, the cadaver embalmed with conventional formaldehyde is not appropriate for dissections when assess surgical approaches. Thiel's method is a novel embalming technique, first reported by W. Theil in 1992. This method can preserve color and softness of the cadaver without risk of infections. We have used cadavers embalmed with Thiel's method for preoperative assessments and have confirmed the usefulness of this method especially for the prevention of complications or in assessing surgical approaches. The cadaver embalmed with this method has several advantages over other embalming methods and it might be also useful for the developments of new surgical devices or evaluation of a surgeon's skill. PMID- 23016273 TI - Bioactive secondary metabolites from Salix tetrasperma Roxb. AB - Column chromatography of the light petroleum fraction from the methanolic extract of the stem bark of Salix tetrasperma Roxb. (Salicaceae) resulted in the isolation of beta-sitosterol acetate, friedelin, 3beta-friedelinol, beta-amyrin, beta-sitosterol, beta-sitosterol-O-glucoside in addition to palmitic acid. From the dichloromethane fraction of the leaves, catechol and tremulacin were isolated. Salicin and its derivatives tremuloidin and 2'-O-p-(E)-coumaroyl salicin were isolated from the ethyl acetate fraction of the leaves. The isolated compounds were identified by MS, and 1D NMR (1H and 13C) and 2D NMR (H-H COSY, HSQC, and HMBC) spectral analyses. The total methanolic extract exhibited significant anti-inflammatory activity (rat hind paw oedema). The extract with a content of 120 mg/kg body weight produced 52% inhibition equivalent to the standard diclofenac sodium (54% inhibition). The antioxidant (DPPH free radical scavenging) and analgesic activities, respectively, were also evaluated. PMID- 23016274 TI - Investigation on anti-inflammatory and antiulcer activities of Anchusa azurea extracts and their major constituent rosmarinic acid. AB - This study investigated the anti-inflammatory and antiulcer activities of different extracts from the aerial parts and the roots of Anchusa azurea Miller var. azurea (Boraginaceae), as well as their major constituent, rosmarinic acid. The extracts were water (AWa, RWa) and methanol (AMe, RMe) extracts prepared from the aerial parts and the roots of A. azurea, respectively. The AMe extract was found to exert anti-inflammatory effects; so it was evaporated to dryness and the residue was dissolved in distilled water (AMeWa) and then further fractionated with n-hexane (AMeHe) and n-butanol (AMeBu). Anti-inflammatory activity was investigated in rats using carrageenan-induced acute inflammation, and antiulcer activity was investigated using indomethacin-induced gastric damage. The methanolic extract from the aerial parts, its n-butanol fraction, and rosmarinic acid, which was isolated from the n-butanol fraction of the AMe extract, showed significant dose-dependent antiinflammatory activity. During the acute phase of inflammation, the anti-inflammatory activity of rosmarinic acid was comparable to that of ibuprofen. No antiulcer activity was observed. The experimental data demonstrate that A. azurea Miller var. azurea and rosmarinic acid display significant anti-inflammatory activity. PMID- 23016275 TI - Biological and chemical study of Astragalus gombiformis. AB - Extracts of aerial parts and roots of wild Astragalus gombiformis Pomel were tested for their antibacterial, antioxidant, and insecticidal activities and contents of phenolic compounds. Antibacterial activity was tested by the paper disk agar diffusion method and determination of the minimal inhibitor concentration. Among the tested extracts, three extracts (methanol, chloroform, and ethyl acetate) from aerial parts and two extracts (water, methanol) from roots exhibited diameters of inhibition zone equal or above 12 mm (at 150 microg/ disk) and minimal inhibitor concentrations ranging between 233 and 1250 microg/ml. Spectrophotometric and HPLC analyses showed that contents of both total polyphenols and flavonoids, as well as antioxidant activity were higher in the methanolic extract of aerial parts as compared to roots. No insecticidal activity of the extracts of the aerial parts was found against Culex pipiens. PMID- 23016276 TI - Antitumour activities of sesquiterpene lactones from Inula helenium and Inula japonica. AB - Eight sesquiterpene lactones were isolated from the roots of Inula helenium and flowers of I. japonica. Among them, isoalantolactone (3) and santamarine (6) exhibited significant growth inhibitory activities against gynecologic cancer cell lines, while others weakly inhibited the growth of the cell lines (IC50 < or = 100 microM). In addition, 3 significantly inhibited the tumour growth of S180 tumour-bearing mice. Compounds 3 and 6 were not toxic to human embryonic lung fibroblast cells in vitro. These results demonstrated that the antitumour activities are closely related to the structures of the compounds, that is, an alpha-exomethylene-gamma-lactone ring is necessary for these activities. PMID- 23016277 TI - Digalacturonide flavones from Egyptian Lantana camara flowers with in vitro antioxidant and in vivo hepatoprotective activities. AB - A new digalacturonide flavone, luteolin 7-O-beta-galacturonyl-(2 --> 1)-O-beta galacturonide (1), was isolated along with nine known flavone glycosides from the aqueous methanolic extract of Lantana camara (L.) flowers. Their structures were determined on the basis of the spectral data. The extract of L. camara was evaluated for antioxidant and hepatoprotective properties in the acetaminophen induced mouse liver damage model. 1 exhibited significant antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay with an IC50 value of 27.2 microM. Pre-treatment with L. camara extract (25 and 75 mg/ kg body weight) decreased the activities of alkaline phosphatase (ALP), serum glutamate oxaloacetate transaminase (SGOT), and serum glutamate pyruvate transaminase (SGPT) enzyme levels that were elevated by acetaminophen. Both doses of the L. camara extract ameliorated the histopathological and histochemical alterations induced by acetaminophen. The results indicate that the L. camara extract possesses hepatoprotective activity against acetaminophen-induced liver damage. PMID- 23016278 TI - Antiadhesive activity of polysaccharide-rich fractions from Lithothamnion muelleri. AB - Red seaweeds are known sources of polysaccharides, some of which possess antiadhesive properties by inhibition of P-selectin-mediated leukocyte rolling. We here report the chemical composition and the antiadhesive activity of polysaccharide-rich fractions from the red alga Lithothamnion muelleri (Hapalidiaceae). The crude fractions enriched in polysaccharides B1 and B2 were obtained, respectively, by sequential extraction with 1% and 2% (w/v) Na2CO3 solution, at 60 degrees C. Fractionation of B1 and B2 by gel permeation chromatography afforded three polysaccharide-rich fractions each, whose compositions were characterized by chemical analysis (total contents of carbohydrates, proteins, sulfate, and uronic acid); their molecular weights were estimated by high-performance gel permeation chromatography (HPGPC). The antiadhesive activity of B1-derived fractions was assayed by visualizing lipopolysaccharides-induced leukocyte rolling under intravital miscroscopy. The intravenous injection of fractions B1a and B1b in mice, at the dose of 10 mg/kg body weight, reduced leukocyte rolling by approximately 90%; fucoidan (10 mg/kg body weight) employed as positive control induced a similar response. Therefore, the sulfated polysaccharides of L. muelleri deserve further evaluation as potential templates for the development of new anti-inflammatory agents. PMID- 23016279 TI - Repellent and insecticide activity of Pelargonium x hortorum against Spodoptera littoralis (Boisd.). AB - Insecticide and repellent activity of an acetone extract and oil from fresh leaves of Pelargonium x hortorum (cv. Orangesonne) were evaluated against the 2nd and 4th instar larvae of Spodoptera littoralis (Boisd.) (Lepidoptera: Noctuidae). The oil showed medium toxicity against the 2nd instar and low toxicity against the 4th instar larvae, while the extract showed high significant toxicity at all concentrations tested against the two instars. On the other hand, both oil and extract exhibited highly significant repellency against the two tested instars. Volatile constituents of the oil were also identified by GC-MS analysis. PMID- 23016281 TI - Microbial transformations of 6- and 7-methoxyflavones in Aspergillus niger and Penicillium chermesinum cultures. AB - A detailed study of the biotransformation of 6- and 7-methoxyflavones by four fungal strains (Aspergillus niger strains MB, KB, and SBP; Penicillium chermesinum 113) was carried out. Products of demethylation and also demethylation combined with hydroxylation at C-4' were identified. The biotransformation products were stronger antioxidants than the substrates. PMID- 23016280 TI - In vivo/in vitro studies of the effects of the type II arabinogalactan isolated from Maytenus ilicifolia Mart. ex Reissek on the gastrointestinal tract of rats. AB - Type II arabinogalactan (AG) is a polysaccharide found in Maytenus ilicifolia (Celastraceae), a plant reputed as gastroprotective. Oral and intraperitoneal administration of the AG protected rats from gastric ulcers induced by ethanol. No alteration of mechanisms related to acid gastric secretion and gastrointestinal motility were observed. In vitro, the AG showed a potent scavenging activity against the radical of DPPH (2,2-diphenyl-1-picrylhydrazyl) with an IC50 value of 9.3 microM. However, the mechanism of the gastroprotective action remains to be identified. PMID- 23016282 TI - Correlations among attributes of senescence and antioxidative status of leaf discs during epiphyllous bud differentiation in Kalanchoe pinnata Lam. (Pers.). AB - Leaf detachment is a common signal that triggers both the differentiation of dormant epiphyllous buds as well as the onset of foliar senescence in Kalanchoe pinnata Lam. (Pers.). The present study looked for any probable correlations among selected attributes of foliar senescence, e.g. soluble proteins, chlorophylls a and b (Chl(a+b)), and membrane stability index (MSI), and the antioxidative status, e.g. phenolics, ferric reducing ability in plasma equivalence (FRAP(eq)), and membrane protection index (MPI), during epiphyllous bud differentiation. The experimental system comprised 0.75-cm leaf discs, with or without a dormant epiphyllous bud, cultured in vitro and exposed for ten days to continuous light or dark. A steady depletion of soluble proteins and Chl(a+b), and lowering of MSI in the leaf discs were observed, the decline being relatively faster and of higher magnitude in discs exposed to dark rather than to light. The pigment loss in discs with differentiating epiphyllous buds was greater and faster than in those lacking buds, a somewhat reverse situation was observed in case of soluble proteins. Simultaneously, a time-dependent decrease in the level of phenolics was also observed. Their content was found to be lower in discs exposed to dark as compared to light, pointing to a relationship with a higher rate of senescence-related degradative processes in the dark. The change in the content of Chl(a+b) was found to be significantly correlated with the variation in the level of phenolics. The average FRAP(eq) after ten days was one half that of the initial level, which could be correlated with the decreasing levels of phenolics (intra-correlation) and maximally correlated with variations in Chl(a+b) and protein contents (inter-correlation). Aqueous alcohol foliar extracts significantly (p < 0.05) protected membranes against peroxidative stress, although the pattern was not found to be in line with that of the phenolics content or FRAP(eq). The diminishing Chl(a+b) content was found to be maximally correlated with alterations in the membrane protection. PMID- 23016283 TI - Enzymatic degradation of Congo Red by turnip (Brassica rapa) peroxidase. AB - The enzyme peroxidase is known for its capacity to remove phenolic compounds and aromatic amines from aqueous solutions and also to decolourize textile effluents. This study aims at evaluating the potential of a turnip (Brassica rapa) peroxidase (TP) preparation in the discolouration of textile azo dyes and effluents. An azo dye, Congo Red (CR), was used as a model pollutant for treatment by the enzyme. The effects of various operating conditions like pH value, temperature, initial dye and hydrogen peroxide concentrations, contact time, and enzyme concentration were evaluated. The optimal conditions for maximal colour removal were at pH 2.0, 40 degrees C, 50 mM hydrogen peroxide, 50 mg/l CR dye, and TP activity of 0.45 U/ml within 10 min of incubation time. Analysis of the by-products from the enzymatic treatment by UV-Vis and IR spectroscopy showed no residual compounds in the aqueous phase and a precipitate of polymeric nature. PMID- 23016284 TI - Attraction of the gypsy moth to volatile organic compounds (VOCs) of damaged Dahurian larch. AB - Olfactory responses of the gypsy moth Lymantria dispar (L.) (Lepidoptera: Lymantriidae), a major defoliator of deciduous trees, were examined in Inner Mongolia, China. We studied whether the gypsy moth adults are attracted by the major volatile organic compounds (VOCs) of damaged Larix gmelinii (Dahurian larch) foliage and compared the attractiveness of the plant volatiles with that of the synthetic sex pheromone. Our results indicated that the VOCs of the Dahurian larch were effective in attracting gypsy moth males especially during the peak flight period. The VOCs also attracted moths significantly better than the sex pheromone of the moth. Our study is the first trial to show the responses of adult gypsy moths to volatile compounds emitted from a host plant. Electroantennogram responses of L. gmelinii volatiles on gypsy moths supported our field observations. A synergistic effect between host plant volatiles and sex pheromone was also obvious, and both can be jointly applied as a new attractant method or population management strategy of the gypsy moth. PMID- 23016285 TI - [Advances in solid-phase extraction based on graphene materiales]. PMID- 23016286 TI - [Trypsin immobilization on silica beads modified by squamous polymer for ultra fast and highly efficient proteome digestion]. AB - Currently, the shotgun based strategy has been widely applied in proteomic research. In this strategy, protein identification relied on the identification of the corresponding proteolytic peptides. Therefore, rapid and efficient protein digestion is crucial for accurate protein identification and characterization. Even though traditional free protein digestion in solution has been widely adopted, it had a few inherent disadvantages including long incubation time, incomplete digestion and non-reusability of the protease. In this work, we developed a new type of trypsin immobilized on squamous polymer modified silica bead (SPMSB) for ultra fast and highly efficient protein digestion. The squamous polymer coated silica beads were prepared by surface initiated atom transfer radical polymerization (SI-ATRP), which leaded to surface confined growth of non crosslinked polymer chains on the sufface of the silica beads for trypsin immobilization. The digestion efficiency of the obtained SPMSB-trypsin was evaluated using both standard proteins and complex protein extracts obtained from E. coil. Highly efficient digestion was achieved in only 1 - 2 mm digestion. Furthermore, the SPMSB-Trypsin exhibited both good stability and excellent recovery, therefore can be applied in proteomic research in the future. PMID- 23016287 TI - [Simultaneous determination of flonicamid and its metabolites in cucumbers and apples by liquid chromatography-tandem mass spectrometry]. AB - A method was developed for the simultaneous determination of flonicamid and its metabolite [N-(4-trifluoromethylnicotinoyl) glycine (TFNG), 4 trifluoromethylnicotinic acid (TFNA) and 4-trifluoromethylnicotinamide (TFNA-AM)] in cucumbers and apples by liquid chromatography-tandem mass spectrometry (LC MS/MS) with liquid-liquid extraction. The sample was extracted twice with phosphate buffer solution (pH 7.0), and the extract was adjusted to pH 1.5 - 2.0, then an aliquot of the extract (3 mL) was extracted with ethyl acetate. The final extract was dried under nitrogen and the residue was dissolved in 0.1% formic acid in water/methanol (80/20, v/v). The sample was analyzed by LC-MS/MS and quantified with the external standard calibration curve method. The detection limits of flonicamid, TFNG, TFNA and TFNA-AM were 0.17, 0.20, 0.35 and 0.60 microg/kg, respectively. The average recoveries of flonicamid and its metabolites in cucumbers and apples were 82.9% - 104.1%. In the intra-assay, the relative standard deviations were 3.6% - 6.9% at the spiked levels of 5.0 - 2 000 microg/kg. There were good linear correlations (the calibration coefficients were above 0.998) between the peak areas and the concentrations of flonicamid and its metabolites in the range of 0.5 - 200 microg/L. The volume of organic solvent used in the whole pretreatment procedure was only 6 mL. The method is accurate, highly sensitive and stable for the determination of flonicamid and its metabolites. PMID- 23016288 TI - [Determination of residues of pesticides and veterinary drugs in milk by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry]. AB - An analytical method was established for the simultaneous determination of 42 pesticides and veterinary drugs in milk by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q TOF-MS). The target compounds are the commonly used drugs including 13 pesticides and 29 veterinary drugs. The QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method was used for sample preparation. The analytes in milk samples were extracted with acetonitrile containing 1.0% (v/v) formic acid, and were salted out by adding anhydrous sodium sulfate and potassium chloride. After that, the extract solution was purified by dispersive solid phase extraction with C18 sorbent. In the chromatographic analysis of 42 target compounds were separated on an ACQUITY UPLC BEH C18 column with the gradient elution using the mobile phases of acetonitrile and water containing 0.1% formic acid. MS(E) (where E represents collision energy) acquisition under positive ion mode was performed to obtain accurate relative molecular masses and fragment ions. As a result, the limits of quantification (LOQ, S/N = 10) of the target compounds were from 1 microg/kg to 100 microg/kg in milk. The average recoveries of the 42 analytes spiked at three concentration levels were ranged from 68.2% to 129.1% with the relative standard deviations of 2.8% - 30.8%. This method can be applied to the analysis of the 42 pesticides and veterinary drugs in milk due to its fastness, simplicity and relatively high sensitivity. PMID- 23016289 TI - [Determination of clavulanic acid residue in milk by high performance liquid chromatography-tandem mass spectrometry]. AB - An analytical method was developed for the determination of clavulanic acid (CLAV) in milk by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). A 2 g milk sample was deproteinized by ethanol. The supernatant was transferred into a pear-shaped bottle to be evaporated to about 0.5 mL, and the residue was dissolved with ammonium acetate solution. The sample was determined by HPLC-MS/MS after the purification. The chromatographic separation was achieved on a Luna 5u C8 column using 0.1% formic acid in water and acetonitrile as mobile phases with gradient elution. The identification of CLAV was carried out by MS/MS equipped with electrospray ionization in negative scanning and multiple reaction monitoring (MRM) modes. Matrix-matched calibration standard was used for the quantification. The calibration curve showed perfect linear in the range of 10 - 400 microg/kg with the correlation coefficient of 0.999. The limit of detection (LOD, S/N > or = 3) was 10 microg/kg in milk, and the limit of quantification (LOQ, S/N > or = 10) was 20 microg/kg. The mean recoveries varied from 80.00% to 91.25% at the four spiked levels of LOQ, 1/2MRL (the maximum residue limit), MRL, and 2MRL with the relative standard deviations of 5.60% -8.77%. In conclusion, the established method can be applied for the determination of CLAV residues in milk. PMID- 23016290 TI - [Determination of 11 anabolic hormones in fish tissue by multi-function impurity adsorption solid-phase extraction-ultrafast liquid chromatography-tandem mass spectrometry]. AB - A method was developed for the determination of 11 anabolic hormones (boldenone, androstenedione, nandrolone, methandrostenolone, methyltestosterone, testosterone, testosterone acetate, trenbolone, testosterone propionate, stanozolol, fluoxymesterone) in fish by multi-function impurity adsorption solid phase extraction-ultrafast liquid chromatography-tandem mass spectrometry. After the sample was extracted by methanol, the extract was cleaned-up quickly by C18 adsorbent, neutral alumina adsorbent and amino-functionalized nano-adsorbent. The separation was performed on a Shim-Pack XR-ODS II column (100 mm x 2.0 mm, 2.2 microm) using the mobile phases of 0.1% (v/v) formic acid in acetonitrile and 0.1% (v/v) formic acid solution in a gradient elution mode. The identification and quantification were achieved by using electrospray ionization in positive ion mode (ESI+) in multiple reaction monitoring (MRM) mode. The matrix-matched external standard calibration curves were used for quantitative determination. The results showed that the calibration curves were in good linearity for the eleven analytes with the correlation coefficients (r) more than 0.999. The limits of detection (LODs, S/N > 3) for the 11 anabolic hormones were from 0.03 microg/kg to 0.4 microg/kg and the limits of quantification (LOQs, S/N > 10) were from 0.1 microg/kg to 1.5 microg/kg. The average recoveries ranged from 80.9% to 98.1% with the relative standard deviations between 5.2% and 11.5%. The method is simple, rapid, sensitive, accurate and suitable for the quantitative determination and confirmation of the 11 anabolic hormones in fish. PMID- 23016291 TI - [Determination of kojic acid in foods using high performance liquid chromatography-tandem mass spectrometry]. AB - The quantification method for the determination of kojic acid in foods using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was developed. For solid samples, the kojic acid was extracted with acetonitrile; for liquid samples, they were diluted with water, then deproteinized by the deposition with zinc acetate and potassium ferrocyanide. The analytes were determined by HPLC-MS/MS on a C18 column with 5 mmol/L ammonium acetate/formic acid solution as mobile phases. The analysis of kojic acid was performed under selected reaction monitoring (SRM) mode by selecting one parent ion and two daughter ions as qualitative ions with [13C6]-kojic acid as the internal standard, and the most abundant daughter ion as quantitative ion. The limits of quantification (S/N > 10) were 0.1 mg/kg for the solid samples, and 2.5 mg/kg for the liquid samples. The good linearity (r > 0.99) was achieved for the target compound over the range of 0.1 - 2.0 mg/L. The recoveries at three levels for kojic acid were from 72.6% to 114% with the relative standard deviations no more than 11.4%. The method is simple and practical, and can be applied to most of matrices which may contain kojic acid as food additives. It can meet the qualitative and quantitative requirements for import and export foods. PMID- 23016292 TI - [Determination of 7 microcystins in Spirulina health food products by ultra performance liquid chromatography-tandem mass spectrometry]. AB - Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/ MS) combined with solid phase extraction (SPE) has been developed for the determination of 7 microcystins (MCs) in Spirulina health food products. The sample was extracted by 70% (v/v) methanol. The lipid substances were isolated by centrifugation under freezing condition, and then followed by clean-up with a Waters Oasis HLB solid phase extraction cartridge. The separation was performed on a Waters ACQUITY UPLC BEH C18 column with gradient elution using acetonitrile and 0.2 mmol/L ammonium acetate. The electrospray ionization (ESI) source in positive ion mode was used for multiple reaction monitoring (MRM). The external standard method was used for the quantification. The linear ranges for 7 MCs were 20 - 400 microg/kg, and the correlation coefficients were not less than 0.995. The limits of detection were 6.7 - 33.3 microg/kg. The limits of quantification were 20.0 - 100.0 microg/kg. The recoveries of the 7 MCs spiked in blank Spirulina samples ranged from 87.5% to 97.9% with the relative standard deviations of 1.6% - 6.9%. The results demonstrated that the method is easy, fast, sensitive, and suitable for the confirmation and quantification of the 7 MCs in Spirulina samples. PMID- 23016293 TI - [Determination of carbon-centred radicals in mainstream cigarette smoke using spin-labelled fluorophore]. AB - A method of the determination of the carbon-centred radicals in mainstream cigarette smoke using a spin-labelled fluorophore, 4-((9-acridinecarbonyl) amino) 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO-9-AC), as a fluorescent probe is presented. After being producted by smoking in International Organization for Standardization (ISO) mode, the carbon-centred radicals in mainstream cigarette smoke were trapped by TEMPO-9-AC, a carbon-centred radical probe with a low fluorescence intensity. Then the latter was transformed to a stable diamagnetic o alkoxyamine, a high-fluorescence compound. Finally, high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to demonstrate the structures of the carbon-centred radicals, and high performance liquid chromatography with a fluorescence detector (HPLC-FLD) was used to determine the concentration of the carbon-centred radicals. The results showed that the 10 carbon-centred radicals were detected in the mainstream cigarette smoke, and the total carbon-centred radicals concentrations for 1R5F, 3R4F, CM6, and two Virginia type cigarettes, were 52.5 nmol/cig, 214.6 nmol/cig, 424.1 nmol/cig, 68.6 nmol/cig, and 334.2 nmol/cig, respectively; and there was positive relation between the concentrations of the total amount of carbon-centred radicals and the tar amounts in the mainstream cigarette smoke. The detection limit was 0.318 nmol/cig, and the relative standard deviations (RSDs) ranged from 3.5% to 9.7%. This method is suitable for the determination of the carbon-centred radicals in the mainstream cigarette smoke. PMID- 23016294 TI - [Determination of chlorophenol and pyrethroid preservatives in wooden furniture by solid phase extraction coupled with gas chromatography-mass spectrometry]. AB - A method for the determination of 10 wood preservatives of chlorophenols (2,4 dichlorophenol, 2, 4, 6-trichlorophenol, 2, 4, 5-trichlorophenol, 2, 3, 4, 6 tetrachlorophenol, pentachlorophenol, lindane) and pyrethroids (permethrin, cyfluthrin, cypermethrin, delta-methrin) in furniture by solid phase extraction (SPE) coupled with gas chromatography-mass spectrometry (GC-MS) was developed. The furniture samples were extracted twice by ultrasonic extraction in methanol. The extract was then evaporated and acetylated by the acetic anhydride and potassium carbonate. Finally the reaction solution was purified by Oasis HLB SPE column. The wood preservatives were eluted by ethyl acetate and collected for analysis by GC-MS. The ten wood preservatives can be separated and determined successfully by this method. Under the optimized conditions, the detection limits of the six chlorophenol compounds were 1 mg/kg, and the four pyrethroid compounds were 5 mg/kg, and the spiked recoveries of the 10 wood preservatives in samples were in the range of 76.0% - 108.8%. Forty commercial wooden furniture samples were tested and lindane was found in some samples. The results showed that the method is accurate, rapid and sensitive. It can be effectively used to analyze the wood preservatives in wooden furniture. PMID- 23016295 TI - [Analysis of 112 pesticide residues in vegetables using dispersive-solid phase extraction and gas chromatography-triple quadrupole mass spectrometry]. AB - A method was developed and validated for the simultaneous analysis of 112 pesticide residues in vegetables by gas chromatography coupled with triple quadrupole mass spectrometry (GC-QQQ-MS/MS). It is demonstrated that the optimized conditions could provide a more accurate quantitation and lower limit of quantification of the analysis by dispersive-solid phase extraction (D-SPE) cleanup. The samples were extracted with acetonitrile and toluene (8: 1, v/v), and cleaned up by D-SPE. To every 5 mL extraction solution, 0.8 g MgSO4, 0.05 g graphitized carbon black (GCB), 0.1 g ethylenediamine-N-propyl silyl (PSA) and 0.05 g C18 were added. The extracts were analyzed by GC-QQQ-MS/MS using internal standard method. The recoveries of the 112 pesticides at three spiked levels of 20, 50 and 200 microg/kg were ranged from 53.1% to 138.7%, and among which those of 86 pesticides were from 65.0% to 120.0%. The relative standard deviations (RSD) were less than 12%. The limits of quantifications (LOQs) (signal/noise at 10) were between 1.6 and 13.4 microg/kg. The vegetable samples collected from the market such as garlic chives, cucumber and purple cabbage were analyzed, and the residues of triazophos and fenpropathrin were detected in some of these samples. The method can be applied to the routine analysis for the determination of the 112 pesticides in vegetable samples. PMID- 23016296 TI - [Determination of homocysteine in plasma by precolumn derivatization-high performance liquid chromatography with fluorescence detection]. AB - A precolumn derivatization-high performance liquid chromatographic method for the determination of homocysteine (Hcy) in plasma was established. Tris (2 carboxyethyl) phosphine hydrochloride (TCEP) and N-(1-pyrenyl) maleimide (NPM) were used as the reduced reagent and derivatization reagent, respectively. The separation was carried out on an Agilent Hypersil C-18 column (250 mm x 4.0 mm, 5 microm) in gradient elution mode. The mobile phase consisted of A (15 mmol/L sodium acetate solution), B (acetonitrile) and C (300 mL water containing 1 mL acetic acid and 1 mL phosphoric acid). The eluate was monitored by the fluorescence detector at an excitation wavelength of 330 nm and an emission wavelength of 380 nm. The mean recovery of Hcy was (102.08 +/- 4.94)%. The linear range was from 0.500 micromol/L to 100 micromol/L, with a detection limit of 0.016 micromol/L. The intra-day and inter-day relative standard deviations (RSDs) for Hcy were less than 5%. Seven plasma samples of patients with hypertension and seven plasma samples of healthy controls were tested, and the results demonstrated that the Hcy in the plasma from the hypertension group was significantly different from that of the control group (p < 0.05). The developed method is simple, fast, accurate, and suitable for clinical measurement. PMID- 23016297 TI - [Separation of coagulation factor VIII with high activity using gigaporous anion exchange chromatography]. AB - A purification process to obtain coagulation factor VIII (F VIII) with high activity from human plasma was established. Based on the analysis of the size ratio between F VIII and matrix porous medium and its effect on the protein activity, a novel purification process designed was superporous ion exchange chromatography (IEC). The operating conditions of gigaporous and traditional anion exchange chromatography were optimized separately. The chromogenic substrate, gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) were used to monitor the bioactivity and purity of the chromatographic products. The results showed that the superporous medium could not only protect structure of macro-protein but also enhance its mass transfer, finally giving FVIII product with high activity. The yield of F VIII in superporous chromatography was about five times of commercially agarose chromatography and the specific activity was up to 154 IU/mg protein. Furthermore, we studied the regeneration process of the superporous medium, washing the column with 5 column volumes of 1 mol/L NaOH at a low flow rate, to ensure the chromatographic stability. This purification process is simple, reproducible and suitable for large-scale production. PMID- 23016298 TI - [Determination of four Sudan dyes in chili oil by high performance liquid chromatography with on-line photochemical derivatization and fluorescence detection]. AB - A method for the measurement of Sudan I, Sudan II, Sudan III and Sudan B in chili oil using high performance liquid chromatography (HPLC) with on-line photochemical derivatization and fluorescence detection has been developed. The Sudan dyes were separated on an SB-C18 column in a single run by the mixed mobile phase of acetonitrile-water with a gradient program. A laboratory-built time/energy programmed photochemical reactor (PCR) with an ultraviolet mercury lamp was installed between a photodiode array detector (PDA) and a fluorescence detector (FLD), and it was applied to convert the non-or weakly fluorescent Sudan dyes into fluorescence emission components. The photochemical derivatization conditions and fluorescence detection parameters have been investigated and optimized. The recoveries of the standards spiked in real chili oil samples for all the dyes were 81.3% - 100.4%. The relative standard deviations (RSDs, n = 6) of the fluorescence signal intensity at the spiked level of 0.8 mg/kg were 2.6% - 3.8%. The limits of detection (LODs) were in the range of 0.009 - 0.054 mg/kg and the limits of quantification (LOQs) were 0.030 - 0.181 mg/kg, which were better than those of the commonly used HPLC coupled with PDA. The developed method which is simple, sensitive, and selective can be applied to the routine analysis of Sudan dyes. PMID- 23016299 TI - [Simultaneous determination of seven naphthalenediols in cosmetics by reversed phase high performance liquid chromatography]. AB - A novel analytical method for the simultaneous determination of seven naphthalenediols (2,6-naphthalenediol, 1,5-naphthalenediol, 1,6-naphthalenediol, 2,7-naphthalenediol, 1,7-naphthalenediol, 1,3-naphthalenediol and 2,3 naphthalenediol) in cosmetics by reversed-phase high performance liquid chromatography (RP-HPLC) with a diode array detector was established. The moisturizer, cream, emulsion and water-like cosmetic samples were extracted with 95% ethanol (v/v), and the powder-like cosmetic samples were extracted with 95% ethanol-0.1% acetic acid (3: 2, v/v), then the extracts were centrifuged, filtrated, and analyzed by RP-HPLC using a C18 column, employing methanol-0.1% acetic acid aqueous solution as the mobile phases under the condition of gradient elution. The naphthalenediols were qualitatively determined by retention times, and confirmed by ultraviolet spectra. The external standard method was applied for the quantification. The results indicated that the limits of quantification (LOQs) of the seven naphthalenediols were ranged from 0.5 mg/kg to 1.2 mg/kg (S/N = 10); meanwhile, the linear correlation coefficients of them were all no less than 0.999 0 within the linear ranges. Their recoveries in spiked samples at the levels of 5.0 - 50 mg/kg were ranged from 84.0% to 102% with the relative standard deviations (RSDs) of 1.3% - 5.7% (n = 6). The method is simple, precise and suitable for the determination of naphthalenediols in cosmetic samples. PMID- 23016300 TI - [Determination of nitrite and nitrate in dairy products by improved ion chromatography]. AB - Nitrite and nitrate are common inorganic salts in the diet and drinking water. It is generally believed that excessive intake of these substances may result in methemoglobinemia or other diseases. However, the traditional detection methods for nitrite and nitrate in dairy products restrain their applications to routine analysis due to the presence of certain limitations. In order to solve this problem, an improved national food safety standard method for the determination of nitrite and nitrate in dairy products has been studied. After water extraction, protein precipitation and centrifugation, the supernatant was cleaned up by a solid phase extraction (SPE) column. The eluent mainly composed of sodium hydroxide with acetonitrile as organic modifier. External water mode was used for suppressor. An AS 19 column was used as the analytical column, and the oven temperature was 30 degrees C while the cell temperature was 35 degrees C. The detection wavelength was 225 nm and the injection volume was 200 microL. The results showed that good linearity existed when the concentrations of nitrite and nitrate were between 0.005 -0.50 and 0.05 - 1.50 mg/L respectively. The detection limits of nitrite and nitrate were 0.2 and 0.04 mg/kg respectively when using a conductivity detector; while the values were only 0.02 and 0.01 mg/kg using an ultraviolet (UV) detector. The recoveries were between 84.0% and 104.1% when analyzing dairy products. It is a simple, fast and highly sensitive way for nitrite and nitrate detections. PMID- 23016301 TI - [Simultaneous determination of 6 antibiotics and metronidazole in acne removal products bt high performance liquid chromatography]. AB - An analytical method for the simultaneous determination of 6 antibiotics (minocycline, oxytetracycline, tetracycline hydrochloride, chlorotetracycline hydrochloride, doxycycline hydrochloride and chloramphenicol) and metronidazole in acne removal products of cosmetic was established using high performance liquid chromatography (HPLC). The drugs in the sample were extracted with methanol. The separation was performed on an Agilent ZORBAX SB-C18 column (250 mm x 4.6 mm, 5 microm) at 20 degrees C with methanol, acetonitrile and 0.002 mol/L oxalic acid solution as mobile phases with gradient elution at a flow rate of 0.8 mL/min. The detection was performed by a diode array detector (DAD) at 268 nm. The injection volume was 10 microL. The quantification was performed by external standard method. The calibration curves showed good linearity within the range of 1 - 30 mg/L with the correlation coefficients no less than 0.997 0. The detection limits were in the range of 1.1 - 1.2 microg/g. The recoveries were between 91.9% and 107.7% in three spiked levels of 5, 10 and 20 mg/L with the relative standard deviations (RSDs) of 0.13% - 1.74%. The method was used in the analysis of acne removal products, and metronidazole was found in 15% of the total test samples. The method is rapid, sensitive, accurate, effective in separation, and can be used in the determination of the six antibiotics and metronidazole in acne removal products. PMID- 23016302 TI - [Single B cell monoclonal antibody technologies and applications]. AB - Monoclonal antibodies (mAbs) contribute a lot to the development of numerous fields in life science as a pivotal tool in modern biological research. Development of the PCR methods and maturation of antibody production have made it possible to generate mAbs from single human B cells by single cell RT-PCR with successional cloning and expression in vitro. Compared to traditional monoclonal antibody technologies, single B cell technologies require relatively fewer cells, which are highly efficient in obtaining specific mAbs in a rapid way with preservation of the natural heavy and light chain pairing. With so many advantages, single B cell technologies have been proved to be an attractive approach for retrieval of naive and antigen-experienced antibody repertoires generated in vivo, design of rationale structure-based vaccine, evaluation and development of basic B cell biology concepts in health and autoimmunity, and prevention of infectious diseases by passive immunization and therapy for disorders. Accordingly, this review introduced recent progresses in the single B cell technologies for generating monoclonal antibodies and applications. PMID- 23016303 TI - [Progress in automatic reconstruction and analysis tools of genome-scale metabolic network]. AB - High-throughput data supply a basis for the reconstruction of genome-scale metabolic networks, and meanwhile bring challenges to the reconstruction and analysis methods. With the increasing of data quantity, the time-consuming manual reconstruction and analysis are far behind the improvement of models. Therefore, various automatic methods emerge. The automatic reconstruction and analysis have irreplaceable effect in the standardization and programming of reconstruction and analysis methods, as well as largely improving the speed of reconstruction and understanding of the metabolic network. In this review, we introduced the progress of automatic reconstruction and the main analysis tools of genome-scale metabolic network. We further summarized the workflow of automatic reconstruction. The difficulties and perspectives on this research field are also discussed. PMID- 23016304 TI - [Progress in molecular biology of Jatropha curcas]. AB - Jatropha curcas L., has been widely recognized as a potential source of biodiesel. In this review, we presented several aspects about the recent progress in molecular biology of J. curcas. First, molecular markers were used to assess its genetic diversity. Second, large-scale genome, transcriptome and proteome analyses were applied for decoding its molecular network. Third, functional characterization of key genes involved in metabolism and regulation of plant development was performed to breed lines with higher quality or higher resistance. Finally, we discussed the limitation of current progress and then proposed the future molecular biology research on J. curcas. PMID- 23016305 TI - [Biotransformation in vivo/vitro and bioactive properties of rare ginsenoside IH901]. AB - Recent metabolomics research revealed a new ginseng ginsenoside IH901 that is synthesized by intestinal microbial transformation in oral administration of ginseng. IH901 shows various biological activities, including anti-tumor, anti inflammatory, anti-diabetic, and anti-aging. In recent years, great effort has been made to prepare IH901 by microbial and enzymatic transformation in a large scale. In this paper, we reviewed the biotransformation pathways both in vivo and in vitro and bioactive properties of rare ginsenoside IH901. PMID- 23016306 TI - [Expression, purification and characterization of K5 lyase in Escherichia coli]. AB - K5 polysaccharide of high molecular weight (HLW) can be splitted into low molecular weight (LMW) K5 polysaccharide by K5 lyase which can be used as the substrate of partial synthesis low molecular heparin sulfate (HS). To prepare recombinant K5 lyase (Elma) and analyze its biological activity. The gene of Elma was cloned by PCR amplification and was ligated with pET-28a. Then the recombinant expression vector pET-28a-Elma was transformed into Escherichia coli BL21 (DE3). After induction with 0.2 mmol/L IPTG at 16 degrees C for 5 h, Elma was successfully expressed, SDS-PAGE analysis demonstrated that the enzyme constituted more than 30% of the total cell proteins. After Ni(2+)-NTA affinity and G-75 chromatography, the purity of enzyme was more than 95%. Enzymatic activity was determined according to the change of absorbance at 232 nm per ml of the sample. The reduction of the polysaccharide molecular weight could be detected by PAGE electrophoresis. Elma can partially split HA and HS. Its optimal reatcion temperature is 37 degrees C and the optimal reaction pH is 7.0. PMID- 23016307 TI - [Identification and characterization of a flavonoid-3-O-glucosyltransferase gene from Saussurea involucrata]. AB - The flavonoid-3-O-glucosyltransferas (3GT) is one of the most important enzymes for biosynthesis of plant secondary metabolites. In this paper, the homology analysis and gene special primers design were used. With the methods of modern molecular biology, the full-length gene of 3GT (GenBank Accession No. JN092127) which was cloned from Saussurea involucrata Kar. et Kir by RT-PCR and RACE. The cDNA sequence of 3GT consisted of 1548 bp open reading frame (ORF) encoding 516 amino acid, the deduced 3GT protein shared 91% and 89% identities with that of Fragaria x ananassa GT6, Manihot esculenta anthocyanidin 3-O-glucosyltransferase. Homology analysis showed that deduced 3GT protein has a glycosyltransferase signature domain PSPG-box. The transcripts of 3GT members were found mainly in leaves and callus. 3GT gene of S. involucrata was under the control of the cauliflower mosaic virus (CaMV) 35S promoter, homologous transformation used an Agrobacterium rihizogenes-mediated transformation system. The results on UV spectrophotometry showed S. involucrata callus after suspension culture that an average of total flavonoids on transgenic callus was 2.06 times higher than non transgenic callus. PMID- 23016308 TI - [Lactobacillus inhibit adhesion of Staphylococcus aureus to HeLa cells]. AB - To assess the ability of the previously selected human vaginal isolates of Lactobacillus crispatus (L. crispatus) T79-3, T90-1 and Lactobacillus jensenii (L. jensenii) T118-3, T231-1 to inhibit the growth of Staphylococcus aureus and block their adhesion to HeLa cells. The inhibitory bioactive substances produced by these Lactobacillus were also identified. Inhibitory substances interaction tests were carried out by using a streak-diffusion method on agar plates. Three types of interaction were performed to determine the inhibitory effect of Lactobacillus on adhesion of Staphylococcus aureus to HeLa cells: Exclusion Group (Lactobacillus and HeLa followed by pathogens), Competition Group (Lactobacillus, HeLa and pathogens together) and Displacement Group (pathogens and HeLa followed by the addition of Lactobacillus). The number of HeLa cells adhered to Staphylococcus aureus was quantified by bacteria colony counts on LB plate. The results showed that lactic acids produced by the Lactobacillus are the main substances that can inhibit Staphylococcus aureus growth and there is variation among the three types of interaction regarding the inhibitory activity against Staphylococcus aureus. The effects of Lactobacillus on blocking the adhesion to HeLa cells were concentration dependent. All four Lactobacillus isolates displayed the ability to inhibit Staphylococcus aureus growth and block Staphylococcus aureus adherence to HeLa cells. Exclusion Group was the most effective, and T79-3 showed greater capacity to block Staphylococcus aureus adherence compared with the other three isolates. The present study suggests the potential ability of L. crispatus T79-3 as probiotic for the treatment and prevention of urogenital infections in women. PMID- 23016309 TI - [Effect of CCH1 or MID1 gene disruption on drug tolerance and pathogenesis of Candida albicans]. AB - The calcium gate encoded by CCH1 and MID1 genes is the main channel for external calcium absorption. As one of the important secondary messengers, the elevation of calcium concentration could activate some pathways to take part in various cell processes. In this study, we used CCH1 and MID1 mutant strains and also constructed their complementary strains to study the effect of drug tolerance and virulence of Candida albicans after CCH1 or MID1 deletion. By drug plate sensitivity assay and the broth microdilution method, we compared the changes between different strains. Moreover, we added calcium channel blocker and inhibitors to analyze the effect of calcium concentration on drug action. After the deletion of CCH1 or MID1 gene, the strain exhibited an obvious sensitivity to FLUC and ITRA, and the drug action was regulated by the calcium concentration. In a mouse model of intravenous infection, we found that attenuated virulence of cch1delta/delta or mid1delta/delta strain is specifically due to a loss of CCH1 or MID1 gene. PMID- 23016310 TI - [Quantification of the curing effects of phenanthridine on yeast prion [PSI+]]. AB - In order to quantify the curing effects of phenanthridine on yeast prion, we introduced semi-denaturing agarose gel electrophoresis and fluorescence recovery after photobleaching techniques to quantify the curing effects of phenanthridine on yeast prion at the protein and cellular levels with the [PSI+] yeast strain expressing GFP-Sup35p (NGMC). The results showed that these two approaches could precisely quantify the curing effects of phenanthridine on [PSI+] cells. After a treatment for 1 through 5 days with phenanthridine, the curing rates of [PSI+] cells were 0%, 0%, 51.7%, 87.5% and 94.4%, respectively. Meanwhile, we quantified the sizes of Sup35p polymers in phenanthridine induced pink phenotype cells. The aggregation status in 1-2 days phenanthridine treated cells were similar to those in [PSI+] cells, while the aggregation status in 3-5 days phenanthridine treated cells were similar to those in [psi(-)] cells. PMID- 23016311 TI - [Alleviated affect of exogenous CaCl2 on the growth, antioxidative enzyme activities and cadmium absorption efficiency of Wedelia trilobata hairy roots under cadmium stress]. AB - In order to study the physiological mechanism of exogenous calcium on the toxicity of heavy metal cadmium (Cd) to Wedelia trilobata hairy roots, the effects of Cd alone, and in combination with different concentrations of Ca on growth, contents of soluble protein and malondialdehyde (MDA), activities of superoxide dismutase (SOD) and peroxidase (POD), Cd2+ absorption in W. trilobata hairy roots were investigated. Cd concentrations lower than 50 micromol/L enhanced the growth of hairy roots, while concentrations higher than 100 micromol/L inhibited growth, making the branched roots short and small, and also turning the root tips brown, even black. In comparison with the control (0 micromol/L Cd), the soluble protein content in hairy roots was found to increase when cultured with 10-50 micromol/L Cd, and decrease when exposed to a cadmium concentration higher than 100 micromol/L Cd. In addition, the activities of POD and SOD activity and MDA content were significantly higher than the control. Compared to the control (hairy roots cultured without 10-30 mmol/L Ca), 100 micromol/L Cd or 300 micromol/L Cd in combination with 10-30 mmol/L Ca resulted in increased growth, causing the main root and secondary roots thicker and also an increase in soluble protein content. On the contrary, MDA content and POD and SOD activities decreased. Quantitative analysis by Atomic Absorption Spectrophotometry showed that W. trilobata hairy roots can absorb and adsorb heavy metal Cd in the ionic form of Cd2+. The maximum content of Cd2+ absorbed by the hairy roots was obtained with a concentration 100 micromol/L Cd2+ while that of Cd2+ adsorbed by hairy roots was achieved with a concentration of 300 micromol/L Cd2+. The exogenous addition of 10-30 mmol/L Ca2+ was found to reduce the absorption, adsorption of Cd2+ and the toxicity of Cd significantly. This reduction in toxicity was caused by the reduction in the absorption of Cd and decreasing the lipid peroxidation through regulating the activities of antioxidant enzymes SOD and POD in the hairy roots. PMID- 23016312 TI - [Expression of thermostable recombiant Luciola lateralis luciferase and development of heat-stable pyrosequencing system]. AB - Pyrosequencing is a tool based on bioluminescence reaction for real-time analyzing DNA sequences. The sensitivity of pyrosequencing mainly depends on luciferase in reaction mixture. However, the instability of pyrosequencing reagents caused by fragile wild Photinus pyralis luciferase (PpL) in conventional pyrosequencing usually leads to unsatisfied results, which limits the application of pyrosequencing. In order to improve the stability of pyrosequencing reagents, the coding sequences of mutant thermostable Luciola lateralis luciferase (rt-LlL) was synthesized, and inserted into the plasmid of pET28a(+) to express the thermostable rt-LlL with a 6 x His-tag in the N terminal. The purified rt-LlL with the molecular mass of 60 kDa was obtained by Ni-affinity chromatography. The specific activity of rt-LlL was determined as 4.29 x 10(10) RLU/mg. Moreover, the thermostability of rt-LlL was investigated, and the results showed that rt-LlL had activity at 50 degrees C, and remained 90% of activity after incubated at 40 degrees C for 25 min. Finally, rt-LlL was used to substitute commercial Photinus pyralis luciferase in conventional pyrosequencing reagent to get thermostable pyrosequencing reagent. Comparing with conventional pyrosequencing reagent, the thermostable pyrosequencing reagent is more stable, and it's activity would not lose when incubated at 37 degrees C for 1 h. This study laid foundation of establishing reliable and stable pyrosequencing system which would be applied in Point-of-Care Testing. PMID- 23016313 TI - [Characteristics of extreme ultraviolet emission from tin plasma using CO2 laser for lithography]. AB - The extreme ultraviolet (EUV) emission characteristics from Sn plasma for lithography produced by a pulse discharge CO2 laser was investigated under different conditions. Extreme ultraviolet spectral measurements were made throughout the wavelength region of 6.5 nm to 16.8 nm using a grazing incidence flat-field spectrograph coupled with an X-ray charge-coupled device camera for detection of time-integrated spectra. The dependence of spectral properties of the EUV emission on pulse duration, incidence pulse energy, and buffer gas pressure was investigated. The results show that the peak of EUV spectra was located at 13.5 nm. The intensity of EUV emission increased with increasing laser energy ranging from 30 mJ to 600 mJ in a nonlinear manner with saturation effect. The critical energy of incident pulse laser for the generation of EUV emission is near 30 mJ in our experiment. The highest conversion efficiency of 1.2% in producing 13.5 nm EUV light with 0.27 nm bandwidth was achieved at pump energy of 425 mJ. The EUV spectra from a plate target produced by laser pulse with full width at half maximum range from 50 ns to 120 ns were recorded and negligible differences in their spectral features noticed even though higher spectral intensity was observed by shorter pulse duration. The 2% in-band EUV intensity with 52 ns pulse duration was 1.6 times higher than that with 120 ns pulse duration due to the increase in laser intensity. It was also found that the detected EUV spectral intensity rapidly decreased with increasing buffer air pressure, and the EUV emission could be totally absorbed at the pressure of 200 Pa, while weak EUV emission could be still detected at the buffer He gas pressure of 7 x 10(4) Pa. The experimental results showed that the absorption coefficient of 13.5 nm light at air buffer gas pressure of 100 Pa was 3.0 m(-1), while the absorption coefficient was 0.96 m(-1) at the same He buffer gas pressure. PMID- 23016314 TI - [Studies on the data processing method in chlorine measurement by differential optical absorption spectroscopy technology]. AB - In this paper, based on Differential Optical Absorption Spectroscopy (DOAS) technique, experimental measurements of chlorine was carried out in the laboratory with a small self-built experimental system. In dealing with the standard cross-section of chlorine, we presented two different methods: triangle filtering and polynomial fitting. Experiments showed that the concentration of chlorine could be accurately retrieved by the latter one. Simulation results showed that the error of retrieval result by fifth-order polynomial fitting was smaller than by other orders and an actual retrieval example shows that the fitting spectrums were nearly coincident with the measured spectrums with a residual delta(peak to peak) below 5 per hundred; The results measured in different sample pools displayed a high linearity of 0.9961 by this method. The main sources of errors during the entire experiment were simply analyzed. According to the experimental result above, it is feasible to detect chlorine using DOAS technology by polynomial fitting. PMID- 23016315 TI - [Calculating the stark broadening of welding arc spectra by Fourier transform method]. AB - It's the most effective and accurate method to calculate the electronic density of plasma by using the Stark width of the plasma spectrum. However, it's difficult to separate Stark width from the composite spectrum linear produced by several mechanisms. In the present paper, Fourier transform was used to separate the Lorentz linear from the spectrum observed, thus to get the accurate Stark width. And we calculated the distribution of the TIG welding arc plasma. This method does not need to measure arc temperature accurately, to measure the width of the plasma spectrum broadened by instrument, and has the function to reject the noise data. The results show that, on the axis, the electron density of TIG welding arc decreases with the distance from tungsten increasing, and changes from 1.21 X 10(17) cm(-3) to 1.58 x 10(17) cm(-3); in the radial, the electron density decreases with the distance from axis increasing, and near the tungsten zone the biggest electronic density is off axis. PMID- 23016316 TI - [Spectral analysis of nitrofurantoin in the terahertz frequency range]. AB - The present article measured the absorption coefficient spectra and refractive index spectra of nitrofurantoin original drug, which is one kind of nitrofuran drugs, in the terahertz frequency range from 0.2 to 1.8 THz using terahertz time domain spectroscopy. The results showed that there exist a number of characteristic absorption peaks of nitrofurantoin with different intensity in the range and the absorption coefficient spectra can be used to identify nitrofurantoin. The article also simulated absorption coefficient spectra of nitrofurantoin molecule within 0.2 - 1.8 THz using density functional theory by Gaussian software, and vibrational modes of some peaks in the experimental absorption coefficient spectra were analyzed and identified. The results show that the experimental absorption peaks at 1.25 and 1.60 THz correspond with the theoretical peaks at 1.30 and 1.67 THz, and these experimental peaks were caused by intramolecular vibrational modes of nitrofurantoin. PMID- 23016317 TI - [Application of near infrared spectroscopy technology (NIRS) in forage field]. AB - The majority of nutrients in ruminants and other herbivores come from forages. Forage quality not only affects the growth and production efficiency of livestock, but also determines the final output and quality of livestock products. Forage quality mainly depends on nutrient concentrations and their digestibility, palatability and the level of presence of antiquality factors and mycotoxins in forage. Near infrared reflectance spectroscopy (NIRS) has been widely used in many research areas because it is a inexpensive, rapid, simple and nondestructive technique offering the potential for qualitative and quantitative analysis. The present paper briefly introduces the principle and characteristics of NIRS, detailedly expounds the application of NIRS in forage quality. In addition, other applications of near infrared spectroscopy technique in forage are also discussed, including forage breeding, identification of variety and classification by kind. This paper comprehensively reviews the status quo of application of NIRS in forage filed, in order to contribute to promoting development of NIRS in this field in China. PMID- 23016318 TI - [Investigation on remote measurement of air pollution by a method of infrared passive scanning imaging]. AB - Passive remote sensing by Fourier-transform infrared (FTIR) spectrometry allows detection of air pollution. However, for the localization of a leak and a complete assessment of the situation in the case of the release of a hazardous cloud, information about the position and the distribution of a cloud is essential. Therefore, an imaging passive remote sensing system comprising an interferometer, a data acquisition and processing software, scan system, a video system, and a personal computer has been developed. The remote sensing of SF6 was done. The column densities of all directions in which a target compound has been identified may be retrieved by a nonlinear least squares fitting algorithm and algorithm of radiation transfer, and a false color image is displayed. The results were visualized by a video image, overlaid by false color concentration distribution image. The system has a high selectivity, and allows visualization and quantification of pollutant clouds. PMID- 23016319 TI - [Spectral investigation of atmospheric pressure plasma column]. AB - Atmospheric pressure plasma column has many important applications in plasma stealth for aircraft. In the present paper, a plasma column with a length of 65 cm was generated in argon at atmospheric pressure by using dielectric barrier discharge device with water electrodes in coaxial configurations. The discharge mechanism of the plasma column was studied by optical method and the result indicates that a moving layer of light emission propagates in the upstream region. The propagation velocity of the plasma bullet is about 0.6 x 10(5) m x s( 1) through optical measurement. Spectral intensity ratios as functions of the applied voltage and driving frequency were also investigated by spectroscopic method. The variation in spectral intensity ratio implies a change in the averaged electron energy. Results show that the averaged electron energy increases with the increase in the applied voltage and the driving frequency. These results have significant values for industrial applications of the atmospheric pressure discharge and have extensive application potentials in stealth for military aircraft. PMID- 23016320 TI - [Near-infrared spectroscopy analysis of adenosine and water in fermentation cordyceps powder and wavelength assignment]. AB - Based on near-infrared spectroscopy, four characteristic wavebands 4 277.63 - 4 3166.20, 4 887.06 - 4 941.07, 5 056.78 - 5 172.50 and 5 218.78 - 5 303.64 cm(-1), and two characteristic wavebands 4 902.49 - 4 817.64 and 4 740.49 - 4 107.91 cm( 1) were chosen to establish the partial least squares (PLS) regression model of water and adenosine in fermentation cordyceps powder, respectively. The prediction results of water and adenosine contents of the whole spectra PLS model were as follows: correlation coefficients (r) were 0.868 3 and 0.788 2, RMS error predictions (RMSEP) were 0.001 999 and 0.000 134, the remaining prediction deviations (RPD) were 1.974 4 and 1.640 7, respectively. However, using characteristic wavebands modeling can achieve a better performance with r of 0.869 1 and 0.829 0, RMSEP of 0.001 934 and 0.001 250, and RPD of 2.040 7 and 1.847 6 for water and adenosine respectively, and can largely improve calibration speed, providing the theoretical basis for the development of the testing instruments. So choosing the characteristic wavebands in this work to determine the water and adenosine in fermentation cordyceps powder is more effective. PMID- 23016321 TI - [Effects of indocyanine green on near-infrared optical properties and optical coherence tomographic image of cerebral blood vessel in vivo in rats]. AB - The scope of this research lies in the effects of indocyanine green (ICG) on the near-infrared optical properties and optical coherence tomographic image of cerebral blood vessel in vivo in rats. The skulls of SD rats were opened under nembutal anesthesia to expose and mark the middle cerebral artery. The reflectance spectra of middle cerebral artery were monitored by Vis/ NIR spectrometer and the optical attenuation coefficients of middle cerebral artery were detected by optical coherence tomography (OCT) when indocyanine green was administrated intravenously through tail veins. It was shown that the reflectance spectra of middle cerebral artery could provide guidance for OCT image, where characteristic changes appeared around 800 nm, an absorption peak of indocyanine green. Additionally, significant difference (p<0.01) was observed between the optical attenuation coefficients of middle cerebral artery with and without indocyanine green, which were 24.692 +/- 1.471 and 15.088 +/- 1.602, respectively. It was concluded that indocyanine green, as an optical contrast agent to enhance detection of cerebral artery by the reflectance spectra and OCT imaging, has the potential for monitoring and imaging of cerebral blood vessels. PMID- 23016322 TI - [Preparation of fluoridated hydroxyapatite coatings on titanium by electrolytic deposition and its FTIR characteristics]. AB - Fluoridated hydroxyapatite coatings (FHAP) were prepared on titanium substrate by electrochemical deposition technique containing Ca2+, PO4(3-), and F(-) ions. The deposition was all conducted at a constant current of 0.9 mA for 60 min at 60 degrees C. The as-prepared coatings were examined by scanning electron microscope (SEM), energy-dispersive Xray spectroscopy (EDS), Fourier transform infrared spectroscopy (FTIR) and Xray diffraction (XRD) tests. The results indicate that the FHAP cryatals take the morphology of nanoscale-rodlike cone rather than the micron-daisy petal, and the composite coating becomes more compact. The FTIR test indicates that the symmetry of stretching and bending vibration modes of hydroxyl changed, simulated body fluid immersion test proved that the FHAP coating had induced carbonate-apatite formation, indicating that the composite coating possesses excellent biocompatibility. PMID- 23016323 TI - [The study of transpiration influence on plant infrared radiation character]. AB - Studying vegetation infrared radiation character is the base of developing infrared camouflage and concealment technology of ground military target. Accurate fusion of target and background can be achieved by simulating formation mechanism of vegetation infrared radiation character. Leaf transpiration is characteristic physiological mechanism of vegetation and one of the main factors that influence its infrared radiation character. In the present paper, physical model of leaf energy balance is set up. Based on this model the influence of plant transpiration on leaf temperature is analyzed and calculated. The daily periodic variation of transpiration, leaf temperature and infrared radiation character of typical plants such as camphor tree and holly is actually measured with porometer and infrared thermal imaging system. By contrasting plant leaf with dryness leaf, experimental data indicates that plant transpiration can regulate leaf energy balance effectively and control leaf temperature in a reasonable range and suppress deep range variation of leaf infrared radiation character. PMID- 23016324 TI - [Study of the effect of temperature on the conformation of ovotransferrin by two dimensional infrared correlation spectroscopy]. AB - The conformation changes of Apo-Ovotransferrin and Holo-Ovotransferrin were studied with the heat treatment 25-95 degrees C by using Fourier transform infrared spectroscopy (FTIR) and two-dimensional correlation spectroscopy analyzer. The results of one-dimensional infrared spectroscopy showed that with the increase in temperature, the peak at 3 300 cm(-1) of Apo-Ovo-transferrin shifted more than that of Holo-Ovotransferrin. The peak at 3 300 cm(-1) derived from stretching vibrations of N-H and O-H indicates that iron-binding enhanced the role of hydrogen bonds and resistance to heat. The changing order of the secondary structure of ovotransferrin was determined by analyzing two-dimensional infrared spectra,witch is beta-sheet>amide II >-CH2 - bending vibration. In addition, it was found that the cross-peaks at 1 652 and 1 688 cm(-1) are different in synchronous and asynchronous counter maps by comparing Apo Ovotransferrin with Holo-Ovotransferrin. It was suggested that the temperature made less impact on the alpha-helix in Holo-Ovotransferrin than on that in Apo Ovotransferrin, however, the beta-turn in Holo-Ovotransferrin was more sensitive to temperature. PMID- 23016325 TI - [Rapid identification of softwood and hardwood by near infrared spectroscopy of cross-sectional surfaces]. AB - The feasibility of wood identification of softwood and hardwood by near infrared spectroscopy (NIR) coupled with partial least squares discriminant analysis (PLS DA) was investigated in the present paper. The near infrared spectra (780 - 2 500 nm) were collected from wood cross-section from one softwood species (Chinese fir) and one hardwood species (eucalyptus). The results show that: (1) The identification accuracy of the calibration samples predicted by the model based on NIR coupled the PLS-DA was 100%. The correlation coefficient between the NIR predicted category variable value and the true value was 0.990, and the SEC was 0.071; (2) The identification accuracy by the model based on the spectra with 780 1 100 nm wavelengths also was 100%, and the correlation coefficient and SEC were 0. 990 and 0. 070, respectively; (3) The identification accuracy for the test samples was 100%. It was suggested that NIR can be used to rapidly and accurately identify softwood and hardwood samples. It also provides a new approach to identifying wood species. PMID- 23016326 TI - [The analysis for silver iodide fine particles of TLC/FTIR matrix]. AB - In situ TLC/FTIR technique has tremendous potential in the analysis of complex mixtures. However, the progress in this technique was quite slow. The reason is that conventional stationary phase has strong absorption in FTIR spectrum and thus brings about severe interference in the detection of samples. To solve the problem, the authors propose to use AgI fine particles as stationary phase of TLC plate. The reasons are as follows: Silver iodide fine particles have no absorbance in an IR region between 4 000 and 800 cm(-1), therefore, the interference caused by IR absorption of stationary phase can be removed. Moreover, silver iodide is stable and insolvable in water and organic solvents and thus it will not be destroyed by mobile phase or react with samples during the TLC separation. To improve TLC separation efficiency and quality of FTIR spectra during the TLC/FTIR analysis, the size of AgI particles should be below 500 nm. We used orthogonal design approach to optimize the experimental condition to AgI particles so that the average size of AgI particles is around 100 nm. No absorption of impurity or adsorbed water were observed in FTIR spectrum of the AgI particles the authors used "settlement volatilization method" to prepare TLC plate without using polymeric adhesive that may bring about significant interference in FTIR analysis. Preliminary TLC experiments proved that the TLC plate using AgI fine particles as stationary phase can separate mixtures of rhodamine B and bromophenol blue successfully. Applications of silver iodide fine particles as stationary phase have bright perspective in the development of in situ TLC/FTIR analysis techniques. PMID- 23016327 TI - [Comparative study on the performance of deformable mirror of NIR based human eye aberration correction system]. AB - The structure features and spatial characteristics of the two kinds of micro machined membrane deformable mirrors, OKO 37-element and BMC 140-element, which work in the NIR based human eye aberration correction system, are compared and analyzed. At same time, the principal component analysis was carried out for the influence function of the mirror, the voltage control model was established and the optimal control mode of deformable mirror can be determined by adjusting the control parameter d. Finally, the simulation experiments for fitting aberration of unit Zernike mode and human eye aberration of Thibos model were carried out. The experiment results show that the capability for fitting the each Zernike mode of BMC 140-element mirror is twice more than the OKO 37-element mirror at least. When correcting the Thibos model human eye aberration whose average RMS error is 0.638 lambda (lambda=0.785 microm), the residual RMS error of BMC mirror is 0.063 lambda which achieves the diffraction limit (lambda/14) of the optical system, but the correction capability of OKO mirror is far less than BMC mirror due to the large cross-linked value between actuators, small density distribution of actuators and some other influencing factors, and the residual wave-front RMS error is 0.168 lambda. The methodology can also be used for other types of deformable mirror performance evaluation. PMID- 23016328 TI - [Nondestructive identification of the root of mountain cultivation ginseng and growth years by near infrared spectroscopy]. AB - Mountain cultivation ginseng (MCG) and garden cultivation ginseng (GCCG) were identified by near infrared spectroscopy, so were MCG of different growth years. 96 MCG samples of different growth years, including 24 of fifteen years and 72 of ten years, and 177 GCG samples were collected. After the near infrared spectra of these samples were collected, discriminant analysis was used to distinguish MCG and GCG, so was MCG of different years. After the original spectra were pretreated, discriminant analysis models of MCG and GCG, MCG of different growth years were developed respectively with selected principa component numbers in full spectra region. The correct discrimination rate of two groups of model was both 100%. The propose methods are accurate, fast and nondestructive, and can be applied to the quality control of MCG. It has an important significance for building market image of MCG. PMID- 23016329 TI - [Infrared spectrum characteristics of vehicle body paint]. AB - Two hundred eighty seven samples of vehicle paint were collected, and 940 spectra were obtained by Fourier transform infrared micro spectrometer. The spectral features of varnish, finish layer, and coated layers of different models and different color were analyzed, and the spectra similarities were compared. The results show that the varnish similarity on the same models with different color is 99.5%, and some similar model with the same manufacturer had high similarity. The finish spectra have remarkable differences with different model and different color, and the similarity degree is under 70%. The coated layer similarity varies between 83.33% and 96.91% among the common lacquer putty, and it ranges between 70.12% and 96.44% among the water-based lacquer putty. The metal components of paint will influence the spectrum characteristics. The spectra of the vehicle paint will change with the usage time. PMID- 23016330 TI - [Study on extracts of active substances from larch bark by FTIR spectroscopy]. AB - The present study is to compare and analyze extracts of active substances from larch bark using ultrasonic wave quickly and undamagedly via Fourier transform infrared spectroscopy, second derivative IR spectroscopy and two dimensional spectroscopy. In the spectra of active substances from larch bark, there are four main components as the structural unit, and (+)-catechin, (-)-epicatechin, gallic acid and vitisinol represented a series of poly polyphenolic compounds. Furthermore the linkage between unit in proanthocyanidins dimmers was confirmed at position C(4)-C(8). Through observing the second derivative IR spectra of active substances from larch bark, the absorption peaks, 1 631, 1 561 and 1 469 cm(-1) of active substances moved to the smaller wave number direction, while 1 606, 1 385, 1 285 and 1 157 cm(-1) of active substances moved to the bigger wave number direction, and the intensity of characteristic peaks can represent the content of corresponding compound. In the two dimensional spectra, the active substances from larch bark have five automatic peaks in 1 345-1 675 cm(-1). The authors developed the new method to analyse and evaluate the active substances from larch bark successfully. PMID- 23016331 TI - [Study on secondary structural changes of protein in the formation of microcapsule by FTIR spectroscopy]. AB - The mixture of whey protein and isolated soy protein with maltodextrin as microcapsules wall material was adopted. The secondary structure constitution of these two kinds of proteins in the process of heating and spray drying together with maltodextrin were studied by Fourier transform infrared spectra. The result showed that both whey protein and isolated soy protein exhibited differences in the secondary structures. The rate of alpha-helix in whey protein decreased 1.9% and beta-turn content of the protein remains virtually unchanged, beta-sheet increased 8.19%, and random coil decreased 7.18%. At the same time the content of alpha-helix in isolated soy protein decreased 1.64%, the change of beta-sheet is not obvious while beta-turn increased 10.20% and random coil decreased 9.03%. Meanwhile, the amide I bands of these two proteins both shifted to the lower wave number direction, indicating that in the formation process of the microcapsule wall structure there are complex interactions between maltodextrin and proteins, and the hydrogen bonds which comes into existence are comparatively strong. With the help of scanning electron microscope, it was discovered that the surface is more smooth and integrated when the microcapsules wall material contains whey protein, which is high in alpha helix. PMID- 23016332 TI - [Study on characteristics of laser ablation in KTP crystal and its influence on the Raman spectroscopy]. AB - The research and development of the KTP crystal with high threshold is of very importance for its application in high-energy laser systems. Ablation characteristics in KTP crystal as well as their influence on the Raman spectroscopy were studied by UV laser with high repetition frequency. The research results show that the laser plasma effects are the main reasons for the damage in the KTP crystal. The inverse bremsstrahlung absorption effect can increase the deposition of the laser pulse energy greatly; the ionization effect can make the crystal dislocated completely; shock wave effect can push away the mixture of melted, vaporized and ionized materials and cause cracks in the pit. Through investigation and comparison of the Raman spectroscopy before and after the laser ablation, it was found that the distribution characteristics of Raman peaks are almost the same, suggesting that the basic structures of KTP crystal do not change. But almost all the Raman characteristic peaks' R1R values have changed and the widths are broadened, which means that the crystalline degree has been decreased. The Raman peaks of TiO6 and PO4 oxygen polyhedron shift to the lower wave number, which indicates that bonding force becomes weaker and the KTP crystal can be damaged easily. PMID- 23016333 TI - [SERS spectroscopy study of three pathogenic bacteria]. AB - The SERS spectra of staphylococcus aureus, proteus, and Escherichia coli was obtained on colloidal Ag nanoparticles prepared by the microwave method with the portable Raman spectrometer. Staphylococcus aureus have obvious Raman vibrating peak at 725, 1 330 and 1 450 cm(-1), proteus have obvious Raman vibrating peaks at 650,725,950, 1 325 and 1 463 cm(-1), while E. coli have obvious Raman vibrating peaks at 650, 950, 1 125, 1 242,1 320 and 1 457 cm(-1). Each peak was assigned preliminarily. Not only the position of Raman vibration peaks but also the intensity of the three bacteria is obviously different, so SERS can be used for identification and distinction of E. coli, staphylococcus aureus and proteus. PMID- 23016334 TI - [Fast discrimination of edible vegetable oil based on Raman spectroscopy]. AB - A novel method to fast discriminate edible vegetable oils by Raman spectroscopy is presented. The training set is composed of different edible vegetable oils with known classes. Based on their original Raman spectra, baseline correction and normalization were applied to obtain standard spectra. Two characteristic peaks describing the unsaturated degree of vegetable oil were selected as feature vectors; then the centers of all classes were calculated. For an edible vegetable oil with unknown class, the same pretreatment and feature extraction methods were used. The Euclidian distances between the feature vector of the unknown sample and the center of each class were calculated, and the class of the unknown sample was finally determined by the minimum distance. For 43 edible vegetable oil samples from seven different classes, experimental results show that the clustering effect of each class was more obvious and the class distance was much larger with the new feature extraction method compared with PCA. The above classification model can be applied to discriminate unknown edible vegetable oils rapidly and accurately. PMID- 23016335 TI - [Fluorescence spectrum monitor for early warning of greenhouse cucumber aphis pests]. AB - The infection and degree of cucumber aphis pests was studied by analyzing chlorophyllfluorescence spectrum in greenhouse. Based on the configuration of the spectrum, characteristic points were established, in which the intensity of waveband F632 was the first characteristic point between healthy and aphis pests leaves. The second characteristic point was K which was the change rate of spectral curve from waveband F512 to F632. The early warning could be executed on plants depending on these two points. The models of the infection and degrees of aphis pests were established for different wavebands by the least square support vector machine classification method (LSSVMR) radial basis function(RBF). The accuracy rate of classification and prediction of the models was compared by different peaks and valleys value in wavebands. The results indicated that the prediction accuracy of the model established by waveband F632 was the most perfect (96.34%). PMID- 23016336 TI - [A method for determination of trace naphthalene and phenanthrene in water using constant-wavelength synchronous fluorescence spectrometry]. AB - In view of synchronous fluorescence possessing the character of good selectivity, high sensitivity, less interference, etc. it can be used for simultaneous determination of multi-component mixtures of polycyclic aromatic hydrocarbons (PAHs). A new method of constant-wavelength synchronous fluorescence spectrometry to determine two naphthalene and phenanthrene of PAHs was developed in this study. The effect of different experimental conditions, such as different disolvents for character of fluorescence spectra and the choose of the optimal wavelength difference were studied. Experiment showed that the simultaneous indentification and quantitative determination of the two PAHs when delta lambda = 100 was chosen. The fluorescence intensity was linearly related to naphthalene and phenanthrene concentration in the range of 0.5-25.0 microg x L(-1) with correlation coefficient 0.999 5 and 0.999 7, respectively. The detection limits were all lower than 0.03 microg x L(-1), and the relative standard deviations for naphthalene and phenanthrene were 1.19% and 180% (n=7), respectively. Results show that the compounds can be analyzed qualitatively and quantitatively by synchronous fluorescence spectrometry. PMID- 23016337 TI - [Research on the degradation of BaP with potassium ferrate characterized by fluorescence]. AB - The degradation of Benzo(a)pyrene (BaP) by potassium ferrate was researched by means of multiple fluorescence spectroscopic methods such as synchronous, time scan, excitation emission matrix (EEM) and photometry, under the optimal condition. Within the degradation process, the characteristics of the BaP's concentration at different time-intervals, and the kinetics of the degradation of BaP by potassium ferrate were discussed. From the experimental data, both synchronous and EEM spectra's results showed that the concentration of BaP was reduced 90% by potassium ferrate within 20 s after degradation, and the reaction process was very slow after 60 s. The degradation kinetic equation, ln(F0/Ft) = 0.563 2t + 0.171 2, (R2 = 0.994 2), was obtained through a convenient and fast way combining the time-scan fluorescence data and photometry data, and the photometry included the synchronous photometry and emission photometry. According to the kinetic equation, the degradation of BaP by potassium ferrate was in accord with the order of the first order reaction. So this article could provide a very useful conference for the research on the pollutant degradation by potassium ferrate, especially for the degradation process and the degradation mechanisms. PMID- 23016338 TI - [The investigation of organic matter removal in water treatment plant by EEM spectra coupled with self-organizing map]. AB - Three-dimensional excitation and emission matrix fluorescence spectra (3D-EEM) has attracted the increasing attention of researchers in water monitoring and water treatment areas. The self-organizing map (SOM) is a kind of non-supervised and self-learning neural network with the feature of high self-stability and noise tolerance. In the present paper, SOM technique was employed for the exploratory analysis of EEM spectra of water samples in a water treatment plant The results showed that EEM spectra could be clustered into three classes, corresponding to tryptophan-like protein substances, tyrosine-like protein substances, and UV fulvic-like substances. The three components could be effectively removed during the whole water treatment process with the high removal of 84.6% (tyrosine-like), 79.9% (tryptophan-like), and 69.1% (UV fulvic like). The results show that SOM technique can be used as an effective tool for EEM spectra analysis, which is helpful for the optimization of water treatment process parameters, the improvement of process performance, and the operation of water treatment plant. PMID- 23016339 TI - [Research on transient temperature detection by spectrum function variation of speckle pattern interferometry]. AB - To improve the accuracy of the transient temperature detection system, transient temperature inversion processing algorithms was proposed based on spectrum analysis of speckle pattern interferometry. The interference fringes were formed by speckle interferometry in the system, and due to transient temperature changes that cause the material strain, the speckle interference pattern changes. The interference fringes on the measured surface were obtained by the area array CCD collection before and after deformation. The corresponding spectrum density function will change with the changes in the transient temperature, and the amplitude changes of center wavelength were inverted by the speckle pattern interferometry. Through detecting and calculating the ratio of the amplitude of the center wavelength, the transient temperature can be obtained by spectrum analysis. In the analysis and calculation for the function of transient temperature and material strain, material strain and interference fringes, the amplitude and phase function of the transient temperature change and interference fringes were derived, providing the necessary conditions for detecting spectral density function temperature. The experiment used 660 nm laser diode and SI6600 type area CCD detector. By extracting the offset of the center wavelength from the spectrum distribution function, the calculation and calibration data were compared to the data obtained with the traditional method of interference temperature detection, and the result showed that the detection accuracy can achieve 0.3%. Compared to traditional direct detection of interference fringes changes, the accuracy improved nearly three times by the method. PMID- 23016340 TI - [Effects of different fertilization treatments on soil humic acid structure characteristics]. AB - The present article used soil humic acid as research object to study effects on the structure characteristics of soil humic acid under the condition of applying cake fertilizer, green manure, straw fertilizer with the same contents of nitrogen and phosphorus. It used element analysis, micro infrared, and solid 13C NMR for structure analysis, the results indicated that: The chemical composition and structure characteristics of humic acids were similar, but they also had many obvious differences. (1) The atomic ratios of H/C, O/C, and C/N were all different for the humic acids, the soil humic acid of cake fertilizer processing had the highest contents of H and N, green manure processing of soil humic acid contained the highest content of O, while straw fertilizer processing of soil humic acid contained highest content of C. (2) Infrared analysis displayed that the three soil humic acids contained protein Cake fertilizer processing of soil humic acid contained the most amino compounds, green manure processing of soil humic acid contained the maximum contents of hydroxyl and aliphatic hydrocarbon, while straw fertilizer processing of soil humic acid contained the highest contents of alcohol and phenol. (3) Solid 13C-NMR data indicated that cake fertilizer processing of soil humic acid contained the most carboxyl carbon, green manure processing of soil humic acid contained the highest contents of alkyl carbon and carbonyl carbon, while straw fertilizer processing of soil humic acids had the most alkoxy carbon and aromatic carbon PMID- 23016341 TI - [An unsupervised classification of hyperspectral images based on pixels reduction with spatial coherence property]. AB - In order to improve classification and edge accuracy, PRSCP and linear regression analysis are introduced; a new algorithm of unsupervised classification based on PRSCP is proposed. The algorithm procedure starts with the similarity of pixel spectral, and then makes use of minimum related window to combine similar pixels spatially adjacent into a block. Linear expression is applied to model the spectral vector of pixels in the same block, and significance of the linear expression is verified by F-statistic. The basic vector of block is estimated via ODLR, and blocks with similar basic vectors are combined into the same class. AVIRIS data is used to evaluate the performance of the proposed algorithm, which is also compared with K-MEANS and ISODATA. Experimental results show that the proposed algorithm outperforms K-MEANS and ISODATA in terms of classification accuracy, edge and robustness. PMID- 23016342 TI - [Influence of composite cathode of Ag/LiF/Al on the performance of P3HT : PCBM solar cells]. AB - The improved photocurrent of regioregular poly(3-hexylthiophene) (P3HT) and 6,6 phenyl C61-butyric acid methylester (PCBM) based polymer solar cells (PSCs) using LiF and Al cathode, modified with a reasonable thin Ag layer, was demonstrated. Using an optimal 4nm Ag layer-modified electrode gave 20% improved short-circuit photocurrent density over PSCs with only LiF/Al cathode under AM1.5G illumination of 100 mW x cm(-2). The increased short-circuit photocurrent density is ascribed to plasmon enhancement of the polymer absorption by nanotextured Ag film. The fill factor and open voltage of PSCs using Ag/LiF/Al cathode are decreased compared with the control PSCs with only LiF/Al cathode, which result in the decrease in power conversion efficiency of PSCs modified with Ag film. The possible reason for the deteriorated performance of PSCs with Ag/LiF/Al is stronger carrier recombination at nanotextured Ag. PMID- 23016343 TI - [On-orbit response variation analysis of FY-3 MERSI reflective solar bands based on Dunhuang site calibration]. AB - MERSI is the keystone payload of FengYun-3 and there have been two sensors operating on-orbit since 2008. The on-orbit response changes obviously at reflective solar bands (RSBs) and must be effectively monitored and corrected. However MERSI can not realize the RSBs onboard absolute radiometric calibration. This paper presents a new vicarious calibration (VC) method for RSBs based on in situ BRDF model, and vector radiometric transfer model 6SV with gaseous absorption correction using MOTRAN. The results of synchronous VC experiments in 4 years show that the calibration uncertainties are within 5% except for band at the center of water vapor absorption, and 3% for most bands. Aqua MODIS was taken as the radiometric reference to evaluate the accuracy of this VC method. By comparison of the simulated radiation at top of atmosphere (TOA) with MODIS measurement, it was revealed that the average relative differences are within 3% for window bands with wavelengths less than 1 microm, and 5% for bands with wavelengths larger than 1 microm (except for band 7 at 2.1 microm). Besides, the synchronous nadir observation cross analysis shows the excellent agreement between re-calibrated MERSI TOA apparent reflectance and MODIS measurements. Based on the multi-year site calibration results, it was found that the calibration coefficients could be fitted with two-order polynomials, thus the daily calibration updates could be realized and the response variation between two calibration experiments could be corrected timely; there are large response changes at bands with wavelengths less than 0.6 microm, the degradation rate of the first year at band 8 (0.41 microm) is about 14%; the on-orbit response degradation is maximum at the beginning, the degradation rates slow down after one year in operation, and after two years the responses even increase at some band with wavelengths larger than 0.6 microm. PMID- 23016344 TI - [The application of spectral geological profile in the alteration mapping]. AB - Geological section can help validating and understanding of the alteration information which is extracted from remote sensing images. In the paper, the concept of spectral geological profile was introduced based on the principle of geological section and the method of spectral information extraction. The spectral profile can realize the storage and vision of spectra along the geological profile, but the spectral geological spectral profile includes more information besides the information of spectral profile. The main object of spectral geological spectral profile is to obtain the distribution of alteration types and content of minerals along the profile which can be extracted from spectra measured by field spectrometer, especially for the spatial distribution and mode of alteration association. Technical method and work flow of alteration information extraction was studied for the spectral geological profile. The spectral geological profile was set up using the ground reflectance spectra and the alteration information was extracted from the remote sensing image with the help of typical spectra geological profile. At last the meaning and effect of the spectral geological profile was discussed. PMID- 23016345 TI - [Research on the spectral feature and identification of the surface vegetation stressed by stored CO2 underground leakage]. AB - With the global climate warming, reducing greenhouse gas emissions becomes a focused problem for the world. The carbon capture and storage (CCS) techniques could mitigate CO2 into atmosphere, but there is a risk in case that the CO2 leaks from underground. The objective of this paper is to study the chlorophyll contents (SPAD value), relative water contents (RWC) and leaf spectra changing features of beetroot under CO2 leakage stress through field experiment. The result shows that the chlorophyll contents and RWC of beetroot under CO2 leakage stress become lower than the control beetroot', and the leaf reflectance increases in the 550 nm region and decreases in the 680nm region. A new vegetation index (R550/R680) was designed for identifying beetroot under CO2 leakage stress, and the result indicates that the vegetation index R550/R680 could identify the beetroots after CO2 leakage for 7 days. The index has strong sensitivity, stability and identification for monitoring the beetroots under CO2 stress. The result of this paper has very important meaning and application values for selecting spots of CCS project, monitoring and evaluating land-surface ecology under CO2 stress and monitoring the leakage spots by using remote sensing. PMID- 23016346 TI - [Effects of spectral resolution and noise on the measurement of indices]. AB - In the present paper, we analysed the effects of spectral resolutions and signal to-noise ratios (SNRs) on 19 atomic absorption line indices of Lick index system. First of all, adopting method of convolving a spectrum with a Gaussian profile, we transformed spectra into those under different resolutions and then measured the line indices on them. Comparisons of the indices under various resolutions allow to investigate the impact of spectral resolution change on the accuracy of measurements of indices. Secondly, by adding random noises with different Gaussian distribution to a spectrum, the authors transformed theoretical spectra with no noises into those under diverse SNRs and then measured line indices on them. Comparisons of the indices under different SNRs greatly helped analyse the influence of SNR on the precision of the measurements of line indices. It comes from comparisons and analysis that the spectral resolution change can cause an index measurement change depending on the extent of the change of spectral resolution. Such a kind of change relationship varies with the indices. The lower the SNR, the less precise the measurements of indices. The effect of SNR on the measurements of indices can be ignored if SNR is larger than 25. PMID- 23016347 TI - [Feasibility of monitoring karst standing conditions with vegetation spectra]. AB - Karst regions are typically ecological fragile zones constrained by geological setting, which resulted in high heterogeneity of vegetation standing conditions. The karst vegetation was featured with stone, dry and high calcium carbonate content growth conditions. Based on vegetation spectral analysis and canonical correspondence analysis (CCA), the present study aimed to examine the feasibility of using vegetation spectra to monitor the heterogeneous karst standing conditions. The results showed that there were significant differences between karst vegetation and non-karst vegetation within the spectral range of 1 300-2 500 nm reflectance and 400 - 680 nm first-derivative spectra. It was found that soil moisture and calcium carbonate contents had the most significant effects on vegetation spectral features in karst regions. Ordination diagrams of CCA could distinguish the differences of karst vegetation and non-karst vegetation. Our study demonstrates that vegetation spectra are highly related to karst standing conditions and it is feasible to monitor karst standing conditions with vegetation spectral features. PMID- 23016348 TI - [Influence of foliar dust on crop reflectance spectrum and nitrogen monitoring]. AB - More researches were carried out to investigate the application of spectral technology on crop nutrition diagnosis. However, the complex conditions in the field results in the uncertainty of spectrum. In this paper, the influence of foliar dust on spectral of the crop beside the nation road was studied, the differences of the raw spectral reflectance and first derivative spectral reflectance between the foliar with dust and the foliar washed with deionised water were analyzed, nitrogen prediction models were built on the disturbance of foliar dust. Result showed that the dust foliar spectral reflectance increased in the visible light (350-720 nm) and shortwave infrared (SWIR) (1 360-2 500 nm) regions whereas the spectral reflectance in the near infrared (NIR) (720-1 360 nm) wavelength regions decreased. There were no change rules for blue edge position, yellow edge position, red edge position, blue edge slope and yellow edge slope on the effect of foliar dust, but red edge slope, blue edge area, yellow edge area, red edge area decreased. Determinate coefficient (R2) of nitrogen prediction models reduced in the condition of foliar dust. The primary research work about the condition of foliar dust was studied which helps to provide foundation for evaluating effect of foliar dust and proposing foliar dust modification model in the future. PMID- 23016349 TI - [Division of winter wheat yield estimation by remote sensing based on MODIS EVI time series data and spectral angle clustering]. AB - Crop yield estimation division is the basis of crop yield estimation; it provides an important scientific basis for estimation research and practice. In the paper, MODIS EVI time-series data during winter wheat growth period is selected as the division data; JiangSu province is study area; A division method combined of advanced spectral angle mapping(SVM) and K-means clustering is presented, and tested in winter wheat yield estimation by remote sensing. The results show that: division method of spectral angle clustering can take full advantage of crop growth process that is reflected by MODIS time series data, and can fully reflect region differences of winter wheat that is brought by climate difference. Compared with the traditional division method, yield estimation result based on division result of spectral angle clustering has higher R2 (0.702 6 than 0.624 8) and lower RMSE (343.34 than 381.34 kg x hm(-2)), reflecting the advantages of the new division method in the winter wheat yield estimation. The division method in the paper only use convenient obtaining time-series remote sensing data of low resolution as division data, can divide winter wheat into similar and well characterized region, accuracy and stability of yield estimation model is also very good, which provides an efficient way for winter wheat estimation by remote sensing, and is conducive to winter wheat yield estimation. PMID- 23016350 TI - [Effect of different distribution of components concentration on the accuracy of quantitative spectral analysis]. AB - In order to discuss the effect of different distribution of components concentration on the accuracy of quantitative spectral analysis, according to the Lambert-Beer law, ideal absorption spectra of samples with three components were established. Gaussian noise was added to the spectra. Correction and prediction models were built by partial least squares regression to reflect the unequal modeling and prediction results between different distributions of components. Results show that, in the case of pure linear absorption, the accuracy of model is related to the distribution of components concentration. Not only to the component we focus on, but also to the non-tested components, the larger covered and more uniform distribution is a significant point of calibration set samples to establish a universal model and provide a satisfactory accuracy. This research supplies a theoretic guidance for reasonable choice of samples with suitable concentration distribution, which enhances the quality of model and reduces the prediction error of the predict set. PMID- 23016351 TI - [Local heating of murine skin by millimeter waves based on HBHE]. AB - The authors deduced Gaussian function of millimeter wave power distribution, and built up a transient thermal multilayer model for the heating of murine skin by high power millimeter waves with finite volume method (FVM) based on HBHE in the present paper. We analyzed the calculated results and compared them with the results calculated by Pennes' equation and the experimental ones; found that the temperature calculated by HBHE was more reasonable. Especially under high power millimeter wave, the calculated results were basically consistent with the experimental ones, and the superiority of the theoretical model was confirmed. PMID- 23016352 TI - [Study on polarization spectral feature of suspended sediment in the water body]. AB - Remote sensing of lake water based on water-leaving radiance is to retrieve the concentrations of suspended sediment, phytoplankton and yellow substance which have great impacts on spectrum to assess the water quality. Howerver, because of the complexity of the lake water compositons and the interference between the different components, it is of great difficulty to get accurate results with the reflectance spectrum method developed recently. In the present paper, the authors firstly discussed the reflectance and polarization spectral feature of suspended sediment water body, found out the relations of the reflectance and the degree of polarization of water-leaving radiance and the concentration of suspended sediment at the sensitive bands. The authors also compared the effectiveness of the retrieval approaches based on reflectance and polarization in laboratory water body and Chaohu water body respectively. The results show that in the lake water body where the constituents are very complex, the polarization information has greater capacity of anti-jamming, therefore it will have great potential applictions in lake water quality remote sensing. PMID- 23016353 TI - [Study on the soil salinization monitoring based on synthetical hyperspectral index]. AB - The present paper selected the spectral reflectivity of saline soil and vegetation of Weigan-Kuqa River Delta Oasis in the northern margin of the Tarim Basin in Xinjiang as objects, and used various spectral transforms to process the data with continum removed methods, derivate spectra, reciprocal, first order differential and root mean square etc, then analyzed the spectrum features and decided the most sensitive band ranges most relevant to salinization, and used field hyperspectral vegetation index, soil salinity index and measured synthetical spectral index to respectively establish hyperspectral quantitative models which could evaluate the soil salinization degrees. By comparing various spectral transformations of hyperspectral data the result showed that the first derivative of measured soil and vegetation hyperspectral were most sensitive to soil salinization degrees. The hyperspectral quantitative model based on measured synthetical spectral index could monitor soil salinization accurately and was better than the models simply based on vegetation index or soil salinity index. The research provided some scientific basis with soil salinization detection. PMID- 23016354 TI - [Analysis of spectral characteristics of oil film on water based on wavelet transform]. AB - The diagnostic features are the basis to detect and characterize the oil film on water through optical remote sensing. This work shows the results of lab spectral measurements of light diesel oil with thickness ranged 1.0 - 127 microm. A wavelet transform were performed to the reflectance, and the singularity (388-393 nm) was explored as the indicators of oil film thickness. The results indicate that the reflectance of light diesel oil film is higher than that of water in the range from 350-2 500 nm. There is a reflectance peak near 388 nm when the thickness of oil film is larger than 6 microm, however, no distinguished features could be recognized when oil films were thinner than 6 microm. The wavelet coefficients of the fifth decomposition level by applying Daubechies 4 (db4) mother wavelets proved successful for identifying the singularity of oil film's reflectance spectra and its accurate position. With the thickness lager than 6 microm, the detail coefficients performed an abrupt change within the range of 388-393 nm, and became more violent while oil films' thickness increased. This research demonstrated that oil films on water with different thickness could be distinguished based on wavelet detail coefficients, with important implications for detection of oils on water using UV and short wave optical remote sensing. PMID- 23016355 TI - [Analysis on the spectral properties of the stilbene 420 laser dye]. AB - Stilbene 420 dye solution was prepared and the laser dye absorption spectrum was measured. Q-switched frequency-doubling Nd : YAG laser was used as the pumping source to realize the stilbene 420 dye laser and fluorescence spectra analysis. Laser spectroscopy reached the strongest peak at 425 nm and full width at half maximun (FWHM) is 1 nm. Spectral range was from 420 nm to 440 nm. Fluorescence spectrum peak was at 428.5 nm. Compared with the strongest peak laser, the wavelength difference was 3.5 nm. The highest dye conversion efficiency was 9.26%. PMID- 23016356 TI - [Determination of acidity in oranges based on emphatic orthogonal signal correction and principal component orthogonal signal correction]. AB - Near infrared (NIR) spectroscopy technology based on a portable NIR analyzer, combined with PC-OSC algorithm, EOSC algorithm and generalized regression neural network (GRNN) has been applied to establishing quantitative models for prediction of acidity in 112 orange samples. The obtained results demonstrated that the fitting and the predictive accuracy of the models with EOSC algorithm were satisfactory and the EOSC algorithm was not as susceptible to overfitting the data as PC-OSC algorithm. The correlation between actual and predicted values of calibration samples (Rc) obtained by the EOSC acidity model was 0.888 0, and prediction samples (Rp) was 0.885 6. The RMSEP was 0.081 65. The results proved that the portable NIR analyzer combined with EOSC algorithm and GRNN can be a feasible tool for the determination of acidity in oranges. PMID- 23016357 TI - [Measuring the density of wood and bamboo using computed tomography]. AB - CT is widespread non-destructive detection technique for wood materials, and the density measurement is a key role during this application. In the present report, the use of CT for air-dry density measurement of wood and bamboo is described. The authors found that there were marked linear correlations between air-dry density (0.303-1.061 g x cm(-3)) of 24 kinds of woods and their respective CT value, as well as 25 kinds of lignin materials (including 24 kinds of woods and 1 kind of bamboo) and the CT value, both with correlation coefficient of 0.99, which belonged to the CT technological breakthrough for wood quantitative detection These research results show that CT is an appropriate way to measure density for wood and bamboo, and would provide technical support for CT used in the field of wood science research and wood processing. PMID- 23016358 TI - [Detection of trace uranium in air with field spectrometry]. AB - As a natural radioactive element, uranium and its compounds exist as aerosol and transfer in air. In gas phase, uranium can cause various kinds of radioactive damage to human body. The change in its concentration in a local area is related to the exploration and utilization of nuclear energy. Therefore, the development of field method for rapid uranium detection in air sample is very important. In this contribution, the air samples over uranium ores collected by a general pump was absorbed with 2.0 mol x L(-1) nitrate and then reacted with solid reagent kit. When the reaction between trace uranium and chromogenic reagent was finished, the homemade portable photometer was used to measure the absorbance. The results showed that the concentration of uranium in air samples over low grade uranium ores can be successfully determined by the present method and the values agree with that obtained by ICP-MS. The RSD measured by the new method was 1.72%. The application of the new field spectrometry in discriminating uranium ores from other ores has the potential advantages of easy operation, cost-saving and high accuracy. PMID- 23016359 TI - [Investigation of spectroscopy of ZnCuInS/ZnS quantum dots and poly-TPD]. AB - In the present paper ZnCuInS/ZnS core/shell quantum dots were prepared with the particle size of 3.2 nm. Its radiation is based on the donoracceptor pair transitions, not the band edge emission. According to the measurement of photoluminescence spectrum emitted by ZnCuInS/ZnS core/shell quantum dots, the emitting peak of 620 nm and the full width at half-maximum of 95 nm were achieved as red emitter; meanwhile, organic poly(N, N'-bis(4-butylphenyl)-N, N' bis(phenyl) benzidine) (Poly-TPD) film was deposited and used as cyan-emitter with the peak of 480 nm. Two structures of Poly-TPD were analyzed and discussed according to the photoluminescence spectrum. Two wavelengths are complementary color. Therefore, two films were deposited one by one as bilayer emitter to obtain the complementary emission. After the suitable bias was applied on the films, the white emission was achieved with the Commission Internationale de l' Eclairage (CIE) chromaticity coordinates of (0.336, 0.339) and color rendering index of 92. Therefore, the bilayer-structure is a promising candidate for white light emitting diodes fabrication. PMID- 23016360 TI - [Synthesis of maleic anhydride-acrylamide copolymer and study of its adsorption properties by ICP-AES]. AB - A novel adsorbent was prepared with maleic anhydride and acrylamide as functional monomer, N, N-methylenebisacrylamide as cross-linking agent, and ammonium persulfate as initiator through aqueous polymerization reaction. The adsorbent was characterized by Fourier transmission infrared spectra (FTIR) and Thermogravimetry (TG). The adsorption properties and selectivity properties were investigated by inductively coupled plasma atomic emission spectrum (ICP-AES). The result indicated that the optimum acidity was pH 3.5 and the reaction attained equilibrium at 1 h under stirring. The polymer adsorbent exhibited high selectivity for Fe3+ and its saturated adsorption capacity was 78.81 mg x g(-1). The adsorption kinetics was well described by pseudo-second kinetic equation, and the adsorption of the copolymer for Fe3+ accorded with Freundlich isothermal model. The adsorption process was found to be endothermic. PMID- 23016361 TI - [Determination and distribution patterns analysis of rare earth elements in sediments of Prydz Bay]. AB - A sensitive quantificational method was developed for the analysis of Sc, Y, La, Ce, Pr, Nd, Sm, Eu, etc. in sediments of Prydz Bay by inductively coupled plasma mass spectrometry, and then the REE distribution patterns were analyzed. The samples were digested by microwave using HNO3-H2O2-HF as oxidant. The results showed that the total contents of rare earth elements in eight sites ranged from 117.35 to 348.63 microg x g(-1) and the maximum value was 2.97 times of the minimum value. The REE distribution patterns of different sites in sediments were basically identical and there was an obvious fractionation between LREEs and HREEs. The linear correlation of the method was preferable (r=0.999 7 - 1.000 0). The RSDs (n=3) were no more than 5.0%, and the relative errors were no more than 10%. The detection limits of rare earth elements reached ng x L(-1) level except for Sc. This method was suitable for the analysis of REEs in sediments with the advantages of rapidness, simplicity, high precision and accuracy. PMID- 23016362 TI - [Characteristics of chemical composition of glass finds from the Qiemo tomb sites on the Silk Road]. AB - Qiemo was an ancient country on the south branch of the Silk Road. The Zagunluke tomb site is located at the Qiemo County of the Xinjiang Uygur Autonomous Region. Glass beads and only colourless glass cup were excavated from the 3rd cultural layer of the tomb site M133 and M49, dated between the 1st AD-6th AD. LA-ICP-AES was applied to analyse chemical composition of these glass finds with the corning glass as reference. According to the result, characteristics of chemical composition are very similar to typical soda-lime glass, which indicates the glasses were imported productions from the west. These soda-lime glasses were divided into two groups in terms of flux source: natron glass and plant ash glass. This analytical research indicates the history of glass trade and communication between the East and the West on the Silk Road. PMID- 23016363 TI - [Determination of six metal elements in animal samples by flame atomic absorption spectrometry with wet digestion]. AB - The contents of 6 metal elements (Ca, Mg, K, Na, Cu and Fe ) were determined in serum, urine, feces and different tissue and organs (heart, kidney, stomach, liver, spleen, intestine and lung) of Wistar rats and mice by flame atomic absorption spectrometry (FAAS) with wet digestion. The samples were digested by the mixture of HNO3 and HClO4 (4 : 1, V/V) at 120 degrees C, the correlation coefficient for the standard curves was 0.999 4-0.999 8, the relative standard deviation (RSD) was from 0.33% to 4.52%, and the recovery for the samples was from 97.7% to 104.2%, meeting the demand of elements content determination in biological samples. The assay method for the determination of the 6 metal elements in animal samples established in this study has the advantages of easy operation, high sensitivity, less sample requiring and accurate results, and the method can be widely used in the determination of various metal elements in biological samples. PMID- 23016364 TI - [Temperature effect correction for Chang'E-3 alpha particle X-ray spectrometer]. AB - Alpha particle X-ray spectrometer (APXS) is one of the payloads of Chang'E-3 lunar rover of China's Lunar Exploration Project. The present paper introduces briefly the components of APXS, how it works and its working environment on the lunar surface. The environmental temperature effect has been studied with simulations and experiments, and the results show that the temperature of the APXS sensor will be varying during the measuring on the lunar surface. And another experiment reveals that the energy resolution becomes worse if the sensor's temperature is varying. In this paper, a correction method based on Pearson's chi-squared test is presented. The method can improve the energy resolution when the sensor's temperature is varying. We have tested the method with the spectra acquired by APXS in the temperature varying period of Temperature Cycling Test, and the results show that the method is efficient and reliable. PMID- 23016365 TI - [The element determination of six samples of petal powders by using XRF spectrometry]. AB - Elements and contents in three kinds of petal powders of white and red rose, carnation, and butterfly orchis were determined by using XRF technic, and the data for every group were compared and analysed. The results indicated that all powders contain no toxic elements determined but have lots of normal elements and trace elements, such as Fe, Cu, Zn, Mn, Ni, Si, Sr, and Rb. The same sort of powder had approximately equivalent elements but their contents are different, and the element content of the white sort. was higher than the red one. PMID- 23016366 TI - [Study of Dioscorea opposita Thunb from different producing areas with XRF and PXRD]. AB - The contents of various elements in rhizoma dioscoreae were analyzed and compared with those of shishou D. opposita Thunb on the whole jointly by XRF and PXRD. The results showed that the element Cu, Al and Mn could not be detected in rhizoma dioscoreae, but the element Mg, Zn and Cr were found, and other elements contents changed to different degrees; there are starch and whewellite in both groups, the crystal type of starches separated from rhizoma dioscoreae cultivars was a typical B-type pattern, but as C-type and V-type in shishou D. opposita Thunb, which is a mixture of A-type, B-type and V-type. The combination of two testing techniques could be applied to the mensuration and analysis of the elements and micro-structural of Dioscorea opposita Thunb which could be from different producing areas. PMID- 23016367 TI - [XANES study of lead speciation in duckweed]. AB - Qixiashan lead-zinc mine of Nanjing was one of the largest lead zinc deposits in East China Its exploitation has been over 50 years, and the environmental pollution has also been increasing. The lead concentration in the local environment was high, but lead migration and toxic mechanism has not been clear. Therefore, biogeochemistry research of the lead zinc mine was carried out. Using ICP-MS and Pb-L III edge XANES, lead concentration and speciation were analyzed respectively, and duckweed which can tolerate and enriched heavy metals was found in the pollution area. The results showed that the lead concentration of duckweed was 39.4 mg x kg(-1). XANES analysis and linear combination fit indicated that lead stearate and lead sulfide accounted for 65% and 36.9% respectively in the lead speciation of duckweed, suggesting that the main lead speciation of duckweed was sulfur-containing lead-organic acid. PMID- 23016368 TI - [Macromolecular aromatic network characteristics of Chinese power coal analyzed by synchronous fluorescence and X-ray diffraction]. AB - Coal structure, especially the macromolecular aromatic skeleton structure, has a strong influence on coke reactivity and coal gasification, so it is the key to grasp the macromolecular aromatic skeleton coal structure for getting the reasonable high efficiency utilization of coal. However, it is difficult to acquire their information due to the complex compositions and structure of coal. It has been found that the macromolecular aromatic network coal structure would be most isolated if small molecular of coal was first extracted. Then the macromolecular aromatic skeleton coal structure would be clearly analyzed by instruments, such as X-ray diffraction (XRD), fluorescence spectroscopy with synchronous mode (Syn-F), Gel permeation chromatography (GPC) etc. Based on the previous results, according to the stepwise fractional liquid extraction, two Chinese typical power coals, PS and HDG, were extracted by silica gel as stationary phase and acetonitrile, tetrahydrofuran (THF), pyridine and 1-methyl-2 pyrollidinone (NMP) as a solvent group for sequential elution. GPC, Syn-F and XRD were applied to investigate molecular mass distribution, condensed aromatic structure and crystal characteristics. The results showed that the size of aromatic layers (La) is small (3-3.95 nm) and the stacking heights (Lc) are 0.8 1.2 nm. The molecular mass distribution of the macromolecular aromatic network structure is between 400 and 1 130 amu, with condensed aromatic numbers of 3-7 in the structure units. PMID- 23016369 TI - [The microstructure and phase composition of metal melting marks caused by different fire]. AB - Four different types of molten metal fire marks were studied through X-ray diffraction (XRD) and 3D image processing software (Image-pro). As a result, the microstructure, average grain size, phase composition and its distribution was obtained. The results showed that on the surface of molten metal fire marks there mainly existed cubic crystal of Cu2O, cellular crystals of Cu and columnar crystals of Cu. And in four different modes of fire, the microstructure and composition of molten metal marks was of significant difference, that is: (1) the average grain size of molten marks by a short circuit fire was about 3 - 5 microm, and its Cu2O was the lowest; melt marks by circuit overload had an average grain size similar to short-circuit, but their Cu2O content was about 30%; (2) melt marks by secondary short-circuit contained a certain number of larger diameter microhole, and their average grain size was about 30 microm; broadening and splitting provision of the diffraction peaks of Cu and Cu2O showed that their ablation was the deepest; (3) melting marks by fire showed the equiaxed maximum intensity of Cu2O diffraction peaks, and there was almost no micro-holes. PMID- 23016370 TI - [Research on the composition characteristics of Chinese ancient southern white porcelain]. AB - The southern white porcelain is the rise in our country's pottery, it is later than the development of northern white porcelain, but it is rising stars, blockbuster, well-grounded, keeping continuous. Jingdezhen kiln and Dehua kiln are the most representative kilns among the southern white porcelain kilns. the present paper used EDXRF to test 30 pieces of Song, Yuan and Ming period' Dehua white porcelains and Jingdezhen Yuan dynasty Shufu white porcelains samples to analyze the different characteristics of the bodies and the glaze of these samples in terms of time and space. The results show that in the bodies and the glaze of Jingdezhen Shufu white porcelains the iron content is obviously on the high side, and the Dehua white porcelains' potassium content is obviously on the high side, and along with time development they have been in a rising trend, which should be the main reason for the sudden rise of Dehua white porcelain sculptures. PMID- 23016371 TI - [Spectral calibration for the large aperture infrared radiometer]. AB - The present paper introduced a spectral calibration method to calibrate a large aperture infrared radiation facility. We developed a radiometer which consisted of optical system, infrared detectors(cavity pyroelectric detector and HgCdTe detector 2 - 14 microm), fine mechanical modulator, lock in amplifier, signal processor, etc. At first, we analyzed the method on how to measure the spectral calibration of the large aperture infrared radiometer, and established the spectral calibration facility. Then, we tested the nonlinear response for the cavity pyroelectric detector and HgCdTe detector. Finally, we used the cavity pyroelectric detector to calibrate the relative spectral responsivity of HgCdTe detector at several wavelengths on the facility. Through the comparison of the two methods for measuring the relative spectral responsivity, the average of multiple measurements and comparative analysis of two methods were given. The uncertainty analysis of the whole system showed that the measurement uncertainty of the facility was better than 3.4%. PMID- 23016372 TI - [Analysis of multi-micromirrors tilt error in space-modulated Fourier transform infrared spectrometry]. AB - The system of space-modulated Fourier transform infrared spectrometer without moving parts is stable and compact, moreover, it can realize the on-line monitoring and real-time detection. The position accuracy of multi-micromirrors as the key components has a great influence on spectrometric performance. In the present paper, the multi-mcromirrors tilt error caused by optical path difference changes was calculated and simulated. The analysis shows that, as the multi micromirrors tilt angle increased, the interference pattern contrast decreased and the signal to noise ratio reduced. The results could be used in the tolerance distribution and the systemic alignment in the next step. PMID- 23016373 TI - [Research on the phase-shifted fiber grating spectrum characteristics in the inhomogeneous strain fields]. AB - Based on the transfer matrix method, the spectrum characteristics of phase shifted fiber grating were analyzed systematically, and the reflection spectra of phase-shifted fiber grating under uniform strain, linear strain, secondary strain and cubic strain were simulated respectively. The regularity conclusion that the influence of different strain distribution functions on reflectivity, transmission bandwidth, wavelength of transmission window and spectral shape came out. In order to verify the simulation result, strain-tuning equipment was designed based on cantilever with different structures. Finite element method was carried out to simulate the strain distribution of phased shift fiber grating fixed on the surface of cantilever during the strain-tuning experiment. Experiment result demonstrated that the reflection spectra of phase-shifted fiber grating under uniform strain, linear strain and secondary strain exhibited a regular change, which is in agreement with simulation results. PMID- 23016374 TI - [The design and experiment of multi-parameter water quality monitoring microsystem based on MOEMS microspectrometer]. AB - Aiming at the monitoring and protecting of water resource environment, a multi parameter water quality monitoring microsystem based on microspectrometer was put forward in the present paper. The microsystem is mainly composed of MOEMS microspectrometer, flow paths system and embedded measuring & controlling system. It has the functions of self-injecting samples and detection regents, automatic constant temperature, self -stirring, self- cleaning and samples' spectrum detection. The principle prototype machine of the microsystem was developed, and its structure principle was introduced in the paper. Through experiment research, it was proved that the principle prototype machine can rapidly detect quite a few water quality parameters and can meet the demands of on-line water quality monitoring, moreover, the principle prototype machine has strong function expansibility. PMID- 23016375 TI - [Minimally invasive technology is an ideal pursuit in treating lumbar degenerative disease]. PMID- 23016376 TI - [Treatment of popliteal cyst by arthroscopy in 20 cases]. AB - OBJECTIVE: To explore the treatment methods and the effects of popliteal cyst with arthroscopy. METHODS: From January 2009 to January 2010,20 patients with popliteal cyst were treated with internal drainage under arthroscope, meanwhile, their joint disease were treated. There were 9 males and 11 females with an average age of (55.7 +/- 7.7) years (ranged, 46 to 70). The lump was found for 1 22 months with an average of (6.2 +/- 2.4) months and accompanying with knee pain of different degrees. All diagnosis depended on B ultrasound or MRI, which clearly showed communication of cyst and articular cavity. According to the grade of Rauschning and Lindgren,grade II was in 8 cases and grade III was in 12 cases. The clinical effects were evaluated by the grade of Rauschning and Lindgren. RESULTS: All the patients were followed up from 6 to 18 months with an average of 12 months. No injuries of blood vessels and nerve or incision infection were found. The grade of Rauschning and Lindgren improved obviously in all patients, grade 0 was in 13 cases, grade I in 6 cases, grade II in 1 case at the 6 months after operation. CONCLUSION: The method not only can cure the popliteal cyst, but also can solve the disease of joint, which is avoiding re-operation and decreasing some shortages of traditional operation, can obtain good function recovery and satisfactory medium-term effects. PMID- 23016377 TI - [Minimally invasive surgical treatment for lumbar degenerative disease with IsoC 3D navigation under Mast Quadrant system]. AB - OBJECTIVE: To evaluate the effects of surgical treatment of IsoC-3D navigation assisted percutaneous pedicle screw fixation,vertebral canal decompression and interbody fusion using Mast Quadrant system in patients with lumbar degenerative disease. METHODS: From January 2009 to February 2010,21 patients with lumbar degenerative disease were treated with IsoC-3D navigation under Mast Quadrant system. There were 12 males and 9 females, with an average age of 50.2 years (ranged,36 to 72 years). All patients underwent discectomy,vertebral canal decompression, cage implantation using Mast Quadrant system and IsoC-3D navigation assisted sextant lumbar fixation. Clinical outcomes were evaluated with Oswestry disability index (ODI), Visual analog scale (VAS) and degree of satisfaction of patients. RESULTS: Eighteen patients (85.7%) were followed up from 6 to 18 months with an average of 10 months. No surgery-related complications were found. The preoperative, postoperative ODI scores was 49.6 +/- 12.2 and 17.2 +/- 9.2, respectively (P < 0.01); VAS score of leg pain decreased from preoperative 75.2 +/- 10.0 to 12.2 +/- 11.8 at final follow-up (P < 0.01); VAS score of lumbago decreased from preoperative 59.9 +/- 17.3 to 16.6 +/- 11.5 at final follow-up (P < 0.01). Sixteen patients obtained satisfactory results. CONCLUSION: IsoC-3D navigation assisted percutaneous pedicle screw fixation,vertebral canal decompression and interbody fusion using Mast Quadrant system could achieve satisfactory clinical results in treating lumbar degenerative disease and may be a better alternative to conventional surgical procedures. It has advantages such as limited tissue damage, less blood loss, short time in hospital. PMID- 23016378 TI - [Treatment of far lateral lumbar disc herniation with unilateral pedicle screw fixation and intervertebral body fusion after decompression]. AB - OBJECTIVE: To investigate the surgical outcomes of unilateral lumbar pedicle screw fixation and intervertebral body fusion in treating far lateral lumber disc herniation. METHODS: From June 2007 to June 2009, 25 patients with far lateral lumbar disc herniation were treated with unilateral lumbar pedicle screw fixation and intervertebral body fusion. There were 12 males and 13 females,which ranged in age from 37 to 68, with an average of 54.6 years. The course of disease was from 3 to 36 months with an average of 8.8 months. All the patients had pain and/or numbness and/or soreness in front and/or the back of unilateral leg and buttocks; muscle strength, sensation and tendon reflexes had declined of different degrees. Lumbar CT or MRI showed far lateral lumbar disc herniation. Neurological function and lumbar function were respectively evaluated according to JOA 29 score system (including subjective, objective symptom and bladder function) and Oswestry disability index (ODI). RESULTS: All the patients were followed-up from 12 to 36 months with an average of 24 months. Postoperative wound healed well and no perioperative complications and follow-up complications were found. Neurological function of patients obtain recovery of difference degrees. At final follow-up, JOA score and ODI improved compared with that of preoperative data (P < 0.01); the mean improvement rate of JOA score was 94.3%. All patients got good bone fusion and no recurrence cases were found. CONCLUSION: Unilateral lumbar pedicle screw fixation and intervertebral body fusion could increase the initial stability after fusion, restore and maintain the intervertebral height, and elevate the improvement rate in treating far lateral lumber disc herniation. The surgical method is safe, effective and reliable, but need to strictly control indications. PMID- 23016379 TI - [Surgical treatment of degenerative lumbar scoliosis with spinal stenosis]. AB - OBJECTIVE: To investigate the clinical effects of limited decomression, fixation, and fusion in treating degenerative scoliosis with spinal stennosis. METHODS: From June 2002 to January 2009, 26 patients of degenerative scoliosis with spinal stenosis were treated with limited decomression, fixation, and fusion. There were 6 males and 20 females with an average age of 61.3 years (ranged, 51 to 72 years). Course of disease of spinal stenosis was from 11 months to 6 years with an average of 36 months. X-ray, CT, MRI examination were performed preoperatively for all the cases and myelography was performed for 6 cases. Preoperative Cobb's angle,focal lordosis angle,the distance between C7 plumb line (C7PL) and upper edge of S1 vertebral body (SVA), and the distance between C7PL and center sacral vertical line (CSVL) were (22.0 +/- 10.1) degrees, (21.6 +/- 10.2) degrees, (7.6 +/- 6.4) cm, (6.8 +/- 5.6) cm respectively. Measured Cobb's angle, focal lordosis angle, SVA, CSVL after operation and final follow-up were compared with preoperative data. JOA score system were used to evaluate clinical effects. RESULTS: The operative time All the patients were followed up from 1.3 to 5 years with an average of 2.5 years. Postoperative and final follow-up, Cobb's angle was (10.5 +/- 8.2) degrees, (8.8 +/- 5.2) degrees, respectively; focal lordosis angle was (25.4 +/- 14.2) degrees, (31.6 +/- 13.2) degrees, respectively; SVA was (0.6 +/- 3.3) cm, (-1.2 +/- 2.5) cm,respectively; CSVL was (2.8 +/- 1.3) cm, (1.6 +/- 1.2) cm, respectively. There was significant difference in data before and after operation. Preoperative, instantly postoperative, final follow-up, JOA score was 11.0 +/- 1.7, 22.4 +/- 2.4, 24.0 +/- 2.1, respectively; 13 cases obtained excellent results, 8 good, 3 fair, 2 poor. Loss of correction occurred in one case. No collapse of intervertebral space, nerve injury, breakage of fixation system were found. CONCLUSION: Surgical treatment with limited decompression, pedicle screw fixation and fusion is effective method for degenerative scoliosis with spinal stenosis, individualized surgery design should be made according to clinical symptoms, signs and imaging features. PMID- 23016380 TI - [Clinical analysis of an interspinous stabilization system (wallis) in treating lumbar degenerative disease]. AB - OBJECTIVE: To evaluate clinical results of an interspinous stabilization system (Wallis) in treating lumbar degenerative disease in the short-term. METHODS: From August 2007 to June 2010,48 patients with lumbar degenerative disease who were treated with interspinous stabilization system, the data of patients were analyzed retrospectively. In all of the 48 cases, there were 30 males and 18 females with an average age of 54.2 years (ranged, 40 to 68 years). Forty-four cases were with single segment and 4 cases with two segments. Of them, 4 cases were in L3, 4, 40 cases were in L4, 5, 4 cases were in L3, 4 and L4, 5. The radiographic data of patients were analyzed. Clinical effects were evaluated by Japanese Orthopedic Association (JOA) score system and low back pain disability questionnaire (Oswestry) and Odom method. RESULTS: All the patients were followed up from 1 to 2 years with an average of 18 months. According to Odom's criteria, 20 cases obtained excellent results, 24 good, 4 fair. JOA score increased from 12.4 +/- 2.7 preoperatively to 26.1 +/- 2.0 postoperatively (P < 0.01). Oswestry score decreased from 14.1 +/- 2.9 preoperatively to 5.5 +/- 1.8 postoperatively (P < 0.01). The posterior height of intervertebral space and height of nerve root canal increased compared with that of preperative height. CONCLUSION: The treatment of lumbar degenerative disease with interspinous stabilization system can obtain satisfactory effects in the near future. It can retain dynamic stable of corresponding segments, expand volume of vertebral canal, and is safe and feasible. PMID- 23016381 TI - [Clinical study on unilateral pedicle screw fixation and interbody fusion for the treatment of lumbar degenerative diseases under Quadrant system]. AB - OBJECTIVE: To compare the clinical effects of unilateral pedicle screw fixation (uni-PS) assisted by Quadrant system and bilateral pedicle screw fixation (bi-PS) for the treatment of lumbar degenerative diseases. METHODS: From October 2008 to October 2010,102 patients with lower back pain, unilateral lower limb radiating pain or paraesthesia were treated with pedicle screw fixation and lumbar interbody fusion. There were 67 males and 35 females with an average age of 51.5 years ranging from 34 to 69 years. The patients were randomly divided into two groups (group A and group B) according to the internal fixation type. The patients of group A (n=50) underwent with minimally transforaminal lumbar interbody fusion (TLIF) and unilateral pedicle screw fixation with one single cage placement assisted by Quadrant system;and the patients of group B (n = 52) underwent with posterior lumbar interbody fusion (PLIF) and bilateral pedicle screw fixation with one single cage placement. There were no significant differences between two groups in general information (P > 0.05). VAS score and ODI score system were used to evaluate the preoperative and postoperative pain and function recovery. Operative time, volume of blood loss, fusion rate and complication rate were compared and analyzed by statistical test. RESULTS: All the patients were followed up from 12 to 21 months with an average of 18.2 months. In the group A,operative time and volume of blood loss were (87.6 +/- 25.5) min and (105.7 +/- 27.2) ml, respectively; VAS score of low back pain and leg pain, ODI score decreased respectively from preoperative 7.2 +/- 1.4, 7.9 +/- 1.1, 42.2 +/- 11.8 to 3.2 +/- 0.6, 3.0 +/- 0.7,15.6 +/- 2.3 at one month after operation; the fusion rate was 96.0% (48/50) and the complication rate was 4.00% (2/50). In the group B,operative time and volume of blood loss were (160.3 +/- 20.5) min and (220.6 +/- 25.5) ml, respectively; VAS score of low back pain and leg pain, ODI score decreased respectively from preoperative 7.3 +/- 1.1, 8.1 +/- 0.9, 43.1 +/- 12.0 to 3.3 +/- 0.4, 3.2 +/- 0.3, 14.9 +/- 2.6; the fusion rate was 96.2% (50/52) and the compli- cation rate was 5.77% (3/52). There were no statistically significant differences between the two groups in fusion rate, complication rate, VAS pain and ODI score. Whereas the operative time and blood loss in group A were significantly lower than that of group B. CONCLUSION: Minimally invasive unilateral pedicle screw fixation is a safe and feasible method for the treatment of lumbar degenerative diseases. It is as effective as the bilateral fixation in lumbar spinal fusion. In addition, it has the advantages of short operative time, less volume of blood loss, high fusion rate, etc. PMID- 23016382 TI - [Comparison of three methods of internal fixations for intertrochanteric femoral fractures in elderly patients]. AB - OBJECTIVE: To compare the clinical effects of three methods of internal fixations in treating intertrochanteric fractures in elderly patients. METHODS: From 2004 to 2008, the clinical data of 112 patients with intertrochanteric fractures were retrospectively analyzed. There were 63 males and 49 females, aged from 60 to 80 years with an average of 66.2 years. The patients were treated respectively with dynamic hip screws (DHS group, 40 cases), anatomic plate (anatomic plate group, 36 cases) and proximal femoral intramedullary nails (PFN group, 36 cases). The data of each group were collected for statistical analysis on the following aspects: operative time, blood loss volume, clinical healing time of fracture, postoperative complications, and hip functional score of Harris. RESULTS: All these patients were followed up from 20 to 24 months with an average of 22.6 months. There was no significant difference in operative time, blood loss volume among three groups; there was significant difference in clinical healing time of fracture, Harris score and postoperative complications among three groups (P < 0.05). In the healing time, the PFN group was significantly less than that of other groups (P = 0.001), but there was no differences between DHS group and anatomic plate group. In the Harris score, the PFN group was significantly higher than that of other groups (P = 0.001), but there was no differences between DHS group and anatomic plate group. In the aspect of postoperation complication, there was 2 cases of coxa vara, 1 case of internal fixation loosening and 1 case of deep venous thrombosis in the DHS group; there were 2 cases of deep venous thrombosis in the PFN group; there were 2 cases of coxa vara and 1 case of internal fixation loosening in the anatomic plate group (P = 0.001). CONCLUSION: In the treatment of intertronchanteric fractures, proximal femoral intramedullary nail may be the best choice, which can decrease healing time as well as complications postoperatively. PMID- 23016383 TI - [Postlaminectomy vertebral lamina reconstruction and pedicle screw reduction and fixation for lumbar spondylolisthesis]. AB - OBJECTIVE: To investigate the clinical effects of spinal canal decompression and pedicle screw reduction and fixation, and intervertebral bone grafting fusion for the treatment of lumbar spondylolisthesis associated with nerve compression symptoms. METHODS: Postlaminectomy vertebral lamina reconstruction and pedicle screw reduction and fixation were performed in 32 patients with lumbar spondylolisthesis between August 2007 and August 2008. Of them, 26 patients were followed up for more than 1 year, including 16 males and 10 females who ranged in age from 55 to 76 years (mean 62.5 years). The course of disease was 2-10 years. All patients had low back pain, numbness and pain in one or both lower extremities and intermittent claudication symptoms. Radiograms showed L3, L4 or L5 anter-olisthesis of I to III degree. There were 18 cases of regressive olisthesis and 8 cases of spondylolysis. The clinical improvement, the vertebral reduction, the lamina fusion rate and canal stenosis state were observed and assessed. RESULTS: The wounds healed well in all 26 cases without occurrence of significant complications. Clinical improvement was assessed according to the JOA lower back pain score scale. The mean preoperative score was 5.2 +/- 1.5, and 23.1 +/- 1.9 at 3 months after operation. The result was excellent in 20 cases, good in 5 cases, and fair in 1 case. The mean score on the last followed-up was 22.9 +/- 2.4, and the result was excellent in 19 cases, good in 5 cases, and fair in 2 cases. JOA score at 3 months after operation and that at the last followed up were significantly different from that before operation (P = 0.00), and there was no significant difference between JOA score at 3 months after operation and that at the last followed-up (P > 0.05). Complete reduction was achieved in 17 degree I case and 5 degree II cases. Two degree II cases were improved to degree I, and 2 degree III cases were improved to degree I. Vertebral fusion was achieved 3 months after operation in 20 cases, and in all cases at the last followed-up. CT examination at the last follow-up showed no stenosis of the vertebral canal, dural sac and nerve root compression. The rebuilt vertebral lamina fused well. No graft bone absorption or failing fixation occurred. CONCLUSION: Postlaminectomy reconstruction of the vertebral lamina and pedicle screw reduction and fixation can achieve satisfactory reduction and spine biomechanical stability in the treatment of lumbar spondylolisthesis, and can prevent latrogenic stenosis of the vertebral canal due to nerve oppression by the postoperative scar and nerve adhesion, with good early and medium-term curative effects. In addition, it provides a new way of thinking in the treatment of lumbar spondylolis-thesis. PMID- 23016384 TI - [Surgical treatment of ossification of ligamentum flavum in thoracic spine and its therapeutic effect analysis]. AB - OBJECTIVE: To explore the correlation between CT classification and operative method and to discuss its therapeutic effect. METHODS: From January of 2001 to June of 2010, 30 patients with thoracic ossification of ligamentum flavum were reviewed retrospectively, including 22 males and 8 females with an average age of 52.8 years old (ranged from 37 to 68 years old). The course of duration ranged from 2 months to 6 years. Single segment lesion was in 11 cases and multiple segments were in 19 cases. Two patients were accompanied by cervical ossification of ligamentum flavum and 1 was accompanied by ossification of posterior longitudinal ligament. The ossified lesions were located at T1,2 to T4,5 in 5 cases,T5,6 to T8,9 in 7 cases, T9,10 to T11,12 in 12 cases, at the upper and middle thoracic levels in 2 cases, at the middle and lower thoracic levels in 4 cases. They were divided into 2 types according to the morphologic features of the CT scan:simple type, 18 segments with lateral, slice or unfused type; complex type, 42 segments with thickened, fused or nodular type. The clinical manifestation was paralysis of upper motor neuron in 21 cases, and of upper and lower motor neuron in other 9 cases. Sphincter dysfunction was found in 26 cases. Preoperative JOA sphincter function score was 1.97 +/- 0.56. Preoperative modified JOA motor function score of lower limb was 1.20 +/- 0.76. Different surgical procedure was applied to one of the 2 types. For the simple type, an en bloc laminectomy was performed. However,for the complex type, a laminar shelling decompression was done. Laminectomy combined with internal fixation and lateral fusion was performed in patients whose decompressive areas were wider. RESULTS: The mean decompression length was 3.1 lamina (2 to 6 lamina). Cerebrospinal fluid leakage was found in 3 cases and hematoma in incision was found in 1 case. The mean follow-up duration was 26 months (12 to 96 months). Twenty-two patients with the feel of constriction of trunk or lower limbs were completely recovered; 18 cases with sensation disturbance, numbness and pain of the lower limb were totally recovered, and relived in 10 cases. Postoperative JOA sphincter function score was 2.73 +/- 0.45, comparing with the preoperative score, and the difference was significant (P < 0.01). Postoperative JOA motor function score was 3.57 +/- 0.77, comparing with the preoperative score, and the difference was significant (P < 0.01 ). The lower limb function relief rate was 86.1%, 24 patients got an excellent results, 3 good, 2 poor and 1 bad. CONCLUSION: Different surgical procedures will be safely and effectively applied to treat thoracic ossification of ligamentum flavum according to CT classification. PMID- 23016385 TI - [Case-control study on minimally invasive plate osteosynthesis for the treatment of proximal humeurs fractures in elderly patients]. AB - OBJECTIVE: To compare clinical efficacy for the treatment of proximal humeurs fractures in elderly patients between the minimally invasive plate osteosynthesis (MIPO) with less invasive stabilization system (LISS) and the open reduction and internal fixation (ORIF) with locking compression plate (LCP). METHODS: From June 2008 to June 2011, 40 elderly patients suffering from proximal humeurs fractures were divided into two groups: 20 cases in minimally invasive group and 20 cases in routine group. Mini-incision approach from the lateral shoulder (minimally invasive group) and LISS can be chosen. It was short for MIPO. The antero-medial incision was used in routine group, LCP can be chosen in the method of ORIF. The operation time, the blood loss, the incision length, soreness at 1st, 3rd and 7th days after operation were recorded. The postoperative Neer score, the healing time of bone were recorded. The curative effects were compared according to Neer score system. RESULTS: The mean operation times were (133.60 +/- 8.90) min and (132.70 +/- 8.41) min in minimally invasive group and routine group (P > 0.05). The blood losses were (155.20 +/- 19.07) ml and (324.05 +/- 48.32) ml (P < 0.05). The incision lengths were (8.15 +/- 1.89) cm and (13.05 +/- 1.95) cm (P < 0.05). The pain scores on the 1st,3rd and 7th days after operation were (6.20 +/- 2.39) and (8.33 +/- 3.01) (P < 0.05), (3.83 +/- 2.09) and (5.31 +/- 2.22) (P < 0.05), (1.22 +/- 0.89) and (3.13 +/- 1.75) (P < 0.05). The postoperative Neer scores were 93.16 +/- 2.55 and 80.31+/- 2.22 (P < 0.05) and the healing times of bone were (6.60 +/- 2.33) months and (8.93 +/- 3.41) months (P < 0.05). There were statistially differences in the blood losses, incision lengths, postoperative pain scores, postoperative Neer scores and the healing times of bone between two groups (P < 0.05). The operation time between the two groups had no statistically different (P > 0.05). According to Neer score system, 13 patients obtained an excellent results, 2 good, 5 fair in minimally invasive group; 6 patients obtained an excellent results, 5 good, 9 fair in routine group. CONCLUSION: To compare with the routine group of ORIF, MIPO with LISS has the advantages of small incision, easier operation, less blood loss and improved postoperative shoulder joint function recovery for treatment of proximal humeurs fracture in elderly patients. It is another better method of internal fixation. PMID- 23016386 TI - [Posteromedial approach for the treatment of distal tibial fractures accompanying with anterior soft tissue injury]. AB - OBJECTIVE: To investigate the clinical results of distal tibia fractures accompanying with anterior soft tissue injury by posteromedial approach. METHODS: From August 2008 to August 2010,31 patients (21 males and 10 females, ranged in age from 24 to 68 years with an average of 46 years) with distal tibia fractures accompanying with anterior soft tissue injury were treated with open reduction and internal fixation through posteromedial approach. Of the 31 cases, 14 cases were open fractures (including 5 cases Gustilo-Anderson type I, 5 type II, 2 type III A, and 2 type III B) and 17 cases were closed fractures (including 3 cases Tcherne-Oestern type I, 12 type II, 2 type III). According to typing of AO, type 43A were in 26 cases and type 43C1 were in 5 cases. Operation time, intraoperative blood loss, fracture healing time, AOFAS ankle score, and complications were recorded to evaluate clinical effects. RESULTS: All the patients were followed up from 12 to 36 months with an average of 21 months. The mean operation time was 70 min (ranged, 40 to 110 min) and the mean blood loss was 100 ml (ranged, 50 to 200 ml). Average healing time for closed fractures was 13 weeks (ranged, 10 to 18 weeks), while open fractures was 19 weeks (ranged, 15 to 29 weeks). Cross-foot of 40 occurred in 1 case and pes valgus of 30 in 1 case at final follow-up; and AOFAS ankle scores were from 69 to 100 with an average of 88.4 +/- 9.7. Of them, 10 cases obtained excellent results, 17 good, 4 fair. CONCLUSION: Postermedial approach is an effective method for distal tibia fractures especially accompanying with local soft tissue injury or bad skin condition. PMID- 23016387 TI - [Combined medial and lateral malleolus operative treatment for severe fracture of ankle]. AB - OBJECTIVE: To explore the clinical effects of combined medial and lateral malleolus in treating severe fracture of ankle. METHODS: From May 2007 to January 2011,89 patients with ankle fracture who underment surgical treatment and had complete follow-up, the data were retrospectively analyzed. In this study, there were 66 males and 23 females with an average age of 30.9 years (ranged, 26 to 62 years). Cause of injury included road accidents in 52 cases,sprains from fall down in 17, construction injury in 16 and other injuries in 4. According to type of Denis-Weber, type A were in 13 cases, type B in 24, type C in 52. Operative technique was as follows. Chosen two-incision of combined medial and lateral malleolus, and reduced lateral malleolus fracture firstly, fixed it with 1/3 tubular armor plate or rebuilt-titanium plate. To chose one or two hollow screws according to the size of fracture block. If fracture of fibula was syntripsis,it can be multi-segmental fixed. If fracture line of posterior malleolus was no more than 1/3 articular surface of ankle or the bone displacement was not serious, it can be disregarded. And if the lesion level was over 1/3, or shift position more than 3 mm,it can be fixed with lag screw after reduction. Either front-to-back or back-to-front fixed direction was OK. At the third day after operation, the patients were instructed to exercise with affected limb, weight training after 6 weeks. RESULTS: Eighty-nine patients were followed up from 6 to 24 months with an average of 16 months. Healing time of the fracture was 10 to 12 months. According to standard of the Baird-Jackson scoring system, 68 cases got excellent results, 18 good and 3 fair. CONCLUSION: Surgical treatment is quite effective for severe fracture of ankle. It should be chosen correctly according to types of the fracture and degree of ligament injury. At the same time, damage degree of the ligament around the ankle should be considered and properly treated. PMID- 23016388 TI - [Manipulative reduction and external fixation for the treatment of Colles fracture]. PMID- 23016389 TI - [Treatment of linguiform calcaneus fracture by close nail-pry reduction and internal fixation with hollow screws]. AB - OBJECTIVE: To study the curative effects of close nail-pry reduction and internal fixation with hollow screws for treatment of linguiform calcaneus fracture. METHODS: From May 2006 to October 2009,32 patients (35 feet) with linguiform calcaneus fracture were treated by close nail-pry reduction and internal fixation with hollow screws, including 23 males and 9 females ranging in age from 25 to 46 years, with a mean of 37.6 years. According to Paley classification, 3 cases were Paley II a, and 29 cases were Paley II b. All cases were close fractures. The time from injury to operation was 3 to 10 days after most swelling subsided. Bohler angle and Gissane angle were measured by X-ray before and after operation. The therapeutic effect was assessed according to ZHANG Tie-liang's foot score. RESULTS: All the patients were followed-up for 6 to 18 months, with a mean of 12 months. All fractures gained bone healing. The time of fracture healing averaged 12 months. The fractures healed completely and no infection occurred. According to ZHANG Tie-liang's foot scale, the postoperative function was excellent in 18 feet, good in 10 feet, moderate in 5 feet and poor in 2 feet. The Bohler angle and Gissane angle were significant improved after treatment (P < 0.01). CONCLUSION: The surgical method of close nail-pry reduction and internal fixation with hollow screws for treatment of linguiform calcaneus fracture can regain the foot function, with minimal injury, fewer complications, earlier recovery and lower costs. PMID- 23016390 TI - [Medial transposition of the radial nerve in humeral shaft fractures fixation]. AB - OBJECTIVE: To summarize clinical outcomes of using medial transposition of the radial nerve in humeral shaft fracture fixation. METHODS: From January 2005 to December 2009, 16 patients with humeral shaft fractures were treated with medial transposition of the radial nerve during open reduction and anterolateral plate fixation, included 12 males and 4 females ranging in age from 26 to 49 years, with a mean of 36 years. There were 7 fractures in the right and 9 in the left. According to AO classification, 6 fractures were type A3.2, 5 fractures were type A2.2, 2 fractures were type A1.2 and 3 fractures were type B2.2. The results were evaluated with DASH (disability of arm-shoulder-hand) Questionnaire by the American Academy of Orthopedic Surgeons (AAOS), where 0 indicates normal upper extremity function, and 1 to 100 indicate varying degrees of damage to the function of the upper extremities. RESULTS: There was no neurologic complication or postoperative would infection in this series. The followed-up period ranged from 20 to 46 (means 29) months postoperatively. The clinical outcomes were evaluated with DASH Questionnaire, indicating that all patients reached a normal value (value of 0). The function of the upper extremities recovered satisfactorily. There was no surgery-related complication. CONCLUSION: Medial transposition of the radial nerve is safe and does not cause iatrogenic nerve injury. It protects the radial nerve during open reduction and anterolateral plate fixation of humeral shaft fractures. PMID- 23016391 TI - [Early clinical research of total hip arthroplasty for the treatment of old acetabular fractures]. AB - OBJECTIVE: To analyze the early clinical effects of total hip arthroplasty(THA) for the treatment of old acetabular fractures. METHODS: From January 2007 to June 2010, thirteen patients with old acetabular fractures were reviewed, including 10 males and 3 females. Ten patients were treated with internal fixation and conservative treatment had been used in three patients. The average Harris Hip Score was used to evaluate therapeutic effects. RESULTS: After operation, all thirteen patients were followed up for one year. Hip X-ray films were taken and prosthesis loosening was not seen on any of the films at the 1st year after operation. The Harris Hip Score improved from preoperative (37.19 +/- 20.12) to postoperative (83.38 +/- 3.33), there was statistically significant difference. CONCLUSION: For reasons of malunion or failure of internal fixation, large and various bone defect, it's difficult to reach the anatomical reduction. THA is a good treatment method, but it needs rich skills and experience compared with ordinary operation. PMID- 23016392 TI - [Preliminary investigation of animal model of tibial defection fracture made by drilling hole method ]. AB - OBJECTIVE: To compare the differences in damage degree, healing time and healing process between two animal models of defection fracture and provide the research data for the establishment of a new animal model. METHODS: Sixty male SPF Spragur Dawley rats were divided randomly into control group, sawing group and drilling hole group, with 20 rats in each group. Animals of drilling hole group were treated with hone drill and made an 1 mm hole on tibial plateau animals of sawing group were treated with saw and made an 3 mm defection on tibial plateau; nothing to do in animals of control group. The rats were respectively killed at 2nd, 4th weeks after operation, bone density, bone ash quantity, contents of bone Ca, P were detected. RESULTS: At the 2nd week after operation, bone density, bone ash quantity, contents of bone Ca, P in drilling hole group and sawing group were significantly lower than that of the control group (P < 0.05 or P < 0.01). Two animal models of drilling hole group and sawing group were similar in X-ray films and pathology investigations. At the 4th week after operation, there were no significant defference in bone density and bone ash quantity among three groups (P > 0.05). Rats of sawing group showed more poroma and inflammatory infiltration in histological examination. CONCLUSION: Drilling hole method and sawing method could be used to make animal model of defection fracture, two methods showed similar damage degree, healing time and healing process, hut drilling hole method have advantages of simple operation, easily control damage degree and less inflammatory infiltration and bone disunion. PMID- 23016393 TI - [Investigation of the anti-terminal maturation effects of parathyroid hormone on human osteoarthritis chondrocytes]. AB - OBJECTIVE: To investigate the inhibition in parathyroid hormone (PTH) to terminal differentiation of human osteoarthritis chondrocytes. METHODS: Human osteoarthritis chondrocytes were isolated and cultured. The cells were divided into PTH group and control group, and the cells of two groups were treated respectively with PTH and saline every day. The morphology of cells was observed by microscope. Alkaline phosphatase (ALP) staining was performed to detect the ALP protein. The hypertrophic marker genes mRNA and protein expressions were detected by real-time RT-PCR and Westernblot. RESULTS: Human osteoarthritis chondrocytes had characteristic of terminal differentiation. Compared with control group, PTH group can obviously degrade ALP staining density, and decrease marker gene mRNA and proteinic expression of promoting terminal differentiation. CONCLUSION: PTH has a role of inhibition of terminal differentiation of human osteoarthritis chondrocytes. PMID- 23016394 TI - [VSD combined with fascio-cutaneous flap transferation staging operation to treat post-traumatic osteomyelitis]. AB - OBJECTIVE: To explore the therapeutic effects of VSD combined with fascio cutaneous flap transferation staging operation for the treatment of post traumatic osteomyelitis. METHODS: From December 2007 to December 2009, 14 patients were treated with the technology of VSD combined with fascio-cutaneous flap transferation staging operatinon. Nine patients were males and 5 patients were females, and mean age was 36 years. All the patients were postoperative wound infection. Osteomyelitis of the tibia was in 9 cases, calcaneus in 3 cases, femur in 1 case, radius and ulna in 1 case; infection of time were from 2 to 96 weeks, an average time of 32 weeks. RESULTS: All the patients were followed up, and the duration ranged from 12 to 36 months, with an average of 19.2 months. All the patients were treated with debridement and VSD for 1 to 3 times, with an average of 1.57 times. The wounds of 13 cases healed well after flaps transferation, but of 1 case leakaged and healed after 3 weeks with the therapy of drainaging and changing dressings. Due to delayed healing or defects of bone, 8 patients had autologous bone grafted on the second stage. All wounds and fractures healed without recurrence of postoperative infection. CONCLUSION: VSD combined with flap transferation is an effective treatment of post-traumatic osteomyelitis, which can shorten the treatment time and have better security and reliability than traditional methods. PMID- 23016395 TI - [Application of artificial skin combined with external fixator in the treatment of severe open fractures of legs]. AB - OBJECTIVE: To investigate therapeutic effects of external fixator combined with artificial skin for the treatment of lower limb open fractures. METHODS: From January 2009 to February 2011,56 patients with lower limb open fractures were treated with external fixator and artificial skin following debridement. There were 42 males and 14 females, with a mean age of 43.6 years (ranged, 18 to 68 years). Wound surface or cavities were filled with artificial skin with embedded drainage tubes connected to vacuum bottle. The wounds were closed with secondary suturing, or free flap, or flap transfer at 5-7 days after primary operation. The therapeutic effects were evaluated by observing the wound healing, wound bacterial culture, healing time, recovery of limb function. RESULTS: The wounds of 56 patients all healed. Fifty-three patients had bone primary union, and 3 patients had delayed union. The average union time was 5.8 months. There was pin tract infection in 3 cases and superficial infection in 1 case. According to Ovadia evaluation criteria,45 patients got an excellent results, 9 good and 2 fair. CONCLUSION: Artificial skin combined with external fixator is a simple and effective treatment method for Gustilo III type severe open fractures of legs, which is effective to provide rapid fixation, seal wounds, and shorten secondary healing time of wounds. PMID- 23016396 TI - [Rosai-Dorfman disease encroached on the skull: a case report]. PMID- 23016397 TI - [Research progress of gene therapy in the treatment of non-traumatic osteonecrosis of femoral head]. AB - There are many methods of conservative treatment for early non-traumatic osteonecrosis of femoral head, but still lack of a mature and effective treatment. Gene therapy is a new treatment method for non-traumatic osteonecrosis of femoral head in recent years. This article showed that the non-traumatic osteonecrosis of femoral head related to progress and problems on pathogenesy, molecular biology foundation, exogenous theoretical gene,carrier selection and so on, discussed some problems and countermeasure and future applications. PMID- 23016398 TI - [The mechanism advance of microRNA in cartilage injury and degeneration]. AB - MicroRNAs are a class of non-coding RNA molecules that regulate the gene expression at the post-transcription levels. They have been implicated in various important cellular processes, such as proliferation, differentiation, apoptosis and lipid metabolism etc. Cartilage injury and degeneration can cause various joint diseases, and the current clinical treatments are unsatisfactory. Current researches have found that miRNA play important roles in the proliferation and differentiation of chondrocyte and their synthesis and catabolism. With novel targets of MicroRNA have been found, their important roles have been further confirmed. The present review summarizes the current evidences of the synthesis and function of the miRNA, and their regulatory roles in the cartilage damage and degeneration. In summary, MicroRNA play important roles in disease pathogenesis resulted by cartilage injury and degeneration,and may have important diagnostic and therapeutic potential, further more, and might provide a novel means of treating degenerative diseases. PMID- 23016399 TI - [Tracking of neural stem cells in high density image sequence based on Topological constraint combined with Hungarian algorithm]. AB - Analysis of neural stem cells' movements is one of the important parts in the fields of cellular and biological research. The main difficulty existing in cells' movement study is whether the cells tracking system can simultaneously track and analyze thousands of neural stem cells (NSCs) automatically. We present a novel cells' tracking algorithm which is based on segmentation and data association in this paper, aiming to improve the tracking accuracy further in high density NSCs' image. Firstly, we adopted different methods of segmentation base on the characteristics of the two cell image sequences in our experiment. Then we formed a data association and constituted a coefficient matrix by all cells between two adjacent frames according to topological constraints. Finally we applied The Hungarian algorithm to implement inter-cells matching optimally. Cells' tracking can be achieved according to this model from the second frame to the last one in a sequence. Experimental results showed that this approaching method has higher accuracy compared with that using the topological constraints tracking alone. The final tracking accuracies of average of sequence I and sequence II have been improved 10.17% and 4%, respectively. PMID- 23016400 TI - [The effects of PEMF on the activation of human monocytes]. AB - The aim of the present study is to investigate the effect of pulsed electromagnetic field (PEMF) on the activation of human monocytes (THP-1). Cultured THP-1 cells were exposed to PEMF stimulation with radiation of 32Hz or 64Hz respectively, using sinusoidal wave, and 1mT, twice a day, 30 minutes each time, with an interval of 8 hours, for 3 days. Those with 0Hz stimulation served as the controls. Monocytes activation was monitored by measuring both the release of monocyte chemoattractant protein-1 (MCP-1) from monocytes and their adhesion to monolayers of human umbilical vein endothelial cells (HUVECs). The adhesion of THP-1 cells to HUVECs was evaluated by cell counting method. The secretion of MCP 1 from THP-1 cells was detected by ELISA and MCP-1 mRNA expression was assessed by real time quantitative RT-PCR. The data showed that exposure to PEMF with above parameters could significantly inhibit the adhesion of THP-1 cells to HUVECs and decrease the MCP-1 mRNA and protein expression. The results demonstrated that exposure to PEMF of 1mT, 32Hz or 64Hz for 3 days could significantly inhibit the activation of THP-1 cells. PMID- 23016401 TI - [Modeling and analysis of volume conduction based on field-circuit coupling]. AB - Numerical simulations of volume conduction can be used to analyze the process of energy transfer and explore the effects of some physical factors on energy transfer efficiency. We analyzed the 3D quasi-static electric field by the finite element method, and developed A 3D coupled field-circuit model of volume conduction basing on the coupling between the circuit and the electric field. The model includes a circuit simulation of the volume conduction to provide direct theoretical guidance for energy transfer optimization design. A field-circuit coupling model with circular cylinder electrodes was established on the platform of the software FEM3.5. Based on this, the effects of electrode cross section area, electrode distance and circuit parameters on the performance of volume conduction system were obtained, which provided a basis for optimized design of energy transfer efficiency. PMID- 23016402 TI - [The sub-microsecond pulser applied for electroporation effect]. AB - A sub-microsecond pulse generation applied for electroporation effects of tumor cell is presented in this paper. The principle of the generator is that the expected pulse waveform is intercepted from the RC discharge curve by controlling the on-off states of two IGBT modules with a synchronous controller. Experimental tests indicate that the generator can produce adjustable pulse waveform parameters with 0.5-3.5kV amplitude, 300-800 ns pulse duration, 1-400Hz repetition frequency rate, and it is suitable for the study of the electroporation effect experiments. PMID- 23016403 TI - [Evaluation of regnant anatomic distribution and metastatic type in skeletal thorax metastasis of breast cancer with multi-detector CT]. AB - To determine the characteristics and regularity of multi-detector CT (MDCT) in breast cancer with skeletal thorax metastasis, we retrospectively analyzed the imaging findings of MDCT in 72 cases of breast cancer with bone metastasis before treatment. There were totally 455 metastasis involved sites. The most common metastatic site was thoracic vertebra. And the fourth left rib was most common lesion in rib metastasis. Right breast cancer was more likely to take place at the bilateral ribs (65%) and pectoral girdle (54.5%) metastasis. The lesions in 28 cases demonstrated osteolytic destruction (38.9%), while 30 cases showed osteogenic appearance (41.7%). In conclusion, the development of breast cancer with skeletal thorax metastasis has certain characteristics and regularity. PMID- 23016404 TI - [MDCT features and anatomic-pathological basis of lymphoid neoplasm in cervico thoracic junctional region]. AB - To determine the relevance between MDCT features and anatomic-pathological basis of lymphoid neoplasm in cervico-thoracic junctional region, we performed a retrospective analysis of 69 patients with lymphoid neoplasm (lymphoma: 41 patients; metastatic tumor: 28 patients) involving the cervico-thoracic junctional region for MDCT features and distribution of lesions. The relevance between MDCT features and the anatomic-pathological basis in this region were evaluated. Among all the 41 patients with lymphoma, 29 with NHL (70.7%), 12 with HD (29.3%). The lymphomatous lymphadenopathy mainly located in superficial lateral cervix (51.2%, 21/41) ,deep jugular chain (65.9%, 27/41), supraclavicular fossa (75.6%, 31/41), paratrachea space in anterior mediastinum (46.3%, 19/41), around aortic arch (56.1%, 23/41), aortopulmonary window (53.7%, 22/41), upper anterior mediastinum (41.5%, 17/41), subcarinal space (26.8%, 11/41) and paraesophageal space (17.1%, 7/41). 28 patients had metastatic lymphoid tumor. The primary tumor were nasopharynx tumor (5 patients), thyroid cancer (7 patients), lung cancer (10 patients), and esophageal cancer (6 patients). Most metastasis took stage by stage in the way of lymphatic return, but a minority of cases migrated jumpily. The main metastatic sites were: beside jugular chain (82.1%), supraclavicular fossa (75%), paratracheal in anterior mediastinum (60.7%), upper anterior mediastinum (64.3%), beside aortic arch (35.7%), aortopulmonary window (39.2%), and paraesophageal space (28.6%). So lymphoid neoplasms in cervico-thoracic junctional region were involving both lower cervix and upper thorax simultaneously. The MDCT features and main distribution of lesions correlated with the anatomic-pathological characteristics in this region. PMID- 23016405 TI - [Analysis of rhythm features of EEG for driving fatigue]. AB - With extracting separately delta, theta, alpha and beta rhythms of electroencephalogram (EEG), we studied the characters of EEG for fatigued drivers by analyzing relative power spectrum, power spectral entropy and brain electrical activity mapping. The experimental results showed that with the average relative power spectrum in delta and theta rhythms of EEG increasing, the average relative power spectrum in alpha and beta rhythms decreased, while the average relative power spectrum in delta, theta and alpha rhythms increased in deep fatigue. The average power spectral entropy of EEG decreases with the increasing fatigue level. The average relative power spectrum and the average power spectral entropy of EEG could be expected to serve as the index for detecting fatigue level of drivers. PMID- 23016406 TI - [Changes of local field potentials in M1 underlying the specific behavior in rat]. AB - The local field potentials (LFPs) underlying specific behavior were recorded and analyzed in this paper from primary motor cortex (M1) with several medium, such as the self-made single channel micro-electrodes, the system of multi-channels physiological signal acquisition and processing and so on. During the experiment, the specific behavior was divided into four periods according to the changes of the recorded LFPs and the changes of the specific behavior recorded simultaneously in rats. The four periods were named prophase of catching period, planning period, catching period and the completion period, respectively. Then several methods were used for the analysis of the LFPs by MATLAB, such as time domain analysis, power spectral distribution analysis and time-frequency analysis. The results suggested that the LFPs which were caused by different behavior from a large number of movement-related neurons of M1 during the specific behavior in the process of catching play an important part in the "code" guiding role in rats. The results demonstrat that the LFPs of M1 may provide a feasibility to discriminate the motor behavior of forelimb. PMID- 23016407 TI - [Study on motion artifact reduction based on periodic component analysis using ECG as a case]. AB - Motion artifacts are a main interference source of ambulatory physiology signals. The interference in wearable detection systems is more serious because of using dry electrodes. On account of the instantaneity in motion artifacts and periodicity in physiological signal, we presented a new method based on periodic component analysis for motion artifact reduction. The single channel signal is transformed into multi-channel signal with multi resolution analysis, and then periodic component analysis can help us to separate the normal physiological signal from motion artifacts. A case study in electrocardiogram (ECG) demonstrates that periodic component analysis is better than the empirical mode decomposition and adaptive filtering methods. Periodic component analysis as a time domain method can discriminate the signal with frequency aliasing, and recover the ECG waveform feature corrupted. This method can be easily extended to other physiological signal processing. PMID- 23016408 TI - [Phase synchronization analysis of EEG signal during audio-visual stimulation]. AB - EEG Synchronization is considered the conformity of the brain functional areas. Advanced brain function requires many nervous systems with a specific function in relevant brain regions (areas) to achieve integration and coordination at different levels. In this paper, a new method for phase synchronization analysis Mutually Approximate Entropy is proposed to process different frequency band of EEG signal during audio-visual stimulation and get Similar results with the method of Synchronization Index and Mutual Information Entropy. This showed that the Mutually Approximate Entropy can lead to a good indication of the phase synchronization between two leads. The paper also explored the brain reaction zone by the results of the phase synchronization analysis. The research work lays the foundation for the brain-computer interface design. PMID- 23016409 TI - [Wavelet analysis for electrocardiogram variation of arrhythmia patients]. AB - To explore the energy proportion of the QRS complexes in the electrocardiogram (ECG), a new method, wavelet analysis, has been presented. Using wavelet transform of ECG, we can calculate the energy proportion of QRS complexes in multiple scales. The electrocardiograms (ECGs) were used as the experimental data, which were collected from a young (21-34 yr) group and an elderly (68-81 yr) group of healthy subjects, as well as from a group of arrhythmia patients (66 81 yr). the data analysis was performed with the energy proportion of the QRS complexes in the ECG using Mexican-Hat as a mother wavelet in multiple scales. Results showed that the energy proportion of the QRS complexes had no changes with ages increasing (P > 0.44), but in the same age group, the arrhythmia patients' energy proportion of the QRS complexes near 17Hz are obviously less than that in the healthy group (P < 0.01), so the energy proportion of the QRS complexes calculated by wavelet analysis can be used as a feature index to judge whether a person is a sinus arrhythmia patient or not. PMID- 23016410 TI - [Electrical impedance spectroscopy for evaluation of the influence of simulated weightlessness on the electrical properties of rat blood]. AB - In the present study, the AC impedance of rat blood was measured with Agilent 4294A impedance analyzer in the frequency range of 10(4)-10(8) Hz, and the effect of simulated weightlessness (SWL)on electrical properties of rat blood was investigated by analyzing the data characteristics with the use of electrical impedance spectroscopy, the Bode diagram, the Nyquist diagram and the Nichols diagram. The results demonstrated 60 days SWL caused some changes: (1) the electrical impedance of rat blood were reduced, mainly in the real part of complex impedance (Z'o and Z'infinity), the electrical impedance modulus amplitude (|Z*|o and |Z*|infinity), the impedance relaxation strength (deltaZ', delta|Z*|) and the logarithm of impedance modulus amplitude at low frequency (Log |Z*|o) were lower than that in the control (CON) group; (2) the characteristic frequency of the electrical impedance spectrum of rat blood and the phase angle were increases, mainly in the characteristic frequency (fc1, fc2) and the phase angle [theta(p) (degree), theta(p) (radian)] increased compared with that in the CON group. These data indicate that SWL leads to reduced resistivity and enhanced conductivity of blood. PMID- 23016411 TI - [Study of anatomy of the lateral attachment of the renal fascia in adult with multidetector computed tomography]. AB - The present paper is aimed to observe the lateral attachment of the renal fascia (RF) in vivo with multidetector computed tomography (MDCT) scanning, and to discuss its diagnostic value. 121 healthy adults were adopted into this experiment. All images were obtained with MDCT and double phase enhancement scanning. Then we observed the lateral attachment of RF. In addition, we mad a fresh body specimen as anatomical basis. The study found that above the renal hilar plane (RHP), the anterior renal fascia laterally fused with the peritoneum of the liver on the right and the peritoneum of the spleen on the left,and the posterior renal fascia fused with the subdiaphragmatic fascia. The lateral attachment of the RF at the RHP and the lower renal pole(LRP)is divided into three types. The RF in Type I is about 47.9% (58/121) at the left RHP, while about 33.9% (41/121) at the right RHP. At the LRP of the kidney is about 55.3% (67/121) on the left, and about 42.1% (51/121) on the right. The RF in Type I is about 38.8% (47/121) on the left side at the RHP, about 26.4% (32/121) on the right side. At the LRP, left side about 27.3% (33/121), right side about 13.3%(16/121). The RF in Type III at the RHP is 13.3% (16/121) on the left side, and on the right side is about 39.7% (48/121). At the LRP, it is about 17.4% (21/121) on the left side, and about 44.6% (54/121) on the right side. MDCT can display the lateral attachment of the RF better as well as the outside connection of the retroperitoneal space. PMID- 23016412 TI - [Application of image processing technique in scoliosis detection]. AB - Scoliosis, the abnormal lateral curvature of the spine, is an idiopathic disease often suffered by teenagers. Normally medical doctors use X-rays to measure the Cobb angle, and then assess the severity of scoliosis with it. In this paper, we point out the superiorities of image processing technique through analyzing the existing methods in the diagnosis of scoliosis. Two kinds of image processing technique are mainly introduced for scoliosis detection. The moire stripe images show an asymmetric deformation pattern between the left-hand side and the right hand side of human back, and these associate with Cobb angle to detect scoliosis. In order to check scoliosis through accurate three-dimensional surface features of human back, we in the second technique use different optical imaging methods to reconstruct the three-dimensional surface model of the patient's back, and extract the characteristics of the reconstructive human back to diagnose the disease. Both approaches tried to describe symmetry discrimination of human back and correlated it with the Cobb angles. Finally, we look forward to the future development in the application of image processing technique for scoliosis detection. PMID- 23016413 TI - [Research of on-line vision inspection technology for width of NC membrane]. AB - This paper presents a vision-based method for the width of NC membrane online inspection. In the production of bio-test strip, the number of antigen or antibody which is coated on the membrane depends on the width and the uniformity of test line T and control line C. People should control the width and the uniformity strictly to ensure the accuracy of lines in order to achieve quantitative inspection with high sensitivity. And online inspection must be done, it cannot be processed when the solution has been dry up. This paper gives a design of online inspection system based on linear charge-coupled device (linear CCD), it makes such advantages in terms of speed, accuracy, and the operation to achieve real-time, online inspection. PMID- 23016414 TI - [Three-dimensional computed tomography in postoperative evaluation of the knees after anterior cruciate ligament reconstruction]. AB - This study evaluated the clinical value of three-dimensional computed tomography (3D-CT) images in the knees following arthroscopic anterior cruciate ligament (ACL) reconstruction. Sixty-five consecutive patients underwent arthroscopic ACL reconstruction with single-incision and single-tunnel techniques. Preoperative and postoperative (12 months in between) clinical evaluation were performed using the Lysholm knee score and a KT-1000 arthrometer (side to side). Computed tomography (CT) of the knees was performed in a week after operation in all cases and at mean follow-up of 12 months. All of the clinical evaluation scales performed showed an overall improvement. 3D-CT images can display not only the bone tunnels of the knees including femoral and tibia very distinctly, but also the contour of the reconstructed ACL including adjacent structures. The average femoral tunnel diameter increased significantly (3%) from (9.15 +/- 0.03) mm postoperatively to (9.48 +/- 0.5) mm after 12 months; tibial tunnel increased significantly (12%) from (9.11 +/- 0.09) mm to (10.2 +/- 0.3) mm. There was no statistical difference between tunnel enlargements. So multi-slices spiral CT can evaluate the contour and changes of contour and changes of the knee after ACL reconstruction, which will be helpful in the intraoperative location and postoperative assessment of the knees. PMID- 23016415 TI - [Influence of gated myocardial perfusion imaging with different acquisition models on the assessment of left ventricular function]. AB - This paper is aimed to investigate the influence of gated myocardial perfusion imaging (G-MPI) with 8- and 16-frame acquisition models on the assessment of left ventricular function. Patients prepared for stress and rest G-MPI were prospectively recruited from January 2010 to January 2011 in the Department of Nuclear Medicine of West China Hospital, Sichuan University. Two separate G-MPI studies, one with 8 and the other with 16 frames, were simultaneously acquired during a single gantry orbit using Concurrent Imaging technique. We calculated the left ventricular ejection fraction (EF) and volumes using the Auto Quant software. Forty-eight patients (29 men, 19 women; average age 51 +/- 16 years old) were finally analyzed. The differences in left ventricular EF between 8- and 16-frame were small: 3.27% (95% CI: 6.41%-0.12%) for post-stress and 3.13% (95% CI: 5.93%-0.32%) for rest. Both using 8 and 16 frames, there were significantly larger volumes and lower EF in patients with stress-induced ischemia than without. As for detecting left ventricular EF, 8-frame and 16-frame acquisition models should not be mutually alternated. PMID- 23016416 TI - [Analysis on changes of sclerotin volume during the self-repairing process of bone defect]. AB - Bone maintenance theory considers that the external load is the direct stimulating source of the bone remodeling. In this article, the method of experimental observation of self-repairing process of the bone defect and related results are introduced. Firstly, a hole was drilled in the rabbit thighbone so that the continuity of the bone was changed. Then bone defect model was established, and the thighbone data were obtained by using CT scanning, and the self-repairing process of bone defects caused by growth factor were observed and analyzed by MIMICS software. Finally, the relationship between volume changes of sclerotin was established, and scientific bases were provided for introducing the bionic topology optimization method to the remodeling process. The experimental results showed that the self-repairing of the each layer sclerotin of the young rabbits was faster than that of the adult ones under the same condition. In addition, the volume always changes contrarily between the spongy bone and enamel bone during the self-repairing process of bone defect. PMID- 23016417 TI - [Tail-suspended model simulating mouse oocytes maturation inhibited with microgravity]. AB - We studied the effects of simulated microgravity on mouse oocytes maturation, and analyzed whether the tail-suspended model can be applied to investigate simulated microgravity effects on reproductive processes in female mice. Mouse oocytes were cultured in vitro with microgravity simulated by a rotating wall vessel bioreactor and by tail-suspended model, and the maturation rate of the mouse oocytes in the two models were examined in vivo. The maturation rate of mouse oocytes cultured in simulated microgravity was 8.93%, and that was 72.33% in 1g gravity. In ratio, oocyte maturation rate had no significant difference between the rotational group and control group. Microgravity simulated by the tail suspended model inhibited mouse oocytes maturation and increased the rate of oocytes abnormity. The maturation rate of tail-suspended mouse oocytes was 14.54%, which was significantly lower than that of control group. Tail-suspended model should be an ideal model to investigate simulated microgravity effects on reproductive processes of female mice. PMID- 23016418 TI - [Effects of hydrostatic pressure in physiological range on bladder smooth muscle cells in vitro]. AB - To explore the effects of the physiological range of hydrostatic pressure on human bladder smooth muscle cells (HBSMCs) cultured in vitro, we used a hydrostatic compression device designed in our laboratory into the experiments, which were grouped by varied hydrostatic pressure gradients. Cellular morphology was observed with HE staining; cytoskeleton F-actin, cell cycle, both proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase 7 (MMP-7) were detected respectively with immunofluorescence, flow cytometry and RT-PCR. We found that the proliferation, cytoskeleton and cycle distribution of HBSMCs were not obviously different among the groups of different hydrostatic pressure; however, the mRNA expression of MMP-7 exhibited a trend of first increasing and then declining as the pressure gradually rises. Thus the physiological range of hydrostatic pressure may not have significant influence on proliferation, morphology, skeleton, and cell cycle of HBSMCs, but it may have great effect on the expression of MMP-7. PMID- 23016419 TI - [A boundary element analysis on hemodynamic characteristics at the bifurcation of abdominal arterial]. AB - The hemodynamic characteristics of abdominal arterial bifurcation, such as blood flowing velocity vector, the shear stress at the vessel wall were calculated, studied and compared using the newly-induced boundary element method in this study. It was analysed why the atherosclerosis is asymmetrical at the bifurcation of abdominal arterial. The hemodynamic causes of production and development of the atherosclerotic were reasonabley explained by the shear stress calculation results of left and right common iliac branch vessel walls before and after the lesions. It is shown that the distribution of blood flowing velocity vector, the shear stress at the vessel wall are asymmetrical because of the asymmetrical geometry at the bifurcation of abdominal arterial, so that the shear stress of inner wall is higher than outside. The inner wall shear stress of right common iliac is higher than left. Blood velocity and shear stress increase at the atherosclerotic lesion because the blood vessel becomes narrower, and the blood velocity and shear stress decrease at the downstream of the lesion. It was also shown that the hemodynamic characteristics played a great important role in the occurrence and development of the atherosclerosis diseases at the bifurcation of abdominal arterial. Because of the increase of the shear stress, the atherosclerotic plaque surface will be damaged, leading to tissue hyperplasia. It will be lead to blood cell coacervation that the blood velocity and shear stress decrease at the atherosclerotic plaque downstream. PMID- 23016420 TI - [Kinetics of carrying and releasing oxygen of red blood cells in hemorrhagic shock]. AB - This paper focuses on the capacity changes of the red blood cells carrying and releasing oxygen. In order to provide theoretical basis and guidance for the clinical treatment of uncontrolled hemorrhagic shock, we investigated cases in the occurrence of uncontrolled hemorrhagic shock, and also analyzed the mechanism of physiological cause. Twenty healthy SD rats were used to build the hemorrhagic shock model. Red blood cells were collected at the initial step, at blood lose 20%, 30%, and 40% to determine the red blood cells capacities of carrying and releasing oxygen. The Hemox-analyzer was used to measure the thermodynamic parameters of the P50, the kinetic parameters of Tc50 and Tr50. The 2,3-DPG, pH value, glucose and lactate dehydrogenase changes were also captured and recorded. With the aggravation of shock, P50 and lactate dehydrogenase are continuously increased, Tr50, pH value and glucose are tended to reduce significantly, and Tc50 does not change significantly. With the increase of blood loss, red blood cell capacity to carry oxygen is stable, and the ability to release oxygen is increased, so that the oxygen consumption cannot be satisfied, which causes organ failure. PMID- 23016421 TI - [Study of process optimization on freeze drying of human amniotic membrane]. AB - The study was aimed to investigate the optimum conditions of freeze drying preservation of amniotic membrane (AM). The AM from the health puerperal woman was preserved by freeze drying at optimized way. The key factors of freeze drying process, including abstersion aqua, conservation liquor, the curve of freezing temperature, and the ingredient of protective agent, were optimized. All their morphologic structure was observed by light microscope and scanning electron microscope. The degradation rates by collagenase IV and the characterization of biomechanics were analyzed. The radio-immunologic method was used to investigate the cytokines quantity. All properties of freeze dried AM were compared with those of fresh AM. Light micrographs showed that the five structure-layers exist both in the fresh AM and in those preserved by freeze drying, while the fibro material was tight-structured in the fresh AM, but loose slightly; the thickness of fibro-material was larger slightly in freeze dried AM. Scanning electron micrographs show that the micro-hairs of epithelial cells in fresh AM were decreased slightly in optimized drying AM, the collagen fibre of fresh AM and of optimized drying AM were well in morphological structures and arranged tightly. The degradation rate by collagenase IV was faster in optimized drying AM,compared with that of the fresh AM. There were insignificant diversity in biomechanical characters (tensile strength, elongation at break and elastic modulus) of the optimized drying AM compared with fresh AM. The cytokines quantity in optimized drying AM decreased significantly compared with fresh AM. The improved freeze drying process has better advantage in keeping the morphological structure, preferable biomechanics and biological vitality of AM, compared with the early research. PMID- 23016422 TI - [A flexion loading system for knee biomechanics research]. AB - It is important to design and build a kinetic loading system for flexing movement of knee joint to study knee biomechanics. The system reported here includes driving device, control device, and flexion angle determination imaging system. The driving device was constructed with a stepper motor and a mechanical transmission with a serried of clamps, shanks and so on, and the driving device was controlled by the control device with micro-control unit, a computer and the serial 232. While the knee joint was driven to move by the stepper motor, the flexion angle of the knee was determined using imaging-based techniques. The system achieved accurate loading and control of speed, extent and duration of knee flexion, as well as fast and non-contract determination of flexion angle during knee flexing movement. The system is simple to build, easy to operate, highly accurate and reliable and it provides an important tool for the study of knee biomechanics, and potentially provides a tool for helping patients of knee surgery during their post operation recovery training. PMID- 23016423 TI - [Biocompatibility analysis of hyaluronic acid sodium gels for medical application]. AB - Hyaluronan acid sodium gels are used in ophthalmic surgery, orthopedic treatment and cosmetic surgery. In 2009,there were 12 domestic manufacturers in China producing 33 kinds of products. 23 kinds of imported products were allowed by SFDA to sale in the meantime. Since manufacturers use different production processes, product performances are quite different. According to the GB/T 16886. 1-2001, we designed a pilot program to evaluate the sodium hyaluronate gel products comprehensively in this paper. The results showed that, except chromosome aberration test of gel A and subchronic systemic toxicity of gel C appeared positive, the remaining samples of the test results were negative. This article provides a reference to write standard of cross-linked hyaluronic sodium gel and the revision of standard YY0308-2004. PMID- 23016424 TI - [Research on cationic vector-mediated RNAi]. AB - In order to study the efficiency of small interfering RNA (siRNA) transfer mediated by cationic liposome, we used luciferase siRNA to evaluate the gene silencing activity in the Hep-2 cells, which were stably transduced with a luciferase gene. The pDNA transfection was studied, and siRNA arrearage assay was conducted to determine the capability of cationic liposome with siRNA. Different concentrations of siRNA was used to silence luciferase gene' activity, and then the result was examined by microplate reader. Cell viability was analyzed after transfection by MTT assay. The results suggested that Lipofectamine 2000 could transfer the pDNA efficiently, and have strong binding capacity with siRNA. The silencing efficiency of luciferase was obtained with low concentration of siRNA. The cell viability was influenced by RNA interference (RNAi) very slightly, but the cell survival rate decreased with the increase of siRNA concentrations. It was well concluded that by optimizing the experimental conditions, cationic liposome can transfer low concentration siRNA to silence target gene's activity efficiently. PMID- 23016425 TI - [Damage effects of chronic hypoxia on medulla oblongata associated with oxidative stress and cell apoptosis]. AB - The aim of this study is to study the damage effects of chronic hypoxia on medulla oblongata and to explore whether the damage is associated with oxidative stress and cell apoptosis. Adult male SD rats were randomly divided into two groups: control group and chronic hypoxia group. Medulla oblongata was obtained for the following methods of analyses. Nissl's staining was used to examine the Niss bodies of neurons in medullary respiratory related nuclei, biochemistry methods were utilized to examine oxidant stress damage induced by chronic hypoxia on medulla oblongata through measuring malondialdehyde (MDA) content and superoxide dismutase (SOD) activity, and RT-PCR technique was used to study the influence of apoptosis induced by chronic hypoxia on medulla oblongata through analyzing the levels of Bax mRNA and Bcl-2 mRNA. The results showed the optical densities of Nissl's staining in pre-BotC, NA, NTS, FN, and 12N were significantly decreased in chronic hypoxia group in comparison with that in control group (P < 0.05). In chronic hypoxia group, MDA level was significantly higher than that in the control group (P < 0.05), whereas SOD level had no significant difference between the two groups (P > 0.05). Bax mRNA expression had no obvious change and Bcl-2 mRNA expression significantly decreased in chronic hypoxia group in comparison with that in control group (P < 0.05). The results suggest that chronic hypoxia could bring about serious damage to medullary respiratory centers through aggravating oxidative stress and increasing cell apoptosis. PMID- 23016426 TI - [Effects of basic fibroblast growth factor on bone marrow mesenchymal stem cell differentiation into temporomandibular joint disc cells]. AB - The present paper is aimed to observe the effects of basic fibroblast growth factor (bFGF) on bone marrow mesenchymal stem cell (BMSCs) differentiation. The bFGF was used to stimulate BMSCs and histology, immunohistochemistry and enzyme linked immunosorbent assay (ELISA) were used to examine the extracellular matrix produced by induced BMSCs, evaluated the feasibility of BMSCs being the seeding cells of temporomandibular joint (TMJ) disc tissue engineering. The results showed that having been induced with bFGF, the BMSCs could differentiate into fibroblast-like cells, which could synthesize GAG and collagen type I matrix. So it is feasible for BMSCs as seeding cells for engineered TMJ disc. PMID- 23016427 TI - [Construction and expression of bisbicistronic expression vector of novel endocrine and exocrine protein gene associated with breast cancer and IRES mediated gene EGFP]. AB - This experimental study was aimed to construct the recombinant bisbicistronic eukaryotic expression vector containing endocrine and exocrine protein (EECP) gene associated with breast cancer and enhanced green fluorescent protein (EGFP) gene. And then we transfected it into breast cancer cells MCF-7 to detect the expression of EECP protein and study preliminary biological function of EECP gene. The EECP sequence was cloned to pBluescript II SK (+) plasmid. After restriction endonuclease reaction of pBluescript II SK(+) plasmid, the EECP fragment was cloned to pIRES2-EGFP vector forming a recombinant eukaryotic expression vector named pEECP-IRES2-EGFP. The potential vector was identified by restriction endonuclease digestion and sequencing. Correct plasmid was extracted and transfected into breast cancer cells MCF-7. The expression of EECP protein was detected by western blot analysis. Its biological function was studied by MTT and Flow-cytometry. It turns out that the recombinant eukaryotic expression vector containing EECP gene and EGFP gene was constructed successfully, and it could transfect MCF-7 cells efficiently. It can get higher expression of EECP protein and higher cell proliferation, thus providing an important and convenient tool for studying the function of EECP gene in vitro and in vivo. PMID- 23016428 TI - [The application of wavelet transform and wavelet lifting in signal processing of EGG]. AB - This paper introduced the definition, structure of basis wavelet functions and wavelet lifting. Wavelet transform and wavelet lifting were applied in signal processing of EGG in our study. The characteristics of signal energy, information entropy and joint entropy were analyzed to introduce general selective method of wavelet basis functions after the signals have been filtered. In order to verify the rationality of evaluation criteria, signals of electrogastrogram (EGG) were processed and filtered with different wavelet basis functions in the experiments. Signals of EGG were filtered by wavelet transform and wavelet lifting, slow wave and spike wave of EGG were filtered. And the rationality of wavelet transform, wavelet lifting and effectiveness of EGG filter algorithm were proved by the experimental data. It provided an effective solution for the diagnosis and measurement of gastric diseases. PMID- 23016429 TI - [Recognition and study of pathological voice based on nonlinear dynamics using gaussian mixture model/support vector machine]. AB - In the traditional identification of pathological voice, linear analysis techniques are usually used to analyze the characteristics of voice, and the linear classical model is often considered to be approximate to of the real voice production process. However, this must have ignored the nonlinear characteristics of voice in the actual generation process. In the paper, based on the nonlinear dynamics analysis method, the pathological voice is analyzed quantitatively and 7 dimensional nonlinear features, Hurst parameter, time delay, the second-order Renyi entropy, Shannon entropy, correlation dimension, Kolmogorov entropy and the largest Lyapunov e exponent are extracted. The experimental results showed that the method of nonlinear dynamics could compensate the deficiencies of the traditional methods, and could analyze normal and pathological voice well. Gaussian mixture model (GMM) and support vector machine (SVM) methods for pattern recognition were used to discriminate the test set including 39 cases of normal and 36 cases of pathological voice, and a better recognition rate is received, 97.22% and 97.30% for each of the mentioned normal and pathological cases, respectively. PMID- 23016430 TI - [Research on and design of visual prosthesis based on visual information processing]. AB - Induced by a variety of retinopathy, visual loss has become the most serious form of disability, which influences the quality of human life. With the rapid development and crossing among the information science, microelectronics, material science and biomedical disciplines, the visual prosthesis makes reparation possible for the visual blindness caused by retinitis pigmentosa, age related macular degeneration, and other eye, retina, optic nerve and visual cortex lesions. With technology innovation, the prosthesis design, manufacturing and surgical technique are no longer the biggest obstacles to the future development of the visual prosthesis, but how to construct effective transmission of information between the brain and the prosthesis. However, due to the complex structure of the human visual system, the visual prosthesis manufacturing and visual information signal mapping are facing some difficulties. Thus, we can only study the representation strategy of image information and micro-electrode array stimulation basing on limited pixels of simulated prosthesis visual information. By studying the visual information processing of the visual prosthesis, we propose a visual prosthesis design which is based on biological, mechanical, and electronic integration. PMID- 23016431 TI - [Symbolic dynamics analysis of epileptic EEG signals of the rat]. AB - Epilepsy is a common chronic neurological disease, which is caused by excessive brain neuron discharge. The epileptic seizure has the characteristic of abruptness and reiteration. Prediction of seizures has great significance for patients to take timely and effective clinical measures. The symbolic dynamics method was introduced to analyze absence epilepsy EEG. The key parameters affecting the symbolic statistical quantities were discussed. The symbolic entropy and time irreversebility were calculated in different epilepsy stages. It was found that the symbolic entropy and the time irreversebility were rather big in interictal stage. The two parameters declined significantly during the transformation process from interictal stage to ictal stage and maintained lower value during ictal stage. The results showed that the symbolic dynamics method could reflect the changes of epilepsy EEG. The symbolic entropy and time irreversebility are sensitive features indicating different stages of seizures and have potential important clinical applications. PMID- 23016432 TI - [Effects and the mechanisms of cardiac short-term memory on cellular electrical excitability]. AB - Electrical instability easily induces a unidirectional conduction block, resulting in ventricular tachycardia (VT) or even fibrillation (VF). Cardiac memory affects dynamic electrical characteristics through previous pacing so that it makes the memory important in arrhythmia study. This paper investigates the impact of the rapid pacing duration on cellular excitability and its mechanism. Based on the canine endocardial single cell, a one-dimensional tissue model was developed. Simulations were realized with OpenMP parallel programming method. The results showed that with repetitive pacing, the cellular excitability became low while the conduction velocity decreased. Accumulation of intracellular [Ca2+]i and [Na+]i and depletion of [K+]i led to the shift of membrane current-voltage curves, changing the membrane resistance. Excitability determined by the resistance at the large width of stimulus pulse, therefore, it suggested that [Ca2+]i and [K+]i-induced memory formed the ionic substrates for the alteration of excitability. PMID- 23016433 TI - [3D reconstruction of multiple views based on trifocal tensor]. AB - Reconstruction of 3D structure of an object from 2D views plays an important role in plastic surgery and orthopedics. This method doesn't need camera to do specific movements, such as translation or rotation independently. It only needs a hand-hold camera arbitrarily to take a few pictures, and apply the geometry relationship among the three views to obtain the projective reconstruction of the object. Then, it needs to introduce cheirality constraint in stratified reconstruction to determine the search area of the infinity plane, and finally achieve the camera intrinsic parameters calibration, and complete the metric reconstruction. This model has also been reconstructed with mouse and keyboard response coordinates to observe the model from different angles. Experiments with both pictures of object and face pictures show that the proposed method is very robust and accurate. PMID- 23016434 TI - [Research progress on the development of the strategies for siRNAs delivery in vivo]. AB - RNA interference (RNAi) is a powerful endogenous process initiated by short double stranded RNAs, which results in sequence-specific posttranscriptional gene silencing. Because any protein that causes or contributes to a disease is susceptible to RNAi, the RNAi has high potential for therapeutic treatments. In a clinical setting, however, there are many obstacles to targeted delivery of small interfering RNA (siRNA) in vivo, specificity and stability of the RNAi reagents. In this review, we focus on recent progress in the development of efficient siRNA delivery vehicles to help the application of siRNA to in vivo therapy. PMID- 23016435 TI - [Review on the research progress of the role of miRNAs in gastric cancer]. AB - MicroRNAs, known as small noncoding MiRNAs, 19 to 24 nt in length, are important gene regulators and recognized as key players in carcinogenesis. The mechanism lies in that the MiRNAs can conjugate with their targeted mRNA and then lead to the targeted mRNA degradation or repress their translation. Bioinformatic analysis indicates that each MiRNA can regulate hundreds of gene targets and could serve functionally as "oncogenes" or "tumor suppressor genes", and therefore regulate multiple cellular processes relevant to carcinogenesis and cancer progression. Up to now, there have been a lot of studies about the MiRNAs which may play an important role in stomach neoplasms. The purpose of this paper is to have a review of the present studies on the MiRNAs related to stomach neoplasms, in order set basis for further study and their clinical application. PMID- 23016436 TI - [Advances in study of vascular endothelial growth factor and thyroid disease]. AB - The basic function of vascular endothelial growth factor (VEGF) is to promote vascular growth. Recent studies show that VEGF plays a vital role in various thyroid diseases through prompting angiogenesis. But the function of VEGF and specific change condition in different thyroid disease still needs further explorations. This review mainly focuses on the molecular characteristics and clinical application of VEGF. PMID- 23016437 TI - [Research progress of abnormal phosphorylation of microtubule-associated tau protein and of the targeted inhibition of the phosphorylation]. AB - Progressive dementia is described as the first and most prominent symptom of Alzheimer's disease (AD), and hyperphosphorylation of microtubule associated Tau protein (MAPT) plays a key role in neurodegeneration and neuronal dysfunction in AD and other neurodegenerative diseases. This paper reviews several protein kinases and phosphatases which can phosphorylate/dephosphorylate Tau protein, and evaluates a therapeutic strategy based on targeted inhibition of Tau kinases and activation of Tau phosphatases. PMID- 23016438 TI - [The application of stereology in radiology imaging and cell biology fields]. AB - Stereology is an interdisciplinary method for 3D morphological study developed from mathematics and morphology. It is widely used in medical image analysis and cell biology studies. Because of its unbiased, simple, fast, reliable and non invasive characteristics, stereology has been widely used in biomedical areas for quantitative analysis and statistics, such as histology, pathology and medical imaging. Because the stereological parameters show distinct differences in different pathology, many scholars use stereological methods to do quantitative analysis in their studies in recent years, for example, in the areas of the condition of cancer cells, tumor grade, disease development and the patient's prognosis, etc. This paper describes the stereological concept and estimation methods, also illustrates the applications of stereology in the fields of CT images, MRI images and cell biology, and finally reflects the universality, the superiority and reliability of stereology. PMID- 23016439 TI - [Research progress of magnesium and its alloys as orthopedic implant biomaterial]. AB - Magnesium based implants have the characteristics of bio-degradability, osteoconductive, and, regulatory strength. After the tissue has healed sufficiently, the burden of a second surgical procedure can be avoided. However, the degradation speed is so fast as to limit its clinical application. Hence, it is crucial for the biomedical magnesium alloys to be able to change their biodegradation behavior and speed. This paper reviews the degradability, biological activity and biocompatibility of magnesium and its alloys as orthopedic biomaterial in vitro and vivo to explore the possible way to modify the characteristics of its degradability, for the purpose of controllable degradation speed. PMID- 23016440 TI - Solid dispersion in pharmaceutical technology. Part II. The methods of analysis of solid dispersions and examples of their application. AB - In the first part of the article solid dispersions were classified the properties and methods of their preparation were described. This section presents methods of analysis of solid dispersions i.e.: thermoanalytical methods, XRPD, FTIR, microscopic methods, dissolution studies and examples of drug forms where solid dispersions were used. PMID- 23016441 TI - [Skin substitutes--the present and the future]. AB - Full-thickness skin deficits are indications to autologic skin graft. In extensive skin injuries an employment of skin substitutes is sometimes necessary. In this study we presented the classification of skin substitutes (permanent, temporary, biological, synthetic). The different kinds of skin substitutes approved to commercial production were described (epidermal substitutes, dermal substitutes, composite dermo-epidermal substitutes). The possibilities of clinical applications of skin equivalents and results obtained by many authors after employment of artificial skin were also presented. Still existing limitations in possibilities of recovery of all skin functions were emphasized and the directions of future development of the studies were presented. PMID- 23016442 TI - [Therapeutically active dressings--biomaterials in a study of collagen glycation]. AB - BACKGROUND: Active dressings (biomaterials, hydrogels) are cross-linked three dimensional macromolecular networks. One of the most important properties of active dressings, is their ability for controlled uptake, release and retention of molecules. The formation of advanced glycation end products AGEs progressively increases with normal aging. However, AGE products are formed at accelerated rates in age and stress-related diseases (burns, in wound healing) and also in vitro. OBJECTIVES: The aim will be also to develop a series of gels showing ability of controlled uptake, release and retention of molecules. The hydrogels can be used as biologically and therapeutically (antibacterial and anticancer) active biomaterials. MATERIAL AND METHODS: The following materials and reagents were used in the examination: dried plants: Equisetum arvense L., Pulmonaria officinalis L., Agropyron repens. Non-defatted films were extracted from the dried plants. The suspension was stirred and extracted. Temperature was controlled using a water bath. The filtrate was vacuum condensed. The gelling precipitate was poured onto Petri plates and dried. The swelling ratio and the percent loading were calculated. The released amount of CaCl2 at different time intervals was determined by measuring the conductivity. The extent of glycation in collagen was measured. RESULTS AND CONCLUSIONS: Novel types of swelling hydrogels have been prepared from dried plants and alginic acid. The active dressings showed swelling in aqueous medium, swelling characteristics were dependent on the chemical composition of hydrogel. The hydrogels were also loaded with CaCl2 and their potential for release was judged by measuring conductivity. The activity of hydrogels--active dressings on collagen incubated with glucose showed an decrease in glycation. So, hydrogels--active dressings, a known antiglycating agent which have therapeutic role in wound healing. PMID- 23016443 TI - [Technological and pharmacotherapeutic properties of selected drugs with modified release of diclofenac sodium]. AB - AIM OF THE STUDY: Diclofenac and its sodium salt is one of the best-known and popular therapeutic agents from the group of NSAIDs used in medicine in many various pharmaceutical forms. Therapeutic products containing diclofenac sodium salt in doses of 100 mg and 75 mg with a qualitatively and quantitatively diversified share of excipients and a variable dosage form of the drug (solid capsules, tablets with modified release) were subjected to technological and pharmaceutical analysis. The effect of solid formulation components of polymer character making the core and the coating of the pharmaceutical form of therapeutic products on the disintegration time and pharmaceutical availability in pharmacopoeial receptor fluids was estimated. MATERIALS AND METHODS: Market therapeutic products with diclofenac sodium in doses of 75 mg and 100 mg, technological analysis of the drug dosage form was conducted, disintegration time of solid oral dosage forms of the drug with diclofenac sodium salt was examined and research on pharmaceutical availability of diclofenac sodium salt from tested therapeutic products was conducted using the acid phase and the buffer phase according to the FP standards for delayed release enteral dosage forms. The experimental data was supplemented with the statistical analysis. RESULTS: There are three formulations in the form of solid capsules and one formulation in the form of a coated tablet. All therapeutic products bear features of a dosage form of modified release of diclofenac sodium salt, frequently of a delayed release formula in the duodenum or the small intestine with regard to the limitation of typical undesirable effects after taking NSAIDs. Considerable diversity between solid capsules and the tablet with modified release during disintegration or hydration and swelling has been observed. In the environment of a receptor fluid- purified water (pH = 7) the capsule Dicloberl retard disintegrates at the fastest rate in 5,49 minutes, and then in the order: DicloDuo 75 mg--8,13 minutes and Olfen 100 SR--11,27 minutes. The hydration degree of gelatin walls of capsules depends on the pH of the receptor fluid. The availability of diclofenac sodium salt in given receptor fluids confirms the fact of significant connection of clinical effectiveness of the tested pharmaceutical forms with the activity of hydrogen ions (pH) of the environment in which there are therapeutic products, and excipients used for making the pharmaceutical phase. CONCLUSIONS: Tested therapeutic products with diclofenac sodium salt are differentiated by the type of a dosage form. Dicloberl retard contains the minimally indispensable number of simple, commonly used excipients. The research on the disintegration time may only be related to the products Dicloberl retard, Olfen 100 SR and DicloDuo 75 mg treating it as the time of deformation and disintegration of a capsule. In all three types of receptor fluids, the capsule Dicloberl retard has the fastest disintegration rate. The "acid phase" demonstrated stability of the products with a slight dissolution of diclofenac sodium salt on the level 1,3-4,18% of the Q release coefficient. In the environment of artificial intestinal juice, Dicloberl retard is more effective releasing larger amounts of diclofenac sodium salt during 4 hours of exposition (differences from 10% to 14% of the Q release coefficient). PMID- 23016444 TI - [Usage of hydrophilic catheters and guidewires in endovascular surgery]. AB - AIM OF STUDY: The aim of this study was to evaluate the effectiveness of hydrophilic catheters and guidewires during endovascular overcoming long stenoses or occlusions of the superficial femoral and popliteal artery. MATERIAL AND METHODS: Based on 142 procedures rated the functionality of the equipment of the hydrophilic coating. The operations were performed in the years 2010-2012 in the Department of Vascular, General and Transplantation, Medical University in Wroclaw. Procedures related to recanalization or enlargement of the superficial femoral artery. Patients were divided into groups according to the Consensus TASC II depending on the length change. Each patient was assessed ankle-brachial ratio (ABI), claudication distance measured and constructed with double ultrasound imaging (USG-DD). In doubtful cases an additional study was performed with contrast computed tomography (angio-CT). The procedure was performed at the Laboratory of angiography using a angiograph Siemens Artis Zee Ceiling. Every time the contrlateral access was made, and as the first step the angiography was performed to verify type of changes in the arteries RESULTS: . A significant benefit of using hydrophilic guidewires and catheters in patients with long stenoses or occlusions. In case of long and calcified changes, hydrophilic catheters was the only option because it gave good support for hydrophilic guidewire. CONCLUSIONS: The changes in the type C and D according to the criteria for TASC II, an essential tool to achieve a positive treatment effect is the use of hydrophilic catheters and guidewires. PMID- 23016445 TI - [The treatment of aorto-duodenal fistula with the use of the endovascular prosthesis]. AB - One of the most common and serious complications after implantation of aortic or aorto-femoral prosthesis are aortoduodenal fistula. Secondary aorto-duodenal fistula is the most commonly observed form of a fistula between the abdominal aorta and gastrointestinal tract. 76 years old male with infected vascular prosthesis was admitted to Clinic with syndroms of active bleeding from aorto duodenal fistula. Because of general condition, patient was qualified to endovascular procedure, and a new stentgraft was implanted. After the procedure patient was treated with antibiotic compatible with inoculation from blood and he did not gave agreement for further surgical operations. He lived next 28 months and died because of lung cancer. PMID- 23016446 TI - Intracellular heat shock protein 70: a possible therapeutic target for preventing postoperative atrial fibrillation. AB - Postoperative atrial fibrillation is a frequent complication after cardiac surgery, associated with an increased risk of mortality and morbidity; thus, additional treatment and increasing costs of postoperative care are required. Inflammation and oxidative stress caused by ischemia-reperfusion during cardiac surgery may play an important role in the pathogenesis of postoperative atrial fibrillation. Stress-inducible heat shock proteins act as molecular chaperones that maintain cell homeostasis against stress in these events. Heat shock protein 70, the 70-kDa family of heat shock proteins, has been shown to closely associate with the incidence of postoperative atrial fibrillation in patients undergoing cardiac surgery. Extracellular heat shock protein 70 may be pro-inflammatory in the myocardial innate immune response caused by ischemia-reperfusion. In contrast, intracellular heat shock protein 70 exerts primarily anti-inflammatory and anti-apoptotic effects by preventing response to inflammatory cytokines, and inhibiting the nuclear factor Kappa B signaling pathway and different stages of mitochondrial-dependent pathways. Furthermore, the intracellular molecule can inhibit the induction and the maintenance of atrial fibrillation by attenuating Ca2+ overload in injuried myocardial cells. It is the intracellular heat shock protein 70, but not the extracellular molecule that holds as a therapeutic strategy for preventing postoperative atrial fibrillation. PMID- 23016447 TI - Synthesis, characterization, drug-loading capacity and safety of novel pH independent amphiphilic amino acid copolymer micelles. AB - A novel block copolymer containing two polymeric components, poly(L-aspartic acid)-b-poly (L-phenylalanine) (PAA-PPA), was synthesized and its potential for the preparation of copolymer micelles with a poorly water-soluble drug was investigated in this study. The chemical structure and physical properties of PAA PPA were characterized by FTIR, 1H NMR and TG. The degree of polymerization of PAA-PPA was calculated by analyzing the relative area of N-CH signal and C-CH3 of 1H NMR spectra. The critical micelle concentration (CMC) of the PAA-PPA achieved a minimum of 11.1 mg/L. Studies on the drug-free PAA-PPA solutions showed PAA-PPA aggregation into micellar type in the sub-150 nm size range. Furthermore, the size of the PAA-PPA micelles was found to be pH-independent between the pH range of 4.0 and 8.0, which could be favorable to avoid the limitation of the size change at the specified pH value seeking drug stability. 4-amino-2 trifluoromethyl-phenyl retinate (ATPR) was studied as a poorly water-soluble model drug. The drug-loading and entrapment efficiency of the ATPR-loaded PAA-PPA micelles were 30.9 wt% and 87.9 %, respectively. The high drug-loading and entrapment efficiency were due to the synergistic effect of the micellar encapsulation and the binding interaction between drug and PAA-PPA. The ATPR loaded PAA-PPA micelles showed a narrow size distribution, low zeta potential, high drug-loading capacity and good stable. The PAA-PPA was safer than Tween-80 and Cremophor EL (CrmEL) as an injectable pharmaceutical adjuvant for ATPR as indicated by the hemolysis and cytotoxicity studies. The novel amphiphilic amino acid copolymer can be considered as a prospective injectable delivery system for ATPR in terms of the pH-independent, greater drug-loading capacity and safety. PMID- 23016448 TI - Monitoring of fluconazole in serum of patients undergoing hemodiafiltration by solid-phase extraction and high-performance liquid chromatography with ultraviolet detection. AB - A high-performance liquid chromatographic assay for monitoring the antifungal drug fluconazole in human serum was developed using a C18 reversed-phase column with isocratic elution. The method involved sample clean-up by solid-phase column extraction, and subsequent analysis required only 14 min per sample for separation and quantitation. The assay was precise, with intra- and inter-assay relative standard deviations of < or = 1.5% and < or = 3.1%. The minimum detectable concentration of fluconazole was 0.3 nmol/ml. This assay has the advantage of minimizing the risk of interference from co-administered drugs to critically ill patients undergoing hemodiafiltration. PMID- 23016449 TI - Capillary electrophoresis with field-amplified sample stacking for rapid and sensitive determination of sulfadiazine and sulfamethoxazole. AB - A new capillary electrophoresis method with field-amplified sample stacking (FASS) was developed for the analysis of sulfadiazine and sulfamethoxazole. After optimization of the separation and concentration conditions, the two compounds can be separated within 7 min and quantified with high sensitivity, with detection limits of 0.48 ng/mL for sulfadiazine and 0.76 ng/mL for sulfamethoxazole. This resulted in a 300-1500-fold improvement in concentration sensitivity relative to conventional capillary electrophoresis methods. The method was useful for qualitative and quantitative analysis of sulfadiazine and sulfamethoxazole in their preparations with recovery of 99.0%-102% for sulfadiazine and 99.5% - 99.7% for sulfamethoxazole. PMID- 23016450 TI - Multivariate analysis approach for correlations between material properties and tablet tensile strength of microcrystalline cellulose. AB - In this study we applied statistical multivariate analysis techniques to establish correlations between material properties and tablet tensile strength (TS) of microcrystalline cellulose (MCC) with different types and manufacturers. There were sixteen MCC samples included in this analysis described by 22 material parameters. For data analysis, principal component analysis (PCA) was used to model and evaluate the various relationships between the material properties and TS. Furthermore, partial least squares regression (PLS) analysis was performed to quantify the relationships between the material properties and TS and to predict the most influential MCC parameters contributing to the compactibility. The results showed that the moisture content, hygroscopicity and crystallinity did not exhibit significant impact on TS. The turgidity, maximum water uptake, degree of polymerization and molecular weight presented a strong positive influence on TS, while the density property, bulk and tap density, exhibited an obvious negative impact. The present work demonstrated that multivariate data analysis techniques (PCA and PLS) are useful for interpreting complex relations between 22 material properties and the tabletting properties of MCC. Furthermore, the method can be used for material classification. PMID- 23016451 TI - Preparation, characterization and anticancer activity of norcantharidin-loaded poly(ethylene glycol)-poly(caprolactone) amphiphilic block copolymer micelles. AB - In this study, a novel amphiphilic block copolymer biomaterial - poly (ethylene glycol)-poly (caprolactone) (PEG-PCL), was used to entrap norcantharidin (NCTD), taking advantage of self-assembly theory. Dialysis and volatilization dialysis were used to prepare copolymer micelles. Drug-loaded micelles were compared with blank micelles in terms of their particle diameter, morphology and IR spectral characteristics. The results revealed that there was no significant difference in respect of morphology and IR spectrum, but particle size differed. Drug-loaded micelles had a smaller particle size than blank micelles. Three important factors influencing particle size, the drug loading content (LC) and the drug entrapment efficiency (EE) of the NCTD-loaded micelles, were studied. The results indicated that the method of preparation and the type of organic solvent had a significant influence on the size of the micelles. LC and EE were greatly affected by the ratio of NCTD to copolymer. In vitro release of NCTD from the conjugate micelles showed that its release rate depended on the pH of the phosphate buffer solution (PBS). The amount released was higher at lower pH than under neutral conditions. In vitro antitumor activity of the NCTD conjugate against human hepatoma (HepG2) cell line and human lung cancer (A549) cell line was evaluated by the MTT method. Micelles loaded with NCTD demonstrated greater and more satisfactory cell viability inhibition than the free drug. In vivo antitumor activity of drug loaded micelles was investigated in mice bearing S180 mouse sarcoma. NCTD-loaded micelles displayed tumor inhibition effects, better than the free drug. As a new drug delivery system, copolymer micelles present many advantages including easy formulation, good water solubility, low toxicity and high treatment efficacy, and show great potential as carriers of hydrophobic drugs. PMID- 23016452 TI - Comparative protein binding of taxotere and SID530, a new docetaxel formulation with hydroxypropyl-beta-cyclodextrin, in human plasma in vitro. AB - The purpose of this study was to evaluate the plasma-protein binding of docetaxel in two different formulations, Taxotere and SID530, a new docetaxel formulation with hydroxypropyl-beta-cyclodextrin (HP-beta-CD), in human plasma in vitro, using equilibrium dialysis. Unbound docetaxel concentration in the human plasma was determined by LC-MS/MS analysis. SID530 showed a plasma-protein binding profile comparable to that of Taxotere in the clinically relevant concentration range of docetaxel. In both formulations, the unbound fraction of docetaxel increased in a concentration-dependent biphasic manner. The resulting data indicate that the excipient used in SID530, HP-beta-CD, generates similar effects as polysorbate 80 of Taxotere in terms of plasma-protein binding of docetaxel. PMID- 23016453 TI - Pharmacokinetics of clopidogrel in healthy Chinese volunteers. AB - There are marked ethnic variabilities in the metabolism of clopidogrel. The pharmacokinetic (PK) characteristics of clopidogrel have been studied previously in whites or Korean volunteers, but these PK characteristics may not be fully extrapolated to the Chinese people. Little is known about the PK characteristics of clopidogrel in Chinese population. The aim of this study was to evaluate the pharmacokinetic profiles of clopidogrel in 20 healthy Chinese volunteers after administration of a single dose of clopidogrel 75 mg. The peak plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve from time 0 h to 36 h (AUC(0-36)), elimination half-life (t1/2), clearance rate (CL/F) and apparent volume of distribution (Vd) were (1.804 +/- 1.706) ng/ml, (0.7 +/- 0.3) h, (2.465 +/- 1.693) ng x h/ml, (7.3 +/- 7.0) h, (53.09 +/- 34.65) x 10(3) L/h and (447.1 +/- 440.8) x 10(3) L, respectively. PMID- 23016454 TI - CYP2C19 681G > A polymorphism and pharmacokinetics of clopidogrel in Chinese healthy volunteers. AB - The aim of this study was to investigate the contribution of the most frequent single nucleotide polymorphism of CYP2C19 681G>A to the pharmacokinetics of clopidogrel in 20 healthy Chinese volunteers after administration of a single dose of clopidogrel 75mg. The peak plasma concentration (Cmax) was higher in the 681GA+681AA group than that in the 681GG group (1.93 +/- 1.77 vs. 1.65 +/- 1.56ng/mL, P=0.613). The area under the curve to the last measurable concentration (AUC(0-36)) and area under the curve extrapolated to infinity (AUC(0-infinity)) of clopidogrel were lower in the 681GG group than that in the 681GA+ 681AA group (2.25 +/- 1.64 vs. 2.64 +/- 1.69 ng h/mL, P = 0.465; 2.26 +/- 1.65 vs. 2.67 +/- 1.71 ng h/mL, P = 0.455) respectively. The oral clearance (CI/F) was lower in the 681GA+681AA group than that in the 681GG group (51.96 +/- 36.13 vs. 54.47 +/- 35.21 x 10(3) L/h, P=0.829). The genetic polymorphism of CYP2C19 681G > A does not cause significant alterations in the pharmacokinetics of clopidogrel at a clinically relevant therapeutic dose in healthy Chinese volunteers. PMID- 23016455 TI - 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone inhibits apoptosis of MIN6 cells via improving mitochondrial function. AB - Mitochondrial dysfunction due to oxidative stress and concomitant beta-cell apoptosis may play a key role in type 2 diabetes. Inhibiting beta-cell apoptosis through ameliorating oxidative mitochondrial dysfunction with specific natural products may have preventive or therapeutic potential. In this study, the anti apoptotic effect of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a isolated chalcone from the buds of Cleistocalyx operculatus, on H2O2 induced MIN6 cells damage was investigated. Exposure to H2O2 at 250 microM for 3 h, the viability of MIN6 cells was significantly decreased and the apoptosis apparently occurred. A pre-treatment with DMC at the concentrations of 12.5-25 microM, before H2O2 addition, reduced nucleus fragmentation, decreased endogenous reactive oxygen species (ROS) production, and improved mitochondrial potential (MMP), and consequently, inhibited apoptosis. Furthermore, decreased activities of caspase-3 and caspase-9 were observed. These results clearly demonstrated DMC protected MIN6 cells against apoptosis due to its highly protective effect on mitochondria, and thus, it has great potential as a candidate drug for the diabetes care. PMID- 23016456 TI - Tacrolimus strongly inhibits multiple human UDP-glucuronosyltransferase (UGT) isoforms. AB - The objective of the present study is to clearly evaluate the inhibitory effects of tacrolimus (tacro) on important UGT isoforms in human liver, including determination of inhibition kinetic type and calculation of inhibition kinetic parameters. An in vitro incubation system was used to investigate the inhibitory effect of tacro on UGT isoforms. The recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. Among the tested UGT isoforms, UGT1A1, UGT1A3, UGT2B7 and UGT2B15 were strongly inhibited by tacro in a concentration-dependent manner. Dixon and Lineweaver-Burk plots showed that the inhibition of UGT1A1, UGT1A3, and UGT2B7 was all best fit to competitive inhibition type, and the inhibition of UGT2B15 was best fit to noncompetitive type. The inhibition kinetic parameters (Ki) were determined to be 4.7, 1.3, 1.9, and 4.3 microM for UGT1A1, UGT1A3, UGT2B7, and UGT2B15, respectively. Inhibition of these important UGT isoforms in human liver might be an important reason for clinically frequent drug-drug interaction between tacro and other drugs. PMID- 23016457 TI - Classification and grading of noninvasive and invasive neoplasms of the urothelium. AB - The classification and grading of the noninvasive, intraepithelial neoplasms of the urothelium are based on the morphological pattern of growth, i.e., papillary and flat (and endophytic), and on their degree of architectural and cytologic abnormalities. Recent advances in the morphological, molecular and quantitative evaluation of these lesions have contributed to the refinement of the current classification and grading schemes. However, some controversies on the precise criteria and terminology, especially when the papillary lesions are concerned, are still present. PMID- 23016458 TI - A framework for quantitative assessment of Ki67 distribution in preneoplastic bronchial epithelial lesions. AB - OBJECTIVE: Deregulated cell proliferation is a hallmark of cancer, and Ki67 immunostaining can be used to identify proliferating cells. Evaluation of cell proliferation may have utility as a biomarker of epithelial malignant transformation risk. To date, most analyses of Ki67 staining have been restricted to semiquantitative estimations of the degree of staining or the measurement of the fraction of Ki67-positive cells within the epithelium. We sought to develop a robust, objective means of quantitatively evaluating Ki67 immunostaining for lung precancerous lesions. STUDY DESIGN: We quantified the spatial distribution of Ki67-expressing cells within the epithelium by means of (1) a cell-based Voronoi tessellation and (2) a basement membrane-referenced distance transform. This was undertaken in a large cohort of 613 lung biopsy sections representing normal, hyperplasia, squamous metaplasia and mild, moderate and severe dysplasia. For each section 21 features quantifying different aspects of the Ki67 staining were calculated. Intraobserver and inter-observer variation were recorded for a subset of the biopsy sections. We examined the behavior of each feature with respect to histopathological grade. RESULTS: These measures demonstrated that proliferation is generally limited to layers 2, 3 and 4 of the epithelium (layer 1 being the basal layer). The proliferation in the basal layer is limited and does not increase with increasing grade of dysplasia. Interobserver and intraobserver effects on these features were assessed, and several were more robust with respect to measuring Ki67 expression pattern than the commonly used fraction of Ki67-positive cells. CONCLUSION: Many of these quantitative features showed associations with histological grade that were as strong as the association that exists based on the fraction of Ki67-positive cells while being much more robust to interobserver- and intraobserver-associated variations. The measured spatial distribution of proliferating cells statistically demonstrated asymmetric cell division behavior in cells in the basal layer, a pattern attributed to stem cells giving rise to transient amplifying cells. PMID- 23016459 TI - Spectrum of prostatic nonepithelial tumors and tumorlike conditions with spindle cell features. AB - There exists a wide and heterogeneous spectrum of spindle cell lesions that can originate from the prostatic stroma. This includes benign and malignant neoplasms as well as tumorlike conditions. Their diagnosis in small biopsy specimens is often difficult because of the potential for sampling error. The utility of ancillary studies, including immunohistochemistry, is often limited and the main criteria for diagnosis are the morphologic findings by routine hematoxylin and eosin stain. PMID- 23016460 TI - Nuclear morphometry in the differential diagnosis of eosinophilic renal epithelial tumors. AB - OBJECTIVE: To assess the potential contribution of nuclear morphometry to the differential diagnosis of renal epithelial tumors with eosinophilic cytoplasm, including chromophobe renal cell carcinoma (ChRCC), the eosinophilic variant of clear cell renal cell carcinoma (EoRCC), and oncocytoma. STUDY DESIGN: A total of 24 tumor tissue samples diagnosed as ChRCC, the EoRCC, or oncocytoma constituted our series. Eight geometric features such as nuclear area, nuclear perimeter, and circular form factor were measured and compared among the groups. RESULT: On the basis of nuclear morphometry, measurements of eight geometric features significantly differ among these problematic eosinophilic renal epithelial neoplasms (p < 0.005). CONCLUSION: Because of their different biologic behaviors, the exact discrimination of the renal epithelial tumors with eosinophilic cytoplasm is crucial. However, this distinction can sometimes be problematic even for highly experienced pathologists. Our results suggest that the morphometric nuclear shape descriptors may be used as an ancillary method in their differential diagnosis. PMID- 23016461 TI - Color deconvolution. Optimizing handling of 3D unitary optical density vectors with polar coordinates. AB - OBJECTIVE: Color deconvolution relies on determination of unitary optical density vectors (OD(3D)) derived from pure constituent stains initially defined as intensity vectors in RGB space. OD(3D) can be defined in polar coordinates (phi, theta, radius); always being equal to one, radius can be ignored. Easier handling of unitary optical density 2D vectors (OD(2D)) is shown. STUDY DESIGN: OD(2D) pure stains used in anatomical pathology were assessed as centroid values (phi, theta) with a measure of variance: inertia based on arc lengths between centroid value and sampled points. These variables were plotted on a stereographic projection plane. In order to assess pure stains OD(2D), different methods of sampling RGB pixels were tested and compared: (2) direct sampling of nuclei from preparations using (a) composite H&E and (b) hematoxylin only and (2) for any pure stain RGB image, different associated 8-bit masks (saturation, brightness and RGB average) were used for sampling and compared. Behaviors of phi, theta and inertia were obtained by moving threshold in 8-bit mask histograms. Phi and theta stability were tested against variable light intensity during image acquisition and by using 2 different image acquisition systems. RESULTS: The more saturated RGB pixels are, the more stable phi, theta and inertia values are obtained. Different commercial hematoxylins have distinct OD(2D) characteristics. UltraView DAB stain shows high inertia and is angularly closer to usual counterstains than ultraView Red stain, which also has a lower inertia. Superior accuracy is expected from the latter stain. Phi and theta OD(2D) values are sensitive to light intensity variation, to the used imaging system and to the used objectives. An ImageJ plugin was designed to plot and interactively modify OD(2D) values with instant update of color deconvolution allowing heuristic segmentation. CONCLUSION: Utilization of polar OD(2D) eases statistical characterization of OD(3D) vectors: conditions of optimal sampling were demonstrated and various factors influencing OD(2D) stability were explored. Stereographic projection plane allows intuitive visualization of OD(3D) vectors as well as heuristic vectorial modification. All findings are not restricted to anatomical pathology but can be applied to bright field microscopy and subtractive color applications in general. PMID- 23016462 TI - Micronuclei and other nuclear anomalies in buccal mucosa following exposure to X ray radiation. AB - OBJECTIVE: To evaluate DNA damage and cellular death in exfoliated buccal mucosa cells from healthy individuals following dental X-ray exposure, to compare effects of different types of radiographic techniques using the buccal cytome assay and to standardize the staining procedure. STUDY DESIGN: This study comprised 90 patients, categorized into 3 groups subjected to intraoral periapical radiography, conventional orthopantomogram and digital orthopantomogram X-ray exposure. Exfoliated oral mucosa cells were collected immediately before the X-ray and 10 days later and stained using DNA-specific stains and nonspecific DNA stains. RESULTS: The results indicated no statistically significant differences in micronucleated cells before and after dental X-ray exposure. On the other hand, X-ray exposure did increase other nuclear alterations closely related to cytotoxicity, such as karyorrhexis, pyknosis and karyolysis. CONCLUSION: These data indicate that dental radiography may not induce chromosomal damage, but it is able to promote cytotoxicity. PMID- 23016463 TI - Clinicopathological significance of lymphovascular invasion in urothelial carcinoma. AB - Lymphovascular invasion is an important prognostic marker in the assessment of bladder cancer, including both cystectomy and transurethral resection of the bladder specimens, and should routinely be reported upon in the pathological report. Strict criteria must be utilized in establishing a diagnosis of lymphovascular invasion in urothelial carcinoma to distinguish it from peritumoral stromal retraction, a common finding that often mimics a vascular space. The use of immunohistochemistry (CD31, CD34, D2-40) for the diagnosis of intravascular invasion in urothelial carcinoma should be used only in selected histologically equivocal cases for confirmation. Routine use of immunohistochemistry for endothelium as a screening test in all cases cannot be recommended. PMID- 23016464 TI - A new method for lung cancer prognosis via centrosome image feature analysis. AB - OBJECTIVE: To predict survival of resected stage I non-small cell lung cancer (NSCLC) patients through quantitative analysis and classification of centrosome features. STUDY DESIGN: Disordered centrosome amplification leads to the loss of regulated chromosome segregation, aneuploidy and chromosome instability and may be a biomarker of cancer prognosis. Resected, stage I NSCLC tissues from survivor and fatal cases were immunostained with gamma-tubulin and scanned by confocal microscopy. Regions of interest were selected to include 1 cell and at least 1 centrosome. Four hundred forty-six regions were imaged, including 903 centrosomes whose features were extracted and measured. After segmentation, 12 centrosome features were measured. After optimization, 6 non-redundant features were selected for statistical analysis and classification. RESULTS: Two statistical methods showed that for each feature, centrosomes from survivors differed significantly from centrosomes of fatalities. Centrosomes were classified into survival or fatal outcomes by centrosome features using linear discriminant analysis, support vector machines (SVMs) and further optimized using SVMs with bagging. Ten-fold cross-validation was applied. Classification accuracies were 74%, 79% and 85%, respectively. CONCLUSION: Centrosome features can be a prognostic biomarker for resected stage I NSCLC and may indicate patients who would benefit from additional adjuvant therapy. PMID- 23016465 TI - Breast cancer and clinical outcome among women over 60 years of age: a plead for more screening and alternative treatments. AB - OBJECTIVE: To study elderly women > or = 60 years of age diagnosed with breast cancer and analyze this cohort according to death from breast cancer and death due to comorbidities. Patients aged 60-69 years of age were included in routine mammography screening, but not women aged > or = 70 years. This enabled a comparison between the 2 groups regarding screening effect, tumor size and survival in breast cancer. STUDY DESIGN: A consecutive sample of 311 breast cancer patients > or = 60 years of age from 1991 were analyzed according to tumor size at diagnosis, frequencies of lymph node metastasis, tumor histological grade and stage, ploidy, proliferation index, stem-line-scatter index and survival rate in breast cancer and other causes of death. Tumor size was compared to a patient group aged 60-69 from 1987, before the introduction of mammography screening in Sweden. RESULTS: In the screening group a significant reduction in tumor size was found at diagnosis compared to the sample from 1987 (p < 0.001) and to the older group > or = 70 years (p < 0.02). In the latter group a higher death rate appeared for breast cancer. CONCLUSION: Older women would have a better outcome if included in the mammography screening program. PMID- 23016466 TI - Quantitative assessment of DNA methylation for the detection of cervical and endometrial adenocarcinomas in liquid-based cytology specimens. AB - OBJECTIVE: To investigate the aberrant promoter hypermethylation as a screening tool for cervical adenocarcinomas (CAs) and endometrial adenocarcinomas (EAs) in cervical scrapings. STUDY DESIGN: A quantitative multiplex methylation-specific polymerase chain reaction approach was used to examine promoter methylation of 5 genes (APC, HIN-1, RAR-beta, RASSF1A and Twist) in biopsy-confirmed CA (n = 31) and EA (n = 27) residual, liquid-based cytology samples. The data of negative for intraepithelial lesions or malignancy and low-grade squamous intraepithelial lesions were used as controls. RESULTS: Methylation levels of APC, RAR-beta, RASSF1A and Twist were significantly higher in CA than in control cervical samples. For EA, only the methylation levels of RASSF1A differed significantly from those of control. Receiver-operating characteristic analysis demonstrated that APC, RAR-beta and RASSF1A had the ability to distinguish CA/EA, CA and EA from control samples. In CA/EA and CA samples, the best 3-gene combination was RASSF1A/RAR-beta/APC. This 3-gene panel had a sensitivity of 87.0% for CA/EA and of 80.6% for CA and a specificity of 79.3% for both CA/EA and CA. In EA samples, RASSF1A showed the best performance in distinguishing EA from control. The estimated sensitivity of RASSF1A for detecting EA was 63.0%, and its specificity was 96.3%. CONCLUSION: This feasibility study demonstrates that quantitative detection of aberrant DNA methylation in cervical scrapings may be a promising new diagnostic tool for the detection of CA and EA. PMID- 23016467 TI - Impact of E-cadherin expression pattern in melanocytic nevi and cutaneous malignant melanoma. AB - OBJECTIVE: To explore the relationship between the immunohistochemical expression of E-cadherin and the relevant clinicopathologic features in various types of melanocytic nevi and cutaneous malignant melanoma (CMM). STUDY DESIGN: Using standard immunohistochemical techniques, we examined 30 CMMs, 30 melanocytic nevi and 10 sex- and age-matched volunteers for the expression of E-cadherin. RESULTS: A total of 90% of melanocytic nevi and all dysplastic nevi showed positive cytoplasmic immunoreactivity for E-cadherin with decreased intensity at the deeply located cells. A significant difference was noticed between types of CMM regarding the pattern of immunostaining of E-cadherin (p < 0.01), whereas all nodular malignant melanomas (NMMs) express the membranous pattern in contrast to the cytoplasmic one in other types of CMM. Reduced overall survival was significantly associated with advanced stage, late Clark level and membranous pattern of E-cadherin expression. CONCLUSION: E-cadherin expression in nevi is related to the degree of melanocytic maturation. Qualitative changes in the expression and cellular localization of E-cadherin are observed in melanoma that may reflect different stages of progression with molecular changes and may imply a prognostic marker. PMID- 23016468 TI - Vibrational spectroscopy as a supporting technique in clinical diagnosis and prognosis of atherosclerotic carotid plaques: a review. AB - There is an imperative need to distinguish stable from unstable and vulnerable plaques because of the occurrence of thrombosis following rupture of the plaque. Imaging techniques, invasive and noninvasive, are used routinely for the assessment of visualization and quantification of this pathology, even if invasive techniques cannot be applied in the screening of atherosclerotic plaques and noninvasive imaging has low reproducibility. The aim of this review was to verify the suitability and the advantages of using vibrational spectroscopy in the study of human atherosclerotic plaques. The utilization of validated vibrational techniques in clinical trials may be of great importance for the ability to diagnose the early onset of a disease, rapidly, noninvasively and unambiguously. These techniques, by using a worldwide accepted protocol in spectral investigation of bioclinical changes in the human body, have been successfully applied to assess vulnerable plaques in ex vivo and in vivo models, constituting a potentially useful support to classical clinical imaging techniques. It is conceivable that this fingerprinting approach, with further clinical validation, is ready to be developed for use and at the disposal of commercial and easy-to-use spectrometers, equipped with catheter-based systems for the in vivo imaging of atherosclerosis plaques. PMID- 23016469 TI - Effect of supplementation of micronutrient fortified biscuits on serum total proteins and vitamin A levels of adolescent girls (10-16 years) of Jaipur city, India. AB - Vitamin A deficiency is widely prevalent amongst women and children in India. The aim of the study is to study the effect of supplementation of micronutrient fortified biscuits on serum total proteins and vitamin A levels of adolescent girls (n = 46, 10-16 years) studying in a government school in Jaipur city, India. The study was designed to be an intervention study. The intervention was with biscuits containing 11.4 g of protein and fortified with 600 mcg vitamin A, 30 mg iron, 100 mcg folic acid, 40 mg vitamin C and 150 mcg iodine per day for all working days in a 4 month period. The results indicated that the protein status of 93.5% of the adolescent girls was adequate prior to intervention, this percentage increased to 97.8% at post intervention. Vitamin A supplementation augmented the percentage of adolescent girls in the 'normal' category from 56.1% to 73.2% and decreased the percentage of adolescent girls in the 'low' category from 41.5% to 26.8%. One girl who was in the 'deficient' category moved to the 'low' category. Hence, supplementation with biscuits fortified with vitamin A and other micronutrients improved the vitamin A status of the adolescent girls markedly. It is, therefore, recommended that the school system can be used for micronutrient supplementation to improve the micronutrient status of children and adolescents as the students are more regimented here for distribution of nutrient fortified food products. PMID- 23016470 TI - Diagnostic dilemma of the single screening test used in the diagnosis of syphilis in Nepal. AB - Syphilis screening by the nontreponemal rapid plasma reagin (RPR) test is not usually followed up by specific treponemal tests in most of the resource poor healthcare settings of Nepal. We analyzed serum specimens of 504 suspected syphilis cases at the immunology department of the national reference laboratory in Nepal during 2007-2009 using RPR test and Treponema pallidum hemagglutination assay (TPHA). In overall, 35.7% were positive by both methods (combination) while 13.1% were RPR positive and TPHA negative, 8.7% were positive by TPHA only and 42.5% were negative by both methods. Among the RPR reactive (n = 246), 73.2% were positive by TPHA. Non-specific agglutination in RPR testing was relatively higher (26.8%) compared to TPHA (19.6%). Although TPHA was found more specific than RPR test, either of the single tests produced inaccurate diagnosis. Since the single RPR testing for syphilis may yield false positive results, specific treponemal test should be routinely used as confirmatory test to rule out false RPR positive cases. More attention needs to be paid on formulation of strict policy on the implementation of the existing guidelines throughout the country to prevent misdiagnosis in syphilis with the use of single RPR test. PMID- 23016471 TI - True palmar pattern in vitiligo--a case control study. AB - Characteristic epidermal ridges formed on the finger pad and on the palm by the end of the second trimester and remain unchanged thereafter and those are responsible for the highly specific finger prints of each individual. These ridges are nither influenced by later prenatal period nor they subject to any influence in the postnatal environmental factors because the formation of ridge patterns gets already completed by about the eighteenth week of gestation. Dermatoglyphics is a scientific study of such epidermal ridges. Dermatoglyphic study of both palms of clinically diagnosed vitiligo patients and control subjects were carried out and statisticaltly analysed in respect to sex and side of hands. The study revealed variable number of deviations of this patterns in Vitiligo patients when compared with that of control. Increased number of true palmar patterns in right hypothenar, right thenar and both inter digital areas 2 (ID-2) and decreased TPP in Rt. ID3, Rt. ID4 in vitiligo male patients and increased TPP in Rt. Hypothenar and Rt. ID1 and decreased TPP in Rt. ID2 and Lt. ID 3 in vitiligo female patients while compared with that of the control group. Some of the variations observed were stastically significant. PMID- 23016472 TI - Association of thyroid dysfunction among infertile women visiting infertility center of Om Hospital, Kathmandu, Nepal. AB - Infertility is one of the medial, social and psychological burdens in this part of world. Thyroid dysfunction can lead to menstrual disturbance, anovulatory cycles, and decreased fecundity. Proper management of thyroid dysfunction canresult restoration of normal fertility. Therefore it is very important to screen thyroid abnormalities among women with infertility. This study aimed to determine association of thyroid dysfunction among infertile women. This study comprises total of 735 primary infertile women with age ranging from 20 to 35 years. Blood samples were collected and subjected for estimation of thyroid hormones. Out of 735 cases 547 (74.4%) were euthyroid. 56 (7.6%) have primary hypothyroidism, 31 (4.2%) have primary hyperthyroidism, 87 (11.8%) have subclinical hypothyroidism, and 8 (1.1%) have subclinical hyperthyroidism. PMID- 23016473 TI - A study on evalution of antidepressant effect of imipramine adjunct with Aswagandha and Bramhi. AB - Depressive disorders increase the risks of self-harm or even suicide in patients. Indigenous drugs are being tried to treat such patient along with conventional antidepressant drugs. This study was planned to investigate the antidepressant action of Ashwagandha and Bramhi and also to confirm its efficacy in the behavioural despair animal model of depression. Normal saline as control (5 ml/kg), Imipramine as standard (16, 32, 64 mg/ kg) and Ashwagandha (50, 100, 150 mg/kg), Bramhi (20, 40, 80 mg/kg) as test drugs were introduced to the albino rats weighing between 200-250 gm for 2 weeks, 1 hr before electric shock in Learned helplessness test (LHT) and swimming in Forced swimming test (FST). Effects of individual drugs as well as their combination were evaluated. Avoidance response, escape failure and immobility period in case of Imipramine and Ashwagandha showed highly significant (p < 0.01) result on individual use. There was no significant result in case of Bramhi used alone except in escape failure and immobility period (FST), where at higher doses it showed significant (p < 0.01) result. But combination of Bramhi and Ashwagandha in low doses with low dose of Imipramine gave a highly significant result (p < 0.01) in all the parameters. Ashwagandha had significant antidepressant action, but Bramhi had not when used alone. Combination of these two indigenous drug with Imipramine showed high efficacy in animal model. PMID- 23016474 TI - Ocular manifestations in diabetes, a hospital based prospective study. AB - Diabetes adversely affects the visual status of elderly persons, lowering their quality of life. Since the incidence of diabetes is increasing in urban Nepal, the present study investigated the ocular status in 128 diabetes patients. The ocular complications of diabetes mellitus are numerous including retinopathy, cataract and others. The ocular evaluations were done including visual acuity, refraction and anterior and posterior segment evaluation. Among 128 diabetes, only 26 patients (20.31%) had some degree of retinopathy; with 13.28% having non proliferative diabetic retinopathy and 7.03% with proliferative diabetes retinopathy. PMID- 23016475 TI - Prospective study of application of biological communication (cybernatics) in management of chronic low back pain--a preliminary report. AB - To observe the effects of application of cybernetics (theories of communication). This is an open level prospective study, involving patients with chronic low back pain of more than 3 months. Assessment were done before the start of therapy and after the completion of therapy every day for consecutive 6 days of treatment protocol. A total of 8 patients were enrolled (4 male, 4 female). The Visual Analogue Scale (VAS) was used to assess pain, Oswestry Disability Scale (ODI) was applied for scoring disability. ODI was scored at the start of treatment on 1st day and at the end of the treatment on 6th day. Mean VAS reduced from 8.12 to 6.93 after 1st day, which was also statistically significant (p < .01) .This trend continued and there was very significant reduction (p < .001) of VAS in the end when means were compared with pretreatment value. Mean Oswestry disability index reduced from 49.875 to 18.44 at the end of treatment which was statistically very significant (p < 0.001). There were significant improvements in all the outcome measured after Scrambler therapy. PMID- 23016476 TI - Diagnostic methods of malaria in Eastern Nepal: a comparative study of traditional and two rapid diagnostic tests. AB - This study compared the diagnostic accuracy of Quantitative Buffy Coat (QBC) a fluorescent microscopy test and OptiMAL, an immunochromatographic dip stick test against conventional microscopy for the detection of malaria at a tertiary teaching hospital situated in Eastern Nepal. 100 clinically suspected malaria patients with positive and negative parasitemia were assessed under conventional microscopy. The blood samples withdrawn from these subjects were further evaluated by the QBC Method and OptiMAL dipstick test. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of QBC and OptiMAL tests as compared with microscopy were 100%, 100%, 100%, 100%, 1 and 96%, 100%, 100%, 96.15% and 0.98 respectively. In Nepal, thick and thin blood smears remain the gold standard for malaria species diagnosis in routine diagnostic laboratories. In this study the efficacy of newer malaria rapid diagnostic tests (RDT) surpassed the diagnostic efficacy of clinical microscopy and hence these RDT's will have a greater role in clinical practice. The cost of QBC technique may impose limitations on its use in Nepal but the OptiMAL test is likely to play an important part in urgent malaria diagnosis. PMID- 23016477 TI - Errors on a handwritten cardex: is it time for a change? AB - A medical order is a medical and legal document and careful writing of this document is necessary. In Nepal the medical order in the admitted patients is written on a cardex which is utilised by the nurses to dispense medicines and to follow the doctor's orders. However, with the dawn of the electronic age this is being replaced by a computerized system, which is suggested to be better. The aim of this study was to identify if the existing cardex was adequate for the purpose of writing orders, or whether this needed modification. This was a prospective observational study were 240 cardexes from eight different Departments from the same Medical College Hospital were randomly looked into for errors. Thirteen different parameters were looked into including the legibility/readability of the handwriting. The results suggested the error rates to be high in certain parameters viz. utilization of the columns (77.9%), documentation of allergy history (77.5%), writing the prescribers name (89.6%) and writing date of discontinuation of medicines (62.5%). The handwriting was unreadable or difficult to read in 49.2% of the documents. However, the other parameters also had errors and no parameter was error free. The study suggested the need of the hour was to modify the existing cardex and also to educate the doctors to minimise errors. However, in the future we may have to move towards a computerized system in order to avoid errors related to bad handwriting. PMID- 23016478 TI - Prevalence of intestinal worm infestations among school children in Kathmandu, Nepal. AB - Intestinal worm infestation is one of the major childhood health problem in Nepal. This study was done to assess the prevalence of intestinal worm infestations among school children aged 6-16 years in a public high school in Kathmandu Nepal. A total of 142 stool samples from healthy students were collected and reported following formol-ether concentration technique. The overall prevalence of intestinal worm infestation was found to be 17.6% (Boys = 22.0% vs girls = 13.5%). Children aged 6-8 years were found to be highly infected with intestinal worms (21.4%) followed by 9-12 years old (18.6%). Those between 13-16 years of age were significantly less infected (10.7%) compared to others (p < 0.05). Ova/cysts of intestinal parasites detected include Trichuris trichiura (32.0%), Ascaris lumbricoides (20.0%), Hymenolepis nana (16.0%), hookworm (8.0%) and 24.0% cases showed mixed parasitic infections. PMID- 23016479 TI - In-vitro assessment of cell-mediated immunity by demonstrating effector-t cells for diagnosis of tuberculosis in Nepalese subjects. AB - The immune response against mycobacterium tuberculosis (MTB) is cell mediated. T cells become sensitized when they encounter MTB antigens and subsequently activated effector T-cells produce a number of cytokines including interferon- gamma (INF-gamma) to fight the infecting organisms. Demonstration of either production of INF-gamma or presence of effector T-cells sensitized to MTB specific antigens in vitro can be diagnostic for TB infection. Aim of this study was to determine the efficacy of commercially available T-SPOT.TB kit which is used for the in vitro diagnosis of TB infection and to determine if this test has any cross reactivity in leprosy patients. Blood sample was taken from 30 sputum AFB positive, 30 sputum AFB negative healthy controls and 10 cases of paucibacillary leprosy patients. The blood samples were processed to separate peripheral blood mononuclear cells. The final cell suspensions were cultured along with MTB specific antigens namely- Early Secretory Antigenic Target (ESAT 6) and Culture Filtrate Protein (CFP 10) along with negative and positive controls. The production of INF-gamma was demonstrated by enzyme linked immunospot (ELISPOT) assay technique. All AFB positive samples produced INF-gamma after exposure to MTB specific antigens. 4 (16.6%) of healthy controls were also found reactive for INF-gamma. The sensitivity and "specificity" for active disease of the ELISPOT (T-SPOT.TB) in respect to AFB microscopy was 100% and 85.7% respectively. Assessment of CMI against tuberculosis, by demonstrating effector T-cell sensitized to MTB antigens can be use to aid the diagnosis of tuberculosis. T-SPOT.TB has no cross reactivity with leprosy patients. PMID- 23016480 TI - Study of patients with painless inguinal hernia in the quality of life. AB - Inguinal hernias are one of the commonest surgical problems in our set up. It is a protrusion of abdominal cavity contents through the inguinal canal. This is a retrospective study done in the Department of Surgery, Nepal Medical College Teaching Hospital (NMCTH) from January 2009 to December 2010. During this period, 120 patients with painless hernia were enrolled in the study. The age range was from 30 years to 76 years with mean age of presentation at 53 years. Out of 120 patients who underwent mesh repair only 74 patients (61.7%) had visible hernia on standing and 46 patients (38.3%) had palpable impulse on cough. 90 patients (75%) were males and indirect hernia (53.3%) was more common than direct hernia. Out of 120 cases, 30 cases underwent inguinal neurectomy which on follow up had no pain at all. In other 90 cases, neurectomy was not confirmed from the operative note. In these 90 cases, 12 patients had mild pain and 10 patients had moderate to severe pain on 6 months follow up. To conclude, surgical repair is recommended for painless inguinal hernia as most of the patients develop symptoms over time and to avoid undue complications. PMID- 23016481 TI - Antibacterial photodynamic therapy on Staphylococcus aureus and Pseudomonas aeruginosa in-vitro. AB - Photodynamic therapy (PDT) involves the use of drugs or dyes known as photosensitizers, and light source which induces cell death by the production of cytotoxic reactive oxygen species (ROS). This principle of cell death can be utilized to kill bacteria in vitro. We propose the use of blue light emitting diodes (LEDs) and Riboflavin as the light source and photosensitizer for in vitro killing of Staphylococcus aureus and Pseudomonas aeruginosa. Circularly arranged 65-blue LED array was designed as the light source to fit exactly over 7cm culture plate. Riboflavin having non-toxic properties and nucleic acid specificity was used as a photosensitizer. Clinical isolates of Staphylococcus aureus and Pseudomonas aeruginosa were used in our study. Effect of PDT on viability on these species of bacteria was compared with control samples that included: control untreated, control treated with light only and control treated with riboflavin only. Statistical analysis was done using one-way ANOVA test. PDT against Pseudomonas aeruginosa and Staphylococcus aureus was significantly (p < 0.05) effective compared to all control samples. Combination of blue LEDs and Riboflavin in PDT against these bacterial species has been successfully demonstrated in-vitro. Therefore, PDT has promising applications in the process of treating superficial wound infections. PMID- 23016482 TI - Acute appendicitis in elderly patients: a challenge for surgeons. AB - The classic symptoms of acute appendicitis are seldom seen in the elderly patient. More subtle symptoms and the more virulent pathologic course allow the disease to progress rapidly and insidiously. This leads to delayed hospitalization, diagnosis and treatment. The high incidence of concomitant diseases and the multiplicity of differential diagnostic possibilities in this age group are also factors. The aim of this study is to compare the results of appendicitis operated at Lumbini Medical College, Pravas, in patients younger than 60 and patient elder than 60 years of age. All patients aged 60 years and older who underwent appendectomy for appendicitis between January 2008, and December 2011, were studied and compared with the patients who were younger than 60 years of age. All the operations were performed by consultant surgeons at Lumbini Medical College, Pravas, Tansen. Preoperative USG was done in all the cases. Preoperative antibiotics were given in all the cases. All patients underwent appendectomy as an emergency basis. The results were compared with regard to age, sex, pre-operative evaluation, operative duration and findings, postoperative course, duration of hospital stay, and mortality rate. There were 50 patients in group 1 and 150 patients in group 2 who met the inclusion criteria. The mean age (64 years for group 1 and 28 years for group 2), sex, preoperative suggestion of appendicitis (group 1, 35 [70%] of 50 patients; group 2, 135 [90%] of 150 patients), and duration of the preoperative hospitalization over 24 hours (group 1, 1 patients [20%]; group 2, 30 patients [20%]) were similar in both groups. Laparoscopy was used in (group 1, 5 patients [10%]; group 2, 6 patients [4%] and associated with no significant difference in the duration of hospitalization, frequency of appendiceal perforation or abscess, occurrence of complications, or mortality. The length of operating time was more in the first group. The mean hospital stay was 5.3 in group 1 and 2.2 in group 2 (p < 0.05). Also duration of Hospital stay was 9.5 days for perforated appendicitis and 5.4 for non perforated appendicitis in both group (p < 0.05). Advanced age adversely affects clinical diagnosis, the stage of the disease and the outcomes. Late presentation, delayed diagnosis, presence of perforation and co-morbidities are associated with poor outcome from surgery. PMID- 23016483 TI - Fine needle aspiration cytology--a reliable diagnostic tool in the diagnosis of thyroid gland enlargements. AB - To evaluate the accuracy and efficacy of fine needle aspiration cytology (FNAC) in the diagnosis of Thyroid gland enlargements. A retrospective analysis was done at Department of Pathology, Government Medical College and General Hospital, Anantapur, Andhra Pradesh, India. One hundred and fifty cases were included in this study. However in 10 cases aspirate was unsatisfactory and in 20 cases surgery was not performed and these cases were excluded from study. A total of 120 cases included in the final study. Detailed history, physical examination, routine investigations and other details of 120 patients were collected. FNAC with minimum two passes were performed in each case. Staining done with Haematoxylin and Eosin stain and Papanicolaou stains. FNAC smears and histopathology slides were reviewed. Among 120 cases 100 (83.66%) were reported cytologically as benign and 20 (16.66%) were malignant. But histologically 98 (81.66%) were benign and 22 (18.33%) were malignant. Commonest benign lesion of thyroid in both cytology and histology was nodular colloid goiter. Follicular adenoma was the second commonest one. Among malignant conditions papillary carcinoma was the commonest one in our FNAC samples, follicular carcinoma was the commonest in our histopathology samples. Four cases of false positive and 6 cases of false negative were observed. Sampling errors were mainly responsible for these false negative diagnoses. FNAC showed an accuracy of 96.6%, sensitivity 75%, specificity 95.83%, positive predicative value (PPV) 81.81% and negative predicative value (NPV) of 93.81%. Our results were similar to other international studies and suggest that FNAC is more specific and sensitive in detecting thyroid malignancy. Therefore its useas a reliable diagnostic test cannot be over emphasized. FNAC is an accurate and reliable diagnostic tool to evaluate the cause of Thyroid gland enlargements provided strict adherence to adequacy criteria are maintained. PMID- 23016484 TI - Prevalence of vaginitis among pregnant women attending Paropakar Maternity and Women's Hospital, Thapathali, Kathmandu, Nepal. AB - Vaginitis is the most prevalent disorder among the pregnant women. The objective of this study was to find out the prevalence of common types of vaginitis among the pregnant women visiting Paropakar Maternity and Women's Hospital in Kathmandu. Among 200 pregnant women included in the study, 78 (39.0%) had vaginitis. Of total 78 positive cases of vaginitis, 29.5% had candidiasis, 52.6% bacterial vaginosis and 1.3% trichomoniasis. Approximately 83% had monomicrobial infection and 16.7% had polymicrobial infection. Vaginitis was common in the age group of 20 to 29 years (41.8%) and 30-39 years (40.0%). Ethnically, Indo-Aryans (40.2%) were mostly infected. The infection rate was the highest among illiterate women (47.6%) and least among the women having education above secondary (23.0%). The positive infection rate was higher in women from rural area (45.2%) than those from urban area (37.3%). Nearly half of the women with agriculture occupation (48.4%) had vaginitis. Vaginitis was common in women with third pregnancy (52.6%). Among 78 vaginitis cases, 53 (67.9%) were asymptomatic cases. PMID- 23016485 TI - Antimicrobial efficacy of metapex (calcium hydroxide with iodoform formulation) at different concentrations against selected microorganisms--an in vitro study. AB - The objective of this study was to assess, in vitro, the effectiveness of several concentrations of Metapex (0.22 gm/ml, 0.022 gm/ml, 0.0022 gm/ml) in the elimination of selected microorganisms. Different concentrations of Metapex were prepared by dissolving it in ethanol (99.9%) Pre-sterilized Whatman paper discs, 6 mm in diameter and soaked with the test solution, were prepared and placed onto the previously seeded agar Petri plates. Plates were incubated aerobically for Enterococcus faecalis (E. Faecalis) and Candida albicans (C. albicans), anaerobically for Bacteroid fragilis (B. fragilis) and Propionibacterium acne respectivally. A zone of inhibition was recorded for each plate and the results were analysed statistically. There was significant reduction in the size of zone of inhibition against P. acne, as the concentration of metapex decreases. At lower concentrations of metapex there was no zone of inhibition observed against E. Faecalis, C. Albicans and B. Fragilis. The result of this study suggested that Metapex is a potent antimicrobial agent at higher concentration. PMID- 23016486 TI - Inguinal herniotomy in children: a one year survey at Nepal Medical College Teaching Hospital. AB - This was a prospective study done at Nepal Medical College Teaching Hospital from July 2008 to June 2009 which covers our experience in inguinal herniotomy in children. Our study included 63inguinal hernia repairs in 61 children up to the age of 15 years. Out of 61 patients 2 had bilateral inguinal hernia and 59 had unilateral. Among 59 patients with unilateral hernias, 7 patients had emergency presentation. In children with unilateral hernias, it was found that it is more common at right side and regarding complication it is more common in emergency group. There were 5 recurrences and 5 wound infection among all patients. PMID- 23016487 TI - Effectiveness of epidural steroid injection for the management of symptomatic herniated lumbar disc. AB - Low-back pain is a common clinical presentation of herniated lumbar disc. This is the most common presenting complain of the young adults. The incidence of low back pain is high in our part of the world. The reason may be hilly terrain, difficult working and living environment. The initial treatment of low back pain is conservative. Epidural steroid injection (ESI) is being slowly established as a simple, effective and minimally invasive treatment modality. The aim of this study is to assess the effectiveness of epidural steroid injection for low back and radicular pain. This is a Prospective observational study. It was carried out on the patients presenting with the complain of low back and radicular pain due to herniated lumbar disc not responding to conservative treatment. All the patients of herniated lumbar disc were proven by Magnetic Resonance Imaging (MRI). Injection Methyl prednisolone 80 mg and 2 ml of 0.5% bupivacaine was diluted in 8 ml of normal saline and injected into the affected lumbar epidural space. The functional status of the patient and the severity of pain were evaluated before injection and after injection during the follow-up period by using Ostrewy disability index and visual analogue score. Sixty two patients received the epidural steroid injections, but only fifty patients came for regular follow up till six months. Among the fifty patients, 26 were male and 24 were female. The functional status and pain response of the patients were improved significantly during all the follow-up periods (p < 0.001). The success rate of this study was 81%. No major complications were encountered. The ESI is a simple, safe, effective and minimally invasive modality for the management of symptomatic herniated discs. PMID- 23016488 TI - Signet ring cell carcinoma of the gallbladder: a case report. AB - Carcinoma of the gall bladder is the most common biliary tract tumor with higher incidence in females and increasing age. The risk is significantly higher in cholelithiasis. Signet ring cell carcinoma is a rare form of mucinous adenocarcinoma and has a worse prognosis. Early diagnosis is rare. We report a case of signet ring cell carcinoma of the gall bladder in a 70 years old female patient. The gross finding was yellowish white mass measuring 4 x 3.5 cm on cut surface of the gall bladder along with thickened wall. Histopathological examination of the specimen shows the sheets of signet ring cells with lateral spread through the lamina propria and large amount of extracellular mucin. There was metastasis in the retroperitoneum and mesenteric lymph node. The tumor was stage IV (according to TNM staging). Patient died 20th post operative day. Since very few cases have been reported, information regarding the behavior and prognosis of gall bladder carcinoma is limited. However it has been seen that stage III and IV carcinoma usually have worse prognosis. PMID- 23016489 TI - Radiomodulation by Hoechst 33258 against radiation-induced damage in murine splenocytes. AB - In this study modulatory effect of Hoechst 33258 on radiation induced membrane related signaling events which ultimately leads to apoptosis has been investigated. Splenocytes from Swiss albino mice were irradiated in air at room temperature in a gamma chamber (240 TBq 60Co Model 4000 A) at the dose-rate of 0.052 Gys(-1). Membrane lipid peroxidation, fluidity, specific activities of antioxidant enzymes, levels of nitric oxide, glutathione and apoptosis in presence and absence of different concentrations of Hoechst 33258 has been assayed. DNA binding activity of nuclear factor kappa B and activator protein-1 was also assayed by electrophoretic mobility shift assay. Modulatory effect of Hoechst 33258 was examined at 3 and 5 Gy using different concentrations (10, 20 and 30 microM). Hoechst 33258 was found to inhibit radiation induced peroxidative damage and fluidity and lowered the level of nitric oxide and apoptosis--as evident by DNA ladder assay and FACS, indicating free radicals scavenging potential. Dot plot diagramme clearly showed that 30 microM Hoechst 33258 caused 14% and 19% decrease in apoptotic cells at 3 Gy and 5 Gy of radiation respectively (compared to irradiated control group). Further DNA binding activity of nuclear factor kappa B and activator protein-1 was also inhibited but the antioxidant potential of the cells was enhanced. These findings support that Hoechst 33258 protects the cell from undergoing apoptosis. Hoechst 33258 may have interacted and has an ability to protect splenocytes against radiation induced apoptosis through modulation of membrane-related signaling events and antioxidant status. PMID- 23016490 TI - Alterations in ambient salinity and pH lead to modulation of developmental gene expression in Microhyla ornata (Dumeril and Bibron) and Xenopus laevis (Daudin). AB - Naturally fertilized Microhyla ornata and Xenopus laevis embryos at dorsal lip of blastopore stage were exposed to 0.3, and 0.6% sodium chloride for high salinity treatment and dilute hydrochloric acid and sodium hydroxide for treatment with low and high pH, respectively. After treatment for different durations, embryos were studied morphologically and using in situ hybridization with selected genes important for normal development and for coping with environmental stress. Altered salinity and pH caused defects in axis formation and neural tube closure, delay in hatching, abnormal swimming of tadpoles and even developmental arrest. This was accompanied by significant decrease in the expression of selected development-regulating genes like goosecoid (required for gastrulation movements), brachyury (mesodermal marker gene), noggin (involved in neural induction), NCAM (required for neural cell adhesion) and MyoD (essential for muscle development), and considerable increase in the transcription of stress response genes hsp30 and hsp70. Altering the expression of embryonic genes could be one of the mechanisms through which environmental factors influence development of amphibian embryos. PMID- 23016491 TI - Role of complement activation and antibody in the interaction between Mycobacterium tuberculosis and human macrophages. AB - Mycobacterium tuberculosis-specific antibodies possess immunomodulatory effects during tuberculosis infection. Prior sensitization to environmental mycobacteria is known to suppress immune responses against BCG and M. tuberculosis. Mycobacteria-induced antibodies can influence events such as complement activation and phagocytosis during infectious process. In the present study role of anti-M. tuberculosis IgG (anti-M. tb IgG) antibody during interaction between M. tuberculosis and human macrophages mediated through complement has been examined in vitro. Anti-M. tb IgG antibody significantly enhanced complement activation by M. tuberculosis. Phagocytosis of M. tuberculosis by macrophages increased significantly in the presence of complement and/or antibody. Moreover, antibody enhanced phagocytosis in the presence of complement. Addition of antibody alone or in combination with complement also augmented intracellular viability of bacilli within macrophages. Results of this study showed that anti mycobacterial antibody enhances complement activation and anti-M. tb IgG antibody probably modulates effects of complement during early stages of tuberculosis infection. PMID- 23016492 TI - Wound healing activity of methanolic and aqueous extracts of Plagiochila beddomei Steph. thallus in rat model. AB - Wound healing occurs as a fundamental response to tissue injury. Polyphenols are considered to be principle constituent to promote wound healing. Plagiochila beddomei was applied clinically by Paliyar tribes of Madurai district to treat intractable wounds. To validate the ethnotherapeutic claims of the plant in skin diseases, the effect of methanolic and aqueous extracts from P. beddomei on wound healing as well as angiogenesis was studied. 7th day and 10th day after excision wounds creation, the percent wound contraction of the extracts group was higher than that of Madecassol (reference drug) group. On 3rd, 7th and 10th day after wounds creation, the wound healing quality of the extracts group was better than that of Madecassol group on terms of granulation formation and collagen organization. On 3rd day after wounds creation, the micro vessel density and vascular endothelial growth factor expression of methanolic extracts group was higher than that of Madecassol group. Phytochemical analysis of the extracts showed the presence of flavonoids, saponins, tannins and phenols. The results show that P. beddomei extract has potent wound healing property probably resulting from the remarkable angiogenic activity. PMID- 23016493 TI - A promising strain of Streptomyces sp. with agricultural traits for growth promotion and disease management. AB - A bacterial strain, Streptomyces sp. CIMAP- A1 was isolated from Geranium rhizosphere and identified by morphological, physiological, biochemical and molecular characters (16S rDNA gene sequence). Phylogenetically, it was found most closely related to S. vinacendrappus, strain NRRL-2363 with 99% sequence similarity. The strain had potential antagonistic activity (in vitro) against wide range of phytopathogenic fungi like Stemphylium sp., Botrytis cinerea, Sclerotinia sclerotiorum, Colletotrichum spp., Curvularia spp., Corynespora cassicola and Thielavia basicola. The extracellular secondary metabolites produced by the strain in the culture filtrates significantly inhibited the spore germination, growth of germ tube of the germinated spores and radial growth of Alternaria alternata, Colletotrichum acutatum, Curvularia andropogonis and Fusarium moniliforme. The extraction of culture filtrate with solvents and purification by following VLC and PTLC methods always yielded a 10th fraction antifungal compound showing activity against wide range of phytopathogenic fungi. The strain was able to produce siderophores and indole-3-acetic acid. The strain was found to enhance the growth and biomass production of Geranium. It increased 11.3% fresh shoot biomass of Geranium and 21.7% essential oil yield. PMID- 23016494 TI - Alkaline protease production, extraction and characterization from alkaliphilic Bacillus licheniformis KBDL4: a Lonar soda lake isolate. AB - A bacterium producing an alkaline protease was isolated from the Lonar soda lake, Buldhana district (19 degrees 58' N; 76 degrees 31' E), Maharashtra, India. The most appropriate medium for the growth and protease production was composed of (g/L): casein 10; yeast extract 4; KH2PO4 0.5, K2HPO4 0.5 and CaCl2 0.5. The enzyme showed maximum activity with and without 5 mM Ca2+ at 70 and 60 degrees C, respectively. The enzyme retained 40 and 82% of its initial activity after heating for 60 min at 60 degrees C, in absence and presence of 5 mM CaCl2 respectively. The enzyme remained active and stable at pH 8-12, with an optimum at pH 10. The enzyme showed stability towards non-ionic and anionic surfactants, and oxidizing agents. It also showed excellent stability and compatibility with commonly used laundry detergents. Wash performance analysis revealed that enzyme could effectively remove blood stains. It also showed decomposition of gelatinous coating on X- ray film. PMID- 23016495 TI - Response of antioxidative and ethanolic fermentation enzymes in maize seedlings of tolerant and sensitive genotypes under short-term waterlogging. AB - Fifteen days old seedlings of waterlogging tolerant (Parkash) and sensitive (Paras) maize genotypes were subjected to short-term waterlogging (18 h) under field conditions. Activities of various antioxidative and anaerobic metabolism enzymes were investigated in leaf and root tissues. Superoxide dismutase (SOD) activity increased in leaf tissue while glutathione reductase (GR) activity was enhanced in leaf as well as root in both the genotypes. However, tolerant genotype had better induction capability of SOD and GR in roots in comparison with sensitive genotype. Catalase activity increased in roots of both genotypes. Waterlogging caused strong induction in alcohol dehydrogenase activity in the roots of Paras and Parkash under stress conditions. Aldehyde dehydrogenase activity was significantly increased only in roots of Parkash in response to waterlogging. In comparison with sensitive genotype, the tolerant genotype had low H2O2 and malondialdehyde content in roots under stress conditions. The present studies suggested that tolerant genotype had a greater protective ability due to higher induced activities of antioxidant and ethanolic fermentation systems than Paras. PMID- 23016496 TI - Influence of genetic relatedness and shoal size on shoaling preferencesin juvenile Puntius sarana subnasutus (Hamilton Valenciennes). AB - When presented with stimulus shoals of siblings and conspecifics in equal number, P. sarana subnasutus were able to discriminate their siblings and preferred to associate with them. Given a choice between large shoal and a small shoal consisting of siblings, the juvenile fish preferred to associate with larger stimulus group to the smaller one. However, juveniles traded off their preference for sibling shoal with large non-sibling conspecific stimulus group, regardless of the possible benefits gained from associating with sibling shoals. The results reveal the ability of fish to discriminate their siblings during their early developmental stage and the overriding influence shoal size in the context of shoaling preference in P. sarana subnasutus. PMID- 23016497 TI - Increase in voltage gated potassium currents of human lymphocytes on culture. AB - Voltage gated potassium channels present in T lymphocytes play an important role during lymphocyte activation. Though an increase in potassium currents has been reported in activated lymphocytes, changes in potassium currents in culture without activation by antigen or mitogen has not been reported. The peak potassium current densities on day 1 and day 5 of culture have been compared in this study. Peripheral blood mononuclear cells (PBMCs) were separated by density gradient centrifugation. Lymphocytes were separated from PBMCs by negative selection using anti-CD14 coated magnetic beads and cultured under appropriate conditions without antigenic or mitogenic stimulation. Lymphocytes were patched on day 1 or day 5 of culture. Voltage gated potassium currents were recorded by whole cell patch clamp technique using a depolarizing protocol. The mean of peak current densities recorded at +60 mV on day 1 of culture was 228.12 +/- 89.39 pA/pF (n = 7) and on day 5 of culture was 468.96 +/- 192.07 pA/pF (n = 7). The difference between the current densities on day 1 and day 5 was found to be significant. Change in electrophysiological characteristics can lead to functional changes in the lymphocytes and this should be considered when culturing lymphocytes in vitro for research and clinical use. PMID- 23016498 TI - TOCCATA: a customized carbon total correlation spectroscopy NMR metabolomics database. AB - A customized metabolomics NMR database, TOCCATA, is introduced, which uses (13)C chemical shift information for the reliable identification of metabolites, their spin systems, and isomeric states. TOCCATA, whose information was derived from the BMRB and HMDB databases and the literature, currently contains 463 compounds and 801 spin systems, and it can be used through a publicly accessible web server. TOCCATA allows the identification of metabolites in the submillimolar concentration range from (13)C-(13)C total correlation spectroscopy experiments of complex mixtures, which is demonstrated for an Escherichia coli cell lysate, a carbohydrate mixture, and an amino acid mixture, all of which were uniformly (13)C-labeled. PMID- 23016499 TI - Salt-leached silk scaffolds with tunable mechanical properties. AB - Substrate mechanical properties have remarkable influences on cell behavior and tissue regeneration. Although salt-leached silk scaffolds have been used in tissue engineering, applications in softer tissue regeneration can be encumbered with excessive stiffness. In the present study, silk-bound water interactions were regulated by controlling processing to allow the preparation of salt-leached porous scaffolds with tunable mechanical properties. Increasing silk-bound water interactions resulted in reduced silk II (beta-sheet crystal) formation during salt-leaching, which resulted in a modulus decrease in the scaffolds. The microstructures as well as degradation behavior were also changed, implying that this water control and salt-leaching approach can be used to achieve tunable mechanical properties. Considering the utility of silk in various fields of biomedicine, the results point to a new approach to generate silk scaffolds with controllable properties to better mimic soft tissues by combining scaffold preparation methods and silk self-assembly in aqueous solutions. PMID- 23016500 TI - Comment on "308 nm photolysis of nitric acid in the gas phase, on aluminum surfaces, and on ice films". PMID- 23016502 TI - Attitudes and program preferences of African-American urban young adults about pre-exposure prophylaxis (PrEP). AB - We elicited attitudes about, and service access preferences for, daily oral antiretroviral pre-exposure prophylaxis (PrEP) from urban, African-American young men and women, ages 18-24 years, at risk for HIV transmission through their sexual and drug-related behaviors participating in eight mixed-gender and two MSM only focus groups in Atlanta, Georgia. Participants reported substantial interest in PrEP associated with its perceived cost, effectiveness, and ease of accessing services and medication near to their homes or by public transportation. Frequent HIV testing was a perceived benefit. Participants differed about whether risk reduction behaviors would change, and in which direction; and whether PrEP use would be associated with HIV stigma or would enhance the reputation for PrEP users. This provides the first information about the interests, concerns, and preferences of young adult African Americans that can be used to inform the introduction of PrEP services into HIV prevention efforts for this critical population group. PMID- 23016501 TI - Straight talk: HIV prevention for African-American heterosexual men: theoretical bases and intervention design. AB - In the United States, racial disparities in HIV/AIDS are stark. Although African Americans comprise an estimated 14% of the U.S. population, they made up 52% of new HIV cases among adults and adolescents diagnosed in 2009. Heterosexual transmission is now the second leading cause of HIV in the United States. African Americans made up a full two-thirds of all heterosexually acquired HIV/AIDS cases between 2005 and 2008. Few demonstrated efficacious HIV prevention interventions designed specifically for adult, African-American heterosexual men exist. Here, we describe the process used to design a theory-based HIV prevention intervention to increase condom use, reduce concurrent partnering, and increase HIV testing among heterosexually active African-American men living in high HIV prevalence areas of New York City. The intervention integrated empowerment, social identity, and rational choices theories and focused on four major content areas: HIV/AIDS testing and education; condom skills training; key relational and behavioral turning points; and masculinity and fatherhood. PMID- 23016503 TI - Sources of personal income and HIV risk among sexually active women. AB - We examined the relationship between sources of income and sex behaviors among a sample of low-income, sexually active women in Baltimore, MD (n = 517). Data were collected through interviews administered by a trained interviewer and audio computer-assisted self-interviewing (ACASI). The study assessed four categories of income: government payments, money from other people, selling items, and irregular jobs (i.e., odds jobs). Having multiple sex partners was associated with receiving income from other people [AOR: 2.60, 95% CI: 1.66-4.09], selling items [AOR: 2.67, 95% CI: 1.64-4.36], and irregular jobs [AOR: 1.57, 95% CI: 1.08, 2.29]. Women who exchanged sex were more likely to acquire income through these sources but less likely to receive government assistance [AOR: 0.62, 95% CI: 0.39-0.97]. Sexual behaviors are associated with multiple sources of personal income. HIV prevention interventions should address the role that economic factors play in risk behaviors. PMID- 23016504 TI - HIV prevention service utilization in the Los Angeles House and Ball communities: past experiences and recommendations for the future. AB - African-American young men who have sex with men and transgender persons are at elevated risk for HIV infection. House and Ball communities, networks of mostly African-American gay, bisexual, and transgender individuals who compete in modeling and dance, represent a prime venue for HIV prevention with these difficult-to-reach populations; however, little research exists on effective approaches to HIV prevention within these communities. Using a mixed-methods approach, the present study sought to document participation in HIV prevention activities of a sample from the Los Angeles House and Ball communities (n = 263) in order to inform future service development. While 80% of participants were tested for HIV within the past 6 months, only 26% report HIV prevention program attendance. House leaders recommend a holistic approach to HIV prevention, one that incorporates attention to social problems beyond HIV, including poverty, housing difficulties, and lack of job training. PMID- 23016505 TI - The prevalence and correlates of receiving confirmatory HIV test results among newly diagnosed HIV-positive individuals at a community-based testing center. AB - This study examined the prevalence and correlates of completing the HIV testing process-specifically receiving a confirmatory HIV test and returning for the results-in a sample of newly diagnosed HIV-positive individuals at an HIV testing center in New York City. Of the 213 individuals who received a reactive rapid HIV test result, 82% received a confirmatory HIV test. Of the 236 individuals who received a positive result on a rapid or traditional HIV test that was validated by a positive confirmatory HIV test, 65% returned for the confirmatory test results. Multivariate analyses revealed that being a non-U.S. citizen, homeless/living in transitional housing, being uninsured, and testing off-site were significantly associated with completing the HIV testing process. The findings indicate the need to explore strategies that address obstacles to receiving confirmatory HIV testing and returning for the results, in addition to the feasibility of a rapid confirmatory HIV test. PMID- 23016506 TI - "It is not easy": challenges for provider-initiated HIV testing and counseling in Flanders, Belgium. AB - This study identified physicians' HIV testing practices and their barriers toward implementing provider-initiated HIV testing and counseling (PITC) for Sub-Saharan African migrants (SAM) in Flanders, Belgium. In-depth interviews were conducted on a purposive sample of 20 physicians (ten GPs and ten internists). GPs performed mainly patient-initiated tests, while internists carried out tests based on disease indicators and risk behavior. For the most part, World Health Organization (WHO) guidelines were not followed. Study participants were not in favor of implementing PITC. Reasons included lack of information on the HIV epidemic among SAM, fear of stigmatizing patients, perceiving testing as unethical for undocumented patients, questionable relevance of pre-test counseling, lack of expertise in discussing sexuality, language barriers, lack of time, and the absence of a national or regional HIV testing policy. Implementing PITC will require appropriate training of service providers. Also, supporting policies should be developed with the participation of stakeholders encouraging "normalization" of HIV testing. PMID- 23016507 TI - Correlates of condom use among chinese college students in hunan province. AB - A cross-sectional survey was conducted to test an integrated model of condom use with a sample of 490 sexually active Chinese college students. A number of variables in the integrated model were predictors of condom use, explaining 33.4% of the variance in use. Partner communication was the strongest predictors (beta = .317, SE = .038, p < .001). Self-efficacy (beta = .252, SE = .076, p < .001), positive attitudes (beta = .150, SE = .060, p < .001), and social norms (beta = .207, SE = .080, p < .001) were also significant predictors of condom use. Additionally, peer communication marginally significantly predicted condom use (beta = .089, SE = .039, p = .055). This study provides evidence of the utility of the theories of reasoned action and planned behavior as an effective underlying theoretical framework for HIV prevention and safe sex intervention programs in a non-Western culture. The study also provides evidence that communication with sexual partners about condom use should be one of the most important factors to be considered in the development of HIV prevention and safer sex education programs for Chinese youth. PMID- 23016508 TI - Prevention of preterm birth: a randomized trial of vaginal compared with intramuscular progesterone. AB - OBJECTIVE: To assess efficacy and tolerability of vaginal compared with intramuscular progesterone in reducing the rate of recurrent preterm birth before 34 weeks of gestation. DESIGN: Prospective randomized study. SETTING: Obstetrics and Gynecology Department, Armed Forces Hospital Southern Region, Kingdom of Saudi Arabia. SAMPLE: Five-hundred and eighteen women with a prior history of preterm birth. METHODS: Women were randomized to receive either 90 mg of vaginal progesterone gel once daily or 250 mg of intramuscular progesterone weekly. Treatment began between 14 and 18 weeks of gestation and continued until 36 complete weeks of gestation, delivery or the occurrence of premature rupture of membranes. MAIN OUTCOME MEASURES: The primary outcome measure was delivery before 34 weeks of gestation. The secondary outcome measures were PTB between 34 and 37 weeks of gestation and neonatal outcomes including birthweight, neonatal death, and the need for admission to the neonatal intensive care unit. RESULTS: The baseline characteristics of the study participants were similar. Two-hundred and thirty-eight (94.1%) patients in the vaginal group and 226 (90.8%) patients in the intramuscular group were compliant with their medications. Vaginal progesterone was associated with a lower percentage of deliveries before 34 weeks of gestation than the intramuscular preparation (p= 0.02). This association was also observed at 28 and 32 weeks of gestation (p= 0.04). Adverse effects were reported in 14.1% of patients in the intramuscular group, but in only 7.5% of patients in the vaginal group (p= 0.017). CONCLUSIONS: Vaginal progesterone was more effective than intramuscular progesterone for the prevention of preterm birth and had fewer adverse effects. PMID- 23016509 TI - Lanthanide complexes based on a diazapyridinophane platform containing picolinate pendants. AB - A new macrocyclic ligand, N,N'-bis[(6-carboxy-2-pyridyl)methyl]-2,11 diaza[3.3](2,6)pyridinophane (H(2)BPDPA), was prepared, and its coordination properties toward the Ln(III) ions were investigated. The hydration numbers (q) obtained from luminescence lifetime measurements in aqueous solution of the Eu(III) and Tb(III) complexes indicate that they contain one inner-sphere water molecule. The structure of the complexes in solution has been investigated by (1)H and (13)C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (B3LYP) level. The minimum-energy conformation calculated for the Yb(III) complex is in excellent agreement with the experimental structure in solution, as demonstrated by analysis of the Yb(III) induced paramagnetic (1)H shifts. Nuclear magnetic relaxation dispersion (NMRD) profiles and (17)O NMR measurements recorded on solutions of the Gd(III) complex were used to determine the parameters governing the relaxivity. The results show that this system is endowed with a relatively fast water-exchange rate k(ex)(298) = 63 * 10(6) s(-1). Thermodynamic stability constants were determined by pH potentiometric titration at 25 degrees C in 0.1 M KCl. The stability constants, which fall within the range logK(LnL) = 12.5-14.2, point to a relatively low stability of the complexes primarily as a consequence of the low basicity of the ligand. PMID- 23016510 TI - Panel studies of air pollution on children's lung function and respiratory symptoms: a literature review. AB - OBJECTIVE: This article reviews panel studies of air pollution on children's respiratory health and proposes future research directions. METHODS: The PubMed electronic database was used to search published original epidemiological studies in peer-reviewed journals from 2000 to November 2011. Children's age was limited to <=18 years old. A total of 33 relevant articles were obtained, with 20 articles relating to lung function, 21 articles relating to respiratory symptoms, and 8 articles examining both. RESULTS: Most studies suggested the adverse effects of air pollution on children's lung function and respiratory symptoms. Particles and NO(2) showed more significant results, whereas effects of SO(2) were not consistent. A few studies indicated that O(3) interacted with temperature and sometimes seemed to be a protective factor for children's respiratory health. Negative associations between air pollutants and pulmonary health were more serious in asthmatic children than in healthy subjects. However, many outcomes depended on the number of lag days. Peak expiratory flow (PEF) was the most usual measurement for children's lung function, followed by forced expiratory volume in 1 second (FEV(1)). CONCLUSIONS: There are significant adverse effects of air pollution on children's pulmonary health, especially for asthmatics. Future studies need to examine the lag effects of air pollution on children's lung function and respiratory symptoms. Ambient temperature is predicted to change worldwide due to climate change, which will threaten population health. Further research is needed to examine the effects of ambient temperature and the interactive effects between air pollution and ambient temperature on children's lung function and respiratory symptoms. PMID- 23016511 TI - Lay people's interpretation of ethical values related to mass vaccination; the case of A(H1N1) vaccination campaign in the province of Quebec (French Canada). AB - BACKGROUND: Pandemic influenza ethics frameworks are based on respect of values and principles such as regard for autonomy, responsibility, transparency, solidarity and social justice. However, very few studies have addressed the way in which the general population views these moral norms. OBJECTIVES: (i) To analyse the receptiveness of the population of French-speaking Quebecers to certain ethical principles promoted by public health authorities during the AH1N1 vaccination campaign. (ii) To add to the limited number of empirical studies that examine the population's perception of ethical values. DESIGN: Eight months after the end of the AH1N1 vaccination campaign in the Province of Quebec (Canada), 100 French-speaking Quebecers were assembled in ten focus groups. Discussions focussed on the level of respect shown by public health authorities for individual autonomy, the limits of appeals for solidarity, the balance between vaccination efficiency and social justice towards non-prioritized subpopulations, vaccination as a demonstration of civic duty and social responsibility. RESULTS: The population acknowledged a high level of individual responsibility towards family members and agreed to vaccination to protect children and ageing parents. However, the concepts of civic duty and solidarity did not elucidate unanimous support, despite the fact that social justice stood out as a dominant value of public morals. CONCLUSION: The ethical principles promoted in influenza pandemic ethics frameworks are subject to reinterpretation by the population. An ethic of public health must consider their understanding of the fundamental values that legitimize mass vaccination. PMID- 23016512 TI - Idiopathic facial aseptic granuloma in a child: a possible expression of childhood rosacea. AB - Idiopathic facial aseptic granuloma is a chronic, benign, and painless facial nodule occurring exclusively in childhood. Its pathogenesis is unclear, although some interesting hypotheses have been advanced. On the basis of the relationship existing between this disease and recurrent chalazions and conjunctivitis, we hypothesize that it could be considered to be a possible marker of childhood rosacea. PMID- 23016513 TI - HIDEN: Hierarchical decomposition of regulatory networks. AB - BACKGROUND: Transcription factors regulate numerous cellular processes by controlling the rate of production of each gene. The regulatory relations are modeled using transcriptional regulatory networks. Recent studies have shown that such networks have an underlying hierarchical organization. We consider the problem of discovering the underlying hierarchy in transcriptional regulatory networks. RESULTS: We first transform this problem to a mixed integer programming problem. We then use existing tools to solve the resulting problem. For larger networks this strategy does not work due to rapid increase in running time and space usage. We use divide and conquer strategy for such networks. We use our method to analyze the transcriptional regulatory networks of E. coli, H. sapiens and S. cerevisiae. CONCLUSIONS: Our experiments demonstrate that: (i) Our method gives statistically better results than three existing state of the art methods; (ii) Our method is robust against errors in the data and (iii) Our method's performance is not affected by the different topologies in the data. PMID- 23016514 TI - Evidence for pathogenicity of autoreactive T cells in autoimmune bullous diseases shown by animal disease models. AB - Autoimmune bullous diseases (AIBDs) are characterized by blisters and erosions on the skin and/or mucous membranes, which are caused by autoantibodies directed to structural proteins of the epidermis and the epidermal basement membrane zone. This Viewpoint Essay discusses the contribution by autoreactive T cells to the pathogenesis of bullous pemphigoid, pemphigus and epidermolysis bullosa acquisita, with an emphasis on studies using active animal mouse models for these diseases. Previous studies have demonstrated that cytokines produced by autoreactive T cells, the interaction between antigen-specific T cells and B cells and the function of regulatory T cells are likely related to the pathogenesis of AIBDs. In interpreting the experimental results, the limitations of those animal models should be considered. Further understanding of the pathogenicity of autoreactive CD4(+) T cells may lead to disease-specific treatments. PMID- 23016515 TI - Test-retest, responsiveness, and minimal important change of the ability to perform physical activities of daily living questionnaire in individuals with type 2 diabetes and obesity. AB - BACKGROUND: The Ability to Perform Physical Activities of Daily Living Questionnaire (APPADL) measures the self-reported ability of individuals with type 2 diabetes mellitus (T2DM) and obesity to perform daily physical activities. The primary objective of this study was to estimate APPADL test-retest reliability, responsiveness, and minimal important change (MIC). SUBJECTS AND METHODS: Study participants were individuals with T2DM and body mass index >=30 kg/m(2) enrolled in clinical weight loss programs in the United States. Data were obtained for clinical measures, APPADL, and other patient-reported instruments. APPADL test-retest reliability was estimated with intraclass correlation coefficient. To estimate responsiveness in a subgroup of participants, baseline and 6-month data were analyzed using paired t test and calculation of responsiveness indices (e.g., effect size [ES]). To estimate MIC, both distribution-based and anchor-based methods were used. RESULTS: Test-retest data for 106 study participants (mean age, 52 years; 69% female; 31% white; mean body mass index, 38 kg/m(2)) yielded an intraclass correlation coefficient of 0.91. In the subgroup (n = 40) used to estimate responsiveness, weight was significantly less at end point than at baseline (mean, 222.0 vs. 231.9 pounds; P < 0.001, ES = 0.24), and APPADL scores were significantly better than at baseline (mean, 77.0 vs. 70.8; P = 0.01, ES = 0.32). Results of distribution- and anchor-based methods to establish MIC suggest values of 6-14 points (0-100 scale). CONCLUSIONS: The APPADL has demonstrated reliability and validity. In addition, it has demonstrated responsiveness to weight loss in individuals with T2DM and obesity, thereby making it a potentially valuable tool in the evaluation of weight loss interventions (e.g., antihyperglycemic medications that produce weight loss) targeted toward patients with T2DM. PMID- 23016516 TI - Sensor-augmented pump therapy at 36 months. AB - BACKGROUND: This follow-up study investigates the metabolic and psychosocial effects of sensor-augmented pump (SAP) therapy in adults with type 1 diabetes 36 months after therapy start. SUBJECTS AND METHODS: We invited all 24 Danish adults with type 1 diabetes who had previously participated in the European multicenter randomized controlled Eurythmics Trial. Thirteen of the 24 patients started SAP therapy during the Eurythmics Trial; 11 patients were controls but started using SAP immediately after completion of the trial. In the current study, we estimated the effects of SAP 36 months after therapy start by change in glycated hemoglobin (HbA1c) and diabetes questionnaire scores (Diabetes Treatment Satisfactions Questionnaire [DTSQs], Problem Areas in Diabetes [PAID] questionnaire, and Hypoglycemia Fear Survey [HFS]). RESULTS: At 36 months, 16 of the 24 patients were still using SAP, 14 of them > 70% of time. The HbA1c level decreased from 8.7% at therapy start to 7.3% at 36 months (P < 0.0001). Similar reductions in HbA1c were obtained regardless of whether SAP therapy was initiated during or after the Eurythmics Trial. DTSQs, PAID questionnaire, and HFS scores improved by 9.0 (P < 0.0001), -10.8 (P = 0.013), and -5.5 (P = 0.152), respectively, in the 16 SAP users. CONCLUSIONS: This study documents persisting beneficial effects of SAP on HbA1c, treatment satisfaction, magnitude of diabetes-related problems, and fear of hypoglycemia 36 months after therapy start. The follow-up is considerably longer than in other published studies; still, the results are in line with the positive short-term outcomes of larger studies of SAP use. PMID- 23016517 TI - Phase I study of concurrent weekly docetaxel, high-dose intensity-modulated radiation therapy (IMRT) and androgen-deprivation therapy (ADT) for high-risk prostate cancer. AB - Study Type - Therapy (phase 1) Level of Evidence 2a What's known on the subject? and What does the study add? High-risk and locally advanced prostate cancers are difficult to cure with the standard regimen of radiation therapy (RT) with concurrent androgen-deprivation therapy (ADT). Multiple studies have explored the addition of docetaxel chemotherapy in attempt to improve patient outcomes. Prior Phase I studies have shown that docetaxel 20 mg/m(2) is a safe dose, when given concurrently with 70 Gy of radiation. But current standard RT for prostate cancer uses higher doses, and it is unclear if concurrent chemotherapy is safe with modern RT. This is a Phase I study that explored the addition of concurrent docetaxel chemotherapy to modern RT (intensity-modulated RT to 78 Gy) plus ADT. The study showed that weekly docetaxel at 20 mg/m(2) is safe with modern RT. At a median follow-up of 2.2 years, biochemical progression-free survival was 94%. This triple-therapy regimen is safe and promising for further evaluation in prospective trials. OBJECTIVE: * To evaluate in a phase I trial, the feasibility of adding concurrent weekly docetaxel chemotherapy to high-dose intensity modulated radiation therapy (IMRT) and androgen-deprivation therapy (ADT) for treatment of high-risk prostate cancer. PATIENTS AND METHODS: * Patients with high-risk prostate cancer were treated with a luteinising hormone-releasing hormone agonist (starting 2-3 months before IMRT and lasting 2 years), IMRT of 78 Gy to the prostate and seminal vesicles, and weekly docetaxel during RT. * All patients had computed tomography and bone scans to exclude metastatic disease. * A standard 3 + 3 design was used for docetaxel dose escalation. Successive patients were treated on dose levels of 10, 15, and 20 mg/m(2) of weekly docetaxel. RESULTS: * In all, 18 patients participated in the study: 15 (83%) had Gleason 8-10 disease; the other three had either clinical T3 disease and/or a prostate-specific antigen (PSA) level of >20 ng/mL. * Grade 3 diarrhoea (a defined dose-limiting toxicity, DLT) occurred in one patient in each of the first two dose levels. However, when the cohorts were expanded, no further DLT was seen. * Weekly docetaxel at 20 mg/m(2) (dose level 3) was successfully given without DLT. * No patient had grade 4 or 5 toxicity. * At a median follow-up of 2.2 years, all patients achieved a PSA nadir of <1 ng/mL, including 13 patients who had an undetectable PSA level. The 2-year biochemical progression-free survival was 94%. CONCLUSION: * A dose of 20 mg/m(2) of weekly docetaxel given concurrently with high-dose IMRT and ADT appears safe for further study in patients with high-risk prostate cancer. PMID- 23016518 TI - Individual differences and evidence-based psychopharmacology. AB - Individual differences in response to pharmacologic treatment limits the usefulness of mean data obtained from randomized controlled trials. These individual differences exist even in genetically uniform inbred mouse strains. While stratification can be of value in large studies, the individual patient history is the most effective currently available guide for personalized medicine in psychopharmacology. PMID- 23016519 TI - Silent Spring, the 50th anniversary of Rachel Carson's book. AB - David Pimentel is a professor of ecology and agricultural sciences at Cornell University, Ithaca, NY 14853-0901. His Ph.D. is from Cornell University and had postdoctoral research at the University of Chicago, MIT, and fellowship at Oxford University (England). He was awarded a distinguished honorary degree from the University of Massachusetts. His research spans the fields of energy, population ecology, biological pest control, pesticides, sustainable agriculture, land and water conservation, livestock, and environmental policy. Pimentel has published more than 700 scientific papers and 37 books and has served on many national and government committees including the National Academy of Sciences; President's Science Advisory Council; U.S Department of Agriculture; U.S. Department of Energy; U.S. Department of Health, Education and Welfare; Office of Technology Assessment of the U.S. Congress; and the U.S. State Department. He is currently Editorial Advisor for BMC Ecology. In this article, he reflects on 50 years since the publication of Rachel Carson's influential book, Silent Spring. PMID- 23016520 TI - Development and validation of a novel Taqman-based real-time RT-PCR assay suitable for demonstrating freedom from viral haemorrhagic septicaemia virus. AB - Viral haemorrhagic septicaemia (VHS) is a serious disease in several fish species. VHS is caused by the rhabdovirus viral haemorrhagic septicaemia virus (VHSV). To prevent spreading of the pathogen, it is important to use a fast, robust, sensitive and specific diagnostic tool to identify the infected fish. Traditional diagnosis based on isolation in cell culture followed by identification using, for example, ELISA is sensitive and specific but slow. By switching to RT-PCR for surveillance and diagnosis of VHS the time needed before a correct diagnosis can be given will be considerably shortened and the need for maintaining expensive cell culture facilities reduced. Here we present the validation, according to OIE guidelines, of a sensitive and specific Taqman-based real-time RT-PCR. The assay detects all isolates in a panel of 79 VHSV isolates covering all known genotypes and subtypes, with amplification efficiencies of approximately 100%. The analytical and diagnostic specificity of the real-time RT PCR is close to 1, and the analytical and diagnostic sensitivity is comparable with traditional cell-based methods. In conclusion, the presented real-time RT PCR assay has the necessary qualities to be used as a VHSV surveillance tool on par with cell culture assays. PMID- 23016521 TI - Long-term anticoagulant effects of CYP2C9 and VKORC1 genotypes in phenprocoumon users. PMID- 23016522 TI - Enhanced DPPH radical scavenging activity and DNA protection effect of litchi pericarp extract by Aspergillus awamori bioconversion. AB - BACKGROUND: Litchi (Litchi chinensis Sonn.) pericarp is a major byproduct which contains a significant amount of polyphenol. This study was designed to biotransformation litchi pericarp extract (LPE) by Aspergillus awamori to produce more bioactive compounds with stronger antioxidant activities. RESULTS: The study exhibited that the 2,2-diphenyl-1-picrylhydrazyl radical scavenging activities significantly (p < 0.05) increased from 15.53% to 18.23% in the water-extracted fraction and from 25.41% to 36.82% in the ethyl acetate-extracted fraction. Application of DNA cleavage assay further demonstrated the enhanced protection effect of the fermented phenolics on DNA damage. It is also noted that the water extracted fraction of the fermented LPE possessed a much stronger capacity than the ethyl acetate-extracted fraction to prevent from damage of supercoiled DNA. Interestingly, it was found that some new compounds such as catechin and quercetin appeared after of A. awamori fermentation of LPE, which could account for the enhanced antioxidant activity. CONCLUSION: The DPPH radical scavenging activity and DNA protection effect of LPE were increased by Aspergillus awamori bioconversion while some compounds responsible for the enhanced antioxidant activity were identified. This study provided an effective way of utilizing fruit pericarp as a readily accessible source of the natural antioxidants in food industry and, thus, extended the application area such as fruit by-products. PMID- 23016523 TI - Anti-diabetic compounds and their patent information: an update. AB - The increasing epidemic of diabetes mellitus around the globe is increasing the risk of various other chronic diseases i.e. coronary artery diseases, myocardial infarction, hypertension, dyslipidemia and number of other complicated disorders. Diabetes mellitus is clinically characterized by a marked increase in blood glucose levels and is associated with mild hyperlipidemia. Although the prevalence of this health ailment is increasing dramatically, various therapeutic compounds have been developed to treat this disease that is available in the market as synthetic, formulated and combined forms. Recently, various compounds have come through preclinical studies and shown the therapeutic efficacy of using multiple/ specific drug targets. Recent research approaches have been based on receptors targeting, islet cell transplantation, gene expression profiling, glucagon-like peptide-1, dipeptidyl peptidase IV inhibitors, insulin therapy, modulators of peroxisome proliferator-activated receptors (PPAR), glucagon receptor antagonists, insulin analogues, sensitizers and combination therapies. Furthermore various, latest findings claimed to identifying new anti-diabetic regimens with novel mechanism of action are being developed. This review provides an update on the use of approaches to the development of preventive and therapeutic strategies against diabetes and recent patents that could develop into novel therapeutics available to the clinical success for the management of the disease. PMID- 23016524 TI - Molecular mechanism aspect of ER stress in Alzheimer's disease: current approaches and future strategies. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by progressive loss of memory and cognitive impairment. Aggregation of amyloid-beta (Abeta) peptides is the crucial factor in the onset of AD. The toxic Abeta peptides Abeta40 and Abeta42 are produced from the Abeta precursor protein (APP), a transmembrane protein which is folded and modified in endoplasmic reticulum (ER). ER is the main organelle for the synthesis and processing of nearly all proteins as well as the main cellular source of Ca2+. Under stress conditions, three main ER pathways including inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor 6 become activated causing the accumulation of unfolded or misfolded proteins within ER lumen. These pathways manage the stress by regulating the expression of chaperones and enzymes involved in protein folding. Several studies have reported the dysfunction of these stress-sensing pathways in pathological conditions, including neurodegenerative diseases. Recent studies have proposed that neuronal death in AD arises from dysfunction of the ER. Here, we will review recent research findings on the interaction between ER and mitochondria, and its effect on apoptotic pathways. We further provide insights into studies which suggest the role of ER in animal and/or cellular models of AD. Therapeutic strategies that modulate ER could represent a promising approach for prevention or treatment of AD. PMID- 23016525 TI - A QSAR study on some series of anticancer tyrosine kinase inhibitors. AB - A quantitative structure-activity relationship (QSAR) study has been made on two different series of anticancer tyrosine kinase inhibitors, namely a series of 4 alkynyl and 4-alkenyl-quinazolines and a series of N-4,6-pyrimidine-N-alkyl- N' phenyl ureas. For the first series, QSAR results indicate that the activity is controlled by the hydrophobicity of the molecules and molecular connectivity index of the substituent, whereas for the second series of compounds the activity is found to be controlled by the molecular connectivity index of the substituent and some indicator variables. PMID- 23016526 TI - Human T-cell lymphotropic virus in patients infected with HIV-1: molecular epidemiology and risk factors for transmission in Piaui, Northeastern Brazil. AB - This study aimed to describe the epidemiological, immunological and molecular features of infection by the human T-lymphotropic virus-1/2 (HTLV-1/2) in individuals with HIV-1 in an urban area of Piaui State, Brazil. Exclusion criteria included patients under 18 years of age, pregnant women or Amerindians. Of 805 individuals analyzed by the serological method (ELISA) for the detection of anti-HTLV-1/2, 18 (2.24%) were positive, but only 13 (1.61%) were confirmed by PCR. The RFLP analysis revealed that nine (1.12%) of these subjects were positive for HTLV-1 and four (0.5%) for HTLV-2. The mean age of these co-infected individuals was 50.9+/-9.1 years, and a significant association was found with age (above 40 years: p = 0.002), minor surgeries (p = 0.004) and blood transfusion (p = 0.031). Quantification of the T CD4+/CD8+ lymphocytes and the HIV-1 viral load showed no significant association of T CD8 + lymphocyte levels with co-infection in the patients with HIV-1/HTLV-1. The sequencing of the LTR region and phylogenetic analysis indicated that the nine HTLV-1 strains belong to the Transcontinental subgroup of the Cosmopolitan group (1a), with a 83% (neighbor-joining) bootstrap value. The HTLV-2 strains were identified as subtype HTLV-2c, supported by a bootstrap value of 79%. Further studies in other population subgroups, such as blood donors and drug users, will be necessary to clarify the dissemination of HTLV-1/2 in Piau and elucidate the developmental profile of the virus in the region. PMID- 23016527 TI - Distinguishing youths at risk for anxiety disorders from self-reported BIS sensitivity and its psychophysiological concomitants. AB - The aim of the study was to explore the psychophysiological concomitants of self reported behavioral inhibition system (BIS) sensitivity in adolescents (12 to 17 years old) supposed to be at risk for anxiety disorders. Twenty participants with high scores in self-reported BIS sensitivity (at-risk group) were matched in age and sex to 20 participants scoring in the normal range in BIS sensitivity (control group). Negative affect, negative emotion regulation style, and anxiety symptomatology were assessed by means of self-reported measures. Cardiac and electrodermal response signals were recorded during baseline, paced breathing, exposure to an attentional task with response cost and fear-relevant slides conditions. The at-risk group exhibited higher scores on measures of negative affect, negative emotion regulation style, and anxiety symptomatology than their control counterparts. After controlling for negative styles of emotion regulation, groups did not differ in skin conductance reactivity during the attentional task with response cost, but participants at risk exhibited more nonspecific skin conductance responses than the control group during baseline recording. Regarding the cardiac concomitants, participants at risk presented lower vagal tone at resting conditions as compared to participants in the control group. Additionally, at-risk participants exhibited lower flexibility across experimental conditions in heart rate and cardiac sample entropy measures than participants in the control group. These findings add knowledge on psychophysiological concomitants of BIS sensitivity and are discussed in light of associations between temperament and development of anxiety disorders in youth. They show how psychophysiological patterns observed in resting conditions could be useful endophenotypes to reliably detect individuals at risk before the disorder onset. PMID- 23016529 TI - Assessment of safety and efficacy of a bipolar fractionated radiofrequency device in the treatment of photodamaged skin. AB - BACKGROUND: A number of devices are available for skin rejuvenation and conventional devices include both ablative and non-ablative lasers. More recently, bipolar fractionated radiofrequency (RF) devices have been introduced. OBJECTIVE: To evaluate the safety and efficacy of a novel 144 pin high density tip bipolar fractionated radiofrequency (RF) device for skin rejuvenation in Fitzpatrick skin types I-IV. METHODS AND MATERIALS: This single-center, prospective, study enrolled 25 female between the ages of 35-60 years, with mild to moderate wrinkling based on the Fitzpatrick Wrinkle Scale. The subjects were of Fitzpatrick skin types I-IV. Each subject underwent 3 full-face treatments with a 144 pin fractional bipolar RF device at 30-day intervals. All subjects underwent clinical evaluations during the study period to evaluate for any adverse events. Subsequently, all subjects were evaluated for improvement in rhytides, dyschromias and skin texture based on photographic evaluation by blinded investigators at 6 months following the final RF treatment. RESULTS: A statistically significant improvement in rhytides, dyschromias and texture was noted. Adverse events were limited to mild erythema and swelling. Post inflammatory pigmentary changes were not observed in any subjects. CONCLUSION: The novel 144 pin high density tip bipolar fractionated RF device is both safe and effective for facial skin rejuvenation in Fitzpatrick skin types I-IV. PMID- 23016530 TI - A split-face comparison of a fractional microneedle radiofrequency device and fractional carbon dioxide laser therapy in acne patients. AB - BACKGROUND: A number of lasers and light-based devices have been reported as promising treatment options for acne vulgaris. OBJECTIVE: To evaluate the efficacy and safety of fractional microneedle radiofrequency (MRF) device treatment compared to CO(2) fractional laser system (FS) for the treatment of acne vulgaris. METHODS: Twenty healthy subjects underwent full-face treatment for acne vulgaris with CO(2) FS and MRF device. For each subject, two passes of CO(2) FS with a pulse energy setting of 80 mJ and a density of 100 spots/cm(2) were used on one side, and two passes of MRF device with a intensity of 8, density of 25 MTZ/cm(2), and a depth of 1.5-2.5 mm were used on the other. Patients were evaluated 3 months postoperatively and were also photographed. RESULTS: Most of the patients improved based on clinical and photographic assessments 3 months after the treatment. No significant differences in physician-measured parameters, patient ratings, or intraoperative pain ratings were found, although downtime was significantly longer for the CO(2) FS treated side. CONCLUSIONS: MRF device and CO(2) FS can be used for acne vulgaris patients and MRF device is more convenient than CO(2) FS because of its short downtime. PMID- 23016531 TI - Treatment of atrophic facial scars of acne vulgaris by Q-Switched Nd:YAG (Neodymium: Yttrium-Aluminum-Garnet) laser 1064 nm wavelength. AB - BACKGROUND: Q-Switched Nd:YAG laser (1064 nm) is a new modality that was reported to be effective in treatment of acne scars. OBJECTIVE: To evaluate the effectiveness and the safety of this laser in treatment of acne scars. PATIENTS AND METHODS: This case series, descriptive and comparative study was conducted in Al-Najaf Teaching Hospital of Kufa Medical College, Iraq from October 2010 to October 2011. A total of 16 patients having mild to moderate facial acne scars were enrolled; 10 of them completed the study. All patients had Fitzpatrick skin type III. They were divided into two groups A and B and were treated with two different energy fluences: 5 J/cm2 for group (A) and 15 J/cm2 for group (B). Five treatment sessions with 2-week intervals were done for all patients and were followed up for 6 months. The improvement was evaluated by objective and subjective methods. RESULTS: Changes in acne scores in both groups were statistically insignificant after 6 months follow-up. Only two patients were satisfied with the improvement after treatment- one patient from each group. No serious side effects were reported. CONCLUSION: Q-Switched Nd:YAG laser (1064 nm) can be used in treating atrophic facial scars of acne vulgaris. PMID- 23016532 TI - A skincare containing retinol adenosine and hyaluronic acid optimises the benefits from a type A botulinum toxin injection. AB - INTRODUCTION: A monocentre double-blind two parallel group clinical study was conducted to assess whether a new skincare regimen containing retinol, adenosine and hyaluronic acid, applied after the injection of botulinum toxin A to the glabellar area, provided a beneficial effect. MATERIAL AND METHODS: Standardised photographs acquired using LifeViz cameras and zoomed pictures of the glabella and of the crow's feet areas were analysed with automatic well-defined procedures. Perceived efficacy and tolerance were also analysed by comparison between the two groups. RESULTS: A beneficial effect versus placebo-treated group was proven in the group having topically applied the new skincare regimen for 2 months following botulinum toxin A injection with no touch up after 1 month. 3D image analysis showed more rapid results on D10 and enhanced efficacy on M2. Moreover, a beneficial effect independent of injection was measured in the crow's feet area, and analysis of the self-evaluation questionnaire showed enhanced efficacy perceived by the volunteers. CONCLUSION: A specially developed skincare regimen applied immediately after botulinum toxin A injection completes the beneficial effect of the injection on the glabellar area and offers clinical benefits in fine lines, wrinkles and smoothness on the whole face. PMID- 23016533 TI - Comparison of sclerotherapy, laser, and radiowave coagulation in treatment of lower extremity telangiectasias. AB - INTRODUCTION: Telangiectasias represent an esthetic problem. Sclerotherapy, laser and radiowave coagulation are established methods of treatment. The aim of the treatment is a cosmetic improvement in the leg appearance. AIM: To define which method provides best results in lower extremity telangiectasias treatment and also to determine which method is most comfortable for the patient. MATERIALS AND METHODS: Thirty female volunteers, ages 30-66 years (mean 49 years), were included in the research, with telangiectasias in the thigh measuring 0,1 to 2 mm in diameter, and skin phototype according to Fitzpatrick I-IV. Three rectangular areas 3 * 5 cm, were marked on the thigh, with nearly same pattern and appearance of telangiectasias in each field. In each rectangle, only one session of sclerotherapy, laser, and radiowave coagulation were performed, respectively. It is completely documented with the digital camera prior to the therapy and 3 months after the treatment. At the end of the study, three blinded experts graded leg telangiectasias for clearance using obtained digital images. Patients were also required to describe the sense of pain during each procedure as minimal, mild, or strong. Chi-square test was used for statistical data processing. RESULTS: After 3 months period, there was a high statistical significant difference among methods of treatment (chi(2) = 45.492, p < 0.01). The most efficient was sclerotherapy. Also there was a high statistical significant difference (chi(2) test = 30.549, p < 0.01) among levels of pain experienced by patients in the study. Minimal sense of pain was associated with sclerotherapy. CONCLUSION: Our study revealed that the most efficient method in terms of telangiectasias clearance is sclerotherapy. It also showed that most comfortable method for the patient is sclerotherapy, since it produces minimal pain during the procedure. It can be concluded that sclerotherapy is a successful method in treating lower extremity telangiectasias leaving both, patient and physician content. PMID- 23016534 TI - Medial septal nucleus theta frequency deep brain stimulation improves spatial working memory after traumatic brain injury. AB - More than 5,000,000 survivors of traumatic brain injury (TBI) live with persistent cognitive deficits, some of which likely derive from hippocampal dysfunction. Oscillatory activity in the hippocampus is critical for normal learning and memory functions, and can be modulated using deep brain stimulation techniques. In this pre-clinical study, we demonstrate that lateral fluid percussion TBI results in the attenuation of hippocampal theta oscillations in the first 6 days after injury, which correlate with deficits in the Barnes maze spatial working memory task. Theta band stimulation of the medial septal nucleus (MSN) results in a transient increase in hippocampal theta activity, and when delivered 1 min prior to training in the Barnes maze, it significantly improves spatial working memory. These results suggest that MSN theta stimulation may be an effective neuromodulatory technique for treatment of persistent learning and memory deficits after TBI. PMID- 23016536 TI - Prevalence of thyroglossal duct cyst carcinoma in adults having surgery for thyroglossal duct cysts. PMID- 23016535 TI - Long-term efficacy and safety of atazanavir/ritonavir treatment in a real-life cohort of treatment-experienced patients with HIV type 1 infection. AB - Atazanavir-based regimens have established efficacy and safety in both antiretroviral (ARV)-naive and -experienced patients. However, data evaluating effectiveness beyond 2 years is sparse. Therefore, we assessed the long-term outcomes of ritonavir-boosted atazanavir (ATV/r)-containing regimens in ARV experienced patients in a clinical setting in a noncomparative, retrospective, observational study collecting data from three European HIV databases on ARV experienced adults with HIV-1 infection starting an ATV/r-based regimen. Data were extracted every 6 months (maximum follow-up 5 years). Primary outcome was the proportion of patients remaining on ATV/r by baseline HIV-1 RNA (<500 or >=500 copies/ml). Secondary outcomes included time to virologic failure, reasons for discontinuation, and long-term safety profile. The duration of treatment and time to virologic failure were analyzed using the Kaplan-Meier method. Data were analyzed for 1,294 ARV-experienced patients (male 74%; mean ART exposure 5.7 years). After 3 years, 56% (95% CI: 52%, 60%) of patients with baseline HIV-1 RNA <500 copies/ml and 53% (95% CI: 49%, 58%) of those with HIV-1 RNA >=500 copies/ml remained on ATV/r. After 3 years, 75% (95% CI: 69%, 80%) of patients with baseline HIV-1 RNA <50 copies/ml remained suppressed and 51% (95% CI: 47%, 55%) of those with baseline HIV-1 RNA >=50 copies/ml achieved and maintained virologic suppression. Although adverse events (AEs) were the main known reason for discontinuation, no unexpected AEs were observed. In a real-life setting ATV/r based regimens demonstrated sustained virologic suppression in ARV-experienced patients. After long-term therapy the majority of patients remained on treatment and no unexpected AEs were observed. PMID- 23016537 TI - Felt obligation and the family life cycle: a study on intergenerational relationships. AB - Since the 1990s researchers have considered as the dominant view on family obligation a set of responsibilities, duties, and obligation of care and assistance,that adult children should assume when parents are old or infirm. This concept is limited, because it assumes that family obligation is salient only in one period of life: when parents reach old age and are infirm. In contrast, a relational approach to family obligation considers family relationships as central to understanding children's duties and responsibilities. Following Stein, family obligation can be defined as felt obligation: expectations for appropriate and negotiated behaviour, perceived within the context of specific personal relationships with kin across life course. Felt obligation is conceptualized in five dimensions: a duty to maintain contact, assistance, avoidance of conflict, personal sharing, and self-sufficiency. The purpose of the present study was to analyze perceptions of felt obligation in intergenerational relationships (parent child and family of origin) in different phases of the family life cycle in a specific cultural context (Italy). The sample was composed of 92 parents with children of different ages (infants, school-aged children, and young adults).The measure addressed the five dimensions of felt obligation, all assessed in various phases of family life. Results indicated differences in dimensions of felt obligation between intergenerational relationships (both parent-child and with family of origin). Some of these differences, such as self-sufficiency and personal sharing, assumed more importance and salience in some periods of the life cycle than in others. PMID- 23016538 TI - Protease inhibitor monotherapy as maintenance regimen in patients with HIV infection. AB - Despite the remarkable success of combination antiretroviral therapy, usually including the association of three antiretroviral drugs selected from two different classes, the possibility of treating HIV-infected patients with one single potent agent as simplified maintenance regimen has attracted clinicians and researchers over the past years. Monotherapy with one ritonavir-boosted protease inhibitor in subjects with persistently suppressed plasma HIV RNA offers several potential advantages, such as avoiding the long-term toxicity associated with nucleoside/nucleotide analog, reducing costs, preventing drug-drug interactions, and preserving future treatment options. Several controlled and uncontrolled studies have assessed efficacy and safety of this monotherapy strategy, and the majority of available data concern lopinavir/ritonavir and darunavir/ritonavir. The virological efficacy of these boosted protease inhibitors as monotherapy is slightly lower than that of standard therapy, but the risk of resistance development is minimal and the re-introduction of nucleoside analogues usually leads to a re-suppression of the plasma viral load. Even though currently there is no consensus about the clinical use of protease inhibitor monotherapy for the treatment of HIV infection, this strategy seems an option for selected patients on stable combination therapy, with persistently suppressed plasma viral load, and without a history of virologic failure while receiving protease inhibitors. The aim of this article is to review and summarize the most recent randomized and observational studies which have evaluated efficacy and safety of the protease inhibitor monotherapy. PMID- 23016540 TI - Is social capital as perceived by the medical director associated with coordination among hospital staff? A nationwide survey in German hospitals. AB - Effective coordination among all members of hospital staff has been shown to be associated with better quality of care. The literature indicates that social capital, a form of organizational resource, may facilitate the task of coordination. However, to the best of our knowledge, no study has yet examined this link within a healthcare setting. Thus, the objective of this study was to analyze the relationship between social capital and coordination among hospital staff, as perceived by the medical director being a key informant of the hospital. In 2008, we surveyed the medical directors of 1224 German hospitals by the use of a standardized questionnaire. We conducted stepwise multivariate linear regression and controlled for hospital size, ownership and teaching status. In total, 551 medical directors (45%) responded to the survey. We found social capital to be a significant predictor of coordination (beta = 0.444, p < 0.001). The regression model explained 28% of the variance in coordination. Higher levels of social capital can be associated with better coordination among members of hospital staff, as perceived by the medical director. Therefore, investment in social capital may facilitate better organization of work processes in hospitals and may therefore help to improve patient outcomes. However, longitudinal studies are needed in order to explain the causal relationship between social capital and coordination among hospital staff. PMID- 23016542 TI - Pharmacokinetic properties and in silico ADME modeling in drug discovery. AB - The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry. PMID- 23016543 TI - Optimizing frequency of CD4 assays in the era of highly active antiretroviral therapy. AB - Current HIV guidelines recommend monitoring CD4 counts every 3-4 months. In the era of highly active antiretroviral therapy (HAART) and HIV PCR, this retrospective study reexamines the required frequency of the CD4 assay. Predictor variables, including age, previous CD4 count, HIV viral load (VL), time interval since last VL and CD4 count (TINT), and antiretroviral history, were abstracted. A recursive partitioning-based regression tree analysis was used to determine if the absolute current CD4 count was above or below the age appropriate Pneumocystis jiroveci pneumonia (PCP) prophylaxis cutoff. We analyzed concurrently obtained VLs and CD4 count including 601 results from 43 HIV infected children aged 1-<6 years (Group I) and 1,364 results from 93 children/adolescents 6-<23 years (Group II). Using 75% of observations to build a predictive model (learning dataset), the ability to correctly predict the range of the outcome variable in the remaining 25% of observations (training dataset) was 93% in Group I and 97% in Group II. Predictor variables included age, recent VL and CD4 count, and TINT. A total of 1,000 repeats of this model building using randomly selected observations showed a correct predictive ability of 89.6% [standard error (SE) 2.3%] in Group I and 95.6% (SE 1%) in Group II. The ability of a classification tree to determine if the current CD4 count is above or below the age-specific cutoff for PCP prophylaxis is very good and allows less frequent CD4 assays. The principles underlying this modeling-based approach have broad applicability and cost saving implications. PMID- 23016544 TI - The influence of pain on cerebral functioning after mild traumatic brain injury. AB - More than 75% of patients with mild traumatic brain injury (MTBI) report chronic pain whose potential detrimental effects on cognitive recovery need to be identified. The objective of this study was to investigate the relationship between pain, performance on a working memory task, gray matter density, and mid dorsolateral prefrontal cortex (mid-DLPFC) activation in subjects with a MTBI. For comparison purposes, we performed identical correlation analyses with a group of subjects without MTBI who sustained sports injuries. Twenty-four subjects who experienced a MTBI in the past 12 months, 16 control subjects, and 29 subjects with sport injuries were included. One hour prior to entering the magnetic resonance scanner, the subjects were asked to fill out the pain Visual Analogue Scale. Subsequently, a high-resolution T1-weighted image was acquired followed by a functional magnetic resonance imaging session using the visual externally ordered working memory task. Results showed that MTBI subjects reporting severe pain in the hour preceding the testing had reduced mid-DLPFC activation during the working memory task and poorer performance on the task. Subjects with sport injuries and severe levels of pain showed the reverse pattern: pain was associated with higher activation in the mid-DLPFC and did not correlate with performance. Gray matter density measures were independent of pain level. This study showed that behavioral performance and cerebral functioning are affected by pain after a MTBI. Moreover, this study suggests that pain, cognition, and cerebral functioning interactions could not easily be generalized from one clinical population to another. PMID- 23016545 TI - DYRK1A kinase inhibitors with emphasis on cancer. AB - Various types of cancers (including gliomas, melanomas, and esophageal, pancreas and non-small-cell lung cancers) display intrinsic resistance to pro-apoptotic stimuli, such as conventional chemotherapy and radiotherapy, and/or the activation of a multidrug resistance phenotype, which are major barriers to effective treatment and lead to poor patient prognosis. The DYRK1A kinase is directly implicated in the resistance of cancer cells to pro-apoptotic stimuli and drives several pathways that enhance proliferation, migration, and the reduction of cell death, leading to very aggressive biological behavior in cancer cell populations. The DYRK1A kinase is also implicated in neurological diseases and in neoangiogenic processes. Thus, the DYRK1A kinase is of great interest for both cancer and neuroscience research. During the last decade, numerous compounds that inhibit DYRK1A have been synthesized. The present review discusses the available molecules known to interfere with DYRK1A activity and the implications of DYRK1A in cancer and other diseases and serves as a rational analysis for researchers who aim to improve the anti-DYRK1A activity of currently available compounds. PMID- 23016546 TI - The management of membranous glomerulopathy in allogeneic stem cells transplantation: updated literature. AB - BACKGROUND: membranous glomerulopathy (MG) is an immunomediated disorder which accounts for the most common cause of nephrotic syndrome (NS) following allogeneic hematopoietic stem cell transplantation (HSCT). OBJECTIVE AND METHODS: to provide an update on the issue by reviewing pertinent literature on the MEDLINE database. RESULTS: sixty-nine post allogenic HSCT patients (42 male) with MG were identified. The median age was 43 (5 to 68) years. Time interval from allogenic HSCT to MG diagnosis ranged from 3 to 134 months (median 17). Most MG patients had a history of acute (70%) or chronic (84%) graft versus host disease (GVHD). Corticosteroids and cyclosporine were the most common therapeutic agents used in this setting; alternative therapies, including rituximab, were given to a lower number of patients. Outcome data were available in 64 out of 69 MG patients; 38 (59%) and 18 (28%) patients achieved a complete and a partial response respectively, whereas treatment failure was recorded in the remaining 8 (13%). CONCLUSION: MG after allogenic HSCT appears to be associated with a sub clinical or overt cGVHD, which follows the discontinuation of immunosuppressive prophylaxis. Although a standard therapeutic approach has not been established, the application of available measures can induce favorable response in more than 80% of affected patients, but treatment-failure and progressive deterioration of the renal function may occur in about one fifth of cases. PMID- 23016547 TI - Development of calixarenes, cyclodextrins and fullerenes as new platforms for anti-HIV drug design: an overview. AB - The research and development of calixarenes, cyclodextrins and fullerenes, which constitute the major classes of supramolecular organic host compounds, have been quite rapidly developing, increasingly active and newly rising highlight interdisciplinary fields. Numerous efforts have been directed toward such molecules as new platforms for anti- HIV drug design. This work briefly reviewed the recent development of calixarenes, cyclodextrins and fullerenes as new chemical entities of distinct anti-HIV activities. It is hoped that this review will serve as a stimulant for new thoughts in the quest for rational designs of more active and less toxic biological molecules as anti-HIV drugs. PMID- 23016548 TI - Virtual screening methods as tools for drug lead discovery from large chemical libraries. AB - Virtual screening methods have been developed and explored as useful tools for searching drug lead compounds from chemical libraries, including large libraries that have become publically available. In this review, we discussed the new developments in exploring virtual screening methods for enhanced performance in searching large chemical libraries, their applications in screening libraries of ~ 1 million or more compounds in the last five years, the difficulties in their applications, and the strategies for further improving these methods. PMID- 23016549 TI - Anticholinergic effects of oral antipsychotic drugs of typicals versus atypicals over medium- and long-term: systematic review and meta-analysis. AB - BACKGROUND: Anticholinergic side-effects of antipsychotic drugs are common and can potentially impact on quality of life as well as concordance with medication. OBJECTIVES: To investigate prevalence/incidence rates of anticholinergic side effects of oral antipsychotic drugs over the medium- and long-term. METHODS: We included all systematic reviews undertaken by the Cochrane Schizophrenia Group for people who are taking antipsychotic drugs and suffering from schizophrenia or Schizophrenia-like illnesses. The prevalence/ incidence of any anticholinergic side-effects was calculated. Relevant papers from the Cochrane Database were identified in January 2007 and the data was pooled. Side-effect data was grouped into the medium (3-6 months) and long-term ( > 6 months). We calculated simple frequencies, proportions and confidence intervals. We undertook a comparison within the group and generated a Forrest plot of the data. RESULTS: We identified 177 studies within 54 reviews (N=27328 participants). Anticholinergic side effects for blurred vision, dry mouth and constipation manifested for antipsychotics ranging from 1 to 40 % over the medium-term and 1 to 41% over long term respectively. There were no statistical differences beween typicals and atypicals over medium- and long-term. CONCLUSION: To the best of our knowledge, we have collated the largest amount of data on anticholinergic side-effects for antipsychotics over the medium- and longterm. Anticholinergic side-effects are common over the medium- and long-term. Over the medium- and long-term there were no statistically significant differences between the typicals and atypicals in the main anticholinergic side-effects with one exception. We found that in the long-term, the typical antipsychotics were associated with a significantly higher prevalence of blurred vision. PMID- 23016550 TI - Drugs for chronic obstructive pulmonary disease. PMID- 23016551 TI - Alveolar epithelial stem and progenitor cells: emerging evidence for their role in lung regeneration. AB - Lung injuries that impact the alveolus, such as emphysema, pulmonary fibrosis, and acute lung injury, are costly and prevalent problems. Moreover, the extent of alveolar injury and impairment of gas exchange is strongly associated with prognosis and survival. Thus, mechanisms of repair and regeneration of the lung alveolar compartment have received mounting attention as newer approaches to the study of stem and progenitor cells in this region unfold. The role of type II alveolar epithelial as the sole source of type I (AECI) and II (AECII) alveolar epithelial cells following lung injury has been recently challenged; recently, investigators have described stemprogenitor cells that function like precursors to AECII either in vitro or in vivo, both in mice and humans. Techniques to explore selfrenewal and multipotency have been rigorously applied to these putative stem-progenitor cell populations and the data thus far is compelling. This review provides background to the study of alveolar regeneration with the aim to provide context to the recent discoveries of putative stem-progenitor cells that may contribute to this process. PMID- 23016552 TI - Management of severe epidermolysis bullosa by haematopoietic transplant: principles, perspectives and pitfalls. AB - People with severe forms of epidermolysis bullosa (EB) develop widespread blistering and progressively debilitating multisystem complications that may result in a shortened lifespan. As some wounds in EB individuals are difficult or impossible to access with topical therapy, we examined the potential of systemic therapy with normal haematopoietic stem cells. In both animal models and children with EB, healthy donor cells from the haematopoietic graft migrated to the injured skin; simultaneously, there was an increase in the production of skin specific structural proteins deficient in EB, increased skin integrity and reduced tendency to blister formation. Even though the majority of evaluable individuals have had a positive response in skin healing, frequently changing their quality of life, the improvement in lifestyle has been varied and the overall clinical response incomplete. To change the current amelioration of disease into a full cure, we propose to (i) increase safety as well as efficacy of haematopoietic cell transplant (HCT) using co-infusion of mesenchymal stromal/stem cells with haematopoietic stem cells and non-myeloablative conditioning for transplant; (ii) optimize homing of donor cells into the skin erosions in animal models of EB; and (iii) discover and test new drugs for EB therapy using patient-specific induced pluripotent stem cells. We conclude that although HCT has always been a risky treatment restricted to those with serious life-threatening or debilitating diseases, by most benchmarks, the results of HCT in EB have shown that HCT has the potential of being a durable, systemic therapy for people with severe forms of EB. PMID- 23016553 TI - Enzyme induction with antiepileptic drugs: cause for concern? AB - Several commonly prescribed antiepileptic drugs (AEDs)-including phenobarbital, phenytoin, and carbamazepine-stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. These agents are well known to reduce the duration and action of many lipid- and non-lipid-soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, immunosuppressants, and of course, other AEDs. This process, therefore, may be associated with a number of clinical problems including higher cancer mortality, progressive AIDS, transplant rejection, and unwanted pregnancy. Withdrawal of enzyme-inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if doses are not concomitantly reduced. Yet the potential widespread adverse health consequences of these interactions, both with AED initiation and withdrawal, remain largely underappreciated. Furthermore, induction also affects enzymes involved in endogenous metabolic pathways, and can alter bone biochemistry, gonadal steroids, and lipid markers. Therefore, enzyme inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. This process continues as long as the patient takes the inducer. Modern AEDs that do not possess this property have similar efficacy for the common epilepsies. Accordingly, perhaps consideration should be given to starting treatment with, or even switching patients to, non-enzyme-inducing AEDs. PMID- 23016554 TI - Ironic effects of compulsive perseveration. AB - Individuals with obsessive-compulsive disorder (OCD) exhibit perseverative behaviours, like checking, to reduce uncertainty, but perseveration paradoxically enhances uncertainty. It is unclear what mechanism might be responsible. We hypothesised that perseverative OC-like behaviour produces "semantic satiation" and interferes with the accessibility of meaning. Healthy participants repeated 20 types of OC-like checking behaviour nonperseveratively (2 times) or perseveratively (20 times). Afterwards, they decided as quickly as possible whether a picture was semantically related to the checked object. The nonperseverative condition showed spreading of activation: Judgements were faster for related than for unrelated objects and pictures. The effect was blocked in the perseverative condition, where reaction times for related and unrelated items were similar. The results suggest that the ironic effects of compulsive perseveration are due to interference with spreading of activation. PMID- 23016556 TI - Is diagnosis enough to guide interventions in mental health? Using case formulation in clinical practice. AB - While diagnosis has traditionally been viewed as an essential concept in medicine, particularly when selecting treatments, we suggest that the use of diagnosis alone may be limited, particularly within mental health. The concept of clinical case formulation advocates for collaboratively working with patients to identify idiosyncratic aspects of their presentation and select interventions on this basis. Identifying individualized contributing factors, and how these could influence the person's presentation, in addition to attending to personal strengths, may allow the clinician a deeper understanding of a patient, result in a more personalized treatment approach, and potentially provide a better clinical outcome. PMID- 23016555 TI - Association of Piebaldism, multiple cafe-au-lait macules, and intertriginous freckling: clinical evidence of a common pathway between KIT and sprouty-related, ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1). AB - Piebaldism is a rare genodermatosis caused by KIT mutations. We report the case of a 5-year-old boy who had the white forelock and leukoderma of piebaldism, but the presence of many cafe-au-lait macules and axillary and inguinal freckling complicated the diagnosis. Patients with similar cutaneous findings have been previously reported, and their disorder has been attributed to an overlap of piebaldism and neurofibromatosis type 1. Legius syndrome is a recently described syndrome caused by Sprouty-related, Ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1) mutations that also has multiple cafe-au-lait macules and intertriginous freckling. Based on our current understanding of KIT and SPRED1 protein interactions, we propose that cafe-au lait macules and freckling may be seen in some patients with piebaldism and does not necessarily represent coexistence of neurofibromatosis type 1. PMID- 23016557 TI - The production of fibers and films from solubilized hagfish slime thread proteins. AB - Hagfish slime threads, which make up the fibrous component of the defensive slime of hagfishes, consist primarily of proteins from the intermediate filament family of proteins and possess impressive mechanical properties that make them attractive biomimetic models. To investigate whether solubilized intermediate filament proteins can be used to make high-performance, environmentally sustainable materials, we cast thin films on the surface of electrolyte buffers using solubilized hagfish slime thread proteins. The films were drawn into fibers, and the tensile properties were measured. Fiber mechanics depended on casting conditions and postspinning processing. Postsecondary drawing resulted in fibers with improved material properties similar to those of regenerated silk fibers. Structural analyses of the fibers revealed increased molecular alignment resulting from the second draw, but no increase in crystallinity. Our findings show promise for intermediate filament proteins as an alternative source for the design and production of high performance protein-based fibers. PMID- 23016558 TI - Coordination polymers utilizing N-oxide functionalized host ligands. AB - Pyridyl functionalized host molecules are oxidized to their N-oxide analogues and form a series of coordination polymers and discrete complexes with transition metal cations. Complex {[Ag(3)(NMP)(6)(L1)(2)].3(ClO(4))}(infinity) where L1 = tris(isonicotinoyl-N-oxide)cyclotriguaiacylene, NMP = N-methylpyrrolidone, is a three-dimensional (3-D) 3,6-connected coordination polymer of pyrite-like (pyr) topology and features ligand unsupported argentophilic interactions, while two dimensional (2-D) 3,6-connected coordination polymers with the rarely reported kagome dual (kgd) topology are found for [M(L1)(2)](2+) where M = Zn, Cd, Cu. Ligand L2 = tris(nicotinoyl-N-oxide)cyclotriguaiacylene forms a 2-D coordination polymer with 4(4) (sql) grid topology in complexes {[M(L2)(2)(DMF)(2)].2ClO(4).8(DMF)}(infinity) M = Cd or Cu, DMF = N,N' dimethylformamide, and a double-linked chain structure in {[Co(L2)(2)(DMF)(2)].2NO(3).4(DMF).H(2)O}(infinity), and both types of structure feature hand-shake self-inclusion motifs either within or between the polymers. 2 D coordination networks with 6(3) (hcb) topologies are found in complexes {[M(L3)(NO(3))(2)].2(DMF)}(infinity) (M = Cd, Zn) and {[Cu(5)(L3)(2)Cl(10)(NMP)(4)]}(infinity) where L3 = tris(2 pyridylmethyl)cyclotriguaiacylene, while [Ag(2)(L3)(2)(NMP)(4)].2(BF(4)).2(NMP) has a discrete dimeric structure which again shows hand-shake host-guest interactions supported by pi-pi stacking. PMID- 23016559 TI - Combining laser microdissection and RNA-seq to chart the transcriptional landscape of fungal development. AB - BACKGROUND: During sexual development, filamentous ascomycetes form complex, three-dimensional fruiting bodies for the protection and dispersal of sexual spores. Fruiting bodies contain a number of cell types not found in vegetative mycelium, and these morphological differences are thought to be mediated by changes in gene expression. However, little is known about the spatial distribution of gene expression in fungal development. Here, we used laser microdissection (LM) and RNA-seq to determine gene expression patterns in young fruiting bodies (protoperithecia) and non-reproductive mycelia of the ascomycete Sordaria macrospora. RESULTS: Quantitative analysis showed major differences in the gene expression patterns between protoperithecia and total mycelium. Among the genes strongly up-regulated in protoperithecia were the pheromone precursor genes ppg1 and ppg2. The up-regulation was confirmed by fluorescence microscopy of egfp expression under the control of ppg1 regulatory sequences. RNA-seq analysis of protoperithecia from the sterile mutant pro1 showed that many genes that are differentially regulated in these structures are under the genetic control of transcription factor PRO1. CONCLUSIONS: We have generated transcriptional profiles of young fungal sexual structures using a combination of LM and RNA-seq. This allowed a high spatial resolution and sensitivity, and yielded a detailed picture of gene expression during development. Our data revealed significant differences in gene expression between protoperithecia and non-reproductive mycelia, and showed that the transcription factor PRO1 is involved in the regulation of many genes expressed specifically in sexual structures. The LM/RNA-seq approach will also be relevant to other eukaryotic systems in which multicellular development is investigated. PMID- 23016560 TI - Comprehensive profiling of carotenoids and fat-soluble vitamins in milk from different animal species by LC-DAD-MS/MS hyphenation. AB - This paper describes a novel and efficient analytical method to define the profile of fat-soluble micronutrients in milk from different animal species. Overnight cold saponification was optimized as a simultaneous extraction procedure. Analytes were separated by nonaqueous reversed-phase (NARP) chromatography: carotenoids on a C(30) column and fat-soluble vitamins on a tandem C(18) column system. Besides 12 target analytes for which standards are available (all-trans-lutein, all-trans-zeaxanthin, all-trans-beta-cryptoxanthin, all-trans-beta-carotene, all-trans-retinol, alpha-tocopherol, gamma-tocopherol, delta-tocopherol, ergocalciferol, cholecalciferol, phylloquinone, and menaquinone 4), the DAD-MS combined detection allowed the provisional identification of other carotenoids on the basis of the expected retention times, the absorbance spectra, and the mass spectrometric data. Retinol and alpha-tocopherol were the most abundant fat-soluble micronutrients and the only ones found in donkey's milk along with gamma-tocopherol. Ewe's milk also proved to be a good source of vitamin K vitamers. Bovine milk showed a large variety of carotenoids that were absent in milk samples from other species with the only exception of all-trans lutein and all-trans-zeaxanthin. PMID- 23016561 TI - Abnormal enhancement of the photoisomerization process in a trans nitroalkoxystilbene dimer sequestered in beta-cyclodextrin cavities. AB - We report on the synthesis and the photophysical properties of a trans nitroalkoxystilbene dimer (DPNS). The fluorescence quantum yield (Phi(f)), the Stokes shift, and the quantum yield for the trans-to-cis photoisomerization (Phi(t->c)) are strongly dependent on the nature of the solvent. Upon increasing solvent polarity, Phi(f) increases together with the decrease of Phi(t->c). This solvent-induced reverse behavior mainly stems from the progressive stabilization of a highly polar twisted internal charge transfer state (TICT) at excited singlet level which opens a competing channel to photoisomerization. In the presence of hydroxylic substrates (i.e., alcohols or water), fluorescence of DPNS is strongly quenched due to a hydrogen bonding interaction at excited state. The efficiency of the process is clearly correlated to the H-bond donor ability of the quencher. In aqueous solution, the major formation of a 2:1 host-guest complex with beta-cyclodextrins (beta-CD) prevents the quenching by H(2)O and leads to a 50-fold increase of the fluorescence signal together with a strong band blue-shift with respect to that of the free chromophore. This latter effect was rationalized in terms of a severe reduction of the solvent-induced stabilization of the TICT state. As a consequence, the trans-to-cis photoisomerization reaction is reactivated and leads to a paradoxical 14-fold increase of Phi(t->c) even though DPNS is sequestered in beta-CD cavities. PMID- 23016562 TI - Treatment of traumatic brain injury using zinc-finger protein gene therapy targeting VEGF-A. AB - Vascular endothelial growth factor (VEGF) plays a role in angiogenesis and has been shown to be neuroprotective following central nervous system trauma. In the present study we evaluated the pro-angiogenic and neuroprotective effects of an engineered zinc-finger protein transcription factor transactivator targeting the vascular endothelial growth factor A (VEGF-ZFP). We used two virus delivery systems, adeno-virus and adeno-associated virus, to examine the effects of early and delayed VEGF-A upregulation after brain trauma, respectively. Male Sprague Dawley rats were subject to a unilateral fluid percussion injury (FPI) of moderate severity (2.2-2.5 atm) followed by intracerebral microinjection of either adenovirus vector (Adv) or an adeno-associated vector (AAV) carrying the VEGF-ZFP construct. Adv-VEGF-ZFP-treated animals had significantly fewer TUNEL positive cells in the injured penumbra of the cortex (p<0.001) and hippocampus (p=0.001) relative to untreated rats at 72 h post-injury. Adv-VEGF-ZFP treatment significantly improved fEPSP values (p=0.007) in the CA1 region relative to injury alone. Treatment with AAV2-VEGF-ZFP resulted in improved post-injury microvascular diameter and improved functional recovery on the balance beam and rotarod task at 30 days post-injury. Collectively, the results provide supportive evidence for the concept of acute and delayed treatment following TBI using VEGF ZFP to induce angiogenesis, reduce cell death, and enhance functional recovery. PMID- 23016563 TI - Does antenatal magnesium sulfate prevent cerebral palsy in preterm infants? The final trial? PMID- 23016564 TI - Occurrence of household mold and efficacy of sodium hypochlorite disinfectant. AB - The occurrence and distribution of mold on household surfaces and the efficacy of bleach-based (sodium hypochlorite, NaOCl) disinfectants on mold viability and allergenicity was documented. Household microenvironments prone to increased moisture were specifically targeted. Using the sticky tape method, 1330 samples were collected from non-porous indoor surfaces of 160 homes across the United States, and analyzed for mold. Homes were randomly selected and recruited via phone interviews. Culture and immunoassays were used to measure the viability and reduction of allergenic properties of Aspergillus fumigatus following 2.4% NaOCl treatment. All homes and 72.9% of surfaces tested positive for mold. Windowsills were the most frequently contaminated site (87.5%) and Cladosporium the most commonly identified mold (31.0%). Five-minute exposures to 2.4% NaOCl resulted in a >3 to >6-log10 reduction of culturable mold counts in controlled laboratory studies. Organisms were nonculturable after 5- and 10-min contact times on non porous and porous ceramic carriers, respectively, and A. fumigatus spore-eluted allergen levels were reduced by an average 95.8% in 30 sec, as indicated by immunoassay. All homes are contaminated with some level of mold, and regrowth is likely in moisture-prone microenvironments. The use of low concentrations (2.4%) of NaOCl for the reduction of culturable indoor mold and related allergens is effective and recommended. PMID- 23016565 TI - Breast imaging: understanding how accuracy is measured when lesions are the unit of analysis. AB - Medical imaging tests of breast cancer patients can be used to detect and provide information on the location of multiple malignant lesions within a patient. Within this context, it is often the case that one needs to evaluate the accuracy of an imaging test for finding the multiple lesions in a patient rather than simply detecting that a patient has disease. A natural way to approach this task is to estimate the accuracy of the test using a lesion-level analysis. Sensitivity, specificity, and receiver operating characteristic (ROC) curves are analytic measures that are frequently used to quantify the accuracy of medical tests. When the test or radiologist must first locate the lesions, however, it is not possible to directly estimate the specificity or an ROC curve keeping the individual lesions as the unit of analysis. The goal of this study is to demonstrate to clinicians conducting or reviewing studies evaluating breast imaging tests what measures of accuracy can and cannot be calculated in different types of studies and to describe in detail the difficulty with calculating specificity and ROC curves in a lesion-level analysis. PMID- 23016566 TI - Pathological findings after primary chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection for advanced germ cell tumours. AB - OBJECTIVE: To determine the differential response to systemic chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection (RPLND) after chemotherapy for metastatic testicular cancer. PATIENTS AND METHODS: Patients who underwent simultaneous RPLND and orchidectomy after chemotherapy were identified from our clinical databases. Postoperative pathological findings and patient characteristics were reviewed. RESULTS: In all, 42 patients were identified. After chemotherapy, necrosis, teratoma and cancer were identified in 25 (59.5%), 14 (33.3%) and three (7.1%) RPLN specimens and 15 (35.7%), 15 (35.7%) and 12 (28.6%) orchidectomy specimens respectively. Of the 25 patients with necrotic RPLN specimens 12 (48.0%) had active disease within the orchidectomy specimen (eight invasive cancer and four mature teratoma). The overall histological discordance rate was 38.1%. Findings in the orchidectomy specimens were more aggressive than those in the RPLN specimens (i.e. cancer worse than teratoma, which is worse than necrosis) in 33.3%. CONCLUSIONS: There is significant disparity between orchidectomy and RPLND findings with viable tumour appearing frequently in the testis despite tumour-free RPLNs. These findings support completion orchidectomy as part of advanced testicular germ cell treatment. PMID- 23016567 TI - The cost effectiveness of palivizumab in congenital heart disease: a review of the current evidence. AB - OBJECTIVE: To review and summarize the literature concerning the cost effectiveness of palivizumab compared to no prophylaxis in infants and young children with congenital heart disease (CHD). METHODS: A systematic literature search (MEDLINE to March 2012, limited to English language) identified studies that examined the cost-effectiveness of palivizumab in CHD populations. The quality of each study was assigned a quality score of 1-100 based on the Quality of Health Economic Studies (QHES) instrument. RESULTS: Ten studies were identified through the search strategy, of which four principally addressed the research question and six additional articles examined CHD in conjunction with other high-risk indications for palivizumab in their economic analyses. QHES for the studies ranged from 58-100, with a median score of 93 (76 for principal articles, 94 for secondary analyses). Cost-utility analyses, which evaluated costs per quality-adjusted life year (QALY), showed favorable results in five analyses (range $10,329-$16,648 per QALY), while the other two suggested no cost effectiveness ($146,061 and $169,971 per QALY). Of three cost-effectiveness analyses, which assessed costs per hospital admission prevented (HAP), two concluded that the drug was not cost-effective ($16,216/day of hospitalization prevented and $868,296/HAP), while one did not interpret the final result ($43,561/HAP). LIMITATIONS: Significant variance exists across study characteristics, analytic models utilized, duration of RSV seasons assessed, primary outcome measures evaluated, sensitivity analyses conducted, and other model assumptions. Further, it was difficult to obtain true CHD-based quality scores for the studies that analyzed more than one indication. CONCLUSIONS: The findings of this review currently remain inconclusive. Although a favorable trend was identified in the cost-utility analyses, additional rigorously conducted studies are necessary to better estimate the cost-effectiveness of palivizumab for CHD infants in clinical practice. PMID- 23016568 TI - Comparative effectiveness of pegfilgrastim, filgrastim, and sargramostim prophylaxis for neutropenia-related hospitalization: two US retrospective claims analyses. AB - OBJECTIVE: Few studies have compared the effectiveness of filgrastim (FIL), pegfilgrastim (PEG), and sargramostim (SAR) to reduce the risk of febrile neutropenia (FN) associated with myelosuppressive chemotherapy (M-CT). Two large commercial database analyses were separately conducted to examine the incidence of neutropenia-related and all-cause hospitalizations associated with FIL, PEG, and SAR prophylaxis for patients receiving M-CT for non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, or solid tumors. METHODS: Separate retrospective US claims database analyses utilized patient data from January 1, 2004 to April 30, 2010 using the HealthCore Integrated Research Database (HIRD(SM)) and January 1, 2001 to August 31, 2009 using OptumInsight's (formerly Ingenix) database. Patients were >=18 years old and treated with M-CT for NHL, Hodgkin lymphoma, and solid tumors. All identified M-CT cycles with prophylactic (first 5 days of cycle) FIL, PEG, or SAR were included in the analysis. Patterns of administration and incidence rates of all-cause and neutropenia-related hospitalization were examined on a per-cycle basis. RESULTS: In total, 9330 and 8762 patients with cancer, representing 30,264 and 24,215 chemotherapy cycles (28,189 and 22,649 (PEG), 1669 and 1351 (FIL), 406 and 215 (SAR)) from the HIRD(SM) and OptumInsight databases, respectively, were included in the separate database analyses. Both the HIRD(SM) and OptumInsight analysis showed that SAR and FIL prophylaxis had a higher risk of neutropenia-related hospitalization (SAR: OR = 3.48 [95%CI = 2.11, 5.74] and 2.81 [1.62, 4.87]; FIL: 1.78 [1.28, 2.48] and 2.36 [1.82, 3.06], respectively) and all-cause hospitalization (SAR: 2.18 [1.41, 3.36] and 2.41 [1.58, 3.68]; FIL:1.57 [1.25, 1.97] and 1.95 [1.60, 2.38], respectively) vs PEG. LIMITATIONS: Medical claims do not contain information about chemotherapy dose, and hospitalizations were not validated against the patient's chart. CONCLUSION: In this comparative effectiveness study, use of PEG was associated with a lower risk of neutropenia-related and all-cause hospitalizations compared to use of FIL or SAR prophylaxis. PMID- 23016569 TI - The cost-effectiveness of paliperidone extended release in Spain. AB - BACKGROUND: Paliperidone Extended Release OROS (ER) is a new atypical antipsychotic for the treatment of schizophrenia. The objective is, based on a previously published model, to analyze the clinical and economic effects of Paliperidone ER in a Spanish setting compared to olanzapine oral and aripiprazole. METHODS: An existing discrete event simulation model was adapted to reflect the treatment of schizophrenia in Spain in terms of costs, resource use, and treatment patterns. Inputs for the model were derived from clinical trial data, literature research, database analysis and interviews with local clinical experts. The time horizon is 5 years and Spanish discount rate was applied. Outputs include direct medical costs and Quality Adjusted Life-Years (QALYs). Extensive sensitivity analyses were carried out to assess the robustness of the results, using ordinary least squares analysis and cost-effectiveness scatter plots. RESULTS: The results show that the mean incremental QALYs (95% CI) compared to olanzpine is 0.033 [-0.143, 0.304] and compared to aripiprazole 0.029 [-0.107, 0.300]. The corresponding mean incremental costs and corresponding confidence intervals are -?1425 [-?10,247, ?3084] and -?759 [-?10,479, ?3404], respectively. The probability that paliperidone ER is cost-saving and health gaining compared to olanzapine and aripiprazole is 76% and 72%, respectively. Paliperidone ER was estimated to have 80% and 81% probability of being cost effective compared to olanzapine at a willingness to pay of ?20,000 and ?30,000 and 73% and 74% compared to aripiprazole, respectively. LIMITATIONS: Some of the modeled inter-relationships had to be based on expert opinion due to a lack of information. Also, foreign sources for the disutility of adverse events had been used due to a lack of Spanish data. Prolactin-related side-effects, indirect costs, and potential compliance advantages of paliperidone ER were not considered. It is unlikely that these limitations affected the conclusions. CONCLUSION: Based on differences in drug acquisition costs, side-effects, and risk of relapse, the model predicts that, in the Spanish healthcare setting, paliperidone ER dominates oral olanzapine and aripiprazole, with a probability of 76% and 72%, respectively. PMID- 23016570 TI - Nitrite reduces acute lung injury and improves survival in a rat lung transplantation model. AB - Ischemia/reperfusion injury (IRI) is the most common cause of early mortality following lung transplantation (LTx). We hypothesized that nitrite, an endogenous source of nitric oxide (NO), may protect lung grafts from IRI. Rat lung grafts were stored in preservation solution at 4 degrees C for 6 hours. Both grafts and recipients were treated with nitrite. Nitrite treatment was associated with significantly higher levels of tissue oxygenation, lower levels of cytokines and neutrophil/macrophage infiltration, lower myeloperoxidase activity, reduced oxidative injury and increased cGMP levels in grafts than in the controls. Treatment with either a nitric oxide scavenger or a soluble guanylyl cyclase (sGC) inhibitor diminished the beneficial effects of nitrite and decreased cGMP concentrations. These results suggest that nitric oxide, generated from nitrite, is the molecule responsible for the effects of nitrite via the nitric oxide/sGC/cGMP pathway. Allopurinol, a xanthine oxidoreductase (XOR) inhibitor, abrogated the protective effects of nitrite, suggesting that XOR is a key enzyme in the conversion of nitrite to nitric oxide. In vitro experiments demonstrated that nitrite prevented apoptosis in pulmonary endothelial cells. Nitrite also exhibits longer survival rate in recipients than control. In conclusion, nitrite inhibits lung IRI following cold preservation and had higher survival rate in LTx model. PMID- 23016571 TI - Partial oligomerization of pyolysin induced by a disulfide-tethered mutant. AB - The bacterial toxin pyolysin (PLO) belongs to the family of cholesterol-dependent cytolysins (CDCs), which form large, ring-shaped oligomeric pores in cholesterol containing membranes. Monomeric CDC molecules have a structure of four domains, with domains 2 and 3 packed against each other. After binding to target membranes containing cholesterol, toxin monomers oligomerize into pre-pore complexes. Trans membrane pores form when the pre-pores insert into the lipid bilayer. Membrane insertion requires each subunit in the pre-pore to undergo a significant change in conformation, including the separation of domains 2 and 3. We here characterize a pyolysin mutant with an engineered disulfide bond between domains 2 and 3. The disulfide-tethered mutant binds to membranes but does not form oligomers. When mixed with wild type PLO, the two proteins form hybrid oligomers, which are reduced in size and arc-shaped rather than ring-shaped. With equimolar mixtures or the disulfide mutant in slight excess, the hybrid oligomers retain pore-forming activity, while a larger excess of the mutant suppresses pore formation. These results support a "partially cooperative" mode of protein activity, in which a limited number of functional subunits within an oligomer have to cooperate to initiate membrane insertion and pore formation. PMID- 23016572 TI - Small RNAs of Sequoia sempervirens during rejuvenation and phase change. AB - In this work, the population of small RNAs (sRNAs) was studied in the gymnosperm Sequoia sempervirens during phase changes, specifically in the juvenile, adult and rejuvenated plants obtained in vitro. The potential target genes of Sequoia sRNAs were predicted through bioinformatics. Rejuvenation is a pivotal process in woody plants that enables them to regain their growth potential, which results in the recovery of physiologic and molecular characteristics that were lost when the juveniles mature into adult plants. The results from the five repeated graftings of juvenile, adult and rejuvenated plants in vitro showed that sRNAs could be classified into structural RNAs (Group I), small interfering RNAs (Group II), annotated microRNAs (Group III, and unannotated sRNAs (Group IV). The results indicate that only 573 among 15,485,415 sRNAs (Groups III and IV) had significantly different expression patterns associated with rejuvenation and phase change. A total of 215 sRNAs exhibited up-regulated expression patterns in adult shoots, and 358 sRNAs were down-regulated. Expression profiling and prediction of possible target genes of these unique small RNAs indicate possible functions in the control of photosynthetic efficiency and rooting competence abundance during plant rejuvenation. Moreover, the increase in SsmiR156 and decrease in SsmiR172 during plant rejuvenation suggested that these two microRNAs extensively affect phase transition. PMID- 23016574 TI - The phylogenetic signal of species co-occurrence in high-diversity shrublands: different patterns for fire-killed and fire-resistant species. AB - BACKGROUND: Using phylogenies in community ecology is now commonplace, but typically, studies assume and test for a single common phylogenetic signal for all species in a community, at a given scale. A possibility that remains little explored is that species differing in demographic or ecological attributes, or facing different selective pressures, show different community phylogenetic patterns, even within the same communities. Here I compare community phylogenetic patterns for fire-killed and fire-resistant Banksia species in the fire-prone shrublands of southwest Australia. RESULTS: Using new Bayesian phylogenies of Banksia, together with ecological trait data and abundance data from 24 field sites, I find that fire regeneration mode influences the phylogenetic and phenotypic signal of species co-occurrence patterns. Fire-killed species (reseeders) show patterns of phylogenetic and phenotypic repulsion consistent with competition-driven niche differentiation, but there are no such patterns for fire-resistant species (resprouters). For pairs of species that differ in fire response, co-occurrence is mediated by environmental filtering based on similarity in edaphic preferences. CONCLUSIONS: These results suggest that it may be simplistic to characterize an entire community by a single structuring process, such as competition or environmental filtering. For this reason, community analyses based on pairwise species co-occurrence patterns may be more informative than those based on whole-community structure metrics. PMID- 23016573 TI - Inflammation, oxidative stress, glomerular filtration rate, and albuminuria in elderly men: a cross-sectional study. AB - BACKGROUND: The role of inflammation and oxidative stress in mild renal impairment in the elderly is not well studied. Accordingly, we aimed at investigating the associations between estimated glomerular filtration rate (eGFR), albumin/creatinine ratio (ACR), and markers of different inflammatory pathways and oxidative stress in a community based cohort of elderly men. FINDINGS: Cystatin C-based GFR, ACR, and biomarkers of cytokine-mediated inflammation (interleukin-6, high-sensitivity C-reactive protein[CRP], serum amyloid A[SAA]), cyclooxygenase-mediated inflammation (urinary prostaglandin F2alpha [PGF2alpha]), and oxidative stress (urinary F2 isoprostanes) were assessed in the Uppsala Longitudinal Study of Adult Men(n = 647, mean age 77 years). RESULTS: In linear regression models adjusting for age, BMI, smoking, blood pressure, LDL-cholesterol, HDL-cholesterol, triglycerides, and treatment with statins, ACE-inhibitors, ASA, and anti-inflammatory agents, eGFR was inversely associated with CRP, interleukin-6, and SAA (beta-coefficient -0.13 to 0.19, p < 0.001 for all), and positively associated with urinary F2-isoprostanes (beta-coefficient 0.09, p = 0.02). In line with this, ACR was positively associated with CRP, interleukin-6, and SAA (beta- coefficient 0.09-0.12, p < 0.02 for all), and negatively associated with urinary F2-isoprostanes (beta coefficient -0.12, p = 0.002). The associations were similar but with lower regression coefficients in a sub-sample with normal eGFR (>60 ml/min/1.73 m2, n = 514), with the exception that F2-isoprostane and SAA were no longer associated with eGFR. CONCLUSION: Our data indicate that cytokine-mediated inflammation is involved in the early stages of impaired kidney function in the elderly, but that cyclooxygenase-mediated inflammation does not play a role at this stage. The unexpected association between higher eGFR/lower albuminuria and increased F2 isoprostanes in urine merits further studies. PMID- 23016575 TI - Role of live/real time three-dimensional transesophageal echocardiography in the percutaneous epicardial closure of the left atrial appendage. AB - We are reporting the use of three-dimensional transesophageal echocardiography as a supplement to two-dimensional transesophageal echocardiography in the percutaneous suture closure of the left atrial appendage. PMID- 23016576 TI - Stereoelectroencephalography in the "difficult to localize" refractory focal epilepsy: early experience from a North American epilepsy center. AB - PURPOSE: Stereo-electroencephalography (SEEG) enables precise recordings from deep cortical structures, multiple noncontiguous lobes, as well as bilateral explorations while avoiding large craniotomies. Despite a long reported successful record, its application in the United States has not been widely adopted. We report on our initial experience with the SEEG methodology in the extraoperative mapping of refractory focal epilepsy in patients who were not considered optimal surgical candidates for other methods of invasive monitoring. We focused on the applied surgical technique and its utility and efficacy in this subgroup of patients. METHODS: Between March 2009 and May 2011, 100 patients with the diagnosis of medically refractory focal epilepsy who were not considered optimal candidates for subdural grids and strips placement underwent SEEG implantation at Cleveland Clinic Epilepsy Center. Demographics, noninvasive clinical data, number and location of implanted electrodes, electrophysiologic localization of the epileptic zone, complications, and short-term seizure outcome after resection were prospectively collected and analyzed. KEY FINDINGS: Mean age was 32 years (range 5-68 years); 54 were male and 46 female. The mean follow-up after resection was 15 months. In total, 1,310 electrodes were implanted. Analyses of the SEEG recordings resulted in the electrographic localization of the epileptogenic focus in 96 patients. In the group of 75 patients who underwent resection, only 53 had at least 12 months follow-up. From this group, 33 patients (62.3%) were seizure-free at the end of the follow-up period. The presence of abnormal pathologic finding was strongly associated with postoperative seizure control (p = 0.005). The risk of hemorrhagic complications per electrode was 0.2%. SIGNIFICANCE: In patients who are not considered to be ideal candidates for subdural grids and strips implantation, the SEEG methodology is a safe, useful and reliable alternative option for invasive monitoring in patients with refractory focal epilepsy, providing an additional mean for seizure localization and control in a "difficult to localize" subgroup of patients. PMID- 23016577 TI - Involuntary memory chains: what do they tell us about autobiographical memory organisation? AB - Involuntary memory chains are spontaneous recollections of the past that occur as a sequence of associated memories. This memory phenomenon has provided some insights into the nature of associations in autobiographical memory. For example, it has shown that conceptually associated memories (memories sharing similar content, such as the same people or themes) are more prevalent than general-event associated memories (memories from the same extended event period, such as a trip). This finding has suggested that conceptual associations are a central organisational principle in the autobiographical memory system. This study used involuntary memories chains to gain additional insights into the associative structure of autobiographical memory. Among the main results, we found that general-event associations have higher rates of forgetting than conceptual associations, and in long memory chains (i.e., those with more than two memories) conceptually associated memories were more likely to activate memories in their associative class, whereas general-event associated memories were less likely to activate memories in their associative class. We interpret the results as further evidence that conceptual associations are a major organising principle in the autobiographical memory system, and attempt to explain why general-event associations have shorter lifespans than conceptual associations. PMID- 23016579 TI - Editorial: peptides and proteins in cancer therapy. PMID- 23016578 TI - Renal cancer biomarkers: the promise of personalized care. AB - Significant advances in our understanding of the biology of renal cell carcinoma (RCC) have been achieved in recent years. These insights have led to the introduction of novel targeted therapies, revolutionising the management of patients with advanced disease. Nevertheless, there are still no biomarkers in routine clinical use in RCC. Tools used routinely to determine prognosis have not changed over the past decade; classification remains largely morphology based; and patients continue to be exposed to potentially toxic therapy with no indication of the likelihood of response. Thus the need for biomarkers in RCC is urgent. Here, we focus on recent advances in our understanding of the genetics and epigenetics of RCC, and the potential for such knowledge to provide novel markers and therapeutic targets. We highlight on-going research that is likely to deliver further candidate markers as well as generating large, well-annotated sample banks that will facilitate future studies. It is imperative that promising candidates are validated using these resources, and in subsequent prospective clinical trials, so that future biomarkers may be used in the clinic to personalize patient care. PMID- 23016580 TI - Red blood cell-encapsulated L-asparaginase: potential therapy of patients with asparagine synthetase deficient acute myeloid leukemia. AB - Red blood cell (RBC) encapsulated L-asparaginase is a novel therapeutic for the treatment of asparagine auxotrophic malignancies. The enzyme-loaded red blood cells function as bioreactors to deplete bloodstream substrate. This delivery system provides improved pharmacodynamics with protection from circulating proteolytic enzymes and avoidance of early liver or renal clearance. The "drug" is manufactured with ABO and Rh compatible donor blood when a prescription is received. Because of the industrial scale manufacturing, the "drug" is transfused the day of receipt at the clinical site. Preliminary clinical studies show utility in childhood and adult acute lymphoblastic leukemia. Based on previous studies of applications in different diseases and assessment of different biomarkers, we propose this agent offers a safe and potentially effective treatment for a subset of chemotherapy refractory acute myeloid leukemia patients. The history, chemistry, biology, pharmacology, and relevant clinical experiences with L-asparaginase as well as the properties and proposed protocols with the red cell-encapsulated enzyme are reviewed. PMID- 23016581 TI - Antiangiogenic function of antithrombin is dependent on its conformational variation: implication for other serpins. AB - Endogenous angiogenesis inhibitor that specifically decreases tumor cell proliferation can be used to treat cancer since angiogenesis is required at every step of tumor progression and metastasis. Endothelial cells are the main target for the antiangiogenic therapy because they are non-transformed and easily accessible to angiogenic inhibitors. Antithrombin functions as a principal plasma protein inhibitor of blood coagulation proteinases and belongs to the family of serine protease inhibitors (serpins) which have common mechanism of inhibition. Antithrombin acquires a potent antiangiogenic activity upon conversion of the native molecule to cleaved or latent conformation. Cleaved and latent preparations of bovine and human plasma derived antithrombin inhibits capillary endothelial cell proliferation and the growth of human SK-NAS neuroblastoma and Lewis lung carcinoma tumors in mice but not the native antithrombin's. The native form of antithrombin binds with high affinity to vascular heparan sulfate proteoglycans containing a specific pentasaccharide sequence and it is this cofactor interaction that activates antithrombin to maximal rate of thrombin inhibition. Upon inhibitory complex formation with target proteinases the antithrombin undergoes stressed to relaxed transformation and lose their high affinity for pentasacchride. Low affinity relaxed conformation with reduced heparin binding like cleaved and latent are antiangiogenic but native high affinity heparin binding stressed conformation is not, indicating the critical importance of heparin affinity in antithrombin antiangiogenic function. Based on evidence of interactions of the endothelial cell growth factors bFGF (basic fibroblast growth factor) and VEGF (vascular endothelial cell growth factor) with heparin like molecule in matrix, the possibility of antiangiogenic antithrombin to interfere with endothelial cell growth and angiogenesis through heparin mediated mechanism deserves serious consideration and investigation. It is also possible that cleaved and latent conformations with reduced affinity for heparins can also induce conformational change in the antithrombin which can open an epitope on the antithrombin surface for appropriate interactions on the endothelial surface for better antiangiogenic activity. This review illustrates the potential of antithrombin and other serpin family members as endogenous antiangiogenic proteins. PMID- 23016582 TI - Chemopreventive properties of Peptide Lunasin: a review. AB - Cancer has become one the most common causes of death in developed countries and has been defined as the medical challenge of our times. Accumulating evidence support the notion that prevention can be a major component of cancer control. Chemoprevention, a relatively new and promising strategy to prevent cancer, is defined as the use of natural and/or synthetic substances to block, reverse, or retard the process of carcinogenesis. Plant-based foods, containing significant amounts of bioactive phytochemicals, may provide desiderable health benefits beyond basic nutrition to reduce the process of cancer. In the last few years, proteins and peptides have become one group of nutraceuticals that show potential results in preventing the different stages of cancer including initiation, promotion, and progression. Lunasin is a 43- amino acid peptide identified in soybean and other plants whose anti-carcinogenic activity has been demonstrated both in in vitro and in vivo assays. Moreover, this peptide has been found to exert anti-inflammatory and antioxidant properties that could contribute to its chemopreventive effects. Lunasin's bioactivity and its molecular mechanism(s) of actions are summarized in this review. PMID- 23016583 TI - Synergistic enhancement of cancer therapy using a combination of fusion protein MG7-scFv/SEB and tumor necrosis factor alpha. AB - The fusion protein MG7-scFv/SEB has shown anti-tumor activity on gastric cancer in vitro and in vivo. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine exerting anti-tumor effectiveness in various models and modes of applications. In this study, we explored the combination effects of MG7-scFv/SEB and TNF-alpha in experimental gastric cancer. Both MG7-scFv/SEB and TNF-alpha could effectively result in a significant inhibition of tumor growth in our experimental models when administered alone. What's more, MG7-scFv/SEB synergized with TNF-alpha in further reducing the growth of gastric tumors in gastric-tumor-bearing rats as compared to mono therapy. Additionally, the survival rate of gastric-tumorbearing rats administrated with combined therapy was significantly higher than that of rats treated with MG7-scFv/SEB or TNF-alpha. These results indicate that combined therapy with MG7-scFv/SEB and TNF-alpha is a promising strategy for human cancer therapy. PMID- 23016584 TI - Immunomodulatory lactoferrin in the regulation of apoptosis modulatory proteins in cancer. AB - Lactoferrin (Lf), an iron binding ~80 kDa glycoprotein is a well characterized multifunctional protein found to be present in mammalian milk and in most exocrine secretions. Besides Lf's important physiological roles in the process of iron homeostasis, iron transportation and sequestration, it is well known for its properties such as anti-microbial, antiviral anti-inflammatory and immunomodulatory functions. In the recent decade, Lf has gained significant attention for its future potential use as a safer natural food (bovine milk) derived anti-cancer therapeutic. With regards to Lf's chemopreventive effects in targeting carcinogenesis, both animal and human studies have widely reported its immunomodulatory properties to play a significant role. The deregulation of apoptosis (programmed cell death) mechanisms has not only major implications for the development of uncontrolled tumour growth but evasion of apoptosis is also an important factor affecting drug resistance and radioresistance in cancer. With the exception of few studies, the molecular basis by Lf treatment remains unclear. In this review, by addressing the main features of Lf's structure and function we discuss the recent developments in delineating the therapeutic mechanisms of Lf and its effects on the proteins and receptors modulating apoptosis. PMID- 23016585 TI - Isolation of a phytase with distinctive characteristics from an edible mushroom, Pleurotus eryngii. AB - From the fresh fruiting bodies of the mushroom Pleurotus eryngii a phytase with a molecular mass of 14 kDa was isolated. The isolation protocol entailed ion exchange chromatography on DEAE-cellulose and CM-cellulose, affinity chromatography on Affi-gel blue gel, and ion exchange chromatography on Q Sepharose. The phytase was unadsorbed on DEAE-cellulose, CM-cellulose and Affi gel blue gel, and adsorbed on Q-Sepharose. It appeared as a single band in SDSPAGE. It exhibited maximal activity at around 37 degrees C. Its activity underwent little changes over the range of pH 3.0 to 9.0. The aforementioned characteristics are different from those of animal, plant and bacterial phytases. The low molecular mass and pH stability of P. eryngii phytase also distinguish it from mushroom phytases and other fungal phytases reported earlier. The purified enzyme exhibited a broad substrate specificity on a range of phosphorylated compounds, and the phytase demonstrated the N-terminal sequence ADNVYRHDNN which shows little homology to known phytases. It inhibited proliferation of human nasopharyngeal carcinoma CNE2 cells, hepatoma HepG2 cells and breast cancer MCF7 cells with an IC(50) of 1.9 MUM, 2.9 MUM, and 1.0 MUM, respectively. PMID- 23016586 TI - Anticancer peptides and proteins: a panoramic view. AB - Despite progress in understanding carcinogenesis, cancer is still a major cause of morbidity and mortality worldwide. Treatment is complicated by the resistance to chemotherapeutics acquired by tumors, ability to repair damaged DNA, alteration of the interaction between drug and its target, and defects in the machinery that leads to apoptosis. The development of novel therapies based on biologically active peptides, especially antimicrobial peptides (AMPs), and proteins has emerged as a new strategy to defeat cancer. PMID- 23016587 TI - Fungal proteins with antiproliferative and anticancer activities. AB - Fungi produce a variety of proteins with antiproliferative activity toward tumor cells and anticancer activity in tumor bearing mice. The aforementioned fungal proteins include ribonucleases, antifungal proteins, ubiquitin-like peptides, ribosome inactivating proteins, hemolysins, hemagglutinins/lectins, laccases, and protein-bound polysaccharopeptides. PMID- 23016588 TI - Type I interferons: ancient peptides with still under-discovered anti-cancer properties. AB - Type I interferons (IFNs) represent a group of cytokines that act through a common receptor composed by two chains (IFNAR-1 and IFNAR-2). Several in vitro and in vivo studies showed a potent antitumor activity induced by these cytokines. IFN-alpha, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. IFN-alpha, is currently the most used cytokine in the treatment of cancer. However, the potential anti-tumour activity of IFN-alpha is limited by the activation of tumour resistance mechanisms. This article reviews the current knowledge about the antitumor activity of type I IFNs, focusing on new potential strategies able to strengthen the antitumor activity of these cytokines. PMID- 23016589 TI - lGnRH-III -- a promising candidate for anticancer drug development. AB - Lamprey gonadotropin-releasing hormone-III (lGnRH-III; Glp-His-Trp-Ser-His-Asp Trp-Lys-Pro-Gly-NH2), a native isoform of human GnRH (GnRH-I), was initially isolated from the brain of the sea lamprey (Petromyzon marinus). It is a weak GnRH agonist, which exerts a direct antiproliferative effect on cancer cells and has an insignificant LH and FSH releasing potency in mammals. These features reveal the advantages of lGnRH-III and its derivatives for use in cancer therapy. Here we give an overview of various strategies to increase the antitumor activity of lGnRH-III, such as amino acid replacement, cyclization, dimerization and conjugation to polymers or to chemotherapeutic agents. In vitro and in vivo antitumor activity of lGnRH-III based compounds was demonstrated both on hormone dependent and independent tumors. PMID- 23016590 TI - Protein serine/threonine phosphotase-1 is essential in governing normal development of vertebrate eye. AB - Protein serine/threonine phosphatase-1 (PP-1) is one of the key enzymes responsible for dephosphorylation in vertebrates. Protein dephosphorylation via PP-1 is implicated in many different biological processes including gene expression, cell cycle control, transformation, neuronal transmission, apoptosis, autophage and senescence. However, whether PP-1 directly controls animal development remains to be investigated. Here, we present direct evidence to show that PP-1 plays an essential role in regulating eye development of vertebrates. Using goldfish as a model system, we have shown the following novel results. First, inhibition of PP-1 activity leads to death of a majority of the treated embryos, and the survived embryos displayed severe phenotype in the eye. Second, knockdown of each catalytic subunit of PP-1 with morpholino oligomers leads to partial (PP-lalpha knockdown) or complete (PP-lbeta or PP-lgamma knockdown) death of the injected embryos. The survived embryos from PP-1alpha knockdown displayed clear retardation in lens differentiation. Finally, overexpression of each subunit of PP-1 also causes death of majority of the injected embryos and leads to abnormal development of goldfish eye. Mechanistically, Pax-6 is one of the major downstream targets mediating the effects of PP-1 function since the eye phenotype in Pax-6 knockdown fish is similar to that derived from overexpression of PP-1. Together, our results for the first time provide direct evidence that protein phosphatase-1 plays a key role in governing normal eye formation during goldfish development. PMID- 23016591 TI - Human amnion-derived cells as a reliable source of stem cells. AB - Human amnion-derived cells possess great potential for the repair of human neural disorders, and recent studies have broadened the spectrum for applications because they exhibit the characteristics of multipotent stem cells. These cells express embryonic stem cell markers such as Oct4, Nanog, Sox2, SSEA-3, SSEA-4 and Rex1, and can differentiate into multiple primary germ layers both in vitro and in vivo. Moreover, induced pluripotent stem cells have been generated from amnion derived cells by virus-mediated delivery of three or four pluripotency-relating transcription factors or by the introduction of only one transcription factor with electroporation. Because human amnion-derived cells are readily available, less likely to contain genetic aberrations and can be reprogrammed earlier and more efficiently than differentiated cells, they can be ideal resources as the donor pluripotent stem cells for therapeutic purposes. We discuss here the highlights of recent studies and potential applications of human amnion-derived multipotent stem cells to stem cell biology as well as to regenerative medicine in the field of aging, heart disease, diabetes and neural disorders. PMID- 23016593 TI - Androgen actions on the human hair follicle: perspectives. AB - Androgens stimulate beard growth but suppress hair growth in androgenetic alopecia (AGA). This condition is known as 'androgen paradox'. Human pilosebaceous units possess enough enzymes to form the active androgens testosterone and dihydrotestosterone. In hair follicles, 5alpha-reductase type 1 and 2, androgen receptors (AR) and AR coactivators can regulate androgen sensitivity of dermal papillae (DP). To regulate hair growth, androgens stimulate production of IGF-1 as positive mediators from beard DP cells and of TGF-beta1, TGF-beta2, dickkopf1 and IL-6 as negative mediators from balding DP cells. In addition, androgens enhance inducible nitric oxide synthase from occipital DP cells and stem cell factor for positive regulation of hair growth in beard and negative regulation of balding DP cells. Moreover, AGA involves crosstalk between androgen and Wnt/beta-catenin signalling. Finally, recent data on susceptibility genes have provided us with the impetus to investigate the molecular pathogenesis of AGA. PMID- 23016594 TI - Cadmium(II) complex formation with selenourea and thiourea in solution: an XAS and 113Cd NMR study. AB - The complexes formed in methanol solutions of Cd(CF(3)SO(3))(2) with selenourea (SeU) or thiourea (TU), for thiourea also in aqueous solution, were studied by combining (113)Cd NMR and X-ray absorption spectroscopy. At low temperature (~200 K), distinct (113)Cd NMR signals were observed, corresponding to CdL(n)(2+) species (n = 0-4, L = TU or SeU) in slow ligand exchange. Peak integrals were used to obtain the speciation in the methanol solutions, allowing stability constants to be estimated. For cadmium(II) complexes with thione (C?S) or selone (C?Se) groups coordinated in Cd(S/Se)O(5) or Cd(S/Se)(2)O(4) (O from MeOH or CF(3)SO(3)(-)) environments, the (113)Cd chemical shifts were quite similar, within 93-97 ppm and 189-193 ppm, respectively. However, the difference in the chemical shift for the Cd(SeU)(4)(2+) (578 pm) and Cd(TU)(4)(2+) (526 ppm) species, with CdSe(4) and CdS(4) coordination, respectively, shows less chemical shielding for the coordinated Se atoms than for S, in contrast to the common trend with increasing shielding in the following order: O > N > Se > S. In solutions dominated by mono- and tetra-thiourea/selenourea complexes, their coordination and bond distances could be evaluated by Cd K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy. At ~200 K and high excess of thiourea, a minor amount (up to ~30%) of [Cd(TU)(5-6)](2+) species was detected by an upfield shift of the (113)Cd NMR signal (up to 423 ppm) and an amplitude reduction of the EXAFS oscillation. The amount was estimated by fitting linear combinations of simulated EXAFS spectra for [Cd(TU)(4)](2+) and [Cd(TU)(6)](2+) complexes. At room temperature, [Cd(TU)(4)](2+) was the highest complex formed, also in aqueous solution. Cd L(3)-edge X-ray absorption near edge structure (XANES) spectra of cadmium(II) thiourea solutions in methanol were used to follow changes in the CdS(x)O(y) coordination. The correlations found from the current and previous studies between (113)Cd NMR chemical shifts and different Cd(II) coordination environments are generally useful for evaluating cadmium coordination to thione-containing or Se-donor ligands in biochemical systems or for monitoring speciation in solution. PMID- 23016595 TI - A cadaver study comparing two approaches for performing maxillary nerve block in dogs. AB - OBJECTIVE: To compare the success by inexperienced anaesthetists of using a modified infraorbital approach to the maxillary nerve with the traditional percutaneous approach. STUDY DESIGN: Prospective, randomized, blinded controlled study. ANIMALS: Heads from 37 euthanized Beagle and Beagle cross dogs. METHODS: Four anaesthetists were recruited to perform two different approaches to block the maxillary nerve of the cadavers. The infraorbital (I) approach advanced an intravenous catheter along the infraorbital canal. Earlier measurements from scans of similar heads were used to assess suitable catheter size. The percutaneous (P) approach introduced a needle percutaneously just below the ventral border of the zygomatic arch. The side of the head where the technique was to be performed was randomized. A total volume of 0.5 mL methylene blue was injected in each approach. After completion of injections, head dissections were performed by an investigator unaware of the approach used and staining of the maxillary and pterygopalatine nerves was evaluated. Chi squared analysis examined the relationship between the methods (p < 0.05). Complications related to the techniques, such as intravascular/intraneural injection and location of the dye, were evaluated macroscopically. RESULTS: Maxillary nerve staining >6 mm was found in 64.9% (I) versus 21.6% (P) attempts; staining <6 mm was found in 27% (I) versus 21.6% (P); and no nerve staining 8.1% (I) versus 56.8% (M). Pterygopalatine nerve staining was found in 70% (I) versus 21% (P). The infraorbital approach demonstrated significantly higher maxillary and pterygopalatine nerve staining compared to the percutaneous approach (p = 0.001 for both nerves). No evidence of intravascular/intraneural injections was found. CONCLUSION AND CLINICAL RELEVANCE: The infraorbital approach was more successful than the percutaneous approach when performed by inexperienced anaesthetists. No macroscopic complications were observed. PMID- 23016596 TI - Electrorheological operation of low-/high-permittivity core/shell SiO2/Au nanoparticle microspheres for display media. AB - In this study, we synthesized core/shell structures comprising monodisperse 3-MUm SiO(2) microspheres and gold nanoparticles (AuNPs, ca. 6.7 nm) as the core and shell components, respectively. Using a layer-by-layer cross-linking process with a dithiol cross-linking agent, we prepared low-permittivity AuNP-encapsulated high-permittivity SiO(2) core/shell microspheres with variable AuNP shell thicknesses. The dispersivity of the microspheres in solution was enhanced after grafting poly(ethylene glycol) monomethyl ether thiol (PEG-SH) onto the AuNP layer on the SiO(2) microspheres. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) images revealed sesame ball-like structures for these SiO(2)@AuNP@PEG microspheres. We encapsulated aqueous dispersions of these SiO(2)@AuNP microspheres into sandwich structured displays (SSDs) to investigate their electrorheological properties, observing reversibly electroresponsive transmittance that is ideally suited for display applications. Increasing the thickness of the AuNP layer dramatically enhanced the stringing behavior of the SiO(2) microspheres, resulting in increased transmittance of the SSD. The response time of the electroresponsive electrorheological fluids also decreased significantly after modifying the SiO(2) with the AuNP layers. The effective permittivities of these composites could be predicted from the real (epsilon) and imaginary (epsilon) parts of the Clausius-Mossotti formalism. PMID- 23016597 TI - Effects of antenatal recognition and follow-up on perinatal outcomes in small-for gestational age infants delivered after 36 weeks. AB - OBJECTIVE: To compare perinatal outcomes of late small-for-gestational age (SGA, birthweight <10th percentile) infants, according to antenatal recognition. DESIGN: Retrospective study. SETTING: Tertiary referral center. POPULATION: All singleton pregnancies with SGA (birthweight <10th percentile) infants born >=36 weeks' gestation from January 2007 to April 2009. METHODS: Chart review of 771 pregnancies. SGA infants identified prior to delivery (group A) were compared with those not identified (group B). MAIN OUTCOME MEASURES: Mode of delivery, perinatal complications, admission to neonatal intensive care unit (NICU). In group A, receiver operating characteristic (ROC) analysis and area under the curve (AUC) of antenatal tests to predict NICU admission were calculated. RESULTS: In 17% of infants, SGA was recognized before birth (group A), whereas in 83% it was recognized only at birth (group B). Infants with the most severe degree of SGA (birthweight <3rd percentile) were more frequently diagnosed antenatally (30%). Admission to NICU (14 vs. 3%, p < 0.001) and cesarean delivery (42 vs. 26%; p < 0.001) were more likely in group A. Adverse outcomes related to hypoxia were all observed in group B, but the difference was not significant. In antenatally detected fetuses a combination of fetal abdominal circumference, umbilical artery pulsatility index and middle cerebral artery pulsatility index z scores was useful for prediction of NICU admission (AUC = 0.94). CONCLUSION: Antenatal recognition of late SGA may improve perinatal outcomes. However, admission to neonatal intensive care and cesarean delivery were more frequent among SGA infants recognized antenatally. PMID- 23016598 TI - A comparison of the effects of nicotinamide and progesterone on functional recovery of cognitive behavior following cortical contusion injury in the rat. AB - The primary goal of this study was to compare clinically relevant doses of progesterone and nicotinamide within the same injury model. Progesterone has been shown to reduce edema and inflammation and improve functional outcomes following brain injury. Nicotinamide has also been shown to be an effective neuroprotective agent in a variety of neurological injury models. In the current study, nicotinamide was administered beginning 4 h post-cortical contusion injury (CCI) with a loading dose (75 mg/kg, i.p.) combined with continuous infusion (12 mg/h/kg, s.c.) for 72 h post-injury. Progesterone was administered beginning 4 h post-CCI at a dose of 10 or 20 mg/kg, i.p. every 12 h for 72 h. This resulted in the following groups: Injured-nicotinamide treated, Injured-progesterone-10 treated, Injured-progesterone-20 treated, Injured-vehicle treated, and Sham. Functional recovery was assessed with two spatial memory tasks in the Morris water maze (MWM) the acquisition of a reference memory task and a reversal learning task. Neuropathological assessments were conducted in the cortex and hippocampus. It was found that both progesterone (10 mg/kg) and nicotinamide improved reference memory acquisition and reversal learning in the MWM compared with vehicle treatment. The lower dose of progesterone and nicotinamide also reduced tissue loss in the injured cortex and ipsilateral hippocampus compared with vehicle. The beneficial effects of progesterone appear to be dose dependent with the lower 10 mg/kg dose producing significant effects that were not observed at the higher dose. Direct comparison between nicotinamide and low dose progesterone appears to suggest that both are equally effective. The general findings of this study suggest that both nicotinamide and progesterone produce significant improvements in recovery of function following CCI. PMID- 23016599 TI - Directed growth of mixed self-assembled monolayers on a nanostructured template: a step toward the patterning of functional molecular domains. AB - We report on the elaboration of networks of SAM domains. More precisely, we show the feasibility in making arrays of functionalized alkylthiol nanodomains bordered with an alkylthiol matrix. The several step process relies on the replication of a self-organized cobalt array grown on Au(111). The SAM process takes place in solution. The chemical affinity of thiol for gold leads to the selective grafting of molecules on the surface. After having removed the inorganic array, alkylthiol functionalized with a terthiophene unit is grafted in free gold areas. The efficiency of the replication of the initial template depends on the stability of the first SAM. We also investigate electronic tunnel transport through oligothiophene islands with the STM. The variation of the molecular contrast with bias voltage between the two molecular species indicates a potential resonant tunneling mechanism through the orbitals of the aromatic compound. PMID- 23016600 TI - Characterization and evolution of exposure to volatile organic compounds in the Spanish shoemaking industry over a 5-year period. AB - This study measured inhalation exposure to 13 volatile organic compounds (VOCs) among workers in the leatherwear industry in Spain, examined the changes in those exposures over a 5-year period, and documented local exhaust ventilation practices that affected exposure. In collaboration with an occupational risk prevention company, air samples were collected from 849 workers' personal breathing zones using personal air pumps with activated charcoal tubes. VOCs were analyzed using a GC/MS-optimized method modified in our laboratory from that proposed by Spanish authorities (INSHT). Airborne concentrations were compared with occupational exposure limit (OEL) values from the European authorities. The most frequently detected VOCs were acetone (98.1%), toluene (94.8%), n-hexane (71.2%) and other C6-C7 branched alkyl hydrocarbons (97.5%). Other frequently detected VOCs were MEK (64.9%), ethylacetate (60.7%), and cyclohexane (29.3%). Benzene was detected in 24.6% of samples. Although all the samples were taken while workers performed tasks judged to have the highest VOC exposure potential, only 14% of samples showed excessive aggregate exposure, and chemical-specific OELs were exceeded in a relatively small number of cases: 7.2% for n-hexane, 2.8% for toluene, 0.6% for acetone, and 0.4% for hexane isomers. Over the study period, a diminished use of n-hexane in solvent formulations and an increased use of branched hexane and heptane isomers were observed. Six factors relating to work location conditions and types were evaluated. Most high-exposure cases were associated with three task types. The presence of local exhaust ventilation was an important exposure control, but significant exposures despite the use of local exhaust were observed. Although n-hexane exposures significantly decreased over the study period, the overall level of VOC exposure did not decrease. More effective exposure prevention measures need to be implemented. PMID- 23016601 TI - Boosting immune response with the invariant chain segments via association with non-peptide binding region of major histocompatibility complex class II molecules. AB - BACKGROUND: Based on binding of invariant chain (Ii) to major histocompatibility complex (MHC) class II molecules to form complexes, Ii-segment hybrids, Ii-key structure linking an epitope, or Ii class II-associated invariant chain peptide (CLIP) replaced with an epitope were used to increase immune response. It is currently unknown whether the Ii-segment cytosolic and transmembrane domains bind to the MHC non-peptide binding region (PBR) and consequently influence immune response. To investigate the potential role of Ii-segments in the immune response via MHC II/peptide complexes, a few hybrids containing Ii-segments and a multiepitope (F306) from Newcastle disease virus fusion protein (F) were constructed, and their binding effects on MHC II molecules and specific antibody production were compared using confocal microscopy, immunoprecipitation, western blotting and animal experiments. RESULTS: One of the Ii-segment/F306 hybrids, containing ND (Asn-Asp) outside the F306 in the Ii-key structure (Ii key/F306/ND), neither co-localized with MHC II molecules on plasma membrane nor bound to MHC II molecules to form complexes. However, stimulation of mice with the structure produced 4-fold higher antibody titers compared with F306 alone. The two other Ii-segment/F306 hybrids, in which the transmembrane and cytosolic domains of Ii were linked to this structure (Cyt/TM/Ii-key/F306/ND), partially co localized on plasma membrane with MHC class II molecules and weakly bound MHC II molecules to form complexes. They induced mice to produce approximately 9-fold higher antibody titers compared with F306 alone. Furthermore, an Ii/F306 hybrid (F306 substituting CLIP) co-localized well with MHC II molecules on the membrane to form complexes, although it increased antibody titer about 3-fold relative to F306 alone. CONCLUSIONS: These results suggest that Ii-segments improve specific immune response by binding to the non-PBR on MHC class II molecules and enabling membrane co-localization with MHC II molecules, resulting in the formation of relatively stable MHC II/peptide complexes on the plasma membrane, and signal transduction. PMID- 23016602 TI - Effects of salt stress and rhizobial inoculation on growth and nitrogen fixation of three peanut cultivars. AB - Increasing soil salinity represents a major constraint for agriculture in arid and semi-arid lands, where mineral nitrogen (N) deficiency is also a frequent characteristic of soils. Biological N fixation by legumes may constitute a sustainable alternative to chemical fertilisation in salinity-affected areas, provided that adapted cultivars and inoculants are available. Here, the performance of three peanut cultivars nodulated with two different rhizobial strains that differ in their salt tolerance was evaluated under moderately saline water irrigation and compared with that of N-fertilised plants. Shoot weight was used as an indicator of yield. Under non-saline conditions, higher yields were obtained using N fertilisation rather than inoculation for all the varieties tested. However, under salt stress, the yield of inoculated plants became comparable to that of N-fertilised plants, with minor differences depending on the peanut cultivar and rhizobial strain. Our results indicate that N fixation might represent an economical, competitive and environmentally friendly choice with respect to mineral N fertilisation for peanut cultivation under moderate saline conditions. PMID- 23016603 TI - Child- and family impacts of infants' oral conditions in Tanzania and Uganda-- a cross sectional study. AB - BACKGROUND: Early childhood dental caries impacts on the quality of life of children and their families. This study set out to assess the psychometric properties of an oral health related quality of life, OHRQoL, measure, based on items emanating from the Child-and Family impact sections of the Early Childhood Oral Health Impact Scale (ECOHIS), in Kiswahili and Luganda speaking communities. It was hypothesized that the Child- and Family impact scores would discriminate between children with and without clinically defined dental problems and reported good and bad oral health. METHOD: Kiswahili and Luganda versions of the Child- and Family impact scores were derived through translation in pilot studies. Totals of 1221 and 816 child/caretaker pairs attending health care facilities in Manyara, Tanzania and Kampala, Uganda, were recruited into the study. After caretakers completed the interview, their children underwent oral clinical examination. RESULTS: Internal consistency reliability (Cronbach's alpha) was > 0.80 with respect to the Child impact score and 0.79 regarding the Family impact score. Multiple variable logistic- and Poisson regression analyses revealed that the Kiswahili and Luganda versions of the Child- and Family impact score associated in the expected direction with child's oral diseases as with their reported health and oral health status. In Manyara, multiple logistic regression revealed that the ORs of reporting Child impacts were 1.8 (95% CI 1.0-3.4) and 2.2 (1.3-3.4) among caretakers who confirmed linear hypoplasia and teething symptoms, respectively. In Kampala, the ORs for reporting Child impacts were 2.3 (95% CI 1.3-3.9), 1.7 (95% CI 1.1-2.5), 1.6 (95% CI 1.2-2.3) and 2.7 (95% CI 1.3 5.8) among those who confirmed teeth present, hypoplasia, teething symptoms and tooth bud extractions, respectively. The odds ratios for reporting Family impacts were 2.7 (95% CI 1.5-4.7), 1.5 (95% CI 1.1- 2.1) and 4.6 (95% CI 2.0-10.7) if reporting LEH, teething symptoms and toothbud experience, respectively. CONCLUSION: The Child and Family impact scores demonstrated acceptable internal consistency reliability and reproducibility whereas the discriminative validity was more ambiguous. The OHRQoL scores should be developed further and tested among Kiswahili and Luganda speaking caretakers. PMID- 23016604 TI - Facial expression influences recognition memory for faces: robust enhancement effect of fearful expression. AB - Memory for faces is important for social interactions. However, it is unclear whether negative or positive expression affects recollection and familiarity for faces and whether the effect can be modulated by retention interval. Two experiments examined the effect of emotional expression on recognition for faces at two delay conditions. In Experiment 1 participants viewed neutral, positive, and negative (including fearful, sad, angry etc.) faces and made gender discrimination for each face. In Experiment 2 they viewed and made gender discrimination for neutral, positive, and fearful faces. Following the incidental learning they were randomly assigned into the immediate and 24-hour (24-h) delay conditions. Findings from the two experiments are as follows: (1) In the immediate and 24-h delay conditions overall recognition and recollection for negative faces (fearful faces in Experiment 2) were better than for neutral faces and positive faces. (2) In the immediate and 24-h delay conditions recollection and familiarity for positive faces was equivalent to recollection for neutral faces. (3) The enhancement effect of fearful expression on recognition and recollection was not due to greater discriminability between the old and new faces in the fearful category. The results indicate that recognition and recollection for faces and the enhancement effect of fearful expression is robust within 24 hours. PMID- 23016605 TI - ONIOM and ab-initio calculations on the mechanism of uncatalyzed peptide bond formation. AB - Finding a proper transition structure for the peptide bond formation process can lead one to a better understanding of the role of ribosome in catalyzing this reaction. Using computer simulations, we performed the potential energy surface scan on the ester bond dissociation of P-site aminoacyl-tRNA and the peptide bond formation of P-site and A-site amino acids. The full fragments of initiator tRNA(i)(met) and elongator tRNA(phe) are attached to both cognate and non-cognate amino acids as the P-site substrate. The A-site amino acid for all four calculations is methionine. We used ONIOM calculations to reduce the computational cost. Our study illustrates the reduced rate of peptide bond formation for misacylated tRNA(i)(met) in the absence of ribosomal bases. The misacylated elongator tRNA(phe), however, did not show any difference in its PES compared with that for the phe-tRNA(phe). This demonstrates the structural specification of initiator tRNA(i)(met) for the amino acids side chain. PMID- 23016606 TI - The impact of endoscopic ultrasound findings on clinical decision making in Barrett's esophagus with high-grade dysplasia or early esophageal adenocarcinoma. AB - The clinical utility of endoscopic ultrasound (EUS) for staging patients with Barrett's esophagus and high-grade dysplasia (HGD) or intramucosal carcinoma (IMC) prior to endoscopic therapy is unclear. We performed a retrospective analysis of patients with HGD or IMC referred to an American medical center for endoscopic treatment between 2004 and 2010. All patients had pretreatment staging by EUS. We examined the frequency that EUS findings consistent with advanced disease (tumor invasion into the submucosa, lymph node involvement, or regional metastasis) led to a change in management. The analysis was stratified by nodularity and pre-EUS histology. We identified one hundred thirty-five patients with HGD (n = 106, 79%) or IMC (n = 29, 21%) had staging by EUS (79 non-nodular, 56 nodular). Pathologic lymph nodes or metastases were not found by EUS. There were no endosonographic abnormalities noted in any patient with non-nodular mucosa (0/79). Abnormal EUS findings were present in 8/56 patients (14%) with nodular neoplasia (five IMC, three HGD). Endoscopic mucosal resection was performed in 44 patients with a nodule, with 13% (6/44) having invasive cancer. In nodular neoplasia, the EUS and endoscopic mucosal resection were abnormal in 24% (5/21) and 40% (6/15) of those with IMC and 9% (3/35) and 0% (0/29) of those with HGD, respectively. In this study we found that EUS did not alter management in patients with non-nodular HGD or IMC. Because the diagnostic utility of EUS in subjects with non-nodular Barrett's esophagus is low, the value of performing endoscopic mucosal resection in this setting is questionable. For patients with nodular neoplasia, resection of the nodule with histological examination had greater utility than staging by EUS. PMID- 23016607 TI - Effect of three different storage media on survival of periodontal ligament cells using collagenase-dispase assay. AB - AIM: To evaluate and compare the efficacy of propolis, egg albumen and Hank's balanced salt solution (HBSS) in maintaining the viability of human periodontal ligament (PDL) cells using a collagenase-dispase assay. METHODOLOGY: Fifty-five freshly extracted human teeth were divided into three experimental (HBSS, egg albumen and propolis) and two control groups. Fifteen teeth per experimental group were stored dry for 30 min and then immersed for 45 min in one of the three experimental media. The positive and negative controls corresponded to 0-min and 1-h dry time, respectively, with five teeth per control group. The teeth were then treated with collagenase II and dispase II for 30 min and labelled with 0.4% trypan blue for determination of viability. The number of viable cells was counted with a haemocytometer and analysed statistically by anova and post hoc Tukey HSD test. RESULTS: Statistical analysis demonstrated there was no significant difference between HBSS, egg albumen and propolis in maintaining cell viability. CONCLUSION: Egg albumen and propolis may be able to maintain PDL cell viability as well as HBSS. PMID- 23016608 TI - Prevalence and patterns of prenatal use of traditional medicine among women at selected harare clinics: a cross-sectional study. AB - BACKGROUND: Prenatal use of traditional medicine or complementary and alternative medicine is widespread globally despite the lack of evidence of the effectiveness of these therapeutic options. Documentation on the prevalence and patterns of this maternal practice in the Zimbabwean setting was also lacking. METHODS: A cross sectional survey of 248 women at selected health centres in Harare was carried out to address the need for such data using an interviewer-administered questionnaire. RESULTS: Fifty-two (52%) (95% C.I. 44%-60%) of the participants reported to have used at least one traditional medicine intervention during the third trimester of their most recent pregnancy to induce labour, avoid perineal tearing and improve the safety of their delivery process. The study found prenatal use of traditional medicine to be significantly associated with nulliparity and nulligravidity. Such practice was also significant among participants residing in a particular high density suburb located in close proximity to informal traders of traditional medicines. Prenatal traditional medicine use was not significantly linked to experiencing an obstetrics-related adverse event. Instead, participants who reported not using any traditional medicine during pregnancy reported experiencing significantly more adverse events, mainly perineal tearing during delivery. CONCLUSIONS: The practice of prenatal use of traditional medicine was significant in the study setting, with a prevalence of 52%. A variety of products were used in various dosage forms for differing indications. Nulliparity, nulligavidity and possible accessibility of these products were the factors significantly associated with prenatal use of traditional medicine. Prenatal use of traditional medicine was not significantly associated with any obstetric adverse event. PMID- 23016610 TI - Prematurity and twinning. AB - AIM OF THE STUDY: Newborns from multiple pregnancies are increasing in number and demonstrate a higher perinatal morbidity and mortality compared to singletons. Prematurity is the main reason for most neonatal diseases in twins, but other variables may play a role and their prenatal evaluation may improve the overall outcome. MAIN FINDINGS: Prematurity is six times more frequent in twins and therefore birth weight is significantly lower compared to singletons. Thus, twins are more exposed to prematurity related diseases (respiratory, cardiovascular, infectious, etc.) and to long-term complications (especially neurological disabilities). RESULTS: It is very difficult to estimate the increased risk of neonatal morbidity related to twinning independently to the increased risk of prematurity and therefore to interpret data on morbidity rates, in particular regarding the neurodevelopmental outcome. CONCLUSION: Prevention of preterm birth is a primary goal in managing multiple pregnancies, together with prophylaxis with corticosteroids in order to improve foetal lung maturity. Accurate risk assessment strategies and adequate obstetrical-neonatological management of multiple pregnancies may reduce the increasing need for neonatal intensive care and for health resources in the long-term follow-up that has been observed over the last decades. PMID- 23016611 TI - Caffeine citrate: when and for how long. A literature review. AB - The efficacy of caffeine in an episode of Apnoea of Prematurity (AOP) has been known for over thirty years. Its use over long periods of time has not only found it to be manageable within the field of neonatology, but it has also been found to have other favourable actions, such as reducing the incidence of extubation failure, preventing Bronchopulmonary Dysplasia (BPD), reducing the need for Patent Ductus Arteriosus treatment and the beneficial effect it has on Retinopathy of Prematurity. Recent in vitro trials have highlighted the neuroprotective role that caffeine plays, which has already partly been observed from in vivo trials. Just recently, caffeine citrate has become a "label" drug and it would be beneficial if more studies could confirm the more significant effects it has on the more severe conditions of prematurity. PMID- 23016612 TI - Current strategies for treating infants with severe bronchopulmonary dysplasia. AB - Advances in neonatal intensive care have markedly improved survival rates for infants born at a very early lung development stage (<26 weeks gestation). In these premature infants, even low inspired oxygen concentrations and gentle ventilatory methods may disrupt distal lung growth, a condition described as "new" bronchopulmonary dysplasia (BPD). BPD usually develops into a mild form, with only few infants requiring ventilator support and oxygen supplementation at 36 weeks post-conception. No magic bullets exist for treating infants with established severe BPD. Current management of the disease aims at maintaining an adequate gas exchange while promoting optimal lung growth. Prolonged oxygen therapy and ventilator support through nasal cannulae or a tracheotomy are often required to maintain blood gases. Short-course, low-dose corticosteroids may improve lung function and accelerate weaning from oxygen and mechanical ventilation. Pulmonary hypertension is a major complication in infants with severe BPD. Pulmonary vasodilators, such as sildenafil followed by bosentan, may improve the oxygenation and pulmonary outcome. PMID- 23016613 TI - Early onset sepsis in very low birth weight newborn infants. AB - Early onset sepsis (EOS) is a severe problem affecting very low birth weight (VLBW) infants and is associated with a threefold increased risk of mortality. Although advances in perinatal care have led to improved survival of VLBW infants over recent decades, survival without major neonatal morbidity has not increased. The authors reviewed the current literature on EOS, focusing on the peculiarities concerning risk factors, etiology, diagnosis, treatment and outcome in very low birth weight infants, and on the recent advances in the management of this condition. PMID- 23016614 TI - Oxygen administration for the resuscitation of term and preterm infants. AB - Oxygen has been widely used in neonatal resuscitation for about 300 years. In October 2010, the International Liaison Committee on Neonatal Resuscitation released new guidelines. Based on experimental studies and randomized clinical trials, the recommendations on evaluation and monitoring of oxygenation status and oxygen supplementation in the delivery room were revised in detail. They include: inaccuracy of oxygenation clinical assessment (colour), mandatory use of pulse oximeter, specific saturation targets and oxygen concentrations during positive pressure ventilation in preterm and term infants. In this review, we describe oxygen management in the delivery room in terms of clinical assessment, monitoring, treatment and the gap of knowledge. PMID- 23016609 TI - Survey of neonatal respiratory support use in very preterm infants in Italy. AB - BACKGROUND: Respiratory support in very preterm infants is often a life-saving procedure and several techniques are available. There is lack of data on the current use of these techniques. METHODS AND AIM: We analyzed a cohort of infants <30 weeks gestation or < 1501 g birth weight, enrolled in the Italian Neonatal Network in 2009 and 2010 (n = 8297, mean gestation = 29.3 weeks, mean birth weight = 1089 g) to ascertain the use of several techniques. We also conducted a questionnaire survey of all neonatal units adhering to the Italian Neonatal Network, inquiring about preferred methods of respiratory support. RESULTS: Conventional ventilation was used in 53% of these infants, high frequency ventilation in 15.8%, CPAP in 71.6%, and surfactant in 56.2%. Huge variations were observed between hospitals for all techniques studied. The survey of centres showed that all respondents considered non-invasive ventilation the first intention treatment for these infants. In case of need of tracheal intubation and mechanical ventilation, two hospitals said they used IPPV/IMV; 20 synchronized IPPV/IMV; 25 "volume guarantee"; and 10 hospitals used HFV as a first intention treatment (in five hospital for all infants, and in other five hospitals, depending upon birth weight/gestation. CONCLUSIONS: This study provides large scale, up to date results of the current methods of respiratory support in very preterm infants in Italy. Huge variations between hospitals, only partly explained by the paucity of evidence-based data, are apparent. These differences point to the possibility of implementing "potentially better practices" with the aim of reducing unwanted, physician-related variation. PMID- 23016615 TI - Is breastfeeding duration influenced by maternal attitude and knowledge? A longitudinal study during the first year of life. AB - OBJECTIVE: To discuss the duration and types of breastfeeding and to identify the factors associated with the early introduction of formula milk. MATERIALS AND METHODS: This longitudinal study was conducted in the largest birthing centre of Turin. 562 mother-infant pairs were selected randomly and enrolled from among all the births that occurred in our Hospital from January to December 2009. Data was collected by means of a questionnaire filled out by the researcher during a face to-face interview at mother's bed side during her hospital stay. This questionnaire included data regarding maternal socio-demographic, biomedical and hospital-related characteristics and some questions regarding family support, maternal attitude and current knowledge on breastfeeding. Mothers were interviewed by telephone at 1, 3, 6 and 12 months postpartum using the 24-h recall technique and definitions recommended by the WHO to investigate the type of breastfeeding adopted. RESULTS: At the age of 6 months only 8.9% of the infants involved were still exclusively breastfed and 44.3% had discontinued breastfeeding. By the age of 12 months 25.3% of infants were still receiving some breast milk. The main factors that had a negative impact on the duration of breastfeeding included maternal smoking habits, early pacifier introduction and the maternal infant feeding attitude. CONCLUSIONS: The rate of initiation and overall duration of breastfeeding reached the WHO objectives, but exclusive breastfeeding duration has still not reached satisfactory levels at 6 months. Given that the maternal infant feeding attitude is the only factor independently related to breastfeeding duration for the whole first year of life, reliable measures of maternal attitude could be used as a first step in targeting and assessing interventions that promote and sustain breastfeeding. PMID- 23016616 TI - Nutrition and bronchopulmonary dysplasia. AB - We aimed to assess the current knowledge on the nutritional management of preterm infants at risk of developing bronchopulmonary dysplasia (BPD) or with BPD. We considered the evidence supporting the actual fluid and energy intake, proteins, lipids, and electrolytes requirement, and need for other nutrients in preterm infant at risk of developing BPD or with BPD. We concluded that, although many areas remain to be investigated, early nutrition support and careful adjustment of parenteral nutrition and appropriate enteral feeding selection may enhance the growth and contribute a better neurodevelopment in these patients. PMID- 23016617 TI - "Physiological" renal regenerating medicine in VLBW preterm infants: could a dream come true? AB - An emerging hypothesis from the recent literature explain how specific adverse factors related with growth retardation as well as of low birth weight (LBW) might influence renal development during fetal life and then the insurgence of hypertension and renal disease in adulthood. In this article, after introducing a brief overview of human nephrogenesis, the most important factors influencing nephron number at birth will be reviewed, focusing on the "in utero" experiences that lead to an increased risk of developing hypertension and/or kidney disease in adult. Since nephrogenesis in preterm human newborns does not stop at birth, but it continues for 4-6 weeks postnatally, a better knowledge of the mechanisms able to accelerate nephrogenesis in the perinatal period, could represent a powerful tool in the hands of neonatologists. We suggest to define this approach to a possible therapy of a deficient nephrogenesis at birth "physiological renal regenerating medicine". Our goal in preterm infants, especially VLBW, could be to prolong the nephrogenesis not only for 6 weeks after birth but until 36 weeks of post conceptual age, allowing newborn kidneys to restore their nephron endowment, escaping susceptibility to hypertension and to renal disease later in life. PMID- 23016618 TI - Effect of nutrition on growth and body composition in infants born preterm. AB - The optimization of the nutritional management of preterm infants has gained importance due to the increased survival of these vulnerable infants. In fact, the achievement of an adequate growth has been associated with a favourable neurodevelopment outcome. Nevertheless, preterm infants still develop severe nutrient deficiencies during the first few weeks of life so that they are frequently growth restricted upon discharge. In addition, preterm infants have been found to show an increased and aberrant adiposity at term-corrected age. The development of strategies immediately after birth has been found to produce excellent results in terms of growth without having any detrimental effect on body composition at term-corrected age. Continuing to monitor growth and body composition changes in relation to different nutrition interventions is essential as growth pattern and body composition appear to have a long term effect on health outcomes. PMID- 23016619 TI - Fluorescein angiography and retinal vascular development in premature infants. AB - OBJECTIVE: To investigate the role of fluorescein angiography (FA) in the management of retinopathy of prematurity (ROP) in preterm newborns. METHODS: An observational case series of 13 extremely low birth weight infants. From September 2009 to March 2010, 13 newborn infants with a gestational age <29 weeks end/or birth weight <1000 g underwent serial fluorescein angiography with RetCam (Clarity, Pleasanton, CA) every 2 weeks. The fluorescein angiograms were examined to optimize the timing of diagnosis of ROP and to investigate development of retinal and choroidal vascularization. RESULTS: There were no side effects related to FA. Variable features of retinal and choroidal circulation in preterm infants with a high risk of developing ROP were noted. FA allows vessels branching at the junction between vascular and avascular retina (V-Av junction) to be viewed easily and shows the ROP findings that sometimes cannot be seen by indirect ophthalmoscopy. Dye leakage is the most significant sign of progression to severe ROP or the need for surgery in newborn babies with ROP. CONCLUSIONS: RetCam-assisted intravenous FA is safe and allows a more objective assessment of the ROP stage and zone. PMID- 23016620 TI - Breast milk-acquired cytomegalovirus infection in very low birth weight infants. AB - Perinatal transmission of human cytomegalovirus (HCMV) infection in very low birth weight (VLBW) premature infants can lead to serious clinical symptoms and it has ben increasingly recognized that breast milk is the most frequent route of transmission. Breast milk is considered ideal food for newborns because of its nutritional value and anti-infectious components, but it can also be vehicle for viral and bacterial infection. The majority of HCMV seropositive mothers shed the virus into their breast milk and can transmit infection to their offspring. Perinatally acquired infections in full-term neonates are usually asymptomatic without sequelae due to protective maternal HCMV-specific antibodies received during pregnancy. In contrast, VLBW preterm infants are at risk of symptomatic infection with neutropaenia, thrombocytopaenia, sepsis-like syndrome and, less frequently, pneumonia and enteric infection. Postnatally acquired infection seems to spontaneously resolve without altering the clinical outcome. Ganciclovir treatment is restricted to severe symptomatic infections. Preterm infants with a gestational age <30 weeks, or with a birth weight <1000 g, are at greater risk of severe postnatal symptomatic HCMV infection, transmitted via maternal milk. The pasteurization of breast milk entirely eliminates infectivity and prevents virus transmission but alters nutritional and immunological milk properties, and freezing reduces, but does not eradicate, infectivity. Most authors encourage fresh maternal breastfeeding because its beneficial effects outweigh the risk of a transient infection, sequelae-free. Nevertheless, an individual decision based on the condition of health of the infant is important. PMID- 23016621 TI - Interaction energies of CO2.amine complexes: effects of amine substituents. AB - To focus on the identification of potential alternative amine carbon capture compounds, CO(2) with methyl, silyl, and trifluoromethyl monosubstituted and disubstituted amine compounds were studied. Interaction energies of these CO(2).amine complexes were determined via two methods: (a) an ab initio composite method, the correlation consistent composite approach (ccCA), to determine interaction energies and (b) density functional theories, B3LYP/aug-cc-pVTZ and B97D/aug-cc-pVTZ. Substituent effects on the interaction energies were examined by interchanging electron donating and electron withdrawing substituents on the amine compounds. The calculations suggested two different binding modes, hydrogen bonding and acid-base interactions, which arise from the modification of the amine substituents, echoing previous work by our group on modeling protein.CO(2) interactions. Recommendations have been noted for the development of improved amine scrubber complexes. PMID- 23016622 TI - Holmium: YAG laser lithotripsy versus pneumatic lithotripsy for treatment of distal ureteral calculi: a meta-analysis. AB - The objective of this study was to estimate the treatment effect of Pneumatic Lithotripsy (PL) versus holmium: YAG laser lithotripsy (LL) in the treatment of distal ureteric calculi. A bibliographic search covering the period from 1990 to April 2012 was conducted using search engines such as MEDLINE, EMBASE, and Cochrane library. Data were extracted and analyzed with RevMan5.1 software. A total of 47 studies were scant, and 4 independent studies were finally recruited. Holmium: YAG LL conveyed significant benefits compared with PL in terms of early stone-free rate [odds ratio (OR)=4.42, 95% confidence interval (CI) (1.14, 17.16), p=0.03], delayed stone-free rate [OR=4.42, 95%CI (1.58, 12.37), p=0.005], mean operative time [WMD=-16.86, 95%CI (-21.33, -12.39), p<0.00001], retaining double-J catheter rate [OR=0.44, 95%CI (0.25, 0.78), p=0.004], and stone migration incidence [OR=0.26, 95%CI (0.11, 0.62), p=0.003], but not yet in the postoperative hematuria rate and the ureteral perforation rate according to this meta-analysis. Precise estimates on larger sample size and trials of high quality may provide more uncovered outcomes in the future. PMID- 23016623 TI - Prediction models of donor arrest and graft utilization in liver transplantation from maastricht-3 donors after circulatory death. AB - Shortage of organs for transplantation has led to the renewed interest in donation after circulatory-determination of death (DCDD). We conducted a retrospective analysis (2001-2009) and a subsequent prospective validation (2010) of liver Maastricht-Category-3-DCDD and donation-after-brain-death (DBD) offers to our program. Accepted and declined offers were compared. Accepted DCDD offers were divided into donors who went on to cardiac arrest and those who did not. Donors who arrested were divided into those producing grafts that were transplanted or remained unused. Descriptive comparisons and regression analyses were performed to assess predictor models of donor cardiac arrest and graft utilization. Variables from the multivariate analysis were prospectively validated. Of 1579 DCDD offers, 621 were accepted, and of these, 400 experienced cardiac arrest after withdrawal of support. Of these, 173 livers were transplanted. In the DCDD group, donor age < 40 years, use of inotropes and absence of gag/cough reflexes were predictors of cardiac arrest. Donor age >50 years, BMI >30, warm ischemia time >25 minutes, ITU stay >7 days and ALT >= 4* normal rates were risk factors for not using the graft. These variables had excellent sensitivity and specificity for the prediction of cardiac arrest (AUROC = 0.835) and graft use (AUROC = 0.748) in the 2010 prospective validation. These models can feasibly predict cardiac arrest in potential DCDDs and graft usability, helping to avoid unnecessary recoveries and healthcare expenditure. PMID- 23016624 TI - Stroke genetics: prospects for personalized medicine. AB - Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice. PMID- 23016625 TI - Antiepileptic drugs and the fetal epigenome. AB - Antiepileptic drugs (AEDs) can lower maternal folate and increase maternal homocysteine levels, which are known to affect the methyl cycle and hence DNA methylation levels. The influence of in utero exposure to AEDs on fetal DNA methylation was investigated. Genome-wide fetal epigenomic profiles were determined using the Infinium 27K BeadArray from Illumina (San Diego, CA, U.S.A.). The Infinium array measures approximately 27,000 CpG loci associated with 14,496 genes at single-nucleotide resolution. Eighteen cord blood samples (nine samples from babies exposed to AEDs and nine controls) from otherwise uncomplicated pregnancies were compared. Unsupervised hierarchic clustering was used to compare the calculated methylation profiles. A clear distinction between the methylation profiles of samples from babies exposed to AEDs in utero compared with controls was detected. These data provide evidence of an epigenetic effect associated with antenatal AED and high-dose folate supplementation during pregnancy. The differences in fetal DNA methylation of those exposed to AEDs shows that a genome-wide effect of methylation is evident. In addition, the epigenetic changes observed appear to be, in this limited sample, independent of extremes of birth weight centiles. These preliminary data highlight possible mechanisms by which AEDs might influence fetal outcomes and the potential of optimizing AED-specific folate supplementation regimens to offset these effects. PMID- 23016626 TI - Titanium(IV) and vitamin C: aqueous complexes of a bioactive form of Ti(IV). AB - Ascorbic acid is among the biorelevant ligands that render Ti(IV) stable in aqueous solution. A series of pH-dependent titanium(IV) coordination complexes of L-ascorbic acid is described. Directed by spectropotentiometric methods, important aspects of the aqueous interactions in this system are investigated, including ligand binding mode, pH-dependent metal-ligand stoichiometry, and the importance of metal ion-promoted hydrolysis and the binding of hydroxide. Stability constants are determined for all metal ion-ligand-proton complexes by a process of model optimization and nonlinear least-squares fitting of the combined spectropotentiometric titration data to the log beta(MLH) values in the model. A speciation diagram is generated from the set of stability constants described in the model. In the range pH 3-10, the aqueous speciation is characterized by the sequential appearance of the following complexes as a function of added base: Ti(asc)(2)(0) -> Ti(asc)(3)(2-) -> Ti(asc)(2)(OH)(2)(2-) -> Ti(asc)(OH)(4)(2-). These species dominate the speciation at pH < 3, pH 4-5, pH ~ 8, and pH > 10, respectively, with minimum log stability constants (beta values) of 25.70, 36.91, 16.43, and -6.91. Results from electrospray mass spectrometry, metal-ligand binding experiments, and kinetics measurements support the speciation, which is characterized by bidentate chelation of the ascorbate dianion to the titanium(IV) ion via proton displacement, and a pH-dependent metal-ligand binding motif of ligand addition followed by metal ion-promoted hydrolysis, stepwise ligand dissociation, and the concomitant binding of hydroxide ion. Additionally, the kinetics of ligand exchange of titanium ascorbate with citrate are reported to understand better the possible fate of titanium ascorbate under biologically relevant conditions. PMID- 23016627 TI - Assessment of unassisted recovery from repeated general isoflurane anesthesia in horses following post-anesthetic administration of xylazine or acepromazine or a combination of xylazine and ketamine. AB - OBJECTIVES: To compare the effects of sedative doses of acepromazine, xylazine or xylazine/ketamine administered to horses after isoflurane anesthesia on the quality of recovery and anesthesia recovery times. To determine if recovery scores improve after repeated consecutive anesthetic episodes. STUDY DESIGN: Prospective, randomized, crossover study. ANIMALS: Fifteen adult research horses, 6.5+/-3.4 years old and weighing 499+/-40 kg. METHODS: Horses undergoing three anesthetic episodes with isoflurane for magnetic resonance of the forelimbs were administered acepromazine (0.02 mg kg(-1) i.v.) or xylazine (0.3 mg kg(-1) i.v.) or xylazine (0.15 mg kg(-1) i.v.) combined with ketamine (0.3 mg kg(-1) i.v.) in random order upon arrival in recovery. The quality of recovery was compared between the three treatments using a composite numerical rating and a general descriptive scoring system. RESULTS: Horses administered xylazine had better recovery scores than horses administered xylazine/ketamine, associated with better scores during their move to sternal, strength and number of attempts to standing. Horses administered acepromazine had similar recovery scores to horses administered xylazine and to horses administered xylazine/ketamine. Time to sternal recumbency and time to extubation were statistically longer for the xylazine treatment. Time to standing was similar between treatments. Horses had better recovery scores during the third anesthetic episode, regardless of the sedative drug administered, associated with better scores for strength and number of attempts to standing. CONCLUSIONS: Xylazine administration was superior to xylazine/ketamine but similar to acepromazine. This study also indicates that horses improve the quality of recovery during consecutive anesthetics associated with longer time to sternal and to standing, regardless of the sedative used. CLINICAL RELEVANCE: All treatments provided good quality recoveries. The experience of the individual horse gained during recent previous anesthetic episodes may have a positive effect in facilitating a better recovery. PMID- 23016628 TI - Constructing the experience of chronic pain through discourse. AB - Abstract The aim of this study was to investigate the discourses used by people with chronic pain. Using qualitative interview data from five Irish people with a variety of chronic pain conditions, Foucauldian discourse analysis was undertaken to identify the discourses in operation in participants' accounts. Three discourses were identified: a moral discourse, a discourse of pain as personal tragedy, and a biomedical discourse. A moral discourse was used to construct participants as moral individuals experiencing real pain who try to accomplish activities and fulfil social roles without burdening others. The discourse of chronic pain as personal tragedy describes the multiple negative consequences of chronic pain including activity, relationship, physical, financial, and emotional consequences, and changed expectations of the future. This discourse bolsters the moral discourse through rejecting any benefits associated with chronic pain. Participants rejected a biomedical discourse by proposing their own explanatory models of pain, resisting psychosocial understandings of pain, criticizing medical professionals and healthcare services, and challenging medical expertise, professionalism, and power. These practices allow participants to reject the patient subject-position with its attendant passivity and requirements for adherence and compliance. PMID- 23016629 TI - Lateral dynamics of surfactants at the free water surface: a computer simulation study. AB - Molecular dynamics simulations of the adsorption layer of five different surfactant molecules, i.e., pentyl alcohol, octyl alcohol, dodecyl alcohol, sodium dodecyl sulfate, and dodecyl trimethyl ammonium chloride are performed at the free surface of their aqueous solution at two surface densities, namely 1 and 4 MUmol/m(2) at 298 K. The results are analyzed in terms of the two-dimensional single molecule dynamics, in particlular, lateral diffusion of the surfactants at the liquid surface, in order to distinguish between two possible adsorption scenarios, namely the assumptions of localized and mobile surfactants. The obtained results, in accordance with the dynamical nature of the liquid phase and liquid surface, clearly support the latter scenario, as the time scale of lateral diffusion of the surfactant molecules is found to be comparable with that of the three-dimensional diffusion of water in the bulk liquid phase. The mechanism of this lateral diffusion is also investigated in detail by calculating binding energy distribution of the water molecules in the first hydration shell of the surfactant headgroups and that of the nonfirst shell surface waters, and by calculating the mean residence time of the water molecules in the first hydration shell of the surfactant headgroups. This time is found to be at least an order of magnitude smaller than the characteristic time of the lateral diffusion of the surfactants, revealing that surfactant molecules move without their first shell hydration water neighbors at the surface. PMID- 23016630 TI - Effect of calibration and environmental condition on the performance of direct reading organic vapor monitors. AB - The performance of three MIRAN SapphIRe Portable Infrared Ambient Air Analyzers and three Century Portable Toxic Vapor Analyzers equipped with photoionization (PID) and flame ionization (FID) detectors was compared with charcoal tube sampling. Relationships were investigated using two different calibration methods at four cyclohexane concentrations, three temperatures, and four relative humidities. For the first method, the TVA monitors were calibrated with a single concentration of methane for the FID, and isobutylene for the PID. The SapphIRe monitors were zeroed and the monitor's manufacturer-supplied library was used. For the second method, a five-point cyclohexane calibration curve was created for each monitor. Comparison of the monitor results of each calibration method (pooled data) indicated a significant difference between methods (t-test, p < 0.001), The SapphIRe group had results closer to the charcoal tubes with the second calibration method, while the PID and FID monitor groups performed better using the first calibration method. The PID monitor group's performance was affected only at the 90% relative humidity (RH) condition. Using the first method, the monitor readings were compared with the charcoal tube average using mixed linear model analyses of variance (ANOVAs) and regression. The ANOVA results showed there was a statistically significant difference among readings from all monitor types (p <0.0001). The regression results demonstrated that the SapphIRe (r2 = 0.97) and FID (r2 = 0.92) monitor groups correlated well with the charcoal tubes. The PID monitor group had a similar correlation when 90% RH was excluded (r2 = 0.94) but had a weaker correlation when it was included (r2 = 0.58). The operator should take care when using these monitors at high concentrations and the PID monitors at high humidities, consider the variability between units of the same monitor, and conduct performance verification of the monitor being used. PMID- 23016631 TI - Crystal structure of a putative methyltransferase SAV1081 from Staphylococcus aureus. AB - Cluster of Orthologous Groups (COG) 1092 contains two distinct types of methylation enzyme from Escherichia coli, YccW and YcbY. YccW is a 5 methylcytosine methyltransferase (m5C MTase) responsible for m5C 1962 in 23S rRNA, whereas YcbY is a dimethyltransferase, of which N- and C-terminal domains are responsible for N2- methylguanosine (m2G) 2445 and 7-methylguanosine (m7G) 2069 in 23S rRNA, respectively. However, proteins in COG1092 other than YccW and YcbY remain functionally unidentified. SAV1081 from Staphylococcus aureus is one of the functionally unassigned proteins of COG1092. Although SAV1081 has an identical domain organization to YccW with 26% sequence identity, it lacks the catalytic cysteine residue essential for m5C formation activity. In the present study, we determined the crystal structure of SAV1081 and compared it with those of other COG1092 proteins. Based on the structure characteristics, such as the presence or absence of the catalytic cysteine residue, beta-hairpin structure, and oligomeric state, as well as domain organization, we propose a functional classification of COG1092 proteins. PMID- 23016632 TI - Biophysical characterization of the membrane-proximal ectodomain of the receptor type protein-tyrosine phosphatase phogrin. AB - The receptor-type protein-tyrosine phosphatase (RPTP) phogrin is localized at the membrane of secretory granules of pancreatic islet beta-cells and, similarly to the closely related ICA512, plays a role in the regulation of insulin secretion, in ensuring proper granulogenesis and stability, and in the regulation of beta cell growth. The mature membraneproximal ectodomain of phogrin (MPE phogrin) was produced as a recombinant protein and characterized. CD, fluorescence, controlled proteolysis, size-exclusion chromatography, and multi-angle light scattering showed that it is a properlyfolded monomeric domain. Equilibrium experiments, in the presence of guanidinium chloride and thermal unfolding, suggest a two-state mechanism with a DeltaG of 2.3-3.3 kcal/mol, respectively. The study establishes common features and differences of MPE phogrin and the homologous ectodomain of ICA512. A homology model of phogrin was built based in the x-ray structure of MPE ICA512. The model is a starting point for modeling the entire receptor and for testing the quaternary structure and interactions of this protein in vivo. A description of the membrane insertion mode and putative interacting surfaces of this large protein is fundamental for the understanding of its biological function. PMID- 23016633 TI - Characterization and decolorization applicability of xerogel matrix immobilized manganese peroxidase produced from Trametes versicolor IBL-04. AB - A novel manganese peroxidase (MnP) isolated from solid state culture of Trametes versicolor IBL-04 was immobilized using xerogel matrix composed of trimethoxysilane (TMOS) and propyltetramethoxysilane (PTMS). FTIR spectroscopy confirmed the successful entrapment of MnP into the xerogel matrix. An immobilization efficiency of 92.2% was achieved with a purified active fraction containing 2 mg/mL MnP. After 24 h incubation at varying pH and temperatures, the immobilized MnP retained 82 and 75% activity at pH 4 and 80 degrees C, respectively. Xerogel matrix immobilization enhanced the catalytic efficiency of entrapped MnP. Metal ions including Cu2+, Mn2+ and Fe2+ stimulated enzyme activity while cysteine, EDTA and Ag+ inhibited the activity. MnP preserved 82% of its initial activity during oxidation of MnSO4 in 10 consecutive cycles, demonstrating the reusability of xerogel entrapped MnP. The immobilized MnP could be stored for up to 75 days at 4 degrees C without significant activity loss. To explore the industrial applicability of MnP, the immobilized MnP was tested for decolorization of textile industry effluent in a Packed Bed Reactor System (PBRS). After five consecutive cycles, 98.8% decolorization of effluent was achieved within 5 h. The kinetic properties, storage stability and reusability of entrapped MnP from T. versicolor IBL-04 reflect its prospects as biocatalyst for bioremediation and other industrial applications. PMID- 23016634 TI - Efficient expression and immunoaffinity purification of human trace amine associated receptor 5 from E. coli cell-free system. AB - G protein-coupled receptors (GPCRs) represent attractive targets for bioactive and drug discovery programs. The availability of purified receptors in milligram quantities is essential to spur the advancement of protein-based analyses in these programs, although it is still a challenging goal to achieve. Here we report the production of a bioengineered GPCR of human trace amine-associated receptor 5 (hTAAR5) from an E. coli cell-free system. Both the hTAAR5 and hTAAR5 T4 lysozyme fusion proteins (hTAAR5-T4L) were cloned and expressed in this process, with the latter designed for further protein crystallization trials. The detergent Brij-35 was found to solubilize the produced hTAAR5 and hTAAR5-T4L effectively. Immunoaffinity purification in combination with gel filtration was employed to purify the receptors to high homogeneity. The final yields of monomeric hTAAR5 and hTAAR5-T4L from a 1 mL cell-free reaction were 0.4 mg and 0.5 mg, respectively. Circular Dichroism (CD) spectroscopy indicated that both hTAAR5 and hTAAR5- T4L were correctly folded after purification, with characteristic high alpha-helical contents ( > 45%). PMID- 23016635 TI - Preferentially grown ultranano c-diamond and n-diamond grains on silicon nanoneedles from energetic species with enhanced field-emission properties. AB - The design and fabrication of well-defined nanostructures have great importance in nanoelectronics. Here we report the precise growth of sub-2 nm (c-diamond) and above 5 nm (n-diamond) size diamond grains from energetic species (chemical vapor deposition process) at low growth temperature of about 460 degrees C. We demonstrate that a pre-nucleation induced interface can be accounted for the growth of c-diamond or n-diamond grains on Si-nanoneedles (Si-NN). These preferentially grown allotropic forms of diamond on Si-NN have shown high electron field-emission properties and signify their high potential towards diamond-based electronic applications. PMID- 23016636 TI - Brain drug delivery systems. PMID- 23016637 TI - Perspectives on brain-targeting drug delivery systems. AB - Due to the presence of the blood-brain barrier, there is limited drug access into the brain. In order to overcome this challenge, various strategies have been developed to enhance penetration of drugs into the brain. Of these, the most frequently used are pharmacological technologies or comparable methods being developed for brain-targeting drug delivery using receptor- or adsorptive- or transporter-mediated transcytosis and the nose-to-brain route. It goes without saying that exploration of Brain-targeting drug delivery systems has created another potential option for the treatment of central nervous system diseases. In addition to above methods, other technologies for brain-targeting drug delivery (e.g. chemical delivery systems, prodrugs, pharmacological disruption of the BBB and inhibition of drug efflux by P-glycoprotein) are also summarized in this review. PMID- 23016638 TI - The physiological characteristics and transcytosis mechanisms of the blood-brain barrier (BBB). AB - The blood-brain barrier (BBB) is the vessel wall made up of specialized capillary endothelial cells, surrounded by astroglial endfeet and neurons, that govern the exchange of compounds between blood and brain. It protects the brain from harmful compounds potentially present in blood, while it is specifically designed to supply the brain with the required nutrients and to get rid of waste products. The BBB is structurally different from blood capillaries in other tissues. The BBB strictly limits the paracellular exchange of compounds by the so-called tight junctions. Moreover, the capillary endothelial cells contain metabolic enzymes that may convert a compound before entering the brain while transcellular passage across the BBB may be limited or increased by active transport systems. Thus the BBB has an important role in the relationship of the concentration-time profile of compounds in blood and those in the brain. The functionality of the BBB is dynamically regulated, depending on the given conditions. Important examples are changes in BBB functionality that may result in or are brought about by (CNS) disease conditions. All together this indicates the importance of investigations on BBB functionality and resulting transport of compounds for the design and optimization of therapeutic regimens. Thus, BBB investigation is an ever growing and dynamic field studied by pharmacologists, neuroscientists, pathologists, physiologists, and clinical practitioners. This review deals with a general introduction on the physiological characteristics of the BBB, its different transport systems, with particular emphasis on supposed transcytosis mechanisms at the BBB. Specific and detailed information on drug delivery approaches aiming at transcytosis into the brain will be dealt with in other parts of this special issue. PMID- 23016639 TI - Targeted blood-to-brain drug delivery --10 key development criteria. AB - Drug delivery to the brain remains challenging due to the presence of the blood brain barrier. In this review, 10 key development criteria are presented that are important for successful drug development to treat CNS diseases by targeted drug delivery systems. Although several routes of delivery are being investigated, such as intranasal delivery, direct injections into the brain or CSF, and transient opening of the blood-brain barrier, the focus of this review is on physiological strategies aiming to target endogenous transport mechanisms. Examples from literature, focusing on targeted drug delivery systems that are being commercially developed, will be discussed to illustrate the 10 key development criteria. The first four criteria apply to the targeting of the blood brain barrier: (1) a proven inherently safe receptor biology, (2) a safe and human applicable ligand, (3) receptor specific binding, and (4) applicable for acute and chronic indications. Next to an efficient and safe targeting strategy, as captured in key criteria 1 to 4, a favorable pharmacokinetic profile is also important (key criterion 5). With regard to the drug carriers, two criteria are important: (6) no modification of active ingredient and (7) able to carry various classes of molecules. The final three criteria apply to the development of a drug from lab to clinic: (8) low costs and straightforward manufacturing, (9) activity in all animal models, and (10) strong intellectual property (IP) protection. Adhering to these 10 key development criteria will allow for a successful brain drug development. PMID- 23016640 TI - Adsorptive-mediated brain delivery systems. AB - The blood-brain barrier (BBB), which impedes drug penetration into the central nervous system, is composed of specific structures formed by brain capillary endothelial cells and sheathed by astrocytic end-feet through basement membrane. Many brain drug delivery strategies have focused on adsorptive-mediated transcytosis (AMT), which is triggered by electrostatic interaction between cationic molecules and anionic microdomains on the cytoplasm membrane of the brain capillary endothelial cells. AMT-based drug delivery to the brain can be achieved by using cationic proteins and basic oligopeptides such as cell penetrating peptides as targetors. Large therapeutic molecules such as neuropeptides and proteins or even drug-encapsulated vectors such as liposomes and nanoparticles can be allowed to access brain parenchyma through AMT when conjugated with these cationic targetors. In this review, I briefly discuss adsorptive-mediated brain delivery systems that may provide physiologic-based strategies for enhanced delivery of therapeutic substances through the BBB. PMID- 23016641 TI - Brain delivery systems via mechanism independent of receptor-mediated endocytosis and adsorptive-mediated endocytosis. AB - The endothelial cells of the brain form the blood-brain barrier (BBB) that denotes a major restraint for drug entry to the brain. Traditional attempts to bypass the BBB have been by formulation of drugs with lipophilicity or low molecular weight designed to enable transport via solute nutrient transporters. The identification of many new targets in the brain cells form new ways of thinking drug design as modern therapeutics could be proteins and molecules of genetic origins like siRNA and cDNA that are prevented from entry into the brain unless encapsulated in drug carriers. In many chronic disorders affecting the central nervous system, the BBB is physically intact which further limits the entry of large molecules. The desirable entry of such molecules will be made by formulation of particular drug carriers that will enable their transport into the brain endothelium, or even through the endothelium and into the brain. This review discusses the potential of different principles for drug therapy to the brain with these main emphases on drug transport through the BBB: i) the effects of molecular lipidization, ii) the involvement of solute nutrient carriers, iii) targeted delivery using small peptides with high membrane penetrating properties, iv) treatment with magnetic nanoparticles. These different principles for therapy are also discussed with focus on possibilities of their improvement for targeted delivery to the brain. PMID- 23016642 TI - Drug delivery systems from nose to brain. AB - The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to deliver drugs selectively and effectively to the brain. Blood-brain-barrier (BBB) constitutes the major obstacle to the uptake of drugs into the brain following systemic administration. Intranasal delivery offers a non-invasive and convenient method to bypass the BBB and delivery of therapeutics directly to the brain. The review discusses the potential of intranasal route to deliver drugs to the brain, the mechanisms and pathways of direct nose to brain drug transport, the various factors influencing transnasal drug absorption, the conventional and novel intranasal drug delivery systems, the various intranasal drug delivery techniques and devices, and examples of brain drug transport that have been feasible in treating various brain disorders. Moreover, products on the market, investigational drugs, and the author's perceptions about the prospect of intranasal delivery for treating brain disorders are also been discussed. PMID- 23016643 TI - The blood-brain/tumor barriers: challenges and chances for malignant gliomas targeted drug delivery. AB - Treatment of malignant gliomas remains a challenge irrespective of the recent improvements. Chemotherapeutic agents for malignant gliomas have been particularly inefficient for the existence of blood-tumor barrier (BTB), which hampers the accumulation and uptake in tumor. Moreover, even though blood-brain barrier (BBB) is compromised to some extent under the situation of malignant gliomas, it remains to be the obstacle influencing the therapeutic efficacies via systemic administration. Fortunately, there are many receptors over-expressed on the BTB (glioma cells and/or tumor microvessels) that can mediate ligand modified drug delivery systems targeting to gliomas and enhance tumor uptake. On the other hand, numerous routes have also been explored to circumvent the BBB. In this manuscript, we elucidate the BBB/BTB status under the situation of malignant gliomas and review the receptors over-expressed on BTB and the malignant gliomas targeted drug delivery strategies. We also discuss the perspective of malignant gliomas targeted drug delivery systems with new concepts. PMID- 23016644 TI - Brain drug delivery systems for neurodegenerative disorders. AB - Neurodegenerative disorders (NDs) are rapidly increasing as population ages. However, successful treatments for NDs have so far been limited and drug delivery to the brain remains one of the major challenges to overcome. There has recently been growing interest in the development of drug delivery systems (DDS) for local or systemic brain administration. DDS are able to improve the pharmacological and therapeutic properties of conventional drugs and reduce their side effects. The present review provides a concise overview of the recent advances made in the field of brain drug delivery for treating neurodegenerative disorders. Examples include polymeric micro and nanoparticles, lipidic nanoparticles, pegylated liposomes, microemulsions and nanogels that have been tested in experimental models of Parkinson's, Alzheimer's and Huntington's disease. Overall, the results reviewed here show that DDS have great potential for NDs treatment. PMID- 23016645 TI - Magnetic nanoparticles for MRI of brain tumors. AB - Despite advances in surgery and drug discovery, brain tumors remain fatal diseases. Early detection and diagnosis of brain tumors is of great importance for improving treatment outcomes. Magnetic resonance imaging (MRI) is a prominent, clinically-relevant imaging modality because of its excellent tissue contrast resolution, direct multiplanar imaging and increased sensitivity to edema. MRI utility is further enhanced with the use of magnetic iron oxide nanoparticles, which can function as both a contrast agent for imaging and as a drug delivery vehicle for treating brain cancer. In this review, the principles of various imaging modalities for brain tumors are discussed with focus on monocrystalline iron oxide nanoparticle (MION)-based MRI contrast agents. A summary is given on the mechanism of contrast effect, magnetophoretic mobility and magnetic retention, and strategies to enhance tumor selectivity, increase spatial resolution and reduce nonspecific uptake of MION. PMID- 23016646 TI - Targeting the brain: advances in drug delivery. AB - The blood-brain barrier (BBB) represents a significant obstacle for drug delivery to the brain. Many therapeutics with potential for treating neurological conditions prove incompatible with intravenous delivery simply because of this barrier. Rather than modifying drugs to penetrate the BBB directly, it has proven more efficacious to either physically bypass the barrier or to use specialized delivery vehicles that circumvent BBB regulatory mechanisms. Controlled-release intracranial polymer implants and particle injections are the clinical state of the art with regard to localized delivery, although these approaches can impose significant surgical risks. Focused ultrasound provides a non-invasive alternative that may prove more desirable for acute treatment of brain tumors and other conditions requiring local tissue necrosis. For targeting the brain as a whole, cell-penetrating peptides (CPPs) and molecular trojan horses (MTHs) have demonstrated particular ability as delivery molecules and will likely see increased application. CPPs are not brain specific but offer the potential for efficient traversal of the BBB, and tandem systems with targeting molecules may produce extremely effective brain drug delivery tools. Molecular trojan horses utilize receptor-mediated transcytosis to transport cargo and are thus limited by the quantity of relevant receptors; however, they can be very selective for the BBB endothelium and have shown promise in gene therapy. PMID- 23016647 TI - Therapeutic gene products delivery by neuron stem cells. AB - Malignant tumors remain virtually untreatable and inevitably lethal despite extensive surgical excision and adjuvant radio- and chemotherapy. Therefore, the development of more effective tumor-selective therapies is necessary. Stem/progenitor cells that self-renew, differentiate and display inherent tumor tropic properties can be exploited for targeted delivery of therapeutic genes to invasive and metastatic tumors. In this review, we mainly introduce the application in Glioma, Breast cancer, Spinal cord injury, AD and so on. The promising field of stem cell research as it applies to regenerative medicine is still in infancy, but its potential appears limitless, and we are blessed to be involved in this exciting realm of research. PMID- 23016648 TI - Serial-position effects for items and relations in short-term memory. AB - Two experiments used immediate probed recall of words to investigate serial position effects. Item memory was tested through probing with a semantic category. Relation memory was tested through probing with the word's spatial location of presentation. Input order and output order were deconfounded by presenting and probing items in different orders. Primacy and recency effects over input position were found for both item memory and relation memory. Both item and relation memory declined over output position. The finding of a U-shaped input position function for item memory rules out an explanation purely in terms of positional confusions (e.g., edge effects). Either these serial-position effects arise from variations in the intrinsic memory strength of the items, or they arise from variations in the strength of item-position bindings, together with retrieval by scanning. PMID- 23016649 TI - Effect of habitat disturbance on pollination biology of the columnar cactus Stenocereus quevedonis at landscape-level in central Mexico. AB - Stenocereus quevedonis ('pitire') is a columnar cactus endemic to central Mexico, grown for its edible fruit. Phenology, pollination biology and behaviour of flower visitors of this species were compared in six conserved and disturbed sites, hypothesising that: (i) pitire pollination is self-incompatible, requiring animal vectors; (ii) higher incidence of radiation on plants in cleared forest may lead to a higher number of flowers per pitire plant and longer blooming season, and disturbing and differential spatial availability of flower resources may determine differential attraction of pollinators to conserved and disturbed areas; (iii) if pitire pollination system is specialised, reproductive success would decrease with pollinator scarcity, or other species may substitute for main pollinators. In all sites, pitire reproduction started in January, flowering peak occurring in April, anthesis duration was 15 h and predominantly nocturnal (9 h), pollen was released at 23:00 h, nectar was produced throughout anthesis, and breeding system was self-incompatible. Flower production per plant was similar in disturbed and conserved sites, but flower availability was higher (because of higher tree density) and longer in disturbed sites. Pollination is nocturnal, the most frequent legitimate pollinator being the bat Leptonycteris yerbabuenae; diurnal pollination is rare but possible, carried out by bee species. Fruit and seed set in control and nocturnal pollination treatments at disturbed sites were higher than in conserved sites. Frequency of L. yerbabuenae visits was similar among site types, but more visits of complementary nocturnal and diurnal pollinators were recorded in disturbed sites, which could explain differences in reproductive success. PMID- 23016651 TI - Leading the charge, year four. PMID- 23016650 TI - PR-39, a porcine host defence peptide, is prominent in mucosa and lymphatic tissue of the respiratory tract in healthy pigs and pigs infected with Actinobacillus pleuropneumoniae. AB - BACKGROUND: Host defence peptides are important components of mammalian innate immunity. We have previously shown that PR-39, a cathelicidin host defence peptide, is an important factor in porcine innate immune mechanisms as a first line of defence after infection with Actinobacillus pleuropneumoniae. PR-39 interacts with bacterial and mammalian cells and is involved in a variety of processes such as killing of bacteria and promotion of wound repair. In bronchoalveolar lavage fluid of infected pigs PR-39 concentrations are elevated during the chronic but not during the acute stage of infection when polymorphonuclear neutrophils (known as the major source of PR-39) are highly increased. Thus it was assumed, that the real impact of PR-39 during infection might not be reflected by its concentration in bronchoalveolar lavage fluid. RESULTS: Using immunohistochemistry this study demonstrates the actual distribution of PR-39 in tissue of the upper and lower respiratory tract of healthy pigs, and of pigs during the acute and chronic stage of experimental infection with Actinobacillus pleuropneumoniae.During the acute stage of infection PR-39 accumulated adjacent to blood vessels and within bronchi. Immune reactions were mainly localized in the cytoplasm of cells with morphological characteristics of polymorphonuclear neutrophils as well as in extracellular fluids. During the chronic stage of infection pigs lacked clinical signs and lung alterations were characterized by reparation and remodelling processes such as tissue sequestration and fibroblastic pleuritis with a high-grade accumulation of small PR-39-positive cells resembling polymorphonuclear neutrophils. In healthy pigs, PR-39 was homogenously expressed in large single cells within the alveoli resembling alveolar macrophages or type 2 pneumocytes. PR-39 was found in all tissue samples of the upper respiratory tract in healthy and diseased pigs. Within the tracheobronchial lymph nodes, PR-39 dominated in the cytoplasm and nuclei of large cells resembling antigen-presenting cells located in the periphery of secondary follicles. CONCLUSIONS: These immunohistochemical findings indicate that, in addition to polymorphonuclear neutrophils, other cells are involved in the expression, storage, or uptake of PR-39. The presence of PR-39 in healthy lung tissue showed that this antibacterial peptide might be important for the maintenance of health. PMID- 23016652 TI - Fat, young, and poor: why breastfeeding is a critical weapon in the fight against childhood obesity. PMID- 23016653 TI - Collaborative engagement to overcome barriers to breastfeeding. PMID- 23016654 TI - Improving maternity care practices in New York: answering the Surgeon General's Call to Action. AB - Hospitals providing maternity care influence breastfeeding mothers and infants during the critical, early postnatal period. Despite concerted public health efforts, there are persistent, large variations across New York State (NYS) hospitals in breastfeeding policies, maternity care, and infant feeding practices and in rates of breastfeeding initiation and exclusivity. An initiative addressing this issue is the Breastfeeding Quality Improvement in Hospitals (BQIH) Learning Collaborative, which was designed and implemented by the NYS Department of Health (NYSDOH). The BQIH Learning Collaborative, adapted from the Institute for Healthcare Improvement Breakthrough Series, embedded evidence-based maternity care best practices in a learning and quality improvement model. The Ten Steps to Successful Breastfeeding served as the backbone for improvement with the aims of increasing the percentages of infants fed any breastmilk and exclusively fed breastmilk while decreasing the percentage of breastfed infants supplemented with formula. Twelve hospitals were selected to participate based on their breastfeeding metrics: 10 of the hospitals were low performing, and two were high performing on these breastfeeding measures. During the 18-month BQIH Learning Collaborative, process improvement occurred for several measures, including breastfeeding within the first hour after birth, breastfeeding mother/infant rooming-in, and receipt of formula samples/discharge bags. NYSDOH plans to spread this Collaborative to all hospitals providing maternity care in NYS. Comprehensive breastfeeding initiatives will continue in NYS in the effort to ensure that all breastfeeding mothers receive optimal support from healthcare providers and hospitals with the goal of making breastfeeding the norm for infant nutrition during the first year of life. PMID- 23016655 TI - State public health agencies' commitment to healthy babies: addressing the goodness and fairness in breastfeeding rates. PMID- 23016656 TI - Breastfeeding: a bridge to addressing disparities in obesity and health. PMID- 23016657 TI - Accelerating our progress. PMID- 23016658 TI - Fourth Annual Summit on Breastfeeding: summary and action items. PMID- 23016659 TI - Final thoughts and ponderings from the chairs. PMID- 23016662 TI - Possible association of severe major depression with acute cessation of long-term excessive triptan use. AB - WHAT IS KNOWN AND OBJECTIVE: Triptans are approved medications introduced for the acute treatment of migraine, classified as high-affinity serotonin 5-HT(1B/D) receptor agonists with lower affinity for 5-HT(1A) receptors. Both migraine and treatment of migraine with triptans have been associated with the development of major depression. However, little is known about the adverse effects of acute cessation of long-term overdose triptan use. CASE SUMMARY: We report a case of a 49-year-old male patient with first onset of severe major depression following cessation of daily excessive triptan use for 8 years. The depressive disorder was resistant to prior serotonergic antidepressant therapy. Antidepressant treatment with a non-serotonergic agent was successful in resolving depressive symptoms. WHAT IS NEW AND CONCLUSION: The present case report demonstrates for the first time that acute cessation of long-term excessive triptan use has the potential to induce severe major depression, presumably due to persistent alterations in the serotonergic system including downregulation and desensitization of 5-HT(1) receptors. In this case, treatment with a non-serotonergic agent could be a promising therapeutic strategy. PMID- 23016663 TI - Procedure versus process: ethical paradigms and the conduct of qualitative research. AB - BACKGROUND: Research is fundamental to improving the quality of health care. The need for regulation of research is clear. However, the bureaucratic complexity of research governance has raised concerns that the regulatory mechanisms intended to protect participants now threaten to undermine or stifle the research enterprise, especially as this relates to sensitive topics and hard to reach groups. DISCUSSION: Much criticism of research governance has focused on long delays in obtaining ethical approvals, restrictions imposed on study conduct, and the inappropriateness of evaluating qualitative studies within the methodological and risk assessment frameworks applied to biomedical and clinical research. Less attention has been given to the different epistemologies underlying biomedical and qualitative investigation. The bioethical framework underpinning current regulatory structures is fundamentally at odds with the practice of emergent, negotiated micro-ethics required in qualitative research. The complex and shifting nature of real world settings delivers unanticipated ethical issues and (occasionally) genuine dilemmas which go beyond easy or formulaic 'procedural' resolution. This is not to say that qualitative studies are 'unethical' but that their ethical nature can only be safeguarded through the practice of 'micro ethics' based on the judgement and integrity of researchers in the field. SUMMARY: This paper considers the implications of contrasting ethical paradigms for the conduct of qualitative research and the value of 'empirical ethics' as a means of liberating qualitative (and other) research from an outmoded and unduly restrictive research governance framework based on abstract prinicipalism, divorced from real world contexts and values. PMID- 23016664 TI - MiR-125b orchestrates cell proliferation, differentiation and migration in neural stem/progenitor cells by targeting Nestin. AB - BACKGROUND: The emerging concept is that microRNAs (miRNAs) play a central role in controlling stem cell self-renewal and fate determination by regulating the expression of stem cell regulators. miR-125b, one of neuronal miRNAs, recently was found to be necessary for neural differentiation of neural stem/progenitor cells (NS/PCs). However, the other specific biological role of miR-125b in NS/PCs is little known. We used rat NS/PCs as a model system to study the role of miR 125b in governing the behavior of NS/PCs. RESULTS: We report here the transfection of exogenous miR-125b inhibited proliferation of NS/PCs but promoted differentiation and migration. Whereas anti-miR-125b had the opposite effect. Similar results were observed when Nestin was knocked down by siRNA. Subsequently, we demonstrated that Nestin was a direct functional target of miR 125b. MiR-125b downregulates the expression of luciferase through Nestin 3'untranslated region (3'-UTR), and the regulation was abolished by mutations in the miR-125b binding site. MiR-125b targeted the 3'-UTR of Nestin and reduced the abundance of Nestin at both mRNA and protein levels. CONCLUSION: The results provided new insight into the function by which miR-125b modulates NS/PCs proliferation, differentiation and migration. The data also indicated the regulatory role of miR-125b in NS/PCs might through the suppression of Nestin expression. PMID- 23016665 TI - Combined crossed beam and theoretical studies of the N(2D) + C2H4 reaction and implications for atmospheric models of Titan. AB - The dynamics of the H displacement channels in the reaction N((2)D) + C(2)H(4) have been investigated by the crossed molecular beam technique with mass spectrometric detection and time-of-flight analysis at two different collision energies (17.2 and 28.2 kJ/mol). The interpretation of the scattering results is assisted by new electronic structure calculations of stationary points and product energetics for the C(2)H(4)N ground state doublet potential energy surface. RRKM statistical calculations have been performed to derive the product branching ratio under the conditions of the present experiments and of the atmosphere of Titan. Similarities and differences with respect to a recent study performed in crossed beam experiments coupled to ionization via tunable VUV synchrotron radiation are discussed (Lee, S.-H.; et al. Phys. Chem. Chem. Phys.2011, 13, 8515-8525). Implications for the atmospheric chemistry of Titan are presented. PMID- 23016667 TI - Electrochemiluminescence properties of [Pt2Ag4(C=CC6H4R)8]n (R = CH3, n = 1; R = H, n = 1 and 2) with amine (TPrA and DBAE) as the coreactant and determination of Sudan I. AB - Two hexanuclear clusters, [Pt(2)Ag(4)(C=CC(6)H(4)R)(8)] (R = CH(3), 1; R = H, 2), together with dimer [Pt(2)Ag(4)(C=CC(6)H(5))(8)](2) (3), have been synthesized and characterized by elemental analyses, electrospray ionization mass spectrometry, and (1)H NMR spectroscopy and by X-ray crystallography for 1 and 3. A considerable enhancement of photoluminescence (PL) and a notable red shift in the emission maximum of 1 (lambda(max) 600 nm) relative to 2 (lambda(max) 545 nm) are observed. Electrogenerated chemiluminescence (ECL) of 1 and 2 in the absence or presence of coreactant tri-n-propylamine (TPrA) or 2-(dibutylamino)ethanol (DBAE) at different working electrodes in different solvents (CH(2)Cl(2), CH(2)ClCH(2)Cl, or CH(3)CN) has been studied. The ECL spectra are identical with the PL spectra, indicating that ECL emissions are also due to a MLM'CT [Pt(d)/pi (C=CC(6)H(4)R-4) -> Pt(p(z))/Ag(sp)/pi* (C=CC(6)H(4)R-4)] state modified by Pt...Ag and Ag...Ag contacts. ECL of 1- and 2/amine systems in CH(2)ClCH(2)Cl was produced at the potentials of 1.14-1.19 V vs SCE, notably negatively shifted by about 0.38 V compared to those of the Ru(bpy)(3)(2+)/amine system. In all cases, ECL quantum efficiencies of 2 are higher than those of 1 and on the same order of magnitude as that of the [Ru(bpy)(3)](PF(6))(2)/amine system. It is noted that Sudan I tends to decrease the ECL intensity of the 1/DBAE system in CH(2)ClCH(2)Cl at a platinum working electrode. A new ECL method for the determination of Sudan I was developed with a linear range of 2.5 * 10(-5)-1.0 * 10(-3) M and a detection limit of 8.0 * 10(-6) M based on 3 times the ratio of signal-to-noise. PMID- 23016668 TI - Antioxidants and physical integrity of lipid bilayers under oxidative stress. AB - Giant unilamellar vesicles (GUVs of diameter 5-25 MUm) of soy phosphatidylcholine (PC), resistant to intense light exposure (400-440 nm, ~15 mW.mm(-2)), underwent budding when containing chlorophyll a (Chla) in the lipid bilayer ([PC]:[Chla] = 1500:1). On the basis of image heterogeneity analysis using inverted microscopy, a dimensionless entropy parameter for the budding process was shown to increase linearly during an initial budding process. Lipophilic beta-carotene (beta-Car, [PC]:[beta-Car] = 500:1) reduced the initial budding rate by a factor of 2.4, while the hydrophilic glycoside rutin ([PC]:[rutin] = 500:1) had no effect. Chla photosensitized oxidation of PC to form linoleoyl hydroperoxides, further leading to domains of higher polarity in the vesicles, is suggested to trigger budding. The average dipole moment (MU) of linoleic acid hydroperoxides was calculated using density functional theory (DFT) to have the value of 2.84 D, while unoxidized linoleic acid has MU = 1.86 D. beta-Carotene as a lipophilic antioxidant and singlet-oxygen quencher seems to hamper oxidation in the lipid bilayers and delay budding in contrast to rutin located in the aqueous phase. The effect on budding of GUVs as a detrimental process for membranes is suggested for use in assays for evaluation of potential protectors of cellular integrity and functions under oxidative stress. PMID- 23016666 TI - Analysis of transmitted drug resistance in Spain in the years 2007-2010 documents a decline in mutations to the non-nucleoside drug class. AB - We have studied transmitted drug resistance (TDR) in 1.864 antiretroviral-naive patients entering CoRIS (Spain) during 2007-2010. An overall 8.58% TDR was observed (3.92%, nucleoside reverse transcriptase inhibitors (NRTIs); 3.86%, non nucleoside reverse transcriptase inhibitors (NNRTIs); 2.31%, protease inhibitors), with a significant decreasing trend over time for NNRTIs (5.53%, 2007; 2.45%, 2010; p for trend = 0.044). Non-B subtype prevalence was 15.93%, with a significant increase (11.95%, 2007; 18.14%, 2010; p for trend = 0.018), mainly related to immigration. Having no formal education increased the risk of TDR to NNRTIs (OR, 7.26), and carrying a non-B subtype reduced the risk of TDR to NRTIs (OR, 0.27). These findings may have important implications for treatment guidelines and laboratory testing recommendations. PMID- 23016669 TI - Rapamycin has age-, treatment paradigm-, and model-specific anticonvulsant effects and modulates neuropeptide Y expression in rats. AB - PURPOSE: Rapamycin (RAP) has certain antiepileptogenic features. However, it is unclear whether these effects can be explained by the anticonvulsant action of RAP, which has not been studied. To address this question, we tested potential anticonvulsant effects of RAP in immature and adult rats using different seizure models and treatment paradigms. In addition, we studied changes in the expression of neuropeptide Y (NPY) induced by RAP, which may serve as an indirect target of the RAP action. METHODS: A complex approach was adopted to evaluate the anticonvulsant potential of RAP: We used flurothyl-, pentylenetetrazole (PTZ)-, N methyl-D-aspartate (NMDA)-, and kainic acid (KA)-induced seizures to test the effects of RAP using different pretreatment protocols in immature and adult rats. We also evaluated expression of NPY within the primary motor cortex, hippocampal CA1, and dentate gyrus (DG) after different pretreatments with RAP in immature rats. KEY FINDINGS: We found the following: (1) RAP administered with short term pretreatment paradigms has a weak anticonvulsant potential in the seizure models with compromised inhibition. (2) Lack of RAP efficacy correlates with decreased NPY expression in the cortex, CA1, and DG. Specifically in immature rats, a single dose of RAP (3 mg/kg) 4 or 24 h before seizure testing had anticonvulsant effects against PTZ-induced seizures. In the flurothyl seizure model only the 4-h pretreatment with RAP was anticonvulsant in the both age groups. Short-term pretreatments with RAP had no effects against NMDA- and KA induced seizures tested in immature rats. Long-term pretreatments with RAP over 8 days did not show beneficial effect in all tested seizure models in developing rats. Moreover, the long-term pretreatment with RAP had a slight proconvulsant effect on KA-induced seizures. In immature rats, any lack of anticonvulsant effect (including proconvulsant effect of multiple doses of RAP) was associated with downregulation of NPY expression in the cortex and DG. In immature animals, after a single dose of RAP with 24 h delay, we found a decrease of NPY expression in DG, and CA1 as well. SIGNIFICANCE: Our data show weak age-, treatment paradigm-, and model-specific anticonvulsant effects of RAP as well as loss of those effects after long-term RAP pretreatment associated with downregulation of NPY expression. These findings suggest that RAP is a poor anticonvulsant and may have beneficial effects only against epileptogenesis. In addition, our data present new insights into mechanisms of RAP action on seizures indicating a possible connection between mammalian target of rapamycin (mTOR) signaling and NPY system. PMID- 23016670 TI - Long-term memories bias sensitivity and target selection in complex scenes. AB - In everyday situations, we often rely on our memories to find what we are looking for in our cluttered environment. Recently, we developed a new experimental paradigm to investigate how long-term memory (LTM) can guide attention and showed how the pre-exposure to a complex scene in which a target location had been learned facilitated the detection of the transient appearance of the target at the remembered location [Summerfield, J. J., Rao, A., Garside, N., & Nobre, A. C. Biasing perception by spatial long-term memory. The Journal of Neuroscience, 31, 14952-14960, 2011; Summerfield, J. J., Lepsien, J., Gitelman, D. R., Mesulam, M. M., & Nobre, A. C. Orienting attention based on long-term memory experience. Neuron, 49, 905-916, 2006]. This study extends these findings by investigating whether and how LTM can enhance perceptual sensitivity to identify targets occurring within their complex scene context. Behavioral measures showed superior perceptual sensitivity (d') for targets located in remembered spatial contexts. We used the N2pc ERP to test whether LTM modulated the process of selecting the target from its scene context. Surprisingly, in contrast to effects of visual spatial cues or implicit contextual cueing, LTM for target locations significantly attenuated the N2pc potential. We propose that the mechanism by which these explicitly available LTMs facilitate perceptual identification of targets may differ from mechanisms triggered by other types of top-down sources of information. PMID- 23016672 TI - Novel inhibitors of inosine monophosphate dehydrogenase in patent literature of the last decade. AB - Inosine monophosphate dehydrogenase (IMPDH), an NAD-dependent enzyme that controls de novo synthesis of guanine nucleotides, has received considerable interest in recent years as an important target enzyme, not only for the discovery of anticancer drugs, but also for antiviral, antiparasitic, and immunosuppressive chemotherapy. The field of IMPDH inhibitor research is highly important for providing potential therapeutics against a validated target for disease intervention. This patent review examines the chemical structures and biological activities of recently reported IMPDH inhibitors. Patent databases SciFinder and Espacenet and Delphion were used to locate patent applications that were published between January 2002 and July 2012, claiming chemical structures for use as IMPDH inhibitors. From 2002 to 2012, around 47 primary patent applications have claimed IMPDH inhibitors, which we analyzed by target and applicant. The level of newly published patent applications covering IMPDH inhibitors remains high and a diverse range of scaffolds has been claimed. PMID- 23016673 TI - The Pandemrix - narcolepsy tragedy: how it started and what we know today. PMID- 23016674 TI - Role of asymmetrical dimethylarginine in the progression of renal disease. AB - Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid found in tissues and cells that circulates in plasma and is excreted in urine. It inhibits nitric oxide synthases (NOs) and produces considerable cardiovascular biological effects. Several studies have suggested that plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. In animal and in population studies ADMA has been associated with progression of CKD. Several mechanisms may be involved in this association, such as compromise of the integrity of the glomerular filtration barrier and development of renal fibrosis. This review summarizes the existing literature on the biology and physiology of ADMA focusing on its role in the progression of renal disease. PMID- 23016676 TI - Conclusive meta-analyses on antenatal magnesium may be inconclusive! Are we underestimating the risk of random error? AB - Results from meta-analyses significantly influence clinical practice. Both simulation and empirical studies have demonstrated that the risk of random error (i.e. spurious chance findings) in meta-analyses is much higher than previously anticipated. Hence, authors and users of systematic reviews and meta-analyses have a responsibility to carefully consider the risk of random errors to avoid misleading conclusions. Trial sequential analysis is a useful meta-analytic method for gauging the risk of random error in meta-analysis and the amount of additional evidence required to reach firm conclusions about the investigated intervention effect(s). We outline the rationale for conducting trial sequential analysis including some examples of the meta-analysis on antenatal magnesium for women at risk of preterm birth. PMID- 23016675 TI - Toll-like receptors 4 and 9 are responsible for the maintenance of the inflammatory reaction in canine steroid-responsive meningitis-arteritis, a large animal model for neutrophilic meningitis. AB - BACKGROUND: Steroid-responsive meningitis-arteritis (SRMA) is a systemic inflammatory disease affecting young adult dogs and a potential large animal model for neutrophilic meningitis. Similarities between SRMA and infectious central nervous system (CNS) diseases in lymphocyte subsets suggest an infectious origin.Toll-like receptors (TLRs) are pattern recognition receptors playing an important role in innate immunity. Due to their ability to recognize both self and non-self antigens, we hypothesize that TLRs are among the key factors for the induction of the inflammatory process in SRMA and provide an indirect hint on the etiology of the disease. METHODS: The expression profile of cell surface TLRs (TLR2, TLR4 and TLR5) and intracellular TLRs (TLR3 and TLR9) of canine leukocytes was analyzed by immunophenotyping and subsequent flow cytometric measurements. Experiments were performed on cerebrospinal fluid (CSF) and peripheral blood (PB) samples of dogs affected with SRMA during the acute phase (n = 14) as well as during treatment (n = 23) and compared with those of dogs with bacterial meningitis (n = 3), meningoencephalitis of unknown etiology (n = 6), neoplasia of the central nervous system (n = 6) and a group of dogs with miscellaneous neurological diseases (n = 9). Two additional control groups consisted of dogs with pyogenic infections (n = 13) and of healthy dogs (n = 6). RESULTS: All examined groups showed a high percentage of TLR2, TLR4 and TLR5 positive PB polymorphonuclear cells (PMNs) in comparison to healthy dogs. Very high values of TLR9 positive PB PMNs were detected in acute SRMA. Only a few similarities were found between SRMA patients and dogs with pyogenic infections, both groups were characterized by high expression of TLR4 positive PB monocytes. Glucocorticosteroid therapy reduced TLR2, TLR4 and TLR9 expression in PB monocytes. CONCLUSIONS: A relatively high expression of TLR4 and TLR9 in acute SRMA suggests that these two receptors might be involved in the inflammatory process in SRMA, enhancing the autoimmune reaction. Systematic CSF cell analysis for TLRs can be performed in future treatment studies in larger animals, such as dogs. PMID- 23016677 TI - Neuron-shaped gold nanocrystals and two-dimensional dendritic gold nanowires fabricated by use of a long-chain amidoamine derivative. AB - We report the synthesis of two-dimensional (2D) dendritic Au nanowires (DNWs) with diameters of 100-200 nm in an aqueous solution of long-chain amidoamine derivative (C18AA), which acted as both capping and reducing agent, and the preparation of large 2D DNWs with diameters of 400-700 nm by seeded growth of the original DNWs. The seeded growth method in the presence of C18AA enables the fabrication of novel neuron-shaped Au nanostructures consisting of two DNWs dangling from both ends of an ultrathin Au nanowire. PMID- 23016678 TI - Risk factors and interventional strategies for BK polyomavirus infection after renal transplantation. AB - OBJECTIVE: BK virus (BKV)-induced viraemia after renal transplantation can be associated with severe impairment of graft function. This study evaluated possible risk factors for BKV replication and examined the outcomes following various currently used treatment approaches. MATERIAL AND METHODS: Fifty-seven renal transplant recipients with BKV viraemia were retrospectively compared with 71 BKV-negative recipients to identify risk factors for BKV viraemia. Furthermore, outcome and graft function in 14 patients with BKV replication, in whom mycophenolate mofetil (MMF) was discontinued with a dose reduction of the remaining immunosuppressants, were compared with 32 patients in whom both MMF and the additional immunosuppressants were reduced. RESULTS: Patients with BKV viraemia received MMF (p < 0.01) and triple immunosuppression (p < 0.01) significantly more often, and displayed tacrolimus (p = 0.034) at higher blood concentrations (p = 0.002), a lower lymphocyte count (p = 0.006) and a longer warm ischaemic time (p = 0.019), and were more often male (p = 0.026). Patients in whom MMF was stopped had a higher chance of clearance of BKV viraemia (p = 0.022), which was achieved more rapidly (p = 0.048). Graft function improved during treatment and no graft losses occurred, compared with eight graft losses in the MMF-treated group (p = 0.04). CONCLUSIONS: MMF and tacrolimus could promote BKV viraemia after renal transplantation. Discontinuation of MMF together with a reduction of calcineurin inhibitors and glucocorticoids could be an option to reduce BKV replication after renal transplantation. PMID- 23016679 TI - Processing and regulation mechanisms within antigen presenting cells: a possibility for therapeutic modulation. AB - Processing of antigens within antigen presenting cells (APCs) is necessary for an immune response. Two pathways exist to present antigens to T cells: the major histocompatibility complex class I (MHC I) pathway to activate cytotoxic T cells (CTLs) and the MHC II route to stimulate T helper cells (Ths). Prior to efficient antigen presentation to MHC II, antigens have to be proteolytically degraded by proteases, the cathepsins, inside the endocytic compartment of APCs. Cathepsins process both antigens and self-antigens to antigenic peptides; the latter are critical for autoimmunity. Remarkably, distribution, substrate specificity, and function of cathepsins located in the antigen processing machinery depend on the cell type, primary or cultured cells, or species analyzed. However, a precise understanding of the antigen processing and presentation machinery is needed to generate specific immune modulators since the MHC antigen- processing pathway is subsequently regulated during tumorigenesis, infection, or autoimmunity. In this review, the latest finding regarding function and regulation of the MHC II proteolytic machinery and its possible target for immunomodulation will be discussed. PMID- 23016680 TI - Natural proteinaceous inhibitors of serine proteases. AB - The deregulated proteolysis is associated with various diseases in humans. Proteases are commonly regarded as the therapeutic targets. Almost one-third of all proteolytic enzymes in humans are serine proteases. This work provides a brief characteristic of the proteinaceous natural inhibitors, mostly of serine proteases. The examples of some classical and recently identified canonical and noncanonical inhibitors as well as serpins are described. Their actual and potential therapeutic applications are discussed. PMID- 23016681 TI - Bacterial proteases in disease - role in intracellular survival, evasion of coagulation/ fibrinolysis innate defenses, toxicoses and viral infections. AB - Pathogenic bacteria have evolved multiple mechanisms aimed to evade host defenses. This review summarizes selected examples of how bacteria utilize proteolytic enzymes to efficiently establish and spread infection systemically. First, the role of proteases in intracellular survival and persistence - the primary means used by bacteria to endure phagocytosis and/or avoid the vigilance of the immune system - is discussed. Second, it is demonstrated how some bacteria escape entanglement in fibrin(ogen) meshes, by inducing their proteolytic dissolution while other species modify the proteolytic cascade of mesh formation to divert this important innate immune defense for their own benefit. Third, bacterial proteolytic toxins are introduced, which allow microorganisms to exert and take advantage of systemic effects already during primary, localized infection. Finally, it is discussed how viruses utilize bacterial proteases by taking advantage of concurrent infection, and how pathogens may even mutually benefit from the joint presence of other pathogens. The reviewed adaptations are often essential for pathogen survival in the hostile environment of a host organism. As such, the potential benefits of pharmacological interference in relevant pathways for the struggle against bacterial pathogens are also discussed. PMID- 23016682 TI - The proteasome in health and disease. AB - The giant proteolytic factory called the proteasome came a long way from a biochemical curio to a major regulator of cellular physiology and a renowned drug target within the ubiquitin proteasome pathway (UPP). Thanks to availability of highly specific inhibitors of the proteasome, in less than twenty years it was possible to identify major transcription factors, cyclins, and products of oncogenes as crucial substrates for the UPP. Nine years passed since the FDA speedily approved bortezomib, the inhibitor of proteasome, for treatment of multiple myeloma. One year after its approval, the field was honored by awarding the Nobel Prize to Hershko, Ciechanover and Rose for introducing the concept of controlled proteolysis of ubiquitin-tagged substrates, with proteasome as the intracellular recycling facility. Taking into consideration the universal involvement of the proteasome in the life of all cells in human body, it comes to no surprise that the enzyme is deeply implicated in etiology, progression, diagnosis or cure of multiple diseases. Below we discuss some aspects of the involvement: from direct causative links to changes in proteasome properties that correlate with pathological conditions. We start with diseases collectively known as cancer, and with immune system-related pathologies. Here, the proteasome inhibitors are either already used in clinics, or undergo advanced preclinical screening. Then, we will continue with cardiovascular disorders, followed by aging. Changes of the proteasome make-up during aging may be a priming factor for neurodegenerative diseases, described last. We discuss the potential for proteasome regulation: inhibition, activation or specificity modulation, to successfully enter the clinical setting. PMID- 23016683 TI - Phosphonic esters and their application of protease control. AB - alpha-Aminoalkylphosphonate diaryl esters are potent, irreversible, and highly selective site-directed inhibitors of serine proteases. The structure of the phosphonate group resembles the transition state observed during a peptide bond hydrolysis and therefore phosphonates are referred as transition state analogues. They react with the hydroxyl group of the active site serine residue leading to formation of a stable enzyme-inhibitor complex. Moreover, incorporation of a peptidyl chain at the N-terminus as well as an introduction of electron withdrawing or electron donating substituents within the ester ring structure allows for a generation of specific inhibitors that react only with target serine protease. The great advantage of the aminophosphonate diaryl esters over other classes of inhibitors is their stability in aqueous solutions, no toxicity and lack of reactivity with cysteine, threonine, aspartyl and metalloproteinases. The above resulted in their application as convenient tools to study proteases function and activity using in vivo and in vitro assays of different pathological disorders (diabetes, cancer metastasis, pulmonary diseases or hypertension); to determine the cellular localization of the proteinases (activity based probes), to be used in proteomic approach or as the reactive antigens to develop a catalytic function within the antibodies binding site. Herein we present the development of alpha-aminoalkylphosphonate diaryl esters as inhibitors of several serine proteases including dipeptidyl peptidase IV, cathepsin G, human neutrophil elastase, mast cell chymase and urokinase-type plasminogen activator. We have provided a historical perspective as well as a comprehensive report of the most recent studies in this field. PMID- 23016685 TI - Matriptase-2, a regulatory protease of iron homeostasis: possible substrates, cleavage sites and inhibitors. AB - Matriptase-2 is a cell surface serine protease with a modular structure. The exploration of its function in iron homeostasis was of significance for the understanding of the regulation of hepcidin expression, the master protein in iron control. Mutations in matriptase- 2 cause iron-refractory iron deficiency anemia (IRIDA), an iron deficiency disorder where the level of hepcidin is inappropriately high. Matriptase-2 controls hepcidin expression through the suppression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic homologue protein (SMAD) signaling, probably by cleaving the BMP co-receptor hemojuvelin. Since prospective studies revealed that genetic inactivation of matriptase-2 reduces iron loading in different mouse models, matriptase-2 becomes highly attractive as a novel target for the design of low molecular weight inhibitors. The first synthetic peptidomimetic matriptase-2 inhibitors have been reported. A computational model of the active site of matriptase-2 based on the X-ray crystal structure of the close homologue matriptase was generated and mutational studies were performed in order to identify critical amino acids specifying the preferred recognition site of matriptase-2. So far, the only known putative natural substrates of matriptase-2 are hemojuvelin and matriptase-2 itself, as this protease undergoes complex auto processing during zymogen activation. Cleavage sites within both natural substrates were identified. PMID- 23016686 TI - Mmp-9 inhibitors in the brain: can old bullets shoot new targets? AB - Matrix metalloproteinases (MMPs) are either secreted or membrane-bound proteases, capable to degrade extracellular matrix (ECM) proteins as well as a large number of non-ECM proteins, such as growth factors, cytokines, chemokines, cell surface receptors, serine proteinase inhibitors and other MMPs. MMPs play major physiological roles in reproduction, growth, development, angiogenesis, immune response, wound healing and brain physiology. MMPs, and especially MMP-2 and -9 were considered to be targets for drug development (especially in oncology) and over fifty MMP inhibitors have been pursued in clinical trials that, however, failed mainly for the reason of insufficient knowledge about complexity of the biology. Recent studies implicating MMP-9 in aberrant synaptic plasticity underlying neuropsychiatric disorders, as well as in aggravating detrimental effects of the brain stroke, appear to offer a new hope for application of MMP inhibitors in treatment of those conditions. PMID- 23016687 TI - Selective inhibitors of human neutrophil proteinase 3. AB - Human neutrophil proteinase 3 (PR3) and elastase (HNE) are homologous serine proteinases involved in the proteolytic events associated with inflammation and infection. Their close structural and functional resemblance makes it difficult to understand their respective biological functions. Thus, all natural inhibitors of PR3 identified to date preferentially target HNE, and only recently have inhibitors that target PR3 selectively been described. This review describes how differences in the structures of the extended active sites of PR3 and HNE can be exploited to produce selective inhibitors of PR3. PMID- 23016684 TI - Mast cell chymase and tryptase as targets for cardiovascular and metabolic diseases. AB - Mast cells are critical effectors in inflammatory diseases, including cardiovascular and metabolic diseases and their associated complications. These cells exert their physiological and pathological activities by releasing granules containing histamine, cytokines, chemokines, and proteases, including mast cell specific chymases and tryptases. Several recent human and animal studies have shown direct or indirect participation of mast cell-specific proteases in atherosclerosis, abdominal aortic aneurysms, obesity, diabetes, and their complications. Animal studies have demonstrated the beneficial effects of highly selective and potent chymase and tryptase inhibitors in several experimental cardiovascular and metabolic diseases. In this review, we summarize recent discoveries from in vitro cell-based studies to experimental animal disease models, from protease knockout mice to treatments with recently developed selective and potent protease inhibitors, and from patients with preclinical disorders to those affected by complications. We hypothesize that inhibition of chymases and tryptases would benefit patients suffering from cardiovascular and metabolic diseases. PMID- 23016688 TI - HtrA protease family as therapeutic targets. AB - The HtrA proteases degrade damaged proteins and thus control the quality of proteins and protect cells against the consequences of various stresses; they also recognize specific protein substrates and in this way participate in regulation of many pathways. In many pathogenic bacteria strains lacking the HtrA function lose virulence or their virulence is decreased. This is due to an increased vulnerability of bacteria to stresses or to a decrease in secretion of virulence factors. In some cases HtrA is secreted outside the cell, where it promotes the pathogen's invasiveness. Thus, the HtrA proteases of bacterial pathogens are attractive targets for new therapeutic approaches aimed at inhibiting their proteolytic activity. The exported HtrAs are considered as especially promising targets for chemical inhibitors. In this review, we characterize the model prokaryotic HtrAs and HtrAs of pathogenic bacteria, focusing on their role in virulence. In humans HtrA1, HtrA2(Omi) and HtrA3 are best characterized. We describe their role in promoting cell death in stress conditions and present evidence indicating that HtrA1 and HtrA2 function as tumor suppressors, while HtrA2 stimulates cancer cell death induced by chemotherapeutic agents. We characterize the HtrA2 involvement in pathogenesis of Parkinson's and Alzheimer's diseases, and briefly describe the involvement of human HtrAs in other diseases. We hypothesize that stimulation of the HtrA's proteolytic activity might be beneficial in therapies of cancer and neurodegenerative disorders, and discuss the possibilities of modulating HtrA proteolytic activity considering the present knowledge about their structure and regulation. PMID- 23016689 TI - Dynorphin convertases and their functions in CNS. AB - Neuropeptides play crucial, mediatory roles in many processes that occur in both CNS and PNS. The commonly accepted dogma for the release of bioactive peptides involves cleavage of inactive precursor by sequential action of proteinases recognizing dibasic stretches, followed by truncation of C-terminal Arg/Lys by the carboxypeptidase-like enzyme(s). Dynorphin convertases play an important role in CNS by regulating dynorphins level and also releasing enkephalins, thus maintaining a balance between these neuropeptides and their distinct functions (dynorphins are preferentially bound to kappa receptors and enkephalins are directed toward delta receptors). Knowledge on the cleavage fragments of dynorphins is important for understanding the pharmacological activity of these peptides. As some new data emerged in the literature, we would like to update recent achievements and progress concerning functions of such convertases, inhibitors, and their potential role in future pharmacotherapy. PMID- 23016690 TI - Viral proteases as targets for drug design. AB - In order to productively infect a host, viruses must enter the cell and force host cell replication mechanisms to produce new infectious virus particles. The success of this process unfortunately results in disease progression and, in the case of infection with many viral species, may cause mortality. The discoveries of Louis Pasteur and Edward Jenner led to one of the greatest advances in modern medicine - the development of vaccines that generate long-lasting memory immune responses to combat viral infection. Widespread use of vaccines has reduced mortality and morbidity associated with viral infection and, in some cases, has completely eradicated virus from the human population. Unfortunately, several viral species maintain a significant ability to mutate and "escape" vaccine induced immune responses. Thus, novel anti-viral agents are required for treatment and prevention of viral disease. Targeting proteases that are crucial in the viral life cycle has proven to be an effective method to control viral infection, and this avenue of investigation continues to generate anti-viral treatments. Herein, we provide the reader with a brief history as well as a comprehensive review of the most recent advances in the design and synthesis of viral protease inhibitors. PMID- 23016691 TI - Future of protease activity assays. AB - Proteolysis is doubtlessly the most widespread mechanism of biological regulation. By controlling protein synthesis, turnover and activity, it is involved in fundamental physiological processes including apoptosis, cell differentiation, growth and signaling, fertilization, immune response, blood coagulation and digestion. Yet, uncontrolled proteolysis can be harmful for organisms, causing - amongst others - such diseases as cancer, emphysema, inflammation, and neurodegenerative, immunological, and cardiovascular disorders. This paper briefly describes recent advances in the development of methodological design to follow up protease activity. Novel methods of protease sensing are described and evaluated. A variety of fluorescent reporter molecules including nanoparticles, and rare metal chelates are also characterized. PMID- 23016692 TI - Proteolysis in health and disease. PMID- 23016693 TI - Cytologic identification of erythrophagocytic neoplasms in dogs. AB - BACKGROUND: Erythrophagia has been identified in multiple types of tumors in human medicine, but information in veterinary medicine is limited. In dogs and cats, erythrophagia has been reported to occur in mast cell and plasma cell tumors, lymphoma, megakaryocytic leukemia, and hemophagocytic histiocytic sarcoma. On the basis of clinical experience, we believed this to be an incomplete list that might bias veterinarians toward a diagnosis of histiocytic sarcoma when erythrophagia is observed in neoplastic spindle-shaped cells. OBJECTIVE: The objective of this retrospective study was to identify neoplasms in dogs that exhibit erythrophagia within the neoplastic cell population. METHODS: Reports of cytologic samples collected from dogs and submitted to the University of Illinois Veterinary Diagnostic Laboratory between January 2003 and May 2011 were searched for a description of erythrophagia. Only cases with a diagnosis confirmed by histopathologic examination using immunohistochemical analysis or by cytochemical staining were included. Slides were reviewed by one pathologist to confirm the presence of erythrophagocytic neoplastic cells. RESULTS: Of 20,016 reports searched, 897 contained the term "erythrophagia." In 55 reports, neoplastic cells exhibiting erythrophagia were identified. Of these, 21 cases were excluded because the cytologic diagnosis was not confirmed, and the remaining 34 cases included 12 hemangiosarcomas, 11 hemophagocytic histiocytic sarcomas, 9 osteosarcomas, one mast cell tumor, and one T-cell lymphoma. CONCLUSION: Erythrophagia can be found in many tumor types. When erythrophagia is observed in spindle-cell sarcomas, osteosarcoma and hemangiosarcoma should be considered in addition to hemophagocytic histiocytic sarcoma. PMID- 23016695 TI - MicroRNAs from the same precursor have different targeting properties. AB - BACKGROUND: The processing of a microRNA results in an intermediate duplex of two potential mature products that derive from the two arms (5' and 3') of the precursor hairpin. It is often suggested that one of the sequences is degraded and the other is incorporated into the RNA-induced silencing complex. However, both precursor arms may give rise to functional levels of mature microRNA and the dominant product may change from species to species, from tissue to tissue, or between developmental stages. Therefore, both arms of the precursor have the potential to produce functional mature microRNAs. RESULTS: We have investigated the relationship between predicted mRNA targets of mature sequences derived from the 5' and 3' arms of the same pre-microRNAs. Using six state-of-the-art target prediction algorithms, we find that 5'/3' microRNA pairs target different sites in 3' untranslated regions of mRNAs. We also find that these pairs do not generally target overlapping sets of genes, or functionally related genes. CONCLUSIONS: We show that alternative mature products produced from the same precursor microRNAs have different targeting properties and therefore different biological functions. These data strongly suggest that developmental or evolutionary changes in arm choice will have significant functional consequences. PMID- 23016697 TI - Modularity and emergence: biology's challenge in understanding life. AB - This essay juxtaposes modularity and emergence in the consideration of biological systems at various scalar levels of spatio-temporal organisation. It is noted that reductionism, specialisation and modularity are basic prerequisites for understanding life. It is realised that increased progress of scientific biology in elucidating mechanisms at the level of modular components supports the accusation that the more it advances in materialistic description of details, the more it diverts from understanding the innate properties of life. It is clear that modularity, by taking the whole as the sum of its parts, is insufficient for understanding living systems. At the same time, however, there is emergence, as advocated by Robert Laughlin. Emergence after the integration of modules leads to completely new properties of individual organisms as unique unitary entities, and also of systems of organisms with synergistic and antagonistic interactions of the integrated species. The discussion is predominantly based on examples from plant biology. At hierarchically higher scalar levels emergent biological systems are networks integrating species, biotopes, ecosystems and the entire biosphere of Earth, also named Gaia by James Lovelock, in a natural scientific respect. While investigating modules remains essential, biology as a nature science needs to merge and integrate such information to be able to unfold emergence. Through efforts towards visualising and understanding emergent diversity and complexity, the research discipline of biology will provide invaluable contributions to understanding life, and thus refute the accusation that it diverts from embracing the innate properties of life. PMID- 23016694 TI - Obesity and addiction: neurobiological overlaps. AB - Drug addiction and obesity appear to share several properties. Both can be defined as disorders in which the saliency of a specific type of reward (food or drug) becomes exaggerated relative to, and at the expense of others rewards. Both drugs and food have powerful reinforcing effects, which are in part mediated by abrupt dopamine increases in the brain reward centres. The abrupt dopamine increases, in vulnerable individuals, can override the brain's homeostatic control mechanisms. These parallels have generated interest in understanding the shared vulnerabilities between addiction and obesity. Predictably, they also engendered a heated debate. Specifically, brain imaging studies are beginning to uncover common features between these two conditions and delineate some of the overlapping brain circuits whose dysfunctions may underlie the observed deficits. The combined results suggest that both obese and drug-addicted individuals suffer from impairments in dopaminergic pathways that regulate neuronal systems associated not only with reward sensitivity and incentive motivation, but also with conditioning, self-control, stress reactivity and interoceptive awareness. In parallel, studies are also delineating differences between them that centre on the key role that peripheral signals involved with homeostatic control exert on food intake. Here, we focus on the shared neurobiological substrates of obesity and addiction. PMID- 23016698 TI - High-quality CMV-specific CD4+ memory is enriched in the lung allograft and is associated with mucosal viral control. AB - The maintenance of CMV-specific T cell memory in lung transplant recipients (LTRs) is critical for host defense and allograft durability, particularly in donor(+) /recipient(-) (D(+) R(-) ) individuals who demonstrate increased mortality. We studied CD4(+) and CD8(+) CMV-specific memory responses to phosphoprotein 65 (pp65) in a prospective cohort of 18 D(+) R(-) LTRs, from bronchoalveolar lavage (BAL)-obtained lung mononuclear cells (LMNC) and PBMC. Unexpectedly, pp65-specific CD4(+) and CD8(+) IFN-gamma memory responses from LMNC were similar, in contrast to persistent CD8(+) predominance in PBMC. Unlike the pulmonary CD8(+) predominance during acute primary infection, compartmental equalization occurred in the CMV-specific CD8(+) memory pool during chronic infection, whereas CMV-specific CD4(+) memory was enriched in the bronchoalveolar space. Moreover, CMV-specific CD4(+) memory T cells with multifunctional production of IFN-gamma, TNF-alpha, IL-2 and MIP-1beta were significantly increased in LMNCs, in contrast to similar intercompartmental CD8(+) memory function. Moreover, the absolute number of CMV-specific CD4(+) IFN-gamma(+) memory cells in BAL was significantly increased in LTRs exhibiting viral control compared to those with CMV early antigen positivity. Collectively, these data demonstrate both preferential distribution and functional quality of CMV-specific CD4(+) memory in the lung allograft during chronic infection, and show an important association with CMV mucosal immunity and viral control. PMID- 23016699 TI - Hospital implementation of health information technology and quality of care: are they related? AB - BACKGROUND: Recently, there has been considerable effort to promote the use of health information technology (HIT) in order to improve health care quality. However, relatively little is known about the extent to which HIT implementation is associated with hospital patient care quality. We undertook this study to determine the association of various HITs with: hospital quality improvement (QI) practices and strategies; adherence to process of care measures; risk-adjusted inpatient mortality; patient satisfaction; and assessment of patient care quality by hospital quality managers and front-line clinicians. METHODS: We conducted surveys of quality managers and front-line clinicians (physicians and nurses) in 470 short-term, general hospitals to obtain data on hospitals' extent of HIT implementation, QI practices and strategies, assessments of quality performance, commitment to quality, and sufficiency of resources for QI. Of the 470 hospitals, 401 submitted complete data necessary for analysis. We also developed measures of hospital performance from several publicly data available sources: Hospital Compare adherence to process of care measures; Medicare Provider Analysis and Review (MEDPAR) file; and Hospital Consumer Assessment of Healthcare Providers and Systems HCAHPS(r) survey. We used Poisson regression analysis to examine the association between HIT implementation and QI practices and strategies, and general linear models to examine the relationship between HIT implementation and hospital performance measures. RESULTS: Controlling for potential confounders, we found that hospitals with high levels of HIT implementation engaged in a statistically significant greater number of QI practices and strategies, and had significantly better performance on mortality rates, patient satisfaction measures, and assessments of patient care quality by hospital quality managers; there was weaker evidence of higher assessments of patient care quality by front line clinicians. CONCLUSIONS: Hospital implementation of HIT was positively associated with activities intended to improve patient care quality and with higher performance on four of six performance measures. PMID- 23016700 TI - The state of nanoparticle-based nanoscience and biotechnology: progress, promises, and challenges. AB - Colloidal nanoparticles (NPs) have become versatile building blocks in a wide variety of fields. Here, we discuss the state-of-the-art, current hot topics, and future directions based on the following aspects: narrow size-distribution NPs can exhibit protein-like properties; monodispersity of NPs is not always required; assembled NPs can exhibit collective behavior; NPs can be assembled one by one; there is more to be connected with NPs; NPs can be designed to be smart; surface-modified NPs can directly reach the cytosols of living cells. PMID- 23016702 TI - Interfacial growth of controllable morphology of silver patterns on plastic substrates. AB - Controllable growth of newly born silver nanoparticles to fractal, cauliflower like, microscale disks and continuous silver layers with high conductivity and reflectivity on plastic substrates has been developed via solid-liquid interfacial reduction and growing of ion-doped polymeric films. Such approaches involve polyimide (PI) films as substrates, its corresponding silver-ion-doped precursors as solid oxidants, and facile immersion of ion-doped polymeric films in aqueous reducing solution. The solution reducing process belongs to liquid solid interfacial reduction processes, during which silver ions doped in polymeric matrix transformed to newly born silver nanoparticles which further aggregated and migrated along the liquid-solid interface to form dendrite, cauliflower-like and lamella disk-like architecture and/or severely compact continuous silver nanolayers with highly reflective and conductive properties. Time-dependent morphology evolutions of silver particles were traced by scanning electron microscopy (SEM), atomic force microscopy (AFM), and transmission electron microscopy (TEM). This strategy can also extend to synthesis of many other metals on polymeric films while maintaining outstanding metal-polymer adhesion based on incorporation of various metal ions, and may offer an opportunity to fabricate large scale, high-output, cost-effective processes for metal patterns on flexible polymeric substrates. PMID- 23016701 TI - Transcriptomic analysis of grape (Vitis vinifera L.) leaves during and after recovery from heat stress. AB - BACKGROUND: Grapes are a major fruit crop around the world. Heat stress can significantly reduce grape yield and quality. Changes at the molecular level in response to heat stress and subsequent recovery are poorly understood. To elucidate the effect of heat stress and subsequent recovery on expression of genes by grape leaves representing the classic heat stress response and thermotolerance mechanisms, transcript abundance of grape (Vitis vinifera L.) leaves was quantified using the Affymetrix Grape Genome oligonucleotide microarray (15,700 transcripts), followed by quantitative Real-Time PCR validation for some transcript profiles. RESULTS: We found that about 8% of the total probe sets were responsive to heat stress and/or to subsequent recovery in grape leaves. The heat stress and recovery responses were characterized by different transcriptional changes. The number of heat stress-regulated genes was almost twice the number of recovery-regulated genes. The responsive genes identified in this study belong to a large number of important traits and biological pathways, including cell rescue (i.e., antioxidant enzymes), protein fate (i.e., HSPs), primary and secondary metabolism, transcription factors, signal transduction, and development. We have identified some common genes and heat shock factors (HSFs) that were modulated differentially by heat stress and recovery. Most HSP genes were upregulated by heat stress but were downregulated by the recovery. On the other hand, some specific HSP genes or HSFs were uniquely responsive to heat stress or recovery. CONCLUSION: The effect of heat stress and recovery on grape appears to be associated with multiple processes and mechanisms including stress-related genes, transcription factors, and metabolism. Heat stress and recovery elicited common up- or downregulated genes as well as unique sets of responsive genes. Moreover, some genes were regulated in opposite directions by heat stress and recovery. The results indicated HSPs, especially small HSPs, antioxidant enzymes (i.e., ascorbate peroxidase), and galactinol synthase may be important to thermotolerance of grape. HSF30 may be a key regulator for heat stress and recovery, while HSF7 and HSF1 may only be specific to recovery. The identification of heat stress or recovery responsive genes in this study provides novel insights into the molecular basis for heat tolerance in grape leaves. PMID- 23016703 TI - Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: humans are more like mice than rats. AB - Isoniazid (INH) is associated with serious liver injury and autoimmunity. Classic studies in rats indicated that a reactive metabolite of acetylhydrazine is responsible for the covalent binding and toxicity of INH. Studies in rabbits suggested that hydrazine might be the toxic species. However, these models involved acute toxicity with high doses of INH, and INH-induced liver injury in humans has very different features than such animal models. In this study, we demonstrated that a reactive metabolite of INH itself can covalently bind in the liver of mice and also to human liver microsomes. Covalent binding also occurred in rats, but it was much less than that in mice. We were able to trap the reactive metabolite of INH with N-alpha-acetyl-l-lysine in incubations with human liver microsomes. This suggests that the reactive intermediate of INH that leads to covalent binding is a diazohydroxide rather than a radical or carbocation because those reactive metabolites would be too reactive to trap in this way. Treatment of mice or rats with INH for up to 5 weeks did not produce severe liver injury. The alanine transaminase assay (ALT) is inhibited by INH, and other assays such as glutamate and sorbitol dehydrogenase (SDH) were better biomarkers of INH-induced liver injury. High doses of INH (200 and 400 mg/kg/day) for one week produced steatosis in rats and an increase in SDH, which suggests that it can cause mitochondrial injury. However, steatosis was not observed when INH was given at lower doses for longer periods of time to either mice or rats. We propose that covalent binding of the parent drug can contribute to INH-induced hepatotoxicity and autoimmunity. We also propose that these are immune-mediated reactions, and there are clinical data to support these hypotheses. PMID- 23016704 TI - Rational design of a ratiometric and targetable fluorescent probe for imaging lysosomal zinc ions. AB - Fluorescent detecting and tracking of zinc ions in living cells has become more and more important because the physiological and pathological functions of zinc are highly associated with the timing and discrete distribution of subcellular zinc ion. For the detection of subcellular zinc concentrations with high spatial and temporal reliability, we report the design, synthesis, properties, and bioimaging evaluation of a fluorescent probe, DQZn4, composed of a quinoline scaffold as the ratiometric signaling unit for Zn(2+) and a dimethylethylamino group as the targeting anchor for lysosomes. In acidic aqueous solution (pH = 5.2), DQZn4 features fluorescence emission maximum at 542 nm due to the resonance charge transfer in 4-alkoxy substituted quinoline. Upon binding Zn(2+), the probe displays significant fluorescent turn-on and ratiometric detection of Zn(2+) with blue shift of 47 nm and remarkable fluorescence ratio changes (R = F(495)/F(542 nm), R/R(0) = 5.1). Confocal imaging experiments establish that DQZn4 is able to localize to lysosomes and respond to lysosomal zinc changes in living cells by using fluorescence ratiometry. PMID- 23016706 TI - tDCS modulation of visually induced analgesia. AB - Multisensory interactions can produce analgesic effects. In particular, viewing one's own body reduces pain levels, perhaps because of changes in connectivity between visual areas specialized for body representation, and sensory areas underlying pain perception. We tested the causal role of the extrastriate visual cortex in triggering visually induced analgesia by modulating the excitability of this region with transcranial direct current stimulation (tDCS). Anodal, cathodal, or sham tDCS (2 mA, 10 min) was administered to 24 healthy participants over the right occipital or over the centro-parietal areas thought to be involved in the sensory processing of pain. Participants were required to rate the intensity of painful electrical stimuli while viewing either their left hand or an object occluding the left hand, both before and immediately after tDCS. We found that the analgesic effect of viewing the body was enhanced selectively by anodal stimulation of the occipital cortex. The effect was specific for the polarity and the site of stimulation. The present results indicate that visually induced analgesia may depend on neural signals from the extrastriate visual cortex. PMID- 23016708 TI - Improving RBC K transport and hemoglobin-O2 binding by amiloride: A novel therapeutic approach for reversion of angina and myocardial ischemia in coronary heart diseases. AB - Coronary heart disease (CHD) is the leading cause of morbidity and mortality across the entire world, in which reversion of angina or improvement of ECG remains an unrealistic therapeutic option for most patients, suggesting that microvascular dysfunction or impaired oxygen delivery might be critical factors in CHD. This research article, thus presents the rationale basis, clinical and experimental, for the first therapeutic innovation addressing the role of red blood cell (RBC) H/K and O2/CO2 exchanges in CHD. It is followed by a randomized single-blind trial of Amiloride and Optimal Medical Therapy (OMT, n=35 cases) vs OMT alone (n=35 cases) in patients having angina, ST-T alteration and a defective RBC-K transport. All patients had serial clinical evaluation, Ion Transport Studies, ECGs and non-invasive aortic waveform and cardiovascular hemodynamic recordings. Statistical analysis was performed by SAS. RESULTS: Amiloride rapidly improved RBC-K (93.5 +/-4 vs 84.5 +/-4 mmol/lc, p= < 0.001), angina (80% of cases, 1.5 +/-0.3 weeks, CI:1.72 to 1.45), CCS Class (1.3 +/-0.5 vs 3.1 +/-0.8, p < 0.001) vs patients with OMT alone CCS Class (3.2 +/- 0.4 vs 3.3 +/- 0.5, p =0.21). Reversion of angina was sustained through the next 6-months (87% vs 26 % in OMT, RR 2.1, odds ratio 6.31, Pearson x2 34.6,p < 0.0001 at 95% CI) and 1-year (85% vs 37% OMT). At 6-months of amiloride, ECG became normal (29% vs 0%, RR infinity uncalculated-time, odds ratio infinity, Pearson x2 42.4 at 95% CI, p < 0.0001), improved (55% vs 29%; RR2.1, odds ratio 3.16, 95% CI, p < 0.0001) or unchanged (15% vs 67% OMT). At 1-year, seven patients on amiloride (18%) exhibited evidence of electrical regeneration of the heart, not observed with placebo. IN CONCLUSION: This therapeutical innovation of amiloride improves RBC H/K and O2/CO2 function, and reverses angina, ST-T alterations while inducing electrical regeneration of the heart, in patients receiving optimal medical treatment for angina. The article has short discussion on the relevant patents to the topic. PMID- 23016709 TI - Actual knowledge of systemic inflammation reaction during cardiopulmonary bypass. AB - Systemic inflammation response is a complex physiopathological host response following aggression. This phenomenon is well described during cardiac surgery under cardiopulmonary bypass but also in the context of off-pump cardiac surhery. The goal of this article is to review the different mechanisms involved in the systemic inflammation response, abusively called "systemic inflammatory response syndrome". The article will describe the different component of this response with a clear definition of different pathways found in this process. The possible relation between systemic inflammation and postoperative outcome will be described. The different therapeutic and prophylactic options evaluated to decrease the systemic inflammation reaction will be summarized. PMID- 23016710 TI - Kangaroo Mother Care in Kangaroo ward for improving the growth and breastfeeding outcomes when reaching term gestational age in very low birth weight infants. AB - AIM: To study the effect of Kangaroo mother care in the Kangaroo ward in comparison with conventional care at neonatal unit on growth and breastfeeding in very low birth weight infants at 40 weeks' corrected gestational age. METHODS: One hundred and forty neonates with birth weight <1500 g were randomized. The primary outcome was the average weight gain (g/kg/day) from the time of randomization to term gestational age. RESULTS: Mean birth weight, age in days and weight at randomization were similar in both the groups. At term gestational age, average weight gain (g/kg/day) post randomization (23.3 +/- 8.7 g vs. 22.64 +/- 9.1 g, p = 0.67) and breastfeeding rate (85.9% vs. 87.0%) were comparable. There was no difference in weight gain (g/kg/day) from randomization to hospital discharge between the Kangaroo care group and conventional care group (18.01 g vs. 15.64 g, p = 0.12). Mortality, morbidities like sepsis, hypothermia, apnoea, hypoglycaemia and duration of hospitalization were equally distributed. On average, 11.5 days of intermediate care were saved in the kangaroo group. CONCLUSION: Kangaroo mother care in the Kangaroo ward is as effective as conventional care in the neonatal unit without any increase in morbidity or mortality in stable VLBW infants. PMID- 23016711 TI - Loss of beta1 accessory Na+ channel subunits causes failure of carbamazepine, but not of lacosamide, in blocking high-frequency firing via differential effects on persistent Na+ currents. AB - PURPOSE: In chronic epilepsy, a substantial proportion of up to 30% of patients remain refractory to antiepileptic drugs (AEDs). An understanding of the mechanisms of pharmacoresistance requires precise knowledge of how AEDs interact with their targets. Many commonly used AEDs act on the transient and/or the persistent components of the voltage-gated Na(+) current (I(NaT) and I(NaP) , respectively). Lacosamide (LCM) is a novel AED with a unique mode of action in that it selectively enhances slow inactivation of fast transient Na(+) channels. Given that functional loss of accessory Na(+) channel subunits is a feature of a number of neurologic disorders, including epilepsy, we examined the effects of LCM versus carbamazepine (CBZ) on the persistent Na(+) current (I(NaP) ), in the presence and absence of accessory subunits within the channel complex. METHODS: Using patch-clamp recordings in intact hippocampal CA1 neurons of Scn1b null mice, I(NaP) was recorded using slow voltage ramps. Application of 100 MUm CBZ or 300 MUm LCM reduced the maximal I(NaP) conductance in both wild-type and control mice. KEY FINDINGS: As shown previously by our group in Scn1b null mice, CBZ induced a paradoxical increase of I(NaP) conductance in the subthreshold voltage range, resulting in an ineffective block of repetitive firing in Scn1b null neurons. In contrast, LCM did not exhibit such a paradoxical increase, and accordingly maintained efficacy in blocking repetitive firing in Scn1b null mice. SIGNIFICANCE: These results suggest that the novel anticonvulsant LCM maintains activity in the presence of impaired Na(+) channel beta(1) subunit expression and thus may offer an improved efficacy profile compared with CBZ in diseases associated with an impaired expression of beta sub-units as observed in epilepsy. PMID- 23016712 TI - Novel anti-platelet agents for the treatment of stable angina pectoris. AB - Antiplatelet treatment is an important element in the medical treatment of patients with stable angina. Single antiplatelet therapy with low-dose aspirin is recommended in the absence of contraindications in all patients with diagnosed chronic stable angina and ischemic heart disease. Dual antiplatelet therapy is recommended initially for all patients with stable angina undergoing elective angioplasty with the duration of P2Y12 antagonist administration depending on the type of coronary stent. Despite the demonstrated clinical benefit in a wide range of patients, residual risk of ischemic events with aspirin and a P2Y12 inhibitor has also been attributed to the fact that these agents do not inhibit all pathways involved in platelet activation and aggregation. Other platelet activation pathways, including the PAR-1 pathway activated by thrombin (the most potent platelet activator), remain active in the presence of current antiplatelet agents. A combination of current therapies with novel agents could provide more comprehensive platelet inhibition leading to incremental decrease of cardiovascular events at the expense of increased bleeding risk. The current review presents traditional and novel antiplatelet treatment options and discusses the indications for aggressive antiplatelet management in patients with stable angina pectoris. PMID- 23016713 TI - Gene delivery strategies targeting stable atheromatous plaque. AB - Conventional therapeutic options to treat chronic angina pectoris are pharmacological interventions, coronary bypass surgery (CABG) and percutaneous coronary intervention (PCI). In animal models, it was shown that gene delivery strategies harbour an exciting potential to support and maybe even replace conventional anti-angina treatments, but the translation of the basic science to clinical practise appears problematic. Gene therapy targeting key elements of neointima formation (e.g. cell cycle regulators, metalloproteinases, inflammation and oxidative stress) reduces vein graft and stent failure in experimental models. Additionally, systemic gene delivery of genes targeting NO production, oxidative stress, inflammation and foam cell formation has been shown to prevent atherosclerosis in different animal models. During CABG the vein graft can be transfected ex vivo and during PCI, a stent carrying transfection vectors can be deployed. Both strategies result in the induction of local transgene expression at the site of interest. This limits unwarranted transgene expression and the toxicity seen with systemic gene delivery. However, with the development of new transfection vectors, able to induce local transgene expression without detrimental side effects, systemic anti-inflammatory and anti-oxidative, gene delivery could be a powerful tool in secondary prevention. PMID- 23016714 TI - Heart rate as a therapeutic target in angina pectoris. AB - Heart rate is a major determinant of cardiac output and myocardial oxygen utilization and is increasingly being nominated as a modifiable risk factor for cardiovascular disease. Despite this evidence, screening strategies for preventing cardiovascular diseases do not include routine assessment of resting heart rate. Reasonably, heart rate reduction has been suggested as a useful approach against angina pectoris in subjects with acute or chronic coronary syndromes. Accordingly, reduction of heart rate in patients with stable angina could be an additional goal of therapy. Important data have shown retrospectively the beneficial effect of heart rate-lowering drugs, such as betaadrenoceptor antagonists, non-dihydropyridine calcium channel antagonists, as well as other agents, on several parameters in patients with coronary artery disease and stable angina. However, additional data are now being sought to assess the impact of this approach on clinical practice. PMID- 23016715 TI - Insight to the pathophysiology of stable angina pectoris. AB - Atherosclerosis is a chronic disease which mainly represents an inflammatory response in the vessels. Myocardial ischemia manifested by angina pectoris can be either acute or chronic and usually is a result of imbalance between myocardial oxygen supply and myocardial oxygen demand. Chronic stable angina is chest discomfort attributed to myocardial ischemia without the presence of necrosis and is the most common symptom encountered by emergency room physicians. A growing amount of data has shown that endothelial dysfunction, is now considered an important early event in the development of atherosclerosis, while in the absence of angiographically obstructive coronary artery disease, anginal chest pain is often attributed to microvascular coronary dysfunction. Moreover, atheroma formation and in turn, atherosclerotic plaques seem to affect coronary flow, given that multivessel flow-limiting obstructions are observed in patients with chronic coronary syndrome. Morphological changes of diseased arteries related to significant atherosclerosis, such as vascular remodeling may also result in stable angina or claudication. However, several issues with respect to the comprehension of the pathophysiology of the chronic coronary syndrome have not been fully elucidated. PMID- 23016716 TI - Targeting myocardial metabolism for the treatment of stable angina. AB - The goals of pharmacological treatment of stable angina pectoris are to improve quality of life by reducing the severity and/or frequency of symptoms and also the long-term prognosis. Patients with coronary artery disease have viable but dysfunctional myocardium. The metabolism of the ischemic myocardium is characterized by a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Targeting myocardial metabolism as a pharmacologic approach for chronic angina is based on the concept that metabolic adaptive mechanisms during ischemia resemble fetal energy metabolism by shifting substrate use towards glucose metabolism. Potential pharmacologic approaches should target i) the suppression of lipolysis and the plasma fatty acid levels and subsequent uptake and oxidation by the heart, ii) direct inhibition of the enzymes of fatty acid beta-oxidation, iii) inhibition of carnitine palmitoyl transferase- I (CPT-1). Currently, there are no approved medications directly targeting myocardial metabolism. However, in the last two years a number of medications indirectly targeting cardiac metabolism have been tested in small clinical trials, and some of them appear to be promising potential therapies for stable angina. This review summarizes the main aspects of myocardial metabolism and focuses on the therapeutic approaches that could offer clinical benefit in patients with stable angina. PMID- 23016717 TI - Stable angina pectoris: current medical treatment. AB - Stable angina represents the main symptom of established coronary artery disease. In addition atherosclerosis is the common pathological substrate of chronic stable angina as well as acute coronary syndromes. The aim of stable angina management is the symptomatic relief and the secondary prevention. Lifestyle modification and pharmacological therapy are the cornerstones of chronic coronary artery disease management irrespectively of possible surgical or percutaneous revascularization. Optimal medical therapy is a combination of antianginal/antiischemic drugs and disease modifying agents, including nitrates, beta-blockers, calcium channel blockers, antiplatelets, statins and angiotensin converting enzyme inhibitors. Novel classes of treatment with different mechanisms of action have been developed in the last years, including nicorandil, ivabradine, trimetazidine and ranolazine. These drugs, which are currently approved as second-line treatments, have dynamically entered the clinical practice and their long-term effects are still under investigation. PMID- 23016718 TI - Novel risk factors related to stable angina. AB - Stable angina (SA) pectoris is a common and disabling disorder in patients with coronary artery disease (CAD), with increasing epidemiology and is associated with myocardial infarction and increased mortality. However, within the population of SA patients, an individual's prognosis can vary considerably. Except from conventional risk factors a variety of biomarkers have been evaluated for their prognostic significance in the settings of SA. Novel biomarkers associated with inflammatory status, such as C reactive protein and tumor necrosis factor alpha, with myocardial performance, such as B-type natriuretic peptide, with extracellular matrix remodeling, with vascular calcification such as osteoprotogerin and osteopontin, with myocardial ischemia, such as ischemia modified albumin have been associated with the progression of CAD and with the prognosis of SA patients. Despite the multiplicity of novel biomarkers there is lack of a clinical useful, highly specific for CAD biomarker with the ability to guide treatment decisions. In the context of this evidence in this review article we summarize the so far acquired knowledge of the most promising biomarkers and we discuss the major clinical correlations of novel risk factors with SA physical history, their predictive value for future cardiovascular events and their use in the treatment monitoring of this population. PMID- 23016719 TI - Is there a role for antioxidants in the treatment of stable angina? AB - Medical treatment plays an important role in the therapy of coronary artery disease and stable angina. Whereas nitrates are used to improve symptoms, beta blockers, statins, and ACE-inhibitors/angiotensin receptor blockers are given also to target prognosis in part by slowing the progression of disease. Major cardiovascular risk factors including tobacco smoking, physical inactivity, obesity, arterial hypertension, hyperlipidemia, and diabetes mellitus were associated with overproduction of reactive oxygen species (ROS). In animal models, increased ROS production was associated with the initial steps of atherosclerosis including vascular cell dysfunction, intimal hypertrophy, the formation and destabilization of plaque. As a consequence, ROS were believed to be major contributors to the development of cardiovascular diseases and antioxidant treatments were proposed as promising therapeutic strategies. Nevertheless, intervention studies with antioxidant vitamins have failed to positively affect cardiovascular outcome in prospective trials. Specific inhibitors of prooxidant enzymes are being developed but their efficacy to improve cardiovascular endpoints has not been tested so far. Newer evidence suggests that phytonutrients including flavanols may posses vascular protective effects that are independent of their antioxidant properties observed in vitro. Taken together, there is currently not enough evidence that treatment with antioxidants per se will play a role in cardiovascular medicine. PMID- 23016720 TI - Infections and atheromatous plaque: current therapeutic implications. AB - Infections are the most common inflammatory triggers and acute and chronic infections have been associated with the development and progression of atherosclerotic disease raising interest in the infectious hypothesis of atherosclerosis. Pathogens have been identified in atherosclerotic plaques and large epidemiological studies have documented conflicting associations between serological evidence of infection and cardiovascular events. Influenza A was mostly studied as a trigger for cardiovascular events during winter months, whilst cytomegalovirus, Chlamydia pneumoniae, helicobacter pylori and porphyromonas ginigivalis were the most studied chronic pathogens which had been associated with the development and progression of cardiovascular disease. Infectious agents can contribute to atherosclerosis by having a direct effect on the vascular wall or via indirect effects including inflammatory responses and molecular mimicry. Efforts to prevent infection with vaccination or treat specific infectious agents with antibiotics have provided mostly negative results, thereby challenging the validity of the infectious hypothesis of atherosclerosis. PMID- 23016721 TI - The role of microRNAs in the initiation and progression of stable atheromatous plaque. AB - Atherosclerosis is a chronic process related to several underlying mechanisms leading to the formation and evolution of atherosclerotic plaque. Of great interest are during the last years short, non-coding RNAs, called microRNAs and responsible for several aspects of homeostasis and disease. According to the available data microRNAs are expressed in the cardiovascular system and have key roles in normal states, as well as in disease development and progression. Moreover, it has been shown that they contribute to atherogenesis, coronary artery disease and myocardial infarction. Importantly, microRNAs circulate in the bloodstream, while they exist in tissues, affect plaque initiation and progression and seem to be essential biomarkers of atherosclerosis. Therefore, understanding the role of these molecules may be of great importance in the understanding of the pathogenesis of atheromatous plaque providing new evidence for diagnosis and treatment of atherosclerosis and its' clinical presentation. PMID- 23016722 TI - Novel strategies to target inflammatory processes in atherosclerosis. AB - Atherosclerosis is characterized by chronic inflammation of the vascular wall. Macrophages, which differentiate from circulating monocytes, give rise to foam cells by excessive accumulation of modified lipoproteins. Atherogenesis subsequently progresses through necrotic core expansion associated with apoptosis and the suppressed clearance of apoptotic macrophage (i.e. efferocytosis), followed by the transition to vulnerable plaques. The vulnerable plaque is characterized by thinning of the fibrous cap and necrotic core expansion. Here, the impact of monocytes/macrophages in both early atherogenesis and advanced plaque progression is discussed with a focus on the potential targeting of inflammatory processes in atherosclerosis. PMID- 23016723 TI - Refractory angina pectoris: lessons from the past and current perspectives. AB - Refractory angina pectoris constitutes a manifestation of severe ischemic heart disease that cannot be treated adequately either with conventional medication or with interventional techniques including percutaneous coronary angioplasty (PTCA). As a result, new therapeutic strategies, aiming on angiogenesis, were evolved in order to improve functional class and health related quality of life (HRQOL) indices. Among them, gene therapy constitutes a very promising alternative treatment for these patients. In this review, we will describe i) the definition of refractory angina ii) pathophysiology of angiogenesis, iii) routine as well as novel imaging techniques of neovascularization and iv) current treatment options for refractory angina. Secondly we will review the main angiogenic clinical trials, which will also be commented regarding their effectiveness to reduce the recurrency of angina symptoms and improve health related quality-of-life, as well as the functional class of patients with chronic ischemic disease. PMID- 23016724 TI - Editorial: stable angina pectoris: novel therapeutic insights. PMID- 23016725 TI - Seniors' self-administration of the Elder Abuse Suspicion Index (EASI): a feasibility study. AB - This study explored the feasibility of seniors aged 65 and over with MMSE >=24 completing the EASI-sa, a self-administrable version of the Elder Abuse Suspicion Index (EASI). A convenience sample of 210 was stratified by age, sex, and language (English and French). All completed the EASI-sa within an estimated 5 minutes, 82.9% within 2 minutes. Completion time decreased with higher education, but was not affected by age, sex, language, or measured physical or mental health. No questions went unanswered; no words were poorly understood or discomforting. The EASI-sa completion was associated with a significantly increased understanding about elder abuse (p < 0.0001). PMID- 23016726 TI - Exploring definitions of financial abuse in elderly Korean immigrants: the contribution of traditional cultural values. AB - The purpose of this study is to explore the cultural definitions of financial abuse from the perspective of 124 elderly Korean immigrants and to examine the role of traditional cultural values in their definitions by using a mixed methods approach. The qualitative analysis generated four themes relevant to definition of financial abuse. A binary logistic regression indicated that those with stronger cultural adherence to traditional values had higher odds of providing culture-based definitions of financial abuse. Education is needed for health professionals, social service providers, and adult protective workers to increase their understanding of culture-specific experiences of financial abuse among ethnic minority elders. PMID- 23016727 TI - Detection scales for the risk of domestic abuse and self-negligent behavior in elderly persons (EDMA). AB - This article presents the results of a study carried out to determine the psychometric properties of an instrument designed for use by social services professionals to detect domestic abuse and self-negligent behavior in elderly persons. After giving a description of the features of the instrument and the design of the study, the results obtained, in terms of the reliability and validity of the instrument, are shown. Finally, the authors compare their instrument and its test results with other established instruments and indicate the limits of their study. PMID- 23016728 TI - Screening for elder mistreatment in a dental clinic population. AB - The purpose of this study was to establish the feasibility and utility of screening for elder mistreatment in a dental clinic population. We approached older adults in a busy dental clinic and enrolled 139 persons over the age of 65 who completed an Audio Computer Assisted Self Interview (ACASI), which included the Hwalek-Sengstock Elder Abuse Screening Test (HS-EAST). Overall, 48.4% of the participants scored 3 or greater on the HS-EAST, and 28.3% scored 4 or greater. Our study suggests that there is an opportunity to screen in busy dental clinics and to facilitate early detection for those patients who screen positive for elder mistreatment. PMID- 23016729 TI - Resident-to-resident abuse in nursing homes as reported by nurse aides. AB - Information on the scale and scope of resident-to-resident abuse, including verbal, physical, material, psychological, and sexual abuse, is presented. Nursing homes (n = 249) from ten states were used, with a total of 4,451 nurse aides in these facilities returning the questionnaire. Most nursing homes experienced verbal, physical, material, and psychological abuse, but sexual abuse was less common. Our findings clearly show that both the scale and scope of resident-to-resident abuse is high in nursing homes. Resident-to-resident abuse is common enough to be considered an issue of concern impacting the quality of life and safety of many residents. PMID- 23016730 TI - Family members' reports of non-staff abuse in Michigan nursing homes. AB - Recent research showed that mistreatment of nursing home residents by other residents may be highly prevalent. The present study examined the issue from family members' perspectives. The data came from the 2005 and 2007 random-digit dial telephone surveys of Michigan households with a family member in long-term care. Based on family members' reports, about 10% of nursing home residents aged 60 and over were abused by non-staff in nursing homes (e.g., other residents and visitors) during the past 12 months. Family members were more likely to report non-staff abuse when the nursing home residents were younger, were female, had behavior problems, and had greater level of physical functioning. Family members who reported staff abuse were four times more likely to also report non-staff abuse. PMID- 23016733 TI - Effect of specialty and recent experience on perioperative decision-making for abdominal aortic aneurysm repair. AB - OBJECTIVES: To determine whether recent experience and specialty choice would affect physician adherence to evidence-based guidelines. DESIGN: In a series of computer-simulated encounters, participants weighed the risk of spontaneous abdominal aortic aneurysm (AAA) rupture against the risk of perioperative death to determine timing for elective repair. Guideline recommendations and statistical information on the risks of rupture and surgical death were provided. SETTING: Annual meetings of the American Geriatrics Society, American College of Surgeons, and American Society of Anesthesiologists. PARTICIPANTS: Physicians. INTERVENTION: Before the simulation, each participant was randomly exposed to one of three simulated outcomes: death during watchful waiting (WWD), perioperative death (PD), or successful outcome (SO). MEASUREMENTS: Adherence to recommended guidelines for AAA treatment. RESULTS: Against guideline recommendations, 67% of geriatricians, 74% of anesthesiologists, and 77% of surgeons chose surgery when the rupture risk was lower than the risk of perioperative death (P < .05). Surgeons exposed to the WWD experience chose surgery significantly earlier than if they were exposed to a PD or SO experience (P < .001). Anesthesiologist choices did not differ with recent experience. CONCLUSION: Geriatrician decisions more closely followed guideline recommendations for AAA management than those of two other specialties typically involved in AAA care. A prior WWD affected surgeons most, geriatricians next, and anesthesiologists least. Geriatricians referring patients for AAA surgery should be aware of specialty-specific differences in perioperative decision behavior. PMID- 23016734 TI - Real-time RT-PCR high-resolution melting curve analysis and multiplex RT-PCR to detect and differentiate grapevine leafroll-associated virus 3 variant groups I, II, III and VI. AB - BACKGROUND: Grapevine leafroll-associated virus 3 (GLRaV-3) is the main contributing agent of leafroll disease worldwide. Four of the six GLRaV-3 variant groups known have been found in South Africa, but their individual contribution to leafroll disease is unknown. In order to study the pathogenesis of leafroll disease, a sensitive and accurate diagnostic assay is required that can detect different variant groups of GLRaV-3. METHODS: In this study, a one-step real-time RT-PCR, followed by high-resolution melting (HRM) curve analysis for the simultaneous detection and identification of GLRaV-3 variants of groups I, II, III and VI, was developed. A melting point confidence interval for each variant group was calculated to include at least 90% of all melting points observed. A multiplex RT-PCR protocol was developed to these four variant groups in order to assess the efficacy of the real-time RT-PCR HRM assay. RESULTS: A universal primer set for GLRaV-3 targeting the heat shock protein 70 homologue (Hsp70h) gene of GLRaV-3 was designed that is able to detect GLRaV-3 variant groups I, II, III and VI and differentiate between them with high-resolution melting curve analysis. The real-time RT-PCR HRM and the multiplex RT-PCR were optimized using 121 GLRaV-3 positive samples. Due to a considerable variation in melting profile observed within each GLRaV-3 group, a confidence interval of above 90% was calculated for each variant group, based on the range and distribution of melting points. The intervals of groups I and II could not be distinguished and a 95% joint confidence interval was calculated for simultaneous detection of group I and II variants. An additional primer pair targeting GLRaV-3 ORF1a was developed that can be used in a subsequent real-time RT-PCR HRM to differentiate between variants of groups I and II. Additionally, the multiplex RT-PCR successfully validated 94.64% of the infections detected with the real-time RT-PCR HRM. CONCLUSION: The real-time RT-PCR HRM provides a sensitive, automated and rapid tool to detect and differentiate different variant groups in order to study the epidemiology of leafroll disease. PMID- 23016736 TI - New light through old windows: nurses, colonists and indigenous survival. AB - The aim of this study was to explore the influences, processes and environments that shaped the practice of European nurses for indigenous New Zealand (NZ) Maori communities who were being overwhelmed by introduced infectious diseases. Historical data were accessed from multiple archival sources and analysed through the lens of colonial theory. Through their work early last century, NZ nurses actively gained professional status and territory through their work with Maori. By living and working alongside Maori, they learned to practise in new ways that influenced Maori health. By developing a new role in new professional territory, nurses extended their practice to include health promotion as well as disease prevention. Maori survival from epidemics improved, and the population grew over that period. For Maori, however, Eurocentric care alleviated their immediate health problems, but the detrimental impact of the mechanisms of colonisation overall has continued to the present day. PMID- 23016735 TI - Personalized approach of medication by indirect anticoagulants tailored to the patient-Russian context: what are the prospects? AB - Indirect anticoagulants such as warfarin are the 'gold standard' for prevention and treatment of thromboembolic complications in patients at risk (in atrial fibrillation of valvular and nonvalvular etiology, the presence of artificial heart valves, orthopedic and trauma interventions, and other pathological conditions). A wide range of doses required to achieve a therapeutic effect indicates the need for a personalized approach to the appointment of warfarin. In addition to the dependence on the patient's clinical characteristics (sex, age, smoking status, diagnosis), there is a clear association between the warfarin dose and the carriage of certain allelic variants of key genes that makes it possible to apply molecular genetic testing for individual dose adjustment. This provides a more rapid target anticoagulant effect and also reduces the risk of bleeding associated with a possible overdose of warfarin. Implementation of this approach will allow more wide and safe application of indirect anticoagulants in Russia for needy patients. PMID- 23016737 TI - Special issue on radiation effects on stem cells and non-targeted effects of radiation. PMID- 23016738 TI - Mechanisms involved in the induction of radiation-induced non-targeted eff ects. Introduction. PMID- 23016742 TI - Unraveling the wonders of platelets. PMID- 23016739 TI - Pharmacoeconomics and its implication on priority-setting for essential medicines in Tanzania: a systematic review. AB - BACKGROUND: Due to escalating treatment costs, pharmacoeconomic analysis has been assigned a key role in the quest for increased efficiency in resource allocation for drug therapies in high-income countries. The extent to which pharmacoeconomic analysis is employed in the same role in low-income countries is less well established. This systematic review identifies and briefly describes pharmacoeconomic studies which have been conducted in Tanzania and further assesses their influence in the selection of essential medicines. METHODS: Pubmed, Embase, Cinahl and Cochrane databases were searched using "economic evaluation", "cost-effectiveness analysis", "cost-benefit analysis" AND "Tanzania" as search terms. We also scanned reference lists and searched in Google to identify other relevant articles. Only articles reporting full economic evaluations about drug therapies and vaccines conducted in Tanzania were included. The national essential medicine list and other relevant policy documents related to the identified articles were screened for information regarding the use of economic evaluation as a criterion for medicine selection. RESULTS: Twelve pharmacoeconomic studies which met our inclusion criteria were identified. Seven studies were on HIV/AIDS, malaria and diarrhoea, the three highest ranked diseases on the disease burden in Tanzania. Six studies were on preventive and treatment interventions targeting pregnant women and children under the age of five years. The national essential medicine list and the other identified policy documents do not state the use of economic evaluation as one of the criteria which has influenced the listing of the drugs. CONCLUSION: Country specific pharmacoeconomic analyses are too scarce and inconsistently used to have had a significant influence on the selection of essential medicines in Tanzania. More studies are required to fill the existing gap and to explore whether decision-makers have the ability to interpret and utilise pharmacoeconomic evidence. Relevant health authorities in Tanzania should also consider how to apply pharmacoeconomic analyses more consistently in the future priority-setting decisions for selection of essential medicines. PMID- 23016743 TI - Diagnosis and treatment of platelet hyperactivity in relation to thrombosis in dogs and cats. AB - OBJECTIVE: To review the mechanisms of platelet activation and options for diagnosing and treating platelet hyperactivity in relation to thrombosis in dogs and cats. DATA SOURCES: Prospective, retrospective, and review articles, as well as textbook chapters in both human and veterinary medicine. Articles were primarily, but not exclusively, retrieved via Medline. HUMAN DATA SYNTHESIS: In people, platelets are known to play a key role in the development of arterial thrombosis in numerous disease states and antiplatelet drugs are the cornerstone in the treatment of acute events and for prevention in patients at risk. For many years, aspirin was used as the sole antiplatelet drug in people, but the introduction of adenosine diphosphate receptor antagonists and integrin alpha(IIb) beta(3) inhibitors has significantly improved outcome in selective groups of patients. VETERINARY DATA SYNTHESIS: The understanding of platelet activation in disease states has increased dramatically over the past decade. Simultaneously, a host of new methods for evaluating platelet function have been developed, which enable primarily researchers, but also clinicians to monitor the activity of platelets. Many of these methods have been validated for research purposes, but few have found their way to the clinics. Not a single correctly randomized clinical trial has been carried out with any antiplatelet drug for any indication in dogs or cats, and consequently, treatment is empiric and largely based on expert opinion or data from experimental studies. CONCLUSIONS: The pathogenesis of thromboembolic disease is complex and multifactorial and the role of hyperactive platelets in this etiology remains to be clarified in most of the diseases associated with thrombosis in dogs and cats. Until efficacy data from well-designed studies are available, antithrombotic therapy should consist of close monitoring, good supportive care, and judicious empirical use of antiplatelet agents. PMID- 23016744 TI - Platelet transfusions: treatment options for hemorrhage secondary to thrombocytopenia. AB - OBJECTIVE: To review current human and veterinary protocols for platelet transfusion triggers, available platelet transfusion products to support veterinary thrombocytopenic patients, and the advantages and disadvantages of each product. DATA SOURCES: Data from human and veterinary literature. HUMAN DATA SYNTHESIS: Prophylactic and therapeutic platelet transfusions are instrumental in managing human patients with thrombocytopenia. The platelet transfusion products used in human medicine consist of platelet concentrates, derived from pooled random donor platelets, or single-donor apheresis platelets. Historically, platelet transfusions in human medicine have been prophylactic in nature; however, recent research suggests changing from a prophylactic transfusion strategy to a therapeutic transfusion strategy may be safe for most patients. The optimal platelet transfusion trigger and the use of prophylactic verses therapeutic platelet transfusions are ever changing in human medicine. VETERINARY DATA SYNTHESIS: There have been many advances in platelet transfusion products, but fresh whole blood remains the most commonly used platelet transfusion product in veterinary medicine. New products such as lyophilized platelets and cryopreserved platelets offer the benefits of long shelf life, immediate availability, and higher concentration of platelets at smaller doses. Veterinary platelet transfusion guidelines are mostly extrapolated from human literature because data on veterinary platelet transfusions are lacking. CONCLUSIONS: In veterinary medicine the most commonly available product for platelet transfusions is fresh whole blood, because of availability of blood donors and lack of a cost effective easily obtainable alternative. Cryopreserved and lyophilized platelets are promising new products being used in the treatment of hemorrhaging patients with thrombocytopenia. These products offer increased platelet concentrations at decreased volumes, longer storage shelf life, and decreased exposure to whole blood products. With the development of newer readily available products, platelet transfusion parameters, to include dose, platelet count trigger, presence of disease, and clinical signs, should be further evaluated in veterinary medicine. PMID- 23016745 TI - Assessment of platelet function. AB - OBJECTIVE: To review the current in vivo and in vitro tests of platelet function (PF) currently available and applicable to companion animals. DATA SOURCES: Scientific reviews, case reports, original clinical and laboratory research publications, and recent veterinary research conference proceedings. HUMAN DATA SYNTHESIS: Disorders of primary hemostasis are very common in human medicine. These include inborn errors of PF and granule storage contents, primary disease mechanisms that alter PF, disorders secondary to surgical interventions, and the effects of anticoagulant medications. Knowledge of PF disorders and the optimal method for assessment must be known to understand the mechanism and to monitor the process or drug therapy. VETERINARY DATA SYNTHESIS: Interest in the study and treatment of primary coagulopathies in clinical veterinary patients has resulted in a surge of recent publications and scientific research presentations. A translational approach that uses laboratory and point-of-care tools to uncover the pathophysiologic mechanisms in the patient with defects in primary hemostasis allows the clinician to plan the diagnosis and treatment more effectively. SUMMARY: Primary hemostatic disorders are being more commonly recognized in clinical veterinary practice. The diagnosis of platelet dysfunction may be obtained via point-of-care analyzers that use relatively small blood samples and have a quick turnaround time. Recent investigations may lead to a better understanding of the pathophysiology of PF disorders and potentially the optimization, or discovery, of novel treatments. CONCLUSIONS: The assessment of PF can be completed through in vivo and in vitro point-of-care techniques as well as by submission of blood samples to more specialized platelet biology laboratories. The information obtained including the physical examination and clinical manifestations of a hemostatic disorder, as well as the benefits of each testing modality, must be known prior to the diagnostic investigation of a patient with a coagulopathy. PMID- 23016746 TI - Evaluation of platelet aggregometry in dogs using the Multiplate platelet analyzer: impact of anticoagulant choice and assay duration. AB - OBJECTIVE: To investigate the performance of the Multiplate platelet function analyzer with regards to: (1) the use of 3 different anticoagulants (ie, citrate, hirudin, and heparin) and (2) the evaluation of optimal assay time. DESIGN: Prospective observational in vitro study. SETTING: University veterinary teaching hospital. ANIMALS: Twenty clinically healthy dogs and 3 ill dogs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 184 analyses were performed with duplicate measurements in each test cell and results are reported as mean of the 2 measurements. Analyses were performed on blood samples from 20 dogs collected in citrate, hirudin, or heparin. A total of 4 analyses were performed on every blood sample using adenosine diphosphate, collagen, and arachidonic acid as agonists as well as a control with 0.9% sodium chloride (buffer). Aggregation in hirudin samples was significantly increased compared with heparin at all analysis times except at 6 minutes when using ADP as agonist; however, hirudin samples also demonstrated significant aggregation in the buffer control, compared to both citrate and heparin. Citrated samples yielded significantly lower aggregation compared with both hirudin- and heparin-stabilized samples at 6 and 12 minutes when ADP and collagen were used as agonists, and at most analysis times with arachidonic acid. The assay performed best at shorter analyses times, whereas longer analyses times yielded larger variation in data. CONCLUSIONS: There was a good aggregation response and acceptable analytical variation in both heparin- and hirudin-anticoagulated samples with all tested agonist at the concentrations recommended by the manufacturer. The results suggest that heparin may be superior as anticoagulant for Multiplate analyses in dogs and that short analyses times are preferable. Spontaneous platelet autoaggregation in hirudin samples warrants careful evaluation of results using this anticoagulant, especially at longer test times. The use of citrate is discouraged for Multiplate analyses in dogs due to a weak aggregation response. PMID- 23016747 TI - Use of fresh platelet concentrate or lyophilized platelets in thrombocytopenic dogs with clinical signs of hemorrhage: a preliminary trial in 37 dogs. AB - OBJECTIVE: To examine the safety and feasibility of using lyophilized platelets (LYO) and fresh platelet concentrate (FRESH) in bleeding thrombocytopenic dogs. DESIGN: Preliminary prospective randomized clinical trial. SETTING: Two private referral centers and 3 university teaching hospitals. ANIMALS: Thirty-seven dogs with a complaint of hemorrhage associated with thrombocytopenia (platelet count <70 * 10(9) /L [70,000/MUL], a hematocrit >15%, and that had received neither vincristine nor platelet-containing transfusions within 72 h of enrollment were studied. INTERVENTIONS: Animals were randomized to receive LYO or FRESH, dosed according to weight. Physical examination, complete blood counts, and coagulation testing (prothrombin time and activated partial thromboplastin time) were performed at enrollment. Physical examinations were also performed immediately post transfusion, and at 1 and 24 h after transfusion. Complete blood counts were repeated immediately post transfusion and at 24 h. Collected data included bleeding score (BLS), response to transfusion, adverse reactions, hospitalization time, need for additional transfusions, survival to discharge, and 28-d survival. MEASUREMENTS AND MAIN RESULTS: Twenty-two dogs received LYO and 15 received FRESH. There was no difference between groups in age, weight, BLS, platelet count, white blood cell count, hematocrit, or presence of melena. There was no difference between groups in transfusion reaction rates, the need for additional transfusions, 24-h BLS, hospitalization time, survival to discharge, or 28-d survival. CONCLUSIONS: Transfusion of LYO was feasible and associated with a low transfusion reaction rate in this limited study of thrombocytopenic canine patients presenting with mild-to-severe hemorrhage. LYO were easy to use and provided storage advantages over FRESH. Further study of this product, including examination of efficacy and platelet life span, is warranted. PMID- 23016753 TI - In search of legitimacy--registered nurses' experience of providing palliative care in a municipal context. AB - BACKGROUND: The palliative care approach was originally developed for hospice care and for persons with cancer diseases, but has gradually expanded to embrace other contexts and people of all ages, with various life-threatening diseases. The palliative care concept thus also applies to older people and the context of municipal care, where Registered Nurses (RNs) hold key care provision positions. The municipal context is not, however, focused primarily on advanced nursing care, and it is important to highlight RNs' prerequisites for care provision. AIM: The study's aim was to describe RNs' experience of providing palliative care for older people in a municipal context. Data were collected through focus group discussions with 20 RNs from four different municipalities in southern Sweden and were analysed using conventional content analysis. FINDINGS: The results showed that the nurses experienced that it was they who cushioned the effects of unclear responsibilities between different organizations, but had limited legitimacy in the municipal context and in relation to other care providers. The results also showed that nurses lacked proper support and prerequisites for providing high quality palliative care to older dying patients. CONCLUSION: The results pinpoint the importance of increased acknowledgement of nurses' knowledge and skills and a critical view on the effects of moving towards an organization composed of different consultants, which can lead to even more unclear responsibility for nursing care provision. PMID- 23016754 TI - Spatial genetic structure of aquatic bryophytes in a connected lake system. AB - Using genetic markers, we investigated the genetic structure of three clonal aquatic moss species, Calliergon megalophyllum Mikut., Fontinalis antipyretica Hedw. and F. hypnoides Hartm. on two scales: among populations in a connected lake system (large-scale spatial genetic structure) and among individuals within populations (fine-scale spatial genetic structure). Mean genetic diversities per population were 0.138, 0.247 and 0.271, respectively, and total diversities equalled 0.223, 0.385 and 0.421, respectively. Relative differentiation levels (FST values of 0.173, 0.280 and 0.142, respectively) were significant but showed that there is a moderate amount of gene flow taking place within the lake system connected with narrow streams. Bayesian STRUCTURE analysis provided some indication that the direction of water flow influences population genetic structuring in the studied aquatic mosses. We propose that dispersal leading to gene flow in C. megalophyllum, F. antipyretica and F. hypnoides takes place both along water via connecting streams and by animal vectors, such as waterfowl. Nevertheless, the slight genetic structuring pattern along the direction of water flow suggests that dispersal of shoots or their fragments along water is a means of dispersal in these mosses. The absence of sexual reproduction and spores may have caused the observed spatial genetic structure within populations, including aggregations of similar genotypes (clones or closely related genotypes) at short distances in populations otherwise showing an isolation by distance effect. Regardless of the results pointing to the dominance of vegetative propagation, it is impossible to completely rule out the potential role of rare long-distance spore dispersal from areas where the species are fertile. PMID- 23016755 TI - Cost effectiveness of epidural steroid injections to manage chronic lower back pain. AB - BACKGROUND: The efficacy of epidural steroid injections in the management of chronic low back pain is disputed, yet the technique remains popular amongst physicians and patients alike. This study assesses the cost effectiveness of injections administered in a routine outpatient setting in England. METHODS: Patients attending the Nottingham University Hospitals' Pain Clinic received two injections of methylprednisolone plus levobupivacaine at different dosages, separated by at least 12 weeks. Prior to each injection, and every week thereafter for 12 weeks, participants completed the EQ-5D health-related quality of life instrument. For each patient for each injection, total health state utility gain relative to baseline was calculated. The cost of the procedure was modelled from observed clinical practice. Cost effectiveness was calculated as procedure cost relative to utility gain. RESULTS: 39 patients provided records. Over a 13-week period commencing with injection, mean quality adjusted life year (QALY) gains per patient for the two dosages were 0.028 (SD 0.063) and 0.021 (SD 0.057). The difference in QALYs gained by dosage was insignificant (paired t test, CIs -0.019 - 0.033). Based on modelled resource use and data from other studies, the mean cost of an injection was estimated at L219 (SD 83). The cost utility ratio of the two injections amounted to L8,975 per QALY gained (CIs 5,480 - 22,915). However, at costs equivalent to the tariff price typically paid to providers by health care purchasers, the ratio increased to L27,459 (CIs 16,779 - 70,091). CONCLUSIONS: When provided in an outpatient setting, epidural steroid injections are a short term, but nevertheless cost effective, means of managing chronic low back pain. However, designation of the procedure as a day case requires the National Health Service to reimburse providers at a price which pushes the procedure to the margin of cost effectiveness. TRIAL REGISTRATION: ISRCTN 43299460. PMID- 23016756 TI - Reaction of human cytochrome P450 3A4 with peroxynitrite: nitrotyrosine formation on the proximal side impairs its interaction with NADPH-cytochrome P450 reductase. AB - The reaction of peroxynitrite (PN) with purified human cytochrome P450 3A4 (CYP3A4) resulted in the loss of the reduced-CO difference spectrum, but the absolute absorption spectrum of the heme was not significantly altered. The loss of 7-benzyloxy-4-(trifluoromethyl)coumarin (BFC) O-debenzylation activity of CYP3A4 was concentration-dependent with respect to PN, and the loss of BFC activity supported by NADPH-cytochrome P450 reductase (CPR) was much greater than that supported by tert-butyl hydroperoxide. Moreover, the PN-treated CYP3A4 exhibited a reduced-CO spectrum when reduced by CPR that was much smaller than when it was reduced by dithionite. These results suggest that modification of CYP3A4 by PN may impair its interaction with CPR, leading to the loss of catalytic activity. Tyrosine nitration, as measured by an increase in mass of 45 Da due to the addition of a nitro group, was used as a biomarker for protein modification by PN. PN-treated CYP3A4 was digested by trypsin and endoproteinase Glu C, and nitrotyrosine formation was then determined by using electrospray ionization-liquid chromatography-tandem mass spectrometry. Tyr residues 99, 307, 347, 430, and 432 were found to be nitrated. Using the GRAMM-X docking program, the structure for the CYP3A4-CPR complex shows that Tyr99, Tyr347, and Tyr430 are on the proximal side of CYP3A4 and are in close contact with three acidic residues in the FMN domain of CPR, suggesting that modification of one or more of these tyrosine residues by PN may influence CPR binding or the transfer of electrons to CYP3A4. Mutagenesis of Tyr430 to Phe or Val revealed that both the aromatic and the hydroxyl groups of Tyr are required for CPR-dependent catalytic activity and thus support the idea that the proximal side Tyr participates in the 3A4-CPR interaction. In conclusion, modification of tyrosine residues by PN and their subsequent identification can be used to enhance our knowledge of the structure/function relationships of the P450s with respect to the electron transfer steps, which are critical for P450 activity. PMID- 23016757 TI - Synthesis of deuterated 1,2,3-triazoles. AB - The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a highly effective method for the selective incorporation of deuterium atom into the C-5 position of the 1,2,3-triazole structure. Reactions of alkynes and azides can be conveniently carried out in a biphasic medium of CH(2)Cl(2)/D(2)O, using the CuSO(4)/Na ascorbate system. The mildness of the method renders it applicable to substrates of relatively high complexity, such as nucleosides. Good yields and high levels of deuterium incorporation were observed. A reaction conducted in equimolar H(2)O and D(2)O showed 2.7 times greater incorporation of hydrogen atom as compared to deuterium. This is consistent with the H(+) and D(+) ion concentrations in H(2)O and D(2)O, respectively. With appropriately deuterated precursors, partially to fully deuterated triazoles were assembled where the final deuterium atom was incorporated in the triazole-forming step. PMID- 23016758 TI - Novel antimicrobial agents against multi-drug-resistant gram-positive bacteria: an overview. AB - Antimicrobial resistance threatens to compromise the treatment of bacterial infectious diseases. Strains resistant to most (if not all) antibiotics available have emerged. Gram-positive such representatives include strains of Methicillinresistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE) and highly-resistant to penicillin Streptococcus pneumoniae. Although the phenomenon of antimicrobial drug resistance is expanding, limited number of new antibiotics has been successfully developed in the last few decades. Several novel antimicrobial agents, however, are currently in diverse phases of development and undergoing clinical trials. This review will summarize the main candidates for novel antibacterial agents active against Gram-positive multi-resistant pathogens along with the discussion of some patents relevant to the topic. PMID- 23016760 TI - Acceptance of the 2012 Henry Baldwin Ward Medal: my experience with parasites. PMID- 23016759 TI - Leptin deficiency modulates allograft survival by favoring a Th2 and a regulatory immune profile. [corrected]. AB - Leptin, an adipose-secreted hormone, links metabolism and immunity. Our aim was to determine whether leptin affects the alloimmune response. We used an allogeneic skin transplant model as a means to analyze the allograft immune response in Lep(ob/ob) and wild-type mice. Leptin deficiency results in an increased frequency of Treg and Th2 cells and a prolonged graft survival. These effects of leptin deficiency indicate the importance of leptin and obesity in modulating the allograft immune responses. Our data suggest a possible explanation for the increased susceptibility of hyperleptinemic obese patients to acute and chronic graft rejection. PMID- 23016761 TI - Effect of high hydrostatic pressure on the production of conjugated fatty acids and trans fatty acids by Bifidobacterium breve LMC520. AB - This study was performed to investigate the effect of high hydrostatic pressure (HHP) on the conversion of linoleic acid, conjugated linoleic acid (CLA), and alpha-linolenic acid (alpha-LNA) as substrates by Bifidobacterium breve LMC520 and to optimize the HHP condition. Cell mixture were tested under HHP in a variety of conditions such as temperature, time, pressure, and pre- or post treatment with substrates. The cis-9,trans-11 CLA producing activity of B. breve LMC520 was increased by HHP, whereas trans-9,trans-11 CLA producing activity was decreased. Optimal HHP conditions for the highest CLA production were obtained at 100 MPa for 12 h at 37 degrees C. Post-treatment groups showed higher conversion activity of substrates than pretreatment groups. Post-treatment groups decreased trans-9,trans-11 CLA and other CLnA, whereas the pretreatment groups increased them. It is concluded that HHP treatment could be an important factor to enhance CLA and CLnA production and for reducing trans-fatty acids. PMID- 23016762 TI - Preservation of chirality and polarity between chiral and polar building units in the solid state. AB - The new lamellar phases [Zn(2,2'-bpy)(2)(H(2)O)(2)](ZrF(6)).3H(2)O (I) and [Ni(2,2'-bpy)(3)](MoO(2)F(4)).5H(2)O (II) (bpy = bipyridine), which are built from a chiral cation and respectively an inherently nonpolar and a polar anion, provide two contrasting structures with respect to chirality and polarity in the solid state. Each nonpolar layer of I contains enantiomers of both handednesses; conversely, each layer of II contains only a Delta or Lambda enantiomer and polar anions oriented along the b or -b axes. A comparison with previously reported structures reveals which combinations and interactions between chiral and polar basic building units can preserve elements of polarity and chirality in the solid state. PMID- 23016763 TI - Protective roles of ascorbic acid in oxidative stress induced by depletion of superoxide dismutase in vertebrate cells. AB - Superoxide dismutases (SODs) are antioxidant proteins that convert superoxide to hydrogen peroxide. In vertebrate cells, SOD1 is mainly present in the cytoplasm, with small levels also found in the nucleus and mitochondrial intermembrane space, and SOD2 is present in the mitochondrial matrix. Previously, the authors conditionally disrupted the SOD1 or SOD2 gene in DT40 cells and found that depletion of SOD1 caused lethality, while depletion of SOD2 led to growth retardation. The observations from previous work showed that the lethality observed in SOD1-depleted cells was completely rescued by ascorbic acid. Ascorbic acid is a water-soluble antioxidant present in biological fluids; however, the exact target for its antioxidant effects is not known. In this study, the authors demonstrated that ascorbic acid offset growth defects observed in SOD2-depleted cells and also lowered mitochondrial superoxide to physiological levels in both SOD1- or SOD2-depleted cells. Moreover, depletion of SOD1 or SOD2 resulted in the accumulation of intracellular oxidative stress, and this increased oxidative stress was reduced by ascorbic acid. Taken together, this study suggests that ascorbic acid can be applied as a nontoxic antioxidant that mimics the functions of cytoplasmic and mitochondrial SODs. PMID- 23016764 TI - Less is not more: neural responses to missing and superfluous accents in context. AB - Prosody, particularly accent, aids comprehension by drawing attention to important elements such as the information that answers a question. A study using ERP registration investigated how the brain deals with the interpretation of prosodic prominence. Sentences were embedded in short dialogues and contained accented elements that were congruous or incongruous with respect to a preceding question. In contrast to previous studies, no explicit prosodic judgment task was added. Robust effects of accentuation were evident in the form of an "accent positivity" (200-500 msec) for accented elements irrespective of their congruity. Our results show that incongruously accented elements, that is, superfluous accents, activate a specific set of neural systems that is inactive in case of incongruously unaccented elements, that is, missing accents. Superfluous accents triggered an early positivity around 100 msec poststimulus, followed by a right lateralized negative effect (N400). This response suggests that redundant information is identified immediately and leads to the activation of a neural system that is associated with semantic processing (N400). No such effects were found when contextually expected accents were missing. In a later time window, both missing and superfluous accents triggered a late positivity on midline electrodes, presumably related to making sense of both kinds of mismatching stimuli. These results challenge previous findings of greater processing for missing accents and suggest that the natural processing of prosody involves a set of distinct, temporally organized neural systems. PMID- 23016765 TI - Normal aging delays and compromises early multifocal visual attention during object tracking. AB - Declines in selective attention are one of the sources contributing to age related impairments in a broad range of cognitive functions. Most previous research on mechanisms underlying older adults' selection deficits has studied the deployment of visual attention to static objects and features. Here we investigate neural correlates of age-related differences in spatial attention to multiple objects as they move. We used a multiple object tracking task, in which younger and older adults were asked to keep track of moving target objects that moved randomly in the visual field among irrelevant distractor objects. By recording the brain's electrophysiological responses during the tracking period, we were able to delineate neural processing for targets and distractors at early stages of visual processing (~100-300 msec). Older adults showed less selective attentional modulation in the early phase of the visual P1 component (100-125 msec) than younger adults, indicating that early selection is compromised in old age. However, with a 25-msec delay relative to younger adults, older adults showed distinct processing of targets (125-150 msec), that is, a delayed yet intact attentional modulation. The magnitude of this delayed attentional modulation was related to tracking performance in older adults. The amplitude of the N1 component (175-210 msec) was smaller in older adults than in younger adults, and the target amplification effect of this component was also smaller in older relative to younger adults. Overall, these results indicate that normal aging affects the efficiency and timing of early visual processing during multiple object tracking. PMID- 23016767 TI - Duplication of the sodium channel gene cluster on 2q24 in children with early onset epilepsy. AB - PURPOSE: Sodium channel gene aberrations are associated with a wide range of seizure disorders, particularly Dravet syndrome. They usually consist of missense or truncating gene mutations or deletions. Duplications involving multiple genes encoding for different sodium channels are not widely known. This article summarizes the clinical, radiologic, and genetic features of patients with 2q24 duplication involving the sodium channel gene cluster. METHODS: A systematic review of the literature and report of two cases. KEY FINDINGS: Nine individuals with 2q24 duplication involving the sodium channel gene cluster are described (seven female, two male). All presented with severe seizures refractory to anticonvulsant drugs. Seizure onset was in the neonatal period in eight patients with SCN1A-involvement, in infancy in one patient with SCN2A and SCN3A, but no SCN1A involvement. Seizure activity decreased and eventually stopped at 5-20 months of age. Seizures recurred at the age of 3 years in the patient with SCN2A and SCN3A, but no SCN1A involvement. Eight patients had a poor neurodevelopmental outcome despite seizure freedom. SIGNIFICANCE: This article describes a distinct seizure disorder associated with a duplication of the sodium gene cluster on 2q24 described in otherwise healthy neonates and infants with severe, anticonvulsant refractory seizures and poor developmental outcome despite seizure freedom occurring at the age of 5-20 months. PMID- 23016766 TI - Disentangling spatial perception and spatial memory in the hippocampus: a univariate and multivariate pattern analysis fMRI study. AB - Although the role of the hippocampus in spatial cognition is well accepted, it is unclear whether its involvement is restricted to the mnemonic domain or also extends to perception. We used fMRI to scan neurologically healthy participants during a scene oddity judgment task that placed no explicit demand on long-term memory. Crucially, a surprise recognition test was administered after scanning so that each trial could be categorized not only according to oddity accuracy but also according to subsequent memory. Univariate analyses showed significant hippocampal activity in association with correct oddity judgment, whereas greater parahippocampal place area (PPA) activity was observed during incorrect oddity trials, both irrespective of subsequent recognition performance. Consistent with this, multivariate pattern analyses revealed that a linear support vector machine was able to distinguish correct from incorrect oddity trials on the basis of activity in voxels within the hippocampus or PPA. Although no significant regions of activity were identified by univariate analyses in association with memory performance, a classifier was able to predict subsequent memory using voxels in either the hippocampus or PPA. Our findings are consistent with the idea that the hippocampus is important for processes beyond long-term declarative memory and that this structure may also play a role in complex spatial perception. PMID- 23016768 TI - Diagnostic tests for the detection of human papillomavirus-associated cervical lesions. AB - Current diagnostic approaches for primary cervical cancer screening, work-up of equivocal or positive screening results or follow- up after treatment of precancerous lesions primarily rely on the morphologic interpretation of squamous epithelial cells (Pap cytology), in some setting accompanied by the detection of human papillomavirus DNA and have largely contributed to remarkable reduction of disease incidence in countries with implemented screening programs. However, these approaches are limited by a poor sensitivity and reproducibility of Pap cytology and low specificity for high grade cervical intraepithelial neoplasia of HPV DNA detection assays. Early detection might be improved by complementing or even replacing these tests by markers which are more directly related to molecular events triggering HPV-induced carcinogenesis and thereby might deliver more accurate diagnostic performance. The delineation of molecular changes which occur during different stages of HPV infections and the identification of changes which induce neoplastic alterations allow for the detection of markers that specifically highlight the transforming stage of the infection where viral oncogenes are overexpressed and therefore allow for a more specific diagnosis of lesions that require treatment. The evaluation of such markers in clinical studies revealed that some indeed show an improved diagnostic performance compared to Pap cytology or HPV DNA tests only. PMID- 23016769 TI - HPV infections: basis of neoplastic transformation and related molecular tests. AB - Cervical cancer is a major health problem and almost all of these cancers are related to a high risk Human Papillomavirus cervical infection. The Human Papillomavirus transforming potential has long been probed and is mainly characterized by the integration of the virus in the host genomes and the expression of the viral oncoproteins such as the E6 and E7 mRNAs. The vast majority of the HPV infections are transient and resolve and just a few percentages of patients are noted to develop a persistent infection. Therefore, there is the need of identifying appropriate biomarkers that can predict and differentiate transient vs persistent and clinical relevant HPV cervical infections. To date, two categories of commercial assays have been introduced, mainly aiming to the detection of the E6 and E7 mRNAs and of the surrogates of the E7 activity (p16ink4A protein). The aim of the present study is to analyse the basis of the HPV-related carcinogenesis and to discuss the commercial biomarkers developed to-date, reviewing those studies that used the above mentioned assays in a clinical setting. PMID- 23016770 TI - HPV pathway profiling: HPV related cervical dysplasia and carcinoma studies. AB - Cervical cancer is the second most common malignancy among women worldwide. While more than 90% of cervical cancers carry one or more high risk HPV types, the exact relationship between HPV oncoproteins and signaling pathways alterations in cervical cancer remains to be clarified. Vaccines and targeted therapies are today considered of great potential for the improvement of patients' outcome. This review will focus on the interaction of HPV with cervical cancer pathway activations. Next generation high throughput screening technologies for molecular and protein profiling as well as innovative logistics, necessary for the implementation of the personalized care of cervical cancer patients will be discussed. PMID- 23016771 TI - Predictors and clinical implications of HPV reservoire districts for genital tract disease. AB - Persistence of human papillomavirus infection (HPV) of the cervix after treatment for cervical intraepithelial neoplasia predisposes to lesion recurrence. Given the weakness of natural immunity against HPV it has been suggested that certain anatomical sites could act as viral reservoirs though which the infection could be retransmitted to the cervix even if the initial HPV tests after treatment are negative. This review examined the possible role of various reservoirs such as the oral cavity, the anus, the fingers and the partner's penis. The available data are insufficient to confirm a significant risk of cervical re-infection from any site other than the penis. It seems that the risk of transmission by the male partner can be reduced by consistent condom use; therefore this should be included in the patient's counselling. Further studies are required to elucidate the role of the other sites especially the anus where some reports imply a possibility for transmission to the cervix. In this context expanding the indications for HPV vaccination to include women who have been treated for CIN should be considered. PMID- 23016772 TI - HPV mRNA testing in triage of women with ASC-US cytology may reduce the time for CIN2+diagnosis compared with repeat cytology. AB - BACKGROUND: In delayed HPV triage women with atypical squamous cells of uncertain significance (ASC-US) cytology are retested after 6-12 months in order to decide whether they should be referred for colposcopy, further follow-up cytology or routine screening in three years. Triage using a specific HPV E6/E7 mRNA test may reduce referrals for colposcopy of women with ASC-US cytology compared to HPV DNA testing. We explored whether HPV mRNA triaging could reduce the time from ASC-US index cytology to biopsy compared with repeat cytology, and whether the positive predictive value (PPV) of the HPV mRNA test for high grade cervical intraepithelial neoplasia (CIN2+) was comparable with the PPV of repeat cytology. MATERIAL AND METHODS: We used repeat cytology and the HPV mRNA test PreTect HPV Proofer, which detects E6/E7 mRNA from HPV subtypes 16, 18, 31, 33 and 45, in the triage of women with ASC-US. We included all women from the two northernmost counties of Norway with a first ASC-US cytology during the period 2004-2008. Two triage methods were evaluated 1) only repeat cytology (n=964) and 2) both HPV mRNA testing and cytology (n=542). Histologically confirmed CIN2+ was the study endpoint. RESULTS: Among 1506 women with an ASC-US index cytology, 59 women (3.9%) had biopsy taken, of whom 49 women had CIN2+ (PPV 83.1%). The mean time from index ASC-US cytology until the case was resolved (biopsy or return to screening) was 10.6 months in the repeat cytology group and 7.3 months in the HPV group (P < 0.001). Of the 964 women in the group with repeat cytology only, 35 women (3.6%) had biopsy and 30 had CIN2+ (PPV 85.7%). Of the 542 women in the group with both HPV test and cytology, 24 women (4.4%) had biopsy and 19 had CIN2+ (PPV 79.2%). CONCLUSION: In triage of women with ASC-US, the HPV mRNA test significantly reduced the time from the first abnormal cytology until biopsy and had predictive values comparable with those of repeat cytology. PMID- 23016773 TI - Liquid-based cytology with HPV triage of low-grade cytological abnormalities versus conventional cytology in cervical cancer screening. AB - OBJECTIVE: Liquid-based cytology with supplementary human papillomavirus triage (LBC+HPV triage) of low-grade cytological abnormalities may improve the detection of cervical intraepithelial neoplasia (CIN) compared with conventional cytology. To investigate this subject, LBC+HPV triage and conventional cytology were alternated in a population-based screening setting. Cases with abnormal cytology were referred for colposcopy. METHODS: We compared the performance of LBC+HPV triage [n=4059] and conventional cytology [n=4261] in detecting CIN2 or worse [CIN2+] and CIN3 or worse [CIN3+]. We used logistic regression to assess CIN detection rates and abnormal cytology rates, which yielded unadjusted odds ratios (OR) and corresponding 95% confidence intervals (CI). We computed adjusted ORs from a multivariate logistic regression model that included potential confounders such as age, screening centre and time period. RESULTS: We found similar detection rates of CIN2+ by LBC+HPV triage and conventional cytology; the adjusted OR for the comparison of CIN detection rates was 0.87 (95% CI: 0.60 1.26) for CIN2+ and 1.00 (95% CI: 0.64-1.58) for CIN3+. We also found similar positive predictive values between methods. Thus, there was no advantage in using LBC+HPV triage as compared to conventional cytology in terms of sensitivity, specificity and positive and negative predictive value to detect histologically confirmed CIN2+ and CIN3+. CONCLUSIONS: LBC+HPV triage may lead to a reduction in unnecessary work-ups for women with abnormal cytological lesions who are negative for high-risk HPV. It is important to continuously monitor abnormal cytology rates, both when testing a new method, and after the new method has become routine. PMID- 23016774 TI - Role of cell cycle biomarkers in human papillomavirus related uterine lesions. AB - Cervical cancer (CC) is caused by a persistent infection by certain human papillomavirus (HPV) genotypes. Although Papanicolaou (Pap) Test is considered the most cost-effective test for reducing CC mortality, a considerable number of high-grade precursor lesions of CC could pass unnoticed with the Pap. The addition of high-risk human papillomavirus (HPV) genotype detection in cervical cytology has improved the sensitivity, but due to its low specificity, further biomarkers of malignancy have been searched for. Given the fact that the oncogenic role of HPV is exerted primarily by affecting cell cycle control it is not surprising that most of the useful biomarkers of HPV-related uterine lesions are cell cycle proteins, with p16 and Ki67 the most widely used. More recently, molecular profiling and marker combination tests have identified the utility of antibody cocktails such as p16/Ki67 dual and ProEx C, which detect both TOP2A and MCM2 cell cycle proteins. In this article we revise the rationale for the use of the most common cell cycle biomarkers, also including p53 and cyclin D1, and their clinical utility drawing attention to novel biomarkers and how HPV vaccination could influence their use. PMID- 23016775 TI - Clinical applicability of microarray technology in the diagnosis, prognostic stratification, treatment and clinical surveillance of cervical adenocarcinoma. AB - Invasive cervical cancer is a common problem worldwide and while rates of squamous cell carcinoma of the cervix (SCC) have been declining with the implementation of community screening programs, adenocarcinoma of the cervix (ADC) has not shown a similar response to screening. At this time, the two entities are tested for and treated with the same clinical algorithms, namely gynecologic cytology and molecular testing for HPV DNA. However, ADC arises more proximally within the cervical canal and frequently occurs below the superficial mucosal lining, precluding it from being easily diagnosed with cytologic examination. Furthermore, ADC has a more aggressive course than SCC and is significantly less responsive to radiotherapy. These factors combine to produce a lesion that is diagnosed at a higher stage and has an overall poorer prognosis than SCC. While both lesions have pathogenic origins with the high-risk species of Human papilloma viruses (HPV), the high association of ADC with HPV 18, a virus with a higher genome integration rate, suggests that the transformation pathway of ADC differs from SCC. Modern methods of molecular analysis can produce gene expression profiles of various cell types and preliminary studies have shown that SCC and ADC do, indeed, produce a distinct genetic signature and can be reproducibly segregated. This technology has promise for clinical applicability in the diagnosis, the prognostic stratification, formation of a treatment care plan and post-therapeutic monitoring of ADC. PMID- 23016776 TI - The immunohistochemical assessment of HPV related adenocarcinoma: pathologic and clinical prognostic significance. AB - Although several epidemiologic studies have confirmed the association between high-risk human papillomavirus (hr-HPV) and adenocarcinoma of the cervix, there are few papers focusing on the molecular immunophenotype of the HPV related cervical adenocarcinoma and its precursor lesions. The present study is aimed to assess the immunohistochemical expression of p16, p53, cyclin D1, EGFR, and COX-2 in benign and malignant lesions of cervical glandular components, and consequently the identification of the relationship between these markers and the HPV L1 capsid protein. We investigated 7 cases of endocervical adenocarcinoma in situ (AIS), 8 cases of adenosquamous carcinoma, 15 cases of invasive adenocarcinoma of endocervical type, and 5 cases without malignant lesions (normal and/or benign endocervical epithelium). The tissue fragments underwent standard laboratory procedures for the histopathological and immunohistochemical exams. For each marker, the semi-quantitative assessment was performed using appropriate scoring systems. Our results showed that: (i) the combination of L1 capsid protein and p16 can predict the progression risk of precursor lesion of endocervical adenocarcinomas; (ii) p53 - COX2 - p16 co-assessment is useful as a panel of relevant biomarkers for L1 - p16 association; (iii) EGFR increases according to the progression in lesions severity; (iv) cyclin D1 is a reliable marker for the invasive capacity. Further studies are necessary to quantify the value of these markers, as prognostic factors in HPV related cervical adenocarcinoma. PMID- 23016777 TI - The problem of false-positive human papillomavirus DNA tests in cervical screening. AB - Human Papillomavirus (HPV) testing has been extensively studied in randomized controlled trials of primary cervical screening. Based on encouraging results concerning its high detection rates and a high negative predictive value for high grade cervical intraepithelial neoplasia (CIN), HPV testing will probably replace cytology in future primary cervical screening. However, HPV testing is associated with more frequent false-positive tests compared to cytology. False-positive tests are defined as positive screening tests which are not subsequently confirmed with high-grade CIN. Several authors have claimed that the frequency of false-positive HPV tests could be reduced if an additional test was used to decide on referral for colposcopy of HPV-positive women. Data from the trials, however, do not support this claim. In fact, when compared to standard cytology screening and triage procedures, HPV testing leads to more screen-positive women being referred for colposcopy without having high-grade CIN, and to more women undergoing repeated testing. The only reasonable solution to the problem of false positive tests appears to be a revised definition of a positive HPV screening test. However, further studies are needed to determine how this definition could be revised while at the same time keeping the high negative predictive value of HPV testing. PMID- 23016778 TI - Detection of residual/recurrent cervical disease after successful LEEP conization: the possible role of mRNA-HPV test. AB - BACKGROUND: Loop Electrosurgical Excision Procedure (LEEP) represents the mainstay technique for CIN2+ removal. The major concern in conservative treatment is to verify whether CIN eradication was complete, since incomplete excision is associated with an increased risk of cervical cancer. The histopathologic evaluation of resection margins status is far from perfect, since cervical lesions may recur in 5-15% of patients who had conisation specimens with clean margins. Current follow-up protocol of patients treated by conisation for high grade CIN is manly based on the combination of cytology-plus- HPV-DNA testing. This approach showed high sensitivity but low specificity level in detecting recurrence. The consequence were overdiagnosis and overtreatment, especially in youngest women, in which spontaneous regression rate of CIN is substantial. In this longitudinal study we investigated whether patient's age, cone depth and pre conisation HPV-load level, may be used as predictive markers for residual/recurrent CIN after conisation. Then we aimed to examined the role of E6/E7 mRNA testing during post-conization follow-up. METHODS: The study, focused on the outcome of 116 patients treated for CIN by LEEP, included three consecutive steps. Firstly, the authors analysed the prevalence of residual/recurrence disease after conization; then, they investigated which factors may influence treatment failure even when resection margins were clean; finally, they evaluated the diagnostic accuracy of E6/E7 mRNA test as predictive marker of recurrence. RESULTS: HPV infection was detected in 31% of patients at 6 month follow-up and in 11.2% of patients, at 24-month follow-up. Younger women showed higher rate of recurrence than older ones. The risk of residual/recurrent infection did not correlate with cone-depth. Recurrence is higher in patients with low viral load level than in those having high load levels. mRNA test showed higher specificity and positive predictive value than the combination cytology plus-HPV-DNA test. CONCLUSION: The inclusion of mRNA test within the current protocol of follow-up would efficiently and earlier predict the risk of residual/ recurrent cervical abnormalities after conisation. This molecular strategy would also reduce overtreatment, particularly in patients above 30 years of age. PMID- 23016779 TI - The mRNA-HPV test utilization in the follow up of HPV related cervical lesions. AB - The biomolecular follow up of Human Papilloma Virus (HPV) is widely investigated in patients treated for HPV related cervical lesions, since the HPV-mRNA test is more specific and have a higher positive predictive value for CIN2-3 in triage of high risk (HR) women and in follow-up of women treated for CIN2/3. MATERIAL & METHODS: We investigated, during a 5 years' study, a cohort of patients divided in: group 1, patients at high risk for HPV-infections, and group 2, women diagnosed for CIN2/3, Cervicocarcinoma in situ (CIS) and Adenocarcinoma in situ (AIS) and surgically treated. The overall scheduled follow up was repeated each 6 months by: Pap Test, HPV-DNA test, m-RNA-HPV test and, in case of CIN2/3, CIS and AIS, also by colposcopy and biopsy. RESULTS: The follow up involved a total of 203 women: 85 women with mRNA-HPV positive test and 118 patients surgically treated for CIN2/3, CIS and AIS. In the group 1, the long term follow up detected, after one year, 32 positive mRNA-HR HPV women and, of these, after more than 2 years, 37.5% developed CIN1 and 21.8% developed CIN2/3. Similarly, in the follow up of group two, women with abnormal Pap test showed positivity of mRNA HR HPV in 71.4% of cases even after 6 months; 65% of these developed a CIN1 within 2.5 years and 20% had CIN2/3 after 2.3 years. CONCLUSIONS: Study results indicate either that patients with mRNA HR-HPV positive controls, on average, after 12 months are all at risk of progression to CIN1 and CIN2/3, or the higher specificity of mRNA-HPV test than Pap Test in follow up of surgical treated patients. This investigation confirmed a strong association between HR mRNA-HPV presence and risk of neoplastic progression. PMID- 23016780 TI - Human papillomavirus (HPV) vaccines as an option for preventing cervical malignancies: (how) effective and safe? AB - We carried out a systematic review of HPV vaccine pre- and post-licensure trials to assess the evidence of their effectiveness and safety. We find that HPV vaccine clinical trials design, and data interpretation of both efficacy and safety outcomes, were largely inadequate. Additionally, we note evidence of selective reporting of results from clinical trials (i.e., exclusion of vaccine efficacy figures related to study subgroups in which efficacy might be lower or even negative from peer-reviewed publications). Given this, the widespread optimism regarding HPV vaccines long-term benefits appears to rest on a number of unproven assumptions (or such which are at odd with factual evidence) and significant misinterpretation of available data. For example, the claim that HPV vaccination will result in approximately 70% reduction of cervical cancers is made despite the fact that the clinical trials data have not demonstrated to date that the vaccines have actually prevented a single case of cervical cancer (let alone cervical cancer death), nor that the current overly optimistic surrogate marker-based extrapolations are justified. Likewise, the notion that HPV vaccines have an impressive safety profile is only supported by highly flawed design of safety trials and is contrary to accumulating evidence from vaccine safety surveillance databases and case reports which continue to link HPV vaccination to serious adverse outcomes (including death and permanent disabilities). We thus conclude that further reduction of cervical cancers might be best achieved by optimizing cervical screening (which carries no such risks) and targeting other factors of the disease rather than by the reliance on vaccines with questionable efficacy and safety profiles. PMID- 23016781 TI - Risk of cervical cancer after HPV vaccination. AB - It will likely be more than 20 years before there is unequivocal evidence available that HPV vaccination decreases the incidence of invasive cervical cancer. However, existing data strongly suggests that as many as 440,000 cervical cancer cases and 220,000 deaths due to this malignancy will be prevented with the establishment of an effective worldwide HPV immunization program. PMID- 23016782 TI - The present and future of cervical cancer screening programmes in Europe. AB - The identification of HPV as the cause of cervical cancer has changed the information required for surveillance. HPV prevalence and screening uptake worldwide are now necessary to describe the epidemiology of this cancer. In low income countries cervical cancer incidence varies from low to very high levels and is strongly influenced by virus prevalence. In high-income countries, instead, incidence is low and little influenced by the virus prevalence, thanks to screening. The European Guidelines currently recommend Pap test every 3-5 years starting at age 22-30 and stopping at age 60-65. HPV testing is now limited to triage of borderline lesions? and to post-CIN follow up. Pilot studies evaluating HPV testing as primary test are recommended. Future governmental agency Guidelines in Europe will probably include HPV testing as viable for primary screening, with cytology triage for HPV-positive women (those positive to cytology will be directly referred to colposcopy, those negative will repeat HPV at one year. Persistence of HPV positivity will refer to colposcopy directly, clearance to regular screening). The interval after an HPV-negative test should be at least 5 years and starting age should be age 30/35. Pap test is still recommended for women under 30. PMID- 23016783 TI - Prevalence and distribution of human papillomavirus genotype in south eastern Italy, in the period 2006-2011: implications for intervention. AB - Persistent infection of High Risk (HR) Human papillomavirus (HPV) infection can lead to cervical cancer. The HPV genotypes are found worldwide, but important regional variations have been found. For a population-based HPV type prevalence study to assess the effect of existing and new prevention methods, frequently updated information on the burden of cervical cancer is essential. We evaluated the prevalence of HPV genotypes in a volunteer population screened for cervical cancer at the Local Health Unit (LHU) of Lecce. A total of 9,720 women were studied. The tests were performed by INNO-Lipa HPV Genotyping and LINEAR ARRAY HPV Genotyping Test. The overall HPV prevalence was 29.7% (95% CI, 28.8-30.6) for any HPV DNA. The prevalent type for all age groups was HPV 16 (7.4%; CI, 6.9-7.9) followed by HPV 31 (3.4%; CI, 3.0-3.7), 51 (3.0%; CI, 2.6-3.3), 52 (2.7%; CI, 2.3 3.0) and 58 (2.4%; CI, 2.1-2.7). HPV 53 was the most common low-risk HPV type with prevalence rate of 3.5 (CI, 3.1-3.8), followed by HPV 66 (3.0; CI, 2.6-3.3), 6 (2.9; CI, 2.6-3.2) and 42 (2.5; CI, 2.2-2.8). Multiple infections were present in 13.6% of HPV-tested women (CI, 12.9-14.3). Among these, the most common combination was of HPV 16 and HPV 52 genotypes. This study reports high prevalence of HPV infection and may serve as a valuable reference for assessing the impact of HPV vaccination programs. Furthermore, it supports the need for new vaccines that contain the most common HPV genotypes present in the population. PMID- 23016784 TI - Sliding screw implants for extracapsular hip fractures. AB - Hip fractures are associated with significant mortality and morbidity for the patients, more dependent residual status, and increased socio-economic cost. Many hip-fracture patients experience severe functional impairment, and most never recover their pre-fracture level of function. Current research has sought to identify the most effective treatments to reduce the incidence of hip fractures, improve survival and quality of life, and minimize complications and disability. The treatment of these fractures in the elderly aims to return these people to their pre-fracture mobility and functional level. This article reviews the surgical treatment options for extracapsular hip fractures and discusses their associated advantages, disadvantages, and complications. Two types of implants are currently available: the dynamic hip screw (DHS), and the intramedullary hip nail with one or two sliding screws. In this review, no clear advantage of one implant over another for the treatment of extracapsular hip fractures was evident. Both the DHS and hip nails can be used successfully for the treatment of stable hip fractures; for unstable fractures and low subtrochanteric fractures, hip nails are preferred. Although hip nails are associated with limited exposure, lower blood loss and transfusion requirements, and shorter operative time, complications are more common with hip nails. Long-term survival and function are similar in the two approaches. Hip nails with two sliding screws do not seem to make the difference in clinical practice that is reported in biomechanical studies. PMID- 23016785 TI - Treatment of neuromuscular scoliosis with posterior spinal fusion using the Galveston procedure: retrospective of eight years of experience with unit rod instrumentation. AB - Posterior spinal fusion with instrumentation to the pelvis (the Galveston Procedure) is widely accepted as an effective treatment for neuromuscular scoliosis. Unit rod instrumentation is commonly used in these cases, but it is not universally accepted as superior to separate Luque rods. This study is a retrospective review of 115 consecutive cases in which the unit rod was used. The following statistics were collected from the records of these patients: operative time, estimated blood loss, PICU stay, hospital stay, transfusion rate, complication rate, scoliosis correction, and correction of pelvic obliquity . Results at 2-year follow-up were compared to those reported in the literature and to results previously reported from the same facility in which separate Luque rods were used. The unit rod provides excellent control of pelvic obliquity and superior scoliosis correction compared with separate Luque rods. Improvements were also found in reduced operative times, lower blood loss, a lower complication rate, and shorter hospital stay. PMID- 23016786 TI - Dynamic condylar screw as a solution to operative dilemma in early sub trochanteric fracture following cannulated screw fixation for slipped capital femoral epiphysis: a case report. AB - A 14-year-old boy presented with a 2-month history of left groin pain and a limp on the left side. Radiographs confirmed slipped capital femoral epiphysis (SCFE) of the left hip. The surgical procedure he received used a single, 8-mm, partially threaded, cannulated screw. Postoperatively he was advised to remain strictly non-weight bearing on the affected lower limb until physeal closure was achieved. Unfortunately, he fell down 4 weeks postoperatively and sustained a subtrochanteric fracture on the same hip, with the cannulated screw still in place. This injury was surgically treated using a dynamic condylar screw and a side plate. PMID- 23016787 TI - Measurements of surface and subsurface damage in retrieved polyethylene tibial inserts of a contemporary design. AB - In the present study, surface and subsurface damage due to wear and creep in retrieved tibial inserts from the Genesis II total knee replacement (Smith & Nephew, Memphis, TN) are quantified. The utility of a number of recently validated micro-computed tomography (micro-CT) techniques for use in retrieval studies are also demonstrated. Sixteen inserts retrieved from patients after an implantation time from 0.5 to 86 months were examined. The inserts were scanned using micro-CT, and the three-dimensional surface deviations (corresponding to wear and creep) between the retrieved inserts and a reference geometry were determined. The subsurface of the inserts was also examined. Deviations within damage features were measured, and a surface deviation rate (mm/ year) was calculated from the length of implantation. No subsurface fatigue damage was found. The mean deviation within the most damaged regions of the articular surface was 0.115 +/- 0.064 mm medially and 0.099 +/- 0.061 mm laterally (p = 0.20). The mean articular deviation rate for inserts in vivo for more than 1 year was 0.049 mm/year and was reduced to 0.026 mm/year in inserts implanted for more than 4 years. Wear and creep of the Genesis II PE insert was comparable to reported values in other total knee replacements. PMID- 23016788 TI - An atypical immune-inflammatory disorder secondary to breast implant exposure. AB - OBJECTIVE: The objectives of this investigation were to determine a diagnosis and identify the underlying etiology. CASE PRESENTATION: A 71-year-old female had experienced a constellation of symptoms stemming from the 1980s, including the following types: neurological, respiratory, gastroenterological, dermatological, skeletal, and ophthalmological. No correlation with an environmental (or other) factor could be found to account for the presence or exacerbation of unexplained signs and symptoms-except that the patient had been exposed to a series of silicone breast implants. Anatomical diagnosis: An atypical immune-inflammatory disorder caused by an originally exogenous noninfectious agent, i.e., breast prostheses, and diagnosed as prosthetic mammoplasty sensitivity syndrome (PMSS). SIGNIFICANCE: This case study underscores the risks of breast implantation using prosthetic devices. It shows the potential for adverse health effects following breast implantation in humans. It highlights the impact of social factors that has adversely affected the medical treatment of this subgroup of patients, and documents postimplantation psychiatric morbidity attributable in part to adverse physical health effects from exposure to breast implants. RELEVANCE TO CLINICAL PRACTICE: Patients that present with symptoms, have a history of breast implants, and no firm diagnosis of disease or disorder etiology attributable to their clinical signs and symptoms, laboratory, and/or imaging results must be considered for PMSS. PMID- 23016789 TI - Investigating the morphology of the proximal femur of the Indian population towards designing more suitable THR implants. AB - There are considerable variations in the femoral geometry of populations across different geographical locations and ethnic groups. The osteological parameters of the proximal femur are very important for the design of suitably sized prostheses of total hip replacement (THR), especially for cementless implantation. Though total hip prostheses in different sizes are available from manufacturers, best-fit implants are often unavailable for Indian patients. To produce hip prostheses of suitable sizes and shapes for Indian patients, important osteological parameters of the proximal femur in the Indian population are needed. In this study, 100 computed tomography (CT) images of hip joints of members of the Indian population were collected, and 20 anatomical parameters of the proximal femur were analyzed. The mean values of these parameters were compared with those of the populations of a few other countries that were available from the literature. The parameter comparison was also performed between males and females in our subsample of the Indian population. Finally, values of the important parameters were grouped suitably for future design of standard sizes of THR implants for the Indian population. We found variations in the morphology of the proximal femur between the Indian population and that of other countries, which illustrates a need for standardizing THR implant sizes for the Indian population, especially for cementless implantation. The variations of a few important parameters of the proximal femur also occur between the male and female Indian populations. This study is likely to be a significant step toward designing suitably sized cementless THR implants for the Indian population. PMID- 23016790 TI - Decision making in nasal implantations by autogenous, synthetic, or mixed implant units: surgeons and patients needs and satisfaction based protocol. AB - Choosing the best nasal implant is an important issue that is still debated, and no implant is ideal. Hence, a protocol to help surgeons choose the best implant for a specific nasal problem is needed. Such a protocol should consider the needs of the patient and the surgeon, the best outcomes, and the satisfaction of both the patient and the surgeon. Rhinoplasties performed on 32 patients in this study involved three implant types: autogenous, synthetic, and mixed. Observational data were collected to determine the technical needs of patients and surgeons and to evaluate their respective satisfaction using an interpretive score ranging from 0 to 2. Autogenous implant was the most commonly used technique, which included filling volume deficiencies; synthetic implants were used to camouflage irregularities, to pad bony edges, or in nasal tip surgeries; and the mixed implants were used in all surgeries, including covering open roofs or fine surface irregularities. Acceptable long-term effects and best quality of the results were 100% for mixed implant units, 87.5% for synthetic implants, and 73% for autogenous grafts. Surgeon satisfaction was greatest when patients were most satisfied (score=2), and surgeon satisfaction was significantly lower when patients were dissatisfied (in cases with complications). Choosing the best implant is difficult; many implant types are applicable for more than on purpose, and a specific implant may be more advantageous in a specific case. Considering many factors involved, an algorithm useful for choosing the appropriate implant type is presented. PMID- 23016791 TI - Advances in biomaterials for the treatment of intervertebral disc degeneration. AB - In the past decade, the number of treatment methods for disc degeneration has dramatically increased due to advances in biomaterials. Disc degeneration is one of the leading causes of lower back pain in the adult population, and a large percentage of patients seek surgical solutions. Therefore, there is a great clinical need for biomaterials to alleviate pain associated with disc degeneration. Increased understanding of spinal physiology and pathophysiology has enabled the development of new surgical techniques as well as novel biomaterials for treatment. In this review, advances in biomaterials used for treating intervertebral disc degeneration are reviewed: cages and implants for spinal fusion, artificial discs for total disc arthroplasty, and emerging methods of synthetic nuclei and annulus repair. In addition, novel biomaterials are being explored to treat disc degeneration using a variety of treatment methods. PMID- 23016792 TI - Comparison of the acceptability of a new scoring system with Misch's classification for dental implant success determination. AB - AIMS: The present study aimed at evaluating the acceptability of the Implant Success Index (ISI) in comparison with the conventional classification system. MATERIALS AND METHODS: A comparative questionnaire was designed to evaluate 10 criteria that were reported to be important for acceptance of a new classification system. We asked 20 experts who had at least 5 years of clinical experience in implant dentistry to complete a questionnaire based on a visual analog scale. Data were analyzed by a blinded statistician using a Wilcoxon non parametric rank test. RESULTS: Measuring all 10 criteria, the acceptability level of ISI was significantly higher than that of the Misch classification (70.90 and 54.90, respectively; P < 0.05). The most significant differences were found in the system's ability to detect early lesions, its lack of overestimation, its quantitative base, and its comprehensiveness. The simplicity and compatibility of the two understudy classification systems were not significantly different. CONCLUSIONS: ISI seems to be a proper scoring system with a high level of acceptability for determining the success rate of dental implants and for selection of procedures used for improving the status of peri-implant tissue. PMID- 23016793 TI - 68Ga-DOTATATE PET/CT for the detection of inflammation of large arteries: correlation with18F-FDG, calcium burden and risk factors. AB - BACKGROUND: Ga-[1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid]-d Phe1,Tyr3-octreotate (DOTATATE) positron emission tomography (PET) is commonly used for the visualization of somatostatin receptor (SSTR)-positive neuroendocrine tumors. SSTR is also known to be expressed on macrophages, which play a major role in inflammatory processes in the walls of coronary arteries and large vessels. Therefore, imaging SSTR expression has the potential to visualize vulnerable plaques. We assessed 68Ga-DOTATATE accumulation in large vessels in comparison to 18F-2-fluorodeoxyglucose (FDG) uptake, calcified plaques (CPs), and cardiovascular risk factors. METHODS: Sixteen consecutive patients with neuroendocrine tumors or thyroid cancer underwent both 68Ga-DOTATATE and 18F-FDG PET/CT for staging or restaging purposes. Detailed clinical data, including common cardiovascular risk factors, were recorded. For a separate assessment, they were divided into a high-risk and a low-risk group. In each patient, we calculated the maximum target-to-background ratio (TBR) of eight arterial segments. The correlation of the TBRmean of both tracers with risk factors including plaque burden was assessed. RESULTS: The mean TBR of 68Ga-DOTATATE in all large arteries correlated significantly with the presence of CPs (r = 0.52; p < 0.05), hypertension (r = 0.60; p < 0.05), age (r = 0.56; p < 0.05), and uptake of 18F-FDG (r = 0.64; p < 0.01). There was one significant correlation between 18F-FDG uptake and hypertension (0.58; p < 0.05). Out of the 37 sites with the highest focal 68Ga-DOTATATE uptake, 16 (43.2%) also had focal 18F-FDG uptake. Of 39 sites with the highest 18F-FDG uptake, only 11 (28.2%) had a colocalized 68Ga DOTATATE accumulation. CONCLUSIONS: In this series of cancer patients, we found a stronger association of increased 68Ga-DOTATATE uptake with known risk factors of cardiovascular disease as compared to 18F-FDG, suggesting a potential role for plaque imaging in large arteries. Strikingly, we found that focal uptake of 68Ga DOTATATE and 18F-FDG does not colocalize in a significant number of lesions. PMID- 23016795 TI - Tuning the thermoelectric properties of conducting polymers in an electrochemical transistor. AB - While organic field-effect transistors allow the investigation of interfacial charge transport at the semiconductor-dielectric interface, an electrochemical transistor truly modifies the oxidation level and conductivity throughout the bulk of an organic semiconductor. In this work, the thermoelectric properties of the bulk of the conducting polymer poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate) were controlled electrically by varying the gate voltage. In light of the growing interest in conducting polymers as thermoelectric generators, this method provides an easy tool to study the physics behind the thermoelectric properties and to optimize polymer thermoelectrics. PMID- 23016794 TI - Investigating effective brain connectivity from fMRI data: past findings and current issues with reference to Granger causality analysis. AB - Interactions between brain regions have been recognized as a critical ingredient required to understand brain function. Two modes of interactions have held prominence-synchronization and causal influence. Efforts to ascertain causal influence from functional magnetic resonance imaging (fMRI) data have relied primarily on confirmatory model-driven approaches, such as dynamic causal modeling and structural equation modeling, and exploratory data-driven approaches such as Granger causality analysis. A slew of recent articles have focused on the relative merits and caveats of these approaches. The relevant studies can be classified into simulations, theoretical developments, and experimental results. In the first part of this review, we will consider each of these themes and critically evaluate their arguments, with regard to Granger causality analysis. Specifically, we argue that simulations are bounded by the assumptions and simplifications made by the simulator, and hence must be regarded only as a guide to experimental design and should not be viewed as the final word. On the theoretical front, we reason that each of the improvements to existing, yet disparate, methods brings them closer to each other with the hope of eventually leading to a unified framework specifically designed for fMRI. We then review latest experimental results that demonstrate the utility and validity of Granger causality analysis under certain experimental conditions. In the second part, we will consider current issues in causal connectivity analysis-hemodynamic variability, sampling, instantaneous versus causal relationship, and task versus resting states. We highlight some of our own work regarding these issues showing the effect of hemodynamic variability and sampling on Granger causality. Further, we discuss recent techniques such as the cubature Kalman filtering, which can perform blind deconvolution of the hemodynamic response robustly well, and hence enabling wider application of Granger causality analysis. Finally, we discuss our previous work on the less-appreciated interactions between instantaneous and causal relationships and the utility and interpretation of Granger causality results obtained from task versus resting state (e.g., ability of causal relationships to provide a mode of connectivity between regions that are instantaneously dissociated in resting state). We conclude by discussing future directions in this area. PMID- 23016796 TI - A comparison of strategies to recruit older patients and carers to end-of-life research in primary care. AB - BACKGROUND: Older adults receive most of their end-of-life care in the community, but there are few published data to guide researchers on recruitment to studies in primary care. The aim of this study was to compare recruitment of patients and bereaved carers from general practices in areas with different research network support, and identify challenges in obtaining samples representative of those in need of end-of-life care. METHODS: Comparative analysis of recruitment from general practices to two face-to-face interview studies concerned with 1) carers' perceptions of transitions between settings for decedents aged over 75 years and 2) the experiences of older patients living with cancer at the end-of-life. RESULTS: 33 (15% of invitees) patients and 118 (25%) carers were interviewed. Carers from disadvantaged areas were under-represented. Recruitment was higher when researchers, rather than research network staff, were in direct contact with general practices. Most practices recruited no more than one carer, despite a seven fold difference in the number of registered patients. The proportion identified as eligible for patient interviews varied by a factor of 38 between practices. Forty-four Primary Care Trusts granted approval to interview carers; two refused. One gave no reason; a second did not believe that general practitioners would be able to identify carers. CONCLUSION: Obtaining a representative sample of patients or carers in end-of-life research is a resource intensive challenge. Review of the regulatory and organisational barriers to end of-life researchers in primary care is required. Research support networks provide invaluable assistance, but researchers should ensure that they are alert to the ways in which they may influence study recruitment. PMID- 23016797 TI - Trainee impact on advanced diagnostic bronchoscopy: an analysis of 607 consecutive procedures in an interventional pulmonary practice. AB - BACKGROUND AND OBJECTIVE: Complications during advanced diagnostic bronchoscopy are rare and include: pneumothorax, bleeding, mediastinitis and lymphadenitis. Increased complications have been demonstrated in patients undergoing routine bronchoscopy procedures performed by trainees. This study aimed to determine the impact of trainees during advanced diagnostic bronchoscopy on procedure time, sedation use and complications. METHODS: A retrospective review of a quality improvement database including consecutive pulmonary procedures performed by an interventional pulmonologist (D.R.S.) at the University of Calgary, from 1 July 2007 to 1 April 2011. RESULTS: Six hundred seven (55.2%) of the 1100 procedures involved an advanced diagnostic procedure defined as: endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA), electromagnetic navigation bronchoscopy (ENB) and/or peripheral EBUS. A trainee participated in 512 (84.3%) procedures. A complication occurred in 25 patients (4.1%), with a trend towards increased complication rates in the trainee group (4.7% vs 1.1%, difference 3.6%, P = 0.076). Significant differences were seen when a trainee participated versus when no trainee participated for procedure length (58.32 min vs 37.69 min, difference 20.63 min (95% confidence interval: 19.07-22.19), P = 0.001) and for the dose of propofol (178.3 mg vs 137.1 mg, difference 41.2 mg (95% confidence interval: 19.81-63.38), P = 0.002). CONCLUSIONS: In an academic interventional pulmonology practice utilizing the apprenticeship model, trainee participation in advanced diagnostic bronchoscopy increased procedure time, increased the amount of sedation used and resulted in a trend to increased complications. Attempts to modify trainee procedural training to reduce the burden of procedural learning for patients are warranted. PMID- 23016798 TI - Endometriosis and infertility - a consensus statement from ACCEPT (Australasian CREI Consensus Expert Panel on Trial evidence). AB - Endometriosis is common in women with infertility but its management is controversial and varied. This article summarises the consensus developed by a group of Australasian subspecialists in reproductive endocrinology and infertility (the Australasian CREI Consensus Expert Panel on Trial evidence group) on the evidence concerning the management of endometriosis in infertility. Endometriosis impairs fertility by causing a local inflammatory state, inducing progesterone resistance, impairing oocyte release and reducing sperm and embryo transport. Medical treatments have a limited role, whereas surgical and assisted reproductive treatments improve pregnancy rates. The role of surgery for deep infiltrative endometriosis and repeat surgery requires further evaluation and there is insufficient evidence for the use of anti-adhesives to improve fertility. Intrauterine insemination (IUI) and in vitro fertilisation (IVF) improve pregnancy rates but women with endometriosis have lower pregnancy rates than those with other causes of infertility. The decision about whether to operate or pursue assisted reproduction will depend on a variety of factors such as the patient's symptoms, the presence of complex masses on ultrasound, ovarian reserve and ovarian access for IVF, risk of surgery and cost. Some women with infertility and endometriosis may benefit from a combination of assisted reproduction and surgery. PMID- 23016799 TI - Adjustment for reporting bias in network meta-analysis of antidepressant trials. AB - BACKGROUND: Network meta-analysis (NMA), a generalization of conventional MA, allows for assessing the relative effectiveness of multiple interventions. Reporting bias is a major threat to the validity of MA and NMA. Numerous methods are available to assess the robustness of MA results to reporting bias. We aimed to extend such methods to NMA. METHODS: We introduced 2 adjustment models for Bayesian NMA. First, we extended a meta-regression model that allows the effect size to depend on its standard error. Second, we used a selection model that estimates the propensity of trial results being published and in which trials with lower propensity are weighted up in the NMA model. Both models rely on the assumption that biases are exchangeable across the network. We applied the models to 2 networks of placebo-controlled trials of 12 antidepressants, with 74 trials in the US Food and Drug Administration (FDA) database but only 51 with published results. NMA and adjustment models were used to estimate the effects of the 12 drugs relative to placebo, the 66 effect sizes for all possible pair-wise comparisons between drugs, probabilities of being the best drug and ranking of drugs. We compared the results from the 2 adjustment models applied to published data and NMAs of published data and NMAs of FDA data, considered as representing the totality of the data. RESULTS: Both adjustment models showed reduced estimated effects for the 12 drugs relative to the placebo as compared with NMA of published data. Pair-wise effect sizes between drugs, probabilities of being the best drug and ranking of drugs were modified. Estimated drug effects relative to the placebo from both adjustment models were corrected (i.e., similar to those from NMA of FDA data) for some drugs but not others, which resulted in differences in pair-wise effect sizes between drugs and ranking. CONCLUSIONS: In this case study, adjustment models showed that NMA of published data was not robust to reporting bias and provided estimates closer to that of NMA of FDA data, although not optimal. The validity of such methods depends on the number of trials in the network and the assumption that conventional MAs in the network share a common mean bias mechanism. PMID- 23016800 TI - Coach behaviours and practice structures in youth soccer: implications for talent development. AB - Coaches are central to talent development in youth soccer and what they say and do impacts on players' achievements and well-being. Researchers have systematically observed coach behaviour and practice activities within this setting (i.e. 'what coaches do'). We review this research in light of contemporary discussion that highlights a potential 'theory-practice' divide. Our main example focuses on the discrepancy between coaching behaviour and research from the sports science sub-discipline areas of motor learning and skill acquisition that relate to how best to design practice sessions and provide instruction (i.e., 'what coaches should probably do'). The underlying reasons for this discrepancy are discussed and recommendations made to address this disparity in research, education and coach behaviours. PMID- 23016802 TI - Skin-to-skin care for dying preterm newborns and their parents--a phenomenological study from the perspective of NICU nurses. AB - BACKGROUND: Consequences of separation between preterm newborns and their parents have been discussed in many aspects, thus skin-to-skin care (SSC) has become common practice in Scandinavian Neonatal Intensive Care Units (NICUs) since the 1980s. The International workshop on Kangaroo Mother Care (KMC), 2009, recommends implementation of continuous KMC as the gold standard pervading all medical and nursing care, based on empirical studies and clinical guidelines and they suggest that KMC may be used during terminal care in agreement with parents. Parents have a strong desire to be near their child and give support and emotional comfort when the condition of the child requires it, and it has been suggested that medical staff expect parents to be with the neonates, and therefore, encourages them to hold the neonate while it is dying. The practice of SSC at the end of life has been under-researched, however. AIM: The aim of this study, which is part of a larger study on neonatal nursing care, was to describe the phenomenon of how nurses enact SSC for dying preterm newborns and their parents. DESIGN: A phenomenological reflective life world design. SETTING AND PARTICIPANTS: A purposive sample of 18 nurses from three Scandinavian NICUs. FINDINGS: The essential meaning of the phenomenon was expressed as strong belief in the urgency of SSC in providing mutual proximity and comfort for dying preterm newborns and their parents. The nurses act upon this belief and upon an engagement in securing the best possible present and future experiences of being close, in which the SSC is understood as a necessary premise in achieving the intended optimal conditions. The findings are elaborated in relation to previous caring and nursing research and phenomenology. CONCLUSIONS: Skin-to-skin care for dying preterm newborns and their parents is the preferred caring practice among Scandinavian NICU nurses who consider it of major importance to facilitate proximity and comfort through SSC when the newborn is still alive. The authors suggest this practical knowledge from NICU nurses perspective to be acknowledged in discussions concerning end-of-life care for preterm newborns and their parents and we recommend more formal establishment of this practice. Further research is needed on parents' experiences of skin-to skin caring in this vulnerable end of life situation of 'being with' their dying newborn. PMID- 23016801 TI - Value of routine voiding cystourethrography after renal transplantation. AB - The impact of vesicoureteral reflux (VUR) on renal allograft outcomes is debatable, with small cohort studies reporting controversial results. The objective of this retrospective study was to evaluate long-term clinical effects of early VUR in a large cohort of kidney transplant patients. Posttransplantation voiding cystourethrography was used to evaluate 646 consecutive kidney transplant recipients before discharge. The study endpoints included VUR grade, death censored graft or patient survival, renal function, proteinuria and occurrence of urinary tract infections (UTIs). Of the 646 recipients, 263 (40.7%) were diagnosed with VUR. VUR grade II was most common (19.8%), followed by grades III (10.2%), I (7.9%) and IV (2.8%). VUR was less common in transplantations performed by experienced compared to inexperienced surgeons (36% vs. 48%; p = 0.004). VUR did not affect death-censored graft or patient survival and was not associated with proteinuria or occurrence of UTIs. Patients with VUR had a lower eGFR at 1 year after transplantation than did patients without VUR (60 vs. 52 mL/min/1.73 m(2) ; p = 0.02), although this difference was not observed at 3 and 5 years after transplantation. We conclude that early VUR, a common finding among renal transplant patients, may not have a meaningful impact on long-term transplant outcomes. PMID- 23016803 TI - Evaluating contemporary pollen dispersal in two common grassland species Ranunculus bulbosus L. (Ranunculaceae) and Trifolium montanum L. (Fabaceae) using an experimental approach. AB - Pollen flow is a key biological process that connects plant populations, preventing genetic impoverishment and inbreeding. Pollen-mediated long-distance dispersal (LDD) events are especially important for plant species in increasingly fragmented landscapes. Patterns of pollen dispersal were directly estimated and dispersal kernels modelled in an experimental population of Ranunculus bulbosus and Trifolium montanum to determine the potential for LDD. Eight and 11 microsatellite markers were used for R. bulbosus and T. montanum, respectively, to run a likelihood-based paternity analysis on randomly chosen offspring (Ntotal = 180 per species) from five maternal plants. High rates of selfing were found in R. bulbosus (average 45.7%), while no selfing was observed in T. montanum. The majority (60%) of mating events occurred at very short distances: the median of the observed dispersal distances was 0.8 m in both species, and the average distances were 15.9 and 10.3 m in R. bulbosus and T. montanum, respectively. Modelling the pollen dispersal kernel with four different distribution functions (exponential-power, geometric, 2Dt and Weibull) indicated that the best fit for both species was given by a Weibull function. Yet, the tail of the T. montanum pollen dispersal kernel was thinner than in R. bulbosus, suggesting that the probability for LDD is higher in the latter species. Even though the majority of pollen dispersal occurred across short distances, the detection of several mating events up to 362 m (R. bulbosus) and 324 m (T. montanum) suggests that pollen flow may be sufficient to ensure population connectivity in these herb species across fragmented grasslands in Swiss agricultural landscapes. PMID- 23016805 TI - Prelude to RECOVER: time is up for veterinary CPR guidelines. PMID- 23016806 TI - Variability in veterinary thromboelastography. PMID- 23016807 TI - Updates in the American Heart Association guidelines for cardiopulmonary resuscitation and potential applications to veterinary patients. AB - OBJECTIVE: To review the updates in the American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and identify potential applications to veterinary patients. ETIOLOGY: Cardiopulmonary arrest is common in veterinary emergency and critical care, and consensus guidelines are lacking. Human resuscitation guidelines are continually evolving as new clinical and experimental studies support updated recommendations. Synthesis of human, experimental animal model, and veterinary literature support the potential for updates and advancement in veterinary CPR practices. THERAPY: This review serves to highlight updates in the AHA guidelines for CPR and evaluate their application to small animal veterinary patients. Interventions identified will be evaluated for trans-species potential, raise questions regarding best resuscitation recommendations, and offer opportunities for further research to continue to advance veterinary CPR. PROGNOSIS: The prognosis for any patient undergoing cardiopulmonary arrest remains guarded. PMID- 23016808 TI - Mechanisms of injury and emergency care of acute spinal cord injury in dogs and cats. AB - OBJECTIVES: To review the literature in regards to the pathophysiology of acute spinal cord injury, and to describe current concepts in regards to patient assessment, diagnostic, and therapeutic measures with a special emphasis on emergency and critical care considerations. ETIOLOGY: Acute spinal cord injury occurs in 2 phases. The primary injury occurs at the time of initial injury and may include intervertebral disk herniation, vertebral fracture or luxation, penetrating injury, and vascular anomalies such as fibrocartilaginous embolic myelopathy. Secondary injury occurs following primary injury and is multifactorial encompassing numerous biochemical and vascular events that result in progression of injury. DIAGNOSIS: The diagnosis is based on history and physical examination findings. A neurologic examination should be performed following initial patient assessment and stabilization. Further diagnostics to characterize acute spinal injury include radiographs and advanced imaging modalities such as myelography, computed tomography, or magnetic resonance imaging. THERAPY: Initial treatment should focus on addressing the patient's cardiovascular and respiratory system. Supportive measures to support systemic perfusion are vital to minimizing secondary injury. Specific therapy toward minimizing secondary injury in veterinary medicine remains controversial, especially in regards to the utilization of methylprednisolone. Other therapies are either in need of additional research or have failed to document clinical difference. PROGNOSIS: The prognosis for acute spinal injury is varied and is dependent upon the presence of concurrent trauma, location, and type of primary injury sustained, and extent of neurologic impairment at the time of initial presentation. The etiology of the underlying trauma is of great importance in determining prognosis and outcome. Loss of deep pain is generally accepted as a poor prognostic indicator; however, even these patients can recover depending on their response to treatment. PMID- 23016809 TI - Severe burn injury, burn shock, and smoke inhalation injury in small animals. Part 1: burn classification and pathophysiology. AB - OBJECTIVE: To review the literature related to severe burn injury (SBI), burn shock, and smoke inhalation injury in domestic animals. Current animal- and human based research and literature were evaluated to provide an overview of thermal burn classification and the pathophysiology of burn shock and smoke inhalation injury. ETIOLOGY: Severe burn injury, burn shock, and smoke inhalation injury may be encountered as a result of thermal injury, radiation injury, chemical injury, or electrical injury. DIAGNOSIS: Burns can be subdivided based on the amount of total body surface area (TBSA) involved and the depth of the burn. Local burn injuries involve <20% of the TBSA whereas SBI involves >20-30% of the TBSA. The modern burn classification system classifies burns by increasing depth: superficial, superficial partial-thickness, deep partial-thickness, and full thickness. SUMMARY: Local burn injury rarely leads to systemic illness whereas SBI leads to significant metabolic derangements that require immediate and intensive management. SBI results in a unique derangement of cardiovascular dysfunction known as "burn shock." The physiologic changes that occur with SBI can be divided into 2 distinct phases; the resuscitation phase and the hyperdynamic hypermetabolic phase. The resuscitation phase occurs immediately following SBI and lasts for approximately 24-72 hours. This period of hemodynamic instability is characterized by the release of inflammatory mediators, increased vascular permeability, reduced cardiac output, and edema formation. The hyperdynamic hypermetabolic phase begins approximately 3-5 days after injury. This phase is characterized by hyperdynamic circulation and an increased metabolic rate that can persist up to 24 months post burn injury in people. PMID- 23016810 TI - Severe burn injury, burn shock, and smoke inhalation injury in small animals. Part 2: diagnosis, therapy, complications, and prognosis. AB - OBJECTIVE: To review the evaluation and treatment of patients suffering from severe burn injury (SBI), burn shock, and smoke inhalation injury. Potential complications and prognosis associated with SBI are also discussed. DIAGNOSIS: Diagnosis of burn injury and burn shock is based on patient history and clinical presentation. Superficial burn wounds may not be readily apparent for the first 48 h whereas more severe wounds will be evident at presentation. Patients are diagnosed with local or SBI by estimating total body surface area involved using the 'Rule of Nines' or the Lund-Browder chart adapted from the human literature. THERAPY: Patients suffering from SBI require immediate and aggressive fluid therapy. Burn wounds require prompt cooling to prevent progressive tissue damage. Due to significant pain associated with burn wounds and therapeutic procedures, multimodal analgesia is recommended. Daily wound management including hydrotherapy, topical medications, and early wound excision and grafting is necessary with SBI. COMPLICATIONS: There are numerous complications associated with SBI. The most common complications include infections, hypothermia, intra abdominal hypertension, and abdominal compartment syndrome. PROGNOSIS: The prognosis of SBI in domestic animals is unknown. Based on information derived from human literature, patients with SBI and concomitant smoke inhalation likely have a worse prognosis than those with SBI or smoke inhalation alone. PMID- 23016811 TI - Comparison of Hb-200 and 6% hetastarch 450/0.7 during initial fluid resuscitation of 20 dogs with gastric dilatation-volvulus. AB - OBJECTIVE: To compare the use of polymerized stroma-free bovine hemoglobin (Hb 200) and 6% hetastarch 450/0.7 (HES 450/0.7) in 0.9% saline during fluid resuscitation of dogs with gastric dilatation-volvulus (GDV). DESIGN: Prospective, randomized clinical case series. SETTING: Private specialty and referral clinic. ANIMALS: Twenty client-owned dogs presenting with GDV. INTERVENTIONS: Dogs presenting with GDV and abnormal perfusion parameters first received rapid IV infusion of a buffered isotonic replacement crystalloid (15 mL/kg) and IV opioids. Patients were then randomized to receive either Hb-200 (N = 10) or HES 450/0.7 (N = 10). Balanced isotonic replacement crystalloids (10-20 mL/kg IV) were rapidly infused along with either Hb-200 or HES in 5 mL/kg IV aliquots to meet resuscitation end points. MEASUREMENTS AND MAIN RESULTS: Resuscitation was defined as meeting at least 2 of 3 criteria: (1) capillary refill time 1-2 seconds, pink mucous membrane color, strong femoral pulse quality; (2) heart rate (HR) <= 150/min; or (3) indirect arterial systolic blood pressure (SBP) > 90 mm Hg. HR, SBP, packed cell volume, hemoglobin, glucose, venous pH, bicarbonate, base excess, anion gap, and colloid osmotic pressure were compared at hospital entry and within 30 minutes post-resuscitation. Compared to the HES group, the Hb-200 group required significantly less colloid (4.2 versus 18.4 mL/kg) and crystalloid (31.3 versus 48.1 mL/kg) to reach resuscitation end points (P = 0.001). Time to resuscitation was significantly shorter in the Hb-200 group (12.5 versus 52.5 min). CONCLUSIONS: Dogs with GDV receiving Hb-200 during initial resuscitation required smaller volumes of both crystalloid and colloid fluids and reached resuscitation end points faster than dogs receiving HES 450/0.7 (P = 0.02). PMID- 23016812 TI - In vitro evaluation of the effect of hypothermia on coagulation in dogs via thromboelastography. AB - OBJECTIVE: To evaluate the effect of temperature alterations on in vitro coagulation in healthy dogs using thromboelastography (TEG). DESIGN: In vitro study. SETTING: University teaching hospital. ANIMALS: Six healthy purpose-bred laboratory dogs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thromboelastograph tracings were created daily for all test subjects and used to generate control values for R, K, alpha, and MA. Control values were compared to test samples incubated at 42, 39, 36, 33, 30, and 27 degrees C. At temperatures <= 30 degrees C, a significant increase in K values and a significant decrease in the alpha values were noted. There were no significant differences detected for R and MA among any of the test temperatures. CONCLUSIONS: Hypothermia results in in vitro coagulation changes in healthy dogs as determined by whole blood analysis using TEG. The data suggest that while clots may form more slowly at decreased temperatures, the ultimate strength of the clot appears unaffected. PMID- 23016813 TI - A comparison of 3 anesthetic protocols for 24 hours of mechanical ventilation in cats. AB - OBJECTIVE: To compare the recovery times, recovery quality, and cardiovascular (CV) effects of 3 anesthetic protocols during 24 hours of mechanical ventilation (MV) in healthy cats. DESIGN: Prospective, randomized, crossover study. SETTING: Research laboratory at a veterinary teaching hospital. ANIMALS: Six healthy intact male purpose-bred cats. INTERVENTIONS: Each cat was randomly assigned to receive 3 anesthetic protocols for 24 hours of MV; Protocol K consisted of ketamine, Protocol P, propofol; and Protocol PK, propofol plus fixed-rate low dose ketamine. Each infusion drug dose was adjusted using a sedation scoring system. All protocols included fixed doses of fentanyl (10 MUg/kg/h) and midazolam (0.5 mg/kg/h). MEASUREMENTS AND MAIN RESULTS: Drug doses and recovery times were recorded. Recovery quality was scored. Blood gas results, CV parameters, and frequency of bradycardia or hypotension requiring interventions were recorded. The mean d dose +/- standard error of K was 81.3 +/- 3.3 MUg/kg/m. The median dose (95% cardiac index) of propofol (MUg/kg/m) in PK was 16.0 (13.1, 19.6) and in P was 48.1 (39.3, 58.9). P necessitated significantly more propofol than PK (P < 0.05). Protocol K (35.6 +/- 3.2 hours) had significantly longer times to full recovery compared to P (18.2 +/- 3.2 hours). Protocol K had significantly longer times to head up, crawling, and standing compared to P and PK. Cats sedated with PK (2.33 +/- 0.47) required significantly more interventions for hypotension than K (0.50 +/- 0.47). Protocol P (3.2 +/- 0.4) and PK (1.4 +/- 0.3) required significantly more interventions for bradycardia compared to K (0.8 +/- 0.3). When comparing protocol K to P and PK, significant differences in blood pressure, lactate, oxygen delivery, and oxygen consumption were noted. CONCLUSIONS: Cats anesthetized with P had shorter times to full recovery compared to K. Cats anesthetized with K required fewer interventions for bradycardia or hypotension but had longer recovery times compared to P or PK. Protocol PK reduced the propofol dose required to maintain optimal anesthesia. PMID- 23016814 TI - Esophageal foreign bodies in dogs: 34 cases (2004-2009). AB - OBJECTIVE: To characterize the clinical and radiographic signs, endoscopic findings, treatment, and outcome for dogs that present with esophageal foreign bodies (EFBs), and to identify factors associated with the severity of secondary esophagitis and length of hospitalization (LOH). DESIGN: Retrospective case series. SETTING: Private referral veterinary center. ANIMALS: Client-owned dogs. INTERVENTIONS: None. MEASUREMENTS: Medical records for 34 client-owned dogs with EFBs that had esophageal radiographs and that had undergone esophagoscopy were evaluated retrospectively. Information regarding clinical history, radiographic signs, findings at esophagoscopy, and outcome were recorded. RESULTS: The most common EFBs were bone (29.7%) and rawhides (29.7%). The median duration of clinical signs prior to initial presentation was 2.75 hours. Radiographically, EFBs were identified definitively in 30 dogs and questionably in 1. The most common location was in the caudal esophagus (59.3%). Esophagitis was not identified in 6 dogs; and was assessed as mild in 14, moderate in 9, and severe in 4. In 1 dog the degree of esophagitis could not be determined due to the presence of contrast agent. Dogs with longer duration of clinical signs and longer anesthesia times were more likely to have moderate or severe esophagitis. Median LOH was 19 hours. Dogs with longer duration of clinical signs, EFBs located in the caudal esophagus, and moderate or severe esophagitis had longer hospital stays. No dogs experienced long-term complications. Complication rate was 82.5% with 8 patients having more than 1 complication. CONCLUSIONS: While long-term prognosis is excellent, early intervention helps reduce short-term esophagitis and LOH. PMID- 23016823 TI - Effect of non-steroidal anti-inflammatory drugs on bone turnover: an evidence based review. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. NSAIDs have been shown to inhibit bone healing in animal studies due to the inhibition of prostaglandin synthesis. However, little evidence exists regarding the effect of NSAID exposure on human bone metabolism. This systematic review summarizes the current literature of randomized controlled trials (RCTs) investigating NSAIDs with bone remodeling-related outcomes in humans. After performing computerized searches in the most widely indexed databases, study selection, data abstraction and risk of bias assessment were conducted in duplicate. The results were controversial regarding the association of NSAID with bone formation or resorption. Increased bone mineral density following NSAID exposure was reported by some studies. Based on the levels of biochemical markers, no effect was seen on bone formation, while some evidence was found for a decreased rate of bone resorption in NSAID patients. Trials investigating the effects of NSAID treatment on bone metabolism outcomes of human patients are limited. Further research is required to confirm or refute the findings of this systematic review. PMID- 23016822 TI - Mindfulness-based cognitive therapy for multiple chemical sensitivity: a study protocol for a randomized controlled trial. AB - BACKGROUND: Multiple chemical sensitivity (MCS) is a condition characterized by recurrent, self-reported symptoms from multiple organ systems, attributable to exposure to a wide range of chemically unrelated substances at low levels. The pathophysiology is unknown, and affected individuals generally favor avoidance of the symptom triggering substances as a coping strategy. The impact of MCS on daily life may thus be severe. An intervention that may effectively reduce the impact of MCS, alleviate the symptoms and the psychological distress associated with the condition is therefore highly needed. In this study we will assess the effects of a mindfulness-based cognitive (MBCT) program on MCS. METHODS/DESIGN: Using a randomized controlled design (RCT), we will compare MBCT with treatment as usual (TAU). The MBCT intervention will include 8 weekly 2.5 hour sessions, and 45 minutes of mindfulness home practice 6 days each week. Participants will be asked to complete questionnaires at baseline, post-treatment, and at 6 and 12 months' follow-up. Based on sample size estimation, 82 participants will be randomized to either the MBCT intervention or to TAU. The primary outcome will be a measure of the impact of MCS on the participants' lives. The secondary outcome measures are physical symptoms of psychological distress, perceived stress, illness perceptions, QOL, and work ability. Lastly, we will assess whether any effect of MBCT on the primary effect measure is mediated by level of mindfulness, self-compassion, perceived stress, and rumination. DISCUSSION: This trial will provide important information on the effects of MBCT on MCS. TRIALS REGISTRATION: Clinical trials identifier NCT01240395. PMID- 23016824 TI - Co-transcriptional assembly of chemically modified RNA nanoparticles functionalized with siRNAs. AB - We report a generalized methodology for the one-pot production of chemically modified functional RNA nanoparticles during in vitro transcription with T7 RNA polymerase. The efficiency of incorporation of 2'-fluoro-dNTP in the transcripts by the wild type T7 RNA polymerase dramatically increases in the presence of manganese ions, resulting in a high-yield production of chemically modified RNA nanoparticles functionalized with siRNAs that are resistant to nucleases from human blood serum. Moreover, the unpurified transcription mixture can be used for functional ex vivo pilot experiments. PMID- 23016825 TI - Topology of the microsomal glycerol-3-phosphate acyltransferase Gpt2p/Gat1p of Saccharomyces cerevisiae. AB - All glycerophospholipids are made from phosphatidic acid, which, according to the traditional view, is generated at the cytosolic surface of the ER. In yeast, phosphatidic acid is synthesized de novo by two acyl-CoA-dependent acylation reactions. The first is catalysed by one of the two homologous glycerol-3 phosphate acyltransferases Gpt2p/Gat1p and Sct1p/Gat2p, the second by one of the two 1-acyl-sn-glycerol-3-phosphate acyltransferases Slc1p and Ale1p/Slc4p. To study the biogenesis and topology of Gpt2p we observed the location of dual topology reporters inserted after various transmembrane helices. Moreover, using microsomes, we probed the accessibility of natural and substituted cysteine residues to a membrane impermeant alkylating agent and tested the protease sensitivity of various epitope tags inserted into Gpt2p. Finally, we assayed the sensitivity of the acyltransferase activity to membrane impermeant agents targeting lysine residues. By all these criteria we find that the most conserved motifs of Gpt2p and its functionally relevant lysines are oriented towards the ER lumen. Thus, the first step in biosynthesis of phosphatidic acid in yeast seems to occur in the ER lumen and substrates may have to cross the ER membrane. PMID- 23016826 TI - The power of a handshake: neural correlates of evaluative judgments in observed social interactions. AB - Effective social interactions require the ability to evaluate other people's actions and intentions, sometimes only on the basis of such subtle factors as body language, and these evaluative judgments may lead to powerful impressions. However, little is known about the impact of affective body language on evaluative responses in social settings and the associated neural correlates. This study investigated the neural correlates of observing social interactions in a business setting, in which whole-body dynamic stimuli displayed approach and avoidance behaviors that were preceded or not by a handshake and were followed by participants' ratings of these behaviors. First, approach was associated with more positive evaluations than avoidance behaviors, and a handshake preceding social interaction enhanced the positive impact of approach and diminished the negative impact of avoidance behavior on the evaluation of social interaction. Second, increased sensitivity to approach than to avoidance behavior in the amygdala and STS was linked to a positive evaluation of approach behavior and a positive impact of handshake. Third, linked to the positive effect of handshake on social evaluation, nucleus accumbens showed greater activity for Handshake than for No-handshake conditions. These findings shed light on the neural correlates of observing and evaluating nonverbal social interactions and on the role of handshake as a way of formal greeting. PMID- 23016827 TI - The global burden of human parasites: who and where are they? How are they transmitted? PMID- 23016828 TI - Effect of exclusive enteral nutrition on gut microflora function in children with Crohn's disease. AB - OBJECTIVE: Exclusive enteral nutrition (EEN) is a first-line treatment in children with active Crohn's disease (CD) but is seldom used in adults with active disease. The mode of action of EEN in suppressing mucosal inflammation is not fully understood, but modulation of intestinal microflora activity is one possible explanation. The aim of this study was to investigate the effect of 6 week EEN in children with active CD, with special reference to intestinal microflora function. MATERIALS AND METHODS: Fecal samples from 18 children (11 boys, 7 girls; median age 13.5 years) with active CD (13 children with small bowel/colonic and 5 with perianal disease) were analyzed for short chain fatty acid (SCFA) pattern as marker of gut microflora function. The children were studied before and after EEN treatment. Results from 12 healthy teenagers were used for comparison. RESULTS: Eleven (79%) of the children with small bowel/colonic CD responded clinically positively to EEN treatment showing decreased levels of pro-inflammatory acetic acid as well as increased concentrations of anti-inflammatory butyric acids and also of valeric acids, similar to the levels in healthy age-matched children. In children with active perianal CD, however, EEN had no positive effect on clinical status or inflammatory parameters. CONCLUSIONS: The authors present new data supporting the hypothesis that the well-documented anti-inflammatory effect of EEN in children with active small bowel/colonic CD is brought about by modulation of gut microflora activity, resulting in an anti-inflammatory SCFA pattern. By contrast, none of the children with perianal disease showed clinical or biochemical improvement after EEN treatment. PMID- 23016829 TI - Alteration of global workspace during loss of consciousness: a study of parietal seizures. AB - PURPOSE: Loss of consciousness (LOC) in epileptic seizures has a strongly negative impact on quality of life. Recently, we showed that LOC occurring during temporal lobe seizures was correlated with a nonlinear increase of neural synchrony in associative--and particularly parietal--cortices. Whether these mechanisms might be observed in other types of seizures is unknown. This study aimed at investigating the relationship between changes in synchrony and degree of LOC during parietal lobe epilepsy (PLE), a form of epilepsy in which seizures directly involve the parietal associative cortices. METHODS: Ten patients undergoing stereoelectroencephalography (SEEG) during presurgical evaluation of PLE were studied. The LOC intensity was scored using the Conscious Seizure Scale (CSS). For each studied seizure (n = 29), interdependencies between signals recorded from six brain regions were estimated as a function of time by using nonlinear regression analysis (h(2) coefficient). KEY FINDINGS: Seizures were divided into three groups according to the CSS scale: group A (no LOC) with a score <=1, group B (intermediate or partial LOC) with a score ranging from 2 to 5, and group C (maximal LOC) with a score >=6. The majority of seizures in patients with PLE disclosed significant LOC (17/29, group C). Mean h(2) values were significantly different between the three groups (p = 0.008), the maximal values of synchrony being observed in group C. In addition, a statistically significant nonlinear relationship (p = 0.0021) was found between the h(2) values and the CSS scores, suggesting a threshold effect. SIGNIFICANCE: This study indicates that excess of EEG signal synchrony within associative cortices is likely to be a crucial phenomenon associated with LOC. PMID- 23016830 TI - Reference values of serum cystatin C in very low-birthweight premature infants. AB - AIM: To determine reference values for cystatin C (CysC) and its correlation with creatinine (Cr), gestational age, birthweight and maternal Cr status in very low birthweight (VLBW) preterm infants. METHOD: The study included 113 VLBW premature infants (<1500 g) of <= 32 gestational week. Serum Cr and CysC of the infant and serum Cr of the mother were analysed. RESULTS: The mean level of CysC was 1.77 +/ 0.38 mg/L on day 1 and 1.61 +/- 0.37 mg/L on day 3, and the decrease was statistically significant. There was a significant correlation only between maternal Cr and first-day Cr values and negative correlations between Cr and gestational age and birthweight on third day. Creatinine was not correlated with CysC both on day 1 (r = -0.077, p = 0.417) and day 3 (r = 0.132, p = 0.164). CONCLUSION: Here, we report the reference ranges for CysC and Cr on first and third day in VLBW infants. CysC concentrations significantly decrease by day 3 compared with day 1 and are independent of gestational week, birthweight and maternal renal function status in VLBW preterm infants. PMID- 23016831 TI - Comment on the melting and decomposition of sugars. PMID- 23016832 TI - Hydrogen bonding between the Q(B) site ubisemiquinone and Ser-L223 in the bacterial reaction center: a combined spectroscopic and computational perspective. AB - In the Q(B) site of the Rhodobacter sphaeroides photosynthetic reaction center, the donation of a hydrogen bond from the hydroxyl group of Ser-L223 to the ubisemiquinone formed after the first flash is debatable. In this study, we use a combination of spectroscopy and quantum mechanics/molecular mechanics (QM/MM) calculations to comprehensively explore this topic. We show that ENDOR, ESEEM, and HYSCORE spectroscopic differences between mutant L223SA and the wild-type sample (WT) are negligible, indicating only minor perturbations in the ubisemiquinone spin density for the mutant sample. Qualitatively, this suggests that a strong hydrogen bond does not exist in the WT between the Ser-L223 hydroxyl group and the semiquinone O(1) atom, as removal of this hydrogen bond in the mutant should cause a significant redistribution of spin density in the semiquinone. We show quantitatively, using QM/MM calculations, that a WT model in which the Ser-L223 hydroxyl group is rotated to prevent hydrogen bond formation with the O(1) atom of the semiquinone predicts negligible change for the L223SA mutant. This, together with the better agreement between key QM/MM calculated and experimental hyperfine couplings for the non-hydrogen-bonded model, leads us to conclude that no strong hydrogen bond is formed between the Ser-L223 hydroxyl group and the semiquinone O(1) atom after the first flash. The implications of this finding for quinone reduction in photosynthetic reaction centers are discussed. PMID- 23016833 TI - Impaired self-other differentiation in frontotemporal dementia due to the C9ORF72 expansion. AB - INTRODUCTION: An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as an important cause of frontotemporal dementia and motor neuron disease; however, the phenotypic spectrum of this entity and its pathophysiologic basis have yet to be fully defined. Psychiatric features may be early and prominent, although a putative cortico-thalamo-cerebellar network has been implicated in the pathogenesis of the clinical phenotype. Differentiation of self from others is a core cognitive operation that could potentially link network disintegration with neuropsychiatric symptoms in C9ORF72-associated frontotemporal dementia. METHODS: We undertook a detailed behavioral analysis of self-other attribution in a 67-year-old male patient with behavioral variant frontotemporal dementia (bvFTD) due to the C9ORF72 expansion by using a novel paradigm requiring differentiation of the effects of self- and non-self-generated actions. The patient's performance was assessed in relation to two older male patients with bvFTD not attributable to the C9ORF72 expansion and four healthy older male subjects. RESULTS: Compared with the healthy control group, the patient with the C9OFR72 mutation showed a deficit of self-other differentiation that was disproportionate to his otherwise relatively indolent clinical phenotype. The performance of the other patients with bvFTD was similar to that of healthy subjects. CONCLUSION: We propose that impaired self-other differentiation is a candidate mechanism for neuropsychiatric decline in association with the C9ORF72 expansion. We offer this preliminary observation as a stimulus to further work. PMID- 23016834 TI - One-pot synthesis of an Fe(II) bis-terpyridine complex with allosterically regulated electronic properties. AB - Herein we report the one-pot synthesis of Fe(II) bis-terpyridine complexes with two peripheral square-planar Pt(II) bis-phosphinoalkylthioether moieties. These novel structures, which exhibit allosterically controllable electronic properties, are made by taking advantage of two orthogonal and high-yielding reactions. The prototypical complex can be structurally regulated through the reversible abstraction and introduction of chloride ions to the Pt(II) centers. This moves the Fe(II) center and two Pt(II) metal centers into and out of communication with each other, causing changes in the electronic structure of the complex and its corresponding optical and redox properties. The start and end points of the allosterically regulated system have been characterized by single crystal X-ray diffraction and NMR, UV-vis, and (57)Fe Mobetabauer spectroscopy. PMID- 23016835 TI - Obstetric anal sphincter injury risk factors and the role of the mediolateral episiotomy. AB - AIMS: Investigate risk factors for obstetric anal sphincter injury (OASI) and their incidence between 2006 and 2010 at a regional teaching hospital in Australia. Determine whether a correlation exists between a decrease in OASI rates and an increase in mediolateral episiotomies. MATERIALS AND METHODS: A retrospective observational study conducted at the Geelong Hospital, Barwon Health, Victoria, Australia. Every adequately documented vaginal birth from 2006 to 2010 in the hospital was included (N = 7314, cases of OASI = 239). Patient data were obtained from the Barwon Health Birth Outcomes System database. Multinomial logistic regression, Pearson's correlation coefficient and relative risk calculations were used for analysis. RESULTS: Risk factors for OASI include nulliparity (OR 2.64, 95% CI 1.95-3.57, P < 0.01), instrumental delivery (OR 2.54, 95% CI 1.82-3.55, P < 0.01) and birth weight greater than 4 kg (OR 1.56, 95% CI 1.11-2.19, P = 0.01). There was a significant correlation between increasing mediolateral episiotomy use from 12.56% to 20.10% and a reduction in OASI rates over the 5-year period (Pearson's correlation coefficient: -0.94, P = 0.02). The correlation remained when analysing normal vaginal births in isolation from instrumental (Pearson's correlation coefficient: -0.89, P = 0.04). CONCLUSIONS: Clear risk factors for OASI include nulliparity, macrosomia and instrumental delivery. There was a significant correlation between increasing mediolateral episiotomy rates from 12.56% to 20.10% and decreasing OASI. PMID- 23016836 TI - Fast eigenvector centrality mapping of voxel-wise connectivity in functional magnetic resonance imaging: implementation, validation, and interpretation. AB - Eigenvector centrality mapping (ECM) has recently emerged as a measure to spatially characterize connectivity in functional brain imaging by attributing network properties to voxels. The main obstacle for widespread use of ECM in functional magnetic resonance imaging (fMRI) is the cost of computing and storing the connectivity matrix. This article presents fast ECM (fECM), an efficient algorithm to estimate voxel-wise eigenvector centralities from fMRI time series. Instead of explicitly storing the connectivity matrix, fECM computes matrix vector products directly from the data, achieving high accelerations for computing voxel-wise centralities in fMRI at standard resolutions for multivariate analyses, and enabling high-resolution analyses performed on standard hardware. We demonstrate the validity of fECM at cluster and voxel levels, using synthetic and in vivo data. Results from synthetic data are compared to the theoretical gold standard, and local centrality changes in fMRI data are measured after experimental intervention. A simple scheme is presented to generate time series with prescribed covariances that represent a connectivity matrix. These time series are used to construct a 4D dataset whose volumes consist of separate regions with known intra- and inter-regional connectivities. The fECM method is tested and validated on these synthetic data. Resting-state fMRI data acquired after real-versus-sham repetitive transcranial magnetic stimulation show fECM connectivity changes in resting-state network regions. A comparison of analyses with and without accounting for motion parameters demonstrates a moderate effect of these parameters on the centrality estimates. Its computational speed and statistical sensitivity make fECM a good candidate for connectivity analyses of multimodality and high-resolution functional neuroimaging data. PMID- 23016837 TI - Neuropsychiatric symptoms in amnestic mild cognitive impairment: increased risk and faster progression to dementia. AB - INTRODUCTION: Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) but its role as a predictive factor for the progression to dementia is still not clear. The objective of this study is to identify NPS that predict the progression from amnestic MCI (a-MCI) to dementia using an easy to administer screening tool for NPS. MATERIAL AND METHODS: 132 patients with a-MCI were assessed for NPS by the Neuropsychiatric Inventory (NPI) and followed to detect progression to dementia. RESULTS: The mean follow-up time was 3.5+/-2.9 years and rate of progression to dementia 28.8%. Two items of NPI were found to be independent risk factors for progression, nighttime behavioural disturbance (hazard ratio(HR)=2.2, 95%CI=1.10-4.43), anxiety (HR=2.5, 95%CI=1.01-6.20) and apathy (HR=2.2, 95%CI=1.003-4.820). The risk of progression increased with higher score on NPI (HR=1.046 per point, 95%CI=1.019- 1.073), and with a higher number of items of NPI affected (HR=3.6 per item, 95%CI=2.0-6.4). Faster progression to dementia was observed in patients with either nighttime behavioural disturbance, apathy or anxiety (4.6 vs. 8.3 years, 5.3 vs. 8.4 years and 3.0 vs. 7.7 years respectively, p < 0.01) as well as in those with a higher number of items affected (no items = 9.2 years, 1-3 items = 6.6 years and > 3 items = 2.9 years, p < 0.001). CONCLUSIONS: Assessing a broad spectrum of NPS can help identify patients with a-MCI presenting a higher risk for progression to dementia. This can be useful to select patients for closer follow-up, clinical trials and future therapeutic interventions. PMID- 23016838 TI - Early hospital readmission after kidney transplantation: patient and center-level associations. AB - Early hospital readmission (EHR) is associated with increased morbidity, costs and transition-of-care errors. We sought to quantify rates of and risk factors for EHR after kidney transplantation (KT). We studied 32 961 Medicare primary KT recipients (2000-2005) linked to Medicare claims through the United States Renal Data System. EHR was defined as at least one hospitalization within 30 days of initial discharge after KT. The association between EHR and recipient and transplant factors was explored using Poisson regression; hierarchical modeling was used to account for study center-level differences. The overall EHR rate was 31%, and 19 independent patient-level factors associated with EHR were identified: recipient factors included older age, African American race and various comorbidities; transplant factors included ECD, length of stay and lack of induction therapy. The unadjusted rate of EHR by center ranged from 18% to 47%, but conventional center-level factors (percent African American, percent age > 60, percent deceased donor and percent expanded criteria donor) were not associated with EHR. However, intermediate total volume and average length of stay were associated with increased EHR risk. Better identification of patients at risk for early hospital readmission following KT may guide discharge planning and early posttransplant outpatient monitoring. PMID- 23016839 TI - Mapping myeloperoxidase to identify its promiscuity properties using docking and molecular dynamics simulations. AB - Myeloperoxidase (MPO) is the most abundant heme protein in neutrophils, and MPO catalyzes hypochlorous acid (HOCl) formation. MPO inhibitors (MPOis) can be used to treat several diseases in which MPO and HOCl levels are elevated. The molecular details of several MPOis have not been extensively studied to elucidate their molecular recognition properties. In addition, it is not known whether MPO has only one binding site or more binding sites for aryl compounds, which would explain its promiscuity properties. Therefore, docking simulations were performed to analyze the MPO binding site recognition using several X-ray structures and snapshots retrieved from molecular dynamics (MD) simulations to simulate the binding of MPO with several known aryl ligands. All of the evaluated ligands were recognized by MPO at the same site, which was identified by the Q-Site Finder as being one of the principal sites and named herein as the "principal binding site" (PBS). The PBS is composed of Q91, H95, F99, R239, E242, F366 and F407. The results indicate that the MPO ligand recognition is mediated by pi-pi interactions with an aromatic cluster (F99, F366, F407 and a heme group), giving rise to high MPO promiscuity. In addition, MD simulations and X-ray crystallography show limited conformational variations in the MPO. In addition, either MPOis or another substrate (tyrosine) reaches the same site, but different interactions were observed. Therefore, the results indicate minor movement in the side chain of the mentioned amino acids that allow ligands to be recognized in the same MPO site with different interactions that are dependent on their chemical structures. Furthermore, docking study samples of several conformations retrieved from the MD simulations showed that ABAH was one of the ligands that always had the same interaction. This result provides potential evidence for hydrazides being very good MPOis. PMID- 23016840 TI - FDA-approved drugs selected using virtual screening bind specifically to G quadruplex DNA. AB - Guanine-rich sequences found in telomeres and oncogene promoters have the ability to form G-quadruplex structures. In this paper we describe the use of a virtual screening assay to search a database of FDA-approved compounds for compounds with the potential to bind G-quadruplex DNA. More than 750 telomerase inhibitors were identified in a literature search as acting through G-quadruplex stabilization, and from evaluation of these compounds, theoretical models capable of discriminating new compounds that bind G-quadruplex DNA were developed. Six compounds predicted to bind to the G-quadruplex structure were tested for their ability to bind to the human telomeric DNA sequence. Prochloroperazine, promazine, and chlorpromazine stabilized the G-quadruplex structure as determined by fluorescence resonance energy transfer techniques. These compounds also bound to promoter sequences of oncogenes such as c-myc and K-ras. Amitriptyline, imipramine, and loxapine were less stabilizing but did bind to the G-quadruplex. The ability of prochloroperazine, promazine, and chlorpromazine to recognize G quadruplex structures was confirmed using a fluorescent intercalator displacement assay, in which displacement of thiazole orange from G-quadruplex structures was demonstrated. Interestingly, these compounds exhibited selectivity for the G quadruplex structure as all had poor affinity for the duplex sequence. PMID- 23016841 TI - Exploring QSARs of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors by MLR, PLS and PC-ANN. AB - Quantitative structure-activity relationship study was performed to understand the inhibitory activity of a set of 192 vascular endothelial growth factor receptor-2 (VEGFR-2) compounds. QSAR models were developed using multiple linear regression (MLR) and partial least squares (PLS) as linear methods. While principal component - artificial neural networks (PC-ANN) modeling method with application of eigenvalue ranking factor selection procedure was used as nonlinear method. The results obtained offer good regression models having good prediction ability. The results obtained by MLR and PLS are close and better than those obtained by principal component- artificial neural network. The best model was obtained with a correlation coefficient of 0.87. The strength and the predictive performance of the proposed models was verified using both internal (cross-validation and Y-scrambling) and external statistical validations. PMID- 23016842 TI - Computational approaches for ligand discovery and design in class-A G protein- coupled receptors. AB - Our structural understanding of the superfamily of G-protein coupled receptors, a group of targets of utmost pharmacological importance, has improved dramatically in the last few years. This was directly translated in an increase of both the number and the relevance of computer-assisted drug design efforts devoted to these receptors. The field, which had been greatly influenced by ligand-based methods, has experienced a radical transformation with a number of successful structure-based ligand design and ligand discovery studies. This revolution has been accompanied by the exponential increase of computational resources, and as a result the scenario in GPCR structural and chemical studies is now more complex and richer than ever. Virtual screens, both structure- and ligand-based, co-exist with accurate computational characterizations of the receptor conformational dynamics and of the energy landscapes of receptor-ligand interactions. We here provide an integrated and updated view of the different computational techniques applied to the ligand design of GPCRs. Particular emphasis is put on the studies that take into account the novel structural information of GPCRs, together with those that consider the enormous amount of chemical information accumulated on these receptors in the last decades. Indeed, we propose that proper combinations of the different computational techniques: ligand-based, structure-based and molecular dynamics studies, should be performed to better integrate all available information whenever possible. With this in mind, a major impact of computational technologies in the ligand design on GPCRs is expected in the forthcoming years. PMID- 23016843 TI - Desirability-based multi-criteria virtual screening of selective antimicrobial cyclic beta-hairpin cationic peptidomimetics. AB - Today, emerging and increasing resistance to antibiotics has become a threat to public health worldwide. Antimicrobial peptides own unique action mechanisms making peptide antibiotics an attractive therapeutic option against resistant bacteria. However, their high haemolytic activity lacks the selectivity required for a human antibiotic. Therefore, additional efforts are needed to develop new antimicrobial peptides that possess greater selectivity for bacterial cells over erythrocytes. In this article, we introduce a chemoinformatics approach to simultaneously deal with these two conflicting properties consisting on a multi criteria virtual screening strategy based on the use of a desirability-based multi-criteria classifier combined with similarity and chemometrics concepts. Here we propose a new quantitative feature encoding information related to the desirability, the degree of credibility ascribed to this desirability and the similarity of a candidate to a highly desirable query, which can be used as ranking criterion in a virtual screening campaign, the Desirability-Credibility- Similarity (DCS) Score. The enrichment ability of a multi-criteria virtual screening strategy based on the use of the DCS Score it is also assessed and compared to other virtual screening options. The results obtained evidenced that the use of the DCS score seems to be an efficient virtual screening strategy rendering promising overall and initial enrichment performance. Specifically, by using the DCS score it was possible to rank a selective antibacterial peptidomimetic earlier than a biologically inactive or non selective antibacterial peptidomimetic with a probability of ca. 0.9. PMID- 23016844 TI - Molecular modeling and virtual screening of DNA methyltransferase inhibitors. AB - Inhibition of DNA methyltransferases (DNMTs) is a promising approach for the therapeutic treatment of cancer and other diseases. In this work, we review the recent progress on the molecular modeling and virtual screening toward the identification of key structural features associated with the enzyme inhibitory action of active compounds and to identify DNMT inhibitors with novel molecular scaffolds. We discuss the molecular modeling with the co-factor binding site using a recent crystallographic structure of the methyltransferase domain of human DNMT1. We also review the emerging synergy of molecular modeling and chemoinformatic approaches applied to epigenetic therapies targeting DNMTs. PMID- 23016846 TI - Macromolecular structure comparison and docking: an algorithmic review. AB - The comparison of macromolecular structures, in terms of functionalities, is a crucial step when aiming to identify potential docking sites. Drug designers require the identification of such docking sites for the binding of two proteins, in order to form a stable complex. This paper presents a review of current approaches to macromolecular structure comparison and docking, following an algorithmic approach. We describe techniques based on the Bayesian framework, kernel-based methods, projection-based techniques and spectral approaches. We introduce the use of quantum particle swarm optimization, in order to aid us to find the most appropriate docking sites. We discuss the importance of the heat and Schrodinger equations to address the non-rigid nature of proteins and highlight the strengths and limitations of the various methods. PMID- 23016845 TI - Modeling of 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one derivatives by several conformational searching tools and molecular docking. AB - Neutrophil elastase, a serine proteinase from the chymotrypsin family, has been the object of comprehensive experimental and theoretical studies to develop efficient human neutrophil elastase inhibitors. The serine protease has been linked to the pathology of a variety of inflammatory diseases, making it an attractive target for the development of anti-inflammatory compounds. In this work, we have built a common binding model of the 2-pyridin-3-yl benzo[d][1,3]oxazin-4-one derivatives into the human neutrophil elastase binding site. This was accomplished through a comparative conformational analysis (using OMEGA, HYPERCHEM, and MOPAC software) of 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one inhibitors followed by rigid and flexible molecular docking (by the FRED and GLIDE programs) into the target protein. We conclude that OMEGA software generates the most representative conformers to model the protein-ligand interactions. PMID- 23016847 TI - Scoring functions for prediction of protein-ligand interactions. AB - The scoring functions for protein-ligand interactions plays central roles in computational drug design, virtual screening of chemical libraries for new lead identification, and prediction of possible binding targets of small chemical molecules. An ideal scoring function for protein-ligand interactions is expected to be able to recognize the native binding pose of a ligand on the protein surface among decoy poses, and to accurately predict the binding affinity (or binding free energy) so that the active molecules can be discriminated from the non-active ones. Due to the empirical nature of most, if not all, scoring functions for protein-ligand interactions, the general applicability of empirical scoring functions, especially to domains far outside training sets, is a major concern. In this review article, we will explore the foundations of different classes of scoring functions, their possible limitations, and their suitable application domains. We also provide assessments of several scoring functions on weakly-interacting protein-ligand complexes, which will be useful information in computational fragment-based drug design or virtual screening. PMID- 23016848 TI - Impact of periictal interventions on respiratory dysfunction, postictal EEG suppression, and postictal immobility. AB - PURPOSE: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Seizure-related respiratory dysfunction (RD), the duration of postictal generalized electroencephalography (EEG) suppression (PGES), and duration of postictal immobility (PI) may be important in the pathophysiology of SUDEP. Periictal interventions may reduce the risk of SUDEP. METHODS: We assessed the impact of periictal nursing interventions on RD, PGES, and PI duration in patients with localization-related epilepsy and secondarily generalized convulsions (GCs) recorded during video-EEG telemetry in the epilepsy monitoring unit. Video-EEG data were retrospectively reviewed. Interventions including administration of supplemental oxygen, oropharyngeal suction, and patient repositioning were evaluated. Interventions were performed based on nursing clinical judgment at the bedside and were not randomized. The two-sided Wilcoxon rank-sum test was used to compare GCs with and those without intervention. Robust simple linear regression was used to assess the association between timing of intervention and duration of hypoxemia (SaO(2) < 90%), PGES, and PI using data from only the first GC for each patient. KEY FINDINGS: Data from 39 patients with 105 GCs were analyzed. PGES >2 s occurred following 31 GCs in 16 patients. There were 21 GCs with no intervention (NOINT) and 84 GC with interventions (INT). In the INT group, the duration of hypoxemia was shorter (p = 0.0014) when intervention occurred before hypoxemia onset (mean duration 53.1 s) than when intervention was delayed (mean duration 132.42 s). Linear regression indicated that in GCs with nursing interventions, earlier intervention was associated with shorter duration of hypoxemia (p < 0.0001) and shorter duration of PGES (p = 0.0012). Seizure duration (p < 0.0001) and convulsion duration (p = 0.0457) were shorter with earlier intervention. PI duration was longer for GCs with PGES than GCs without PGES (p < 0.0001). The mean delay to first active nonrespiratory movement following GCs with PGES was 251.96 s and for GC without PGES was 66.06 s. The duration of PI was positively associated with lower SaO(2) nadir (p = 0.003) and longer duration of oxygen desaturation (p = 0.0026). There was no association between PI duration and seizure duration (p = 0.773), between PI duration and PGES duration (p = 0.758), or between PI duration and the timing of first intervention relative to seizure onset (p = 0.823). PGES did not occur in the NOINT group. The mean duration of desaturation was longer (110.9 vs. 49.9 s) (p < 0.0001), mean SaO(2) nadir was lower (72.8% vs. 79.7%) (p = 0.0086), and mean end-tidal CO(2) was higher (58.6 vs. 50.3 mmHg) (p = 0.0359) in the INT group compared with the NOINT group. The duration of the seizure or of the convulsive component was not significantly different between the INT and NOINT groups. SIGNIFICANCE: Early periictal nursing intervention was associated with reduced duration of RD and reduced duration of PGES. These findings suggest the possibility that such interventions may be effective in reducing the risk of SUDEP in the outpatient setting. Validation of these preliminary data with a prospective study is needed before definitive conclusions can be reached regarding the efficacy of periictal interventions in reducing the risk of SUDEP. PMID- 23016849 TI - Iraqi primary care system in Kurdistan region: providers' perspectives on problems and opportunities for improvement. AB - BACKGROUND: As part of a comprehensive study on the primary health care system in Iraq, we sought to explore primary care providers' perspectives about the main problems influencing the provision of primary care services and opportunities to improve the system. METHODS: A qualitative study based on four focus groups involving 40 primary care providers from 12 primary health care centres was conducted in Erbil governorate in the Iraqi Kurdistan region between July and October 2010. A topic guide was used to lead discussions and covered questions on positive aspects of and current problems with the primary care system in addition to the priority needs for its improvement. The discussions were fully transcribed and the qualitative data was analyzed by content analysis, followed by a thematic analysis. RESULTS: Problems facing the primary care system included inappropriate health service delivery (irrational use of health services, irrational treatment, poor referral system, poor infrastructure and poor hygiene), health workforce challenges (high number of specialists, uneven distribution of the health workforce, rapid turnover, lack of training and educational opportunities and discrepancies in the salary system), shortage in resources (shortage and low quality of medical supplies and shortage in financing), poor information technology and poor leadership/governance. The greatest emphasis was placed on poor organization of health services delivery, particularly the irrational use of health services and the related overcrowding and overload on primary care providers and health facilities. Suggestions for improving the system included application of a family medicine approach and ensuring effective planning and monitoring. CONCLUSIONS: This study has provided a comprehensive understanding of the factors that negatively affect the primary care system in Iraq's Kurdistan region from the perspective of primary care providers. From their experience, primary care providers have a role in informing the community and policy makers about the main problems affecting this system, though improvements to the health care system must be taken up at the national level and involve other key stakeholders. PMID- 23016850 TI - Columnar processing in primate pFC: evidence for executive control microcircuits. AB - A common denominator for many cognitive disorders of human brain is the disruption of neural activity within pFC, whose structural basis is primarily interlaminar (columnar) microcircuits or "minicolumns." The importance of this brain region for executive decision-making has been well documented; however, because of technological constraints, the minicolumnar basis is not well understood. Here, via implementation of a unique conformal multielectrode recording array, the role of interlaminar pFC minicolumns in the executive control of task-related target selection is demonstrated in nonhuman primates performing a visuomotor DMS task. The results reveal target-specific, interlaminar correlated firing during the decision phase of the trial between multielectrode recording array-isolated minicolumnar pairs of neurons located in parallel in layers 2/3 and layer 5 of pFC. The functional significance of individual pFC minicolumns (separated by 40 MUm) was shown by reduced correlated firing between cell pairs within single minicolumns on error trials with inappropriate target selection. To further demonstrate dependence on performance, a task-disrupting drug (cocaine) was administered in the middle of the session, which also reduced interlaminar firing in minicolumns that fired appropriately in the early (nondrug) portion of the session. The results provide a direct demonstration of task-specific, real-time columnar processing in pFC indicating the role of this type of microcircuit in executive control of decision-making in primate brain. PMID- 23016852 TI - Anti-cancer drug development: computational strategies to identify and target proteins involved in cancer metabolism. AB - Cancer remains a fundamental burden to public health despite substantial efforts aimed at developing effective chemotherapeutics and significant advances in chemotherapeutic regimens. The major challenge in anti-cancer drug design is to selectively target cancer cells with high specificity. Research into treating malignancies by targeting altered metabolism in cancer cells is supported by computational approaches, which can take a leading role in identifying candidate targets for anti-cancer therapy as well as assist in the discovery and optimisation of anti-cancer agents. Natural products appear to have privileged structures for anti-cancer drug development and the bulk of this particularly valuable chemical space still remains to be explored. In this review we aim to provide a comprehensive overview of current strategies for computer-guided anti cancer drug development. We start with a discussion of state-of-the art bioinformatics methods applied to the identification of novel anti-cancer targets, including machine learning techniques, the Connectivity Map and biological network analysis. This is followed by an extensive survey of molecular modelling and cheminformatics techniques employed to develop agents targeting proteins involved in the glycolytic, lipid, NAD+, mitochondrial (TCA cycle), amino acid and nucleic acid metabolism of cancer cells. A dedicated section highlights the most promising strategies to develop anti-cancer therapeutics from natural products and the role of metabolism and some of the many targets which are under investigation are reviewed. Recent success stories are reported for all the areas covered in this review. We conclude with a brief summary of the most interesting strategies identified and with an outlook on future directions in anti-cancer drug development. PMID- 23016854 TI - Regulation and function of DNA and histone methylations. AB - Cell type specification, transcription factor binding site selection and transcriptional regulation are specific processes that require a fine regulation that cannot be simply explained by the mere DNA sequence. Similarly, genome stability, damage response as well as genomic imprints and X-chromosome inactivation are all processes that involve an epigenetic level of regulation. This includes the activity of several enzymes that act in concert to "place" or "remove" specific modifications shaping cells epigenomes with posttranslational modifications of histone proteins and modifications of DNA cytosine residues. In this review, we discuss the role of histone and DNA methylation in regulating different cellular processes with a particular emphasis on transcriptional regulation and on the mechanistic insights behind different enzymatic activities with a perspective towards their implications in human diseases. PMID- 23016855 TI - Exploring patterns of epigenetic information with data mining techniques. AB - Data mining, a part of the Knowledge Discovery in Databases process (KDD), is the process of extracting patterns from large data sets by combining methods from statistics and artificial intelligence with database management. Analyses of epigenetic data have evolved towards genome-wide and high-throughput approaches, thus generating great amounts of data for which data mining is essential. Part of these data may contain patterns of epigenetic information which are mitotically and/or meiotically heritable determining gene expression and cellular differentiation, as well as cellular fate. Epigenetic lesions and genetic mutations are acquired by individuals during their life and accumulate with ageing. Both defects, either together or individually, can result in losing control over cell growth and, thus, causing cancer development. Data mining techniques could be then used to extract the previous patterns. This work reviews some of the most important applications of data mining to epigenetics. PMID- 23016853 TI - New insights into the treatment of multiple myeloma with histone deacetylase inhibitors. AB - Multiple Myeloma (MM) is a common hematologic malignancy of plasma cells representing an excellent model of epigenomics dysregulation in human disease. Importantly, these findings, in addition to providing a better understanding of the underlying molecular changes leading to this malignance, furnish the basis for an innovative therapeutic approach. Histone deacetylase inhibitors (HDACIs), including Vorinostat and Panobinostat, represent a novel class of drugs targeting enzymes involved in epigenetic regulation of gene expression, which have been evaluated also for the treatment of multiple myeloma. Although the clinical role in this setting is evolving and their precise utility remains to be determined, to date that single-agent anti-MM activity is modest. More importantly, HDACIs appear to be synergistic both in vitro and in vivo when combined with other anti MM agents, mainly proteasome inhibitors including bortezomib. The molecular basis underlying this synergism seems to be multifactorial and involves interference with protein degradation as well as the interaction of myeloma cells with microenvironment. Here we review molecular events underling antitumor effects of HDACIs and the most recent results of clinical trials in relapsed and refractory MM. PMID- 23016856 TI - microRNA biogenesis pathway as a therapeutic target for human disease and cancer. AB - The deregulation of microRNAs expression and activity is frequently observed in a wide variety of human pathologies including cancer. Accordingly, growing evidence indicates that the targeting of microRNAs biogenesis and pathways is emerging as a central tool for the development of novel RNA-based drugs and therapies to defeat diseases in humans. In this review we describe the various strategies that can be used to target microRNAs and specific RNA-binding proteins, involved in the regulation of their production, localization, stability and activity, in human cancer and cardiovascular diseases. We also focus on the efforts that are currently made to enhance the potency and stability of these therapeutic agents and their delivery to modulate in vivo microRNAs pathways. Finally, we present structural data on proteins that belong to the microRNA pathway for small molecules-based target therapy design. PMID- 23016858 TI - ADP-ribosylated proteins as old and new drug targets for anticancer therapy: the example of ARF6. AB - Post-translational modifications of cellular proteins by mono- or poly-ADP ribosylation are associated with numerous cellular processes. ADP-ribosylation reactions are important in the nucleus, and in mitochondrial activity, stress response signaling, intracellular trafficking, and cell senescence and apoptosis decisions. These reversible reactions add ADP-ribose to target proteins via specific enzymes to form the ADP-ribosylated protein; the cleaveage of this covalent bond is performed via hydrolases. Deficiencies in these enzymatic activities lead to cell death or tumor formation, thus defining their functional roles and impact on human disease. Unlike mono- ADP-ribosyltransferases, poly-ADP ribose polymerases (PARPs) have been at the frontline of drug discovery since the 1980s. PARP1 is a valuable therapeutic target, with a central role in responses to DNA damage. With mono-ADP-ribosylation now linked to human diseases, such as inflammation, diabetes, neurodegeneration and cancer metastasis, novel and equally important functions of mono-ADPribosylation in cell signaling pathways can now be defined. Recently, we reported mono-ADP-ribosylation of ADP ribosylation factor 6 (ARF6), a small G-protein of the Ras superfamily. In addition to its involvement in actin remodeling, plasma membrane reorganization and vesicular transport, ARF6 contributes to cancer progression through activation of cell motility and invasion. Consequently, targeting this modification will counteract the pro-invasive effects of ARF6, providing innovative anti-tumor therapy. This review summarizes our present knowledge of the enzymes and targets involved in ADP-ribosylation reactions, and describes in silico approaches to visualize their site of interaction and to identify the precise site for ADP-ribosylation. This should ultimately improve pharmacological strategies to enhance both anti-tumor efficacy and treatment of a number of inflammatory and neurodegenerative disorders. PMID- 23016859 TI - Immunoproteasome in cancer and neuropathologies: a new therapeutic target? AB - Immunoproteasome is an emerging biological target that constitutes a key element not only in antigen presentation but also in T cell and cytokine regulation as well as cellular homeostasis. Respect to standard proteasome, the inducible expression and different sensitivity towards activity modulators of immunoproteasome render it a potential therapeutic target for tumours and central nervous system diseases. In this review we report the cutting edge studies for understanding when immunoproteasome expression is induced and how it regulates pivotal pathways involved in tumours and neuropathologies, including apoptosis and inflammation. We emphasize its role as a new pharmacological target by describing the recent medicinal chemistry efforts aimed at design selective small molecule modulators of both standard- and immuno-proteasome forms. Finally, we also present an in silico model of the human immunoproteasome structure by the major molecular differences with the 20S standard proteasome and discuss the perspective for the design of novel specific smallmolecule modulators for the different proteasome isoforms. PMID- 23016857 TI - Rejuvenating sirtuins: the rise of a new family of cancer drug targets. AB - Sirtuins are a family of NAD+-dependent enzymes that was proposed to control organismal life span about a decade ago. While such role of sirtuins is now debated, mounting evidence involves these enzymes in numerous physiological processes and disease conditions, including metabolism, nutritional behavior, circadian rhythm, but also inflammation and cancer. SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7 have all been linked to carcinogenesis either as tumor suppressor or as cancer promoting proteins. Here, we review the biological rationale for the search of sirtuin inhibitors and activators for treating cancer and the experimental approaches to their identification. PMID- 23016860 TI - Genetic and epigenetic regulation of phosphoinositide 3-kinase isoforms. AB - The last quarter of a century has witnessed remarkable progress in the understanding of phosphoinositide 3-kinases (PI3K) signalling and their involvement in different diseases such as cancer, diabetes and inflammation. Nevertheless, many questions remain open and among these the role of genetic and epigenetic regulation of PI3K isoforms is one of the most prominent. Emerging evidence Indicates that levels of isoforms can be modulated upon stimulation or in both physiological and pathological conditions including increased gene copy number and transcription regulation. In addition, an intriguing role for epigenetic regulation of PI3K expression, caused by mechanisms other than changes in the underlying DNA sequence, are starting to get appreciated. In this review, we summarize the genetic and epigenetic regulation of PI3Ks in physiology and the role played by their alterations in different diseases. PMID- 23016851 TI - Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives. AB - Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives. PMID- 23016861 TI - Glycogen synthase kinase 3 as an anticancer drug target: novel experimental findings and trends in the design of inhibitors. AB - Glycogen synthase kinase 3 (GSK-3) is a ubiquitous serine/threonine protein kinase participating in numerous pathways. Very important among them are cancer related pathways, such as Wnt pathway and nuclear factor kappaB pathway. The recent findings concerning possible applicability of GSK-3 inhibitors as anticancer agents are summarized in this review, and controversies in the data are highlighted. The most actual concepts of GSK-3 inhibitor design are also thoroughly discussed. PMID- 23016863 TI - Accessing cancer metabolic pathways by the use of microarray technology. AB - Cancer metabolism is currently re-evaluated by the research community with the aim to investigate possible opportunities for the development of targeted therapies. Firstly discovered by Warburg et al. in the beginning of the last century, it is now a widely accepted hypothesis that cancer cells possess a severely deregulated form of glycolysis also under aerobic conditions. Accompanied by a deregulated glycolysis is an increasing dependence on glucose and glutamine, this characteristic offers a striking opportunity for new kinds of anti-cancer drugs. A feasible approach in this endeavour is the combined use of metabolic and transcriptomic information. Microarrays provide nowadays a reliable way for accessing the transcriptomic layer, even higher layers of biological information are in the scope. In this review we present the possibilities and also the limitations of this technique starting from the early phase of the microarray to the modern concepts of bioinformatics and systems biology. By highlighting also clinicopathological possibilities it is demonstrated that microarray technology is able to integrate various layers of biological information. Case studies incorporating aspects of cancer metabolism into therapy relevant applications and some potential new targets of cancer metabolism for novel cancer therapies are pointed out. These new cancer therapies can lead to the establishment of personalized medicine by use of custom based microarray platforms introducing treatment options in clinical decision making. PMID- 23016864 TI - Fibroblast growth factor receptor inhibitors. AB - Fibroblast growth factor receptors (FGFRs) play an important role in embryonic development, angiogenesis, wound healing, cell proliferation and differentiation. The fibroblast growth factor receptor (FGFR) isoforms have been under intense scrutiny for effective anticancer drug candidates. The fibroblast growth factor (FGF) and its receptor (FGFR) provide another pathway that seems critical to monitoring angiogenesis. Recent findings suggest that FGFR mediates signaling, regulates the PKM2 activity, and plays a crucial role in cancer metabolism. The current review also covers the recent findings on the role of FGFR1 in cancer metabolism. This paper reviews the progress, mechanism, and binding modes of recently known kinase inhibitors such as PD173074, SU series and other inhibitors still under clinical development. Some of the structural classes that will be highlighted in this review include Pyrido[2,3-d]pyrimidines, Indolin- 2-one, Pyrrolo[2,1-f][1,2,4]triazine, Pyrido[2,3-d]pyrimidin-7(8H)-one, and 1,6- Naphthyridin-2(1H)-ones. PMID- 23016865 TI - Colorectal cancer microenvironment: among nutrition, gut microbiota, inflammation and epigenetics. AB - Colorectal cancer (CRC) is a major health problem causing significant morbidity and mortality. During the last decade, results from different studies indicate that the pathogenetic mechanisms of CRC encompass tumour microenvironment, emphasizing a tight correlation with aging, inflammation, nutrition, gut microbiome composition and epigenetic modifications. Aging is one of the most important risk factors for the development of a wide range of neoplasies, including CRC, as it represents the general framework in which the tumor environment evolves. Together, these elements likely contribute to the carcinogenic process with specific effects, impacts and roles in the different stages of the tumor progression. CRCs evolve through loops of deregulated inflammatory stimuli which are sustained by DNA damage signaling pathways, dysbiosis of gut microbiota (GM) and epigenetic re-modelling (DNA methylation). To date no studies address those elements simultaneously. The synergic analysis of such parameters could provide new biological insights and effective biomarkers that could have applications in prevention, molecular diagnosis, prognosis and treatment of CRC. PMID- 23016866 TI - Editorial: cross-talking metabolism and epigenetics in anti-cancer drug design. PMID- 23016867 TI - Metronidazole alone or with amoxicillin as adjuncts to non-surgical treatment of chronic periodontitis: a 1-year double-blinded, placebo-controlled, randomized clinical trial. AB - AIM: To evaluate the effects of the adjunctive use of metronidazole (MTZ) or MTZ + amoxicillin (AMX) in the treatment of generalized chronic periodontitis (ChP). A secondary aim was to examine a possible added effect of chlorhexidine to these therapies. METHODS: One hundred and eighteen subjects received scaling and root planing (SRP) only or with MTZ [400 mg/thrice a day (TID)] or MTZ+AMX (500 mg/TID) for 14 days. Half of the subjects in each group rinsed with 0.12% chlorhexidine twice a day (BID) for 2 months. Subjects were clinically monitored at baseline, 3, 6 and 12-months post-therapy. RESULTS: The two antibiotic groups showed lower mean number of sites with probing depth (PD) >=5 mm and fewer subjects exhibiting >=9 of these sites at 1-year post-treatment. Logistic regression analysis showed that antibiotics were the only significant predictors of subjects presenting <=4 sites with PD >=5 mm at 1 year (MTZ+AMX: OR, 13.33; 95%CI, 3.75-47.39/p = 0.0000; MTZ: OR, 7.26; 95%CI, 2.26-23.30/p = 0.0004). The frequency of adverse events did not differ between the two antibiotic treatments (p > 0.05). The chlorhexidine subgroups showed a trend (p > 0.05) to present fewer residual sites >=5 mm compared with the placebo subgroups at 1 year. CONCLUSION: Treatment of generalized ChP is significantly improved by the adjunctive use of MTZ+AMX and MTZ. PMID- 23016868 TI - Microbial cell budgets of an Arctic glacier surface quantified using flow cytometry. AB - Uncertainty surrounds estimates of microbial cell and organic detritus fluxes from glacier surfaces. Here, we present the first enumeration of biological particles draining from a supraglacial catchment, on Midtre Lovenbreen (Svalbard) over 36 days. A stream cell flux of 1.08 * 10(7) cells m(-2) h(-1) was found, with strong inverse, non-linear associations between water discharge and biological particle concentrations. Over the study period, a significant decrease in cell-like particles exhibiting 530 nm autofluorescence was noted. The observed total fluvial export of ~7.5 * 10(14) cells equates to 15.1-72.7 g C, and a large proportion of these cells were small (< 0.5 MUm in diameter). Differences between the observed fluvial export and inputs from ice-melt and aeolian deposition were marked: results indicate an apparent storage rate of 8.83 * 10(7) cells m(-2) h(-1). Analysis of surface ice cores revealed cell concentrations comparable to previous studies (6 * 10(4) cells ml(-1)) but, critically, showed no variation with depth in the uppermost 1 m. The physical retention and growth of particulates at glacier surfaces has two implications: to contribute to ice mass thinning through feedbacks altering surface albedo, and to potentially seed recently deglaciated terrain with cells, genes and labile organic matter. This highlights the merit of further study into glacier surface hydraulics and biological processes. PMID- 23016870 TI - Episodic memory impairment in frontotemporal dementia; a 99mTc- HMPAO SPECT study. AB - Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most common types of dementia in the presenile population. Episodic memory impairment, the clinical hallmark of AD, can also be encountered in patients with FTD, complicating accurate diagnosis. Several studies in FTD have correlated memory deficits with neuroimaging findings, but lacked to compare neuroimaging results in FTD patients with and without memory impairment, while this latter analysis may give us insight into the underlying mechanisms of memory impairment in FTD. The aim of the present study was to compare (99m)Tc-HMPAO SPECT hypoperfusion patterns between FTD with episodic memory impairment (n = 13), FTD patients without episodic memory impairment (n = 10) as well as early onset (< 70 yrs) AD patients (n = 13), and controls (n = 15). We performed our analyses by means of Statistical Parametric Mapping software (SPM5), and showed that FTD patients with episodic memory impairment had lower perfusion in the right temporal lobe compared with FTD patients without memory impairment. Lower perfusion in this region correlated with worse memory performance on the Clinical Dementia Rating scale in FTD patients. With equal performances on memory tests, patients with early onset AD showed posterior temporal and parietal lobe hypoperfusion in comparison with patients with FTD and memory impairment, while vice versa hypoperfusion in the anterior frontotemporal regions was found in FTD patients with memory impairment in comparison with AD. PMID- 23016869 TI - Erythropoietin in the critically ill: do we ask the right questions? AB - There is a plethora of experimental data on the potential therapeutic benefits of recombinant human erythropoietin (rhEPO) and its synthetic derivatives in critical care medicine, in particular in ischemia/reperfusion injury. Most of the recent clinical trials have not shown clear benefits, and, in some patients, EPO aggravated morbidity and mortality was even reported. Treatment with rhEPO has been successfully used in patients with anemia resulting from chronic kidney disease, but even a subset of this patient population does not adequately respond to rhEPO therapy. The following viewpoint uses rhEPO as an example to highlight the possible pitfalls in current practice using young healthy animals for the evaluation of therapies to treat patients of variable age and underlying chronic co-morbidity. PMID- 23016871 TI - Endoparasites of the Eurasian lynx (Lynx lynx) in Finland. AB - We sampled 339 fecal samples, 296 intestines, and 82 lungs from 371 lynx hunted during the 2010-2011 season in Finland. The fecal samples were analyzed for endoparasites by a quantitative flotation method, and helminths from intestines were studied morphologically, while lungs were investigated for pulmonary parasites. From fecal samples, eggs and oocysts of at least 6 different endoparasite species were identified, with a mean of 1.5 (range 0-4) parasite species per host. In the intestines, at least 4 different helminth species were found, with the mean of 2.0 (range 1-4) species per infected host. The prevalence of eggs in feces and the prevalence of worms in intestines were 71% and 93% for Toxocara cati , 29% and 68% for Taenia spp., and 5% and 2% for Diphyllobothrium sp., respectively. Only eggs were detected for Capillaria sp. (46%) and Uncinaria sp. (0.6%) nematodes, and only adults were detected for Mesocestoides sp. cestodes (0.3%). Significant positive correlations were evident between the number of T. cati (r = 0.664; P = 0.01) and Diphyllobothrium sp. (r = 0.645; P = 0.01) eggs per gram of feces and adult worms detected in intestine. In addition to the metazoan parasites, protozoan Isospora sp. oocysts were also found (0.6%). Pulmonary samples were all negative for parasites. These data demonstrate that lynx commonly harbor various endoparasites, some of which are zoonotic. PMID- 23016862 TI - Wnt/beta-catenin signaling and small molecule inhibitors. AB - Wnt/beta-catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/beta-catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, beta-catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where beta-catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where beta-catenin levels are regulated and the nucleus where beta-catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of beta-catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellular beta- catenin levels. However, beta-catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/beta-catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of beta catenin at its various locations provides alternative points for therapeutic interventions. PMID- 23016872 TI - Ionic strength effects on amyloid formation by amylin are a complicated interplay among Debye screening, ion selectivity, and Hofmeister effects. AB - Amyloid formation plays a role in a wide range of human diseases. The rate and extent of amyloid formation depend on solution conditions, including pH and ionic strength. Amyloid fibrils often adopt structures with parallel, in-register beta sheets, which generate quasi-infinite arrays of aligned side chains. These arrangements can lead to significant electrostatic interactions between adjacent polypeptide chains. The effect of ionic strength and ion composition on the kinetics of amyloid formation by islet amyloid polypeptide (IAPP) is examined. IAPP is a basic 37-residue polypeptide responsible for islet amyloid formation in type 2 diabetes. Poisson-Boltzmann calculations revealed significant electrostatic repulsion in a model of the IAPP fibrillar state. The kinetics of IAPP amyloid formation are strongly dependent on ionic strength, varying by a factor of >10 over the range of 20-600 mM NaCl at pH 8.0, but the effect is not entirely due to Debye screening. At low ionic strengths, the rate depends strongly on the identity of the anion, varying by a factor of nearly 4, and scales with the electroselectivity series, implicating anion binding. At high ionic strengths, the rate varies by only 8% and scales with the Hofmeister series. At intermediate ionic strengths, no clear trend is detected, likely because of the convolution of different effects. The effects of salts on the growth phase and lag phase of IAPP amyloid formation are strongly correlated. At pH 5.5, where the net charge on IAPP is higher, the effect of different anions scales with the electroselectivity series at all salt concentrations. PMID- 23016873 TI - PDZ domains of RseP are not essential for sequential cleavage of RseA or stress induced sigma(E) activation in vivo. AB - The Escherichia coli sigma(E) extracytoplasmic stress response monitors and responds to folding stress in the cell envelope. A protease cascade directed at RseA, a membrane-spanning anti-sigma that inhibits sigma(E) activity, controls this critical signal-transduction system. Stress cues activate DegS to cleave RseA; a second cleavage by RseP releases RseA from the membrane, enabling its rapid degradation. Stress control of proteolysis requires that RseP cleavage is dependent on DegS cleavage. Recent in vitro and structural studies found that RseP cleavage requires binding of RseP PDZ-C to the newly exposed C-terminal residue (Val148) of RseA, generated by DegS cleavage, explaining dependence. We tested this mechanism in vivo. Neither mutation in the putative PDZ ligand binding regions nor even deletion of entire RseP PDZ domains had significant effects on RseA cleavage in vivo, and the C-terminal residue of DegS-processed RseA also little affected RseA cleavage. Indeed, strains with a chromosomal rseP gene deleted for either PDZ domain and strains with a chromosomal rseA V148 mutation grew normally and exhibited almost normal sigma(E) activation in response to stress signals. We conclude that recognition of the cleaved amino acid by the RseP PDZ domain is not essential for sequential cleavage of RseA and sigma(E) stress response in vivo. PMID- 23016874 TI - Phosphonium-functionalized polyethylene: a new class of base-stable alkaline anion exchange membranes. AB - A tetrakis(dialkylamino)phosphonium cation was evaluated as a functional group for alkaline anion exchange membranes (AAEMs). The base stability of [P(N(Me)Cy)(4)](+) was directly compared to that of [BnNMe(3)](+) in 1 M NaOD/CD(3)OD. The high base stability of [P(N(Me)Cy)(4)](+) relative to [BnNMe(3)](+) inspired the preparation of AAEM materials composed of phosphonium units attached to polyethylene. The AAEMs (hydroxide conductivity of 22 +/- 1 mS cm(-1) at 22 degrees C) were prepared using ring-opening metathesis polymerization, and their stabilities were evaluated in 15 M KOH at 22 degrees C and in 1 M KOH at 80 degrees C. PMID- 23016875 TI - Association of overtime urine volume and ultrafiltration changes with patient survival in continuous ambulatory peritoneal dialysis patients. AB - BACKGROUND: Associations between patient survival and baseline urine volume (UV), ultrafiltration (UF) volume, and combined UV and UF were evaluated in Iranian continuous ambulatory peritoneal dialysis (CAPD) patients. METHODS: From 1995 to 2006, data on 1472 CAPD patients from 26 centers were collected. Demographic, clinical, and laboratory characteristics were analyzed using STATA software. Baseline UV was considered as an indicator of residual renal function and patients with an annual decrease of more than 250 cc/day were placed in decreasing UV group. The role of a new variable, net positive fluid removal, which defines as the combination of baseline UV and UF, was also evaluated. RESULTS: Patients with higher baseline UV were significantly more married and educated and candidate for CAPD based on positive selection criteria. In dichotomous categorization, mean of serum creatinine was lower and albumin was higher in patients with UV >= 1000 cc/day compared with UV < 250 cc/day. A significant correlation was found between baseline UV <250 cc/day and >=1000 cc/day and patient survival. Patients with stable UV had better survival compared with patients with decreasing UV (p = 0.04). There was no correlation between UF and patient survival. Remarkable association with patient and technique survival and net positive fluid removal >=2000 cc/day and <500 cc/day was observed. Multiple Cox regression analysis revealed significant correlation between net positive fluid removal >=2000 cc/day and higher patient survival [p = 0.01, hazard ratio (HR) = 13.2], higher first albumin (albumin >= 3.5 mg/dL, p = 0.01, HR = 0.02), and lower negative selection (p = 0.0001, HR = 11.8). CONCLUSION: Loss of UV over time and lower net positive fluid removal increase mortality of PD patients. PMID- 23016876 TI - Long-term effects of daily hemodialysis on vascular access outcomes: a prospective controlled study. AB - Daily hemodialysis has been associated with surrogate markers of improved survival among hemodialysis patients. A potential disadvantage of daily hemodialysis is that frequent vascular access cannulations may affect long-term vascular access patency. The study design was a 4-year, nonrandomized, contemporary control, prospective study of 77 subjects in either 3-h daily hemodialysis (six 3-h dialysis treatments weekly; n = 26) or conventional dialysis (three 4-h dialysis treatments weekly; n = 51). Outcomes of interest were vascular access procedures (fistulagram, thrombectomy and access revision). Total access procedures (fistulagram, thrombectomy and access revision) were 543.2 (95% confidence interval [CI]: 432.9, 673.0) per 1000 person-years in the conventional dialysis group vs. 400.8 (95% CI: 270.2, 572.4) per 1000 person years in the daily hemodialysis dialysis group (incidence rate ratio = 0.74 with 95% CI: from 0.40 to 1.36, P = 0.33), after adjusting for age, gender, diabetes status, serum phosphorus, hemoglobin level and erythropoietin dose, there was no significant differences in incidence rate of total access procedures (P-value > 0.05). There was no difference in time to first access revision between the daily dialysis and the conventional dialysis groups after adjustment for covariates (hazard ratio = 0.99 95% CI: 0.42, 2.36, P = 0.96). Daily hemodialysis is not associated with increased vascular access complications, or increased vascular access failure rates. PMID- 23016877 TI - TfR1 interacts with the IKK complex and is involved in IKK-NF-kappaB signalling. AB - The IKK [inhibitor of NF-kappaB (nuclear factor kappaB) kinase] complex has an essential role in the activation of the family of NF-kappaB transcription factors in response to a variety of stimuli. To identify novel IKK-interacting proteins, we performed an unbiased proteomics screen where we identified TfR1 (transferrin receptor 1). TfR1 is required for transferrin binding and internalization and ultimately for iron homoeostasis. TfR1 depletion does not lead to changes in IKK subunit protein levels; however, it does reduce the formation of the IKK complex, and inhibits TNFalpha (tumour necrosis factor alpha)-induced NF-kappaB-dependent transcription. We find that, in the absence of TfR1, NF-kappaB does not translocate to the nucleus efficiently, and there is a reduction in the binding to target gene promoters and consequentially less target gene activation. Significantly, depletion of TfR1 results in an increase in apoptosis in response to TNFalpha treatment, which is rescued by elevating the levels of RelA/NF kappaB. Taken together, these results indicate a new function for TfR1 in the control of IKK and NF-kappaB. Our data indicate that IKK-NF-kappaB responds to changes in iron within the cell. PMID- 23016878 TI - Rituximab, used alone or in combination, is superior to other treatment modalities in splenic marginal zone lymphoma. AB - Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy, with no standard treatment other than splenectomy. Rituximab has shown encouraging results. We therefore retrospectively assessed 43 patients from two centres, who received rituximab, either alone or with chemotherapy. All patients responded, 34/43 (79%) achieving a complete response (CR), compared with 3/10 (30%) after chemotherapy without rituximab (P = 0.005). Of these 10 patients, 9 (90%) subsequently achieved a CR after rituximab (P = 0.02). Rituximab monotherapy appeared equally as effective as rituximab combination therapy (90% vs. 79% CR, P = 0.7) with significantly less toxicity (12.5% vs. 83%, P = 0.002). Splenectomized patients were more likely to obtain a CR with rituximab (16/16, 100%) than unsplenectomized patients (18/27, 67%, P = 0.008). Disease-free survival (DFS) at 3 years was better after rituximab than after splenectomy alone [79% (95% confidence interval 60-89) vs. 29% (8-54), Hazard ratio (HR) 0.28 (0.12 0.68), P = 0.003] and better than after chemotherapy without rituximab [25% (4 55), HR 0.21 (0.08-0.51), P = 0.0004]. Survival at 3 years after rituximab was 98%. In summary, the CR and DFS rates after rituximab, given alone or with chemotherapy, were significantly better than after chemotherapy without rituximab in the same patients, with manageable toxicity. Rituximab, with or without splenectomy, should be considered for the treatment of SMZL. PMID- 23016879 TI - Cord blood T cells retain early differentiation phenotype suitable for immunotherapy after TCR gene transfer to confer EBV specificity. AB - Adoptive T cell therapy can be effective for Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease and melanoma. Transducing high affinity TCR genes into T lymphocytes is an emerging method to improve potency and specificity of tumor-specific T cells. However, both methods necessitate in vitro lymphocyte proliferation, generating highly differentiated effector cells that display reduced survival and antitumor efficacy postinfusion. TCR transduction of naive lymphocytes isolated from peripheral blood is reported to provide superior in vivo survival and function. We utilized cord blood (CB) lymphocytes, which comprise mainly naive cells, for transducing EBV-specific TCR. Comparable TCR expression was achieved in adult and CB cells, but the latter expressed an earlier differentiation profile. Further antigen-driven stimulation skewed adult lymphocytes to a late differentiation phenotype associated with immune exhaustion. In contrast, CB T cells retained a less differentiated phenotype after antigen stimulation, remaining CD57-negative but were still capable of antigen-specific polyfunctional cytokine expression and cytotoxicity in response to EBV antigen. CB T cells also retained longer telomeres and in general possessed higher telomerase activity indicative of greater proliferative potential. CB lymphocytes therefore have qualities indicating prolonged survival and effector function favorable to immunotherapy, especially in settings where donor lymphocytes are unavailable such as in solid organ and CB transplantation. PMID- 23016880 TI - Prognostic significance of fibroblastic foci in usual interstitial pneumonia and non-specific interstitial pneumonia. AB - BACKGROUND AND OBJECTIVE: Fibroblastic foci (FF) composed of an accumulation of fibroblasts or myofibroblasts may be related to the progression of pulmonary fibrosis leading to respiratory insufficiency. Several studies have shown that the number of FF is a significant prognostic factor in usual interstitial pneumonia (UIP). The purpose of the present study was to examine whether the extent of FF is related to impairment of respiratory function and prognosis in patients with biopsy-proven fibrosing interstitial pneumonia, including UIP and fibrotic non-specific interstitial pneumonia (fNSIP). METHODS: Fifty patients with histologically confirmed interstitial pneumonia including UIP or fNSIP were investigated, and correlations between FF and pulmonary function were evaluated. FF area was calculated as the proportion of total area (%FF) and the number of FF (FF/cm(2)) in the whole histological specimen from each patient. RESULTS: The UIP group showed significantly higher %FF and FF/cm(2) than the fNSIP group. When UIP and fNSIP patients were analysed together, the group of patients who had died (death group) revealed significantly higher %FF and FF/cm(2) compared with the group of survivors, and the impairment of vital capacity and diffusing capacity of carbon monoxide was correlated with %FF and FF/cm(2). CONCLUSIONS: FF correlated with impaired pulmonary function and may be a useful parameter to predict prognosis in patients with UIP and fNSIP. PMID- 23016881 TI - Ecosystem effects of a tropical cyclone on a network of lakes in northeastern North America. AB - Here we document the regional effects of Tropical Cyclone Irene on thermal structure and ecosystem metabolism in nine lakes and reservoirs in northeastern North America using a network of high-frequency, in situ, automated sensors. Thermal stability declined within hours in all systems following passage of Irene, and the magnitude of change was related to the volume of water falling on the lake and catchment relative to lake volume. Across systems, temperature change predicted the change in primary production, but changes in mixed-layer thickness did not affect metabolism. Instead, respiration became a driver of ecosystem metabolism that was decoupled from in-lake primary production, likely due to addition of terrestrially derived carbon. Regionally, energetic disturbance of thermal structure was shorter-lived than disturbance from inflows of terrestrial materials. Given predicted regional increases in intense rain events with climate change, the magnitude and longevity of ecological impacts of these storms will be greater in systems with large catchments relative to lake volume, particularly when significant material is available for transport from the catchment. This case illustrates the power of automated sensor networks and associated human networks in assessing both system response and the characteristics that mediate physical and ecological responses to extreme events. PMID- 23016883 TI - Dynamic microwave-assisted extraction coupled with salting-out liquid-liquid extraction for determination of steroid hormones in fish tissues. AB - In this work, a simple and fast sample pretreatment method was proposed for determination of steroid hormones in fish tissues by coupling dynamic microwave assisted extraction with salting-out liquid-liquid extraction. The steroid hormones were successively extracted with acetonitrile and water under the action of microwave energy. Subsequently, the extract was separated into an acetonitrile phase and an aqueous phase with ammonium acetate. The acetonitrile phase containing the target analytes was concentrated and determined by LC-MS/MS. The limits of detection for the steroid hormones were in the range of 0.03-0.15 ng g( 1). This method was successfully applied to analyze seven kinds of fish tissues, and the recoveries of the steroid hormones for the spiked samples were in the range of 75.3 +/- 4.9% to 95.4 +/- 6.2%. Compared with the traditional method, the proposed method could reduce the consumption of the organic solvent, shorten the sample preparation time, and increase the sample throughput. PMID- 23016882 TI - The Hip Fracture Surgery in Elderly Patients (HIPELD) study: protocol for a randomized, multicenter controlled trial evaluating the effect of xenon on postoperative delirium in older patients undergoing hip fracture surgery. AB - BACKGROUND: Strategies to protect the brain from postoperative delirium (POD) after hip fracture are urgently needed. The development of delirium often is associated with the loss of independence, poor functional recovery, and increased morbidity, as well as increases in length of hospital stay, discharges to nursing facilities, and healthcare costs. We hypothesize that xenon may reduce the burden of POD, (i) by avoiding the need to provide anesthesia with a drug that targets the gamma-amino-butyric acid (GABA)A receptor and (ii) through beneficial anesthetic and organ-protective effects. METHODS AND DESIGN: An international, multicenter, phase 2, prospective, randomized, blinded, parallel group and controlled trial to evaluate the incidence of POD, diagnosed with the Confusion Assessment Method (CAM), in older patients undergoing hip fracture surgery under general anesthesia with xenon or sevoflurane, for a period of 4 days post surgery (primary outcome) is planned. Secondary objectives are to compare the incidence of POD between xenon and sevoflurane, to evaluate the incidence of POD from day 5 post surgery until discharge from hospital, to determine the time to first POD diagnosis, to evaluate the duration of POD, to evaluate the evolution of the physiological status of the patients in the postoperative period, to evaluate the recovery parameters, to collect preliminary data to evaluate the economical impact of POD in the postoperative period and to collect safety data. Patients are eligible if they are older aged (>= 75 years) and assigned to a planned hip fracture surgery within 48 h after the hip fracture. Furthermore, patients need to be willing and able to complete the requirements of this study including the signature of the written informed consent. A total of 256 randomized patients in the 10 participating centers will be recruited, that is, 128 randomized patients in each of the 2 study groups (receiving either xenon or sevoflurane). TRIAL REGISTRATION: EudraCT Identifier: 2009-017153-35; ClinicalTrials.gov Identifier: NCT01199276. PMID- 23016884 TI - Acute and recurrent pancreatitis in children: exploring etiological factors. AB - OBJECTIVE: Etiologies of acute pancreatitis (AP) in children are more variable than in adults, including drugs, traumas, infections and multisystem disorders as well as biliary anomalies. While causes of pancreatitis have been extensively analyzed, different series reported different causes. The aims of this study were: 1) to assess the etiological factors of acute and recurrent pancreatitis in a pediatric population from a tertiary care hospital; 2) to assess the usefulness of imaging studies in diagnosing etiologies of pancreatitis. MATERIAL AND METHODS: Thirty-four children (median age 11 years, 23 males) with AP and 11 with recurrent pancreatitis were retrospectively studied to assess etiology of pancreatitis in children. RESULTS: The most common etiologies of AP were medications (11/34) and biliary tract diseases (9/34), whereas systemic diseases accounted for a small percentage of case. Among patients with recurrent episodes, biliary anomalies were the most common cause (6/11), whereas only 2 out of 11 patients with recurrent pancreatitis presented a hereditary cause. CONCLUSIONS: This study highlights that etiologies of AP in children are variable. Epidemiology of AP could be influenced by single center's characteristics. Anatomic anomalies should be ruled out and genetic causes should be considered in recurrent cases. PMID- 23016885 TI - Does the neurobiology of migraine make migraine patients "difficult"? PMID- 23016886 TI - Surgical management of supravalvar aortic stenosis with coronary artery involvement. AB - Supravalvar aortic stenosis is characterized by an obstruction of the left ventricular outflow tract distal to the aortic valve. Its association with left main coronary artery stenosis is well known but right coronary artery involvement has not been reported. We describe two cases of supravalvar aortic stenosis with coronary artery stenosis and its surgical management. PMID- 23016887 TI - Erythropoietin, ferritin, haptoglobin, hemoglobin and transferrin receptor in metabolic syndrome: a case control study. AB - BACKGROUND: Increased ferritin concentrations are associated with metabolic syndrome (MetS). The association between ferritin as well as hemoglobin level and individual MetS components is unclear. Erythropoietin levels in subjects with MetS have not been determined previously. The aim of this study was to compare serum erythropoietin, ferritin, haptoglobin, hemoglobin, and transferrin receptor (sTFR) levels between subjects with and without MetS and subjects with individual MetS components. METHODS: A population based cross-sectional study of 766 Caucasian, middle-aged subjects (341 men and 425 women) from five age groups born in Pieksamaki, Finland who were invited to a health check-up in 2004 with no exclusion criteria. Laboratory analyzes of blood samples collected in 2004 were done during year 2010. MetS was defined by National Cholesterol Education Program criteria. RESULTS: 159 (53%) men and 170 (40%) women of study population met MetS criteria. Hemoglobin and ferritin levels as well as erythropoietin and haptoglobin levels were higher in subjects with MetS (p < 0.001, p = 0.018). sTFR level did not differ significantly between subjects with or without MetS. Hemoglobin level was significantly higher in subjects with any of the MetS components (p < 0.001, p = 0.002). Ferritin level was significantly higher in subjects with abdominal obesity or high TG or elevated glucose or low high density cholesterol component (p < 0.001, p = 0.002, p = 0.02). Erythropoietin level was significantly higher in subjects with abdominal obesity component (p = 0.015) but did not differ significantly between subjects with or without other MetS components. Haptoglobin level was significantly higher in subjects with blood pressure or elevated glucose component o MetS (p = 0.028, p = 0.025). CONCLUSION: Subjects with MetS have elevated hemoglobin, ferritin, erythropoietin and haptoglobin concentrations. Higher hemoglobin levels are related to all components of MetS. Higher ferritin levels associate with TG, abdominal obesity, elevated glucose or low high density cholesterol. Haptoglobin levels associate with blood pressure or elevated glucose. However, erythropoietin levels are related only with abdominal obesity. Higher serum erythropoietin concentrations may suggest underlying adipose tissue hypoxemia in MetS. PMID- 23016888 TI - A randomised titrated crossover study comparing two oral appliances in the treatment for mild to moderate obstructive sleep apnoea/hypopnoea syndrome. AB - The objective of this study was to compare the efficiency of two oral appliances in patients with mild to moderate obstructive sleep apnoea/hypopnoea syndrome (OSAHS) by the analysis of objective and subjective evaluations and measurement of upper airway parameter. A randomised crossover design trial was carried out on 16 patients with OSAHS. Two different types of oral appliances were tested in each patient, a one-piece monoblock and the SILENT NITE((r)) (GlideWell Laboratories, Newport Beach, CA, USA), a two-piece appliance. Each oral appliance needed to be worn for two 3-month periods separated by a 2-week wash-out period in between. The objective and subjective efficiency and upper airway parameters associated with the oral appliances were assessed. One-way analysis of variance (anova) test was performed to compare the changes in upper airway morphology and the treatment efficiency between the appliances. The monoblock and SILENT NITE((r)) (GlideWell Laboratories) appliances reduced Apnoea Hypopnoea Index (AHI) from 26.38 +/- 4.13 to 7.58 +/- 2.28 (P < 0.001) and 8.87 +/- 2.88 (P < 0.001), respectively. The monoblock appliance was statistically more efficient in reducing AHI and Apnoea Index (AI) than the SILENT NITE((r)) (GlideWell Laboratories) (P < 0.05). The scores on Epworth's Sleepiness Scale (ESS) and Snoring Scale (SS) were improved significantly by both appliances. The upper airway spaces showed considerable enlargement by both mandibular advancement appliances (MAAs) (P < 0.05), while no significant differences were found between the two appliances (P > 0.05). Both MAAs showed good efficacy in the treatment for mild to moderate OSAHS. Use of the monoblock appliance should be considered when patients with OSAHS choose MAA treatment, as it was more efficient in reducing the AHI and AI compared to the two-piece appliance and was preferred by most patients. Long-term efficiency should be evaluated in future prospective studies. PMID- 23016890 TI - Understanding the electrolyte background for biochemical sensing with ion sensitive field-effect transistors. AB - Silicon nanowire field-effect transistors have attracted substantial interest for various biochemical sensing applications, yet there remains uncertainty concerning their response to changes in the supporting electrolyte concentration. In this study, we use silicon nanowires coated with highly pH-sensitive hafnium oxide (HfO(2)) and aluminum oxide (Al(2)O(3)) to determine their response to variations in KCl concentration at several constant pH values. We observe a nonlinear sensor response as a function of ionic strength, which is independent of the pH value. Our results suggest that the signal is caused by the adsorption of anions (Cl(-)) rather than cations (K(+)) on both oxide surfaces. By comparing the data to three well-established models, we have found that none of those can explain the present data set. Finally, we propose a new model which gives excellent quantitative agreement with the data. PMID- 23016889 TI - Use of health care services and pharmaceutical agents in coeliac disease: a prospective nationwide study. AB - BACKGROUND: Approximately 1% of the population suffer from coeliac disease. However, the disease is heavily underdiagnosed. Unexplained symptoms may lead to incremented medical consultations and productivity losses. The aim here was to estimate the possible concealed burden of untreated coeliac disease and the effects of a gluten-free diet. METHODS: A nationwide cohort of 700 newly detected adult coeliac patients were prospectively evaluated. Health care service use and sickness absence from work during the year before diagnosis were compared with those in the general population; the data obtained from an earlier study. Additionally, the effect of one year on dietary treatment on the aforementioned parameters and on consumption of pharmaceutical agents was assessed. RESULTS: Untreated coeliac patients used primary health care services more frequently than the general population. On a gluten-free diet, visits to primary care decreased significantly from a mean 3.6 to 2.3. The consumption of medicines for dyspepsia (from 3.7 to 2.4 pills/month) and painkillers (6.8-5.5 pills/month) and the number of antibiotic courses (0.6-0.5 prescriptions/year) was reduced. There were no changes in hospitalizations, outpatient visits to secondary and tertiary care, use of other medical services, or sickness absence, but the consumption of nutritional supplements increased on treatment. CONCLUSIONS: Coeliac disease was associated with excessive health care service use and consumption of drugs before diagnosis. Dietary treatment resulted in a diminished burden to the health care system and lower use of on-demand medicines and antibiotic treatment. The results support an augmented diagnostic approach to reduce underdiagnosis of coeliac disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01145287. PMID- 23016891 TI - Estimating prevalence: a confidence game. AB - Prevalence is one of the few estimates that rarely are reported with an appropriate measure of error in the parasitological literature. A minimum sample size recommendation of 15 samples, based on the relationship between sample size and standard error, likely has led to a false degree of confidence because of the nonlinear relationship between standard error and "true" 95% confidence intervals (as determined by Monte Carlo simulation or integration of the Bayesian posterior). Given that 95% confidence intervals for proportions are influenced by both sample size and the actual estimate of the proportion, there is no "gold standard" sample size beyond which estimates of binomial proportions can be considered "reliable." This necessitates the reporting of confidence interval estimates that have been shown to be conservative, such as the Clopper-Pearson estimate, or robust, such as the Wilson score approximation, or the computationally intensive integration of the Bayesian posterior. PMID- 23016892 TI - Validating scores: a good business for a trauma register. AB - Acute hemorrhage after life-threatening injury is still one of the main killers after trauma. The article by Brockamp and colleagues presents a good overview of recent scores for estimation of blood loss and transfusion requirement. PMID- 23016893 TI - Angular trapping of anisometric nano-objects in a fluid. AB - We demonstrate the ability to trap, levitate, and orient single anisometric nanoscale objects with high angular precision in a fluid. An electrostatic fluidic trap confines a spherical object at a spatial location defined by the minimum of the electrostatic system free energy. For an anisometric object and a potential well lacking angular symmetry, the system free energy can further strongly depend on the object's orientation in the trap. Engineering the morphology of the trap thus enables precise spatial and angular confinement of a single levitating nano-object, and the process can be massively parallelized. Since the physics of the trap depends strongly on the surface charge of the object, the method is insensitive to the object's dielectric function. Furthermore, levitation of the assembled objects renders them amenable to individual manipulation using externally applied optical, electrical, or hydrodynamic fields, raising prospects for reconfigurable chip-based nano-object assemblies. PMID- 23016894 TI - Competitive binding of cations to duplex DNA revealed through molecular dynamics simulations. AB - The concept of "ion atmosphere" is prevalent in both theoretical and experimental studies of nucleic acid systems, yet the spatial arrangement and the composition of ions in the ion atmosphere remain elusive, in particular when several ionic species (e.g., Na(+), K(+), and Mg(2+)) compete to neutralize the charge of a nucleic acid polyanion. Complementing the experimental study of Bai and co workers (J. Am. Chem. Soc.2007, 129, 14981), here we characterize ion atmosphere around double-stranded DNA through all-atom molecular dynamics simulations. We demonstrate that our improved parametrization of the all-atom model can quantitatively reproduce the experimental ion-count data. Our simulations determine the size of the ion atmosphere, the concentration profiles of ionic species competing to neutralize the DNA charge, and the sites of the cations' preferential binding at the surface of double-stranded DNA. We find that the effective size of the ion atmosphere depends on both the bulk concentration and valence of ions: increasing either reduces the size of the atmosphere. Near DNA, the concentration of Mg(2+) is strongly enhanced compared to monovalent cations. Within the DNA grooves, the relative concentrations of cations depend on their bulk values. Nevertheless, the total charge of competing cations buried in the DNA grooves is constant and compensates for about ~30% of the total DNA charge. PMID- 23016895 TI - Natural competence in Vibrio cholerae is controlled by a nucleoside scavenging response that requires CytR-dependent anti-activation. AB - Competence for genetic transformation in Vibrio cholerae is triggered by chitin induced transcription factor TfoX and quorum sensing (QS) regulator HapR. Transformation requires expression of ComEA, described as a DNA receptor in other competent bacteria. A screen for mutants that poorly expressed a comEA-luciferase fusion identified cytR, encoding the nucleoside scavenging cytidine repressor, previously shown in V. cholerae to be a biofilm repressor and positively regulated by TfoX, but not linked to transformation. A DeltacytR mutant was non transformable and defective in expression of comEA and additional TfoX-induced genes, including pilA (transformation pseudopilus) and chiA-1 (chitinase). In Escherichia coli, 'anti-activation' of nucleoside metabolism genes, via protein protein interactions between critical residues in CytR and CRP (cAMP receptor protein), is disrupted by exogenous cytidine. Amino acid substitutions of the corresponding V. cholerae CytR residues impaired expression of comEA, pilA and chiA-1, and halted DNA uptake; while exogenous cytidine hampered comEA expression levels and prevented transformation. Our results support a speculative model that when V. cholerae reaches high density on chitin, CytR-CRP interactions 'anti activate' multiple genes, including a possible factor that negatively controls DNA uptake. Thus, a nucleoside scavenging mechanism couples nutrient stress and cell-cell signalling to natural transformation in V. cholerae as described in other bacterial pathogens. PMID- 23016896 TI - Predominance of thaumarchaeal ammonia oxidizer abundance and transcriptional activity in an acidic fen. AB - We investigated the abundance, community composition and transcriptional activity of ammonia-oxidizing archaea (AOA) and bacteria (AOB) in the acidic fen Schloppnerbrunnen (Germany) that was subjected to water table manipulations. Quantitative PCR targeting amoA gene copies and transcripts showed that AOA dominated the ammonia-oxidizing community in the upper 20 cm of the peat soil. Numbers of archaeal amoA gene copies and transcripts as well as the relative fraction of AOA of the total archaea decreased with depth. AOA-AmoA sequences were 96.2-98.9% identical to that of Candidatus Nitrosotalea devanaterra while bacterial AmoA sequences affiliated with Nitrosospira clusters 2 and 4. Archaeal but not bacterial amoA transcripts were detected in short-term laboratory incubations of peat that showed nitrifying activity. Nitrate accumulated in the peat pore water after 6 weeks of induced drought during a field experiment. Subsequent rewetting resulted in a significant decrease of AOA transcriptional activity, indicating that AOA responded to water table fluctuations on the transcriptional level. Our results suggest that nitrification in this fen is primarily linked to archaeal ammonia oxidation. pH and anoxia appear to be key factors regulating AOA community composition, vertical distribution and activity in acidic fens. PMID- 23016897 TI - Anti-Fab aptamers for shielding virus from neutralizing antibodies. AB - Oncolytic viruses are promising therapeutics that can selectively replicate in and kill tumor cells. However, repetitive administration of viruses provokes the generation of neutralizing antibodies (nAbs) that can diminish their anticancer effect. In this work, we selected DNA aptamers against the antigen binding fragment (Fab) of antivesicular stomatitis virus polyclonal antibodies to shield the virus from nAbs and enhance its in vivo survival. For the first time, we used flow cytometry and electrochemical immunosensing to identify aptamers targeting the Fab region of antibodies. We evaluated the aptamers in a cell-based infection assay and found that several aptamer clones provide more than 50% shielding of VSV from nAbs and thus have the potential to enhance the delivery of VSV without compromising the patient's immune system. In addition, we developed a bifunctional label-free electrochemical immunosensor for the quantitation of aptamer-mediated degree of shielding and the amount of vesicular stomatitis virus (VSV) particles. Electrochemical impedance spectroscopy was employed to interrogate the level of VSV in a linear range from 5 * 10(4) to 5 * 10(6) PFU mL(-1) with a detection limit of 10(4) PFU mL(-1). PMID- 23016898 TI - Statins in Heart Failure. AB - Clinical trials demonstrated that statin therapy is associated with a significant reduction in cardiovascular morbidity and mortality when used for either primary or secondary prevention of cardiovascular events. Several studies have shown that statins, having an important effect in the prevention of acute coronary syndromes, are also able to prevent heart failure (HF) in patients with coronary artery disease. This review summarizes the experimental and clinical evidence regarding the role of statins in the management of HF. PMID- 23016899 TI - Lipid-lowering therapy in the diabetic foot: seeing the whole iceberg and not just the tip. AB - Diabetic foot ulcers arise from neuropathy and/or ischaemia. The diabetic foot is associated with cardiovascular disease (CVD) and excess mortality. Lipid-lowering therapy reduces CVD morbidity and mortality in diabetic patients with foot ulcers. In particular, statins decrease CVD mortality and improve survival in diabetic foot patients, while fibrates benefit patients with a specific lipid profile. Statins reduce progression of the local disease, improving symptoms and reducing amputations, mainly due to their impact on peripheral arterial disease. Fibrates appear to reduce amputations by improving neuropathy. They also improve ulcer healing and reduce recurrence. This review assesses the role of hypolipidaemic treatment in diabetic foot patients. PMID- 23016900 TI - Molecular mechanisms of pathology and treatment in Diamond Blackfan Anaemia. AB - Diamond Blackfan Anaemia (DBA) is a rare congenital pure red cell aplasia that may be associated with facio-skeletal developmental defects. The disease is caused by mutations in one of at least ten ribosomal proteins, which results in haploinsufficiency and an imbalance between the synthesis of rRNA and ribosomal proteins during ribosome biogenesis. Such imbalance results in stabilization and activation of the tumour suppressor gene TP53. The loss of ribosomes also results in reduced mRNA translation capacity, and may affect translation of specific erythroid transcripts more than average. The contribution of these two mechanisms to impaired erythropoiesis is discussed. The most effective and relatively safe therapy is treatment with glucocorticoid hormone, but responsiveness differs between patients. The molecular and cellular mechanisms involved in treatment are discussed in the context of DBA. PMID- 23016901 TI - Searching for evo-devo's Holy Grail: the nature of developmental variation. PMID- 23016902 TI - Eoandromeda and the origin of Ctenophora. AB - The Ediacaran fossil Eoandromeda octobrachiata had a high conical body with eight arms in helicospiral arrangement along the flanks. The arms carried transverse bands proposed to be homologous to ctenophore ctenes (comb plates). Eoandromeda is interpreted as an early stem-group ctenophore, characterized by the synapomorphies ctenes, comb rows, and octoradial symmetry but lacking crown-group synapomorphies such as tentacles, statoliths, polar fields, and biradial symmetry. It probably had a pelagic mode of life. The early appearance in the fossil record of octoradial ctenophores is most consistent with the Planulozoa hypothesis (Ctenophora is the sister group of Cnidaria + Bilateria) of metazoan phylogeny. PMID- 23016904 TI - Tail regression induced by elevated retinoic acid signaling in amphioxus larvae occurs by tissue remodeling, not cell death. AB - The vitamin A derived morphogen retinoic acid (RA) is known to function in the regulation of tissue proliferation and differentiation. Here, we show that exogenous RA applied to late larvae of the invertebrate chordate amphioxus can reverse some differentiated states. Although treatment with the RA antagonist BMS009 has no obvious effect on late larvae of amphioxus, administration of excess RA alters the morphology of the posterior end of the body. The anus closes over, and gut contents accumulate in the hindgut. In addition, the larval tail fin regresses, although little apoptosis takes place. This fin normally consists of columnar epidermal cells, each characterized by a ciliary rootlet running all the way from an apical centriole to the base of the cell and likely contributing substantial cytoskeletal support. After a few days of RA treatment, the rootlet becomes disrupted, and the cell shape changes from columnar to cuboidal. Transmission electron microscopy (TEM) shows fragments of the rootlet in the basal cytoplasm of the cuboidal cell. A major component of the ciliary rootlet in amphioxus is the protein Rootletin, which is encoded by a single AmphiRootletin gene. This gene is highly expressed in the tail epithelial cells of control larvae, but becomes downregulated after about a day of RA treatment, and the breakup of the ciliary rootlet soon follows. The effect of excess RA on these epidermal cells of the larval tail in amphioxus is unlike posterior regression in developing zebrafish, where elevated RA signaling alters connective tissues of mesodermal origin. In contrast, however, the RA-induced closure of the amphioxus anus has parallels in the RA-induced caudal regression syndrome of mammals. PMID- 23016903 TI - Molecular anatomy of the developing limb in the coqui frog, Eleutherodactylus coqui. AB - The vertebrate limb demonstrates remarkable similarity in basic organization across phylogenetically disparate groups. To gain further insight into how this morphological similarity is maintained in different developmental contexts, we explored the molecular anatomy of size-reduced embryos of the Puerto Rican coqui frog, Eleutherodactylus coqui. This animal demonstrates direct development, a life-history strategy marked by rapid progression from egg to adult and absence of a free-living, aquatic larva. Nonetheless, coqui exhibits a basal anuran limb structure, with four toes on the forelimb and five toes on the hind limb. We investigated the extent to which coqui limb bud development conforms to the model of limb development derived from amniote studies. Toward this end, we characterized dynamic patterns of expression for 13 critical patterning genes across three principle stages of limb development. As expected, most genes demonstrate expression patterns that are essentially unchanged compared to amniote species. For example, we identified an EcFgf8-expression domain within the apical ectodermal ridge (AER). This expression pattern defines a putatively functional AER signaling domain, despite the absence of a morphological ridge in coqui embryos. However, two genes, EcMeis2 and EcAlx4, demonstrate altered domains of expression, which imply a potential shift in gene function between coqui frogs and amniote model systems. Unexpectedly, several genes thought to be critical for limb patterning in other systems, including EcFgf4, EcWnt3a, EcWnt7a, and EcGremlin, demonstrated no evident expression pattern in the limb at the three stages we analyzed. The absence of EcFgf4 and EcWnt3a expression during limb patterning is perhaps not surprising, given that neither gene is critical for proper limb development in the mouse, based on knockout and expression analyses. In contrast, absence of EcWnt7a and EcGremlin is surprising, given that expression of these molecules appears to be absolutely essential in all other model systems so far examined. Although this analysis substantiates the existence of a core set of ancient limb-patterning molecules, which likely mediate identical functions across highly diverse vertebrate forms, it also reveals remarkable evolutionary flexibility in the genetic control of a conserved morphological pattern across evolutionary time. PMID- 23016905 TI - Early patterning and blastodermal fate map of the head in the milkweed bug Oncopeltus fasciatus. AB - The process of head development in insects utilizes a set of widely conserved genes, but this process and its evolution are not well understood. Recent data from Tribolium castaneum have provided a baseline for an understanding of insect head development. However, work on a wider range of insect species, including members of the hemimetabolous orders, is needed in order to draw general conclusions about the evolution of head differentiation and regionalization. We have cloned and studied the expression and function of a number of candidate genes for head development in the hemipteran Oncopeltus fasciatus. These include orthodenticle, empty spiracles, collier, cap 'n' collar, and crocodile. The expression patterns of these genes show a broad conservation relative to Tribolium, as well as differences from Drosophila indicating that Tribolium + Oncopeltus represent a more ancestral pattern. In addition, our data provide a blastodermal fate map for different head regions in later developmental stages and supply us with a "roadmap" for future studies on head development in this species. PMID- 23016907 TI - Skeletal ossification and sequence heterochrony in xenarthran evolution. AB - Previous analyses of how mammals vary in their ossification sequences have focused on monotremes, marsupials, and boreoeutherian placentals. Here, we focus on the sequence of cranial and postcranial ossification events during growth in the xenarthran skull and skeleton, including armadillos, anteaters, and sloths. We use two different methods to quantify sequence heterochrony: sequence analysis of variance (ANOVA) and event-paring/Parsimov. Our results indicate that Parsimov is conservative and does not detect clear heterochronic shifts between xenarthran and boreoeutherian placentals. Sequence-ANOVA performs better, but both methods exhibit sensitivity to the artifactual accumulation of ties. By controlling for ties and taking into account results that the methods have in common, our analysis suggests that xenarthrans significantly differ from other placentals by a late ossification of the sternum and an early ossification of the phalanges and pubis. We interpret these differences as showing that heterochrony plays a role in the skeletal development of xenarthrans, a change from previous studies that have emphasized the developmental homogeneity of the skeleton across placental mammals. PMID- 23016906 TI - Co-orthology of Pax4 and Pax6 to the fly eyeless gene: molecular phylogenetic, comparative genomic, and embryological analyses. AB - The functional equivalence of Pax6/eyeless genes across distantly related animal phyla has been one of central findings on which evo-devo studies is based. In this study, we show that Pax4, in addition to Pax6, is a vertebrate ortholog of the fly eyeless gene (and its duplicate, twin of eyeless [toy] gene, unique to Insecta). Molecular phylogenetic trees published to date placed the Pax4 gene outside the Pax6/eyeless subgroup as if the Pax4 gene originated from a gene duplication before the origin of bilaterians. However, Pax4 genes had only been reported for mammals. Our molecular phylogenetic analysis, including previously unidentified teleost fish pax4 genes, equally supported two scenarios: one with the Pax4-Pax6 duplication early in vertebrate evolution and the other with this duplication before the bilaterian radiation. We then investigated gene compositions in the genomic regions containing Pax4 and Pax6, and identified (1) conserved synteny between these two regions, suggesting that the Pax4-Pax6 split was caused by a large-scale duplication and (2) its timing within early vertebrate evolution based on the duplication timing of the members of neighboring gene families. Our results are consistent with the so-called two round genome duplications in early vertebrates. Overall, the Pax6/eyeless ortholog is merely part of a 2:2 orthology relationship between vertebrates (with Pax4 and Pax6) and the fly (with eyeless and toy). In this context, evolution of transcriptional regulation associated with the Pax4-Pax6 split is also discussed in light of the zebrafish pax4 expression pattern that is analyzed here for the first time. PMID- 23016908 TI - Diplosegmentation in the pill millipede Glomeris marginata is the result of dorsal fusion. AB - All trunk segments in the pill millipede Glomeris marginata (Myriapoda: Diplopoda) are initially patterned genetically, (as visualized by the embryonic expression pattern of the even-skipped gene) and formed morphologically, (as visualized by 4-6-diamidin-2-phenylindol stained embryos) in a single segmental period. In addition, formation of every nascent trunk segment concerns ventral as well as dorsal segmental units. Only after the formation of the nascent posterior trunk segments, the dorsal segmental units of two adjacent segments fuse to form a single dorsal segmental unit that subsequently covers two ventral leg-bearing segmental units. The formation of a diplosegmental unit, or in short a diplosegment, is thus the result of dorsal fusion of embryonic tissue and not the result of any splitting-process or fusion of dorsal tergites. The new data also argue against heterochrony as a primary causative factor for the formation of the diplosegments during the formation of dorsal versus ventral segmental units. Furthermore, no evidence was found supporting the hypothesis that anterior trunk segments in diplopods represent degenerate diplosegments. Two possible scenarios arise from the ontogenetic data presented here, whether this represents an ancestral feature of the diplopods, or alternatively if they represent an isolated case only found in Glomeris (and close relatives). If the former is the case, my work may provide an impressive example of Haeckel's recapitulation theory. PMID- 23016910 TI - Impact of synthesis methods on the transport of single walled carbon nanotubes in the aquatic environment. AB - In this study, a systematic approach has been followed to investigate the fate and transport of single walled carbon nanotubes (SWCNTs) from synthesis to environmentally relevant conditions. Three widely used SWCNT synthesis methods have been investigated in this study including high pressure carbon monoxide (HiPco), SWeNT CoMoCat, and electric arc discharge technique (EA). This study relates the transport of three SWCNTs (HiPco-D, SG65-D, and P2-D) with different synthesis methods and residual catalyst content revealing their influence on the subsequent fate of the nanotubes. To minimize nanotube bundling and aggregation, the SWCNTs were dispersed using the biocompatible triblock copolymer Pluronic, which allowed the comparison in the transport trends among these SWCNTs. After purification, the residual metal catalyst between the SWCNTs follows the trend: HiPco-D > SG65-D > P2-D. The electrophoretic mobility (EPM) and hydrodynamic diameter of SWCNTs remained insensitive to SWCNT type, pH, and presence of natural organic matter (NOM); but were affected by ionic strength (IS) and ion valence (K(+), Ca(2+)). In monovalent ions, the hydrodynamic diameter of SWCNTs was not influenced by IS, whereas larger aggregation was observed for HiPco-D with IS than P2-D and SG65-D in the presence of Ca(2+). Transport of HiPco-D in the porous media was significantly higher than SG65-D followed by P2-D. Release of HiPco-D from porous media was higher than SG65-D followed by P2-D, though negligible amount of all types of SWCNTs (<5%) was released. Both transport and release patterns follow a similar trend to what was observed for residual metal catalysts in SWCNTs. Addition of NOM increased the transport of all SWCNTs primarily due to electrosteric repulsion. HiPco-D was notably more acidic than SG65-D followed by P2-D, which is similar to the transport trend. Overall, it was observed that the synthesis methods resulted in distinctive breakthrough trends, which were correlated to metal content. These findings will facilitate the safe design of environmental friendly SWCNTs by minimizing mobility in aquatic environments. PMID- 23016911 TI - Major determinants of BMP-2 serum levels in hemodialysis patients. PMID- 23016912 TI - Novel HSP90 inhibitor NVP-AUY922 enhances the anti-tumor effect of temsirolimus against oral squamous cell carcinoma. AB - BACKGROUND AND AIM: Heat shock protein 90 (HSP90) and mammalian target of rapamycin (mTOR) are involved in the molecular pathogenesis of advanced oral squamous cell carcinoma. HSP90 inhibitors are capable of effectively interfering with multiple signaling pathways, including the mTOR signaling pathway. However, the combined effects of HSP90 and mTOR inhibitors on oral squamous cell carcinoma are still unknown. In this study, we investigated the dual treatment of the novel HSP90 inhibitor NVP-AUY922 and temsirolimus against oral squamous cell carcinoma. MATERIALS AND METHODS: The effect of the combination of NVP-AUY922 and temsirolimus on oral squamous cell carcinoma in vitro and in vivo was determined by MTS assay and mouse xenograft models. The effect of the combination on angiogenesis was determined by tube formation assay and angioreactor. RESULTS: The combination treatment of NVP-AUY922 and temsirolimus significantly inhibited the proliferation of SAS oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. We have clearly shown that the combination treatment of NVP-AUY922 and temsirolimus inhibited vascular formation both in vitro and in vivo. Moreover, the combination treatment of NVP-AUY922 and temsirolimus prolonged the survival rate in mice xenografted with oral squamous cell carcinoma. CONCLUSIONS: Here, we showed the activity of a combination of mTOR and HSP90 inhibitors for the treatment of advanced oral squamous carcinoma. PMID- 23016913 TI - Transcatheter aortic valve implantation for the treatment of surgical valve dysfunction ("valve-in-valve"): assessing the risk of coronary obstruction. AB - Acute coronary obstruction is one of the most feared complications associated with transcatheter aortic valve-in-valve implantation. Strategies for assessing the risk of coronary occlusion during these procedures as well as preventive measures are discussed. PMID- 23016914 TI - Bronchoscopic practice in Japan: a survey by the Japan Society for Respiratory Endoscopy in 2010. AB - BACKGROUND AND OBJECTIVE: To ensure the safety of bronchoscopic practice, the Japan Society for Respiratory Endoscopy conducted a national survey to investigate the current state of procedure for this technique. METHODS: A questionnaire survey about procedures carried out during the whole of the year 2010 was mailed to 538 facilities accredited by the society. RESULTS: Responses were obtained from 511 facilities (95.0%). Rigid bronchoscopes were used in only 18.5% of the facilities, while mobile/thin bronchoscopes were used in >= 50%, and fluoroscopy systems were used in 99.8%. Biopsies were performed after discontinuation of therapy in patients receiving antiplatelet drugs and anticoagulants in 96.7% and 97.4% of the facilities, respectively. Atropine was administered for premedication in 67.5% of the facilities, a decrease from previous surveys. Intravenous sedation was given in 36.1% of the facilities. In 21.9% of these, the procedure was conducted in the outpatient clinic for >= 70% of patients. A bronchoscope was orally inserted in >= 70% of patients in 95.7% of the facilities. Intravenous access was maintained during the examination in 92.5% of the facilities, oxygen saturation was monitored during examinations in 99.0%, oxygen was administered in 97.6% and resuscitation equipment was available in 96%. In 98.6% of the facilities, bronchoscopes were disinfected using an automatic washing machine, with glutaraldehyde used in 42.2%. CONCLUSIONS: Japan specific characteristics of bronchoscopic practice were identified. Whether procedures used in Japan meet international guidelines with respect to safety should be monitored continuously. In addition, a Japanese evidence-based consensus is needed. PMID- 23016915 TI - Comprehensive molecular motion capture for sphingomyelin by site-specific deuterium labeling. AB - Lipid rafts have attracted much attention because of their significant functional roles in membrane-associated processes. It is thought that sphingomyelin and cholesterol are essential for forming lipid rafts; however, their motion characteristics are not fully understood despite numerous studies. Here we show accurate local motions encompassing an entire sphingomyelin molecule, which were captured by measuring quadrupole splittings for 19 kinds of site-specifically deuterated sphingomyelins (that is, molecular motion capture of sphingomyelin). The quadrupole splitting profiles, which are distinct from those reported from perdeuterated sphingomyelins or simulation studies, reveal that cholesterol enhances the order in the middle parts of the alkyl chains more efficaciously than at the shallow positions. Comparison with dimyristoylphosphocholine bilayers suggests that cholesterol is deeper in sphingomyelin bilayers, which likely explains the so-called umbrella effect. The experiments also demonstrate that (i) the C2'-C3' bond predominantly takes the gauche conformation, (ii) the net ordering effect of cholesterol in sphingomyelin bilayers is not larger than that in phosphatidylcholine bilayers, (iii) cholesterol has no specific preference for the acyl or sphingosine chain, (iv) the acyl and sphingosine chains seem mismatched by about two methylene lengths, and (v) the motion of the upper regions of sphingomyelin chains is less temperature dependent than that of lower regions probably due to intermolecular hydrogen bond formation among SM molecules. These insights into the atomic-level dynamics of sphingomyelin provide critical clues to understanding the mechanism of raft formation. PMID- 23016916 TI - Are collagenous and lymphocytic colitis different aspects of the same disease? AB - OBJECTIVE: Collagenous colitis (CC) and lymphocytic colitis (LC) are two subtypes of microscopic colitis (MC). Even though they most often are described as different entities they share many clinical and histological features. The aim of this study was to investigate the occurrence of conversion between CC and LC in a larger cohort of patients. MATERIALS AND METHODS: All 664 patients in our Pathology register with a diagnosis of CC and LC were scrutinized and those where additional endoscopies had been carried out were included, and their biopsies were re-examined. RESULTS: Sixty-five patients (55 women, 10 men, median age 58 years; range 29-86) fulfilled our criteria for inclusion. The primary diagnosis was CC in 47 patients (39 women, 8 men, median age 58 years; range 29-86) and LC in 18 patients (16 women, 2 men, median age 58 years; range 33-74). Conversion occurred in nine of the 65 patients (14%, all women, median age 59 years; range 41-72), three from CC to LC and six from LC to CC. CONCLUSION: This study has found that patients can show histological features consistent with both CC and LC over time. These patients could represent a subgroup with a true conversion between two separate entities. Alternatively, MC could be a spectral disease where the varying histological features are manifestations of the natural fluctuation. A third possibility could be that the histological changes reflect different manifestations during the disease course and consequently, the diagnostic criteria could be too vague. PMID- 23016917 TI - Can p63 serve as a biomarker for giant cell tumor of bone? A Moroccan experience. AB - BACKGROUND: Multinucleated giant cell-containing tumors and pseudotumors of bone represent a heterogeneous group of benign and malignant lesions. Differential diagnosis can be challenging, particularly in instances of limited sampling. The purpose of this study was to evaluate the contribution of the P63 in the positive and differential diagnosis of giant cell tumor of bone. METHODS: This study includes 48 giant cell-containing tumors and pseudotumors of bone. P63 expression was evaluated by immunohistochemistry. Data analysis was performed using Epi-info software and SPSS software package (version 17). RESULTS: Immunohistochemical analysis showed a P63 nuclear expression in all giant cell tumors of bone, in 50% of osteoid osteomas, 40% of aneurysmal bone cysts, 37.5% of osteoblastomas, 33.3% of chondromyxoide fibromas, 25% of non ossifiant fibromas and 8.3% of osteosarcomas. Only one case of chondroblastoma was included in this series and expressed p63. No P63 immunoreactivity was detected in any of the cases of central giant cell granulomas or langerhans cells histiocytosis. The sensitivity and negative predictive value (NPV) of P63 immunohistochemistry for the diagnosis of giant cell tumor of bone were 100%. The specificity and positive predictive value (PPV) were 74.42% and 59.26% respectively. CONCLUSIONS: This study found not only that GCTOB expresses the P63 but it also shows that this protein may serve as a biomarker for the differential diagnosis between two morphologically similar lesions particularly in instances of limited sampling. Indeed, P63 expression seems to differentiate between giant cell tumor of bone and central giant cell granuloma since the latter does not express P63. Other benign and malignant giant cell-containing lesions express P63, decreasing its specificity as a diagnostic marker, but a strong staining was seen, except a case of chondroblastoma, only in giant cell tumor of bone. Clinical and radiological confrontation remains essential for an accurate diagnosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1838562590777252. PMID- 23016918 TI - Rezymogenation of active urokinase induced by an inhibitory antibody. AB - An important regulatory mechanism of serine proteases is the proteolytic conversion of the inactive pro-enzyme, or zymogen, into the active enzyme. This activation process is generally considered an irreversible process. In the present study, we demonstrate that an active enzyme can be converted back into its zymogen form. We determined the crystal structure of uPA (urokinase-type plasminogen activator) in complex with an inhibitory antibody, revealing that the antibody 'rezymogenizes' already activated uPA. The present study demonstrates a new regulatory mechanism of protease activity, which is also an extreme case of protein allostery. Mechanistically, the antibody binds a single surface-exposed loop, named the autolysis loop, thereby preventing the stabilization of uPA in its active conformation. We argue that this autolysis loop is a key structural element for rezymogenation of other proteases, and will be a new target site for pharmacological intervention with serine protease activity. PMID- 23016920 TI - Letter to the editor: re: role of smoking and type 2 diabetes in the immunobalance of advanced chronic periodontitis. PMID- 23016921 TI - Does the neurobiology of migraine make migraine patients "difficult"? PMID- 23016922 TI - Mechanism of metal-free hydrogen transfer between amine-boranes and aminoboranes. AB - The kinetics of the metal-free hydrogen transfer from amine-borane Me(2)NH.BH(3) to aminoborane iPr(2)N?BH(2), yielding iPr(2)NH.BH(3) and cyclodiborazane [Me(2)N BH(2)](2) via transient Me(2)N?BH(2), have been investigated in detail, with further information derived from isotopic labeling and DFT computations. The approach of the system toward equilibrium was monitored in both directions by (11)B{(1)H} NMR spectroscopy in a range of solvents and at variable temperatures in THF. Simulation of the resulting temporal-concentration data according to a simple two-stage hydrogen transfer/dimerization process yielded the rate constants and thermodynamic parameters attending both equilibria. At ambient temperature, the bimolecular hydrogen transfer is slightly endergonic in the forward direction (DeltaG(1) degrees ((295)) = 10 +/- 7 kJ.mol(-1); DeltaG(1)(?)((295)) = 91 +/- 5 kJ.mol(-1)), with the overall equilibrium being driven forward by the subsequent exergonic dimerization of the aminoborane Me(2)N?BH(2) (DeltaG(2) degrees ((295)) = -28 +/- 14 kJ.mol(-1)). Systematic deuterium labeling of the NH and BH moieties in Me(2)NH.BH(3) and iPr(2)N?BH(2) allowed the kinetic isotope effects (KIEs) attending the hydrogen transfer to be determined. A small inverse KIE at boron (k(H)/k(D) = 0.9 +/- 0.2) and a large normal KIE at nitrogen (k(H)/k(D) = 6.7 +/- 0.9) are consistent with either a pre equilibrium involving a B-to-B hydrogen transfer or a concerted but asynchronous hydrogen transfer via a cyclic six-membered transition state in which the B-to-B hydrogen transfer is highly advanced. DFT calculations are fully consistent with a concerted but asynchronous process. PMID- 23016923 TI - QSAR study and the hydrolysis activity prediction of three alkaline lipases from different lipase-producing microorganisms. AB - The hydrolysis activities of three alkaline lipases, L-A1, L-A2 and L-A3 secreted by different lipase-producing microorganisms isolated from the Bay of Bohai, P. R. China were characterized with 16 kinds of esters. It was found that all the lipases have the ability to catalyze the hydrolysis of the glycerides, methyl esters, ethyl esters, especially for triglycerides, which shows that they have broad substrate spectra, and this property is very important for them to be used in detergent industry. Three QSAR models were built for L-A1, L-A2 and L-A3 respectively with GFA using Discovery studio 2.1. The models equations 1, 2 and 3 can explain 95.80%, 97.45% and 97.09% of the variances (R(2)(adj)) respectively while they could predict 95.44%, 89.61% and 93.41% of the variances (R(2)(cv)) respectively. With these models the hydrolysis activities of these lipases to mixed esters were predicted and the result showed that the predicted values are in good agreement with the measured values, which indicates that this method can be used as a simple tool to predict the lipase activities for single or mixed esters. PMID- 23016924 TI - Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers. AB - AIM: The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. METHODS: Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT 288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. RESULTS: ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. CONCLUSIONS: Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. PMID- 23016925 TI - Plastic compressed collagen constructs for ocular cell culture and transplantation: a new and improved technique of confined fluid loss. AB - PURPOSE: Cultured limbal epithelial cell transplantation is a commonly used clinical treatment for ocular surface repair. We have previously shown that plastic compressed (PC) type I collagen constructs are a suitable substrate for human limbal epithelial cell (HLEC) culture for transplantation. For this process to achieve compliance with Good Manufacturing Practice, and therefore be suitable for therapeutic cell therapy manufacture, the original method required substantial modification. METHODS: The compression method was changed from unconfined (highly variable reproducibility) to confined compression (CC) (highly reproducible manufacture) and we assessed whether this altered the physical characteristics of the substrate. We have measured transparency, assessed scanning electron microscope images of the surface and performed live/dead cell viability assays of cells within the constructs. HLECs were then cultured on the surface of both types of construct and the resulting cell phenotype characterized. RESULTS: We have determined that the change in process does not alter the physical characteristics of the substrate. Furthermore, there is no change to the substrate's ability to support HLEC culture and maintenance of a mixed population of stem and differentiated cells. Additionally, cells were able to form a confluent sheet and multilayer to produce an intact epithelium. CONCLUSIONS: This modification allows scaling up of the process in a well-plate format, which is essential for creation of multiple corneal epithelial models for in vitro testing. This improvement to the original plastic compression method also allows the process to be employed in custom-made cassettes, the design of which takes into consideration the manufacturing and regulatory requirements for delivery of a cell therapy. PMID- 23016926 TI - Can dexmedetomidine be a safe and efficacious sedative agent in post-cardiac surgery patients? a meta-analysis. AB - INTRODUCTION: The aim of this study was to explore the use of dexmedetomidine as a safe and efficacious sedative agent in post-cardiac surgery patients. METHODS: A systematic literature search of MEDLINE, EMBASE, the Cochrane Library and Science Citation Index until January 2012 and review of studies was conducted. Eligible studies were of randomized controlled trials or cohort studies, comparing dexmedetomidine with a placebo or an alternative sedative agent in elective cardiac surgery, using dexmedetomidine for postoperative sedation and available in full text. Two reviewers independently performed study selection, quality assessment, and data extraction. RESULTS: The search identified 530 potentially relevant publications; 11 met selection criteria in this meta analysis. Our results revealed that dexmedetomidine was associated with a shorter length of mechanical ventilation (mean difference -2.70 [-5.05, -0.35]), a lower risk of delirium (risk ratio 0.36 [0.21, 0.64]), ventricular tachycardia (risk ratio 0.27 [0.08, 0.97]) and hyperglycemia (risk ratio 0.78 [0.61, 0.99]), but may increase the risk of bradycardia (risk ratio 2.08 [1.16, 3.74]). But there was no significant difference in ICU stay, hospital stay, and morphine equivalents between the included studies. Dexmedetomidine may not increase the risk of hypotension, atrial fibrillation, postoperative nausea and vomiting, reintubation within 5 days, cardiovascular complications, postoperative infection or hospital mortality. CONCLUSIONS: Dexmedetomidine was associated with shorter length of mechanical ventilation and lower risk of delirium following cardiac surgery. Although the risk of bradycardia was significantly higher compared with traditional sedatives, it may not increase length of hospital stay and hospital mortality. Moreover, dexmedetomidine may decrease the risk of ventricular tachycardia and hyperglycemia. Thus, dexmedetomidine could be a safe and efficacious sedative agent in cardiac surgical patients. PMID- 23016927 TI - Dynamic ultrasound imaging--a multivariate approach for the analysis and comparison of time-dependent musculoskeletal movements. AB - BACKGROUND: Muscle functions are generally assumed to affect a wide variety of conditions and activities, including pain, ischemic and neurological disorders, exercise and injury. It is therefore very desirable to obtain more information on musculoskeletal contributions to and activity during clinical processes such as the treatment of muscle injuries, post-surgery evaluations, and the monitoring of progressive degeneration in neuromuscular disorders.The spatial image resolution achievable with ultrasound systems has improved tremendously in the last few years and it is nowadays possible to study skeletal muscles in real-time during activity. However, ultrasound imaging has an inherent problem that makes it difficult to compare different measurement series or image sequences from two or more subjects. Due to physiological differences between different subjects, the ultrasound sequences will be visually different - partly because of variation in probe placement and partly because of the difficulty of perfectly reproducing any given movement. METHODS: Ultrasound images of the biceps and calf of a single subject were transformed to achieve congruence and then efficiently compressed and stacked to facilitate analysis using a multivariate method known as O2PLS. O2PLS identifies related and unrelated variation in and between two sets of data such that different phases of the studied movements can be analysed. The methodology was used to study the dynamics of the Achilles tendon and the calf and also the Biceps brachii and upper arm. The movements of these parts of the body are both of interest in clinical orthopaedic research. RESULTS: This study extends the novel method of multivariate analysis of congruent images (MACI) to facilitate comparisons between two series of ultrasound images. This increases its potential range of medical applications and its utility for detecting, visualising and quantifying the dynamics and functions of skeletal muscle. CONCLUSIONS: The most important results of this study are that MACI with O2PLS is able to consistently extract meaningful variability from pairs of ultrasound sequences. The MACI method with O2PLS is a powerful tool with great potential for visualising and comparing dynamics between movements. It has many potential clinical applications in the study of muscle injuries, post-surgery evaluations and evaluations of rehabilitation, and the assessment of athletic training interventions. PMID- 23016928 TI - An electrochemical method for investigation of conformational flexibility of active sites of Trametes versicolor laccase based on sensitive determination of copper ion with cysteine-modified electrodes. AB - This study demonstrates a facile yet effective electrochemical method to investigate the conformational flexibility of the active sites of Trametes versicolor (Tv) laccase based on sensitive determination of copper ions (Cu(2+)) dissociated from the enzyme with the cysteine-modified Au electrodes. In the native state, the multicopper active sites are deeply buried in the polypeptide of Tv laccase and are thus not electrochemically detectable even at the cysteine modified Au electrodes. Upon the unfolding of Tv laccase induced by guanidine hydrochloride (GdnHCl), copper ions dissociate from the peptide chain and, as a consequence, are electrochemically reduced and thus detected at the cysteine modified Au electrodes. Such a property could be used to investigate the conformational flexibility of multicopper active sites of Tv laccase in a simple way. We find that both the conformation of the multicopper active sites in Tv laccase and the enzyme activity change with the presence of a low concentration of GdnHCl denaturant (midpoint, where 50% of the enzyme is unfolded, at 0.7 M). This concentration is lower than that required to induce the conformational changes of Tv laccase molecule as a whole (midpoint at 3.4 M), as investigated by the intrinsic fluorescence of Tv laccase. This observation suggests that the multicopper active sites are formed by relatively weak interactions and hence may be conformationally more flexible than the intact enzyme. The electrochemical method demonstrated in this study is technically simple yet effective and could be potentially useful for investigation on the thermodynamics and kinetics of the conformational changes of multicopper oxidases induced by different denaturants. PMID- 23016929 TI - Wzx flippase-mediated membrane translocation of sugar polymer precursors in bacteria. AB - Bacterial cell surface polysaccharides confer resistance to external stress and promote survival in biotic and abiotic environments. Glycan assembly often occurs at the periplasmic leaflet of the inner membrane (IM) from undecaprenyl pyrophosphate (UndPP)-linked polysaccharide units via the Wzx/Wzy-dependent pathway. Wzx is an integral IM protein found in Gram-negative and Gram-positive bacteria that mediates IM translocation of UndPP-linked sugar repeats from the cytoplasmic to the periplasmic leaflet; interaction of Wzx with other assembly proteins is indirectly supported by genetic evidence. Topological mapping has indicated 12 alpha-helical transmembrane segments (TMS), with the number of charged TMS residues fluctuating based on the mapping method used. A novel Wzx tertiary structure model has been built, allowing for substrate-binding or energy coupling roles to be proposed for functionally important charged and aromatic TMS residues. It has also led to a proposed antiport-like mechanism of Wzx function. Exquisite substrate specificity of Wzx proteins was recently revealed in distinguishing between UndPP-linked substrates with identical main-chain sugar repeats, but differing in the chemical composition of a terminal sugar side branch cap. The objective of this review is to synthesize the most up-to-date knowledge concerning Wzx flippases and to provide perspective for future investigations in this burgeoning field. PMID- 23016930 TI - First-principles study on core-level spectroscopy of arginine in gas and solid phases. AB - First-principles simulations have been performed for near-edge X-ray absorption fine-structure (NEXAFS) spectra of neutral arginine at different K-edges in the solid phase as well as X-ray photoelectron spectra (XPS) of neutral, deprotonated, and protonated arginines in the gas phase. Influences of the intra- and intermolecular hydrogen bonds (HBs) and different charge states have been carefully examined to obtain useful structure-property relationships. Our calculations show a noticeable difference in the NEXAFS/XPS spectra of the canonical and zwitterionic species that can be used for unambiguously identifying the dominant form in the gas phase. It is found that the deprotonation/protonation always results in red/blue shifts of several electronvolts for the core binding energies (BEs) at all edges. The normal hydrogen bond Y-H...X (X, Y = N, O) can cause a blue/red shift of ca. 1 eV to the core BEs of the proton acceptor X/donor Y, while the weak C-H...Y hydrogen bond may also lead to a weak red shift (less than 1 eV) of the C1s BEs. Moreover, the influence of intermolecular interactions in the solid state is reflected as a broadening in the sigma* region of the NEXAFS spectra at each edge, while in the pi* region, these interactions lead to a strengthening or weakening of individual transitions from different carbons, although no evident visual change is found in the resolved total spectra. Our results provide a better understanding of the influences of the intra- and intermolecular forces on the electronic structure of arginine. PMID- 23016932 TI - Exciton dynamics within the band-edge manifold states: the onset of an acoustic phonon bottleneck. AB - Exciton dynamics within the band-edge state manifold of CdSe/ZnS and CdSe/CdS quantum dots (QDs) have been investigated. Low-temperature time-resolved photoluminescence (PL) experiments demonstrate that exciton relaxation is mediated by LO phonons, whereas an acoustic phonon bottleneck is observed for splitting energies lower than the optical phonon energy. This has important implications since the main source affecting exciton dephasing is considered to be a spin-flip process. Our results concur with recent observations of long exciton dephasing times in CdSe/CdS QDs and show a way to engineer nanoparticles with enhanced coherence time, a prerequisite for their use in quantum optical applications. PMID- 23016931 TI - Nitric oxide-mediated regulation of beta-amyloid clearance via alterations of MMP 9/TIMP-1. AB - Fibrillar amyloid plaques are largely composed of amyloid-beta (Abeta) peptides that are metabolized into products, including Abeta1-16, by proteases including matrix metalloproteinase 9 (MMP-9). The balance between production and degradation of Abeta proteins is critical to amyloid accumulation and resulting disease. Regulation of MMP-9 and its endogenous inhibitor tissue inhibitor of metalloproteinase (TIMP)-1 by nitric oxide (NO) has been shown. We hypothesize that nitric oxide synthase (NOS2) protects against Alzheimer's disease pathology by increasing amyloid clearance through NO regulation of MMP-9/TIMP-1 balance. We show NO-mediated increased MMP-9/TIMP-1 ratios enhanced the degradation of fibrillar Abeta in vitro, which was abolished when silenced for MMP-9 protein translation. The in vivo relationship between MMP-9, NO and Abeta degradation was examined by comparing an Alzheimer's disease mouse model that expresses NOS2 with a model lacking NOS2. To quantitate MMP-9 mediated changes, we generated an antibody recognizing the Abeta1-16 fragment, and used mass spectrometry multi reaction monitoring assay for detection of immunoprecipitated Abeta1-16 peptides. Abeta1-16 levels decreased in brain lysates lacking NOS2 when compared with strains that express human amyloid precursor protein on the NOS2 background. TIMP 1 increased in the APPSwDI/NOS2(-/-) mice with decreased MMP activity and increased amyloid burden, thereby supporting roles for NO in the regulation of MMP/TIMP balance and plaque clearance. PMID- 23016933 TI - Identification and characterization of the first SLC11A2 isoform 1a mutation causing a defect in splicing process and an hypomorphic allele expression of the SLC11A2 gene. PMID- 23016934 TI - Phylogeography and reproductive variation of the poecilogonous polychaete Boccardia proboscidea (Annelida: Spionidae) along the West Coast of North America. AB - The ability to produce more than one kind of offspring, or poecilogony, is a striking example of reproductive variability. Traditionally, larval nutrition has been classified as a dichotomy: if offspring obtain nutrition from their mothers (lecithotrophy), there is lower fecundity and greater chance of offspring survival than when they get their nutrition from plankton (planktotrophy). The polychaete Boccardia proboscidea (Spionidae) produces both types of embryos using three different reproductive strategies. In this study, we examined the roles of genetic history and phenotypic plasticity on explaining natural variation in B. proboscidea along the Pacific coast of the United States using two genetic mitochondrial markers, 16S rDNA and Cyt b, and common garden experiments. These data show a single North American West Coast network that is structured, geographically, by the well-documented biogeographic break near Point Conception, California. The southern group within this network covers a smaller range, but has larger haplotype diversity, than the northern group. Some individuals differing in reproductive type had the same haplotype, indicating independence of these features; however, differences between laboratory and field data suggest additional geographic variation within one of the reproductive types. Females from higher latitudes provide offspring with larger supplies of extra embryonic nutrition than females from southern latitudes. Results herein suggest that both genetic history and developmental plasticity are playing a role in the maintenance of this reproductive polymorphism. PMID- 23016936 TI - Teeth before jaws? Comparative analysis of the structure and development of the external and internal scales in the extinct jawless vertebrate Loganellia scotica. AB - Traditional hypotheses posit that teeth evolved from dermal scales, through the expansion of odontogenetically competent ectoderm into the mouth of jawless vertebrates. The discovery of tooth-like scales inside thelodonts, an extinct group of jawless vertebrates, led to the alternative hypothesis that teeth evolved from endodermal derivatives and that there exists a fundamental developmental and phylogenetic distinction between oral/pharyngeal and external odontodes. We set out a test of this latter hypothesis, examining the development of scales of the thelodont Loganellia scotica using synchrotron radiation X-ray tomographic microscopy (SRXTM). We reveal that the internal scales are organized into fused patches and rows, a key distinction from the discrete dermal scales. The pattern of growth of oral scale patches is polarized, but not along a particular vector, whereas pharyngeal scale rows grew along a vector. Our test of the phylogenetic distribution of oral and pharyngeal scales and teeth in vertebrates indicates that odontodes are first expressed in an external position. Internal scales, where present, are always located near to external orifices; the sequential development of pharyngeal scales in Loganellia is peculiar among thelodonts and other stem gnathostomes. It represents a convergence on, rather than the establishment of, the developmental pattern underpinning tooth replacement in jawed vertebrates. The available evidence suggests that internal odontodes evolved through the expansion of odontogenic competence from external to internal epithelia. PMID- 23016935 TI - Drosophila sex combs as a model of evolutionary innovations. AB - The diversity of animal and plant forms is shaped by nested evolutionary innovations. Understanding the genetic and molecular changes responsible for these innovations is therefore one of the key goals of evolutionary biology. From the genetic point of view, the origin of novel traits implies the origin of new regulatory pathways to control their development. To understand how these new pathways are assembled in the course of evolution, we need model systems that combine relatively recent innovations with a powerful set of genetic and molecular tools. One such model is provided by the Drosophila sex comb-a male specific morphological structure that evolved in a relatively small lineage related to the model species D. melanogaster. Our extensive knowledge of sex comb development in D. melanogaster provides the basis for investigating the genetic changes responsible for sex comb origin and diversification. At the same time, sex combs can change on microevolutionary timescales and differ spectacularly among closely related species, providing opportunities for direct genetic analysis and for integrating developmental and population-genetic approaches. Sex comb evolution is associated with the origin of novel interactions between Hox and sex determination genes. Activity of the sex determination pathway was brought under the control of the Hox code to become segment-specific, while Hox gene expression became sexually dimorphic. At the same time, both Hox and sex determination genes were integrated into the intrasegmental spatial patterning network, and acquired new joint downstream targets. Phylogenetic analysis shows that similar sex comb morphologies evolved independently in different lineages. Convergent evolution at the phenotypic level reflects convergent changes in the expression of Hox and sex determination genes, involving both independent gains and losses of regulatory interactions. However, the downstream cell differentiation programs have diverged between species, and in some lineages, similar adult morphologies are produced by different morphogenetic mechanisms. These features make the sex comb an excellent model for examining not only the genetic changes responsible for its evolution, but also the cellular processes that translate DNA sequence changes into morphological diversity. The origin and diversification of sex combs provides insights into the roles of modularity, cooption, and regulatory changes in evolutionary innovations, and can serve as a model for understanding the origin of the more drastic novelties that define higher order taxa. PMID- 23016937 TI - Developmental basis of mammalian digit reduction: a case study in pigs. AB - Digit reduction has occurred in parallel in many mammalian lineages. However, despite this pattern's prevalence, the developmental mechanisms underlying mammalian digit reduction remain controversial. We therefore undertook a study of digit development in the pig (Sus scrofa), a mammal with reduced first, second, and fifth digits. Our results indicate that from its earliest formation, the pig limb bud is significantly narrower than that of the model pentadactyl mammal, mouse. Furthermore, the cartilage condensations of the pig's reduced digits are noticeably smaller than those of their nonreduced counterparts from the time of their formation. In addition, growth rates of pig digits are comparable, as are the patterns of cell death in developing pig and mouse limbs. Taken together, results suggest that pig's first, second, and fifth digits are primarily reduced through evolutionary modifications in the early developmental patterning of their limbs. Results of this study, coupled with those from study of limb development in other mammals, suggest that although major developmental reorganizations (e.g., complete digit or limb loss) during early limb development may be selected against, it may be common for more subtle evolutionary modifications in limb development (e.g., changes in relative digit size) to occur at this time. PMID- 23016938 TI - A genetic basis for intraspecific differences in developmental timing? AB - Heterochrony, altered developmental timing between ancestors and their descendents, has been proposed as a pervasive evolutionary feature and recent analytical approaches have confirmed its existence as an evolutionary pattern. Yet, the mechanistic basis for heterochrony remains unclear and, in particular, whether intraspecific variation in the timing of developmental events generates, or has the potential to generate, future between-species differences. Here we make a key step in linking heterochrony at the inter- and intraspecific level by reporting an association between interindividual variation in both the absolute and relative timing (position within the sequence of developmental events) of key embryonic developmental events and genetic distance for the pond snail, Radix balthica. We report significant differences in the genetic distance of individuals exhibiting different levels of dissimilarity in their absolute and relative timing of developmental events such as spinning activity, eyespot formation, heart ontogeny, and hatching. This relationship between genetic and developmental dissimilarity is consistent with there being a genetic basis for variation in developmental timing and so suggests that intraspecific heterochrony could provide the raw material for natural selection to produce speciation. PMID- 23016939 TI - Satb2, modularity, and the evolvability of the vertebrate jaw. AB - Modularity is a key mechanism bridging development and evolution and is fundamental to evolvability. Herein, we investigate modularity of the Vertebrate jaw with the aim of understanding mechanisms of its morphological evolution. Conservation of the basic structural bauplan of Vertebrate jaws led to a Hinge and Caps model, in which polarity in the patterning system of developing jaws predicts modularity. We have tested the hypothesis that the Satb2+ cell population delineates a developmental module within the mandibular jaw. Satb2 is expressed in the mesenchyme of the jaw primordia that gives rise to distal elements of both the upper and lower jaws. Loss of Satb2 specifically affects structural elements of the distal (incisor) domain, reflecting the integration of these elements as well as their independence from other mandibular domains. Reducing Satb2 dosage leads to an increase in variation in mandibular length, providing insight into the developmental potential to generate variation. Inter taxa comparisons reveal that the Satb2 domain is conserved within gnathostomes. We complement previous loss of function studies in mice with gene knock-down experiments in Xenopus, providing evidence for functional conservation of Satb2 in regulating size. Finally, we present evidence that the relative size of the amniote mandibular Satb2+ domain varies in relation to epithelial Fgf8 expression, suggesting a mechanism for evolutionary change in this domain. Taken together, our data support the Hinge and Caps model and provide evidence that Satb2 regulates coordinated distal jaw modules that are subject to evolutionary modification by signals emanating from the Hinge. PMID- 23016940 TI - HomeoDB2: functional expansion of a comparative homeobox gene database for evolutionary developmental biology. AB - Homeobox gene database (HomeoDB), a manually curated database of homeobox genes and their classification, has been well received since its release in 2008. Here, we report HomeoDB2, an expansion and improvement of the original database that provides greater functionality for the user. HomeoDB2 includes all homeobox loci from 10 animal genomes (human, mouse, chicken, frog, zebrafish, amphioxus, nematode, fruitfly, beetle, honeybee) plus tools for downloading sequences, comparing between species and BLAST searching. HomeoDB2 provides a resource for studying the dynamics of homeobox gene evolution, and is freely accessible at http://homeodb.zoo.ox.ac.uk. PMID- 23016943 TI - Spectroscopic characterization and fusogenic properties of preS domains of duck hepatitis B virus. AB - In order to shed light on the hepatitis B virus fusion mechanism and to explore the fusogenic capabilities of preS regions, a recombinant duck hepatitis B virus (DHBV) preS protein (DpreS) containing six histidines at the carboxy-terminal end has been obtained. The DpreS domain, which has an open and mostly nonordered conformation as indicated by fluorescence and circular dichroism spectroscopies, has the ability to interact with negatively charged phospholipid vesicles. The observed interaction differences between neutral and acidic phospholipids can be interpreted in terms of an initial ionic interaction between the phospholipid polar headgroup and the protein followed by the insertion of probably the N terminal region in the cellular membrane. Fluorescence polarization studies detect a decrease of the transition enthalpy together with a small modification of the transition temperature, typical effects of integral membrane proteins. The interaction of the protein with acidic phospholipid vesicles induces aggregation, lipid mixing, and leakage of internal contents, properties that have been ascribed to membrane destabilizing proteins. The fact that the preS domains of the hepadnaviruses have little similarity but share a very similar hydrophobic profile points to the importance of the overall three-dimensional structure as well as to its conformational flexibility and the distribution of polar and apolar amino acids on the expression of their destabilizing properties rather than to a particular amino acid sequence. The results presented herein argue for the involvement of DpreS in the initial steps of DHBV infection. Taken together with previously reported results, the conclusion that both S and preS regions participate in the fusion process of the hepadnaviridae family may be drawn. PMID- 23016944 TI - Oxygen saturation of healthy term neonates during the first 30 minutes of life. AB - BACKGROUND: The purpose of this study was to document the oxygen saturation (SpO(2) ), general physical signs and laboratory characteristics during the first 30 min of life. METHODS: Forty healthy singleton full-term neonates delivered vaginally (n = 33) or by cesarean section (n = 7) were included in this prospective observational study. After delivery, the SpO(2) levels of the upper (right hand; 'preductal') and lower (dorsum of the right foot; 'postductal') extremities of the neonates lying on the servo-controlled radiant heater in the delivery room were measured simultaneously with oximeter probes (Oxiprobe BM-270) placed at 1, 5, 10, 15, 20, 25, and 30 min. The correlation between pre- and postductal SpO(2) level and different variables (vital signs, capillary refill time recorded at 1 and 15 min, cord pH and hemoglobin values, and Apgar scores at 1 and 5 min) was examined. RESULTS: The 1 min pre- and postductal SpO(2) were 82.3 +/- 7.34% and 79.08 +/- 8.16% (P > 0.05), respectively. The preductal values at 5, 10, and 15 min were statistically higher than the postductal values (89.73 +/- 6.01%, 93.43 +/- 4.06%, and 94.53 +/- 3.19% vs 85.53 +/- 6.92%, 89.9 +/- 4.91%, 92.83 +/- 3.92%, respectively). SpO(2) was the same regardless of the mode of delivery. No correlations were found between pre- and postductal SpO(2) and other variables. CONCLUSIONS: Oxygen saturation was not affected by mode of delivery, was independent of Apgar score, cord hemoglobin, cord pH, vital signs, and capillary refill time in the first few minutes of life, and did not reach 90% in the first 5 min of life in healthy full-term neonates. PMID- 23016945 TI - A new metastrongyloidean species (Nematoda) parasitizing pulmonary arteries of Puma (Herpailurus) yagouaroundi (E. Geoffroy, 1803) (Carnivora: Felidae) from Brazil. AB - Angiostrongylus felineus n. sp. (Nematoda, Metastrongyloidea), parasitic in Puma (Herpailurus) yagouaroundi (E. Geoffroy, 1803) (Carnivora, Felidae) from the municipality of Juiz de Fora, Minas Gerais state, Brazil, is described and illustrated herein. Angiostrongylus felineus n. sp. differs from all congeneric species by having the anterior extremity with accentuated cuticular expansion and by smaller size of spicules. This study describes for the first time a species of Angiostrongylus in a wild Felidae in Brazil. PMID- 23016946 TI - Synthesis and catalytic properties of metal clusters encapsulated within small pore (SOD, GIS, ANA) zeolites. AB - The synthesis protocols for encapsulation of metal clusters reported here expand the diversity in catalytic chemistries made possible by the ability of microporous solids to select reactants, transition states, and products on the basis of their molecular size. We report a synthesis strategy for the encapsulation of noble metals and their oxides within SOD (Sodalite, 0.28 nm * 0.28 nm), GIS (Gismondine, 0.45 nm * 0.31 nm), and ANA (Analcime, 0.42 nm * 0.16 nm) zeolites. Encapsulation was achieved via direct hydrothermal synthesis for SOD and GIS using metal precursors stabilized by ammonia or organic amine ligands, which prevent their decomposition or precipitation as colloidal hydroxides at the conditions of hydrothermal synthesis (<380 K) and favor interactions between metal precursors and incipient aluminosilicate nuclei during self-assembly of microporous frameworks. The synthesis of ANA requires higher crystallization temperatures (~415 K) and high pH (>12), thereby causing precipitation of even ligand-stabilized metal precursors as hydroxides. As a result, encapsulation was achieved by the recrystallization of metal clusters containing GIS into ANA, which retained these metal clusters within voids throughout the GIS-ANA transformation. PMID- 23016947 TI - Growth requirements and chromosomal instability of induced pluripotent stem cells generated from adult canine fibroblasts. AB - In mice and humans, it has been shown that embryonic and adult fibroblasts can be reprogrammed into pluripotency by introducing 4 transcription factors, Oct3/4, Klf4, Sox2, and c-Myc (OKSM). Here, we report the derivation of induced pluripotent stem cells (iPSCs) from adult canine fibroblasts by retroviral OKSM transduction. The isolated canine iPSCs (ciPSCs) were expanded in 3 different culture media [fibroblast growth factor 2 (FGF2), leukemia inhibitory factor (LIF), or FGF2 plus LIF]. Cells cultured in both FGF2 and LIF expressed pluripotency markers [POU5F1 (OCT4), SOX2, NANOG, and LIN28] and embryonic stem cell (ESC)-specific genes (PODXL, DPPA5, FGF5, REX1, and LAMP1) and showed strong levels of alkaline phosphatase expression. In vitro differentiation by formation of embryoid bodies and by directed differentiation generated cell derivatives of all 3 germ layers as confirmed by mRNA and protein expression. In vivo, the ciPSCs created solid tumors, which failed to reach epithelial structure formation, but expressed markers for all 3 germ layers. Array comparative genomic hybridization and chromosomal fluorescence in situ hybridization analyses revealed that while retroviral transduction per se did not result in significant DNA copy number imbalance, there was evidence for the emergence of low-level aneuploidy during prolonged culture or tumor formation. In summary, we were able to derive ciPSCs from adult fibroblasts by using 4 transcription factors. The isolated iPSCs have similar characteristics to ESCs from other species, but the exact cellular mechanisms behind their unique co-dependency on both FGF2 and LIF are still unknown. PMID- 23016948 TI - Controls on soluble Pu concentrations in PuO2/magnetite suspensions. AB - Time-dependent reduction of PuO(2)(am) was studied over a range of pH values in the presence of aqueous Fe(II) and magnetite (Fe(3)O(4)) nanoparticles. At early time frames (up to 56 days) very little aqueous Pu was mobilized from PuO(2)(am), even though measured pH and redox potentials, coupled to equilibrium thermodynamic modeling, indicated the potential for significant reduction of PuO(2)(am) to relatively soluble Pu(III). Introduction of Eu(III) or Nd(III) to the suspensions as competitive cations to displace possible sorbed Pu(III) resulted in the release of significant concentrations of aqueous Pu. However, the similarity of aqueous Pu concentrations that resulted from the introduction of Eu(III)/Nd(III) to suspensions with and without magnetite indicated that the Pu was solubilized from PuO(2)(am), not from magnetite. PMID- 23016950 TI - Does the neurobiology of migraine make migraine patients "difficult"? PMID- 23016949 TI - Prophylactic ranitidine treatment in critically ill children--a population pharmacokinetic study. AB - AIMS: To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. METHODS: Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. RESULTS: A one compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h(-1) for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h(-1) and 27.5%, respectively. No significant relationship was found between age and weight corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. CONCLUSIONS: Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary. PMID- 23016951 TI - Plasma proteomics shows an elevation of the anti-inflammatory protein APOA-IV in chronic equine laminitis. AB - BACKGROUND: Equine laminitis is a devastating disease that causes severe pain in afflicted horses and places a major economic burden on the horse industry. In acute laminitis, the disintegration of the dermal-epidermal junction can cause the third phalanx to detach from the hoof wall, leaving the horse unable to bear weight on the affected limbs. Horses that survive the acute phase transition into a chronic form of laminitis, which is often termed "founder". Some evidence suggests that chronic laminar inflammation might be associated with alterations in the endocrine and immune systems. We investigated this broad hypothesis by using DIGE to assess global differences in the plasma proteome between horses with chronic laminitis and controls. RESULTS: We identified 16 differentially expressed proteins; the majority of these were involved in the interrelated coagulation, clotting, and kininogen cascades. Clinical testing of functional coagulation parameters in foundered horses revealed a slight delay in prothrombin (PT) clotting time, although most other indices were within normal ranges. Upregulation of the intestinal apolipoprotein APOA-IV in horses with chronic laminitis was confirmed by western blot. CONCLUSIONS: Our results support the hypothesis that localized laminar inflammation may be linked to systemic alterations in immune regulation, particularly in the gastrointestinal system. Gastrointestinal inflammation has been implicated in the development of acute laminitis but has not previously been associated with chronic laminitis. PMID- 23016953 TI - Does a positive response to spermatic cord block predict response to microdenervation of the spermatic cord for chronic scrotal content pain? AB - INTRODUCTION: Microdenervation of the spermatic cord (MDSC) has been demonstrated to be an effective treatment for men with intractable scrotal content pain. AIM: This study evaluates the correlation between a positive response to a spermatic cord block with local anesthetic and the subsequent surgical outcome following MDSC. MAIN OUTCOME MEASURES: Pre- and post-cord block pain and pre- and post-MDSC pain. METHODS: A retrospective review of 74 patients (77 testicular units) who underwent MDSC from 2006 to 2010 was performed. Pre- and post-spermatic cord block pain scores based on a 0-10 visual analog scale (VAS) were compared with pre- and post-MDSC pain scores. A positive response to the block was defined as greater than or equal to 50% temporary reduction of pain based on VAS. RESULTS: The average patient age was 42 years with a mean follow-up of 10 months. The mean duration of symptoms before surgery was 69 months. Mean pre-cord block pain score was 8 with an 89% average decrease in pain following the block. Mean post-MDSC pain score was 2 with an average decrease of 73%. The level of temporary improvement from the cord block appeared to be a useful predictor of sustained improvement with MDSC (P = 0.05). Positive response to spermatic cord block was an independent predictor of MDSC response (P = 0.03). CONCLUSIONS: Men with chronic orchialgia who have a positive response to a spermatic cord block are likely to have durable and complete resolution of symptoms after undergoing MDSC. The amount of pain relief obtained after the cord block correlates with pain relief after undergoing a MDSC. Men with chronic orchialgia who desire surgical correction should undergo a preoperative spermatic cord block as part of their complete evaluation. The result of the cord block can help guide the practitioner and the patient toward definitive surgical management via MDSC. PMID- 23016952 TI - 14-Alkoxy- and 14-acyloxypyridomorphinans: MU agonist/delta antagonist opioid analgesics with diminished tolerance and dependence side effects. AB - In the search for opioid ligands with mixed functional activity, a series of 5' (4-chlorophenyl)-4,5alpha-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects. PMID- 23016954 TI - The history of blood transfusion prior to the 20th century--part 2. AB - Although there are a number of descriptions of 'blood infusion' in antiquity, it was the publication of the discovery of the circulation of blood in 1628 by William Harvey and the work of Christopher Wren and Robert Boyle in 1663 on the infusion of different materials into dogs that paved the way to the possible practical attempts at actual blood transfusion. Although these early experiments, principally by Richard Lower in England and Jean Denis in France provided valuable information regarding inter-species incompatibility and the problems of blood coagulation, it was not until the work of James Blundell in the early part of the 19th century that blood transfusion was used as a means of blood replacement. However, blood transfusion was not to become an accepted therapeutic possibility until the discovery of practical anticoagulation and the ABO blood groups at the start of the 20th century. PMID- 23016955 TI - The novel HLA-A*03:143 allele, identified by sequence-based typing in an Italian family. AB - HLA-A*03:143 has one nucleotide change from A*03:01: 01:01 at nt 406 from G to C, resulting in an amino acid change at codon 112 of exon 3 from Gly to Arg. PMID- 23016956 TI - Effectiveness of esomeprazole-based triple therapy of H. pylori in young patients in Japan. PMID- 23016957 TI - Nutritional status and clinical outcome of children on continuous renal replacement therapy: a prospective observational study. AB - BACKGROUND: No studies on continuous renal replacement therapy (CRRT) have analyzed nutritional status in children. The objective of this study was to assess the association between mortality and nutritional status of children receiving CRRT. METHODS: Prospective observational study to analyze the nutritional status of children receiving CRRT and its association with mortality. The variables recorded were age, weight, sex, diagnosis, albumin, creatinine, urea, uric acid, severity of illness scores, CRRT-related complications, duration of admission to the pediatric intensive care unit, and mortality. RESULTS: The sample comprised 174 critically ill children on CRRT. The median weight of the patients was 10 kg, 35% were under percentile (P) 3, and 56% had a weight/P50 ratio of less than 0.85. Only two patients were above P95. The mean age for patients under P3 was significantly lower than that of the other patients (p = 0.03). The incidence of weight under P3 was greater in younger children (p = 0.007) and in cardiac patients and in those who had previous chronic renal insufficiency (p = 0.047). The mortality analysis did not include patients with pre-existing renal disease. Mortality was 38.9%. Mortality for patients with weight < P3 was greater than that of children with weight > P3 (51% vs 33%; p = 0.037). In the univariate and multivariate logistic regression analyses, the only factor associated with mortality was protein-energy wasting (malnutrition) (OR, 2.11; 95% CI, 1.067-4.173; p = 0.032). CONCLUSIONS: The frequency of protein energy wasting in children who require CRRT is high, and the frequency of obesity is low. Protein-energy wasting is more frequent in children with previous end stage renal disease and heart disease. Underweight children present a higher mortality rate than patients with normal body weight. PMID- 23016958 TI - An exploratory study of the perceived impact of health problems of landmine/UXO victims versus another disability group. AB - BACKGROUND: The purpose of this exploratory study is to pilot a biopsychosocial instrument called the Perceived Impact of Problem Profile (PIPP) on a cohort of landmine/Unexploded Ordnance (UXO) victims with lower limb disability versus a cohort of persons with similar disability due to other trauma or medical causes. The aim is to provide greater understanding of the psychosocial impact of landmine/UXO injury to inform victim assistance a interventions within Lao PDR. METHODS: This study employs a mixed methods design, which involved piloting the PIPP instrument through an interviewer administered questionnaire and demographic questionnaire. Fifty one participants were interviewed in both urban and rural locations within Lao PDR. RESULTS: An analysis of the data reveals significant differences in perceived impact for pain, anxiety and how recently the injury/illness occurred. Both groups complained of high levels of anxiety and depression; landmine/UXO victims who complained of anxiety and depression reported a much greater impact on life satisfaction and mood. CONCLUSION: The perceived impact of the disability is greatest on psychosocial factors for both cohorts, but especially in landmine/UXO victims emphasising the need to focus on improving psychosocial interventions for landmine/UXO victims within Victim assistance programmes in Lao PDR. PMID- 23016959 TI - Single carbon fiber decorated with RuO2 nanorods as a highly electrocatalytic sensing element. AB - We demonstrate highly efficient electocatalytic activities of single crystalline RuO(2) nanorods grown on carbon fiber (CF), i.e., RuO(2) nanorod-CF hybrid microelectrode, prepared by a simple thermal annealing process from the Ru(OH)(3) precursor at 300 degrees C. The general electrochemical activity of a RuO(2) nanorod-CF microelectrode represents faster electron transfer for the [Fe(CN)(6)](3-/4-) couple than that of the bare CF microelectrode which are confirmed from the cyclic voltammetry (CV) measurement. Also, the amperometric response for the H(2)O(2) oxidation is remarkably facilitated at the RuO(2) nanorod-CF microelectrode by not only the enlarged surface area but the high electrocatalytic activity of the RuO(2) nanorod material itself. Furthermore, a single microelectrode of RuO(2) nanorod-CF exhibits the superior tolerance to Cl( ) ion poisoning unlike Pt-based electrocatalysts, indicating the promising sensor candidate in physiological conditions. PMID- 23016961 TI - Successful treatment of a gravida with acute A type aortic dissection in late gestation. AB - This case report describes a woman at 35 weeks gestation, who presented with an acute type A aortic dissection involving the total aortic arch and descending aorta. She underwent a successful ascending aorta replacement, total arch replacement, and stented elephant trunk implantation at the time of cesarean section with favorable maternal and fetal outcomes. PMID- 23016960 TI - A nicotinic acetylcholine receptor transmembrane point mutation (G275E) associated with resistance to spinosad in Frankliniella occidentalis. AB - High levels of resistance to spinosad, a macrocyclic lactone insecticide, have been reported previously in western flower thrips, Frankliniella occidentalis, an economically important insect pest of vegetables, fruit and ornamental crops. We have cloned the nicotinic acetylcholine receptor (nAChR) alpha6 subunit from F. occidentalis (Foalpha6) and compared the nucleotide sequence of Foalpha6 from susceptible and spinosad-resistant insect populations (MLFOM and R1S respectively). A single nucleotide change has been identified in Foalpha6, resulting in the replacement of a glycine (G) residue in susceptible insects with a glutamic acid (E) in resistant insects. The resistance-associated mutation (G275E) is predicted to lie at the top of the third alpha-helical transmembrane domain of Foalpha6. Although there is no direct evidence identifying the location of the spinosad binding site, the analogous amino acid in the C. elegans glutamate-gated chloride channel lies in close proximity (4.4 A) to the known binding site of ivermectin, another macrocyclic lactone pesticide. The functional consequences of the resistance-associated mutation have been examined in the human nAChR alpha7 subunit. Introduction of an analogous (A272E) mutation in alpha7 abolishes the modulatory effects of spinosad whilst having no significant effect upon activation by acetylcholine, consistent with spinosad having an allosteric mechanism of action. PMID- 23016962 TI - Genetic polymorphisms in ARID5B, CEBPE, IKZF1 and CDKN2A in relation with risk of acute lymphoblastic leukaemia in adults: a Group for Research on Adult Acute Lymphoblastic Leukaemia (GRAALL) study. PMID- 23016963 TI - Aerobic organocatalytic oxidation of aryl aldehydes: flavin catalyst turnover by Hantzsch's ester. AB - The first Dakin oxidation fueled by molecular oxygen as the terminal oxidant is reported. Flavin and NAD(P)H coenzymes, from natural enzymatic redox systems, inspired the use of flavin organocatalysts and a Hantzsch ester to perform transition-metal-free, aerobic oxidations. Catechols and electron-rich phenols are achieved with as low as a 0.1 mol % catalyst loading, 1 equiv of Hantzsch ester, and O(2) or air as the stoichiometric oxidant source. PMID- 23016964 TI - Non-dipping status in arterial hypertension: an overview. AB - Non-dipping is a common pattern of arterial hypertension and it is associated with increased cardiovascular risk. Use of ambulatory blood pressure monitoring, as suggested in recent guidelines, could further increase its prevalence among subjects with hypertension. In this review we discuss assessment, relevance and associated factors. Non-dipping could be addressed through chronotherapy, the use of specific classes of anti-hypertensives, such as renin-angiotensin blockers, or modification of associated factors. However, more data are needed in order to comprehensively estimate factors associated with non-dipping and how they could be modified. PMID- 23016965 TI - Difficult patient loss and physician culture for oncologists grieving patient loss. AB - BACKGROUND: While caring for critically ill and terminal patients can elicit grief symptoms in health care professionals, few studies have examined oncologists' grief over patient loss using a qualitative approach to inquiry. OBJECTIVES: To explore what makes patient loss difficult for oncologists and to explore the context in which these losses were occurring. METHOD: Twenty oncologists were interviewed at three oncology centers in Canada about their experiences of grief over patient loss. Exclusion criteria included never having lost a patient in their care and being unable to speak English. Data was analyzed using the grounded theory method. RESULTS: Oncologists found patient loss particularly difficult for relational reasons including instances where they felt close to patients and their families, when they had a transference to the patient, when patients died young, when they had long-term patients, and when deaths were unexpected. Contextual reasons included when patients and their families were unprepared for death, had unrealistic expectations about cure, when excessive treatments were perceived to be used, when physicians were blamed for the loss, or when families were chaotic or had high needs. Findings further revealed that these losses were occurring within a physician culture that had a stigma around death and dying, viewed emotion as weakness, was focused on cure, and was gendered. CONCLUSIONS: Effective interventions to help oncologists cope with grief must identify the expectation gaps between physicians and patients when it comes to end-of-life care. PMID- 23016966 TI - Supramolecular anchoring of DNA polyplexes in cyclodextrin-based polypseudorotaxane hydrogels for sustained gene delivery. AB - A cyclodextrin-based supramolecular hydrogel system with supramolecularly anchored active cationic copolymer/plasmid DNA (pDNA) polyplexes was studied as a sustained gene delivery carrier. A few biodegradable triblock copolymers of methoxy-poly(ethylene glycol)-b-poly(epsilon-caprolactone)-b-poly[2 (dimethylamino)ethyl methacrylate] (MPEG-PCL-PDMAEMA) with well-defined cationic block lengths were prepared to condense pDNA. The MPEG-PCL-PDMAEMA copolymers exhibit good ability to condense pDNA into 275-405 nm polyplexes with hydrophilic MPEG in the outer corona. The MPEG corona imparted greater stability to the pDNA polyplexes and also served as an anchoring segment when the pDNA polyplexes were encapsulated in alpha-CD-based supramolecular polypseudorotaxane hydrogels. More interestingly, the resultant hydrogels were able to sustain release of pDNA up to 6 days. The pDNA was released in the form of polyplex nanoparticles as it was bound electrostatically to the cationic segment of the MPEG-PCL-PDMAEMA copolymers. The bioactivity of the released pDNA polyplexes at various durations was further investigated. Protein expression level of pDNA polyplexes released over the durations was comparable to that of freshly prepared PEI polyplexes. Being thixotropic and easily prepared without using organic solvent, this supramolecular in situ gelling system has immense potential as an injectable carrier for sustained gene delivery. PMID- 23016967 TI - Efficacy of telaprevir and boceprevir in treatment-naive and treatment experienced genotype 1 chronic hepatitis C patients: an indirect comparison using Bayesian network meta-analysis. AB - BACKGROUND AND AIMS: To indirectly compare the efficacy of telaprevir (TVR) and boceprevir (BOC) combined with peginterferon/ribavirin alpha-2a/2b (PR) in achieving sustained viral response (SVR) in treatment-naive and treatment experienced patients with genotype 1 chronic hepatitis C virus (HCV) infection. METHODS: A systematic literature review was conducted to identify randomized controlled trials reporting the efficacy of PR-based treatment in genotype 1 chronic HCV patients. A Bayesian network meta-analysis was performed on the endpoint of SVR, assuming fixed study effects. For treatment-experienced patients, only previous relapsers and partial responders were included, as no results in prior null responders were available for boceprevir. RESULTS: Eleven publications were included. In treatment-naive patients, the odds ratios (OR) (posterior median [95% credible interval]) for telaprevir (12 weeks + response guided treatment [RGT] 24/48 weeks PR) and boceprevir (24 weeks + RGT 28/48 weeks PR) versus PR were respectively 3.80 (2.78-5.22) and 2.99 (2.23-4.01). The OR for telaprevir versus boceprevir was 1.42 (0.89-2.25), with a probability for telaprevir being more effective (P[OR > 1]) of 0.93. In treatment-experienced patients, the OR of telaprevir (12 weeks + 48 weeks PR) and boceprevir (32 weeks + RGT 36/48 weeks PR) versus PR were respectively 13.11 (7.30-24.43) and 5.36 (2.90-10.30). The OR for telaprevir versus boceprevir was 2.45 (1.02-5.80), with telaprevir having a probability of 0.98 of being more effective. LIMITATIONS: The main limitation of this study is the low number of trials included in the analysis, especially for the treatment-experienced patient population, which only allowed random-effect models to be explored. We tried to identify potential biases due to study heterogeneity. CONCLUSIONS: In the absence of direct comparative head-to-head studies between telaprevir and boceprevir for the treatment of chronic HCV genotype 1 patients, an indirect comparison based on Bayesian network meta-analysis suggests better efficacy for telaprevir than boceprevir in both treatment-naive and treatment-experienced patients. PMID- 23016968 TI - Introduction to the Kowalevsky medal issue. PMID- 23016969 TI - Life of Alexander Onufrievich Kowalevsky (1840-1901). AB - A short description of the life of the famous Russian embryologist and zoologist Alexander O. Kowalevsky is presented, including some rare photos of the scientist. PMID- 23016970 TI - Russian comparative embryology takes form: a conceptual metamorphosis toward "evo devo". AB - This essay recapitulates major paths followed by the Russian tradition of what we refer to today as evolutionary developmental biology ("evo-devo"). The article addresses several questions regarding the conceptual history of evolutionary embryological thought in its particularly Russian perspective: (1) the assertion by the St. Petersburg academician Wolff regarding the possible connections between environmental modifications during morphogenesis and the "transformation" of species, (2) the discovery of shared "principles" underlying animal development by von Baer, (3) the experimental expression of Baer's principles by Kowalevsky and Mechnikoff, (4) Severtsov's theory of phylembryogenesis, (5) Filatov's approach to the study of evolution using comparative "developmental mechanics", and (6) Shmalgausen's concept of "stabilizing" selection as an attempt to elucidate the evolution of developmental mechanisms. The focus on comparative evolutionary embryology, which was established by Kowalevsky and Mechnikoff, still continues to be popular in present-day "evo-devo" research in Russia. PMID- 23016971 TI - Ecological developmental biology: environmental signals for normal animal development. AB - The environment plays instructive roles in development and selective roles in evolution. This essay reviews several of the instructive roles whereby the organism has evolved to receive cues from the environment in order to modulate its developmental trajectory. The environmental cues can be abiotic (such as temperature or photoperiod) or biotic (such as those emanating from predators, conspecifics, or food), and the "alteration" produces a normal, not a pathological, phenotype, that is appropriate for the environment. In addition, symbiotic organisms can produce important signals during normal development. Environmental cues can be obligatory, such that the organism cannot develop without the environmental cue. These cues often permit and instruct the organism to proceed from one developmental stage to another, as when larvae receive cues to settle and undergo metamorphosis from substrates. Such obligatory cues can also be given by symbionts, as when Wolbachia bacteria prevent apoptosis in developing ovaries of some wasps. Other environmental cues can be used facultatively, allowing organisms to follow different developmental trajectories depending on whether the cue is present or not. This can be seen in the temperature-dependent determination of sex in many reptiles and in the determination of thermotolerance in aphids by their symbiotic bacteria. Signaling from the environment is essential in development, and co-development appears to be normative between symbionts and their hosts. Here, one sees the reciprocal induction of gene expression, just as within the embryonic organism. The ability of organisms to respond to environmental cues by producing different phenotypes may be critically important in evolution, and it may be an essential feature that can facilitate or limit evolution. PMID- 23016972 TI - Parallelism, deep homology, and evo-devo. AB - Parallelism has been the subject of a number of recent studies that have resulted in reassessment of the term and the process. Parallelism has been aligned with homology leaving convergence as the only case of homoplasy, regarded as a transition between homologous and convergent characters, and defined as the independent evolution of genetic traits. Another study advocates abolishing the term parallelism and treating all cases of the independent evolution of characters as convergence. With the sophistication of modern genomics and genetic analysis, parallelism of characters of the phenotype is being discovered to reflect parallel genetic evolution. Approaching parallelism from developmental and genetic perspectives enables us to tease out the degree to which the reuse of pathways represent deep homology and is a major task for evolutionary developmental biology in the coming decades. PMID- 23016973 TI - The animal body plan, the prototypic body segment, and eye evolution. AB - Developmental genetics of Drosophila continue to have a great impact on our understanding of evolution. The specification of the body plan involves four conceptual steps: 1) Localization of maternal mRNAs in the egg cytoplasm. 2) Translation of these RNAs and formation of morphogen gradients. 3) Subdivision of the antero-posterior gradient into a repetitive pattern of body segments. 4) Assignment of a specific identity to each segment by the Hox genes. The discovery of the Hox genes has uncovered a universal principle shared by all bilaterians; they serve as master control genes specifying organization along the antero posterior axis. The ancestral arthropods presumably consisted of a series of more or less identical segments, which may be represented by recently discovered precambrian Lobopodia which have a pair of legs and a pair of eyes in each segment. The progressive divergence of Hox genes has led to progressive cephalization and caudalization. From the amino acid sequences of the clustered homeodomains we can deduce that the mesothoracic segment represents the prototype from the more anterior and the more posterior segments evolved. Pax6 has been identified as a master control gene for eye development in all bilaterians. Since Pax6 is involved in eye development in all bilaterian phyla, this argues strongly for a monophyletic origin of the metazoan eye. With the same tool box of transcription factors all the different eye-types can be constructed. PMID- 23016974 TI - Are the anticipatory pathways in lecithotrophic larvae that delay metamorphosis adaptations? (A review). AB - During anticipatory development in lecithotrophic larvae that delay metamorphosis, the growth and differentiation of features of the adult action system continue to develop at a slow pace even though they do not become functional. After metamorphosis occurs, the larger size and advanced development of these components may allow juveniles to initially grow at a faster rate than they normally would. Anticipatory development has been demonstrated in archeogastropods, some solitary ascidians and a hydrozoan. In the gastropod Haliotis and the hydrozoan Phialidium anticipatory development increases the initial growth rate of juveniles. In Haliotis and ascidians all of the larvae of a given female that live long enough exhibit anticipatory development. In Phialidium, the ability of a given female to produce larvae that can exhibit anticipatory development is a maternal polymorphic character. In Haliotis and solitary ascidians that exhibit anticipatory development, it appears to be a slower version of the rapid developmental changes that occur in parts of the adult action system at metamorphosis. In Phialidium, developmental changes in relative sizes of the different presumptive regions of the polyp are slowly altered prior to and independently of metamorphosis. Anticipatory development is not linked to the decrease in the size or nutrient reserves of older larvae but to the length of their larval period. From an evolutionary perspective, the mechanisms that operate during anticipatory development are probably of adaptive significance for lecithotrophic larvae of species that spend variable amounts of time in the water column because of a patchy distribution of appropriate settlement cues. The developmental mechanisms that underlie anticipatory development may have been used during the transition from lecithotrophy to planktotrophy. PMID- 23016976 TI - Evolution of the vertebrate jaw from developmental perspectives. AB - Attainment of the biting jaw is regarded as one of the major novelties in the early history of vertebrates. Based on a comparison between lamprey and gnathostome embryos, evolutionary developmental studies have tried to explain this novelty as changes in the developmental patterning of the mandibular arch, the rostralmost pharyngeal arch, at the molecular and cellular levels. On the other hand, classical theories in the field of comparative morphology assumed the involvement of hypothetical premandibular arch(es) that ancestral animals would have possessed rostral to the mandibular arch, in the transition from agnathan to gnathostome states. These theories are highly biased toward the segmental scheme of the vertebrate head, and the concept of premandibular "arches" is no longer accepted by the current understanding. Instead, the premandibular domain has now become of interest in the understanding of cranial development, especially in its rostral part. As newer theories that consider involvement of the premandibular domain, the neoclassical and heterotopy theories are here compared from evolutionary developmental perspectives, in conjunction with the development of nasal and hypophyseal placodes, in the context of the evolutionary acquisition of the jaw. Given recent advances in understanding of the lamprey development, evolution of the Dlx code is also discussed together with the evolutionary scenario of jaw acquisition. PMID- 23016975 TI - How was the notochord born? AB - More than 550 million years ago, chordates originated from a common ancestor shared with nonchordate deuterostomes by developing a novel type of larva, the "tadpole larva." The notochord is the supporting organ of the larval tail and the most prominent feature of chordates; indeed, phylum Chordata is named after this organ. In this review, we discuss the molecular mechanisms involved in the formation of the notochord over the course of chordate evolution with a special emphasis on a member of T-box gene family, Brachyury. Comparison of the decoded genome of a unicellular choanoflagellate with the genomes of sponge and cnidarians suggests that T-box gene family arose at the time of the evolution of multicellular animals. Gastrulation is a morphogenetic movement that is essential for the formation of two- or three-germ-layered embryos. Brachyury is transiently expressed in the blastopore (bp) region, where it confers on cells the ability to undergo invagination. This process is involved in the formation of the archenteron in all metazoans. This is a "primary" function of Brachyury. During the evolution of chordates, Brachyury gained an additional expression domain at the dorsal midline region of the bp. In this new expression domain, Brachyury served its "secondary" function, recruiting another set of target genes to form a dorsal axial organ, notochord. The Wnt/beta-catenin, BMP/Nodal, and FGF-signaling pathways are involved in the transcriptional activation of Brachyury. We discuss the molecular mechanisms of Brachyury secondary function in the context of the dorsal-ventral (D-V) inversion theory and the aboral-dorsalization hypothesis. Although the scope of this review requires some degree of oversimplification of Brachyury function, it is beneficial to facilitate studies on the notochord formation, a central evolutionary developmental biology problem in the history of metazoan evolution, pointed out first by Alexander Kowalevsky. PMID- 23016977 TI - Heterochrony in somitogenesis rate in a model marsupial, Monodelphis domestica. AB - Marsupial newborns are highly altricial and also show a wide array of shifts in the rate or timing of developmental events so that certain neonatal structures are quite mature. One particularly notable feature is the steep gradient in development along the anterior-posterior axis such that anterior structures are generally well developed relative to posterior ones. Here, we study somitogenesis in the marsupial, Monodelphis domestica, and document two heterochronies that may be important in generating the unusual body plan of the newborn marsupial. First, we demonstrate a 4-fold change in somitogenesis rate along the anterior-posterior axis, which appears to be due to somitogenesis slowing posteriorly. Second, we show that somitogenesis, particularly in the cervical region, initiates earlier in Monodelphis relative to other developmental events in the embryo. The early initiation of somitogenesis may contribute to the early development of the cervical region and forelimbs. Other elements of somitogenesis appear to be conserved. When compared to mouse, we see similar expression of genes involved in the clock and wavefront, and genes of the Wnt, Notch, and fibroblast growth factor (FGF) pathways also cycle in Monodelphis. Further, we could not discern differences in somite maturation rate along the anterior-posterior axis in Monodelphis, and thus rate of maturation of the somites does not appear to contribute to the steep anterior-posterior gradient. PMID- 23016979 TI - Vestiges, rudiments and fusion events: the zebrafish caudal fin endoskeleton in an evo-devo perspective. AB - The vertebral column results from a controlled segmentation process associated with two main structures, the notochord and the somites. Pathological fusion of vertebral bodies can result from impaired segmentation during embryonic development or occur postnatally. Here, we explore the process of formation and subsequent fusion of the caudalmost vertebral bodies in zebrafish, where fusion is a normal process, mechanically required to support the caudal fin. To reveal whether the product of fusion is on an evolutionary or a developmental scale, we analyze the mode of formation of vertebral bodies, identify transitory rudiments, and characterize vestiges that indicate previous fusion events. Based on a series of closely spaced ontogenetic stages of cleared and stained zebrafish, parasagittal sections, and detection methods for elastin and mineral, we conclude that the formation of the urostyle involves four fusion events. Although fusion of preural 1 (PU1(+) ) with ural 1 (U1) and fusion within ural 2 (U2(+) ) are no longer traceable during centrum formation (phylogenetic fusion), fusion between the compound centrum [PU1(+) +U1] and U2(+) (ontogenetic fusion) occurs after individualization of the centra. This slow process is the last fusion and perhaps the latest fusion during the evolution of the zebrafish caudal fin endoskeleton. Newly described characters, such as a mineralized subdivision within U2(+) , together with the reinterpretation of known features in an evolutionary developmental context, strongly suggest that the zebrafish caudal fin endoskeleton is made from more fused vertebral bodies than previously assumed. In addition, these fusion events occur at different developmental levels depending on their evolutionary status, allowing the dissection of fusion processes that have taken place over different evolutionary times. PMID- 23016978 TI - A maternally established SoxB1/SoxF axis is a conserved feature of chordate germ layer patterning. AB - Despite deep evolutionary roots in the metazoa, the gene regulatory network driving germ layer specification is surprisingly labile both between and within phyla. In Xenopus laevis, SoxB1- and SoxF-type transcription factors are intimately involved in germ-layer specification, in part through their regulation of Nodal signaling. However, it is unclear if X. laevis is representative of the ancestral vertebrate condition, as the precise roles of SoxF and SoxB1 in germ layer specification vary among vertebrates, and there is no evidence that SoxF mediates germ-layer specification in any invertebrate. To better understand the evolution of germ-layer specification in the vertebrate lineage, we analyzed the expression of soxB1 and soxF genes in embryos and larvae of the basal vertebrate lamprey, and the basal chordate amphioxus. We find that both species maternally deposit soxB1 mRNA in the animal pole, soxF mRNA in the vegetal hemisphere, and zygotically express soxB1 and soxF throughout nascent ectoderm and mesendoderm, respectively. We also find that soxF is excluded from the vegetalmost blastomeres in lamprey and that, in contrast to vertebrates, amphioxus does not express soxF in the oral epithelium. In the context of recent work, our results suggest that a maternally established animal/vegetal Sox axis is a deeply conserved feature of chordate development that predates the role of Nodal in vertebrate germ-layer specification. Furthermore, exclusion of this axis from the vegetal pole in lamprey is consistent with the presence of an extraembryonic yolk mass, as has been previously proposed. Finally, conserved expression of SoxF in the forming mouth across the vertebrates, but not in amphioxus, lends support to the idea that the larval amphioxus mouth is nonhomologous to the vertebrate mouth. PMID- 23016980 TI - Comparative studies on the structure and development of the venom-delivery system of centipedes, and a hypothesis on the origin of this evolutionary novelty. AB - The venom-injecting forcipules of centipedes represent an evolutionary novelty that appeared in the centipede stem lineage more than 400 Ma. No other lineage of arthropods (or indeed of animals) has evolved claws for injecting venom from a pair of walking legs. However, little is known of the development, ultrastructure, or detailed function of centipede forcipules. Here, we provide comparative structural information on the venom duct apparatus that is the main functional system within each forcipule, based on scanning electron microscopy and transmission electron microscopy studies. We also give comparative developmental information, using DAPI staining, on embryonic forcipules from the four main centipede orders, including Scutigeromorpha. The photographs of Scutigera embryos we present are the first to be published for any species belonging to this order. The structure of the venom apparatus within each forcipule represents a discrete element of the novelty, whose origin requires a special explanation. This is in contrast to the novel external shape of the forcipules, which can be arrived at gradually by a series of changes from the starting point of a standard walking leg. Drawing on a proposed structural homology between venom glands and epidermal glands, we present a hypothesis of how the venom gland and duct may have arisen in evolution. PMID- 23016982 TI - Inactivation kinetics of Cryptosporidium parvum oocysts in a swine waste lagoon and spray field. AB - Because of outbreaks of cryptosporidiosis in humans, some Cryptosporidium spp. have become a public health concern. Commercial swine operations can be a source of this protozoan parasite. Although the species distribution of Cryptosporidium is likely dominated by Cryptosporidium suis , a fraction may be comprised of other Cryptosporidium species infectious to humans such as Cryptosporidium parvum . To better understand the survival dynamics of Cryptosporidium spp., oocysts associated with swine operations, 2 experiments were performed to determine die off rates of C. parvum oocysts in a swine waste lagoon (2009 and 2010) and its spray field (2010 and 2011). Sentinel chambers containing a lagoon effluent suspension of C. parvum oocysts were submerged in the lagoon, and triplicate chambers were removed over time; oocysts were extracted and assayed for viability. For comparative purposes, inactivation rates of Ascaris suum eggs contained in sentinel chambers were also determined. For 2 spray field experiments, air-dried and sieved surface soil was placed in sentinel chambers, hydrated, and inoculated with a lagoon effluent suspension of C. parvum oocysts. Sentinel chambers and control oocysts in PBS contained in microcentrifuge tubes were buried 1.5 cm below the soil surface in 3 blocks. Triplicate chambers and controls were removed over time; oocysts were extracted and assayed for viability. Based on the first order decay equation, days to reach 99% die-off (T(99)) were determined. T(99)-values determined for the 2 lagoon experiments were 13.1 and 20.1 wk, respectively. A T(99)-value for C. parvum in the spray field was significantly longer at 38.0 wk than the control oocysts in PBS at 29.0 wk. The waste lagoon and spray field system of manure management at this large scale farrowing operation appeared to reduce the load of C. parvum oocysts before they can be hydrologically transported off the operation and reduces their likelihood of contaminating surface waters and threatening public health. PMID- 23016983 TI - Tandem metal-coordination copolymerization and organocatalytic ring-opening polymerization via water to synthesize diblock copolymers of styrene oxide/CO2 and lactide. AB - Selective transformation of carbon dioxide and epoxides into degradable polycarbonates (CO(2)-based copolymer) has been regarded as a most promising green polymerization process. Although tremendous progress has been made during the past decade, very few successful examples have been reported to synthesize well-defined block copolymers to expand the scope of these green copolymers. Herein, we report a tandem strategy combining two living polymerization techniques, salenCo(III)X-catalyzed styrene oxide SO/CO(2) copolymerization and ring-opening polymerization of lactide with DBU (1,8-diazabicyclo[5.4.0]undec-7 ene), for the synthesis of poly(styrene carbonate-block-lactide) copolymers. The key to the success of this tandem strategy is the judicious choice of water as the chain transfer and/or chain terminator reagent, which is added at the end of the salenCo(III)X-catalyzed SO/CO(2) copolymerization to in situ generate hydroxyl groups at the end of the polymer chains. The resulting polycarbonates with -OH end groups can thus be directly used as macroinitiators to subsequently initiate ring-opening polymerization of lactide to synthesize the diblock copolymers. Because of the living polymerization nature of both steps in this tandem strategy, we have demonstrated that the diblock copolymers synthesized possess well-defined structures with narrow molecular weight distributions and controllable lengths of both styrene carbonate and lactide blocks. PMID- 23016984 TI - Dechlorane-related compounds in franciscana dolphin (Pontoporia blainvillei) from southeastern and southern coast of Brazil. AB - Concentrations of Dechlorane (Dec) 603 (0.75 ng/g lipid weight (lw); mean) and Dec 602 (0.38 ng/g lw; mean) were quantified in more than 95% of the franciscana (Pontoporia blainvillei) dolphin samples, whereas the frequency of detection decreased to 75% for Dechlorane Plus (DP) (1.53 ng/g lw, mean). The presence of Chlordene Plus (CP) was also observed (0.13 ng/g lw, mean) in half of the samples. On the contrary, Dec 604, decachloropentacyclooctadecadiene (aCl(10)DP), and undecachloropentacyclooctadecadiene (aCl(11)DP) concentrations were below the limit of quantifications in all cases. To the best of our knowledge, this is the first article reporting the presence of Dec 603, Dec 602, and CP in mammals. For comparative purposes, levels of Mirex, polybrominated diphenyl ethers (PBDEs), and decabromodiphenylethane (DBDPE) are also reported. Considering geographic distribution evaluation together with the strong positive correlations found between DP and PBDEs (r(s) = 0.63; p < 0.01), highly anthropogenic areas were identified as potential sources of these chemicals in this dolphin species. However, local sources for Dec 602, 603, Mirex, CP, and DBDPE were not found indicating that in this case historical use and/or atmospheric transport and deposition may play an important role in their fate. PMID- 23016985 TI - Targeting tyrosine kinase receptors in hepatocellular carcinoma. AB - The recent discoveries of genomic and molecular markers in hepatocellular carcinoma (HCC) have improved the understanding about the complexity of the signal transduction pathways as well as their relevance in normal and liver cancer cells. The identification of the functional repercussions of punctual mutations and crosstalk among cell signaling will promote the identification of specific combinatorial targeted molecular therapies to specific subsets of patients which will allow the development of personalized-based therapy and increase the survival of patients. Numerous molecular targets are in the cross road between oncogenic and anti-apoptotic programs, genetic or epigenetic alterations, which overall may have a similar cellular phenotype. The standard antineoplastic chemotherapeutic regimes based on cytotoxic agents leads to significant side effect and modest response rates, marginal changes in natural history, and toxicities that may impact the quality of life of patients. Different strategies involving gene therapy, targeted antibodies or small molecules have been used to regulate cell death/proliferation signals, as well as angiogenesis in liver tumors. In this sense, Sorafenib recently approved for renal cell carcinoma, represents the first tyrosine kinase inhibitor (TKI) licensed for the treatment of patients with advanced HCC. This review summarizes the current status of molecular receptor TKI-based targeted therapy in HCC driving different pathways involved in cell survival, proliferation, migration, angiogenesis and metastasis, which include the regulation of Raf/MEK/ERK, PI3K/Akt/mTOR, and Jak/STAT cell signaling. The study also provides information about cell signaling crosstalk relevant in tyrosine kinase receptors (TKR)-based systemic therapy in HCC. PMID- 23016986 TI - The preoperative sexual functioning and quality of sexual life in colorectal cancer: a study among patients and their partners. AB - INTRODUCTION: Even though the body of literature on sexual functioning is growing, information on the preoperative sexual functioning and the quality of sexual life after colorectal cancer is lacking. Research focusing on female patients and on partners is also rather scarce. AIM: This cross-sectional study aimed to describe the preoperative sexual functioning, quality of sexual life, and relationship functioning for male and female colorectal cancer patients and their partners. In addition, the mean scores of the patients and partners were compared with mean norm scores. METHODS: Patients diagnosed with colorectal cancer (N = 136) and their partners (N = 106) were recruited before surgical treatment in six Dutch hospitals. MAIN OUTCOME MEASURES: Men completed the International Index of Erectile Functioning, while women completed the Female Sexual Function Index. All partnered participants completed the Golombok-Rust Inventory of Sexual Satisfaction and the Maudsley Marital Questionnaire. The mean scores were compared with mean norm scores derived from the manuals of the questionnaires. RESULTS: All participants were in a heterosexual relationship. Female patients reported a lower quality of sexual life compared with male patients. Male partners reported a lower sexual functioning and a lower quality of sexual life compared with male patients. Colorectal cancer patients and partners (both sexes) reported a lower sexual functioning and a lower quality of sexual life compared with norm populations but scored similar on relationship functioning. CONCLUSION: A lower sexual functioning and a lower quality of sexual life are already reported preoperatively; however, relationship functioning was comparable with a norm population. Therefore, all the impairment seen after treatment should not be solely attributed to the effects of treatment. PMID- 23016987 TI - Psychological factors affecting equine performance. AB - For optimal individual performance within any equestrian discipline horses must be in peak physical condition and have the correct psychological state. This review discusses the psychological factors that affect the performance of the horse and, in turn, identifies areas within the competition horse industry where current behavioral research and established behavioral modification techniques could be applied to further enhance the performance of animals. In particular, the role of affective processes underpinning temperament, mood and emotional reaction in determining discipline-specific performance is discussed. A comparison is then made between the training and the competition environment and the review completes with a discussion on how behavioral modification techniques and general husbandry can be used advantageously from a performance perspective. PMID- 23016988 TI - Music and suicidality: a quantitative review and extension. AB - This article provides the first quantitative review of the literature on music and suicidality. Multivariate logistic regression techniques are applied to 90 findings from 21 studies. Investigations employing ecological data on suicide completions are 19.2 times more apt than other studies to report a link between music and suicide. More recent and studies with large samples are also more apt than their counterparts to report significant results. Further, none of the studies based on experimental research designs found a link between music and suicide ideation, prompting us to do a brief content analysis of 24 suicide songs versus 24 nonsuicide songs from the same album. Using Linguistic Inquiry and Word Count software, we found no difference in the content of the suicide songs and controls, including the percentage of sad words, negative affect, and mentions of death, thus providing an explanation for nonfindings from experimental research. In summary, ecologically based (which capture at-risk persons not in typical school-based samples) and more recent investigations (which have used superior or new methodologies) tend to demonstrate a linkage between music and suicidality. Experimental research is needed with a control group of songs from an alternative genre with low suicidogenic content. PMID- 23016989 TI - New trends in peptide-based anti-biofilm strategies: a review of recent achievements and bioinformatic approaches. AB - Antimicrobial peptides (AMPs) have a broad spectrum of activity and unspecific mechanisms of action. Therefore, they are seen as valid alternatives to overcome clinically relevant biofilms and reduce the chance of acquired resistance. This paper reviews AMPs and anti-biofilm AMP-based strategies and discusses ongoing and future work. Recent studies report successful AMP-based prophylactic and therapeutic strategies, several databases catalogue AMP information and analysis tools, and novel bioinformatics tools are supporting AMP discovery and design. However, most AMP studies are performed with planktonic cultures, and most studies on sessile cells test AMPs on growing rather than mature biofilms. Promising preliminary synergistic studies have to be consubstantiated and the study of functionalized coatings with AMPs must be further explored. Standardized operating protocols, to enforce the repeatability and reproducibility of AMP anti biofilm tests, and automated means of screening and processing the ever-expanding literature are still missing. PMID- 23016990 TI - Efficacy of an internet-based tool for improving physician knowledge of chronic kidney disease: an observational study. AB - BACKGROUND: Early recognition and management of chronic kidney disease (CKD) are associated with better outcomes. Internal medicine residency should prepare physicians to diagnose and manage CKD. METHODS: To examine whether residency training and program characteristics were associated with CKD knowledge and investigate the effectiveness of an internet-based training module in improving CKD knowledge, we analyzed data from CKD training modules administered annually to U.S. internal medicine residents from July 1, 2005 to June 30, 2009. Baseline CKD knowledge was assessed using pre-tests. The modules' effectiveness was evaluated by post-tests. Comparisons were performed using X2 tests and paired t tests. RESULTS: Of 4,702 residents, 38%, 33%, and 29% were program year (PGY)-1, PGY-2, and PGY-3, respectively. Baseline CKD knowledge was poor, with mean pre test scores of 45.1-57.0% across the four years. The lowest pre-test performance was on CKD recognition. Pre-test scores were better with higher training levels (P-trend < 0.001 except 2005-2006 [P-trend = 0.35]). Affiliation with a renal fellowship program or program location within a region of high end-stage kidney disease prevalence was not associated with better baseline CKD knowledge. Completion of the CKD module led to significant improvements from pre- to post test scores (mean improvement 27.8% [SD: 21.3%] which were consistent from 2005 to 2009. CONCLUSIONS: Knowledge of diagnosis and management of CKD improves during residency training but remains poor among graduating residents. Web-based training can be effective in educating physicians on CKD-related issues. Studies are needed to determine whether knowledge gained from such an intervention translates to improved care of CKD patients. PMID- 23016991 TI - Do elderly intensive care unit patients receive less intensive care treatment and have higher mortality? AB - BACKGROUND: The number of elderly (>= 80 years) will increase markedly in Norway over the next 20 years, increasing the demand for health-care services, including intensive care. The aims of this study were to see if intensive care unit (ICU) resource use and survival are different for elderly ICU patients than for younger adult ICU patients. MATERIALS AND METHODS: A retrospective cohort study comparing ICU patients between 50 and 79.9 years (Group I) with patients over 80 years (Group II) registered in the Norwegian Intensive Care Registry from 2006 to 2009. A subgroup analysis of 5-year age groups was performed. RESULTS: A total of 27,921 patients were analysed. The ICU/hospital mortalities were 14.3%/21.4% (Group I) and 19.8%/32.4% (Group II). Overall mortality increased with increasing age, and hospital mortality rate increased more than ICU mortality. The observed difference in admission categories could not explain the significant difference in median length of stay (LOS), 2.3 days (Group I) vs. 2.0 days (Group II). The elderly received less mechanical ventilatory support (40.6% vs. 56.1%) and had shorter median ventilatory support time, 0.8 days vs. 1.9 days. Median LOS dropped from around 80 years on, ventilator support time from around 65-70 years. CONCLUSION: Octogenarians had shorter ICU stays, had higher overall mortality, had a shift of dying at the ward rather than in the ICU, and received less and shorter mechanical ventilatory support. PMID- 23016992 TI - Metaproteome analysis and molecular genetics of rat intestinal microbiota reveals section and localization resolved species distribution and enzymatic functionalities. AB - The digestion of food ingredients depends on the action of the gut microbiota and has a significant influence on the health, especially in the case of metabolic diseases, of the host organism. Despite the relevance of the structure and functionalities in the microbiota for the metabolism of the host, the spatial resolution of microbial consortia and the functionalities in the different gut sections of the rat are mostly unknown. Since there are suitable rat models for human metabolic diseases, the microbiota of the rat is of special interest. Samples along the intestinal tract of rats were investigated using metaproteomics and 16S rRNA gene pyrosequencing. The procedures for harvesting bacteria from the mucus and the content of the gut sections and feces were optimized leading to 2802 nonredundant bacterial protein groups in total that were assigned to spectra measured by liquid chromatography-tandem mass spectrometry. The majority of 16S rRNA genes and protein groups belonged to members of Firmicutes, Bacteroidetes and Proteobacteria. The functionalities in the enzyme repertoire were compared between the mucus and the content of the large intestine sections and the feces samples. This spatial resolution allowed pinpointing changes in the community to specific metabolic capacities like carbohydrate transport and energy conservation. The results showed that the mere analysis of feces samples reflects the functions of the gut microbiota only to a minor extent and sheds light on the metabolic interchange between the microbiota and the host organism. PMID- 23016993 TI - Effect of cosputtering and sample rotation on improving C60(+) depth profiling of materials. AB - In the past decade, buckminsterfullerene (C(60))-based ion beams have been utilized in surface analysis instruments to expand their application to profiling organic materials. Although it had excellent performance for many organic and biological materials, its drawbacks, including carbon deposition, carbon penetration, continuous decay of the sputtering rate, and a rough sputtered surface, hindered its application. Cosputtering with C(60)(+) and auxiliary Ar(+) simultaneously and sample rotation during sputtering were proposed as methods to reduce the above-mentioned phenomena. However, the improvement from these methods has not been compared or studied under identical conditions; thus, the pros and cons of these methods are not yet known experimentally. In this work, a series of specimens including bulk materials and thin films were used to explore the differences between cosputtering and sample rotation on the analytical results. The results show that both of these methods can alleviate the problems associated with C(60)(+) sputtering, but each method showed better improvement in different situations. The cosputtering technique better suppressed carbon deposition, and could be used to generally improve results, especially with continuous spectra acquisition during sputtering (e.g., dynamic secondary ion mass spectrometry (SIMS) depth profiling). In contrast, for the scheme of sputter-then-acquire (e.g., alternative X-ray photoelectron spectrometry or dual-beam static SIMS depth profiling), a better result was achieved by sample rotation because it resulted in a flatter sputtered surface. Therefore, depending on the analytical scheme, a different method should be used to optimize the experimental conditions. PMID- 23016994 TI - Identification of dihydropyrimidine dehydrogenase as a virulence factor essential for the survival of Entamoeba histolytica in glucose-poor environments. AB - Adaptation to nutritional changes is a key feature for successful survival of a pathogen within its host. The protozoan parasite Entamoeba histolytica normally colonizes the human colon and in rare occasions, this parasite spread to distant organs, such as the liver. E. histolytica obtains most of its energy from the fermentation of glucose into ethanol. In this study, we were intrigued to know how this parasite reacts to changes in glucose availability and we addressed this issue by performing a DNA microarray analysis of gene expression. Results show that parasites that were adapted to growth in absence of glucose increased their virulence and altered the transcription of several genes. One of these genes is the dihydropyrimidine dehydrogenase (DPD), which is involved in degradation of pyrimidines. We showed that this gene is crucial for the parasite's growth when the availability of glucose is limited. These data contribute to our understanding of the parasite's ability to survive in glucose-poor environments and reveal a new role for the DPD enzyme. PMID- 23016995 TI - Traumatic dental injury with treatment needs negatively affects the quality of life of Brazilian schoolchildren. AB - BACKGROUND: Traumatic dental injury (TDI) has been considered a significant problem in youth, not only because of its consequences to the craniofacial structures but also for its potential impact on the quality of life of affected individuals. AIM: The aim of this study was to investigate the impact of TDI with treatment needs on the oral health-related quality of life (OHRQoL) of South Brazilian schoolchildren. DESIGN: A cross-sectional study was performed in Porto Alegre, Brazil, using a multistage probability sampling strategy. Of 1837 eligible 12-year-old schoolchildren attending public and private schools, 1528 were examined. OHRQoL was assessed by the Brazilian version of the Child Perceptions Questionnaire for 11-to 14-year-old children (CPQ11-14) - 16-item short form. Clinical examination was conducted to assess the presence of TDI in permanent incisors (Children's Dental Health Survey criteria), malocclusion, and dental caries. Parents/legal guardians answered questions on socioeconomic status. Statistical analyses were performed using Poisson regression models. RESULTS: The overall CPQ11-14 score was not associated with TDI. In the functional limitations domain, individuals presenting TDIs with treatment needs experienced significantly higher mean CPQ11-14 than individuals with no TDI or without treatment needs (RR = 1.21; 95% CI = 1.05-1.39), after adjusting for malocclusion, dental caries, gender, and socioeconomic status. No other domains were associated with TDI. CONCLUSIONS: This study revealed that TDI with treatment needs negatively affects the OHRQoL in this population of 12-year-old schoolchildren and that this impact is related to oral functions. PMID- 23016996 TI - Total synthesis of 7',8'-dihydroaigialospirol. AB - A highly convergent total synthesis of 7',8'-dihydroaigialospirol is described. Key steps of the synthesis include a Nozaki-Hiyama-Kishi (NHK) coupling of an iodoalkyne with an advanced phthalide-aldehyde and a remarkable one-pot acid mediated global deprotection/spiroacetalization. PMID- 23016997 TI - FDI Global Caries Initiative phase 2: preparing the profession for change. PMID- 23016998 TI - FDI Global Caries Initiative; implementing a paradigm shift in dental practice and the global policy context. AB - The implementation of a new paradigm for caries management is necessary for the profession to respond effectively to changing population health needs. The FDI Global Caries Initiative (GCI) is a 10 year programme aimed at developing and implementing a new paradigm for caries management, one that would contribute to a common vision of health. The article reviews the global health policy landscape and examines how it might influence and shape the implementation of the GCI. PMID- 23016999 TI - Effect of xylitol versus sorbitol: a quantitative systematic review of clinical trials. AB - OBJECTIVES: This study aimed to appraise, within the context of tooth caries, the current clinical evidence and its risk for bias regarding the effects of xylitol in comparison with sorbitol. METHODS: Databases were searched for clinical trials to 19 March 2011. Inclusion criteria required studies to: test a caries-related primary outcome; compare the effects of xylitol with those of sorbitol; describe a clinical trial with two or more arms, and utilise a prospective study design. Articles were excluded if they did not report computable data or did not follow up test and control groups in the same way. Individual dichotomous and continuous datasets were extracted from accepted articles. Selection and performance/detection bias were assessed. Sensitivity analysis was used to investigate attrition bias. Egger's regression and funnel plotting were used to investigate risk for publication bias. RESULTS: Nine articles were identified. Of these, eight were accepted and one was excluded. Ten continuous and eight dichotomous datasets were extracted. Because of high clinical heterogeneity, no meta-analysis was performed. Most of the datasets favoured xylitol, but this was not consistent. The accepted trials may be limited by selection bias. Results of the sensitivity analysis indicate a high risk for attrition bias. The funnel plot and Egger's regression results suggest a low publication bias risk. External fluoride exposure and stimulated saliva flow may have confounded the measured anticariogenic effect of xylitol. CONCLUSIONS: The evidence identified in support of xylitol over sorbitol is contradictory, is at high risk for selection and attrition bias and may be limited by confounder effects. Future high-quality randomised controlled trials are needed to show whether xylitol has a greater anticariogenic effect than sorbitol. PMID- 23017000 TI - Patient safety and dentistry: what do we need to know? Fundamentals of patient safety, the safety culture and implementation of patient safety measures in dental practice. AB - Although concern for patient safety is inherent to the practice of the health care professions, its transformation into a specific body of knowledge is relatively recent and thus patient safety may be considered as a comparatively 'new' discipline. Its main objectives are to avoid the occurrence of preventable adverse events (accidents, errors and complications) associated with health care and to limit the impact of inevitable adverse events. Despite these simple definitions, patient safety is multifaceted, quite complex in nature and includes many key elements. Thus, it cannot be simply defined as the provision of safe health care or the protection of patients from harm by health care providers because there are economic, fiscal, social, cultural and organisational aspects of a patient safety climate. It is essential for all health care practitioners and health care organisations to become more familiar with the general context of patient safety, to actively participate in efforts to implement patient safety measures in daily practice and to establish a patient safety culture. PMID- 23017001 TI - Oral lesions associated with HIV/AIDS in HIV-seropositive patients attending a counselling and treatment centre in Dar es Salaam. AB - OBJECTIVE: To assess the prevalences and patterns of oral lesions occurring in human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS). METHODS: A cross-sectional study was conducted among 200 people living with HIV/AIDS (PlwHA) who regularly attended a counselling and treatment centre in Dar es Salaam, Tanzania. A questionnaire-guided interview and clinical oral assessment were used. Strict confidentiality and adherence to ethical codes were observed. RESULTS: The mean age of participants was 38.91 years (standard deviation: 10.424; mode: 35 years; median: 37.0 years; range: 15-76 years). Most participants (58.5%) were aware of predispositions towards the occurrence of oral lesions such as oral candidiasis (60.0%) in HIV/AIDS and most of these (72.0%) were aware that the lesions are treatable. Some participants reported occurrences of oral thrush (22.5%) and lip ulcerations (28.5%), although only 47.0% of these had sought medical advice. Examinations revealed that 29.0% of participants had at least one oral lesion associated with HIV/AIDS. Prevalences of the various types of lesion were: 11.5% for herpes simplex; 7.5% for oral candidiasis; 4.0% for oral hairy leukoplakia; 3.5% for Kaposi's sarcoma; 1.5% for dry mouth; 0.5% for angular cheilitis, and 0.5% for acute necrotising ulcerative gingivitis. Herpes simplex and Kaposi's sarcoma were more frequently observed in males (56.5% and 71.4%, respectively), whereas oral candidiasis and dry mouth were observed more often in females (86.7% and 66.7%, respectively) (chi(2) = 16.692, P = 0.016). CONCLUSIONS: Prevalences of oral lesions associated with HIV/AIDS in PlwHA and using antiretroviral therapy are persistent, of moderate intensity and vary according to individual immune status. These patients' level of awareness about oral lesions was satisfactory, but formal medicodental lines of management were not prioritised. Contemporary protocol for the management of oral lesions should be understood and disseminated to the general public by dentists. PMID- 23017002 TI - A cross-sectional survey investigating care of the primary dentition by paediatric dental specialists in Japan and the UK. AB - OBJECTIVE: The aim of this study was to compare treatment decisions in primary dentistry between Japanese and UK-based paediatric dental specialists. METHODS: Four clinical scenarios involving a 6-year-old boy were used to ascertain the clinical opinions of participants. The scenarios presented: (i) a single distal cavity, vital and without pain; (ii) a distal occlusal cavity, vital and without pain; (iii) a large distal occlusal cavity, non-vital and without pain, and (iv) a large distal occlusal cavity, non-vital and painful. Participants were 104 Japanese and 115 UK-based paediatric dental specialists. RESULTS: In the first scenario, some UK specialists showed a preference for vital pulpotomy with a stainless steel crown (10.3% compared with 0.9% in Japan). In the second scenario, Japanese participants were more likely than UK participants to offer traditional restorative care (73.6% vs. 24.1%). In the third scenario, 54.7% of Japanese specialists chose to open the pulp chamber, whereas 51.8% of UK specialists selected non-vital pulpotomy with stainless steel crown. In the final scenario, 74.0% of Japanese specialists chose to open the pulp chamber, whereas 51.8% of UK specialists chose not to offer any treatment other than extraction. CONCLUSIONS: Japanese and UK specialists in paediatric dental care choose different interventions for the same clinical problems. PMID- 23017003 TI - Effects of 0.05% sodium hypochlorite oral rinse on supragingival biofilm and gingival inflammation. AB - OBJECTIVES: This study aimed to evaluate the clinical effects of 0.05% sodium hypochlorite mouth rinse on supragingival biofilm and gingival inflammation. METHODS: The study was performed as a controlled, randomised, investigator blinded, parallel group trial in 40 prison inmates. Following a preparatory period to obtain a plaque- and gingivitis-free dentition, tooth-brushing was substituted for 21 days by supervised twice daily rinsing with either 15 ml of fresh solution 0.05% sodium hypochlorite or 15 ml of distilled water. Clinical outcomes were assessed using the Quigley-Hein Plaque Index (QHPI), the Loe and Silness Gingival Index (L&SGI) and bleeding on probing. Adverse events were evaluated by questionnaire, visual examination and clinical photographs. RESULTS: At day 21, the average QHPI score had increased to 3.82 in the water rinse group and 1.98 in the sodium hypochlorite rinse group. The average L&SGI score had increased to 2.1 in the water rinse group and 1.0 in the sodium hypochlorite rinse group, and the average percentage of sites that bled on probing had increased to 93.1% in the water rinse group and 56.7% in the sodium hypochlorite rinse group. Differences were statistically significant (P = 0.001). A brown extrinsic tooth stain along the gingival margin appeared in 100% of participants in the sodium hypochlorite rinse group and in 35.0% of participants in the water rinse group (P < 0.05). CONCLUSIONS: An oral rinse with 0.05% sodium hypochlorite resulted in significant reductions in supragingival biofilm accumulation and gingival inflammation. Dilute sodium hypochlorite may represent an efficacious, safe and affordable antimicrobial agent in the prevention and treatment of periodontal disease. PMID- 23017004 TI - Total and free available fluoride in toothpastes in Brunei, Cambodia, Laos, the Netherlands and Suriname. AB - OBJECTIVES: This study assessed total and free fluoride concentrations in samples of toothpaste from Brunei, Cambodia, Laos, the Netherlands and Suriname, and investigated the labelling practices of the respective manufacturers. MATERIALS AND METHODS: Convenience samples were bought in the five countries and sent for analysis to the Netherlands. Levels of total and free available fluoride were measured. Details of the information declared on the packaging about type of fluoride and abrasives were recorded, and manufacturing and expiry dates were noted. RESULTS: A total of 119 samples of toothpaste were analysed. With one exception, all samples from the Netherlands complied with ISO (International Organisation for Standardisation) labelling requirements and there were no differences between the fluoride content declared and that found to be present on analysis. In samples purchased in the other countries, sodium monofluorophosphate (SMFP) toothpastes predominantly showed a low percentage of free available fluoride and the majority of toothpastes did not follow standard labelling guidelines. DISCUSSION: This study is not representative of any of the brands analysed, yet it highlights problematic discrepancies in products across countries. These may be related to the lack of a generally accepted methodology for analysing total and free fluoride content, absence of an agreement on the minimum concentration of fluoride required to ensure efficacy, weak regulating institutions that are unable to control labelling and consumer information, as well as a possible influx of counterfeit low-quality toothpaste. CONCLUSIONS: Renewed international focus should be directed towards closing gaps in guidelines and standards. Consumers should use only non-expired toothpaste, which should preferably be silica-based fluoride toothpaste that does not include abrasives containing calcium and that is properly labelled. PMID- 23017005 TI - Preterm children quality of life evaluation: a qualitative study to approach physicians' perception. AB - BACKGROUND: While data for preterm children health-related quality of life are available, there are little data on the perception of health-related quality of life evaluation by physicians who manage preterm children, or its use in real life and decision making. The aim of this qualitative study is to highlight among physicians, themes of reflection about health-related quality of life in extremely preterm children (less than 28 weeks' gestation). METHODS: Focus groups at a French University Hospital with physicians who manage extremely preterm children: obstetricians, intensive care physicians, neonatal physicians and paediatric neurologists. The focus groups allowed the participants to discuss (drawing on their personal experience), three principal topics regarding the health-related quality of life of preterm children: representation, expectations in daily practice and evaluation method. RESULTS: We included fourteen participants in the three focus groups. Many themes emerged from the focus groups: approaches for defining health-related quality of life and difficulties of utilization, the role that health-related quality of life should have in the system of care, the problem of standards and evidence-based decision making. Physicians had difficulties with taking positions regarding this concept. There were no differences by gender, age or seniority, but points of view varied by specialty and type of practice. Physicians who had longer specialized care for extremely preterm children were more sensitive to the impact of preterm complications on health-related quality of life. CONCLUSIONS: This study provides preliminary results about physicians' perspective on the health-related quality of life of extremely preterm children. The themes emerged from the focus groups are classically described in other domains but not all in so clear a way (definition, interests and limits, ethical reflection). This approach was never developed in the field of prematurity with well-knowed consequences on quality of life. These results require to be confirmed on a larger representative sample. The themes and questions of this broad opinion survey will rest on the information issued from our preliminary interviews. PMID- 23017006 TI - The impact of living in rural and urban areas: vitamin D and medical costs in veterans. AB - PURPOSE: Living in a rural region is associated with significant health disparities and increased medical costs. Vitamin D deficiency, which is increasingly common, is also associated with many adverse health outcomes. The purpose of this study was to determine whether rural-urban residence status of veterans was related to vitamin D levels, and to determine if this factor also influenced medical costs/service utilization. Additionally explored was whether vitamin D differences accounted for part of the association between area of residence and medical costs/service utilization. METHODS: Medical records of 9,396 veterans from 6 Veterans Administration Medical Centers were reviewed for variables of interest including county of residence, vitamin D level, medical costs and service utilization, and background variables. Rurality status was classified as large metropolitan, urban, and rural. FINDINGS: The 3 rurality status groups differed significantly in vitamin D levels, with the highest levels observed for urban residents, followed by rural residents, and the lowest for large metro residents. Compared with urban residents, large metro residents were 49% more likely, while rural residents were 20% more likely, to be vitamin D deficient. Both rural and large metro residents had higher medical costs, and they were significantly more likely to be hospitalized. Vitamin D levels explained a statistically significant amount of the relationship between rurality status and medical costs/service utilization. CONCLUSIONS: Vitamin D deficiency may be an additional health disparity experienced by both rural and inner-city veterans, and patients residing in these locations should be considered at increased risk for deficiency and routinely tested. PMID- 23017007 TI - Associations between serotonin transporter polymorphisms and cognitive processing applying the Emo 1-back task. AB - Down regulation of serotonin transporter (5-HTT) expression has been associated with brain function and major depression. The aim of this study was to explore the allelic variation (short and long) of the 5-HTTLPR polymorphism in attention bias associated with top-down processing of emotion. One hundred sixty-two healthy participants underwent genotyping (5-HTTLPR), background interviews, psychological screening, and a computerised test session (The Emo 1-back task). Carriers of the short 5-HTTLPR alleles in the serotonin transporter gene (SLC6A4) demonstrated less accuracy in The Emo 1-back task when presented with successive images of sad or fearful faces, but not for happy or neutral emotional faces. The study suggests an association between 5-HTTLPR variation in the serotonin transporter gene and altered emotion processing. PMID- 23017008 TI - Exploring the interactions of unsaturated glucuronides with influenza virus sialidase. AB - A series of C3 O-functionalized 2-acetamido-2-deoxy-Delta4-beta-D-glucuronides were synthesized to explore noncharge interactions in subsite 2 of the influenza virus sialidase active site. In complex with A/N8 sialidase, the parent compound (C3 OH) inverts its solution conformation to bind with all substituents well positioned in the active site. The parent compound inhibits influenza virus sialidase at a sub-MUM level; the introduction of small alkyl substituents or an acetyl group at C3 is also tolerated. PMID- 23017009 TI - Comment on Gelman and Shalizi. PMID- 23017010 TI - Comparison of the molecular dynamics and calculated binding free energies for nine FDA-approved HIV-1 PR drugs against subtype B and C-SA HIV PR. AB - We report the first account of a comparative analysis of the binding affinities of nine FDA-approved drugs against subtype B as well as the South African subtype C HIV PR (C-SA). A standardized protocol was used to generate the inhibitor/C-SA PR complexes with the relative positions of the inhibitors taken from the corresponding X-ray structures for subtype B complexes. The dynamics and stability of these complexes were investigated using molecular dynamics calculations. Average relative binding free energies for these inhibitors were calculated from the molecular dynamics simulation using the molecular mechanics generalized Born surface area method. The calculated energies followed a similar trend to the reported experimental binding free energies. Postdynamic hydrogen bonding and electrostatic interaction analysis of the inhibitors with both subtypes reveal similar interactions. Most inhibitors show slightly weaker binding affinities for C-SA PR. Molecular dynamics studies demonstrated increased flap movement for C-SA PR, which can perhaps explain the weaker affinities. This study serves as a standardized platform for optimizing the design of future more potent HIV C-SA PR inhibitors. PMID- 23017011 TI - Reliability of quantitative echocardiography in adult sheep and goats. AB - BACKGROUND: Echocardiography is a non-invasive method for assessment of the ovine and caprine heart. Complete reference ranges for cardiac dimensions and time indices for both species are not currently available and reliability of these measurements has not been evaluated. The objectives for this study are to report reliability, normal cardiac dimensions and time indices in a large group of adult sheep and goats.Fifty-one adult sheep and forty adult goats were recruited. Full echocardiographic examinations were performed in the standing unsedated animal. All animals underwent echocardiography four times in a 72-hour period. Echocardiography was performed three times by one author and once by another. Images were stored and measured offline. Technique and measurement repeatability and reproducibility and any differences due to animal or day were evaluated. Reference ranges (mean +/- 2 standard deviations) were calculated for both species. RESULTS: Majority of the images obtained were of good to excellent quality. Image acquisition was straightforward with 5.4% of animals demonstrating a small scanning window. Reliability was excellent for majority of dimensions and time indices. There was less variation in repeatability when compared with reproducibility and differences were greater for technique than for measurements. Dimensions that were less reliable included those for right ventricular diameter and left ventricular free wall. There were many differences in cardiac dimensions between sheep and goats. CONCLUSIONS: This study has demonstrated that specific reference ranges are required for these two species. Repeatability and reproducibility were excellent for the majority of cardiac dimensions and time indices suggesting that this technique is reliable and valuable for examination of clinical cases over time and for longitudinal research studies. PMID- 23017012 TI - Displacement behaviour regulates the experience of stress in men. AB - Behavioural coping strategies represent a key means by which people regulate their stress levels. Attention has recently focused on the potential role in coping of 'displacement behaviour' - activities such as scratching, lip biting and face touching. Increased levels of displacement behaviour are associated with feelings of anxiety and stress; however, the extent to which displacement behaviour, as a short-term behavioural response to emotionally challenging stimuli, influences the subsequent experience of stress remains poorly understood. The aim of this study was to investigate the potential role of displacement behaviour in coping with stress. In a study population of 42 healthy adult men (mean age = 28.09 years, SD = 7.98), we quantified displacement behaviour during a Trier Social Stress Test (TSST), and used self-report questionnaires to assess trait and state anxiety before the TSST, and the experience of stress afterwards. We predicted displacement behaviour would diminish the negative impact of the stressful situation, and hence be associated with lower post-TSST stress levels. Furthermore, we predicted displacement behaviour would mediate the link between state and trait anxiety on the one hand and the experience of stress on the other. Results showed the rate of displacement behaviour was positively correlated with state anxiety but unrelated to trait anxiety, and negatively correlated with the self-reported experience of stress, in agreement with the idea that displacement behaviour has a crucial impact on regulation of stress. Moreover, serial mediation analyses using a bias corrected bootstrapping approach indicated displacement behaviour mediated the relationship between state anxiety and the experience of stress, and that state anxiety and displacement behaviour - in combination, respectively - mediated the link between trait anxiety and experience of stress. These results shed important new light on the function of displacement behaviour, and highlight promising new avenues for research into emotional expression and stress regulation. PMID- 23017013 TI - Mitochondrial thioredoxin-responding off-on fluorescent probe. AB - We synthesized a new probe, Mito-Naph, to visualize mitochondrial thioredoxin (Trx) activity in cells. A fluorescence off-on change is induced by disulfide cleavage of the probe, resulting from a reaction with Trx and subsequent intramolecular cyclization by the released thiolate to give a fluorescent product. By measuring the fluorescence at 540 nm, Trx activity can be detected at nanomolar concentrations (down to 50 nM) well below its physiological levels. The in vitro and in vivo Trx preference of Mito-Naph was demonstrated by fluorometric and confocal microscopic experiments. In vitro kinetic analysis of the disulfide bond cleavage revealed that the second-order rate constant for Trx is (4.04 +/- 0.26) * 10(3) (M s)(-1), approximately 5000 times faster than that for GSH. The inhibition experiments involving PX-12, a selective inhibitor of Trx, also revealed that the emission from Mito-Naph significantly decreased in PX-12 dose dependent manners, both in living cells and in cellular protein extracts. The Trx preference was further supported by an observation that the fluorescence intensity of rat liver extract was decreased according to the Trx depletion by immunoprecipitation. On the basis of these results, it is concluded that Mito Naph preferentially reacts with Trx, compared with other biological thiols containing amino acids in vitro and in vivo. PMID- 23017015 TI - Comment on "determination of neo- and D-chiro-inositol hexakisphosphate in soils by solution (31)P NMR spectroscopy". PMID- 23017014 TI - Role of TrkB expression in rat adrenal gland during acute immobilization stress. AB - Expression of tyrosine receptor kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), is markedly elevated in the adrenal medulla during immobilization stress. Catecholamine release was confirmed in vitro by stimulating chromaffin cells with recombinant BDNF. We investigated the role of TrkB and the localization of BDNF in the adrenal gland during immobilization stress for 60 min. Blood catecholamine levels increased after stimulation with TrkB expressed in the adrenal medulla during 60-min stress; however, blood catecholamine levels did not increase in adrenalectomized rats. Furthermore, expression of BDNF mRNA and protein was detected in the adrenal medulla during 60 min stress. Similarly, in rats undergoing sympathetic nerve block with propranolol, BDNF mRNA and protein were detected in the adrenal medulla during 60 min stress. These results suggest that signal transduction of TrkB in the adrenal medulla evokes catecholamine release. In addition, catecholamine release was evoked by both the hypothalamic-pituitary-adrenal axis and autocrine signaling by BDNF in the adrenal gland. BDNF-TrkB interaction may play a role in a positive feedback loop in the adrenal medulla during immobilization stress. PMID- 23017016 TI - Evolutionary insights into genome-wide nucleosome positioning. AB - A new study takes an evolutionary approach to investigate to what extent nucleosome positioning is determined by underlying sequence or by trans-acting factors. PMID- 23017018 TI - Monoclonal antibodies anti-TGFbeta1 and anti-VEGF inhibit the experimental pleurodesis induced by silver nitrate. AB - BACKGROUND: The mechanisms underlying pleural inflammation and pleurodesis are poorly understood. We hypothesized that the cytokines transforming growth factor beta (TGFbeta1) and vascular endothelial growth factor (VEGF) play a major role in pleurodesis after intrapleural silver nitrate (SN) injection. METHOD: Forty rabbits received intrapleurally 0.5% SN alone or 0.5% SN + anti-TGFbeta1, anti-IL 8, or anti-VEGF. After 28 days, the animals were euthanized and macroscopic pleural adhesions, microscopic pleural fibrosis, and collagen deposition were analyzed for characterization of the degree of pleurodesis (scores 0-4). RESULTS: Scores of pleural adhesions, pleural fibrosis, total collagen, and thin collagen fibers deposition after 28 days were significantly lower for 0.5% SN + anti TGFbeta1 and 0.5% SN + anti-VEGF. Significant correlations were found between macroscopic adhesion and microscopic pleural fibrosis with total collagen and thin collagen fibers. CONCLUSIONS: We conclude that both TGFbeta1 and VEGF, but not IL-8, mediate the pleural inflammatory response and pleurodesis induced by SN. PMID- 23017019 TI - Osteogenic response of human adipose-derived stem cells to BMP-6, VEGF, and combined VEGF plus BMP-6 in vitro. AB - Exogenous addition of three factors-mesenchymal stem cells (MSCs), vascular endothelial growth factor (VEGF), and bone morphogenetic proteins (BMPs)-has proven to be more beneficial than delivery of any single factor for fracture repair in animal models. We studied the osteogenic differentiation of human adipose-derived stem cells (hADSCs) in the presence of VEGF, BMP-6, or VEGF plus BMP-6 to better understand their enhancement of osteoblastic differentiation of MSCs. The VEGF plus BMP-6 group demonstrated an additive effect on the enhancement of mineralization and expression of ALP and Msx2 genes. Unlike VEGF or BMP-6 alone, the combination of VEGF and BMP-6 significantly enhanced the expression of COL1A1, osterix, and Dlx5 genes. The data indicate that a cross talk between VEGF and BMP-6 signaling pathways enhances osteogenic differentiation of hADSCs. PMID- 23017017 TI - Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors. AB - Modafinil may be useful for treating stimulant abuse, but the mechanisms by which it acts to do so are unknown. Indeed, a primary effect of modafinil is to inhibit dopamine transport, which typically promotes rather than inhibits motivated behavior. Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects. One group of rats was trained to self-administer cocaine for 10 days and extinguished, then given priming injections of cocaine to elicit reinstatement. Modafinil (300 mg/kg, intraperitoneal) inhibited reinstated cocaine seeking (but did not alter extinction responding by itself), and this effect was prevented by pre-treatment with bilateral microinjections of the mGluR2/3 antagonist LY-341495 (LY) into nucleus accumbens core. No reversal of modafinil effects was seen after unilateral accumbens core LY, or bilateral LY in the rostral pole of accumbens. Next, we sought to explore effects of modafinil on extracellular glutamate levels in accumbens after chronic cocaine. Separate rats were administered non-contingent cocaine, and after 3 weeks of withdrawal underwent accumbens microdialysis. Modafinil increased extracellular accumbens glutamate in chronic cocaine, but not chronic saline-pre-treated animals. This increase was prevented by reverse dialysis of cystine-glutamate exchange or voltage-dependent calcium channel antagonists. Voltage-dependent sodium channel blockade partly attenuated the increase in glutamate, but mGluR1 blockade did not. We conclude that modafinil increases extracellular glutamate in nucleus accumbens from glial and neuronal sources in cocaine-exposed rats, which may be important for its mGluR2/3-mediated antirelapse properties. PMID- 23017020 TI - Large-scale quantitative assessment of different in-solution protein digestion protocols reveals superior cleavage efficiency of tandem Lys-C/trypsin proteolysis over trypsin digestion. AB - The complete and specific proteolytic cleavage of protein samples into peptides is crucial for the success of every shotgun LC-MS/MS experiment. In particular, popular peptide-based label-free and targeted mass spectrometry approaches rely on efficient generation of fully cleaved peptides to ensure accurate and sensitive protein quantification. In contrast to previous studies, we globally and quantitatively assessed the efficiency of different digestion strategies using a yeast cell lysate, label-free quantification, and statistical analysis. Digestion conditions include double tryptic, surfactant-assisted, and tandem combinatorial Lys-C/trypsin digestion. In comparison to tryptic digests, Lys C/trypsin digests were found most efficient to yield fully cleaved peptides while reducing the abundance of miscleaved peptides. Subsequent sequence context analysis revealed improved digestion performances of Lys-C/trypsin for miscleaved sequence stretches flanked by charged basic and particulary acidic residues. Furthermore, targeted MS analysis demonstrated a more comprehensive protein cleavage only after Lys-C/trypsin digestion, resulting in a more accurrate absolute protein quantification and extending the number of peptides suitable for SRM assay development. Therefore, we conclude that a serial Lys-C/trypsin digestion is highly attractive for most applications in quantitative MS-based proteomics building on in-solution digestion schemes. PMID- 23017021 TI - Prevalence of essential tremor in urban Lagos, Nigeria: a door-to-door community based study. AB - BACKGROUND: Essential tremor (ET) is one of the commonest movement disorders though the prevalence varies globally. There is paucity of data on ET prevalence in sub-Saharan Africa. The study aimed to determine the prevalence of ET in a Nigerian community. METHODS: This door-to-door survey was conducted in two stages. In Stage 1, 3000 randomly selected residents of an urban centre in Lagos, Nigeria, were screened using a questionnaire to detect symptoms of movement disorder. 234 participants who responded positively regarding presence of tremors were rescreened using an ET-specific questionnaire, a face-to-face interview and neurological examination. Diagnosis of ET was based on the Movement Disorders Society (MDS) consensus diagnostic criteria for ET. RESULTS: Of the 3000 participants, forty responded positively to the ET screening questionnaire, of which 36 (19 females and 17 males) had a final diagnosis of ET, giving a crude prevalence of 12 per 1000 (95% CI = 8.1- 15.9). Gender specific prevalence was 10.3 /1000 in males and 14.3/1000 in females. Age specific prevalence increased with advancing age in both sexes. Age adjusted prevalence (WHO New world population) was 23.8 per 1000. CONCLUSIONS: We documented a high prevalence of ET in this study, with typical increasing prevalence with advancing age as previously reported in other populations. PMID- 23017022 TI - Cerebral energy metabolism during induced mitochondrial dysfunction. AB - BACKGROUND: In patients with traumatic brain injury as well as stroke, impaired cerebral oxidative energy metabolism may be an important factor contributing to the ultimate degree of tissue damage. We hypothesize that mitochondrial dysfunction can be diagnosed bedside by comparing the simultaneous changes in brain tissue oxygen tension (PbtO(2)) and cerebral cytoplasmatic redox state. The study describes cerebral energy metabolism during mitochondrial dysfunction induced by sevoflurane in piglets. METHODS: Ten piglets were included, seven in the experimental group (anesthetized with sevoflurane) and three in the control group (anesthetized with midazolam). PbtO(2) and cerebral levels of glucose, lactate, and pyruvate were monitored bilaterally. The biochemical variables were obtained by intracerebral microdialysis. RESULTS: All global variables were within normal range and did not differ significantly between the groups except for blood lactate that was slightly higher in the experimental group. Mitochondrial dysfunction was observed in the group of animals initially anesthetized with sevoflurane. Cerebral glucose was significantly lower in the experimental group than in the control group whereas lactate and lactate/pyruvate ratio were significantly higher. Pyruvate and tissue oxygen tension remained within normal range in both groups. Changes of intracerebral variables indicating mitochondrial dysfunction were present already from the very start of the monitoring period. CONCLUSION: Intracerebral microdialysis revealed mitochondrial dysfunction by marked increases in cerebral lactate and lactate/pyruvate ratio simultaneously with normal levels of pyruvate and a normal PbtO(2). This metabolic pattern is distinctively different from cerebral ischemia, which is characterized by simultaneous decreases in PbtO(2) and intracerebral pyruvate. PMID- 23017023 TI - Evolution of yolk protein genes in the Echinodermata. AB - Vitellogenin genes (vtg) encode large lipid transfer proteins (LLTPs) that are typically female-specific, functioning as precursors to major yolk proteins (MYPs). Within the phylum Echinodermata, however, the MYP of the Echinozoa (Echinoidea + Holothuroidea) is expressed by an unrelated transferrin-like gene that has a reproductive function in both sexes. We investigated egg proteins in the Asterozoa (Asteroidea + Ophiuroidea), a sister clade to the Echinozoa, showing that eggs of the asteroid Parvulastra exigua contain a vitellogenin protein (Vtg). vtg is expressed by P. exigua, a species with large eggs and nonfeeding larvae, and by the related asterinid Patiriella regularis which has small eggs and feeding larvae. In the Asteroidea, therefore, the reproductive function of vtg is conserved despite significant life history evolution. Like the echinozoan MYP gene, asteroid vtg is expressed in both sexes and may play a role in the development of both ovaries and testes. Phylogenetic analysis indicated that a putative Vtg from the sea urchin genome, a likely pseudogene, does not clade with asteroid Vtg. We propose the following sequence as a potential pathway for the evolution of YP genes in the Echinodermata: (1) the ancestral echinoderm produced YPs derived from Vtg, (2) bisexual vtg expression subsequently evolved in the echinoderm lineage, (3) the reproductive function of vtg was assumed by a transferrin-like gene in the ancestral echinozoan, and (4) redundant echinozoan vtg was released from stabilizing selection. PMID- 23017024 TI - Population genetics of cis-regulatory sequences that operate during embryonic development in the sea urchin Strongylocentrotus purpuratus. AB - Despite the fact that noncoding sequences comprise a substantial fraction of functional sites within all genomes, the evolutionary mechanisms that operate on genetic variation within regulatory elements remain poorly understood. In this study, we examine the population genetics of the core, upstream cis-regulatory regions of eight genes (AN, CyIIa, CyIIIa, Endo16, FoxB, HE, SM30 a, and SM50) that function during the early development of the purple sea urchin, Strongylocentrotus purpuratus. Quantitative and qualitative measures of segregating variation are not conspicuously different between cis-regulatory and closely linked "proxy neutral" noncoding regions containing no known functional sites. Length and compound mutations are common in noncoding sequences; conventional descriptive statistics ignore such mutations, under-representing true genetic variation by approximately 28% for these loci in this population. Patterns of variation in the cis-regulatory regions of six of the genes examined (CyIIa, CyIIIa, Endo16, FoxB, AN, and HE) are consistent with directional selection. Genetic variation within annotated transcription factor binding sites is comparable to, and frequently greater than, that of surrounding sequences. Comparisons of two paralog pairs (CyIIa/CyIIIa and AN/HE) suggest that distinct evolutionary processes have operated on their cis-regulatory regions following gene duplication. Together, these analyses provide a detailed view of the evolutionary mechanisms operating on noncoding sequences within a natural population, and underscore how little is known about how these processes operate on cis-regulatory sequences. PMID- 23017025 TI - Characterization of sFRP2-like in amphioxus: insights into the evolutionary conservation of Wnt antagonizing function. AB - Wnt signaling plays a key role in embryonic patterning and morphogenetic movements. The secreted Frizzled-related proteins (sFRPs) antagonize Wnt signaling, but their roles in development are poorly understood. To determine whether function of sFRPs is conserved between amphioxus and vertebrates, we characterized sFRP2-like function in the amphioxus, Branchiostoma belcheri tsingtauense (B. belcheri). As in other species of Branchiostome, in B. belcheri, expression of sFRP2-like is restricted to the mesendoderm during gastrulation and to the anterior mesoderm and endoderm during neurulation. Functional analyses in frog (Xenopus laevis) indicate that amphioxus sFRP2-like potently inhibits both canonical and non-canonical Wnts. Thus, sFRP-2 probably functions in amphioxus embryos to inhibit Wnt signaling anteriorly. Moreover, dorsal overexpression of amphioxus sFRP2-like in Xenopus embryos, like inhibition of Wnt11, blocks gastrulation movements. This implies that sFRP2-like may also modulate Wnt signaling during gastrulation movements in amphioxus. PMID- 23017026 TI - Differential deployment of paralogous Wnt genes in the mouse and chick embryo during development. AB - Genes encoding Wnt ligands are crucial in body patterning and are highly conserved among metazoans. Given their conservation at the protein-coding level, it is likely that changes in where and when these genes are active are important in generating evolutionary variations. However, we lack detailed knowledge about how their deployment has diverged. Here, we focus on four Wnt subfamilies (Wnt2, Wnt5, Wnt7, and Wnt8) in mammalian and avian species, consisting of a paralogous gene pair in each, believed to have duplicated in the last common ancestor of vertebrates. We use three-dimensional imaging to capture expression patterns in detail and carry out systematic comparisons. We find evidence of greater divergence between these subgroup paralogues than the respective orthologues, consistent with some level of subfunctionalization/neofunctionalization in the common vertebrate ancestor that has been conserved. However, there were exceptions; in the case of chick Wnt2b, individual sites were shared with both mouse Wnt2 and Wnt2b. We also find greater divergence, between paralogues and orthologues, in some subfamilies (Wnt2 and Wnt8) compared to others (Wnt5 and Wnt7) with the more highly similar expression patterns showing more extensive expression in more structures in the embryo. Wnt8 genes were most restricted and most divergent. Major sites of expression for all subfamilies include CNS, limbs, and facial region, and in general there were more similarities in gene deployment in these territories with divergent patterns featuring more in organs such as heart and gut. A detailed comparison of gene expression patterns in the limb showed similarities in overall combined domains across species with notable differences that may relate to lineage-specific morphogenesis. PMID- 23017027 TI - Evolution of albinism in cave planthoppers by a convergent defect in the first step of melanin biosynthesis. AB - Albinism, the reduction or loss of melanin pigment, is found in many diverse cave dwelling animals. The mechanisms responsible for loss of melanin pigment are poorly understood. In this study we use a melanogenic substrate assay to determine the position where melanin synthesis is blocked in independently evolved cave planthoppers from Hawaii and Croatia. In this assay, substrates of enzymes responsible for melanin biosynthesis are added to fixed specimens in vitro and their ability to rescue black melanin pigmentation is determined. L tyrosine, the first substrate in the pathway, did not produce melanin pigment, whereas L-DOPA, the second substrate, restored black pigment. Substrates in combination with enzyme inhibitors were used to test the possibility of additional downstream defects in the pathway. The results showed that downstream reactions leading from L-DOPA and dopamine to DOPA-melanin and dopamine-melanin, the two types of insect melanin, are functional. It is concluded that albinism is caused by a defect in the first step of the melanin synthesis pathway in cave adapted planthoppers from widely separated parts of the world. However, Western blots indicated that tyrosine hydroxylase (TH), the only enzyme shown to operate at the first step in insects, is present in Hawaiian cave planthoppers. Thus, an unknown factor(s) operating at this step may be important in the evolution of planthopper albinism. In the cavefish Astyanax mexicanus, a genetic defect has also been described at the first step of melanin synthesis suggesting convergent evolution of albinism in both cave-adapted insects and teleosts. PMID- 23017028 TI - The Paleozoic evolution of the gastropod larval shell: larval armor and tight coiling as a result of predation-driven heterochronic character displacement. AB - Early and middle Paleozoic gastropod protoconchs generally differ strongly from their corresponding adult morphologies, that is, most known protoconchs are smooth and openly coiled, whereas the majority of adult shells are ornamented and tightly coiled. In contrast, larval and adult shells of late Paleozoic gastropods with planktotrophic larval development (Caenogastropoda, Neritimorpha) commonly resemble each other in shape and principle ornamentation. This is surprising because habitat and mode of life of planktonic larvae and benthic adults differ strongly from each other. Generally, late Paleozoic to Recent protoconchs are tightly coiled. This modern type of larval shell resembles the adult shell morphology and was obviously predisplaced onto the larval stage during the middle Paleozoic. The oldest known planktonic-armored (strongly ornamented) larval shells are known from the late Paleozoic. However, smooth larval shells are also common among the studied late Paleozoic gastropods. The appearance of larval armor at the beginning of the late Paleozoic could reflect an increase of predation pressure in the plankton. Although there are counter examples in which larval and adult shell morphology differ strongly from each other, there is statistical evidence for a heterochronic predisplacement of adult characters onto the larval stage. Larval and adult shells are built in the same way, by accretionary secretion at the mantle edge. It is likely that the same underlying gene expression is responsible for that. If so, similarities of larval and adult shell may be explained by gene sharing, whereas differences may be due to different (planktic vs. benthic life) epigenetic patterns. PMID- 23017030 TI - Treatment options to improve anorectal function following rectal resection: a systematic review. AB - AIM: Common problems after rectal resection are loose stools, faecal incontinence, increased frequency and evacuation difficulties, for which there are various therapeutic options. A systematic review was conducted to assess the outcome of treatment options aimed to improve anorectal function after rectal surgery. METHOD: Publications including a therapeutic approach to improve anorectal function after rectal surgery were searched using the following databases: MEDLINE, PubMed, EMBASE, Pedro, CINAHL, Web of Science, PsychInfo and the Cochrane Library. The focus was on outcome parameters of symptomatic improvement of faecal incontinence, evaluation of defaecation and quality of life. RESULTS: The degree of agreement on eligibility and methodological quality between reviewers calculated with kappa was 0.85. Fifteen studies were included. Treatment options included pelvic floor re-education (n=7), colonic irrigation (n=2) and sacral nerve stimulation (SNS) (n=6). Nine studies reported reduced incontinence scores and a decreased number of incontinent episodes. In 10 studies an improvement in resting and squeeze pressure was observed after treatment with pelvic floor re-education or SNS. Three studies reported improved quality of life after pelvic floor re-education. Significant improvement of the Fecal Incontinence Quality of Life Scale was found in three studies after SNS. CONCLUSION: Conservative therapies such as pelvic floor re-education and colonic irrigation can improve anorectal function. SNS might be an effective solution in selected patients. However, methodologically qualitative studies are limited and randomized controlled trials are needed to draw evidence-based conclusions. PMID- 23017031 TI - Editorial. Random RNAi screening data analysis: a call for standardization. PMID- 23017032 TI - Effect of sesamol on the pathophysiological changes induced by surgical menopause in rodents. AB - OBJECTIVE: Estrogen deprivation after menopause is associated with increased oxidative stress. The present study was designed to study the role of sesamol (3,4-methylenedioxyphenol), a phenolic antioxidant and anti-inflammatory molecule, in oxidative stress-induced changes in three major affected organ systems, the central nervous system, the cardiovascular system and the skeletal system in ovariectomized rats, a widely used animal model of menopause. DESIGN: Animals were divided into eight different groups (n = 6-8). Five groups underwent ovariectomy; starting from the 2nd day of ovariectomy, three of these groups received sesamol (2, 4, 8 mg/kg) and the fourth group was administered alpha tocopherol (100 mg/kg) orally for 7 weeks. The fifth ovariectomized group did not receive any drug treatment. Rats in the naive (non-operated) and sham-operated groups did not receive any drug treatment, while the eighth group consisted of naive animals which were treated for 7 weeks with only sesamol 8 mg/kg orally daily. After 7 weeks, animals were subjected to testing of behavioral paradigms (elevated plus maze and Morris water maze for assessment of anxiety and memory, respectively) 24 h after the last dose. After behavioral studies, animals were sacrificed for various biochemical estimations. RESULT: Administration of sesamol (2, 4, 8 mg/kg orally) to ovariectomized rats for 7 weeks significantly and dose dependently improved memory, attenuated anxiety, decreased oxidative stress in brain, improved the serum lipid profile and reduced serum tumor necrosis factor alpha levels when compared with ovariectomized control rats. Similar protective effects were observed in the case of the skeletal system studies. Sesamol increased the bone ash content and the mechanical stress parameters in treated groups. CONCLUSION: The results emphasize the involvement of oxidative stress and inflammation in the development of ovariectomy-induced pathophysiological changes and point towards the therapeutic potential of sesamol in menopausal pathologies. PMID- 23017033 TI - Fluorescence resonance energy transfer mediated large Stokes shifting near infrared fluorescent silica nanoparticles for in vivo small-animal imaging. AB - Fluorescent dye-doped silica nanoparticles are increasingly used for in vivo imaging due to their unique biocompatibility and easy surface modification. However, the utility of existing fluorescent dye-doped silica nanoparticles for in vivo imaging is still limited because most studies are focused on doping single near-infrared (NIR) dyes in the silica matrix, which would cause background and crosstalk between the excitation light and the emitting signals due to the small Stokes shift of the traditional NIR dyes. To address this issue, we present a novel large Stokes shifting NIR fluorescent silica nanoparticles (LSS-NFSiNPs) based on the principle of fluorescence resonance energy transfer. Two highly water-soluble dyes, tris(2,2-bipyridyl)dichlororuthenium(II) hexahydrate (RuBpy) and methylene blue (MB), were chose as the model donor acceptor pair. The LSS-NFSiNPs were prepared by synchronously doping RuBpy and MB in the silica nanoparticles. By optimizing the molar ratio of RuBpy and MB for doping in the silica nanoparticles, the energy transfer from RuBpy to MB occurred in the silica matrix, resulting in a near-infrared fluorescent silica nanoparticles with strong fluorescence and large Stokes shift (>200 nm). As a result, it can effectively help to increase the discrimination of fluorescence signal of interest over other background signals. With a combination of excellent stability, large Stokes shift, and near-infrared spectral properties, this novel LSS-NFSiNPs provides real-time, deep-tissue fluorescent imaging of live animals. More importantly, the LSS-NFSiNPs can also be gradually cleared from the body through the urinary clearance system. We anticipate this design concept can lay a foundation for further development of in vivo optical nanoparticulate contrast toward clinical applications. PMID- 23017034 TI - Asymmetric synthesis of cyclopropanes with a monofluorinated quaternary stereocenter. AB - New chiral fluorinated reagents (N-(dibromofluoroacetyl)oxazolidinones) were easily synthesized and used in an asymmetric cyclopropanation process. The Michael initiated ring closure reaction provided chiral cyclopropanes bearing a fluorinated quaternary stereocenter. Various electron-deficient alkenes can be used to efficiently obtain chiral polysubtituted fluorinated cyclopropanes in good yields. Moderate to very good cis/trans ratios were obtained with a high level of diastereoselectivity for each isomer. PMID- 23017035 TI - Allergic rhinitis as a possible risk factor for malocclusion: a case-control study in children. AB - BACKGROUND: Prolonged oral respiration is known to cause postural alterations, which can lead to dental malocclusions. Allergic rhinitis, a common cause of upper airway obstruction in children, must therefore be seen as a possible risk factor in the development of malocclusions. AIM: Aim of this study was to investigate the association between allergic rhinitis and malocclusions in primary and early-mixed dentition. DESIGN: A case-control study was carried out involving 275 Italian children aged 5-9. The case group and the control group were composed of 125 individuals affected by malocclusions and by 150 healthy patients, respectively. Through a questionnaire, we assessed the presence of professionally diagnosed allergic rhinitis. Data were analysed to identify associations between these variables and the presence of malocclusions. RESULTS: Children with a history of allergic rhinitis had a threefold increased risk to develop one or more dento-skeletal alterations [OR = 3.16; 95% CI (1.79-5.58), P < 0.001]. Statistically significant associations were found between allergic rhinitis and the development of posterior crossbite and increased overjet. No significant association was found for anterior openbite. CONCLUSIONS: Allergic rhinitis is a significant risk factor for the development of malocclusions in general and is associated with the development of posterior crossbite and increased overjet. PMID- 23017036 TI - Annual Research Review: Resilience--clinical implications. AB - BACKGROUND: It is a universal finding that there is huge heterogeneity in people's responses to all kinds of stress and adversity. Resilience is an interactive phenomenon that is inferred from findings indicating that some individuals have a relatively good outcome despite having experienced serious adversities. METHODS: Resilience can only be inferred if there has been testing of environmental mediation of risks and quantification of the degree of risk. The use of 'natural experiments' to test environmental mediation is briefly discussed. The literature is then reviewed on features associated with resilience in terms of (a) those that are neutral or risky in the absence of the risk experience (such as adoption); (b) brief exposure to risks and inoculation effects; (c) mental features (such as planning, self-regulation or a sense of personal agency); (d) features that foster those mental features; (e) turning point effects; (f) gene-environment interactions; (g) social relationships and promotive effects; and (h) the biology of resilience. RESULTS: Clinical implications are considered with respect to (a) conceptual implications; (b) prevention; and (c) treatment. CONCLUSION: Resilience findings do not translate into a clear programme of prevention and treatment, but they do provide numerous leads that focus on the dynamic view of what may be involved in overcoming seriously adverse experiences. PMID- 23017037 TI - The utility of hyperthermia for local recurrence of breast cancer. AB - BACKGROUND: Hyperthermia has long been used in combination with chemotherapy or radiation therapy for the treatment of superficial malignancies, in part due to its sensitizing capabilities. Patients who suffer from superficial recurrences of breast cancer have poor clinical outcomes. Skin metastases may particularly impair the quality of life due to the physical appearance, odor and bleeding. CASE PRESENTATION: A 66-year-old woman underwent mastectomy and axillary lymph node dissection for breast cancer. Nine years post-operatively, local metastases developed in the left axillary area (measuring 5 cm in diameter). Initially the tumor did not respond to radiation therapy and chemotherapy. Therefore, we added hyperthermia combined with them. Eight weeks later, the tumor became nearly flat and the patient noted improved activity in her daily life. CONCLUSION: Hyperthermia may accelerate the antitumor effects of radiation therapy and chemotherapy. This treatment provides an alternative for unresectable breast cancer skin metastases. PMID- 23017038 TI - Guest editorial: Mental health reform: the path of least resistance is no longer an option. PMID- 23017040 TI - Resilience in family members of persons with autism spectrum disorder: a review of the literature. AB - Worldwide, caregivers find caring for children with Autism Spectrum Disorder (ASD) challenging. Family members must manage many aspects of care giving, which is demanding, overwhelming, and can affect the family members' mental health. However learning how to be resilient may help family members overcome the stress and burden associated with caring for a person with ASD. A search was completed in Medline, PsycINFO, Proquest, Web of Science, and CINAHL using the key words "autism," "caregivers," "mothers," and "fathers," alone and in combination. Inclusion criteria were English language articles reporting studies with samples of children with ASD, as distinct from children with other intellectual or developmental disabilities. Fifty-eight articles that met these inclusion criteria were summarized and, from those, the authors selected 22 articles that included indicators of resilience. This integrative review highlights current research on resilience in adult family members of persons with ASD. Indicators of resilience, risk factors, protective factors, and outcomes of resilience were identified. The review indicates that parents of children with ASD who possess indicators of resilience are better able to manage the adversity associated with caring for children with ASD. Thus, enhancing resilience among family members of persons with autism may be beneficial to both the caregivers and care recipients. PMID- 23017039 TI - Correlates of depressed mood among young stimulant-using homeless gay and bisexual men. AB - Homeless gay and bisexual (G/B) men are at risk for suicide attempts and have high risk of depressed mood, defined as elevated level of depressive symptoms. This study describes baseline socio-demographic, cognitive, psychosocial, and health- and drug-related correlates of depressed mood in 267 stimulant-using homeless G/B young men who entered a study designed to reduce drug use. G/B men without social support were 11 times more likely to experience depressed mood than their counterparts who had support; those who reported severe body pain were almost six times more likely to report depressed mood than those without pain. Other factors that increased risk of depressed mood included being homeless in the last four months, injecting drugs, reporting poor or fair health status, and high levels of internalized homophobia. This study is one of the first studies to draw a link between pain experienced and depressed mood in homeless young G/B men. Understanding the correlates of depressed mood among homeless G/B young men can help service providers design more targeted treatment plans and provide more appropriate referrals to ancillary care services. PMID- 23017041 TI - Implementing a competence framework for administering medication: reporting the experiences of mental health nurses and students in the UK. AB - Medicine administration is a high risk activity that most nurses undertake frequently. In this paper, the views of registered mental health nurses and final year student nurses are evaluated about the usefulness of the Medicines with Respect Assessment of the Administration of Medicines Competency Framework. A questionnaire using 22 items with closed and open response questions was distributed to 827 practising mental health nurses and 44 final year mental health nursing students. This article presents a content analysis of written replies to the open response questions. Four overlapping themes were identified in response to the open questions posed in the survey: (1) reasons for undertaking the Medicines with Respect Framework; (2) positive aspects; (3) negative aspects; and (4) service user benefits. PMID- 23017042 TI - Adverse neuropsychiatric events associated with varenicline use in veterans: a case series. AB - Varenicline represents a major advance in the treatment of nicotine addiction and has been shown to be safe and effective to promote abstinence. However, in a small number of patients, neuropsychiatric adverse events and worsening of underlying psychiatric conditions have been reported. As the veteran population has higher rates of co-morbid psychiatric conditions and nicotine dependence this population may be at higher risk for serious adverse effects to varenicline warranting close monitoring. Herein we report seven cases of varenicline associated neuropsychiatric adverse events and describe an institutional response to adequately monitor patients to ensure safety and efficacy. PMID- 23017043 TI - Predictive validity and psychiatric nursing staff's perception of the clinical usefulness of the French version of the Dynamic Appraisal of Situational Aggression. AB - This study seeks to evaluate the predictive validity of the French version of the Dynamic Appraisal of Situational Aggression (DASAfr) and psychiatric nurses' perceptions of the clinical usefulness of the scale. The study was conducted in a 12-bed psychiatric intensive care unit in a large adult general psychiatric hospital. We found that the total score on the DASAfr has acceptable predictive accuracy for aggression against others and against staff and for seclusion with restraints; predictive accuracy was poorer for aggression against objects. Moreover, the nurses though the scale would be useful to their practice; and, indeed, the team still uses the DASAfr. PMID- 23017044 TI - Physical activities and their importance to the health of people with severe mental illness in Sweden. AB - It is well known that people with severe mental illness often suffer from constant fatigue, insomnia, and somatic complaints that are too often overlooked. In addition, these persons die earlier in life than others in the population. The purpose of this study was to investigate patients' descriptions of activities and the importance of these activities for their health. Eight persons living in their own home were interviewed about both their views about exercise and their exercising activities. Two themes emerged: Getting Control over One's Life and The Need for Contact with Family & Friends. All of the informants were aware of the importance of physical activity to feel good. The informants described three different forms of activities: daily activities in the home, activities in a rehabilitation centre, and various forms of jogging. These different forms of activity were important to the informants since they reduced their anxiety and stress. PMID- 23017045 TI - Resourcefulness training for grandmothers raising grandchildren: is there a need? AB - Grandmothers raising grandchildren may experience stress that adversely affects their health and, thus, they may benefit from interventions to promote resourcefulness. Before conducting definitive tests about the effectiveness of resourcefulness training (RT), it is essential to determine the need for the training. This study of 126 grandmothers examined baseline resourcefulness, attrition rates from the resourcefulness training, and perceived need for RT. Baseline resourcefulness scores indicated that 72% of the grandmothers had more than a moderate need for RT. Reasons for attrition were unrelated to perceived need. After receiving RT, 88% perceived that they needed it. The results support testing RT effectiveness as the next step. PMID- 23017046 TI - Psychometric properties of the Center for Epidemiologic Studies Depression Scale in African American and Black Caribbean US adults. AB - A 12-item version of the 20-item Center for Epidemiological Studies-Depression (CES-D) Scale was not validated in Black US adults but demonstrated strong psychometrics in other populations. Using data from the National Survey of American Life (n = 4,815), the psychometric properties of the scale were tested in African American and Black Caribbean adults. When compared with the DSM-IV-TR criteria for Major Depressive Disorder (MDD) and Dysthymia, most items in the CES D Scale focus on depressed mood, providing evidence for content validity. Construct validity was questionable in African American and Black Caribbean men. The CES-D scores of African American men who met the DSM-IV-TR (APA, 2000) criteria for Dysthymia were not significantly different than African American men who did not (t = 1.9, p = .109). The CES-D scores of Black Caribbean men who met the DSM-IV-TR criteria for MDD were not significantly different than Black Caribbean men who did not (t = 1.6, p = .198), and none of the Black Caribbean men met the DSM-IV-TR criteria for Dysthymia. For the item, "I felt like everything I did was an effort," all groups had item-to-total correlations and inter-item correlations below .30. After eliminating this item, the alpha for the remaining 11 items was .80 and .76 in African American and Black Caribbean women, respectively. African American and Black Caribbean men also had item-to-total correlations and inter-item correlations below .30 for the item "I felt that I was just as good as other people." After eliminating these items, the alpha for the remaining 10 items was .73 in African American and Black Caribbean men. The cut-off score was 9 for the 11-item CES-D and 8 for the 10-item CES-D. PMID- 23017047 TI - Facing the challenges and building solutions in clinical psychiatric nursing in Iran: a qualitative study. AB - Psychiatric nurses play an important role in the process of caring for mentally ill patients and are continually faced with the numerous challenges and complex issues related to this field. This study aimed to understand the perspectives of psychiatric nurses regarding the issues they face while providing care and examine the possible solutions for improvement of inpatient care in clinical settings. The study adopted a qualitative approach that utilized a content analysis of audio taped, semi-structured interviews that had been conducted with 24 nurses. Two main themes emerged from the data. The first, Challenges in Providing Care within Psychiatric Wards, had the following subthemes: Politics and Rules of Organization, Safety and Security Issues, Uncertainty about the Role, Lack of Trained Staff, and Sociocultural Issues. The second theme, Solutions for Improving Psychiatric Care, had the subthemes of Empowerment across four domains: Psychiatric Nurses, Mentally Ill Patients and their Families, The Psychiatric Mental Health System, and the Cultural Context. The results indicated that if nurses are expected to provide optimal nursing care within a psychiatric ward, then there is a need for a stable and responsible organizational structure, skilled psychiatric nurses, and community-based care along with an anti-stigma program. PMID- 23017048 TI - The research basis for Robert Whitaker's "Anatomy of an epidemic: magic bullets, psychiatric drugs and the astonishing rise of mental illness in America. PMID- 23017049 TI - Coping and health status: John Henryism. PMID- 23017051 TI - New aminoimidazoles as beta-secretase (BACE-1) inhibitors showing amyloid-beta (Abeta) lowering in brain. AB - Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Abeta40 and Abeta42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Abeta was 40 50%, 1.5 h after oral dosing (100 MUmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo. PMID- 23017052 TI - Vitamin D in dialysis: defining deficiency and rationale for supplementation. AB - Vitamin D status is determined by the serum concentration of one of its metabolites, 25-hydroxy-D. Defining vitamin D deficiency based on its classical roles in gut calcium absorption and bone mineralization is problematic in dialysis patients and, until recently, was ignored in the nephrology literature. The newly recognized nonclassical functions of vitamin D include effects on the immune system, cardiovascular disease, and cancer. The nonclassical effects are likely to be equally relevant in the dialysis population, but suffer from a lack of strong evidence on which to base therapeutic targets. Past medical opinion in the nondialysis population warned that higher dose vitamin D supplementation may be toxic and was unnecessary. This is because older supplementation recommendations were based on early twentieth century studies using cod-liver oil to treat rickets. The clinical resolution of rickets requires a relatively low dose of vitamin D. Current vitamin D guidelines generally target higher 25 hydroxy-D levels of 30 ng/ml, based on optimizing markers of bone health. This results in very high estimates of 50-100% for the prevalence of vitamin D deficiency in dialysis patients. This review examines the relevance of data on the classical and nonclassical effects of vitamin D in dialysis patients. An evidence-based dosing regimen for use in dialysis patients is suggested to safely and reliably achieve vitamin D sufficiency. PMID- 23017054 TI - The humble Bayesian: model checking from a fully Bayesian perspective. AB - Gelman and Shalizi (2012) criticize what they call the 'usual story' in Bayesian statistics: that the distribution over hypotheses or models is the sole means of statistical inference, thus excluding model checking and revision, and that inference is inductivist rather than deductivist. They present an alternative hypothetico-deductive approach to remedy both shortcomings. We agree with Gelman and Shalizi's criticism of the usual story, but disagree on whether Bayesian confirmation theory should be abandoned. We advocate a humble Bayesian approach, in which Bayesian confirmation theory is the central inferential method. A humble Bayesian checks her models and critically assesses whether the Bayesian statistical inferences can reasonably be called upon to support real-world inferences. PMID- 23017053 TI - Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma. AB - BACKGROUND: The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials. METHODS: Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models. RESULTS: Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth. CONCLUSIONS: Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials. PMID- 23017055 TI - Who do you trust? The impact of facial emotion and behaviour on decision making. AB - During social interactions, we use available information to guide our decisions, including behaviour and emotional displays. In some situations, behaviour and emotional displays may be incongruent, complicating decision making. This study had two main aims: first, to investigate the independent contributions of behaviour and facial displays of emotion on decisions to trust, and, second, to examine what happens when the information being signalled by a facial display is incongruent with behaviour. Participants played a modified version of the Trust Game in which they learned simulated players' behaviour with or without concurrent displays of facial emotion. Results indicated that displays of anger, but not happiness, influenced decisions to trust during initial encounters. Over the course of repeated interactions, however, emotional displays consistent with an established pattern of behaviour made independent contributions to decision making, strengthening decisions to trust. When facial display and behaviour were incongruent, participants used current behaviour to inform decision making. PMID- 23017056 TI - Ultra-small, highly stable, and sensitive dual nanosensors for imaging intracellular oxygen and pH in cytosol. AB - We report on the first dual nanosensors for imaging of pH values and oxygen partial pressure in cells. The sensors have a unique nanostructure in that a soft core structure is rigidized with a silane reagent, while poly(ethylene glycol) chains form an outer shell. Lipophilic oxygen-sensitive probes and reference dyes are encapsulated inside the hydrophobic core, while a pH-sensitive probe is covalently attached to the poly(ethylene glycol) end-group on the shell. The core/shell structure renders the nanosensors well dispersed and highly stable in various kinds of aqueous media. Their average size is 12 nm, and they respond to both pH and oxygen in the physiological range. They do not pass cell membranes, but can be internalized into the cellular cytosol by electroporation, upon which they enable sensing and imaging of pH values and oxygen with high spatial resolution. The nanosensor strategy shown here is expected to be applicable to the development of various other kinds of multiple nanosensors for in vivo studies. PMID- 23017058 TI - Activation of the P2X7 receptor induces migration of glial cells by inducing cathepsin B degradation of tissue inhibitor of metalloproteinase 1. AB - The P2X(7) receptor is an ion-gated channel, which is activated by high extracellular concentrations of adenosine triphosphate (ATP). Activation of P2X(7) receptors has been shown to induce neuroinflammatory changes associated with several neurological conditions. The matrix metalloproteinases (MMPs) are a family of endopeptidases that have several functions including degradation of the extracellular matrix, cell migration and modulation of bioactive molecules. The actions of MMPs are prevented by a family of protease inhibitors called tissue inhibitors of metalloproteinases (TIMPs). In this study, we show that ATP-treated glial cultures from neonatal C57BL/6 mice release and increase MMP-9 activity, which is coupled with a decrease in release of TIMP-1 and an increase in activated cathepsin B within the extracellular space. This process occurs independently of NLRP3-inflammasome formation. Treatment with a P2X(7) receptor antagonist prevents ATP-induced MMP-9 activity, inhibition of active cathepsin B release and allows for TIMP-1 to be released from the cell. We have shown that cathepsin B degrades TIMP-1, and inhibition of cathepsin B allows for release of TIMP-1 and inhibits MMP-9 activity. We also present data that indicate that ATP or cell damage induces glial cell migration, which is inhibited by P2X(7) antagonism, depletion of MMP-9 or inhibition of cathepsin B. PMID- 23017057 TI - Development of a risk reduction intervention to reduce bacterial and viral infections for injection drug users. AB - Bacterial infections are widespread problems among drug injectors, requiring novel preventive intervention. As part of a NIDA-funded study, we developed an intervention based on the Information-Motivation-Behavioral Skills model, past research, injection hygiene protocols, and data collected from focus groups with 32 injectors in Denver in 2009. Qualitative responses from focus groups indicated that most participants had experienced skin abscesses and believed that bacterial infections were commonly a result of drug cut, injecting intramuscularly, and reusing needles. Access to injection supplies and experiencing withdrawal were the most frequently reported barriers to utilizing risk reduction. Implications for intervention development are discussed. PMID- 23017059 TI - Potent effects of, and mechanisms for, modification of crosstalk between macrophages and adipocytes by lactobacilli. AB - The murine macrophage-like cell line J774.1 was treated with heat-killed cells of Lactobacillus GG (LGG) and L. gasseri TMC0356 (TMC 0356). Interleukin (IL)-6, IL 12, and tumor necrosis factor-alpha were profiled from the J774.1 cells using enzyme-linked immunosorbent assay methods. The conditioned medium from cultured J774.1 cells was transferred to the preadipocyte cell line 3T3-L1 (which is a mouse embryonic fibroblast-adipose-like cell line). Growth and differentiation of 3T3-L1 cells were monitored by analyzing lipid accumulation and expression of peroxisome proliferator-activated receptor (PPAR)-gamma mRNA. The medium conditioned by 3T3-L1 cells was added to J774.1 cells and the cytokines in the supernatant analyzed. Compared with that of cells exposed to a PBS-conditioned medium, lipid accumulation in 3T3-L1 cells was significantly suppressed in a dose dependent manner by each medium that had been conditioned with LGG and TMC0356. PPAR-gamma mRNA expression in 3T3-L1 cells was also significantly downregulated (P < 0.01, P < 0.05, respectively). The conditioned medium of 3T3-L1 adipose phenotype significantly stimulated production of IL-6 and IL-12 in J774.1 cells treated with LGG and TMC0356. These results suggest that lactobacilli may suppress differentiation of preadipocytes through macrophage activation and alter the immune responses of macrophages to adipose cells. PMID- 23017061 TI - Hyperthermia exposure impaired the early stage of face recognition: an ERP study. AB - We investigated the effect of hyperthermia exposure on the early stages of face processing by recording event-related potentials (ERPs) elicited by faces and non face stimuli presented in upright and inverted orientations. Across all conditions, both the peak latencies of P1 and N170 components were earlier in the hyperthermia group than in the control participants. Although no effects of P1 amplitudes were influenced by hyperthermia, the face effect (larger amplitude for faces relative to other object categories) of the N170 was modulated by hyperthermia, whereas the face effect was significant in the control group, it was minimised in the hyperthermia group. The inversion effect of faces on N170 amplitudes, however, was not affected by hyperthermia. These data suggest that the detection of faces in the visual field and their initial streaming to face specific structural encoding mechanisms are impaired by hyperthermia. However, subsequent face-specific configural processing revealed by the N170 inversion effect is not affected by hyperthermia. In addition, hyperthermia accelerates the early stage of visual perception, regardless of faces or non-face objects. PMID- 23017062 TI - Systematic comparison between ecological momentary assessment and day reconstruction method for fatigue and mood states in healthy adults. AB - OBJECTIVES: While both ecological momentary assessment (EMA) and the day reconstruction method (DRM) have been used to overcome recall bias, a full systematic comparison of these methods has not been conducted. This study was aimed to investigate the differences and correlations between momentary fatigue and mood states recorded by EMA and reconstructed ones recorded by simultaneous DRM in healthy adults. DESIGN: Each of two different designs (time-based and episode-based) of EMA and DRM were simultaneously conducted. METHODS: Twenty-five healthy adults recorded momentary fatigue and mood states with EMA, and then, reconstructed them with DRM. Differences between the mean and the variability of momentary and reconstructed recordings, and the correlations between them, are analysed for different EMA designs. RESULTS: No significant differences are found between the mean or the variability of EMA and DRM estimated over the monitoring period. However, correlations between EMA and DRM are low, albeit statistically significant. CONCLUSIONS: Although the overall mean and variability of EMA recordings may be accessible with DRM, detailed changes over time of momentary fatigue and mood states are not retrieved by DRM. Statement of contribution What is already known on this subject? Day reconstruction method (DRM) may be a reliable substitute strategy for the measurement of subjective symptoms instead of ecological momentary assessment (EMA). Remembering the context of daily activities with DRM is assumed to be helpful in reconstructing subjective symptoms without recall bias. What does this study add? We are not able to reconstruct our diurnal time course (i.e. detailed changes over time) of subjective symptoms (e.g. fatigue and mood states in this study) with DRM, while their approximate mean and overall variability during the study period may be accessible with DRM. Reconstructed depression by DRM could be biased when the subjects remembered whether their behaviour was active or inactive. PMID- 23017063 TI - Development and validation of the Menopause-specific Quality of Life Scale for menopausal Thai women. AB - OBJECTIVES: To develop a new instrument, the Menopause-specific Quality of Life Scale (MS-QoLS), for Thai women and to study the experience of menopausal aspects in peri- and postmenopausal Thai women. MATERIALS AND METHODS: Item generation was developed from a focus group discussion and in-depth interview, and the content validity index (CVI) was computed, using item relevance ratings by content experts. Items with CVI values higher than 0.7 were selected. The draft questionnaire was tested for language, format and content. The final questionnaire was administered and the construct validity and reliability were then assessed. RESULTS: Fifty-seven peri- and postmenopausal women participated in the focus group discussion and in-depth interview. Sixty-eight items across eight dimensions were generated based on content analysis result. The dimensions included Physical health, Psychological health, Sexual health, Daily activity, Family, Social, Treatment, and Economics. A total of 280 menopausal women were recruited from four collaborative hospitals for psychometric validation. After factor analysis, 22 items remained with six dimensions identified, that is, well being, emotionality, anxiety/fear, family, social and sexual health. Cronbach's coefficient alpha of each domain was between 0.61 and 0.83. CONCLUSION: The Thai MS-QoLS was systematically developed and validated for peri- or postmenopausal women. The initial assessment of the questionnaire showed an acceptable level of validity and reliability. PMID- 23017064 TI - Quantification of antibiotic in biofilm-inhibiting multilayers by 7.87 eV laser desorption postionization MS imaging. AB - The potential of laser desorption postionization mass spectrometry (LDPI-MS) imaging for small molecule quantification is demonstrated here. The N methylpiperazine acetamide (MPA) of ampicillin was adsorbed into polyelectrolyte multilayer surface coatings composed of chitosan and alginate, both high molecular weight biopolymers. These MPA-ampicillin spiked multilayers were then shown to inhibit the growth of Enterococcus faecalis biofilms that play a role in early stage infection of implanted medical devices. Finally, LDPI-MS imaging using 7.87 eV single-photon ionization was found to detect MPA-ampicillin within the multilayers before and after biofilm growth with limits of quantification and detection of 0.6 and 0.3 nmol, respectively. The capabilities of LDPI-MS imaging for small molecule quantification are compared to those of MALDI-MS. Furthermore, these results indicate that 7.87 eV LDPI-MS imaging should be applicable to quantification of a range of small molecular species on a variety of complex organic and biological surfaces. Finally, while MS imaging for quantification was demonstrated here using LDPI, it is a generally useful strategy that can be applied to other methods. PMID- 23017066 TI - Reply: To PMID 22524487. PMID- 23017065 TI - Common genetic and nonshared environmental factors contribute to the association between socioemotional dispositions and the externalizing factor in children. AB - BACKGROUND: Childhood behavioral disorders including conduct disorder (CD), oppositional defiant disorder (ODD), and attention-deficit/hyperactivity disorder (ADHD) often co-occur. Prior twin research shows that common sets of genetic and environmental factors are associated with these various disorders and they form a latent factor called Externalizing. The developmental propensity model posits that CD develops in part from socioemotional dispositions of prosociality, negative emotionality, and daring; and recent research has supported the expected genetic and environmental associations between these dispositions and CD. This study examined the developmental propensity model in relation to the broader Externalizing factor that represents the covariance among behavior disorders in children. METHODS: Parents of 686 six- to twelve-year-old twin pairs rated them on symptoms of CD, ADHD, and ODD using the disruptive behavior disorder scale and on prosociality, negative emotionality, and daring using the child and adolescent dispositions scale. A latent factor multivariate Cholesky model was used with each disposition latent factor comprised of respective questionnaire items and the Externalizing factor comprised of symptom dimensions of CD, ADHD inattention, ADHD hyperactivity/impulsivity, and ODD. RESULTS: Results supported the hypothesis that the socioemotional dispositions and the Externalizing factor have genetic factors in common, but there was not a single genetic factor associated with all of the constructs. As expected, nonshared environment factors were shared by the dispositions and externalizing factor but, again, no single nonshared environmental factor was common to all constructs. A shared environmental factor was associated with both negative emotionality and externalizing. CONCLUSIONS: The developmental propensity model was supported and appears to extend to the broader externalizing spectrum of childhood disorders. Socioemotional dispositions of prosociality, negative emotionality, and (to a lesser extent) daring may contribute to the covariation among behavioral disorders and perhaps to their comorbid expression through common sets of primarily genetic but also environmental factors. PMID- 23017067 TI - Cumulative response curves to enhance interpretation of treatment differences on the Self-Esteem And Relationship questionnaire for men with erectile dysfunction. AB - What's known on the subject? and What does the study add? Studies on erectile dysfunction (ED) therapies rely heavily on patient-reported outcomes (PROs) to measure efficacy on treatment response. A challenge when using PROs is interpretation of the clinical meaning of changes in scores. A responder analysis provides a threshold score to indicate whether a change in score qualifies a patient as a responder. However, a major consideration with responder analysis is the sometimes arbitrary nature of defining the threshold for a response. By contrast, cumulative response curves (CRCs) display patient response rates over a continuum of possible thresholds, thus eliminating problems with a rigid threshold definition, allowing for a variety of response thresholds to be examined simultaneously, and encompassing all data. With respect to the psychosocial factors addressed in the Self-Esteem And Relationship questionnaire in ED, CRCs clearly, distinctly, and meaningfully highlighted the favourable profiles of responses to sildenafil compared with placebo. CRCs for PROs in urology can provide a clear, transparent and meaningful visual depiction of efficacy data that can supplement and complement other analyses. OBJECTIVE: To use cumulative response curves (CRCs) to enrich meaning and enhance interpretation of scores on the Self-Esteem And Relationship (SEAR) questionnaire with respect to treatment differences for men with erectile dysfunction (ED). PATIENTS AND METHODS: This post hoc analysis used data from all patients who took at least one dose of study drug and had at least one post-baseline efficacy evaluation in a previously published 12-week, multicentre, randomized, double blind, placebo-controlled trial of flexible-dose (25, 50, or 100 mg) sildenafil citrate (Viagra) in adult men with ED who had scored <= 75 out of 100 on the Self Esteem subscale of the SEAR questionnaire. CRCs were used on the numeric change in transformed SEAR scores from baseline to end-of-study for each SEAR component. The horizontal axis of the CRC represented change from baseline on the SEAR score, and the vertical axis represented the percentage of patients experiencing that change or greater. The differences between CRCs for the sildenafil group vs the placebo group were assessed using the Kolmogorov-Smirov test. RESULTS: For each of the SEAR components, there was essentially no overlap in the CRCs between the sildenafil group (n = 113) and placebo group (n = 115 or 116, depending on the component), showing that a greater percentage of sildenafil recipients compared with placebo recipients had a more favourable change across the spectrum of response thresholds (P <= 0.01). Previous research showed that a 10-point score increase is the minimal clinically meaningful improvement for most SEAR components. In the sildenafil vs placebo groups, a >=10-point score increase occurred in 72 vs 37% of patients, respectively, on the Sexual Relationship Satisfaction domain, 71 vs 41% on the Confidence domain, 76 vs 49% on the Self Esteem subscale, 60 vs 44% on the Overall Relationship Satisfaction subscale, and 75 vs 38% on the Overall score. CONCLUSIONS: With respect to the psychosocial factors addressed in the SEAR questionnaire, CRCs clearly, distinctly, and meaningfully highlighted the favourable profiles of responses to sildenafil compared with placebo. CRCs for patient-reported outcomes in urology can provide a clear, transparent, and meaningful visual depiction of efficacy data that can supplement and complement other analyses. PMID- 23017068 TI - A three-component reaction toward the synthesis of 1-carboxamido-isoindoles. AB - An efficient three-component reaction toward the facile synthesis of structurally diverse 1-carboxamido-isoindoles has been developed. The resultant isoindoles can be used in Diels-Alder reactions. PMID- 23017071 TI - Approaching the Holy Grail: development variation and adult morphology. PMID- 23017069 TI - A novel conceptual framework for balance training in Parkinson's disease-study protocol for a randomised controlled trial. AB - BACKGROUND: There is increasing scientific knowledge about the interaction between physiological (musculoskeletal, neuromuscular, cognitive and sensory) systems and their influence on balance and walking impairments in Parkinson's disease. We have developed a new conceptual framework for balance training, emphasising specific components of balance control related to Parkinson's disease symptoms by using highly challenging, progressive and varying training conditions. The primary aim of this proposed randomised controlled trial will be to investigate the short-term and long-term effects of a 10-week balance training regime in elderly with Parkinson's disease. METHODS/DESIGN: Eighty participants with mild to moderate idiopathic Parkinson's disease will be recruited and randomly allocated to an intervention group receiving balance training or a control group whose participants will continue to receive their usual care. The intervention will consist of a 10-week group training regime (1-hour training, three times per week), which will be led by two physiotherapists to ensure training progression and safety. The conceptual framework will be applied by addressing specific balance components (sensory integration, anticipatory postural adjustments, motor agility, stability limits) through varying training conditions and structured progression. Assessment will be conducted through a multi-dimensional battery of outcomes, prior to and immediately after the 10-week intervention, and at 9 and 15 months' follow-up after entering the study. Primary outcome measures will be balance performance (assessed using the Mini Balance Evaluation Systems Test), change in gait velocity (m/s) between single and dual task walking, and fear of falling (evaluated using the Fall Efficacy Scale International). DISCUSSION: This study has the potential to provide new insight and knowledge of the effects of specific, varied and challenging balance training on a wide health spectrum in elderly with PD. If found to be effective, this pragmatic approach with translation of theory into practice, can be implemented in existing outpatient care. TRIAL REGISTRATION: NCT01417598. PMID- 23017072 TI - The emergence of squamates as model systems for integrative biology. PMID- 23017073 TI - Development of head and trunk mesoderm in the dogfish, Scyliorhinus torazame: I. Embryology and morphology of the head cavities and related structures. AB - Vertebrate head segmentation has attracted the attention of comparative and evolutionary morphologists for centuries, given its importance for understanding the developmental body plan of vertebrates and its evolutionary origin. In particular, the segmentation of the mesoderm is central to the problem. The shark embryo has provided a canonical morphological scheme of the head, with its epithelialized coelomic cavities (head cavities), which have often been regarded as head somites. To understand the evolutionary significance of the head cavities, the embryonic development of the mesoderm was investigated at the morphological and histological levels in the shark, Scyliorhinus torazame. Unlike somites and some enterocoelic mesodermal components in other vertebrates, the head cavities in S. torazame appeared as irregular cyst(s) in the originally unsegmented mesenchymal head mesoderm, and not via segmentation of an undivided coelom. The mandibular cavity appeared first in the paraxial part of the mandibular mesoderm, followed by the hyoid cavity, and the premandibular cavity was the last to form. The prechordal plate was recognized as a rhomboid roof of the preoral gut, continuous with the rostral notochord, and was divided anteroposteriorly into two parts by the growth of the hypothalamic primordium. Of those, the posterior part was likely to differentiate into the premandibular cavity, and the anterior part disappeared later. The head cavities and somites in the trunk exhibited significant differences, in terms of histological appearance and timing of differentiation. The mandibular cavity developed a rostral process secondarily; its homology to the anterior cavity reported in some elasmobranch embryos is discussed. PMID- 23017074 TI - Development of the head and trunk mesoderm in the dogfish, Scyliorhinus torazame: II. Comparison of gene expression between the head mesoderm and somites with reference to the origin of the vertebrate head. AB - The vertebrate mesoderm differs distinctly between the head and trunk, and the evolutionary origin of the head mesoderm remains enigmatic. Although the presence of somite-like segmentation in the head mesoderm of model animals is generally denied at molecular developmental levels, the appearance of head cavities in elasmobranch embryos has not been explained, and the possibility that they may represent vestigial head somites once present in an amphioxus-like ancestor has not been ruled out entirely. To examine whether the head cavities in the shark embryo exhibit any molecular signatures reminiscent of trunk somites, we isolated several developmentally key genes, including Pax1, Pax3, Pax7, Pax9, Myf5, Sonic hedgehog, and Patched2, which are involved in myogenic and chondrogenic differentiation in somites, and Pitx2, Tbx1, and Engrailed2, which are related to the patterning of the head mesoderm, from an elasmobranch species, Scyliorhinus torazame. Observation of the expression patterns of these genes revealed that most were expressed in patterns that resembled those found in amniote embryos. In addition, the head cavities did not exhibit an overt similarity to somites; that is, the similarity was no greater than that of the unsegmented head mesoderm in other vertebrates. Moreover, the shark head mesoderm showed an amniote-like somatic/visceral distinction according to the expression of Pitx2, Tbx1, and Engrailed2. We conclude that the head cavities do not represent a manifestation of ancestral head somites; rather, they are more likely to represent a derived trait obtained in the lineage of gnathostomes. PMID- 23017075 TI - Evolution of electrosensory ampullary organs: conservation of Eya4 expression during lateral line development in jawed vertebrates. AB - The lateral line system of fishes and amphibians comprises two ancient sensory systems: mechanoreception and electroreception. Electroreception is found in all major vertebrate groups (i.e. jawless fishes, cartilaginous fishes, and bony fishes); however, it was lost in several groups including anuran amphibians (frogs) and amniotes (reptiles, birds, and mammals), as well as in the lineage leading to the neopterygian clade of bony fishes (bowfins, gars, and teleosts). Electroreception is mediated by modified "hair cells," which are collected in ampullary organs that flank lines of mechanosensory hair cell containing neuromasts. In the axolotl (a urodele amphibian), grafting and ablation studies have shown a lateral line placode origin for both mechanosensory neuromasts and electrosensory ampullary organs (and the neurons that innervate them). However, little is known at the molecular level about the development of the amphibian lateral line system in general and electrosensory ampullary organs in particular. Previously, we identified Eya4 as a marker for lateral line (and otic) placodes, neuromasts, and ampullary organs in a shark (a cartilaginous fish) and a paddlefish (a basal ray-finned fish). Here, we show that Eya4 is similarly expressed during otic and lateral line placode development in the axolotl (a representative of the lobe-finned fish clade). Furthermore, Eya4 expression is specifically restricted to hair cells in both neuromasts and ampullary organs, as identified by coexpression with the calcium-buffering protein Parvalbumin3. As well as identifying new molecular markers for amphibian mechanosensory and electrosensory hair cells, these data demonstrate that Eya4 is a conserved marker for lateral line placodes and their derivatives in all jawed vertebrates. PMID- 23017076 TI - Expression and function of a limb-patterning gene Distal-less in the soldier specific morphogenesis in the nasute termite Nasutitermes takasagoensis. AB - One of the major foci in evolutionary developmental biology is to understand developmental mechanisms that underlie the acquisition of morphological novelties. Termite soldiers, the highly specialized defensive caste, show exaggerated species-specific morphologies, mostly enlarged mandibles. Soldiers of the subfamily Nasutitermitinae (Termitidae), however, possess a novel structure for defense in their heads, that is a horn-like frontal projection (nasus) from which defensive chemicals are discharged. Just prior to the molt into presoldiers (the preceding stage to soldiers) from workers, a nasus disc, or a nasus primordium, is observed under the worker head cuticle. In order to understand the developmental underpinnings of this evolutionarily novel structure, the role of a homeobox gene Distal-less (Dll) during nasus development was examined in this study, using a nasute termite Nasutitermes takasagoensis. Histological observations showed that complex developmental processes comprising epidermal evagination and invagination through changes in cell shape and cell proliferation formed the projection and the gland. Immunohistochemistry showed that Dll was localized in the developing nasus disc, but not in the frontal-gland primordium. Consistent with this finding, Dll RNA interference only repressed nasus growth not the frontal-gland formation. Taken together, the co-option of Dll is suggested to contribute to the acquisition of a novel defensive structure in a termite lineage, coupled with the acquisition of adaptive defensive behaviors. PMID- 23017077 TI - Functional conservation and divergence of BMP ligands in limb development and lipid homeostasis of holometabolous insects. AB - Bone morphogenetic protein (BMP) ligands play key roles in regulating morphological and physiological traits. To investigate how the functions of BMP ligands have evolved among insects, the roles of two key BMP ligands, decapentaplegic (dpp) and glass bottom boat (gbb), were studied in the flour beetle, Tribolium castaneum. RNA interference-mediated knockdown revealed that the role of dpp in establishing limb segmentation is conserved among insects. Based on the expression pattern of dpp in the presumptive leg tarsal segments, we propose that the function of dpp has evolved through heterochronic changes during the evolution of complete metamorphosis. Gbb1 was found to be necessary for sculpting the tarsal segment morphology characteristic of beetles. Knockdown of Dpp and Gbb1 expression also resulted in transparent larvae and reduced triglyceride levels, indicating their critical roles in maintaining lipid homeostasis. Both knockdown phenotypes were mediated by larval translucida. Because only Gbb regulates lipid metabolism in Drosophila, regulation of lipid homeostasis appears to have evolved by developmental systems drift. Thus, developmental systems drift may underlie evolution of both morphology and physiological processes. PMID- 23017078 TI - 4-Oxo-1,4-dihydropyridines as selective CB2 cannabinoid receptor ligands. Part 2: discovery of new agonists endowed with protective effect against experimental colitis. AB - Further on to our earlier work on the 4-oxo-1,4-dihydropyridine, we describe herein our strategy to get access to potent selective CB2 receptor agonists. Thus, we designed and synthesized 29 compounds, evaluated on both hCB1 and hCB2 cannabinoid receptors, and assessed 11 of them in the TNBS-induced colitis model in mice. Compound 48 was found to be the most efficient of our series, exhibiting an exquisite protection against experimental colitis, superior to the one observed after treatment with Pentasa. PMID- 23017079 TI - Deep mitochondrial introgression and hybridization among ecologically divergent vole species. AB - The completion of speciation is typically difficult to ascertain in rapidly diverging taxa but the amount of hybridization and gene flow in sympatry or parapatry contains important information about the level of reproductive isolation achieved. Here, we examined the progress in speciation between the Mediterranean (Microtus duodecimcostatus) and the Lusitanian pine vole (M. lusitanicus), which are part of the most rapid radiation of species known in mammals. These two Iberian pine voles are classified as separate species because of differences in morphology and ecology, but relatively many ambiguous individuals can be found in sympatric conditions. Our phylogenetic analyses of rangewide data from the mitochondrial cytochrome b gene (mtDNA) demonstrated high levels of diversity and a basal separation in two parapatric lineages. However, mtDNA affiliation was at odds with morphological classification or geographical distribution of the taxa. In contrast, statistical analyses of microsatellites (nucDNA) showed two clear genetic clusters in allopatry and sympatry generally matching morphological classification. This cytonuclear discordance over a large geographic area suggests historical introgression of mtDNA from M. duodecimcostatus to M. lusitanicus. There was statistical evidence for at least two recent hybrids in the sympatry zone but gene flow is apparently low given clear-cut differences in nucDNA. Our results indicate a relatively advanced speciation process in these Iberian pine voles without fully established reproductive isolation. This situation enables use of combined population genomic and experimental approaches for the separation of patterns and mechanisms in the ongoing explosive diversification of these and other Arvicoline rodents in the future. PMID- 23017080 TI - Optimal carbon dioxide insufflation pressure during robot-assisted thyroidectomy in patients with various benign and malignant thyroid diseases. AB - BACKGROUND: Currently, data are not available concerning a safe insufflation pressure that provides a proper view of the surgical field without adverse metabolic and hemodynamic changes in humans undergoing the robot-assisted thyroidectomy bilateral axillo-breast approach (BABA) using the da Vinci robotic surgical system. The purpose of this study was to determine the optimal carbon dioxide (CO2) insufflation pressure in patients with various benign and malignant thyroid diseases when using the da Vinci robotic surgical system. METHODS: A total of 32 patients underwent thyroid surgery at 6 (n = 15), 9 (n = 15), and 12 (n = 2) mmHg. The partial pressure of carbon dioxide (PaCO2), pH, cardiac output, heart rate, and mean arterial pressure were measured at baseline, 30 min and 1, 1.5, and 2 hours after CO2 insufflation, and 30 min after desufflation. RESULTS: CO2 insufflation of 12 mmHg caused severe facial subcutaneous emphysema, hypercarbia, and acidosis during robot-assisted thyroidectomy with BABA. The study was stopped before completion for the patients' safety in accordance with the study protocol. Applying 6- or 9- mmHg of CO2 insufflation pressure caused increases in PaCO2 and decreases in arterial pH. However, vital signs were stable and pH and PaCO2 were within the physiologic range during the surgery in the 6- and 9-mmHg groups. CONCLUSIONS: We propose that a CO2 insufflation pressure under 10 mmHg in robot-assisted thyroidectomy with BABA is the optimal insufflation pressure for patient safety. PMID- 23017081 TI - Sterile folliculitis as an important diagnostic clue to Crohn's disease. AB - Sterile folliculitis is known to be one of the rare cutaneous manifestations of Crohn's disease (CD). To our knowledge it has never been emphasized as a marker of significant diagnostic value, perhaps maybe even more significant than more common cutaneous manifestations such as erythema nodosum (EN). PMID- 23017082 TI - Gingival advanced glycation end-products in diabetes mellitus-associated chronic periodontitis: an immunohistochemical study. AB - BACKGROUND AND OBJECTIVE: The accumulation of advanced glycation end-products (AGEs) seems to play an important role in the development of diabetes mellitus (DM)-associated periodontitis; however, some aspects of this issue are still scarcely known, such as the expression of AGEs in type 1 DM-associated periodontitis and the clinical factors able to affect their accumulation. This study aimed to clarify these points by evaluating the expression of AGEs in DM associated periodontitis. MATERIAL AND METHODS: Sixteen systemically and periodontally healthy subjects and 48 subjects suffering from generalized, severe, chronic periodontitis (16 with type 1 DM, 16 with type 2 DM and 16 systemically healthy subjects) were studied clinically, periodontally and metabolically. The immunohistochemical expression of AGEs in gingival tissues was also evaluated. RESULTS: Subjects affected with type 1 DM presented a significantly higher percentage of AGE-positive cells than did subjects affected with type 2 DM, not only in the epithelium, but also in vessels and fibroblasts. A positive and significant correlation was found between gingival expression of AGEs and length of time affected with DM both in type 1 and type 2 DM; glycated hemoglobin, lipid profile, body mass index and age did not correlate significantly with gingival AGEs in any of the classes of subjects studied. CONCLUSIONS: Gingival AGEs are increased in both type 1 and type 2 DM-associated periodontitis; however, the clinical parameter that determines their accumulation, and therefore their degree of influence on the development of DM associated periodontitis, may be the duration of DM. PMID- 23017084 TI - Editorial overview for this special issue on understanding cognitive development: approaches from mind and brain. PMID- 23017083 TI - Bistable isoelectric point photoswitching in green fluorescent proteins observed by dynamic immunoprobed isoelectric focusing. AB - We describe a novel isoelectric point photoswitching phenomenon in both wild-type Aequorea victoria (av) GFP and the amino acid 222 E-to-G mutant Aequorea coerulescens (ac) GFP. A combination of time-resolved microfluidic isoelectric focusing (IEF) and in situ antibody blotting IEF was employed to monitor dark (nonfluorescent) and bright (fluorescent) GFP populations. Through IEF, each population was observed to exhibit distinct isoelectric points (pI) and, thus, distinct formal electrostatic charges. Experimentally observed interconversion between the dark, higher pI and bright, lower pI GFP populations is tightly controlled by differential UV and blue light exposure. The stoichiometry and kinetics of charge transfer tied to this reversible photobleaching process are deduced. In concert with a reaction-transport model of bistable reversible charge and fluorescence photoswitching, the on-chip measurements of population interconversion rates suggest the potential for both rheostatic and discrete switch-like modulation of the electrostatic charge of GFPs depending on the illumination profile. We estimate that 3-4 formal charges distinguish the bright and dark populations of avGFP, as compared to one charge for those of acGFP. Given the proposed role of E222 as a bridge between internal and exit hydrogen bond clusters within the GFP beta-barrel, the difference in charge switching magnitude between the two mutants provides intriguing evidence for the proton wire hypothesis of proton transport within the GFP structure, and of proton exchange with the bulk solvent. Our facile dynamic and probed IEF assays should find widespread use in analytical screening and quantitative kinetic analysis of photoswitching and other charge switching processes in response to stimuli including light, temperature, or binding/cleavage events. PMID- 23017085 TI - The maps problem and the mapping problem: two challenges for a cognitive neuroscience of speech and language. AB - Research on the brain basis of speech and language faces theoretical and empirical challenges. Most current research, dominated by imaging, deficit lesion, and electrophysiological techniques, seeks to identify regions that underpin aspects of language processing such as phonology, syntax, or semantics. The emphasis lies on localization and spatial characterization of function. The first part of the paper deals with a practical challenge that arises in the context of such a research programme. This maps problem concerns the extent to which spatial information and localization can satisfy the explanatory needs for perception and cognition. Several areas of investigation exemplify how the neural basis of speech and language is discussed in those terms (regions, streams, hemispheres, networks). The second part of the paper turns to a more troublesome challenge, namely how to formulate the formal links between neurobiology and cognition. This principled problem thus addresses the relation between the primitives of cognition (here speech, language) and neurobiology. Dealing with this mapping problem invites the development of linking hypotheses between the domains. The cognitive sciences provide granular, theoretically motivated claims about the structure of various domains (the "cognome"); neurobiology, similarly, provides a list of the available neural structures. However, explanatory connections will require crafting of computationally explicit linking hypotheses at the right level of abstraction. For both the practical maps problem and the principled mapping problem, developmental approaches and evidence can play a central role in the resolution. PMID- 23017086 TI - Insights into the origins of knowledge from the cognitive neuroscience of blindness. AB - Children learn about the world through senses such as touch, smell, vision, and audition, but they conceive of the world in terms of objects, events, agents, and their mental states. A fundamental question in cognitive science is how nature and nurture contribute to the development of such conceptual categories. What innate mechanisms do children bring to the learning problem? How does experience contribute to development? In this article we discuss insights into these longstanding questions from cognitive neuroscience studies of blindness. Despite drastically different sensory experiences, behavioural and neuroscientific work suggests that blind children acquire typical concepts of objects, actions, and mental states. Blind people think and talk about these categories in ways that are similar to sighted people. Neuroimaging reveals that blind people make such judgements relying on the same neural mechanisms as sighted people. One way to interpret these findings is that neurocognitive development is largely hardwired, and so differences in experience have little consequence. Contrary to this interpretation, neuroimaging studies also show that blindness profoundly reorganizes the visual system. Most strikingly, developmental blindness enables "visual" circuits to participate in high-level cognitive functions, including language processing. Thus, blindness qualitatively changes sensory representations, but leaves conceptual representations largely unchanged. The effect of sensory experience on concepts is modest, despite the brain's potential for neuroplasticity. PMID- 23017087 TI - Genes, language, and the nature of scientific explanations: the case of Williams syndrome. AB - In this article, we discuss two experiments of nature and their implications for the sciences of the mind. The first, Williams syndrome, bears on one of cognitive science's holy grails: the possibility of unravelling the causal chain between genes and cognition. We sketch the outline of a general framework to study the relationship between genes and cognition, focusing as our case study on the development of language in individuals with Williams syndrome. Our approach emphasizes the role of three key ingredients: the need to specify a clear level of analysis, the need to provide a theoretical account of the relevant cognitive structure at that level, and the importance of the (typical) developmental process itself. The promise offered by the case of Williams syndrome has also given rise to two strongly conflicting theoretical approaches-modularity and neuroconstructivism-themselves offshoots of a perennial debate between nativism and empiricism. We apply our framework to explore the tension created by these two conflicting perspectives. To this end, we discuss a second experiment of nature, which allows us to compare the two competing perspectives in what comes close to a controlled experimental setting. From this comparison, we conclude that the "meaningful debate assumption", a widespread assumption suggesting that neuroconstructivism and modularity address the same questions and represent genuine theoretical alternatives, rests on a fallacy. PMID- 23017089 TI - Challenges in device closure of a large patent ductus arteriosus in infants weighing less than 6 kg. AB - INTRODUCTION: Transcatheter closure of patent ductus arteriosus (PDA) has replaced surgery in most institutions. Despite improvements in techniques and the devices available, closure of large PDA in very small infants remains a challenge. AIM: To assess the challenges, feasibility, and efficacy of device closure of large PDA, in infants weighing <=6 kg. MATERIALS AND METHODS: Analysis of device closure of a PDA was done in 61 infants <=6 kg. Their ages, ranged from 9 days-12 months (mean 8.9 months), weight ranged from 2.2 to 6 kg (mean 5.3 kg), and PDA measured 3.2-8.7 mm (mean 4.8 mm). The fluoroscopy time was 3-18 minutes. The largest device used was 12 * 10 mm. RESULTS: Successful device placement was achieved in 60/61 infants (98.4%). Mild aortic obstruction occurred in 2 cases (3.3%), as the device got displaced towards the aorta after release. The device embolized in 2 cases (3.3%). In one it was retrieved by a novel method like fastening the screw in the aorta and was closed with a 4 * 6 ADO II. In the other infant, with a single kidney, died of uremia after device retrieval. Mild left pulmonary artery (LPA) obstruction occurred in one case (1.6%). Four cases (6.6%) had minor vascular complications. The postprocedure weight gain after 3 months was between 2.5 kg +/- 250 mg. CONCLUSIONS: Device closure of large PDA in infants weighing <=6 kg with left ventricular failure is challenging but possible, safe and effective. Retrieval of embolized device could be tricky. PMID- 23017088 TI - Thromboelastography in patients with acute ischemic stroke. AB - BACKGROUND: Thromboelastography measures the dynamics of coagulation. There are limited data about thromboelastography in acute ischemic stroke other than a single study from 1974 suggesting that acute ischemic stroke patients are hypercoagulable. There have been no studies of thromboelastography in the thrombolytic era despite its potential usefulness as a measure of clot lysis. This study was designed to provide initial thromboelastography data in stroke patients before and after tissue plasminogen activator therapy and to provide the necessary preliminary data for further study of thromboelastography's ability to identify clot subtype and predict response to tissue plasminogen activator therapy. METHODS: All acute ischemic stroke patients presenting between 11/2009 and 2/2011 eligible for tissue plasminogen activator therapy were screened and 56 enrolled. Blood was drawn before (52 patients) and 10 mins after tissue plasminogen activator bolus (30 patients). Demographics, vitals, labs, 24 h National Institutes of Health Stroke Scale, and computed tomography scan results were collected. Patients were compared with normal controls. RESULTS: Acute ischemic stroke patients had shorter R (4.8 +/- 1.5 vs. 6.0 +/- 1.7 min, P = 0.0004), greater alpha Angle (65.0 +/- 7.6 vs. 61.5 +/- 5.9 degrees , P = 0.01), and shorter K (1.7 +/- 0.7 vs. 2.1 +/- 0.7 min, P = 0.002) indicating faster clotting. Additionally, a subset formed clots with stronger platelet-fibrin matrices. Treatment with tissue plasminogen activator resulted in reduction in all indices of clot strength (LY30 = 0 (0-0.4) vs. 94.4 (15.2-95.3) P < 0.0001); however, there was considerable variability in response. CONCLUSIONS: Thromboelastography demonstrates that many acute ischemic stroke patients are hypercoaguable. Thromboelastography values reflect variable clot subtype and response to tissue plasminogen activator. Further study based on these data will determine if thromboelastography is useful for measuring the dynamic aspects of clot formation and monitoring lytic therapy. PMID- 23017090 TI - Chitosan and gelatin based prototype delivery systems for the treatment of oral mucositis: from material to performance in vitro. AB - In this study we developed and evaluated a prototype of an effective occlusive mucoadhesive system for prophylaxis and/or treatment of oral mucositis based on chitosan and gelatine models together with nystatin as a prophylactic agent incorporated into the formulation and investigated drug release in-vitro. Results of in vitro studies showed that chitosan and gelatine based gels posses properties that makes them excellent candidates for treatment of oral mucositis. These properties include not only the palliative effects of an occlusive dressing but also the potential for delivering therapeutic compounds with chitosan gels providing drug concentrations above their minimum inhibition concentration and extending the retention time in the oral cavity due to their bioadhesive properties. Chitosan also offers an advantage over suspensions because of its inherent antimicrobial properties. The performance of gelatin-based gels highlights the novel, non-toxic, in situ forming gelatine based hydrogel. The results of in vitro drug release experiments demonstrated that all the hydrogel showed sustained release properties. PMID- 23017092 TI - Formulation development of metoprolol succinate and hydrochlorothiazide compression coated tablets. AB - The purpose of present research work was to design and optimize compression coated tablet to provide an immediate release of hydrochlorothiazide in stomach and extended release of metoprolol succinate in intestine. Compression coated tablet was prepared by direct compression method which consisted of metoprolol succinate extended release core tablet and hydrochlorothiazide immediate release coat layer. Barrier coating of Hydroxy Propyl Methyl Cellulose (HPMC) E15LV was applied onto the core tablets to prevent burst release of metoprolol succinate in acidic medium. A 32 full factorial design was employed for optimization of the amount of polymers required to achieve extended release of drug. The percentage drug release at given time Q3, Q6, Q10, Q22; were selected as dependent variables. Core and compression coated tablets were evaluated for pharmaco technical parameters. In vitro drug release of optimized batch was found to comply with Pharmacopoeial specifications. Desired release of metoprolol succinate was obtained by suitable combination of HPMC having high gelling capacity and polyethylene oxide having quick gelling capacity. The mechanism of release of metoprolol succinate from all batches was anomalous diffusion. Optimised batch was stable at accelerated conditions up to 3 months. Thus, compression coated tablet of metoprolol succinate and hydrochlorothiazide was successfully formulated. PMID- 23017094 TI - Functionalized graphene-coated cobalt nanoparticles for highly efficient surface assisted laser desorption/ionization mass spectrometry analysis. AB - Graphene-coated cobalt nanoparticles surface-functionalized with benzylamine groups (CoC-NH(2) nanomagnets) were shown to effectively enrich analytes for surface-assisted laser desorption/ionization mass spectrometry (affinity SALDI MS) analysis. These CoC-NH(2) nanomagnets are highly suited for use with affinity SALDI-MS because their mean diameter of 30 nm, high specific surface area of 15 m(2) g(-1), and high-strength saturation magnetization of 158 emu g(-1) led to efficient extraction of analytes by magnetic separation, which in turn enabled excellent SALDI-MS performance. Surface modification of CoC nanomagnets with benzylamine groups increased the yield of peptide ions and decreased fragmentation of benzylpyridinium ions, so-called "thermometer ions" formed through soft ionization. The CoC-NH(2) nanomagnets were used to extract perfluorooctanesulfonate from large volumes of aqueous solutions by magnetic separation, which was identified directly by SALDI-MS analysis with high sensitivity even at the sub-part-per-trillion level (~0.1 ng/L). The applicability of CoC-NH(2) nanomagnets in conjunction with SALDI-MS for the enrichment and detection of pentachlorophenol, bisphenol A, and polyfluorinated compounds (PFCs) with varying chain length, which are environmentally significant compounds, as well as small drugs, was also evaluated. PMID- 23017093 TI - Biomechanical stability of a supra-acetabular pedicle screw internal fixation device (INFIX) vs external fixation and plates for vertically unstable pelvic fractures. AB - BACKGROUND: We have recently developed a subcutaneous anterior pelvic fixation technique (INFIX). This internal fixator permits patients to sit, roll over in bed and lie on their sides without the cumbersome external appliances or their complications. The purpose of this study was to evaluate the biomechanical stability of this novel supraacetabular pedicle screw internal fixation construct (INFIX) and compare it to standard internal fixation and external fixation techniques in a single stance pelvic fracture model. METHODS: Nine synthetic pelves with a simulated anterior posterior compression type III injury were placed into three groups (External Fixator, INFIX and Internal Fixation). Displacement, total axial stiffness, and the stiffness at the pubic symphysis and SI joint were calculated. Displacement and stiffness were compared by ANOVA with a Bonferroni adjustment for multiple comparisons RESULTS: The mean displacement at the pubic symphysis was 20, 9 and 0.8 mm for external fixation, INFIX and internal fixation, respectively. Plate fixation was significantly stiffer than the INFIX and external Fixator (P = 0.01) at the symphysis pubis. The INFIX device was significantly stiffer than external fixation (P = 0.017) at the symphysis pubis. There was no significant difference in SI joint displacement between any of the groups. CONCLUSIONS: Anterior plate fixation is stiffer than both the INFIX and external fixation in single stance pelvic fracture model. The INFIX was stiffer than external fixation for both overall axial stiffness, and stiffness at the pubic symphysis. Combined with the presumed benefit of minimizing the complications associated with external fixation, the INFIX may be a more preferable option for temporary anterior pelvic fixation in situations where external fixation may have otherwise been used. PMID- 23017095 TI - Urinary calculi increase the risk for adverse pregnancy outcomes: a nationwide study. AB - OBJECTIVE: Using two large-scale nationwide population-based data sets, this study aimed to assess the risk of adverse pregnancy outcomes between mothers with and without urinary calculi. DESIGN: Cross-sectional study. SETTING: Taiwan. SAMPLE: This study included 3694 women who had live singleton births and received a diagnosis of urinary calculi (UC) in the year prior to their delivery, as well as 18 470 matched women without UC, who were used as a comparison group. METHODS: Conditional logistic regression analyses were performed. MAIN OUTCOME MEASURES: Low birthweight, preterm birth, small for gestational age, cesarean section, lower Apgar score and pre-eclampsia/eclampsia. RESULTS: Women with UC had a higher prevalence of low-birthweight neonates (7.4 vs. 6.0%, p = 0.003), preterm births (9.5 vs. 7.3%, p < 0.001) and cesarean sections (43.1 vs. 35.4%, p < 0.001) than women without UC. After adjusting for potential confounding factors, women with UC were more likely than women without UC to have low-birthweight neonates (odds ratio 1.21, 95% confidence interval 1.05-1.39), preterm birth (odds ratio 1.28, 95% confidence interval 1.13-1.43) and cesarean sections (odds ratio 1.37, 95% confidence interval 1.28-1.48). CONCLUSIONS: There were increased risks for having low-birthweight, preterm infants and for experiencing cesarean section among women with UC in comparison to women without UC. PMID- 23017097 TI - Stellate-ganglion block as a treatment for severe postmenopausal flushing. AB - OBJECTIVE: Hormone replacement therapy is the most effective treatment for postmenopausal flushing. Unfortunately, its use is often contraindicated. A limited amount of uncontrolled data suggests that stellate-ganglion block (SGB) may be useful for the treatment of hot flushes. In the present study, we examined whether previously reported results could be reproduced in women with severe postmenopausal flushing. METHODS: Twenty postmenopausal women with a baseline hot flush score >= 15 were treated with SGB in an open, uncontrolled setting. This mean daily hot flush score was calculated as the product of flush frequency and flush severity over a period of 1 week. The response to treatment was evaluated by flush scores and assessment of quality of life at baseline and 4 weeks after SGB. RESULTS: The per-protocol analysis included 19 women. One woman was excluded because of lack of Horner syndrome after SGB. Four weeks after SGB, the mean flush score had decreased by 34 +/- 7.4% (95% confidence interval (CI) 18-49%; p < 0.005). Nine women had a decrease in flush score between 40 and 90%, with a mean response of 65 +/- 4.9% (95% CI 53-76%). The other ten women were non responders with a decrease in flush score between 0 and 11%. Quality of life and sleep, both assessed by questionnaire, improved significantly. CONCLUSIONS: The results of this study support the observation that SGB may be a useful therapy for a subset of women with severe postmenopausal flushing. A sham-controlled, single-blinded study is warranted to improve the evidence of efficacy. PMID- 23017096 TI - Using stop signals to reduce impulsive choices for palatable unhealthy foods. AB - OBJECTIVE: Exposure to palatable foods in the environment can trigger impulsive reactions to obtain them, which may lead to unhealthy food choices and eating behaviour. Two studies tested the fundamental question whether impulsive unhealthy food choices can be altered by means of linking unhealthy palatable foods to behavioural stop signals. DESIGN: Study 1 adopted a 2 (signal condition: stop signal vs. control) by 2 (appetite: low vs. high) between-subjects design. Study 2 adopted a 2 (signal condition: stop signal vs. control) between-subjects design with frequency to consume unhealthy palatable foods as a continuous factor. METHODS: Participants performed a task in which behavioural stop signals were either consistently (or not) presented in close temporal proximity to unhealthy palatable snack foods. Next, participants were given the opportunity to select snacks that they would like to consume. RESULTS: Two studies showed that participants were less likely to select unhealthy palatable foods that had been presented near stop signals, and that they selected healthy foods instead. Importantly, this reduction in choices for palatable foods was especially observed when participants' appetite was relatively high (Study 1), or when this food was part of their habit to frequently consume this food (Study 2). CONCLUSION: These findings show that a short stop signal intervention in which palatable foods are presented in close temporal proximity of stop signals can reduce palatable food choices by modifying an impulsive determinant of eating behaviour. STATEMENT OF CONTRIBUTION: What is already known on this subject? Exposure to unhealthy palatable foods in the environment can lead to impulsive food choices. People's habits towards unhealthy palatable foods and their current state of appetite are important determinants of such impulsive food choices. This impulsive behaviour is hard to change. What this study add? Linking unhealthy palatable foods to behavioural stop signals reduces choices for these foods, and increases healthy food choices. This effect is particularly strong when people's food choices are driven by their current state of appetite or habits. Behavioural stop signals foster healthy eating behaviour by modifying an impulsive determinant of behaviour. PMID- 23017098 TI - Carbon and nitrogen isotope effects associated with the dioxygenation of aniline and diphenylamine. AB - Dioxygenation of aromatic rings is frequently the initial step of biodegradation of organic subsurface pollutants. This process can be tracked by compound specific isotope analysis to assess the extent of contaminant transformation, but the corresponding isotope effects, especially for dioxygenation of N-substituted, aromatic contaminants, are not well understood. We investigated the C and N isotope fractionation associated with the biodegradation of aniline and diphenylamine using pure cultures of Burkholderia sp. strain JS667, which can biodegrade both compounds, each by a distinct dioxygenase enzyme. For diphenylamine, the C and N isotope enrichment was normal with epsilon(C)- and epsilon(N)-values of -0.6 +/- 0.10/00 and -1.0 +/- 0.10/00, respectively. In contrast, N isotopes of aniline were subject to substantial inverse fractionation (epsilon(N) of +13 +/- 0.50/00), whereas the epsilon(C)-value was identical to that of diphenylamine. A comparison of the apparent kinetic isotope effects for aniline and diphenylamine dioxygenation with those from abiotic oxidation by manganese oxide (MnO(2)) suggest that the oxidation of a diarylamine system leads to distinct C-N bonding changes compared to aniline regardless of reaction mechanism and oxidant involved. Combined evaluation of the C and N isotope signatures of the contaminants reveals characteristic Deltadelta(15)N/Deltadelta(13)C-trends for the identification of diphenylamine and aniline oxidation in contaminated subsurfaces and for the distinction of aniline oxidation from its formation by microbial and/or abiotic reduction of nitrobenzene. PMID- 23017099 TI - Epigenetics: filling in the 'heritability gap' and identifying gene-environment interactions in ulcerative colitis. AB - Ulcerative colitis is a common inflammatory bowel disorder associated with considerable morbidity. Its incidence is increasing worldwide. While familial aggregation of ulcerative colitis is a common phenomenon, genome-wide association studies, identifying a plethora of associated genes, have failed to reveal a unifying causative pathway. The well-documented impact of a number of environmental factors on disease occurrence and natural history suggests a major role for epigenetic events. The epigenome-wide association study discussed in this highlight has revealed novel loci linked to colitis and has provided unique insights into the pathophysiology of this disorder information that could translate into new therapeutic approaches. PMID- 23017100 TI - Statin use and the risk of biochemical recurrence of prostate cancer after definitive local therapy: a meta-analysis of eight cohort studies. AB - What's known on the subject? and What does the study add? Over the last few years, several observational studies examined the association of statin use with the risk of biochemical recurrence of prostate cancer after definitive local therapy. The objective of our present study was to summarise available evidence on this subject using the method of meta-analysis. Combined evidence from eight cohort studies did not definitively support the hypothesis that statins influence the risk of biochemical recurrence. However, there was considerable disagreement between individual studies in reported findings and conclusions. OBJECTIVE: To perform a systematic review and meta-analysis of clinical studies with statin use as the exposure variable and biochemical recurrence after definitive local therapy for prostate cancer as the outcome. METHODS: Relevant publications were identified through PubMed/Medline/Embase databases. Pooled estimates of the hazard ratios (HRs) were computed using the inverse-variance weighting approach. Heterogeneity was assessed using the Cochran's Q test. RESULTS: We identified a total of eight eligible studies, all based on the retrospective cohort design. Five of these were based on radical prostatectomy (RP) series and three on radiotherapy (RT) series. There was evidence of heterogeneity in the entire set of eight studies (P = 0.002) as well as in the RP series (P = 0.05) and in the RT series (P = 0.01), when these were considered separately. Based on the random effects inverse-variance weighting approach, pooled estimates of the HRs for the risk of biochemical recurrence in statin users v non-users were 0.91 (95% confidence interval [CI] 0.72-1.13) for the entire set of eight studies, 1.02 (95% CI 0.80-1.29) for the RP series and 0.71 (95% CI 0.44-1.16) for the RT series. CONCLUSION: The pooled estimates of the HRs were not significantly different from the null value in this meta-analysis; however, evidence of heterogeneity between the studies was present. PMID- 23017101 TI - Environmental conditions affect spatial genetic structures and dispersal patterns in a solitary rodent. AB - The study of the spatial distribution of relatives in a population under contrasted environmental conditions provides critical insights into the flexibility of dispersal behaviour and the role of environmental conditions in shaping population relatedness and social structure. Yet few studies have evaluated the effects of fluctuating environmental conditions on relatedness structure of solitary species in the wild. The aim of this study was to determine the impact of interannual variations in environmental conditions on the spatial distribution of relatives [spatial genetic structure (SGS)] and dispersal patterns of a wild population of eastern chipmunks (Tamias striatus), a solitary rodent of North America. Eastern chipmunks depend on the seed of masting trees for reproduction and survival. Here, we combined the analysis of the SGS of adults with direct estimates of juvenile dispersal distance during six contrasted years with different dispersal seasons, population sizes and seed production. We found that environmental conditions influences the dispersal distances of juveniles and that male juveniles dispersed farther than females. The extent of the SGS of adult females varied between years and matched the variation in environmental conditions. In contrast, the SGS of males did not vary between years. We also found a difference in SGS between males and females that was consistent with male-biased dispersal. This study suggests that both the dispersal behaviour and the relatedness structure in a population of a solitary species can be relatively labile and change according to environmental conditions. PMID- 23017102 TI - Ischaemia, reperfusion, pre-and post-conditioning: telling friend from foe. PMID- 23017103 TI - Dystonia--a disorder of dynamics of brain plasticity modulation? PMID- 23017105 TI - Reporting, representation, and subgroup analysis of race and ethnicity in published clinical trials of atopic dermatitis in the United States between 2000 and 2009. AB - To review the literature on atopic dermatitis (AD) clinical trials published in the United States between 2000 and 2009 to examine the representation of racial and ethnic minorities in those trials and determine the extent to which investigators reported on demographic variables and performed a subanalysis. A PubMed search was performed including all clinical trials for management of AD published between 2000 and 2009. Three reviewers analyzed articles matching the search criteria. Data recorded included incorporation of demographic data at baseline and in the analysis and result interpretations. Of 645 PubMed search results, only 78 articles originated in the United States and fit the search criteria; 59.5% of these included reports of race or ethnicity. Of the studies reporting race or ethnicity, the subject population mainly included 62.1% white, 18.0% black, 6.9% Asian, and 2.0% Hispanic. Despite increasing awareness in the United States of the importance of reporting demographic data in clinical trials, there has been no significant improvement in reporting in AD clinical trials over the past 10 years. When reporting occurs, the categorization of ethnicities, methods of reporting data, and incorporation of the data into the results are lacking or flawed. In addition, aside from blacks, U.S. minorities appear to be underrepresented in AD clinical trials. PMID- 23017106 TI - Using primary health care (PHC) workers and key informants for community based detection of blindness in children in Southern Malawi. AB - BACKGROUND: There is great interest in providing primary eye care (PEC) through integration into primary health care (PHC). However, there is little evidence of the productivity of PHC workers in offering primary eye care after training and integration, and there is need to compare their effectiveness to alternative methods. The current study compared the effectiveness of trained Health Surveillance Assistants (HSAs) versus trained volunteer Key Informants (KIs) in identifying blind children in southern Malawi. METHODS: A cluster community based study was conducted in Mulanje district, population 435 753. Six clusters each with a population of approximately 70 000 to 80 000, 42% of whom were children were identified and randomly allocated to either HSA or KI training. From each cluster 20 HSAs or 20 KIs were selected for training. Training emphasized the causes of blindness in children and their management, and how to identify and list children suspected of being blind. HSAs and KIs used multiple methods (door to door, school screening, health education talks, village announcements, etc.) to identify children. Using the World Health Organization (WHO) estimates (eight blind children per 10 000 children); approximately 144 to 162 blind children were expected in the chosen clusters. Listed children were brought to a centre within the community where they were examined by an ophthalmologist and findings recorded using the WHO form for examining blindness in children. RESULTS: A total of 59 HSAs and 64 KIs were trained. HSAs identified five children of whom two were confirmed as blind (one blind child per 29.5 HSAs trained). On the other hand, the KIs identified a total of 158 children of whom 20 were confirmed blind (one blind child per 3.2 KIs trained). More blind boys than girls were identified (77.3% versus 22.7%) respectively. CONCLUSION: Key Informants were much better at identifying blind children than HSAs, even though both groups identified far fewer blind children compared with WHO estimates. HSAs reported lack of time as a major constraint in identifying blind children. Based on these findings using HSAs for identifying blind children would not be successful in Malawi. Gender differences need to be addressed in all childhood blindness programs to counteract the imbalance. PMID- 23017107 TI - Dental caries in a cohort of very young American Indian children. AB - OBJECTIVES: This paper reports the prevalence and severity of caries in a group of 16-month-old American Indian children. METHODS: The study is an ongoing longitudinal study of risk factors for caries in children from a Northern Plains Tribal community. Children were examined for caries and risk factor data collected at approximately 1, 4, 8, 12, and 16 months of age. Surface-specific caries data were collected and the presence of precavitated "white spot" lesions was recorded at the subject level. RESULTS: The mean age was 15.4 months for the sample of 232 children. Caries prevalence was 31.9 percent, while an additional 29.3 percent had white spot lesions only. Mean dmfs was 1.57, and ranged from 0 to 44 surfaces. Nearly 3 percent of all erupted tooth surfaces were affected and maxillary central incisors had the highest prevalence of caries (22 percent). CONCLUSIONS: Among the very youngest children, dental caries prevalence was very high among these American Indian children. PMID- 23017108 TI - Proinsulin slows retinal degeneration and vision loss in the P23H rat model of retinitis pigmentosa. AB - Proinsulin has been characterized as a neuroprotective molecule. In this work we assess the therapeutic potential of proinsulin on photoreceptor degeneration, synaptic connectivity, and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa (RP). P23H homozygous rats received an intramuscular injection of an adeno-associated viral vector serotype 1 (AAV1) expressing human proinsulin (hPi+) or AAV1-null vector (hPi-) at P20. Levels of hPi in serum were determined by enzyme-linked immunosorbent assay (ELISA), and visual function was evaluated by electroretinographic (ERG) recording at P30, P60, P90, and P120. Preservation of retinal structure was assessed by immunohistochemistry at P120. Human proinsulin was detected in serum from rats injected with hPi+ at all times tested, with average hPi levels ranging from 1.1 nM (P30) to 1.4 nM (P120). ERG recordings showed an amelioration of vision loss in hPi+ animals. The scotopic b-waves were significantly higher in hPi+ animals than in control rats at P90 and P120. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. hPi+ animals had 48.7% more photoreceptors than control animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were preserved in hPi+ P23H rats. Furthermore, in hPi+ rat retinas the number of rod bipolar cell bodies was greater than in control rats. Our data demonstrate that hPi expression preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in the P23H rat. These data strongly support the further development of proinsulin-based therapy to counteract retinitis pigmentosa. PMID- 23017109 TI - Combined exposure to Maneb and Paraquat alters transcriptional regulation of neurogenesis-related genes in mice models of Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a multifactorial disease where environmental factors act on genetically predisposed individuals. Although only 5% of PD manifestations are associated with specific mutations, majority of PD cases are of idiopathic origin, where environment plays a prominent role. Concurrent exposure to Paraquat (PQ) and Maneb (MB) in rural workers increases the risk for PD and exposure of adult mice to MB/PQ results in dopamine fiber loss and decreased locomotor activity. While PD is characterized by neuronal loss in the substantia nigra, we previously showed that accumulation of alpha synuclein in the limbic system contributes to neurodegeneration by interfering with adult neurogenesis. RESULTS: We investigated the effect of pesticides on adult hippocampal neurogenesis in two transgenic models: Line 61, expressing the human wild type SNCA gene and Line LRRK2(G2019S), expressing the human LRRK2 gene with the mutation G2019S. Combined exposure to MB/PQ resulted in significant reduction of neuronal precursors and proliferating cells in non-transgenic animals, and this effect was increased in transgenic mice, in particular for Line 61, suggesting that alpha-synuclein accumulation and environmental toxins have a synergistic effect. We further investigated the transcription of 84 genes with direct function on neurogenesis. Overexpresion of alpha-synuclein resulted in the downregulation of 12% of target genes, most of which were functionally related to cell differentiation, while LRRK2 mutation had a minor impact on gene expression. MB/PQ also affected transcription in non-transgenic backgrounds, but when transgenic mice were exposed to the pesticides, profound alterations in gene expression affecting 27% of the studied targets were observed in both transgenic lines. Gene enrichment analysis showed that 1:3 of those genes were under the regulation of FoxF2 and FoxO3A, suggesting a primary role of these proteins in the response to genetic and environmental cues. CONCLUSIONS: We report that adult neurogenesis is highly susceptible to multiple "risk factors" for PD, including alpha-synuclein accumulation, LRRK2 G2019 mutation and exposure to environmental toxins. We identified specific groups of genes that are responsive to each stressor, while uncovering a novel function for Fox transcription factors in PD. PMID- 23017110 TI - Bridging Therapy: A Challenging Area in the Management of Patients with Atrial Fibrillation. PMID- 23017112 TI - Hemangioma of the umbilical cord with amnionic epithelial inclusion cyst. AB - A case of hemangioma of the umbilical cord with an associated amnionic epithelial inclusion cyst (4.5 cm in maximum dimension), diagnosed by pathological examination at 26 weeks of gestation following in utero fetal demise, is reported. These are both uncommon lesions of the umbilical cord, and to our knowledge, have not been reported together. Prenatal ultrasound at 20 weeks of gestation had shown no fetal or placental abnormalities. The cyst formation may have been secondary to the hemangioma, possibly the result of damage to the amnion caused by the associated edema and myxomatous degeneration of Wharton's jelly. PMID- 23017113 TI - Clinico-pathologic findings in children with hepatopulmonary syndrome. AB - Hepatopulmonary syndrome (HPS) is infrequently reported in children. Clinical pathological findings in 10 HPS children were compared with non-HPS controls. Six patients had cirrhosis and four had noncirrhotic portal hypertension (NCPH) 40%. Polysplenia and abnormal venous malformations were exclusive to this group. This prevalence of NCPH with systemic venous anomalies suggests that HPS is associated with pulmonary vasoactive factors not cleared by the liver. Hepatopulmonary syndrome should be considered in any patient with hypoxemia and intrapulmonary shunting whether there is overt clinical liver disease or not. PMID- 23017111 TI - Temporal trends in the frequency of twins and higher-order multiple births in Canada and the United States. AB - BACKGROUND: The dramatic increase in multiple births is an important public health issue, since such births have elevated risks for adverse perinatal outcomes. Our objective was to explore the most recent temporal trends in rates of multiple births in Canada and the United States. METHODS: Live birth data from Canada (excluding Ontario) and the United States from 1991-2009 were used to calculate rates of twins, and triplet and higher-order multiples (triplet+). Temporal trends were assessed using tests for linear trend and absolute and relative changes in rates. RESULTS: Twin live births in the United States increased from 23.1 in 1991 to 32.2 per 1,000 live births in 2004, remained stable between 2004 and 2007, and then increased slightly to an all-time high of 33.2 per 1,000 live births in 2009. In Canada, rates also increased from 20.0 in 1991 to 28.3 per 1,000 live births in 2004, continued to increase modestly between 2004 and 2007, and rose to a high of 31.4 per 1,000 in 2009. Rates of triplet+ live births in the United States increased dramatically from 81.4 in 1991 to 193.5 per 100,000 live births in 1998, remained stable between 1998 and 2003 and then decreased to 148.9 per 100,000 in 2007. The rate declined marginally in 2008, but then rose again in 2009 to 153.5 per 100,000. Rates of triplet+ live births were much lower in Canada, although the temporal pattern of change was similar. CONCLUSION: The rate of twin live births in the United States and Canada continues to increase, though more modestly than during the 1990s. Recent declines in rates of triplet+ live births in both countries have been followed by unstable trends. PMID- 23017114 TI - Diketopyrrolopyrrole-diketopyrrolopyrrole-based conjugated copolymer for high mobility organic field-effect transistors. AB - In this communication, we report the synthesis of a novel diketopyrrolopyrrole diketopyrrolopyrrole (DPP-DPP)-based conjugated copolymer and its application in high-mobility organic field-effect transistors. Copolymerization of DPP with DPP yields a copolymer with exceptional properties such as extended absorption characteristics (up to ~1100 nm) and field-effect electron mobility values of >1 cm(2) V(-1) s(-1). The synthesis of this novel DPP-DPP copolymer in combination with the demonstration of transistors with extremely high electron mobility makes this work an important step toward a new family of DPP-DPP copolymers for application in the general area of organic optoelectronics. PMID- 23017115 TI - Longitudinal deformation of contemporary coronary stents: an integrated analysis of clinical experience and observations from the bench. AB - OBJECTIVE: To report clinical experience with longitudinal stent deformation (LSD) and observations from the bench. BACKGROUND: LSD was recently reported with thin-strut coronary stents. Whether it is related to a particular stent or constitutes a class-effect remains debatable. METHODS: After 2 cases of LSD were reported, information was sent to operators to warn of this event and identify possible cases. All cases were reviewed to ensure LSD had occurred. Simultaneously, bench testing was conducted to identify the susceptibility of stents to longitudinal compression and whether LSD detection is influenced by fluoroscopic stent visibility. RESULTS: Between July 2010 and November 2011, 2,705 coronary interventions were performed with 4,588 stents (Promus Element = 41.6%, Xience Prime = 24.4%). Six patients with LSD were identified, all with Promus Element (0.31%). Wire bias was a predisposing factor in 4 cases. All patients were treated with postdilatation and/or additional stenting. No adverse events occurred (mean 5.8 months). In bench testing, LSD occured in all examined stents, but at different levels of applied force (weight). Most shortening at 50 g was observed with Promus Element (38.9%), as was the best visibility of LSD on x-ray images. With postdilatation all stents showed some re-elongation. CONCLUSION: In our practice LSD was a rare observation only seen with the Promus Element stent. When subjected to longitudinal compression in a bench test all contemporary stents can be compressed. Compression of Promus Element occurs at a lower force, but it is the only stent where deformations are detected with x ray. Postdilatation can partially improve LSD. PMID- 23017117 TI - Playing in or out of character: user role differences in the experience of interactive storytelling. AB - Interactive storytelling (IS) is a promising new entertainment technology synthesizing preauthored narrative with dynamic user interaction. Existing IS prototypes employ different modes to involve users in a story, ranging from individual avatar control to comprehensive control over the virtual environment. The current experiment tested whether different player modes (exerting local vs. global influence) yield different user experiences (e.g., senses of immersion vs. control). A within-subject design involved 34 participants playing the cinematic IS drama "Emo Emma"( 1 ) both in the local (actor) and in global (ghost) mode. The latter mode allowed free movement in the virtual environment and hidden influence on characters, objects, and story development. As expected, control related experiential qualities (effectance, autonomy, flow, and pride) were more intense for players in the global (ghost) mode. Immersion-related experiences did not differ over modes. Additionally, men preferred the sense of command facilitated by the ghost mode, whereas women preferred the sense of involvement facilitated by the actor mode. PMID- 23017116 TI - Adipose tissue engineering in three-dimensional levitation tissue culture system based on magnetic nanoparticles. AB - White adipose tissue (WAT) is becoming widely used in regenerative medicine/cell therapy applications, and its physiological and pathological importance is increasingly appreciated. WAT is a complex organ composed of differentiated adipocytes, stromal mesenchymal progenitors known as adipose stromal cells (ASC), as well as endothelial vascular cells and infiltrating leukocytes. Two dimensional (2D) culture that has been typically used for studying adipose cells does not adequately recapitulate WAT complexity. Improved methods for reconstruction of functional WAT ex vivo are instrumental for understanding of physiological interactions between the composing cell populations. Here, we used a three-dimensional (3D) levitation tissue culture system based on magnetic nanoparticle assembly to model WAT development and growth in organoids termed adipospheres. We show that 3T3-L1 preadipocytes remain viable in spheroids for a long period of time, while in 2D culture, they lose adherence and die after reaching confluence. Upon adipogenesis induction in 3T3-L1 adipospheres, cells efficiently formed large lipid droplets typical of white adipocytes in vivo, while only smaller lipid droplet formation is achievable in 2D. Adiposphere-based coculture of 3T3-L1 preadipocytes with murine endothelial bEND.3 cells led to a vascular-like network assembly concomitantly with lipogenesis in perivascular cells. Adipocyte-depleted stromal vascular fraction (SVF) of mouse WAT cultured in 3D underwent assembly into organoids with vascular-like structures containing luminal endothelial and perivascular stromal cell layers. Adipospheres made from primary WAT cells displayed robust proliferation and complex hierarchical organization reflected by a matricellular gradient incorporating ASC, endothelial cells, and leukocytes, while ASC quickly outgrew other cell types in adherent culture. Upon adipogenesis induction, adipospheres derived from the SVF displayed more efficient lipid droplet accumulation than 2D cultures. This indicates that 3D intercellular signaling better recapitulates WAT organogenesis. Combined, our studies show that adipospheres are appropriate for WAT modeling ex vivo and provide a new platform for functional screens to identify molecules bioactive toward individual adipose cell populations. This 3D methodology could be adopted for WAT transplantation applications and aid approaches to WAT-based cell therapy. PMID- 23017118 TI - Mirrored morality: an exploration of moral choice in video games. AB - This exploratory study was designed to examine how players make moral choices in video games and what effects these choices have on emotional responses to the games. Participants (n=75) filled out a moral foundations questionnaire (MFQ) and then played through the first full act of the video game Fallout 3. Game play was recorded and content analyzed for the moral decisions made. Players also reported their enjoyment of and emotional reactions to the game and reflected on the decisions they made. The majority of players made moral decisions and behaved toward the nonplayer game characters they encountered as if these were actual interpersonal interactions. Individual differences in decision making were predicted by the MFQ. Behaving in antisocial ways did increase guilt, but had no impact on enjoyment. PMID- 23017119 TI - Intracavity DNA melting analysis with optofluidic lasers. AB - DNA melting analysis holds great promise for simple and fast DNA sequence discrimination. However, conventional fluorescence-based methods suffer from a small differential signal and demanding melting curve analysis, both of which make it difficult to distinguish the target DNA from the mismatched one. Herein, we propose and demonstrate a highly specific intracavity DNA melting analysis scheme utilizing an optofluidic laser. The laser optically amplifies the small yet intrinsic thermal dynamic difference between the target and the single-base mismatched DNA, resulting in a differential signal that is orders of magnitude greater than with fluorescence-based methods. In particular, the existence of a phase transition between the stimulated laser emission and fluorescence (i.e., spontaneous emission) enables accurate determination of the DNA transition temperature difference. Furthermore, the high differential signal in the intracavity detection allows for scanning of the laser excitation at a fixed temperature to distinguish two DNA sequences, which provides another means for rapid DNA analysis. In this paper, we first theoretically investigate DNA melting analysis using an optofluidic laser and then experimentally explore this scheme with a high-quality optofluidic ring resonator. Distinction of two DNA sequences of up to 100 bases long is demonstrated. The intracavity detection developed here will lead to novel optofluidic devices that enable rapid and simple analysis of DNAs with very long sequences. PMID- 23017120 TI - A threat to one is a threat to all - biosecurity for the western world starts in developing countries: do we speak the same language of hygiene. PMID- 23017121 TI - Anoxia-induced release of colloid- and nanoparticle-bound phosphorus in grassland soils. AB - Particle-facilitated transport is a key mechanism of phosphorus (P) loss in agroecosystems. We assessed contributions of colloid- and nanoparticle-bound P (nPP; 1-415 nm) to total P released from grassland soils receiving biannual poultry litter applications since 1995. In laboratory incubations, soils were subjected to 7 days of anoxic conditions or equilibrated at pH 6 and 8 under oxic conditions and then the extract was size fractionated by differential centrifugation/ultrafiltration for analysis of P, Al, Fe, Si, Ti, and Ca. Selected samples were characterized by transmission electron microscopy-energy dispersive spectroscopy (TEM-EDS) and field flow fractionation (FFF-ICP-MS). Particles released were present as nanoaggregates with a mean diameter of 200-250 nm, composed of ~50-nm aluminosilicate flakes studded with Fe and Ti-rich clusters (<10 nm) that contained most of the P detected by EDS. Anoxic incubation of stimulated nPP release with seasonally saturated soils released more nPP and Fe(2+)(aq) than well-drained soils; whereas, nonreductive particle dispersion, accomplished by raising the pH, yielded no increase in nPP release. This suggests Fe acts as a cementing agent, binding to the bulk soil P-bearing colloids that can be released during reducing conditions. Furthermore, it suggests prior periodic exposure to anoxic conditions increases susceptibility to redox-induced P mobilization. PMID- 23017122 TI - Arginase enzymes in the human prostate: expression of arginase isoenzymes and effects of arginase inhibitors on isolated human prostate tissue. AB - What's known on the subject? and What does the study add? A previous study by Lexander et al. in 2005, using two-dimensional gel electrophoresis, demonstrated the expression of arginase type II in the different anatomical regions of the prostate; however, to date, no study has addressed, using an in vitro approach, the role of arginase isoenzymes in the human prostate. The results of the present study demonstrate that: both arginase isoenzymes, Arg I and Arg II, are expressed in the transition zone of the human prostate; the inhibition of arginase antagonized, to a certain degree, the tension brought about by noradrenaline in isolated human prostate tissue; exposure of human prostate tissue to arginase inhibitors enhanced the local production of cyclic GMP; and inhibition of arginase enzymes in the human prostate may augment the activity of the nitric oxide/cyclicGMP pathway. OBJECTIVE: * To investigate the expression of arginase isoenzymes type I (Arg I) and type II (Arg II) in the transition zone of the human prostate and the functional significance of arginase enzymes in the control of prostate smooth muscle. MATERIALS AND METHODS: * Human prostate tissue was obtained from male patients who had undergone pelvic surgery. * The expression of Arg I and Arg II was investigated using Western blot analysis. * Using the organ bath technique, the effects of cumulative administration of difluoromethylornithine (DFMO), H-Orn-OH * HCl, H-Ile-OH and N-omega-hydroxy-nor L-arginine (nor-NOHA; 1 nM-10 uM) on the tension induced by noradrenaline in isolated prostate tissue were assessed. * Tissue strips were also exposed to arginase inhibitors and the production of cyclic GMP was determined. RESULTS: * Western blot analysis showed the expression of Arg I and Arg II in the transition zone of the prostate. * The tension induced by noradrenaline was antagonized by the drugs in the following rank order of efficacy: H-Orn-OH * HCl >= H-Ile-OH >= DFMO > nor-NOHA; however, the maximum reversion of tension recorded ranged from only -25 to -13%. * The enhancement in cyclic GMP production registered in the presence of the arginase inhibitors ranged from four- to 14-fold. CONCLUSIONS: * Arg I and Arg II are expressed in the transition zone of the human prostate. * Isometric tension studies and measurement of cyclic GMP showed that inhibition of arginase can reverse, to a certain degree, the tension of human prostate tissue induced by the activation of alpha-adrenoceptors and enhance the accumulation of cyclic GMP. * Future studies should explore further the role of arginase enzymes in the relaxation mediated by nitric oxide in prostate smooth muscle. PMID- 23017128 TI - Illness perception among patients with chest pain and palpitations before and after negative cardiac evaluation. AB - BACKGROUND: Patients with chest pain or palpitations often have poor outcomes following a negative cardiac evaluation, with symptom persistence, limitations in everyday activities, and reduced health-related quality of life. The aims of this study were to evaluate illness perceptions before and after negative cardiac evaluations and measure the ability of a self-report questionnaire to predict outcomes. METHODS: Patients (N = 138) referred for chest pain or palpitations to a cardiac outpatient clinic were assessed before and six months after a negative cardiac evaluation. In addition to Brief Illness Perception Questionnaire (BIPQ), all patients completed the Beck Depression Inventory and SF-36 Health Survey. RESULTS: The emotional reactions to and understanding of symptoms had not improved six months after a negative cardiac evaluation. A stronger correlation between illness perceptions and health at follow-up than before the cardiac evaluation might explain the tendency for poor outcomes among these patients. Most of the eight BIPQ item scores before the negative cardiac evaluation were predictive of the outcome six months later. A single question asking about the perceived consequences of the complaints (BIPQ Item 1) rated before the cardiac evaluation was collapsed into a dichotomous variable with a cut-off at >=4 which yields a sensitivity of 51%, a specificity of 85%, a positive predictive value of 71%, a negative predictive value of 69%, and an odds ratio of 5.7 (r = .38, p < .001) in predicting poor outcomes. CONCLUSIONS: Assessing illness perceptions is important in patients with negative cardiac tests for understanding and predicting outcomes. PMID- 23017129 TI - Quadrivalent human papillomavirus (HPV) types 6, 11, 16, 18 vaccine for the prevention of genital warts in males: profile report. demail@springer.com. AB - ?Adapted and reproduced from the original article published in Drugs 2011; 71 (5): 591-602.[1]. PMID- 23017130 TI - Pharmacoeconomic spotlight on rotavirus vaccine RIX4414 (RotarixTM) in developed countries. AB - The most common cause of severe diarrhea in infants and young children is rotavirus gastroenteritis (RVGE), which is associated with significant morbidity, healthcare resource use, and direct and indirect costs in industrialized nations. The monovalent rotavirus vaccine RIX4414 (RotarixTM) is administered as a two dose oral series in infants and has demonstrated protective efficacy against RVGE in clinical trials conducted in developed countries. In addition, various naturalistic studies have demonstrated 'real-world' effectiveness after the introduction of widespread rotavirus vaccination programs in the community setting. Numerous cost-effectiveness analyses have been conducted in developed countries in which a universal rotavirus vaccination program using RIX4414 was compared with no universal rotavirus vaccination program. There was a high degree of variability in base-case results across studies even when the studies were conducted in the same country, often reflecting differences in the selection of data sources or assumptions used to populate the models. In addition, results were sensitive to plausible changes in a number of key input parameters. As such, it is not possible to definitively state whether a universal rotavirus vaccination program with RIX4414 is cost effective in developed countries, although results of some analyses in some countries suggest this is the case. In addition, international guidelines advocate universal vaccination of infants and children against rotavirus. It is also difficult to draw conclusions regarding the cost effectiveness of rotavirus vaccine RIX4414 relative to that of the pentavalent rotavirus vaccine, which is administered as a three-dose oral series. Although indirect comparisons in cost-effectiveness analyses indicate that RIX4414 provided more favorable incremental cost-effectiveness ratios when each vaccine was compared with no universal rotavirus vaccination program, results were generally sensitive to vaccine costs. Actual tender prices of a full vaccination course for each vaccine were not known at the time of the analyses and therefore had to be estimated. PMID- 23017131 TI - Increasing community health worker productivity and effectiveness: a review of the influence of the work environment. AB - BACKGROUND: Community health workers (CHWs) are increasingly recognized as a critical link in improving access to services and achieving the health-related Millennium Development Goals. Given the financial and human resources constraints in developing countries, CHWs are expected to do more without necessarily receiving the needed support to do their jobs well. How much can be expected of CHWs before work overload and reduced organizational support negatively affect their productivity, the quality of services, and in turn the effectiveness of the community-based programmes that rely on them? This article presents policy-makers and programme managers with key considerations for a model to improve the work environment as an important approach to increase CHW productivity and, ultimately, the effectiveness of community-based strategies. METHODS: A desk review of selective published and unpublished articles and reports on CHW programs in developing countries was conducted to analyse and organize findings on the elements that influence CHW productivity. The search was not exhaustive but rather was meant to gather information on general themes that run through the various documents to generate perspectives on the issue and provide evidence on which to formulate ideas. After an initial search for key terminology related to CHW productivity, a snowball technique was used where a reference in one article led to the discovery of additional documents and reports. RESULTS: CHW productivity is determined in large part by the conditions under which they work. Attention to the provision of an enabling work environment for CHWs is essential for achieving high levels of productivity. We present a model in which the work environment encompasses four essential elements-workload, supportive supervision, supplies and equipment, and respect from the community and the health system-that affect the productivity of CHWs. We propose that when CHWs have a manageable workload in terms of a realistic number of tasks and clients, an organized manner of carrying out these tasks, a reasonable geographic distance to cover, the needed supplies and equipment, a supportive supervisor, and respect and acceptance from the community and the health system, they can function more productively and contribute to an effective community-based strategy. CONCLUSIONS: As more countries look to scale up CHW programmes or shift additional tasks to CHWs, it is critical to pay attention to the elements that affect CHW productivity during programme design as well as implementation. An enabling work environment is crucial to maximize CHW productivity. Policy-makers, programme managers, and other stakeholders need to carefully consider how the productivity elements related to the work environment are defined and incorporated in the overall CHW strategy. Establishing a balance among the four elements that constitute a CHW's work environment will help make great strides in improving the effectiveness and quality of the services provided by CHWs. PMID- 23017132 TI - Cutaneous and disseminated blastomycosis: a pediatric case series. AB - Blastomycosis is a rare fungal infection that most often initially infects the lungs and can progress to disseminated involvement of the skin, bones, and central nervous system (CNS). Pediatric blastomycosis constitutes a small portion of total cases, but delay in diagnosis may result in significant morbidity. Seventeen pediatric cases of blastomycosis were identified at Children's Hospital of Wisconsin from 1999 to 2009 through retrospective chart review; 53% had evidence of dissemination (bone, skin, or CNS) confirmed by culture. Six cases presented with cutaneous lesions, and five of these were found to have other systemic involvement. These five nonimmunosuppressed cases of primary pulmonary disease with cutaneous involvement plus dissemination to bone or the CNS are reported in detail. The diagnosis of blastomycosis in children is often delayed, and dissemination by the time of diagnosis may be more common than in adults. Cutaneous dissemination may occur in immunocompetent children, may indicate underlying systemic involvement, and can be more readily identified than symptoms of bony or neurologic involvement. These reported cases indicate the importance of dermatologists recognizing and investigating all potentially involved organ systems when a patient presents with characteristic skin lesions with or without a history of respiratory illness. PMID- 23017123 TI - Single-nucleotide polymorphism discovery and diversity in the model legume Medicago truncatula. AB - Extensive genomic resources are available in the model legume Medicago truncatula. Here, we present the discovery and design of the first array of single-nucleotide polymorphism (SNP) markers in M. truncatula through large-scale Sanger resequencing of genomic fragments spanning the genome, in a diverse panel of 16 M. truncatula accessions. Both anonymous fragments and fragments targeting candidate genes for flowering phenology and symbiosis were surveyed for nucleotide variation in almost 230 kb of unique genomic regions. A set of 384 SNP markers was designed for an Illumina's GoldenGate assay, genotyped on a collection of 192 inbred lines (CC192) representing the geographical range of the species and used to survey the diversity of two natural populations. Finally, 86% of the tested SNPs were of high quality and exhibited polymorphism in the CC192 collection. Even at the population level, we detected polymorphism for more than 50% of the selected SNPs. Analysis of the allele frequency spectrum in the CC192 showed a reduced ascertainment bias, mostly limited to very rare alleles (frequency <0.01). The substantial polymorphism detected at the species and population levels, the high marker quality and the potential to survey large samples of individuals make this set of SNP markers a valuable tool to improve our understanding of the effect of demographic and selective factors that shape the natural genetic diversity within the selfing species Medicago truncatula. PMID- 23017134 TI - Guest editorial. PMID- 23017135 TI - Negative regulation of myeloid-derived suppressor cells in cancer. AB - Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with suppressive function on immune response. In this review, we discuss recent studies about mechanisms of expansion and suppressive function of MDSCs during inflammation, infection and autoimmune diseases, as well as pro-angiogenic and pro-metastatic functions of these cells in tumor development. Further, we focus on novel studies of MDSCs and therapeutic approaches to eliminate these cells in cancer. PMID- 23017136 TI - Immune suppression: the hallmark of myeloid derived suppressor cells. AB - Myeloid derived suppressor cells (MDSC) are heterogeneous cell population consisting of myeloid progenitor cells and immature myeloid cells. These cells have essential immunoregulatory role in tumor bearing hosts and under different inflammatory conditions. No specific marker has been described to identify MDSC, which leaves their suppressor activity as their only hallmark function. In this review, we discuss the current in vivo and in vitro developed assays for elucidation of MDSC function and describe the discrepancies between murine and human MDSC in regard to their suppressor function. We also discuss antigen specificity of MDSC function and approaches to determine the effector function of these cells in vivo. Finally, we summarize different approaches currently being employed to target MDSC with the aim to enhance immune based therapies. PMID- 23017137 TI - Myeloid-derived suppressor cells and anti-tumor T cells: a complex relationship. AB - Myeloid-Derived Suppressor Cells (MDSC) are immature myeloid cells that are potent inhibitors of immune cell function and which accumulate under conditions of inflammation, especially cancer. MDSC are suggested to promote the growth of cancer by both enhancement of tumor angiogenesis and metastasis and also inhibition of antitumor immune responses. The presence of deficient and/or defective antitumor adaptive and innate immune responses, coincident with accumulation of MDSC in lymphoid organs and tumor parenchyma, supports the notion of a causal relationship. The potent ability of MDSC to inhibit several components and phases of immune response highlights the likelihood that targeting the inhibitory functions of MDSC may maximize the therapeutic potential of antitumor immunotherapy. In order to guide the rational development of immunotherapeutic strategies that incorporate inhibition of MDSC activity and enzymatic functions, thorough understanding of the role of MDSC in antitumor immune responses is required. In this manuscript we review the multifaceted inhibitory functions of MDSC and consider the role of MDSC-induced inhibition of antitumor T cell effector phase. Support for this research is from NIH R01 CA108573. PMID- 23017139 TI - PGE(2)-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells. AB - Myeloid-derived suppressor cells (MDSCs) are critical mediators of tumor associated immune suppression, with their numbers and activity strongly increased in most human cancers and animal models. MDSCs suppress anti-tumor immunity through multiple mechanisms, including the manipulation of arginine and tryptophan metabolism by such factors as arginase (Arg), inducible nitric oxide synthase (iNOS/NOS2), and indoleamine-2,3-dioxygenase (IDO). Prostaglandin E(2) (PGE(2)), a mediator of chronic inflammation and tumor progression, has emerged as a key molecule in MDSC biology. PGE(2) promotes MDSC development and their induction by additional factors, directly suppresses T cell immune responses and participates in the induction of other MDSC-associated suppressive factors, including Arg, iNOS and IDO. It further promotes MDSC recruitment to tumor environments through the local induction of CXCL12/SDF-1 and the induction and stabilization of the CXCL12 receptor, CXCR4, on tumor-associated MDSCs. The establishment of a positive feedback loop between PGE(2) and cyclooxygenase 2 (COX-2), the key regulator of PGE(2) synthesis, stabilizes the MDSC phenotype and is required for their suppressive function. The central role of PGE(2) in MDSC biology provides for a feasible target for counteracting MDSC-mediated immune suppression in cancer. PMID- 23017138 TI - Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. AB - Patients with cancer have an impaired T cell response that can decrease the potential therapeutic benefit of cancer vaccines and other forms of immunotherapy. The establishment of a chronic inflammatory environment in patients with cancer plays a critical role in the induction of T cell dysfunction. The accumulation of myeloid-derived suppressor cells (MDSC) in tumor bearing hosts is a hallmark of malignancy-associated inflammation and a major mediator of the induction of T cell suppression in cancer. Recent findings in tumor bearing mice and cancer patients indicate that the increased metabolism of L-Arginine (L-Arg) by MDSC producing Arginase I inhibits T cell lymphocyte responses. Here, we discuss some of the most recent concepts of how MDSC expressing Arginase I may regulate T cell function in cancer and suggest possible therapeutic interventions to overcome this inhibitory effect. PMID- 23017140 TI - Myeloid-derived suppressor cells (MDSCs) in gliomas and glioma-development. AB - Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells that inhibit anti-tumor immunity through a variety of mechanisms. Malignant gliomas are heavily infiltrated by myeloid cells, some of which appear to share biological functions of MDSCs. Our data with mouse de novo gliomas indicate critical roles of these cells in glioma development. This review summarizes the current understanding of MDSC biology in gliomas and discusses therapeutic interventions that can safely reverse the suppressive effects of MDSCs. The insight gained from these findings may lead to the development of novel immunotherapeutic strategies for gliomas. PMID- 23017142 TI - Phenotypic plasticity of MDSC in cancers. AB - Myeloid-derived suppressor cells (MDSCs) were initially reported as suppressor of the adaptive immune responses against cancer and other diseases. However, emerging evidence suggest that MDSCs may also support anti-tumor immune responses under certain conditions or may inhibit tumor growth. In the present mini-review, we suggest that such opposing functions of MDSCs are due to phenotypic plasticity of the myeloid cells, allowing them to produce a diverse form of morphology, physiological state, and function in response to environmental conditions. Therefore, they can be manipulated by means of immune modulators to overcome their immune suppressive function. PMID- 23017143 TI - Highlights on molecular mechanisms of MDSC-mediated immune suppression: paving the way for new working hypotheses. AB - MDSCs have been recognized in the last years as tolerogenic cells, potentially dangerous in the context of neoplasia, since they are able to induce tolerance to a variety of anti-tumor effectors, including CD4(+) and CD8(+) T cells. It is currently believed that the origin of MDSCs is due to an arrest of the myeloid differentiation process caused by tumor-secreted factors released in the tumor microenvironment that are able to exert an effect on myeloid progenitors, rendering them unable to terminally differentiate into dendritic cells, granulocytes and macrophages. As a consequence, these immature myeloid cells acquire suppressive activity through the activation of several mechanisms, controlled by different transcription factors. The lack of consensus about the phenotypical characterization of human MDSCs is the result of the existence of different MDSC subsets, most likely depending on the tumor in which they expand and on the tumor specific cytokine cocktail driving their activation. This, in turn, might also influence the mechanisms of MDSC-mediated immune suppression. In this review article we address the role of tumor-derived factors (TDFs) in MDSC recruitment and activation, discuss the complex heterogeneity of MDSC phenotype and analyze the crosstalk between activated T cells and MDSCs. PMID- 23017141 TI - Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape. AB - The receptor tyrosine kinase inhibitor, sunitinib, is astonishingly effective in its capacity to reduce MDSCs in peripheral tissues such as blood (human) and spleen (mouse), restoring responsiveness of bystander T lymphocytes to TcR stimulation. Sunitinib blocks proliferation of undifferentiated MDSCs and decreases survival of more differentiated neutrophilic MDSC (n-MDSC) progeny. Ironically, sunitinib's profound effects are observed even in a total absence of detectable anti-tumor therapeutic response. This is best explained by the presence of disparate MDSC-conditioning stimuli within individual body compartments, allowing sensitivity and resistance to sunitinib to coexist within the same mouse or patient. The presence or absence of GM-CSF is likely the major determinant in each compartment, given that GM-CSF's capacity to preempt STAT3 dependent with dominant STAT5-dependent hematopoietic programming confers sunitinib resistance and redirects differentiation from the n-MDSC lineage to the more versatile monocytoid (m-MDSC) lineage. The clinical sunitinib experience underscores that strategies for MDSC and Treg depletions must be mindful of disparities among body compartments to avoid sanctuary effects. Ironically, m MDSCs manifesting resistance to sunitinib also have the greatest potential to differentiate into tumoricidal accessory cells, by virtue of their capacity to respond to T cell-secreted IFN-gamma or to TLR agonists with nitric oxide and peroxynitrate production. PMID- 23017145 TI - Host indoleamine 2,3-dioxygenase: contribution to systemic acquired tumor tolerance. AB - Indoleamine 2,3-dioxygenase (IDO) is a natural mechanism of creating acquired tolerance in a variety of physiological settings. This endogenous tolerogenic pathway has important functions in regulating the magnitude of immune responses in settings of infection, pregnancy, tissue transplantation, mucosal interfaces and others. Whether for angiogenesis, stromal formation or immunologic tolerance, tumors often rely on recruiting host mechanisms. IDO is one such potent endogenous mechanism that appears to be frequently hijacked by tumors to establish systemic immune tolerance to tumor antigens. IDO can be expressed by tumors themselves, but, in addition, its natural site of expression is the host immune cells recruited by the tumor (particularly dendritic cells and macrophages). Therapeutic strategies that target the IDO pathway have been shown to synergize with standard chemotherapy and experimental immunotherapies to break tumor-induced tolerance. When such strategies target IDO expressed in host cells, they may be able to disrupt tolerance without creating intrinsic tumor cell drug resistance. PMID- 23017146 TI - NIR-responsive and lectin-binding doxorubicin-loaded nanomedicine from Janus-type dendritic PAMAM amphiphiles. AB - Janus-type dendritic poly(amido amine) (PAMAM) amphiphiles Dm-Lac-D3DNQ were synthesized by connecting hydrophobic diazonaphthoquinone (DNQ)-decorated PAMAM dendron D3 (generation 3) and hydrophilic lactose (Lac)-decorated PAMAM dendrons Dm (generations 0-2, m = 0-2) via click chemistry. They self-assembled into the DNQ-cored micelles dangled by densely free Lac groups in aqueous solution. Irradiated by 808 nm laser and 365 nm lamp, both NIR- and UV-sensitivity of micelles were characterized by time-resolved UV-vis spectroscopy. The characteristic absorption intensity of DNQ progressively decreased and then leveled off. Moreover, the bigger the micelles, the more the irradiation time for finishing Wolff rearrangement of DNQ. TEM further confirmed that most of the micelles disassembled after 30 min of 808 nm laser irradiation. The Lac-coated micelles showed binding with RCA(120) lectin, as monitored by UV-vis and DLS. The apparent drug-release rate of doxorubicin (DOX) loaded nanomedicine nearly doubled after 10 min of 808 nm laser irradiation, presenting a NIR-triggered drug release profile. Moreover, the DOX-loaded nanomedicine presented a phototriggered cytotoxicity that was close to free DOX, and they could quickly enter into HeLa cells, as evidenced by MTT assay, flow cytometry, and CLSM. Importantly, this work provides a versatile strategy for the fabrication of NIR-responsive and lectin-binding dendrimer nanomedicine, opening a new avenue for "on-demand" and spatiotemporal drug delivery. PMID- 23017147 TI - Reduced cancer incidence in Huntington's disease: record linkage study clue to an evolutionary trade-off? PMID- 23017144 TI - Indoleamine 2,3-dioxygenase and dendritic cell tolerogenicity. AB - This article summarizes the molecular and cellular mechanisms that regulate the activity of indoleamine 2,3-dioxygenase (IDO), a potent immune-suppressive enzyme, in dendritic cells (DCs). Specific attention is given to differential up regulation of IDO in distinct DC subsets, its function in immune homeostasis/autoimmunity, infection and cancer; and the associated immunological outcomes. The review will conclude with a discussion of the poorly defined mechanisms that mediate the long-term maintenance of IDO-expression in response to inflammatory stimuli and how selective modulation of IDO activity may be used in the treatment of disease. PMID- 23017149 TI - Biodegradable composite scaffolds: a strategy to modulate stem cell behaviour. AB - The application of new biomaterial technologies offers the potential to direct the stem cell fate, targeting the delivery of cells and reducing immune rejection, thereby supporting the development of regenerative medicine. Cells respond to their surrounding structure and with nanostructures exhibit unique proliferative and differentiation properties. This review presents the relevance, the promising perspectives and challenges of current biodegradable composite scaffolds in terms of material properties, processing technology and surface modification, focusing on significant recent patents in these fields. It has been reported how biodegradable porous composite scaffolds can be engineered with initial properties that reproduce the anisotropy, viscoelasticity, tension compression non-linearity of different tissues by introducing specific nanostructures. Moreover the modulation of electrical, morphological, surface and topographic scaffold properties enables specific stem cell response. Recent advances in nanotechnology have allowed to engineer novel biomaterials with these complexity levels. Understanding the specific biological response triggered by various aspects of the fibrous environment is important in guiding the design and engineering of novel substrates that mimic the native cell matrix interactions in vivo. PMID- 23017148 TI - Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs. AB - BACKGROUND: Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite 5'-deoxy-5-fluorouridine (5'-DFUR) trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3) mRNA in cancer cells treated with 5'-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3 participates in the activity of genotoxic agents. METHODS: The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches. RESULTS: 5'-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU) also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced. CONCLUSIONS: Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5'-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest. PMID- 23017150 TI - Stem cell technologies based on hemangioblast technology focusing on human blood cells. AB - The in vitro generation of hematopoietic stem cells (HSCs) and mature hematopoietic cells from hemangioblast derived from embryonic stem (ES) or induced pluripotent stem (iPS) cells promises to provide an alternative source of cells that could replace total bone marrow cells or HSC-enriched fractions. This mini-review deals with innovation related to hemangioblast-based methods for blood cells production as disclosed in recent patent literature and current barriers to clinical translation are discussed. PMID- 23017151 TI - Geographical and ecological stability of the symbiotic mid-gut microbiota in European firebugs, Pyrrhocoris apterus (Hemiptera, Pyrrhocoridae). AB - Symbiotic bacteria often play an essential nutritional role for insects, thereby allowing them to exploit novel food sources and expand into otherwise inaccessible ecological niches. Although many insects are inhabited by complex microbial communities, most studies on insect mutualists so far have focused on single endosymbionts and their interactions with the host. Here, we provide a comprehensive characterization of the gut microbiota of the red firebug (Pyrrhocoris apterus, Hemiptera, Pyrrhocoridae), a model organism for physiological and endocrinological research. A combination of several culture independent techniques (454 pyrosequencing, quantitative PCR and cloning/sequencing) revealed a diverse community of likely transient bacterial taxa in the mid-gut regions M1, M2 and M4. However, the completely anoxic M3 region harboured a distinct microbiota consisting of facultative and obligate anaerobes including Actinobacteria (Coriobacterium glomerans and Gordonibacter sp.), Firmicutes (Clostri-dium sp. and Lactococcus lactis) and Proteobacteria (Klebsiella sp. and a previously undescribed Rickettsiales bacterium). Characterization of the M3 microbiota in different life stages of P. apterus indicated that the symbiotic bacterial community is vertically transmitted and becomes well defined between the second and third nymphal instar, which coincides with the initiation of feeding. Comparing the mid-gut M3 microbial communities of P. apterus individuals from five different populations and after feeding on three different diets revealed that the community composition is qualitatively and quantitatively very stable, with the six predominant taxa being consistently abundant. Our findings suggest that the firebug mid-gut microbiota constitutes a functionally important and possibly coevolved symbiotic community. PMID- 23017152 TI - Mercury methylation rates for geochemically relevant Hg(II) species in sediments. AB - Monomethylmercury (MeHg) in fish from freshwater, estuarine, and marine environments is a major global environmental issue. Mercury levels in biota are mainly controlled by the methylation of inorganic mercuric mercury (Hg(II)) to MeHg in water, sediments, and soils. There is, however, a knowledge gap concerning the mechanisms and rates of methylation of specific geochemical Hg(II) species. Such information is crucial for a better understanding of variations in MeHg concentrations among ecosystems and, in particular, for predicting the outcome of currently proposed measures to mitigate mercury emissions and reduce MeHg concentrations in fish. To fill this knowledge gap we propose an experimental approach using Hg(II) isotope tracers, with defined and geochemically important adsorbed and solid Hg(II) forms in sediments, to study MeHg formation. We report Hg(II) methylation rate constants, k(m), in estuarine sediments which span over 2 orders of magnitude depending on chemical form of added tracer: metacinnabar (beta-(201)HgS(s)) < cinnabar (alpha-(199)HgS(s)) < Hg(II) reacted with mackinawite (=FeS-(202)Hg(II)) < Hg(II) bonded to natural organic matter (NOM-(196)Hg(II)) < a typical aqueous tracer ((198)Hg(NO(3))(2)(aq)). We conclude that a combination of thermodynamic and kinetic effects of Hg(II) solid-phase dissolution and surface desorption control the Hg(II) methylation rate in sediments and cause the large observed differences in k(m)-values. The selection of relevant solid-phase and surface-adsorbed Hg(II) tracers will therefore be crucial to achieving biogeochemically accurate estimates of ambient Hg(II) methylation rates. PMID- 23017153 TI - Low intensity, long-term outpatient rehabilitation in COPD: a randomised controlled trial. AB - BACKGROUND: Most pulmonary rehabilitation programmes currently involve 2-3 sessions per week as recommended by international guidelines. We aimed to investigate whether relevant improvements in physical capabilities and quality of life in patients with chronic obstructive pulmonary disease (COPD) could be achieved by a long-term, low intensity, once weekly rehabilitation programme using limited resources. METHODS: 100 patients with moderate to severe COPD were randomised to a continuous outpatient interdisciplinary rehabilitation programme or standard care. Physiotherapy-led supervised outpatient training sessions were performed once weekly in addition to educational elements. Outcome measures at baseline and after 26 weeks were 6-minute-walk-test, cycle ergometry, and health related quality of life. RESULTS: 37 patients in the training group and 44 patients in the control group completed the study. After 26 weeks there were clinically significant differences between the groups for 6 minute-walk-distance (+59 m, 95% CI 28-89 m), maximum work load (+7.4 Watt, 95% CI 0.5-13.4 Watt) and St. George's Respiratory Questionnaire score (-5 points, 95% CI -10 to -1 points). Total staff costs of the programme per participant were <= ?625. CONCLUSION: Clinically meaningful improvements in physical capabilities and health-related quality of life may be achieved using long-term pulmonary rehabilitation programmes of lower intensity than currently recommended. TRIAL REGISTRATION: clinicaltrials.gov NCT01195402. PMID- 23017154 TI - Effective pharmacological treatment of painful diabetic neuropathy by nurse practitioners: results of an algorithm-based experience. AB - OBJECTIVE: To improve the care of patients with painful diabetic polyneuropathy (PDP) by a specialized outpatient clinic for individuals referred by general practitioners and to determine the effects on pain, quality of life, and patient satisfaction. MATERIAL AND METHODS: One hundred twenty-one patients were prospectively enrolled. At baseline and after 12 months at end of treatment, patients filled in a set of validated questionnaires on severity and interference of pain, quality of life, anxiety and depression, and patient satisfaction with the service offered. SETTING: The outpatient clinic is part of a regional chronic care management program, which includes both hospital-based endocrinologists and general practitioners. RESULTS: Twenty-eight patients (27%) did not need any further treatment after one visit to the outpatient clinic. As initial drug, pregabalin was the most commonly prescribed drug (65%); amitriptyline was prescribed in only 30% due to its contraindications. Improvements were found in all pain scores (P < 0.05). Pain interference was improved in sleep (P < 0.01), general activity, and mood (P < 0.05). More than half of the patients (65%) were satisfied with the treatment and wished no further medication changes; 52% had a treatment success defined as pain relief >= 30%. Medication was stopped due to inefficacy in 9% of patients and changed due to adverse effects in 20% of the patients. CONCLUSIONS: A specialized outpatient clinic for patients with PDP is an effective health care service. Using diagnostic instruments and a defined treatment algorithm, significant pain reduction was achieved in the majority of patients in a relative short period of time. PMID- 23017155 TI - Disseminated fusariosis in a pediatric population. AB - Members of the genus Fusarium are ubiquitous filamentous fungi that can cause disease in immunocompromised patients. We present a case in which the resistance to conventional antifungal therapies led to a fatal outcome. PMID- 23017156 TI - Protein stickiness, rather than number of functional protein-protein interactions, predicts expression noise and plasticity in yeast. AB - BACKGROUND: A hub protein is one that interacts with many functional partners. The annotation of hub proteins, or more generally the protein-protein interaction "degree" of each gene, requires quality genome-wide data. Data obtained using yeast two-hybrid methods contain many false positive interactions between proteins that rarely encounter each other in living cells, and such data have fallen out of favor. RESULTS: We find that protein "stickiness", measured as network degree in ostensibly low quality yeast two-hybrid data, is a more predictive genomic metric than the number of functional protein-protein interactions, as assessed by supposedly higher quality high throughput affinity capture mass spectrometry data. In the yeast Saccharomyces cerevisiae, a protein's high stickiness, but not its high number of functional interactions, predicts low stochastic noise in gene expression, low plasticity of gene expression across different environments, and high probability of forming a homo oligomer. Our results are robust to a multiple regression analysis correcting for other known predictors including protein abundance, presence of a TATA box and whether a gene is essential. Once the higher stickiness of homo-oligomers is controlled for, we find that homo-oligomers have noisier and more plastic gene expression than other proteins, consistent with a role for homo-oligomerization in mediating robustness. CONCLUSIONS: Our work validates use of the number of yeast two-hybrid interactions as a metric for protein stickiness. Sticky proteins exhibit low stochastic noise in gene expression, and low plasticity in expression across different environments. PMID- 23017157 TI - Factors associated with treatment received by men diagnosed with prostate cancer in Queensland, Australia. AB - What's known on the subject? and What does the study add? Men diagnosed with prostate cancer are increasingly involved in making their own treatment decisions and the current recommendations for treatment are based on informed choice. The absence of scientific evidence regarding optimum treatment choices underlines the importance of understanding which factors influence the selection of treatment by men diagnosed with prostate cancer. Previous studies have found that men diagnosed with prostate cancer were more likely to choose radiation therapy over radical prostatectomy if they were older and had a higher PSA level. This is the first large-scale prospective study conducted outside the USA to quantify the factors associated with treatment decisions for men diagnosed with prostate cancer. It found that men who chose surgery were younger, above average physical health, and had lower grade cancers on the Gleason scale; men who had radiation therapy were older and had reduced physical health, with ADT added when men had more advanced disease. About two-thirds of the men said they primarily made the decision about treatment themselves, with the remaining men either sharing the decision-making process with their doctor or else leaving the decision more or less completely up to their doctor. These results highlight the importance of having quality up-to-date information readily available to guide these decisions. OBJECTIVE: * To examine demographic, clinical and quality-of-life indicators for the treatments received by men diagnosed with prostate cancer in Australia. SUBJECTS AND METHODS: * This prospective trial included men diagnosed with prostate cancer (n= 1064, response rate = 82%) between 2005 and 2007 in Queensland, Australia, sampled from urologists and hospital outpatient clinics. * Data were collected through telephone interviews and self-administered questionnaires. * Treatment received was categorized into five groups: radical prostatectomy; radiation therapy with neoadjuvant androgen deprivation therapy (ADT); radiation therapy alone; ADT alone; and monitoring. RESULTS: * Sharp contrasts in the choice between radical prostatectomy (47% of men) vs radiation therapy with ADT (30%) were evident among age at diagnosis, travel time to facilities offering radiation treatment, Gleason score, stage, body mass index and physical health. * Men who underwent surgery were younger and of above average physical health, and had lower grade cancers; men who underwent radiation therapy were older and less fit. ADT, in both neoadjuvant and definitive forms, was administered for high-risk and more advanced disease. * Two-thirds (66%) of men stated that they made the final treatment selection themselves. CONCLUSIONS: * These results suggest that men's baseline health and tumour characteristics influence treatment choices. * Distance from tertiary treatment centres also influenced the treatment received and access to specialist urologists may play a role. * With most men indicating high levels of decisional control, the importance of having quality up-to-date information readily available to guide their decisions cannot be overstated. PMID- 23017159 TI - Antimicrobials targeted to the replication-specific DNA polymerases of gram positive bacteria: target potential of dnaE. AB - DNA polymerases pol IIIC and dnaE [i.e. pol IIIE] are essential for replicative DNA synthesis in low G:C Gram-positive eubacteria. Therefore, they have strong potential as targets for development of Gram-positive-selective antibacterial agents. This work has sought to extend to dnaE the recent discovery of antimicrobial agents based on pol IIIC-specific dGTP analogs. Compound 324C, a member of the same dGTP analog family, was found to be a potent and selective inhibitor of isolated dnaE in vitro. Surprisingly, 324C had no inhibitory effect in either intact Bacillus subtilis cells or in permeabilized cell preparations used to assess replicative DNA synthesis directly. It is proposed that the failure of 324C in the intact cell is a consequence of two major factors: (i) its template-dependent base pairing mechanism, and (ii) a specific subordinate role which dnaE apparently plays to pol IIIC. To generate an effective dnaE-selective inhibitor of replicative DNA synthesis in Gram-positive bacteria, it will likely be necessary to develop a molecule that attacks the enzyme's active site directly, without binding to template DNA. PMID- 23017158 TI - Epidemiology of foodborne norovirus outbreaks, United States, 2001-2008. AB - Noroviruses are the leading cause of foodborne illness in the United States. To better guide interventions, we analyzed 2,922 foodborne disease outbreaks for which norovirus was the suspected or confirmed cause, which had been reported to the Foodborne Disease Outbreak Surveillance System of the Centers for Disease Control and Prevention during 2001-2008. On average, 365 foodborne norovirus outbreaks were reported annually, resulting in an estimated 10,324 illnesses, 1,247 health care provider visits, 156 hospitalizations, and 1 death. In 364 outbreaks attributed to a single commodity, leafy vegetables (33%), fruits/nuts (16%), and mollusks (13%) were implicated most commonly. Infected food handlers were the source of 53% of outbreaks and may have contributed to 82% of outbreaks. Most foods were likely contaminated during preparation and service, except for mollusks, and occasionally, produce was contaminated during production and processing. Interventions to reduce the frequency of foodborne norovirus outbreaks should focus on food workers and production of produce and shellfish. PMID- 23017160 TI - Chromium-picolinate therapy in diabetes care: individual outcomes require new guidelines and navigation by predictive diagnostics. AB - AIMS: Nephropathy is the leading secondary complication of metabolic syndrome. Nutritional supplement by chromium-picolinate is assumed to have renoprotective effects. However, potential toxic effects reported increase the concerns about the safety of chromium-picolinate. The experimental design aimed at determining, whether the treatment with clinically relevant doses of chromium-picolinate can harm individual oucomes through DNA damage and extensive alterations in central detoxification / cell-cycle regulating pathways in treatment of diabetes. METHODS: The study was performed in a double-blind manner. Well-acknowledged animal model of db/db-mice and clinically relevant doses of chromium- picolinate were used. As an index of DNA-damage, measurement of DNA-breaks was performed using "Comet Assay"-analysis. Individual and group-specific expression patterns of SOD-1 and P53 were evaluated to get insights into central detoxification and cell-cycle regulating pathways under the treatment conditions. RESULTS: Experimental data revealed highly individual reaction towards the treatment conditions. The highest variability of DNA-damage was monitored under the prolonged treatment with high dosage of CrPic. Expression patterns demonstrated a correlation with the subcellular imaging and dosage-dependent suppression under the chromium-picolinate treatment. INTERPRETATION AND RECOMMENDATIONS: Population at-risk for diabetes is huge and increasing in pandemic scale. One of the reasons might be the failed attempt to prevent the disease by application of artificial supplements and drugs with hardly recognised individual risks. Consequently, a multimodal approach of integrative medicine by predictive diagnostics, targeted prevention and individually created treatment algorithms is highly desirable. PMID- 23017161 TI - Shooting at the DARC: potential issues with species-specific antimalarials. AB - Scientific drug design enables the production of novel agents that may be specific for individual malaria species, particularly by targeting their methods of cellular entry. Though there are practical and theoretical barriers to introducing novel agents into clinical practice, there may also be theoretical benefits to encourage further investigation of such agents, including a reduction in the rate of development of falciparum resistance. This paper discusses the potential risks and benefits such agents using the example of CCR5 blockers, drugs which are already in use for HIV treatment, but may be able to block DARC, the site of Plasmodium vivax into the human red blood cell. PMID- 23017162 TI - Is Helicobacter pylori the infectious target to prevent gastric cancer? An interdisciplinary point of view. AB - Gastric carcinogenesis, which may well extend over decades, is characterized by a slow stepwise evolution from superficial gastritis to glandular atrophy, intestinal metaplasia, dysplasia, and finally, adenocarcinoma. This sequence provides an excellent opportunity for the prevention or early detection of the events preceding development of the neoplasm. In 1994, the International Agency for Research on Cancer defined Helicobacter pylori (H. pylori) as a group I carcinogen for gastric cancer (GC). Evidence supporting a causal association has been demonstrated by epidemiological data as well as by experimental animal models. A meta-analysis has shown an higher risk (odds ratio: 1.92) of progression to GC in infected compare to uninfected subjects, that increased to a value > 8 considering the surveys having a follow-up of more than 8 years. A crucial question remains whether and when precancerous lesions can reverse after H. pylori eradication. While several prospective studies have cast doubts about this reversibility others obtained opposing results. Currently, H. pylori is recognized as a necessary but insufficient cause of GC. The most accepted model of gastric carcinogenesis provides, like for other cancers, a multifactorial pathogenesis, linked with a number of initiators and other continuator agents. This review presents a multidisciplinary point of view to approaching the relationship between H. pylori infection and GC, focusing on the potential benefits of bacterial eradication in slowing down or in inducing regression of precancerous lesions. PMID- 23017163 TI - Adherence to anti-retroviral therapy and its determinants in HIV/AIDS patients: a review. AB - Although Highly Active Anti-Retroviral Therapy (HAART) significantly reduced HIV/AIDS mortality, appropriate adherence level is recommended for viral suppression and therapeutic response in People Living with HIV/AIDS (PLWHA). In the most studies, adherence is defined as taking >=95% of prescribed medications. Poor or non-adherence may lead to treatment failure and drug resistance. There is no golden standard for evaluation of adherence to medication and many measurement methods are used to assess adherence rate. Moreover, several determinants have been contemplated for adherence in different studies; however, the exact roles of some determinants are not well established. The goals of this review are to describe the adherence rates, to discuss the advantages and disadvantages of common adherence measurement methods, to examine significant correlations related to adherence and to recommend strategies for improving adherence in clinical care. PMID- 23017164 TI - Visceral leishmaniasis in rural bihar, India. AB - To identify factors associated with incidence of visceral leishmaniasis (VL), we surveyed 13,416 households in Bihar State, India. VL was associated with socioeconomic status, type of housing, and belonging to the Musahar caste. Annual coverage of indoor residual insecticide spraying was 12%. Increasing such spraying can greatly contribute to VL control. PMID- 23017165 TI - Mapping pH-induced protein structural changes under equilibrium conditions by pulsed oxidative labeling and mass spectrometry. AB - Mass spectrometry (MS)-based protein conformational studies are a rapidly growing field. The characterization of partially disordered conformers is of particular interest because these species are not amenable to classical high-resolution techniques. Such equilibrium intermediates can often be populated by exposure to mildly acidic pH. Hydroxyl radical (.OH) introduces oxidative modifications at solvent-accessible side chains, while buried sites are protected. .OH can be generated by laser photolysis of H(2)O(2) (fast photochemical oxidation of proteins-FPOP). The resulting labeling pattern can be analyzed by MS. The characterization of partially disordered intermediates usually involves comparative measurements under different solvent conditions. It can be challenging to separate structurally induced labeling changes from pH-mediated "secondary" effects. The issue of secondary effects in FPOP has received little prior attention. We demonstrate that with a proper choice of conditions (e.g., in the absence of pH-dependent .OH scavengers) such undesired phenomena can be almost completely eliminated. Using apomyoglobin as a model system, we map the structure of an intermediate that is formed at pH 4. This species retains a highly protected helix G that is surrounded by partially protected helices A, B, and H. Our results demonstrate the utility of FPOP for the structural characterization of equilibrium intermediates. The near absence of an intrinsic pH dependence represents an advantage compared to hydrogen/deuterium exchange MS. PMID- 23017166 TI - Absence of PMS2 mutations in colon-CFR participants whose colorectal cancers demonstrate unexplained loss of MLH1 expression. PMID- 23017169 TI - Pediatric photosensitivity. AB - Photosensitivity is a rarely encountered problem in the pediatric population. It may be caused by a diverse group of primary, idiopathic photosensitivity conditions, or may reflect photoexacerbation of an existing dermatosis. In addition, there are several genodermatoses, metabolic disorders, and connective tissue disorders that can present with photosensitivity, usually in addition to other extracutaneous clinical and laboratory findings. It is important that both dermatologic and pediatric practitioners be able to recognize the various causes of photosensitivity, as well as be familiar with the associated stigmata and necessary workup, if needed, of each particular disorder. This review offers an approach to the pediatric patient who presents with photosensitivity, with emphasis on arriving at the proper diagnosis, necessary evaluations, and management strategies. PMID- 23017167 TI - Quantitative biomedical annotation using medical subject heading over representation profiles (MeSHOPs). AB - BACKGROUND: MEDLINE(r)/PubMed(r) indexes over 20 million biomedical articles, providing curated annotation of its contents using a controlled vocabulary known as Medical Subject Headings (MeSH). The MeSH vocabulary, developed over 50+ years, provides a broad coverage of topics across biomedical research. Distilling the essential biomedical themes for a topic of interest from the relevant literature is important to both understand the importance of related concepts and discover new relationships. RESULTS: We introduce a novel method for determining enriched curator-assigned MeSH annotations in a set of papers associated to a topic, such as a gene, an author or a disease. We generate MeSH Over representation Profiles (MeSHOPs) to quantitatively summarize the annotations in a form convenient for further computational analysis and visualization. Based on a hypergeometric distribution of assigned terms, MeSHOPs statistically account for the prevalence of the associated biomedical annotation while highlighting unusually prevalent terms based on a specified background. MeSHOPs can be visualized using word clouds, providing a succinct quantitative graphical representation of the relative importance of terms. Using the publication dates of articles, MeSHOPs track changing patterns of annotation over time. Since MeSHOPs are quantitative vectors, MeSHOPs can be compared using standard techniques such as hierarchical clustering. The reliability of MeSHOP annotations is assessed based on the capacity to re-derive the subset of the Gene Ontology annotations with equivalent MeSH terms. CONCLUSIONS: MeSHOPs allows quantitative measurement of the degree of association between any entity and the annotated medical concepts, based directly on relevant primary literature. Comparison of MeSHOPs allows entities to be related based on shared medical themes in their literature. A web interface is provided for generating and visualizing MeSHOPs. PMID- 23017170 TI - Phototherapy for hypopigmented mycosis fungoides in Asians. AB - BACKGROUND: Hypopigmented mycosis fungoides (MF) is an uncommon variant of MF. It is rare in Caucasians but more common in young skin-of-color individuals. To date, there are only a few reports on UV-based treatment for this condition. OBJECTIVES: To analyze the efficacy of PUVA photochemotherapy and narrowband UVB (NBUVB) phototherapy for hypopigmented MF. METHODS: A retrospective study of nine patients who received PUVA or NBUVB was performed. The clinical response, total number of treatments, cumulative UV doses, disease-free interval and adverse effects were recorded. RESULT: Eight patients had stage IA and one patient had stage IB. Six patients received NBUVB and three patients received PUVA. Three patients (50%) in the NBUVB group and three patients (100%) in the PUVA group had complete response (CR). Total UV dose to get maximal clinical response ranged from 27.1-59.6 J/cm(2) in the NBUVB group and 244-669.1 J/cm(2) in the PUVA group. In six patients who had CR, recurrence was found in four (66.7%), and the disease-free interval ranged from 2 months to 6 years. CONCLUSION: PUVA and NBUVB are effective for hypopigmented MF. Comparing between these two methods, PUVA provided a better response than NBUVB. Although the disease responded well to phototherapy, relapse was common. PMID- 23017171 TI - Evidence for a new paradigm for ultraviolet exposure: a universal schedule that is skin phototype independent. AB - BACKGROUND: The Food and Drug Administration has published guidelines for manufacturer-recommended exposure schedules for ultraviolet (UV) tanning, intended to limit acute and delayed damage from UV exposure. These guidelines recommend that exposure schedules be adjusted for skin phototype. However, it has been shown that the dose necessary to produce tanning is similar for phototypes 2 4. METHODS: We observed tanning in phototypes 2 and 3 from repeated UV exposures over a 5-week period. Pigmentation was evaluated visually, instrumentally, and through Fontana-Masson staining of biopsies. RESULTS: The resultant pigmentation was equal or greater in phototype 3 compared with phototype 2 - both visually and instrumentally - measured on day 31 of the exposure protocol. The amount of melanin measured in biopsies taken 24 h postexposure was also greater in phototype 3 compared with phototype 2. CONCLUSION: Published data on tanning in phototypes 4 and 5 support our findings that higher phototypes can develop pigmentation more efficiently than lower phototypes. Therefore, a universal exposure schedule (based on sensitivity of phototype 2) can be used for all phototypes that are expected to engage in indoor tanning. This approach will result in a reduction of the UV burden for skin phototypes 3 and above. PMID- 23017172 TI - Q-switched alexandrite laser treatment of facial and labial lentigines associated with Peutz-Jeghers syndrome. AB - BACKGROUND: The Q-switched alexandrite laser used at 752 nm, a wavelength well absorbed by melanin relative to other optically absorbing structures in skin, causes highly selective destruction of pigment-laden cells. In addition, the 75 nanosecond pulse duration produced by this laser approximates the thermal relaxation time for melanosomes, thereby confining the energy to the target. Facial and labial dark brown macules quickly identify patients with Peutz-Jeghers syndrome. These lentigines may be cosmetically disfiguring. The Q-switched alexandrite laser produces clinically significant fading of mucocutaneous melanosis in association with Peutz-Jeghers syndrome without complications often seen with other therapeutic modalities. OBJECTIVES: To evaluate the efficacy and safety of the Q-switched alexandrite laser in treating facial and labial lentigines of Peutz-Jeghers syndrome. SUBJECTS: 43 patients diagnosed with Peutz Jeghers syndrome were treated and studied in our laser center from 2000 to 2010. METHODS: We used a Q-switched alexandrite laser specified with 75 ns pulse length, emitting at 752 nm and with a 2.4 mm-diameter spot size. The lesional skin was irradiated with fluences of 5-7 J/cm2. The treatment intervals were 3 months. RESULTS: After treatment with the Q-switched alexandrite laser, 55.8% (24/43) of the patients had excellent results in which more than 75% of the pigments cleared, and 44.2% (19/43) showed good results. Three sessions were required to obtain excellent results. We observed no serious complications. CONCLUSIONS: We obtain a successful outcome in the treatment of these lentigines with Q-switched alexandrite laser and consider it the treatment of choice for these lesions. PMID- 23017173 TI - Attitudes, knowledge, and behaviors of secondary school adolescents regarding protection from sun exposure: a survey in Bangkok, Thailand. AB - BACKGROUND: Sun protection behavior is a proven intervention for aging skin and skin cancer prevention, especially if training on prolonged sun exposure can be performed early in life. Despite the fact that there are several study reports from multicenters in the West, there are limited data on sun protection in tropical countries where the prevalence of sunburn as well as sun protection behavior and knowledge are low. In Bangkok, sun protection behavior among adolescents is different from the studies performed in the West. Schools are key institutions in encouraging students to prevent themselves from acquiring problems of long-time sun exposure. OBJECTIVE: To assess the amount of time exposed to the sun, sun protection behavior, attitudes, and knowledge about sun exposure protection among secondary school adolescents in Bangkok, Thailand. METHODS: This is a nonrandomized, cross-sectional survey. All students from seven secondary schools in Bangkok (public/private, male/female/coed) were recruited in to the study. RESULTS: A total of 10,387 students were enrolled in to the study; 6176 (59.5%) and 4211 (40.5%) students were from grades 7 to 9 and 10 to 12, respectively. Male students significantly lacked proper sun-protecting behaviors when compared to the female students in the use of sunscreen (9.4% vs. 28.0%, P < 0.001), staying under the shade (55.5% vs. 65.2%, P < 0.001), and use of umbrellas (5.2% vs. 12.1%, P < 0.001). Proper attitudes and sun-protecting behaviors among junior high school students were deficient when compared to high school students in the use of sunscreen (57.1% vs. 60.6%, P < 0.001), types of clothing (10.5% vs. 15.3%, P < 0.001), and hat (3.2% vs. 3.9%, P < 0.001). CONCLUSION: Sun protection behavior among adolescents in Bangkok was poor compared to Western countries. The attitudes and general knowledge about sun protection were significantly different among male and female students from grades 7 to 9 and 10 to 12. LIMITATION: The limitation of the study is the use of self-reported questionnaires in assessing sun exposure and protection. PMID- 23017174 TI - Topical nutlin-3a does not decrease photocarcinogenesis induced by simulated solar radiation in hairless mice. AB - BACKGROUND: Nutlin-3a increases p53 levels after UVB radiation, which could result in a decrease in DNA damage and thus lead to a lower risk of non-melanoma skin cancer. Especially, organ transplant recipients might derive benefit from such a topical formulation with an active ingredient to prevent DNA damage. PURPOSE: To investigate whether topical nutlin-3a can decrease photocarcinogenesis induced by simulated solar radiation. METHODS: 72 hairless C3.Cg/TifBomTac mice were treated 3 days/week topically with 100 MUl nutlin-3a (9 mM) [Groups 1 and 3 (120 days)) or 100 MUl vehicle (Group 2). Three hours later, all mice were exposed to simulated solar radiation (a radiometric equivalent of three standard erythema dose units). RESULTS: The median time to tumours did not differ between the mice treated with nutlin-3a and with the vehicle. The median time to the first and second tumours did not differ between 'nutlin-3a-120 days' and vehicle-treated mice, but there was a small significant difference in the median time to the third tumour (211 vs. 196 days, P = 0.043). However, after Bonferroni correction, there was no difference at all. CONCLUSION: Nutlin-3a had no reductive effect on photocarcinogenesis and we do not believe in nutlin-3a as a potential drug against DNA damage in a topical formulation for organ transplant patients. PMID- 23017175 TI - Quantitative skin color measurements in acanthosis nigricans patients: colorimetry and diffuse reflectance spectroscopy. AB - Tristimulus colorimetry and diffuse reflectance spectroscopy (DRS) are white light skin reflectance techniques used to measure the intensity of skin pigmentation. The tristimulus colorimeter is an instrument that measures a perceived color and the DRS instrument measures biological chromophores of the skin, including oxy- and deoxyhemoglobin, melanin and scattering. Data gathered from these tools can be used to understand morphological changes induced in skin chromophores due to conditions of the skin or their treatments. The purpose of this study was to evaluate the use of these two instruments in color measurements of acanthosis nigricans (AN) lesions. Eight patients with hyperinsulinemia and clinically diagnosable AN were seen monthly. Skin pigmentation was measured at three sites: the inner forearm, the medial aspect of the posterior neck, and anterior neck unaffected by AN. Of the three, measured tristimulus L*a*b* color parameters, the luminosity parameter L* was found to most reliably distinguish lesion from normally pigmented skin. The DRS instrument was able to characterize a lesion on the basis of the calculated melanin concentration, though melanin is a weak indicator of skin change and not a reliable measure to be used independently. Calculated oxyhemoglobin and deoxyhemoglobin concentrations were not found to be reliable indicators of AN. Tristimulus colorimetry may provide reliable methods for respectively quantifying and characterizing the objective color change in AN, while DRS may be useful in characterizing changes in skin melanin content associated with this skin condition. PMID- 23017176 TI - Long lasting interstitial generalized granuloma annulare on sun-exposed areas. AB - Granuloma annulare (GA) is a benign inflammatory dermatosis of unknown etiology and chronic course, with different clinical variants. The cases associated with a photodistributed pattern are rare and show a palisading histopathological pattern. We report a case of generalized GA affecting sun-exposed areas with an interstitial pattern. The patient has been followed-up for 6 years, presenting a recurrent course of the disease, with a good response to chloroquine and relapse when no treatment was prescribed. PMID- 23017177 TI - Recalcitrant eosinophilic pustular folliculitis of Ofuji with palmoplantar pustulosis: dramatic response to narrowband UVB phototherapy. AB - Eosinophilic pustular folliculitis of Ofuji is a recalcitrant disease typified by non-infective eosinophilic spongiosis involving the infundibular region of the hair follicle. We present a case of a 49-year-old Chinese man with known palmoplantar pustulosis and acrodermatitis continua of Hallopeau which was promptly resolved with methotrexate therapy. He returned with an erythematous papulopustular eruption with coalescence to annular plaques, occurring over the face, chest and back with active palmoplantar pustulation. Histology from skin biopsy of the palmar lesion was in keeping with palmoplantar psoriasis, while biopsy of the facial and truncal lesions revealed florid perifollicular eosinophilic congregation diagnostic of eosinophilic pustular folliculitis of Ofuji. Indomethacin was initiated with partial improvement of lesions with cyclical flares. A trial of narrowband ultraviolet-B phototherapy at a frequency of thrice weekly achieved sustained clearance of both eosinophilic pustular folliculitis and palmoplantar lesions. Indomethacin was tailed down and eventually discontinued with maintenance of narrowband ultraviolet-B therapy; this achieved successful control of the disease. PMID- 23017178 TI - Docetaxel-induced photo-recall phenomenon. AB - Photo-recall phenomenon is a phototoxic eruption occurring on areas of previous ultraviolet-induced solar erythema following a systemic administration of a drug. It has been mostly described with methotrexate but remains rare with other antineoplastic drugs. We describe a case of docetaxel-induced photo-recall skin rash in a woman treated for a non-small-cell lung cancer. Although the patient has refused to receive a second infusion, chemotherapy can be carried on with photoprotection and the use of topical and/or systemic corticosteroids. In contrast, radiation recall is a well-known reaction by oncologists, most of them may not be aware of a similar phenomenon called photo-recall phenomenon. Recognizing this entity may avoid misdiagnosing a drug allergy and should avoid inappropriate decisions of drug discontinuation. PMID- 23017179 TI - Sunbathing and sunlamp exposure: awareness and risk among Italian teenagers. PMID- 23017180 TI - Attributing cause of death for patients with Clostridium difficile infection. PMID- 23017181 TI - Predicting survival in oldest old people. AB - OBJECTIVE: Measures of physical performance are regarded as useful objective clinical tools to estimate survival in elderly people. However, oldest old people, aged 85 years or more, are underrepresented in earlier studies and frequently unable to perform functional tests. We studied the association of gait speed and survival in a cohort of oldest old people and the association of Instrumental Activities of Daily Living by questionnaire and survival as an alternative prognostic marker of survival. METHODS: The Leiden 85-plus Study was used, a prospective population-based study with a follow-up period of 12 years. The study comprised 599 participants all aged 85 years at baseline. Survival rate was the measurement. RESULTS: At age 85 years, 73 participants (12.2%) did not perform the walking test. Gait speed faster than 0.8 m/s was present in only 48 participants (9%), and gait speed faster than 1.0 m/s was present in 10 participants (1.9%). Risk for all-cause mortality was higher in participants with slow gait speed after 2 and 12 years of follow-up (hazard ratio [HR], 2.66; 95% confidence interval [CI], 1.49-4.75; P<.001; and HR, 2.04; 95% CI, 1.61-2.59; P=.100, respectively). Significance was lost after adjustment for common confounders. Poor Instrumental Activities of Daily Living ability was associated with an increased risk of mortality after 2 and 12 years of follow-up (HR, 6.11; 95% CI, 3.44-10.87; P<.001; and HR, 2.75; 95% CI, 2.22-3.40; P<.001, respectively). Adjustment for possible confounders attenuated the relation but remained significant. CONCLUSIONS: The cutoff points for gait speed in oldest old people need to be reevaluated. In oldest old people aged 85 years, slow gait speed (<=0.40 m/s in women and <=0.45 m/s in men) and Instrumental Activities of Daily Living disability are both predictors of survival. Assessment of Instrumental Activities of Daily Living could be a better tool for short- and long-term prognostication of survival in oldest old people. PMID- 23017182 TI - Special focus on spinal manipulation. PMID- 23017183 TI - Effect of surface ligands on the optical properties of aqueous soluble CdTe quantum dots. AB - We investigate systematically the influence of the nature of thiol-type capping ligands on the optical and structural properties of highly luminescent CdTe quantum dots synthesized in aqueous media, comparing mercaptopropionic acid (MPA), thioglycolic acid (TGA), 1-thioglycerol (TGH), and glutathione (GSH). The growth rate, size distribution, and quantum yield strongly depend on the type of surface ligand used. While TGH binds too strongly to the nanocrystal surface inhibiting growth, the use of GSH results in the fastest growth kinetics. TGA and MPA show intermediate growth kinetics, but MPA yields a much lower initial size distribution than TGA. The obtained fluorescence quantum yields range from 38% to 73%. XPS studies unambiguously put into evidence the formation of a CdS shell on the CdTe core due to the thermal decomposition of the capping ligands. This shell is thicker when GSH is used as ligand, as compared with TGA ligands. PMID- 23017184 TI - Changes in intraocular pressure after pharmacologic pupil dilation. AB - BACKGROUND: Intraocular pressure (IOP) may vary according to the change of ocular conditions. In this study, we want to assess the effect and mechanism of pupil dilation on IOP in normal subjects. METHODS: We prospectively evaluated 32 eyes of 32 patients (age; 61.7+/-8.2 years) with normal open angles under diurnal IOP. IOP was measured every two hours from 9 AM to 11 PM for one day to establish baseline values and was measured again for one day to assess the differences after dilation. To induce dilation, we administered 2.5% phenylephrine and 1% tropicamide every 5 minutes from 8:30 AM to 8:45 AM and for every two hours from 11 AM to 9 PM to keep the pupil dilated. Diurnal IOP, biometry, Visante OCT, and laser flare photometry were measured before and after dilation. RESULTS: We observed a significant increase in IOP after dilation, 1.85+/-2.01 mmHg (p=0.002). IOP elevation remained significant until about four hours after dilation. Thereafter, IOP decreased slowly and eventually reached pre-dilation level (p>0.05). Flare values decreased, and the anterior chamber angle became wider after mydriasis. CONCLUSIONS: Dilation of the pupil significantly and incidentally elevated IOP in normal subjects. Further related studies are warranted to characterize the mechanism of the increased IOP after dilation. PMID- 23017185 TI - Role of the gut microbiota in age-related chronic inflammation. AB - Changing demographics have made aging and age-related chronic diseases an enormous and growing biomedical and societal challenge. The biological processes of aging may involve a role for the gut microbiota. Aspects of host physiology such as immune homeostasis and energy balance are profoundly influenced by the microbiota. Immune dysregulation characterizes old age and constitutes a major pathomechanism underlying frailty and age-associated chronic diseases. A growing body of literature implicates age-related perturbations in the gut microbial ecology as contributing to a global inflammatory state in the elderly. A better understanding of the nature and determinants of the host-microbe relationship in old age has the potential to translate into strategies that promote healthy aging and extend life span. This review summarizes our current understanding of the configuration of the age-related gut microbiota and its likely role in determining the immune phenotype in the elderly. It also highlights the specific components of the microbiota that can be targeted to modulate the age-related chronic inflammation. PMID- 23017186 TI - A checkpoints capturing timing-robust Boolean model of the budding yeast cell cycle regulatory network. AB - BACKGROUND: Cell cycle process of budding yeast (Saccharomyces cerevisiae) consists of four phases: G1, S, G2 and M. Initiated by stimulation of the G1 phase, cell cycle returns to the G1 stationary phase through a sequence of the S, G2 and M phases. During the cell cycle, a cell verifies whether necessary conditions are satisfied at the end of each phase (i.e., checkpoint) since damages of any phase can cause severe cell cycle defect. The cell cycle can proceed to the next phase properly only if checkpoint conditions are met. Over the last decade, there have been several studies to construct Boolean models that capture checkpoint conditions. However, they mostly focused on robustness to network perturbations, and the timing robustness has not been much addressed. Only recently, some studies suggested extension of such models towards timing robust models, but they have not considered checkpoint conditions. RESULTS: To construct a timing-robust Boolean model that preserves checkpoint conditions of the budding yeast cell cycle, we used a model verification technique, 'model checking'. By utilizing automatic and exhaustive verification of model checking, we found that previous models cannot properly capture essential checkpoint conditions in the presence of timing variations. In particular, such models violate the M phase checkpoint condition so that it allows a division of a budding yeast cell into two before the completion of its full DNA replication and synthesis. In this paper, we present a timing-robust model that preserves all the essential checkpoint conditions properly against timing variations. Our simulation results show that the proposed timing-robust model is more robust even against network perturbations and can better represent the nature of cell cycle than previous models. CONCLUSIONS: To our knowledge this is the first work that rigorously examined the timing robustness of the cell cycle process of budding yeast with respect to checkpoint conditions using Boolean models. The proposed timing-robust model is the complete state-of-the-art model that guarantees no violation in terms of checkpoints known to date. PMID- 23017187 TI - My child you must have patience and Kreng Jai: Thai parents and child pain. AB - PURPOSE: To elicit the experiences of parents in providing care for their hospitalized child's acute pain needs. DESIGN: Phenomenology, using in-depth interviews with 45 parents whose children were being cared for in five hospitals in Northeastern (Isan) Thailand. FINDINGS: The findings address Thai cultural beliefs regarding the experience of pain and the role societal expectations have on parental behavior in trying to meet their child's acute pain needs. Two themes emerged-"Understanding my child's pain: it's karma" and "Maintaining Kreng Jai" which identify parent beliefs toward pain and pain treatment, as well as perceived barriers in securing pain management for their children. Together these two themes describe the essence of this study as parents experienced an "inner struggle in providing pain care." Pain was perceived as an inescapable part of life, and participants identified a preference for traditional remedies. Parents experienced a tension as they wanted to provide and secure pain care for their child but at the same time were reticent to approach staff with concerns about their child's care. CONCLUSIONS: Thai parents viewed pain as a normal consequence of life, and one had to use traditional remedies in addition to medicine to successfully treat pain. Societal behavioral expectations required children to have patience. Nevertheless, parents wanted professionals to show more empathy and provide more effective pain care. CLINICAL RELEVANCE: Improvements in pediatric pain care must formally include parents. Culturally sensitive approaches that do not stereotype parents and children are needed to ensure that evidence-informed pain care is available for all children. PMID- 23017188 TI - Identification of the CFTR p.Phe508Del founder mutation in the absence of a polythymidine 9T allele in a Hispanic patient. PMID- 23017189 TI - Factors associated with treatment received by men diagnosed with prostate cancer in queensland, australia. PMID- 23017190 TI - Evaluation of the efficacy of the guideline on reading CT images of malignant pleural mesothelioma with reference CT films for improving the proficiency of radiologists. AB - PURPOSE: To assess the efficacy of the developed guideline on reading CT images of malignant pleural mesothelioma for improving radiologists' reading proficiency. MATERIALS AND METHODS: Three radiologists independently read the CT films of 22 cases including definite mesothelioma and non-mesothelioma cases at two times before and after studying the malignant pleural mesothelioma CT Guideline. The sensitivity and specificity for mesothelioma were calculated and compared between the 1st and 2nd trials. The kappa statistics was examined for agreement with experts for mesothelioma probability and for mesothelioma features recorded by three radiologists. RESULTS: After studying the mesothelioma CT Guideline, the sensitivity for mesothelioma shown by the three radiologists at the 2nd trial was 100%, 100% and 80%, which were higher than 80%, 85% and 60% at the 1st trial, respectively. The average kappa for agreement between radiologists and experts on dichotomized mesothelioma probability were 0.69 (good) at the 2nd trial vs. 0.38 (fair) at the 1st trial. The average kappa for the agreement with experts for each of 7 features by three radiologists were 0.52-0.80 at the 2nd trial, which were significantly higher than 0.34-0.58 at the 1st trial (Wilcoxon Signed Rank Test: P<0.01), and as to five features "unilateral pleural effusion", "nodular pleural thickening", "tumoral encasement of lung", "mediastinal pleural thickening", and "diminished lung", they achieved good agreement with average kappa of 0.61-0.80. CONCLUSION: The developed mesothelioma CT Guideline was suggested to have substantial effect in improving the radiologists' proficiency for reading CT images of mesothelioma, and may contribute to accurate diagnosis of mesothelioma. PMID- 23017191 TI - Can preoperative MR imaging predict optic nerve invasion of retinoblastoma? AB - PURPOSE: To evaluate the accuracy of pre-operative MRI for the detection of optic nerve invasion in retinoblastoma. MATERIALS AND METHODS: Institutional review board approval and informed consent were waived for this retrospective study. A total of 41 patients were included. Inclusion criteria were histologically proven retinoblastoma, availability of diagnostic-quality preoperative MR images acquired during the 4 weeks before surgery, unilateral retinoblastoma, and normal sized optic nerve. Two radiologists retrospectively reviewed the MR images independently. Five imaging findings (diffuse mild optic nerve enhancement, focal strong optic nerve enhancement, optic sheath enhancement, tumor location, and tumor size) were evaluated against optic nerve invasion of retinoblastoma. The predictive performance of all MR imaging findings for optic nerve invasion was also evaluated by the receiver operating characteristic curve analysis. RESULTS: Optic nerve invasion was histopathologically confirmed in 24% of study population (10/41). The differences in diffuse mild enhancement, focal strong enhancement, optic sheath enhancement, and tumor location between patients with optic nerve invasion and patients without optic nerve invasion were not significant. Tumor sizes were 16.1mm (SD: 2.2mm) and 14.9 mm (SD: 3.6mm) in patients with and without optic nerve involvement, respectively (P=0.444). P-Values from binary logistic regression indicated that all five imaging findings were not significant predictors of tumor invasion of optic nerve. The AUC values of all MR imaging findings for the prediction of optic nerve invasion were 0.689 (95% confidence interval: 0.499-0.879) and 0.653 (95% confidence interval: 0.445-0.861) for observer 1 and observer 2, respectively. CONCLUSION: Findings of MRI in patients with normal-sized optic nerves have limited usefulness in preoperatively predicting the presence of optic nerve invasion in retinoblastoma. PMID- 23017192 TI - Automatic multi-modal MR tissue classification for the assessment of response to bevacizumab in patients with glioblastoma. AB - BACKGROUND: Current methods for evaluation of treatment response in glioblastoma are inaccurate, limited and time-consuming. This study aimed to develop a multi modal MRI automatic classification method to improve accuracy and efficiency of treatment response assessment in patients with recurrent glioblastoma (GB). MATERIALS AND METHODS: A modification of the k-Nearest-Neighbors (kNN) classification method was developed and applied to 59 longitudinal MR data sets of 13 patients with recurrent GB undergoing bevacizumab (anti-angiogenic) therapy. Changes in the enhancing tumor volume were assessed using the proposed method and compared with Macdonald's criteria and with manual volumetric measurements. The edema-like area was further subclassified into peri- and non peri-tumoral edema, using both the kNN method and an unsupervised method, to monitor longitudinal changes. RESULTS: Automatic classification using the modified kNN method was applicable in all scans, even when the tumors were infiltrative with unclear borders. The enhancing tumor volume obtained using the automatic method was highly correlated with manual measurements (N=33, r=0.96, p<0.0001), while standard radiographic assessment based on Macdonald's criteria matched manual delineation and automatic results in only 68% of cases. A graded pattern of tumor infiltration within the edema-like area was revealed by both automatic methods, showing high agreement. All classification results were confirmed by a senior neuro-radiologist and validated using MR spectroscopy. CONCLUSION: This study emphasizes the important role of automatic tools based on a multi-modal view of the tissue in monitoring therapy response in patients with high grade gliomas specifically under anti-angiogenic therapy. PMID- 23017193 TI - Imaging differentiation of pathologic fractures caused by primary and secondary bone tumors. AB - OBJECTIVE: To describe pre-treatment imaging features of pathologic fractures caused by primary bone tumors (PBTs) and metastatic bone tumors (MBTs) and determine if radiographic or cross-sectional features can differentiate the underlying pathologies associated with the fractures. METHODS: Sixty-nine patients with a diagnosis of a pathologic fracture were enrolled. Biopsy established PBT as the cause of the pathologic fracture in 16 (23%) cases and MBT in 53 (77%) cases. The radiographs, computed tomography (CT) scans, and magnetic resonance imaging (MRI) scans of the subjects were retrospectively reviewed for the presence of multiple imaging features. RESULTS: Compared to pathologic fractures caused by MBTs, the fractures caused by PBTs demonstrated a higher incidence of lytic bone cortex, mineralization and a soft-tissue mass on radiographs, mineralization and a soft-tissue mass on CT scans, and periosteal abnormality on MRI scans (P<0.01). These features also exhibited a high negative predictive value in supporting the diagnosis of an underlying PBT over MBT. CONCLUSION: Pathologic fractures caused by PBT and MBT may be differentiated by a few specific radiographic and CT imaging features, though MRI was poor for characterization of the underlying lesion. Such knowledge may assist radiologists in raising the possibility of a PBT as the cause of a pathologic fracture. PMID- 23017194 TI - Causes of discordant or negative ultrasound of parathyroid glands in treatment naive patients with primary hyperparathyroidism. AB - OBJECTIVES: To describe causes of discordant or negative parathyroid ultrasound and to assess factors influencing them. MATERIALS AND METHODS: Retrospective review of patients who underwent parathyroidectomy between 2000 and 2012 was done. Imaging findings were compared with operative findings and pathology to identify discrepant (n=60; 32 negative, 28 incorrect) parathyroid ultrasounds. RESULTS: Fifty (83.3%) patients had parathyroid adenoma, of which 10 (16.6%) were ectopic and three were double adenomas; 8 (13.3%) had multigland hyperplasia and two had parathyroid carcinoma. Discrepant reports were due to incorrect localisation in 8 (13.3%); difficulty in differentiating thyroid from parathyroid lesion in 12 (20%); large and small size in two and three patients, respectively; overcall in 5 (8.3%) and satisfaction of search in 7 (11.7%) patients. There was significant correlation between presence of multi-nodular goitre and incorrect reports (chi(2)=4.112, p=0.04). Experience of ultrasound operators performing initial and second look ultrasound was significantly different (p<0.0001). Second look ultrasound was concordant with surgical findings in 39(65%) patients; 21 (66%) patients with initially negative ultrasound and four out of five extra mediastinal ectopic lesions. Ten patients with negative initial ultrasound had elongated parathyroid lesion. Scintigraphy was concordant in 44 (73.3%) patients and nine were ectopic. CONCLUSION: Second look ultrasound performed by experienced operator for negative or discordant initial ultrasound of parathyroid is a useful strategy which will improve the accuracy of parathyroid ultrasound. Being able to differentiate thyroid from parathyroid lesion is a factor which will influence performance of parathyroid ultrasound. PMID- 23017195 TI - Age-related distribution of vertebral bone-marrow diffusivity. AB - PURPOSE: To determine age-related diffusivity changes of the lumbar bone marrow by measurement of apparent diffusion coefficient (ADC) values. MATERIALS AND METHODS: The local ethics committee approved this study and written informed consent was obtained. The study group comprised 88 individuals including 75 healthy volunteers and 13 patients (48 female, 40 male; mean age 36 years, range 0-84 years). The pediatric cases were recruited from patients. Echo-planar diffusion weighted imaging (DWI) was performed with b-values of 50, 400 and 800 s/mm(2). ADC-values were calculated and measured in the 1st and 2nd vertebral body of the lumbar spine. Correlation between age and ADC-values was analyzed with Spearman's rho test. RESULTS: The ADC values of the vertebral bone marrow of the lumbar spine showed a significant negative correlation with age (rho=-0.398, p=0.001). The mean ADC values (*10(-3)mm(2)/s) in the age groups 0-29 years (mean age 18.0 years, n=42) and 30-88 years (mean age 51.6 years, n=46) were 0.54 +/- 0.07 and 0.47 +/- 0.08, respectively (p<0.001, T-test). No significant differences were found between children and young adults. CONCLUSION: Bone marrow ADC values of the lumbar spine show a linear decrease with growing age and thereby reflect the gradual changes of cell composition occurring during marrow conversion. PMID- 23017196 TI - Computed tomography scout views vs. conventional radiography in body-packers - delineation of body-packs and radiation dose in a porcine model. AB - OBJECTIVE: To compare abdominal computed tomography (CT) scout views with conventional radiography regarding radiation dose and delineation of drug packages in a porcine body-packer model. MATERIALS AND METHODS: Nine samples of illicit drugs packed in ovoid plastic containers were consecutively placed in the rectum of a 121.5 kg pig cadaver. Antero-posterior and lateral scout views were obtained at 120 kVp and 80 mA, 150 mA and 200 mA, respectively, using a 64-row MDCT. Scout views were compared with conventional abdominal antero-posterior radiographs (77 kV and 106 +/- 13 mAs). Visibility of three body pack characteristics (wrapping, content, shape) was rated independently by two radiologists and summarized to a delineation score ranging from 0 to 9 with a score >= 6 representing sufficient delineation. Mean delineation scores were calculated for each conventional radiography and single plane scout view separately and for a combined rating of antero-posterior and lateral scout views. RESULTS: Even the lowest single plane scout view delineation score (5.3 +/- 2.0 for 80 mA lateral; 0.4 mSv; sensitivity=44%) was significantly higher than for conventional radiographs (3.1 +/- 2.5, p<0.001; 2.4 +/- 0.3 mSv; sensitivity=11%). Combined reading of antero-posterior and lateral scout views 80 mA yielded sufficient delineation (6.2 +/- 1.4; 0.8 mSv; sensitivity=56%). CONCLUSIONS: All CT scout views showed significantly better delineation ratings and sensitivity than conventional radiographs. Scout views in two planes at 80 mA provided a sufficient level of delineation and a sensitivity five times higher than conventional radiography at less than one third of the radiation dose. In case of diagnostic insecurity, CT can be performed without additional logistical effort. PMID- 23017197 TI - Expression of retinoic acid receptors and retinoid X receptors in normal and vitamin A deficient adult rat brain. AB - The importance of retinoic acid and retinoid X receptors (RARs and RXRs) in the metabolism and functioning of the nervous tissue is well documented, but few data are available about the differences on their distribution in males and females, as well as about the possible changes in a vitamin A deficient state (VAD). Therefore, the aim of this study has been to use immunohistochemistry to determine the cellular localization of RARs (alpha, beta, gamma) and RXR (alpha, beta, gamma) in brain areas in the normal and vitamin A deficient rat, in both males and females. RARalpha and beta isotypes were detected in practically all the male brain areas whereas immunostaining was weak or absent in the female brain except RARalpha. RXRgamma was absent in the female brain, while it was observed in some regions in the male. RXRbeta and gamma were the most abundant receptors in both sexes, but RXRalpha were hardly detected in female brain, but were detected more frequently in male. With a vitamin A-free diet, RARs expression was increased in males, but not in females. In the male brain of VAD rats, RXRalpha expression was increased in some zones and diminished in others. RXRbeta and gamma expression was decreased in the male brain, but increased or was not modified in those areas of the female brain in which it was observed. These findings indicate that the brain management of retinoic acid differs between males and females, also leading to differences in their response to VAD diet in terms of receptor expression. PMID- 23017198 TI - The influence of grip on oxygen consumption and leg forces when using classical style roller skis. AB - The purpose of this study was to investigate the influence of classical style roller skis' grip (static friction coefficients, MUS) on cross-country skiers' oxygen consumption and leg forces during treadmill roller skiing, when using the diagonal stride and kick double poling techniques. The study used ratcheted wheel roller skis from the open market and a uniquely designed roller ski with an adjustable camber and grip function. The results showed significantly (P <= 0.05) higher oxygen consumption (~ 14%), heart rate (~ 7%), and lower propulsive forces from the legs during submaximal exercise and a shorter time to exhaustion (~ 30%) in incremental maximal tests when using roller skis with a MUS similar to on-snow skiing, while there was no difference between tests when using different pairs of roller skis with a similar, higher MUS. Thus, we concluded that oxygen consumption (skiing economy), propulsive leg forces, and performance time are highly changed for the worse when using roller skis with a lower MUS, such as for on-snow skiing with grip-waxed cross-country skis, in comparison to ratcheted wheel roller skis with several times higher MUS. PMID- 23017199 TI - Characterization of Mycobacterium orygis. PMID- 23017201 TI - Late correction of orbital deformities. AB - Orbital fractures are some of the most challenging injuries the oral surgeon deals with on a daily basis. Delay of the treatment of orbital fractures impacts the final result. Late orbital reconstruction is sometimes necessary for inadequate primary reconstruction or for severe injuries with adequate primary reconstruction. Healing and wound contraction make secondary reconstruction more difficult to restore the orbital contents back to normal. There are different materials available for orbital reconstruction, and there is no consensus about which is best. Early surgical intervention may improve the ultimate outcome, but identifying patients at risk of late complications is difficult. PMID- 23017200 TI - Quetiapine monotherapy in acute phase for major depressive disorder: a meta analysis of randomized, placebo-controlled trials. AB - BACKGROUND: Schizophrenia and bipolar depression trials suggest that quetiapine may have an antidepressant effect. OBJECTIVES: This meta-analysis aimed to determine the efficacy, acceptability and tolerability of quetiapine treatment for major depressive disorder (MDD). Only the randomized controlled trials (RCTs) comparison between quetiapine and placebo were included. The authors searched such clinical trials carried out between 1991 and February 2012. DATA SOURCES: MEDLINE, EMBASE, CINHL, PsycINFO and Cochrane Controlled Trials Register were searched in February 2012. Study populations comprised adults with MDD or major depression. STUDY ELIGIBLE CRITERIA, PARTICIPANTS AND INTERVENTIONS: Eligible studies were randomized, placebo-controlled trials of quetiapine monotherapy carried out in adults with MDD and presenting endpoint outcomes relevant to: i) depression severity, ii) response rate, iii) overall discontinuation rate, or iv) discontinuation rate due to adverse events. No language restriction was applied. STUDY APPRAISAL AND SYNTHESIS METHODS: All abstracts identified by the electronic searches were examined. The full reports of relevant studies were assessed, and the data of interest were extracted. Based on the Cochrane methods of bias assessment, risks of bias were determined. The studies with two risks or less were included. The efficacy outcomes were the mean change scores of depression rating scales, the overall response rate, and the overall remission rates. The overall discontinuation rate was considered as a measure of acceptability. The discontinuation rate due to adverse events was a measure of tolerability. Relative risks (RRs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were computed by using a random effect model. RESULTS: A total of 1,497 participants in three RCTs were included. All trials examined the quetiapine extended-release (XR). The pooled mean change scores of the Montgomery Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HAM-D) of the quetiapine-treated group were higher than those of the placebo treated group with the WMDs (95%CI) of -3.37 (-3.95, -2.79) and -2.46 (-3.47, 1.45), respectively. All studies defined the response and remission as >= 50% reduction of the MADRS total score and the MADRS total score of <=8 at endpoint, respectively. The overall response and remission rates were significantly greater in the quetiapine-treated group with RRs (95%CIs) of 1.44 (1.26, 1.64) and 1.37 (1.12, 1.68), respectively. The pooled discontinuation rate was not significantly different between groups with an RR (95%CI) of 1.16 (0.97, 1.39). The pooled discontinuation rate due to adverse event was greater in the quetiapine group with an RR (95%CI) of 2.90 (1.87, 4.48). With respect to sleep time, the pooled mean change Pittsburgh Sleep Quality Index (PSQI) scores of the quetiapine treated group was also significantly higher than that of the placebo-treated group [WMD (95%CI) of -1.21 (-1.81, -0.61)]. LIMITATIONS: Variety of quetiapine XR doses and the small number of RCTs were key limitations of this meta-analysis. CONCLUSIONS: Based on the limited evidence obtained from three RCTs, quetiapine XR is effective for adult patients with MDD. The high dropout rate due to adverse events suggests that some MDD patients may not be able to tolerate quetiapine XR. Due to the balance of its efficacy benefit and risk of side effects, as the overall discontinuation rate shown, the acceptability of this agent is not more than placebo. These results should be viewed as the very preliminary one. Further studies in this area are warranted. IMPLICATION OF KEY FINDINGS: Quetiapine may be an alternative antidepressant. However, both risk and benefit of this agent should be taken into account for an individual patient with MDD. PMID- 23017202 TI - Constant transmission properties of variant Creutzfeldt-Jakob disease in 5 countries. AB - Variant Creutzfeldt-Jakob disease (vCJD) has been reported in 12 countries. We hypothesized that a common strain of agent is responsible for all vCJD cases, regardless of geographic origin. To test this hypothesis, we inoculated strain typing panels of wild-type mice with brain material from human vCJD case-patients from France, the Netherlands, Italy, and the United States. Mice were assessed for clinical disease, neuropathologic changes, and glycoform profile; results were compared with those for 2 reference vCJD cases from the United Kingdom. Transmission to mice occurred from each sample tested, and data were similar between non-UK and UK cases, with the exception of the ranking of mean clinical incubation times of mouse lines. These findings support the hypothesis that a single strain of infectious agent is responsible for all vCJD infections. However, differences in incubation times require further subpassage in mice to establish any true differences in strain properties between cases. PMID- 23017203 TI - Gintonin: a novel ginseng-derived ligand that targets G protein- coupled lysophosphatidic acid receptors. AB - Ginseng, the root of Panax ginseng C.A. Meyer, is one of the oldest herbal medicines and induces a variety of physiological and pharmacological effects. Ginseng contains saponins called ginsenosides, which are considered as the biologically active ingredients in ginseng. Increasing evidences indicate that ginsenosides are non-selective in their actions and high concentrations are required for cellular effects. Crude ginseng total saponin (cGTS) fraction is about 50% ginsenoside in composition, but the remainder is not defined clearly. Biochemically, cGTS fraction triggers differing patterns of ginsenoside activity; for example, the cGTS fraction itself functions as an agent that activates a G protein-coupled receptor because it induces endogenous calcium (Ca2+)-activating chloride (Cl-) channel activations in Xenopus oocytes via the same signaling pathways used by Galphaq/11 protein-coupled receptors. Recent reports have revealed that the cGTS fraction contains novel glycolipoproteins, designated the gintonin. It was discovered that gintonin, but not ginsenosides, interacts with unidentified membrane proteins to generate [Ca2+]i transient in mammalian cells and to activate endogenous Ca2+-activating Cl- channels in Xenopus oocytes. Further studies have shown that gintonin is a novel lysophosphatidic acids (LPAs) ginseng protein complex and can selectively activate LPA receptors with an affinity greater than that of LPA. This review aims to characterize gintonin as an LPA receptor ligand, explain the reasons why gintonin remained unidentified for a long time, list the advantages of LPA-ginseng protein complexes over free LPAs, compare the activities of gintonin and ginsenoside, and describe the pharmacological applications of gintonin as a drug that targets LPA receptors. PMID- 23017204 TI - Influenza A(H1N1)pdm09 virus in pigs, Reunion Island. AB - During 2009, pandemic influenza A(H1N1)pdm09 virus affected humans on Reunion Island. Since then, the virus has sustained circulation among local swine herds, raising concerns about the potential for genetic evolution of the virus and possible retransmission back to humans of variants with increased virulence. Continuous surveillance of A(H1N1)pdm09 infection in pigs is recommended. PMID- 23017205 TI - Low population genetic differentiation in the Orchidaceae: implications for the diversification of the family. AB - A leading hypothesis for the immense diversity of the Orchidaceae is that skewed mating success and small, disjunct populations lead to strong genetic drift and switches between adaptive peaks. This mechanism is only possible under conditions of low gene flow that lead to high genetic differentiation among populations. We tested whether orchids typically exhibit high levels of population genetic differentiation by conducting a meta-analysis to compare mean levels of population genetic differentiation (F(ST)) between orchids and other diverse families and between rare and common orchids. Compared with other families, the Orchidaceae is typically characterized by relatively low genetic differentiation among populations (mean F(ST) = 0.146) at allozyme loci. Rare terrestrial orchids showed higher population genetic differentiation than common orchids, although this value was still lower than the mean for most plant families. All lines of evidence suggest that orchids are typically characterized by low levels of population genetic differentiation, even in species with naturally disjunct populations. As such, we found no strong evidence that genetic drift in isolated populations has played a major role in the diversification of the Orchidaceae. Further research into the diversification of the family needs to unravel the relative roles of biotic and environmental selective pressures in the speciation of orchids. PMID- 23017206 TI - Dictyostelium phenylalanine hydroxylase is activated by its substrate phenylalanine. AB - We have studied the regulatory function of Dictyostelium discoideum Ax2 phenylalanine hydroxylase (dicPAH) via characterization of domain structures. Including the full-length protein, partial proteins truncated in regulatory, tetramerization, or both, were prepared from Escherichia coli as his-tag proteins and examined for oligomeric status and catalytic parameters for phenylalanine. The proteins were also expressed extrachromosomally in the dicPAH knockout strain to examine their in vivo compatibility. The results suggest that phenylalanine activates dicPAH, which is functional in vivo as a tetramer, although cooperativity was not observed. In addition, the results of kinetic study suggest that the regulatory domain of dicPAH may play a role different from that of the domain in mammalian PAH. PMID- 23017207 TI - Regulation of mean and noise of the in vivo kinetics of transcription under the control of the lac/ara-1 promoter. AB - The kinetics of transcription initiation in Escherichia coli depend on the duration of two rate-limiting steps, the closed and the open complex formation. In a lac promoter variant, P(lac/ara-1), the kinetics of these steps is controlled by IPTG and arabinose. From in vivo single-RNA measurements, we find that induction affects the mean and normalized variance of the intervals between consecutive RNA productions. Transcript production is sub-Poissonian in all conditions tested. The kinetics of each step is independently controlled by a different inducer. We conclude that the regulatory mechanism of P(lac/ara-1) allows the stochasticity of gene expression to be environment-dependent. PMID- 23017208 TI - Engineering a naturally inactive isoform of type III antifreeze protein into one that can stop the growth of ice. AB - Type III antifreeze proteins (AFPs) can be sub-divided into three classes of isoforms. SP and QAE2 isoforms can slow, but not stop, the growth of ice crystals by binding to pyramidal ice planes. The other class (QAE1) binds both pyramidal and primary prism planes and is able to halt the growth of ice. Here we describe the conversion of a QAE2 isoform into a fully-active QAE1-like isoform by changing four surface-exposed residues to develop a primary prism plane binding site. Molecular dynamics analyses suggest that the basis for gain in antifreeze activity is the formation of ice-like waters on the mutated protein surface. PMID- 23017209 TI - RBM5 promotes exon 4 skipping of AID pre-mRNA by competing with the binding of U2AF65 to the polypyrimidine tract. AB - Alternative splicing is involved in functional regulation of the mutagenic enzyme activation-induced cytidine deaminase (AID). However, the molecular basis for AID splicing regulation remains undefined. Using a mini-gene-based screen in HeLa cells, we found that overexpression of RNA binding motif protein 5 (RBM5, or LUCA 15/H37) significantly promoted AID exon 4 skipping by suppressing the splicing of intron 3. The inhibitive effect of RBM5 on intron 3 splicing required a weak 3' splice site (ss). Indicative of the underlying mechanism, RBM5 interfered with the binding of U2AF65 to the polypyrimidine tract at the 3'-ss in vitro. Our findings thus not only shed lights on the regulatory mechanism of AID exon 4 skipping, but also provide new insights into how RBM5 functions in splicing regulation. PMID- 23017210 TI - Assessment of research quality of telehealth trials in pain management: a meta analysis. AB - Although telehealth-based pain management research has grown over the last decade, it is difficult to determine the state of the research because of methodological differences and variability in quality among existing studies. In a previous systematic review, we outlined these differences and preliminarily explored the promise of telehealth for pain intervention. We completed a PRISMA compliant meta-analysis of telehealth pain management research to more precisely describe the state of the research and to uncover gaps in the existing literature that highlight directions for future research. We identified 10 relevant studies completed between 2000 and 2011 including 3 noninferiority and 7 superiority studies. Meta-analysis revealed an overall benefit of telehealth interventions over control conditions and equivalence with in-person intervention. However, some of the reviewed studies found no benefit for telehealth over control conditions. Some methodological concerns among the examined research included poor research quality, small sample sizes, and the examination of telehealth pain interventions without proven efficacy for in-person treatment. Recommendations for future studies are reviewed. PMID- 23017211 TI - Correlation of Back Optic Zone Radius measurement of rigid contact lenses with radiuscope and keratometer. AB - PURPOSE: To investigate the accuracy of Back Optic Zone Radius (BOZR, base curve) measurements with manual keratometer for spherical polymethylmethacrylate (PMMA) lenses. METHODS: 100 spherical PMMA contact lenses were selected randomly from the trial sets. One investigator measured the BOZR with radiuscope. The second investigator measured the BOZR with keratometer. The two investigators were masked to each other's readings. As the keratometer is designed to measure a convex corneal surface, the BOZR readings are less than actual radii. A correction factor of 0.025 was used to have corrected keratometers readings. RESULTS: There was a high correlation between the BOZR measurement with radiuscope and the uncorrected (Pearson's correlation coefficient, r=0.99) and corrected (r=0.99) measurements with keratometer. The mean difference between BOZR measurement with radiuscope and the uncorrected and corrected measurements with keratometer were 0.003 mm (p=0.62) and -0.024 mm (p<0.001) respectively. The 95% limits of agreement for the BOZR measurements with radiuscope and the uncorrected and corrected measurements with keratometer were -0.11 to 0.11 mm and -0.14 to 0.09 mm respectively. CONCLUSION: We found that the uncorrected BOZR measurements with keratometer were similar to the BOZR measurements with radiuscope. With unavailability of radiuscope in majority of contact lens practice, keratometer can be used to measure the BOZR of contact lenses. PMID- 23017212 TI - Genome scans reveal candidate regions involved in the adaptation to host plant in the pea aphid complex. AB - A major goal in evolutionary biology is to uncover the genetic basis of adaptation. Divergent selection exerted on ecological traits may result in adaptive population differentiation and reproductive isolation and affect differentially the level of genetic divergence along the genome. Genome-wide scan of large sets of individuals from multiple populations is a powerful approach to identify loci or genomic regions under ecologically divergent selection. Here, we focused on the pea aphid, a species complex of divergent host races, to explore the organization of the genomic divergence associated with host plant adaptation and ecological speciation. We analysed 390 microsatellite markers located at variable distances from predicted genes in replicate samples of sympatric populations of the pea aphid collected on alfalfa, red clover and pea, which correspond to three common host-adapted races reported in this species complex. Using a method that accounts for the hierarchical structure of our data set, we found a set of 11 outlier loci that show higher genetic differentiation between host races than expected under the null hypothesis of neutral evolution. Two of the outliers are close to olfactory receptor genes and three other nearby genes encoding salivary proteins. The remaining outliers are located in regions with genes of unknown functions, or which functions are unlikely to be involved in interactions with the host plant. This study reveals genetic signatures of divergent selection across the genome and provides an inventory of candidate genes responsible for plant specialization in the pea aphid, thereby setting the stage for future functional studies. PMID- 23017213 TI - WU and KI polyomaviruses in respiratory samples from allogeneic hematopoietic cell transplant recipients. AB - Data are limited regarding 2 new human polyomaviruses, KI polyomavirus (KIPyV) and WU polyomavirus (WUPyV), in immunocompromised patients. We used real-time PCR to test for these and 12 respiratory viruses in 2,732 nasal wash samples collected during the first year after allogeneic hematopoietic cell transplantation from 222 patients. Specimens were collected weekly until day 100; then at least every 3 months. One year after hematopoietic cell transplantation, the cumulative incidence estimate was 26% for KIPyV and 8% for WUPyV. Age <20 years predicted detection of KIPyV (hazard ratio [HR] 4.6) and WUPyV (HR 4.4), and detection of a respiratory virus in the previous 2 weeks predicted KIPyV detection (HR 3.4). Sputum production and wheezing were associated with detection of KIPyV in the past week and WUPyV in the past month. There were no associations with polyomavirus detection and acute graft versus host disease, cytomegalovirus reactivation, neutropenia, lymphopenia, hospitalization, or death. PMID- 23017214 TI - Identification of genes containing ecdysone response elements in the genome of Brugia malayi. AB - Recent studies have demonstrated that filarial parasites contain a functional homologue of the insect ecdysone receptor (EcR). As a first step in deciphering the physiological role that ecdysteroids play in filarial parasites, adult female parasites cultured in the presence and absence of 20-OH ecdysone were metabolically labeled. Gel electrophoretic analysis of proteins extracted from the cultured parasites revealed changes in the level of expression of several proteins, indicating that adult female parasites contained an ecdysone-responsive gene network. A bioinformatic analysis was then conducted to identify putative ecdysone response elements (EcREs) in the Brugia malayi genome. A total of 18 genes were identified that contained putative EcREs located in the 4 kbp upstream from the start of their open reading frames. The most common functional classifications of the encoded proteins were factors involved in transcription and metabolism. These genes revealed a number of different developmental patterns of transcription. The promoter of one EcRE-containing gene was cloned into a luciferase reporter vector and transfected into B. malayi embryos. Reporter gene expression from embryos transfected with this construct was up-regulated by 20-OH ecdysone. Deletion and substitution mutations in the canonical EcRE resulted in a loss of the ecdysone response. These results demonstrate the presence of functional EcREs in the B. malayi genome. PMID- 23017215 TI - Epsilonproteobacteria in humans, New Zealand. PMID- 23017216 TI - In-situ revascularisation for secondary aorto-enteric fistulae: the success of silver-coated Dacron is closely linked to a suitable bowel repair. AB - OBJECTIVES: The purpose of this study was to assess short- and mid-term results of in-situ revascularisation (ISR) using silver-coated Dacron prostheses and bowel repair for management of secondary aorto-enteric fistulae (SAEF). DESIGN: Single-centre retrospective chart review. MATERIAL AND METHODS: This study includes all the patients treated by ISR using silver-coated Dacron for SAEF between 2006 and 2010. Primary end points were mortality and survival rates. Secondary end points were reinfection-free survival and secondary patency rates. RESULTS: Eighteen male patients with SAEF with a median age of 64 years were operated by ISR using silver-coated Dacron during the study period without operative death. The 30-day mortality was 22% and the in-hospital mortality rate was 39%. Indeed, during hospitalisation, a duodenal leak was observed in four patients including three who died. Four others patients died due to multi-system organ failure. Median follow-up was 16 months (range 1-66). The survival rate at 12 months was 55%. One duodenal leak was observed leading to death. The reinfection-free survival and the secondary patency rates at 12 months were 60% and 89%, respectively. CONCLUSION: In-situ revascularisation with silver-coated Dacron provides acceptable results in terms of mortality. This treatment may be useful for simple vascular reconstruction and allow greater attention to bowel repair that is a determinant in short- and mid-term survival. PMID- 23017217 TI - Cervical cancer screening in Middle Eastern and Asian migrants to Australia: a record linkage study. AB - BACKGROUND: Australia's organized cervical screening program recommends two yearly screening for women aged 18-69 years and reminder letters are sent at 27 months. Cervical screening registers hold comprehensive information on screening, but not country of birth. A linkage study was performed in order to assess cervical screening behavior in migrants. METHODS: To assess screening participation, we linked year 2000 records for 12,541 Middle Eastern/Asian-born women 20-54 years of age, and an age and area matched random sample of 12,143 Australian-born women in the New South Wales (NSW) Midwives Data Collection (MDC), which records country of birth, to screening register records. Screening behavior after 2000 was assessed in women without a recorded prior cervical abnormality. RESULTS: The odds ratios for being screened at least once within a 3 year period, with reference to Australian-born women and adjusted for age, parity, socioeconomic status and smoking, were 0.88 (95% CI: 0.81-0.97) and 0.74 (95% CI: 0.70-0.79) in women born in the Middle East and Asia, respectively. Screening increased with increasing socioeconomic status (SES), absence of smoking and greater parity in Australian-born women but little, if at all, in migrant women. In a sensitivity analysis in which hospital admitted patients were the source of population samples, some patterns were sufficiently different to suggest that selection for illness can affect the strength and direction of associations in linked data. CONCLUSION: Migrant women from Asian and Middle eastern countries are less likely than Australian-born women to participate in cervical screening at the recommended interval. Their likelihood of screening is also less related to socioeconomic status, smoking and parity than that in Australian-born women. PMID- 23017218 TI - Childhood school segregation and later life sense of control and physical performance in the African American Health cohort. AB - BACKGROUND: The association between childhood school desegregation and later life sense of control and physical performance among African Americans is not clear. We hypothesized that childhood school desegregation adversely affected the sense of control of in later life, and that this reduced sense of control accounts in part for reduced physical performance. METHODS: In-home follow-up assessments were completed in 2010 with 582 of the 58-74 year old men and women participating in the on-going African American Health cohort. We used these data to examine the relationship between (a) retrospective self-reports of attending segregated schools during one's 1st-to-12th grade education and one's current sense of control, as well as (b) the association between current sense of control and physical performance. Multiple linear regression analysis with propensity score re-weighting was used. RESULTS: Attending segregated schools for at least half of one's 1st-to-12th grade education was significantly associated with higher scores on the sense of control. Adjusting for all covariates and potential confounders, those receiving half or more of their 1st-to-12th grade education in segregated schools had sense of control scores that were .886 points higher (p <= .01; standardized effect size = .22). Sense of control scores were independently (all p < .01) associated with better systolic blood pressure, grip strength, peak expiratory flow, chair stands, balance tests, and the Short Portable Physical Battery even after adjusting for all covariates and potential confounders. Moreover, sense of control scores either partially or fully mediated the statistically significant beneficial associations between childhood school segregation and physical performance. CONCLUSIONS: Childhood school desegregation was adversely associated with the sense of control of African Americans in later life, and this reduced sense of control appears, in part, to account for their poorer physical performance. The etiologic mechanism through which childhood school segregation at the time that this cohort experienced it improved the sense of control in later life, which subsequently led to better physical performance, has not been identified. We suspect, however, that the pathway involves greater exposure to racial solidarity, same-race students as peer role models and same race teachers and principals as authority role models, the reduced likelihood of exposure to race-based discrimination or antagonism during their formative early lives, and greater exposure to encouragement and support for academic and life success. PMID- 23017219 TI - Biphenyl-type neolignans from Magnolia officinalis and their anti-inflammatory activities. AB - Reactive oxygen species (ROS) and granule proteases produced by human neutrophils contribute to the pathogenesis of inflammatory diseases. The MeOH extract of the stem bark of Magnolia officinalis showed potent inhibitory effects on superoxide anion generation and elastase release by human neutrophils in response to formyl L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Five biphenyl-type neolignan derivatives, 5-allyl-5'-(1"-hydroxyallyloxy)biphenyl-2,2'-diol, 5,5' diallyl-2'-(allyloxy)biphenyl-2-ol, 5,5'-diallyl-2'-(3-methylbut-2 enyloxy)biphenyl-2-ol, (E)-5-allyl-3'-(prop-1-enyl)biphenyl-2,4'-diol, and 4 allyl-2-(2'-methylbenzofuran-5'-yl)phenol, have been isolated from the stem bark of M. officinalis, together with 12 known compounds. Several exhibited inhibition (IC50) values <=10.7 MUM) of superoxide anion generation by human neutrophils in response to fMLP/CB. Others inhibited fMLP/CB-induced elastase release with IC50) values <=8.76 MUM. PMID- 23017220 TI - Healthcare organizations' attitudes toward pay-for-performance in Korea. AB - This study was conducted to assess views of healthcare organizations on pay-for performance (P4P) in terms of its design, possible effects, and unintended consequences. This is a cross-sectional, self-administered, internet-based survey. Eligible healthcare organizations were 3605 organizations in Korea. Healthcare organizations of 522, including 31 tertiary teaching hospitals, 182 general hospitals, 158 hospitals, and 152 clinics, were participated in this survey. Rates of awareness and support of P4P, preferred P4P program design, and possible effects and unintended consequences resulting from the P4P program were identified. There were variations in the awareness and support from the type of healthcare organization. The preferred design was quite different from the current design of the P4P program. They believed that the P4P program would not have a significant economic impact on their organizations, but that the P4P program could stimulate positive changes in their practice behaviors. They also showed considerable concerns about unintended consequences. P4P implementing agency such as HIRA in Korea should make an effort to improve healthcare organizations' understanding of the program. Also, HIRA could take into consideration of reflecting their reasonable opinions regarding its design components and unintended consequences. PMID- 23017221 TI - Stress, depression, and intention to leave among nurses in different medical units: implications for healthcare management/nursing practice. AB - AIMS: The aim of the present study was to compare the levels of stress, depression, and intention to leave among clinical nurses employed in different medical units in relation to their demographic characteristics under the National Health Insurance (NHI) System in Taiwan. METHODS: Cross-sectional Spearman's correlation, one-way ANOVA with Scheffe post hoc analysis tests, and multiple regression analyses were conducted. Several self-report questionnaires, such as the Center for Epidemiological Studies Depression Scale, the Perceived Stress Scale and Intention to Leave Scale, were administered. A total of 314 research participants were surveyed, all of whom came from regional hospitals in Northern Taiwan. RESULTS: Marital status and working tenure were significant predictors to the levels of stress, depression, and intention to leave among nurses before taking the medical units into consideration. However, with adding medical units as predictors, the effect of marital status and working tenure were insignificant except for the stress model, indicating medical units were showing dominant effect over other variables. In particular, internal medical ward (IMW) nurses experienced a higher prevalence of depression than emergency room (ER) nurses and professional nursing practitioners. External medical ward (EMW) nurses also experienced greater depression than emergency room (ER) nurses. Both IMW and EMW nurses perceived significantly greater stress than ER and dialysis center. Moreover, IMW nurses also perceived greater stress than operating room (OR) nurses and showed stronger intention to leave than their counterparts in the outpatient service departments. CONCLUSIONS: The results indicated that significant differences existed among various medical units with regards to nurses' stress, depression, and intention to leave. Nurses working in internal and external medical wards, especially the inexperienced and married ones, experienced greater depression and stress, thereby developing stronger intention to leave their job. PMID- 23017222 TI - Powassan virus encephalitis, Minnesota, USA. AB - Powassan virus (POWV) is a rare tick-borne agent of encephalitis in North America. Historically, confirmed cases occurred mainly in the northeastern United States. Since 2008, confirmed cases in Minnesota and Wisconsin have increased. We report a fatal case of POWV encephalitis in Minnesota. POWV infection should be suspected in tick-exposed patients with viral encephalitis. PMID- 23017223 TI - Adenocarcinoma of the lower female genital tract in patients with Herlyn-Werner Wunderlich syndrome. AB - We report 2 patients with Herlyn-Werner-Wunderlich syndrome, 1 with advanced endometrioid adenocarcinoma of the semiobstructed side of the uterine cervix and 1 with primary clear cell carcinoma of the obstructed side of the upper vagina. PMID- 23017224 TI - Neonatal outcome following elective cesarean section of twin pregnancies beyond 35 weeks of gestation. AB - OBJECTIVE: We sought to assess neonatal morbidity and mortality of elective cesarean section (CS) of uncomplicated twin pregnancies per week of gestation >35(+0). STUDY DESIGN: We performed a retrospective cohort study in our nationwide database including all elective CS of twin pregnancies. Two main composite outcome measures were defined, ie, severe adverse neonatal outcome and mild neonatal morbidity. RESULTS: We report on 2228 neonates. More than 17% were born <37(+0) weeks of gestation. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for severe adverse neonatal outcome at 35(+0-6), 36(+0-6), and 37(+0-6) weeks were, OR, 9.4; 95% CI, 3.2-27.6; OR, 1.7; 95% CI, 0.5-5.3; and OR, 0.7; 95% CI, 0.2-2.0, respectively; and for mild neonatal morbidity, OR, 4.7; 95% CI, 2.6-8.7; OR, 4.9; 95% CI, 3.1-7.9; and 1.4; 95% CI, 0.9-2.1, respectively, compared to neonates born >=38(+0) weeks of gestation. CONCLUSION: In uncomplicated twin pregnancies elective CS can best be performed between 37(+0) and 39(+6) weeks of gestation. PMID- 23017225 TI - High efficacy of arsenic trioxide plus all-trans retinoic acid based induction and maintenance therapy in newly diagnosed acute promyelocytic leukemia. AB - We conducted a retrospective study to evaluate the efficacy of combining arsenic trioxide (ATO) with all-trans-retinoic acid (ATRA) based induction therapy, followed by 3 courses of consolidation chemotherapy and 2-year sequential ATO/ATRA maintenance therapy in acute promyelocytic leukemia (APL). 137 patients were enrolled in the study. The complete remission (CR) rate was 93.4%. All the 9 (6.6%) induction failures were due to early death. With a median follow-up of 35 months, 5 relapses (4%) in CR patients were recorded, including 3 isolated CNS relapses. By using the Kaplan-Meier analysis, the 5-year overall survival and relapse-free survival of the low/intermediate risk group and high-risk group was 98.9% versus 97.4% and 98.7% versus 87.9%, respectively. The results indicated that ATO based first-line protocol is highly effective for treatment of newly diagnosed APL. PMID- 23017226 TI - Spectrum of antimicrobial activity associated with ionic colloidal silver. AB - OBJECTIVES: Silver has historically and extensively been used as a broad-spectrum antimicrobial agent. However, the Food and Drug Administration currently does not recognize colloidal silver as a safe and effective antimicrobial agent. The goal of this study was to further evaluate the antimicrobial efficacy of colloidal silver. DESIGN: Several strains of bacteria, fungi, and viruses were grown under multicycle growth conditions in the presence or absence of ionic colloidal silver in order to assess the antimicrobial activity. RESULTS: For bacteria grown under aerobic or anaerobic conditions, significant growth inhibition was observed, although multiple treatments were typically required. For fungal cultures, the effects of ionic colloidal silver varied significantly between different genera. No viral growth inhibition was observed with any strains tested. CONCLUSIONS: The study data support ionic colloidal silver as a broad-spectrum antimicrobial agent against aerobic and anaerobic bacteria, while having a more limited and specific spectrum of activity against fungi. PMID- 23017227 TI - Functional capability of IL-15-Akt signaling in the denervated muscle. AB - INTRODUCTION: Denervation of skeletal muscles results in timely muscle-T cell cross-talk, but the mechanistic details of the orchestrated local circuits, as well as the potential regulatory link to the muscular function have not been established. METHODS: We used a combination of techniques to measure: (i) timely expression of IL-1beta-ERK1/2 and IL-15-Akt signaling and (ii) cellular events controlled by IL-15-Akt signaling. Techniques included gastrocnemius strip, satellite cell culture, real time PCR, immunoprecipitation, Western blotting and subcellular fractionation. Besides that, muscle cell survival was determined by MTT assay. RESULTS: We found that there were two events: rapid IL-1beta-ERK1/2 (1 day) and the later IL-15-Akt signaling (7 day) were selectively triggered by sciatic nerve injury. IL-15-Akt signaling was mostly targeted on CD2 phosphorylation and strengthened CD2-CD48 adhesion within gastrocnemius lipid rafts, in the same time, it exerted a restriction on TAB2 via miR155 pathway, thereby prevented muscle cell from inflammatory damage. CONCLUSIONS: Our results suggested that IL-15-Akt signaling harbored the complex signals for muscle-T cell interaction, the regulatory networks have significant potential for the restriction on IL-1beta inflammatory signaling. These results are likely to provide new insights into the therapy of neuromuscular injury. PMID- 23017228 TI - Differential activation of the inflammasome in THP-1 cells exposed to chrysotile asbestos and Libby "six-mix" amphiboles and subsequent activation of BEAS-2B cells. AB - Inflammatory responses of THP-1 cells (macrophage cell line) exposed to chrysotile asbestos (Chry) and Libby six-mix (LIB) and the subsequent impact on bronchial epithelial cells were determined. Direct treatment of THP-1 cells with Chry caused cell death, activation of caspase-1 and release of IL-1beta, while the addition of caspase-1 inhibitor, Z-YVAD-FMK, reduced IL-1beta, suggesting that Chry activated the caspase-1 mediated Nod-like receptor protein 3 (NLRP3) inflammasome; by comparison, LIB had less effects on all of these parameters. Expression of antioxidant enzymes, protein oxidation and nitration, and lipid peroxides in THP-1 cells treated with the two particles suggest that LIB generated more reactive oxygen species (ROS) than the same dose of Chry. Differences in fiber length and surface area suggest a possible role for particulate size in the differential activation of the inflammasome. BEAS-2B cells, representing the bronchial epithelium, treated with supernatants of medium from Chry- or LIB-treated THP-1 cells (conditioned medium) activated the MAPK cascade, increased phosphorylation of ERK and Cot (MAP3K8), increased AP-1 binding activity and induced IL-6 release. To verify that IL-1beta from THP-1 cells was responsible for activation of BEAS-2B, conditioned medium with added IL 1Ra, an IL-1beta antagonist, was applied to BEAS-2B. Results show that IL-1Ra attenuated effects of conditioned medium, supporting a role of IL-1beta, as a secondary mediator, in the transduction of inflammatory signaling from the macrophage to epithelial cells. The effects of LIB-conditioned medium appeared to be less dependent on IL-1beta. In conclusion, Chry and LIB induce differential inflammatory responses in THP-1 cells that subsequently lead to differential effects in epithelial cells. PMID- 23017230 TI - Interleukin-10 promoter polymorphisms and asthma risk: a meta-analysis. AB - Several studies assessed the associations of interleukin-10 (IL-10) polymorphisms with asthma in different populations. However, the results were inconclusive. The aim of the present study was to further assess the associations by the method of meta-analysis. Pubmed, EMBASE, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Weipu Database were searched. Data were extracted independently by two authors. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Seventeen potentially eligible articles were identified (4478 cases and 4803 controls). Significant associations between -1082A/G and -592A/C polymorphisms and asthma were observed. However, there was no significant association between -819T/C polymorphism and asthma risk. In addition, there were significant associations of the IL-10 haplotypes with asthma. In summary, this meta-analysis suggested that IL-10 promoter polymorphisms were associated with asthma risk. PMID- 23017229 TI - Genome-wide association replicates the association of Duffy antigen receptor for chemokines (DARC) polymorphisms with serum monocyte chemoattractant protein-1 (MCP-1) levels in Hispanic children. AB - Obesity is associated with a chronic low inflammatory state characterized by elevated levels of chemokines. Monocyte chemoattractant protein-1 (MCP-1) is a member of the cysteine-cysteine (CC) chemokine family and is increased in obesity. The purpose of this study was to identify loci regulating serum MCP-1 in obese Hispanic children from the Viva La Familia Study. A genome-wide association (GWA) analysis was performed in 815 children, ages 4-19 years, using genotypes assayed with the Illumina HumanOmni1-Quad v1.0 BeadChips. All analyses were performed in SOLAR using a linear regression-based test under an additive model of allelic effect, while accounting for the relatedness of family members via a kinship variance component. The strongest association for MCP-1 levels was found with a non-synonymous single nucleotide polymorphism (SNP), rs12075, resulting in an amino acid substitution (Asp42Gly) in the Duffy antigen receptor for chemokines (DARC) gene product (minor allele frequency=43.6%, p=1.3 * 10(-21)) on chromosome 1. Four other DARC SNPs were also significantly associated with MCP-1 levels (p<10(-16)-10(-6)). The Asp42Gly variant was associated with higher levels of MCP-1 and accounted for approximately 10% of its variability. In addition, MCP 1 levels were significantly associated with SNPs in chemokine receptor 3 (CCR3) and caspase recruitment domain family, member 9 (CARD9). In summary, the association of the DARC Asp42Gly variant with MCP-1 levels replicates previous GWA results substantiating a potential role for DARC in the regulation of pro inflammatory cytokines. PMID- 23017231 TI - Metal ion dependence of DNA cleavage by SepMI and EhoI restriction endonucleases. AB - Most of type II restriction endonucleases show an absolute requirement for divalent metal ions as cofactors for DNA cleavage. While Mg(2+) is the natural cofactor other metal ions can substitute it and mediate the catalysis, however Ca(2+) (alone) only supports DNA binding. To investigate the role of Mg(2+) in DNA cleavage by restriction endonucleases, we have studied the Mg(2+) and Mn(2+) concentration dependence of DNA cleavage by SepMI and EhoI. Digestion reactions were carried out at different Mg(2+) and Mn(2+) concentrations at constant ionic strength. These enzymes showed different behavior regarding the ions requirement, SepMI reached near maximal level of activity between 10 and 20mM while no activity was detected in the presence of Mn(2+) and in the presence of Ca(2+) cleavage activity was significantly decreased. However, EhoI was more highly active in the presence of Mn(2+) than in the presence of Mg(2+) and can be activated by Ca(2+). Our results propose the two-metal ion mechanism for EhoI and the one-metal ion mechanism for SepMI restriction endonuclease. The analysis of the kinetic parameters under steady state conditions showed that SepMI had a K(m) value for pTrcHisB DNA of 6.15 nM and a V(max) of 1.79*10(-2)nM min(-1), while EhoI had a K(m) for pUC19 plasmid of 8.66 nM and a V(max) of 2*10(-2)nM min(-1). PMID- 23017232 TI - Identification and evaluation of a novel peptide binding to the cell surface of Staphylococcus aureus. AB - Identification of short peptides that serve as specific ligands to biological materials such as microbial cell surfaces has major implications in better understanding the molecular recognition of cell surfaces. In this study we screened a commercially available random phage-display library against Staphylococcus aureus cells and identified peptides specifically binding to the bacteria. A synthetic peptide (SA5-1) representing the consensus sequence (VPHNPGLISLQG) of the bacteria-binding peptide was evaluated for its binding potential against S. aureus. Dot-blot, immunoblot assay and ELISA results revealed the SA5-1 peptide to be highly specific to S. aureus. The SA5-1 peptide binding was optimal between pH 6.0 and 8.0. Nanogold Transmission Electron Microscopy demonstrated that the SA5-1 binds to the outer membrane surface of S. aureus. Diagnostic potential of the SA5-1 peptide was evaluated in human platelet samples spiked with S. aureus and specific detection of the bacteria by biotinylated-SA5-1 and streptavidin-conjugated fluorescent quantum dots. Fluorometry results indicated that the peptide was able to detect ~100 organisms per ml in a spiked biological sample providing a proof-of-concept towards potential of this peptide as a S. aureus diagnostic tool that can be of use in different detection platforms. PMID- 23017233 TI - Characterization of murine anti-human Fab antibodies for use in an immunoassay for generic quantification of human Fab fragments in non-human serum samples including cynomolgus monkey samples. AB - Generic immunoassay formats in animal serum have been described for pharmacokinetic (PK) analysis of human full-length antibodies, but not of human antigen binding fragment (Fab) proteins. Here we characterize two murine monoclonal antibodies (mAb) raised against human immunoglobulin G (IgG) which bind to unique epitopes in the Fab region of human IgG. mAb M-1.7.10 is directed against the constant domain of the kappa light chain and mAb M-1.19.31 binds to the constant domain 1 (CH1) of the heavy chain. Surface plasmon resonance analysis showed that mAb M-1.7.10 does not cross-react with sera from mouse, rat, rabbit, dog, marmoset, rhesus macaque, baboon and cynomolgus monkey, but binds to human and chimpanzee serum (dissociation constant K(D) of 6.8 * 10(-12) and 3.1 * 10(-11)M, respectively). mAb M-1.19.31 shows a higher K(D) for human and chimpanzee IgG (2.0 * 10(-9)M and 5.8 * 10(-10)M, respectively), but also does not bind to serum of the other species. Therefore, mAb M-1.7.10 was used as capture and mAb M-1.19.31 as detection reagent in a generic enzyme linked immunosorbent assay (ELISA) to quantify the human anti-IGF-1R Fab in mouse serum. The generic human Fab assay showed a limit of detection of 31.5 ng/mL anti-IGF-1R Fab. Intra- and inter-assay precision was less than 12% and the accuracy range for all controls was within +/-20% of the target concentration. The generic human Fab ELISA was applied to determine serum levels of human anti-IGF-1R Fab after intravenous (iv) administration of 10mg/kg to mice. The resulting concentration time profile was nearly identical to that obtained by analysis with a validated specific ELISA for anti-IGF-1R Fab. The mean relative concentration of anti-IGF 1R Fab analyzed by the generic assay was 82-118% of that of the specific assay. This equivalence was confirmed in a cynomolgus monkey study with the full length human mAb anti-TROP-2 IgG. Both specific ELISAs used mAb M-1.7.10 as detection reagent and their targets for capturing. In conclusion, the two murine anti-human Fabs are versatile tools as capture and detection reagents for human antibodies in generic and specific PK ELISA formats for animal studies. Their use in specific ELISAs as detection reagents allows the usage of Fc-fusion proteins as capture reagents. PMID- 23017234 TI - Acute aerobic exercise in humans increases cytokine expression in CD27(-) but not CD27(+) CD8(+) T-cells. AB - Exercise alters the percentage of CD8(+) T-cells in the bloodstream expressing type I and type II cytokines. It is unknown if this reflects a change in cytokine expression within individual cells, or whether these observations result from the exercise-induced shift in the proportions of early/intermediate (CD27(+)) and late (CD27(-)) differentiated cells, which have vastly different cytokine profiles. 16 males cycled for 60 min at 95% maximal steady state. Mononuclear cells isolated from blood collected before, immediately after, and 1 h after exercise were cultured overnight with and without phytohaemagglutinin stimulation. CD8(+) T-cells were assessed for differentiation markers and intracellular cytokine expression by flow cytometry. The numbers and percentage of CD27(-)CD8(+) T-cells increased immediately after exercise and fell below pre exercise values 1 h later. At 1 h after exercise, an increased number and percentage of CD8(+) T-cells expressing IL-2, IFN-gamma, TNF-alpha, IL-6, IL-4, and IL-10 was observed in both stimulated and unstimulated cells. The cytokine response to exercise was confined to CD27(-)CD8(+) T-cells, although cytokine expression among CD8(+) T-cells was highest when the proportion of CD27(-)CD8(+) T-cells was lowest. Moreover, the cytokine response to exercise could be predicted by the number of late cells in resting blood: cytokine expression was highest among those with low resting proportions of late cells. We conclude that exercise-induced changes in the percentage of CD8(+) T-cells expressing cytokines are not due to proportional shifts in early/intermediate and late differentiated T-cells. Exercise may prime late-differentiated blood CD8(+) T-cells to initiate effector functions in preparation for their extravasation into the tissues. PMID- 23017235 TI - African Plasmodium vivax: distribution and origins. AB - There is increasing evidence that the malaria parasite, Plasmodium vivax, is endemic in west and central Africa, a region from which it was previously thought to be almost completely absent due to the very high prevalence of the Duffy negative phenotype in the local human populations. Furthermore, P. vivax, or very closely related parasites, has been identified in both chimpanzees and gorillas from this region. In this review, we discuss the implications of these findings for the current understanding of the origins of P. vivax as a human parasite. With the support of new evidence from mitochondrial genome sequencing, we propose that the evidence is consistent with current, extant P. vivax populations having their origins in Africa. PMID- 23017236 TI - Enhanced arsenic removal by in situ formed Fe-Mn binary oxide in the aeration direct filtration process. AB - Field studies were conducted to evaluate the feasibility of an in situ formed Fe Mn binary oxide (in situ FMBO) for improving arsenic (As) removal in the aeration direct filtration process. The transformation and transportation of As, Fe, and Mn in the filter bed were also investigated. The in situ FMBO increased the As removal efficiency by 20-50% to keep the residual As below 10 MUg/L. The optimum FMBO dosage was determined to be 0.55 mg/L with the Fe/Mn ratio as 10:1. The removal of Fe, Mn, turbidity, and particles was also improved to a large extent. The in situ FMBO favored the transformation of soluble As, Fe, and Mn into the solid phases, benefiting the removal of these pollutants by the subsequent filtration. Moreover, the deposited precipitates onto the filter media were characterized, as indicated by the analyses of SEM/EDS and particle size distribution. The long-term experiments exhibited decreased head loss growth and prolonged run length, suggesting an enhanced pollutant catching capacity of the filter media. The full-scale field study with a flow of 10,000 m3/d confirmed positive effects of in situ FMBO on As removal, with the average effluent As concentration reduced from 20 MUg/L to 6 MUg/L (reagent cost=0.006 Y/m3). PMID- 23017237 TI - In situ preparation of novel p-n junction photocatalyst BiOI/(BiO)2CO3 with enhanced visible light photocatalytic activity. AB - Novel p-n junction photocatalysts BiOI/(BiO)2CO3 with different contents of BiOI were in situ synthesized by etching (BiO)2CO3 precursor with hydroiodic acid (HI) solution. X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectrometry (FT-IR), energy-dispersive spectroscopy (EDS) and UV-vis diffuse reflectance spectroscopy (DRS) were employed to study the structures, morphologies and optical properties of the as prepared samples. Under visible light (lambda>420 nm), BiOI/(BiO)2CO3 hybrid displayed much higher photocatalytic activity than pure (BiO)2CO3 and BiOI for the degradation of methyl orange (MO). The increased photocatalytic activity of BiOI/(BiO)2CO3 could be attributed to the formation of the p-n junction between p BiOI and n-(BiO)2CO3, which effectively suppresses the recombination of photoinduced electron-hole pairs. Moreover, the tests of radical scavengers confirmed that *O2- and h+ were the main reactive species for the degradation of MO. PMID- 23017238 TI - Design of a visible light driven photo-electrochemical/electro-Fenton coupling oxidation system for wastewater treatment. AB - In this study, we report on a photo-electrochemical/electro-Fenton oxidation (PEC/EF) system by coupling visible light driven photo-electrochemical oxidation (PEC) and electro-Fenton oxidation (EF) in an undivided cell. Bi2WO6 nanoplates deposited on FTO glass (Bi2WO6/FTO) and Fe@Fe2O3 core-shell nanowires supported on activated carbon fiber (Fe@Fe2O3/ACF) were used as the anode and the cathode in the PEC/EF system, respectively. This novel PEC/EF system showed much higher activity than the single PEC and EF systems on degradation of rhodamine B in aqueous solution at natural pH. Moreover, the degradation and the instantaneous current efficiencies of the PEC/EF system were increased by 154% and 26% in comparison with the sum of those of single PEC and EF systems, respectively. These significant enhancements could be attributed to the synergetic effect from better separation of photo-generated carriers in the photo-anode and the transfer of photo-electrons to the oxygen diffusion cathode to generate more electro generated H2O2 and hydroxyl radicals on the Fenton cathode. The better separation of photo-generated carriers contribute more to the overall degradation enhancement than the photo-electrons generated H2O2 and the subsequent Fenton reaction on the cathode during the PEC/EF process. PMID- 23017239 TI - The role of dissolved organic matters in the aquatic photodegradation of atenolol. AB - Atenolol (ATL) is a photostable and hydrolysis resistant beta-blocker and has been frequently detected in natural water. In this study, mechanism on aquatic photodegradation of ATL was investigated with an emphasis on the role of dissolved organic matters (DOMs) as well as other natural water compositions (nitrate, bicarbonate and ferric ions). Significant acceleration of photodegradtion of ATL was observed in the presence of each DOMs added, namely Suwannee River Fulvic Acid (SRFA), Suwannee River Humic Acid (SRHA), Nordic Lake Fulvic Acid (NOFA) and Nordic Lake Humic Acid (NOHA). Hydroxyl radical (*OH) was determined as the main reactive species in this process, instead of singlet oxygen or excited triplet of DOM. Addition of these four DOMs all inhibited photodegradation of ATL in nitrate solutions through reducing nitrated-derived *OH and screening photons absorbed by nitrate. No loss of ATL was detected in bicarbonate solution with or without DOMs. Bicarbonate exhibited a scavenger of *OH derived from DOMs. However, in the presence of iron species, photodegradation of ATL was significantly enhanced by the addition of each DOM, due to the high yield of *OH in the photoprocess of Fe(III)-DOM complex. The photoproducts distribution of ATL demonstrated that SRFA promote the hydroxylation on aromatic ring in the presence of nitrate and reduce the ketone moiety to alcohol in the system of ferric ions. Our findings indicate that DOMs should be considered in aquatic photoprocesses of organic pollutants induced by themselves as well as other coexisting photoactive water compositions. PMID- 23017240 TI - Paramutation: a trans-homolog interaction affecting heritable gene regulation. AB - Paramutation describes both the process and results of trans-sensing between chromosomes that causes specific heritable changes in gene regulation. RNA molecules are implicated in mediating similar events in maize, mouse, and Drosophila. Changes in both small RNA profiles and cytosine methylation patterns in Arabidopsis hybrids represent a potential molecular equivalent to the interactions responsible for paramutations. Despite a seemingly unifying feature of RNA-directed changes, both recent and historical works show that paramutations in maize require plant-specific proteins and lack expected hallmarks of a trans effect mediated solely by RNAs. Recent examples of nearby transposons affecting RNA polymerase II functions lead to an opinion that paramutations represent an emergent property of the transcriptional dynamics ongoing in plant genomes between repetitious features and nearby genes. PMID- 23017241 TI - Control of meiotic recombination frequency in plant genomes. AB - Sexual eukaryotes reproduce via the meiotic cell division, where ploidy is halved and homologous chromosomes undergo reciprocal genetic exchange, termed crossover (CO). CO frequency has a profound effect on patterns of genetic variation and species evolution. Relative CO rates vary extensively both within and between plant genomes. Plant genome size varies by over 1000-fold, largely due to differential expansion of repetitive sequences, and increased genome size is associated with reduced CO frequency. Gene versus repeat sequences associate with distinct chromatin modifications, and evidence from plant genomes indicates that this epigenetic information influences CO patterns. This is consistent with data from diverse eukaryotes that demonstrate the importance of chromatin structure for control of meiotic recombination. In this review I will discuss CO frequency patterns in plant genomes and recent advances in understanding recombination distributions. PMID- 23017242 TI - Gender differences in the presence of drugs in violent deaths. AB - AIMS: To investigate differences in the presence of drugs, by gender, when considering deaths attributable to homicides and suicides. DESIGN: Logistic regression analysis of mortality data collected by the Colorado Violent Death Reporting System. PARTICIPANTS AND SETTING: A total of 5791 Colorado decedents who died of violent causes from 2004 to 2009. MEASUREMENT: Forensic pathologist autopsy data on drug presence at time of death, coded as present, not present or missing. FINDINGS: Postmortem presence of drugs is associated strongly with the specific cause of violent death. Compared with suicide decedents, homicide decedents are significantly more likely to test positive for amphetamines [odds ratio (OR): 1.79; confidence interval (CI): 1.34, 2.39], marijuana (OR: 2.03; CI: 1.60, 2.58) and cocaine (OR: 2.60; CI: 2.04, 3.31), and are less likely to test positive for opiates (OR: 0.27; CI: 0.18, 0.39) and antidepressants (OR: 0.17; CI: 0.10, 0.28). When other drugs are controlled for the influence of alcohol is abated dramatically. The patterns of drug prevalence associated with homicide (particularly marijuana) are stronger among males; the patterns of drug prevalence associated with suicide are stronger among females. CONCLUSIONS: Suicide and homicide decedents are characterized by varying patterns of licit and illicit drug use that differ by gender. Drugs associated with homicide (marijuana, cocaine and amphetamines) are stronger among males, while drugs associated with suicide are stronger among females (antidepressants and opiates). Taking these differences into consideration may allow for targeted interventions to reduce violent deaths. PMID- 23017243 TI - Novel involvement of leukotriene B4 receptor 2 through ERK activation by PP2A down-regulation in leukotriene B4-induced keratin phosphorylation and reorganization of pancreatic cancer cells. AB - Perinuclear reorganization via phosphorylation of specific serine residues in keratin is involved in the deformability of metastatic cancer cells. The level of leukotriene B4 is high in pancreatic cancers. However, the roles of LTB4 and its cognate receptors in keratin reorganization of pancreatic cancers are not known. LTB4 dose-dependently induced phosphorylation and reorganization of Keratin 8 (K8) and these processes were reversed by LY255283 (BLT2 antagonist). BLT2 agonists such as Comp A and 15(S)-HETE also induced phosphorylation of serine 431 in K8. Moreover, Comp A-induced K8 phosphorylation and reorganization were blocked by LY255283. Gene silencing of BLT2 suppressed Comp A-induced K8 phosphorylation and reorganization in PANC-1 cells. Over-expression of BLT2 promoted K8 phosphorylation. Comp A promoted the migration of PANC-1 cells in a dose-dependent manner, and LY255283 blocked Comp A-induced migration, respectively. PD98059 (ERK inhibitor) suppressed Comp A-induced phosphorylation of serine 431 and reorganization of K8. Gene silencing of BLT2 suppressed the expression of pERK, and over-expression of BLT2 increased the expression of pERK even without Comp A. Comp A induced the expression of active ERK (pERK) and BLT2. These inductions were blocked by PD98059. Comp A decreased PP2A expression and hindered the binding of PP2A to the K8, leading to the activation of ERK. PD98059 suppressed the Comp A-induced migration of PANC-1 cells and BLT2 over-expression induced migration of PANC-1 cells. Overall, these results suggest that BLT2 is involved in LTB(4)-induced phosphorylation and reorganization through ERK activation by PP2A downregulation, leading to increased migration of PANC-1 cells. PMID- 23017245 TI - Towards an integrated molecular model of plant-virus interactions. AB - The application in recent years of network theory methods to the study of host virus interactions is providing a new perspective to the way viruses manipulate the host to promote their own replication. An integrated molecular model of such pathosystems require three detailed maps describing, firstly, the interactions between viral elements, secondly, the interactions between host elements, and thirdly, the cross-interactions between viral and host elements. Here, we compile available information for Potyvirus infecting Arabidopsis thaliana. With an integrated model, it is possible to analyze the mode of virus action and how the perturbation of the virus targets propagates along the network. These studies suggest that viral pathogenicity results not only from the alteration of individual elements but it is a systemic property. PMID- 23017244 TI - Wild birds and urban ecology of ticks and tick-borne pathogens, Chicago, Illinois, USA, 2005-2010. AB - Bird-facilitated introduction of ticks and associated pathogens is postulated to promote invasion of tick-borne zoonotic diseases into urban areas. Results of a longitudinal study conducted in suburban Chicago, Illinois, USA, during 2005-2010 show that 1.6% of 6,180 wild birds captured in mist nets harbored ticks. Tick species in order of abundance were Haemaphysalis leporispalustris, Ixodes dentatus, and I. scapularis, but 2 neotropical tick species of the genus Amblyomma were sampled during the spring migration. I. scapularis ticks were absent at the beginning of the study but constituted the majority of ticks by study end and were found predominantly on birds captured in areas designated as urban green spaces. Of 120 ticks, 5 were infected with Borrelia burgdorferi, spanning 3 ribotypes, but none were infected with Anaplasma phagocytophilum. Results allow inferences about propagule pressure for introduction of tick-borne diseases and emphasize the large sample sizes required to estimate this pressure. PMID- 23017246 TI - Regulators of innate immunity as novel targets for panviral therapeutics. AB - Interferons (IFNs) have long been used as an immunomodulatory therapy for a large array of acute and chronic viral infections. However, IFN therapies have been plagued by severe side effects. The discovery of pathogen recognition receptors (PRR) rejuvenated the interest for immunomodulatory therapies. The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. Better characterization of pathogen-induced immune disorders and newly discovered regulators of innate immunity have now the potential to specifically withdraw prevailing subversion mechanisms and to transform antiviral treatments by introducing panviral therapeutics with less adverse effects than IFN therapies. PMID- 23017247 TI - Factors associated with poor glycemic control or wide glycemic variability among diabetes patients in Hawaii, 2006-2009. AB - INTRODUCTION: Although glycemic control is known to reduce complications associated with diabetes, it is an elusive goal for many patients with diabetes. The objective of this study was to identify factors associated with sustained poor glycemic control, some glycemic variability, and wide glycemic variability among diabetes patients over 3 years. METHODS: This retrospective study was conducted among 2,970 diabetes patients with poor glycemic control (hemoglobin A1c [HbA1c] >9%) who were enrolled in a health plan in Hawaii in 2006. We conducted multivariable logistic regressions to examine factors related to sustained poor control, some glycemic variability, and wide glycemic variability during the next 3 years. Independent variables evaluated as possible predictors were age, sex, type of insurance coverage, morbidity, diabetes duration, history of cardiovascular disease, and number of medications. RESULTS: Longer duration of diabetes, being under age 35, and taking 15 or more medications were significantly associated with sustained poor glycemic control. Preferred provider organization and Medicare (vs health maintenance organization) enrollees and patients with high morbidity were less likely to have sustained poor glycemic control. Wide glycemic variability was significantly related to being younger than age 50, longer duration of diabetes, having coronary artery disease, and taking 5 to 9 medications per year. CONCLUSION: Results indicate that duration of diabetes, age, number of medications, morbidity, and type of insurance coverage are risk factors for sustained poor glycemic control. Patients with these characteristics may need additional therapies and targeted interventions to improve glycemic control. Patients younger than age 50 and those with a history of coronary heart disease should be warned of the health risks of wide glycemic variability. PMID- 23017248 TI - Smoking in top-grossing US movies, 2011. AB - We reviewed the number of incidents of tobacco use (almost exclusively smoking) depicted in movies in the United States in 2011 to compare that with previously reported trends. We counted use or implied use of a tobacco product by an actor in all movies whose box office gross ranked in the top 10 for at least 1 week. Total tobacco incidents per movie rose 7% from 2010 to 2011, ending 5 years of decline; incidents rose 34% per movie rated G, PG, or PG-13 and 7% per R-rated movie. The reversal of progress toward less onscreen smoking in youth-rated movies underscores the need to rate movies with tobacco imagery as R, establishing an industry-wide market incentive to keep youth-marketed movies tobacco-free. PMID- 23017249 TI - Development of polyploidy of scale-building cells in the wings of Manduca sexta. AB - The developing wings of butterflies and moths are composed of two epithelial monolayers. Each epithelial sheet is made up of two kinds of cells, diploid cells that make up the epidermal surface and body of the wing, and large polyploid cells that become the scale-building cells whose cytoplasmic projections develop into the scales that will cover the adult wing and bear the pigment pattern. We studied the development of polyploidization of the scale-building cells during the pupal stage of the tobacco hornworm moth, Manduca sexta. The endomitotic divisions of the presumptive scale-building cells and the mitotic divisions of the diploid epithelial cells begin on day 3 of the pupal stage and continue until day 7. We show that scales of different colors and positions on the wing differ in size, and that the size of the scale is proportional to the ploidy of the scale-building cell. Scale-building cells are arranged in irregular rows and within each row there is an alternation of ploidy levels, with the lower ploidy cells giving rise to the underscales and the higher ploidy cells giving rise to the cover scales that carry the color pattern. Along the wing there is a proximo distal decreasing gradient of average ploidy and scale size. Scale-building cells of high ploidy are surrounded by fewer epidermal cells than those of low ploidy. This inverse relationship is known as Henke's compensation principle, which posits that the number of endomitoses of a pre-polyploid cell and the number of mitotic divisions of its diploid daughter cell add up to a constant. We show that the inverse relationship fits the predictions of the compensation principle and does not fit constraints imposed by packing density, and we discuss mechanisms that could give rise to the inverse relationship. PMID- 23017250 TI - smcure: an R-package for estimating semiparametric mixture cure models. AB - The mixture cure model is a special type of survival models and it assumes that the studied population is a mixture of susceptible individuals who may experience the event of interest, and cure/non-susceptible individuals who will never experience the event. For such data, standard survival models are usually not appropriate because they do not account for the possibility of cure. This paper presents an R package smcure to fit the semiparametric proportional hazards mixture cure model and the accelerated failure time mixture cure model. PMID- 23017251 TI - WIMP: web server tool for missing data imputation. AB - The imputation of unknown or missing data is a crucial task on the analysis of biomedical datasets. There are several situations where it is necessary to classify or identify instances given incomplete vectors, and the existence of missing values can much degrade the performance of the algorithms used for the classification/recognition. The task of learning accurately from incomplete data raises a number of issues some of which have not been completely solved in machine learning applications. In this sense, effective missing value estimation methods are required. Different methods for missing data imputations exist but most of the times the selection of the appropriate technique involves testing several methods, comparing them and choosing the right one. Furthermore, applying these methods, in most cases, is not straightforward, as they involve several technical details, and in particular in cases such as when dealing with microarray datasets, the application of the methods requires huge computational resources. As far as we know, there is not a public software application that can provide the computing capabilities required for carrying the task of data imputation. This paper presents a new public tool for missing data imputation that is attached to a computer cluster in order to execute high computational tasks. The software WIMP (Web IMPutation) is a public available web site where registered users can create, execute, analyze and store their simulations related to missing data imputation. PMID- 23017252 TI - Antioxidant responses and degradation of two antibiotic contaminants in Microcystis aeruginosa. AB - Cyanobacteria may interact with antibiotic contaminants in aquatic environments, but the interaction effects and mechanisms remain unclear. In the present study, aqueous culture of Microcystis aeruginosa was exposed to 50ng/l-1MUg/l of spiramycin and amoxicillin for seven days. The influences of antibiotics on the antioxidant system of M. aeruginosa and the degradation of antibiotics by M. aeruginosa were investigated. The activities of superoxide dismutase (SOD) in spiramycin-treated M. aeruginosa were stimulated by up to 2.2 folds, while the activities of peroxidase (POD) and catalase (CAT) were inhibited by spiramycin at test concentrations of 500ng/l-1MUg/l, with a decrease of up to 71% and 76% compared to the control, respectively. The activities of SOD, POD and CAT in M. aeruginosa were stimulated by amoxicillin during the whole exposure period, with respective increases of up to 60%, 30% and 120% relative to the control. At test concentrations of 500ng/l-1MUg/l, the higher MDA contents in spiramycin-treated M. aeruginosa indicated a higher toxicity of spiramycin than amoxicillin, possibly due to the accumulation of hydrogen peroxide caused by the inhibited activities of POD and CAT under exposure to spiramycin. The increase of glutathione content, the stimulation of glutathione S-transferase activity and the degradation of each antibiotic were observed in M. aeruginosa during the 7 day exposure. At the end of exposure, 12.5%-32.9% of spiramycin and 30.5%-33.6% of amoxicillin could be degraded by M. aeruginosa from the culture medium, indicating the ability of M. aeruginosa to eliminate coexisting contaminants via detoxification. PMID- 23017253 TI - Predicting resource utilization of elderly burn patients in the baby boomer era. AB - BACKGROUND: Census predictions for Florida suggest a 3-fold increase in the 65 and older population within 20 years. We predict resource utilization for burn patients in this age group. METHODS: Using the Florida Agency for Healthcare Administration admission dataset, we evaluated the effect of age on length of stay, hospital charges, and discharge disposition while adjusting for clinical and demographic factors. Using US Census Bureau data and burn incidence rates from this dataset, we estimated future resource use. RESULTS: Elderly patients were discharged to home less often and were discharged to short-term general hospitals, intermediate-care facilities, and skilled nursing facilities more often than the other age groups (P < .05). They also required home health care and intravenous medications significantly more often (P < .05). Their length of stay was longer, and total hospital charges were greater (P < .05) after adjusting for sex, race, Charleson comorbidity index, payer, total body surface area burned, and burn center treatment. CONCLUSIONS: Our data show an age dependent increase in the use of posthospitalization resources, the length of stay, and the total charges for elderly burn patients. PMID- 23017254 TI - Differential effect of nutritional status on vascular surgery outcomes in a Veterans Affairs versus private hospital setting. AB - BACKGROUND: The goal of this study was to determine whether preoperative albumin level in vascular surgery patients is predictive of postoperative outcomes in the Veterans Affairs (VA) versus private sector and in open versus endovascular interventions. METHODS: A retrospective analysis of male patients with peripheral arterial disease, carotid artery disease, and abdominal aortic aneurysms who underwent open or endovascular interventions at the Jesse Brown VA Medical Center or Northwestern Memorial Hospital from January 2006 to June 2009 was conducted. Preoperative demographics and postoperative outcomes were assessed. Major adverse events (MAE) were defined as myocardial infarction, stroke, or death. RESULTS: A total of 591 men were included. Preoperative albumin level was significantly higher in VA versus private sector patients (3.6 +/- .5 g/dL vs 3.2 +/- .8 g/dL, respectively; P = .0001) and endovascular versus open patients (3.6 +/- .6 g/dL vs 3.3 +/- .7 g/dL, respectively; P < .0001). Albumin level was an independent predictor of MAE (odds ratio [OR], .46; P = .04) and 1-year death (OR, .35; P = .01) for all patients, and was predictive of MAE (OR, .40; P = .05) and 1-year death (OR, .23; P = .0008) in the open cohort. CONCLUSIONS: Preoperative malnutrition has important prognostic implications for vascular surgery patients in both the VA and private hospital settings, especially for those patients undergoing open repair. PMID- 23017255 TI - Isolation, culture and characterization of caprine mesenchymal stem cells derived from amniotic fluid. AB - Amniotic fluid (AF) represents heterologous cell types and a specific group of these cells show high growth rate and multipotent characteristics. The aim of the present study was to culture and fully characterize the putative stem cell population isolated from caprine mesenchymal stem cells. Plastic adherent fibroblastoid cell population could be successfully isolated from the caprine amniotic fluid. In vitro expanded caprine amniotic fluid derived mesenchymal stem cells (cAF-MSCs) showed high proliferation ratio with a doubling time of 33.1h and stained positive for alkaline phosphatase. Relative transcript abundance of CD-73, CD-90 and CD-105 surface markers were analyzed by SYBR green based real time PCR and their respective proteins were localized through immunocytochemistry, however cAF-MSCs were found negative for haematopoietic marker CD-34. When exposed to corresponding induction condition, cAF-MSCs differentiated into osteogenic, adipogenic and chondrogenic lineages which was confirmed through von Kossa, Oil Red O and Alcian blue staining respectively. Furthermore, these cells were found positive for undifferentiated embryonic stem cell markers like Oct-4, Nanog, Sox-2, SSEA-1 and SSEA-4 which accentuate their pluripotent property. In conclusion, caprine amniotic fluid represents a promising source of mesenchymal stem cells with high proliferative and differentiation potential and these cells offer their scope for multiple regenerative therapies. PMID- 23017256 TI - Influenza virus infection in nonhuman primates. AB - To determine whether nonhuman primates are infected with influenza viruses in nature, we conducted serologic and swab studies among macaques from several parts of the world. Our detection of influenza virus and antibodies to influenza virus raises questions about the role of nonhuman primates in the ecology of influenza. PMID- 23017257 TI - Use of an improved quantitative polymerase chain reaction assay to determine differences in human rhinovirus viral loads in different populations. AB - Human rhinoviruses (HRV) frequently cause acute respiratory infections and chronic respiratory disease exacerbations. However, testing is not generally offered. We developed a modified HRV quantitative polymerase chain reaction (qPCR) assay to assess viral loads in the community and hospital patients. The assay had a lower limit of detection of 2 log(10) viral copies/mL and displayed linearity over 5 log(10) viral copies, with a lower limit of quantitation of 4 log(10) viral copies/mL. Mean viral loads (95% confidence interval) for hospitalized children, university students, and institutionalized elderly, were 7.08 log(10) viral copies/mL (6.7-7.5), 6.87 log(10) viral copies/mL (6.5-7.2), and 7.09 log(10) viral copies/mL (6.9-7.3), respectively (P = 0.67). Serial specimens of 14 university students showed a decrease of mean viral loads from 6.36 log(10) viral copies/mL on day 1 to 2.32 log(10) viral copies/mL 7 days past symptom onset (P < 0.001). Using an HRV qPCR, we showed that viral loads did not differ between the community and hospitalized populations and significantly decreased following symptoms onset in healthy individuals. PMID- 23017258 TI - Antimicrobial resistance and molecular epidemiology of Panton-Valentine leukocidin-positive community-associated methicillin-resistant Staphylococcus aureus from Gran Canaria (Canary Islands, Spain). AB - Among 3967 Staphylococcus aureus recovered from a Gran Canaria hospital (2003 2010), 28 strains were Panton-Valentine leukocidin-positive community-associated methicillin-resistant Staphylococcus aureus and were included in this study. Most isolates (89.3%) caused skin and skin-structure infections. Isolates belonging to clonal complex (CC)8 (ST8 and ST931; USA300) prevailed (82.1%). Among these, 5 (21.7%) were resistant to at least 3 antimicrobial classes. PMID- 23017259 TI - Diagnostic accuracy of indirect immunofluorescence assay for intestinal invasive amebiasis and impact of HIV infection in a non-endemic country. AB - To diagnose amebic colitis (AC), serologic tests have the advantage of being inexpensive, noninvasive, and easy to perform, but few studies have investigated their utility, especially in a non-endemic country. A total of 299 symptomatic patients (165 HIV-infected patients) who underwent endoscopy and indirect immunofluorescence (IF) assay were analyzed between 2003 and 2009. The diagnosis of AC was defined as detection of amebic trophozoites from biopsy specimens or intestinal fluid sample via endoscopy. Forty-five patients (29 HIV-infected patients) were diagnosed with AC. The area under the receiver-operating characteristic curve (ROC-AUC) for the IF assay was excellent (0.90), and a cut off value of 100 provided 89% sensitivity and 87% specificity. ROC-AUC was slightly lower in patients with HIV infection (0.88) than in those without HIV infection (0.94). Among HIV-infected patients, ROC-AUC showed no significant differences between different CD4+ cell counts. The IF assay is useful for diagnosing AC in symptomatic patients with and those without HIV infection. PMID- 23017260 TI - Development of a diagnostic real-time polymerase chain reaction assay for the detection of invasive Haemophilus influenzae in clinical samples. AB - Since the introduction of the Haemophilus influenzae serotype b vaccine, invasive H. influenzae disease has become dominated by nontypeable (NT) strains. Several widely used molecular diagnostic methods have been shown to lack sensitivity or specificity in the detection of some of these strains. Novel real-time assays targeting the fucK, licA, and ompP2 genes were developed and evaluated. The fucK assay detected all strains of H. influenzae tested (n = 116) and had an analytical sensitivity of 10 genome copies/polymerase chain reaction (PCR). This assay detected both serotype b and NT H. influenzae in 12 previously positive specimens (culture and/or bexA PCR) and also detected H. influenzae in a further 5 of 883 culture-negative blood and cerebrospinal fluid (CSF) samples. The fucK assay has excellent potential as a diagnostic test for detection of typeable and nontypeable strains of invasive H. influenzae in clinical samples of blood and CSF. PMID- 23017261 TI - Numerical simulation of isotope fractionation in steady-state bioreactive transport controlled by transverse mixing. AB - Compound-specific stable isotope analysis (CSIA) has increasingly been used as a tool to assess intrinsic biodegradation at contaminated field sites. Typically, the Rayleigh equation is used to estimate the extent of biodegradation from measured isotope ratios of the contaminant. However, if the rate-limiting step in overall degradation is not the microbial reaction itself, the Rayleigh equation may no more be applicable. In this study we simulate biodegradation of continuously emitted petroleum hydrocarbons in groundwater systems. These contaminants are effectively degraded at the plume fringe where transverse dispersion makes them mix with dissolved electron acceptors present in the ambient groundwater. We simulate reactive transport to study the coupled effects of transverse mixing and biodegradation on the spatial patterns of carbon isotope signatures and their interpretation based on depth-integrated sampling which represents the most common setup in the assessment of contaminated sites. We present scenarios mimicking a hydraulically uniform laboratory experiment and a field-scale application considering heterogeneous conductivity fields. We compare cases in which isotopologue-specific transverse dispersion is considered to those where this additional fractionation process is neglected. We show that these effects cause significant shifts in the isotopic signals and may lead to overestimation of biodegradation. Moreover, our results provide evidence that the rate-limiting effect of transverse mixing on the overall degradation spatially varies along the length of a steady-state contaminant plume. The control of biodegradation by transverse dispersion and the fractionating effect of dispersion modulate the fractionation caused by the microbial reaction alone. As a consequence, significantly nonlinear isotopic patterns are observed in a Rayleigh plot. Simulations in heterogeneous flow domains show that these effects persist at larger field scales and are sensitive to the degree of mixing enhancement, determined by the heterogeneity of the hydraulic conductivity fields, and to the groundwater flow velocity. PMID- 23017262 TI - Statistical evaluations of viral clearance studies for biological products. AB - Since most biological products are derived from living cell culture, it is possible that viral contaminants be transmitted to the final product. Regulatory guidance requires that viral clearance studies be conducted to demonstrate the capacity of the production process in viral removal and inactivation. The key is accurate estimation of viral titer and reduction factor (RF), defined as the difference in log(10) virus titers before and after each step of purification. Darling et al. (1998) [1] suggested a method for analysis of clearance studies. However it is unable to establish an estimate of RF when the post-process viral counts are zero. In this paper, we provide theoretical justification of the method based on normal distribution and discuss the caveats regarding the degrees of freedom. We propose two alternative methods under the assumption that the number of plaques follows a Poisson distribution. Through simulation studies, the Poisson-based methods are shown to provide better estimates of viral titers. Under the Poisson model, we also derive a method to calculate the exact confidence limits for the viral titer and reduction factor even if the post process viral counts are zero. The use of the methods is illustrated through numerical examples. PMID- 23017263 TI - [Not Available]. PMID- 23017264 TI - [Not Available]. PMID- 23017265 TI - [Not Available]. PMID- 23017266 TI - [Not Available]. PMID- 23017267 TI - [Not Available]. PMID- 23017268 TI - [Not Available]. PMID- 23017269 TI - Association between maternal blood cadmium during pregnancy and birth weight and the risk of fetal growth restriction: the EDEN mother-child cohort study. AB - The objective of this study is to investigate the potential effect of maternal environmental cadmium (Cd) exposure on birth weight and fetal growth restriction (FGR). A total of 901 pregnant women from the EDEN cohort study were enrolled from two maternity units. Blood Cd was measured at mid-pregnancy and associations with birth weight and FGR were analyzed. Maternal Cd levels were associated with reduced birth weight in the offspring of women who smoked during pregnancy (b= 113.7; p=0.001). Smoking during pregnancy and maternal blood Cd concentrations had comparable effects on FGR incidence (OR 1.89; 95% CI: 1.00-3.58 and OR=1.41; 95% CI: 1.00-1.99, respectively). This study highlights the effect of Cd toxicity on fetal growth through the probable accumulation and transmission of this metal through the placenta. The close relationship between blood Cd levels and smoking habits indicates that Cd may be a relevant biomarker for smoking toxicity on fetal development. PMID- 23017270 TI - Rapid production of antigen-specific monoclonal antibodies from a variety of animals. AB - BACKGROUND: Although a variety of animals have been used to produce polyclonal antibodies against antigens, the production of antigen-specific monoclonal antibodies from animals remains challenging. RESULTS: We propose a simple and rapid strategy to produce monoclonal antibodies from a variety of animals. By staining lymph node cells with an antibody against immunoglobulin and a fluorescent dye specific for the endoplasmic reticulum, plasma/plasmablast cells were identified without using a series of antibodies against lineage markers. By using a fluorescently labeled antigen as a tag for a complementary cell surface immunoglobulin, antigen-specific plasma/plasmablast cells were sorted from the rest of the cell population by fluorescence-activated cell sorting. Amplification of cognate pairs of immunoglobulin heavy and light chain genes followed by DNA transfection into 293FT cells resulted in the highly efficient production of antigen-specific monoclonal antibodies from a variety of immunized animals. CONCLUSIONS: Our technology eliminates the need for both cell propagation and screening processes, offering a significant advantage over hybridoma and display strategies. PMID- 23017271 TI - Suppression of BSEP and MRP2 in mouse liver by miroestrol and deoxymiroestrol isolated from Pueraria candollei. AB - Miroestrol and deoxymiroestrol are highly active phytoestrogens isolated from the tuberous root of Pueraria candollei var. mirifica (Leguminosae). Modulatory effects of miroestrol and deoxymiroestrol on the mRNAs of BSEP and MRP2 genes involved in bile salt transportation, in C57BL/6 mice were investigated. In contrast to estradiol, miroestrol and deoxymiroestrol suppressed the expression of BSEP and MRP2 mRNA in both male and female mice. The results suggest for the first time that the use of miroestrol and deoxymiroestrol-containing products as alternative medicines or health supplements should be concerned according to their effects on key genes that regulate the bile salt export pump, which could result in the risk of hepatotoxicity and intrahepatic cholestasis. PMID- 23017272 TI - Forensic fictions: science, television production, and modern storytelling. AB - This essay uses interviews with television creators, writers, and producers to examine how media practitioners utilise, negotiate and transform forensic science in the production of televisual stories including the creation of unique visuals, character exploration, narrative progression, plot complication, thematic development, and adding a sense of authenticity. Television as a medium has its own structures and conventions, including adherence to a show's franchise, which put constraints on how stories are told. I demonstrate how television writers find forensic science to be an ideal tool in navigating television's narrative constraints by using forensics to create conflicts, new obstacles, potential solutions, and final solutions in their stories. I show how television writers utilise forensic science to provide the scientific certainty their characters require to catch the criminal, but also how uncertainty is introduced in a story through the interpretation of the forensics by the show's characters. I also argue that televisual storytellers maintain a flexible notion of scientific realism based on the notion of possibility that puts them at odds with scientists who take a more demanding conception of scientific accuracy based on the concept of probability. PMID- 23017273 TI - Spread of influenza virus A (H5N1) clade 2.3.2.1 to Bulgaria in common buzzards. AB - On March 15, 2010, a highly pathogenic avian influenza virus was isolated from the carcass of a common buzzard (Buteo buteo) in Bulgaria. Phylogenetic analyses of the virus showed a close genetic relationship with influenza virus A (H5N1) clade 2.3.2.1 viruses isolated from wild birds in the Tyva Republic and Mongolia during 2009-2010. Designated A/common buzzard/Bulgaria/38WB/2010, this strain was highly pathogenic in chickens but had low pathogenicity in mice and ferrets and no molecular markers of increased pathogenicity in mammals. The establishment of clade 2.3.2.1 highly pathogenic avian influenza viruses of the H5N1 subtype in wild birds in Europe would increase the likelihood of health threats to humans and poultry in the region. PMID- 23017274 TI - Synchronous bilateral acinic cell carcinoma of the parotid: when a tumor reveals another one. AB - INTRODUCTION: Acinic cell carcinoma is a rare form (2-4%) of parotid tumor. It is, however, the most frequent form of bilateral parotid tumor and the second most frequent form in children. CASE REPORT: A 22-year-old man had several years' history of left parotid tumor, discovered to be acinic cell carcinoma. MRI found a synchronous contralateral tumor of the same histologic nature. DISCUSSION/CONCLUSION: This case highlights the need for rigorous examination of the contralateral parotid in case of parotid tumor and especially of acinic cell carcinoma. PMID- 23017275 TI - Laryngeal chondrosarcoma: repeated laser and radiofrequency ablation in the palliative setting. AB - OBJECTIVE: The purpose of this article is to illustrate the use of radiofrequency and laser ablation in head and neck oncology and to describe the management of a case of laryngeal chondrosarcoma in a 90-year-old patient. CASE REPORT: A 90-year old man, WHO performance status 3, with low-grade laryngeal chondrosarcoma was seen in the outpatients department at the end of 2008 for assessment of dysphonia. Total laryngectomy was considered to be too invasive and was consequently excluded. The patient was initially tracheotomized under local anaesthesia to relieve dyspnoea and was subsequently managed symptomatically by radiofrequency and laser ablation to ensure laryngeal disobstruction, allowing the patient to be extubated followed by speech therapy and oral feeding rehabilitation. DISCUSSION/CONCLUSION: This patient received symptomatic palliative treatment with a combination of radiofrequency and laser. Radiofrequency ablation can be applied in head and neck oncology as an alternative treatment to surgery allowing improvement of quality of life and survival. PMID- 23017276 TI - Studying the effects of genistein on gene expression of fish embryos as an alternative testing approach for endocrine disruption. AB - Assessment of endocrine disruption currently relies on testing strategies involving adult vertebrates. In order to minimize the use of animal tests according to the 3Rs principle of replacement, reduction and refinement, we propose a transcriptomics and fish embryo based approach as an alternative to identify and analyze an estrogenic activity of environmental chemicals. For this purpose, the suitability of 48 h and 7 days post-fertilization zebrafish and medaka embryos to test for estrogenic disruption was evaluated. The embryos were exposed to the phytoestrogen genistein and subsequently analyzed by microarrays and quantitative real-time PCR. The functional analysis showed that the genes affected related to multiple metabolic and signaling pathways in the early fish embryo, which reflect the known components of genistein's mode of actions, like apoptosis, estrogenic response, hox gene expression and steroid hormone synthesis. Moreover, the transcriptomic data also suggested a thyroidal mode of action and disruption of the nervous system development. The parallel testing of two fish species provided complementary data on the effects of genistein at gene expression level and facilitated the separation of common from species-dependent effects. Overall, the study demonstrated that combining fish embryo testing with transcriptomics can deliver abundant information about the mechanistic effects of endocrine disrupting chemicals, rendering this strategy a promising alternative approach to test for endocrine disruption in a whole organism in-vitro scale system. PMID- 23017277 TI - Isolation of IL-12p70-competent human monocyte-derived dendritic cells. AB - Diverse methodologies ranging from experimental immunological studies to immunotherapy involve the application of human monocyte-derived dendritic cells (moDCs). Considerable donor-dependent variations in the moDC production of IL 12p70 affect the outcome of these methodologies. It has been shown that moDCs generated under standard conditions develop into two subsets based on CD1a expression with the CD1a+ moDCs being the main IL-12p70 producers. This has however not been generally accepted, which we show here because the subset described as CD1a-negative does express CD1a, but at a lower level than the other subset. We further characterize the phenotype of these two subsets, showing that the CD1a-hi subset has a greater immunogenic phenotype, making this subset more suitable for immunotherapy. The two subsets have previously been separated by cell sorting, but as this technique is not available to many laboratories and has incompatibility with clinical settings, a more widely useable technique is warranted. Therefore we tested if magnetic-activated cell sorting is useful for the purpose, and show that it is possible to isolate IL-12p70-competent CD1a-hi moDCs to a <92% purity, irrespective of the starting purity. PMID- 23017278 TI - Comparison of penetrating keratoplasty and deep lamellar keratoplasty for macular corneal dystrophy and risk factors of recurrence. AB - PURPOSE: To compare the therapeutic effects of penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) on patients with macular corneal dystrophy (MCD) and to analyze the risk factors of postoperative recurrence. DESIGN: Retrospective, interventional, comparative case series. PARTICIPANTS: Fifty-one patients (78 eyes) with MCD treated by PK or DALK at Shandong Eye Institute between January 1992 and December 2010. METHODS: The medical records of the patients were reviewed retrospectively. MAIN OUTCOME MEASURES: Best-corrected visual acuity, corneal endothelial density, complications, recurrence, graft survival, and risk factors for recurrence. RESULTS: Penetrating keratoplasty was performed in 57 eyes, and DALK was performed in 21 eyes. The mean follow-up time was 5.1+/-4.1 years (range, 1.0-18.0 years). The best-corrected visual acuity of the PK group was much better than that of the DALK group at 1, 2, 3, and 5 years. The corneal endothelial density was reduced to 1000 cells/mm2 or less within 5 years in 21.6% (11/51) of eyes treated by PK and in none of the eyes treated by DALK. The 1-year incidence rate of complications was 21.1% in the PK group, higher than the 4.8% rate in the DALK group. At the last visit, the rate of graft clarity was 87.7% and 85.7% in the 2 groups, respectively. Ten eyes (17.5%) treated by PK had recurrent MCD, with a rate of 0.8%, 7.7%, and 40% at 1, 5, and 10 years, respectively, whereas 9 eyes (42.9%) treated by DALK demonstrated recurrence, with a rate of 14.3% and 49.5% at 1 and 5 years, respectively. The recurrence risk was higher in patients whose age was 18 years or younger at onset or younger than 30 years at surgery. The recurrence risk after DALK was 5.066 times higher than that after PK. CONCLUSIONS: Penetrating keratoplasty more often immediately improves the visual acuity of patients with MCD, but many complications seem to be inevitable, especially continuous loss of corneal endothelium. Despite poor visual acuity and recurrence after surgery, DALK may produce fewer complications overall and more durable stability of the ocular surface compared with PK. The selection of PK or DALK for MCD should depend on the actual need and situation of certain patients. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23017279 TI - [Optimizing biopsies of the oral mucosa]. AB - We had for aim to describe and illustrate the artefacts observed in biopsies of the oral mucosa, as well as the impact of sending non-representative histological material to a laboratory. This article was based on an international literature review, as well as on our experience. We analysed the problems raised, for the pathologists and the histology lab-technicians, by these artefacts as well as their impact on the pathology report patient management. We suggest simple solutions. PMID- 23017280 TI - [Desmoid infantile mandibular fibromatosis]. AB - INTRODUCTION: A desmoid tumor, or aggressive fibromatosis, is a benign fibrous tumor with a high potential for locoregional extension. This tumor is very rarely located in the mandible. OBSERVATION: A 2-year-old boy presented with an extensive mandibular desmoid tumor. The diagnosis was proved on histological examination. Two years after surgery, there was no recurrence. DISCUSSION: Aggressive fibromatosis is rarely located in the mandible. The differential diagnosis with malignant tumors is difficult. Surgery is the first-line treatment. However, alternative therapies should be considered, especially in children, to avoid mutilating operations. PMID- 23017281 TI - [Management of head and neck giant congenital nevi with skin expansion]. AB - INTRODUCTION: Giant congenital pigmented nevi are benign melanocytic tumors. The lesion transformation to a malignant melanoma is a rare but severe condition. Treatment is complex and often difficult. The purpose of this study was to analyze the results and discuss the contribution of expansion technique in the treatment of giant nevi of the cephalic extremity. MATERIAL AND METHODS: Six giant nevi (five children and one adult) were treated by skin expansion between 1993 and 2010. RESULTS: The nevus had a fronto-temporal region and vertex location (one case), and hemifacial in five cases. Subtotal resection of the nevus was performed in every case. The defect was filled by a double rotation flap of expanded scalp (one case), and an expanded total skin graft (five cases). Two complications were observed: a depression of the frontal bone in a 6-year-old child who had received a total prosthesis volume of 2000 mL; and migration of the valve under a prosthesis, which required repositioning. These complications did not alter the final results. DISCUSSION: The risk of evolution to a malignant melanoma is considerably decreased after exeresis of congenital nevi. Tissue expansion is a true skin bank. It allows treating giant congenital nevi of the scalp and face, with good esthetic results and less morbidity. PMID- 23017283 TI - On the need of standards for reporting on esophageal perforation. AB - Esophageal perforation is associated with significant mortality and morbidity. Its etiology is as heterogenous as modalities currently employed for its treatment. There is no clear evidence which is the treatment of choice for esophageal perforation. This is partly due to the suboptimal quality of available studies and failure to accurately report on the characteristics, treatment and outcome of these patients. Indeed, baseline, operative and outcome data are important for a better evaluation of published data and possibly for including them in meta-analyses of aggregate or individual patient data. We propose a checklist for reporting data on esophageal perforation in order to standardize reporting of data of studies on this severe condition. PMID- 23017284 TI - Laparoscopic colorectal resections performed over a seven-years period in a single Italian Centre. AB - INTRODUCTION: Laparoscopic approach for treatment of colorectal lesion is gaining acceptance gradually. Evidence from numerous randomised controlled trials has shown the short-term benefits of laparoscopic colon resection over open surgery, and its long-term outcomes also does not differ considerably from those of open surgery. This study aims at a retrospective analysis of operative and short term outcomes of patients. PATIENTS AND METHODS: All laparoscopic colon and rectal resections performed between September 2004 and September 2011 were included. The clinical parameters, operative parameters and short-term outcome details of laparoscopic colorectal surgery patients were collected from the retrospectively reviewed database. RESULTS: A total of 347 patients, median age 71 years (range 32 to 96), underwent laparoscopic resection of the colon and rectum. The median Body Mass Index (BMI) was 26.5. The majority of the procedures were performed for malignant disease (97,1%) and the most common procedure was right colectomy (41%). The median duration of surgery was 202,3 minutes, with conversion to open surgery in 40 patients (11.5%). Complications occurred in 23 patients (6.6%). The median length of hospital stay was 8.9 days. In patients with malignant disease, the median number of lymph nodes removed was 14.9. CONCLUSION: Our results show that laparoscopic approach for colon-rectal lesions is safe, feasible and produces favourable results. The most important aspect of surgery for malignant disease is the ability to remove radically the disease. However all data are still related to the experience of the operator. PMID- 23017285 TI - Laparoscopic versus open appendectomy for the treatment of complicated appendicitis. AB - AIM: Laparoscopic Appendectomy (LA) is widely performed for the treatment of acute appendicitis. However the use of laparoscopic approach for complicated appendicitis is controversial, in particular because it has been reported an increased risk of postoperative IntraAbdominal Abscess (IAA). The aim of this study was to compare the outcomes of LA versus Open Appendectomy (OA) in the treatment of complicated appendicitis, especially with regard to the incidence of postoperative IAA. PATIENTS AND METHODS: A retrospective study of all patients treated at our institution for complicated appendicitis, from May 2004 to June 2009, was performed. Data collection included demographic characteristics, postoperative complications, conversion rate, and length of hospital stay. RESULTS: Thirty-eight patients with complicated appendicitis were analysed. Among these, 18 (47,3%) had LA and 20 (52,7%) had OA. There were no statistical differences in characteristics between the two groups. The incidence of postoperative IAA was higher (16,6%), although not statistically significant, in the LA compared with OA group (5%). On the other hand the rate of wound infection was lower (5%) in the LA versus OA (20%). CONCLUSION: Our study indicated that LA should be utilised with caution in case of perforated appendicitis, because it is associated with an increased risk of postoperative IAA compared with OA. PMID- 23017286 TI - A rare case of postpartum thrombocytosis. Differential diagnosis and management. AB - This is a case of a 43-year-old primigravida primipara woman who presented in our Department in 36 weeks gestational age and underwent caesarean section due to preeclampsia. From her history, it was known that her pregnancy was an in vitro fertilization (IVF) result. She also received low molecular weight heparin because of thrombophilia (protein S insufficiency). We present this case of postpartum thrombocytosis and discuss the differential diagnosis of this condition through the presentation of its management. PMID- 23017287 TI - Small bowel mesentery solitary fibrous tumor. A rare neoplasia in a young male. AB - Extrapleural Solitary Fibrous Tumors (SFT), in particular small bowel mesentery SFTs, are extremely rare neoplasms. We describe the case of a young male hospitalized for unspecific abdominal symptoms and evidence of a well circumscribed mass arising from the small bowel mesentery. Histopathological and immunohistochemical analysis on the surgical specimen confirmed the diagnosis of SFT. A Pubmed search revealed only another case of small bowel mesentery SFT, confirming the extremely rarity of this tumor. PMID- 23017288 TI - Polyp of the cecum. Laparoscopic-assisted polypectomy. AB - The Authors discuss on a laparoscopic-assisted approach for excision of a sessile villous adenomatous polyp of the cecum, unresectable by endoscopy. Because of the large implant of the polyp, endoscopic polypectomy was considered at high risk and a surgical laparoscopic procedure was scheduled for removal of the lesion. After right colon mobilization, an intraoperative endoscopy confirmed the location of th polyp in the posterior wall of the cecum, closed to the ileo-cecal valve. A small 10 cm laparotomy, through which the cecum was pulled out the abdominal cavity, was performed. Then, a minimal colotomy along the intestinal taenia was carried out to allow a safe and complete excision of the polyp. This laparoscopic approach differs from the other laparoscopic-assisted methods reported in the Literature since it provides at the same time the postoperative advantages associated with minimal access surgery and a safe oncological removal of the polyp with low risks of complications. PMID- 23017289 TI - Traumatic abdominal wall hernia. Case report. AB - Despite the high incidence of abdominal traumas, traumatic abdominal wall hernias (TAWHs) remain rare probably because of elasticity of the abdominal wall. The TAWH is due to blunt abdominal trauma with disruption of the abdominal wall muscles and fascia with intact overlying skin. TAWH can be classified into high energy injures (generally motor vehicle accidents) and low energy injures (impact on a small blunt object). Common example of the latter type is a fall onto a bicycle handlebar. The mechanism of the trauma includes sudden increase of intra abdominal pressure and extensive shear forces applied to the abdominal wall. The diagnosis of TAWH is difficult in the Emergency Room because during the primary diagnostic process most attention is directed toward the detection of internal injures and TAWH can be missed. In this article we report a case of TAWH caused by a work accident (an heavy steel tube fallen onto the abdominal wall of the patient from a height of five meters) with delayed diagnosis. PMID- 23017290 TI - Cholecystectomy by single incision laparoscopic surgery (SILS): early experience and technique standardization. AB - Single Incision Laparoscopic Surgery (SILS) is a recent surgical technique, first described in the 1990s. Its aim is to optimize the esthetic result offered by laparoscopy by minimizing the number of abdominal incisions. Various preliminary studies have been carried out on the application of SILS, especially in cholecystectomy and appendectomy. This study evaluates the preliminary results of cholecystectomy by SILS (SILSTM Port) conducted between October 2009 and February 2011 on 21 patients (4 men and 17 women) with a mean age of 49.9 years and a mean Body Mass Index (BMI) of 22.8. All patients were treated by the same team, which had previously undergone six months' simulator training. There were two main selection criteria, both evaluated intraoperatively: absence of adhesions and of significant inflammatory sequelae from previous cholecystitis; and suitable distance between gallbladder and SILS access port. Conversion to traditional laparoscopy was necessary in just two cases, while an accessory trocar was introduced in another two cases. Conversion to open surgery was not necessary in any case. One case of SILS cholecystectomy was complicated by postoperative bile leakage, which was treated conservatively, as the fistula had a low output. The mean duration of hospitalization was 3.6 days. This preliminary experience led us to conclude that SILS is safe and highly satisfactory in the postoperative phase, thanks to the reduced need for painkillers and the improved esthetic result. PMID- 23017291 TI - Role of emergency thoracic ultrasonography in spontaneous pneumomediastinum. Two case report. AB - Early identification of spontaneous pneumomediastinum in an Emergency Department is possible with thoracic ultrasound. We report two cases of spontaneous pneumomediastinum, diagnosed in a 26-year old man with chronic asthma and a 19 year old athlete, and discuss the role of thoracic US alongside conventional X ray and thoracic CT in emergency medicine. The patients were transferred to an Emergency Department, where conservative treatment produced a good outcome. The greater sensitivity and specificity of thoracic US over conventional supine X-ray in the detection of occult pneumothorax is ever more appreciated. However, training in the diagnosis of pneumomediastinum is required. PMID- 23017292 TI - Digital photography in the treatment assessment of grade II-III haemorrhoids. PMID- 23017293 TI - Human polyomaviruses in children undergoing transplantation, United States, 2008 2010. AB - Immunocompromised patients are at risk for disease caused by infection by some polyomaviruses. To define the prevalence of polyomaviruses in children undergoing transplantation, we collected samples from a longitudinal cohort and tested for the 9 known human polyomaviruses. All were detected; several were present in previously unreported specimen types. PMID- 23017294 TI - Simplified detection of food-borne pathogens: an in situ high affinity capture and staining concept. AB - Food industries need simple, rapid and cost-effective solutions for pathogen detection in food and environmental samples. In this paper, we describe a simple but novel detection concept combining an affinity capture surface and intracellular metabolic marker to visualize the bacterial presence on the affinity surface. The surface of a Solid Phase Support (SPS) is functionalized with specific phage tail proteins targeted to the bacterial pathogen of interest. The SPS is placed directly into the primary food enrichment bag after stomaching. Following incubation, the captured bacteria are visually detected in situ as a result of the bacterial reduction of the colorless soluble substrate triphenyltetrazolium chloride (TTC) (present in the primary culture medium) to an intracellular red insoluble formazan product. Detection on the SPS is observed as an intense red color after 22 to 40 hours of enrichment. This is not impaired by the presence of food particles and the natural background microflora. The in situ method significantly simplifies pathogen detection by eliminating any post enrichment intervention that is necessary in the traditional methods of analysis. We have demonstrated the application of this new approach for the detection of Escherichia coli O157: H7, Listeria spp. and Salmonella spp. in artificially contaminated food samples. PMID- 23017295 TI - Combining principles of Cognitive Load Theory and diagnostic error analysis for designing job aids: Effects on motivation and diagnostic performance in a process control task. AB - Two studies are presented in which the design of a procedural aid and the impact of an additional decision aid for process control were assessed. In Study 1, a procedural aid was developed that avoids imposing unnecessary extraneous cognitive load on novices when controlling a complex technical system. This newly designed procedural aid positively affected germane load, attention, satisfaction, motivation, knowledge acquisition and diagnostic speed for novel faults. In Study 2, the effect of a decision aid for use before the procedural aid was investigated, which was developed based on an analysis of diagnostic errors committed in Study 1. Results showed that novices were able to diagnose both novel faults and practised faults, and were even faster at diagnosing novel faults. This research contributes to the question of how to optimally support novices in dealing with technical faults in process control. PMID- 23017296 TI - Nurse-patient collaboration: a grounded theory study of patients with chronic obstructive pulmonary disease on non-invasive ventilation. AB - OBJECTIVES: This paper provides a theoretical account of nurses' collaboration with patients with chronic obstructive pulmonary disease during non-invasive ventilation treatment in hospital. BACKGROUND: Despite strong evidence for the effect of non-invasive ventilation treatment, success remains a huge challenge. Nurse-patient collaboration may be vital for treatment tolerance and success. A better understanding of how nurses and patients collaborate during non-invasive ventilation may therefore contribute to improvement in treatment success. DESIGN: A constant comparative classical grounded theory. METHOD: The data comprised sessions of qualitative participant observation during the treatment of 21 patients with non-invasive ventilation that included informal conversations with the nurses and semi-structured interviews with 11 patients after treatment completion. Data were collected at three intensive care units and one general respiratory ward in Denmark. RESULTS: Succeeding emerged as the nurses' main concern in the nurse-patient collaboration during non-invasive ventilation treatment. Four collaborative typologies emerged as processing their main concern: (1) twofold oriented collaboration; (2) well-being oriented collaboration; (3) outcome oriented collaboration; and (4) absent collaboration. CONCLUSIONS: This study offers a theoretical account of nurses' main concern and how they activate different ways of collaboration to achieve successful treatment. We offer a theoretical basis for developing complex interventions. PMID- 23017297 TI - Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: possible pathways for antinociception. AB - Motor cortex stimulation is generally suggested as a therapy for patients with chronic and refractory neuropathic pain. However, the mechanisms underlying its analgesic effects are still unknown. In a previous study, we demonstrated that cortical stimulation increases the nociceptive threshold of naive conscious rats with opioid participation. In the present study, we investigated the neurocircuitry involved during the antinociception induced by transdural stimulation of motor cortex in naive rats considering that little is known about the relation between motor cortex and analgesia. The neuronal activation patterns were evaluated in the thalamic nuclei and midbrain periaqueductal gray. Neuronal inactivation in response to motor cortex stimulation was detected in thalamic sites both in terms of immunolabeling (Zif268/Fos) and in the neuronal firing rates in ventral posterolateral nuclei and centromedian-parafascicular thalamic complex. This effect was particularly visible for neurons responsive to nociceptive peripheral stimulation. Furthermore, motor cortex stimulation enhanced neuronal firing rate and Fos immunoreactivity in the ipsilateral periaqueductal gray. We have also observed a decreased Zif268, delta-aminobutyric acid (GABA), and glutamic acid decarboxylase expression within the same region, suggesting an inhibition of GABAergic interneurons of the midbrain periaqueductal gray, consequently activating neurons responsible for the descending pain inhibitory control system. Taken together, the present findings suggest that inhibition of thalamic sensory neurons and disinhibition of the neurons in periaqueductal gray are at least in part responsible for the motor cortex stimulation-induced antinociception. PMID- 23017298 TI - Attentional biases and their role in the management of pain. PMID- 23017299 TI - Developmental expression of cellular prion protein and apoptotic molecules in the rat cerebellum: effects of platinum compounds. AB - Programmed cell death is regulated by prototypes of a large family of Bcl-2-like proteins such as Bax and Bcl-2. A neuroprotective role for cellular prion protein (PrPc) on programmed cell death has been reported, although the cytosolic accumulation of PrPc correlates with toxicity and death of some neurons by apoptosis. In order to understand the signalling function of PrPc in promoting survival or suppressing cell death, we analyzed the expression and co localization of PrPc, Bax and Bcl-2 proteins in the developing cerebellum of rats treated at PD10 (postnatal day 10) with the chemotherapeutic drug cisplatin (cisPt) or the new platinum (Pt) compound [Pt(O,O'-acac)(gamma-acac)(DMS)] (PtAcacDMS). Differences in the expression of PrPc, Bax and Bcl-2 were found in proliferating cells and immature Purkinje neurons. One day after administration (PD11), cisPt markedly increased the apoptosis of the proliferating cells of the EGL (external granular layer); at the same time, several apoptotic bodies with strong Bax immunoreactivity were noticed. After PtAcacDMS, changes in PrPc and apoptotic proteins, with respect to the controls, were found but Bax immunopositive apoptotic bodies were not detectable, which could mean that apoptotic cell death of proliferating cells is preserved. Co-localization was clearly detected in the Purkinje cell population and may explain better the mechanisms by which PrPc and the apoptotic proteins function, and particularly the role of PrPc. Considering the reactivity of Purkinje neurons to these proteins at PD11 and Pd17, at least PrPc expression increased after cisPt and PtAcacDMS treatments or, if PrPc decreased, balanced itself with Bcl-2. The noteworthiness of this finding is that it emphasizes that most of the post mitotic Purkinje cells need to be rescued, otherwise they undergo degeneration and are not replaced. Based on the effects of both Pt compounds on Purkinje cell differentiation, it should be emphasized that PrPc, together with the synergistic action of the co-localized anti-apoptotic protein, acts as a neuroprotective protein countering cytotoxicity in the postnatal critical phases of cerebellum development. PMID- 23017300 TI - [Not Available]. PMID- 23017301 TI - [Not Available]. PMID- 23017302 TI - [Not Available]. PMID- 23017303 TI - A proteomic analysis of the effect of growth hormone on mammary alveolar cell-T (MAC-T) cells in the presence of lactogenic hormones. AB - The bovine mammary alveolar cell-T (MAC-T) cell line is able to uniformly differentiate and secrete casein proteins in response to dexamethasone, insulin, and prolactin and is extensively used to study bovine mammary epithelial cell (MEC) function. Somatotropin, or growth hormone (GH), has been shown to increase milk protein synthesis both in vivo and in mammary cell models and to induce cytoskeletal rearrangement in a 3T3 fibroblast cell line and a Chinese hamster ovary cell line. To identify the nature of the effects of GH in MECs cultured with lactogenic hormones, changes in global protein expression were assessed in the MAC-T cell line with the use of two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization tandem time of flight mass spectrometry. Forty proteins were differentially expressed in response to GH (P < 0.05) and were related to metabolism, the cytoskeleton, protein folding, RNA and DNA processing, and oxidant stress. These widespread changes in protein expression are indicative of a global role of GH in overall cellular differentiation that may underlie the direct modulation of milk component synthesis in MEC models that have been described to date. PMID- 23017304 TI - Paradoxes with weight disorders for health systems. AB - The body mass index (BMI) has served public health and clinical medicine well in the recognition of obesity. However, its use has generated some instructive paradoxes and misunderstandings which argue for the appreciation of body compositional disorders (BCD) as such and, in particular, for the parallel evaluation of muscle mass with a definition of 'orthosarcal' conditions to enable the early detection of sarcopenia. Across the life-span, and with gender and ethnic differentials, BCD is basic to the full spectrum of nutritionally-related disorders and diseases. In the case of metabolic diseases like diabetes, muscle, fatness and its distribution, and even bone seem to play pathogenetic roles. Optimal body fat and distribution are relevant to child development, maternal health and healthy ageing, with much more to learn about the mechanisms. The economic and societal costs of obesity tend to increase progressively with the BMI, but the health outcomes, at least for mortality, are J-or U-shaped. With some established chronic diseases, like diabetes, renal failure or cardiac failure, overfatness may be protective; sometimes this may be because contaminant fat-soluble endocrine disrupters are segregated in fat tissue. This means that some of the relatively favourable survival in the elderly who have more body fat is at the expense of the health care system. Younger children with chronic energy deficiency, on the other hand, may succumb before expenditure saves them. In these respects, our species is more vulnerable than we have thought. Fortunately, a better understanding of BMI and health is emerging. PMID- 23017305 TI - Micronutrient interventions on cognitive performance of children aged 5-15 years in developing countries. AB - It is estimated that more than 200 million young children worldwide fail to reach their potential in cognitive development owing to undernutrition. Numerous studies have assessed the effects of micronutrient supplementation on growth and cognitive development in infants, toddlers and preschoolers. However, micronutrient interventions on the cognitive performance of older children are limited. This article seeks to provide an update on micronutrient interventions and cognitive outcomes among children aged 5-15 years in developing countries. A total of 13 randomized controlled trials published since 2000 were identified. Majority of these studies assessed the effects of micronutrient-fortified foods on various domains of cognitive function. Among key micronutrients assessed were iron, zinc, iodine and vitamin A. This review found a lack of consistency in the impact of micronutrient supplementation on intelligence, long term mental functions and school examination grades of the children. A beneficial effect of micronutrient supplementation on short term memory was more consistently reported. Overall, the evidence from this review for the impact of micronutrients on cognitive performance in older children remains equivocal. In light of the growing interest on the influence of nutrition on cognition, it is important that culturally-appropriate and sufficiently sensitive assessment tools be used for measuring the desired cognitive outcomes that are most likely to be affected by the nutrients under study. PMID- 23017306 TI - Fish advisories in the USA and Japan: risk communication and public awareness of a common idea with different backgrounds. AB - Some countries have established fish advisories to manage fish consumption to minimize methylmercury exposure. Our objective was to compare the fish advisories and the resultant consumer behavior in the United States of America (USA) and Japan. Both countries have national consumption guidelines, but American states enjoy greater independence in issuing guidelines for local water bodies and vary in the information that is provided for the public. The proportion of the American public that has heard of state fish advisories is thought to be close to 30%. There is a concern that this low level of awareness extends to pregnant women. In Japan, the current problem is the lack of comprehensive studies on the public awareness of fish advisories. Nonetheless, there is evidence that fish consumption has decreased in both countries. In USA, there is a possibility that the strong emphasis on mercury toxicity drives the general population towards a trend of lower fish consumption. In Japan, the fish advisory encourages seafood consumption for nutritional benefits. Consequently, the decrease may be due to the shift towards a "Western diet". Also, the Japanese fish advisory seems to be less active in advocating the issue of fish consumption and mercury exposure, which may be partly responsible for the possible lesser attention of the consumers. Cultural factors may explain for the baseline difference in consumption and account partly for the change in Japanese consumer behavior. However, the dissimilarities in fish advisories may also be responsible for the variations in consumer behavior. PMID- 23017307 TI - Chest circumference in infancy predicts obesity in 3-year-old children. AB - The purpose of this study was to investigate the associations between chest circumference in infancy and rapid growth or obesity at 3 years of age. We conducted a retrospective observational study of 1353 children in Kumamoto, Japan. Data collected included chest circumference, head circumference, weight, and body mass index. The area under the receiver operating characteristic curves for chest circumference were analyzed to determine the ability of this index to identify obesity at 3 years of age. Chest circumference at 3-4 months of age and increases in chest circumference during the first 3-4 months of life had higher mean standard deviation scores for rapid growth than for slow or no change in growth (p<0.05). Chest circumference and the increase in chest circumference were also positively correlated with rapid weight gain, and were associated with obesity at 3 years of age. The area under the curve for chest circumference was significantly different from the area under the curve for weight z-score at 6-9 months but not for weight z-score at 3-4 months. In conclusion, we found that chest circumference is associated with obesity in young children, and is positively correlated with rapid growth. Therefore, chest circumference may be a useful marker for rapid growth, and may help clinicians to identify obese children at 3 years of age. PMID- 23017308 TI - Fish oil supplementation is beneficial on caloric intake, appetite and mid upper arm muscle circumference in children with leukaemia. AB - A randomised trial was carried out to determine the effect of supplementation of fish oil among 51 children with leukaemia aged 4 to 12 years on appetite level, caloric intake, body weight and lean body mass. They were randomly allocated into the trial group (TG) and the control group (CG). At baseline, 30.8% of TG subjects and 44.0% of CG subjects were malnourished and 7.7% of subject from TG and 28.0% from CG were classified as stunted. The majority of subjects from TG and CG were in the mild malnutrition category for mid upper arm muscle circumference (MUAMC)-for-age. The TG group showed significant increment in MUAMC (0.13 cm vs -0.09 cm) compared with CG at 8 weeks (p<0.001). There was a significant higher increase for appetite level (0.12+/-0.33) (p<0.05) and an increasing trend on energy and protein intake in the TG group (213+/-554 kcal; 3.64 +/-26.8 g) than in the CG group. In conclusion, supplementation of fish oil has a positive effect on appetite level, caloric intake and MUAMC among children with leukaemia. PMID- 23017309 TI - Effects of omega-3 fatty acids supplementation on serum adiponectin levels and some metabolic risk factors in women with polycystic ovary syndrome. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common female endocrine disorder associated with several risk factors of type 2 diabetes and cardiovascular diseases. The objectives of this study were to investigate the effects of omega-3 fatty acids on serum adiponectin levels and some metabolic risk factors in PCOS patients. METHODS: This double-blind randomized controlled clinical trial was conducted on 64 overweight or obese PCOS patients; aged 20-35 years. Subjects in omega-3 fatty acids (n=32) and placebo (n=32) groups were given 4 omega- 3 fatty acids capsules (each one contained 180 mg eicosapentaenoic acid and 120 mg docosahexanoic acid) or placebo daily for 8 weeks. Fasting blood samples, anthropometric measurements and 3-day, 24-hour dietary recalls were collected at the baseline and at the end of the trial. RESULTS: The study was completed by 61 subjects. Omega-3 fatty acids significantly increased serum levels of adiponectin (p=0.003) and decreased glucose (p<0.001), insulin (p=0.002), homeostatic model assessment for insulin resistance (p<0.001), total cholesterol (p=0.002) and low density lipoprotein cholesterol (p=0.003) compared with placebo. Serum levels of triglyceride significantly decreased (p=0.024) and high-density lipoprotein cholesterol increased (p=0.018) in the omega-3 fatty acids group, in comparison with baseline values. No significant changes were shown in serum high sensitive C reactive protein (hs-CRP) levels in both groups. CONCLUSION: Omega-3 fatty acids had some beneficial effects on serum adiponectin levels, insulin resistance and lipid profile in PCOS patients and may contribute to the improvement of metabolic complications in these patients. PMID- 23017310 TI - Plasma omega-3 fatty acid levels negatively and omega-6 fatty acid levels positively associated with other cardiovascular risk factors including homocysteine in severe obese subjects. AB - Obesity and homocysteine (tHcy) are important risk factors for cardiovascular diseases (CVD). Plasma omega-3 fatty acids (omega-3 FAs) and omega-6 fatty acids (omega-6 FAs) are essential fatty acids with diverse biological effects in human health and disease. We have investigated the relation of plasma omega-3 FAs and omega-6 FAs levels with other cardiovascular risk factors including tHcy in severe obese subjects. This study was performed on 96 severe obese and 65 normal weight subjects. Plasma fatty acid composition was measured by GC/MS and serum tHcy level was measured by HPLC methods. There were no differences between groups in terms of concentrations of serum tHcy, plasma omega-3 FAs, omega-6 FAs and omega-3/omega-6 ratio, whereas serum vitamin B-12 (p<0.01) and folic acid (p<0.05) levels were lower than those of the normal weight subjects. Homocysteine positively correlated with omega-6 FAs and negatively correlated with omega-3 FAs in severe obese and normal weight subjects. Serum vitamin B-12 positively correlated with omega-3 FAs (p<0.01) and omega-3/omega-6 ratio (p<0.01) and negatively correlated with omega-6 FAs (p<0.05) in severe obese subjects. Serum folic acid positively correlated with omega-3 FAs (p<0.01) in severe obese subjects. Our results suggest an association between the plasma omega-3 FAs and omega-6 FAs and serum tHcy concentrations in severe obese and normal weight subjects. Low levels vitamin B-12 and folic acid may have been responsible for the elevated tHcy levels in severe obese subjects, increasing the risk for future development of cardiovascular diseases. PMID- 23017311 TI - 25(OH)D status and demographic and lifestyle determinants of 25(OH)D among Korean adults. AB - PURPOSE: Vitamin D deficiency is a global health problem that is associated with increased risks of major diseases. This study investigated the status of 25 hydroxyvitamin D [25(OH)D] and its demographic and lifestyle determinants among Korean adults. METHODS: A total of 5,847 adults who had participated in the Korean National Health and Nutrition Examination Survey of 2008 (KNHANES) were included in the present study. Stepwise linear regression analysis was performed to determine the demographic and lifestyle determinants of 25(OH)D concentration. RESULTS: The weighted prevalence (standard error) of 25(OH)D deficiency (<20 ng/mL) was 49.9 (2.1)% among the males and 67.4 (1.7)% among the females. Severe 25(OH)D deficiencies (<10 ng/mL) were found in 5.7 (0.8)% of the males and 11.1 (1.0)% of the females. These peaked in spring and winter. Only 12.2 (1.1)% of the males and 6.4 (0.6)% of the females exhibited 25(OH)D sufficiency (>=30 ng/mL). The correlates with higher 25(OH)D concentration for both genders included summer, fall (vs spring), the 60s age group (vs 20s), rural residence (vs urban), moderate and vigorous physical activity (vs sedentary), alcohol consumption, and multivitamin supplementation. Higher education and unmarried status were inversely associated with 25(OH)D concentration for both genders. The strongest predictors of 25(OH)D concentration were season and residential area. CONCLUSIONS: 25(OH)D deficiency is a prevalent condition in Korea. Understanding the determinants of 25(OH)D can facilitate identification of persons at risk of 25(OH)D deficiency. PMID- 23017312 TI - Age- and gender-specific associations between low serum 25-hydroxyvitamin D level and type 2 diabetes in the Korean general population: analysis of 2008-2009 Korean National Health and Nutrition Examination Survey data. AB - INTRODUCTION: We present data from the Korean National Health and Nutritional Examination Survey (KNHANES) 2008-2009 on the association between 25 hydroxyvitamin D[25(OH)D] status and type 2 diabetes in a representative sample of the adult Korean population. METHODS: This study was based on data obtained from the KNHANES 2008-2009, which was conducted for 3 years (2007-2009) using a rolling sampling design that involved a complex, stratified, multistage, probability-cluster survey of a representative sample of the noninstitutionalized civilian population of South Korea. RESULTS: We showed that serum 25(OH)D concentration is inversely associated with type 2 diabetes in the Korean general population. In particular, low serum 25(OH)D concentration was associated with an increased prevalence of type 2 diabetes in young women and old men. The present study showed that 25(OH)D has a significant negative association with fasting insulin and insulin resistance. CONCLUSION: The age- and gender-specific association between low 25(OH)D level and type 2 diabetes may be related to interactions between vitamin D, sex hormone concentrations, and type 2 diabetes. In conclusion, we showed that low 25(OH)D concentration is associated with type 2 diabetes in the Korean general population in an age- and gender-specific pattern. PMID- 23017313 TI - Choline and betaine food sources and intakes in Taiwanese. AB - Choline and betaine are involved in several similar health-relevant metabolic pathways, but the foods sources are different. We have assessed their intakes (individual, sums and ratios) from a dominantly Chinese food cultural point of view. A representative free-living Taiwanese population aged 13-64 years was drawn from the Nutrition and Health Survey in Taiwan (NAHSIT) 1993-1996. Food intake was derived from interviews as 24-hour recalls. The USDA database, with adaptations for Taiwan, provided choline and betaine food compositions. Major food contributors of these nutrients were identified and compared with data from the US Framingham offspring study. Mean and variance reduced median nutrient intakes were calculated. Top ten major food contributors of choline in Taiwan were eggs, pork, chicken, fish, soybean and its products, dark leafy vegetables, dairy, fruit, wheat products and light leafy vegetables in sequence. For betaine, the top ten were dark leafy vegetables, wheat products, fish, pork, bread, chicken, cake/cookies, grain-based alcoholic beverages, rice and its products and sauces. The main contributors of choline in Taiwan and the USA were, respectively, eggs and red meat; and for betaine, greens were similarly best contributor. The rankings of the main food contributors of choline and betaine differed substantially between Taiwan and the USA. The total daily intakes (mean+/-SE, mg) in Taiwan for choline were 372+/-19 (median=348) in men and 265+/ 9 (median 261) for women; for betaine, values were 101+/-3 (median 93) in men and 78+/-8 (median 76) for women. These allow for health outcome considerations. PMID- 23017314 TI - Snack foods consumption contributes to poor nutrition of rural children in West Java, Indonesia. AB - Dietary habits of children, including snack foods consumption, in developing countries have seldom been investigated in relation to their nutrition and health. To assess the effects of snack foods consumption of 154 children aged 1 12 years in a rural village of West Java, Indonesia, a 3-hour-interval food recall survey for all meals and snack foods consumed in seven consecutive days for each subject, anthropometry, and interviews for sociodemographic indicators were conducted. Their overall prevalence of stunting and underweight was 69.5% and 35.7%. There were 221 foods consumed by the subjects, among which 68 foods were categorized as snack foods. Though the children of both <7 year and >=7 year age groups consumed snack foods similarly throughout the day, the latter group only consumed larger amounts of energy from snack foods at school recess-times. The mean percent contribution of snack foods was 59.6% for fat, 40.0% for energy, 20.6% for calcium, and <10% for vitamins A and C. Half number of the subjects who snacked more than the median amount consumed less carbohydrate and vitamin C than the remaining half. Furthermore, the more snack-consuming group the lower z score for height-for-age (HAZ) among schoolchildren. To improve this nutritionally vulnerable situation, consumption of snack foods should be replaced by the non snack foods which contain much higher nutrient density; i.e. 15 times for calcium and 32 times for vitamin A. Moreover, considering high snack foods consumption of >=7 y age group at school, appropriate school nutrition programs should be promoted. PMID- 23017315 TI - Trends in the prevalence of undernutrition, nutrient and food intake and predictors of undernutrition among under five year tribal children in India. AB - Undernutrition among children under five year is a significant public health problem in India. The present study was carried out to assess trends in nutritional status, nutrient and food intake among children under five year over two time periods. It was a community-based cross-sectional study, carried out in tribal areas of India. A total of 14,587 children, 0-5 years old were covered for nutritional assessment in terms of underweight, stunting and wasting. A 24 hour diet survey was carried out in a sub-sample of households surveyed. Wealth index was constructed using principle component analysis. The prevalence of underweight and stunting had declined significantly over the periods (49% vs 57%, 51% vs 58%, respectively), while the prevalence of wasting remained similar (22% vs 23%). There was marginal decrease in the intake of foods and nutrients over the periods, and was below recommended levels. Stepwise regression showed that the risk of underweight and stunting was significantly (p<0.01) higher among children of illiterate mothers and children from lowest and middle households wealth index. Morbidities during preceding fortnight had 1.3 times higher risk of underweight and wasting. In conclusion, undernutrition is a significant health problem among tribal children and is associated with literacy status of mothers, household wealth index and morbidities. Therefore implementation of appropriate nutritional intervention strategies and improvement in households food security through public distribution systems, food intakes, socioeconomic condition, literacy of parents and personal hygiene may help in improving the nutritional status of tribal children. PMID- 23017316 TI - The U-shaped relationship between BMI and all-cause mortality contrasts with a progressive increase in medical expenditure: a prospective cohort study. AB - The U-shaped relationship between body mass index (BMI) and all-cause mortality has generated uncertainty about optimal BMI. For clarification, we have related BMI to both mortality and medical expenditure. The MJ Health examination cohort of 111,949 examinees established during 1994-1996 was followed with endpoint information derived from death certificates and National Health Insurance records from 1996 to 2007. Age- and gender-specific relative risks between BMI groups were estimated by Cox and logistic regressions. The BMI and all-cause mortality relationship is U-shaped with the concave regions sitting in the region of BMI 22 26, butshifted rightward for the elderly. After excluding smokers and cancer patients at baseline, the low mortality region moved leftward to BMI 20-22. Cause specific mortalities from respiratory disease, injury, and senility increased in the underweight group (BMI <18.5). Above 18.5, BMI was negatively associated with mortality from respiratory diseases and senility, but not with others. In contrast, irrespective of age and gender, the overall median and mean medical expenditures progressively increased with BMI, particularly beyond 22. Expenditures for injury, respiratory, circulatory diseases and senility all increased with BMI. The U-shaped BMI-mortality relation was a result of elevated death rate at both ends of the BMI scale. Increased mortality at the low end did not contribute to higher medical expenditure, maybe because the lean and frail deceased tend to die abruptly before large amount of medical expenditure was consumed. Our findings suggest that current recommendations to maintain BMI at the lower end of the desirable range remain tenable for the apparently healthy general public. PMID- 23017317 TI - Alcohol consumption and the risk of type 2 diabetes mellitus: effect modification by hypercholesterolemia: the Third Korea National Health and Nutrition Examination Survey (2005). AB - OBJECTIVE: While the protective nature of moderate alcohol consumption against diabetes mellitus is well known, inconsistent findings continue to be reported. The possibility of different mixes of effect modifiers has been raised as a reason for those inconsistent findings. Our study aim was to examine potential effect modifiers that can change the effect of alcohol consumption on type 2 diabetes. METHODS: From data in the third Korea National Health and Nutrition Examination Survey, 3,982 individuals over the age of 30 years who had not been diagnosed with diabetes were selected for inclusion in the study population. Breslow and Day's test and the Wald test between hypercholesterolemia and alcohol consumption in a multiple logistic regression model were used to assess effect modification. RESULTS: Odds ratios for diabetes stratified by alcohol consumption strata and assessed using Breslow and Day's tests for homogeneity indicated that hypercholesterolemia was not a significant confounding factor (p=0.01). However, the Wald test for interaction terms, which is a conservative method of effect modification, was significant (p=0.03). CONCLUSIONS: The results indicate that moderate alcohol consumption is not necessarily protective for type 2 diabetes mellitus, if a person has hypercholesterolemia. People who have hypercholesterolemia should be aware of the risk associated with alcohol consumption, a risk that contrasts with the reported protective effect of moderate alcohol consumption on diabetes. PMID- 23017318 TI - Prevalence of functional gastrointestinal disorders in Taiwan: questionnaire based survey for adults based on the Rome III criteria. AB - Functional gastrointestinal disorders (FGID) are a group of disorders of the digestive system in which the chronic or recurrent symptoms cannot be explained by the presence of structural or tissue abnormality. This survey used a modified Rome III questionnaire on the health and nutrition status of a general population in Taiwan during 2005-2008. A total of 4,275 responders completed the questionnaire. The sample was evenly distributed for men (n=2,137) and women (n=2,138). The prevalence of FGID was 26.2%. Unspecified functional bowel disorder was the most prevalent (8.9%). The second was functional dyspepsia (5.3%), and the third were irritable bowel syndrome (4.4%) and functional constipation (4.4%). Women had a greater prevalence than males (33.2% compared to 22.4%, p<0.05) with regards to total FGID. Most categories of FGID were significantly prominent in women, except functional diarrhea. The FGID groups took fewer servings of vegetables and fruits than the non-FGID group each day (vegetables 2.51 vs 2.70, p<0.001; fruits 0.82 vs 0.91, p<0.001). Smoking, alcohol consumption, and betel nut chewing had no significant impaction on prevalence of FGID. The mean BSRS (brief-symptom rating scale) for screening depression and suicide ideation was higher in the FGID group (2.86 vs 1.63, p<0.001). In conclusion, FGID diagnosed with Rome III criteria are not uncommon in Taiwan's general population. Subjects who met the Rome III criteria for FGID in Taiwan were younger, had less vegetables and fruits intake, higher BSRS scores and were of greater female predominance. PMID- 23017319 TI - Effects of healthy dietary pattern and other lifestyle factors on incidence of diabetes in a rural Japanese population. AB - This study assessed the effects of dietary habits and other lifestyle factors on the incidence of diabetes in a rural Japanese population. This 10.3-year study investigated a cohort of 1,995 men and 3,670 women aged 40-69 years without diabetes at baseline who underwent health check-ups between April 1990 and March 1992. Participants were followed up until diabetes was confirmed or until the end of 2006. The incidence of diabetes was determined from fasting and random levels of plasma glucose, HbA1c levels or being under medical treatment for diabetes. Principal component analysis identified a major dietary pattern characterized by more frequent consumption of vegetables, potatoes, seaweeds, fruits and soybean products that we labeled "healthy". Diabetes developed in 446 of the participants during 58,151 person-years of follow-up. Consuming a healthy diet was associated with a lower risk of diabetes (multivariable-adjusted hazard ratio for highest vs lowest quartiles, 0.78 [95% CI, 0.61- 0.95]. In addition, scores for a healthy diet were associated with a lower risk for diabetes among persons who consumed regular meals (0.76 [0.58-0.96]), persons with an exercise habit (0.65 [0.44 0.96]) and non- and ex-smokers (0.72 [0.53-0.96]). Our findings suggest that consuming a healthy diet is associated with a lower risk for diabetes among the Japanese, particularly among those who eat regularly, those who habitually exercise and non- and ex-smokers. PMID- 23017320 TI - Public support for restrictions on fast food company sponsorship of community events. AB - This study investigated community attitudes to fast food companies' sponsorship of community events. The aim was to inform future efforts to introduce greater restrictions on these marketing activities to reduce child obesity. While previous research has focused on the sponsorship of sporting events, the present study included all community events and gauged public support for fast food company sponsorships in general as well as specific sponsorship activities such as securing event naming rights, advertising on event premises, and distributing free items to children in the form of food and redeemable vouchers. A large and diverse sample of Western Australian adults (n=2,005) responded to a community attitudes telephone survey that included questions relating to event sponsorship. Almost half of the respondents reported that the promotion of fast foods is inappropriate at community events, and only a third considered it appropriate at events where children are likely to be present. Around two-thirds agreed that promoting fast foods at such events sends contradictory messages to children and just a quarter of respondents considered it acceptable for free fast food to be distributed at events or for children to be rewarded for participation with fast food vouchers. The results suggest that efforts to reduce child obesity that involve restrictions on the sponsorship of community events by organisations promoting unhealthy foods may be supported by a substantial proportion of the population. PMID- 23017321 TI - South Korea's entry to the global food economy: shifts in consumption of food between 1998 and 2009. AB - Korea has undergone a major opening of its food markets and economy in the past decade. Little is understood about the impact of these shifts on the diet of Koreans. This analysis studies the shifts in consumption of foods between 1998 and 2009 to provide a thorough understanding of the transition and insights into directions in the next decades in Korea. Data are from the Korea National Health and Nutrition Examination Survey (KNHANES). The sample used was a nationally representative sample of individuals age >=2 in 1998 and 2009 (n=10,267 and 9,264, respectively). The data was corrected for seasonality, and the original raw food data was regrouped into 53 food groups. SAS was used to adjust for design effects and weight. Despite a decade of efforts to increase whole grains intake, and fruit and vegetable intake, the mean intake of whole grains increased only a small amount (16 kcal/person/day); however, the proportion consuming any whole grains doubled from 24% to 46.3%. Rice declined significantly, and several important less healthful food trends emerged: total alcohol intake increased from 39 kcal/person/day to 82 kcal/person/day. Also, energy from sugar-sweetened beverages increased among teens and energy from tea and coffee increased among adults. Remarkably, compared to other Asian countries and a general worldwide trend, vegetable intake remained relative high in South Korea during this last decade while fat energy increased modestly from relative low levels. Dynamic causes of these trends and the government's response are discussed. PMID- 23017322 TI - Do registered dietitians search for evidence-based information? A nationwide survey of regional hospitals in Taiwan. AB - Dietitians can obtain nutrition-related information from a variety of sources. The current study was to investigate how registered dietitians look for nutritional information and perceive evidence-based nutrition (EBN). A postal questionnaire survey was conducted, with 67 valid returns collected. The most common informational sources were Web portals, followed by continuing education, colleague consultation, textbooks, online databases, electronic journals, printed journals, and electronic textbooks. Among the 11 commonly used online databases, dietitians preferred to access MEDLINE and three databases in Chinese. Sixty-two dietitians (92.5%) were aware of EBN. Although they had a favorable impression of EBN, their knowledge of and skills in EBN were relatively lacking. The most common barrier to the implementation of EBN was a lack of library resources in Chinese (58.1%), followed by deficient skill in critical appraisal (54.8%), insufficient convenient kits (53.2%), and time constraints (50.0%). In conclusion, most registered dietitians search for information through non-EBN resources. Language is an important element relevant to the implementation of EBN. These findings may help the refining of strategies to promote the accessing of evidence-based information. PMID- 23017323 TI - Repeated lung lavage with extracorporeal membrane oxygenation treating severe acute respiratory distress syndrome due to nasogastric tube malposition for enternal nutrition: a case report. AB - Enternal nutritional support, a frequently applied technique for providing nutrition and energy, played a pivotal role in the treatment of high risk patients. However, severe complications induced by malposition of nasogastric tube caused great danger and even death to the patients. In this case report, we present a patient with severe acute respiratory distress syndrome (ARDS) induced by bronchopleural fistula (BPF) due to malposition of nasogastric tube. Repeated lung lavage combined with extracorporeal membrane oxygenation (ECMO) was performed after transferring to the ICU of our hospital. Finally, the patient recovered and discharged 7 days after admission. PMID- 23017324 TI - Bleeding tendency in an adolescent with chronic small bowel obstruction. AB - We report a case of fat-soluble vitamin deficiency in a 14-year old boy who had chronic duodenal obstruction. He presented with periodic unexplained bleeding tendency. The laboratory results showed positive fat globules in stool and prolonged prothrombin time. His further investigation revealed low plasma vitamin A and undetectable plasma vitamin E. After parenteral vitamin K and oral vitamin A and E supplement, these abnormalities resolved although he still had absent knee jerk. We propose that fat malabsorption and fat-soluble vitamin deficiency can occur after prolonged duodenal obstruction that induce bacterial overgrowth following by bile acid deconjugation. Despite very few case reports, screening for fat malabsorption and fat-soluble vitamin deficiency might be warranted in patients with chronic small bowel obstruction. PMID- 23017326 TI - [Assessment of anterior segment anatomy by OCT after non penetrating deep sclerectomy]. AB - PURPOSE: Thanks to recent progress in imaging techniques, the anatomy of the anterior segment can be measured accurately and noninvasively. The objective of this study was to assess early postoperative changes induced by non penetrating deep sclerectomy (NPDS) on anterior chamber depth, anterior chamber angle and central corneal thickness. PATIENTS AND METHODS: Twenty eyes of 20 patients with primary open-angle glaucoma (POAG) that underwent NPDS were studied. All patients underwent ophthalmologic examination including non invasive analysis of the anterior segment architecture. Visante((r)) OCT was used to determine anterior chamber depth, central corneal thickness, scleral spur angle (SSA), angle opening distance at 500MUm (AOD 500), and trabecular-iris space area at 500 MUm (TISA 500) in the nasal and temporal quadrants. These evaluations were performed at 1 day preop, then day 1, day 7 and day 30 after surgery. RESULTS: Preoperatively, SSA, AOD 500 and TISA 500 were 37.24 +/- 12.67 degrees , 0.42 +/- 0.25 mm and 0.15 +/- 0.1 mm(2), respectively, in the nasal quadrant, and 39.62 +/- 12.41 degrees , 0.46 +/- 0.25 mm and 0.16 +/- 0.08 mm(2), respectively, in the temporal quadrant. Mean anterior chamber depth, central corneal thickness and intraocular pressure (IOP) were 3.09 +/- 0.54 mm, 530 +/- 34.3 MUm and 20.43+/- 7.25 mmHg respectively. After NPDS, aside from IOP being significantly decreased on day 1 (5.57 +/- 2.78 mmHg, P<0.0001), day 7 (8.2 +/- 3.12 mmHg, P<0.0001) and day 30 (13.4 +/- 3.47 mmHg, P=0.001), none of the other study parameters was significantly modified. CONCLUSION: No relationship was found between IOP and anterior chamber architecture after NPDS. NPDS appears to significantly reduce IOP while maintaining the architecture of the anterior chamber, and in particular, the anterior chamber angle. PMID- 23017327 TI - [Severe bacterial keratitis referred to ophthalmology emergency departments: a retrospective study of 268 cases]. AB - PURPOSE: To investigate epidemiological, microbiological and clinical aspects of severe bacterial keratitis, in order to update current understanding of risk factors (RF) and prognosis. PATIENTS AND METHODS: We conducted a monocentric retrospective study from January 2005 to January 2011, identifying and collecting data from inpatients admitted for severe documented bacterial keratitis. RESULTS: We found 268 unilateral corneal ulcers. At least one local or systemic risk factor was identified in 255/268 patients (95%). The leading risk factor was contact lens wear (129/268), followed by underlying corneal disease (50/268) and prior corneal surgery (47/268). Initial and final visual acuities were 0.06 and 0.2 (1.20 and 0.72 LogMAR) respectively. Contact lens wear was associated with better prognosis and shorter hospitalization (P<0.05). Corneal healing was obtained in 255/268 patients (95%), with adjuvant surgery for 33 patients. The most frequently isolated pathogens were Gram+ cocci, more commonly associated with degenerative keratopathy or prior corneal surgery, and Gram- bacilli, more commonly associated with contact lenses (P<0.05). Both demonstrated a similar prognosis. CONCLUSION: Specific risk factors should be investigated in cases of severe bacterial keratitis. Contact lens wear is the most frequent risk factor, but with a better prognosis than underlying corneal disease, prior corneal surgery or systemic risk factors. The specific bacterial pathogen no longer appears to dramatically influence the outcome of severe corneal ulcers. PMID- 23017325 TI - The combination of EPA+DHA and low-dose aspirin ingestion reduces platelet function acutely whereas each alone may not in healthy humans. AB - INTRODUCTION: Aspirin's effectiveness in reducing cardiovascular disease events is inadequate in some individuals, a phenomenon termed aspirin "resistance". The hypothesis that combining low dose aspirin with eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA) reduces platelet function in the acute setting has not been investigated. PATIENTS AND METHODS: We conducted a clinical trial of EPA+DHA and aspirin ingestion in healthy adults. Fasting blood samples were drawn at baseline and 4 h after supplementation with EPA/DHA (3.4 g/d), aspirin (81 mg), and both. Platelet function was measured using the Platelet Function Analyzer-100 (PFA-100). Plasma lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), autotaxin, angiogenesis activators, and cytokines were measured. RESULTS: Platelet function decreased with the combination of aspirin+EPA/DHA (p=0.03) but not with either alone (p>0.05). EPA-LPC increased (p=0.002). DISCUSSION AND CONCLUSIONS: Our results demonstrate that a potentially beneficial effect on platelet function occurred within 4h after ingestion of low-dose aspirin and EPA+DHA in healthy adults. PMID- 23017328 TI - Application of SSH and quantitative real time PCR to construction of gene expression profiles from scallop Chlamys farreri in response to exposure to tetrabromobisphenol A. AB - TBBPA-induced genes were identified using suppression subtractive hybridization (SSH) from Chlamys farreri. A total of 203 and 44 clones from SSH forward and reverse library were respectively obtained including cellular process, immune system process, response to stimulus, metabolic process and signaling etc. Differential gene expressions were compared between scallops from control and TBBPA treatment groups (400 MUg/L, 15 days) using quantitative real time RT-PCR. For further research, eight significant genes expression from scallops exposed to TBBPA (0; 100; 200; 400 MUg/L) sampling at 0, 1, 3, 6 and 15 days, were utilized for Q-RT-PCR. The results revealed that the expression level of most selected cDNAs was dominantly up-regulated or down-regulated in the TBBPA-induced scallops. These findings provide basic genomic information of the bivalve and the selected genes may be the potential molecular biomarkers for TBBPA pollution in aquatic environment. PMID- 23017330 TI - Effect of acetazolamide on respiratory muscle fatigue in humans. AB - Previous studies have demonstrated that carbonic anhydrase inhibition with acetazolamide reduces exercise capacity. The mechanism responsible for this early fatigue is unclear, but may be partly mediated by impaired respiratory muscle function. Inspiratory muscle strength and endurance were assessed in seven healthy men (age 28 +/- 5 yrs, +/-SD) by measuring maximal inspiratory pressure (MIP) and time to task failure during a constant-load breathing test (CLBT), respectively, under control (CON) and acetazolamide (ACZ; 500 mg/8 h po for 3 days) conditions that were separated by two weeks and randomized between subjects. In addition, MIP was measured before and after moderate-intensity cycling exercise to fatigue while pulmonary gas exchange, plasma pH, and ventilation were measured during exercise. ACZ did not alter pulmonary function (FVC, FEV1, MVV) or MIP measured at rest (CON, -157 +/- 47 vs. ACZ, -154 +/- 45 cmH(2)O, p>0.05), but decreased time to task failure during the CLBT (CON, 1340 +/- 820 vs. ACZ, 698 +/- 434 s; p=0.01). Exercise duration during cycling exercise was reduced (p=0.003) with ACZ (1090 +/- 254 s) compared to CON (1944 +/ 532 s) in the presence of a significantly lower plasma pH and higher ventilation compared to control (p<0.05). Compared to resting values, MIP was reduced (p=0.03) in ACZ but not CON at exhaustion. In conclusion, carbonic anhydrase inhibition with ACZ is associated with impaired respiratory muscle function at rest and following constant load cycling which may contribute to reduced exercise tolerance with carbonic anhydrase inhibition. PMID- 23017329 TI - Effects of clonidine on breathing during sleep and susceptibility to central apnoea. AB - We hypothesized that administration of clonidine would decrease the hypocapnic apnoeic threshold (HAT) and widen the CO(2) reserve during non-REM sleep. METHODS: Ten healthy subjects (4 females) (age 22.3 +/- 3.0 years; BMI 25.5 +/- 3.4 kg/m(2)) were randomized to receive placebo or 0.1 mg/45 kg of clonidine on 2 separate nights. Ventilation and upper airway resistance were monitored during wakefulness and sleep. Two separate experiments were performed: Protocol 1 (n=8), CO(2) reserve, HAT and HcVR were determined using non-invasive hyperventilation (NIV) to induce hypocapnia for at least 3 min; Protocol 2 (n=6), peripheral hypocapnic ventilatory response (HcVR) was determined by NIV using short (3 breaths) hyperventilation. RESULTS: Clonidine decreased the systolic blood pressure by 12 +/- 10 mmHg but did not affect baseline ventilation or upper airway resistance during wakefulness or sleep. Protocol (1), clonidine was associated with decreased HAT relative to placebo (37.3 +/- 3.3 mmHg vs. 39.7 +/- 3.4 mmHg, P<0.05), increased CO(2) reserve (-3.8 +/- 1.3 mmHg vs. -2.8 +/- 1.2 mmHg, P<0.05), and decreased HcVR (1.6 +/- 0.6 L/min/mmHg vs. 2.5 +/- 1.3 L/min/mmHg, P<0.05). Protocol (2), administration of clonidine did not decrease peripheral HcVR compared to placebo (0.5 +/- 0.3 L/min/mmHg vs. 0.7 +/- 0.3 L/min/mmHg, P=NS). CONCLUSION: Clonidine is associated with diminished susceptibility to hypocapnic central apnoea without significant effect on ventilation or upper airway mechanics. Reduced susceptibility to hypocapnic central apnoea is not explained by the peripheral chemoreceptor pathway. This suggests a central rather than a peripheral effect of clonidine on the susceptibility to hypocapnic central apnoea. PMID- 23017331 TI - High response rate for treatment with gemtuzumab ozogamicin and cytarabine in elderly patients with acute myeloid leukemia and favorable and intermediate-I cytogenetic risk. AB - Recent studies have reevaluated whether gemtuzumab ozogamicin (GO) improves the outcome of acute myeloid leukemia (AML) in elderly patients. Over 5 years, we treated 16 elderly patients with AML with GO and cytarabine. A high response rate, prolonged survival, and low toxicity were observed in the favorable and intermediate-I genetic groups of AML. Our study raises the issue about the optimal protocol for these patients. BACKGROUND: The benefit of gemtuzumab ozogamicin (GO) in combination with chemotherapy as frontline therapy in patients with acute myeloid leukemia (AML) is still debated. PATIENTS AND METHODS: We evaluated the safety and efficacy of low-dose GO with cytarabine in elderly patients with newly diagnosed AML. Over the past 5 years, we have treated 16 elderly patients with AML (64-82 years) with GO (3 mg/m(2)) followed by continuous infusion of cytarabine (100 mg/m(2)) for 7 days. RESULTS: Complete remission (CR) was achieved in 68.8% of patients; however, this was true only in patients in the favorable or intermediate-I cytogenetic risk groups. Of the 12 patients with AML in the favorable and intermediate-I genetic groups, 11 (91.7%) achieved CR. By comparison, of all 4 patients in the intermediate-II or adverse genetic groups, none of the patients achieved CR (P = .003). The median disease free survival and overall survival (OS) was 10.9 and 18.8 months, respectively, for patients who achieved CR. The estimated median survival was 15 months in the favorable and intermediate-I cytogenetic groups and only 4.4 months in the intermediate-II and unfavorable risk groups (P = .008). The toxicity profile was also manageable in patients with AML who were mainly older than 70 years with good performance status (PS). The 8-week mortality rate was 6.25%, which is relatively low in this high-risk group of patients. These data are in line with results from 2 randomized trials suggesting that the addition of low-dose GO should be further investigated to reevaluate its role in selected elderly patients with AML and raises the issue of the optimal protocol. PMID- 23017332 TI - Ocular granulocytic sarcoma: a case report and literature review of ocular extramedullary acute myeloid leukemia. PMID- 23017333 TI - Role of D1- and D2-like receptors in age-specific regulation of juvenile hormone and 20-hydroxyecdysone levels by dopamine in Drosophila. AB - In Drosophila females, the precursor of 20-hydroxyecdysone (20E), ecdysone, is synthesized in the ovary follicular cells. Juvenile hormone (JH) is synthesized de novo in the specialized endocrine gland, corpus allatum (CA); JH degradation is carried out by the enzymes synthesized in the fat body (FB). Earlier we have shown that in Drosophila females, dopamine up- or down-regulates 20E and JH levels depending on the developmental stage. The present study focuses on the role of D1- and D2-like receptors in the age-specific regulation of 20E and JH metabolism by dopamine. We show that in Drosophila melanogaster females D1- and D2-like receptor genes (DopR and DD2R accordingly) are expressed in CA and FB, but not in follicular cells. The level of DopR expression in CA is much higher in the young than in the mature females, whereas DD2R expression is much higher in the mature than in the young females. The DopR and DD2R expression patterns in FB are opposite to those observed in CA. In addition, we obtained data suggesting that the age-specific changes of DopR and DD2R expression in FB are under the control of 20E. PMID- 23017334 TI - Cold hardening modulates K+ homeostasis in the brain of Drosophila melanogaster during chill coma. AB - Environmental temperature is one of the most important abiotic factors affecting insect behaviour; virtually all physiological processes, including those which regulate nervous system function, are affected. At both low and high temperature extremes insects enter a coma during which individuals do not display behaviour and are unresponsive to stimulation. We investigated neurophysiological correlates of chill and hyperthermic coma in Drosophila melanogaster. Coma resulting from anoxia causes a profound loss of K(+) homeostasis characterized by a surge in extracellular K(+) concentration ([K(+)](o)) in the brain. We recorded [K(+)](o) in the brain during exposure to both low and high temperatures and observed a similar surge in [K(+)](o) which recovered to baseline concentrations following return to room temperature. We also found that rapid cold hardening (RCH) using a cold pretreatment (4 degrees C for 2h; 2h recovery at room temperature) increased the peak brain [K(+)](o) reached during a subsequent chill coma and increased the rates of accumulation and clearance of [K(+)](o). We conclude that RCH preserves K(+) homeostasis in the fly brain during exposure to cold by reducing the temperature sensitivity of the rates of homeostatic processes. PMID- 23017335 TI - Thyroid dysfunction in patients treated with sunitinib or sorafenib. AB - INTRODUCTION: Sunitinib and sorafenib are tyrosine kinase inhibitors used in metastatic renal cell carcinoma and are known to cause hypothyroidism in a subset of patients. The goal of this study was to better characterize the development of hypothyroidism in patients and to examine its relationship to progression-free survival. PATIENTS AND METHODS: A retrospective chart review was performed on patients treated with sunitinib or sorafenib from January 1, 2005, to January 1, 2011. Data pertaining to the treatment course and development of hypothyroidism were extracted. Patients with hypothyroidism at the beginning of treatment were analyzed separately. RESULTS: A total of 73 treatment periods had sufficient data to analyze. Among patients with normal baseline thyroid function, 15 (44%) of 34 patients treated with sunitinib and 6 (27%) of 22 patients treated with sorafenib developed hypothyroidism. The hazard ratio for the development of hypothyroidism with sorafenib vs. sunitinib treatment was significant, at 0.38 (95% CI, 0.14 0.97). There was a statistically significant difference in the progression-free survival between patients who developed hypothyroidism while receiving treatment compared with those who did not, 18.2 vs. 10.1 months (P = .01). CONCLUSIONS: This study demonstrated a significant difference in the incidence of hypothyroidism during treatment with sunitinib and sorafenib, with a higher incidence of hypothyroidism in patients treated with sunitinib. The development of hypothyroidism was associated with a longer progression-free survival. PMID- 23017336 TI - Predictive factors for late recurrence in patients with stage T1 clear cell renal cell carcinoma: a multiinstitutional study. AB - BACKGROUND: The purpose of this study was to identify predictive factors for late recurrence in Korean patients with stage T1 clear cell renal cell carcinoma (RCC) more than 5 years after treatment with radical nephrectomy (RN) or partial nephrectomy (PN). PATIENTS AND METHODS: Between 1999 and 2011, 3567 patients with RCC underwent RN or PN at 5 institutions in Korea. Of these, 423 patients with pathologically confirmed stage T1 clear cell RCC remained free of disease for at least 5 years. To determine the pathologic and clinical factors that influenced late recurrence, univariate and multivariate analyses using the Cox proportional hazards model were performed. Recurrence-free survival curves were estimated by using the Kaplan-Meier method. RESULTS: During a median follow-up period of 83.9 months (range 60.0-156.4 months), late recurrence was observed in 14 of the 423 (3.3%) patients. Univariate and multivariate analyses revealed that symptoms at diagnosis and pathologic T stage were independent predictive factors for late recurrence. Patients with symptoms at diagnosis or stage T1b disease had a significantly shorter time to late recurrence than did those who were asymptomatic or had stage T1a disease (log-rank test P = .027 and P = .034, respectively). CONCLUSIONS: Late recurrence in stage T1 clear cell RCC is a relatively rare event. Predictive factors for late recurrence were identified in the present study. Careful long-term follow-up is necessary, especially in patients who have symptoms at diagnosis or stage T1b tumors, even if they have been free of disease for more than 5 years. PMID- 23017338 TI - Preventing maritime transfer of toxigenic Vibrio cholerae. AB - Organisms, including Vibrio cholerae, can be transferred between harbors in the ballast water of ships. Zones in the Caribbean region where distance from shore and water depth meet International Maritime Organization guidelines for ballast water exchange are extremely limited. Use of ballast water treatment systems could mitigate the risk for organism transfer. PMID- 23017339 TI - The expression patterns of Msi1 related with the glioma grade and the cytoplasmic Msi1 promotes angiogenesis. AB - To investigate the expression patterns of Msi1 and its relationship with tumour grading and angiogenesis in human glioma. Msi1 expression and the angiogenesis labelled by CD31 were detected by immunohistochemical staining in glioma from Grade I to Grade IV. MVD-CD31 was counted respectively in nuclear and cytoplasmic positive areas of Msi1. There was weak expression of Msi1 in the adjacent normal brain tissue of glioma, and there were less MVD-CD31 than in glioma. Glioma showed strong expression and different patterns of Msi1. From Grade I to Grade IV glioma, the expression pattern of Msi1 was changed from nuclear into cytoplasmic pattern gradually (P<0.05), and the expression patterns of Msi1 were related with the angiogenesis of glioma (P<0.05). It suggested that cytoplasmic Msi1 promoted angiogenesis and nuclear Msi-1 inhibited angiogenesis in glioma (P<0.05). Msi1 has different expression patterns in glioma from Grade I to Grade IV, and the different expression patterns play diverse roles in angiogenesis of glioma. This might explain that from Grade I to IV, glioma showed worse and worse prognosis. PMID- 23017340 TI - Occasional musings. PMID- 23017342 TI - President's message. Qui tacet consentire videtur. PMID- 23017344 TI - Epidural steroid injections for low back pain in rural practice: a 5-year retrospective study. AB - INTRODUCTION: Epidural steroid injections (ESIs) are a safe and accessible therapy for chronic low back pain, one of the most common and challenging chronic conditions seen in primary care. However, the indications for and effectiveness of ESI remain controversial. In rural settings with limited public transportation infrastructure, such a mobility-limiting condition can have even more negative effects on quality of life and function. Furthermore, diagnostic and specialist services are often limited. A paucity of safe, effective and accessible treatments leads to heavy reliance on oral analgesics, especially opioids, which have well-known complications. METHODS: We reviewed the use of ESI for the 2 most common types of chronic low back pain in those with neurologic symptoms: lumbar disc herniation (LDH) and lumbar spinal stenosis (LSS). We did a retrospective chart review of all patients who underwent ESI between Jan. 1, 2005, and Feb. 25, 2010, at our rural hospital in northwestern Ontario. RESULTS: During the study period, 123 ESIs were administered to 65 patients. After the first injection, 40 patients (62%) reported improvement, 10 (15%) reported worsening or no change, and 15 (23%) had no follow-up documented. CONCLUSION: Some patients with neurologic compromise from LDH or LSS have improvement in symptoms after ESI. A prospective study is underway to more rigorously assess the effectiveness of this treatment. PMID- 23017345 TI - Joint position paper on rural maternity care. PMID- 23017337 TI - A protein ballet around the viral genome orchestrated by HIV-1 reverse transcriptase leads to an architectural switch: from nucleocapsid-condensed RNA to Vpr-bridged DNA. AB - HIV-1 reverse transcription is achieved in the newly infected cell before viral DNA (vDNA) nuclear import. Reverse transcriptase (RT) has previously been shown to function as a molecular motor, dismantling the nucleocapsid complex that binds the viral genome as soon as plus-strand DNA synthesis initiates. We first propose a detailed model of this dismantling in close relationship with the sequential conversion from RNA to double-stranded (ds) DNA, focusing on the nucleocapsid protein (NCp7). The HIV-1 DNA-containing pre-integration complex (PIC) resulting from completion of reverse transcription is translocated through the nuclear pore. The PIC nucleoprotein architecture is poorly understood but contains at least two HIV-1 proteins initially from the virion core, namely integrase (IN) and the viral protein r (Vpr). We next present a set of electron micrographs supporting that Vpr behaves as a DNA architectural protein, initiating multiple DNA bridges over more than 500 base pairs (bp). These complexes are shown to interact with NCp7 bound to single-stranded nucleic acid regions that are thought to maintain IN binding during dsDNA synthesis, concurrently with nucleocapsid complex dismantling. This unexpected binding of Vpr conveniently leads to a compacted but filamentous folding of the vDNA that should favor its nuclear import. Finally, nucleocapsid-like aggregates engaged in dsDNA synthesis appear to efficiently bind to F-actin filaments, a property that may be involved in targeting complexes to the nuclear envelope. More generally, this article highlights unique possibilities offered by in vitro reconstitution approaches combined with macromolecular imaging to gain insights into the mechanisms that alter the nucleoprotein architecture of the HIV-1 genome, ultimately enabling its insertion into the nuclear chromatin. PMID- 23017347 TI - Country cardiograms case 45. PMID- 23017348 TI - Caudal epidural injection. PMID- 23017349 TI - The occasional epidural steroid injection. PMID- 23017350 TI - Medical software for smartphones. PMID- 23017353 TI - Dissolution testing and potentiometric determination of famciclovir in pure, dosage forms and biological fluids. AB - The performance characteristics of two new plastic membrane ion selective electrodes (ISEs) used for the determination of famciclovir (Fcv) based on the ion associate of Fcv with phosphotungstic acid (PTA) or phosphomolybdic acid (PMA) are described. Different experimental conditions as type of plasticizer to be incorporated in the membrane, life span, effect of soaking, pH, temperature, and interferences were studied. Both electrodes showed similar performance under these conditions, exhibiting Nernstian slopes of S (Fcv-PTA)=58.60+/-0.84 mV/decade and S (Fcv-PMA)=58.77+/-0.68 mV/decade within a usable concentration range of 10-5-10-2 [Fcv/M] at 298/K. Famciclovir was assayed potentiometrically in its pure solution, pharmaceutical preparations and biological fluids (urine and plasma) using proposed electrodes under batch and flow injection analysis (FIA) conditions with a recovery % ranging between 96.76% and 102.83% having RSD of 0.66%-1.81%. The electrodes were also successfully applied in the determination of the dissolution profile of Fcv tablets and the results came in agreement with the validated results of the HPLC method obtained from the quality control unit of the company producing the tablets. PMID- 23017354 TI - The association between regional arterial stiffness and diabetic retinopathy in type 2 diabetes. AB - OBJECTIVES: Although several studies have reported that PWV is associated with diabetic retinopathy, it remains controversial as to which segment provides the PWV that might best reflect the presence of retinopathy. The aim of this study was to determine the pulse wave velocity (PWV) of arterial segments that is most closely associated with diabetic retinopathy in subjects without a history of macrovascular complications. METHODS: After excluding subjects with a history of ischemic heart disease, peripheral artery disease, ischemic stroke, renal insufficiency, overt proteinuria, and other nondiabetic ophthalmic lesions or insufficient retinal examinations, a total of 494 subjects were analyzed by cross sectional study. The central PWVs, including the heart-femoral (hf), heart carotid (hc), heart-ankle (ha), and carotid-brachial (cb) segments, and the peripheral PWVs, including brachial-ankle (ba) and femoral-ankle (fa), were measured for each subject. RESULTS: The group with diabetic retinopathy exhibited significantly higher hfPWV, hcPWV, haPWV and baPWV, but notcbPWV, faPWV or augmentation index (AI). Age, duration of diabetes, systolic and diastolic BP and pulse pressure were all positively associated with hfPWV, hcPWV, haPWV and baPWV. Quartiles of hfPWV were significantly associated with diabetic retinopathy after adjustment for covariates and known risk factors of diabetic retinopathy (P for trend = 0.023). Conversely, all quartiles of haPWV, hcPWV and baPWV lost significance after adjustment. CONCLUSIONS: We found that diabetic retinopathy was most closely associated with hfPWV, suggesting the most reliable index of regional arterial stiffness index in retinopathy. PMID- 23017355 TI - LDL subclasses and lipoprotein-phospholipase A2 activity in suppressed HIV infected patients switching to raltegravir: Spiral substudy. AB - OBJECTIVE: To analyze the effect of switching the ritonavir-boosted protease inhibitor (PI/r) in a stable combined antiretroviral therapy (cART) regimen to raltegravir on low-density lipoprotein (LDL) particles, and lipoprotein associated phospholipase A2 (Lp-PLA2). DESIGN: Substudy of a multicenter randomized trial that compared the efficacy of switching a PI/r to raltegravir based cART in stable HIV-infected patients. METHODS: LDL size and phenotype (by gel-gradient electrophoresis), Lp-PLA2 (by 2-thio-PAF [Cayman]), proprotein convertase subtilisin/kexin type 9 (PCSK9) (by ELISA), and standard lipid parameters were measured at baseline and week 48. RESULTS: Eighty-one (PI/r n = 41 and raltegravir n = 40) patients were evaluated. No differences in baseline demographic and metabolic variables between arms were found except in apolipoprotein (Apo) B (p = 0.042). At week 48, total cholesterol (TC) (p < 0.001), LDL-c (p = 0.023), non-high density lipoprotein cholesterol non-high density lipoprotein cholesterol (non-HDL-c) (p < 0.001), TC/HDL (p = 0.026), triglyceride (p < 0.001), Apo B (p < 0.001), Apo A-I (p = 0.004) and Lp (a) (p = 0.005) decreased in raltegravir arm compared to PI/r arm. At week 48, a shift from LDL phenotype B to the less atherogenic phenotype A was observed only in raltegravir arm (p < 0.001). LDL size increased (PI/r 2.1 nm, p = 0.019; raltegravir 3.8 nm, p = 0.001) and cholesterol content in small and dense LDL subfractions (LDL 4,5,6) decreased (PI/r p = 0.007, raltegravir p = 0.006) at week 48 in both arms. Total Lp-PLA2 activity (PI/r p = 0.037 and raltegravir p = 0.051) and PCSK9 plasma concentration decreased in both arms (PI/r p = 0.034 and raltegravir p < 0.001). CONCLUSIONS: Switching a PI/r to a raltegravir-based cART in virologically suppressed HIV-infected patients was associated with an overall improvement in lipid profile, including a shift to a less atherogenic LDL phenotype. PMID- 23017356 TI - Effects of omega-3 fatty acids on postprandial triglycerides and monocyte activation. AB - OBJECTIVE: Epidemiologic studies suggest that elevated postprandial triglycerides (ppTG) are associated with future cardiovascular events. Monocyte activation plays an important role in vascular diseases. Omega-3 fatty acids (n3-FA) lower fasting TG levels. The effects of n3-FA on ppTG and the role of ppTG for monocyte activation are insufficiently understood. METHODS AND RESULTS: 23 healthy volunteers and 30 non-diabetic patients with documented coronary artery disease were subjected to an oral TG tolerance test (OTTT) consisting of 80 g cream fat or to water as control (H(2)O). Patients were treated with 4 g n3-FA/day or placebo for 3 weeks in a randomized, placebo-controlled, double-blind, crossover study. Relative postprandial TG increase reached its maximum 4 h after fat intake (185.1 +/- 10.9% of baseline). n3-FA reduced fasting TG from 137.1 +/- 12.9 to 112.2 +/- 8.6 mg/dl (p < 0.05), and maximum ppTG concentrations from 243.6 +/- 24.6 to 205.8 +/- 17.1 mg/dl (p < 0.05), while relative TG increase (192.8 +/- 12.7%) was comparable to placebo. Relative monocytopenia and neutrophilia were detected following fat intake, which was unaffected by n3-FA and also detectable in the H(2)O group. Serum chemotactic cytokine (MCP1 and fractalkine) concentrations and monocyte migration were not affected by fat intake or n3-FA. Monocyte activation markers CD11b and CD14, monocyte subpopulations CD16(+)CD14(high) and CD16(+)CD14(low), sICAM serum levels and markers of oxidative stress remained unchanged by fat intake or n3-FA. CONCLUSION: The postprandial TG increase does not stimulate monocytes beyond their circadian activation patterns. n3-FA reduce fasting TG and the postprandial TG increase. n3 FA may therefore allow to prospectively study whether selected patients benefit from TG-lowering independent of LDL- and HDL-cholesterol. PMID- 23017357 TI - Toxoplasma gondii: an unknown quantity. PMID- 23017359 TI - Pre-existing immunity in human challenge studies of influenza transmission. PMID- 23017360 TI - Treatment of sepsis. PMID- 23017361 TI - Virus suppression, eradication, or tolerance to treatment in patients with chronic hepatitis B. PMID- 23017362 TI - Treatment of sepsis. PMID- 23017363 TI - Chronic maternal infections during pregnancy. PMID- 23017364 TI - Tom Gottlieb: a genuine infectious diseases all-rounder. PMID- 23017365 TI - Burden of disease associated with human cytomegalovirus and prospects for elimination by universal immunisation. AB - Cytomegalovirus is the most frequent cause of intrauterine infection and the commonest infectious agent to affect allograft recipients, yet the virus is acknowledged rarely as an occupational hazard for women of childbearing age or as a nosocomial infection. The potential role of cytomegalovirus in hastening the death of patients with AIDS, elderly people, individuals admitted to intensive care units, and the general population is not emphasised. Development of vaccines against this important human pathogen has been delayed by reluctance to initiate proof-of-concept studies, but after recent trials, protection is a distinct possibility. Cytomegalovirus deserves to be eliminated from selected populations by means of universal immunisation as soon as suitable vaccines become licensed. This action should control disease in neonates and transplant recipients and could provide substantial additional benefits if other disease associations prove to be causal. PMID- 23017366 TI - Could we miss congenital neurosyphilis? PMID- 23017367 TI - Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration. AB - During chronic kidney disease (CKD), drug metabolism is affected leading to changes in drug disposition. Furthermore, there is a progressive accumulation of uremic retention solutes due to impaired renal clearance. Here, we investigated whether uremic toxins can influence the metabolic functionality of human conditionally immortalized renal proximal tubule epithelial cells (ciPTEC) with the focus on UDP-glucuronosyltransferases (UGTs) and mitochondrial activity. Our results showed that ciPTEC express a wide variety of metabolic enzymes, including UGTs. These enzymes were functionally active as demonstrated by the glucuronidation of 7-hydroxycoumarin (7-OHC; K(m) of 12+/-2MUM and a V(max) of 76+/-3pmol/min/mg) and p-cresol (K(m) of 33+/-13MUM and a V(max) of 266+/ 25pmol/min/mg). Furthermore, a wide variety of uremic toxins, including indole-3 acetic acid, indoxyl sulfate, phenylacetic acid and kynurenic acid, reduced 7-OHC glucuronidation with more than 30% as compared with controls (p<0.05), whereas UGT1A and UGT2B protein expressions remained unaltered. In addition, our results showed that several uremic toxins inhibited mitochondrial succinate dehydrogenase (i.e. complex II) activity with more than 20% as compared with controls (p<0.05). Moreover, indole-3-acetic acid decreased the reserve capacity of the electron transport system with 18% (p<0.03). In conclusion, this study shows that multiple uremic toxins inhibit UGT activity and mitochondrial activity in ciPTEC, thereby affecting the metabolic capacity of the kidney during CKD. This may have a significant impact on drug and uremic retention solute disposition in CKD patients. PMID- 23017369 TI - Dengue outbreaks in high-income area, Kaohsiung City, Taiwan, 2003-2009. AB - Kaohsiung City, a modern metropolis of 1.5 million persons, has been the focus of dengue virus activity in Taiwan for several decades. The aim of this study was to provide a temporal and spatial description of dengue virus epidemiology in Kaohsiung City by using data for all laboratory-confirmed dengue cases during 2003-2009. We investigated age- and sex-dependent incidence rates and the spatiotemporal patterns of all cases confirmed through passive or active surveillance. Elderly persons were at particularly high risk for dengue virus related sickness and death. Of all confirmed cases, ~75% were detected through passive surveillance activities; case-patients detected through active surveillance included immediate family members, neighbors, and colleagues of confirmed case-patients. Changing patterns of case clustering could be due to the effect of unmeasured environmental and demographic factors. PMID- 23017370 TI - Identification of Babesia species infecting dogs using reverse line blot hybridization for six canine piroplasms, and evaluation of co-infection by other vector-borne pathogens. AB - Canine infection by vector-borne hemoparasites is frequent in tropical and sub tropical areas where exposure to hematophageous ectoparasites is intensive. A reverse line blot (RLB) assay was designed to improve the simultaneous detection of all named canine piroplasm species combined with other vector-borne pathogens of dogs including Ehrlichia canis, Hepatozoon canis and Leishmania infantum common in the Mediterranean basin. Blood samples of 110 dogs from Spain (n=21), Portugal (n=14) and Israel (n=75) were analyzed. The study evaluated 2 groups of dogs, 49 dogs with piroplasm infection detected by blood smear microscopy from Portugal, Spain and Israel, and 61 dogs surveyed from rural areas in Israel, for which infection status with vector-borne pathogens was unknown. Among the dogs previously diagnosed with piroplasmosis, infection with Babesia canis, Babesia vogeli, Babesia gibsoni and Theileria annae was detected in the Iberian dogs while only B. vogeli was found in Israeli dogs. These differences are attributed to the absence of tick vectors for some piroplasm species such as Dermacentor reticulatus in Israel. Eleven (79%) of the Babesia-positive dogs from Portugal were co-infected with other pathogens including L. infantum, H. canis and E. canis. Eight of 61 (13%) rural Israeli dogs were co-infected with two or more pathogens including B. vogeli, L. infantum, E. canis, and H. canis. Triple infections were demonstrated in 2 dogs. The RLB detection limit for Babesia was 50-fold lower than that of PCR. This study presents a RLB to simultaneously detect and separate the major vector-borne dog pathogens in southern Europe and the Middle East. PMID- 23017371 TI - Statins and other agents for vascular inflammation. AB - During the past 2 decades, atherosclerosis and its clinical sequelae have increasingly been recognized as an inflammatory disease. Examination of multiple circulating inflammatory biomarkers has shown that they independently predict cardiovascular risk in patients with and without overt cardiovascular disease. Among these, high-sensitivity C-reactive protein has proved to be most robust in adding to global risk prediction models. Statins, a class of drugs that reduce levels of high-sensitivity C-reactive protein and other inflammatory biomarkers, have been the most thoroughly studied anti-inflammatory agents to reduce cardiovascular risk. However, all such trials are necessarily confounded by the ability of statins to markedly reduce cholesterol, a well-known causal risk factor for adverse vascular outcomes. Nevertheless, the provocative results of several key statin trials have provided the scientific basis to test the hypothesis that reducing inflammation will improve cardiovascular outcomes with novel and specific anti-inflammatory agents. These newer drugs promise to reduce inflammatory marker levels without affecting lipids, glucose, or blood pressure. The results of these trials will provide key data to help us understand the relationship between inflammation and vascular risk. PMID- 23017368 TI - S-adenosyl-L-homocysteine hydrolase and methylation disorders: yeast as a model system. AB - S-adenosyl-L-methionine (AdoMet)-dependent methylation is central to the regulation of many biological processes: more than 50 AdoMet-dependent methyltransferases methylate a broad spectrum of cellular compounds including nucleic acids, proteins and lipids. Common to all AdoMet-dependent methyltransferase reactions is the release of the strong product inhibitor S adenosyl-L-homocysteine (AdoHcy), as a by-product of the reaction. S-adenosyl-L homocysteine hydrolase is the only eukaryotic enzyme capable of reversible AdoHcy hydrolysis to adenosine and homocysteine and, thus, relief from AdoHcy inhibition. Impaired S-adenosyl-L-homocysteine hydrolase activity in humans results in AdoHcy accumulation and severe pathological consequences. Hyperhomocysteinemia, which is characterized by elevated levels of homocysteine in blood, also exhibits a similar phenotype of AdoHcy accumulation due to the reversal of the direction of the S-adenosyl-L-homocysteine hydrolase reaction. Inhibition of S-adenosyl-L-homocysteine hydrolase is also linked to antiviral effects. In this review the advantages of yeast as an experimental system to understand pathologies associated with AdoHcy accumulation will be discussed. PMID- 23017372 TI - Characterisation of indeterminate pulmonary nodules in colorectal cancer. AB - BACKGROUND: Management of indeterminate pulmonary nodules (IPN) in colorectal cancer (CRC) is challenging, with no clear guidance for management. We aimed to study whether certain patient and disease based factors can be used to give guidance about further investigation, treatment and outcome of these lesions. METHODS: Data was collected via a 2-year retrospective case-note review of patients discussed at the multi-disciplinary meeting with a confirmed diagnosis of CRC and IPN on CT scan. Further studies were identified by a Pubmed search with no limitations and a review of references within those papers. Pooled analysis was performed where the data was available. RESULTS: Over the two year period, 539 new cases of CRC were discussed locally. Of these, 28 (5.2%) were found to have IPN. Malignancy was more likely when multiple nodules were detected at presentation (p<0.05). Pooled analysis of a further 7 studies was performed where data was available. This confirmed the significance of multiple nodules in terms of predicting malignancy (p<0.01) and additionally demonstrated the significance of nodal disease (p<0.01). CONCLUSION: This study demonstrates the difficulties of determining the nature of IPN using either patient or tumour characteristics. Significant factors appear to be the presence of multiple nodules and nodal disease. In such cases we recommend further imaging at time of detection. If absent, we recommend an interval CT scan at six months. PMID- 23017373 TI - What have we learned from six years of GWAS in autoimmune diseases, and what is next? AB - Genome-wide association studies (GWAS) have discovered hundreds of common genetic variants that predispose humans to autoimmune diseases, opening up unprecedented potential for elucidating the pathways and processes of disease. To understand the role of these variants in susceptibility, we need to derive mechanistic insight by integration of genetic results with other biological data types and also with careful functional studies. In many cases, such studies have highlighted coherent biological processes at a high level and elucidated specific mechanisms that contribute to autoimmunity and inflammation. The understanding of the genetic component of autoimmune etiology will become more complete as fine mapping and sequencing data become readily available. A comprehensive catalog of human immune phenotypes could provide a functional basis for assessing genetic influence on immune function and variation in response to therapeutic interventions, as well as for rationally designing new targeted therapeutics. PMID- 23017374 TI - Sentinel lesions in osteoarticular traumatology: signs to watch out for. AB - Sentinel lesions are lesions of the bone or soft tissue, visible in standard X rays carried out within a traumatic context, indicating bone or more severe capsular ligament lesions not visible on these X-rays. A detailed review of the peripheral joints as well as the spine is carried out with an example of each type of lesion in a standard X-ray. Confrontation with the reference examination, CT or MRI, depending on the case, is then carried out. PMID- 23017376 TI - Trypanososma brucei rhodesiense sleeping sickness, Uganda. PMID- 23017375 TI - The smartphone in medicine: a review of current and potential use among physicians and students. AB - BACKGROUND: Advancements in technology have always had major impacts in medicine. The smartphone is one of the most ubiquitous and dynamic trends in communication, in which one's mobile phone can also be used for communicating via email, performing Internet searches, and using specific applications. The smartphone is one of the fastest growing sectors in the technology industry, and its impact in medicine has already been significant. OBJECTIVE: To provide a comprehensive and up-to-date summary of the role of the smartphone in medicine by highlighting the ways in which it can enhance continuing medical education, patient care, and communication. We also examine the evidence base for this technology. METHODS: We conducted a review of all published uses of the smartphone that could be applicable to the field of medicine and medical education with the exclusion of only surgical-related uses. RESULTS: In the 60 studies that were identified, we found many uses for the smartphone in medicine; however, we also found that very few high-quality studies exist to help us understand how best to use this technology. CONCLUSIONS: While the smartphone's role in medicine and education appears promising and exciting, more high-quality studies are needed to better understand the role it will have in this field. We recommend popular smartphone applications for physicians that are lacking in evidence and discuss future studies to support their use. PMID- 23017377 TI - Regional variations in fascicle curvatures within a muscle belly change during contraction. AB - During muscle contraction, the fascicles curve in response to changes in internal pressures within the muscle. Muscle modelling studies have predicted that fascicles curve to different extents in different regions of the muscle and, as such, curvature is expected to vary along and across the muscle belly. In the present study, the local variations in fascicle curvature within the muscle belly were investigated for a range of contractile conditions. B-mode ultrasound scans of the medial and lateral gastrocnemii muscles were collected at five ankle positions-ranging from dorsiflexion to plantarflexion. An automated algorithm was applied to the images in order to extract the local curvatures from the muscle belly regions. Significant variations in fascicle curvature were seen in the superficial-to-deep direction. Curvatures were positive in the superficial layer, negative in the deep layer, and had intermediate values close to zero in the central muscle region. This is indicative of the fascicles following an S-shaped trajectory across the muscle image. The relation between external pressure and curvature regionalization was also investigated by applying elastic compression bandages on the calf. The application of pressure was associated with greater negative curvatures in the distal and central regions of the middle layer, but appeared to have little effect on the superficial and deep layers. The results from this study showed that (1) fascicle curvature increases with contraction level, (2) there is curvature regionalization within the muscle belly, (3) curvature increases with pressure, and (4) fascicles follow an S-shaped trajectory across the muscle images. PMID- 23017378 TI - Finite element modelling of nanoindentation based methods for mechanical properties of cells. AB - The viscoelastic properties of the living cells are for quantifying the biomechanical effects of drug treatment, diseases and aging. Nanoindentation techniques have proven effective to characterize the viscoelastic properties of living cells. However, most studies utilized the Hertz contact model and assumed the Heaviside step loading, which does not represent real tests. Therefore, new mathematical models have been developed to determine the viscoelastic properties of the cells for nanoindentation tests. Finite element method was used to determine the empirical correction parameter in the mathematical model to account for large deformation, in which case the combined effect of finite lateral and vertical dimensions of the cell is essential. The viscoelastic integral operator was used to account for the realistic deformation rate. The predictive model captures the mechanical responses of the cells observed from previous experimental study. This work has demonstrated that the new model consistently predicts viscoelastic properties for both ramping and stress relaxation periods, which cannot be achieved by the commonly used models. Utilization of this new model can enrich the experimental cell mechanics in interpretation of nanoindentation of cells. PMID- 23017379 TI - A new approach to determine the accuracy of morphology-elasticity relationships in continuum FE analyses of human proximal femur. AB - Continuum finite element (FE) models of bones are commonly generated based on CT scans. Element material properties in such models are usually derived from bone density values using some empirical relationships. However, many different empirical relationships have been proposed. Most of these will provide isotropic material properties but relationships that can provide a full orthotropic elastic stiffness tensor have been proposed as well. Presently it is not clear which of these relationships best describes the material behavior of bone in continuum models, nor is it clear to what extent anisotropic models can improve upon isotropic models. The best way to determine the accuracy of such relationships for continuum analyses would be by quantifying the accuracy of the calculated stress/strain distribution, but this requires an accurate reference distribution that does not depend on such empirical relationships. In the present study, we propose a novel approach to generate such a reference stress distribution. With this approach, stress results obtained from a micro-FE model of a whole bone, that can represent the bone trabecular architecture in detail, are homogenized and the homogenized stresses are then used as a reference for stress results obtained from continuum models. The goal of the present study was to demonstrate this new approach and to provide examples of comparing continuum models with anisotropic versus isotropic material properties. Continuum models that implemented isotropic and orthotropic material definitions were generated for two proximal femurs for which micro-FE results were available as well, one representing a healthy and the other an osteoporotic femur. It was found that the continuum FE stress distributions calculated for the healthy femur compared well to the homogenized results of the micro-FE although slightly better for the orthotropic model (r=0.83) than for the isotropic model (r=0.79). For the osteoporotic bone also, the orthotropic model did better (r=0.83) than the isotropic model (r=0.77). We propose that this approach will enable a more relevant and accurate validation of different material models than experimental methods used so far. PMID- 23017380 TI - Intravital microscopy at the single vessel level brings new insights of vascular modification mechanisms induced by electropermeabilization. AB - Electroporation/electropermeabilization, i.e. the result of the application of electric pulses to tissues, is a physical method for delivery of exogenous molecules into cells. It is effective particularly for compounds with limited transmembrane transport. In vivo, electropermeabilization facilitates the delivery of chemotherapeutic drugs into tumor cells that is the basic mechanism of the antitumor effectiveness of electrochemotherapy. This therapy has also blood flow modifying effects in tissues. The aim of our present study was to understand and explain the effects of electropermeabilization on the dynamics (vasomotricity, permeability and recovery) of subcutaneous blood vessels towards different size of molecules. These features were measured in C57Bl/6 mice via a dorsal skin fold window chamber, using fluorescently labeled dextrans of different sizes, intravital fluorescence microscopy imaging and specific image analysis. Application of electric pulses on the skin in vivo resulted in a rapid increase in vascular permeability that gradually recovered to basal levels at different times post-treatment, depending on dextran size. Simultaneously, the immediate constriction of the blood vessels occurred that was more pronounced for arterioles compared to venules. This vasoconstriction of arterioles results in a transient "vascular lock". The increased permeability of small vessels walls whatever the dextran size associated with delayed perfusion explains the improved delivery of the intravenous injected molecules (i.e. drugs, gene delivery) into the tissues induced by electropermeabilization in vivo. PMID- 23017381 TI - Nontuberculous Mycobacteria in household plumbing as possible cause of chronic rhinosinusitis. AB - Symptoms of chronic rhinosinusitis (CRS) often persist despite treatment. Because nontuberculous mycobacteria (NTM) are resistant to commonly used antimicrobial drugs and are found in drinking water that patients may use for sinus irrigation, we investigated whether some CRS patients were infected with NTM in New York, New York, USA, during 2001-2011. Two approaches were chosen: 1) records of NTM infected CRS patients were reviewed to identify common features of infection and Mycobacterium species; 2) samples from plumbing in households of 8 NTM-infected patients were cultured for NTM presence. In 3 households sampled, M. avium sharing rep-PCR and pulsed field gel electrophoresis fingerprints identified M. avium isolates clonally related to the patients' isolates. We conclude that patients with treatment-resistant CRS may be infected with NTM and should have cultures performed for NTM so appropriate therapy can be instituted. In addition, the results suggest that CRS patients can be infected by NTM in their household plumbing. PMID- 23017382 TI - Impact of the suspending medium on susceptibility of meticillin-resistant Staphylococcus aureus to hydrogen peroxide vapour decontamination. AB - Several factors influence the in vitro susceptibility of microbes to disinfectants. We evaluated the impact of various suspending media on the susceptibility of meticillin-resistant Staphylococcus aureus (MRSA) to hydrogen peroxide vapour (HPV) decontamination. From a >6 log(10) inoculum, relative susceptibility was 10% bovine serum albumin (BSA) < TSB < 3% BSA < saline < 0.3% BSA = water. MRSA was not recovered after >60 min exposure to HPV for all suspensions. These findings indicate that the suspending medium has an effect on the in vitro susceptibility of MRSA to HPV, which may have implications in the case of suboptimal cleaning. PMID- 23017383 TI - Reply to Destrez: efficacy, efficiency and safety aspects of hydrogen peroxide vapour and aerosolized hydrogen peroxide room disinfection systems. PMID- 23017384 TI - Impact of the Ottawa Influenza Decision Aid on healthcare personnel's influenza immunization decision: a randomized trial. AB - BACKGROUND: Influenza immunization for healthcare personnel reduces frequency and severity of nosocomial influenza outbreaks and influenza-associated morbidity and mortality among patients. The Ottawa Influenza Decision Aid (OIDA) was developed to assist undecided healthcare workers in deciding whether or not to be immunized. AIM: To assess the impact of the OIDA, and to ascertain whether its use would increase the level of confidence in healthcare workers' influenza immunization decision and positively affect their intent to be immunized. METHODS: Single-centre, single-blind, parallel-group, randomized controlled trial. FINDINGS: Eight per cent (151 of 1886) of the unimmunized healthcare personnel were randomized. Of 107 eligible respondents, 48 were in the Ottawa Influenza Decision Aid (OIDA) group and 59 in the control group. A statistically significant (P = 0.020) greater improvement in confidence in immunization decision was observed in the OIDA group compared with the control group. Whereas the odds of changing intent to be immunized from 'no/unsure' to 'yes' was 2.4 times greater in the OIDA group, this result did not reach statistical significance after adjusting for intent to be immunized at baseline. The post OIDA intent to be immunized in the OIDA and control groups compared to the pre OIDA intent to be immunized showed that the OIDA had a significant effect on reducing uncertainty (P = 0.035). CONCLUSIONS: Using an accessible, balanced, understandable format for all healthcare personnel about their influenza immunization decision appears to have an impact on both healthcare personnel's confidence in their immunization decision and in their intent to be immunized. PMID- 23017385 TI - Phenolic profiles of cultivated, in vitro cultured and commercial samples of Melissa officinalis L. infusions. AB - Melissa officinalis L. (lemon balm) is normally consumed as an infusion and presents therapeutic properties, such as sedative, carminative and antispasmodic, also being included in some pharmaceutical preparations. The phenolic profiles of different samples of lemon balm, prepared as infusions, were evaluated by HPLC DAD-ESI/MS. The profiles were compared in order to understand the differences between cultivated, in vitro cultured and commercial (bags and granulated) samples. All the samples showed a similar phenolic profile, presenting differences only in the quantities found of each compound. Rosmarinic acid was the most abundant compound, being higher in commercial samples, especially in tea bag sample (55.68mg/g of infusion) and lower in in vitro cultured sample (15.46mg/g). Moreover, dimers, trimers and tetramers of caffeic acid were identified and quantified for the first time in lemon balm. Only one flavonoid, luteolin-3'-O-glucuronide was found in all the samples, ranging from 8.43mg/g in commercial granulate sample to 1.22mg/g in in vitro cultured sample. Overall, cultivated and in vitro cultured samples presented the lowest amounts of phenolic compounds (59.59 and 30.21mg/g, respectively); otherwise, commercial samples showed the highest contents (109.24mg/g for tea bag and 101.03mg/g for granulate sample). The present study shows that infusion of lemon balm can be a source of phenolic compounds, known for their bioactive effects. PMID- 23017386 TI - Cytoprotective and pro-apoptotic activities of native Australian herbs polyphenolic-rich extracts. AB - Three commercially grown native herbs unique to Australia, Tasmannia pepper leaf (Tasmannia lanceolata R. Br., Winteracea; TPL), anise myrtle (Syzygium anisatum Vickery, Craven & Biffen, Myrtaceae; AM) and lemon myrtle (Backhousia citriodora F. Muell, Myrtaceae; LM) as well as a reference sample bay leaf (Laurus nobilis L., Lauraceae; BL) were examined for potential cytoprotective properties. All native herbs exhibited greater cellular antioxidant activity as measured by the cellular antioxidant activity (CAA) assay than bay leaf and reduced the hydrogen peroxide (H(2)O(2)) induced death of hepatocellular carcinoma (HepG2) cells by 25 50%. All herb extracts reduced the proliferation of colon (HT-29; IC(50)=0.75 1.39mg/ml), stomach (AGS; IC(50)=0.59-1.88mg/ml), bladder (BL13; IC(50)=0.56 1.12mg/ml) and liver (HepG2; IC(50)=0.38-1.36mg/ml) cancer cells. No significant reduction of cell viability of non-transformed colon (CCD-18Co; IC(50)>2.0mg/ml) and mixed stomach and intestine (Hs 738.St/Int; IC(50)>2.0mg/ml) cells was observed. Flow cytometry analysis and the results of the cytokinesis block micronucleus cytome (CBMNCyt) assay conducted with respectively, promyelocytic leukaemia (HL-60) and colon adenocarcinoma (HT-29) cells suggest an increase in apoptosis following treatment with the herb extracts. The occurrence of apoptotic cells coincided with an increase in caspase-3 enzyme activity. The results of the CBMNCyt assay suggested no direct DNA damage in colon adenocarcinoma (HT-29) cells as a result of treatment with all extracts, applied at final concentrations of 0.5 and 1.0mg/ml. PMID- 23017387 TI - Cellular assessment of the extract of bambangan (Mangifera pajang) as a potential cytoprotective agent for the human hepatocellular HepG2 cell line. AB - This study was conducted to investigate the potential of bambangan (Mangifera pajang) fruit extracts in the protection against oxidative damage caused by tert butyl hydroperoxide in the human hepatocellular HepG2 cell line. Proteins which might be involved in the cytoprotective mechanism were investigated using western blotting technique. Quercetin was used as a positive control. The results showed that only the kernel extract of M. pajang and quercetin displayed cytoprotective activity in HepG2 cells, with EC(50) values of 1.2 and 5.3MUg/ml, respectively. Expression of quinone reductase, glutathione reductase and methionine sulfoxide reductase A proteins were significantly up-regulated by quercetin, suggesting their involvement in the cytoprotective activity of quercetin. However, expressions of only glutathione reductase and methionine sulfoxide reductase A proteins were significantly up-regulated by the kernel extract, again suggesting their involvement in the cytoprotective activity of bambangan kernel extract. Future study is needed to investigate the involvement of other cytoprotective proteins in the cytoprotection mechanism. PMID- 23017388 TI - SB365, Pulsatilla saponin D suppresses the proliferation of human colon cancer cells and induces apoptosis by modulating the AKT/mTOR signalling pathway. AB - Pulsatilla koreana has been used as a traditional medicine for the treatment of several diseases. The purpose of this study was to determine if SB365, Pulsatilla saponin D isolated from the root of P. koreana inhibits the progression of colon cancer. We found that SB365 strongly suppressed the growth and proliferation of colon cancer cells and induced their apoptosis. Also, SB365 showed anti angiogenic activity by decreasing the expression of HIF-1alpha and VEGF. These results were confirmed by an in vivo study showing that SB365 significantly inhibited tumor growth by the induction of apoptosis and inhibition of angiogenesis with stronger anticancer activity than 5-FU. When further examined for its anticancer mechanism, SB365 effectively suppressed the AKT/mTOR pathway both in vitro and in vivo. Taken together, our study demonstrated that SB365 inhibits the AKT/mTOR pathway, leading to the suppression of tumor growth and angiogenesis together with induction of apoptosis. Therefore, SB365 is a good candidate as a natural product for use in the treatment of colon cancer. PMID- 23017389 TI - Studies on the antioxidant potential of flavones of Allium vineale isolated from its water-soluble fraction. AB - The aim of this work was to examine the chemical constituents and antioxidant potential of water-soluble fractions from the commonly consumed vegetable, Allium vineale. The water-soluble fraction, containing phenolic compounds, was extracted with ethyl acetate to obtain flavonoids which were separated and purified by repeated column chromatography over Sephadex LH-20, RP C18 and silica gel. The isolated compounds were identified according to their physicochemical properties and spectral data (UV, HPLC-TOF/MS, (1)H NMR, (13)C NMR and 2D NMR). Three flavonoids were isolated and identified as chrysoeriol-7-O-[2"-O-E-feruloyl]-beta d-glucoside (1), chrysoeriol (2), and isorhamnetin-3-beta-d-glucoside (3). Antioxidant studies of the aqueous extract and three isolated compounds, 1, 2, 3, were undertaken and they were found to have significant antioxidant activity. Antioxidant activities were evaluated for total antioxidant activity by the ferric thiocyanate method, ferric ion (Fe(3+)) reducing antioxidant power assay (FRAP), ferrous ion (Fe(2+)) metal chelating activity, and DPPH free radical scavenging activity. The water-soluble ethyl acetate and methanol extraction methods were also compared using HPLC-TOF/MS. PMID- 23017390 TI - Phenolics profiles of olive fruits (Olea europaea L.) and oils from Ayvalik, Domat and Gemlik varieties at different ripening stages. AB - Phenolic compounds in olive fruit and oils obtained from Ayvalik, Domat and Gemlik olive varieties collected at different ripening periods were evaluated by High Performance Liquid Chromatography (HPLC). Gallic acid and p-cumaric acid were identified for Ayvalik and Domat at each period of ripening, respectively. In addition, gallic acid, p-cumaric acid, sinapinic and apigenin acids were detected in Gemlik olive fruit. Hydroxytyrosol, rutin, oleoropein, luteolin, tyrosol, vanilic acid and gallic acid in Ayvalik olive fruit in all ripening periods were determined. The tyrasol contents varied between 0.18 to 1.57mg/kg. Luteolin contents of olive oils ranged at the levels between 0.12 to 2.28mg/kg. In contrast, oils had the lowest syringic, p-cumaric, chlorogenic and ferulic acids. Vanillic acid contents of oils ranged between 0.08 to 2.38mg/kg. PMID- 23017391 TI - Stability of bioactive polyphenols from honey during different extraction methods. AB - The LC-MS/MS technique was applied to the stability study of several flavonoids and phenolic acids in honey samples during the ultrasonic extraction (USE) and microwave-assisted extraction (MAE). Phenolic compounds from the standard mixture were stable under ultrasounds action with the mean recovery of (90.4%+/-7.1%), but during microwave-assisted extraction the benzoic acid derivatives and aglycones of flavonoids showed lower recovery (70-80%). In honey matrix, the phenolic acids and the glycosides exhibited the high stability for MAE and USE treatments. However, the recoveries of tested aglycones were below 10%. In the presence of an artificial sugar matrix, flavonols were almost completely degraded after successive treatment under MAE and USE conditions. The obtained results indicated that standard addition method for flavonoids quantification in honey samples should not be recommended. Application of the USE conditions provided higher and/or similar extraction yields for phenolic acids than usually applied shaking with solvent. It also allowed shortening the time required for the whole sample preparation procedure. Phenolic acids and glycosides such as quercetrin, rutin and hesperidin appeared to be stable under such conditions. PMID- 23017392 TI - Optimization of frozen sour cherries vacuum drying process. AB - The objective of this research was to optimize the vacuum-drying of frozen sour cherries in order to preserve health-beneficial phytochemicals, as well as textural characteristics. Investigated range of temperature was 46-74 degrees C and, of pressure, 17-583mbar, in a new design of vacuum-dryer equipment. The total solids, a(w) value, total phenolics, vitamin C, antioxidant activity, anthocyanin content, total colour change and firmness were used as quality indicators of dried sour cherry. Within the experimental range of studied variables, the optimum conditions of 54.03 degrees C and 148.16mbar were established for vacuum drying of sour cherry. Separate validation experiments were conducted, under optimum conditions, to verify predictions and adequacy of the second-order polynomial models. Under these optimal conditions, the predicted amount of total phenolics was 744mg CAE/100 dw, vitamin C 1.44mg/100g per dry weight (g dw), anthocyanin content 125mg/100g dw, IC(50) 3.23mg/ml, total solids 70.72%, a(w) value 0.646, total colour change 52.61 and firmness 3395.4g. The investigated parameters had a significant effect on the quality of the dried sour cherries. PMID- 23017393 TI - Proteomic evaluation of myofibrillar carbonylation in chilled fish mince and its inhibition by catechin. AB - The present study investigates the susceptibility of individual myofibrillar proteins from mackerel (Scomber scombrus) mince to undergo carbonylation reactions during chilled storage, and the antioxidant capacity of (+)-catechin to prevent oxidative processes of proteins. The carbonylation of each particular protein was quantified by combining the labelling of protein carbonyls by fluorescein-5-thiosemicarbazide (FTSC) with 1-D or 2-D gel electrophoresis. Alpha skeletal actin, glycogen phosphorylase, unnamed protein product (UNP) similar to enolase, pyruvate kinase, isoforms of creatine kinase, aldolase A and an isoform of glyceraldehyde 3-phosphate dehydrogenase (G3PDH) showed elevated oxidation in chilled non-supplemented mince. Myosin heavy chain (MHC) was not carbonylated in chilled muscle, but an extensive MHC degradation was observed in those samples. The supplementation of catechin reduced protein oxidation and lipid oxidation in a concentration-dependent manner: control>25>100~200ppm. Therefore, the highest catechin concentrations (100 and 200ppm) exhibited the strongest antioxidant activity. Catechin (200ppm) reduced significantly carbonylation of protein spots identified as glycogen phosphorylase, pyruvate kinase muscle isozyme, isoforms of creatine kinase. Conversely, catechin was ineffective to inhibit the oxidation of actin and UNP similar to enolase. These results draw attention to the inefficiency of catechin to prevent actin oxidation, in contrast to the extremely high efficiency of catechin in inhibiting oxidation of lipids and other proteins. PMID- 23017394 TI - A novel one-step microbial transformation of betulin to betulinic acid catalysed by Cunninghamella blakesleeana. AB - Betulinic acid and its derivatives are potential bioactive compounds present in nature. This study investigated the biotransformation of betulin to betulinic acid by Cunninghamella blakesleeana cells. LC-MS analysis demonstrated that betulin could be transformed into at least five products from cultured C. blakesleeana cells, among which betulinic acid was the most important. The presented method provides an attractive alternative approach to chemical synthesis, because is less time-consuming and more environmentally friendly. C. blakesleeana can transform betulin into potent derivatives with high pharmacological activities. PMID- 23017395 TI - Bioefficacy of EPA-DHA from lipids recovered from fish processing wastes through biotechnological approaches. AB - The effect of fish oil recovered from fish visceral waste (FVW-FO) on serum and liver lipids, activity of HMG-CoA reductase in liver microsomes and EPA+DHA incorporation in liver, heart and brain were evaluated. Rats were fed different concentrations of FVW-FO providing 1.25%, 2.50%, 5.0% EPA+DHA recovered by either fermentation or enzymatic hydrolysis for 8weeks. Feeding FVW-FO reduce triacylglycerols (5.96-20.3%), total cholesterol (7.9-21.5%) and LDL (7.39-21.7%) cholesterol levels in serum compared to group fed on a control diet (groundnut oil). The activity of HMG-CoA reductase was reduced (p<0.05) in the FVW-FO fed groups compared to the control. EPA+DHA level in serum, liver, brain and heart increased with increments in dietary EPA+DHA. Results show the hypolipidemic property of FVW-FO and reduced HMG-CoA reductase activity which is proportional to the incorporation of EPA+DHA. Recovery of FVW-FO will address the increasing demand for fish oil and reduce pollution problems. PMID- 23017396 TI - Content of zinc, iron and their absorption inhibitors in Nicaraguan common beans (Phaseolus vulgaris L.). AB - Common bean (Phaseolus vulgaris L.), the staple crop of Nicaragua, provides protein and nonhaem iron, but inhibitors such as phytate may prevent absorption of iron and zinc by the consumer. Warehouses in Nicaragua do not have controlled atmospheres, so beans are exposed to high temperatures and humidities that may accelerate quality loss. To evaluate the impact of 6months of storage on quality, four national accessions of common bean were submitted to two treatments, a conventional warehouse with uncontrolled temperature and humidity, and accelerated ageing at 40 degrees C and 75% RH. Iron content was 61-81mg/kg of which 3-4% was bioavailable, and zinc content was 21-25mg/kg, of which 10-12% was bioavailable. Bioavailability generally increased in storage, significantly so in year-old INTA Linea 628 in accelerated ageing. The concentration of phytate was 8.6-9.6mg/g and it contained 54-63% of the total phosphorus. Improvement in bioavailability of divalent cations is needed. PMID- 23017397 TI - C-dideoxyhexosyl flavones from the stems and leaves of Passiflora edulis Sims. AB - The stems and leaves of Passiflora edulis Sims, are used as a folk medicine for treating both anxiety and nervousness in American countries. Phytochemical investigation of the n-butanol (n-BuOH) fraction of this plant led to the isolation of four new 2,6-dideoxyhexose-C-glycosyl flavones, including luteolin-8 C-beta-digitoxopyranosyl-4'-O-beta-d-glucopyranoside (1), apigenin-8-C-beta digitoxopyranoside (2), apigenin-8-C-beta-boivinopyranoside (3) and luteolin-8-C beta-boivinopyranoside (4), together with five known compounds (5-9). The structures of these compounds were elucidated by extensive spectroscopic methods. All compounds were evaluated for their neurite outgrowth enhancing activities and the results indicated that luteolin (7) enhanced NGF-induced neurite outgrowth in PC12 cells at 50.0MUM. PMID- 23017398 TI - Occurrence of ochratoxin A in cocoa by-products and determination of its reduction during chocolate manufacture. AB - This work reports an investigation carried out to assess the natural occurrence of ochratoxin A in 168 samples from different fractions obtained during the technological processing of cocoa (shell, nibs, liquor, butter, cake and cocoa powder) and the reduction of ochratoxin A during chocolate manufacture. Ochratoxin A analyses were performed with immunoaffinity columns and detection by high performance liquid chromatography. Concerning the natural ochratoxin A contamination in cocoa by-products, the highest levels of ochratoxin A were found in the shell, cocoa powder and cocoa cake. The cocoa butter was the least contaminated, showing that ochratoxin A seems to remain in the defatted cocoa solids. Under the technological conditions applied during the manufacture of chocolate in this study and the level of contamination present in the cocoa beans, this experiment demonstrated that 93.6% of ochratoxin A present in the beans was reduced during the chocolate producing. PMID- 23017399 TI - Can the dietary element content of virgin argan oils really be used for adulteration detection? AB - Levels of eight dietary elements were assessed by ICP-AES in virgin edible and beauty argan oil samples prepared from four remote locations of the argan forest, and over a three-year period. The data showed sufficiently little variability to assess that all argan oil samples present, in terms of dietary elements, a similar composition, independently from the tree location within the argan forest. Therefore, adulteration detection by trace element analysis in edible and beauty argan oil is a method that can be generalised. PMID- 23017400 TI - Quality and antioxidant properties of a reduced-sugar pomegranate juice jelly with an aqueous extract of pomegranate peels. AB - In the present study, the production of a reduced-sugar pomegranate juice jelly supplemented with an aqueous extract of pomegranate peel (PE) is described. Influence of different carbohydrate polymers (guar (G), xanthan (X) and tragacanth (T) gums) on rheological properties was studied. Combination GXT presented the most similar rheological behaviour to commercial jelly. Jelly (J) and jelly with PE (JE) were stored at 4 degrees C over an 8week period for physical, chemical, antioxidant, microbiological and sensory analysis. J and JE showed similar values for degrees Brix, colour and Aw, though the pH of JE was lower than J. Thiol and phenolic compounds were higher in JE than in J. Antioxidant activity (radical scavenging activity and autoxidation of linoleic acid) was higher in JE than in J at 0weeks, and were decreasing with time. Pomegranate juice with additives was generally less accepted than J and JE. PMID- 23017401 TI - Genistein and dicarboximide fungicides in infant formulae from the EU market. AB - A method based on ultrasonic extraction and purification by solid phase extraction followed by LC-MS/MS and GC-MS analysis was developed for the determination of genistein, genistin, iprodione, vinclozolin and procymidone in infant powdered formulas. The method was tested for different formulations: milk, soy and hypoallergenic, and was applied to European pooled samples. Spike recoveries ranged from 53.1% to 91.5% and the relative standard deviation values for repeatability ranged from 9.6% to 17.7%, except for iprodione in milk formula (22.3%). None of the fungicides were found in the European pooled formulae, while genistein was found at 9.7MUg/g in soy formula and the concentration of genistin, its beta-glycosylated form, was respectively 31.4ng/g and 476ng/g in milk and soy formula. PMID- 23017402 TI - Phytochemical profile of Rosmarinus officinalis and Salvia officinalis extracts and correlation to their antioxidant and anti-proliferative activity. AB - The goal of this study was to monitor the anti-proliferative activity of Rosmarinus officinalis and Salvia officinalis extracts against cancer cells and to correlate this activity with their phytochemical profiles using liquid chromatography/diode array detection/electrospray ion trap tandem mass spectrometry (LC/DAD/ESI-MS(n)). For the quantitative estimation of triterpenic acids in the crude extracts an NMR based methodology was used and compared with the HPLC measurements, both applied for the first time, for the case of betulinic acid. Both extracts exerted cytotoxic activity through dose-dependent impairment of viability and mitochondrial activity of rat insulinoma m5F (RINm5F) cells. Decrease of RINm5F viability was mediated by nitric oxide (NO)-induced apoptosis. Importantly, these extracts potentiated NO and TNF-alpha release from macrophages therefore enhancing their cytocidal action. The rosemary extract developed more pronounced antioxidant, cytotoxic and immunomodifying activities, probably due to the presence of betulinic acid and a higher concentration of carnosic acid in its phytochemical profile. PMID- 23017403 TI - Molecular structure of large-scale extracted beta-glucan from barley and oat: Identification of a significantly changed block structure in a high beta-glucan barley mutant. AB - Health effects of beta-glucan are typically related to dose, size and viscosity without taking the specific molecular structure into account. High beta-glucan mutant barley, mother barley and oat beta-glucans were large-scale extracted by comparable protocols using hot water, enzyme assisted hydrolysis and ethanol precipitation leading to similar molecular masses (200-300kDa). Multivariate data analysis on all compositional, structural and functional features demonstrated that the main variance among the samples was primarily explained by block structural differences as determined by HPSEC-PAD. In particular the barley high beta-glucan mutant proved to exhibit a unique block structure with DP3 and DP4 contributions of: 78.9% and 16.7% as compared to the barley mother (72.1% and 21.4%) and oat (66.1% and 29.1%). This unique block structure was further confirmed by the (1)H NMR determination of the beta-1,4 to beta-1,3 linkage ratio. Low solubility of the barley samples was potentially an effect of substructures consisting of longer repetitive cellotriosyl sequences. FT-Raman and NMR spectroscopy were useful in measuring sample impurities of alpha-glucans and prediction of beta-linkage characteristics. PMID- 23017404 TI - Sugar metabolism in relation to chilling tolerance of loquat fruit. AB - The relationship between chilling injury and sugar metabolism was investigated in loquat fruit stored at 1 degrees C for 35days. No symptoms of chilling injury occurred in the fruit, of 'Ninghaibai' cultivar, during the whole storage whereas, in 'Dahongpao' fruit, severe chilling symptoms were observed after 20days of storage at 1 degrees C. 'Ninghaibai' fruit had higher levels of glucose and fructose and higher activities of sucrose hydrolyzing enzymes, such as sucrose synthase-cleavage and invertase, than had 'Dahongpao'. Furthermore, the chilling resistant 'Ninghaibai' fruit also showed higher activities of hexokinase and fructokinase, involved in hexose phoshorylation and sugar signal generation. These results suggest that the higher content of hexoses and activities of hexose sensors were likely part of the mechanism for chilling tolerance of loquat fruit. PMID- 23017405 TI - Transglutaminase cross-linking effect on sensory characteristics and antioxidant activities of Maillard reaction products from soybean protein hydrolysates. AB - To improve the yield of Maillard peptides, a microbial transglutaminase (MTGase) was used to increase the content of 1000-5000Da peptides in soybean protein hydrolysates by using a cross-linking reaction. The sensory characteristics and antioxidant activities of corresponding Maillard Reaction Products (MSPC) was then evaluated. After cross-linking treatment the content of 1000-5000Da peptides in protein hydrolysates and the yield of Maillard peptides increased by 21.19% and 8.71%, respectively, which contributed to the improved mouthfulness of MSPC. The bitter amino acids were significantly decreased and the umami acids were markedly increased in MSPC. Volatile compounds identified by GC-MS analysis showed that the content of the important meaty flavour compounds (such as 2 methyl-3-furanthiol, bis(2-methyl-3-furyl)disulfide) of MSPC were dramatically higher than that of MRPs from uncross-linking peptides. Combined with sensory evaluation, it was confirmed that MTGase cross-linking improved the flavour Characteristics and did not affect the antioxidant activity of MSPC. PMID- 23017406 TI - GABA shunt and polyamine degradation pathway on gamma-aminobutyric acid accumulation in germinating fava bean (Vicia faba L.) under hypoxia. AB - GABA shunt and polyamine degradation pathway on gamma-aminobutyric acid (GABA) accumulation in germinating fava bean under hypoxia was investigated. GABA content, GAD and DAO activity were significantly increased under hypoxia treatment. Glu and polyamine contents enhanced largely and thus supplied as sufficient substrates for GABA formation. In contrast, GABA content decreased, mainly in the embryo, after removing the hypoxia stress. DAO activity, Glu and polyamines contents decreased, while an increment of GAD activity was observed. This indicated that GAD activity can be not only regulated by hypoxia, but by the rapid growth of embryo after the recovery from hypoxia stress. When treated with AG, DAO activity was almost inhibited completely, and the GABA content decreased by 32.96% and 32.07% after treated for 3 and 5 days, respectively. Hence, it can be inferred that about 30% of GABA formed in germinating fava bean under hypoxia was supplied by polyamine degradation pathway. PMID- 23017407 TI - Green and gold kiwifruit peel ethanol extracts potentiate pentobarbital-induced sleep in mice via a GABAergic mechanism. AB - Kiwifruit is one of the most popular fruits worldwide, and it has various biological properties, including antioxidant, anti-allergic, and cardiovascular protective effects. The peel of kiwifruit, which is a by-product of processing, is a good source of flavonoids; however, its bioactivity has not been widely investigated. In this study, we evaluated the hypnotic effects of green (GRPE, Actinidia deliciosa) and gold (GOPE, Actinidia chinensis) kiwifruit peel ethanol extracts and their solvent fractions, and the possible underlying mechanisms. Oral GRPE and GOPE administration (125-1000mg/kg) produced a dose-dependent decrease in sleep latency and an increase in sleep duration in pentobarbital treated mice. Among three different solvent fractions of GRPE and GOPE, ethyl acetate (EA) fractions had the greatest effect on sleep duration at 250mg/kg. The total flavonoid contents of solvent fractions were proportional to sleep duration. Like diazepam (a GABA(A)-benzodiazepine (BZD) receptor agonist), the hypnotic effects of GRPE, GOPE, and their EA fractions were fully inhibited by flumazenil (a GABA(A)-BZD receptor antagonist). These results suggest that potentiation effects of GRPE and GOPE on pentobarbital-induced sleep in mice may be modulated by a GABAergic mechanism. PMID- 23017408 TI - Phenylalanine ammonia lyase (PAL) enzyme activity and antioxidant properties of some cyanobacteria isolates. AB - In the present study, six cyanobacteria isolates were evaluated for the PAL enzyme activity, and their methanol extracts were assessed for the total phenolic amount and other antioxidant parameters. Synechocystis sp. BASO444 and Synechocystis sp. BASO673 isolates with high levels of total phenols (66.0+/ 1.2MUg/mg, 78.1+/-1.8MUg/mg, respectively) also showed high levels of PAL activities (20.5+/-3.1U/mg protein, 17.2+/-2.3U/mg protein, respectively) and strong antioxidant activities. To understand the effect of l-phenylalanine (l phe) on the PAL activity, total phenolic amount, and phenolic constituents, isolates were evaluated with 100mg/l l-phe. While PAL activities exhibited no significant change with l-phe addition, total phenolic amount of the isolates significantly increased. HPLC analysis revealed gallic acid, trans-cinnamic acid, p-coumaric acid, and ferulic acid as the main compounds. Results suggested that the two isolate mights be an important source for the l-phe inducible phenolic compounds. PMID- 23017409 TI - Ginger extract and zingerone ameliorated trinitrobenzene sulphonic acid-induced colitis in mice via modulation of nuclear factor-kappaB activity and interleukin 1beta signalling pathway. AB - Ginger is a commonly used spice with anti-inflammatory potential. Colitis is the common pathological lesion of inflammatory bowel diseases. In this study, we investigated the therapeutic effects of ginger and its component zingerone in mice with 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis. Ginger and zingerone ameliorated TNBS-induced colonic injury in a dose-dependent manner. Pathway analysis of ginger- and zingerone-regulated gene expression profiles showed that ginger and zingerone significantly regulated cytokine-related pathways. Network analysis showed that nuclear factor-kappaB (NF-kappaB) and interleukin-1beta (IL-1beta) were key molecules involved in the expression of ginger- and zingerone-affected genes. Ex vivo imaging and immunohistochemical staining further verified that ginger and zingerone suppressed TNBS-induced NF kappaB activation and IL-1beta protein level in the colon. In conclusion, ginger improved TNBS-induced colitis via modulation of NF-kappaB activity and IL-1beta signalling pathway. Moreover, zingerone might be the active component of ginger responsible for the amelioration of colitis induced by TNBS. PMID- 23017410 TI - Citrus phenylpropanoids and defence against pathogens. Part I: metabolic profiling in elicited fruits. AB - Penicillium spp. are among the major postharvest pathogens of citrus fruit. Induction of natural resistance in fruits constitutes one of the alternatives to chemical fungicides. Here, we investigated the involvement of the phenylpropanoid pathway in the induction of resistance in Navelate oranges by examining changes in the metabolic profile of upon eliciting citrus fruits. By using both HPLC-PDA FD and HPLC-PDA-QTOF-MS allowed the identification of several compounds that seem to be relevant for induced resistance. In elicited fruits, a greater diversity of phenolic compounds was observed in the flavedo (outer coloured part of the peel) when compared to the albedo (inner white part). Moreover, only small changes were detected in the most abundant citrus flavonoids. The coumarin scoparone was among the compounds with the highest induction upon elicitation. Two other highly induced compounds were identified as citrusnin A and drupanin aldehyde. All three compounds are known to exert antimicrobial activity. Our results suggest that phenylpropanoids and their derivatives play an important role in the induction of resistance in citrus fruit. PMID- 23017411 TI - An investigation into the supramolecular structure, solubility, stability and antioxidant activity of rutin/cyclodextrin inclusion complex. AB - The formation of supramolecular inclusion complexes between rutin and four cyclodextrins, namely beta-cyclodextrin (beta-CD), (2-hydroxypropyl)-alpha cyclodextrin (HP-alpha-CD), (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CD) and (2-hydroxypropyl)-gamma-cyclodextrin (HP-gamma-CD), and the effects of the complexation on the stability and antioxidant activity of rutin were investigated. Results from phase-solubility studies showed that rutin formed 1:1 stoichiometric inclusion complexes with HP-alpha-CD, beta-CD, HP-beta-CD and HP gamma-CD; the complexes formed with HP-gamma-CD and HP-beta-CD had the greatest stability constants, followed by beta-CD and HP-alpha-CD. Thermodynamic studies demonstrate that the inclusion of rutin into HP-beta-CD was an exothermic process which occurred spontaneously. Two-dimensional rotating-frame nuclear Overhauser effect spectroscopy (2D ROESY) (1)H NMR analyses show that the A ring of rutin was the part of the molecule that most likely inserted into the cavity of HP-beta CD, thus forming a supramolecular inclusion complex. Formation of such an inclusion complex conferred moderate degrees of protection to rutin from degradation by heat and UV radiation during storage, and significantly enhanced its antioxidant capacity as determined by three different procedures. PMID- 23017412 TI - Contamination of commercial cane sugars by some organic acids and some inorganic anions. AB - The aim of the paper was the identification and the quantitative evaluation of the following inorganic anions: chloride, phosphate, nitrate, nitrite, sulphate and the following organic acids: lactic, acetic, formic, malic and citric in commercial "unrefined" brown cane sugars and in cane raw sugars. The determination was carried out by high performance anion exchange chromatography with conductivity detector HPAEC-CD. The conducted analyses have shown that the content of some inorganic anions and organic acids in cane sugars may be an important criterion of the quality of commercial "unrefined" brown cane sugars. PMID- 23017413 TI - Metabolite profiling of phenolic and carotenoid contents in tomatoes after moderate-intensity pulsed electric field treatments. AB - A metabolite profiling approach was used to study the effect of moderate intensity pulsed electric field (MIPEF) treatments on the individual polyphenol and carotenoid contents of tomato fruit after refrigeration at 4 degrees C for 24h. The MIPEF processing variables studied were electric field strength (from 0.4 to 2.0kV/cm) and number of pulses (from 5 to 30). Twenty four hours after MIPEF treatments, an increase was observed in hydroxycinnamic acids and flavanones, whereas flavonols, coumaric and ferulic acid-O-glucoside were not affected. Major changes were also observed for carotenoids, except for the 5-cis lycopene isomer, which remain unchanged after 24h of MIPEF treatments. MIPEF treatments, conducted at 1.2kV/cm and 30 pulses, led to the greatest increases in chlorogenic (152%), caffeic acid-O-glucoside (170%) and caffeic (140%) acids. On the other hand, treatments at 1.2kV/cm and 5 pulses led to maximum increases of alpha-carotene, 9- and 13-cis-lycopene, which increased by 93%, 94% and 140%, respectively. Therefore, MIPEF could stimulate synthesis of secondary metabolites and contribute to production of tomatoes with high individual polyphenol and carotenoid contents. PMID- 23017414 TI - Soymilk phenolic compounds, isoflavones and antioxidant activity as affected by in vitro gastrointestinal digestion. AB - The aim of this research was to evaluate changes in the phenolic compounds, isoflavones and antioxidant activity of soymilk following in vitro gastrointestinal digestion (including dialysis). Gastric digestion significantly influenced the release of bioactive substances from the soymilk matrix, increasing the concentration of total phenolic components (35% as the sum of individuals and 14% by Folin-Ciocalteu [F-C] method), total isoflavone content (22%) and total antioxidant activity (76%). The concentration of all those compounds was reduced significantly in the duodenal fraction in comparison to gastric digestion and their lowest concentration was observed in the dialysed fraction, where phenolic acids were not detected. The bioaccessibility of soymilk phenolic compounds was 15% as the sum of individuals and 20% by F-C assay; isoflavones 36% and constituents with antioxidant activity 27%. Results suggest that most of these compounds were sufficiently available to be absorbed and could contribute health benefits. PMID- 23017415 TI - Amino acid composition, antinutrients and allergens in the peanut protein fraction obtained by an aqueous enzymatic process. AB - Enzyme-assisted aqueous extraction (EAE) of peanut kernel was used to extract oil and protein. The aqueous fraction (AF) obtained by EAE had a better essential amino acid profile than the residues obtained by solvent extraction (Rs) and cold pressing (Rc). No major difference in the trypsin inhibitor activity among AF, Rs and Rc was observed; however, the trypsin inhibitor activity was drastically reduced in the residue obtained after EAE. AF was subjected to MALDI-TOF/MS, revealing it to be rich in peptides (107) with molecular masses from m/z 700 to 2369Da. AF had an extremely low phytate content and was rich in peptides, which could be used as a food supplement. ESI-MS/MS data were used for the identification of major peanut allergens, viz., Ara h1, h3, h6-8. Their allergenic potential needs to be established. PMID- 23017416 TI - Determination of volatile compounds in New Zealand GreenshellTM mussels (Perna canaliculus) during chilled storage using solid phase microextraction gas chromatography-mass spectrometry. AB - GreenshellTM mussels (Perna canaliculus) were dry-stored at 6.44+/-0.54 degrees C for 8 days during which time volatile organic compounds (VOCs) were monitored using SPME GC-MS. Thirty-four VOCs were identified in homogenised mussel meat and 29 in the mussel liquor (i.e. the seawater enclosed in the mantle cavity). Of the 34 VOCs identified 20 were reliably identified throughout the storage treatment and 9 were found to change in relative concentration in homogenised mussel meat. Dimethyl sulphide, 1-penten-3-ol, 1-hexen-3-ol and 1-octen-3-ol increased during storage, whereas pentanal, hexanal, heptanal, octanal and 3-undecen-2-one decreased. In the mussel liquor, dimethyl sulphide was undetectable pre-storage, becoming detectable after 2 days, and a large increase was noted after 6 days. SPME GC-MS was a useful tool for monitoring VOC profiles of GreenshellTM mussels and could aid in the development of technologies that monitor and improve product quality and consistency. PMID- 23017417 TI - Pre-bottling use of dehydrated waste grape skins to improve colour, phenolic and aroma composition of red wines. AB - Different dehydrated waste grape skins from the juice industry were added into aged and young red wines as an innovative way of compensating for colour loss before bottling. After addition of grape skins, colour intensity of wines increased a mean 11% and a maximum of 31% with predominance of the red component. Total polyphenols mean increase was 10% with a maximum value of 20%. Analysis of low molecular weight phenolic compounds by HPLC-DAD showed a significant (p<0.05) content increase of the bioactive compounds gallic acid, (+)-catechin, (-) epicatechin, and (E)-resveratrol. Anthocyanins content also increased at an average of 50mg/l. The volatile profile of wines analysed by SBSE-GC-MS was only moderately influenced by the treatments. Mixtures of dehydrated waste grape skins were useful to improve the colour and polyphenol profile of red wines, considering them a useful tool for correcting colour loss before bottling. PMID- 23017418 TI - Phytochemical composition and in vitro antimicrobial and antioxidant activities of some medicinal plants. AB - Different parts of three plants (Primula auriculata, Fumaria vaillantii and Falcaria vulgaris) were extracted with three different solvents to yield 72 crude extracts. The phytochemical analysis (chemical screening, GC-MS) of three plants was investigated for their antioxidant and antibacterial activity using nine Gram positive and Gram-negative bacteria. The principal antioxidant and antimicrobial components were determined using HPLC with UV detection. All extracts possessed antibacterial activity especially methanolic extracts from flowers of P. auriculata. The DPPH-radical scavenging assay exhibited high antioxidant activities in three plants (more than 80% at 50MUg). The F. vulgaris showed high content of carvacrol (29.8%) as main component. The contents of carvacrol and fumaric acid in the methanolic-water extracts were 1119 and 1966mg/l respectively. Our results indicate that these plants would be able to promise sources of natural products with potential antibacterial and antioxidant activity. PMID- 23017419 TI - A nanosised oxygen scavenger: preparation and antioxidant application to roasted sunflower seeds and walnuts. AB - A novel oxygen scavenger using iron nanoparticle was produced and evaluated as a potential oxygen scavenger. Iron nanoparticle was prepared by liquid phase reduction method in microemulsion systems. The absorption capacity of different kinds of oxygen scavengers was measured as a function of time, and the absorption rate constant was evaluated at 25 degrees C. The absorption kinetic analysis showed that the absorption process followed a first-order reaction. The absorption rate constant of nanosised and conventional oxygen scavenger were 0.45+/-0.044h(-1) and 0.05+/-0.006h(-1), respectively. Successful application of the nanosised oxygen scavenger on roasted sunflower seed and walnut demonstrated its ability to inhibit lipid oxidation in lipid-containing food. Roasted nut treated with nanosised oxygen scavenger possessed the lowest PV and AnV in all treatments after 120 days of storage. Therefore, it has the potential for broad application as an active packaging in a variety of oxygen-sensitive foods. PMID- 23017420 TI - Sterols and triterpene diols in olive oil as indicators of variety and degree of ripening. AB - Sterols and triterpene diols in olive oil as indicators of variety and degree of ripening derived from three olive varieties and produced at three different harvesting periods were studied. In order to test the stability of the proposed indicators, oils obtained were stored for 12 months at three different temperatures. Thirty-six samples in total were subjected to GC analysis and results were processed by multivariate chemometric methods (MANOVA, PCA, and SLDA). Campesterol, beta-sitosterol, Delta(7)-campesterol/Delta(5,24) stigmastadienol, clerosterol, uvaol, and campestanol/Delta(7)-avenasterol were established as the indicators of variety of fresh oils, while when stored oils were included in the model, the final three compounds were substituted by 24 methylene-cholesterol/stigmasterol. The most important variables for differentiating fresh oils according to degree of ripening were Delta(7) campesterol/beta-sitosterol, uvaol/stigmasterol, clerosterol/Delta(5)-avenasterol and sitostanol/uvaol, while stored oils were differentiated by campestanol/stigmasterol, erythrodiol, stigmasterol/Delta(7)-campesterol, Delta(5)-avenasterol, 24-methylene-cholesterol/beta-sitosterol and 24-methylene cholesterol. Results demonstrated that sterols and triterpene diols can be used as indicators of variety and degree of ripening among virgin olive oils. PMID- 23017421 TI - Hypocholesterolemic effects of low calorie structured lipids on rats and rabbits fed on normal and atherogenic diet. AB - The hypocholesterolemic effects of two low calorie structured lipids (SL1 and SL2) containing essential fatty acids, prepared by lipase catalysed interesterification of ethyl behenate respectively with sunflower and soybean oils were studied in rats and rabbits. The feeding experiment conducted on rats as well as rabbits, fed on normal and atherogenic diet containing 10% of SL1 and SL2 (experimental) and sunflower oil (control) indicated no adverse effects on growth and food intake. However, the structured lipids beneficially lowered serum and liver lipids, particularly cholesterol, LDL cholesterol, triglycerides and also maintains the essential fatty acid status in serum and liver. The lipid deposition observed in the arteries of rabbits fed on atherogenic diets was significantly reduced when structured lipids were included in the diet. These observations coincided with reduced levels of serum cholesterol particularly LDL cholesterol observed in experimental groups. Therefore the structured lipids, designed to have low calorific value also beneficially lower serum lipids and lipid deposition in animals fed on atherogenic diets. PMID- 23017422 TI - Effects of solvent and alkaline earth metals on the heat-induced precipitation process of sodium caseinate. AB - The precipitation temperatures of sodium caseinate in H(2)O and D(2)O in the presence of Mg(2+), Ca(2+), Sr(2+) and Ba(2+) were investigated through fluorescence, turbidity and conductivity experiments. As for the ability of the divalent cations (1-17.5mM) to induce the precipitation process in H(2)O, the sequence Ba(2+) >= Ca(2+)>Mg(2+)>Sr(2+) was found. Remarkably, while at low salt concentrations (<10mM) precipitation temperatures (T(Ps)) were found to change significantly depending on the specific cation, at higher concentrations (>10mM) the differences among the different cations were greatly reduced. By fitting these results with a modified Jones-Dole equation, we confirmed that the less hydrated ions possess a greater capacity to induce precipitation. In D(2)O, the order of ion ability to induce caseinate precipitation was Ba(2+)>Ca(2+)>Sr(2+)>Mg(2+). The different hydrophobicity between D(2)O and H(2)O was shown to affect significantly the T(Ps) of caseinate in the presence of calcium, strontium and barium. PMID- 23017423 TI - Light exposure during storage preserving soluble sugar and l-ascorbic acid content of minimally processed romaine lettuce (Lactuca sativa L.var. longifolia). AB - Minimally processed romaine lettuce (MPRL) leaves were stored in light condition (2500lux) or darkness at 4 degrees C for 7d. Light exposure significantly delayed the degradation of chlorophyll and decrease of glucose, reducing sugar, and sucrose content, and thus preserved more total soluble solid (TSS) content at the end of storage in comparison with darkness. While, it did not influenced starch content that progressively decreased over time. The l-ascorbic acid (AA) accumulated in light-stored leaves, but deteriorated in dark-stored leaves during storage. The dehydroascorbic acid (DHA) increased in all leaves stored in both light and dark condition, of which light condition resulted in less DHA than darkness. In addition, the fresh weight loss and dry matter significantly increased and these increases were accelerated by light exposure. Conclusively, light exposure in applied intensity effectively alleviated MPRL quality deterioration by delaying the decreases of pigments, soluble sugar, TSS content and accumulating AA. PMID- 23017424 TI - Purification and characterisation of antibacterial peptide-containing compound derived from palm kernel cake. AB - Palm kernel cake (PKC), the most useful by-product resulted from palm kernel oil production. In this study, PKC-derived protein product was found suitable for use as an antimicrobial agent with potent antibacterial activity, particularly against Bacillus species, after enzymatic hydrolysis with alcalase. The hydrolysate was further purified by gel filtration chromatography. The purified fraction was found to have 14.63+/-0.70% (w/w) protein, a molecular mass of 2.4kDa and low hemolytic activity (<50% hemolysis of human erythrocytes at concentration of 1000MUg/ml). The presence of lysine and the major component lauric acid derivative, as indicated by electrospray ionisation-mass spectrometry (ESI-MS) direct infusion and nuclear magnetic resonance (NMR) spectroscopy, may have contributed to the antibacterial effect of purified PKC fraction. This study suggests that the antibacterial PKC compound may be not a pure peptide but instead a peptide-containing compound high in lauric acid derivative. PMID- 23017425 TI - Citrus phenylpropanoids and defence against pathogens. Part II: gene expression and metabolite accumulation in the response of fruits to Penicillium digitatum infection. AB - The effect of infection of Citrus sinensis (var. Navelina) fruits with Penicillium digitatum was studied at gene expression and metabolite levels. In this study, expression of genes involved in the phenylpropanoid pathway was studied in the flavedo (outer coloured part of the peel) and albedo (inner white part) in response to pathogen infection. Results of the time-course experiment showed that maximal expression of 10 out of 17 phenylpropanoid genes analysed occurred at 48h post-inoculation, when decay symptoms started to appear, and mRNA levels either kept constant or decreased after 72h post-inoculation. To further investigate the putative involvement of the phenylpropanoid pathway in the defence of citrus fruit, changes in the metabolic profile of both tissues infected with P. digitatum was studied by means of HPLC-PDA-FD. Metabolite accumulation levels along the time course suggest that flavanones, flavones, polymethoxylated flavones and scoparone are induced in citrus fruit in response to P. digitatum infection, although with different trends depending on the tissue. PMID- 23017426 TI - Positron emission tomography in bronchioloalveolar carcinoma of the lung. AB - OBJECTIVES: This study assessed the maximum standard uptake value of positron emission tomography-computed tomography in patients of pulmonary adenocarcinoma with bronchioloalveolar carcinoma features and whether SUVmax correlates with pathological status, lymph node metastasis, and prognosis. METHODS: We retrospectively reviewed 674 patients diagnosed with non-small-cell lung cancer between January 2002 and June 2009. Patients with clinical stage I-II disease underwent a preoperative PET-CT scan followed by anatomic resection. We reviewed the clinical features of 209 patients with an average follow-up of 87 months. RESULTS: We analyzed clinical variables for 40 patients with BAC features and 169 patients without BAC features. Age, sex, location, and number of dissected lymph nodes, carcinoembryonic antigen level, and lymphovascular invasion had no difference between the two groups. Compared with non-BAC patients, patients with BAC features had a lower SUVmax (2.51 +/- 2.02 vs 4.98 +/- 4.03, p < 0.001), lower ratio of SUVmax (1.10 +/- 0.34 vs 1.22 +/- 0.27, p = 0.014), better tumor differentiation (p < 0.001), and smaller tumor size (2.30 +/- 1.41 vs 2.97 +/- 1.71, p < 0.03). The negative prediction rate was 87.08% for N2 and 80.80% for N1 disease. All patients in the BAC group were alive after the operation. The five year survival rate of patients without BAC features was 71.2%. CONCLUSIONS: Preoperative SUVmax of PET-CT was more accurate at predicting negative N2 than N1 disease. BAC is associated with markedly better prognosis compared with invasive adenocarcinoma and may be cured with surgical resection Aggressive surgical resection is recommended even for patients with false-negative N2 disease. PMID- 23017427 TI - Solution structure of CCP modules 10-12 illuminates functional architecture of the complement regulator, factor H. AB - The 155-kDa plasma glycoprotein factor H (FH), which consists of 20 complement control protein (CCP) modules, protects self-tissue but not foreign organisms from damage by the complement cascade. Protection is achieved by selective engagement of FH, via CCPs 1-4, CCPs 6-8 and CCPs 19-20, with polyanion-rich host surfaces that bear covalently attached, activation-specific, fragments of complement component C3. The role of intervening CCPs 9-18 in this process is obscured by lack of structural knowledge. We have concatenated new high resolution solution structures of overlapping recombinant CCP pairs, 10-11 and 11 12, to form a three-dimensional structure of CCPs 10-12 and validated it by small angle X-ray scattering of the recombinant triple-module fragment. Superimposing CCP 12 of this 10-12 structure with CCP 12 from the previously solved CCP 12-13 structure yielded an S-shaped structure for CCPs 10-13 in which modules are tilted by 80-110 degrees with respect to immediate neighbors, but the bend between CCPs 10 and 11 is counter to the arc traced by CCPs 11-13. Including this four-CCP structure in interpretation of scattering data for the longer recombinant segments, CCPs 10-15 and 8-15, implied flexible attachment of CCPs 8 and 9 to CCP 10 but compact and intimate arrangements of CCP 14 with CCPs 12, 13 and 15. Taken together with difficulties in recombinant production of module pairs 13-14 and 14-15, the aberrant structure of CCP 13 and the variability of 13 14 linker sequences among orthologues, a structural dependency of CCP 14 on its neighbors is suggested; this has implications for the FH mechanism. PMID- 23017429 TI - Melatonin receptor agonists for treating delirium in elderly patients with acute stroke. AB - BACKGROUND: Delirium is considered to worsen life prognosis in elderly patients with stroke. We examined the effects of the melatonin receptor agonist ramelteon for treating delirium in elderly stroke patients with insomnia in comparison to the other drugs. METHODS: Elderly patients with delirium and insomnia after acute stroke who were treated with ramelteon (7 patients; mean age 76 years) and the other drugs (21 patients; mean age 77.3 years) between July 2011 and March 2012 at our hospital were retrospectively examined. RESULTS: All patients treated with ramelteon had a significant improvement within a week and were started on early and aggressive rehabilitation. No patient experienced oversedation, neurologic deterioration, or any other worsening effect associated with ramelteon treatment. CONCLUSIONS: Melatonin receptor agonists may be effective for the treatment of delirium in elderly patients with acute stroke. PMID- 23017428 TI - Deep sequencing of systematic combinatorial libraries reveals beta-lactamase sequence constraints at high resolution. AB - In this study, combinatorial libraries were used in conjunction with ultrahigh throughput sequencing to comprehensively determine the impact of each of the 19 possible amino acid substitutions at each residue position in the TEM-1 beta lactamase enzyme. The libraries were introduced into Escherichiacoli, and mutants were selected for ampicillin resistance. The selected colonies were pooled and subjected to ultrahigh-throughput sequencing to reveal the sequence preferences at each position. The depth of sequencing provided a clear, statistically significant picture of what amino acids are favored for ampicillin hydrolysis for all 263 positions of the enzyme in one experiment. Although the enzyme is generally tolerant of amino acid substitutions, several surface positions far from the active site are sensitive to substitutions suggesting a role for these residues in enzyme stability, solubility, or catalysis. In addition, information on the frequency of substitutions was used to identify mutations that increase enzyme thermodynamic stability. Finally, a comparison of sequence requirements based on the mutagenesis results versus those inferred from sequence conservation in an alignment of 156 class A beta-lactamases reveals significant differences in that several residues in TEM-1 do not tolerate substitutions and yet extensive variation is observed in the alignment and vice versa. An analysis of the TEM-1 and other class A structures suggests that residues that vary in the alignment may nevertheless make unique, but important, interactions within individual enzymes. PMID- 23017430 TI - Mechanical thrombectomy in acute stroke: utilization variances and impact of procedural volume on inpatient mortality. AB - BACKGROUND: An increasing number of endovascular mechanical thrombectomy procedures are being performed for the treatment of acute ischemic stroke. This study examines variances in the allocation of these procedures in the United States at the hospital level. We investigate operative volume across centers performing mechanical revascularization and establish that procedural volume is independently associated with inpatient mortality. METHODS: Data was collected using the Nationwide Inpatient Sample database in the United States for 2008. Medical centers performing mechanical thrombectomy were identified using International Classification of Diseases, 9th revision codes, and procedural volumes were evaluated according to hospital size, location, control/ownership, geographic characteristics, and teaching status. Inpatient mortality was compared for hospitals performing >=10 mechanical thrombectomy procedures versus those performing<10 procedures annually. After univariate analysis identified the factors that were significantly related to mortality, multivariable logistic regression was performed to compare mortality outcome by hospital procedure volume independent of covariates. RESULTS: Significant allocation differences existed for mechanical thrombectomy procedures according to hospital size (P<.001), location (P<.0001), control/ownership (P<.0001), geography (P<.05), and teaching status (P<.0001). Substantial procedural volume was independently associated with decreased mortality (P=.0002; odds ratio 0.49) when adjusting for demographic covariates. CONCLUSIONS: The number of mechanical thrombectomy procedures performed nationally remains relatively low, with a disproportionate distribution of neurointerventional centers in high-volume, urban teaching hospitals. Procedural volume is associated with mortality in facilities performing mechanical thrombectomy for acute ischemic stroke patients. These results suggest a potential benefit for treatment centralization to facilities with substantial operative volume. PMID- 23017431 TI - Crack simulation of nano-bioceramic composite microstructures with cohesive failure law: effects of sintering, loads and time. AB - Crack behaviour of zirconia toughened alumina (ZTA) microstructures are simulated with a two-dimensional finite element simulation. Finite element models are developed using actual microstructure images of zirconia toughened alumina and a bilinear cohesive zone law. Simulation conditions are similar to those found at frictional contact between a femoral head and an acetabular cup of hip prosthesis. Effects of microstructures and contact stresses are investigated in terms of crack generation. Moreover, fatigue behaviour of a microstructure is determined by performing simulations under cyclic loading conditions. It is identified that total crack length observed in a microstructure increases with increasing the magnitude of applied contact stress. Cyclic simulation results show that progressive crack growth occurs with respect to number of fatigue cycles. In addition, it is demonstrated that zirconia grains resist crack growth in microstructures. PMID- 23017432 TI - Anticancer activity, toxicity and pharmacokinetic profile of an indanone derivative. AB - The present study describes anticancer effect of gallic acid based indanone derivative (1). Indanone 1 exhibited in vivo anticancer activity against Erhlich ascites carcinoma in Swiss albino mice by inhibiting tumor growth by 54.3% at 50 mg/kg b.wt. It showed antitubulin effect by inhibiting tubulin polymerase enzyme. In cell cycle analysis, it inhibited G2/M phase and induced apoptosis. It significantly suppressed VEGF-R1, VEGF-R2 and HIF-alpha in human breast cancer MCF-7 cells, thus exhibiting antiangiogenic activity. In acute oral toxicity, indanone 1 was well tolerated and was found to be non-toxic up to 1000 mg/kg b.wt. in Swiss albino mice. Pharmacokinetic studies in rabbits revealed rate of absorption, half life, volume of distribution with high plasma and blood clearance after i.v. administration. Indanone 1, is a safe and moderately active anticancer agent. PMID- 23017433 TI - Activated charcoal for GHB intoxication: an in vitro study. AB - CONTEXT: Intoxications with gamma-hydroxybutyrate (GHB) are occurring more frequently. Patients are primarily treated symptomatically. The use of activated charcoal (AC) has been suggested in several guidelines and in literature, although the clinical value of AC in GHB intoxication is a matter of debate. However, it has never been demonstrated that GHB binds to AC. Under certain conditions, prevention of absorption could be clinically relevant. Therefore, adsorption of GHB to AC in an in vitro model was tested. MATERIALS AND METHODS: A previously described in vitro model was used. Dosages of 2.5, 5, 7.5, or 10 g of standard AC (simulating in vivo dosages of approximately 25-100 g) were mixed with a dose of 800 mg GHB at 37 degrees C in 100 mL simulated gastric or intestinal fluid, respectively. Subsequently, the AC was separated from the liquid by centrifugation and the remaining GHB quantified by gas chromatography. GHB adsorption capacity was plotted in an adsorption curve. RESULTS: Binding of GHB to AC was dose-dependent. At gastric pH, adsorption was higher than at intestinal pH, with a maximum adsorption of 84.3% and 23.3%, respectively, with 10 g of AC, corresponding with a high adult dose. DISCUSSION AND CONCLUSION: AC has clinically relevant GHB binding capacity, which is pH dependent. The normally rapid adsorption and the need for intubation argue against AC treatment in GHB intoxications. However, under certain circumstances e.g. in case of unintentional intake of GHB by children or in case of very high doses of GHB, rapid treatment with AC may still be appropriate. In vivo studies are needed to establish the clinical relevance of GHB adsorption to AC. PMID- 23017434 TI - Anal sex and associated HIV-related sexual risk factors among female sex workers in Andhra Pradesh, India. AB - BACKGROUND: This study aims to understand the correlates of anal sex practices among female sex workers (FSWs) and examine the association of anal sex with HIV related sexual risk factors in Andhra Pradesh, India. METHODS: A cross-sectional behavioural survey was conducted in 2011 among 795 FSWs aged 18 years or older. Probability-based cluster sampling was used to select respondents from sex work hotspots. RESULTS: One-quarter (23%) of FSWs had practiced anal sex in the last year. The odds of practicing anal sex were higher among FSWs aged 35 years or more than in those aged less than 25 years (adjusted odds ratio (AOR): 2.05, P<0.05), in those formerly married compared to those currently married (AOR: 1.88, P<0.01), in those having an income only from sex work compared to those having additional sources of income (AOR: 1.54, P<0.05), those reporting heavy alcohol consumption compared to those who did not (AOR: 2.80, P<0.01) and those who experienced violence compared to those who had not (AOR: 2.80, P<0.01). FSWs practicing anal sex were more likely to experience sexually transmissible infection (STI) related symptoms than those practicing only vaginal sex. There was no association between anal sex practice and condom use. CONCLUSIONS: Anal sex is associated with STI symptoms, a factor for HIV risk. HIV intervention programmes need to educate FSWs about the risks associated with anal sex. PMID- 23017435 TI - Vaginal self-sampling without preservative for human papillomavirus testing shows good sensitivity. AB - BACKGROUND: Several strategies have been used to reach non-attending women in organized cervical-cancer-screening programs, with varying success. Self-sampling (SS) for HPV is effective for increasing coverage in screening programs, but requires expensive commercial sampling kits. OBJECTIVE: We aimed to evaluate if vaginal SS, without commercial preservatives was adequate for HPV testing. STUDY DESIGN: Women with abnormal cervical smears as determined from the organized screening program were invited to a colposcopy clinic. The 121 women were asked to insert a cotton swab into the vagina and rotate it, put the cotton swab into a sterile cryotube, break the upper part of the stick and put the cap on. Thereafter, the gynaecologist collected a liquid based cytology (LBC) sample. The presence of HPV-types in SS and LBC samples was analysed with PCR and luminex based typing. RESULTS: High-risk-HPV (hr-HPV) DNA was found in 65 of the tested 108 SS (60%; 95% CI 0.50-0.69), whereas LBC found hr-HPV in 64/108 samples (59%; 95% CI 0.49-0.69). The agreement between sampling with SS and LBC was good, kappa value 0.67 (95% CI; 0.53-0.81). The sensitivity for SS with hr-HPV to find HSIL was 77% (95% CI; 62-91%), specificity 47% (95% CI; 35-59%) [corrected] and the sensitivity for LBC with hr-HPV to find HSIL was 79% (95% CI 66-93%), specificity 50% (95% CI; 38-62%). [corrected] CONCLUSIONS: This new vaginal self-sampling method detects hr-HPV-infections with similar sensitivity as a cervical smear taken by a gynaecologist. This self-sampling method is cost-effective and well tolerated, and the kit is suitable for regular mail transport. PMID- 23017436 TI - Relationship between red blood cell distribution width and prognostic biomarkers in patients admitted to the emergency department with acute infections. PMID- 23017437 TI - Rickettsia felis in Aedes albopictus mosquitoes, Libreville, Gabon. PMID- 23017438 TI - Small supernumerary marker chromosomes derived from chromosomes 6 and 20 in a woman with recurrent spontaneous abortions. AB - In this report, we describe a case of multiple small supernumerary marker chromosomes (sSMC) presenting with recurrent abortions. Peripheral blood lymphocytes of a young, healthy and non-consanguineous couple who asked for genetic evaluation after two spontaneous miscarriages were obtained for karyotypes. Lymphocytes of the woman were analyzed by FISH techniques and DNA was extracted and used for array CGH investigation. Karyotyping revealed 48,XX,+2mar[24]/47,XX,+mar[5]/46,XX[3] for the woman and 46,XY for her husband. FISH analysis showed that the two sSMC consisted of chromosomes 6 and 20. Array CGH analysis showed gains of the 6p11.2q12 (9 Mb) and 20 p11.21 (3.3 Mb) chromosomal regions with a total of 42 genes present on both sSMC. Our findings support also the hypothesis that the modification of the expression of some genes involved in embryo implantation, like THBD gene, could be responsible in the recurrent abortions. This report underpins the necessity of array CGH for characterizing precisely sSMC and helping in genotype-phenotype correlations. Furthermore, a literature review on sSMC is included. PMID- 23017439 TI - Correlation-based imaging technique using ultrasonic transmit-receive array for Non-Destructive Evaluation. AB - This paper describes a novel array post-processing method for Non-Destructive Evaluation (NDE) using phased-array ultrasonic probes. The approach uses the capture and processing of the full matrix of all transmit-receive time-domain signals from a transducer array as in the case of the Total Focusing Method (TFM), referred as the standard of imaging algorithms. The proposed technique is based on correlation of measured signals with theoretical propagated signals computed over a given grid of points. In that case, real-time imaging can be simply implemented using discrete signal product. The advantage of the present technique is to take into account transducer directivity, dynamics and complex propagation patterns, such that the number of required array elements for a given imaging performance can be greatly reduced. Numerical and experimental application to contact inspection of isotropic structure is presented and real time implementation issues are discussed. PMID- 23017441 TI - Effects of acute consumption of a fruit and vegetable puree-based drink on vasodilation and oxidative status. AB - Epidemiological studies indicate that diets rich in fruits and vegetables (F&V) are protective against CVD. Pureed F&V products retain many beneficial components, including flavonoids, carotenoids, vitamin C and dietary fibres. The present study aimed to establish the physiological effects of acute ingestion of a F&V puree-based drink (FVPD) on vasodilation, antioxidant status, phytochemical bioavailability and other CVD risk factors. A total of twenty-four subjects, aged 30-70 years, completed the randomised, single-blind, controlled, crossover test meal study. Subjects consumed 400 ml of the FVPD, or a fruit-flavoured sugar matched control, after following a low-flavonoid diet for 5 d. Blood and urine samples were collected throughout the study day, and vascular reactivity was assessed at 90 min intervals using laser Doppler iontophoresis. The FVPD significantly increased plasma vitamin C (P= 0.002) and total nitrate/nitrite (P= 0.001) concentrations. There was a near significant time by treatment effect on ex vivo LDL oxidation (P= 0.068), with a longer lag phase after consuming the FVPD. During the 6 h after juice consumption, the antioxidant capacity of plasma increased significantly (P= 0.003) and there was a simultaneous increase in plasma and urinary phenolic metabolites (P< 0.05). There were significantly lower glucose and insulin peaks after ingestion of the FVPD compared with control (P= 0.019 and 0.003) and a trend towards increased endothelium-dependent vasodilation following FVPD consumption (P= 0.061). Overall, FVPD consumption significantly increased plasma vitamin C and total nitrate/nitrite concentrations, with a trend towards increased endothelium-dependent vasodilation. Pureed F&V products are useful vehicles for increasing micronutrient status, plasma antioxidant capacity and in vivo NO generation, which may contribute to CVD risk reduction. PMID- 23017442 TI - Autochthonous and dormant Cryptococcus gattii infections in Europe. AB - Until recently, Cryptococcus gattii infections occurred mainly in tropical and subtropical climate zones. However, during the past decade, C. gattii infections in humans and animals in Europe have increased. To determine whether the infections in Europe were acquired from an autochthonous source or associated with travel, we used multilocus sequence typing to compare 100 isolates from Europe (57 from 40 human patients, 22 from the environment, and 21 from animals) with 191 isolates from around the world. Of the 57 human patient isolates, 47 (83%) were obtained since 1995. Among the 40 patients, 24 (60%) probably acquired the C. gattii infection outside Europe; the remaining 16 (40%) probably acquired the infection within Europe. Human patient isolates from Mediterranean Europe clustered into a distinct genotype with animal and environmental isolates. These results indicate that reactivation of dormant C. gattii infections can occur many years after the infectious agent was acquired elsewhere. PMID- 23017443 TI - Selected natural and fallout radionuclides in plant foods around the Kudankulam Nuclear Power Project, India. AB - The activity concentrations of certain radionuclides were quantified in some plant foods cultivated around Kudankulam, where a mega-nuclear power plant is being established. The activity concentrations were found more in the 'pulses' group and were the lowest in 'other vegetable' category. The annual effective dose was computed based on the activity concentration of radionuclides and it was found to be higher due to the consumption of cereals and pulses. Other vegetables, cereals, pulses and nuts recorded high transfer factors for the radionuclide (228)Ra. Fruits, leafy vegetables, tubers and roots, and palm embryo registered high transfer factors for (226)Ra. Group-wise activity concentration, radiation dose to the public and soil-plant-to-transfer factor are discussed in detail. PMID- 23017444 TI - Retaliation and the role for punishment in the evolution of cooperation. AB - Models of evolutionary game theory have shown that punishment may be an adaptive behaviour in environments characterised by a social-dilemma situation. Experimental evidence closely corresponds to this finding but questions the cooperation-enhancing effect of punishment if players are allowed to retaliate against their punishers. This study provides a theoretical explanation for the existence of retaliating behaviour in the context of repeated social dilemmas and analyses the role punishment can play in the evolution of cooperation under these conditions. We show a punishing strategy can pave the way for a partially cooperative equilibrium of conditional cooperators and defecting types and, under positive mutation rates, foster the cooperation level in this equilibrium by prompting reluctant cooperators to cooperate. However, when rare mutations occur, it cannot sustain cooperation by itself as punishment costs favour the spread of non-punishing cooperators. PMID- 23017445 TI - Predator-prey oscillations can shift when diseases become endemic. AB - In epidemiology, knowing when a disease is endemic is important. This is usually done by finding the basic reproductive number, R(0), using equilibrium-based calculations. However, oscillatory dynamics are common in nature. Here, we model a disease with density dependent transmission in an oscillating predator-prey system. The condition for disease persistence in predator-prey cycles is based on the time-average density of the host and not the equilibrium density. Consequently, the time-averaged basic reproductive number R(0)- is what determines whether a disease is endemic, and not on the equilibrium-based basic reproductive number R(0)(*). These findings undermine any R(0) analysis based solely on steady states when predator-prey oscillations exist for density dependent diseases. PMID- 23017446 TI - Validation of a method for simultaneous determination of nitroimidazoles, benzimidazoles and chloramphenicols in swine tissues by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - This paper presents a sensitive and confirmatory multi-residue method for the analysis of 23 veterinary drugs and metabolites belonging to three classes (nitroimidazoles, benzimidazoles, and chloramphenicols) in porcine muscle, liver, and kidney. After extracted with ethyl acetate and basic ethyl acetate sequentially, the crude extracts were defatted with hexane and further purified using Oasis MCX solid-phase extraction cartridges. Rapid determination was carried out by ultra-high performance liquid chromatography-electrospray ionization tandem mass spectrometry. Data acquisition was performed under positive and negative mode simultaneously. Recoveries based on matrix-matched calibrations for meat, liver, and kidney ranged from 50.6 to 108.1%. The method quantification limits were in the range of 3-100ng/kg. PMID- 23017447 TI - [Postoperative pain management on surgical wards; impact of using a validated reference tool in a short, medium and long term]. AB - OBJECTIVES: To evaluate the short medium and long-term impact of a quality improvement program (QIP) in a university hospital using a validated reference tool. METHODS: Seven surgical departments were audited before and after implementation of a QIP in postoperative pain management. Audits were conducted in 2005, 2007, 2009 and 2012. In each audit, 10 medical charts from each surgical department were analyzed for 9 quality criteria. A surgical department score (SDS) was calculated for each department (maximum score=90). The surgical departments with a SDS<45 received targeted training sessions. RESULTS: In 2005, three surgical departments had a SDS<45. After the first audit, a targeted training sessions was conducted in the three surgical departments, all seven departments improved their scores with a SDS>45 in 2007. Between 2007 and 2009, all seven departments improved their scores. Conversely, between 2009 and 2012, the SDS diminished in six of the seven surgical departments and four of the nine evaluated quality criteria decreased significantly: right detailed order for postoperative pain analgesia (prescriber identifier, agent used, unit doses, mode of administration; 100% versus 53; P=0.027), appropriate dosing of steps I and II analgesics (96% versus 80%; P=0.041), morphine (90% versus 76%; P=0.039), based on corresponding physician orders and monitor morphine side effects (87% versus 29; P=0.027). CONCLUSION: Audits should be performed regularly (at least every two years) for detecting postoperative pain management degradation. Lack of targeted training sessions can explain partially this degradation. PMID- 23017448 TI - [The development of zebrafish research in China]. AB - As one of the most important vertebrate model systems, the zebrafish plays increasingly important roles in the field of life sciences. At present, zebrafish is widely used in studies on developmental biology, molecular biology, cell biology, genetics, neurobiology, oncology, immunology, marine biology, pharmacology, toxicology, and environmental protection. The zebrafish-based studies have led to many important discoveries that contribute to the development of modern life sciences. The zebrafish model system was introduced into China in the late 1990s; since then, the Chinese zebrafish community has being expanded fast with more influencing research outcomes, promoting a wide range of disciplines. This review gives an overview of zebrafish-based studies and representative findings in the mainland and Hong Kang of China, aiming to promote wider utilization of zebrafish for high-level studies. PMID- 23017449 TI - [Zebrafish research in Taiwan]. AB - The initiation time for zebrafish research in Taiwan was around 1996 and experienced eight years (1996-2003) to establish the fundamental base. From 2004 onwards, zebrafish research project and population in Taiwan is exponentially increasing to a total number of 83 independent research laboratories at this moment. Three major research topics of developmental biology, human disease, and biotechnology are conducted by zebrafish community in Taiwan. Up to now, 342 scientific refereed papers have been published by Taiwan researchers. By 2010, two zebrafish stock centers of TZCAS and ZeTH have been established to provide fish resources to zebrafish community. By the fully support of two zebrafish stock centers, attending physicians and experts in the fields of engineering and bioinformatics are working together with zebrafish people and obtained fruitful results in zebrafish researches in recent years. PMID- 23017450 TI - [Progress on pluripotency factors in zebrafish]. AB - The mammalian pluripotency factors, including transcription factors such as Pou5f1/Oct4, Sox2, Klf4 and Nanog, play critical roles in maintaining pluripotency of embryonic stem cells and inducing reprogramming of differentiated cells. However, the functions of vertebrate pluripotency factors in vivo have not been elucidated. Zebrafish(Danio rerio H.) is an excellent model for studying vertebrates' early embryo development. It allows functional studies of pluripotency factors to be conducted in an in vivo environment and therefore provides more accurate information on their roles. Nowadays, several homologs of mammalian pluripotency factors including oct4, nanog etc. have been identified in zebrafish. This review aimed at introducing the progress of the functional study on zebrafish pluripotency factors and comparing to those of other vertebrates. PMID- 23017451 TI - [DNA methylation in vertebrate embryogenesis]. AB - DNA methylation is an important epigenetic modification that regulates temporal and spatial expression of genes for controlling cell fate and differentiation. Recently, DNA methylation has been demonstrated to be required for vertebrate early embryogenesis. Loss of Dnmt genes in zebrafish and mice caused defects in organogenesis and tissue terminal differentiation. This paper summarizes the dynamic expression pattern of Dnmt genes and the roles of DNA methylation from early embryogenesis to organogenesis in both mice and zebrafish, specifically, how DNA methylation and histone modifications cooperatively regulate gene transcription during these processes. Better understanding of DNA methylation in vertebrate embryogenesis will provide insights for new treatment of DNA methylation-related human diseases. PMID- 23017452 TI - [Vascular endothelial cell development and underlying mechanisms]. AB - The cardiovascular system is one of the first organs formed during embryogenesis. Vessel development involves generating primary vascular endothelial tubes by aggregation of angioblasts (vasculogenesis), creating a vascular network through endothelial sprouting (angiogenesis), and pruning primary vascular tubes by recruiting smooth muscle cells to the vessel walls (vessel maturation). Angioblast, the endothelial progenitor, is generated from hemangioblasts that are derived from the Flk1+ mesodermal cells, or directly from the Flk1+ mesodermal cells. Although several factors such as vegf, flk1, cloche, lycat and estrp are essential for angioblast development, much of the signaling pathways underlying the derivation of angioblasts from the hemangioblasts or Flk1+ mesodermal cells remain unknown. This review will summarize our current knowledge, challenge, and future directions on molecular and cellular mechanisms of endothelial cell development. PMID- 23017453 TI - [Advance in biomechanical study of embryonic vascular system development]. AB - Embryonic vascular system development is a complex process, whose progress is regulated by a variety of the stimulation and inhibition signals, and these signals must play synergistic effect so as to ensure that each stage of vascular development can proceed normally. The vascular development is controlled by the gene to a certain extent, and has received extensive attention. Recent studies have revealed the biomechanical role is necessary to embryonic vascular development, in which different mechanism of cell biomechanics is involved. In this review, we summarize the latest research progress on the role of biomechanical factors during embryonic vascular system development. PMID- 23017454 TI - [Advances in the zebrafish circadian clock mechanisms]. AB - Zebrafish has recently become an emerging vertebrate model for circadian studies. Here we summarized recent advances in the field of zebrafish circadian research. The characteristics and advantages of zebrafish as a circadian model, as well as its time-keeping mechanisms, were highlighted. Because light and temperature as external time cues both play important roles in the circadian regulation of zebrafish, we focused on recent studies concerning the effects of light and temperature on circadian clock genes and circadian regulatory pathways in zebrafish. We also provided the perspectives on prospective zebrafish circadian studies. PMID- 23017455 TI - [Application of zebrafish models in drug screening]. AB - Due to its small size, fast external development, transparent embryos, and amenability to genetic analysis, zebrafish has become an ideal vertebrate animal model. In addition to studies in genetics and developmental biology, zebrafish has also been widely used in human disease modeling and drug screening. As a small whole-organism model, zebrafish can be used to comprehensively test and evaluate the activity and side effect of a compound at the same time, fulfilling high content screening. Recently, new zebrafish disease models and screening technologies have been developed. A number of active compounds were identified and most of them have similar functions in mammal models. One compound prostaglandin E2 has been subjected to clinical trial to test if it can promote the growth of umbilical cord blood units after transplantation. Another compound leflunomide has also been approved in clinical trial to cure melanoma in combination with vemurafenib. These findings demonstrate that zebrafish model is appropriate for drug screening. This review summarizes the unique features of zebrafish model and the recent progresses of zebrafish based drug screening. PMID- 23017456 TI - [The Nodal regulated dusp4 inhibits mesendoderm formation during zebrafish gastrulation]. AB - MAP kinase phosphatase-2 (MKP-2/DUSP4), a dual specificity protein phosphatase with tyrosine/serine/ threonine phosphatase activity, is associated with cellular proliferation and differentiation, but its functions during embryo development are unclear. To study the developmental function of dusp4, we first examined the spatiotemporal expression pattern of this gene during zebrafish embryonic development by whole mount in situ hybridization. We found that dusp4 was maternally expressed since its transcripts were present from the one-cell to the 256-cell stages. At early gastrulation stages, dusp4 transcripts specifically distributed at margin region, where the mesendodermal cells were located. Further more, Nodal signal was crucial for dusp4 expression. The expression of dusp4 was obviously increased in Nodal ligand overexpressed embryos, while its expression was almost lost in the Nodal signal-deficient MZoep mutants. In addition, dusp4 MO was also designed to knock down its expression in embryos. The mesendoderm formation was significantly in-creased in dusp4 morphants, but not obviously changed in dusp4 overexpressed embryos, suggesting that dusp4 is necessary, but not sufficient for the inhibitory of mesendoderm induction. Thus, our results indicate that Nodal regulated dusp4 plays a repressive role in mesendoderm induction. PMID- 23017457 TI - [Vitamin A deficiency causes asymmetric somitogenesis and abnormal hindbrain patterning in zebrafish embryos]. AB - Retinoic acid (RA) plays essential roles in vertebrate embryogenesis. However, vertebrates cannot synthesize RA de novo. They synthesize it by two oxidative steps, first converting the precursor vitamin A into retinal by retinol dehydrogenase, and then oxidizing retinal into RA irreversibly by retinal dehydrogenase. It is known that vitamin A deficiency (VAD) causes Vitamin A Deficiency Syndrome in animals including quail, mouse, rat, and human. However, little is known about the effects of VAD on zebrafish embryogenesis. In this study, we obtained zebrafish VAD embryos from the zebrafish fed a retinoids-free diet. By analyzing the VAD embryos, we found that VAD caused asymmetric somitogenesis and abnormal hindbrain patterning in zebrafish embryos. However, the phenotype of defected hindbrain in VAD embryos was not as severe as that in the embryos in which aldh1a2, the major gene that is responsible for RA synthesis in zebrafish early development, was knocked down, or the embryos treated with 10 mmol/L DEAB (diethylaminobenzaldehyde, inhibitor of retinal dehydrogenases). Our results indicated that the VAD embryos were short of but not free of vitamin A, and they might also have a RA generation pathway independent of retinal dehydrogenase. PMID- 23017458 TI - [Toxic effects of trimethadione on zebrafish early development]. AB - To further understand the neural toxicity and teratogenicity of antiepileptic drugs in clinic, we established a zebrafish model for antiepileptic toxicity using trimethadione as a probe drug. The results indicated that embryonic malformation occurred under trimethadione treatment in a concentration-dependent manner. The defects included growth retardation, small head, eyes and acoustic capsule, deficient semicircular canals and otolith, and abnormal cardiovascular system. The number of hair cells in neuromast ML2 was obviously reduced in the treated larvae. Whole mount in situ hybridization indicated that the gene expression patterns of brain marker genes, such as zic1 and xb51, and autophagic gene atg5 was changed significantly. The result of RT-PCR showed that the expressions of hearing genes val and hmx2 were also changed in the trimethadione treated embryos. All these findings suggest that brain tissue and the neural sensors for body balance and hearing are the main targets of trimethadione toxicity, and that zebrafish is able to mimic mammal responses to the teratogenicity and the neural toxicity of trimethadione in the embryonic and larva development. PMID- 23017459 TI - [Analysis of expression pattern of zebrafish leg1 homologus gene mu-leg1 in mouse]. AB - Gene leg1 (liver-enriched gene 1) was first identified as a novel gene whose expression was enriched in the liver of zebrafish. Further studies revealed that Leg1 protein was a novel secretory protein, which played a role in the liver development in zebrafish. Here we reported the analysis of expression pattern of zb-leg1 homologus gene mu-leg1. The cDNA of mu-leg1 was isolated from adult mouse liver by nested PCR. This gene encodes a putative protein, mu-Leg1, which shares 31% similarity with zb-Leg1 of zebrafish. Both Northern blotting and semi quantitative RT-PCR demonstrated that the expression of mu-leg1 was enriched in the small intestine rather than in the liver in adult mouse. We also produced a recombined mu-Leg1 protein and a mu-Leg1 specific antibody. Western blottingdemonstrated that mu-Leg1 was a secretory protein. In addition, we have established a mu-leg1 conditional knock-out heterozygous mouse. Our work builds a basis for further studies of mu-leg1. PMID- 23017460 TI - [Detection of dynamic expression of microRNAs in vivo using a dual-fluorescence reporter system/miRNA Tracer in zebrafish]. AB - microRNAs (miRNAs) are short noncoding RNAs that have been found in a wide variety of organisms and many have been shown to play essential roles by regulating the stability and translation of target messenger RNAs (mRNAs) in animals and plants. Temporal and spatial expression is critical for the regulatory function of miRNAs. To analyze the dynamic expression of particular miRNA in vivo, we constructed a dual-fluorescence reporter system based on Tol2 transposon, in which two reporter genes, enhanced green fluorescent protein (eGFP) and monomeric red fluorescent protein 1 (mRFP1), were driven by the heat shock promoter (hsp) from zebrafish hsp70 gene in an opposite orientation. To sense the existence of a particular miRNA, the complementary DNA sequence of the corresponding miRNA was inserted into the 3'-UTR region of one of the two reporter genes. By injecting the corresponding plasmid DNA into zebrafish embryos, we were able to monitor the abundance and dynamics of miRNA miR-206 in live embryos. To further evaluate this method, we made a collection of transgenic zebrafish with stable integration of dual-fluorescence reporter plasmids targeting different miRNAs, including miR-206 and miR-219. Our results showed that this dual-fluorescence reporter system, which is also called miRNA Tracer, could faithfully monitor the appearance and disappearance of target miRNAs in defined cell lineages during zebrafish development in these fish lines. Our dual fluorescence reporter/Tracer system provides an important tool for further in depth studies on miRNAs in zebrafish. PMID- 23017461 TI - [Analysis of adult zebrafish OKR behavior]. AB - As a means of visual function testing and visual related mutants screening, the optokinetic response (OKR) and the optomotor response (OMR) behaviour tests are simple and effective tools for visual functional testing, which have been widely used in studying zebrafish larvae. However, adult zebrafish OKR analysis method is rarely reported. In this study, the methods of inducing adult zebrafish OKR behaviour, as well as tracking the movement of eyes using Pattern Match approaches, are presented. The quantitative measurement of the adult zebrafish OKR behaviour was successfully established. Using these methods, the binocular vision area was found to make a certain contribution to OKR behaviour. Moreover, the monocular vision of adult zebrafish showed a certain degree of directional sensitivity to moving gratings. Such approaches can also be applied to the zebrafish larvae OKR. The abnormal OKR behaviour phenomenon of period1b mutant larvae fish was detected. PMID- 23017462 TI - [Hereditary quality standards for laboratory fish]. AB - Although laboratory fish are increasingly used in genetics and other life science research fields, standard quality control and supervision are needed. In China, laboratory animals are all put into a strict licensing and quality management system by the government. The standardization of genetic quality control is crucial to a laboratory fish quality control management system. The goal of Laboratory Animal Regulation is to control genetic quality, avoid hereditary degeneration and genetic drift, and circumvent experimental errors. To achieve this goal, Laboratory Animal Regulations are being developed by consulting experimental data and research findings throughout the world, combining the best known practices in laboratory fish production, and consulting specialists. A new set of laboratory fish genetic quality standards focusing on zebrafish and swordtail fish has been established as a reference for scientific researchers. The new standards define inbred and outbred zebrafish and swordtail fish hereditary classifications, naming principles, breeding methods, and hereditary quality surveying. The new standards provide a frame of reference for laboratory fish users and managers. PMID- 23017463 TI - [A brief protocol for sperm cryopreservation and revival in zebrafish]. AB - Zebrafish is an important vertebrate model organism for the study of embryonic development and the underlying genetic mechanism. Numerous mutants and transgenics have been generated in recent years, long-term and safe storage of these fish lines is of crucial importance for every zebrafish community/lab. Sperm cryopreservation and revival has become a preferred method for this purpose, which provides extra and reliable security as a backup for the cost effective maintenance of genetic stocks in addition to reducing space demanding for housing large amount of live fish. This is especially critical for invaluable fish lines against accidental loss. Generally, the sperm are obtained by either squeezing the male fish or dissecting out and homogenizing the testes, then they are mixed with the freezing medium before gradually frozen as aliquots in liquid nitrogen. They can be easily revived through in vitro fertilization whenever necessary. This technique was introduced into zebrafish research three decades ago and has gradually become mature and more reliable following the im-provement of many critical factors and steps, including cryoprotectants and conditions for freezing and revival. Base on pioneers' work, our lab has established and improved a simple method for sperm cryopreservation and revival which shows high recovery rate after relatively long storage time. Here we briefly summarize the history and development of the methods for sperm cryopreservation and revival in zebrafish and present a brief protocol for the practice of sperm cryopreservation and revival, which is routinely used in our lab. PMID- 23017464 TI - Oral processing characteristics of solid savoury meal components, and relationship with food composition, sensory attributes and expected satiation. AB - BACKGROUND: The modern food supply is often dominated by a large variety of energy dense, softly textured foods that can be eaten quickly. Previous studies suggest that particular oral processing characteristics such as large bite size and lack of chewing activity contribute to the low satiating efficiency of these foods. To better design meals that promote greater feelings of satiation, we need an accurate picture of the oral processing characteristics of a range of solid food items that could be used to replace softer textures during a normal hot meal. AIM: The primary aim of this study was to establish an accurate picture of the oral processing characteristics of a set of solid savoury meal components. The secondary aim was to determine the associations between oral processing characteristics, food composition, sensory properties, and expected satiation. METHODS: In a within subjects design, 15 subjects consumed 50 g of 35 different savoury food items over 5 sessions. The 35 foods represented various staples, vegetables and protein rich foods such a meat and fish. Subjects were video recorded during consumption and measures included observed number of bites, number of chews, number of swallows and derived measures such as chewing rate, eating rate, bite size, and oral exposure time. Subjects rated expected satiation for a standard 200 g portion of each food using a 100mm and the sensory differences between foods were quantified using descriptive analysis with a trained sensory panel. Statistical analysis focussed on the oral processing characteristics and associations between nutritional, sensory and expected satiation parameters of each food. RESULTS: Average number of chews for 50 g of food varied from 27 for mashed potatoes to 488 for tortilla chips. Oral exposure time was highly correlated with the total number of chews, and varied from 27 s for canned tomatoes to 350 s for tortilla chips. Chewing rate was relatively constant with an overall average chewing rate of approximately 1 chew/s. Differences in oral processing were not correlated with any macronutrients specifically. Expected satiation was positively related to protein and the sensory attributes chewiness and saltiness. Foods that consumed in smaller bites, were chewed more and for longer and expected to impart a higher satiation. DISCUSSION: This study shows a large and reliable variation in oral exposure time, number of required chews before swallowing and expected satiation across a wide variety of foods. We conclude that bite size and oral-sensory exposure time could contribute to higher satiation within a meal for equal calories. PMID- 23017465 TI - Successful restrained eating and trait impulsiveness. AB - Restrained eaters with high scores on the Perceived Self-Regulatory Success in Dieting Scale (PSRS) are more successful than low scorers in regulating their food intake. According to the theory of temptation-elicited goal activation (Fishbach, Friedman, & Kruglanski, 2003), they have become successful because, due to earlier repeated instances of successful self-control, they formed an associative link between temptations and thoughts of dieting. It is unclear, however, why they should have been more successful in earlier attempts at self control than their unsuccessful counterparts. We examined whether trait impulsiveness plays a role by investigating the associations between dietary restraint, trait impulsiveness, and PSRS. Results showed that the interaction between dietary restraint and impulsiveness predicted dieting success: A lower level of impulsiveness was associated with greater dieting success among restrained eaters. These results suggest that restrained eaters who are less impulsive are more likely to become successful restrained eaters as identified with the PSRS. PMID- 23017466 TI - Nutritional supplement use among fitness club participants in Tehran, Iran. AB - The aim of this study was to assess nutritional supplement use among fitness club participants in Tehran, Iran. A cross sectional study was conducted in 24 fitness clubs throughout the city of Tehran, Iran. A total of 1625 fitness club participants were recruited to participate in this study. They were asked to complete a self-administered pre-tested questionnaire. Descriptive statistics and chi-square test were performed to determine the characteristics of participants, reasons for supplement use, sources of information and also the influential advisors regarding nutritional supplement use. A high prevalence rate of nutritional supplement use (66.7%) was reported. Overall, multivitamin-mineral (43.8%) and iron tablets (30.5%) were the common nutritional supplements used and only a small number of participants used illegal substances (0.5%). Younger participants were more likely to use ergogenic aids, whereas, older participants were more likely to use vitamin D. Males were more likely than females to use creatine and amino acids, whereas, iron tablets and mint water were more common among females. Also, males were more likely to use nutritional supplements for increasing energy, whereas, females were more likely to use nutritional supplements for nutritional deficiencies. In conclusion, a high prevalence rate of nutritional supplement use was seen among participants. PMID- 23017467 TI - Food addiction in adults seeking weight loss treatment. Implications for psychosocial health and weight loss. AB - The present study examined food addiction symptomology and its relationship to eating pathology and psychological distress among adults seeking weight loss treatment. A primary interest was an examination of the relationship between food addiction symptoms and short-term weight loss. Adults beginning a behavioral weight loss program (N=57) were given the Yale Food Addiction Scale (YFAS) as well as measures of psychological distress, disordered eating, weight bias, and weight-focused attitudes. Weight loss was measured after 7 weeks. Severity of food addiction was related to increased depression, emotional eating, binge eating, anti-fat attitudes, internalized weight bias, body shame, and low eating self-efficacy, but not body satisfaction. Increased food addiction symptomology was also related to less weight lost at 7 weeks. Findings suggest that individuals attempting to lose weight while combating symptoms of food addiction may be especially prone to eating-related pathologies, internalized weight bias, and body shame. Importantly, findings provide evidence that food addiction may undermine efforts to lose weight. The pathology associated with addiction (e.g., tolerance, withdrawal) could make the adoption of more healthful eating habits especially difficult. PMID- 23017468 TI - Parental influences on children's eating behaviour and characteristics of successful parent-focussed interventions. AB - Parental reports suggest that difficulties related to child-feeding and children's eating behaviour are extremely common. While 'fussy eating' does not pose an immediate threat to health, over the long-term, consumption of a poor diet can contribute to the development of a range of otherwise preventable diseases. In addition, the stress and anxiety that can surround difficult mealtimes can have a detrimental impact upon both child and parental psychological wellbeing. Since parents have a great influence over what, when, and how much food is offered, feeding difficulties may be preventable by better parental awareness. The aim of this review is to describe how parental factors contribute to the development of common feeding problems, and to discuss the merits of existing interventions aimed at parents/primary caregivers to improve child-feeding and children's eating behaviour. The potential for different technologies to be harnessed in order to deliver interventions in new ways will also be discussed. PMID- 23017469 TI - The taxonomy of emergency department consultations--results of an expert consensus panel. PMID- 23017470 TI - Identification of microRNAs as a potential novel regulatory mechanism in HSD11B1 expression. AB - 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1, gene HSD11B1) converts glucocorticoid receptor-inert cortisone to receptor-active cortisol. Multiple evidence supports a causal role for 11beta-HSD1 in the current obesity epidemic. In obese, HSD11B1 expression is increased in adipose tissue but typically decreased in liver, and the underlying tissue-specific mechanisms are largely unknown. In this context, we investigated a potential role of microRNAs (miRNAs). We used several miRNA target prediction tools to identify possible candidates and a publicly available miRNA expression atlas to further select candidates expressed in hepatocytes. Using a dual luciferase reporter assay, we identified three potential miRNAs, hsa-miR-340, -561 and -579, as potential negative regulators of HSD11B1 expression. Disruption of the corresponding microRNA response elements abolished repression of luciferase activity for hsa-miR-561 and -579, but not for hsa-miR-340. Furthermore, levels of firefly luciferase mRNA were not changed by miR-561 and -579, indicating a mechanism based on translational repression rather than mRNA degradation. Finally, we were able to detect both, miR-561 and -579, in human total liver RNA by reverse-transcription polymerase chain reaction (RT-PCR). According to the presented results, miR-561 and -579 are likely to be involved in the tissue-specific regulation of HSD11B1 expression. Moreover, literature findings and a pathway enrichment analysis support a potential role of these two miRNAs in glucocorticoid metabolism and signalling and associated diseases. PMID- 23017472 TI - Collaborating for organizational success and cultural change. PMID- 23017471 TI - Multimodal magnetic resonance imaging assessment of white matter aging trajectories over the lifespan of healthy individuals. AB - BACKGROUND: Postmortem and volumetric imaging data suggest that brain myelination is a dynamic lifelong process that, in vulnerable late-myelinating regions, peaks in middle age. We examined whether known regional differences in axon size and age at myelination influence the timing and rates of development and degeneration/repair trajectories of white matter (WM) microstructure biomarkers. METHODS: Healthy subjects (n = 171) 14-93 years of age were examined with transverse relaxation rate (R(2)) and four diffusion tensor imaging measures (fractional anisotropy [FA] and radial, axial, and mean diffusivity [RD, AxD, MD, respectively]) of frontal lobe, genu, and splenium of the corpus callosum WM (FWM, GWM, and SWM, respectively). RESULTS: Only R(2) reflected known levels of myelin content with high values in late-myelinating FWM and GWM regions and low ones in early-myelinating SWM. In FWM and GWM, all metrics except FA had significant quadratic components that peaked at different ages (R(2) < RD < MD < AxD), with FWM peaking later than GWM. Factor analysis revealed that, although they defined different factors, R(2) and RD were the metrics most closely associated with each other and differed from AxD, which entered into a third factor. CONCLUSIONS: The R(2) and RD trajectories were most dynamic in late myelinating regions and reflect age-related differences in myelination, whereas AxD reflects axonal size and extra-axonal space. The FA and MD had limited specificity. The data suggest that the healthy adult brain undergoes continual change driven by development and repair processes devoted to creating and maintaining synchronous function among neural networks on which optimal cognition and behavior depend. PMID- 23017474 TI - A few minutes with Nancy F. Langston. PMID- 23017475 TI - An integrative review of factors related to patient satisfaction with general anesthesia care. AB - Surgery is typically performed using one or more types of anesthesia. An important patient outcome related to the anesthetic, and a measure of quality from the patient's perspective, is patient satisfaction with anesthesia care. Currently, no psychometrically validated instruments that measure patient satisfaction with general anesthesia care are available in the United States. This integrative review focuses on identifying factors related to adult patients' satisfaction with general anesthesia care. We found the most frequently mentioned modifiable factors related to patient satisfaction were information provided and pain or discomfort. The only nonmodifiable factor with sufficient evidence to include in future studies on instrument development is the patient's age. This review provides information that can help in the design and implementation of quality improvement initiatives and in the development of an instrument to measure patient satisfaction with general anesthesia care. PMID- 23017476 TI - Implementing AORN recommended practices for MIS: Part II. AB - This article focuses on the equipment and workplace safety aspects of the revised AORN "Recommended practices for minimally invasive surgery." A multidisciplinary team that includes the perioperative nurse should be established to discuss aspects of the development and design of new construction or renovation (eg, room access, ergonomics, low-lighting, OR integration, hybrid OR considerations, design development). Equipment safety considerations during minimally invasive surgical procedures include using active electrode monitoring; verifying the properties of distention media; using smoke evacuation systems; reducing equipment, electrical, thermal, and fire hazards; performing routine safety checks on insufflation accessories; and minimizing the risk of ergonomic injuries to staff members. Additional considerations include using video recording devices, nonmagnetic equipment during magnetic resonance imaging, and fluid containment methods for fluid management. PMID- 23017478 TI - Prewarming critically ill patients. PMID- 23017477 TI - Propofol allergy: assessing for patient risks. AB - Allergies to certain foods such as soybeans and eggs contraindicate the use of propofol, a short-acting hypnotic medication used by many anesthesia care providers. Understanding the safe use and handling of propofol and communicating known patient allergies to all surgical team members is crucial to providing safe perioperative care. The perioperative nurse's preoperative assessment supports and improves the plan of care for the patient by identifying the patient's risk factors. Obtaining a correct and precise history of allergies, not only to medication but to food, and concise hand-off reporting are essential for patient safety. PMID- 23017479 TI - Evaluation of potential noise exposures in hospital operating rooms. AB - The National Institute for Occupational Safety and Health received a health hazard evaluation request from West Virginia University Hospital, Morgantown, to evaluate noise exposures from surgical instruments in the OR. Four surgical technologists, four RNs, and one surgeon wore noise dosimeters to measure full shift personal noise exposures during two days while they performed typical daily activities. Measurements did not exceed Occupational Safety and Health Administration or National Institute for Occupational Safety and Health noise exposure limits; however, area sound level measurements indicated that some intermittent activities can generate sound levels above 90 A-weighted decibels. Examples include surgery preparation, drilling or noise from other powered surgical instruments during surgeries, and clean up. Preventive maintenance of powered surgical instruments can reduce noise exposures, and noise output should be considered when selecting replacement instruments. Keeping music at a low level and using hearing protection are other interventions to consider to improve noise levels in an OR. PMID- 23017480 TI - Aftermath of an earthquake: a first responder's perspective. PMID- 23017482 TI - Perioperative nurses and nutrition. PMID- 23017484 TI - "Superficial" report leads to "deep" problem. PMID- 23017485 TI - It is time for a new paradigm for the Study of Psychoses. PMID- 23017486 TI - Depressive comorbidity in personality disorders. AB - INTRODUCTION: We aimed to investigate the nature of the associations between PD clusters and MDs, functionality and mental health services use. METHODS: This is a case register study of all cases with a diagnosis of PD detected clinically in a well-defined area in the province of Barcelona covered by 7 Community Mental Health Teams. DSM-IV diagnoses were established by fully trained psychiatrists. Data was also gathered on socio-demographic variables; functional status (GAF) and data on use of health resources, using a systematic computerized method. We performed a non-parametric univariate statistical analysis. RESULTS: We found a higher percentage of major depressive disorder (MDD) among cluster C patients (17%), followed by cluster A (10%) and cluster B (9, 8%). As for the comorbidity between PD clusters and dysthymic disorder, we found that the prevalence was higher among cluster B patients (23,7%) than cluster C (20,2%) or cluster A (7,1%). When considering both MDs together, we found the highest prevalence among cluster C patients (36,87%), followed by cluster B (33,5%) and cluster A (17,1%). Cluster A patients showed worse functioning and visited hospitals most. CONCLUSIONS: A high comorbidity between all MDs analyzed and personality disorders was found, being particularly prominent among cluster C PDs. PMID- 23017487 TI - Quality of the written information about suicide attempters. AB - INTRODUCTION: The aim of the study was to assess the quality of the clinical records of the patients who are seen in public hospitals in Madrid after a suicide attempt in a blind observation. METHODS: Observational, descriptive cross sectional study conducted at four general public hospitals in Madrid (Spain). Analyses of the presence of seven indicators of information quality (previous psychiatric treatment, recent suicidal ideation, recent suicide planning behaviour, medical lethality of suicide attempt, previous suicide attempts, attitude towards the attempt, and social or family support) in 993 clinical records of 907 patients (64.5% women), ages ranging from 6 to 92 years (mean 37.1+/-15), admitted to hospital after a suicide attempt or who committed an attempt whilst in hospital. RESULTS: Of patients who attempted suicide, 94.9% received a psychosocial assessment. All seven indicators were documented in 22.5% of the records, whilst 23.6% recorded four or less than four indicators. Previous suicide attempts and medical lethality of current attempt were the indicators most often missed in the records. The study found no difference between the records of men and women (z=0.296; p=0.767, two tailed Mann-Whitney U test), although clinical records of patients discharged after an emergency unit intervention were more incomplete than the ones from hospitalised patients (z=2.731; p=0.006), and clinical records of repeaters were also more incomplete than the ones from non-repeaters (z=3.511; p<0.001). CONCLUSIONS: Clinical records of patients who have attempted suicide are not complete. The use of semi structured screening instruments may improve the evaluation of patients who have self- harmed. PMID- 23017488 TI - Burns and mental disorder. AB - INTRODUCTION: The study aimed to explore the prevalence of previous mental disorder and the incidence of adjustment and posttraumatic stress disorder in 60 patients with burn injuries admitted to a major burn unit in the greater Madrid area. METHODS: A total of 57 patients were assessed for serious past and present mental illness by using a semi-structured clinical interview. Current DSM-IV adjustment and posttraumatic stress disorder were assessed 6 months post burn with the structured clinical interview SCID. RESULTS: 60 patients were hospitalized for severe burns during the study period. 11 (17,9%) burns took place intentionally. 9 patients had tried to commit suicide. 33.5% of the participants had suffered any kind of mental disorder previously. 23 (52.3%) patients met criteria for adjustment disorder and 8 (18%) for posttraumatic stress disorder 6 months post burn. CONCLUSIONS: The results demonstrate the importance of routine screenings of psychological symptons in burned patients. It is also necessary to promote specific psychopharmacological measures and specific psychotherapeutic interventions in this population in order to improve their medical and psychiatric prognosis and their quality of life a long-term basis. PMID- 23017489 TI - The high prevalence of thyroid dysfunction in psychiatric inpatients. AB - INTRODUCTION: The relation of the neuroendocrine system with the psychiatric disorders has been described by different authors throughout history. OBJECTIVES: To evaluate the presence of thyroid disfunction in psychiatric inpatients. METHODS: Observacional, descriptive, retrospective study of all the psychiatric inpatients in the UHP of Vigo during the year 2006, in which the presence of thyroid dysfunction is evaluated immediately when they are admitted. RESULTS: Prevalence of thyroide dysfunction is 7.5%, representing the hypothyroidism a 6.4%, and the hyperthyroidism a 1.1%. The presence of thyroid dysfunction calculated by sex was significantly superior (p=0.010) for the feminine sex (10.1%), that masculine sex (2.3%). No specific associations were found between psychiatric diagnosis, years of evolution, toxic consume or treatment and endocrine abnormalities. CONCLUSIONS: Given the high prevalence of thyroid dysfunction in psychiatric inpatients obtained in our study we advised the screening of thyroid hormones to an under-population in which is feminine sex, people who present mood disorders,unipolar or bipolar disorder, especially in rapid cycling or mixed episodies; in refractay mood disease, in the psychotics patients and whom they are to treatment with psychiatric drugs, especially lithium. PMID- 23017490 TI - Laughter and positive therapies: modern approach and practical use in medicine. AB - The exploration of the possible strategies centered in positive emotions is a suggestion to investigate and probably useful to raise the efficiency of therapeutic interventions. Laughter and humor have been classified as part of the 24 personal strengths and are considered as one of the activities that encourage personal well-being, savoring, and promoting flow states. Laughter therapy, classified within alternative or complementary therapies in medicine, includes a group of techniques and therapeutic interventions aimed to achieve laughter experiences which result in health-related outcomes, both physiological and psychological. Recent advent of positive psychology has developed high interest and expectations in the benefits of adding positive techniques to laughter therapy (and to other mind-body therapies). Consequently with this modern approach positive laughter therapy was born, as add-on to conventional laughter therapy and positive psychology, with its contributions and limitations. Health professionals can exert an important role in order to disseminate overall benefits of "positive therapies" while applying them in real-world clinical settings, for both patients and themselves. PMID- 23017491 TI - Mini Nutritional Assessment predicts gait status and mortality 6 months after hip fracture. AB - The aim of the present study was to evaluate the Mini Nutritional Assessment (MNA), the Nutritional Risk Screening (NRS) 2002 and the American Society of Anesthesiologists Physical Status Score (ASA) as predictors of gait status and mortality 6 months after hip fracture. A total of eighty-eight consecutive patients over the age of 65 years with hip fracture admitted to an orthopaedic unit were prospectively evaluated. Within the first 72 h of admission, each patient's characteristics were recorded, and the MNA, the NRS 2002 and the ASA were performed. Gait status and mortality were evaluated 6 months after hip fracture. Of the total patients, two were excluded because of pathological fractures. The remaining eighty-six patients (aged 80.2 (sd 7.3) years) were studied. Among these patients 76.7 % were female, 69.8 % walked with or without support and 12.8 % died 6 months after the fracture. In a multivariate analysis, only the MNA was associated with gait status 6 months after hip fracture (OR 0.773, 95 % CI 0.663, 0.901; P= 0.001). In the Cox regression model, only the MNA was associated with mortality 6 months after hip fracture (hazard ratio 0.869, 95 % CI 0.757, 0.998; P= 0.04). In conclusion, the MNA best predicts gait status and mortality 6 months after hip fracture. These results suggest that the MNA should be included in the clinical stratification of patients with hip fracture to identify and treat malnutrition in order to improve the outcomes. PMID- 23017492 TI - Abdominal apoplexy: A rare case of spontaneous rupture of the superior mesenteric artery in a hypertensive patient. AB - INTRODUCTION: Spontaneous rupture of an intra-abdominal visceral artery is an exceptionally rare and potentially fatal cause of abdominal apoplexy. PRESENTATION OF CASE: We present a case of a 54-year-old hypertensive male who developed hypovolemic shock in our Emergency Department after presenting with abrupt onset of abdominal pain and diarrhea. Intra-operative findings revealed rupture of the superior mesenteric artery with massive hemoperitoneum. The bleeding vessel was ligated and the patient made a full recovery after 3 weeks in the Intensive Care Unit. DISCUSSION: High index of suspicion is necessary for early preoperative diagnosis and must be considered in any patient with a history of hypertension presenting with abrupt abdominal pain, signs of peritoneal irritation and unexplained hypovolemic shock. Immediate resuscitation and prompt surgical control of bleeding is paramount in patient prognosis. CONCLUSION: The seemingly unpredictable nature of abdominal apoplexy must be noted, a precipitating cause in most cases is untraceable and early diagnosis relies solely on awareness of the condition. PMID- 23017493 TI - Inflammatory myofibroblastic tumor of spermatic cord. AB - INTRODUCTION: Inflammatory myofibroblastic tumor (IMT) is a neoplasm of intermediate biologic potential. Only a few cases of IMT in the spermatic cord have been reported. It was earlier included in a wide spectrum of reactive and neoplastic lesions called "inflammatory pseudotumors". It commonly presents as a painless scrotal mass, usually in children and young adults. PRESENTATION OF CASE: We present a case of IMT in the spermatic cord who based on clinical, radiological and cytological findings underwent surgical exploration of left scrotal sac. The mass was separate from the left testis and left epididymis, and was closely adherent to pampiniform plexus of veins. Wide excision of the mass was done. Histology and immunohistochemistry suggested IMT. DISCUSSION: IMT is a myofibroblastic spindle cell proliferation with chronic inflammatory infiltrate. Surgical exploration is essential as clinically and radiologically benign or malignant nature of mass cannot be distinguished. The diagnosis of IMT is based on the histological features and is substantiated by immunomarkers. CONCLUSION: In clinically distinct masses, based on frozen section, either tumor excision or radical orchidectomy can be performed. The prognosis is excellent after complete surgical excision of spermatic cord IMT. Careful long-term follow-up is essential, because of the possibility of recurrence, though rare in this site. PMID- 23017494 TI - BTNL2 gene polymorphism associations with susceptibility and phenotype expression in sarcoidosis. AB - A functional polymorphism within butyrophilin-like 2 (BTNL2) gene has been described as a potential risk factor for sarcoidosis. The association between chronicity and the rs2076530 SNP A allele has also been reported. This study evaluates the BTNL2 rs2076530 G/A allele associations with sarcoidosis susceptibility and disease evolution in a Portuguese cohort of patients. A case control study of 151 patients and 150 controls was performed. Allele frequencies were compared with Chi-square test in a univariate analysis and with logistic regression in a multivariate analysis. BTNL2 rs206530 A allele frequencies were significantly higher in sarcoidosis with no linkage disequilibrium with HLA-DRB1 alleles, except in the subgroup of patients with Lofgren syndrome where the determinant allele was HLA-DRB1*03. The A allele was also increased in those with isolated thoracic disease, with no differences regarding radiological stages or disease evolution. HLA-DRB1*03, besides the association with Lofgren syndrome was significantly related with disease resolution. Our data confirms the association of BTNL2 rs2076530 A allele with sarcoidosis susceptibility in a Portuguese population. We found independent genetic risk factors in clinically distinct disease phenotypes: BTNL2 rs2076530 A allele in patients without Lofgren syndrome or with isolated thoracic disease, and HLA-DRB1*03 in Lofgren syndrome or disease resolution. PMID- 23017495 TI - The chains of the heterodimeric amphibian skin antimicrobial peptide, distinctin, are encoded by separate messenger RNAs. AB - Using a primer to a conserved nucleotide sequence of previously cloned skin peptides of Phyllomedusa species, two distinct cDNAs were "shotgun" cloned from a skin secretion-derived cDNA library of the frog, Phyllomedusa burmeisteri. The two ORFs separately encode chains A and B of an analog of the previously reported heterodimeric peptide, distinctin. LC-MS/MS analysis of native versus dithiotreitol reduced crude venom, confirmed the predicted primary sequences as well as the cystine link between the two monomers. Distinctin predominantly exists in the venom as a heterodimer (A-B), neither of the constituent peptides were detected as monomer, whereas of the two possible homodimers (A-A or B-B), only B-B was detected in comparatively low quantity. In vitro dimerization of synthetic replicates of the monomers demonstrated that besides heterodimer, both homodimers are also formed in considerable amounts. Distinctin is the first example of an amphibian skin dimeric peptide that is formed by covalent linkage of two chains that are the products of different mRNAs. How this phenomenon occurs in vivo, to exclude significant homodimer formation, is unclear at present but a "favored steric state" type of interaction between chains is most likely. PMID- 23017496 TI - Functional proteomics strategy for validation of protein kinase inhibitors reveals new targets for a TBB-derived inhibitor of protein kinase CK2. AB - CK2 is a constitutively active protein kinase with key regulatory roles in many cellular signaling events which has been implicated in several human diseases. To investigate its roles in biological events and potential as a therapeutic target, several potent CK2 inhibitors have been developed including TBB and its derivatives that have been employed in many studies. Despite the utility of these compounds, a precise understanding of their mode of action within cells remains incomplete. In fact, cells are typically treated with inhibitor concentrations (>5 MUM) that are orders of magnitude higher than their in vitro inhibitory constants (<0.05 MUM). Accordingly, we hypothesized that CK2 inhibitors could have off-target effects that are not recognized when inhibitors are profiled using panels of recombinant protein kinases. To address this issue, we combined structural modeling with inhibitor-affinity purification and proteomics to test the specificity of derivatives of TBB using whole cell lysates of HeLa cells. While these studies confirmed that CK2 does bind to the immobilized inhibitor, several other abundant ATP/GTP-binding proteins were also identified and confirmed. These results suggest that highly abundant nucleotide binding proteins may limit the bioavailability of the free inhibitor and interactions with CK2 in the cellular environment. This article is part of a Special Issue entitled: From protein structures to clinical applications. PMID- 23017497 TI - Phosphoproteome analyses reveal specific implications of Hcls1, p21-activated kinase 1 and Ezrin in proliferation of a myeloid progenitor cell line downstream of wild-type and ITD mutant Fms-like tyrosine kinase 3 receptors. AB - The tyrosine kinase receptor Flt3 (Fms-like tyrosine kinase 3) is almost always expressed in AML (acute myeloid leukemia) cells, and constitutive activation of Flt3 by ITD (internal tandem duplication) mutations is one of the most common molecular alterations known in AML, especially monocytic AML. Furthermore, Flt3 ligand (FL) was shown as an in vitro growth factor for monocytic precursors, pointing to the important role of Flt3 in the regulation of monocyte/macrophage production. To get a relevant model for studying the molecular mechanisms underlying the physiopathological role of Flt3 on monocytic lineage development, we used the IL-3 dependent murine myeloid progenitors FDC-P1 cell line to generate cells stably co-expressing murine Fms (M-CSF receptor) and human Flt3. Wild type (WT)-Flt3 expressing cells could proliferate in an FL-dependent manner, whereas those expressing Flt3-ITD all survived IL-3 deprivation and showed autonomous proliferation, whereas both types of cells could differentiate to monocytic cells in response to M-CSF. Next, by combining phosphoprotein detection or purification, comparative 2D-PAGE and mass spectrometry sequencing, we sought for downstream mediators of Flt3-WT or Flt3-ITD in FD/Fms cell proliferation. Amongst the differentially expressed and/or phosphorylated proteins, 3 showed a specific implication in FD/Fms cell proliferation: Hcls1 and the Pak1/2 in FL dependent proliferation of Flt3-WT expressing cells and Ezrin in autonomous proliferation of Flt3-ITD expressing cells. PMID- 23017498 TI - Intimate partner abuse and suicidality: a systematic review. AB - Research has demonstrated an association between intimate partner abuse and suicidality, presenting a serious mental health issue. However, studies have differed widely in the samples and methods employed, and in the depth of the investigation. Given the level of heterogeneity in the literature, this systematic review examines, for the first time, the nature of the relationship between intimate partner abuse and suicidality. The three main psychological and medical databases (PsychInfo 1887-March 2011; Medline, 1966-March 2011; Web of Knowledge 1981-March 2011) were searched. Thirty-seven papers on the topic of intimate partner abuse and suicidality were found. With only one exception, all of the studies found a strong and consistent association between intimate partner abuse and suicidality. Significantly, this relationship held irrespective of study design, sample and measurement of abuse and suicidality, thus demonstrating a consistently strong relationship between intimate partner abuse and suicidality. This review highlights that intimate partner abuse is a significant risk factor for suicidal thoughts and behaviours, which has important clinical implications. PMID- 23017499 TI - Annexin-A1 protein and its relationship to cortisol in human saliva. AB - Salivary cortisol is commonly used as a clinical biomarker of endocrine status and also as a marker of psychosocial stress. Annexin-A1 (AnxA1) is an anti inflammatory protein whose expression is modulated by glucocorticoids. Our principal objectives were to (i) detect the presence of and (ii) measure AnxA1 protein in whole human saliva and to (iii) investigate whether salivary cortisol and AnxA1 are correlated in healthy humans. A total of 37 healthy participants (male and female) were used in the study. Saliva was collected using salivette tubes. Salivary cortisol and AnxA1 protein were sampled at between 3 and 6 time points over 24h and measured for cortisol and AnxA1 protein using specific ELISA's. The presence of salivary AnxA1 protein was confirmed by Western blotting. AnxA1 protein is detectable in whole human saliva, as detected by Western blot analysis and ELISA. A diurnal rhythm was evident in both salivary cortisol (P<0.01) and AnxA1 (P<0.01) and was defined as a significant difference in time 0 (waking) samples compared to 'bed' (2300 h) samples. AnxA1 protein did not exhibit an awakening response (P>0.05), whereas salivary cortisol was significantly elevated between time 0 and 30 min post waking (P<0.001). AnxA1 protein correlates positively with salivary cortisol, indicating that cortisol is most likely a regulator of AnxA1 in human saliva. PMID- 23017500 TI - Hypertriglyceridemia is associated with insulin levels in adult cystic fibrosis patients. AB - BACKGROUND: Recent studies have identified hypertriglyceridemic cystic fibrosis patients (CF-TG). However, whether hypertriglyceridemia is associated with an altered metabolic profile remains unknown. OBJECTIVE: To characterize CF-TG and determine whether triglycerides (TG) levels are associated with metabolic alterations. METHODS: 210 adult CF subjects from the Montreal Cystic Fibrosis Cohort without known diabetes were included in the analysis. All subjects underwent an OGTT to assess glucose tolerance, insulin secretion (insulin AUC) and insulin sensitivity (Stumvoll index). Fasting lipid profiles, pulmonary function (%FEV1) and BMI were determined. Hypertriglyceridemia (TG>1.7mmol/L) was observed in 20 CF patients. These subjects were matched for age, sex and glucose tolerance category with 20 CF patients (CF-normal-TG) and 20 healthy controls that had TG levels below 1.7mmol/L. Pearson correlations were performed in the complete study sample (n=210) to examine the associations between TG levels and other parameters. RESULTS: The prevalence of hypertriglyceridemia was 9.5%. Compared to CF-normal-TG, CF-TG subjects displayed significantly higher %FEV1, insulin AUC (AUC0-120, AUC0-30, AUC30-120), cholesterol levels and a higher ratio of total cholesterol to HDL-cholesterol. Pearson analysis demonstrated that TG levels were associated with BMI, %FEV1, fasting insulin, insulin AUC0-120 and AUC30-120, Stumvoll index, cholesterol levels and the ratio of total cholesterol to HDL-cholesterol. All these correlations remained significant after correction for BMI except %FEV1. CONCLUSION: TG levels are associated with a mild alteration of the metabolic profile. Whether these changes will increase the long-term risk of CF patients in developing cardiometabolic complications remains to be investigated. PMID- 23017501 TI - Bartonella spp. infection rate and B. grahamii in ticks. PMID- 23017502 TI - Infectivity of H7 LP and HP influenza viruses at different temperatures and pH and persistence of H7 HP virus in poultry meat at refrigeration temperature. AB - The aims of this study were to assess the infectivity of highly pathogenic (HP) and low pathogenicity (LP) H7 AI viruses at different temperatures and pH values and to investigate the persistance of HP H7 virus in chicken, turkey and duck meat. The H7 viruses tested remained infectious at +4 degrees C and +20 degrees C for 200 and >50 days, respectively. At pH 5, H7 viruses retained their infectivity for a shorter period of time compared to pH 7. The infectivity of HP H7 was detected >2 months in meat maintained at +4 degrees C and was higher in chicken meat compared to turkey and duck meat. Results of this study show that higher temperatures and lower pH values both reduce virus infectivity and demonstrate that HP H7 virus can remain infectious in meat for extended periods of time. PMID- 23017503 TI - Split-hand index for the diagnosis of amyotrophic lateral sclerosis. AB - OBJECTIVE: Preferential wasting of the thenar group of muscles, the split hand sign, appears to be a specific feature of ALS. The present study developed a novel split-hand index (SI) and assessed its diagnostic utility in ALS. METHODS: One hundred and seventy consecutive patients with neuromuscular symptoms (44 ALS, 126 patients with other neuromuscular disorders) were prospectively recruited according to standards for reporting of diagnostic accuracy (STARD) criteria. The SI was derived by dividing the product of the compound muscle action potential (CMAP) amplitude recorded over the first dorsal interosseous and abductor pollicis brevis by the CMAP amplitude recorded over the abductor digiti minimi. RESULTS: The SI was significantly reduced in ALS patients (ALS 3.5 +/- 0.6; patients with other neuromuscular disorders 9.1 +/- 0.3, P < 0.0001), particularly in limb-onset ALS (2.3 +/- 0.5, P < 0.0001). Receiver operating characteristic curve analysis indicated that SI reliably differentiated ALS from patients with other neuromuscular disorders (area under curve ALS 0.83, P < 0.0001) with an optimal SI cut-off value of 5.2 exhibiting a sensitivity of 74% and specificity 80%. CONCLUSIONS: The split-hand index robustly differentiates ALS from mimic disorders. SIGNIFICANCE: The split-hand index is a simple measure that could be utilized in a standard neurophysiology setting. A reduction in SI distinguishes ALS from mimic disorders, potentially facilitating an earlier diagnosis of ALS. PMID- 23017504 TI - Severe obstructive disease: similarities and differences between smoker and non smoker patients with COPD and/or bronchiectasis. AB - INTRODUCTION: Poorly reversible airflow obstruction may or may not be related to smoking. OBJECTIVES: To describe patients with severe obstructive lung disease including etiology, imaging, functional aspects, systemic manifestations, and the pattern of bronchodilator response. METHODS: Sixty-eight patients (age 55.9+/ 13.7 years, FEV(1) [forced expiratory volume in one second] 31.9+/-10.2% predicted) underwent spirometry, evaluation of body mass composition, 6-minute walk test, X-ray, thorax high-resolution CT scanning, and clinical evaluation. RESULTS: Of 68 patients enrolled, 37 had chronic obstructive pulmonary disease (COPD) and 31, extensive bronchiectasis. Among COPD patients the CT scans showed emphysema in 78.4%, and bronchiectasis in 48.6%. There were no significant differences between smokers and non-smokers, except for vital capacity, significantly smaller in non-smokers (p<0.001). We found 29 and 20 volume responders (VR) according to Pare et al. (FEV(1)/FVC>1=flow responder or <1=VR) and ATS/ERS criteria, respectively. According to Pare et al. criteria, there were 18 patients with FEV(1)<30% predicted among 29 VR, and 12 with FEV(1)<30% predicted among 39 without volume response (p=0.0101). CONCLUSIONS: In patients with severe obstruction, smoking does not appear to be relevant in determining functional or systemic differences, and Pare et al. criteria can detect more VR. Bronchiectasis is a common finding in severe COPD. PMID- 23017505 TI - Echinococcus multilocularis in urban coyotes, Alberta, Canada. AB - Echinococcus multilocularis is a zoonotic parasite in wild canids. We determined its frequency in urban coyotes (Canis latrans) in Alberta, Canada. We detected E. multilocularis in 23 of 91 coyotes in this region. This parasite is a public health concern throughout the Northern Hemisphere, partly because of increased urbanization of wild canids. PMID- 23017506 TI - Hexene-1 isomerization on NaNp/CpTiCl3/Al2O3SiO2 (Np-naphthenide; Cp cyclopentadienyl) system. AB - NaNp/CpTiCl(3)/Al(2)O(3)SiO(2) (Cp=cyclopentadienyl; Np=napthenide anion) systems are new catalysts active in the C=C hexene-1 bond isomerization reaction. Their activity depends on amount of titanium[III] hydride surface complexes and the support Lewis acidity. As results showed, all these properties are a function of the Al(2)O(3)-SiO(2) gels composition. The highest yields were obtained for the 90 and 100 wt.% Al(2)O(3) catalysts (Lewis acidity) and for the 10 and 60 wt.% Al(2)O(3) catalysts (amount of Ti[III]+Lewis acidity). PMID- 23017507 TI - Comparison of donor, and early and late recipient outcomes following hand assisted and laparoscopic donor nephrectomy. AB - PURPOSE: While laparoscopic donor nephrectomy has encouraged living kidney donation, debate exists about the safest laparoscopic technique. We compared purely laparoscopic and hand assisted laparoscopic donor nephrectomies in terms of donor outcome, early graft function and long-term graft outcome. MATERIALS AND METHODS: We reviewed the records of consecutive laparoscopic and hand assisted laparoscopic donor nephrectomies performed by a single surgeon from 2002 to 2011. Donor operative time and perioperative morbidity were compared. Early graft function for kidneys procured by each technique was evaluated by rates of delayed graft function, need for dialysis and recipient discharge creatinine. Long-term outcomes were evaluated by graft function. RESULTS: A total of 152 laparoscopic donor nephrectomies were compared with 116 hand assisted laparoscopic donor nephrectomies. Hand assisted procedures were more often done for the right kidney (41.1% vs 17.1%, p <0.001) and in older donors (age 41.4 vs 37.5 years, p = 0.011). Warm ischemia time was shorter for hand assisted than for purely laparoscopic nephrectomy (120 seconds, IQR 50 vs 145, IQR 64, p <0.001). Median operative time was slightly shorter for the hand assisted than for the purely laparoscopic procedure (155 vs 165 minutes, p = 0.038). In each group 2 intraoperative complications required intervention (open conversion in 1 case each). Postoperatively complications developed after 5 purely laparoscopic and 5 hand assisted operations (1 Clavien 3b in each). Median length of stay was 2 days for each surgery. Postoperatively recipient outcomes were also similar. Delayed function occurred after 0% hand assisted vs 0.9% purely laparoscopic nephrectomies, dialysis was required in 0.9% vs 1.7% and rejection episodes developed in 9.7% vs 18.4% (p >0.05). At last followup the organ was nonfunctioning in 6.1% of hand assisted and 7.7% of purely laparoscopic cases (p >0.05). The recipient glomerular filtration rate at discharge home was similar in the 2 groups. CONCLUSIONS: Hand assisted laparoscopic donor nephrectomy had shorter warm ischemia time but perioperative donor morbidity and graft outcome were comparable. The choice of technique should be based on patient and surgeon preference. PMID- 23017508 TI - Readability assessment of online urology patient education materials. AB - PURPOSE: The National Institutes of Health, American Medical Association, and United States Department of Health and Human Services recommend that patient education materials be written at a fourth to sixth grade reading level to facilitate comprehension. We examined and compared the readability and difficulty of online patient education materials from the American Urological Association and academic urology departments in the Northeastern United States. MATERIALS AND METHODS: We assessed the online patient education materials for difficulty level with 10 commonly used readability assessment tools, including the Flesch Reading Ease Score, Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook, Gunning Frequency of Gobbledygook, New Dale-Chall Test, Coleman-Liau index, New Fog Count, Raygor Readability Estimate, FORCAST test and Fry score. RESULTS: Most patient education materials on the websites of these programs were written at or above the eleventh grade reading level. CONCLUSIONS: Urological online patient education materials are written above the recommended reading level. They may need to be simplified to facilitate better patient understanding of urological topics. PMID- 23017509 TI - Increased water intake as a prevention strategy for recurrent urolithiasis: major impact of compliance on cost-effectiveness. AB - PURPOSE: We evaluated the economic impact of preventing recurrent stones using a strategy of increased water intake and determined the impact of compliance on cost-effectiveness for the French health care system. MATERIALS AND METHODS: A Markov model was constructed to compare costs and outcomes for recurrent kidney stone formers with less than 2 L vs 2 L or more daily fluid intake. Model assumptions included an annual prevalence of 120,000 stone episodes in France, 14.4% annual risk of stone recurrence and a 55% risk reduction in subjects with adequate water intake. Costs were based on resource use as estimated by a panel of experts and official national price lists. Outcomes were from the perspective of the public health payer, and encompassed direct and indirect costs. RESULTS: The total cost of an episode of urolithiasis was estimated at ?4,267 including the cost of treatment and complications. This corresponds to an annual budget impact of ?88 million for recurrent stones based on 21,000 stone events. Assuming 100% compliance with fluid intake recommendations of 2 L daily, 11,572 new stones might be prevented, resulting in a cost savings of ?49 million. Compliance with water intake in only 25% of patients would still result in 2,893 fewer stones and a cost savings of ?10 million. Varying the costs of managing stones had a smaller impact on outcomes since in many patients stones do not form. Varying the incidence of complications did not change the incidence of stones and had a negligible effect on overall cost. CONCLUSIONS: Preventing recurrent urolithiasis has a significant cost savings potential for a payer as a result of a reduced stone burden. However, compliance is an important factor in determining cost effectiveness. PMID- 23017511 TI - Prostate volume did not affect voiding function improvements in diode laser enucleation of the prostate. AB - PURPOSE: We compared safety and surgical outcomes in patients with different prostate sizes treated with diode laser enucleation of the prostate. MATERIALS AND METHODS: From 2008 to 2012 consecutive patients with benign prostatic obstruction undergoing diode laser prostate enucleation at our institution were enrolled for analysis. A single surgeon performed diode laser prostate enucleation with an end firing, continuous wave diode laser (980 nm). Based on preoperative prostate volume on transrectal ultrasound, patients were stratified into 2 groups, including group 1-65 with less than 60 ml and group 2-55 with 60 ml or greater. Baseline and perioperative characteristics, and postoperative surgical outcomes were compared between the 2 groups. RESULTS: A total of 120 men with a mean +/- SD age of 70.2 +/- 9.0 years were enrolled for analysis. Compared with group 1 patients, those in group 2 had larger mean total prostate volume (85.0 +/- 24.6 vs 40.9 +/- 10.8 ml), longer mean operative time (117.7 +/- 48.2 vs 60.7 +/- 25.0 minutes), higher mean retrieved prostate weight (37.3 +/- 16.1 vs 12.5 +/- 7.3 gm) and a higher mean tissue retrieval ratio (74.4% +/- 22.2% vs 58.8% +/- 23.2%, p <0.01). There was no significant difference in the postoperative hemoglobin decrease in the 2 groups (median 0.5 vs 0.9 mg/dl, p = 0.11). The rate of temporary postoperative urinary retention after Foley catheter removal was significantly lower in group 2 (15.4% vs 3.6%, p = 0.04). Postoperative improvements in the peak flow rate, post-void residual urine volume and International Prostate Symptom Score were comparable in the 2 groups. CONCLUSIONS: Although patients with a larger prostate required significantly longer operative time and laser energy, voiding function improvements and surgical complication rates of diode laser prostate enucleation were comparable in patients with a larger vs smaller prostate. PMID- 23017510 TI - Relationships among participant international prostate symptom score, benign prostatic hyperplasia impact index changes and global ratings of change in a trial of phytotherapy in men with lower urinary tract symptoms. AB - PURPOSE: We related changes in American Urological Association symptom index scores with bother measures and global ratings of change in men with lower urinary tract symptoms who were enrolled in a saw palmetto trial. MATERIALS AND METHODS: To be eligible for study men were 45 years old or older, and had a peak uroflow of 4 ml per second or greater and an American Urological Association symptom index score of 8 to 24. Participants self-administered the American Urological Association symptom index, International Prostate Symptom Score quality of life item, Benign Prostatic Hyperplasia Impact Index and 2 global change questions at baseline, and at 24, 48 and 72 weeks. RESULTS: In 357 participants global ratings of a little better were associated with a mean decrease in American Urological Association symptom index scores from 2.8 to 4.1 points across 3 time points. The analogous range for mean decreases in Benign Prostatic Hyperplasia Impact Index scores was 1.0 to 1.7 points and for the International Prostate Symptom Score quality of life item it was 0.5 to 0.8 points. At 72 weeks for the first global change question each change measure discriminated between participants who rated themselves at least a little better vs unchanged or worse 70% to 72% of the time. A multivariate model increased discrimination to 77%. For the second global change question each change measure correctly discriminated ratings of at least a little better vs unchanged or worse 69% to 74% of the time and a multivariate model increased discrimination to 79%. CONCLUSIONS: Changes in American Urological Association symptom index scores could discriminate between participants rating themselves at least a little better vs unchanged or worse. Our findings support the practice of powering studies to detect group mean differences in American Urological Association symptom index scores of at least 3 points. PMID- 23017512 TI - Impact of complete bladder neck preservation on urinary continence, quality of life and surgical margins after radical prostatectomy: a randomized, controlled, single blind trial. AB - PURPOSE: We investigated the influence of bladder neck preservation on urinary continence, quality of life and surgical margins after radical prostatectomy. MATERIALS AND METHODS: A total of 208 men who presented for radical prostatectomy were randomized to complete bladder neck preservation with subsequent urethro urethral anastomosis or to no preservation as controls. Patients with failed bladder neck preservation were not included in study. We documented objective continence by the 24-hour pad test, social continence by the number of pads per day and quality of life outcomes by the validated Incontinence Quality of Life questionnaire in a single blind setting. Cancer resection was assessed by surgical margin status. RESULTS: At 0, 3, 6 and 12 months mean urine loss in the control vs the bladder neck preservation group was 713.3 vs 237.0, 49.6 vs 15.6, 44.4 vs 5.5 and 25.4 vs 3.1 gm, respectively (each p <0.001). At 3, 6 and 12 months in the control vs the preservation group the social continence rate was 55.3% vs 84.2% (p <0.001), 74.8% vs 89.5% (p = 0.05) and 81.4% vs 94.7% (p = 0.027), and the quality of life score was 80.4 vs 90.3 (p <0.001), 85.4 vs 91.7 (p = 0.016) and 86.0 vs 93.8 (p = 0.001), respectively. We noted significantly less urine loss, higher objective and social continence rates, and higher quality of life scores after complete bladder neck preservation at all followup points. On multiple logistic regression analysis complete bladder neck preservation was an independent positive predictor of continence. No significant difference was found in surgical margin status between the control and bladder neck preservation groups (12.5% vs 14.7%, p = 0.65). CONCLUSIONS: In what is to our knowledge the first prospective, randomized, controlled, single blind trial complete bladder neck preservation during radical prostatectomy was associated with a significantly higher urinary continence rate and increased patient satisfaction without compromising resection margins. PMID- 23017513 TI - Disease specific mortality in patients with low risk bladder cancer and the impact of cystoscopic surveillance. AB - PURPOSE: We determined the risk of disease specific mortality in patients with primary, low risk, noninvasive (G1pTa) bladder cancer and compared it to disease specific mortality in age and gender matched general populations. MATERIALS AND METHODS: We identified all patients with primary low risk cancer at our institution. We excluded those with adverse pathological features and then matched histopathology, pharmacy, hospital episode and Cancer Registry records. We reviewed case notes on patients with subsequent muscle invasion (progression) or disease specific mortality. Patients underwent post-resection surveillance and treatment using standard regimens. National and regional disease specific mortality rates were calculated from appropriate data. RESULTS: A total of 699 patients met study inclusion criteria. Median followup was 61 months (IQR 24 105). Of the patients 17 (2.4%) died of bladder cancer, including 13 of 14 with progression to muscle invasion and 4 of 19 with grade progression to high grade, nonmuscle invasive disease. On Cox regression analyses low grade dysplasia in the initial resection specimen and tumor weight were associated with disease specific mortality (p <0.003). Disease specific mortality in these patients was 5 times the background rate in matched populations. Limitations of this study include its retrospective nature and the low frequency of adverse events. CONCLUSIONS: Patients with low risk bladder cancer rarely progress to muscle invasion but they are at higher risk for disease specific mortality than the general population. Current surveillance regimens appear ineffective for detecting progression in time to alter prognosis. PMID- 23017514 TI - Favorable patient reported outcomes after penile plication for wide array of peyronie disease abnormalities. AB - PURPOSE: We present patient reported outcomes from our 5-year experience using penile plication to correct a wide variety of Peyronie disease malformations. MATERIALS AND METHODS: We reviewed the records of all men who underwent penile plication for Peyronie disease, as performed by one of us (AFM). All patients were treated with tunical plication without penile degloving via a 2 cm longitudinal penile incision regardless of curvature severity or erectile function. A concomitant inflatable penile prosthesis was placed in men with refractory erectile dysfunction. A questionnaire was administered to assess the patient perception of postoperative penile curvature, length, rigidity and adequacy for intercourse. RESULTS: Of 154 treated patients 78 (51%) and 65 (42%) had simple (less than 60 degrees) and complex (biplanar curvature, or curvature 60 degrees or greater) malformation, respectively, while 11 (7%) underwent plication plus inflatable penile prosthesis placement. A total of 132 patients responded to the questionnaire a mean 14 months after surgery. Overall, 96% of patients reported curvature improvement after penile plication, 93% reported erection adequate for sexual intercourse and 95% considered that the overall condition improved after surgery. Despite a significant difference in the number of plication sutures (mean 10 vs 7) and curvature angle correction (mean 57 vs 30 degrees, each p <0.005), self-reported outcomes of complex cases were equivalent to those of simple cases. While 84% of patients had no measureable decrease in stretched penile length, 103 of 154 (78%) reported a perceived penile length reduction after surgery. CONCLUSIONS: Penile plication without degloving is effective for correcting a wide variety of Peyronie disease malformations. It can be safely combined with inflatable penile prosthesis placement. PMID- 23017515 TI - Symptoms and risk factors associated with first urinary tract infection in college age women: a prospective cohort study. AB - PURPOSE: We identified epidemiological risk factors for the initial urinary tract infection in females of college age compared to age matched controls. MATERIALS AND METHODS: We performed a prospective cohort study from July 2001 to January 2006 at the student health care facility at our institution. A total of 180 women experiencing a first urinary tract infection were compared to 80 asymptomatic women with no urinary tract infection history who served as controls. Urinalysis and urine culture were done at study enrollment. Questionnaires were used to obtain information on clinical symptoms and behaviors, including sexual and dietary practices, and alcohol consumption. Logistic regression was performed to identify potential risk factors in women who presented with an initial urinary tract infection compared with controls. Principal component analysis was then done to identify key sexual activity variables for multiple regression models. RESULTS: Urinary frequency and urgency were the most common urinary tract infection symptoms. Recent sexual activity was a significant risk factor for urinary tract infection with vaginal intercourse (p = 0.002) and the number of sexual partners in the last 2 weeks (p <0.001) as the 2 primary variables. Alcohol consumption was associated with 2 of the 3 main principal components of sexual activity. Caffeinated beverage consumption also increased the risk of urinary tract infection (p <0.04). Escherichia coli was the predominant pathogen isolated, followed by urease positive microbes. CONCLUSIONS: Recent sexual activity, the frequency of that activity and the number of sexual partners pose an increased risk of urinary tract infection. Alcohol consumption frequency and amount correlated with these behaviors. PMID- 23017516 TI - A prospective longitudinal survey of erectile dysfunction in patients with localized prostate cancer treated with permanent prostate brachytherapy. AB - PURPOSE: Few studies have evaluated changes in erectile function with time before and after prostate brachytherapy using the International Index of Erectile Function-15, a sensitive, validated tool for assessing male sexual dysfunction. In this prospective study we evaluated the natural history of erectile function after prostate brachytherapy without supplemental therapy (external beam radiotherapy, phosphodiesterase-5 inhibitors or androgen deprivation therapy) using the International Index of Erectile Function-15. MATERIALS AND METHODS: We identified 119 patients who were followed at least 12 months after prostate brachytherapy between 2004 and 2010. Sexual and erectile function status were assessed before brachytherapy (baseline), and 3, 6, 12, 18, 24 and 36 months postoperatively using the International Index of Erectile Function-15. RESULTS: Mean total International Index of Erectile Function-15 score, and scores on the erectile function, orgasmic function, sexual desire and intercourse satisfaction domains 3 months after brachytherapy were significantly lower than at baseline (p <0.05). They remained lower until 36 months after prostate brachytherapy. Erectile function was maintained 12 months after brachytherapy in 16 of the 48 men (33.3%) with a baseline erectile function domain score of 11 or greater. There was no significant difference in clinical features except the age of patients who maintained the erectile function domain score and their counterparts 12 months after brachytherapy. Multivariate analysis revealed that age 70 years or greater was the only predictive factor for deteriorating erectile function after brachytherapy (p = 0.035). CONCLUSIONS: Findings indicate a global decrease in all domains of the International Index of Erectile Function-15 score 12 months after prostate brachytherapy. Also, patient age may influence the preservation of brachytherapy related potency. PMID- 23017517 TI - Clinical and pathological features predictive of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection. AB - PURPOSE: We determined the clinical and pathological features associated with nephrectomy at post-chemotherapy retroperitoneal lymph node dissection. MATERIALS AND METHODS: We retrospectively reviewed the testis cancer database from 1980 to 2007 to identify all patients treated with post-chemotherapy retroperitoneal lymph node dissection. Patients with pure seminoma and nongerm cell histology were excluded from study. A total of 1,807 patients were identified, of whom 17 without recorded mass size were excluded from further study. Pathological and clinical variables were assessed by bivariate analysis. Multivariate logistic regression was used to determine predictors of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection. RESULTS: The overall incidence of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection was 14.8% (265 of 1,790 cases). The incidence of nephrectomy was 17.0%, 18.9%, 13.6% and 8.0% in 1980 to 1988 (group 1), 1989 to 1997 (group 2), 1998 to 2002 (group 3) and 2002 to 2007 (group 4) (p = 0.0001). The nephrectomy rate for tumors less than 2, 2 to 5, 5 to 10 and greater than 10 cm was 6.0%, 5.8%, 13.9% and 31.9%, respectively (p = 0.0001). The incidence of nephrectomy based on retroperitoneal histology was 10.3% for fibrosis, 14.5% for teratoma and 20.4% for cancer (p = 0.0001). The strongest predictor of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection was retroperitoneal mass size greater than 10 cm (OR 9.30, 95% CI 3.8-22.7). CONCLUSIONS: The incidence of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection has decreased in the last 3 decades. A higher incidence was observed in patients with larger volume tumors, those who received salvage chemotherapy, those with a left primary testicular tumor and those with increased markers at post-chemotherapy surgery. PMID- 23017518 TI - Cost analysis of pediatric robot-assisted and laparoscopic pyeloplasty. AB - PURPOSE: An increasing percentage of pediatric pyeloplasties are being performed with assistance of the da Vinci(r) Surgical System. A review of the recent literature shows decreased operative times and length of hospital stays when robotic procedures are performed, although there are few published data comparing the cost of pediatric robotic and pure laparoscopic pyeloplasty. We reviewed a representative sample of pyeloplasties performed at our institution and performed a cost analysis. MATERIALS AND METHODS: We retrospectively identified 23 robot assisted and 23 laparoscopic pyeloplasties performed at our institution between August 2008 and April 2012. Total cost was calculated from direct and indirect costs provided by our billing department. RESULTS: Robotic procedures were shorter than pure laparoscopic procedures (200 vs 265 minutes, p <0.001) but there was no significant difference in the total cost of the 2 procedures ($15,337 vs $16,067, p <0.46). When compared to laparoscopic cases, subgroup analysis demonstrated decreased operative times (140 vs 265 minutes, p <0.00001) and total cost ($11,949 vs $16,067, p <0.0001) in robotic cases where stents were placed in an antegrade fashion. CONCLUSIONS: With widespread use the cost of robotic instrumentation may decrease, and experience may further shorten operative times. However, it currently remains to be seen whether robotic technology will become a cost-effective replacement for pure laparoscopy in the management of pediatric ureteropelvic junction obstruction. PMID- 23017519 TI - Surgical decompression is associated with decreased mortality in patients with sepsis and ureteral calculi. AB - PURPOSE: The combination of sepsis and ureteral calculus is a urological emergency. Traditional teaching advocates urgent decompression with nephrostomy tube or ureteral stent placement, although published outcomes validating this treatment are lacking. National practice patterns for such scenarios are currently undefined. Using a retrospective study design, we defined the surgical decompression rate in patients admitted to the hospital with severe infection and ureteral calculi. We determined whether a mortality benefit is associated with this intervention. MATERIALS AND METHODS: Patient demographics and hospital characteristics were extracted from the 2007 to 2009 Nationwide Inpatient Sample. We identified 1,712 patients with ureteral calculi and sepsis. Multivariate logistic regression was performed to determine the association between mortality and surgical decompression. RESULTS: Of the patients 78% underwent surgical decompression. Mortality was higher in those not treated with surgical decompression (19.2% vs 8.82%, p <0.001). Lack of surgical decompression was independently associated with an increased OR of mortality even when adjusting for patient demographics, comorbidities and geographic region of treatment (OR 2.6, 95% CI 1.9-3.7). CONCLUSIONS: Absent surgical decompression is associated with higher odds of mortality in patients with sepsis and ureteral calculi. Further research to determine predictors of surgical decompression is necessary to ensure that all patients have access to this life saving therapy. PMID- 23017520 TI - Enterocystoplasty vs detrusorectomy: outcome in the adult with spina bifida. AB - PURPOSE: Bladder augmentation by enterocystoplasty or detrusorectomy might prevent renal damage, help achieve dryness and decrease the need for antimuscarinics. We compared the long-term outcomes of enterocystoplasty and detrusorectomy in adults with spina bifida. MATERIALS AND METHODS: A retrospective study using the hospital electronic database was performed. We identified 47 patients with spina bifida (median age at followup 26.8 years) who underwent either enterocystoplasty or detrusorectomy between 1988 and 2004. Median followup was 13.1 years in the detrusorectomy group and 15.3 years in the enterocystoplasty group. RESULTS: In the detrusorectomy group 4 patients with treatment failure were identified. All 4 patients underwent secondary enterocystoplasty. No reoperation was necessary in the enterocystoplasty group. Preoperative bladder volume was approximately 100 ml higher in the detrusorectomy group (not significant). There was a significantly greater improvement of median bladder volume in the enterocystoplasty group (increase of 300 vs 77.5 ml, p = 0.006). No differences in continence rate, antimuscarinic use or condition of the upper tract were found. CONCLUSIONS: In this series of 47 patients long-term outcomes were good after enterocystoplasty and detrusorectomy, although bladder volume exhibited a greater increase in the enterocystoplasty group. No differences were observed among the other outcomes. If preoperative bladder volume is sufficient, detrusorectomy can be considered before enterocystoplasty is done. PMID- 23017521 TI - Development of an instrument to assess the health related quality of life of kidney stone formers. AB - PURPOSE: Urolithiasis is associated with pain and other decreases in health related quality of life, yet there is no urolithiasis specific instrument to measure quality of life. Quality of life is an important end point in the management of urolithiasis. Therefore, we developed the Wisconsin StoneQOL, a disease specific instrument to assess the quality of life of patients with urolithiasis. MATERIALS AND METHODS: Patients and urology providers identified important concepts related to quality of life of stone formers in groups and in individual cognitive interviews. Patients were recurrent stone formers including those with and those without current stones. A preliminary instrument was created, followed by patient feedback and item reduction. A 28-question instrument was ultimately developed which was tested for reliability as well as internal face, construct and discriminant validity in 248 stone formers. RESULTS: The internal consistency (for questions within domains) was high (mean Cronbach's alpha = 0.81). Correlation between domains was confirmed (Cronbach's alpha = 0.86). Discriminant validity was shown as stone formers with current stones scored lower than those who were stone-free. Among patients with active stones, those with symptoms scored lower on most questions and for the total score (p <0.0001) than those who were asymptomatic. CONCLUSIONS: The Wisconsin StoneQOL holds promise as a disease specific instrument that captures the unique symptoms and challenges associated with urolithiasis. As such, the Wisconsin StoneQOL is capable of assessing the health related quality of life of stone formers at various points along the disease continuum. Future assessment will establish minimal clinically important differences for use in individual patients. PMID- 23017523 TI - Masked pneumothorax: risk of valveless trocar systems. AB - PURPOSE: Unlike traditional valved trocars, the valveless trocar maintains pneumoperitoneum during laparoscopy by forming a CO(2) curtain at the proximal end of the trocar. This gas barrier instantaneously maintains exact intraperitoneal pressure that yields to the transient physiological changes seen with breathing. Due to this different mechanism of action, pneumothorax development may be masked by the valveless trocar system. MATERIALS AND METHODS: We retrospectively reviewed 850 transperitoneal laparoscopic kidney and adrenal surgeries in which a valveless trocar system was used to determine any record of pneumothorax detected intraoperatively or postoperatively. A patient with pneumothorax was considered a case and anesthetic parameters were reviewed. A matched control group was generated from patients treated with transperitoneal laparoscopic kidney and adrenal surgery using the valveless trocar with no complications. RESULTS: Pneumothorax was diagnosed in 10 patients (1.2%). Two cases were the result of intentional excision of the diaphragm, which were repaired intraoperatively, while 8 were not recognized until the postoperative period. Five of the patients (63%) with unintentional pneumothorax required chest tube placement for a mean of 2.4 days. The remaining 3 patients (37%) were treated conservatively and followed with serial chest x-rays. The only anesthetic variable that was significantly different between the groups was Delta end tidal CO(2) with greater fluctuations in end tidal CO(2) in the pneumothorax group than in controls (p = 0.03). CONCLUSIONS: Pneumothorax is a rare complication of laparoscopic urological surgery that is usually recognized intraoperatively through physiological changes. Valveless trocar systems mask these findings and can delay identification until the postoperative period. PMID- 23017522 TI - Toward the detection of prostate cancer in urine: a critical analysis. AB - PURPOSE: Prostate specific antigen and digital rectal examination have low specificity for detecting prostate cancer and they poorly predict the presence of aggressive disease. Urine is readily available and noninvasive, and it represents a promising source of biomarkers for the early detection and prediction of prostate cancer prognosis. We identified promising biomarkers for urine based prostate cancer, examined trends and outlined potential pitfalls. MATERIALS AND METHODS: We performed PubMed(r) and Web of Science(r) database searches of the peer reviewed literature on urine based testing for prostate cancer. Original studies of this subject as well as a small number of reviews were analyzed, including the strengths and weaknesses. We provide a comprehensive review of urine based testing for prostate cancer that covers the technical aspects, including the methodology of urine collection, as well as recent developments in biomarkers spanning the fields of genomics, epigenetics, transcriptomics, proteomics and metabolomics. RESULTS: The process of urine collection is subject to variability, which may result in conflicting clinical results. Detecting prostate cancer in urine is technically feasible, as demonstrated by numerous proof of principle studies, but few markers have been validated in multiple large sample sets. Biomarker development using urine has been accelerating in recent years with numerous studies identifying DNA, RNA, protein and metabolite based biomarkers in urine. Advanced clinical studies have identified PCA3 and TMPRSS2:ERG fusion transcripts as promising RNA markers for cancer detection and possibly prognosis. DNA methylation analysis of multiple genes improves specificity and represents a promising platform for developing clinical grade assays. CONCLUSIONS: Urine based testing is noninvasive and represents a rich source of novel biomarkers for prostate cancer. Although urine shows promise for detecting cancer, the ability to identify aggressive subsets of prostate cancer needs further development. PMID- 23017524 TI - Corporal Burnett "Snake" surgical maneuver for the treatment of ischemic priapism: long-term followup. AB - PURPOSE: We provide long-term followup on a modification of the Al-Ghorab distal penile corporoglanular shunt surgery for the treatment of ischemic priapism. MATERIALS AND METHODS: We conducted a retrospective review of patients surgically treated for ischemic priapism at The Johns Hopkins Hospital from January 2008 to April 2012 with the Burnett "Snake" maneuver of the Al-Ghorab shunt. Electronic medical records were reviewed to collect demographic information and telephone followup was performed to verify treatment outcomes. Patients completed the SHIM (Sexual Health Inventory for Men) to assess current erectile function. RESULTS: A total of 10 patients were analyzed (age range 31 to 59 years). Mean followup was 6.7 months (range 0.5 to 17). Priapism etiologies were idiopathic (3), trazodone (2), trazodone and cocaine (3), intracavernous injection of trimix (1) and spinal cord injury (1). There were 6 patients who had previously undergone unsuccessful surgical attempts at priapism decompression and mean priapism duration was 75 hours (range 24 to 288). Of the 10 men 8 achieved successful resolution of priapism with no recurrence. There were 2 men with recurrent priapism refractory to all management who were definitively treated with insertion of an inflatable penile prosthesis. Of 9 men 6 had normal erectile function preoperatively, of whom 2 achieved at least partial erectile function postoperatively. Complications were sustained by 2 men, including wound infection with skin necrosis in 1, and an intraoperative urethral injury in the other with subsequent urethrocutaneous fistula formation and wound infection with skin necrosis. CONCLUSIONS: The modified Al-Ghorab corporoglanular shunt using the Burnett snake maneuver is successful in resolving ischemic priapism, particularly in cases refractory to first line management, and in preventing further episodes of priapism. PMID- 23017525 TI - Delayed relief of ureteral obstruction is implicated in the long-term development of renal damage and arterial hypertension in patients with unilateral ureteral injury. AB - PURPOSE: A delay in the diagnosis and treatment of iatrogenic obstructive ureteral injury is the most important prognostic factor for worse results in terms of lesion repair and renal function recovery. The role of the time of relief in determining the onset of renal failure and arterial hypertension in patients with obstructive ureteral injury was evaluated. In addition, we analyzed the prognostic value of the ratio of urinary epidermal growth factor-to-monocyte chemotactic peptide-1 in predicting long-term renal function deterioration. MATERIALS AND METHODS: A total of 76 patients with obstructive ureteral injury and treated with reconstructive procedures were prospectively enrolled in the study. The ratio of epidermal growth factor-to-monocyte chemotactic peptide-1 was evaluated 4 weeks after the relief of obstruction. After a median followup of 60.8 months, estimated creatinine clearance and (99m)technetium mercaptoacetyltriglycine scan were evaluated. RESULTS: Within 2 weeks of the obstructive ureteral injury 36 patients underwent surgery for relief of obstruction while in the remaining 40 patients the surgery was performed after more than 2 weeks. Significant differences between the 2 groups were observed regarding mean mercaptoacetyltriglycine clearance of the obstructed kidney (p <0.0001), estimated creatinine clearance (p <0.001) and ratio of epidermal growth factor-to-monocyte chemotactic peptide-1 (p <0.0001). There was a direct correlation between mercaptoacetyltriglycine clearance and epidermal growth factor-to-monocyte chemotactic peptide-1 (rs = 0.78, p <0.0001). Patients with a time of relief greater than 2 weeks had a higher incidence of postoperative hypertension. On logistic regression the time of relief was the only significant variable predicting renal function deterioration (OR 1.49, p = 0.01). CONCLUSIONS: Patients who experience delayed relief of obstructive ureteral injury have decreased long-term renal function as suggested by the lower values of estimated creatinine clearance and mercaptoacetyltriglycine clearance, and are at risk for hypertension or exacerbation of preexisting hypertension. PMID- 23017526 TI - Predictive value of current imaging modalities for the detection of urolithiasis during pregnancy: a multicenter, longitudinal study. AB - PURPOSE: We determined the optimal imaging study by which to diagnose and treat pregnant patients with suspected urolithiasis. MATERIALS AND METHODS: A retrospective, multicenter study was performed to determine the comparative accuracy of imaging modalities used before the surgical management of suspected urolithiasis in pregnant patients. Patients with a clinical suspicion of urolithiasis were evaluated with directed imaging including renal ultrasound alone, renal ultrasound and low dose computerized tomography, or renal ultrasound and magnetic resonance urography. When indicated, patients underwent therapeutic ureteroscopy. The rate of negative ureteroscopy was determined and the positive predictive values of the imaging modalities were calculated. RESULTS: A total of 51 pregnant patients underwent ureteroscopy. The mean age of the cohort was 27 years. Mean gestational age was 24.4 weeks. Of the women 24 (47%) underwent renal ultrasound and low dose computerized tomography, 22 (43%) underwent ultrasound alone, and 5 (10%) underwent renal ultrasound and magnetic resonance urography. Negative ureteroscopy occurred in 7 of the 51 patients (14%). The rate of negative ureteroscopy among patients who underwent renal ultrasound alone, renal ultrasound and low dose computerized tomography, and renal ultrasound and magnetic resonance urography was 23%, 4.2% and 20%, respectively. The positive predictive value of computerized tomography, magnetic resonance and ultrasound was 95.8%, 80% and 77%, respectively. CONCLUSIONS: The rate of negative ureteroscopy was 14% among pregnant women undergoing intervention in our series. Of the group treated surgically after imaging with ultrasound alone, 23% had no ureteral stone, resulting in the lowest positive predictive value of the modalities used. Alternative imaging techniques, particularly low dose computerized tomography, offer improved diagnostic information that can optimize management and obviate unnecessary intervention. PMID- 23017527 TI - Safety and efficacy of once daily administration of 50 mg mirodenafil in patients with erectile dysfunction: a multicenter, double-blind, placebo controlled trial. AB - PURPOSE: We evaluated the improvement in erectile dysfunction and lower urinary tract symptoms as well as the safety of once daily administration of 50 mg mirodenafil in men with erectile dysfunction. MATERIALS AND METHODS: A total of 226 patients visited for treatment of erectile dysfunction and were recruited for the study. Of these men 180 met the study inclusion criteria after completing a 2 week screening period (visit [V]1). The patients were randomly allocated into 2 groups. Group 1 (90 patients) received 50 mg mirodenafil once daily and group 2 (90 patients) received a placebo daily. Blood pressure, heart rate, IIEF-5 (5 item version of the International Index of Erectile Function), and SEP (Sexual Encounter Profile) questions 2 and 3 were assessed at 4 (V2), 8 (V3) and 12 weeks after the start of treatment (V4). I-PSS (International Prostate Symptom Score), maximal flow rate and post-void residual volume were also assessed for the evaluation of lower urinary tract symptoms. RESULTS: Of the 180 patients 71 in group 1 and 63 in group 2 completed the 12-week clinical trial. IIEF-5 and I-PSS significantly improved in group 1 (p <0.001 for both). Facial flushing was the most common adverse effect, followed by headaches. Notably there were no statistically significant differences in either of the variables related to the cardiovascular system. CONCLUSIONS: Once daily administration of 50 mg mirodenafil was efficacious and safe for the treatment of erectile dysfunction and lower urinary tract symptoms. PMID- 23017528 TI - Trends in the use of incontinence procedures after radical prostatectomy: a population based analysis. AB - PURPOSE: Urinary incontinence is a frequent complication of radical prostatectomy with a detrimental impact on quality of life. We identified predictors and trends in the use of procedures for post-prostatectomy incontinence. MATERIALS AND METHODS: Using SEER (Surveillance, Epidemiology and End Results) cancer registry data linked with Medicare claims, we identified men 66 years old or older who were treated with radical prostatectomy in 2000 to 2007. The primary outcome was performance of an incontinence procedure. Demographic and clinical predictors of incontinence surgery were evaluated by multivariable regression analysis. RESULTS: Of 16,348 men treated with radical prostatectomy 1,057 (6%) had undergone at least 1 incontinence procedure by a median of 20 months after the procedure, including 61% who underwent the first incontinence procedure within 2 years of prostatectomy. Older age and residence in the South were associated with greater probability of an incontinence procedure. Black men and those living in nonmetropolitan areas were less likely than their peers to undergo an incontinence procedure. Of men treated with any incontinence procedure 15% underwent more than 1 type. Of those treated with bulking agents 39% also received a urethral sling or artificial urinary sphincter and 13% who received a sling also had an artificial urinary sphincter. In 34% of the men who underwent any incontinence surgery artificial urinary sphincter placement was the only procedure performed. CONCLUSIONS: In this population based cohort of older men with prostate cancer only 6% underwent an incontinence procedure after prostatectomy. This low rate may reflect the underuse of potentially beneficial procedures. PMID- 23017529 TI - Perioperative outcomes and oncologic efficacy from a pilot prospective randomized clinical trial of open versus robotic assisted radical cystectomy. AB - PURPOSE: Robotic assisted laparoscopic radical cystectomy for bladder cancer has been reported with potential for improvement in perioperative morbidity compared to the open approach. However, most studies are retrospective with significant selection bias. MATERIALS AND METHODS: A pilot prospective randomized trial evaluating perioperative outcomes and oncologic efficacy of open vs robotic assisted laparoscopic radical cystectomy for consecutive patients was performed from July 2009 to June 2011. RESULTS: To date 47 patients have been randomized with data available on 40 patients for analysis. Each group was similar with regard to age, gender, race, body mass index and comorbidities, as well as previous surgeries, operative time, postoperative complications and final pathological stage. We observed no significant differences between oncologic outcomes of positive margins (5% each, p = 0.50) or number of lymph nodes removed for open radical cystectomy (23, IQR 15-28) vs robotic assisted laparoscopic radical cystectomy (11, IQR 8.75-21.5) groups (p = 0.135). The robotic assisted laparoscopic radical cystectomy group (400 ml, IQR 300-762.5) was noted to have decreased estimated blood loss compared to the open radical cystectomy group (800 ml, IQR 400-1,100) and trended toward a decreased rate of excessive length of stay (greater than 5 days) (65% vs 90%, p = 0.11) compared to the open radical cystectomy group. The robotic group also trended toward fewer transfusions (40% vs 50%, p = 0.26). CONCLUSIONS: Our study validates the concept of randomizing patients with bladder cancer undergoing radical cystectomy to an open or robotic approach. Our results suggest no significant differences in surrogates of oncologic efficacy. Robotic assisted laparoscopic radical cystectomy demonstrates potential benefits of decreased estimated blood loss and decreased hospital stay compared to open radical cystectomy. Our results need to be validated in a larger multicenter prospective randomized clinical trial. PMID- 23017530 TI - Circulating obestatin is increased in patients with cardiorenal syndrome and positively correlated with vasopressin. AB - Obestatin regulates fluid and electrolyte homeostasis mainly by opposing the action of vasopressin (AVP). We measured plasma concentration of obestatin and AVP in patients with cardiorenal syndrome (CRS). Plasma AVP and obestatin concentration were measured in 34 patients with type II CRS. The data were compared to that in 31 patients with chronic kidney disease (CKD), 41 patients with chronic heart failure (CHF) and 30 healthy subjects. Obestatin was significantly higher in the patients with CRS (355.8 +/- 85.1 pg/ml) than that in the healthy controls (212.3 +/- 37.9 pg/ml, P<0.01), the patients with CKD (246.7 +/- 34.3 pg/ml, P<0.01) and the patients with CHF (258.4 +/- 112.1 pg/ml, P<0.01). AVP was also significantly higher in the patients with CRS (65.1 +/- 36.0 pg/ml) than that in the healthy controls (38.5 +/- 20.1 pg/ml, P<0.01), the patients with CKD (50.4 +/- 24.8 pg/ml, P<0.01) and the patients with CHF (54.6 +/- 16.3 pg/ml, P<0.01). Plasma concentration of obestatin was positively correlated with AVP plasma concentration in the overall analysis that included subjects from all disease categories (r = 0.219, P<0.05), but not within the CRS group. Plasma obestatin and vasopressin were elevated in patients with CRS. Plasma obestatin concentration seemed to be positively correlated with plasma AVP. PMID- 23017531 TI - Clinical and angiographic outcomes of patients treated with everolimus-eluting stents or first-generation Paclitaxel-eluting stents for unprotected left main disease. AB - OBJECTIVES: The goal of this study was to compare the outcomes of patients treated with everolimus-eluting stents (EES) with outcomes of patients treated with first-generation paclitaxel-eluting stents (PES) for unprotected left main disease (ULMD). BACKGROUND: No data exist about the comparison of these 2 types of stents in ULMD. METHODS: The primary endpoint of the study was a 1-year composite of cardiac death, nonfatal myocardial infarction, target vessel revascularization, and stroke (MACE). Secondary endpoints were 1-year target vessel failure (TVF) and 9-month angiographic in-segment restenosis >50%. RESULTS: From 2004 to 2010, a total of 390 patients underwent ULMD percutaneous coronary intervention (224 received PES and 166 EES). The 1-year MACE rate was 21.9% in the PES group and 10.2% in the EES group (p = 0.002). TVF rate was 20.5% in the PES group and 7.8% in the EES group (p < 0.001). The in-segment restenosis rate was 5.2% in the EES group and 15.6% in the PES group (p = 0.002). EES and EuroSCORE were the only variables related to the risk of MACE. EES (odds ratio: 0.32; p = 0.007) was also independently related to the risk of restenosis. CONCLUSIONS: EES implantation for ULMD is associated with a reduced incidence of 1-year MACE, TVF, and restenosis as compared with PES implantation. PMID- 23017532 TI - Reduction in mortality as a result of direct transport from the field to a receiving center for primary percutaneous coronary intervention. AB - OBJECTIVES: This study sought to determine whether mortality complicating ST segment elevation myocardial infarction (STEMI) was impacted by the design of transport systems. BACKGROUND: It is recommended that regions develop systems to facilitate rapid transfer of STEMI patients to centers equipped to perform primary percutaneous coronary intervention (PCI), yet the impact on mortality from the design of such systems remains unknown. METHODS: Within the framework of a citywide system where all STEMI patients are referred for primary PCI, we compared patients referred directly from the field to a PCI center to patients transported beforehand from the field to a non-PCI-capable hospital. The primary outcome was all-cause mortality at 180 days. RESULTS: A total of 1,389 consecutive patients with STEMI were assessed by the emergency medical services (EMS) and referred for primary PCI: 822 (59.2%) were referred directly from the field to a PCI center, and 567 (40.8%) were transported to a non-PCI-capable hospital first. Death at 180 days occurred in 5.0% of patients transferred directly from the field, and in 11.5% of patients transported from the field to a non-PCI-capable hospital (p < 0.0001. After adjusting for baseline characteristics in a multivariable logistic regression model, mortality remained lower among patients referred directly from the field to the PCI center (odds ratio: 0.52, 95% confidence interval: 0.31 to 0.88, p = 0.01). Similar results were obtained by using propensity score methods for adjustment. CONCLUSIONS: A STEMI system allowing EMS to transport patients directly to a primary PCI center was associated with a significant reduction in mortality. Our results support the concept of STEMI systems that include pre-hospital referral by EMS. PMID- 23017533 TI - Impact of home versus clinic-based management of chronic heart failure: the WHICH? (Which Heart Failure Intervention Is Most Cost-Effective & Consumer Friendly in Reducing Hospital Care) multicenter, randomized trial. AB - OBJECTIVES: The goal of this study was to make a head-to-head comparison of 2 common forms of multidisciplinary chronic heart failure (CHF) management. BACKGROUND: Although direct patient contact appears to be best in delivering CHF management overall, the precise form to optimize health outcomes is less clear. METHODS: This prospective, multicenter randomized controlled trial with blinded endpoint adjudication comprised 280 hospitalized CHF patients (73% male, age 71 +/- 14 years, and 73% with left ventricular ejection fraction <=45%) randomized to home-based intervention (HBI) or specialized CHF clinic-based intervention (CBI). The primary endpoint was all-cause, unplanned hospitalization or death during 12- to 18-month follow-up. Secondary endpoints included type/duration of hospitalization and healthcare costs. RESULTS: The primary endpoint occurred in 102 of 143 (71%) HBI versus 104 of 137 (76%) CBI patients (adjusted hazard ratio [HR]: 0.97 [95% confidence interval (CI): 0.73 to 1.30], p = 0.861): 96 (67.1%) HBI versus 95 (69.3%) CBI patients had an unplanned hospitalization (p = 0.887), and 31 (21.7%) versus 38 (27.7%) died (p = 0.252). The median duration of each unplanned hospitalization was significantly less in the HBI group (4.0 [interquartile range (IQR): 2.0 to 7.0] days vs. 6.0 [IQR: 3.5 to 13] days; p = 0.004). Overall, 75% of all hospitalization was attributable to 64 (22.9%) patients, of whom 43 (67%) were CBI patients (adjusted odds ratio: 2.55 [95% CI: 1.37 to 4.73], p = 0.003). HBI was associated with significantly fewer days of all-cause hospitalization (-35%; p = 0.003) and from cardiovascular causes (-37%; p = 0.025) but not for CHF (-24%; p = 0.218). Consequently, healthcare costs ($AU3.93 vs. $AU5.53 million) were significantly less for the HBI group (median: $AU34 [IQR: 13 to 81] per day vs. $AU52 [17 to 140] per day; p = 0.030). CONCLUSIONS: HBI was not superior to CBI in reducing all-cause death or hospitalization. However, HBI was associated with significantly lower healthcare costs, attributable to fewer days of hospitalization. (Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care [WHICH?]; ACTRN12607000069459). PMID- 23017534 TI - 4-dimensional magnetic resonance imaging of the levoatriocardinal vein. PMID- 23017535 TI - President's page: ACC councils, sections, and committees: where membership makes a difference. PMID- 23017536 TI - Interferon-Beta improves survival in enterovirus-associated cardiomyopathy. PMID- 23017537 TI - Takayasu arteritis presenting as dilated cardiomyopathy with left ventricular thrombus in association with ulcerative colitis. PMID- 23017538 TI - Age and gender differences in medical care utilization prior to suicide. AB - BACKGROUND: Analysis of temporal patterns of medical care utilization prior to suicide may aid in developing suicide prevention programs. The aim of this study was to investigate age and gender differences in temporal patterns of medical care utilization during 1 year prior to suicide. METHODS: Medical care utilization data of all suicide completers in the Republic of Korea whose death occurred in 2004 (7903 men and 3620 women) was used. Differences among the quarters in medical expenditures and number of medical care visits were analyzed using a repeated measures analysis. Total medical expenditures were compared to those of age- and gender-matched controls by multiple logistic regression analysis. RESULTS: Among suicides, 84% (81% in men, 91% in women) contacted medical care in the year prior to suicide. In 10-39 year-old women, the number of medical care visits for gastrointestinal disease increased significantly during the final 3 months prior to suicide. All suicide completers showed that the number of medical care visits for psychiatric disorders increased significantly during the final 3 months with the exception of 10-19 year age group. Total medical expenditures during the year prior to suicide were elevated significantly and associated significantly with suicide risk (OR, 1.20; 95% CI, 1.19-1.21). LIMITATIONS: Inaccuracies in the underlying disease and death statistics data may have led to misclassification bias. CONCLUSIONS: Medical care utilization increased as the date of suicide approached. There are age and gender differences in medical care utilization in the year prior to suicide. PMID- 23017539 TI - Risk factors at medical school for later severe depression: a 15-year longitudinal, nationwide study (NORDOC). AB - BACKGROUND: Doctors have an increased risk of suicide, and depressive symptoms are prominent among young doctors. We lack prospective studies that identify risk factors to be targeted in medical schools. METHODS: From 1993 to 2008, graduating medical students (n=631) from all four Norwegian universities participated in the Longitudinal Study of Norwegian Medical Students and Doctors (NORDOC). After their graduating term (T1), they were followed up 1 (T2), 4 (T3), 10 (T4), and 15 (T5) years later with postal surveys. Severe depressive symptoms were measured by the General Health Questionnaire-28 (T1, T2, T3, T4, and T5) and analyzed by generalized estimating equations. RESULTS: At T1 and T5, 13.7% and 7.2%, respectively, of the doctors reported severe depressive symptoms; a significant reduction over time (p=0.001) in both genders (response rates 56-83%). Independent risk factors for future depressive symptoms were: young age (odds ratio [OR] 1.1, 95% confidence interval [CI] 1.04-1.2, p=0.003); high neuroticism (OR 3.4, 95% CI 1.5-7.6, p=0.003); high reality weakness (OR 2.3, 95% CI 1.2-4.2, p=0.008); and severe depressive symptoms at T1 (OR 3.6, 95% CI 2.1-6.1, p<0.001). LIMITATIONS: Selection bias and concurrent life and work stress may have influenced the results. CONCLUSIONS: In addition to low age, high neuroticism yielded a threefold increased risk over the 15-year follow-up, whereas high reality weakness, which is linked to personality pathology, doubled the risk. These factors are clinically relevant for identification of students at risk. PMID- 23017540 TI - The prevalence of metabolic syndrome in drug-naive bipolar II disorder patients before and after twelve week pharmacological intervention. AB - BACKGROUND: Accumulating evidence indicates a high prevalence rate of metabolic disturbance in bipolar disorder (BP) patients. However, the prevalence across BP subtypes has been investigated to a lesser degree. In the current study, we surveyed the prevalence of metabolic syndrome among drug-naive bipolar II patients. Moreover, the effects of pharmacological treatment on metabolic indexes were also evaluated. METHODS: This study recruited fifty-six drug-naive BP II patients diagnosed according to the DSM-IV criteria. Among them, forty-four patients completed a 12-week pharmacological intervention with valproic acid, fluoxetine and lorazepam. Metabolic profiles and body mass index (BMI) were measured at baseline and 2 weeks, 8 weeks, and 12 weeks after receiving medication. RESULTS: The mean age of the 56 patients was 30.3+/-11.1. Before receiving medication, 6.5% of the patients met the ATP III criterion for metabolic syndrome. Among the 44 patients who completed the 12-week pharmacological intervention, the prevalence of metabolic syndrome increased from 7% to 10%. Repeated measurements showed that the changes in metabolic indexes were not significant, with the exceptions of BMI, waist circumference, and buttock circumference. In addition, the interaction between the improvement of hypomanic symptoms and BMI change was significant. LIMITATIONS: The study was limited by the follow-up duration and sample size. CONCLUSIONS: In drug-naive BP II patients, the prevalence of metabolic syndrome was significantly lower than that observed before in BP I patients. However, medications use was also associated with an increased risk of metabolic disturbance, although the impact was lesser. Clinical evidence suggests that metabolism and emotion homeostasis might share common mechanisms. PMID- 23017541 TI - Is bipolar disorder a risk factor for HIV infection? AB - HIV/AIDS is an extremely important public health challenge. Bipolar disorder spectrum has a significant prevalence, reported to be around 2.6%. This study analyses the relationship between sexual behaviors among MDQ positive and MDQ negative patients and its influence in HIV infection, and the impact of HIV diagnosis in both groups. Two hundred outpatients from a specialized clinic for HIV-care located in Walter Cantidio's University Hospital in Fortaleza, Brazil answered to a demographic questionnaire, the Mood Disorder Questionnaire (MDQ) and a sexual behavior questionnaire based on WHO's Behavioral Surveillance Surveys (BSS). Fifteen percent (N=30) of all HIV positive patients were MDQ+. The MDQ+ group was more likely to: be or have been married, have offspring, have sex with commercial and non-regular partners, have infrequent condom use with non regular partners and of not have used condom in their first sex. Despite more sexual practices among MDQ+ patients before HIV diagnosis, these patients had a more significant reduction of all behaviors after HIV diagnosis than the MDQ- group. PMID- 23017542 TI - Lifetime depressive disorders and adherence to anti-retroviral therapy in HIV infected Ugandan adults: a case-control study. AB - BACKGROUND: There is limited information on the impact of lifetime depressive disorders on adherence to ART. AIM: We examined the association between lifetime depressive disorders and adherence to anti-retroviral therapy (ART) among a rural clinic-based HIV positive population. We further explored whether this association was mediated by current depression and moderated by gender. METHODS: Two hundred HIV positive individuals who had<95% adherence and two hundred HIV positive individuals who had >=95% adherence were screened for depression using the self-reporting questionnaire (SRQ-20) and evaluated with the Mini neuropsychiatric interview (MINI). Multivariate logistic regression was used to assess the association between lifetime depressive disorders and adherence to ART. The logistic regression model of Baron and Kenny was used to evaluate the mediating effect of current depression. Hierarchical binomial logistic regression was used to evaluate the moderating effect of gender. RESULTS: HIV positive individuals with lifetime depressive disorders had an increased risk of non adherence to ART after controlling for education status, income, self-efficacy, perceived social support, cognitive impairment and current alcohol use disorders [AOR=1.68, 95%CI (1.02-2.79), p=0.04]. This association was stronger in females than males [AOR= 4.76, 95%CI (1.52-14.97), p=0.008]. LIMITATIONS: Findings cannot be generalized to ART naive individuals or those using ART for less than six months. CONCLUSION: Lifetime depressive disorders are associated with increased risk of non-adherence to ART in rural women with HIV infection in southern Uganda. Detection and treatment of depression can potentially improve adherence with HIV treatment in this setting. PMID- 23017543 TI - Prevalence, correlates, comorbidity and severity of bipolar disorder: results from the Singapore Mental Health Study. AB - BACKGROUND: Bipolar disorder (BPD) is a serious mental disorder and a leading cause of premature mortality worldwide. Prevalence and risk factors of BPD have not been well studied in multi-ethnic Asian populations. The study aimed to establish the prevalence of BPD and examine the associated socio-demographic correlates, comorbidity, severity, impairment and treatment contact in the Singapore resident population. METHODS: The Singapore Mental Health Study was a cross-sectional epidemiological survey of a nationally representative sample of the resident (citizens and permanent residents) population in Singapore. The diagnoses were established using the World Mental Health Composite International Diagnostic Interview version 3.0 (CIDI 3.0) diagnostic modules for lifetime and 12-month prevalence of select mental illnesses including BPD. RESULTS: The lifetime and 12-month prevalence estimates for BPD were 1.2% and 0.6%, respectively. More than two-thirds (69.4%) of respondents with lifetime BPD had other lifetime mental disorders, and approximately half (52.6%) of respondents with lifetime BPD also had at least one chronic physical condition; chronic pain was the most prevalent comorbid condition. LIMITATIONS: The data was based on respondents' self-report and there could be an element of recall bias and under reporting. We also did not obtain information on mixed episodes and rapid cycling disorders. CONCLUSIONS: The high comorbidity, clinical severity, and role impairment associated with BPD exert a heavy toll at an individual and societal level. PMID- 23017544 TI - Antidepressant effects of sertraline associated with volume increases in dorsolateral prefrontal cortex. AB - BACKGROUND: Structural brain imaging has revealed differences in gray matter volume between depressed individuals and control subjects in key structures related to emotion. The aim of the present study was to assess within subjects whether regional changes in gray matter volume were observed over time in depressed patients treated with sertraline. METHODS: Thirteen depressed patients were assigned to selective serotonin reuptake inhibitor (SSRI) treatment with sertraline. Structural magnetic resonance imaging (MRI) was performed at four time points over 12 weeks of treatment. Depressed individuals were compared to a control group of 10 subjects scanned at the same time points using voxel based morphometry and a statistical growth modeling technique. RESULTS: SSRI-treated patients showed a region of significantly increasing gray matter volume over time within the left dorsolateral prefrontal cortex (DLPFC) that specifically correlated with decreases in self-reported depression levels. No statistically significant changes were observed related to time in controls. LIMITATIONS: This study included a small sample size and the method of analysis was capable of detecting only linear changes in volume. CONCLUSIONS: Effective antidepressant treatment with sertraline is associated with left DLPFC volume increases. These volume increases may reflect cortical architectural changes associated with top down neuronal modulation of emotion. PMID- 23017545 TI - A hemocyte-derived Kunitz-BPTI-type chymotrypsin inhibitor, HlChI, from the ixodid tick Haemaphysalis longicornis, plays regulatory functions in tick blood feeding processes. AB - Inhibitors of proteases play key roles in the biological processes of vertebrate and invertebrate animals, including arthropod parasites. Here, we describe a cDNA that encodes a functionally active chymotrypsin inhibitor of the BPTI/Kunitz family of serine protease inhibitors from the hemocytes of the ixodid tick, Haemaphysalis longicornis, herein called HlChI. HlChI sequence is evolutionarily conserved and contains six cysteine residues and three disulfide bonds with a calculated molecular weight of 9.1 kDa. HlChI-specific mRNA was expressed in all developmental stages of ticks and the expression was up-regulated by host's blood feeding processes. Endogenous HlChI was localized mainly in the hemocytes. HlChI potently inhibited bovine pancreatic alpha-chymotrypsin for hydrolyzing the fluorogenic substrate (IC(50) 8.32 nM, K(d) 5.35 +/- 1.01 nM) and bovine casein digestion. However, HlChI weakly inhibited bovine pancreatic trypsin and could not affect the porcine elastase activity, suggesting its narrow specificity to chymotrypsin. HlChI was stable over the pH range 2-11 and heating up to 70 degrees C at pH 8. HlChI was highly stable to 8 M urea and 2% SDS at pH 8.0, when treated for 24 h at 37 degrees C. However, 0.2 M 2-mercaptoethanol caused complete but reversible inactivation of HlChI. Knockdown of HlChI gene by RNA interference (RNAi) caused death of the feeding ticks, failure of ticks to engorge and significantly reduced body weight gain. RNAi also resulted in significantly decreased egg conversion ratio and fecundity. These results suggest that HlChI is a chymotrypsin-specific inhibitor with high stability and may play regulatory functions in host's blood-feeding processes and tick reproduction. PMID- 23017546 TI - Evaluation with a focus on both the antimicrobial efficacy and cumulative skin irritation potential of chlorhexidine gluconate alcohol-containing preoperative skin preparations. AB - BACKGROUND: Important characteristics for ideal skin preparations include long lasting antimicrobial efficacy and low potential for skin irritation. METHODS: A total of 55 healthy adult subjects were enrolled to evaluate the antimicrobial effects of 3 test formulations applied to inguinal, abdominal, and antecubital sites at post-treatment time points of 30 seconds, 72 hours, and 7 days. To investigate skin irritation potential, the 3 formulations were tested in a 21-day repeat-insult patch test conducted on the skin of the backs of 23 healthy subjects. RESULTS: The mean log(10) reduction (MLR) at 7 days post-treatment produced by a 79% vol/vol ethanol containing 1% wt/vol chlorhexidine gluconate (1% CHG-EtOH) applied to abdominal sites was significantly superior to that produced by a 10% povidone-iodine solution (2.45 MLR vs 0.90 MLR; P < .05). The 1% CHG-EtOH and a 70% vol/vol isopropanol containing 2% wt/vol CHG (2% CHG-IPA) provided statistically equivalent persistence at 72 hours and 7 days post treatment. The 1% CHG-EtOH had less skin irritation potential than the 2% CHG-IPA and the 10% povidone-iodine solution, although the differences were not statistically significant (P > .05). CONCLUSION: Considering its persistent effect and low skin irritation potential, the 1% CHG-EtOH preparation is expected to perform well in surgical site preparation to reduce the risk of surgery- and catheter-related bloodstream infection. PMID- 23017547 TI - Primary care, the dental profession, and the prevalence of chronic diseases in the United States. AB - The population of the United States is aging rapidly, and the prevalence of chronic diseases will increase as the population grows and ages. The management of chronic illnesses will become an increasing burden for primary care providers. This article suggests that dentists may need to monitor chronic disease and control the risk factors (ie, provide primary care) for their own dental patients. PMID- 23017548 TI - The assessment and importance of hypertension in the dental setting. AB - Many patients with hypertension have uncontrolled disease. The dental visit presents a unique opportunity to screen patients for undiagnosed and undertreated hypertension, which may lead to improved monitoring and treatment. Although there are no clinical studies, it is generally recommended that nonemergent procedures be avoided in patients with a blood pressure of greater than 180/110 mm Hg. Because of the high prevalence of disease and medication use for hypertension, dentists should be aware of the oral side effects of antihypertensive medications as well as the cardiovascular effects of medications commonly used during dental visits. PMID- 23017549 TI - Tobacco cessation in the dental office. AB - Evidence-based tobacco-cessation guidelines when used by clinicians are effective in reducing tobacco use and obtaining successful quits by patients. Dentists have been encouraged to provide instruction and intervention on tobacco cessation in the dental office. The dental provider is in the unique position to relate oral findings to the patient and to provide advice to tobacco-using patients to quit. In addition, dentists are able to assess patients' self-addiction and level of readiness to quit tobacco use. With this information, dentists can assist in helping patients to stop using tobacco by providing appropriate pharmacotherapeutic aid and thus improve their oral and overall health. PMID- 23017550 TI - Dermatology of the head and neck: skin cancer and benign skin lesions. AB - Skin lesions are extremely common, and early detection of dangerous lesions makes skin cancer one of the most highly curable malignancies. By simply becoming aware of common lesions and their phenotypic presentation, dental professionals are empowered to detect suspicious dermatologic lesions in unaware patients. This article serves as an introduction to skin cancer and benign skin lesions for dental professionals. PMID- 23017551 TI - Nutrition and physical activity in health promotion and disease prevention: potential role for the dental profession. AB - Nutrition contributes to many of the leading causes of death in the United States, yet less than one-third of dental students feel competent to discuss the relationship of nutrition and systemic disease with their patients. The American Dental Association policy statements acknowledge a need for health professionals and organizations to provide continuing education to professionals and counseling to patients to combat the growing problems of overweight and obesity. Dentists can play a major role in educating patients to adopt a healthier lifestyle, including nutrition and physical activity recommendations. An understanding of the complexity of behavior change may enhance the dentist's ability to assist their patients in making desired changes. PMID- 23017552 TI - Screening for infectious diseases in the dental setting. AB - Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are 2 systemic infectious diseases that dental health care professionals can help identify with the goal of improving health outcomes, addressing health disparities, and improving the quality and quantity of life. Whether by identifying suspect oral lesions, as is the case with HIV infection, or offering rapid screening tests in the dental setting for both HIV and HCV, the dental team can play an important role in linkage to confirmatory diagnosis and care. PMID- 23017553 TI - Assessment and management of patients with diabetes mellitus in the dental office. AB - Diabetes mellitus is a serious chronic disease that affects many dental patients. Dental professionals have the potential and responsibility to assume an active role in the early identification, assessment, and management of their patients who present with or are at risk of developing diabetes. Close maintenance, meticulous monitoring of individual patient needs, and close collaboration with other health care professionals involved in the care will enable better control of the oral complications of diabetes and contribute to the better management of the patient's overall health status. PMID- 23017554 TI - Obesity prevention and intervention in dental practice. AB - Dentists have an important role in preventing and detecting oral and systemic diseases because of their diagnostic and screening abilities and the frequency of patient visits. These skills and practice paradigms should be considered in solving the obesity epidemic. The well-described connection between periodontal disease and diabetes is a reason for dentists to intervene in the rise of obesity. Dentists are in a unique position to identify and aid in treatment of obstructive sleep apnea, a condition associated with obesity and diabetes. Dentists can play a role in raising awareness of overweight status and obesity risk behaviors in children. PMID- 23017555 TI - Identification of the risk for osteoporosis in dental patients. AB - This article describes how dentists can recognize osteoporosis before fractures develop, and discusses whether osteoporosis affects tooth loss or inhibits implant osseointegration. Some success in diagnosing osteoporosis has been obtained using clinical questionnaires that attempt to identify those who have strong risk factors for the disease, and analysis of the sparse trabeculation and thinning of the mandibular cortex often seen in dental panoramic radiographs. The role of osteoporosis in periodontal disease is unclear as there are many conflicting reports, but the evidence suggests that tooth loss may be more prevalent in patients with osteoporosis. PMID- 23017556 TI - Assessing systemic disease risk in a dental setting: a public health perspective. AB - Screening and monitoring for systemic disease risk in a dental setting are valuable components for more effective disease prevention and control and health care delivery. This strategy can identify patients at increased risk of disease yet unaware of their increased risk and who may benefit from proven prevention/intervention strategies. The involvement of oral health care professionals in strategies to identify individuals at risk for coronary heart disease and diabetes will extend preventive and screening efforts necessary to slow the development of these diseases, and provide a portal for individuals who do not see a physician on a regular basis to enter into the general health care system. PMID- 23017557 TI - Concluding remarks. PMID- 23017558 TI - Preface. Primary health care in the dental office. PMID- 23017561 TI - Making SuperTracker work for you. PMID- 23017562 TI - Service-learning in dietetics courses: a benefit to the community and an opportunity for students to gain dietetics-related experience. PMID- 23017563 TI - Career development in nutrition and dietetics: carving out your own route. PMID- 23017564 TI - MySmileBuddy: an iPad-based interactive program to assess dietary risk for early childhood caries. PMID- 23017565 TI - Comparison between nutritional risk tools and parameters derived from bioelectrical impedance analysis with subjective global assessment. AB - BACKGROUND: Nutritional risk and malnutrition are highly prevalent among hospitalized patients. As a result, several methods have been developed to produce an adequate nutritional diagnosis. OBJECTIVE: We aimed to assess the relationship between nutritional risk tools and parameters derived from bioelectrical impedance analysis with a Subjective Global Assessment (SGA). DESIGN: A cross-sectional study was conducted from April to September 2010. PARTICIPANTS/SETTING: The study included 124 patients admitted to the Surgical Clinic I, University Hospital, Federal University of Santa Catarina, Florianopolis, Brazil, to undergo elective surgery. MAIN OUTCOME MEASURES: We utilized SGA and Nutritional Risk Screening 2002 (NRS 2002), Nutritional Risk Index (NRI), Fat-Free Mass Index (FFMI), Fat Mass Index (FMI), body cell mass as a percentage of the total weight (%BCM), and standardized phase angle (SPA). STATISTICAL ANALYSIS PERFORMED: The agreement was tested by kappa coefficient, while bivariate associations were tested by Mann-Whitney U test. RESULTS: Prevalence of nutritional risk by NRS 2002 and NRI or malnutrition by SGA, FFMI, FMI, %BCM, and SPA was 19.3%, 69.5%, 35.5%, 12.9%, 8.1%, 46.8%, and 4.8%, respectively. The best agreement was between SGA and NRS 2002 (kappa=.490), possibly because they constitute similar instruments. Patients identified as malnourished by SGA (B+C) showed considerably lower values of FFMI, FMI, BCM, and SPA. CONCLUSIONS: The results suggest that the NRS 2002 and parameters derived from bioelectrical impedance analysis identify patients with impaired nutritional status. PMID- 23017566 TI - Dietary pattern classifications and the association with general obesity and abdominal obesity in Korean women. AB - OBJECTIVES: This study was done to identify dietary patterns and determine relationships between obesity and dietary patterns in Korean women. SUBJECTS/METHODS: Using 3,742 cases of baseline data from the Korean Health and Genome Study, dietary patterns were identified using factor analysis of data from a validated food frequency questionnaire. Relationships between dietary patterns and obesity were analyzed. RESULTS: Four dietary patterns were identified: (a) "animal food" (greater intake of meats and fish), (b) "rice-vegetable" (greater intake of steamed rice, tofu, Kimchi, vegetables, dried anchovy, and seaweeds), (c) "bread-dairy" (greater intake of bread, eggs, milk, and dairy products), and (d) "noodle" (greater intake of ramyun, noodles, and Chajangmyeon). The "animal food," "bread-dairy," and "noodle" dietary patterns were preferred by younger people with higher education levels (P<0.01), but the "rice-vegetable" dietary pattern was preferred by older people with lower incomes and education levels (P<0.01). In Korean women, dietary patterns were related to abdominal obesity but not obesity. The "rice-vegetable" and "noodle" dietary patterns were associated with an increased risk of abdominal obesity. However, the "bread-dairy" dietary pattern had an inverse relationship with abdominal obesity. CONCLUSION: In this study we identified four unique dietary patterns in Korean women that were independently associated with abdominal obesity. Abdominal obesity was positively related to the "rice-vegetable" and "noodle" dietary patterns. These finding may be useful in the development of dietary guidelines and the prevention of abdominal obesity in Korean women. PMID- 23017567 TI - Evaluation of three short dietary instruments to assess fruit and vegetable intake: the National Cancer Institute's food attitudes and behaviors survey. AB - BACKGROUND: Fruit and vegetable (F/V) intake assessment tools that are valid, reliable, brief, and easy to administer and code are vital to the field of public health nutrition. OBJECTIVE: To evaluate three short F/V intake screeners (ie, a 2-item serving tool, a 2-item cup tool, and a 16-item F/V intake screener) among adults using multiple 24-hour dietary recalls (24-hour recalls) as the reference instrument and evaluate test-retest reliability of the screeners across a 2- to 3 week time period. DESIGN: Validity and reliability study. PARTICIPANTS/SETTING: Two hundred forty-four adults for the validity study and 335 adults for test retest reliability. STATISTICAL ANALYSES PERFORMED: Median values for F/V intakes were calculated for the screeners and 24-hour recalls. The Wilcoxon signed rank test was used to compare screeners with the 24-hour recalls. Deattenuated Pearson correlations were reported for validity and intraclass correlation coefficient used for reliability. RESULTS: The estimated median daily servings/cups of F/V for the 2-item serving screener was lower, for the 2-item cup screener was equivalent for men but higher for women, and for the 16-item F/V intake screener were about the same when compared with 24-hour recall values. The deattenuated correlations comparing the 24-hour recalls with the screeners were positive but weak for the 2-item serving screener, and were positive and moderate in strength for the 2-item cup and 16-item F/V intake screeners. The test-retest intraclass correlation coefficients were all positive and fairly strong for all of the screeners. CONCLUSIONS: Although dietary screeners offer a more cost-effective, less burdensome way to obtain gross estimates to rank individuals with regard to F/V intake, these methods are not recommended for assessing precise intake levels. PMID- 23017568 TI - A review of methods to assess parental feeding practices and preschool children's eating behavior: the need for further development of tools. AB - We reviewed tools developed to measure parental feeding practices and eating behavior and food intake or preferences of children aged 0 to 5 years. Two electronic literature databases (Medline and Psycinfo) were used to search for both observational and experimental studies in human beings. The articles selected for review were those presenting tools with data on internal consistency and/or test-retest reliability and/or construct validity. A total of 3,445 articles were retrieved, and further searching of reference lists and contact with experts produced an additional 18 articles. We identified three tools on the qualitative dimension of children's eating behavior, two tools on food intake or preferences, and one tool on parental feeding practices with rigorous testing of internal consistency, construct validity, and test-retest reliability. All other tools presented in this review need further evaluation of their validity or reliability. Because major gaps exist, we highlight the need for more tools on parental attention to children's hunger and satiety cues, and the need to evaluate the degree of control allowed to children younger than age 2 years in feeding events. Food avoidance (ie, behaviors or strategies to take away and to reject food) and food approach (ie, attractiveness for food stimuli) have not been assessed in children aged 12 to 24 months. Food preference tests based on sensory aspects rather than nutritional quality may be worth investigating. We identified a need for further evaluation of quality, especially test-retest reliability and construct validity, for most tools developed for use in studying children aged 0 to 5 years. PMID- 23017569 TI - Accuracy and reliability of direct observations of home-packed lunches in elementary schools by trained nutrition students. AB - Increased attention has been directed toward the school food environment because children consume important contributions toward their daily food intake while at school. In Canada, most elementary school students bring a lunch to school and there are minimal data on the composition and consumption of these lunches. Dietary assessment of home-packed lunches is challenging compared with assessment of standardized school meals due to greater diversity of items, nonstandard portions, and opaque containers. We assessed accuracy and reliability of a food observation method whereby upper-year nutrition students (n=15) were trained to assess packed lunch contents and intake in elementary schools. Accuracy and reliability was assessed during 2010-2011 in three observational phases: sample lunches, volunteer-consumed lunches, and elementary school students' lunches (n=32). Observers accurately identified 96% and 95% of items in the sample and volunteer lunches, respectively. Similarly, they accurately reported portion sizes for 86% and 94% of the items in the sample and volunteer lunches, thus showing improvements in successive phases. Interobserver reliability for amount consumed, by portion size and macronutrient content, ranged from 0.79 to 0.88 in the volunteer-consumed lunches and 0.78 to 0.86 in the students' lunches, with a majority >=0.80. It is noteworthy that the analyses for the amount consumed were conducted as absolute amounts with no allowances for discrepancies, which differs from other interobserver reliability assessments where as much as 25% discrepancy is considered agreement. Observers with prior nutrition knowledge assessed packed lunch contents and intake accurately and reliably by direct observation in an elementary school setting. PMID- 23017571 TI - Statistical innovations improve prevalence estimates of nutrient risk populations: applications in Sao Paulo, Brazil. AB - The objective of this study was to estimate the prevalence of inadequate micronutrient intake and excess sodium intake among adults age 19 years and older in the city of Sao Paulo, Brazil. Twenty-four-hour dietary recall and sociodemographic data were collected from each participant (n=1,663) in a cross sectional study, Inquiry of Health of Sao Paulo, of a representative sample of the adult population of the city of Sao Paulo in 2003 (ISA-2003). The variability in intake was measured through two replications of the 24-hour recall in a subsample of this population in 2007 (ISA-2007). Usual intake was estimated by the PC-SIDE program (version 1.0, 2003, Department of Statistics, Iowa State University), which uses an approach developed by Iowa State University. The prevalence of nutrient inadequacy was calculated using the Estimated Average Requirement cut-point method for vitamins A and C, thiamin, riboflavin, niacin, copper, phosphorus, and selenium. For vitamin D, pantothenic acid, manganese, and sodium, the proportion of individuals with usual intake equal to or more than the Adequate Intake value was calculated. The percentage of individuals with intake equal to more than the Tolerable Upper Intake Level was calculated for sodium. The highest prevalence of inadequacy for males and females, respectively, occurred for vitamin A (67% and 58%), vitamin C (52% and 62%), thiamin (41% and 50%), and riboflavin (29% and 19%). The adjustment for the within-person variation presented lower prevalence of inadequacy due to removal of within person variability. All adult residents of Sao Paulo had excess sodium intake, and the rates of nutrient inadequacy were high for certain key micronutrients. PMID- 23017570 TI - Relationship between adolescents' and their friends' eating behaviors: breakfast, fruit, vegetable, whole-grain, and dairy intake. AB - We examined associations between adolescents' and their friends' healthy eating behaviors, specifically breakfast, fruit, vegetable, whole-grain, and dairy food intake as reported by both adolescents and their friends. Data for this study were drawn from EAT-2010 (Eating and Activity among Teens), a population-based study examining multilevel factors of eating, physical activity, and weight related outcomes among adolescents (80% racial/ethnic minority) in Minneapolis/St Paul, MN, during the 2009-2010 academic year. In-class surveys were completed by 2,043 adolescents in 20 schools. Adolescents identified friends from a class roster; friends' survey data were then linked to each participant. Generalized estimating equation linear regression models were used to examine associations between adolescents' healthy eating behaviors and these behaviors from their friends (friend group and best friends), adjusting for sociodemographic characteristics. Significant positive associations were found for breakfast eating between adolescents and their friend groups and best friends (friend groups beta=.26, P<0.001; best friends beta=.19, P=0.004), as well was for whole grain intake (friend groups beta=.14, P<0.001; best friends beta=.13, P=0.003) and dairy food intake (friend groups beta=.08, P=0.014; best friends beta=.09, P=0.002). Adolescents' and their best friends' vegetable intake were also significantly related (beta=.09, P=0.038). No associations were seen among friends for fruit intake. Findings from our study suggest that adolescent friends exhibit similarities in healthy eating patterns. Registered dietitians and health professionals may consider developing strategies to engage friends to promote adolescents' healthy dietary behaviors. PMID- 23017572 TI - Stress, depression, social support, and eating habits reduce diet quality in the first trimester in low-income women: a pilot study. AB - Maternal diet quality influences birth outcomes. Yet, little research exists that assesses women's diet quality during the first trimester of pregnancy, a crucial time of placental and fetal development. This cross-sectional study, describing diet quality and its relationship with stress, depression, social support, and eating habits in the first trimester, may identify low-income women needing intensive dietary intervention. Seventy-one low-income women completed validated instruments measuring stress, depression, social support, and eating habits; had their height and weight measured; received training on portion-size estimation; and completed three 24-hour dietary recalls (1 weekend day and 2 nonconsecutive weekdays) from July 2009 to February 2010. Comparative and correlational analyses were done. Women with diet quality scores below the median (n=35) had more depression (9.6+/-5.1 vs 6.7+/-5.1) and stress (22.1+/-5.4 vs 19.3+/-4.8) and less control over meal preparation (5.0+/-1.5 vs 4.2+/-1.5) and support from others (52.0+/-12.0 vs 57.4+/-7.2) than did women with high diet quality scores (n=36). Diet quality was negatively related to depression (r=-0.41), stress (r= 0.35), skipping meals (r=-0.41), and control over meal preparation (r=-0.33), and positively related to support from others (r=0.38). Low-income women experiencing life stressors represent an at-risk group for low diet quality and may need intensive dietary intervention before and during pregnancy. More research designed to improve diet quality in low-income pregnant women is needed. PMID- 23017573 TI - Dietary total antioxidant capacity is associated with diet and plasma antioxidant status in healthy young adults. AB - Dietary total antioxidant capacity (TAC), based on the cumulative antioxidant activities of all the antioxidants present in food, has been shown to be inversely associated with risks of chronic diseases. However, dietary TAC has not been validated for its relevance in a healthy young population or for reliability and predictability for antioxidant status. Our study aimed to validate TAC as a tool in assessing antioxidant intake and to investigate whether dietary TAC predicts plasma antioxidant status in a healthy young population. Sixty healthy, nonsmoking college students at the University of Connecticut ages 18 to 25 years were recruited. Thirty-day food records and two 12-hour fasting blood samples were collected for dietary and plasma antioxidant assessments. After adjustment for total energy intake, TAC from diet and supplement was positively correlated with intakes of carotenoids (P<0.01), beta carotene (P<0.05), beta-cryptoxanthin (P<0.05), flavonoids (P<0.0001), isoflavones (P<0.01), flavan-3-ols (P<0.01), flavones (P<0.05), and flavonols (P<0.0001). Dietary TAC was an independent predictor of plasma TAC determined by vitamin C equivalent antioxidant capacity (P<0.01) and by ferric-reducing ability of plasma (P<0.0001), plasma glutathione peroxidase (P<0.01), red blood cell glutathione peroxidase (P<0.05), alpha tocopherol (P<0.05), and lutein (P<0.05). Results were similar for TAC from diet sources only. The findings suggest that dietary TAC is a good predictor of dietary and plasma antioxidant status in this sample of young adult men and women. PMID- 23017574 TI - Comparison of visual estimation methods for regular and modified textures: real time vs digital imaging. AB - A variety of methods are available for assessing diet; however, many are impractical for large research studies in an institutional environment. Technology, specifically digital imaging, can make diet estimations more feasible for research. Our goal was to compare a digital imaging method of estimating regular and modified-texture main plate food waste with traditional on-site visual estimations, in a continuing and long-term care setting using a meal-tray delivery service. Food waste was estimated for participants on regular (n=36) and modified-texture (n=42) diets. A tracking system to ensure collection and digital imaging of all main meal plates was developed. Four observers used a modified Comstock method to assess food waste for vegetables, starches, and main courses on 551 main meal plates. Intermodal, inter-rater, and intra-rater reliability were calculated using intraclass correlation for absolute agreement. Intermodal reliability was based on one rater's assessments. The digital imaging method results were in high agreement with the real-time visual method for both regular and modified-texture food (intraclass correlation=0.90 and 0.88, respectively). Agreements between observers for regular diets were higher than those for modified-texture food (range=0.91 to 0.94; 0.82 to 0.91, respectively). Intra rater agreements were very high for both regular and modified-texture food (range=0.93 to 0.99; 0.91 to 0.98). The digital imaging method is a reliable alternative to estimating regular and modified-texture food waste for main meal plates when compared with real-time visual estimation. Color, shape, reheating, mixing, and use of sauces made modified-texture food waste slightly more difficult to estimate, regardless of estimation method. PMID- 23017575 TI - Academy of Nutrition and Dietetics: Standards of professional performance for registered dietitians (competent, proficient, expert) in clinical nutrition management. PMID- 23017576 TI - What is the FODMAP diet? PMID- 23017582 TI - Expression of NSAID-activated gene-1 by EGCG in head and neck cancer: involvement of ATM-dependent p53 expression. AB - Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea, possesses remarkable chemopreventive and therapeutic potential against various types of cancer, including head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanism involved is not completely understood. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), a transforming growth factor beta superfamily protein, is shown to be induced by several antitumorigenic compounds and to exhibit proapoptotic and antitumorigenic activities. In this report, we demonstrate that EGCG transcriptionally induced the expression of NAG-1 during EGCG-induced apoptosis of HNSCC cells. Reporter assays, using the luciferase constructs containing the NAG-1 promoter, demonstrate that p53 is required for EGCG-mediated activation of NAG-1. Overexpression of NAG-1 enhanced the apoptotic effect of EGCG, whereas suppression of NAG-1 expression by small interfering RNA attenuated EGCG-induced apoptosis in HNSCC cells. Subsequently, we found that ataxia-telangiectasia mutated (ATM) plays an important role in activating these proapoptotic proteins (NAG-1 and p53) and cell cycle inhibitor (p21). Furthermore, EGCG significantly inhibited tumor formation as assessed by xenograft models, and this result is accompanied with induction of apoptotic cells and NAG-1 expression in tumor tissue samples. Taken together, these results demonstrate for the first time that EGCG induces apoptosis via ATM/p53-dependent NAG-1 expression in HNSCC, providing an additional mechanistic explanation for the apoptotic activity of EGCG. PMID- 23017583 TI - Early zebrafish embryogenesis is susceptible to developmental TDCPP exposure. AB - BACKGROUND: Chlorinated phosphate esters (CPEs) are widely used as additive flame retardants for low-density polyurethane foams and have frequently been detected at elevated concentrations within indoor environmental media. OBJECTIVES: To begin characterizing the potential toxicity of CPEs on early vertebrate development, we examined the developmental toxicity of four CPEs used in polyurethane foam: tris(1,3-dichloro-2-propyl) phosphate (TDCPP), tris(2 chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCPP), and 2,2 bis(chloromethyl)propane-1,3-diyl tetrakis(2-chlorethyl) bis(phosphate) (V6). METHODS: Using zebrafish as a model for vertebrate embryogenesis, we first screened the potential teratogenic effects of TDCPP, TCEP, TCPP, and V6 using a developmental toxicity assay. Based on these results, we focused on identification of susceptible windows of developmental TDCPP exposure as well as evaluation of uptake and elimination of TDCPP and bis(1,3-dichloro-2 propyl)phosphate (BDCPP, the primary metabolite) within whole embryos. Finally, because TDCPP-specific genotoxicity assays have, for the most part, been negative in vivo and because zygotic genome remethylation is a key biological event during cleavage, we investigated whether TDCPP altered the status of zygotic genome methylation during early zebrafish embryogenesis. RESULTS: Overall, our findings suggest that the cleavage period during zebrafish embryogenesis is susceptible to TDCPP-induced delays in remethylation of the zygotic genome, a mechanism that may be associated with enhanced developmental toxicity following initiation of TDCPP exposure at the start of cleavage. CONCLUSIONS: Our results suggest that further research is needed to better understand the effects of a widely used and detected CPE within susceptible windows of early vertebrate development. PMID- 23017584 TI - Utilization of Savannah Harbor river sediment as the primary raw material in production of fired brick. AB - A laboratory-scale study was conducted to assess the feasibility of the production of fired bricks from sediments dredged from the Savannah Harbor (Savannah, GA, USA). The dredged sediment was used as the sole raw material, or as a 50% replacement for natural brick-making clay. Sediment bricks were prepared using the stiff mud extrusion process from raw mixes consisted of 100% dredged sediment, or 50% dredged sediment and 50% brick clay. The bricks were fired at temperatures between 900 and 1000 degrees C. Physical and mechanical properties of the dredged sediment brick were found to generally comply with ASTM criteria for building brick. Water absorption of the dredged sediment bricks was in compliance with the criteria for brick graded for severe (SW) or moderate (MW) weathering. Compressive strength of 100% dredged sediment bricks ranged from 8.3 to 11.7 MPa; the bricks sintered at 1000 degrees C met the requirements for negligible weathering (NW) building brick. Mixing the dredged sediment with natural clay resulted in an increase of the compressive strength. The compressive strength of the sediment-clay bricks fired at 1000 degrees C was 29.4 MPa, thus meeting the ASTM requirements for the SW grade building brick. Results of this study demonstrate that production of fired bricks is a promising and achievable productive reuse alternative for Savannah Harbor dredged sediments. PMID- 23017585 TI - Cholesterol-lowering efficacy of Lactobacillus plantarum CECT 7527, 7528 and 7529 in hypercholesterolaemic adults. AB - Previous studies have indicated that supplementation with probiotic bacteria may improve lipid metabolism. The present study was aimed at investigating the effects of a mixture of three strains of Lactobacillus plantarum (CECT 7527, CECT 7528 and CECT 7529) on cholesterol-lowering efficacy in hypercholesterolaemic patients. A total of sixty volunteers (thirty participants in the placebo group and thirty counterparts in the L. plantarum group), aged 18-65 years old, participated in a controlled, randomised, double-blind trial. The study group received one capsule daily containing 1.2 * 10(9) colony-forming units of Lactobacillus strains in a unique dose; the placebo group consumed the same product without bacteria for 12 weeks. A significant reduction of 13.6 % in plasma total cholesterol (TC) levels was observed after 12 weeks of consumption in the L. plantarum group when compared with the placebo group. The lipidic outcomes were also analysed based on TC values at baseline: low initial values (LIV, 2000-2500 mg/l) v. high initial values (HIV, 2510-3000 mg/l). In the HIV group, the L. plantarum treatment showed a reduction after 12 weeks of consumption compared with the placebo group in TC, LDL-cholesterol (LDL-C) and oxidised LDL-C (17.4, 17.6 and 15.6 %, respectively). In the LIV, the L. plantarum treatment only showed a reduction after 12 weeks of consumption when compared with the placebo group in TC (9.4 %). The present results showed that the biofunctionality of L. plantarum (CECT 7527, CECT 7528 and CECT 7529) is proportional to the cardiovascular risk of the patient, having a better effect in patients with higher levels of cholesterol. PMID- 23017586 TI - The role of cognitive attributions for smoking in subsequent smoking progression and regression among adolescents in China. AB - Previous studies have documented that cognitive attributions are correlated with adolescent smoking. The present study further explored whether cognitive attributions for smoking influenced adolescents' future smoking behaviors, especially transitions to more advanced stages of smoking. Participants were 12,382 middle and high school students (48.5% males and 51.5% females) in seven large cities in China. They completed two waves of surveys one year apart. Cognitive attributions for smoking and three smoking behavior outcomes (lifetime smoking, past 30-day smoking, and daily smoking) were assessed. Changes in smoking, including progression from lower stages to higher stages and regression from higher stages to lower stages, over a one-year period, were defined longitudinally. Polychotomous logistic regression was used to examine associations between cognitive attributions for smoking and changes in smoking status over one year, adjusting for demographic characteristics and other plausible confounders. Seven out of eight cognitive attributions for smoking were associated with subsequent smoking behaviors (p<0.05). Curiosity, autonomy, social image, social belonging, and coping influenced earlier stages of smoking, whereas mental enhancement and engagement influenced later stages of smoking. Curiosity, autonomy, social image, and mental enhancement preceded smoking progression; social belonging prevented smoking regression; and coping and engagement both preceded smoking progression and prevented smoking regression. This study demonstrates that different cognitive attributions influence smoking at different stages in different ways. These findings could inform smoking prevention and cessation programs targeting Chinese adolescents. PMID- 23017587 TI - Distal aneurysms of intracranial arteries: application of numerical nomenclature, predilection for cerebellar arteries, and results of surgical management. AB - BACKGROUND: Distal intracranial aneurysms are rare, have unclear origins, and are frequently nonsaccular. Published clinical experience with these aneurysms is limited. OBJECTIVE: To examine differences between distal aneurysms of cerebral and cerebellar arteries and to examine results associated with surgical therapy in 140 patients. METHODS: Distal aneurysms in the cerebral arteries were defined as outside the circle of Willis, on or beyond the A2 anterior cerebral artery, M2 middle cerebral artery, or P2 posterior cerebral segments. Distal aneurysms in the cerebellar arteries were on or beyond the s2 superior cerebellar artery, a2 anterior inferior cerebellar artery, or p2 posterior inferior cerebellar artery segments. Clinical data, microsurgical technique, and patient outcomes were reviewed. RESULTS: The incidence of distal cerebellar artery aneurysms was 4.3 times greater than distal cerebral artery aneurysms (6.5% vs. 28.6%; P< 0.01). The A3 anterior cerebral artery segment and the p2 and p3 posterior inferior cerebellar artery segments were the most common sites. Presentation with aneurysm rupture was more frequent with cerebellar aneurysms (65% vs. 40%; P< 0.05). Distal cerebellar artery aneurysms were less likely than distal cerebral artery aneurysms to be clipable (40% vs. 72%; P< 0.01), with 42% treated with trapping alone. Overall, 14% required a bypass. CONCLUSIONS: Distal intracranial aneurysms have a predilection for cerebellar arteries and are not as rare as the literature suggests. Application of standardized nomenclature for segmental anatomy to these lesions will increase the precision of anatomic description and clarity of clinical discourse. Although technically difficult, good clinical results can be expected with surgical management. PMID- 23017588 TI - Gross total resection correlates with long-term survival in pediatric patients with glioblastoma. AB - OBJECTIVE: Glioblastoma is a rare central nervous system neoplasm in pediatric patients. Few studies focused exclusively on this disease in this population. Available literature suggests that this disease behaves differently between pediatric and adult patients. We set out to study patients younger than 18 years of age, carrying the diagnosis of glioblastoma not of the brainstem, their clinical characteristics and clinical factors associated with clinical outcome. METHODS: Thirty-seven pediatric patients with the diagnosis of glioblastoma not of the brainstem, who were treated in our institution from 1982-2011, were identified and studied retrospectively. RESULTS: All patients underwent surgical intervention. Seventeen patients (45.9%) had gross total resection (GTR). Thirteen patients (35.1%) had subtotal resection and seven (18.9%) had biopsy. After surgery, 35 patients received radiation therapy (94.6%) and 34 patients (91.9%) received chemotherapy (various agents depending on the institutional protocols established at the time of treatment and family choice). Median follow up time was 17.5 months, ranging from 0.5-186 months. The median overall survival is 18.7 months (95% confidence interval 15.7-21.8 months). The survival rate at 1, 2, and 5 years is 63.9%, 44.5%, and 17.6%, respectively. The median overall survival for patients with GTR is 45.1 months (95% confidence interval 27.5-62.8 months), 8.7 or 11.5 months for patients with subtotal resection or biopsy, respectively. GTR was accomplished only in patients with superficially located tumors. CONCLUSIONS: GTR significantly associates with long-term survival in our population of pediatric patients with glioblastoma not of the brainstem. PMID- 23017590 TI - Human parvovirus 4 viremia in young children, Ghana. PMID- 23017589 TI - Surgical resection of cavernous malformations of the brainstem: evolution of a minimally invasive technique. AB - OBJECTIVE: The purpose of this study is to provide an institutional retrospective review of surgically treated brainstem cavernous malformations. METHODS: Between 2005 and 2010, 22 consecutive patients with brainstem cavernous malformations (15 female and 7 male) with a mean age of 43 years underwent surgical treatment. Mean volume of the resected cavernous malformations was 0.65 cm(3). A minimally invasive resection technique was used for these cases, in conjunction with skull base approaches. RESULTS: The mean follow-up period was 26.6 months (range, 4-68 months). Of the 22 patients, 9% did not have clear evidence of hemorrhage at the time of presentation. Of the remainder, 22% had two or more instances of hemorrhage documented by magnetic resonance imaging. After resection and during follow-up, 54% of patients had an improvement in their modified Rankin scale, whereas 14% were worse compared with their preoperative presentation; 32% were unchanged and 9% of patients were found to have residual cavernoma post-surgery. CONCLUSION: Our longitudinal experience has guided us to emphasize minimally invasive approaches during resection of the brainstem cavernous malformations, occasionally at the expense of achieving a complete resection, to improve patient outcomes. PMID- 23017591 TI - Intravascular stent implantation for the management of pulmonary artery stenosis. AB - Pulmonary artery stenosis is a challenging problem in the management of congenital heart disease. Untreated pulmonary artery stenosis may contribute to increased mortality and morbidity, and lead to suboptimal results following surgical repair of congenital heart disease. Intravascular stent implantation has emerged as one of the preferred treatment options for pulmonary artery stenosis. However, issues regarding the effectiveness and complications of stent implantation for pulmonary artery stenosis need to be identified. In addition, difficulties of stent implantation in the paediatric setting, as a consequence of small vessel size and subsequent vessel growth, are also important considerations. This review will evaluate the short and long-term effectiveness, the outcomes and complications, and discuss the potential problems of stent implantation for pulmonary artery stenosis. PMID- 23017592 TI - Orthobunyavirus antibodies in humans, Yucatan Peninsula, Mexico. AB - We performed a serologic investigation to determine whether orthobunyaviruses commonly infect humans in the Yucatan Peninsula of Mexico. Orthobunyavirus specific antibodies were detected by plaque reduction neutralization test in 146 (18%) of 823 persons tested. Further studies are needed to determine health risks for humans from this potentially deadly group of viruses. PMID- 23017593 TI - Urban energy mining from sewage sludge. AB - This work showed that sewage sludge could be a strong candidate for biodiesel production. High lipid content (18-20%) with C(16-18)-carbon range was experimentally identified and measured. These lipids from sewage sludge were converted into biodiesel via the transesterification reaction with MgO CaO/Al(2)O(3) derived from magnesium slag, and biodiesel conversion was ~98%. The experimental work enabled explaining that temperature is the main driving force for the transesterification reaction, which can be enhanced in the presence of CO(2). This also enables combination of esterification of free fatty acids and transesterification of triglycerides into a single process within 1 min in the temperature range of 350-500 degrees C. Sewage sludge residue after extracting lipids was also a good feedstock for recovering energy via thermo-chemical processes. The impact of CO(2) co-feed on the pyrolysis/gasification process of SS residue was also investigated in this work. The CO(2) injected into the thermo chemical process remarkably increased the generation of CO by a factor of 2. Moreover, the introduction of CO(2) into the pyrolysis/gasification process enabled reducing condensable hydrocarbons (tar) by expediting cracking; thus, utilizing CO(2) as chemical feedstock for the gasification process not only leads to higher thermal efficiency but also has environmental benefits. PMID- 23017594 TI - Formation of automatic letter-colour associations in non-synaesthetes through likelihood manipulation of letter-colour pairings. AB - Grapheme-colour synaesthesia is a well-characterized phenomenon in which achromatic letters and/or digits automatically and systematically trigger specific colour sensations. Models of its underlying mechanisms diverge on a central question: whether triggered sensations reflect (1) an overdeveloped capacity in normal cross-modal processing (i.e., sharing characteristics with the general population), or rather (2) qualitatively deviant processing (i.e., unique to a few individuals). To test to what extent synaesthesia-like (automatic) letter-colour associations may be learned by non-synaesthetes into adulthood, implied by (1), we developed a learning paradigm that aimed to implicitly train such associations via a visual search task that employed statistical probability learning of specific letter-colour pairs. In contrast to previous synaesthesia training studies (Cohen Kadosh, Henik, Catena, Walsh, & Fuentes, 2009; Meier & Rothen, 2009), here all participants were naive as to the end-goal of the experiment (i.e., the formation of letter-colour associations), mimicking the learning conditions of acquired grapheme-colour synaesthesia (Hancock, 2006; Witthoft & Winawer, 2006). In two experiments, we found evidence for significant binding of colours to letters by non-synaesthetes. These newly-formed associations showed synaesthesia-like characteristics, because they correlated in strength with performance on individual synaesthetic Stroop-tasks (experiment 1), and because interference between the learned (associated) colour and the real colour during letter processing depended on their relative positions in colour space (opponent vs. non-opponent colours, experiment 2) suggesting automatic formation on a perceptual rather than conceptual level, analogous to synaesthesia. Although not evoking conscious colour percepts, these learned, synaesthesia-like associations in non-synaesthetes support that common mechanisms may underlie letter-colour associations in synaesthetes and non-synaesthetes. PMID- 23017595 TI - Spatial attention modulates early face processing. AB - It is widely reported that inverting a face dramatically affects its recognition. Previous studies have shown that face inversion increases the amplitude and delays the latency of the face-specific N170 component of the event-related potential (ERP) and also enhances the amplitude of the occipital P1 component (latency 100-132 ms). The present study investigates whether these effects of face inversion can be modulated by visual spatial attention. Participants viewed two streams of visual stimuli, one to the left and one to the right of fixation. One stream consisted of a sequence of alphanumeric characters at 6.67 Hz, and the other stream consisted of a series of upright and inverted images of faces and houses presented in randomized order. The participants' task was to attend selectively to one or the other of the streams (during different blocks) in order to detect infrequent target stimuli. ERPs elicited by inverted faces showed larger P1 amplitudes compared to upright faces, but only when the faces were attended. In contrast, the N170 amplitude was larger to inverted than to upright faces only when the faces were not attended. The N170 peak latency was delayed to inverted faces regardless of attention condition. These inversion effects were face specific, as similar effects were absent for houses. These results suggest that early stages of face-specific processing can be enhanced by attention, but when faces are not attended the onset of face-specific processing is delayed until the latency range of the N170. PMID- 23017596 TI - The effects of aging on emotion-induced modulations of source retrieval ERPs: evidence for valence biases. AB - Many behavioral studies have shown that memory is enhanced for emotionally salient events across the lifespan. It has been suggested that this mnemonic boost may be observed for both age groups, particularly the old, in part because emotional information is retrieved with less effort than neutral information. Neuroimaging evidence suggests that inefficient retrieval processing (temporally delayed and attenuated) may contribute to age-related impairments in episodic memory for neutral events. It is not entirely clear whether emotional salience may reduce these age-related changes in neural activity associated with episodic retrieval for neutral events. Here, we investigated these ideas using event related potentials (ERPs) to assess the neural correlates of successful source memory retrieval ("old-new effects") for neutral and emotional (negative and positive) images. Behavioral results showed that older adults demonstrated source memory impairments compared to the young but that both groups showed reduced source memory accuracy for negative compared to positive and neutral images; most likely due to an arousal-induced memory tradeoff for the negative images, which were subjectively more arousing than both positive and neutral images. ERP results showed that early onsetting old-new effects, between 100 and 300 ms, were observed for emotional but not neutral images in both age groups. Interestingly, these early effects were observed for negative items in the young and for positive items in the old. These ERP findings offer support for the idea that emotional events may be retrieved more automatically than neutral events across the lifespan. Furthermore, we suggest that very early retrieval mechanisms, possibly perceptual priming or familiarity, may underlie the negativity and positivity effects sometimes observed in the young and old, respectively, for various behavioral measures of attention and memory. PMID- 23017597 TI - Neural mechanisms of encoding social and non-social context information in autism spectrum disorder. AB - Individuals with autism spectrum disorder (ASD) often fail to attach context to their memories and are specifically impaired in processing social aspects of contextual information. The aim of the present study was to investigate the modulatory influence of social vs. non-social context on neural mechanisms during encoding in ASD. Using event-related fMRI, 13 boys with ASD and 13 typically developing boys comparable for age and IQ were investigated during encoding of neutral objects presented either with a social (faces) or a non-social (houses) context. A memory paradigm was then applied to identify brain activation patterns associated with encoding of subsequently recollected versus non-recollected objects. On the behavioural level, no significant between-group differences emerged. In particular, no differential effects of context on memory performance were observed. Neurally, however, context-specific group differences were observed in several brain regions. During encoding of subsequently recollected objects presented with a face, ASD subjects (compared to controls) showed reduced neural activation in the bilateral inferior frontal gyrus, bilateral middle frontal gyrus and right inferior parietal lobule. Neural activation in the right inferior frontal gyrus was positively correlated with memory performance in controls, but negatively in ASD individuals. During encoding of subsequently non recollected objects presented in the non-social context, ASD subjects showed increased activation in the dorsal MPFC. Our findings suggest that in ASD subjects, fronto-parietal brain regions subserving memory formation and the association of contextual information are activated atypically when a social context is presented at encoding. The data add to findings from related research fields indicating that in ASD, socioemotional impairment extends into domains beyond social cognition. Increased activation in the dorsal MPFC in ASD individuals might reflect supervisory cognitive processes related to the suppression of a distracting non-social context. PMID- 23017599 TI - Formaldehyde induces rapid glutathione export from viable oligodendroglial OLN-93 cells. AB - Formaldehyde is a neurotoxic environmental pollutant that can also be produced in the body by certain enzymatic reactions. To test for the potential consequences of an exposure of oligodendrocytes to formaldehyde, we used OLN-93 cells as a model system. Treatment with formaldehyde altered the cellular glutathione (GSH) content of these cells by inducing a rapid time- and concentration-dependent export of GSH. Half-maximal effects were observed for a formaldehyde concentration of about 0.2 mM. While the basal GSH efflux from OLN-93 cells was negligible even when the cellular GSH content was doubled by pre-incubation of the cells with cadmium chloride, the formaldehyde-stimulated export increased almost proportionally to the cellular GSH content. In addition, the stimulated GSH export required the presence of formaldehyde and was almost completely abolished after removal of the aldehyde. Analysis of kinetic parameters of the formaldehyde-induced GSH export revealed similar K(m) and V(max) values of around 100 nmol/mg and 40 nmol/(hmg), respectively, for both OLN-93 cells and cultured astrocytes. The transporter responsible for the formaldehyde-induced GSH export from OLN-93 cells is most likely the multidrug resistance protein 1 (Mrp1), since this transporter is expressed in these cells and since the inhibitor MK571 completely prevented the formaldehyde-induced GSH export. The rapid export of GSH from formaldehyde-treated viable oligodendroglial cells is likely to compromise the cellular antioxidative and detoxification potential which may contribute to the known neurotoxicity of formaldehyde. PMID- 23017600 TI - Aralar mRNA and protein levels in neurons and astrocytes freshly isolated from young and adult mouse brain and in maturing cultured astrocytes. AB - Intense glucose-based energy metabolism and glutamate synthesis by astrocytes require malate-aspartate-shuttle (MAS) activity to regenerate NAD+ from NADH formed during glycolysis, since brain lacks significant glycerophosphate shuttle activity. Aralar is a necessary aspartate/glutamate exchanger for MAS function in brain. Based on cytochemical immunoassays the absence of aralar in adult astrocytes was repeatedly reported. This would mean that adult astrocytes must regenerate NAD+ by producing lactate from pyruvate, eliminating its use by oxidative and biosynthetic pathways. We alternatively used astrocytes and neurons from adult brain, freshly isolated by fluorescence-activated cell sorting, to determine aralar protein by a specific antibody and its mRNA by real-time PCR. Both protein and mRNA expressions were identical in adult neurons and astrocytes and similar to whole brain levels. The same level of aralar expression was reached in well-differentiated astrocyte cultures, but not until late development, coinciding with the late-maturing brain capability for glutamate formation and degradation. PMID- 23017598 TI - Reading without the left ventral occipito-temporal cortex. AB - The left ventral occipito-temporal cortex (LvOT) is thought to be essential for the rapid parallel letter processing that is required for skilled reading. Here we investigate whether rapid written word identification in skilled readers can be supported by neural pathways that do not involve LvOT. Hypotheses were derived from a stroke patient who acquired dyslexia following extensive LvOT damage. The patient followed a reading trajectory typical of that associated with pure alexia, re-gaining the ability to read aloud many words with declining performance as the length of words increased. Using functional MRI and dynamic causal modelling (DCM), we found that, when short (three to five letter) familiar words were read successfully, visual inputs to the patient's occipital cortex were connected to left motor and premotor regions via activity in a central part of the left superior temporal sulcus (STS). The patient analysis therefore implied a left hemisphere "reading-without-LvOT" pathway that involved STS. We then investigated whether the same reading-without-LvOT pathway could be identified in 29 skilled readers and whether there was inter-subject variability in the degree to which skilled reading engaged LvOT. We found that functional connectivity in the reading-without-LvOT pathway was strongest in individuals who had the weakest functional connectivity in the LvOT pathway. This observation validates the findings of our patient's case study. Our findings highlight the contribution of a left hemisphere reading pathway that is activated during the rapid identification of short familiar written words, particularly when LvOT is not involved. Preservation and use of this pathway may explain how patients are still able to read short words accurately when LvOT has been damaged. PMID- 23017603 TI - "Who will take the blame?": understanding the reasons why Romanian mothers decline HPV vaccination for their daughters. AB - Because Romania has the highest incidence of cervical cancer in Europe, in 2008 a HPV vaccination campaign was introduced targeting 10-11 year old girls. However, only 2.5% of the eligible girls were given parental for vaccination. Campaign failure makes it important to look for possible reasons and investigate mothers' attitudes and perceptions of the HPV vaccine. Three focus groups and 11 interviews were conducted with mothers from urban areas. Data were transcribed verbatim and analysed with thematic analysis. Results show as main reasons for not vaccinating their daughters perceiving the vaccine as risky, the belief that the vaccine represents an experiment that uses their daughters as guinea pigs, the belief that the vaccine embodies a conspiracy theory that aims to reduce the world's population and general mistrust in the ineffective health system. Mothers stated they would need clear, factual information about the HPV vaccine and its link to cervical cancer in order to motivate them to accept it for their daughters. The study offers insight into the beliefs and attitudes towards the vaccine and provides ideas for structuring future health communication campaigns regarding the HPV vaccine. PMID- 23017604 TI - The identification of plasma proteins associated with cancer-related fatigue syndrome (CRFS) in disease-free breast cancer patients using proteomic analysis. AB - CONTEXT: Cancer-related fatigue syndrome (CRFS) affects a significant minority of women successfully treated for breast cancer, with symptoms lasting up to several years after finishing therapy. OBJECTIVES: This analysis was conducted to identify plasma proteins associated with CRFS in disease-free breast cancer patients. METHODS: Women were divided into those meeting the CRFS criteria (cases) and a control group on the basis of a diagnostic interview. Plasma samples were collected from 45 cases and 45 controls. Proteomic analysis was conducted using surface-enhanced laser desorption/ionization, a mass spectrometry (MS) technique. This was followed by further sample processing using one dimensional gels and trypsin digest for protein identification using liquid chromatography and database searching. RESULTS: CRFS was associated with a statistically significant increase in the intensity of seven MS spectra. A subsequent search of proteins corresponding to the MS spectra identified four acute phase proteins associated with a nonspecific immune response (serum amyloid A, collectin, and subunits of immunoglobulin G and complement C1Q). CONCLUSION: These novel results (using a technique not previously used in fatigue research) add further weight to the hypothesis that CRFS may be precipitated and prolonged by a nonspecific sustained inflammatory response. Importantly, this has been identified from a global analysis of plasma, which was conducted with no prior assumptions. Although these results need confirmation, we would suggest that future treatments for CRFS should consider focusing on the modulation of this presumed prolonged immune response. PMID- 23017601 TI - TRAF6 and p62 inhibit amyloid beta-induced neuronal death through p75 neurotrophin receptor. AB - Amyloid beta (Abeta) aggregates are the primary component of senile plaques in Alzheimer disease (AD) patient's brain. Abeta is known to bind p75 neurotrophin receptor (p75(NTR)) and mediates Abeta-induced neuronal death. Recently, we showed that NGF leads to p75(NTR) polyubiquitination, which promotes neuronal cell survival. Here, we demonstrate that Abeta stimulation impaired the p75(NTR) polyubiquitination. TRAF6 and p62 are required for polyubiquitination of p75(NTR) on NGF stimulation. Interestingly, we found that overexpression of TRAF6/p62 restored p75(NTR) polyubiquitination upon Abeta/NGF treatment. Abeta significantly reduced NF-kappaB activity by attenuating the interaction of p75(NTR) with IKKbeta. p75(NTR) increased NF-kappaB activity by recruiting TRAF6/p62, which thereby mediated cell survival. These findings indicate that TRAF6/p62 abrogated the Abeta-mediated inhibition of p75(NTR) polyubiquitination and restored neuronal cell survival. PMID- 23017605 TI - Opioid prescribing practices before and after initiation of palliative care in outpatients. AB - CONTEXT: Prescription Monitoring Programs (PMPs) are being developed and implemented in many states to deter abuse, diversion, and overdose, and physicians may use PMPs to help guide their treatment choices for individual patients. OBJECTIVES: To evaluate the changes in prescribing practices and pain score outcomes in patients with cancer before and after an initial consult in an outpatient palliative care clinic. METHODS: This is a retrospective study with a sample of 60 consecutive patients who had been referred by oncologists for difficult-to-manage pain and whose initial palliative care consult was with either of the two physicians in the outpatient palliative care clinic. For each patient, lists were compiled of all prescriptions for controlled medications and filled for the 90-day periods immediately before and after the initial consult. Data from patient charts were combined with information from the Virginia PMP, which included prescriptions written before and after the initiation of palliative care, written by prescribers both inside and outside the palliative care clinic. RESULTS: After the palliative care consult, the proportion of patients on long-acting opioids increased from 45% to 73%. Self-reported pain outcomes, which were compiled for the subset of patients who continued palliative care for at least 60 days, showed a median decrease of two units on a 0-10 scale. A decrease was seen in the use of medications that compound acetaminophen with opioids. CONCLUSION: Data from a PMP proved useful in understanding the changes in a population of patients. Favorable changes were observed in prescribing practices and pain outcomes. PMID- 23017606 TI - Palliative care providers' opinions of the edmonton symptom assessment system revised (ESAS-r) in clinical practice. PMID- 23017608 TI - Episodic and continuous breathlessness: a new categorization of breathlessness. AB - CONTEXT: Unlike pain, where the concept of breakthrough and background pain has been widely characterized and defined, breathlessness as a symptom has not yet been fully explored and has been rarely categorized. OBJECTIVES: To explore patients' experiences and descriptions of breathlessness to categorize breathlessness. METHODS: Qualitative study using in-depth interviews with patients suffering from four life-limiting and advanced diseases (chronic heart failure, chronic obstructive pulmonary disease, lung cancer, and motor neuron disease). Interviews were tape-recorded, transcribed verbatim, and analyzed using Framework analysis. RESULTS: A total of 51 participants were interviewed (mean +/ SD age 68.2 +/- 11.6 years; 30 of 51 male; median Karnofsky 60%; mean +/- SD breathlessness intensity 3.2 +/- 1.7 of 10). Episodic breathlessness and continuous breathlessness were the main categories, with subcategories of triggered and non-triggered episodic breathlessness and continuous breathlessness for short and long periods. Episodic breathlessness triggered by exertion, non triggered episodic breathlessness, and continuous breathlessness for a long period ("constant variable") were the most frequent and important categories with a high impact on daily living. Exertional breathlessness occurred in nearly all participants. Participants could differentiate episodic breathlessness (seconds, minutes, or hours) and continuous breathlessness (days, weeks, or months) by time. Episodic breathlessness occurred in isolation or in conjunction with continuous breathlessness. CONCLUSION: Participants categorize their breathlessness by time and triggers. The categorization needs further verification, similar to that already established in pain, and can be used as a new evidence-based categorization to advance our understanding of this under researched, yet high impact, symptom to optimize management. PMID- 23017607 TI - Understanding palliative care on the heart failure care team: an innovative research methodology. AB - CONTEXT: There is a growing call to integrate palliative care for patients with advanced heart failure (HF). However, the knowledge to inform integration efforts comes largely from interview and survey research with individual patients and providers. This work has been critically important in raising awareness of the need for integration, but it is insufficient to inform solutions that must be enacted not by isolated individuals but by complex care teams. Research methods are urgently required to support systematic exploration of the experiences of patients with HF, family caregivers, and health care providers as they interact as a care team. OBJECTIVES: To design a research methodology that can support systematic exploration of the experiences of patients with HF, caregivers, and health care providers as they interact as a care team. METHODS: This article describes in detail a methodology that we have piloted and are currently using in a multisite study of HF care teams. RESULTS: We describe three aspects of the methodology: the theoretical framework, an innovative sampling strategy, and an iterative system of data collection and analysis that incorporates four data sources and four analytical steps. CONCLUSION: We anticipate that this innovative methodology will support groundbreaking research in both HF care and other team settings in which palliative integration efforts are emerging for patients with advanced nonmalignant disease. PMID- 23017609 TI - Music therapy reduces pain in palliative care patients: a randomized controlled trial. AB - CONTEXT: Treatment of pain in palliative care patients is challenging. Adjunctive methods of pain management are desirable. Music therapy offers a nonpharmacologic and safe alternative. OBJECTIVES: To determine the efficacy of a single music therapy session to reduce pain in palliative care patients. METHODS: Two hundred inpatients at University Hospitals Case Medical Center were enrolled in the study from 2009 to 2011. Patients were randomly assigned to one of two groups: standard care alone (medical and nursing care that included scheduled analgesics) or standard care with music therapy. A clinical nurse specialist administered pre- and post-tests to assess the level of pain using a numeric rating scale as the primary outcome, and the Face, Legs, Activity, Cry, Consolability Scale and the Functional Pain Scale as secondary outcomes. The intervention incorporated music therapist-guided autogenic relaxation and live music. RESULTS: A significantly greater decrease in numeric rating scale pain scores was seen in the music therapy group (difference in means [95% CI] -1.4 [-2.0, -0.8]; P<0.0001). Mean changes in Face, Legs, Activity, Cry, Consolability scores did not differ between study groups (mean difference -0.3, [95% CI] -0.8, 0.1; P>0.05). Mean change in Functional Pain Scale scores was significantly greater in the music therapy group (difference in means -0.5 [95% CI] -0.8, 0.3; P<0.0001) [corrected]: A single music therapy intervention incorporating therapist-guided autogenic relaxation and live music was effective in lowering pain in palliative care patients. PMID- 23017610 TI - A pilot cluster-randomized trial of a 20-week Tai Chi program in elders with cognitive impairment and osteoarthritic knee: effects on pain and other health outcomes. AB - CONTEXT: Because Tai Chi (TC) is beneficial to elders without cognitive impairment (CI), it also may benefit elders with CI. But elders with CI have generally been excluded from TC studies because many measurement tools require verbal reports that some elders with CI are unable to provide. OBJECTIVES: To test the efficacy of a TC program in improving pain and other health outcomes in community-dwelling elders with knee osteoarthritis (OA) and CI. METHODS: This pilot cluster-randomized trial was conducted between January 2008 and June 2010 (ClinicalTrials.gov Identifier: NCT01528566). The TC group attended Sun style TC classes, three sessions a week for 20 weeks; the control group attended classes providing health and cultural information for the same length of time. Measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, physical function and stiffness subscales; the Get Up and Go test; the Sit-to-Stand test; and the Mini-Mental State Examination (MMSE), administered at baseline, every four weeks during the intervention and at the end of the study (post-test). RESULTS: Eight sites participated in either the TC group (four sites, 28 participants) or control group (four sites, 27 participants). The WOMAC pain (P = 0.006) and stiffness scores (P = 0.010) differed significantly between the two groups at post-test, whereas differences between the two groups in the WOMAC physical function score (P = 0.071) and the MMSE (P = 0.096) showed borderline significance at the post-test. WOMAC pain (P = 0.001), physical function (P = 0.021), and stiffness (P <= 0.001) scores improved significantly more over time in the TC group than in controls. No adverse events were found in either group. CONCLUSION: Practicing TC can be efficacious in reducing pain and stiffness in elders with knee OA and CI. PMID- 23017611 TI - Life-sustaining treatment preferences: matches and mismatches between patients' preferences and clinicians' perceptions. AB - CONTEXT: Better clinician understanding of patients' end-of-life treatment preferences has the potential for reducing unwanted treatment, decreasing health care costs, and improving end-of-life care. OBJECTIVES: To investigate patient preferences for life-sustaining therapies, clinicians' accuracy in understanding those preferences, and predictors of patient preference and clinician error. METHODS: This was an observational study of 196 male veterans with chronic obstructive pulmonary disease who participated in a randomized trial. Measures included patients' preferences for mechanical ventilation (MV) and cardiopulmonary resuscitation (CPR) if needed in their current state of health, and outpatient clinicians' beliefs about those preferences. RESULTS: Analyses were based on 54% of participants in the trial who had complete patient/clinician data on treatment preferences. Patients were more receptive to CPR than MV (76% vs. 61%; P<0.001). Preferences for both treatments were significantly associated with the importance patients assigned to avoiding life-sustaining therapies during the final week of life (MV: b=-0.11, P<0.001; CPR: b=-0.09, P=0.001). When responses were dichotomized (would/would not want treatment), clinicians' perceptions matched patient preferences in 75% of CPR cases and 61% of MV cases. Clinician errors increased as patients preferred less aggressive treatment (MV: b=-0.28, P<0.001; CPR: b=-0.32, P<0.001). CONCLUSION: Clinicians erred more often about patients' wishes when patients did not want treatment than when they wanted it. Treatment decisions based on clinicians' perceptions could result in costly and unwanted treatments. End-of-life care could benefit from increased clinician patient discussion about end-of-life care, particularly if discussions included patient education about risks of treatment and allowed clinicians to form and maintain accurate impressions of patients' preferences. PMID- 23017612 TI - Facilitating needs-based support and palliative care for people with chronic heart failure: preliminary evidence for the acceptability, inter-rater reliability, and validity of a needs assessment tool. AB - CONTEXT: Understanding the types and extent of need is critical to informing needs-based care for people with chronic heart failure (CHF). OBJECTIVES: To explore the psychometric quality of a newly developed rapid screening measure to assess the supportive and palliative care needs of people with CHF. METHODS: A convenience sample of multidisciplinary health professionals working in heart failure care was invited to comment, via an online survey and consultation, on suitability and required modifications to a validated cancer care needs assessment measure to inform the support and palliative care needs of patients with CHF and their caregivers. Psychometric testing was then undertaken with 52 patients with CHF recruited from a multidisciplinary heart failure service to explore inter-rater reliability and concurrent validity of the newly adapted Needs Assessment Tool: Progressive Disease-Heart Failure (NAT: PD-HF). RESULTS: Health professionals (n=21) rated the tool as easy to administer, comprehensive, and relevant for the CHF population. Prevalence- and bias-adjusted kappa values indicated good agreement between pairs of raters for each item in the NAT: PD-HF (range 0.54-0.90). Participants indicating a higher severity of concern in the NAT: PD-HF physical, daily living, and spiritual items reported significantly higher Heart Failure Needs Assessment Questionnaire physical and existential scores. CONCLUSION: This study provides preliminary evidence for the NAT: PD-HF as a potential strategy for identifying and informing the management of physical and psychosocial issues experienced by people with CHF. Further work is needed to examine additional psychometrics, benefits relating to unnecessary symptom burden, futile treatments, and admissions to hospital. PMID- 23017613 TI - Evolution of cancer-related symptoms over an 18-month period. AB - CONTEXT: Previous studies have revealed inconsistent findings about the longitudinal evolution of cancer-related symptoms. In addition, the contribution of medical factors (e.g., cancer site, and treatments) in explaining the changes in these symptoms is yet to be established. OBJECTIVES: This prospective study investigated longitudinal changes of five symptoms (i.e., depression, anxiety, insomnia, fatigue, and pain) in patients scheduled to undergo surgery for cancer (N=828). METHODS: The patients completed the Hospital Anxiety and Depression Scale, the Insomnia Severity Index, the Multidimensional Fatigue Inventory, and a pain questionnaire at baseline and after 2, 6, 10, 14 and 18 months. RESULTS: Several time changes were statistically significant but effect sizes only revealed one change of a medium magnitude, that is, a reduction of anxiety from T1 to T2 (d=-0.58). Women with breast or gynecological cancer were the only subgroups to exhibit significant changes (i.e., reduction of a small magnitude of anxiety symptoms from T1 to T2; ds=-0.27 and -0.30, respectively). However, numerous differences were found across adjuvant treatments, including greater variations in depression and insomnia scores in the chemotherapy group (ds=-0.71 to 0.20) and a transient increase in fatigue symptoms in patients receiving "all" adjuvant treatments (ds=-0.24 to 0.37). CONCLUSION: The severity of cancer related symptoms varies during the cancer care trajectory, especially anxiety scores, which importantly decrease during the first few months after the surgery. This study also suggests that treatment regimens better account for individual differences than cancer site in the evolution of symptoms. PMID- 23017614 TI - Using a morphine equivalence metric to quantify opioid consumption: examining the capacity to provide effective treatment of debilitating pain at the global, regional, and country levels. AB - CONTEXT: Morphine has been considered the gold standard for treating moderate-to severe pain, although many new opioid products and formulations have been marketed in the last two decades and should be considered when examining opioid consumption. Understanding opioid consumption is improved by using an equianalgesic measure that controls for the strengths of all examined opioids. OBJECTIVES: The research objective was to use a morphine equivalence (ME) metric to determine the extent that morphine consumption relates to the total consumption of all other study opioids. METHODS: An ME metric was created for morphine and the aggregate consumption of each study opioid (Total ME), adjusted for country population to allow for uniform equianalgesic comparisons. Graphical and statistical evaluations of morphine use and Total ME consumption trends (between 1980 and 2009) were made for the global and geographic regional levels and selected developed and developing countries. RESULTS: Global morphine consumption rose dramatically in the early 1980s but has been significantly outpaced by Total ME since 1996. As expected, the extent of morphine and Total ME consumption varied notably among regions, with the Americas, Europe, and Oceania regions accounting for the highest morphine use and Total ME in 2009. Developing and least developed countries, compared with developed countries, demonstrated lower overall Total ME consumption. CONCLUSION: Generally, worldwide morphine use has not increased at the rate of Total ME, especially in recent years. Examining a country's ability to effectively manage moderate-to-severe pain should extend beyond morphine to account for all available potent opioids. PMID- 23017615 TI - This chronic patient becomes a humanistic patient who helps clinicians. AB - A historian of aging, privileged to work with an interdisciplinary team of caregivers and researchers in a division of geriatric and palliative care of a major medical school and teaching hospital, discovers that his history of chronic illnesses secures him a useful role as a humanistic patient who helps clinicians to respond to the concerns, fears, and needs of aging Boomers. PMID- 23017616 TI - The evidence base for oxygen for chronic refractory breathlessness: issues, gaps, and a future work plan. AB - Breathlessness or "shortness of breath," medically termed dyspnea, is a common and distressing symptom featuring strongly in advanced lung, cardiac, and neuromuscular diseases; its prevalence and intensity increase as death approaches. However, despite the increasing understanding in the genesis of breathlessness, as well as an increasing portfolio of treatment options, breathlessness is still difficult to manage and engenders helplessness in caregivers and health care professionals and fear for patients. Although hypoxemia does not appear to be the dominant driver for breathlessness in advanced disease, the belief that oxygen is important for the relief of acute, chronic, and acute-on-chronic shortness of breath is firmly embedded in the minds of patients, caregivers, and health care professionals. This article presents current understanding of the use of oxygen for treating refractory breathlessness in advanced disease. The objective is to highlight what is still unknown, set a research agenda to resolve these questions, and highlight methodological issues for consideration in planned studies. PMID- 23017617 TI - Cut points on 0-10 numeric rating scales for symptoms included in the Edmonton Symptom Assessment Scale in cancer patients: a systematic review. AB - CONTEXT: To improve the management of cancer-related symptoms, systematic screening is necessary, often performed by using 0-10 numeric rating scales. Cut points are used to determine if scores represent clinically relevant burden. OBJECTIVES: The aim of this systematic review was to explore the evidence on cut points for the symptoms of the Edmonton Symptom Assessment Scale. METHODS: Relevant literature was searched in PubMed, CINAHL(r), Embase, and PsycINFO(r). We defined a cut point as the lower bound of the scores representing moderate or severe burden. RESULTS: Eighteen articles were eligible for this review. Cut points were determined using the interference with daily life, another symptom related method, or a verbal scale. For pain, cut point 5 and, to a lesser extent, cut point 7 were found as the optimal cut points for moderate pain and severe pain, respectively. For moderate tiredness, the best cut point seemed to be cut point 4. For severe tiredness, both cut points 7 and 8 were suggested frequently. A lack of evidence exists for nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath. Few studies suggested a cut point below 4. CONCLUSION: For many symptoms, there is no clear evidence as to what the optimal cut points are. In daily clinical practice, a symptom score >=4 is recommended as a trigger for a more comprehensive symptom assessment. Until there is more evidence on the optimal cut points, we should hold back using a certain cut point in quality indicators and be cautious about strongly recommending a certain cut point in guidelines. PMID- 23017618 TI - Bupropion for control of hot flashes in breast cancer survivors: a prospective, double-blind, randomized, crossover, pilot phase II trial. AB - CONTEXT: Hot flashes (HFs) and sexual dysfunction often affect breast cancer (BC) survivors and compromise their quality of life. Bupropion is an antidepressive medication used for smoking cessation and also has been previously studied for the treatment of sexual dysfunction. OBJECTIVES: We aimed to evaluate bupropion's efficacy in controlling HFs in BC survivors. METHODS: This was a randomized, double-blind, crossover, placebo-controlled pilot study that enrolled 55 BC survivors who reported more than seven HFs per week. Subjects were randomized to receive either bupropion 150mg twice daily for four weeks followed by one week of washout and four more weeks of placebo twice daily or vice versa. The primary end point was average daily HF activity (number of HFs and a score combining number and severity) reported while on bupropion or on placebo. Secondary end points were sexual dysfunction, depression, and quality of life evaluated with the Arizona Sexual Experience Scale, Beck Depression Inventory, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, respectively. RESULTS: Bupropion reduced HFs by 1.26 per day and the HF score by 6.31%, whereas placebo reduced HFs by 2.11 per day (P>0.05) and the HF score by 30.47% (P>0.05). There were no statistically significant differences between bupropion and placebo in the Arizona Sexual Experience Scale, Beck Depression Inventory, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. At the end of the study, 47% of the patients preferred bupropion, whereas 53% preferred placebo. There were no statistically significant differences in side effects between the study groups. CONCLUSION: Compared with placebo, bupropion did not control HFs in this group of BC survivors. PMID- 23017619 TI - How to analyze palliative care outcome data for patients in Sub-Saharan Africa: an international, multicenter, factor analytic examination of the APCA African POS. AB - CONTEXT: The incidence of life-limiting progressive disease in sub-Saharan Africa presents a significant clinical and public health challenge. The ability to easily measure patient outcomes is essential to improving care. OBJECTIVES: The present study aims to determine the specific factors (if any) that underpin the African Palliative Care Association African Palliative Outcome Scale to assist the analysis of data in routine clinical care and audit. METHODS: Using self reported data collected from patients with HIV infection in eastern and southern Africa, an exploratory factor analysis was undertaken with 1337 patients; subsequently, a confirmatory analysis was done on two samples from separate data sets (n = 445). RESULTS: Using exploratory factor analysis initially, both two- and three-factor solutions were examined and found to meet the criteria for simple structure and be readily interpretable. Then using confirmatory factor analysis on two separate samples, the three-factor solution demonstrated better fit, with Goodness-of-Fit Index values greater than 0.95 and Normative Fit Index values close to 0.90. The resulting three factors were 1) physical and psychological well-being, 2) interpersonal well-being, and 3) existential well being. CONCLUSION: This analysis presents an important new opportunity in the analysis of outcome data for patients with progressive disease. It has advantages over both the total scoring of multidimensional scaling (which masks differences between domains) and of item scoring (which requires repeated analyses). The three factors map well onto the underlying concept and clinical goals of palliative care, and will enable audit of facility care. PMID- 23017620 TI - Family factors affect clinician attitudes in pediatric end-of-life decision making: a randomized vignette study. AB - CONTEXT: Conflicts between families and clinicians in pediatric end-of-life (EOL) care cause distress for providers, dissatisfaction for patients' families, and potential suffering for terminally ill children. OBJECTIVES: We hypothesized that family factors might influence clinician decision making in these circumstances. METHODS: We presented vignettes concerning difficult EOL decision making, randomized for religious objection to therapy withdrawal and perceived level of family involvement, to clinicians working in three Children's Hospital intensive care units. Additionally, attitudes about EOL care were assessed. RESULTS: Three hundred sixty-four respondents completed the questionnaire, for an overall response rate of 54%. Respondents receiving the "involved family" vignette were more likely to agree to continue medical care indefinitely (P<0.0005). Respondents were marginally more likely to pursue a court-appointed guardian for those patients whose families had nonreligious objections to withdrawal (P=0.05). Respondents who thought that a fear of being sued affected decisions were less likely to pursue unilateral withdrawal (odds ratio 0.8, 95% CI=0.6-0.9). Those who felt personal distress as a result of difficult EOL decision making, thought they often provided "futile" care, or those who felt EOL care was effectively addressed at the institution were less likely to want to defer to the parents' wishes (range of odds ratios 0.7-1). CONCLUSION: In this randomized vignette study, we have shown that family factors, particularly how involved a family seems to be in a child's life, affect what clinicians think is ethically appropriate in challenging EOL cases. Knowledge of how a family's degree of involvement may affect clinicians should be helpful to the clinical ethics consultants and offer some degree of insight to the clinicians themselves. PMID- 23017621 TI - Intranasal fentanyl in the palliative care of newborns and infants. AB - CONTEXT: Perinatal palliative care is an area of increasing focus among clinicians supporting newborns and their families. Although not every newborn will survive the neonatal period, assuring their comfort and quality of life remains an imperative for their care providers. It can be challenging to administer medications such as opioids in a minimally invasive yet effective manner. OBJECTIVES: To describe the experience using intranasal (IN) fentanyl in the management of distress in a case series of 11 dying neonates. METHODS: A retrospective chart review was undertaken of 58 consecutive referrals of newborns and infants aged six months or younger between November 2006 and July 2010 to the Winnipeg Regional Health Authority Pediatric Palliative Care Service to determine how often IN fentanyl was used and review documented responses after the medication. RESULTS: Of 58 referrals, IN fentanyl was used in 11 patients, in all cases for concerns regarding respiratory distress. Chart documentation indicated that fentanyl was tolerated well, with no circumstances of drug-related apnea and no occurrences of chest wall rigidity. In most cases, labored breathing and restlessness settled after medication administration. The average time from administration of the last dose of fentanyl until death was 61 minutes. CONCLUSION: We found IN fentanyl, which can be administered in a variety of care settings, to be a minimally invasive means of palliating distress in dying newborns and infants. No adverse events related to its use were noted. PMID- 23017622 TI - Evaluation of treatment- and disease-related symptoms in advanced head and neck cancer: validation of the national comprehensive cancer network-functional assessment of cancer therapy-head and neck cancer symptom index-22 (NFHNSI-22). AB - CONTEXT: The Functional Assessment of Cancer Therapy-Head and Neck is a well validated assessment of quality of life used with patients diagnosed with head and neck cancers (HCNs). The present study is an attempt to evaluate and modify this instrument as necessary in light of the recent regulatory guidelines from the Food and Drug Administration on the use of patient-reported outcomes in clinical trials. OBJECTIVES: Overall, the goal was to identify patients' highest priority cancer symptoms, compare these symptoms with those suggested by oncology experts, and construct a brief symptom index to assess these symptoms and categorize them as treatment-related, disease-related, or related to general function and well-being. METHODS: Patients (N=49) with advanced (Stages III and IV) HCNs were recruited from participating National Comprehensive Cancer Network institutions and community cancer support organizations in the Chicago area. Patients completed open-ended interviews and symptom checklists. Participating oncology physician experts also rated symptoms. Content validity was obtained by evaluating results alongside items in the Functional Assessment of Chronic Illness Therapy system. Eleven oncologists categorized symptoms in terms of importance and also whether the symptoms were primarily related to disease, treatment, or functional well-being. RESULTS: HCN-related symptoms endorsed as high priority by both patients and oncology experts were selected for the new National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy Head and Neck Cancer Symptom Index-22. The final version includes 22 items, which are broken down into disease-related symptoms, treatment side effects, or general function and well-being. The new scale has acceptable internal consistency (Cronbach's coefficient alpha=0.86), content validity for use in chemotherapy trials of patients with advanced disease, and concurrent validity as demonstrated by moderate-to-strong correlations with the existing Functional Assessment of Chronic Illness Therapy measure. CONCLUSION: The National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Head and Neck Cancer Symptom Index-22 adequately reflects symptom and side effect concerns of advanced HCN patients as well as oncology physicians. This instrument can be used to evaluate the most important disease-related symptoms, treatment side effects, and function/well-being in patients with advanced HCNs in clinical practice and research. PMID- 23017623 TI - Measuring relatives' perspectives on the quality of palliative care: the Consumer Quality Index Palliative Care. AB - CONTEXT: A Consumer Quality Index (CQ-index) is a questionnaire assessing the actual care experiences and how important the recipient finds certain care aspects, as well as the priorities for improving quality. A CQ-index Palliative Care (CQ-index PC) for bereaved relatives was developed to measure the quality of palliative care. OBJECTIVES: This article provides insight into the development and psychometric characteristics of this questionnaire, as well as quality improvement priorities. METHODS: The content of the CQ-index PC was based on existing questionnaires, literature, and interviews and focus group discussions with relatives, patients, and caregivers. The questionnaire was tested in 31 care facilities providing palliative care. Close relatives/contact persons of patients who died non-suddenly six weeks to six months earlier were eligible for inclusion. Psychometric analyses were performed to shorten the questionnaire and to assess its reliability. "Need for improvement scores" also were computed to identify care aspects with the highest priority for quality improvement. RESULTS: Three hundred ninety-two bereaved relatives were eligible for inclusion. The net response was 52% (n=204). Psychometric analyses resulted in six scales (Cronbach's alphas ranging from 0.71 to 0.90). The quality aspects relatives considered most important were dying peacefully, getting help in good time in acute situations, and personal attention. Aftercare was the aspect with the highest priority for quality improvement. CONCLUSION: The CQ-index PC for relatives can be used to assess the quality of palliative care from the perspective of bereaved relatives. This instrument gives health care professionals insight into care aspects with the highest priority for quality improvement. PMID- 23017624 TI - A home-based exercise program to improve function, fatigue, and sleep quality in patients with Stage IV lung and colorectal cancer: a randomized controlled trial. AB - CONTEXT: Exercise benefits patients with cancer, but studies of home-based approaches, particularly among those with Stage IV disease, remain small and exploratory. OBJECTIVES: To conduct an adequately powered trial of a home-based exercise intervention that can be facilely integrated into established delivery and reimbursement structures. METHODS: Sixty-six adults with Stage IV lung or colorectal cancer were randomized, in an eight-week trial, to usual care or incremental walking and home-based strength training. The exercising participants were instructed during a single physiotherapy visit and subsequently exercised four days or more per week; training and step-count goals were advanced during bimonthly telephone calls. The primary outcome measure was mobility assessed with the Ambulatory Post Acute Care Basic Mobility Short Form. Secondary outcomes included ratings of pain and sleep quality as well as the ability to perform daily activities (Ambulatory Post Acute Care Daily Activities Short Form), quality of life (Functional Assessment of Cancer Therapy-General), and fatigue (Functional Assessment of Cancer Therapy-Fatigue). RESULTS: Three participants dropped out and seven died (five in the intervention and two in the control group, P=0.28). At Week 8, the intervention group reported improved mobility (P=0.01), fatigue (P=0.02), and sleep quality (P=0.05) compared with the usual care group, but did not differ on the other measures. CONCLUSION: A home-based exercise program seems capable of improving the mobility, fatigue, and sleep quality of patients with Stage IV lung and colorectal cancer. PMID- 23017625 TI - Prognostic factors of survival in patients with advanced cancer admitted to home care. AB - CONTEXT: Data regarding prognostication of life expectancy in patients with advanced cancer are of paramount importance to patients, families, and clinicians. However, data regarding patients followed at home are lacking. OBJECTIVES: The aim of this study was to evaluate the correlation between various factors recorded at the beginning of home care assistance and survival. METHODS: A sample of consecutive patients admitted to two home care programs was surveyed. A preliminary consensus was achieved as to the possible variables easy to be recorded at home. These included age at the time of home care admission, gender, residence, marital status, primary cancer diagnosis, Karnofsky Performance Status (KPS) score, measures of systolic blood pressure and heart rate, cyanosis, use of oxygen, and body temperature. The Edmonton Symptom Assessment System was used to record the intensity of each symptom. Patients were divided into two groups: patients with a survival of less than 10 days (short survival) and patients with a survival of 10 days or more (medium-long survival). RESULTS: Three hundred seventy-four consecutive patients admitted to home care programs were surveyed, of which 187 were male. The mean+/-SD age was 72.1+/-12.7 years. The mean survival was 56.2+/-65 days. Mean survival was 71.5+/-67 days (287 patients) and 5.6+/-2.7 days (87 patients) in the short and medium-long survival groups, respectively. No association between type of tumor and survival was observed (P=0.162). Univariate logistic regression analysis revealed that male gender (P=0.020), older age (P=0.012), lower KPS scores (P<0.0005), systolic blood pressure less than 100 mmHg (P=0.003), heart rate greater than 100 beats per minute (P=0.0006), delirium (P=0.004), the use of oxygen (P=0.002), intensity of fatigue (P=0.006), drowsiness (P<0.0005), anorexia (P<0.0005), dyspnea (P<0.0005), poor sense of well-being (P<0.0005), and distress score (P<0.0005) were associated with a survival of less than 10 days. Marital status, residence, cognitive function, fever, pain, depression, and anxiety were not found to be significantly correlated with survival. In a multiple logistic regression model, low systolic blood pressure and high heart rate, gender, delirium, use of oxygen, KPS score, drowsiness, anorexia, and dyspnea were significantly correlated with a shorter survival. CONCLUSION: Low systolic blood pressure and high heart rate, male gender, poor KPS score, anorexia, and dyspnea were correlated with a shorter survival. Moreover, patients with low systolic blood pressure and high heart rate, male gender, poor KPS score, and greater intensity of anorexia and dyspnea are more likely to die within one week. The combination of physical symptoms from the Edmonton Symptom Assessment System and other parameters included in this study, which are simple to assess and are repeatable at home, should be further explored in future studies to provide a simple tool for use with patients with advanced cancer admitted to a home care program. PMID- 23017626 TI - Activity as a measure of symptom control. PMID- 23017628 TI - Mapping levels of palliative care development: a global update. AB - Our purpose is to categorize palliative care development, country by country, throughout the world, showing changes over time. We adopt a multi-method approach. Development is categorized using a six-part typology: Group 1 (no known hospice-palliative care activity) and Group 2 (capacity-building activity) are the same as developed during a previous study (2006), but Groups 3 and 4 have been subdivided to produce two additional levels of categorization: 3a) Isolated palliative care provision, 3b) Generalized palliative care provision, 4a) Countries where hospice-palliative care services are at a stage of preliminary integration into mainstream service provision, and 4b) Countries where hospice palliative care services are at a stage of advanced integration into mainstream service provision. In 2011, 136 of the world's 234 countries (58%) had at least one palliative care service--an increase of 21 (+9%) from 2006, with the most significant gains having been made in Africa. Advanced integration of palliative care has been achieved in only 20 countries (8.5%). Total countries in each category are as follows: Group 1, 75 (32%); Group 2, 23 (10%); Group 3a, 74 (31.6%); Group 3b, 17 (7.3%); Group 4a, 25 (10.7%); and Group 4b, 20 (8.5%). Ratio of services to population among Group 4a/4b countries ranges from 1:34,000 (in Austria) to 1:8.5 million (in China); among Group 3a/3b countries, from 1:1000 (in Niue) to 1:90 million (in Pakistan). Although more than half of the world's countries have a palliative care service, many countries still have no provision, and major increases are needed before palliative care is generally accessible worldwide. PMID- 23017627 TI - Use of opioid analgesics among older persons with colorectal cancer in two health districts with palliative care programs. AB - CONTEXT: Prescription of opioid analgesics is a key component of pain management among persons with cancer at the end of life. OBJECTIVES: To use a population based method to assess the use of opioid analgesics within the community among older persons with colorectal cancer (CRC) before death and determine factors associated with the use of opioid analgesics. METHODS: Data were derived from a retrospective, linked administrative database study of all persons who were diagnosed with CRC between January 1, 2001 and December 31, 2005 in Nova Scotia, Canada. This study included all persons who 1) were 66 years or older at the date of diagnosis; 2) died between January 1, 2001 and April 1, 2008; and 3) resided in health districts with formal palliative care programs (PCPs) (n=657). Factors associated with having filled at least one prescription for a so-called "strong" opioid analgesic in the six months before death were examined using multivariate logistic regression. RESULTS: In all, 36.7% filled at least one prescription for any opioid in the six months before death. Adjusting for all covariates, filling a prescription for a strong opioid was associated with enrollment in a PCP (odds ratio [OR]=3.18, 95% CI=2.05-4.94), residence in a long-term care facility (OR=2.19, 95% CI=1.23-3.89), and a CRC cause of death (OR=1.75, 95% CI=1.14 2.68). Persons were less likely to fill a prescription for a strong opioid if they were older (OR=0.97, 95% CI=0.95-0.99), male (OR=0.59, 95% 0.40-0.86), and diagnosed less than six months before death (OR=0.62, 95% CI=0.41-0.93). CONCLUSION: PCPs may play an important role in enabling access to end-of-life care within the community. PMID- 23017629 TI - [L-carnitine in valproic acid-induced hyperammonemia]. PMID- 23017630 TI - The American-European Consensus Conference definition of the acute respiratory distress syndrome is dead, long live positive end-expiratory pressure! AB - In 1994, an American-European Consensus Conference (AECC) formalized the criteria for the diagnosis of the acute respiratory distress syndrome (ARDS). Although that definition is simple to apply in the clinical setting, it has been challenged over the years in several studies since the assessment of the oxygenation defect does not require standardized ventilatory support. We were the first to propose new guidelines, based on a specific, standard method of evaluating oxygenation status, a proposal that was later advocated by others. To address the limitations of the AECC definition, a modified ARDS definition has been proposed by a task force panel of experts, referred to as the Berlin Defintion, using a terminology similar to that we previously proposed. However, that proposal has several methodological flaws. Since all ARDS patients start off with terrible oxygenation, the Berlin Definition offers no room for stratifying and identifyng true ARDS patients since there is no further re-evaluation of the hypoxemia under standard ventilator setting in a specific time period. In this Point of View, we review the history of the definition of ARDS and discussed the methodological concerns regarding adopting this new, revised ARDS definition. PMID- 23017631 TI - What is 'best evidence'? PMID- 23017632 TI - The appropriateness method has acceptable reliability and validity for assessing overuse and underuse of surgical procedures. AB - OBJECTIVE: To summarize the findings of methodological studies on the RAND/University of California Los Angeles (RAND/UCLA) appropriateness method, which was developed to assess if variation in the use of surgical procedures is because of overuse and/or underuse. STUDY DESIGN AND SETTING: A MEDLINE literature search was performed. Studies were included if they assessed the reliability or validity of the RAND/UCLA appropriateness method for a surgical procedure or the effect of altering panelist composition or eliminating in-person discussion between rating rounds. Information was abstracted on procedure, study design, and findings. RESULTS: One thousand six hundred one titles were identified, and 37 met the inclusion criteria. The test-retest reliability is good to very good (kappa, 0.64-0.81) for total knee and hip joint replacement, coronary artery bypass grafting (CABG), and carotid endarterectomy (CEA). The interpanel reliability is moderate to very good (kappa, 0.52-0.83) for CABG and hysterectomy. Construct validity has been demonstrated by comparing the appropriateness method with guidelines and/or evidence-based approaches for endoscopy, colonoscopy, CABG, hysterectomy, and CEA. Predictive validity has been studied for cardiac revascularization, in which concordance with appropriateness classification is associated with better clinical outcomes. CONCLUSION: Our findings support use of the appropriateness method to assess variation in the rates of the procedures studied by identifying overuse and underuse. Further methodological research should be conducted as appropriateness criteria are developed and implemented for a broader range of procedures. PMID- 23017634 TI - A framework for best evidence approaches can improve the transparency of systematic reviews. AB - OBJECTIVE: Systematic reviewers often use a "best evidence" approach to address the key questions, but what is meant by "best" is often unclear. The goal of this project was to create a decision framework for "best evidence" approaches to increase transparency in systematic reviews. STUDY DESIGN AND SETTING: The project was separated into three areas: 1) inclusion criteria, 2) evidence prioritization strategies, and 3) evaluative approaches. This commentary focuses only on the second task. The full report is available on the Effective Healthcare Web site of the Agency for Healthcare Research and Quality. RESULTS: The four identified strategies were as follows: 1) Use only the single best study; 2) Use the best set of studies; 3) Same as 2, but also consider whether the evidence permits a conclusion; and 4) Same as 3, but also consider the overall strength of the evidence. Simpler strategies (such as #1) are less likely to produce false conclusions, but are also more likely to yield insufficient evidence (possibly because of imprecise data). CONCLUSION: Systematic reviewers routinely prioritize evidence in numerous ways. This document provides a conceptual construct to enhance the transparency of systematic reviewers' decisions. PMID- 23017633 TI - A framework for understanding cancer comparative effectiveness research data needs. AB - OBJECTIVES: Randomized controlled trials remain the gold standard for evaluating cancer intervention efficacy. Randomized trials are not always feasible, practical, or timely and often don't adequately reflect patient heterogeneity and real-world clinical practice. Comparative effectiveness research can leverage secondary data to help fill knowledge gaps randomized trials leave unaddressed; however, comparative effectiveness research also faces shortcomings. The goal of this project was to develop a new model and inform an evolving framework articulating cancer comparative effectiveness research data needs. STUDY DESIGN AND SETTING: We examined prevalent models and conducted semi-structured discussions with 76 clinicians and comparative effectiveness research researchers affiliated with the Agency for Healthcare Research and Quality's cancer comparative effectiveness research programs. RESULTS: A new model was iteratively developed and presents cancer comparative effectiveness research and important measures in a patient-centered, longitudinal chronic care model better reflecting contemporary cancer care in the context of the cancer care continuum, rather than a single-episode, acute-care perspective. CONCLUSION: Immediately relevant for federally funded comparative effectiveness research programs, the model informs an evolving framework articulating cancer comparative effectiveness research data needs, including evolutionary enhancements to registries and epidemiologic research data systems. We discuss elements of contemporary clinical practice, methodology improvements, and related needs affecting comparative effectiveness research's ability to yield findings clinicians, policy makers, and stakeholders can confidently act on. PMID- 23017635 TI - Time-dependent study entries and exposures in cohort studies can easily be sources of different and avoidable types of bias. AB - OBJECTIVES: To display and discuss the reasons and consequences of length and time-dependent bias. They might occur in presence of a time-dependent study entry or a time-dependent exposure which might change from unexposed to exposed. STUDY DESIGN AND SETTING: Recalling the popular study of Oscar nominees and using a real-data example from hospital epidemiology, we give innovative and easy-to understand graphical presentations of how these biases corrupt the analyses via distorted time-at-risk. Cumulative hazard plots and Cox proportional hazards models were used. We are building bridges to medical disciplines such as critical care medicine, hepatology, pharmaco-epidemiology, transplantation medicine, neurology, gynecology and cardiology. RESULTS: In presence of time-dependent bias, the hazard ratio (comparing exposed with unexposed) is artificially underestimated. The length bias leads to an artificial underestimation of the overall hazard. When both biases coexist it can lead to different directions of biased hazard ratios. CONCLUSION: Since length and time-dependent bias might occur in several medical disciplines, we conclude that understanding and awareness are the best prevention of survival bias. PMID- 23017637 TI - Monte Carlo simulation of the cost-effectiveness of sample size maintenance programs revealed the need to consider substitution sampling. AB - OBJECTIVE: To assess the cost-effectiveness of sample size maintenance programs in a prospective cohort. STUDY DESIGN AND SETTING: The Living with Diabetes Study in Queensland, Australia is a longitudinal survey providing a comprehensive examination of health care utilization and disease progression among people with diabetes. Data from this study were used to compare the cost-effectiveness of a program incorporating substitution sampling with two alternative programs: "no follow-up" and "usual practice." RESULTS: A program involving substitution sampling was shown to be the most effective with an additional 3,556 complete responses (compared with a "no follow-up" program) and an additional 2,099 complete responses (compared with "usual practice"). An incremental analysis through a Monte Carlo simulation found substitution sampling to be the most cost effective option for maintaining sample size with an incremental cost-effective ratio of $54.87 (95% uncertainty interval $52.68-$57.25) compared with $87.58 ($77.89-$100.09) for "usual practice." CONCLUSIONS: Based on the available data, a program involving substitution sampling is economically justified and should be considered in any approach with the aim of maintaining sample size. There is, however, a continuing need to evaluate the effectiveness of this option on other outcome measures, such as bias. PMID- 23017636 TI - External adjustment for unmeasured confounders improved drug-outcome association estimates based on health care utilization data. AB - OBJECTIVES: Health care utilization (HCU) databases are widespread sources of data for pharmacoepidemiologic investigations. Possible confounders are typically not measured in such databases. We show how to assess the impact of confounders in a study aimed at comparing cardiovascular (CV) risk according to drug regimen prescribed at starting antihypertensive therapy, nominally one agent (monotherapy) or a combination of agents in a unique tablet (fixed-dose combination) or in at least two distinct tablets (extemporaneous combination). STUDY DESIGN AND SETTINGS: A nested case-control study was carried out by including the 209,650 patients from Lombardy (Italy) newly treated between 2000 and 2001. Cases were the 10,688 patients who were hospitalized for CV disease until 2007. Three controls were selected for each case. Logistic regression was used to model the CV risk associated with initial therapeutic regimen. A Monte Carlo sensitivity analysis was performed for accounting unmeasured confounders (hypertension severity and chronic disease score) by means of external adjustment with medical record (MR) data. RESULTS: Compared with patients on fixed-dose combination, those on extemporaneous combination or monotherapy, respectively, had CV risk increased to 15% (95% confidence interval [CI]: 3%, 29%) or 17% (95% CI: 8%, 26%). External adjustment did not modify the risk associated with monotherapy. In contrast, the excess of risk associated with extemporaneous combination was annulled when external adjustment was applied. CONCLUSION: MR data can be used to assess confounding bias unmeasured from HCU database. Starting antihypertensive therapy with a combination of agents probably reduces the CV risk with respect to monotherapy, even in the setting of primary prevention. PMID- 23017638 TI - Calculating sample sizes for cluster randomized trials: we can keep it simple and efficient! AB - OBJECTIVE: Simple guidelines for calculating efficient sample sizes in cluster randomized trials with unknown intraclass correlation (ICC) and varying cluster sizes. METHODS: A simple equation is given for the optimal number of clusters and sample size per cluster. Here, optimal means maximizing power for a given budget or minimizing total cost for a given power. The problems of cluster size variation and specification of the ICC of the outcome are solved in a simple yet efficient way. RESULTS: The optimal number of clusters goes up, and the optimal sample size per cluster goes down as the ICC goes up or as the cluster-to-person cost ratio goes down. The available budget, desired power, and effect size only affect the number of clusters and not the sample size per cluster, which is between 7 and 70 for a wide range of cost ratios and ICCs. Power loss because of cluster size variation is compensated by sampling 10% more clusters. The optimal design for the ICC halfway the range of realistic ICC values is a good choice for the first stage of a two-stage design. The second stage is needed only if the first stage shows the ICC to be higher than assumed. CONCLUSION: Efficient sample sizes for cluster randomized trials are easily computed, provided the cost per cluster and cost per person are specified. PMID- 23017639 TI - Research on injury compensation and health outcomes: ignoring the problem of reverse causality led to a biased conclusion. AB - OBJECTIVE: This study highlights the serious consequences of ignoring reverse causality bias in studies on compensation-related factors and health outcomes and demonstrates a technique for resolving this problem of observational data. STUDY DESIGN AND SETTING: Data from an English longitudinal study on factors, including claims for compensation, associated with recovery from neck pain (whiplash) after rear-end collisions are used to demonstrate the potential for reverse causality bias. Although it is commonly believed that claiming compensation leads to worse recovery, it is also possible that poor recovery may lead to compensation claims- a point that is seldom considered and never addressed empirically. This pedagogical study compares the association between compensation claiming and recovery when reverse causality bias is ignored and when it is addressed, controlling for the same observable factors. RESULTS: When reverse causality is ignored, claimants appear to have a worse recovery than nonclaimants; however, when reverse causality bias is addressed, claiming compensation appears to have a beneficial effect on recovery, ceteris paribus. CONCLUSION: To avert biased policy and judicial decisions that might inadvertently disadvantage people with compensable injuries, there is an urgent need for researchers to address reverse causality bias in studies on compensation-related factors and health. PMID- 23017640 TI - The Bengali Short Form-36 was acceptable, reliable, and valid in patients with rheumatoid arthritis. AB - OBJECTIVE: To develop a culturally adapted Bengali version of the Short Form-36 (SF-36) Health Survey and to test its acceptability, reliability, and validity in patients with rheumatoid arthritis (RA). STUDY DESIGN AND SETTING: The US English SF-36 was translated into Bengali after established cross-cultural adaptation procedures. The questionnaire was interviewer administered to 125 consecutive outpatients with RA and readministered after 2 weeks to 40 randomly selected patients. RESULTS: Most participants (86.4%) did not have any problem in understanding the Bengali SF-36 and 98.4% of the questionnaires were fully completed. Only the role-physical and role-emotional scales showed substantial floor and ceiling effects. Principal component analysis confirmed that the hypothesized two-factor structure and tests of scaling assumptions were 100% successful for all eight scales expect physical functioning (98.8%) and general health (77.5%). Cronbach's alpha was higher than 0.78 and the test-retest reliability was high (r>0.82) for all scales. Correlations with other disease activity parameters were generally as expected and summary scores were able to discriminate between relevant subgroups. CONCLUSION: The interviewer-administered Bengali SF-36 appears to be an acceptable, reliable, and valid instrument for measuring health-related quality of life in Bangladeshi patients with RA. The questionnaire should be further evaluated in people from the general population and in patients with different medical conditions. PMID- 23017642 TI - De facto masking and other measures to prevent contamination. PMID- 23017643 TI - Conservative handling of missing information. PMID- 23017645 TI - The contribution of the SPINK1 c.194+2T>C mutation to the clinical course of idiopathic chronic pancreatitis in Chinese patients. AB - BACKGROUND: Recent data suggest that the serine protease inhibitor Kazal type 1 (SPINK1) gene mutation is associated with idiopathic chronic pancreatitis. However, few studies have focused on the serine protease inhibitor Kazal type 1 c.194+2T>C mutation. Therefore, our goal was to study the prevalence and impact of serine protease inhibitor Kazal type 1 mutations on the clinical profile of idiopathic chronic pancreatitis patients in China. METHODS: A retrospective cohort study of 118 Chinese patients with idiopathic chronic pancreatitis was performed, and genetic tests were carried out to detect SPINK1 mutations. Subjects without pancreatitis were used as controls. In total, 118 idiopathic chronic pancreatitis patients and 100 control subjects were evaluated. RESULTS: The serine protease inhibitor Kazal type 1 c.194+2T>C variant was present in 44.9% of patients with idiopathic chronic pancreatitis. The frequency of diabetes in idiopathic chronic pancreatitis patients with the serine protease inhibitor Kazal type 1 c.194+2T>C mutation (39.6%) was higher than that of patients without the mutation (9.2%). The time to occurrence of diabetes mellitus after idiopathic chronic pancreatitis symptom onset is significantly influenced by the c.194+2T>C mutation (p<0.001). In addition, the mean age of diabetes onset in patients with the serine protease inhibitor Kazal type 1 c.194+2T>C mutation (38.33 +/- 9.50) was significantly younger than that of patients without this mutation (49.67 +/- 6.74). CONCLUSIONS: The presence of the serine protease inhibitor Kazal type 1 c.194+2T>C mutation seems to be associated with idiopathic chronic pancreatitis and could predispose individuals to pancreatic diabetes onset at an earlier age. PMID- 23017646 TI - Formation of deposits on the surfaces of superheaters and economisers of MSW incinerator plants. AB - Mineralogical and chemical investigations of deposits from superheaters and economisers from a MSWI plant in Mannheim, Germany, lead to a classification system which provides information about the most critical parameters leading to fouling and corrosion. With the help of this classification system parameters like the geometry of boilers and the waste input can be changed in order to prolong run times between revisions and enhance energy efficiency of MSWI plants. PMID- 23017647 TI - Part Two: Against the motion. All TEVAR patients do not require lifelong follow up by annual CTA/MRA.[Con]. PMID- 23017648 TI - Colonic inflammation in Parkinson's disease. AB - Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and data from recent genetic studies suggest a link between PD and gut inflammation. We therefore undertook the present survey to investigate whether gastrointestinal inflammation occurs in PD patients. Nineteen PD patients and 14 age-matched healthy controls were included. For each PD patients, neurological and gastrointestinal symptoms were assessed using the Unified Parkinson's Disease Rating Scale part III and the Rome III questionnaire, respectively and cumulative lifetime dose of L-dopa was calculated. Four biopsies were taken from the ascending colon during the course of a total colonoscopy in controls and PD patients. The mRNA expression levels of pro-inflammatory cytokines (tumor necrosis factor alpha, interferon gamma, interleukin-6 and interleukin-1 beta) and glial marker (Glial fibrillary acidic protein, Sox-10 and S100-beta) were analyzed using real-time PCR in two-pooled biopsies. Immunohistochemical analysis was performed on the two remaining biopsies using antibodies against phosphorylated alpha-synuclein to detect Lewy pathology. The mRNA expression levels of pro-inflammatory cytokines as well as of two glial markers (Glial fibrillary acidic protein and Sox-10) were significantly elevated in the ascending colon of PD patients with respect to controls. The levels of tumor necrosis factor alpha, interferon gamma, interleukin-6, interleukin-1 beta and Sox-10 were negatively correlated with disease duration. By contrast, no correlations were found between the levels of pro-inflammatory cytokines or glial markers and disease severity, gastrointestinal symptoms or cumulative lifetime dose of L-dopa. There was no significant difference in the expression of pro inflammatory cytokines or glial marker between patients with and without enteric Lewy pathology. Our findings provide evidence that enteric inflammation occurs in PD and further reinforce the role of peripheral inflammation in the initiation and/or the progression of the disease. PMID- 23017649 TI - Overweight and obesity in rural girls from Poland: changes between 1987 and 2001. AB - Several studies have documented increased prevalence of overweight and obesity in inhabitants of rural regions, but determinants of their prevalence are complex and not always in one direction. The aim of this study was to estimate both the prevalence and extent of overweight and obesity among rural girls in Poland between 1987 and 2001, as well as to assess differentiation of the phenomenon between regions of different social structures. The data come from two series of cross-sectional studies; the first in 1987 included 7764 girls, and the second in 2001 included 9431 girls aged 9-18. Body mass index (according to the International Obesity Task Force, IOTF) and the EOW index (extent of overweight), which shows by what mean BMI value the overweight boundaries are exceeded, were calculated. Overweight and obesity prevalences in the whole sample, were, respectively, 14.9% and 2.7% in 1987 and 15.5% and 2.5% in 2001, but significant differentiation in the direction of the changes was observed between the examined regions. In one of them, characterized by sudden, mass and long-term unemployment, there was a considerable decrease in overweight and obesity prevalence, whereas in a relatively wealthier region no changes were observed during the 14-year period. Two other regions with a relatively low standard of living and low incomes and education status presented a significant increase in overweight and obesity prevalence. The EOW index increased from 1.9 to 2.1 in the whole examined sample, and it also confirmed significant differences in expansion of overweight and obesity between the examined regions. The complex character of political and socioeconomic changes in Poland during the 1990 s has resulted in two-directional changes in biological measures of living conditions. The analysis of the whole sample led to different results in comparison to separate analyses of each of the examined regions. PMID- 23017650 TI - Correlations between executive function, decision-making and impulsivity are disrupted in schizophrenia versus controls. AB - Schizophrenia (n=68) and control (n=62) participants matched on cigarette smoking history were assessed on executive function, decision-making and impulsivity tasks. In controls, executive function and decision-making correlated positively with each other and negatively with impulsivity. There were no inter-task correlations in schizophrenia participants. The significance of these findings is discussed. PMID- 23017651 TI - Body image concerns in professional fashion models: are they really an at-risk group? AB - Although professional models are thought to be a high-risk group for body image concerns, only a handful of studies have empirically investigated this possibility. The present study sought to overcome this dearth of information by comparing professional models and a matched sample on key indices of body image and appeared-related concerns. A group of 52 professional fashion models was compared with a matched sample of 51 non-models from London, England, on indices of weight discrepancy, body appreciation, social physique anxiety, body dissatisfaction, drive for thinness, internalization of sociocultural messages about appearance, and dysfunctional investment in appearance. Results indicated that professional models only evidenced significantly higher drive for thinness and dysfunctional investment in appearance than the control group. Greater duration of engagement as a professional model was associated with more positive body appreciation but also greater drive for thinness. These results indicate that models, who are already underweight, have a strong desire to maintain their low body mass or become thinner. Taken together, the present results suggest that interventions aimed at promoting healthy body image among fashion models may require different strategies than those aimed at the general population. PMID- 23017652 TI - Response randomization of one- and two-person rock-paper-scissors games in individuals with schizophrenia. AB - Randomization among successive choices is important in adaptive decision-making, particularly for strategic interactions in which the optimal strategy is a mixed strategy. Patients with schizophrenia have been reported to have deficits in random sequential behaviors arising from impaired executive function. However, whether schizophrenic patients exhibit distinct behaviors for response randomization in one- and two-person games requiring different behavioral strategies is not known. The aim of this study was to examine the response randomization of 48 schizophrenic patients and 50 healthy subjects in one- and two-person rock-paper-scissors games. Here we found that the schizophrenic patients exhibited non-random biases distinct from those of the healthy subjects (i.e., stereotypic switching in the one-person game and the tendency to choose the best response against the opponent's previous choice in the two-person game). The entropy of the choice sequences was prominently decreased in the schizophrenic patients for both games, thereby indicating an overall disturbance in the behavioral randomization in adaptive decision-making. These results suggest that the impairment of response randomization in schizophrenic patients manifests differently in interactive and non-interactive situations, which may be useful for the diagnosis and quantification of the severity of the disease. PMID- 23017654 TI - Sensory and sensorimotor gating in adult attention-deficit/hyperactivity disorder (ADHD). AB - Even though there is an impaired perceptual capacity in attention deficit/hyperactivity disorder (ADHD) patients, psychophysiological alterations, such as impaired gating as indexed by prepulse inhibition (PPI) or suppression of P50 auditory event-related potentials, have not been found in patients with ADHD. Hence, potential relationships of psychophysiological measures of gating to psychopathology and cognitive performance remain unclear. The present study investigates two distinct operational measures of gating as well as cognitive performance within adult ADHD patients in order to assess the relationship of these measures to psychopathology. PPI, P50 suppression, cognitive performance, and psychopathologic symptoms were assessed in 26 ADHD patients and 26 healthy control subjects. ADHD patients compared to healthy control subjects exhibited impaired P50 suppression, performed worse in cognitive tasks, and reported more psychopathological symptoms, but were normal in the test of PPI. Thus, P50 gating deficits are not specific to schizophrenia-spectrum disorders. These findings highlight the differences between P50 gating and PPI as measures of the gating construct. In keeping with the lack of correlations between these two putative operational measures of gating seen in both humans and animals, adult ADHD patients exhibit deficient P50 suppression and poor cognitive performance, despite exhibiting normal levels of PPI. PMID- 23017653 TI - Personality features of obese women in relation to binge eating and night eating. AB - Personality traits can affect eating behaviors, the development of obesity, and obesity treatment failure. We investigated the personality characteristics and their relation with disordered eating in 586 obese women consecutively seeking treatment at eight Italian medical centers (age, 47.7+/-9.8 years) and 185 age matched, normal weight women without symptoms of eating disorders (Eating Attitude Test<20). The assessment included anthropometry, the Temperament and Character Inventory (TCI), the Binge Eating Scale (BES) and the Night Eating Questionnaire (NEQ). Logistic regression analyses were carried out in different models with BES score>=27 and NEQ>=30 as dependent variables and TCI scores as independent factors. Personality traits of obese individuals included significantly lower self-directedness and cooperativeness on TCI. BES and NEQ scores were higher in obese women, and values above the defined cut-offs were present in 77 and 18 cases (14 with high BES), respectively. After controlling for age and BMI, high BES values were associated with high novelty seeking and harm avoidance and low self-directedness, the last two scales being also associated with high NEQ. We conclude that personality traits differ between obese patients seeking treatment and controls, and the presence of disordered eating is associated with specific personality characteristics. PMID- 23017655 TI - Social cognitive deficits in schizophrenia and their relationship to clinical and functional status. AB - While research on social cognitive impairments in schizophrenia is quickly growing, relatively little is still known about the severity and correlates of these impairments. The few studies that have examined this issue suggest that social cognitive impairments may be positively related to psychiatric symptoms and negatively related to functioning. In the current analyses of 119 stable outpatients with schizophrenia spectrum diagnoses, we sought to further characterize the nature of social cognitive impairments in schizophrenia. Specifically, we examined (1) social cognitive impairments on four different social cognitive tasks including measures of emotional processing and Theory of Mind and (2) the demographic, symptom and functional correlates of these impairments. For three of the four social cognitive tasks examined, the majority of participants performed 1 or more S.D. worse than healthy controls, with variability in the degree of impairment across tasks. Contrary to expectation, correlations between social cognitive performance on each of the four tasks and clinical and functional features were few and weak, and for the most part did not replicate the previously reported relationship of social cognition to severity of symptoms or current functional status. PMID- 23017656 TI - PTSD's latent structure in Malaysian tsunami victims: assessing the newly proposed Dysphoric Arousal model. AB - The underlying latent structure of Posttraumatic Stress Disorder (PTSD) is widely researched. However, despite a plethora of factor analytic studies, no single model has consistently been shown as superior to alternative models. The two most often supported models are the Emotional Numbing and the Dysphoria models. However, a recently proposed five-factor Dysphoric Arousal model has been gathering support over and above existing models. Data for the current study were gathered from Malaysian Tsunami survivors (N=250). Three competing models (Emotional Numbing/Dysphoria/Dysphoric Arousal) were specified and estimated using Confirmatory Factor Analysis (CFA). The Dysphoria model provided superior fit to the data compared to the Emotional Numbing model. However, using chi square difference tests, the Dysphoric Arousal model showed a superior fit compared to both the Emotional Numbing and Dysphoria models. In conclusion, the current results suggest that the Dysphoric Arousal model better represents PTSD's latent structure and that items measuring sleeping difficulties, irritability/anger and concentration difficulties form a separate, unique PTSD factor. These results are discussed in relation to the role of Hyperarousal in PTSD's on-going symptom maintenance and in relation to the DSM-5. PMID- 23017657 TI - Non-HIV Kaposi's sarcoma: a review and therapeutic perspectives. AB - "Classic" Kaposi's sarcoma (CKS) not related to HIV is a multifocal angioproliferative neoplasm that is linked to human herpesvirus. CKS is a cutaneous cancer frequently occurring with an indolent course. However, it can compromise the quality of life by causing pain, disfigurement and functional disability. For this reason, the main treatment goals are not only to reduce the cutaneous lesions but also to alleviate organ involvement and psychological stress by delaying disease progression and ultimately cure. This report summarizes systemic treatment options of CKS, including chemotherapy, immunotherapy and anti-HHV8 therapy. In addition, this review will focus on the recent understanding of carcinogenesis and consequently highlight potential "targeted" therapeutic interventions. PMID- 23017658 TI - Tetanus as cause of mass die-off of captive Japanese macaques, Japan, 2008. AB - In 2008 in Japan, 15/60 captive Japanese macaques died. Clostridium tetani was isolated from 1 monkey, and 11 had tetanus-specific symptoms. We conclude the outbreak resulted from severe environmental C. tetani contamination. Similar outbreaks could be prevented by vaccinating all monkeys, disinfecting housing areas/play equipment, replacing highly C. tetani-contaminated soil, and conducting epidemiologic surveys. PMID- 23017660 TI - Discordant recovery of bone mass and mechanical properties during prolonged recovery from disuse. AB - Profound bone loss at weight bearing sites is a primary effect of long-duration spaceflight. Moreover, a significant increase in estimated fracture risk remains even 1 year after returning to Earth; hence, it is important to define how quickly bone integrity can recover following prolonged disuse. This study characterized the loss and recovery dynamics of bone following a period of rodent hindlimb unloading in three anatomic sites. We hypothesized that the rat femoral neck would exhibit a discordant recovery dynamic most similar to that observed in astronauts' proximal femur; that is, bone mineral content (absolute mass) at this site would recover faster and more completely than would bone density and cortical area, and they will all recover before bone strength does. We characterized loss and long-term recovery of densitometric properties at the femoral neck, proximal tibia metaphysis, and tibia diaphysis, and also mechanical properties at the femoral neck and tibia diaphysis for which mechanical testing is amenable. We assessed the relationship between calculated strength indices and measured mechanical properties. Adult male Sprague-Dawley rats (6 months) were assigned to baseline, age-matched control (AC), and hindlimb unloaded (HU) groups. The HU group was unloaded for 28 days and then returned to normal cage activity for 84 days of weight bearing recovery (3 times the duration of HU). Fifteen animals were euthanized from each of the HU and AC groups on days 28, 56, 84, and 112 of the study. At baseline and then every 28 days in vivo longitudinal pQCT scans were taken at proximal tibia metaphysis (PTM) and tibia diaphysis (TD); ex vivo pQCT scans were taken later at the femoral neck (FN). TD and FN were tested to failure to measure mechanical properties. The hypothesis that the femoral neck in rats will exhibit a discordant recovery dynamic most similar to that observed in astronauts' proximal femurs was not supported by our data. At the femoral neck, densitometric and geometric variables (total BMC, total vBMD, cancellous vBMD, and cortical area) recovered to age-matched control levels after a recovery period twice the duration of unloading. Contrary to our hypothesis, changes in densitometric variables at the PTM provided a better model for changes in the human femoral neck with prolonged weightlessness. Following 28 days of HU, PTM total BMC recovered to age-matched control levels after roughly two times the duration of unloading; however, total vBMD did not recover even after three recovery periods. Cortical thinning occurred at the PTM following HU likely due to inhibition of periosteal growth; cortical shell thickness did not recover even after three recovery periods. Calculated strength indices suggested a loss in strength at the tibial diaphysis, which was not confirmed with direct testing of mechanical properties. HU had no effect on maximum fracture force at mid-tibia diaphysis; however, femoral neck experienced a significant loss of maximum force due to unloading that fully recovered after 28 days. Estimated strength indices for the femoral neck suggested a recovery period of 56 days in contrast to the 28 day recovery that was observed with mechanical testing. However, the inaccuracy of strength indices vs. directly measured mechanical properties highlights the continued importance of ground based animal models and mechanical testing. Our results demonstrate that the PTM in the rat better matches loss and recovery dynamics observed in astronauts' proximal femur than does the rat FN, at least in terms of densitometric variables. More complete utility of the rat PTM as a model in this case, however, depends upon meaningful characterization of changes in mechanical properties as well. PMID- 23017659 TI - Effects of PTH on osteocyte function. AB - Osteocytes are ideally positioned to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. However, evidence supporting the involvement of osteocytes in specific aspects of skeletal biology has been limited mainly due to the lack of suitable experimental approaches. Few crucial advances in the field in the past several years have markedly increased our understanding of the function of osteocytes. The development of osteocytic cell lines initiated a plethora of in vitro studies that have provided insights into the unique biology of osteocytes and continue to generate novel hypotheses. Genetic approaches using promoter fragments that direct gene expression to osteocytes allowed the generation of mice with gain or loss of function of particular genes revealing their role in osteocyte function. Furthermore, evidence that Sost/sclerostin is expressed primarily in osteocytes and inhibits bone formation by osteoblasts, fueled research attempting to identify regulators of this gene as well as other osteocyte products that impact the function of osteoblasts and osteoclasts. The discovery that parathyroid hormone (PTH), a central regulator of bone homeostasis, inhibits sclerostin expression generated a cascade of studies that revealed that osteocytes are crucial target cells of the actions of PTH. This review highlights these investigations and discusses their significance for advancing our understanding of the mechanisms by which osteocytes regulate bone homeostasis and for developing therapies for bone diseases targeting osteocytes. PMID- 23017661 TI - Osteoclast progenitor cells present in significant amounts in mouse calvarial osteoblast isolations and osteoclastogenesis increased by BMP-2. AB - Enzymatically released cells from neonatal mouse calvarial bones are frequently used as primary mouse osteoblasts for in vitro studies. We, here, report that although these cells lack mRNA expression of the osteoclastic genes Calcr, Acp5 and Mmp-9 at early time points after their isolation, these transcripts are gradually upregulated when the calvarial osteoblast cultures are differentiated to more mature osteoblasts in long term cultures. Similarly, Calcr, Acp5, Mmp-9, as well as Rank and Nfatc1 mRNA expressions are robustly increased when the osteoblast cultures were induced to differentiate by treatment with bone morphogenetic protein (BMP-2). The increased Calcr mRNA resulted in functionally active calcitonin receptors. Enhanced osteoblastic differentiation was associated with increased Rankl mRNA expression and decreased Opg and Cfs1 mRNA expression. Treatment of the osteoblastic cells with BMP-2 or RANKL, either on plastic dishes or bone slices, resulted in the formation of multinucleated tartrate-resistant acid phosphatase positive cells, which were able to excavate resorption pits and release CTX from the bones. In contrast, increased osteoblastic differentiation induced by BMP-2 in the mouse calvarial osteoblastic cell line MC3T3-E1 was not associated with increased mRNA expression of Calcr, Acp5, Rank, c-Fms or Oscar. Interestingly, Ctsk mRNA was increased during osteoblastic differentiation in both mouse calvarial osteoblast cultures and in MC3T3-E1 cultures. Also osteoblasts isolated from mouse long bones by outgrowth from explant cultures were contaminated with osteoclast progenitors able to differentiate into bone resorbing osteoclasts. These data indicate that mouse calvarial osteoblast cultures contain osteoclast progenitor cells, which will be differentiated along the osteoclastic lineage during osteoblastic differentiation. Moreover, the data show that BMP-2 not only stimulates osteoblastic differentiation but can also induce osteoclastogenesis through increased RANKL. PMID- 23017663 TI - Systematic vertebral fracture assessment in asymptomatic postmenopausal women. AB - INTRODUCTION: Recognition of vertebral fractures (VFs) changes the patient's diagnostic classification, estimation of fracture risk, and threshold for pharmacological intervention. Vertebral fracture assessment (VFA) enables the detection of VFs in the same session as bone mineral density (BMD) testing. OBJECTIVE: To study prevalence and risk factors of VFs using VFA in asymptomatic women and measure its effect on treatment recommendations. METHODS: We enrolled 908 postmenopausal women (mean age, weight and BMI of 60.9 +/- 7.7 (50-91) years, 73.2 +/- 13.2 (35-150) kg and 29.8 +/- 5.3 (14.5-50.8) kg/m(2), respectively. Lateral VFA images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative (SQ) approach and morphometry. RESULTS: VFs were identified in 382 patients (42.0%): 203 (22.3%) had grade 1 and 179 (19.7%) had grade 2 or 3. The prevalence of VFA-detected fractures globally increased significantly with age and as BMI and BMD declined. A fracture was identified on VFA in 63 (28.3%) women with normal BMD (8.5% had grade 2/3 VFs) and in 145 (38.5%) with osteopenia (15.7% had grade 2/3 VFs). Stepwise regression analysis showed that presence of VFs was independently related to age, BMI, number of parity, history of peripheral fracture and lumbar spine BMD. CONCLUSION: A high proportion of women with asymptomatic VFs would not receive treatment if screening were based only on BMD evaluation. Our results support the recommendation to enlarge the indications of VFA in the presence of risk factors such as age over 60, multiparity, history of peripheral traumatic fractures and low BMI. PMID- 23017662 TI - LIM kinase 1 deficient mice have reduced bone mass. AB - The cytoskeleton determines cell shape and is involved in cell motility. It also plays a role in differentiation and in modulating specialized cellular functions. LIM kinase 1 (LIMK1) participates in cytoskeletal remodeling by phosphorylating and inactivating the actin-severing protein, cofilin. Severing F-actin to release G-actin monomers is required for actin cytoskeletal remodeling. Although less well established, LIMK1 may also influence the cell cycle and modulate metalloproteinase activity. Since the role of LIMK1 in bone cell biology has not been reported, the skeletal phenotype of LIMK1(-/-) mice was examined. LIMK1(-/-) mice had significantly reduced trabecular bone mass when analyzed by microCT (p<0.01). Histomorphometric analyses demonstrated a 31% reduction in the number of osteoblasts (p=0.0003) and a 23% reduction in osteoid surface (p=0.0005). The number of osteoclasts was no different in control and knock out animals. Consistent with the in vivo findings in osteoblasts, the number of osteoblast colony forming units in LIMK1(-/-) bone marrow was reduced by nearly 50%. Further, osteoblasts isolated from LIMK1(-/-) mice showed significantly reduced rates of mineralization in vitro. Osteoclasts from LIMK1(-/-) mice evidenced more rapid cytoskeletal remodeling in response to treatment with CSF1. In keeping with this latter finding, basal levels of phospho-cofilin were reduced in LIMK1(-/-) osteoclasts. LIMK1(-/-) osteoclasts also resorbed dentine slices to a greater extent in vitro and were more active in a pit assay. These data support the hypothesis that LIMK1 is required for normal osteoblast differentiation. In addition, its absence leads to increased cytoskeletal remodeling and bone resorption in osteoclasts. PMID- 23017664 TI - Fish age, instead of weight and size, as a determining factor for time course differences in cortisol response to stress. AB - In many vertebrate species, including humans, the developmental stage directly influences an organism's reactivity to stress. For instance, fishes appear to exhibit "stress insensitive" periods early in development, which contributes to important alterations in stress responses. This phenomenon raises the important question of whether size or age influences fish stress responses, as there may be large discrepancies in size at any stage of ontogeny. We therefore posed the following question: what key role does the age and/or weight/length of fish play in contributing to different stress levels? To address this question, we conducted 2 simple experiments to compare the cortisol response to stress in the fish Rhamdia quelen. In the first experiment, we compared the cortisol response of fish of 2 different age groups (3 vs. 12 months) with the same body size, whereas in the second experiment we compared 2 groups of the same age (3 months) but with different body sizes. The results showed a similar stress response in fish of the same age but different size, but a large difference in the stress response in fish of the same size but different age. Both tests indicate that age is the determining factor for the functioning of the hypothalamo-pituitary interrenal (HPI) axis, and is probably related to the stage of maturation. This study makes a significant contribution to our knowledge of the stress, behavior, and welfare of fish of different age classes, primarily with respect to the timing of measurements and the accurate determination of fish age, regardless of size. PMID- 23017665 TI - Multidrug-resistant Salmonella enterica, Democratic Republic of the Congo. PMID- 23017667 TI - Comparison of immunohistochemical analysis with estrogen receptor SP1 and 1D5 monoclonal antibodies in breast cancer. AB - In the present study, we aimed to evaluate estrogen receptor ER-alpha status in 61 breast cancer cases using Sp1 and 1D5 monoclonal antibodies. Tissue array platforms were generated containing samples of breast cancer and positive controls that were assayed by immunohistochemistry applying monoclonal primary antibodies anti-ER alpha, SP1 and 1D5. We noted a high concordance rate (96.7%) between the referred antibodies. Moreover, we calculated the Kappa factor (0.921), indicating that 1D5 and SP1 provided overlapping ERalpha expression results. Indeed, we observed controversial results only in 2 samples studied, which were ER-negative when stained with 1D5 and ER-positive when assessed with SP1. Total concordance of PS was obtained (Pearson and intraclass CF, 0.7351 and 0.6193, respectively). However, concordance between the antibodies seems to be more accurate in higher PS values. An excellent IS correlation between antibodies was observed throughout the population (Spearman's CF, rho=0.9150). Following the Allred score, 17 out of 42 positive BC samples diverged, with 1D5 always pointing to weaker staining than SP1. When calculating Spearman's CF of Total Score (TS) within the population, an excellent correlation between both the antibodies (rho=0.9238) was noted. Nonetheless, the results were less concordant among the BC-positive cases (rho=0.7743). Indeed, 20 samples were differentially classified using the antibodies (only 3 had higher TS with 1D5). Considering the mean TS of all samples or of invasive ductal carcinoma, SP1 provided higher scores than 1D5 (p<0.05). We recommend the use of the anti-ER RMAb SP1 due to the high probability that the BC ERalpha status can be determined accurately as the reagent provides higher IS. Therefore, the A-score was higher than the MMAb 1D5. Ultimately, higher IS and A-score decrease the possibility of ERalpha status misinterpretation and, consequently, inappropriate BC treatment that would compromise the patient's quality of life and overall survival. We recommend the use of anti-ER RMAb SP1 due to the high probability that the BC ER status can be determined accurately as the reagent provides higher IS, therefore higher A score, than the MMAb 1D5. PMID- 23017666 TI - Hyaluronan turnover and hypoxic brown adipocytic differentiation are co-localized with ossification in calcified human aortic valves. AB - The calcification process in aortic stenosis has garnered considerable interest but only limited investigation into selected signaling pathways. This study investigated mechanisms related to hypoxia, hyaluronan homeostasis, brown adipocytic differentiation, and ossification within calcified valves. Surgically explanted calcified aortic valves (n=14) were immunostained for markers relevant to these mechanisms and evaluated in the center (NodCtr) and edge (NodEdge) of the calcified nodule (NodCtr), tissue directly surrounding nodule (NodSurr); center and tissue surrounding small "prenodules" (PreNod, PreNodSurr); and normal fibrosa layer (CollFibr). Pearson correlations were determined between staining intensities of markers within regions. Ossification markers primarily localized to NodCtr and NodEdge, along with markers related to hyaluronan turnover and hypoxia. Markers of brown adipocytic differentiation were frequently co-localized with markers of hypoxia. In NodCtr and NodSurr, brown fat and ossification markers correlated with hyaluronidase-1, whereas these markers, as well as hypoxia, correlated with hyaluronan synthases in NodEdge. The protein product of tumor necrosis factor-alpha stimulated gene-6 strongly correlated with ossification markers and hyaluronidase in the regions surrounding the nodules (NodSurr, PreNodSurr). In conclusion, this study suggests roles for hyaluronan homeostasis and the promotion of hypoxia by cells demonstrating brown fat markers in calcific aortic valve disease. PMID- 23017668 TI - Preoperative chemotherapy for colon cancer is getting closer. PMID- 23017669 TI - Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. AB - BACKGROUND: Preoperative (neoadjuvant) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and efficacy of preoperative chemotherapy for colon cancer. METHODS: In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with >=5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m(2), l-folinic acid 175 mg, fluorouracil 400 mg/m(2) bolus, then 2400 mg/m(2) by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the first 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratification variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. FINDINGS: 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3-4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no significant differences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0.81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0.10). Preoperative therapy resulted in significant downstaging of TNM5 compared with the postoperative group (p=0.04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0.0001), resection margin involvement (4% [four of 99] vs 20% [ten of 50], p=0.002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0.0001). INTERPRETATION: Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate. FUNDING: Cancer Research UK. PMID- 23017670 TI - CD4+ CD25+ Foxp3+ IFNgamma+ CD178+ human induced Treg (iTreg) contribute to suppression of alloresponses by apoptosis of responder cells. AB - Induced Treg with the phenotype CD4(+)CD25(+)Foxp3(+)IFNgamma(+) were shown to be associated with good long-term graft outcome in renal transplant recipients and inhibition of allogeneic T-cell responses in vitro. In the present study, we investigated whether apoptosis and Fas/FasL-dependent pathways contribute to the inhibition of T-cell activation. Early apoptosis and necrosis rates as well as co expression of immunostimulatory and immunosuppressive proteins in/on CD4(+)CD25(+)Foxp3(+), CD4(+)IFNgamma(+)Foxp3(+) and CD4(+)CD25(+)IFNgamma(+) PBL were analyzed using cells from healthy controls and four-color flow cytometry, PMA/Ionomycin-stimulated PBL, and MLC. Sixteen hours PMA/Ionomycin stimulation induced iTreg subsets with the phenotype CD4(+)CD25(+)Foxp3(+), CD4(+)IFNgamma(+)Foxp3(+) and CD4(+)CD25(+)IFNgamma(+) co-expressing CD95, CD152, CD178, CD279, Granzyme A, Granzyme B, Perforin, IL-10, and TGFbeta(1). CD178(+) iTreg increased within 3h after PMA/Ionomycin stimulation in parallel to early apoptotic Annexin(+)/PI(-) PBL, suggesting CD178-mediated apoptosis of responder cells by CD4(+)CD25(+)Foxp3(+)IFNgamma(+)CD178(+) iTreg. CD4(+)CD25(+)IFNgamma(+) and CD4(+)CD25(+)CD178(+) PBL separated from primary cell cultures and added to autologous PMA/Ionomycin stimulated secondary cell cultures induced apoptosis immediately. Early apoptosis was not antigen-specific as shown in secondary MLC with separated CD4(+)CD25(+)IFNgamma(+) and CD4(+)CD25(+)CD178(+) PBL and third party cells as stimulator. CD4(+)CD25(+)Foxp3(+)IFNgamma(+)CD178(+) iTreg differentiate after cell stimulation and induce antigen-unspecific apoptosis of activated CD95(+) responder/effector cells in vitro that might contribute to iTreg-mediated inhibition of T-cell activation. PMID- 23017671 TI - MBL serum concentration in women with HPV presenting CIN III lesions. AB - PURPOSE: This study proposes to assess MBL serum concentrations in HPV positive women that developed high risk preinvasive lesions, CIN III. MATERIALS AND METHODS: A total of 90 consecutive women (mean age 32.2 years, range 18-45 years) with CIN III lesions confirmed by cone biopsy were enrolled as cases at the gynecology cancer department of the Erasto Gaertner Hospital, a center of reference for cancer treatment in Southern Brazil. All the patients were HPV positive. In addition, 81 healthy women, voluntary blood donors, were enrolled as healthy control subjects (mean age 33.3 years, range 14-71 years) with no evidence of HPV infection, tested by hybrid capture, or CIN lesions, from the same geographic area. RESULTS: The median concentration of MBL in the cases was 912 ng/ml (IQR: 100-5820 ng/ml) and in the controls was 1207.3 ng/ml (IQR 100 4320.6 ng/ml). No statistically significant difference was observed between cases and controls. CONCLUSION: This study reports data on MBL serum concentrations in HPV infected women for the first time. The analysis of our findings did not show a statistically significant difference between MBL serum concentrations in HPV women that developed CIN III lesions and healthy controls. PMID- 23017672 TI - Autophagy in adipose tissue biology. AB - Obesity, which predisposes individuals to type II diabetes and cardiovascular diseases, results from accumulation of white adipose tissue (WAT). WAT comprises mainly white adipocytes that have a unique cellular structure in which almost the entire intracellular space is occupied by one single lipid droplet. The cytoplasm envelopes this lipid droplet and occupies negligible space. Differentiation of WAT, or adipogenesis, requires dramatic cytoplasmic reorganization, including a dynamic change in mitochondrial mass. Autophagy is a major cytoplasmic degradation pathway and a primary pathway for mitochondrial degradation. Recent studies indicate that autophagy is implicated in adipogenesis. In this review, we summarize our current knowledge on autophagy in adipose tissue biology, with the emphasis on its role in mitochondrial degradation. Adipose tissue is a central component for whole-body energy homeostasis regulation. Advancement in this research area may provide novel venues for the intervention of obesity and obesity related diseases. PMID- 23017673 TI - Therapeutic modulation of intestinal dysbiosis. AB - The human gastrointestinal tract is home to an extremely numerous and diverse collection of microbes, collectively termed the "intestinal microbiota". This microbiota is considered to play a number of key roles in the maintenance of host health, including aiding digestion of otherwise indigestible dietary compounds, synthesis of vitamins and other beneficial metabolites, immune system regulation and enhanced resistance against colonisation by pathogenic microorganisms. Conversely, the intestinal microbiota is also a potent source of antigens and potentially harmful compounds. In health, humans can therefore be considered to exist in a state of natural balance with their microbial inhabitants. A shift in the balance of microbiota composition such that it may become deleterious to host health is termed "dysbiosis". Dysbiosis of the gut microbiota has been implicated in numerous disorders, ranging from intestinal maladies such as inflammatory bowel diseases and colorectal cancer to disorders with more systemic effects such as diabetes, metabolic syndrome and atopy. Given the far reaching influence of the intestinal microbiota on human health a clear future goal must be to develop reliable means to alter the composition of the microbiota and restore a healthy balance of microbial species. While it is clear that much fundamental research remains to be done, potentially important therapeutic options include narrow spectrum antibiotics, novel probiotics, dietary interventions and more radical techniques such as faecal transplantation, all of which aim to suppress clinical dysbiosis, restore intestinal microbiota diversity and improve host health. PMID- 23017674 TI - Detection and imaging the expression of the trans-membrane protein CD44 in RT112 cells by use of enzyme-labeled antibodies and SECM. AB - The deposition of human RT112 cells in a patterned fashion onto glass substrates and subsequent imaging of the expression of the trans-membrane protein CD44 have been studied using scanning electrochemical microscopy (SECM). Patterns of RT112 cells derived from a transitional cell carcinoma of the bladder could be deposited on amino-modified glass substrates by cytospinning. These were then treated with horseradish peroxidase (HRP) labeled secondary antibodies to the trans-membrane protein CD44. Expression of CD44 protein by the cells directly leads to immobilisation of the labeled antibodies. The presence of the enzyme substrate (hydrogen peroxide) along with a hydroquinone mediator then allowed an enzymatic reaction to proceed, generating benzoquinone. Reduction of benzoquinone gave rise to positive feedback between the substrate and the SECM microelectrode tip. Control samples such as blank slides or slides not treated with HRP-labeled antibody showed negative feedback effects. Patterns of RT112 cells could be assembled and their expression of the target protein imaged whereas control samples showed minimal activity. PMID- 23017675 TI - From DVD to dendritic nanostructure silver electrode for hydrogen peroxide detection. AB - A facile method of multi-potential step-scan has been employed to fabricate the dendritic silver nanostructures on a silver thin film based digital video disc (DVD) electrode. The morphologies of the nanostructures, the chemical composition, and the crystal structure have been characterized by field-emission scanning electron microscopy, energy-dispersed x-ray spectroscopy, and x-ray diffraction, respectively. The electrocatalytic activity of the resulting electrode toward the electro-reduction of hydrogen peroxide (H(2)O(2)) has been examined via cyclic voltammetry and amperometric analysis. The excellent linear relationship between current response and H(2)O(2) concentration is observed in the range from 5.88*10(-7) to 6.73*10(-5) mol L(-1) and the detection limit is 2*10(-7) mol L(-1) (S/N=3). The as-developed method has been employed to determine H(2)O(2) concentration in real samples. PMID- 23017677 TI - A novel and rapid assay for HIV-1 protease detection using magnetic bead mediation. AB - A simple sensing assay was established for label-free detection of HIV-1 protease. HIV-1 protease peptide substrate conjugated to magnetic beads via its N terminus is directly fixed onto the sensor gold surface through the sulphur atom of cysteine. Surface plasmon resonance (SPR) was used to study the peptide substrate cleavage efficiency of the protease with magnetic beads of different sizes (1 MUm and 30 nm). Cyclic voltammetry and faradic impedance spectroscopy were employed in order to characterize the functionalized gold electrode. It was found that the nano-sized beads are a more efficient sensing probe for the protease. Electrochemical biosensing showed a gradual decrease in charge transfer resistance after injection of the HIV-1 protease. The experimental data established a detection limit of 10 pg/ml, as well as demonstrated a drug screening assay. This HIV-1 protease biosensor represents a new detection approach which will lead to low-cost point-of-care devices for sensitive HIV-1 diagnosis, as well as high-throughput drug screening platforms. PMID- 23017676 TI - Application of suspension array for simultaneous detection of four different mycotoxins in corn and peanut. AB - Mycotoxins are highly toxic contaminants in foodstuffs and feedstuffs. The study presents a novel suspension array technology for quantifying four mycotoxins, namely, aflatoxin B1, deoxynivalenol, T-2 toxin, and zearalenone, in corn and peanut. Using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, the complete antigens of the mycotoxins became attached to the microspheres with viable activity. The optimal concentrations of each antibody and biotin-rabbit anti-goat IgG were obtained through chessboard titration. The four mycotoxins were detected simultaneously and quantitatively in corn and peanut using indirect competitive immunoassay. Multi-channel standard curves with appropriate logistic correlation (R(2)>0.9819) were respectively plotted. The broad working ranges with three to four orders of magnitude were calculated, and limits of detection at the pg level were found to be better than those obtained using high performance liquid chromatography. The recovery rates in the actual samples generally ranged from 80.16% to 117.65%, with an intra-assay coefficient of variation lower than 15%, which indicated high accuracy and repeatability. A suspension array method for the simultaneous detection of the four mycotoxins within 4h was successfully developed using minimal samples; the method was proven to have high throughput, flexibility, accuracy and reproducibility. The approach could detect multiple contaminants in actual samples. PMID- 23017678 TI - Highly sensitive detection of organophosphorus pesticides by acetylcholinesterase coated thin film bulk acoustic resonator mass-loading sensor. AB - An acetylcholinesterase-coated thin film bulk acoustic resonator has been developed for the detection of organophosphorus pesticides. The thin film bulk acoustic resonator acts as a robust mass-sensitive transducer for bio-sensing. This device works in thickness shear mode with a resonance at 1.97 GHz. The detection is based on the inhibitory effects of organophosphorus compounds on the enzymatic activity of the acetylcholinesterase immobilized on one of the faces of the acoustic resonator. The enzyme reaction in the substrate solution and the inhibitory effect is observed are real time by measuring the frequency shift. The presence of organophosphorus pesticides can be detected from the diminution of the frequency shift compared with the levels found in their absence. The device exhibits linear responses, good reproducibility, simple operation, portability and a low detection limit of 5.3*10(-11) M for paraoxon. The detection results of organophosphorus pesticide residues in practical samples show that the proposed sensor has the feasibility and sensing accuracy comparable to gas chromatography. PMID- 23017679 TI - Improvement of protein immobilization for the elaboration of tumor-associated antigen microarrays: application to the sensitive and specific detection of tumor markers from breast cancer sera. AB - There is an urgent need to identify relevant tumor markers showing high sensitivity and specificity for early diagnosis and prognosis of breast cancer. Protein microarrays have demonstrated to be cost-effective, high through-put and powerful tools for screening and identifying tumor markers with only minute samples. Autoantibodies directed against tumor-associated antigens (TAAs) were shown to be relevant tumor markers. However, due to the variability of immune response from one individual to another and depending on the type of cancer, detection of only one type of anti-TAA autoantibody is not sufficient to give a reliable and precise diagnosis. It is necessary to use a set of several TAAs for determining specific autoimmune profiles. Therefore, combining various TAAs on different surfaces could improve sensitivity and specificity for anti-TAA autoantibody detection. Herein a panel of 10 proteins, including well-known tumor associated antigens (TAAs) and potential new biomarkers of breast cancer, were immobilized onto microstructured microarray under optimized conditions (spotting pH buffer, surface chemistry, blocking procedure), in order to determine an autoimmune signature of breast cancer. Sera from 29 breast cancer patients and 28 healthy donors were screened in sandwich immunoassays on the miniaturized system to detect the eventual presence of anti-TAAs autoantibodies. Results indicated that the detection level of each anti-TAA autoantibody in a given serum sample was strongly dependant on the surface chemistry. Combining five TAAs (p53, Hsp60, Hsp70, Her2-Fc, NY-ESO-1) on two different surface chemistries (NHS and APDMES) allowed the significant detection of more than 82% breast cancer sera. PMID- 23017680 TI - Template and catalytic effects of DNA in the construction of polypyrrole/DNA composite macro and microelectrodes. AB - Electrochemical DNA hybridization-based sensors show great promise as portable and automated analytical devices for routine screening of pathogenic or foreign nucleic acid sequences in biological samples. However, current sensor technologies still exhibit some unresolved issues which hampers their direct application into everyday life. Conducting polymers, such as polypyrrole (PPy), are increasingly being adopted as suitable platforms for DNA probe immobilization and signal transduction. Immobilization of DNA probes during pyrrole electropolymerization is a simple and efficient strategy to build composite electrodes suitable for DNA sensing. However, the effects of the probe state and sequence on PPy growth kinetics have not been studied yet. Here, we show that growth of PPy is drastically affected by the presence of guanine in the DNA probes and whether DNA is present in its single-stranded or double-stranded form. We show that some immobilization protocols may provoke irreversible oxidation of guanine moieties in the probe and that this issue deserves careful investigation as it may interfere with hybridization processes. We have also explored new procedures to build microelectrode arrays bearing immobilized DNA molecules, which are known to show beneficial properties in stirred samples. Overall, we present new techniques and concerns regarding the development of DNA-containing PPy-based composite electrodes, which may be taken into consideration for increasing genosensor reproducibility, response and performance. PMID- 23017681 TI - Graphene oxide-hairpin probe nanocomposite as a homogeneous assay platform for DNA base excision repair screening. AB - Uracil-DNA glycosylase (UDG) as one of the most important base excision repair enzymes plays a crucial role in protecting the genome from endogenous DNA damage and sustaining the genome integrity. Quantitative activity analysis of UDG is a central challenge and of fundamental importance in bioanalysis. Here, we proposed a novel biosensor constituted by adsorbing a fluorophore-labeled hairpin probe onto the surface of graphene oxide (GO) as a homogeneous assay platform for sensitive UDG activity assay. Active UDG could excise the uracil base in the hairpin probe, and further hydrolysis of the leaving abasic site gave rise to high fluorescence. Thus, it provided a convenient approach for UDG activity quantification. Because of the unique ability of GO in universal fluorescence quenching, a low background fluorescence signal can be obtained for the efficient fluorescence resonant energy transfer from the fluorophore-labeled on the hairpin probe to GO sheet. A quite wide dynamic range from 0.0017 U/mL to 0.8 U/mL was achieved for UDG assay and the detection limit was estimated to be 0.0008 U/mL. The results indicated that this strategy offers a simple, cost-effective, highly sensitive and selective homogeneous detection platform for UDG activity assay related biochemical studies. PMID- 23017682 TI - Characterization of a modified gold platform for the development of a label-free anti-thrombin aptasensor. AB - This work reports the characterization of a modified gold surface as a platform for the development of a label free aptasensor for thrombin detection. The biorecognition platform was obtained by the self-assembly of 4-mercaptobenzoic acid onto a gold surface, covalent attachment of streptavidin and further immobilization of the biotinylated anti-thrombin aptamer. The biosensing platform was characterized by cyclic voltammetry, electrochemical impedance spectroscopy, surface plasmon resonance (SPR) and quartz crystal microbalance with dissipation monitoring. The biorecognition event aptamer-thrombin was detected from changes in the SPR angle produced as a consequence of the molecular interaction between the aptasensor and the target protein. The biosensing platform demonstrated to be highly selective for human thrombin even in the presence of large excess of bovine thrombin, bovine serum albumin, cytochrome C, lysozyme and myoglobin. The relationship between the changes in the SPR angle and thrombin concentration was linear up to 0.19 MUmol L(-1) (R(2)=0.992) while the detection limit was of 12.0 nmol L(-1) (240 fmol in the sample). This new sensing approach represents an interesting and promising alternative for the SPR-based quantification of thrombin. PMID- 23017683 TI - Development of pH-based ElecFET biosensors for lactate ion detection. AB - In this work, we report on ElecFET (Electrochemical Field Effect Transistor) devices potentially of interest for the detection of different molecules in solution. ElecFET are electrochemical microsensors in liquid phase, based on two elements: (i) a pH-sensitive chemical field effect transistor (pH-ChemFET) and (ii) a metallic microelectrode deposited around the sensitive gate. The coexistence of these two elements combines (i) potentiometric and (ii) amperometric detection effects at the microscale. Design, fabrication and experimental validation of ElecFETs based on silicon and polymer micro technologies, are reported. We first demonstrate the detection of hydrogen peroxide (H(2)O(2)) in solution, showing a sensitivity of 5 mV/mM in the [10-100 mM] concentration range. The ElecFET concept is then extended to the detection of glucose and lactate in the [1-30 mM] and [1-6 mM] concentration range respectively. The sensitivities are between 2-6 mV/mM and 8-20 mV/mM respectively. PMID- 23017684 TI - Fabrication of GO/PANi/CdSe nanocomposites for sensitive electrochemiluminescence biosensor. AB - A novel graphene oxide sheets/polyaniline/CdSe quantum dots (GO/PANi/CdSe) nanocomposites were successfully synthesized and used for the sensitive electrochemiluminescence (ECL) biosensing. The GO/PANi/CdSe nanocomposites were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), ultraviolet-visible (UV-vis) absorption spectroscopy, photoluminescence (PL) spectroscopy and Fourier transform infrared (FTIR) spectroscopy. Finally, the nanocomposites were employed to construct the biosensor via layer-by-layer assembly for the ECL detection of Cytochrome C (Cyt C). The whole process was characterized by cyclic voltammogram (CV) and electrochemical impedance spectroscopy (EIS). Experimental parameters such as the ratio of GO/PANi, the K(2)S(4)O(8) concentration and the pH value of electrolyte solution were studied to investigate the effect on the ECL intensity. Under the optimized conditions, the ECL intensity decreased linearly with the Cyt C concentrations in the range from 5.0*10(-8) to 1.0*10(-4) M with detection limit of 2.0*10(-8) M. Besides, the as-proposed biosensor exhibits high specificity, good reproducibility, and stability, and may be applied in more bioanalytical systems. PMID- 23017685 TI - Ultrasensitive and real-time detection of proteins in blood using a potentiometric carbon-nanotube aptasensor. AB - Potentiometric sensing represents the preferred technique in many routine measurements of pH and ions. Unfortunately, the simplicity of the technique has not been exploited so far in high throughput biomolecular sensing. In this work, we demonstrate the capabilities of the hybrid functional material carbon nanotubes/aptamer for the creation of a new generation of nuclease-resistant aptasensors using the potentiometric transduction capabilities of single-walled carbon nanotubes in combination with the recognition capabilities of a protein specific RNA aptamer. The aptasensor was used to detect and identify disease related proteins at attomolar concentration values in a rapid and non-expensive way. The variable surface glycoprotein from African Trypanosomes was chosen as an ideal model system for a pathogenic exoantigen protein in a clinical sample. Variations in the electromotive force are achieved in real-time upon the direct addition of diluted real blood samples containing the target protein thus eliminating the need of preliminary matrix removal. This work would open the door to real-time diagnostic assays for a wide range of diseases, but also to the rapid molecular detection of several proteins in truly customizable protein biosensing platforms. PMID- 23017686 TI - Immune-independent and label-free fluorescent assay for Cystatin C detection based on protein-stabilized Au nanoclusters. AB - Cystatin C (Cys C) is a significant cysteine protease inhibitor in human bodies, and is proposed as a fascinating novel marker of glomerular filtration rate for kidney injury detection. Almost all traditional methods for Cys C measurement are immunoassays. In this article, we report a simple, immune-independent (no need to rely on immunoassay) and label-free method for Cystatin C detection using BSA stabilized Au nanoclusters (Au NCs) as a fluorescent probe. This method relies on the BSA scaffold degradation caused by the cysteine protease activity of papain and the specific inhibition of papain activity by Cys C. The fluorescence of BSA Au NCs can be effectively quenched by papain, and restored by the coexistence of Cys C. Under optimized conditions, this method enables sensitive and selective measurement of Cys C concentration in the range of 25 ng/mL-2.0 MUg/mL with the detection limit of 4.0 ng/mL, which is above 40 fold lower than that of commercial immune-based methods. SDS-PAGE, the absorption spectroscopy, transmission electron microscope, dynamic light scattering, and X-ray photoelectron spectroscopy were performed to discuss the quenching mechanism. In addition, percentage recoveries of Cys C in the spiked urine samples were ranged from 102.2% to 114.9% with the relative standard deviation ranging from 0.9-1.8%, demonstrating the applicability of the developed method in clinical samples. Furthermore, the present approach would be potentially extended to other proteases and their inhibitors detection with different protein-stabilized Au NCs. PMID- 23017687 TI - CRP detection from serum for chip-based point-of-care testing system. AB - Most of point-of-care testing (POCT) to improve facilitates in diagnosis, treatment, and monitoring of patients. POCT technique has still remained a quantitatively and accurately detective effect. In this article, we demonstrated that real human C-reactive protein (CRP) in serum was detected for a chip-based point-of-care testing application based on a nanogap-embedded field effect transistor (FET), and the results were compared with those obtained via the enzyme-linked immunosorbent assay (ELISA) method. The limit of detection (LOD), determined from the standard curve, was 0.1 ng/ml, which is comparable to that of commercialized ELISAs. We evaluated that an improved detection range (0.1 ng/ml to 100 ng/ml) was achieved by comparing with commercialized ELISA. Control experiments to determine selectivity and to discern false-positive/false-negative rates were also performed. This report is the first description of the detection of CRP in human serum using a silicon-based biosensor. PMID- 23017688 TI - The three-way junction DNAzyme based probe for label-free colorimetric detection of DNA. AB - A novel three-way junction DNAzyme based probe has been designed for the colorimetric sensing of target DNA. Specifically, a DNAzyme-linked hairpin DNA is used as a signal probe. In the presence of target DNA, the signal probe, assistant probe and target DNA can hybridize with each other, resulting in the formation of a three-way junction DNA. At the same time, the signal probe is opened and the DNAzyme sequence in the signal probe is dehybridized. Subsequently, in the presence of hemin, the DNAzyme sequence forms a G-quadruplex hemin complex, which catalyzes oxidation of 2, 2'-azinobis (3-ethylbenzthiazoline 6-sulfonic acid) (ABTS) by H(2)O(2) to the colored ABTS(.-)radical. The significant color changes can be distinguished visually. By the combination of the hairpin probe and the three-way junction DNA probe, the proposed sensor exhibits high recognition property for single-nucleotide polymorphisms (SNPs). This sensor allows the detection of target DNA at a concentration as low as 0.25 nmol L(-1). The proposed sensor is easy to fabricate, which avoids the tedious and expensive labeling procedures, and exhibits high selectivity against single base mismatched DNA. PMID- 23017689 TI - Infective endocarditis due to Enterobacter cloacae resistant to third- and fourth generation cephalosporins. AB - We report the case of using a long-term combination of meropenem and amikacin to treat infective endocarditis caused by Enterobacter cloacae resistant to third- and fourth-generation cephalosporins. Multi-drug resistant Gram-negative bacilli, such as the E. cloacae in our study, may become possible pathogens of infective endocarditis. Our experience with this case indicates that long-term use of a combination of beta-lactam and aminoglycosides might represent a suitable management option for future infective endocarditis cases due to non-Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella spp. (HACEK group) Gram negative bacilli such as ours. PMID- 23017690 TI - Nanoscopic analysis on pH induced morphological changes of flagella in Escherichia coli. AB - BACKGROUND AND PURPOSE: Flagella contribute to the virulence of pathogenic bacteria through chemotaxis, motility, and adhesion. Understanding the various functions of flagella may provide insight into mechanisms of bacterial infection and transmission. The objectives of our study were to apply biophysical and biochemical methods to investigate the mechanisms of pH-dependent changes in flagella functions. METHODS: Atomic force microscopy (AFM) was used to analyze the flagellum morphology of Escherichia coli cultured in various pH conditions. The swarming plate method was used to identify pH-dependent changes in bacterial motility. Western blot analysis and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) were also carried out to study pH-dependent expression and structural changes of flagellin C. RESULTS: E coli cultured at pH 7 produced the flagella with the greatest average length and diameter. When the bacteria were grown at pH 6 or pH 8, shorter and thinner forms of flagella were produced. The morphology of the flagella was correlated to the bacterial motility. While western blot analysis showed only a slight change in the expression of the flagellin C protein in response to changes in the pH of the culture medium, ATR-FTIR showed significant pH-dependent changes in the secondary structure of the flagellin C assembled in sheared flagella. CONCLUSION: Our results show that both acidification and alkalization of the culture medium restricted bacterial motility, and indicate that the reduced motility may be caused by incorrect assembly of the flagellum proteins. PMID- 23017691 TI - Pulmonary nocardiosis in southern Taiwan. AB - BACKGROUND/PURPOSE: Nocardiosis mainly affects immunocompromised patients. The objectives of this study were to better understand the epidemiologic, demographic, clinical, and laboratory information in patients with pulmonary nocardiosis in southern Taiwan. METHODS: Retrospective analyzing patients aged >=18 years with culture-proven pulmonary nocardiosis received treatment at KCGMH between January 2004 and June 2010. Nocardiae were identified by 16S rRNA gene sequence analysis. Patients with pulmonary nocardiosis caused by the mostly commonly encountered Nocardia sp. were compared with those with pulmonary nocardiosis due to other Nocardia spp. RESULTS: Among the 20 patients included, cough (80%) and fever (50%) were the 2 leading symptoms/signs, while lobar consolidation (50%) and pleural effusion (40%) were the most frequent radiographic manifestations. Eighteen patients (90%) had at least one underlying disease/condition. Nocardia cyriacigeorgica was most commonly found. Compared with those whose pathogens were other Nocardia spp., patients with pulmonary nocardiosis caused by N cyriacigeorgica experienced higher clinical severity as measured by APACHE II score (19.8 +/- 7.0 vs. 12.8 +/- 6.7; p = 0.04) and ICU admission rate (100% vs. 25%; p < 0.01). Thirteen patients (65%) turned out to be fatal. The severity (APACHE II score, 18 +/- 6 vs. 10 +/- 8; p = 0.02) and the proportion of acute and subacute pulmonary nocardiosis (76% vs. 0%, p = 0.03) between fatal and survived patients differed significantly. CONCLUSIONS: N cyriacigeorgica was the most common pathogen in southern Taiwan. Higher mortality rate in patients with pulmonary nocardiosis was related to disease severity and acute and subacute infection. PMID- 23017693 TI - Social and behavioral skills and the gender gap in early educational achievement. AB - Though many studies have suggested that social and behavioral skills play a central role in gender stratification processes, we know little about the extent to which these skills affect gender gaps in academic achievement. Analyzing data from the Early Child Longitudinal Study-Kindergarten Cohort, we demonstrate that social and behavioral skills have substantively important effects on academic outcomes from kindergarten through fifth grade. Gender differences in the acquisition of these skills, moreover, explain a considerable fraction of the gender gap in academic outcomes during early elementary school. Boys get roughly the same academic return to social and behavioral skills as their female peers, but girls begin school with more advanced social and behavioral skills and their skill advantage grows over time. While part of the effect may reflect an evaluation process that rewards students who better conform to school norms, our results imply that the acquisition of social and behavioral skills enhances learning as well. Our results call for a reconsideration of the family and school level processes that produce gender gaps in social and behavioral skills and the advantages they confer for academic and later success. PMID- 23017692 TI - Correlation of NT-proBNP levels and cardiac iron concentration in patients with transfusion-dependent thalassemia major. AB - Iron-induced cardiotoxicity remains the leading cause of morbidity and mortality in patients with transfusion-dependent beta-thalassemia major. Heart failure in these patients, which may be reversible but has a poor prognosis, is characterized by myocardial iron deposition-related early diastolic dysfunction. Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is a sensitive biomarker for the detection of asymptomatic left ventricular dysfunction. In this study, we prospectively evaluated plasma NT-proBNP levels in 187 adult patients aged 19-54 years with beta-TM. Possible correlations with the proposed recently cardiac iron concentration based on an equation derived from heart T2* assessment by MRI: [Fe] = 45.0 * [T2*](-1.22) with [Fe] in milligrams per gram dry weight and T2* in milliseconds were explored. We found that: 143 patients had no cardiac hemosiderosis, defined as [Fe] < 1.1 mg/g dry weight, corresponding to T2* > 20 ms and 44 patients had cardiac hemosiderosis, defined as [Fe] > 1.2mg/g dry weight. The main results of the study showed that: a) NT-proBNP levels were markedly increased in thalassemic patients (152.2 +/- 190.1 pg/mL, ranged from 6.0 to 1336.0 pg/mL compared to normal control levels 40.1 +/- 19.7 pg/mL, p < 0.001, b) NT-proBNP levels were significantly higher in patients with cardiac hemosiderosis compared to patients without cardiac hemosiderosis (185.1 +/- 78.0 vs 128.9 +/- 20.2 pg/mL, p < 0.05), c) NT-proBNP levels correlated with [Fe] values (r = 0.387, p < 0.001). This correlation was significant in patients with cardiac hemosiderosis (r = 0.520, p < 0.001), but not in patients without cardiac hemosiderosis (p > 0.1), and d) no significant correlation was found between NT proBNP levels and left ventricular ejection fraction values, (p > 0.3). Our study demonstrated for first time the significant association of NT-proBNP levels and cardiac iron concentration in patients with beta-thalassemia major linking blood chemistry and imaging techniques. Multicenter studies of these parameters during iron chelation therapies are needed to validate their association and further exploit its clinical use. PMID- 23017694 TI - Whither the virtuous cycle? Past and future trends in black-white inequality in educational attainment. AB - The inequality in the relative years of education between blacks and whites has diminished dramatically over the 20th century. One possible explanation for this convergence is a virtuous cycle of parents passing on educational advantage, from one generation to the next, leading to an overall educational upgrading. In this paper we test the virtuous cycle hypothesis by estimating the three way interaction of cohort, race, and family background. We find that the convergence in educational attainment between blacks and whites over the past century was driven by processes unrelated to family background. PMID- 23017695 TI - Family structure and the intergenerational transmission of educational advantage. AB - I examine whether the effect of parents' education on children's educational achievement and attainment varies by family structure and, if so, whether this can be explained by differential parenting practices. Using data from the National Education Longitudinal Study of 1988, I find that as parents' education increases, children in single mother families experience a lower boost in their achievement test scores, likelihood of attending any post-secondary schooling, likelihood of completing a 4-year college degree, and years of completed schooling relative to children living with both biological parents. Differences in parents' educational expectations, intergenerational closure, and children's involvement in structured leisure activities partially explain these status transmission differences by family structure. The findings imply that, among children with highly educated parents, children of single mothers are less likely to be highly educated themselves relative to children who grow up with both biological parents. PMID- 23017696 TI - Complement or competition: Latino employment in a nontraditional settlement area. AB - The migration of Latinos to nontraditional settlement areas in the United States is renewing interest in how an established low-skilled work force is affected by the inflow of a minority group whose members tend to have a weak basket of human capital. Some scholars focus on how the incoming group creates head-to-head competition with established workers. An alternative view posits that, depending on the context of the receiving labor market, incoming workers may primarily fill roles that complement preexisting labor market arrangements. I study these issues in the region of the country that has experienced the most pronounced in migration of Latinos during the past few years. The findings indicate migrating Latinos tend to complement preexisting labor market conditions rather than spark job competition and undercut the earning power of non-Latinos. PMID- 23017697 TI - Implicit and explicit interethnic attitudes and ethnic discrimination in hiring. AB - We study effects of explicit and implicit interethnic attitudes on ethnic discrimination in hiring. Unlike explicit attitudes, implicit attitudes are characterised by reduced controllability, awareness or intention. Effects of implicit interethnic attitudes on ethnic discrimination in the labour market remain under-researched. Moreover, previous experiments on the effects of explicit interethnic attitudes on discrimination have important drawbacks. We use data from a laboratory experiment (n=272) consisting of an Implicit Association Test, a questionnaire and a recruitment test in which participants reviewed resumes representing fictitious applicants who varied regarding ethnicity, gender, education and work experience. Participants graded applicants and selected applicants for an interview. Results show that only explicit interethnic attitudes affect discrimination in grades, but both explicit and implicit interethnic attitudes increase discrimination in selection. PMID- 23017698 TI - Imprisonment and (inequality in) population health. AB - This article extends research on the consequences of mass imprisonment and the factors shaping population health and health inequalities by considering the associations between imprisonment and population health-measured as life expectancy at birth and the infant mortality rate-and black-white differences in population health using state-level panel data from the United States (N=669), 1980-2004. Results show that imprisonment is significantly associated with poorer population health, though associations between imprisonment and infant mortality and female life expectancy are somewhat more consistently statistically significant than are associations with male life expectancy, and associations are more pronounced and statistically significant for blacks than they are for whites. Results also show, however, that increases in imprisonment are associated with decreases in the mortality rates of young black men. Thus, though imprisonment tends to be associated with higher mortality risk and greater black white differences in mortality, it may, in the short-run, have some paradoxical mortality benefits for young black men. PMID- 23017699 TI - Comparative modeling approaches for understanding urban violence. AB - The purpose of this paper is to provide a comparative analysis of three different modeling approaches for exploring structural theories of violence. Specifically, ordinary least squares regression, geographically weighted regression and data envelopment analysis will be utilized to evaluate violent crime. This type of analysis expands upon traditional theory testing by deepening our understanding of differences in crime generation and its underlying demographic and socio economic stimuli via different methodological lenses. A case study for the city of Cincinnati, Ohio is presented and the results suggest that a combination of approaches is likely the best strategy for evaluating violence in urban areas. PMID- 23017700 TI - The burdens of social capital: How socially-involved people dealt with stress after Hurricane Katrina. AB - Research shows that those with greater social capital enjoy better physical and mental health. The current study illuminates a paradox of social capital which may afflict those involved in traumatic events. Several years of survey data reveal a dynamic picture of the link between social capital and stress following Hurricane Katrina. Results reveal that initially after Katrina, those who were more socially embedded carried the greatest load with respect to helping the displaced population, thus experiencing more stress. But over time, the most socially-involved then snapped back from their stressful experiences more rapidly than isolates. This confirms that over the course of stressful events, social involvement first exposes people to more stress, but as time passes, provides them a significant buffer against negative psychosocial experiences. PMID- 23017701 TI - Bribery or just desserts? Evidence on the influence of Congressional reproductive policy voting patterns on PAC contributions from exogenous variation in the sex mix of legislator offspring. AB - Evidence on the relationship between political contributions and legislators' voting behavior is marred by concerns about endogeneity in the estimation process. Using a legislator's offspring sex mix as a truly exogenous variable, we employ an instrumental variable estimation procedure to predict the effect of voting behavior on political contributions. Following previous research, we find that a legislator's proportion daughters has a significant effect on voting behavior for women's issues, as measured by score in the "Congressional Record on Choice" issued by NARAL Pro-Choice America. In the second stage, we make a unique contribution by demonstrating a significant impact of exogenous voting behavior on PAC contributions, lending further credibility to the hypothesis that Political Action Committees respond to legislators' voting patterns by "rewarding" political candidates that vote in line with the positions of the PAC, rather than affecting those same votes - at least in this high-profile policy domain. PMID- 23017702 TI - State activism and the hidden incentives behind bank acquisitions. AB - A number of studies have shown that, as a result of the ambiguity of US legal mandates, organizations have considerable latitude in how they comply with regulations. In this paper, we address how the different agendas of the federal and state governments increase ambiguities in state-firm relations and how states are interested actors in creating opportunities for firms to navigate the federal legislation. We analyze the institutional forces behind bank acquisitions within and across state lines in order to illuminate the ways that US states take advantage of federal ambiguity and are able to shape corporate practices to their benefit. We specifically examine how patterns of bank acquisitions are shaped by the crucial relationship between the federal Community Reinvestment Act (CRA) and a little-understood provision in the federal tax code that is implemented at the state level, the Low-Income Housing Tax Credit (LIHTC). The relationship is complex because, while the federal government uses the CRA to control bank acquisition activity, states promote use of the LIHTC, through which banks can address federal CRA concerns, and thereby promote bank acquisitions in their jurisdictions. Thus, our findings suggest that the implementation of social legislation at one level in a federal regulatory system undermines the mechanisms of social legislation at another level. We use archival research and in-depth interviews to examine the interaction between these institutional processes and formulate hypotheses that predict the ways in which bank acquisitions are constrained by banks' CRA ratings and the way states in turn help banks overcome their CRA constraints. Quantitative analyses of all bank acquisitions in the United States from 1990-2000 largely support these hypotheses. PMID- 23017703 TI - Spatial variation in poverty-generating processes: Child poverty in the United States. AB - This study builds on research demonstrating that sub-regions within the United States have different processes that abet poverty and that child poverty is spatially differentiated. We focus on the social attributes of the local area to assess what the geographic place represents in terms of social characteristics, namely racial/ethnic composition and economic structure, and to resolve apparent inconsistencies in poverty research. Using spatial regime and spatial error regression techniques to analyze county census data, we examine spatial differentiation in the relationships that generate child poverty. Our approach addresses the conceptual and technical aspects of spatial inequality. Results show that local-area processes are at play with implications for more nuanced theoretical models and anti-poverty policies that consider systematic differences in factors contributing to child poverty according to the racial/ethnic and economic contexts. PMID- 23017704 TI - Restrictive abortion laws, antiabortion attitudes and women's contraceptive use. AB - This study empirically examines the public and social policy question: Do state restrictive abortion laws affect the likelihood that women use more highly effective contraceptive methods? Using contraceptive use data from the Behavioral Risk Factor Surveillance System 2002 survey, the empirical results show that Medicaid Funding Restrictions, Informed Consent Laws, and Two-Visit Laws have no significant impact on adult women's (ages 18-44, 18-24, 25-34, 35-44) use of highly effective contraceptive methods. A state's antiabortion attitudes, which likely contribute to the enactment of restrictive abortion laws in a state, are a major factor in inducing greater use of highly effective contraceptive methods by adult women at-risk of an unintended pregnancy. The empirical findings remain robust for various population subgroups of adult women (i.e., married, single, employed, unemployed, with children, no children and college educated). PMID- 23017705 TI - Deriving equity from expectations: A cross-cultural evaluation. AB - This paper develops and evaluates a new model for predicting just rewards. The model produces point predictions for individual just rewards based on status characteristics and the expected value of a valued good. The equity model borrows from Berger and colleagues' (1998) reward expectations theory the ability to define different reward expectations. Drawing from Melamed and Walker's (2010) recent generalization of the mathematics of reward expectations theory, I illustrate how the model generates a continuous distribution of just rewards. The general model is applied to data from thirteen countries using the International Social Justice Project. The results illustrate the predictive power of the model using data from over 10,000 respondents. Implications and future directions are discussed. PMID- 23017706 TI - The proportional odds with partial proportionality constraints model for ordinal response variables. AB - The proportional odds assumption in ordered logit models is a restrictive assumption that is often violated in practice. A violation of the assumption indicates that the effects of one or more independent variables significantly vary across cutpoint equations in the model. In order to relax this assumption for the cumulative odds model, researchers may use either a "partial" model that relaxes the assumption for a subset of variables or the "generalized" model that relaxes the assumption for every independent variable. In this paper, we propose a relatively new and under-utilized third alternative, the proportional odds with partial proportionality constraints (POPPC) model, which allows the effects of a subset of variables to vary across cutpoint equations by a common factor. We improve upon an earlier formulation of the POPPC model by offering an additional conceptual justification for the model and an estimation method that does not require the use of person-threshold data. We illustrate the POPPC model with two examples from the 2008 General Social Survey. PMID- 23017707 TI - Happiness is not normally distributed: A comment to Delhey and Kohler. AB - Delhey and Kohler assume that the happiness distribution at the population level is essentially normal, but that this is distorted by the fact that happiness is measured in samples using scales that are discrete and two-sided bounded. This assumption is tested using the probit method and rejected. PMID- 23017708 TI - The medicine is worse than the disease: Comment on Delhey and Kohler's proposal to measure inequality in happiness using 'instrument-effect-corrected' standard deviations. AB - Inequality of happiness in nations can be measured using the standard deviation of responses to surveys questions. The standard-deviation is not quite independent of the mean, being zero when everybody is maximally happy or unhappy while the possible value of the standard deviation is highest when the mean is in the middle of the response scale. Delhey and Kohler see this intrinsic dependency as a problem and propose two ways to compute 'corrected' standard deviations. I advise against this medicine. One reason is that there is no real disease, since the presumed problem does not occur with commonly used numerical rating scales of 10 or more steps. The second reason is that one of Delhey and Kohler's medicines have side effects, their first correction affects the mean and their second correction is based on implausible assumptions. A third reason is that there are better ways to estimate the effect happiness-inequality net happiness-level. Partialling out mean happiness did not affect the non-correlation between inequality of income and inequality of happiness in an analysis of 116 nations. PMID- 23017709 TI - Mycobacterium mageritense meningitis in an immunocompetent patient with an intrathecal catheter. PMID- 23017710 TI - Lifestyle factors increasing adiponectin synthesis and secretion. AB - Adiponectin is an anti-inflammatory adipokine released from adipose tissue that is known to exert insulin-sensitizing effects in skeletal muscle and liver. Given that the secretion of adiponectin is impaired in obesity and related pathologies, strategies to enhance its synthesis and secretion are of interest. There is evidence that several lifestyle factors, including consumption of dietary long chain n-3 PUFA, TZD administration, and weight loss can increase adiponectin synthesis and secretion. The effect of chronic exercise, independent of weight loss, is variable and less convincing. Potential mechanisms by which such lifestyle factors exert their favorable effects on adiponectin include activation of PPARgamma and AMPK, regulation of posttranslational modifications, and changes in adipose tissue morphology and macrophage infiltration. As a clear role for adiponectin in mitigating obesity-related impairments in lipid metabolism and insulin sensitivity is evident, further research investigating factors that enhance adiponectin synthesis and secretion is distinctly warranted. PMID- 23017711 TI - Molecular tools to characterize adiponectin activity. AB - Within the past years, numerous hormones were found to be secreted by adipose tissue. As these adipokines exert different physiological effects with great importance in obesity, they provide new strategies for the treatment of obesity associated disorders. Adiponectin is one of the most promising targets due to its protective properties in glucose and lipid metabolism, which are mediated by the adiponectin receptor 1 and 2. Within the past decades, substantial progress in understanding the molecular function of this unique ligand-receptor system could be achieved. This review summarizes the most important approaches for the investigation of adiponectin activity. Even though many insights into adipokine function could be achieved, clarification of the detailed mode of action is still challenging. For this reason, this review gives an overview of frequently used methods, which led to the molecular characterization of adiponectin and might help to get more detailed insights into the broad aspects of obesity. PMID- 23017712 TI - Nutritional and hormonal modulation of adiponectin and its receptors adipoR1 and adipoR2. AB - Adiponectin is the most abundant plasma protein synthesized mostly by adipose tissue and is an insulin-sensitive hormone, playing a central role in glucose and lipid metabolism. Adiponectin effects are mediated via two receptors, adipoR1 and adipoR2. Several hormones and diet components that are involved in insulin resistance may impair insulin sensitivity at least in part by decreasing adiponectin and adiponectin receptors. Adiponectin expression and serum levels are associated with the amount and type of fatty acids and carbohydrate consumed. Other food items, such as vitamins, alcohol, sodium, green tea, and coffee, have been reported to modify adiponectin levels. Several hormones, including testosterone, estrogen, prolactin, glucocorticoids, catecholamines, and growth hormone, have been shown to inhibit adiponectin production, but the studies are still controversial. Even so, adiponectin is a potential therapeutic target in the treatment of diabetes mellitus and other diseases associated with hypoadiponectinemia. PMID- 23017713 TI - Regulation and function of adiponectin receptors in skeletal muscle. AB - Obesity-induced insulin resistance is a primary contributing factor in the pathogenesis of type 2 diabetes. Adiponectin, an adipocyte-derived abundant plasma protein, has profound effects on systemic insulin sensitivity through direct action of the hormone on liver and muscle. The biological responses to adiponectin are mediated by two distinct receptors, AdipoR1 and AdipoR2, which differ in their affinities for adiponectin isoforms and exhibit cell type specific effects. Disruption of AdipoR1 expression in muscle revealed a pivotal role of adiponectin/AdipoR1 in the regulation of mitochondrial biogenesis and insulin resistance. Here, we review the recent progress regarding adiponectin/AdipoRs signaling and function in skeletal muscle and summarize a range of physiological and pathophysiological conditions, as well as transcriptional and posttranscriptional mechanisms, controlling muscle AdipoR1 mRNA, and protein levels. Comprehensive understanding of the pathways that regulate AdipoRs expression in muscle is critical to benefit from the full therapeutic potential of the adiponectin-AdipoR system. PMID- 23017714 TI - Screening for adiponectin secretion regulators. AB - Adiponectin is an adipokine secreted from adipocytes and plays important roles in the suppression of metabolic syndromes that can result in type 2 diabetes, obesity, and atherosclerosis. Adiponectin is a promising drug target because a number of studies have shown that upregulation of adiponectin has a number of therapeutic benefits. Extensive efforts have revealed various adiponectin regulators, such as cytokines, transcription factors, and drugs. Cytokines, such as tumor necrosis factor alpha, IL-6, and IL-18, downregulate adiponectin production. On the other hand, transcription factors such as peroxisome proliferator-activated receptor-gamma (PPARgamma), CCAAT-enhancer-binding protein alpha, and forkhead box O1 (FoxO1) upregulate adiponectin expression, although the activating transcription factor 3 and cAMP response element-binding protein downregulate it. Although a number of therapeutic drugs have been reported as adiponectin secretion regulators, most of them act through PPARgamma-dependent mechanisms, leaving PPARgamma-derived side effects as a concern. Using high throughput screening, we have identified PPARgamma-independent adiponectin secretion regulators as potential drug candidates with a novel mechanism of action. PMID- 23017715 TI - Adiponectin and PPARgamma: cooperative and interdependent actions of two key regulators of metabolism. AB - The recent advances in the understanding of adiponectin and other adipokines have highlighted the role of adipose tissue as an active endocrine organ. One of the central regulators of adipocyte biology is peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor that induces the adipogenic gene expression program during development, promotes adipose remodeling, and regulates the functions of adipocytes in lipid storage, adipokine secretion, and energy homeostasis. Activation of PPARgamma results in increased insulin sensitivity in skeletal muscle and liver and improves the secretory profile of adipose tissue, favoring release of insulin-sensitizing adipokines, such as adiponectin, and reducing inflammatory cytokines. Increased adiponectin production is likely a significant mediator of the systemic effects of PPARgamma activation. This chapter will review the interplay between PPARgamma and adiponectin in regulating metabolism, presenting evidence that PPARgamma regulates adiponectin gene expression, processing, and secretion and that the two proteins have overlapping effects on downstream metabolic pathways. PMID- 23017717 TI - Adiponectin and reproduction. AB - Adiponectin is an adipocyte-derived cytokine that acts as a major regulator of insulin sensitivity. Adiponectin deficiency can result in severe diabetes and metabolic disorders in humans. Since its discovery, our understanding of adiponectin's biological functions has expanded from insulin sensitization properties to new effects on inflammation, immunology, and human reproduction. Indeed, both obesity and excessive leanness are associated with reproductive dysfunction. The objective of this chapter is to review such biological actions and the potential roles of adiponectin on human reproduction. There is accumulative evidence for direct effects of this adipokine on the late stages of folliculogenesis and on the development of a functional placenta. In addition, clinical and genomic studies associate hypoadiponectinemia with pregnancy-related disorders, including polycystic ovarian syndrome. PMID- 23017718 TI - Adiponectin and its receptors in preimplantation embryo development. AB - Adiponectin can play an important role in regulating the female reproductive function and embryo development and can affect the embryo at very early stages of pregnancy--during the preimplantation period. Disturbances in the maternal adiponectin system are associated with several diseases, including diabetes type 2, obesity, and some female reproductive disorders. Adiponectin receptors are expressed in oocytes and preimplantation embryos and can be activated by adiponectin produced by maternal adipose tissue or organs of the female reproductive tract. Adiponectin can affect proliferation and survival of cells in preimplantation embryos, and these effects are isoform dependent. Experimental results suggest involvement of various protein kinases, including mitogen activated protein kinases, in the regulation of these processes by adiponectin. Actions of adiponectin on lipid and glucose metabolism can increase the energy supply to the embryo, and final targets of adiponectin signaling are metabolic enzymes, glucose transporters, and fatty acid transporters. The involvement of several signaling molecules, such as AMPK/PRKA, PI3K, or AKT/PKB, in the regulation of metabolic processes by adiponectin has been demonstrated in preimplantation embryos. In summary, adiponectin produced in an endocrine/paracrine/autocrine manner can significantly influence preimplantation embryo development, uterine receptivity, and embryo implantation. PMID- 23017716 TI - Glucocorticoid effects on adiponectin expression. AB - Maintenance of energy metabolism and glucose homeostasis is achieved by the regulatory effects of many hormones and their interactions. Glucocorticoids produced from adrenal cortex and adiponectin produced by adipose tissue play important roles in the production, distribution, storage, and utilization of energy substrates. Glucocorticoids are involved in the activation of a number of catabolic processes by affecting the expression of a plethora of genes, while adiponectin acts primarily as an insulin sensitizer. Both are regulated by a number of physiological and pharmacological factors. Although the effects of glucocorticoids on adiponectin expression have been extensively studied in different in vitro, animal and clinical study settings, no consensus has been reached. This report reviews the primary literature concerning the effects of glucocorticoids on adiponectin expression and identifies potential reasons for the contradictory results between different studies. In addition, methods to gain better insights pertaining to the regulation of adiponectin expression are discussed. PMID- 23017719 TI - Adiponectin and the control of female reproductive functions. AB - Adiponectin is the most abundant protein secreted by the white adipose tissue. It circulates at high levels in the bloodstream and its serum concentration is inversely correlated with body fat mass. The wide distribution of adiponectin receptors (AdipoR1, AdipoR2, and T-cadherin) in peripheral tissues and organs allows adiponectin to exert pleiotropic effects on whole-body metabolism. Besides its well-known antidiabetic, antiatherogenic, and anti-inflammatory properties, accumulating evidence suggests a direct role for adiponectin in reproductive tissues. The mammalian ovary and the ovarian follicle express AdipoR1 and AdipoR2, and treating pig granulosa cells with adiponectin induces changes characteristic of the periovulatory period. Moreover, additive effects are observed between adiponectin and insulin in induction of granulosa cell gene expression, thus suggesting that adiponectin actions on the ovary may be mediated through its insulin-sensitizing effects. Adiponectin receptors are also detected in the uterus. In women, higher AdipoR1 and AdipoR2 gene expression was observed during the mid-secretory phase of the menstrual cycle, suggesting that adiponectin is implicated in the endometrial changes in preparation for embryo implantation. Adiponectin receptors are found in oocytes and early developing pig, rabbit, and mice embryos, and it has been demonstrated that adiponectin can increase the success of porcine embryo development to the blastocyst stage in vitro. Moreover, adiponectin concentration is two to three times greater in human fetal circulation and in umbilical cord blood, compared to adult plasma. This further indicates a role for adiponectin in fetal growth. It has been further suggested that adipose-derived and locally produced adiponectin may act as a key neuromodulator of reproductive functions. For example, the inhibition of LH and GnRH release from rat pituitary and hypothalamic cells following treatment with adiponectin provides evidence that adiponectin may also act on the release of gonadotropins. Adipose tissue is now recognized as an important factor in the complex equation by which the nutritional status regulates female reproductive functions. For example, underweight women have delayed puberty and higher risk of premature delivery, whereas overweight and obese women have early puberty and are prone to develop polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and preeclampsia. Because hypoadiponectinemia is often associated with the abovementioned disorders, it has been suggested that this adipokine might play a role in the development of these pregnancy-related complications. Moreover, as these reproductive disorders often come with metabolic complications such as insulin and glucose resistance, the insulin-sensitizing effects of adiponectin may explain the observed association of this adipokine with PCOS, GDM, and preeclampsia. This review summarizes current knowledge on the role of adiponectin in female reproductive tissues and highlights mechanisms where information is available. We also discuss about the known and potential roles of adiponectin in the development of reproductive disorders. PMID- 23017720 TI - Adiponectin in the heart and vascular system. AB - Adipose tissue is not only a storage depot for energy, but also an active endocrine tissue. Adipokines, hormones and cytokines secreted from adipocytes, relay information about energy stores to peripheral tissues throughout the body. Most adipokines are produced in direct proportion to fat mass, and many have proinflammatory or otherwise adverse effects on the cardiovascular system. The notable exception is the cardioprotective adipokine adiponectin, which is secreted in inverse proportion to fat mass. Circulating adiponectin levels are highest in lean individuals and inversely correlate with fat mass. Low levels of serum adiponectin are now appreciated as a risk factor in a variety of cardiovascular diseases including coronary artery disease and restenosis, type 2 diabetes mellitus, and hypertension. In this chapter, we provide an introduction to adiponectin and review the extensive evidence in humans and in mouse and in vitro models for adiponectin's cardioprotective effects. PMID- 23017721 TI - Adiponectin interactions in bone and cartilage biology and disease. AB - The adipokine adiponectin promotes insulin sensitivity and fat beta-oxidation. In addition to its metabolic effects, adiponectin is an important local and systemic modulator of bone remodeling and cartilage biology, involving direct and indirect mechanisms and a large set of downstream molecular signals. Moreover, data suggest that changes in adiponectin signaling may be associated with bone and cartilage diseases. Adiponectin seems to exert a negative net effect on bone mass and to be an independent predictor of lower bone mass, whereas available data about actions on cartilage are more controversial, showing both pro- and anti inflammatory actions. Adiponectin-bone cross talk seems to be reciprocal, as osteocalcin, produced by osteoblasts, has been shown to stimulate adiponectin expression and to improve glucose tolerance. Adiponectin-related signaling in bone and cartilage should be considered within the network of hormonal and nutritional signals that may influence skeleton biology, together with body homeostasis and adipose mass changes. PMID- 23017722 TI - Lipid-lowering drugs and circulating adiponectin. AB - Pharmacological agents used to treat primary and combined hyperlipidemia reduce cardiovascular disease morbidity and mortality. Risk reduction has been attributed to improvements in blood lipid and lipoprotein characteristics. However, each class of available lipid-lowering drugs has been shown to exhibit pleiotropic effects that broaden their anticipated actions. Indeed, the results of a growing number of available studies suggest that a strong relationship exists between pharmacological reductions in blood lipids and circulating concentrations of the adipose tissue derived protein, adiponectin. Adiponectin is the most abundantly secreted protein from adipose tissue and has been shown to decrease hepatic glucose production, increase fatty acid oxidation in liver and skeletal muscle, and decrease vascular inflammation. In this chapter, we present a comprehensive analysis of the effects of the available classes of lipid lowering drugs (statins, fibrates, niacin, and omega-3-fatty acids) on circulating adiponectin and the known mechanisms which produce these important events. PMID- 23017723 TI - Adiponectin and interleukin-6 in inflammation-associated disease. AB - Numerous lines of evidence implicate a role for adipose tissue in the development of a systemic inflammatory state that contributes to metabolic, cardiovascular, and autoimmune disorders. Serum levels of adiponectin, a cytokine that is mainly produced by adipocytes, are paradoxically decreased in individuals with obesity, type 2 diabetes, and cardiovascular disease compared with healthy individuals. Mounting experimental data have revealed that adiponectin exhibits beneficial effects on energy homeostasis and cardiovascular functions that are attributed to its direct modulation of a proinflammatory factor, interleukin-6. However, some recent studies indicate that adiponectin appears to function as an inducer of proinflammatory factors and the elevated adiponectin level aggravates inflammation response in autoimmune disease. In this review, we focus on the action of adiponectin in chronic inflammation-associated metabolic, cardiovascular, and autoimmune disorders. In particular, we discuss the interaction between adiponectin and interleukin-6 in adipocytes and cardiovascular cells. PMID- 23017724 TI - New insights into anticarcinogenic properties of adiponectin: a potential therapeutic approach in breast cancer? AB - Obesity is a recognized breast cancer risk factor in postmenopausal women. A recent hypothesis suggests a major role for adipose tissue in carcinogenesis. During many years, the adipose tissue was only considered as a fat storage of energy. This tissue is now described as an endocrine organ secreting a large range of molecules called adipokines. Among these adipokines, adiponectin may play a major role in breast cancer. Plasma adiponectin levels were found to be decreased in cases of breast cancer and in obese patients. Adiponectin may act directly on breast cancer cells by inhibiting proliferation and angiogenesis or by stimulating apoptosis. Increasing adiponectin levels may be of major importance in the prevention and/or the treatment of breast cancer. This therapeutic approach may be of particular significance for obese patients. The beneficial effects of adiponectin and its possible therapeutic applications will be discussed in this review. PMID- 23017725 TI - Adiponectin: a novel link between adipocytes and COPD. AB - Adiponectin (APN) is a unique adipokine with multiple salutary effects such as antiapoptotic, anti-inflammatory, and anti-oxidative activities in numerous organs and cells. Chronic obstructive pulmonary disease (COPD), a growing cause of mortality and morbidity worldwide, often results from the smoking habit and is considered a lifestyle-related disease. COPD is frequently complicated with comorbidities, such as cardiovascular disease, diabetes mellitus, and osteoporosis; however, the molecular mechanisms linking COPD and the associated comorbidities are poorly understood. Recent data have revealed a role for APN in the lung; mice lacking APN spontaneously develop a COPD-like phenotype with extrapulmonary effects, including systemic inflammation, body weight loss, and osteoporosis. This finding highlights the key role of APN in lung pathology and the novel cross talk between lung and adipose tissues. This review summarizes recent advances in understanding the physiological and pathological role of APN in the lung. PMID- 23017726 TI - Adiponectin. Preface. PMID- 23017727 TI - Co-circulation and persistence of genetically distinct saffold viruses, Denmark. PMID- 23017728 TI - Human infection with Candidatus Neoehrlichia mikurensis, China. AB - To identify Candidatus Neoehrlichia mikurensis infection in northeastern China, we tested blood samples from 622 febrile patients. We identified in 7 infected patients and natural foci for this bacterium. Field surveys showed that 1.6% of ticks and 3.8% of rodents collected from residences of patients were also infected. PMID- 23017729 TI - [Advantages and weaknesses of the tumor board meeting in validating prophylactic mastectomy]. AB - The evolution of our health care system strengthens multidisciplinary collaboration in medical practice. Today, the tumor board meeting (TBM) has become mandatory for treatment decision-making in oncology. Experts recommend that such a multidisciplinary tool be extended to prophylactic mastectomy. We will discuss the relevance of this extension on the basis of a survey with female patients and health professionals confronted with prophylactic mastectomy. Health professionals find the TBM necessary because it allows more reasoned and consensual proposals to be made, reduces the burden of difficult decisions, and promotes a comprehensive view of those who receive care. However, this approach has also drawn criticism. Unlike medical consultation, which focuses on a patient's singularity, the TBM seems poorly suited to take into account psychosocial factors governing the decision-making process. It may be easier for a group to reach a complex decision, but it does not mean that the TBM allows for decisions to be adapted on a singular basis. Therefore, we suggest to modify the TBM so that it better suits the needs of patients susceptible to breast cancer. The referring physician, who knows the patient best, should guide the content of multidisciplinary deliberations and put the focus on individual criteria raised during medical consultations. PMID- 23017730 TI - Sustainable resource use requires "clean cycles" and safe "final sinks". AB - In order to fulfill the objectives of environmental protection, today's focus on quantitative recycling rates must be amended by a more qualitative approach. Because modern products represent a mix of numerous and sometimes hazardous substances, ways must be explored to remove detrimental substances during recycling and to establish "clean cycles". On the one hand, such a "clean cycle" strategy will result in better recycling qualities of secondary products and less dissipation of hazardous substances during further product use. On the other hand, the elimination of hazardous substances during recycling requires sinks for the disposal of the eliminated materials. These topics are presented in general as well as by case studies. In particular, the sink issue is addressed, differentiating between sinks and final sinks and discussing the challenge to supply appropriate final sinks for all materials that cannot be recycled. PMID- 23017732 TI - Increase of complement fragment C5a in cerebrospinal fluid during exacerbation of neuromyelitis optica. AB - Complement is thought to play a pivotal role in neuromyelitis optica (NMO) pathogenesis. Anaphylatoxins (C3a, C4a, and C5a), produced in complement activation, have proinflammatory potential, and thereby may play an important role. We measured concentrations of anaphylatoxins in CSF and sera, obtained from patients with NMO (n=15), multiple sclerosis (MS) (n=15), and other neurological disease (OND) (n=12), and evaluated their clinical implications. The CSF-C5a levels were elevated significantly in NMO patients, especially in patients with multiple enhanced lesions on MRI. The CSF-C5a levels correlated with the severity of exacerbation. Our results may provide a rationale for anti-complement therapies of NMO. PMID- 23017731 TI - Invariant natural killer T cells as sensors and managers of inflammation. AB - Invariant natural killer T (iNKT) cells are a subset of innate-like lymphocytes that recognize glycolipid antigens bound by the major histocompatibility complex (MHC)-class-I-related protein CD1d. iNKT cells are activated early during a variety of infections and inflammatory diseases and contribute to the subsequent development of adaptive immune responses. Consequently, iNKT cells play a critical role in the development and resolution of inflammatory diseases and represent attractive targets for the development of immunotherapies. Recent studies have provided important insight into the mechanisms by which iNKT cells become activated in response to diverse inflammatory stimuli. These new findings should be instrumental to promote the immunomodulatory properties of iNKT cells for treatment of inflammatory diseases. PMID- 23017734 TI - Drinking consequence types in the first college semester differentially predict drinking the following year. AB - The objectives of the present study were to examine the utility of distinguishing among negative consequence types when seeking to predict drinking later in college, to understand which consequences in particular were associated with future drinking, and to determine the direction of those associations. We also examined whether there were differences in the types of drinking outcomes (quantity, frequency, binge) predicted by unique consequences. Finally, we tested whether the link between consequences and future drinking was different for men versus for women. Incoming first year college students (n=997; 65% female) completed an online assessment in September of the first college year, and again at the same time the following year. Results of structural equation model tests offered support for the utility of distinguishing among different consequence types, as specific consequences experienced during the first semester of college were associated differently with drinking at the beginning of the second school year. Gender differences also were observed. For both men and women, social consequences were associated with increases in drinking over time. Blackout drinking also evidenced prospective prediction, but differentially for men and women. For men, these consequences were associated with later increases in drinking, whereas for women, they were associated with a diminution in drinking the next year. For men, only consequences associated with self-care (impairment in physical activity, physical appearance, less time to pursue recreation) predicted decreases in drinking at Year 2. Prediction was generally similar across drinking outcomes. Results suggest that whether negative consequences result in downward titration, escalation, or no change at all in later drinking depends on the type of consequence experienced, and who experiences it. PMID- 23017733 TI - Relationships among parental monitoring and sensation seeking on the development of substance use disorder among college students. AB - Substance use disorder is a serious health problem that tends to manifest in late adolescence. Attempting to influence targetable risk and protective factors holds promise for prevention and treatment. Survey data from 1253 college students (48.5% male, 26.9% non-White) were used to investigate the independent and combined effects of two prominent factors, sensation seeking and parental monitoring, on the probability of alcohol and/or cannabis dependence during the first year of college. In multivariate analyses that controlled for high school use, gender, race, mother's education, and importance of religion, retrospective reports by the student of parental behavior during the last year of high school indicated that higher levels of parental monitoring had a direct effect on reducing risk for alcohol dependence during the first year of college, but not on cannabis dependence. High levels of sensation seeking were associated with increased risk for both alcohol and cannabis dependence. No interaction effects were found. The results extend prior findings by highlighting influences of pre college parental monitoring and sensation seeking on the probability of alcohol and/or cannabis dependence during the first year of college. The findings also suggest that these two factors are useful in identifying college students at high risk for alcohol and/or cannabis dependence. PMID- 23017735 TI - Understanding treatment-seeking smokers' motivation to change: content analysis of the decisional balance worksheet. AB - The Decisional Balance Worksheet (DBW), an open-ended measure of motivation to change, may be used to record the pros and cons of smoking versus abstinence among treatment-seeking smokers. Recent findings indicated that the open-ended DBW could be quantified to validly reflect people's level of motivation to stop smoking (Collins, Eck, Torchalla, Schroter, & Batra, 2010). The goal of the current study was to enhance our understanding of these participants' motivation to change by examining the qualitative content of their decisional balance. Participants were treatment-seeking smokers (N=268) who had participated in a larger randomized controlled trial of tailored smoking cessation interventions (Batra et al., 2010). Using the DBW, participants recorded their pros and cons of smoking versus abstinence, and content analysis methods were used to extract common themes. Findings indicated that the physical and psychological effects/functions of smoking and abstinence were most commonly mentioned as both pros and cons. Although the decisional balance categories were substantively similar over time, their relative frequency shifted from pre- to posttreatment. For the sample as a whole, the number of pros of smoking generally decreased, whereas the pros of abstinence increased from pre- to posttreatment. Findings suggest that clinicians can expect certain perceived pros and cons to characterize their clients' decision-making process about smoking and abstinence. At the same time, the use of the decisional balance allows for assessment of individuals' unique motivational set. PMID- 23017737 TI - The fear of others: a pilot study of social anxiety processes in paranoia. AB - BACKGROUND AND AIMS: There is good reason to consider the role of social anxiety processes in paranoia; both the research and clinical literature indicate significant overlap between the two presentations. The aim of this study was to explore cognition and behaviour that are typically associated with social phobia, in people with paranoia, and then to draw out theoretical and clinical implications. METHOD: We used a cross-sectional between-subjects design to compare participants with persecutory delusions (without social phobia), social phobia, a clinical control group with panic disorder, and a non-clinical control group. Ten to 15 people were recruited to each of four groups, with a final total of 48 participants. Each person completed measures of automatic thoughts, underlying assumptions, core beliefs and behaviour, and took part in a semi structured interview designed to assess process (self-consciousness and attentional focus) and metacognitive beliefs. RESULTS: Surprisingly, measures of cognition and behaviour yielded no systematic differences between people with persecutory delusions and social phobia. CONCLUSIONS: People with persecutory delusions may experience overt and underlying cognition typically associated with social phobia, and behave in similar ways in response to perceived social threat. These initial results indicate: (i) that larger scale research is now warranted in order to draw firm conclusions about social anxiety processes in paranoia; (ii) more specific hypotheses to be tested; and (iii) a clinical model of paranoia, based on the cognitive model of social phobia, which might now usefully be validated. PMID- 23017736 TI - Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. AB - Nrf2, a master regulator of intracellular redox homeostasis, is indicated to participate in fatty acid metabolism in liver. However, its role in diet-induced obesity remains controversial. In the current study, genetically engineered Nrf2 null, wild-type (WT), and Nrf2-activated, Keap1-knockdown (K1-KD) mice were fed either a control or a high-fat Western diet (HFD) for 12 weeks. The results indicate that the absence or enhancement of Nrf2 activity did not prevent diet induced obesity, had limited effects on lipid metabolism, but affected blood glucose homeostasis. Whereas the Nrf2-null mice were resistant to HFD-induced glucose intolerance, the Nrf2-activated K1-KD mice exhibited prolonged elevation of circulating glucose during a glucose tolerance test even on the control diet. Feeding a HFD did not activate the Nrf2 signaling pathway in mouse livers. Fibroblast growth factor 21 (Fgf21) is a liver-derived anti-diabetic hormone that exerts glucose- and lipid-lowering effects. Fgf21 mRNA and protein were both elevated in livers of Nrf2-null mice, and Fgf21 protein was lower in K1-KD mice than WT mice. The inverse correlation between Nrf2 activity and hepatic expression of Fgf21 might explain the improved glucose tolerance in Nrf2-null mice. Furthermore, a more oxidative cellular environment in Nrf2-null mice could affect insulin signaling in liver. For example, mRNA of insulin-like growth factor binding protein 1, a gene repressed by insulin in hepatocytes, was markedly elevated in livers of Nrf2-null mice. In conclusion, genetic alteration of Nrf2 does not prevent diet-induced obesity in mice, but deficiency of Nrf2 improves glucose homeostasis, possibly through its effects on Fgf21 and/or insulin signaling. PMID- 23017738 TI - [Prenatal diagnosis of cleft lip with or without cleft palate: retrospective study and review]. AB - OBJECTIVES: To evaluate the management of prenatally diagnosed cleft lip with or without cleft palate and the immediate postnatal outcome. MATERIAL AND METHODS: Retrospective study of all cases of cleft lip with or without cleft palate referred to our fetal medicine unit, between January 2005 and January 2011. The anatomical type of cleft, associated malformations, and the postnatal outcome were reviewed. RESULTS: Forty-three cases of fetal cleft lip with or without cleft palate were reviewed. The mean gestational age at diagnosis was 24 weeks +/ 4. The postnatal distribution of clefts was: 30 cleft lip and palate (70%) and 13 cleft lip (30%). The prenatal diagnosis of the cleft type was exact in 27 cases (62.8%). Nine cases had associated anomalies (21%), detected prenatally in three cases (37.5%). There was no karyotypical abnormality. Six pregnancies were terminated (14%). The immediate postnatal outcome was comparable with unselected newborns. CONCLUSION: The prenatal diagnosis of cleft lip with or without cleft palate is correct, with two thirds of exact diagnoses. Large clefts palate are the best detected. Associated malformations cannot always be diagnosed by prenatal ultrasound, but have to be searched for because they modify the fetal outcome. PMID- 23017739 TI - Coil embolization using the self-expandable closed-cell stent for intracranial saccular aneurysm: a single-center experience of 289 consecutive aneurysms. AB - AIM: To present the clinical and radiological follow-up results of coil embolization using the Enterprise stent for intracranial saccular aneurysms. MATERIALS AND METHODS: The clinical and morphological outcomes of 261 consecutive patients with a total of 289 aneurysms that were treated with a stent-protected coiling technique using the Enterprise stent from June 2008 to August 2011 were assessed. RESULTS: Stents were delivered before first coil insertion in 162 aneurysms (56.1%), during coiling in 68 (23.5%), and after completion of coil insertion in 59 (20.4%). Procedure-related complications occurred in 36 patients (13.8%), and four (1.5%) suffered permanent neurological sequelae. Successful occlusion after coil embolization was achieved in 205 aneurysms (70.9%) and subtotal occlusion was achieved in 84. During the mean follow-up of 12.4 (+/-5.8) months, follow-up imaging of 229 aneurysms (79.2%) documented stable occlusion in 183 (79.9%) of the lesions, minor recanalization in 17 (7.4%), and major recanalization in 29 (12.7%). Follow-up angiography of 110 aneurysms (38.1%) demonstrated in-stent stenosis in 14 (12.7%) and stent migration in five (4.5%). Eleven patients (4.2%) suffered late delayed infarction during the follow-up period, which was related to cessation or modification of anti-platelet medication. CONCLUSION: The stent-protection technique using the Enterprise stent is useful and effective for coil embolization of wide-necked aneurysms due to easy navigation and precise placement. However, the possibility of procedure related complications, in-stent stenosis, and delayed cerebral infarction should be noted. PMID- 23017740 TI - Affinity purification of protein complexes for analysis by multidimensional protein identification technology. AB - Characterizing protein complexes and identifying their subunits promote our understanding of the machinery involved in many in vivo processes. Proteomic studies can identify a protein's binding partners, and this can provide insight into how protein complexes function and how they are regulated. In addition, the composition of a protein complex within an organism can be investigated as a function of time, as a function of location, or during the response of an organism to a change in environment. There are many ways to isolate a complex and identify its constituents. This review will focus on complex isolation using affinity purification and will address issues that biochemists should bear in mind as they isolate protein complexes for mass spectrometric analysis by multidimensional protein identification technology (MudPIT)(1). Protein complex analysis by mass spectrometry frequently involves the collaborative efforts of biochemists or biologists who purify protein complexes and proteomic specialists who analyze the samples - for fruitful collaborations it can be helpful for these specialized groups to be acquainted with basic principles of their collaborator's discipline. With this in mind, we first review the variety of affinity purification methods which might be considered for preparing complexes for analysis, and then provide brief primers on the principles of MudPIT mass spectrometry and data analysis. From this foundation, we then discuss how these techniques are integrated and optimized and suggest salient points to consider when preparing purified samples for protein identification, performing mass spectrometry runs, and analyzing the resulting data. PMID- 23017741 TI - 2,4-D exposure and risk assessment: comparison of external dose and biomonitoring based approaches. AB - Conventional chemical exposure assessment relies upon measurements or estimates of chemical concentrations in environmental media, food, or products, in combination with assumptions regarding contact rates, in order to estimate external doses (ppm in air) or intake rates of chemicals (e.g., mg/kg/day ingested). A risk assessment is conducted by comparing these external or intake dose estimates to appropriate (e.g., route-specific) exposure guidance values (e.g., Reference Dose or Reference Concentration) to assess whether exposures are exceeding levels of concern. Human biomonitoring, in which concentrations of chemicals are measured in blood or urine, is being increasingly used as an alternative or complementary exposure assessment. The Biomonitoring Equivalent, which is the translation of a Reference Dose to an equivalent concentration of a compound in blood or urine, provides a parallel means to interpret biomonitoring data in order to assess whether chemical-specific exposures exceed levels of concern. This manuscript presents a side-by-side comparison of the two approaches for assessing exposures and risks for a case study compound, 2,4 dichlorophenoxyacetic acid (2,4-D). The findings from this case study indicate that the external dose-based assessments result in estimates of exposure and resulting hazard quotients that are consistently several-fold higher than those based on biomonitoring data. These comparisons support a conclusion that exposure assessments conducted as part of the registration process for 2,4-D incorporate sufficiently conservative assumptions. PMID- 23017742 TI - [Hepatotoxicity due to drugs or natural products in children]. AB - INTRODUCTION: The incidence of adverse drug reactions in children has recently been established at 15.1 reactions per 1000 children. This represents 2% of admissions to a paediatric hospital, and is similar to adult patients. Only a small percentage (less than 8%) may have liver involvement, which can range from a slight increase in transaminases to fulminant hepatitis. The aim of this study was to determine the importance (frequency, types of presentation, severity and chronicity) of hepatotoxicity by drugs or natural remedies in the paediatric population. PATIENTS AND METHOD: All paediatric patients, neonates and children who had suspected hepatotoxic reactions notified by the eight participating Spanish hospitals. The Council for International Organizations of Medical Sciences (CIOMS) scale was used for the analysis of causality in each case. RESULTS AND CONCLUSIONS: We studied a total of 36 hepatotoxic reactions in 33 children. The drug classes most frequently involved were antimicrobials (71%). Amoxicillin-clavulanate was the individual drug responsible for the greatest number of cases (31.4%). We conclude that the registration of drugs associated with liver disease has proved a useful tool for creating an active network of motivated specialists in detecting and reporting incidents of toxic liver disease, ensuring increasing diagnostic accuracy. PMID- 23017743 TI - Microbial processes influencing the transport, fate and groundwater impacts of fuel ethanol releases. AB - Fuel releases that impact groundwater are a common occurrence, and the growing use of ethanol as a transportation biofuel is increasing the likelihood of encountering ethanol in such releases. Microorganisms play a critical role in the fate of ethanol-blended fuel releases, often determining their region of influence and potential impacts. This review summarizes current understanding on the biogeochemical footprint of such releases and the factors that influence their natural attenuation. Implications for site investigation, risk assessment and remediation strategies are also addressed along with research priorities. PMID- 23017744 TI - A classic case of a plastic bowing deformation. PMID- 23017745 TI - Secondhand smoke and influenza severity in children: another nail in the coffin of the tobacco industry? PMID- 23017746 TI - Parental wealth and resource transfers: How they matter in France for home ownership and living standards. AB - The role played by parental wealth in facilitating the life chances and living standards of offspring is a topic of growing interest in stratification research. For working and middle class households much of their intervivos transfers to children is provided in the form of assistance with a home purchase. This paper examines the impact of parental wealth and transfers of wealth on several aspects of the homeownership decision - the timing of the purchase, the cost of the home, and the downpayment proportion, as well as living standards subsequent to the purchase. We utilize a unique data set from France which contains information on parental wealth and wealth transfers from both sets of parents of a couple. We correct for possible endogeneity of parental transfers and model the joint determination of the downpayment proportion and home value. The results make clear the complex pathways by which parental wealth influences the tenancy arrangements and living standards of offspring. PMID- 23017747 TI - Patterns of intergenerational mobility of the old and new middle classes in a post-industrial society: Netherlands 1970-2006. AB - It has often been proposed that new cleavages have emerged within the middle class. In this paper, we examine the distinction between social and cultural specialists and technocrats, and investigate whether these new and old middle class fractions are differentiated by their patterns of intergenerational mobility. To what extent do these newly distinguished middle class fractions have specific external and internal intergenerational mobility patterns? And to what extent have mobility boundaries between them been rising over time? To answer these questions, we use 47 Dutch national population sample surveys with detailed occupation codes collected between 1970 and 2006 (N=60,978). Our analyses of internal and external homogeneity show that the middle class fractions each have characteristic mobility and immobility patterns and therefore a necessary condition is satisfied to declare them as separate classes. Furthermore, in the early periods, the social and cultural specialists were differentiated by a high level of immobility but in the later periods, the distance between the old and new middle classes has decreased significantly. PMID- 23017748 TI - The sociology of ecologically unequal exchange and carbon dioxide emissions, 1960 2005. AB - The author engages the sociological theory of ecologically unequal exchange to assess the extent to which levels of per capita anthropogenic carbon dioxide emissions are a function of the "vertical flow" of exports to high-income nations. Results of cross-national fixed effects panel model estimates indicate that levels of such emissions are positively associated with the vertical flow of exports, and the relationship is much more pronounced for lower-income countries than for high-income countries. Additional findings suggest that the observed relationship for lower-income nations has grown in magnitude through time, indicating that structural associations between high-income and lower-income countries have become increasingly ecologically unequal, at least in the context of greenhouse gas emissions. These results hold, net of various important controls. PMID- 23017749 TI - Assessing reporting patterns of child sexual abuse within the Catholic Church using discontinuities in model parameter timeseries. AB - Prior to 2002, little was known about sexual abuse within the Catholic Church. After the Boston Globe broke the story about John Geoghan - a priest in the Boston Archdiocese who was accused of abusing numerous children, convicted of one count of indecent assault, and eventually murdered in prison - the Church had many questions to answer. To this end, the United States Conference of Catholic Bishops (USCCB) commissioned John Jay College of Criminal Justice to research the nature and scope, as well as the causes and context of child sexual abuse within the Catholic Church. This research analyzes the data from the John Jay studies using a new quantitative technique, capable of adjusting for distortions introduced by delays in abuse reporting. By isolating discontinuities in model parameter timeseries, we determine changes in reporting patterns occurred during the period 1982-1988. A posteriori to the analysis, we provide some possible explanations for the changes in abuse reporting associated with the change-point. While the scope of this paper is limited to presenting a new methodological approach within the frame of a particular case study, the techniques are more broadly applicable in settings where reporting lag is manifested. PMID- 23017750 TI - Understanding the geography of food stamp program participation: Do space and place matter? AB - This study examines the extent to which geographic variation in Food Stamp Program (FSP) participation is explained by place-based factors, with special attention to the case of the three poorest regions of the United States: Central Appalachia, the Texas Borderland, and the Lower Mississippi Delta. We use descriptive statistics and regression models to assess the prevalence and correlates of county-level FSP participation circa 2005. Our findings show that the economic distress that has long characterized Appalachia, the Borderland, and the Delta clearly translates into greater reliance on the FSP relative to other areas of the country. State-level effects and local-level variations in poverty, labor market conditions, population structure, human capital, and residential context explain much of this reality. Yet, even after taking all of these factors into account, these regional geographies remain home to particularly high FSP participation. Our findings underscore the importance of considering these regions as key cases of study in the stratification of American society and hold a variety of implications for public policy. PMID- 23017751 TI - Perception vs. reality: The relationship between low-income homeownership, perceived financial stress, and financial hardship. AB - This research examines how homeowners and renters were impacted by the financial crisis in 2009. We build from the hypothesis that homeownership provides people a sense of stability which decreases the extent to which they feel stressed as a result of financial hardship. Our study tests whether owning a home affected either the degree to which lower-income households experienced financial hardship or the extent to which they perceived they were financially stressed. Using a sample of lower-income borrowers who obtained affordable mortgages through the Community Advantage Program (CAP) and a comparison panel of renters, we collected data on the effects of the financial crisis. From a portfolio performance standpoint, CAP loans have performed relatively well. Our analysis of the survey data finds that, although both renters and owners experienced similar levels of financial hardship, the homeowners were less psychologically stressed overall and reported feeling more satisfied with their financial situation. PMID- 23017752 TI - The effects of attending selective college tiers in China. AB - We estimate the effects of attending the first versus second-tier of higher education institutions on Chinese students' at-college and expected post-college outcomes using various quasi-experimental methods such as regression discontinuity, genetic matching, and regression discontinuity controlling for covariates. Overall we find that just attending the first versus second-tier makes little difference in terms of students' class ranking, net tuition, expected wages, or likelihood of applying for graduate school. The results do show, however, that just attending the first versus second tier makes it less likely that students will get their preferred major choice. PMID- 23017753 TI - Learning to do well or learning to do good? Estimating the effects of schooling on civic engagement, social cohesion, and labor market outcomes in the presence of endowments. AB - Although some point to the large effects of schooling on civic engagement (usually measured in terms of volunteering and participation in civic organizations) and social cohesion (usually measured in terms of social networks and relationship quality), the effects of schooling on social outcomes have not been estimated with the same rigor as the effects of schooling on labor-market outcomes, such as earnings. In particular, previous research has failed to consider (i) the many potential and often unobserved confounding factors ("endowments") influencing both schooling and social outcomes, including family upbringing, innate characteristics, and personality, and (ii) the ways in which schooling pushes individuals in multiple directions simultaneously, including toward greater social engagement, but also toward more independent and market driven pursuits. Using samples of unrelated persons, ordinary siblings, and identical twins, this study explores the effects of schooling on measures of civic engagement and social relationships, as well as labor-force earnings and labor-force participation. The siblings models reveal a more complex picture than typically suggested by standard individual estimates. On one hand, the results reveal a robust positive effect of schooling on earnings: well-schooled persons work more and earn more, albeit not as much as associations without control for endowments suggest. On the other hand, the results reveal more tenuous and occasionally negative effects of schooling on social outcomes. The effects of schooling on volunteering and membership in civic organizations, for example, disappear almost entirely with control for endowments. Also, within-identical twins models reverse the positive effects of schooling on reports of support from friends, family, and coworkers. These results may reflect the tension schooling creates between market and non-market commitments, as well as between independence and interpersonal reliability. Schooling may, indeed, induce some pro-social behaviors, but schooling allows individuals choices of whether to pursue more personal interests as well. PMID- 23017754 TI - Similarity in peer college preferences: New evidence from texas. AB - In this paper, I use survey data from high school students in Texas to examine the magnitude of peer correlation in college preferences and choices. In this survey, respondents (and their classmates) recorded their preferences for attending specific colleges, and a follow up survey recorded their college enrollment decisions. This paper uses this information to present the first empirical examination of whether individuals who report preferences for "popular" colleges are more likely to attend their preferred college. The rich data set allows the use of often unavailable information such as distance to college, and the construction of the "popularity" variable allows the use of school-level fixed effects. Results indicate that individuals with 10 percentage points more classmates with matching college preferences are 3 percentage points more likely to enroll in their preferred college. PMID- 23017755 TI - Roommate's race and the racial composition of white college students' ego networks. AB - We develop and test a new hypothesis about how the race of a college freshman's roommate affects the racial composition of the student's ego network. Together, three principles of social structure-proximity, homophily, and transitivity logically imply that college students assigned a roommate of a given race will have more friends (other than their roommate) of that race than will students assigned a roommate not of that race. A test with data collected from 195 white freshmen at Stanford University in the spring of 2002 supports this prediction. Our analysis advances earlier work by predicting and providing evidence of race specific effects: While students assigned a different-race roommate of a given race have more friends (other than their roommate) of their roommate's race, they do not have more different-race friends not of their roommate's race. PMID- 23017756 TI - I wouldn't, but you can: Attitudes toward interracial relationships. AB - Using the 2008 Cooperative Congressional Election Study (CCES), we study Whites' attitudes towards dating, cohabiting with, marrying, and having children with African Americans and Asian Americans. We find that 29% of White respondents reject all types of relationships with both groups whereas 31% endorse all types. Second, Whites are somewhat less willing to marry and bear children interracially than to date interracially. These attitudes and behaviors are related to warmth toward racial outgroups, political conservatism, age, gender, education, and region. Third, White women are likely to approve of interracial relationships for others but not themselves, while White men express more willingness to engage in such relationships personally, particularly with Asians. However, neither White men nor White women are very likely to actually engage in interracial relationships. Thus, positive globalattitudes toward interracial relationships do not translate into high rates of actual interracial cohabitation or marriage. PMID- 23017757 TI - The effects of scope condition-based participant exclusion on experimental outcomes in expectation states research: A meta-analysis. AB - Expectation states theory employs several scope statements to specify the situational conditions that must be met for any test of the theory to be considered valid (Foschi, 1997). Collective orientation and task orientation are two scope conditions that researchers frequently implement as selection criteria for a participant's inclusion in an analytic sample. Although excluding participants who fail to meet scope conditions is theoretically consistent, researchers have yet to establish how this practice affects experimental outcomes. I employ meta-analysis to compare studies within the expectation states tradition in which participants are excluded for failure to meet scope conditions to studies in which no similar exclusions are made. Results suggest that studies that exclude participants for scope violations demonstrate a decreased baseline tendency to reject influence. I contend that adopting a more universal approach to the measurement and application of scope conditions would be methodologically and theoretically beneficial to expectation states research. PMID- 23017758 TI - Bargaining over waiting time in ultimatum game experiments. AB - While preference-based explanations play an increasing role in economics and sociology, the accurate measurement of social preferences deserves more attention. Most laboratory experiments measure social preferences by studying the division of "a cake that nobody had to bake" (Guth and Kliemt, 2003). This article reports results of the first ultimatum game experiment with bargaining over waiting time. The experiment was created to avoid effects of windfall gains. In contrast to donated money, time is not endowed by the experimenter and implies a natural loss to subjects. This allows for a better measurement of the inherent conflict in the ultimatum game. We implemented three anonymity conditions; one baseline condition, one condition with anonymity among subjects and one double blind condition in which the experimenter did not know the division of waiting time. While we expected to observe less other-regarding behavior in ultimatum game bargaining over time, our experimental results rather confirm previous ultimatum game experiments, in which people bargained over money. The modal offer was half of the waiting time and only one offer was rejected. Interestingly, anonymity did not change the results significantly. In conclusion, our experiment confirms other-regarding behavior in the ultimatum game. PMID- 23017759 TI - Revisiting the gap between stylized and diary estimates of market work time. AB - Previous studies find that workers of longer work weeks report more market hours in stylized measure than in time diary, while those of shorter work weeks report fewer hours. Using data from the American Time Use Survey (ATUS) 2003-2007, this paper attempts to explain this dilemma. I argue that market work time is composed of activity time, committed time, and constrained time. Thus, part of the difference found between the two estimates is due to the calculation of the diary estimate. I also argue that the wording of the stylized question is consequential. Some stylized questions (e.g., How many hours per week do you usually work?) might capture the mode, instead of the mean, of work time. Thus, when the distribution of work time is skewed, the mismatch between the two estimates is expected. A sequence-based identification for diary estimate and a non-parametric adjustment for stylized estimate are proposed and empirically examined. The result indicates that both methods significantly reduce the observed gap between the two estimates. I discuss the implications for future time use survey design in the concluding section. PMID- 23017760 TI - He said, she said: The gender wage gap according to self and proxy reports in the Current Population Survey. AB - Roughly half the labor force data in the Current Population Survey (CPS) are provided by proxy respondents, and since 1979, men's reliance on proxies has dropped dramatically while women's reliance on proxies has increased. Few authors, however, have examined how combining these first-hand and second-hand reports may influence our understanding of long-term economic trends. We exploit the outgoing rotation group structure of the CPS by matching individual records one year apart, and we find that self-reported wages are higher than proxy reported wages even after controlling for all time invariant characteristics. Furthermore, we find that changes in the use of proxy respondents by men and women since 1979 have made current estimates of the gender wage gap larger than they would have been without changes in reporting status. This suggests that the gender wage gap has closed more than previously estimated. We recommend that researchers combine self and proxy responses with great care, especially when analyzing time trends or making gender comparisons. PMID- 23017761 TI - Extracurricular activities and teens' alcohol use: The role of religious and secular sponsorship. AB - Much research has found that more religious youth are less likely to engage in riskier health-related behaviors. However, very little research has examined the role that religion may play in shaping the health-related behaviors of secular youth. There is reason to think that more and less religious youth may gain some health-related benefits from involvement with religious organizations through activities such as basketball and volunteering. Using two waves of data from the National Study of Youth and Religion, this study finds that involvement in religion-supported secular activities is associated with less alcohol use for all involved teens. The number of friends who belong to a religious youth group, in part, explains the relationship. Conversely, network overlap between parents and teens, the number of friends who drink or use drugs, and having an adult confidant from a religious group are not mechanisms that mediate the relationship. PMID- 23017762 TI - Have children adapted to their mothers working, or was adaptation unnecessary? Cohort effects and the relationship between maternal employment and child well being. AB - Drawing on previous theoretical and empirical work, we posit that maternal employment influences on child well-being vary across birth cohorts. We investigate this possibility by analyzing longitudinal data from a sample of children and their mothers drawn from the National Longitudinal Survey of Youth. We introduce a series of age, cohort, and maternal employment interaction terms into multilevel models predicting child well-being to assess whether any potential short-term or long-term effects of early and current maternal employment vary across birth cohorts. Results indicate that maternal employment largely is inconsequential to child well-being regardless of birth cohort, with a few exceptions. For instance, children born in earlier cohorts may have experienced long-term positive effects of having an employed mother; however, as maternal employment became more commonplace in recent cohorts, these beneficial effects appear to have disappeared. We discuss theoretical and methodological implications of these findings. PMID- 23017763 TI - Time dynamics of elder victimization: Evidence from the NCVS, 1992 to 2005. AB - Persons who are relatively younger have a comparably higher incidence of crime victimization than those who are older. Comparative studies of crime rates among those 65 and older with those for younger persons across time are virtually nonexistent. This study provides these analyses. Data from the National Crime Victimization Survey are used to study the relative victimization rate among US elders. Macroeconomic indicators and environmental interventions were included to examine whether structural forces influence elder crime victimization rates. Such influences are fractionally cointegrated with the long-term elder property and personal crime rates, with each having a distinct data-generating process. The results of these analyses suggest that personal, but not property, crime rates have declined since the passage of the Crime Bill of 1994. As well, the summer months are associated with elevated rates of property crime committed against elders but not personal crime. PMID- 23017764 TI - Housing crowding effects on children's wellbeing. AB - The degree to which children grow up in crowded housing is a neglected but potentially important aspect of social inequality. Poor living conditions can serve as a mechanism of social stratification, affecting children's wellbeing and resulting in the intergenerational transmission of social inequality. This paper reports an investigation of housing crowding on children's academic achievement, behavior, and health in the US and Los Angeles, a city with atypically high levels of crowding. We use data from the Panel Study of Income Dynamics' Child Development Supplement and the Los Angeles Family and Neighborhood Survey to explore the effect of living in a crowded home on an array of child wellbeing indicators. We find that several dimensions of children's wellbeing suffer when exposed to crowded living conditions, particularly in Los Angeles, even after controlling for socioeconomic status. The negative effects on children raised in crowded homes can persist throughout life, affecting their future socioeconomic status and adult wellbeing. PMID- 23017765 TI - Composition and decomposition in US gender-specific self-reported health disparities, 1984-2007. AB - Variance function regression models and demographic decomposition methods are applied to identify two dimensions of changes in health disparities (SES demographic effects vs. compositional effects, between-group disparities vs. within-group disparities) in the US from 1984 to 2007. Using National Health Interview Survey data on self-reported health, we find that disparities in men's health increased, while those of women decreased, for the whole period. Widening men's health disparities are largely driven by increases in the effects of SES demographic statuses on within-group disparities. These increases are moderated by increasing levels of men's college attainment. But decreasing middle and upper income attainment and a decreasing employment rate further increase men's health disparities. For women, the effects of SES-demographic statuses on health disparities also increased over time. This, however, was outweighed by increases in women's college attainment, middle and upper income attainment, and employment rate. The result is overall declining self-reported health disparities for women. PMID- 23017767 TI - Erratum on "Eyes on the block: Measuring urban physical disorder through in person observation, by Malia Jones, Anne R. Pebley, Narayan Sastry, Social Science Research 40 (2) 523-537". PMID- 23017766 TI - Parenthood and psychological well-being: Clarifying the role of child age and parent-child relationship quality. AB - Although recent scholarship has emphasized the importance of examining the rewards of raising children in understanding variations in psychological consequences of parenthood, empirical research remains focused on the demands of parenthood. Using a sample of parents with children aged 0-22 in the National Survey of Families and Households (N=6228), this paper examines the association between age of children and parental psychological well-being, focusing on a key element of rewards of parenthood, parental relationship satisfaction with their children, as a mediator of the link. Findings indicate that parents whose oldest child is under age five report higher satisfaction with the relationship with their children, higher self-esteem, higher self-efficacy, and less depression than do parents whose oldest child is school-age or adolescent. When parental satisfaction is taken into account, the differences in self-esteem, self efficacy, and depression by age of children disappear. PMID- 23017768 TI - Pathogenic Leptospira spp. in bats, Madagascar and Union of the Comoros. PMID- 23017769 TI - [Breast cancer follow-up by primary care physician: patient satisfaction in the Metropolitan Paris region]. AB - Because of increasing breast cancer incidence and improvement in long-term prognosis, follow-up of patients cannot be carried out entirely in specialized cancer centres. The Reseau Gynecomed was created to transfer the follow-up of patients to primary care physicians (PCP). In 2009, to evaluate the quality of PCP follow-up, a satisfaction study was performed for the 1,245 women followed after breast cancer. Sixty-four percent of the women participate in the study. Before starting follow-up, 87% were informed about its purpose and 93% about its schedule. The satisfaction score was excellent (91%). Old age, perception of a good health status, a high quality of information about and a confident relationship with their PCP were associated with a better satisfaction level. Forty-eight percent of patients thought easy to accept the PCP follow-up. Considering this data, PCP monitoring seems to provide a good follow-up and may be developed. Nonetheless, conditions of patients' choice should be improved and particularly exclude patients with financial difficulties. It would facilitate the growing transfer of follow-up to the PCP. PMID- 23017770 TI - The complex architecture of mycobacterial promoters. AB - The genus Mycobacterium includes a variety of species with differing phenotypic properties, including growth rate, pathogenicity and environment- and host specificity. Although many mycobacterial species have been extensively studied and their genomes sequenced, the reasons for phenotypic variation between closely related species remain unclear. Variation in gene expression may contribute to these characteristics and enable the bacteria to respond to changing environmental conditions. Gene expression is controlled primarily at the level of transcription, where the main element of regulation is the promoter. Transcriptional regulation and associated promoter sequences have been studied extensively in E. coli. This review describes the complex structure and characteristics of mycobacterial promoters, in comparison to the classical E. coli prokaryotic promoter structure. Some components of mycobacterial promoters are similar to those of E. coli. These include the predominant guanine residue at the transcriptional start point, conserved -10 hexamer, similar interhexameric distances, the use of ATG as a start codon, the guanine- and adenine-rich ribosome binding site and the presence of extended -10 (TGn) motifs in strong promoters. However, these components are much more variable in sequence in mycobacterial promoters and no conserved -35 hexamer sequence (clearly defined in E. coli) can be identified. This may be a result of the high G+C content of mycobacterial genomes, as well as the large number of sigma factors present in mycobacteria, which may recognise different promoter sequences. Mycobacteria possess a complex transcriptional regulatory network. Numerous regulatory motifs have been identified in mycobacterial promoters, predominantly in the interhexameric region. These are bound by specific transcriptional regulators in response to environmental changes. The combination of specific promoter sequences, transcriptional regulators and a variety of sigma factors enables rapid and specific responses to diverse conditions and different stages of infection. This review aims to provide an overview of the complex architecture of mycobacterial transcriptional regulation. PMID- 23017771 TI - Squalamine and its derivatives as potential antitubercular compounds. PMID- 23017772 TI - Axial length and choroidal thickness changes accompanying prolonged accommodation in myopes and emmetropes. AB - The time course of elongation and recovery of axial length associated with a 30min accommodative task was studied using optical low coherence reflectometry in a population of young adult myopic (n=37) and emmetropic (n=22) subjects. Ten of the 59 subjects were excluded from analysis either due to inconsistent accommodative response, or incomplete anterior biometry data. Those subjects with valid data (n=49) were found to exhibit a significant axial elongation immediately following the commencement of a 30min, 4 D accommodation task, which was sustained for the duration of the task, and was evident to a lesser extent immediately following task cessation. During the accommodation task, on average, the myopic subjects exhibited 22+/-34MUm, and the emmetropic subjects 6+/-22MUm of axial elongation, however the differences in axial elongation between the myopic and emmetropic subjects were not statistically significant (p=0.136). Immediately following the completion of the task, the myopic subjects still exhibited an axial elongation (mean magnitude 12+/-28MUm), that was significantly greater (p<0.05) than the changes in axial length observed in the emmetropic subjects (mean change -3+/-16MUm). Axial length had returned to baseline levels 10min after completion of the accommodation task. The time for recovery from accommodation-induced axial elongation was greater in myopes, which may reflect differences in the biomechanical properties of the globe associated with refractive error. Changes in subfoveal choroidal thickness were able to be measured in 37 of the 59 subjects, and a small amount of choroidal thinning was observed during the accommodation task that was statistically significant in the myopic subjects (p<0.05). These subfoveal choroidal changes could account for some but not all of the increased axial length during accommodation. PMID- 23017773 TI - Perception of dynamic glass patterns. AB - In the mammalian brain, form and motion are processed through two distinct pathways at early stages of visual processing. However, recent evidence suggests that these two pathways may interact. Here we used dynamic Glass patterns, which have been previously shown to create the perception of coherent motion in humans, despite containing no motion coherence. Glass patterns are static stimuli that consist of randomly positioned dot pairs that are integrated spatially to create the perception of a global form, whereas dynamic Glass patterns consist of several independently generated static Glass patterns presented sequentially. In the current study, we measured the detection threshold of five types of dynamic Glass patterns and compared the rank order of the detection thresholds with those found for static Glass patterns and real motion patterns (using random dot stimuli). With both the static Glass patterns and dynamic Glass patterns, detection thresholds were lowest for concentric and radial patterns and highest for horizontal patterns. We also found that vertical patterns were better detected than horizontal patterns, consistent with prior evidence of a "horizontal effect" in the perception of natural scene images. With real motion, detection thresholds were equivalent across all patterns, with the exception of higher thresholds for spiral patterns. Our results suggest that dynamic Glass patterns are processed primarily as form prior to input into the motion system. PMID- 23017774 TI - Cognitive mediation of cognitive-behavioural therapy outcomes for anxiety-based school refusal. AB - BACKGROUND: Cognitive-behavioural therapy (CBT) has proven to be effective for anxiety-based school refusal, but it is still unknown how CBT for school refusal works, or through which mechanisms. AIMS: Innovative statistical approaches for analyzing small uncontrolled samples were used to investigate the role of self efficacy in mediating CBT outcomes for anxiety-based school refusal. METHOD: Participants were 19 adolescents (12 to 17 years) who completed a manual-based cognitive-behavioural treatment. Primary outcomes (school attendance; school related fear; anxiety) and secondary outcomes (depression; internalizing problems) were assessed at post-treatment and 2-month follow-up. RESULTS: Post treatment increases in school attendance and decreases in fear about attending school the next day were found to be mediated by self-efficacy. Mediating effects were not observed at 2-month follow-up. CONCLUSIONS: These findings provide partial support for the role of self-efficacy in mediating the outcome of CBT for school refusal. They contribute to a small body of literature suggesting that cognitive change enhances CBT outcomes for young people with internalizing problems. Regarding methodology, the product of coefficient test appears to be a valuable way to study mediation in outcome studies involving small samples. PMID- 23017775 TI - Expression profile of toll-like receptor 2 mRNA in selected tissues of shark (Chiloscyllium sp.). AB - Sharks are a species of delight for immunologists from the evolutionary perspective since it is considered as the first species to have evolved the adaptive immune responses in addition to the innate immune system. One of the components of the highly conserved innate immune system is the toll-like receptors (TLR) which has a conserved overall protein structure throughout deuterostome evolution. There is no report that demonstrates the expression of these receptors in sharks. In this study we successfully amplified a 270 bp amplicon using a degenerate primer design strategy that corresponded to the Toll/IL-1 receptor (TIR) domain of TLR2 (GenBank ID: JF792813). BLAST analysis revealed a maximum nucleotide identity of 87% and 76% with the TLR2 of higher mammals and teleost fishes respectively. Domain prediction revealed a TIR structure between 1 and 87 amino acids that had a maximum identity of 58% and 76% with TLR2 - TIR protein of teleost fishes and higher mammals respectively. Phylogenetic analysis revealed a closer clustering of the shark TIR sequence with those from human, cattle, goat, sheep and chicken than with other fish species. Basal expression levels of the TLR2-TIR mRNA were found to be significantly higher in kidneys followed by fins, spleen and intestinal spiral valve (ISV). In tissues such as spleen and kidney the expression of the TLR2-TIR mRNA could be localized to lymphoid and macrophages like cells and tubular epithelial cells respectively. In-vivo exposure of sharks to peptidoglycan (TLR 2 ligand) resulted in 9 folds higher expression of TLR2-TIR mRNA in gills followed by 5 folds in the fins. However, when inoculated with a TLR ligand pool, the expression levels significantly increased to 12 fold in skin followed by epigonal, kidneys and ISV. These findings not only support the presence of the TLRs in sharks but also their induction upon exposure to specific ligands. Further studies are needed to identify their numbers, their ligand specificity and downstream cytokine responses. PMID- 23017776 TI - Anthroponotic enteric parasites in monkeys in public park, China. AB - Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi were detected in 45, 35, and 116 of 411 free-range rhesus monkeys, respectively, in a popular public park in the People's Republic of China. Most genotypes and subtypes detected were anthroponotic, indicating these animals might be reservoirs for human cryptosporidiosis, giardiasis, and microsporidiosis. PMID- 23017777 TI - Ischiofemoral impingement: hip pain of infrequent cause. AB - Hip pain is a frequent cause of medical attention in the daily clinical practice. Among the different causes included in the differential diagnosis we find ischiofemoral impingement, described initially in patients after joint replacement surgery, but later found in patients with no history of a causal disease. PMID- 23017779 TI - Identification of an O-linked repetitive glycan chain of the polar flagellum flagellin of Azospirillum brasilense Sp7. AB - This is the first report to have identified an O-linked repetitive glycan in bacterial flagellin, a structural protein of the flagellum. Studies by sugar analysis, Smith degradation, (1)H and (13)C NMR spectroscopy, and mass spectrometry showed that the glycan chains of the polar flagellum flagellin of the plant-growth-promoting rhizobacterium Azospirillum brasilense Sp7 are represented by a polysaccharide with a molecular mass of 7.7 kDa, which has a branched tetrasaccharide repeating unit of the following structure: PMID- 23017778 TI - Influence of glycerol on molecular mobility and hydrogen bond network in amorphous glucose matrix. AB - The effect of glycerol on molecular mobility and hydrogen bonding in amorphous glucose matrix was studied. Phosphorescence from erythrosin B (Ery B) was used to characterize the temperature dependence of mobility in glucose/glycerol films over the temperature range from 100 degrees C down to -10 degrees C. Analysis of emission energy and excited state decay kinetics from Ery B provided information about thermally activated modes of matrix dipolar relaxation around and collisions with the excited triplet state of the probe. Both the average rate of matrix mobility and the width of the distribution of matrix mobility rates largely scaled with the effect of glycerol on the glass transition temperature of the glucose/glycerol mixture. The IR hydrogen bond bandwidth increased at higher glycerol content, suggesting that the strength of the bond became more widely distributed with the added glycerol. An increase with temperature in the hydrogen bond peak frequency indicated the transformation of associated hydroxyl to free hydroxyl. These results support a model in which glycerol plasticizes the glucose matrix at mole ratios of 0.1 and above while providing no evidence for the antiplasticization seen in other sugar matrices. PMID- 23017780 TI - Exploration of CH...pi mediated stacking interactions in saccharide: aromatic residue complexes through conformational sampling. AB - Saccharides interact with aromatic residues mostly through CH...pi mediated stacking interactions. The energetics of such interactions depends upon the mutual position-orientations (POs) of the two moieties. The POs found in the crystal structures are only a subset of the various possible ways of interaction. Hence, potential energy surfaces of saccharide-aromatic residue complexes have been explored by mixed Monte Carlo multiple minimum/low mode sampling. The saccharides considered in this study are alpha/beta-D-glucose, beta-D-galactose, alpha-D-mannose, and alpha/beta-L-fucose. p-Hydroxytoluene, toluene, and 3 methylindole were used as analogs of tyrosine, phenylalanine, and tryptophan, respectively. The saccharides interact from either above or below the pi-cloud of an aromatic ring but not along the edges. The POs preferred by different saccharides, both in the preferred chair and skew-boat forms, for interacting with different aromatic amino acid residue analogs have been identified. Aromatic residues can interact with the same -CH group in many POs but not so with the -OH groups. Changes in the configurations of pyranose ring carbon atoms cause remarkable changes in stacking preferences. beta-D-Galactose and beta-L-fructose interact only through their b- and a-faces, respectively. Saccharides use a wide variety of apolar patches for stacking against aromatic residues and these have been analyzed in detail. As many as four -CH groups can simultaneously participate in CH...pi interactions, especially with 3-methylindole owing to its larger surface area. PMID- 23017781 TI - The role of ethnicity in treatment refractory schizophrenia. AB - OBJECTIVE: The goal of this research was to describe the relationship between treatment resistant schizophrenia, defined using the APA criteria and ethnic background in patients with schizophrenia spectrum disorders in a Canadian sample. A secondary goal was to analyze the number of antipsychotics failed due to side effects and number of antipsychotics failed due to non-response. METHOD: We included 497 patients diagnosed with schizophrenia spectrum disorders using the SCID. The medication history was extracted from the electronic health records. Data collection included demographics (sex, age, ethnicity), principal diagnosis according to SCID (Diagnostic and Statistical Manual of Mental Disorders, 4th edition), duration of mental illness, number of psychiatric admissions and treatment information. If patients were on clozapine or polypharmacy treatment, this was recorded at the time of the SCID interview. Additional data, including prior antipsychotic history, were collected from the health records. RESULTS: Thirty per cent of the patients were classified as resistant according to the APA criteria. There were significantly more white European subjects in the treatment resistant group (p=0.031). The duration of illness was significantly higher in the resistant group then in the non-resistant group (21.0 vs 15.1 years; p<0.001). Patients who were treatment resistant were more likely to be on polypharmacy compared with non-resistant patients (p=0.001; OR=2.424; 95%CI=1.446-4.065). When we considered the number of drug trials failed due to non response and drug trial failed because of side effects, we found a strong negative correlation in both white Europeans and non-white Europeans. CONCLUSIONS: White European ethnicity is associated with treatment resistant schizophrenia. In addition, patients with treatment-resistant schizophrenia were on polypharmacy at higher rate than non resistant patients. PMID- 23017782 TI - A review on antioxidants, prooxidants and related controversy: natural and synthetic compounds, screening and analysis methodologies and future perspectives. AB - Many studies have been conducted with regard to free radicals, oxidative stress and antioxidant activity of food, giving antioxidants a prominent beneficial role, but, recently many authors have questioned their importance, whilst trying to understand the mechanisms behind oxidative stress. Many scientists defend that regardless of the quantity of ingested antioxidants, the absorption is very limited, and that in some cases prooxidants are beneficial to human health. The detection of antioxidant activity as well as specific antioxidant compounds can be carried out with a large number of different assays, all of them with advantages and disadvantages. The controversy around antioxidant in vivo benefits has become intense in the past few decades and the present review tries to shed some light on research on antioxidants (natural and synthetic) and prooxidants, showing the potential benefits and adverse effects of these opposing events, as well as their mechanisms of action and detection methodologies. It also identifies the limitations of antioxidants and provides a perspective on the likely future trends in this field. PMID- 23017783 TI - Docile splay graft for middle vault reconstruction. PMID- 23017784 TI - Urinary stone risk and cola consumption. AB - OBJECTIVE: To evaluate the effect of cola consumption on urinary stone risk factors in a controlled metabolic environment with a prospective cross-over study. METHODS: Thirteen participants (10 normal and 3 calcium oxalate stone formers) underwent 2 6-day phases on a controlled metabolic diet. During phase 1, subjects ingested 1 liter of cola daily, followed by a 3-week washout period. During phase 2, subjects ingested 1 liter of deionized water daily. Twenty-four hour urine collections and serum metabolic panels were obtained for stone risk factors at the end of each phase. Urine and serum results of the cola phase were compared with those of the water phase. RESULT: Normal subjects and stone-formers were combined for analysis after determining no significant difference between the 2 groups. No significant differences were found among cola and water treatment groups for normal subjects, stone-formers, or the pooled group. CONCLUSION: Cola exerts no detectable change in urinary risk factors associated with calcium oxalate stone formation. Cola consumption may not increase stone risk and may be an acceptable alternative source of daily fluid for patients unwilling to increase water consumption. PMID- 23017785 TI - Prostate extract with aluminum hydroxide injection as a novel animal model for chronic prostatitis/chronic pelvic pain syndrome. AB - OBJECTIVES: To establish a new animal model to mimic the clinical condition of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). CP/CPPS is a highly prevalent condition with detrimental effect on the quality of life, but the etiology, pathogenesis, and optimal treatment of CP/CPPS remain unknown. This new animal model would greatly contribute to the understanding and treatment of CP/CPPS. METHODS: Forty Wistar rats were averagely and randomly divided into 5 groups (3 experimental groups, a normal control group, and a positive group) of 8 rats each. Experimental groups were subcutaneously injected with the mixture of prostate extract and aluminum hydroxide, the positive control group with prostate extract and complete Freund adjuvant (CFA), and the normal control group with 0.01 mol/L phosphate-buffered saline (0.01 M PBS). Hematoxylin and eosin stain and immunohistochemistry were respectively used to investigate the inflammatory lesion and the expression of tumor necrosis factor-alpha (TNF)-alpha in the prostate. In addition, the serum IgG was also evaluated. The t test was used to compare the statistical differences among groups. RESULTS: Histopathological analyses indicated that prostate lesions in the group immunized with high concentrations of aluminum hydroxide in the presence of prostate extract 3 times was most severe, in addition there was also the highest expression of TNF-alpha and IgG in this group. CONCLUSIONS: Prostate extract with aluminum hydroxide injection could successfully induce CP/CPPS in Wistar rats, which was in a dose dependent and injection number-dependent fashion. This animal model might greatly benefit with further understanding of the etiology, pathogenesis, and optimal treatment of CP/CPPS. PMID- 23017786 TI - Evaluation of trigeminal nerve injuries in relation to third molar surgery in a prospective patient cohort. Recommendations for prevention. AB - Trigeminal nerve injury is the most problematic consequence of dental surgical procedures with major medico-legal implications. This study reports the signs and symptoms that are the features of trigeminal nerve injuries caused by mandibular third molar (M3M) surgery. 120 patients with nerve injury following M3M surgery were assessed. All data were analysed using the SPSS statistical programme and Microsoft Excel. 53 (44.2%) inferior alveolar nerve (IAN) injury cases and 67 (55.8%) lingual nerve injury (LNI) cases were caused by third molar surgery (TMS). Neuropathy was demonstrable in all patients with varying degrees of paraesthesia, dysaesthesia (in the form of burning pain), allodynia and hyperalgesia. Pain was one of the presenting signs and symptoms in 70% of all cases. Significantly more females had IAN injuries and LNIs (p<0.05). The mean ages of the two groups of patients were similar. Speech and eating were significantly more problematic for patients with LNIs. In conclusion, chronic pain is often a symptom after TMS-related nerve injury, resulting in significant functional problems. Better dissemination of good practice in TMS will significantly minimize these complex nerve injuries and prevent unnecessary suffering. PMID- 23017787 TI - [beta-Human chorionic gonadotropin (HCG) dosage and lung cancer: a pitfall when screening patients for clinical trials]. AB - beta-HCG belongs to the glycoprotein hormone family and is usually assess to exclude pregnancy for patients potentially eligible to chemotherapy, especially during clinical trials. We studied non-small-cell lung cancer (NSCLC) patients that were found with elevated serum beta-HCG level during clinical trial screening. The first case is a 45-year-old woman who presented with a stage IV undifferentiated carcinoma of the lung eligible for chemotherapy. When screening the patient for a clinical trial combining platinum-based chemotherapy and targeted therapy, the plasma beta-HCG level was 19 IU/L (0-5 IU/L). The second case is a 64-year-old woman presented with stage IV poorly differentiated adenocarcinoma of the lung. When screening the patient for the same clinical trial combining platinum-based chemotherapy and targeted therapy, the plasma beta HCG level was beta-HCG 13 IU/L (0-5 IU/L). The serum dosages were double-checked and confirmed elevated beta-HCG level. The gynecological work-up definitely rules out an improbable pregnancy. The pathological examination was also checked and confirmed in the two cases a primary lung cancer. An immuno-histochemical reassessment of the pathological specimens with additional tests was performed: for one patient 25% of tumor cells expressed beta-HCG. As pregnancies were ruled out, the two cases were extensively discussed with the promoter and the patients finally treated within this clinical trial. The treatments are ongoing. beta-HCG is a specific marker for trophoblastic tumors of placenta and gestational tumors. Ectopic expression of beta-HCG was found in 20-40% of all common epithelial carcinoma, especially for tumors of the stomach, ovary, liver and lung. Only few cases have been reported in the literature. However, in a young patient with high serum levels of beta-HCG two questions arise: is there a place for pregnancy? Are the pathology results accurate? All this could delay the appropriate management of these patients and also potentially prevents the participation of innovative therapeutic strategies. Therefore, knowing this rare but possible expression of beta-HCG by lung tumors may speed out the gynecological work-up and the reevaluation of the histological samples in order to minimize the delay in the care of these patients and give them a chance to have new innovative drugs within clinical trial. PMID- 23017788 TI - Why is the sex gap in feelings of depression wider in high gender equity countries? The effect of children on the psychological well-being of men and women. AB - This study uses data from 23 countries in the World Values Survey and the National Survey of Families and Households and finds that the sex gap in feelings of depression is wider in high gender equity societies even though overall levels of feelings of depression are lower. Using hierarchical logistic modeling, we find that the sex difference in feelings of depression is wider in high gender equity societies because children increase depression for women in high gender equity societies, while they reduce depression for women without paid employment in low gender equity societies. There is little difference in the effect of children on feelings of depression for men across societies. PMID- 23017789 TI - The "new" military and income inequality: A cross national analysis. AB - Military expenditures have escalated over the last three decades in both developed and less developed countries, without a corresponding expansion of military personnel. Spending has instead been directed towards hi-tech weaponry, what we refer to as the "new" military. We hypothesize that this new, increasingly capital-intensive military is no longer a pathway of upward mobility or employer of last resort for many uneducated, unskilled, or unemployed people, with significant consequences for those individuals and society as a whole. One such consequence, we argue, is an increase in income inequality. We test this hypothesis with cross-national panel models, estimated for 82 developed and less developed countries from 1970 to 2000. Findings indicate that military capital intensiveness, as measured by military expenditures per soldier, exacerbates income inequality net of control variables. Neither total military expenditures/GDP nor military participation has a significant effect. It appears from these findings that today's "new" military establishment is abrogating its historical role as an equalizing force in society, with important policy implications. PMID- 23017790 TI - Social mobility in 20 modern societies: The role of economic and political context. AB - It is commonly argued that social mobility rates are influenced by economic and political conditions. Nevertheless, research on this issue has tended to be hindered by two limitations that make it difficult to draw strong conclusions about contextual effects: (1) seldom have country-level and individual-level influences been tested simultaneously, and (2) only rarely have data more recent than the 1970s been employed. We improve on previous research by employing multilevel models fitted to relatively recent survey data collected from 20 modern societies by the International Social Survey Program (ISSP) and national level characteristics derived from various official sources. Our findings demonstrate systematic cross-national variation in the association between the occupational status of respondents and their fathers. Consistent with the industrialization thesis, this variation is positively associated with per-capita GDP, suggesting that more affluent nations are characterized by more open and fluid stratification structures. Our results also suggest the importance of political regimes and migration for social mobility. In contrast, economic inequality appears to explain very little of the cross-national variation in mobility rates. PMID- 23017791 TI - Institutionalizing shame: The effect of Human Rights Committee rulings on abuse, 1981-2007. AB - What motivates compliance with "toothless" international human rights norms? This article analyzes the effectiveness of procedures that allow individuals to petition an international human rights body, the Human Rights Committee, alleging state abuse of their treaty-protected rights under the International Covenant on Civil and Political Rights. Using methodological tools that account for selection biases arising from a country's decision to authorize petitions and its subsequent propensity to be targeted by abuse claims, I find that basic civil rights and religious freedoms improved after states were found to have violated their human rights treaty obligations, whereas physical integrity abuses such as disappearances and extrajudicial killing were somewhat more impervious to change. These findings are interpreted with reference to the concept of "coupling" as borrowed from organizational sociology, and their implications for treaty design and enforcement are considered. PMID- 23017792 TI - Ethnic concentration in the neighbourhood and majority and minority language: A study of first and second-generation immigrants. AB - Ethnic residential concentration is often found to hamper immigrants' majority language proficiency. However, there are still several gaps in our understanding of the relationship between ethnic concentration and ethnic minorities' language practices. This study examines the extent to which ethnic concentration also constrains immigrants' majority language use, whether contact with natives and co ethnics mediates these relationships, and whether ethnic concentration relates to second-generation minorities' minority language proficiency. Structural equation models on data for people of Turkish and Moroccan origin living in the Netherlands (N=2163) showed that ethnic concentration is indirectly related to weaker majority language proficiency and less majority language use through contact with natives and co-ethnics. For second-generation minorities, ethnic concentration is related to better minority language proficiency. PMID- 23017793 TI - Motivation vs. relevance: Using strong ties to find a job in Urban China. AB - While the idea that contacts matter in finding a job is intuitively appealing, we still do not know-after decades of research-how and why strong ties benefit job seekers. To resolve this confusion, we need to theorize how specific characteristics of ties are related to the mechanisms that make job search through contacts effective. We have reasons to expect that, while a contact's motivation influences the likelihood that a job seeker receives an offer, her homophily with the job seeker on occupation and other job-relevant attributes influences the quality of the offer. The use of strong ties among university students to find jobs in China provides a unique opportunity to empirically isolate the relationship between contact characteristics and the mechanisms through which contacts benefit the job seeker. I tested my hypotheses with data on both the successful and unsuccessful job searches of 478 graduates of China's flagship universities, who, as first-time job seekers, primarily used strong ties. Survey results are consistent with my hypotheses: job seekers who used strong ties to look for jobs had more offers-but not better offers-than those who used only formal methods. PMID- 23017794 TI - Social support and the working hours of employed mothers in Europe: The relevance of the state, the workplace, and the family. AB - This paper studies the influence of state, workplace, and family support on the working hours of employed mothers and how these different support sources interact. Data taken from the European Social Survey 2004/2005 as well as country specific information were used to estimate several hierarchical models. We find evidence that the availability of supportive workplace arrangements and family support positively impact the working hours of employed mothers and that state policies facilitating the traditional family have a negative effect. There is weak support for a positive relationship between state policies facilitating the dual-earner family and working hours of employed mothers. In addition, most of the sources of support appear to be complementary. Supportive family role models and supportive workplace arrangements have a reinforcing relationship, as do publicly funded child care and supportive workplace arrangements. PMID- 23017795 TI - Household energy consumption: Community context and the fuelwood transition. AB - We examine the influence of community context on change over time in households' use of non-wood fuels. Our theoretical framework builds on sociological concepts in order to study energy consumption at the micro-level. The framework emphasizes the importance of nonfamily organizations and services in the local community as determinants of the transition from use of fuelwood to use of alternative fuels. We use multilevel longitudinal data on household fuel choice and community context from rural Nepal to provide empirical tests of our theoretical model. Results reveal that increased exposure to nonfamily organizations in the local community increases the use of alternative fuels. The findings illustrate key features of human impacts on the local environment and motivate greater incorporation of social organization into research on environmental change. PMID- 23017797 TI - Modeling the impact of supra-structural network nodes: The case of anonymous syringe sharing and HIV among people who inject drugs. AB - Networks are well understood as crucial to the diffusion of HIV among injection drug users (IDUs), but quasi-anonymous risk nodes - such as shooting galleries - resist measurement and incorporation into empirical analyses of disease diffusion. Drawing on network data from 767 IDUs in Bushwick, Brooklyn, we illustrate the use of calibrated agent-based models (CABMs) to account for network structure, injection practices, and quasi-anonymous transmission in shooting galleries. Results confirm the importance of network structure and actor heterogeneity to the magnitude and speed of HIV transmission. Models further demonstrate that quasi-anonymous injections in shooting galleries increase the speed of HIV diffusion across the whole network and have the greatest impact on HIV seroconversion levels for IDUs at the network periphery. Shooting galleries are shown to be transmission hubs that operate independently of traceable structural ties, linking otherwise unconnected network components. CABMs potentially increase understandings of HIV diffusion dynamics by infusing computer simulations with empirical data. PMID- 23017796 TI - A cluster analysis of service utilization and incarceration among homeless youth. AB - Our paper examines service usage (e.g., shelter) as well as a typology of individuals who are most likely to use groupings of services among 249 homeless youth. Our results revealed that the majority of homeless young people have used food programs (66%) and street outreach (65%) on at least one occasion within the past year. Cluster analysis of services revealed four distinct groups: (1) basic survival service use, characterized by above average shelter, food, and outreach service use, but below average on counseling, substance abuse/mental health services, and incarceration; (2) multiple service use, which included above average use of all six services; (3) incarceration experience, characterized by above average incarceration experience, but below average use of all other five services; and (4) minimal service use, which included slightly above average use of counseling, but below average use of all other services. These findings have the potential to provide important information that may assist with targeting services to homeless youth. PMID- 23017798 TI - A lay-statistician explanation of minority discrimination. AB - We outline a new explanation of discrimination against numerical minorities. In contrast to prior work that focuses on how the content of categories affects discrimination, our argument describes how the size of categories leads to discrimination. Specifically, we argue that, when comparing multiple categories, actors tend to view larger categories as more closely approximating an underlying population than smaller ones. As a result, a decision maker will tend to expect that members of a numerical majority are more likely to be what he/she is searching for, whether it is the best or worst candidate. We report the results of two studies designed to test these arguments. To demonstrate the generality of the proposed mechanism, Study 1 tested the argument in a non-social domain. Participants disproportionately favored the majority (vs. minority) category when searching for a single winning lottery ticket, and favored the minority category when the goal was to avoid a single losing ticket. Our second study supported an additional implication of the argument in a social domain: decision makers tended to rank highly qualified majority job candidates as better than equally qualified minority candidates, and relatively unqualified majority candidates as worse than equally unqualified minority candidates. PMID- 23017799 TI - Who loses in direct democracy? AB - We examine the success of California's black, Latino, and Asian voters in ballot proposition elections, showing that minority voters lose more often than whites across all ballot propositions, and that this disadvantage is not limited to a small subset of racially-targeted propositions. Minority voters are 2-5 percentage points less likely than otherwise-similar white voters to be on the winning side of ballot propositions. These differences persist after excluding racially-targeted propositions because minority voters are more likely to lose on several issues including elections, the environment, health, housing, taxes, and transportation. We demonstrate that race is more important than class in describing which voters lose. PMID- 23017800 TI - Workplace racial composition, perceived discrimination, and organizational attachment. AB - Prior research has devoted considerable attention to the relationship between the racial and ethnic composition of jobs and various indicators of organizational attachment. Fewer studies, however, examine how workplace racial composition affects individuals' experiences of racial discrimination or how these experiences impact workers' organizational attachment. To address this lacuna, we first examine the effects of workplace racial composition on perceived racial and ethnic discrimination. Next, we examine whether perceived racial discrimination mediates the association between racial composition and organizational attachment observed in prior studies. Finally, we explore whether these relationships are similar (symmetric) or different (non-symmetric) for non-Whites and Whites. The analyses indicate: (1) working with predominately same-race coworkers tends to diminish perceptions of racial discrimination, (2) perceived racial discrimination mediates some of the effects of racial/ethnic composition on organizational attachment, and (3) some non-symmetric effects between non-Whites and Whites are found. We conclude with implications for future research. PMID- 23017801 TI - Looking for homogeneous groups of respondents and nonrespondents using latent class analysis. AB - Concerns about decreasing response rates have led to many nonresponse studies. Unfortunately, usually only a limited amount of data is available on nonrespondents. Linking administrative data makes information available on all the sampled units including nonrespondents. Statistics Netherlands has constructed a database in which several administrative records and several surveys are connected. In this explorative study we use this dataset to look for homogenous groups of respondents and nonrespondents in survey research using latent class cluster analysis. Latent class techniques can provide insight into the problem of selective nonresponse and currently under-represented societal groups. We identify four different latent classes in a recent Dutch survey and replicate the findings for the same survey conducted 4 years later. Two of the types of sampled units have above-average response rates and the other two have below-average response rates. We also evaluate various latent class models with other response outcomes to gain insight into the contact and cooperation process. PMID- 23017802 TI - The link between unemployment and crime rate fluctuations: An analysis at the county, state, and national levels. AB - Cantor and Land (1985) developed a theoretical model that proposed two pathways through which economic activity - as indexed by the aggregate unemployment rate - could affect the rate of criminal activity. The first is by increasing levels of criminal motivation within the population as deteriorating economic conditions affect social strain and social control; the second is by influencing the availability and vulnerability of criminal targets and thus the number of criminal opportunities. Although much empirical research has applied this theoretical model, few analyses have done so at disaggregated units of analysis. We present the most comprehensive analysis to date by empirically evaluating this model with data on 400 of the largest US counties - and examine the effects of aggregation on results as these county data are combined to the state and national levels - for the years 1978-2005. For seven Index crimes at each of the three levels of analysis, and with or without controls for structural covariates at each level, the directional effects hypothesized by Cantor and Land are found for 78 out of 84 estimated relationships. Even after taking into account the lack of statistical independence of these estimates by drawing on recently developed statistical theory, this is a very unlikely outcome. In accordance with expectations based on theory and prior research, (a) some of these relationships are weak and not statistically significant, and (b) the strongest and most consistent patterns of relationships for both the crime opportunity and crime motivation effects are found for three property crimes: burglary, larceny, and motor vehicle theft. Suggestions for further research on this topic are given. PMID- 23017803 TI - Should Mom go back to school? Post-natal educational attainment and parenting practices. AB - Although the relationship between educational attainment and parenting practices is well documented, it is typically examined at only one point in time. What happens if mothers acquire more education after the birth of their children: do they alter their parenting practices? Panel data models based on longitudinal data from ECLS-K indicate that changes in mother's educational attainment are positively associated with increases in parental school involvement, having books in the home, and participating in non-academic family activities, but not with attitudes toward discipline. Although post-natal maternal education does not change all aspects of parenting, our findings are broadly consistent with the theory of cultural mobility and provide insights into the extent of socio cultural mobility in contemporary American society. PMID- 23017804 TI - The 9th grade shock and the high school dropout crisis. AB - Retrospective questions on educational attainment in national surveys and censuses tend to over-estimate high school graduation rates by 15-20% points relative to administrative records. Administrative data on educational enrollment are, however, only available at the aggregate level (state, school district, and school levels) and the recording of inter-school transfers are generally incomplete. With access to linked individual-level administrative records from a very large "West Coast metropolitan school district" we track patterns of high school attrition and on-time high school graduation of individual students. Even with adjustments for the omission of out-of-district transfers (estimates of omission are presented), the results of this study show that failure in high school, as indexed by retention and attrition, are almost as common as on-time high school graduation. In addition to the usual risk factors of disadvantaged background, we find that the "9th grade shock"-an unpredicted decline in academic performance upon entering high school-is a key mechanism behind the continuing crisis of high school attrition. PMID- 23017805 TI - Happiness inequality: Adding meaning to numbers - A reply to Veenhoven and Kalmijn. AB - In SSR 40 (3), we proposed two new measures for happiness inequality, which have spurred a debate. With this rebuttal we disprove the arguments of our critics and demonstrate that our recommended measure, the percent-maximum standard deviation, is a valuable tool for cross-national comparative research. PMID- 23017806 TI - West Nile virus meningoencephalitis imported into Germany. PMID- 23017807 TI - Steroid refractory psoriasiform cutaneous graft versus host disease successfully treated by extracorporeal photopheresis: a case report. AB - Graft-versus-host disease (GVHD) is a frequent complication occurring after allogeneic hematopoietic stem cell transplantation. It can be classified as acute and chronic GVHD based on the time of onset following transplantation and clinical presentation. Cutaneous involvement is the most common feature of acute GVHD, with maculopapular exanthema and perifollicular papular lesions. Steroid refractory GVHD is associated with a significant morbidity and mortality. We present a very rare case with acute cutaneous GVHD mimicking psoriasis vulgaris occurring after allogeneic peripheral blood stem cell transplantation for chronic lymphocytic leukemia. The patient's rash resembled psoriasis vulgaris and showed histologic features of both psoriasis and acute GVHD. Despite concomitant cyclosporine A and methylprednisolone therapy no response was obtained. Therefore, we administered extracorporeal photopheresis and achieved the desired therapeutic effect. PMID- 23017808 TI - WITHDRAWN: The frequency of RBC alloantibodies in Chinese surgical patients. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.transci.2012.07.013. The duplicate article has therefore been withdrawn. PMID- 23017809 TI - Glutamate receptor delta 1 (GRID1) genetic variation and brain structure in schizophrenia. AB - Common genetic variation in the promoter region of the glutamate receptor delta 1 (GRID1) gene has recently been shown to confer increased risk for schizophrenia in several independent large samples. We analysed high-resolution magnetic resonance imaging (MRI) data from 62 patients with schizophrenia and 54 healthy controls using voxel-based morphometry (VBM) to assess the effect of single nucleotide polymorphism rs3814614 (located in the GRID1 promoter region), of which the T allele was identified as a risk factor in a previous association study. There were no effects of genotype or group * genotype interactions on total brain grey matter or white matter, but on regional grey matter. In healthy subjects, we identified a significant effect of rs3814614 genotype in the anterior thalamus (bilaterally), superior prefrontal cortex, and orbitofrontal cortex - in all cases with the homozygous risk genotype TT resulting in higher grey matter density. We did not find this association within the schizophrenia sample, where rs3814614 variation was only associated with grey matter reduction in TT homozygous subjects in medial parietal cortex and increased grey matter in right medial cerebellum. For white matter, we did not find significant genotype effects in healthy controls, and only minor effects within schizophrenia patients in the posterior temporal lobe white matter. Our data indicate that GRID1 rs3814614 genotype is related to grey matter variation in prefrontal and anterior thalamic brain areas in healthy subjects, but not in patients indicating a potential role of this schizophrenia candidate gene in thalamo-cortical functioning. PMID- 23017810 TI - Quality of life in patients with primary aldosteronism: gender differences in untreated and long-term treated patients and associations with treatment and aldosterone. AB - Psychopathological symptoms in patients with primary aldosteronism (PA) have been reported. In a cross-sectional design the self-reported physical and mental condition among patients with PA of the German Conn's Registry differently treated during the course of the disease were analysed. 27 patients were investigated before initiation of specific therapy (U), 56 patients were on chronic mineralocorticoid antagonist treatment (MRA) and 49 patients had undergone adrenalectomy (ADX). Patient's quality of life was analysed with the SF 12 for a Physical (PCS) and a Mental Component (MCS). Statistically significant lower scores for PCS were found for female PA patients treated with MRA in comparison to ADX patients and the German reference population (36.4 +/- 11.1 vs. 49.1 +/- 10.9 (p = 0.024) vs. 47.9 +/- 9.7 (p = 0.001)), respectively. Concerning MCS, untreated female patients scored significantly lower (36.5 +/- 7.4) than females from the German population (51.3 +/- 8.4, p = 0.000). Furthermore, untreated females appear to differ significantly from MRA and ADX females, scoring the lowest reading (U vs. MRA: p = 0.029; U vs. ADX: p = 0.005). Significant correlations were found between plasma aldosterone (r = -0.819, p = 0.013) and the MCS and between plasma renin concentration and MCS (r = -0.938, p = 0.001) in female MRA patients. In summary, PA patients report a worse physical and mental condition than the one reported for the German reference population. Untreated and mineralocorticoid antagonist treated patients report the lowest readings. Females were found to be more impaired than males in QoL. MRA treatment seems to affect the MCS of female patients. PMID- 23017811 TI - Depression, anxiety and cognition in community-dwelling adults aged 70 years and over. AB - Although there is evidence of associations between anxiety, depression and cognitive function in old age, there is little work investigating relations between those variables over an extended period of time. Therefore, we used data from the Canberra Longitudinal Study to investigate 12-year cognitive change over four measurement points in relation to anxiety and depression symptoms. Latent growth models on over 836 community-dwelling persons aged 70 years and over, recruited from the electoral roll suggested that higher depression symptom scores were associated with poorer initial performance in processing speed, verbal fluency and episodic memory while higher anxiety symptom scores were associated with verbal fluency. We found no evidence that mental health variables affected change in cognition over time. Importantly, when possible mild cognitive impairment or dementia cases were removed from the models, associations between the cognitive variables and depression symptoms disappeared while those for anxiety symptoms strengthened. The findings are consistent with the possibility that depression-related cognitive deficits represent a prodrome or risk factor for dementia while associations between anxiety and cognition may be more characteristic of normal aging. PMID- 23017813 TI - Agoraphobia: an outreach treatment programme. AB - BACKGROUND: Agoraphobia is disabling and clients find it hard to access effective treatment. AIMS: This paper describes the development of an inexpensive service, delivered by trained volunteers in or near the client's own home. METHOD: We describe the development of the service, including selection, training and supervision. Outcomes were evaluated over 5 years, and compared with those available from the local psychology service. RESULTS: Effect sizes on all measures were high. Benchmarking indicated that results on comparable measures were not significantly different from the local psychology service. As in many previous studies drop-out rate was fairly high. CONCLUSIONS: This model worked well, and was inexpensive and effective. Further research on long term outcome and methods of enhancing engagement is needed. PMID- 23017812 TI - Evidence for stimulus-general impairments on auditory stream segregation tasks in schizophrenia. AB - BACKGROUND: Auditory impairments in schizophrenia have been demonstrated previously, especially for tasks requiring precise encoding of frequency, although it is unclear the extent to which they have difficulty using pitch information and other cues to segregate sounds. We determined the extent to which those with schizophrenia have difficulty using pitch information and other auditory cues to segregate sounds that are presented sequentially. METHODS: Ten participants with schizophrenia and nine healthy/normal control participants completed a battery of tasks that tested for the ability to perform sequential auditory stream segregation using pitch, amplitude modulation, or inter-aural phase difference as cues to segregation. RESULTS: All three sequential segregation tasks showed reduced tendency for those with schizophrenia to perceive segregated sounds, compared to control participants. CONCLUSIONS: These findings extend prior research by demonstrating a general impairment on sequential sound segregation tasks in schizophrenia, and not just on tasks that require precise encoding of frequency. Together, the pattern of results provide evidence that auditory impairments in schizophrenia result from selective abnormalities in neural circuits that carry out specific computations necessary for stream segregation, as opposed to an impairment in processing specific cues. PMID- 23017814 TI - Impact of accelerated ventricular tachyarrhythmias on mortality in patients with implantable cardioverter-defibrillator therapy. AB - BACKGROUND: Anti-tachycardia pacing (ATP) and shock delivery may induce or accelerate tachyarrhythmias in patients with implantable cardioverter defibrillator (ICD). We investigated the incidence, triggers and impact on mortality of accelerated ventricular tachyarrhythmias. METHODS: Database analysis concerning ventricular tachyarrhythmias accelerated by ATP or shock in 1275 ICD patients (age at implantation 59.7 +/- 14.0 years; 81% male). RESULTS: Within a mean follow-up period of 5.3 +/- 4.0 years, intracardiac electrograms were available in 1170 patients (91.8%). Overall 157 episodes of accelerated ventricular tachyarrhythmias were found in 100 of 1170 patients (8.5%). Termination of tachyarrhythmias was achieved by shock delivery in 153 episodes (96.8%). Triggers of accelerated tachyarrhythmias were appropriate ATP in 139 (88.5%) and inappropriate ATP in 14 (8.9%), as well as appropriate and inappropriate shocks in 2 (1.3%) episodes, respectively. Chronic heart failure was significantly correlated with the occurrence and recurrence of acceleration (p<0.001). Patients with accelerated ventricular tachyarrhythmia and subsequent shock therapy revealed higher all-cause mortality (HR 1.760; 95% CI 1.286-2.410; p<0.001) as well as higher cardiac mortality (HR 2.555; 95% CI 1.446-4.513; p=0.001). The correlation between acceleration and all-cause mortality was independent of left ventricular function (HR 2.076; 95% CI 1.633-2.639; p<0.001). CONCLUSIONS: Ventricular ATP with arrhythmia acceleration and subsequent shock delivery is a frequent and serious complication of ICD therapy that predominantly occurs in patients with reduced left ventricular function. Finally, occurrence of accelerated ventricular tachyarrhythmias was associated with increased all-cause mortality. PMID- 23017815 TI - Time-dependent Cox regression: serial measurement of the cardiovascular biomarker proadrenomedullin improves survival prediction in patients with lower respiratory tract infection. AB - BACKGROUND: The aim of this study was to determine the prognostic utility of serial measurement of the cardiovascular biomarker midregion proadrenomedullin (MR-proADM) in patients admitted with lower respiratory tract infection. In a previous trial in dyspneic patients (BACH trial) we could show that serial measurement of MR-proADM proves useful for risk assessment and patient monitoring. Models designed to evaluate serial biomarker measurements usually fail to answer two fundamental questions necessary to judge their clinical relevance: whether serial measurements provide additional information on top of the first measurement, and, if yes, at which time point a re-evaluation may be clinically useful. METHOD: We apply an adapted time-dependent Cox model to data from the ProHosp trial, a prospective trial, which was observational in regards to application of prognostic biomarkers, where blood draws for biomarker evaluation were collected at day of patient inclusion, days 3, 5 and 7. In this trial, the cardiovascular biomarker MR-proADM was evaluated for its ability to predict survival in comparison to clinical risk scores. RESULTS: With the adapted time-dependent Cox model, we could demonstrate a significant added value of the follow up measurements on top of that obtained on admission. Despite a high correlation between serial measurements, the gain can be observed as early as 3 days after inclusion. We illustrate the added prognostic value and clinical relevance of re-evaluation via Kaplan-Meier plots. CONCLUSION: We could demonstrate that the prognostic biomarker MR-proADM can potentially serve as a outcome monitoring marker in patients admitted with lower respiratory tract infections. PMID- 23017816 TI - The changing electrocardiogram in Brugada syndrome. PMID- 23017817 TI - Avicenna's view of reperfusion in myocardial infarction. PMID- 23017818 TI - Extraperitoneal para-aortic lymphadenectomy: laparoscopic single port approach. PMID- 23017819 TI - Parenchymal splenic metastasis is an independent negative predictor of overall survival in advanced ovarian, fallopian tube, and primary peritoneal cancer. AB - OBJECTIVE: The purpose of this study was to evaluate the significance of parenchymal splenic metastasis (PSM) in ovarian (OC), fallopian tube (FTC), and primary peritoneal cancer (PPC). METHODS: All patients with stage IIIB-IV OC, FTC, and PPC undergoing primary cytoreduction from 2001 to 2010 at our institution were identified. In patients undergoing splenectomy, pathology was reviewed for the presence of PSM. Multivariate Cox regression and Kaplan-Meier survival analysis were used to evaluate factors associated with overall survival (OS). RESULTS: Of 576 patients identified, stage was: IIIB - 23 (4%), IIIC - 468 (81.2%), and IV - 85 (14.8%). Optimal cytoreduction was achieved in 430 patients (74.7%), including 85 of 97 patients (87.6%) undergoing splenectomy. PSM was identified in 20 patients (20.6%) undergoing splenectomy, including 3 of 5 patients (60%) with radiographically identified parenchymal liver metastases and 17 of 92 patients (18.5%) without such radiographic findings (P=0.059). Age, preoperative albumin, residual disease, stage, bulky upper abdominal disease, IP chemotherapy, and PSM were associated with OS on univariate analysis. Splenectomy was not associated with survival. Age, preoperative albumin, residual disease, stage, and PSM (HR=0.46; 95% CI, 0.27-0.77) were associated with OS on multivariate analysis. In the subset of patients undergoing splenectomy, OS was lower for patients with PSM versus those without PSM (28.5 v 51.2months, P=0.004). CONCLUSIONS: PSM is independently associated with decreased OS in patients with advanced OC, FTC, and PPC. PSM occurs in the setting of other evidence of hematogenously disseminated disease, but also occurs outside this setting. PSM should be considered a criterion for stage IV disease. PMID- 23017820 TI - Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance -- a study of the OVCAD consortium. AB - OBJECTIVE: The study aims at identifying novel markers for circulating tumor cells (CTCs) in patients with epithelial ovarian cancer (EOC), and at evaluating their impact on outcome. METHODS: Microarray analysis comparing matched EOC tissues and peripheral blood leucocytes (N=35) was performed to identify novel CTC markers. Gene expression of these novel markers and of EpCAM was analyzed using RT-qPCR in blood samples taken from healthy females (N=39) and from EOC patients (N=216) before primary treatment and six months after adjuvant chemotherapy. All samples were enriched by density gradient centrifugation. CTC positivity was defined by over-expression of at least one gene as compared to the healthy control group. RESULTS: CTC were detected in 24.5% of the baseline and 20.4% of the follow-up samples, of which two thirds were identified by overexpression of the cyclophilin C gene (PPIC), and just a few by EpCAM overexpression. The presence of CTCs at baseline correlated with the presence of ascites, sub-optimal debulking, and elevated CA-125 and HE-4 levels, whereas CTC during follow-up occurred more often in older and platinum resistant patients. PPIC positive CTCs during follow-up were significantly more often detected in the platinum resistant than in the platinum sensitive patient group, and indicated poor outcome independent from classical prognostic parameters. CONCLUSIONS: Molecular characterization of CTC is superior to a mere CTC enumeration or even be the rationale for CTC diagnostics at all. Ultimately CTC diagnostics may lead to more personalized treatment of EOC, especially in the recurrent situation. PMID- 23017821 TI - Interaction of epithelial biomarkers, local immune response and condom use in cervical intraepithelial neoplasia 2-3 regression. AB - OBJECTIVE: Cervical intraepithelial neoplasia grades 2-3 (CIN2-3) are usually treated by cone excision, although only 30% progress to cancer and 6-50% regress spontaneously. Biomarkers predicting CIN2-3 regression would be of great clinical value and could reduce unnecessary cone excision and associated complications. The aim of this study was to investigate whether punch-biopsy derived immunohistochemical biomarkers, local immune response, CIN lesion size and condom use are independently correlated to regression of CIN2-3. METHODS: A prospective population-based cohort study of 162 women aged 25-40, with first-time onset diagnosis of CIN2-3 in colposcopy-directed biopsies was carried out. The median biopsy-cone interval was 16 weeks. Regression was defined as CIN1 or less in the cone biopsy. RESULTS: The regression rate was 21% (34/162). pRb>30% in the lower epithelial half was the strongest predictor for regression (30% regression, p<0.0001). If additionally a CIN-lesion was smaller than 2.5mm and CD4+ lymphoid cells in the subepithelial stroma <= 195 per 1.04 mm basal membrane, the regression rate was 53%. In CIN-lesions>2.5mm and CD4+-stroma <=195, consistent condom use increased the regression rate from 13% to 67% (p=0.003). If pRb was <=30%, the regression rate was low (6%). CONCLUSION: Biomarkers and CIN lesion length can predict CIN2-3 regression, and might be helpful to identify patients who can increase the regression rate of CIN lesions by consistent condom use. PMID- 23017822 TI - Multilocus phylogeny of the lichen-forming fungal genus Melanohalea (Parmeliaceae, Ascomycota): insights on diversity, distributions, and a comparison of species tree and concatenated topologies. AB - Accurate species circumscriptions are central for many biological disciplines and have critical implications for ecological and conservation studies. An increasing body of evidence suggests that in some cases traditional morphology-based taxonomy have underestimated diversity in lichen-forming fungi. Therefore, genetic data play an increasing role for recognizing distinct lineages of lichenized fungi that it would otherwise be improbable to recognize using classical phenotypic characters. Melanohalea (Parmeliaceae, Ascomycota) is one of the most widespread and common lichen-forming genera in the northern Hemisphere. In this study, we assess traditional phenotype-based species boundaries, identify previously unrecognized species-level lineages and discuss biogeographic patterns in Melanohalea. We sampled 487 individuals worldwide, representing 18 of the 22 described Melanohalea species, and generated DNA sequence data from mitochondrial, nuclear ribosomal, and protein-coding markers. Diversity previously hidden within traditional species was identified using a genealogical concordance approach. We inferred relationships among sampled species-level lineages within Melanohalea using both concatenated phylogenetic methods and a coalescent-based multilocus species tree approach. Although lineages identified from genetic data are largely congruent with traditional taxonomy, we found strong evidence supporting the presence of previously unrecognized species in six of the 18 sampled taxa. Strong nodal support and overall congruence among independent loci suggest long-term reproductive isolation among most species level lineages. While some Melanohalea taxa are truly widespread, a limited number of clades appear to have much more restricted distributional ranges. In most instances the concatenated gene tree and multilocus species tree approaches provided similar estimates of relationships. However, nodal support was generally higher in the phylogeny estimated from concatenated data, and relationships among taxa within one major clade were largely unresolved in the species tree. This study contributes to our understanding of diversity and evolution in common lichen-forming fungi by incorporating multiple locus sequence data to circumscribe morphologicallly cryptic lineages and infer relationships within a coalescent-based species tree approach. PMID- 23017823 TI - Prolonged exposure times of one-step self-etch adhesives on adhesive properties and durability of dentine bonds. AB - OBJECTIVES: To evaluate the effect of prolonged exposure times on immediate and 6 month adhesive properties: degree of conversion (DC), nanoleakage (NL) and resin dentine bond strength (MUTBS) of three one-step self-etch adhesive systems (Adper Easy One [EO], Clearfil S(3) Bond [CS3] and Go [GO]). MATERIAL AND METHODS: The adhesives were applied on exposed dentine surfaces of 90 human molars according to manufacturers' instructions and light polymerized for 10, 20, and 40 s at 600 mW/cm(2). Bonded teeth were sectioned to obtain stick-shaped specimens (0.8 mm(2)) and tested under tensile stress (0.5 mm/min) immediately (IM) or after 6 months of water storage. Two bonded sticks from each tooth at each storage time interval were analysed by SEM for NL evaluation. The in situ DC was evaluated by micro-Raman spectroscopy. Data were analysed by appropriate ANOVA and Tukey's test (alpha = 0.05). RESULTS: Prolonged exposure times significantly increased the DC (%) (10 s [67.4 +/- 17.3]; 20 s [85.9 +/- 8.9] and 40 s [85.2 +/- 9.0]) and decreased the NL (%) (10 s [24.8 +/- 13.2]; 20 s [13.3 +/- 7.5] and 40 s [13.5 +/- 9.3]) for all adhesives; however it did not increase the IM MUTBS for two (EO, GO) out of the three adhesives. Furthermore, this technique did not minimize dentine bond degradation. CONCLUSION: Although longer exposure times than those recommended could not prevent degradation of dentine bonds, they could increase DC within the hybrid layer and reduced NL for all adhesives tested. PMID- 23017824 TI - Does congenital trichinellosis exist? PMID- 23017825 TI - Cognitive and clinical predictors of functional capacity in patients with first episode schizophrenia. AB - BACKGROUND: The predictors of functional capacity in first episode schizophrenia among seven separable cognitive domains and clinical variables are unknown. AIM: To investigate predictors of functional capacity in first episode schizophrenia and the associations between functional capacity and measures of real-world functioning. METHODS: Socio-demographic, clinical, and cognitive measures from a sample of patients with first episode schizophrenia spectrum disorders aged 18 34years (N=117) were examined at baseline, 4-month follow-up, and 10-month follow up and used to predict concurrent and longitudinal functional capacity. Symptoms were assessed with the Positive and Negative Syndrome Scale, cognitive functioning with the MATRICS Cognitive Consensus Battery, and functional capacity with the brief version of the University of California San Diego Performance based Skills Assessment. Linear and logistic regression analyses were adjusted for age, gender, and site. RESULTS: Working memory, negative symptoms, and social cognition accounted for 41% of the variance in functional capacity at baseline. Longitudinally, verbal learning, working memory, and negative symptoms predicted 4-month functional capacity. Working memory and visual learning predicted 10 month functional capacity. Functional capacity was associated to global functioning in the univariate analysis, but in multivariable analyses global functioning, financial independence, and independent living were predicted by negative symptoms or general symptoms explaining 15-23% of the variance. CONCLUSIONS: The strongest single predictor of functional capacity is working memory, followed by negative symptoms. Clinical symptoms, but not functional capacity, predicted real-world functioning. The usability of the UPSA-B in first episode schizophrenia is discussed. Neurocom, ClinicalTrials.gov Identifier: NCT00472862, http://clinicaltrials.gov/ct2/show/NCT00472862?term=neurocom&rank=1. PMID- 23017826 TI - Genetic variation at the synaptic vesicle gene SV2A is associated with schizophrenia. AB - Convergent evidence from pharmacological and animal studies suggests a possible role for the synaptic vesicle glycoprotein 2A gene (SV2A) in schizophrenia susceptibility. To test systematically all common variants in the SV2A gene region for an association with schizophrenia, we used a HapMap-based haplotype tagging approach and tested five SNPs in 794 patients and 843 controls. The SNP rs15931 showed evidence for an association with schizophrenia and was followed-up in an independent sample of 2581 individuals (overall p-value=0.0042, OR=0.779). Our study in the German population provides evidence, at a genetic level, for the involvement of the SV2A gene region in schizophrenia. PMID- 23017827 TI - REPYFLEC cognitive remediation group training in schizophrenia: Looking for an integrative approach. AB - BACKGROUND: Overall results from Cognitive Remediation (CR) indicate robust and long-lasting effects with medium effect size on global cognition and functioning, and a small ES on symptoms present at post-treatment but not at follow-up. However, results are not the same in all CR therapies and in some cases no efficacy results are achieved. AIMS: To develop an integrative intervention taking into account previous efficacious therapies. To evaluate the efficacy of our cognitive remediation group training: Problem Solving and Cognitive Flexibility training (REPYFLEC), with the aim of improving cognition and functioning in schizophrenia patients. METHOD: Participants with a diagnosis of schizophrenia or schizoaffective disorder (n=62) were randomized to 32 group sessions of REPYFLEC CR, or to 32 group sessions of activities without specific objectives and focused on leisure. In both groups the sessions were conducted twice a week. Functioning and psychiatric symptoms were measured at baseline (week 0) and thereafter at 8, 16 and 40 weeks. Cognition was measured at weeks 0, 16 and 40. Mixed Models were used to estimate statistical differences. RESULTS: Patients in the cognitive remediation group demonstrated significant improvements in executive function, negative symptoms and functioning at post-treatment compared with patients in the control group. At 6-month follow-up, significant improvements in executive function and functioning remained. CONCLUSION: These results apparently show that REPYFLEC works as cognitive remediation training, improving executive thinking and functioning outcomes compared with a control group. PMID- 23017828 TI - Evaluation of different stimulation and measurement patterns based on internal electrode: application in cardiac impedance tomography. AB - The conductivity distribution around the thorax is altered during the cardiac cycle due to the blood perfusion, heart contraction and lung inflation. Previous studies showed that these bio-impedance changes are appropriate for non-invasive cardiac function imaging using Electrical Impedance Tomography (EIT) techniques. However, the spatial resolution is presently low. One of the main obstacles in cardiac imaging at the heart location is the large impedance variation of the lungs by respiration and muscles on the dorsal and posterior side of the body. In critical care units there is a potential to insert an internal electrode inside the esophagus directly behind the heart in the same plane of the external electrodes. The aim of the present study is to evaluate different current stimulation and measurement patterns with both external and internal electrodes. Analysis is performed with planar arrangement of 16 electrodes for a simulated 3D cylindrical tank and pig thorax model. In our study we evaluated current injection patterns consisting of adjacent, diagonal, trigonometric, and radial to the internal electrode. The performance of these arrangements was assessed using quantitative methods based on distinguishability, sensitivity and GREIT (Graz consensus Reconstruction algorithm for Electrical Impedance Tomography). Our evaluation shows that an internal electrode configuration based on the trigonometric injection patterns has better performance and improves pixel intensity of the small conductivity changes related to heart near 1.7 times in reconstructed images and also shows more stability with different levels of added noise. For the internal electrode, when we combined radial or adjacent injection with trigonometric injection pattern, we found an improvement in amplitude response. However, the combination of diagonal with trigonometric injection pattern deteriorated the shape deformation (correlation coefficient r=0.344) more than combination of radial and trigonometric injection (correlation coefficient r=0.836) for the perturbations in the area close to the center of the cylinder. We also find that trigonometric stimulation pattern performance is degraded in a realistic thorax model with anatomical asymmetry. For that reason we recommend using internal electrodes only for voltage measurements and as a reference electrode during trigonometric stimulation patterns in practical measurements. PMID- 23017829 TI - Genome-wide computational approach for the prediction of duplications generating protein localization signals. AB - Investigating the possible generation of motifs accountable for aberrant protein dislocation subsequent to the rise of short tandem duplications is interesting, given the pathogenic potential of this mechanism, as demonstrated in diseases such adult myeloid leukemia (AML). In this paper we introduce a new computational method for predicting genomic points which, after hypothetical mutation events such as micro-duplications, might encode molecular patterns such as localization or export signals. The proposed framework allows to study motifs of unconstrained length defined as regular expressions at a genome-wide level, providing an in silico platform capable of analyzing the potential effect of duplications on abnormal cellular localization. PMID- 23017830 TI - Chest pain, fever and vesicular rash presenting as symptoms of Sweet syndrome. PMID- 23017831 TI - Full-length genome analysis of G2, G9 and G11 porcine group A rotaviruses. AB - Group A rotaviruses with G2 and G9 VP7 specificity are common in humans, while G11 strains have been detected only sporadically. G2, G9 and G11 rotaviruses also circulate in pigs and swine rotaviruses have been suspected of interspecies and zoonotic transmissions in numerous studies. However, the complete gene constellation of G2 and G9 porcine rotaviruses has not yet been determined. In order to start filling this gap, the genomic make up of two G2, one G9 and one G11 porcine rotavirus strains, detected in Canada in 2005-2007, was determined. With the exception of a G2P[34] strain, with E9 NSP4 type and mixed I5+I14 VP6 type, the constellation of genomic segments was rather conserved and were closely related to prototype porcine strains in the four viruses characterized (I5-R1-C1 M1-A8-N1-T7-E1-H1). Most notably, all the viruses displayed a rare NSP3 genotype, T7, which has also been identified in rare human reassortant strains and in the reference strain RVA/Cow-tc/GBR/UK/1973/G6P[5]. This study provides crucial genetic data on these complex viruses and will help understand the origin and ecological niche of gene segments and the role played by pigs in their evolution. PMID- 23017832 TI - MiR-135a promotes growth and invasion of colorectal cancer via metastasis suppressor 1 in vitro. AB - MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases. The miR-135a is considered to be oncogenic; however, the functions and mechanisms of miR-135a in colorectal cancer (CRC) are largely unknown. Thus, we investigated the functions and mechanisms of miR-135a, especially its relationship with the metastasis suppressor 1 (MTSS1) gene in CRC. The expression of miR-135a was determined by real-time polymerase chain reaction, while its effect on cell proliferation, migration, and invasion was determined by MTT, without and with matrigel, respectively. The expression of MTSS1 was detected by western blot analysis. It was found that miR-135a expression was higher in human CRC samples than in non tumor control tissue. Using SW480 and SW620 CRC cell lines, increased proliferation was observed in response to miR-135a. We also demonstrated that miR 135a promoted mobility and invasion via transwell assay with and without Matrigel, respectively, of CRC cells. In contrast, inhibition of miR-135a reduced their proliferative and invasive capability. MTSS1 was identified as a candidate target gene of miR-135a by luciferase report assay. Western blot analysis showed that the expression of MTSS1 was regulated by miR-135a overexpression and knockdown. Similarly, miR-135a-mediated cell mobility and invasion were reduced after MTSS1 was knocked down by small interfering RNA. These data indicated that miR-135a promotes the growth and invasion of CRC cells, at least partially, through targeting MTSS1. PMID- 23017833 TI - Curcumin potentiates the antitumor effects of 5-FU in treatment of esophageal squamous carcinoma cells through downregulating the activation of NF-kappaB signaling pathway in vitro and in vivo. AB - Although constitutive activation of nuclear factor-kappaB (NF-kappaB) signaling pathway has been reported in multiple different human tumors, the role of NF kappaB pathway in esophageal squamous cell carcinoma (ESCC) remains ill-defined. Abundant sources have provided interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancer. In this study, we first analyzed the status of NF-kappaB pathway in the two ESCC cell lines Eca109 and EC9706, and then further investigated whether curcumin alone or in combination with 5-fluorouracil (5-FU) could modulate NF-kappaB pathway in vitro and in vivo. The results showed that NF-kappaB signaling pathway was constitutively activated in the ESCC cell lines. Curcumin suppressed the activation of NF-kappaB via the inhibition of IkappaBalpha phosphorylation, and downregulated the expressions of Bcl-2 and CyclinD1 in ESCC cell lines. Curcumin combined with 5-FU led to the lower cell viability and higher apoptosis than 5-FU treated alone. In a human ESCC xenograft model, curcumin or 5-FU alone reduced the tumor volume, but their combination had the strongest anticancer effects. Besides, curcumin could also inhibit NF-kappaB signaling pathway through downregulation of the IkappaBalpha phosphorylation and induction of cell apoptosis in vivo. Overall, our results indicated that constitutively activated NF-kappaB signaling pathway exists in the two ESCC cells and the chemopreventive effects of curcumin were associated with downregulation of NF-kappaB signaling pathway and its downstream genes. PMID- 23017834 TI - Lentiviral-mediated gene transfer into human adipose-derived stem cells: role of NELL1 versus BMP2 in osteogenesis and adipogenesis in vitro. AB - NEL-like molecule 1 (NELL1) is a potent osteogenic factor associated with craniosynostosis. Adenoviruses, the most commonly used viral vectors for gene therapy, have several disadvantages that may restrict osteogenesis. Previous studies have shown that lentiviruses can serve as ideal vectors for gene therapy for bone regeneration. In this study, two lentiviral vectors (LvNELL1 and LvBMP2) that encode human NELL1 and bone morphogenetic protein-2 (BMP2), respectively, were constructed. The effect of LvNELL1 infection on the proliferation, osteogenesis, and adipogenesis of human adipose-derived stem cells (hADSCs) in vitro was assessed and compared with that of LvBMP2. The results showed that hADSCs infected with LvNELL1 could efficiently and stably overexpress the target genes. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay results demonstrated that LvBMP2, but not LvNELL1, enhanced the proliferation of hADSCs. Assessment of alkaline phosphatase activity and cellular mineralization indicated that LvNELL1 infection promoted the osteogenic differentiation of hADSCs, and the effect was comparable with that of LvBMP2. Real-time polymerase chain reaction (PCR) revealed that LvNELL1 infection upregulated OSX expression but not RUNX2 expression in hADSCs. In addition, adipogenic markers (lipid droplets, peroxisome proliferator-activating receptor gamma, and lipoprotein lipase) analysis showed that LvNELL1 could dramatically inhibit the adipogenic differentiation of hADSCs, but LvBMP2 had no such effect. Taken together, these findings suggested that lentiviral-mediated NELL1 gene transfer in hADSCs may be a novel and promising approach to achieve effective and precise bone regeneration. PMID- 23017835 TI - The comprehensive effects of hyperlipidemia and hyperhomocysteinemia on pathogenesis of atherosclerosis and DNA hypomethylation in ApoE-/- mice. AB - Atherosclerosis (AS) is a disease induced by multiple factors, including genetic and environmental elements. The aim of the present study is to investigate the comprehensive effects of high cholesterol, high methionine diet, and apolipoprotein E deficiency (ApoE(-/-)) on the pathogenesis of AS. ApoE(-/-) mice were fed with high cholesterol and methionine diet for 15 weeks to induce hyperlipidemia and hyperhomocysteinemia. The methylation levels of genomic DNA (gDNA) and B1 repetitive elements in aortic tissues were measured by both methylation-dependent restriction analysis and nested methylation-specific polymerase chain reaction (PCR). Methylation sequence-bias pattern was assayed by DNA methyl-accepting capacity with restriction endonuclease digestion. The mRNA expression of DNA methyltransferase-1, 3 (DNMT1, 3) was detected by real-time PCR. The concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were determined by high-performance liquid chromatography. The results showed hypomethylation of gDNA and B1 repetitive elements. The mRNA expression of DNMT1 was reduced. The levels of SAM, SAH, and SAM/SAH ratio were increased. The atherosclerotic lesion areas strongly correlated with the risk factors. The distribution of DNA demethylation was preferred to non-CpG islands, which may suggest the major impact of hypomethylation on DNA integrity and genomic instability. Overall, our data unequivocally showed that the comprehensive role of high cholesterol, high methionine diet, and ApoE(-/-) is not uniformly consistent with the role of a single risk factor. The DNA methylation pattern in AS is quite complex and depends on genetic background and many involved risk factors. PMID- 23017836 TI - Cloning and primary characterizations of rLcn9, a new member of epididymal lipocalins in rat. AB - Lipocalins are a structurally conserved and diversely functional family of proteins that are of potential importance in epididymis functions. The rat Lcn9 gene was cloned by in silico methods and genome walking based on homology to the rhesus monkey epididymal ESC513 and its polyclonal antisera were prepared. The rat Lcn9 gene is located on chromosome 3p13 spanning 7 exons, contains 2.3 kb and encodes 179 amino acids with a 17-amino acid signal peptide. Northern blot, western blot, and immunohistochemical staining analysis revealed that rat Lcn9 was a novel epididymis-specific gene, expressed selectively in the proximal caput region, influenced by luminal fluid testicular factors. Moreover, Lcn9 protein was modified by N-glycosylation and bound on the postacrosomal domain of caput sperm. In conclusion, the rat Lcn9 exhibited tissue-, region-, and temporal specific expression patterns and its expression was regulated by luminal testicular factors. Its potential roles in sperm maturation are discussed. PMID- 23017837 TI - Heteroexpression of the wheat phytochelatin synthase gene (TaPCS1) in rice enhances cadmium sensitivity. AB - Phytochelatin synthase (PCS) (EC 2.3.2.15) catalyzes the final step of phytochelatins (PCs) biosynthesis. PCs are a family of cysteine-rich thiol reactive and heavy metal-binding peptides that play an important role in sequestration and detoxification of heavy metals in plants. Previous studies have indicated that plants that overexpressed PCS displayed contrasting phenotypes, ranging from enhanced cadmium (Cd) tolerance to Cd hypersensitivity in Arabidopsis thaliana. In this study, the wheat phytochelatin synthase gene, TaPCS1, was heteroexpressed in wild-type rice (Oryza sativa L., cv. Zhonghua 11) to evaluate the relationship between synthesis of PCs and Cd tolerance in rice. Data showed that the heteroexpression of TaPCS1 in rice enhanced Cd sensitivity and significantly increased Cd accumulation in shoots, but not in roots. Additionally, the PCS line exhibited a much higher content of PCs and non-protein thiols (NPTs) in shoots. Prominent changes in NPT composition led to reduced glutathione pool depletion and higher Cd content in cell organelles in shoots, followed by higher oxidative stress, which might result in Cd sensitivity. Therefore, the heteroexpression of TaPCS1 in rice is capable of increasing Cd accumulation in rice shoots and enhancing Cd sensitivity. PMID- 23017838 TI - The female millipede reproductive system and its dynamical changes, with a partial review. AB - The structure of the millipede female reproductive system is described, discussed and reviewed. The different reproductive systems of female millipedes are illustrated, some of them for the first time. The various families appear to have developed several different structures of this organ. Nevertheless, more detailed studies on the female reproductive systems, especially the changes taking place during the oogenetic cycle, are needed in all millipede orders. Only this way can it be ascertained, whether ovarian structures observed are not only a transitional phase. This was done in two millipedes, Archispirostreptus tumuliporus judaicus (Attems 1927) and Catamicrophyllum caifanum (Verhoeff 1900), where these changes were followed for a longer period of time and on a large number of specimens. The evolutionary meaning of this diversity in reproductive systems cannot be clarified at the present time, nor its significance for the survival of the such diversified forms in the Class Diplopoda. PMID- 23017839 TI - Formation of median nerve from single root on left side and communicating branch from median nerve to musculocutaneous nerve on right side. AB - We report here a rare variation of median nerve in an adult male cadaver observed during routine cadaveric dissection. A meticulous dissection was performed and the observations were noted. On left side, median nerve was formed from lateral cord. On right side, median nerve was formed by fusion of two slightly longer roots. The communicating branch from median nerve goes laterally to join musculocutaneous nerve. This communicating branch lies between biceps brachii and brachialis muscle and gives small branches to brachialis muscle. Knowledge of these variations is important to anatomists, radiologists, anaesthesiologists and surgeons, which may contribute to the explanation of diagnosis and surgical treatment, which can prevent any postoperative complications during surgery. The knowledge of this anatomical variation is important specially when performing plexus bloc or Latarjet's procedure. PMID- 23017840 TI - Do Fitflops increase lower limb muscle activity? AB - BACKGROUND: Fitness toning shoes are becoming increasingly popular, they aim to increase muscle activity, raise energy expenditure and improve overall health while wearing them. Yet there is a lack of consensus in the literature regarding their effectiveness. One such shoe on the market is the Fitflop designed to activate leg muscles through density shifts in the shoe's sole. The purpose of this study was to investigate the effect of wearing Fitflops on the muscle activity of the lower limb. METHODS: Twenty three females (age 20.8 (1.3)years, mass 62.9 (11.9)kg, height 165.4 (5.6)cm) participated in the study. Muscle activity of the medial gastrocnemius, biceps femoris, rectus femoris and gluteus maximus of the participants' right limb were recorded using surface electromyography during participation in three different tasks to simulate daily living activities. These were a) treadmill walking b) stair climbing and c) zigzag walking around cones. The participants completed the tasks barefoot, while wearing Fitflops and while wearing regular flip flops so that comparisons between muscle activity in the different shoe conditions could be made. FINDINGS: The results show that there was no significant difference in the activity of the medial gastrocnemius, biceps femoris, rectus femoris and gluteus maximus muscles across all shoe conditions and simulated daily activities (P>0.05). INTERPRETATION: Based on these results, the use of Fitflops is not recommended as a means of increasing muscle activity of the medial gastrocnemius, biceps femoris, rectus femoris and gluteus maximus during activities of daily living in a healthy recreationally active female population. PMID- 23017841 TI - Familial testicular torsion: a meta analysis suggests inheritance. AB - OBJECTIVE: Familial occurrence of testicular torsion has been infrequently reported. To date, no systematic analysis has been published. We systematically analyzed the literature to elucidate the epidemiology, presentation, management, and whether the observed prevalence of testicular torsion in families is consistent with absence of inheritance and is randomly distributed. PATIENTS AND METHODS: We searched electronic databases using keywords "testicular torsion", "spermatic cord torsion", "familial torsion" and "sibling torsion". Reports with genetically related first degree relatives were included in the analysis. Levene's nonparametric test was used to compare the variance of the age of presentation within families to that between different families to differentiate between familial predisposition and chance events. RESULTS: Up to 10% of patients with testicular torsion have an affected first degree relative. We were able to reject the null hypothesis that the observed prevalence of testicular torsion is due to chance (p < 0.001). Family history is missed in at least 27% of affected families. There is a high incidence of bilateral testicular torsion in families (37%) and probands (17%) and a high concordance rate for bilaterality among monozygous twins. CONCLUSIONS: Current evidence from clinical and animal studies suggests the presence of a genetically determined component in familiar testicular torsion. Increased awareness may lead to earlier clinical presentation and higher testicular salvage rates. PMID- 23017842 TI - Schmallenberg virus as possible ancestor of Shamonda virus. AB - Schmallenberg virus (SBV), an orthobunyavirus of the Simbu serogroup, recently emerged in Europe and has been suggested to be a Shamonda/Sathuperi virus reassortant. Results of full-genome and serologic investigations indicate that SBV belongs to the species Sathuperi virus and is a possible ancestor of the reassortant Shamonda virus. PMID- 23017844 TI - Same-sex parenting and children's outcomes: A closer examination of the American psychological association's brief on lesbian and gay parenting. AB - In 2005, the American Psychological Association (APA) issued an official brief on lesbian and gay parenting. This brief included the assertion: "Not a single study has found children of lesbian or gay parents to be disadvantaged in any significant respect relative to children of heterosexual parents" (p. 15). The present article closely examines this assertion and the 59 published studies cited by the APA to support it. Seven central questions address: (1) homogeneous sampling, (2) absence of comparison groups, (3) comparison group characteristics, (4) contradictory data, (5) the limited scope of children's outcomes studied, (6) paucity of long-term outcome data, and (7) lack of APA-urged statistical power. The conclusion is that strong assertions, including those made by the APA, were not empirically warranted. Recommendations for future research are offered. PMID- 23017843 TI - Scarlet fever outbreak, Hong Kong, 2011. PMID- 23017845 TI - How different are the adult children of parents who have same-sex relationships? Findings from the New Family Structures Study. AB - The New Family Structures Study (NFSS) is a social-science data-collection project that fielded a survey to a large, random sample of American young adults (ages 18-39) who were raised in different types of family arrangements. In this debut article of the NFSS, I compare how the young-adult children of a parent who has had a same-sex romantic relationship fare on 40 different social, emotional, and relational outcome variables when compared with six other family-of-origin types. The results reveal numerous, consistent differences, especially between the children of women who have had a lesbian relationship and those with still married (heterosexual) biological parents. The results are typically robust in multivariate contexts as well, suggesting far greater diversity in lesbian-parent household experiences than convenience-sample studies of lesbian families have revealed. The NFSS proves to be an illuminating, versatile dataset that can assist family scholars in understanding the long reach of family structure and transitions. PMID- 23017846 TI - The well-being of children with gay and lesbian parents. PMID- 23017847 TI - What can we learn from studies of children raised by gay or lesbian parents? PMID- 23017848 TI - Further comments on the papers by Marks and Regnerus. PMID- 23017849 TI - "We see what we seek": A rejoinder to the responses of Amato, Eggebeen, and Osborne. PMID- 23017850 TI - Response to paul amato, david eggebeen, and cynthia osborne. PMID- 23017851 TI - Neighborhood poverty and children's exposure to danger: Examining gender differences in impacts of the Moving to Opportunity experiment. AB - The Moving to Opportunity (MTO) program offered public housing residents in distressed communities a chance to move to low-poverty neighborhoods. The present study examined whether the resulting decline in neighborhood poverty led to lower levels of exposure to danger among children and youth ages 8-19years old (n=4606), and specifically, if there was a gender difference that matched the pattern of more beneficial program effects for girls and more adverse affects for boys. The study goes beyond previous research by using fixed effects to control for family factors that may influence moving behavior and confound estimates of gender differences in program impacts. Results showed that children experienced a decline in exposure to danger, with one key gender difference. Models based on brother-sister comparisons indicated that MTO had a more beneficial impact on exposure to drug activity for females than males. The findings suggest that neighborhood poverty is tied to children's exposure to danger. Moreover, exposure to drug activity may help explain the gender differences in impacts on children's mental health and risky behavior. PMID- 23017852 TI - Neighborhood disorder and individual economic self-sufficiency: New evidence from a quasi-experimental study. AB - This paper draws on data from the Monitoring Mt. Laurel Study, a new survey-based study that enables us to compare residents living in an affordable housing project in a middle-class New Jersey suburb to a comparable group of non residents. Building on the theoretical and empirical contributions of the Gautreaux and Moving to Opportunity studies, we test the hypothesis that living in this housing project improves a poor person's economic prospects relative to what they would have experienced in the absence of such housing, and that these improved prospects can be explained at least in part by reduced exposure to disorder and stressful life events. We find that residents in the Ethel Lawrence Homes are significantly less likely to experience disorder and negative life events and that this improvement in circumstances indirectly improves the likelihood of being employed, their earnings, and the share of income from work. We find no relationship between residence in the housing project and the likelihood of using welfare. PMID- 23017853 TI - Family structure and obesity in early childhood. AB - This study informs family and child health research by using longitudinal Fragile Families data to assess how family structure and transitions are associated with changes in children's BMI and weight status between ages three and five. Concerns in family structure literature about biases due to selectivity are reduced through the use of change score models and by controlling for parental BMI. The findings indicate unhealthy BMI gain and an increased risk of becoming overweight/obese among children living with a mother who recently dissolved a union or had been living without a partner for at least 2years compared with those in stable married parent families. Children with single mothers who entered a new union had significantly healthier BMI trajectories than those whose mothers remained single or recently became single. These results suggest the importance of two-parent family contexts for children's healthy physical development, and that single mothers may need additional support to better manage their children's BMI. PMID- 23017854 TI - Apron strings of working mothers: Maternal employment and housework in cross national perspective. AB - This paper asks whether maternal employment has a lasting influence on the division of household labor for married women and men. Employing multi-level models with 2002 ISSP survey data for 31 countries, we test the lagged accommodation hypothesis that a long societal history of maternal employment contributes to more egalitarian household arrangements. Our results find that living in a country with a legacy of high maternal employment is positively associated with housework task-sharing, even controlling for the personal socialization experience of growing up with a mother who worked for pay. In formerly socialist countries, however, there is less gender parity in housework than predicted by the high historical level of maternal employment. PMID- 23017855 TI - Buffering income loss due to unemployment: Family and welfare state influences on income after job loss in the United States and western Germany. AB - This article analyzes how the family and the welfare state influence household income trajectories after job loss in the United States and in western Germany. Drawing on panel data from the Panel Study of Income Dynamics (PSID) and the German Socio-Economic Panel (GSOEP), I study the income buffering effects of the family and the welfare state in the short an in the long run after job loss. I demonstrate that household income trajectories after job loss in the two countries are similar for couple households. However, men in the United States rely relatively more on family resources to overcome income loss, whereas German men's incomes are secured mostly by the welfare state. Women's unemployment in both countries is mainly buffered by their partners' higher earnings. Because single households have no access to family support, they face much higher losses in the United States than in Germany. I also show that the more generous German welfare state triggers less private self-help in the form of increased labor force participation on the part of women when their partners lose their jobs. Over time, the family has become more important in buffering incomes after job loss in the United States which smoothed men's and roughened women's income trajectories in couple households. In Germany, worsening re-employment chances increased income losses in the long run after job loss. PMID- 23017856 TI - Family environments and the relationship context of first adolescent sex: Correlates of first sex in a casual versus steady relationship. AB - Limited research has examined how family environments are associated with the relationship context of first sex, an important indicator of reproductive health risk. We use data from the 1997 National Longitudinal Survey of Youth to assess the association between the family environment - parent-parent relationships, parent-adolescent relationships, and family structure - and relationship context of first heterosexual sexual intercourse, distinguishing between the transition to first sex in serious and casual relationships. Twenty-five percent of females and 43% of males who had sex by age 18 did so in a casual relationship. All dimensions of the family environment were linked to the relationship context of first sex. Notably, higher parental monitoring was associated with a reduced risk of transitioning to first sex in a casual relationship versus no sex, and greater family routines were associated with a reduced risk of transitioning to sex in a steady relationship versus having no sex, for males and females. A strong maternal-adolescent relationship was associated with a reduced risk of first sex in a casual relationship but only for males. Additionally, in two-parent families, a strong father-adolescent relationship was associated with reduced risk of transitioning to casual sex, but only for females. Pregnancy and STI prevention programs should work with parents to foster positive parent-adolescent relationships, to become aware of their adolescents' activities and to recognize that parents are important models for adolescent relationship behaviors. PMID- 23017857 TI - Family structure and the reproduction of inequality: Parents' contribution to children's college costs. AB - This article examines the role of family structure in the financial support parents provide for their children's college education. Data are from the Health and Retirement Study. We focus on aspects of family structure that affect parental support and estimate shared family variance in investments as well as within-family variation using a multilevel model. Family membership accounts for about 60% of the variance in payment of college costs. Small family size, living with both biological parents (compared to one biological parent and a stepparent), higher parental education, and having older parents are associated with greater parental expenditures. PMID- 23017858 TI - Different preferences or different opportunities? Explaining race differentials in the academic achievement of friends. AB - A popular explanation for race and ethnic disparities in academic achievement is that minorities are exposed to different peers and have different opportunities to make friends with high-achievers. Although we know that adolescents from different race and ethnic groups attend different schools and that they choose different friends, we do not know how these different opportunities affect the friends they make. This paper fills this gap by studying how the opportunities within adolescents' schools affect race and ethnic differences in the academic characteristics of friends. Using data from the National Longitudinal Study of Adolescent Health and the conditional logit and opportunities framework, I account for adolescents' different opportunities to make friends both within and across schools. Ignoring their different opportunities, Black and Latino adolescents' nominated friends have significantly lower levels of achievement than white adolescents. After accounting for their different opportunities to make friends within and between schools, race and ethnic differences in the achievement characteristics of friends disappear. If Black and Latino adolescents' opportunity structures were identical to white adolescents', their probabilities of nominating high-achieving friends would not differ. PMID- 23017859 TI - Stepping stones: Principal career paths and school outcomes. AB - More than one out of every five principals leaves their school each year. In some cases, these career changes are driven by the choices of district leadership. In other cases, principals initiate the move, often demonstrating preferences to work in schools with higher achieving students from more advantaged socioeconomic backgrounds. Principals often use schools with many poor or low-achieving students as stepping stones to what they view as more desirable assignments. We use longitudinal data from one large urban school district to study the relationship between principal turnover and school outcomes. We find that principal turnover is, on average, detrimental to school performance. Frequent turnover of school leadership results in lower teacher retention and lower student achievement gains. Leadership changes are particularly harmful for high poverty schools, low-achieving schools, and schools with many inexperienced teachers. These schools not only suffer from high rates of principal turnover but are also unable to attract experienced successors. The negative effect of leadership changes can be mitigated when vacancies are filled by individuals with prior experience leading other schools. However, the majority of new principals in high poverty and low-performing schools lack prior leadership experience and leave when more attractive positions become available in other schools. PMID- 23017860 TI - The impact of the promise of scholarships and altering school structure on college plans, preparation, and enrollment. AB - The Washington State Achiever (WSA) program was a large-scale educational intervention of scholarships, mentoring, and school redesign designed to encourage students from moderate and low income families to attend college in Washington State. Using a quasi-experimental design based on pre- and post intervention surveys of high school seniors in program and non-program schools, we find a significant WSA effect on educational outcomes, net of the demographic and socioeconomic composition of students across schools. Across the three intervention high schools, the program is strongly significant in one school, significant after a lag in another school, and not significant in a third. We speculate about the potential reasons for the differential program effect across high schools. PMID- 23017861 TI - Shaking things up or business as usual? The influence of female corporate executives and board of directors on women's managerial representation. AB - Previous theory and research suggests that workplace gender composition at the highest organizational levels should play a crucial role in reducing gender linked inequalities in the workplace. In this article, we examine how the presence of women in top corporate positions influences female managerial representation at the establishment-level. Using a unique multi-level dataset of 5679 establishments nested within 81 Fortune 1000 corporations, we find that having more women on corporate boards, but not in executive positions, at the firm-level is associated with greater female managerial representation at the establishment-level. The results also show that women are more likely to be in management positions when employed in young, large, and managerially intensive workplaces, as well as those with a larger percentage of female non-managers. Implications for future research and policy implementation are discussed. PMID- 23017862 TI - Who is the better applicant? Effects from gender, academic record, and type of decision. AB - This experiment recreates several features of the selection of candidates for junior professional positions. The situation of central interest involves an assessor (either male or female) and a pair consisting of a male and a female applicant with either equivalent or slightly different academic records. We also investigate effects from quality of record (either excellent or poor) and type of decision (namely, choice between applicants, and ratings of competence and suitability). Our hypotheses consider both gender as social status and as social identity, and predict different outcomes depending on decision type. In line with those predictions, findings show that, at both levels of performance, the question about competence elicited effects only from the two applicants' relative academic standing, while the choice and suitability measures show effects from that standing as well as from sex category of applicant and of assessor. Results and their interpretation are presented and discussed in detail. PMID- 23017863 TI - Women's status and carbon dioxide emissions: A quantitative cross-national analysis. AB - Global climate change is one of the most severe problems facing societies around the world. Very few assessments of the social forces that influence greenhouse gas emissions have examined gender inequality. Empirical research suggests that women are more likely than men to support environmental protection. Various strands of feminist theory suggest that this is due to women's traditional roles as caregivers, subsistence food producers, water and fuelwood collectors, and reproducers of human life. Other theorists argue that women's status and environmental protection are linked because the exploitation of women and the exploitation of nature are interconnected processes. For these theoretical and empirical reasons, we hypothesize that in societies with greater gender equality there will be relatively lower impacts on the environment, controlling for other factors. We test this hypothesis using quantitative analysis of cross-national data, focusing on the connection between women's political status and CO(2) emissions per capita. We find that CO(2) emissions per capita are lower in nations where women have higher political status, controlling for GDP per capita, urbanization, industrialization, militarization, world-system position, foreign direct investment, the age dependency ratio, and level of democracy. This finding suggests that efforts to improve gender equality around the world may work synergistically with efforts to curtail global climate change and environmental degradation more generally. PMID- 23017864 TI - Underage drinking, alcohol sales and collective efficacy: Informal control and opportunity in the study of alcohol use. AB - Underage drinking among American youth is a growing public concern. However, while extensive research has identified individual level predictors of this phenomenon, few studies have theorized and tested the effect of structural social forces on children's and youths' alcohol consumption. In an attempt to address this gap, we study the effects of residential environments on children's and youths' underage drinking (while accounting for personality and familial processes). Integrating informal social control and opportunity explanations of deviance, we first suggest that while neighborhood collective efficacy prevents adolescents' underage drinking, individuals' access to local alcohol retail shops encourages such behavior. Focusing on the interactive effects of communal opportunities and controls, we then suggest that high presence of alcohol outlets and sales in the neighborhood is likely to increase youths' probability of alcohol consumption in the absence of communal mechanisms of informal social control. We test our theoretical model using the unprecedented data design available in the PHDCN. Results from a series of multilevel logit models with robust standard errors reveal partial support for our hypotheses; specifically, we find that alcohol sales in a given neighborhood increase adolescents' alcohol use. In addition, while the direct effect of collective efficacy is insignificantly related to children's and youths' alcohol consumption, our models suggest that it significantly attenuates the effect of local alcohol retailers and sales on underage drinking. PMID- 23017865 TI - How far do children move? Spatial distances after leaving the parental home. AB - This research used geocoded data from 11 waves (2000-2010) of the German Socio economic Panel Study to investigate the spatial distances of young adults' initial move-outs (N=2113) from their parents' homes. Linear regression models predicted moving distances by factors at individual, family, household, and community level. Overall, home leavers moved across very small distances with a median value of less than 10km. Greater distances were found for well-educated and childless home leavers who moved out at relatively young ages from high income households located in less-urbanized regions. In line with developmental models of migration, young adults stayed closer if the parental household was still located at their place of childhood. We conclude that considering the spatial distance of move-outs may advance our understanding of individual passages to adulthood and intergenerational relations across the life course. PMID- 23017866 TI - Magnetic resonance imaging for predicting prostate biopsy findings in patients considered for active surveillance of clinically low risk prostate cancer. AB - PURPOSE: A barrier to the acceptance of active surveillance for men with prostate cancer is the risk of underestimating the cancer burden on initial biopsy. We assessed the value of endorectal magnetic resonance imaging in predicting upgrading on confirmatory biopsy in men with low risk prostate cancer. MATERIALS AND METHODS: A total of 388 consecutive men (mean age 60.6 years, range 33 to 89) with clinically low risk prostate cancer (initial biopsy Gleason score 6 or less, prostate specific antigen less than 10 ng/ml, clinical stage T2a or less) underwent endorectal magnetic resonance imaging before confirmatory biopsy. Three radiologists independently and retrospectively scored tumor visibility on endorectal magnetic resonance imaging using a 5-point scale (1-definitely no tumor to 5-definitely tumor). Inter-reader agreement was assessed with weighted kappa statistics. Associations between magnetic resonance imaging scores and confirmatory biopsy findings were evaluated using measures of diagnostic performance and multivariate logistic regression. RESULTS: On confirmatory biopsy, Gleason score was upgraded in 79 of 388 (20%) patients. Magnetic resonance imaging scores of 2 or less had a high negative predictive value (0.96 1.0) and specificity (0.95-1.0) for upgrading on confirmatory biopsy. A magnetic resonance imaging score of 5 was highly sensitive for upgrading on confirmatory biopsy (0.87-0.98). At multivariate analysis patients with higher magnetic resonance imaging scores were more likely to have disease upgraded on confirmatory biopsy (odds ratio 2.16-3.97). Inter-reader agreement and diagnostic performance were higher for the more experienced readers (kappa 0.41-0.61, AUC 0.76-0.79) than for the least experienced reader (kappa 0.15-0.39, AUC 0.61 0.69). Magnetic resonance imaging performed similarly in predicting low risk and very low risk (Gleason score 6, less than 3 positive cores, less than 50% involvement in all cores) prostate cancer. CONCLUSIONS: Adding endorectal magnetic resonance imaging to the initial clinical evaluation of men with clinically low risk prostate cancer helps predict findings on confirmatory biopsy and assess eligibility for active surveillance. PMID- 23017867 TI - Pilot study of an investigation of psychological factors associated with first appointment nonattendance in a low-intensity service. AB - BACKGROUND: Nonattendance rates remain high for first therapy appointments, despite initiatives to increase access to psychological therapy. The reasons for nonattendance are poorly understood and studies of demographic and clinical predictors have produced conflicting findings. AIMS: We aimed to pilot a method for investigating psychological factors associated with first appointment attendance in a primary care mental health service. METHOD: Questionnaires were completed by individuals at the point of referral to CBT with a low-intensity service in one general practice (n = 67), including a measure of beliefs, goals and attitudes towards therapy, as well as anxiety and depression scales. Subsequent attendance at the first appointment was used as an outcome. RESULTS: Preliminary results showed that attendance was not associated with age or gender, severity of distress, or overall ratings for positive or negative attitudes towards therapy; although distress itself was associated with increased endorsement of negative attitudes. However, one specific psychological item, "Talking to a therapist will help me understand better how my mind works" had a significant association with subsequent attendance. CONCLUSIONS: The psychological factor that was associated with increased attendance may reflect the concept of psychological mindedness; however, this requires replication in a larger study. A full-scale study was deemed to be warranted based on this prospective design. PMID- 23017869 TI - Cognitive control over motor output in Tourette syndrome. AB - Tourette syndrome [TS] is a neurodevelopmental disorder characterised by chronic vocal and motor tics. TS has been associated with dysfunctional cognitive (inhibitory) control of behaviour, however the evidence for this, beyond the occurrence of tics, is scant. Furthermore, in recent studies of uncomplicated TS, it has been shown that adolescents with TS exhibit paradoxically enhanced cognitive control of motor output, consistent with the typical developmental profile of increasing control of tics during adolescence. Here we present arguments, together with new data, that run counter to the widely held view that prefrontal cortex (PFC) is the source of inhibitory task-control signals. Instead, we argue that PFC should be viewed as a source of facilitatory signals that bias competition in brain areas more directly involved in motor execution. Importantly, we argue that in TS, over-activation of PFC may contribute to the hyper-excitability of motor regions and the occurrence of tics; and that compensatory changes, leading to enhanced cognitive control in TS, may primarily be implemented by distributed changes in local cortical excitability. PMID- 23017868 TI - Update: studies of prepulse inhibition of startle, with particular relevance to the pathophysiology or treatment of Tourette Syndrome. AB - Prepulse inhibition of the startle reflex (PPI) is an operational measure of sensorimotor gating, in which the motor response to an abrupt, intense stimulus is inhibited by a weak lead stimulus. PPI is reduced in several brain disorders, including Tourette Syndrome (TS); it is regulated by forebrain circuitry, including portions of the basal ganglia implicated in the pathophysiology of TS, and is also heritable and under strong genetic control. PPI has been the focus of numerous translational models, because it is expressed by most mammalian species, with remarkable conservation of response characteristics and underlying neural circuitry between rodents and primates. Several of these models have recently explored causative factors in TS - from genes to specific basal ganglia perturbations - as well as potential TS therapeutics, including novel pharmacological and neurosurgical interventions. With the focus on Comprehensive Behavioral Interventions for Tics (CBIT) in the evolving treatment model for TS, future studies might apply PPI as a predictive measure for CBIT response, or for identifying medications that might augment CBIT efficacy. In the end, a measure based on a simple pontine-based reflex will have limitations in its ability to explicate any complex behavioral phenotype. PMID- 23017870 TI - Different effects of carbon ion beams and X-rays on clonogenic survival and DNA repair in human pancreatic cancer stem-like cells. AB - PURPOSE: The effects of a carbon ion beam and X-rays on human pancreatic cancer stem-like cells were examined from the point of view of clonogenic survival and DNA repair. MATERIALS AND METHODS: Human pancreatic cancer stem-like cells were treated with and without carbon ion and X-ray irradiation, and then colony, spheroid and tumor formation assays as well as gammaH2AX foci formation assay were performed. RESULTS: The relative biological effectiveness (RBE) values of a carbon ion beam relative to X-ray for the MIA PaCa-2 and BxPc-3 cells at the D10 values were 1.85-2.10. The ability for colony, spheroid formation, and tumorigenicity from cancer stem-like CD44(+)/CD24(+) cells is significantly higher than that from non-cancer stem-like CD44(-)/CD24(-)cells. FACS data showed that CD44(+)/CD24(+) cells were more highly enriched after X-rays compared to carbon ion irradiation at isoeffective doses. The RBE values for the carbon ion beam relative to X-ray at the D10 levels for CD44(+)/CD24(+) cells were 2.0-2.19. The number of gammaH2AX foci in CD44(-)/CD24(-) cells was higher than that of CD44(+)/CD24(+) cells after irradiation with either X-ray or carbon ion beam. The number of gammaH2AX foci in CD44(+)/CD24(+) cells was almost the same in the early time, but it persists significantly longer in carbon ion beam irradiated cells compared to X-rays. CONCLUSIONS: Carbon ion beam has superior potential to kill pancreatic cancer stem cell-like cells, and prolonged induction of DNA damage might be one of the pivotal mechanisms of its high radiobiological effects compared to X-rays. PMID- 23017871 TI - Histone deacetylase inhibitors suppress mechanical stress-induced expression of RUNX-2 and ADAMTS-5 through the inhibition of the MAPK signaling pathway in cultured human chondrocytes. AB - OBJECTIVE: To investigate the inhibitory effects and the regulatory mechanisms of histone deacetylase (HDAC) inhibitors on mechanical stress-induced gene expression of runt-related transcription factor (RUNX)-2 and adisintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-5 in human chondrocytes. METHODS: Human chondrocytes were seeded in stretch chambers at a concentration of 5 * 10(4)cells/chamber. Cells were pre-incubated with or without HDAC inhibitors (MS-275 or trichostatin A; TSA) for 12h, followed by uniaxial cyclic tensile strain (CTS) (0.5Hz, 10% elongation), which was applied for 30 min using the ST 140-10 system (STREX, Osaka, Japan). Total RNA was extracted and the expression of RUNX-2, ADAMTS-5, matrix metalloproteinase (MMP)-3, and MMP-13 at the mRNA and protein levels were examined by real-time polymerase chain reaction (PCR) and immunocytochemistry, respectively. The activation of diverse mitogen-activated protein kinase (MAPK) pathways with or without HDAC inhibitors during CTS was examined by western blotting. RESULTS: HDAC inhibitors (TSA: 10 nM, MS-275: 100 nM) suppressed CTS-induced expression of RUNX-2, ADAMTS-5, and MMP-3 at both the mRNA and protein levels within 1h. CTS-induced activation of p38 MAPK (p38), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) MAPKs was downregulated by both HDAC inhibitors. CONCLUSION: The CTS-induced expression of RUNX-2 and ADAMTS-5 was suppressed by HDAC inhibitors via the inhibition of the MAPK pathway activation in human chondrocytes. The results of the current study suggested a novel therapeutic role for HDAC inhibitors against degenerative joint disease such as osteoarthritis. PMID- 23017872 TI - Phone call simulator. PMID- 23017873 TI - Abnormal baseline brain activity in bipolar depression: a resting state functional magnetic resonance imaging study. AB - We examined resting state brain activity in the depressive phase of bipolar disorder (BD) by measuring the amplitude of low-frequency fluctuations (ALFF) in the functional magnetic resonance imaging (fMRI) signal. Unlike functional connectivity, the ALFF approach reflects local properties in specific regions and provides direct information about impaired foci. Groups of 26 patients with BD depression and 26 gender-, age-, and education-matched healthy subjects participated in fMRI scans. We examined group differences in ALFF findings as well as correlations between clinical measurements and ALFF in the regions showing significant group differences. Our results showed that patients with BD depression had significantly increased ALFF in the left insula, the right caudate nucleus, the temporal gyrus, the bilateral inferior frontal gyrus, and the posterior lobe of the cerebellum. They also had decreased ALFF in the left postcentral gyrus, the left parahippocampal gyrus, and the cerebellum. Moderate negative correlations were found between the Hamilton Depression Rating Scale score and ALFF in the left insular cortex in the patient group. These results support a model of BD that involves dysfunction in the prefrontal-limbic networks and associated striatal systems. We also demonstrated the feasibility of ALFF as a technique to investigate persistent cerebral dysfunction in BD. PMID- 23017874 TI - Development and evaluation of an entirely solution-based combinative sample preparation method for membrane proteomics. AB - The hydrophobic nature of many membrane proteins, especially integral membrane proteins, brings great difficulties to their analysis. To improve the analysis of membrane proteins, an entirely solution-based combinative sample preparation (CSP) method was developed and its application to the shotgun analysis of rat liver membrane proteomes was evaluated in this study. This CSP method comprehensively uses the strong ability of sodium dodecyl sulfate (SDS) to lyse the membranes and solubilize hydrophobic membrane proteins, the high efficiency of the optimized acetone precipitation method in sample cleanup and protein recovery, and the advantages of sodium deoxycholate (SDC) in improving protein solubilization/digestion as well as being compatible with trypsin activity. Compared with two other representative sample preparation methods, the SDC assisted membrane-lysing method and the tube gel method, the newly established CSP method exhibited superiority in the recovery and identification of hydrophobic peptides, larger peptides, and highly hydrophobic membrane proteins with multiple transmembrane domains. The CSP method has characteristics of easy operation, low cost, and suitability for treating protein samples in various volumes, particularly large volumes, thereby having potential in the analysis of membrane proteomes with mass spectrometry. PMID- 23017876 TI - Simultaneous electrochemical measurement method of histamine and N(tau) methylhistamine by high-performance liquid chromatography-amperometry with o phthalaldehyde-sodium sulfite derivatization. AB - An electrochemical detection (ECD) method for analyzing sub-micro amounts of histamine (HA) and N(tau)-methylhistamine (N(tau)-MHA) in biological samples by high-performance liquid chromatography (HPLC)-amperometry has been developed. The method consists of a precolumn derivatization of the amines with o-phthalaldehyde (OPA) and sodium sulfite (Na(2)SO(3)) to N-alkyl-1-isoindole sulfonate and posterior separation with the HPLC system. Biological samples were pretreated by using a Vivapure sulfonic acid minifilter in which the reaction of the reagent with the amines took place during filtering. HA and N(tau)-MHA retention times were 11.8 +/- 0.02 and 18.3 +/- 0.03 min, respectively (means +/- standard deviations, n = 3). The lowest limit of amperometric detection at a signal-to noise ratio of 3:1 was 0.125 pmol in both cases. HA and N(tau)-MHA contents in hypothalamus, cortex, skin, and fundic gland, as well as histamine N methyltransferase (HMT) activities of mast cell-deficient (Ws/Ws) and Wistar rats, were measured and compared with an HPLC-fluorometry system, among other experiments, in order to validate and demonstrate the usefulness of this assay system. Hence, this consequently confirms not only the sensitivity and specificity of the assay but also the potential and convenience it offers to laboratory work, especially in the analysis of the regulation of histaminergic neurons as well as enzymatic investigation of HA metabolism. PMID- 23017875 TI - Improved detection of botulinum neurotoxin serotype A by Endopep-MS through peptide substrate modification. AB - Botulinum neurotoxins (BoNTs) are a family of seven toxin serotypes that are the most toxic substances known to humans. Intoxication with BoNT causes flaccid paralysis and can lead to death if untreated with serotype-specific antibodies. Supportive care, including ventilation, may be necessary. Rapid and sensitive detection of BoNT is necessary for timely clinical confirmation of clinical botulism. Previously, our laboratory developed a fast and sensitive mass spectrometry (MS) method termed the Endopep-MS assay. The BoNT serotypes are rapidly detected and differentiated by extracting the toxin with serotype specific antibodies and detecting the unique and serotype-specific cleavage products of peptide substrates that mimic the sequence of the BoNT native targets. To further improve the sensitivity of the Endopep-MS assay, we report here the optimization of the substrate peptide for the detection of BoNT/A. Modifications on the terminal groups of the original peptide substrate with acetylation and amidation significantly improved the detection of BoNT/A cleavage products. The replacement of some internal amino acid residues with single or multiple substitutions led to further improvement. An optimized peptide increased assay sensitivity 5-fold with toxin spiked into buffer solution or different biological matrices. PMID- 23017877 TI - Quantitation of asparagine deamidation by isotope labeling and liquid chromatography coupled with mass spectrometry analysis. AB - Nonenzymatic asparagine (Asn) deamidation is one of the commonly observed posttranslational modifications of proteins. Recent development of several specific analytical methods has allowed for efficient identification and differentiation of the deamidation products (i.e., isoaspartate [isoAsp] and aspartate [Asp]). Isotope labeling of isoAsp and Asp that are generated during sample preparation by 18O has been developed and can differentiate isoAsp and Asp as analytical artifacts from those present in the samples prior to sample preparation for an accurate quantitation. However, the 18O labeling procedure has a limitation due to the additional incorporation of up to two 18O atoms into the peptide C-terminal carboxyl groups. Variability in the incorporation of 18O atoms into the peptide C-terminal carboxyl groups results in complicated mass spectra and hinders data interpretation. This limitation can be overcome by the dissection of the complicated mass spectra using a calculation method presented in the current study. The multiple-step calculation procedure has been successfully employed to determine the levels of isoAsp and Asp that are present in the sample prior to sample treatment. PMID- 23017878 TI - The use of epitope arrays in immunodiagnosis of infectious disease: hepatitis C virus, a case study. AB - Serodiagnosis of infectious disease is often based on the detection of pathogen specific antibodies in a patient's blood. For this, mixtures of pathogen-related antigens are used as bait to capture corresponding antibodies in solid phase immunoassays such as enzyme immunoassay (EIA). Western blots provide improved diagnostic power as compared with EIA due to the fact that the mixture of markers in the EIA well is resolved and tested as individual antigens on the Western blot. Hence, confirmation of EIA results is accomplished using the antigen arrays of Western blots. Here we took this approach one step further and tested the attributes of using epitope arrays in a diagnostic platform coined "combinatorial diagnostics." As a case in point, we tested a panel of phage-displayed epitope based markers in the serodiagnosis of hepatitis C virus (HCV). The repertoire of HCV antigens was deconvoluted into panels of distinct linear and conformational epitopes and tested individually by quantitative EIA. Combinatorial diagnostics proved to be effective for the discrimination between positive and negative sera as well as serotyping of HCV. PMID- 23017879 TI - Congenital and acquired developmental problems of the upper airway in newborns and infants. AB - AIM: To review the current knowledge on congenital and acquired developmental problems of the upper airway in newborns and infants. DATA SYNTHESIS: Causes of airway obstruction include problems with the nasal airway (choanal atresia), craniofacial syndromes (Apert syndrome, Crouzon syndrome), problems with facial/tongue anatomy (Pierre-Robin syndrome), the tongue (Down syndrome), or the larynx (laryngomalacia, vocal cord palsy, subglottic stenosis, subglottic hemangioma), along with lower developmental problems (tracheo/bronchomalacia). After establishing a safe airway, a detailed assessment and appropriate management are necessary. Treatment may involve simple observation, conservative management, chest physiotherapy, CPAP ventilation, and surgery, urgently or in a second phase. CONCLUSION: Upper airway diseases in neonates and infants may be life threatening, or challenging regarding diagnosis and management. There should be a very low threshold for referring these children, after establishing a safe airway, for a specialist opinion and care in a tertiary unit, if local facilities are limited or unavailable. PMID- 23017880 TI - Digit ratio (2D:4D) in newborns: influences of prenatal testosterone and maternal environment. AB - INTRODUCTION: The 2D:4D digit ratio is sexually-dimorphic, probably due to testosterone action through the perinatal period. We characterize the 2D:4D ratio in newborn (NB) infants, in between the pre- and postnatal surges of testosterone, and relate it to the mother's 2D:4D and to testosterone levels in the amniotic fluid (AF). SUBJECTS AND METHODS: Testosterone was assayed in samples of maternal plasma and AF collected at amniocentesis. Shortly after birth, 106 NBs and their mothers were measured for 2D:4D ratio. RESULTS: NB males had lower mean 2D:4D ratios than females but this dimorphism was significant only for the left hand (males: 0.927; females: 0.950; p=0.004). Mothers who had sons had lower 2D:4D ratios than those who had daughters and the mother's 2D:4D were higher than those of NBs regardless of sex. Both hands of NB females were negatively correlated with AF testosterone and positively correlated with the mother's 2D:4D, but males showed no significant associations. Maternal plasma testosterone also showed a negative weak correlation with NB's digit ratio in both sexes. CONCLUSIONS: Sexual dimorphism at birth was only significant for the left hand, in contrast with reports of greater right hand dimorphism, suggesting that postnatal testosterone is determinant for 2D:4D stabilization. The lower 2D:4D ratios in mothers who had sons support claims that hormone levels in parents are influential for determining their children's sex. NB female's digit ratio, but not males', was associated to the level of AF testosterone. The mother's 2D:4D ratios were positively correlated with their daughters' 2D:4D, but the same was not observed for male NBs, suggesting that prenatal testosterone levels in male fetus lead their 2D:4D ratios to stray from their mothers' with high individual variability. PMID- 23017881 TI - Dominant dystrophic epidermolysis bullosa pruriginosa with the G2287R mutation. PMID- 23017882 TI - 3,3'-Disubstituted bipolar biphenyls as inhibitors of nuclear receptor coactivator binding. AB - A series of bipolar biphenyl compounds was synthesized as proteomimetic analogs of the LXXLL penta-peptide motif responsible for the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were subjected to multiple in vitro assays to evaluate their effectiveness as competitive binding inhibitors. The results from this initial study indicate that these proteomimetics possess the ability to inhibit this protein-protein interaction. PMID- 23017883 TI - Evaluation of structure-derived pharmacophore of soluble epoxide hydrolase inhibitors by virtual screening. AB - The soluble epoxide hydrolase (sEH) is an enzyme located downstream of the CYP 450 branch of the arachidonic acid cascade and can be linked to a number of indications, including cardiovascular disorders, diabetes and inflammatory processes. Numerous inhibitors (sEHI) have been reported, mostly based on urea or amide scaffolds. The search for valid bioisosteric replacements is an ongoing challenge in the discovery of sEHI. We developed a receptor-based pharmacophore model on the basis of 13 crystal structures of the sEH and performed a virtual screening for novel compounds. The virtual screening hits were verified in vitro proving the basic applicability of the model and leading to novel non-urea sEHI. PMID- 23017884 TI - Formylated polyamines as peptidomimetics. AB - A new construct for imitating a natural peptide ligand using a modified retro inverso sequence is described. It is demonstrated through the synthesis of a peptidomimetic derived from the endogenous sequence of leucine enkephalin. The product was active at 400 nM and selective for MU-opioid receptors. PMID- 23017885 TI - Part II. Development of novel colchicine-derived immunosuppressants with improved pharmacokinetic properties. AB - We have developed a new series of immunosuppressant with improved pharmacokinetic properties as the second-generation of colchicine analogs, which were designed based on the privileged structure derived from our previous work. In particular, we identified an analog (14), which exhibited a potent in vitro activity (IC(50): 5 nM) in MLR and excellent in vivo efficacy in the Zymosan A-induced arthritis model, in the Carrageenan-induced edema model and in the local lymph node assay (LLNA). Analog 14 also revealed a good oral bioavailability (F: 67.3%) in BALB/c mice. PMID- 23017886 TI - A hierarchical method for molecular docking using cloud computing. AB - Discovering small molecules that interact with protein targets will be a key part of future drug discovery efforts. Molecular docking of drug-like molecules is likely to be valuable in this field; however, the great number of such molecules makes the potential size of this task enormous. In this paper, a method to screen small molecular databases using cloud computing is proposed. This method is called the hierarchical method for molecular docking and can be completed in a relatively short period of time. In this method, the optimization of molecular docking is divided into two subproblems based on the different effects on the protein-ligand interaction energy. An adaptive genetic algorithm is developed to solve the optimization problem and a new docking program (FlexGAsDock) based on the hierarchical docking method has been developed. The implementation of docking on a cloud computing platform is then discussed. The docking results show that this method can be conveniently used for the efficient molecular design of drugs. PMID- 23017887 TI - Effect of substituents at phenyl group of 7,7'-dioxo-9,9'-epoxylignane on antifungal activity. AB - Using 21 newly synthesized 7,7'-dioxo-9,9'-epoxylignane derivatives having a modified 7-phenyl group, we examined the relationship between their structure and antifungal activity against plant pathogens such as Bipolaris oryzae to determine the effects of various substituents on the antifungal activity. Compared with the lead compound having a 4-OH-3-CH(3)O-phenyl moiety, several analogs showed higher antifungal activity against B. oryzae, including the compound having an unsubstituted phenyl group and those having either of the following phenyl substituents: 2-OH, 4-CH(3)O, 4-C(2)H(5)O, 4-n-C(3)H(7)O, 4-n-C(4)H(9)O, 4 CF(3)O, 4-C(2)H(5), or 4-Cl. On the other hand, the activity of compounds having a branched substituent, such as 4-i-C(3)H(7)O or 4-i-C(3)H(7), on the 7-phenyl group or a multi-substituted phenyl group was equipotent or inferior to that of the lead compound. These results as well as correlations between the antifungal activity of the test compounds and the physicochemical parameters of the varied substituents suggest that the position of substitution on the 7-phenyl group and the incorporation of substituents with optimal physicochemical properties are important for exerting the antifungal activity. PMID- 23017888 TI - 4-Substituted-2-phenylquinazolines as inhibitors of BCRP. AB - We investigated several 2-phenylquinazolines with different substitutions at position 4 for their BCRP inhibition. Compounds with phenyl ring attached via an amine-containing linker at position 4 were found to be potent inhibitors of BCRP. In general compounds with meta substitution of phenyl ring at position 4 were found to have higher inhibitory effect, compound 12 being the most potent and selective towards BCRP. PMID- 23017892 TI - Leveraging health capital at the workplace: an examination of health reporting behavior among Latino immigrant restaurant workers in the United States. AB - This article examines the choices made by a sample of Latino immigrant restaurant workers in regard to their health management, particularly in response to illness and injury. I draw on 33 interviews with kitchen staff employed in the mainstream restaurant industry in San Jose, California, and Houston, Texas, in 2006 and 2007. I argue that workers must consider complex power relationships at work in weighing the advantages of calling in sick, using protective equipment, seeking medical care, or filing a workers' compensation claim. These decisions implicate direct and opportunity costs, such as risk of job loss and missed opportunities for advancement. Workers consequently leverage their health capital to meet their economic needs, to assert their autonomy at the workplace, and to ultimately reject the stigma of illness and injury. PMID- 23017891 TI - Balancing healthy meals and busy lives: associations between work, school, and family responsibilities and perceived time constraints among young adults. AB - OBJECTIVE: To characterize associations between perceived time constraints for healthy eating and work, school, and family responsibilities among young adults. DESIGN: Cross-sectional survey. SETTING: A large, Midwestern metropolitan region. PARTICIPANTS: A diverse sample of community college (n = 598) and public university (n = 603) students. MAIN OUTCOME MEASURES: Time constraints in general, as well as those specific to meal preparation/structure, and perceptions of a healthy life balance. ANALYSIS: Chi-square tests and multivariate logistic regression (alpha = .005). RESULTS: Women, 4-year students, and students with lower socioeconomic status perceived more time constraints (P < .001-.002); students with lower socioeconomic status were less likely to have a healthy balance (P <= .003). Having a heavy course load and working longer hours were important predictors of time constraints among men (P < .001-.004), whereas living situation and being in a relationship were more important among women (P = .002-.003). CONCLUSIONS AND IMPLICATIONS: Most young adults perceive time constraints on healthy dietary behaviors, yet some young adults appear able to maintain a healthy life balance despite multiple time demands. Interventions focused on improved time management strategies and nutrition-related messaging to achieve healthy diets on a low time budget may be more successful if tailored to the factors that contribute to time constraints separately among men and women. PMID- 23017893 TI - Hand, foot, and mouth disease caused by coxsackievirus a6. PMID- 23017894 TI - Oxidative post translational modifications of proteins related to cell cycle are involved in cadmium toxicity in wheat seedlings. AB - Abiotic stress is greatly associated with plant growth inhibition and redox cell imbalance. In the present work, we have investigated in which way oxidative posttranslational modifications (PTM) of proteins related to cell cycle may be implicated in post-germinative root growth reduction caused by cadmium, by methyl viologen (MV) and by hydrogen peroxide (H2O2) in wheat seedlings. Although cadmium is considered a redox inactive metal, reactive oxygen species were detected in the apex root of metal-treated seedlings. Oxidative stress hastened cells displacement from the cell division zone to elongation/differentiation zone, resulting in a shortened meristem. The number of cells in the proliferation zone was lower after MV, H2O2 and 10 MUM Cd2+ treatments compared to control. All treatments increased protein carbonylation. Although no modification in total Ub conjugated proteins was detected, oxidative treatments reduced cyclin D and CDKA protein ubiquitination, concomitantly with a decrease in expression of cyclin D/CDKA/Rb/E2F-regulated genes. We postulate that ROS and oxidative PTM could be part of a general mechanism, specifically affecting G1/S transition and progression through S phase. This would rapidly block cell cycle progression and would allow the cellular defence system to be activated. PMID- 23017895 TI - Photosynthesis, photoinhibition, and antioxidant system in tomato leaves stressed by low night temperature and their subsequent recovery. AB - The effects of low night temperature (LNT, i.e., 9 and 6 degrees C) stress and rewarming (15 degrees C night temperature) on the photosynthesis, photosystems I and II (PSI and PSII), and antioxidant system of tomato leaves were studied. The results showed that 9 d of LNT treatment led to an irreversible reduction in the photosynthetic rate. This reduction was accompanied by stomatal limitation of CO2 supply and significant decline in ribulose-1,5-bisphosphate carboxylase/oxygenase activity at the transcription level, as well as sucrose accumulation. LNT treatment induced the reversible photoinhibition of PSII, decreased PSII activity, increased the photochemical yield of PSI Y(I), and markedly caused the acceptor side limitation of PSI. This finding was reflected by the higher value of Y(NA) in the treated plants than in the control. At the same time, a downregulation of electron transport for photosynthetic carbon reduction under LNT was mostly compensated by Ja(O2-dependent) driven by the water-water cycle. PMID- 23017896 TI - "And yet it moves": cell-to-cell and long-distance signaling by plant microRNAs. AB - MicroRNAs (miRNAs) are key regulators of numerous genes in many eukaryotes. Some plant miRNAs are involved in developmental and physiological processes that require intercellular or inter-organ signaling. Movement of other small RNAs within plants has been established. Recent findings also demonstrate intercellular signaling by miRNAs and strongly support that a subset of these regulatory molecules move from one cell to another or over long distances. Phloem exudates contain diverse miRNAs and at least two of them, involved in responses to nutrient availability, are transmitted through grafts, indicating long distance movement. Two miRNAs that regulate developmental processes are present in cells outside their domains of expression. Several results strongly support that one of them moves from cell to cell. Research on a mutant affected in plasmodesmata trafficking indicates that these intercellular channels are required for transmission of miRNA activity to adjacent cells. Moreover, ARGONAUTE proteins might be involved in the regulation of miRNA trafficking. Hypothesis on the features and mechanisms that may determine miRNA mobility are presented. Future challenges include identifying other mobile miRNAs; demonstrating that miRNA movement is required for non-cell autonomous action; and characterizing the mechanisms of translocation and genetic pathways that regulate miRNA movement. PMID- 23017897 TI - Identification of candidate genes related to rice grain weight under high temperature stress. AB - The rise of global warming presents a problem for all living organisms, including rice and other staple plants. High temperatures impair rice grain weight by inhibiting the filling of the caryopses during the milky stage. The molecular mechanism behind this process, however, is poorly understood. Identifying candidate genes involved in responses to high-temperature stress may provide a basis for the improvement of heat tolerance in rice. Using paired, genetically similar heat-tolerant and heat-sensitive rice lines as plant materials, cDNA-AFLP analysis revealed a total of 54 transcript derived fragments (TDFs), mainly from the heat-tolerant lines. This clearly indicated variations in gene expression between the two rice lines. BLAST results showed that 28 of the 54 TDFs were homologous sequences. These homologous genes were found to encode proteins involved in signal transduction, oxidation, transcriptional regulation, transport, and metabolism. The functions and differential expression patterns of some important genes are further discussed. High temperature stress may trigger a wide range of changes in gene expression in rice caryopses, in turn affecting functions ranging from signal transduction to cellular metabolism. Forty-five of the 54 TDFs were mapped to rice chromosomes. The genes identified in the present study would make good candidates for further study into the molecular mechanisms underlying rice adaptation to high-temperature stress. PMID- 23017898 TI - The Arabidopsis ortholog of the YEATS domain containing protein YAF9a regulates flowering by controlling H4 acetylation levels at the FLC locus. AB - Histone acetylation and complexes associated with this process are directly involved in chromatin regulation and gene expression. Among these, NuA4 complex is directly involved in acetylation of histone H4, H2A and H2A.Z. In yeast, the NuA4 complex contains the catalytic subunit, the histone acetyltransferase ESA1, and several associated components including YAF9. In this report we explored the biological role of YAF9a in Arabidopsis thaliana. Homozygous yaf9a-1 and yaf9a-3 mutants show early flowering phenotypes. Moreover, yaf9a-1 mutants displayed reduced expression of the flowering repressor FLC, whereas the expression of the flowering activators FT and SOC1 was induced in comparison to wild-type plants. Using chromatin immunoprecipitation assays with H4 tetra-acetylated antibodies we observed a positive correlation with gene expression profile of FLC and FT in yaf9a-1 mutants under long days. We therefore conclude that YAF9a in Arabidopsis is a negative regulator of flowering by controlling the H4 acetylation levels in the FLC and FT chromatin. PMID- 23017899 TI - Differential subcellular targeting of recombinant human alpha1-proteinase inhibitor influences yield, biological activity and in planta stability of the protein in transgenic tomato plants. AB - The response of protein accumulation site on yield, biological activity and in planta stability of therapeutic recombinant human proteinase inhibitor (alpha1 PI) was analyzed via targeting to different subcellular locations, like endoplasmic reticulum (ER), apoplast, vacuole and cytosol in leaves of transgenic tomato plants. In situ localization of the recombinant alpha1-PI protein in transgenic plant cells was monitored by immunohistochemical staining. Maximum accumulation of recombinant alpha1-PI in T0 and T1 transgenic tomato plants was achieved from 1.5 to 3.2% of total soluble protein (TSP) by retention in ER lumen, followed by vacuole and apoplast, whereas cytosolic targeting resulted into degradation of the protein. The plant-derived recombinant alpha1-PI showed biological activity for elastase inhibition, as monitored by residual porcine pancreatic elastase (PPE) activity assay and band-shift assay. Recombinant alpha1 PI was purified from transgenic tomato plants with high yield, homogeneity and biological activity. Purified protein appeared as a single band of ~48-50 kDa on SDS-PAGE with pI value ranging between 5.1 and 5.3. Results of mass spectrometry and optical spectroscopy of purified recombinant alpha1-PI revealed the structural integrity of the recombinant protein comparable to native serum alpha1 PI. Enzymatic deglycosylation and lectin-binding assays with the purified recombinant alpha1-PI showed compartment-specific N-glycosylation of the protein targeted to ER, apoplast and vacuole. Conformational studies based on urea induced denaturation and circular dichroism (CD) spectroscopy revealed relatively lower stability of the recombinant alpha1-PI protein, compared to its serum counterpart. Pharmacokinetic evaluation of plant derived recombinant and human plasma-purified alpha1-PI in rat, by intravenous route, revealed significantly faster plasma clearance and lower area under curve (AUC) of recombinant protein. Our data suggested significance of protein sorting sequences and feasibility to use transgenic plants for the production of stable, glycosylated and biologically active recombinant alpha1-PI for further therapeutic applications. PMID- 23017900 TI - Flavonoids as antioxidants in plants: location and functional significance. AB - Stress-responsive dihydroxy B-ring-substituted flavonoids have great potential to inhibit the generation of reactive oxygen species (ROS) and reduce the levels of ROS once they are formed, i.e., to perform antioxidant functions. These flavonoids are located within or in the proximity of centers of ROS generation in severely stressed plants. Efficient mechanisms have been recently identified for the transport of flavonoids from the endoplasmic reticulum, the site of their biosynthesis, to different cellular compartments. The mechanism underlying flavonoid-mediated ROS reduction in plants is still unclear. 'Antioxidant' flavonoids are found in the chloroplast, which suggests a role as scavengers of singlet oxygen and stabilizers of the chloroplast outer envelope membrane. Dihydroxy B-ring substituted flavonoids are present in the nucleus of mesophyll cells and may inhibit ROS-generation making complexes with Fe and Cu ions. The genes that govern the biosynthesis of antioxidant flavonoids are present in liverworts and mosses and are mostly up-regulated as a consequence of severe stress. This suggests that the antioxidant flavonoid metabolism is a robust trait of terrestrial plants. Vacuolar dihydroxy B-ring flavonoids have been reported to serve as co-substrates for vacuolar peroxidases to reduce H(2)O(2) escape from the chloroplast, following the depletion of ascorbate peroxidase activity. Antioxidant flavonoids may effectively control key steps of cell growth and differentiation, thus acting regulating the development of the whole plant and individual organs. PMID- 23017901 TI - The acclimation potential of Acacia longifolia to water stress: implications for invasiveness. AB - The ability of an invasive species to establish and spread to new areas may depend on its ability to tolerate a broad range of environmental conditions. Due to climate change, increasing occurrences of extreme events such as droughts are expected in the Mediterranean region and invasive species may expand if they cope with water stress. Limited information is available on the responses of Acacia longifolia, one of the most aggressive plant species in Portuguese coastal sand dune ecosystems, to prolonged water stress. In this study, we exposed A. longifolia plants from two distinct populations, one from the wet (northern) and another from the dry (southern) climate regions of Portugal, to drought conditions, and monitored morphological, physiological and biochemical responses. One-month-old seedlings were submitted to three different water treatments which involved watering twice a week, every 7 days and every 10 days, respectively, for three months, under controlled conditions. Overall, the progressive drought stress significantly affected most of the growth parameters considered, except the root:shoot ratio. Water stress also increased the uptake of ions (Ca2+, Mg2+, K+ and Na+) and N concentration. On the contrary, the C/N ratio decreased under water stress conditions. Isotopic analysis did not reveal significant differences in delta13C with water treatments but the same pattern was not observed in delta15N values. Compared with the wet climate population, the dry climate population showed somewhat differing responses to water stress, indicating a genetic difference between populations. These results provide insights into limitations and opportunities for establishment of A. longifolia in a drought prone scenario. PMID- 23017902 TI - Intraspecific variations in growth, yield and photosynthesis of sorghum varieties to ambient UV (280-400 nm) radiation. AB - A field study was conducted to investigate the impact of ambient solar UV on the various growth, physiological and yield parameters of four sorghum (Sorghum bicolor L.) varieties-Indore-12, Indore-26, CSV-23 and Indore-27 by excluding either UV-B (<315 nm) or UV-A/B (<400 nm) components of solar spectrum. Exclusion of UV significantly enhanced plant height, area and specific leaf weight of flag leaf, biomass accumulation, yield parameters and harvest index in all the sorghum varieties. Chlorophyll b was significantly enhanced and chlorophyll a increased to a lesser extent, UV-B absorbing substances and chlorophyll a/b ratio were significantly decreased by the exclusion of solar UV. The enhancement in the vegetative growth and yield by UV exclusion might be linked to the remarkable increase in rate of photosynthesis in sorghum varieties. The magnitude of the response was high in I-26 and I-27 as compared to CSV-23 and I-12 after exclusion of solar UV. All the varieties of sorghum had a negative cumulative stress response index (CSRI), the sensitivity of the sorghum varieties was in the following sequence I-12>CSV-23>I-26>I-27. Thus I-27 was the most sensitive and I 12 the least sensitive variety to present level of solar UV radiation. The differences in UV sensitivity identified among sorghum varieties might be useful in breeding programs for increased tolerance to UV-B radiation. PMID- 23017903 TI - Plasma membrane potential depolarization and cytosolic calcium flux are early events involved in tomato (Solanum lycopersicon) plant-to-plant communication. AB - Tomato plants respond to herbivory by emitting volatile organic compounds (VOCs), which are released into the surrounding atmosphere. We analyzed the tomato herbivore-induced VOCs and tested the ability of tomato receiver plants to detect tomato donor volatiles by analyzing early responses, including plasma membrane potential (V(m)) variations and cytosolic calcium ([Ca2+](cyt)) fluxes. Receiver tomato plants responded within seconds to herbivore-induced VOCs with a strong V(m) depolarization, which was only partly recovered by fluxing receiver plants with clean air. Among emitted volatiles, we identified by GC-MS some green leaf volatiles (GLVs) such as (E)-2-hexenal, (Z)-3-hexenal, (Z)-3-hexenyl acetate, the monoterpene alpha-pinene, and the sesquiterpene beta-caryophyllene. GLVs were found to exert the stronger V(m) depolarization, when compared to alpha-pinene and beta-caryophyllene. Furthermore, V(m) depolarization was found to increase with increasing GLVs concentration. GLVs were also found to induce a strong [Ca2+](cyt) increase, particularly when (Z)-3-hexenyl acetate was tested both in solution and with a gas. On the other hand, alpha-pinene and beta-caryophyllene, which also induced a significant V(m) depolarization with respect to controls, did not exert any significant effect on [Ca2+](cyt) homeostasis. Our results show for the first time that plant perception of volatile cues (especially GLVs) from the surrounding environment is mediated by early events, occurring within seconds and involving the alteration of the plasma membrane potential and the [Ca2+](cyt) flux. PMID- 23017904 TI - Molecular identification of a new powdery mildew resistance gene on chromosome 2BS from Triticum turgidum ssp. dicoccum. AB - Powdery mildew caused by the fungal pathogen Blumeria graminis f. sp. tritici (Bgt), is a destructive foliar disease on wheat in many regions of the world. Triticum turgidum ssp. dicoccum (2n=4x=28) shows particular promises as a donor source of useful genetic variation for several traits, including disease resistances that could be introgressed to cultivated wheats. Accession MG5323, resistant to powdery mildew, was crossed to the susceptible durum cultivar Latino and a set of 122 recombinant inbred lines (RILs) was produced. F1 and F2 progenies and the RIL population were tested with one isolate of Blumeria graminis and data obtained indicated that a single dominant gene, temporarily designated Ml5323, controlled resistance at the seedling stage. Molecular markers were used to characterize and map the powdery mildew resistance gene. Twelve microsatellite markers were linked to the resistance gene, and among them, EST SSR CA695634 was tightly linked to the resistance gene, which was assigned to chromosome arm 2BS and physically mapped to the gene rich region of fragment length (FL) 0.84-1.00. An allelism test showed that the Ml5323 gene and the resistant gene Pm26 of ssp. dicoccoides localized in the same bin, are not allelic and tightly linked. PMID- 23017905 TI - The chlorotic symptom induced by Sunflower chlorotic mottle virus is associated with changes in redox-related gene expression and metabolites. AB - Systemic infections are commonly associated with changes in host metabolism and gene expression. Sunflower chlorotic mottle virus (SuCMoV) causes systemic infection with sugar increase, photoinhibition and increase in antioxidant enzyme activities before chlorotic symptom appearance in sunflower leaves. The aim of this study was to determine if chlorotic symptom development induced by SuCMoV infection is accompanied by changes in different redox-related metabolites and transcripts. Symptom development was analyzed in the second pair of leaves (systemic infection) at different post-inoculation times: before symptom appearance (BS, 4 dpi), and at an early (ES, 7 dpi) and later stage (LS, 12 dpi) of symptom expression. The results showed that the virus reaches the second pair of leaves at 4 dpi. A positive correlation between chlorotic symptom and number of viral copies was also observed. Changes in hydrogen peroxide, glutathione, pyridine nucleotides and ATP content were observed since symptom appearance (ES, 7 dpi). The expression of some of the genes analyzed was also strongly affected by SuCMoV infection. Specifically, down-regulation of both chloroplast-encoded genes and chloroplast-targeted genes: psbA, rbcS, Cu/Zn sod, Fe sod, phosphoglycolate phosphatase, psbO, psaH and fnr was present, whereas the expression of cytoplasmic-targeted genes, apx1, and Cu/Zn sod was up-regulated. Mitochondrial Mn sod decreased at BS stage and aox decreased only at ES stage. Peroxisomal catalase (cat-2) was lower at BS and LS stages. All these results suggest that SuCMoV infection induces progressive changes in determinants of redox homeostasis associated with chlorotic symptom development. PMID- 23017906 TI - A missense mutation in the transmembrane domain of CESA9 affects cell wall biosynthesis and plant growth in rice. AB - Rice is a model organism in poaceae plants to study cell wall biosynthesis. In this study, a mutant S1-60 isolated from an EMS mutagenized japonica cultivar Nipponbare, is characterized by brittle culms that can be easily broken by bending. The reduction in mechanical strength was due to defect in thickening of the sclerenchyma cell wall. The amount of cellulose in S1-60 culms was reduced to 44.7% of that of wild-type plants. Besides, the mutant also exhibited pleiotropic phenotypes, such as dwarfism and partial sterility. Genetic analysis and map based cloning showed that all the phenotype of S1-60 mutant was caused by a recessive point mutation in the OsCESA9 gene, which encodes the cellulose synthase A subunit 9. This yet uncharacterized missense mutation changed the highly conserved G905 to D at the beginning of the fifth transmembrane domain. The OsCESA9 gene is predominantly expressed in the culms of mature stage plants, consistent with the brittle phenotype in the culm. These results indicate that OsCESA9 plays an important role in cell wall biosynthesis and plant growth. PMID- 23017907 TI - Genome-wide association study (GWAS) of resistance to head smut in maize. AB - Head smut, caused by the fungus Sphacelotheca reiliana (Kuhn) Clint, is a devastating global disease in maize, leading to severe quality and yield loss each year. The present study is the first to conduct a genome-wide association study (GWAS) of head smut resistance using the Illumina MaizeSNP50 array. Out of 45,868 single nucleotide polymorphisms in a panel of 144 inbred lines, 18 novel candidate genes were associated with head smut resistance in maize. These candidate genes were classified into three groups, namely, resistance genes, disease response genes, and other genes with possible plant disease resistance functions. The data suggested a complicated molecular mechanism of maize resistance against S. reiliana. This study also suggested that GWAS is a useful approach for identifying causal genetic factors for head smut resistance in maize. PMID- 23017908 TI - Large-scale characterization of promoters from grapevine (Vitis spp.) using quantitative anthocyanin and GUS assay systems. AB - Successful implementation of cisgenic/intragenic/ingenic technology for crop improvement necessitates a better understanding of the function of native promoters for driving desired gene expression in host plant. Although the genome of grapevine (Vitis vinifera) has been determined, efforts to explore promoter resources for the development of cisgenics are still lacking. Particularly, there is a shortage of constitutive promoters for marker and/or target gene expression in this species. In this work, we utilized an anthocyanin-based color histogram analysis method to evaluate quantitatively a large number of promoters for their ability to activate transgene expression. Promoter fragments corresponding to known genes were amplified from various genotypes and used to drive the VvMybA1 gene of 'Merlot' for anthocyanin production in non-pigmented somatic embryo (SE) explants to infer transcriptional activity. Results revealed that among 15 tested promoters belonging to seven ubiquitin genes, at least three promoters generated constitutive activities reaching up to 100% value of the d35S promoter. In particular, the high activity levels of VvUb6-1 and VvUb7-2 promoters were verified by transient GUS quantitative assay as well as stable anthocyanin expression in sepal and corolla of transgenic tobacco. Variations in promoter activity of different ubiquitin genes in grapevine did not correlate with the presence and sizes of 5' UTR intron, but seemed to be related positively and negatively to the number of positive cis-acting elements and root-specific elements respectively. In addition, several of the 13 promoters derived from a PR1 gene and a PAL gene produced a higher basal activity as compared to previously reported inducible promoters and might be useful for further identification of strong inducible promoters. Our study contributed invaluable information on transcriptional activity of many previously uncharacterized native promoters that could be used for genetic engineering of grapevine. PMID- 23017909 TI - OsMIOX, a myo-inositol oxygenase gene, improves drought tolerance through scavenging of reactive oxygen species in rice (Oryza sativa L.). AB - Myo-inositol oxygenase (MIOX), a unique monooxygenase, catalyzes the oxidation of myo-inositol to d-glucuronic acid. However, the protective role of MIOX in plants against oxidative stress or drought stress remains unknown. In this study, the functional characterization of MIOX obtained from the cDNA library of upland rice (Oryza sativa L. cv. IRAT109), was performed. OsMIOX was expressed predominantly in the roots and induced by drought, H2O2, salt, cold and abscisic acid. The transgenic rice lines overexpressing OsMIOX showed obviously improved growth performance in the medium containing 200 mM mannitol. Further, the survival rate of leaves from the transgenic rice lines was significantly higher than that of the wild type plants under polyethylene glycol treatment. It was discovered that the activity of ROS-scavenging enzymes and proline content, as well as the transcript levels of many ROS scavenging genes were significantly increased in transgenic plants compared to the wild type plants under drought stress conditions. Together, these data suggest that OsMIOX has a specific function in drought stress tolerance by decreasing oxidative damage. PMID- 23017910 TI - Functional studies of soybean (Glycine max L.) seed LEA proteins GmPM6, GmPM11, and GmPM30 by CD and FTIR spectroscopy. AB - The protein and mRNA levels of late embryogenesis abundant (LEA) genes may be linked to osmotic stresses. Here, we characterized three soybean hydrophilic LEA proteins--GmPM11 (LEA I), GmPM6 (LEA II), and GmPM30 (LEA III)--by circular dichroism and Fourier transform infrared spectroscopy. Structural analysis revealed that the LEA proteins adopted high amounts of disordered conformations in solution and underwent conformational changes with hydrophobicity and desiccation induction. Macromolecular interaction studies revealed that the GmPM proteins interact with non-reducing sugars and phospholipids. GmPM6 and GmPM30 but not GmPM11 could prevent beta-aggregation of poly-L-lysine after slow drying. We discuss the possible functions of hydrophilic LEA proteins in maturing seeds. PMID- 23017911 TI - Early-life exposure to lithium and boron from drinking water. AB - The transfer of lithium and boron from exposed mothers to fetuses and breast-fed infants was investigated in areas in northern Argentina and Chile with up to 700 MUg lithium/L and 5-10 mg boron/L in drinking water. Maternal and cord blood concentrations were strongly correlated and similar in size for both lithium (47 and 70 MUg/L, respectively) and boron (220 and 145 MUg/L, respectively). The first infant urine produced after birth contained the highest concentrations (up to 1700 MUg lithium/L and 14,000 MUg boron/L). Breast-milk contained 40 and 60% of maternal blood concentrations of lithium and boron, respectively (i.e. about 30 and 250 MUg/L, respectively, in high exposure areas), and infant urine concentrations decreased immediately after birth (120 MUg lithium/L and 920 MUg boron/L). We conclude that lithium and boron easily passed the placenta to the fetus, and that exclusively breast-fed infants seemed to have lower exposure than formula-fed infants. PMID- 23017912 TI - Consistency of morphological endpoints used to assess developmental timing in zebrafish (Danio rerio) across a temperature gradient. AB - Zebrafish (Danio rerio) are model organisms for testing developmental toxicity at the morphological level. In this study, influence of temperature (24.5-28.5 degrees C) and silver nanoparticles on developmental staging, ear-eye distance, and ratio of ear-eye distance to inner ear diameter was investigated. As temperature decreased, all endpoints showed developmental delay, with differences between endpoints in amount and type of delay measured. Differences in developmental delay patterns were observed, with rate delays increasing over time when staging endpoints were utilized and rates remaining constant when using ear eye measurements. Integrated predictive equations were created to normalize each endpoint for temperature. Influence of image rotation on ear-eye distance accuracy showed that more than 75% eye overlap during analysis is necessary to minimize error. Exposure to silver nanoparticles demonstrated a lack of consistency between developmental endpoints and highlighted the usefulness of a multi-endpoint approach when measuring changes to developmental timing. PMID- 23017913 TI - Improving ability measurement in surveys by following the principles of IRT: The Wordsum vocabulary test in the General Social Survey. AB - Survey researchers often administer batteries of questions to measure respondents' abilities, but these batteries are not always designed in keeping with the principles of optimal test construction. This paper illustrates one instance in which following these principles can improve a measurement tool used widely in the social and behavioral sciences: the GSS's vocabulary test called "Wordsum". This ten-item test is composed of very difficult items and very easy items, and item response theory (IRT) suggests that the omission of moderately difficult items is likely to have handicapped Wordsum's effectiveness. Analyses of data from national samples of thousands of American adults show that after adding four moderately difficult items to create a 14-item battery, "Wordsumplus" (1) outperformed the original battery in terms of quality indicators suggested by classical test theory; (2) reduced the standard error of IRT ability estimates in the middle of the latent ability dimension; and (3) exhibited higher concurrent validity. These findings show how to improve Wordsum and suggest that analysts should use a score based on all 14 items instead of using the summary score provided by the GSS, which is based on only the original 10 items. These results also show more generally how surveys measuring abilities (and other constructs) can benefit from careful application of insights from the contemporary educational testing literature. PMID- 23017914 TI - Latent class analysis of response inconsistencies across modes of data collection. AB - Latent class analysis (LCA) has been hailed as a promising technique for studying measurement errors in surveys, because the models produce estimates of the error rates associated with a given question. Still, the issue arises as to how accurate these error estimates are and under what circumstances they can be relied on. Skeptics argue that latent class models can understate the true error rates and at least one paper (Kreuter et al., 2008) demonstrates such underestimation empirically. We applied latent class models to data from two waves of the National Survey of Family Growth (NSFG), focusing on a pair of similar items about abortion that are administered under different modes of data collection. The first item is administered by computer-assisted personal interviewing (CAPI); the second, by audio computer-assisted self-interviewing (ACASI). Evidence shows that abortions are underreported in the NSFG and the conventional wisdom is that ACASI item yields fewer false negatives than the CAPI item. To evaluate these items, we made assumptions about the error rates within various subgroups of the population; these assumptions were needed to achieve an identifiable LCA model. Because there are external data available on the actual prevalence of abortion (by subgroup), we were able to form subgroups for which the identifying restrictions were likely to be (approximately) met and other subgroups for which the assumptions were likely to be violated. We also ran more complex models that took potential heterogeneity within subgroups into account. Most of the models yielded implausibly low error rates, supporting the argument that, under specific conditions, LCA models underestimate the error rates. PMID- 23017915 TI - Does it matter how you ask? Question wording and males' reporting of contraceptive use at last sex. AB - This paper reports results from a unique experiment conducted in the 2002 National Survey of Family Growth (NSFG) to gauge the effect of question format on men's reports of contraceptive use at last sexual intercourse. Respondents received separate questions about their own and their partners' contraceptive use or one combined question about either partner's contraceptive use. We examine whether receiving separate questions, as opposed to one combined question, is related to higher reports of using any contraceptive method, specific methods, female methods in addition to male methods, and the number of methods reported. We find that reports of any contraceptive use at last sex and use of the most common methods, condoms and the pill, were stable across question formats. However, we find significantly higher reports of withdrawal, combining male and female methods, and multiple method use among men who received the separate question format. We also find that characteristics of the sexual experience in question condition the effect of question format on men's reports. PMID- 23017916 TI - Measuring time use in surveys - Concordance of survey and experience sampling measures. AB - It is still unclear to what extent time allocation retrospectively reported in questionnaires reflects people's actual behavior. Addressing this research gap, we analyze the congruence of time use information assessed through retrospective questionnaires and through experience sampling methodology. Participants completed standard survey questions on time allocation. In addition, a mobile phone-based experience sampling technology obtained snapshots of, on average, 54 momentary activities in which respondents participated while pursuing their normal daily routines. Results indicate that the associations between standard survey questions and experience sampling methods are quite substantial for long lasting and externally structured activities, such as paid work. In contrast, associations between survey and experience sampling methods are somewhat weaker for less externally structured, short-term and infrequent activities, such as errands, housework, and leisure. However, further research is required to elucidate which method (experience sampling method or survey questions) results in more reliable and valid measures for short-term and sporadic activities. PMID- 23017917 TI - Knowledge and beliefs about national development and developmental hierarchies: The viewpoints of ordinary people in thirteen countries. AB - Scholars and policy makers have for centuries constructed and used developmental hierarchies to characterize different countries. The hypotheses motivating this paper are that such social constructions have been circulated internationally, are constructed similarly in various countries, and follow the social constructions of elite international organizations, such as the United Nations. This paper uses data from 15 surveys in 13 diverse countries to study how developmental hierarchies are understood in everyday life. Our research shows that most people have constructions of developmental hierarchies that are similar across countries and are similar to the developmental hierarchies constructed by the United Nations. These findings suggest that developmental hierarchies are widely understood around the world and are widely available to ordinary people as they make decisions about many aspects of life. PMID- 23017918 TI - Societal projection: Beliefs concerning the relationship between development and inequality in China. AB - We examine how the relationship between development and inequality at the societal level is perceived and evaluated by ordinary Chinese people. We hypothesize that because the Chinese have recently experienced rapid increases in both economic growth and social inequality, they tend to view economic development as a driving force of social inequality. To address this question, we conducted a social survey in 2006 in six Chinese provinces (n=4898). The survey data reveal that a large proportion of Chinese people have internalized a causal model in which they project high levels of inequality onto countries they view as more developed and low levels of inequality onto countries they see as less developed. However, results also show that a smaller proportion of Chinese believe in a negative relationship between development and inequality. Hence, the study reveals heterogeneity among ordinary Chinese in their perceptions of the causal relationship between development and inequality. Surprisingly, socioeconomic and demographic characteristics provide no explanatory power in explaining this heterogeneity. PMID- 23017919 TI - Contextual influences on environmental concerns cross-nationally: A multilevel investigation. AB - Environmental issues continue to grow in international prominence, as environmental conditions are recognized as some of the most important problems facing the world. Research examining this globalization of environmental concern shown in public opinion surveys emphasizes the importance of context yet is currently underspecified. To address this gap, this research uses a multi-level, cross-national study to examine individual-level and country-level influences on three measures of environmental concern: environmental threat awareness, environmental efficacy, and willingness to pay. At the individual level, education, age, and gender affect environmental concerns. At the national level, economic, political, and environmental factors affect environmental concerns. Importantly, contextual factors differ in their effects depending on the dimension of environmental concern measured. Results from cross-level interactions for education confirm these complexities across these measures, supporting a dimensionality argument. The importance of the measurement of environmental concern shown in this research is emphasized for future cross national scholarship. PMID- 23017920 TI - Uneven transitions: Period- and cohort-related changes in gender attitudes in China, 1995-2007. AB - This paper analyzes temporal variations in two gender attitudes in China: beliefs about gender equality and perspectives on women's combined work and family roles. It uses the most currently available population series from the 1995, 2001 and 2007 World Value Surveys of 4500 respondents and a series of multilevel cross classified models to properly estimate period and cohort effects. Attitudes toward women's dual roles manifest neither period nor cohort effects; the population displays a universal high level of acceptance of women's paid employment. Orientations toward gender equality manifest both cohort and period effects: members of the youngest cohort of both sexes hold the most liberal attitudes; the positive effect of college education has increased over time. Attitude toward gender equality in China displays neither a shift toward conservatism nor an over-time trend toward egalitarianism in 1995-2007, a time of rapid economic growth. PMID- 23017921 TI - Assimilation by the third generation? Marital choices of white ethnics at the dawn of the twentieth century. AB - It is well known that marital ethnic endogamy declines by immigrant generation, but there is little information on how many generations are required for full marital assimilation. This study for 1880-1910 includes information on the birthplace of men's grandparents, so we can compare the first, second, third, and later generations. We estimate the odds of marrying a native white woman with native-born parents (NWNP) for Irish, Germans, British, and men of other ethnicities. Most groups even in their third generation still show a significantly lower rate of marital assimilation than native stock men. But mixed ancestry (having at least one NWNP parent or grandparent) can result in nearly complete marital assimilation by the third generation. PMID- 23017922 TI - Irreconcilable differences? Ethnic intermarriage and divorce in the Netherlands, 1995-2008. AB - This study uses population data of the Netherlands (municipality registers) between 1995 and 2008 to describe and explain the occurrence of divorce among recently newlywed interethnic and mono-ethnic couples (N=116,745). In line with homogamy theory, divorce risks are higher for interethnic couples, in particular if the spouses were born and raised in countries that are culturally distant from each other. In addition, the effect of cultural distance is smaller for second generation immigrants than for first generation immigrants. There is no evidence for a higher risk of divorce among Black-White marriages. In line with convergence theory, results show that the higher the divorce propensity in the wife's origin country, the higher the divorce risk of a couple is. PMID- 23017923 TI - Unintended fertility and the stability of coresidential relationships. AB - Having an unintended birth is associated with maternal and child health outcomes, the mother-child relationship, and subsequent fertility. Unintended fertility likely also increases the risk of union dissolution for parents, but it is unclear whether this association derives from a causal effect or selection processes and whether it differs by union type. This article uses data from the 2002 National Survey of Family Growth to compare union stability after intended and unintended births in coresidential relationships. Results show that coresidential couples are more likely to break up after an unintended first or higher-order birth than after an intended first or higher-order birth, even when accounting for stable unobserved characteristics using fixed-effects models. The negative association is stronger for marriages than cohabitations, despite the overall higher dissolution rate of cohabiting unions. We conclude that unintended fertility at any parity is disruptive for coresidential couples in ways that increase the risk of union dissolution. PMID- 23017925 TI - Income inequality and participation: A comparison of 24 European countries. AB - Previous research suggests that when there is a high level of inequality, there is a low rate of participation. Two arguments are generally offered: First, inequality depresses participation because people from different status groups have fewer opportunities to share common goals. Second, people may participate more in civic and social life when they have more resources. However, until now, these explanations have not been separated empirically. Using EU-SILC data for 24 European countries, we analyze how income inequality is related to civic and social participation. Our results indicate that the main effects of inequality manifest via resources at the individual and societal level. However, independent of these resources, higher inequality is associated with lower civic participation. Furthermore, inequality magnifies the relationship between income and participation. This finding is in line with the view that inter-individual processes explain why inequality diminishes participation. PMID- 23017924 TI - Extended household transitions, race/ethnicity, and early childhood cognitive outcomes. AB - Beyond mothers' union status transitions, other adults' transitions into and out of the household contribute to family instability, particularly in early childhood. Using the Early Childhood Longitudinal Study-Birth Cohort (N?8550), this study examines associations between extended household transitions and age 2 cognitive development. A substantial minority of toddlers experiences these transitions, and their consequences vary by household member type, entry versus exit, and race/ethnicity. Extended household transitions predict lower cognitive scores for white children, but the selection of low-socioeconomic status families into extended households explains these disparities. Grandparent transitions predict significantly higher cognitive scores for African American and Latino children than whites, and some "other adult" transitions predict higher scores for Latinos than African Americans and whites. Extended household transitions' consequences are independent of co-occurring residential moves and partner transitions. Findings suggest that studying extended household transitions is useful for understanding children's early development, and their consequences vary by race/ethnicity. PMID- 23017926 TI - Compensating differentials, labor market segmentation, and wage inequality. AB - Two literatures on work and the labor market draw attention to the importance of non-pecuniary job amenities. Social psychological perspectives on work suggest that workers have preferences for a range of job amenities (e.g. Halaby, 2003). The compensating differentials hypothesis predicts that workers navigate tradeoffs among different job amenities such that wage inequality overstates inequality in utility (Smith, 1979). This paper joins these perspectives by constructing a new measure of labor market success that evaluates the degree to which workers' job amenity preferences and outcomes match. This measure of subjective success is used to predict workers' job satisfaction and to test the hypothesis that some degree of labor force inequality in wages is due to preference-based tradeoffs among all job amenities. Findings demonstrate that the new measure predicts workers' job satisfaction and provides evidence for the presence of compensating differentials in the primary and intermediate, but not secondary, labor markets. PMID- 23017927 TI - The 'friendship dynamics of religion,' or the 'religious dynamics of friendship'? A social network analysis of adolescents who attend small schools. AB - Longitudinal social network data on adolescents in seven schools are analyzed to reach a new understanding about how the personal and interpersonal social dimensions of adolescent religion intertwine together in small school settings. We primarily address two issues relevant to the sociology of religion and sociology in general: (1) social selection as a source of religious homophily and (2) friend socialization of religion. Analysis results are consistent with Collins' interaction ritual chain theory, which stresses the social dimensions of religion, since network-religion autocorrelations are relatively substantial in magnitude and both selection and socialization mechanisms play key roles in generating them. Results suggest that socialization plays a stronger role than social selection in four of six religious outcomes, and that more religious youth are more cliquish. Implications for our understanding of the social context of religion, religious homophily, and the ways we model religious influence, as well as limitations and considerations for future research, are discussed. PMID- 23017928 TI - High political participation, high social capital? A relational analysis of youth social capital and political participation. AB - Social capital has been alleged to increase the capacity for political mobilization. Yet, until now, the empirical debate has not succeeded in rendering a detailed account of the relationships between social capital and political participation partly because of the use of a reductive conception and operationalization of both concepts. Using a multidimensional and relational technique (multiple correspondence analysis) and a detailed youth survey data from Belgium, the article demonstrates that youth draw on diverse forms of social capital and that these forms vary along socio-economic status and ethnic origin. Six classes based on the forms of social capital were identified. Two of them - the 'Committed' and 'Religious' are highly political active. The 'Committed' Class, based on a diversified social capital, consists mainly of non-immigrant youth with a high socio-economic background undertaking a large diversity of political activities. The 'Religious' Class, based on a narrow social capital built around religious activities, is mostly composed of ethnic minority youth with a low SES involved in more specific political activities. PMID- 23017930 TI - Another cost of being a young black male: Race, weaponry, and lethal outcomes in assaults. AB - We examine the effect of the race, age, and gender of victims of assault on the offenders' use of weapons and lethal intent. Evidence from the National Incident Based Reporting System (NIBRS) suggests that offenders are particularly likely to use guns against young black men-a three-way interaction - and to kill black males and young black adults. Black offenders respond more strongly to the victim's race than do white offenders. As a result of these effects, a violent incident between two young black men is about six times more likely to involve a gun than a violent incident between two young white men. We suggest that adversary effects, i.e., an offender's tactical response to the threat posed by adversaries, help explain why violence in black communities tends to be much more serious than violence in white communities. PMID- 23017929 TI - Marijuana use development over the course of adolescence among North American Indigenous youth. AB - This study investigated the links between marijuana use trajectories and marijuana abuse/dependence (DSM-IV) using five waves of data from 718 North American Indigenous adolescents between 10 and 17years from eight reservations sharing a common language and culture. Growth mixture models indicated that 15% of youth began using by 11-12years of age and that another 20% began shortly thereafter. These early users had odds of abuse/dependence 6.5 times larger than abstainers. Girls were also unexpectedly found to be particularly at risk of early use, and this did not reflect other background and psychosocial factors, including friend use. While the timing, patterns, and consequences of use were similar to those reported for alcohol use previously, the social influences on use differed in important ways. PMID- 23017932 TI - Rush to the border? Market liberalization and urban- and rural-origin internal migration in Mexico. AB - In this study we examine the social and economic factors driving internal migration flows in Mexico. We pay particular attention to the effect that economic liberalization has had in encouraging migration to border cities. Our analysis of the origin and destination of migrants is carried out at a finer level of geographical detail than ever before. Microdata files from the 2000 population census allow us to distinguish urban- and rural-origin migrants to the largest 115 cities and metropolitan areas in the country. Our results indicate that economic liberalization, measured by the level of foreign investment and employment in the maquiladora export industry, strongly influences migrants' choice of destinations. However, economic liberalization fails to fully account for the attraction of the border, as do the higher emigration rates to the United States from border cities. Our analysis also reveals that migrants to the border region and to cities with high levels of foreign investment are younger, less educated and more likely to be men than migrants to other parts of Mexico. Rural migrants are significantly more likely to move to the border and to cities with high levels of foreign investment than urban migrants. The results of our study have important implication for other countries opening their economies to foreign investment and international trade. PMID- 23017931 TI - Participation in international human rights NGOs: The effect of democracy and state capacity. AB - This study examines the effect of the state on participation in human rights international non-governmental organizations (INGOs) from 1966 through 2006, using random effects negative binomial models. Civic participation in human rights INGOs is not responsive to human rights abuses of the state, but is affected by the institutional environment provided by the state. Two intertwined dimensions within the state, democracy and state capacity, are found to be important in explaining cross-national variation in this participation. Strong state capacity magnifies the effect of democracy. A strong democratic state generates the most favorable condition. A strong but authoritarian state, however, is the most unfavorable, because it has both the motive and the capacity to restrain its citizens' global civic engagement. In contrast, an authoritarian but weak state lacks adequate capacity to intervene, and thus tolerates more participation than its strong counterpart. Over time differential participation across different types of states has not been diminished. This study reveals the role of the state in mediating between local citizens and global civil society, and develops a state-centered explanation for unequal participation in human rights INGOs across countries. PMID- 23017933 TI - White ethnic residential segregation in historical perspective: US cities in 1880. AB - Investigating immigrant residential patterns in 1880 offers a baseline for understanding residential assimilation trajectories in subsequent eras. This study uses 100% count information from the 1880 Census to estimate a multilevel model of ethnic isolation and exposure to native whites in 67 cities for individual Irish, German and British residents. At the individual level, the key predictors are drawn from assimilation theory: nativity, occupation, and marital status. The multilevel model makes it possible to control for these predictors and to study independent sources of variation in segregation across cities. There is considerable variation at the city level, especially due to differences in the relative sizes of groups. Other significant city-level predictors of people's neighborhood composition include the share of group members who are foreign-born, the disparity in occupational standing between group members and native whites, and the degree of occupational segregation between them. PMID- 23017934 TI - Doubling up when times are tough: A study of obligations to share a home in response to economic hardship. AB - This study uses a factorial vignette design embedded in an Internet survey to investigate attitudes toward an adult child and parent living together in response to economic hardship. Over half of Americans said the desirability of intergenerational co-residence depends on particularistic aspects of the family, notably the quality of family relationships. Support for co-residence is greatest when the adult child is single rather than partnered. Support is weaker if the adult child is cohabiting rather than married to the partner, although groups with greater exposure to cohabitation make less of a distinction between cohabitation and marriage. Presence of a grandchild does not affect views about co-residence. There is more support for sharing a home when a mother needs a place to live than when the adult child does. Responses to open-ended questions show that individuals invoke both universalistic family obligations and particularistic qualities of family relationships to explain their attitudes. PMID- 23017935 TI - School co-ethnicity and Hispanic parental involvement. AB - Scholars of immigration disagree about the role ethnic communities play in immigrant families' engagement in educational institutions. While some researchers argue that the concentration of disadvantaged ethnic groups may prevent meaningful engagement with schools, others argue that ethnic communities can possess resources that help immigrant families be involved in their children's schooling. In this study we use a nationally representative dataset of Hispanic children from the Early Childhood Longitudinal Study, Kindergarten Cohort (ECLS-K) to determine if the relative size of the Hispanic population in the school affects levels of their parents' involvement in their education, as well as parents' perceptions of barriers to their involvement. Our results suggest that a large Hispanic presence in a child's school can help increase immigrant Hispanic parents' involvement in their children's schooling, but there are no benefits for US-born Hispanic parents, indicating that ethnic communities help immigrant families acculturate to American institutions. PMID- 23017936 TI - Decision-making in DIEP and ms-TRAM flaps: the potential role for a combined laser Doppler spectrophotometry system. AB - BACKGROUND: Three-dimensional (3D)-imaging modalities for pre-operative mapping of perforators in DIEP and ms-TRAM flap surgery are well established. While zonal perfusion of such flaps has been extensively studied pre-, intra- and post operatively, the role of objective perfusion assessment for decision making between different possible perforator configurations has not been investigated yet. In this study, a combined lased Doppler spectrophotometry (CLDS) system was applied intra-operatively to support the surgeon's decision-making process. METHODS: In this prospective study, 25 consecutive unilateral abdominal flaps were included. Computed tomographic angiography (CTA) was performed prior to surgery. By CLDS the post-capillary oxygen saturation, relative haemoglobin content and relative bloodflow were determined at different time points and in four standardised zones in dependence of different possible perforator/pedicle vessel configurations (with selective clamping of different perforators and/or the superficial inferior epigastric vein). Results were correlated with clinical findings and late results were evaluated after 6-16 months. RESULTS: Ninety-six percent of the flaps survived. No significant fat necrosis was observed. While there was a high correlation between clinical findings and CLDS results, CLDS was more sensitive in identification of venous congestion of DIEP flaps. The technique helped to identify the dominant perforator(s) in flaps where perfusion patterns were unclear. CLDS influenced intra-operative decision making in five cases (two venous and one arterial in-flap anastomosis and inclusion of additional perforators in two flaps). CONCLUSION: Intra-operative use of CLDS helps to objectively determine perfusion patterns in abdominal flaps. CLDS might be applicable in 'complex' abdominal flaps (e.g., after previous abdominal surgery or when preoperative CTA does not provide conclusive results) and supports, in these cases, intra-operative decision-making. PMID- 23017937 TI - Qualified kidney biomarkers and their potential significance in drug safety evaluation and prediction. AB - The kidney is one of the major organs drug toxicity may target. Some renal safety biomarkers have been proposed to measure kidney injury and function accordingly. Despite the widespread use for diagnosis and monitoring of renal injury and function for decades, serum creatinine and blood urea nitrogen are nonspecific biomarkers with insensitive and delayed response in the clinical setting. There is an urgent need to identify and qualify novel kidney safety biomarkers that would be used to detect and predict drug-induced nephrotoxicity in preclinical toxicological studies, clinical trials and patient care in sequence. To do that, eight novel renal safety biomarkers have been well characterized and qualified for preclinical drug safety screening, and their clinical bridging validation is underway as well. Of them, some are used to detect or predict proximal tubular injury, and others are used to diagnose and monitor glomerular damage. Thus, measurement of a panel of kidney safety biomarkers in parallel would help maximally capture all potential safety signals for a more informative decision to be made in drug research and development as well as for optimal selection of the drug and its dose in clinical practice. PMID- 23017938 TI - Integrative physiology of depression and antidepressant drug action: implications for serotonergic mechanisms of action and novel therapeutic strategies for treatment of depression. AB - Major depressive disorder (MDD) is predicted to be the second leading cause of disability worldwide by the year 2020. Currently available treatments for MDD are suboptimal. Only 50% of MDD patients recover in less than 12 weeks with adequate treatment, and up to 20% of patients will fail to adequately respond to all currently available interventions. Moreover, current treatments come at the cost of significant central nervous system (CNS) side effects, further highlighting the need for more effective treatments with fewer side effects. A greater mechanistic understanding of MDD and the actions of antidepressant drugs would provide opportunities for development of novel therapeutic approaches to treatment. With this aim in mind, we explore the novel, but empirically supported, hypothesis that an evolutionarily ancient thermoafferent pathway, signaling via the spinoparabrachial pathway from serotonergic sensory cells in the skin and other epithelial linings to serotonergic neurons and depression related circuits in the brain, is dysfunctional in MDD and that antidepressant therapies, including antidepressant drugs and exercise, act by restoring its function. PMID- 23017939 TI - Monkey bites among US military members, Afghanistan, 2011. AB - Bites from Macaca mulatta monkeys, native to Afghanistan, can cause serious infections. To determine risk for US military members in Afghanistan, we reviewed records for September-December 2011. Among 126 animal bites and exposures, 10 were monkey bites. Command emphasis is vital for preventing monkey bites; provider training and bite reporting promote postexposure treatment. PMID- 23017940 TI - Clostridium difficile clinical isolates exhibit variable susceptibility and proteome alterations upon exposure to mammalian cationic antimicrobial peptides. AB - Clostridium difficile is a leading cause of hospital-acquired bacterial infections in the United States, and the increased incidence of recurrent C. difficile infections is particularly problematic. The molecular mechanisms of C. difficile colonization, including its ability to evade host innate immune responses, is poorly understood. We hypothesized that epidemic-associated C. difficile clinical isolates would exhibit increased resistance to mammalian, gut associated, cationic antimicrobial peptides such as the cathelicidin LL-37. Standardized susceptibility tests as well as comparative proteomic analyses revealed that C. difficile strains varied in their responses to LL-37, with epidemic-associated 027 ribotype isolates displaying greater resistance. Further, exposure of C. difficile strains to sub-lethal concentrations of LL-37 resulted in increased resistance to subsequent peptide challenge, suggesting the presence of inducible resistance mechanisms. Correspondingly, LL-37 exposure altered the C. difficile proteome, with marked changes in abundance of cell wall biosynthesis proteins, surface layer proteins, ABC transporters and lysine metabolism pathway components. Taken together, these results suggest that innate immune avoidance mechanisms could facilitate robust colonization by C. difficile. PMID- 23017941 TI - Colon cancer stem cells resist antiangiogenesis therapy-induced apoptosis. AB - Antiangiogenesis is an efficient therapy for eliminating colon cancers, but because of recurrence it remains only palliative. We hypothesized that certain populations of tumor cells resist antiangiogenesis-induced apoptosis and explored the underlying mechanism. We demonstrated that the CD133(+) population of cells in colon cancer is resistant to anti-angiogenesis therapy. Additionally, we identified an anti-apoptotic signaling pathway responsible for this resistance involving PP2A, p38MAPK, MAPKAPK2, and Hsp27. Thus, this pathway may offer a new avenue to develop target therapy for colorectal cancer. PMID- 23017942 TI - Nanophotosensitizers toward advanced photodynamic therapy of Cancer. AB - Photodynamic therapy (PDT) is a non-invasive treatment modality for selective destruction of cancer and other diseases and involves the colocalization of light, oxygen, and a photosensitizer (PS) to achieve photocytotoxicity. Although this therapeutic method has considerably improved the quality of life and life expectancy of cancer patients, further advances in selectivity and therapeutic efficacy are required to overcome numerous side effects related to classical PDT. The application of nanoscale photosensitizers (NPSs) comprising molecular PSs and nanocarriers with or without other biological/photophysical functions is a promising approach for improving PDT. In this review, we focus on four nanomedical approaches for advanced PDT: (1) nanocarriers for targeted delivery of PS, (2) introduction of active targeting moieties for disease-specific PDT, (3) stimulus-responsive NPSs for selective PDT, and (4) photophysical improvements in NPS for enhanced PDT efficacy. HIGHLIGHTS: ? Conservation of normal tissues demands non-invasive therapeutic methods. ? PDT is a light activated, non-invasive modality for selective destruction of cancers.? Success of PDT requires further advances to overcome the limitations of classical PDT. ?Nanophotosensitizers help improve target selectivity and therapeutic efficacy of PDT. PMID- 23017943 TI - Treatment of intractable oral lichen planus with intravenous immunoglobulin therapy. PMID- 23017945 TI - Bloom forming and toxic phytoplankton in transitional and coastal waters of Cantabria region coast (Southeastern Bay of Biscay, Spain). AB - Phytoplankton monitoring has extended to practically all the regions of the European coast due to the implementation of the European Water Framework Directive. In this way, the study of phytoplankton taxonomic composition and dynamic is being performed in many areas poorly studied or not studied before. During the last years, a monitoring programme has been carried out at the coast of Cantabria region (SE Bay of Biscay); the presence of some potentially toxic and bloom forming species (>7.5 * 105 cells per litre) has been observed. Diatoms and cryptophytes are the main blooming taxa in this region in the majority of the estuaries and in some of the coastal sites. All estuaries and coastal stations showed at least one potentially toxic species, being the dinoflagellates the group with the highest number of taxa observed. The potentially toxic species found in highest concentrations were the genera Pseudo-nitzschia and Chrysochromulina. PMID- 23017944 TI - The management of osteoporosis in breast cancer survivors. AB - Breast cancer is a common diagnosis and the majority of women treated will be cured. Women with early stage breast cancer may be at increased risk for osteoporosis due to anticancer therapies. Chemotherapy induced amenorrhea and the use of anti-estrogens can promote bone loss; thus, the management of bone health in women with breast cancer is an important component of survivorship care. Osteoporosis is considered a "silent" disease as there are often no discrete warning signs, until a fracture occurs; therefore, clinicians must be cognizant of the underlying risk for osteoporosis and co-morbid conditions and/or medications that accelerate risk of fracture. Breast cancer therapies that effect bone, screening for bone loss and interventions to mitigate the treatment toxicities are reviewed. PMID- 23017946 TI - Mercury levels in selected bycatch fish species from industrial shrimp-trawl fishery in the SE Gulf of California. AB - Baseline Hg concentration in bycatch fish from the SE Gulf of California were determined in muscle and liver of 19 species. Levels of Hg in muscle were compared with legal limits of this element in national and international legislation. Considering all fish species, mean concentrations in liver (2.458+/ 1.997 MUg g-1) were significantly higher (p<0.05) than in muscle (0.993+/-0.670 MUg g-1). The sequence of averaged Hg concentrations in most ichthyofauna was liver>muscle. Highest level of Hg in muscle (2.556 MUg g-1) and liver (7.515 MUg g-1) corresponded to Diapterus peruvianus and Ophioscion strabo, respectively. Considering muscle samples, none of the species had levels of Hg above the limit (1.0 MUg g-1 wet weight) in the Mexican legislation; with respect to the Japanese (0.4 MUg g-1 wet weight) and British (0.3 MUg g-1 wet weight) legislations, 26.3% and 31.6% of the species respectively, were above the corresponding limits. PMID- 23017947 TI - Remediation of muddy tidal flat sediments using hot air-dried crushed oyster shells. AB - In order to prove that hot air-dried crushed oyster shells (HACOS) are effective in reducing hydrogen sulfide in muddy tidal flat sediments and increasing the biomass, field experiments were carried out. The concentration of hydrogen sulfide in the interstitial water, which was 16 mg SL(-1) before the application of HACOS, decreased sharply and maintained almost zero in the experimental sites (HACOS application sites) for one year, whereas it was remained at ca. 5 mg SL( 1) in the control sites. The number of macrobenthos individuals increased to 2 4.5 times higher than that in the control site. Using a simple numerical model, the effective periods for suppression of hydrogen sulfide were estimated to be 3.2-7.6 and 6.4-15.2 years for the experimental sites with 4 and 8 tons per 10 * 10 * 0.2m area, respectively. From these results, it is concluded that HACOS is an effective material to remediate muddy tidal flats. PMID- 23017948 TI - Evaluation of spatial and temporal variations of inorganic nutrient species in the eastern Aegean Sea waters. AB - In this study, the state of the five stations' quality was assessed on the basis of determination of temporal and spatial variability of nutrients with physicochemical variables. Besides this, organic matter of sediment, secchi disc depth and suspended solids were also determined. The samples were collected seasonally from different areas such as harbor and important touristic marinas along the eastern Aegean during June 2008-2009. As a result, the nutrients ranged between NH4: 0.10-25.6, NO2: 0.01-1.5, NO3: 0.19-7.0, o.PO4: 0.17-6.8, TPO4: 0.32 9.6 and Si: 0.30-13.8 MUM, respectively. Precipitation leads to large changes in temperature, salinity, dissolved oxygen and nutrients. The highest nutrient values in this study were observed during the rainy season except o.PO4-P and TPO4-P. However, the physico-chemical variables have exhibited considerable temporal variations while nutrients showed spatial differences. The relatively high nutrient increase in the sampling stations coupled with surface runoff events during rainy period and pollution arising from both point and non-point sources. PMID- 23017949 TI - Seagrass burial by dredged sediments: benthic community alteration, secondary production loss, biotic index reaction and recovery possibility. AB - In 2005, dredging activities in Arcachon Bay (France) led in burying 320,000 m(2) of Zostera noltii intertidal seagrass. Recovery by macrobenthos and seagrass was monitored. Six months after works, seagrass was absent and macrobenthos drastically different from surrounding vegetated stations. Rapidly and due to sediment dispersal, disposal area was divided into a sandflat with a specific benthic community which maintained its difference until the end of the survey (2010), and a mudflat where associated fauna became similar to those in adjacent seagrass. Macrobenthic community needs 3 years to recover while seagrass needs 5 years to recover in the station impacted by mud. The secondary production loss due to works was low. In this naturally carbon enriched system, univariate biotic indices did not perform well to detect seagrass destruction and recovery. Multivariate index MISS gave more relevant conclusions and a simplified version was tested with success, at this local scale. PMID- 23017950 TI - On the relevance of meiobenthic research for policy-makers. AB - The need for scientific advice to manage the aquatic environment in an ecosystem context has never been greater. Many assessments of ecosystem state and change use inadequate data on non-conspicuous, non-target organisms. These include meiofauna, a diverse group of small-sized organisms (<1 mm) that live in a range of terrestrial and aquatic environments. Meiobenthic research published between 2007 and 2011 has failed to underpin ecosystem management and conservation practices. This is partly because of the belief amongst decision-makers and the public that microscopic organisms beyond our normal range of perception are ecologically unimportant. Methodological limitations related to the taxonomic identification of small-sized organisms and the narrow scope of many contemporary meiofauna studies are also to blame. This article explores ways in which meiobenthologists can improve the impact and uptake of their research. PMID- 23017951 TI - Trace elements in two marine fish species during estuarine residency: non essential versus essential. AB - Trace element levels in fish are of particular interest, owing the potential risk to human health. In accordance, juveniles of Dicentrarchus labrax and of Liza aurata were sampled and arsenic, cadmium, chromium, selenium and zinc were determined in the muscle. The levels of trace elements in muscle demonstrated to be similar for both species and sites, with the exception of selenium levels at reference, which seemed to be higher in D. labrax. Moreover, apart from arsenic levels in muscle, all elements were in conformity with the existent regulatory guidelines for fish consumption. The dietary intake of each element was also calculated, with arsenic and selenium showing intakes above the recommended dietary allowances. Nevertheless, no arsenic speciation was carried out and thus no accurate risk evaluation could be established. Additionally, selenium levels never exceeded the dietary allowances more than five times, which are considered safe. PMID- 23017952 TI - Hair sampling location in harbor seals (Phoca vitulina) affects selenium and mercury concentrations: implications for study design of trace element determination in pinnipeds. AB - Hair is used to determine trace elements exposure and status of pinnipeds because it is an excretory route for many elements and can be collected non-lethally. Despite increased use, there have been few studies on how sampling designs and procedures (e.g., hair type, collection site) affect results. The objective of this study was to determine whether concentrations of an essential (selenium; Se) and non-essential element (mercury; Hg) differed between hair samples collected from two body locations on harbor seals (Phoca vitulina). Concentrations of Se and total Hg (THg) differed between mid-dorsal midline and neck samples, and although the absolute differences were relatively small (Delta(absolute) Se = 0.69 MUg g(-1), Delta(absolute) THg = 2.86 MUg g(-1)), the relative differences were large (Delta(relative) Se = 49%, Delta(relative) THg = 17%). These differences highlight the need to standardize the collection site for trace element determination in pinnipeds. PMID- 23017953 TI - Duffy phenotype and Plasmodium vivax infections in humans and apes, Africa. PMID- 23017954 TI - Introductory remarks. PMID- 23017955 TI - The editorial process and politicized scholarship: monday morning editorial quarterbacking and a call for scientific vigilance. PMID- 23017956 TI - Letter to the editors and advisory editors of Social Science Research. PMID- 23017957 TI - Letter to the editor. PMID- 23017958 TI - Presentation, politics, and editing: The Marks/Regnerus articles. PMID- 23017959 TI - Methodological decisions and the evaluation of possible effects of different family structures on children: The new family structures survey (NFSS). AB - Every social science researcher must make a number of methodological decisions when planning and implementing research projects. Each such decision carries with it both advantages and limitations. The decisions faced and made by Regnerus (2012) are discussed here in the wider context of social science literature regarding same-sex parenting. Even though the apparent outcomes of Regnerus's study were unpopular, the methodological decisions he made in the design and implementation of the New Family Structures Survey were not uncommon among social scientists, including many progressive, gay and lesbian scholars. These decisions and the research they produced deserve considerable and continued discussion, but criticisms of the underlying ethics and professionalism are misplaced because nearly every methodological decision that was made has ample precedents in research published by many other credible and distinguished scholars. PMID- 23017960 TI - Parental same-sex relationships, family instability, and subsequent life outcomes for adult children: Answering critics of the new family structures study with additional analyses. AB - The July 2012 publication of my study on the outcomes of young adults who report parental same-sex relationship behavior raised a variety of questions about the New Family Structures Study and my analyses and interpretations of it. This follow-up article seeks to address a variety of the more common criticisms that have been raised, to offer new commentary and analyses, and to pose questions for future analysts of the NFSS and other datasets that are poised to consider how household dynamics are associated with youth and young-adult outcomes. The new analyses I present here still reveal numerous differences between adult children who report maternal same-sex behavior (and residence with her partner) and those with still-married (heterosexual) biological parents. Far fewer differences appear between the former and several other groups, most notably never-married single mothers. PMID- 23017961 TI - Comment. PMID- 23017962 TI - Residualization is not the answer: Rethinking how to address multicollinearity. AB - Here I show that a commonly used procedure to address problems stemming from collinearity and multicollinearity among independent variables in regression analysis, "residualization", leads to biased coefficient and standard error estimates and does not address the fundamental problem of collinearity, which is a lack of information. I demonstrate this using visual representations of collinearity, hypothetical experimental designs, and analyses of both artificial and real world data. I conclude by noting the importance of examining methodological practices to ensure that their validity can be established based on rational criteria. PMID- 23017963 TI - Estimating the prevalence of xenophobia and anti-Semitism in Germany: A comparison of randomized response and direct questioning. AB - An experimental CATI-survey (N=2041), asking sensitive questions about xenophobia and anti-Semitism in Germany, was conducted to compare the randomized response technique (RRT) and the direct questioning technique. Unlike the vast majority of RRT surveys measuring the prevalence of socially undesirable behaviors, only few studies have explored the effectiveness of the RRT with respect to the disclosure of socially undesirable opinions. Results suggest that the RRT is an effective method eliciting more socially undesirable opinions and yielding more valid prevalence estimates of xenophobia and anti-Semitism than direct questioning ('more-is-better' assumption). Furthermore, the results indicate that with increasing topic sensitivity, the benefits of using the RRT also increase. Finally, adapted logistic regression analyses show that several covariates such as education and generalized trust are related to the likelihood of being prejudiced towards foreigners and Jews. PMID- 23017964 TI - Understanding the resilience of mail-back survey methods: An analysis of 20years of change in response rates to national park surveys. AB - Coverage and response rate challenges facing telephone and internet surveys have encouraged scientists to reconsider mail data collection methods. Although response rates to telephone surveys have declined sharply in the last 20years, it is unclear how response rates to mail have fared during this time. This study analyzes 179 mail-back surveys of visitors to US National Parks from 1988 to 2007, which used virtually the same administration procedures throughout the period. Results show that response rates, based on only those who initially agreed to return a questionnaire, have remained at a high level with a 76% average while the number of questions and pages steadily increased. Despite this rise in response burden, rates have declined only moderately from about 80% in the late 1980s to about 70% more recently. The roles of additional contacts and survey salience in maintaining high response rates are examined. Results suggest that mail-back surveys for obtaining information from quasi-general public populations remain an effective data collection procedure. PMID- 23017965 TI - Item non-response in open-ended questions: Who does not answer on the meaning of left and right? AB - The left-right ideological dimension plays a central role in political science research. The meaning of left and right is often based on analyses of responses to open-ended survey questions. In the 2008 German General Social Survey, item non-response to two particular open-ended questions on the meaning of left and right was considerable and calls for analyses of the value of the data have been received. In our paper we investigate item non-response to these two open-ended questions in terms of cognitive abilities, motivational aspects, and finally, in relation to the left-right self-placement scale itself. Item non-response in the open-ended questions is not based on randomness alone, and analyses show some significant systematic results. Thus, the open-ended questions seem to be biased and the validity of this data is questionable in some respect. In this context, left-right self-placement of non-respondents and "cognitive don't knowers" need to be given careful consideration. PMID- 23017966 TI - The source of Black-White inequality in early language acquisition: Evidence from Early Head Start. AB - I compare language learning trajectories for Black and White children over the first 3years of life using data from the Early Head Start Research and Evaluation study (EHSRE) in order to determine the timing and source of divergence in early language skill. Results indicate that that while controlling for racial differences in family background and a measure of the home language environment cannot entirely account for disparities in language acquisition, interactions between age, race and maternal education, and between race and a time-varying measure of the home language environment play a significant role. I show that returns to parental education and the home language environment, in terms of language learning, are higher for White children than their Black peers. Specification checks confirm that these results are robust to alternate definitions of child language and the home language environment, and that no interactions between race, age and any of the other covariates are significant. I discuss possible explanations for these race specific education gradients, including measurement error and test bias. In addition, I address relevant empirical issues in estimating language growth with respect to linguistic inputs and the home language environment. PMID- 23017967 TI - College-bound friends and college application choices: Heterogeneous effects for Latino and White students. AB - Friends are among the most influential social forces affecting adolescent behavior, yet little work has focused on the influence of friends on the decision to apply to college. Using data from the senior cohort of the Texas Higher Education Opportunity Project, we employed propensity score matching with sensitivity analyses to investigate links between having college-oriented friends and applying to college. We found that college-oriented friends increased the likelihood of applying to any college and to 4-year colleges, both for White and Latino students. However, Latino students benefited less from college-oriented friends compared to White students. Our findings suggest that college-choice models should more directly account for the influence of friends in applying to college, taking account of racial and ethnic differences, and future research should explore why Latino students benefit less. PMID- 23017968 TI - The role of exchange and emotion on commitment: A study of teachers. AB - Recent experimental work in social exchange offers keen insight into factors that enhance commitment to individuals, groups, and relationships. In this article we explore the relevance of this work to school settings. Specifically, we use structural equation modeling and data from the 2004 Schools and Staffing Survey (SASS) to test whether the commitment-enhancing processes laid out in Lawler's affect theory of social exchange might reduce teacher turnover, an issue plaguing school districts across the country. Our results support such a model and demonstrate the importance of interdependence for fostering commitment among teachers, with interaction, affect, and cohesion as intervening factors. PMID- 23017969 TI - "Like Parent, Like Child?": The intergenerational transmission of nonmarital childbearing. AB - Data from the 2002 National Survey of Family Growth (N=11,180) are used to examine the intergenerational transmission of nonmarital childbearing for US men and women. Findings suggest that being born to unmarried parents increases the risk of offspring having a nonmarital first birth, net of various confounding characteristics. This intergenerational link appears to particularly operate via parents' breaking up before offspring are age 14 and offspring's young age at first sex. While the link across two generations in nonmarital childbearing is not accounted for by parents' socioeconomic status (measured as fathers' education), several mediating factors vary by socioeconomic background. Gender and race/ethnicity also moderate the intergenerational transmission of nonmarital childbearing. This research sheds light on the prevalence of, and process by which, nonmarital childbearing is repeated across generations, which has important implications for long-term social stratification and inequality. PMID- 23017970 TI - Intergenerational effects of shifts in women's educational distribution in South Korea: Transmission, differential fertility, and assortative mating. AB - This study examines the intergenerational effects of changes in women's education in South Korea. We define intergenerational effects as changes in the distribution of educational attainment in an offspring generation associated with the changes in a parental generation. Departing from the previous approach in research on social mobility that has focused on intergenerational association, we examine the changes in the distribution of educational attainment across generations. Using a simulation method based on Mare and Maralani's recursive population renewal model, we examine how intergenerational transmission, assortative mating, and differential fertility influence intergenerational effects. The results point to the following conclusions. First, we find a positive intergenerational effect: improvement in women's education leads to improvement in daughter's education. Second, we find that the magnitude of intergenerational effects substantially depends on assortative marriage and differential fertility: assortative mating amplifies and differential fertility dampens the intergenerational effects. Third, intergenerational effects become bigger for the less educated and smaller for the better educated over time, which is a consequence of educational expansion. We compare our results with Mare and Maralani's original Indonesian study to illustrate how the model of intergenerational effects works in different socioeconomic circumstances. PMID- 23017971 TI - Examining fear and stress as mediators between disorder perceptions and personal health, depression, and anxiety. AB - Research examining the effect of neighborhoods on personal health has often focused on neighborhood disorder, or visual cues in neighborhoods perceived as personally threatening or noxious. Neighborhood disorderliness is thought to elevate individuals' fear of crime, thereby negatively impacting personal and mental health. Unfortunately, the pathways between disorder, fear of crime, and health have yet to be established. This study examines the pathways between neighborhood disorder, fear of crime, and three health outcomes. Using the Community, Crime and Health Survey, this study employs structural equation modeling to examine how general (being afraid of walking alone) and offense specific fear of crime (being afraid of specific crimes) mediate the relationship between individuals' disorder perceptions and self-rated health, depression and anxiety. Results show that fear of crime does mediate the relationship between disorder perceptions, self-rated health and depression, though the mediating pathways are weak. This study suggests that the disorder-fear of crime-health nexus should be re-examined theoretically. PMID- 23017972 TI - Widening the social context of disablement among married older adults: Considering the role of nonmarital relationships for loneliness. AB - Utilizing the stress process and life course perspectives, we investigated the influence of non-spousal social support on the associations between marital quality, physical disability, and loneliness among married older adults. Using data from the National Social Life, Health, and Aging Project (NSHAP), we found that the association between physical disability and loneliness was partially accounted for by the fact that physical disability was associated with less supportive nonmarital relationships. While physically-disabled older adults in higher-quality marriages were buffered from loneliness, supportive non-martial relationships did not offset elevated loneliness among those in low-quality marriages. These associations were largely similar for men and women. Thus, although both marital and nonmarital relationships are important for loneliness, when confronted with a stressor such as disablement it is the marital relationship alone that matters. PMID- 23017973 TI - Pathways of disadvantage: Explaining the relationship between maternal depression and children's problem behaviors. AB - A large body of literature documents that children of depressed mothers have impaired cognitive, behavioral, and health outcomes throughout the life course, though much less is known about the mechanisms linking maternal depression to children's outcomes. In this paper, I use data from the Fragile Families and Child Wellbeing Study to estimate and explain the consequences of maternal depression for 5-year-old children's internalizing and externalizing problem behaviors. Ordinary least squared (OLS) regression models and propensity score models show that children exposed to both chronic and intermittent maternal depression have more problem behaviors than their counterparts with never depressed mothers. Results also show that economic resources and maternal parenting behaviors mediate much of the association between maternal depression and children's problem behaviors, but that relationships with romantic partners and social support do little to explain this association. This research extends past literature by illuminating some mechanisms through which maternal depression matters for children; by utilizing longitudinal measures of depression; by employing rigorous statistical techniques to lend confidence to the findings; and by using a large, diverse, and non-clinical sample of children most susceptible to maternal depression. Given that early childhood problem behaviors lay a crucial foundation for short- and long-term life trajectories, the social consequences of maternal depression may be far-reaching. PMID- 23017974 TI - Opinions toward suicide: Cross-national evaluation of cultural and religious effects on individuals. AB - This study evaluates the role that religious and cultural values have on individual opinions toward suicide worldwide. Using multilevel modeling with data from the fourth wave of the World Values Survey (42,299 individuals in 43 countries), the current study is designed to analyze the effect of individual (i.e., micro-level), and country (i.e., macro-level) characteristics on opinions toward suicide. Specifically, cultural values, religious affiliation, religious importance, and church attendance are analyzed at both the individual and country levels to evaluate the impact of individual and country level effects on opinions toward suicide. The results show that individual opinions toward suicide are influenced by individual belief as well as by the cultural and religious characteristics of their country. The results suggest that evaluation of individual opinions toward controversial behavior should account for the unique and cross-interaction effects of micro- and macro-level effects. PMID- 23017975 TI - Filling holes in the safety net? Material hardship and subjective well-being among disability benefit applicants and recipients after the 1996 welfare reform. AB - Some of the rapid recent growth in disability income receipt in the United States is attributable to single mothers post-welfare reform. Yet, we know little about how disability benefit receipt affects the economic well-being of single mother families, or how unsuccessful disability applicants fare. We compare disability recipients to unsuccessful applicants and those who never applied among current and former welfare recipients, and examine how application and receipt affect material hardships and subjective measures of well-being. We then examine whether alternative ways of making ends meet mediate differences in well-being. After controlling for alternative sources of support, no significant differences in overall actual hardships or difficulty living on current income remained between the three groups. However, even after controlling for these strategies, unsuccessful applicants were significantly more likely to report that they expected hardships in the next two months. Our results suggest a pervasive level of economic insecurity among unsuccessful applicants. PMID- 23017976 TI - The contemporary foreclosure crisis and US crime rates. AB - Foreclosure rates in America reached unprecedented levels during the last half of the 2000s, and many observers have speculated that elevated crime rates were one of the probable negative collateral consequences of this trend. We examine this issue with a comprehensive county-level analysis of the role of foreclosure in shaping contemporary crime patterns, highlighting the possibility of theoretically informed non-linear and conditional relationships. Multivariate regression models that account for the well-documented spatial autocorrelation of crime rates and the possible endogeneity of foreclosure reveal a positive association between rates of foreclosure and property crime that accelerates significantly once foreclosure rates attain historically high levels. Multiplicative models indicate that this pattern holds for burglary across diverse county conditions, but the observed non-linear effect of foreclosure on robbery rates is limited primarily to areas that also exhibit relatively high levels of resource deprivation and limited new housing construction. PMID- 23017977 TI - Unemployment and crime: A neighborhood level panel data approach. AB - Twenty-five years ago, David Cantor and Kenneth Land presented a model of the relationship between unemployment and crime. This model showed the complexity of this seemingly simple relationship. Namely, there are two independent and counteracting effects from unemployment that affect crime: motivation and guardianship. In their analysis, Cantor and Land found that the guardianship effect dominates the motivation effect, but subsequent research has questioned this result. In this paper, the unemployment and crime relationship is tested using a neighborhood level hybrid modeling approach. Such a method allows for the nuances of Cantor and Land's model to be tested at a fine ecological resolution for the first time. It is found that both motivation and guardianship matter for crime, but at different time frames: motivation matters in the long-run whereas guardianship matters in the short-run, similar to what Cantor and Land hypothesized. PMID- 23017978 TI - Air gun injury with deadly aftermath--case report. AB - In Republic of Macedonia the use of air guns is quite widespread. They are used mainly for target practice. They are regulated by the Law of Arms, where they are defined as pneumatic weapons. There is no legal limit on type or quantity of ammunition that one may possess. Our Institute performs at least 90% of the forensic autopsies in Macedonia. In this report we describe the only fatality by pneumatic weapon to come to our attention over the past 10 years. A 6-year-old girl was accidentally wounded by her brother when he and his father were trying a new air gun, a 4.5mm single shot, break barrel, spring piston air rifle manufactured in China under the brand "Westlake". She died within minutes. Autopsy showed cardiac tamponade due to penetration of the aorta. A 0.5g metal projectile, 4.5mm in diameter, with a pointed, conical shape, was recovered from the pericardial sac. PMID- 23017979 TI - Synaptoneurosome micromethod for fractionation of mouse and human brain, and primary neuronal cultures. AB - Brain and primary neuron fractions enriched in synaptic terminals are important tools for neuroscientists in biochemical, neuroanatomical and physiological studies. We describe an annotated updated micro-method for preparing synaptoneurosomes (SNs) enriched in presynaptic and postsynaptic elements. An easy to follow, step-by-step, protocol is provided for making SNs from small amounts of mammalian brain tissue. This includes novel applications for material obtained from human neurosurgical procedures and primary rat neuronal cultures. Our updated method for preparing SNs using smaller amounts of tissue provides a valuable new tool and expands the capabilities of neuroscientists. PMID- 23017980 TI - Automatic isotropic fractionation for large-scale quantitative cell analysis of nervous tissue. AB - Isotropic fractionation is a quantitative technique that allows reliable estimates of absolute numbers of neuronal and non-neuronal brain cells. However, being fast for single small brains, it requires a long time for processing large brains or many small ones, if done manually. To solve this problem, we developed a machine to automate the method, and tested its efficiency, consistency, and reliability as compared with manual processing. The machine consists of a set of electronically controlled rotation and translation motors coupled to tissue grinders, which automatically transform fixed tissue into homogeneous nuclei suspensions. Speed and torque of the motors can be independently regulated by electronic circuits, according to the volume of tissue being processed and its mechanical resistance to fractionation. To test the machine, twelve paraformaldehyde-fixed rat brains and eight human cerebella were separated into two groups, respectively: one processed automatically and the other, manually. Both pairs of groups (rat and human tissue) followed the same, published protocol of the method. We compared the groups according to nuclei morphology, degree of clustering and number of cells. The machine proved superior for yielding faster results due to simultaneous processing in multiple grinders. Quantitative analysis of machine-processed tissue resulted in similar average numbers of total brain cells, neurons, and non-neuronal cells, statistically similar to the manually processed tissue and equivalent to previously published data. We concluded that the machine is more efficient because it utilizes many homogenizers simultaneously, equally consistent in producing high quality material for counting, and quantitatively reliable as compared to manual processing. PMID- 23017981 TI - A method for visually guided whole-cell recordings in brain slices exhibiting spontaneous rhythmic activity. AB - In vitro brain slice electrophysiology is a powerful method to investigate the network and cellular bases of brain function. Ideally, slices should be able to spontaneously express the ensemble rhythms that characterize the intact brain, but this is only rarely the case in the submerged configuration required for visualization of cells. In contrast, the interface configuration often preserves in vivo-like activity but does not allow optically guided whole-cell recording. Here we present a chamber design that, when used with a heated air objective, offers the experimenter the benefits of both visualization and the interface environment. The chamber is based on the design of the traditional Oslo-style interface chamber but modified to fit an upright microscope. Spontaneous slow (0.1-1 Hz) oscillations could be recorded extracellularly from slices of the rat somatosensory cortex with similar success, duration and frequency as the traditional interface chamber. Slow oscillations could also be readily recorded in the whole-cell configuration from visually selected pyramidal neurons. In hippocampal slices spontaneous gamma oscillations (20-80 Hz) were observed both extracellularly and in whole-cell recordings. The design presented here may be useful to the in vitro study of a range of brain circuits where the combination of visualization and spontaneous patterned network activity is desired. PMID- 23017983 TI - The effect of preoperative smoking cessation or preoperative pulmonary rehabilitation on outcomes after lung cancer surgery: a systematic review. AB - The preferred treatment for lung cancer is surgery if the disease is considered resectable and the patient is considered surgically fit. Preoperative smoking cessation and/or preoperative pulmonary rehabilitation might improve postoperative outcomes after lung cancer surgery. The objectives of this systematic review were to determine the effectiveness of (1) preoperative smoking cessation and (2) preoperative pulmonary rehabilitation on peri- and postoperative outcomes in patients who undergo resection for lung cancer. We searched MEDLINE, PreMedline, Embase, Cochrane Library, Cinahl, BNI, Psychinfo, Amed, Web of Science (SCI and SSCI), and Biomed Central. Original studies published in English investigating the effect of preoperative smoking cessation or preoperative pulmonary rehabilitation on operative and longer-term outcomes in >= 50 patients who received surgery with curative intent for lung cancer were included. Of the 7 included studies that examined the effect of preoperative smoking cessation (n = 6) and preoperative pulmonary rehabilitation (n = 1) on outcomes after lung cancer surgery, none were randomized controlled trials and only 1 was prospective. The studies used different smoking classifications, the baseline characteristics differed between the study groups in some of the studies, and most had small sample sizes. No formal data synthesis was therefore possible. The included studies were marked by methodological limitations. On the basis of the reported bodies of evidence, it is not possible to make any firm conclusions about the effect of preoperative smoking cessation or of preoperative pulmonary rehabilitation on operative outcomes in patients undergoing surgery for lung cancer. PMID- 23017984 TI - Non invasive classification system of scoliosis curve types using least-squares support vector machines. AB - OBJECTIVE: To determine scoliosis curve types using non invasive surface acquisition, without prior knowledge from X-ray data. METHODS: Classification of scoliosis deformities according to curve type is used in the clinical management of scoliotic patients. In this work, we propose a robust system that can determine the scoliosis curve type from non invasive acquisition of the 3D back surface of the patients. The 3D image of the surface of the trunk is divided into patches and local geometric descriptors characterizing the back surface are computed from each patch and constitute the features. We reduce the dimensionality by using principal component analysis and retain 53 components using an overlap criterion combined with the total variance in the observed variables. In this work, a multi-class classifier is built with least-squares support vector machines (LS-SVM). The original LS-SVM formulation was modified by weighting the positive and negative samples differently and a new kernel was designed in order to achieve a robust classifier. The proposed system is validated using data from 165 patients with different scoliosis curve types. The results of our non invasive classification were compared with those obtained by an expert using X-ray images. RESULTS: The average rate of successful classification was computed using a leave-one-out cross-validation procedure. The overall accuracy of the system was 95%. As for the correct classification rates per class, we obtained 96%, 84% and 97% for the thoracic, double major and lumbar/thoracolumbar curve types, respectively. CONCLUSION: This study shows that it is possible to find a relationship between the internal deformity and the back surface deformity in scoliosis with machine learning methods. The proposed system uses non invasive surface acquisition, which is safe for the patient as it involves no radiation. Also, the design of a specific kernel improved classification performance. PMID- 23017982 TI - Quantitative analysis of the excitability of hypoglossal motoneurons during natural sleep in the rat. AB - We describe a novel approach to assess the excitability of hypoglossal motoneurons in rats during naturally occurring states of sleep and wakefulness. Adult rats were surgically prepared with permanently placed electrodes to record the EEG, EOG and neck EMG. A stimulating/recording miniature tripolar cuff electrode was implanted around the intact hypoglossal nerve and a head restraining device was bonded to the calvarium. After a period of adaptation to head-restraint, the animals did not exhibit any sign of discomfort and readily transitioned between the states of wakefulness, NREM and REM sleep. There was no spontaneous respiratory or tonic activity present in the hypoglossal nerve during sleep or wakefulness. Hypoglossal motoneurons were activated by electrical stimulation of the hypoglossal nerve (antidromically) or by microstimulation directly applied to the hypoglossal nucleus. Microstimulation of hypoglossal motoneurons evoked compound action potentials in the ipsilateral hypoglossal nerve. The magnitude of their integrals tended to be higher during wakefulness (112.6% +/- 15; standard deviation) and were strongly depressed during REM sleep (24.7% +/- 3.4), compared to the integral magnitude during NREM sleep. Lidocaine, which was delivered using pressure microinjection to the microstimulation site, verified that the responses evoked in hypoglossal nerve can be affected pharmacologically. We conclude that this animal model can be utilized to study the neurotransmitter mechanisms that control the excitability of hypoglossal motoneurons during naturally occurring states of sleep and wakefulness. PMID- 23017986 TI - ERM proteins. PMID- 23017985 TI - The effectiveness of a deep water aquatic exercise program in cancer-related fatigue in breast cancer survivors: a randomized controlled trial. AB - OBJECTIVE: To investigate the effectiveness of an 8-week aquatic program on cancer-related fatigue, as well as physical and psychological outcomes in breast cancer survivors. DESIGN: A randomized controlled trial. SETTING: Outpatient clinic, urban, academic medical center, and a sport university swimming pool. PARTICIPANTS: Breast cancer survivors (N=68) were randomly assigned to either an experimental (aquatic exercise group in deep water pool) group or a control (usual care) group. INTERVENTIONS: The intervention group attended aquatic exercise sessions 3 times per week for 8 weeks in a heated deep swimming pool. Sessions lasted 60 minutes in duration: 10 minutes of warm-up, 40 minutes of aerobic and endurance exercises, and 10 minutes of cool-down exercises. Patients allocated to the usual care group followed the oncologist's recommendations in relation to a healthy lifestyle. MAIN OUTCOME MEASURES: Values for fatigue (Piper Fatigue Scale), mood state (Profile of Mood States), and abdominal (trunk curl static endurance test) and leg (multiple sit-to-stand test) strength were collected at baseline, after the last treatment session, and at a 6-month follow up. RESULTS: Immediately after discharge, the aquatic exercise group showed a large effect size in total fatigue score (d=.87; 95% confidence interval, .48 1.26), trunk curl endurance (d=.92; 95% confidence interval, 1.97-3.83), and leg strength (d=1.10; .55-2.76), but negligible effects in vigor, confusion, and disturbance of mood (d<.25). At the 6-month follow-up period, the aquatic exercise group maintained large to small effect sizes in fatigue scores, multiple sit-to-stand test, and trunk curl static endurance (.25>d>.90) and negligible effects for the fatigue-severity dimension and different scales of the Profile of Mood States (d<.25). CONCLUSION: An aquatic exercise program conducted in deep water was effective for improving cancer-related fatigue and strength in breast cancer survivors. PMID- 23017987 TI - Primates. PMID- 23017988 TI - Fetal brain development in chimpanzees versus humans. PMID- 23017989 TI - The lifespan of Korean eunuchs. PMID- 23017990 TI - Cerebellar rTMS disrupts predictive language processing. PMID- 23017991 TI - Motor control: spinal circuits help tadpoles see clearly. AB - A recent study suggests that animals can rely on internal expectations about their head movements, rather than vestibular sensations, to see what's in front of them. PMID- 23017992 TI - Evolution: mitochondrial burden on male health. AB - In many animal species, males suffer more from age-related disease than females. Is there a common cause for this burden on male health? Recent work supports the theory that the female transmission of mitochondria disproportionately increases the mutation load in males. PMID- 23017993 TI - Brain imaging: your brain scan doesn't lie about your age. AB - Multi-modal MRI data analysis can be used to predict a child or young adult's age. Most, but not all, individuals' brain-derived age estimate is close to their chronological age. PMID- 23017994 TI - Microtubules: sizing up the GTP cap. AB - The 'GTP cap' of the microtubule has long been postulated to exist, but a recent experiment gives us the first quantitative measurements of the cap size in the cell. PMID- 23017995 TI - Neuronal networks: enhanced feedback feeds forward. AB - Modulatory projection neurons gate neuronal networks, such as those comprising motor central pattern generators; in turn, they receive feedback from the networks they gate. A recent study has shown that, in the crab stomatogastric ganglion, this feedback is also subject to modulation: the enhanced feedback feeds forward through the projection neurons to modify circuit output. PMID- 23017996 TI - Optogenetics: eye movements at light speed. AB - The use of optogenetics to alter behavior in primates has been challenging, but now a group has managed to activate neurons in the monkey frontal cortex with light and show that this speeds up their performance. PMID- 23017997 TI - DNA damage: placing BRCA1 in the proper context. AB - How does BRCA1's evolutionarily conserved E3 ligase activity contribute to DNA damage responses? Genetically engineered cells containing a BRCA1 RING domain mutation have been used to identify Claspin as a new target of BRCA1 E3 ligase activity in response to specific forms of DNA damage. PMID- 23017998 TI - Decision making: how the brain weighs the evidence. AB - The brain has to weigh incoming sensory evidence against prior beliefs, the relative weight given to each depending on the relative uncertainties. Neuroscience now shows how the human brain accomplishes this. PMID- 23017999 TI - The operation of the visual system in relation to action. AB - Neurophysiologists studying the visual representation of the world in the parietal lobe generally find that it is based in a gaze-centred (retinotopic) frame. Students of orientation, however, find that the brain also contains a more panoramic egocentric representation that allows appropriate motor actions to take place independent of the orientation of the eyes and head. This representation can operate temporarily without visual input, but is updated from the vestibular system and from other modalities. In this minireview, I shall consider how these two representations are kept aligned with each other, and how they relate to the organisation of motor actions and to the phenomenal world that we see. PMID- 23018000 TI - Age and sex affect spatial and emotional behaviors in rats: the role of repeated elevated plus maze test. AB - The main objective of the study was to investigate the effects of age and sex differences on locomotor activity, learning and memory in rats. Another objective was to investigate whether repeated elevated plus maze tests induce anxiety in rats. Eighty Wistar rats were divided into eight groups according to their sex, age and anxiety status. Locomotor activity was assessed in open field. Repeated anxiety tests were performed in elevated plus maze. Spatial learning and memory were evaluated with the Morris water maze. All behavioral tests were recorded online and analyzed offline with an analytical software. Exploratory behavior was lower in anxiety-induced rats. Male rats had lower anxiety levels, locomotor activity and exploratory behavior compared to females. During the training period of Morris water maze latency to find platform, total distance traveled and average swimming speed decreased in all groups with repeated tests and young rats generally were faster than aged rats. During the probe trial, although the number of platform crossings was not affected, time spent in the platform zone was higher in the young groups compared to the aged groups. In conclusion, age and sex affect locomotor activity, learning and memory in different aspects. PMID- 23018002 TI - [Presenting the latest novelties in gastroenterology]. PMID- 23018001 TI - Neurotransmitter phenotypes of descending systems in the rat lumbar spinal cord. AB - Descending systems from the brain exert a major influence over sensory and motor processes within the spinal cord. Although it is known that many descending systems have an excitatory effect on spinal neurons, there are still gaps in our knowledge regarding the transmitter phenotypes used by them. In this study we investigated transmitter phenotypes of axons in the corticospinal tract (CST); the rubrospinal tract (RST); the lateral component of the vestibulospinal tract (VST); and the reticulospinal tract (ReST). They were labelled anterogradely by stereotaxic injection of the b subunit of cholera toxin (CTb) into the motor cortex, red nucleus, lateral vestibular nucleus and medial longitudinal fascicle (MLF) to label CST, RST, VST and ReST axons respectively. Neurotransmitter content of labelled axons was investigated in lumbar segments by using immunoflurescence; antibodies against vesicular glutamate transporters (VGLUT1 and VGLUT2) were used to identify glutamatergic terminals and the vesicular GABA transporter (VGAT) was used to identify GABA- and glycinergic terminals. The results show that almost all CST (96%) axons contain VGLUT1 whereas almost all RST (97%) and VST (97%) axons contain VGLUT2. Although the majority of ReST axons contain VGLUT2 (59%), a sizable minority contains VGAT (20%) and most of these terminals can be subdivided into those that are GABAergic or those that are glycinergic because only limited evidence for co-localisation was found for the two transmitters. In addition, there is a population of ReST terminals that apparently does not contain markers for the transmitters tested and is not serotoninergic. We can conclude that the CST, RST and VST are 'pure' excitatory systems whereas the ReST consists of a heterogeneous population of excitatory and inhibitory axons. It is anticipated that this information will enable inputs to spinal networks to be defined with greater confidence. PMID- 23018003 TI - [Functional and motility gastrointestinal disorders]. AB - We summarize and discuss the studies presented at the congress of the American Association of Gastroenterology (Digestive Disease Week) that, in our opinion, are of greatest interest. Both clinically and physiopathologically, functional gastrointestinal (GI) disorders are highly complex. A single cause is unlikely to explain symptoms as heterogeneous as those of functional dyspepsia and irritable bowel syndrome (IBS). Therefore, it is easier (and more useful) to try to understand functional GI disorders using a bio-psycho-social model. Moreover, data supporting the combined importance of genetic, organic and psychological factors in the onset and persistence of functional GI disorders are increasingly convincing. This year, new data have been provided on pharmacogenetics in gastroparesis, on microinflammation or alterations in the modulation of somatic and visceral sensitivity in functional dyspepsia, and on the impact of psychological factors in IBS. From the therapeutic point of view, further information has been provided on the role of probiotics, the antinociceptive effect of linaclotide (demonstrated in several studies presented this year), and on the high efficacy of hypnotherapy in patients with IBS. Finally, data on the clinical management of patients with constipation due to pelvic floor dyssynergia and on the safety and efficacy of prucalopride in patients with severe constipation were also of interest. PMID- 23018004 TI - [Helicobacter pylori-related diseases]. AB - This article summarizes the main conclusions drawn from the studies presented in Digestive Disease Week in 2012 on Helicobacter pylori infection. In developed countries, the prevalence of this infection has decreased, although it continues to be high. The prevalence in Spain is high (50%) and does not seem to be decreasing. There is an increase in antibiotic resistance, which is correlated with the frequency of prior antibiotic prescription. H. pylori eradication improves the symptoms of "epigastric pain syndrome" in functional dyspepsia. The frequency of idiopathic peptic ulcers seems to be increasing. To prevent the development of gastric cancer, eradication therapy should be administered early (before intestinal metaplasia develops). H. pylori eradication in patients undergoing early endoscopic resection of gastric cancer reduces the incidence of metachronous tumors, although endoscopic follow-up should be performed periodically. H. pylori eradication induces MALT lymphoma regression in most patients and tumoral recurrence in the long term is exceptional; radiotherapy is an excellent second-line option; a watch and wait approach to histologic recurrence after initial MALT lymphoma remission is a reasonable alternative. Idiopathic thrombocytopenic purpura is an indication for eradication therapy in children as well as adults. There are several diagnostic innovations, such as high-resolution endoscopy, narrow-band imaging, a method based on the electrochemical properties of H. pylori, and the cytosponge. Quadruple therapy with bismuth is at least as effective as standard triple therapy. The superiority of "sequential" therapy over standard triple therapy should be confirmed in distinct settings. The efficacy of "concomitant" therapy is similar -or even better- than that of "sequential" therapy, but has the advantage of being simpler. A hybrid sequential-concomitant therapy is highly effective. In patients allergic to beta-lactams, the efficacy of treatment with a proton pump inhibitor clarithromycin-metronidazole is insufficient. When standard triple therapy fails, the second-line option of a 10-day course of levofloxacin is effective and is simpler and better tolerated than quadruple therapy. Triple therapy with levofloxacin is also a promising alternative after failure of "sequential" and "concomitant" therapy. New-generation quinolones, such as moxifloxacin and sitafloxacin, could be useful as eradication therapy, especially as rescue therapy. When two eradication therapies have failed, empirical administration of a third (e.g. levofloxacin) is a valid option. Even after three eradication therapies have failed, an empirical rescue therapy (with rifabutin) can be effective. H. pylori reinfection is highly frequent in developing countries, probably due to intrafamilial transmission. PMID- 23018005 TI - [Esophageal diseases: gastroesophageal reflux disease and Barrett's esophagus]. AB - Digestive Disease Week always offers interesting advances. Among the notable advances concerning gastroesophageal reflux disease (GERD) in the 2012 meeting were studies on its association with functional dyspepsia. Furthermore, novel data suggest that undetected reflux plays a role in certain extraesophageal diseases. We also discuss the potential utility of impedanciometry of the esophageal mucosa in the diagnosis of GERD and review the management and implications of lack of response to proton pump inhibitors. We also review promising new techniques for screening for esophageal adenocarcinoma in Barrett's esophagus and new data on the efficacy and durability of radiofrequency ablation as the treatment of choice in cases associated with dysplasia or neoplasia in situ. PMID- 23018006 TI - [Gastrointestinal bleeding associated with NSAIDs, antiplatelet therapy and anticoagulant agent]. AB - Following the trends observed for the last 2-3 years, the most significant and recent advances in the area of gastrointestinal lesions associated with anti inflammatory drugs (NSAIDs) have focused on adverse effects in the distal intestine and on issues related to the toxicity associated with antiplatelet therapy. New data reinforce evidence that NSAIDs and antiplatelet therapy are associated with an increased risk of serious complications in both the upper and lower gastrointestinal tract, opening up several lines of research in prevention and therapy based on probiotics, antibiotics and mucosal protectants. The interaction between Helicobacter pylori infection and NSAIDs or aspirin remains controversial but a positive interaction between this bacterium and NSAIDs seems to be reinforced. Several systematic reviews confirm that the combination of gastrotoxic drugs significantly increases the risk of gastrointestinal bleeding, which should reinforce existing prevention strategies, and that new anticoagulant agents do not appear to reduce the risk of gastrointestinal bleeding. Once gastrointestinal hemorrhage has occurred, several studies have indicated the need to implement simpler prognostic scales than those used today. Notable innovations are the development of a disposable endoscope for acute upper gastrointestinal bleeding events and a promising new hemostatic technique, hemospray, applied locally over the bleeding lesion. PMID- 23018007 TI - [The future of inflammatory bowel disease from the perspective of Digestive Disease Week 2012]. AB - The new information presented in Digestive Disease Week has allowed us to speculate on the future of inflammatory bowel disease. Manipulation of diet and the microbioma will probably play an increasingly important role in the treatment of this disease and, in the long term, in its prevention. Biological agents will probably be used earlier and more widely; new information on levels of biological agents, mucosal healing and new comparative studies will also allow these agents to be used in a more precise and personalized way. In addition to infliximab, adalimumab, natalizumab and certolizumab, other biological agents will be employed; among the first of these to be used will be ustekinumab, golimumab and vedolizumab. In the near future, biological agents will be used as frequently in ulcerative colitis as in Crohn's disease. New healthcare models will be developed that will progressively include greater participation among patients and nurses. The ability to predict new diagnostic and prognostic models will allow decisions to be more individualized. PMID- 23018008 TI - [Epidemiology, diagnosis, complications and surgery in inflammatory bowel disease]. AB - In Digestive Disease Week 2012, held in San Diego, numerous studies were presented on the epidemiology of inflammatory bowel disease. Some of these studies were population-based, providing greater information on known risk factors and helping to eliminate proposed risk factors for which there is no known evidence. In this meeting, special attention was paid to the natural history of the disease as well as surgery in patients aged more than 65 years old who should clearly be treated as a separate subgroup from the standard population in clinical trials from which older individuals are excluded. Another especially important topic were extraintestinal complications and manifestations, with Clostridium difficile and primary sclerosing cholangitis as the main culprits. Finally, with reference to diagnosis, calprotectin was confirmed as an essential marker in distinct scenarios and new imaging techniques such as virtual chromoendoscopy (i-scan) will be important in the management of these patients, although their precise role remains to be defined. PMID- 23018009 TI - [Advances in the efficacy, optimization and safety of treatments for inflammatory bowel disease]. AB - In Digestive Disease Week 2012, numerous studies were presented on the treatment, monitoring and safety of drugs in inflammatory bowel diseases. New indications for previously approved treatments were evaluated, mainly in perianal disease and the prevention of postsurgical recurrence. New data were provided on biological markers that could help in the follow-up of patients with inflammatory bowel disease. Several studies were presented on the safety of thiopurine drugs and anti-tumor necrosis factor (TNF) agents during pregnancy. However, much of the meeting was centered on studies determining levels of anti-TNF agents and antibodies against them, evaluating new techniques with greater accuracy in determining levels of these agents and antibodies against them, their correlation with clinical response and their utility in optimizing the treatment of patients with inflammatory bowel disease. PMID- 23018010 TI - [Colorectal cancer screening]. AB - Colorectal cancer is one of the neoplasms most suitable for preventive measures, especially screening. Several cost-effective screening strategies are available: detection of fecal occult bleeding through chemical (guaiac tests) or immunological tests and endoscopic procedures such as flexible sigmoidoscopy or colonoscopy. This article reviews the most important studies on colorectal cancer screening presented at the annual congress of the American Gastroenterological Association, held in San Diego in May 2012, with special emphasis on its effectiveness in reducing the incidence and/or mortality associated with this neoplasm. PMID- 23018011 TI - [Genetics of colorectal cancer]. AB - Colorectal cancer (CRC) is one of the most frequent neoplasms in developed countries and up to 5% of all cases occur in the context of a hereditary syndrome. These hereditary forms often require a high index of suspicion for their diagnosis and specific and specialized management. Moreover, a diagnosis of hereditary CRC has major consequences not only for the patient--for whom there are highly effective preventive measures--but also for the patient's relatives, who may carry the same condition. The most significant advances in the field of hereditary CRC have been produced in the diagnosis and characterization of Lynch's syndrome and serrated polyposis syndrome. PMID- 23018012 TI - [Update on colorectal cancer precursor lesions]. AB - The adenoma-carcinoma sequence is currently well established, and therefore, the potential for adenomas to progress to colorectal cancer (CRC). In the last decade, there has been a change in the paradigm that considered these lesions as the only precursors of CRC and nowadays serrated polyps are also considered to have the potential for malignant transformation. The studies presented this year at the congress of the American Gastroenterological Association provide important information to improve the characterization of CRC precursor lesions, especially as regards their detection, prevalence and treatment and surveillance strategies. Notable among these studies were those focussing on evaluating the epidemiological characteristics of serrated polyps and those attempting to improve the quality of colonoscopy -with the ultimate aim of achieving greater detection of these precursor lesions- by evaluating colon cleansing, the polyp detection rate, withdrawal times, the use of endoscopic caps, narrow band imaging, high-definition endoscopy and, lastly, adequate endoscopic surveillance. PMID- 23018013 TI - [Latest advances in chronic pancreatitis]. AB - The most important advances in chronic pancreatitis concern its etiopathogenesis, nutritional aspects, and improvements in diagnostic techniques and some treatment options. In the etiopathogenesis of this disease, the importance of smoking and its association with alcohol have been confirmed. Exocrine pancreatic insufficiency (EPI) secondary to chronic pancreatitis is associated with bone metabolism alterations (osteopenia and osteoporosis), a reduction in liposoluble vitamins and alterations in essential amino acid levels. Endoscopic ultrasound has been confirmed as the most highly developed technique for the diagnosis of chronic pancreatitis, especially due to new image optimization technologies. Breath tests for the diagnosis of EPI continue to be developed (optimization of the C-13 mixed triglyceride test and the development of a new test based on C-13 labelled bicarbonate determination). Modest results in pain treatment have been achieved with the use of antioxidants, pancreatic enzymes and/or intravenous secretin. The association of chronic pancreatitis with pancreatic cancer requires strict follow-up, especially in patients with inflammatory masses in the context of chronic pancreatitis. PMID- 23018014 TI - [Latest advances in pancreatic tumors]. AB - Pancreatic cancer is difficult to diagnose and treat. Prognosis is poor, since this disease is usually detected at advanced stages, when the possibilities of any treatment with curative intent are 20% or less. To improve prognosis, new screening strategies are being designed, especially with the development of a new international consensus with recommendations on the management of patients at high risk of developing pancreatic cancer. Two especially useful techniques in the diagnosis of this disease are elastography and contrast-enhanced endoscopic ultrasound (EUS). Advances have been made in EUS-guided biopsy with the development of histology needles that increase diagnostic efficacy and the quality of the samples. Finally, there have been a few advances in treatment. The role of neoadjuvant therapy in locally advanced tumors and the efficacy of distinct neurolysis strategies in pain therapy have been confirmed. Covered metallic stents seem to be the best option to treat biliary obstruction. A notable development is the development of EUS-guided confocal endomicroscopy to improve the diagnosis and follow-up of cystic tumors of the pancreas, especially intraductal papillary mucinous tumors of the lateral branch. PMID- 23018015 TI - [Latest advances in acute pancreatitis]. AB - Cardiovascular diseases could be a risk factor for acute pancreatitis (AP), specifically hypertension and ischemic heart disease. Smoking is associated with AP (OR 2.34), with the association being less marked than with chronic pancreatitis. Moreover, smoking may worsen the prognosis of AP. The bedside index for severity in AP (BISAP) prognostic system has a similar ability to predict mortality to the Acute Physiology and Chronic Health Evaluation II (APACHE II) index and is much simpler to calculate. Magnetic resonance imaging is a safe technique (it does not radiate the patient) and is useful in the diagnosis of complications, severity prediction and clinical decision making. Peripancreatic venous thrombosis is frequent in AP and is rarely associated with gastric variceal bleeding or mesenteric ischemia. The treatment of organized pancreatic necrosis by combined endoscopic and percutaneous drainage is safe and effective, avoiding the need for surgery. Aggressive fluid therapy does not seem to improve the outcome of patients with AP. The administration of early enteral nutrition in mild-moderate AP reduces abdominal pain and the risk of intolerance of oral refeeding. PMID- 23018016 TI - Epidermal development and homeostasis. PMID- 23018017 TI - The spectrum of reticulate pigment disorders of the skin revisited. AB - Within the group of classical reticulate pigment disorders of the skin, Galli Galli disease (GGD), Dowling-Degos disease (DDD), Kitamura's disease (RPK), Haber's syndrome (HS), and reticulate acropigmentation of Dohi (RAD) are included and distinguished clinically and histopathologically. The clinical appearance of the reticulate pigment disorders of the skin is similar, with slight differences in age of onset and associated disorders. The histopathologic features of reticulate pigment disorders of the skin are comparable, with the exception of the unique hallmark of suprabasal acantholysis, which can be observed exclusively in GGD. Based on a critical discussion, we recommend using major and minor defining criteria for diagnosing skin lesions compatible with the reticulate pigment dermatoses of the skin. Herein we discuss a unifying nosological concept to provide straightforward diagnoses of the reticulate pigment disorders of the skin with a therapeutic impact. PMID- 23018018 TI - Cross-cultural effect on suboptimal effort detection: an example of the Digit Span subtest of the WAIS-III in Taiwan. AB - Suppressed Digit Span performance has been proposed as an embedded indicator for suboptimal effort detection in neuropsychological evaluations in Western societies, particularly in the USA. However, its effectiveness in Chinese countries remains unexplored. The purposes of this study were first to explore normative Digit Span performance patterns between the Taiwan and American standardization samples, then to examine performances of patients with traumatic brain injury and with psychiatric diseases on the embedded measures (the Digit Span Scaled Score, Vocabulary minus Digit Span difference score, Reliable Digit Span, and the longest string of digits forward and backward) through retrospective data analysis. The normative Digit Span performance differs between the two cultural populations. Although litigating and nonlitigating participants perform differently on these measures, further prospective studies are needed to explore this issue with comprehensive external corroborating validity data. PMID- 23018019 TI - Quartz tuning fork studies on the surface properties of Pseudomonas aeruginosa during early stages of biofilm formation. AB - Scanning probe microscopy techniques are powerful tools for studying the nanoscale surface properties of biofilms, such as their morphology and mechanical behavior. Typically, these studies are conducted using atomic force microscopy probes, which are force nanosensors based on microfabricated cantilevers. In recent years, quartz tuning fork (QTF) probes have been used in morphological studies due to their better performance in certain experiments with respect to standard AFM probes. In the present work QTF probes were used to measure not only the morphology but also the nanomechanical properties of Pseudomonas aeruginosa during early stages of biofilm formation. Changes in bacterium size and the membrane spring constant were determined in biofilms grown for 20, 24 and 28 h on gold with and without glucose in the culture media. The results obtained using the standard AFM and QTF probes were compared. Both probes showed that the bacteria forming the biofilm increased in size over time, but that there was no dependence on the presence of glucose in the culture media. On the other hand, the spring constant increased over time and there was a clear difference between biofilms grown with and without glucose. This is the first time that QTF probes have been used to measure the nanomechanical properties of microbial cell surfaces and the results obtained highlight their potential for studying biological samples beyond topographic measurements. PMID- 23018020 TI - Hepatocurative activity of biosynthesized silver nanoparticles fabricated using Andrographis paniculata. AB - The current investigation was aimed to determine the hepatocurative role of silver nanoparticles (AgNPs) synthesized rapidly using Andrographis paniculata. The nanoparticles fabricated at varying temperatures were characterized by UV visible spectroscopy (UV-vis), transmission electron microscopy (TEM), fourier transform infra-red spectroscopy (FTIR), energy dispersive X-ray (EDX) and inductively coupled plasma optical emission spectroscopy (ICP-OES) alongside zeta potential measurement. UV-vis spectroscopic readings indicated a prominent peak at 423 nm. TEM analysis indicated that the biosynthesized nanospheres were in the size range of 13-27 nm. EDX spectrum indicated strong signal for AgNPs with 90.1% purity. The total concentration of AgNps was 216.7 mg/L after synthesis as by ICP OES. Zeta potential was -34.3 mV indicating stable AgNPs. In vitro radical scavenging assay proved strong antioxidant effect of the AgNPs compared to 5% aqueous leaf extract. CCl(4) was used to induce hepatic injury in mice model. The biosynthesized AgNPs at three different doses (25, 50, 100mg/kg BW of the animal) were used for treatment. Silymarin was used as a standard. Low dose (25mg/kg BW) was effective in revival of all biological parameters to near normal in all intoxicated groups indicating the curing effects on CCl(4) induced liver injury. PMID- 23018022 TI - Preparation and properties of composite MAO/ECD coatings on magnesium alloy. AB - Magnesium alloys are potential biodegradable implants because of their outstanding biological performance and biodegradability in the bioenvironment. However, the rapid corrosion of magnesium and its alloys in human body fluids or blood plasma limits their clinical application. In the present work, we first fabricated porous micro-arc oxidation (MAO) coatings containing Ca/P on the magnesium alloy substrate by conducting MAO in the electrolyte containing calcium gluconate. Subsequently, hydroxyapatite (HA) coatings were prepared using electrochemical deposition (ECD) on the MAO coatings. Finally, a MAO/ECD composite coating was successfully fabricated on the magnesium alloy. The phase, morphology and composition of the biological coatings were monitored with X-ray diffraction and scanning electron microscopy with energy dispersive X-ray spectroscopy, and corrosion resistance was evaluated by means of electrochemical methods in a simulated body fluid. The experimental results indicated that the formation of HA-containing composite coatings on magnesium alloy effectively decreases its corrosion rate and more importantly endows it with a potential bioactivity. We believe that the combined use of MAO and ECD to modify magnesium alloys would make them more attractive for clinical applications. PMID- 23018021 TI - Synthesis of anisotropic silver nanoparticles using novel strain, Bacillus flexus and its biomedical application. AB - Synthesis of metallic nanoparticles has attracted by bacterial based production and alternative to physical and chemical approaches. The present work was focused to nominate a bacterial strain for synthesis of potential silver nanoparticles. The target was achieved by screening of 127 isolates from silver mining wastes. A strain designated S-27 found to be a potential candidate for rapid synthesis of silver nanoparticles among tested microorganisms. It was subjected to molecular characterization by 16S rDNA sequence analysis. It was found that S-27 belonging to Bacillus flexus. Synthesis of silver nanoparticles was achieved by addition of culture supernatants with aqueous silver nitrate solution, immediately it turns to brown colour solution showed a peak at 420 nm corresponding to the plasmon absorbance of silver nanoparticles by UV-vis spectroscopy. Various instrumentation techniques, such as AFM, FESEM, XRD and FTIR, were adopted to characterize the synthesized nanoparticles. Anisotropic nanoparticles, such as spherical and triangular shaped nanoparticles, have been synthesized and sizes were found to be 12 and 65 nm, respectively. It was stable in aqueous solution in five months period of storage at room temperature in the dark. Synthesized nanoparticles showed efficacy on antibacterial property against clinically isolated multi-drug resistant (MDR) microorganisms. It is suggested that biogenic synthesis of nanoparticles have wide-application in medicine and physical chemistry and it can produce with eco-friendly, easy downstream processing and rapid scale-up processing. PMID- 23018023 TI - Surface biocompatible modification of polyurethane by entrapment of a macromolecular modifier. AB - A macromolecular biocompatible surface modifier for polyurethane (PU), namely, polyurethane-block-poly(vinylpyrrolidone) (PU-b-PVP) copolymer, was synthesized by coupling hydroxyl-terminated PVP with diisocyanate-terminated poly(ethylene glycol) using 1,6-hexamethylene diisocyanate (HDI) as coupling agent. The chemical structure and molecular weight of the synthesized copolymer were systematically characterized by nuclear magnetic resonance spectrum ((1)H NMR), Fourier transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC). The synthesized surface modifier was blended with PU and effectively increased the hydrophilicity of PU. To evaluate the hemocompatibility of the PU/PU-b-PVP blend films, the extent of platelet adsorption, plasma recalcification time and hemolysis were measured. To determine if the blend films were toxic to mammalian cells, viability of the cells cultured on the blend films was assayed. All results indicated that the blood and cell compatibilities of the PU films were improved significantly after entrapment of a few PU-b-PVP copolymers into PU. PMID- 23018024 TI - Human parvovirus 4 in nasal and fecal specimens from children, Ghana. AB - Nonparenteral transmission might contribute to human parvovirus 4 (PARV4) infections in sub-Saharan Africa. PARV4 DNA was detected in 8 (0.83%) of 961 nasal samples and 5 (0.53%) of 943 fecal samples from 1,904 children in Ghana. Virus concentrations <= 6-7 log(10) copies/mL suggest respiratory or fecal-oral modes of PARV4 transmission. PMID- 23018026 TI - Rickettsia parkeri and Candidatus Rickettsia andeanae in Gulf Coast ticks, Mississippi, USA. PMID- 23018025 TI - Methicillin-resistant Staphylococcus aureus sequence type 239-III, Ohio, USA, 2007-2009. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a human pathogen that has diverse molecular heterogeneity. Most MRSA strains in the United States are pulsed-field gel electrophoresis USA100 sequence type (ST) 5 and USA300 ST8. Infections with MRSA ST239-III are common and found during health care-associated outbreaks. However, this strain has been rarely reported in the United States. As part of a study supported by the Prevention Epicenter Program of the Centers for Disease Control and Prevention (Atlanta, GA, USA), which evaluated transmission of MRSA among hospitals in Ohio, molecular typing identified 78 (6%) of 1,286 patients with MRSA ST239-III infections. Ninety-five percent (74/78) of these infections were health care associated, and 65% (51/78) of patients had histories of invasive device use. The crude case-fatality rate was 22% (17/78). Identification of these strains, which belong to a virulent clonal group, emphasizes the need for molecular surveillance. PMID- 23018027 TI - Center of pressure progression characteristics under the plantar region for elderly adults. AB - This investigation identifies the center of pressure (COP) progression characteristics under the plantar region for elderly adults during barefoot walking. A total of 60 healthy adults (30 young and 30 old) were recruited. The young and elderly participants had average ages of 23.6 (SD=2.7) and 70.8 (SD=4.1) years old, respectively. All subjects had normal foot arch and no relevant musculoskeletal disease in the lower extremities. The foot pressure measurement system (RS-scan((r)) system) was used to measure the center of pressure coordinates (COP), progression angle and COP velocity. Four sub-phases of the stance phase were calculated. The initial contact (ICP) and forefoot contact phase (FFCP) corresponded to the loading response. The foot flat phase (FFP) coincided with the mid-stance. The forefoot push-off phase (FFPOP) corresponded to the terminal stance and pre-swing phases. The analytical results revealed that age effects were found in the relative time percentages for the initial contact, foot flat and forefoot push-off phases during foot movement. The elderly subjects exhibited significant medial COP curve and faster COP velocity during the initial contact phase and more pronated mid-foot posture and slower COP velocity during the mid-stance. The older adults tended to have a more pronated foot and displayed a significant medial COP curve compared to young adults. These COP progression characteristics can provide further insight into relevant foot function and gait performance evaluations for older adults. PMID- 23018028 TI - Gait patterns in a community-dwelling population aged 50 years and older. AB - Poor gait is an important risk factor for falls and associated with higher morbidity and mortality. It is well established that older age is associated with worse gait, but it remains unclear at what age this association is first seen. Moreover, previous studies focused mainly on normal walking, but gait also encompasses turning and tandem walking. In a large study of community-dwelling middle-aged and elderly persons we investigated the association of age with gait, focusing on normal walking, turning and tandem walking. In 1500 persons aged 50 years and over, we measured gait using an electronic walkway. Participants performed normal walks, turning and a tandem walk. With principal components analysis of 30 variables we summarized gait into five known gait factors: Rhythm, Variability, Phases, Pace and Base of Support; and uncovered two novel gait factors: Tandem and Turning. The strongest associations with age were found for Variability (difference in Z-score -0.29 per 10 years increase (95% confidence interval: -0.34; -0.24)), Phases (-0.31 per 10 years (-0.36; -0.27)) and Tandem ( 0.25 per 10 years (-0.30; -0.20)). Additionally, these factors already showed association with the youngest age groups, from 55 to 60 years of age and older. Our study shows that Variability, Phases and Tandem have the strongest association with age and are the earliest to demonstrate a poorer gait pattern with higher age. Future research should further investigate how these gait factors relate with gait-related diseases in their earliest stages. PMID- 23018029 TI - Long-term effects after conversion of biarticular to monoarticular muscles compared with musculotendinous lengthening in children with spastic diplegia. AB - Adverse effects such as increased anterior pelvic tilt (APT) are reported after muscle-tendon lengthening (MTL) for the correction of flexed knee gait in cerebral palsy. The conversion of biarticular muscles (CBM) to monoarticular muscles represents an alternative treatment, but only few short-term results have been published, without comparison with MTL. The long-term outcome of 21 diplegic patients treated with CBM in a prospective study was compared with the results in MTL patients in a matched-pair analysis. Standardized clinical examination and three-dimensional gait analysis were done before surgery, 1 year thereafter, and at long-term follow-up a mean of 9.2 years postoperatively. Mean APT increased one year after surgery in both groups. This increase was higher in MTL patients and statistically significant only for this group. Knee flexion at initial contact and minimum knee flexion in stance were significantly decreased in both groups, while in swing the CBM group tended to show more of a decrease in knee flexion but at the cost of reduced peak flexion. Both groups showed deterioration of kinematic knee parameters through to long-term follow-up; the favourable effects of CBM disappeared, and the two groups displayed comparable average pelvic and knee kinematics. Considering individual patterns the prevalence of increased APT was lower in the CBM group 1 year after surgery, indicating that sparing the semitendinosus may have a positive effect on pelvic stability. However, after 9 years 30% of the patients in both groups showed increased APT indicative of persistent hamstring insufficiency. These results demonstrate that CBM, a significantly more extensive procedure, has no long-term advantage over MTL. PMID- 23018030 TI - Automatic detection of EEG artefacts arising from head movements using EEG and gyroscope signals. AB - Contamination of EEG signals by artefacts arising from head movements has been a serious obstacle in the deployment of automatic neurological event detection systems in ambulatory EEG. In this paper, we present work on categorizing these head-movement artefacts as one distinct class and on using support vector machines to automatically detect their presence. The use of additional physical signals in detecting head-movement artefacts is also investigated by means of support vector machines classifiers implemented with gyroscope waveforms. Finally, the combination of features extracted from EEG and gyroscope signals is explored in order to design an algorithm which incorporates both physical and physiological signals in accurately detecting artefacts arising from head movements. PMID- 23018031 TI - Dysregulation of miRNA146a versus IRAK1 induces IL-17 persistence in the psoriatic skin lesions. AB - Psoriasis is a common chronic inflammatory skin disorder with dysregulation of miRNAs. The expression pattern of miR-146a and target gene IRAK1 in lesions and PBMCs of plaque psoriasis remains unclear. In our study, we found the expression of miR-146a was up-regulated both in lesions and PBMCs of psoriatic patients, and positively correlated with IL-17 expression, whereas the target gene IRAK1 expression was expressed differentially in lesions and peripheral blood. Inability of miR-146a inhibiting target gene IRAK1 may contribute to the persistent inflammation in lesions of psoriasis. PMID- 23018032 TI - The anti-inflammatory effect of alloferon on UVB-induced skin inflammation through the down-regulation of pro-inflammatory cytokines. AB - UVB irradiation can induce biological changes in the skin, modulate immune responses and activate inflammatory reactions leading to skin damage. Alloferon, which is isolated from the blood of an experimentally infected insect, the blow fly Calliphora vicina, is known for its anti-viral and anti-tumor activities in mice model. However, the effect of alloferon against UVB irradiation and its specific mechanism are still unknown. In this study, we investigated the effect of alloferon on UVB-induced cutaneous inflammation in a human keratinocyte cell line, HaCaT. RPA and ELISA data showed that alloferon decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-1alpha, IL-1beta, IL-6 and IL 18, both on the mRNA and protein level. Western blot analysis was done to determine if alloferon regulates the MAPK signaling pathway since the MAPK signaling pathway is activated by numerous inflammatory mediators and environmental stresses including UVB irradiation. Alloferon inhibited the activation of p38 mitogen-activated protein kinase (MAPK) induced by UVB irradiation. Furthermore, the topical application of alloferon on the UVB exposed skin of hairless mice showed that alloferon treatment significantly inhibited an increase in epithelial thickness in chronic UVB-irradiated mouse skin. These findings suggest that alloferon has significant anti-inflammatory effects not only on UVB-induced inflammation in the human keratinocyte cell line, HaCaT, but also on mouse skin. PMID- 23018033 TI - Considerations on safety concerns about citalopram prescribing. PMID- 23018034 TI - Identification of novel Sp1 targets involved in proliferation and cancer by functional genomics. AB - Sp1 is a transcription factor regulating many genes through its DNA binding domain, containing three zinc fingers. We were interested in identifying target genes regulated by Sp1, particularly those involved in proliferation and cancer. Our approach was to treat HeLa cells with a siRNA directed against Sp1 mRNA to decrease the expression of Sp1 and, in turn, the genes activated by this transcription factor. Sp1-siRNA treatment led to a great number of differentially expressed genes as determined by whole genome cDNA microarray analysis. Underexpressed genes were selected since they represent putative genes activated by Sp1 and classified in six Gene Onthology categories, namely proliferation and cancer, mRNA processing, lipid metabolism, glucidic metabolism, transcription and translation. Putative Sp1 binding sites were found in the promoters of the selected genes using the MatchTM software. After literature mining, 11 genes were selected for further validation. Underexpression by qRT-PCR was confirmed for the 11 genes plus Sp1 in HeLa cells after Sp1-siRNA treatment. EMSA and ChIP assays were performed to test for binding of Sp1 to the promoters of these genes. We observed binding of Sp1 to the promoters of RAB20, FGF21, IHPK2, ARHGAP18, NPM3, SRSF7, CALM3, PGD and Sp1 itself. Furthermore, the mRNA levels of RAB20, FGF21 and IHPK2 and luciferase activity for these three genes related to proliferation and cancer, were determined after overexpression of Sp1 in HeLa cells, to confirm their regulation by Sp1. Involvement of these three genes in proliferation was validated by gene silencing using polypurine reverse hoogsteen hairpins. PMID- 23018035 TI - Gauging popular support for traffic safety in the United States. AB - BACKGROUND: Recent concerns have been raised about the United States' "Traffic Safety Culture." While the "safety culture" construct has been studied in occupational settings, it appears that no assessments of national traffic safety culture have been published in the scientific literature. PURPOSE: To assess whether current public attitudes and behaviors support traffic safety advancement in the United States. METHODS: A mail survey containing items that had been endorsed by traffic safety experts was fielded to a nationally representative sample of U.S. households in 2009. Completed surveys were returned by 46% of recipients. RESULTS: Mean ratings indicated that respondents support a majority of the items that were developed to reflect positive Traffic Safety Culture. They "neither agreed nor disagreed," however, with 43% of pro-safety statements. The item that was mostly highly rated by subjects suggested that "the whole key to road safety" lies in educating drivers. When items were grouped by topic, those which focused on the control of alcohol-impaired driving were most popular. Female respondents and older respondents demonstrated more support for traffic safety advancement. CONCLUSIONS: The U.S. public appears to be favorably disposed to traffic safety but their support is not uniform across topics or population subgroups. Their responses also suggest they may not know or like some of the evidence-based recommendations being promoted by traffic safety experts. Future research should explore the bases for public resistance to policies and practices that have been shown to save lives. PMID- 23018036 TI - Depth-based hotspot identification and multivariate ranking using the full Bayes approach. AB - Although the multivariate structure of traffic accidents has been recognized in the safety literature for over a decade now, univariate identification and ranking of hotspots is still dominant. The present paper advocates the use of multivariate identification and ranking of hotspots based on statistical depth functions, which are useful tools for non-parametric multivariate analysis as they provide center-out ordering of multivariate data. Thus, a depth-based multivariate method is proposed for the identification and ranking of hotspots using the full Bayes (FB) approach. The proposed method is applied to a sample of 236 signalized intersections in the Greater Vancouver Area. Various multivariate Poisson log-normal (MVPLN) models were used for data analysis. For each model, the FB posterior estimates were obtained using the Markov Chains Monte Carlo (MCMC) techniques and several goodness-of-fit measures were used for model selection. Using a depth threshold of 0.025, the proposed method identified 26 intersections (11%) as potential hotspots. The choice of a depth threshold is a delicate decision and it is suggested to determine the threshold according to the amount of funding available for safety improvement, which is the usual practice in univariate hotspot identification (HSID). Also, the results show that the performance of the proposed multivariate depth-based FB HSID method is superior to that of an analogous method based on the depths of accident frequency (AF) in terms of sensitivity, specificity and the sum of norms (lengths) of Poisson mean vectors. PMID- 23018037 TI - Priority for elderly persons with behavioral and psychological symptoms of dementia on waiting lists for placement in nursing homes in Japan: do nursing homes change priorities based on their own guidelines? AB - OBJECTIVES: In Japan, individuals seeking to be placed in nursing homes under the public long term care insurance program are subject to long waiting lists. Applicants are evaluated according to their needs for nursing home placement and assigned to homes based on their relative priority. The aim of the present study was to examine differences between the admission guidelines used by nursing homes and their attitudes regarding the priority for admitting elderly persons with behavioral and psychological symptoms of dementia (BPSD) from their waiting lists. DESIGN: This study was conducted using a cross-sectional study design. SETTING/PARTICIPANTS: Two hundred and eight different facilities provided sets of completed questionnaires and copies of their placement guidelines. MEASUREMENTS: The managing director or social worker at each facility provided self-reports of whether they would increase the priority of applicants with BPSD and whether they would admit applicants who require treatment for BPSD. Each facility's placement guidelines were also collected. RESULTS: Most evaluation guidelines (65.9%) considered an applicant's BPSD as a condition that required nursing home placement; however, only 16.8% of the respondents actually increased the placement priority of applicants with BPSD. Some respondents refused to admit applicants who require treatment for BPSD but did not explicitly state in their guidelines that the priority of applicants with BPSD would be reduced because of the facility's inability to address BPSD. CONCLUSION: The present study revealed differences between nursing homes' official guidelines and their attitudes toward the priority of admitting elderly persons with BPSD from their waiting lists. Future studies should explore the factors that influence the placement of individuals with BPSD into nursing homes. PMID- 23018038 TI - Antipsychotic prescription: the logic of medicine versus the logic of the patients. PMID- 23018039 TI - Prioritizing partners across the continuum. AB - With the advent of accountable care organizations, bundled payments, value-based purchasing, and penalties for preventable hospital readmission, tight connections and collaboration across the care continuum will become critical to achieve successful patient outcomes and to reduce the cost of care delivery. Lehigh Valley Health Network (LVHN), the largest provider of health services in eastern Pennsylvania, set out on a journey to build collaborative relationships with skilled nursing facilities (SNFs) in their eastern Pennsylvania community. LVHN desired SNF partners with mutual interests in improving quality of care and lowering costs of delivery where possible. Recognizing that not all SNFs are alike, LVHN developed a Collaborative Partner Prioritization Tool to assess and prioritize skilled nursing facilities in an effort to determine those that would make the best collaborators. SNFs were reviewed based on their volume of mutual patients, quality of care delivery, and their perceived willingness to align with LVHN. Six variables were used to assess these facilities, including (1) patient discharge destination volume by SNF; (2) 30-day all-cause readmission rate to an LVHN hospital; (3) Medicare's Nursing Home Compare 5-Star Overall Rating; (4) the health network affiliation of the SNF's medical director; (5) the level of LVHN employed or -affiliated physician presence at the SNF; and (6) the SNF's current participation in LVHN-sponsored programs and meetings. Through use of the Collaborative Partner Prioritization Tool, it was discovered that roughly 70% of LVHN patients who required skilled nursing care following their inpatient stay received care at 1 of 20 SNFs. Of these, 5 facilities performed well on the 6 variable assessment, deeming them the "Tier 1 Facilities" to initially focus collaborative efforts. LVHN has strategically deployed physician resources and has increased physician presence at these "Tier 1 SNFs." These facilities have also gained remote read-only access to LVHN's inpatient electronic medical record and have had opportunity to participate in LVHN-sponsored programs. Special projects have been co-developed with several SNFs, including a telemedicine-based Parkinson's disease program to increase patient access to a neurologist specially trained in movement disorders. The Collaborative Partner Prioritization Tool has become a powerful tool when used for prioritization of relationships and allocation of LVHN physicians and resources. Collaboration with strong SNF partners has offered a shared opportunity to improve quality of care, reduce costs, and prepare for the many policies affecting the health care industry. Future outcomes of this work will include quality metrics, such as readmissions, patient satisfaction with care, time for decision to admit, and overall costs of care. The data and metrics used to define the prioritization tool will continue to be adapted as the post-acute market and hospital-SNF relationships continue to evolve. PMID- 23018041 TI - Arterial function and structure after a 1-year lifestyle intervention in children with nonalcoholic fatty liver disease. AB - BACKGROUND AND AIMS: Lifestyle modification has been the mainstay of controlling childhood obesity and has proved to be effective in reducing cardiovascular risk factors. However, it is currently unknown whether the subclinical atherosclerotic changes associated with nonalcoholic fatty liver disease (NAFLD) in such population are reversible. METHODS AND RESULTS: We analyzed changes of brachial flow-mediated dilation (FMD), carotid intima-media thickness (cIMT), clinical, laboratory, and imaging data in 120 obese children with NAFLD, at the end of a 1 year intervention program with diet and physical exercise. The lifestyle intervention led to a significant mean decrease of body mass index (BMI)-standard deviation score (SDS), waist circumference (WC) and fat mass, along with diastolic blood pressure, triglycerides, liver enzymes, insulin, insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR), and high-sensitivity C-reactive protein. At the end of the study, FMD improved (P < 0.0001), while cIMT did not change significantly (P = 0.20). A significant decrease in hepatic fat content as measured by magnetic resonance imaging was also observed. Changes in FMD were inversely associated with changes in BMI-SDS, WC, total cholesterol, non-HDL cholesterol, liver enzymes, HOMA-IR, physical activity, and hepatic fat content. After including in the model all the significant variables as well as age, gender, pubertal status, and baseline FMD values, changes in FMD were significantly and independently associated with changes in WC and total cholesterol. CONCLUSION: Also in obese children with NAFLD arterial function may be restored by improving metabolic risk factors and reducing visceral adiposity following a 1-year lifestyle intervention. PMID- 23018042 TI - [Cinacalcet treatment for secondary hyperparathyroidism in dialysis patients in real-world clinical practice - the ECHO observational study: French experience]. AB - In chronic kidney disease patients with secondary hyperparathyroidism (SHPT), the recommended K/DOQITM target serum levels of parathyroid hormone (PTH), calcium (Ca) and phosphorus (P) are difficult to reach and maintain stable. We present the results of the French cohort from the European study ECHO which investigated the use and effectiveness of cinacalcet in real-world clinical practice. METHODS: An observational study of the SHPT management in dialysis patients, partially retrospective (from 6 months prior to cinacalcet initiation) and partially prospective (up to 12 months of cinacalcet treatment). RESULTS: Four hundred and eighty-five French patients were enrolled from 44 centres. Cinacalcet was given in combination with active vitamin D treatment (39%) and phosphate binders (87%). After 12 months, the proportion of patients reaching recommended K/DOQITM target levels had increased from 2.5% to 28.8% for PTH, from 46.8% to 50.1% for Ca, from 40.0% to 49.9% for P and 54.8% to 77.7% for the CaxP product. The proportions of patients using active vitamin D and sevelamer decreased by 6% and 20% respectively. Adverse events were reported in 37 (7.6%) patients, mainly nausea (2.1%), vomiting (2.1%) and dyspepsia (1.2%). CONCLUSIONS: The results of this study are consistent with data from controlled and randomized studies showing that cinacalcet increases the proportion of patients achieving the K/DOQITM targets for PTH, Ca, P and CaxP in real-world clinical practice. PMID- 23018043 TI - Candidate-gene exclusion in a family with inherited non-syndromic dental disorders. AB - OBJECTIVES: Amelogenesis imperfecta, dentinogenesis imperfecta, and dentin dysplasia are the most common non-syndromic dental disorders. In this study, we analysed and localised the gene(s) responsible for inherited non-syndromic dental disorders in a Chinese family. METHODS: This study identified and researched non syndromic dental disorders in a four-generation Chinese family, including four affected individuals whose clinical phenotype was atypical. Linkage analysis with seven polymorphic markers that localise to six different autochromosomes showed that the family was linked through chromosome 4q. All exons and exon-intron boundaries of dentin sialophosphoprotein (DSPP), enamelin (ENAM), and ameloblastin (AMBN), which are located on chromosome 4q, were sequenced in nine of the family members. RESULTS: Direct DNA sequence analysis revealed the existence of a G to A transversion in exon 4 (g.13081786G>A, c.727G>A, p.Asp243Asn, based on reference sequences NM_014208.3) of the DSPP gene, and this sequence variation correlated exactly with the presence of the disease. CONCLUSION: These results indicate that mutation p.Asp243Asn is a highly probable cause of non-syndromic dental disorder in this Chinese family. The presence of symptom heterogeneity is possible, as the clinical classification system is hampered by the lack of close correlation between the subtype and the molecular defect. PMID- 23018044 TI - The efficacy of laser-assisted hair removal in the treatment of acne keloidalis nuchae; a pilot study. AB - BACKGROUND: Laser-assisted hair removal causes miniaturization of hair shafts which are the principal contributors to inflammation in acne keloidalis nuchae (AKN). OBJECTIVE: To assess the efficacy of hair reduction by long pulsed Nd-YAG laser as a therapeutic modality for AKN. METHODS: This interventional pilot trial included 16 patients with AKN who received 5 sessions of long pulsed Nd-YAG laser. Lesions were objectively and subjectively assessed at the third and fifth laser sessions, and 1 year after. Global response to treatment was rated using a quartile grading scale regarding the percentage improvement in the count of papules and the size of the plaques. Biopsies were taken before and 2 weeks after the fifth session to evaluate the pathological changes associated with improvement of the treated lesions. RESULTS: All patients showed a significant improvement. The percentage of improvement in the early caseswas significantly higher when compared to late cases.Two weeks after the fifth session, all biopsies showed a significant decrease in the inflammatory infiltrate except one case. Sclerosis was markedly decreased. Complete absence of hair follicles and adenexawas observed, apart from in 2 cases. CONCLUSION: Laser hair depilation can significantly improve this disfiguring chronic disorder. Starting treatment as early as possible achieves the best results and can stop the disease process if followed by maintenance sessions. PMID- 23018051 TI - Engineering of an N-acetylneuraminic acid synthetic pathway in Escherichia coli. AB - N-acetylneuraminic acid (NeuAc) has recently drawn much attention owing to its wide applications in many aspects. Besides extraction from natural materials, production of NeuAc was recently focused on enzymatic synthesis and whole-cell biocatalysis. In this study, we designed an artificial NeuAc biosynthetic pathway through intermediate N-acetylglucosamine 6-phosphate in Escherichia coli. In this pathway, N-acetylglucosamine 2-epimerase (slr1975) and glucosamine-6-phosphate acetyltransferase (GNA1) were heterologously introduced into E. coli from Synechocystis sp. PCC6803 and Saccharomyces cerevisiae EBY100, respectively. By derepressing the feedback inhibition of glucosamine-6-phosphate synthase, increasing the accumulation of N-acetylglucosamine and pyruvate, and blocking the catabolism of NeuAc, we were able to produce 1.62 g l-1 NeuAc in recombinant E. coli directly from glucose. The NeuAc yield reached 7.85g l-1 in fed-batch fermentation. This process offered an efficient fermentative method to produce NeuAc in microorganisms using glucose as carbon source and can be optimized for further improvement. PMID- 23018053 TI - A novel approach to estimating potential maximum heavy metal exposure to ship recycling yard workers in Alang, India. AB - The 180 ship recycling yards located on Alang-Sosiya beach in the State of Gujarat on the west coast of India is the world's largest cluster engaged in dismantling. Yearly 350 ships have been dismantled (avg. 10,000 ton steel/ship) with the involvement of about 60,000 workers. Cutting and scrapping of plates or scraping of painted metal surfaces happens to be the commonly performed operation during ship breaking. The pollutants released from a typical plate-cutting operation can potentially either affect workers directly by contaminating the breathing zone (air pollution) or can potentially add pollution load into the intertidal zone and contaminate sediments when pollutants get emitted in the secondary working zone and gets subjected to tidal forces. There was a two pronged purpose behind the mathematical modeling exercise performed in this study. First, to estimate the zone of influence up to which the effect of plume would extend. Second, to estimate the cumulative maximum concentration of heavy metals that can potentially occur in ambient atmosphere of a given yard. The cumulative maximum heavy metal concentration was predicted by the model to be between 113 MUg/Nm(3) and 428 MUg/Nm(3) (at 4m/s and 1m/s near-ground wind speeds, respectively). For example, centerline concentrations of lead (Pb) in the yard could be placed between 8 and 30 MUg/Nm(3). These estimates are much higher than the Indian National Ambient Air Quality Standards (NAAQS) for Pb (0.5 MUg/Nm(3)). This research has already become the critical science and technology inputs for formulation of policies for eco-friendly dismantling of ships, formulation of ideal procedure and corresponding health, safety, and environment provisions. The insights obtained from this research are also being used in developing appropriate technologies for minimizing exposure to workers and minimizing possibilities of causing heavy metal pollution in the intertidal zone of ship recycling yards in India. PMID- 23018052 TI - Conditional disorder in chaperone action. AB - Protein disorder remains an intrinsically fuzzy concept. Its role in protein function is difficult to conceptualize and its experimental study is challenging. Although a wide variety of roles for protein disorder have been proposed, establishing that disorder is functionally important, particularly in vivo, is not a trivial task. Several molecular chaperones have now been identified as conditionally disordered proteins; fully folded and chaperone-inactive under non stress conditions, they adopt a partially disordered conformation upon exposure to distinct stress conditions. This disorder appears to be vital for their ability to bind multiple aggregation-sensitive client proteins and to protect cells against the stressors. The study of these conditionally disordered chaperones should prove useful in understanding the functional role for protein disorder in molecular recognition. PMID- 23018054 TI - Herbicide contamination and dispersion pattern in lowland springs. AB - Herbicides reduce the diversity of flora and fauna in freshwater ecosystems and also contaminate groundwater due to leaching. Herbicide contamination can be a serious threat for all groundwater-dependent ecosystems (GDE), altering their chemical and biological quality. Successful management to protect GDE is dependent on detailed knowledge of the hydrogeological and hydrochemical features of the surrounding environment. We consider the possible diffuse contamination by herbicides of groundwater and of GDE as lowland springs, semi-artificial ecosystems with elevated biodiversity. The main objectives of the present work were thus: (1) to map herbicide contamination in lowland springs, (2) to evaluate the potential risk for biota and (3) to quantify the extent of the area from which the herbicide use can affect the water quality of lowland springs. In June and August 2009, nearly 23 springs within the Po River Plain (Northern Italy) were sampled and analyzed for five herbicides used to control weeds in maize. Hydrogeological properties, half-lives of the herbicides and their concentrations in both groundwater and springs were used to quantify the area from which the contamination could originate. Such evaluation was performed by means of GIS techniques. Terbuthylazine were the only herbicide found, together with its metabolite desethylterbuthylazine. In 16 out of 84 measurements, their concentrations were above the threshold for drinking water; however, they were always below the ecotoxicological end-points of aquatic flora and fauna. Spatial analyses reveal that the theoretical area from which herbicides can contaminate spring water is within a distance varying between a few and 1800 m. Our findings indicate that conservation plans should focus on the fields adjacent to or surrounding the springs and should address the optimization of irrigation practices, restoration of buffer strips, crop rotation and in general more sustainable agricultural practices in the proximity of these fragile GDE. PMID- 23018055 TI - Hepatitis E virus seroprevalence among adults, Germany. AB - We assessed hepatitis E virus (HEV) antibody seroprevalence in a sample of the adult population in Germany. Overall HEV IgG prevalence was 16.8% (95% CI 15.6% 17.9%) and increased with age, leveling off at >60 years of age. HEV is endemic in Germany, and the lifetime risk for exposure is high. PMID- 23018056 TI - [Importance of medication reconciliation process for ensuring continuity and safety of patient care]. PMID- 23018057 TI - Relaxin-3 is associated with metabolic syndrome and its component traits in women. AB - OBJECTIVES: Relaxin-3 was found to play a role in appetite regulation, increasing food intake and body weight. The current study aimed to investigate the relation of relaxin-3 to metabolic syndrome and its component traits in women. DESIGN AND METHODS: The study was conducted on 300 female subjects, 150 healthy control and 150 metabolic syndrome patients. The component traits of metabolic syndrome were determined for all participants. RESULTS: Serum relaxin-3 level was significantly higher in the metabolic syndrome patients than in the healthy control group. It was also significantly correlated with all the component traits of metabolic syndrome. CONCLUSION: The results suggest that metabolic syndrome is associated with increased serum relaxin-3 levels in women. Relaxin-3 might be considered as a potential biomarker of metabolic syndrome. PMID- 23018058 TI - Quantification of measles, mumps and rubella viruses using real-time quantitative TaqMan-based RT-PCR assay. AB - In this study, a rapid quantitative method using TaqMan-based real-time reverse transcription-polymerase chain reaction (qPCR-RT) has been developed for estimating the titers of measles, mumps and rubella (MMR) viruses in infected cell culture supernatants. The qPCR-RT assay was demonstrated to be a specific, sensitive, efficient and reproducible method. For MMR viral samples obtained during MMR viral propagations in Vero cells at a different multiplicity of infection, titers determined by the qPCR-RT assay have been compared with estimates of infectious virus obtained by a traditional commonly used method for MMR viruses - 50% cell culture infective dose (CCID(50)) assay, in paired samples. Pearson analysis evidenced a significant correlation between both methods for a certain period after viral inoculation. Furthermore, the established qPCR-RT assay was faster and less-laborious. The developed method could be used as an alternative method or a supplementary tool for the routine titer estimation during MMR vaccine production. PMID- 23018059 TI - A recombinant cottontail rabbit papillomavirus genome for ectopic expression of genes in cells infected with virus in vivo. AB - The objective of this study was to construct a cottontail rabbit papillomavirus (CRPV) genome that would co-express a gene of choice and the viral genome simultaneously. Using this construct, the effects of the ectopic expression of diverse viral or cellular genes on PV-infected cells can be examined to elucidate which genes are essential for tumor formation. CRPV-pLAIIdelXba1, which lacks the major portion of L2 (designated the XbaI fragment), has been previously shown to fully retain the ability to induce tumors, and this ability was confirmed in this study. Insertion of the XbaI fragment in an antisense orientation did not change the efficiency of tumor induction. An SV40 overexpression cassette that originated from pSG5 and contains a more diverse multiple cloning site (MCS) was cloned into CRPV-Xba1-mcs, a CRPV genome based on CRPV-pLAIIdelXba1 that contains an additional MCS inserted via XbaI digestion. Additionally, the L1 ATG initiation codon of this construct, designated CRPV-Xba1-oe-WT, was mutated to avoid unnecessary L1 protein expression, which produced the CRPV-Xba1-oe-L1mut construct. Injection of these constructs into two New Zealand White rabbits and monitoring of tumor growth for two to six months showed that CRPV-Xba1-oe-WT induced tumors at 1/10 and 1/10 of the injection sites in two animals, while the control injections in each rabbit induced tumors at 3/10 and 4/10 injection sites, respectively. However, CRPV-Xba1-oe-L1mut induced tumors at 3/10, 6/10, 7/12 and 11/12 sites in four injected animals, and the control injections induced tumor growth in these animals at 6/10, 10/10, 12/12 and 12/12 of the injected sites, respectively. Thus, CRPV-Xba1-oe-L1mut could potentially be used to conduct overexpression experiments in vivo that can be used to measure the negative or positive influences of ectopically expressed foreign or HPV genes on tumor growth. PMID- 23018060 TI - A real-time PCR approach based on SPF10 primers and the INNO-LiPA HPV Genotyping Extra assay for the detection and typing of human papillomavirus. AB - The SPF10 PCR targets a conserved 65bp region of the HPV L1 gene for broad spectrum amplification. The LiPA assay allows subsequent genotyping of the HPV amplicons. This study aims to develop a SPF10 real-time PCR to achieve simultaneous amplification and detection of the HPV target. That way, LiPA analysis of the HPV-negative samples can be avoided, reducing workload and cost. The real-time PCR shows an analytical sensitivity of 29.7 copies for HPV 6, 16, 18 and 31 and an HPV-specific melting peak. Thirty-one HPV DNA plasmids were genotyped correctly using the SPF10 real-time PCR in combination with the LiPA. Here, the LiPA assay was performed at an increased hybridisation temperature (49.5 degrees C) in combination with a reduced amplicon volume (1MUl) to avoid cross-reactivity. In conclusion, the SPF10 real-time PCR proves to be very sensitive and generates amplicons, which are compatible with the LiPA. PMID- 23018061 TI - Recombinant envelope protein-based enzyme immunoassay for IgG antibodies is comparable to neutralization tests for epidemiological studies of dengue infection. AB - Dengue virus (DENV) is the most prevalent arbovirus in the world, found mainly in tropical regions. As clinical manifestations present frequently as nonspecific febrile illness, laboratory diagnosis is essential to confirm DENV infections and for epidemiological studies. Recombinant envelope (E) antigens of four serotypes of DENV were used to develop an immunoglobulin G enzyme-linked immunosorbent assay (IgG-ELISA). To evaluate the IgG-ELISA, a panel of serum samples that had been tested previously by a plaque reduction neutralization test (PRNT) was investigated for the presence of anti-E antibodies against the four DENV serotypes. IgG-ELISA was found to have a sensitivity (91%) and specificity (98%) at a receiver-operating characteristic (ROC) optimized cutoff and demonstrated high performance as well as good indexes. A concordance of 97% was achieved between both assays, and only 21/704 (3%) samples were not concordant. The results of the present study demonstrate a moderate correlation between neutralizing antibody titers and IgG-ELISA values. These findings indicate that the recombinant protein-based IgG-ELISA is a suitable method for routine serodiagnosis, monitoring and seroepidemiological studies of DENV infections. PMID- 23018062 TI - Satisfied patients, burnout doctors! PMID- 23018063 TI - Emergency management of dental trauma: knowledge of Hong Kong primary and secondary school teachers. AB - OBJECTIVES. To investigate the level of knowledge about emergency management of dental trauma among Hong Kong primary and secondary school teachers. DESIGN. Questionnaire survey. SETTING. A teachers' union that unites 90% of teachers in Hong Kong. PARTICIPANTS. Randomly selected primary and secondary school teachers. RESULTS. Only 32.8% of respondents correctly stated that a person sustaining dental trauma should go to dentists directly. In all, 73.1% of teachers correctly stated that a dental trauma patient should go for treatment immediately. Only 32.5% knew that a fractured tooth should be put in liquid. Even fewer (23.2%) realised that the displaced tooth should be repositioned back to the original position. Relatively more respondents (74.7%) understood that an avulsed baby tooth should not be put back. Disappointingly, only 16.3% of teachers knew that an avulsed permanent tooth should be replanted. Furthermore, only 29.6% of teachers thought that they were able to distinguish between deciduous teeth and permanent teeth, whilst 20.4% correctly identified at least one of the appropriate mediums: milk, physiological saline or saliva, for storing an avulsed tooth. Teachers who previously received first-aid training with dental content or acquired dental injury information from other sources, scored significantly higher than teachers without such training or acquired information. CONCLUSION. The knowledge on emergency management of dental trauma among primary and secondary school teachers in Hong Kong is insufficient, particularly on the handling of permanent tooth avulsion and the appropriate storage medium for avulsed teeth. Receipt of first-aid training with dental contents and acquisition of dental injury information from other sources were positively correlated with knowledge in managing dental trauma. PMID- 23018064 TI - Patient experiences with public hospital care: first benchmark survey in Hong Kong. AB - OBJECTIVE. To measure patient satisfaction in relation to in-patient experience in public hospitals. DESIGN. Cross-sectional study. SETTING. Twenty-five selected Hospital Authority acute and convalescence hospitals in Hong Kong. PARTICIPANTS. Eligible patients discharged between 15 June and 27 September 2010 from the selected Hospital Authority public hospitals. MAIN OUTCOME MEASURES. A total of 54 items were used to measure patient experience on aspects of hospital care. They included the process of admission to hospital, staying in the hospital and ward (environment, food and facilities; hospital staff; patient care and treatment), the process of leaving hospital, and the overall impression of hospital care. Free-text comments from respondents were also recorded. RESULTS. A total of 5030 patients were successfully interviewed, amounting to a response rate of 52%. The findings showed that 80% (confidence interval, 79-81%) of patients rated the care they received in hospital as good or better. However, there were a few areas where performance was relatively low, including waiting time for a ward bed for accident and emergency cases, food quality, infection control, information provided about their condition/treatment, seeking patient input about their opinions and quality of care, and patient engagement in the decisions about their treatment and care, as well as the discharge process. CONCLUSIONS. This patient experience survey used a validated instrument (Hong Kong Inpatient Experience Questionnaire) to provide important insights to executives and health care professionals on their care to patients and to identify areas for improvement in public hospitals. Further surveys should be carried out to monitor changes in patient experience and satisfaction on a regular basis. Such surveys could facilitate improvements through analysis of results on patient satisfaction. PMID- 23018065 TI - Prospective cross-sectional study using questionnaire to assess the effect of a different nomenclature for psychiatric illnesses on the perception of these diseases by university students. AB - OBJECTIVE. To assess the effect of a difference in nomenclature for psychiatric illness on perceptions of university students. DESIGN. Cross-sectional study. SETTING. Three local universities in Hong Kong. PARTICIPANTS. A total of 201 university students (undergraduates or postgraduates) were interviewed with a questionnaire. MAIN OUTCOME MEASURES. Score difference between the new and old nomenclature of each disease for each question of the questionnaire, using a 5 point Likert scale and an integrated score difference for each disease. RESULTS. Of the seven diseases investigated, six yielded a significant yet mild increase in positive perceptions with the new nomenclature. These diseases included schizophrenia (integrated score difference: +0.158, P<0.001), neurasthenia (integrated score difference: +0.117, P<0.001), paranoia (integrated score difference: +0.209, P<0.001), personality disorder (integrated score difference: +0.282, P<0.001), attention deficit hyperactivity disorder (integrated score difference: +0.086, P=0.005), and bipolar disorder (integrated score difference: +0.154, P<0.001). Epilepsy showed a negative perception with its new nomenclature (integrated score difference: -0.119, P<0.001). CONCLUSIONS. The new nomenclature system for psychiatric diseases achieves more positive perceptions among the university students than the old nomenclature. Epilepsy was the exception for which the old nomenclature conferred a more positive perception. Further studies on this topic involving a more general population should be advocated to confirm the improvements in perception with the new naming system for psychiatric diseases. PMID- 23018066 TI - A pilot study on the efficacy of Picolax given as a four-week course for the treatment of refractory constipation. AB - OBJECTIVES. Although Picolax (sodium picosulphate and magnesium citrate) has been widely documented for use in bowel preparation, there is limited literature on its efficacy in the treatment of constipation. Refractory constipation is a more difficult situation with limited treatment options available. The primary objective of this study was to investigate the efficacy of Picolax in the treatment of refractory constipation. DESIGN. Prospective single-centre cohort study. SETTING. The Gastroenterology and Hepatology Centre of a major private hospital in Hong Kong. PATIENTS. Patients aged 18 years or more with chronic constipation refractory to tegaserod or polyethylene glycol and attending the centre in the period of July 2009 to June 2010. RESULTS. A total of 20 patients completed this 6-week single-centre study, with a 2-week baseline assessment and 4-week treatment period. Complete data sets were available for analysis from 17 of these patients. The mean (standard deviation) age of the cohort was 50 (9) years, of which 94% were female. Treatment consisted of half-a-sachet of Picolax taken orally on alternate days, 3 times a week. Patients were required to fill in daily and weekly diary entries of their bowel habit. The mean (standard deviation) number of weekly complete spontaneous bowel movements increased from 0.5 (0.9) to 2.4 (2.6) times per week (P=0.02) after initiation of the treatment, which was a clinically and statistically significant difference; with a mean change of +1.9 (95% confidence interval, 0.3 to 3.4) per week. As a secondary endpoint, 11 patients recorded the use of rescue medication before and after the 4-week treatment. The ratio of patients who took rescue medication decreased significantly from 73% (n=8) to 0% (n=0) [P=0.008]. The mean reduction in the frequency of resorting to rescue medication was 2.6 times (95% confidence interval, -4.2 to -1.1) per week. CONCLUSIONS. Picolax improved the number of complete spontaneous bowel movements and significantly reduced resorting to rescue medication. This formulation could therefore be considered as a treatment option in patients with chronic constipation who are refractory to conventional treatment regimens. PMID- 23018067 TI - The CEPHEUS Pan-Asian survey: high low-density lipoprotein cholesterol goal attainment rate among hypercholesterolaemic patients undergoing lipid-lowering treatment in a Hong Kong regional centre. AB - OBJECTIVES. To evaluate attainment of low-density lipoprotein cholesterol goals among hypercholesterolaemic patients undergoing lipid-lowering drug treatment in Hong Kong and to identify potential determinants of treatment outcomes. DESIGN. Cross-sectional observational study. SETTING. A single site in Hong Kong, as part of the CEPHEUS Pan-Asian survey. PATIENTS. Subjects with hypercholesterolaemia aged 18 years or above, who had been on lipid-lowering drug treatment for at least 3 months with no dose adjustment for at least 6 weeks. RESULTS. A total of 561 such patients (mean age, 65.3; standard deviation, 9.7 years) were evaluated. Most had major cardiovascular risk factors; 534 (95.2%) of 561 patients had coronary heart disease and 534 (95.4%) of 560 patients had low-density lipoprotein cholesterol goals set at lower than 70 mg/dL. In all, 465 (82.9%) patients attained their respective low-density lipoprotein cholesterol goals. Among 75 patients who had coronary heart disease or equivalent risk, and multiple risk factors with a 10-year coronary heart disease risk of over 20%, 62 (82.7%) attained their respective low-density lipoprotein cholesterol goals. Significant predictors of low-density lipoprotein cholesterol goal attainment included the patient's baseline lipid profile (total cholesterol and low-density lipoprotein cholesterol levels), blood pressure, and drugs (statin/non-statin) used for treatment. CONCLUSIONS. Hypercholesterolaemic patients undergoing lipid-lowering drug treatment in the present Hong Kong study were able to achieve a very high attainment rate for the low-density lipoprotein cholesterol goal, despite the fact that most of them had major cardiovascular risk factors. PMID- 23018068 TI - Frequency of developmental dysplasia of the hip in breech-presented Chinese neonates in Hong Kong. AB - OBJECTIVES. To clarify the use of ultrasonography by determining the frequency of developmental dysplasia of the hip among breech-presented Chinese neonates in Hong Kong. DESIGN. Prospective case series. SETTING. Regional hospital, Hong Kong. PATIENTS. All breech-presented Chinese neonates born during January 2008 to June 2009 were included (except premature neonates). They were examined clinically from birth till the age of 1 year. Ultrasound of the hips was performed at the age of 2 weeks, and X-ray of the pelvis at the age of 1 year. RESULTS. A total of 209 breech-presented neonates were born during the study period; 110 neonates completed all necessary investigations and follow-up. Among the latter, there were three neonates with developmental dysplasia of the hip warranting treatment, which amounted to a frequency of 2.7%. CONCLUSION. Developmental dysplasia of the hip among breech-presented Chinese babies is only slightly less common than in corresponding populations in other regions in the world. Since early diagnosis is important, ultrasonography screening in high-risk cases such as those with breech presentation may be useful. PMID- 23018069 TI - Stereotactic ablative radiotherapy for medically inoperable early stage lung cancer: early outcomes. AB - OBJECTIVE. To evaluate the clinical outcome and safety of stereotactic ablative radiotherapy for medically inoperable stage I non-small-cell lung carcinoma. DESIGN. Retrospective case series. SETTING. Pamela Youde Nethersole Eastern Hospital, Hong Kong. PATIENTS. All patients with medically inoperable stage I non small-cell lung carcinoma receiving stereotactic ablative radiotherapy since its establishment in 2008. MAIN OUTCOME MEASURES. Disease control rate, overall survival, and treatment toxicities. RESULTS. Sixteen stage I non-small-cell lung carcinoma patients underwent the procedure from June 2008 to November 2011. The median patient age was 82 years and the majority (81%) had moderate-to-severe co morbidity based on the Adult Comorbidity Evaluation 27 index. With a median follow-up of 22 months, the 2-year primary tumour control rate, disease-free survival and overall survival rates were 91%, 71% and 87%, respectively. No grade 3 (National Cancer Institute Common Terminology Criteria for Adverse Events) or higher treatment-related complications were reported. CONCLUSION. Stereotactic ablative radiotherapy can achieve a high degree of local control safely in medically inoperable patients with early lung cancer. PMID- 23018070 TI - Clinical Epidemiology Workshop 8--appraising a study on therapy. PMID- 23018071 TI - Gastroesophageal reflux disease in children. AB - Reflux of gastric contents is common in young infants but usually self-limiting and not pathological. Gastroesophageal reflux disease refers to persistent reflux due to pathological factors that results in significant symptoms. Patients may exhibit oesophagitis, bleeding, nutritional failure, or respiratory problems. A high index of suspicion must thus be maintained for all patients. The aim of this article was to provide a concise review of the understanding of this disease, and also to discuss current diagnosis and management strategies for children with gastroesophageal reflux disease. PMID- 23018072 TI - Developing primary care in Hong Kong: evidence into practice and the development of reference frameworks. AB - Enhancing primary care is one of the proposals put forward in the Healthcare Reform Consultation Document "Your Health, Your Life" issued in March 2008. In 2009, the Working Group on Primary Care, chaired by the Secretary for Food and Health, recommended the development of age-group and disease-specific primary care conceptual models and reference frameworks. Drawing on international experience and best evidence, the Task Force on Conceptual Model and Preventive Protocols of the Working Group on Primary Care has developed two reference frameworks for the management of two common chronic diseases in Hong Kong, namely diabetes and hypertension, in primary care settings. Adopting a population approach for the prevention and control of diabetes and hypertension across the life course, the reference frameworks aim to provide evidence-based and appropriate recommendations for the provision of continuing and comprehensive care for patients with chronic diseases in the community. PMID- 23018073 TI - Transarterial embolisation with Guglielmi detachable coils in an infant with a vein of Galen aneurysmal malformation. AB - Vein of Galen aneurysmal malformation is a rare entity in the paediatric population. However, it is being recognised with increasing frequency due to better diagnostic techniques. Neonates usually present with congestive heart failure, while in older infants and children it tends to manifest with seizures, hydrocephalus, intracerebral or subarachnoid haemorrhages. We present a case of ruptured vein of Galen aneurysmal malformation in a 3-month-old baby boy treated by transarterial embolisation using Guglielmi detachable coils. PMID- 23018074 TI - Hong Kong experiences the 'Ultimate superbug': NDM-1 Enterobacteriaceae. AB - We report the second imported case of New Delhi metallo-beta-lactamase (NDM-1) Enterobacteriaceae encountered in Hong Kong soon after the patient's arrival in the territory for medical care. As NDM-1 is spreading throughout the world via international travel, being an international city, Hong Kong was always expected to encounter the same public health threat. This case also illustrates the importance of active surveillance of at-risk patients in preventing the spread of this 'superbug'. PMID- 23018075 TI - De Garengeot's hernia: an unusual right groin mass due to acute appendicitis in an incarcerated femoral hernia. AB - The presence of an acutely inflamed vermiform appendix in a femoral hernia sac is extremely rare; the condition is termed De Garengeot's hernia. Here we describe an elderly patient for whom preoperative computed tomography aided the diagnosis of this rare entity. This Chinese woman had presented with a painful right groin mass. The patient successfully underwent an emergency appendicectomy and primary femoral hernia repair. Once diagnosed, it is imperative to follow key surgical principles to limit the spread of infection. PMID- 23018076 TI - A proposal for an appropriate nomenclature to late-onset cognitive impairment for Hong Kong in the 21st century: dementia revisited. PMID- 23018077 TI - Artery of Percheron infarction. PMID- 23018078 TI - Profunda femoris arteriovenous fistula: clinical and radiological features. PMID- 23018079 TI - Improving the positive predictive value of exercise testing in women for coronary artery disease. AB - The exercise treadmill test (ETT) in women has been limited by a low positive predictive value (PPV) for coronary artery disease (CAD). However, the reliability of previous studies was unsatisfactory because of the inclusion of younger women with a low prevalence of CAD. To further evaluate the diagnostic properties of the ETT in women, we evaluated a group of women with chest pain who had a positive ETT result and subsequent coronary angiography. Of the 111 women, 56 had significant CAD on angiogram, yielding a PPV of 51% for the group. However, inclusion in the analysis of several pretest attributes and specific exercise test responses improved the PPV of the ETT. Age had a major effect, with the youngest group (35 to 50 years old) having a PPV of 36% compared to 68% in the oldest group (>65 years old). Several specific exercise responses (ST-segment depression >2 mm and delayed ST-segment recovery >3.0 minutes) further separated true from false positives across all age groups, increasing the PPV to approximately 80%. Onset of ischemia at a relatively low cardiac workload of <80% maximum predicted heart rate was not a significant predictor. In conclusion, the standard ETT should remain the test of choice in ambulatory women with chest pain and no significant abnormalities on baseline electrocardiogram especially in those >65 years of age. PMID- 23018080 TI - Clinical screening tests for assessing movement control in non-specific low-back pain. A systematic review of intra- and inter-observer reliability studies. AB - BACKGROUND: Most people experience back pain at some point during their lives. Reports suggest that core stability interventions in subjects with non-specific low-back pain may increase function, thus decreasing pain. Reliable and validated clinical tests are required for implementing adequate rehabilitation and for evaluating such interventions. OBJECTIVE: This systematic literature overview seeks to assess the risk of bias and summarise the results of articles assessing the inter-and intra-observer reliability of clinical screening tests for movement control in subjects with non-specific low-back pain. METHOD: A search was conducted in electronic search engines up until October 2011. The terms 'low-back pain', 'test', 'movement control', 'motor control' and 'physical examination' were defined and used. An appraisal tool (QAREL) was used to assess the risk of bias. Results of the studies were summarised. RESULTS: Eight studies were included and assessed. All examined inter-observer reliability and three also examined intra-observer reliability. The grading of the studies varied from five to nine positive items out of eleven possible. Inter-observer reliability ranged between poor and very good agreement. Intra-observer reliability ranged between moderate and very good agreement. CONCLUSION: Most of the tests are presented in studies conducted with a high risk of bias. Their clinical implications can therefore not be suggested. Two tests, prone knee bend and one leg stance are assessed across studies with moderate and good reliability respectively and presented in studies conducted with a lower risk of bias. Their utilisation in clinical work may be recommended. PMID- 23018081 TI - The predictive validity of the Orebro Musculoskeletal Pain Questionnaire and the clinicians' prognostic assessment following manual therapy treatment of patients with LBP and neck pain. AB - The purpose of this study was to compare the predictive ability of the standardised screening tool Orebro Musculoskeletal Pain Questionnaire (OMPQ) and the clinicians' prognostic assessment in identifying patients with low back pain (LBP) and neck pain at risk for persistent pain and disability at eight weeks follow-up. Patients seeking care for LBP or neck pain were recruited by 19 manual therapists in Norway. Patients completed the OMPQ and the low back- or neck specific Oswestry Disability Index/Neck Disability Index at baseline and 8 weeks after first consultation. The manual therapists filled in their assessment of patient's prognosis immediately after the first consultation, blinded for patient's answers to the questionnaire. A total of 157 patients (81with neck pain and 76 with LBP) were included. The best odds for predicting the outcome for LBP patients was found for the clinicians' assessment of prognosis (LR+ = 2.1 and LR- = 0.55), whereas the likelihood ratios were similar for the two tools in the neck group. For LBP patients, both the clinicians' assessment and the OMPQ contributed significantly in the separate regression models (p = 0.02 and p = 0.002, resp), whereas none of the tools where significant contributors for neck patients (p = 0.67 and 0.07). Neither of the two methods showed high precision in their predictions of follow-up at eight weeks. However, for LBP patients, the OMPQ and the clinicians' prognostic assessment contributed significantly in the prediction of functional outcome 8 weeks after the initial assessment of manual therapist, whereas the prediction for neck patients was unsure. PMID- 23018082 TI - Porous zirconia/hydroxyapatite scaffolds for bone reconstruction. AB - OBJECTIVE: Highly porous apatite-based bioceramic scaffolds have been widely investigated as three-dimensional (3D) templates for cell adhesion, proliferation, and differentiation promoting the bone regeneration. Their fragility, however, limits their clinical application especially for a large bone defect. METHODS: To address the hypothesis that using a ZrO(2)/hydroxyapatite (HAp) composite might improve both the mechanical properties and cellular compatibility of the porous material, we fabricated ZrO(2)/HAp composite scaffolds with different ZrO(2)/HAp ratios, and evaluated their characteristics. In addition, porous ZrO(2)/HAp scaffolds containing bone marrow derived stromal cells (BMSCs) were implanted into critical-size bone defects for 6 weeks in order to evaluate the bone tissue reconstruction with this material. RESULTS: The porosity of a ZrO(2)/HAp scaffold can be adjusted from 72% to 91%, and the compressive strength of the scaffold increased from 2.5 to 13.8MPa when the ZrO(2) content increased from 50 to 100wt%. The cell adhesion and proliferation in the ZrO(2)/HAp scaffold was greatly improved when compared to the scaffold made with ZrO(2) alone. Moreover, in vivo study showed that a BMSCs-loaded ZrO(2)/HAp scaffold provided a suitable 3D environment for BMSC survival and enhanced bone regeneration around the implanted material. SIGNIFICANCE: We thus showed that a porous ZrO(2)/HAp composite scaffold has excellent mechanical properties, and cellular/tissue compatibility, and would be a promising substrate to achieve both bone reconstruction and regeneration needed in the treatment of large bone defects. PMID- 23018083 TI - Simultaneous determination of polymerization shrinkage, exotherm and thermal expansion coefficient for dental resin-composites. AB - OBJECTIVES: To measure shrinkage strain, exotherm, and coefficient of thermal expansion (CTE), simultaneously for a set of representative resin-composites. METHODS: Six commercially available resin-composites with different filler loadings were selected. A modified bonded-disk instrument that includes temperature-monitoring apparatus was used to measure simultaneously: shrinkage strain, exotherm, and CTE. Shrinkage strain and temperature of disk specimens (n=3/materials) were monitored for 1h after irradiation for 20s at 1200mW/cm(2) (energy density=24J/cm(2)). Disks were irradiated for a second time 60min after the first irradiation. Axial expansion strain and temperature were monitored for 3min. Exotherm was obtained from differences between temperature rise during 1st and 2nd irradiations. CTE was calculated from disk axial expansion due to irradiation heat (DeltaL) and rise in temperature (DeltaT) during the second irradiation. RESULTS: The final shrinkage strain values ranged from 1.7% to 2.34%, exotherm values ranged from 4.66 to 9.43 degrees C, and CTE ranged from 18.44 to 24.63 (10(-6)/ degrees C). Negative correlations were found between filler loading and shrinkage strain, exotherm, and CTE. Positive correlation was apparent between shrinkage strain and CTE. SIGNIFICANCE: The modified bonded-disk instrument could be used to measure simultaneously shrinkage strain, exotherm, and CTE of resin-composites. PMID- 23018086 TI - [Simultaneous submission: a scientific misconduct case which is detected incidentally and may be ended in the different ways]. PMID- 23018084 TI - Effect of a non-thermal, atmospheric-pressure, plasma brush on conversion of model self-etch adhesive formulations compared to conventional photo polymerization. AB - OBJECTIVE: To determine the effectiveness and efficiency of non-thermal, atmospheric plasmas for inducing polymerization of model dental self-etch adhesives. METHODS: The monomer mixtures used were bis-[2-(methacryloyloxy)ethyl] phosphate (2MP) and 2-hydroxyethyl methacrylate (HEMA), with mass ratios of 70/30, 50/50 and 30/70. Water was added to the above formulations: 10-30wt%. These monomer/water mixtures were treated steadily for 40s under a non-thermal atmospheric plasma brush working at temperatures from 32 to 35 degrees C. For comparison, photo-initiators were added to the above formulations for photo polymerization studies, which were light-cured for 40s. The degree of conversion (DC) of both the plasma- and light-cured samples was measured using FTIR spectroscopy with an attenuated total reflectance attachment. RESULTS: The non thermal plasma brush was effective in inducing polymerization of the model self etch adhesives. The presence of water did not negatively affect the DC of plasma cured samples. Indeed, DC values slightly increased, with increasing water content in adhesives: from 58.3% to 68.7% when the water content increased from 10% to 30% in the adhesives with a 50/50 (2MP/HEMA) mass ratio. Conversion values of the plasma-cured groups were higher than those of light-cured samples with the same mass ratio and water content. Spectral differences between the plasma- and light-cured groups indicate subtle structural distinctions in the resultant polymer networks. SIGNIFICANCE: This research if the first to demonstrate that the non-thermal plasma brush induces polymerization of model adhesives under clinical settings by direct/indirect energy transfer. This device shows promise for polymerization of dental composite restorations having enhanced properties and performance. PMID- 23018088 TI - Coronary artery ectasia and atrial electrical and mechanical dysfunction. PMID- 23018089 TI - Right ventricular functions in pulmonary embolism. PMID- 23018090 TI - Long-term high +Gz effects on cardiac functions in the pilots. PMID- 23018091 TI - [Prof. Dr. Naci Bor - a man chasing curiosity]. PMID- 23018092 TI - Multiple fatal images in right heart. Behcet's disease. PMID- 23018093 TI - Targeting conserved water molecules: design of 4-aryl-5-cyanopyrrolo[2,3 d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization. AB - Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design. PMID- 23018094 TI - Identification of a 2-phenyl-substituted octahydrobenzo[f]quinoline as a dopamine D3 receptor-selective full agonist ligand. AB - This work describes the identification of a novel class of octahydrobenzo[f]quinolines as dopamine D(3)-selective full agonists. We developed a facile method that utilizes Suzuki coupling for easy incorporations of various substituted pendant rings into the scaffold. A small focused library of octahydrobenzo[f]quinolines 5 was synthesized, and these compounds demonstrated at least 14-fold D(2)-like selectivity over D(1) in native porcine striatal tissue. Furthermore, n-propyl analog 5f was found to be a high affinity (K(i)=1.1 nM) D(3) dopamine full agonist with 145-fold selectivity over the D(2) receptor and about 840-fold selectivity over the D(1) receptor. PMID- 23018095 TI - Salicylaldoxime derivatives as new leads for the development of carbonic anhydrase inhibitors. AB - New compounds containing a novel zinc binding group (salicylaldoxime system) were identified as effective inhibitors of carbonic anhydrases (CAs). This structural motif seems to bind the catalytic zinc ion of CAs, revealing itself as a new valid alternative to the sulfonamide group. Computational procedures were used to investigate the binding mode of this class of compounds, within the active site of CAII. This study suggests that the salicylaldoxime moiety binds the zinc ion through the oxime oxygen atom that also forms an H-bond with T199. The results herein obtained will allow the development of new CA-inhibitors bearing the salicylaldoxime moiety. PMID- 23018096 TI - Design, synthesis and biological evaluation of heterocyclic azoles derivatives containing pyrazine moiety as potential telomerase inhibitors. AB - Three series of novel heterocyclic azoles derivatives containing pyrazine (5a-5k, 8a-8k and 11a-11k) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential telomerase inhibitors. Among the oxadiazole derivatives, compound 5c showed the most potent biological activity against SW1116 cancer cell line (IC(50)=2.46 MUM against SW1116 and IC(50)=3.55 MUM for telomerase). Compound 8h performed the best in the thiadiazole derivatives (IC(50)=0.78 MUM against HEPG2 and IC(50)=1.24 MUM for telomerase), which was comparable to the positive control. While compound 11f showed the most potent biological activity (IC(50)=4.12 MUM against SW1116 and IC(50)=15.03 MUM for telomerase) among the triazole derivatives. Docking simulation by positioning compounds 5c, 8h and 11f into the telomerase structure active site was performed to explore the possible binding model. The results of apoptosis demonstrated that compound 8h possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 8h with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell. Therefore, the introduction of oxadiazole, thiadiazole and triazole structures reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. PMID- 23018097 TI - Treatment and outcomes of primary breast lymphoma. AB - PURPOSE: To evaluate treatment and outcomes in a population-based cohort of patients diagnosed with primary breast lymphoma. METHODS AND MATERIALS: Prognostic factors, management, and outcomes (local control, lymphoma-specific survival, and overall survival) were analyzed for all patients diagnosed with limited-stage, primary breast non-Hodgkin lymphoma (n = 50) diagnosed in British Columbia between 1981 and 2009. RESULTS: The median follow-up was 3.5 years; 64% presented with a breast mass. Histologic subtypes were indolent (n = 16 [32%]) or aggressive (n = 34 [68%]). Of those with indolent lymphoma, 81% had stage I, and 19% had stage II disease; 13% received no initial treatment; 75% received radiotherapy (RT) alone. One (6%) patient received surgical resection alone, and 1 (6%) patient received surgical resection in addition to RT. Of those with aggressive lymphoma, 62% had stage I and 38% had stage II disease; 3% received no initial treatment; 6%, RT alone; 38%, chemotherapy only; 41%, chemotherapy and RT; 9%, surgical resection alone; and 3%, surgical resection in addition to chemotherapy and RT. In patients with indolent and aggressive disease, 5-year local control estimates were 92% and 96%, lymphoma-specific survivals were 91% and 71%, and overall survivals were 75% and 54%, respectively. On univariate analysis, stage (I vs. II) (P = .006) and RT use (P = .032) were statistically significant predictors of improved overall survival in patients with indolent breast lymphoma. Combined chemoradiation was associated with a trend for improved overall survival (P = .061) in patients with aggressive disease. There were 4 cases of central nervous system relapse, all occurred in subjects with aggressive primary breast lymphoma. CONCLUSIONS: Patients with indolent breast lymphoma were most frequently treated with RT alone and achieved high rates of local control and survival. Patients with aggressive histology most often treated with chemotherapy, alone or combined with RT, had excellent local control but lower survival compared with indolent disease. Improved systemic therapies are needed to improve outcomes for patients with aggressive breast lymphoma. PMID- 23018098 TI - Polymorphic variants of DNMT3A and the risk of endometriosis. AB - OBJECTIVE: Overexpression of DNA methyltransferase 3A (DNMT3A) and aberrant methylation of various genes in eutopic endometrium have been demonstrated in women with endometriosis. We aimed to study whether DNMT3A polymorphisms could be a genetic risk factor for endometriosis and endometriosis-related infertility. STUDY DESIGN: We studied 5 SNPs (rs2289195, rs7590760, rs13401241, rs749131 and rs1550117) located in the DNMT3A gene in 357 women with endometriosis and 640 controls. RESULTS: We did not observe significant differences between genotype and allele frequencies of rs2289195, rs7590760, rs13401241, rs749131 and rs1550117 SNPs in women with endometriosis, endometriosis-related infertility, and controls. The lowest p values of the trend test were observed for DNMT3A rs1550117 in endometriosis and endometriosis-related infertility (p(trend)=0.049 and p(trend)=0.055, respectively). CONCLUSIONS: Our results did not supply evidence for the contribution of SNPs located in DNMT3A to either endometriosis or endometriosis-related infertility. PMID- 23018099 TI - Time interval from elective removal of cervical cerclage to onset of spontaneous labour. AB - OBJECTIVE: To determine the time interval between elective removal of a cervical cerclage to the onset of spontaneous labour in women who had either a history- or ultrasound-indicated cervical cerclage. STUDY DESIGN: A retrospective cohort study of women with a singleton pregnancy that had either a modified Shirodkar or McDonald cervical cerclage inserted were evaluated for the time interval between elective cerclage removal and onset of spontaneous labour and also spontaneous labour with 72 h of cervical cerclage removal. RESULTS: Two hundred and sixty nine singleton pregnancies with either a modified Shirodkar or McDonald cervical cerclage were analysed. The mean gestational age at cerclage removal was 36.7 +/- 1.10 weeks and gestational age at spontaneous labour was 39.0 +/- 1.94 weeks (mean +/- SD). The median interval between cerclage removal and spontaneous labour was 14 days. Only 18% of women laboured spontaneously within 72 h. Women with ultrasound-indicated cerclage were more likely to deliver within 72 h, compared with women with a history-indicated cervical cerclage (odds ratio, 3.68; 95% confidence interval, 1.31-10.85, p=0.01). CONCLUSION: Independent of the indication or technique used for cervical cerclage, the rate of early spontaneous labour following elective removal of cervical cerclage is sufficiently low to justify outpatient management. PMID- 23018104 TI - Activation of liver X receptor attenuates endothelin-1 expression in vascular endothelial cells. AB - Endothelin-1 (ET-1), predominantly produced by vascular endothelial cells (VECs), plays an important role in the pathogenesis of inflammatory diseases. Liver X receptor (LXR), a typical nuclear receptor, is known for inhibiting expression of inflammatory molecules. However, it remains unclear whether LXR suppresses ET-1 expression. In the present study, we showed that pretreatment with GW3965, a specific ligand of LXR, significantly attenuated lipopolysaccharide (LPS)-induced ET-1 in mice plasma. The in vitro experiments showed that both LXRalpha and beta were expressed in human VECs, and they are functional as demonstrated by induction of the target gene ABCA1 after treatment with GW3965. Moreover, activation of LXR with GW3965 in human VECs dramatically attenuated the basal and LPS-stimulated ET-1 production at both transcriptional and translational levels. Luciferase reporter assays indicated that LXR activation suppressed the transcriptional activity of the human ET-1 gene promoter, and repressed the activity of a heterologous promoter driven by the response elements of activator 1 (AP-1) or nuclear factor-kappaB (NF-kappaB). Electrophoretic mobility shift and chromatin immunoprecipitation assays showed that activation of LXR reduced the binding of the transcriptional factors AP-1 and NF-kappaB to the ET-1 gene promoter region. In conclusion, activation of LXR represses ET-1 expression in vivo and in vitro, which may be involved in the negatively interfering with AP 1/NF-kappaB signaling. These results suggest that LXRs may serve as a novel molecular target for modulating ET-1 expression in VECs, and even for the treatment of ET-1-associated inflammatory diseases. PMID- 23018105 TI - Podocytes: a new player for glutamate signaling. AB - In the renal glomerulus, podocytes envelop the external side of the capillary basement membrane with their intertwining ramifications, and ensure elimination of metabolic waste within the urine, while proteins and important blood components are retained into the circulation. To preserve the integrity of the glomerular filter, which is constantly exposed to a high variety of stimuli, podocytes need to communicate by rapid and precise signaling, likely similar to that used by neuronal cells. In the last years, we and others have shown that podocytes are indeed molecularly equipped for communicating in a synaptic-like way, where glutamate and its receptors seem to have a pivotal role, because altering glutamatergic communication leads to podocyte damage and increased filter permeability. Major components of glutamatergic signaling are organized at foot process junctions by adhesion molecules, chiefly by nephrin, and are connected to the actin cytoskeleton, that governs the health of podocytes. Further advances in understanding podocyte physiological behavior and signaling properties have the potential to improve the knowledge of podocyte diseases, first among them idiopathic focal segmental glomerulosclerosis that still needs more precise molecular-based diagnosis and targeted treatment. PMID- 23018106 TI - International variation in medication prescription rates among elderly patients with inflammatory bowel disease. AB - BACKGROUND AND AIMS: The elderly represent a growing demographic of patients with IBD. No study has previously described variations in care or medication prescriptions in senior patients with IBD. We compared prescription rates among elderly patients with IBD in four countries using health administrative data. METHODS: Databases from the United States (US), United Kingdom (UK), Denmark and Canada were queried. Variation in prescription rates between countries was assessed in patients >=65y with prevalent IBD who had >=1 prescription for an IBD related medication in a given quarter between 2004 and 2009. Patients were identified using previously-reported, validated algorithms. Country-specific rates were compared in each quarter using Fisher's exact test. RESULTS: In patients with Crohn's disease, Canada and US had higher prescription rates for oral 5-ASA (P<0.0001 in all quarters) and infliximab (P<0.05 in 22/24 quarters), while the US had higher rates of thiopurine usage (P<0.05 in 23/24 quarters). Canada had greater rates of methotrexate prescriptions (P<0.05 in 21/24 quarters analyzed). In patients with ulcerative colitis (UC), rates of oral steroid usage was lowest in the US (P<0.05 in 22/24 quarters) and oral 5-ASA use was highest in the US and Canada (P<0.0001 in all quarters). Canada and Denmark used more rectal therapy than the US. Infliximab usage in UC was significantly higher in the US and Canada after 2006. CONCLUSIONS: Significant variation in medication prescription rates exists among countries. Future research should assess whether these differences were associated with disparities in outcomes and health care costs. PMID- 23018107 TI - Investigation of fatty acids accumulation in Nannochloropsis oculata for biodiesel application. AB - Lipids production of the marine microalga species Nannochloropsis oculata was deeply investigated by studying under continuous light the effects of different nitrogen starvation strategies in photobioreactors of various thicknesses. Operating parameters like incident photons flux density (PFD), initial nitrogen (progressive starvation strategy) or biomass concentrations (sudden starvation strategy) were examined, with a detailed analysis of their effects on the quality and production kinetics of total (TL) and triglycerides (TG). In addition to the already known effect of nitrogen starvation to trigger reserve lipids accumulation (mainly TG), it was demonstrated the relevance of the light received per cell affecting TG content and productivities, as well as fatty acids (FA) profiles. With appropriate optimization, N. oculata was confirmed as an interesting candidate for biodiesel application, with high FA accumulation (up to around 50%DW with 43%DW in TG-FA), high productivity (maximum 3.6*10(-3)kg(TG FA)m(-2)d(-1)) and a TG-FA profile close to palm oil. PMID- 23018108 TI - Optimization of dilute acid-based pretreatment and application of laccase on apple pomace. AB - The present study was aimed to optimize acid-based pretreatment of apple pomace in relation to acid concentration, temperature and reaction time using response surface method with glucose as response variable. In addition, laccase (EC. 1.10.3.2) from Trametes versicolor was applied for degradation of polyphenols in apple pomace that could inhibit the further bioconversion steps involving enzymes and fermenting micro-organisms. The optimized conditions were: 1.5 g/100mL acid concentration, 16 min reaction time and 91 degrees C reaction temperature, producing 13.9 g glucose/100g on a dry matter basis. Subsequent application of laccase to hydrolyzates degraded most of the phenolic compounds in apple pomace by more than 85%. The optimized pretreatment conditions resulted in lower concentrations of other inhibitors such as furan compounds and acetic acid. Therefore, dilute acid pretreatment in combination with laccase application can be used for enhancing subsequent hydrolysis of polysaccharides and fermentation of apple pomace. PMID- 23018109 TI - Hydrolysis of cellulose to glucose at the low temperature of 423 K with CaFe2O4 based solid catalyst. AB - Weakly magnetic CaFe(2)O(4) was synthesized by calcination of the hydroxides co precipitated from aqueous Ca(NO(3))(2).6H(2)O and Fe(NO(3))(3).9H(2)O solutions in the presence of urea. Microcrystalline cellulose was treated with ionic liquid (IL) [AMIM]Cl (1-allyl-3-methylimidazolium chloride) and hydrolyzed in the presence of the catalyst at 423K. No IL contamination was detected in the treated cellulose by energy-dispersive X-ray spectrometry (EDX). A maximum hydrolysis yield of 49.8% and glucose selectivity of 74.1% was obtained. The catalyst was separated and reused four times, showing only a slight decrease in activity. The catalyst was stable and only minor leaching into water occurred as indicated by inductively coupled plasma atomic emission spectrometry (ICP), X-ray diffraction (XRD), and temperature programmed desorption (TPD) measurements and a neutral pH after reactions. Hydrolysis of cellulose with CaFe(2)O(4) catalyst combined with [AMIM]Cl pretreatment is a green, energy-saving and efficient process. PMID- 23018110 TI - Effects of pretreatment of wheat bran on the quality of protein-rich residue for animal feeding and on monosaccharide release for ethanol production. AB - The effects of hydrothermal conditions for pretreating wheat bran on the quality of residual protein for animal feeding, and on monosaccharide release for ethanol production were studied according to a 4*2*2 design with the factors, temperature (120, 140, 160, and 180 degrees C), acidity (pH 2.3 and 3.9), and retention time (5 and 10 min). Temperature affected the quality of residual protein for animal feeding. Pretreatment at 120 and 140 degrees C did not affect O-methylisourea reactive lysine in protein-rich wheat bran residue, although total lysine decreased with increasing temperature at pH 2.3. At temperatures higher than 140 degrees C, reactive lysine decreased and melanoidins, furfural and 5-HMF increased. Lower acidity during pretreatment at 120 and 140 degrees C increased the digestibility of the residual wheat protein in vitro by 36%. Pretreatment conditions did not substantially affect the release of monomeric xylose and arabinose by hemicellulases, which suggests that arabinoxylans in wheat bran are well accessible for enzymes. PMID- 23018111 TI - Upscaling and in-line process monitoring via spectroscopic techniques of ethylene vinyl acetate hot-melt extruded formulations. AB - The aim of the present work was to evaluate drug release and quality of EVA/drug matrices at different PEO 7M concentrations (5 and 15%), manufactured using two different hot-melt extruders: a lab-scale mini extruder and a pilot-scale extruder. The process parameters used on both extruders (temperature and screw speed) and drug release from the matrices were compared. On the lab-scale extruder all formulations were extruded at 90 degrees C, whereas on the pilot scale extruder the temperature of the die was adjusted to 100 degrees C in order to achieve a constant pressure at the extrusion die, hence constant material flow through the die to yield smooth extrudates. Screw speed was also adjusted from 60 rpm (lab-scale extruder) to 90 rpm (pilot-scale extruder) in order to obtain a balance between feeding rate and screw speed. Drug release from the obtained matrices on both extruders was also assessed. Despite the differences in diameter (diameter of 2 and 3mm for the lab-scale extruder and pilot-scale extruder, respectively), temperature and screw speed, drug release per surface area was similar. DSC analysis of a formulation [EVA40/MPT (50/50, w/w) with 5% PEO] indicated small changes in its solid state after extrusion on both extruders: drug crystallinity was reduced by max. 20%, PEO recrystallized after cooling and EVA remained semi-crystalline. Extrusion experiments on the pilot-scale extruder of EVA/MPT, 50/50 (w/w) formulations were also monitored in-line using Raman and NIR spectroscopy in order to evaluate the material behavior at a molecular level in the extrusion barrel as function of the process settings (extrusion temperature: 90, 110 and 140 degrees C; screw speed: 90 and 110 rpm). At 90 and 110 degrees C the crystallinity of the drug was reduced, but the majority of MPT remained in its crystalline state as specific peaks in the Raman spectra of the drug became broader. These differences were accentuated when extrusion was performed at 140 degrees C as the drug completely melted. Peak shifts to lower frequencies [(CO) groups of the drug and (CH(3)COO) groups of EVA] were registered at all extrusion temperatures, with maximum effect at 140 degrees C indicating molecular interactions. Increasing the screw speed did not result in peak shifts of Raman spectra. NIR confirmed these observations and showed an additional peak in the spectra characteristic of (OH) bounds. PMID- 23018112 TI - Robot-assisted preparation of oncology drugs: the role of nurses. AB - Since 2007, the preparation of cancer drugs at the Pharmacy of the University Hospital of Ancona has been progressively robotized. Currently, the process of preparation of intravenous cancer drugs is almost totally automated (95%). At present, the Cytotoxic laboratory of Ancona is the sole, in Europe, that can count on two robots. The robots handle 56 oncology molecules, which correspond to more than 160 different vials. The production rate in 2011 exceeded 19,000 preparations. The quality of compounding and the sterility controls are satisfactory, every step of the process is traceable. The nursing staff played a fundamental role in the robot development process. The nursing staff and the pharmacists are still collaborating with the robotic engineers in order to increase efficiency, ergonomics and user-friendliness of the robots. PMID- 23018113 TI - Loading antifungal drugs onto silica particles grafted with cyclodextrins by means of inclusion complex formation at the solid surface. AB - Immobilization of antifungal drugs to solid particles has been addressed in order to limit the skin penetration to the skin surface during topical administration. Antifungal drug griseofulvin has been immobilized at the surface of silica particles by formation of its inclusion complex with beta-cyclodextrins grafted to silica. A simple and fast process for loading griseofulvin into the hydrophobic cavity of cyclodextrins at the surface of the solid particles in aqueous suspension has been designed. It allowed the formation of the griseofulvin:cyclodextrin inclusion complex of 1:1 stoichiometry to completion. Grafting beta-cyclodextrins to silica surface has been performed in a two-step procedure. The coupling agent 3-amino-propylmethyldiethoxysilane was reacted onto fumed silica particles as a first step. The second step was the reaction of grafted primary amino groups with tosylated beta-cyclodextrin that led to beta cyclodextrin grafted silica. Loading griseofulvin onto grafted silica particles have been investigated by IR spectroscopy and by tracking possible crystals of griseofulvin in aqueous suspension by optical and scanning electron microscopy and X-ray diffraction. Successful formation of the inclusion complex at the surface of grafted silica suggested a strong adsorption of griseofulvin by means of heterogeneous nucleation of crystals, followed by inclusion complexation taking place between the partners being in close proximity at the surface of silica particles. The high adsorption capacity of CD-grafted silica for griseofulvin compared to bare silica and amino-grafted silica supports this interpretation. PMID- 23018114 TI - A combined microhydrodynamics-polymer adsorption analysis for elucidation of the roles of stabilizers in wet stirred media milling. AB - Although polymers and surfactants are commonly used as stabilizers to impart physical stability to the suspensions produced by wet stirred media milling of poorly water-soluble drugs, scant information is available in pharmaceutical literature regarding their impact on the breakage kinetics. We present a combined microhydrodynamics-polymer adsorption analysis to elucidate the roles of stabilizers with a focus on the kinetics. Griseofulvin (GF), a model poorly water soluble drug, was milled at various concentrations of hydroxypropyl cellulose (HPC) in the presence-absence of sodium dodecyl sulfate (SDS). Particle sizing, scanning electron microscopy, thermal analysis, and rheometry were used to determine the breakage kinetics, adsorption isotherm, and apparent viscosity, which were then used to analyze the aggregation state of the milled suspensions and the microhydrodynamics. In the absence of SDS, an increase in HPC concentration slowed the particle aggregation leading to faster apparent breakage. On the other hand, due to a synergistic stabilizing action of HPC with SDS, lower HPC concentration was needed to stabilize the suspensions, and an optimum HPC concentration for the fastest apparent breakage was identified. The microhydrodynamic analysis quantified, for the first time, the viscous dampening effect of polymers, while only the combined analysis could explain the observed optimum. PMID- 23018115 TI - Application of knockout mouse models to investigate the influence of FcgammaR on the tissue distribution and elimination of 8C2, a murine IgG1 monoclonal antibody. AB - The current work examines the role of Fcgamma-receptors on the elimination and tissue distribution of 8C2, a model murine IgG1 monoclonal antibody. The plasma pharmacokinetics of (125)Iodine-labeled 8C2 were investigated in C57BL/6 control mice, FcgammaRI/RIII knockout mice, and FcgammaRIIb knockout mice, following intravenous doses of 0.04, 0.1 and 0.4 mg/kg. Plasma samples were collected and radioactivity was counted. Concentration data were analyzed with a population pharmacokinetic model. Additionally, the tissue disposition of 8C2 was investigated using whole body autoradioluminography (WBAL) and via counting excised tissues. Areas under the plasma concentration vs. time curves AUC(0-10 days) +/-SD (nM*days) were: 12.3+/-0.3, 12.5+/-1.3 and 15.1+/-1.2 at 0.04 mg/kg; 39.3+/-2.0, 28.9+/-2.7 and 42.0+/-9.4 at 0.1 mg/kg; and 225+/-19, 158+/-19 and 204+/-26 at 0.4 mg/kg in C57BL/6, FcgammaRI/RIII(-/-) and FcgammaRIIb(-/-) mice. Strain was not a statistically significant predictor for any of the parameters of the population model. 8C2 plasma clearance, distribution clearance, and central compartment volume were 0.00543 L/days/kg, 0.0598 L/days/kg, and 0.057 L/kg. No substantial differences in 8C2 tissue uptake were identified by analysis of excised tissues or by WBAL. In conclusion, FcgammaR knockout is associated with only minor effects on the plasma and tissue disposition of 8C2, a model murine IgG1 mAb. PMID- 23018116 TI - Micro-computed tomography imaging of composite nanoparticle distribution in the lung. AB - Nanomedicine comprises a significant potential to approach the therapy of severe diseases. Knowledge of nanoparticle behavior at the target site would contribute to the development of specialized tools for respiratory medicine. Here, we were interested in the potential of micro-computed tomography (MUCT) imaging to monitor the pulmonary distribution of polymeric nanoparticles. Composite nanoparticles were analyzed for physicochemical properties, morphology and composition. MUCT was employed to visualize the pulmonary distribution of composite nanoparticles in an ex vivo lung model. Employed composite nanoparticles were composed of poly(styrene) cores coated by a thin shell of colloidal iron oxide. Particles were mainly located in the interstitial space and associated with pulmonary cells, as observed by light microscopy. MUCT detected enhanced X-ray opacities in the conducting (linear pattern) and respiratory airways (aciniform X-ray attenuations). In conclusion, multifunctional nanoparticles will prompt the development of novel therapeutic and diagnostic tools in respiratory medicine. PMID- 23018117 TI - Mental health, service use and social capital among Indian-Australians: findings of a wellbeing survey. AB - OBJECTIVE: Indian-Australians represent a distinct immigrant group both demographically and culturally. Yet, despite an expanding body of research on transcultural mental health in Australia, there is a paucity of studies regarding mental health of Indian-Australians. This paper explores the extent of psychological morbidity and related service use in a representative sample of Indian-Australians. It further examines the association of mental health with social participation and networking in this ethnic community. METHOD: Measures to assess current levels of psychological distress, functional disability, service use, and social capital were administered in a random sample of 71 Indian Australian family groups living in Sydney. RESULTS: Amongst participants, 15% reported high to very high levels of psychological distress. Psychological distress was associated with increased days of functional disability and higher levels of functional impairment, and an increased likelihood of a GP consultation. However, 91% of participants with identifiable mental health needs did not seek any mental health consultation. Social capital was not found to be a significant predictor of psychological health or service use in this sample. CONCLUSION: Psychological morbidity in the Indian-Australian community is associated with high levels of functional disability, both in number of days and extent of severity, but only a small proportion seeks mental health help. PMID- 23018118 TI - Depression, financial problems and other reasons for suspending medical studies, and requested support services: findings from a qualitative study. AB - OBJECTIVES: This study aimed to qualitatively explore medical students' reasons for suspending, or thinking of suspending, their studies and the types of support services they request. METHOD: Data were collected through an anonymous online survey. Medical students' responses to open-ended questions were analyzed thematically. RESULTS: Responses were received from 475 students. Financial problems, doubts as to whether medicine was the right vocation, and depression were the most commonly reported themes. Students endorsed a wide range of other pressures and concerns, barriers to obtaining assistance, and also suggested solutions and services to address their concerns. CONCLUSIONS: Medical students' financial concerns and potential depressive symptoms should be addressed by university and faculty support services. Government financial support mechanisms for students should also be reviewed. Students' suggestions of the types of services and their location must be borne in mind when allocating resources. PMID- 23018119 TI - Serum biomarker kinetics with three different courses of HHV-6B encephalitis. AB - Human herpesvirus-6B (HHV-6B) encephalitis can clinically manifest as hemorrhagic shock and encephalopathy syndrome (HSES), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), and acute necrotizing encephalopathy (ANE). To compare the underlying pathophysiology, we measured several biomarkers of interest in patients with these three different courses. Based on their clinical course and neuroimaging analysis, Cases 1, 2 and 3 were diagnosed as HSES, AESD, and ANE, respectively. HHV-6B was isolated from peripheral blood obtained during the acute phase in all three patients, and was detected in the cerebrospinal fluid of Cases 2 and 3. In Case 1, a marked increase in levels of several serum cytokines (IL-1beta, IL-6, and IL-10) and chemokines (IL-8, MIG, MCP-1, and IP-10) was observed at disease onset. Subsequently, serum cytokine levels gradually became undetectable and chemokine levels stabilized by day 11 of illness. In Case 2, only two cytokines (IL-6 and IL-10) were slightly elevated at disease onset. In Case 3, the kinetics appeared to follow an up-and-down pattern. Additionally, in all three patients, TIMP-1 concentrations remained high during the observation period, and MMP-9 decreased quickly a few days after disease onset, and then returned to normal level. PMID- 23018120 TI - Scarlet fever epidemic, Hong Kong, 2011. AB - More than 900 cases of scarlet fever were recorded in Hong Kong during January July, 2011. Six cases were complicated by toxic shock syndrome, of which 2 were fatal. Pulsed-field gel electrophoresis patterns suggested a multiclonal epidemic; emm12 was the predominant circulating type. We recommend genetic testing of and antimicrobial resistance monitoring for this reportable disease. PMID- 23018121 TI - Amygdala activation to fearful faces under attentional load. AB - While some functional imaging studies suggested an automatic activation of the amygdala to fearful vs. neutral faces, recent studies showed the absence of amygdala activation to fearful faces under high attentional load induced by distracting tasks. The present fMRI study investigated whether this outcome can be modulated by changing the saliency of the eyes of fearful faces. Subjects had to solve a high perceptual load task while they were presented either with normal faces (Exp. 1) or with normal faces intermixed with faces, in which pupil and iris of eyes were erased to increase the saliency of the normal eyes (Exp. 2). There was no differential amygdala activation to fearful versus neutral faces under standard conditions without any manipulation of the faces (Exp. 1). In contrast to this outcome, Experiment 2 led to differential amygdala activation to the normal but not to the manipulated fearful vs. neutral faces. These findings propose a concept of relative automaticity of the activation of the amygdala. The activation depends on available cognitive resources and on the saliency of specific parts of fearful faces. PMID- 23018122 TI - Differential sensitivity of cranial and limb motor function to nigrostriatal dopamine depletion. AB - The present study determined the differential effects of unilateral striatal dopamine depletion on cranial motor versus limb motor function. Forty male Long Evans rats were first trained on a comprehensive motor testing battery that dissociated cranial versus limb motor function and included: cylinder forepaw placement, single pellet reaching, vermicelli pasta handling; sunflower seed opening, pasta biting acoustics, and a licking task. Following baseline testing, animals were randomized to either a 6-hydroxydopamine (6-OHDA) (n=20) or control (n=20) group. Animals in the 6-OHDA group received unilateral intrastriatal 6 OHDA infusions to induce striatal dopamine depletion. Six-weeks following infusion, all animals were re-tested on the same battery of motor tests. Near infrared densitometry was performed on sections taken through the striatum that were immunohistochemically stained for tyrosine hydroxylase (TH). Animals in the 6-OHDA condition showed a mean reduction in TH staining of 88.27%. Although 6 OHDA animals were significantly impaired on all motor tasks, limb motor deficits were more severe than cranial motor impairments. Further, performance on limb motor tasks was correlated with degree of TH depletion while performance on cranial motor impairments showed no significant correlation. These results suggest that limb motor function may be more sensitive to striatal dopaminergic depletion than cranial motor function and is consistent with the clinical observation that therapies targeting the nigrostriatal dopaminergic system in Parkinson's disease are more effective for limb motor symptoms than cranial motor impairments. PMID- 23018123 TI - Neural substrates of fear conditioning, extinction, and spontaneous recovery in passive avoidance learning: a c-fos study in rats. AB - Extinguishing fear conditioning and preventing the return of fear are the goal in the treatment of anxiety disorders. However, the neural substrates that mediate fear conditioning, extinction, and spontaneous recovery (i.e., the return of fear) remain uncertain. We utilized the aversive passive avoidance learning paradigm and Fos-like immunoreactivity to elucidate this issue. Exception for naive rats that did not receive any treatment served as the control group, the other rats were subjected to three sessions of context/footshock (0.5 mA, 2s) pairings followed by 12 extinction sessions (context-no footshock). After the last extinction test, these rats were assigned to one of three groups reflecting the number of resting days before the test session (context-no footshock): Day 8, Day 9, and Day 10 groups. Only the Day 10 group exhibited spontaneous recovery during the test session. Fos-like immunoreactivity associated with fear conditioning was seen in the amygdala and cingulate cortex area 1 (Cg1). The extinction of fear was seen to be related to Cg1, cingulate cortex area 2 (Cg2), piriform cortex (Pir), and entorhinal cortex (Ect). Spontaneous recovery was seen to be related to amygdala, Pir, and Ect. The present findings indicate that the brain substrates of fear acquisition, extinction and spontaneous recovery have different ensembles of brain activations. These differences suggest that different brain targets may be considered for fear extinction and for avoiding the return of fear in anxiety disorders. PMID- 23018124 TI - ApoE isoform modulates effects of cranial 56Fe irradiation on spatial learning and memory in the water maze. AB - Apolipoprotein E, which plays an important role in lipid transport and metabolism and neuronal repair, might modulate the CNS risk following (56)Fe irradiation exposure during space missions. In this study, we investigated this risk by behavioral and cognitive testing male E2, E3, and E4 mice 3 months following cranial (56)Fe irradiation. In the open field, mice irradiated with 2 Gy showed higher activity levels than sham-irradiated mice or mice irradiated with 1 Gy. In addition, E2 mice showed higher activity and lower measures of anxiety than E3 and E4 mice in the open field and elevated zero maze. During hidden platform training, sham-irradiated mice showed most robust learning, 1 Gy irradiated mice reduced learning, and 2 Gy irradiated mice no improvement over the four sessions. In the water maze probe trials, sham-irradiated E2, E3, and E4 mice and E2 and E4 mice irradiated with 1 Gy showed spatial memory retention, but E3 mice irradiated with 1 Gy, and E2, E3, and E4 mice irradiated with 2 Gy did not. Thus, cranial (56)Fe irradiation increases activity levels in the open field and impairs spatial learning and memory in the water maze. E3 mice are more susceptible than E2 or E4 mice to impairments in spatial memory retention in the water maze, indicating that apoE isoform modulates the CNS risk following space missions. PMID- 23018125 TI - Maternal behavior as an early modulator of neurobehavioral offspring responses by Sprague-Dawley rats. AB - Maternal care plays an important role as an early modeler of neurodevelopment and brain function, and its effects remain until adulthood. Such modeling or programming has shown to influence the stress response and represents a key susceptibility factor in the development of mood disorders. In order to characterize such process which is still not clear, male offspring were classified in animals with low, medium and high licking/grooming (LG) according to the maternal behavior. Juvenile animals were subjected to the open field test (OFT) and the forced swimming test (FST), and offspring of low and high LG mothers were compared. Seven days after the FST, neurochemical and gene expression analyses were carried out in order to identify possible changes on relevant targets. Maternal care did determine locomotor behaviors in the OFT, supporting an anxiogenic effect of low maternal investment. This effect seems to be associated with the serotonergic systems in both nucleus accumbens (NAc) and hippocampus (HPC), since offspring of low LG mothers showed decreased 5-HT neurotransmission in those brain regions compared with animals of high LG mothers. Furthermore, TrkB expression was higher in offspring of high LG compared to the group of low LG mothers, supporting its influence as a mechanistic intermediate of such effect, at least in the NAc. Taken together, these findings strongly support the influence of differential maternal care on the neurodevelopment and responsivity of juvenile rats. PMID- 23018126 TI - Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice. AB - The olfactory bulbectomy (OB) animal model of depression is a well-established model that is capable of detecting antidepressant activity following chronic drug therapy, and the surgery results in behavioral and biochemical changes that are reminiscent of various symptoms of depression. In the present study, we investigated the degree to which 14 days of p.o. administration of the classic antidepressant fluoxetine (10mg/kg) were able to reverse OB-induced changes in behavior (namely, hyperactivity in the open-field test and reduced motivational and self-care behaviors in the splash test) and in the activation of hippocampal cell signaling pathways that are thought to be involved in synaptic plasticity. OB caused significant increases in ERK1 and CREB (Ser(133)) phosphorylation and in the expression of BDNF immunocontent, all of which were prevented by fluoxetine administration. Moreover, fluoxetine administration also caused a significant decrease in ERK2 phosphorylation in mice that had undergone OB. Neither Akt nor GSK-3beta phosphorylation was altered in any experimental condition. In conclusion, the present study shows that OB can induce significant behavioral changes that are accompanied by the activation of hippocampal signaling pathways, namely the ERK1/CREB/BDNF pathway, which is involved in the synaptic plasticity. Conversely, fluoxetine prevented these OB-induced behavioral changes and avoided the activation of ERK1/CREB/BDNF in the hippocampus. Taken together, our results extend the data from the existing literature regarding OB induced behavioral and neurochemical changes, and suggest a possible underlying mechanism that can account for the antidepressant effect of fluoxetine in this model. PMID- 23018127 TI - D(1) receptor agonists reverse the subchronic phencyclidine (PCP)-induced novel object recognition (NOR) deficit in female rats. AB - Development of dopamine (DA) D(1) receptor agonists is a priority to improve cognitive impairment in schizophrenia (CIS). This study examined the dose response relationship of the selective D(1) agonist, SKF38393 (0.5-40 mg/kg), to reverse the deficit in novel object recognition (NOR), an analog of declarative memory in man, produced by subchronic phencyclidine (PCP), an N-methyl-D aspartate (NMDA) receptor non-competitive antagonist, and the ability of the D(1) antagonists, SCH23390 (0.05 mg/kg) and SKF83566 (0.15 mg/kg), to impair NOR in normal Long-Evans female rats. We also examined the ability of tandospirone, a serotonin (5-HT)(1A) receptor partial agonist, and LY341495, a mGluR2/3 receptor antagonist, to potentiate or block the effects of SKF38393 on NOR, respectively. SKF38393 reversed the persistent NOR deficit produced by subchronic PCP; the dose response curve for SKF38393 was an inverted U-shape, with the peak effect at 6 mg/kg. SKF83566 and SCH23390 impaired NOR in normal rats. Co-administration of sub-effective doses of SKF38393 (0.25 mg/kg) and tandospirone (0.2 mg/kg) improved the PCP-induced NOR deficit, while LY341495 (1 mg/kg) blocked the ameliorating effect of SKF38393 (6 mg/kg), respectively. These data provide the first evidence that the reversal of the PCP-induced NOR deficit by D(1) agonism has an inverted U-shaped dose-response curve and that 5-HT(1A) and mGluR2/3 receptor signalling facilitates the efficacy of D(1) agonism to improve these deficits. These data suggest that although D(1) agonists may be useful to improve CIS, these agents, particularly higher doses, may also worsen cognitive function in some patients, because of an inverted U-shaped dose response curve. PMID- 23018128 TI - CB1 receptor activation in the nucleus accumbens core impairs contextual fear learning. AB - Contextual fear conditioning is a behavioral model in which a subject learns that a specific context is predictive of danger occurrence. There is evidence suggesting an important role for both the nucleus accumbens (NAc) and the endocannabinoid system in contextual fear conditioning formation. The purpose of this study was to assess whether endocannabinoids within the NAc modulate fear memory formation. Pre-training anandamide (AEA) infusions into the NAc core (NAcC) of male Wistar rats decreased freezing behavior in the contextual fear conditioning paradigm, as evaluated 24h after training. However, AEA did not induce any effect on the cued fear-conditioning paradigm. Likewise, AEA infusions into the NAc shell did not interfere with the contextual fear learning. AEA's effect was blocked when co-infused with AM251 (CB1R inverse agonist). Post training AEA infusions failed to exert an effect on contextual conditioning. These results suggest a cannabinergic regulation in the NAcC of the acquisition of contextual fear conditioning. PMID- 23018129 TI - Premature differentiation of vascular smooth muscle cells in human congenital diaphragmatic hernia. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterized by the herniation of abdominal organs into the chest cavity. The high mortality and morbidity of CDH patients are primarily caused by the associated pulmonary hypertension (PH), characterized by the thickening of the vascular media and adventitia. The media consist of heterogeneous populations of vascular smooth muscle cells (VSMC), ranging from synthetic to the characteristic contractile cells. VSMCs are influenced by developmental and environmental cues and may play a role in the development of the structural changes observed in CDH patients. Therefore, we hypothesized that the distribution of the VSMC populations may already be different at the origin of CDH development. METHODOLOGY: We analyzed the protein expression of specific markers associated with synthetic and contractile VSMC phenotypes in human lungs at different developmental stages. Next, we compared lungs of premature and term CDH patients, as well as patients with lung hypoplasia due to renal agenesis or PROM, with age matched controls. RESULTS: Synthetic and contractile VSMCs are distributed in a temporal and spatial specific pattern along the proximodistal axis of the lung. CDH patients have more abundant contractile VSMCs which are also more distally distributed. This different distribution pattern is already observed from 19 weeks of gestation onwards. CONCLUSION: Our data suggest that the more extensive distribution of contractile VSMCs is associated with an early maturation of the pulmonary vasculature, contrasting the concept that CDH might be the result of delayed maturation of the epithelium. PMID- 23018130 TI - Induction of antigen-specific human T suppressor cells by membrane and soluble ILT3. AB - Antigen-specific CD8 suppressor T cells (CD8(+) Ts) are adaptive regulatory T cells that are induced in vivo and in vitro by chronic antigenic stimulation of human T cells. CD8(+) Ts induce the upregulation of the inhibitory receptors ILT3 and ILT4 on monocytes and dendritic cells rendering these antigen presenting cells (APCs) tolerogenic. Tolerogenic APCs induce CD4(+) T helper anergy and elicit the differentiation of CD4(+) and CD8(+) T regulatory/suppressor cells. Overexpression of membrane ILT3 in APC results in inhibition of NF-kappaB activation, transcription of inflammatory cytokines and costimulatory molecules. Soluble ILT3-Fc which contains only the extracellular, Ig-like domain linked to mutated IgG1 Fc, is strongly immunosuppressive. ILT3-Fc, induces the differentiation of human CD8(+) Ts which inhibit CD4(+) Th and CD8(+) CTL effector function both in vitro and in vivo. The acquisition of Ts' function by primed CD8(+) T cells treated with ILT3-Fc was demonstrated to be the effect of the significant upregulation of BCL6, a transcriptional repressor of IL-2, IFN gamma, IL-5 and granzyme B. The upregulated expression of BCL6, SOCS1 and DUSP10 is integral to the signature of ILT3-Fc-induced CD8(+) Ts. These genes are known inhibitors of cytokine production and TCR signaling and are targeted by miRNAs which are suppressed by ILT3-Fc. ILT3-Fc induces tolerance to allogeneic human islets and reverses rejection after its onset in a humanized NOD/SCID mouse model. Based on these findings we postulate that ILT3-Fc may become an important new agent for treatment of autoimmunity and transplant rejection. PMID- 23018131 TI - Sonic hedgehog intradermal gene therapy using a biodegradable poly(beta-amino esters) nanoparticle to enhance wound healing. AB - Biodegradable cationic poly(beta-amino esters) (PBAE) nanoparticles are promising tools for delivering genes into various types of cells and tissues. Specific end modification of the PBAE terminal parts significantly improves the efficiency of gene delivery in vitro and in vivo, and reduces cytotoxicity. Here, we demonstrated that amine end-modified PBAE nanoparticles can be used for intradermal delivery of therapeutic genes for wound healing in an animal skin wound model. Sonic hedgehog (SHH), a prototypical morphogen with angiogenic potential, was applied as a therapeutic gene to regenerate skin tissue. Amine end modified PBAEs showed higher gene transfection efficiency in vitro than the commercial reagent, Lipofectamine 2000. Intradermal delivery of the SHH gene using amine end-modified PBAEs was tested in a readout mouse model of SHH signaling. We evaluated its therapeutic efficacy in mice with full-thickness skin wounds. SHH gene therapy significantly increased the expression of the angiogenic growth factor, vascular endothelial growth factor, and the stromal cell-derived factor-1alpha chemokine within the wounded regions early after injection. Ultimately, wound closure was accelerated in mice receiving the PBAE/SHH gene therapy compared to mice receiving intradermal delivery of a control gene (beta galactosidase plasmid) by PBAE nanoparticles. Quantitative real-time polymerase chain reaction and histological analysis revealed that there were significant improvements in epidermis regeneration and blood vessel formation in the mice treated with PBAE/SHH nanoparticles. In conclusion, SHH intradermal gene therapy using biodegradable PBAE nanoparticles is a potential treatment to promote wound healing. PMID- 23018133 TI - Der p 2 recombinant bacille Calmette-Guerin targets dendritic cells to inhibit allergic airway inflammation in a mouse model of asthma. AB - BACKGROUND: Previous studies showed that a recombinant bacille Calmette-Guerin (rBCG) which expressed the Der p 2 of house dust mites (Der p 2 rBCG) could suppress asthmatic airway inflammation. There are two possible mechanisms: (1) Der p 2 rBCG elicits immune deviation from Th2 to Th1, and (2) Der p 2 rBCG induces antigen-specific regulatory T cells. However, the role of dendritic cell (DC) Der p 2 rBCG in this protective effect and in reprogramming T-cell commitment still needs to be studied. OBJECTIVES: The aim of this study was to determine whether DCs play a central role in the Der p 2 rBCG-mediated inhibition of allergic airway inflammation. METHODS: DCs were collected from Der p 2 rBCG immunized mice (Der p 2 rBCG-DCs) and adoptively transferred to Der p 2 sensitized mice. The effects of DCs on airway inflammation and immune regulation were analyzed. RESULTS: Adoptive transfer of DCs from Der p 2 rBCG-immunized mice suppressed asthmatic responses, including airway inflammation, mucin secretion and airway responsiveness. Der p 2 rBCG-DCs could effectively inhibit excessive Th2 immune responses and induced a subtype of CD4+CD25+Foxp3+ anti-specific regulatory T cells in this asthma model. Furthermore, Der p 2 rBCG immunization recruited more plasmacytoid DCs in abdominal draining lymph nodes. CONCLUSIONS: These findings suggest that DCs played a key role in Der p 2 rBCG-induced immunoregulation. Compared with BCG, Der p 2 rBCG displayed a more potent inhibitory effect on asthma responses, which may be related to the increase in plasmacytoid DC recruitment. These results improve our understanding of the cellular basis of Der p 2 BCG-mediated inhibition of asthma. PMID- 23018132 TI - Directed endothelial cell morphogenesis in micropatterned gelatin methacrylate hydrogels. AB - Engineering of organized vasculature is a crucial step in the development of functional and clinically relevant tissue constructs. A number of previous techniques have been proposed to spatially regulate the distribution of angiogenic biomolecules and vascular cells within biomaterial matrices to promote vascularization. Most of these approaches have been limited to two-dimensional (2D) micropatterned features or have resulted in formation of random vasculature within three-dimensional (3D) microenvironments. In this study, we investigate 3D endothelial cord formation within micropatterned gelatin methacrylate (GelMA) hydrogels with varying geometrical features (50-150 MUm height). We demonstrated the significant dependence of endothelial cells proliferation, alignment and cord formation on geometrical dimensions of the patterned features. The cells were able to align and organize within the micropatterned constructs and assemble to form cord structures with organized actin fibers and circular/elliptical cross sections. The inner layer of the cord structure was filled with gel showing that the micropatterned hydrogel constructs guided the assembly of endothelial cells into cord structures. Notably, the endothelial cords were retained within the hydrogel microconstructs for all geometries after two weeks of culture; however, only the 100 MUm-high constructs provided the optimal microenvironment for the formation of circular and stable cord structures. Our findings suggest that endothelial cord formation is a preceding step to tubulogenesis and the proposed system can be used to develop organized vasculature for engineered tissue constructs. PMID- 23018134 TI - The incidence of menstrual regulation procedures and abortion in Bangladesh, 2010. AB - CONTEXT: Bangladesh is unique in including menstrual regulation (MR) services as part of the government family planning program, despite having a highly restrictive abortion law. The only national estimates of MR and abortion incidence are from a 1995 study, and updated information is needed to inform policies and programs regarding the provision of MR and related reproductive health services. METHODS: Surveys of a nationally representative sample of 670 health facilities that provide MR and postabortion care services and of 151 knowledgeable professionals were conducted in 2010, and MR service statistics of nongovernmental organizations were compiled. Indirect estimation techniques were applied to calculate the incidence and rates of MR and induced abortion. RESULTS: In 2010, an estimated 647,000 induced abortions were performed in Bangladesh, and 231,400 women were treated for complications of such abortions. Furthermore, an estimated 653,000 MR procedures were performed at facilities nationwide. However, an estimated 26% of all women seeking an MR at facilities were turned away, and about one in 10 of those who had an MR were treated for complications. Nationally, the annual abortion rate was 18.2 per 1,000 women aged 15-44, and the MR rate was 18.3 per 1,000 women. CONCLUSIONS: The incidence of induced abortion is the same as that of MR, which suggests considerable unsatisfied demand for the latter service. Furthermore, the high rates of complications from MRs highlight the need to improve the quality of clinical services. Increased access to contraceptives and MR services would help reduce rates of unplanned pregnancy and unsafe abortion. PMID- 23018135 TI - Feasibility of expanding the medication abortion provider base in India to include ayurvedic physicians and nurses. AB - CONTEXT: The availability of trained abortion providers is limited in India. Allowing ayurvedic physicians and nurses to perform medication abortions may improve women's access to the procedure, but it is unclear whether these clinicians can provide these services safely and effectively. METHODS: Allopathic physicians, ayurvedic physicians and nurses (10 of each), none of whom had experience in abortion provision, were trained to perform medication abortions. In 2008-2010, these providers performed medication abortions in five clinics in Bihar and Jharkhand for 1,225 women with a pregnancy of up to eight weeks' gestation. A two-sided equivalence design was used to test whether providers' assessments of client eligibility and completeness of abortion matched those of an experienced physician "verifier," and whether medication abortions performed by nurses and ayurvedic physicians were as safe and effective as those done by allopathic physicians. RESULTS: Failure rates were low (5-6%), and those for nurses and ayurvedic physicians were statistically equivalent to those for allopathic physicians. Provider assessments of client eligibility and completeness of abortion differed from those of the verifier in only a small proportion of cases (3-4% for eligibility and 4-5% for completeness); these proportions, and rates of loss to follow-up, were statistically equivalent among provider types. No serious complications were observed, and services by all three groups of providers were acceptable to women. CONCLUSION: Findings support amending existing laws to improve women's access to medication abortion by expanding the provider base to include ayurvedic physicians and nurses. PMID- 23018136 TI - Legal abortion levels and trends by woman's age at termination. AB - CONTEXT: Assessments of abortion levels and trends by women's age at termination can be used to monitor trends in unintended pregnancy by age and can inform relevant programs and policies. METHODS: Legal abortion incidence data were compiled from national statistical offices and nationally representative surveys of more than 40 countries where legal abortion is generally available. Age specific abortion rates and percentage distributions of abortions by age were computed, and trends since 1996 and 2003 were examined. Subregional and regional estimates were developed for geographic areas where the majority of the population was represented by the data. RESULTS: The median year for the most recent estimates of abortions by woman's age was 2009. Adolescents accounted for a smaller share of abortions than their share of the population in the majority of eligible countries with data. In most countries, the highest age-specific abortion rates and proportions of abortions were among women aged 20-29. Since 1996, adolescent abortion rates have increased the most in Belgium, the Netherlands and Scotland (22-42%), and have decreased the most in Estonia, Hungary, Iceland, Slovakia and Slovenia (40-55%). The proportion of abortions obtained by adolescents was higher in North America (18%) than in Europe overall (11%), although the proportion in Northern Europe (18%) was the same as that in North America. CONCLUSIONS: Higher abortion rates in particular age-groups probably reflect higher-than-average levels of unmet need for contraception or difficulty using methods consistently and effectively, and a stronger desire to avoid childbearing. Each of the patterns observed has implications for service and information needs within countries. PMID- 23018138 TI - Use of medicines changing the face of abortion. PMID- 23018137 TI - Attitudes and intentions regarding abortion provision among medical school students in South Africa. AB - CONTEXT: Although South Africa liberalized its abortion law in 1996, significant barriers still impede service provision, including the lack of trained and willing providers. A better understanding is needed of medical students' attitudes, beliefs and intentions regarding abortion provision. METHODS: Surveys about abortion attitudes, beliefs and practice intentions were conducted in 2005 and 2007 among 1,308 medical school students attending the University of Cape Town and Walter Sisulu University in South Africa. Bivariate and multivariate analyses identified associations between students' characteristics and their general and conditional support for abortion provision, as well as their intention to act according to personal attitudes and beliefs. RESULTS: Seventy percent of medical students believed that women should have the right to decide whether to have an abortion, and large majorities thought that abortion should be legal in a variety of medical circumstances. Nearly one-quarter of students intended to perform abortions once they were qualified, and 72% said that conscientiously objecting clinicians should be required to refer women for such services. However, one-fifth of students believed that abortion should not be allowed for any reason. Advanced medical students were more likely than others to support abortion provision. In multivariate analyses, year in medical school, race or ethnicity, religious affiliation, relationship status and sexual experience were associated with attitudes, beliefs and intentions regarding provision. CONCLUSIONS: Academic medical institutions must ensure that students understand their responsibilities with respect to abortion care--regardless of their personal views--and must provide appropriate abortion training to those who are willing to offer these services in the future. PMID- 23018139 TI - Previous exposure to cigarette smoke aggravates experimental cyclosporine-induced nephrotoxicity. AB - BACKGROUND/AIMS: The effects of cigarette smoke (CS) on cyclosporine (CsA) induced nephrotoxicity are poorly studied. This study aims to assess the effects of previous exposure to CS on CsA nephrotoxicity. METHODS: Rats were either exposed to CS or sham (S) procedures for 10 min twice a day for 20 weeks. From the 16th to the 20th week, they received a low-salt diet. Beginning with the 17th week, they were given 2.5 mg/day CsA or vehicle (VH) for 3 weeks. The final groups were VH/CS, CsA/CS, VH/S, and CsA/S. On day 141, glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), tubulointerstitial fibrosis, and CsA blood levels were measured and immunohistochemistry was analyzed for renal alpha-smooth muscle actin (SMA), nitrotyrosine, and vimentin. RESULTS: CsA decrease in GFR was enhanced by CS exposure. CsA associated with CS induced higher periglomerular alpha-SMA and renal nitrotyrosine expression. CsA decreased RBF, but increased RVR, tubulointerstitial fibrosis, and alpha-SMA and renal vimentin expression. These changes and the CsA blood levels were not affected by CS exposure. CONCLUSION: CS aggravated the CsA-induced impairment of GFR and CS associated with CsA caused the development of periglomerular structural lesions and oxidative stress in a rat model of CsA nephrotoxicity. PMID- 23018140 TI - Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV. AB - BACKGROUND: Monocytes transmigrating to the brain play a central role in HIV neuropathology. We hypothesized that the continued existence of neurocognitive impairment (NCI) despite potent antiretroviral (ARV) therapy is mediated by the inability of such therapy to control this monocyte/macrophage reservoir. METHODS: Cross-sectional and longitudinal analyses were conducted within a prospectively enrolled cohort. We devised a monocyte efficacy (ME) score based on the anticipated effectiveness of ARV medications against monocytes/macrophages using published macrophage in vitro drug efficacy data. We examined, within an HIV neurocognitive database, its association with composite neuropsychological test scores (NPZ8) and clinical cognitive diagnoses among subjects on stable ARV medications unchanged for >6 months prior to assessment. RESULTS: Among 139 subjects on ARV therapy, higher ME score correlated with better NPZ8 performance (r=0.23, P<0.01), whereas a score devised to quantify expected penetration effectiveness of ARVs into the brain (CPE score) did not (r=0.12, P=0.15). In an adjusted model (adjusted r(2)=0.12), ME score (beta=0.003, P=0.02), CD4(+) T-cell nadir (beta=0.001, P<0.01) and gender (beta=-0.456, P=0.02) were associated with NPZ8, whereas CPE score was not (beta=0.003, P=0.94). A higher ME score was associated with better clinical cognitive status (P<0.01). With a range of 12.5 433.0 units, a 100-unit increase in ME score resulted in a 10.6-fold decrease in the odds of a dementia diagnosis compared with normal cognition (P=0.01). CONCLUSIONS: ARV efficacy against monocytes/macrophages correlates with cognitive function in HIV-infected individuals on ARV therapy within this cohort. If validated, efficacy against monocytes/macrophages may provide a new target to improve HIV NCI. PMID- 23018142 TI - Controlling the morphology of gold nanoparticles synthesized photochemically in a polymer matrix through photonic parameters. AB - A facile method for the preparation of gold nanoparticles (AuNPs) with various morphologies, including triangles, cubes and nanospheres into a urethane methacrylate polymer matrix, has been developed. The hybrid nanocomposites have been obtained by photoreduction of a gold precursor in the presence of a 30 wt% urethane methacrylate containing quaternary ammonium structure and 70 wt% functional monomer, carboxyl oligo-urethane dimethacrylate. The final materials contain gold nanoparticles with a morphology dependant on the reaction conditions. The influence of photonic and chemical parameters on the shape of the nanoparticles has been examined. Specific interactions between the macromolecular network and the nascent particles play an important role insofar as they control the access of metal atoms to the different crystalline planes of the growing nanoparticles, which is necessary to obtain anisotropic objects. A common mechanism for the formation of the various types of AuNPs is proposed. Coupling the intrinsic characteristics of metal nanoparticles with those of the copolymer substrate could result in materials with innovative properties. PMID- 23018141 TI - Evaluation of a bayesian model integration-based method for censored data. AB - OBJECTIVE: Non-random missing data can adversely affect family-based linkage detection through loss of power and possible introduction of bias depending on how censoring is modeled. We examined the statistical properties of a previously proposed quantitative trait threshold (QTT) model developed for when censored data can be reasonably inferred to be beyond an unknown threshold. METHODS: The QTT model is a Bayesian model integration approach implemented in the PPL framework that requires neither specification of the threshold nor imputation of the missing data. This model was evaluated under a range of simulated data sets and compared to other methods with missing data imputed. RESULTS: Across the simulated conditions, the addition of a threshold parameter did not change the PPL's properties relative to quantitative trait analysis on non-censored data except for a slight reduction in the average PPL as a reflection of the lowered information content due to censoring. This remained the case for non-normally distributed data and extreme sampling of pedigrees. CONCLUSIONS: Overall, the QTT model showed the smallest loss of linkage information relative to alternative approaches and therefore provides a unique analysis tool that obviates the need for ad hoc imputation of censored data in gene mapping studies. PMID- 23018143 TI - The role of personalized medicine in identifying appropriate candidates for menopausal estrogen therapy. AB - Menopausal estrogen therapy has a complex balance of benefits and risks and is no longer routinely recommended for the majority of women during or after the transition to menopause. Recent findings from the Women's Health Initiative (WHI) and other studies suggest that a woman's clinical and biological characteristics may modify her health outcomes on hormone therapy (HT) and that some women may be more appropriate candidates for therapy than others. An emerging body of evidence suggests that it may be possible to identify women who are more likely to have favorable outcomes and less likely to have adverse events on HT, as well as to tailor the optimal dose, formulation, and route of delivery of treatment, by the use of individual risk stratification and a personalized approach. Several clinical characteristics that have been proposed for this purpose include a woman's age, time since menopause, symptom severity, baseline vascular health, risk for breast cancer, biomarker levels, and genetic predisposition. The underlying rationale for personalized medicine, that each person has a unique biologic profile that can help to guide the choice of therapy, applies well to HT decision making and holds promise for improved treatment efficacy and safety. This report, which focuses on vascular health, reviews the evidence on the role of such markers in tailoring the use of hormone therapy to appropriate candidates, with the ultimate goal of developing a personalized risk:benefit prediction model that takes into account clinical and genetic factors, "patient centered" outcomes including sense of well being and quality of life, and other variables. The proposed personalized approach to HT decision making has the potential to improve the quality of health care. PMID- 23018144 TI - Personalized medicine: the medicine of tomorrow. Foreword. PMID- 23018145 TI - Linkage between C-reactive protein and triglyceride-rich lipoprotein metabolism. AB - OBJECTIVE: Inflammation plays an important role in atherosclerosis. Elevated C reactive protein (CRP) levels are associated with a greater risk of cardiovascular disease. Our goal was to study CRP metabolism, and to determine its relationship with lipoprotein metabolism using stable isotope methodology. MATERIAL/METHODS: Eight subjects with combined hyperlipidemia underwent a 15-h primed-constant infusion with deuterated leucine. CRP was purified from the plasma density fraction greater than 1.21g/ml by affinity chromatography. Lipoprotein fractions were separated by sequential ultracentrifugation. Isotope enrichment was determined by gas chromatography/mass spectrometry. RESULTS: The subjects had mean LDL-C levels of 147.5mg/dl and mean CRP levels of 3.4mg/l. The mean CRP production rate (PR) was 0.050+/-0.012mg/kg/day and the mean CRP fractional catabolic rate (FCR) was 0.343+/-0.056 pools/day (residence time 2.92days). CRP pool size (PS) was significantly related to production (r=0.93; p<0.001), but not FCR. CRP PS was also related to body mass index (r=0.79; p=0.02). There was a significant association between CRP FCR and TRL apoB-100 FCR (r=0.74, p=0.04), as well as between CRP PS and TRL apoB-48 FCR (r=-0.90, p=0.002), indicating linkage between CRP and TRL metabolism. CONCLUSION: The main determinant of plasma CRP levels was CRP production rate. Moreover a significant linkage between CRP metabolism and both TRL apoB-100 and apoB-48 catabolism was noted. PMID- 23018146 TI - FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. AB - OBJECTIVE: In mouse, PGC1-alpha overexpression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. One prior study has shown that FNDC5 induces browning of subcutaneous fat in mice and mediates beneficial effects of exercise on metabolism, but a more recent study using gene expression arrays failed to detect a robust increase in FNDC5 mRNA in human muscles from exercising subjects. No prior study has reported on the physiological regulation and role of circulating irisin and FNDC5 in humans. MATERIALS/METHODS: A. FNDC5 gene expression studies: We first examined tissue distribution of FNDC5 in humans. B. Cross-sectional studies: Predictors of FNDC5 mRNA expression levels were examined in muscle tissues from 18 healthy subjects with a wide range of BMI. Assays were optimized to measure circulating FNDC5 and irisin levels, and their associations with anthropometric and metabolic parameters were analyzed in two cross-sectional studies that examined 117 middle-aged healthy women and 14 obese subjects, respectively. C. Interventional studies: The effect of weight loss on FNDC5 mRNA and/or circulating irisin levels was examined in 14 obese subjects before and after bariatric surgery. The effect of acute and chronic exercise was then assessed in 15 young healthy adults who performed intermittent sprint running sessions over an 8 week period. RESULTS: Tissue arrays demonstrated that in humans, the FNDC5 gene is predominantly expressed in muscle. Circulating irisin was detected in the serum or plasma of all subjects studied, whereas circulating FNDC5 was detected in only a distinct minority of the subjects. Cross-sectional studies revealed that circulating irisin levels were positively correlated with biceps circumference (used as a surrogate marker of muscle mass herein), BMI, glucose, ghrelin, and IGF-1. In contrast, irisin levels were negatively correlated with age, insulin, cholesterol, and adiponectin levels, indicating a possible compensatory role of irisin in metabolic regulation. Multivariate regression analysis revealed that biceps circumference was the strongest predictor of circulating irisin levels underlying the association between irisin and metabolic factors in humans at baseline. Both muscle FNDC5 mRNA levels and circulating irisin levels were significantly downregulated 6 months after bariatric surgery. Circulating irisin levels were significantly upregulated 30 min after acute exercise and were correlated mainly with ATP levels and secondarily with metabolites related to glycolysis and lipolysis in muscle. CONCLUSIONS: Similar to mice, the FNDC5 gene is expressed in human muscle. Age and muscle mass are the primary predictors of circulating irisin, with young male athletes having several fold higher irisin levels than middle-aged obese women. Circulating irisin levels increase in response to acute exercise whereas muscle FNDC5 mRNA and circulating irisin levels decrease after surgically induced weight loss in parallel to decrease in body mass. Further studies are needed to study the regulation of irisin levels and its physiological effects in humans and to elucidate the mechanisms underlying these effects. PMID- 23018147 TI - Personalized medicine in neurosurgery. AB - Personalized medicine (PM) in neurosurgery is possible today thanks to newly accessible imaging technologies, and to genomic, proteomic and epigenetic biomarkers capable of providing clinically useful information about individual patients. PM is becoming increasingly indispensable in neurosurgery because this specialty offers a wide range of therapeutic options such as surgery and/or radiotherapy and/or chemotherapy. Moreover, the effectiveness of these procedures varies from one patient to another, depending inter alia on the patients' individual genomic traits. A prime example is glioblastoma multiforme, which exhibits at least five genomic biomarkers related to distinct therapeutic and prognostic outcomes. At least one of these biomarkers, the omega-6 methylguanine DNA methyltransferase promoter of methylation status, has already been used in clinical trials. New functional imaging techniques allow the surgeon to circumvent crucial brain areas whose location may vary among patients, thus allowing the safe and complete excision of an adjacent tumor. Functional imaging, together with an increasing number of genomic and other 'omic' biomarkers, has also given rise to an improved classification based on molecular signatures of tumors like glioblastoma multiforme that will facilitate the correspondence between type of glioma and choice of biologically tailored-to-patient therapy. PMID- 23018148 TI - Personalized medicine in psychiatry: new technologies and approaches. AB - Psychiatric patients tend to exhibit significant interindividual variability in their responses to psychoactive drugs, as well as an irregular clinical course. For these (and other) reasons, increasing numbers of psychiatrists are turning to genotyping for help in selecting the psychopharmacologic agents best suited to an individual patient's distinctive metabolic characteristics and clinical presentation. Fortunately, routine genotyping is already available for gene variations that code for proteins involved in neurotransmission, and for drug metabolizing enzymes involved in the elimination of many medications. Thus, genotyping-based personalized psychiatry is now in sight. Increasing numbers of clinically useful DNA microarrays are in the development stage, including a simplified procedure for genotyping patients for CYP2D6, which metabolizes a high proportion of the currently prescribed antidepressants and antipsychotics. It has been pointed out that psychiatric disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of complex intracellular networks in the brain. Thus, analysis of functional neuronal networks is becoming an essential component of drug development strategies. The integrated use of technologies such as electroencephalography, magnetoencephalography, functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI), in combination with pharmacogenetics, promises to transform our understanding of the mechanisms of psychiatric disorders and their treatment. The concept of network medicine envisions a time to come when drugs will be used to target a neural network rather than simply components within the network. Personalized medicine in psychiatry is still at an early stage, but it has a very promising future. PMID- 23018149 TI - Diagnosis of obstructive thrombosis in a porcine bioprosthesis in the aortic position by contrast-enhanced ECG-gated computer tomography. PMID- 23018150 TI - Ruptured giant major aortopulmonary collateral artery. PMID- 23018151 TI - The CHA2DS2-VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy. AB - AIMS: The CHA(2)DS(2)-VASc score is a modification of the CHADS(2) score that aims to improve stroke risk prediction in patients with atrial fibrillation (AF) by adding three risk factors: age 65-74, female sex, and history of vascular disease. Whereas previous evaluations of the CHA(2)DS(2)-VASc score included all AF patients, the aim of this analysis was to evaluate its discriminative ability only in those patients for whom recommendations on antithrombotic treatment are uncertain (i.e. CHADS(2) score of 1). METHODS AND RESULTS: We selected all patients with a CHADS(2) score of 1 from the AVERROES and ACTIVE trials who were treated with acetylsalicylic acid with or without clopidogrel and calculated the incidences of ischaemic or unspecified stroke or systemic embolus (SSE) according to their CHA(2)DS(2)-VASc score. Of 4670 patients with a baseline CHADS(2) score of 1, 26% had a CHA(2)DS(2)-VASc score of 1 and 74% had a score of >= 2. After 11 414 patient-years of follow-up, the annual incidence of SSE was 0.9% (95% CI: 0.6 1.3) and 2.1% (95% CI: 1.8-2.5) for patients with a CHA(2)DS(2)-VASc score of 1 and >= 2, respectively. The c-statistic of the CHA(2)DS(2)-VASc score was 0.587 (95% CI: 0.550-0.624). Age 65 to <75 years was the strongest of the three new risk factors in the CHA(2)DS(2)-VASc score. CONCLUSION: The CHA(2)DS(2)-VASc score reclassifies 26% of patients with a CHADS(2) score of 1 to a low annual risk of SSE of 1%. This risk seems low enough to consider withholding anticoagulant treatment. PMID- 23018152 TI - Evaluation of serological prenatal screening to detect Toxoplasma gondii infections in Austria. AB - BACKGROUND: In Austria, a nationally mandated prenatal serological congenital toxoplasmosis screening program was introduced in 1974 in response to a high incidence of 7.8 per 1,000 infected infants. Maternal prenatal recognition of acute gestational infection and early treatment of infants with congenital infection are important because prenatal and accurate postnatal antibiotic therapy improves the outcomes of infected infants. OBJECTIVE: To determine the impact of additional maternal and/or fetal cord blood serology at birth on improving current prenatal maternal screening in detecting congenital toxoplasmosis. METHODS: In this prospective observational study, 5,545 consecutive women were included over a 19-month period. Routine prenatal maternal toxoplasmosis serology screening was performed along with additional cord blood serology screening at delivery. Fetal cord blood serology included Sabin-Feldman dye and IgM immunosorbent agglutination assay testing. RESULTS: Based on the initial prenatal maternal screening serology results, there was evidence of a prior chronic infection manifest in 1,830 (33.0%) women and 3,708 (66.9%) were not infected. Seven (0.13%) were diagnosed with acute toxoplasma infection based on seroconversion. Of these, 4 manifested transmission, and 3 did not. Of the seven infected women, routine prenatal maternal screening identified acute infection in only 2 of the women, 1 of whom had an infected fetus with abnormal prenatal ultrasound. Fetal cord blood serology screening identified an additional 5 women, 3 with infected fetuses. CONCLUSIONS: Identification of Toxoplasma gondii infection by prenatal maternal serological testing is significantly improved by the addition of maternal and/or fetal serological testing at birth. PMID- 23018153 TI - EPR dosimetric properties of radiation--formed radicals in arginine monohydrochloride. AB - Arginine monohydrochloride rods (3*10 mm) were irradiated with (60)Co gamma-rays to study radicals for dosimetric materials with Electron Paramagnetic Resonance (EPR). The rods have significant signal which develops upon irradiation and the intensity of signal increases upon the increase in irradiation dose. The rods can be used in the dose range from 5 to 120 KGy. The temperature coefficient was found to equal +0.22% degrees C(-1). The dose response, influence of humidity and post-irradiation storage at different conditions are discussed. The overall uncertainty for calibration of arginine monohydrochloride rode dosimeters at 2sigma was found to be 2.85%. PMID- 23018154 TI - Detection of hyaluronidase activity using fluorescein labeled hyaluronic acid and Fluorescence Correlation Spectroscopy. AB - The over-expression of hyaluronidase has been observed in many types of cancer, suggesting that it may have utility for diagnosis. Here we present a technique for the detection of hyaluronidase using Fluorescence Correlation Spectroscopy (FCS). Hyaluronan macromolecules (HAs) have been heavily labeled with fluorescein amine resulting in strong self-quenching. In the presence of hyaluronidase, HA is cleaved into smaller, fluorescein-labeled fragments and the self-quenching is released. Such cleavage is manifested by the increased average diffusion rate of the HA fragments, increased concentration of individual, fluorescent HA fragments, and increased intensity. All three of these properties are monitored simultaneously throughout FCS measurements, both as a function of time and hyaluronidase concentration. The method we present provides a sensitive measure of hyaluronidase activity and requires extremely small amounts of the HA substrate. PMID- 23018155 TI - A seven-coordinated manganese(II) complex with V-shaped ligand bis(N benzylbenzimidazol-2-ylmethyl)benzylamine: synthesis, structure, DNA-binding properties and antioxidant activities. AB - A manganese(II) complex of the type, [MnL(pic)(2)].H(2)O, was obtained by the reaction of the V-shaped ligand bis(N-benzylbenzimidazol-2-ylmethyl)benzylamine (L) with Mn(pic)(2) (pic=picrate). The ligand L and Mn(II) complex were confirmed on the basis of elemental analysis, molarconductivities, (1)H NMR, IR, UV-vis spectra and X-ray crystallography. Single-crystal X-ray revealed that central Mn(II) atom is seven-coordinate with a MnN(3)O(4) environment, in which ligand L acts as a tridentate N-donor. The remaining coordination sites were occupied by four O atoms afforded by two picrate anion. Interaction of the free ligand L and Mn(II) complex with DNA were investigated by spectrophotometric methods and viscosity measurements. The results suggested that both ligand L and Mn(II) complex bind to DNA in an intercalative binding mode, and DNA-binding affinity of the Mn(II) complex is stronger than that of ligand L. Moreover, antioxidant assay in vitro shows the Mn(II) complex possesses significant antioxidant activities. PMID- 23018156 TI - Highly bright avidin-based affinity probes carrying multiple lanthanide chelates. AB - Lanthanide ion luminescence has a long lifetime enabling highly sensitive detection in time-gated mode. The sensitivity can be further increased by using multiple luminescent labels attached to a carrier molecule, which can be conjugated to an object of interest. We found that up to 30 lanthanide chelates can be attached to avidin creating highly bright constructs. These constructs with Eu(3+) chelates display synergistic effect that enhance the brightness of heavily modified samples, while the opposite effect was observed for Tb(3+) chelates thereby significantly reducing their light emission. This undesirable quenching of Tb(3+) luminophores was completely suppressed by the introduction of an aromatic spacer between the chelate and the protein attachment site. The estimated detection limit for the conjugates is in the 10(-14)-10(-15) M range. We demonstrated a high sensitivity for the new probes by using them to label living cells of bacterial and mammalian origin. PMID- 23018157 TI - Changes in toxicity during in situ bioremediation of weathered drill wastes contaminated with petroleum hydrocarbons. AB - Bioremediation of weathered drill wastes severely contaminated with total petroleum hydrocarbons (TPH) (90,000-170,000 mg kg(-1)) and BTEX (51.2-95.5 mg kg(-1)) to soil standards was achieved over a 3-year period in three phases: initial remediation, basic bioremediation and inoculation with a biopreparation. Fourteen non-pathogenic indigenous bacteria species belonging mainly to the Actinomycetales were identified and shown to be able to degrade 63-75% of nC(9) nC(20), 36-51% of nC(21)-nC(36), 36% of BTEX and 20% of PAHs (polycyclic aromatic hydrocarbons). Addition of five non-pathogenic fungi species to the bacterial consortium allowed degradation of 69-89% of nC(9)-nC(20), 47-80% of nC(21) nC(36), 76% of BTEX, and 68% of PAHs. Microtox, Ostacodtoxkit, Phytotoxkit and Ames tests indicated that changes in toxicity were not connected with the decrease in TPH contents, possibly due to the formation of toxic indirect metabolites during bioremediation. No toxicity was found in the soil after bioremediation. PMID- 23018158 TI - Efficient production of L-asparaginase from Bacillus licheniformis with low glutaminase activity: optimization, scale up and acrylamide degradation studies. AB - L-Asparaginase has potential as an anti-cancer drug and for prevention of acrylamide formation in fried and baked foods. Production of the enzyme by Bacillus licheniformis (RAM-8) was optimized by process engineering using a statistical modeling approach and a maximum yield of 32.26 IU/ml was achieved. The L-asparaginase exhibited glutaminase activity of only 0.8 IU/ml and would therefore be less prone to cause the side effects associated with asparaginase therapy compared to enzyme preparations with higher glutaminase activities. When production was carried out in a 30-L bioreactor, enzyme production reached 29.94 IU/ml in 15 h. The enzyme inhibited poly-acrylamide formation in 10% acrylamide solution and reduced acrylamide formation in fried potatoes by 80%. PMID- 23018159 TI - Extraction of nickel by microbial reduction of lateritic chromite overburden of Sukinda, India. AB - Microbial extraction of nickel from lateritic chromite overburden (COB), Sukinda by Acidithiobacillus ferrooxidans has been investigated in this work. In anoxic environment, A. ferrooxidans reduced the ferric iron in goethite [Fe(O)OH] mineral of COB by using elemental sulphur as electron donor. Nickel embedded in the complex goethite matrix of COB was successfully recovered by cumulative action of sulphuric acid, generated by oxidation of elemental sulphur and reduction of ferric iron in goethite matrix by A. ferrooxidans. Forty one percent of the nickel present in COB was extracted in a 3 L scale bioreactor (pH of 1.8 +/- 0.05, temperature of 28 +/- 2 degrees C) maintained in anoxic environment. In contrast, only 11% of the nickel present in COB was extracted with continuous supply of air to the bioreactor keeping all the parameters unchanged. Kinetics study of anoxic microbial processing of COB revealed that the chemical reaction rate control model fits to the rate of nickel dissolution (R(2)=0.975). PMID- 23018160 TI - Urban energy mining from municipal solid waste (MSW) via the enhanced thermo chemical process by carbon dioxide (CO2) as a reaction medium. AB - The enhanced gasification of municipal solid waste (MSW) using carbon dioxide (CO(2)) as the gasification medium was investigated to achieve environmentally benign and energy efficient ways for the disposal of MSW. Two main steps of thermal decomposition of MSW were observed. The first thermal degradation step occurs at temperature between 280 and 350 degrees C and consists of the decomposition of the biomass component into light C(1-3)-hydrocarbons. The second thermal degradation step occurs between 380 and 450 degrees C and is mainly attributed to polymer components, such as plastics and rubber, in MSW. To extend this understanding to a more practical level, MSW samples were tested in a drop tube reactor (DTR) at a temperature range from 500 to 1000 degrees C under various atmospheres with CO(2) concentrations of 0-30%. The release of major chemical species from the DTR has been determined using a micro-GC. For example, CO (~ 30%), H(2) (~ 25%) and CH(4) (~ 10%) were generated. PMID- 23018161 TI - Re: Andrew J. Stephenson, Michel Bolla, Alberto Briganti, et al. Postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. Eur Urol 2012;61:443-51. PMID- 23018162 TI - Prostate cancer antigen 3 to select men for prostate biopsy: stop, go, or proceed with caution? PMID- 23018163 TI - The mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. AB - CONTEXT: Clinical trials of phosphodiesterase type 5 inhibitors (PDE5-Is) have consistently demonstrated a significant reduction in lower urinary tract symptoms (LUTS) and small urinary flow rate changes in men with benign prostatic hyperplasia (BPH). OBJECTIVE: This review presents the proposed mechanisms of action of PDE5-Is in the treatment of BPH-LUTS focusing on the localization of PDE5 isoenzymes in the pelvic structures; smooth muscle relaxation in the bladder, prostate, and supporting vasculature; increased blood perfusion of the bladder and prostate; and modulation of sensory impulses from these organs. EVIDENCE ACQUISITION: Literature describing in vitro, preclinical, or clinical studies of pathologic processes contributing to LUTS or effects of PDE5 inhibition on the lower urinary tract (LUT) was selected for review. EVIDENCE SYNTHESIS: We objectively assessed and summarized the published data focusing on articles published within the past 10 yr. Articles before the time cut-off were included if historically relevant. CONCLUSIONS: The PDE5 isoenzymes are highly expressed in the LUT including the bladder, prostate, and their supporting vasculature. In vitro assays have demonstrated PDE5-Is by regulating cyclic guanosine monophosphate (cGMP) degradation and enhancing the nitric oxide/cGMP signaling pathway to relax human smooth muscle strips from the prostate, bladder, and LUT arteries. In animals characterized by ischemia/hypoxia of the genitourinary tract, treatment with PDE5-Is increases bladder and prostate tissue oxygenation. PDE5-Is have been shown to reduce nonvoiding contractions and bladder afferent nerve firing in decerebrate spinal cord-injured rats, and to reduce mechanosensitive afferent activities of both Adelta- and C-fibers in an irritated or overextended bladder model. PMID- 23018164 TI - Clinical validation of coronal and sagittal spinal curve measurements based on three-dimensional vertebra vector parameters. AB - BACKGROUND CONTEXT: For many decades, visualization and evaluation of three dimensional (3D) spinal deformities have only been possible by two-dimensional (2D) radiodiagnostic methods, and as a result, characterization and classification were based on 2D terminologies. Recent developments in medical digital imaging and 3D visualization techniques including surface 3D reconstructions opened a chance for a long-sought change in this field. Supported by a 3D Terminology on Spinal Deformities of the Scoliosis Research Society, an approach for 3D measurements and a new 3D classification of scoliosis yielded several compelling concepts on 3D visualization and new proposals for 3D classification in recent years. More recently, a new proposal for visualization and complete 3D evaluation of the spine by 3D vertebra vectors has been introduced by our workgroup, a concept, based on EOS 2D/3D, a groundbreaking new ultralow radiation dose integrated orthopedic imaging device with sterEOS 3D spine reconstruction software. PURPOSE: Comparison of accuracy, correlation of measurement values, intraobserver and interrater reliability of methods by conventional manual 2D and vertebra vector-based 3D measurements in a routine clinical setting. STUDY DESIGN: Retrospective, nonrandomized study of diagnostic X-ray images created as part of a routine clinical protocol of eligible patients examined at our clinic during a 30-month period between July 2007 and December 2009. PATIENT SAMPLE: In total, 201 individuals (170 females, 31 males; mean age, 19.88 years) including 10 healthy athletes with normal spine and patients with adolescent idiopathic scoliosis (175 cases), adult degenerative scoliosis (11 cases), and Scheuermann hyperkyphosis (5 cases). Overall range of coronal curves was between 2.4 and 117.5 degrees . Analysis of accuracy and reliability of measurements was carried out on a group of all patients and in subgroups based on coronal plane deviation: 0 to 10 degrees (Group 1; n=36), 10 to 25 degrees (Group 2; n=25), 25 to 50 degrees (Group 3; n=69), 50 to 75 degrees (Group 4; n=49), and above 75 degrees (Group 5; n=22). METHODS: All study subjects were examined by EOS 2D imaging, resulting in anteroposterior (AP) and lateral (LAT) full spine, orthogonal digital X-ray images, in standing position. Conventional coronal and sagittal curvature measurements including sagittal L5 vertebra wedges were determined by 3 experienced examiners, using traditional Cobb methods on EOS 2D AP and LAT images. Vertebra vector-based measurements were performed as published earlier, based on computer-assisted calculations of corresponding spinal curvature. Vertebra vectors were generated by dedicated software from sterEOS 3D spine models reconstructed from EOS 2D images by the same three examiners. Manual measurements were performed by each examiner, thrice for sterEOS 3D reconstructions and twice for vertebra vector-based measurements. Means comparison t test, Pearson bivariate correlation analysis, reliability analysis by intraclass correlation coefficients for intraobserver reproducibility and interrater reliability were performed using SPSS v16.0 software. RESULTS: In comparison with manual 2D methods, only small and nonsignificant differences were detectable in vertebra vector-based curvature data for coronal curves and thoracic kyphosis, whereas the found difference in L1-L5 lordosis values was shown to be strongly related to the magnitude of corresponding L5 wedge. Intraobserver reliability was excellent for both methods, and interrater reproducibility was consistently higher for vertebra vector-based methods that was also found to be unaffected by the magnitude of coronal curves or sagittal plane deviations. CONCLUSIONS: Vertebra vector-based angulation measurements could fully substitute conventional manual 2D measurements, with similar accuracy and higher intraobserver reliability and interrater reproducibility. Vertebra vectors represent a truly 3D solution for clear and comprehensible 3D visualization of spinal deformities while preserving crucial parametric information for vertebral size, 3D position, orientation, and rotation. The concept of vertebra vectors may serve as a starting point to a valid and clinically useful alternative for a new 3D classification of scoliosis. PMID- 23018165 TI - Association membership: it isn't all about you. PMID- 23018166 TI - Reiki as a pain management adjunct in screening colonoscopy. AB - The purpose of this study was to determine whether the use of Reiki decreases the amount of meperidine administered to patients undergoing screening colonoscopy. The literature review reveals limited studies to show whether Reiki has been able to decrease the amount of opioid the patient receives during screening colonoscopy. A chart review of 300 patients was conducted to obtain baseline average doses of meperidine patients received as the control. Following the chart review, 30 patients were recruited to the Reiki study. Twenty-five of the study arm patients received Reiki in conjunction with meperidine. Five randomly chosen study arm patients received placebo Reiki in conjunction with meperidine in an attempt to blind the clinicians to the treatment received by the patients. Results showed that there were no significant differences in meperidine administration between the patients in the chart review group (control) and the Reiki group. The study revealed that 16% who received Reiki, together with intravenous administration of conscious sedation, received less than 50 mg of meperidine. All the patients in the chart review group received more than 50 mg of meperidine. Results from this pilot study suggest that there may be a decrease in meperidine needed during screening colonoscopy when patients receive Reiki treatments before the procedure. A larger study powered to detect smaller medication differences is the next step in more accurately determining the effect of Reiki on pain management. PMID- 23018167 TI - A resource-efficient tool for training novices in wireless capsule endoscopy. AB - Nurses often function as capsule endoscopy "pre-readers" to save physicians' time and potentially increase diagnostic yield. Training pre-readers is time consuming, not standardized, and may not be feasible during regular business hours. A way to evaluate the progress and accuracy of pre-readers is needed to ensure competency. The aim of this study was to introduce a feedback and progress assessment tool for training novice capsule endoscopy pre-readers. We created a 1 page form with listings of potential findings for each segment of the examination. Findings could be circled or written in. The trainee reviewed capsule studies and filled out the form on each of 220 patients. The physician reviewers subsequently critiqued the data forms, providing feedback regarding missed lesions, overcalls, and overall agreement. Our trainee achieved consistent agreement with the physician reviewers, after reading 80 studies. In conclusion, a simple, 1-page standardized data sheet can be used to facilitate training of novice capsule pre-readers without significant time commitment from the supervising physician. Future studies may validate this resource-efficient instrument as a training and assessment tool for nurses, physicians, and other practitioners learning capsule endoscopy. PMID- 23018168 TI - Is reprocessing after disuse a safety procedure for bronchoscopy?: A cross sectional study in a teaching hospital in Rome. AB - A bacteriological assessment of flexible bronchoscopes that were stored after a reprocessing procedure was performed to determine whether reprocessing removes microbiological contamination and whether the instruments could be used safely after extended storage without repeating the disinfection before bronchoscopy. The microbiological quality of manual and automated reprocessed bronchoscopes was examined by collecting a pre-reprocessing and a post-reprocessing liquid sample from the stored instruments' channels. A qualitative microbiological analysis was performed to evaluate bacterial contamination. Among the 264 pre-reprocessing bronchoscopes, 10 were contaminated (13 human flora strains and 1 environmental strain were detected). After reprocessing, 8 were decontaminated and 2 remained contaminated. Furthermore, 12 other bronchoscopes had a new contamination post reprocessing (11 human flora and 3 environmental strains were detected). In addition, 2 sampled bronchoscopes were contaminated both pre- and posttreatment. Our findings support the suggestion that reprocessing after storage can be avoided in the safe usage of the instrument if earlier decontaminations are performed correctly. Having found that reprocessing could contaminate bronchoscopes, additional studies are needed to identify the risk factors for contamination and avoid controversial suggestions for first-use reprocessing. PMID- 23018169 TI - Effects of a self-care education program on quality of life after surgery in patients with esophageal cancer. AB - In recent years, the number of quality-of-life (QOL) studies on patients with esophageal cancer has increased; however, the number of studies related to the effects of self-care education programs on QOL of these patients is scarce. This article reports on the effects of a self-care education program on QOL for patients with esophageal cancer in Babol, Iran. The quasi-experimental study had a convenience sample of 105 patients with esophageal cancer referred to oncology centers in Babol City. A quasi-random allocation technique was used to divide the sample into experimental (n = 55) and control (n = 50) groups. Appropriate instruments were used to measure QOL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-30 and Quality of Life Questionnaire-Oesophageal 18). Questionnaires were completed by the respondents before and 3 months after implementing the educational program that consisted of group discussion, lectures, and pamphlets. There was no significant difference between QOL mean score of both groups before the intervention; however, after implementing the educational program, the QOL significantly improved in the experimental group (p = .001), whereas QOL decreased in the controls. We conclude that self-care education programs have positive effects on the QOL of patients with esophageal cancer. Planning and implementing such self-care education programs, when patients are under treatment, can help them improve their QOL. PMID- 23018170 TI - Evaluation and diagnosis of constipation. AB - Constipation is one of the most common gastrointestinal complaints in the United States and can seriously affect quality of life. It is an acute or chronic condition in which bowel movements are infrequent and difficult to eliminate. In severe cases, constipation may cause bowel obstruction. Constipation is a symptom, rather than a disease, resulting from a number of causes and disorders, including dietary factors, neurologic disorders, psychiatric disorders, colon disease, metabolic abnormalities, and medication side effects. This may explain the high prevalence rates and associated excessive costs. This article assists the provider in identifying the correct diagnoses associated with constipation and guiding the practitioner through obtaining a pertinent medical history, performing a comprehensive physical examination, and prescribing the appropriate diagnostics tests. A diagnostic algorithm that considers an extensive list of differential diagnoses including medications contributing to constipation is provided to assist the practitioner in evaluating and diagnosing the cause(s) of the constipation. PMID- 23018171 TI - The importance of the physical examination. PMID- 23018172 TI - Defining service. PMID- 23018177 TI - Influence of the Gly1057Asp variant of the insulin receptor substrate 2 (IRS2) on insulin resistance and relationship with epicardial fat thickness in the elderly. AB - Insulin receptor substrate 2 (IRS2) plays a crucial role in the regulation of insulin signaling. Several polymorphisms of the gene encoding IRS2 have been identified. The variant causing Gly1057Asp substitution is relatively frequent in humans and its impact on insulin sensitivity seems to be dependent on age and body weight. The aim of our study was to evaluate the relationships between Gly1057Asp variant and insulin sensitivity assessed by HOMA, and adiposity evaluated by measurement of epicardial fat (EpiF) thickness in the elderly. We studied 87 subjects, 42 men and 45 women, mean age+/-SD: 74.23+/-7.24years. In the subjects carrying the Gly1057Asp variant of the IRS2 gene we found higher HOMA index values (3.40+/-1.14 vs. 2.21+/-1.25, p<0.001) and increased epicardial adipose tissue (11.77+/-1.65 vs. 10.43+/-1.93mm, p<0.001) compared to wild type subjects. Univariate linear regression analyses evidenced that HOMA index was correlated with BMI (beta=0.152, p<0.001), fasting plasma glucose (beta=0.018, p=0.002), LDL cholesterol (beta=0.008, p=0.024), total cholesterol (beta=0.007, p=0.039), weight (beta=0.054, p<0.001), presence of Gly1057Asp variant (beta=1.185, p<0.001) and EpiF thickness (beta=0.540, p<0.001). In multivariate analysis HOMA index was still associated with the presence of the Gly1057Asp variant of the IRS-2 gene (beta=0.568, p=0.002) and with EpiF thickness (beta=0.414, p<0.001). Furthermore, a statistically significant positive correlation between EpiF thickness and HOMA was found (r=0.773, p<0.001) and this was not different between wild type control subjects and carriers of Gly1057Asp variant of the IRS2 gene (p=0.718). Similar results were obtained in comparing subjects with normal fasting glucose levels. In conclusion, in our elderly subjects the presence of the allelic variant Gly1057Asp of IRS2 gene was associated to the degree of insulin resistance assessed by HOMA index and with EpiF thickness, independently from the extent of obesity, suggesting its contribution to global cardiometabolic risk. PMID- 23018178 TI - Targeting chronic central nervous system HIV infection. AB - Central nervous system (CNS) HIV infection is a nearly universal facet of systemic infection. Although antiretroviral therapy is generally effective in suppressing this infection and reducing its severe complications, reports of continued neurological abnormalities have questioned whether treatment developed for systemic efficacy is optimized for CNS infection. Shikuma et al. report that a 'monocyte efficacy' score based on cell culture studies and applied to antiretroviral drugs correlated with neuropsychological performance in a previously reported cohort. Although there are important questions regarding the theoretical underpinnings of both this score and its application, the findings present a novel slant on therapy. PMID- 23018179 TI - Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1. AB - Identification of Protein Tyrosine Phosphatase (PTP) substrates is critical in understanding cellular role in normal cells as well as cancer cells. We have previously shown that reduction of PTPL1 protein levels in Ewings sarcoma (ES) inhibit cell growth and tumorigenesis. Therefore, we sought to identify novel PTPL1 substrates that may be important for tumorigenesis. In this current work, we demonstrated that mouse embryonic fibroblasts without PTPL1 catalytic activity fail to form foci when transfected with oncogenes. We proved that catalytic activity of PTPL1 is important for ES cell growth. Using a substrate-trapping mutant of PTPL1 we identified putative PTPL1 substrates by mass-spectrometry. One of these putative substrates was characterized as Valosin Containing Protein (VCP/p97). Using multiple biochemical assays we validated VCP as a novel substrate of PTPL1. We also provide evidence that tyrosine phosphorylation of VCP might be important for its midbody localization during cytokinesis. In conclusion, our work identifies VCP as a new substrate for PTPL1, which may be important in cellular transformation. Our investigation link an oncogenic transcription factor EWS-FLI1, with a key transcriptional target protein tyrosine phosphatase PTPL1, and its substrate VCP. Given our observation that PTPL1 catalytic activity is important for cell transformation, our results may also suggest that VCP regulation by PTPL1 might be important for tumorigenesis. PMID- 23018180 TI - Predictors of quality of life gains among people with type 1 diabetes participating in the Dose Adjustment for Normal Eating (DAFNE) structured education programme. AB - AIMS: To examine predictors of quality of life gains among people with type 1 diabetes following the Dose Adjustment for Normal Eating (DAFNE) self-management training programme. METHODS: Clinical and questionnaire data were collected from 437 patients from 6 hospital centres before, and 18 months post-DAFNE intervention. Glycated haemoglobin (HbA(1c)), weight, height, and blood pressure levels were recorded by clinicians during clinic appointments. Questionnaires included the Diabetes-Specific Quality of Life Scale (DSQOLS), the Problem Areas in Diabetes Scale (PAID) and the Hospital Anxiety and Depression Scale (HADS). Basic demographics were recorded at baseline. Linear mixed models were fitted to identify predictors of change in quality of life at an 18 month follow-up assessment. RESULTS: Patients with high levels of diabetes-related distress experienced greatest improvement in DSQOLS quality of life scores (p = 0.001). Patients with poor glycaemic control (higher levels of HbA(1c); p = 0.03) and those with high levels of anxiety (p = 0.001) experienced the greatest reductions in diabetes-related distress. CONCLUSIONS: Patients with higher baseline levels of anxiety, higher levels of diabetes-related distress and higher baseline levels of HbA(1c) are most likely to experience quality of life gain from participation in self-management programmes such as DAFNE. PMID- 23018181 TI - Viability assessment for artificial gametes: the need for biomarkers of functional competency. AB - Assisted reproductive technology (ART) has resulted in more than 5 million births worldwide. However, mainstream ART techniques are not always successful for an estimated 30% of infertile patients in whom gametes are nonviable. Most patients would clearly prefer genetic parenthood, currently possible only via the use of donated gametes or, in future, via the clinical use of artificial gametes (AGs) incorporating parental DNA. Despite much recent progress in the derivation of AGs, significant obstacles remain. Although it is possible to create artificial cells exhibiting some of the molecular and physiological traits of human gametes, they do not yet exhibit the same level of functionality as their in vivo counterparts. Most current effort pays scant attention to confirmation of molecular integrity and clinical applicability of AGs. Here we discuss the various clinical parameters used to assess gamete and embryo viability and discuss markers of gamete function that may be used within future studies attempting to derive AGs. The use of AGs may prove controversial to some members of the general public, and, as such, there is significant need for an appropriate ethical and legal framework governing the clinical use of such cells. However, provided these issues can be successfully overcome, it is highly likely that AGs will represent powerful biological tools for reproductive science, a valuable training resource for embryologists and for potential use in the clinical treatment of human infertility. PMID- 23018182 TI - Expression patterns of gonadotropin hormones and their receptors during early sexual differentiation in Nile tilapia Oreochromis niloticus. AB - In Nile tilapia, sex-specific expression of foxl2 and cyp19a1a in XX gonads and dmrt1 in XY gonads at 5-6 days after hatching (dah) is critical for differentiation of the gonads into either ovaries or testes. The factors triggering sexually dimorphic expression of these genes are unknown, and whether the gonadotropin hormones are involved in early gonadal sex differentiation of the Nile tilapia has been unclear. In the present study, we determined the precise timing of expression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the pituitary and that of their receptors (fshra and lhcgrbb) in the undifferentiated gonad in both XX and XY tilapia fry by quantitative RT-PCR and immunohistochemical analysis. Expression of fshb mRNA and Fsh protein in the pituitary was detected from the first sampling day (3 dah) to 25 dah in both XX and XY tilapia larvae without sexual dimorphism and increased gradually after 25 dah in the pituitary. fshra mRNA was expressed beginning 5 dah and was present at significantly higher levels in XX gonads than in the XY gonads at 6-25 dah. These results indicate that the level of Fsh protein in the pituitary was not critical for differentiation of gonads into ovaries or testes, but the expression level of its receptor, fshra, in undifferentiated gonads appeared to be involved in determining gonadal sexual differentiation. Based on these observations, it is likely that in XX gonads, up-regulation of fshra may be necessary to induce cyp19a1a expression, which stimulates estradiol-17beta (E(2)) production and subsequent ovarian differentiation. On the other hand, lhb mRNA was not detected until 25 dah in the pituitaries of both sexes, and sexual dimorphism in lhcgrbb mRNA levels appeared later (10-25 dah) than that of fshra in the gonads, indicating the limited role of LH and lhcgrbb in gonadal differentiation of the Nile tilapia. PMID- 23018183 TI - The recruitment and activation of leukocytes into the immune cervix: further support that cervical remodeling involves an immune and inflammatory mechanism. PMID- 23018184 TI - Effects of low progesterone on the endometrial transcriptome in cattle. AB - The objective of the present study was to determine how low progesterone (P4) affects the endometrial transcriptome, with specific emphasis on those changes that may impact conceptus elongation. Following estrous synchronization and detection (estrus = Day 0, n = 40), heifers were randomly assigned to a control group (n = 12) or a low P4 group (n = 28). Heifers in the low P4 group had consistently lower P4 concentrations compared to controls (P < 0.05). Microarray analysis of endometrial gene expression revealed low P4 altered the expression of 498 differentially expressed genes (DEGs; 215 up- and 283 down-regulated) on Day 7 and 351 DEGs (272 up- and 79 down-regulated) on Day 13. A similar number of temporal changes occurred between Day 7 and Day 13 in both groups (2212 in heifers with normal P4 compared with 2247 in heifers with low P4); of these DEGs, 1278 were common to both groups. Little overlap in the number of DEGs affected by high or low P4 was observed across days. Comparison of the temporal changes that occur during normal estrous cycle progression (i.e., from Day 7 to Day 13) to those affected by altered P4 found significant numbers of genes were modulated by elevated (4157) and decreased (809) P4 alone. Analysis of selected genes by quantitative real-time PCR and in situ hybridization revealed that expression of MEP1B, NID2, and PRSS23 increased on Day 13 compared to Day 7 (P < 0.05) and that the magnitude of increase was significantly diminished in heifers with low P4 compared to controls. MEP1B predominantly localized to the both the superficial and deep glandular epithelium (GE), NID2 localized to the deep GE, whereas PRSS23 localized only to the luminal epithelium. In conclusion, we have determined the global changes in the endometrial transcriptome induced by decreasing the output of P4 from the corpus luteum in vivo using a unique animal model. Placing these data into context with previous data in which P4 was supplemented or elevated after ovulation, we have identified a panel of genes that are truly regulated in the endometrium by circulating concentrations of P4 in vivo and that likely impact conceptus elongation. PMID- 23018185 TI - Incorporation of coenzyme Q10 into bovine oocytes improves mitochondrial features and alleviates the effects of summer thermal stress on developmental competence. AB - Environmental stress-induced alterations in oocyte mitochondria are suggested to deleteriously affect developmental competence of the ovarian pool of oocytes. We examined the association between seasonal effects on oocyte developmental competence and mitochondrial distribution, polarization, mitochondrial DNA (mtDNA) content, and RNA expression, and whether the incorporation of coenzyme Q10 (CoQ10) might improve these effects. Bovine oocytes were collected during the summer (June-August), fall (September-November), and winter (December-May), matured in vitro with or without 50 MUM CoQ10, fertilized, and cultured for 8 days. The proportion of developed blastocysts was highest in the winter, intermediate in the fall, and lowest in the summer. Matured oocytes were classified into categories I-IV according to their mitochondrial distribution pattern (MitoTracker green). The proportion of high- and low-polarized mitochondria (JC-1 assay) differed between oocyte categories but was not affected by season. On the other hand, oocyte distribution into categories differed between seasons and was affected by CoQ10, with an increased proportion of category I oocytes in the fall. Oocyte mtDNA did not differ between seasons, but expression of mitochondrion-associated genes involved in the respiratory chain (ND2, SDHD, CYTB, COXII, ATP5B, and TFAM) did. Coenzyme Q10 increased the expression of CYTB, COXII, and ATP5B and the proportions of blastocysts developed in the fall. In summary, season-induced alterations in mitochondrial functions might explain, in part, the reduced oocyte developmental competence. It seems that in the fall, under modest harm, CoQ10 incorporation can alleviate these deleterious effects somewhat. PMID- 23018186 TI - Characterization of the constitutive pig ovary heat shock chaperone machinery and its response to acute thermal stress or to seasonal variations. AB - Reduced oocyte competence causes the lower fertility reported in domestic sows during the warm months of the year. Somatic cells express heat shock proteins (HSPs) to protect themselves from damage caused by thermal stress. HSPs are classified as molecular chaperones and control the correct folding of newly synthesized or damaged proteins. The present work performed a comprehensive survey of the different components of the heat shock chaperone machinery in the pig ovary, which included the HSP40, HSP70, HSP90, and HSP110 families, as well as heat shock factors (HSF) 1 and 2. Pig ovarian follicles constitutively expressed different members of these families; therefore, we examined their ability to respond to heat stress. In order to take into account the role of the complex follicular architecture, whole pig ovaries were exposed to 41.5 degrees C for 1 h. This exposure significantly disrupted oocyte maturation and determined the upregulation of the HSP70, HSP40, HSPH1, HSPA4, HSPA4L, HSF1, and HFS2 genes, whereas expression levels of HSP90A and HSP90B, as well as those of genes unrelated to heat stress were not altered. Unexpectedly HSP and HSF expression levels changed only in oocytes but not in cumulus cells. Cumulus-oocyte complexes isolated from ovaries collected in summer showed the same pattern as those collected in winter. We conclude that the HSP chaperone machinery is constitutively fully operational in the pig ovary. However, following thermal stimuli or seasonal variations, cumulus cell HS-related gene expression remains unchanged, and only oocytes activate a response, suggesting why this mechanism is insufficient to preserve their competence both in vitro and in vivo. PMID- 23018187 TI - Loss of occludin expression and impairment of blood-testis barrier permeability in rats with autoimmune orchitis: effect of interleukin 6 on Sertoli cell tight junctions. AB - Inflammation of the male reproductive tract is accepted as being an important etiological factor of infertility. Experimental autoimmune orchitis (EAO) is characterized by interstitial lymphomononuclear cell infiltration and severe damage of seminiferous tubules with germ cells that undergo apoptosis and sloughing. Because the blood-testis barrier (BTB) is relevant for the protection of haploid germ cells against immune attack, the aim of this study was to analyze BTB permeability and the expression of tight junction proteins (occludin, claudin 11, and tight junction protein 1 [TJP1]) in rats during development of autoimmune orchitis. The role of IL6 as modulator of tight junction dynamics was also evaluated because intratesticular content of this cytokine is increased in EAO rats. Orchitis was induced in Sprague-Dawley adult rats by active immunization with testicular homogenate and adjuvants. Control rats (C) were injected with saline solution and adjuvants. Untreated (N) rats were also studied. Concomitant with early signs of germ cell sloughing, a reduced expression of occludin and delocalization of claudin 11 and TJP1 were detected in the testes of rats with EAO compared to C and N groups. The use of tracers showed increased BTB permeability in EAO rats. Intratesticular injection of IL6 induced focal testicular inflammation, which is associated with damaged seminiferous tubules. Rat Sertoli cells cultured in the presence of IL6 exhibited a redistribution of tight junction proteins and reduced transepithelial electrical resistance. These data indicate the possibility that IL6 might be involved in the downregulation of occludin expression and in the modulation of BTB permeability that occur in rats undergoing autoimmune orchitis. PMID- 23018188 TI - Increased placental nutrient transporter expression at midgestation after maternal growth hormone treatment in pigs: a placental mechanism for increased fetal growth. AB - Growth hormone (GH) is important in maternal adaptation to pregnancy, and maternal circulating GH concentrations are reduced in human growth-restricted pregnancies. In the pig, maternal GH treatment throughout early to mid pregnancy increases fetal growth, despite constraining effects of adolescent and primiparous pregnancy, high litter size, and restricted maternal nutrition. Because GH cannot cross the placenta and does not increase placental weight, we hypothesized that its effects on fetal growth might be via improved placental structure or function. We therefore investigated effects of maternal GH treatment in pigs on structural correlates of placental function and placental expression of nutrient transporters important to fetal growth. Multiparous (sows) and primiparous pregnant pigs (gilts) were treated with GH (~15 MUg kg(-1) day(-1)) or vehicle from Days 25-50 of gestation (n = 7-8 per group, term ~115 days). Placentas were collected at Day 50 of gestation, and we measured structural correlates of function and expression of SLC2A1 (previously known as GLUT1) and SLC38A2 (previously known as SNAT2) nutrient transporters. Maternal GH treatment did not alter placental size or structure, increased protein expression of SLC2A1 in trophoblast (+35%; P = 0.037) and on its basal membrane (+44%; P = 0.011), and increased SLC38A2 protein expression in the basal (+44%; P = 0.001) but not the apical cytoplasm of trophoblast. Our findings suggest that maternal GH treatment increases fetal growth, in part, by enhancing placental nutrient transporter protein expression and hence fetal nutrient supply as well as trophoblast proliferation and differentiation and may have the potential to ameliorate intrauterine growth restriction. PMID- 23018189 TI - Ru-based donor-acceptor photosensitizer that retards charge recombination in a p type dye-sensitized solar cell. AB - We report on the synthesis and characterization of a donor-acceptor ruthenium polypyridyl complex as a photosensitizer for p-type dye-sensitized solar cells (DSSCs). The electrochemical, photophysical, and photovoltaic performance of two ruthenium-based photosensitizers were tested in NiO-based DSSCs; bis-(2,2' bipyridine-4,4'-dicarboxylic acid)(2)N-(1,10-phenanthroline)-4-nitronaphthalene 1,8-dicarboximide ruthenium(II), ([Ru(dcb)(2)(NMI-phen)](PF(6))(2)) and tris (2,2'-bipyridine-4,4'-dicarboxylic acid)(3) ruthenium(ii), [(Ru(dcb)(3))Cl(2)]. The presence of an electron-accepting group, 4-nitronaphthalene-1,8-dicarboximide (NMI), attached to the phenanthroline of [Ru(dcb)(2)(NMI-phen)](2+) resulted in long-lived charge separation between reduced [Ru(dcb)(2)(NMI-phen)](2+) and NiO valence band holes; 10-50 MUs. In the reduced state for [Ru(dcb)(2)(NMI phen)](2+), the electron localized on the distal NMI group. In tests with I(3)( )/I(-) and Co(4,4'-di-tert-butyl-bipyridine)(3)(2+/3+) electrolytes, [Ru(dcb)(2)(NMI-phen)](2+) outperformed [Ru(dcb)(3)](2+) in solar cell efficiency in devices. A record APCE (25%) was achieved for a ruthenium photosensitizer in a p-type DSSC. Insights on photosensitizer regeneration kinetics are included. PMID- 23018190 TI - A cell-free system for functional centromere and kinetochore assembly. AB - This protocol describes a cell-free system for studying vertebrate centromere and kinetochore formation. We reconstitute tandem arrays of centromere protein A (CENP-A) nucleosomes as a substrate for centromere and kinetochore assembly. These chromatin substrates are immobilized on magnetic beads and then incubated in Xenopus egg extracts that provide a source for centromere and kinetochore proteins and that can be cycled between mitotic and interphase cell cycle states. This cell-free system lends itself to use in protein immunodepletion, complementation and drug inhibition as a tool to perturb centromere and kinetochore assembly, cytoskeletal dynamics, DNA modification and protein post translational modification. This system provides a distinct advantage over cell based investigations in which perturbing centromere and kinetochore function often results in lethality. After incubation in egg extract, reconstituted CENP-A chromatin specifically assembles centromere and kinetochore proteins, which locally stabilize microtubules and, on microtubule depolymerization with nocodazole, activate the mitotic checkpoint. A typical experiment takes 3 d. PMID- 23018191 TI - Synthesis of an electron-rich KITPHOS monophosphine, preparation of derived metal complexes and applications in catalysis. AB - This protocol describes the synthesis of a representative example of the electron rich biaryl-like KITPHOS class of monophosphine, 11-dicyclohexylphosphino-12 phenyl-9,10-dihydro-9,10-ethenoanthracene (H-KITPHOS). The bicyclic architecture of H-KITPHOS is constructed via [4+2] Diels-Alder cycloaddition between 1 (dicyclohexylphosphinoylethynyl)benzene and anthracene. H-KITPHOS monophosphine is prepared via an operationally straightforward three-step procedure and is isolated in an overall yield of ~55%. The synthesis of palladium and gold precatalysts of H-KITPHOS are also described; the yields of analytically pure complexes are high (75-85% and 85-90%, respectively). The palladium complex of H KITPHOS forms a highly active catalyst for C-C and C-N cross-coupling of a range of aryl and heteroaryl chlorides and bromides, and the electrophilic Lewis acid gold complex efficiently catalyzes a host of cycloisomerizations. The total time required for the synthesis of H-KITPHOS is 95 h; the preparation of corresponding palladium and gold precatalysts requires an additional 7-8 h, and, if necessary, crystallizations will require a further 48 h. PMID- 23018192 TI - Synthesis and resolution of the biaryl-like diphosphine (S)-Me2-CATPHOS, preparation of a derived rhodium precatalyst and applications in asymmetric hydrogenation. AB - This protocol describes the synthesis of a representative example of the enantiopure biaryl-like CATPHOS class of diphosphines, (S)-9,9'-dimethyl 9,9',10,10'-tetrahydro-9,10,9',10'-biethenobianthracene-11,11' bis(diphenylphosphino)-12,12'-diyl ((S)-Me(2)-CATPHOS), and its derived cationic rhodium-based hydrogenation precatalyst. The C(2)-symmetric framework of Me(2) CATPHOS is the result of a regioselective Diels-Alder cycloaddition between 1,4 bis(diphenylphosphinoyl)buta-1,3-diyne and 9-methylanthracene, such that the bulky methyl-substituted bridgehead carbon atoms are attached to C2 and C3 of the 1,3-butadiene tether. Enantiopure Me(2)-CATPHOS is obtained in an operationally straightforward three-step procedure and isolated in ~50-60% overall yield and <99% enantiopurity, after diastereoselective resolution with (2R,3R)-(-)-2,3-O dibenzoyltartaric acid. The derived rhodium complex forms a highly effective catalyst for the asymmetric hydrogenation of a range of dehydroamino acid derivatives, as well as (E)-beta-aryl-(enamido)phosphonates, giving ee values in excess of 99%, the highest to be reported for the latter class of substrate. The total time required for the synthesis of (S)-Me(2)-CATPHOS, including resolution, reduction and crystallizations, is 130 h and preparation of the corresponding rhodium precatalyst requires an additional 24-26 h. PMID- 23018193 TI - The anti-CMS technique for genome-wide mapping of 5-hydroxymethylcytosine. AB - 5-Hydroxymethylcytosine (5hmC) is a recently discovered base in the mammalian genome, produced upon oxidation of 5-methylcytosine (5mC) in a process catalyzed by TET proteins. The biological functions of 5hmC and further oxidation products of 5mC are under intense investigation, as they are likely intermediates in DNA demethylation pathways. Here we describe a novel protocol to profile 5hmC at a genome-wide scale. This approach is based on sodium bisulfite-mediated conversion of 5hmC to cytosine-5-methylenesulfonate (CMS); CMS-containing DNA fragments are then immunoprecipitated using a CMS-specific antiserum. The anti-CMS technique is highly specific with a low background, and is much less dependent on 5hmC density than anti-5hmC immunoprecipitation (IP). Moreover, it does not enrich for CA and CT repeats, as noted for 5hmC DNA IP using antibodies to 5hmC. The anti-CMS protocol takes 3 d to complete. PMID- 23018194 TI - The GLIB technique for genome-wide mapping of 5-hydroxymethylcytosine. AB - 5-Hydroxymethylcytosine (5hmC) is a newly discovered DNA base present at detectable levels in most mammalian cell types and tissues. It is generated by Tet-enzyme-mediated oxidation of 5-methylcytosine (5mC). 5hmC is important both because of its potential role in regulating gene expression and because it may be an intermediate in DNA demethylation. Here we describe a technique termed GLIB (glucosylation, periodate oxidation and biotinylation), which combines several enzymatic and chemical modification steps to attach biotin to 5hmC. Biotin containing genomic DNA fragments are then enriched using streptavidin beads, eluted and sequenced. GLIB is capable of quantitatively tagging and precipitating fragments containing a single 5hmC molecule. Sample preparation and GLIB can be conducted in 2-3 d. PMID- 23018196 TI - Observation of phonon sideband emission in intrinsic InN nanowires: a photoluminescence and micro-Raman scattering study. AB - In this work, photoluminescence and micro-Raman scattering experiments were performed on undoped InN nanowires. It was found that, besides the main photoluminescence peak, a clear phonon sideband emission peak, with an extremely narrow linewidth ~9 meV, was measured. The phonon spectrum revealed by micro Raman scattering indicates only uncoupled LO phonons are involved in such phonon sideband emission. The clearly resolved phonon sideband emission peak with a narrow linewidth, together with the uncoupled LO phonon modes, suggests the superior quality of the presented InN nanowires, i.e., extremely low residual electron density and the absence of surface electron accumulation, which is consistent with the physical properties of intrinsic InN nanowires as in the previous studies. The detailed phonon sideband properties are also discussed in the text. PMID- 23018195 TI - Evaluation of bone regeneration using the rat critical size calvarial defect. AB - Animal models that are reliably reproducible, appropriate analogs to the clinical condition they are used to investigate, and that offer minimal morbidity and periprocedural mortality to the subject, are the keystone to the preclinical development of translational technologies. For bone tissue engineering, a number of small animal models exist. Here we describe the protocol for one such model, the rat calvarial defect. This versatile model allows for evaluation of biomaterials and bone tissue engineering approaches within a reproducible, non load-bearing orthotopic site. Crucial steps for ensuring appropriate experimental control and troubleshooting tips learned through extensive experience with this model are provided. The surgical procedure itself takes ~30 min to complete, with ~2 h of perioperative care, and tissue collection is generally performed 4-12 weeks postoperatively. Several analytical techniques are presented, which evaluate the cellular and extracellular matrix components, functionality and mineralization, including histological, mechanical and radiographic methods. PMID- 23018197 TI - The electronic nose in respiratory medicine. AB - Several volatile organic compounds have been identified in exhaled breath in healthy subjects and patients with respiratory diseases by gas chromatography/mass spectrometry. Identification of selective patterns of volatile organic compounds in exhaled breath could be used as a biomarker of inflammatory lung diseases. An electronic nose (e-nose) is an artificial sensor system that generally consists of an array of chemical sensors for detection of volatile organic compound profiles (breathprints) and an algorithm for pattern recognition. E-noses are handheld, portable devices that provide immediate results. E-noses discriminate between patients with respiratory disease, including asthma, COPD and lung cancer, and healthy control subjects, and also among patients with different respiratory diseases. E-nose breathprints are associated with airway inflammation activity. In combination with other 'omics' platforms, e-nose technology might contribute to the identification of new surrogate markers of pulmonary inflammation and subphenotypes of patients with respiratory diseases, provide a molecular basis to a personalized pharmacological treatment, and facilitate the development of new drugs. PMID- 23018198 TI - Genotoxicity assessment in iron deficiency anemia patients using sister chromatid exchanges and chromosomal aberrations assays. AB - Previous studies have shown that iron deficiency anemia is associated with oxidative stress produced by a decrease in antioxidant enzyme activities and/or a high level of oxidants. Because oxidative stress induces DNA damage, we investigated genotoxicity in lymphocytes from patients with iron deficiency anemia (IDA) using chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs) assays. Eighteen IDA subjects and a similar number of age-matched healthy controls were included in the study. The results demonstrated that IDA was associated with a slight increase in the frequency of spontaneous CAs and a decrease in the frequency of SCEs (P<0.05). In addition, the level of SCEs was positively correlated with both the ferritin concentration (r=0.485, P<0.05) and hemoglobin content (r=0.514, P<0.05) in subjects. Moreover, vitamin E treatment reduced the frequency of SCEs in IDA patients and control subjects by the same percentage (~30%) without affecting the magnitude of the difference in the levels of SCEs between the two groups. In conclusion, our results demonstrated that IDA has a differential effect on the frequency of spontaneous CAs and SCEs. PMID- 23018199 TI - Tumor necrosis factor alpha-mediated asthma?. PMID- 23018200 TI - Care of the patient after renal allograft failure: managing the present and planning for the future. AB - The number of patients with end-stage renal disease undergoing kidney transplantation - both cadaveric and living-donor - continues to rise. With long term graft survival relatively fixed, this trend means that increasing numbers of patients are returning to dialysis after graft loss. Most will never be retransplanted, which introduces a host of clinical questions regarding optimal management of this unique patient population. In this paper, we explore data that informs astute care of the patient requiring dialysis after graft loss. We address new data about the increased clinical risk and the optimal dialysis modality in renal allograft loss, explore new approaches to immunosuppression and transfusion management, and examine the risks and benefits of allograft nephrectomy and timing thereof. While there are no randomized clinical trials in this field, rapidly evolving data will aid the clinician whose practice includes patients who have been transplanted and are returning to dialysis. PMID- 23018201 TI - Dietary exposure to perfluoroalkyl acids for the Swedish population in 1999, 2005 and 2010. AB - Dietary intake has been hypothesized to be the major pathway of human exposure to perfluoroalkyl acids (PFAAs). However, difficulties associated with the analysis of PFAAs at ultra trace levels in food samples have prevented the confirmation of this hypothesis. In this study, the dietary intake of PFAAs for the general Swedish population was estimated by applying a highly sensitive analytical method to a set of archived food market basket samples from 1999, 2005 and 2010. Dietary exposure to perfluorooctane sulfonic acid (PFOS) (860-1440 pg kg-1 day-1), perfluoroundecanoic acid (PFUnDA) (90-210 pg kg-1 day-1), perfluorodecanoic acid (PFDA) (50-110 pg kg-1 day-1) and perfluorononanoic acid (PFNA) (70-80 pg kg-1 day-1) was dominated by the consumption of fish and meat. In contrast, dietary exposure to PFOA (350-690 pg kg-1 day-1) originated from low levels (8-62 pg g-1) found in several high consumption food categories including cereals, dairy products, vegetables and fruit. The dietary intakes of PFOS and PFOA estimated in this study were 4 to 10 times lower compared to previous exposure modeling studies. Nevertheless, the dietary intake of PFOS and PFOA was still a factor of 6 to 10 higher than exposure through ingestion of household dust and drinking water estimated for the general Swedish population. For perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA) and perfluorohexane sulfonic acid (PFHxS) drinking water intake was the major exposure pathway (36-53% of the total exposure) whereas dust ingestion made a significant contribution (27-49%) to the total exposure for PFHxA, PFHpA, PFNA, perfluorotridecanoic acid (PFTrDA) and perfluorotetradecanoic acid (PFTeDA). Dietary intakes varied by less than a factor of three for all PFAAs during the different sampling years which demonstrates that dietary intake has been fairly constant over the past decade when many manufacturing changes occurred. PMID- 23018202 TI - Herpes simplex virus-1 encephalitis: a review of current disease management with three case reports. AB - Herpes simplex virus-1 (HSV-1) is the most common cause of lethal sporadic encephalitis. Despite improved therapy with intraveneous acyclovir, HSV-1 encephalitis is associated with persistent severe neurological deficits. We report three cases of adult patients with HSV-1 encephalitis (HSE), discuss the current accepted guidelines for treatment as published by the Infectious Disease Society of America (IDSA) and review the literature pertaining to HSE. Our case presentations are consistent with the literature review noting a broad spectrum of clinical outcomes with HSE. We include the first published case of successful early transition to oral antiviral therapy. In the other two cases, repeat cerebrospinal fluid (CSF) analysis showed persistent lymphocytic pleocytosis necessitating prolonged viral suppression. Long-term neurological sequelae were noted in these two patients. The IDSA recommendation of 2-3 weeks of intraveneous acyclovir at 10 mg/kg every 8 h, depending on the clinical course, is sufficient for most cases of HSE. We recommend individualization of duration of treatment based on follow-up CSF analysis with quantification of HSV-1. PMID- 23018204 TI - Modification of rat model of sciatica induced by lumber disc herniation and the anti-inflammatory effect of osthole given by epidural catheterization. AB - One of the most treatable causes of lower back pain and associated sciatica is lumbar disc herniation (LDH), which is characterized by rupture of the hard outer wall (annulus fibrosis) in a lumbar intervertebral disc. In the current study, we aimed to: (1) develop and characterize a rat model of sciatica induced by LDH, while introducing a novel method of epidural catheterization; (2) use this model to evaluate the effect of osthole on pain due to LDH, and (3) gain insight into the mechanisms through which osthole affects sciatica induced by LDH. The results indicate that our newly developed rat model maintained mechanical allodynia for 28 days without reduction. Moreover, cyclooxygenase-2 (COX-2) and nitric oxide synthase (NOS) were overexpressed in the associated inflammatory response, which is consistent with clinical manifestations of the disease. We then used this model to study the effect and mechanisms through which osthole affected pain due to LDH. Our study suggests that osthole is capable of reversing hyperalgesia due to LDH, potentially through modulation of activity of COX-2 and NOS, two important proteins for the exacerbation of pain due to LDH. Finally, a molecular modeling simulation showed that osthole has unique binding capabilities to both NOS and COX-2. As the model-induced mechanical hyperalgesia response was consistent, and the position of the catheter tip and the extension/spreading of the drug in the epidural space were reliable, this study developed an improved model to study remedies for sciatic pain. Moreover, our studies demonstrate that osthole may be a feasible treatment for the reduction of pain due to hyperalgesia. PMID- 23018206 TI - Effect of acute lung injury on VLA-4 and CXCR4 expression in resident and circulating hematopoietic stem/progenitor cells. AB - BACKGROUND: The effect of acute lung injury on adhesion molecule expression in hematopoietic stem/progenitor cells (HSPCs) is poorly understood. OBJECTIVES: The aim of this study was to determine whether there is a relationship -between pulmonary inflammation, expression of VLA-4 (CD49d), LFA-1 (CD11a), L-selectin (CD62L), CXCR4, and chemotaxis in resident HSPCs, as well as the level of circulating HSPCs. METHODS: Following intratracheal administration of a single LPS bolus in C57Bl/6 mice, the number of inflammatory cells, differential counts, and amounts of cytokines/ chemokines were studied in cytospins and bronchoalveolar lavage fluid (BALF) specimens. Expressions of adhesion -molecules and CXCR4 were analyzed in HSPCs by flow cytometry, as well as SDF-1-directed chemotaxis. Levels of HSPCs in the blood were studied in ungated and circulating subpopulations. RESULTS: In coincidence with a peak of airway neutrophils, cytokine (IL-1beta, TNF-alpha, and IL-6), chemokine (KC, MIP-2, and SDF-1) levels in BALF and the number of marrow HSPCs expressing CD49d and CXCR4 significantly increased at 48 h. The number of CD49d- and CXCR4-positive HSPCs dropped at 72 h. The HSPC subset comprising bigger cells behaved the same for CD49d. Chemotaxis of the marrow HSPC subset of bigger cells was higher in LPS-treated animals than in controls at 72 h. Finally, we could detect a significant decrease in circulating Sca-1(+) cells in the mononuclear population at 72 h in LPS-treated mice. CONCLUSIONS: Our data provide evidence for a temporal relationship between pulmonary inflammation, CD49d and CXCR4 expression fluctuation in resident HSPCs, and the level of circulating HSPCs. PMID- 23018207 TI - Low-grade smooth muscle tumors of the primary and the secondary mullerian system: a proposed concept of multicentricity. AB - Some patients with bland smooth muscle tumors in the uterus have synchronous or asynchronous smooth muscle tumors in the peritoneum and/or the retroperitoneum. It is usually assumed that the uterine tumor is the primary lesion, and the extrauterine neoplasm represents its metastasis. Thus, they are designated as low grade leiomyosarcomas because they lack the diagnostic features of a conventional spindle cell leiomyosarcoma. Nineteen such cases were retrieved from the files of the Department of Pathology at The University of Texas M.D. Anderson Cancer Center, covering a period of 18 yr. Institutional Review Board approval was obtained before the initiation of this study. In addition, 31 cases of conventional uterine leiomyosarcomas of a high grade were reviewed for comparison. Clinicopathologic features such as patients' age, tumor location, histologic features, stage, treatment, and follow-up were recorded. Immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), p53, Ki-67, and WT-1 were performed in the initially detected tumor and the subsequent neoplasm of all cases with available material in the low-grade group and selected cases in the high-grade group. Compared with high-grade leiomyosarcomas, the low-grade group cases were found at an early age (45 vs. 52.8 yr), had a longer median time of "recurrence" (42 mo for the low-grade group vs. 12 mo for high-grade leiomyosarcomas), longer median survival (165 mo for the low-grade group vs. 41 mo for the high-grade group), and a much better overall survival (84% vs. 13%). Three (16%) patients died of disease in the low-grade group versus 27 (87%) patients in the high-grade leiomyosarcoma group. We also found a difference in the location of the extrauterine tumors. Most cases of low grade tumors were found in the pelvis, abdomen, or retroperitoneum, whereas most high-grade leiomyosarcomas involved the lung. In the low-grade tumors, there were some differences in the immunophenotype between the uterine and the extrauterine neoplasms, but in the high-grade tumors, there were no differences in the immunohistochemistry between the primary tumor and the metastasis. In addition to these differences between the 2 groups in the age of the patients, sites of recurrences, and the immunophenotype of the uterine and extrauterine tumor, neither the uterine nor the extrauterine low-grade lesions had histologic features of malignancy. On the basis of these differences, the possibility that the extrauterine lesions in the low-grade group represent independent primaries involving the secondary mullerian system is proposed. PMID- 23018208 TI - Collision tumor of the ovary: adult granulosa cell tumor and endometrioid carcinoma. AB - We report the first case of a combined adult granulosa cell tumor and endometrioid carcinoma collision tumor occurring in an ovary. PMID- 23018209 TI - Ovarian paraganglioma arising from mature cystic teratoma. PMID- 23018210 TI - Adenoid cystic carcinoma of skene glands: a rare origin in the female genital tract and the characteristic clinical course. AB - Adenoid cystic carcinoma (ACC) is a relatively uncommon malignancy that most frequently arises in the salivary glands. In the genital tract, approximately 60 cases of ACC that originated from Bartholin glands have been reported to date. In this report, we describe a case of ACC that arose from Skene glands, a very rare origin for this disease. In this patient, the disease had an indolent clinical course, with few symptoms other than localized pain. During the surgical operation, the tumor was found to have invaded more extensively than had been estimated preoperatively, and it required pelvic exenteration with radical vulvectomy. Although the precise preoperative assessment and the preparation for an extended operation are difficult, they are necessary for the successful treatment of this rare disease. PMID- 23018211 TI - Multifocal uterine myxoid change: a newly recognized association with neurofibromatosis type 1. AB - Stromal myxoid change is a rare feature of non-neoplastic disease of the uterus. "Myometrial myxoidosis" with secondary myometrial hypertrophy was reported in 2 patients with systemic lupus erythematosus. Uterine myxoid stromal change was also described as an unusual pseudoneoplastic condition of uncertain etiology in 3 patients, one of whom had neurofibromatosis type 1 (NF1; von Recklinghausen disease). We have now identified multifocal uterine myxoid change in the hysterectomy specimen of another patient with NF1; we describe the findings in both patients and review the relevant literature. The myometrium and cervical stroma in both NF1 patients contained tracts and nodules of hypocellular myxoid stromal material composed of bland spindle-shaped cells and interspersed small blood vessels. The myxoid stromal material was strongly and diffusely immunopositive for CD34 and CD10 but did not label for desmin, smooth muscle actin, h-caldesmon, neurofilament protein, S100, or epithelial membrane antigen. The myxoid material in the NF1 patients was better demarcated than in the 2 reported cases of myometrial myxoidosis in systemic lupus erythematosus, and more widely distributed, extensively involving the cervix and the myometrium. The occurrence of this rare, distinctive pattern of multifocal uterine myxoid change in 2 patients with NF1 seems unlikely to represent simply a chance association. The identification of multifocal uterine myxoid change in non-neoplastic myometrium or cervical stroma should raise the possibility of underlying NF1. PMID- 23018212 TI - Transitional cell carcinoma of the ovary is related to high-grade serous carcinoma and is distinct from malignant brenner tumor. AB - Transitional cell tumors of the ovary include benign, borderline (atypically proliferating), and malignant Brenner tumors (BT), as well as transitional cell carcinoma (TCC). Some TCCs could conceivably be examples of malignant BT where the benign component has been overgrown. Our objectives were: (A) compare the immunophenotypes of BT and TCC and (B) examine a large cohort of ovarian carcinomas for cases with the immunophenotype of BT and transitional features but lacking a benign BT component. Seven BTs (3 benign, 3 borderline/atypically proliferating, 1 malignant) and 7 TCCs were stained for WT1, ER, p53, and p16(INK4a). The BTs were negative for WT1, p53 overexpression, ER (except for weak positivity in 1), and negative or weakly positive for p16(INK4a). In contrast, the TCCs stained as follows: 4/6 positive for WT1, 5/7 positive for ER, 2/7 strongly positive for p16(INK4a), and 6/7 showed abnormal p53, an immunophenotype resembling that of high-grade serous carcinoma. A database of 500 cases of ovarian carcinoma was searched and 116 showed an immunoprofile characteristic of BT: WT1 negative, ER negative, p16(INK4a) or weak positive, p53 negative (77 clear cell carcinoma, 14 endometrioid carcinoma, 12 mucinous carcinoma, 8 high-grade serous carcinoma). None of these tumors showed transitional features on review, indicating that if examples of malignant BT where there has been overgrowth of benign BT components exist, they are rare. Our results suggest that BT and TCC are unrelated, and should not be combined for classification purposes. PMID- 23018213 TI - ATF5 is overexpressed in epithelial ovarian carcinomas and interference with its function increases apoptosis through the downregulation of Bcl-2 in SKOV-3 cells. AB - The activating transcription factor 5 (ATF5) is highly expressed in many kinds of tumors including glioblastoma and breast cancers, but its expression in epithelial ovarian neoplasms has not been investigated. Here, we show that ATF5 is highly expressed in the majority of epithelial ovarian cancer samples (43/60) as compared with benign ovarian tumor tissues (4/13) and normal ovarian tissues (1/10). Furthermore, we found that ATF5 expression significantly correlated with advanced clinical stage (P<0.05) and poor differentiation of epithelial ovarian carcinomas (P<0.05). Previous studies suggested that ATF5 is required for the survival of cancer cells, but the mechanisms by which ATF5 regulates genes and promotes cell survival are not clear. Our data additionally demonstrated that interference with the function of ATF5 could markedly increase the apoptosis of ovarian cancer cells and identified B-cell leukemia lymphoma-2 as an ATF5 targeted apoptosis-related gene. These findings may provide potential therapeutic application in epithelial ovarian cancer. PMID- 23018214 TI - Immunohistochemical localization of HE4 in benign, borderline, and malignant lesions of the ovary. AB - Despite advances in the development of novel methods to improve treatment, ovarian carcinoma is still the leading cause of gynecologic cancer death in the United States and other industrialized nations. Improvements in the clinical outcome of ovarian cancer will be achieved if methods can be developed to enable the detection of these tumors at the earliest possible stage. Thus, it is critically important to identify and validate new biomarkers of ovarian cancer. HE4 expression was defined by immunohistochemical analysis of a wide range of benign, borderline, and malignant ovarian lesions, including serous, endometrioid, mucinous, and clear cell lesions of the ovary and in primary tubal carcinomas and the normal fallopian tube. At the cellular level, HE4 was highly expressed in malignant ovarian tumors and in a wide range of benign and borderline ovarian lesions. In addition, HE4 was highly expressed in primary fallopian tube carcinomas and benign fallopian tubal epithelial cells. These results support the conclusion that HE4 is widely expressed in most benign, borderline, and malignant lesions of the ovary and the fallopian tube. The detection of HE4 expression at high levels in some benign lesions and normal tissues suggests that HE4 could have limited specificity as a marker of ovarian or tubal carcinoma. Furthermore, the relatively weak expression that was observed in many ovarian carcinomas indicates that HE4 could fail to detect some cases of primary or recurrent disease. PMID- 23018215 TI - Tyrosine kinase receptor status in endometrial stromal sarcoma: an immunohistochemical and genetic-molecular analysis. AB - Endometrial stromal sarcomas (ESS) are rare uterine malignant mesenchymal neoplasms, which are currently treated by surgery, as effective adjuvant therapies have not yet been established. Tyrosine kinase inhibitors have rarely been applied in ESS therapy, with few reports describing imatinib responsivity. The aim of this study was to analyze the status of different tyrosine kinase receptors in an ESS series, in order to evaluate their potential role as molecular targets. Immunohistochemistry was performed for EGFR, c-KIT, PDGFR alpha, PDGFR-beta, and ABL on 28 ESS. EGFR, PDGFR-alpha, and PDGFR-beta gene expression was investigated by real-time polymerase chain reaction (qRT-PCR) on selected cases. "Hot-spot" mutations were screened for on EGFR, c-KIT, PDGFR alpha, and PDGFR-beta genes, by sequencing. All analysis was executed from formalin-fixed, paraffin-embedded specimens. Immunohistochemical overexpression of 2 or more tyrosine kinase receptors was observed in 18 of 28 tumors (64%), whereas only 5 tumors were consistently negative. Gene expression profiles were concordant with immunohistochemical overexpression in only 1 tumor, which displayed both high mRNA levels and specific immunoreactivity for PDGFR-alpha, and PDGFR-beta. No activating mutations were found on the tumors included in the study. This study confirms that TKRs expression is frequently observed in ESS. Considering that the responsiveness to tyrosine kinase inhibitors is known to be related to the presence of specific activating mutations or gene over-expression, which are not detectable in ESS, TKRs immunohistochemical over-expression alone should not be considered as a reliable marker for targeted therapies in ESS. Specific post-translational abnormalities, responsible for activation of TKRs, should be further investigated. PMID- 23018216 TI - Prevalence of loss of expression of DNA mismatch repair proteins in primary epithelial ovarian tumors. AB - Although different histologic subtypes of epithelial ovarian tumors have long been recognized, their molecular abnormalities have not been fully defined. We examined the prevalence of DNA mismatch repair (MMR) protein loss in these tumors. Tissue microarrays (TMA) of suspected ovarian carcinomas were stained for hMLH1, hMSH2, hMSH6, and hPMS2 and scored separately by 2 groups of investigators. Loss of staining (negative) or discrepant staining results on TMA were verified on whole-section slides. Intact (positive) staining results were also verified for an additional 25 randomly selected cases. Clinical data for cases demonstrating MMR protein loss were collected. A second set of TMA composed purely of mucinous tumors was also stained for antibodies to MMR proteins and scored by 1 group of investigators. TMA was an effective method for screening a large number of ovarian tumors for MMR protein expression, with a sensitivity of 100% for all 4 MMR proteins, and a specificity of 22.2%-53.8% for different MMR proteins. Of the primary epithelial tumors of the ovary, loss of expression of MMR proteins was significantly more common in the endometriosis-associated carcinomas (7/69; 10.1%) than in high-grade serous carcinomas (2/182; 1.1%): P=0.0021. The former group also showed more frequent loss of MMR proteins compared with mucinous intestinal-type carcinomas (0/32; P=0.0940). Cases within the group of endometriosis-associated carcinomas were endometrioid (2/29 cases), clear cell (1/27 cases), undifferentiated (1/8 cases), and mixed carcinomas with an endometrioid, clear cell, and/or undifferentiated component (3/5 cases). No loss of MMR protein expression was identified in epithelial tumors of other histologic subtypes. Our study demonstrated the loss of MMR protein expression in 10.1% of endometriosis-associated ovarian carcinomas. These results raise the possibility of selective screening for Lynch syndrome in patients with these types of ovarian carcinoma. PMID- 23018217 TI - Foreign body reaction after laparoscopic oxiplex administration mimicking peritoneal adenomucinosis: a potential pitfall in frozen section. PMID- 23018218 TI - Comparison of primary and recurrent adult granulosa cell tumors. PMID- 23018220 TI - Extramedullary hematopoiesis involving uterus, fallopian tubes, and ovaries, mimicking bilateral tuboovarian abscesses. AB - Extramedullary hematopoiesis (EMH) is normal during fetal life, but after birth, the presence of EMH is considered to be abnormal. The most common sites for EMH are the liver, the spleen, and paraspinal regions of the thorax; however, it has been reported to involve virtually any organ or tissue. To our knowledge, this is the first reported case of EMH involving the entire upper genital tract, including the uterus, fallopian tubes, and ovaries. A 43-yr-old African American woman presented with a tender pelvic mass and a markedly elevated white blood cell count. Imaging was consistent with bilateral tuboovarian abscesses. Laparotomy and removal of uterus, tubes, and ovaries and bone marrow biopsy confirmed chronic myelogenous leukemia in the chronic phase and EMH in the cervix, endometrium, and ovaries, and no evidence of infection. We believe this to be the first reported case of EMH involving all organs of the upper genital tract presenting in a patient who has chronic myelogenous leukemia but not in blast crisis. This case illustrates the importance of a broad differential diagnosis when managing a patient with a pelvic mass and the value of a multidisciplinary team approach. PMID- 23018219 TI - Endometrial morphology after treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate. AB - Selective progesterone receptor modulators (SPRMs) have beneficial effects in reducing the size of uterine fibroids and the amount of bleeding, but their endometrial effects have not been seen with other agents. This report describes the morphology of the endometrium after 3 mo of treatment with the SPRM, ulipristal acetate (UPA). In 2 Phase III randomized double-blind controlled clinical trials, 546 patients with uterine myomas were treated with 5 or 10 mg of UPA daily for 13 wk or placebo or gonadotropin-releasing hormone agonist. Endometrial biopsies were taken at screening, end of treatment (13 wk), and after treatment-free follow-up (38 wk). Biopsies were assessed independently by 3 pathologists according to a preset morphologic scheme. After 13 wk, the UPA treated endometrium showed altered architectural glandular features including extensive cystic dilatation. The glandular epithelium appeared inactive or contained abortive subnuclear vacuolization, occasional mitoses, and apoptosis. Abnormal stromal vessels were commonly seen. There was a high level of agreement between pathologists on the presence or the absence of nonphysiological changes. One case of hyperplasia without atypia and 4 polyps were seen at 13 wk of UPA treatment. Six months after treatment, the endometrium returned to normal histology in the majority of the patients, with 1 polyp and no cases of hyperplasia in the UPA-treated groups, and 2 hyperplasias (1 with and 1 without atypia) in the placebo or the gonadotropin-releasing hormone-agonist groups. Mild reversible thickening of the endometrium occurs in a minority of cases. It is important that pathologists are aware of the spectrum of changes induced by SPRMs to avoid misdiagnoses of endometrial hyperplasia or polyps. PMID- 23018221 TI - Clinicopathologic and immunohistochemical features of ovarian clear cell carcinomas in comparison with type I and type II tumors. AB - Two types of ovarian carcinomas are distinguished with respect to morphology, biology, and clinical course, and are designated as Type I and Type II tumors. However, placement of clear cell carcinomas into one of these 2 groups has been problematic as they exhibit morphologic, molecular, and clinical features that do not entirely resemble either Type I or Type II tumors. The present study aimed at better elucidating the clinicopathologic and immunohistochemical features of clear cell carcinomas, in comparison with the 2 main broad categories. To this end, a panel of classic clinicopathologic and immunohistochemical parameters, including estrogen receptor alpha (ERalpha), ERbeta, progesterone receptor, Ki67, p53, and HER2/neu was evaluated in 71 Type I, 157 Type II, and 21 clear cell carcinomas. Overall, findings from the present study support the idea that ovarian clear cell carcinomas are neither Type I nor Type II carcinomas of the ovary; indeed, results obtained showed that similarities between clear cell carcinomas and Type I were limited to the patient's age, tumor dimension, incidence of lymph node and extranodal metastases, and p53 labeling index, whereas the patient's age and incidence of extranodal metastases were the only parameters comparable with the Type II group. The hormonal receptor profile of clear cell carcinomas was characterized by low expression of nuclear ERalpha and progesterone receptor, and by almost exclusively nuclear ERbeta immunopositivity, features significantly different from both Type I and II tumors. Finally, the percentage of HER2/neu-positive samples in clear cell carcinomas was 10- and 2.5 fold higher than Type I and Type II ovarian tumors, respectively. In conclusion, our study provides insights into clear cell carcinoma that could help in explaining its unique prognostic features, and, eventually, in orienting toward new therapeutic options. PMID- 23018222 TI - Adjunctive HPV in-situ hybridization (ISH) assay as an aid in the diagnosis of cervical intraepithelial neoplasia in cervical tissue specimens: an analytical and functional characterization. AB - The purpose of this study was to develop and analytically and functionally validate a new human papillomavirus (HPV) in-situ hybridization (ISH) assay and to determine whether the use of this assay combined with hemotoxylin and eosin (H&E) staining could potentially improve the diagnostic accuracy of interpreting cervical intraepithelial neoplasia (CIN) in human cervical tissue specimens. An automated HPV ISH assay was developed using probes that targeted the broad spectrum of HPV genotypes most commonly associated with CIN. In an exploratory study, tissue sections (n=118) were stained with H&E alone and H&E with HPV ISH and evaluated by 6 general surgical pathologists. Results were compared with diagnoses established by expert pathologists on H&E alone. The change in specificity (diagnosis of no-CIN) and sensitivity (diagnosis of CIN) using H&E plus HPV versus H&E alone was determined. The HPV ISH assay detected 21 HPV genotypes and demonstrated no cross-reactivity to Epstein-Barr virus, cytomegalovirus, herpes simplex virus (HSV)-1, HSV-2, or human placental DNA. The assay detected HPV in a range of 1 to 600 copies on CaSki, HeLa, and SiHa xenografts. Use of this assay with H&E staining improved the average diagnostic specificity of the surgical pathologists from 68.5% to 89.9% (P<0.001), with fewer false-positive CIN 1 results (122 vs. 39). The diagnostic sensitivity was similar for assessments made with H&E alone and those made with HPV plus H&E (93.1% vs. 93.6%). In conclusion, a new automated broad-spectrum HPV ISH assay combined with H&E-stained slides contributed to better ascertainment of CIN than H&E staining alone. PMID- 23018223 TI - Minutes of the annual business meeting of International Society of Gynecological Pathologists (ISGyP), March 18, 2012, Vancouver Convention Center, Vancouver. PMID- 23018225 TI - Can social capital contribute to the improvement of oral health? PMID- 23018226 TI - Risk indicators for tooth loss in adult workers. AB - Tooth loss continues to be a prevalent condition in Brazilian adults and elderly individuals. The aim of this cross-sectional study, conducted among workers in a wholesale grocery chain in the State of Sao Paulo, was to identify risk indicators for tooth loss in adults. The presence of caries and periodontal status were examined in 387 adults aged 20-64 years, according to World Health Organization criteria. Two outcomes were analyzed: loss of one or more teeth, and loss of four or more teeth. Independent variables analyzed were demographic and socioeconomic factors, clinical conditions, use of dental services, and self perceived oral health. Poisson regression models were used for multivariate statistical analysis. Participants were missing a mean of 5.38 teeth, and 76.9% (n = 297) had lost at least one tooth; the most frequently lost teeth were permanent molars. Older age and the presence of visible dental biofilm were associated significantly with the two tooth loss outcomes (p < 0.05). Individuals who had visited the dentist 3 or more years previously showed a lower prevalence of tooth loss (prevalence ratio = 0.79; 95% confidence interval, 0.68-0.91). Those with lower household incomes were significantly more likely to have lost four or more teeth (prevalence ratio = 1.35; 95% confidence interval, 1.07-1.70). Study results indicated that age and dental biofilm were risk indicators for tooth loss, independently of socioeconomic factors. These risk indicators should be considered when planning oral health programs for adults. PMID- 23018227 TI - Influence of delayed pouring on irreversible hydrocolloid properties. AB - The aim of this study was to evaluate the physical properties of irreversible hydrocolloid materials poured immediately and after different storage periods. Four alginates were tested: Color Change (Cavex); Hydrogum (Zhermack); Hydrogum 5 (Zhermack); and Hydro Print Premium (Coltene). Their physical properties, including the recovery from deformation (n = 3), compressive strength (n = 3), and detail reproduction and gypsum compatibility (n = 3), were analyzed according to ANSI/ADA specification no. 18. Specimens were stored at 23oC and humidity and were then poured with gypsum immediately and after 1, 2, 3, 4, and 5 days. The data were analyzed by two-way analysis of variance (ANOVA) and Tukey's test at p < 0.05. All of the alginate impression materials tested exhibited detail reproduction and gypsum compatibility at all times. Hydro Print Premium and Hydrogum 5 showed recovery from deformation, as established by ANSI/ADA specification no. 18, after 5 days of storage. As the storage time increased, the compressive strength values also increased. Considering the properties of compounds' recovery from deformation, compressive strength, and detail reproduction and gypsum compatibility, irreversible hydrocolloids should be poured immediately. PMID- 23018228 TI - Effect of desensitizing toothpastes on dentin. AB - The objective of this study was to analyze the effects of toothbrushing with desensitizing toothpastes on dentin permeability and dentinal tubule occlusion. Fifty rats provided two hundred incisor teeth divided into five groups: DW, brushed with distilled water (control); FT, brushed with fluoride toothpaste; SCT, brushed with strontium chloride toothpaste; PCT, brushed with potassium citrate toothpaste; and PNT, brushed with potassium nitrate toothpaste. Cavities were prepared to expose the dentinal tubules, and the incisor teeth were brushed using the experimental agents. After each treatment, Evans blue dye solution was applied to the teeth. Dentin permeability was analyzed using scanning electron microscopy and energy-dispersive X-rays (EDX). There were significant differences (p < 0.0001, ANOVA) among the groups regarding dentin permeability, number of dentinal tubules, diameter of dentinal tubules, and opened tubular area. In the SCT, PCT and PNT groups, opened and partially occluded tubules, deposits, and a few smear layers were observed. In the DW and FT groups, most of the dentinal tubules were open, with no deposits or smear layers on the dentin. EDX revealed peaks of calcium and phosphorus in all of the groups, as well as traces of strontium in the SCT group and of potassium in the PCT and PNT groups. Desensitizing toothpaste decreased dentin permeability, although it produced only partial dentin tubule occlusion. PMID- 23018229 TI - Effect of time of extraction on the biocompatibility of endodontic sealers with primary human fibroblasts. AB - The aim of this work was to evaluate the effects of different times of extraction on the cytotoxicity of six representatives of different root canal sealer groups Real Seal SE, AH Plus, GuttaFlow, Sealapex, Roth 801, and ThermaSeal Plus-with human gingival fibroblasts. The materials were prepared according to manufacturers' specifications, and were incubated in culture medium (DMEM) at 37oC for 1, 7, 14, 21, and 28 days, with daily washing, to simulate periodontal ligament clearance. Human fibroblasts were exposed to the final extracts at 24 hours, and cell viability was determined by MTT assay, with exposure to unconditioned DMEM as a negative control. Statistical analysis comparing cytotoxicities at each exposure time was performed by ANOVA with Scheffe adjustment for multiple comparisons at a 95% confidence level. Results indicated that GuttaFlow was significantly less cytotoxic than all other sealers (p < 0.05) at 1 day of extraction. After 7 days of extraction, cell viability for GuttaFlow was significantly increased as compared with that of all groups except sealer AH Plus. At day 14, cytotoxicity of Sealapex was significantly higher than that of all other sealers (p < 0.05). At days 21 and 28, there were no significant differences in cytotoxicity among sealer groups. All materials presented some level of cytotoxicity to fibroblasts, while GuttaFlow was the least cytotoxic sealer tested. However, the cytotoxicity of all materials seemed to decrease similarly in a time-dependent manner. PMID- 23018230 TI - Detection and enumeration of periodontopathogenic bacteria in subgingival biofilm of pregnant women. AB - The aim of this study was to use the fluorescence in situ hybridization (FISH) technique to test the hypothesis of qualitative and quantitative differences of 8 periodontopathogens between pregnant and non-pregnant women. This cross-sectional study included 20 pregnant women in their second trimester of pregnancy and 20 non-pregnant women. Probing depth, bleeding on probing, clinical attachment level, and presence of calculus were recorded. Subgingival plaque samples were collected and the FISH technique identified the presence and numbers of Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Campylobacter rectus, Porphyromonas gingivalis, Treponema denticola, Fusobacterium nucleatum, Prevotella intermedia and Prevotella nigrescens. The Mann-Whitney U-test was applied to compare the data between the two groups. The mean age, ethnicity, marital status, education, and economic level in both groups were similar. The clinical parameters showed no significant differences between pregnant and non pregnant women. The numbers of subgingival periodontopathogens were not found to be significantly different between groups, despite the higher mean counts of P. intermedia in pregnant women. Colonization patterns of the different bacteria most commonly associated with periodontal disease were not different in the subgingival plaque of pregnant and non-pregnant women. PMID- 23018231 TI - Hausdorff Distance evaluation of orthodontic accessories' streaking artifacts in 3D model superimposition. AB - The aim of this study was to determine whether image artifacts caused by orthodontic metal accessories interfere with the accuracy of 3D CBCT model superimposition. A human dry skull was subjected three times to a CBCT scan: at first without orthodontic brackets (T1), then with stainless steel brackets bonded without (T2) and with orthodontic arch wires (T3) inserted into the brackets' slots. The registration of image surfaces and the superimposition of 3D models were performed. Within-subject surface distances between T1-T2, T1-T3 and T2-T3 were computed and calculated for comparison among the three data sets. The minimum and maximum Hausdorff Distance units (HDu) computed between the corresponding data points of the T1 and T2 CBCT 3D surface images were 0.000000 and 0.049280 HDu, respectively, and the mean distance was 0.002497 HDu. The minimum and maximum Hausdorff Distances between T1 and T3 were 0.000000 and 0.047440 HDu, respectively, with a mean distance of 0.002585 HDu. In the comparison between T2 and T3, the minimum, maximum and mean Hausdorff Distances were 0.000000, 0.025616 and 0.000347 HDu, respectively. In the current study, the image artifacts caused by metal orthodontic accessories did not compromise the accuracy of the 3D model superimposition. Color-coded maps of overlaid structures complemented the computed Hausdorff Distances and demonstrated a precise fusion between the data sets. PMID- 23018232 TI - Socioeconomic and clinical factors associated with traumatic dental injuries in Brazilian preschool children. AB - The aim of this paper was to assess the epidemiology of traumatic dental injury (TDI) in preschool children and its relation to socioeconomic and clinical factors. This study was carried out in Santa Maria, Brazil, during National Children's Vaccination Day, and 441 children aged 12 to 59 months were included. Data about socioeconomic status were collected through a semi-structured questionnaire administered to parents. Calibrated examiners evaluated the prevalence of TDI, overjet, and lip coverage. Data were analyzed with a Poisson regression model (PR; 95% confidence intervals). The TDI prevalence was 31.7%. The maxillary central incisors were the most frequently traumatized teeth. The most common TDI was enamel fracture. No association was found between TDI prevalence and the socioeconomic status of children. After adjustments were performed, the eldest children with an overjet > 3 mm were more likely to have TDI than their counterparts. The data indicated a high prevalence of TDI. Only overjet was a strong predictor for TDI, whereas socioeconomic factors were not associated with TDI in this age group. PMID- 23018233 TI - Clopidogrel two doses comparative 1-year assessment of safety and efficacy (COMPASS) study in Japanese patients with ischemic stroke. AB - BACKGROUND: Clopidogrel 75 mg once daily is licensed in Japan for the prevention of recurrent ischemic cerebrovascular events in adults as the usual dosage. However, a lower dose (50 mg) is an option in patients at an increased risk of bleeding depending on age, body weight and symptoms. This study compared the safety of both 75- and 50-mg doses of clopidogrel in patients with noncardioembolic ischemic stroke. METHODS: This was a double-blind, double-dummy postmarketing clinical trial carried out across 118 Japanese institutions. Patients with an episode of noncardioembolic ischemic stroke at least 8 days prior to randomization, who were aged <75 years or had a body weight >50 kg were randomized to 50 or 75 mg clopidogrel once daily for 52 weeks. The primary endpoint was the incidence of bleeding adverse events. The secondary safety endpoints included the incidence of serious adverse events, serious bleeding adverse events and other prespecified adverse events. The secondary efficacy endpoint was the incidence of vascular events, including ischemic stroke, myocardial infarction, and peripheral artery disease. RESULTS: A total of 1,110 patients were randomized to clopidogrel 50 mg (n = 558) or 75 mg (n = 552). No significant difference between the groups was detected in the incidence of bleeding adverse events, which was 14.0 and 16.5% in the clopidogrel 50- and 75 mg groups, respectively (hazard ratio = 0.831, 95% CI = 0.615-1.124, p = 0.2274). Additionally, there was no statistical difference with respect to any of the secondary safety endpoints. No significant difference between the groups was detected in the incidence of serious adverse events, which was 8.6 and 9.5% in the clopidogrel 50- and 75-mg groups, respectively (hazard ratio = 0.877, 95% CI = 0.597-1.289, p = 0.5035), and there was no significant difference between the groups in the incidence of serious bleeding events, which was 1.7 and 1.5% in the clopidogrel 50- and 75-mg groups, respectively (hazard ratio = 1.240, 95% CI = 0.489-3.142, p = 0.6496). The percentages of intracranial hemorrhage in the 50- and 75-mg groups were 0.18% (1/558) and 0.18% (1/552), respectively. The cumulative incidence of vascular events was somewhat lower in the 75-mg group, but was not statistically different (2.6 vs. 3.8%; p = 0.4118). CONCLUSIONS: Clopidogrel 75 mg provides a clinically acceptable safety profile and suggests better clinical benefit as compared to clopidogrel 50 mg for the secondary prevention of ischemic stroke in Japanese patients who are <75 years old with a body weight >50 kg, considering the balance of safety and efficacy on this trial. PMID- 23018234 TI - The NAD metabolome--a key determinant of cancer cell biology. AB - NAD is a vital molecule in all organisms. It is a key component of both energy and signal transduction--processes that undergo crucial changes in cancer cells. NAD(+)-dependent signalling pathways are many and varied, and they regulate fundamental events such as transcription, DNA repair, cell cycle progression, apoptosis and metabolism. Many of these processes have been linked to cancer development. Given that NAD(+)-dependent signalling reactions involve the degradation of the molecule, permanent nucleotide resynthesis through different biosynthetic pathways is crucial for incessant cancer cell proliferation. This necessity supports the targeting of NAD metabolism as a new therapeutic concept for cancer treatment. PMID- 23018236 TI - Advances in osteoimmunology: pathophysiologic concepts and treatment opportunities. AB - Osteoimmunology is an emerging research area that deals with the mutual interactions between bone and the immune system. Osteoclasts have long been the center of attention in osteoimmunological research due to their hematopoietic origin and strong activation through cytokines. However, also the osteoclast's opponent - the osteoblast - has recently sought the spotlight, and novel functions of its descendant - the osteocyte - have been unraveled. A considerable number of investigations carried out over the past decade have identified critical proteins with osteoimmune functions including the pro-osteoclastic cytokine receptor activator of NF-KB ligand and inhibitors of the pro osteoblastic Wnt signaling pathway. These discoveries have also led to the development of targeted therapies to counteract not only inflammation-induced bone loss but also postmenopausal osteoporosis and osteoporosis associated with aging. PMID- 23018237 TI - Genes promoting and disturbing testis development. AB - Mammals have an XX/XY sex chromosomal sex determination system in which males represent the heterogametic sex. The Y-linked gene, SRY, determines sex by inducing the undifferentiated, bipotential gonads to differentiate as testes, which produce androgens and promote in this way the development of a male phenotype. Thus, in mammals, sex determination can be equated to testis determination, which involves several important cell processes, including Sertoli cell differentiation, mesonephric cell migration, testis cord formation, testis specific vascularization, and myoid and Leydig cell differentiation. Many genes are currently known to be involved in testis development. Some of them, including SF1, WT1, GATA4 and FOG2, are necessary for the formation of the bipotential, undifferentiated gonad but also have important roles in testis differentiation. Others can be considered testis-promoting, differentaition and/or maintenance genes: these include SRY, SOX9, FGF9, PTGDS, SOX8, SOX3, NR0B1, PDGFRa, DMRT1, AMH, NGF, NTF3 and NGFR as the most important examples. Finally, there is a smaller group of genes which are involved in ovarian development and which can cause aberrant testis development if mutated, including RSPO1, WNT4, CTNNB1, FST, BMP2 and FOXL2. In this paper, we review our current knowledge on the function, spatio-temporal expression pattern and mutant sexual phenotypes associated with these genes, and discuss the various roles they play in gonad development. PMID- 23018238 TI - IQGAP1: A microtubule-microfilament scaffolding protein with multiple roles in nerve cell development and synaptic plasticity. AB - In this article, we review our current understanding of the biology of IQ domain containing GTPase-Activating Protein 1, IQGAP1, a scaffolding protein with multiple binding partners, which is widely expressed among different cell types, including neurons, and capable of linking Rho-GTPase signaling with cytosleletal elements and environmental cues. Interestingly, a series of recent studies suggest that IQGAP family members have an important role in neuronal development, synaptic plasticity and nervous system disorders involving alterations in spine density. PMID- 23018239 TI - Rho GTPases and Nox dependent ROS production in skin. Is there a connection? AB - Rho GTPases are a family of small GTP binding proteins most commonly known for the regulation of many cellular processes, including actin cytoskeleton re organisation, cell proliferation, signal transduction and regulation of apoptosis. Additionally, a link between Rho GTPases and reactive oxygen species (ROS) has been shown. In line with the growing interest in the role of ROS in cell biology, the relevance of this connection is becoming increasingly clearer. ROS production is classically associated with oxidative metabolic pathways (e.g. respiratory chain, arachidonic acid). During these metabolic pathways, ROS are produced as by-products and these can be potentially toxic. However, numerous cell types contain dedicated enzymatic complexes, i.e., NADPH oxidase (Nox) complexes, for regulated production of ROS. This regulated production of ROS seems to be important for a number of fundamental cell biological processes, including cell growth, differentiation, migration, angiogenesis, aimed at maintaining tissue homeostasis. Data suggests that skin cells are capable of a regulated ROS production via Nox complexes. Members of the Rho GTPase family have been found to play a central regulatory role in Nox activity. In the present review we will focus on the involvement of Rho GTPases in regulated production of ROS with special emphasis on the skin. We will also discuss the possibility that some in vivo effects of the deletion of members of the Rho GTPase family in skin cells could potentially be linked to a reduced ability of regulated ROS production. PMID- 23018240 TI - Review of renal oncocytosis (multiple oncocytic lesions) with focus on clinical and pathobiological aspects. AB - Renal oncocytosis is a recently established disease entity characterized by numerous oncocytic tumors and diffuse involvement of oncocytic changes in renal parenchymal epithelia. In this article, we review this disease with a focus on its clinical and pathobiological aspects. Clinically, renal oncocytosis may occur in a sporadic form without any underlying disease or may be associated with chronic renal failure/long-term hemodialysis. However, Birt-Hogg-Dube syndrome, characterized by skin tumors such as fibrofolliculoma or trichodiscoma, pulmonary lesions including bullae and spontaneous pneumothorax, and renal tumors should be evaluated in the differential diagnosis. The disease can develop either unilaterally or bilaterally. The involved renal parenchyma contains several to multiple brownish-colored nodules of varying size and is entirely replaced by lesions at the overt stage. Histologically, oncocytic tumors in both the dominant mass and smaller lesions encompass so-called hybrid tumor, chromophobe renal cell carcinoma (RCC), and renal oncocytoma (RO). Regarding renal parenchymal abnormalities, infiltrative growth of oncocytic cells, cortical cysts with oncocytic features, or extensive oncocytic change in non-neoplastic tubules can also be observed. Histochemical, immunohistochemical, and molecular genetic features of chromophobe RCC and RO arising in the setting of renal oncocytosis are generally identical to those in the sporadic type. However, hybrid tumors seem to be histologically distinct from chromophobe RCC and RO. In FISH analyses of some hybrid tumors, a gain of chromosomes 1, 2, 6, 10, and 17 was identified. In one tumor, no germ line mutation of folliculin gene was identified. Published data show that tumors follow a benign course. Further studies will be necessary to clarify the pathogenesis of renal oncocytosis. PMID- 23018241 TI - Angiotensinergic innervation of the kidney: Localization and relationship with catecholaminergic postganglionic and sensory nerve fibers. AB - We describe an angiotensin (Ang) II-containing innervation of the kidney. Cryosections of rat, pig and human kidneys were investigated for the presence of Ang II-containing nerve fibers using a mouse monoclonal antibody against Ang II (4B3). Co-staining was performed with antibodies against synaptophysin, tyrosine 3-hydroxylase, and dopamine beta-hydroxylase to detect catecholaminergic efferent fibers and against calcitonin gene-related peptide to detect sensory fibers. Tagged secondary antibodies and confocal light or laser scanning microscopy were used for immunofluorescence detection. Ang II-containing nerve fibers were densely present in the renal pelvis, the subepithelial layer of the urothelium, the arterial nervous plexus, and the peritubular interstitium of the cortex and outer medulla. They were infrequent in central veins and the renal capsule and absent within glomeruli and the renal papilla. Ang II-positive fibers represented phenotypic subgroups of catecholaminergic postganglionic or sensory fibers with different morphology and intrarenal distribution compared to their Ang II negative counterparts. The Ang II-positive postganglionic fibers were thicker, produced typically fusiform varicosities and preferentially innervated the outer medulla and periglomerular arterioles. Ang II-negative sensory fibers were highly varicose, prevailing in the pelvis and scarce in the renal periphery compared to the rarely varicose Ang II-positive fibers. Neurons within renal microganglia displayed angiotensinergic, catecholaminergic, or combined phenotypes. Our results suggest that autonomic fibers may be an independent source of intrarenal Ang II acting as a neuropeptide co-transmitter or neuromodulator. The angiotensinergic renal innervation may play a distinct role in the neuronal control of renal sodium reabsorption, vasomotion and renin secretion. PMID- 23018242 TI - Melatonin-synthesizing enzymes and melatonin receptor in rat thyroid cells. AB - Melatonin is an indoleamine with a wide spectrum of biological activities other than transmitting photoperiod information, including antioxidant, oncostatic, anti-aging and immunomodulatory properties. Although melatonin is synthesized mainly in the pineal gland, other tissues have the same capacity. In the present study, we examined whether two key enzymes in melatonin biosynthesis, arylalkylamine Nacetyltransferase (AANAT) and hydroxyindole-O-methyltransferase (HIOMT) and its receptor MT1 are expressed in the two endocrine thyroid cells of the rat, follicular cells and C cells. Reverse transcriptase polymerase chain reaction analyses demonstrated that both AANAT and HIOMT mRNAs are expressed in the rat thyroid C-cells, and MT1 expression has been detected in C cells and follicular cells. Immunofluorescence revealed that AANAT protein is localized in C-cell cytoplasm, and MT1 protein in both cell populations. These findings demonstrate that the rat thyroid expresses AANAT, HIOMT, and its receptor MT1, showing that C cells are the main melatonin-synthesizing sites in the thyroid. This local C-cell-secreted melatonin may protect follicular cells from the oxidative stress inherent to the thyroid gland, and could also have paracrine and autocrine functions. PMID- 23018243 TI - Identification of S100A8 and S100A9 as negative regulators for lymph node metastasis of gastric adenocarcinoma. AB - With increasing therapeutic use of minimally invasive therapy for treatment of early gastric cancer, prediction of lymph node metastasis is important. In search of tissue biomarkers for prediction of lymph node metastasis of gastric adenocarcinoma, we analyzed gastric adenocarcinoma tissue using proteomic methods. We have done 2D-PAGE and MALDI-TOF MS analysis in matched normal and gastric cancer tissues. We also evaluated the clinicopathological significance of expression of S100A8 and S100A9 in gastric adenocarcinoma using a tissue microarray of 218 gastric adenocarcinoma specimens. Cell invasion and migration assay were performed to confirm functional role of S100A8 and S100A9 using small hairpin RNA lentivirus. We identified 8 up-regulated and 5 down-regulated proteins in gastric cancer tissues compared to matched normal mucosa. Of these, expression of S100A8 and S100A9 occurred mainly in stromal cells and inflammatory cells between tumor cells. Correlation was observed between small lesion size, decreased depth of invasion, a tendency to absence of lymphovascular tumor emboli, a decrease in perineural invasion and lymph node metastasis, and expression of stromal S100A8. In addition, increased expression of stromal S100A9 in gastric adenocarcinoma was associated with small lesion size and a decrease in lymph node metastasis. Functional analysis confirmed that down-regulation of S100A8 and S100A9 by small hairpin RNA lentivirus induced an increase of migration and invasion in gastric cancer cell lines. Taken together, these findings suggest that S100A8 and S100A9 are negative regulators of lymph node metastasis of gastric adenocarcinoma and can be used as biomarkers for prediction of lymph node metastasis in gastric adenocarcinoma. PMID- 23018244 TI - Regulation of neuronal and endothelial nitric oxide synthase by anabolic androgenic steroid in skeletal muscles. AB - Anabolic-androgenic steroids (AAS) and exercise share comparable effects on myogenic differentiation, force development, fiber growth and skeletal muscle plasticity. The participation of nitric oxide synthase (NOS) on these effects was only demonstrated in response to exercise. Using immunohistochemistry and western blotting we examined the effect of AAS on the expression of NOS I and III isoforms in three muscles, distinct metabolically and physiologically: soleus (SOL), tibialis anterioris (TA) and gastrocnemius (GAS). Mice with a lipid profile akin to humans were used. Sedentary mice (Sed-C) or exercised, submitted to six-weeks of aerobic treadmill running (one hour/day, 5 days/week) were administered mesterolone (Sed-M and Ex-M, respectively) or gum arabic (vehicle, Ex-C) during the last three weeks, three alternate days per week. Consistently, The TA showed the strongest labeling and the SOL the weakest with NOS III predominating over NOS I. Mesterolone administered to sedentary mice (Sed-C x Sed M) significantly upregulated NOS I in TA and SOL and NOS III in all three muscles. Mesterolone administered to exercised mice (Ex-C x Ex-M) upregulated NOS I in all three muscles and NOS III in TA and SOL. The exercise to mesterolone treated mice (Sed-M x Ex-M) produced a strong increase in NOS I expression in GAS; in contrast it antagonized the mesterolone-induced upregulation of NOS I in TA muscle and NOS III in SOL and GAS. The data show nitric oxide (NO) as a potential signaling mediator of AAS effects in skeletal muscle and that NOS I and NOS III upregulations were muscle phenotype-specific. These may be regarded as an indication of the complex NOS/NO signaling mechanism related with AAS effects vs. metabolic/physiological muscle characteristics. PMID- 23018245 TI - Distribution of exogenous metallothionein following intraperitoneal and intramuscular injection of metallothionein-deficient mice. AB - Metallothionein-I/II (MT-I/II) is a small metal-binding protein with antioxidant and neuroprotective properties, which has been used experimentally as a neurotherapeutic agent in multiple conditions. Therefore it is important to determine whether exogenous MT-I/II is retained in specific organs or expelled from the body following intramuscular and intraperitoneal injection. The distribution of exogenous MT-IIA (the major human MT-I/II isoform) was examined in MT-I/II-deficient mice, by immunohistochemistry of tissue samples and western blotting of urine samples. MT-IIA was detected within epithelial cells of the kidney cortical and medullary tubules within 1 hour of either intramuscular or intraperitoneal injection. Additionally, MT-IIA was detected within the urine at 1 hour after injection, indicating rapid absorbance into the circulation and filtration through the kidney glomerulus. A portion of the intramuscularly injected MT-IIA remained within the muscle for at least 24 hours after injection. No MT-IIA was observed within the liver or the brain after either a single injection or a series of MT-IIA injections. These results are consistent with earlier reports that exogenously administered MT-IIA does not cross the intact blood-brain barrier, although a receptor for MT-I/II (megalin) is present in the choroid plexus. We postulate that due to losses through the urine, circulating MT IIA levels drop rapidly after injection and do not permit transport across the choroid plexus. Peptide analogues of MT-I/II with similar neuroactive properties (emtins) may be more suited for CNS delivery. PMID- 23018246 TI - Experimental diabetes modulates collagen remodelling of joints in rats. AB - The aim of this study was to evaluate extracellular matrix components in articular cartilage, ligaments and synovia in an experimental model of diabetes. Young Wistar rats were divided into a streptozotocin-induced (STZ; 35 mg/kg) diabetic group (DG; n=15) and a control group (CG; n=15). Weight, blood glucose and plasma anti-carboxymethyllysine were measured 70 days after STZ infusions. Knee joints, patellar ligaments, and lateral and medial collateral ligaments were isolated and stained with hematoxylin-eosin and Picrosirius. The total collagen content was determined by morphometry. Immunofluorescence was employed to evaluate types I, III, and V collagen in ligaments and synovial tissues and types II and XI collagen in cartilage. RESULTS: Higher blood glucose levels and plasma anti-carboxymethyllysine were observed in DG rats when compared to those in CG rats. The final weight was significantly lower in the DG rats than in the CG rats. Histomorphometric evaluation depicted a small quantity of collagen fibers in ligaments and articular cartilage in DG rats, as well as increased collagen in synovial tissue. There was a decrease in cartilage proteoglycans in DG rats when compared with CG rats. Immunofluorescence staining revealed an increase of collagen III and V in ligaments, collagen XI in cartilage, and collagen I in synovial tissue of DG rats compared with CG rats. CONCLUSION: The ligaments, cartilage and synovia are highly affected following STZ-induced diabetes in rats, due the remodeling of collagen types in these tissues. This process may promote the degradation of the extracellular matrix, thus compromising joint function. Our data may help to better understand the pathogenesis of joint involvement related to diabetes. PMID- 23018247 TI - Clinicopathologic features of molecular subtypes of triple negative breast cancer based on immunohistochemical markers. AB - This study was performed to identify molecular subtypes of triple negative breast carcinoma (TNBC) based on immunohistochemical markers. We prepared a tissue microarray from TNBC specimens of 122 patients and performed immunohistochemical staining for cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR), claudin 3, claudin 4, claudin 7, E-cadherin, androgen receptor (AR), and gammma glutamyltransferase (GGT1). Based on immunoreactivity, tumors were classified into basal-like (CK5/6 positive and/or EGFR positive), molecular apocrine (AR positive and/or GGT1 positive), claudin low (claudin 3, claudin 4, claudin 7 negative and/or E-cadherin negative), mixed (tumors belonging to two or more subtypes), and null (tumors not matching any other subtypes). The TNBC specimens of 122 patients included 27 basal-like (22.1%), 28 claudin low (23.0%), 12 molecular apocrine (9.8%), 23 mixed (18.9%) and 32 null (26.2%) subtype tumors. The molecular apocrine subtype showed the highest percentage of apocrine differentiation and the lowest Ki-67 labeling index (p<0.001 and p=0.040, respectively). In univariate analysis, tumor cell discohesiveness was related with shorter disease free survival (DFS) and overall survival (OS) (p=0.005, and 0.002, respectively). In multivariate analysis, tumor cell discohesiveness was related with shorter OS and CK5/6 positivity (p=0.018), and claudin 7 positivity (p=0.019) was related with shorter DFS. In conclusion, using immunohistochemical staining for CK5/6, EGFR, claudin 3, claudin 4, claudin 7, E-cadherin, AR, and GGT1, we categorized TNBC into a basal-like subtype, a claudin low subtype, a molecular apocrine subtype, a mixed subtype showing characteristics of two different subtypes, and a null subtype not belonging to any of the subtypes identified. PMID- 23018248 TI - Expression of matricellular proteins in human uterine leiomyomas and normal myometrium. AB - Growth of human leiomyomas can probably be initiated as a response to injury, in a way similar to the development of keloids. Among many bioactive molecules, which are implicated in tissue repair, a pivotal role is attributed to matricellular proteins. The aim of the current study was to evaluate the immunohistochemical expression of tenascin-C (TNC), thrombospondin-1 (TSP-1), SPARC/osteonectin and tenascin-X (TNX) in human uterine leiomyomas and normal myometrium. Immunostaining was performed on 33 pairs of paraffin-fixed sections and 9 cell-lines derived from uterine leiomyomas and normal myometrium. Fifteen (45.5%) leiomyomas investigated were positive for TNC, whereas all normal myometrial samples were immunonegative (chi2=19.41; p<0.001). Immunostaining for TSP-1 was observed in 20 (60.6%) uterine fibroids and in 12 (36.4%) control samples (chi2=3.88; p<0.05). The expression of SPARC/osteonectin protein was more frequently found in leiomyomas than in normal myometrium, but this difference was not significant. Apart from one fibroid culture and one myometrial culture, all the others revealed strong TNC immunostaining. Expression of TSP-1 and SPARC/osteonectin was weak to moderate in all established cell-lines. None of the tissues or cell lines investigated showed positive staining for TNX. In conclusion, TSP-1 and TNC are likely to play important roles in the pathogenesis of uterine leiomyomas, presumably affecting cell proliferation and/or extracellular matrix deposition. PMID- 23018249 TI - Increased expression of adenylyl cyclase 3 in pancreatic islets and central nervous system of diabetic Goto-Kakizaki rats: a possible regulatory role in glucose homeostasis. AB - Adenylyl cyclase 3 (AC3) is expressed in pancreatic islets of the Goto-Kakizaki (GK) rat, a spontaneous animal model of type 2 diabetes (T2D), and also exerts genetic effects on the regulation of body weight in man. In addition to pancreatic islets, the central nervous system (CNS) plays an important role in the pathogenesis of T2D and obesity by regulating feeding behavior, body weight and glucose metabolism. In the present study, we have investigated AC3 expression in pancreatic islets, striatum and hypothalamus of GK rats to evaluate its role in the regulation of glucose homeostasis. GK and Wistar rats at the age of 2.5 mo were used. A group of GK rats were implanted with sustained insulin release chips for 15 d. Plasma glucose and serum insulin levels were measured. AC3 gene expression levels in pancreatic islets, striatum and hypothalamus were determined by using real-time RT-PCR. Results indicated that plasma glucose levels in Wistar rats were found to be similar to insulin-treated GK rats, and significantly lower compared with non-treated GK rats. AC3 expression levels in pancreatic islets, striatum and hypothalamus of GK rats were higher compared with Wistar rats, while the levels were intermediate in insulin-treated GK rats. The AC3 expression display patterns between pancreatic islets and striatum-hypothalamus were similar. The present study thus provides the first evidence that AC3 is overexpressed in the regions of striatum and hypothalamus of brain, and similarly in pancreatic islets of GK rats suggesting that AC3 plays a role in regulation of glucose homeostasis via CNS and insulin secretion. PMID- 23018250 TI - The Donor-Risk-Index, ECD-Score and D-MELD-Score all fail to predict short-term outcome after liver transplantation with acceptable sensitivity and specificity. AB - BACKGROUND: Expansion of the donor pool by the use of grafts with extended donor criteria reduces waiting list mortality with an increased risk for graft and patient survival after liver transplantation. This study investigates the ability of the Donor-Risk-Index (DRI), the Extended-Criteria-Donor-Score (ECD-score) and the D-MELD-score to predict early outcome after liver transplantation. MATERIAL/METHODS: 291 consecutive adult liver transplants (01.01.2007-31.12.2010) were analysed in a single centre study with ongoing data collection. Primary study endpoints were 30-day mortality, 3-month mortality, 3-month patient and graft survival and the necessity of acute retransplantation within 30 days. For the primary study endpoints ROC-curve analysis was performed to calculate the sensitivity, specificity, and overall model correctness of the Donor-Risk-Index (DRI), Extended-Criteria-Donor-Score (ECD-score) and the D-MELD-Score as predictive models. Cut-off values were selected with the best Youden index. RESULTS: ROC-curve analysis showed areas under the curve (AUROCs) <0.7 for the DRI, the ECD-Score and the D-MELD-Score as models for the prediction of 30-day mortality, 3-month mortality, 3-month patient survival, 3-month graft survival as well as the necessity of acute retransplantation within 30 days after transplantation with unacceptable low levels of overall model correctness (<62%) and specificity (<56%). CONCLUSIONS: The DRI, the ECD-Score and the D-MELD-Score all fail to predict short-term outcome after liver transplantation with acceptable overall model correctness in a current European transplant setting. PMID- 23018251 TI - Pancreas survival in simultaneous pancreas-kidney and pancreas-after-kidney transplantations: a five-year follow-up report. AB - BACKGROUND: Pancreas transplantation methods, such as simultaneous pancreas kidney (SPK) transplantation and pancreas-after-kidney (PAK) transplantation, have become the most important treatments for patients with type-1 diabetes mellitus (DM)-related end-stage renal diseases (ESRD). The purpose of the study was to compare the clinical results of the pancreas graft in patients after SPK and PAK transplantations and to present the findings of our 5-year follow-up. MATERIAL/METHOD: A total of 55 patients who had kidney and pancreas transplantation between February 2003 and December 2010 were included in the study. The patients were divided into 2 groups based on the timing of the pancreas transplantation: SPK (n=21) and PAK (n=34). RESULT: The patients in the SPK group consisted of 13 males and 8 females, with a mean age of 33.6+/-6.8 years; whereas 25 males and 9 females formed the PAK group, with a mean age of 32.0+/-6.0 years. In the early postoperative period, the SPK group had 3 patients with vascular thrombosis (2 venous, 1 arterial) and the PAK group had 7 patients with thrombosis (4 venous, 3 arterial) (p=0.319). At the end of the 5-year follow up, the patient, kidney and pancreas survival rates in the SPK group were 95.2%, 95.2%, and 61.9% respectively, and the corresponding values in the PAK group were 97%, 91.2%, 61.8% (p=0.382, p=0.504, p=0.927). CONCLUSIONS: We concluded that PAK is just as effective as SPK to prevent the destructive effects of DM when the waiting time for SPK is long and a potential live donor is present. PMID- 23018252 TI - Incidence, pattern and clinical relevance of microbial contamination of preservation fluid in liver transplantation. AB - BACKGROUND: Transmission of pathogens via preservation fluid (PF) is a potential cause of infection among liver transplant recipients. Here, we evaluated the incidence and pattern of microbial contamination of PF and its impact on postoperative graft function after liver transplantation. MATERIAL/METHODS: This longitudinal study included data from 41 primary liver transplantations and 5 re transplantations performed between December 2010 and September 2011. Results of microbiological analyses of 92 PF samples collected before and after the back table procedure were evaluated in order to establish the incidence and pattern of contamination. The impact of positive PF cultures on early graft function and rate of pathogen transmission was assessed. Post-transplant antibiotic protocol was based on piperacillin/tazobactam administration for a minimum of 10 days. RESULTS: The incidence of contamination was 84.8% (39/46), both for samples collected before and after the back-table procedure. Gram-positive low-virulence organisms typical for superficial saprophytic flora, mainly coagulase-negative staphylococci, were predominant. There were no cases of pathogen transmission from PF to the recipient. Positive cultures of PF samples obtained after the back table procedure were associated with significant elevation of aspartate (p=0.034) and alanine aminotransferase (p=0.048) on the first 5 postoperative days. No significant differences were found regarding serum bilirubin concentration (p=0.335) and international normalized ratio (p=0.137). CONCLUSIONS: Despite high incidence of PF contamination, infections caused by pathogens isolated from PF were not observed. However, presence of pathogens in PF might lead to temporary impairment of graft function. PMID- 23018253 TI - The impact of rs231775 (+49AG) CTLA4 gene polymorphism on transplanted kidney function. AB - BACKGROUND: CTLA4 is expressed on the surface of T helper cells and has a suppressive role in the lymphocytes' activation process. It transmits an inhibitory signal to T cells. Studies suggest that the rate of CTLA4 synthesis has a genetic background. There are several polymorphisms of the CTLA4 gene that can influence the expression of this molecule and may therefore affect immune response and allograft function after kidney transplantation. The aim of this study was to examine the impact of the rs231775 (+49AG) CTLA4 gene polymorphism on transplanted kidney function. MATERIAL/METHODS: The study enrolled 269 Caucasian renal transplant recipients (166 males, 103 females, mean age 47.63+/ 12.96 years). Genotyping of the rs231775 (+49AG) CTLA4 gene polymorphism was performed using real-time PCR. RESULTS: The frequency of DGF was higher in the individuals with the G allele of the rs231775 (+49AG) CTLA4 gene polymorphism compared with the carriers of the A allele (GG+AG vs. AA, OR 1.80; 95% CI 1.02 3.18, p=0.05). In multivariate analysis, rs231775 CTLA4 gene polymorphism G allele was an independent factor associated with increased risk of DGF (p=0.03). CONCLUSIONS: Rs231775 (+49AG) CTLA4 gene polymorphism may be associated with increased risk of delayed graft function after kidney transplantation. PMID- 23018254 TI - Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients. AB - BACKGROUND: Calcineurin inhibitor (cyclosporine, CsA) and mTOR inhibitors (sirolimus, SRL) - immunosuppressants used to prevent allograft rejection after renal transplantation - have a narrow therapeutic index and show considerable inter-individual pharmacokinetic differences. Differences in expression and activity of cytochrome P450 (CYP) 3A4 and 3A5 affect these pharmacokinetics; cytochrome activity differences are associated with CYP genetic polymorphisms. MATERIAL/METHODS: This study evaluated the effects of polymorphisms in CYP3A4 and CYP3A5 on immunosuppressive drug-dose adjusted trough blood concentrations. One hundred renal transplant recipients were genotyped for CYP3A4*1B and CYP3A5*3 using PCR-RFLP. Blood concentrations of CsA and SRL were determined by EMIT and HPLC/UV, respectively. RESULTS: The allelic frequencies of CYP3A4*1B and CYP3A5*3 in the study group were 2.5% and 96.5%, respectively. The mean cyclosporine dose in CYP3A4*1/*1B subjects was 455.04+/-128.68 mg/day vs. 261.68+/-64.72 mg/day in CYP3A4*1/*1 subjects (p<0.001). The mean cyclosporine dose-adjusted trough blood concentrations (ng/ml per mg/kg body weight) in CYP3A4*1/*1B subjects were lower than in the CYP3A4*1/*1 group (37.06+/-10.38 vs. 44.63+/-13.99; p<0.218). The mean cyclosporine dose in CYP3A5*1/*3 subjects was 400.65+/-164.97 mg/day vs. 263.52+/-64.39 mg/day in CYP3A5*3/*3 subjects (p<0.022). No association was detected between sirolimus trough blood concentration (C0) or dose requirement, and CYP3A4 or CYP3A5 genotype. CONCLUSIONS: Genetic polymorphisms in CYP3A4 and CYP3A5 may underlie inter-individual differences in cyclosporine pharmacokinetics after renal transplantation. Patients with at least 1 functional CYP3A5*1 or CYP3A4*1B allele require significantly higher doses of cyclosporine to reach target drug levels compared to patients with the CYP3A4*1 or CYP3A5*3 alleles. PMID- 23018255 TI - Renal transplantation outcome in selected recipients with IgA nephropathy as native disease: a bicentric study. AB - BACKGROUND: IgA nephropathy (IgAN) is the causative disease of at most 10% of patients on dialysis and waiting for kidney transplantation. The disease can recur on the graft and it is important to know the exact impact of such recurrence on overall results of transplantation in this subgroup of young recipients. MATERIAL/METHODS: This is a retrospective study done in two closed centers over three decades with a final number of 142 recipients (111 men; median age of 42.2 years at surgery) with biopsy-proven IgAN among 1979 transplanted patients (7.2%). The mean follow-up time was 6.6 years. Recurrence was defined clinically as proteinuria over 1 g/day +/- haematuria and associated with >=1+ IgA mesangial deposits on the graft biopsy. We used Cox regression and Kaplan Meier survival curves to study the event. RESULTS: Patient survival was excellent: 92% at 10 y; graft survival was 53% at 10y and similar to other recipients. The clinico-pathological (full) recurrence (CPR) was observed overall in 25 cases (17.6%) leading to graft loss in 10 cases (7%). The cumulative rate at 10 y of full recurrence and graft loss due to CPR was 21% and 13% respectively. We could not demonstrate any major influence of immunosuppression (induction or maintenance) or other factors on full recurrence. In addition, 10.5% of recipients disclosed only pathological recurrence without significant clinical consequences. CONCLUSIONS: Despite significant prevalence of full recurrence after grafting, the overall good results observed still validate renal transplantation in this subgroup of IgAN recipients. PMID- 23018256 TI - Predictive diagnostic of chronic allograft dysfunction using urinary proteomics analysis. AB - BACKGROUND: Kidney transplant Chronic Allograft Dysfunction (CAD), a major cause of long-term graft failure, is currently diagnosed at a late and irreversible stage by graft biopsies. Our goal was to identify predictive urinary biomarkers of CAD before renal lesions appeared by analysis of the urine proteomic profile. METHODS/METHODS: Twenty-nine urinary samples withdrawn three months post transplant were analyzed by SELDI-TOF technology. CAD development was evaluated by serum creatinine level and confirmed by allograft biopsy one year after transplantation. Comparison of protein profile of both groups revealed 18 biomarkers predictive of CAD occurrence. RESULTS: The biomarker demonstrating the highest diagnostic performance was a protein of 8860 Da that predicted CAD with a sensitivity of 93% and a specificity of 65%. Moreover combination of these biomarkers in two multivariate analyses improved the diagnostic potential of CAD. Relevance of these individual biomarkers and a decisional algorithm constituted of 3 proteins was confirmed in an independent cohort of patients with undetermined CAD status one year post-transplant. CONCLUSIONS: These non invasive biomarkers, detected as soon as three months post-grafting, allowed identification of patients who would develop CAD as late as 4 years after graft. Systematic measurement of these biomarkers would greatly improve the management of immunosuppressive therapy of kidney grafted patients. PMID- 23018257 TI - Influence of conversion from cyclosporine A to tacrolimus on insulin sensitivity assessed by euglicaemic hyperinsulinemic clamp technique in patients after kidney transplantation. AB - BACKGROUND: Recent studies have shown diabetogenic properties of calcineurin inhibitors, but the mechanism of more pronounced diabetogenic effect of tacrolimus (TAC) has not been completely elucidated. The study was designed to answer 2 questions: Does conversion from CyA to TAC influence tissue insulin sensitivity in patients after kidney transplantation? Are there any additional factors influencing insulin sensitivity in these patients? MATERIAL/METHODS: Fifteen non-diabetic kidney transplant recipients, receiving CyA-based regimen were recruited to the study. Enrolled patients required conversion to TAC-based treatment due to CyA adverse effects. Euglicaemic-hyperinsulinemic clamp was performed shortly before and 3 months after conversion from CyA to TAC. RESULTS: Two out of 15 patients developed PTDM shortly after conversion. Mean insulin sensitivity indices: glucose cell uptake (M value) and glucose cell uptake to insulin plasma concentration ratio (M/I) did not change significantly after 3 months of TAC treatment compared to initial values. Significant negative correlations between increase of body mass and both: changes of M values (-0.576; p=0.02) and M/I ratios (-0.819; p<0.001) were observed. Similar correlations were observed between changes of BMI and M values (-0.575; p=0.02) or M/I ratios ( 0.800; p<0.001). A significant positive correlation between changes of eGFR values and M/I ratios (0.591; p=0.03) was noted. CONCLUSIONS: Tissue insulin sensitivity estimated by hyperinsulinemic, euglycaemic clamp technique did not change significantly after conversion from CyA to TAC therapy in patients after kidney transplantation. Weight gain and eGFR decrease are associated with decrease of insulin sensitivity in these patients. PMID- 23018258 TI - Delayed graft function (DGF) after living donor kidney transplantation: a study of possible explanatory factors. AB - BACKGROUND: Delayed graft function (DGF), caused by failure of the kidney to function properly after transplantation, has a lower incidence rate in living donor transplantation compared to deceased donor transplantation. The aim of this study was to investigate the possible risk factors related to DGF in living donor transplantations. MATERIAL/METHOD: A prospective, observational cohort study of patients undergoing living donor renal transplantation was designed. The incidence of DGF was investigated; the urine levels of neutrophil gelatinase associated lipocalin (NGAL) and interleukin 18 (IL-18) were measured on the 1st and 3rd day after transplantation, and the relationships of DGF incidence and potential explanatory factors were studied. RESULT: DGF was observed in 16.2% of patients. Preliminary univariate analyses showed that older donors, retransplantation, previous blood transfusion, and low urinary output could be eligible predictors for DGF. Analysis of the urinary biomarkers revealed an association between DGF incidence with the level of NGAL on the 1st day after transplantation, level of IL 18 on the 3rd post-operative day, and with the differences in urine NGAL levels measured in 2 samplings. Multivariate logistic regression analysis showed that only the differences between the 1st and 3rd days of urinary NGAL levels could remain in the final model. CONCLUSIONS: Although, possibly due to living donor transplantation, none of the patient/donor characteristics could act as an explanatory factor for DGF; however, special attention is still required to target post-operation inflammation and oxidative stress, confirmed by relationship observed between DGF and urine NGAL levels on postoperative days. PMID- 23018259 TI - The utility of amylase and lipase as reliable predictive markers for functioning renal graft. AB - BACKGROUND: The aim of this study was to evaluate the utility of amylase and lipase as reliable predictive markers for functioning renal grafts, either short- or long-term. MATERIAL/METHODS: Serum amylase (Amyl), lipase, creatinine (Cr), creatinine clearance (Cr Cl) and 24-hr proteinuria (Prot) were studied in 190 kidney recipients. The correlation of these outcomes for each parameter was tested. Sensitivity and specificity of the variables were obtained in patients with graft failure (GF) and acute cellular rejection (ACR). RESULTS: Mean follow up was 66.7 month. Amyl and lipase were elevated 67% vs. 45% in GF (N=23); 60% vs. 44% in ACR (N=42) patients and were inversely correlated with Cr Cl (p>.05). Lipase was notably superior to amylase and creatinine; the specificity of lipase (Amyl, Cr) was 87% (59%, 28%). Increases in amylase were more predictive in the presence of mild or moderate kidney failure (33% and 52%, respectively). However, the highest intensity of lipase elevation (39%) was in advanced kidney failure (Cr Cl <30 ml/min). CONCLUSIONS: Serum amylase and lipase should be used as markers monitoring graft function. For early detection of graft dysfunction, amylase seems to be superior to lipase. PMID- 23018260 TI - The significance of oral labial biopsy in hepatic graft-versus-host disease diagnosis in patients following allogeneic hematopoietic stem cell transplantation--a preliminary report. AB - BACKGROUND: Graft-versus-host disease (GvHD) is the most important complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) responsible for increased mortality. Recent studies have discussed the use of oral GvHD screening tests in the diagnosis of systemic GvHD. This is the first study of the significance of oral labial biopsy in diagnosis of hepatic graft-versus-host disease (H-GvHD) following allo-HSCT. MATERIAL/METHODS: Twenty-one patients after alloHSCT were selected: 12 patients with H-GvHD established clinically and in laboratory tests, and 9 patients without features of GvHD (control group). Histopathological and immunohistochemical evaluations of tissue samples included the following: 15 samples of oral mucosa (OM), 19 of lip salivary glands (LSG), and 5 of the liver, were performed in both groups. RESULTS: All patients had clinically normal oral mucosa and 4 patients with H-GvHD manifested with xerostomia symptoms. Histological examination of LSG and/or OM confirmed the GvHD diagnosis in 9 of 12 patients with H-GvHD. The microscopic changes included: mild inflammatory lymphocytic infiltrates and apoptotic bodies in OM, and inflammatory infiltrates of mild degree with minimal CD8+ T cells predominance in the invaded ducts epithelium in LSG. In the control group, 4 of 9 patients had mild chronic inflammation, which did not fulfill the criteria of GvHD. The histopathological image of liver biopsies correlated with the clinical GvHD diagnosis. CONCLUSIONS: The microscopic evaluation of LSG and/or OM biopsy confirms the clinical diagnosis of H-GvHD, regardless of the absence of clinical oral symptoms of GVHD. The histopathological features of oral GvHD may be subtle; the diagnosis requires a clinico-pathological and laboratory approach to exclude the other diseases with similar histopathological features. PMID- 23018261 TI - The attitude and knowledge of intensive care physicians and nurses regarding organ donation in Hungary--it needs to be changed. AB - BACKGROUND: The education of intensive care professionals can influence the number of transplantable organs. The aim of this cross-sectional study is to estimate the attitude and knowledge of intensive care staff as about organ donation. MATERIAL/METHODS: The self-completed questionnaire was completed at the Congress of the Hungarian Society of Anesthesiology and Intensive Therapy in 2011. Data, including attitudes about donation, attendance in an organ donation course, donation activity, self-reported knowledge of donor management, legislation, transplantation, and aftercare were collected from intensive care specialists (n=179) and nurses (n=103). RESULTS: An organ donation course was attended by 53.6% of physicians and 16.7% of nurses (p=0.000); the 59% of doctors and 64.7% of nurses who did not participate in education were not willing to do so. Older staff were more likely to attend the course (p<0.01). Organ donation activity was not influenced by age or type of staff (physician or nurse), but it was higher among staff who attended training (p<0.01). Independently from accepting the presumed consent legislation (91.1%), 66% of intensive care professionals supported the practice of requesting the consent of family for organ retrieval. Self-reported knowledge regarding the Eurotransplant, donor management, the law and ethics of donation, transplantation, and after care for transplanted patients was influenced by age, donation activity, education, type of staff (p<0.01). CONCLUSIONS: Education, including knowledge concerning brain death, donor management and communication with family, needs to be part of the specialist training of intensive care professionals, with a refresher course every fifth year. PMID- 23018262 TI - Effective optimization of living donor kidney transplantation activity ensuring adequate donor safety. AB - Results of kidney transplantation are excellent, but the number of patients on the waiting lists far exceeds the number of available organs. Living kidney donation must be considered as an important part of organ transplantation programmes. In the European Union countries, nearly 20% of all kidney transplants in 2010 were done with organs from living donors. However, the proportion of live donor kidney transplantation between EU countries varies greatly: from 3% to 54% of all kidney transplantations. Multiple initiatives have been undertaken in most of the European countries to increase the number of living donor kidney transplantations. In some countries widening of the donor pool has nearly reached the limits by accepting altruistic donors, paired and group exchanges, and even by performing live donor kidney transplantation in highly immunized recipients. There is a great need to optimize living donor kidney transplantation programmes by using a new strategy of: a. Detailed and adequate medical and psychosocial evaluation, ensuring that the need to increase programme activity will not overshadow the most important principle--donor safety. b. Total removal of all disincentives and financial obstacles that discourage potential donors, and provision of financial coverage for the follow-up. c. Sufficient detailed information about the option of living donor kidney transplantation, its results, and donor safety, delivered to relatives of patients with end-stage renal disease and to the patients themselves. PMID- 23018263 TI - Post-transplantation tertiary hyperparathyroidism. AB - Tertiary hyperparathyroidism is intended as a state of excessive autonomous excretion of parathyroid hormone after longstanding secondary hyperparathyroidism. It is a condition of a severe hyperparathyroidism that persists in the renal recipient despite a successful transplantation. The high levels of parathyroid hormone lead to a worsening of graft function accompanied by systemic symptoms. This article reviews the main aspects related to tertiary hyperparathyroidism from mechanism of pathogenesis to prevention and treatment, suggesting some indications about the best management of patients on a waiting list for kidney transplant. PMID- 23018264 TI - Pregnancy after living related liver transplantation--a report of two cases. AB - BACKGROUND: Living related liver transplantation (LRLT) is currently the only available alternative to orthotopic liver transplantation that is of use in children with acute liver failure. There are reports of long-term survival in liver graft recipients who had been transplanted in childhood. In female patients of reproductive age it may also mean ability to conceive. CASE REPORT: We report 2 cases of successful pregnancies in women after living related liver transplantation. During the 6-month follow-up, no obstetric complications during pregnancy, delivery and postpartum period, and no deterioration of graft function were noted. The neonates were delivered full-term in good general condition, with no signs of intrauterine hypotrophy, congenital malformations or infection, and their psycho-motor development is perfectly normal. CONCLUSIONS: These 2 cases of pregnancies with favorable perinatal outcomes in women after living related liver transplantation, who delivered in our Department with no deterioration of graft function, may be regarded as evidence of full recovery in women after the LRTL procedure. PMID- 23018265 TI - Result of arm-level upper-limb transplantation in two recipients at 19- and 30 month follow-up. AB - BACKGROUND: Arm transplantation (ATx) is a novelty in the field of upper-limb transplantation, with only 7 procedures performed world-wide. CASE REPORT: In this paper we report on early results of unilateral arm transplantation recipients. Patient 1, a 30-year-old man, examined 30 months post-transplant, is able to actively flex the elbow, has 160 degree of ROM in the fingers of the grafted limb, and scored 92 points in the DASH questionnaire and 62 points in the Comprehensive Functional Score System (CFSS). The post-transplant period was complicated with 1 acute rejection episode due to CMV infection, and delayed bony union. Patient 2, a 55-year-old woman, examined 19 months post-transplant, is able to actively flex the elbow, has 180 degree of ROM in the fingers of the grafted limb, and scored 89 points in the DASH questionnaire and 64 points in the Comprehensive Functional Score System (CFSS). CONCLUSIONS: The post-transplant period was complicated with a delayed bony union. The ATx seems to be a valuable reconstructive therapeutic modality. PMID- 23018266 TI - Guillain-Barre syndrome in the course of EBV infection after kidney transplantation--a case report. AB - BACKGROUND: Neurological complications are quite frequent in patients after solid organ transplantation, mostly affecting the central nervous system, and less frequently the peripheral nerves. Guillain-Barre syndrome (GBS), a reactive autoimmune disease of the nervous tissue, is the most common cause of acute polyneuropathy in adults following a viral or bacterial infection. GBS has been also linked to neurotoxic adverse effects of calcineurin inhibitors. This syndrome occurs relatively frequently in patients after bone marrow transplantation, but has been a rare complication in solid organ transplant recipients. Epstein-Barr virus (EBV) infection is relatively common in transplant recipients and in some cases may lead to neurological complications. CASE REPORT: In this report we present an interesting case of a patient who developed GBS in the course of EBV infection 1 year after kidney transplantation. CONCLUSIONS: In patients with rapid development of polyneuropathy after transplantation, Guillain Barre syndrome should be excluded. PMID- 23018267 TI - Emphysematous pyelonephritis in a renal transplant recipient--is it possible to salvage the graft? AB - BACKGROUND: Emphysematous pyelonephritis (EPN) is a rare but potentially devastating complication after renal transplantation. It carries the risk of graft loss and is associated with a high mortality. The majority of cases reported thus far have undergone graft nephrectomy. CASE REPORT: We report the case of a live-related renal transplant recipient who presented 10 years later with fever, graft tenderness and worsening serum creatinine. Computed tomography (CT) revealed emphysematous pyelonephritis, with a large perinephric collection. The case was managed successfully by percutaneous drainage. CONCLUSIONS: Percutaneous drainage is a safe and effective therapeutic modality in cases of EPN in transplant recipients, and allows salvage of the renal allograft in most cases. PMID- 23018268 TI - Acetylcholine, drug reward and substance use disorder treatment: intra- and interindividual striatal and accumbal neuron ensemble heterogeneity may explain apparent discrepant findings. AB - Converging evidence from different independent laboratories suggests that acetylcholine may play an important role in drug reward and that modulation of the cholinergic system may be useful for the treatment of substance use disorders. In this commentary, we try to reconcile apparently discrepant animal behavioral, human behavioral and clinical data with a unifying hypothesis positing that the modulation of drug-versus natural stimuli-mediated reward by cholinergic interneurons in the nucleus accumbens (and the dorsal striatum) is restricted to distinct neuron ensembles that show considerable intra- and interindividual variation with respect to their spatial distribution. The precise targeting of these interindividually variable neuron ensembles would be a prerequisite for a successful pharmacotherapy based on the modulation of the cholinergic system. We also provide experimental data to support our unifying hypothesis. PMID- 23018269 TI - Gadolinium complexes of monophosphinic acid DOTA derivatives conjugated to cyclodextrin scaffolds: efficient MRI contrast agents for higher magnetic fields. AB - Middle-molecular-weight MRI contrast agents based on conjugates of a phosphinic acid DOTA analogue, 1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1-{methyl[(4 aminophenyl)methyl]phosphinic acid} (DO3AP(ABn)), with amino-substituted cyclodextrins were prepared and studied by a variety of physico-chemical methods. The conjugates were formed by reaction of the corresponding isothiocyanate with per-6-amino-alpha/beta-cyclodextrin and were complexed with the Ln(III) ion to get the final complexes, (LnL)(6)-alpha-CD and (LnL)(7)-beta-CD. Solution structure of the complexes was estimated by investigation of the Eu(III) complexes. The Gd(III) conjugate complexes are endowed with a short water residence time (tau(M) ~ 10-15 ns at 298 K) and a high abundance of the twisted square antiprismatic diastereoisomer. They show a high (1)H relaxivity at high fields due to a convenient combination of the fast water exchange rate and the slow rate of the molecular tumbling given by their macromolecular nature. The (1)H relaxation enhancements per molecule of a contrast agent (CA) are very high reaching for a larger (GdL)(7)-beta-CD conjugate ~140 s(-1) mM(-1) and ~100 s(-1) mM(-1) at 25 degrees C and magnetic fields 1.5 T and 3 T, respectively, which is the highest reported longitudinal relaxivity for kinetically stable contrast agents of an intermediate molecular mass (<10 kDa) with one water molecule in the first coordination sphere. PMID- 23018270 TI - Sprayed nanostructured TiO2 films for efficient photocatalytic degradation of textile azo dye. AB - Spray pyrolysis procedure for preparation of nanostructured TiO(2) films with higher photocatalytic effectiveness and longer exploitation life is presented in this study. Thin films of active nanocrystalline TiO(2) were obtained from titanium isopropoxide, stabilized with acetyl acetone and characterized by X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and X-ray diffraction (XRD). The activity of sprayed nanostructured TiO(2) is tested for photocatalytic degradation of Reactive Black 5 dye with concentrations up to 80 ppm. Interesting result of the work is the reduction of toxicity after photocatalytic treatment of RB5 with TiO(2), which was confirmed by the lower percentage of mortality of Artemia salina. It was proved that the film thickness, conditions of post deposition treatment and the type of the substrate affected significantly the photocatalytic reaction. Taking into account that the parameters are interdependent, it is necessary to optimize the preparation conditions in order to synthesize photocatalytic active films. PMID- 23018271 TI - Serum depletion of holo-ceruloplasmin induced by silver ions in vivo reduces uptake of cisplatin. AB - There is an emerging link between extracellular copper concentration and the uptake of cisplatin mediated by copper transporter CTR1 in cell cultures and unicellular eukaryotes. To test the link between extracellular copper level and cisplatin uptake by organs in vivo we used mice with low copper status parameters induced by AgCl-containing diet (Ag-mice). In Ag-mice, serum copper status and liver copper metabolism were characterized. It was shown that the expression level of copper transporter genes and activity of ubiquitous intracellular cuproenzymes were not affected but the level of serum holo-ceruloplasmin was not detectable. Silver was selectively absorbed by liver and accumulated in the mitochondrial matrix. Silver was present in an exchangeable form and was excreted through bile. Ag-mice model is characterized by high reproducibility, reversibility, synchronicity, and definiteness of ceruloplasmin-associated copper deficiency. After cisplatin treatment Ag-mice, as compared to control mice, demonstrated the delay in platinum uptake by organs during first 30 min. This effect was not observed at later time points probably due to cisplatin induced copper release to blood, which resulted in the recovery of copper status. These data allowed us to conclude that cisplatin uptake was coupled to copper transport in vivo. PMID- 23018272 TI - Synthesis, structures and antibacterial activities of benzoylthiourea derivatives and their complexes with cobalt. AB - Four new thiocarbonyl fluorobenzamides and their complexes with cobalt have been synthesized and characterized by elemental analysis, FTIR, and (1)H NMR. Five crystal structures of the thioylbenzamides complexes of Co(PTCB)(3), Co(2FPTCB)(3), Co(4FPTCB)(3), Co(2FMTCB)(2) and Co(4FMTCB)(3) have been determined by X-ray diffraction. The antibacterial properties of these compounds against the bacteria, E. coli, Staphylococcus aureus, B. subtilis, P. aeruginosa, and Shewanella sp. were investigated. The experiments showed that both compounds and the complexes had the antibacterial activities against all of the studied bacteria. The thioylbenzamides had stronger controls for the bacteria of E. coli, S. aureus, B. subtilis and P. aeruginosa than their corresponding cobalt complexes. There was the contrary result against the bacteria of Shewanella sp. The para-substitution of fluorine atom increased antibacterial activities, while fluorine atom was substituted on ortho-benzoyl, the antibacterial activity weakened. The thioylbenzamides linked to piperidine instead of a morpholine group may increase the antibacterial activities. PMID- 23018273 TI - Enhancing the peroxidatic activity of KatG by deletion mutagenesis. AB - Catalase-peroxidase (KatG) enzymes use a peroxidase active site to facilitate robust catalase activity, an ability all other members of its superfamily lack. KatG's have a Met-Tyr-Trp covalent adduct that is essential for catalatic but not peroxidatic turnover. The tyrosine (Y226 in E. coli KatG) is supplied by a large loop (LL1) that is absent from all other plant peroxidases. Elimination of Y226 from the KatG structure, either by site directed mutagenesis (i.e., Y226F KatG) or by deletion of larger portions of LL1 invariably eliminates catalase activity, but deletion variants were substantially more active as peroxidases, up to an order of magnitude. Moreover, the deletion variants were more resistant to H(2)O(2)-dependent inactivation than Y226F KatG. Stopped-flow evaluation of reactions of H(2)O(2) with Y226F KatG and the most peroxidase active deletion variant (KatG[Delta209-228]) produced highly similar rate constants for formation of compounds I and II, and about a four-fold faster formation of compound III for the deletion variant as opposed to Y226F. Conversely, single turnover experiments showed a 60-fold slower return of Y226F KatG to its ferric state in the presence of the exogenous electron donor 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) than was determined for KatG(Delta209-228). Our data suggest that the peroxidatic output of KatG cannot be optimized simply by elimination of catalase activity alone, but also requires modifications that increase electron transfer between exogenous electron donors and the heme prosthetic group. PMID- 23018274 TI - Interaction of [Ru(eta6-p-cym)(H2O)3]2+ with citrate and tricarballate ions in aqueous solution; X-ray crystal structure of novel half-sandwich Ru(II)-citrato complexes. AB - The interaction between [Ru(eta(6)-p-cym)(H(2)O)(3)](2+) and an important low molecular weight serum component, citric acid (citrH(3)), was studied with the aid of combined pH-potentiometric, (1)H NMR, (13)C NMR and electrospray ionization mass spectrometry (ESI-MS) methods in aqueous solution. For comparative purposes propane-1,2,3-tricarboxylic acid (tricarballylic acid, tricH(3)) having no alcoholic-OH group in position 2 was also investigated. Stoichiometries, stability constants and the most plausible solution structures of the complexes formed in the systems were determined. Depending upon the pH, citrate was found to coordinate to the metal ion via [COO(-), COO(-), OH] or [COO(-), COO(-), O(-)] fashion yielding mononuclear complexes with high stability. As a consequence at physiological pH the hydrolysis of the metal ion is completely hindered even at 1:1 metal to ligand ratio. Crucial role of the alcoholic/alcoholate function of the citric acid in [Ru(eta(6)-p cym)(H(2)O)(3)](2+) binding is reflected in the low stability of the species formed with tricarballylic acid. The X-ray crystal structures of [Ru(eta(6)-p cym)(citrH)].H(2)O.CH(3)OH and 2[Ru(eta(6)-p-cym)(citrH)].3H(2)O being the first published structures of an organometallic Ru(II)-citrate and both featuring a [COO(-), COO(-), OH] coordinated ligand, are also reported. PMID- 23018275 TI - Separate FeS scaffold and carrier functions for SufB2C2 and SufA during in vitro maturation of [2Fe2S] Fdx. AB - Iron-sulfur (FeS) clusters are inorganic cofactors required for a variety of biological processes. In vivo biogenesis of FeS clusters proceeds via complex pathways involving multiple protein complexes. In the Suf FeS cluster biogenesis system, SufB may be a scaffold for nascent FeS cluster assembly whereas SufA is proposed to act as either a scaffold or an FeS cluster carrier from the scaffold to target apo-proteins. However, SufB can form multiple stable complexes with other Suf proteins, such as SufB(2)C(2) and SufBC(2)D and the specific functions of these complexes in FeS cluster assembly are not clear. Here we compare the ability of the SufB(2)C(2) and SufBC(2)D complexes as well as SufA to promote in vitro maturation of the [2Fe2S] ferredoxin (Fdx). We found that SufB(2)C(2) was most proficient as a scaffold for de novo assembly of holo-Fdx using sulfide and iron as freely available building blocks while SufA was best at direct transfer of a pre-formed FeS cluster to Fdx. Furthermore, cluster transfer from [4Fe4S] SufB(2)C(2) or SufBC(2)D to Fdx will proceed through a SufA intermediate to Fdx if SufA is present. Finally, addition of ATP repressed cluster transfer from [4Fe4S] SufB(2)C(2) to Fdx and from SufBC(2)D to [2Fe2S] SufA or Fdx. These studies indicate that SufB(2)C(2) can serve as a terminal scaffold to load the SufA FeS cluster carrier for in vitro maturation of [2Fe2S] enzymes like Fdx. This work is the first to systematically compare the cluster transfer rates of a scaffold (SufB) to the transfer rates of a carrier (SufA) under the same conditions to the same target enzyme and is also the first to reconstitute the full transfer pathway (from scaffold to carrier to target enzyme) in a single reaction. PMID- 23018276 TI - A new, bioactive structural motif: Visible light induced DNA photobinding and oxygen independent photocleavage by RuII, RhIII bimetallics. AB - The Ru,Rh bimetallic complexes, [(bpy)(2)Ru(dpp)RhCl(2)(phen)](3+) and [(bpy)(2)Ru(bpm)RhCl(2)(phen)](3+) (bpy=2,2'-bipyridine, dpp=2,3-bis(2 pyridyl)pyrazine, phen=1,10-phenanthroline, and bpm=2,2'-bipyrimidine), couple one ruthenium polyazine light absorber to a cis-Rh(III)Cl(2) center through a dpp or bpm bridging ligand in contrast to the previously studied Ru,Rh,Ru trimetallics. This motif provides a sterically accessible Rh reactive site. These bimetallics are efficient visible light absorbers possessing many advantages compared to the previously reported trimetallics: lower cationic charges, reduced stereoisomerization, and independent variation of terminal ligands at each metal center to modulate properties. The bimetallic systems display efficient visible light induced bioreactivities with DNA. In addition to the known DNA photocleavage in related Ru,Rh,Ru trimetallics, these Ru,Rh bimetallic systems display visible light induced DNA binding. Low lying triplet metal to metal charge transfer ((3)MMCT) excited states provide oxygen independent photoreactivity. This previously unexplored structural motif for DNA modification holds promises in photodynamic therapy and DNA modification schemes. PMID- 23018277 TI - A speciation model of essential trace metal ions in phloem. AB - Phloem sap is the nutrient rich fluid that transports sugars, amino acids and metal ions from leaves to other parts of the plant. A computer model for the speciation of the trace elements Fe(3+), Fe(2+), Cu(2+), Zn(2+), and Mn(2+) in phloem sap has been developed. The literature on phloem has been reviewed to determine the appropriate concentrations for the metal ions, amino acids and carboxylic acids in phloem sap. Stability constants for the metal complexes with these ligands have been selected from the literature. These data have been used with the program ECCLES to calculate the speciation of the trace elements in the phloem sap. The macronutrients Ca(2+) and Mg(2+) were also included in the model. The model indicates that the hexadentate chelating agent nicotianamine is the most important chelating agent in phloem. This ligand binds almost all the Fe(2+), but it binds only 20 to 50% of the other trace elements. The remainder of each trace element is bound primarily by a combination of several amino acids, most importantly glutamic acid (Fe(3+)), cysteine (Zn(2+)) and histidine (Cu(2+)). The carboxylic acids, including citrate, play a minor role in binding Mn(2+) and Fe(3+), but have almost no impact on the speciation of the other trace elements. PMID- 23018278 TI - Easy sample treatment for the determination of enrofloxacin and ciprofloxacin residues in raw bovine milk by capillary electrophoresis. AB - An easy, selective, and sensitive method has been developed for the determination of enrofloxacin (ENR) and its main active metabolite, ciprofloxacin (CIP), in raw bovine milk using CE with UV detection at 268 nm. Milk samples were prepared by a clean-up/extraction procedure based on protein precipitation with hydrochloride acid followed by being defatted by centrifugation and SPE using a hydrophilic lipophilic balance cartridge. Optimum separation was obtained using a 50 mM phosphoric acid at pH 8.4 and the total electrophoretic run time was 6 min. Sample preparation by this method yielded clean extracts with quantitative and consistent mean recoveries from 89 to 97% for CIP and from 93 to 98% for ENR. LODs obtained were lower to the maximum residue limits for these fluoroquinolones. The precision of the ensuing method is acceptable; thus, the RSD for peak area and migration time was less than 8.5 and 0.5% for CIP and 9.9 and 0.9% for ENR, respectively. The results showed that the proposed method was efficient showing good recoveries, sensitivity, and precision for the studied compounds and could be satisfactorily applied in routine analysis for the monitoring of ENR and CIP residues in milk, due to its ruggedness and feasibility demonstrated. PMID- 23018280 TI - First-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer : analysis of the Italian patients enrolled in the SAiL study. AB - BACKGROUND AND OBJECTIVE: First-line bevacizumab-based therapy has been shown to improve outcomes in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The recent international phase IV SAiL study (a Study of Avastin [bevacizumab] in combination with platinum-containing chemotherapy in patients with advanced or recurrent non-squamous cell Lung cancer) evaluated the safety and efficacy of bevacizumab combined with standard chemotherapy regimens in routine clinical practice. Here we report the results of a subanalysis of baseline characteristics and efficacy data for Italian patients enrolled in SAiL. METHODS: In the SAiL study, patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC received bevacizumab (7.5 or 15 mg/kg) every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Efficacy was assessed in terms of time to disease progression (TTP) and overall survival (OS). RESULTS: The Italian intent to-treat population comprised 215 patients from a SAiL population of 2212 patients. At baseline, Italian patients tended to have less advanced disease than the overall population. Thus, the proportion of patients at enrollment with tumour stage IIIb and IV was 23.7 and 76.3 %, respectively, for the Italian population versus 19.7 and 80.3 % for the whole SAiL population. In addition, a higher proportion of Italian patients had an Eastern Cooperative Oncology Group performance status of 0 (72.6 vs. 37.2 %) and the prevalence of co-morbid conditions was lower in Italian patients (59.5 % of Italian patients reported a co-morbid condition and 60.0 % were receiving non-oncological treatment compared with 73.3 and 73.4 %, respectively, of SAiL patients overall). The mean exposures to bevacizumab and to chemotherapy were comparable between the Italian patient group and overall patient population, although cisplatin doublets were more commonly employed in Italian patients whereas carboplatin doublets were more commonly employed in the overall SAiL population. The median TTP and OS times for Italian and SAiL populations were comparable (TTP, 7.8 months vs. 7.8 months; OS, 14.8 months vs. 14.6 months). CONCLUSION: The results of this subanalysis of the SAiL study of bevacizumab treatment in routine clinical practice suggest that Italian oncologists tend to prescribe bevacizumab to a selected population of patients with less advanced disease than is the case in the overall population. Nevertheless, the first-line use of bevacizumab in combination with chemotherapy offers clinical benefits to Italian patients with advanced or recurrent non squamous NSCLC. PMID- 23018281 TI - A 6-week, randomized, multicentre, open-label study comparing efficacy and tolerability of amisulpride at a starting dose of 400 mg/day versus 800 mg/day in patients with acute exacerbations of schizophrenia. AB - BACKGROUND: It has been suggested that neither dose titration nor the use of a loading dose was required for amisulpride and that 800 mg/day could be given from the first day with a low risk of extrapyramidal symptoms (EPS). However, no direct study of the need for dose titration has been conducted. OBJECTIVE: This study aimed to compare the efficacy, tolerability and subjective experience of amisulpride between a group receiving an initial dose of 800 mg/day (AMI-800 group) and a group titrating up from an initial dose of 400 mg/day (AMI-400 group) over a period of 6 weeks. METHODS: A total of 68 patients with acute exacerbations of schizophrenia participated in this 6-week randomized, multicentre, open-label study of amisulpride. Thirty patients were randomly assigned to the group that received an initial dose of 400 mg/day, which was then titrated up during the first 4 weeks following a fixed schedule. Thirty-eight patients were randomly assigned to the group receiving an initial dose of amisulpride 800 mg/day, which they took until the end of the fourth week. During the fifth and sixth weeks, the doses were adjusted flexibly in both groups. Our primary outcome measures were the Clinical Global Impression (CGI) scale and the changes over time in the total and subscale scores of the Positive and Negative Syndrome Scale (PANSS). RESULTS: We found no significant between-group differences in clinical improvement on the CGI and the PANSS. However, when responders were defined as those patients who experienced at least a 30 % reduction in the PANSS total scores obtained at baseline, a higher proportion of those in the AMI-800 group met the criterion for responsiveness from week 4 (week 4: 68.4 % vs 40.0 %, p = 0.02; week 6: 71.1 % vs 43.3 %, p = 0.02). Irrespective of treatment group, significant proportions of patients developed hyperprolactinaemia (86 %) and EPS (35 %). However, no statistically significant differences in the overall incidence of adverse events were observed between the two treatment groups. There were also no group differences in subjective quality of life and attitudes toward antipsychotic medication. CONCLUSION: These results suggest that it may be useful to begin therapy, especially for acute exacerbations of schizophrenia, with an initial dose of amisulpride 800 mg/day to obtain maximal efficacy without any significant side effects. PMID- 23018282 TI - Long-term efficacy of olmesartan medoxomil in Chinese hypertensive patients as assessed by clinic, ambulatory and home blood pressure measurements. AB - BACKGROUND AND OBJECTIVES: There is limited information on the long-term efficacy and safety of olmesartan medoxomil in the management of hypertension in Chinese patients. We therefore conducted the present multicentre, single-arm, prospective, observational study to investigate the 24-week efficacy and safety of olmesartan medoxomil in patients with mild to moderate hypertension. METHODS: Eligible patients (diastolic blood pressure [BP] 90-109 mmHg and systolic BP <180 mmHg off antihypertensive medication) were started on olmesartan medoxomil 20 mg once daily, with the possible up-titration to 40 mg once daily during 24 weeks of follow-up, to control clinic BP to the target level (<140/90 and <130/80 mmHg in diabetes mellitus). In a subset of enrolled patients, 24-h ambulatory and home BP monitoring were also performed. RESULTS: In the intent-to-treat analysis (n = 348), at 24 weeks of follow-up, the mean +/- SD changes from baseline in clinic systolic/diastolic BP were 21.2 +/- 14.2/16.0 +/- 8.8 mmHg (p < 0.001). The proportions of patients who achieved the goal BP for systolic, diastolic and both were 81, 80 and 75 %, respectively. Olmesartan medoxomil also significantly (p < 0.001) reduced systolic/diastolic BP measured at patients' homes by 17.7 +/- 13.1/12.1 +/- 7.9 mmHg from baseline (n = 109), and reduced mean 24-h, daytime and night-time ambulatory BP by 13.3 +/- 16.3/7.6 +/- 9.5 mmHg, 13.9 +/- 17.4/8.0 +/- 10.4 mmHg and 12.3 +/- 18.1/6.8 +/- 10.2 mmHg, respectively (n = 87). Seven (2.0 %) serious adverse events were reported during follow-up. CONCLUSION: In Chinese hypertensive patients, olmesartan medoxomil is efficacious in lowering BP as assessed by three different BP-measuring methods and has an acceptable long term safety and tolerability profile. PMID- 23018283 TI - Evaluation of bioequivalence between clozapine suspension and tablet formulations : a multiple-dose, fed and fasted study. AB - BACKGROUND AND OBJECTIVE: Clozapine is the most effective drug for schizophrenia. A suspension formulation of clozapine for patients who may have difficulty swallowing tablets was approved based on the 1996 US Food and Drug Administration (FDA) Guidance and has been launched in Australia, New Zealand and the UK. The objective of this study was to compare the bioequivalence of a new suspension formulation of clozapine with clozapine tablets (Clozaril((r))). METHODS: The steady-state bioequivalence of a 50-mg/mL clozapine suspension and Clozaril((r)) tablets was compared under fasting and fed conditions in a randomized, multiple dose, two-way crossover study, consistent with the 2005 FDA Bioequivalence Guidance. Adult patients with schizophrenia established on once-daily doses of clozapine were administered Clozaril((r)) tablets or clozapine suspension for 11 days, then switched to the other formulation for the next 11 days. On days 10 and 11 of each period, fasted (day 10) and fed (day 11) pharmacokinetic profiles were obtained over 24 h. RESULTS: Compared with the tablet formulation, point estimates for maximum plasma concentration (C(max)) and area under the plasma concentration-time curve during a dosage interval (tau) [AUCtau] for the suspension formulation were close to 100 %, and all 90 % confidence intervals (CIs) were between 80 % and 125 % under fasted (C(max) 99.91; 90 % CI 94.60, 104.70; AUC(tau) 99.55; 90 % CI 92.40, 100.70) and fed (C(max) 99.72; 90 % CI 93.70, 103.50; AUC(tau) 99.68; 90 % CI 93.40, 101.80) conditions. Food did not affect AUC(tau); however, C(max) was reduced by ~20 %, with a similar magnitude of change for both formulations. Safety/tolerability profiles were similar between the two formulations. CONCLUSION: The tablet and suspension formulations are bioequivalent, with similar safety profiles, under fed and fasted conditions. PMID- 23018284 TI - Diagnosis and management of atrial fibrillation by primary care physicians in Italy : a retrospective, observational analysis. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a heavy burden of morbidity and mortality, mainly due to an increased risk of cerebrovascular events and cardiac failure. Oral anticoagulant (OAC) treatment prevents stroke and systemic thromboembolism in patients with AF and its use is strongly recommended in guidelines. However, its use in this patient group remains limited. Primary care physicians (PCPs) have an important role to play in this context. OBJECTIVE: The primary objective was to estimate prevalence and epidemiological features of AF in the primary care setting, focusing on ischaemic and bleeding risk assessment. A secondary objective was to examine the PCPs' level of adherence to the guidelines for the prevention of thromboembolic risk in these patients. METHODS: This retrospective, observational study was based on data entered by 128 PCPs into the Health Search (HS) Thales database, identifying patients with a diagnosis of AF at the time of the analysis. RESULTS: Out of 167,056 patients analysed, 2,173 (1.3 %) were diagnosed with AF, with 86 % at high risk for ischaemic stroke, according to CHA(2)DS(2) VASc (congestive heart failure, hypertension, age >=75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65-74 years, sex category [female]) stratification. After the diagnosis of AF, 84 % of patients were prescribed OAC treatment. However, at 2 years' follow-up, only 29.6 % were still being treated with OACs. CONCLUSION: The prevalence of AF in this analysis was consistent with previously reported Italian national epidemiological data. Adherence to the European Society of Cardiology AF guidelines by PCPs was low, despite the high levels of stroke risk. At the end of the observation period less than one-third of patients were still on OAC therapy. Awareness of the benefits of OACs in stroke prevention in AF patients needs to be improved. PMID- 23018285 TI - Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Abeta levels in healthy young men. AB - BACKGROUND: The concentration of amyloid beta (Abeta) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of gamma-secretase inhibition. Avagacestat is a selective gamma-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF Abeta concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability. METHODS: This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses. RESULTS: 34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Abeta(1-38), Abeta(1-40) and Abeta(1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups. CONCLUSION: Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Abeta concentrations, suggestive of gamma-secretase inhibition. The results warrant further clinical study in patients with AD. PMID- 23018286 TI - Ceramide expression and cell homeostasis in chronic obstructive pulmonary disease. AB - BACKGROUND: Increased expression of ceramide has been detected in emphysema. Ceramide promotes autophagy and apoptosis, which concur with cellular homeostasis. OBJECTIVES: To determine whether ceramide expression is associated with the development of chronic obstructive pulmonary disease (COPD) and with altered cellular homeostasis in lung parenchyma. METHODS: We studied 10 subjects with severe COPD, 13 with mild/moderate COPD, 11 with idiopathic pulmonary fibrosis (IPF), 12 non-COPD smokers, and 11 nonsmoking controls. The immunoreactivity for ceramide along with markers of autophagy (LC3B), apoptosis (cleaved caspase-3), and cell proliferation (MIB1) was quantified in alveolar walls. RESULTS: Ceramide expression was increased in COPD patients compared with control smokers and was related to the impairment of gas exchange but not to the degree of airflow limitation. In COPD, an important activation of apoptosis and autophagy pathways was observed, particularly in patients with severe disease, that was not counterbalanced by cell proliferation. Upregulation of ceramide was observed even in subjects with IPF in whom activation of apoptosis and autophagy was negligible and cell proliferation was instead the most prominent feature. CONCLUSIONS: Ceramide expression, which is increased in COPD and even more so in IPF, appears to be neither specific nor related to COPD severity, probably representing a broader marker of lung damage. In contrast, apoptosis and autophagy are characteristics of the COPD pathology, particularly in its most severe stage. PMID- 23018287 TI - Efficacy of metronome sound guidance via a phone speaker during dispatcher assisted compression-only cardiopulmonary resuscitation by an untrained layperson: a randomised controlled simulation study using a manikin. AB - AIM: Untrained laypersons should perform compression-only cardiopulmonary resuscitation (COCPR) under a dispatcher's guidance, but the quality of the chest compressions may be suboptimal. We hypothesised that providing metronome sounds via a phone speaker may improve the quality of chest compressions during dispatcher-assisted COCPR (DA-COCPR). METHODS: Untrained laypersons were allocated to either the metronome sound-guided group (MG), who performed DA-COCPR with metronome sounds (110 ticks/min), or the control group (CG), who performed conventional DA-COCPR. The participants of each group performed DA-COCPR for 4 min using a manikin with Skill-Reporter, and the data regarding chest compression quality were collected. RESULTS: The data from 33 cases of DA-COCPR in the MG and 34 cases in the CG were compared. The MG showed a faster compression rate than the CG (111.9 vs 96.7/min; p=0.018). A significantly higher proportion of subjects in the MG performed the DA-COCPR with an accurate chest compression rate (100-120/min) compared with the subjects in the CG (32/33 (97.0%) vs 5/34 (14.7%); p<0.0001). The mean compression depth was not different between the MG and the CG (45.9 vs 46.8 mm; p=0.692). However, a higher proportion of subjects in the MG performed shallow compressions (compression depth <38 mm) compared with subjects in the CG (median % was 69.2 vs 15.7; p=0.035). CONCLUSIONS: Metronome sound guidance during DA-COCPR for the untrained bystanders improved the chest compression rates, but was associated more with shallow compressions than the conventional DA-COCPR in a manikin model. PMID- 23018288 TI - Vomiting should be a prompt predictor of stroke outcome. AB - BACKGROUND: To predict the outcome of stroke at an acute stage is important but still difficult. Vomiting is one of the commonest symptoms in stroke patients. The aim of this study is threefold: first, to examine the percentage of vomiting in each of the three major categories of strokes; second, to investigate the association between vomiting and other characteristics and third, to determine the correlation between vomiting and mortality. METHODS: We investigated the existence or absence of vomiting in stroke patients in the Kyoto prefecture cohort. We compared the characteristics of patients with and without vomiting. We calculated the HR for death in both types of patients, adjusted for age, sex, blood pressure, arrhythmia, tobacco and alcohol use and paresis. RESULTS: Of the 1968 confirmed stroke patients, 1349 (68.5%) had cerebral infarction (CI), 459 (23.3%) had cerebral haemorrhage (CH) and 152 (7.7%) had subarachnoid haemorrhage (SAH). Vomiting was seen in 14.5% of all stroke patients. When subdivided according to stroke type, vomiting was observed in 8.7% of CI, 23.7% of CH and 36.8% of SAH cases. HR for death and 95% CI were 5.06 and 3.26 to 7.84 (p<0.001) when all stroke patients were considered, 5.27 and 2.56 to 10.83 (p<0.001) in CI, 2.82 and 1.33 to 5.99 (p=0.007) in CH and 5.07 and 1.87 to 13.76 (p=0.001) in SAH. CONCLUSIONS: Compared with patients without vomiting, the risk of death was significantly higher in patients with vomiting at the onset of stroke. Vomiting should be an early predictor of the outcome. PMID- 23018289 TI - Brain natriuretic peptide is associated with worsening and mortality in acute stroke patients but adds no prognostic value to clinical predictors of outcome. AB - BACKGROUND: At the present time, the determination of the outcome of stroke patients is based on the analysis of clinical and neuroimaging data. The use of prognostic blood biomarkers could aid in decision-making processes, e.g. admitting patients to specialized stroke units. Although the prognostic role of natriuretic peptides has been studied in heart failure and coronary diseases, the value of brain natriuretic peptide (BNP) is less known within the field of strokes. OBJECTIVE: We aimed to study the relationship between plasma levels of BNP and acute neurological worsening or mortality after stroke in a large cohort of patients (investigating both ischemic and hemorrhagic disease). METHODS: Consecutive stroke patients (ischemic and hemorrhagic) admitted to the Stroke Unit of our University Hospital within 24 h of the onset of symptoms were included. Stroke severity was assessed according to the National Institutes of Health Stroke Scale (NIHSS) at admission and at discharge. Neurological worsening was defined as an increase of 4 or more points in the NIHSS score or death during the patient's stay at the Stroke Unit. Blood samples were drawn upon admission to measure plasma levels of BNP (Biosite Inc., San Diego, Calif., USA). Statistical analysis was performed using SPSS 15.0 and R software. RESULTS: Altogether, 896 patients were included in the study. BNP plasma levels were higher among patients who deteriorated the most over time (n = 112; 90.5 vs. 61.2 ng/l; p = 0.006) or died (n = 83; 118.2 vs. 60.9 ng/l; p < 0.001). Multivariate logistic regression analysis indicated that plasma BNP level was an independent predictor of neurological worsening [BNP >56.7 ng/l; odds ratio (OR) = 1.64; p = 0.04] and death after stroke (BNP >65.3 ng/l; OR = 1.97; p = 0.034). Adding BNP level to other well-known clinical predictors of bad outcome did not significantly increase the predictive value. CONCLUSIONS: Plasma levels of BNP measured during the acute phase of stroke are associated both with early neurological worsening and mortality. However, this biological information does not supply prognostic information which would add to clinical variables, which limits its use as a biomarker. Further investigation and systematic reviews are needed to clarify the role of natriuretic peptides in stroke outcome. PMID- 23018290 TI - T cells: neuropilin 1 - distinguishing TReg cell subsets. PMID- 23018291 TI - HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. AB - In search of foreign antigens, lymphocytes recirculate from the blood, through lymph nodes, into lymphatics and back to the blood. Dendritic cells also migrate to lymph nodes for optimal interaction with lymphocytes. This continuous trafficking of immune cells into and out of lymph nodes is essential for immune surveillance of foreign invaders. In this article, we review our current understanding of the functions of high endothelial venules (HEVs), stroma and lymphatics in the entry, positioning and exit of immune cells in lymph nodes during homeostasis, and we highlight the unexpected role of dendritic cells in the control of lymphocyte homing through HEVs. PMID- 23018292 TI - Contrasting diagnosis performance of forced oscillation and spirometry in patients with rheumatoid arthritis and respiratory symptoms. AB - OBJECTIVES: Pulmonary involvement in rheumatoid arthritis is directly responsible for 10% to 20% of all mortality. The best way to improve the prognosis is early detection and treatment. The forced oscillation technique is easy to perform and offers a detailed exam, which may be helpful in the early detection of respiratory changes. This study was undertaken to (1) evaluate the clinical potential of the forced oscillation technique in the detection of early respiratory alterations in rheumatoid arthritis patients with respiratory complaints and (2) to compare the sensitivity of forced oscillation technique and spirometric parameters. METHODS: A total of 40 individuals were analyzed: 20 healthy and 20 with rheumatoid arthritis (90% with respiratory complaints). The clinical usefulness of the parameters was evaluated by investigating the sensibility, the specificity and the area under the receiver operating characteristic curve. ClinicalTrials.gov: NCT01641705. RESULTS: The early adverse respiratory effects of rheumatoid arthritis were adequately detected by the forced oscillation technique parameters, and a high accuracy for clinical use was obtained (AUC.0.9, Se = 80%, Sp = 95%). The use of spirometric parameters did not obtain an appropriate accuracy for clinical use. The diagnostic performance of the forced oscillation technique parameters was significantly higher than that of spirometry. CONCLUSIONS: The results of the present study provide substantial evidence that the forced oscillation technique can contribute to the easy identification of initial respiratory abnormalities in rheumatoid arthritis patients that are not detectable by spirometric exams. Therefore, we believe that the forced oscillation technique can be used as a complementary exam that may help to improve the treatment of breathing disorders in rheumatoid arthritis patients. PMID- 23018293 TI - Low mechanical ventilation times and reintubation rates associated with a specific weaning protocol in an intensive care unit setting: a retrospective study. AB - OBJECTIVES: A number of complications exist with invasive mechanical ventilation and with the use of and withdrawal from prolonged ventilator support. The use of protocols that enable the systematic identification of patients eligible for an interruption in mechanical ventilation can significantly reduce the number of complications. This study describes the application of a weaning protocol and its results. METHODS: Patients who required invasive mechanical ventilation for more than 24 hours were included and assessed daily to identify individuals who were ready to begin the weaning process. RESULTS: We studied 252 patients with a median mechanical ventilation time of 3.7 days (interquartile range of 1 to 23 days), a rapid shallow breathing index value of 48 (median), a maximum inspiratory pressure of 40 cmH(2)0, and a maximum expiratory pressure of 40 cm H(2)0 (median). Of these 252 patients, 32 (12.7%) had to be reintubated, which represented weaning failure. Noninvasive ventilation was used postextubation in 170 (73%) patients, and 15% of these patients were reintubated, which also represented weaning failure. The mortality rate of the 252 patients studied was 8.73% (22), and there was no significant difference in the age, gender, mechanical ventilation time, and maximum inspiratory pressure between the survivors and nonsurvivors. CONCLUSIONS: The use of a specific weaning protocol resulted in a lower mechanical ventilation time and an acceptable reintubation rate. This protocol can be used as a comparative index in hospitals to improve the weaning system, its monitoring and the informative reporting of patient outcomes and may represent a future tool and source of quality markers for patient care. PMID- 23018294 TI - Etiological diagnosis reduces the use of antibiotics in infants with bronchiolitis. AB - OBJECTIVE: Acute bronchiolitis is a leading cause of infant hospitalization and is most commonly caused by respiratory syncytial virus. Etiological tests are not required for its diagnosis, but the influence of viral screening on the therapeutic approach for acute bronchiolitis remains unclear. METHODS: A historical cohort was performed to assess the impact of viral screening on drug prescriptions. The study included infants up to one year of age who were hospitalized for bronchiolitis. Virus screening was performed using immunofluorescence assays in nasopharyngeal aspirates. The clinical data were obtained from the patients' medical records. Therapeutic changes were considered to be associated with viral screening when made within 24 hours of the release of the results. RESULTS: The frequency of prescriptions for beta agonists, corticosteroids and antibiotics was high at the time of admission and was similar among the 230 patients. The diagnosis of pneumonia and otitis was associated with the introduction of antibiotics but did not influence antibiotics maintenance after the results of the virus screening were obtained. Changes in the prescriptions were more frequent for the respiratory syncytial virus patients compared to patients who had negative viral screening results (p =0.004), especially the discontinuation of antibiotics (p<0.001). The identification of respiratory syncytial virus was associated with the suspension of antibiotics (p= 0.003), even after adjusting for confounding variables (p = 0.004); however, it did not influence the suspension of beta-agonists or corticosteroids. CONCLUSION: The identification of respiratory syncytial virus in infants with bronchiolitis was independently associated with the discontinuation of antibiotics during hospitalization. PMID- 23018295 TI - Reduced salivary flow and colonization by mutans streptococci in children with Down syndrome. AB - OBJECTIVES: Although individuals with Down syndrome have considerable oral disease, the prevalence of dental caries in this group is low. The present study aimed to compare known risk factors for dental caries development in children with Down syndrome and a matched population (siblings). In both populations, the number of acidogenic microorganisms, such as mutans streptococci, lactobacilli and Candida species, and the paraffin-stimulated pH, flow rate and IgA concentration in whole saliva were evaluated and compared. METHOD: Saliva was collected, and the caries index was evaluated in 45 sibling pairs aged between 6 and 18 years old. The salivary IgA concentration was determined by immunoturbidimetry. Salivary mutans streptococci, lactobacilli and Candida species were quantified on mitis salivarius agar containing bacitracin and 20% sucrose, rogosa agar supplemented with glacial acetic acid and sabouraud agar supplemented with chloramphenicol, respectively. RESULTS: Down syndrome children had a higher caries-free rate (p<0.05) and lower salivary mutans streptococci counts (p<0.03) compared to their siblings. Similar numbers of lactobacilli and Candida species were found in both groups. Salivary flow rates were 36% lower in Down syndrome children compared to their siblings (p<0.05). The salivary pH did not differ between Down syndrome children and controls. The Down syndrome children had an IgA secretion rate 29% lower than that of their siblings, but this difference was not statistically significant. CONCLUSIONS: In conclusion, the lower number of mutans streptococci in the saliva may be one of the factors contributing to the lower caries rate observed in Down syndrome children, despite evidence of hyposalivation. PMID- 23018297 TI - Evaluation of the mean platelet volume in patients with cardiac syndrome X. AB - OBJECTIVE: Cardiac syndrome X is characterized by angina-like chest pain, a positive stress test, and normal coronary arteries. A patient's mean platelet volume, which potentially reflects platelet function and activity, is associated with coronary atherosclerosis and endothelial dysfunction. The aim of the present study was to evaluate the mean platelet volumes of patients with cardiac syndrome X, those with coronary artery disease and normal subjects. METHODS: Two hundred thirty-six subjects (76 patients with cardiac syndrome X, 78 patients with coronary artery disease, and 82 controls) were enrolled in the study. All of the subjects were evaluated with a detailed medical history, physical examination, and biochemical analyses. The mean platelet volumes were compared between the three groups. RESULTS: The mean platelet volumes in the patients with cardiac syndrome X and with coronary artery disease were significantly higher than those that were observed in the control group. There were no significant differences in the mean platelet volumes between the cardiac syndrome X and the coronary artery disease groups. CONCLUSION: We have established that patients with cardiac syndrome X and coronary artery disease exhibit higher mean platelet volumes compared to controls. Patients with cardiac syndrome X exhibited higher mean platelet volumes compared to the controls, reflecting the presence of subclinical atherosclerosis. These findings suggest that, in addition to endothelial dysfunction, the presence of atherosclerosis may also contribute to the etiopathogenesis of cardiac syndrome X. PMID- 23018296 TI - Prevalence of celiac disease among blood donors in Sao Paulo: the most populated city in Brazil. AB - OBJECTIVE: Celiac disease is a permanent enteropathy caused by the ingestion of gluten, which leads to an immunemediated inflammation of the small intestine mucosa. The prevalence of celiac disease varies among different nations and ethnic backgrounds, and its diversity is determined by genetic and environmental factors. Sao Paulo city is one of the largest cities in the world, with a vast population and an important history of internal migratory flow from other Brazilian regions, as well as immigration from other, primarily European, countries, resulting in significant miscegenation. The aim of the present study was to estimate the prevalence of adults with undiagnosed celiac disease among blood donors of Sao Paulo by collecting information on the ancestry of the population studied. METHODS: The prevalence of celiac disease was assessed by screening for positive IgA transglutaminase and IgA endomysium antibodies in 4,000 donors (volunteers) in the Fundacao Pro-Sangue Blood Center of Sao Paulo, Sao Paulo, Brazil. The antibody-positive subjects were asked to undergo a small bowel biopsy. RESULTS: Of the 4,000 subjects, twenty-four had positive tests, although both antibody tests were not always concordant. For example, ten subjects were positive for IgA tissue transglutaminase only. In twenty-one positive patients, duodenal biopsies were performed, and the diagnosis of celiac disease was confirmed in fourteen patients (Marsh criteria modified by Oberhuber). In this group, 67% claimed to have European ancestry, mainly from Italy, Portugal and Spain. CONCLUSION: The prevalence of celiac disease is at least 1:286 among supposedly healthy blood bank volunteers in Sao Paulo, Brazil. PMID- 23018298 TI - Isokinetic analysis of ankle and ground reaction forces in runners and triathletes. AB - OBJECTIVE: To analyze and compare the vertical component of ground reaction forces and isokinetic muscle parameters for plantar flexion and dorsiflexion of the ankle between long-distance runners, triathletes, and nonathletes. METHODS: Seventy-five males with a mean age of 30.26 (+/-6.5) years were divided into three groups: a triathlete group (n=26), a long-distance runner group (n = 23), and a non-athlete control group. The kinetic parameters were measured during running using a force platform, and the isokinetic parameters were measured using an isokinetic dynamometer. RESULTS: The non-athlete control group and the triathlete group exhibited smaller vertical forces, a greater ground contact time, and a greater application of force during maximum vertical acceleration than the long-distance runner group. The total work (180o/s) was greater in eccentric dorsiflexion and concentric plantar flexion for the non-athlete control group and the triathlete group than the long-distance runner group. The peak torque (60o/s) was greater in eccentric plantar flexion and concentric dorsiflexion for the control group than the athlete groups. CONCLUSIONS: The athlete groups exhibited less muscle strength and resistance than the control group, and the triathletes exhibited less impact and better endurance performance than the runners. PMID- 23018299 TI - Hyperventilation accelerates the rise of arterial blood concentrations of desflurane in gynecologic patients. AB - OBJECTIVES: Under a constant inspired concentration, the uptake of a volatile anesthetic into the arterial blood should mainly be governed by alveolar ventilation, according to the assumption that the patient's cardiac output remains stable during anesthesia. We investigated whether ventilation volume affects the rate of desflurane uptake by examining arterial blood concentrations. METHOD: Thirty female patients were randomly allocated into the following three groups: hyperventilation, normal ventilation and hypoventilation. Hemodynamic variables were measured using a Finometer, inspiratory and end-tidal concentrations of desflurane were measured by infrared analysis, and the desflurane concentration in the arterial blood (Ades) was analyzed by gas chromatography. RESULTS: During the first 10 minutes after the administration of desflurane, the Ades was highest in the hyperventilation group, and this value was significantly different from those obtained for the normal and hypoventilation groups. In addition, hyperventilation significantly increased the slope of Ades-over-time during the first 5 minutes compared with patients experiencing normal ventilation and hypoventilation, but there were no differences in these slopes during the periods from 5-10, 10-20 and 20-40 minutes after the administration of desflurane. This finding indicates that there were no differences in desflurane uptake between the three groups after the first 5 minutes within desflurane administration. CONCLUSIONS: Hyperventilation accelerated the rate of the rise in Ades following desflurane administration, which was time-dependent with respect to different alveolar ventilations levels. PMID- 23018300 TI - Comparison of standard 4-row versus 6-row3-D linear cutter stapler in creation of gastrointestinal system anastomoses: a prospective randomized trial. AB - OBJECTIVE: This prospective study was conducted to compare the clinical outcomes of a 6-row 3-D linear cutter with the standard 4-row linear cutter in patients who underwent elective gastrointestinal surgery anastomosis. METHOD: Patients who underwent elective open gastrointestinal surgery that included stapled anastomosis using a linear cutter (Proximate(r), Ethicon Endo-Surgery, Cincinnati, OH) between January 2011 and May 2011 were included in the study. The patients were randomly assigned to two groups according to the linear cutter that was used in the surgery: the standard 4-row cutter (the S group) or the new 6-row cutter (the N group). The groups were compared based on the patient demographic data, the laboratory parameters, the preoperative diagnosis, the surgery performed, the operation time, intra-or postoperative complications, the time to oral tolerance and the length of the hospital stay. RESULTS: The S group included 11 male and nine female patients with a mean age of 65 +/- 12 (35-84) years, while the N group included 13 male and eight female patients with a mean age of 62 +/- 11 (46-79) years (p =0.448, p = 0.443, respectively). Anastomotic line bleeding was observed in eight (40%) patients in the S group and in one (4.7%) patient in the N group (p = 0.006). Dehiscence of the anastomosis line was observed in two (10%) patients in the S group and none in the N group (p =0.131). Anastomotic leakage developed in three (15%) patients in the S group and in one (4.7%) patient in the N group (p = 0.269). The mean hospital stay was 12.65 +/- 6.1 days in theS group and 9.52 +/- 2.9 days in the N group (p = 0.043). CONCLUSION: The 6-row 3-D linear cutter is a safe and easily applied instrument that can be used to create anastomoses in gastrointestinal surgery. The new stapler provides some usage benefits and is also superior to the standard linear cutter with regard to anastomotic line bleeding. PMID- 23018301 TI - Increased fibroblast telomerase expression precedes myofibroblast alpha-smooth muscle actin expression in idiopathic pulmonary fibrosis. AB - OBJECTIVE: This study sought to identify the relationship between fibroblast telomerase expression, myofibroblasts, and telomerase-mediated regulatory signals in idiopathic pulmonary fibrosis. METHODS: Thirty-four surgical lung biopsies, which had been obtained from patients with idiopathic pulmonary fibrosis and histologically classified as usual interstitial pneumonia, were examined. Immunohistochemistry was used to evaluate fibroblast telomerase expression, myofibroblast alpha-smooth muscle actin expression and the tissue expression of inter leu kin-4, transforming growth factor-beta, and basic fibroblast growth factor. The point-counting technique was used to quantify the expression of these markers in unaffected, collapsed, mural fibrosis, and honeycombing areas. The results were correlated to patient survival. RESULTS: Fibroblast telomerase expression and basic fibroblast growth factor tissue expression were higher in collapsed areas, whereas myofibroblast expression and interleukine-4 tissue expression were higher in areas of mural fibrosis. Transforming growth factor beta expression was higher in collapsed, mural fibrosis and honeycombing areas in comparison to unaffected areas. Positive correlations were found between basic fibroblast growth factor tissue expression and fibroblast telomerase expression and between interleukin-4 tissue expression and myofibroblast alpha-smooth muscle actin expression. Negative correlations were observed between interleukin-4 expression and basic fibroblast growth factor tissue expression in areas of mural fibrosis. Myofibroblast alpha-smooth muscle actin expression and interleukin-4 tissue expression in areas of mural fibrosis were negatively associated with patient survival. CONCLUSION: Fibroblast telomerase expression is higher in areas of early remodeling in lung tissues demonstrating typical interstitial pneumonia, whereas myofibroblast alpha-smooth muscle actin expression predominates in areas of late remodeling. These events seem to be regulated by basic fibroblast growth factor and interleukin-4 tissue expression, respectively. PMID- 23018302 TI - Helicobacter pylori as a potential target for the treatment of central serous chorioretinopathy. AB - OBJECTIVES: The objective of this study was to evaluate the relationship between the treatment of Helicobacter pylori gastric infection and changes in best corrected visual acuity and macular detachment in patients with chronic central serous chorioretinopathy. METHODS: Seventeen patients diagnosed with central serous chorioretinopathy were examined for gastric infection with Helicobacter pylori using the urease test and gastric biopsy. Helicobacter pylory-positive patients were treated with the appropriate medication. The response to therapy was monitored by evaluating the best-corrected visual acuity and optical coherence tomography. The data were analyzed using Student's t-test before and after treatment. RESULTS: Fourteen patients (15 eyes) aged 30-56 years (mean 43.4 +/- 8.3 years) were positive for Helicobacter pylori. Most of the positive patients had gastric symptoms (78.5%); one had bilateral central serous chorioretinopathy. The mean baseline best-corrected visual acuity was 20/98 (logMAR = 0.53 +/- 0.28). Three months after starting treatment with antibiotics, the serous detachment had resolved in 14 of 15 eyes, but two cases required laser treatment. The follow-up period ranged from 6 to 27 months. The mean final best corrected visual acuity differed significantly from baseline. CONCLUSION: Our findings suggest that Helicobacter pylori infection may be present in many chronic central serous chorioretinopathy patients and that treatment for the infection may have a favorable effect on the outcome of chronic central serous chorioretinopathy. Due to the possibility of the spontaneous regression of chronic central serous chorioretinopathy and the high prevalence of the infection in the general population, prospective and masked clinical trials are necessary to confirm that treatment for Helicobacter pylori infection may benefit patients with chronic central serous chorioretinopathy. PMID- 23018303 TI - The influence of tourniquet use and operative time on the incidence of deep vein thrombosis in total knee arthroplasty. AB - OBJECTIVE: To evaluate the association between tourniquet and total operative time during total knee arthroplasty and the occurrence of deep vein thrombosis. METHODS: Seventy-eight consecutive patients from our institution underwent cemented total knee arthroplasty for degenerative knee disorders. The pneumatic tourniquet time and total operative time were recorded in minutes. Four categories were established for total tourniquet time: <60, 61 to 90, 91 to 120, and >120 minutes. Three categories were defined for operative time: <120, 121 to 150, and >150 minutes. Between 7 and 12 days after surgery, the patients underwent ascending venography to evaluate the presence of distal or proximal deep vein thrombosis. We evaluated the association between the tourniquet time and total operative time and the occurrence of deep vein thrombosis after total knee arthroplasty. RESULTS: In total, 33 cases (42.3%) were positive for deep vein thrombosis; 13 (16.7%) cases involved the proximal type. We found no statistically significant difference in tourniquet time or operative time between patients with or without deep vein thrombosis. We did observe a higher frequency of proximal deep vein thrombosis in patients who underwent surgery lasting longer than 120 minutes. The mean total operative time was also higher in patients with proximal deep vein thrombosis. The tourniquet time did not significantly differ in these patients. CONCLUSION: We concluded that surgery lasting longer than 120 minutes increases the risk of proximal deep vein thrombosis. PMID- 23018304 TI - A clinical comparison between DisCoVisc and 2% hydroxypropylmethylcellulose in phacoemulsification: a fellow eye study. AB - OBJECTIVE: This study sought to compare the effects and outcomes of two ophthalmic viscosurgical devices, 1.6% hyaluronic acid/4.0% chondroitin sulfate and 2.0% hydroxypropylmethylcellulose, during phacoemulsification. METHODS: This prospective, randomized clinical trial comprised 78 eyes (39 patients) that received phacoemulsification performed by the same surgeon using a standardized technique. Patients were randomly assigned to receive either 1.6% hyaluronic acid/4.0% chondroitin sulfate or 2.0% hydroxypropylmethylcellulose on the first eye. The other eye was treated later and received the other viscoelastic agent. Preoperative and postoperative examinations (5, 24 and 48 hours; 7 and 14 days; 3 and 6 months) included measurements of the total volume of the ophthalmic viscosurgical device, ultrasound and washout times to completely remove the ophthalmic viscosurgical device, intraocular pressure, central corneal thickness and best-corrected visual acuity. The corneal endothelial cell count was measured at baseline and at six months postoperatively. ClinicalTrials.gov: NCT01387620. RESULTS: There were no statistically significant differences between groups in terms of cataract density or ultrasound time. However, it took longer to remove 2.0% hydroxypropylmethylcellulose than 1.6% hyaluronic acid/ 4.0% chondroitin sulfate, and the amount of viscoelastic material used was greater in the 2.0% hydroxypropylmethylcellulose group. In addition, the best-corrected visual acuity was significantly better in the hyaluronic acid/ chondroitin sulfate group, but this preferable outcome was only observed at 24 hours after the operation. There were no statistically significant differences between the two ophthalmic viscosurgical devices regarding the central corneal thickness or intraocular pressure measurements at any point in time. The corneal endothelial cell count was significantly higher in the hyaluronic acid/chondroitin sulfate group. CONCLUSION: The ophthalmic viscosurgical device consisting of 1.6% hyaluronic acid/4.0% chondroitin sulfate was more efficient during phacoemulsification and was easier to remove after IOL implantation than 2.0% hydroxypropylmethylcellulose. In addition, the corneal endothelial cell count was significantly higher following the use of hyaluronic acid/chondroitin sulfate than with hydroxypropylmethylcellulose, which promoted an improved level of corneal endothelium protection. PMID- 23018305 TI - The effect of beta-blockade on myocardial remodelling in Chagas' cardiomyopathy. AB - OBJECTIVE: Chagas' disease has spread throughout Latin America because of the high rate of migration among these countries. Approximately 30% of Chagas' patients will develop cardiomyopathy, and 10% of these will develop severe cardiac damage leading to heart failure. Beta-blockade improves symptoms and survival in heart failure patients; however, its efficacy has not been well established in Chagas' disease. We evaluated the role of carvedilol in cardiac remodeling and mortality in a Chagas' cardiomyopathy animal model. METHODS: We studied Trypanosoma cruzi infection in 55 Syrian hamsters that were divided into three groups: control (15), infected (20), and infected + carvedilol (20). Animals underwent echocardiography, electrocardiography, and morphometry for collagen evaluation in ventricles stained with picrosirius red. RESULTS: The left ventricular diastolic diameter did not change between groups, although it was slightly larger in infected groups, as was left ventricular systolic diameter. Fractional shortening also did not change between groups, although it was slightly lower in infected groups. Collagen accumulation in the interstitial myocardial space was significantly higher in infected groups and was not attenuated by carvedilol. The same response was observed in the perivascular space. The survival curve showed significantly better survival in the control group compared with the infected groups; but no benefit of carvedilol was observed during the study. However, in the acute phase (up to 100 days of infection), carvedilol did reduce mortality. CONCLUSION: Carvedilol did not attenuate cardiac remodeling or mortality in this model of Chagas' cardiomyopathy. The treatment did improve survival in the acute phase of the disease. PMID- 23018306 TI - Correlation of lifetime progress of atherosclerosis and morphologic markers of severity in humans: new tools for a more sensitive evaluation. AB - OBJECTIVES: To describe the morphological features of atherosclerosis in the aortas of autopsied patients (ranging from young adults to the elderly), thus providing new tools for a more sensitive morphological evaluation. METHOD: We collected 141 aorta samples. We assessed the macroscopic degree of atherosclerosis, thickness of the intima and media, lipid and collagen depositions in the intima, and the infiltration of mast cells into the layers of the aorta. We correlated the findings with gender, age, race and cause of death. RESULTS: The degree of atherosclerosis was significantly higher in the elderly. The aorta was thicker in the elderly and in cases with a cardiovascular cause of death. The thickness of the intima was significantly greater in the elderly, in males and in cases with a cardiovascular cause of death. The lipid content in the intima of the aorta was significantly higher in Caucasians. Older people and men had a significantly higher number of mast cells. CONCLUSION: A macroscopic evaluation is a good indicator of the severity of atherosclerosis, but a more detailed analysis, namely evaluating the thickness of the layers of the aorta and the number of mast cells, may further elucidate the changes in the constituents of this vessel. PMID- 23018307 TI - The effects of alpha-tocopherol supplementation on fracture healing in a postmenopausal osteoporotic rat model. AB - OBJECTIVE: Osteoporosis increases the risk of bone fractures and may impair fracture healing. The aim of this study was to investigate whether alpha tocopherol can improve the late-phase fracture healing of osteoporotic bones in ovariectomized rats. METHOD: In total, 24 female Sprague-Dawley rats were divided into three groups. The first group was sham-operated, and the other two groups were ovariectomized. After two months, the right femora of the rats were fractured under anesthesia and internally repaired with K-wires. The sham operated and ovariectomized control rat groups were administered olive oil (a vehicle), whereas 60 mg/kg of alpha-tocopherol was administered via oral gavage to the alpha-tocopherol group for six days per week over the course of 8 weeks. The rats were sacrificed, and the femora were dissected out. Computed tomography scans and X-rays were performed to assess fracture healing and callus staging, followed by the assessment of callus strengths through the biomechanical testing of the bones. RESULTS: Significantly higher callus volume and callus staging were observed in the ovariectomized control group compared with the sham-operated and alpha-tocopherol groups. The ovariectomized control group also had significantly lower fracture healing scores than the sham-operated group. There were no differences between the alpha-tocopherol and sham-operated groups with respect to the above parameters. The healed femora of the ovariectomized control group demonstrated significantly lower load and strain parameters than the healed femora of the sham-operated group. Alpha-tocopherol supplementation was not able to restore these biomechanical properties. CONCLUSION: Alpha-tocopherol supplementation appeared to promote bone fracture healing in osteoporotic rats but failed to restore the strength of the fractured bone. PMID- 23018308 TI - Exercise alleviates hypoalgesia and increases the level of calcitonin gene related peptide in the dorsal horn of the spinal cord of diabetic rats. AB - OBJECTIVE: The aim of this study was to evaluate the effects of treadmill training on nociceptive sensitivity and immunoreactivity to calcitonin gene related peptide in the dorsal horn of the spinal cord of diabetic rats. METHODS: Male Wistar rats were divided into three groups: control, diabetic and trained diabetic. Treadmill training was performed for 8 weeks. The blood glucose concentrations and body weight were evaluated 48 h after diabetes induction and every 30 days thereafter. The nociceptive sensitivity was evaluated using the tail-flick apparatus. The animals were then transcardially perfused, and the spinal cords were post-fixed, cryoprotected and sectioned in a cryostat. Immunohistochemistry for calcitonin gene-related peptide analysis was performed on the dorsal horn of the spinal cord. RESULTS: The nociceptive sensitivity analysis revealed that, compared with the control and trained diabetic animals, the latency to tail deflection on the apparatus was longer for the diabetic animals. Optical densitometry demonstrated decreased calcitonin gene-related peptide immunoreactivity in the dorsal horn of the spinal cord in diabetic animals, which was reversed by treadmill training. CONCLUSION: We concluded that treadmill training can alleviate nociceptive hypoalgesia and reverse decreased calcitonin gene-related peptide immunoreactivity in the dorsal horn of the spinal cord of diabetic animals without pharmacological treatment. PMID- 23018309 TI - Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells. AB - OBJECTIVE: Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. METHODS: Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects. RESULTS: Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice. CONCLUSIONS: Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients with poor liver tolerance. PMID- 23018310 TI - Comparison of lung preservation solutions in human lungs using an ex vivo lung perfusion experimental model. AB - OBJECTIVE: Experimental studies on lung preservation have always been performed using animal models. We present ex vivo lung perfusion as a new model for the study of lung preservation. Using human lungs instead of animal models may bring the results of experimental studies closer to what could be expected in clinical practice. METHOD: Brain-dead donors whose lungs had been declined by transplantation teams were used. The cases were randomized into two groups. In Group 1, Perfadex(r)was used for pulmonary preservation, and in Group 2, LPDnac, a solution manufactured in Brazil, was used. An ex vivo lung perfusion system was used, and the lungs were ventilated and perfused after 10 hours of cold ischemia. The extent of ischemic-reperfusion injury was measured using functional and histological parameters. RESULTS: After reperfusion, the mean oxygenation capacity was 405.3 mmHg in Group 1 and 406.0 mmHg in Group 2 (p = 0.98). The mean pulmonary vascular resistance values were 697.6 and 378.3 dyn.s.cm-5, respectively (p =0.035). The mean pulmonary compliance was 46.8 cm H20 in Group 1 and 49.3 ml/cm H20 in Group 2 (p =0.816). The mean wet/dry weight ratios were 2.06 and 2.02, respectively (p=0.87). The mean Lung Injury Scores for the biopsy performed after reperfusion were 4.37 and 4.37 in Groups 1 and 2, respectively (p = 1.0), and the apoptotic cell counts were 118.75/mm2 and 137.50/mm2, respectively (p=0.71). CONCLUSION: The locally produced preservation solution proved to be as good as Perfadex(r). The clinical use of LPDnac may reduce costs in our centers. Therefore, it is important to develop new models to study lung preservation. PMID- 23018311 TI - What types of unintentional injuries kill our children? Do infants die of the same types of injuries? A systematic review. AB - The objective of this study was to review mortality from external causes (accidental injury) in children and adolescents in systematically selected journals. This was a systematic review of the literature on mortality from accidental injury in children and adolescents. We searched the Pubrvled, Latin American and Caribbean Health Sciences and Excerpta Medica databases for articles published between July of 2001 and June of 2011. National data from official agencies, retrieved by manual searches, were also reviewed. We reviewed 15 journal articles, the 2011 edition of a National Safety Council publication and 2010 statistical data from the Brazilian National Ministry of Health Mortality Database. Most published data were related to high-income countries. Mortality from accidental injury was highest among children less than 1 year of age. Accidental threats to breathing (non-drowning threats) constituted the leading cause of death among this age group in the published articles. Across the pediatric age group in the surveyed studies, traffic accidents were the leading cause of death, followed by accidental drowning and submersion. Traffic accidents constitute the leading external cause of accidental death among children in the countries understudy. However, infants were vulnerable to external causes, particularly to accidental non-drowning threats to breathing, and this age group had the highest mortality rates for external causes. Actions to reduce such events are suggested. Further studies investigating the occurrence of accidental deaths in low-income countries are needed to improve the understanding of these preventable events. PMID- 23018314 TI - Energetics and stability of dangling-bond silicon wires on H passivated Si(100). AB - We evaluate the electronic, geometric and energetic properties of quasi 1D wires formed by dangling-bonds on Si(100)-H(2 * 1). The calculations are performed with density functional theory (DFT). Infinite wires are found to be insulating and Peierls distorted, however finite wires develop localized electronic states that can be of great use for atomic scale devices. The ground state solution of finite wires does not correspond to a geometrical distortion but rather to an antiferromagnetic ordering. For the stability of wires, the presence of abundant H atoms in nearby Si atoms can be a problem. We have evaluated the energy barriers for intradimer and intrarow diffusion, finding all of them about 1 eV or larger, even in the case where a H impurity is already sitting on the wire. These results are encouraging for using dangling-bond wires in future devices. PMID- 23018312 TI - Inflammation and circulating endothelial progenitor cells in patients with coronary artery disease and residual platelet reactivity. PMID- 23018315 TI - Clinical management of patients with a history of urticaria/angioedema induced by multiple NSAIDs: an expert panel review. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most frequent causes of drug-induced urticaria/angioedema worldwide. Recent review articles have classified patients experiencing NSAID-induced urticaria/angioedema into different categories, including single reactors, multiple reactors, and multiple reactors with underlying chronic urticaria. Each of these categories requires a different clinical approach. The present article, written by a panel of experts, reports the main recommendations for the practical clinical management of patients with a history of urticaria/angioedema induced by multiple NSAID based on current knowledge. PMID- 23018316 TI - Tomographic imaging of small airways. AB - Three-dimensional lung imaging has become a routine investigation in clinical medicine. The clinical needs have driven the development of tomographic imaging, as much as the research into better imaging itself has driven some of the improvements in imaging. There has been a steady stream of publications in which tomographic imaging has been used to measure small airway structure and function in obstructive airway diseases. These data provide unique insights and information on pulmonary physiology because they provide direct measurements of the airways, rather than global information from lung function, and they provide topographical information, i.e. spatial distribution. Their utility is magnified when combined with other information such as lung function. In this article, the application of topographic imaging in relation to small airway function is discussed. PMID- 23018317 TI - Hydrogen peroxide in exhaled breath condensate in asthmatic children during acute exacerbation and after treatment. AB - BACKGROUND: In asthmatics, the concentration of hydrogen peroxide (H(2)O(2)) in exhaled breath condensate (EBC) has been found to be increased and to be related to airway inflammation. OBJECTIVE: The aim of this study was to determine whether in children with acute exacerbation, exhaled H(2)O(2) levels could be influenced by treatment and linked to airway obstruction. METHODS: Twenty-two asthmatic children (mean age 9.4 years, range 6-14) with asthma exacerbation and 12 healthy children (mean age 11.7 years, range 7-15) were enrolled. Concentrations of exhaled H(2)O(2) before and after standard treatment for asthma attack were compared with those of controls and with clinical observation. Asthmatic children and controls underwent spirometry and skin prick tests to common aeroallergens. RESULTS: Exhaled H(2)O(2) concentrations were significantly higher in children with asthma both before (median 0.273 uM; p < 0.001) and after pharmacologic treatment (median 0.303 uM; p = 0.001) compared to control values (median 0.045 uM). After treatment, exhaled H(2)O(2) concentrations remained significantly higher in children with and without auscultatory wheezing than in controls (p = 0.034 and p < 0.001, respectively). EBC H(2)O(2) levels in asthmatics before treatment did not differ from those after treatment. No correlation was found between H(2)O(2) and forced expiratory volume in 1 s values. All asthmatics but one were atopics. CONCLUSIONS: In children with acute asthma exacerbation, exhaled H(2)O(2) concentrations in EBC are significantly elevated. In the short term follow-up, H(2)O(2) levels remain at high levels and are not correlated with lung function or improvement in symptoms. PMID- 23018320 TI - The scope and variety of combined baccalaureate-MD programs in the United States. AB - The landscape of combined baccalaureate-MD programs has changed substantially in the last two decades but has not been documented in detail. The authors review the current state of these programs and discuss opportunities for future study of their evolving role and potential impact.In 2011, using a definition of baccalaureate-MD program built on prior research, the authors reviewed Association of American Medical Colleges sources and medical school Web sites to identify and characterize 81 active programs. In addition, they surveyed the 57 medical schools offering those programs; 31 schools with 39 programs responded. The resulting database inventories the number and distribution of programs; institutional affiliations; missions or goals; length; size; admissions criteria; curricula; and retention requirements.Since the inception of combined programs in 1961, their number and curricular length have increased. Pressures that spurred earlier programs remain evident in the goals of today's programs: attract talented high school or early college students, especially from diverse backgrounds; prepare physicians to meet societal needs; and offer an enriched premedical environment. Baccalaureate educational activities achieve program goals through special courses, medical experiences, community service, and learning communities tailored to students' needs. Admission and retention criteria are comparable to those of traditional medical schools.Combined baccalaureate-MD programs have evolved along several paths during the last half century and have enriched the baccalaureate experiences of medical students. Shifting expectations for the selection and education of future physicians warrant focused research on these programs to document their effectiveness in addressing those expectations. PMID- 23018321 TI - The ABIM's clinical supervision practice improvement module and its effect on faculty's supervisory skills. AB - PURPOSE: Inadequate supervision of medical trainees hampers education and patient care. The authors examine the use of the American Board of Internal Medicine's Clinical Supervision Practice Improvement Module (CS-PIM) to determine whether it facilitated and enhanced faculty's skills in direct observation, providing feedback, identifying errors, and auditing medical records. METHOD: In this descriptive cohort study, module satisfaction was assessed using a five-point Likert scale. Changes in supervisory skills were measured using a retrospective pre-/postmodule self-assessment; deltas were compared by the Wilcoxon signed rank test. RESULTS: Between March 2009 and October 2010, 644 faculty completed 647 CS PIMs. Asked how effective the module was for improving their observation and evaluation skills, 91% rated it excellent, very good, or good. Similarly high percentages of the faculty gave those same ratings to the module for facilitating documenting trainee evaluations, documenting feedback to trainees, reflecting on the summary report, developing an improvement plan, and documenting their self assessment of supervisory skills. Faculty self-reported improved skills in observation, giving feedback, identifying errors, and auditing medical records. CONCLUSION: The CS-PIM facilitated and improved faculty skills in the supervision of trainees and led to self-reported changes in supervisory practices. Future research should evaluate trainees' perceptions and the actual impact on quality of care in the teaching setting. PMID- 23018322 TI - Career satisfaction among general surgeons in Canada: a qualitative study of enablers and barriers to improve recruitment and retention in general surgery. AB - PURPOSE: To understand what influences career satisfaction among general surgeons in urban and rural areas in Canada in order to improve recruitment and retention in general surgery. METHOD: Semistructured interviews were conducted with 32 general surgeons in 2010 who were members of the Canadian Association of General Surgeons and who currently practice in either an urban or rural area. Interviews explored factors contributing to career satisfaction, as well as suggestions for preventive, screening, or management strategies to support general surgery practice. RESULTS: Findings revealed that both urban and rural general surgeons experienced the most satisfaction from their ability to resolve patient problems quickly and effectively, enhancing their sense of the meaningfulness of their clinical practice. The supportive relationships with colleagues, trainees, and patients was also cited as a key source of career satisfaction. Conversely, insufficient access to resources and a perceived disconnect between hospital administration and clinical practice priorities were raised as key "systems level" problems. As a result, many participants felt alienated from their work by these systems-level barriers that were perceived to hinder the provision of high quality patient care. CONCLUSIONS: Career satisfaction among both urban and rural general surgeons was influenced positively by the social aspects of their work, such as patient and colleague relationships, as well as a perception of an increasing amount of control and autonomy over their professional commitments. The modern general surgeon values a balance between professional obligations and personal time that may be difficult to achieve given the current system constraints. PMID- 23018323 TI - The long, winding road: one university's quest for minority health care professionals and services. AB - U.S. universities have created programs that seek to increase the number of minority health care professionals practicing in underserved communities. One such program, the Urban Health Program (UHP), established at the University of Illinois at Chicago (UIC) in 1978, has graduated more than 5,000 members of underrepresented minorities (African Americans, Latinos, and Native Americans) into the health professions from the graduate college and the colleges of medicine, dentistry, pharmacy, nursing, applied health, and public health at UIC.The author provides a history and description of the UHP and an analysis of the key factors that were fundamental in creating the program and sustaining a commitment to its continuance. These factors include community action and demand for a clear and decisive legislative mandate to increase the number of minority health professionals, early outreach and academic pipeline initiatives designed to increase interest in health-related careers among underrepresented minority elementary and secondary students, changes in the culture and commitment of health professions colleges, and institutional commitment at the highest levels.The author seeks to stimulate greater awareness of the rewards, challenges, and complexities associated with maintaining such efforts; his article can serve as a primer for the creation of university programs dedicated to diversifying the health professions and the delivery of health care services. PMID- 23018324 TI - Performance of physicians trained through the research pathway in internal medicine. AB - PURPOSE: Educators in internal medicine are concerned that reducing clinical training from three years to two could negatively affect physicians' ability to provide good patient care. Physician-scientists already follow a short-track research pathway that shortens clinical training to two years. The authors examine whether this shortened training affects ability. METHOD: The authors use a national sample of 101,031 physicians who took their first internal medicine certification examination between 1993 and 2008 and trained in either a traditional or research pathway. They collected data, including demographics, exam information, and maintenance of certification (MOC) return rates. They used regression models to assess the relationship between training pathway and MOC exam scores and eventual certification status, adjusting for physician characteristics. RESULTS: In this study, research pathway training did not adversely impact internal medicine certification status. Although the scores of physicians who followed the research pathway were slightly lower, the effect size was small. In a subset of research pathway physicians, 63% remained in academic medicine and 37% continued to spend a substantial portion of time in medical research 10 years later. CONCLUSIONS: Different training pathways can lead to similar achievements in clinical judgment. The educational model, competency based rather than time-dependent, that works for research pathway physicians could be extended to other talented trainees who would benefit by customizing training to meet career goals. PMID- 23018325 TI - An environmental scan of faculty diversity programs at U.S. medical schools. AB - PURPOSE: To update the information available on the number and type of faculty diversity programs at U.S. MD-degree-granting medical schools. METHOD: The authors conducted an environmental scan of the 124 MD-degree-granting medical schools included in the 2010 Faculty Roster. They interviewed key informants in the faculty affairs and/or minority affairs offices and conducted Web site searches to identify relevant schoolwide programs. Using a conceptual framework, they categorized the faculty programs that they identified into four domains: mentorship, career development, social climate, and financial support. RESULTS: Of 124 eligible schools, the authors interviewed key informants from 84 schools (67.7%) and conducted Web site searches for 40 schools (32.2%). They identified diversity programs at 36 schools (29.0%) including mentoring (20/36; 16.1%), career development (20/36; 16.1%), social climate (17/36; 13.7%), and financial support programs (15/36; 12.1%). Schools with diversity programs were similar to schools without diversity programs in terms of year established, public/private status, and designation as historically black but were more likely to rank in the highest quartile and have a greater number of total faculty, and less likely to be located in the South. CONCLUSIONS: Less than a third of medical schools had programs targeting underrepresented minority (URM) faculty, and those programs that existed differed in scope and goals. These findings suggest that a lack of resources and a preference for programs that target all faculty may limit the development of programs targeting URM faculty. Future research should examine whether diversity programs contribute to URM faculty recruitment and retention. PMID- 23018326 TI - Building institutional capacity for diversity and inclusion in academic medicine. AB - Today, most agree that the health care system in the United States is in need of reform and that existing health disparities have huge implications for both that system and society as a whole. As a result, academic medicine has come to play a central role in addressing health disparities in a pluralistic society. Today, diversity is no longer a projection; it is a reality. Yet, most diversity efforts continue to run parallel to core institutional processes, rather than as part of the mission of the institution. Researchers agree that, to promote a healthy and vital society, leaders in academic medicine must create institutions that can serve diverse populations. To do so, they must first increase their institutional capacity for diversity. This article outlines the next generation of work on diversity and inclusion, drawing on a broad body of research and practice to identify some of the key elements for building the kind of institutional capacity necessary for sustained change in academic medicine, including a deeper engagement of mission, one that considers diversity as core to excellence; an inclusive and differentiated understanding of diversity institutionally; alignment and intentionality with respect to key institutional elements; key metrics associated with success and a serious process to monitor progress; and the identification of diverse talent for leadership at all levels. PMID- 23018327 TI - The deaf strong hospital program: a model of diversity and inclusion training for first-year medical students. AB - Recent research indicates that the cultural competence training students receive during medical school might not adequately address the issues that arise when caring for patients of different cultures. Because of their unique communication, linguistic, and cultural issues, incorporating deaf people who use sign language into cultural competence education at medical schools might help to bridge this gap in cross-cultural education. The Deaf Strong Hospital (DSH) program at the University of Rochester School of Medicine and Dentistry, started in 1998, exposes first-year medical students to the issues that are relevant to providing effective patient care and to establishing multicultural sensitivity early in their medical education. Because medical students better acquire cross-cultural competence through hands-on experience rather than through lectures, the DSH program, which includes a role-reversal exercise in which medical students play the role of the patients, provides such a model for other medical schools and health care training centers to use in teaching future health care providers how to address the relevant cultural, linguistic, and communication needs of both their deaf patients and their non-English-speaking patients. This article describes the DSH program curriculum, shares findings from both medical students' short-term and long-term postprogram evaluations, and provides a framework for the implementation of a broader cultural and linguistic sensitivity training program specific to working with and improving the quality of health care among deaf people. PMID- 23018328 TI - The impact of cross-cultural interactions on medical students' preparedness to care for diverse patients. AB - PURPOSE: Medical students who graduate from schools with diverse student populations are more likely to rate themselves as prepared to care for diverse patients compared with students who graduate from more homogenous schools. This study aimed to identify the types of cross-cultural interactions associated with students' self-rated preparedness. METHOD: In 2010, the authors developed and administered a Web-based survey that queried Harvard Medical School students about their voluntary interethnic interactions (studying, socializing), participation in diversity-related extracurricular activities, and self-rated preparedness to care for diverse patients. The authors separated students' responses regarding interethnic interactions and participation in diversity related extracurricular activities into high and low participation, then determined the association between these responses and those to questions about students' self-rated preparedness to care for diverse patients. They used ANOVA and Z tests of proportion to analyze their data. RESULTS: Of 724 eligible students, 460 completed the survey (64%). Seventy-five percent (324/433) believed they were prepared to care for patients from backgrounds different from their own. Students who spent >75% of their study time with students from different backgrounds or who participated in a greater number of diversity-related extracurricular activities were more likely to rate themselves as prepared to care for diverse patients overall and to perform seven other skills. CONCLUSIONS: Voluntary cross-cultural interactions, both studying and socializing, are associated with higher self-rated preparedness to care for patients from diverse backgrounds. Medical schools should continue to support multicultural pursuits to prepare students to become physicians sensitive to the needs of diverse patients. PMID- 23018329 TI - Perspective: adopting an asset bundles model to support and advance minority students' careers in academic medicine and the scientific pipeline. AB - The authors contend that increasing diversity in academic medicine, science, technology, engineering, and mathematics requires the adoption of a systematic approach to retain minority high school and college students as they navigate the scientific pipeline. Such an approach should focus on the interrelated and multilayered challenges that these students face. The authors fuse an alternative conceptualization of the scientific and technical human capital theoretical framework and the theory of social identity contingencies to offer a conceptual model for targeting the critical areas in which minority students may need additional support to continue toward careers in science. Their proposed asset bundles model is grounded in the central premise that making greater progress in recruiting and retaining minorities likely requires institutions to respond simultaneously to various social cues that signal devaluation of certain identities (e.g., gender, race, socioeconomic status). The authors define "asset bundles" as the specific sets of abilities and resources individuals develop that help them succeed in educational and professional tasks, including but not limited to science and research. The model consists of five asset bundles, each of which is supported in the research literature as a factor relevant to educational achievement and, the authors contend, may lead to improved and sustained diversity: educational endowments, science socialization, network development, family expectations, and material resources. Using this framework, they suggest possible ways of thinking about the task of achieving diversity as well as guideposts for next steps. Finally, they discuss the feasibility of implementing such an approach. PMID- 23018330 TI - Are disadvantaged and underrepresented minority applicants more likely to apply to the program in medical education-health equity? AB - PURPOSE: To determine whether underrepresented minority (URM) students and students from disadvantaged backgrounds were more likely to apply to a combined MD-master's degree program designed to train physician leaders in providing care to underserved communities. METHOD: University of California, San Diego (UCSD), School of Medicine applications from the 2008-2010 incoming classes were analyzed. American Medical College Application Service and UCSD secondary application data were used to build a logistic regression model to determine which characteristics were most associated with applying to the MD-master's degree Program in Medical Education-Health Equity (PRIME-HEq). RESULTS: Of the total UCSD applications reviewed from disadvantaged students, 61.5% also applied to PRIME-HEq (319/519) compared with 23.5% of nondisadvantaged students (917/3,895, chi = 326.665, P < .001). Of URM student applications, 55.6% also applied to PRIME-HEq (358/644) compared with 23.3% of non-URM students (878/3,770, chi = 284.654, P < .001). Results of a backward stepwise logistic regression analysis showed that disadvantagedstatus was the greatest predictor of applying to PRIME-HEq (odds ratio = 3.15; 95%confidence interval = 2.50-3.966; P< .001). CONCLUSIONS: URM students and students from disadvantaged backgrounds were more likely to be interested in a curriculum designed to train them to work with underserved communities. These results suggest that PRIME-HEq, or similarly focused programs, may influence URM and disadvantaged students' application decisions. PMID- 23018331 TI - Improving diversity through strategic planning: a 10-year (2002-2012) experience at theMedical University of South Carolina. AB - The Medical University of South Carolina launched a systematic plan to infuse diversity among its students, resident physicians, and faculty in 2002. The dean and stakeholders of the College of Medicine (COM) embraced the concept that a more population-representative physician workforce could contribute to the goals of providing quality medical education and addressing health care disparities in South Carolina. Diversity became a central component of the COM's strategic plan, and all departments developed diversity plans consistent with the overarching plan of the COM. Liaisons from the COM diversity committee facilitated the development of the department's diversity plans. By 2011, the efforts resulted in a doubling of the number of underrepresented-in-medicine (URM, defined as African American, Latino, Native American) students (21% of student body); matriculation of 10 African American males as first-year medical students annually for four consecutive years; more than a threefold increase in URM residents/fellows; expansion of pipeline programs; expansion of mentoring programs; almost twice as many URM faculty; integration of cultural competency throughout the medical school curriculum; advancement of women and URM individuals into leadership positions; and enhanced learning for individuals from all backgrounds. This article reports the implementation of an institutional plan to create a more racially representative workforce across the academic continuum. The authors emphasize the role of the stakeholders in promoting diversity, the value of annual assessment to evaluate outcomes, and the positive benefits for individuals of all backgrounds. PMID- 23018332 TI - PROMISE: Maryland's Alliance for Graduate Education and the Professoriate enhances recruitment and retention of underrepresented minority graduate students. AB - PROMISE: Maryland's Alliance for Graduate Education and the Professoriate (AGEP), sponsored by the National Science Foundation, is a consortium that is designed to increase the numbers of underrepresented minority (URM) PhDs in science, technology, engineering, and mathematics fields who will pursue academic careers. A strength of PROMISE is its alliance infrastructure that connects URM graduate students on different campuses through centralized programming for the three research universities in Maryland: the University of Maryland Baltimore County (the lead institution in the alliance), the University of Maryland College Park, and the University of Maryland Baltimore (UMB). PROMISE initiatives cover graduate student recruitment, retention, community building, PhD completion, and transition to careers.Although it is not a fellowship, PROMISE offers professional development and skill-building programs that provide academic and personal support for URM students on all three campuses. PROMISE on UMB's campus includes the School of Medicine, which sponsors tricampus programs that promote health and wellness to accompany traditional professional development programs. PROMISE uniquely and atypically includes a medical school within its alliance. The PROMISE programs serve as interventions that reduce isolation and facilitate degree completion among diverse students on each campus. This article describes details of the PROMISE AGEP and presents suggestions for replicating professional development programs for URMs in biomedical, MD/master's, and MD/PhD programs on other campuses. PMID- 23018333 TI - Changes in the representation of women and minorities in biomedical careers. AB - PURPOSE: To examine how efforts and policies to increase diversity affect the relative representation of women and of minority groups within medicine and related science fields. METHOD: The authors of this report used data from the Current Population Survey March Supplement (a product of the U.S. Census Bureau and the Bureau of Labor Statistics that tracks race, ethnicity, and employment) to compute the representation ratios of persons employed in biology, chemistry, and medicine from 1968 to 2009 (inclusive). They derived the representation ratios by computing the ratio of the conditional probability that a member of a given group is employed in a specific skilled science field to the overall probability of employment in that field. Their analysis tested for differences in representation ratios among racial, gender, and ethnic groups and across time among those employed as biologists, chemists, and medical doctors. RESULTS: Representation ratios rose for white females, whose percentage increase in medicine was larger than for any other racial/ethnic group. The representation ratios fell for Hispanics in biology, chemistry, and medicine. The representation ratio rose for African Americans, whose highest percentage increase occurred in biology. Asian Americans, who had the highest representation ratios in all three disciplines, saw a decline in their relative representation in medicine. CONCLUSIONS: The authors have demonstrated that all groups do not benefit equally from diversity initiatives and that competition across related fields can confound efforts to increase diversity in medicine. PMID- 23018335 TI - Calling for a broader conceptualization of diversity: surface and deep diversity in four Canadian medical schools. AB - PURPOSE: Policy groups recommend monitoring and supporting more diversity among medical students and the medical workforce. In Canada, few data are available regarding the diversity of medical students, which poses challenges for policy development and evaluation. The authors examine diversity through a framework of surface (visible) and deep (less visible) dimensions and present data regarding a sample of Canadian medical students. METHOD: Between 2009 and 2011, nine cohorts from four Canadian medical schools completed the Health Professions Student Diversity Survey (HPSDS) either on paper or online. Items asked each participant's age, gender, gender identity, sexual identity, marital status, ethnicity, rural status, parental income, and disability. Data were analyzed descriptively and compared, when available, with national data. RESULTS: Of 1,892 students invited, 1,552 (82.0%) completed the HPSDS. Students tended to be 21 to 25 years old (68.3%; 1,048/1,534), female (59.0%; 902/1,529), heterosexual (94.6%; 1,422/1,503), single (90.1%; 1,369/1,520), and unlikely to report any disability (96.5%; 1,463/1,516). The majority of students identified with the gender on their birth certificate (99.8%; 1,512/1,515). About half had spent the majority of their lives in urban environments (46.7%; 711/1,521), and most reported parental household incomes of over $100,000/year (57.6%; 791/1,373). Overall, they were overrepresentative of higher-income groups and underrepresentative of populations of Aboriginal, black, or Filipino ethnicities in Canada. CONCLUSIONS: The authors propose the development of a National Student Diversity Database to support both locally relevant policies regarding pipeline programs and an examination of current application and selection procedures to identify potential barriers for underrepresented students. PMID- 23018334 TI - Are race, ethnicity, and medical school affiliation associated with NIH R01 type 1 award probability for physician investigators? AB - PURPOSE: To analyze the relationship among National Institutes of Health (NIH) R01 Type 1 applicant degree, institution type, and race/ethnicity, and application award probability. METHOD: The authors used 2000-2006 data from the NIH IMPAC II grants database and other sources to determine which individual and institutional characteristics of applicants may affect the probability of applications being awarded funding. They used descriptive statistics and probit models to estimate correlations between race/ethnicity, degree (MD or PhD), and institution type (medical school or other institution), and application award probability, controlling for a large set of observable characteristics. RESULTS: Applications from medical schools were significantly more likely than those from other institutions to receive funding, as were applications from MDs versus PhDs. Overall, applications from blacks and Asians were less likely than those from whites to be awarded funding; however, among applications from MDs at medical schools, there was no difference in funding probability between whites and Asians, and the difference between blacks and whites decreased to 7.8%. The inclusion of human subjects significantly decreased the likelihood of receiving funding. CONCLUSIONS: Compared with applications from whites, applications from blacks have a lower probability of being awarded R01 Type 1 funding, regardless of the investigator's degree. However, funding probability is increased for applications with MD investigators and for those from medical schools. To some degree, these advantages combine so that applications from black MDs at medical schools have the smallest difference in funding probability compared with those from whites. PMID- 23018336 TI - The academic health center in complex humanitarian emergencies: lessons learned from the 2010 Haiti earthquake. AB - On January 12, 2010, a 7.0-magnitude earthquake struck Haiti. The event disrupted infrastructure and was marked by extreme morbidity and mortality. The global response to the disaster was rapid and immense, comprising multiple actors including academic health centers (AHCs)-that provided assistance in the field and from home. The authors retrospectively examine the multidisciplinary approach that the University of Chicago Medicine (UCM) applied to postearthquake Haiti, which included the application of institutional structure and strategy, systematic deployment of teams tailored to evolving needs, and the actual response and recovery. The university mobilized significant human and material resources for deployment within 48 hours and sustained the effort for over four months. In partnership with international and local nongovernmental organizations as well as other AHCs, the UCM operated one of the largest and more efficient acute field hospitals in the country. The UCM's efforts in postearthquake Haiti provide insight into the role AHCs can play, including their strengths and limitations, in complex disasters. AHCs can provide necessary intellectual and material resources as well as technical expertise, but the cost and speed required for responding to an emergency, and ongoing domestic responsibilities, may limit the response of a large university and hospital system. The authors describe the strong institutional backing, the detailed predeployment planning and logistical support UCM provided, the engagement of faculty and staff who had previous experience in complex humanitarian emergencies, and the help of volunteers fluent in the local language which, together, made UCM's mission in postearthquake Haiti successful. PMID- 23018338 TI - Diversity in academic medicine. (foreword). PMID- 23018337 TI - A culture conducive to women's academic success: development of a measure. AB - PURPOSE: The work environment culture inhibits women's career success in academic medicine. The lack of clarity and consistency in the definition, measurement, and analysis of culture constrains current research on the topic. The authors addressed this gap by defining the construct of a culture conducive to women's academic success (CCWAS) and creating a measure (i.e., tool) to evaluate it. METHOD: First, the authors conducted a review of published literature, held focus groups, and consulted with subject matter experts to develop a measure of academic workplace culture for women. Then they developed and pilot-tested the measure with a convenience sample of women assistant professors. After refining the measure, they administered it, along with additional scales for validation, to 133 women assistant professors at the University of Pennsylvania. Finally, they conducted statistical analyses to explore the measure's nature and validity. RESULTS: A CCWAS consists of four distinct, but related, dimensions: equal access, work-life balance, freedom from gender biases, and supportive leadership. The authors found evidence that women within departments/divisions agree on the supportiveness of their units but that substantial differences among units exist. The analyses provided strong evidence for the reliability and validity of their measure. CONCLUSIONS: This report contributes to a growing understanding of women's academic medicine careers and provides a measure that researchers can use to assess the supportiveness of the culture for women assistant professors and that leaders can use to evaluate the effectiveness of interventions designed to increase the supportiveness of the environment for women faculty. PMID- 23018339 TI - Do research activities during college, medical school, and residency mediate racial/ethnic disparities in full-time faculty appointments at U.S. Medical schools? AB - PURPOSE: To determine whether postsecondary research experiences (in college, medical school, and residency) and other variables mediate racial/ethnic disparities in U.S. medical school graduates' full-time faculty appointments in academic medicine. METHOD: Individualized, deidentified records for 1994-2000U.S. medical school matriculants who graduated with MDs before 2005, completed graduate medical education before 2009, and had data for all variables were examined for potential mediators of racial/ethnic disparities in full-time faculty appointments using the SAS macro "MEDIATE" for estimation and statistical inference. Controlling for gender, parents' occupation, and graduation year, the authors estimatedthe effects of potential mediators in separate models comparing Asian/Pacific Islander (PI) versus underrepresented minority (URM; including African American, Hispanic, and Native American/Alaska Native) graduates and white versus URM graduates. RESULTS: Of 82,758 eligible graduates, 62,749 (75.8%) had complete data; of these, 11,234 (17.9%) had full-time faculty appointments, including 18.4% (7,848/42,733) of white, 18.8% (2,125/11,297) of Asian/PI, and 14.5% (1,261/8,719) of URM graduates. Proportion of total race/ethnicity effect on full-time faculty appointment explained by all mediators was 66.0% (95% CI, 44.7%-87.4%) in a model comparing Asians/PIs with URMs and 64.8% (95% CI, 52.2% 77.4%) in one comparing whites with URMs. Participation in postsecondary research activities, authorship during medical school, academic achievement, and faculty career intentions at graduation were among the significant mediators explaining the effect of race/ethnicityonfull-time faculty appointment. CONCLUSIONS: Postsecondary research experiences for URM students are among the mediators of racial/ethnic disparities in full-time faculty appointments and, therefore, may increase academic medicine faculty diversity. PMID- 23018340 TI - Cytotoxic platinum(II) intercalators that incorporate 1R,2R-diaminocyclopentane. AB - Twelve metallointercalators of the type [Pt(I(L))(A(L))](2+), where A(L) is either the R,R or S,S enantiomer of 1,2-diaminocyclopentane (DACP) and I(L) is either 1,10-phenathroline, 4-methyl-1,10-phenanthroline, 5-methyl-1,10 phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5,6-dimethyl-1,10 phenanthroline or 3,4,7,8-tetramethyl-1,10-phenanthroline, were synthesised, characterised and the cytotoxicity to the L1210 cell line was determined. The crystal structures of PHENRRDACP and PHENSS were obtained as monoclinic with a space group of P2(1) (a/A = 11.4966, b/A = 6.6983, c/A = 12.0235) and P2(1) (a/A = 11.5777, b/A = 7.0009, c/A = 12.5079), respectively. The R,R enantiomer of 1,2 diaminocyclopentane (RRDACP) produced the most cytotoxic metallointercalators. The most cytotoxic metallointercalators were 56MERRDACP and 47MERRDACP with IC(50) values of 0.16 and 0.17 MUM, respectively, in comparison to cisplatin (1 MUM). PMID- 23018341 TI - Evaluation of removable statistical interaction for binary traits. AB - This paper is concerned with evaluating whether an interaction between two sets of risk factors for a binary trait is removable and, when it is removable, fitting a parsimonious additive model using a suitable link function to estimate the disease odds (on the natural logarithm scale). Statisticians define the term 'interaction' as a departure from additivity in a linear model on a specific scale on which the data are measured. Certain interactions may be eliminated via a transformation of the outcome such that the relationship between the risk factors and the outcome is additive on the transformed scale. Such interactions are known as removable interactions. We develop a novel test statistic for detecting the presence of a removable interaction in case-control studies. We consider the Guerrero and Johnson family of transformations and show that this family constitutes an appropriate link function for fitting an additive model when an interaction is removable. We use simulation studies to examine the type I error and power of the proposed test and to show that, when an interaction is removable, an additive model based on the Guerrero and Johnson link function leads to more precise estimates of the disease odds parameters and a better fit. We illustrate the proposed test and use of the transformation by using case control data from three published studies. Finally, we indicate how one can check that, after transformation, no further interaction is significant. PMID- 23018342 TI - Thrombolysis in an ischemic stroke patient on dabigatran anticoagulation: a case report. PMID- 23018343 TI - Therapeutic effect of transplanting magnetically labeled bone marrow stromal stem cells in a liver injury rat model with 70%-hepatectomy. AB - BACKGROUND: There are only few reports about the use of bone marrow stromal stem cells (BMSCs) for the treatment of traumatic liver injury. This study aimed to study the therapeutic effect of fluorescence-labeled BMSCs administered to rats subject to traumatic liver injury. MATERIAL/METHODS: Male SD rats with a 70% resection of the liver were injected with feridex-labeled BMSCs which could be induced to functional hepatocytes in vitro. Liver function was assayed and the liver scanned by 1.5-T MRI at 12 hrs and on days 1, 3, 5, 7, and 14 post operation. The pathological changes of liver sections were monitored. RESULTS: The serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, direct bilirubin, and total bilirubin in the transplantation group were significantly lower than the control group. The MRI showed rats of the transplantation group had an oval low signal area at 12 hr after operation; the low signal range gradually expanded and the signal intensity gradually decreased over 14 days after operation. The low signal range in the control group disappeared 12 hr after the operation. After Prussian blue staining, rats of the transplantation group contained blue granules with no significant hypertrophy or edema in hepatocytes, while the control group showed no blue granules with significant hypertrophy and edema. CONCLUSIONS: The BMSCs transplanted into the injured rat liver gradually migrate to the surrounding liver tissue and partially repair the liver surgical injury in rats. BMSCs may represent an effective therapeutic approach for acute liver injury. PMID- 23018344 TI - Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells. AB - BACKGROUND: Several studies have shown that multidrug transporters, such as P glycoprotein (PGP), are involved in cell resistance to chemotherapy and refractory epilepsy. The p38 mitogen-activated protein kinase (MAPK) signaling pathway may increase PGP activity. However, p38-mediated drug resistance associated with PGP is unclear. Here, we investigated p38-mediated doxorubicin induced drug resistance in human leukemia K562 cells. MATERIAL/METHODS: The expression of PGP was detected by RT-PCR, Western blot, and immunocytochemistry. Cell viability and half-inhibitory concentrations (IC50) were determined by CCK-8 assay. The intracellular concentration of drugs was measured by HPLC. RESULTS: A doxorubicin-induced PGP overexpression cell line, K562/Dox, was generated. The p38 inhibitor SB202190 significantly decreased MDR1 mRNA expression, as well as PGP, in K562/Dox cells. The IC50 of phenytoin sodium and doxorubicin in K562/Dox cells was significantly higher than that in wild-type K562 cells, indicating the drug resistance of K562/Dox cells. During the blocking of p38 activity in the presence of SB202190, cell number was significantly reduced after the phenytoin sodium and doxorubicin treatment, and the IC50 of phenytoin sodium and doxorubicin was decreased in K562/Dox cells. HPLC showed that the intracellular levels of phenytoin sodium and doxorubicin were significantly lower in K562/Dox cells than those in K562 cells. The decrease of the intracellular level of these drugs was significantly abolished in the presence of SB202190. CONCLUSIONS: Our study demonstrated that p38 is, at least in part, involved in doxorubicin-induced drug resistance. The mechanistic study of MAPK-mediated PGP and the action of SB202190 need further investigation. PMID- 23018345 TI - The effect of AVE 0991, nebivolol and doxycycline on inflammatory mediators in an apoE-knockout mouse model of atherosclerosis. AB - BACKGROUND: The aim of this study was to investigate whether the 3 different substances that can decrease the development of atherosclerosis--nebivolol, AVE 0991 and doxycycline--could at the same time diminish the level of inflammatory indicators interleukin-6 (IL-6), interleukin-12 (IL-12), serum amyloid A (SAA), and monocyte chemotactic protein-1 (MCP-1). MATERIAL/METHODS: Forty 8-week-old female apoE-knockout mice on the C57BL/6J background were divided into 4 groups and put on chow diet for 4 months. Three experimental groups received the same diet as a control group, mixed with AVE 0991 at a dose 0.58 umol per kg of body weight per day, nebivolol at a dose 2.0 umol per kg of body weight per day, and doxycycline at a dose 1.5 mg per kg of body weight per day. At the age of 6 months, the mice were sacrificed. RESULTS: All inflammatory indicators (MCP-1, IL 6, IL-12 and SAA) were diminished by AVE 0991. There was also a tendency to lower MCP-1, IL-6, IL-12 and SAA levels by nebivolol and doxycycline; however, it did not reach statistical significance. CONCLUSIONS: Of the 3 presented substances, only AVE 0991 was able to diminish the rise of inflammatory markers. Therefore, drug manipulations in the renin-angiotensin-aldosterone axis seem to be the most promising in the future treatment of atherogenesis. PMID- 23018346 TI - Coexpression of Smad7 and UPA attenuates carbon tetrachloride-induced rat liver fibrosis. AB - BACKGROUND: There is a great need for developing novel therapies to treat liver fibrosis. Previous studies showed that both Smad7 and uPA were inhibitors of liver fibrosis. Therefore, we explored the therapeutic effects of combinational gene therapy with Smad7 and uPA on CCl4-induced liver fibrosis. MATERIAL/METHODS: Smad7 and uPA genes were cloned into an adenovirus vector. To observe the therapeutic effects of coexpression of Smad7 and uPA genes, the recombinant adenovirus were delivered into CCL4-induced fibrosis models. Fibrillar collagen, hydroxyproline, alpha-SMA, TGF-beta1, MMP-13, TIMP-1, HGF and PCNA were detected to evaluate the fibrosis and to explore the mechanisms underlying the treatment with Smad7 and uPA. RESULTS: The results showed that single Smad7 or uPA adenovirus reduced CCL4 induced liver fibrosis significantly; while combination of Smad7 and uPA had more significant therapeutic effect on CCl4 induced liver fibrosis. Then the markers underlying the therapeutic effect of combination of Smad7 and uPA were also explored. Over-expression of Smad7 and uPA inhibited the expression of alpha-SMA and TGF- beta1 significantly. Combinational gene therapy also enhanced extracellular matrix degradation by increasing the expression of MMP-13, inhibiting TIMP-1 expression, and promoted hepatocyte proliferation, while single Smad7 or uPA only induced part of these changes. CONCLUSIONS: These results suggest that combinational gene therapy with Smad7 and uPA inhibited CCl4 induced rat liver fibrosis by simultaneously targeting multiple pathogenic pathways. PMID- 23018347 TI - Intrascleral outflow after deep sclerectomy with absorbable and non-absorbable implants in the rabbit eye. AB - BACKGROUND: The purpose of the study is an analysis of intrascleral drainage vessels formed in rabbits' eyes after non-penetrating deep sclerectomy (NPDS) with absorbable and non-absorbable implants, and comparison to eyes in which surgery was performed without implanted material. MATERIAL/METHODS: NPDS was carried out in 12 rabbits, with implantation of non-absorbable methacrylic hydrogel (N=10 eyes) or absorbable cross-linked sodium hyaluronate (N=6 eyes), or without any implant (N=8 eyes). All the animals were euthanized 1 year after surgery. Twenty-one eyeballs were prepared for light microscopy and 3 were prepared for transmission electron microscope (TEM) analysis. Aqueous humour pathways were stained with ferritin in 6 eyeballs. RESULTS: By light microscopy, small vessels adjacent to the areas of scarring were the most common abnormality. Vessel density was significantly higher in operated sclera compared to normal, healthy tissue, regardless of the type of implant used. The average vessel densities were 2.18+/-1.48 vessels/mm2 in non-implanted sclera, 2.34+/-1.69 vessels/mm2 in eyes with absorbable implants, and 3.64+/-1.78 vessels/mm2 in eyes with non-absorbable implants. Analysis of iron distribution in ferritin-injected eyes showed a positive reaction inside new aqueous draining vessels in all groups. TEM analysis showed that the ultrastructure of new vessels matched the features of the small veins. CONCLUSIONS: Aqueous outflow after NPDS can be achieved through the newly formed network of small intrascleral veins. Use of non absorbable implants significantly increases vessel density in the sclera adjacent to implanted material compared to eyes in which absorbable implants or no implants were used. PMID- 23018348 TI - Stricture of ileo-anal J pouch anastomosis increased the intensity of pouchitis in an experimental rat model. AB - BACKGROUND: Pouchitis appears to be the most common complication after restorative proctocolectomy. MATERIAL/METHODS: In experimental models we investigated the correlation between the width of anastomosis and the frequency of pouchitis. Twenty-three Wistar rats underwent restorative proctocolectomy under pentobarbital anesthesia. Normal width anastomosis was performed in 11 animals (Group I). In the remaining 12 animals (Group II) the diameter of anastomosis was reduced by 50%. All animals were sacrificed and the pouch mucosa was histologically (Moskowitz score) and immunohistochemically (IL-1, IL-6, IL 10, IL-12 expression) examined. RESULTS: Morphological assessment of pouchitis symptoms based on Moskowitz scale revealed considerably more severe inflammation (p=0.0079) in the animals from Group II than in the rats from Group I. The expressions of investigated cytokines, assessed qualitatively in histopathological examination, were higher in rats with narrow anastomosis in comparison with animals with normal anastomosis. CONCLUSIONS: The stricture of anastomosis increases the intensity of pouchitis and stimulates the production of interleukins. It seems that anastomotic stricture plays an important role in the development of pouchitis. PMID- 23018349 TI - Probing the use of fluorescence spectroscopy as a novel diagnostic tool in patients with rheumatoid arthritis: applicability in the detection of secondary amyloidosis. AB - BACKGROUND: Secondary amyloidosis is a frequently reported complication of rheumatoid arthritis. Currently, accepted diagnostic protocols for secondary amyloidosis involve histopathological and histochemical examinations of collected tissue specimens. The purpose of the current report was to evaluate the value of fluorescence spectroscopy as a supplementary tool in the diagnosis of secondary amyloidosis. MATERIAL/METHODS: Tissue specimens were collected from abdominal folds, gingiva or rectal mucosa of 99 patients affected with rheumatoid arthritis. Tissue samples were subjected to preliminary clinical observations, histopathological examinations and laboratory tests. These procedures were used to subdivide tissue samples into either amyloid-containing or amyloid-free control subgroups. All collected tissue samples were examined with the use of a designated spectrofluorometer and fluorescence spectral images were generated. RESULTS: It was found that fluorescence spectra for amyloid-containing tissues were typically characterized by a double emittance peak. In contrast, amyloid free samples were characterized by fluorescence spectra with a single lambdamax value. Specimen collection site, age and sex did not appear to influence the morphology of electromagnetic spectra, which were generated for both amyloid containing and amyloid-free tissue samples. The sensitivity of the fluorometric approach was ~78% and the specificity was 100%. Possible shortcomings of the technique may be due to the limit of detection of the instrument used. CONCLUSIONS: Fluorescence spectroscopy may potentially be used as an effective, instantaneous and low-cost diagnostic tool for suspected secondary amyloidosis in patients affected with rheumatoid arthritis. PMID- 23018350 TI - Quantitative anatomy of the growing abdominal aorta in human fetuses: an anatomical, digital and statistical study. AB - BACKGROUND: Advances in perinatal medicine have required an extensive knowledge of fetal aorto-iliac measurements. The present study was performed to compile reference data for dimensions of the abdominal aorta at varying gestational ages. MATERIAL/METHODS: Using the methods of anatomical dissection, digital-image analysis (Leica QWin Pro 16 system), and statistical analysis (Student's t-test, one-way ANOVA, post-hoc RIR Tukey test, regression analysis, and Wilcoxon signed rank test), the growth of length (mm), proximal and distal external diameters (mm), and volume (mm3) of the abdominal aorta in 124 (60 male, 64 female) spontaneously aborted human fetuses aged 15-34 weeks was examined. RESULTS: No significant male-female differences were found. The length ranged from 9.35+/ 1.24 to 36.29+/-4.98 mm, according to the linear function y=-14.596+1.519 * Age +/-2.639 (R2=0.92; p<0.0001). The proximal external diameter varied from 1.18+/ 0.25 to 5.19+/-0.49 mm, according to the linear pattern y=-2.065+0.212 * Age +/ 0.348 (R2=0.92; p<0.0001). The distal external diameter increased from 1.03+/ 0.23 to 4.92+/-0.46 mm, in accordance with the linear model y=-2.097+0.203 * Age +/-0.351 (R2=0.92; p<0.0001). Both length and proximal external diameter of the abdominal aorta indicated a proportionate evolution, because the length-to proximal external diameter ratio was stable, following the linear function y=7.724-0.017 * Age +/-0.925. The abdominal aorta volume ranged from 9.6+/-4.5 to 740.5+/-201.8 mm3, given by the quadratic function y=911-101 * Age +2.838 * Age2 +/-78 (R2=0.89; p<0.0001). CONCLUSIONS: There are no significant differences between males and females for morphometric parameters of the abdominal aorta. The abdominal aorta grows linearly in both length and diameters, and parabolically in volume. These detailed morphometric data of the abdominal aorta provide a database for intra-uterine echographic examinations in the early diagnosis, monitoring and management of aorto-iliac malformations. PMID- 23018351 TI - Correlation between bispectral index, observational sedation scale, and lower esophageal sphincter pressure in volunteers using dexmedetomidine or propofol. AB - BACKGROUND: Many anesthetics reduce lower esophageal sphincter pressure (LESP) and consequently the gastro-esophageal pressure gradient (GEPG); thus they may promote gastro-esophageal reflux and contribute to aspiration pneumonia. Our goals were to evaluate the association between LESP and 2 measures of sedation: bispectral index (BIS) and the responsiveness component of the Observer's Assessment of Alertness score (OAA/S). MATERIAL/METHODS: Eleven healthy volunteers were each sedated on 2 separate days. Subjects were given sedative infusions of increasing target plasma concentrations of dexmedetomidine or propofol. LESP and GEPG were recorded after starting each infusion phase. Generalized estimating equation modeling was used to assess the relationship between LESP and, respectively, BIS and OAA/S. The existence of a drug-dependent association was evaluated within these models by testing an interaction term. Wald tests were used to evaluate the relationships within the models. RESULTS: We found a significant relationship between LESP and BIS (P=0.0043) after adjusting for the main effect of sedative type--a deepening of sedation as measured by a decrease in BIS of 10% was associated with a decrease [Bonferroni-adjusted 95% CI] in LESP of -1.34 [-2.39, -0.29] mmHg. After adjusting for the main effect of sedative drug, LESP significantly declined with declining OAA/S (P=0.001); a unit decrease of OAA/S was associated with a decrease [Bonferroni-adjusted 95% CI] in LESP of -2.01 [-3.20, -0.81] mmHg. CONCLUSIONS: Deeper sedation, as measured by either BIS or OAA/S, significantly reduces LESP. PMID- 23018352 TI - Correlation of plasma osteoprotegerin (OPG) and receptor activator of the nuclear factor kappaB ligand (RANKL) levels with clinical risk factors in patients with advanced carotid atherosclerosis. AB - BACKGROUND: Osteoprotegerin (OPG) is considered to be a crucial regulatory mediator of bone metabolism by acting as a decoy receptor of the receptor activator of nuclear factor kappaB ligand (RANKL). OPG and RANKL have further become the subject of intense interest for their potential role in cardiovascular disease. The present study aimed to assess the clinical implication of plasma OPG and RANKL levels in patients with advanced carotid atherosclerosis. MATERIAL/METHODS: Plasma OPG and RANKL concentrations measured by solid-phase enzyme-linked immunosorbent assay (ELISA) were correlated with medical history, risk factors and medication intake in 131 patients who underwent carotid endarterectomy for vascular repair. RESULTS: Plasma OPG concentrations were associated with patients' age (p=0.0258), homocysteine levels (p<0.00001), eGFR (p=0.0254), history of diabetes (p=0.0324), statins therapy (p=0.0044), hyperlipidemia (p=0.0407), smoking (p=0.0226) and CAD (p=0.0377). Plasma RANKL concentrations were associated with patients' age (p=0.0191), homocysteine levels (p<0.00001), history of smoking (p=0.0185) and statins therapy (p=0.0004). Diabetes, CAD, smoking status, statins therapy and homocysteine were identified as independent predictors of OPG concentrations (p=0.0157, p=0.0030, p=0.0249, p=0.0047 and p=0.0072, respectively), whereas smoking showed an independent effect for RANKL (p=0.0010). CONCLUSIONS: The present data reinforce the clinical utility of OPG in carotid atherosclerosis, whereas the clinical implication of RANKL seems uncertain. PMID- 23018354 TI - Importance of anemia in the chronic Cardiorenal syndrome: effects on renal function after heart transplantation. AB - BACKGROUND: Cardiorenal syndrome has been recently divided into 5 categories, according to acute or chronic evolution and primary organ dysfunction. Anemia can also accompany this disorder, leading to a more complex situation. This study aims to analyze the renal outcomes of patients, specifically patients with chronic Cardiorenal syndrome, with or without anemia, long-term after heart transplantation. MATERIAL/METHODS: This was a retrospective cohort study on chronic Cardiorenal syndrome patients submitted to heart transplantation. Patients were divided according to presence of anemia and renal dysfunction before heart transplantation. RESULTS: A total of 108 patients (92 males) with the mean age of 45+/-12 years were included. The etiologies of the heart failure were hypertensive dilated myocardiopathy (66%), ischemic (14%) and Chagasic (12%). Before the heart transplantation, 51 patients had an eGFR less than 60 mL/min. From these, 24 had concomitant anemia. One year after the transplantation, patients with previous isolated renal dysfunction ameliorates eGFR (45+/-11 vs. 65+/-26 mL/min, p<0.001), while those patients with previous renal dysfunction and anemia presented no improvement (eGFR 44+/-14 vs. 47+/-13 mL/min, p=0.619) 1 year after heart transplantation. Moreover, higher hemoglobin was an independent predictor of eGFR improvement after heart transplantation when associated with previous renal dysfunction (OR 1.8; CI 1.2-3.6, p<0.01 for each hemoglobin increment of 1 g/dL). CONCLUSIONS: Patients with isolated Cardiorenal syndrome presented partial renal function recovery after heart transplantation, while the presence of cardiorenal anemia was a marker of renal function non recovery 1 year after heart transplantation. PMID- 23018353 TI - Detecting of breast cancer metastasis by means of regional lymph node sampling during autologous breast reconstruction--a screening of 519 consecutive patients. AB - BACKGROUND: The internal mammary artery and vein is often used as a site of anastomoses in microvascular breast reconstruction. This area supports lymphatic drainage of the breast and its role in breast cancer metastasis remains unclear. We hypothesize that sampling of internal mammary lymph nodes at the time of microvascular anastomoses preparation may identify persistent or recurrent local disease and mandate the need for additional treatment in this area. MATERIAL/METHODS: A retrospective chart review from 519 patients in the time between January 2006 and September 2009 was performed on all patients who underwent internal mammary lymph node sampling at the time of microvascular breast reconstruction. RESULTS: Microvascular breast reconstruction was performed in 519 patients. Enlarged internal mammary lymph nodes were found and harvested in 195 patients for histological review. Six of 195 (3.08%) were found positive for metastatic disease requiring additional oncologic treatment. CONCLUSIONS: The internal mammary lymphatic drainage system is an important and often underappreciated pathway for breast metastasis. Routine sampling of these lymph nodes at the time of microvascular breast reconstruction is easy to perform and is a useful tool to identify women, who might require additional treatment and increase cancer-free survival. PMID- 23018355 TI - Soluble trail as a marker of efficacy of allergen-specific immunotherapy in patients with allergic rhinoconjunctivitis. AB - BACKGROUND: Allergic rhinitis is a common health problem affecting the immune system. The homeostasis of the immune system is regulated by apoptosis. In this study, serum circulating soluble TRAIL levels of allergic rhinoconjunctivitis patients before and after allergen-specific immunotherapy were evaluated. MATERIAL/METHODS: The sTRAIL levels of pre- and post-treated allergic rhinoconjunctivitis patients (n=25) were compared to age- and sex-matched healthy individuals (n=25). sTRAIL levels were measured by ELISA. The skin prick test (SPT) results were recorded before and after treatment. RESULTS: The sTRAIL levels between the pre-treated and control groups were significantly different (p<0.0001). However, there was no significant difference between the post-treated group and healthy individuals (p=0,801). SPT was a statistically significant difference between the values of the research group before and after immunotherapy (grasses mixture, barley mixture, Oleaauropeae, D. Pteronyssinus, D. farinae). CONCLUSIONS: The sTRAIL levels were decreased after allergen specific immunotherapy to healthy levels and may be of use as a marker of efficacy of immunotherapy in allergic rhinoconjunctivitis patients. PMID- 23018356 TI - Iranian hereditary hemochromatosis patients: baseline characteristics, laboratory data and gene mutations. AB - BACKGROUND: Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder in white people, characterized by highly abnormal uptake of iron from the gastrointestinal tracts. Recently, mutation studies have focused to detect the genes responsible for HH. MATERIAL/METHODS: In this cross-sectional study, 12 HH patients were recruited, who were referred to Firoozgar Hospital, Tehran, Iran. In addition to the clinical assessments, a complete laboratory evaluation, imaging modalities, histopathologic assessment, atomic absorption spectrophotometry and gene mutation study were performed. The genetic study for HFE gene mutation was examined for all of the patients since 2006, while non-HFE mutation was conducted since December 2010 (only for 1 of them). RESULTS: Twelve patients were evaluated consisting of 11 men and 1 woman, with the mean age of 39.58+/-12.68 yr. The average of atomic iron loads was 13.25+/-4.83-fold higher than normal standards. Four patients had heterozygotic mutation of H63D (33.3%). There was no significant difference in either the iron load of liver (P=0.927) and heart (P=0.164) or serum concentration of ferritin (P=0.907) and TIBC (P=0.937) between the HFE-mutant and without HFE mutation HH cases. CONCLUSIONS: In contrast to other studies, C282Y mutation was not detected in any of our Iranian HH patients. Heterozygotic mutations of H63D (HFE) and TFR2 (non-HFE) genes were found to be more common in these patients. Similar to previous reports, these mutations were not found to be significantly associated with severity of presentation in HH patients. PMID- 23018357 TI - Expression of estrogen receptors alpha and beta in paratesticular tissues in boys operated on for unilateral cryptorchidism between the 1st and 4th years of life. AB - BACKGROUND: The aim of this study was to assess the expression of estrogen receptors alpha and beta in paratesticular tissues in a group of boys with and without cryptorchidism, and evaluation of karyotypes, localization, morphology and the major length of the undescended testes. MATERIAL/METHODS: Fifty boys (1-4 years old) with unilateral cryptorchidism were evaluated. Fifty healthy boys within the same age range, with inguinal hernia, served as a control group. Measurements concerning expression of ERalpha ERbeta receptors were preformed using monoclonal mouse antibodies against human receptor alpha and beta. RESULTS: In the mesothelial layer, the expression of ERalpha was higher in the patients group with undescended testes and it was statistically significant (p=0.04). There was no difference in the expression of ERbeta in this layer between groups. In the stromal cell layer there was statistically significant higher expression of ERbeta (p<0.05) in the group of patients with undescended testes. CONCLUSIONS: There was no difference between expressions of ERalpha in stromal cell layer. In the endothelial layer there was no difference in expression of ERalpha and ERbeta. In the smooth muscle layer there was no expression of ERalpha in either group. The expression of ERbeta in the smooth muscle layer was nearly identical in both groups. Undescended testes were generally found in the superficial inguinal pouch (n=46). The major lengths of the undescended testes were smaller in comparison to the testes positioned normally. In 9 of the cases the testes had different shape, and turgor deficit, and epididymides were smaller, dysplastic and separated from the testis. PMID- 23018358 TI - Chondrosarcoma from the sternum: reconstruction with titanium mesh and a transverse rectus abdominis myocutaneous flap after subtotal sternal excision. AB - BACKGROUND: Chondrosarcoma arising from the sternum is extremely rare and is often untreatable. Removal of the sternum for malignant tumor results in large defects in bone and soft tissue, causing deformity and paradoxical movement of the chest wall and making subsequent repair of the thorax very important. We report a very rare patient with a chondrosarcoma of the sternum who underwent case chest wall resection, followed by reconstruction using a titanium mesh covered with a transverse rectus abdominis myocutaneous (TRAM) flap. CASE REPORT: A 63-year-old man was referred to our hospital with progressively enlarged swelling of his anterior chest wall. Physical examination showed a 2.5*2.0 cm mass fixed to the sternum, which was diagnosed as a chondrosarcoma based on clinical findings, imaging characteristics and incision biopsy results. The patient underwent a subtotal sternal and chest wall resection to remove the tumor, followed by reconstruction with a titanium mesh and a TRAM flap. There were no complications associated with surgery. CONCLUSIONS: We report an extremely rare case of a patient who underwent subtotal sternal resection, followed by reconstruction, for a large chondrosarcoma. The elasticity and rigidity provided by the titanium mesh and the complete coverage of the surgical wound by a TRAM flap suggest that these procedures may be useful in reconstructing large defects in the chest wall. PMID- 23018359 TI - Visual evoked potentials in early diagnosis of demyelinating diseases--a case report of Devic's disease. AB - BACKGROUND: Devic's disease, also known as neuromyelinitis optica (NMO), is a severe, rare demyelinating disorder, previously considered to be a form of multiple sclerosis (MS). The aim of this study was to present the case report of 21-year-old woman with a very early diagnosis of Devic's disease, established following electrophysiological testing. CASE REPORT: A 21-year-old woman was referred to Warsaw Medical University, Department of Ophthalmology, with subjective visual impairment. The patient underwent a full clinical examination, colour vision and Goldmann visual field testing, fluorescein angiography, OCT, multifocal ERG, and visual evoked potentials (VEPs). CONCLUSIONS: Visual evoked potentials are a very useful diagnostic tool in optic nerve neuropathies. In our patient, the electrophysiological testing allowed us to establish a proper diagnosis very early, before typical clinical signs of Devic's disease. PMID- 23018360 TI - A cry for help, do not omit the signs. Dermatitis artefacta--psychiatric problems in dermatological diseases (a review of 5 cases). AB - BACKGROUND: Dermatitis artefacta (DA) is a dermatologicopsychiatric illness that is a conscious self-infliction of lesions to accessible regions of the body. The lesions usually do not resemble those of any know skin disease and there are no specific diagnostic tests to recognize them. This makes dermatitis artefacta a very slow, challenging and expensive disease to diagnose. CASE REPORT: We present 5 different clinical cases of dermatitis artefacta treated in the Department of Dermatology, Venereology and Allergology, Medical University of Gdansk in 2011. Detailed anamnesis and physical examination were performed at the day of admission. All patients had biochemical and hematological blood tests, skin biopsies and swabs for bacteriological examination, and photographs were taken. Psychiatric consultation was recommended in all cases. Clinical symptoms before diagnosis lasted from 1 to 10 years. The female-to-male ratio is 1:0.7, with age range of 57-62 years. Of our patients, only 2 refused a psychiatric consultation. Three out of 5 patients denied self-mutilation (2 of those 3 patients finally admitted to self-manipulations). Lesions were usually within the reach of the dominant hand. Two patients have other personality disorders. In 4/5 cases visible improvement after treatment with occlusive dressings were observed. CONCLUSIONS: We discuss and attempt to depict issues associated with collaboration between dermatologists and psychiatrists, reasons for poor recognition of the disease, very long diagnosis and high costs. To conclude, we found that close collaboration between dermatologists and psychiatrists is important in diagnosing and treating DA patients. PMID- 23018361 TI - Shadows and darkness in the brain of a genius: aspects of the neuropsychological literature about the final illness of Maurice Ravel (1875-1937). AB - In 1948 the famous French neurologist Theophile Alajouanine published the article "Aphasia and artistic realization", a landmark in the field of research about aphasia, which discussed the case of the composer Maurice Ravel (1875-1937). Since then, many researchers have explored the final illness of the composer. In 2003 Medical Science Monitor published 2 articles about the case. In this article we intend to present works published on the Ravel case, to discuss them, and to suggest a general overview on the topic. Many hypotheses have been proposed by researchers, but complete diagnosis is still an enigma, since no post-mortem was made. The most up-to-date perspective seems to point to comorbidity of superimposed elements, which might date back to the composer's fragile youth. PMID- 23018362 TI - Respiratory changes in the E/A wave pattern can be an early sign of diastolic dysfunction: an echocardiographic long-term follow-up study. AB - BACKGROUND: The left ventricular filling pattern may show changes during respiration, which are generally used in the diagnosis of diastolic dysfunction. The clinical importance of the respiratory E/A wave pattern change has been investigated in a limited number of studies. The aim of the present study was to assess the diastolic function of hypertensive patients with respiratory changes in mitral flow over a long-term follow-up period. MATERIAL/METHODS: Our study included 107 newly diagnosed and untreated hypertensive patients (49 males; mean age, 46+/-10 years) with respiratory changes during transthoracic echocardiography (TTE). In addition, the patient group was classified into 2 groups according to the change in E/A pattern by the Valsalva maneuver. After a mean follow-up period of 44+/-7 month, 90% of the hypertensive patients and the entire control group were re-examined. RESULTS: Relaxation abnormalities developed in 84% of the patients (58/80) in the Valsalva-positive group after the follow-up period. The frequency of relaxation abnormalities was 60% in the Valsalva-negative group and 3.1% in the control group (p<0.001). Based on multivariate regression analysis, the echocardiographic predictors of the development of relaxation impairment were mitral E velocity, A velocity, deceleration time, isovolumetric contraction time, E/E' ratio, and the presence of respiratory change. The most important parameter for the development of an abnormal relaxation pattern was the presence of respiratory change after adjustment according to the changes with the Valsalva maneuver. CONCLUSIONS: Respiratory change in mitral flow can be evaluated as an early sign of diastolic dysfunction in patients with hypertension. PMID- 23018363 TI - Melanocyte stem cells: biology and current aspects. AB - Epidermal stem cells have become an object of intensive research. The epidermis constitutes one of the main sources of stem cells and is a tissue of choice for use in exploring their biology. Stratified squamous epithelium (epidermis) possesses the capacity for self-renewal and repair due to the presence of epidermal stem cells (ESC). They have been identified within basal layer of the interfollicular epidermis (IFE), in the "bulge" of the hair follicles of rodents, and also in the human follicular bulge. Melanocyte stem cells (MSC) from hair follicles (precisely from the bulge region, which also contains epidermal stem cells) provide an attractive model for the study of stem cells and their regulation at the niche. This review summarizes the rapidly developing field of epidermal stem cell research and their application in regenerative medicine, paying particular attention to melanocyte stem cells, their biology and some of the processes that occur during hair graying and regeneration of the pigmentary system, as well as discussing how aged-associated changes in the melanocyte stem cells compartment impact hair graying. This review also includes differentiation of human skin stem cells into functional epidermal melanocytes. PMID- 23018370 TI - Toward an AIDS-free generation with option B+: reconceptualizing and integrating prevention of mother to child transmission (PMTCT) with pediatric antiretroviral therapy initiatives. PMID- 23018371 TI - Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid. AB - OBJECTIVES: To determine HIV-1 RNA in cerebrospinal fluid (CSF) of successfully treated patients and to evaluate if combination antiretroviral treatments with higher central nervous system penetration-effectiveness (CPE) achieve better CSF viral suppression. METHODS: Viral loads (VLs) and drug concentrations of lopinavir, atazanavir, and efavirenz were measured in plasma and CSF. The CPE was calculated using 2 different methods. RESULTS: The authors analyzed 87 CSF samples of 60 patients. In 4 CSF samples, HIV-1 RNA was detectable with 43-82 copies per milliliter. Median CPE in patients with detectable CSF VL was significantly lower compared with individuals with undetectable VL: CPE of 1.0 (range, 1.0-1.5) versus 2.3 (range, 1.0-3.5) using the method of 2008 (P = 0.011) and CPE of 6 (range, 6-8) versus 8 (range, 5-12) using the method of 2010 (P = 0.022). The extrapolated CSF trough levels for atazanavir (n = 12) were clearly above the 50% inhibitory concentration (IC50) in only 25% of samples; both patients on atazanavir/ritonavir with detectable CSF HIV-1 RNA had trough levels in the range of the presumed IC50. The extrapolated CSF trough level for lopinavir (n = 42) and efavirenz (n = 18) were above the IC50 in 98% and 78%, respectively, of samples, including the patients with detectable CSF HIV-1 RNA. CONCLUSIONS: This study suggests that treatment regimens with high intracerebral efficacy reflected by a high CPE score are essential to achieve CSF HIV-1 RNA suppression. The CPE score including all drug components was a better predictor for treatment failure in the CSF than the sole concentrations of protease inhibitor or nonnucleoside reverse transcriptase inhibitor in plasma or CSF. PMID- 23018372 TI - Frailty in HIV-infected adults in South Africa. AB - OBJECTIVES: Some evidence suggests that HIV infection is associated with premature frailty-a syndrome typically viewed as being related to ageing. We determined the prevalence and predictors of frailty in a population of HIV infected individuals in South Africa. DESIGN: Case-control study of 504 adults more than the age of 30 years, composed of 248 HIV-infected adults and 256 age- and gender-matched, frequency-matched HIV-seronegative individuals. METHODS: Frailty was defined by standardized assessment comprised of >= 3 of weight loss, low physical activity, exhaustion, weak grip strength, and slow walking time. Independent predictors of frailty were evaluated using multivariable logistic regression. RESULTS: The mean ages of the HIV-infected and HIV-seronegative groups were 41.1 +/- 7.9 years and 42.6 +/- 9.6 years, respectively. Of the HIV infected adults, 87.1% were receiving antiretroviral treatment (median duration, 58 months), their median CD4 count was 468 cells/MUL (interquartile range = 325 607 cells/MUL) and 84.3% had undetectable plasma viral load. HIV-infected adults were more likely to be frail than HIV-seronegative individuals (19.4% vs. 13.3%; P = 0.07), and this association persisted after adjustment for confounding variables [adjusted OR = 2.14; 95% confidence interval (95% CI): 1.16-3.92, P = 0.01]. Among HIV-infected individuals, older age was a strong predictor of frailty, especially among women (women: OR = 2.55 per 10-year age increase; men: OR = 1.29 per 10-year age increase, P-interaction = 0.01). Lower current CD4 count (<500 cells/MUL) was also independently associated with frailty (OR = 2.84; 95% CI: 1.02 -7.92, P = 0.04). CONCLUSIONS: HIV infection is associated with premature development of frailty, especially in women. Since higher CD4 counts were associated with lower risk of frailty, earlier initiation of antiretroviral treatment may be protective. PMID- 23018373 TI - How to choose appropriate ring size for Shang Ring male circumcision. AB - We investigated effects of ring size choosing strategy for Shang Ring male circumcision. Seventy-four cases were recruited and assigned into the larger or smaller ring group. Compared with the larger ring group, there was shorter operation time (7.5 +/- 1.9 vs. 6.7 +/- 1.4 minutes, P = 0.035) and less blood loss (1.6 +/- 0.7 vs. 1.1 +/- 0.8 mL, P = 0.014) in the smaller ring group. The smaller ring group also exhibited shorter healing duration than the larger ring group (22.3 +/- 4.1 days vs. 24.4 +/- 4.5 days, P = 0.041). When the measured size does not fit into commercially available size, it is better to choose the smaller one. PMID- 23018374 TI - Mediation of HIV/STI risk by mental health disorders among persons living in the United States reporting childhood sexual abuse. AB - BACKGROUND: Individuals who experience childhood sexual abuse (CSA) have higher rates of unsafe sexual behaviors and/or HIV or sexually transmitted infection (STI) incidence. Accordingly, sexual minorities also have higher rates of HIV/STI incidence compared with heterosexuals among those abused as children and those who were not. However, little is known concerning the mechanisms by which CSA confers increased sexual risk. METHODS: Using data from the National Epidemiologic Survey on Alcohol and Related Conditions, we prospectively analyzed the relationship between CSA and recent incident HIV/STIs at wave 2 (2004-2005) while examining mental health and substance-use disorders reported during wave 1 (2001-2002) as putative mediators. RESULTS: For women, mental health disorders mediated 35% of the effect of CSA on the risk of HIV/STI. Neither alcohol nor drug-use disorders were mediators for HIV/STI risk because of CSA in women. For heterosexual men, mental health disorders (90%), alcohol (24%), and drug-use (46%) disorders mediated some or all of the HIV/STI risk. None of the disorders mediated the risk of HIV/STI in sexual minority men, who had the highest HIV/STI risk among the groups measured. CONCLUSIONS: CSA is a strong risk factor for risky sexual behavior in adulthood. Our findings indicate that there may be multiple causal pathways from CSA to HIV risk, with different mediators to be targeted for intervention. These differences need to be further studied to design appropriate HIV interventions to reduce the high-risk behaviors among individuals who were sexually abused as children. PMID- 23018375 TI - The effect of migration on HIV high-risk behaviors among Mexican migrants. AB - BACKGROUND: Previous studies have shown an association between Mexican migration to the United States and an increased frequency of HIV high-risk behaviors among male Mexican migrants. However, the individual level change in these behaviors after migration has not been quantified. OBJECTIVE: To estimate the change in HIV high-risk behaviors among Mexican migrants after migration to the United States. METHODS: A case-crossover study was embedded in the California-Mexico Epidemiological Surveillance Pilot, a targeted, venue-based, sampling survey. We implemented the study from July to November 2005, studying 458 Mexican migrants at sites in rural and urban areas in Fresno County and San Diego County and directly comparing individual HIV high-risk behaviors before and after migration. RESULTS: After migration, there were increases in the odds of male migrants engaging in sex with a sex worker [odds ratio (OR) = 2.64, P < 0.0001], sex while under the influence of drugs or alcohol (OR = 5.00, P < 0.0001), performing sex work (OR = 6.00, P = 0.070), and sex with a male partner (OR = 13.00, P = 0.001). Those male Mexican migrant subgroups at particularly elevated risk were those in the United States for more than 5 years, those from the youngest age cohort (18 29 years old), or those frequenting high-risk behavior venues and male work venues. CONCLUSIONS: Our results show that Mexican migrant men were significantly more likely to engage in several HIV high-risk behaviors after migration to the United States. However, a smaller proportion of men reported low condom use after migration, indicating increased adoption of some prevention methods. Our results also identified subgroups of Mexican migrants at elevated risk who should be targeted for HIV prevention interventions. PMID- 23018376 TI - Monitoring HIV testing at visits to emergency departments in the United States: very-low rate of HIV testing. AB - BACKGROUND: Early diagnosis and treatment of HIV infection result in improved clinical outcomes and decreased transmission, yet many infected persons are unaware of their infection or are diagnosed late. The Centers for Disease Control and Prevention recommends routine opt-out testing of all persons aged 13-64 years in high prevalence settings. STUDY OBJECTIVE: To describe methods to estimate HIV testing rates at visits to emergency departments (EDs) for monitoring adherence to recommendations for opt-out testing. METHODS: We analyzed data from the 2009 National Hospital Ambulatory Medical Care Survey. In 2009, 2 questions were added to the survey about HIV status and testing. We estimated the frequency of HIV testing at ED visits made by persons aged 13-64 years not known to be HIV infected. RESULTS: In 2009, 90.5 million visits were made to EDs, including 60.0% by whites, 24.5% by blacks, and 12.1% by Hispanics and 38.4% by privately insured, 25.7% by Medicaid insured, and 21.4% by uninsured persons. Among 89.9 million visits by patients not known to be HIV infected, HIV testing was performed at only 0.2% of visits. Among 3.4 million visits made by persons in whom targeted testing is recommended-those with increased risk for HIV and other sexually transmitted diseases or pregnancy-only 2.3% were tested for HIV. CONCLUSIONS: National Hospital Ambulatory Medical Care Survey can be a useful tool to monitor trends in HIV testing in US EDs. A high proportion of visits to EDs in the United States were made by uninsured and Medicaid insured persons, and routine HIV testing was a rare event during ED visits. PMID- 23018378 TI - NKG2D expression on HIV-specific CD8+ T cells is reduced in viremic HIV-1 infected patients but maintained in HIV controllers. AB - NKG2D mediates an important costimulatory pathway in CD8 T cells. In HIV infection, the authors found that NKG2D expression on both total CD8 and HIV specific CD8 T cells was significantly lower in viremic patients than in HIV controllers. Antiretroviral therapy partially restored NKG2D expression on HIV specific CD8 T cells. The authors observed a negative correlation between the respective expression levels of CD38 and NKG2D on total CD8 and HIV-specific CD8 T cells. The maintenance of NKG2D expression on CD8 T cells in HIV controllers may contribute to better cell function. PMID- 23018377 TI - Associations between genital tract infections, genital tract inflammation, and cervical cytobrush HIV-1 DNA in US versus Kenyan women. AB - Cervical shedding of HIV-1 DNA may influence HIV-1 sexual transmission. HIV-1 DNA was detected in 250 (80%) of 316 and 207 (79%) of 259 cervical cytobrush specimens from 56 US and 80 Kenyan women, respectively. Plasma HIV-1 RNA concentration was associated with increased HIV-1 DNA shedding among US and Kenyan women. Kenyan women had higher cervicovaginal concentrations of proinflammatory interleukins (IL)-1beta, IL-6, IL-8, and anti-inflammatory secretory leukocyte protease inhibitor compared with US women (all P < 0.01). HIV 1 DNA shedding was associated with increased concentrations of IL-1beta and IL-6 and lower secretory leukocyte protease inhibitor among US women but not Kenyan women. PMID- 23018379 TI - Low-level HIV viremia is associated with microbial translocation and inflammation. AB - BACKGROUND: Decrease in HIV viral load (VL) is accompanied by decrease in microbial translocation (MT) and chronic inflammation, but the behavior of these markers in patients with HIV-VL <20 copies per milliliter is unknown. The aim of this study was to determine whether strict control of HIV-VL is associated with MT and chronic inflammation. METHODS: Observational cross-sectional study. INCLUSION CRITERIA: HIV patients receiving antiretroviral therapy and HIV-VL <200 copies per milliliter for more than 6 months. EXCLUSION CRITERIA: chronic liver disease, active infection, or antibiotic consumption. Recruitment: patients who consecutively visited the outpatient clinic in November 2011. Primary endpoint: molecular MT as determined by detection in plasma of 16S ribosomal DNA. Secondary variables: lipopolysaccharide, soluble CD14, tumor necrosis factor alpha, and interleukin 6. Primary explanatory variable: HIV-VL (COBAS AmpliPrep/COBAS TaqMan HIV-1 test, version 2.0) with a detection limit of 20 copies per milliliter. RESULTS: Fifty-two patients were included: 65% men, median age 45 years, HIV acquired predominantly through sex (75%), 40% Centers for Disease Control and Prevention stage C, and median CD4 lymphocyte count 552 cells per cubic millimeter (range, 126-1640 cells/mm). Molecular MT was observed in 46% and 18% of patients with low-level (20-200 copies/mL) and negative (<20 copies/mL) HIV VL, respectively (P < 0.05). Plasma levels of inflammatory markers (tumor necrosis factor alpha and interleukin 6) were higher in patients with molecular MT (P < 0.01) and were not influenced for HIV-VL. CONCLUSIONS: Patients with HIV infection receiving treatment and negative HIV-VL (<20 copies/mL) present less frequently MT than patients with low-level HIV viremias (20-200 copies/mL). MT is associated with higher levels of inflammation markers, independent of HIV-VL. PMID- 23018381 TI - Naturally occurring variation in vasopressin immunoreactivity is associated with maternal behavior in female Peromyscus mice. AB - In many mammals, species-appropriate social behavior is necessary for an individual's ability to survive and reproduce. In the present study, we examined whether arginine-vasopressin (AVP) pathways that have been associated with social behavior differed between two closely related species of Peromyscus mice with different patterns of maternal behavior. We also tested whether individual levels of AVP-immunoreactive staining (AVP-ir) were associated with individual levels of maternal behavior as measured using a composite score consisting of huddling, nursing, grooming and time spent inside the nest (HNGI score). In addition, we examined whether these associations between vasopressin and behavior differed between species. Females from the highly biparental species, California mice, displayed higher AVP-ir in the bed nucleus of the stria terminalis (BNST), which corresponded with a higher level of nest building and a higher HNGI score than was found in the less parental white-footed mice. The HNGI score was positively associated with AVP-ir in the medial amygdala in female California mice but not white-footed mice. Finally, we examined whether AVP-ir in these pathways varied based on the species-specific rearing environments by reciprocally cross fostering California mice and white-footed mice. In contrast to previous research with male California mice, cross-fostering itself had no effect on maternal behavior or any consistent effect on AVP-ir staining in brain areas such as the BNST and associated brain areas. This suggests that there is little plasticity in maternal behavior and that the underlying AVP system in females does not respond to the postnatal environment provided by the parents. The positive associations between maternal behavior and AVP-ir indicate that AVP may regulate maternal behavior despite the lack of plasticity in AVP and maternal behavior. PMID- 23018382 TI - Epitaxial growth of TiO2 films with the rutile (110) structure on Ag(100). AB - Ultrathin films of TiO(2) were grown on Ag(100) by evaporation of titanium in the presence of O(2) at a pressure in the 10(-4) Pa range and annealing at 770 K. The composition of the deposited films was monitored by XPS and LEIS. The morphology at the nanometric scale of the TiO(2) films and their crystallographic structure were investigated by means of STM, LEED and XPD. Above the monolayer coverage (at which the oxide film has a lepidocrocite-like structure), STM images show the formation of multilayer islands with a distribution of heights. XPD results indicate that these oxide islands have the rutile (110) structure and are epitaxially oriented with the sides of the oxide unit cell parallel to those of the substrate unit cell. The results of the DFT calculations justify the 3D growth of rutile (110) on Ag(100). The calculated strain energy required to match the metal substrate can explain the incommensurate growth of the overlayer in the direction of the long side of the oxide unit cell. The results of the calculations indicate that a commensurate growth of rutile (110) may be possible along the short side of the oxide unit cell, taking into account the relatively small strain energy to fit the lattice parameter of the substrate. The DFT calculations predict a considerable increase of the work function upon deposition of titania films on Ag(100), which can be attributed to a charge transfer from the metal to the 3d Ti empty states. PMID- 23018380 TI - News and Views into the SNARE Complexity in Arabidopsis. AB - Secretory organelles are engaged in a continuous flux of membranes, which is believed to occur mostly via transport vesicles. Being critical in maintaining several cellular functions, transport vesicles are membrane-enclosed sacs that temporarily store and then deliver membrane lipids, protein, and polysaccharides. SNAREs have a crucial role in vesicle traffic by driving membrane fusion and conferring fidelity through the formation of specific SNARE complexes. Additionally, specific roles of SNAREs in growth and development implicate that they are versatile components for the life of a plant. Here, we summarize the recent progress on the understanding of the role of SNAREs and highlight some of the questions that are still unsolved. PMID- 23018383 TI - Food-cooking processes modulate allergenic properties of hen's egg white proteins. AB - BACKGROUND AND OBJECTIVE: Reducing the allergenicity of food allergens can suppress the clinical symptoms of food allergy. The objective of the present study was to investigate the effects of processing on the allergenic properties of hen's egg white proteins. METHODS: Eggs were processed by traditional Chinese cooking, including steaming, water boiling, frying, spicing and tea boiling. The contents of processed egg protein were assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis; the allergenicity was evaluated by Western blotting, enzyme-linked immunosorbent assay and enzyme allergosorbent test inhibition. Circular dichroism spectrum analysis of four major egg allergens from various egg products was performed as well. A mouse model of food allergy was developed to test the allergenicity of processed egg protein in vivo. RESULTS: Protein degradation was significant following tea boiling and spiced-tea boiling. The total allergenic potential of water-boiled egg and fried egg was relatively higher than that of steamed egg, spiced egg and tea-boiled egg. Challenge with proteins from raw egg, water-boiled egg and fried egg induced skewed T-helper 2 pattern responses (Th2 responses) in the intestine of mice sensitized to egg proteins; however, when the mice sensitized to egg proteins were challenged with proteins from steamed egg, spiced egg and tea-boiled egg, respectively, only weak Th2 responses were induced in their intestine. CONCLUSION: Processing by steaming, spicing, or tea boiling can weaken the allergenicity of egg proteins. PMID- 23018384 TI - The contribution of the University of Sao Paulo School of Nursing in the health scenario. PMID- 23018385 TI - [The effects of infertility on the spouses' relationship]. AB - The present study investigated the effects of infertility on the spouses' relationship, with the objectives to describe the profile of the studied population, and analyze the effects of infertility on their emotional, sexual and marital life. To do this, a cross-sectional and prospective study was performed in a specialist institution. The sample consisted of 50 infertile couples with a mean of six years of infertility. The women manifested negative feelings in view of the infertility, while the men assumed an attitude of support. The effects on the couples' sexual life were more pronounced in women, and the infertility treatment resulted in positive changes for both spouses. No differences were found regarding the effects of infertility between the women who had undergone more than one treatment and those undergoing treatment for the first time; between the men there were differences in the emotional aspect (frustration and relief) and in the marital relationship (strengthening and maturing). PMID- 23018386 TI - [The production of knowledge regarding gestational hypertension in the stricto sensu graduate nursing studies in Brazil]. AB - This documental study analyzed the Brazilian production of stricto sensu nursing graduate programs related to gestational hypertension. The data source used was the Brazilian Nursing Association Theses and Dissertations Database. The survey located 14 studies produced between 1979-2008, produced mainly in the Southeast region between 1996 and2008. The analytical process revealed a concern with the subjectivity of pregnant women and with aspects regarding nursing care. Furthermore, it showed that most studies used a qualitative methodology supported by nursing theories. The experience lived by pregnant women with hypertension is marked by negative feelings and socioeconomic problems, and is also affected by how the family is organized. The culture of pregnant women with hypertension is disregarded and they receive care in a context in which the disease is the priority. In conclusion, despite some scientific advancements, this topic has not raised the interest it deserves among nurses attending graduate study programs. PMID- 23018387 TI - [Breastfeeding: knowledge and practice]. AB - The objective of this study was to characterize the practices of breastfeeding promotion developed by nursing professionals of the Family Health Strategy and analyze the correlation between their knowledge of breastfeeding and how often they provided teaching regarding this topic. This cross-sectional, descriptive study was performed at the Family Health Strategy units of Uberaba, Minas Gerais with 85 nursing professionals, using two questionnaires. Data analysis was performed using frequency distribution and Spearman's correlation analysis. Most professionals said that they often addressed breastfeeding in the investigated practices. However, a poor correlation was observed between the frequency of this approach and the mean score on knowledge test. The nursing professionals' statements indicate that breastfeeding recommendations were provided regardless of their knowledge on the topic. PMID- 23018388 TI - [The evaluation of an instrument for pediatric oncology patient classification]. AB - The objectives of this study were to assess the interrater reproducibility of the instrument to classify pediatric patients with cancer; verify the adequacy of the patient classification instrument for pediatric patients with cancer; and make a proposal for changing the instrument, thus allowing for the necessary adjustments for pediatric oncology patients. A total of 34 pediatric inpatients of a Cancer Hospital were evaluated by the teams of physicians, nurses and nursing technicians. The Kappa coefficient was used to rate the agreement between the scores, which revealed a moderate to high value in the objective classifications, and a low value in the subjective. In conclusion, the instrument is reliable and reproducible, however, it is suggested that to classify pediatric oncology patients, some items should be complemented in order to reach an outcome that is more compatible with the reality of this specific population. PMID- 23018389 TI - Social support, socioeconomic and clinical risk: comparison between neighborhoods in a Brazilian upcountry town. AB - The objective of this study was to compare the perceptions of two families living in two different neighborhoods (rated according to risk levels) regarding social support. A questionnaire was designed to assess social support according to the following dimensions: instrumental, emotional, religious, and support from friends, neighbors and family. The sample was comprised as follows: considering the 114 families living in neighborhood 1, 52 families were interviewed; and among the 162 families living in neighborhood 2, 60 families were interviewed. No significant difference was found related to instrumental, religious and emotional support, including the support from relatives among the families from both neighborhoods. The results disagree with the reviewed literature, which indicated a strong association between social support and families living at socioeconomic risk. In conclusion, social support is important for families, regardless of their risk stratification. PMID- 23018390 TI - [Differences between female and male adolescents regarding individual vulnerability to HIV]. AB - The objective of this study was to comparatively analyze male and female adolescents' vulnerability to HIV/AIDS, based on their knowledge, values and practices. This is an exploratory-descriptive study, performed using a quantitative approach. The students answered a questionnaire from which relevant questions were selected for the analysis. The participants were 207 adolescents, 43.5% male and 56.5% female. Most adolescents report having initiated sexual activities. It was observed that the participants have knowledge deficits regarding HIV transmission and safe sexual practices. Although they report knowing about condom use as a method of protection against HIV, they do not always use them. It was observed that there are values connected to the representations of gender, but it is noticed there is an evolution regarding the autonomy and power of the girls' negotiation regarding condom use. PMID- 23018391 TI - [Religious/spiritual coping in people with chronic kidney disease undergoing hemodialysis]. AB - The objective of the present study is to investigate the use of religious/spiritual coping mechanisms in patients with chronic kidney disease undergoing hemodialysis, by means of interviews using a sociodemographic questionnaire and the religious/spiritual coping scale. Data analysis was performed using descriptive statistics and multiple linear regression. A total of 123 individuals were interviewed, 79.6% of whom presented a high score for religious/spiritual coping and none of whom presented low or irrelevant scores. The variables that affected the religious/spiritual coping behavior were: gender, age group, treatment time, family income, and religious practice. In conclusion, the participants used religious/spiritual coping mechanisms as a strategy to cope with the disease, particularly women with a higher family income who attend church every week. PMID- 23018393 TI - [Educational intervention regarding hypothermia: a teaching strategy for education in the surgery department]. AB - This is a quasi-experimental study performed using a short-term educational intervention involving nursing aides working in a Surgery Department, with the objective to identify the social and professional characteristics of the nursing aides, identify the differences in their knowledge regarding hypothermia following the educational intervention, and relate the nursing actions to the studied variables. It was found that the educational intervention was effective, considering that the difference in the mean nursing actions was 5.35 following the intervention. However, no significant difference was found regarding the nursing actions related to the studied variables. Further studies should be performed to investigate the education of nursing professionals considering their significant learning requirements in different units. PMID- 23018392 TI - [The use of severity indexes to estimate the risk of death in Intensive Care]. AB - The Simplified Acute Physiology Score II (SAPS II) and Logistic Organ Dysfunction System (LODS) are instruments used to classify Intensive Care Unit (ICU) inpatients according to the severity of their condition and risk of death, and evaluate the quality of nursing care. The objective of this study is to evaluate and compare the performance of SAPS II and LODS to predict the mortality of patients admitted to the ICU. The participants were 600 patients from four ICUs located in Sao Paulo, Brazil. Receiver Operator Characteristic (ROC) curves were used to compare the performance of the indexes. RESULTS: The areas under the ROC curves of LODS (0.69) and SAPS II (0.71) indicated moderate discriminatory capacity to identify death or survival. No statistically significant differences were found between these areas (p=0.26). In conclusion, there was equivalence between SAPS II and LODS to estimate the risk of death of ICU patients. PMID- 23018394 TI - [Using the braden scale and photographs to assess pressure ulcer risk]. AB - The objective of this paper was to identify critically ill patients at risk for pressure ulcer (PU) using the Braden scale and digital photographs. A sample of 42 subjects was evaluated for 15 days, between March and June 2009, in Fortaleza, Brazil. A total of 47 lesions were identified, 23 (48.9%) as stage I and 24 (51.1%) as stage II. It is necessary for nurses to become familiar with and adopt the technologies used to assess and treat PU in order to lessen the negative effects of this public health problem. PMID- 23018395 TI - [Post-operative mediastinitis in a heart hospital of Recife: contributions for nursing care]. AB - The objective of this study was to determine the prevalence of post-operative mediastinitis with the purpose to contribute to nursing care knowledge. To do this, an analysis was performed on 896 medical records of patients who underwent heart surgery involving sternotomy at the Cardiology Emergency Room of Recife-PE, in the period between June 2007 and June 2009. The following variables were considered: gender, age, type of surgery, personal history, length of stay, use of antibiotics, and culture of the surgical wound. A high death rate from mediastinitis was observed (33.3%). Several risk factors were identified, including: systemic arterial hypertension (80.9%); smoking (61.9%); diabetes mellitus (42.8%); and obesity (33.3%), most of which (76.2%) were identified in patients who underwent surgery for myocardial revascularization. It is concluded that mediastinitis is a serious infection that needs continuous nursing supervision and preventive measures to assure an early diagnosis and, thus, reduce mortality. PMID- 23018396 TI - [Body temperature, Aldrete-Kroulik index, and patient discharge from the post anesthetic recovery unit]. AB - Patient discharge from post-anesthetic recovery (PAR) depends, among other factors, on normothermia and the patient's score on the Aldrete-Kroulik index. The objective of this study was to verify the relationship between the Aldrete Kroulik index and body temperature in patients. This study was performed at the University of Sao Paulo University Hospital. Convenience sampling was used, and the sample consisted of 60 patients of ages between 18 and 60 years who underwent general anesthesia. The patients' body temperature was obtained by tympanic measurement, and the Aldrete-Kroulik index was measured on admission and at discharge from post-anesthetic recovery. The data were processed using SPSS, considering a significance level of 5%, and the Spearman and Wilcoxon tests were applied. In conclusion, no significant correlation was found between the two parameters for discharge. PMID- 23018397 TI - [Characteristics of a population of sex workers and their association with the presence of sexually transmitted diseases]. AB - The objectives of this study were to describe a population of sex workers considering their sociodemographic characteristics, gyneco-obstetric history and behavioral factors, and to verify the association of these characteristics with the presence of sexually transmitted diseases. This epidemiological cross sectional study was performed with 102 female sex workers. Data were collected using structured interviews and gold-standard exams for diagnosis of the diseases of interest. The women's mean age was 26.1 years. Most of them had attended school for nine years or more, were single and reported becoming sexually active before 15 years of age. Performing oral sex on partners was cited by 90.2% of women, and 99% reported the use of condoms at work; only 26.3% used condoms with permanent partners, and 42.2% used illicit drugs. No association was observed between sociodemographic factors, gyneco-obstetric history or behavioral factors and sexually transmitted diseases, which may have been due to their educational status and the fact that the population had very similar characteristics, thus making it difficult to determine such associations. PMID- 23018398 TI - [The profile of women with HIV/AIDS and their adherence to the antiretroviral therapy]. AB - The objectives of this study were to characterize the sociodemographic and clinical profiles, health behaviors, beliefs and attitudes towards the disease and treatment of women with HIV/AIDS, outpatients of a university hospital located in the interior of Sao Paulo state, and to identify the factors that affect their adherence to antiretroviral therapy. The participants were 60 female outpatients of the referred service. The data were collected through semi structured interviews. The women's mean age was 39.8 (standard deviation of 9.1) years; most of the women had a low education level, lived in deprived socioeconomic conditions, and were in a stable relationship. The most frequent form of infection was through a heterosexual relationship; 55% of the women had abandoned treatment, and their main reasons were the imposed therapeutic schemes, the side effects of antiretroviral drugs, coping with the disease, and the perspective of imminent death; 35% did not meet the adherence criteria, considered as taking 95% of the prescribed antiretroviral therapy. PMID- 23018399 TI - [Sleep quality in HIV-positive outpatients]. AB - The objective of this study was to characterize the sleep quality of Human Immuno Deficiency Virus (HIV) seropositive outpatients with or without AIDS symptoms. This is a descriptive and cross-sectional study. Sociodemographic and clinical data were collected by means of a questionnaire, and sleep quality by means of the Pittsburgh Sleep Quality Index, Brazilian version. Participants were 122 subjects (55.7% male, 44.3% female; mean age 42.3 +/- 8.9 years); 53.3% reported good sleep quality and 46.7% reported poor sleep quality. Subjects reported sleeping a mean of 7.3 (+/- 1.8) hours; sleep latency was 23.2 (+/- 26.2) minutes, and sleep efficiency, 87.8% (+/- 14.4). A significant association was found between good sleep quality and: having a partner; undetectable viral load; and maintenance of risk behavior. It is recommended that nursing professionals systematically include questions regarding sleep when evaluating patients with HIV/AIDS, so that changes are detected early and relevant background information is obtained in order to plan interventions. PMID- 23018400 TI - [The evaluation of the level of hope of elderly chronic kidney disease patients undergoing hemodialysis]. AB - The objective of the present study was to evaluate the level of hope of elderly chronic kidney disease patients undergoing hemodialysis, using the Herth Hope Scale (HHS). This cross-sectional descriptive study was performed at a Renal Replacement Therapy Unit located in upstate Sao Paulo. The sample consisted of 50 elderly patients currently undergoing hemodialysis treatment. After obtaining the participants' consent to participate, individual interviews were performed with the elderly individuals, utilizing a characterization instrument and the Herth Hope Scale. All of the ethical premises were complied with (protocol 512/2009). Regarding the results, most participants were male (60%) and their mean age was 70.20 (+/-6.1) years. The mean score on the Herth Hope Scale was 36.20 (+/-2.90). In conclusion, compared with the Brazilian study regarding the validation of the Herth Hope Scale, the subjects' level of hope was lower, thus indicating a need to intervene regarding this feeling. PMID- 23018401 TI - [The elderly with cognitive alterations in the context of poverty: a study of the social support network]. AB - The objective of this study was to analyze the structure and role of social support networks for the elderly with cognitive alterations, who lived in a context of high or very high social vulnerability, and identify the associations between the characteristics of the networks and functional capacity. The participants were 38 aged individuals living in a context of high or very high social vulnerability whose score on the Mini-Mental State Examination was below the cut-off point. All ethical considerations were observed. The following were administered: Mini-Mental State Examination, Convoy of Social Support, Katz Index, and Pfeffer Questionnaire. The results show that the elderly participants have a large social network, with most members in their inner circle, but only a few of the members play functional roles. A correlation was observed between the gender variable and the number of social network members. No significant correlation was observed between network characteristics and the functional capacity of the elderly. PMID- 23018402 TI - [Nurses' representations regarding the care of women experiencing unsafe abortion]. AB - Abortion, a current reality in our society, is a complex challenge for healthcare professionals. The objective of this article is to report the representations that Primary Healthcare nurses from the city of Chapeco (SC) have regarding the care of women experiencing abortion/unsafe abortion. This is a qualitative, exploratory-descriptive study. Data were collected by means of focal groups comprised of eight nurses, and then analyzed using the method of Collective Subject Discourse Analysis. The discourses indicate that the care provided is permeated with conflicts between assuming an attitude against abortion, supporting the women or remaining impartial. The representation of the preservation of life, a principle taught by professional training and Christian tradition, triggers attempts to convince the women to avoid the abortion. When nurses are not successful in trying to help women find a safe alternative, they advise them to go home and think about the situation, making it clear to the women that she is not the professional who performs the abortion and abandoning the women... PMID- 23018403 TI - [Home blood pressure monitoring and control in a group of hypertensive patients]. AB - This qualitative study was performed with 71 hypertensive patients, with the objectives to compare outpatient and home blood pressure monitoring (HBPM), to assess blood pressure control, and characterize white-coat hypertension. A nurse performed the outpatient blood pressure measurement. The home blood pressure monitoring was carried out over seven days. White-coat hypertension was quantified as a difference between the outpatient measurement and home blood pressure monitoring in the ranges from 1 to 5, 6 to 10 and > 10 mmHg. The outpatient blood pressure measurement was significantly higher (p<0.05) than the home blood pressure measurement. Pressure control corresponded to 9.9% in the outpatient measurement and 23.9% in the home blood pressure measurement. The white-coat effect > 10 mmHg was 57.7% for systolic and 32.4% for diastolic pressure, in the range from 6 to 10 mmHg. Home blood pressure measurement provided a better assessment of hypertensive patients' control. PMID- 23018404 TI - [Maternal care of the premature child: a study of the social representations]. AB - The objective of this study was to identify the social representations of mothers regarding the maternal care provided to a premature child. The participants were 30 mothers of premature infants, who attended three early stimulation classes in Jequie-BA. The Free Words Association Test was used for data collection. Participants were asked to say five words about provision of maternal care to the premature child and to rank the words according to importance. The data were processed using EVOC 2003, generating a four-place chart. In the upper left corner, the words love and affection appeared; in the upper right, anguish, attention, affection, and patience; in the lower left, fear and prevention; and in the lower right, joy, devotion, dependence, difficulty, experience, protection, responsibility, and overcoming. Love and care appear to be the center of the representations. Love refers to the exercise of the mother role. Care may represent the wish to find improvements for their child. PMID- 23018405 TI - [The family planning of women with mental disorders: what CAPS professionals have to say]. AB - The objective of this study was to explore the family planning demands that occur at the Psychosocial Care Center (Centro de Atendimento Psicossocial - CAPS) and investigate the contributions of this service to women with mental disorders. This qualitative study was performed with eight workers from a CAPS located in Fortaleza-CE. Data collection was performed through interviews, and the data were submitted to content analysis. The following demands were identified: relatives' request for information on how to cope with a sexually active patient; patients susceptible to sexual violence and pregnancy; and women with depression taking lithium carbonate. Contributions identified were: the need for an integrated network (primary healthcare/CAPS) with professionals who understand the complexities regarding these women's family planning; supportive care should be provided in the primary healthcare setting, emphasizing matrix organization as a strategy to make both centers co-responsible, thus avoiding unnecessary patient referrals to the CAPS by strengthening the ability to deal with these cases in the primary healthcare setting. PMID- 23018406 TI - [Comprehensiveness according to the perception of Family Health Unit workers]. AB - The objective of this study was to identify the perceptions of healthcare workers regarding the principle of comprehensiveness. To do this, a research was performed with five workers from a Family Health Unit located on the east side of Sao Paulo. This study was performed with a qualitative approach, using interviews and thematic analysis. Three categories emerged from the discourses: comprehensiveness as the profile and practice of healthcare professionals, focused on the humanization of care; comprehensiveness as the organization of the health service and working process; and comprehensiveness as the integration of the unit with other health services. In each dimension, it was revealed that the workers perceived the absence or presence of this principle as a guide for healthcare, problematizing the advancements and problems they experienced, as well as the challenges involved in changing the healthcare model. PMID- 23018407 TI - [Alternative experiences rescuing knowledge for working processes in health]. AB - This descriptive study was performed using a qualitative approach, with the objective to understand the working process of nurses and physicians of the Family Health Strategy (FHS) in Joao Pessoa-PB, and identify the alternative strategies and procedures they developed. The material was analyzed according to the discourse analysis technique. It was shown that the elements of the working process were disconnected, allied with a possibility of change by overcoming the invisibility of the subjects and their knowledge in healthcare services. In conclusion, the identified alternative strategies and procedures are in the embryonic stage in terms of the transformation of working processes and overcoming of hegemonic healthcare models, therefore demanding a continuous problematization of concepts and practices. PMID- 23018408 TI - [Correlation between quality of life and morbidity of the caregivers of elderly stroke patients]. AB - The objective of this study was to describe the sociodemographic characteristics and the quality of life of the caregivers of elderly individuals with a stroke history, and correlate morbidity with the caregivers' quality of life scores. This is a cross-sectional household survey that interviewed the caregivers of elderly individuals using the following tools: a semi-structured instrument; the World Health Organization Quality of life-BREF; and the Brazilian Multidimensional Functional Assessment Questionnaire. Descriptive analysis and Pearson's correlation (p<0.05) were performed. Most participants were female (93.5%), with a mean age of 55.4+/-14.17 years, married or living with a partner (58.7%), with four to eight years of education (28.3%), and an income equivalent to one minimum wage salary (34.8%). The highest quality of life score was in the social relations domain (67.57) and the lowest was in the environmental domain (54.82). The highest number of caregiver morbidities correlated with the lowest scores in all quality of life domains. PMID- 23018409 TI - [Software CMAP TOOLS TM to build concept maps: an evaluation by nursing students]. AB - Concept mapping (CM) is a teaching strategy that can be used to solve clinical cases, but the maps are difficult to write. The objective of this study was to describe the challenges and contributions of the Cmap Tools(r) software in building concept maps to solve clinical cases. To do this, a descriptive and qualitative method was used with junior nursing students from the Federal University of Sao Paulo. The teaching strategy was applied and the data were collected using the focal group technique. The results showed that the software facilitates and guarantees the organization, visualization, and correlation of the data, but there are difficulties related to the handling of its tools initially. In conclusion, the formatting and auto formatting resources of Cmap Tools(r) facilitated the construction of concept maps; however, orientation strategies should be implemented for the initial stage of the software utilization. PMID- 23018410 TI - [Nursing process: what does it mean to nurses from Santa Cruz (Bolivia)?]. AB - Bolivian nurses have not yet incorporated the scientific method and taxonomies into nursing care. This qualitative study aims at understanding the meaning that faculty and nursing professionals from the Department of Santa Cruz de la Sierra (Bolivia) attribute to the nursing process. Data collection was performed through interviews and participant observation. The analysis was performed using the theoretical and methodological framework of Symbolic Interactionism and Grounded Theory, utilizing ATLAS.ti.6.0. The following topics emerged from the data: difficulties in implementing the nursing process due to a lack of preparation and training in leadership, dominance by physicians, lack of records, and poor support from the institution. Advantages were that it combines criteria and language and facilitates the autonomous role of nursing. In conclusion, nurses should establish their professional expectations regarding the implementation of the nursing process and care plans, which is a cultural change that involves faculty, management and clinical nurses. PMID- 23018411 TI - [The evaluation of nursing graduates' scientific reasoning and oral and written communication]. AB - This descriptive, cross-sectional study was performed in Santiago de Chile, with the objective to evaluate the scientific reasoning and the oral and written communication of nursing graduates. The sample consisted of 37 nursing graduates who participated in the three stages of the study: I) creation and validation of the instrument; II) training the faculty participating in the study to apply the instrument uniformly; and III) application of the instrument and data analysis. The data show different percentages regarding this competency, with the predominance of scientific reasoning (83.16%), followed by oral and written communication (78.37%). In conclusion, this study demonstrates the value for nursing schools to implement a formal evaluation that allows for determining the profile of nursing graduates, guaranteeing the quality of their training and education. PMID- 23018412 TI - [The identification of the pillars of education in the class comprehensiveness in healthcare]. AB - The objective of the present study was to verify, based on the analysis of student portfolio narratives, if the four pillars of education were approached in the class Comprehensiveness in health care, part of the integrated curriculum of the Baccalaureate in Nursing Program of the University of Sao Paulo at Ribeirao Preto College of Nursing. A qualitative, documental study was performed using 46 portfolios constructed during the classes. Data collection was performed using an assessment tool that contained items addressing cognitive and affective dimensions. The data were submitted to thematic categorical analysis using the pillars of education as predefined categories. The results show that the pillars of education were, apparently, included in the class. Despite the present study findings, no evidence was found that the expected competencies were actually discussed among students and faculty, according to the records regarding the evaluations of each pedagogical cycle of the studied class. PMID- 23018413 TI - [Nursing diagnoses analysis under the bayesian perspective]. AB - The use of Bayesian statistical techniques is an approach that is well accepted and established in fields outside of nursing as a paradigm to reduce the uncertainty present in a given clinical situation. The purpose of this article is to provide guidance regarding the specific use of the Bayesian paradigm in the analysis of nursing diagnoses. The steps and interpretations of Bayesian analysis are discussed. One theoretical and one practical example of Bayesian analysis of nursing diagnoses are presented. It describes how the Bayesian approach can be used to summarize the available knowledge and make point and interval estimates of the true probability of a nursing diagnosis. It was concluded that the application of Bayesian statistical methods is an important tool for more accurate definition of probabilities related to nursing diagnoses. PMID- 23018414 TI - [Do the physical discomforts from breast cancer treatments affect the sexuality of women who underwent mastectomy?]. AB - The objective of this integrative review is to analyze the scientific production addressing the sexuality of women with breast cancer following mastectomy, focused on the effects that the physical discomfort due to cancer treatments have on their sex life. The search included articles published in the period between 2000 and 2009 on the MEDLINE, LILACS and PsycINFO databases, using the following descriptors: mastectomy, breast neoplasms, sexuality, sexual behavior, amputation, psychosexual development, and marital relations. Nine articles were selected, which addressed the effects of the physical discomfort from cancer treatments on the patients' sexuality. The findings revealed that, even when the patient's sex life is intense and fulfilling before the disease, factors such as stress, pain, fatigue, insult to body image, and low self-esteem due to the treatments may alter the sexual functioning of the affected woman. Healthcare professionals must be sensitized in order to welcome and include the topic in policies as well as in preventive, diagnostic, and therapeutic strategies. PMID- 23018415 TI - [The impact of urinary incontinence of the lives of wives of men with incontinence: an integrative review]. AB - Male urinary incontinence has been related to several factors, among which benign prostatic hyperplasia and prostate cancer treatment are highlighted. Urinary incontinence has negative effects on patients as well as on their relatives and caregivers. In the present study, an integrative review was performed with the purpose to identify the impact that urinary incontinence has on the lives of the patients' partners. The article survey was performed on the following databases: CINAHL, EMBASE, SCOPUS, MEDLINE, and PubMed. Articles were included if they were written in Portuguese, English or Spanish, and excluded if they did not mention the patients' wives. The final sample was comprised of 15 articles from seven countries. The articles were distributed into the following categories: Psychological Distress, Fatigue, Change in Sex Life, and Limitations on Social Life. The category Psychological Distress was present in all articles and was rated as having the most impact on these women's lives. PMID- 23018416 TI - [The cultural history of palliative care in primitive societies: an integrative review]. AB - The objective of this study is to describe the evolution of palliative care in order to reflect on the possibility of its origin in primitive cultures and their relationship with the beginnings of the cult of the dead. It describes the change in the symbolic structures and social interactions involved in palliative care during prehistory: functional unit, functional framework and functional element. The theoretical framework is based on cultural history, the dialectical structural model and symbolic interactionism. Categorization techniques, cultural history and dialectic structuralism analyses were performed. Palliative care existed in primitive societies, mostly associated with the rites of passage with a high symbolic content. The social structures - functional unit, functional framework and functional element - are the pillars that supported palliative care in prehistory societies. PMID- 23018417 TI - Long-term effects of deep brain stimulation for essential tremor with subjective and objective quantification via mailed-in questionnaires. AB - BACKGROUND: Deep brain stimulation (DBS) is a standard treatment for patients with disabling essential tremor. The short-term efficacy rate is well established. OBJECTIVES: To assess the long-term effects of DBS in our series and evaluate the durability of the effects over time. METHODS: Eighty-four patients implanted with unilateral or bilateral DBS for essential tremor were asked to complete three mailed-in questionnaires to assess DBS efficacy objectively and subjectively. RESULTS: Twenty-six patients responded, with a median follow-up of 41 months. Approximately half of the patients had more than 48 months of follow up. At the time of follow-up, the Tremor Rating Scale was reduced from a mean score of 7 (5-8) to 3 (2-3) with DBS OFF and ON, respectively. Quality of life, measured with a subset of items of the ADL Taxonomy, improved from a mean of 26 (23-33) to 12 (12-14), comparing DBS OFF and ON. No significant differences were seen when comparing efficacy at short- (<12 months), middle- (12-48 months) or long-term (>48 months) follow-ups. CONCLUSION: DBS has long-term efficacy for tremor control. This is associated with sustained benefits in quality of life. The duration of the follow-up was not associated with any significant difference in efficacy. PMID- 23018418 TI - Detection of abnormalities in the superficial zone of cartilage repaired using a tissue engineered construct derived from synovial stem cells. AB - The present study investigated the surface structure and mechanical properties of repair cartilage generated from a tissue engineered construct (TEC) derived from synovial mesenchymal stem cells at six months post-implantation compared to those of uninjured cartilage. TEC-mediated repair tissue was cartilaginous with Safranin O staining, and had comparable macro-scale compressive properties with uninjured cartilage. However, morphological assessments revealed that the superficial zone of TEC-mediated tissue was more fibrocartilage-like, in contrast to the middle or deep zones that were more hyaline cartilage-like with Safranin O staining. Histological scoring of the TEC-mediated tissue was significantly lower in the superficial zone than in the middle and deep zones. Scanning electron microscopy showed a thick tangential bundle of collagen fibres at the most superficial layer of uninjured cartilage, while no corresponding structure was detected at the surface of TEC-mediated tissue. Immunohistochemical analysis revealed that PRG4 was localised in the superficial area of uninjured cartilage, as well as the TEC-mediated tissue. Friction testing showed that the lubrication properties of the two tissues was similar, however, micro-indentation analysis revealed that the surface stiffness of the TEC-repair tissue was significantly lower than that of uninjured cartilage. Permeability testing indicated that the TEC-mediated tissue exhibited lower water retaining capacity than did uninjured cartilage, specifically at the superficial zone. Thus, TEC-mediated tissue exhibited compromised mechanical properties at the superficial zone, properties which need improvement in the future for maintenance of long term repair cartilage integrity. PMID- 23018419 TI - Intraoperative engineering of osteogenic grafts combining freshly harvested, human adipose-derived cells and physiological doses of bone morphogenetic protein 2. AB - Engineered osteogenic constructs for bone repair typically involve complex and costly processes for cell expansion. Adipose tissue includes mesenchymal precursors in large amounts, in principle allowing for an intraoperative production of osteogenic grafts and their immediate implantation. However, stromal vascular fraction (SVF) cells from adipose tissue were reported to require a molecular trigger to differentiate into functional osteoblasts. The present study tested whether physiological doses of recombinant human BMP-2 (rhBMP-2) could induce freshly harvested human SVF cells to generate ectopic bone tissue. Enzymatically dissociated SVF cells from 7 healthy donors (1 x 10(6) or 4 x 10(6)) were immediately embedded in a fibrin gel with or without 250 ng rhBMP 2, mixed with porous silicated calcium-phosphate granules (Actifuse((r)), Apatech) (final construct size: 0.1 cm(3)) and implanted ectopically for eight weeks in nude mice. In the presence of rhBMP-2, SVF cells not only supported but directly contributed to the formation of bone ossicles, which were not observed in control cell-free, rhBMP-2 loaded implants. In vitro analysis indicated that rhBMP-2 did not involve an increase in the percentage of SVF cells recruited to the osteogenic lineage, but rather induced a stimulation of the osteoblastic differentiation of the committed progenitors. These findings confirm the feasibility of generating fully osteogenic grafts using an easily accessible autologous cell source and low amounts of rhBMP-2, in a timing compatible with an intraoperative schedule. The study warrants further investigation at an orthotopic site of implantation, where the delivery of rhBMP-2 could be bypassed thanks to the properties of the local milieu. PMID- 23018420 TI - Covalent modification of reduced graphene oxide by means of diazonium chemistry and use as a drug-delivery system. AB - Under acidic conditions, reduced graphene oxide (rGO) was functionalized with p aminobenzoic acid, which formed the diazonium ions through the diazotization with a wet-chemical method. Surfactants or stabilizers were not applied during the diazotization. After the functionalized rGO was treated through mild sonication in aqueous solution, these functionalized rGO sheets were less than two layers, which was determined by atomic force microscopy (AFM) imaging. The water solubility of functionalized rGO after the introduction of polyethyleneimine (PEI) was improved significantly; it was followed by covalent binding of folic acid (FA) molecules to the functionalized rGO to allow us to specifically target CBRH7919 cancer cells by using FA as a receptor. The loading and release behaviors of elsinochrome A (EA) and doxorubicin (DOX) on the functionalized rGO sheets were investigated. The EA loading ratio onto rGO-C(6)H(4)-CO-NH-PEI-NH-CO FA (abbreviated rGO-PEI-FA, the weight ratio of drug loaded onto rGO-PEI-FA) was approximately 45.56 %, and that of DOX was approximately 28.62 %. It was interesting that the drug release from rGO-PEI-FA was pH- and salt-dependent. The results of cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM) assays, as well as cell morphology observations) clearly showed that the concentration of rGO-PEI-FA as the drug delivery composite should be less than 12.5 mg L(-1). The conjugation of DOX and rGO-PEI-FA can enhance the cancer-cell apoptosis effectively and can also push the cancer cells to the vulnerable G2 phase of the cell cycle, which is most sensitive and susceptible to damage by drugs or radiation. PMID- 23018421 TI - Membrane trafficking components in cytokinesis. AB - Cytokinesis, the last major step of cell division, is a complex multistage process involving specific rearrangement of cellular cytoskeleton and a flurry of vesicular transport activities at the cell division plane. Vesicular traffic from the exocytic pathway and the endocytic/recycling pathway, operating again after being shut down since prophase, are engaged to supply the mitotic midzone with materials that would facilitate furrowing, midbody thinning and subsequent abscission of daughter cells. Cytokinesis is spatial and temporally regulated by mitotic kinases, and involves modulation by Arf and Rab small GTPases and their effectors. The latter include vesicle targeting and tethering molecules such as motor proteins, tethering complexes and SNAREs. The process of abscission requires the ultimate engagement of endosomal sorting complex required for transport (ESCRT) complexes. Although a good deal of details remains to be deciphered, cytokinesis in eukaryotes could essentially be visualized as a specialized cellular event requiring complex spatial and temporal regulated processes of membrane traffic. PMID- 23018422 TI - Intravenous 'pulse' methylprednisolone for the treatment of inflammatory cystoid macular oedema. PMID- 23018423 TI - How would you manage this small melanocytic choroidal tumour? Small choroidal melanoma hiding a large extrascleral extension. PMID- 23018424 TI - Intravitreal injections: is there benefit for a theatre setting? AB - OBJECTIVE: To investigate and compare the rate of endophthalmitis after intravitreal injections performed in an in-office (dedicated procedure room) versus in-theatre setting. METHODS: A retrospective comparative cohort study was performed of all patients consecutively treated by a single surgeon with intravitreal injection with either ranibizimab or bevacizumab for any recognised clinical indication. All cases received injections between March 2006 and March 2012, during which time all injections were prospectively recorded on an electronic medical record system. A search of the electronic database using a report building system was used to extract the total number of injections into location-specific grouping (ie, in office vs in theatre). RESULTS: 12 249 injections were performed over a 6-year period. 3376 of these were performed in the in-office procedure room, compared with 8873 in the operating theatre. Of the 3376 injections performed in office, there were four cases of infective endophthalmitis compared with none of the 8873 injections performed in theatre (p=0.006). In-theatre intravitreal injections were associated with a 13-fold lower risk of endophthalmitis compared to in-office injections. CONCLUSIONS: The theatre environment is a clinically appropriate location for any intravitreal injection procedures and was associated with a significantly lower risk of infective endophthalmitis in this single-surgeon comparative cohort study. PMID- 23018426 TI - Strategy for cardiovascular repair: role of stem cells in 2012 and beyond. AB - Stem cell based repair of the heart has captured the mind and imagination of cardiovascular specialists and the lay public. Significant progress has been made at the bench defining the mechanisms of action. This work has gone on further to demonstrate that there is an endogenous stem cell based repair process that attempts to repair the myocardium in response to acute ischemic injury. At the same time investigators at both the bench and in clinical populations have investigated the effects of distinct adult stem cell populations in the peri infarct period as well as patients with chronic heart failure. In this review we attempt to lay a framework to review how cardiovascular regenerative medicine has progressed to date, summarize what we have learned to date, and discuss how the field may evolve in the future. PMID- 23018425 TI - Macular assessment using optical coherence tomography for glaucoma diagnosis. AB - Optical coherence tomography (OCT) is an interferometry-based imaging modality that generates high-resolution cross-sectional images of the retina. Circumpapillary retinal nerve fibre layer (cpRNFL) and optic disc assessments are the mainstay of glaucomatous structural measurements. However, because these measurements are not always available or precise, it would be useful to have another reliable indicator. The macula has been suggested as an alternative scanning location for glaucoma diagnosis. Using time-domain (TD) OCT, macular measurements have been shown to provide good glaucoma diagnostic capabilities. Performance of cpRNFL measurement was generally superior to macular assessment. However, macular measurement showed better glaucoma diagnostic performance and progression detection capability in some specific cases, which suggests that these two measurements may be combined to produce a better diagnostic strategy. With the adoption of spectral-domain OCT, which allows a higher image resolution than TD-OCT, segmentation of inner macular layers becomes possible. The role of macular measurements for detection of glaucoma progression is still under investigation. Improvement of image quality would allow better visualisation, development of various scanning modes would optimise macular measurements, and further refining of the analytical algorithm would provide more accurate segmentation. With these achievements, macular measurement can be an important surrogate for glaucomatous structural assessment. PMID- 23018427 TI - Retrograde approach for revascularization of coronary chronic total occlusion. AB - Retrograde approach via collateral channels in coronary angioplasty for chronic total occlusion (CTO) can improve recanalization success rate. Most interventionalists will meet few cases where the retrograde approach will provide unequaled advantages, but many are held back from taking retrograde approach by lack of proper equipment and expertise. In this article, we give detailed description of all techniques to traverse the collateral channels, and to cross the CTO by retrograde approach. We also illustrate the difficulties in collateral channel crossing with different examples providing a basic guide for case selection purposes. PMID- 23018428 TI - Restenosis in bare metal and drug-eluting stents: distinct mechanistic insights from histopathology and optical intravascular imaging. AB - An increasing body of evidence points to the existence of important differences in the processes of restenosis following drug-eluting stent (DES) as compared to bare metal stent implantation. Preclinical investigation and human autopsy studies have shown that the high efficacy of DES in comparison with bare metal stents in preventing restenosis is achieved at the collateral cost of a delay in healing of the stented arterial segment. Moreover bare metal stent restenosis is typically characterised by a homogeneous tissue rich in smooth muscle cells; whereas DES restenosis is more often hypocellular and proteoglycan-rich. In addition, in-stent neoatherosclerosis appears to have an accelerated course in DES. Angiographic surveillance studies show that while neointimal formation peaks six months after bare metal stenting, neointimal formation after DES therapy is temporally right shifted and remains a dynamic ongoing process (late luminal loss creep) even out to five years. The widespread availability of high resolution optical coherence tomography (OCT) is affording better understanding of the pathophysiology of in-stent restenosis. While bare metal stent restenosis is characterized by predominantly homogenous high-signal tissue echogenicity, layered pattern or heterogeneous tissue composition is more common in DES restenosis. Moreover, preliminary data suggests that tissue attenuation may increase in a time-dependent manner. Nevertheless, the paucity of direct histopathological correlation studies means that the tissue composition of these lesions remains speculative. Data from specifically designed imaging-pathology correlation studies in suitable preclinical models of restenosis and in autopsy specimens is eagerly awaited. Furthermore, although long-term longitudinal clinical follow-up is necessary to define the clinical relevance of optical imaging findings, the nature of restenosis as a disease entity means that its natural history is often altered by a mandate for repeat intervention directly following data acquisition. PMID- 23018429 TI - Left main and bifurcation stenting. AB - Coronary artery bypass graft (CABG) is considered as the gold standard treatment of unprotected left main coronary artery disease. Over the last 10 years, improvement in stent technology and operators experience explained the increased number of reports on the results of percutaneous coronary interventions for the treatment of left main (LM) coronary artery lesion particularly in the distal part of the trunk. Patient selection for bifurcation stenting is fundamental and directly impacts the clinical outcome. Many trials are conducted using bifurcated stenting technology. Further randomized trials must be conducted to precise the indications of both techniques (CABG-PCI) of revascularization in the treatment of LM disease. PMID- 23018430 TI - From bench to bedside: initial experience with the Primus drug-coated balloon catheter. AB - AIM: Drug-coated balloon (DCB) technology has emerged as a promising therapy particularly in the treatment of coronary in-stent restenosis. Although a variety of devices are available for clinical use, clinical outcomes have been variable and scope for significant improvement exists. METHODS: In a preclinical study, a total of 10 juvenile healthy farm pigs underwent catheter-based DCB deployment in coronary arteries with angiographic and pathological follow-up at 7 or 28 days. Animals were randomly allocated to the PRIMUS or Dior(r) DCB (N.=10 per group) and evaluated by histopathology and morphometric analysis. In a first-in-man clinical study a total of 19 consecutive patients presenting with restenosis within drug-eluting stents were treated with the PRIMUS DCB. Clinical follow-up was performed out to 6 months. RESULTS: Neointimal thickness was similar between the PRIMUS and Dior(r) DCB groups, while fibrin deposition and inflammation were more sustained in the PRIMUS group at 28 days. In 19 consecutive patients presenting with in-stent restenosis of drug-eluting stents, treatment with the PRIMUS DCB catheter resulted in high procedural efficacy. There were no adverse clinical events observed out to 6 months. CONCLUSION: The PRIMUS DCB demonstrates high preclinical safety and excellent acute performance and safety. Further studies are needed to delineate the relative merits of this novel DCB compared to other devices. PMID- 23018431 TI - In right or biventricular chronic heart failure addition of thiazides to loop diuretics to achieve a sequential blockade of the nephron is associated with increased risk of dilutional hyponatremia: results of a case-control study. AB - AIM: Chronic hyponatremia is frequently found in some syndromes characterized by widespread edema coupled to impairment in arterial effective circulating volume, such as congestive chronic heart failure (CHF). In this setting, it is unclear whether the hyponatremia itself makes this condition worse or whether it represents a simply marker of decompensation. The factors responsible for development of hyponatremia in CHF have not exhaustively been elucidated yet. The aim of this paper was to ascertain whether some laboratory, clinical and therapeutical factors are able to predict occurrence of hyponatremia in CHF patients. METHODS: A case-control study was carried out by recruiting 57 CHF patients, whose 19 characterized by hyponatremia (serum Na+<135 mEq/L) and 38 controls, matched for age, sex, etiology of CHF, time elapsed since beginning of both symptoms and diuretic therapy. Eligibility criteria included right or biventricular heart failure in NYHA class III, absence of hyponatremia at the first visit and therapy at enrollment with oral dose not less than 175 mg per week of furosemide or equivalent weekly dose of torsemide. Exclusion criteria were electrostimulation therapies (pace-maker or cardiac resynchronization therapy), documented episodes- one or more- of infective gastroenteritis or diarrhea and use of any drug influencing neuroendocrine mechanisms of arginin vasopressin (AVP) secretion, such as opiates, tetracyclines, phenothiazines, lithium, serotonin selective reuptake inhibitors (SSRIs) etc. RESULTS: At univariate analysis, intensive intravenous (iv) therapy with furosemide (one or more courses), ascites, mixed regimen with thiazide diuretic plus furosemide, high (>3 ng/mL/h) plasma renin activity, serum creatinine >=2,2 mg/dl and oligoanuria were shown to be associated with hyponatremia. At multivariate analysis a role of predictor of hyponatremia was maintained by combined therapy with thiazide diuretic plus furosemide (OR=35.68 95%CI: 2.83-449.37 P=0.0057) as well as by intensive iv furosemide therapy (OR=12.44 95%CI: 1.207-128.27 P=0.0342). CONCLUSION: Inhibition of free water clearance by thiazides may account for association found between their use and hyponatremia development in congestive CHF setting. Even though loop diuretics are known to promote free water excretion, in our experience hyponatremia might have been favored by iv furosemide high doses, because drop in effective circulating volume and further impairment in arterial underfilling due to overzealous iv loop diuretic administration are able to foster AVP non osmotic release, thereby leading to hemodilution hyponatremia. PMID- 23018432 TI - Innovative approaches to percutaneous bifurcation interventions using drug eluting balloons. AB - Coronary bifurcations are frequently found complex coronary lesions that continue to be associated to worse outcomes than simpler ones, despite dedicated techniques and use of drug-eluting stents (DES). Moreover, besides concerns regarding DES thrombosis and late restenosis in complex lesions, several issues might limit DES use in real world conditions. If a widespread use of DES might therefore appeared unjustified, local treatment by an anti-proliferative drug remains attractive. This is the reason why drug-eluting balloons (DEB) have been developed, with several potential advantages over DES including homogeneous drug transfer to the vessel wall with local drug delivery over a very short period of time and absence of both a polymer matrix and a metal platform. When approaching bifurcation lesions, actual evidences do not support increased benefit of a two stent technique over stenting the main vessel only. However, provisional stenting is often associated with suboptimal results in the side branch, thus leaving room for some improvement that could be very well managed by drug-eluting balloon technology. To date, two different approaches to percutaneous bifurcation intervention with DEB have been developed, namely sequential DEB treatment of the bifurcation branches followed by provisional bare metal stent implantation and simple main vessel stenting followed by kissing DEB. The kissing DEB approach has also shown promising results in the treatment of bifurcation restenosis that represent particularly challenging lesions to treat. Available data suggest that DEB offers a new opportunity to implement innovative, simpler and possibly safer and more effective percutaneous bifurcation interventions. PMID- 23018433 TI - Fractional flow reserve (FFR): changing the practice of interventional cardiology. AB - Fractional flow reserve (FFR) has become an extremely valuable tool for assessing the hemodynamic significance of intermediate coronary lesions. This manuscript delineates the current guidelines regarding the use of FFR and discusses emerging indications for the use of this diagnostic tool and how they compare with and complement non-invasive or other invasive diagnostic modalities. The manuscript addresses some of the key unanswered questions related to FFR, the potential pitfalls of this tool and discusses future directions of use and research. PMID- 23018434 TI - Acute myopericarditis in a young with autoimmune disorders. PMID- 23018435 TI - Raltegravir intensification shows differing effects on CD8 and CD4 T cells in HIV infected HAART-suppressed individuals with poor CD4 T-cell recovery. AB - BACKGROUND: Immunodiscordant HIV-infected patients show viral suppression during antiretroviral therapy but fail to recover CD4 T cells. Immunodiscordance is characterized by partial CD4 T-cell immunodeficiency and increased inflammation, activation and immunosenescence in both CD4 and CD8 T cells. METHODS: A randomized, controlled, 48-week intensification study to assess the effect of raltegravir on immunological parameters in immunodiscordant patients (CD4 cell counts <350 cells/MUl; viral load <50 copies/ml for >2 years). Patients were randomized (2 : 1) to intensify therapy with raltegravir (intensified arm, n = 30) or continue with the same therapy (control arm, n = 14). RESULTS: Both groups showed similar immunological baseline characteristics. CD4 T-cell counts increased faster in the intensified arm (P = 0.01, week 12). However, no differences between groups were observed at week 48. Additionally, no changes in thymic output (CD45RA(+)CD31(+) cells), activation (HLA-DR(+)CD95(+) cells) or ex vivo cell death were observed in CD4 T cells at any time point intergroups or intragroups. Conversely, intensified arm showed significant decreases in the expression of the CD8 T-cell activation marker CD38 at weeks 24-48, which were more evident in memory cells. Despite this, the levels of HLA-DR expression in CD8 T cells and plasma soluble CD14 remained stable in both arms overtime. CONCLUSION: Long-term (48-week) raltegravir intensification failed to counterbalance CD4 T-cell deficiency and its associated features: hyperactivation and death of CD4 T cells. However, raltegravir induced a specific reduction of CD38 expression in CD8 T cells, suggesting a beneficial effect on CD8 T-cell hyperactivation, which has been linked with HIV-associated comorbidities. PMID- 23018436 TI - Human papillomavirus genotyping, human papillomavirus mRNA expression, and p16/Ki 67 cytology to detect anal cancer precursors in HIV-infected MSM. AB - OBJECTIVE: Anal cancer incidence is high in HIV-infected MSM. Screening for anal intraepithelial lesions and cancers is performed at specialized clinics and relies on high-resolution anoscopy (HRA) and anal cytology. Both approaches have limited reproducibility and sensitivity for detecting anal cancer precursors. We evaluated biomarkers for human papillomavirus (HPV)-related disease in a population of HIV-infected MSM. METHODS: A cross-sectional screening study with passive follow-up included 363 MSM followed at a HIV/AIDS clinic. All men had anal cytology samples taken and were evaluated using HRA and anal biopsies. Using a composite endpoint of biopsy results and cytology, we compared the performance of HPV16/18 genotyping, HPVE6/E7 mRNA expression, and p16/Ki-67 cytology to detect high-grade anal intraepithelial neoplasias (AINs). RESULTS: For all biomarkers analyzed, there was a significant trend of increasing percentage of men testing positive with increasing severity of disease (P < 0.001). HPV DNA testing had the highest sensitivity for anal intraepithelial neoplasia grade 2 and anal intraepithelial neoplasia grade 3 (AIN3), followed by p16/Ki-67, HPVE6/E7 mRNA testing, and HPV16/18 genotyping. The highest Youden's index was observed for HPVE6/E7 mRNA testing, followed by HPV16/18 genotyping, p16/Ki-67 cytology, and HPV DNA testing. Increasing the threshold for positivity of p16/Ki 67 to five or more positive cells led to significantly higher specificity, but unchanged sensitivity for detecting AIN3. CONCLUSION: Molecular features of anal disease categories are similar to those of corresponding cervical lesions. Biomarkers evaluated for cervical cancer screening may be used for primary anal cancer screening or to decide who should require immediate treatment vs. expectant management. PMID- 23018439 TI - A tale of two vaccines: lessons from polio that could inform the development of an HIV vaccine. AB - Two vaccine trials that were conducted 50 years apart are reviewed and compared: the 1954 field trial of the Salk inactivated polio vaccine and the RV144 HIV vaccine trial conducted in Thailand between 2003 and 2009. Despite the obvious differences in science and historical periods, several lessons were identified that could inform the future HIV vaccine effort. Those lessons are related to paradigm changes that occur when science progresses, the need to test scientific hypothesis in efficacy trials, the controversies surrounding those trials, the need for strong community and political support, the participation of government and nongovernment institutions, the balance between implementation of other preventive and therapeutic interventions, and the priority given by society to develop a vaccine. If we have the humility and courage to apply some of those lessons, we may be able accelerate the development of an urgently needed HIV vaccine. PMID- 23018438 TI - Changes in cardiovascular biomarkers in HIV-infected patients switching from ritonavir-boosted protease inhibitors to raltegravir. AB - BACKGROUND: : Switching from boosted protease inhibitors (PI/r) to raltegravir (RAL) results in a better plasma lipid profile than continuing PI/r. Whether this strategy affects plasma biomarkers associated with atherosclerosis is unknown. METHODS: : We assessed 48-week changes in fasting lipids and several biomarkers including serum high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein 1 (MCP-1), osteoprotegerin, interleukin (IL) 6, IL-10, tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM 1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin and P-selectin, adiponectin, insulin, and D-dimer in otherwise healthy, virologically suppressed HIV-infected patients treated with PI/r who randomly switched from PI/r to RAL or continued with PI/r in the SPIRAL trial. Biomarkers and lipids at baseline and 48 week changes between both study arms were compared. Correlations between changes in biomarkers and changes in lipids were also evaluated. RESULTS: : Of 273 patients initiating study drugs in the SPIRAL trial, 233 (119 RAL, 114 PI/r) remained on allocated therapy for 48 weeks and had sera available for the purpose of this substudy. Triglycerides (-28%, P < 0.0001), total (-14%, P < 0.0001), low density lipoprotein (-9%, P = 0.0069), and high-density lipoprotein (-10%, P = 0.0017) cholesterol decreased in RAL relative to the PI/r group. Among biomarkers, hsCRP (-40%, P < 0.0001), MCP-1 (-20%, P = 0.0003), osteoprotegerin ( 13%, P = 0.0024), IL-6 (-46%,P < 0.0001), TNF-alpha (-27%, P = 0.0011), insulin ( 26%, P < 0.0001), and D-dimer (-8%, P = 0.0187) decreased in RAL relative to PI/r group, whereas IL-10 (+1%, P = 0.7773), ICAM-1 (-6%, P = 0.1255), VCAM-1(0%, P = 0.8671), E-selectin (-9%, P = 0.2174), P-selectin (-6%, P = 0.3865), and adiponectin (+8%, P = 0.2028) remained unchanged. Biomarkers and lipids changes at 48 weeks were weakly correlated. CONCLUSION: : Switching from PI/r to RAL induced significant changes in several cardiovascular biomarkers that were not completely explained by lipid changes. PMID- 23018437 TI - Long-term immunogenicity of two doses of 2009 A/H1N1v vaccine with and without AS03(A) adjuvant in HIV-1-infected adults. AB - OBJECTIVE: In immunocompromised patients, alternative schedules more immunogenic than the standard influenza vaccine regimen are necessary to enhance and prolong vaccine efficacy. We previously reported that the AS03A-adjuvanted 2009 A/H1N1v vaccine yielded a higher short-term immune response than the nonadjuvanted one in HIV-1-infected adults. This study reports the long-term persistence of the immune response. DESIGN AND METHODS: In a prospective, multicenter, randomized, patient blinded trial, two doses of AS03A-adjuvanted H1N1v vaccine containing 3.75 MUg haemagglutinin (n = 155; group A) or nonadjuvanted H1N1v vaccine containing 15 MUg haemagglutinin (n = 151; group B), were administered 21 days apart. Haemagglutination inhibition and neutralizing antibodies were assessed 6 and 12 months after vaccination. RESULTS: In group A and B, the seroprotection rates were 83.7 and 59.4% at month 6, and 70.4 and 49.3 at month 12, respectively. In a multivariate analysis, persistence of seroprotection 12 months after vaccination was negatively associated with current smoking (odds ratio = 0.6, P = 0.03) and positively related with the AS03A-adjuvanted H1N1v vaccine (odds ratio = 2.7, P = 0.0002). CONCLUSION: In HIV-1-infected adults, two doses of adjuvanted influenza vaccine induce long-term persistence of immune response up to 1 year after vaccination. PMID- 23018441 TI - Impact of gag genetic determinants on virological outcome to boosted lopinavir containing regimen in HIV-2-infected patients. AB - OBJECTIVE: This study investigated the impact on virological outcome of the gag cleavage sites and the protease-coding region mutations in protease inhibitor naive and protease inhibitor-experienced patients infected with HIV-2 receiving lopinavir (LPV) containing regimen. METHODS: Baseline gag and protease-coding region were sequenced in 46 HIV-2 group A-infected patients receiving lopinavir. Virological response was defined as plasma viral load less than 100 copies/ml at month 3. Associations between virological response and frequencies of mutations in gag [matrix/capsid (CA), CA/p2, p2/nucleocapsid (NC), NC/p1, p1/p6] and gag pol (NC/p6) cleavage site and protease-coding region, with respect to the HIV 2ROD strain, were tested using Fisher's exact test. RESULTS: Virological response occurred in 14 of 17 (82%) protease inhibitor-naive and 17 of 29 (59%) protease inhibitor-experienced patients. Virological failure was associated with higher baseline viral load (median: 6765 versus 1098 copies/ml, P = 0.02). More protease coding region mutations were observed in protease inhibitor-experienced compared with protease inhibitor-naive patients (median: 8 versus 5, P = 0.003). In protease inhibitor-naive patients, T435A (NC/p6), V447M (p1/p6), and Y14H (protease-coding region) were associated with virological failure (P = 0.011, P = 0.033, P = 0.022, respectively). T435A and V447M were associated with Y14H (P = 0.018, P = 0.039, respectively). In protease inhibitor-experienced patients, D427E (NC/p1) was associated with virological response (P = 0.014). A430V (NC/p1) and I82F (protease-coding region) were associated with virological failure (P = 0.046, P = 0.050, respectively). Mutations at position 430 were associated with a higher number of mutations in protease-coding region (median: 10 versus 7, P = 0.008). CONCLUSION: We have demonstrated, for the first time, an association between gag, gag-pol cleavage site and protease-coding region mutations, with distinct profiles between protease inhibitor-naive and protease inhibitor experienced patients. These mutations might impact the virological outcome of HIV 2-infected patients receiving LPV-containing regimen. PMID- 23018442 TI - Risk, predictors, and mortality associated with non-AIDS events in newly diagnosed HIV-infected patients: role of antiretroviral therapy. AB - OBJECTIVE: We aimed to characterize non-AIDS events (NAEs) occurring in newly diagnosed HIV-infected patients in a contemporary cohort. METHODS: The Cohort of the AIDS Research Network (CoRIS) is a prospective, multicenter cohort of HIV infected adults antiretroviral naive at entry, established in 2004. We evaluated the incidence of and the mortality due to NAEs and AIDS events through October 2010. Poisson regression was used to investigate factors associated with a higher incidence of NAEs. RESULTS: Overall, 5185 patients (13.306 person-years of follow up), median age (interquartile range) 36 (29-43) years, participated in the study. A total of 86.5% patients had been diagnosed in 2004 or later. The incidence rate of NAEs was 28.93 per 1000 person-years [95% confidence interval (CI) 26.15-32.07], and of AIDS-defining events 25.23 per 1000 person-years (95% CI 22.60-28.16). The most common NAEs were psychiatric, hepatic, malignant, renal, and cardiovascular related. After adjustment, age, higher HIV-viral load, and lower CD4 cell count at cohort entry were associated with the occurrence of NAEs, whereas likelihood significantly decreased with sexual transmission and higher educational level. Additionally, antiretroviral therapy was inversely associated with the development of some NAEs, specifically of psychiatric [incidence rate ratio (95% CI) 0.54 (0.30-0.96)] and renal-related [incidence rate ratio (95% CI) 0.31 (0.13-0.72)] events. One hundred and seventy-three (3.33%) patients died during the study period. NAEs contributed to 28.9% of all deaths, with an incidence rate (95% CI) of 3.75 (2.84-4.94) per 1000 person years. CONCLUSION: In patients newly diagnosed with HIV infection, NAEs are a significant cause of morbidity and mortality. Our results suggest a protective effect of antiretroviral therapy in the occurrence of NAEs, in particular of psychiatric and renal-related events. PMID- 23018444 TI - A study of the reaction of perfluoroalkyl Grignard reagents with phosphoryl chloride and phenylphosphonic dichloride. AB - Perfluoroalkyl Grignard reagents react with phosphoryl halides at -78 degrees C to room temperature to selectively produce bis(perfluoroalkyl)phosphonyl halides, which after aqueous work up, give bis(perfluoroalkyl)phosphinic acids in high overall yields. Reaction of perfluoroalkyl Grignards with phenylphosphonic dichloride gives high yields of bis(perfluoroalkyl)phenyl phosphine oxides which are readily hydrolysed to perfluoroalkyl(phenyl)phosphinic acids. PMID- 23018443 TI - Cerebral beta-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE epsilon4 carriers. AB - OBJECTIVE: The apolipoprotein E (APOE) epsilon4 allele enhances cerebral accumulation of beta-amyloid (Abeta) and is a major risk factor for sporadic Alzheimer's disease. We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE epsilon4 genotype and cerebral Abeta deposition. DESIGN: Clinicopathological study of HIV-infected adults from four prospective cohorts in the US National NeuroAIDS Tissue Consortium. METHODS: We used multivariable logistic regressions to model outcomes [Abeta plaques (immunohistochemistry) and HAND (standard criteria)] on predictors [APOE epsilon4 (allelic discrimination assay), older age (>=50 years), Abeta plaques, and their two-way interactions] and comorbid factors. RESULTS: Isocortical Abeta deposits generally occurred as diffuse plaques and mild-to-moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE epsilon4 and older age were independently associated with the presence of Abeta plaques [adjusted odds ratio (OR) 10.16 and 5.77, 95% confidence interval (CI) 2.89 - 35.76 and 1.91-17.48, P = 0.0003 and 0.0019, respectively, n = 96]. The probability of HAND was increased in the presence of Abeta plaques among APOE epsilon4 carriers (adjusted OR 30.00, 95% CI 1.41-638.63, P = 0.029, n = 15), but not in non-epsilon4 carriers (n = 57). CONCLUSION: The APOE epsilon4 and older age increased the likelihood of cerebral Abeta plaque deposition in HIV-infected adults. Generally, Abeta plaques in HIV brains were immunohistologically different from those in symptomatic Alzheimer's disease brains. Nonetheless, Abeta plaques were associated with HAND among APOE epsilon4 carriers. The detection of APOE epsilon4 genotype and cerebral Abeta deposition biomarkers may be useful in identifying living HAND patients who could benefit from Abeta targeted therapies. PMID- 23018445 TI - Comparison of cytochrome p450 mediated metabolism of three central nervous system acting drugs. AB - The investigation of cytochrome P450 (CYP) mediated metabolism reactions by determination of enzyme kinetic parameters, Michaelis constant (K(m)), maximum reaction velocity (V(max)), and intrinsic clearance (CL(int)) is important aspects in discovery and development of drugs. The kinetic parameters can be used to predict the clearance prior to human administration and for better understanding the mechanism of clearance in vivo. In this study, the metabolic activities of three major hepatic CYP isoforms (2C19, 2D6, and 3A4) were investigated on structurally different central nervous system (CNS) acting drugs, amitriptyline, fluphenazine, and dothiepin. By using our novel in vitro evaluation system, we could compare the kinetic parameters for the metabolism of fluphenazine and dothiepin for the first time. Comparing CL(int) values thus obtained, we concluded that 2C19 could be predominant for metabolic activity on tricyclic antidepressants as expected, but not on phenothiazine-related antipsychotic drugs. Since the metabolism of CNS drugs is susceptible to single nucleotide polymorphisms of human gene, our results suggest that phenothiazine could be an alternative to clinical application of CNS drugs. PMID- 23018447 TI - Modeling volatilization and adsorption of disinfection byproducts in natural watersheds. AB - It is an emerging concern that a series of disinfection byproducts (DBPs) produced in wastewater effluent have adversely impacted the downstream aquatic system and drinking water resources. The occurrence, fate, and transport of DBPs on receiving waterbodies, however, are currently not well-documented. To fill the knowledge gap, this study simulated the effects of volatilization and adsorption processes on the removals of DBPs (THM, HAA, HAN, HNM, and NA) in different types of watersheds (lake, stream, river, and aquifer). The effects of a series of variables, including hydrogeological characteristics (e.g., water depth, flow rate, roughness), environmental conditions (e.g., temperature, wind velocity), and chemical properties (e.g., octanol-water partition coefficient, Henry's law constant, molecular weight, density) were evaluated and their relative importance were compared. The results indicate that volatilization mechanism was preferred in the stream-type watershed and effective in reducing THMs, but unlikely to reduce HAAs. Adsorption and removal of DBPs on settling suspended solid in surface waters appears insignificant, accounting for less than 8% of the DBP content. Adsorption of DBPs on aquifer soil does not reduce DBPs directly; nonetheless, it reduces the mobility of DBPs in the aquifer and provides a place for other mechanisms to degrade/transform DBPs. The results of this study therefore may help understand the occurrence, fate, and risk of wastewater derived DBPs in downstream waterbodies, and trigger more laboratory tests in the future to dedicate to the mechanisms and DBPs with significant impact. PMID- 23018448 TI - Ion beam sputtered surface dynamics investigated with two-time correlation functions: a model study. AB - Ion beam sputtering is a widely used technique to obtain patterned surfaces. Despite the wide use of this approach on different materials to create surface nanostructures, the theoretical model to explain the time evolution of the erosion process is still debated. We show, with the help of simulations, that two time correlation functions can serve to assess the validity of different models. These functions can be measured experimentally with the x-ray photon correlation spectroscopy technique. PMID- 23018449 TI - An investigation of airborne allergenic pollen at different heights. AB - BACKGROUND AND AIMS: Airborne pollen is an important source of allergens in a number of allergic diseases. Data on the concentrations of pollen at different heights in the air are scarce. The aim of the present study was to investigate different types and numbers of airborne pollen and their seasonal variation at different heights in the urban area of Shenzhen (China) and their associations with meteorological factors. METHODS: The concentration of airborne pollen at different heights was monitored with Burkard traps from July 1, 2006, to June 30, 2007, in Shenzhen; the results were analyzed with SAS 9.13 software. RESULTS: In total, 1,095 films (at 3 heights, 365 films at each height) were exposed throughout the year, and 48 families and 85 genera of pollen taxa were identified. The total pollen count was 55,830 grains (25,204 grains at 1.5 m; 16,218 grains at 35 m, and 14,408 grains at 70 m); pollen grains were present in the atmosphere throughout the year, with two peaks of airborne pollen: one peak in February to April and the other in September to November. CONCLUSIONS: On the basis of our local investigations, the pollen concentrations and the pollen types in the air decrease gradually with increasing height. The distribution and concentrations of airborne pollen at different heights in the atmosphere were influenced by composite factors such as the season and meteorological factors. PMID- 23018450 TI - Abstracts of the XXth Congress of the European Society for Stereotactic and Functional Neurosurgery. Lisbon, Portugal. September 26-29, 2012. PMID- 23018440 TI - Platelet count kinetics following interruption of antiretroviral treatment. AB - OBJECTIVES: To investigate the mechanisms of platelet kinetics in the Strategies for Management of Antiretroviral Therapy (SMART) study that demonstrated excess mortality with CD4 guided episodic antiretroviral therapy (ART) drug conservation compared with continuous treatment viral suppression. Follow-up analyses of stored plasma samples demonstrated increased activation of both inflammatory and coagulation pathways after stopping ART. DESIGN: SMART patients from sites that determined platelets routinely. METHODS: Platelet counts were retrospectively collected from 2206 patients from visits at study entry, and during follow-up. D dimer levels were measured at study entry, month 1, and 2. RESULTS: Platelet levels decreased in the drug conservation group following randomization, but remained stable in the viral suppression group [median (IQR) decline from study entry to month 4: -24 000/MUl (-54 000 to 4000) vs. 3000 (-22 000 to 24 000), respectively, P < 0.0001)] and the rate of developing thrombocytopenia (<100 000/MUl) was significantly higher in the drug conservation vs. the viral suppression arm (unadjusted drug conservation/viral suppression [HR (95%CI) = 1.8 (1.2-2.7)]. The decline in platelet count among drug conservation participants on fully suppressive ART correlated with the rise in D-dimer from study entry to either month 1 or 2 (r = -0.41; P = 0.02). Among drug conservation participants who resumed ART 74% recovered to their study entry platelet levels. CONCLUSION: Interrupting ART increases the risk of thrombocytopenia, but reinitiation of ART typically reverses it. Factors contributing to declines in platelets after interrupting ART may include activation of coagulation pathways or HIV-1 replication itself. The contribution of platelets in HIV-related procoagulant activity requires further study. PMID- 23018451 TI - Three-dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes. AB - Podosomes, specialized actin-rich structures in macrophages (Mfs), degrade the extra-cellular matrix (ECM) and are involved in cell migration. On two dimensional (2D) surfaces Mfs form spot-like podosomes at the ventral cell surface that develop into protrusive structures in a three-dimensional (3D) environment resembling the ECM. We have shown that the tips of these protrusive podosomes are characterized by increased accumulation of cysteine cathepsins (Cts) B, X, S, H, and L, both in human blood Mfs and in human monocytic cell line U-937. Monocyte-to-Mf differentiation induces an increase in cysteine cathepsin expression and activity, promoting their translocation to the cell surface, where they interact with ECM. This group of proteases is crucial for the extracellular as well as intracellular degradation of ECM, as demonstrated by quantitative monitoring of collagen IV degradation. Furthermore, inhibiting CtsB, X, and S significantly impairs Mf invasion through the 3D matrix. Time-lapse live-cell imaging of CtsB activity revealed that the extracellular and the intracellular ECM degradation are associated with extensive endocytosis at the tip of protrusive podosomes. The targeting of cysteine cathepsins, as the major mediators of human Mf 3D invasion, could be an approach to the treatment of inflammatory and cancerous diseases. PMID- 23018453 TI - C-reactive protein increases BBB permeability: implications for obesity and neuroinflammation. AB - BACKGROUND/AIMS: Acute phase C-reactive protein (CRP), elevated in obesity and inflammation, is a major binding protein for leptin. It is thought that CRP contributes to leptin resistance by preventing leptin from crossing the blood brain barrier (BBB). Here we determined how CRP interacts with the BBB and whether it deters leptin from reaching CNS targets. METHODS: BBB permeability, compartmental distribution, tracer stability, and expression of tight junction protein and inflammatory marker were determined. RESULTS: CRP was stable in blood, but did not permeate the BBB in trace amounts. However, it increased paracellular permeability at a higher dose. Agouti viable (A(vy)) mice with adult onset obesity show higher CRP entry into the brain. CRP did not permeate hCMEC/D3 cells nor change zona occludin-1 or cyclooxygenase-2 expression. An intermediate dose of CRP had no effect on leptin transport across the BBB after co-treatment. Thus, acute interactions between CRP and leptin at the BBB level were negligible and did not explain the leptin resistance seen in obesity. CONCLUSIONS: The interactions of CRP and the BBB are a two-phase process, with increased paracellular permeability at a high dose that enables its entry into the CNS and serves to induce reactive gliosis and impair CNS function. PMID- 23018452 TI - Quantitative proteomic analyses of cerebrospinal fluid using iTRAQ in a primate model of iron deficiency anemia. AB - Iron deficiency affects nearly 2 billion people worldwide, with pregnant women and young children being most severely impacted. Sustained anemia during the first year of life can cause cognitive, attention and motor deficits, which may persist despite iron supplementation. We conducted iTRAQ analyses on cerebrospinal fluid (CSF) from infant monkeys (Macaca mulatta) to identify differential protein expression associated with early iron deficiency. CSF was collected from 5 iron-sufficient and 8 iron-deficient anemic monkeys at weaning age (6-7 months) and again at 12-14 months. Despite consumption of iron-fortified food after weaning, which restored hematological indices into the normal range, expression of 5 proteins in the CSF remained altered. Most of the proteins identified are involved in neurite outgrowth, migration or synapse formation. The results reveal novel ways in which iron deficiency undermines brain growth and results in aberrant neuronal migration and connections. Taken together with gene expression data from rodent models of iron deficiency, we conclude that significant alterations in neuroconnectivity occur in the iron-deficient brain, which may persist even after resolution of the hematological anemia. The compromised brain infrastructure could account for observations of behavioral deficits in children during and after the period of anemia. PMID- 23018454 TI - Role of hepatocyte-derived IL-7 in maintenance of intrahepatic NKT cells and T cells and development of B cells in fetal liver. AB - The liver contains a variety of resident immune cells, such as NK cells, NKT cells, T cells, macrophages, and dendritic cells. However, little is known about how IL-7, which is produced by hepatocytes, functions locally in development and maintenance of liver immune cells. To address this question, we established IL-7 floxed mice and crossed them with albumin promoter-driven Cre (Alb-Cre) transgenic mice to establish conditional knockout of IL-7 in hepatocytes. The levels of IL-7 transcripts were reduced 10-fold in hepatocyte fraction. We found that the absolute numbers of NKT and T cells were significantly decreased in adult liver of IL-7(f/f) Alb-Cre mice compared with IL-7(f/f) control mice. In contrast, NK cells, dendritic cells, and B cells were unchanged in the IL-7(f/f) Alb-Cre liver. The number of Valpha14(+) invariant NKT cells was significantly reduced in liver, but not in thymus and spleen, of IL-7(f/f) Alb-Cre mice. Furthermore, B cell development was impaired in perinatal liver of IL-7(f/f) Alb Cre mice. This study demonstrates that hepatocyte-derived IL-7 plays an indispensable role in maintenance of NKT and T cells in adult liver and development of B cells in fetal liver, and suggests that hepatocytes provide a unique IL-7 niche for intrahepatic lymphocytes. PMID- 23018455 TI - Coordinate stimulation of macrophages by microparticles and TLR ligands induces foam cell formation. AB - Aberrant activation of macrophages in arterial walls by oxidized lipoproteins can lead to atherosclerosis. Oxidized lipoproteins convert macrophages to foam cells through lipid uptake and TLR signaling. To investigate the relative contributions of lipid uptake and TLR signaling in foam cell formation, we established an in vitro assay using liposomes of defined lipid compositions. We found that TLRs signaling through Toll/IL-1R domain-containing adapter inducing IFN-beta promoted foam cell formation by inducing both NF-kappaB signaling and type I IFN production, whereas TLRs that do not induce IFN, like TLR2, did not enhance foam cell formation. Addition of IFN-alpha to TLR2 activator promoted robust foam cell formation. TLR signaling further required peroxisome proliferator-activated receptor alpha, as inhibition of peroxisome proliferator-activated receptor alpha blocked foam cell formation. We then investigated the ability of endogenous microparticles (MP) to contribute to foam cell formation. We found that lipid containing MP promoted foam cell formation, which was enhanced by TLR stimulation or IFN-alpha. These MP also stimulated foam cell formation in a human skin model. However, these MP suppressed TNF-alpha production and T cell activation, showing that foam cell formation can occur by immunosuppressive MP. Taken together, the data reveal novel signaling requirements for foam cell formation and suggest that uptake of distinct types of MP in the context of activation of multiple distinct TLR can induce foam cell formation. PMID- 23018456 TI - Targeting the genital tract mucosa with a lipopeptide/recombinant adenovirus prime/boost vaccine induces potent and long-lasting CD8+ T cell immunity against herpes: importance of MyD88. AB - Targeting of the mucosal immune system of the genital tract with subunit vaccines has failed to induce potent and durable local CD8(+) T cell immunity, which is crucial for protection against many sexually transmitted viral pathogens, including HSV type 2 (HSV-2), which causes genital herpes. In this study, we aimed to investigate the potential of a novel lipopeptide/adenovirus type 5 (Lipo/rAdv5) prime/boost mucosal vaccine for induction of CD8(+) T cell immunity to protect the female genital tract from herpes. The lipopeptide vaccine and the rAdv5 vaccine express the immunodominant HSV-2 CD8(+) T cell epitope (gB(498 505)), and both were delivered intravaginally in the progesterone-induced B6 mouse model of genital herpes. Compared with mice immunized with the homologous lipopeptide/lipopeptide (Lipo/Lipo) vaccine, the Lipo/rAdv5 prime/boost immunized mice 1) developed potent and sustained HSV-specific CD8(+) T cells, detected in both the genital tract draining nodes and in the vaginal mucosa; 2) had significantly lower virus titers; 3) had decreased overt signs of genital herpes disease; and 4) did not succumb to lethal infection (p < 0.005) after intravaginal HSV-2 challenge. Polyfunctional CD8(+) T cells, producing IFN-gamma, TNF-alpha, and IL-2 and exhibiting cytotoxic activity, were associated with protection (p < 0.005). The protective CD8(+) T cell response was significantly compromised in the absence of the adapter MyD88 (p = 0.0001). Taken together, these findings indicate that targeting of the vaginal mucosa with a Lipo/rAdv5 prime/boost vaccine elicits a potent, MyD88-dependent, and long-lasting mucosal CD8(+) T cell protective immunity against sexually transmitted herpes infection and disease. PMID- 23018457 TI - Reciprocal control of G1-phase progression is required for Th-POK/Runx3-mediated CD4/8 thymocyte cell fate decision. AB - After receiving a TCR-mediated differentiation signal, CD4 and CD8 double positive thymocytes diverge into CD4 or CD8 single-positive T cells, for which Th POK and Runx3 have been identified as pivotal transcription factors, respectively. The cross-antagonistic regulation of Th-POK and Runx3 seems to be essential for CD4/8 thymocyte lineage commitment. However, the process for determining which pivotal factor acts dominantly has not been established. To explore the determining process, we used an in vitro culture system in which CD4 or CD8 single-positive cells are selectively induced from CD4/8 double-positive cells. Surprisingly, we found that control of G(1) cell cycle phase progression is critical for the determination. In the CD4 pathway, sustained TCR signal, as well as Th-POK, induces G(1)-phase extension and represses CD8 expression in a G(1) extension-dependent manner. In the CD8 pathway, after receiving a transient TCR signal, the IL-7R signal, as well as Runx3, antagonizes TCR signal-mediated G(1) extension and CD8 repression. Importantly, forced G(1) extension cancels the functions of Runx3 to repress Th-POK and CD4 and to reactivate CD8. In contrast, it is suggested that forced G(1) progression inhibits Th-POK function to repress CD8. Collectively, Th-POK and Runx3 are reciprocally involved in the control of G(1)-phase progression, on which they exert their functions dependently. These findings may provide novel insight into how CD4/CD8 cell lineages are determined by Th-POK and Runx3. PMID- 23018459 TI - Affinity and cross-reactivity engineering of CTLA4-Ig to modulate T cell costimulation. AB - CTLA4-Ig is an Fc fusion protein containing the extracellular domain of CTLA-4, a receptor known to deliver a negative signal to T cells. CTLA4-Ig modulates T cell costimulatory signals by blocking the CD80 and CD86 ligands from binding to CD28, which delivers a positive T cell costimulatory signal. To engineer CTLA4-Ig variants with altered binding affinity to CD80 and CD86, we employed a high throughput protein engineering method to map the ligand binding surface of CTLA 4. The resulting mutagenesis map identified positions critical for the recognition of each ligand on the three CDR-like loops of CTLA-4, consistent with the published site-directed mutagenesis and x-ray crystal structures of the CTLA 4/CD80 and CTLA-4/CD86 complexes. A number of single amino acid substitutions were identified that equally affected the binding affinity of CTLA4-Ig for both ligands as well as those that differentially affected binding. All of the high affinity variants showed improved off-rates, with the best one being a 17.5-fold improved off-rate over parental CTLA4-Ig binding to CD86. Allostimulation of human CD4(+) T cells showed that improvement of CD80 and CD86 binding activity augmented inhibition of naive and primed T cell activation. In general, increased affinity for CD86 resulted in more potent inhibition of T cell response than did increased affinity for CD80. Optimization of the affinity balance to CD80 and CD86 to particular disease settings may lead to development of a CTLA4-Ig molecule with improved efficacy and safety profiles. PMID- 23018458 TI - Insulin modulates the inflammatory granulocyte response to streptococci via phosphatidylinositol 3-kinase. AB - Group B streptococci (GBS; Streptococcus agalactiae) are a major cause of invasive infections in newborn infants and in patients with type 2 diabetes. Both patient groups exhibit peripheral insulin resistance and alterations in polymorphonuclear leukocyte (PML) function. In this investigation, we studied the PML response repertoire to GBS with a focus on TLR signaling and the modulation of this response by insulin in mice and humans. We found that GBS-induced, MyD88 dependent chemokine formation of PML was specifically downmodulated by insulin via insulin receptor-mediated induction of PI3K. PI3K inhibited transcription of chemokine genes on the level of NF-kappaB activation and binding. Insulin specifically modulated the chemokine response of PML to whole bacteria, but affected neither activation by purified TLR agonists nor antimicrobial properties, such as migration, phagocytosis, bacterial killing, and formation of reactive oxygen species. The targeted modulation of bacteria-induced chemokine formation by insulin via PI3K may form a basis for the development of novel targets of adjunctive sepsis therapy. PMID- 23018460 TI - Efficient xenoengraftment in severe immunodeficient NOD/Shi-scid IL2rgammanull mice is attributed to a lack of CD11c+B220+CD122+ cells. AB - Xenograft animal models using immunodeficient mice have been widely applied in medical research on various human diseases. NOD/Shi-scid-IL2rgamma(null) (NOG) mice are known to show an extremely high engraftment rate of xenotransplants compared with conventional immunodeficient mice. This high engraftment rate of xenotransplants in NOG mice was substantially suppressed by the transfer of spleen cells from NOD-scid mice that were devoid of NK cells. These results indicate that cell types other than splenic NK cells present in NOD-scid mice but not in NOG mice may be involved in this suppression. To identify the cell types responsible for this effect, we transferred subpopulations of spleen cells from NOD-scid mice into NOG mice and assessed the levels of human cell engraftment after human PBMC (hPBMC) transplantation. These experiments revealed that CD11c(+)B220(+) plasmacytoid dendritic cells (pDCs) from NOD-scid mice markedly inhibited engraftment of human cells. The CD11c(+)B220(+)CD122(+) cells further fractionated from the pDCs based on the expression of CD122, which is an NK cell marker strongly inhibited during hPBMC engraftment in NOG mice. Moreover, the CD122(+) cells in the pDC fraction were morphologically distinguishable from conventional CD122(+) NK cells and showed a higher rejection efficiency. The current results suggest that CD11c(+)B220(+)CD122(+) cells play an important role in xenograft rejection, and their absence in NOG mice may be critical in supporting the successful engraftment of xenotransplants. PMID- 23018461 TI - Transient enhanced IL-2R signaling early during priming rapidly amplifies development of functional CD8+ T effector-memory cells. AB - Much is known concerning the cellular and molecular basis for CD8(+) T memory immune responses. Nevertheless, conditions that selectively support memory generation have remained elusive. In this study, we show that an immunization regimen that delivers TCR signals through a defined antigenic peptide, inflammatory signals through LPS, and growth and differentiation signals through the IL-2R initially favors Ag-specific CD8(+) T cells to develop rapidly and substantially into T effector-memory cells by TCR transgenic OVA-specific OT-I CD8(+) T cells. Amplified CD8(+) T memory development depends upon a critical frequency of Ag-specific T cells and direct responsiveness to IL-2. A homologous prime-boost immunization protocol with transiently enhanced IL-2R signaling in normal mice led to persistent polyclonal Ag-specific CD8(+) T cells that supported protective immunity to Listeria monocytogenes. These results identify a general approach for amplified T memory development that may be useful to optimize vaccines aimed at generating robust cell-mediated immunity. PMID- 23018462 TI - Depletion of plasmacytoid dendritic cells inhibits tumor growth and prevents bone metastasis of breast cancer cells. AB - Elevated levels of plasmacytoid dendritic cells (pDC) have been reported in breast cancer patients, but the significance remains undefined. Using three immunocompetent mouse models of breast cancer bone metastasis, we identified a key role for pDC in facilitating tumor growth through immunosuppression and aggressive osteolysis. Following infiltration of macrophages upon breast cancer dissemination, there was a steady increase in pDC within the bone, which resulted in a sustained Th2 response along with elevated levels of regulatory T cells and myeloid-derived suppressor cells. Subsequently, pDC and CD4(+) T cells, producing osteolytic cytokines, increased with tumor burden, causing severe bone damage. Microcomputed tomography and histology analyses of bone showed destruction of femur and tibia. The therapeutic significance of this finding was confirmed by depletion of pDC, which resulted in decreased tumor burden and bone loss by activating tumor-specific cytolytic CD8(+) T cells and decreasing suppressor cell populations. Thus, pDC depletion may offer a novel adjuvant strategy to therapeutically influence breast cancer bone metastasis. PMID- 23018463 TI - Cutting edge: Pseudomonas aeruginosa abolishes established lung transplant tolerance by stimulating B7 expression on neutrophils. AB - The mechanisms that link bacterial infection to solid organ rejection remain unclear. In this study, we show that following the establishment of lung allograft acceptance in mice, Pseudomonas aeruginosa airway infection induces a G CSF-dependent neutrophilia that stimulates acute rejection. Graft-infiltrating neutrophils sharply upregulate the B7 molecules CD80 and CD86, but they do not express CD40 or MHC class II in response to P. aeruginosa infection. Neutrophil B7 promotes naive CD4(+) T cell activation and intragraft IL-2(+), IFN-gamma(+), and IL-17(+) T lymphocyte accumulation. Intravital two-photon microscopy reveals direct interactions between neutrophils and CD4(+) T cells within pulmonary allografts. Importantly, lung rejection in P. aeruginosa-infected recipients is triggered by CD80/86 on neutrophils and can be prevented by B7 blockade without affecting clearance of this pathogen. These data show that neutrophils enhance T cell activation through B7 trans-costimulation and suggest that inhibiting neutrophil-mediated alloimmunity can be accomplished without compromising bacterial immune surveillance. PMID- 23018466 TI - Pharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma. AB - BACKGROUND AND OBJECTIVES: The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma (MM) and, in the US, for the treatment of mantle cell lymphoma following at least one prior therapy; the recommended dose and schedule is 1.3 mg/m(2) on days 1, 4, 8 and 11 of 21-day cycles, and the approved routes of administration in the US prescribing information are by intravenous and, following a recent update, subcutaneous injection. Findings from a phase III study demonstrated that subcutaneous administration of bortezomib, using the same dose and schedule, resulted in similar efficacy with an improved systemic safety profile (including significantly lower rates of peripheral neuropathy) versus intravenous bortezomib in patients with relapsed MM. The objectives of this report were to present a comprehensive analysis of the pharmacokinetics and pharmacodynamics of subcutaneous versus intravenous bortezomib, and to evaluate the impact of the subcutaneous administration site, subcutaneous injection concentration and demographic characteristics on bortezomib pharmacokinetics and pharmacodynamics. PATIENTS AND METHODS: Data were analysed from the pharmacokinetic substudy of the randomized phase III MMY-3021 study and the phase I CAN-1004 study of subcutaneous versus intravenous bortezomib in patients aged >=18 (MMY-3021) or <=75 (CAN-1004) years with symptomatic relapsed or refractory MM after 1-3 (MMY-3021) or >=1 (CAN-1004) prior therapies. Patients received up to eight 21-day cycles of subcutaneous or intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11. Pharmacokinetic and pharmacodynamic (20S proteasome inhibition) parameters of bortezomib following subcutaneous or intravenous administration were evaluated on day 11, cycle 1. RESULTS: Bortezomib systemic exposure was equivalent with subcutaneous versus intravenous administration in MMY-3021 [mean area under the plasma concentration time curve from time zero to the last quantifiable timepoint (AUC(last)): 155 vs. 151 ng.h/mL; geometric mean ratio 0.992 (90 % CI 80.18, 122.80)] and comparable in CAN-1004 (mean AUC(last): 195 vs. 241 ng.h/mL); maximum (peak) plasma drug concentration (C(max)) was lower with subcutaneous administration in both MMY 3021 (mean 20.4 vs. 223 ng/mL) and CAN-1004 (mean 22.5 vs. 162 ng/mL), and time to C(max) (t(max)) was longer with subcutaneous administration in both studies (median 30 vs. 2 min). Blood 20S proteasome inhibition pharmacodynamic parameters were also similar with subcutaneous versus intravenous bortezomib: mean maximum effect (E(max)) was 63.7 versus 69.3 % in MMY-3021 and 57.0 versus 68.8 % in CAN 1004, and mean area under the effect-time curve from time zero to 72 h was 1,714 versus 1,383 %.h in MMY-3021 and 1,619 versus 1,283 %.h in CAN-1004. Time to E(max) was longer with subcutaneous administration in MMY-3021 (median 120 vs. 5 min) and CAN-1004 (median 120 vs. 3 min). Concentration of the subcutaneous injected solution had no appreciable effect on pharmacokinetic or pharmacodynamic parameters. There were no apparent differences in bortezomib pharmacokinetic and pharmacodynamic parameters between subcutaneous administration in the thigh or abdomen. There were also no apparent differences in bortezomib exposure related to body mass index, body surface area or age. CONCLUSION: Subcutaneous administration results in equivalent bortezomib plasma exposure to intravenous administration, together with comparable blood 20S proteasome inhibition pharmacodynamic effects. These findings, together with the non-inferior efficacy of subcutaneous versus intravenous bortezomib demonstrated in MMY-3021, support the use of bortezomib via the subcutaneous route across the settings of clinical use in which the safety and efficacy of intravenous bortezomib has been established. PMID- 23018467 TI - Prediction of morphine clearance in the paediatric population : how accurate are the available pharmacokinetic models? AB - The pharmacokinetics of morphine in paediatrics have been widely studied using different approaches and modelling techniques. In this review, we explore advantages and disadvantages of the different data analysis techniques that have been applied, with specific focus on the accuracy of morphine clearance predictions by reported paediatric pharmacokinetic models. Twenty paediatric studies reported a wide range in morphine clearance values using traditional, rather descriptive methods. Clearance values were expressed per kilogram bodyweight, while maturation in clearance was described by comparing mean clearance per kilogram bodyweight between age-stratified subgroups. Population modelling allows for the analysis of sparse data, thereby limiting the burden to individual patients. Using this technique, continuous maturation profiles can be obtained on the basis of either fixed allometric scaling or comprehensive covariate analysis. While the models based on fixed allometric scaling resulted in complex maturation functions, all three paediatric population models for morphine yielded quite similar clearance predictions. The largest difference in clearance predictions between these three population models occurred in the first months of life, particularly in preterm neonates. Morphine clearance predictions by a physiologically based pharmacokinetic model were based on many continuous equations describing changes in underlying physiological processes across the full paediatric age range, and resulted in similar clearance predictions as well. However, preterm neonates could not be integrated in this model. In conclusion, the value of paediatric pharmacokinetic models is mostly dependent on clearance predictions and population concentration predictions, rather than on the individual description of data. For most pharmacokinetic models, however, the assessment of model performance was very limited and the accuracy of morphine clearance predictions as well as population concentration predictions was confirmed by formal evaluation and validation procedures for only one model. PMID- 23018469 TI - Effect of type 2 diabetes mellitus on the pharmacokinetics of metformin in obese pregnant women. AB - BACKGROUND AND OBJECTIVE: The use of metformin throughout gestation by women with polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus (T2DM) significantly reduces the number of first-trimester spontaneous abortions and the rate of occurrence of gestational diabetes and hypertensive syndromes. Metformin is taken up into renal tubular cells by organic cation transport 2 (OCT2) and eliminated unchanged into the urine. The objective of this study was to analyse the influence of T2DM on the pharmacokinetics of metformin in obese pregnant women and in a control group of non-diabetic obese pregnant women with PCOS. METHODS: Eight non-diabetic obese pregnant women with PCOS and nine obese pregnant women with T2DM taking oral metformin 850 mg every 12 h were evaluated throughout gestation. Serial blood samples were collected over a 12-h period during the third trimester of pregnancy. Steady-state plasma concentrations of metformin were determined by high-performance liquid chromatography with a UV detector. The pharmacokinetic results of the two groups, reported as median and 25th and 75th percentile, were compared statistically using the Mann-Whitney test, with the level of significance set at p < 0.05. RESULTS: The pharmacokinetic parameters detected for PCOS versus T2DM patients, reported as median, were, respectively: elimination half-life 3.75 versus 4.00 h; time to maximum concentration 2.00 versus 3.00 h; maximum concentration 1.42 versus 1.21 MUg/mL; mean concentration 0.53 versus 0.56 MUg/mL; area under the plasma concentration-time curve from time zero to 12 h 6.42 versus 6.73 MUg.h/mL; apparent total oral clearance 105.39 versus 98.38 L/h; apparent volume of distribution after oral administration 550.51 versus 490.98 L; and fluctuation (maximum-minimum concentration variation) of 179.56 versus 181.73 %. No significant differences in pharmacokinetic parameters were observed between the groups. CONCLUSION: T2DM in the presence of insulin use does not influence the pharmacokinetics of metformin in pregnant patients, demonstrating the absence of a need to increase the dose, and consequently does not influence the OCT2 mediated transport in pregnant women with PCOS. PMID- 23018470 TI - Inter-individual differences in baseline coagulation activities and their implications for international normalized ratio control during warfarin initiation therapy. AB - BACKGROUND AND OBJECTIVE: Genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) and patient demographic characteristics are responsible for inter-individual differences in warfarin maintenance dosage requirements. At present, however, the factors associated with over-anticoagulation responses, especially before achieving the maintenance phase, have not been completely clarified. In this study, we investigated the effects of baseline coagulation activity assessed in terms of the level of fully carboxylated plasma normal prothrombin (NPT) on international normalized ratio (INR) control during the induction phase of warfarin therapy. Our objectives were to (1) identify factors associated with inter-patient variability in baseline NPT (NPT(0)); (2) estimate the therapeutic NPT (NPT(tx)) levels that can achieve an INR of 2-3; and (3) investigate the influence of NPT(0) on the INR response to warfarin by employing modelling and simulation techniques. METHODS: We measured NPT before (NPT(0)) and during the introduction of warfarin therapy for up to 3 months and analysed functional single nucleotide polymorphisms (SNPs) of VKORC1 and CYP4F2 in 179 Chinese patients. The patients were classified into tertile groups according to NPT(0) values (i.e. high, intermediate and low groups), and in each group the NPT(tx) achieving therapeutic INR, the absolute reduction of NPT from NPT(0) to NPT(tx), and the percentage inhibition of NPT(0) [{(NPT(0) - NPT(tx))/NPT(0)} * 100] were obtained. The nonlinear relationship between NPT and INR was modelled on the basis of the INR value before warfarin treatment (INR(0)) added by the nonlinear increase in INR after warfarin initiation, which was predicted using the percentage inhibition of NPT(0) and a nonlinear coefficient (lambda). The population parameter lambda and its inter-individual variability and intra-individual variability in INR in the NPT-INR model were estimated by nonlinear mixed-effect modelling software NONMEM((r)). RESULTS: Multivariate analysis identified age and liver disease as covariates of NPT(0), but none of the SNPs had a significant influence. Although the mean absolute NPT reduction necessary to achieve NPT(tx) was dependent on NPT(0) (i.e. the higher the NPT(0), the larger the reduction in NPT), the percentage inhibition was within the narrow range of 67-72 % of NPT(0), irrespective of NPT(0). However, a significantly higher percentage inhibition (80 % on average) was observed in patients with INR values exceeding 4.0. As the nonlinear coefficient lambda in the developed model was dependent on NPT(0) (i.e. the higher the NPT(0), the larger the nonlinear lambda value), the simulated nonlinear NPT-INR curves were superimposable in the three respective NPT(0) groups, and the only difference was the starting median NPT(0) level. As a result, a steeper increase in the slope of the nonlinear NPT-INR curve might be expected in patients with a lower NPT(0) after initiation of warfarin. CONCLUSIONS: The present study suggests that INR may be prolonged by warfarin nonlinearly as a function of the percentage inhibition of NPT(0). Furthermore, these results indicate that NPT(0) may contribute to inter-individual variability in the INR response, and that patients with low NPT(0) may have the potential to show a sharp increase in INR during initiation therapy with warfarin. PMID- 23018475 TI - Coronary angiography and percutaneous interventions in pregnancy. AB - Pregnancy and the need for cardiac catheterization poises a unique challenge that requires the balance of risk and benefit both to the mother and the fetus. Fortunately, the need for radiological invasive procedures for cardiac diagnosis has been markedly reduced with the widespread growth in imaging technology using non-ionizing energies such as ultrasound for diagnosis of underlying cardiac pathology. As the age of active childbearing has increased in many countries, an increasing overlap has developed with the childbearing overlapping the early years of acute coronary artery disease. Both acute coronary syndromes and classic congenital valve disorders are increasingly being treated successfully with invasive cath lab technologies that require some degree of risk to the pregnancy. We review the pathophysiology of both valvular and coronary pathologies that may become symptomatic or acutely decompensated and require consideration for invasive cardiac therapy. Potential risks both from radiation, acute medication use and potential need for longer term oral medications resulting from the invasive cardiac procedures are reviewed. Final specific measures to reduce the risks most pertinent to pregnancy are discussed. While risks are present during pregnancy that are unique, emergently indicated invasive cardiac procedures should not be denied or delayed solely on the pregnant state as many of these procedures have highly time responsive benefits that can be lost by irrational delays. PMID- 23018474 TI - Reduced quality-of-life ratings in mild cognitive impairment: analyses of subject and informant responses. AB - OBJECTIVES: To determine whether quality-of-life (QOL) ratings are reduced in mild cognitive impairment (MCI) and analyze correlations between QOL ratings and cognitive, neuropsychiatric, and functional indices in MCI. DESIGN: Cross sectional. SETTING: The Easton Center for Alzheimer's Disease Research at the University of California, Los Angeles. PARTICIPANTS: A total of 205 individuals who met criteria for normal cognition (n = 97) or MCI (n = 108). The MCI group included amnestic (n = 72) and nonamnestic (n = 36) MCI. MEASUREMENTS: QOL was assessed using subject and informant ratings on the Quality of Life-Alzheimer's Disease (QOL-AD) scale. Cognitive performance was assessed with the National Alzheimer's Disease Coordinating Center Uniform Data Set neuropsychological battery. Neuropsychiatric symptoms were assessed with the Geriatric Depression Scale (GDS) and the Neuropsychiatric Inventory. Functional abilities were assessed with the Functional Activities Questionnaire (FAQ). RESULTS: The normal cognition group had significantly higher QOL-AD scores than the MCI group on both subject and informant assessments. Individual item analyses indicated that the largest group differences were seen on the mood and memory items. Similar QOL-AD scores were seen in the amnestic and nonamnestic MCI subgroups. Multiple regression analyses within the MCI group indicated that QOL-AD ratings were not correlated with neuropsychological performance. Subject QOL-AD ratings were inversely correlated with GDS scores and informant QOL-AD ratings were inversely correlated with GDS, Neuropsychiatric Inventory, and FAQ scores. CONCLUSIONS: Significant declines in QOL are seen in MCI and are associated with neuropsychiatric symptoms and functional decline. Interventions targeting mood symptoms and/or instrumental activities of daily living may improve QOL in MCI. PMID- 23018476 TI - Peripartum cardiomyopathy. An update. AB - Peripartum cardiomyopathy (PPCM) is a rare disease of the heart muscle that affects women with previously unknown heart diseases during pregnancy or in the first months after delivery. Cardinal symptoms are dyspnoea and fluid retention. However, tachycardia, cardiogenic thromboembolism and other clinical signs of cardiac dysfunction may also herald this uncommon cause of heart failure. The estimated incidence of PPCM shows large regional variations: in Europe and the United States it is between 1:2000 and 1:4000. The markedly higher incidence rates observed in Haitian or South African women (up to 1:300) suggest that genetic or environmental factors may play a pathogenetic role. However, the underlying aetiology of PPCM still is unclear. Besides genetic susceptibility an abnormal autoimmune response against cardiac tissue components, viral infections or an irregular activity of cathepsin D generating a potentially cardio-toxic splice variant of prolactin have been discussed. New therapeutic strategies as immune modulation or prolactin inhibition were therefore suggested, but are not yet established. Treatment strategies focus on the standard therapies for heart failure and its complications. During pregnancy heart failure therapy is limited to substances without fetotoxic effects. But even with optimal heart failure therapy the course of the disease exhibits large variations ranging from full recovery to deterioration of heart function and even early cardiac death. This review cumulates the current knowledge on PPCM and aims to raise awareness for this rare and potentially life-threatening disorder amongst all medical professionals involved in the care for pregnant women. PMID- 23018477 TI - First trimester fetal echocardiography: where are we now? AB - The detailed study of the fetal cardiac anatomy in the first trimester of pregnancy by means of ultrasound is feasible whether using a transvaginal or a transabdominal approach. There is nowadays enough evidence that ultrasound in the first trimester of pregnancy is a safe procedure provided thermal and mechanical indices are taken into account. The best timing for successful imaging of the four chambers and great arteries in early gestation appears to be between around 13 to 14 weeks rather than 11 to 12 weeks. In experienced hands, first-trimester fetal echocardiography is quite sensitive for the detection of major structural cardiac abnormalities. Besides the nasal bone, markers for first trimester screening of chromosomal abnormalities such as nuchal translucency thickness, the flow in the ductus venosus and the flow through the tricuspid valve constitute also markers for cardiac abnormalities. The finding of an increased nuchal translucency, an abnormal flow in the ductus venosus or a tricuspid regurgitation constitutes an indication for more detailed fetal cardiac assessment. Other indication for a detailed cardiac assessment is the finding of an aberrant right subclavian artery and vascular anomalies. The emerging importance of these markers has caused renewed interest in the early study of the fetal heart. PMID- 23018478 TI - Pulmonary embolism in pregnancy. Consensus and controversies. AB - Venous thrombotic events (VTE) occur 1-2 per 10,000 pregnancies and remain one of the leading causes of maternal mortality in the developed world. The two largest risk factors are a personal history of VTE and heritable thrombophilias. D-dimer tests for VTE in pregnancy have a high false positive rate and at least some false negatives have been reported. Compression ultrasound should be used to evaluate pregnant women for deep venous thrombosis followed by magnetic resonance imaging of the pelvis for a negative test and strong remaining clinical suspicion. For pulmonary embolism, a chest x-ray should be used to triage the patient to either a ventilation/perfusion study after a normal X-ray or a CT pulmonary angiogram after an abnormal one. Treatment generally consists of low molecular weight heparin through a minimum of six weeks post-partum. Thombolysis might have merit in life-threatening, massive pulmonary embolism. VTE prophylaxis in at-risk populations remains a major area of uncertainty. Mechanical prophylaxis for all women undergoing cesarean, in particular, has a paucity of supportive evidence. PMID- 23018468 TI - Clinical pharmacokinetics and pharmacodynamics of prednisolone and prednisone in solid organ transplantation. AB - Prednisolone and prednisone are integral components of induction and maintenance immunosuppressive regimens in solid organ transplantation. The pharmacokinetics of these agents are extremely complex. Prednisolone is the active drug moiety while prednisone is both a pro-drug and inactive metabolite of prednisolone. Within the dosage range used in transplantation, prednisolone and prednisone exhibit concentration-dependent non-linear pharmacokinetics when parameters are measured with reference to total drug concentration. Dose dependency disappears when free (unbound) prednisolone is measured. Altered organ function, changing biochemistry and use of a number of concomitant medicines in transplantation appear to lead to pharmacokinetic differences in transplant recipients compared with other patient groups. Greater than threefold variability in dose-adjusted exposure to total prednisolone in transplant recipients is evident. Time post transplant, hepatic and renal dysfunction, patient age, sex, bodyweight, serum albumin concentration, concomitant medication exposure, various disease states and genetic polymorphisms in metabolic enzymes and drug transporters have sometimes been associated with prednisolone pharmacokinetic variability. The clinical impact of corticosteroid therapy on the disposition of ciclosporin, tacrolimus and sirolimus and the impact of different immunosuppressant therapy combinations on prednisolone exposure needs to be further elucidated. Patient response patterns to prednisolone are consistent with delayed and indirect mechanisms of corticosteroid action involving modification of nuclear transcription and protein synthesis. Many adverse effects have been linked with prednisolone and prednisone therapy, but not all of these have been investigated thoroughly in transplant populations. Dyslipidaemia, growth restriction, diabetogenesis, hypertension and cataracts are well studied toxicities. Evidence is less clear for prednisolone-induced osteonecrosis, obesity and hypertriglyceridaemia. There have been some reports of a relationship between prednisolone pharmacokinetics and incidence of acute rejection, Cushing's syndrome and adverse cardiovascular and metabolic events. Dosing of prednisolone and prednisone in transplantation is typically empirical and varies significantly across transplant centres. Currently, authoritative guidelines are conflicting in their opinions regarding corticosteroid avoidance and early discontinuation in adult kidney transplantation. Overall, data suggest the promise of corticosteroid free immunosuppression in paediatric patients. Further investigation of the pharmacokinetics and pharmacodynamics of prednisolone and prednisone in transplant recipients based on new chromatography assay techniques and free drug measurement, population pharmacokinetic/pharmacodynamic modelling approaches, genetic testing and larger studies in patients on modern day immunosuppressant protocols may lead to better individualization of corticosteroid therapy in the future. PMID- 23018479 TI - Hypertrophic cardiomyopathy and pregnancy. AB - Women with pre-existing cardiomyopathies have limited cardiovascular reserve. The hemodynamic challenges of pregnancy, labor, and delivery pose unique risks to this group of patients, which can result in clinical decompensation with overt heart failure, arrhythmias, and rarely, maternal death. A multidisciplinary team approach and a controlled delivery are crucial to adequate management of patients with underlying heart disease. Preconception planning and risk assessment are essential and proper counseling should be offered to expectant mothers regarding both the risks that pregnancy poses, and the implications for future offspring. In this paper, we will review the hemodynamic stressors that pregnancy places upon women with hypertrophic cardiomyopathies, risk assessment and discuss what evidence exists regarding the management during pregnancy, labor, and delivery for hypertrophic cardiomyopathy. PMID- 23018480 TI - Marfan syndrome and vascular dissections during pregnancy. AB - Pregnancy in a patient with Marfan syndrome may pose significant maternal and fetal risks, and pregnancy outcome is most impacted by the extent of cardiovascular involvement present at conception. This review addresses principles to guide preconception counseling of a Marfan patient, in addition to antepartum and intrapartum management considerations. Multidisciplinary care is recommended during pregnancy, given the potential for multiorgan involvement and various complications which may occur. Mode of delivery planning is guided by the degree of aortic root dilatation. Dissection of a dilated aortic root can present a surgical emergency during pregnancy, and principles for cardiopulmonary bypass in a pregnant patient are reviewed. PMID- 23018481 TI - Axillary reverse mapping (ARM): initial results of phase II trial in preventing lymphedema after lymphadenectomy. AB - INTRODUCTION: Axillary reverse mapping (ARM) is unproven in preventing lymphedema. The purpose of this study is to evaluate lymphedema rates with ARM added to lymphadenectomy. METHODS: In this IRB approved study, 156 cases of SLNB/ALND from May 2007 to March 2010 were prospectively accrued to the study. Patients with an increase in arm volume greater than 20% over the contralateral side were considered to have lymphedema. Data was collected on identification and variations in lymphatic drainage, nodal status, ARM lymphatics preservation rate, adjuvant treatment (XRT, chemo) and lymphedema rate. RESULTS: 114 patients underwent SLNB only and 42 patients underwent ALND after SLNB, with a SLN identification rate of 100%. Median age was 56.9(+/-12.5) and BMI was 29.4(+/ 6.9). Mean follow up was 14.6+/-9.4 months. ARM lymphatics were near or in the SLN field in 45/114 (39%) of the SLNB cases and in 34/42 (81%) of the ALND. ARM nodes were preserved in 92.3% of the cases (144/156). A total of 12 ARM nodes were resected because of crossover or suspicious appearance. The 2 ARM nodes involved by malignancy were in heavily positive axilla (>5 positive nodes). Lymphedema was diagnosed in 3.5% (4/114) of the SLNB cases and 7%(3/42) of the combined SLNB+ALND cases. 2.9% (4/140) of the patients who had the ARM lymphatics preserved and 18.7%(3/16) who had it transected developed clinical lymphedema. No regional recurrences were seen. CONCLUSION: Preserving the ARM nodes is safe and resulted in a low incidence of postoperative lymphedema after SLNB and ALND. PMID- 23018482 TI - Use of a lipid-lowering food supplement in patients on hormone therapy following breast cancer. AB - AIM: The aim of this paper was to determine the activity of a natural nutraceuticals combination (AP=Berberine+Red Yeast Rice) on dyslipidemia which frequently persists after life style changes in patients on hormone-therapy following breast cancer (HT-BC). METHODS: Twenty-one HT-BC patients, free of tumor, mean age 59.9 years, BMI 28,9 kg/m2, waist circumference 95.9 cm, with altered lipid profile (total cholesterol 269.0 mg/dL, high-density lipoprotein (HDL) cholesterol 54.9 mg/dL, low-density lipoprotein (LDL) cholesterol 184.0 mg/dL, and triglycerides 263.3 mg/dL) were recruited. They were recommended a 3 month period of diet followed by a 3-month period of treatment with AP 1 tablet/day. AP tablets contain berberine 500 mg, red yeast rice extract 200 mg (equivalent to 3 mg monacolins), policosanol 10 mg, folic acid 0.2 mg, coenzyme Q10 2 mg, and asthaxantin 0.5 mg. RESULTS: The lipid profile was significantly improved by AP vs. diet: 1.8% decrease in total cholesterol on diet and a further 15.3% decrease with AP vs. diet (P<0.001); a 3.1% decrease in LDL cholesterol after diet and an 18.9% decrease after AP treatment vs diet alone (P<0.01); a 2.3% decrease in triglycerides after diet alone and a 36.5% decrease after AP vs. diet (P<0.05). CONCLUSION: Adequate life style therapy is effective in reducing, but not in normalizing, the lipid profile in patients on hormone-therapy following breast cancer. The use of natural nutraceuticals as AP, combined with diet, leads to a good therapeutic response and optimal acceptance by the patients. PMID- 23018483 TI - Clinical and therapeutic aspects of vulvodynia: the importance of physical therapy. AB - Vulvodynia affects a large number of women worldwide. It is estimated that the prevalence rate of vulvodynia is 16% in women aged 18 to 64 years, resulting in constant demand for specialized medical care, although little therapeutic success is achieved. Furthermore, the cause of this disorder remains unknown and involves different symptoms that are implicated in important chronic vulvar pain with disastrous consequences for the afflicted women. In view of these data, the authors have proposed a bibliographic review of the pathophysiology and treatment of vulvodynia. The aim of this review was to assist in clinical diagnosis and elucidate the multidisciplinary treatment that appears to be associated with a higher success rate in these women. Physical therapy using diverse techniques has an important role in multidisciplinary care, obtaining satisfactory results in the treatment of pelvic floor muscle dysfunction and thus improving the symptoms and quality of life in women with vulvodynia. PMID- 23018484 TI - [Medical humanities in gynecology and obstetrics]. AB - Medicine is a collection of science, technology and human values. Nowadays, the most modern paradigm of medicine is based on the combination of man's vulnerability and his need for healthcare, both in a technical-pharmacological sense, but more importantly, with regard to human relations. Of course, the solidarity perspective must represent the strong relational foundation of the doctor-patient relationship, considering that this perspective is now a clear indicator of the civilization level of a nation. The notion of healthcare must therefore be understood in its twofold and inseparable meaning: firstly, the act of "curing" and secondly, the act of "taking care of". In Italy, the term for both of these acts is unique ("curare" meaning to treat, to cure, to care for). However, it is necessary to encompass all meanings as they are inseparable. The responsibility of the doctor is, therefore, to treat, assist, understand and to be at the service of each human being in their interest and in their centrality. PMID- 23018485 TI - An orbital-overlap model for minimal work functions of cesiated metal surfaces. AB - We introduce a model for the effect of cesium adsorbates on the work function of transition metal surfaces. The model builds on the classical point-dipole equation by adding exponential terms that characterize the degree of orbital overlap between the 6s states of neighboring cesium adsorbates and its effect on the strength and orientation of electric dipoles along the adsorbate-substrate interface. The new model improves upon earlier models in terms of agreement with the work function-coverage curves obtained via first-principles calculations based on density functional theory. All the cesiated metal surfaces have optimal coverages between 0.6 and 0.8 monolayers, in accordance with experimental data. Of all the cesiated metal surfaces that we have considered, tungsten has the lowest minimum work function, also in accordance with experiments. PMID- 23018487 TI - Chemical vapour deposition of amorphous Ru(P) thin films from Ru trialkylphosphite hydride complexes. AB - The ruthenium phosphite hydride complexes H(2)Ru(P(OR)(3))(4) (R = Me (1), Et (2), (i)Pr (3)) were used as CVD precursors for the deposition of films of amorphous ruthenium-phosphorus alloys. The as-deposited films were X-ray amorphous and XPS analysis revealed that they were predominantly comprised of Ru and P in zero oxidation states. XPS analysis also showed the presence of small amounts of oxidized ruthenium and phosphorus. The composition of the films was found to depend on ligand chemistry as well as the deposition conditions. The use of H(2) as the carrier gas had the effect of increasing the relative concentrations of P and O for all films. Annealing films to 700 degrees C under vacuum produced films of polycrystalline hcp Ru while a flowing stream of H(2) resulted in polycrystalline hcp RuP. PMID- 23018486 TI - Increased low-grade inflammation is associated with lack of functional response to carvedilol in patients with systolic heart failure. AB - BACKGROUND: The aim of this study was to evaluate, according to functional response, the neuroendocrine and inflammatory status in patients with chronic heart failure before and after therapy with carvedilol. METHODS AND RESULTS: Serum tumor necrosis factor-alpha (TNF-alpha) soluble receptors (sTNF-R1 and sTNF R2), interleukin (IL)-10 and IL-18, chromogranin A (CgA) and brain natriuretic peptide (pro-BNP) were measured in 37 New York Heart Association class II to IV heart failure patients, at baseline and after 6 months of therapy with carvedilol. Patients were divided in two groups according to whether, following carvedilol, left-ventricular ejection fraction (LVEF) had increased by at least 5% (17 patients) or not (20 patients). Baseline LVEF was higher in nonresponders (38 +/- 5 vs. 31 +/- 7%, P = 0.002). In responders, LVEF increased from 31 +/- 7 to 51 +/- 7% (P < 0.0001), whereas in nonresponders it decreased from 38 +/- 5 to 33 +/- 7%, (P = 0.02). sTNF-R1 (P = 0.019) and sTNF-R2 (P = 0.025) increased in nonresponders, whereas they did not change in responders. After carvedilol, IL-10 was significantly higher in responders (P = 0.03). Conversely, no significant IL 18 and CgA changes were observed in either group. CgA was not significantly different between groups at baseline and after carvedilol in either group, whereas pro-BNP significantly increased in nonresponders (from 438 +/- 582 to 1324 +/- 1664 pg/ml, P = 0.04) and decreased in responders (from 848 +/- 1221 to 420 +/- 530 pg/ml, P = 0.08). CONCLUSION: Increased inflammatory activation observed only in heart failure patients not improving left-ventricular function after carvedilol may indicate that inflammation, either as a direct cause or as a consequence, is associated with progressive ventricular dysfunction. PMID- 23018488 TI - A novel mammalian ER-located J-protein, DNAJB14, can accelerate ERAD of misfolded membrane proteins. AB - Misfolded proteins in the endoplasmic reticulum (ER) are dislocated out of the ER to the cytosol, polyubiquitinated, and degraded by the ubiquitin-proteasome system in a process collectively termed ER-associated degradation (ERAD). Recent studies have established that a mammalian ER-localized transmembrane J-protein, DNAJB12, cooperates with Hsc70, a cytosolic Hsp70 family member, to promote the ERAD of misfolded membrane proteins. Interestingly, mammalian genomes have another J-protein called DNAJB14 that shows a high sequence similarity to DNAJB12. Yet, very little was known about this protein. Here, we report the characterization of DNAJB14. Immunofluorescence study and protease protection assay showed that, like DNAJB12, DNAJB14 is an ER-localized, single membrane spanning J-protein with its J-domain facing the cytosol. We used co immunoprecipitation assay to find that DNAJB14 can also specifically bind Hsc70 via its J-domain to recruit this chaperone to ER membrane. Remarkably, the overexpression of DNAJB14 accelerated the degradation of misfolded membrane proteins including a mutant of cystic fibrosis transmembrane conductance regulator (CFTRDeltaF508), but not that of a misfolded luminal protein. Furthermore, the DNAJB14-dependent degradation of CFTRDeltaF508 was compromised by MG132, a proteasome inhibitor, indicating that DNAJB14 can enhance the degradation of a misfolded membrane protein using the ubiquitin-proteasome system. Thus, the mammalian ER possesses two analogous J-proteins (DNAJB14 and DNAJB12) that both can promote the ERAD of misfolded transmembrane proteins. Compared with DNAJB12 mRNA that was widely expressed in mouse tissues, DNAJB14 mRNA was expressed more weakly, being most abundant in testis, implying its specific role in this tissue. PMID- 23018489 TI - (Pro)renin receptor and vacuolar H(+)-ATPase. AB - The (pro)renin receptor [(P)RR] is a molecule that binds prorenin and renin in tissues, leading not only to their activation, but also carrying out intracellular signaling. As a key player in the tissue renin-angiotensin system, (P)RR activation plays an important role in the development of end-organ damage in hypertension and diabetes. One fragment of (P)RR is also known as ATP6AP2 because it is associated with vacuolar H(+)-ATPase (V-ATPase). V-ATPase is a multi-subunit proton pump involved in diverse and fundamental aspects of cellular physiology, including receptor-mediated endocytosis and recycling, processing of proteins and signaling molecules, membrane sorting and trafficking, and activation of lysosomal/autophagosomal enzymes. The role of (P)RR in the function of V-ATPase has been investigated in recent studies using conditional knockout mice. Furthermore, the novel function of (P)RR as an adaptor protein between the Wnt receptor complex and V-ATPase has been demonstrated. Thus, (P)RR is a multi functional molecule that has complex structure and functionality. This review focuses on current insights into the possibility of (P)RR acting as a modulator of V-ATPase and future perspectives in translational research. PMID- 23018490 TI - Blood cholesterol level and risk of stroke in community-based or worksite cohort studies: a review of Japanese cohort studies in the past 20 years. AB - Evidence of the causal relationship between hypercholesterolemia and coronary artery disease (CAD) has been established worldwide. However, little attention has been paid to the relationship between hypercholesterolemia and stroke, despite stroke being the most common cardiovascular disease in Japan. We therefore reviewed cohort studies that investigated this relationship in the Japanese population over the past 20 years, and compared their findings with clinical trials and cohort studies in Western countries. Fourteen cohort studies were carried out in Japan during this period. The number of subjects in the studies ranged from 1621 to 91,219 and the mean follow-up period ranged from 7.6 to 32 years. The majority of studies showed no association between hypercholesterolemia and total stroke. However, one report showed a positive association between low-density lipoprotein cholesterol and atherothrombotic cerebral infarction. The relationship between hypercholesterolemia and cerebral infarction may be modified by the proportion of atherothrombotic infarctions in the population surveyed. Randomized controlled trials on statins have shown a substantial reduction in cerebral infarction, and so the discrepancy between cohort studies and clinical trials requires further study. However, some studies have reported that subjects with low blood cholesterol are more susceptible to intracerebral hemorrhage. Two hypotheses have been proposed to explain this association between low cholesterol and intracerebral hemorrhage. First, low blood cholesterol may induce angionecrosis, possibly in combination with hypertension, and second, low blood cholesterol may reflect a poor nutritional status. Either way, further continuous research in various fields of medical science is required to clarify the overall effect of blood cholesterol on stroke in humans. PMID- 23018491 TI - Preimplant factors affecting prostate D90 after transperineal interstitial prostate brachytherapy with loose (125)I seeds. AB - The dose received by 90% of the prostate volume (D90) is the key parameter of dosimetric analysis in prostate brachytherapy. The aim of this analysis was to identify preimplant factors affecting prostate D90 after transperineal interstitial prostate brachytherapy with loose (125)I seeds. We reviewed the records of 210 patients who underwent transperineal interstitial prostate brachytherapy with loose (125)I seeds for clinical T1/T2 prostate cancer at our institution. Patients who received supplemental external-beam radiation therapy were excluded. One hundred and nine patients (51.9%) received neoadjuvant hormonal therapy (NHT). One month after seed implantation, postimplant computed tomography and dosimetric analysis were performed. Univariate and multivariate analyses were carried out to identify preimplant factors affecting postimplant prostate D90. The postimplant prostate D90 values ranged from 123.3 to 234.1 Gy (mean +/- standard error, 177.1 +/- 1.4 Gy). Postimplant prostate D90 differed significantly between patients who had and had not undergone NHT (P = 0.001). In addition, simple regression analyses showed positive correlations with the estimated preimplant prostate D90, preimplant prostate volume by transrectal ultrasound (TRUS), total radioactivity, number of needles, and number of seeds. On stepwise multiple regression analysis, postimplant prostate D90 showed significant negative correlations with NHT and preimplant prostate volume by TRUS, and a significant positive correlation with total radioactivity. In conclusion, NHT, preimplant prostate volume by TRUS, and total radioactivity are significant preimplant factors affecting postimplant prostate D90 in prostate cancer patients treated with transperineal interstitial prostate brachytherapy with loose (125)I seeds. PMID- 23018492 TI - Angiotensin receptor blockers reduce left ventricular hypertrophy in dialysis patients: a meta-analysis. AB - INTRODUCTION: Left ventricular hypertrophy (LVH) is a major cardiovascular complication and an important predictor of mortality in patients with end-stage renal disease. Angiotensin II blockades have been widely used in the treatment of hypertension; however, the influence of angiotensin receptor blockers (ARBs) on LVH in dialysis patients has not been thoroughly studied. In this meta-analysis, the authors analyzed the effect of ARBs on LVH and left ventricular function in patients on maintenance dialysis. METHODS: The authors did systematic search of PubMed, Embase and Cochrane Central Register of Controlled Trials, until November 2010. Data extracted from the literature were analyzed with the Review Manager. RESULTS: The results of 6 randomized controlled trials (207 participants) reveal that ARB group had a greater regression of left ventricular mass index (LVMi) when compared with non-ARB group (P = 0.002) in dialysis patients while no significant difference for left ventricular ejection fraction (LVEF; P = 0.30). The ARB group had a nonsignificantly greater therapeutic value of LVMi or LVEF when compared with angiotensin-converting enzyme inhibitor (ACEI; P = 0.74 and 0.49, respectively). No significant alterations were observed in LVMi and LVEF between the combination of ARBs and ACEIs and ARBs group (P = 0.43 and 0.24, respectively). CONCLUSIONS: ARBs are associated with a greater reduction in LVH in patients on dialysis. The ARB therapy tends to have a similar favorable effectiveness as ACEI; however, the combination of ARBs with ACEIs did not show additional benefit to LVH in patients on hemodialysis. PMID- 23018493 TI - Ocular anatomy, ganglion cell distribution and retinal resolution of a killer whale (Orcinus orca). AB - Retinal topography, cell density and sizes of ganglion cells in the killer whale (Orcinus orca) were analyzed in retinal whole mounts stained with cresyl violet. A distinctive feature of the killer whale's retina is the large size of ganglion cells and low cell density compared to terrestrial mammals. The ganglion cell diameter ranged from 8 to 100 um, with the majority of cells within a range of 20 40 um. The topographic distribution of ganglion cells displayed two spots of high cell density located in the temporal and nasal quadrants, 20 mm from the optic disk. The high-density areas were connected by a horizontal belt-like area passing below the optic disk of the retina. Peak cell densities in these areas were evaluated. Mean peak cell densities were 334 and 288 cells/mm(2) in the temporal and nasal high-density areas, respectively. With a posterior nodal distance of 19.5 mm, these high-density data predict a retinal resolution of 9.6' (3.1 cycles/deg.) and 12.6' (2.4 cycles/deg.) in the temporal and nasal areas, respectively, in water. PMID- 23018494 TI - Microbes as forensic indicators. AB - The forensic potential of microorganisms is becoming increasingly apparent as a consequence of advances in molecular sciences and genomics. This review discusses instances in which microbes, and in particular bacteria, can impact upon forensic investigations. There is increasing evidence that humans have an extremely diverse 'microbiome' that may prove useful in determining ethnicity, country of origin, and even personal identity. The human microbiome differs between regions of the body and may prove useful for determining the nature of stains such as those caused by saliva and vaginal fluid: it may even be possible to link the stains to the person responsible for them. Similarly, the composition of the microbiome present in a soil sample may prove a useful indicator of geographic origin or as a means of linking people, animals, or objects together or to a specific location. Microorganisms are important in the decay process and also influence the presence and concentration of alcohol, drugs, and other chemicals of forensic relevance. There is also a possibility that the entry of microorganisms into the body during the agonal period may prove useful for the diagnosis of drowning. The transmission of infectious diseases, and in particular sexually-transmitted diseases, can provide evidence linking a victim and a suspect. Microorganisms that cause fatal infections are not always identified at the time of death and may lead to the death being considered 'suspicious'. If a fatal infection can be linked to a hospital or medical procedure it can lead to prosecutions and therefore it is important to determine when and where an infection was acquired. Similarly, naturally acquired infections need to be distinguished from those that result from malicious transmission. Microorganisms can therefore provide evidence in many different forensic scenarios but most of the work is still at the experimental stage and there are therefore many opportunities for further research. PMID- 23018495 TI - Prevalence of giardiasis and genotypic characterization of Giardia duodenalis in hilltribe children, Northern Thailand. AB - A cross-sectional study was performed to determine the prevalence of giardiasis in hilltribe children of 2 different remote districts (Mae-chaem and Hod), Chiang Mai, Northern Thailand from November 2006-April 2007. The overall prevalence of giardiasis was 5.2%. Genetic characterization of Giardia duodenalis isolated from these children was performed using PCR methods specific for small subunit ribosomal rRNA (SSU-rRNA) and glutamate dehydrogenase (gdh) gene. This study shows that the distribution of Giardia assemblages varied in these 2 populations. Assemblage BIV was found predominantly in children from Hod District while assemblage AII was more common in children from Mae-Chaem District. Our result showed that assemblage A was significantly associated with loose/watery stool (p = 0.001). In addition, children harbouring assemblage B had shed a significantly higher number of cysts (p = 0.019) in stools than those infected with assemblage A. Further study on the epidemiology of giardiasis especially risk factors associated with genotyping would help to understand the nature of this disease in each population. PMID- 23018496 TI - Assessing the temporal modelling for prediction of dengue infection in northern and north-eastern, Thailand. AB - This study aimed at developing a predicting model on the incidence rate of dengue fever in four locations of Thailand--i.e. the northern region, Chiang Rai province, the north-eastern region and Sisaket province--using time series analysis. Seasonal Autoregressive Integrated Moving Average (SARIMA) model was performed using data on monthly incidence rate of dengue fever from 1981 to 2009, and validated using the monthly rate collected for the period January 2010 to October 2011. The results show that the SARIMA(1,0,1)(0,1,1)12 model is the most suitable model in all locations. The model for all locations indicated that the predicted dengue incidence rate and the actual dengue incidence rate matched reasonably well. The model was further validated by the Portmanteau test with no significant autocorrelation between residuals at different lag times. Our findings indicate that SARIMA model is a useful tool for monitoring dengue incidence in Thailand. Furthermore, this model can be applied to surveillance data for early warning systems for control and reduction of dengue transmission. PMID- 23018497 TI - Abattoir prevalence, organ distribution, public health and economic importance of major metacestodes in sheep, goats and cattle in Fars, southern Iran. AB - Some of the metacestodes are not only zoonotic but are also responsible for severe tissue damage, reduction in milk and meat production, and considerable economic loss due to condemnation of the infected organs of the herbivorous animals. The aim of the present study was to determine the prevalence of Cysticercus ovis, Cysticercus tenuicollis, hydatid cyst and Coenurus gaigeri in sheep and goats and Cysticercus bovis, Cysticereus tenuicollis and hydatid cyst in cattle. A total of 1050 sheep, 950 goats and 500 cattle slaughtered at Shiraz Slaughterhouse were carefully examined for these metacestodes. Cysticercus tenuicollis was found in 184 (17.52%) sheep and 523 (55.05%) goats. The prevalence of C. tenuicollis was higher in males than females (P<0.01), and was higher in goats compared to sheep (P<0.01). Hydatid cyst was found in 478 (45.52%) sheep and 95 (10.0%) goats and its prevalence was higher in older animals compared to the younger ones. Coenurus gaigeri was found in 5 (0.48%) sheep and 17 (1.79%) goats and Cysticercus ovis was found in one male sheep only (0.09%). Cysticercus bovis was found in 3 male cattle (0.6%) and hydatid cyst was found in 58 (11.6%) cattle. The prevalence of hydatid cyst was higher in older cattle compared to the younger ones and higher in females than males. These results suggest that the high prevalence of the metacestodes infestations in this area is a great concern for both medical and veterinary authorities to design therapeutic and preventive programs to overcome this problem. PMID- 23018498 TI - The role of worm infestation in allergic rhinitis. AB - The purpose of this study is to determine the relevance of the hygiene hypothesis; that is to determine if worm infestation has a protective role against the development of allergic rhinitis. A prospective case controlled study was conducted. Specific IgG levels to Toxocara were studied in 85 patients confirmed to have allergic rhinitis and were compared to levels in another 85 controls, with no form of allergy. The IgG assay was done using ELISA technique. There was a higher incidence of positive specific IgG to Toxocara in the controls as compared to allergic patients. The values were statistically significant [Chi square test (p=0.002)]. This negative association between worm infestation and allergic rhinitis suggests that a previous worm infestation could protect against the development of allergic rhinitis. PMID- 23018499 TI - Genotyping of Giardia lamblia isolates from human in southern Iran. AB - Giardia lamblia cysts isolated from human faeces in South of Iran were analyzed with PCR-restriction fragment length polymorphism (RFLP) assay, based on the detection of glutamate dehydrogenase (gdh) genes. Among 205 faecal samples from microscopically diagnosed giardiasis patients, the gdh gene was amplified from 172 cases with a semi nested PCR assay and typed by RFLP analysis. Of the 172 positive samples, 128 (74.41%) were typed as assemblage AII, 30 (17.44%) assemblage BIII, 6 (3.49%) assemblage BIV and in 8 (4.66%) isolates, mixed assemblages AII and BIV were detected. Clinical features were available for 52 successfully typed cases and the possible correlation of Giardia assemblages and clinical symptoms was evaluated. Both assemblages caused similar illness, but assemblage AII was significantly more frequently associated with abdominal pain, nausea and vomiting. Since these isolates, A and B, are of human origin, anthroponotic transmission of Giardia can be suggested for the route of infection in this region. PMID- 23018500 TI - Antibiotic susceptibility profile of Haemophilus influenzae and transfer of co trimoxazole resistance determinants. AB - Prior to the implementation of Haemophilus influenzae type b vaccination worldwide, H. influenzae has been one of the main causative agents of community acquired pneumonia and meningitis in children. Due to the lack of information on the characteristics of the H. influenzae isolates that have previously been collected in Malaysia, the H. influenzae were assessed of their microbial susceptibility to commonly used antibiotics. Emphasis was made on strains that were resistance to co-trimoxazole (SXT) and their mode of transfer of the antibiotic resistance determinants were examined. A collection of 34 H. influenzae isolates was serotyped and antimicrobial susceptibility tests were performed to 11 antibiotics. To the isolates that were found to be resistant to co-trimoxazole, minimum inhibition concentration (MIC) to SXT was performed using Etest while agar dilution method was used to measure the individual MICs of trimethoprim (TMP) and sulfamethoxazole (SUL). These isolates were also examined for presence of plasmid by PCR and isolation method. Conjugal transfers of SXT-resistant genes to SXT-susceptible hosts were performed to determine their rate of transfer. Result showed that 20.6% of the total number of isolates was serotype B while the remaining was non-typeable. Antimicrobial susceptibility profile of all the isolates revealed that 58.8% was resistant to at least one antibiotic. Majority of these isolates were equally resistant to ampicillin and tetracycline (29.4% each), followed by resistance to SXT (26.5%). From nine isolates that were found to be SXT-resistant, five contained plasmid/s. Conjugal transfer experiment showed that these five isolates with plasmid transferred SXT-resistance determinants at a higher frequency than those without. From these observations, it is postulated that plasmid is not involved in the transfer of SXT-resistance genes but presence of plasmid facilitates their transfer. The information obtained from this study provides some basic knowledge on the antimicrobial susceptibility pattern of the H. influenzae isolates and their mode of transfer of SXT-resistance genes. PMID- 23018501 TI - Simulium (Nevermannia) chomthongense, a new species of black fly (Diptera: Simuliidae) from Chiang Mai, Thailand. AB - Simulium (Nevermannia) chomthongense sp. nov. is described from female, male, pupal and larval specimens collected from Doi Inthanon National Park and Doi Phahompok National Park, Chiang Mai, Thailand. This new species, first reported as S. (Eusimulium) sp. A, and later regarded as S. (N.) caudisclerum Takaoka & Davies, described from peninsular Malaysia, is distinguished from S. (N.) caudisclerum in the male by the number of enlarged upper-eye facets and the relative size of the hind basitarsus against the hind tibia and femur, and in the pupa by the relative length of the stalks of paired filaments against the common basal stalk and the color of the dorsal surface of abdominal segments 1- 3 (or 4). Taxonomic and molecular notes are provided to separate this new species from four other known species of the vernum species-group, which share an accessory sclerite on the larval abdomen, a rare characteristic in this species group. PMID- 23018502 TI - Field evaluation of repellency of a polyherbal essential oil against blackflies and its dermal toxicity using rat model. AB - In the present study we have evaluated the repellent activity of mixture of Curcuma longa, Zanthoxylum limonella and Pogostemon heyneanus essential oils in 1:1:2 ratio at 5%, 10% and 20% concentration against blackflies in northeastern India. Initially the essential oil mixture tested here has been found effective against Aedes albopictus mosquitoes. The average protection recorded in 20% concentration (170.56 +/- 4.0; 95% CI = 162.09-179.02) was higher as compared to other two concentrations (F = 90.2; p<0.0001; df = 53). Percentage repellency and repellency index was found to be higher in 20% concentration (p <= 0.017). No appreciable clinical and behavioral signs were observed in the acute dermal toxicity using rat model. No changes were observed in biochemical profiles of treatment group animals. Similarly, no prominent lesions were observed in vital organs of treatment in both the sexes. The study concludes that tested repellent is safe for use and has multi-insects repellent property. PMID- 23018503 TI - Case series of naturally acquired Plasmodium knowlesi infection in a tertiary teaching hospital. AB - Plasmodium knowlesi is a simian malaria parasite and is recently recognized as the fifth malaria parasite infecting humans. Manifestation of the infection may resemble other infection particularly dengue fever leading to inappropriate management and delay in treatment. We reported three cases of naturally acquired P. knowlesi in Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Clinical manifestations were quite similar in those cases. Microscopically, the diagnosis might be challenging. These cases were confirmed by polymerase chain reaction method which serves as a gold standard. PMID- 23018504 TI - Modulation of interleukin-18 release produced positive outcomes on parasitaemia development and cytokines production during malaria in mice. AB - The involvement of interleukin-18 (IL-18) and the effects of modulating its release on the course of malaria infection were investigated using Plasmodium berghei ANKA infection in ICR mice as a model. Results demonstrated that plasma IL-18 concentrations in malarial mice were significantly elevated and positively correlated with the percentage parasitaemia development. Significant expressions of IL-18 were also observed in the brain, spleen and liver tissues. Slower development of parasitaemia was observed significantly upon inhibition and neutralization of IL-18, whereas faster development of parasitaemia was recorded when the circulating levels of IL-18 were further augmented during the infection. Inhibition and neutralization of IL-18 production also resulted in a significant decrease of plasma concentrations of pro-inflammatory cytokines (TNFalpha, IFNgamma, IL-1alpha and IL-6), whereas the anti-inflammatory cytokine, IL-10, was significantly increased. Augmenting the release of IL- 18 during the infection on the other hand resulted in the opposite. Early mortality in malarial mice was also observed when the circulating levels of IL-18 were further augmented. Results proved the important role of IL-18 in immune response against malaria and suggest that IL-8 is pro-inflammatory in nature and may involve in mediating the severity of the infection through a pathway of elevating the pro-inflammatory cytokine and limiting the release of anti inflammatory cytokine. PMID- 23018505 TI - A multiplex touchdown PCR for detection of Streptococcus pneumoniae, Haemophilus influenzae type b and Mycobacterium tuberculosis complex in sputum samples. AB - Rapid and accurate detection of Streptococcus pneumoniae (Sp), Haemophilus influenzae type b (Hib) and Mycobacterium tuberculosis complex (MTBC) in sputum by conventional methods remains problematic. Primers based on capsular polysaccharide biosynthesis gene (cpsA), the region II of the capsulation locus (cap), the insertion sequence IS6110 were designed for Sp, Hib, MTBC respectively. These primers were incorporated in a multiplex touchdown PCR assay for simultaneous detection of Sp, Hib and MTBC. The multiplex touchdown PCR assay was evaluated using standard strains and clinical sputum samples. The multiplex touchdown PCR assay showed 100% specificity in identifying Sp, Hib, MTBC from pure culture of standard strains. The sensitivities of the multiplex touchdown PCR assay were 94%, 98%, 98% for detection of Sp, Hib and MTBC respectively based on culture results while evaluated using 492 consecutive qualified clinical sputum samples; the specificities were all 100%. This highly sensitive and specific multiplex touchdown PCR assay offers a rapid and simple method for detection of Sp, Hib and MTBC in clinical sputum samples. PMID- 23018506 TI - Methicillin sensitive Staphylococcus aureus (MSSA) isolates as a potential source for the emergence of USA 300 methicillin resistant Staphylococcus aureus (MRSA) in Malaysia. AB - We investigated the potential of USA300 MRSA emergence in Malaysia by examining 268 MSSA isolates from both community (110) and healthcare (158) settings. Nine isolates from both the environments were similar to the USA300 MRSA background based on MLST, spa and PFGE type. These results underscore the importance of continued surveillance to monitor the emergence of USA300 MRSA in Malaysia. PMID- 23018507 TI - Detection of selected intestinal helminths and protozoa at Hospital Universiti Sains Malaysia using multiplex real-time PCR. AB - Intestinal parasites are the causative agents of a number of important human infections in developing countries. The objective of this study was to determine the prevalence of selected helminths and protozoan infections among patients admitted with gastrointestinal disorders at Hospital Universiti Sains Malaysia, Kelantan, Malaysia using multiplex real-time PCR. In addition microscopic examination was also performed following direct smear, zinc sulphate concentration and Kato-Katz thick smear techniques; and the presence of protozoan parasites was confirmed using trichrome and acid-fast stains. Of the 225 faecal samples analysed, 26.2% were positive for intestinal parasites by the multiplex real-time PCR, while 5.3% were positive by microscopy. As compared to microscopy, the multiplex real-time PCR detected 5.8 and 4.5 times more positives for the selected helminth and protozoan infections respectively. Among the selected helminths detected in this study, hookworm was the most prevalent by real-time PCR, while Ascaris lumbricoides was detected the most by microscopy. Meanwhile, among the selected protozoa detected in this study, Entamoeba histolytica was the most prevalent by real-time PCR, however microscopy detected equal number of cases with E. histolytica and Giardia lamblia. This study showed that real-time PCR can be used to obtain a more accurate prevalence data on intestinal helminths and protozoa. PMID- 23018508 TI - Infestation of gill copepod Lernanthropus latis (Copepoda: Lernanthropidae) and its effect on cage-cultured Asian sea bass Lates calcarifer. AB - Twenty Asian sea bass Lates calcarifer from a floating cage in Bt. Tambun, Penang were examined for the presence of parasitic gill copepod, Lernanthropus latis. The prevalence of L. latis was 100% with the intensity of infection ranging from 1 to 18 parasites per host or 3.75 of mean intensity. Female parasites having oblong cephalothorax and egg-strings were seen mainly on the entire gill of examined Asian sea bass. The infected gill of Asian sea bass was pale and had eccessive mucus production. Under light and scanning electron microscopies (SEM), L. latis was seen grasping or holding tightly to the gill filament using their antenna, maxilla and maxilliped. These structures are characteristically prehensile and uncinate for the parasite to attach onto the host tissue. The damage was clearly seen under SEM as the hooked end of the antenna was embedded into the gill filament. The parasite also has the mandible which is styliform with eight teeth on the inner margin. The pathological effects such as erosion, haemorrhages, hyperplasia and necrosis along the secondary lamellae of gill filaments were seen and more severe at the attachment site. The combined actions of the antenna, maxilla and maxilliped together with the mandible resulted in extensive damage as L. latis attached and fed on the host tissues. PMID- 23018509 TI - Comparative genetic analysis of VP4, VP1 and 3D gene regions of enterovirus 71 and coxsackievirus A16 circulating in Malaysia between 1997-2008. AB - Three genomic regions, VP4 capsid, VP1 capsid and 3D RNA polymerase of human enterovirus 71 (EV-71) and coxsackievirus A16 (CV-A16) were sequenced to understand the evolution of these viruses in Malaysia. A total of 42 EV-71 and 36 CV-A16 isolates from 1997- 2008 were sequenced. Despite the presence of many EV-71 subgenotypes worldwide, only subgenotypes B3, B4, B5, C1 and C2 were present in Malaysia. Importation of other subgenotypes such as C3, C4/D and C5 from other countries was infrequent. For CV-A16, the earlier subgenotype B1 was replaced by subgenotypes B2a and the recent B2c. Subgenotype B2a was present throughout the study while B2c only emerged in 2005. No genetic signatures could be attributed to viral virulence suggesting that host factors have a major role in determining the outcome of infection. Only three EV-71 B3 isolates showed non-consistent phylogeny in the 3D RNA polymerase region which indicated occurrence of recombination in EV-71. High genetic diversity was observed in the Malaysian EV-71 but Malaysian CV-A16 showed low genetic diversity in the three genomic regions sequenced. EV-71 showed strong purifying selection, but that occurred to a lesser extent in CV-A16. PMID- 23018510 TI - Identification of tropomyosin and arginine kinase as major allergens of Portunus pelagicus (blue swimming crab). AB - Crab is an important source of food allergen. Tropomyosin represents the main crab allergen and is responsible for IgE cross-reactivity between various species of crustaceans. Recently, other new crab allergens including arginine kinase have been identified. However, information on allergens of the local Portunidcrab is not available. Thus, the aim of this study was to identify the major allergens of Portunus pelagicus (blue swimming crab) using the allergenomics approach. Raw and cooked extracts of the crab were prepared from the crab meat. Protein profile and IgE binding pattern were demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting using sera from 30 patients with crab allergy. The major allergens of the crab were then identified by two-dimensional electrophoresis (2-DE), followed by mass spectrometry analysis of the peptide digests. The SDS PAGE of raw extract revealed approximately 20 protein fractions over a wide molecular weight range, while cooked extract demonstrated fewer protein bands. The raw extract also demonstrated a higher number of IgE reactive bands than the cooked extract. A heat-resistant protein of 36 kDa has been identified as the major allergen in both raw and cooked extracts. In addition, a heat sensitive protein of 41 kDa was also recognized as a major allergen in raw crab. The 2-DE gel profile of the raw extract demonstrated about >100 distinct proteins spots and immunoblotting of the 2-DE profile demonstrated at least 12 different major IgE reactive spots with molecular masses between 13 to 250 kDa and isoelectric point (pI) values ranging from 4.0 to 7.0. The 36 and 41 kDa proteins were identified as the crab tropomyosin and arginine kinase, respectively by mass spectrometry. Therefore, this study confirmed that tropomyosin and arginine kinase are the major allergens of the local Portunid crab, P. pelagicus. PMID- 23018511 TI - Symptomatic chronic strongyloidiasis in children following treatment for solid organ malignancies: case reports and literature review. AB - Strongyloidiasis is an infection caused by the intestinal nematode Strongyloides stercoralis. Infected healthy individuals are usually asymptomatic, however it is potentially fatal in immunocompromised hosts due to its capacity to cause an overwhelming hyperinfection. Strongyloidiasis could be missed during routine screening because of low and intermittent larval output in stool and variable manifestations of the symptoms. We present two cases of strongyloidiasis occurring in children with solid organ malignancies suspected to have the infection based on their clinical conditions and treatment history for cancer. Both patients were diagnosed by molecular and serological tests and were successfully treated. Thus, strongyloidiasis in patients undergoing intensive treatment for malignancies should be suspected, properly investigated and treated accordingly. PMID- 23018512 TI - A new record for Lispe orientalis Wiedemann, 1824 (Diptera: Muscidae) from peninsular Malaysia. AB - Lispe orientalis Wiedemann, 1824 is recorded for the first time in peninsular Malaysia. Specimens were collected from a mushroom cultivation farm in Genting Highlands, Pahang (3 degrees 25'18"N 101 degrees 47'48"E). Previously, this species had been recorded from Azerbaijin, India, Russia, Tajikistan, Thailand, Turkey and South Korea. The male of Lispe orientalis can be determined by the following characteristics: body non-metallic, ashy gray, third antennal segment black, R5 cell not narrow apically, hind metatarsus normal, legs entirely black, femora with long bristle-like hairs on av and pv surfaces, hind tibia without av and pv seta and the palpi orangish in colour. PMID- 23018513 TI - Identification of the forensically important beetles Nicrophorus japonicus, Ptomascopus plagiatus and Silpha carinata (Coleoptera: Silphidae) based on 16S rRNA gene in China. AB - Sarcophagous beetles play an important role in estimating postmortem interval time (PMI) in the later stages decomposition of carcasses. However, the morphological similarity of beetles usually poses a challenge for forensic scientists within their routine work. As a supplementary to traditional morphological method, molecular genetics identification is simple and time saving. A molecular identification method involving a 288-bp segment of the 16S ribosomal RNA (16S rRNA) gene from 15 beetles of Silphidae (Coleoptera), collected from 5 locations in 4 Chinese provinces, was evaluated. Phenogram analysis of the sequenced segments by the unweighted pairgroup method analysis (UPGMA) method showed that all specimens were properly assigned into four species with strong similarity, which indicated the possibility of separation congeneric species with the short 16S rRNA fragment. These results will be instrumental for implementation of the Chinese database of forensically relevant beetles. PMID- 23018516 TI - Assessment of statistical significance and clinical relevance. AB - In drug development, it is well accepted that a successful study will demonstrate not only a statistically significant result but also a clinically relevant effect size. Whereas standard hypothesis tests are used to demonstrate the former, it is less clear how the latter should be established. In the first part of this paper, we consider the responder analysis approach and study the performance of locally optimal rank tests when the outcome distribution is a mixture of responder and non-responder distributions. We find that these tests are quite sensitive to their planning assumptions and have therefore not really any advantage over standard tests such as the t-test and the Wilcoxon-Mann-Whitney test, which perform overall well and can be recommended for applications. In the second part, we present a new approach to the assessment of clinical relevance based on the so called relative effect (or probabilistic index) and derive appropriate sample size formulae for the design of studies aiming at demonstrating both a statistically significant and clinically relevant effect. Referring to recent studies in multiple sclerosis, we discuss potential issues in the application of this approach. PMID- 23018521 TI - Cytokine secretion from human monocytes potentiated by P-selectin-mediated cell adhesion. AB - BACKGROUND/AIM: P-selectin is a carbohydrate-recognizing cell adhesion molecule expressed on activated platelets and endothelial cells. It plays a crucial role in the recruitment of leukocytes to inflammatory and hemorrhagic sites. Cell adhesion mediated by P-selectin induces leukocyte activation, such as the generation of reactive oxygen species and the expression of blood coagulation factors. We assessed how P-selectin-mediated cell adhesion affects cytokine secretion from monocytes. METHODS: Human peripheral blood monocytes were cultured in a plate that had been coated with P-selectin purified from human platelets, and cytokines released in the culture supernatant from monocytes were determined by ELISA. RESULTS: The secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-12 and macrophage inflammatory protein 1beta increased 3- to 10-fold in response to P-selectin compared with unstimulated monocytes. We next examined the effects of cytokine treatment of monocytes on their susceptibility to P-selectin. The secretion of TNF-alpha from monocytes in response to P-selectin was increased when monocytes were preincubated with granulocyte/macrophage colony-stimulating factor, monocyte chemotactic protein-1 or interferon-gamma (IFN-gamma); IFN-gamma was the most effective in potentiating TNF-alpha secretion from monocytes. CONCLUSION: These results suggest that the interaction of monocytes with P-selectin plays an important role not only in their trafficking but also in the regulation of cytokine production by these cells. PMID- 23018523 TI - Coordination chemistry of gold catalysts in solution: a detailed NMR study. AB - Coordination chemistry of gold catalysts bearing eight different ligands [L=PPh(3), JohnPhos (L2), Xphos (L3), DTBP, IMes, IPr, dppf, S-tolBINAP (L8)] has been studied by NMR spectroscopy in solution at room temperature. Cationic or neutral mononuclear complexes LAuX (L=L2, L3, IMes, IPr; X=charged or neutral ligand) underwent simple ligand exchange without giving any higher coordinate complexes. For L2AuX the following ligand strength series was determined: MeOH?hex-3-yne = $100,000) associated with short acting and long-acting opioids (vs no opioids) were 4.28 and 12.19. The ORs for catastrophic claims associated with a spinal surgical procedure or spinal fusion (vs no procedure) were 4.27 and 11.40. Spinal surgical procedures plus opioid use significantly increased the OR for catastrophic claims; for example, spinal fusion plus long-acting opioids had an OR of 138.96. CONCLUSION: Spinal surgery and opioid utilization are associated with catastrophic claim costs. PMID- 23018526 TI - Exercise training for refractory angina: improving the coronary collateral circulation. PMID- 23018527 TI - Necessity and risks of arterial blood sampling in healthy volunteer studies. AB - Arterial blood sampling is necessary when drugs such as the fast-acting opioid analgesic remifentanil exhibit relevant differences between arterial and venous blood concentrations. Arterial cannulation is generally considered to be clinically safe and has thus become a standard procedure in pharmacokinetic pharmacodynamic assessments. However, rare cases of arterial occlusions have to be considered in risk-benefit assessments of arterial sampling in pharmacokinetic studies, especially when including healthy volunteers. In an actual case, arterial occlusion requiring surgical repair was caused by a factor V Leiden thrombophilia associated genetic variant F5 1691G>A (rs6025) and aggravated by a hypoplastic radial artery. Neither risk factor had been identified prior to enrolment by routine laboratory tests such as the prothrombin time (international normalized ratio), partial thromboplastin time and the clinical Allen's test of arterial function. Re-assessment of the necessity of arterial sampling showed that none of the potential alternatives, target concentrations of computerized infusions or venous concentrations during non-steady-state and steady-state conditions could provide the arterial concentrations. Relying on venous concentrations may result in erroneous pharmacodynamic parameters. Accurate pharmacokinetic-pharmacodynamic studies relying on precisely measured blood concentrations require serial sampling techniques during both steady-state and non-steady-state conditions. However, as illustrated by the presented case, incidents involving the generally safe procedure of arterial sampling are possible, although rare. To further minimize the risks, screening of subjects for prothrombotic risks and careful assessment of the suitability of the artery should be considered in pharmacokinetic studies requiring arterial cannulation. PMID- 23018529 TI - Pharmacokinetics of aliskiren in patients with end-stage renal disease undergoing haemodialysis. AB - BACKGROUND AND OBJECTIVES: Aliskiren represents a novel class of orally active renin inhibitors. This study analyses the pharmacokinetics, tolerability and safety of single-dose aliskiren inpatients with end-stage renal disease (ESRD) undergoing haemodialysis. METHODS: Six ESRD patients and six matched healthy volunteers were enrolled in an open-label, parallel-group, single-sequence study. The ESRD patients underwent two treatment periods where 300 mg of aliskiren was administered 48 or 1 h before a standardized haemodialysis session (4 h, 1.4 m(2) high-flux filter, blood flow 300 mL/min, dialysate flow 500 mL/min). Washout was >10 days between both periods. Blood and dialysis samples were taken for up to 96 h postdose to determine aliskiren concentrations. RESULTS: Compared with the healthy subjects (1681 +/- 1034 ng.h/mL), the area under the plasma concentration time curve (AUC) from time zero to infinity was 61% (haemodialysis at 48 h) and 41% (haemodialysis at 1 h) higher in ESRD patients receiving single-dose aliskiren 300 mg. The maximum (peak) plasma drug concentration (481 +/- 497 ng/mL in healthy subjects) was 17% higher (haemodialysis at 48 h) and 16% lower (haemodialysis at 1 h). In both treatment periods, dialysis clearance was below 2% of oral clearance and the mean fraction eliminated from circulation was 10 and 12% in period 1 and 2, respectively. Drug AUCs were similar in ESRD patients receiving aliskiren 1 or 48 h before dialysis. No severe adverse events occurred. CONCLUSION: The exposure of aliskiren is moderately higher in ESRD patients. Only a minor portion is removed by a typical haemodialysis session. Aliskiren exposure is not significantly affected by intermittent haemodialysis, suggesting that no dose adjustment is necessary in this population. PMID- 23018528 TI - Pharmacokinetic optimization of antiretroviral therapy in pregnancy. AB - Antiretroviral therapy suppresses replication of HIV allowing restoration and/or preservation of the immune system. Providing combination antiretroviral therapy during pregnancy can treat maternal HIV infection and/or reduce perinatal HIV transmission. However, providing treatment to pregnant women is challenging due to physiological changes that can alter antiretroviral pharmacokinetics. Suboptimal drug exposure can result in HIV RNA rebound, the selection of resistant virus or an increased risk of HIV-1 transmission to the infant. Increased drug exposure can produce unwarranted maternal adverse effects and/or fetal toxicity. Subsequently, dose adjustments may be necessary during pregnancy to achieve comparable antiretroviral exposure to non-pregnant adults. For several antiretrovirals, systemic exposure is decreased during the last trimester of pregnancy. By 6-12 weeks postpartum, concentrations return to those prior to pregnancy. Also, the extent of antiretroviral placental transfer to the fetus and degree of antiretroviral excretion into breast milk varies within, and between, antiretroviral drug classes. It is necessary to consider the pharmacological characteristics of each antiretroviral when optimizing combination therapy during pregnancy to treat maternal HIV infection and prevent perinatal HIV transmission. PMID- 23018530 TI - Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. AB - BACKGROUND AND OBJECTIVES: Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. PATIENTS AND METHODS: Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1-2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously. RESULTS AND CONCLUSION: A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66%. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10-20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern. PMID- 23018531 TI - A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. AB - BACKGROUND AND OBJECTIVES: Avagacestat is an orally active gamma-secretase inhibitor that selectively inhibits amyloid beta (Abeta) synthesis in cell culture and animal models. The objective of the current study was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple doses of avagacestat over 28 days in healthy young men and elderly men and women in a placebo-controlled, sequential-panel, ascending multiple-dose study. METHODS: Thirty-three young men were assigned to four serial dose groups of avagacestat 15, 50, 100 or 150 mg (n = 6-7 per dose), or placebo (n = 2 per dose panel; 8 subjects total) once daily for 28 days. Elderly men and women were assigned to serial dose groups of avagacestat 50 mg and then 100 mg (n = 7 men, 6 women) or placebo (n = 2 men, 2 women) once daily for 14 days per dose level. RESULTS: Avagacestat was rapidly absorbed, had a terminal elimination half-life of 38-65 h, and reached a steady-state concentration by day 10 of daily dosing. Exposure in young subjects increased in proportion to dose. There were no apparent differences in steady-state area under the plasma concentration-time curve between young and elderly subjects; however, elderly subjects demonstrated a higher maximum plasma concentration for avagacestat. Doses of avagacestat >50 mg/day reduced steady-state trough concentrations of CSF Abeta(1-38), Abeta(1-40) and Abeta(1-42) in a dose-dependent fashion over 28 days of daily dosing. There were no signs of potential Notch-related dose-limiting toxicities. CONCLUSION: The results support continued evaluation of avagacestat in an elderly target population with predementia and mild to moderate Alzheimer's disease. PMID- 23018533 TI - [Medical ethics as professional ethics]. AB - Contemporary medical ethics is far from the traditional concept of "In-Sul (benevolent art)" or "Yul-Li (?, ethics), which emphasizes so much the personality or the character of a doctor. Nowadays, medical ethics should be considered as "professional ethics" which regulates the acts and medical practices of ordinary doctors in their daily practice. The key concepts of the professional ethics are "autonomy", "integrity", and "professional standard" established by medical organizations such as medical societies or associations. Most of Korean doctors have not been familiar with the concept of professional ethics or professionalism, which is due to the modern history of Korea. However, the concept of professional ethics is really critical to Korean doctors from the perspective of professional dignity and social respect to this profession. The current healthcare system of Korea is suffering from many problems of both private and public sector. Nonetheless, the professional ethics is urgently demanded for that very reason. PMID- 23018532 TI - Downregulation of histone methyltransferase genes SUV39H1 and SUV39H2 increases telomere length in embryonic stem-like cells and embryonic fibroblasts in pigs. AB - Telomere is a nucleoprotein structure at the ends of chromosomes that helps to protect the ends of chromosomes from being fused with other chromosomes. Knockout of histone methyltransferases Suv39h1 and Suv39h2 increases the telomere length in murine cells, whereas downregulation of SUV39H1 and SUV39H2 genes decreases the telomere length in human cells, suggesting that telomere biology is different among mammalian species. However, epigenetic regulation of the telomere has not been studied in mammals other than the human and mouse. In the present study, the effect of knockdown of SUV39H1 and SUV39H2 genes on telomere length was examined in porcine embryonic stem-like cells (pESLCs) and porcine embryonic fibroblasts (PEFs). The telomeres in SUV39H1 and SUV39H2 knockdown (SUV39KD) pESLCs (37.1 +/- 0.9 kb) were longer (P<0.05) compared with those of the control (33.0 +/- 0.7 kb). Similarly, SUV39KD PEFs had longer telomeres (22.1 +/- 0.4 kb; P<0.05) compared with the control (17.8 +/- 1.1 kb). Telomerase activities were not different between SUV39KD pESLCs (10.4 +/- 1.7) and the control (10.1 +/- 1.7) or between SUV39KD PEFs (1.0 +/- 0.3) and the control (1.0 +/- 0.4), suggesting that telomerase activities did not contribute to the telomere elongation in SUV39KD pESLCs and SUV39KD PEFs. Relative levels of trimethylation of histone H3 lysine 9 and expressions of DNMT1, DNMT3A and DNMT3B were decreased in SUV39KD cells, suggesting that telomere lengthening in SUV39KD pESLCs and SUV39KD PEFs might be not only related to the loss of histone modification marks but also linked to the decrease in DNA methyltransferase in pigs. PMID- 23018534 TI - [Death education for medical personnel utilizing cinema]. AB - Death and dying is an ultimate process that every human being must experience. However, in these days we do not like to think or discuss about death and dying. Actually, hatred and denial is the usual feeling when we encounter death and dying. Dying is more than a biological occurrence. It is a human, social, and spiritual event, but the spiritual dimension of patients is too often neglected. Whether death is viewed as a "wall" or as a "door" can have significantly important consequences for how we live our lives. Near death experience is one of the excellent evidences to prove that there should be spiritual component being separated from the human physical body when we experience death. People have called it soul, spirit, or nonlocal consciousness. Caregivers need to recognize and acknowledge the spiritual component of patient care. Learning about death and dying helps us encounter death in ways that are meaningful for our own lives. Among the several learning tools, utilizing cinema with its audio and visual components can be one of the most powerful learning tools in death education. PMID- 23018535 TI - [Conflict of interest in medical practice and research]. AB - In recent years, medical professionals are in charge with multiple roles. They have to work as an educator, researcher, and administrator, as well as medical practitioner. In addition, they experience a conflict between the primary responsibilities that each role requires of them. A conflict of interest (COI) is a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest. It occurs when an individual or organization is involved in multiple interests, one of which could possibly corrupt the motivation for an act in the other. The COI should be managed appropriately to preserve the value of public trust, scientific objectivity, and the benefit and safety of patients. Primary interest of medical professionals refers to the principal goals of the medical profession, such as the health and safety of patients, and the integrity of research. Secondary interest includes not only financial gain but also such motives as the desire for professional advancement and the wish to do favors for family and friends, but COI rules usually focus on financial relationships because they are relatively more objective, fungible, and quantifiable. This article will briefly review the COI in medical practice and research, discuss about what is COI, why we should manage it, and how we can manage it. PMID- 23018536 TI - [Understanding of patients suffering from gastroenterologic incurable disease: perspective of celebrities' embracement]. AB - Diagnosis and treatment of gastroenterologic disease have been progressed after twentieth century. Now days a lot of diseases, which were called incurable diseases before have been treated or managed successfully. But, there are still many incurable diseases left, including advanced cancer and inflammatory bowel disease in gastroenterology. Here we reviewed some cases of celebrities' gastroenterologic incurable diseases. We hoped to widen our understandings of those diseases and give opportunities for the better treatment. Embracements of patients suffering from gastroenterologic incurable diseases were diverse. We can find out they ended their lives doing the most precious things. Among them, the love for their family members were the most universal and important concerns. We hope the patients suffering from gastroenterologic incurable diseases can have more opportunities for better treatments and to be understood in their situations. PMID- 23018537 TI - [To be a gastroenterologist who communicates well with patients]. AB - There are many reasons why doctors would not to be able to communicate with patients. First, medicine is science or humanity? Although object of medicine is human, modern medicine tends to regard human as broken machine. Second, gastroenterologists are overloaded by treatment of patients, providing education, attending academic conference, and writing papers. Above all things, it is much worse for gastroenterologists because of endoscopic procedures. The other problem is attitude of modern society about human suffering. Sufferings come from not only body but also mind or spirit. Although there are may difficult problems, if doctors listen to patients' history by their side, it will help to restore their faith. In addition, we need humanity education and improvement plans for medical service system. PMID- 23018538 TI - AIDS-related gastrointestinal kaposi sarcoma in Korea: a case report and review of the literature. AB - Kaposi sarcoma (KS) is a vascular neoplasm, which is fairly prevalent in acquired immunodeficiency syndrome (AIDS) patients. Mucocutaneous and lymph node involvements are characteristic features of KS in AIDS patients. The involvement of gastrointestinal tract occurs in 40% of KS patients and leads to significant morbidity and mortality. In the highly active antiretroviral therapy (HAART) era, the rate of AIDS related KS has fallen with control of human immunodeficiency virus (HIV) viremia. However, it is still recognized as the primary AIDS-defining illness, and the proportion of AIDS diagnoses made due to KS ranged from 4.1% to 7.5%. In Korea, AIDS-related KS has been report in low rate incidence. Its gastrointestinal involvements are rarely reported. To date, five cases have been recorded in Korea. Herein, we present an additional case of gastrointestinal KS as the AIDS-defining illness and review of the Korean medical literature. PMID- 23018539 TI - Intestinal amyloidosis with intractable diarrhea and intestinal pseudo obstruction. AB - We report herein a case of intestinal amyloidosis with grave prognosis that caused intractable diarrhea and intestinal pseudo-obstruction, alternately in spite of intensive conservative treatment. A 44-year-old woman was admitted for fever, diarrhea, and crampy abdominal pain which had been continuned during 6 months. Abdomen CT scan showed edematous wall thickening of the small bowel and right colon, and colonoscopic biopsy revealed amyloid deposition in the mucosa. Monoclonal light chains in serum and/or urine were not detected and highly elevated serum amyloid A was shown. In spite of intensive treatment including oral prednisolone and colchicine, diarrhea and intestinal pseudo-obstruction developed alternately, general status rapidly got worsened and died after two months. PMID- 23018540 TI - A case of severe acute hepatitis a complicated with pure red cell aplasia. AB - Hepatitis A is typically a self-limited acute illness that does not progress to chronic hepatitis. In rare cases, acute hepatitis A can be associated with serious complications (such as fulminant hepatitis or acute kidney injury) and may result in death or liver transplantation. Pure red cell aplasia (PRCA) is a rare hematologic disorder characterized by anemia, reticulocytopenia in the blood, and isolated erythroblastopenia with normal granulopoiesis and megakaryopoiesis in the bone marrow. PRCA is a rare hematopoietic complication of acute viral hepatitis, and few cases associated with hepatitis A virus infection have been reported. Recently, we experienced a case of severe hepatitis A complicated by fulminant hepatitis and acute kidney injury followed by PRCA which showed a favorable response to oral corticosteroids. PMID- 23018541 TI - A case of breast cancer in a male patient with cryptogenic cirrhosis. AB - Breast cancer is a rare disease in men. We report a case of 53-year-old obese male, with known cryptogenic cirrhosis and hepatocellular carcinoma, presenting a tender mass on left breast. He was diagnosed with invasive intraductal carcinoma, which was consistent with a sporadic lesion. On the basis of previous literatures, obesity can be regarded as a cause for breast cancer even in men. However, there has been inconsistent data about link between liver cirrhosis and male breast cancer, which can be due to heterogenity in the etiology of cirrhosis. Through this case, it can be postulated that the risk for male breast cancer may vary according to the etiology of cirrhosis. PMID- 23018542 TI - Home mechanical ventilation through mask: monitoring leakage and nocturnal oxygenation at home. AB - BACKGROUND: Leakage is common in patients receiving home mechanical ventilation (HMV) via a face mask. Although pressure ventilators have partial compensatory capacity, excessive leakage can compromise the effectiveness of treatment. Home ventilators are equipped with built-in software which provides information on leakage. However, the values of leakage and their effects in routine clinical practice are currently little known. OBJECTIVE: To measure leakage in stable patients on nocturnal HMV and its impact on treatment effectiveness. METHODS: Consecutive outpatients on HMV were recruited. Nocturnal pulse oximetry was performed at home and leakage was measured using the ventilator's built-in software. We measured: mean SpO(2), percentage of time with SpO(2) <90% (T90), mean leakage (meanL), maximum leakage (maxL), and minimum leakage (minL) during the ventilation session. We estimated ventilator capacity to compensate for leakage according to inspiratory positive airway pressure and divided the patients into two groups: those with leak compensation and those without. RESULTS: The study included 41 patients [mean age, 64 years (SD 11.9); 23 (56%) women]. Nocturnal pulse oximetry showed an SpO(2) of 94% (+/-2.9) and a T90 of 10% (+/-21.7). Leakage (in l/min) was: meanL, 32.2 (+/-15.3); maxL, 64.8 (+/ 28.5), and minL, 18.8 (+/-10.6). Seven cases (17%) had leakage greater than the ventilator compensatory capacity, but no significant difference in SpO(2) or T90 was observed between patients with or without leak compensation. CONCLUSIONS: A wide variation between maxL and minL was observed in our series; 17% of cases had higher leakage values than the compensatory capacity of the ventilator, but this did not affect nocturnal oxygenation. PMID- 23018543 TI - Matrix metalloproteinase-9 increases in the sputum from allergic occupational asthma patients after specific inhalation challenge. AB - BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the pathogenesis of asthma. MMP-9 increases in the sputum of asthmatic patients after bronchial challenge with common allergens. We sought to assess whether a high-molecular-weight occupational allergen was able to induce changes in MMP-9 as well as in other MMPs and TIMPs in subjects with occupational asthma. METHODS: Ten patients underwent specific inhalation challenge (SIC) on 2 consecutive days. We monitored changes in lung function by measuring FEV(1) for 7 h. Induced sputum test was performed at 6 h after sham and flour challenge. The total and differential cell counts were analyzed. Levels of MMPs (specifically MMP-2, MMP-7, MMP-9 and MMP 13) were measured using Fluorokine(r) MultiAnalyte Profiling kits and a Luminex(r) Bioanalyzer, while levels of TIMP-1 and TIMP-2 were measured by ELISA. RESULTS: Flour challenge increased the percentage of eosinophils in sputum samples. Asthmatic reactions induced by flour were associated with a significant increase in the sputum level of MMP-9 (p = 0.05), but not in the levels of MMP-2, MMP-7, MMP-13, TIMP-1 and TIMP-2. Sputum levels of MMP-9 measured after flour challenge were nearly significantly correlated (r = 0.67; p = 0.06) with the maximal fall in FEV(1) observed during the asthmatic reaction, but they did not correlate with the number of neutrophils (r = 0.18; p = 0.7) and eosinophils (r = 0.55; p = 0.2). CONCLUSIONS: This study showed that MMP-9 increases in sputum samples from sensitized occupational asthma patients after SIC with flour. PMID- 23018544 TI - Complexation of Cm(III) and Eu(III) with a hydrophilic 2,6-bis(1,2,4-triazin-3 yl)-pyridine studied by time-resolved laser fluorescence spectroscopy. AB - The complexation of Cm(III) and Eu(III) with 2,6-bis(5,6-di(sulfophenyl)-1,2,4 triazin-3-yl)pyridine (aq-BTP) is studied in water at pH 3.0 applying time resolved laser fluorescence spectroscopy. With increasing ligand concentration [M(H(2)O)(9-3n)(aq-BTP)(n)] (M = Cm(III)/Eu(III), n = 1, 2, 3) complex species are spectroscopically identified. The conditional stability constants of the M(III) 1 : 3 complex species with aq-BTP are log beta(03) = 12.2 for Cm(III) and log beta(03) = 10.2 for Eu(III). The complexation reaction is enthalpy- and entropy-driven for both metal ions, while the enthalpy change DeltaH(03) is 9.7 kJ mol(-1) more negative for Cm(III); changes in DeltaS(03) are marginal. The difference in DeltaG(03) of -12.7 kJ mol(-1) between the formation of the [M(aq BTP)(3)] complexes agrees with aq-BTP's selectivity in liquid-liquid extraction studies. PMID- 23018545 TI - Volatile substance misuse : clinical considerations, neuropsychopharmacology and potential role of pharmacotherapy in management. AB - Volatile substance misuse is among the most prevalent and toxic forms of psychoactive drug use, and often results in highly deleterious social, psychological and medical consequences. The prevalence of this pernicious form of substance misuse owes in part to the fact that volatile substances of misuse are ubiquitous in the natural environment. Commonly misused commercial products include glue, shoe polish, nail polish remover, butane lighter fluid, gasoline and computer duster spray. National samples of volatile substance misusers tend to exhibit high rates of psychiatric problems and antisocial behaviour. In addition, cognitive impairments and affective dysregulation are often observed among these individuals. Volatile substances exert their complex neuropharmacological effects on dopaminergic, glutamatergic, GABAergic and serotoninergic receptor systems, as well as on cell membranes and ion channels. Concomitantly, pharmacotherapies for volatile substance abuse might profitably target a number of mechanisms, including reward circuitry in the brain, symptoms of craving and withdrawal, neuropsychiatric and emotional impairments that promote volatile substance abuse, and cognitive enhancement to rectify deficits in executive function. This review details the modes of use, subjective effects, epidemiology, adverse consequences, neuropsychopharmacology and drug treatment of volatile substance misuse, and discusses the potential role of novel forms of pharmacological intervention for this oft-overlooked public health threat of epidemic proportions. PMID- 23018546 TI - Drug interactions with triptans : which are clinically significant? AB - The triptans are a group of compounds with high efficacy for the acute treatment of migraine and cluster headache. They have a relatively wide therapeutic index, and although a number of minor pharmacokinetic interactions have been observed, few are likely to be clinically significant. Given the differences in principal elimination pathways, potentially interacting drugs on a pharmacokinetic basis are not common across all compounds. Of more concern than pharmacokinetic interactions are pharmacodynamic interactions. Of most concern, additive vasoconstrictor effects are likely to occur with other vasoconstrictors, especially the ergots used for migraine. Serotonin syndrome has been observed due to coadministration of triptans with selective serotonin reuptake inhibitors (SSRIs), but the absolute rate of such a clinical response to coadministration is probably low. Most patients can take triptans with other medications without dose alteration, although vigilance is required for pharmacodynamic interactions. PMID- 23018547 TI - Effect of aripiprazole on verbal memory and fluency in schizophrenic patients : results from the ESCAPE study. AB - BACKGROUND: Second-generation antipsychotics have gradually replaced first generation antipsychotics as first-line treatment for patients with schizophrenia. Some positive effects on verbal cognition have been shown for the second-generation antipsychotics, but most studies are based on relatively small numbers of patients. OBJECTIVE: In the frame of the prospective, multi-centre, open-label study ESCAPE (A Prospective, Multicenter, Open-Label Study to Evaluate the Effectiveness and the Effect on Cognitive Function of a Treatment With Aripiprazole in a Broad Range of Schizophrenic Patients; clinicaltrials.gov identifier NCT00329810) evaluating the effectiveness and effect on cognitive functioning of aripiprazole in schizophrenic patients, we conducted a post hoc analysis to examine changes in verbal cognition and investigate the predictive value of a cognitive improvement on quality of life. STUDY DESIGN: This was a prospective, multi-centre, non-comparative, open-label study of aripiprazole in schizophrenic patients. At study enrolment, these patients were being treated with various first- or second-generation antipsychotics or were without previous antipsychotic treatment. On entering the study, all patients were treated with aripiprazole (Abilify((r)); Otsuka, Tokyo, Japan) monotherapy; those patients who had received prior treatment with antipsychotics had their current drug(s) tapered off over a 2-week period. A post hoc analysis of the effect of aripiprazole on two verbal cognitive measures and their correlation with efficacy measures and quality of life was conducted. SETTING: Patients with schizophrenia were recruited in 56 psychiatric hospitals. PATIENTS: A total of 361 patients with schizophrenia, ranging from 18 to 65 years, entered the study. INTERVENTION: Patients were treated with aripiprazole monotherapy at a dosage of 10-30 mg/day. Those who were receiving first- or second-generation antipsychotics at enrolment were switched to aripiprazole monotherapy by tapering off their current drug(s) over a 2-week period. MAIN OUTCOME MEASURE: Physician- and patient-rated parameters were measured to gain a complete view of the effectiveness of aripiprazole on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q LES-Q) at baseline and at weeks 4, 8 and 12 and on the Clinical Global Impression Severity of Illness (CGI-S) scale at baseline and at weeks 1, 2, 4, 8 and 12. A secondary endpoint of verbal cognitive function was measured by the California Verbal Learning Test (CVLT) and the Verbal Fluency (VF) test at baseline and at weeks 4 and 12. The hypothesis of an improvement in verbal cognition and its predictive value on the quality of life was formulated during data collection. RESULTS: 238 patients completed the study. A significant improvement in verbal cognition was observed from week 4 with the long term free recall (LTFR) in the CVLT over the scheduled visits in the trial (F(2,519) = 29.67, p < 0.0001). For the phonemic (letter) subtest of the VF test, patients scored significantly better at week 12 in comparison with baseline (F(2,519) = 3.57, p = 0.0289). There was no significant effect on the semantic (categories) subtest of the VF test (F(2,518) = 0.57, p = 0.5614). Improvement in CGI-S scores at a particular moment in time predicted improvement in LTFR scores at that same moment (F(1,519) = 38.38, p < 0.0001) and in the phonemic (F(1,519) = 42.77, p < 0.0001) and semantic (F(1,518) = 67.43, p < 0.0001) subtests of the VF test. Similarly, CGI-S score improvement globally predicted quality-of-life improvement over visits. The Q-LES-Q scales leisure (F(1,144) = 14.03, p < 0.0001) and social relations (F(1,469) = 5.28, p = 0.0220) also directly correlated with verbal cognition. CONCLUSION: The findings suggest that switching to, or initiating aripiprazole in schizophrenic patients results in improvement in verbal cognitive functioning. The observed improvement on quality of life is explained by the effect of aripiprazole on the CGI-S score, though the leisure and social relations scales of the Q-LES-Q also independently correlated with verbal fluency. Randomized, controlled, clinical trials of this effect of aripiprazole for selected patients are needed. PMID- 23018548 TI - Stiripentol : in severe myoclonic epilepsy of infancy (dravet syndrome). AB - Stiripentol is an anticonvulsant used as adjunctive therapy with valproate and clobazam in the management of patients with severe myoclonic epilepsy of infancy (SMEI; Dravet syndrome), a rare form of epilepsy that develops in the first year of life and is subsequently associated with significant morbidity and mortality. Results of a randomized, double-blind trial, in which patients (>=3 years of age) whose SMEI was inadequately controlled with valproate and clobazam received adjunctive therapy with stiripentol or placebo for 2 months, showed a significantly higher response rate in the stiripentol group compared with the placebo group (71 % vs. 5 %; p < 0.0001; primary endpoint). Responders were defined as those patients who experienced a >=50 % reduction in clonic or tonic clonic seizure frequency during the second month of the double-blind period compared with baseline. Almost half of the stiripentol recipients were seizure free during this period compared with none in the placebo group. Stiripentol was also statistically superior to placebo for secondary efficacy outcomes in the randomized controlled trial, which included the median number of seizures during the second month of the double-blind period and the mean percentage change from baseline in seizure frequency. These results are supported by efficacy data from other studies in patients with SMEI treated with stiripentol as adjunctive therapy, including a long-term retrospective analysis, prospectively conducted open-label studies and a meta-analysis. Drowsiness, loss of appetite and weight loss are the most frequently reported adverse events with stiripentol, and the drug inhibits various cytochrome P450 isoenzymes, potentially leading to clinically significant drug interactions. Stiripentol is an important addition to the limited treatment options available for the management of patients with SMEI. PMID- 23018556 TI - p53 regulates epithelial-mesenchymal transition induced by transforming growth factor beta. AB - Epithelial plasticity characterizes embryonic development and diseases such as cancer. Epithelial-mesenchymal transition (EMT) is a reversible and guided process of plasticity whereby embryonic or adult epithelia acquire mesenchymal properties. Multiple signaling pathways control EMT, and the transforming growth factor beta (TGFbeta) pathway plays a central role as its inducer. Here, we analyzed the role of the tumor suppressor protein p53 in TGFbeta-induced EMT in a well-established mammary epithelial cell model. We found that diploid NMuMG mammary cells bi-allelically express a wild type and a missense mutant (R277C) form of p53. Global reduction of both forms of p53 led to an enhanced EMT response to TGFbeta. Conversely, stabilization of wild type p53 using the compound nutlin had a negative impact on EMT. After silencing both p53 forms, rescue experiments using either wild type or R277C mutant p53 revealed that wild type p53 inhibited, whereas the R277C mutant did not significantly affect, the TGFbeta-driven EMT response. Under serum-free culture conditions, silencing of total p53 levels led to higher numbers of mammospheres characterized by larger size. Rescue of the silenced endogenous p53 with R277C mutant p53, in contrast, suppressed both size and numbers of the mammospheres. This work proposes that wild type p53 controls the efficiency by which mammary epithelial cells undergo EMT in response to TGFbeta. PMID- 23018557 TI - Synthesis and evaluation of novel 4-substituted styryl quinazolines as potential antimicrobial agents. AB - In an attempt to afford possible antibacterial and anti-human immunodeficiency virus (HIV) agents, a series of 22 novel styryl quinazoline-based heterocyclic entities were designed and synthesized. Various substituted aryl urea and thiourea cores were incorporated at position 4 of quinazoline, followed by styrylation of position 2, aiming at an augmented biological potential. The synthesized compounds were well characterized through IR, (1) H NMR, (13) C NMR and elemental analyses. All compounds were screened for their in vitro anti-HIV activity against the HIV-1 (IIIB) and HIV-2 (ROD) strains. The antibacterial activity was also evaluated against various pathogenic Gram-positive and Gram negative bacterial strains. PMID- 23018559 TI - KRAS mutation in colorectal cancer metastases after adjuvant FOLFOX for the primary. PMID- 23018560 TI - Cycloruthenated complexes from imine-based heterocycles: synthesis, characterization, and reactivity toward alkynes. AB - Novel cycloruthenated complexes 2 a-c, 4 a-c, and 6 a, b based on heteroaromatic cores have been synthesized by reaction of a series of heterocycle-based imines with [{RuCl(eta(6)-p-cymene)}(2)(MU-Cl)(2)] and Cu(OAc)(2). This approach has proved efficient for the cyclometalation of thiophene, benzothiophene, furan, benzofuran, pyrrole, and indole derivatives. In addition, even a double cyclometalation process over the same heterocyclic ring is possible, yielding unprecedented bimetallic complexes. These ruthenacycles react with 3-hexyne through an unexpected pathway, which involves the coupling of the original imino heterocycle and acetylene followed by dearomatization to afford fused hetero hydropyridyl ligands bonded to the {Ru(p-cymene)} organometallic moiety (i.e., 7 a-c and 8 a-c). These complexes represent, as far as we know, the first examples of this type of compound within the context of cyclometalation, and an exhaustive analysis of their structure was carried out in solution and solid state. Furthermore, these unique species react with CuCl(2), which promotes the rearomatization and the release of highly valuable aromatic fused bis heterocycles (i.e., 9 a-c, 10 a-c, 11 a, and 12 a/12 a'), providing a novel and appealing synthetic route to this extraordinary family of molecules. PMID- 23018561 TI - Nanoscale tipped microwire arrays enhance electrical trap and depth injection of nanoparticles. AB - Nanoscale devices have the potential to measure biological tissues as well as individual cells/neurons. However, three-dimensional (3D) multi-site probing remains problematic because only planar-type device designs are applicable to sample surfaces. Herein we report 3D nanoscale electrode tipped microwire arrays with high aspect ratios. A nanoscale tipped wire is formed by isotropic silicon etching to the tip of a vapor-liquid-solid grown silicon microwire. After coating the wire with a metal (e.g., Pt and Au), only the nanotip section can be exposed from the surrounding outer shell (e.g., SiO(2) and parylene) by photoresist spray coating and subsequent cycled photoresist etchings. As a promising device application, we demonstrate the trapping of polystyrene nanoparticles in a solution using a fabricated Au-nanotip wire array. The sharpened nanotip has a 150 nm curvature radius and a 4.2 MUm(2) electrode area. The nanotip wires exhibit a locally enhanced trapping performance with a low trapping voltage of 20 mV. Moreover, these trapped nanoparticles can be injected into a soft material (gelatin), demonstrating a multi-site wide-area batch depth injection and an assembly of nanoparticles. Such nanotip wire arrays should be applicable to trap numerous particles, including DNA/molecules attached to Au particles, and may realize injection into biological tissues and individual cells/neurons. PMID- 23018564 TI - Hemorrhagic shock due to spontaneous rupture of adrenal neuroblastoma in an infant: a rare case and review of the literature. AB - Spontaneous rupture of adrenal neuroblastoma is very rare in infants, in contrast to neonates. This report describes a 9-month-old boy presenting with acute hemorrhagic shock due to spontaneous rupture of adrenal neuroblastoma. MYCN oncogene amplification may be a predisposing factor for spontaneous rupture and bleeding of neuroblastoma. An appropriate surgical treatment for this condition must be discussed according to the patient's general state and the tumor features, such as staging, the origin, and local invasiveness. PMID- 23018565 TI - Macrohematuria as initial presentation in a girl with factor VIII and factor IX inhibitors associated with systemic lupus erythematosus. AB - Acquired hemophilia is rarely observed in a pediatric population. We report a case of a 14-year-old girl presented with ecchymoses and macrohematuria. She developed factor VIII and factor IX inhibitors, and was diagnosed with simultaneous acquired hemophilia and systemic lupus erythematosus (SLE). Recombinant-activated FVII and corticosteroid were prescribed due to macrohematuria-related hypovolemia and anemia, which resolved satisfactorily. This case is a reminder that the rare concurrent presence of factor VIII and factor IX inhibitors could be associated with SLE in a pediatric population. Children with SLE-associated-acquired hemophilia may develop macrohematuria as well. PMID- 23018566 TI - Importance of adjusting dual-energy X-ray output for body size: an example from survivors of childhood acute lymphoblastic leukemia. AB - We compared DXA whole body and lumbar spine bone mineral density (BMD) using manufacturers software with a body size correction which derived bone mineral content (BMC) for bone area in survivors of acute lymphoblastic leukemia in Saudi Arabia (n = 51, mean age 13.5 y). With no corrections, 29 patients (57%) had lumbar spine BMD Z score < -1.0 and 21 (41%) had whole body BMD Z score < -2. After correction, only 6 (12%) had lumbar spine BMC Z score < -1.0 and 4 (8%) had whole body BMC Z score < -2. Agreement between the methods was "poor" by weighted kappa analysis. PMID- 23018567 TI - Phenocopy of warfarin syndrome in an infant born to a mother with sickle cell anemia and severe transfusional iron overload. AB - Neonatal chondrodysplasia punctata (CDP) is characterized by epiphyseal stippling and midfacial hypoplasia. CDP is usually inherited, but can be acquired because of maternal vitamin K deficiency. We describe an infant with CDP born to a teenager with sickle cell anemia and transfusional iron overload. The mother had severe liver fibrosis, elevated liver iron concentration (34 mg Fe/g), and coagulopathy, but no gestational use of warfarin. Fetal abnormalities were attributed to vitamin K deficiency secondary to liver dysfunction from iron toxicity. Treatment of iron overload among women with sickle cell anemia of childbearing potential is important to avoid possible CDP in newborns. PMID- 23018568 TI - A novel G6PC3 gene mutation in a patient with severe congenital neutropenia. AB - Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency is a newly described syndromic type of severe congenital neutropenia, associated with multiple organ abnormalities including facial, cardiac, and urogenital abnormalities, and increased visibility of superficial veins. The molecular pathophysiology of G6PC3 deficiency is associated with the disturbed glucose homeostasis, increased endoplasmic reticulum stress, and apoptosis in neutrophils. We report a new case of G6PC3 deficiency caused by a novel homozygous G6PC3 gene mutation (p.Leu154Pro). Most remarkable is that the chronic neutropenia that originated from this novel G6PC3 genetic defect is also accompanied by some other unusual manifestations in this patient: myelokathexis and hypercholesterolemia. PMID- 23018569 TI - Immunologic consequences of chemotherapy for acute myeloid leukemia. AB - There are few data characterizing the immunologic consequences of chemotherapy for acute myeloid leukemia (AML) and almost nothing is known about the effects of chemotherapy in a pediatric AML cohort. We identified T-cell subsets, B-cell subsets, and used Enzyme-linked immunosorbent spot analyses to define the function of T cells and B cells in 7 pediatric patients with AML on chemotherapy. The data show that the effects of chemotherapy disproportionately target the B cell and depletion of B cells is associated with impaired responses to the inactivated influenza vaccine. Diminished T-cell numbers were also observed although the magnitude of the effect was less than what was seen for B cells. Furthermore, measures of T-cell function were largely intact. We conclude that humoral immunity is significantly affected by chemotherapy for AML. PMID- 23018571 TI - Use of cardiac markers for monitoring of doxorubixin-induced cardiotoxicity in children with cancer. AB - The aim of this study was to evaluate N-terminal probrain natriuretic peptides (NT-pro-BNP), cardiac troponin T, and creatinine kinase, MB isoenzyme (CK-MB) in the determination of subclinical left ventricular (LV) dysfunction by echocardiography in patients treated with doxorubicin. We performed a cross sectional case study of systolic, diastolic function and tissue Doppler imaging by echocardiography in children with cancer who received a certain cumulative dose of doxorubicin. Blood levels for NT-pro-BNP, cardiac troponin T, and CK-MB were analyzed within 6 hours of the cardiac study. Of 30 patients, 5 (16.7%) had LV dysfunction with an abnormally high NT-pro-BNP level of 363 +/- 78 pg/mL, whereas patients with normal LV function had an NT-pro-BNP level of 148 +/- 173 pg/mL (P = 0.012). The NT-pro-BNP level not only inversely correlated with fractional shortening (r = -0.43, P = 0.017) and ejection fraction (r = - 0.45, P = 0.013) but also correlated with mitral deceleration time ( r = 0.41, P = 0.021) and a cumulative dose of doxorubicin (r = 0.44, P = 0.014). For tissue Doppler imaging, NT-pro-BNP correlated with a peak systolic velocity at the myocardial segment (Sm) (r = -0.40, P = 0.027). NT-pro-BNP is a sensitive test and has a moderate relationship with the LV systolic and diastolic function, thus making it a useful cardiac marker for the monitoring of early anthracycline cardiotoxicity. PMID- 23018573 TI - An unusual abdominal cystic mass. AB - We report a case of a multicystic abdominal mass in a 12 year old girl. PMID- 23018574 TI - Treatment of acquired aplastic anemia in patients with acute liver failure occurring concurrently: a case series. AB - The association between acquired aplastic anemia (AA) and hepatitis/acute liver failure has been well characterized as AA temporally after the presentation of acute hepatitis. In this case series we report 2 cases of patients who present with AA occurring simultaneously with the development of acute liver failure. This is among only a few reported cases known to date in which AA occurs simultaneously with impending liver failure. More importantly, this is the first report that demonstrates the feasibility of administering immunosuppressive therapy before complete resolution of the hepatic dysfunction and with excellent results. Both of our cases avoided orthotopic liver transplantation through the use of timely immunosuppressive therapy, demonstrating the potential role of medical management to avoid transplantation in these patients. Previous studies have suggested a link between an unidentified viral process and immune dysregulation that may lead to the development of AA after acute hepatitis. These 2 cases support the rationale that in our patients the 2 disease processes may share a common etiology and encourage further research into the complex pathogenic mechanism affecting these 2 different organ systems at varying points in time. PMID- 23018575 TI - The treatment of crimean-congo hemorrhagic fever with high-dose methylprednisolone, intravenous immunoglobulin, and fresh frozen plasma. AB - Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne disease caused by Nairovirus, and it is sometimes characterized by reactive hemophagocytic histiocytosis (HLH). The reasons for reactive HLH are macrophage-activating syndrome and disseminated intravascular coagulation due to cytokine storm, liver dysfunction, and endothelial damage by the virus. In this study, the effectiveness of high-dose methylprednisolone (HDMP) (5 to 30 mg/kg/d), fresh frozen plasma (FFP), and intravenous immunoglobulin (IVIG) was investigated in patients with CCHF associated with reactive HLH. Twelve patients with CCHF in association with reactive HLH were included in the study. The patients were successfully treated with HDMP to suppress the macrophage activation, FFP to treat disseminated intravascular coagulation, and IVIG to treat severe thrombocytopenia. No patients received ribavirin. Fever reduced in 1.6 +/- 0.8 days, WBC count increased above 4.500/uL in 4.0 +/- 2.4 days, platelet count increased above 150.000/uL in 8.5 +/- 2.5 days, and D-dimer level decreased under 1 mcg/dL in 5.8 +/- 3.6 days. Consequently, HDMP, FFP, and IVIG may be effective in patients with CCHF associated with reactive HLH during hemorrhagic period of the disease. PMID- 23018576 TI - Williams-Beuren Syndrome and Burkitt Leukemia. AB - Williams-Beuren Syndrome (WBS) is associated with constitutional deletion of 7q11.23, which includes the elastin gene. Cytogenetic abnormalities of chromosome 7 are frequently described in several human malignancies. Here, we report Burkitt Leukemia in an 8-year-old boy with WBS. In this patient, constitutional deletion of chromosome 7q11.23 including BCL7B was confirmed. WBS may predispose patients to Burkitt Leukemia. PMID- 23018577 TI - Accurate integration over atomic regions bounded by zero-flux surfaces. AB - The approach for the integration over a region covered by zero-flux surface is described. This approach based on the surface triangulation technique is efficiently realized in a newly developed program TWOE. The elaborated method is tested on several atomic properties including the source function. TWOE results are compared with those produced by using well-known existing programs. Absolute errors in computed atomic properties are shown to range usually from 10(-6) to 10(-5) au. The demonstrative examples prove that present realization has perfect convergence of atomic properties with increasing size of angular grid and allows to obtain highly accurate data even in the most difficult cases. It is believed that the developed program can be bridgehead that allows to implement atomic partitioning of any desired molecular property with high accuracy. PMID- 23018578 TI - Anti-angiogenic activity of Erxian Decoction, a traditional Chinese herbal formula, in zebrafish. AB - Erxian Decoction (EXD), a traditional Chinese herbal formula, has been used to treat menopausal symptoms and other aging diseases for several decades. Recently, our laboratory found that EXD could inhibit the proliferation of breast cancer cells. This activity may be mediated by anti-angiogenic action. To investigate the anti-angiogenic activity of EXD, its inhibitory effect on blood vessel formation was evaluated using both wild type and transgenic zebrafish embryos with fluorescent vasculature in vivo. Both semi-quantitative and real-time quantitative polymerase chain reaction (qPCR) were carried out to evaluate the effect of EXD on the expression of several genes closely associated with angiogenesis in zebrafish. EXD was found to inhibit vessel formation in zebrafish embryos in a dose- and time-dependent manner. Furthermore, it reduced the mRNA expression of vascular endothelial growth factor A (VEGF-A) and the protein level of hypoxia inducible factor 1alpha (HIF-1alpha) in the embryos, suggesting the involvement of HIF-1 mediated VEGF-A signaling pathway in the anti-angiogenic action of EXD. The anti-angiogenic activity of EXD provides new insights to its clinical application and may in the future lead to the development of potential drugs for treating various cancers, especially in menopausal period. PMID- 23018579 TI - Recent development of gastric cancer prevention. AB - A mass screening program using photofluorography has been used as a secondary prophylaxis of gastric cancer in Japan. However, we are at a turning point for reconsidering the strategy of gastric cancer prevention because of various problems with photofluorography. The shift from current secondary prophylaxis to primary prophylaxis is now required. After a Japanese multicenter randomized controlled trial showed that Helicobacter pylori eradication reduced the incidence of metachronous gastric cancer after endoscopic resection of early gastric cancer, primary prophylaxis of gastric cancer has gained greater attention. The combination of H. pylori eradication as a primary prophylaxis and screening as a secondary prophylaxis is necessary for the elimination of gastric cancer in Japan. The strategy of test, treat and screening for H. pylori infection is effective in reducing the incidence and mortality of gastric cancer in communities with a high incidence of gastric cancer. We have proposed a program of risk stratification based on the presence of H. pylori infection with or without atrophic gastritis followed by targeted interventions. PMID- 23018580 TI - Psychotherapy for depression among patients with advanced cancer. AB - Cancer causes profound suffering for patients, and previous reports have demonstrated that psychological distress, particularly depression, is frequently observed in advanced and/or terminally ill cancer patients. Such depression can lead to serious and far-reaching negative consequences in patients with advanced cancer: reducing their quality of life and causing severe suffering, a desire for early death, and suicide, as well as psychological distress in family members. For the management of their distress, cancer patients are more likely to prefer psychotherapeutic interventions to pharmacotherapy, and psychotherapy is known to be effective for the management of depression among advanced cancer patients. Hence, psychotherapy is an important treatment strategy for alleviating their depression. Furthermore, patients with advanced and/or terminal cancer suffer from various physical symptoms and are forced to face a continuous decline in physical function. In addition, psychological defense mechanisms such as denial are frequently observed in these patients. Hence, an individually tailored and careful psychotherapeutic approach should be followed, which considers the specific nature of the advanced and/or terminal cancer. This review focuses on psychological interventions that can be utilized in the clinical oncology practice to ameliorate depression among advanced and/or terminally ill cancer patients, rather than focusing on the level of evidence for each intervention. In addition, the current review introduces some novel therapeutic strategies that have not yet been proved to be effective but show promise for future studies. PMID- 23018581 TI - Age, dementia and care patterns after admission for acute coronary syndrome: an analysis from a nationwide cohort under the National Health Insurance coverage. AB - BACKGROUND: The number of elderly and the prevalence of dementia have grown considerably in recent years. Little is known about how aging and dementia affect care patterns after discharge for acute coronary syndrome (ACS). OBJECTIVE: This study was designed to assess the impact of dementia on care patterns after admission for patients with ACS across different age groups. METHODS: Of 87,321 patients hospitalized for ACS between 1 January 2006 and 31 December 2007, 1,835 patients with dementia and 3,670 matched patients without dementia (1:2 ratio, matched by age, sex and hospital level) were identified from Taiwan's National Health Insurance Research Database. Use of interventional therapies at hospitalization and guideline-recommended medications post-discharge were compared between patients with and without dementia across different age groups (<=65, 66-75, 76-85, >=86 years). Multivariate logistic regression models were performed to examine the impact of dementia on care patterns. RESULTS: Overall, dementia was associated with a 27% lower likelihood of receipt of interventional therapies [adjusted odds ratio (OR) = 0.73; 95% CI 0.63, 0.83] and a 22% lower likelihood of guideline-recommended medications (adjusted OR = 0.78; 95% CI 0.68, 0.89) in ACS patients. The use of interventional therapies and guideline recommended medications decreased with age, and interactions between age and dementia were found. The proportions of patients receiving interventional therapies were 39.4% (without dementia) versus 21.8% (with dementia) in the youngest age group and 18.6% (without dementia) versus 14.5% (with dementia) in the oldest age group. Patients with dementia (age <=65 years 73.6%; age 66-75 years 82.3%; age 76-85 years 71.8%; age >=86 years 55.6%) were less likely to receive guideline-recommended medications as compared with those without dementia (age <=65 years 85.6%; age 66-75 years 87.5%; age 76-85 years 81.2%; age >=86 years 62.0%). CONCLUSION: Dementia and aging were associated with decreased use of interventional therapies and guideline-recommended medications in ACS patients. PMID- 23018582 TI - Comparative risk of cerebrovascular adverse events in community-dwelling older adults using risperidone, olanzapine and quetiapine: a multiple propensity score adjusted retrospective cohort study. AB - BACKGROUND: Atypical antipsychotic agents have been associated with cerebrovascular adverse events, particularly in elderly dementia patients. However, limited evidence exists regarding comparative cerebrovascular profiles of individual atypical agents, particularly in community settings. OBJECTIVE: The objective of this study was to evaluate the risk of cerebrovascular events associated with use of risperidone, olanzapine and quetiapine in community dwelling older adults in the US. METHODS: A propensity score-adjusted retrospective cohort design involving the IMS LifeLinkTM Health Plan Claims Database was used for the study. The study population included all older adults (aged >=50 years) who initiated risperidone, olanzapine or quetiapine anytime during 1 July 2000 to 30 June 2008. Patients were followed until hospitalization or an emergency room visit for a cerebrovascular event, or the end of the study period, whichever occurred earlier. The Cox proportional hazard regression model with time-varying covariates was used to evaluate the risk of cerebrovascular events during the follow-up period, using olanzapine as the reference. The covariates adjusted for in the final model included multiple propensity scores and exposure to other medications that could be associated with the risk of cerebrovascular events. RESULTS: A total of 2,458 cerebrovascular events were identified in the study cohort: 1,081 (21.38%) for risperidone users, 816 (18.75%) for olanzapine users and 561 (21.05%) for quetiapine users. After adjusting for propensity scores and other covariates, the Cox proportional hazard model revealed that use of quetiapine [hazard ratio (HR) 0.88; 95% CI 0.78, 0.99] but not risperidone (HR 1.05; 95% CI 0.95, 1.16) was associated with a decrease in the risk of cerebrovascular adverse events compared with olanzapine. CONCLUSIONS: The study suggested that quetiapine use may be associated with a moderately lower risk of cerebrovascular events than olanzapine in older adults. Prescribers should closely monitor the patients treated with atypical agents for the incidence of cerebrovascular adverse events. PMID- 23018583 TI - Drugs in clinical development for osteoporosis: summary and table. PMID- 23018584 TI - Pharmacological and clinical profile of recently approved second-generation antipsychotics: implications for treatment of schizophrenia in older patients. AB - Antipsychotics are frequently used in elderly patients to treat a variety of conditions, including schizophrenia. While extensively studied for their impact in younger populations, there is comparatively limited evidence about the effectiveness of these agents in older patients. Further complicating this situation are the high comorbidity rates (both psychiatric and medical) in the elderly; age-related changes in pharmacokinetics that lead to a heightened proclivity for adverse effects; and the potential for multiple, clinically relevant drug interactions. With this background in mind, we review diagnostic and treatment-related issues specific to elderly patients suffering from schizophrenia. We then focus on the potential role of the most recently approved second-generation antipsychotics, paliperidone (both the extended-release oral formulation and the long-acting injectable formulation), iloperidone, asenapine and lurasidone, given the limited clinical experience with these agents in the elderly. While there is limited data to support their safety, tolerability and efficacy in older patients with schizophrenia, each has unique characteristics that should be considered when used in this population. PMID- 23018585 TI - Approach to a successful selection of antihypertensive drugs for the patient with atherosclerosis. AB - Coronary heart disease has become a medical and public health issue associated with multiple risk factors such as age, diet, and sedentary life style. Associations between hypertension and atherosclerosis have been extensively studied, and several trials have demonstrated antiatherosclerotic properties in some of the most widely used antihypertensive agents. Hence, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers have been the target for a number of controlled randomized trials studying its effect on atherosclerosis progression. Carotid intima-media thickness measurement by ultrasound is used as surrogate of atherosclerosis in most of these controlled trials. This review of the literature aims to summarize the most significant controlled trials involving antihypertensive therapy and atherosclerosis regression based on the carotid intima-media thickness measurement. PMID- 23018586 TI - Gabapentin to pregabalin therapy transition: a pharmacokinetic simulation. AB - The objective of this modeling study was to assess different dosage regimens that might be used to guide clinicians in transitioning patients from gabapentin to pregabalin therapy when such a transition is clinically warranted. Two different gabapentin to pregabalin transition designs were simulated based on their respective population pharmacokinetic profiles. The first design involved immediate discontinuation of gabapentin therapy with initiation of pregabalin therapy at the next scheduled dose period. The second design featured a gradual transition involving coadministration of 50% of the gabapentin dosage and 50% of the desired pregabalin dosage for 4 days, followed by discontinuation of gabapentin and fully targeted dosages of pregabalin. Both transition designs were studied at 3 dosage levels: gabapentin 900 mg/d to pregabalin 150 mg/d, gabapentin 1800 mg/d to pregabalin 300 mg/d, and gabapentin 3600 mg/d to pregabalin 600 mg/d. Overall drug exposure achieved during the 2 transition designs was the sum of the gabapentin and pregabalin concentrations, expressed as pregabalin-equivalent concentrations. The pharmacokinetic simulations show that during the transition period in both designs, predicted pregabalin-equivalent concentrations did not depart from those calculated during periods of steady state gabapentin or pregabalin monotherapy. Transition from gabapentin to pregabalin was seamless and rapid, with predicted pregabalin-equivalent concentrations highly comparable with plasma pregabalin concentrations within 1 day of pregabalin initiation in the immediate discontinuation model and within 1 day of gabapentin cessation in the gradual discontinuation model. These data suggest that transitioning patients from gabapentin to pregabalin could theoretically be achieved by either of the 2 approaches assessed. PMID- 23018587 TI - Two reflections about Amadori products: biomarkers or therapeutic targets for coronary artery disease?. PMID- 23018588 TI - Differences in systemic and skin migrating-specific CD4 T cells in papular urticaria by flea bite. AB - BACKGROUND: Papular urticaria by flea bite is a chronic allergic condition in which clinical improvement may occur at the age of 7 years, thus representing a natural model of acquired immunologic tolerance in humans. The aim of this study was to characterize regulatory cells and specific responses to flea antigens of CD4(+) T lymphocytes expressing cutaneous migration markers in patients with papular urticaria caused by flea bite and with different disease evolution times. METHODS: Cell populations were characterized by flow cytometry in samples from patients and healthy controls. Specific cell stimulation was performed with a complete flea body extract. The Mann-Whitney U test was used for comparisons. RESULTS: Total dendritic cells were lower in patients than in healthy controls. No quantitative differences were found in CD4 regulatory T cells. CD4(+) T cells from patients produced more IL-4, lL-10, IL-17, and IFN-gamma. Patients who experienced the onset of symptoms within the first 5 years of age showed a greater percentage of local (cutaneous lymphocyte antigen +) IL-4- and IL-17 producing cells, while patients who experienced the onset of symptoms after the age of 5 years had a higher percentage of systemic (cutaneous lymphocyte antigen ) IL-10-producing cells. CONCLUSION: Analysis of the cellular immune response against whole flea antigen in patients with papular urticaria by flea bites suggests a possible participation of inflammatory cytokines in the skin reaction (Th17) and a systemic control mechanism (IL-10). This pattern of cytokine production in patients could be a consequence of an impaired dendritic cell population. PMID- 23018589 TI - Small particle-size talc is associated with poor outcome and increased inflammation in thoracoscopic pleurodesis. AB - RATIONALE: Talc is very effective for pleurodesis, but there is concern about complications, especially acute respiratory distress syndrome. OBJECTIVES: It was the aim of this study to investigate if talc with a high concentration of small particles induces greater production of cytokines, and if pleural tumor burden has any influence on the local production and spillover of cytokines to the systemic circulation and eventual complications. METHODS: We investigated 227 consecutive patients with malignant effusion submitted to talc pleurodesis. One hundred and three patients received 'small-particle talc' (ST; containing about 50% particles <10 um) and 124 received 'large-particle talc' (with <20% particles <10 um). Serial samples of both pleural fluid and blood were taken before and 3, 24, 48 and 72 h after thoracoscopy. Also, mesothelial cells were stimulated with both types of talc in vitro. MEASUREMENTS AND RESULTS: Interleukin-8, tumor necrosis factor-alpha, vascular endothelial growth factor, basic fibroblast growth factor and thrombin-antithrombin complex were measured in all samples. Early death (<7 days after talc) occurred in 8 of 103 patients in the ST and in 1 of 124 in the 'large-particle talc' group (p = 0.007). Patients who received ST had significantly higher proinflammatory cytokines in pleural fluid and serum after talc application, and also in supernatants of the in vitro study. Pleural tumor burden correlated positively with proinflammatory cytokines in serum, suggesting that advanced tumor states induce stronger systemic reactions after talc application. CONCLUSIONS: ST provokes a strong inflammatory reaction in both pleural space and serum, which is associated with a higher rate of early deaths observed in patients receiving it. PMID- 23018594 TI - Molecular pharmacology and cell death research in St-Petersburg. PMID- 23018590 TI - Functional coupling of TRPC2 cation channels and the calcium-activated anion channels in rat thyroid cells: implications for iodide homeostasis. AB - The initial step in a synthesis of thyroid hormones is the uptake of iodide from the circulation. Iodide (I(-)) is transported into thyroid cells via a Na(+)/I(-) symporter (NIS), which is electrogenic and thus sensitive to alterations in membrane potential (V(m)). I(-) is then released to the lumen of thyroid follicles where the hormones are synthesised and stored. The mechanisms of I(-) release to follicle lumen are poorly characterised. Our whole-cell voltage clamp recordings revealed the presence of a Ca(2+) activated Cl(-) current (CaCC) in Fisher rat thyroid cell line 5 (FRTL-5). Transcripts of anoctamin 1 (ANO1) and anoctamin 10 (ANO10), putative molecular constituents of CaCC, were detected. The anion channels underlying CaCC are highly permeable to I(-). Both niflumic acid (NFA) and 2-aminoethyl diphenylborinate (2-APB), antagonists of CaCC and transient receptor potential channels, respectively, inhibited CaCC. Canonical transient receptor potential channel 2 (TRPC2) is the only TRPC member present in FRTL-5 cells. The activation rate of CaCC was markedly slower in shTRPC2 knock down cells, indicating that Ca(2+) entry via TRPC2 contributes to CaCC activation. The uptake of iodide was enhanced and the resting V(m) was more depolarised in TRPC2 knock-down cells. We suggest that the interplay between TRPC2 and ANO1 may have dual effects on iodide transport, modulating I(-) release via ANO channels and I(-) uptake via the V(m) sensitive NIS. PMID- 23018596 TI - Neutral Ni(II), Pd(II) and Pt(II) ONS-pincer complexes of 5-acetylbarbituric-4N dimethylthiosemicarbazone: synthesis, characterization and properties. AB - Octahedral 1:1 Ni(II) and square-planar 1:1 Pd(II) and Pt(II) complexes of formulae [Ni(HAcb4DM)(AcO)(H2O)2].H2O (1), [Pd(HAcb4DM)Cl].5H2O (2) and [Pt(HAcb4DM)Cl].3H2O (3), where H2Acb4DM = 5-acetylbarbituric-4N dimethylthiosemicarbazone (H2 denoting its two dissociable protons, one enolic and one thiolic), have been synthesized and characterized by elemental analysis and by 1H and 13C NMR, UV-vis, and IR spectroscopy. Crystallisation of compounds 1-3 from DMSO afforded complexes of formulae [Ni(HAcb4DM)2].2H2O (1a), [Pd(Acb4DM)(DMSO)].DMSO (2a) and [Pt(Acb4DM)(DMSO)].DMSO (3a), the molecular and crystal structures of which were determined by X-ray diffractometry. The thiosemicarbazone in 1a coordinates to the metal ions in an ONS-tridentate manner in the O-enolate/S-thione form, but in complexes 2a and 3a the thiosemicarbazone binds Pd(II) or Pt(II) as an ONS-pincer ligand in the O-enolate/S-thiolate form. The 195Pt NMR spectrum of 3 shows a signal at -2950 ppm along with two new signals at -3348 and -2731 ppm, indicating the presence of solvolysis products. The catalytic activity of complex 2a has been explored in aryl-aryl Suzuki cross coupling reactions. H2Acb4DM and complexes 2 and 3 were screened for in vitro cytotoxicity against a human tumour cell line (HeLa-229), with the clinically employed drug cisplatin as a reference. PMID- 23018595 TI - Non-cell autonomous control of apoptosis by ligand-independent Hedgehog signaling in Drosophila. AB - Hedgehog (Hh) signaling is important for development and homeostasis in vertebrates and invertebrates. Ligand-independent, deregulated Hh signaling caused by loss of negative regulators such as Patched causes excessive cell proliferation, leading to overgrowth in Drosophila and tumors in humans, including basal-cell carcinoma and medulloblastoma. We show that in Drosophila deregulated Hh signaling also promotes cell survival by increasing the resistance to apoptosis. Surprisingly, cells with deregulated Hh activity do not protect themselves from apoptosis; instead, they promote cell survival of neighboring wild-type cells. This non-cell autonomous effect is mediated by Hh-induced Notch signaling, which elevates the protein levels of Drosophila inhibitor of apoptosis protein-1 (Diap-1), conferring resistance to apoptosis. In summary, we demonstrate that deregulated Hh signaling not only promotes proliferation but also cell survival of neighboring cells. This non-cell autonomous control of apoptosis highlights an underappreciated function of deregulated Hh signaling, which may help to generate a supportive micro-environment for tumor development. PMID- 23018597 TI - Theoretical assessment of binding and mass-transport effects in electrochemical affinity biosensors that utilize nanoparticle labels for signal amplification. AB - This paper presents a theoretical study of electrochemical affinity biosensors for the detection of DNA/protein that utilize nanoparticle labels for signal amplification. This study analyzes the effects of binding and mass transport of the analytes on biosensor performance by using numerical simulations. Four cases were considered: 1) nanoparticles used to increase the loading of an electroactive species, or used as catalysts under pseudo-first-order conditions; 2) nanoparticles used as ultramicroelectrode arrays for the electrolysis of large concentrations of substrate; 3) nanoparticles used as seeds to deposit electrochemically detectable species; and 4) nanoparticles used to mediate the deposition of electrocatalysts. By using nanoparticle labels, high sensitivity is possible under all conditions considered. However, theoretical findings suggested that nonspecific adsorption could be more problematic in cases 2-4 due to the mismatch between the chemistry of surface binding and the principle of signal amplification that originates from the effect of mass transport. Under these conditions, any given signal would plateau at a much lower analyte concentration, well before the analyte binding had actually reached a plateau. Views on possible solutions to the above limitations are also presented. PMID- 23018599 TI - Nanostructured arrays of stacked graphene sheets. AB - Molecular oxygen etching of HOPG surfaces prepatterned by Ga(+) focused-ion-beam irradiation (FIB) has been used to generate large-area arrays of nanometer-sized graphite blocks. AFM and SEM imaging show that structures with lateral sizes down to ~100 nm and heights of between 30 and 55 nm can be routinely fabricated. The trenches separating the graphite blocks form in the early oxidation stages via preferential gasification (into CO and CO(2)) of the gridlike amorphized carbon regions written by FIB. In the later oxidative etching stages, gasification of the graphite nanoprism faces laterally terminating the graphite blocks becomes the major reaction channel. Correspondingly, graphite blocks are (further) reduced in lateral extent while the trenches in between are widened. Raman and photoionization spectroscopies indicate that the quality of the topmost nG sheet(s) covering the blocks also decreases with increasing etching time-as the size and lateral density of defect-mediated etch pits increases. nG block arrays are useful substrates with which to probe the size-dependent properties of nanographene, as they comprise large numbers of uniform sheets (ca. 4 * 10(10) cm(-2) for an array of 0.5 * 0.5 MUm(2)) thus allowing for the application of area-integrating spectroscopic methods. We demonstrate this by examining the Raman features of nG block arrays which include a graphene-rim-region fingerprint mode. Individual nG sheets can be exfoliated from nG stacks by means of electron irradiation-induced charging. We have explored a number of printing/manipulation strategies aimed at controllable electromechanical transfer of nG sheet arrays to silicon wafers. PMID- 23018598 TI - Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis-associated epithelial-to-mesenchymal transitions. AB - Increased tissue stiffness and epithelial-to-mesenchymal transitions (EMTs) are two seemingly discrete hallmarks of fibrotic diseases. Despite recent findings highlighting the influence of tissue mechanical properties on cell phenotype, it remains unclear what role increased tissue stiffness has in the regulation of previously reported fibronectin-mediated EMTs associated with pulmonary fibrosis. Nano-indentation testing of lung interstitial spaces showed that in vivo cell level Young's moduli increase with the onset of fibrosis from ~2 to ~17 kPa. In vitro, we found that stiff, but not soft, fibronectin substrates induce EMT, a response dependent on cell contraction-mediated integrin activation of TGFbeta. Activation or suppression of cell contractility with exogenous factors was sufficient to overcome the effect of substrate stiffness. Pulse-chase experiments indicate that the effect of cell contractility is dose- and time-dependent. In response to low levels of TGFbeta on soft surfaces, either added exogenously or produced through thrombin-induced contraction, cells will initiate the EMT programme, but upon removal revert to an epithelial phenotype. These results identify matrix stiffness and/or cell contractility as critical targets for novel therapeutics for fibrotic diseases. PMID- 23018601 TI - Esters flash point prediction using artificial neural networks. AB - In this article, an artificial neural network to predict the flash point of 95 esters was implemented. Four variables were used for its development. A neural network with 4-5-8-5-1 topology was encountered to gain the best agreement of the experimental results with those predicted (square correlation coefficient (R(2)) and root mean square error were 0.99 and 5.46 K for the training phase and 0.96 and 13.02 K for the testing set). PMID- 23018602 TI - Glycated albumin is superior to hemoglobin A1c for evaluating the presence and severity of coronary artery disease in type 2 diabetic patients. AB - OBJECTIVES: This study aimed to compare the value of serum glycated albumin (GA) level versus glycated hemoglobin A(1c) (HbA(1c)) for evaluating the presence and severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). METHODS: Serum GA and blood HbA(1c) levels were measured in 829 consecutive T2DM patients with or without angiographically documented significant CAD (>=70% diameter stenosis). RESULTS: Serum GA levels were higher in diabetic patients with significant CAD than in those without (20.57 +/- 4.23 vs. 19.00 +/- 4.48%; p < 0.001), but HbA(1c) was similar in the two groups (7.74 +/- 1.34 vs. 7.51 +/- 1.37% p > 0.05). Compared to HbA(1c), GA correlated more closely with the sum of significant stenotic lesions (r = 0.275, p < 0.001 and r = 0.092, p = 0.019) and the extent index (r = 0.375, p < 0.001 and r = 0.091, p = 0.019). The area under the curve of GA was larger than that of HbA(1c) for detecting the presence of significant CAD (0.637 vs. 0.568; p = 0.046) and 3-vessel disease (0.620 vs. 0.536; p = 0.039). GA, but not HbA(1c), was independently associated with significant CAD. CONCLUSIONS: Serum GA level is a better indicator than HbA(1c) for evaluating the presence and severity of CAD and predicting major adverse cardiac events in patients with T2DM. PMID- 23018603 TI - Novel compound SK-1009 suppresses interleukin-6 expression through modulation of activation of nuclear factor-kappaB pathway. AB - Although interleukin-6 (IL-6) is an important biological mediator playing an indispensable role in inflammation and cancer, few inhibitors and suppressors are known. In the present study, the underlying mechanisms of a novel chemically synthesized compound SK-1009, which has suppressive properties on IL-6 production in human macrophage cells, were examined. SK-1009 suppressed IL-6 mRNA levels in human colon cancer cells. Thus, the influence of SK-1009 on transcription factor, nuclear factor-kappaB (NF-kappaB), which is involved in expression of the IL-6 gene was assessed. SK-1009 was found to suppress degradation of I-kappaB, an NF kappaB inhibitory factor, and consequently inhibited the NF-kappaB activation pathway. The inhibitory property was almost the same as other NF-kappaB inhibitors, such as 5HPP-33. Thus, SK-1009 exerts a potent inhibitory effect on IL-6 expression, apparently mediated by modulation of activation of NF-kappaB transcription factor. PMID- 23018605 TI - Biphasic late airway hyperresponsiveness in a murine model of asthma. AB - BACKGROUND: Nonspecific airway hyperresponsiveness (AHR) is one of the cardinal features of bronchial asthma. Early AHR is caused by chemical mediators released from pulmonary mast cells activated in an IgE-dependent way. However, the mechanism of late AHR remains unclear. METHODS: Features of airway allergic inflammation were analyzed, including antigen-induced AHR, using a murine model of asthma. The model was suitable for examining the sequential early molecular events occurring after the initial airway exposure to antigen. RESULTS: AHR increased at 10-12 h after airway challenge, followed by the second-phase response, which was larger and broader in resistance at 18-30 h. Pretreatment of sensitized animals with anti-tumor necrosis factor (TNF) before airway challenge or induction of allergic asthma in TNF(-/-) mice resulted in abrogation of the first-phase late AHR. Intratracheal instillation of TNF induced a single peak of AHR at 10 h. IgE and IgG immune complexes induced the development of the first phase late AHR by TNF production. Pretreatment with cytosolic phospholipase inhibitor and 5-lipoxygenase inhibitors abolished the first-phase late AHR as well as the leukotriene B(4) levels in the airway. CpG-oligodeoxynucleotide (ODN) pretreatment reduced airway levels of Th2 cytokines, eosinophil infiltration and second-phase late AHR. However, CpG-ODN did not reduce TNF levels or the magnitude of first-phase late AHR. CONCLUSION: Biphasic late AHR occurs in a murine model of asthma. First- and second-phase late AHR is caused by TNF and Th2 response, respectively. PMID- 23018606 TI - Assessment and management of pain, with particular emphasis on central neuropathic pain, in moderate to severe dementia. AB - In patients with dementia, undertreatment of pain, irrespective of its aetiology, is widely recognized; the risk for undertreatment increases with the severity of dementia. We argue, however, that central neuropathic pain is by far the most undertreated type of pain in patients with dementia. Central pain is a type of neuropathic pain that is known to occur in stroke patients and is caused by white matter lesions. Although white matter lesions are also a neuropathological hallmark of dementia, central neuropathic pain has hardly been described in dementia. Therefore, the goal of this review was to address assessment and management of pain, with particular emphasis on central neuropathic pain, in moderate to severe dementia. Concerning pain assessment, the findings of this review suggest that self-report pain rating scales, in particular the Verbal Rating Scale, the Horizontal Visual Analogue Scale and the Faces Pain Scale can be administered to patients in a more advanced stage of dementia. For those who are no longer able to communicate pain, pain observation scales are most appropriate. Self-report and pain observation should be combined, if possible. For an overview of assessment tools to measure pain with older people unable to verbally communicate, we refer readers to the City of Hope Pain and Palliative Care Resource Center ( http://prc.coh.org/PAIN-NOA.htm ). The review further highlights that behavioural disturbances, e.g. agitation and physical inactivity, as well as autonomic responses, e.g. an increase in blood pressure and heart rate, may contribute to a more reliable assessment of pain. With respect to central neuropathic pain in particular, assessment of sensory abilities (touch, pinprick, temperature and vibration), mood (e.g. anxiety) and determination of the presence of a Babinsky reflex, accelerated tendon reflexes, and spasticity may contribute to reliable assessment. Management of pain, not of a central origin, starts with paracetamol (acetaminophen), which, together with opioids, is the most frequently prescribed analgesic drug in dementia. Non-steroidal anti inflammatory drugs are hardly prescribed in a residential setting. Some authors advise starting treatment with a low dose of opioids. Antidepressants and antiepileptic drugs appear to have a positive effect on central neuropathic pain. In the review, advantages and disadvantages of amitriptyline, carbamazepine, lamotrigine, gabapentin and pregabalin are discussed; a negative effect of these drugs on liver and kidney functions, as well as on cognitive functions in patients who already suffer from cognitive impairment is highlighted. Next to pharmacotherapy, non-pharmacological treatment strategies such as transcutaneous electrical nerve stimulation may be effective as long as afferent pathways transmitting the electrical stimulus are still intact. PMID- 23018607 TI - Management of lower gastrointestinal bleeding in older adults. AB - Lower gastrointestinal bleeding, acute overt, occult or obscure in nature, causes significant morbidity and mortality in older adults. As the elderly population is expected to increase in the future, healthcare costs and the clinical burden of lower gastrointestinal bleeding will rise. Lower gastrointestinal bleeding, by definition, originates from a site distal to the ligament of Treitz and is usually suspected when patients present with haematochezia, or maroon stools per rectum. A thorough history is paramount in guiding the diagnostic steps and management but is frequently inadequate in elderly, poorly communicating, nursing home patients. The causes of lower gastrointestinal bleeding in older adults may be anatomic, vascular, inflammatory, neoplastic or iatrogenic. Comorbidity from cardiopulmonary disease, renal disease, diabetes or underlying cancer, all prevalent in older adults, may affect the incidence, severity, morbidity and mortality of lower gastrointestinal bleeding in the elderly. The use of multiple medications, particularly non-steroidal anti-inflammatory, antiplatelet and anticoagulant agents, needs to be always considered in elderly patients with lower gastrointestinal bleeding and anaemia. CT imaging and early colonoscopy are useful in determining the site of bleeding and allowing haemostasis. If unsuccessful, angiographic intervention and surgery need to be considered. Videocapsule endoscopy is useful in cases where the small bowel is suspected as the source, and its results guide the performance of double- or single-balloon enteroscopy. Optimal care should involve a coordinated effort among the primary physician, endoscopist, interventional radiologist and surgeon in order to improve prognosis and subsequent management and reduce morbidity, mortality, length of stay and overall healthcare costs. PMID- 23018608 TI - Nutraceuticals in the management of osteoarthritis : a critical review. AB - Osteoarthritis (OA) is a chronic, highly prevalent and disabling disease that is expected to increase in prevalence secondary to longer life expectancy and a disproportionately aging population. Treatment of OA is only marginally effective and has been focused primarily on symptom control using weight loss, physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, intra articular steroids or viscosupplementation, topical NSAIDs and analgesics, diacerein (an oral interleukin-1beta inhibitor) and finally joint replacement surgery. The use of nutraceuticals in the treatment of OA is common, and scientific studies examining the effects of nutraceuticals on the pathogenesis and treatment of OA are increasing. This review examines the efficacy and safety of select nutraceuticals for the treatment of OA. The reviewed nutraceuticals include glucosamine, chondroitin, collagen hydrolysates (CHs) and avocado-soybean unsaponifiables (ASUs). There have been several clinical trials examining the efficacy of these products and the results demonstrate significant heterogeneity. Significant improvements in pain, function and structural outcomes have been shown for some of the treatment arms or subgroups of patients, but the effects are not consistent across the studies. Glucosamine, chondroitin and the two in combination have been the most extensively studied. Significant improvement in pain and functional indices and a decrease in the loss of joint space width were demonstrated in some but not all studies. CHs showed significant improvement in pain and functional indices for several subgroups of patients, but these findings were not pervasive amongst the treatment arms. ASU has demonstrated positive results with respect to decreased NSAID use in several studies and functional and pain end points in most of the reviewed studies; however, in the two studies examining structural end points, the results were mixed. The safety of these nutraceuticals has been demonstrated across all of the reviewed trials, and there were no significant issues with tolerance. Given the good safety profile of nutraceuticals, the marginal efficacy of conventional treatments, the high prevalence and rate of disability from OA and the possible benefit of nutraceuticals to patients with OA, use of nutraceuticals in select patients is appropriate. An overall recommendation to use nutraceuticals in the treatment of all patients with OA is not strongly supported by the available data. Future studies should focus on standardization of symptomatic and structural outcome measures, be of longer duration and pay careful attention to the content of the investigational product. PMID- 23018609 TI - Consumption of pharmaceuticals in primary non-Alzheimer's degenerative dementias : a cross-sectional study by the Registry of Dementias of Girona (ReDeGi). AB - BACKGROUND: Limited information exists regarding the consumption of psychopharmaceuticals for non-Alzheimer's degenerative dementias (n-ADDs), despite the fact that the treatment of neuropsychiatric symptoms of these diseases is an important challenge for clinicians. OBJECTIVE: The aim of this study was to describe sociodemographic and clinical data from 235 patients with various subtypes of n-ADD, together with the level of consumption of pharmaceuticals with central nervous system activity. METHODS: A descriptive, observational, cross-sectional study was conducted using the data registered by the Registry of Dementias of Girona, northeast Catalunya, Spain. All drugs were categorized according to the Anatomical Therapeutic Chemical Classification System. RESULTS: The results showed a high level of psychopharmaceutical prescription: 48.9 % of the n-ADD patients used acetylcholinesterase inhibitors and 9.8 % used memantine. Antipsychotics and benzodiazepines were prescribed to 45.5 and 46.8 % of the patients, respectively. Antidepressants were consumed by 70.2 % of the registered cases. CONCLUSIONS: High levels of psychopharmaceutical prescribing were observed in our study and many of these prescriptions lacked specific indications for n-ADDs. It is necessary to consider the risk-benefit relationship before prescribing pharmaceuticals. Specific training programmes will be necessary to improve the use of pharmaceuticals in n-ADD patients. PMID- 23018610 TI - High prevalence of medication non-adherence in a sample of community-dwelling older adults with adult protective services-validated self-neglect. AB - BACKGROUND: Medication non-adherence can exacerbate disease severity, leading to impairments that interfere with self-care activities in older adults, and, ultimately, death. Elder self-neglect is the most common report to Adult Protective Services (APS) across the USA and is a significant risk factor for early mortality. These individuals often suffer from multiple comorbid diseases that require careful management, but for various reasons they are unwilling or unable to provide themselves with the self-care resources necessary for maintaining health and safety. No studies have assessed whether medication adherence is associated with elder self-neglect. OBJECTIVE: The purpose of this study was to assess and describe medication adherence in this population, as well as evaluate associations between medication adherence and cognitive impairment, depression, physical function, and abilities to perform basic and instrumental activities of daily living (BADLs and IADLs). METHODS: A cross-sectional study of 100 community-dwelling adults 65 years of age and older with APS-substantiated elder self-neglect were assessed. In-home comprehensive geriatric assessments (CGAs) were completed and included medication reviews. Information on each medication, including the amount taken from the date dispensed, was collected and used to determine adherence. The criteria for non-adherence were taking <80 or >110 % of at least one medication. The sample was also split into groups of low adherence (<=29 %), moderate adherence (29-86 %) and high adherence (>=86 %). Scores on the CGA measures Mini-Mental State Examination, Geriatric Depression Scale, Physical Performance Test (PPT) and Kohlman Evaluation of Living Skills were assessed to determine whether cognitive impairment, depression, physical function, and/or ability to perform BADLs and IADLs were associated with non adherence or low, moderate or high levels of adherence. RESULTS: Twenty-five per cent of the sample was taking more than seven medications daily. The average rate of adherence was 59 %. Only eight participants (10 %) were adherent to their entire medication regimen, and thus, 90 % were considered non-adherent to at least one medication. The mean number of medications to which individuals were non-adherent was 3.4. The cognitive impairment, depression, physical function and BADL/IADL measures were not statistically associated with medication non adherence using the cut-points of <80 or >110 %. However, when split into tertiles, the lowest medication adherence level (<=29 %) was significantly associated with a greater number of medications being consumed and lower objective physical function levels as measured by the PPT. CONCLUSIONS: Medication non-adherence is a very prevalent problem among older adults who are self-neglecting, and higher non-adherence levels were associated with the number of medications being consumed as well as lower physical function. Physicians who find high rates of medication non-adherence in their patients should consider barriers to adherence, including a large number of medications, lower physical function and the possibility of elder self-neglect. Future efforts should focus on studying the underlying reasons for medication non-adherence in larger samples of older adults who are self-neglecting. This would facilitate the development of interventions to reduce medication non-adherence in this population. PMID- 23018611 TI - Comparison of prescription drug use between community-dwelling and institutionalized elderly in Sweden. AB - BACKGROUND: Most previous studies about drug use in the elderly population have either investigated drug use in institutions or in the community-dwelling setting. Hence, very few studies have compared drug use in institutionalized and community-dwelling elderly, maybe because of a lack of sufficiently large databases. OBJECTIVE: The aim of the study was to investigate differences in drug use patterns between community-dwelling and institutionalized elderly, after adjustment for age, gender and number of other drugs (used as a proxy for overall co-morbidity). METHODS: We analysed data from individuals aged >=65 years who filled at least one drug prescription between July and September 2008 and were consequently registered in the Swedish Prescribed Drug Register (n = 1,347,564; 1,260,843 community-dwelling and 86,721 institutionalized elderly). A list of current prescriptions was constructed for every individual on the arbitrarily chosen date 30 September 2008. Outcome measures were the 20 most common drug classes and the 20 most common individual drugs. Logistic regression analysis was used to investigate whether institutionalization was associated with use of these drugs, after adjustment for age, gender and number of other drugs. RESULTS: Institutionalized elderly were more likely than community-dwelling elderly to use antidepressants, laxatives, minor analgesics, opioids and hypnotics/sedatives, after adjustment for age, gender and number of other drugs. On the contrary, institutionalization was negatively associated with use of lipid modifying agents, angiotensin II antagonists, selective calcium channel blockers, beta blocking agents and ACE inhibitors, after adjustment for age, gender and number of other drugs. CONCLUSIONS: Our results indicate that institutionalized elderly are more likely than community-dwelling elderly to use psychotropics, analgesics and laxatives, but less likely to receive recommended cardiovascular drug therapy, which may indicate a need for implementation of evidence-based guidelines for drug treatment in this vulnerable group of elderly patients. Further research is needed to elucidate to what extent the differences in drug use between community-dwelling and institutionalized elderly are explained by different underlying disease patterns and by different prescribing traditions in the different settings. PMID- 23018612 TI - The use of antidepressants in Belgian nursing homes: focus on indications and dosages in the PHEBE study. AB - BACKGROUND: Since antidepressants are prescribed for multiple indications, the use of an antidepressant cannot be equated with a diagnosis of depression. OBJECTIVE: The objective of this study was to examine the quality of antidepressant prescribing in Belgian nursing homes, with a critical evaluation of indications and dosages, to see whether depression was appropriately treated in terms of drug choice, the indications for which antidepressants were being prescribed and whether there was underdosing. METHODS: This analysis was based on data obtained in the Prescribing in Homes for the Elderly in Belgium (PHEBE) study, a cross-sectional, descriptive study of a representative, stratified, random sample of 1,730 residents from 76 Belgian nursing homes. The PHEBE study investigated overall drug utilization in Belgian nursing homes in 2006. Clinical and medication data for the present study were obtained from this study. A 28 item checklist of clinical conditions was designed ad hoc for the PHEBE study and sent to the residents' general practitioners (GPs) to collect clinical information. We copied the residents' medication charts, classified the drugs using the Anatomical Therapeutic Chemical (ATC) classification system codes and transferred the drug names and dosages into a database. Information on indications was retrospectively obtained from the GPs, so that we could link the indication to each medication. Minimum effective doses (MEDs) of antidepressants to treat major depression were obtained from the literature to assess underdosing. RESULTS: The overall use of antidepressants in nursing homes was 39.5 % (95 % CI 37.2, 41.8). The physicians classified 34.2 % (95 % CI 32.0, 36.4) of the residents as having depression, and 80.9 % of these patients were treated with an antidepressant. Indications among the single antidepressant users (n = 551) were depression (66.2 %), insomnia (13.4 %), anxiety (6.2 %) and neuropathic pain (1.6 %). In the indication of depression, 74.8 % used a selective serotonin reuptake inhibitor (SSRI), predominantly citalopram, sertraline and escitalopram. Venlafaxine was used by 10.7 % of the residents. Dosages for these antidepressants were equal to or higher than the MED. But when trazodone, amitriptyline or mirtazapine were used to treat depression, respectively, 92.3, 55.5 and 44.5 % of prescribed dosages were below the MED. In the indication of insomnia, most of the time, trazodone (90.5 %) or mirtazapine (5.4 %) were used, and in lower dosages than those required for depression treatment (= 2 ms/year) and QRS duration (>= 3 ms/year) with HF hospitalization (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.36-4.05; P=0.002 and HR, 2.08; 95% CI, 1.25-3.53; P=0.01, respectively) and (2) a significant association of temporal incremental rate of PR interval (>= 4 ms/year) and QRS duration (>= 5 ms/year) with cardiovascular mortality (HR, 6.9; 95% CI, 1.47-36.96; P=0.02 and HR, 4.31; 95% CI, 1.19-16.5; P=0.03, respectively). CONCLUSIONS: The severity of PCCD was independently and significantly associated with HF hospitalization and cardiovascular mortality. PMID- 23018637 TI - TRAIL, a new weapon against neointimal hyperplasia. PMID- 23018636 TI - MultiBac turns sweet. AB - The baculovirus/insect cell system has proven to be a powerful tool for the expression of eukaryotic proteins. Therapeutics, especially in the field of vaccinology, are often composed of several different protein subunits. Conventional baculoviral expression schemes largely lack efficient strategies for simultaneous multi-gene expression. The MultiBac technology which is based on an engineered genome of Autographa californica nuclear polyhedrosis virus in combination with specially designed transfer vectors is an elegant way for flexible generation of multi-subunit proteins in insect cells. Yet, the glycosylation pattern of insect cell-derived products is not favorable for many applications. Therefore, a modified version of MultiBac, SweetBac, was generated allowing for a flexible glycosylation of target proteins in insect cells. Beyond the SweetBac technology MultiBac can further be designed for bridging the gap between cell engineering and transient modulation of host genes for improved and product tailored expression of recombinant proteins. PMID- 23018631 TI - Individualized therapy for type 2 diabetes: clinical implications of pharmacogenetic data. AB - Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, abnormally elevated hepatic glucose production, and reduced glucose-stimulated insulin secretion. Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary for many patients, in order to restore acceptable glycemic control and to reduce the risk of development and progression of disease complications. Notably, even patients who appear to have similar requirements of antidiabetic regimens show great variability in drug disposition, glycemic response, tolerability, and incidence of adverse effects during treatment. Pharmacogenomics is a promising area of investigation and involves the search for genetic polymorphisms that may explain the interindividual variability in antidiabetic therapy response. The initial positive results portend that genomic efforts will be able to shed important light on variability in pharmacologic traits. In this review, we summarize the current understanding of genetic polymorphisms that may affect the responses of subjects with T2DM to antidiabetic treatment. These genes belong to three major classes: genes involved in drug metabolism and transporters that influence pharmacokinetics (including the cytochrome P450 [CYP] superfamily, the organic anion transporting polypeptide [OATP] family, and the polyspecific organic cation transporter [OCT] family); genes encoding drug targets and receptors (including peroxisome proliferator-activated receptor gamma [PPARG], the adenosine triphosphate [ATP]-sensitive potassium channel [K(ATP)], and incretin receptors); and genes involved in the causal pathway of T2DM that are able to modify the effects of drugs (including adipokines, transcription factor 7-like 2 (T cell specific, HMG-box) [TCF7L2], insulin receptor substrate 1 [IRS1], nitric oxide synthase 1 (neuronal) adaptor protein [NOS1AP], and solute carrier family 30 (zinc transporter), member 8 [SLC30A8]). In addition to these three major classes, we also review the available evidence on novel genes (CDK5 regulatory subunit associated protein 1-like 1 [CDKAL1], insulin-like growth factor 2 mRNA binding protein 2 [IGF2BP2], potassium voltage-gated channel, KQT-like subfamily, member 1 [KCNQ1], paired box 4 [PAX4] and neuronal differentiation 1 [NEUROD1] transcription factors, ataxia telangiectasia mutated [ATM], and serine racemase [SRR]) that have recently been proposed as possible modulators of therapeutic response in subjects with T2DM. PMID- 23018638 TI - The BAF53a subunit of SWI/SNF-like BAF complexes is essential for hemopoietic stem cell function. AB - ATP-dependent SWI/SNF-like BAF chromatin remodeling complexes are emerging as key regulators of embryonic and adult stem cell function. Particularly intriguing are the findings that specialized assemblies of BAF complexes are required for establishing and maintaining pluripotent and multipotent states in cells. However, little is known on the importance of these complexes in normal and leukemic hemopoiesis. Here we provide the first evidence that the actin-related protein BAF53a, a subunit of BAF complexes preferentially expressed in long-term repopulating stem cells, is essential for adult hemopoiesis. Conditional deletion of BAF53a resulted in multilineage BM failure, aplastic anemia, and rapid lethality. These severe hemopoietic defects originate from a proliferative impairment of BM HSCs and progenitors and decreased progenitor survival. Using hemopoietic chimeras, we show that the impaired function of BAF53a-deficient HSCs is cell-autonomous and independent of the BM microenvironment. Altogether, our studies highlight an unsuspected role for BAF chromatin remodeling complexes in the maintenance of HSC and progenitor cell properties. PMID- 23018639 TI - BMP9 regulates endoglin-dependent chemokine responses in endothelial cells. AB - BMP9 signaling has been implicated in hereditary hemorrhagic telangiectasia (HHT) and vascular remodeling, acting via the HHT target genes, endoglin and ALK1. This study sought to identify endothelial BMP9-regulated proteins that could affect the HHT phenotype. Gene ontology analysis of cDNA microarray data obtained after BMP9 treatment of primary human endothelial cells indicated regulation of chemokine, adhesion, and inflammation pathways. These responses included the up regulation of the chemokine CXCL12/SDF1 and down-regulation of its receptor CXCR4. Quantitative mass spectrometry identified additional secreted proteins, including the chemokine CXCL10/IP10. RNA knockdown of endoglin and ALK1 impaired SDF1/CXCR4 regulation by BMP9. Because of the association of SDF1 with ischemia, we analyzed its expression under hypoxia in response to BMP9 in vitro, and during the response to hindlimb ischemia, in endoglin-deficient mice. BMP9 and hypoxia were additive inducers of SDF1 expression. Moreover, the data suggest that endoglin deficiency impaired SDF1 expression in endothelial cells in vivo. Our data implicate BMP9 in regulation of the SDF1/CXCR4 chemokine axis in endothelial cells and point to a role for BMP9 signaling via endoglin in a switch from an SDF1-responsive autocrine phenotype to an SDF1 nonresponsive paracrine state that represses endothelial cell migration and may promote vessel maturation. PMID- 23018640 TI - Sequence analysis of beta-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone. AB - Variations within proteasome beta (PSMB) genes, which encode the beta subunits of the 20S proteasome, may affect proteasome function, assembly, and/or binding of proteasome inhibitors. To investigate the potential association between PSMB gene variants and treatment-emergent resistance to bortezomib and/or long-term outcomes, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity. PMID- 23018642 TI - Human hematopoietic stem/progenitor cells overexpressing Smad4 exhibit impaired reconstitution potential in vivo. AB - Hematopoietic stem cells (HSCs) constitute a rare population of tissue-specific cells that can self-renew and differentiate into all lineages of the blood cell system. These properties are critical for tissue regeneration and clinical applications of HSCs. Cord blood is an easily accessible source of HSCs. However, the number of HSCs from one unit is too low to effectively transplant most adult patients, and expansion of HSCs in vitro has met with limited success because of incomplete knowledge regarding mechanisms regulating self-renewal. Members of the TGF-beta superfamily have been shown to regulate HSCs through the Smad signaling pathway; however, its role in human HSCs has remained relatively uncharted in vivo. Therefore, we asked whether enforced expression of the common-Smad, Smad4, could reveal a role for TGF-beta in human hematopoietic stem/progenitor cells (HSPCs) from cord blood. Using a lentiviral overexpression approach, we demonstrate that Smad4 overexpression sensitizes HSPCs to TGF-beta, resulting in growth arrest and apoptosis in vitro. This phenotype translates in vivo into reduced HSPC reconstitution capacity yet intact lineage distribution. This suggests that the Smad pathway regulates self-renewal independently of differentiation. These findings demonstrate that the Smad signaling circuitry negatively regulates the regeneration capacity of human HSPCs in vivo. PMID- 23018641 TI - The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans. AB - Aberrations in the p53 tumor suppressor pathway are associated with hematologic malignancies. p53-dependent cell cycle control, senescence, and apoptosis functions are actively involved in maintaining hematopoietic homeostasis under normal and stress conditions. Whereas loss of p53 function promotes leukemia and lymphoma development in humans and mice, increased p53 activity inhibits hematopoietic stem cell function and results in myelodysplasia. Thus, exquisite regulation of p53 activity is critical for homeostasis. Most of our understanding of p53 function in hematopoiesis is derived from genetically engineered mice. Here we summarize some of these models, the various mechanisms that disrupt the regulation of p53 activity, and their relevance to human disease. PMID- 23018643 TI - gamma9 and delta2CDR3 domains regulate functional avidity of T cells harboring gamma9delta2TCRs. AB - Immunotherapy with innate immune cells has recently evoked broad interest as a novel treatment option for cancer patients. gamma9delta2T cells in particular are emerging as an innate cell population with high frequency and strong antitumor reactivity, which makes them and their receptors promising candidates for immune interventions. However, clinical trials have so far reported only limited tumor control by adoptively transferred gamma9delta2T cells. As a potential explanation for this lack of efficacy, we found unexpectedly high variability in tumor recognition within the physiologic human gamma9delta2T-cell repertoire, which is substantially regulated by the CDR3 domains of individual gamma9delta2TCRs. In the present study, we demonstrate that the reported molecular requirements of CDR3 domains to interact with target cells shape the physiologic gamma9delta2T cell repertoire and, most likely, limit the protective and therapeutic antitumor efficacy of gamma9delta2T cells. Based on these findings, we propose combinatorial-gammadeltaTCR-chain exchange as an efficient method for designing high-affinity gamma9delta2TCRs that mediate improved antitumor responses when expressed in alphabetaT cells both in vitro and in vivo in a humanized mouse model. PMID- 23018645 TI - Squamomelanocytic tumor of the nail unit metastasizing to a sentinel lymph node: a dermoscopic and histologic investigation. PMID- 23018644 TI - Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP. AB - STAT3 regulates cell growth by up-regulating downstream targets, such as Myc. The frequency of phosphorylated STAT3 (pSTAT3) and Myc expression and their prognostic relevance is unknown within diffuse large B-cell lymphoma (DLBCL) germinal center B-cell (GCB) and non-GCB subtypes. pSTAT3 and Myc were studied by immunohistochemistry (IHC) on tumors from 40 DLBCL patients uniformly treated on a clinical trial of epratuzumab/rituximab-CHOP. A total of 35% of cases were pSTAT3-positive, and pSTAT3 positivity was more frequent in the non-GCB (P = .06) type but did not correlate with event-free survival (EFS). Myc expression was observed in 50% of cases and was more frequent in non-GCB type (P = .07). Myc positive cases had inferior EFS in all patients, including the GCB and pSTAT3 positive cases, were more likely to express Myc (P = .06). Myc translocations involving the major breakpoint regions were found in 10% (3 of 29) of cases, and all 3 cases were GCB and had an inferior EFS (P = .09). pSTAT3, but not Myc expression, was correlated with elevated pretreatment serum cytokines, such as IL 10 (P = .05), G-CSF (P = .03), and TNF-alpha (P = .04). pSTAT3 IHC in DLBCL tumors has the potential to identify patients for STAT3 pathway-directed therapy; Myc IHC is a potential marker for inferior EFS in GCB patients. PMID- 23018646 TI - The association of red blood cell n-3 and n-6 fatty acids with bone mineral density and hip fracture risk in the women's health initiative. AB - Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFA) in red blood cells (RBCs) are an objective indicator of PUFA status and may be related to hip fracture risk. The primary objective of this study was to examine RBC PUFAs as predictors of hip fracture risk in postmenopausal women. A nested case-control study (n = 400 pairs) was completed within the Women's Health Initiative (WHI) using 201 incident hip fracture cases from the Bone Mineral Density (BMD) cohort, along with 199 additional incident hip fracture cases randomly selected from the WHI Observational Study. Cases were 1:1 matched on age, race, and hormone use with non-hip fracture controls. Stored baseline RBCs were analyzed for fatty acids using gas chromatography. After removing degraded samples, 324 matched pairs were included in statistical analyses. Stratified Cox proportional hazard models were constructed according to case-control pair status; risk of fracture was estimated for tertiles of RBC PUFA. In adjusted hazard models, lower hip fracture risk was associated with higher RBC alpha-linolenic acid (tertile 3 [T3] hazard ratio [HR]: 0.44; 95% confidence interval [CI], 0.23-0.85; p for linear trend 0.0154), eicosapentaenoic acid (T3 HR: 0.46; 95% CI, 0.24-0.87; p for linear trend 0.0181), and total n-3 PUFAs (T3 HR: 0.55; 95% CI, 0.30-1.01; p for linear trend 0.0492). Conversely, hip fracture nearly doubled with the highest RBC n-6/n-3 ratio (T3 HR: 1.96; 95% CI, 1.03-3.70; p for linear trend 0.0399). RBC PUFAs were not associated with BMD. RBC PUFAs were indicative of dietary intake of marine n-3 PUFAs (Spearman's rho = 0.45, p < 0.0001), total n-6 PUFAs (rho = 0.17, p < 0.0001) and linoleic acid (rho = 0.09, p < 0.05). These results suggest that higher RBC alpha-linolenic acid, as well as eicosapentaenoic acid and total n-3 PUFAs, may predict lower hip fracture risk. Contrastingly, a higher RBC n-6/n-3 ratio may predict higher hip fracture risk in postmenopausal women. PMID- 23018648 TI - Characteristics of laser stimulation by near infrared pulses of retinal and vestibular primary neurons. AB - BACKGROUND AND OBJECTIVE: The optical stimulation of neurons from pulsed infrared lasers has appeared over the last years as an alternative to classical electric stimulations based on conventional electrodes. Laser stimulation could provide a better spatial selectivity allowing single-cell stimulation without prerequisite contact. In this work we present relevant physical characteristics of a non lethal stimulation of cultured mouse vestibular and retinal ganglion neurons by single infrared laser pulses. STUDY DESIGN/MATERIALS AND METHODS: Vestibular and retinal ganglion neurons were stimulated by a 100-400 mW pulsed laser diode beam (wavelengths at 1,470, 1,535, 1,875 nm) launched into a multimode optical fiber positioned at a few hundred micrometers away from the neurons. Ionic exchange measurements at the neuron membrane were achieved by whole-cell patch-clamp recordings. Stimulation and damage thresholds, duration and repetition rate of stimulation and temperature were investigated. RESULTS: All three lasers induced safe and reproducible action potentials (APs) on both types of neurons. The radiant exposure thresholds required to elicit APs range from 15 +/- 5 to 100 +/- 5 J cm(-2) depending on the laser power and on the pulse duration. The damage thresholds, observed by a vital dye, were significantly greater than the stimulation thresholds. In the pulse duration range of our study (2-30 milliseconds), similar effects were observed for the three lasers. Measurements of the local temperature of the neuron area show that radiant exposures required for reliable stimulations at various pulse durations or laser powers correspond to a temperature increase from 22 degrees C (room temperature) to 55-60 degrees C. Stimulations by laser pulses at repetition rate of 1, 2, and 10 Hz during 10 minutes confirmed that the neurons were not damaged and were able to survive such temperatures. CONCLUSION: These results show that infrared laser radiations provide a possible way to safely stimulate retinal and vestibular ganglion neurons. A similar temperature threshold is required to trigger neurons independently of variable energy thresholds, suggesting that an absolute temperature is required. PMID- 23018649 TI - Contribution of neurogenic and allergic ways to the pathophysiology of nonallergic rhinitis. AB - BACKGROUND: A neuroallergic interaction was reported in the pathogenesis of allergic rhinitis (AR), but the pathophysiology of nonallergic rhinitis (NAR) is poorly understood. We aimed to explore the contribution of neuroallergic mechanisms to the pathogenesis of NAR. METHODS: Subjects were divided into three groups - NAR patients (n = 25), AR patients (n = 16) and the control group (n = 10) - and were assessed using the nasal provocation test (NPT) with house dust mite. Total symptom scores, nasal inspiratory peak flow and nasal lavage were performed before and after NPT. Nasal brushing and scraping was done after NPT. RESULTS: NPT was positive in NAR (52%) and AR (100%) patients and negative in all controls. After NPT, total symptom scores increased in both rhinitis groups. Post NPT values of nasal inspiratory peak flow decreased only in AR patients. NAR patients showed a similar inflammatory cell profile in the nasal smears to AR patients which was different in controls. There were more tryptase- and immunoglobulin E (IgE)-positive cells in the nasal mucosa of AR patients, and more substance-p-positive cells were observed in NAR patients compared with controls. However, IgE- and tryptase-positive cells in NAR patients and substance p-positive cells in AR patients were detectable in nasal mucosa, but rarely in the controls. Comparing the values before and after NPT, tryptase significantly increased in the nasal lavages of AR and NAR patients, while house dust mite specific IgE did not change. CONCLUSIONS: We showed the existence of a common pathophysiological mechanism with different contributions in AR and NAR. We conclude that the difference in dominance of neuroallergic ways may determine the major phenotype of rhinitis. PMID- 23018651 TI - High throughput fabrication of plasmonic nanostructures in nanofluidic pores for biosensing applications. AB - One of the primary advantages of nanoscale sensors is that they often can provide conceptually new ways of performing sensing that are not feasible with their large-scale analogs. For example, the small size of nanoscale sensor elements, such as plasmonic metal nanoparticles, allows them to be combined with nanofluidic systems. Among the potential applications of such a combination is the efficient delivery of analyte to the sensor surface. With this in mind, in this work we look to address the challenge of creating and positioning nanoplasmonic sensor elements within nanofluidic pores. A scheme is presented that allows for the production of arrays of pores in a thin (220 nm) silicon nitride membrane with one plasmonic nanoparticle sensor element in each pore. The high throughput fabrication protocol is parallel and enables multiple sensor chips to be produced simultaneously, yet with accurate tuning of the dimension and shape of the nanoparticles. The presented system is shown to possess polarization-sensitive plasmonic resonances that can be tuned significantly in the visible wavelength range by just varying one process parameter. The thickness of the membrane could be optimized to minimize the influence of the optical membrane interference on the plasmonic readout. The sensitivity of the plasmon resonances to changes in refractive index, which forms the basis for using the system for biosensing, was found to be competitive with other nanoplasmonic sensors. PMID- 23018652 TI - Selective growth of metallic Ag nanocrystals on Ag3PO4 submicro-cubes for photocatalytic applications. AB - Thinking outside the box: The position- and number-selective growth of Ag nanocrystals on Ag(3)PO(4) submicro-cubes by an in situ reduction technique is demonstrated (see figure). These new Ag/Ag(3)PO(4) heterocubes exhibit higher photocatalytic activities than pure Ag(3)PO(4) cubes for the degradation of organic dyes under visible-light irradiation. PMID- 23018647 TI - Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells. AB - Malignant mesothelioma (MM) is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure to asbestos. Recently, we described an interplay between mitochondrial-derived oxidants and expression of FOXM1, a redox responsive transcription factor that has emerged as a promising therapeutic target in solid malignancies. Here we have investigated the effects of nitroxides targeted to mitochondria via triphenylphosphonium (TPP) moieties on mitochondrial oxidant production, expression of FOXM1 and peroxiredoxin 3 (PRX3), and cell viability in MM cells in culture. Both Mito-carboxy-proxyl (MCP) and Mito-TEMPOL (MT) caused dose-dependent increases in mitochondrial oxidant production that was accompanied by inhibition of expression of FOXM1 and PRX3 and loss of cell viability. At equivalent concentrations TPP, CP, and TEMPOL had no effect on these endpoints. Live cell ratiometric imaging with a redox-responsive green fluorescent protein targeted to mitochondria (mito-roGFP) showed that MCP and MT, but not CP, TEMPOL, or TPP, rapidly induced mitochondrial fragmentation and swelling, morphological transitions that were associated with diminished ATP levels and increased production of mitochondrial oxidants. Mdivi-1, an inhibitor of mitochondrial fission, did not rescue mitochondria from fragmentation by MCP. Immunofluorescence microscopy experiments indicate a fraction of FOXM1 coexists in the cytoplasm with mitochondrial PRX3. Our results indicate that MCP and MT inhibit FOXM1 expression and MM tumor cell viability via perturbations in redox homeostasis caused by marked disruption of mitochondrial architecture, and suggest that both compounds, either alone or in combination with thiostrepton or other agents, may provide credible therapeutic options for the management of MM. PMID- 23018655 TI - Protein deposition and clinical symptoms in daily wear of etafilcon lenses. AB - PURPOSE: To determine the relationship between clinical signs and symptoms and protein deposition over 8 h of wear of etafilcon A lenses in symptomatic and asymptomatic contact lens wearers. METHODS: Thirty adapted soft contact lens wearers (16 symptomatic and 14 asymptomatic) were fitted with etafilcon A lenses. In vivo wettability, non-invasive tear break-up time, and subjective symptoms (vision, comfort, and dryness) were assessed at baseline and after 2, 4, 6, and 8 h. After 2, 4, 6, and 8 h time points, lenses were collected, and total protein, total lysozyme, and active lysozyme deposition were assessed. RESULTS: There was a significant reduction (p = 0.032) in the non-invasive tear break-up time at 8 h in both groups. In the symptomatic group, there was a significant reduction in subjective comfort and dryness ratings at 6 and 8 h measurement with respect to baseline (p < 0.05). There was a significant increase in total lysozyme and total protein deposition (p = 0.027) across all time points in both groups; most of the lysozyme remained active (>94% at 8 h). Pearson's correlations between subjective symptoms and protein deposition showed poor correlations for total protein/lysozyme and any subjective factor (r < 0.3; p > 0.05), and only weak correlations between dryness and % active lysozyme (r = 0.3 to 0.5 for all time points). However, stronger correlations were found between active lysozyme and subjective comfort (r = 0.6 to 0.7; p < 0.001). CONCLUSIONS: In addition to investigating total protein deposited on contact lenses, it is of significant clinical relevance to determine the conformational state of the deposited protein. PMID- 23018656 TI - Effect of multipurpose solutions on cell morphology and cytokine production by corneal epithelial cells. AB - PURPOSE: We sought to determine whether human corneal limbal epithelial cells (HCLE) differ in their physiological response and production of inflammatory mediators during exposure to two multipurpose disinfecting solutions that differ in only four excipients. METHODS: HCLE were exposed to dilutions (1%-20%) of OPTI FREE Express and OPTI-FREE RepleniSH for 2, 6, or 18 h. Cell numbers were measured using CyQuant and metabolic activity assays. Morphology, viability, and apoptotic changes were examined by confocal microscopy after staining with Calcein AM/propidium iodide or Hoechst 33,342/propidiun iodide/YO-PRO-1. Cytokine responses and arachidonic acid metabolites were examined by enzyme-linked immunosorbent assay. RESULTS: OPTI-FREE Express showed greater reductions in corneal cell metabolic activity (up to 3-fold) than OPTI-FREE RepleniSH over 18 h. Cells exposed to OPTI-FREE Express were highly vacuolated, whereas those exposed to OPTI-FREE RepleniSH had morphology consistent with a presumed apoptotic response. OPTI-FREE Express elicited higher levels of interleukin (IL) 6 (maximum 4225 +/- 300 pg/mL) and IL-8 (maximum 1094 +/- 250 pg/mL) from cells than OPTI-FREE RepleniSH (maximum of 1717 +/- 225 pg/mL and 930 +/- 300 pg/mL, respectively) at all concentrations tested after 18 h. HCLE did not produce leukotriene B4 or prostaglandin E2 on stimulation, and IL-1beta was produced in low levels, but its production was not different between multipurpose disinfecting solution types. CONCLUSIONS: The findings reported here are the first to describe the pattern of cytokine production produced in corneal epithelial cells in response to contact lens solutions. Alteration of only four excipients in the formulations had such effects on corneal epithelia; however, these differences do not explain differences in the incidences of corneal infiltrative events between these solutions. This might indicate that changes in the rates of infiltrative events result from interactions of the solutions with the contact lens surface, or directly with the corneal immune system, or as the result of gram-negative contamination of lens cases. PMID- 23018659 TI - Using imaging for education and clinical excellence. PMID- 23018661 TI - Lenstar vs. ultrasound for ocular biometry in a pediatric population. PMID- 23018664 TI - Posterior capsule opacification following 20- and 23-gauge phacovitrectomy (posterior capsule opacification following phacovitrectomy). AB - PURPOSE: To compare the development of posterior capsule opacification (PCO) for idiopathic epi-retinal membrane cases between 20- and 23-gauge phacovitrectomy. METHODS: Cataract surgery of phacoemulsification with the SA60AT implantation and 20- or 23-gauge vitrectomy was performed for 20 patients in both groups. Cataract surgery alone was performed for 50 patients as the control. The PCO density values were measured using Scheimpflug video photography at 1 week, 1, 3, 6, 12, 18, and 24 months after surgery. The number of eyes that required Nd:YAG laser capsulotomy was also examined. RESULTS: The mean PCO value in the 20-gauge phacovitrectomy group increased significantly with time (P<0.001), whereas those in the 23-gauge phacovitrectomy group and the cataract surgery group did not show any significant change. Furthermore, the PCO value in the 20-gauge phacovitrectomy group was significantly greater than that in the 23-gauge phacovitrectomy group at 6, 12, 18 (P<0.05), and 24 months (P<0.01) after surgery. The PCO value in the 23-gauge phacovitrectomy group was significantly greater than that in the cataract surgery group 24 months after surgery (P<0.05). The rate of capsulotomy in the 20-gauge phacovitrectomy group was significantly higher than that in the cataract surgery group (P=0.007), whereas there was no significant difference between the 23-gauge phacovitrectomy group and the cataract surgery group. CONCLUSION: PCO rate in eyes with the 23-gauge phacovitrectomy was lower than in those with the 20-gauge phacovitrectomy, and PCO rate even in the 23-gauge phacovitrectomy was higher than in those with cataract surgery. PMID- 23018666 TI - Synthesis and characterization of compounds with the Al-O-X (X = Si, P, C) structural motif. AB - The reactions of LAlH2 (L = HC(CMeNAr)2, Ar = 2,6-iPr2C6H3) (1) with diphenylsilanediol, phenylphosphonic acid, diphenylphosphinic acid, and pyrocatechol afford compounds with the Al-O-X (X = Si, P, C) motif of composition [LAl(MU-O)]2Si(Ph)2 (2), [LAl(MU-O)]2PO(Ph) (3), LAl[OPO(Ph)2]2 (4), and LAl(MU O)2(o-C6H4) (5), respectively. Compound 2 contains the Al-O-Si-O-Al heterotrimetallic dioxide chain. Compound 3 features an Al(MU-O)]2P four-membered ring, while compound 4 exhibits a P-O-Al-O-P chain structure. Compound 5 contains the benzo-aluminum-dioxide organic-inorganic hybrid five-membered ring. Complexes 2, 3, 4, and 5 were characterized by NMR, elementary analysis, and single-crystal X-ray diffraction. PMID- 23018667 TI - Remote patient monitoring in chronic heart failure. AB - Heart failure (HF) poses a significant economic burden on our health-care resources with very high readmission rates. Remote monitoring has a substantial potential to improve the management and outcome of patients with HF. Readmission for decompensated HF is often preceded by a stage of subclinical hemodynamic decompensation, where therapeutic interventions would prevent subsequent clinical decompensation and hospitalization. Various methods of remote patient monitoring include structured telephone support, advanced telemonitoring technologies, remote monitoring of patients with implanted cardiac devices such as pacemakers and defibrillators, and implantable hemodynamic monitors. Current data examining the efficacy of remote monitoring technologies in improving outcomes have shown inconsistent results. Various medicolegal and financial issues need to be addressed before widespread implementation of this exciting technology can take place. PMID- 23018668 TI - The polypill: a potential global solution to cardiovascular disease. AB - Despite groundbreaking advances in health care, cardiovascular disease (CVD) remains the leading cause of death and disability worldwide, making it one of the most pressing global health issues to face the modern world. In 2002, Wald and Law proposed the concept of the polypill as a potential solution to this global health epidemic. The polypill represents a powerhouse pill that would consist of a combination of several key medications commonly prescribed for CVD prevention, such as a statin, diuretic, beta blocker, or angiotensin converting enzyme inhibitor, in one pill. It was suggested that it could be a novel, tactical measure in the approach to CVD prevention in that it greatly simplifies the healthcare delivery system. Not only does it increase medication compliance for those currently receiving health care, but it also has the potential to access those in underserved healthcare sectors of the world, primarily low- and middle income countries, which have been identified as areas of highest CVD risk. A major drawback of the polypill is that there are limited data demonstrating its safety and efficacy in the prevention of cardiovascular morbidity and mortality. Thus far, research shows that the polypill has promise but needs to be approached with a few considerations, such as desired target patient population and formulation. This article will examine the published and ongoing studies associated with the polypill, outline the advantages and disadvantages of using the polypill as a global CVD prevention strategy, and discuss the design and availability of the polypill in the United States. PMID- 23018669 TI - A new approach to inotropic therapy in the treatment of heart failure: cardiac myosin activators in treatment of HF. AB - Systolic heart failure remains a leading cause of death and disability, and available pharmacologic treatments for heart failure are limited in both safety and effectiveness. Existing drugs focus on diverse mechanisms related to the pathophysiology of heart failure, yet none directly target the central feature of systolic heart failure, decreased cardiac contractility. Cardiac myosin activators, specifically omecamtiv mecarbil (formerly CK-1827452), directly activate the enzymatic pathway within the cardiac myocyte leading to ventricular contraction. This unique inotropic agent has been shown in preclinical and clinical studies to be effective in improving cardiac contractility by increasing systolic ejection time without the unwanted effects of the currently available indirect inotropic drugs. Cardiac myosin activators show great promise and may prove to be a safer and more effective therapeutic approach for the treatment of systolic heart failure. PMID- 23018670 TI - Pulmonary hypertension in pregnancy. AB - The presence of pulmonary arterial hypertension (PAH) in pregnancy is rare and signifies a high-risk pregnancy. Although the majority of mothers have knowledge of their condition before pregnancy, approximately one-third of patients are diagnosed during pregnancy. Termination of pregnancy should be discussed, and is often advised; however, a significant proportion of patients will choose to proceed with the pregnancy despite increased maternal and fetal mortality. Currently, most pregnant patients receive advanced therapy for treatment of PAH, particularly prostacyclin analogues. Particular attention is paid to volume status and blood loss and there has been a major trend toward delivery by cesarean section under controlled conditions involving an expert multidisciplinary team. The time of greatest maternal risk is in the first month after delivery. Transplantation of these patients in the nonpregnant state may be considered when those with idiopathic pulmonary hypertension have poor functional status despite optimal therapy and their projected 2-year survival is less than 50%. For patients with Eisenmenger syndrome, severe symptoms and an unacceptable quality of life may lead to transplantation. PMID- 23018671 TI - Inverse association of coronary soluble tumor necrosis factor-related apoptosis inducing ligand (sTRAIL) levels to in-stent neointimal hyperplasia. AB - OBJECTIVES: Soluble tumor necrosis factor-related apoptosis inducing ligand (sTRAIL) has been shown to exert protective action against atherosclerosis. The aim of this study was to investigate potential associations of coronary sTRAIL levels with indices of in-stent neointimal hyperplasia. METHODS: 67 patients who underwent percutaneous coronary intervention with drug-eluting stent were followed up at approximately 12 months with determination of coronary sTRAIL concentration, angiography and intravascular ultrasound evaluation of the stent sites. RESULTS: Mean sTRAIL concentration was 72.2 +/- 2.8 pg/ml. sTRAIL was negatively correlated to indices of neointimal hyperplasia and positively correlated to in-stent minimum lumen area (p < 0.001). Neointimal obstruction and maximal in-stent cross-sectional neointima burden in patients in the upper sTRAIL quartile were 3.8 +/- 1.2 and 12.6 +/- 3.3%, respectively, versus 14.0 +/- 0.7 and 49.8 +/- 2.7% in the lower quartile (p < 0.001 for both). sTRAIL levels were significantly lower in patients with binary restenosis (48.7 +/- 3.0 vs. 75.2 +/- 2.9 pg/ml; p < 0.001). In the multivariate analysis, sTRAIL was an independent predictor of neointimal hyperplasia. CONCLUSION: This study demonstrates a negative association of sTRAIL to in-stent neointima formation. The potential pathophysiologic substrate of this effect implicates modulation of apoptosis in various cell types. These observations should prompt further evaluation of the link between sTRAIL and in-stent restenosis. PMID- 23018672 TI - Interaction of N-acetylcysteine and cysteine in human plasma. AB - N-acetyl-L-cysteine (NAC), a well-known antioxidant, has been successfully used as adjuvant therapy for late-stage childhood cerebral adrenoleukodystrophy (c ALD); however, the mechanisms of NAC action are poorly understood. Previous research indicates that NAC serves as a precursor to L-cysteine (Cys), the rate limiting substrate in the biosynthesis of glutathione (GSH), a potent, endogenous antioxidant. We hypothesized that NAC acts by liberating protein-bound Cys in plasma in an NAC concentration-dependent manner, which increases unbound Cys available for GSH biosynthesis. Human plasma was incubated for 1 h with varying, clinically relevant concentrations of NAC (0-1000 ug/mL). The effect of this interaction over time was evaluated by incubating plasma for 5-90 min with 100 ug/mL NAC. Unbound and bound Cys and NAC were separated by ultrafiltration, and concentrations were measured using high-performance liquid chromatography-mass spectrometry. Significant increases in unbound Cys were observed with increasing NAC concentrations. Also, Cys plasma protein binding decreased from 85% (10 ug/mL NAC) to approximately 0% (1000 ug/mL). Total endogenous Cys was 66% unbound at 5 min after incubation. These results demonstrate that NAC liberates endogenous, protein-bound Cys in human plasma at clinically relevant NAC concentrations. A greater understanding of NAC actions will aid in the optimization of NAC therapy including its use in c-ALD. PMID- 23018677 TI - Sub-cellular tumor identification and markerless differentiation in the rat brain in vivo by multiphoton microscopy. AB - OBJECTIVE/BACKGROUND: Aim of the current study was to localize and differentiate between tumor (glioma) and healthy tissue in rat brains on a cellular level. Near infrared multiphoton microscopy takes advantage of the simultaneous absorption of two or more photons to analyze various materials such as cell and tissue components via the observation of endogenous fluorophores such as NAD(P)H, FAD, porphyrins, melanin, elastin, and collagen, with a very high resolution, without inducing the problems of photo-bleaching on out-of-focus areas. METHODS: In vitro and in vivo studies on healthy rat brains as well as C6 glioma cell line allografts have been performed. Near-infrared laser pulses (lambda = 690-1060 nm, tau ~140 fs) generated by an ultrafast Ti:Sapphire tunable laser system (Chameleon, Coherent GmbH, Santa Clara, CA) were coupled into a laser scanning microscope (LSM 510 META, Carl Zeiss, Germany) to observe high quality images. RESULTS: Several image acquisitions have been performed by varying the zoom scale of the multiphoton microscope, image acquisition time and the wavelength (765, 840 nm) to detect various tissue components. With a penetration depth of ~200 um in vitro and about 30-60 um in vivo into the brain tissue it was possible to differentiate between tumor and healthy brain tissue even through thin layers of blood. CONCLUSION: Near-infrared multiphoton microscopy allows the observation and possibly differentiation between tumor (glioma) and healthy tissue in rat brains on a cellular level. Our findings suggest that a further miniaturization of this technology might be very useful for scientific and clinical applications in neurosurgery. PMID- 23018676 TI - Neurogenesis and neuronal migration in the forebrain of the TorsinA knockout mouse embryo. AB - Early-onset generalized torsion dystonia, also known as DYT1 dystonia, is a childhood onset heritable neurological movement disorder involving painful, involuntary muscle contractions, sustained abnormal postures, and repetitive movements. It is caused by a GAG deletion in the Tor1A gene located on chromosome 9. TorsinA, the product of the Tor1A gene, is expressed throughout the brain beginning early in embryonic development. It plays a role in the regulation of nuclear envelope-cytoskeletal interactions, and presumably nuclear translocation. Since nuclear translocation, powered by cytoskeletal traction, is critical for cell proliferation and migration, we examined whether neurogenesis and neuronal migration are affected in Tor1A-/- mouse brain. Our data show that interkinetic nuclear migration and the pattern of migration of newly generated neurons are impaired in the dorsal forebrain of the Tor1A-/- embryo. However, neurogenesis is not altered significantly. The rate of migration of cells from explants of the medial ganglionic eminence is also impaired in the Tor1A-/- embryo. Thus, loss of torsinA results in subtle but significant alterations in cell proliferation and migration in the embryonic forebrain. These subtle developmental changes are consistent with a lack of significant changes in neuronal numbers, neuronal positioning or size of brain regions in DYT1 dystonia patients. PMID- 23018678 TI - Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. AB - 3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children and using fibroblast cell lines assess signalling responses to GH or IGF1. Eleven CUL7, three OBSL1 and one CCDC8 mutations in nine, three and one families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF1. While the generation of IGF binding proteins by 3-M cells was dysregulated, activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls. Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells. The prevalence of 3-M mutations was 69% CUL7, 23% OBSL1 and 8% CCDC8. The GH-IGF axis evaluation could reflect a degree of GH resistance and/or IGF1 resistance. This is consistent with the signalling data in which the CUL7(-/-) cells showed impaired IGF1 signalling, CCDC8(-/-) cells showed impaired GH signalling and the OBSL1(-/-) cells showed impairment in both pathways. Dysregulation of the GH-IGF IGF binding protein axis is a feature of 3-M syndrome. PMID- 23018679 TI - Late cardiac remodeling after primary percutaneous coronary intervention-five year cardiac magnetic resonance imaging follow-up. AB - BACKGROUND: Primary percutaneous coronary intervention (PPCI) preserves function and improves survival. The late effects of PPCI on left ventricular remodeling, however, have not yet been investigated on cardiac magnetic resonance imaging (CMRI). METHODS AND RESULTS: Twenty-five patients with acute myocardial infarction (AMI) treated with PPCI underwent CMRI within 10 days, at 4 months and at 5 years. Left ventricular ejection fraction (LVEF), end-diastolic volume (EDV) and end-systolic volume were quantified on cine images. Infarct mass and transmural extent of infarction were quantified on contrast-enhanced imaging. In all patients EDV increased significantly in the early phase (192 +/- 40 ml to 211 +/- 49 ml, P <= 0.01) and LVEF improved significantly (42 +/- 9% to 46 +/- 9%, P=0.02). In the late phase (>4 months) no significant changes were observed (LVEF 44 +/- 9%, P=0.07; EDV 216 +/- 68 ml, P=0.38). Three different groups could be identified. One-third (32%) had no dilatation at all; one-third (32%) had limited dilatation at 4 months without progression later; and 36% had progressive dilatation both at 4 months and at late follow-up. This third group had an average increase in EDV of 20% in the acute phase followed by an additional 13%. The strongest predictor for progressive dilatation was infarct mass. CONCLUSIONS: Even in the era of PPCI for AMI followed by optimal medical therapy, one-third of patients had progressive dilatation, which was best predicted by infarct mass. PMID- 23018680 TI - Combined assessment of baroreflex sensitivity with iodine 123 metaiodobenzylguanidine scintigraphic findings strengthens the power of predictive value for cerebral and cardiovascular events in type 2 diabetic patients. AB - BACKGROUND: We previously reported that baroreflex sensitivity (BRS) or cardiac iodine 123 metaiodobenzylguanidine ((123)I-MIBG) scintigraphic findings can predict cardiovascular prognosis in type 2 diabetic patients. We therefore tested the hypothesis that the combination of BRS and (123)I-MIBG scintigraphic findings could strengthen the predictive power for major adverse cerebral and cardiovascular events (MACCE). METHODS AND RESULTS: From 1998, we have evaluated both BRS and (123)I-MIBG scintigraphy in 165 type 2 diabetic patients (77 females, 88 males, mean age 59 +/- 12 years). Based on the ROC curves, depressed BRS was defined as <5.63 mmHg/s, and enhanced washout ratio (WR) was defined as >= 41.4%. Each patient was divided into 3 groups based on the "BRS-MIBG combination score" as follows: 0, patients having both preserved BRS and preserved WR; 1, patients having either depressed BRS or enhanced WR; 2, patients having both depressed BRS and enhanced WR. During the mean of 4.7 +/- 2.7 years of follow-up, 19 patients developed MACCE. The MACCE-free ratio was significantly higher in the lower BRS-MIBG combination score group (log-rank 16.41, P=0.0003). Cox proportional hazards regression analysis revealed that BRS-MIBG combination score was independently associated with the incidence of MACCE (hazard ratio 4.06, P=0.0237). CONCLUSIONS: Our results suggest that combined assessment of the BRS and (123)I-MIBG scintigraphic findings is more useful for identifying the type 2 diabetic patients at high risk for MACCE. PMID- 23018681 TI - Thyroid and brain natriuretic Peptide response in children undergoing cardiac surgery for congenital heart disease- age-related variations and prognostic value. AB - BACKGROUND: Interest in hormonal response after pediatric cardiac surgery is growing, but many aspects remain unclear. The aim of this study was to test age related variations and prognostic values of thyroid hormones, and brain natriuretic peptide (BNP) levels before and after surgery. METHODS AND RESULTS: A total of 162 children undergoing cardiac surgery were divided into 3 age groups (group 1, n=57 neonates; group 2, n=58 infants; group 3, n=47 toddlers). Free thyroid hormones (fT3 and fT4), thyrotropin (thyroid-stimulating hormone [TSH]) and BNP were measured preoperatively, daily postoperatively in the intensive care unit and after 15 days. The primary outcome was time to extubation (TTE; variable used as time to event by survival analysis). The hormonal response differed among age groups. In older children the TSH nadir occurred at 6-12h after surgery (0.42 mIU/L, P<0.001), with a progressive recovery thereafter, while in neonates the TSH nadir occurred later, at 36-60 h (0.14 mIU/L, P<0.001), followed by a much slower recovery. In neonates, BNP also dropped after surgery (from 2,899 to 824.0 ng/L, P<0.001) while increased in older children (from 71.00 to 527.00 ng/L, P<0.001). On multivariate analysis independent predictors of TTE were fT3 nadir in all age groups, together with TSH nadir and Aristotle score in neonates, and body surface area and BNP peak in older children. CONCLUSIONS: BNP and thyroid response after pediatric cardiac surgery differs widely according to age. Beside Aristotle score, combined measurement of fT3 and TSH are the strongest predictors of TTE, especially in neonates. PMID- 23018682 TI - On the applicability of carbon nanotubes as nanomechanical probes and manipulators. AB - Carbon nanotube (CNT) probes offer improved imaging resolution in atomic force microscopy (AFM) and nanomanipulating devices due to their excellent mechanical properties and high aspect ratios. The basis of ascertaining scanning image quality using CNT probes is often centered on whether axial buckling has occurred or not. Here we explore the mechanical behavior and applicability of CNTs in surface scanning using molecular dynamics simulations in which the influence of van der Waals interactions is accounted for. Our results indicate the possible deleterious effects from van der Waals interaction dominated buckling of the probe, which is exacerbated by surface corrugations at the atomic scale. Under the premise that these issues can be surmounted, a cantilever model developed under known requirements for the structural characteristics of CNT probes is shown to be able to assess imaging fidelity. This model offers an effective guide to the selection and design of CNT probes for AFM. PMID- 23018683 TI - Usefulness and limitations of sequential serum tryptase for the diagnosis of anaphylaxis in 102 patients. AB - BACKGROUND: The diagnosis of anaphylaxis is based on clinical history since no reliable biological marker is currently available to confirm the diagnosis. OBJECTIVE: It was the aim of this study to determine sequential serum tryptase concentrations during anaphylaxis and to evaluate its potential as a diagnostic marker. METHODS: We performed a prospective study including patients with acute anaphylaxis (according to the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria) attending the emergency department. Demographic characteristics, anaphylactic triggers, specific risk factors, clinical characteristics and management of anaphylaxis were recorded. Serum tryptase was measured at 1-2 h (T1), 4-6 h (T2) and 12-24 h (T3) following onset of the episode and at basal conditions (TB). RESULTS: A total of 102 patients were included (63 females, mean age 47.4 +/- 19.1 years). Tryptase concentration at T1 (19.3 +/- 15.4 ug/l) was significantly higher than at T2, T3 and TB (all <11.4 ug/l; p < 0.0001). Importantly, tryptase was not raised in 36.3% of cases; furthermore, in 60.6% of these patients, no changes were observed in tryptase levels comparing T1 and TB (DeltaT1-TB = 0). Tryptase was more frequently elevated in more severe anaphylaxis (p < 0.0001) and positively correlated with the grades of severity (p < 0.001, r = 0.49). Anaphylaxis was more severe and tryptase concentration higher when the causative agent was a drug compared to food, both at T1 (p = 0.045) and at TB (p = 0.019). Age and coronary risk factors were associated with more severe anaphylaxis (p = 0.001). CONCLUSION: Tryptase is a biomarker related to the severity of anaphylaxis. However, since its concentration remains unaltered in a considerable number of patients during acute anaphylaxis, there is a need for more reliable diagnostic biological tests. PMID- 23018684 TI - A prospective study of thyroid function, bone loss, and fractures in older men: The MrOS study. AB - Excess thyroid hormone is associated with increased bone loss and fracture risk in older women, but few data exist for men. We sought to determine if thyroid function is independently associated with bone loss and fracture risk in older men. Data were analyzed from the Osteoporotic Fractures in Men (MrOS) study, a cohort of community-dwelling U.S. men aged 65 years and older. Using a case cohort design, fasting baseline serum archived at -80 degrees C was assayed for thyroid-stimulating hormone (thyrotropin) (TSH) and free thyroxine (FT4) in 397 men with confirmed nonspine fracture, including 157 hip fractures, and 1420 randomly selected men without fracture. TSH and FT4 were analyzed as continuous variables and as thyroid function categories (subclinical hyperthyroid, euthyroid, and subclinical hypothyroid). Hip dual-energy X-ray absorptiometry (DXA) (Hologic QDR4500) was measured at baseline and after a mean follow-up of 4.6 years. Incident nonspine fractures were centrally adjudicated. Bone loss was evaluated with multivariate regression methods and fractures risk was evaluated using hazard models that accounted for the case-cohort sampling, adjusted for age, clinic-site, body mass index (BMI), race, physical activity, corticosteroid use, smoking, alcohol intake, and thyroid medication use. In fully adjusted analyses, TSH was not associated with risk of nonspine fracture (relative hazard [RH] 0.92 per SD decrease in TSH; 95% confidence interval [CI], 0.74-1.14), but was significantly associated with risk of hip fracture (RH 1.31; 95% CI, 1.01 1.71), which persisted among normal range TSH values (RH 1.21; 95% CI, 1.00 1.47). There was no association between TSH or FT4 and bone loss, and fracture risk did not differ significantly by thyroid function category. We conclude that although neither TSH nor FT4 are associated with bone loss, lower serum TSH may be associated with an increased risk of hip fractures in older men. PMID- 23018685 TI - Human acellular dermis versus no acellular dermis in tissue expansion breast reconstruction. AB - BACKGROUND: Human acellular dermis has been adopted for routine use in tissue expander reconstruction. The purported benefits include higher intraoperative fill volume, facilitation of lower pole expansion, and enhanced definition of the lower pole of the breast. Recently, concerns have arisen about an increase in postoperative complications with its use. METHODS: A retrospective review was conducted of patients who had immediate postmastectomy breast reconstruction with a tissue expander from July of 2001 to July of 2011. All tissue expander reconstructions before 2005 were performed submuscularly only and all subsequent to 2005 with the use of AlloDerm (LifeCell, Branchburg, N.J.) acellular dermis. Patient demographics were collected, and complications were recorded. RESULTS: The study cohort included 346 patients and 511 immediate breast reconstructions; 232 patients and 346 breasts were reconstructed with and 114 patients and 165 breasts without acellular dermis. Age, body mass index, diabetes, and tobacco use were equivalent in the two groups. Seroma occurrence in the acellular dermis group was nearly twice (30.0 versus 15.1 percent) that of the no acellular dermis breasts, but the tissue expander loss was only slightly higher (11.6 versus 8.5 percent) and not statistically significant. Body mass index in patients who lost their tissue expander was 31 kg/m, statistically significantly higher than in those who did not. CONCLUSIONS: The presence of acellular dermis did not increase the incidence of tissue expander loss, despite a doubling of frequency of seroma. Prior radiation and use of acellular dermis did culminate in a prohibitively high loss rate of the tissue expander. PMID- 23018686 TI - Discussion: Human acellular dermis versus no acellular dermis in tissue expansion breast reconstruction. PMID- 23018687 TI - Utility of acellular dermis-assisted breast reconstruction in the setting of radiation: a comparative analysis. AB - BACKGROUND: The role of acellular dermis in immediate prosthetic breast reconstruction remains unclear, particularly within a radiated field. The authors evaluated and compare outcomes following reconstruction with and without acellular dermis, and analyzed patients exposed to radiation therapy. METHODS: Retrospective review of 417 consecutive patients (592 breasts) treated from January of 2006 to October of 2008 at one institution was performed. Relevant patient characteristics and follow-up were recorded. Complications were categorized by type and end outcome, including nonoperative, operative, or explantation. Both groups had comparable follow-up (acellular dermis, 23.2 +/- 8.9 months; no acellular dermis, 24.4 +/- 12.7 months; p = 0.23). Appropriate statistical analyses, including multiple regression, were performed. RESULTS: Acellular dermis patients (n = 199 breasts) had larger body mass indexes (p = 0.0001) and more nipple-sparing mastectomies (p = 0.04) than non-acellular dermis patients (n = 393 breasts). Breasts with acellular dermis had larger intraoperative fill volumes (p < 0.0001) and decreased postoperative expansions (p = 0.02), but no decrease in time to implant exchange. There were no significant differences in complication profiles between acellular dermis and non acellular dermis breasts, after adjusting for other relevant patient variables on regression analysis. After stratifying patients by exposure to radiation, acellular dermis breasts had a decreased risk of all complications related to radiation as compared with non-acellular dermis breasts. CONCLUSIONS: This study suggests that acellular dermis does not adversely affect complication rates following prosthetic breast reconstruction. It may be advantageous, however, in select patients, particularly those undergoing postoperative radiation therapy. Therefore, the choice to use acellular dermis does not compromise outcomes but should be individualized to each patient. PMID- 23018688 TI - Discussion: Utility of acellular dermis-assisted breast reconstruction in the setting of radiation: a comparative analysis. PMID- 23018689 TI - Differentiating fat necrosis from recurrent malignancy in fat-grafted breasts: an imaging classification system to guide management. AB - BACKGROUND: In breast reconstruction with autologous fat grafting, concerns persist about the ability to differentiate palpable masses representing fat necrosis from recurrent cancer. The authors' objective was to develop standardized imaging classifications to distinguish benign from malignant lesions after fat grafting. METHODS: A database of 286 breast reconstruction patients undergoing fat grafting from 2006 to 2011 was retrospectively reviewed to identify patients with imaging of clinically palpable masses. All images were reviewed independently by a radiologist blinded to prior results. Lesions were classified, using the American College of Radiology Breast Imaging Reporting and Data System ultrasound lexicon, as follows: A, solid mass, hypoechoic; B, solid mass, isoechoic; C, solid mass, hyperechoic; D, solid mass, complex echogenicity; E, anechoic mass with posterior acoustic enhancement; F, cystic mass with internal echoes; and G, negative. Evolutions in lesions on follow-up ultrasound were recorded. Images were correlated with histopathologic results. RESULTS: On ultrasound, 66 lesions were visualized in 37 patients with palpable masses. Twenty-two lesions (33 percent) were Breast Imaging Reporting and Data System category 4 lesions; biopsies were performed on all of them. Histopathologic results revealed that 85.7 percent (six of seven) with classification D and 100 percent with classifications A, B, C, E, F, and G were fat necrosis. The one malignant lesion (classification D) exhibited vascularity and angular margins on ultrasound and was not in the location of fat injection. Negative predictive value of avascularity and circumscribed margins for malignancy was 100 percent. Follow-up ultrasound of 29 lesions at a median of 6.5 months revealed that no masses increased in size or developed vascularity. CONCLUSION: Ultrasound analysis, with a standardized classification system, is reliable at differentiating benign from malignant lesions after fat grafting in breast reconstruction. PMID- 23018690 TI - Infiltration of epinephrine in reduction mammaplasty: a systematic review of the literature. AB - BACKGROUND: Evidence of the benefit of dilute epinephrine infiltration before reduction mammaplasty is provided by several controlled trials. Despite variation in operative technique and data collection, a reduction in intraoperative blood loss has been shown. The aim of this review of the literature is to weigh the available evidence with respect to reducing blood loss during surgery and other outcome measures such as postoperative drainage. METHODS: Two researchers independently selected articles for review, and data were extracted from each primary article and used for statistical and descriptive comparisons. RESULTS: A meta-analysis of operative blood loss showed a highly significant drop in operative blood loss in breasts infiltrated with epinephrine and a reduction in the need for blood transfusion. Operative time, postoperative drainage, and complications were not significantly affected by epinephrine infiltration. CONCLUSION: The authors' recommendation would be for the use of dilute epinephrine infiltration before reduction mammaplasty. PMID- 23018691 TI - Breast and chest wall reconstruction with the transverse musculocutaneous gracilis flap in Poland syndrome. AB - Poland syndrome is a complex chest wall deformity with unilateral hypoplasia of the breast and pectoralis muscle, with a missing anterior axillary fold in its most common form. The authors report their combined experience and technique with the transverse myocutaneous gracilis flap to reconstruct the chest wall and breast either alone or simultaneously. Between June of 2004 and July of 2010, 11 patients (two male patients) were operated on and 14 flaps were transplanted. The authors found that the transverse myocutaneous gracilis flap proved to be a very valuable microsurgical alternative for reconstructing the chest wall and female breast in Poland syndrome with autologous tissue. The flap provides the surgeon maximal freedom of flap insetting for optimal symmetry together with a very inconspicuous donor site regardless of unilateral or bilateral harvesting. PMID- 23018693 TI - Discussion: ASPS clinical practice guideline summary on reduction mammaplasty. PMID- 23018692 TI - ASPS clinical practice guideline summary on reduction mammaplasty. AB - In May of 2011, the Executive Committee of the American Society of Plastic Surgeons approved an evidence-based guideline on reduction mammaplasty developed by the American Society of Plastic Surgeons Health Policy Committee. The guideline addresses six clinical questions: procedural efficacy as noted by relief of symptoms, resection weight, the impact of body mass index on surgical complications, use of prophylactic antibiotics, use of drains, and effect on quality of life. The evidence indicates that resection volume is not correlated directly to the degree of postoperative symptom relief. Increased breast resection weight may increase the risks of complication. The evidence is inconclusive on whether increased body mass index is associated with increased risk of complications. Perioperative antibiotics may reduce the risk of infection associated with reduction mammaplasty, and in standard reduction mammaplasty procedures without liposuction, the use of drains is not beneficial. Reduction mammaplasty has been shown to improve quality of life. PMID- 23018694 TI - Treating fat grafts with human endothelial progenitor cells promotes their vascularization and improves their survival in diabetes mellitus. AB - BACKGROUND: Bone marrow-derived endothelial progenitor cells are required for vascularization of a fat graft to form a functional microvasculature within the graft and to facilitate its integration into the surrounding tissues. Organ transplantation carries a high risk of graft loss and rejection in patients with diabetes mellitus because endothelial progenitor cell function is impaired. The authors investigated the influence of endothelial progenitor cell treatment on the phenotype and survival of human fat grafts in immunocompromised mice with experimentally induced diabetes mellitus. METHODS: The authors injected 1 ml of human fat tissue into the scalps of 14 nondiabetic and 28 diabetic immunocompromised mice, and then treated some of the grafts with endothelial progenitor cells that was isolated from the blood of a human donor. The phenotype of the endothelial progenitor cell-treated fat grafts from the 14 diabetic mice was compared with that of the untreated fat grafts from 14 nondiabetic and 14 diabetic mice, 18 days and 15 weeks after fat transplantation. Determination of graft phenotype included measurements of weight and volume, vascular endothelial growth factor levels, vascular endothelial growth factor receptor-2, endothelial nitric oxide synthase, and caspase 3 expression levels, and histologic analysis of the extent of vascularization. RESULTS: The untreated grafts from the diabetic mice were fully resorbed 15 weeks after fat transplantation. The phenotype of endothelial progenitor cell-treated fat grafts from the diabetic mice was similar to that of the untreated fat grafts from the nondiabetic mice. CONCLUSION: Endothelial progenitor cell treatment of transplanted fat can increase the survival of a fat graft by inducing its vascularization and decreasing the extent of apoptosis. PMID- 23018696 TI - Use of progressive tension sutures in components separation: merging cosmetic surgery techniques with reconstructive surgery outcomes. AB - Components separation is a widely used technique for defect size reduction in abdominal wall reconstruction, and ultimately helps achieve gold standard primary fascial reapproximation in many cases. Even with perforator-sparing techniques, oftentimes there are undermined skin flaps to varying degrees that can lead to complications such as seromas. In this article, the author describes the previously published technique of "progressive tension sutures" reported in the cosmetic literature and extrapolates it to reconstructive abdominal surgery with statistically significant decreases in drain output. This technique also enables recruitment of skin to the midline to afford tension-free reapproximation and excision of redundancy, thereby discarding the most random portion of the skin flaps. PMID- 23018695 TI - A comparison of a new skin closure device and intradermal sutures in the closure of full-thickness surgical incisions. AB - BACKGROUND: A novel topical skin adhesive system was developed to close the outermost layer of skin in an expeditious manner. To determine its clinical utility, a clinical investigation was undertaken to demonstrate equivalence of a new adhesive skin closure system (Prineo Skin Closure System) to intradermal sutures in wound closure. METHODS: The investigation included 83 patients who underwent elective abdominoplasty, circumferential body lift procedures, and breast reconstruction with deep inferior epigastric perforator flaps. Incisions were divided in half, and each half was randomized to wound closure with the new skin closure system, including a pressure-sensitive adhesive mesh tape for wound edge approximation and next-generation cyanoacrylate or intradermal sutures. Postoperative evaluations took place at 24 hours, 7 days, 12 to 25 days, 90 days, 6 months, and 12 months. RESULTS: The new skin closure system was found to be equivalent to intradermal sutures for the continuous approximation of wounds. The upper limit of the two-sided 90 percent confidence interval for difference in proportions was 10.9 percent. The mean time to closure for the new skin closure system was 1.46 minutes, approximately 5 minutes faster than that for intradermal sutures (p < 0.0001). Both treatments had similar incision healing and cosmetic outcomes. No quantitative or qualitative differences of clinical significance were evident between the treatment groups. CONCLUSIONS: The Prineo Skin Closure System can be considered equivalent to intradermal sutures for full-thickness surgical incisions with regard to safety and effectiveness. The ease and speed of application contribute to shortened operative times (4.5 times faster than intradermal sutures). PMID- 23018697 TI - Sustained bFGF-release tubes for peripheral nerve regeneration: comparison with autograft. AB - BACKGROUND: Despite numerous articles on the use of artificial nerve conduits, autologous nerve transplants remain the most effective for nerve repair. To improve this technique, the authors examined conduits containing gelatin hydrogel as a carrier enabling the sustained release of basic fibroblast growth factor (bFGF). METHODS: To confirm sustained bFGF release in vivo, nerve-guide tubes containing iodine-125-labeled bFGF with or without gelatin hydrogel were implanted under the skin of mice, and the remaining radioactivity was measured. Next, a 15-mm segment of the sciatic nerve was resected and repaired with autologous nerve (group 1), a tube with gelatin hydrogel and bFGF (group 2), a tube with bFGF alone (group 3), or a tube only (group 4). Histologic and functional analyses were performed for 16 weeks after surgery. RESULTS: The radioactivity from iodine-125-labeled bFGF incorporated into gelatin hydrogel decreased more slowly than iodine-125-labeled bFGF alone. Four weeks after surgery, significantly more regenerating axons were detected in group 2 than in groups 3 and 4, but the axonal density in group 2 was lower than in group 1. Similarly, the animals in group 2 showed significantly better motor performance than those in groups 3 and 4, but worse than those in group 1. The animals in groups 1 and 2 showed significantly better sensory recovery than those in groups 3 and 4. CONCLUSIONS: The nerve-guide tube containing gelatin hydrogel and bFGF promoted axonal regeneration after peripheral nerve injury, but not as well as autologous transplants. Understanding the limitations of this technique will facilitate its improvement for clinical applications. PMID- 23018698 TI - Cognitive and behavioral functioning in 82 patients with trigonocephaly. AB - BACKGROUND: The main objective of the present study was to assess the prevalence rates of attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, and features of autism spectrum disorders in trigonocephalic patients, using validated instruments and by ruling out the confounding influence of IQ. The second aim was to assess the association between extracranial anomalies and cognitive and/or behavioral problems in patients with trigonocephaly. METHODS: Objectives were studied in 82 trigonocephalic patients aged 4 to 18 years at the Erasmus Medical Center in Rotterdam, The Netherlands. Features of autism spectrum disorders were assessed using the Social Communication Questionnaire. Attention deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder were assessed with the Diagnostic Interview Schedule for Children-Parent Version. The presence and nature of extracranial anomalies were ascertained by a clinician. RESULTS: Mental retardation (IQ <70) was present in 9 percent of patients with trigonocephaly. Findings indicated a 70 percent versus 24 percent prevalence of psychopathology (attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, or features of autism spectrum disorder) in patients with IQ levels of, respectively, <85 and >=85. In the latter group, psychopathology was not significantly more common than expected based on prevalence rates reported in community samples. Extracranial anomalies were significantly correlated with lower IQ levels. However, when adjusted for IQ, the presence of extracranial malformations was not associated with an increased risk of behavioral problems. CONCLUSION: The relatively high prevalence of behavioral problems in patients with trigonocephaly seems to be mainly attributable to the co-occurrence of trigonocephaly and low intelligence. PMID- 23018699 TI - Discussion: Cognitive and behavioral functioning in 82 patients with trigonocephaly. PMID- 23018700 TI - The usability of the upper eyelid crease approach for correction of medial orbital wall blowout fracture. AB - BACKGROUND: There are many approaches to the medial orbital wall. However, most of them have problems with limitation of exposure, scarring, and postoperative inflammatory symptoms related to the eye. The authors used an upper eyelid crease approach to overcome these problems and investigate the usefulness of this approach. METHODS: Between 2009 and 2011, the authors used this approach in 22 patients with medial orbital wall fractures. Incisions were performed on the medial one-third of the crease and a 2- to 3-mm superomedial extension along a relaxed skin tension line. RESULTS: Postoperative computed tomographic scans demonstrated complete reduction and accurate reconstitution of the bony defect in all cases. The initial two cases had revision to correct the implant position. Follow-up ranged from 8 to 28 months, with an average of 12 months. Complications related to the operation were not observed. Diplopia and limitation of eye movement resolved in most cases. Two patients had persistent diplopia for more than 6 months that decreased with time. Enophthalmos of more than 2 mm was not observed in any orbit. The operative scar was inconspicuous. CONCLUSIONS: This approach provides several advantages, including ease of exposure, and is more familiar to the plastic surgeon than the transconjunctival approach. There is little need to retract the globe laterally, thus minimizing postoperative inflammatory symptoms related to the eye. Therefore, the authors suggest that this method should be considered as a natural and useful surgical approach to medial orbital blowout fractures. PMID- 23018701 TI - The effect of the columellar strut graft on nasal tip position in primary rhinoplasty. AB - BACKGROUND: The columellar strut cartilage graft has historically been assumed to be a technique that increases tip projection. The purpose of this study was to retrospectively analyze a series of 100 consecutive rhinoplasty cases by the senior author (R.J.R.) with a specific focus directed toward the effect of the columellar strut on final tip position, namely, tip projection and tip rotation. METHODS: Medical information and digital images were obtained from 100 consecutive primary rhinoplasty patients. All postoperative images were obtained from 1-year or greater follow-up visits. Preoperative and postoperative digital images were compared using a software application that quantitatively analyzed various facial anatomical features, including the nasofrontal angle, the nasolabial angle, tip projection, and tip translation. RESULTS: Tip projection (defined as the tip position on the x axis) actually decreased in 65 percent, increased in 27 percent, and was unchanged in 8 percent of subjects. Tip translation (defined as the tip position on the y axis) was decreased in 59 percent, increased in 34 percent, and unchanged in 7 percent. The nasofrontal angle was increased in 67 percent, decreased in 23 percent, and unchanged in 10 percent of patients. The nasolabial angle was increased in 46 percent, decreased in 34 percent, and unchanged in 20 percent. CONCLUSION: Use of the columellar strut cartilage graft does not necessarily imply an increase in tip projection, but rather serves as a means of unifying the nasal tip and helping to control final tip position. PMID- 23018702 TI - Gluteal augmentation: technique, indications, and implant selection. AB - Silicone implants have been used for gluteal augmentation for the past 40 years. Several techniques have been described for cosmetic purposes, but many plastic surgeons do not feel that performing the operation is safe. In this article, a technique is described to reduce the complication rate, improve the final results, and develop an easy way of understanding and learning this procedure. Based on surgical simulation involving 10 fresh cadavers, the authors have determined the goals for making the operation simpler and safer. One hundred three patients have undergone the operation performed by the staff or by the plastic surgery resident under supervision. There was seroma in 3.88 percent, dehiscence of the sutures in 5.8 percent, infection and removal of the implant in one case (0.97 percent), and no hematoma. The patient satisfaction rate was high. Anatomical dissections allowed the authors to gain experience and confidence regarding the plane of undermining, avoiding damage to the sciatic nerve, and the placement of the prosthesis, keeping it in place. The technique is easy to understand and learn. PMID- 23018703 TI - Pubic contouring after massive weight loss in men and women: correction of hidden penis, mons ptosis, and labia majora enlargement. AB - BACKGROUND: Weight gain and subsequent weight loss usually result in unsightly large fat deposition in the pubic areas along with ptosis of the fat pad and skin. Men also complain of burying of the penis and the woman complains of labia majora enlargement, both causing secondary sexual dysfunction, hygiene issues, discomfort, and aesthetic concerns. Even with weight loss, most of these deformities persist. METHODS: The hidden (buried) penis is characterized by a lack of firm attachments between the Buck fascia surrounding the tunica albuginea of the corpora and the dartos fascia and skin. Successful treatment requires the penile skin and dartos fascia to be stabilized to the penile corporal bodies to make the penis one integrated unit. The method of surgery is usually to excise and lift excess pubic skin, eliminate the pubic fat without creating a significant pubic concavity, and stabilize the penile skin to the corporal bodies with tacking sutures dorsally and ventrally. If inadequate penile skin is present, scrotal flaps or skin grafts are used to cover the penis. Treatment of the mons pubis requires similar pubic lifting, fat excision, and pubic tacking. Labia majora reduction requires skin and usually fat excision. RESULTS: Results are excellent with the use of these techniques. CONCLUSIONS: Pubic contouring after massive weight loss in men and women is very successful and safe if performed meticulously. Treatment improves self-esteem along with the associated physical and aesthetic deformities. PMID- 23018704 TI - Bariatric surgery for the management of obesity: state of the field. AB - BACKGROUND: Obesity, defined as a body mass index (weight in kilograms divided by the square of height in meters) greater than 30, has been increasing in incidence over the past 20 years. The treatment of obesity has evolved in concert with this growing obesity epidemic. Bariatric surgery is the only intervention found to consistently induce sustained weight loss that has also decreased the rate of concomitant diseases and mortality in this population. METHODS: The latest literature on the operative details and surgical outcomes of Roux-en-Y gastric bypass, sleeve gastrectomy, biliopancreatic bypass, and adjustable gastric banding procedures are reviewed in this article. RESULTS: Bariatric surgery is effective, safe, and well tolerated. CONCLUSION: Given the increasing incidence of morbid obesity and the effectiveness of bariatric surgery for treating this disease, it will likely continue to increase in popularity. PMID- 23018705 TI - The choice of controls for providing validity and evidence in clinical research. AB - BACKGROUND: Selection of controls, a group of subjects who are identical to the treatment group in all aspects that affect the outcome except the intervention of interest, is a significant criterion for conducting a study in evidence-based medical research. Few studies emphasize the appropriate selection of control groups in the plastic surgery literature. METHODS: The authors performed a literature search in Plastic and Reconstructive Surgery from January 1, 2010, through December 31, 2011, for studies in which controls were needed. The number of studies using a control group, control selection criteria, and the characteristics of the control populations were evaluated. RESULTS: Three hundred twenty-seven articles were obtained from our search using the keywords "case control studies" and "retrospective cohort studies." Among these studies, 121 articles were studies conducted in humans. All of these studies based on the study design required a control group, yet only 63 studies (52 percent) had a comparative control group. Of these studies, the authors found biases regarding the choice of controls, including selection bias, misclassification bias, and chronology bias. CONCLUSIONS: The authors' review shows that 48 percent of the studies published in Plastic and Reconstructive Surgery that were required to have a control group failed to incorporate a well-defined control group. Specific details pertaining to the methods used and the success obtained with those methods in recruiting controls need to be stated explicitly in the article to ensure uniformity and to support the validity of the research. PMID- 23018706 TI - Globalization of plastic surgery: the world of plastic and reconstructive surgery in Brazil. PMID- 23018707 TI - Beyond the checklist: achieving practice excellence. PMID- 23018710 TI - Contradicting an established mantra: microsurgeon experience determines free flap outcome. AB - BACKGROUND: Since the inception and popularization of microsurgery in the 1960s and 1970s, it has been commonly accepted that the outcome of free tissue transfer directly correlates with surgeon experience. METHODS: The clinical outcomes of three young microsurgeons at a single institution were retrospectively reviewed. Free flaps performed by these individuals were categorized according to the surgeon's years of practice and analyzed using statistical methods. RESULTS: A total of 410 free flaps were identified. No correlation was found between the surgeon's years of experience and the outcomes measured. CONCLUSIONS: There has been increased exposure to microsurgery during plastic surgery training at many programs, and consequently, residents have often already surpassed the learning curve. The imperfect correlation between experience and superior outcomes in medicine serves to suggest that further research in the specific underlying principles of surgical learning is needed to understand the relationship between experience and superior surgical outcomes. PMID- 23018712 TI - Discussion: Current status of implant-based breast reconstruction in patients receiving postmastectomy radiation therapy. PMID- 23018711 TI - Current status of implant-based breast reconstruction in patients receiving postmastectomy radiation therapy. AB - BACKGROUND: Increasing numbers of patients with breast cancer are being treated with postmastectomy radiation therapy. The author reviewed the literature to determine the clinical impact of this increasing use of postmastectomy radiation therapy in patients with breast cancer who desire implant-based breast reconstruction. METHODS: The author searched the MEDLINE database for articles on breast reconstruction and radiation therapy published between January of 2008 and June of 2011 and reviewed the abstracts of those articles to identify articles with information about the impact of irradiation on implant-based breast reconstruction. This subgroup of articles was reviewed in detail. RESULTS: Two hundred eighty-five articles were identified. Nineteen articles were reviewed in detail. Eight articles provided level III evidence; one provided level I or II evidence from high-quality multicenter or single-center randomized controlled trials or prospective cohort studies. Two articles provided level IV evidence from case series and were included in the review because they offered a novel approach or perspective. The most recent studies find a significant need for unplanned or major corrective surgery in irradiated breasts reconstructed with implants. Although breast implant reconstruction in irradiated breasts is associated with high rates of complications, only a minority of patients require conversion to an autologous tissue flap. CONCLUSION: Although the majority of patients who undergo implant-based reconstruction and irradiation ultimately keep the implant reconstruction, patient surveys show that irradiation has a significantly negative effect on patient satisfaction. PMID- 23018713 TI - Biomechanical comparison of calcium phosphate cements for split cranial bone graft donor sites. AB - BACKGROUND: Although harvesting of in situ split cranial bone is a well established technique, few data have been generated regarding the biomechanical effect of bone harvest on the cranial bone donor site, and even fewer data have been generated regarding the biomechanical effect of calcium phosphate bone cement inlay on the donor site. The authors documented the weakening of the skull at the in situ cranial harvest site and determined the benefit, if any, when the site is inlayed with calcium phosphate cements. METHODS: Cadaver skulls were divided into three groups: group 1, an in situ cranial bone defect was created in the frontal bone area on one side and the mirror-image, full-thickness area was untreated; group 2, a similar defect was created in the parietal area and repaired with calcium phosphate bone cement inlay, and on the opposite side, a similar defect was created but not repaired; and group 3, donor sites were created in the parietal area bilaterally and reconstructed with different cements. Mirror-image areas were harvested and testing was performed. The Wilcoxon rank sum test was used to evaluate all mirror-image specimens. RESULTS: There was a statistically significant difference in strength to fracture when the in situ defect was compared with the in situ calcium phosphate construct (p = 0.008). No difference was demonstrated when the defect was compared with full thickness bone or when calcium phosphate cements were compared. CONCLUSION: Repair of the defect with calcium phosphate cement significantly increased strength at the donor site and may provide added safety from injury. PMID- 23018714 TI - A comparison between barbed and nonbarbed absorbable suture for fascial closure in a porcine model. AB - BACKGROUND: The use of knotless barbed sutures has shortened operation times for wound closure. In experimental models, their use in tendon surgery is still under investigation. This study looks at the use of barbed sutures in a porcine model for fascial repair when compared with traditional absorbable suture to further extend their clinical use. METHODS: Six animals were included in this study. Each had two paramedian incisions, down to the fascia at the junction between the lateral edge of the rectus abdominis muscle and the transverse abdominis/oblique muscles of the abdominal wall. One fascial incision was closed with 2-0 Quill polydioxanone barbed suture and the other was closed with the control suture 1-0 PDS II (polydioxanone). The overlying skin was closed with Quill polydioxanone barbed suture for both incisions. At 6 weeks, the fascia was excised and the suture lines were tested for tensile strength. RESULTS: There were no wound infections and no incisional hernias. The Quill polydioxanone barbed suture had a mean tissue tensile strength of 265.59 N (range, 206.86 to 306.38 N) and the control suture (polydioxanone) had a mean tissue tensile strength of 227.28 N (range, 132.79 to 290.35 N). The difference was not statistically significant (p = 0.341). CONCLUSIONS: This study demonstrated that barbed sutures for fascial repair have equivalent tensile strength when compared with traditional nonbarbed sutures, with no adverse events such as wound dehiscence or incisional hernia. This preclinical study lends support to the practice of using barbed sutures for indications such as rectus sheath plication. PMID- 23018715 TI - A prospective study of preoperative computed tomographic angiographic mapping of free fibula osteocutaneous flaps for head and neck reconstruction. AB - BACKGROUND: In designing an osteocutaneous fibula flap, poor planning, aberrant anatomy, or inadequate perforators may necessitate modification of the flap design, exploration of the contralateral leg, or additional flap harvest. The authors studied the predictive power of computed tomographic angiography in osteocutaneous fibula flap planning and execution. METHODS: The authors studied a prospective cohort of 40 consecutive patients who underwent preoperative computed tomographic angiography mapping of the peroneal artery and its perforators and subsequent free fibula flap reconstruction of mandibular or maxillary defects. The authors compared their analysis of perforator anatomy, peroneal artery origin, and fibula length with intraoperative clinical findings. RESULTS: Overall, computed tomographic angiography identified 94.9 percent of the cutaneous perforators found intraoperatively. Clinically, perforators were located an average of 8.7 mm from their predicted locations. The peroneal artery origin from the tibioperoneal trunk averaged 6.0 mm from its predicted location. The average length of the fibula differed from the predicted length by 8.0 mm. Computed tomographic angiography accurately predicted perforators as either septocutaneous or musculocutaneous 93.0 percent of the time. Perforator size was accurately predicted 66.7 percent of the time. Skin islands and osteotomies were modified in 25.0 percent of the cases on the basis of computed tomographic angiography findings. Two patients had hypoplastic posterior tibial arteries, prompting selection of the contralateral leg. There were no total flap or skin paddle losses. CONCLUSIONS: Computed tomographic angiography accurately predicted the course and location of the peroneal artery and perforators; perforator size was less accurately estimated. Computed tomographic angiography provides valuable information to facilitate osteocutaneous fibula flap harvest. PMID- 23018716 TI - Tracking the learning curve in microsurgical skill acquisition. AB - BACKGROUND: Despite advances in surgical training, microsurgery is still based on an apprenticeship model. To evaluate skill acquisition and apply targeted feedback to improve their training model, the authors applied the Structured Assessment of Microsurgery Skills to the training of microsurgical fellows. They hypothesized that subjects would demonstrate measurable improvement in performance throughout the study period and consistently across evaluators. METHODS: Seven fellows were evaluated during 118 microsurgical cases by 16 evaluators over three 1-month evaluation periods in 1 year (2010 to 2011). Evaluators used the Structured Assessment of Microsurgery Skills questionnaire, which measures dexterity, visuospatial ability, operative flow, and judgment. To validate the data, microsurgical anastomoses in rodents performed by the fellows in a laboratory at the beginning and end of the study period were evaluated by five blinded plastic surgeons using the same questionnaire. Primary outcomes were change in scores between evaluation periods and interevaluator reliability. RESULTS: Between the first two evaluation periods, all skill areas and overall performance improved significantly. Between the second two periods, most skill areas improved, but only a few improved significantly. Operative errors decreased significantly between the first and subsequent periods (81 versus 36; p < 0.05). In the laboratory study, all skills were significantly (p < 0.05) or marginally (0.05 <= p < 0.10) improved between time points. The overall interevaluator reliability of the questionnaire was acceptable (alpha = 0.67). CONCLUSIONS: The Structured Assessment of Microsurgery Skills questionnaire is a valid instrument for assessing microsurgical skill, providing individualized feedback with acceptable interevaluator reliability. Use of the questionnaire is anticipated to enhance microsurgical training. PMID- 23018717 TI - Limb length differences after obstetrical brachial plexus injury: a growing concern. AB - BACKGROUND: Residual size discrepancy between the affected and unaffected limbs is a distinct but not well-understood consequence of an obstetrical brachial plexus injury. This study aimed to document the extent of limb length differences in children with obstetrical brachial plexus injury compared with typically developing children. The effects of age, growth patterns, severity, and surgical intervention were also explored. Also, this study examined the reliability of the clinical measurement technique. METHODS: A prospective cohort of 179 children with obstetrical brachial plexus injury was systematically evaluated for limb length and girth by a multidisciplinary team. Clinical measurements were obtained at regular intervals until 12 months and then yearly. A control group of typically developing children aged 6 months to 17 years had limb length and girth measured on one occasion. RESULTS: Interrater reliability of clinical measurement techniques demonstrated high consistency, with an intraclass correlation of 0.90 (p < 0.0001). Limb measurements were recorded at nine time points. Paired t tests of children with and without surgical intervention found significant differences between affected and unaffected sides in arm, forearm, and total length as early as the 1-month measurement and at most other time points (p < 0.05). The 3-month total limb length difference was a statistically significant predictor of 12 month limb length difference (p < 0.05). CONCLUSIONS: Obstetrical brachial plexus injury significantly affects the length of the arm and forearm. Early detectable limb length deficits are associated with the likelihood of requiring surgical reconstruction. Clinical limb length measurement can be performed reliably and noninvasively. PMID- 23018718 TI - Children with Apert syndrome as adults: a follow-up study of 28 Scandinavian patients. AB - BACKGROUND: Apert syndrome (acrocephalosyndactyly type 1) includes craniofacial deformities, malformations of the extremities and the central nervous system, and often mental retardation. The aim of this study was to investigate the life situation of adult patients with Apert syndrome. METHODS: Thirty-three patients with Apert syndrome born before 1990 were identified in the Goteborg craniofacial registry. The authors used a questionnaire mainly dealing with education, employment, social relations, and quality of life. A matched control group was created for comparison. RESULTS: Five of the patients had died. Twenty-four of the remaining patients answered the questionnaire. The level of education was lower in patients than in controls (p = 0.007), but there was no significant difference in the extent of employment between the two groups. The difference in housing was significant (p < 0.001) and the majority of patients lived with their parents. Patients were less often married (p < 0.001), had fewer friends (p < 0.001), and had less experience with sexual relationships (p < 0.001). The somatic health was lower in patients [e.g., they had more hearing problems (p < 0.001) and more epilepsy (p = 0.005)]. Depressive mood periods were more common in patients (p < 0.001), but there was no difference between the groups regarding a generally positive attitude toward life. CONCLUSIONS: This study shows that patients with Apert syndrome manage relatively well in adulthood. The discrepancy in social relations between the Apert patients and the healthy control group indicates that further improvement of the treatment is desirable. PMID- 23018719 TI - Speech outcome after palatal repair in nonsyndromic versus syndromic Robin sequence. AB - BACKGROUND: The authors' purpose was to document speech outcome after cleft palate repair in patients with syndromic versus nonsyndromic Robin sequence. Results of secondary correction of velopharyngeal insufficiency using a superiorly based pharyngeal flap or double-opposing Z-palatoplasty are also reported. METHODS: Charts of patients with Robin sequence and cleft palate between 1980 and 2007 were reviewed. Data collected included date of birth, sex, syndrome/association, cleft palatal type (Veau I or II), age at palatoplasty, incidence of palatal fistula, postoperative speech assessment, videofluoroscopic results, need for secondary operation for velopharyngeal insufficiency, and type of secondary operation (pharyngeal flap or double-opposing Z-palatoplasty). RESULTS: The authors identified 140 patients with Robin sequence who had palatal closure. Postoperative speech evaluation was available for 96 patients (69 percent). A syndrome or association was identified in 42 patients (30 percent). Primary palatoplasty was successful in 74 patients (77 percent); speech was characterized as competent and competent to borderline competent. The authors found a significantly higher incidence of velopharyngeal insufficiency following palatal repair for syndromic (38 percent) than nonsyndromic Robin sequence (16 percent). (p = 0.039). In patients with velopharyngeal insufficiency, competent or borderline competent speech was determined after double-opposing Z palatoplasty (two of five patients) or pharyngeal flap (eight of 10 patients). CONCLUSIONS: The rate of velopharyngeal insufficiency in syndromic Robin sequence is significantly greater than in nonsyndromic Robin sequence. The authors prefer pharyngeal flap for velopharyngeal insufficiency in patients with Robin sequence, whether syndromic or nonsyndromic, without retrognathism or signs/symptoms of obstructive sleep apnea. PMID- 23018720 TI - Pearls and perils of caring for the postbariatric body contouring patient. AB - Postbariatric body contouring surgery has grown in prevalence, mirroring the ascent of weight loss surgery. With the rise in prevalence of this subset of plastic surgery procedures, we are gaining wisdom about technique, safety, and outcomes associated with this patient population. The pearls of patient management include discussion about characteristics specific to massive weight loss patients, patient preparation for surgery, intraoperative safety measures, markings, surgical options in a landscape of scars, management of the total body lift, volumetric augmentation, and postoperative care. The aim of this review is to share these pearls and pitfalls to assist in patient management and in optimization of outcomes. PMID- 23018721 TI - Breast augmentation. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Cite the key concepts in the process of breast augmentation that optimize outcomes; 2. Cite key components of tissue-based planning for implant selection; 3. Discuss complications and risks of breast augmentation. SUMMARY: Breast augmentation remains one of the top surgical procedures performed by plastic surgeons. Current literature supports the concept that breast augmentation outcomes are optimized using a concept of "the process of breast augmentation." Breast augmentation is often thought of as a surgical procedure; however, the nonsurgical aspects of the procedure are more important for optimizing outcomes and minimizing reoperation and complications. The process of breast augmentation includes patient education, tissue-based preoperative planning, refined surgical technique, and defined postoperative management. This CME article reviews and discusses the current relevant topics and issues surrounding breast implants. There are also supporting videos to enhance the reader's experience. CME questions are present at the end for a self-assessment. PMID- 23018722 TI - Incidence of breast hematoma after placement of breast prostheses. PMID- 23018724 TI - Risk factors for eventful outcomes following skin-sparing mastectomy and immediate prosthetic reconstruction. PMID- 23018726 TI - Re: Does knowledge of the initial technique affect outcomes after repeated breast reduction? PMID- 23018727 TI - The BREAST-Q: further validation in independent clinical samples. PMID- 23018729 TI - The effects of ketorolac on microvascular thrombosis in lower extremity reconstruction. PMID- 23018731 TI - Simplified negative-pressure wound therapy system for skin graft wounds. PMID- 23018732 TI - Should plastic surgeons operate on patients diagnosed with body dysmorphic disorders? PMID- 23018734 TI - A modified template for microtia reconstruction tested by surgical simulation on Ipomoea batatas. PMID- 23018735 TI - Ocular findings in children with orbital hypertelorism. PMID- 23018736 TI - Angular artery perforator flap for reconstruction of nasal sidewall and medial canthal defects. PMID- 23018737 TI - Successful replantation of upper lip avulsion injury using an arterialized venous anastomosis. PMID- 23018738 TI - The use of three-dimensional digital technology and additive manufacturing to create templates for soft-tissue reconstruction. PMID- 23018739 TI - Superiorly based single mastectomy flap with inferiorly based dermal flap and anchorage of the inframammary crease procedure for immediate breast reconstruction in patients with ptosis. PMID- 23018740 TI - A simple technique to enhance breast aesthetics using porcine acellular dermal matrix (Strattice) in breast reconstruction. PMID- 23018741 TI - The crossover composite filet of hand flap and heterotopic thumb replantation: a unique indication. PMID- 23018742 TI - Medical devices for aesthetic medicine: the four stages model for the search for the "Holy Grail". PMID- 23018743 TI - Versatility of a near-infrared vein visualization device in plastic and reconstructive surgery. PMID- 23018744 TI - Art, artistry, and plastic surgery. PMID- 23018745 TI - First perphenylated carbo-oligoacetylenes: an extension of the polytriacetylene family. AB - The first examples of a novel family of sp-carbon-rich n-pi-conjugated oligomers/polymers, namely carbo-mers of polyacetylene, also referred to as "1,4 PTA" isomers of the classical polytriacetylenes (1,2-PTAs), are described in the perphenylated series. The two first representatives proved to be stable in solution, and exhibit a zig-zag arrangement in the crystal state. The third member of the family, isolated in SnCl(2) matrix, proved to be stable in the solid state and was characterized by MALDI-TOF MS, (1)H NMR, CPMAS (13)C NMR, and absorption spectroscopy. An explanation for its reactivity in solution is proposed. The chromophoric properties in the visible region are shown to vary significantly and consistently along the series. PMID- 23018746 TI - Why imatinib remains an exception of cancer research. AB - The archetype driving the drug targeting approach to cancer therapy is the success of imatinib against chronic phase chronic myeloid leukemia (CML-CP). Molecular targeting success of this magnitude has yet to be repeated for most solid tumors. To answer why imatinib remains an exception of cancer research, we summarize key features and patterns of evolution that contrast CML-CP from prostate cancer, an example of a solid tumor that also shares a signature fusion gene. Distinctive properties of CML-CP include: a large cell population size that is not geographically constrained, a highly penetrant dominant oncogene that sweeps the entire cell population, subsequent progressive and ordered clonal genetic changes, and the effectiveness of molecular targeting within the chronic phase, which is comparable to the benign phase of solid tumors. CML-CP progression resembles a clonal, stepwise model of evolution, whereas the pattern of solid tumor evolution is highly dynamic and stochastic. The distinguishing features and evolutionary pattern of CML-CP support why the success of imatinib does not carry over to most solid tumors. Changing the focus of cancer research from a gene-based view to a genome-based theory will provide insight into solid tumor evolutionary dynamics. PMID- 23018749 TI - Leveraging the electronic health record to implement genomic medicine. PMID- 23018750 TI - Health behaviors and cancer screening among Californians with a family history of cancer. AB - PURPOSE: The purpose of this study was to compare health behaviors and cancer screening among Californians with and without a family history of cancer. METHODS: We analyzed data from the 2005 California Health Interview Survey to ascertain cancer screening test use and to estimate the prevalence of health behaviors that may reduce the risk of cancer. We used logistic regression to control for demographic factors and health-care access. RESULTS: Women with a family history of breast or ovarian cancer were more likely to be up to date with mammography as compared with women with no family history of cancer (odds ratio = 1.69, 95% confidence interval (1.39, 2.04)); their health behaviors were similar to other women. Men and women with a family history of colorectal cancer were more likely to be up to date with colorectal cancer screening as compared with individuals with no family history of cancer (odds ratio = 2.77, 95% confidence interval (2.20, 3.49)) but were less likely to have a body mass index <25 kg/m(2) (odds ratio = 0.80, 95% confidence interval (0.67, 0.94)). CONCLUSION: Innovative methods are needed to encourage those with a moderate-to-strong familial risk for breast cancer and colorectal cancer to increase their physical activity levels, strive to maintain a healthy weight, quit smoking, and reduce alcohol use.Genet Med 2013:15(3):212-221. PMID- 23018753 TI - Neurochemical imaging and depressive behaviours. AB - Neurochemical imaging is frequently applied to measure markers of pathological change so as to understand mechanisms that create symptoms of major depressive disorder. For example, indices of greater monoamine oxidase A(MAO-A) level, particularly in the prefrontal and anterior cingulate cortex, are associated with depressed mood states, and high-risk states for onset of major depressive episodes. MAO-A metabolises monoamines, and greater metabolism of monoamines occurs when MAO-A is elevated in brain. Lower extracellular serotonin is associated with greater pessimism in humans and chronic serotonin deficiency is associated with upregulation of 5-HT2A (serotonin2A) receptors in cortex. During major depressive episodes when pessimism is more severe, greater 5-HT2A BPND, an index of density occurs in prefrontal and anterior cingulate cortex. These results argue for a mechanism of lowering extracellular serotonin in the prefrontal and anterior cingulate cortex, consequent to elevated MAO-A level. The relationship between elevated 5-HTT BPND and greater pessimism during major depressive episodes suggests that greater 5-HTT density in the context of elevated MAO-A level further contributes to serotonin deficiency in these brain regions. A similar mechanism may explain the association between neuroimaging indices of greater dorsal striatal D2 density, DAT density and symptoms of motor retardation: Greater MAO-A level and relatively greater DAT density lower extracellular dopamine in the dorsal striatum, leading to motor retardation. Indices of greater 5-HT1A density, particularly in the cingulate cortex, have been associated with major depressive disorder, and well as anxiety disorders, suggesting that this abnormality is mechanistically related to presence of anxiety symptoms. To date, abnormalities of Glx a measure reflecting glutamate and glutamine levels have been most strongly associated with presence of major depressive episodes, with greater levels in occipital cortex, and reduced levels in prefrontal cortex. Ultimately, the future for neurochemical imaging is to better understand the mechanisms that predispose toward onset of MDE so as to create biologically informed, novel, methods of prevention, and superior, more symptom-targeted treatments. PMID- 23018751 TI - Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity. AB - PURPOSE: Sickle cell disease is estimated to occur in 1:300-400 African-American births, with higher rates among immigrants from Africa and the Caribbean, and is less common among Hispanic births. This study determined sickle cell disease incidence among New York State newborns stratified by maternal race/ethnicity and nativity. METHODS: Newborns with confirmed sickle cell disease born to New York State residents were identified by the New York State newborn screening program for the years 2000-2008 and matched to birth records to obtain birth and maternal information. Annual incidence rates were computed and bivariate analyses were conducted to examine associations with maternal race/ethnicity and nativity. RESULTS: From 2000 to 2008, 1,911 New York State newborns were diagnosed with sickle cell disease and matched to the birth certificate files. One in every 1,146 live births was diagnosed with sickle cell disease. Newborns of non Hispanic black mothers accounted for 86% of sickle cell disease cases whereas newborns of Hispanic mothers accounted for 12% of cases. The estimated incidence was 1:230 live births for non-Hispanic black mothers, 1:2,320 births for Hispanic mothers, and 1:41,647 births for non-Hispanic white mothers. Newborns of foreign born non-Hispanic black mothers had a twofold higher incidence of sickle cell disease than those born to US-born non-Hispanic black mothers (P < 0.001). CONCLUSION: This study provides the first US estimates of sickle cell disease incidence by maternal nativity. Women born outside the United States account for the majority of children with sickle cell disease born in New York State. Such findings identify at-risk populations and inform outreach activities that promote ongoing, high-quality medical management to affected children. PMID- 23018752 TI - 1q21.1 Microduplication expression in adults. AB - PURPOSE: Rare, recurrent chromosome 1q21.1 duplications have been associated with developmental delay, congenital anomalies, and macrocephaly in children. Data on adult clinical expression would help to inform genetic counseling. METHODS: A systematic review of 22 studies reporting 107 individuals (59 children and 48 adults) with 1q21.1 duplications was conducted. We compiled the available phenotypic data to attempt to identify the most highly associated clinical features and to determine expression in adults. We also report on seven adult cases newly identified in the studies of schizophrenia and tetralogy of Fallot at our center. RESULTS: Five cases were ascertained as controls, 32 as relatives of probands, and 70 as having clinical features: autism spectrum disorder (n = 15), congenital heart disease (n = 12), schizophrenia (n = 10), or other, mostly developmental, features (n = 33). The 1q21.1 duplication was significantly enriched in the cohorts with schizophrenia (P = 0.0155) and tetralogy of Fallot (P = 0.0040) at our center as compared with controls. There was a paucity of clinical data for adults; the most common features, other than those used for ascertainment, included macrocephaly and abnormalities of possible connective tissue origin (e.g., carpal tunnel syndrome). CONCLUSION: Further data are needed to characterize lifetime expression of 1q21.1 duplications. These initial results, however, suggest that anticipatory care should include attention to later-onset conditions such as schizophrenia. PMID- 23018754 TI - Genetic analysis of NR0B1 in congenital adrenal hypoplasia patients: identification of a rare regulatory variant resulting in congenital adrenal hypoplasia and hypogonadal hypogonadism without testicular carcinoma in situ. AB - There have been few testicular histology reports of adult patients with congenital adrenal hypoplasia/hypogonadal hypogonadism (AHC/HH), but Leydig cell hyperplasia has been observed, an indicator of the possibility of malignant transformation. We aimed to define the basis of AHC/HH in 4 pedigrees of different ethnic backgrounds. One patient was elected to have testicular biopsy which was examined for evidence of carcinoma in situ (CIS). NR0B1 mutation analysis was performed by sequence analysis. NR0B1 expression was investigated by RT-PCR. Testicular biopsy sections were stained with HE or immunostained for OCT3/4, an established marker of CIS. We identified NR0B1 variants in the 4 AHC pedigrees: pedigree 1 (United Arab Emirates), c.1130A>G predicting p.(Glu377Gly); pedigree 2 (English Caucasian), c.327C>A predicting p.(Cys109*); pedigree 3 (Oman), a 6-bp deletion of a direct repeat, c.857_862delTGGTGC predicting p.(Leu286_Val287del); pedigree 4 (English Caucasian), c.1168+1G>A, a regulatory variant within the NR0B1 splice donor site. This last male patient, aged 30 years, presented with evidence of HH but incomplete gonadotrophin deficiency, following an earlier diagnosis of Addison's disease at 3 years. Hormonal therapy induced virilisation. Testicular biopsy was performed. The c.1168+1G>A variant abrogated normal splicing of testicular mRNA. Histological examination showed poorly organised testicular architecture and absence of spermatozoa. Morphological analyses and the absence of immunohistochemical staining for OCT3/4 excluded the presence of malignant germ cell cancer and its precursor lesion, CIS. These studies add to the knowledge of the types and ethnic diversity of NR0B1 mutations and their associated phenotypes, and provide insight into the assessment and interpretation of testicular histology in AHC and HH. PMID- 23018755 TI - A case of fatal fulminant myocarditis presenting as an acute ST-segment elevation myocardial infarction and persistent ventricular tachyarrhythmia associated with influenza A (H1N1) virus in a previously healthy pregnant woman. AB - Several studies have reported influenza A (H1N1) virus as a cause of fulminant myocarditis. We report the first fatal case of fulminant myocarditis presenting as an acute ST-segment elevation myocardial infarction and ventricular tachyarrhythmia associated with influenza A (H1N1) in a previously healthy pregnant woman. A 38-year-old Asian woman, gravida 3, para 1-0-1-1, presented with flu-like symptoms. Initially, she developed wide-complex tachycardia requiring several defibrillations and was later intubated. Electrocardiogram showed ST-segment elevation. Coronary angiogram was negative and a pulmonary angiogram ruled out pulmonary embolism. Fetal compromise was noted on the monitor, and the patient underwent an emergent cesarean section. She subsequently expired. Autopsy confirmed severe myocarditis. Further testing confirmed influenza A (H1N1) virus. This case of a rare, yet lethal, complication of H1N1 infection underscores the importance of increased awareness among health care professionals to provide pregnant women with vaccination and prompt treatment. PMID- 23018756 TI - High-intensity diode laser in combination with bipolar transurethral resection of the prostate: a new strategy for the treatment of large prostates (>80 ml). AB - BACKGROUND AND OBJECTIVE: The ideal treatment of large prostates with symptomatic benign prostatic hyperplasia (BPH) remains controversial. We compare the efficacy and safety of monopolar transurethral resection of the prostate (TURP) with high intensity diode laser in combination with bipolar TURP (DL + b-TURP) in the treatment of large prostates. MATERIALS AND METHODS: We retrospectively analyzed all patients with lower urinary tract symptoms (LUTS) secondary to BPH with prostates larger than 80 ml, undergoing monopolar TURP (n = 36) or DL + b-TURP (n = 37) between January 2008 and March 2010. The preoperative and follow-up functional parameters including International Prostate Symptom Score (IPSS), post void residual urine (PVR), maximum flow rate (Q(max) ), quality of life score (QoLs), prostate size, and prostate-specific antigen (PSA) were assessed. The operative data, peri- and post-operative complications were also recorded. RESULTS: The demographic data were comparable between the two groups. Preoperative prostate volume was 110.8 +/- 28.9 ml in the DL + b-TURP group and 103.7 +/- 31.2 ml in the TURP group. TURP group had significantly shorter operative time; however, the catheterization time and hospital stay were in favor of the DL + b-TURP group (P < 0.001). The decrease in hemoglobin was statistically significantly greater in the TURP group. Late complications were also comparable. Both groups could achieve significant improvements in functional outcomes during the follow-up of 24 months. CONCLUSIONS: With regard to the operative safety and functional results, high-intensity diode laser combined with bipolar TURP is feasible for BPH treatment with large prostates. PMID- 23018759 TI - Precursor flow rate manipulation for the controlled fabrication of twin-free GaAs nanowires on silicon substrates. AB - Vertically oriented GaAs nanowires (NWs) are grown on Si(111) substrates using metal-organic chemical vapor deposition. Controlled epitaxial growth along the <111> direction is demonstrated following the deposition of thin GaAs buffer layers and the elimination of structural defects, such as twin defects and stacking faults, is found for high growth rates. By systematically manipulating the AsH(3) (group-V) and TMGa (group-III) precursor flow rates, it is found that the TMGa flow rate has the most significant effect on the nanowire quality. After capping the minimal tapering and twin-free GaAs NWs with an AlGaAs shell, long exciton lifetimes (over 700 ps) are obtained for high TMGa flow rate samples. It is observed that the Ga adatom concentration significantly affects the growth of GaAs NWs, with a high concentration and rapid growth leading to desirable characteristics for optoelectronic nanowire device applications including improved morphology, crystal structure and optical performance. PMID- 23018760 TI - Antimicrobials: Strategies for targeting obesity and metabolic health? AB - Obesity is associated with a number of serious health consequences, including type 2 diabetes, cardiovascular disease and a variety of cancers among others and has been repeatedly shown to be associated with a higher risk of mortality. The relatively recent discovery that the composition and metabolic activity of the gut microbiota may affect the risk of developing obesity and related disorders has led to an explosion of interest in this distinct research field. A corollary of these findings would suggest that modulation of gut microbial populations can have beneficial effects with respect to controlling obesity. In this addendum, we summarize our recent data, showing that therapeutic manipulation of the microbiota using different antimicrobial strategies may be a useful approach for the management of obesity and metabolic conditions. In addition, we will explore some of the mechanisms that may contribute to microbiota-induced susceptibility to obesity and metabolic diseases. PMID- 23018763 TI - Application of pharmacokinetics-pharmacodynamics/clinical response modeling and simulation for biologics drug development. AB - Biologics, specifically monoclonal antibody (mAb) drugs, have unique pharmacokinetic (PK) and pharmacodynamic (PD) characteristics as opposed to small molecules. Under the paradigm of model-based drug development, PK-PD/clinical response models offer critical insight in guiding biologics development at various stages. On the basis of the molecular structure and corresponding properties of biologics, typical mechanism-based [target-mediated drug disposition (TMDD)], physiologically based PK, PK-PD, and dose-response meta analysis models are summarized. Examples of using TMDD, PK-PD, and meta-analysis in helping starting dose determination in first-in-human studies and dosing regimen optimization in phase II/III trials are discussed. Instead of covering the entirety of model-based biologics development, this review focuses on the guiding principles and the core mathematical descriptions underlying the PK or PK PD models most used. PMID- 23018764 TI - Glioma cell growth inhibition following photochemical internalization enhanced non-viral PTEN gene transfection. AB - BACKGROUND AND OBJECTIVE: One of many limitations for cancer gene therapy is the inability of the therapeutic gene to transfect a sufficient number of tumor cells. Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. The utility of PCI for the delivery of the GFP reporter gene on the same plasmid as a tumor suppressor gene (PTEN) was investigated in monolayers of U251 human glioma cells and muticell U87 glioma spheroids. MATERIALS AND METHODS: U251 monolayers or U87 spheroids were incubated in AlPcS(2a) and non-viral vector polyplexes for 18 hours. In all cases, light treatment was performed with a diode laser at a wavelength of 670 nm. The non-viral transfection agents, branched polyethylenimine (bPEI), or protamine sulfate (PS), were used with the plasmid constructs GFP/PTEN or GFP. RESULTS: PS/GFP polyplexes were much less toxic to the glioma cells compared to bPEI/GFP polyplexes but were highly inefficient at gene transfection if used alone. PCI resulted in a 5- to 10-fold increase in GFP protein expression compared to controls. PCI-bPEI/PTEN or PCI-PS/PTEN transfection of either U251 monolayers or U87 spheroids significantly inhibited their growth. but had no effect on MCF-7 cells containing a wild-type PTEN gene. In addition PCI-GFP transfection of gliomas cells had no effect on their growth pattern. CONCLUSIONS: Collectively, the results suggest that AlPcS(2a) -mediated PCI can be used to enhance cell growth inhibition via transfection of tumor suppressor genes in glioma cells containing mutant PTEN genes. PMID- 23018765 TI - Volumetric and functional assessment of ventricles in pulmonary hypertension on 3 dimensional echocardiography. AB - BACKGROUND: Non-invasive assessment of volume and function on the right ventricle (RV) for pulmonary hypertension (PH) is limited. METHODS AND RESULTS: Patients with PH (n=23) underwent 3-dimensional (D) echocardiography (3DECHO), with cardiac magnetic resonance imaging to confirm its precision, and right heart catheterization. On linear regression analysis the RV end-systolic volume index (ESVI) was positively correlated with pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (mPAP; R=0.42 and 0.46, P=0.03 and 0.03, respectively). The RV end-diastolic volume index (EDVI) was positively correlated with mPAP (R=0.41, P<0.05). The left ventricular (LV) EDVI was inversely correlated with PVR (R=-0.48, P=0.02). The RV ejection fraction was inversely correlated with PVR and mean right atrial pressure (mRAP; R=-0.57, and -0.45, P=0.004, and 0.03, respectively). RVEDVI/LVEDVI and RVESVI/LVESVI (the diastolic and systolic remodeling indices, respectively) had a significantly positive linear relationship with PVR (R=0.67 and 0.55, P=0.0005 and 0.006, respectively), and the former had a significantly positive linear relationship with mRAP (R=0.42, P<0.05). During the recovery process in 1 specific case, the remodeling indices maintained a significant linear relationship with the hemodynamic parameters. CONCLUSIONS: Novel indices provided by 3DECHO may be utilized as alternative indicators of hemodynamic changes in PH patients. PMID- 23018766 TI - Impact of cardiometabolic risk factors on major cardiovascular events in patients with familial combined hyperlipidemia. AB - BACKGROUND: Familial combined hyperlipidemia (FCH) is an inherited lipid disorder associated with premature cardiovascular disease. It has not been established whether the cardiometabolic risk factors, which frequently accompany FCH, such as diabetes, metabolic syndrome (MetS) and hypertension, modulate cardiovascular risk in FCH patients. METHODS AND RESULTS: In this single-center, retrospective study, 695 FCH patients with adequate follow-up were enrolled (mean age, 48.9 years; 455 male). Risk factors including lipid levels were evaluated before the initiation of treatment. Acute myocardial infarction (AMI) and cardiovascular death were recorded during a mean follow-up of 9 years. The combined endpoint (AMI and/or cardiovascular death) occurred in 41 patients (5.9% of the total). Those FCH patients who reached the combined endpoint had lower high-density lipoprotein cholesterol (HDL-C) than those who did not, but levels of other lipid variables were similar. Presence of hypertension, diabetes or MetS was a predictor of the combined endpoint on univariate Kaplan-Meier analysis (all P<0.005). Multivariate Cox proportional analysis showed that hypertension and MetS were associated with the combined endpoint independently of age, gender, HDL C and presence of coronary artery disease at enrollment (adjusted hazard ratios [HRs], 3.00; 95% confidence interval [CI]: 1.46-6.17, P=0.003; HR, 2.43; 95CI%: 1.11-5.33, P=0.026, respectively). CONCLUSIONS: Cardiometabolic risk factors such as hypertension and MetS are independent predictors of major cardiovascular events in FCH patients. PMID- 23018767 TI - Hyponatremia as a predictor for worsening heart failure in patients receiving cardiac resynchronization therapy. AB - BACKGROUND: Various factors associated with worsening heart failure (HF) events have been investigated in HF subjects. The purpose of this study was to identify the predictive factor(s) for worsening HF events after cardiac resynchronization therapy (CRT) among baseline parameters, as well as baseline factors associated with responsiveness or non-responsiveness to CRT. METHODS AND RESULTS: Seventy seven HF patients with an indication for CRT were enrolled. Baseline parameters of blood chemistry, electrocardiogram, echocardiogram and cardiac catheterization before device implantation were measured, and subsequent clinical HF events after CRT were investigated. During the follow-up period (median 601 days), 22 of 77 (29%) recipients had HF events (unscheduled HF hospitalization: 16; use of left ventricular assist system: 1; heart transplantation: 1; cardiac death: 4). In the multivariate Cox proportional hazards model, low serum sodium concentration was associated with the occurrence of HF events after CRT (hazard ratio 0.82, 95% confidence interval 0.68-0.99, P=0.034). At baseline, serum sodium concentration negatively correlated with pulmonary capillary wedge pressure (r=-0.71, P<0.001) and with plasma arginine vasopressin level (r=-0.68, P=0.008). CONCLUSIONS: Hyponatremia is an independent predictor for worsening HF events after CRT implantation, which may be partly explained by elevated level of plasma arginine vasopressin. PMID- 23018768 TI - Prevalence of allergic sensitization versus allergic rhinitis symptoms in an unselected population. AB - BACKGROUND: Allergic rhinitis (AR) is the most common allergic disorder and its prevalence has significantly increased worldwide, nowadays affecting up to 40% of the population in young adults. The objective of the present survey was to evaluate the prevalence of allergic sensitization and the prevalence of clinically diagnosed AR in a sample of the Belgian population, and to estimate the effect of age and gender. METHODS: We performed a cross-sectional population based study at an annual public fair in Ghent. Participants underwent a skin prick test (SPT) to 3 aeroallergens: a mix of trees (hazel, alder, and birch), grass pollen, and house dust mite (HDM). The clinical relevance of sensitization was assessed by relating relevant symptoms of AR to the corresponding SPT. RESULTS: A total of 2,320 participants (1,475 females, median age 44.7 years, range 3-86) were included in this study. The standardized prevalence rates of sensitization were 13.2% for tree mix, 25.9% for grass pollen, and 25.9% for HDM. Sensitization to at least one of the allergens was present in 40.3% of the subjects. Symptomatic sensitization related to trees was reported in 9.7% of cases, grass-related AR was 17.6%, and HDM-related AR was 17.1%. The overall prevalence of AR was 30.9%. CONCLUSION: In this study we demonstrated a 40.3% prevalence of a positive SPT to one or more common aeroallergens. A clinical diagnosis of AR was present in 30.9% of cases, peaking in the third and fourth decades of life. It is to be expected that in the next decades, when this generation grows older, the general AR prevalence will further increase. PMID- 23018769 TI - A survey of putative anxiety-associated genes in panic disorder patients with and without bladder symptoms. AB - BACKGROUND: We have previously described a subtype of panic disorder (PD) that we termed 'bladder syndrome', characterized by urological and bladder symptoms (and possibly interstitial cystitis) in the patients and/or their family members and confirmed the validity of this subset in family linkage and association analysis. In this study, we determine (a) whether 20 single-nucleotide polymorphisms (SNPs) reported in the literature can be replicated in a new PD dataset and (b) whether dividing the sample into those with and without the 'bladder syndrome' can help to resolve the genetic heterogeneity within this new sample. METHODS: We selected 20 putative associated SNPs from the literature, taken from studies published since 2004. We tested these SNPs for association in a sample of 351 PD patients and 552 controls, and then divided them into subgroups of 92 patients from bladder families and 259 from nonbladder families. RESULTS: (a) When analyzed in all PD patients, none of the 20 SNPs appeared to be replicated (except for SLC6A4 from our previous study, but in a sample that overlaps substantially with that in our previous report). (b) However, some intriguing findings emerged when we separated bladder from nonbladder families: SLC6A4, reported by us previously, yielded stronger evidence than before (P=0.0018) when examined only in nonbladder families, and in contrast, is not statistically significant in bladder families. Two other markers yielded nominally significant results in bladder families - rs5751876 in ADORA2A (P=0.046) and rs12579350 in TMEM16B (P=0.035) - but were not significant in nonbladder families. (c) Two markers had noticeably lower P-values when we differentiated the women and analyzed them separately - rs12579350 in TMEM16B (P-value decreased from 0.035, as above, to 0.00055) and a different SNP in ADORA2A, rs4822492 (P-value decreases from 0.07 to 0.028). SIGNIFICANCE: Our results indicate that most of the 20 reported associations do not hold up when PD is analyzed as one group. However, our findings provide further evidence that PD with bladder symptoms may be genetically different from PD without bladder. We suggest that it is worth pursuing SLC6A4 in nonbladder PD, and ADORA2A and TMEM16B in bladder PD. Also, the possibility of a male-female difference in PD is worth pursuing. We also briefly discuss issues of replication and multiple tests. PMID- 23018770 TI - Transcription of the pain-related TRPV1 gene requires Runx1 and C/EBPbeta factors. AB - Transient Receptor Potential Vanilloid type 1 channel (TRPV1) is an important endogenous transducer of noxious heat and chemical stimuli and is required during development of inflammatory hypersensitivity. The transcription factor Runx1 is known to play a relevant role in sensory neuron differentiation as it controls the expression of several sensory nociceptive receptors, including TRPV1. Here, we show that Runx1 up-regulates TRPV1 transcription activity by interacting directly with the proximal TRPV1 gene promoter sequence. Importantly, C/EBPbeta a well-established heterodimer partner of Runx1 also binds to the TRPV1 promoter and cooperates with Runx1 to further stimulate TRPV1 transcription. Our results support a mechanism where Runx1-C/EBPbeta-containing transcription regulatory complexes are recruited to the TRPV1 gene promoter to modulate TRPV1 expression in dorsal root ganglia neurons. PMID- 23018771 TI - Secondary structure improves OTU assignments of 16S rRNA gene sequences. PMID- 23018772 TI - Photophysiology and albedo-changing potential of the ice algal community on the surface of the Greenland ice sheet. AB - Darkening of parts of the Greenland ice sheet surface during the summer months leads to reduced albedo and increased melting. Here we show that heavily pigmented, actively photosynthesising microalgae and cyanobacteria are present on the bare ice. We demonstrate the widespread abundance of green algae in the Zygnematophyceae on the ice sheet surface in Southwest Greenland. Photophysiological measurements (variable chlorophyll fluorescence) indicate that the ice algae likely use screening mechanisms to downregulate photosynthesis when exposed to high intensities of visible and ultraviolet radiation, rather than non photochemical quenching or cell movement. Using imaging microspectrophotometry, we demonstrate that intact cells and filaments absorb light with characteristic spectral profiles across ultraviolet and visible wavelengths, whereas inorganic dust particles typical for these areas display little absorption. Our results indicate that the phototrophic community growing directly on the bare ice, through their photophysiology, most likely have an important role in changing albedo, and subsequently may impact melt rates on the ice sheet. PMID- 23018773 TI - Surface quality after implantoplasty. AB - Implantoplasty describes a method using rotating instruments to smoothen rough implant surfaces which are exposed to the oral cavity. The goal of this procedure is to reduce the adherence of plaque and to facilitate the cleaning of the implant surfaces. The aim of this study was to compare different rotary instruments for their effectiveness and efficiency to smoothen micro-rough implant surfaces. For this purpose, 22 implants were processed with 10 different cutters and one diamond bur under standardized conditions, and then analyzed by scanning electron microscopy. In addition, collection of roughness data (Ra values, arithmetic mean roughness, Rz values, and average roughness) was obtained by using tactile surface measurement. The time needed to reach a subjectively assessed smooth surface was determined for each instrument. The statistical analysis included the calculation of the mean values (+/- SD) for the required time, Ra and Rz values and the examination of correlations between these parameters, taking the logarithm of the values obtained and comparing them with linear mixed models. Irrespective of the drill design (spherical or conical) all rotary instruments used in the study showed obvious variations in processing times as well as significant differences (p < 0.001) of Ra and Rz values. The processing time required did not correlate with the Ra-(p = 0.44) or the Rz values (p = 0.83). Compared to spherical carbide cutters with transversal grooves, the conical cutters had the lowest mean roughness values (<1 micron). PMID- 23018775 TI - Direct C-H functionalization of enamides and enecarbamates by using visible-light photoredox catalysis. AB - Direct C-H functionalization of various enamides and enecarbamates was realized through visible-light photoredox catalyzed reactions. Under the optimized conditions using [Ir(ppy)(2)(dtbbpy)PF(6)] as photocatalyst in combination with Na(2)HPO(4), enamides such as N-vinylpyrrolidinone could be easily functionalized by irradiation of the reaction mixture overnight in acetonitrile with visible light. The scope of the reaction with respect to enamide and enecarbamate substrates by using diethyl 2-bromomalonate for the alkylation reaction was explored, followed by an investigation of the scope of alkylating reagents used to react with the enamides and enecarbamates. The results indicated that reaction takes place with quite broad substrate scope, however, tertiary enamides with an internal C=C double bond in the E configuration could not be alkylated. Alkylation of N-vinyl tertiary enamides and enecarbamates gave monoalkylated products exclusively in the E configuration. Alkylation of N-vinyl secondary enamides gave doubly alkylated products. Double bond migration was observed in the reaction of electron-deficient bromides such as 3-bromoacetyl acetate with N vinylpyrrolidinone. A mechanism is proposed for the reaction that is different from reported reactions of SOMOphiles with a nonfunctionalized C=C double bond. Further tests on the trifluoromethylation and arylation of enamides and enecarbamates under similar conditions showed that the reactions could serve as a mild, practical, and environmentally friendly approach to various functionalized enamides and enecarbamates. PMID- 23018776 TI - Increased allergic sensitization to mugwort in chronic urticaria. AB - BACKGROUND: Mugwort pollen is known to cross-react with a variety of spices and vegetables that are typically part of elimination diets used in the treatment of chronic urticaria (CU). OBJECTIVE: We sought to investigate the association between CU and allergic sensitization to mugwort pollen. METHODS: We conducted 2 case-control studies comparing aeroallergen skin prick test results between patients with and without CU and with or without allergic rhinitis (total n = 202). RESULTS: CU patients with coexisting allergic rhinitis were more than twice as likely to be sensitized to mugwort as subjects not suffering from CU (67 vs. 30%; p = 0.004). Ragweed, cat, rat and mite sensitization were also significantly associated with CU. Overall, patients with CU had more positive aeroallergen skin tests than patients without CU (p < 0.005). CONCLUSION: Mugwort sensitization was associated with CU, possibly contributing to beneficial effect of elimination diets. PMID- 23018778 TI - Ribonuclease P-mediated inhibition of human cytomegalovirus gene expression and replication induced by engineered external guide sequences. AB - External guide sequences (EGSs) are RNA molecules that can bind to a target mRNA and direct ribonuclease P (RNase P), a tRNA processing enzyme, for specific cleavage of the target mRNA. Using an in vitro selection procedure, we have previously generated EGS variants that efficiently direct human RNase P to cleave a target mRNA in vitro. In this study, we constructed EGSs from a variant to target the overlapping region of the mRNAs coding for human cytomegalovirus (HCMV) capsid scaffolding protein (CSP) and assemblin, which are essential for viral capsid formation. The EGS variant was about 40-fold more active in directing human RNase P to cleave the mRNA in vitro than the EGS derived from a natural tRNA. Moreover, a reduction of about 98% and 75% in CSP/assemblin gene expression and a reduction of 7000- and 250-fold in viral growth were observed in HCMV-infected cells that expressed the variant and the tRNA-derived EGS, respectively. Our study shows that the EGS variant is more effective in blocking HCMV gene expression and growth than the tRNA-derived EGS. Moreover, these results demonstrate the utility of highly active EGS RNA variants in gene targeting applications including anti-HCMV therapy. PMID- 23018779 TI - Armless mitochondrial tRNAs in Enoplea (Nematoda). AB - The mitochondrial genome of metazoan animal typically encodes 22 tRNAs. Nematode mt-tRNAs normally lack the T-stem and instead feature a replacement loop. In the class Enoplea, putative mt-tRNAs that are even further reduced have been predicted to lack both the T- and the D-arm. Here we investigate these tRNA candidates in detail. Three lines of computational evidence support that they are indeed minimal functional mt-tRNAs: (1) the high level of conservation of both sequence and secondary structure, (2) the perfect preservation of the anticodons, and (3) the persistence of these sequence elements throughout several genome rearrangements that place them between different flanking genes. PMID- 23018780 TI - Modeling the Thermoproteaceae RNase P RNA. AB - The RNA component of the RNase P complex is found throughout most branches of the tree of life and is principally responsible for removing the 5' leader sequence from pre-tRNA transcripts during tRNA maturation. RNase P RNA has a number of universal core features, however variations in sequence and structure found in homologs across the tree of life require multiple Rfam covariance search models to detect accurately. We describe a new Rfam search model to enable efficient detection of the diminutive archaeal Type T RNase P RNAs, which are missed by existing Rfam models. Using the new model, we establish effective score detection thresholds, and detect four new RNase P RNA genes in recently completed genomes from the crenarchaeal family Thermoproteaceae. PMID- 23018782 TI - Genes come and go: the evolutionarily plastic path of budding yeast RNase III enzymes. AB - Our recent finding that the Candida albicans RNase III enzyme CaDcr1 is an unusual, multifunctional RNase III coupled with data on the RNase III enzymes from other fungal species prompted us to seek a model that explained the evolution of RNase III's in modern budding yeast species. CaDcr1 has both dicer function (generates small RNA molecules from dsRNA precursors) and Rnt1 function, (catalyzes the maturation of 35S rRNA and U4 snRNA). Some budding yeast species have two distinct genes that encode these functions, a Dicer and RNT1, whereas others have only an RNT1 and no Dicer. As none of the budding yeast species has the canonical Dicer found in many other fungal lineages and most eukaryotes, the extant species must have evolved from an ancestor that lost the canonical Dicer, and evolved a novel Dicer from the essential RNT1 gene. No single, simple model could explain the evolution of RNase III enzymes from this ancestor because existing sequence data are consistent with two equally plausible models. The models share an architecture for RNase III evolution that involves gene duplication, loss, subfunctionalization, and neofunctionalization. This commentary explains our reasoning, and offers the prospect that further genomic data could further resolve the dilemma surrounding the budding yeast RNase III's evolution. PMID- 23018781 TI - Emerging roles for Sam68 in adipogenesis and neuronal development. AB - Sam68, the Src-associated substrate during mitosis of 68 kDa, belongs to the large class of heteronuclear ribonucleoprotein particle K (hnRNP K) homology (KH) domain family of RNA-binding proteins. Sam68 contains a single KH domain harboring conserved N- and C-terminal sequences required for RNA binding and homodimerization. The KH domain is one of the most prevalent RNA binding domains that directly contacts single-stranded RNA. Sam68 has been implicated in numerous aspects of RNA metabolism including alternative splicing and polysomal recruitment of mRNAs. Studies in mice have revealed physiological roles linking Sam68 to osteoporosis, obesity, cancer, infertility and ataxia. Recent publications have greatly enhanced our understanding of Sam68 mechanism of action in addition to its cellular role. Herein, we will discuss the latest advances in the literature pertaining to obesity and neuronal development. PMID- 23018783 TI - Human mirtrons can express functional microRNAs simultaneously from both arms in a flanking exon-independent manner. AB - Mirtrons are short intronic microRNA (miRNA) precursors representing an alternative, Drosha/DGCR8-independent miRNA biogenesis pathway. In this study we characterized three predicted human mirtrons. Their expression was proven to be context-independent, since functional mirtrons could be derived either from their endogenous or from a heterologous coding environment. Systematic testing revealed that both 5'- and 3'-arms of mir-877 are capable of producing functional miRNA simultaneously in the various cell types examined. On the other hand, experimental validations revealed that the predicted mir-1233 is not a bona fide mirtron. For functional mirtrons, we were able to detect mature mirtron-derived miRNAs for the first time by qRT-PCR or northern blot analysis, when silencing activity was proven by functional assays. Our results emphasize the need for functional testing of both arms of miRNAs and the importance of experimentally validating human mirtrons since, in spite of being localized in a short intron, predicted species could mature via other miRNA processing pathways. PMID- 23018784 TI - Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: a three-year study. AB - The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual-energy X-ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean +/- SD) were similar between groups in terms of age, 76.8 +/- 5.0 years; body mass index (BMI), 24.5 +/- 3.6 kg/m(2) ; TBS, 1.178 +/- 0.1 but for LS T-score (ZOL-2.9 +/- 1.5 versus PLB-2.1 +/- 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus-0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once-yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years. PMID- 23018789 TI - Microfluidic extraction, stretching and analysis of human chromosomal DNA from single cells. AB - We describe a microfluidic device for the extraction, purification and stretching of human chromosomal DNA from single cells. A two-dimensional array of micropillars in a microfluidic polydimethylsiloxane channel was designed to capture a single human cell. Megabase-long DNA strands released from the cell upon lysis are trapped in the micropillar array and stretched under optimal hydrodynamic flow conditions. Intact chromosomal DNA is entangled in the array, while other cellular components are washed from the channel. To demonstrate the entrapment principle, a single chromosome was hybridized to whole chromosome paints, and imaged by fluorescence microscopy. DNA extracted from a single cell and small cell populations (less than 100) was released from the device by restriction endonuclease digestion under continuous flow and collected for off chip analysis. Quantification of the extracted material reveals that the microdevice efficiently extracts essentially all chromosomal DNA. The device described represents a novel platform to perform a variety of analyses on chromosomal DNA at the single cell level. PMID- 23018791 TI - WITHDRAWN: Pretreatment of Cats with Vitamin B6 Reduces Vomiting Episodes Following Xylazine Administration. AB - Ahead of Print article withdrawn by publisher. PMID- 23018790 TI - The effect of electron beam irradiation on WS2 nanotubes. AB - WS(2) nanotubes were irradiated with a focused electron beam in an electron microscope. The results show that the nanotubes are destroyed from the outer layer to the inside. The displaced atoms can leave the irradiated area by sputtering events or by diffusive migration along the shells and the inner hollow. The smaller tubes have a lower stability. The stability of the tube increases after the central hollow is closed and the asymmetric irradiation can lead to a bending of the tube. Electron irradiation causes the change of WS(2) nanotubes into a polycrystalline structure. The primary cause of the electron irradiation damage in WS(2) nanotubes is knock-on collisions. PMID- 23018792 TI - Histological and genetic characterization of true hermaphroditism in Korean pigs. AB - True hermaphrodites are animals of equivocal sex in which both male and female gonads develop simultaneously in the same individual. The frequency of true hermaphroditism is relatively higher in pigs than in other domestic animals. Two Korean pigs were diagnosed with true hermaphroditism showing ovotestes, epididymides, a penis and uteri. The testicular tissues consisted of Sertoli cells that were devoid of spermatogenic cells and showed proliferation of interstitial cells. However, uteri looked normal and had well-developed endometrial glands. Samples showed the interpretation of 38, XX female karyotype and sex-determining region Y (SRY) gene expression was negative. These findings could be helpful to understand true porcine hermaphroditism for animal research as well as for the industry of Korean domestic animals. PMID- 23018793 TI - Long-term methylglyoxal treatment causes endothelial dysfunction of rat isolated mesenteric artery. AB - Methylglyoxal (MGO) is a metabolite of glucose and likely related to pathogenesis of diabetes-related vascular complications including hypertension. In this study, long-term effects of MGO on endothelial function were examined. Rat isolated mesenteric artery was treated for 3 days with MGO using an organ culture method. The contractility, morphology and protein expression of organ-cultured artery were examined. MGO (42 uM, 3 days) impaired acetylcholine (ACh: 1 nM-300 uM) induced endothelium-dependent relaxation, while it had no effect on sodium nitroprusside (0.1 nM-10 uM)-induced endothelium-independent relaxation. MGO decreased ACh (3 uM)-induced nitric oxide (NO) production as measured by a fluorescence NO indicator, diaminofluorescein-2. Consistently, MGO inhibited ACh (3 uM)-induced phosphorylation of vasodilator stimulated phosphoprotein (an indicator of cyclic GMP production). MGO induced apoptosis in endothelium as detected by TdT-mediated dUTP-biotin nick-end labeling staining. MGO induced accumulation of superoxide in endothelium as detected by dihydroethidium staining. MGO decreased protein expression of endothelial NO synthase (eNOS). Gp91ds-tat (0.1 uM), an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), prevented the impairment of endothelium-dependent relaxation and the decrease in eNOS protein caused by MGO. The present results demonstrated that long-term MGO treatment impairs endothelium-dependent relaxation through NOX-derived increased superoxide-mediated endothelial apoptosis. PMID- 23018794 TI - Importance of puppy training for future behavior of the dog. AB - In this study, we attempted to clarify whether puppy socialization and command training class, which was limited to puppies approximately 4 months of age, prevented behavior problems in dogs. We evaluated the behaviors of 142 dogs with 4 types of training experience by using a behavior test and the Canine Behavior Assessment and Research Questionnaire (C-BARQ). Dogs in the puppy class (PC) group (n=44) attended the class for 1 hr each week for 6 weeks, dogs in the puppy party (PP) group (n=39) attended a 1-hr "puppy party," dogs in the adult class (AC) group (n=27) undertook basic obedience lessons for adolescent/adult dogs for 1 hr each week for 6 weeks, and dogs in the no class (NC) group (n=32) underwent no formal training. The behavior test evaluated each dog's response to commands, owner's recall, separation, a novel stimulus and strangers. The C-BARQ evaluated 15 canine behavioral factors. The behavior test results indicated that the PC and AC groups showed significantly higher response to commands than the PP or NC group. Thus, participation in puppy and adult classes improved the obedience behavior of dogs, regardless of age. Positive response to strangers in the PC group was significantly higher than that in the AC and NC groups and tended to be higher than that in the PP group. Therefore, PC may help prevent canine behavioral problems such as disobedience or fear of strangers. PMID- 23018795 TI - A novel mutation in VKORC1 and its effect on enzymatic activity in Japanese warfarin-resistant rats. AB - Warfarin is a rodenticide commonly used worldwide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. Recently, warfarin-resistant brown rats (Rattus norvegicus) were found around the Aomori area of Japan. There is no significant difference in the metabolic activity of warfarin in sensitive and resistant brown rats. To clarify the mechanism underlying warfarin resistance, we cloned the VKORC1 gene from rats and identified a novel substitution of arginine to proline at position 33 of the VKORC1 amino acid sequence. Then, we determined the differences in kinetics of VKOR activity between warfarin-resistant and sensitive rats. Hepatic microsomal VKOR-dependent activity was measured over a range of vitamin K epoxide concentrations from 6.25 to 150 uM. The Vmax values of resistant rats (0.0029 +/- 0.020 nmol/min/mg) were about one tenth of those of sensitive rats (0.29 +/- 0.12 nmol/min/mg). The Km values of resistant rats (47 +/- 32 uM) were similar to those of sensitive rats (59 +/- 18 uM). Warfarin-sensitive rats exhibited enzyme efficiencies (Vmax/Km) which were ten-fold greater than those observed in resistant rats. It may mean that VKOR activity of warfarin-resistant Aomori rats is almost lost, because their enzymatic efficiencies are very low even without warfarin. Further studies are needed to clarify how these rats can survive with a markedly reduced VKOR activity and how they simultaneously exhibit warfarin resistance. PMID- 23018796 TI - Practice variation in late-preterm deliveries: a physician survey. AB - OBJECTIVE: Late-preterm (LPT) neonates account for over 70% of all preterm births in the US. Approximately 60% of LPT births are the result of non-spontaneous deliveries. The optimal timing of delivery for many obstetric conditions at LPT gestations is unclear, likely resulting in obstetric practice variation. The purpose of this study is to identify variation in the obstetrical management of LPT pregnancies. STUDY DESIGN: We surveyed obstetrical providers in North Carolina identified from North Carolina Medical Board and North Carolina Obstetrical and Gynecological Society membership lists. Participants answered demographic questions and six multiple-choice vignettes on management of LPT pregnancies. RESULT: We obtained 215/859 (29%) completed surveys which are as follows: 167 (78%) from obstetrics/gynecology, 27 (13%) from maternal-fetal medicine, and 21 (10%) from family medicine physicians. Overall, we found more agreement on respondents' management of chorioamnionitis (97% would proceed with delivery), mild pre-eclampsia (84% would delay delivery/expectantly manage) and fetal growth restriction (FGR) (80% would delay delivery/expectantly manage). We found less agreement on the management of severe preeclampsia (71% would proceed with delivery), premature preterm rupture of membranes (69% would proceed with delivery) and placenta previa (67% would delay delivery/expectantly manage). Management of LPT pregnancies complicated by preterm premature rupture of membranes, FGR and placenta previa vary by specialty. CONCLUSION: Obstetrical providers report practice variation in the management of LPT pregnancies. Variation might be influenced by provider specialty. The absence of widespread agreement on best practice might be a source of modifiable LPT birth. PMID- 23018798 TI - Frequency and mechanism of ischemic stroke associated with malignancy: a retrospective series. AB - BACKGROUND: Cerebrovascular disease is the second most common non-metastatic neurological disorder in oncological patients. The aims of this study were to determine the prevalence of cancer in stroke patients and to compare mechanisms of stroke between patients with and without malignancy. PATIENTS AND METHODS: This retrospective study involved patients with ischemic stroke admitted over 1 year to a Neurology Department. Demographic and clinical data, cardiovascular risk factors, and laboratory findings were recorded. The etiology was classified following the TOAST criteria. Participants were classified as stroke and cancer patients (diagnosis of malignancy before stroke or cancer diagnosed after admission) or as control stroke patients. RESULTS: Over 1 year, 291 stroke patients (268 ischemic) were admitted. Sixteen ischemic patients had a malignancy (5.9%), and in 12 patients, malignancy was the only cause found for the stroke; in 4 patients, malignancy was a coexisting condition. Coexistent stroke and cancer was significantly related to higher median levels of fibrinogen, D-dimers, and erythrocyte sedimentation rate (ESR). Logistic regression analysis showed that D-dimer and ESR levels were independently related to cancer, with odds ratios of 1.004 (95% CI 1.001-1.007, p=0.02) and 1.075 (95% CI 1.031-1.121, p=0.001), respectively. CONCLUSIONS: Almost 6% of ischemic stroke patients had a concomitant malignancy. In most of them, cancer was the only cause of stroke found. Patients with stroke and malignancy exhibited raised D-dimer, fibrinogen, and ESR levels, suggesting the prothrombotic state was a principal mechanism underlying stroke. D-dimer and ESR assessments may be useful in identifying underlying disorders in ischemic stroke. PMID- 23018797 TI - Polymorphisms in the fetal progesterone receptor and a calcium-activated potassium channel isoform are associated with preterm birth in an Argentinian population. AB - OBJECTIVE: To investigate genetic etiologies of preterm birth (PTB) in Argentina through evaluation of single-nucleotide polymorphisms (SNPs) in candidate genes and population genetic admixture. STUDY DESIGN: Genotyping was performed in 389 families. Maternal, paternal and fetal effects were studied separately. Mitochondrial DNA (mtDNA) was sequenced in 50 males and 50 females. Y-chromosome anthropological markers were evaluated in 50 males. RESULT: Fetal association with PTB was found in the progesterone receptor (PGR, rs1942836; P=0.004). Maternal association with PTB was found in small conductance calcium activated potassium channel isoform 3 (KCNN3, rs883319; P=0.01). Gestational age associated with PTB in PGR rs1942836 at 32-36 weeks (P=0.0004). MtDNA sequencing determined 88 individuals had Amerindian consistent haplogroups. Two individuals had Amerindian Y-chromosome consistent haplotypes. CONCLUSION: This study replicates single locus fetal associations with PTB in PGR, maternal association in KCNN3, and demonstrates possible effects for divergent racial admixture on PTB. PMID- 23018799 TI - 18F-fluorodeoxythymidine micro-positron-emission tomography versus 18F fluorodeoxyglucose micro-positron-emission tomography for in vivo minimal residual disease imaging. AB - OBJECTIVES/HYPOTHESIS: The early detection of persistent/recurrent disease of head and neck squamous cell carcinoma (HNSCC) after treatment can be challenging. The currently used radioisotope (18)F-fluorodeoxyglucose (FDG) is a nonspecific tracer for cancer cells as it detects all metabolically active cells including inflammation. (18)F-fluorodeoxythymidine (FLT) is a radioactive tracer for rapidly proliferating cells, and therefore is more specific for detecting cancer. Our aim was to compare FLT and FDG microPET (positron-emission tomography) to the gold standard in vivo bioluminescence imaging for serial assessment of neoplastic growth in a minimal residual disease in vivo model. STUDY DESIGN: Prospective outcomes research. METHODS: In order to mimic the postsurgical environment of HNSCC patients FaDu cells transfected with a luciferase-expressing retrovirus were inoculated into the skin flap of Balb/c nu/nu mice. Three days later before tumors formed, mice were randomized into (18)F-FLT or (18) F-FDG groups, and microPET imaging was performed on days 3, 6, 10, 18, and 24 after tumor cell inoculation. RESULTS: (18)F-FLT detected tumors as early as day 3 even before tumors were palpable, whereas (18)F-FDG only detected palpable tumors. The average overall normalized radioactivity in the FLT group was significantly higher than the FDG group (P = .025). CONCLUSIONS: (18)F-FLT identified tumor cells before tumors were palpable and can potentially be used for early detection of persistence/recurrence of HNSCC. In addition, this radioisotope can be used to monitor adjuvant therapy with novel targeted therapeutics in preclinical models of persistent disease. PMID- 23018801 TI - Identification of isoquercitrin metabolites produced by human intestinal bacteria using UPLC-Q-TOF/MS. AB - In this paper, ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) and the MetaboLynxTM software combined with mass defect filtering were applied to identity the metabolites of isoquercitrin using an intestinal mixture of bacteria and 96 isolated strains from human feces. The human incubated samples collected for 72 h in the anaerobic incubator and extracted with ethyl acetate were analyzed by UPLC-Q-TOF/MS within 10 min. The parent compound and five metabolites were identified by eight isolated strains, including Bacillus sp. 17, Veillonella sp. 23 and 32 and Bacteroides sp. 40, 41, 56, 75 and 88 in vitro. The results indicate that quercetin, acetylated isoquercitrin, dehydroxylated isoquercitrin, hydroxylated quercetin and hydroxymethylated quercetin are the major metabolites of isoquercitrin. Furthermore, a possible metabolic pathway for the biotransformation of isoquercitrin was established in intestinal flora. This study will be helpful for understanding the metabolic route of isoquercitrin and the role of different intestinal bacteria in the metabolism of natural compounds. PMID- 23018804 TI - Dopamine inhibits high-frequency stimulation-induced long-term potentiation of intrinsic excitability in CA1 hippocampal pyramidal neurons. AB - The efficiency of neural circuits is modified by changes not only in synaptic strength, but also in intrinsic excitability of neurons. In CA1 hippocampal pyramidal neurons, bidirectional changes in the intrinsic excitability are often presented after induction of synaptic long-term potentiation or depression. This plasticity of intrinsic excitability has been identified as a cellular correlate of learning. Besides, behavioral learning often involves action of reinforcement or rewarding mediated by dopamine (DA). Here, we examined how DA influences the intrinsic plasticity of CA1 hippocampal pyramidal neurons when high-frequency stimulation (HFS) was applied to Schaffer collaterals. The results showed that DA inhibits the decrease in rheobase and increase in mean firing rate of pyramidal neurons induced by HFS, and that this inhibition was abolished by the D1-like receptor antagonist SCH23390 but not by the D2-like receptor antagonist sulpiride. The results suggest that DA inhibits the potentiation of excitability induced by presynaptic HFS, and that this inhibition depends on the activation of D1-like receptors. PMID- 23018800 TI - The pur protein family: genetic and structural features in development and disease. AB - The Pur proteins are an ancient family of sequence-specific single-stranded nucleic acid-binding proteins. They bind a G-rich element in either single- or double-stranded nucleic acids and are capable of displacing the complementary C rich strand. Recently several reports have described Pur family member knockouts, mutations, and disease aberrations. Together with a recent crystal structure of Puralpha, these data reveal conserved structural features of these proteins that have been adapted to serve functions unique to higher eukaryotes. In humans Pur proteins are critical for myeloid cell development, muscle development, and brain development, including trafficking of mRNA to neuronal dendrites. Pur family members have been implicated in diseases as diverse as cancer, premature aging, and fragile-X mental retardation syndrome. PMID- 23018807 TI - Iridium-catalyzed allylic substitutions with cyclometalated phosphoramidite complexes bearing a dibenzocyclooctatetraene ligand: preparation of (pi-allyl)Ir complexes and computational and NMR spectroscopic studies. AB - (pi-Allyl)Ir complexes derived from dibenzocyclooctatetraene and phosphoramidites by cyclometalation are effective catalysts for allylic substitution reactions of linear monosubstituted allylic carbonates. These catalysts provide exceptionally high degrees of regioselectivity and allow the reactions to be run under aerobic conditions. A series of (pi-allyl)Ir complexes were prepared and characterized by X-ray crystal structure analyses. An allylic amination with aniline displayed different resting states depending on the presence of a strong base. DFT calculations were carried out on the mechanistic aspects of these reactions. The results suggest that for the (pi-allyl)Ir complexes, the formation and reactions with nucleophiles proceed with comparable rates. PMID- 23018805 TI - Who should have surgery for spinal stenosis? Treatment effect predictors in SPORT. AB - STUDY DESIGN: Combined prospective randomized controlled trial and observational cohort study of spinal stenosis (SpS) with an as-treated analysis. OBJECTIVE: To determine modifiers of the treatment effect (TE) of surgery (the difference between surgical and nonoperative outcomes) for SpS using subgroup analysis. SUMMARY OF BACKGROUND DATA: The Spine Patient Outcomes Research Trial demonstrated a positive surgical TE for SpS at the group level. However, individual characteristics may affect TE. No previous studies have evaluated TE modifiers in SpS. METHODS: SpS patients were treated with either surgery (n = 419) or nonoperative care (n = 235) and were analyzed according to treatment received. Fifty-three baseline variables were used to define subgroups for calculating the time-weighted average TE for the Oswestry Disability Index (ODI) over 4 years (TE = DeltaODIsurgery - DeltaODInonoperative). Variables with significant subgroup * treatment interactions (P < 0.05) were simultaneously entered into a multivariate model to select independent TE predictors. RESULTS: Other than smokers, all analyzed subgroups including at least 50 patients improved significantly more with surgery than with nonoperative treatment (P < 0.05). Multivariate analysis demonstrated: baseline ODI <= 56 (TE -15.0 vs. -4.4, ODI > 56, P < 0.001), not smoking (TE -11.7 vs. -1.6 smokers, P < 0.001), neuroforaminal stenosis (TE -14.2 vs. -8.7 no neuroforaminal stenosis, P = 0.002), predominant leg pain (TE -11.5 vs. -7.3 predominant back pain, P = 0.035), not lifting at work (TE -12.5 vs. -0.5 lifting at work, P = 0.017), and the presence of a neurological deficit (TE -13.3 vs. -7.2 no neurological deficit, P < 0.001) were associated with greater TE. CONCLUSION: With the exception of smokers, patients who met strict inclusion criteria improved more with surgery than with nonoperative treatment, regardless of other specific characteristics. However, TE varied significantly across certain subgroups, and these data can be used to individualize shared decision making discussions about likely outcomes. Smoking cessation should be considered before surgery for SpS. PMID- 23018811 TI - Fabrication of polypyrrole nano-arrays in lysozyme single crystals. AB - A template-directed method for the synthesis and organization of partially oxidized polypyrrole (PPy) nanoscale arrays within the solvent channels of glutaraldehyde-cross-linked lysozyme single crystals is presented. Macroscopic single crystals of the periodically arranged protein-polymer superstructure are electrically conductive, insoluble in water and organic solvents, and display increased levels of mechanical plasticity compared with native cross-linked lysozyme crystals. PMID- 23018810 TI - Identification of a single base-pair mutation of TAA (Stop codon) -> GAA (Glu) that causes light chain extension in a CHO cell derived IgG1. AB - We describe here the identification of a stop codon TAA (Stop) -> GAA (Glu) = Stop221E mutation on the light chain of a recombinant IgG1 antibody expressed in a Chinese hamster ovary (CHO) cell line. The extended light chain variants, which were caused by translation beyond the mutated stop codon to the next alternative in-frame stop codon, were observed by mass spectra analysis. The abnormal peptide peaks present in tryptic and chymotryptic LC-MS peptide mapping were confirmed by N-terminal sequencing as C-terminal light chain extension peptides. Furthermore, LC-MS/MS of Glu-C peptide mapping confirmed the stop221E mutation, which is consistent with a single base-pair mutation in TAA (stop codon) to GAA (Glu). The light chain variants were approximately 13.6% of wild type light chain as estimated by RP-HPLC analysis. DNA sequencing techniques determined a single base pair stop codon mutation, instead of a stop codon read-through, as the cause of this light chain extension. To our knowledge, the stop codon mutation has not been reported for IgGs expressed in CHO cells. These results demonstrate orthogonal techniques should be implemented to characterize recombinant proteins and select appropriate cell lines for production of therapeutic proteins because modifications could occur at unexpected locations. PMID- 23018812 TI - Evaluation of natural regulatory T cells in subjects with selective IgA deficiency: from senior idea to novel opportunities. AB - BACKGROUND: Selective IgA deficiency (SIgAD) is the most common primary immunodeficiency disorder, which is characterized by significantly decreased serum levels of IgA. Abnormalities of CD4+CD25(high)forkhead box P3 (FoxP3)+ regulatory T cells (T(reg)) have been shown in association with autoimmune and inflammatory disorders. METHODS: In order to evaluate the relationship between autoimmunity and T(reg) in SIgAD, we studied 26 IgA-deficient patients (aged 4-17 years) with serum IgA levels <7 mg/dl, 26 age- and sex-matched healthy controls and 26 age- and sex matched idiopathic thrombocytopenic purpura cases with normal immune system. T(reg) were determined by flow cytometry using T(reg) markers, including CD4, CD25 and FoxP3. RESULTS: The mean percentage of CD4, CD25+FoxP3+ T(reg) from all CD4+ cells was 4.08 +/- 0.86 in healthy controls, which was significantly higher than in SIgAD patients (2.93 +/- 1.3; p = 0.003). We set a cutoff point (2.36%) for T(reg), which was two standard deviations lower than the mean of normal controls. According to this cutoff point and in order to assess the role of T(reg) in clinical SIgAD manifestation, we classified patients into two groups: 16 patients in G1 with T(reg) <2.36% and 10 patients in G2 with T(reg) >2.36%. Autoimmunity was recorded in 9 patients (53.3%) of G1 and only 1 patient of G2, respectively (p = 0.034). Although a defect in class switching recombination was observed in 40% of the patients in G1, none of the G2 patients had such a defect (p = 0.028). CONCLUSION: This study showed decreased proportions of T(reg) in SIgAD patients, particularly in those with signs of chronic inflammation. PMID- 23018813 TI - Periosteum, bone's "smart" bounding membrane, exhibits direction-dependent permeability. AB - The periosteum serves as bone's bounding membrane, exhibits hallmarks of semipermeable epithelial barrier membranes, and contains mechanically sensitive progenitor cells capable of generating bone. The current paucity of data regarding the periosteum's permeability and bidirectional transport properties provided the impetus for the current study. In ovine femur and tibia samples, the periosteum's hydraulic permeability coefficient, k, was calculated using Darcy's Law and a custom-designed permeability tester to apply controlled, volumetric flow of phosphate-buffered saline through periosteum samples. Based on these data, ovine periosteum demonstrates mechanically responsive and directionally dependent (anisotropic) permeability properties. At baseline flow rates comparable to interstitial fluid flow (0.5 uL/s), permeability is low and does not exhibit anisotropy. In contrast, at high flow rates comparable to those prevailing during traumatic injury, femoral periosteum exhibits an order of magnitude higher permeability compared to baseline flow rates. In addition, at high flow rates permeability exhibits significant directional dependence, with permeability higher in the bone to muscle direction than vice versa. Furthermore, compared to periosteum in which the intrinsic tension (pre-stress) is maintained, free relaxation of the tibial periosteum after resection significantly increases its permeability in both flow directions. Hence, the structure and mechanical stress state of periosteum influences its role as bone's bounding membrane. During periods of homeostasis, periosteum may serve as a barrier membrane on the outer surface of bone, allowing for equal albeit low quiescent molecular communication between tissue compartments including bone and muscle. In contrast, increases in pressure and baseline flow rates within the periosteum resulting from injury, trauma, and/or disease may result in a significant increase in periosteum permeability and consequently in increased molecular communication between tissue compartments. Elucidation of the periosteum's permeability properties is key to understanding periosteal mechanobiology in bone health and healing, as well as to elucidate periosteum structure and function as a smart biomaterial that allows bidirectional and mechanically responsive fluid transport. PMID- 23018814 TI - Observation of intermediate template directed SiC nanowire growth in Si-C-N systems. AB - SiC nanowires (NWs) are commonly prepared in a Si-C-N system, but its formation mechanism is not fully understood. High resolution transmission electron microscopy and electron energy loss spectroscopy observation recorded the growth process of how Si(3)N(4) NWs were transformed into SiC NWs, and demonstrated the validity of an intermediate template directed SiC NW growth via carbothermal reduction of intermediate Si(3)N(4) NWs in a Si-C-N system. Based on this discovery, an intermediate-template growth mechanism of SiC NWs was proposed. PMID- 23018815 TI - ERK is involved in tooth-pressure-induced Fos expression in Vc neurons. AB - Discomfort and pain encountered during orthodontic treatment are major problems for patients, but the details of the underlying neural processes and molecular mechanisms are not well-understood. Here we show that noxious tooth mechanical pressure induced by orthodontic elastics resulted in a rapid and transient activation of extracellular signal-regulated protein kinase (ERK) in the trigeminal spinal subnucleus interpolaris and caudalis transition zone (Vi/Vc), trigeminal spinal subnucleus caudalis (Vc), and upper cervical spinal cord (Vc/C2). The phosphorylated ERK (pERK) was observed in neurons but not in astroglia and microglia. Single-plane scanning analysis indicated that the pERK was localized to the nucleus of Vc neurons. In addition, the tooth mechanical pressure led to Fos expression in the pERK-positive Vc neurons that would be suppressed by intrathecal administration of an MEK1/2 inhibitor (PD98059). Taken together, these findings suggest that activation of the ERK signaling cascade following noxious mechanical pressure on the teeth regulates Fos expression in Vc neurons and may thereby contribute to pain associated with orthodontic treatment. PMID- 23018817 TI - Effect of local anesthesia on trigeminal somatosensory-evoked magnetic fields. AB - For objective neurophysiological evaluation of the function of the trigeminal system, magnetoencephalography- based TSEF (trigeminal somatosensory-evoked field) assessment would be valuable in providing spatial and temporal profiles of cortical responses. However, this necessitates knowledge of how TSEF varies with trigeminal nerve dysfunctions. We introduced a conduction block of the trigeminal nerve using local anesthesia (lidocaine) to temporally mimic nerve dysfunctions, and monitored TSEF changes. Following an electrical stimulation of the lower lip, a magnetic response with peak latency of approximately 20 ms was identified in all participants. Dipole for the peak was estimated on the post-central gyrus in the participant's own magnetic resonance image. After normalization to Montreal Neurological Institute (MNI) space and inter-participant data integration, the summary equivalent current dipole localization among participants remained in the post-central gyrus, suggesting validity of the use of MNI space. Partial anesthesia of the lower lip led to a loss of the waveform characteristics of TSEF for electrical stimulation to the trigeminal nerve. We verified that the 20-ms latency cortical response of TSEF components localized at the primary sensory cortex can serve as a robust neurofunctional marker of experimental trigeminal nerve dysfunction. PMID- 23018816 TI - Assessment of the plasma/serum IgG test to screen for periodontitis. AB - Chronic periodontitis is a silent infectious disease prevalent worldwide and affects lifestyle-related diseases. Therefore, efficient screening of patients is essential for general health. This study was performed to evaluate prospectively the diagnostic utility of a blood IgG antibody titer test against periodontal pathogens. Oral examination was performed, and IgG titers against periodontal pathogens were measured by ELISA in 1,387 individuals. The cut-off value of the IgG titer was determined in receiver operating characteristic curve analysis, and changes in periodontal clinical parameters and IgG titers by periodontal treatment were evaluated. The relationships between IgG titers and severity of periodontitis were analyzed. The best cut-off value of IgG titer against Porphyromonas gingivalis for screening periodontitis was 1.682. Both clinical parameters and IgG titers decreased significantly under periodontal treatment. IgG titers of periodontitis patients were significantly higher than those of healthy controls, especially in those with sites of probing pocket depth over 4 mm. Multiplied cut-off values were useful to select patients with severe periodontitis. A blood IgG antibody titer test for Porphyromonas gingivalis is useful to screen hitherto chronic periodontitis patients. PMID- 23018818 TI - New insights into the composition and functions of the acquired enamel pellicle. AB - The acquired enamel pellicle (AEP) is a thin acellular film that forms on tooth surfaces upon exposure to the oral environment. It consists predominantly of salivary proteins, but also includes non-salivary-derived proteins, carbohydrates, and lipids. Since it is the interface between teeth and the oral environment, the AEP plays a key role in the maintenance of oral health by regulating processes including lubrication, demineralization, and remineralization and shaping the composition of early microbial flora adhering to tooth surfaces. Knowledge of the 3D structure of the AEP and how that correlates with its protective functions may provide insight into several oral pathological states, including caries, erosion, and periodontal disease. This review intends to update readers about the latest discoveries related to the formation, ultrastructure, composition, and functions of the AEP, as well as the future of pellicle research, with particular emphasis on the emerging role of proteomic and microscopy techniques in oral diagnosis and therapeutics. PMID- 23018819 TI - Are dental health behaviors rational, after all? PMID- 23018820 TI - Enhancing oral health via sense of coherence: a cluster-randomized trial. AB - Sense of coherence (SOC) has been related to oral health behaviors and oral health-related quality of life (OHRQoL) in observational studies. This cluster randomized trial aimed to test the effect of an intervention to enhance SOC on OHRQoL in children. Twelve primary schools were randomly allocated to intervention and control groups. The intervention was comprised of 7 sessions over 2 mos, focusing on child participation and empowerment. The first 4 sessions were classroom activities, and the last 3 involved working on healthy school projects. Trained teachers who received a one-day course delivered the intervention. Socio-demographic and clinical data, together with self-reported measures of OHRQoL, SOC, and oral health beliefs, were obtained from 261 total 10 to 12-year-olds (133 in the intervention and 128 in the control groups). Data were collected at baseline, 2 wks after the intervention, and at three-month follow-up. Mixed-effects models indicated that the intervention increased SOC and improved OHRQoL, together with oral health beliefs and gingival health. The findings offer experimental evidence that OHRQoL can be influenced by SOC. SOC may also provide an avenue for oral health promotion (Australian New Zealand Clinical Trials Registry ACTRN12612000547842). PMID- 23018821 TI - Therapeutic endoscopic retrograde cholangiography and cholangioscopy (ERCC) combining a single-balloon enteroscope and an ultraslim endoscope in altered gastrointestinal anatomy. PMID- 23018824 TI - Bisphosphonate safety and efficacy in chronic kidney disease. AB - A new population-based study of elderly patients hospitalized for a fracture and treated with an oral bisphosphonate finds no increased risk of acute kidney injury. The safety and efficacy of bisphosphonates may be different in patients with chronic kidney disease (CKD). The effects on vascular calcifications need further study, because low bone turnover might exacerbate vascular calcifications in patients with CKD. Even if bisphosphonates prove safe, their efficacy in this population is uncertain. PMID- 23018825 TI - Mononuclear phagocyte depletion strategies in models of acute kidney disease: what are they trying to tell us? AB - Mononuclear phagocytes (macrophages, dendritic cells, and monocytes) play a complex role in kidney disease. Techniques for selectively depleting them in rodents have made important contributions but have also generated some contradictory results. Ferenbach et al. report that two widely used mononuclear phagocyte depletion techniques differentially affect early severity of renal ischemia/reperfusion injury and provide evidence that this may be due to a residual, protective subset that persists in the kidney after one of the two techniques. PMID- 23018826 TI - Direct or indirect endothelial cell transforming growth factor-beta receptor activation initiates arteriolar hyalinosis. AB - Tacrolimus (FK-506) controls organ rejection; however, arteriolar hyalinosis is a frequent complication. By use of mice lacking FK-506-binding protein-12 in endothelial cells, Chiasson and co-workers explored the contribution of endothelial cells and the transforming growth factor-beta pathway to define mechanisms of hyalinosis. Absence of this binding protein removed a tonic inhibition to activate the transforming growth factor-beta system, causing arteriolar hyalinosis. However, tacrolimus can have effects on any biologic process involving receptors with a GS domain. PMID- 23018827 TI - Is there no future for renal BOLD-MRI? PMID- 23018828 TI - Limitations of BOLD-MRI for assessment of hypoxia in chronically diseased human kidneys. PMID- 23018830 TI - Drug use and nephrotoxicity in the intensive care unit: are we under-dosing antimicrobials in patients with acute kidney injury with the need of extended dialysis? PMID- 23018831 TI - Drug use in the intensive care unit. PMID- 23018833 TI - Combining a fruit and vegetable diet with sodium bicarbonate supplementation seems the best dietary option for chronic kidney disease patients. PMID- 23018835 TI - Renal artery embolization after intravenous mercury injection. PMID- 23018836 TI - Mimicker of subarachnoid hemorrhage in a hemodialysis patient. PMID- 23018837 TI - Replication of respiratory syncytial virus is inhibited by the host defense molecule viperin. AB - Respiratory syncytial virus (RSV) is an important viral pathogen of otitis media, bronchiolitis, and pneumonia. As infection of the upper airways is a precondition for the development of these diseases, understanding RSV pathogenesis and the host response induced by RSV in this niche may enable the development of novel therapeutic strategies against this virus. We have used a microarray approach and showed that expression of the gene that encodes the antiviral protein viperin was significantly upregulated in the chinchilla nasopharynx up to 1 week after RSV challenge. Overexpression of human viperin in vitro diminished the ability of RSV to infect HeLa or A549 cells. Furthermore, transduction of the chinchilla airways with a recombinant adeno-associated virus vector that encodes viperin resulted in reduced titers of RSV in the nasopharyngeal lavage fluid. Collectively, these data indicated that viperin plays a significant role in the innate immune defense against RSV. PMID- 23018838 TI - EGFR through STAT3 modulates DeltaN63alpha expression to sustain tumor-initiating cell proliferation in squamous cell carcinomas. AB - Many squamous cell carcinomas (SCCs) are characterized by high levels of EGFR and by overexpression of the DeltaNp63alpha isoform. Here, we investigated the regulation of DeltaNp63alpha expression upon EGFR activation and the role of the EGFR-DeltaNp63alpha axis in proliferation of SCC tumor-initiating cells (TICs). SCC cell lines A-431, Cal-27, and SCC-25 treated with EGF showed a time-dependent increase in DeltaNp63alpha expression at the protein and mRNA levels, which was blocked by the tyrosine kinase inhibitor (TKI) Lapatinib. RNA interference experiments suggested the role of STAT3 in regulating DeltaNp63alpha expression downstream of EGFR. Inactivation of EGFR by the monoclonal antibody Cetuximab and RNA interference against STAT3 or DeltaNp63alpha impaired the TICs ability to grow under non-differentiating conditions. Radiation treatment, which triggers EGFR activation, induced DeltaNp63alpha accumulation without affecting TICs proliferation, whereas the combination Cetuximab plus radiation significantly reduced TICs growth under non-differentiating conditions. Together, our findings provide evidence that DeltaNp63alpha expression is regulated by EGFR activation through STAT3 and that the EGFR-DeltaNp63alpha axis is crucial for proliferation of TICs present in SCCs. PMID- 23018840 TI - Preliminary study of sural nerve morphological changes in uremic hemodialysis patients using 22-MHz high-frequency ultrasound. AB - INTRODUCTION: The aim of this study was to evaluate the ultrasound (US) morphological changes of sural nerves (SNs) of uremic patients on hemodialysis. METHODS: Sixty-six SNs in 33 uremic patients were examined by 22-MHZ high frequency US and routine nerve conduction studies (NCS), and 76 SNs in 38 controls were also examined. Cross-sectional area (CSA) and maximal fascicular thickness (MFT) of the SNs were measured. RESULTS: The inner parts of the SN were clearly identified in all participants. There were significant increases in CSA and MFT in the patient group (1.86 +/- 0.53 mm(2) and 0.37 +/- 0.08 mm, respectively) compared with the control group (1.38 +/- 0.25 mm(2) and 0.32 +/- 0.03 mm, respectively) (P < 0.001). Fifty-seven SNs (86.36%) had abnormal CSAs, and 51 SNs (77.27%) had abnormal MFTs in the patient group, which was higher than NCS abnormalities (66.67%). CONCLUSIONS: A 22-MHZ US can show morphological changes in the SNs of uremic patients and may be a valuable tool. PMID- 23018841 TI - Determination of limonin in dog plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. AB - A highly sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of limonin in beagle dog plasma using nimodipine as internal standard. The analyte and internal standard (IS) were extracted with ether followed by a rapid isocratic elution with 10 mm ammonium acetate buffer-methanol (26:74, v/v) on a C18 column (150 * 2.1 mm i.d.) and subsequent analysis by mass spectrometry in the multiple reaction monitoring mode. The precursor to product ion transitions of m/z 469.4 -> 229.3 and m/z 417.2 -> 122.0 were used to measure the analyte and the IS. The assay was linear over the concentration range of 0.625-100 ng/mL for limonin in dog plasma. The lower limit of quantification was 0.312 ng/mL and the extraction recovery was >90.4% for limonin. The inter- and intra-day precision of the method at three concentrations was less than 9.9%. The method was successfully applied to pharmacokinetic study of limonin in dogs. PMID- 23018844 TI - The impacts of population subdivision on the viability of Brachyteles hypoxanthus. AB - Habitat loss and fragmentation turn continuous large populations into metapopulations of smaller populations, more prone to the negative effects of stochastic processes. We modeled scenarios simulating the subdivision of Brachyteles hypoxanthus populations under different dispersal rates. Results show the existence of a population subdivision threshold, below which subdivision causes the metapopulation structure to collapse. Management should target first the increase in local populations through habitat restoration/protection, and only after populations are sufficiently large, connectivity strategies should take place. PMID- 23018845 TI - Successful desensitization to imiglucerase of an adult patient diagnosed with type I Gaucher disease. AB - Gaucher disease is the most common lysosomal storage disorder, and enzyme replacement therapy, such as administration of imiglucerase, is the standard therapy. Anaphylaxis to imiglucerase is rarely reported. Here, we report a 26 year-old female who was diagnosed with type 1 Gaucher disease and referred to our Allergy Outpatient Clinic because of an anaphylactic reaction due to imiglucerase enzyme therapy. A desensitization protocol was administered with two different dilutions with an increasing rate of administration delivered in 10 consecutive steps by intravenous infusion in an intensive care setting. No reactions occurred during the procedure, and the total final dose of 2,000 U was successfully administered. To our knowledge, this is the first adult case with successful desensitization to imiglucerase. Desensitization protocols to drugs in chronic disease patients for whom no alternative therapies are available can be lifesaving. PMID- 23018848 TI - A facile top-down etching to create a Cu2O jagged polyhedron covered with numerous {110} edges and {111} corners with enhanced photocatalytic activity. AB - Cutting edge: A Cu(2)O jagged polyhedron, with numerous {110} edges and {111} corners, has been developed through a top-down selective oxidative etching process at the expense of the original {111} facet (see figure). The as-prepared nanocrystals exhibited higher photocatalytic activities for the degradation of methylene orange, which may be primarily ascribed to the increased edges and corners. PMID- 23018849 TI - Effect of microwave and enzymatic treatment on the recovery of protein from Indian defatted rice bran meal. AB - Defatted rice bran meal is an important source of protein along with other micronutrients. Rice bran meal has been utilized to produce protein isolates for potential application in various food products. Attempt has been made to increase the protein solubility by physical means like microwave digestion as well as by microwave digestion followed by homogenization. Simple 40 sec microwave treatment could give the protein recovery of 78.4% as against 28.9% after 1 min of conventional boiling and 40 sec is taken as optimum time for microwave treatment. The protein recovery is further increased by microwave treatment followed by homogenization. Defatted rice bran meal has also been treated with enzyme papain and viscozyme separately to increase the protein solubility. The yield of protein isolate (RPI), prepared by alkaline extraction followed by acidic precipitation is 10.2%, which is further increased to 14.5 & 22.4% by papain, viscozyme modification and 21.1 & 22.3% by microwave treatment and microwave treatment followed by homogenization respectively. A maximum of 82.5 and 82.6% protein has been recovered as soluble protein from de-oiled bran by viscozyme treatment and by 40 sec microwave treatment followed by 10 min of homogenization. So, microwave treatment along with homogenization is a suitable alternative processes in extracting protein from rice bran meal. PMID- 23018850 TI - Rapid determination of saponification value and polymer content of vegetable and fish oils by terahertz spectroscopy. AB - A rapid method for determining the saponification value (SV) and polymer content of vegetable and fish oils using the terahertz (THz) spectroscopy was developed. When the THz absorption spectra for vegetable and fish oils were measured in the range of 20 to 400 cm-1, two peaks were seen at 77 and 328 cm-1. The level of absorbance at 77 cm-1 correlated well with the SV. When the THz absorption spectra of thermally treated high-oleic safflower oils were measured, the absorbance increased with heating time. The polymer content in thermally treated oil correlated with the absorbance at 77 cm-1. These results demonstrate that the THz spectrometry is a suitable non-destructive technique for the rapid determination of the SV and polymer content of vegetable and fish oils. PMID- 23018851 TI - Distillation time alters essential oil yield, composition, and antioxidant activity of male Juniperus scopulorum trees. AB - The objective of this study was to evaluate the effect of 15 distillation times (DT), ranging from 1.25 to 960 min, on oil yield, essential oil profiles, and antioxidant capacity of male J. scopulorum trees. Essential oil yields were 0.07% at 1.25 min DT and reached a maximum of 1.48% at 840 min DT. The concentrations of alpha-thujene (1.76-2.75%), alpha-pinene (2.9-8.7%), sabinene (45-74.7%), myrcene (2.4-3.4%), and para-cymene (0.8-3.1%) were highest at the shortest DT (1.5 to 5 min) and decreased with increasing DT. Cis-sabinene hydrate (0.5-0.97%) and linalool plus trans-sabinene (0.56-1.6%) reached maximum levels at 40 min DT. Maximum concentrations of limonene (2.3-2.8%) and pregeijerene-B (0.06-1.4%) were obtained at 360-480 min DT, and 4-terpinenol (0.7-5.7%) at 480 min DT. Alpha terpinene (0.16-2.9%), gamma-terpinene (0.3-4.9%) and terpinolene (0.3-1.4%) reached maximum at 720 min DT. The concentrations of delta-cadinene (0.06-1.65%), elemol (0-6.0%), and 8-alpha-acetoxyelemol (0-4.4%) reached maximum at 840 min DT. The yield of the essential oil constituents increased with increasing DT. Only linalool/transsabinene hydrate reached a maximum yield at 360 min DT. Maximum yields of the following constituents were obtained at 720 min DT: alpha thujene, alpha-pinene, camphene, sabinene, myrcene, alpha-terpinene, para-cimene, limonene, gamma-terpinene, terpinolene, and 4-terpinenol. At 840 min DT, cis sabinene hydrate, prejeijerene-B, gamma muurolene, delta-cadinene, reached maximum. At 960 min DT, maximum yields of beta-pinene, elemol, alphaeudesmol/betaeudesmol, 8-alpha-acetoxyelemol were reached. These changes were adequately modeled by either the Michaelis-Menten or the Power (Convex) nonlinear regression models. Oils from the 480 min DT showed higher antioxidant activity compared to samples collected at 40, 160, or 960 min DT. These results show the potential for obtaining essential oils with various compositions and antioxidant capacity from male J. scopulorum by varying DT. This study can be used as a reference paper for comparing results of reports where different lengths of the DT were used. PMID- 23018852 TI - Characteristic of lipids and fatty acid compositions of the neon flying squid, Ommastrephes bartramii. AB - The lipids and fatty acids of the neon flying squid (Ommastrephes bartramii) were an-alyzed to clarify its lipid physiology and health benefit as marine food. Triacylglycerols were the only major component in the digestive gland (liver). In all other organs (mantle, arm, integument, and ovary), sterols and phospholipids were the major components with noticeable levels of ceramide aminoethyl phosphonate and sphingomyelin. The significant levels of sphingolipids suggest the O. bartramii lipids is a useful source for cosmetics. Although the lipid content between the liver and all other tissues markedly differed from each other, the same nine dominant fatty acids in the triacylglycerols were found in all organs; 14:0, 16:0, 18:0, 18:1n-9, 20:1n-9, 20:1n-11, 22:1n-11, 20:5n-3 (icosapentaenoic acid, EPA), and 22:6n-3 (docosahexaenoic acid, DHA). Unusually high 20:1n-11 levels in the O. bartramii triacylglycerols were probably characteristic for western Pacific animal depot lipids, compared with non detectable levels of 20:1n-11 reported in other marine animals. O. bartramii concurrently has high levels of DHA in their triacylglycerols. The major fatty acids in the phospholipids were 16:0, 18:0, 20:1n-9, EPA, and DHA without 20:1n 11. Markedly high levels of both EPA and DHA were observed in phosphatidylethanolamine, while only DHA was found as the major one in phosphatidylcholine. In particular, high levels of DHA were found both in its depot triacylglycerols and tissue phospholipids in all organs of O. bartramii, similar to that in highly migratory fishes. The high DHA levels in all its organs suggest that O. bartramii lipids is a healthy marine source for DHA supplements. PMID- 23018853 TI - Calcination-free liftoff photolithography of mixed dip-coated films consisting of rare-Earth-ion-doped nanoparticles on plastic sheets. AB - We discuss the calcination-free liftoff photolithography of inorganic phosphor films consisting of two kinds of rare-earth-ion-doped (RE) nanoparticles dip coated onto plastic sheets. Green and red upconversion luminescence were emitted from the RE-nanoparticles prepared from Y2O3 nanoparticles doped with 1 mol% Er3+ and 0.75 mol% Yb3+ (RE-1-nanoparticles) and those doped with 3 mol% Er3+ and 7 mol% Yb3+ (RE-2-nanoparticles), respectively. Near-infrared (NIR) fluorescence was also observed in the RE-1- and RE-2-nanoparticles. The visible transmittance of the RE-nanoparticle films was more than 90%. The intensity ratio of the green to red upconversion luminescence was controlled by adjusting the mixing ratio of the RE-1- and RE-2-nanoparticles. These results indicate that the multicolor emitting devices can be fabricated easily for applications of flexible inorganic phosphor films to displays, emitting devices, and sensors with long operating lifetimes and resistance to UV light, air, and water. PMID- 23018854 TI - Water induced microstructure transformation of diglycerol monolaurate reverse micelles in ethylbenzene. AB - Water induced microstructure transitions of diglycerol monolaurate (C(12)G(2)) reverse micelles in aromatic liquid ethylbenzene have been investigated using small-angle X-ray scattering (SAXS) and rheometry. The SAXS data have been evaluated by generalized indirect Fourier transformation (GIFT) and geometrical model fittings. We found that the C(12)G(2) spontaneously self-assembles into ellipsoidal prolate micelles in ethylbenzene under ambient conditions. The maximum diameter of the micellar core is ca. 5.0 nm. We noted that 5% C(12)G(2)/ethylbenzene solubilize 0.8% water and the water causes micellar growth; micellar size is ~ 3 times bigger than the empty micelles. Rheology data showed that viscosity of 5% C(12)G(2)/ethylbenzene increases with increase in the water concentration sustaining the SAXS results that the viscosity increase is caused due to micellar growth. We found that increase in temperature of the water incorporated system decreases micellar size, which is equivalent to a rod-to sphere type transition. The water induced microstructure transformations can be explained in terms of critical packing parameter, cpp. Water hydrates hydrophilic headgroup of surfactant so that effective cross-sectional area of surfactant increases. As a result the cpp decreases and micelles grow. On the other hand, increasing temperature promotes interpenetration of solvent and surfactant chain as a result cpp increases due to decrease in the effective cross-sectional area of surfactant. Moreover dehydration may occur and micelles with more curved interface are formed due to increases in the cpp. PMID- 23018855 TI - A novel bioactive chalcone of Morus australis inhibits tyrosinase activity and melanin biosynthesis in B16 melanoma cells. AB - The methanol extract of Morus australis (shimaguwa) acts as a whitening agent due to the inhibition of tyrosinase activity. In order to explore the mechanism(s) of the whitening action, constituents of the 95% methanol extract from the dried stems of shimaguwa were isolated and their skin-whitening capacity was examined. Bioassay-guided fractionation of the methanol soluble extract of shimaguwa led to the isolation of 2, 4, 2', 4'-hydroxycalcone (chalcone 1) and three analogues of chalcone 1 with 3'-substituted resorcinol moieties (chalcones 2-4). Chalcone derivative 4 proved to be a novel compound and was fully characterized. Chalcones 1-4 were evaluated for inhibition activity on mushroom tyrosinase using L tyrosine as the substrate. The parent chalcone 1 was a highly effective inhibitor of tyrosinase activity (IC50 = 0.21 MUM) compared to arbutin (IC50 = 164 MUM). Compared to chalcone 1, chalcones 2 and 3, which possess 3'-substituted isoprenyl or bulky 2-benzoylbiphenyl, showed significantly decreased tyrosinase activity, while chalcone 4, possessing 3'-substituted 2-hydroxy-1-pentene group, showed slightly increased activity.The effects of chalcones 1-4 on melanin synthesis, without affecting cell growth, were assayed in melanin-producing B16 murine melanoma cells. Chalcone 3 significantly reduced cell viability before reaching the IC50 value for melanin synthesis. In contrast, the inhibitory effects of chalcones 1, 2 and 4 were more than 100-fold greater than that of arbutin, with little or no cytotoxicity. More significantly, chalcone 2, which exhibited less tyrosinase inhibitory activity compared to the parent chalcone 1, showed the highest inhibition of melanin synthesis in B16 cells among the chalcones tested. Accordingly, chalcones 1 and 2, and the novel chalcone 4 might be the active components responsible for the whitening ability of shimaguwa. Moreover, whitening ability was not exclusively due to tyrosinase inhibition. PMID- 23018856 TI - Development of novel carbon fiber produced from waste fiber by carbonization. AB - The volume of waste fiber has increased rapidly in recent years, and this trend is expected to continue. In this study, therefore, we attempted to convert waste fiber to carbonaceous materials by carbonization and investigated the basic properties of the resulting carbonized fibers. The results demonstrated that pores tend to form and specific surface areas change substantially, depending on the carbonization conditions. The carbonization conditions resulting in the largest specific surface areas included a temperature increase and retention times of 2 h. Carbonization temperatures resulting in the maximum values of 1000 degrees C were 900-1000 degrees C for wool and 1000 degrees C for both polyester and cotton. In particular, the specific surface area of cotton after carbonization at 1000 degrees C was 1253 m2/g, and scanning electron microscopy (SEM) micrographs showed that cotton retained its fibrous form after carbonization. Thus, it is possible to inexpensively convert waste fibers to carbonaceous material by carbonization. The results indicate that for cotton fiber in particular, the practical application of this process to the production of low-cost fibrous activated carbon would be possible, since cotton fiber retains its fibrous form under carbonization. PMID- 23018857 TI - Update: biomarkers for idiopathic inflammatory myopathies. AB - PURPOSE OF REVIEW: Establishing diagnoses and distinguishing active disease from chronic injury remain significant clinical challenges in idiopathic inflammatory myopathies (IIM). Recent 'discovery' approaches utilizing novel genomic and proteomic techniques have revealed candidate molecular biomarkers to augment clinical and classical histological data. RECENT FINDINGS: Whole blood and serum Type 1 interferons (IFN-1) and IFN-1 inducible genes are gaining traction as disease biomarkers in IIM. IFNbeta is emerging as a disease activity marker specifically for dermatomyositis. Recently, molecules associated with innate immune-cell function, including TLR-3, high mobility group box (HMGB)-1, B7 Homolog 1, S100A4, and resistin have been detected in tissues of dermatomyositis patients. Serum Interleukin-17 (IL-17) and IL-23 correlate with active disease in early IIM. Antibodies recognizing the Survival Motor Neuron complex have been newly identified in a subset of patients with polymyositis. Protein aggregates are potential disease activity sensors for inclusion body myositis. Skin and lung harbor potential biomarkers for IIM. SUMMARY: Recent advances in understanding the pathogenesis of IIM have led to discovery of molecules that are candidate biomarkers of disease activity. Type 1 interferon and myeloid-cell signatures are leading candidate markers for use in IIM activity monitoring. PMID- 23018858 TI - Morphea and other localized forms of scleroderma. AB - PURPOSE OF REVIEW: Morphea, also known as localized scleroderma, is a disorder of excessive collagen deposition leading to thickening of the dermis and/or subcutaneous tissues and may cause significant morbidity. This review will describe new developments in the evaluation and management of morphea as well as its pathophysiology. The reader will be able to apply these findings to patient management. RECENT FINDINGS: The recent development of validated outcome measures (i.e. the localized scleroderma cutaneous assessment tool) as well as consensus treatment recommendations provide a platform for collaboration among specialties to develop both standardized assessment tools and therapeutic trials. New studies have also begun to investigate the immunological underpinnings of morphea. SUMMARY: The promise of evidence-based treatments for morphea in the near future will provide better care for patients with morphea and understanding its pathophysiology will lay groundwork for the development of new treatments. PMID- 23018859 TI - Current world literature. PMID- 23018861 TI - Striking improvement in peroxidase activity of cytochrome c by modulating hydrophobicity of surface-functionalized gold nanoparticles within cationic reverse micelles. AB - This work demonstrates a remarkable enhancement in the peroxidase activity of mitochondrial membrane protein cytochrome c (cyt c) by perturbing its tertiary structure in the presence of surface-functionalised gold nanoparticles (GNPs) within cetyltrimethylammonium bromide (CTAB) reverse micelles. The loss in the tertiary structure of cyt c exposes its heme moiety (which is buried inside in the native globular form), which provides greater substrate (pyrogallol and H(2)O(2)) accessibility to the reactive heme residue. The surfactant shell of the CTAB reverse micelle in the presence of co-surfactant (n-hexanol) exerted higher crowding effects on the interfacially bound cyt c than similar anionic systems. The congested interface led to protein unfolding, which resulted in a 56-fold higher peroxidase activity of cyt c than that in water. Further perturbation in the protein's structure was achieved by doping amphiphile-capped GNPs with varying hydrophobicities in the water pool of the reverse micelles. The hydrophobic moiety on the surface of the GNPs was directed towards the interfacial region, which induced major steric strain at the interface. Consequently, interaction of the protein with the hydrophobic domain of the amphiphile further disrupted its tertiary structure, which led to better opening up of the heme residue and, thereby, superior activity of the cyt c. The cyt c activity in the reverse micelles proportionately enhanced with an increase in the hydrophobicity of the GNP-capping amphiphiles. A rigid cholesterol moiety as the hydrophobic end group of the GNP strikingly improved the cyt c activity by up to 200-fold relative to that found in aqueous buffer. Fluorescence studies with both a tryptophan residue (Trp59) of the native protein and the sodium salt of fluorescein delineated the crucial role of the hydrophobicity of the GNP-capping amphiphiles in improving the peroxidase activity of cyt c by unfolding its tertiary structure within the reverse micelles. PMID- 23018863 TI - Efficient expression systems for cysteine proteases of malaria parasites: too good to be true? AB - Papain-like cysteine proteases of malaria parasites are considered important chemotherapeutic targets or valuable models for the evaluation of drug candidates. Consequently, many of these enzymes have been cloned and expressed in Escherichia coli for their biochemical characterization. However, their expression has been problematic, showing low yield and leading to the formation of insoluble aggregates. Given that highly-productive expression systems are required for the high-throughput evaluation of inhibitors, we analyzed the existing expression systems to identify the causes of such apparent issues. We found that significant divergences in codon and nucleotide composition from host genes are the most probable cause of expression failure, and propose several strategies to overcome these limitations. Finally we predict that yeast hosts Saccharomyces cerevisiae and Pichia pastoris may be better suited than E. coli for the efficient expression of plasmodial genes, presumably leading to soluble and active products reproducing structural and functional characteristics of the natural enzymes. PMID- 23018864 TI - HOX and TALE signatures specify human stromal stem cell populations from different sources. AB - Human stromal stem cell populations reside in different tissues and anatomical sites, however a critical question related to their efficient use in regenerative medicine is whether they exhibit equivalent biological properties. Here, we compared cellular and molecular characteristics of stromal stem cells derived from the bone marrow, at different body sites (iliac crest, sternum, and vertebrae) and other tissues (dental pulp and colon). In particular, we investigated whether homeobox genes of the HOX and TALE subfamilies might provide suitable markers to identify distinct stromal cell populations, as HOX proteins control cell positional identity and, together with their co-factors TALE, are involved in orchestrating differentiation of adult tissues. Our results show that stromal populations from different sources, although immunophenotypically similar, display distinct HOX and TALE signatures, as well as different growth and differentiation abilities. Stromal stem cells from different tissues are characterized by specific HOX profiles, differing in the number and type of active genes, as well as in their level of expression. Conversely, bone marrow derived cell populations can be essentially distinguished for the expression levels of specific HOX members, strongly suggesting that quantitative differences in HOX activity may be crucial. Taken together, our data indicate that the HOX and TALE profiles provide positional, embryological and hierarchical identity of human stromal stem cells. Furthermore, our data suggest that cell populations derived from different body sites may not represent equivalent cell sources for cell-based therapeutical strategies for regeneration and repair of specific tissues. PMID- 23018866 TI - Mediastinal lymphangioma treated using endobronchial ultrasound-guided transbronchial needle aspiration. AB - Lymphangiomas are localized malformations of the lymphatic system that most commonly occur in the head and neck. However, less than 1% of all lymphangiomas are confined to the mediastinum. The standard treatment has been surgical excision, but the involvement of vital structures in the area local to the lymphangioma makes total excision virtually impossible in most cases. To our knowledge, there has been no report of mediastinal lymphangioma treated with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). We report here the first case of safe, effective treatment of a very large mediastinal lymphangioma using EBUS-TBNA in a 29-year-old man. PMID- 23018865 TI - ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. AB - We aimed at evaluating ASXL1mut in 740 AML with intermediate risk karyotype for frequency, association with other mutations and impact on outcome. Five hundred fifty-three cases had a normal karyotype (NK) and 187 had intermediate risk aberrant cytogenetics. Overall, ASXL1mut were detected in 127/740 patients (17.2%). ASXL1mut were more frequent in males than in females (23.5% vs 9.9%, P<0.001). They were associated with higher age (median: 71.8 vs 61.8, P<0.001), a history of preceding myelodysplastic syndromes, and with a more immature immunophenotype compared with patients with wild-type ASXL1 (ASXL1wt). ASXL1mut were more frequent in patients with aberrant karyotype (58/187; 31.0%), especially in cases with trisomy 8 (39/74; 52.7%), than in those with NK (69/553; 12.5%; P<0.001). ASXL1mut were observed more frequent in RUNX1mut (P<0.001), and less frequent in NPM1mut (P<0.001), FLT3-internal tandem duplication (ITD) (P<0.001), FLT3-TKD (P=0.001) and DNMT3Amut (P<0.001). Patients with ASXL1mut had a shorter overall survival (OS) (P<0.001) and event free survival (P=0.012) compared with ASXL1wt. In multivariable analysis, ASXL1mut was an independent adverse factor for OS (P=0.032, relative risk: 1.70). In conclusion, ASXL1mut belong to the most frequent mutations in intermediate risk group AML. Their strong and independent dismal prognostic impact suggests the inclusion into the diagnostic work-up of AML. PMID- 23018867 TI - Genome-wide methylation profiling identifies hypermethylated biomarkers in high grade cervical intraepithelial neoplasia. AB - Epigenetic modifications, such as aberrant DNA promoter methylation, are frequently observed in cervical cancer. Identification of hypermethylated regions allowing discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3), or worse, may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions was studied using genome-wide DNA methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methylated DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium. Hypermethylated differentially methylated regions (DMRs) were identified. Validation of nine selected DMRs using BSP and MSP in cervical tissue revealed methylation in 63.2-94.7% high-grade CIN and in 59.3-100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was conducted exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples. Clinical validation of both markers in cervical scrapings from patients with an abnormal cervical smear confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion and that ROC analysis was discriminative. These markers represent the COL25A1 and KATNAL2 and their observed increased methylation upon progression could intimate the regulatory role in carcinogenesis. In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and are candidate biomarkers for early detection. PMID- 23018868 TI - Residual nodal disease in patients with advanced-stage oropharyngeal squamous cell carcinoma treated with definitive radiation therapy and posttreatment neck dissection: Association with locoregional recurrence, distant metastasis, and decreased survival. AB - BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in frequency. We reviewed patients with advanced-stage OPSCC treated with chemoradiation to assess the impact of residual neck disease on survival. METHODS: We reviewed 202 patients with OPSCC between 1990 and 2010 treated with primary chemoradiation followed by neck dissection. Imaging was analyzed using RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria. Survival was evaluated using both univariate and multivariate analyses. RESULTS: Overall survival at 5 years was 89%. Forty-two patients (21%) had residual disease in the neck (pN+). pN+ was associated with greater locoregional recurrence (LRR) and distant metastasis (DM) and decreased survival. No clinicopathologic factors were predictive of pN+. Contrasted posttreatment CT had low sensitivity and specificity. CONCLUSIONS: In advanced OPSCC pN+, patients have higher rates of LRR and DM. Neither clinicopathologic factors nor posttreatment imaging was predictive of pN+, although increased use of modern imaging may reduce the rate of negative neck dissections. PMID- 23018869 TI - Sensory relearning after surgical treatment for carpal tunnel syndrome: a pilot clinical trial. AB - INTRODUCTION: Surgical treatment for carpal tunnel syndrome does not always alleviate sensory deficits, especially in patients with severe disease. No proven treatment is currently available for these patients. METHODS: We conducted a pilot randomized, controlled trial to evaluate the feasibility, patient acceptability, and efficacy of a sensory relearning (SR) program in patients who have ongoing sensory deficits after carpal tunnel decompression. Patients were randomized to receive either: (i) a 4-week sensory relearning home program; or (ii) no further treatment. Outcomes were assessed at baseline and 4 and 8 weeks after randomization. RESULTS: Thirty-one patients were randomized. Efficacy analysis adjusted for baseline score and age showed a potentially clinically worthwhile benefit of SR. CONCLUSIONS: Data on screening, eligibility, and patient acceptability of the intervention confirm the feasibility of undertaking a definitive randomized, controlled trial. PMID- 23018870 TI - Downregulation of endogenous intermedin augmented myocardial injury in rats with ischemia/reperfusion. AB - Intermedin (IMD) plays an important regulatory role in cardiovascular function. We aimed to explore the protein expression of IMD and its receptors, calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs), and the role of endogenous IMD in myocardial ischemia/reperfusion (I/R) injury in rats. The rat model of I/R was created by ligating cardiac left anterior descending artery. Western blot was used to determine protein expression of CRLR and RAMPs, and radioimmunoassay was used to detect IMD content. Compared with control, protein levels of CRLR and RAMPs in both ischemic and nonischemic region were upregulated at different stages of reperfusion. IMD protein content in nonischemic area myocardium also increased. However, IMD protein content in ischemic area downregulated at 3-, 6-, and 12-h reperfusion. In hypoxia/reoxygenation model of neonatal cardiomyocytes, IMD attenuated myocyte injury, and IMD receptor antagonist IMD17-47 aggravated myocyte impairment by blocking endogenous IMD. In conclusion, the downregulation of IMD at early stage of reperfusion might augment myocardium injury. PMID- 23018871 TI - T(14;18)(q32;q21) involving MALT1 and IGH genes occurs in extranodal diffuse large B-cell lymphomas of the breast and testis. AB - Primary B-cell lymphoma of the testis, breast and thyroid are rare and data concerning cytogenetic aberrations at these extranodal sites are scarce. We examined the presence of extranodal marginal zone lymphoma-associated translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(p14.1;q32) and numerical aberrations of chromosomes 1, 3, 12 and 18 by fluorescence in situ hybridization in 6 extranodal marginal zone lymphomas and 24 diffuse large B-cell lymphomas with (n=9) or without (n=15) marginal zone lymphoma components, with primary localizations in the breast (n=15), testis (n=9) and thyroid (n=6). We found t(14;18)(q32;q21), with breakpoints in IGH and MALT1, in one testicular diffuse large B-cell lymphoma and in two diffuse large B cell lymphomas of the breast. No other translocations, amplifications or deletions involving IGH, BCL-10, BCL-2, MALT1 and IAP2 were detected. Numerical aberrations occurred in 67% of the lymphomas, 67% of extranodal marginal zone lymphomas, 56% of diffuse large B-cell lymphomas with marginal zone lymphoma components and in 73% of 'de novo' diffuse large B-cell lymphomas. These included 78% of testis, 67% of thyroid and 60% of breast lymphomas, and included mainly trisomy 18 (n=16), trisomy 3 (n=8) and trisomy 1 (n=3). One testicular diffuse large B-cell lymphoma harbored both t(14;18)(q32;q21) and trisomy 3. Our results indicate that at least a few cases of diffuse large B-cell lymphoma of the testis and the breast belong to the spectrum of extranodal marginal zone lymphoma. PMID- 23018872 TI - Amyloidosis of the breast: predominantly AL type and over half have concurrent breast hematologic disorders. AB - Amyloidosis is a disorder characterized by extracellular deposition of proteins in an abnormal fibrillar configuration. Amyloidosis can be localized or systemic and may affect any organ. Breast involvement by amyloidosis has rarely been reported. In this study, we described the characteristics of 40 cases of breast amyloidosis that were reviewed at the Division of Anatomic Pathology at Mayo Clinic from 1995 to 2011. The cohort included 39 women and 1 man with a mean age of 60 years. The type of amyloidosis, determined by immunohistochemistry or mass spectrometry-based proteomics in 26 patients, was immunoglobulin-associated in all cases (AL-kappa type in 15 (58%) cases, AL-lambda in 10 (38%) and mixed heavy and light chains (AH/AL) in 1 (4%) case). Mass spectrometry-based proteomics was able to determine the type of amyloidosis in 95% of cases tested compared with 69% of cases by immunohistochemistry. In addition to amyloidosis, the breast biopsy showed a hematologic disorder in 55% of cases, most commonly MALT lymphoma. One patient had concurrent intraductal carcinoma, but none had invasive carcinoma. Of the 15 patients seen in our institution, 53% had localized amyloidosis and 47% had extramammary amyloid involvement, which was diagnosed before breast amyloidosis in most patients. M-spike was detected in the blood in 62%. After a median follow-up of 33.5 months in 12 patients, 5 died, mostly of complications of lymphoma or leukemia. In conclusion, our findings indicate that breast amyloidosis is of the AL type in the vast majority of patients (usually kappa). It is associated with systemic amyloidosis in close to half of patients and with hematologic malignancy in the breast in over half of patients. Therefore, further work up to rule out hematologic malignancy and/or systemic amyloidosis is recommended. Mass spectrometry-based proteomics is superior to immunohistochemistry for typing of breast amyloidosis. PMID- 23018873 TI - Genomic profiles and CRTC1-MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma. AB - Mucoepidermoid carcinoma is the most common salivary gland malignancy, and includes a spectrum of lesions ranging from non-aggressive low-grade tumors to aggressive high-grade tumors. To further characterize this heterogeneous group of tumors we have performed a comprehensive analysis of copy number alterations and CRTC1-MAML2 fusion status in a series of 28 mucoepidermoid carcinomas. The CRTC1 MAML2 fusion was detected by RT-PCR or fluorescence in situ hybridization in 18 of 28 mucoepidermoid carcinomas (64%). All 15 low-grade tumors were fusion positive whereas only 3 of 13 high-grade tumors were fusion-positive. High resolution array-based comparative genomic hybridization revealed that fusion positive tumors had significantly fewer copy number alterations/tumor compared with fusion-negative tumors (1.5 vs 9.5; P=0.002). Twelve of 18 fusion-positive tumors had normal genomic profiles whereas only 1 out of 10 fusion-negative tumors lacked copy number alterations. The profiles of fusion-positive and fusion negative tumors were very similar to those of low- and high-grade tumors. Thus, low-grade mucoepidermoid carcinomas had significantly fewer copy number alterations/tumor compared with high-grade mucoepidermoid carcinomas (0.7 vs 8.6; P<0.0001). The most frequent copy number alterations detected were losses of 18q12.2-qter (including the tumor suppressor genes DCC, SMAD4, and GALR1), 9p21.3 (including the tumor suppressor genes CDKN2A/B), 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3 (including the oncogene MAFA), 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2 (including the oncogenes LYN, MOS, and PLAG1). On the basis of these results we propose that mucoepidermoid carcinoma may be subdivided in (i) low-grade, fusion-positive mucoepidermoid carcinomas with no or few genomic imbalances and favorable prognosis, (ii) high-grade, fusion-positive mucoepidermoid carcinomas with multiple genomic imbalances and unfavorable prognosis, and (iii) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcome. Taken together, our studies indicate that molecular genetic analysis can be a useful adjunct to histologic scoring of mucoepidermoid carcinoma and may lead to development of new clinical guidelines for management of these patients. PMID- 23018874 TI - PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade. AB - Prostatic adenocarcinoma is an epithelial malignancy characterized by marked histological heterogeneity. It most often has a multifocal distribution within the gland, and different Gleason grades may be present within different foci. Data from our group and others have shown that the genomic deletion of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and the disruption of the ETS gene family have a central role in prostate cancer and are likely to be associated with Gleason grade. In this study, prostate cancer samples were systematically analyzed to determine whether there was concordance between PTEN losses and TMPRSS2-ERG fusion rearrangements, within or between foci in multifocal disease, using well-annotated tissue microarrays (TMAs) consisting of 724 cores derived from 142 radical prostatectomy specimens. Three-color fluorescence in situ hybridization analysis of both the PTEN deletion and the TMPRSS2-ERG fusion was used to precisely map genetic heterogeneity, both within and between tumor foci represented on the TMA. PTEN deletion was observed in 56 of 134 (42%) patients (hemizygous=42 and homozygous=14). TMPRSS2-ERG fusion was observed in 63 of 139 (45%) patients. When analyzed by Gleason pattern for a given TMA core, PTEN deletions were significantly associated with Gleason grades 4 or 5 over grade 3 (P<0.001). Although TMPRSS2-ERG fusions showed a strong relationship with PTEN deletions (P=0.007), TMPRSS2-ERG fusions did not show correlation with Gleason grade. The pattern of genetic heterogeneity of PTEN deletion was more diverse than that observed for TMPRSS2-ERG fusions in multifocal disease. However, the marked interfocal discordance for both TMPRSS2 ERG fusions and PTEN deletions was consistent with the concept that multiple foci of prostate cancer arise independently within the same prostate, and that individual tumor foci can have distinct patterns of genetic rearrangements. PMID- 23018875 TI - Proposal for a 10-high-power-fields scoring method for the assessment of tumor budding in colorectal cancer. AB - Although tumor budding is linked to adverse prognosis in colorectal cancer, it remains largely unreported in daily diagnostic work due to the absence of a standardized scoring method. Our aim was to assess the inter-observer agreement of a novel 10-high-power-fields method for assessment of tumor budding at the invasive front and to confirm the prognostic value of tumor budding in our setting of colorectal cancers. Whole tissue sections of 215 colorectal cancers with full clinico-pathological and follow-up information were stained with cytokeratin AE1/AE3 antibody. Presence of buds was scored across 10-high-power fields at the invasive front by two pathologists and two additional observers were asked to score 50 cases of tumor budding randomly selected from the larger cohort. The measurements were correlated to the patient and tumor characteristics. Inter-observer agreement and correlation between observers' scores were excellent (P<0.0001; intraclass correlation coefficient=0.96). A test subgroup of 65 patients (30%) was used to define a valid cutoff score for high grade tumor budding and the remaining 70% of the patients were entered into the analysis. High-grade budding was defined as an average of >=10 buds across 10 high-power fields. High-grade budding was associated with a higher tumor grade (P<0.0001), higher TNM stage (P=0.0003), vascular invasion (P<0.0001), infiltrating tumor border configuration (P<0.0001) and reduced survival (P<0.0001). Multivariate analysis confirmed its independent prognostic effect (P=0.007) when adjusting for TNM stage and adjuvant therapy. Using 10-high-power fields for evaluating tumor budding has independent prognostic value and shows excellent inter-observer agreement. Like the BRE and Gleason scores in breast and prostate cancers, respectively, tumor budding could be a basis for a prognostic score in colorectal cancer. PMID- 23018876 TI - Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease. AB - Primary myelofibrosis is a type of chronic myeloproliferative neoplasm characterized by progressive bone marrow failure with worsening cytopenia and in a subset of patients, progression to acute leukemia. Published data in patients with myelodysplastic syndromes have shown that the development of monocytosis in the course of myelodysplastic syndromes is associated with a poor prognosis. A similar occurrence has been only sporadically reported in patients with primary myelofibrosis. Over a period of four years we identified 10 out of 237 cases of primary myelofibrosis who developed persistent absolute monocytosis (>1 * 10(9)/l) during the course of disease (5 men and 5 women; median age/range: 68 years/52-82). Monocytosis developed at a median interval of 42 months from diagnosis (range: 1-180) and persisted for a median period of 23 months (range: 2 57). Five patients died after developing monocytosis (range: 20-188 months) and two experienced worsening disease and became transfusion dependent. Monocytosis was associated with increased white blood cells, decreased hemoglobin, decreased platelet count, and the presence of circulating blasts. In three cases, bone marrow biopsies after the onset of monocytosis showed marked myelomonocytic proliferation with morphological shifting from a typical primary myelofibrosis marrow appearance to aspects compatible with an overt 'secondary' chronic myelomonocytic leukemia. Before the development of monocytosis, 5 of 10 patients carried the JAK2V617F mutation; five patients showed karyotypic alterations. No change in JAK2 mutational status or cytogenetic evolution were associated with the development of monocytosis. Four of nine patients analyzed showed KRAS mutation in codon 12 or 13 with low allele burden. This is the first study correlating monocytosis developing in primary myelofibrosis patients with bone marrow morphology, laboratory data, molecular analysis and clinical follow-up. Development of monocytosis in patients with established primary myelofibrosis is associated with rapid disease progression and these patients should be considered as a high-risk group associated with short survival. PMID- 23018877 TI - Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. AB - We previously described restrictive allograft syndrome as a form of chronic lung allograft dysfunction, demonstrating restrictive pulmonary function decline. However, the histopathological correlates of restrictive allograft syndrome have yet to be satisfactorily described. We hypothesized that pulmonary pleuroparenchymal fibroelastosis, as has recently been described in bone marrow transplant recipients, may also be present in the lungs of patients with restrictive allograft syndrome. Retrospective review of 493 patients who underwent lung transplantation between 1 January 1996 and 30 June 2009, was conducted. Out of 47 patients with clinical features of restrictive allograft syndrome, 16 had wedge biopsy, re-transplant lung explant, or autopsy lung specimens available for review. All lungs showed varying degrees of pleural fibrosis. Fifteen of 16 showed parenchymal fibroelastosis, characterized by hypocellular collagen deposition with preservation and thickening of the underlying alveolar septal elastic network. The fibroelastosis was predominantly subpleural in distribution, with some cases also showing centrilobular and paraseptal distribution. A sharp demarcation was often seen between areas of fibroelastosis and unaffected lung parenchyma, with fibroblastic foci often present at this interface. Concurrent features of obliterative bronchiolitis were present in 14 cases. Another common finding was the presence of diffuse alveolar damage (13 cases), usually in specimens obtained <1 year after clinical onset of restrictive allograft syndrome. The single specimen in which fibroelastosis was not identified was obtained before the clinical onset of chronic lung allograft dysfunction, and showed features of diffuse alveolar damage. In conclusion, pleuroparenchymal fibroelastosis is a major histopathologic correlate of restrictive allograft syndrome, and was often found concurrently with diffuse alveolar damage. Our findings support a temporal sequence of diffuse alveolar damage followed by the development of pleuroparenchymal fibroelastosis in the histopathologic evolution of restrictive allograft syndrome. PMID- 23018878 TI - Is decedent race an independent predictor of organ donor consent or merely a surrogate marker of socioeconomic status? AB - BACKGROUND: Studies have demonstrated that African American race is a strong predictor of nondonation. However, it is often and correctly argued that African American race is a crude explanatory variable that is a surrogate marker of socioeconomic status, education, and access to health care. We hypothesized that, when controlling for these factors, African American race would cease to be a predictor of organ donation. METHODS: A retrospective review of 1292 Alabama decedents who were approached for organ donation between 2006 and 2009 was performed. Multivariable logistic regression models were constructed to identify the most parsimonious model that could explain the variation in the log odds of obtaining consent. RESULTS: Consent for donation was obtained from 49% of the decedents' families. Household income was a predictor of organ donor consent only in whites. Surprisingly, household income was not statistically different between consented and nonconsented African American decedents (U.S. $25,147 vs. U.S. $26,137, P=0.90). On multivariable analysis, education, urban residence, and shorter distance between the decedent's residence and donor hospital were significantly associated with obtaining consent for organ donation. On univariate analysis, the odds ratio of donor consent in whites compared with African Americans was 2.76 (95% confidence interval, 2.17-3.57). When controlling for socioeconomic status and access to health care variables, the odds ratio of donor consent increased to 4.36 (95% confidence interval, 2.88-6.61). CONCLUSIONS: We interpret this result to indicate that there remains unknown but important factor(s) associated with both race and obtaining organ donor consent. Further studies are required to isolate and determine whether this factor(s) is modifiable. PMID- 23018879 TI - Earlier decrease of FGF-23 and less hypophosphatemia in preemptive kidney transplant recipients. AB - BACKGROUND: Levels of fibroblast growth factor (FGF)-23, a phosphaturic hormone, increase from the early stages of CKD and are dramatically elevated in dialysis patients. Excessive FGF-23 may be involved in the hypophosphatemia and inappropriately low calcitriol levels observed after kidney transplantation (KT).This prospective observational cohort study was carried out to determine whether there are any differences in the changes in FGF-23 levels after surgery in KT recipients according to whether they were or not on dialysis before transplantation and to assess the influence of FGF-23 in the development of posttransplantation hypophosphatemia. METHODS: Consecutive KT recipients at the Hospital Clinic of Barcelona were recruited. Patients developing delayed graft function were excluded. Mineral metabolism parameters, including C-terminal fragment of FGF-23, intact parathyroid hormone, and 1,25(OH)(2)D(3), were measured in 72 KT recipients (58 on dialysis before transplantation and 14 preemptive transplant recipients) at baseline, on day 15, and at 1, 3, and 6 months after transplantation. No patients received treatment with calcimimetics, bisphosphonates, vitamin D, or phosphate supplementation during the follow-up. RESULTS: FGF-23 decreased significantly in the first month after transplantation. Baseline and FGF-23 levels within the first posttransplantation month were lower in preemptive transplant recipients than in patients on dialysis at transplantation. Serum phosphate levels were lower in dialysis patients until the third month after transplantation. Pretransplantation FGF-23 was the main predictor of posttransplantation phosphate blood levels. CONCLUSIONS: FGF-23 levels and the risk of developing posttransplantation hypophosphatemia were lower in preemptive kidney transplant recipients than in patients on dialysis before transplantation. PMID- 23018880 TI - Combined liver-intestine grafts compared with isolated intestinal transplantation in children: a single-center experience. AB - BACKGROUND: Intestinal transplantation is known to be associated with a high risk of early complications and mortality. METHODS: We analyzed prospective data of 51 primary small bowel transplantations from December 1999 to August 2009 and identified perioperative factors that impact on early mortality (<=6 months after transplantation) after isolated intestinal (IITx; n=12) and combined liver intestinal transplantation (CLITx group; n=39). RESULTS: Ten patients died during the first 6 months after transplantation, all of them in CLITx group (n=10/51, 19%). Multivariate analyses demonstrated intraoperative red blood cell transfusion greater than 70 mL/kg (P=0.019, odds ratio [OR]=13.79) and base excess 30-min after reperfusion less than -16 (P=0.001, OR=14.05), thrombocytopenia (<50,000 per dL) between day 1 and day 15 after transplantation (P=0.047, OR=5.22), and occurrence of vascular complications (P=0.003, OR=8.96) during the posttransplantation period as predictors of early mortality in CLITx group. CONCLUSION: Risk of mortality at 6 months after intestinal transplantation increased when the liver is included as combined graft. Strategies to reduce mortality such as refining selection for transplantation and early referral before the development of liver failure should be a priority. PMID- 23018881 TI - Management and outcome of BK viremia in renal transplant recipients: a prospective single-center study. AB - BACKGROUND: BK viremia can lead to nephritis, which can progress to irreversible kidney transplant failure. Our prospective study provides management and outcome of BK viremia in renal transplant recipients. METHODS: Two hundred forty de novo kidney-only recipients were enrolled from July 2007 to July 2010 and followed for 1 year. Standard immunosuppression with Thymoglobulin/interleukin 2 receptor blocker and mycophenolate mofetil/tacrolimus (Tac)/prednisone was employed. Quantitative BK virus (BKV) DNA surveillance in plasma/urine was performed at 1, 3, 6, 12, and 24 months after transplantation. Patients with significant viremia (defined as >=10,000 viral copies/mL) underwent renal biopsy and treated with 30% to 50% reduction in doses of both mycophenolate mofetil and Tac without antiviral therapy. The target 12-hr Tac trough levels were lowered to 4 to 6 ng/mL in the significant viremia group, whereas the target levels remained unchanged at 5 to 8 ng/mL for all other groups. RESULTS: Sixty-five patients (27%) developed BK viremia; 28 (12%) of whom had significant viremia. A total of five (21%) of the 23 (of 28) patients who underwent biopsy presented with subclinical BKV nephritis. The mean plasma BKV DNA declined by 98% (range, 76%-100%) at 1 year after peak viremia. Acute cellular rejection seen in four (14%) of 28 patients, responded to bolus steroids. There was no decline in estimated glomerular filtration rate over time from 1 month after transplantation to 1 year after peak viremia (P=0.57). CONCLUSION: Reduction in immunosuppression alone resulted in the successful resolution of viremia with preservation of renal function and prevention of clinical BKV nephritis and graft loss. PMID- 23018882 TI - Bispalladacycle-catalyzed Michael addition of in situ formed azlactones to enones. AB - The development and further evolution of the first catalytic asymmetric conjugate additions of azlactones as activated amino acid derivatives to enones is described. Whereas the first-generation approach started from isolated azlactones, in the second-generation approach the azlactones could be generated in situ starting from racemic N-benzoylated amino acids. The third evolution stage could make use of racemic unprotected alpha-amino acids to directly form highly enantioenriched and diastereomerically pure masked quaternary amino acid products bearing an additional tertiary stereocenter. The step-economic transformations were accomplished by cooperative activation by using a robust planar chiral bis-Pd catalyst, a Bronsted acid (HOAc or BzOH; Ac=acetyl, Bz=benzoyl), and a Bronsted base (NaOAc). In particular the second- and third generation approaches provide a rapid and divergent access to biologically interesting unnatural quaternary amino acid derivatives from inexpensive bulk chemicals. In that way highly enantioenriched acyclic alpha-amino acids, alpha alkyl proline, and alpha-alkyl pyroglutamic acid derivatives could be prepared in diastereomerically pure form. In addition, a unique way is presented to prepare diastereomerically pure bicyclic dipeptides in just two steps from unprotected tertiary alpha-amino acids. PMID- 23018888 TI - No association between serum vitamin D status and the prevalence of allergic diseases in Japanese children. PMID- 23018889 TI - Involvement of Akt2/protein kinase B beta (PKBbeta) in the 8-Cl-cAMP-induced cancer cell growth inhibition. AB - 8-chloro-cyclic AMP (8-Cl-cAMP), which induces differentiation, growth inhibition, and apoptosis in various cancer cells, has been investigated as a putative anti-cancer drug. However, the exact mechanism of 8-Cl-cAMP functioning in cancer cells is not fully understood. Akt/protein kinase B (PKB) genes (Akt1, Akt2, and Akt3) encode enzymes belonging to the serine/threonine-specific protein kinase family. It has been suggested that Akt/PKB enhances cell survival by inhibiting apoptosis. Recently, we showed that 8-Cl-cAMP and 5-aminoimidazole-4 carboxamide ribonucleoside (AICAR) inhibited cancer cell growth through the activation of AMPK and p38 MAPK. Therefore, we anticipated that the phosphorylation of Akt/PKB would be decreased upon treatment with 8-Cl-cAMP. However, treatment with 8-Cl-cAMP and AICAR induced the phosphorylation of Akt/PKB, which was inhibited by ABT702 (an adenosine kinase inhibitor) and NBTI (an adenosine transporter inhibitor). Furthermore, whereas Compound C (an AMPK inhibitor), AMPK-DN (AMPK-dominant negative) mutant, and SB203580 (a p38 MAPK inhibitor) did not block the 8-Cl-cAMP-induced phosphorylation of Akt/PKB, TCN (an Akt1/2/3 specific inhibitor) and an Akt2/PKBbeta-targeted siRNA inhibited the 8-Cl-cAMP- and AICAR-mediated phosphorylation of AMPK and p38 MAPK. TCN also reversed the growth inhibition mediated by 8-Cl-cAMP and AICAR. Moreover, an Akt1/PKBalpha-targeted siRNA did not reduce the phosphorylation of AMPK and p38 MAPK after treatment with 8-Cl-cAMP. These results suggest that Akt2/PKBbeta activation promotes the phosphorylation of AMPK and p38 MAPK during the 8-Cl-cAMP and AICAR-induced growth inhibition. PMID- 23018892 TI - The stable o-phthalaldehyde-ferrocene/6-ferrocenyl-1-hexanethiol pre-column derivatization high-performance liquid chromatography of dimethylarginine by novel dual fluorescence and electrochemical detector. AB - Monomethylarginine, asymmetric dimethylarginine and symmetric dimethylarginine were separated on a Wakopak Combi ODS with an acetonitrile-100 mm potassium phosphate buffer (pH 7.0; 1:1, v/v). Dimethylarginines were derived from o phthalaldehyde for the fluorescence detector and from 6-ferrocenyl-1-hexanethiol for the electrochemical detector. The detection limits of the dimethylarginines in spiked plasma were 0.3-0.5 pmol by electrochemical detection and 1-2 pmol by fluorescence detection. The detection limits were improved over 30 times by electrochemical detection and 10 times by fluorescence detection compared with previous reports. In previous derivatization liquid chromatography, the reaction solutions, o-phthalaldehyde, 2-mercaptethanol and dimethylarginines were unstable and required quick derivatization at 4 degrees C. By our proposed pre-column methods, the dimethylarginines were derivatized at room temperature and the fluorescent products were stable for 6 h. The manipulation performance was greatly advanced compared with previous LC reports. This is the first report on stable and sensitive dimethylarginines by dual detection. The selectivity was also improved by dual detection. The proposed method was applied to preliminary monitoring of dimethylargines in plasma and urine. PMID- 23018896 TI - Synthesis and biological evaluation of a library of glycoporphyrin compounds. AB - A library of glycosylated porphyrins (glycoporphyrins) was prepared and the compounds were evaluated for their photodynamic therapy (PDT) activity against the oesophageal squamous-cell carcinoma cell line OE21 in vitro. A synthetic methodology was developed to allow incorporation of biologically active carbohydrates, including the histo-blood-group antigen trisaccharide Lewis(X), onto the porphyrin backbone. The effect of the carbohydrate group and substitution pattern on the PDT activity, cell uptake and subcellular localisation of the glycoporphyrin compounds is reported. PMID- 23018897 TI - Chronopharmacology of mizoribine in collagen-induced arthritis rats. AB - We previously reported that higher therapeutic effects were obtained in rheumatoid arthritis (RA) patients and RA model animals when the dosing-times of methotrexate and tacrolimus were chosen according to the 24-h rhythms of the inflammatory response. Mizoribine (MZR) is an immunosuppressive agent and is used against RA in the same manner as methotrexate and tacrolimus. In this study, we examined whether a dosing-time dependency of the therapeutic effect of MZR could be detected in collagen-induced arthritis (CIA) rats. To measure C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha levels, blood was collected from CIA rats at different times. MZR was administered at two different dosing times based on these findings and its effects and toxicity were examined. CRP and TNF-alpha concentrations in blood showed significant 24-h rhythms. The exacerbation of arthritis and excessive increase in leukocytes in CIA rats were markedly lower in the group treated with MZR at the dark phase than those of the group treated with MZR at the light phase. These findings suggest that the therapeutic index of RA therapy may be improved by administering MZR at a time in the day when the inflammatory reaction begins to activate. PMID- 23018898 TI - In vivo brain oxidative stress model induced by microinjection of sodium nitroprusside in mice. AB - Sodium nitroprusside (SNP) is widely used as a potent vasodilator and a nitric oxide (NO) donor, whereas the cytotoxicity of SNP has been well documented. SNP releases several potentially toxic products such as cyanide anion, NO, and iron. We investigated the mechanisms of cell death and motor dysfunction induced by microinjection of SNP in mice to establish a brain oxidative stress model and then examined the anti-oxidant activity of glutathione. Intrastriatal microinjection of SNP (1 - 10 nmol) induced brain damage and motor dysfunction in a dose-dependent manner when the effects were evaluated with behavioral tests and TTC staining. NOC-18 (10 nmol), another NO donor, and KCN (10 nmol) did not cause motor dysfunction. However, FeCl(2) (10 nmol) caused motor dysfunction. In addition, simultaneous injection of SNP and deferoxamine (10 nmol), an iron chelating agent, prevented SNP-induced brain damage and motor dysfunction, suggesting a role of iron-related radicals in SNP-toxicity. Moreover, reduced glutathione (1 - 10 nmol), a natural anti-oxidant substance, dose-dependently prevented motor dysfunction induced by SNP-toxicity. Finally, deferoxamine and glutathione (10 nmol) significantly protected against brain damage and motor dysfunction induced by FeCl(2) toxicity. These results suggest that cell death induced by injection of SNP is caused by iron-related radical reactions, but not by NO and cyanide anion. PMID- 23018899 TI - Miglitol, an anti-diabetic drug, inhibits oxidative stress-induced apoptosis and mitochondrial ROS over-production in endothelial cells by enhancement of AMP activated protein kinase. AB - Endothelial dysfunction caused by oxidative stress plays a key role in atherogenesis. This study investigated whether the anti-diabetic drug miglitol, an alpha-glucosidase inhibitor, which is currently available in clinical practice, can prevent endothelial cell apoptosis and whether it might restore impaired vascular relaxation under oxidative stress. The bEnd.3 cells, a microvascular endothelial cell line, were pre-treated with various concentrations of miglitol and then were incubated with H(2)O(2) for 1 - 2 h. Treatment of bEnd.3 cells with miglitol resulted in the protection of cell viability, suppression of mitochondrial superoxide production, and DNA strand breakage under the oxidative stress. These effects of miglitol were associated with the activation of AMP-activated protein kinase (AMPK) and the phosphorylation of endothelial nitric oxide synthase (eNOS). In aortic rings with endothelium, acetylcholine (Ach)-induced relaxation was attenuated by H(2)O(2). We found that this impaired relaxation was restored by acute treatment with miglitol. Compound C, an AMPK inhibitor, inhibited the amelioration of vascular relaxations treated with miglitol. These results suggest that miglitol might protect against endothelial cells damage under oxidative stress via inhibition of endothelial cell apoptosis and mitochondrial superoxide production, which are mediated by the activation of AMPK and the phosphorylation of eNOS. PMID- 23018900 TI - Premotor potential study in carpal tunnel syndrome. AB - INTRODUCTION: Premotor potentials (PMPs) precede compound muscle action potentials evoked from the second lumbrical muscle after median nerve stimulation. Although PMP has been identified as a median sensory nerve action potential, few reports have documented the significance of PMP parameters for diagnosing carpal tunnel syndrome (CTS). METHODS: We investigated the relationships between PMP parameters and results of 6 standard median nerve conduction studies in 74 CTS hands. RESULTS: Significant correlations were noted in all comparisons. PMP conduction velocity was strongly correlated with the sensory conduction velocity between wrist and digit 2 (r(2) = 0.91). Moreover, PMP parameters were significantly correlated with neurophysiological severity of CTS. CONCLUSION: Measuring PMP parameters with a second lumbrical-interosseous study may be useful for diagnosing CTS. PMID- 23018901 TI - In vivo probe-based confocal laser endomicroscopy in amiodarone-related pneumonia. AB - Probe-based confocal laser endomicroscopy (pCLE) allows microscopic imaging of the alveoli during bronchoscopy. The objective of the study was to assess the diagnostic accuracy of pCLE for amiodarone-related pneumonia (AMR-IP). Alveolar pCLE was performed in 36 nonsmoking patients, including 33 consecutive patients with acute or subacute interstitial lung disease (ILD), of which 17 were undergoing treatment with amiodarone, and three were amiodarone-treated patients without ILD. Nine out of 17 patients were diagnosed with high-probability AMR-IP (HP-AMR-IP) by four experts, and three separate observers. Bronchoalveolar lavage findings did not differ between HP-AMR-IP and low-probability AMR-IP (LP-AMR-IP) patients. In HP-AMR-IP patients, pCLE showed large (>20 MUm) and strongly fluorescent cells in 32 out of 38 alveolar areas. In contrast, these cells were observed in only two out of 39 areas from LP-AMR-IP patients, in one out of 59 areas from ILD patients not receiving amiodarone and in none of the 10 areas from amiodarone-treated patients without ILD (p<0.001; HP-AMR-IP versus other groups). The presence of at least one alveolar area with large and fluorescent cells had a sensitivity, specificity, negative predictive value and positive predictive value for the diagnosis of AMR-IP of 100%, 88%, 100% and 90%, respectively. In conclusion, pCLE appears to be a valuable tool for the in vivo diagnosis of AMR IP in subacute ILD patients. PMID- 23018902 TI - Sleep clinical record: an aid to rapid and accurate diagnosis of paediatric sleep disordered breathing. AB - Overnight polysomnography (PSG) is an expensive procedure which can only be used in a minority of cases, although it remains the gold standard for the diagnosis of sleep disordered breathing (SDB). The objective of this study was to develop a simple, PSG-validated tool to screen SDB, thus reducing the use of PSG. For every participant we performed PSG and a sleep clinical record was completed. The sleep clinical record consists of three items: physical examination, subjective symptoms and clinical history. The clinical history analyses behavioural and cognitive problems. All three items were used to create a sleep clinical score (SCS). We studied 279 children, mean +/- SD age 6.1 +/- 3.1 years, 63.8% male; 27.2% with primary snoring and 72.8% with obstructive sleep apnoea (OSA) syndrome. The SCS was higher in the OSA syndrome group compared to the primary snoring group (8.1 +/- 9.6 versus 0.4 +/- 0.3, p<0.005), correlated with apnoea/hypopnoea index (p=0.001) and had a sensitivity of 96.05%. Positive and negative likelihood ratios were 2.91 and 0.06, respectively. SCS may effectively be used to screen patients as candidates for PSG study for suspected OSA syndrome, and to enable those with a mild form of SDB to receive early treatment. PMID- 23018903 TI - Imaging the inflammatory activity of sarcoidosis. AB - Accurate assessment of pulmonary and extrapulmonary organ involvement in sarcoidosis is one of the great challenges for clinicians. This assessment includes the evaluation of symptoms and of sarcoidosis activity in a specific organ and its functional consequences. In this review, radiological and nuclear techniques to image the inflammatory activity of sarcoidosis are described, in particular (18)F-FDG positron emission tomography/computed tomography. The current use of this technique in clinical practice is explained, particularly in patients with persistent symptoms, stage IV disease and cardiac sarcoidosis. PMID- 23018904 TI - Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study. AB - This phase II, randomised, double-blind, multicentre study (NCT00930982) investigated the safety and efficacy of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis. Adults who were culture positive for pre-defined potential respiratory pathogens (including Pseudomonas aeruginosa and Haemophilus influenzae) were randomised to ciprofloxacin DPI 32.5 mg or placebo administered twice daily for 28 days (with 56 days of follow-up). Bacterial density in sputum (primary end-point), pulmonary function tests, health-related quality of life and safety were monitored throughout the study. 60 subjects received ciprofloxacin DPI 32.5 mg and 64 received placebo. Subjects on ciprofloxacin DPI had a significant reduction (p<0.001) in total sputum bacterial load at the end of treatment (-3.62 log10 CFU.g(-1) (range -9.78-5.02 log10 CFU.g(-1))) compared with placebo (-0.27 log10 CFU.g(-1) (range -7.96-5.25 log10 CFU.g(-1))); the counts increased thereafter. In the ciprofloxacin DPI group, 14 (35%) out of 40 subjects reported pathogen eradication at end of treatment versus four (8%) out of 49 in the placebo group (p=0.001). No abnormal safety results were reported and rates of bronchospasm were low. Ciprofloxacin DPI 32.5 mg twice daily for 28 days was well tolerated and achieved significant reductions in total bacterial load compared with placebo in subjects with non-cystic fibrosis bronchiectasis. PMID- 23018905 TI - Management-based risk prediction in community-acquired pneumonia by scores and biomarkers. AB - Community-acquired pneumonia (CAP) represents a major life-threatening infection, but disease course and outcome is highly variable. Major drivers of prognosis are respiratory failure, sepsis-related organ dysfunction and unstable comorbidities. Current risk stratification tools have been primarily designed to predict mortality and identify low risk patients potentially suitable for ambulatory management. Detection of patients at high risk for clinical deterioration by current scores remains suboptimal. Therefore, management-related risk stratification tools designed to predict benefit from early intensified monitoring and treatment strategies in hospitalised CAP are advocated. An approach including early and repeatedly evaluated clinical markers of respiratory failure, sepsis-related organ dysfunction or decompensating comorbidity combined with individual definition of treatment goals is suggested. Inflammatory biomarkers can add prognostic information. New cardiovascular or stress-related biomarkers like copeptin, midregional proadrenomedullin and cortisol have been repeatedly linked with outcome and disease course in CAP and improved clinical scoring in observational studies. Thus they represent promising tools for individualised risk stratification. A major task in future CAP research will be the evaluation of their additional value in large interventional trials with control groups incorporating strict management guidance by clinical criteria. PMID- 23018906 TI - Survival of lung adenocarcinoma patients with malignant pleural effusion. AB - In the era of targeted therapy, the association between lung adenocarcinoma patient survival and malignant pleural effusions (MPEs) remains unclear. This study investigated the clinical characteristics, survival and epidermal growth factor receptor (EGFR) gene (EGFR) mutation status of lung adenocarcinoma patients with MPE. From June 2005 to December 2010, consecutive pleural effusions were collected prospectively. Patient clinical characteristics, EGFR mutation status, and overall survival were analysed. We collected MPEs from 448 patients in stage IV lung adenocarcinoma at initial diagnosis. Median overall survival for patients with MPEs at initial diagnosis and following disease progression were 14.3 months and 21.4 months, respectively (p=0.001). There were 296 (66.1%) patients harbouring EGFR mutations, the mutation rates among patients with an MPE at initial diagnosis and one following disease progression were 68.2% and 56.6%, respectively (p=0.044); the L858R mutation rate was also higher among the former (32.6% versus 18.1%; p=0.009). Multivariate analysis revealed that patients who: developed MPEs following disease progression, harboured EGFR mutations, and received EGFR-tyrosine kinase inhibitor therapy, had longer overall survival. Patients in stage IV lung adenocarcinoma with MPEs at initial diagnosis have shorter overall survival and higher EGFR mutation rate, especially for L858R, than patients who develop MPEs following disease progression. PMID- 23018907 TI - Obstructive sleep apnoea: longer respiratory event lengths in patients with heart failure. AB - This study investigated the effect of heart failure on respiratory patterns in patients with obstructive sleep apnoea (OSA). 39 patients with established OSA (apnoea/hypopnoea index (AHI) >10 events.h(-1)) and either with heart failure (New York Heart Association (NYHA) class II and III, left ventricular-ejection fraction (LVEF) <=40%; n=26, age mean +/- SD 67 +/- 9 years) or without heart failure (LVEF >=50%, N-terminal pro-brain naturic peptide <400 pg.mL(-1); n=13, age 73 +/- 6 years) underwent simultaneous right- and left-heart catheterisation within 12 h of cardiorespiratory polygraphy recording. Respiratory patterns of OSA were significantly longer in OSA patients with heart failure versus without heart failure, including mean +/- SD cycle length (46.0 +/- 10.0 versus 37.8 +/- 10.6 s; p=0.024), ventilation length (25.4 +/- 6.3 versus 21.3 +/- 7.1 s; p=0.044), apnoea length (20.5 +/- 4.9 versus 16.5 +/- 3.9 s; p=0.013), time-to peak ventilation (10.6 +/- 3.0 versus 8.3 +/- 2.5 sc; p=0.021) and circulatory delay (28.5 +/- 7.5 versus 22.6 +/- 3.7 s; p=0.005). Positive and robust correlations were found between some of these parameters and the degree of congestion in heart failure: cycle length (r=0.53; p=0.006), ventilation length (r=0.55; p=0.004) and time-to-peak ventilation (r=0.47; p=0.015) all increased with a rise in pulmonary capillary wedge pressure. Respiratory patterns in OSA appear to be dependent on cardiac function, with an increase in event lengths as cardiac function decreases. In patients with heart failure, some of these events correlate with the degree of pulmonary congestion. PMID- 23018908 TI - The Study to Understand Mortality and Morbidity in COPD (SUMMIT) study protocol. AB - Chronic obstructive pulmonary disease (COPD) often coexists with other chronic diseases and comorbidities that can markedly influence patients' health status and prognosis. This is particularly true for cardiovascular disease (CVD). However, there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases. The "Study to Understand Mortality and Morbidity in COPD" (SUMMIT) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD. SUMMIT is a multicentre, randomised, double-blind, parallel-group, placebo controlled trial of 16 000 patients with moderate COPD randomly assigned to once daily treatment with fluticasone furoate/vilanterol (100/25 MUg), fluticasone furoate (100 MUg), vilanterol (25 MUg) or matched placebo; mortality is the primary end-point. The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo. Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point. This article describes the design of the SUMMIT study. PMID- 23018909 TI - Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition. AB - Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of this remodelling, peribronchiolar fibrosis is observed in the small airways of COPD patients and contributes to airway obstruction. Fibroblast-to-myofibroblast transition is a key step in peribronchiolar fibrosis formation. This in vitro study examined the effect of cigarette smoke on bronchial fibroblast-to-myofibroblast transition, and whether aclidinium bromide inhibits this process. Human bronchial fibroblasts were incubated with aclidinium bromide (10(-9)-10(-7) M) and exposed to cigarette smoke extract. Collagen type I and alpha-smooth muscle actin (alpha-SMA) expression were measured by real-time PCR and Western blotting, as myofibroblast markers. Intracellular reactive oxygen species, cyclic AMP (cAMP), extracellular signal-regulated kinase (ERK)1/2 and choline acetyltransferase were measured as intracellular signalling mediators. Cigarette smoke-induced collagen type I and alpha-SMA was mediated by the production of reactive oxygen species, the depletion of intracellular cAMP and the increase of ERK1/2 phosphorylation and choline acetyltransferase. These effects could be reversed by treatment with the anticholinergic aclidinium bromide, by silencing the mRNA of muscarinic receptors M1, M2 or M3, or by the depletion of extracellular acetylcholine by treatment with acetylcholinesterase. A non-neuronal cholinergic system is implicated in cigarette smoke-induced bronchial fibroblast-to-myofibroblast transition, which is inhibited by aclidinium bromide. PMID- 23018910 TI - Nocturnal gastro-oesophageal reflux, asthma and symptoms of OSA: a longitudinal, general population study. AB - Nocturnal gastro-oesophageal reflux (nGOR) is associated with asthma and obstructive sleep apnoea (OSA). Our aim was to investigate whether nGOR is a risk factor for onset of asthma and onset of respiratory and OSA symptoms in a prospective population-based study. We invited 2640 subjects from Iceland, Sweden and Belgium for two evaluations over a 9-year interval. They participated in structured interviews, answered questionnaires, and underwent spirometries and methacholine challenge testing. nGOR was defined by reported symptoms. Subjects with persistent nGOR (n=123) had an independent increased risk of new asthma at follow-up (OR 2.3, 95% CI 1.1-4.9). Persistent nGOR was independently related to onset of respiratory symptoms (OR 3.0, 95% CI 1.6-5.6). The risk of developing symptoms of OSA was increased in subjects with new and persistent nGOR (OR 2.2, 95% CI 1.3-1.6, and OR 2.0, 95% CI 1.0-3.7, respectively). No significant association was found between nGOR and lung function or bronchial responsiveness. Persistent symptoms of nGOR contribute to the development of asthma and respiratory symptoms. New onset of OSA symptoms is higher among subjects with symptoms of nGOR. These findings provide evidence that nGOR may play a role in the genesis of respiratory symptoms and diseases. PMID- 23018911 TI - Expression of the nuclear factor-kappaB inhibitor A20 is altered in the cystic fibrosis epithelium. AB - A20 is a lipopolysaccharide (LPS)-inducible, cytoplasmic zinc finger protein, which inhibits Toll-like receptor-activated nuclear factor (NF)-kappaB signalling by deubiquitinating tumour necrosis factor receptor-associated factor (TRAF)-6. The action of A20 is facilitated by complex formation with ring finger protein (RNF)-11, Itch and TAX-1 binding protein-1 (TAX1BP1). This study investigated whether the expression of A20 is altered in the chronically inflamed cystic fibrosis (CF) airway epithelium. Nasal epithelial cells from CF patients (F508del homozygous), non-CF controls and immortalised epithelial cells (16HBE14o- and CFBE41o-) were stimulated with LPS. Cytoplasmic expression of A20 and expression of NF-kappaB subunits were analysed. Formation of the A20 ubiquitin editing complex was also investigated. In CFBE41o-, peak LPS-induced A20 expression was delayed compared with 16HBE14o- and fell significantly below basal levels 12-24 h after LPS stimulation. This was confirmed in primary CF airway cells. Additionally, a significant inverse relationship between A20 and p65 expression was observed. Inhibitor studies showed that A20 does not undergo proteasomal degradation in CFBE41o-. A20 interacted with TAX1BP1, RNF11 and TRAF6 in 16HBE14o cells, but these interactions were not observed in CFBE41o-. The expression of A20 is significantly altered in CF, and important interactions with complex members and target proteins are lost, which may contribute to the state of chronic NF-kappaB-driven inflammation. PMID- 23018912 TI - Childhood tuberculosis in Israel: epidemiological trends and treatment outcomes, 1999-2010. AB - Childhood tuberculosis (TB) poses a high risk for morbidity and death. This study describes the characteristics of childhood TB in Israel and examines treatment outcomes. Data sources were the National TB Registry and the National Civil Census. Between 1999 and 2010, 416 children (aged <18 years) had TB, averaging 1.5 per 100 000 children (range 0.6-3.2), demonstrating a declining trend. The average proportion of all TB cases reported annually that were in children was 8.4% (range 5.4-11.8%). Most (n=320, 79%) of the childhood TB cases were pulmonary. TB rates were highest for the 0-4-year age group and lowest for the 10 14-year age group. Of all childhood TB cases, 236 (56.7%) were born in countries with high prevalence of TB: 214 were Israeli citizens who were Ethiopian-born and 22 were non-Israeli citizens. The overall childhood TB incidence in 2010 was 1.05 cases per 100 000 children. The incidence of TB for Israeli-born children, children whose parents were Ethiopian-born and children of migrant workers was 0.55 per 100 000, 7.5 per 100 000 and 50-100 per 100 000, respectively. Cultures were taken from 60% of all childhood TB cases. Most children (97.8%) achieved treatment success, while three children (0.7%) died. Overall, rates of childhood TB rates in Israel are decreasing. However, children of parents born in countries with a high prevalence of TB are still at high risk of developing TB. Bacteriological confirmation should be encouraged to improve control of childhood TB. PMID- 23018913 TI - Dysfunctional breathing in children with asthma: a rare but relevant comorbidity. AB - Hyperventilation and other clinical manifestations of dysfunctional breathing have been reported in childhood, but the prevalence is unknown. In adults, dysfunctional breathing may be a relevant comorbidity in asthma. We aimed to determine the prevalence of dysfunctional breathing in children with asthma and its impact on asthma control. We performed a cross-sectional survey in 203 asthmatic children (aged 5-18 years), using the Nijmegen Questionnaire and the paediatric Asthma Control Questionnaire. Dysfunctional breathing was found in 11 (5.3%) children; more females (eight (12.9%) out of 62) than males (three (2.1%) out 144, p=0.002). There was a dose-dependent relationship between increasing Nijmegen Questionnaire scores (increased risk of dysfunctional breathing) and poorer asthma control. Poor asthma control was more common in patients with dysfunctional breathing (10 (90.9%) out of 11 children) than in children without (65 (32.3%) out of 192 children; OR 19.3, 95% CI 3.14-430.70; p<0.0001). The median Asthma Control Questionnaire in children with dysfunctional breathing was higher (median (range) 2.00 (1.50-3.17)) than in children without (0.50 (0.17 1.17); p<0.001). The prevalence of dysfunctional breathing in children and adolescents referred to a hospital-based paediatric asthma clinic for severe or difficult-to-control asthma is 5%. The association between dysfunctional breathing and asthma control suggests that this may be a clinically relevant comorbidity in paediatric asthma. PMID- 23018915 TI - Prevalence and prognosis of COPD in critically ill patients between 1998 and 2008. AB - The epidemiology of chronic obstructive pulmonary disease (COPD) in critically ill patients is largely unknown. The aims of the study were: 1) to determine whether COPD, either as the cause of intensive care unit (ICU) admission or as a comorbid condition, is an independent risk factor for increased morbidity and mortality; and 2) to investigate time trends in proportion and outcome of acute respiratory failure in patients with COPD admitted to ICUs. Prospectively recorded data from 194 453 adults consecutively admitted to 87 Austrian ICUs over a period of 11 years (1998-2008) were retrospectively analysed. COPD was present in 8.6% of all patients. The risk-adjusted mortality of patients with COPD was higher than in patients without COPD. The presence of COPD was an independent risk factor for increased mortality and was associated with prolonged mechanical ventilation and prolonged weaning. During the course of the 11 years, the proportion of acute respiratory failure due to COPD increased by about two thirds, and the use of noninvasive ventilation within the COPD cohort more than doubled. Simultaneously, the risk-adjusted mortality of patients with COPD improved. In critically ill patients, the presence of COPD is increasing and is an independent risk factor for mortality and morbidity. PMID- 23018914 TI - Echocardiographic abnormalities in patients with COPD at their first hospital admission. AB - Cardiovascular disease accounts for significant morbidity and mortality in chronic obstructive pulmonary disease (COPD). Its prevalence and mechanisms of association have not been elucidated. The study aimed to assess the prevalence of echocardiographic abnormalities and potential risk factors in patients with COPD at their first exacerbation requiring hospital admission. Transthoracic echocardiography was prospectively performed in 342 patients (forced expiratory volume in 1 s 52 +/- 16% predicted) 3 months after discharge. Significant cardiac alterations were present in 64% of patients; 27% left- and 48% right-heart disorders. The most common were right ventricle enlargement (30%) and pulmonary hypertension (19%). Left ventricle enlargement was present in 6%, left ventricle systolic dysfunction in 13%, left ventricle diastolic impairment in 12% and left atrial dilatation in 29%. Echocardiographic abnormalities were unrelated to COPD severity and were more frequent in patients with self-reported cardiac disease. They were also observed in 63% of patients with no known cardiac disease or cardiovascular risk factors other than smoking. We conclude that cardiac abnormalities are highly prevalent in COPD patients at the time of their first severe exacerbation, even in the absence of established cardiac disease or cardiovascular risk factors. Considering the prognostic and therapeutic implications of cardiac comorbidity, echocardiography should be considered in the assessment of patients with clinically significant COPD. PMID- 23018916 TI - Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. AB - Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are associated with worse treatment outcomes for patients, including higher mortality, than for drug-sensitive tuberculosis. Delamanid (OPC-67683) is a novel anti-TB medication with demonstrated activity against multidrug-resistant disease. Patients who participated in the previously reported randomised, placebo controlled trial of delamanid and the subsequent open-label extension trial were eligible to participate in a 24-month observational study designed to capture treatment outcomes. Treatment outcomes, as assessed by clinicians and defined by the World Health Organization, were categorised as favourable and unfavourable. Delamanid treatment groups were combined for analysis, based on their duration of treatment. In total, for 421 (87.5%) out of 481 patients from the original randomised controlled trial, consent was granted for follow-up assessments. Favourable outcomes were observed in 143 (74.5%) out of 192 patients who received delamanid for >=6 months, compared to 126 (55%) out of 229 patients who received delamanid for <=2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid versus short-term/no delamanid (8.3%; p<0.001). Treatment benefit was also seen among patients with extensively drug-resistant TB. This analysis suggests that treatment with delamanid for 6 months in combination with an optimised background regimen can improve outcomes and reduce mortality among patients with both multidrug-resistant and extensively drug-resistant TB. PMID- 23018917 TI - Pulmonary hypertension in COPD: results from the ASPIRE registry. AB - The phenotype and outcome of severe pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is described in small numbers, and predictors of survival are unknown. Data was retrieved for 101 consecutive, treatment-naive cases of pulmonary hypertension in COPD. Mean +/- SD follow-up was 2.3 +/- 1.9 years. 59 patients with COPD and severe pulmonary hypertension, defined by catheter mean pulmonary artery pressure >=40 mmHg, had significantly lower carbon monoxide diffusion, less severe airflow obstruction but not significantly different emphysema scores on computed tomography compared to 42 patients with mild-moderate pulmonary hypertension. 1- and 3-year survival for severe pulmonary hypertension, at 70% and 33%, respectively, was inferior to 83% and 55%, respectively, for mild-moderate pulmonary hypertension. Mixed venous oxygen saturation, carbon monoxide diffusion, World Health Organization functional class and age, but not severity of airflow obstruction, were independent predictors of outcome. Compassionate treatment with targeted therapies in 43 patients with severe pulmonary hypertension was not associated with a survival benefit, although improvement in functional class and/or fall in pulmonary vascular resistance >20% following treatment identified patients with improved survival. Standard prognostic markers in COPD have limited value in patients with pulmonary hypertension. This study identifies variables that predict outcome in this phenotype. Despite poor prognosis, our data suggest that further evaluation of targeted therapies is warranted. PMID- 23018918 TI - Increased astrocytic ATP release results in enhanced excitability of the hippocampus. AB - Astrocytes, a major subtype of glia, interact with neurons as a supportive partner supplying energy sources and growth factors. Astrocytes regulate the activity of neighboring neurons by releasing chemical transmitters (gliotransmitters). However, the precise role of gilotransmitters in regulating neuronal activity is still under debate. Here, we report that a subtle enhancement in the release of one gliotransmitter, ATP, affects synaptic potentiation from an analysis of mice containing an astrocyte-selective (GFAP) mutation. We found that, relative to normal mice, weaker stimulation induced long term potentiation (LTP) in mutant mice, indicating that the threshold to induce LTP was lowered in the mutant. While excitatory transmission was normal in the mutant, inhibitory GABAergic transmission was suppressed. We found that a low concentration of adenosine selectively attenuated inhibitory neuronal activity and lowered the threshold to induce LTP in wild type mice. In comparison, adenosine A(1) receptor antagonism reversed the lowered LTP threshold back to normal in the mutant mouse. We verified that adenosine levels in the cerebrospinal fluid of mutant mice were slightly elevated compared to wild type mice. This was apparently caused by an increase in ATP release from mutant astrocytes that could provide a source of augmented adenosine levels in the mutant. ATP is thought to suppress the excitability of neuronal circuits; however, a small increase in ATP release can result in a suppressed inhibitory tone and enhanced excitability of neuronal circuitry. These findings demonstrate that ATP released from astrocytes acts in a bidirectional fashion to regulate neuronal excitability depending on concentration. PMID- 23018919 TI - Extended voice-sparing surgery in selected pyriform sinus carcinoma: techniques and outcomes. AB - BACKGROUND: Organ-preservation approaches are frequently favored in the treatment of advanced pyriform sinus carcinoma. In selected cases, use of free flaps allows voice-sparing surgery. METHODS: Thirteen patients underwent conservative extended laryngopharyngectomy. In 11 patients, the resection included the supraglottic larynx, whereas the whole hemilarynx was resected in 2. Reconstruction was achieved with a radial forearm free flap with the palmaris longus tendon. In hemilarynx resection, a costal graft was also used. Functional results were assessed by nasofibroscopy and swallowing videofluoroscopic tests. RESULTS: At 12 months, no patient was gastrostomy dependent, whereas 1 patient remained tracheostomy dependent. At 1, 3, and 5 years, the locoregional control was 100%, 100%, and 83%; overall survival was 69.4%, 46.3%, and 30.8%; and disease-specific survival was 81.2%, 54.5%, and 36.4%, respectively. CONCLUSIONS: In selected patients, extended conservative laryngopharyngectomy challenges the oncologic results of organ-preservation protocols and allows a good quality of life. PMID- 23018920 TI - Chemical characterization of volatile compounds of Lantana camara L. and L. radula Sw. and their antifungal activity. AB - A comparative study of the chemical composition of essential oils of two very similar species of the Verbenaceae family (Lantana camara and L. radula) revealed that the main components of essential oil of L. camara were germacrene-D (19.8%) and E-caryophyllene (19.7%), while those of L. radula were E-caryophyllene (25.3%), phytol (29.2%) and E-nerolidol (19.0%). We have hypothesized that the observed differences could contribute to the differentiated reaction of the two species of Lantana to the attack of the phytopathogenic fungi Corynespora cassiicola. An experiment, involving C. cassiicola cultivation in culture media containing volatile oils of the two species demonstrated that the oils of L. radula were more fungistatic than the oils of L. camara, in accordance with the in vivo observations. It is likely that E-nerolidol and phytol, only found in the oil of L. radula, play a significant role in the effects of L. radula on C. cassiicola. PMID- 23018921 TI - Synthesis and anticancer activity of di(3-thienyl)methanol and di(3 thienyl)methane. AB - Di(3-thienyl)methanol (2) and di(3-thienyl)methane (3) have been synthesized and screened against the T98G (brain cancer) cell line. Treatment induced cell death (MTT and macro-colony assay), growth inhibition, cytogenetic damage (micronuclei formation), were studied as cellular response parameters. Treatment with the compounds enhanced growth inhibition and cell death in a concentration dependent manner in both T98G and HEK (normal) cell lines. At higher concentrations (>20 ug/mL) the cytotoxic effects of the compounds were highly significant. The effect on clonogenic capacity and micronuclei formation observed after treatment of cells. Amongst the compounds, compound 2 exhibited potent activity against T98G brain cancer cells. Despite potent in vitro activity, both compounds exhibited less cytotoxicity against normal human HEK cells at all effective concentrations. PMID- 23018922 TI - Silica gel-mediated organic reactions under organic solvent-free conditions. AB - Silica gel was found to be an excellent medium for some useful organic transformations under organic solvent-free conditions, such as (1) the Friedel Crafts-type nitration of arenes using commercial aqueous 69% nitric acid alone at room temperature, (2) one-pot Wittig-type olefination of aldehydes with activated organic halides in the presence of tributyl- or triphenylphosphine and Hunig's base, and (3) the Morita-Baylis-Hillman reaction of aldehydes with methyl acrylate. After the reactions, the desired products were easily obtained in good to excellent yields through simple manipulation. PMID- 23018923 TI - The antioxidant and anti-inflammatory effects of phenolic compounds isolated from the root of Rhodiola sachalinensis A. BOR. AB - Isolation of compounds from the root of Rhodiola sachalinensis (RRS) yielded tyrosol (1), salidroside (2), multiflorin B (3), kaempferol-3,4'-di-O-beta-D glucopyranoside (4), afzelin (5), kaempferol (6), rhodionin (7), and rhodiosin (8). Quantification of these compounds was performed by high-performance liquid chromatography (HPLC). To investigate the antioxidant and anti-inflammatory effects of the compounds, DPPH radical scavenging, NBT superoxide scavenging and nitric oxide production inhibitory activities were examined in LPS-stimulated Raw 264.7 cells. We suggest that the major active components of RRS are herbacetin glycosides, exhibiting antioxidant activity, and kaempferol, exhibiting anti inflammatory activity. PMID- 23018924 TI - A facile synthesis of arylazonicotinates for dyeing polyester fabrics under microwave irradiation and their biological activity profiles. AB - A as textile dyes and the fastness properties of the dyed samples were measured. Most of the dyed fabrics tested displayed very good washing and perspiration fastness and series of 2-hydroxy- and 2-amino-6-substituted-5-arylazonicotinate monoazo compounds 7a-e and 9a-c were prepared via condensation of 3-oxo-3 substituted-2-arylhydrazonals 2a-e with active methylene nitriles 3a-d using microwave irradiation as an energy source. These substances were then tested moderate light fastness. Finally, the biological activity of the synthesized compounds against gram positive bacteria, gram negative bacteria and yeast were evaluated. PMID- 23018925 TI - The expanding role of electrospray ionization mass spectrometry for probing reactive intermediates in solution. AB - Within the past decade, electrospray ionization mass spectrometry (ESI-MS) has rapidly occupied a prominent position for liquid-phase mechanistic studies due to its intrinsic advantages allowing for efficient "fishing" (rapid, sensitive, specific and simultaneous detection/identification) of multiple intermediates and products directly from a "real-world" solution. In this review we attempt to offer a comprehensive overview of the ESI-MS-based methodologies and strategies developed up to date to study reactive species in reaction solutions. A full description of general issues involved with probing reacting species from complex (bio)chemical reaction systems is briefly covered, including the potential sources of reactive intermediate (metabolite) generation, analytical aspects and challenges, basic rudiments of ESI-MS and the state-of-the-art technology. The main purpose of the present review is to highlight the utility of ESI-MS and its expanding role in probing reactive intermediates from various reactions in solution, with special focus on current progress in ESI-MS-based approaches for improving throughput, testing reality and real-time detection by using newly developed MS instruments and emerging ionization sources (such as ambient ESI techniques). In addition, the limitations of modern ESI-MS in detecting intermediates in organic reactions is also discussed. PMID- 23018926 TI - 3-Amino-8-hydroxy-4-imino-6-methyl-5-phenyl-4,5-dihydro-3H-chromeno [2,3 d]pyrimidine: an effecient key precursor for novel synthesis of some interesting triazines and triazepines as potential anti-tumor agents. AB - A number of interesting heterocycles were prepared through interaction of the intermediate 3-amino-8-hydroxy-4-imino-6-methyl-5-phenyl-4,5-dihydro-3H-chromeno [2,3-d]pyrimidine (1) and reagents such as hydrazonyl halides 2 to furnish triazine derivatives 4a-l. Reaction of 1 with phenacyl bromide afforded compound 5. Moreover, the title compound 1 was subjected to condensation with active methylene compounds (ethyl acetoacetate and ethyl benzoylacetate) to give triazipinones 8a,b. The condensation with aromatic aldehydes afforded either the triazole derivatives 10a-d or Schiff base 11. In addition, the behaviour of compound 1 towards activated unsaturated compounds namely dimethyl acetylene dicarboxylate and ethoxymethylenemalonitrile was studied and it was found to furnish the triazine 13 and triazepine derivative 15, respectively. Combination of title compound 1 with chlorinated active methylene compounds delivered the triazine derivatives 18a-c. Reaction of 1 with chloroacetonitrile furnished compound 20. The structures of the products were elucidated based on their microanalyses and spectroscopic data. Finally, the antitumor activity of the new compounds 4a and 8a against human breast cell MCF-7 line and liver carcinoma cell line HepG2 were recorded. PMID- 23018928 TI - It is time for full disclosure of author contributions. PMID- 23018927 TI - Ranolazine inhibits shear sensitivity of endogenous Na+ current and spontaneous action potentials in HL-1 cells. AB - Na(V)1.5 is a mechanosensitive voltage-gated Na(+) channel encoded by the gene SCN5A, expressed in cardiac myocytes and required for phase 0 of the cardiac action potential (AP). In the cardiomyocyte, ranolazine inhibits depolarizing Na(+) current and delayed rectifier (I(Kr)) currents. Recently, ranolazine was also shown to be an inhibitor of Na(V)1.5 mechanosensitivity. Stretch also accelerates the firing frequency of the SA node, and fluid shear stress increases the beating rate of cultured cardiomyocytes in vitro. However, no cultured cell platform exists currently for examination of spontaneous electrical activity in response to mechanical stimulation. In the present study, flow of solution over atrial myocyte-derived HL-1 cultured cells was used to study shear stress mechanosensitivity of Na(+) current and spontaneous, endogenous rhythmic action potentials. In voltage-clamped HL-1 cells, bath flow increased peak Na(+) current by 14 +/- 5%. In current-clamped cells, bath flow increased the frequency and decay rate of AP by 27 +/- 12% and 18 +/- 4%, respectively. Ranolazine blocked both responses to shear stress. This study suggests that cultured HL-1 cells are a viable in vitro model for detailed study of the effects of mechanical stimulation on spontaneous cardiac action potentials. Inhibition of the frequency and decay rate of action potentials in HL-1 cells are potential mechanisms behind the antiarrhythmic effect of ranolazine. PMID- 23018940 TI - Researchers campaign to free jailed Russian chemist. PMID- 23018941 TI - Chemical society tried to block business competitor. PMID- 23018942 TI - Rat study sparks GM furore. PMID- 23018943 TI - China buys US sequencing firm. PMID- 23018944 TI - Open-access deal for particle physics. PMID- 23018946 TI - US science: The Obama experiment. PMID- 23018947 TI - US election: Politicians should think like scientists. PMID- 23018948 TI - US election: Know your representatives. PMID- 23018949 TI - Sociology: Honour the helpful. PMID- 23018953 TI - Pollution protests: Green issues are catching on in China. PMID- 23018954 TI - Rationality: Evidence must prevail. PMID- 23018955 TI - Rationality: Science is not bad faith. PMID- 23018956 TI - Competing interests: Follow the money on climate controversy. PMID- 23018957 TI - Farming: Redirect research to control coffee pest. PMID- 23018958 TI - Rationality: Religion defies understanding. PMID- 23018959 TI - Regenerative biology: Skin, heal thyself. PMID- 23018960 TI - Electronics: 'Cut and stick' ion gels. PMID- 23018962 TI - Cancer metabolism: When more is less. PMID- 23018963 TI - No surviving evolved companions of the progenitor of SN 1006. AB - Type Ia supernovae are thought to occur when a white dwarf made of carbon and oxygen accretes sufficient mass to trigger a thermonuclear explosion. The accretion could be slow, from an unevolved (main-sequence) or evolved (subgiant or giant) star (the single-degenerate channel), or rapid, as the primary star breaks up a smaller orbiting white dwarf (the double-degenerate channel). A companion star will survive the explosion only in the single-degenerate channel. Both channels might contribute to the production of type Ia supernovae, but the relative proportions of their contributions remain a fundamental puzzle in astronomy. Previous searches for remnant companions have revealed one possible case for SN 1572 (refs 8, 9), although that has been questioned. More recently, observations have restricted surviving companions to be small, main-sequence stars, ruling out giant companions but still allowing the single-degenerate channel. Here we report the results of a search for surviving companions of the progenitor of SN 1006 (ref. 14). None of the stars within 4 arc minutes of the apparent site of the explosion is associated with the supernova remnant, and we can firmly exclude all giant and subgiant stars from being companions of the progenitor. In combination with previous results, our findings indicate that fewer than 20 per cent of type Ia supernovae occur through the single-degenerate channel. PMID- 23018964 TI - Ocean oxygenation in the wake of the Marinoan glaciation. AB - Metazoans are likely to have their roots in the Cryogenian period, but there is a marked increase in the appearance of novel animal and algae fossils shortly after the termination of the late Cryogenian (Marinoan) glaciation about 635 million years ago. It has been suggested that an oxygenation event in the wake of the severe Marinoan glaciation was the driving factor behind this early diversification of metazoans and the shift in ecosystem complexity. But there is little evidence for an increase in oceanic or atmospheric oxygen following the Marinoan glaciation, or for a direct link between early animal evolution and redox conditions in general. Models linking trends in early biological evolution to shifts in Earth system processes thus remain controversial. Here we report geochemical data from early Ediacaran organic-rich black shales (~635-630 million years old) of the basal Doushantuo Formation in South China. High enrichments of molybdenum and vanadium and low pyrite sulphur isotope values (Delta(34)S values >=65 per mil) in these shales record expansion of the oceanic inventory of redox sensitive metals and the growth of the marine sulphate reservoir in response to a widely oxygenated ocean. The data provide evidence for an early Ediacaran oxygenation event, which pre-dates the previous estimates for post-Marinoan oxygenation by more than 50 million years. Our findings seem to support a link between the most severe glaciations in Earth's history, the oxygenation of the Earth's surface environments, and the earliest diversification of animals. PMID- 23018965 TI - Response of salt-marsh carbon accumulation to climate change. AB - About half of annual marine carbon burial takes place in shallow water ecosystems where geomorphic and ecological stability is driven by interactions between the flow of water, vegetation growth and sediment transport. Although the sensitivity of terrestrial and deep marine carbon pools to climate change has been studied for decades, there is little understanding of how coastal carbon accumulation rates will change and potentially feed back on climate. Here we develop a numerical model of salt marsh evolution, informed by recent measurements of productivity and decomposition, and demonstrate that competition between mineral sediment deposition and organic-matter accumulation determines the net impact of climate change on carbon accumulation in intertidal wetlands. We find that the direct impact of warming on soil carbon accumulation rates is more subtle than the impact of warming-driven sea level rise, although the impact of warming increases with increasing rates of sea level rise. Our simulations suggest that the net impact of climate change will be to increase carbon burial rates in the first half of the twenty-first century, but that carbon-climate feedbacks are likely to diminish over time. PMID- 23018966 TI - Skin shedding and tissue regeneration in African spiny mice (Acomys). AB - Evolutionary modification has produced a spectrum of animal defence traits to escape predation, including the ability to autotomize body parts to elude capture. After autotomy, the missing part is either replaced through regeneration (for example, in urodeles, lizards, arthropods and crustaceans) or permanently lost (such as in mammals). Although most autotomy involves the loss of appendages (legs, chelipeds, antennae or tails, for example), skin autotomy can occur in certain taxa of scincid and gekkonid lizards. Here we report the first demonstration of skin autotomy in Mammalia (African spiny mice, Acomys). Mechanical testing showed a propensity for skin to tear under very low tension and the absence of a fracture plane. After skin loss, rapid wound contraction was followed by hair follicle regeneration in dorsal skin wounds. Notably, we found that regenerative capacity in Acomys was extended to ear holes, where the mice exhibited complete regeneration of hair follicles, sebaceous glands, dermis and cartilage. Salamanders capable of limb regeneration form a blastema (a mass of lineage-restricted progenitor cells) after limb loss, and our findings suggest that ear tissue regeneration in Acomys may proceed through the assembly of a similar structure. This study underscores the importance of investigating regenerative phenomena outside of conventional model organisms, and suggests that mammals may retain a higher capacity for regeneration than was previously believed. As re-emergent interest in regenerative medicine seeks to isolate molecular pathways controlling tissue regeneration in mammals, Acomys may prove useful in identifying mechanisms to promote regeneration in lieu of fibrosis and scarring. PMID- 23018969 TI - Estimation of household transmission rates of pertussis and the effect of cocooning vaccination strategies on infant pertussis. AB - BACKGROUND: Despite >50 years of universal vaccination, pertussis remains the most prevalent vaccine-preventable infectious disease in developed countries. Pertussis is often mild in adults, but can run a severe course in young infants. METHODS: Data on transmission of pertussis within households were captured in a population-based, nationwide, prospective study performed in the Netherlands between February 2006 and December 2009. We estimated the transmission rates of pertussis with a clinically confirmed infection in 140 households, using stochastic epidemic models. Parameter estimates were used to gauge the effect of vaccinating household members (cocooning) to prevent the infection in young infants. RESULTS: Overall transmission rates in the household were high. Fathers were less susceptible than other household members (estimated relative susceptibility of fathers = 0.44 [95% confidence interval (CI) = 0.27-0.72]), whereas mothers may be more infectious to their infants than are other household members (estimated relative infectiousness of mothers = 3.9 [95% CI = 0.59-14]). Targeted vaccination of mothers would approximately halve the probability of infants' infection. Vaccination of siblings is less effective in preventing transmission within the household, but may be as effective overall because siblings more often introduce an infection in the household. Vaccination of fathers is expected to be least effective. CONCLUSIONS: Selective vaccination of persons in households with a young infant may substantially reduce the disease burden of pertussis in infants by reducing transmission within the household. PMID- 23018968 TI - Possible mechanical roles of glycosaminoglycans in thoracic aortic dissection and associations with dysregulated transforming growth factor-beta. AB - BACKGROUND: Four distinguishing histopathological characteristics of thoracic aortic aneurysms and dissections (TAADs) are the fragmentation or degradation of elastic fibers, loss of smooth muscle, pooling of glycosaminoglycans, and remodeling of fibrillar collagens. Of these, pooling of glycosaminoglycans appears to be unique to these lesions. METHODS: This review acknowledges the importance of dysregulated transforming growth factor-beta (TGF-beta) in TAADs and offers a complementary hypothesis that increased TGF-beta could contribute to the accumulation of glycosaminoglycans in the media of the proximal thoracic aorta. Regardless, observed pools of glycosaminoglycans could decrease tensile strength, cause stress concentrations, and increase intralamellar swelling pressure, all of which could initiate local delaminations that could subsequently propagate as dissections and result in a false lumen or rupture. CONCLUSIONS: There is a pressing need to investigate potential mechanical as well as biological consequences of accumulated glycosaminoglycans in TAADs and to elucidate responsible signaling pathways, with particular attention to synthetic cells of nonmesodermal lineage. Such research could provide insight into the mechanisms of dissection and the seemingly paradoxical role of the over expression of a cytokine that is typically associated with fibrosis but is implicated in a degenerative disease of the aorta that can result in a catastrophic mechanical failure. PMID- 23018970 TI - Short-term effects of air pollution in a cohort of patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Although damage to the respiratory system from air pollutants has been recognized, research on susceptibility to air pollution in patients with chronic obstructive respiratory disease (COPD) has produced contradictory results. We studied the short-term effects of particulate matter (PM10, PM2.5), nitrogen dioxide (NO2), and ozone (O3) on cardiac and respiratory mortality in a COPD cohort. We assessed age, sex, and previous diseases as effect modifiers. METHODS: Using hospital data (1998-2009) and pharmaceutical data (2005-2009), we enrolled 145,681 COPD subjects, aged 35+ years and residents of Rome, and followed them from 2005 to 2009. A comparison group of people without COPD (1,710,557 subjects) was also studied. We analyzed deaths due to all natural causes (International Classification of Diseases - Ninth Revision codes 1-799). Statistical analyses were carried out using Poisson regression and a case crossover approach. RESULTS: PM10, PM2.5, and NO2 (0- to 5-day lag) were associated with daily mortality, with stronger effects in people with COPD. The mortality associated with PM10 (per interquartile range [IQR] = 16 MUg/m) was five times more in COPD patients (3.5% [95% confidence interval = -0.1% to 7.2%]) than in other subjects (0.7% [-0.8% to 2.2%]). Effects on respiratory mortality among COPD subjects were particularly elevated from PM2.5 (IQR = 11 MUg/m) (11.6% [2.0% to 22.2%]) and NO2 (IQR = 24 MUg/m) (19.6% [3.5% to 38.2%]). Older age, male sex, preexisting heart conduction disorders, and cerebrovascular diseases were associated with stronger effects in COPD subjects. CONCLUSIONS: COPD patients are more susceptible to air pollutants, especially PM10 and NO2. These results suggest a need for more protective air pollution standards for susceptible groups. PMID- 23018971 TI - Indoor exposure to "outdoor PM10": assessing its influence on the relationship between PM10 and short-term mortality in U.S. cities. AB - BACKGROUND: Seasonal and regional differences have been reported for the increase in short-term mortality associated with a given increase in the concentration of outdoor particulate matter with an aerodynamic diameter smaller than 10 MUm (PM(10) mortality coefficient). Some of this difference may be because of seasonal and regional differences in indoor exposure to PM(10) of outdoor origin. METHODS: From a previous study, we obtained PM(10) mortality coefficients for each season in seven U.S. regions. We then estimated the change in the sum of indoor and outdoor PM(10) exposure per unit change in outdoor PM(10) exposure (PM(10) exposure coefficient) for each season in each region. This was originally accomplished by estimating PM(10) exposure coefficients for 19 cities within the regions for which we had modeled building infiltration rates. We subsequently expanded the analysis to include 64 additional cities with less well characterized building infiltration rates. RESULTS: The correlation (r = 0.71 [95% confidence interval = 0.46 to 0.86]) between PM(10) mortality coefficients and PM(10) exposure coefficients (28 data pairs; four seasons in each of seven regions) was strong using exposure coefficients derived from the originally targeted 19 National Morbidity, Mortality, and Air Pollutions Study cities within the regions. The correlation remained strong (r = 0.67 [0.40 to 0.84]) when PM(10) exposure coefficients were derived using 83 cities within the regions (the original 19 plus the additional 64). CONCLUSIONS: Seasonal and regional differences in PM(10) mortality coefficients appear to partially reflect seasonal and regional differences in total PM(10) exposure per unit change in outdoor exposure. PMID- 23018973 TI - Quantitative determination of paclitaxel and its metabolites, 6alpha hydroxypaclitaxel and p-3'-hydroxypaclitaxel, in human plasma using column switching liquid chromatography/tandem mass spectrometry. AB - A column-switching liquid chromatography/electrospray ionization tandem mass spectrometry to determine paclitaxel and its metabolites, 6alpha hydroxypaclitaxel and p-3'-hydroxypaclitaxel, in human plasma was developed. The analytical system had a Shim-Pack MAYI-ODS (10 * 4.6 mm i.d.) trapping column with deproteinization ability that concentrates analytes and removes water soluble components. This method covered a linearity range of 5-5000 ng/mL of concentrations in plasma for paclitaxel, a range of 0.87-870 ng/mL for 6alpha hydroxypaclitaxel and a range of 0.87-435 ng/mL for p-3'-hydroxypaclitaxel. The intra-day precision and inter-day precision of analysis were less than 11.1%, and the accuracy was within +/-14.4% at concentrations of 5, 50, 500 and 5000 ng/mL for paclitaxel, 0.87, 8.7, 87 and 870 ng/mL for 6alpha-hydroxypaclitaxel, and 0.87, 8.7, 87 and 435 ng/mL for p-3'-hydroxypaclitaxel. The total run time was 30 min. Our method was successfully applied to clinical pharmacokinetic investigation. PMID- 23018978 TI - Longitudinal analysis of growth and body composition of Japanese 21-OHD patients in childhood. AB - Substitution therapy of glucocorticoid is a major part of the treatment for 21 OHD (21-hydroxylase deficiency). However, the therapy causes two major adverse effects, impairment of linear growth and obesity, so that collecting precise growth data is essential for optimizing the therapy. We longitudinally evaluated the linear growth and the body composition of Japanese 21-OHD patients during childhood. For the present study, we chose 16 patients (eight of each sex) who were diagnosed during the newborn period, and continuously observed them in our institute until they were at least 15 years old. All patients were treated according to the guidelines from The Japanese Society for Pediatric Endocrinology. The final height standard deviation score (Ht-SDS) of all the patients was -1.18 +/- 0.85 SD, and no significant differences were observed between males and females or between the simple virilizing form and the salt wasting form. As previously reported, in spite of nearly normal height at the onset of puberty, the pubertal height gains were severely impaired, resulting in reduced final heights. Body composition of the patients was evaluated with BMI SDS. Our longitudinal data showed that BMI was increased up to +1.23 SD in males and up to +1.75 SD in females, and that adiposity rebound was precipitated. Our study should alert physicians to the risk of metabolic syndrome and provide a framework for further studies of metabolic syndrome in 21-OHD patients. PMID- 23018979 TI - Less variation of R-R interval of electrocardiogram in nonobese type 2 diabetes with nocturnal intermittent hypoxia. AB - Obesity is a major risk factor for sleep-disordered breathing (SDB). However, many Japanese subjects with diabetes are less obese despite compared with Caucasian. We evaluated the relationship between SDB and clinical characteristics other than obesity, especially in relation to cardiac autonomic neuropathy (CAN) in Japanese subjects with diabetes. The study included a total of 261 consecutive Japanese subjects with type 2 diabetes, including nonobese subjects defined as BMI <25 kg/m2 for Japanese. SDB was screened by 4% oxygen desaturation index (ODI) level of 5 or more events per hour, which was measured by nocturnal pulse oximetry. CAN was examined with the variation of R-R intervals (CVRR). The SDB were found in 24.5% of total subjects and 16.3% of nonobese subjects with type 2 diabetes, respectively. The nonobese type 2 diabetes subjects with SDB had significantly lower coefficient of CVRR than those without SDB. Multiple regression analysis revealed that BMI and heart rate were significant independent factors for SDB in total subjects with type 2 diabetes, but CVRR was the only significant independent factor for SDB in nonobese subjects with type 2 diabetes. These findings suggest that the presence of SDB should be kept in mind in type 2 diabetic patients with abnormality in CVRR variation in electrocardiogram even though they are not obese. PMID- 23018980 TI - Two novel mutations of the CYP11B2 gene in a Japanese patient with aldosterone deficiency type 1. AB - Isolated hypoaldosteronism is a rare and occasionally life-threatening cause of salt wasting in infancy. A 2-month-old Japanese boy of unrelated parents was examined for failure to thrive and poor weight gain. Laboratory findings were hyponatremia, hyperkalemia, high plasma renin and low aldosterone levels. Spot urine analysis by gas chromatography-mass spectrometry (GC-MS) showed that urinary excretion of corticosterone metabolites was elevated. Whereas excretion of 18-hydroxycortricosterone metabolites was within the normal range, excretion of aldosterone metabolites was undetectable. The patient was therefore suspected to have aldosterone synthase deficiency type 1. Sequence analysis of CYP11B2, the gene encoding aldosterone synthase (CYP11B2), showed that the patient was a compound heterozygote for c.168G>A, p.W56X in exon 1 and c.1149C>T, p.R384X in exon 7. p.W56X was inherited from his mother and p.R384X was from his father. Since both alleles contain nonsense mutations, a lack of CYP11B2 activity was speculated to cause his condition. To our knowledge, this is the first Japanese patient in which the molecular basis of aldosterone synthase deficiency type 1 has been clarified. This case also indicates that spot urinary steroid analysis is useful for diagnosis. PMID- 23018981 TI - Copper-catalyzed Huisgen and oxidative Huisgen coupling reactions controlled by polysiloxane-supported amines (AFPs) for the divergent synthesis of triazoles and bistriazoles. AB - An interesting example of a divergent catalysis with a copper(I) and amine functional macromolecular polysiloxanes system was successfully presented in click chemistry. In this manuscript, we demonstrate the remarkable ability of the secondary amine-functional polysiloxane to induce oxidative coupling in the copper-mediated Huisgen reactions of azides and alkynes, thereby achieving good yields and selectivities. The click reactions mediated by a polysiloxane supported secondary amine allow the preparation of novel heterocyclic compounds, that is, bistriazoles. Comparably, it is also surprising that the use of a diamine-functional polysiloxane as ligand led to a classic Huisgen [3+2] cycloaddition in excellent yields. From the results of the present amine functional polysiloxanes-controlled Huisgen reaction or oxidative Huisgen coupling reaction to divergent products and the proposed mechanism, we suggested that the mononuclear bistriazole-copper complex stabilized and dispersed by the secondary amine-functional polysiloxane was beneficial to prevalent the way to oxidative coupling. PMID- 23018982 TI - A pi-stacked porphyrin-fullerene electron donor-acceptor conjugate that features a surprising frozen geometry. AB - A "frozen" electron donor-acceptor array that bears porphyrin and fullerene units covalently linked through the ortho position of a phenyl ring and the nitrogen of a pyrrolidine ring, respectively, is reported. Electrochemical and photophysical features suggest that the chosen linkage supports both through-space and through bond interactions. In particular, it has been found that the porphyrin singlet excited state decays within a few picoseconds by means of a photoinduced electron transfer to give the rapid formation of a long-lived charge-separated state. Density functional theory (DFT) calculations show HOMO and LUMO to be localized on the electron-donating porphyrin and the electron-accepting fullerene moiety, respectively, at this level of theory. More specifically, semiempirical molecular orbital (MO) configuration interaction (CI) and unrestricted natural orbital (UNO)-CI methods shed light on the nature of the charge-transfer states and emphasize the importance of the close proximity of donor and acceptor for effective electron transfer. PMID- 23018984 TI - Aging influences central motor conduction less than peripheral motor conduction: a transcranial magnetic stimulation study. AB - INTRODUCTION: In this study we investigated the effects of aging on corticospinal tract conduction by measuring the corticoconus motor conduction time (CCCT). METHODS: Motor evoked potentials were recorded from the right tibialis anterior muscle in 100 healthy volunteers. To activate the most proximal part of the cauda equina, magnetic stimulation was performed using a MATS coil over the L1 spinous process (L1-level latency). Transcranial magnetic stimulation of the motor cortex was also conducted (cortical latency). To obtain the CCCT, the L1-level latency was subtracted from the cortical latency. RESULTS: Age was significantly correlated with L1-level latency, but it was not significantly correlated with CCCT. CONCLUSIONS: CCCT is the most direct indicator of corticospinal tract conduction, whereas L1-level latency reflects whole peripheral motor conduction. Central motor conduction was found to be relatively less affected by aging compared with peripheral motor conduction. PMID- 23018985 TI - Flow cytometric testing for paroxysmal nocturnal hemoglobinuria: CD64 is better for gating monocytes than CD33. AB - BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is diagnosed by documenting partial or complete absence of glycosyl phosphatidyl inositol (GPI)-associated ligands in neutrophils, monocytes, and red blood cells (RBCs). The monocytes can be separated by their bright expression of either CD33 or CD64. This paper compares the utility of CD33- vs CD64-based monocyte gating in flow cytometric testing for PNH. METHODS: One hundred and nineteen cases tested for PNH by flow cytometry were included in the study. Both the total number of monocytes and the number of GPI-deficient monocytes gated with CD33 or CD64 were compared. The clustering pattern and any other unusual patterns were noted and investigated. RESULTS: CD64 staining showed more distinct separation of the monocyte cluster than did CD33 staining. The difference between the number of monocytes gated by CD33 and CD64 staining ranged from -26 to +32% (median 1.60%, average 1.69%). Six patients had GPI-deficient monocytes by both CD33- and CD64-based gating, ranging from 0.02 to 83.23%. There were no patients who showed GPI-deficient monocytes by one but not the other gating. The presence of blasts in patients with acute leukemia resulted in abnormal cluster patterns, both by CD33- and CD64-based gating. CONCLUSIONS: CD64-based gating showed more distinct clustering of monocytes than CD33-based gating, allowing for objective separation. The number of monocytes in total and GPI-deficient monocytes derived from both gating strategies was comparable. PMID- 23018986 TI - Influenza vaccine 2012-2013. PMID- 23018987 TI - Choice of an oral anticoagulant in atrial fibrillation. PMID- 23018988 TI - Antimicrobial and antifouling hydrogels formed in situ from polycarbonate and poly(ethylene glycol) via Michael addition. AB - A novel class of antimicrobial cationic polycarbonate/PEG hydrogels are designed and synthesized by Michael addition chemistry. These hydrogels demonstrate strong broad-spectrum antimicrobial activities against various clinically isolated multidrug-resistant microbes. Moreover, they exhibit nonfouling properties and prevent the substrate from microbial adhesion. These antimicrobial and antifouling gels are promising materials as catheter coatings and wound dressings to prevent infections. PMID- 23018989 TI - Evaluation of therapeutic response to concurrent chemoradiotherapy in patients with cervical cancer using diffusion-weighted MR imaging. AB - PURPOSE: To investigate the changes in apparent diffusion coefficients (ADCs) in cervical cancer patients receiving concurrent chemoradiotherapy (CCRT), and to assess the relationship between tumor ADCs or changes in tumor ADCs and final tumor responses to therapy. MATERIALS AND METHODS: Twenty-four patients with cervical cancer who received CCRT were examined with 3 Tesla (T) MRI including diffusion-weighted imaging (DWI). All patients had three serial MR examinations: before therapy (pre-Tx); at 4 weeks of therapy (mid-Tx); and 1 month after completion of therapy (post-Tx). At each examination, ADC was measured in tumors and normal gluteus muscles. Final tumor response as determined by change in tumor size or volume using MRI was correlated with tumor ADCs at each therapeutic time or changes in tumor ADCs at mid-Tx. RESULTS: From pre-Tx to post-Tx, mean tumor ADCs were 0.88, 1.30, and 1.47 * 10(-3) mm(2)/s in sequence (P < 0.001), while those of normal gluteus muscles were 1.24, 1.29, and 1.21 * 10(-3) mm(2)/s in sequence (P > 0.05). At mid-Tx, tumor ADCs and changes in tumor ADCs had a significant correlation with final tumor size responses (P = 0.029 and 0.025, respectively). However, the tumor ADC values at pre-Tx were not associated with the final tumor size response (P = 0.47). The final tumor volume response was not associated with tumor ADC at pre-Tx or mid-Tx (P > 0.05) or changes in tumor ADCs at mid-Tx (P > 0.05). CONCLUSION: DWI may have potentials in evaluating the therapeutic response to CCRT in patients with cervical cancer. PMID- 23018990 TI - Doppler-assessed cerebral blood flow velocity in the neonate as estimator of global cerebral blood volume flow measured using phase-contrast magnetic resonance angiography. AB - BACKGROUND: We hypothesized that color Doppler-measured cerebral blood flow velocity (CD-CBFV) as measured in the three feeding arteries of the brain can be used as an estimator of global cerebral blood flow. PATIENTS AND METHODS: CD-CBFV was determined as soon as possible after determination of phase-contrast magnetic resonance angiography-measured blood volume flow (PC-MRA BVF) by adding up angle corrected time-averaged mean flow velocities of both internal carotid arteries and basilar artery. 30 newborns (gestational age ranging from 25 to 42 weeks; actual weight ranging from 1,050 to 5,858 g; postconceptional age ranging from 225 to 369 days) were investigated. RESULTS: Doppler-determined CBFV ranged from 37 to 131 cm/s with a median of 69 cm/s. CD-CBFV showed a positive correlation with actual weight (r = 0.56, p < 0.01) and postconceptional age (r = 0.53, p < 0.01). CD-CBFV correlated positively with PC-MRA-measured BVF (r = 0.51, p < 0.01). Gestational age at birth, mechanical ventilation or gender did not influence this relationship. The limits of agreement, however, are wide, especially at higher CD-CBFV- and PC-MRA-measured BVF. CONCLUSION: CD-CBFV may be used as a non-invasive trend-monitoring tool to detect gross changes in global cerebral blood flow in the unstable and sick neonate. PMID- 23018991 TI - Permanent left atrial pacing therapy may improve symptoms in heart failure patients with preserved ejection fraction and atrial dyssynchrony: a pilot study prior to a national clinical research programme. AB - AIMS: Our group has recently shown that in some patients, heart failure with preserved ejection fraction (HFPEF) may be explained by 'atrial dyssynchrony syndrome' (ADS) due to interatrial conduction delay (IACD), a short left atrioventricular interval (LAVI), and increased left atrial (LA) stiffness. Our primary objective was to evaluate LA pacing therapy as a new treatment to restore left ventricular active filling in patients with no other known causes for HF than ADS. METHODS AND RESULTS: Six patients with severe HFPEF with IACD (P wave duration >120 ms in lead II), short LAVI during electrophysiological studies (<70 ms), a restrictive filling pattern (E/e' >15), and no standard indication for a pacemaker were implanted with a lead screwed inside the coronary sinus for active LA pacing. After 3 months of active pacing, a 2 week randomized double-blind crossover phase compared active vs. inactive LA pacing. After 3 months of pacing, the mean distance walked in 6 min (6MWD) was 21% greater (240 +/- 25 m vs. 190 +/ 15m, P < 0.05), mitral A wave duration was longer (104 +/- 8 vs. 158 +/- 25 ms, P = 0.002), and E/A and E/e' ratios were smaller (3.4 +/- 1.3 vs. 1.8 +/- 0.9, P = 0.009, and 22.6 +/- 4.6 vs. 15.3 +/- 4.3, P = 0.006, respectively). Inactivation of pacing for 1 week led to a significant reduction in the 6MWD, with an on/off response. CONCLUSION: The beneficial effects of LA pacing observed in this pilot study will have to be confirmed by the randomized, controlled crossover 'LEAD' study. PMID- 23018994 TI - A coincidence reporter-gene system for high-throughput screening. PMID- 23018995 TI - Aptamers as potential tools for super-resolution microscopy. PMID- 23018996 TI - Rendering the brain-behavior link visible. PMID- 23018997 TI - Zooming in on genome organization. PMID- 23018998 TI - Shedding light on G protein-coupled receptor signaling. PMID- 23018999 TI - Is saccade averaging determined by visual processing or movement planning? AB - Saccadic averaging that causes subjects' gaze to land between the location of two targets when faced with simultaneously or sequentially presented stimuli has been often used as a probe to investigate the nature of computations that transform sensory representations into an oculomotor plan. Since saccadic movements involve at least two processing stages-a visual stage that selects a target and a movement stage that prepares the response-saccade averaging can either occur due to interference in visual processing or movement planning. By having human subjects perform two versions of a saccadic double-step task, in which the stimuli remained the same, but different instructions were provided (REDIRECT gaze to the later-appearing target vs. FOLLOW the sequence of targets in their order of appearance), we tested two alternative hypotheses. If saccade averaging were due to visual processing alone, the pattern of saccade averaging is expected to remain the same across task conditions. However, whereas subjects produced averaged saccades between two targets in the FOLLOW condition, they produced hypometric saccades in the direction of the initial target in the REDIRECT condition, suggesting that the interaction between competing movement plans produces saccade averaging. PMID- 23019000 TI - Choice ball: a response interface for two-choice psychometric discrimination in head-fixed mice. AB - The mouse is an important model system for investigating the neural circuits mediating behavior. Because of advances in imaging and optogenetic methods, head fixed mouse preparations provide an unparalleled opportunity to observe and control neural circuits. To investigate how neural circuits produce behavior, these methods need to be paired with equally well-controlled and monitored behavioral paradigms. Here, we introduce the choice ball, a response device that enables two-alternative forced-choice (2AFC) tasks in head-fixed mice based on the readout of lateral paw movements. We demonstrate the advantages of the choice ball by training mice in the random-click task, a two-choice auditory discrimination behavior. For each trial, mice listened to binaural streams of Poisson-distributed clicks and were required to roll the choice ball laterally toward the side with the greater click rate. In this assay, mice performed hundreds of trials per session with accuracy ranging from 95% for easy stimuli (large interaural click-rate contrast) to near chance level for low-contrast stimuli. We also show, using the record of individual paw strokes, that mice often reverse decisions they have already initiated and that decision reversals correlate with improved performance. The choice ball enables head-fixed 2AFC paradigms, facilitating the circuit-level analysis of sensory processing, decision making, and motor control in mice. PMID- 23019001 TI - Frequency distribution of causal connectivity in rat sensorimotor network: resting-state fMRI analyses. AB - Resting-state functional MRI (fMRI) has emerged as an important method for assessing neural networks, enabling extensive connectivity analyses between multiple brain regions. Among the analysis techniques proposed, partial directed coherence (PDC) provides a promising tool to unveil causal connectivity networks in the frequency domain. Using the MRI time series obtained from the rat sensorimotor system, we applied PDC analysis to determine the frequency-dependent causality networks. In particular, we compared in vivo and postmortem conditions to establish the statistical significance of directional PDC values. Our results demonstrate that two distinctive frequency populations drive the causality networks in rat; significant, high-frequency causal connections clustered in the range of 0.2-0.4 Hz, and the frequently documented low-frequency connections <0.15 Hz. Frequency-dependence and directionality of the causal connection are characteristic between sensorimotor regions, implying the functional role of frequency bands to transport specific resting-state signals. In particular, whereas both intra- and interhemispheric causal connections between heterologous sensorimotor regions are robust over all frequency levels, the bilaterally homologous regions are interhemispherically linked mostly via low-frequency components. We also discovered a significant, frequency-independent, unidirectional connection from motor cortex to thalamus, indicating dominant cortical inputs to the thalamus in the absence of external stimuli. Additionally, to address factors underlying the measurement error, we performed signal simulations and revealed that the interactive MRI system noise alone is a likely source of the inaccurate PDC values. This work demonstrates technical basis for the PDC analysis of resting-state fMRI time series and the presence of frequency dependent causality networks in the sensorimotor system. PMID- 23019002 TI - Neural coding of taste by simultaneously recorded cells in the nucleus of the solitary tract of the rat. AB - The nucleus of the solitary tract (NTS) receives input from taste buds on the rostral tongue from the chorda tympani (CT) nerve. How this input is processed by the NTS was the subject of the present investigation. Here we used tetrodes to record from pairs or small groups of NTS cells as they responded to taste stimuli or electrical stimulation of the CT nerve in urethane-anesthetized rats. Once a pair (or small group) of NTS cells were isolated and identified as showing an evoked response to CT nerve stimulation, taste stimuli were presented in separate trials. Tastants consisted of 0.1 M NaCl, 0.01 M HCl, 0.01 M quinine HCl, and 0.5 M sucrose. Responses to various patterns of CT stimulation were then recorded. Functional connections among simultaneously recorded NTS cells were implied from analysis of cross-correlation functions of spike trains. We identified four groups of cells, not all of which responded to taste, with staggered latencies of response to CT nerve stimulation, ranging from ~3 to 35 ms in ~8- to 12-ms increments. Analyses of putative functional connectivity along with latencies of CT-evoked responses suggested that CT input arrives at the NTS in pulses or waves, each of which activates recurrent excitatory connections among NTS cells. These actions may amplify the incoming signal and refine its temporal pattern. PMID- 23019004 TI - Lateralization in intrinsic functional connectivity of the temporoparietal junction with salience- and attention-related brain networks. AB - Neuroimaging studies have demonstrated that the right temporoparietal junction (TPJ) is activated during detection of salient stimuli, including pain, in the sensory environment. Right TPJ damage more often produces spatial neglect than left TPJ damage. We recently reported a right lateralized system of white matter connectivity of the TPJ. However, lateralization in intrinsic TPJ functional connectivity during a task/stimuli-independent state has not been fully characterized. Here we used resting-state functional MRI in healthy humans to compare the functional connectivity of right and left TPJ with salience- and attention-related brain networks. Independent components analysis revealed that both right and left TPJ were functionally connected with a network that included the anterior insula, dorsolateral prefrontal cortex (PFC), and mid-cingulate cortex, considered to be the salience/ventral attention network. Dual regression revealed this network was more strongly connected with right TPJ than left TPJ. Seed-based functional connectivity analysis showed 1) negative connectivity the TPJ bilaterally with the "default mode network"; 2) positive connectivity of TPJ bilaterally with the salience/ventral attention network; 3) stronger connectivity between right TPJ compared with left TPJ with regions within the salience/ventral attention network and mid-insula, S2, and temporal/parietal opercula (implicated in pain); and 4) stronger connectivity of left TPJ compared with right TPJ with the "executive control network," including the dorsomedial/medial PFC, inferior frontal gyrus, and cerebellum (crus I/II). Our findings build on classic lesion and neuroimaging studies, demonstrating a complex spatial network organization of lateralization in TPJ functional connectivity in the absence of an overt stimulus. PMID- 23019003 TI - Effects of spatiotemporal stimulus properties on spike timing correlations in owl monkey primary somatosensory cortex. AB - The correlated discharges of cortical neurons in primary somatosensory cortex are a potential source of information about somatosensory stimuli. One aspect of neuronal correlations that has not been well studied is how the spatiotemporal properties of tactile stimuli affect the presence and magnitude of correlations. We presented single- and dual-point stimuli with varying spatiotemporal relationships to the hands of three anesthetized owl monkeys and recorded neuronal activity from 100-electrode arrays implanted in primary somatosensory cortex. Correlation magnitudes derived from joint peristimulus time histogram (JPSTH) analysis of single neuron pairs were used to determine the level of spike timing correlations under selected spatiotemporal stimulus conditions. Correlated activities between neuron pairs were commonly observed, and the proportions of correlated pairs tended to decrease with distance between the recorded neurons. Distance between stimulus sites also affected correlations. When stimuli were presented simultaneously at two sites, ~37% of the recorded neuron pairs showed significant correlations when adjacent phalanges were stimulated, and ~21% of the pairs were significantly correlated when nonadjacent digits were stimulated. Spatial proximity of paired stimuli also increased the average correlation magnitude. Stimulus onset asynchronies in the paired stimuli had small effects on the correlation magnitude. These results show that correlated discharges between neurons at the first level of cortical processing provide information about the relative locations of two stimuli on the hand. PMID- 23019006 TI - Virtual biomechanics: a new method for online reconstruction of force from EMG recordings. AB - Current methods to reconstruct muscle contributions to joint torque usually combine electromyograms (EMGs) with cadaver-based estimates of biomechanics, but both are imperfect representations of reality. Here, we describe a new method that enables online force reconstruction in which we optimize a "virtual" representation of muscle biomechanics. We first obtain tuning curves for the five major wrist muscles from the mean rectified EMG during the hold phase of an isometric aiming task when a cursor is driven by actual force recordings. We then apply a custom, gradient-descent algorithm to determine the set of "virtual pulling vectors" that best reach the target forces when combined with the observed muscle activity. When these pulling vectors are multiplied by the rectified and low-pass-filtered (1.3 Hz) EMG of the five muscles online, the reconstructed force provides a close spatiotemporal match to the true force exerted at the wrist. In three separate experiments, we demonstrate that the technique works equally well for surface and fine-wire recordings and is sensitive to biomechanical changes elicited by a modification of the forearm posture. In all conditions tested, muscle tuning curves obtained when the task was performed with feedback of reconstructed force were similar to those obtained when the task was performed with real force feedback. This online force reconstruction technique provides new avenues to study the relationship between neural control and limb biomechanics since the "virtual biomechanics" can be systematically altered at will. PMID- 23019005 TI - Sensitivity to musical structure in the human brain. AB - Evidence from brain-damaged patients suggests that regions in the temporal lobes, distinct from those engaged in lower-level auditory analysis, process the pitch and rhythmic structure in music. In contrast, neuroimaging studies targeting the representation of music structure have primarily implicated regions in the inferior frontal cortices. Combining individual-subject fMRI analyses with a scrambling method that manipulated musical structure, we provide evidence of brain regions sensitive to musical structure bilaterally in the temporal lobes, thus reconciling the neuroimaging and patient findings. We further show that these regions are sensitive to the scrambling of both pitch and rhythmic structure but are insensitive to high-level linguistic structure. Our results suggest the existence of brain regions with representations of musical structure that are distinct from high-level linguistic representations and lower-level acoustic representations. These regions provide targets for future research investigating possible neural specialization for music or its associated mental processes. PMID- 23019007 TI - Working with memory: evidence for a role for the medial prefrontal cortex in performance monitoring during spatial delayed alternation. AB - Neuronal spike activity was recorded in the medial prefrontal cortex (mPFC) as rats performed an operant spatial delayed alternation task. The sensitivities of neurons to choice, outcome, and temporal information-related aspects of the task were examined. About one-third of neurons were sensitive to the location of delayed responding while animals were at one of two spatially distinct response ports. However, many fewer neurons (<10%) maintained choice information over the delay, each exhibiting persistent differences in firing rates for only a portion of the delay. Another third of cells encoded information about behavioral outcomes, and some of these neurons (>20% of all cells) fired at distinct rates in advance of correct and incorrect responses (i.e., prospective encoding of outcome). Other cells were sensitive to reward-related feedback stimuli (>20%), the outcome of the preceding trial (retrospective encoding, 5-10%), and/or the time since a trial was last performed (10-20%). An anatomical analysis of the recording sites found that cells that were sensitive to choice, temporal, and outcome information were commingled within the middle layers of the mPFC. Together, our results suggest that spatial processing is only part of what drives mPFC neurons to become active during spatial working memory tasks. We propose that the primary role of mPFC in these tasks is to monitor behavioral performance by encoding information about recent trial outcomes to guide expectations and responses on the current trial. By encoding these variables, the mPFC is able to exert control over action and ensure that tasks are performed effectively and efficiently. PMID- 23019008 TI - Coding of digit displacement by cell spiking and network oscillations in the monkey sensorimotor cortex. AB - beta-Band oscillations occur in motor and somatosensory cortices and muscle activity. Oscillations appear most strongly after movements, suggesting that they may represent or probe the limb's final sensory state. We tested this idea by training two macaque monkeys to perform a finger flexion to one of four displacements, which was then held for 2 s without visual feedback of absolute displacement. Local field potential (LFP) and single unit spiking were recorded from the rostral and caudal primary motor cortex and parietal areas 3a, 3b, 2, and 5. Information theoretic analysis determined how well unit firing rate or the power of LFP oscillations coded finger displacement. All areas encoded significant information about finger displacement after the movement into target, both in beta-band (~20 Hz) oscillatory activity and unit firing rate. On average, the information carried by unit firing was greater (0.07 bits) and peaked earlier (0.73 s after peak velocity) than that by LFP beta-oscillations (0.05 bits and 0.95 s). However, there was considerable heterogeneity among units: some cells did not encode maximal information until midway through the holding phase. In 30% of cells, information in rate lagged information in LFP oscillations recorded at the same site. Finger displacement may be represented in the cortex in multiple ways. Coding the digit configuration immediately after a movement probably relies on nonoscillatory feedback, or efference copy. With increasing delay after movement cessation, oscillatory processing may also play a part. PMID- 23019010 TI - Determination of cnidilin and its two metabolites in rat bile and stool after oral administration by HPLC/electrospray ionization tandem mass spectrometry. AB - A simple, fast and sensitive method for the simultaneous determination of cnidilin and its two metabolites (M1 and M2) in rat bile and stool using HPLC coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) has been developed. The sample pretreatment was simple, because methanol was the only additive used for dilution of bile and ultrasound of stool. Pimpinellin was used as internal standard (IS). The separation was performed on a reverse phase C18 column with gradient elution consisting of 0.50/00 aqueous formic acid and methanol (containing 0.50/00 formic acid). The detection was in the multiple reaction monitoring mode within 7 min. All the analytes were in accordance with the requirement of the validation of the method in vivo (linearity, precision, accuracy, limit of detection and limit of quantification). After oral administrating 24 mg/kg of the prototype drug cnidilin, M1 and M2 were determined in bile within 36 h, and in stool within 60 h. Cnidilin in bile was completely excreted in 24 h, and the main excretive amount of cnidilin was 80% in the first 6 h, but the drug recovery in bile within 24 h was <1.95%. In stool, the main excretive amount of cnidilin was 95.8% in the first 24 h, and the drug recovery within 48 h was lower than 1.48%. PMID- 23019011 TI - Spiky mesoporous anatase titania beads: a metastable ammonium titanate-mediated synthesis. AB - A complex titania nanostructure of monodisperse spiky mesoporous anatase beads composed of anatase nanocrystals with diameters of less than 15 nm in the core and much larger hollow-cone shaped spikes on the surface was fabricated using a facile solvothermal process in the presence of ammonia. This proceeded through a controllable phase transformation from an amorphous titania to a metastable amorphous titania/ammonium titanate core-shell structure then finally to anatase titania. The size of the spiky anatase nanostructures can be increased from approximately 55 * 100 nm to 160 * 410 nm (square edge * length) by increasing the ammonia concentration used in the solvothermal treatment step from 2.2 to 17.4 wt. %. Such hollow-cone shaped nanostructures, as revealed by HRTEM characterization, are single crystals elongated along the c axis of the tetragonal anatase titania. The resultant spiky titania beads have high surface areas of up to 112 m(2) g(-1) and pore diameters and pore volumes that vary depending on the ammonia concentration and solvothermal treatment time. The morphological evolution and crystallization process of the spiky titania beads was investigated using SEM and XRD techniques. A metastable amorphous titania/ammonium titanate core-shell structure evolved from the smooth amorphous precursor beads producing a "fluffy" titanate intermediate, on further heating the final spiky mesoporous titania beads were clearly observed. This titanate phase-mediated approach allows control over the size of the nanocrystals in the core of the bead, as well as the anatase spikes on the surface, and thereby, tuning of the surface area and porosity of the resultant products. The spiky mesoporous titania beads have been used to prepare working electrodes for dye sensitized solar cells achieving a solar to electric power conversion efficiency of 10.30 %, indicating their potential for application in the photovoltaic field. Such complex titania nanostructures would have a number of other possible applications, such as photocatalysis, lithium ion batteries, and catalysis. PMID- 23019009 TI - Short-term synchrony in diverse motor nuclei presumed to receive different extents of direct cortical input. AB - Motor units within human muscles usually exhibit a significant degree of short term synchronization. Such coincident spiking typically has been attributed to last-order projections that provide common synaptic input across motor neurons. The extent of branched input arising directly from cortical neurons has often been suggested as a critical factor determining the magnitude of short-term synchrony. The purpose of this study, therefore, was to quantify motor unit synchrony in a variety of human muscles differing in the presumed extent of cortical input to their respective motor nuclei. Cross-correlation histograms were generated from the firing times of 551 pairs of motor units in 16 human muscles. Motor unit synchrony tended to be weakest for proximal muscles and strongest for more distal muscles. Previous work in monkeys and humans has shown that the strength of cortical inputs to motor neurons also exhibits a similar proximal-to-distal gradient. However, in the present study, proximal-distal location was not an exclusive predictor of synchrony magnitude. The muscle that exhibited the least synchrony was an elbow flexor, whereas the greatest synchrony was most often found in intrinsic foot muscles. Furthermore, the strength of corticospinal inputs to the abductor hallucis muscle, an intrinsic foot muscle, as assessed through transcranial magnetic stimulation, was weaker than that projecting to the tibialis anterior muscle, even though the abductor hallucis muscle had higher synchrony values compared with the tibialis anterior muscle. We argue, therefore, that factors other than the potency of cortical inputs to motor neurons, such as the number of motor neurons innervating a muscle, significantly affects motor unit synchrony. PMID- 23019012 TI - Linker-free, silica-bound olefin-metathesis catalysts: applications in heterogeneous catalysis. AB - A set of heterogenized olefin-metathesis catalysts, which consisted of Ru complexes with the H(2)ITap ligand (1,3-bis(2',6'-dimethyl-4'dimethyl aminophenyl)-4,5-dihydroimidazol-2-ylidene) that had been adsorbed onto a silica support, has been prepared. These complexes showed strong binding to the solid support without the need for tethering groups on the complex or functionalized silica. The catalysts were tested in the ring-opening-ring-closing-metathesis (RO RCM) of cyclooctene (COE) and the self-metathesis of methyl oleate under continuous-flow conditions. The best complexes showed a TON>4000, which surpasses the previously reported materials that were either based on the Grubbs-Hoveyda II complex on silica or on the classical heterogeneous Re(2)O(7)/B(2)O(3) catalyst. PMID- 23019013 TI - G31P, an antagonist against CXC chemokine receptors 1 and 2, inhibits growth of human prostate cancer cells in nude mice. AB - Prostate cancer is the most common malignancy in Western countries. Chemokine C X-C motif receptor 1 (CXCR1) and CXCR2 play a key role in generation and regulation of CXC chemokine signaling. CXCR1 is a receptor for interleukin 8 (IL8), a pro-inflammatory chemokine, and CXCR1/2 are crucially involved in the prostate cancer development and progression. Thus, we generated a high-affinity human CXCR1/CXCR2 inhibitor, CXCL8 (3-72) K11R/G31P, named G31P, which is a synthetic derivative of the human cytokine, IL-8. In this study, we investigated the effects of G31P on regulation of prostate cancer cell growth in vitro and in nude mouse xenografts. Cell viability, adhesion, and wound healing assays were used to assess the effects of G31P on growth, adhesion, and migration of PC-3 human prostate cancer cells in vitro, respectively. Nude mouse xenografts and xenograft implantation assays were performed to determine the effect of G31P on PC-3 cells in vivo. Immunohistochemistry was used to detect gene expression, and fluorescence imaging was used to detect tumor volume and microvessel density in tumor xenografts. The data showed that G31P treatment significantly reduced PC-3 cell viability, adhesion and migration capacity in a dose-dependent manner (up to 100 ng/ml). Additionally, G31P treatment of nude mice suppressed the growth of orthotopically transplanted tumor xenografts. G31P also inhibited tumor tissue vascularization, which was associated with the decreased expression of vascular endothelial growth factor and nuclear transcription factor (NF)-kappaB in orthotopic xenograft tissues. This study provides evidence that G31P, a CXCR1/2 inhibitor, may effectively control prostate cancer. PMID- 23019014 TI - Short-term hypoxia transiently increases dopamine beta-hydroxylase immunoreactivity in glomus cells of the rat carotid body. AB - Under long-term hypoxia, noradrenaline (NA) content in the carotid body (CB) increases, suggesting that NA plays an important role in CB chemotransduction. However, it is unknown whether short-term hypoxia upregulates NA biosynthesis in CB. Therefore, we examined dopamine beta-hydroxylase (DBH) expression in the CB of rats exposed to hypoxia (10% O(2)) for 0 to 24 hr with immunoblotting and immunohistochemistry. Using immunoblotting, the signal intensity for DBH appeared to be the most intense in rats exposed to hypoxia for 12 hr. Using immunohistochemistry, DBH immunoreactivity was observed in the cytoplasm of some glomus cells and varicosities in controls and rats exposed to hypoxia for 6 hr. In rats exposed to hypoxia for 12 hr, DBH immunoreactive intensities in DBH positive glomus cells were significantly higher compared with controls (p<0.05). In the CB of rats exposed to hypoxia for 18 and 24 hr, DBH immunoreactive intensities in DBH-positive glomus cells were significantly lower than that of rats exposed to hypoxia for 12 hr (p<0.05). These results demonstrate that DBH immunoreactivity is transiently increased in glomus cells by short-term hypoxia, suggesting that NA biosynthesis is transiently facilitated in glomus cells at an early stage of hypoxia. PMID- 23019015 TI - An introduction to proteoglycans and their localization. AB - Proteoglycans comprise a core protein to which one or more glycosaminoglycan chains are covalently attached. Although a small number of proteins have the capacity to be glycanated and become proteoglycans, it is now realized that these macromolecules have a range of functions, dependent on type and in vivo location, and have important roles in invertebrate and vertebrate development, maintenance, and tissue repair. Many biologically potent small proteins can bind glycosaminoglycan chains as a key part of their function in the extracellular matrix, at the cell surface, and also in some intracellular locations. Therefore, the participation of proteoglycans in disease is receiving increased attention. In this short review, proteoglycan structure, function, and localizations are summarized, with reference to accompanying reviews in this issue as well as other recent literature. Included are some remarks on proteoglycan and glycosaminoglycan localization techniques, with reference to the special physicochemical properties of these complex molecules. PMID- 23019018 TI - CD4+CD25+CD127- assessment as a surrogate phenotype for FOXP3+ regulatory T cells in HIV-1 infected viremic and aviremic subjects. AB - BACKGROUND: Although likely pivotal, the role of regulatory T cells (Tregs) in HIV pathogenesis remains elusive. This can be partly explained by analytical issues regarding their phenotypic identification in clinical studies. Instead of intracellular FOXP3 staining, CD4+CD25+CD127- phenotype has been proposed as an alternative to identify Tregs in clinical samples. However, its use remains controversial in viremic patients. Therefore, the objective of the present study was to assess the correlation between frequencies of CD4+CD25+CD127- and CD4+CD25+FOXP3+ lymphocytes in viremic and matched aviremic HIV-infected patients. METHODS: Peripheral blood was collected from HIV-1 infected patients. Eleven viremic patients (Viral Load > 40 copies/mL) were matched (age, sex, CD4+ cell number) with 8 aviremic patients under highly active antiretroviral therapy (HAART). Fresh whole blood was immediately stained to analyze by flow cytometry the correlation between CD4+CD25+CD127- and the reference phenotype CD4+CD25+FOXP3+ lymphocytes in the same tube (four color staining CD4/CD25/CD127/FOXP3 for concomitant analysis of cell surface and intracellular markers). RESULTS: In both groups, no significant differences were observed when comparing CD4+CD25+CD127- and CD4+CD25+FOXP3+ cell frequencies. In line, a strong correlation between CD4+CD25+CD127- and CD4+CD25+FOXP3+ lymphocyte percentages was observed in the whole patient population (r: 0.948, P < 0.001) or each group separately: aviremic (r: 0.968, P < 0.001), viremic (r: 0.9, P < 0.001). Finally, we found that most CD4+FOXP3+ cells were indeed CD25+CD127-, both in viremic and aviremic groups (88.5% and 90.9%, respectively). CONCLUSIONS: We observed that CD4+CD25+CD127- phenotype is a good and easy-to-perform surrogate identification strategy for FOXP3+ regulatory T cells in both viremic and aviremic HIV-1 infected subjects. Thus, it represents a useful tool for monitoring Tregs in clinical research studies based on large cohorts of patients prospectively monitored, including HIV-infected subjects. PMID- 23019016 TI - The different roles of aggrecan interaction domains. AB - The aggregating proteoglycans of the lectican family are important components of extracellular matrices. Aggrecan is the most well studied of these and is central to cartilage biomechanical properties and skeletal development. Key to its biological function is the fixed charge of the many glycosaminoglycan chains, that provide the basis for the viscoelastic properties necessary for load distribution over the articular surface. This review is focused on the globular domains of aggrecan and their role in anchoring the proteoglycans to other extracellular matrix components. The N-terminal G1 domain is vital in that it binds the proteoglycan to hyaluronan in ternary complex with link protein, retaining the proteoglycan in the tissue. The importance of the C-terminal G3 domain interactions has recently been emphasized by two different human hereditary disorders: autosomal recessive aggrecan-type spondyloepimetaphyseal dysplasia and autosomal dominant familial osteochondritis dissecans. In these two conditions, different missense mutations in the aggrecan C-type lectin repeat have been described. The resulting amino acid replacements affect the ligand interactions of the G3 domain, albeit with widely different phenotypic outcomes. PMID- 23019020 TI - Relating applied strain to the type and severity of structural damage in the rat median nerve using second harmonic generation microscopy. AB - INTRODUCTION: Stretch injuries in peripheral nerves can cause pain, paralysis, and loss of sensation. Although optimal treatment depends on the degree of injury, it is difficult to determine the severity of induced nerve damage. METHODS: The load-deformation curves of rat median nerves were generated from monotonic load-to-failure experiments to determine low, medium, and high strain levels. Additional excised median nerves were then elongated to induce damage at low (4%), medium (10% and 12%), and high (14% and 20%) tensile strains and the resulting structural damage was evaluated using second harmonic generation (SHG) imaging and light microscopy. RESULTS: No substantial structural changes occurred at 4% strain, but higher strain values resulted in disruption of the normal collagen architecture. CONCLUSIONS: The results demonstrate a spectrum of structural damage that can be monitored using SHG, a non-destructive imaging modality, and that the pattern of damage may correspond to functional deficit. PMID- 23019017 TI - H3K9 trimethylation precedes DNA methylation during sheep oogenesis: HDAC1, SUV39H1, G9a, HP1, and Dnmts are involved in these epigenetic events. AB - The oocyte, to become a fully mature gamete, has to acquire a correct pattern of DNA methylation on its genome; this epigenetic event represents the major point of the molecular mechanisms that occur during postnatal oogenesis. It is known that an intimate link exists between DNA methylation and histone posttranslational modifications, such as trimethylation of lysine 9 on histone 3 (H3K9me3), that is essential in the silencing of gene transcription. What remains unclear is the precise sequence of these two epigenetic events and the protein expression of the enzymes that catalyze this epigenetic maturation during oogenesis. To identify the key molecules involved in global DNA methylation and H3K9me3, a biological network-based computational model was realized. Then, the spatiotemporal distribution of the proteins, identified from the biological network, was assessed during postnatal oogenesis. The results obtained suggest the existence of a sequential cascade of events in which H3K9me3 is the primary step followed by DNA methylation. These two epigenetic marks are realized due to the recruitment of the HDAC1, SUV39H1, G9a, HP1, and Dnmt3a, which were always localized in the nuclei of the oocytes and were dependent on chromatin configuration. These results involving DNA methylation and H3K9me3 are crucial in defining the oocyte developmental competence. PMID- 23019021 TI - Malachite green derivative-functionalized single nanochannel: light-and-pH dual driven ionic gating. AB - A highly efficient and perfectly reversible ionic gate that can be activated by pH or UV light is demonstrated. Switching between the OFF state and the ON state is mainly dependent on the surface charge transition brought about by a malachite green derivative attached to the interior surface of an ion track-etched conical nanochannel, which makes it suitable for confined spaces. Applications in electronics, actuators, and biosensors can be foreseen. PMID- 23019022 TI - [Natural fruit colour selection by frugivorous birds in Xishuangbanna]. AB - Black and red are the most common colors of fruit, but the reason behind this has been subject to debate. Food preferences of avian frugivores for certain colors of food have been proposed as a selection mechanism that explains these traits, but there is little evidence supporting this hypothesis. Here, we conducted a lab experiment using four colors of natural fruit to evaluate color preferences of five avian species, and we also conducted this experiment in open area and understory habitats. Our results showed that red and black fruits were selected most often in lab experiment; in field experiment, red and black fruits were also the most preferred food, but the total amount of consumed fruits differed significantly between open areas and understory habitats. Our study suggested that differences in color preferences among frugivores may potentially reflect the diversity of fruit color and frequency in Xishuangbanna. PMID- 23019023 TI - [Seasonal feeding site selection of the Nonggang Babbler (Stachyris nonggangensis) in Nonggang, Guangxi, China]. AB - We investigated the feeding sites of the Nonggang Babbler (Stachyris nonggangensis) during three time periods (July-September, 2010; November December, 2010; January-February, 2011) in Nonggang National Nature Reserve, Guangxi, China with the line transect method and sampling method. Principal component analysis of the data identified that the feeding sites in the rainy season were dominated by factors consisting of tree layer, the layer of fallen leaves and the herb layer; whereas the feeding sites in the dry season were dominated by factors dependant on terrain, herb layer and shrub layer. The results of a circular distribution analysis showed that the Nonggang Babbler preferred feeding sites with a gentle slope in both the rainy season and dry season. The tests of differences of the variables between used and control plots indicated that with low arbor coverage in the rainy season, whereas with a low slope position, high shrub and thick fallen leaves in the dry season. In comparison with the rainy season, the feeding sites in the dry season tended to be at lower altitude, to have a lower slope position, lower grass coverage, and to be covered with a larger and thicker bed of fallen leaves. A logistic regression analysis suggested that altitude, slope, and shatter cover were the most important factors influencing feeding site selection in the rainy season. Slope position, arbor cover, grass cover, and the thickness of the shatter cover were the most important factors influencing feeding site selection in the dry season. PMID- 23019024 TI - [Nested species subsets of amphibians and reptiles in Thousand Island Lake]. AB - Habitat fragmentation is a main cause for the loss of biological diversity. Combining line-transect methods to survey the amphibians and reptiles on 23 islands on Thousand Island Lake in Zhejiang province, along with survey data on nearby plant species and habitat variables collected by GIS, we used the"BINMATNEST (binary matrix nestedness temperature calculator)" software and the Spearman rank correlation to examine whether amphibians and reptiles followed nested subsets and their influencing factors. The results showed that amphibians and reptiles were significantly nested, and that the island area and habitat type were significantly associated with their nested ranks. Therefore, to effectively protect amphibians and reptiles in the Thousand Islands Lake area we should pay prior attention to islands with larger areas and more habitat types. PMID- 23019025 TI - [Ultrastructure of Ericerus pela (Chavannes) nymph mouthparts and ecological adaptations]. AB - The ultrastructure of nymph mouthparts of the Chinese white wax scale (CWWS), Ericerus pela, consists internally of the crumena, tentorium, the stylet bundle, comprised of two mandibular stylets and two maxillary stylets, and the external clypeolabral shield, labium and sensilla. The mouthpart morphology and structures of the female nymphs are similar to the male. The mouthparts of CWWS have significantly different features in comparison to aphids and other coccids. First, the mouthparts of CWWS have a crumena and a developed tentorium. Second, the labrum is highly degraded and the labium is short and one-segmented. Third, the maxillary stylets have two 'T' type locks. Lastly, the hairs of the mouthpart are sparse and the sensilla are simple. As the labrum and labium of CWWS displayed a high degree of degradation and the tentorium was found to be highly developed, the stretching of the stylet bundle was considered to be controlled by the tentorium and crumena together. Furthermore, the degraded sensilla may be related to a specialization of feeding behavior. There were no significant differences in the length and diameter of the stylet bundles between the female and male. However, the length and diameter of the stylet bundles were significantly different between the first instar nymphs and the second instar nymphs. The first instar nymphs had stylet fascicles that were shorter and soft and initially lived on the leaves of the host trees, presumably because the leaves were thinner and they were able to pierce the leaves while the stylet bundle was relatively soft. However, the second instar nymphs had stylet bundles that were relatively hard. After the numphs molted, the degree of ossification of the stylet bundles was enhanced (increased) and the nymphs returned to the branches for living, where the strengthened stylet bundles may provide a better adaption for the thicker bark. All told, the first and second stage instar CWWS nymphs switched from leaves to the branches in order to find a safe habitat and stable food source. PMID- 23019026 TI - [Characterization of the structure, function and regulation of the chicken mir-17 92 cluster]. AB - The miRNA cluster mir-17-92 is conserved in vertebrates and plays crucial roles in cell proliferation, differentiation, apoptosis and animal development. The mir 17-92 cluster also acts as an oncogene that is expressed in variety of cancers. Despite extensive study, the molecular mechanism underlying its functions is not fully understood. The fact that miRNAs in the same cluster are functionally related was used in the present study to investigate the function, and regulation of the chicken mir-17-92 cluster with GO analysis, pathway analysis, and binding site distribution analysis. The investigation found that the chicken mir-17-92 cluster regulated several vital cellular signaling pathways, including the MAPK, Wnt and TGF-beta signaling pathway. A miRNA binding site distribution analysis found that multiple miRNAs within the mir-17-92 cluster targeted the same genes, suggesting that the miRNA members of the mir-17-92 cluster act synergetically to regulate target genes. This study paves the way for future investigation into how the mir-17-92 cluster may regulate key cellular processes involved in cancer and development. PMID- 23019027 TI - [DNA barcoding and species and subspecies classification within genus Carassius]. AB - The classification of Carassius has not been well established due to its great variability and wide distribution. Usually, Carassius is identified as three species: C. carassius, C. cuvieri and C. auratus, the latter including several subspecies, such as goldfish. Out of these subspecies, C. auratus gibelio have recently been thought of as a valid species of Carassius. In this study we collected the 5'end 651 bp segments of the mitochondrial cytochrome c oxidase I (COI) gene from 128 specimens, including C. carassius, C. cuvieri, C. auratus auratus, C. auratus gibelio and C. auratus langsdorfii. All three species of Carassius (C. carassius, C. cuvieri, C. auratus) were found to be valid, meanwhile genetic differentiation between the Eurasian C. auratus and Japanese C. auratus has reached a high level. However, several haplotypes were shared between C. auratus auratus and C. auratus gibelio. Consequently, C. auratus gibelio should be regarded as a subspecies of C. auratus rather than a valid species. Moreover, because both diploids and triploids exist in C. auratus auratus and C. auratus gibelio, ploidy level should not be used as criteria for the classification of species or subspecies in Carassius. PMID- 23019028 TI - [cDNA cloning and expression analysis of MSTN gene from Schizopygopsis pylzovi]. AB - Myostatin (MSTN) is a member of the TGF-beta superfamily that acts as a negative regulator of skeletal muscle growth. A full-length, 2 180 bp, cDNA sequence of the myostatin gene from Schizopygopisis pylzovi was cloned with RT-PCR,5'-RACE and 3'-RACE and the cDNA clone included a 1 128 bp ORF, encoding a 375 amino acid peptide. Using PCR, we obtained the sequences of two introns of the MSTN gene and found that its structure in Schizopygopsis pylzovi was similar to that of other vertebrates, including three exons and two introns. Likewise, the putative MSTN peptide of Schizopygopsis pylzovi contains a conserved RXXR proteolytic cleavage domain, and 8 conserved cysteine residues in the C terminal of the protein, similar to other vertebrates. Phylogenetic analysis showed that the MSTN of Schizopygopsis pylzovi has high homology with other cyprinid fishes, but a low homology with mammals and birds. In the 9 examined tissues, the MSTN gene was highly expressed in heart, kidney, intestine and spermary, while weakly expressed in muscle, brain, fat, gill and hepatopancreas. Quantitative real-time PCR analysis showed that the expression of MSTN gene was different during embryo development, suggesting that the fish MSTN may not only play roles in muscle development but also contribute to other biological functions. PMID- 23019029 TI - [Cloning, physical and chemical property analysis of the Japanese sea bass Wap65 2 gene and its expression following Vibrio harveyi infection]. AB - The warm temperature acclimation related 65 kDa protein-2 (Wap65-2), a teleost plasma glycoprotein, plays an important role in immune regulation against bacterial infection. Here, for the first time we determined the full length cDNA sequence of the Japanese sea bass Wap65-2 gene (1 601 bp in length excluding the 3'-polyA tail). The sequence contains an open reading frame that encodes a protein of 436 amino acids with a molecular weight of 4.87*10(4). The predicted protein had a signal peptide in the N-terminal domain containing 19 residues. Sequence comparison and phylogenetic tree analysis showed that the Japanese sea bass Wap65-2 has a relatively high similarity to the Dicentrarchus labrax Wap65 2. In the healthy Japanese sea bass, Wap65-2 mRNA was expressed mainly in the liver and weakly in the heart and muscle. qRT-PCR results revealed that liver Wap65-2 transcripts were significantly increased after a Vibrio harveyi infection, and peaked 24 hour post injection (6.89 fold increase). The Japanese sea bass Wap65-2 protein was expressed in Escherichia coli and subsequently used for antiserum preparation. Western blot analysis showed that Wap65-2 was significantly increased in V. harveyi infected Japanese sea bass and reached a maximum of 5.33-fold increase at 36 h. In conclusion, the alteration of Japanese sea bass Wap65-2 expression was tightly associated with the progression of the V. harveyi bacterial infection. PMID- 23019030 TI - [Analysis of differentially expressed genes from female and male postparasitic Ovomermis sinensis juveniles]. AB - Mermithidae, as an important natural predator of pests such as Bollworm, has great potential for natural biological control of invasive pests. Unfortunately, the in vitro culture of the nematode has not yet been successful, delaying the commercial application of this pest control method. The key reason for this failure is the inability of the worms to accomplish sex differentiation, sparking a strong interest in this process. Here, we analyzed the differences in gene expression of female and male postparasitic Ovomermis sinensis juveniles by mRNA differential display. In total, 20 gene fragments that had differential expression in male and female worms were isolated, including 8 male- and 12 female-specific ones. Bioinformatics methods were employed to analyze sequences of these fragments, in which ensembl analysis shows 4 fragments have comparable parts with C. elegence's X chromosome, we speculate those fragments are important genes which influence sex differentiation of Ovomermis sinensis, This data provides an idea for further study of the molecular mechanism of sex differentiation in mermithids. PMID- 23019031 TI - [Mice cope with parabiosis - assessment of their physiological changes of life]. AB - The purpose of this study was to establish a parabiotic mice model and assess the physiological changes of the mice under the parabiotic state. Thirteen pairs of isogenic partners were studied. The model was created by preparing a bridge of skin and subcutaneous tissues between the two mice starting distal of the elbow joint along the humerus along the lateral costal region until the end of the waist line. Physiological, social and affective qualities of life were studied in the mice through behavioural observations for 120 days following the parabiotic surgery. During the first 2-3 days following the operation, the animals suffered from severe pain and distress. During the following days and weeks, the physiological system began to recover and the animals displayed behavioral adaptations to the parabiotic condition. All animals survived at day 120. At three days post operation, the body weight began to decrease. Following this, the animals experienced a continual body weight recovery and reached pre-surgical measures at about 30 days post op. Forty-eight h post op., faecal corticosterone metabolites were extremely elevated, but their levels returned to two to four times of levels in control females within 72 hours post op. The faecal corticosterone-metabolite levels decreased near to control values on day 75. Out of the 13 pairs, the blood exchange rate of three parabiotic partners was tested, with the result being normal post op. After 12 weeks, the total blood exchange between both partners needed 63 or 46 or 107 min, respectively. These results demonstrated that the animals could adapt behaviourally to the parabiotic situation. Therefore, this parabiosis mouse model may provide useful insights in many research areas, such as transplantation immunity, hematological system and metabolism, etc. PMID- 23019032 TI - [Aging affects early stage direction selectivity of MT cells in rhesus monkeys]. AB - The middle temporal area (MT/V5) plays an important role in motion processing. Neurons in this area have a strongly selective response to the moving direction of objects and as such, the selectivity of MT neurons was proposed to be a neural mechanism for the perception of motion. Our previous studies have found degradation in direction selectivity of MT neurons in old monkeys, but this direction selectivity was calculated during the whole response time and the results were not able to uncover the mechanism of motion perception over a time course. Furthermore, experiments have found that direction selectivity was enhanced by attention at a later stage. Therefore, the response should be excluded in experiments with anesthesia. To further characterize the neural mechanism over a time course, we investigated the age-related changes of direction selectivity in the early stage by comparing the proportions of direction selective MT cells in old and young macaque monkeys using in vivo single-cell recording techniques. Our results show that the proportion of early stage-direction-selective cells is lower in old monkeys than in young monkeys, and that the early stage direction bias (esDB) of old MT cells decreased relative to young MT cells. Furthermore, the proportion of MT cells having strong early stage direction selectivity in old monkeys was decreased. Accordingly, the functional degradation in the early stage of MT cells may mediate perceptual declines of old primates in visual motion tasks. PMID- 23019033 TI - [Effects of three antigens extracted from Vibrio vulnificus on the immunological protection of Nibea albiflora]. AB - Nibea albiflora was immunized by intraperitoneal injection with either Lipopolysaccharide (LPS) or outer membrane protein (OMP) extracted from Vibrio vulnificus or formalin killed Vibrio vulnificus (FKC). The influence of the three antigens on the immunological function of Nibea albiflora was determined at different time points following the injection by testing the agglutinating antibody titers of the serum, lysozyme activity of the serum, phagocytic activity of the blood and the relative survival percentage. The results showed that the three antigens have higher immunogenicity and antigenicity than the control group(injection with sterile saline). The agglutinating antibody titers of the immune challenged groups increased quickly, and were highest on the day 28. The lysozyme activity and phagocytic activity were raised significantly (P<0.01), reaching their top value on day 21, and then the index gradually reduced. The immunological indexes of three immune groups were higher than the control group (P<0.05). The agglutinating antibody titers of the LPS group or the OMP group were lower than the control group, but the relative survival percentage was adverse when challenged with a Vibrio vulnificus infection. The order of relative survival percentage was group LPS>OMP>FKC>Control. PMID- 23019034 TI - [Diversity and development of positional behavior in non-human primates]. AB - In long-term evolution, wildlife in general and primates in particular have formed specific patterns of behavior to adapt to a diverse variety of habitat environments. Current research on positional behavior in non-human primates has been found to explain a great deal about primate adaptability diversification, ecology, anatomy and evolution. Here, we summarize the noted classifications and differences in seasonal, site-specific and sex-age positional behaviors while also reviewing the development and status of non-human primate positional behavior research. This review is intended to provide reference for the future research of non-human primates and aid in further research on behavioral ecology of primates. PMID- 23019035 TI - [Progress in cathelicidins antimicrobial peptides research]. AB - Cathelicidins are a family of multi-functional antimicrobial peptides found in almost all types of vertebrates, where they play vital roles in the immune system. As they possess broad-spectrum antimicrobial properties, cathelicidins are not only strongly resistant to Gram-positive and Gram-negative bacteria, fungi, and viruses, but they are also active against many antibiotic-resistant clinical bacteria, adopting a special antimicrobial mechanism that is unlikely to lead to microbial resistance. Cathelicidins likewise possess simple structures, and low hemolytic and cytotoxic activities. Collectively, these features suggest potentially novel and exciting prospects for cathelicidins' application in medicine. Here, we review the structures, classification, activities, mechanisms, as well as prospective developments in the usage and application of cathelicidin antimicrobial peptides. PMID- 23019036 TI - [Progress in activity-dependent structural plasticity of neural circuits in cortex]. AB - Neural circuits of mammalian cerebral cortex have exhibited amazing abilities of structural and functional plasticity in development, learning and memory, neurological and psychiatric diseases. With the new imaging techniques and the application of molecular biology methods, observation neural circuits' structural dynamics within the cortex in vivo at the cellular and synaptic level was possible, so there were many great progresses in the field of the activity dependent structural plasticity over the past decade. This paper reviewed some of the aspects of the experimental results, focused on the characteristics of dendritic structural plasticity in individual growth and development, rich environment, sensory deprivation, and pathological conditions, as well as learning and memory, especially the dynamics of dendritic spines on morphology and quantity; after that, we introduced axonal structural plasticity, the molecular and cellular mechanisms of structural plasticity, and proposed some future problems to be solved at last. PMID- 23019037 TI - [SAMHD1 - a HIV-1 restriction factor derived from Myeloid lineage monocytes]. AB - HIV-1 restriction factors have became one of the hottest fields of AIDS researches. In 2011, SAMHD1 was demonstrated to be a novel HIV-1 restriction factor, adding to a list of HIV-1 restriction factors that include APOBEC3G, TRIM5alpha and Tetherin. SAMHD1 is highly expressed in myeloid-lineage monocytes, such as macrophages and dendritic cells. In this paper, we review the current research progress on the structure of SAMHD1, its antiviral mechanism, interaction with the lentivirus Vpx, and evolution. The identification of SAMHD1 opens the door towards understanding the role of SAMHD1 in lentiviral pathogenesis. PMID- 23019038 TI - [First record of Van sung's shrew (Chodsigoa caovansunga) in China]. AB - On December 5, 2012, a specimen of Chodsigoa caovansunga Lunde, Musser and Son, 2003 was collected at Manhao, Gejiu, Yunnan (N23Degrees Celsius00'43.0'', E103Degrees Celsius26'18.9'', 350 m asl). This finding is the first recorded distribution of C. caovansunga in China and outside of the type locality (Mt. Tay Con Linh II, Ha Giang, Vietnam). The length of the head, body, tail and condylo incisive are longer than those of the specimens from type locality in Vietnam, indicating a generally larger size. Likewise, the cyt-b sequence (GenBank accession number: JX508288) is 98.6% similar to specimens from type locality. The habitat of collection site was a ravine rain forest with banana plantation nearby. PMID- 23019039 TI - [White-tailed Lapwing Vanellus leucurus - a newly recorded of bird in China]. AB - On August 15, 2012, a local photographer recorded a new species, the White-tailed Lapwing (Vanellus leucurus) in the Dongfanghong Reservoir, 38 Degrees Celsius 26'N and 77 Degrees Celsius 07'E, altitude 1230 m, Yarkand County, in southern Xinjiang, China. PMID- 23019041 TI - T2-based arterial spin labeling measurements of blood to tissue water transfer in human brain. AB - PURPOSE: To investigate blood to tissue water transfer in human brain, in vivo and spatially resolved using a T2-based arterial spin labeling (ASL) method with 3D readout. MATERIALS AND METHODS: A T2-ASL method is introduced to measure the water transfer processes between arterial blood and brain tissue based on a 3D GRASE (gradient and spin echo) pulsed ASL sequence with multiecho readout. An analytical mathematical model is derived based on the General Kinetic Model, including blood and tissue compartment, T1 and T2 relaxation, and a blood-to tissue transfer term. Data were collected from healthy volunteers on a 3 T system. The mean transfer time parameter T(bl -> ex) (blood to extravascular compartment transfer time) was derived voxelwise by nonlinear least-squares fitting. RESULTS: Whole-brain maps of T(bl -> ex) show stable results in cortical regions, yielding different values depending on the brain region. The mean value across subjects and regions of interest (ROIs) in gray matter was 440 +/- 30 msec. CONCLUSION: A novel method to derive whole-brain maps of blood to tissue water transfer dynamics is demonstrated. It is promising for the investigation of underlying physiological mechanisms and development of diagnostic applications in cerebrovascular diseases. PMID- 23019045 TI - Synthesis and characterization of terminal [Re(XCO)(CO)2(triphos)] (X=N, P): isocyanate versus phosphaethynolate complexes. AB - The terminal rhenium(I) phosphaethynolate complex [Re(PCO)(CO)(2)(triphos)] has been prepared in a salt metathesis reaction from Na(OCP) and [Re(OTf)(CO)(2)(triphos)]. The analogous isocyanato complex [Re(NCO)(CO)(2)(triphos)] has been likewise prepared for comparison. The structure of both complexes was elucidated by X-ray diffraction studies. While the isocyanato complex is linear, the phosphaethynolate complex is strongly bent around the pnictogen center. Computations including natural bond orbital (NBO) theory, natural resonance theory (NRT), and natural population analysis (NPA) indicate that the isocyanato complex can be viewed as a classic Werner-type complex, that is, with an electrostatic interaction between the Re(I) and the NCO group. The phosphaethynolate complex [Re(P=C=O)(CO)(2)(triphos)] is best described as a metallaphosphaketene with a Re(I)-phosphorus bond of highly covalent character. PMID- 23019044 TI - Association between work-family conflict and musculoskeletal pain among hospital patient care workers. AB - BACKGROUND: A growing body of evidence suggests that work-family conflict is an important risk factor for workers' health and well-being. The goal of this study is to examine association between work-family conflict and musculoskeletal pain among hospital patient care workers. METHODS: We analyzed a cross-sectional survey of 1,119 hospital patient care workers in 105 units in two urban, academic hospitals. Work-family conflict was measured by 5-item Work-Family Conflict Scale questionnaire. Multilevel logistic regression was applied to examine associations between work-family conflict and self-reported musculoskeletal pain in the past 3 months, adjusting for covariates including work-related psychosocial factors and physical work factors. RESULTS: In fully adjusted models, high work-family conflict was strongly associated with neck or shoulder pain (OR: 2.34, 95% CI: 1.64-3.34), arm pain (OR: 2.79, 95% CI: 1.64-4.75), lower extremity pain (OR: 2.20, 95% CI: 1.54-3.15) and any musculoskeletal pain (OR: 2.45, 95% CI: 1.56 3.85), and a number of body areas in pain (OR: 2.47, 95% CI: 1.82-3.36) in the past 3 months. The association with low back pain was attenuated and became non significant after adjusting for covariates. CONCLUSIONS: Given the consistent associations between work-family conflict and self-reported musculoskeletal pains, the results suggest that work-family conflict could be an important domain for health promotion and workplace policy development among hospital patient care workers. PMID- 23019046 TI - Amidation of aldehydes and alcohols through alpha-iminonitriles and a sequential oxidative three-component Strecker reaction/thio-Michael addition/alumina promoted hydrolysis process to access beta-mercaptoamides from aldehydes, amines, and thiols. AB - Mild and general alumina-promoted hydrolysis conditions for converting alpha iminonitriles into carboxamides have been developed. In combination with the oxidative three-component Strecker reaction, the one-pot direct amidation of aldehydes and alcohols is reported. Subsequently, an Yb(OTf)(3)-catalyzed Michael addition of thiols to alpha,beta-unsaturated alpha-iminonitriles is reported for the synthesis of beta-mercapto-alpha-iminonitriles. The successful integration of an oxidative Strecker reaction, thio-Michael addition, and neutral-alumina promoted hydrolysis of beta-mercapto-alpha-iminonitriles into a three-component one-pot process allowed us to develop the direct conversion of amines, aldehydes, and thiols into beta-mercaptoamides. All of these procedures were applicable to aromatic and aliphatic amines and aldehydes. PMID- 23019047 TI - Maternal hemodynamics at 11-13 weeks of gestation in pregnancies delivering small for gestational age neonates. AB - OBJECTIVE: To examine aortic systolic blood pressure (SBP(Ao)), pulse wave velocity (PWV) and augmentation index (adjusted to a heart rate of 75 beats per minute, AIx-75) at 11-13 weeks' gestation in pregnancies delivering small for gestational age (SGA) neonates with and without preeclampsia (PE). METHODS: At 11+0 to 13+6 weeks' gestation, maternal history was recorded and PWV, AIx-75, SBP(Ao), uterine artery pulsatility index (PI) and maternal serum pregnancy associated plasma protein-A (PAPP-A) were measured. We compared women with (n = 337) and without (n = 48) PE that delivered SGA neonates with unaffected controls (n = 6,429). RESULTS: In the SGA group without PE, compared to unaffected controls, there was no significant difference in AIx-75 (1.03 vs. 1.00 multiple of the median, MoM), PWV (0.98 vs. 1.00 MoM) or SBP(Ao) (1.01 vs. 1.00 MoM), but uterine artery PI was increased (1.10 vs. 1.00 MoM) and PAPP-A decreased (0.85 vs. 1.00 MoM). In SGA with PE, compared to unaffected controls, there was increased AIx-75 (1.13 vs. 1.00 MoM), SBP(Ao) (1.09 vs. 1.00 MoM), uterine artery PI (1.40 vs. 1.00 MoM) and decreased PAPP-A (0.72 vs. 1.00 MoM), but no significant difference in PWV (1.05 vs. 1.00 MoM). CONCLUSION: In pregnancies with SGA neonates, impaired placentation is reflected in low PAPP-A and high uterine artery PI at 11-13 weeks' gestation. In the SGA group with PE, but not in those without PE, there is increased SBP(Ao) and AIx-75. PMID- 23019049 TI - Unexpected zirconium-mediated multicomponent reactions of conjugated 1,3 butadiynes and monoynes with acyl cyanide derivatives. AB - Going ber(zirc): zirconium-butadiyne complexes react with acyl cyanide derivatives through diverse reaction pathways. The complexes react with two molecules of carbamoyl cyanide to form 1,4-benzodiazepin-2-one-derivatives containing azazirconacycles. Reactions with either aroyl cyanides or alkyl cyanoformates lead to azazirconacyclopentenes containing a quaternary carbon center. PMID- 23019048 TI - Systematic meta-analyses and field synopsis of genetic association studies in colorectal cancer. AB - BACKGROUND: Colorectal cancer is a major global public health problem, with approximately 950,000 patients newly diagnosed each year. We report the first comprehensive field synopsis and creation of a parallel publicly available and regularly updated database (CRCgene) that catalogs all genetic association studies on colorectal cancer (http://www.chs.med.ed.ac.uk/CRCgene/). METHODS: We performed two independent systematic reviews, reviewing 10 145 titles, then collated and extracted data from 635 publications reporting on 445 polymorphisms in 110 different genes. We carried out meta-analyses to derive summary effect estimates for 92 polymorphisms in 64 different genes. For assessing the credibility of associations, we applied the Venice criteria and the Bayesian False Discovery Probability (BFDP) test. RESULTS: We consider 16 independent variants at 13 loci (MUTYH, MTHFR, SMAD7, and common variants tagging the loci 8q24, 8q23.3, 11q23.1, 14q22.2, 1q41, 20p12.3, 20q13.33, 3q26.2, 16q22.1, and 19q13.1) to have the most highly credible associations with colorectal cancer, with all variants except those in MUTYH and 19q13.1 reaching genome-wide statistical significance in at least one meta-analysis model. We identified less-credible (higher heterogeneity, lower statistical power, BFDP >0.2) associations with 23 more variants at 22 loci. The meta-analyses of a further 20 variants for which associations have previously been reported found no evidence to support these as true associations. CONCLUSION: The CRCgene database provides the context for genetic association data to be interpreted appropriately and helps inform future research direction. PMID- 23019054 TI - Endovascular treatment and the long-term results of postpartum deep vein thrombosis in 18 patients. AB - PURPOSE: We aimed to describe the long-term outcome of endovascular treatment of iliofemoral deep vein thrombosis in the postpartum period. MATERIALS AND METHODS: Between 2002 and 2010, 18 consecutive female patients with acute or subacute iliofemoral deep vein thrombosis in the postpartum period who had endovascular treatment were retrospectively evaluated. Treatment consisted of manual aspiration thrombectomy with or without catheter-directed thrombolysis. Stents were placed in the iliac veins, if deemed necessary. Clot removal was graded as complete (>95%), partial (50%-95%), and poor (<50%). RESULTS: The initial treatment was technically successful in 17 patients (94%). There was complete clot removal in 15 of 22 limbs (68%). Twenty-three stents were implanted in 15 patients (83%). The primary and secondary patencies were 58% and 82% at one year, 58% and 72% at three years, and 58% and 58% at five years, respectively. There were recurrent thromboses in 11 patients (61%), which occurred within the first month in nine of these patients (81%). Ten patients had repeated intervention, and five had successful outcomes. At a mean follow-up of 30 months, 11 patients had uninterrupted in-line flow in the affected lim b, and six patients did not. Six of the patients with uninterrupted flow were asymptomatic, and five patients had minimal swelling at the ankle. CONCLUSION: Endovascular treatment of postpartum iliofemoral deep vein thrombosis with percutaneous aspiration thrombectomy alone or combined with catheter-directed thrombolysis and iliac vein stenting is an effective therapy resulting in a high rate of thrombus removal. However, recurrences are high, particularly in the first post-intervention month. Frequent patient followup in the first post-intervention month is necessary. PMID- 23019055 TI - Factors that impact the upgrading of atypical ductal hyperplasia. AB - PURPOSE: The purpose of this study was to identify the factors that may have an impact on upgrading atypical ductal hyperplasia (ADH) lesions to malignancy. MATERIALS AND METHODS: Between February 1999 and December 2010, the records of 150 ADH lesions that had been biopsied were retrospectively reviewed. The biopsy types included 11-gauge stereotactic vacuum-assisted biopsy (SVAB) (n=102) and ultrasonography (US)-guided 14-gauge automated biopsy (n=48). The patients were divided into two groups: those who had cancer in the final pathology and those who did not. Variables associated with underestimation of ADH lesions were compared between the groups. RESULTS: The underestimation rates according to the biopsy types were 41.7% (20/48) for the US-guided 14-gauge automated biopsy and 20.6% (21/102) for the 11-gauge SVAB (P = 0.007). The rate of underestimation was significantly higher in lesions greater than 7 mm than it was in smaller lesions, with both US-guided 14-gauge automated biopsy and 11-gauge SVAB (P = 0.024 and P = 0.042, respectively). The rate of underestimation was significantly higher with the 11-gauge SVAB (P = 0.025) in lesions that were suspicious (R4) and highly suggestive of malignancy (R5) than in those that were probably benign (R3). CONCLUSION: The underestimation rate in ADH lesions was significantly higher with US-guided 14-gauge automated biopsy compared to the 11-gauge SVAB. The underestimation rate was also significantly higher in lesions greater than 7 mm regardless of the biopsy type, and in lesions biopsied using SVAB that were regarded as suspicious (R4) or highly suggestive of malignancy (R5) on imaging. PMID- 23019056 TI - A long-term outcome of therapeutic angiogenesis by transplantation of peripheral blood stem cells in critical limb ischemia after interventional revascularization. AB - A 61-year-old male patient with atherosclerotic critical limb ischemia in the left leg underwent stent insertion into the left superficial femoral artery. Stenting procedures improved Rutherford grade from III-5 to II-4. Granulocyte colony-stimulating factor stimulated the production of white blood cells over four-fold and mononuclear cells (MNCs) 1.5-fold in the whole blood. Transplantation of 7.9x10(9) autologous MNCs into the left femoral artery rapidly decreased the leg pain intensity, with further improvement of Rutherford grades from II-4 to 0-0 without any side effects. In the four-year follow-up, significant improvement was found in terms of ankle brachial index, from nondetectable to 0.67, and peak systolic velocity, from 14.8 to 36.1 cm/s. Limb salvage and decreased resting pain were the notable outcomes of the treatment. PMID- 23019057 TI - CT findings in apical versus basal involvement of pulmonary tuberculosis. AB - PURPOSE: We aimed to compare clinical features and computed tomography (CT) findings of pulmonary tuberculosis (TB) in lower lobe basal segments and upper lobe apical or apicoposterior segments. MATERIALS AND METHODS: We retrospectively reviewed medical records and chest CT scans of 986 adults who were diagnosed with active pulmonary TB. Active pulmonary TB confined to the basal segments was found in 21 patients. Sixty patients had disease localized to the apical or apicoposterior segments only. Clinical features and CT abnormalities of the lung parenchyma, airways, mediastinal and hilar lymph nodes, and pleura were compared between these two groups. RESULTS: A significant difference was observed between two groups in terms of underlying disease prevalence associated with an immunocompromised state (basal, 6/21, 28.6%; apical or apico- posterior, 3/60, 5%; P = 0.008). Chest CT findings, including consolidation (P = 0.0016), lymphadenopathy (P = 0.0297), and pleural effusion (P = 0.008), were more common in basal segment TB than in apical or apicoposterior segment TB. Small nodules were less common in basal segment TB than in apical or apicoposterior segment TB (P = 0.0299). The tree-in-bud sign was the most common CT finding in both basal segment TB (17/21, 81%) and apical or apicoposterior segment TB groups (53/60, 88.3%) (P = 0.4633). CONCLUSION: Lower lobe basal segment TB was more commonly present with common CT findings of primary pulmonary TB including consolidation, mediastinal and hilar lymphadenopathy, and pleural effusion than apical or apicoposterior segment TB. PMID- 23019062 TI - Carbon nanotubes as plant growth regulators: effects on tomato growth, reproductive system, and soil microbial community. AB - Multi-walled carbon nanotubes (CNTs) can affect plant phenotype and the composition of soil microbiota. Tomato plants grown in soil supplemented with CNTs produce two times more flowers and fruit compared to plants grown in control soil. The effect of carbon nanotubes on microbial community of CNT-treated soil is determined by denaturing gradient gel electrophoresis and pyrosequencing analysis. Phylogenetic analysis indicates that Proteobacteria and Bacteroidetes are the most dominant groups in the microbial community of soil. The relative abundances of Bacteroidetes and Firmicutes are found to increase, whereas Proteobacteria and Verrucomicorbia decrease with increasing concentration of CNTs. The results of comparing diversity indices and species level phylotypes (OTUs) between samples showed that there is not a significant affect on bacterial diversity. PMID- 23019063 TI - Direct MR arthrography of the shoulder under axial traction: feasibility study to evaluate the superior labrum-biceps tendon complex and articular cartilage. AB - PURPOSE: To assess the value of adding axial traction to direct MR arthrography of the shoulder, in terms of subacromial and glenohumeral joint space widths, and coverage of the superior labrum-biceps tendon complex and articular cartilage by contrast material. MATERIALS AND METHODS: Twenty-one patients investigated by direct MR arthrography of the shoulder were prospectively included. Studies were performed with a 3 Tesla (T) unit and included a three-dimensional isotropic fat suppressed T1-weighted gradient-recalled echo sequence, without and with axial traction (4 kg). Two radiologists independently measured the width of the subacromial, superior, and inferior glenohumeral joint spaces. They subsequently rated the amount of contrast material around the superior labrum-biceps tendon complex and between glenohumeral cartilage surfaces, using a three-point scale: 0 = no, 1 = partial, 2 = full. RESULTS: Under traction, the subacromial (Delta = 2.0 mm, P = 0.0003), superior (Delta = 0.7 mm, P = 0.0001) and inferior (Delta = 1.4 mm, P = 0.0006) glenohumeral joint space widths were all significantly increased, and both readers noted significantly more contrast material around the superior labrum-biceps tendon complex (P = 0.014), and between the superior (P = 0.001) and inferior (P = 0.025) glenohumeral cartilage surfaces. CONCLUSION: Direct MR arthrography of the shoulder under axial traction increases subacromial and glenohumeral joint space widths, and prompts better coverage of the superior labrum-biceps tendon complex and articular cartilage by contrast material. PMID- 23019064 TI - Indole synthesis by conjugate addition of anilines to activated acetylenes and an unusual ligand-free copper(II)-mediated intramolecular cross-coupling. AB - A versatile new synthesis of indoles was achieved by the conjugate addition of N formyl-2-haloanilines to acetylenic sulfones, ketones, and esters followed by a copper-catalyzed intramolecular C-arylation. The conjugate addition step was conducted under exceptionally mild conditions at room temperature in basic, aqueous DMF. Surprisingly, the C-arylation was performed most effectively by employing copper(II) acetate as the catalyst in the absence of external ligands, without the need for protection from air or water. An unusual feature of this process, for the case of acetylenic ketones, is the ability of the initial conjugate-addition product to serve as a ligand for the catalyst, which enables it to participate in the catalysis of its further transformation to the final indole product. Mechanistic studies, including EPR experiments, indicated that copper(II) is reduced to the active copper(I) species by the formate ion that is produced by the base-catalyzed hydrolysis of DMF. This process also served to recycle any copper(II) that was produced by the adventitious oxidation of copper(I), thereby preventing deactivation of the catalyst. Several examples of reactions involving acetylenic sulfones attached to a modified Merrifield resin demonstrated the feasibility of solid-phase synthesis of indoles by using this protocol, and tricyclic products were obtained in one pot by employing acetylenic sulfones that contain chloroalkyl substituents. PMID- 23019065 TI - Assessment of the association between colchicine therapy and serious adverse events. AB - STUDY OBJECTIVE: As data that prompted a 2009 labeling change detailing contraindications, precautions, and dosing recommendations for the first branded colchicine product were limited to case reports of myotoxicity and blood dyscrasias ascribed to the drug, we sought to quantify the association of colchicine therapy with serious adverse outcomes in a cohort of insured patients. DESIGN: Case-control study. DATA SOURCE: Kaiser Permanente Colorado electronic data warehouses and electronic medical records. PATIENTS: Cases were patients with a creatine kinase (CK) level of at least 2000 U/L or who developed a clinically significant non-cancer-related blood dyscrasia (thrombocytopenia, neutropenia, leukopenia, aplastic anemia, or pancytopenia) between January 1, 2006, and June 30, 2009 (954 cases). Each case was matched to up to 10 controls by age, sex, and index date (date of the increased CK level or blood dyscrasia supporting laboratory value). Controls were patients without elevated CK levels or blood dyscrasias who had a routine health maintenance examination during the same time period (index date was the date of their health maintenance examination [9007 controls]). MEASUREMENTS AND MAIN RESULTS: The primary study outcome was colchicine exposure, defined as a colchicine prescription purchase in the 100 days before the index date. The likelihood of colchicine exposure was examined with conditional logistic regression. Cases experienced a higher rate of previous colchicine exposure compared with controls (0.6% vs 0.2%, odds ratio 3.9, 95% confidence interval 1.4-10.7). In addition, cases had higher hospitalization rates (14.9% vs 5.0%, p<0.001), higher mean chronic disease scores (2.5 vs 0.0, p<0.001), and were more likely to have been exposed to drugs that may increase the risk of adverse events due to an interaction with a CYP3A4 inhibitor drug (6.9% vs 2.3%, p<0.001). CONCLUSION: Patients with confirmed elevations in CK level and/or blood dyscrasias had a higher rate of previous colchicine exposure, although low overall, and greater hospitalization rates and exposure to drugs that may increase the risk of adverse events compared with controls. These findings support the 2009 United States Food and Drug Administration labeling for the first branded colchicine product, cautioning use in patients with liver impairment or renal dysfunction and/or those receiving concurrent drugs that may increase risk of adverse events. PMID- 23019066 TI - Abundant gene-by-environment interactions in gene expression reaction norms to copper within Saccharomyces cerevisiae. AB - Genetic variation for plastic phenotypes potentially contributes phenotypic variation to populations that can be selected during adaptation to novel ecological contexts. However, the basis and extent of plastic variation that manifests in diverse environments remains elusive. Here, we characterize copper reaction norms for mRNA abundance among five Saccharomyces cerevisiae strains to 1) describe population variation across the full range of ecologically relevant copper concentrations, from starvation to toxicity, and 2) to test the hypothesis that plastic networks exhibit increased population variation for gene expression. We find that although the vast majority of the variation is small in magnitude (considerably <2-fold), not just some, but most genes demonstrate variable expression across environments, across genetic backgrounds, or both. Plastically expressed genes included both genes regulated directly by copper-binding transcription factors Mac1 and Ace1 and genes indirectly responding to the downstream metabolic consequences of the copper gradient, particularly genes involved in copper, iron, and sulfur homeostasis. Copper-regulated gene networks exhibited more similar behavior within the population in environments where those networks have a large impact on fitness. Nevertheless, expression variation in genes like Cup1, important to surviving copper stress, was linked with variation in mitotic fitness and in the breadth of differential expression across the genome. By revealing a broader and deeper range of population variation, our results provide further evidence for the interconnectedness of genome-wide mRNA levels, their dependence on environmental context and genetic background, and the abundance of variation in gene expression that can contribute to future evolution. PMID- 23019067 TI - Variance in epistasis links gene regulation and evolutionary rate in the yeast genetic interaction network. AB - Organisms face a constantly shifting landscape of environmental conditions and internal physiological states. How gene regulation and cellular functions are maintained across genetic and environmental variation is therefore a fundamental question in biology. Here, we analyze the Saccharomyces cerevisiae genetic interaction network to understand how the yeast cell maintains regulatory capacity across genetic backgrounds and environmental conditions. We used the recently characterized synthetic sick/lethal network in yeast, which measures the fitness effects of knocking out pairs of genes, to analyze interactions among 4,364 genes. Genes with large variance in epistatic effects on fitness are highly and ubiquitously expressed (with open chromatin conformations in their promoter regions) and evolve more slowly than genes with weak effects on fitness. Thus, rather than being the elements responsible for the regulation and responsiveness of the genetic network, genes with large epistatic effects tend to be more mundane "housekeeping" genes whose consistent expression is critical to fitness under all environments and that are thereby deeply embedded within the regulatory structure of the network. Our analysis shows that the yeast cell has evolved a system whereby a physical mechanism of regulation (nucleosome occupancy) buffers key genes from the variability experienced by the cell as a whole. PMID- 23019070 TI - Access to a responsiveness to intervention model: does beginning intervention in kindergarten matter? AB - In this study, we tested the outcomes of access to a response to intervention (RtI) model in kindergarten or in first grade on end-of-Grade-2 reading achievement and placement in special education. Across five schools, 214 students who began having access to Tier 2 intervention in kindergarten or first grade were compared in Grades 1 and 2 with 208 cohort peers who were average readers and 102 historical control condition second grade poor readers who did not receive Tier 2 intervention. Results demonstrated significant effects on reading achievement for access to RtI in kindergarten at the end of first grade (effects averaged 0.48), but not in second grade, except for students who were English language learners (ELLs), who showed an advantage through the end of second grade. Students with access to RtI overall had significantly higher outcomes at the end of Grade 2 than students in the historical control, with no differences resulting from ELL status. No significant difference in the proportion of students placed in special education was noted; however, a greater proportion of the students found eligible as with learning disabilities had poor reading scores if they were placed after participating in RtI. PMID- 23019068 TI - SP transcription factor paralogs and DNA-binding sites coevolve and adaptively converge in mammals and birds. AB - Functional modification of regulatory proteins can affect hundreds of genes throughout the genome, and is therefore thought to be almost universally deleterious. This belief, however, has recently been challenged. A potential example comes from transcription factor SP1, for which statistical evidence indicates that motif preferences were altered in eutherian mammals. Here, we set out to discover possible structural and theoretical explanations, evaluate the role of selection in SP1 evolution, and discover effects on coregulatory proteins. We show that SP1 motif preferences were convergently altered in birds as well as mammals, inducing coevolutionary changes in over 800 regulatory regions. Structural and phylogenic evidence implicates a single causative amino acid replacement at the same SP1 position along both lineages. Furthermore, paralogs SP3 and SP4, which coregulate SP1 target genes through competitive binding to the same sites, have accumulated convergent replacements at the homologous position multiple times during eutherian and bird evolution, presumably to preserve competitive binding. To determine plausibility, we developed and implemented a simple model of transcription factor and binding site coevolution. This model predicts that, in contrast to prevailing beliefs, even small selective benefits per locus can drive concurrent fixation of transcription factor and binding site mutants under a broad range of conditions. Novel binding sites tend to arise de novo, rather than by mutation from ancestral sites, a prediction substantiated by SP1-binding site alignments. Thus, multiple lines of evidence indicate that selection has driven convergent evolution of transcription factors along with their binding sites and coregulatory proteins. PMID- 23019071 TI - The effect of grade norms in college students: using the Woodcock-Johnson III Tests of Achievement. AB - The Woodcock-Johnson III Tests of Achievement grade norms versus age norms were examined in the calculation of discrepancy scores in 202 college students. Difference scores were calculated between the Wechsler Adult Intelligence Scale 3rd Edition Full Scale IQ and the Woodcock-Johnson III Total Achievement, Broad Reading, Math, and Written Language scores. The proportion meeting the substantial discrepancy criterion of two standard deviations plus or minus the standard error of the difference between means was 7.9% using age norms and 37.6% using grade norms. Using mixed analyses of variance, the authors found main effects for type of norm for all difference scores, with grade norms yielding significantly higher difference scores than age norms. A main effect for student status (traditional-age students n = 124, non-traditional-age students n = 78) was found for Total Achievement, Broad Reading, and Math such that traditional age students had greater discrepancies. Discrepancy scores are contrasted with absolute scores (SS < 85) in the identification of learning disabilities as well. Implications of using grade versus age norms are discussed. PMID- 23019069 TI - Unraveling oxyntomodulin, GLP1's enigmatic brother. AB - Oxyntomodulin (OXM) is a peptide secreted from the L cells of the gut following nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP1 and glucagon to act as a potentially more effective treatment for obesity than GLP1R agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvement in glycemic control beyond those of GLP1R agonists. PMID- 23019072 TI - A convergent approach to (-)-callystatin A based on local symmetry. AB - The key is symmetry! A convergent synthetic approach of the highly cytotoxic natural product (-)-callystatin A was developed assembling three fragments through Julia-Kocienski olefination and Stille cross-coupling. The new strategy relies on a pivotal local symmetry of the target molecule. In this preliminary study, particular attention was devoted to facilitate the catalytic enantiocontrol of strategic stereogenic centers present in each of the fragments (see scheme). PMID- 23019075 TI - Coexistence of CMT1A and diabetes mellitus in a young woman with a severe and progressive neuropathy and respiratory insufficiency. PMID- 23019074 TI - T(H)2-like chemokine patterns correlate with disease severity in patients with recurrent respiratory papillomatosis. AB - Recurrent respiratory papillomatosis (RRP), characterized by the recurrent growth of benign tumors of the respiratory tract, is caused by infection with human papillomavirus (HPV), predominantly types 6 and 11. Surgical removal of these lesions can be required as frequently as every 3 to 4 wks to maintain a patent airway. There is no approved medical treatment for this disease. In this study, we have characterized the T(H)2-like chemokine profile (CCL17, CCL18, CCL20, CCL22) in patients with RRP and asked whether it was modulated in patients who had achieved significant clinical improvement. CCL17, CCL18 and CCL22 messenger RNAs (mRNAs) were increased in papillomas compared with clinically normal laryngeal epithelium of the RRP patients. Overall, CCL20 mRNA expression was not increased, but there was intense, selective CCL20 protein expression in the basal layer of the papillomas. Patients with RRP expressed more CCL17 (p = 0.003), CCL18 (p = 0.0003), and CCL22 (p = 0.007) in their plasma than controls. Plasma CCL18 decreased over time in three patients enrolled in a pilot clinical trial of celecoxib, and the decrease occurred in conjunction with clinical improvement. There was a significant correlation between sustained clinical remission in additional patients with RRP and reduced levels of CCL17 (p = 0.01), CCL22 (p = 0.002) and CCL18 (p = 0.05). Thus, the change in expression of these three plasma T(H)2-like chemokines may, with future studies, prove to serve as a useful biomarker for predicting disease prognosis. PMID- 23019076 TI - Monomer-dimer equilibrium for the 5'-5' stacking of propeller-type parallel stranded G-quadruplexes: NMR structural study. AB - Guanine-rich sequence motifs, which contain tracts of three consecutive guanines connected by single non-guanine nucleotides, are abundant in the human genome and can form a robust G-quadruplex structure with high stability. Herein, by using NMR spectroscopy, we investigate the equilibrium between monomeric and 5'-5' stacked dimeric propeller-type G-quadruplexes that are formed by DNA sequences containing GGGT motifs. We show that the monomer-dimer equilibrium depends on a number of parameters, including the DNA concentration, DNA flanking sequences, the concentration and type of cations, and the temperature. We report on the high definition structure of a simple monomeric G-quadruplex containing three single residue loops, which could serve as a reference for propeller-type G-quadruplex structures in solution. PMID- 23019073 TI - Pigment epithelium-derived factor (PEDF) peptide eye drops reduce inflammation, cell death and vascular leakage in diabetic retinopathy in Ins2(Akita) mice. AB - Inflammation, neurodegeneration and microvascular irregularities are included in the spectrum of defects associated with diabetic retinopathy. Here, we evaluated intraocular deliverability features of two pigment epithelium-derived factor (PEDF) derivatives given as eye drops and their efficacy in modulating diabetes induced retinal complications. The antiangiogenic PEDF60-77 (P60) and neuroprotective PEDF78-121 (P78) derivatives were applied to Ins2(Akita) mouse eyes once a week for 15 wks at the onset of hyperglycemia. Peptides, labeled with Alexa Fluor 488, were observed penetrating the cornea by 1-4 h and gained access to the ciliary body, retinal pigment epithelium (RPE)-choroid complex, retina microvasculature and vitreous. Peak vitreous levels were 0.2 MUg/mL for P60 and 0.9 MUg/mL for P78 after 0.5 and 4 h, respectively. Both peptides reduced vascular leakage by ~60% and increased zona occludens 1 (ZO1) and occludin expression in the microvasculature to nondiabetic levels. P60 induced pERK1/2 and P78 promoted pAKT in Muller glia, two signals that were dampened in diabetic conditions. Pharmacologically inhibiting AKT signaling in the retina blocked effects of the peptides on ZO1 and occludin expression. P78 reduced levels of 9/20 cytokines in diabetic vitreous including interferon (IFN)-gamma, interleukin (IL)-6, IL-3 and tumor necrosis factor (TNF)-alpha. P60 lowered levels of 6/20 cytokines but was less effective than P78. Neuroprotective P78 prevented diabetes induced microglia activation by ~60%, retinal ganglion cell (RGC) death by ~22% and inner plexiform layer thinning by ~13%. In summary, we provide evidence that PEDF bioactive derivatives gained access to the retina by topical delivery and validated their efficacy in reducing diabetic retinopathy complications. Our findings argue for glia regulation of microvascular leakage and an early root cause for RGC degeneration embedded in microglia activation. PMID- 23019077 TI - Multicomponent assembly of macrocycles and polymers by coordination of pyridyl ligands to 1,4-bis(benzodioxaborole)benzene. AB - Multicomponent reactions between 1,4-benzenediboronic acid, catechol, and different pyridyl ligands are reported. The condensation of 1,4-benzenediboronic acid with catechol gives 1,4-bis(benzodioxaborole)benzene. Upon crystallization, the ester aggregates with the N-donor ligands through dative B-N bonds. Depending on the nature of the pyridyl ligand, molecularly defined macrocycles or polymeric structures are obtained. 1D polymers are formed with 4,4-bipyridine and 1,2-di(4 pyridyl)ethylene, whereas a 2D network is obtained with the tetradentate ligand tetra(4-pyridylphenyl)ethylene. These results highlight the utility of dative B-N bonds in structural supramolecular chemistry and crystal engineering. PMID- 23019078 TI - Charge stabilization of superparamagnetic colloids for high-performance responsive photonic structures. PMID- 23019079 TI - Predictors of desire for help in oncology outpatients reporting pain or distress. AB - OBJECTIVE: Although effective treatments for pain and distress are available, many patients do not access them. Improved understanding of patients' desire for help may improve uptake of services. METHODS: Data were collected as part of the QUICATOUCH screening program at an Australian regional hospital. Patients over threshold for pain were asked if they would like help with their pain and those over threshold for distress were asked if they would like help with their distress. Multivariate logistic regression analyses were conducted to identify independent predictors of desire for help. RESULTS: Of 305 patients over threshold for pain; 59% wanted help, increasing from 13% at a pain score of one to 90% at a pain score of 10. Of 274 patients over threshold for distress, 30% wanted help, increasing from 21% at a distress score of four to 41% at a distress score of 10. Pain score was the only significant independent predictor of desire for help with pain, with an odds ratio (OR) of 1.50 (95%CI 1.33-1.70) for every point increase in pain score. Distress score was the only significant independent predictor of desire for help with distress with an OR of 1.29 (95%CI 1.11-1.50) for every point increase in distress score. CONCLUSIONS: Although desire for help with pain and distress increased with respective symptom intensity, many patients indicated they did not want help with these symptoms. Patient reluctance to seek help may constitute a barrier to realising the full potential of screening programs in reducing pain and distress. PMID- 23019080 TI - Aspirin for primary prevention of cardiovascular disease events. AB - Aspirin has been used for the prevention and treatment of cardiovascular disease (CVD) for several decades. The efficacy of aspirin for secondary prevention of cardiovascular disease is well established, but the clinical benefit of aspirin for primary prevention of CVD is less clear. The primary literature suggests that aspirin may provide a reduction in CVD events, but the absolute benefit is small and accompanied by an increase in bleeding. For aspirin to be beneficial for an individual patient, the risk of a future CVD event must be large enough to outweigh the risk of bleeding. The estimation of CVD risk is multifaceted and can involve numerous risk scores and assessments of concomitant comorbidities that confer additional CVD risk. Numerous guidelines provide recommendations for the use of aspirin for primary prevention, but they often contradict one another despite being based on the same clinical trials. Additional literature suggests that the presence of comorbidities that increase CVD risk, such as diabetes mellitus, asymptomatic peripheral arterial disease, or chronic kidney disease, does not ensure that aspirin therapy will be beneficial. Ongoing clinical trials may provide additional insight, but until more data are available, an individualized assessment of CVD risk with careful evaluation of risk and benefit should be performed before recommending aspirin therapy for primary prevention of CVD. PMID- 23019081 TI - Transition-metal-free atropo-selective synthesis of biaryl compounds based on arynes. AB - A modular way towards biaryls: Highly enantioenriched biphenyls can be prepared based on a transition-metal-free aryl-aryl coupling followed by efficient desymmetrization or deracemization and chemoselective functionalization (see scheme). PMID- 23019083 TI - Degradation of resin-dentin bonds of etch-and-rinse adhesive system to primary and permanent teeth. AB - The aim of this in vitro study was to compare the degradation of resin-dentin bonds of an etch-and-rinse adhesive system to primary and permanent teeth. Flat superficial coronal dentin surfaces from 5 primary second molars and 5 permanent third molars were etched with phosphoric acid and bonded with an adhesive system (Adper Single Bond 2, 3M ESPE). Blocks of resin composite (Z250, 3M ESPE) were built up and the teeth sectioned to produce bonded sticks with a 0.8 mm2 cross sectional area. The sticks of each tooth were randomly divided and assigned to be subjected to microtensile testing immediately (24 h) or after aging by water storage (6 months). Data were analyzed by two-way repeated measures ANOVA and Tukey post hoc test (alpha = 0.05). Failure mode was evaluated using a stereomicroscope (400*). Microtensile values significantly decreased after the 6 months aging, independent of the dentin substrate. In 24 h, the values obtained to primary dentin were lower compared with permanent dentin. This difference was not maintained after aging. Adhesive/mixed failure was predominant in all experimental groups. In conclusion, degradation of resin-dentin bonds of the etch and-rinse adhesive system occurred after 6 months of water storage; however, the reduction in bond strength values was higher for permanent teeth. PMID- 23019082 TI - Gender differences in penetrance and phenotype in hypokalemic periodic paralysis. AB - INTRODUCTION: Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant skeletal muscle ion channelopathy. Sex hormones are natural ion channel regulators. Different sex hormones have different effects on ion channels. A comparison of the penetrance and phenotype between males and females with HypoPP mutations should aid in proving that sex hormones play different roles in HypoPP and also provide the basis for the development of therapies against HypoPP. METHODS: We identified all mutation carriers in 4 HypoPP families using PCR sequencing techniques. All patients underwent clinical investigation. RESULTS: There were 8 men and 7 women mutation carriers in the 4 families. Male carriers had 100% penetrance, but female penetrance was only 28.57%. The highest attack frequency was 50-150 times/year for the men, whereas it was 30-50 times/year for the women. The attacks disappeared during pregnancy. CONCLUSIONS: The penetrance and attack frequency were lower in women than in men with HypoPP mutations. PMID- 23019085 TI - The effect of a Lucia jig for 30 minutes on neuromuscular re-programming, in normal subjects. AB - The Lucia jig is a technique that promotes neuromuscular reprogramming of the masticatory system and allows the stabilization of the mandible without the interference of dental contacts, maintaining the mandible position in harmonic condition with the musculature in normal subjects or in patients with temporomandibular dysfunction (TMD). This study aimed to electromyographically analyze the activity (RMS) of the masseter and temporal muscles in normal subjects (control group) during the use of an anterior programming device, the Lucia jig, in place for 0, 5, 10, 20 and 30 minutes to demonstrate its effect on the stomatognathic system. Forty-two healthy dentate individuals (aged 21 to 40 years) with normal occlusion and without parafunctional habits or temporomandibular dysfunction (RDC/TMD) were evaluated on the basis of the electromyographic activity of the masseter and temporal muscles before placement of a neuromuscular re-programming device, the Lucia jig, on the upper central incisors. There were no statistically significant differences (p < 0.05) in the electromyographic activity of the masticatory muscles in the different time periods. The Lucia jig changed the electromyographic activity by promoting a neuromuscular reprogramming. In most of the time periods, it decreased the activation of the masticatory muscles, showing that this device has wide applicability in dentistry. The use of a Lucia jig over 0, 5, 10, 15, 20 and 30 minutes did not promote any statistically significant increase in muscle activity despite differences in the data, thus showing that this intra-oral device can be used in dentistry. PMID- 23019084 TI - Effects of the medicinal plants Curcuma zedoaria and Camellia sinensis on halitosis control. AB - Volatile sulphur compounds (VSC) are the gases mainly responsible for halitosis (bad breath). The aim of this research was to evaluate the effects of medicinal plants on halitosis control. Two commonly used plants were tested: Curcuma zedoaria and Camellia sinensis (green tea). These plants were prepared as an aqueous solution and used as mouthwashes, compared with a standard mouthwash of 0.12% chlorhexidine gluconate and a placebo (water). The experiment was conducted with 30 volunteers from the School of Dentistry of Sao Jose dos Campos, Univ. Estadual Paulista - UNESP, SP, Brazil. Each volunteer tested the four mouthwashes. The Cysteine Challenge Method, modified for this study, was used for initial breath standardization. Four breath assessments were conducted after volunteers rinsed orally with acetylcysteine: one before the test mouthwash was used; the second, one minute after its use; a third 90 minutes later; and the last 180 minutes later. The results showed that chlorhexidine gluconate lowered VSC production immediately, and that this effect lasted up to 3 hours, while the tested plants had immediate inhibitory effects but no residual inhibitory effects on VSC. We concluded that Curcuma zedoaria and Camellia sinensis, prepared as infusions and used as mouthwashes, did not have a residual neutralizing effect on VSC. PMID- 23019086 TI - Oral leukoplakia manifests differently in smokers and non-smokers. AB - Oral leukoplakias (OL) are potentially malignant lesions that are typically white in color. Smoking is considered a risk factor for developing OL, and dysplastic lesions are more prone to malignant transformation. The aim of this study was to describe the clinical features observed in dysplastic and non-dysplastic OL in both smokers and non-smokers. A total of 315 cases of OL were retrieved and separated into either dysplastic or non-dysplastic lesions, and these cases were further categorized as originating in either smokers or non-smokers. Frequencies of the type of OL lesion, with respect to whether the patients smoked, were established. The results demonstrated that 131 cases of OL were dysplastic (74 smokers and 57 non-smokers), and 184 were non-dysplastic (96 smokers and 88 non smokers). For OL cases in smokers for which information about alcohol consumption was also available (84 cases), the results revealed no significant difference in the amount of dysplastic and non-dysplastic lesions. Dysplastic lesions were more frequent in male smokers and in non-smoking females. The median age of smokers with cases of OL was significantly lower than in non-smokers; the lowest median ages were observed for female smokers with dysplastic OL. The most frequent anatomical sites of dysplastic lesions were the floor of the mouth in smokers and the tongue in non-smokers. Dysplastic lesions in smokers were significantly smaller than non-dysplastic lesions in non-smokers. Being a male smoker, being female, being younger, and having smaller lesions were associated with dysplastic features in OL. These clinical data may be important for predicting OL malignant transformation. PMID- 23019087 TI - CIE L*a*b*: comparison of digital images obtained photographically by manual and automatic modes. AB - The aim of this study was to analyze the color alterations performed by the CIE L*a*b* system in the digital imaging of shade guide tabs, which were obtained photographically according to the automatic and manual modes. This study also sought to examine the observers' agreement in quantifying the coordinates. Four Vita Lumin Vaccum shade guide tabs were used: A3.5, B1, B3 and C4. An EOS Canon digital camera was used to record the digital images of the shade tabs, and the images were processed using Adobe Photoshop software. A total of 80 observations (five replicates of each shade according to two observers in two modes, specifically, automatic and manual) were obtained, leading to color values of L*, a* and b*. The color difference (DeltaE) between the modes was calculated and classified as either clinically acceptable or unacceptable. The results indicated that there was agreement between the two observers in obtaining the L*, a* and b* values related to all guides. However, the B1, B3, and C4 shade tabs had DeltaE values classified as clinically acceptable (DeltaE = 0.44, DeltaE = 2.04 and DeltaE = 2.69, respectively). The A3.5 shade tab had a DeltaE value classified as clinically unacceptable (DeltaE = 4.17), as it presented higher values for luminosity in the automatic mode (L* = 54.0) than in the manual mode (L* = 50.6). It was concluded that the B1, B3 and C4 shade tabs can be used at any of the modes in digital camera (manual or automatic), which was a different finding from that observed for the A3.5 shade tab. PMID- 23019088 TI - Fusion pores, SNAREs, and exocytosis. AB - Exocytosis is a multistage process involving a merger between the vesicle and the plasma membranes, leading to the formation of a fusion pore, a channel, through which secretions are released from the vesicle to the cell exterior. A stimulus may influence the pore by either dilating it completely (full-fusion exocytosis) or mediating a reversible closure (transient exocytosis). In neurons, these transitions are short-lived and not accessible for experimentation. However, in some neuroendocrine cells, initial fusion pores may reopen several hundred times, indicating their stability. Moreover, these pores are too narrow to pass luminal molecules to the extracellular space, termed release-unproductive. However, on stimulation, their diameter dilates, initiating the release of cargo without de novo fusion pore formation. To explain the stability of the initial narrow fusion pores, anisotropic membrane constituents with non-axisymmetrical shape were proposed to accumulate in the fusion pore membrane. Although the nature of these is unclear, they may consist of lipids and proteins, including SNAREs, which may facilitate and regulate the pre- and post-fusional stages of exocytosis. In the future, a more detailed insight into the molecular control of fusion pore stabilization and regulation will generate a better understanding of fusion pore physiology in health and disease. PMID- 23019089 TI - Molecular description of the propagation of chirality from molecules to complex systems: different mechanisms controlled by hydrophobic interactions. AB - In this work a combined theoretical and experimental approach was used to elucidate and describe at the molecular level the basic interactions that drive the transfer of the chiral information from chiral surfactant molecules to dye/surfactant assemblies. It was found that both hydrophobic interactions and relative concentrations strongly influence the chiroptical features of the heteroaggregates. In particular it was observed that, depending on the length of the surfactant hydrophobic chain, the chiral information is transferred to the dye by stabilizing an enantiomer either of a chiral conformer or of a chiral topological arrangement. These findings underline the role of hydrophobic interactions in the transfer of chirality and provide an example of the potential of in silico simulations for providing an accurate description of the process of chirality propagation. PMID- 23019090 TI - Self-assembly studies of a chiral bisurea-based superhydrogelator. AB - A chiral bisurea-based superhydrogelator that is capable of forming supramolecular hydrogels at concentrations as low as 0.2 mM is reported. This soft material has been characterized by thermal studies, rheology, X-ray diffraction analysis, transmission electron microscopy (TEM), and by various spectroscopic techniques (electronic and vibrational circular dichroism and by FTIR and Raman spectroscopy). The expression of chirality on the molecular and supramolecular levels has been studied and a clear amplification of its chirality into the achiral analogue has been observed. Furthermore, thermal analysis showed that the hydrogelation of compound 1 has a high response to temperature, which corresponds to an enthalpy-driven self-assembly process. These particular thermal characteristics make these materials easy to handle for soft-application technologies. PMID- 23019091 TI - Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking. AB - Nanoparticles have many potential applications in tumor therapy. Systemically administered nanoparticles should remain in circulation for a long time to increase their accumulation in targeted tissues before being cleared by the reticuloendothelial system, and be effectively internalized by the targeted cells, which can be influenced significantly by the physicochemical characteristics of nanoparticles, such as particle size, surface properties, and particle shape. This review highlights the impact of the main affects of physicochemical properties on nanoparticle transport behavior in blood, their uptake and clearance by macrophages and their consequent biodistribution, as well as their interaction with targeted cells. PMID- 23019092 TI - Do prostate cancer patients suffer more from depressed mood or anhedonia? AB - OBJECTIVE: This study aimed to compare the prevalence of depressed mood and anhedonia in a sample of men with prostate cancer (PCa) and to determine which of these key symptoms contributed most to the overall depressive status of that sample. METHOD: From Zung Self-rating Depression Scale (SDS) responses collected on 526 PCa patients, direct comparisons were made between the prevalence of the first two DSM-IV-TR symptoms of Major Depressive Episode. These symptoms were then tested for their predictive power on depression total score and Zung's criteria for 'clinically significant' depression. RESULTS: Mean scores for anhedonia were significantly higher than for depressed mood, and nearly 25 times as many patients had a high score for anhedonia as for depressed mood. The same pattern of results was apparent for those patients who had clinically significant levels of depression. Anhedonia was a more powerful predictor of total SDS depression score for the entire sample as well as for those patients with more severe depression. CONCLUSION: Because the biological basis for anhedonia is different to that for depressed mood, treatment options also differ for patients who show a preponderance of anhedonia in their depressive symptomatology. Suggestions are made for treatment choices for these PCa patients. PMID- 23019093 TI - Robust estimation of causal effects of binary treatments in unconfounded studies with dichotomous outcomes. AB - The estimation of causal effects has been the subject of extensive research. In unconfounded studies with a dichotomous outcome, Y, Cangul, Chretien, Gutman and Rubin (2009) demonstrated that logistic regression for a scalar continuous covariate X is generally statistically invalid for testing null treatment effects when the distributions of X in the treated and control populations differ and the logistic model for Y given X is misspecified. In addition, they showed that an approximately valid statistical test can be generally obtained by discretizing X followed by regression adjustment within each interval defined by the discretized X. This paper extends the work of Cangul et al. 2009 in three major directions. First, we consider additional estimation procedures, including a new one that is based on two independent splines and multiple imputation; second, we consider additional distributional factors; and third, we examine the performance of the procedures when the treatment effect is non-null. Of all the methods considered and in most of the experimental conditions that were examined, our proposed new methodology appears to work best in terms of point and interval estimation. PMID- 23019094 TI - MALDI mass spectrometry for nucleic acid analysis. AB - With the discovery of several matrices which enable the ionization of DNA and RNA, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has become a powerful platform for the study of nucleic acid sequence changes (e.g., mutations, single nucleotide polymorphisms (SNPs), insertion/deletion, alternative splicing, etc.), amount changes (e.g., copy number variation, gene expression, allele expression, etc.), as well as modifications (e.g., methylation of genomic DNA, post transcriptional modification of tRNAs and rRNAs). Two major strategies have been employed to characterize these changes. Primer extension reactions are designed for genotyping of known polymorphic sites and determining the levels of gene or allele expressions. Base-specific cleavage reactions are used for discovery of unknown polymorphisms and characterization of modifications. These two assays usually generate nucleic acid fragments less than 30 bases in length, which is the ideal mass range for MALDI-MS. Here we review the basic concepts of these assays, sample analysis techniques, and their applications published in recent years. PMID- 23019095 TI - Chirality and protein biosynthesis. AB - Chirality is present at all levels of structural hierarchy of protein and plays a significant role in protein biosynthesis. The macromolecules involved in protein biosynthesis such as aminoacyl tRNA synthetase and ribosome have chiral subunits. Despite the omnipresence of chirality in the biosynthetic pathway, its origin, role in current pathway, and importance is far from understood. In this review we first present an introduction to biochirality and its relevance to protein biosynthesis. Major propositions about the prebiotic origin of biomolecules are presented with particular reference to proteins and nucleic acids. The problem of the origin of homochirality is unresolved at present. The chiral discrimination by enzymes involved in protein synthesis is essential for keeping the life process going. However, questions remained pertaining to the mechanism of chiral discrimination and concomitant retention of biochirality. We discuss the experimental evidence which shows that it is virtually impossible to incorporate D-amino acids in protein structures in present biosynthetic pathways via any of the two major steps of protein synthesis, namely aminoacylation and peptide bond formation reactions. Molecular level explanations of the stringent chiral specificity in each step are extended based on computational analysis. A detailed account of the current state of understanding of the mechanism of chiral discrimination during aminoacylation in the active site of aminoacyl tRNA synthetase and peptide bond formation in ribosomal peptidyl transferase center is presented. Finally, it is pointed out that the understanding of the mechanism of retention of enantiopurity has implications in developing novel enzyme mimetic systems and biocatalysts and might be useful in chiral drug design. PMID- 23019096 TI - Reactions of phosphine-boranes and related frustrated Lewis pairs with transition metal complexes. AB - Over the last few years, the coordination of phosphine-boranes and related Frustrated Lewis Pairs to transition metals has attracted considerable interest. These polyfunctional, ambiphilic ligands are very versatile. In particular, the Lewis acid site may participate in different ways to coordination, directly at the metal or in near periphery. These recent achievements are presented and discussed in this chapter. PMID- 23019097 TI - Does antenatal ultrasound labeling predict birth order in twin pregnancies? AB - OBJECTIVE: It is often assumed by obstetricians, neonatologists and parents that the prenatal nomenclature used to identify twins on ultrasound is consistent with twin labeling after their birth. The aim of this study was to use a large regional database of twin ultrasound scans to validate the effectiveness of a scan before delivery in predicting twin birth-order. METHODS: A large regional database of twin ultrasound scans with data from nine hospitals over a 10-year period was used to identify all ultrasound examinations carried out just before birth. The discordance in twin order between the last scan and birth was evaluated by observing discrepancies in fetal sex and weight. RESULTS: In total, 2103 twin pregnancies with ultrasound estimated fetal weights (EFWs) and birth weights were assessed. Of these, fetal sex was recorded in 149 different-sex pregnancies. Discrepancy between antenatal labeling and the anticipated birth order was noted in 37.6% (56/149) of cases when judged by sex discordance and in 36% (757/2103) of cases when judged by weight discordance. Multiple logistic regression analyses demonstrated that weight discordance, but not chorionicity, scan-to-delivery interval, gestation at scan or gestation at delivery, significantly influenced the change in birth order (P < 0.001). CONCLUSION: Antenatal ultrasound labeling does not predict twin birth-order in a significant proportion of twin deliveries. This finding should be borne in mind not only by parents, but also by physicians when delivering twins discordant for anomalies that are not evident on external examination. PMID- 23019098 TI - Identification of avocado (Persea americana) pulp proteins by nano-LC-MS/MS via combinatorial peptide ligand libraries. AB - Avocado (Persea americana) proteins have been scarcely studied despite their importance, especially in food related allergies. The proteome of avocado pulp was explored in depth by extracting proteins with capture by combinatorial peptide ligand libraries at pH 7.4 and under conditions mimicking reverse-phase capture at pH 2.2. The total number of unique gene products identified amounts to 1012 proteins, of which 174 are in common with the control, untreated sample, 190 are present only in the control and 648 represent the new species detected via combinatorial peptide ligand libraries of all combined eluates and likely represent low-abundance proteins. Among the 1012 proteins, it was possible to identify the already known avocado allergen Pers a 1 and different proteins susceptible to be allergens such as a profilin, a polygalacturonase, a thaumatin like protein, a glucanase, and an isoflavone reductase like protein. PMID- 23019099 TI - Recombinant p53 displays heterogeneity during isoelectric focusing. AB - Human recombinant, baculovirus-expressed p53 protein focuses on 2D gels in multiple spots in the narrow pI range. Re-electrophoresis of the individual spots resulted in the appearance of multiple spots. The strings of spots were neither species specific, nor characteristic for baculovirus-expressed p53. Moreover, mutant p53 did not deviate from wild-type p53, indicating that this is an inherent property of p53. Okadaic acid treatment of insect cells, phosphate substitution reaction of purified p53, and individual analysis of all spots by mass spectrometry revealed that only a fraction of the recombinant p53 is phosphorylated. This finding excluded that the individual p53 spots in 2D gels reflect charge isomers generated by phosphorylation, but rather suggest that they are due to conformational flexibility of urea-denatured monomeric p53 molecules or deamidation of asparagine and glutamine residues. The latter possibility was confirmed by NanoLC-ESI MS/MS analysis. Our data provide a putative hint for a novel regulatory level for function and stability of p53, particularly the long lived mutant p53 overexpressed in diverse tumor types. PMID- 23019100 TI - Development of PCR internal controls for DNA profiling with the AmpFlSTR(r) SGM Plus(r) amplification kit. AB - Forensic DNA profiling uses a series of commercial kits that co-amplify several loci in one reaction; the products of the PCR are fluorescently labelled and analysed using CE. Before CE, an aliquot of the PCR is mixed with formamide and an internal lane size standard. Using the SGM Plus amplification kit, we have developed two internal non-amplified controls of 80 bp and 380 bp that are labelled with ROX fluorescent dye and added to the PCR. Combined with two internal amplification controls of 90 bp and 410 bp, they provide additional controls for the PCR, electrokinetic injection, and CE and also function as an internal size standard. PMID- 23019101 TI - Technical improvement of the TBP (tubulin-based polymorphism) method for plant species detection, based on capillary electrophoresis. AB - Nowadays, feed and food safety and traceability are of primary importance. Hence, a correct labeling of the different products is highly desirable in general, but mandatory for those people who are suffering from eating disorders and food allergies. Among the technologies that have been developed for feed and food analysis, the patented tubulin-based polymorphism (TBP) method emerges as an easy, versatile, and inexpensive diagnostic tool. Initially used to fingerprint different plant species and varieties, TBP was then successfully applied to trace species in mixtures of plant origin such as commercial feeds. TBP is a DNA-based molecular marker, that makes use of PCR for the selective amplification of plant beta-tubulin introns. Amplified fragments are then separated by PAGE and visualized by silver staining. We have now developed an improved version of TBP. Based on capillary electrophoresis and fluorescence detection, it makes the method automatic, more sensible, reproducible, and faster. Compared to the classic TBP, this new version allows to obtain a better data resolution and an easier interpretation of the results, clearing the way to large-scale feed/food diagnostics. PMID- 23019102 TI - Genetic and expression analysis of SNPs in the human deoxyribonuclease II: SNPs in the promoter region reduce its in vivo activity through decreased promoter activity. AB - Five SNPs in the human DNase II gene have been reported to be associated with rheumatoid arthritis (RA). Genotype and haplotype analysis of 14 SNPs, nine SNPs of which reported in the NCBI dbSNP database in addition to these five SNPs, was performed in healthy subjects. The enzymatic activities of the amino acid substituted DNase II corresponding to each SNP and serum DNase II in healthy Japanese, and promoter activities derived from each haplotype of the RA-related SNPs were measured. Significant correlations between genotype in each RA-related SNP and enzymatic activity levels were found; alleles associated with RA exhibited a reduction in serum DNase II activity. Furthermore, the promoter activities of each reporter construct corresponding to predominant haplotypes in three SNPs in the promoter region of the gene exhibited significant correlation with levels of serum DNase II activity. These findings indicate these three SNPs could alter the promoter activity of DNASE2, leading to a decline in DNase II activity in the serum through gene expression. Since the three SNPs in the promoter region of the DNase II gene could affect in vivo DNase II activity through reduction of the promoter activity, it is feasible to identify these SNPs susceptible to RA. PMID- 23019103 TI - Retrotransposon-microsatellite amplified polymorphism, an electrophoretic approach for studying genetic variability among Schistosoma japonicum geographical isolates. AB - In the present study, retrotransposon-microsatellite amplified polymorphism (REMAP) was used to examine genetic variability among Schistosoma japonicum isolates from different endemic provinces in mainland China, using S. japonicum from Japan and the Philippines for comparison. Of the 50 primer combinations screened, eight produced highly reproducible REMAP fragments. Using these primers, 190 distinct DNA fragments were generated in total, of which 147 (77.37%) were polymorphic, indicating considerable genetic variation among the 43 S. japonicum isolates examined. The percentage of polymorphic bands (PPB) among S. japonicum isolates from mainland China, Japan, and the Philippines was 77.37%; PPB values of 18.42% and 53.68% were found among isolates from southwestern (SW) China and the lower Yangtze/Zhejiang province in eastern (E) China, respectively. Based on REMAP profiles, unweighted pair-group method with arithmetic averages (UPGMA) dendrogram analysis revealed that all of the S. japonicum samples grouped into three distinct clusters: parasites from mainland China, Japan, and the Philippines were clustered in each individual clade. Within the mainland China cluster, SW China isolates (from Sichuan and Yunnan provinces) grouped together, whereas worms from E China (Zhejiang, Anhui, Jiangxi, Jiangsu, Hunan, and Hubei provinces) grouped together. These results demonstrated that the REMAP marker system provides a reliable electrophoretic technique for studying genetic diversity and population structures of S. japonicum isolates from mainland China, and could be applied to other pathogens of human and animal health significance. PMID- 23019104 TI - Dielectrophoretic field-flow fractionation of electroporated cells. AB - We describe the development and testing of a setup that allows for DEP field-flow fractionation (DEP-FFF) of irreversibly electroporated, reversibly electroporated, and nonelectroporated cells based on their different polarizabilities. We first optimized the channel and electrode dimensions, flow rate, and electric field parameters for efficient DEP-FFF separation of moderately heat-treated CHO cells (50 degrees C for 15 min) from untreated ones, with the former used as a uniform and stable model of electroporated cells. We then used CHO cells exposed to electric field pulses with amplitudes from 1200 to 2800 V/cm, yielding six groups containing various fractions of nonporated, reversibly porated, and irreversibly porated cells, testing their fractionation in the chamber. DEP-FFF at 65 kHz resulted in distinctive flow rates for nonporated and each of the porated cell groups. At lower frequencies, the efficiency of fractionation deteriorated, while at higher frequencies the separation of individual elution profiles was further improved, but at the cost of cell flow rate slowdown in all the cell groups, implying undesired transition from negative into positive DEP, where the cells are pulled toward the electrodes. Our results demonstrate that fractionation of irreversibly electroporated, reversibly electroporated, and nonelectroporated cells is feasible at a properly selected frequency. PMID- 23019106 TI - Metal-organic framework ZIF-8 nanocrystals as pseudostationary phase for capillary electrokinetic chromatography. AB - The outstanding properties such as large surface area, diverse structure, and accessible tunnels and cages make metal organic frameworks (MOFs) attractive as novel separation media in separation sciences. However, the utilization of MOFs in EKC has not been reported before. Here we show the exploration of zeolitic imidazolate framework-8 (ZIF-8), one of famous MOFs, as the pseudostationary phase (PSP) in EKC. ZIF-8 nanocrystals were used as the PSP through dispersing in the running buffer (20 mM phosphate solution containing a 1% v/v methanol (pH 9.2)) to enhance the separation of the phenolic isomers (p-benzenediol, m benzenediol, o-benzenediol, m-nitrophenol, p-nitrophenol, and o-nitrophenol). ZIF 8 nanocrystals in the running buffer were negatively charged, and interacted with the phenolic hydroxyl groups of the analytes, and thus greatly improved the separation of the phenolic isomers. Inclusion of 200 mg L-(1) ZIF-8 in the running buffer as the background electrolyte gave a baseline separation of the phenolic isomers within 4 min. The relative standard deviations for five replicate separations of the phenolic isomers were 0.2-1.1% for migration time and 4.5-9.7% for peak area. The limits of detection varied from 0.44 to 2.0 mg L (1) . The results show that nanosized MOFs are promising for application in EKC. PMID- 23019105 TI - Electrophoretic separations in poly(dimethylsiloxane) microchips using mixtures of ionic, nonionic and zwitterionic surfactants. AB - The use of surfactant mixtures to affect both EOF and separation selectivity in electrophoresis with PDMS substrates is reported, and capacitively coupled contactless conductivity detection is introduced for EOF measurement on PDMS microchips. First, the EOF was measured for two nonionic surfactants (Tween 20 and Triton X-100), mixed ionic/nonionic surfactant systems (SDS/Tween 20 and SDS/Triton X-100), and finally for the first time, mixed zwitterionic/nonionic surfactant systems (TDAPS/Tween 20 and TDAPS/Triton X-100). EOF for the nonionic surfactants decreased with increasing surfactant concentration. The addition of SDS or TDAPS to a nonionic surfactant increased EOF. After establishing the EOF behavior, the separation of model catecholamines was explored to show the impact on separations. Similar analyte resolution with greater peak heights was achieved with mixed surfactant systems containing Tween 20 and TDAPS relative to the single surfactant system. Finally, the detection of catecholamine release from PC12 cells by stimulation with 80 mM K(+) was performed to demonstrate the usefulness of mixed surfactant systems to provide resolution of biological compounds in complex samples. PMID- 23019107 TI - A poly (4-vinylpridine-co-ethylene glycol dimethacrylate) monolithic concentrator for in-line concentration-capillary electrophoresis analysis of phenols in water samples. AB - A poly(4-vinylpridine-co-ethylene glycol dimethacrylate) monolith was synthesized in a capillary and constructed as a concentrator for the in-line polymeric monolith microextraction coupling with capillary electrophoresis. The integrated system was then used for the simultaneous determination of five trace phenols (2 nitrophenol, 3-nitrophenol, 4-nitrophenol, 2-chlorophenol, and 2,4 dichlorophenol) in water samples. The experimental parameters for in-line solid phase extraction, such as composition and volume of the elution plug, pH of sample solution, and the time for sample loading were optimized. The sensitivity for the mixture of phenols (2-nitrophenol, 3-nitrophenol, 4-nitrophenol, 2 chlorophenol, and 2,4-dichlorophenol) enhanced to 615-2222 folds at the optimum condition was compared to the sensitivity for a normal hydrodynamic injection in capillary electrophoresis. Linearity ranged from concentration of 10-500 ng mL( 1) (R(2) > 0.999) for all five phenols with the detection limits of 1.3-3.3 ng mL(-1) . In tap, snow and Yangtze River water spiked with 20 ng mL(-1) and 200 ng mL(-1) , respectively, the recoveries of 84-105% were obtained. It has been demonstrated that this work has great potential for the analysis of phenols in genuine water samples. PMID- 23019113 TI - Oligo(borolyl)benzenes--synthesis and properties. AB - Herein, we report the synthesis of boroles that are linked by a conjugated phenylene spacer. The characterization of these compounds was completed by NMR and UV/Vis spectroscopy, as well as X-ray crystal diffraction. Furthermore, the coordination behavior of these oligoboroles towards five electronically and sterically disparate pyridine derivatives was studied and revealed fundamental differences in the properties of the resulting adducts. The experimental results were supported by density functional theory (DFT) calculations that showed a charge-transfer effect upon formation of the pyridine-4-carbonitrile adduct. By chemical reduction of a tris(borolyl)-substituted benzene derivative, a hexaanion was isolated as a result of a two-electron reduction of each borolyl moiety. The interaction of the borolyl units through the aryl spacer, and the possible increase of the Lewis acidity due to the conjugation of the borolyl moieties, were investigated by base transfer reactions. PMID- 23019114 TI - f-Element-metal bonding and the use of the bond polarity to build molecular intermetalloids. AB - Metal-metal bonding in heterobimetallic complexes is of fundamental interest due to its implications to both bonding theory and new reactivities. In this Concept, structurally authenticated molecular compounds with direct bonds between rare earth metals or actinoids and transition or main group metals are summarized. Special attention is given to the use of bond polarity as a tool for designing molecular intermetalloids incorporating rare-earth atoms and transition metals. PMID- 23019115 TI - Emerging in vitro models for safety screening of high-volume production nanomaterials under environmentally relevant exposure conditions. AB - The rising production of nanomaterial-based consumer products has raised safety concerns. Testing these with animal and other direct models is neither ethically nor economically viable, nor quick enough. This review aims to discuss the strength of in vitro testing, including the use of 2D and 3D cultures, stem cells, and tissue constructs, etc., which would give fast and repeatable answers of a highly specific nature, while remaining relevant to in vivo outcomes. These results can then be combined and the overall toxicity predicted with relative accuracy. Such in vitro models can screen potentially toxic nanomaterials which, if required, can undergo further stringent studies in animals. The cyto- and phototoxicity of some high-volume production nanomaterials, using in vitro models, is also reviewed. PMID- 23019116 TI - Phasor-FLIM analysis of NADH distribution and localization in the nucleus of live progenitor myoblast cells. AB - Analysis of the cellular distributions of coenzymes including NADH may aid in understanding a cells metabolic status. We altered serum concentration (0, 2, and 10%) to induce living myoblast cells to undergo the early stages of differentiation. Through microscopy and phasor-FLIM, we spatially mapped and identified variations in the distribution of free and bound NADH. Undifferentiated cells displayed abundant free NADH within the nucleus along with specific regions of more bound NADH. Complete serum starvation dramatically increased the fraction of bound NADH in the nucleus, indicating heightened requirement for transcriptional processes. In comparison, cells exposed to 2% serum exhibited intermediate free nuclear NADH fraction. Overall our results suggest an order of events in which a cell metabolic status alters significantly during the early stages of serum induced differentiation. PMID- 23019117 TI - Evaluation of clinical pharmacists' follow-up service in an oncology pain clinic. AB - BACKGROUND: Patients who present with pain in an oncology setting are often complex and require a multidisciplinary approach for symptom control. The Pain and Symptom Control Clinic at Tom Baker Cancer Center includes two pharmacists who participate in weekly multidisciplinary clinics and provide a follow-up service to patients. OBJECTIVE: This study will assess the impact of the pharmacists' follow-up service with respect to activities performed as well as patient and health care professional satisfaction. The activities performed will also be compared to defined objectives for pharmacy practice in a hospital setting. METHODS: Activities performed by the pharmacists over a 10-week period were recorded and tabulated. Online surveys were completed by health care professionals and telephone surveys were completed by patients 1 month post clinic visit. RESULTS: Over 6 weeks, 44 patients assessed in clinic required follow-up from a pharmacist. There was an average of 2.3 interactions per patient and an average time of 85 min was spent on each patient outside of clinic. The three activities that occurred most frequently included: (1) interacting with other health care professionals, (2) making alterations to patients' medication regimens, and (3) organizing refills. All health care professionals surveyed felt that the pharmacists' follow-up service was a valuable component of the Pain and Symptom Control Clinic and nearly all patients surveyed reported a positive experience with the service received. CONCLUSION: The inclusion of pharmacists in the Pain and Symptom Control Clinic is favored by patients and health care professionals and provides increased efficiency to the clinic. PMID- 23019118 TI - Grouping, pooling, and when bigger is better in visual crowding. AB - In crowding, perception of a target is strongly deteriorated by nearby elements. Crowding is often explained by pooling models predicting that adding flankers increases crowding. In contrast, the centroid hypothesis proposes that adding flankers decreases crowding--"bigger is better." In foveal vision, we have recently shown that adding flankers can increase or decrease crowding depending on whether the target groups or ungroups from the flankers. We have further shown how configural effects, such as good and global Gestalt, determine crowding. Foveal and peripheral crowding do not always reveal the same characteristics. Here, we show that the very same grouping and Gestalt results of foveal vision are also found in the periphery. These results can neither be explained by simple pooling nor by centroid models. We discuss when bigger is better and how grouping might shape crowding. PMID- 23019119 TI - Extensive visual training in adulthood significantly reduces the face inversion effect. AB - The poorer recognition performance for inverted as compared to upright faces is one of the most well-known and robust behavioral effects observed in the field of face perception. Here we investigated whether extensive training at individualizing a large set of inverted faces in adulthood could significantly reduce this inversion effect for novel faces. This issue is important because inverted faces are as complex as upright faces but they are not visually experienced during development. Moreover, inverted faces violate the biological constraints, present at birth, for preferential looking (i.e., a larger number of elements in the top part than the bottom part of the stimulus). Eight adult observers were trained for 2 weeks (16 hr) to individualize 30 inverted face identities presented under different depth-rotated views. Following training, all participants showed a significant reduction of their inversion effect for novel face identities presented in a challenging four-alternatives delayed matching task. This reduction of the face inversion effect was observed in comparison to the magnitude of the same observers' effect before training, and to the magnitude of the face inversion effect of a group of untrained participants. These observations indicate that extensive training in adulthood can lead to a significant reduction of the inversion effect that generalizes to novel faces, suggesting a larger degree of flexibility of the adult face processing system than previously thought. PMID- 23019121 TI - Binocular rivalry of spiral and linear moving random dot patterns in human observers. AB - Binocular rivalry describes the alternating perception of two competing monocular images. It is hypothesized to arise at multiple levels of the visual pathway due to competition between neuronal populations representing the displayed images. We tested whether an enhanced neural representation of expanding motion yields a bias over other spiral motion (i.e., contraction and rotation) and linear motion stimuli during binocular rivalry. We presented random dot patterns of different motion types (i.e., linear and spiral), matched in contrast and speed, to human subjects through a mirror stereoscope. During spiral rivalry, expansion rivalry periods dominated over those of contraction and rotation, and contraction dominated over rotation. During linear motion rivalry, up, down, left, and right directions had similar rivalry periods. All spiral motions dominated over linear motions. Interestingly, when these motion types rivaled against each other, the rivalry periods of spiral motion slightly decreased while those of linear motion significantly increased. This rivalry also caused the bias for expansion relative to other spirals to disappear. Our results suggest a correlation between neuronal representations of different moving patterns and their perception during binocular motion rivalry and provide further evidence that rivalry periods are constrained by the ecologic relevance of stimuli. PMID- 23019120 TI - Distinct effects of attention on the neural responses to form and motion processing: a SSVEP source-imaging study. AB - We measured neural responses to local and global aspects of form and motion stimuli using frequency-tagged, steady-state visual evoked potentials (SSVEPs) combined with magnetic resonance imaging (MRI) data. Random dot stimuli were used to portray either dynamic Glass patterns (Glass, 1969) or coherent motion displays. SSVEPs were used to estimate neural activity in a set of fMRI-defined visual areas in each subject. To compare activity associated with local versus global processing, we analyzed two frequency components of the SSVEP in each visual area: the high temporal frequency at which the local dots were updated (30 Hz) and the much lower frequency corresponding to updates in the global structure (0.83 Hz). Local and global responses were evaluated in the context of two different behavioral tasks--subjects had to either direct their attention toward or away from the global coherence of the stimuli. The data show that the effect of attention on global and local responses is both stimulus and visual area dependent. When attention was directed away from stimulus coherence, both local and global responses were higher in the coherent motion than Glass pattern condition. Directing attention to coherence in Glass patterns enhanced global activity in areas LOC, hMT+, V4, V3a, and V1, while attention to global motion modulated responses by a smaller amount in a smaller set of areas: V4, hMT+, and LOC. In contrast, directing attention towards stimulus coherence weakly increased local responses to both coherent motion and Glass patterns. These results suggest that visual attention differentially modulates the activity of early visual areas at both local and global levels of structural encoding. PMID- 23019122 TI - Choice as a strategy to enhance engagement in a colouring task in children with autism spectrum disorders. AB - This study investigated the effect of choice on a colouring task in children with autism spectrum disorders (ASD). Children with ASD typically have difficulty engaging in purposeful activities, which makes progress toward skill development difficult in therapeutic or educational settings. Participants included 26 male and female children with ASD, aged 8 to 15 years. In this counterbalanced design, participants either chose which picture to colour or were given a picture to colour. When given a choice, participants spent more time colouring (p=0.005) and used more coloured markers (p=0.016), but did not colour more of the page (p=498). This study demonstrated that when offering a choice in a colouring activity, children with ASD participated and engaged in the colouring task for a longer period of time and used a larger array of markers while doing so. However, associated small effect sizes require caution with generalization. Future research should focus upon offering choice with other age-appropriate activities to determine its efficacy as a useful strategy for facilitating activity engagement for children with ASD. PMID- 23019123 TI - ELAV mediates 3' UTR extension in the Drosophila nervous system. AB - Post-transcriptional gene regulation is prevalent in the nervous system, where multiple tiers of regulatory complexity contribute to the development and function of highly specialized cell types. Whole-genome studies in Drosophila have identified several hundred genes containing long 3' extensions in neural tissues. We show that ELAV (embryonic-lethal abnormal visual system) is a key mediator of these neural-specific extensions. Misexpression of ELAV results in the ectopic synthesis of long messenger RNAs (mRNAs) in transgenic embryos. RNA immunoprecipitation assays suggest that ELAV directly binds the proximal polyadenylation signals of many target mRNAs. Finally, ELAV is sufficient to suppress 3' end formation at a strong polyadenylation signal when tethered to a synthetic RNA. We propose that this mechanism for coordinating 3' UTR extension may be generally used in a variety of cellular processes. PMID- 23019124 TI - Ncoa3 functions as an essential Esrrb coactivator to sustain embryonic stem cell self-renewal and reprogramming. AB - Embryonic stem cell (ESC) pluripotency depends on a well-characterized gene regulatory network centered on Oct4, Sox2, and Nanog. In contrast, little is known about the identity of the key coregulators and the mechanisms by which they may potentiate transcription in ESCs. Alongside core transcription factors, the orphan nuclear receptor Esrrb (estrogen-related receptor beta) is vital for the maintenance of ESC identity and furthermore is uniquely associated with the basal transcription machinery. Here, we show that Ncoa3, an essential coactivator, is required to mediate Esrrb function in ESCs. Ncoa3 interacts with Esrrb via its ligand-binding domain and bridges Esrrb to RNA polymerase II complexes. Functionally, Ncoa3 is critical for both the induction and maintenance of pluripotency. Through chromatin immunoprecipitation (ChIP) sequencing and microarray experiments, we further demonstrate that Ncoa3 shares overlapping gene regulatory functions with Esrrb and cooperates genome-wide with the Oct4-Sox2 Nanog circuitry at active enhancers to up-regulate genes involved in self-renewal and pluripotency. We propose an integrated model of transcriptional and coactivator control, mediated by Ncoa3, for the maintenance of ESC self-renewal and somatic cell reprogramming. PMID- 23019125 TI - Nuclear lamina defects cause ATM-dependent NF-kappaB activation and link accelerated aging to a systemic inflammatory response. AB - Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-kappaB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24(-/-) and Lmna(G609G/G609G) mice). Causal involvement of NF-kappaB in accelerated aging was demonstrated by the fact that both genetic and pharmacological inhibition of NF-kappaB signaling prevents age-associated features in these animal models, significantly extending their longevity. Our findings provide in vivo proof of principle for the feasibility of pharmacological modulation of the NF-kappaB pathway to slow down the progression of physiological and pathological aging. PMID- 23019127 TI - Recent advances in enrichment techniques for trace analysis in capillary electrophoresis. AB - CE is gaining great popularity as a well-established separation technique for many fields such as pharmaceutical research, clinical application, environmental monitoring, and food analysis, owing to its high resolving power, rapidity, and small amount of samples and reagents required. However, the sensitivity in CE analysis is still considered as being inferior to that in HPLC analysis. Diverse enrichment methods and techniques have been increasingly developed for overcoming this issue. In this review, we summarize the recent advances in enrichment techniques containing off-line preconcentration (sample preparation) and on-line concentration (sample stacking) to enhancing sensitivity in CE for trace analysis over the last 5 years. Some relatively new cleanup and preconcentration methods involving the use of dispersive liquid-liquid microextraction, supercritical fluid extraction, matrix solid-phase dispersion, etc., and the continued use and improvement of conventional SPE, have been comprehensively reviewed and proved effective preconcentration alternatives for liquid, semisolid, and solid samples. As for CE on-line stacking, we give an overview of field amplication, sweeping, pH regulation, and transient isotachophoresis, and the coupling of multiple modes. Moreover, some limitations and comparisons related to such methods/techniques are also discussed. Finally, the combined use of various enrichment techniques and some significant attempts are proposed to further promote analytical merits in CE. PMID- 23019126 TI - DeltaNp63alpha represses anti-proliferative genes via H2A.Z deposition. AB - DeltaNp63alpha is a member of the p53 family of transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because DeltaNp63alpha and p53 bind virtually identical DNA sequence motifs, it has been proposed that DeltaNp63alpha functions as a dominant-negative inhibitor of p53 to promote proliferation and block apoptosis. However, most SCCs concurrently overexpress DeltaNp63alpha and inactivate p53, suggesting the autonomous action of these oncogenic events. Here we report the discovery of a novel mechanism of transcriptional repression by DeltaNp63alpha that reconciles these observations. We found that although both proteins bind the same genomic sites, they regulate largely nonoverlapping gene sets. Upon activation, p53 binds all enhancers regardless of DeltaNp63alpha status but fails to transactivate genes repressed by DeltaNp63alpha. We found that DeltaNp63alpha associates with the SRCAP chromatin regulatory complex involved in H2A/H2A.Z exchange and mediates H2A.Z deposition at its target loci. Interestingly, knockdown of SRCAP subunits or H2A.Z leads to specific induction of DeltaNp63alpha-repressed genes. We identified SAMD9L as a key anti-proliferative gene repressed by DeltaNp63alpha and H2A.Z whose depletion suffices to reverse the arrest phenotype caused by DeltaNp63alpha knockdown. Collectively, these results illuminate a molecular pathway contributing to the autonomous oncogenic effects of DeltaNp63alpha. PMID- 23019128 TI - Dissociated neural correlates of quantity processing of quantifiers, numbers, and numerosities. AB - Quantities can be represented using either mathematical language (i.e., numbers) or natural language (i.e., quantifiers). Previous studies have shown that numerical processing elicits greater activation in the brain regions around the intraparietal sulcus (IPS) relative to other semantic processes. However, little research has been conducted to investigate whether the IPS is also critical for the semantic processing of quantifiers in natural language. In this study, 20 adults were scanned with functional magnetic resonance imaging while they performed semantic distance judgment involving six types of materials (i.e., frequency adverbs, quantity pronouns and nouns, animal names, Arabic digits, number words, and dot arrays). Conjunction analyses of brain activation showed that numbers and dot arrays elicited greater activation in the right IPS than did words (i.e., animal names) or quantifiers (i.e., frequency adverbs and quantity pronouns and nouns). Quantifiers elicited more activation in left middle temporal gyrus and inferior frontal gyrus than did numbers and dot arrays. No differences were found between quantifiers and animal names. These findings suggest that, although quantity processing for numbers and dot arrays typically relies on the right IPS region, quantity processing for quantifiers typically relies on brain regions for general semantic processing. Thus, the IPS does not appear to be the only brain region for quantity processing. PMID- 23019129 TI - Applications and potential toxicity of magnetic iron oxide nanoparticles. AB - Owing to their unique physical and chemical properties, magnetic iron oxide nanoparticles have become a powerful platform in many diverse aspects of biomedicine, including magnetic resonance imaging, drug and gene delivery, biological sensing, and hyperthermia. However, the biomedical applications of magnetic iron oxide nanoparticles arouse serious concerns about their pharmacokinetics, metabolism, and toxicity. In this review, the updated research on the biomedical applications and potential toxicity of magnetic iron oxide nanoparticles is summarized. Much more effort is required to develop magnetic iron oxide nanoparticles with improved biocompatible surface engineering to achieve minimal toxicity, for various applications in biomedicine. PMID- 23019130 TI - The effect of body mass index on the outcome of critically ill surgical patients. AB - BACKGROUND: The incidence of obesity is rising, and an increasing number of obese patients are admitted to surgical intensive care units (SICUs). However, it is not clear whether obesity is an independent risk factor for increased morbidity and mortality in SICU patients. We examined the effect of obesity on morbidity and mortality in patients admitted to the SICU in this study. METHOD: We reviewed prospectively acquired SICU data in normal and obese patients with an SICU length of stay >24 hours. Comparability of the groups was assessed using a chi(2) test or Fisher exact test, as appropriate, for categorical variables and analysis of variance (ANOVA) or the Kruskal-Wallis test, as appropriate, for continuous variables. RESULTS: Of the 1792 consecutive patients evaluated, 711 had a normal body mass index (BMI), and 993 were either preobese or obese. There was no statistically significant difference across the 5 BMI groups with respect to any of the 3 comorbidity indices (Acute Physiology and Chronic Health Evaluation III [APACHE III], Simplified Acute Physiology Score, or Multiple Organ Dysfunction Score). There was no statistically significant difference in the intensive care unit (ICU) length of stay and hospital length of stay or time-to-ICU mortality (log-rank test P = .054) among the 5 BMI groups. A Cox regression analysis and backward elimination algorithm selected APACHE III to be the most important explanatory variable for survival time. CONCLUSION: Obesity does not affect the mortality of patients admitted to the SICU. We conclude that obesity cannot be used as an independent predictive mortality outcome variable in patients admitted to the SICU. PMID- 23019131 TI - Facile Soap-Free Miniemulsion Polymerization of Methyl Methacrylate via Reverse Atom Transfer Radical Polymerization. AB - A facile soap-free miniemulsion polymerization of methyl methacrylate (MMA) was successfully carried out via a reverse ATRP technique, using a water-soluble potassium persulfate (KPS) or 2,2'-azobis(2-methylpropionamidine) dihydrochloride (V-50) both as the initiator and the stabilizer, and using an oil-soluble N,N-n butyldithiocarbamate copper (Cu(S2CN(C4H9)2)2) as the catalyst without adding any additional ligand. Polymerization results demonstrated the "living"/controlled characteristics of ATRP and the resultant latexes showed good colloidal stability with average particle size around 300-700 nm in diameter. The monomer droplet nucleation mechanism was proposed. NMR spectroscopy and chain-extension experiments under UV light irradiation confirmed the attachment and livingness of UV light sensitive -S-C(=S)-N(C4H9)2 group in the chain end. PMID- 23019132 TI - The association between parent PTSD/depression symptoms and child PTSD symptoms: a meta-analysis. AB - OBJECTIVE: The present article presents a meta-analysis of studies examining the association between parent posttraumatic stress disorder (PTSD)/depression symptoms and child PTSD symptoms (PTSS) after a child's exposure to a traumatic event while considering multiple moderating factors to explain heterogeneity of effect sizes. METHODS: 35 studies were included: 32 involving the association between parent and child PTSS and 9 involving the association between parent depression and child PTSS. RESULTS: Across existing studies, both parent and child PTSS (r = 0.31) and parent depression and child PTSS (r = 0.32) yielded significant effect sizes. Parent gender, assessment type (interview vs. questionnaire), differences in assessment type for parents and children, and study design (cross-sectional vs. longitudinal) moderated the relationship between parent and child PTSS. CONCLUSIONS: The current findings confirm the associations between parental posttraumatic responses and child PTSS and highlight important moderating factors to include in future studies of child PTSS. PMID- 23019133 TI - Determination of musk fragrances in sewage sludge by pressurized liquid extraction coupled to automated ionic liquid-based headspace single-drop microextraction followed by GC-MS/MS. AB - A method for the quantitative determination of ten musk fragrances extensively used in personal care products from sewage sludge was developed by using a pressurized liquid extraction (PLE) followed by an automated ionic liquid-based headspace single-drop microextraction and gas chromatography-tandem mass spectrometry. The influence of main factors on the efficiency of PLE was studied. For all musks, the highest recovery values were achieved using 1 g of pretreated sewage sludge, H(2) O/methanol (1:1) as an extraction solvent, a temperature of 80 degrees C, a pressure of 1500 psi, an extraction time of 5 min, 2 cycles, a 100% flush volume, a purge time of 120 s, and 1 g Florisil as in-cell clean-up extraction sorbent. The use and optimization of an in-cell clean-up sorbent was necessary to remove fatty interferents of the PLE extract that make the subsequent ionic liquid-based headspace single-drop microextraction difficult. Validation parameters, namely LODs and LOQs, ranged from 0.5-1.5 to 2.5-5 ng/g, respectively. Good levels of intra- and interday repeatabilities were obtained analyzing sewage sludge samples spiked at 10 ng/g (n = 3, RSDs < 10%). The method applicability was tested with sewage sludge from different wastewater treatment plants. The analysis revealed the presence of all the polycyclic musks studied at concentrations higher than the LOQs, ranging from 6 to 530 ng/g. However, the nitro musk concentrations were below the LOQs or, in the case of musk xylene, was not detected. PMID- 23019134 TI - New design of thiol-responsive degradable polylactide-based block copolymer micelles. AB - A new design to synthesize thiol-responsive degradable polylactide (PLA)-based micelles having a disulfide linkage in the middle of triblock copolymers is reported. They were synthesized by a new method that centers on the use of a disulfide-labeled diol as an initiator for ring-opening polymerization, followed by controlled radical polymerization. These well-controlled copolymers with monomodal and narrow molecular weight distribution (M(w) /M(n) < 1.15) self assembled to form aqueous micellar aggregates with disulfide-containing PLA cores, which is not toxic to cells. Central disulfide linkages were cleaved in response to thiols; such thiol-triggered degradation enhanced the release of encapsulated anticancer drugs. PMID- 23019136 TI - Endovascular acute ischemic stroke therapy: Society of Vascular and Interventional Neurology roundtable proceedings. PMID- 23019135 TI - Mouse models of growth hormone action and aging: a proteomic perspective. AB - Growth hormone (GH) is a protein secreted by the anterior pituitary and circulates throughout the body to exert important actions on growth and metabolism. GH stimulates the secretion of insulin-like growth factor-I (IGF-I) that mediates some of the growth promoting actions of GH. The GH/IGF-I axis has recently been recognized as important in terms of longevity in organisms ranging from Caenorhabditis elegans to mice. For example, GH transgenic mice possess short lifespans while GH receptor null (GHR-/-) mice have extended longevity. Thus, the actions of GH (or IGF-I) or lack thereof impact the aging process. In this review, we summarize the proteomic analyses of plasma and white adipose tissue in these two mouse models of GH action, i.e. GH transgenic and GHR-/- mice. At the protein level, we wanted to establish novel plasma biomarkers of GH action as a function of age and to determine differences in adipose tissue depots. We have shown that these proteomic approaches have not only confirmed several known physiological actions of GH, but also resulted in novel protein biomarkers and targets that may be indicative of the aging process and/or new functions of GH. These results may generate new directions for GH and/or aging research. PMID- 23019137 TI - Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin. AB - Dopaminergic neurons of the ventral tegmental area are important components of brain pathways related to addiction. Prolonged exposure of these neurons to moderate concentrations of dopamine (DA) decreases their sensitivity to inhibition by DA, a process called DA-inhibition reversal (DIR). DIR is mediated by phospholipase C and conventional subtype of protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of 5-HT(2) or neurotensin receptors. In the present study, we further characterized this phenomenon by use of extracellular recordings in brain slices to examine whether DIR is linked to G protein-coupled receptor kinase-2 (GRK2) or dynamin by assessing DIR in the presence of antagonists of these enzymes. DIR was blocked by beta-ARK1 inhibitor, which inhibits GRK2, and by dynasore, which blocks dynamin. Reversal of inhibition by D2 agonist quinpirole was produced by serotonin (50 uM) and by neurotensin (5-10 nM). Serotonin-induced or neurotensin-induced reversal was blocked by beta-ARK1 inhibitor, dynasore, or cPKC antagonist 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H indolo[2,3-a]pyrrolo[3,4c]carbazole-12-propanenitrile (Go6976). This further characterization of DIR indicates that cPKC, GRK2, and dynamin play important roles in the desensitization of D2 receptors. As drugs of abuse produce persistent increases in DA concentration in the ventral tegmental area, reduction of D2 receptor sensitivity as a result of drug abuse may be a critical factor in the processes of addiction. PMID- 23019139 TI - A comparative analysis of computational approaches to relative protein quantification using peptide peak intensities in label-free LC-MS proteomics experiments. AB - Liquid chromatography coupled with mass spectrometry (LC-MS) is widely used to identify and quantify peptides in complex biological samples. In particular, label-free shotgun proteomics is highly effective for the identification of peptides and subsequently obtaining a global protein profile of a sample. As a result, this approach is widely used for discovery studies. Typically, the objective of these discovery studies is to identify proteins that are affected by some condition of interest (e.g. disease, exposure). However, for complex biological samples, label-free LC-MS proteomics experiments measure peptides and do not directly yield protein quantities. Thus, protein quantification must be inferred from one or more measured peptides. In recent years, many computational approaches to relative protein quantification of label-free LC-MS data have been published. In this review, we examine the most commonly employed quantification approaches to relative protein abundance from peak intensity values, evaluate their individual merits, and discuss challenges in the use of the various computational approaches. PMID- 23019140 TI - Long-term mortality risks associated with mild anaemia in older persons: the Busselton Health Study. AB - BACKGROUND: up to 25% of older people in the USA and other Western countries are anaemic by World Health Organization (WHO) criteria. The objective of this study was to examine the long-term relationships of haemoglobin concentration with all cause and cause-specific mortality in a community-based sample of Australian adults surveyed in 1978. METHODS: a community survey of 2,194 adults aged 40+ years in Busselton, Western Australia in 1978 with mortality follow-up to 2001. Cox regression models were used to investigate the relationships of haemoglobin as a continuous measure and anaemia by WHO criteria (women <12 g/dl (7.5 mmol/l); men <13 g/dl (8.1 mmol/l)) with all-cause, cardiovascular and cancer mortality. RESULTS: anaemia was predominantly mild (>10 g/dl) and normocytic. There was an increased risk of death from all causes and from cancer for men with low haemoglobin. Cancers were predominantly of the prostate and genito-urinary organs, and to a lesser extent the gastrointestinal tract. There was no increased risk of all cause or cancer death in women. CONCLUSION: mild, normocytic anaemia is associated with survival reductions in middle-aged and older men, where it often occurs with prostate, gastrointestinal and other cancers, and should be investigated to exclude treatable causes. PMID- 23019138 TI - Diuretic effects of cannabinoids. AB - In vivo effects of cannabinoid (CB) agonists are often assessed using four well established measures: locomotor activity, hypothermia, cataleptic-like effects, and analgesia. The present studies demonstrate that doses of CB agonists that produce these effects also reliably increase diuresis. Diuretic effects of several CB agonists were measured in female rats over 2 hours immediately after drug injection, and results were compared with hypothermic effects. Direct-acting CB1 agonists, including Delta(9)-tetrahydrocannabinol, WIN 55,212 [R-(1)-[2,3 dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1 naphthalenyl)methanone mesylate], AM2389 [9beta-hydroxy-3-(1-hexyl-cyclobut-1-yl) hexahydrocannabinol], and AM4054 [9beta-(hydroxymethyl)-3-(1-adamantyl) hexahydrocannabinol], produced dose-dependent increases in diuresis and decreases in colonic temperature, with slightly lower ED(50) values for diuresis than for hypothermia. The highest doses of cannabinoid drugs yielded, on average, 26-32 g/kg urine; comparable effects were obtained with 10 mg/kg furosemide and 3.0 mg/kg trans-(-)-3,4-dichloro-N-methyl-N-[2-(1 pyrrolidinyl)cyclohexyl]benzeneacetamide (U50-488). Methanandamide (10.0 mg/kg) had lesser effect than other CB agonists, and the CB2 agonist AM1241 [1 (methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole], the anandamide transport inhibitor AM404, and the CB antagonist rimonabant did not have diuretic effects. In further studies, the diuretic effects of the CB1 agonist AM4054 were similar in male and female rats, displayed a relatively rapid onset to action, and were dose-dependently antagonized by 30 minutes pretreatment with rimonabant, but not by the vanilloid receptor type I antagonist capsazepine, nor were the effects of WIN 55,212 antagonized by the CB2 antagonist AM630 [(6-iodo-2-methyl-1 [2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)]. These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms. PMID- 23019141 TI - Chemosignals communicate human emotions. AB - Can humans communicate emotional states via chemical signals? In the experiment reported here, we addressed this question by examining the function of chemosignals in a framework furnished by embodied social communication theory. Following this theory, we hypothesized that the processes a sender experiences during distinctive emotional states are transmitted to receivers by means of the chemicals that the sender produces, thus establishing a multilevel correspondence between sender and receiver. In a double-blind experiment, we examined facial reactions, sensory-regulation processes, and visual search in response to chemosignals. We demonstrated that fear chemosignals generated a fearful facial expression and sensory acquisition (increased sniff magnitude and eye scanning); in contrast, disgust chemosignals evoked a disgusted facial expression and sensory rejection (decreased sniff magnitude, target-detection sensitivity, and eye scanning). These findings underline the neglected social relevance of chemosignals in regulating communicative correspondence outside of conscious access. PMID- 23019142 TI - "Treating" prejudice: an exposure-therapy approach to reducing negative reactions toward stigmatized groups. AB - One of the ways in which therapists treat anxiety disorders is to expose patients to a fear-evoking stimulus within a safe environment before encouraging more positive stimulus-related thoughts. In the study reported here, we adapted these psychotherapeutic principles of exposure therapy to test the hypothesis that imagining a positive encounter with a member of a stigmatized group would be more likely to promote positive perceptions when it was preceded by an imagined negative encounter. The results of three experiments targeting a range of stigmatized groups (adults with schizophrenia, gay men, and British Muslims) supported this hypothesis. Compared with purely positive interventions, interventions in which a single negative encounter was imagined just prior to imagining a positive encounter resulted in significantly reduced prejudice. Furthermore, reduced anxiety uniquely derived from the mixed-valence imagery task statistically explained enhanced intentions to engage positively with the previously stigmatized group in the future. PMID- 23019143 TI - Orientation perception of occluded objects is based on perceptually completed objects. PMID- 23019144 TI - Factors predisposing to chyle leakage following thyroid cancer surgery without lateral neck dissection. AB - BACKGROUND: The aims of this study were to assess the clinicopathologic features of patients with chyle leakage following thyroid cancer surgery without lateral neck dissection and to evaluate the factors associated with chyle leakage. METHODS: Of 3137 patients who underwent thyroid surgery between January 2006 and December 2007, 2314 patients (73.8%) satisfied our inclusion criteria. Patients were divided into those with (group I, n = 14) and without (group II, n = 2300) chyle leakage. RESULTS: There were no significant differences between the 2 groups in clinicopathologic features including age, body mass index, extent of thyroidectomy, pathologic type, tumor size, multiplicity, capsular invasion, and coexisting thyroiditis. In univariate and multivariate analyses, male sex, age >45 years, and number of harvested central nodes were significantly associated with chyle leakage. CONCLUSIONS: If extensive central compartment node dissection is needed, meticulous dissection is required, especially in male patients, and aged >45 years, even without lateral neck dissection. PMID- 23019145 TI - Integration of ChIP-seq and machine learning reveals enhancers and a predictive regulatory sequence vocabulary in melanocytes. AB - We take a comprehensive approach to the study of regulatory control of gene expression in melanocytes that proceeds from large-scale enhancer discovery facilitated by ChIP-seq; to rigorous validation in silico, in vitro, and in vivo; and finally to the use of machine learning to elucidate a regulatory vocabulary with genome-wide predictive power. We identify 2489 putative melanocyte enhancer loci in the mouse genome by ChIP-seq for EP300 and H3K4me1. We demonstrate that these putative enhancers are evolutionarily constrained, enriched for sequence motifs predicted to bind key melanocyte transcription factors, located near genes relevant to melanocyte biology, and capable of driving reporter gene expression in melanocytes in culture (86%; 43/50) and in transgenic zebrafish (70%; 7/10). Next, using the sequences of these putative enhancers as a training set for a supervised machine learning algorithm, we develop a vocabulary of 6-mers predictive of melanocyte enhancer function. Lastly, we demonstrate that this vocabulary has genome-wide predictive power in both the mouse and human genomes. This study provides deep insight into the regulation of gene expression in melanocytes and demonstrates a powerful approach to the investigation of regulatory sequences that can be applied to other cell types. PMID- 23019146 TI - Translating genomic information into clinical medicine: lung cancer as a paradigm. AB - We are currently in an era of rapidly expanding knowledge about the genetic landscape and architectural blueprints of various cancers. These discoveries have led to a new taxonomy of malignant diseases based upon clinically relevant molecular alterations in addition to histology or tissue of origin. The new molecularly based classification holds the promise of rational rather than empiric approaches for the treatment of cancer patients. However, the accelerated pace of discovery and the expanding number of targeted anti-cancer therapies present a significant challenge for healthcare practitioners to remain informed and up-to-date on how to apply cutting-edge discoveries into daily clinical practice. In this Perspective, we use lung cancer as a paradigm to discuss challenges related to translating genomic information into the clinic, and we present one approach we took at Vanderbilt-Ingram Cancer Center to address these challenges. PMID- 23019147 TI - Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. AB - Endogenous estrogens that are synthesized in the body impact gene regulation by activating estrogen receptors in diverse cell types. Exogenous compounds that have estrogenic properties can also be found circulating in the blood in both children and adults. The genome-wide impact of these environmental estrogens on gene regulation is unclear. To obtain an integrated view of gene regulation in response to environmental and endogenous estrogens on a genome-wide scale, we performed ChIP-seq to identify estrogen receptor 1 (ESR1; previously estrogen receptor alpha) binding sites, and RNA-seq in endometrial cancer cells exposed to bisphenol A (BPA; found in plastics), genistein (GEN; found in soybean), or 17beta-estradiol (E2; an endogenous estrogen). GEN and BPA treatment induces thousands of ESR1 binding sites and >50 gene expression changes, representing a subset of E2-induced gene regulation changes. Genes affected by E2 were highly enriched for ribosome-associated proteins; however, GEN and BPA failed to regulate most ribosome-associated proteins and instead enriched for transporters of carboxylic acids. Treatment-dependent changes in gene expression were associated with treatment-dependent ESR1 binding sites, with the exception that many genes up-regulated by E2 harbored a BPA-induced ESR1 binding site but failed to show any expression change after BPA treatment. GEN and BPA exhibited a similar relationship to E2 in the breast cancer line T-47D, where cell type specificity played a much larger role than treatment specificity. Overall, both environmental estrogens clearly regulate gene expression through ESR1 on a genome wide scale, although with lower potency resulting in less ESR1 binding sites and less gene expression changes compared to the endogenous estrogen, E2. PMID- 23019148 TI - Unraveling the ubiquitin-regulated signaling networks by mass spectrometry-based proteomics. AB - Ubiquitin (Ub) is a small protein modifier that is covalently attached to the epsilon-amino group of lysine residues of protein substrates, generally targeting them for degradation. Due to the emergence of specific anti-diglycine (-GG) antibodies and the improvement in MS, it is now possible to identify more than 10 000 ubiquitylated sites in a single proteomics study. Besides cataloging ubiquitylated sites, it is equally important to unravel the biological relationship between ubiquitylated substrates and the ubiquitin conjugation machinery. Relevant to this, we discuss the role of affinity purification-MS (AP MS), in characterizing E3 ligase-substrate complexes. Recently, such strategies have also been adapted to screen for binding partners of both deubiquitylating enzymes (DUBs) and ubiquitin-binding domains (UBDs). The complexity of the "ubiquitome" is further expanded by the fact that Ub itself can be ubiquitylated at any of its seven lysine residues forming polyubiquitin (polyUb), thus diversifying its lengths and topologies to suit a variety of molecular recognition processes. Therefore, applying MS to study polyUb linkages is also becoming an emerging and important area. Finally, we discuss the future of MS based proteomics in answering important questions with respect to ubiquitylation. PMID- 23019149 TI - The crystal structure of samarosporin I at atomic resolution. AB - The atomic resolution structures of samarosporin I have been determined at 100 and 293 K. This is the first crystal structure of a natural 15-residue peptaibol. The amino acid sequence in samarosporin I is identical to emerimicin IV and stilbellin I. Samarosporin is a peptide antibiotic produced by the ascomycetous fungus Samarospora rostrup and belongs to peptaibol subfamily 2. The structures at both temperatures are very similar to each other adopting mainly a 310-helical and a minor fraction of alpha-helical conformation. The helices are significantly bent and packed in an antiparallel fashion in the centered monoclinic lattice leaving among them an approximately 10-A channel extending along the crystallographic twofold axis. Only two ordered water molecules per peptide molecule were located in the channel. Comparisons have been carried out with crystal structures of subfamily 2 16-residue peptaibols antiamoebin and cephaibols. The repercussion of the structural analysis of samarosporin on membrane function is discussed. PMID- 23019150 TI - The role of elective neck dissection in patients undergoing salvage laryngectomy. AB - BACKGROUND: We investigated the risk of neck metastases in patients undergoing salvage total laryngectomy in association with previous radiotherapy. METHODS: The medical records of 42 patients (51 neck specimens) with clinical N0 classification who underwent salvage total laryngectomy in 2 cancer centers were reviewed. Fourteen patients had previous radiotherapy to the central neck and 28 to the central and lateral neck. RESULTS: Staging before salvage total laryngectomy was similar in both groups. The risk of neck metastases in the central and central/lateral radiation groups was 12% and 18%, respectively (p = .69). Subgroup analysis revealed that 4 of 8 patients initially presenting with clinically N+ had neck metastases before surgery, versus 2 of 26 for those with clinically N0 (p = .015; relative risk [RR] = 4.67). The risk or metastases in the contralateral neck was 0 of 9. CONCLUSION: The risk of neck metastases in patients who undergo either central or central/lateral neck radiotherapy is similar. Elective neck dissection seems appropriate in patients undergoing SLR. PMID- 23019151 TI - Radiation therapy following surgery for localized breast cancer: outcome prediction by classical prognostic factors and approximated genetic subtypes. AB - The purpose of this study was to evaluate the outcome prediction power of classical prognostic factors along with surrogate approximation of genetic signatures (AGS) subtypes in patients affected by localized breast cancer (BC) and treated with postoperative radiotherapy. We retrospectively analyzed 468 consecutive female patients affected by localized BC with complete immunohistochemical and pathological information available. All patients underwent surgery plus radiotherapy. Median follow-up was 59 months (range, 6 132) from the diagnosis. Disease recurrences (DR), local and/or distant, and contralateral breast cancer (CBC) were registered and analyzed in relation to subtypes (luminal A, luminal B, HER-2, and basal), and classical prognostic factors (PFs), namely age, nodal status (N), tumor classification (T), grading (G), estrogen receptors (ER), progesterone receptors and erb-B2 status. Bootstrap technique for variable selection and bootstrap resampling to test selection stability were used. Regarding AGS subtypes, HER-2 and basal were more likely to recur than luminal A and B subtypes, while patients in the basal group were more likely to have CBC. However, considering PFs along with AGS subtypes, the optimal multivariable predictive model for DR consisted of age, T, N, G and ER. A single variable model including basal subtype resulted again as the optimal predictive model for CBC. In patients bearing localized BC the combination of classical clinical variables age, T, N, G and ER was still confirmed to be the best predictor of DR, while the basal subtype was demonstrated to be significantly and exclusively correlated with CBC. PMID- 23019152 TI - Diffusion-barrier-free porous carbon monoliths as a new form of activated carbon. AB - For the practical use of activated carbon (AC) as an adsorbent of CH(4) , tightly packed monoliths with high microporosity are supposed to be one of the best morphologies in terms of storage capacity per apparent volume of the adsorbent material. However, monolith-type ACs may cause diffusion obstacles in adsorption processes owing to their necked pore structures among the densely packed particles, which result in a lower adsorption performance than that of the corresponding powder ACs. To clarify the relationship between the pore structure and CH4 adsorptivity, microscopic observations, structural studies on the nanoscale, and conductivity measurements (thermal and electrical) were performed on recently developed binder-free, self-sinterable ACs in both powder and monolithic forms. The monolith samples exhibited higher surface areas and electrical conductivities than the corresponding powder samples. Supercritical CH4 adsorption isotherms were measured for each powder and monolith sample at up to 7 MPa at 263, 273, and 303 K to elucidate their isosteric heats of adsorption and adsorption rate constants, which revealed that the morphologies of the monolith samples did not cause serious drawbacks for the adsorption and desorption processes. This will further facilitate the availability of diffusion barrier-free microporous carbon monoliths as practical CH4 storage adsorbents. PMID- 23019153 TI - Stem cell recovering effect of copper-free GHK in skin. AB - The peptide Gly-His-Lys (GHK) is a naturally occurring copper(II)-chelating motifs in human serum and cerebrospinal fluid. In industry, GHK (with or without copper) is used to make hair and skin care products. Copper-GHK plays a physiological role in the process of wound healing and tissue repair by stimulating collagen synthesis in fibroblasts. We also reported that copper-GHK promotes the survival of basal stem cells in the skin. However, the effects of copper-free GHK (GHK) have not been investigated well. In this study, the effects of GHK were studied using cultured normal human keratinocytes and skin equivalent (SE) models. In monolayer cultured keratinocytes, GHK increased the proliferation of keratinocytes. When GHK was added during the culture of SE models, the basal cells became more cuboidal than control model. In addition, there was linear and intense staining of alpha6 and beta1 integrin along the basement membrane. The number of p63 and proliferating cell nuclear antigen positive cells was also significantly increased in GHK-treated SEs than in control SEs. Western blot and slide culture experiment showed that GHK increased the expression of integrin by keratinocytes. All these results showed that GHK increased the stemness and proliferative potential of epidermal basal cells, which is associated with increased expression of integrin. In conclusion, copper-free GHK showed similar effects with copper-GHK. Thus, it can be said that copper-free GHK can be used in industry to obtain the effects of copper-GHK in vivo. Further study is necessary to explore the relationship between copper-free GHK and copper-GHK. PMID- 23019154 TI - Highly sulfated hexasaccharide sequences isolated from chondroitin sulfate of shark fin cartilage: insights into the sugar sequences with bioactivities. AB - Chondroitin sulfate (CS) chains regulate the development of the central nervous system in vertebrates and are linear polysaccharides consisting of variously sulfated repeating disaccharides, [-4GlcUAbeta1-3GalNAcbeta1-](n), where GlcUA and GalNAc represent D-glucuronic acid and N-acetyl-D-galactosamine, respectively. CS chains containing D-disaccharide units [GlcUA(2-O-sulfate) GalNAc(6-O-sulfate)] are involved in the development of cerebellar Purkinje cells and neurite outgrowth-promoting activity through interaction with a neurotrophic factor, pleiotrophin, resulting in the regulation of signaling. In this study, to obtain further structural information on the CS chains containing d-disaccharide units involved in brain development, oligosaccharides containing D-units were isolated from a shark fin cartilage. Seven novel hexasaccharide sequences, DeltaO D-D, DeltaA-D-D, DeltaC-D-D, DeltaE-A-D, DeltaD-D-C, DeltaE-D-D and DeltaA-B-D, in addition to three previously reported sequences, DeltaC-A-D, DeltaC-D-C and DeltaA-D-A, were isolated from a CS preparation of shark fin cartilage after exhaustive digestion with chondroitinase AC-I, which cannot act on the galactosaminidic linkages bound to D-units. The symbol Delta stands for a 4,5 unsaturated bond of uronic acids, whereas A, B, C, D, E and O represent [GlcUA GalNAc(4-O-sulfate)], [GlcUA(2-O-sulfate)-GalNAc(4-O-sulfate)], [GlcUA-GalNAc(6-O sulfate)], [GlcUA(2-O-sulfate)-GalNAc(6-O-sulfate)], [GlcUA-GalNAc(4-O-, 6-O sulfate)] and [GlcUA-GalNAc], respectively. In binding studies using an anti-CS monoclonal antibody, MO-225, the epitopes of which are involved in cerebellar development in mammals, novel epitope structures, DeltaA-D-A, DeltaA-D-D and DeltaA-B-D, were revealed. Hexasaccharides containing two consecutive D-units or a B-unit will be useful for the structural and functional analyses of CS chains particularly in the neuroglycobiological fields. PMID- 23019155 TI - Investigation of the substrate specificity of K5 lyase A from K5A bacteriophage. AB - K5 lyase A (KflA) is a tailspike protein from the K5A phage that catalyzes the degradation of the capsule polysaccharide of K5 strains of Escherichia coli. The K5 E. coli capsule polysaccharide, also known as heparosan, is composed of the disaccharide repeating unit of [-4)-GlcA-beta(1,4)-GlcNAc-alpha(1-] and therefore identical to the biological precursor of heparin and heparan sulfate (HS). KflA could supplement the heparin lyases for heparin and HS analysis. The first part of this study aimed to clarify ambiguity resulting from the revision of the KflA amino acid sequence in 2010 from that published in 2000. We found that only the expression of the updated sequence gave a soluble active enzyme, which produced heparosan degradation products similar to those of previous studies. Next, we examined the specificity of KflA toward heparosan oligosaccharides of varying sizes, all containing a single N-sulfated glucosamine (GlcNS) residue. The presence of GlcNS in an octasaccharide and a nonasaccharide chain directed cleavage by KflA to a single position at the reducing end of the substrate. However, an N-sulfated decasaccharide exhibited extensive cleavage at the nonreducing end of the chain, illustrating a distinct change in the cleavage pattern of KflA toward substrates of differing sizes. Because KflA is able to cleave a substrate containing isolated GlcNS residues, this enzyme could be used for the analysis of low-sulfate content HS domains. PMID- 23019156 TI - Case of high-risk epithelioid hemangioendothelioma of the neck. AB - BACKGROUND: Epithelioid hemangioendotheliomas (EHEs) of the head and neck region are uncommon malignant neoplasms that exhibit various biologic behaviors characteristic of both low- and high-grade malignancy. A subgroup of EHEs identified as "high-risk" EHEs because of their size and mitotic activity is associated with an unfavorable clinical course and poor prognosis. MATERIALS AND RESULTS: We describe the treatment of the first and, in terms of size, largest case of high-risk EHE arising from the neck. Despite wide excision, recurrence occurred 9 months after surgery, as had been expected. However, the tumor was found to express both vascular endothelial growth factor (VEGF) and VEGF receptor 2, indicating the potential of anti-VEGF therapy in the treatment of such cases. CONCLUSION: The finding that a high-risk EHE arising from the head and neck region is characterized by expression of VEGF and its receptor provides further support for the development of targeted molecular therapies. PMID- 23019157 TI - Comparison of multiple API techniques for the simultaneous detection of microconstituents in water by on-line SPE-LC-MS/MS. AB - This study described a fully automated method using on-line solid phase extraction of large volume injections coupled with high performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS) to simultaneously detect a group of recalcitrant microconstituents (pharmaceuticals and personal care products, steroid hormones and sterols) in aqueous matrices. Samples (1 mL to 20 mL) were loaded to the preconcentration column at 1 mL/min, and the column was washed with 1000 MUL of 25% methanol in LC/MS water to remove polar and ionic interferences before LC-MS/MS analysis. Three different atmospheric pressure ionization (API) techniques, including photoionization (APPI) with four different dopants (acetone, anisole, chlorobenzene and toluene), heated electrospray ionization (HESI) and atmospheric pressure chemical ionization (APCI), were evaluated on the basis of method detection limits (MDLs) and recoveries from different aqueous matrixes. Results indicated that APPI with toluene as dopant was the most sensitive ionization method for the majority of the analytes. When using 5 mL of sample, MDLs for pharmaceuticals and personal care products, including carbamazepine, DEET, caffeine, naproxen, acetaminophen and primidone, were between 0.3 ng/L and 15 ng/L. MDLs of hormones, including testosterone, equilenin, progesterone, equilin, 17beta-estradiol, 17alpha-ethynylestradiol, estrone, androsterone, mestranol and estriol, were between 1.2 ng/L and 37 ng/L. The combination of APPI with dopant allowed the detection of two difficult to ionize fecal related sterols, such as coprostan-3-ol and coprostan-3-one with MDLs of 5.4 ng/L and 11 ng/L, respectively. Calculated MDLs are more than adequate for analysis of wastewater using 1 to 5 mL sample size and for surface waters using up to 20 mL sample size. PMID- 23019158 TI - Structural determination of glycopeptidolipids of Mycobacterium smegmatis by high resolution multiple-stage linear ion-trap mass spectrometry with electrospray ionization. AB - Glycopeptidolipids (GPLs) are abundant in the cell walls of different species of mycobacteria and consist of tripeptide-amino-alcohol core of D-Phe-D-allo-Thr-D Ala-L-alaninol linked to 3-hydroxy or 3-methoxy C(26-34) fatty acyl chain at the N-terminal of D-Phe via amide linkage, and a 6-deoxytalose (6-dTal) and an O methyl rhamnose residues, respectively, attach to D-allo-Thr and the terminal L alaninol. They are important cell-surface antigens that are implicated in the pathogenesis of opportunistic mycobacteria belonging to the Mycobacterium avium complex. In this contribution, we described multiple-stage linear ion trap in conjunction with high-resolution mass spectrometry towards structural characterization of complex GPLs as [M + Na](+) ions isolated from Mycobacterium smegmatis, a fast-growing and non-pathogenic mycobacterial species. Following resonance excitation in an ion trap, MS(n) spectra of the [M + Na](+) ions of GPLs contained mainly b and y series ions that readily determine the peptide sequence. Fragment ions from MS(n) also afford locating the 6-dTal and O-methyl rhamnose residues linked to the D-allo-Thr and terminal L-alaninol of the peptide core, respectively, as well as recognizing the modifications of the glycosides, including their acetylation and methylation states and the presence of succinyl group. The GPL families consisting of 3-hydroxy fatty acyl and of 3-methoxy fatty acyl substituents are readily distinguishable. The MS profiles of the GPLs from cells are dependant on the conditions they were grown, and several isobaric isomers were identified for many of the molecular species. These multiple-stage mass spectrometric approaches give detailed structures of GPL in complex mixtures of which the isomeric structures are difficult to define using other analytical methods. PMID- 23019159 TI - Structures of oxaliplatin-oligonucleotide adducts from DNA. AB - Oxaliplatin, [(1R,2R)-cyclohexane-1,2-diamine](ethanedioato-O,O')platinum(II) shows a great efficiency against colorectal cancer. Although the mode of action of oxaliplatin is not yet understood, it is commonly accepted that binding of oxaliplatin to DNA prevents DNA synthesis and alters protein to DNA binding. In order to elucidate the modified DNA-protein interaction and thus to understand the mechanisms leading to cellular misinterpretation of DNA information and apoptosis, we have identified the preferential binding sites and the dynamics of the oxaliplatin-DNA intrastrand and interstrand adducts at the oligomer level using high-performance liquid chromatography/electrospray ionization-tandem mass spectrometry (HPLC/ESI-MS/MS) and HPLC/inductively coupled plasma-MS for quantitative studies. We used a combination of benzonase, alkaline phosphatase and Nuclease S1 for digestion. This digestion procedure allows the study of platinated oligomeric nucleotides and more complex interstrand adducts. The digestion products were mostly chromatographically separated and characterized using HPLC/ESI-ion trap MS/MS experiments. We could show that the adducts to guanine and adenine are quite dynamic; that is, the ratios are changing for several days. In addition, the resulting adducts provide evidence for the action of the digesting enzymes and indicate that the adduct spectrum at the oligomeric level is different to that at the commonly studies dinucleotide level. PMID- 23019160 TI - In-situ enrichment of phosphopeptides on MALDI plates modified by ambient ion landing. AB - We report substantial in-situ enrichment of phosphopeptides in peptide mixtures using titanium and zirconium dioxide-coated matrix assisted laser desorption ionization (MALDI) plates prepared by recently reported ambient ion landing deposition technique. The technique was able to modify four common materials currently used for MALDI targets (stainless steel, aluminum, indium-tin oxide glass and polymeric anchor chip). The structure of the deposited dioxide was investigated by electron microscopy, and different surfaces were compared and discussed in this study. Two standard proteins were used to test the enrichment capabilities of modified MALDI plates: casein and in-vitro phosphorylated trehalase. The enrichment of casein tryptic digest resulted in identification of 20 phosphopeptides (including miscleavages). Trehalase was used as a suitable model of larger protein that provided more complex peptide mixture after the trypsin digestion. All four possible phosphorylation sites in trehalase were identified and up to seven phosphopetides were found (including methionine oxidations and miscleavages). Two different mass spectrometers, MALDI-Fourier transform ion cyclotron resonance (FTICR) and MALDI-time of flight, were used to detect the phosphopeptides from modified MALDI plates after the enrichment procedure. It was observed that the desorption-ionization phenomena on the modified surfaces are not critically influenced by the parameters of the different MALDI ion sources (e.g. different pressure, different extraction voltages), and thus the presence of dioxide layer on the standard MALDI plate does not significantly interfere with the main MALDI processes. The detection of phosphopeptides after the enrichment could be done by both instruments. Desorption electrospray ionization coupled to the FTICR was also tested, but, unlike MALDI, it did not provide satisfactory results. PMID- 23019161 TI - Characterization of protein adducts formed by toxic alkaloids by nano-scale liquid chromatography with mass spectrometry. AB - Betel quid chewing is associated with cytotoxicity, genotoxicity and carcinogenicity in diseases such as oral cancer, liver cirrhosis, hepatocellular carcinoma and diabetes mellitus. Arecoline and arecaidine, which are the main alkaloids in the areca nut, are potential exposure biomarkers in habitual betel quid users. This study developed a method of detecting arecoline- and arecaidine protein adducts by mass spectrometry (MS). First, bovine serum albumin was used to predict and confirm the binding sites of proteins modified by arecoline or arecaidine. Cells were then treated with arecoline to identify new protein adducts after cellular metabolic processing. Finally, human plasma was used to model long-term exposure to arecoline and arecaidine. Following isolation proteins were tryspin digested. The peptides afforded were separated and analyzed by nano-scale liquid chromatography with MS using an LTQ Orbitrap mass spectrometer. The experimental findings showed that cysteine is the predominant amino acid in protein adduct formation. The goal of this study was to establish a screening platform for identifying novel protein adducts that form covalent bonds with arecoline or arecaidine. Use of this strategy to survey new protein-toxic adducts may help to identify novel biomarkers of betel nut exposure. PMID- 23019162 TI - Silver (Iota)-assisted enantiomeric analysis of ginsenosides using electrospray ionization tandem mass spectrometry. AB - For identification of ginsenoside enantiomers, electrospray ionization mass spectrometry (ESI-MS) was used to generate silver complexes of the type [ginsenoside + Ag](+). Collision induced dissociation of the silver-ginsenoside complexes produced fragment ions by dehydration, allowing differentiation of ginsenoside enantiomers by the intensity of [M + Ag - H(2)O](+) ion. In the meanwhile, an approach based on the distinct profiles of enantiomer-selective fragment ion intensity varied with collision energy was introduced to refine the identification and quantitation of ginsenoside enantiomers. Five pairs of enantiomeric ginsenosides were distinguished and quantified on the basis of the distribution of fragment ion [M + Ag - H(2)O](+). This method was also extended to the identification of other type of ginsenoside isomers such as ginsenoside Rb2 and Rb3. For demonstrating the practicability of this novel approach, it was utilized to analyze the molar ratio of 20-(S) and 20-(R) type enantiomeric ginsenosides in enantiomer mixture in red ginseng extract. The generation of characteristic fragment ion [M + Ag - H(2)O](+) likely results from the reduction of potential energy barrier of dehydration because of the catalysis of silver ion. The mechanism of enantiomer identification of ginsenosides was discussed from the aspects of computational modeling and internal energy. PMID- 23019163 TI - Infrared laser ablation sample transfer for on-line liquid chromatography electrospray ionization mass spectrometry. AB - We have demonstrated an on-line laser ablation sampling system and coupling of the system to liquid chromatography (LC) using an infrared (IR) laser to ablate and transfer materials into a flowing solvent stream. With this approach, samples are deposited on a microscope slide mounted on a translation stage and ablated in transmission geometry using a pulsed mid-IR laser. The ablated material is captured in an exposed flowing solvent stream that carries the ablated material to the electrospray source. Post-ablation separation is accomplished using a capillary column downstream of the capture zone. The performance of the system was assessed using peptide and protein mixtures ablated from the target and analyzed with and without LC separation. PMID- 23019165 TI - A UFLC-MS/MS method for simultaneous quantitation of spinosin, mangiferin and ferulic acid in rat plasma: application to a comparative pharmacokinetic study in normal and insomnic rats. AB - Suan-Zao-Ren (SZR) decoction, consisting of Ziziphi Spinosae Semen, Poria, Chuanxiong Rhizoma, Anemarrhenae Rhizoma and Glycyrrhizae Radix Et Rhizoma, is a Traditional Chinese Medicine prescription, clinically used for the treatment of insomnia. The objective of this study was to develop a sensitive and reliable UFLC-MS/MS method for simultaneous quantitation of spinosin, mangiferin and ferulic acid, the main active ingredients in SZR decoction, and to compare the pharmacokinetics of these active ingredients in normal and insomnic rats orally administrated with the prescription. Analytes and IS were separated on a Shim pack XR-ODS column (75 mm * 3.0 mm, 2.2 um particles) using gradient elution with the mobile phase consisting of methanol and 0.1% formic acid in water at a flow rate of 0.4 mL/min. The detection of the analytes was performed on 4000Q UFLC MS/MS system with turbo ion spray source in the negative ion and multiple reaction-monitoring mode. The lower limits of quantification were 1, 6 and 1 ng/mL for spinosin, mangiferin and ferulic acid, respectively. Intra- and inter day precision and accuracy of analytes were well within acceptance criteria (15%). The mean extraction recoveries of analytes and IS from rats plasma were all more than 85.0%. The validated method has been successfully applied to comparing pharmacokinetic profiles of analytes in rat plasma. The results indicated that no significant difference in pharmacokinetic parameters of ferulic acid was observed between two groups, while absorptions of spinosin and mangiferin in insomnic group were significantly lower than those in normal group. PMID- 23019164 TI - Investigation and reduction of sub-microgram peptide loss using molecular weight cut-off fractionation prior to mass spectrometric analysis. AB - This work investigates the introduction of methanol and a salt modifier to molecular weight cut-off membrane-based centrifugal filters (MWCO) to enrich sub microgram peptide quantities. Using a neuropeptide standard, bradykinin, sample loss was reduced over two orders of magnitude with and without undigested protein present. Additionally, a bovine serum albumin tryptic digestion was investigated. Twenty-seven tryptic peptides were identified from MALDI mass spectra after enriching with methanol while only two tryptic peptides were identified after MWCO separation using H(2)O. The strategy presented here enhances recovery from MWCO separation for sub-ug peptide samples. PMID- 23019166 TI - Determination of polyamines in human plasma by high-performance liquid chromatography coupled with Q-TOF mass spectrometry. AB - A high-performance liquid chromatography coupled with Q-time of flight mass spectrometry (HPLC/Q-TOF MS) method was developed and validated for the determination of 1, 3-diaminopropane, putrescine, cadaverine, spermidine and spermine in human plasma. The plasma samples were first pretreated by 10% HClO(4) and then derived by benzoyl chloride with 1, 6-diaminohexane as internal standard. The derived polyamines were separated on a C(18) column using a gradient program. The detection was performed on a Q-TOF MS by positive ionization mode. Calibration curve for each polyamine was obtained in the concentration range of 0.4 ~ 200.0 ng * ml(-1), with limit of detection of 0.02 ~ 0.1 ng * ml(-1). The intra- and inter-day RSD for all polyamines were 2.5-14.0% and 2.9 ~ 13.4%, respectively. The method was applied to determine the polyamines in human plasma from cancer patients and healthy volunteers. Results showed that the mean levels of polyamines in the plasma of cancer patients were higher than that of healthy volunteers, which suggested that the plasma polyamines could be employed as cancer diagnostic indicators in clinical testing. PMID- 23019167 TI - Application of the ETD/PTR reactions in top-down proteomics as a faster alternative to bottom-up nanoLC-MS/MS protein identification. AB - Our goal was to compare two popular analytical techniques used nowadays in proteomic investigations for proteins/peptides sequencing and identification, a widely used nanoLC-MS/MS approach applied in the bottom-up proteomics and electron transfer dissociation/proton transfer reaction fragmentation preferably used when top-down strategy is applied. Comparison was carried out with the aid of the ESI-quadrupole ion-trap instrument using the following criteria: total time of analysis including sample preparation, sequence coverage, Mascot scoring, capability to detect modifications, quality of the results as a function of protein molecular weight and sample consumption. PMID- 23019168 TI - PSAQTM standards for accurate MS-based quantification of proteins: from the concept to biomedical applications. AB - Absolute protein quantification, i.e. determining protein concentrations in biological samples, is essential to our understanding of biological and physiopathological phenomena. Protein quantification methods based on the use of antibodies are very effective and widely used. However, over the last ten years, absolute protein quantification by mass spectrometry has attracted considerable interest, particularly for the study of systems biology and as part of biomarker development. This interest is mainly linked to the high multiplexing capacity of MS analysis, and to the availability of stable-isotope-labelled standards for quantification. This article describes the details of how to produce, control the quality and use a specific type of standard: Protein Standard Absolute Quantification (PSAQTM) standards. These standards are whole isotopically labelled proteins, analogues of the proteins to be assayed. PSAQ standards can be added early during sample treatment, thus they can correct for protein losses during sample prefractionation and for incomplete sample digestion. Because of this, quantification of target proteins is very accurate and precise using these standards. To illustrate the advantages of the PSAQ method, and to contribute to the increase in its use, selected applications in the biomedical field are detailed here. PMID- 23019169 TI - Study of the fragmentation of arginine isobutyl ester applied to arginine quantification in Aedes aegypti mosquito excreta. AB - It has been demonstrated that argininolysis and uricolysis are involved in the synthesis and excretion of urea in Aedes aegypti female mosquitoes. To further investigate the metabolic regulation of urea in female mosquitoes, it is desirable to have a rapid and efficient method to monitor arginine (Arg) concentration in mosquito excreta. Thus, a procedure currently used for the identification of Arg in urea cycle disorders in newborn babies was adapted to analyze Arg in A. aegypti excreta. The fragmentation patterns of the isobutyl esters of Arg and (15)N(2)-Arg (labeled at the guanidino group) were explored by electrospray ionization (ESI)-tandem mass spectrometry and fragmentation pathways not described before were characterized. In addition, Arg, (18)O(2)-Arg, (15)N(2) Arg and (15)N(2)-(18)O(2)-Arg were also analyzed to elucidate some of the minor fragments in greater detail. Mosquito excreta from individual females were collected before and at different times after feeding a blood meal, mixed with (15)N(2)-Arg, an internal standard, and then derivatized as isobutyl esters. Based on the fragmentation mechanisms of Arg standards, studied by MS(2) and MS(3), Arg in the mosquito excreta was successfully analyzed by ESI-multiple reaction monitoring in a triple-quadrupole mass spectrometer. Arg excretion was monitored over a 120 h window before and after feeding female mosquitoes with a blood meal, with the maximum level of Arg excretion observed at 36-48 h post blood feeding. This method provides an efficient and rapid tool to quantify Arg in individual blood-fed mosquitoes, and can be applied to other organisms, whose small size severally limits the use of conventional biochemical analysis. PMID- 23019170 TI - Interactions of Zn(II) with single and multiple amino acids. Insights from density functional and ab initio calculations. AB - Calculations were performed to study the interactions of metal ions (M) with (multiple) amino acids (AA) and fill the gap between single AA and proteins. A complete conformational search results in nine and eleven ZnGly isomers at B3P86 and MP2 levels, respectively, and four populated conformers of glycine are responsible for production of these isomers. For all M, the isomers via the OO and NO binding modes are the main constituents, and the OO mode is favored by stronger electrostatic interactions. Binding with more glycines causes larger structural distortions, improves relative stabilities of monodentate binding isomers and generates new binding modes (e.g. ZnB(III) via only the hydroxyl group). The scaling factor of Zn(Gly)(n) structures, the ratio of its binding affinity versus the sum of comprising ZnGly isomers, is linear with glycine number (n), and the linear relationship may not be altered by mutations of glycines and M. It thus allows to estimate M(AA)(n) binding affinities (n >= 2) from the comprising MAA structures and analyze their structures with kinetic methods. The DFT and MP2 results become comparable by increasing metal coordination, e.g. the ZnB(III) versus ZnA(I) (zwitterionic) relative energy differs by 41.9 kcal mol(-1) at B3P86 and MP2 levels and is close by addition of three water molecules (4.1 kcal mol(-1)). The presence of water solvent improves the relative stabilities of monodentate binding isomers and results in a broader conformational distribution. PMID- 23019171 TI - Cytosine to uracil conversion through hydrolytic deamination of cytidine monophosphate hydroxy-alkylated on the amino group: a liquid chromatography- electrospray ionization--mass spectrometry investigation. AB - A novel pathway for cytosine to uracil conversion performed in a micellar environment, leading to the generation of uridine monophosphate (UMP), was evidenced during the alkylation reaction of cytidine monophosphate (CMP) by dodecyl epoxide. Liquid chromatography-electrospray ionization - ion trap - mass spectrometry was used to separate and identify the reaction products and to follow their formation over time. The detection of hydroxy-amino-dodecane, concurrently with free UMP, in the reaction mixture suggested that, among the various alkyl-derivatives formed, CMP alkylated on the amino group of cytosine could undergo tautomerization to an imine and hydrolytic deamination, generating UMP. Interestingly, no evidence for this peculiar conversion pathway was obtained when guanosine monophosphate (GMP), the complementary ribonucleotide of CMP, was also present in the reaction mixture, due to the fact that NH(2)-alkylated CMP was not formed in this case. The last finding emphasized the role played by CMP GMP molecular interactions, mediated by a micellar environment, in hindering the alkylation reaction at the level of the cytosine amino group. PMID- 23019172 TI - Synthesis-structure-morphology interplay of bimetallic "core-shell" carbon nitride nano-electrocatalysts. AB - An extensive morphological and structural study of two bimetallic "core-shell" carbon nitride nano-electrocatalysts with active sites based on Pt and Ni or on Pt and Fe is reported. The core-shell electrocatalysts are obtained by the pyrolysis of a precursor obtained by decorating a support composed of conducting particles with a hybrid inorganic-organic material. The electrocatalysts were investigated by high-resolution TEM, powder X-ray diffraction, and MU-Raman spectroscopy. The morphological and structural information presented here provides 1) insight into the microscopic features, affecting the electrochemical performance of the electrocatalyst materials determined in both ex situ measurements and single-cell configurations; and 2) an opportunity to study the effect of the different precursor chemistries on the structure and morphology of the bimetallic core-shell carbon nitride nano-electrocatalysts. PMID- 23019173 TI - Intra-aneurysmal pressure and flow changes induced by flow diverters: relation to aneurysm size and shape. AB - BACKGROUND AND PURPOSE: Effects of blood flow modification by flow diverters are observed to lead often to aneurysm thrombosis and reverse remodeling. For this process, to further understand the potential roles of intra-aneurysmal blood pressure changes and aneurysm morphologies, 23 patients were studied by numeric simulation. MATERIALS AND METHODS: 3D imaging of aneurysms of different sizes and shapes, all located at the supraclinoid segment of the ICA (n=23), was prepared for CFD simulations. Hemodynamic variables were calculated for conditions before and after virtual FD implantation, reconstituting a vessel wall scaffold across the aneurysm neck. WSS, velocity, residence time, turnover time, and intra aneurysmal pressure were assessed statistically. RESULTS: After placement of FDs, significant reductions inside the aneurysm were observed for most hemodynamic variables (P<.01) except mean intra-aneurysmal pressures. For minimum/maximum intra-aneurysmal pressure values, small but significant changes were found; however, they were considered too small to be of relevance. CONCLUSIONS: Calculations in 23 cases did not reveal significant intra-aneurysmal mean or peak pressure changes, indicating a minor role of pressure changes in the rare event of secondary ruptures after FD use. Other hemodynamic variables (WSS and velocity) exhibited more significant changes, indicating their role in intra aneurysmal thrombus formation. Size-dependent, significantly higher reduction in WSS (P=.069) and velocity (P=.013) was observed in small aneurysms compared with larger ones. When it came to shape, there were significantly higher reductions in WSS (P=.055) and velocity (P=.065) and a significantly higher increase in turnover time in fusiform aneurysms compared with saccular aneurysms. PMID- 23019174 TI - Diagnostic yield of catheter angiography in patients with subarachnoid hemorrhage and negative initial noninvasive neurovascular examinations. AB - BACKGROUND AND PURPOSE: The yield of DSA in patients with SAH and negative initial noninvasive neurovascular examinations (CTA or MRA) is not well understood. This study aimed to determine the yield of DSA for the detection of causative vascular lesions in this clinical scenario. MATERIALS AND METHODS: We examined the yield of DSA for the detection of causative vascular lesions in a cohort of patients presenting to our institution with SAH and negative initial noninvasive neurovascular examinations during a 5-year period. Two experienced neuroradiologists independently evaluated the NCCT to determine the SAH pattern (diffuse, perimesencephalic, or peripheral sulcal) and the catheter angiograms to assess the presence of a causative vascular lesion. RESULTS: Fifty-five patients were included in the study, with a mean age of 58.2 years (median, 58 years; range, 25-88 years). Twenty-eight patients were men (50.9%), and 27 were women (49.1%). The initial noninvasive examination was a CTA in 47 patients (85.5%) and an MRA in 8 patients (14.5%). Thirty-three patients had diffuse SAH (60%); 11, perimesencephalic SAH (20%); and 11, peripheral sulcal SAH (20%). DSA demonstrated a causative vascular lesion in 6 patients (10.9%), 5 of whom had diffuse SAH (yield of 15.2%) and 1 of whom had peripheral sulcal SAH (yield of 9.1%). No causative vascular lesions were found in patients with perimesencephalic SAH. CONCLUSIONS: DSA is a valuable tool in the evaluation of patients with diffuse and peripheral sulcal SAH who have negative initial noninvasive neurovascular examinations, demonstrating a causative vascular lesion in 15.2% and 9.1% of patients, respectively. PMID- 23019175 TI - Endovascular procedures in elderly patients. PMID- 23019177 TI - Population-based trends in overweight and obesity: a comparative study of 2,148,342 Israeli male and female adolescents born 1950-1993. AB - BACKGROUND: The epidemic of obesity has been identified as a major source of morbidity, not just in developed countries but globally, in adults as well as at younger ages. OBJECTIVE: The aims of this study were to describe trends in obesity and overweight in Israeli adolescents and observe temporal changes and association by risk factors. METHODS: The research analyzed records of 2,148,342 Jewish adolescents, over a span of 44 years and included data for individual body measurements, place of residence, area of origin and education levels. Body mass index (BMI) was measured by professionals, calculated and categorized as overweight or obesity according to age- and gender-specific BMI curves established in recent years. We processed the data in multinomial logistic regression model and calculated odds ratios for various risk factors. RESULTS: Obesity and overweight are on the rise for male and female adolescents born from the mid-1960s onwards, and especially for men from the 1980s onwards. Risk factors for male adolescents include lower socioeconomic status, inferior education levels and Western origins (vs. Asian, African or Israeli origins). Risk modifiers for women were similar, except for African origins, which were associated with increased risk rather than decreased risk. Asian and Israeli origins were protective for both genders, and education was more strongly associated with obesity for women. CONCLUSIONS: We recommend stronger preventive efforts directed at adolescents as a whole, and particularly vulnerable groups with lower education levels and poverty, or those with specific geographical origins. Gender disparities are evident and should be considered in these efforts and in further research. PMID- 23019178 TI - Luminescence in Li3 Al 2 (PO4)3 :Eu(2+). AB - A series of efficient Li3 Al 2 (PO4)3 :Eu(2+) novel phosphors were synthesized by the facile combustion method. The effects of dopant on the luminescence behavior of Li3 Al 2 (PO4)3 phosphor were also investigated. The phosphors were characterized by X-ray diffraction, field emission scanning electron microscope and photoluminescence techniques. The result shows that all samples can be excited efficiently by near-ultraviolet excitation under 310 nm. The emission was observed for Li3 Al 2 (PO4)3 :Eu(2+) phosphor at 425 nm, which corresponded to the d -> f transition. The concentration quenching of Eu(2+) was observed in Li3 Al 2 (PO4)3 :Eu(2+) when the Eu concentration was at 0.5 mol%. The prepared powders exhibited intense blue emission at the 425 nm owing to the Eu(2+) ion by Hg-free excitation at 310 nm (i.e., solid-state lighting excitation). Consequently, the availability of such a phosphor will significantly help in the development of blue-emitting solid-state lighting applications. PMID- 23019179 TI - Efficacy of granulocyte/monocyte apheresis for moderate to severe Crohn's disease. PMID- 23019180 TI - Value of human papillomavirus testing in the diagnostic workup of lymph node metastases from an unknown primary tumor to the neck. PMID- 23019181 TI - Treatment interventions for severe traumatic brain injury: limited evidence, choice limitations. PMID- 23019182 TI - The moral status of post-persons. PMID- 23019183 TI - Attitudes toward clinical autopsy in unexpected patient deaths in Japan: a nation wide survey of the general public and physicians. AB - CONTEXT: Autopsy is a useful tool for understanding the cause and manner of unexpected patient death. However, the attitudes of the general public and physicians in Japan about clinical autopsy are limited. OBJECTIVE: To describe the beliefs of the general public about whether autopsy should be performed and ascertain if they would actually request one given specific clinical situations where patient death occurred with the additional variable of medical error. To compare these attitudes with previously obtained attitudes of physicians practising at Japanese teaching hospitals. DESIGN, SETTING AND PARTICIPANTS: We conducted a cross-sectional study of the general public. We sent standardised questionnaires in 2010 to a randomly selected non-physician adult population using a survey company for participant selection. Respondents gave their opinions about the necessity of autopsy and how they might act given various clinical scenarios of patient death. We compared these results with those of a previous survey of Japanese physicians conducted in 2009. RESULTS: Of the 2300 eligible general adult population, 1575 (68.5%) responded. The majority of the general public indicated they believed an autopsy was necessary. However, in cases of unclear medical error or unclear cause and effect relationship of medical care and patient death, the general public were much less likely to indicate they would actually request an autopsy than were physicians (p<0.0001). Currently in Japan the debate about the role autopsy should play in the case of error related to death is underway. The results from this study will be important in informing related decisions. PMID- 23019184 TI - A heat-inducible CRE/LOXP gene induction system in medaka. AB - We established three lines of transgenic medaka, a heat-shock element (HSE) monitor line (hse-GFP line), heat-inducible driver lines (hse-cre lines), and effector lines (gapdh-loxP[DsRed]-GFP lines). We employed these to comprehensively analyze gene induction at different time points in various tissues. These analyses demonstrate a good response of synthetic HSEs by heat treatment during embryogenesis and the mosaic gene induction by cre/loxP-mediated recombination, thus providing practical information regarding the feasibility of a heat-inducible cre/loxP-mediated system in medaka. We also activated recombination by local heat-treatment using a metal probe and an infrared laser. Our results collectively indicate that these lines allow us to perform lineage tracing and mosaic analysis and provide the platform to investigate gene functions at later developmental stage and adult. PMID- 23019185 TI - Making greater use of dedicated hospital observation units for many short-stay patients could save $3.1 billion a year. AB - Using observation units in hospitals to provide care to certain patients can be more efficient than admitting them to the hospital and can result in shorter lengths-of-stay and lower costs. However, such units are present in only about one-third of US hospitals. We estimated national cost savings that would result from increasing the prevalence and use of observation units for patients whose stay there would be shorter than twenty-four hours. Using a systematic literature review, national survey data, and a simulation model, we estimated that if hospitals without observation units had them in place, the average cost savings per patient would be $1,572, annual hospital savings would be $4.6 million, and national cost savings would be $3.1 billion. Future policies intended to increase the cost-efficiency of hospital care should include support for observation unit care as an alternative to short-stay inpatient admission. PMID- 23019187 TI - Inability of a monoclonal anti-light chain antibody to detect clonal plasma cells in a patient with multiple myeloma by multicolor flow cytometry. AB - BACKGROUND: Multicolor flow cytometry (MFC) is increasingly important for the diagnosis and minimal residual disease (MRD) assessment of patients with plasma cells (PC) dyscrasias, like multiple myeloma. Recently published information shows that immunophenotype of myeloma PC can change over time and normal PC are heterogeneous in the expression of CD19 and CD56. This implies that for a sensitive, reliable detection of MRD clonality assessment by the detection of cytoplasmic kappa and lambda light chains is advisable. METHODS: Eight-color MFC was used to detect normal and myeloma PC by the expression of CD38 and CD138. Analysis of additional surface antigens like CD45, CD19, CD56, CD27, and the intracellular immunoglobulin light chain distribution were used to differentiate polyclonal from clonal PC. RESULTS: Absence of cytoplasmic light chains expression in a PC subpopulation with an abnormal phenotype suggested the presence of non-secretory plasma cells in the bone marrow (BM) of this patient. This observation however, was contradicted by the presence of free lambda light chains in the patient's serum. After repeating the analysis with polyclonal antibodies against intracellular immunoglobulin light chains instead of monoclonal antibodies, the abnormal PC subpopulation appeared to express lambda light chains. CONCLUSION: These data illustrate that if clonality assessment of PC is included in disease monitoring, the use of polyclonal over monoclonal antibodies is preferred for the detection of intracellular immunoglobulin light chains. PMID- 23019186 TI - Determining how defects in connexin43 cause skeletal disease. AB - Gap junction channels mediate direct cell-cell communication via the exchange of second messengers, ions, and metabolites from one cell to another. Mutations in several human connexin (cx) genes, the subunits of gap junction channels, disturb the development and function of multiple tissues/organs. In particular, appropriate function of Cx43 is required for skeletal development in all vertebrate model organisms. Importantly, it remains largely unclear how disruption of gap junctional intercellular communication causes developmental defects. Two groups have taken distinct approaches toward defining the tangible molecular changes occurring downstream of Cx43-based gap junctional communication. Here, these strategies for determining how Cx43 modulates downstream events relevant to skeletal morphogenesis were reviewed. PMID- 23019188 TI - Synergistic bactericidal activity between hyperosmotic stress and membrane disrupting nanoemulsions. AB - There is a clear clinical need for alternative types of non-antibiotic biocides due to the rising global health concern of microbial drug resistance. In this work, a novel antibacterial concept was delineated that utilized hyperosmotic stress (H) in concert with membrane-disrupting nanoemulsions (NEs). The antibacterial effects of either H or a NE, as well as in combination (H+NE), were assessed in vitro using an Escherichia coli model. It was found that exposure to H or NE alone produced dose-dependent bacteriostatic and bactericidal effects, respectively. However, the bactericidal action of NE was significantly amplified in the presence of H. Outcomes following H+NE exposure included rapid efflux of K(+) and nucleic acids, increased membrane permeability and a reduction in both intracellular ATP and cell viability. Further inspection of morphology by electron microscopy highlighted cell shrinkage, membrane dissolution and bacteriolysis. Pathogen inactivation occurred immediately upon contact with H+NE. The effects of H, NE and H+NE against Enterococcus faecalis, Staphylococcus aureus and meticillin-resistant S. aureus isolates were also examined. Similar to the Escherichia coli model, H+NE showed antibacterial synergism in these organisms when classified by the Chou-Talalay combination index for two-agent interactions. This synergistic interaction suggests that the H+NE platform may potentially serve as a new paradigm in disinfectants, antiseptics and antibacterial wound dressings. The H+NE mechanism of action was termed osmopermeation, as a descriptor for the underlying inactivation process. PMID- 23019189 TI - Antibacterial mechanisms of rhodomyrtone against important hospital-acquired antibiotic-resistant pathogenic bacteria. AB - The antibacterial mechanisms of rhodomyrtone, a member of the acylphloroglucinols isolated from Rhodomyrtus tomentosa leaves, against important hospital-acquired antibiotic-resistant pathogenic bacteria were assessed. The results indicated that rhodomyrtone exhibited pronounced antibacterial activity against key antibiotic-resistant pathogens including epidemic meticillin-resistant Staphylococcus aureus (EMRSA), vancomycin-intermediate S. aureus and vancomycin resistant enterococcal strains. The strains EMRSA-16, Enterococcus faecalis ATCC 29212 and VRE-3 demonstrated a significant decrease in survival ability after treatment with rhodomyrtone at 1* (0.5 ug ml(-1)), 2*, 4* and 8* MIC for 24 h. Moreover, the compound was observed in the cytoplasmic fraction of rhodomyrtone treated S. aureus, and only a very fine band of the compound was seen following separation of the cell-wall and cell-membrane fractions of the treated cells. In addition, exposure of S. aureus to rhodomyrtone at 4*, 2* and 1* MIC for 24 h produced no significant effect on the bacterial cell membrane and cell lysis, suggesting that neither of these is the main target of rhodomyrtone action in these organisms. Stepwise isolation of the bacterial cells with increasing resistance to rhodomyrtone was not induced in either S. aureus or EMRSA-16 after 45 passages on Luria-Bertani agar supplemented with rhodomyrtone. In addition, in vitro toxicity of rhodomyrtone at 128* MIC on human erythrocytes was not observed. These results provide evidence to support therapeutic challenges of rhodomyrtone against Gram-positive pathogens. PMID- 23019190 TI - Analysis of mutations in the gyrA and gyrB genes and their association with the resistance of Mycobacterium tuberculosis to levofloxacin, moxifloxacin and gatifloxacin. AB - The purpose of the present study was to analyse mutations in the gyrA and gyrB genes of Mycobacterium tuberculosis and define the possible correlation between these mutations and resistance to levofloxacin (LVX), moxifloxacin (MFX) and gatifloxacin (GAT), based on their MICs. One hundred and forty-two M. tuberculosis clinical isolates were collected from pulmonary tuberculosis patients in the Moscow region. All M. tuberculosis strains were tested for drug susceptibility to rifampicin and isoniazid using the BACTEC MGIT 960 System and to ofloxacin (OFX) using the absolute concentration method on solid Lowenstein Jensen slants. All in all, 68 strains were selected at random (38 strains were resistant and 30 were susceptible to OFX) for further analysis using the TB BIOCHIP-2 test system and DNA sequence analysis. The MICs of LVX, MFX and GAT for selected strains were determined using the BACTEC MGIT 960 System. Mutations in the gyrA gene were observed in 36 out of 38 (94.7 %) OFX-resistant M. tuberculosis strains. Asn538Asp and Asp500His substitutions in the gyrB gene only were found in two (5.3 %) strains. Twenty-nine out of 30 OFX-sensitive M. tuberculosis strains had no mutations in either gene. One (3.3 %) OFX-sensitive M. tuberculosis strain carried an Arg485His substitution in gyrB. The results of our investigation showed that there is no clear correlation between the type of mutation in the genes gyrA and gyrB, and the MIC levels of LVX, MFX and GAT for resistant strains. Mutations in gyrA and Asn538Asp, and Asp500His substitutions in gyrB were associated with cross-resistance of M. tuberculosis to fluoroquinolones. The substitution Arg485His in gyrB does not confer resistance to LVX, MFX and GAT in M. tuberculosis. PMID- 23019191 TI - Occurrence and characterization of multidrug-resistant New Delhi metallo-beta lactamase-1-producing bacteria isolated between 2003 and 2010 in Bangladesh. AB - The purpose of this study was to screen for reduced susceptibility against imipenem and the presence of the New Delhi metallo-beta-lactamase-1 (NDM-1) gene in a collection of Enterobacteriaceae (Escherichia coli, Shigella spp. and Klebsiella pneumoniae) from different surveillance studies between 2003 and 2010 at the International Centre for Diarrhoeal Disease Research, Bangladesh. None of the E. coli (n = 1789) and Shigella spp. (n = 90) isolated between 2009 and 2010 from stool samples was resistant or had intermediate susceptibility to imipenem. Among 127 extended-spectrum beta-lactamase-producing strains isolated during 2003 2009, three Klebsiella pneumoniae isolates (2.4 %) were resistant to imipenem and were positive for bla(NDM-1). All these NDM-1-producing strains were isolated in 2008 and were resistant to all antibiotics tested except for tigecycline and colistin. All three isolates were positive for bla(OXA-1) group, bla(CTX-M-1) group (bla(CTX-M-15)) and bla(SHV) genes, whilst two isolates were positive for 16S rRNA methylase (armA) and qnr (qnrB) genes. One isolate was positive for the bla(CMY) gene and one for the rmtB gene. The bla(NDM-1) gene was located on a conjugative plasmid of ~23-24 MDa. The PFGE patterns of the isolates were different from each other. This study highlights the occurrence of NDM-1 producing organisms in Bangladesh in 2008. The clonal diversity of the isolates and the transferability of bla(NDM-1) plasmids suggest a wider distribution of NDM-1-producing bacteria in Bangladesh. PMID- 23019193 TI - Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1. AB - Tumor-associated macrophages are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. However, its role on tumorigenesis in a genetic mouse model of colon cancer has not been explored. We examined the role of MCP-1 on tumor-associated macrophages, inflammation, and intestinal tumorigenesis. Male Apc(Min/+), Apc(Min/+)/MCP-1(-/ ) or wild-type mice were euthanized at 18 wk of age and intestines were analyzed for polyp burden, apoptosis, proliferation, beta-catenin, macrophage number and phenotype, markers for cytotoxic T lymphocytes and regulatory T cells, and inflammatory mediators. MCP-1 deficiency decreased overall polyp number by 20% and specifically large polyp number by 45% (P < 0.05). This was consistent with an increase in apoptotic cells (P < 0.05), but there was no change detected in proliferation or beta-catenin. MCP-1 deficiency decreased F4/80-positive cells in both the polyp tissue and surrounding intestinal tissue (P < 0.05) as well as expression of markers associated with M1 (IL-12 and IL-23) and M2 macrophages (IL 13, CD206, TGF-beta, and CCL17) (P < 0.05). MCP-1 knockout was also associated with increased cytotoxic T lymphocytes and decreased regulatory T cells (P < 0.05). In addition, MCP-1(-/-) offset the increased mRNA expression of IL-1beta and IL-6 in intestinal tissue and IL-1beta and TNF-alpha in polyp tissue (P < 0.05), and prevented the decrease in SOCS1 expression (P < 0.05). We demonstrate that MCP-1 is an important mediator of tumor growth and immune regulation that may serve as an important biomarker and/or therapeutic target in colon cancer. PMID- 23019192 TI - Tissue remodeling in eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a recently recognized, immune-mediated disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. The chronic esophageal eosinophilia of EoE is associated with tissue remodeling that includes epithelial hyperplasia, subepithelial fibrosis, and hypertrophy of esophageal smooth muscle. This remodeling causes the esophageal rings and strictures that frequently complicate EoE and underlies the mucosal fragility that predisposes to painful mucosal tears in the EoE esophagus. The pathogenesis of tissue remodeling in EoE is not completely understood, but emerging studies suggest that secretory products of eosinophils and mast cells, as well as cytokines produced by other inflammatory cells, epithelial cells, and stromal cells in the esophagus, all contribute to the process. Interleukin (IL)-4 and IL-13, Th2 cytokines overproduced in allergic disorders, have direct profibrotic and remodeling effects in EoE. The EoE esophagus exhibits increased expression of transforming growth factor (TGF) beta1, which is a potent activator of fibroblasts and a strong inducer of epithelial-mesenchymal transition. In addition, IL-4, IL-13, and TGF-beta all have a role in regulating periostin, an extracellular matrix protein that might influence remodeling by acting as a ligand for integrins, by its effects on eosinophils or by activating fibrogenic genes in the esophagus. Presently, few treatments have been shown to affect the tissue remodeling that causes EoE complications. This report reviews the potential roles of fibroblasts, eosinophils, mast cells, and profibrotic cytokines in esophageal remodeling in EoE and identifies potential targets for future therapies that might prevent EoE complications. PMID- 23019194 TI - Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility to Citrobacter rodentium by suppressing mucosal Th17 responses. AB - Vitamin D deficiency affects more that 1 billion people worldwide and is associated with an increased risk of developing a number of inflammatory/autoimmune diseases, including inflammatory bowel disease (IBD). At present, the basis for the impact of vitamin D on IBD and mucosal immune responses is unclear; however, IBD is known to reflect exaggerated immune responses to luminal bacteria, and vitamin D has been shown to play a role in regulating bacteria-host interactions. Therefore, to test the effect of active vitamin D on host responses to enteric bacteria, we gave 1,25(OH)(2)D(3) to mice infected with the bacterial pathogen Citrobacter rodentium, an extracellular microbe that causes acute colitis characterized by a strong Th1/Th17 immune response. 1,25(OH)(2)D(3) treatment of infected mice led to increased pathogen burdens and exaggerated tissue pathology. In association with their increased susceptibility, 1,25(OH)(2)D(3)-treated mice showed substantially reduced numbers of Th17 T cells within their infected colons, whereas only modest differences were noted in Th1 and Treg numbers. In accordance with the impaired Th17 responses, 1,25(OH)(2)D(3)-treated mice showed defects in their production of the antimicrobial peptide REG3gamma. Taken together, these studies show that 1,25(OH)(2)D(3) suppresses Th17 T-cell responses in vivo and impairs mucosal host defense against an enteric bacterial pathogen. PMID- 23019195 TI - BMP4 is a novel paracrine inhibitor of liver regeneration. AB - Transforming growth factor (TGF)-beta family members exert strong effects on restoration of liver mass after injury. Bone morphogenetic proteins (BMPs) are members of the TGF-beta family and are found in the liver, suggesting that these proteins may play a role in liver regeneration. We examined BMP signaling in the liver during hepatectomy. We found that BMP4 is constitutively expressed in the peribiliary stroma and endothelial cells of the liver and that expression is decreased after hepatectomy. Mice driven to maintain BMP4 expression in the liver display inhibited hepatocyte proliferation and restoration of liver mass after hepatectomy, suggesting that reduced BMP4 is necessary for normal regeneration. Consistent with this finding, hepatocyte-specific deletion of the BMP receptor activin receptor-like kinase 3 (Alk3) enhances regeneration and reduces phosphorylation of SMAD1/5/8, a transducer of BMP signaling. In contrast to experiments in wild-type mice, maintaining BMP4 levels has no effect on liver regeneration in hepatocyte-specific Alk3 null mice, providing evidence that BMP4 signals through Alk3 to inhibit liver regeneration. Consistent with these findings, the BMP4 antagonist Noggin enhances regeneration. Furthermore, high dose BMP4 inhibits proliferation of primary hepatocytes and HepG2 cells in culture. These findings elucidate a new, potentially clinically relevant paradigm in which a constitutively expressed paracrine inhibitory factor plays a critical role in liver regeneration. PMID- 23019196 TI - Cardiac sympathetic imaging with mIBG in cirrhosis and portal hypertension: relation to autonomic and cardiac function. AB - Autonomic and cardiac dysfunction is frequent in cirrhosis and includes increased sympathetic nervous activity, impaired heart rate variability (HRV), and baroreflex sensitivity (BRS). Quantified (123)I-metaiodobenzylguanidine (mIBG) scintigraphy reflects cardiac noradrenaline uptake, and in patients with cardiac failure it predicts outcome. In this study, we aimed to investigate cardiac sympathetic neuronal function in cirrhosis by mIBG scintigraphy in relation to cardiovascular function. Ten patients with alcoholic cirrhosis and 10 age- and sex-matched healthy controls participated in the study. Heart/mediastinum (H/M) ratios of mIBG uptake were calculated 15 and 230 min after intravenous injection of mIBG. Furthermore, washout rate (WOR) of mIBG was calculated. The patients underwent a liver vein catheterization with determination of splanchnic and systemic hemodynamics and measurement of HRV and BRS. mIBG-scintigraphy revealed significantly increased WOR in patients with cirrhosis compared with controls (P < 0.005), whereas H/M uptakes were equal in the groups. Forty percent of the patients had reduced uptake of mIBG in the infero-lateral segment of the left ventricle. WOR correlated significantly with central circulation time, an estimate of central hypovolemia (r = -0.64, P < 0.05) and frequency-corrected QT(F) interval (r = 0.71, P = 0.01). Patients with cirrhosis had significantly decreased HRV and BRS correlating with indicators of abnormal cathecholamine uptake by mIBG although the catecholamine level was normal in the patients. In conclusion, in alcoholic cirrhosis, mIBG scintigraphy reveals autonomic dysfunction and impaired myocardial distribution of sympathetic nervous activity. It is associated to indicators of central hypovolemia, QT interval, and decreased HRV and BRS. Measurement of myocardial catecholamine uptake by mIBG may add important information on autonomic and cardiac dysfunction in cirrhosis. PMID- 23019197 TI - Telomere shortening is associated with reduced duodenal HCOFormula secretory but normal gastric acid secretory capacity in aging mice. AB - The incidence of duodenal ulcer, especially Helicobacter pylori-negative duodenal ulcer, strongly increases with age. In humans, telomere length shortening is considered to be one critical factor in cellular senescence and organ survival. In this study, we compared basal and stimulated gastric acid and duodenal HCO(3)( ) secretory rates in aged late-generation (G(3)) telomerase-deficient (mTERC(-/ )) mice, which are characterized by severe telomere dysfunction due to the inability to elongate telomeres during cell division. We found that basal and forskolin-stimulated HCO(3)(-) secretion and short-circuit current (I(sc)) in isolated duodenal mucosa of G(3) mTERC(-/-) mice were markedly reduced compared with age-matched wild-type mice. In contrast, basal and forskolin-stimulated acid secretory rates in isolated G(3) mTERC(-/-) gastric mucosa were not significantly altered. Correspondingly, duodenal mucosa of G(3) mTERC(-/-) mice showed slimming and shortening of villi, whereas gastric mucosal histology was not significantly altered. However, the ratios of cystic fibrosis transmembrane conductance regulator (CFTR) and solute-linked carrier 26 gene family (Slc26a6) mRNA expression in relation to cytokeratin-18 were not altered in duodenal mucosa. The further knockout of p21, which is a downstream effector of telomere shortening induced senescence, rescued villus atrophy of duodenal mucosa, and basal and forskolin-stimulated duodenal HCO(3)(-) secretion and I(sc) in mTERC(-/-) p21(-/ ) double-knockout mice were not different from wild-type controls. In conclusion, genetic ablation of telomerase resulted in p21-dependent duodenal mucosal atrophy and reduced duodenal HCO(3)(-) secretory capacity, whereas gastric morphology and acid secretory function were preserved. This suggests that telomere shortening during aging may result in an imbalance between aggressive and protective secretions against duodenal mucosa and thus predispose to ulcer formation. PMID- 23019198 TI - OSR1-sensitive small intestinal Na+ transport. AB - The oxidative stress responsive kinase 1 (OSR1) contributes to WNK (with no K) dependent regulation of renal tubular salt transport, renal salt excretion, and blood pressure. Little is known, however, about a role of OSR1 in the regulation of intestinal salt transport. The present study thus explored whether OSR1 is expressed in intestinal tissue and whether small intestinal Na(+)/H(+) exchanger (NHE), small intestinal Na(+)-glucose cotransport (SGLT1), and/or colonic epithelium Na(+) channel (ENaC) differ between knockin mice carrying one allele of WNK-resistant OSR1 (osr1(+/KI)) and wild-type mice (osr1(+/+)). OSR1 protein abundance was determined by Western blotting, cytosolic pH from BCECF fluorescence, NHE activity from Na(+)-dependent realkalinization following an ammonium pulse, SGLT1 activity from glucose-induced current, and colonic ENaC activity from amiloride-sensitive transepithelial current in Ussing chamber experiments. As a result, OSR1 protein was expressed in small intestine of both osr1(+/KI) mice and osr1(+/+) mice. Daily fecal Na(+), K(+), and H(2)O excretion and jejunal SGLT1 activity were lower, whereas small intestinal NHE activity and colonic ENaC activity were higher in osr1(+/KI) mice than in osr1(+/+) mice. NHE3 inhibitor S-3226 significantly reduced NHE activity in both genotypes but did not abrogate the difference between the genotypes. Plasma osmolarity, serum antidiuretic hormone, plasma aldosterone, and plasma corticosterone concentrations were similar in both genotypes. Small intestinal NHE3 and colonic alpha-ENaC protein abundance were not significantly different between genotypes, but colonic phospho-beta-ENaC (ser633) was significantly higher in osr1(+/KI) mice. In conclusion, OSR1 is expressed in intestine and partial WNK insensitivity of OSR1 increases intestinal NHE activity and colonic ENaC activity. PMID- 23019199 TI - cGVHD of skin: simple tools, great advances. PMID- 23019200 TI - Keep up the heat on IL-1. PMID- 23019201 TI - MM-associated anemia: more than "crowding out" HSPCs. PMID- 23019202 TI - MiRly regulating metabolism. PMID- 23019203 TI - KIT's ship comes in. PMID- 23019204 TI - Therapeutic effects of ruxolitinib in patients with myelofibrosis without clinically significant splenomegaly. PMID- 23019205 TI - Intravenous immunoglobulin (IVIg) inhibits CD8 cytotoxic T-cell activation. PMID- 23019206 TI - Lack of association between KIR genes and acute lymphoblastic leukemia in children. PMID- 23019209 TI - Correction. PMID- 23019208 TI - Assessing community health workers' performance motivation: a mixed-methods approach on India's Accredited Social Health Activists (ASHA) programme. AB - OBJECTIVE: This study examined the performance motivation of community health workers (CHWs) and its determinants on India's Accredited Social Health Activist (ASHA) programme. DESIGN: Cross-sectional study employing mixed-methods approach involved survey and focus group discussions. SETTING: The state of Orissa. PARTICIPANTS: 386 CHWs representing 10% of the total CHWs in the chosen districts and from settings selected through a multi-stage stratified sampling. PRIMARY AND SECONDARY OUTCOME MEASURES: The level of performance motivation among the CHWs, its determinants and their current status as per the perceptions of the CHWs. RESULTS: The level of performance motivation was the highest for the individual and the community level factors (mean score 5.94-4.06), while the health system factors scored the least (2.70-3.279). Those ASHAs who felt having more community and system-level recognition also had higher levels of earning as CHWs (p=0.040, 95% CI 0.06 to 0.12), a sense of social responsibility (p=0.0005, 95% CI 0.12 to 0.25) and a feeling of self-efficacy (p=0.000, 95% CI 0.38 to 0.54) on their responsibilities. There was no association established between their level of dissatisfaction on the incentives (p=0.385) and the extent of motivation. The inadequate healthcare delivery status and certain working modalities reduced their motivation. Gender mainstreaming in the community health approach, especially on the demand-side and community participation were the positive externalities of the CHW programme. CONCLUSIONS: The CHW programme could motivate and empower local lay women on community health largely. The desire to gain social recognition, a sense of social responsibility and self-efficacy motivated them to perform. The healthcare delivery system improvements might further motivate and enable them to gain the community trust. The CHW management needs amendments to ensure adequate supportive supervision, skill and knowledge enhancement and enabling working modalities. PMID- 23019210 TI - CYP-epoxygenases contribute to A2A receptor-mediated aortic relaxation via sarcolemmal KATP channels. AB - Previously, we have shown that A(2A) adenosine receptor (A(2A)AR) mediates aortic relaxation via cytochrome P-450 (CYP)-epoxygenases. However, the signaling mechanism is not understood properly. We hypothesized that ATP-sensitive K(+) (K(ATP)) channels play an important role in A(2A)AR-mediated relaxation. Organ bath and Western blot experiments were done using isolated aorta from A(2A)KO and corresponding wild-type (WT) mice. Aortic rings from WT and A(2A) knockout (KO) mice were precontracted with submaximal dose of phenylephrine (PE, 10(-6) M), and concentration-response curves for pinacidil, cromakalim (nonselective K(ATP) openers), and diazoxide (mitochondrial K(ATP) opener) were obtained. Diazoxide did not have any relaxation effect on PE-precontracted tissues, whereas relaxation to pinacidil (48.09 +/- 5.23% in WT vs. 25.41 +/- 2.73% in A(2A)KO; P < 0.05) and cromakalim (51.19 +/- 2.05% in WT vs. 38.50 +/- 2.26% in A(2A)KO; P < 0.05) was higher in WT than A(2A)KO aorta. This suggested the involvement of sarcolemmal rather than mitochondrial K(ATP) channels. Endothelium removal, treatment with SCH 58651 (A(2A)AR antagonist; 10(-6) M), N(G)-nitro-l-arginine methyl ester (l-NAME, nitric oxide synthase inhibitor) and methylsulfonyl propargyloxyphenylhexanamide (MS-PPOH, CYP-epoxygenases inhibitor; 10(-5) M) significantly reduced pinacidil-induced relaxation in WT compared with controls, whereas these treatments did not have any effect in A(2A)KO aorta. Glibenclamide (K(ATP) channel inhibitor, 10(-5) M) blocked 2-p-(2-carboxyethyl)phenethylamino 5'N-ethylcarboxamido adenosine hydrochloride (CGS 21680, A(2A)AR agonist)-induced relaxation in WT and changed 5'-N-ethylcarboxamide (NECA) (nonselective adenosine analog)-induced response to higher contraction in WT and A(2A)KO. 5 Hydroxydecanoate (5-HD, mitochondrial K(ATP) channel inhibitor, 10(-4) M) had no effect on CGS 21680-mediated response in WT aorta. Our data suggest that A(2A)AR mediated vasorelaxation occurs through opening of sarcolemmal K(ATP) channels via CYP-epoxygenases and possibly, nitric oxide, contributing to pinacidil-induced responses. PMID- 23019211 TI - Bradycardic effects of microinjections of urocortin 3 into the nucleus ambiguus of the rat. AB - The presence of urocortin 3 (UCN3) and CRF2 receptors (CRF2R) has been demonstrated in brain tissue. Nucleus ambiguus (nAmb) is the predominant brain area providing parasympathetic innervation to the heart. On the basis of these reports, it was hypothesized that activation of CRF2Rs in the nAmb may elicit cardiac effects. Experiments were carried out in urethane-anesthetized, artificially ventilated, and adult male Wistar rats. Microinjections of l glutamate (l-GLU, 5 mM) were used to identify the nAmb. Different concentrations of UCN3 (0.031, 0.062, 0.125, 0.25, and 0.5 mM) microinjected into the nAmb elicited decreases in heart rate (HR) (5.3 +/- 1, 22 +/- 3.3, 38 +/- 4.9, 45.7 +/ 2.7, and 27.3 +/- 2.3 bpm, respectively). The volume of all microinjections was 30 nl. Blood pressure changes concomitant with decreases in HR were not observed. Bradycardia elicited by microinjections of UCN3 (0.25 mM; maximally effective concentration) into the nAmb was significantly (P < 0.05) attenuated by microinjections of selective CRF2R antagonists (K41498, 0.5 mM, and astressin 2B, 0.25 mM) at the same site. Bilateral vagotomy abolished the bradycardic responses to UCN3. These results indicated that activation of CRF2Rs in the nAmb by UCN3 elicited bradycardia, which was vagally mediated. UCNs have been reported to exert cardioprotective effects in heart failure and ischemia/reperfusion injury. In this situation, centrally induced bradycardia by UCN3 would be beneficial. The results of the present investigation provide a platform for future studies on the role of CRF2Rs in the nAmb in pathological states such as heart failure. PMID- 23019212 TI - Blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro- or chemoreceptor reflex responses. AB - Orexin neurons form a restricted group in the dorsal hypothalamus. The group is centered on the perifornical area within the classic hypothalamic defense area, an area which when activated produces marked cardiovascular and respiratory effects. Central administration of orexin can produce cardiorespiratory effects, but the extent to which orexin contributes to such responses evoked from the perifornical hypothalamus is not clear. To determine this, we used the dual orexin receptor antagonist Almorexant to challenge the cardiorespiratory effects evoked by disinhibition of the perifornical hypothalamus. Bicuculline (10 and 20 pmol) was microinjected in the perifornical area before and after administration of Almorexant (15 mg/kg iv) or vehicle in urethane-anesthetized rats. Almorexant significantly reduced the pressor, tachycardic, renal sympathoexcitatory, and tachypneic responses to bicuculline (10 pmol, by 55%, 53%, 28%, 77%; 20 pmol, by 54%, 27%, 51%, 72%, respectively). Reductions of similar magnitude were observed with bicuculline microinjections centered on more caudal sites just peripheral to the orexin neuron group, which would likely have activated fewer orexin neurons. In contrast, Almorexant had no effect on the cardiorespiratory response of the chemoreflex (sodium cyanide injection) or the sympathetic component of the baroreflex. Thus orexin makes a major contribution to the cardiorespiratory response evoked from the perifornical area even though orexin neurons represent only a fraction of the output of this area. Orexin neurons may also mediate cardiorespiratory responses from non-orexin neurons in the caudal hypothalamus. However, under resting conditions, blockade of orexin receptors does not affect the chemo- and baroreflexes. PMID- 23019213 TI - beta-Adrenergic regulation of Na+ uptake by larval zebrafish Danio rerio in acidic and ion-poor environments. AB - The potential role of adrenergic systems in regulating Na(+) uptake in zebrafish (Danio rerio) larvae was investigated. Treatment with isoproterenol (a generic beta-adrenergic receptor agonist) stimulated Na(+) uptake, whereas treatment with phenylephrine (an alpha(1)-adrenergic receptor agonist) as well as clonidine (an alpha(2)-adrenergic receptor agonist) significantly reduced Na(+) uptake, suggesting opposing roles of alpha- and beta-adrenergic receptors in Na(+) uptake regulation. The increase in Na(+) uptake associated with exposure to acidic water (pH = 4.0) was attenuated in the presence of the nonselective beta-receptor antagonist propranolol or the beta(1)-receptor blocker atenolol; the beta(2) receptor antagonist ICI-118551 was without effect. The stimulation of Na(+) uptake associated with ion-poor water (32-fold dilution of Ottawa tapwater) was unaffected by beta-receptor blockade. Translational gene knockdown of beta receptors using antisense oligonucleotide morpholinos was used as a second method to assess the role of adrenergic systems in the regulation of Na(+) uptake. Whereas beta(1)- or beta(2B)-receptor knockdown led to significant decreases in Na(+) uptake during exposure to acidic water, only beta(2A)-receptor morphants failed to increase Na(+) uptake in response to ion-poor water. In support of the pharmacology and knockdown experiments that demonstrated an involvement of beta adrenergic systems in the control of Na(+) uptake, we showed that the H(+)-ATPase rich (HR) cell, a subtype of ionocyte known to be a site of Na(+) uptake, is innervated and appears to express beta-adrenergic receptors (propranolol binding sites) at 4 days postfertilization. These data indicate an important role of adrenergic systems in regulating Na(+) uptake in developing zebrafish. PMID- 23019214 TI - Postprandial heat production in skeletal muscle is associated with altered mitochondrial function and altered futile calcium cycling. AB - This study aimed to determine whether postprandial temperature excursions in skeletal muscle are consistent with thermogenesis or altered blood flow. Temperature probes were implanted into the vastus lateralis muscle of ovariectomized ewes, and blood flow was assessed using laser-Doppler flowmetry (tissue flow) and transit-time ultrasound flowmetry (femoral artery flow). The animals were program-fed between 1100 and 1600, and temperature and blood flow were measured during intravenous administration of either isoprenaline or phenylephrine and during feeding and meal anticipation. In addition, muscle biopsies were collected prefeeding and postfeeding to measure uncoupling protein (UCP) expression and mitochondrial function, as well as indices of calcium cycling (ryanodine 1 receptor: RyR1 and sarcoendoplasmic calcium-dependent ATPases SERCA1/ SERCA2a). Isoprenaline increased femoral artery blood flow, whereas phenylephrine reduced blood flow. At high doses only, isoprenaline treatment increased heat production in muscle. Phenylephrine treatment did not alter muscle temperature. Meal anticipation was evoked in fasted animals (previously program-fed) that were housed beside animals that were fed. Increases in muscle temperature were elicited by feeding and meal anticipation, without changes in blood flow during either paradigm. Analyses of respiration in isolated mitochondria indicated that the postprandial increase in heat production was associated with an increase in state 4 respiration, without increased UCP1, UCP2, or UCP3 expression. Feeding increased the expression of RyR1 and SERCA2a. We conclude that excursions in muscle temperature may occur independent of blood flow, suggesting that postprandial heat production is driven by altered mitochondrial function and changes in calcium cycling. PMID- 23019215 TI - Loss of muscle strength during sepsis is in part regulated by glucocorticoids and is associated with reduced muscle fiber stiffness. AB - Sepsis is associated with impaired muscle function but the role of glucocorticoids in sepsis-induced muscle weakness is not known. We tested the role of glucocorticoids in sepsis-induced muscle weakness by treating septic rats with the glucocorticoid receptor antagonist RU38486. In addition, normal rats were treated with dexamethasone to further examine the role of glucocorticoids in the regulation of muscle strength. Sepsis was induced in rats by cecal ligation and puncture, and muscle force generation (peak twitch and tetanic tension) was determined in lower extremity muscles. In other experiments, absolute and specific force as well as stiffness (reflecting the function of actomyosin cross bridges) were determined in isolated skinned muscle fibers from control and septic rats. Sepsis and treatment with dexamethasone resulted in reduced maximal twitch and tetanic force in intact isolated extensor digitorum longus muscles. The absolute and specific maximal force in isolated muscle fibers was reduced during sepsis together with decreased fiber stiffness. These effects of sepsis were blunted (but not abolished) by RU38486. The results suggest that muscle weakness during sepsis is at least in part regulated by glucocorticoids and reflects loss of contractility at the cellular (individual muscle fiber) level. In addition, the results suggest that reduced function of the cross bridges between actin and myosin (documented as reduced muscle fiber stiffness) may be involved in sepsis-induced muscle weakness. An increased understanding of mechanisms involved in loss of muscle strength will be important for the development of new treatment strategies in patients with this debilitating consequence of sepsis. PMID- 23019216 TI - Frog urinary bladder epithelial cells express TLR4 and respond to bacterial LPS by increase of iNOS expression and L-arginine uptake. AB - As in mammals, epithelium of the amphibian urinary bladder forms a barrier to pathogen entry and is a first line of defense against penetrating microorganisms. We investigated the effect of Escherichia coli LPS on generation of nitric oxide (NO), a critically important mediator during infectious processes, by primary cultured frog (Rana temporaria) urinary bladder epithelial cells (FUBEC). It was found that FUBEC constitutively express Toll-like receptor 4 (TLR4), a receptor of LPS, and respond to LPS (10 MUg/ml) by stimulation of inducible nitric oxide synthase (iNOS) mRNA/protein expression and NOS activity measured by nitrite produced in the culture medium and by citrulline assay. We characterized uptake of l-arginine, a precursor in NO synthesis, by FUBEC and showed that it is mediated mainly by the y+ cationic amino acid transport system. LPS stimulated l arginine uptake, and this effect was blocked by the iNOS inhibitor 1400W. Arginase II was found to be expressed in FUBEC. Inhibition of arginase activity by (S)-(boronoethyl)-l-cysteine increased generation of NO, suggesting contribution of arginase to NO production via competing with NOS for the substrate. LPS altered neither total arginase activity nor arginase II expression. Among epithelial cells, phagocytic macrophage-like cells were observed, but they did not contribute to LPS-induced NO production. These data demonstrate that amphibian urinary bladder epithelial cells recognize LPS and respond to it by increased generation of NO via stimulation of iNOS expression and l-arginine uptake, which appears to be essential for the regulation of the innate immune response and the inflammation in bladder epithelium. PMID- 23019217 TI - Mithramycin A inhibits myeloid cell leukemia-1 to induce apoptosis in oral squamous cell carcinomas and tumor xenograft through activation of Bax and oligomerization. AB - In several human malignancies, overexpression of myeloid cell leukemia-1 (Mcl-1) confers resistance to induction of apoptosis; however, Mcl-1-mediated inhibition of apoptosis in oral squamous cell carcinoma (OSCC) is not fully understood and has been investigated in this study. The Mcl-1 promoter activators (TPA) and epidermal growth factor (EGF) enhanced neoplastic transformation of JB6 cells and this response was accompanied by enhanced expression of Mcl-1, and knockdown of Mcl-1 by RNA interference (RNAi) decreased JB6 cell transformation. In the same cell line, we also demonstrated that mithramycin A (Mith) decreased TPA-induced JB6 cell transformation and Mcl-1 expression. Mcl-1 was overexpressed in human oral tumors compared with normal oral mucosa and also in several OSCC cell lines including HN22 and HSC-4 cells. Treatment of these cells with Mith also decreased Mcl-1 expression and neoplastic cell transformation, and this was accompanied by induction of several markers of apoptosis. Knockdown of Mcl-1 by RNAi also induced apoptotic cell death. The downregulation of Mcl-1 by Mith and RNAi increased pro-apoptotic protein Bax, resulting in the Bax translocation into mitochondria and its oligomerization. Mith also suppressed tumor growth in vivo and induced apoptosis in tumor by also regulating expression of Mcl-1 and Bax proteins. These indicate a critical role for Mcl-1 in the growth and survival of OSCC and demonstrate that Mith may be a potential anticancer drug candidate for clinical treatment of OSCC. PMID- 23019218 TI - RecOR complex including RecR N-N dimer and RecO monomer displays a high affinity for ssDNA. AB - RecR is an important recombination mediator protein in the RecFOR pathway. RecR together with RecO and RecF facilitates RecA nucleoprotein filament formation and homologous pairing. Structural and biochemical studies of Thermoanaerobacter tengcongensis RecR (TTERecR) and its series mutants revealed that TTERecR uses the N-N dimer as a basic functional unit to interact with TTERecO monomer. Two TTERecR N-N dimers form a ring-shaped tetramer via an interaction between their C terminal regions. The tetramer is a result of crystallization only. Hydrophobic interactions between the entire helix-hairpin-helix domains within the N-terminal regions of two TTERecR monomers are necessary for formation of a RecR functional N-N dimer. The TTERecR N-N dimer conformation also affects formation of a hydrophobic patch, which creates a binding site for TTERecO in the TTERecR Toprim domain. In addition, we demonstrate that TTERecR does not bind single-stranded DNA (ssDNA) and binds double-stranded DNA very weakly, whereas TTERecOR complex can stably bind DNA, with a higher affinity for ssDNA than double-stranded DNA. Based on these results, we propose an interaction model for the RecOR:ssDNA complex. PMID- 23019219 TI - METscout: a pathfinder exploring the landscape of metabolites, enzymes and transporters. AB - METscout (http://metscout.mpg.de) brings together metabolism and gene expression landscapes. It is a MySQL relational database linking biochemical pathway information with 3D patterns of gene expression determined by robotic in situ hybridization in the E14.5 mouse embryo. The sites of expression of ~1500 metabolic enzymes and of ~350 solute carriers (SLCs) were included and are accessible as single cell resolution images and in the form of semi-quantitative image abstractions. METscout provides several graphical web-interfaces allowing navigation through complex anatomical and metabolic information. Specifically, the database shows where in the organism each of the many metabolic reactions take place and where SLCs transport metabolites. To link enzymatic reactions and transport, the KEGG metabolic reaction network was extended to include metabolite transport. This network in conjunction with spatial expression pattern of the network genes allows for a tracing of metabolic reactions and transport processes across the entire body of the embryo. PMID- 23019220 TI - Evolutionarily divergent spliceosomal snRNAs and a conserved non-coding RNA processing motif in Giardia lamblia. AB - Non-coding RNAs (ncRNAs) have diverse essential biological functions in all organisms, and in eukaryotes, two such classes of ncRNAs are the small nucleolar (sno) and small nuclear (sn) RNAs. In this study, we have identified and characterized a collection of sno and snRNAs in Giardia lamblia, by exploiting our discovery of a conserved 12 nt RNA processing sequence motif found in the 3' end regions of a large number of G. lamblia ncRNA genes. RNA end mapping and other experiments indicate the motif serves to mediate ncRNA 3' end formation from mono- and di-cistronic RNA precursor transcripts. Remarkably, we find the motif is also utilized in the processing pathway of all four previously identified trans-spliced G. lamblia introns, revealing a common RNA processing pathway for ncRNAs and trans-spliced introns in this organism. Motif sequence conservation then allowed for the bioinformatic and experimental identification of additional G. lamblia ncRNAs, including new U1 and U6 spliceosomal snRNA candidates. The U6 snRNA candidate was then used as a tool to identity novel U2 and U4 snRNAs, based on predicted phylogenetically conserved snRNA-snRNA base pairing interactions, from a set of previously identified G. lamblia ncRNAs without assigned function. The Giardia snRNAs retain the core features of spliceosomal snRNAs but are sufficiently evolutionarily divergent to explain the difficulties in their identification. Most intriguingly, all of these snRNAs show structural features diagnostic of U2-dependent/major and U12-dependent/minor spliceosomal snRNAs. PMID- 23019221 TI - Persistent androgen receptor-mediated transcription in castration-resistant prostate cancer under androgen-deprived conditions. AB - The androgen receptor (AR) is a ligand-inducible transcription factor that mediates androgen action in target tissues. Upon ligand binding, the AR binds to thousands of genomic loci and activates a cell-type specific gene program. Prostate cancer growth and progression depend on androgen-induced AR signaling. Treatment of advanced prostate cancer through medical or surgical castration leads to initial response and durable remission, but resistance inevitably develops. In castration-resistant prostate cancer (CRPC), AR activity remains critical for tumor growth despite androgen deprivation. Although previous studies have focused on ligand-dependent AR signaling, in this study we explore AR function under the androgen-deprived conditions characteristic of CRPC. Our data demonstrate that AR persistently occupies a distinct set of genomic loci after androgen deprivation in CRPC. These androgen-independent AR occupied regions have constitutively open chromatin structures that lack the canonical androgen response element and are independent of FoxA1, a transcription factor involved in ligand-dependent AR targeting. Many AR binding events occur at proximal promoters, which can act as enhancers to augment transcriptional activities of other promoters through DNA looping. We further show that androgen-independent AR binding directs a gene expression program in CRPC, which is necessary for the growth of CRPC after androgen withdrawal. PMID- 23019222 TI - Chimeric TALE recombinases with programmable DNA sequence specificity. AB - Site-specific recombinases are powerful tools for genome engineering. Hyperactivated variants of the resolvase/invertase family of serine recombinases function without accessory factors, and thus can be re-targeted to sequences of interest by replacing native DNA-binding domains (DBDs) with engineered zinc finger proteins (ZFPs). However, imperfect modularity with particular domains, lack of high-affinity binding to all DNA triplets, and difficulty in construction has hindered the widespread adoption of ZFPs in unspecialized laboratories. The discovery of a novel type of DBD in transcription activator-like effector (TALE) proteins from Xanthomonas provides an alternative to ZFPs. Here we describe chimeric TALE recombinases (TALERs): engineered fusions between a hyperactivated catalytic domain from the DNA invertase Gin and an optimized TALE architecture. We use a library of incrementally truncated TALE variants to identify TALER fusions that modify DNA with efficiency and specificity comparable to zinc-finger recombinases in bacterial cells. We also show that TALERs recombine DNA in mammalian cells. The TALER architecture described herein provides a platform for insertion of customized TALE domains, thus significantly expanding the targeting capacity of engineered recombinases and their potential applications in biotechnology and medicine. PMID- 23019223 TI - Contributions of recent and past sexual partnerships on incident human papillomavirus detection: acquisition and reactivation in older women. AB - Understanding the fraction of newly detected human papillomavirus (HPV) infections due to acquisition and reactivation has important implications on screening strategies and prevention of HPV-associated neoplasia. Information on sexual activity and cervical samples for HPV DNA detection using Roche Linear Array were collected semiannually for two years from 700 women ages 35 to 60 years. Incidence and potential fraction of HPV associated with new and lifetime sexual partnerships were estimated using Poisson regression. Cox frailty models were used to estimate hazard ratios (HR) for potential risk factors of incident HPV detection. Recent and lifetime numbers of sexual partners were both strongly associated with incident HPV detection. However, only 13% of incident detections were attributed to new sexual partners, whereas 72% were attributed to 5 or more lifetime sexual partners. Furthermore, 155 of 183 (85%) incident HPV detections occurred during periods of sexual abstinence or monogamy, and were strongly associated with cumulative lifetime sexual exposure [HR: 4.1, 95% confidence interval (CI): 2.0-8.4). This association increased with increasing age. These data challenge the paradigm that incident HPV detection is driven by current sexual behavior and new viral acquisition in older women. Our observation that most incident HPV infection was attributable to past, not current, sexual behavior at older ages supports a natural history model of viral latency and reactivation. As the more highly exposed baby-boomer generation of women with sexual debut after the sexual revolution transition to menopause, the implications of HPV reactivation at older ages on cervical cancer risk and screening recommendations should be carefully evaluated. PMID- 23019224 TI - DDX31 regulates the p53-HDM2 pathway and rRNA gene transcription through its interaction with NPM1 in renal cell carcinomas. AB - Studies of renal cell carcinoma (RCC) have led to the development of new molecular-targeted drugs but its oncogenic origins remain poorly understood. Here, we report the identification and critical roles in renal carcinogenesis for DDX31, a novel nucleolar protein upregulated in the vast majority of human RCC. Immunohistochemical overexpression of DDX31 was an independent prognostic factor for patients with RCC. RNA interference (RNAi)-mediated attenuation of DDX31 in RCC cells significantly suppressed outgrowth, whereas ectopic DDX31 overexpression in human 293 kidney cells drove their proliferation. Endogenous DDX31 interacted and colocalized with nucleophosmin (NPM1) in the nucleoli of RCC cells, and attenuation of DDX31 or NPM1 expression decreased pre-ribosomal RNA biogenesis. Notably, in DDX31-attenuated cells, NPM1 was translocated from nucleoli to the nucleoplasm or cytoplasm where it bound to HDM2. As a result, HDM2 binding to p53 was reduced, causing p53 stablization with concomitant G(1) phase cell-cycle arrest and apoptosis. Taken together, our findings define a mechanism through which control of the DDX31-NPM1 complex is likely to play critical roles in renal carcinogenesis. PMID- 23019225 TI - FGFR3 stimulates stearoyl CoA desaturase 1 activity to promote bladder tumor growth. AB - Fibroblast growth factor receptor 3 (FGFR3) belongs to a family of receptor tyrosine kinases that control cell proliferation, differentiation, and survival. Aberrant activation of FGFR3 via overexpression or mutation is a frequent feature of bladder cancer; however, its molecular and cellular consequences and functional relevance to carcinogenesis are not well understood. Through transcriptional profiling of bladder carcinoma cells subjected to short hairpin RNA knockdown of FGFR3, we identified a gene-signature linking FGFR3 signaling with de novo sterol and lipid biosynthesis and metabolism. We found that FGFR3 signaling promotes the cleavage and activation of the master transcriptional regulator of lipogenesis, sterol regulatory element-binding protein 1(SREBP1/SREBF1), in a PI3K-mTORC1-dependent fashion. In turn, SREBP1 regulates the expression of key lipogenic enzymes, including stearoyl CoA desaturase 1 (SCD1/SCD). SCD1 is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids and is crucial for lipid homeostasis. In human bladder cancer cell lines expressing constitutively active FGFR3, knockdown of SCD1 by siRNA markedly attenuated cell-cycle progression, reduced proliferation, and induced apoptosis. Furthermore, inducible knockdown of SCD1 in a bladder cancer xenograft model substantially inhibited tumor progression. Pharmacologic inhibition of SCD1 blocked fatty acid desaturation and also exerted antitumor activity in vitro and in vivo. Together, these findings reveal a previously unrecognized role of FGFR3 in regulating lipid metabolism to maintain tumor growth and survival, and also identify SCD1 as a potential therapeutic target for FGFR3-driven bladder cancer. PMID- 23019226 TI - Loss of SNAIL regulated miR-128-2 on chromosome 3p22.3 targets multiple stem cell factors to promote transformation of mammary epithelial cells. AB - A discontinuous pattern of LOH at chromosome 3p has been reported in 87% of primary breast cancers. Despite the identification of several tumor suppressor genes in this region, there has yet to be a detailed analysis of noncoding RNAs including miRNAs in this region. In this study, we identified 16 aberrant miRNAs in this region and determined several that are frequently lost or amplified in breast cancer. miR-128-2 was the most commonly deleted miRNA. Embedded in the intron of the ARPP21 gene at chromosome 3p22.3, miR-128-2 was frequently downregulated along with ARPP21 in breast cancer, where it was negatively associated with clinicopathologic characteristics and survival outcome. Forced expression of miR-128 impeded several oncogenic traits of mammary carcinoma cells, whereas depleting miR-128-2 expression was sufficient for oncogenic transformation and stem cell-like behaviors in immortalized nontumorigenic mammary epithelial cells, both in vitro and in vivo. miR-128-2 silencing enabled transforming capacity partly by derepressing a cohort of direct targets (BMI1, CSF1, KLF4, LIN28A, NANOG, and SNAIL), which together acted to stimulate the PI3K/AKT and STAT3 signaling pathways. We also found that miR-128-2 was directly downregulated by SNAIL and repressed by TGF-beta signaling, adding 2 additional negative feedback loops to this network. In summary, we have identified a novel TGF-beta/SNAIL/miR-128 axis that provides a new avenue to understand the basis for oncogenic transformation of mammary epithelial cells. PMID- 23019227 TI - Concurrent binding and modifications of AUF1 and HuR mediate the pH-responsive stabilization of phosphoenolpyruvate carboxykinase mRNA in kidney cells. AB - Onset of metabolic acidosis leads to a pronounced increase in renal expression of phosphoenolpyruvate carboxykinase (PEPCK). This response, which is mediated in part by stabilization of PEPCK mRNA, is effectively modeled by treating LLC-PK(1) F(+)-9C cells with an acidic medium. siRNA knockdown of HuR prevented the pH responsive increase in PEPCK mRNA half-life suggesting that HuR is necessary for this response. A recruitment assay, using a reporter mRNA in which the pH response elements of the PEPCK 3'-UTR were replaced with six MS2 stem-loop sequences, was developed to test this hypothesis. The individual recruitment of a chimeric protein containing the MS2 coat protein and either HuR or p40AUF1 failed to produce a pH-responsive stabilization. However, the concurrent expression of both chimeric proteins was sufficient to produce a pH-responsive increase in the half-life of the reporter mRNA. siRNA knockdown of AUF1 produced slight increases in basal levels of PEPCK mRNA and protein, but partially inhibited the pH responsive increases. Complete inhibition of the latter response was achieved by knockdown of both RNA-binding proteins. The results suggest that binding of HuR and AUF1 has opposite effects on basal expression, but may interact to mediate the pH-responsive increase in PEPCK mRNA. Two-dimensional gel electrophoresis indicated that treatment with acidic medium caused a decrease in phosphorylation of HuR, but may increase phosphorylation of the multiple AUF1 isoforms. Thus, the pH-responsive stabilization of PEPCK mRNA requires the concurrent binding of HuR and AUF1 and may be mediated by changes in their extent of covalent modification. PMID- 23019228 TI - B7-1 expression regulates the hypoxia-driven cytoskeleton rearrangement in glomerular podocytes. AB - Chronic hypoxia has been recognized as a common mechanism driving the progression of many glomerular diseases. Glomerular cells, although susceptible to hypoxic injuries, are less studied to unravel the hypoxia-related influences. In the present study, we showed that both lipopolysaccharide (LPS) and hypoxia induced B7-1 and hypoxia-inducible factor (HIF)-1alpha expression in podocytes. B7-1, an essential player in the regulation of podocyte stress fibers, interacted directly with the NH(2)-terminal oxygenation domain of HIF-1alpha protein and, therefore, might interfere with the HIF-related oxidative events. The suggestion was supported by the changes in the expression of inducible nitric oxide synthase and nitric oxide. The orderly arranged stress fibers in differentiated podocytes were disrupted by either LPS or hypoxic stimulation, and the disruption could be rescued if they were brought back to normal oxygen tension. Cell motility increased with the stimulation by LPS and hypoxia, most probably mediated by the induction of B7-1 and HIF-1alpha, respectively. We generated a B7-1 knockdown podocyte cell line using the lentiviral small interfering RNA system. The LPS- and hypoxia-induced stress fiber disruption was largely prevented in the B7-1 knockdown podocytes. The increased cell motility by LPS and hypoxia stimulations was also ameliorated in the B7-knockdown podocytes. In summary, we found that both B7-1 and HIF were upregulated by LPS and hypoxic stimulations in podocytes and they interacted with each other. Hypoxia disrupted the abundant stress fibers and increased cell motility. These hypoxia-induced changes were prevented in B7 knockdown podocytes, and they highlighted the importance of B7-1 expression in the hypoxia-related podocyte injuries. PMID- 23019229 TI - The impact of peptidase activity on clear cell renal cell carcinoma survival. AB - Several studies have proposed that protease expression and activity may have a predictive value in the survival of clear cell renal cell carcinoma (CCRCC). Most efforts on this issue have been focused on the analysis of matrix metalloproteinases (MMP) and very little on the role of other proteases, such as peptidases. The catalytic activity of 9 peptidases (APN, APB, ASP, CAP, DPP-IV, NEP/CD10, PEP, PGI, and PSA) was quantified by fluorometric methods in a series of 79 CCRCC patients, and the results obtained were analyzed for survival (Kaplan Meier curves, log-rank test, and Cox multivariate analysis). CCRCC patients with higher activity levels of membrane-bound APN and soluble APN, DPP-IV, and CAP had significantly shorter 5-yr survival rates than those with lower levels. By contrast, higher soluble APB activity significantly correlated with longer survival. Our data suggest the involvement of peptidases in the biological aggressiveness of CCRCC and support the usefulness of measuring these proteases to assess the prognosis of patients with CCRCC. PMID- 23019231 TI - A balancing act: protein-energy wasting in chronic kidney disease. PMID- 23019230 TI - Null mutations at the p66 and bradykinin 2 receptor loci induce divergent phenotypes in the diabetic kidney. AB - Candidate genes have been identified that confer increased risk for diabetic glomerulosclerosis (DG). Mice heterozygous for the Akita (Ins2(+/C96Y)) diabetogenic mutation with a second mutation introduced at the bradykinin 2 receptor (B2R(-/-)) locus express a disease phenotype that approximates human DG. Src homology 2 domain transforming protein 1 (p66) controls mitochondrial metabolism and cellular responses to oxidative stress, aging, and apoptosis. We generated p66-null Akita mice to test whether inactivating mutations at the p66 locus will rescue kidneys of Akita mice from disease-causing mutations at the Ins2 and B2R loci. Here we show null mutations at the p66 and B2R loci interact with the Akita (Ins2(+/C96Y)) mutation, independently and in combination, inducing divergent phenotypes in the kidney. The B2R(-/-) mutation induces detrimental phenotypes, as judged by increased systemic and renal levels of oxidative stress, histology, and urine albumin excretion, whereas the p66-null mutation confers a powerful protection phenotype. To elucidate the mechanism(s) of the protection phenotype, we turned to our in vitro system. Experiments with cultured podocytes revealed previously unrecognized cross talk between p66 and the redox-sensitive transcription factor p53 that controls hyperglycemia-induced ROS metabolism, transcription of p53 target genes (angiotensinogen, angiotensin II type-1 receptor, and bax), angiotensin II generation, and apoptosis. RNA interference targeting p66 inhibits all of the above. Finally, protein levels of p53 target genes were upregulated in kidneys of Akita mice but unchanged in p66 null Akita mice. Taken together, p66 is a potential molecular target for therapeutic intervention in DG. PMID- 23019232 TI - Glucagon-like peptide-1 receptor stimulation increases GFR and suppresses proximal reabsorption in the rat. AB - The incretin hormone glucagon-like peptide-1 (GLP-1) is released from the gut in response to fat or carbohydrate and contributes to negative feedback control of blood glucose by stimulating insulin secretion, inhibiting glucagon, and slowing gastric emptying. GLP-1 receptors (GLP-1R) are also expressed in the proximal tubule, and possibly elsewhere in the kidney. Presently, we examined the effect of a GLP-1R agonist on single-nephron glomerular filtration rate (GFR; SNGFR), proximal reabsorption (Jprox), tubuloglomerular feedback (TGF) responses, and urine flow rate in hydropenic male Wistar and Wistar-Froemter rats. Micropuncture and whole-kidney data were obtained before and during infusion of the GLP-1 agonist exenatide (1 nmol/h iv). SNGFR and Jprox were measured by late proximal collection at both extremes of TGF activation, which was achieved by perfusing Henle's loop at 0 or 50 nl/min. Primary changes in Jprox were revealed by analysis of covariance for Jprox with SNGFR as a covariate. Effects on TGF activation were determined in a separate set of experiments by comparing early distal and late proximal collections. Exenatide increased SNGFR by 33-50%, suppressed proximal tubular reabsorption by 20-40%, doubled early distal flow rate, and increased urine flow rate sixfold without altering the efficiency of glomerulotubular balance, TGF responsiveness, or the tonic influence of TGF. This implies that exenatide is both a proximal diuretic and a renal vasodilator. Since the natural agonist for the GLP-1R is regulated by intake of fat and carbohydrate, but not by salt or fluid, the control of salt excretion by the GLP 1R system departs from the usual negative-feedback paradigm for regulating salt balance. PMID- 23019233 TI - Lack of efficacy of bevacizumab + irinotecan in cases of pediatric recurrent ependymoma--a Pediatric Brain Tumor Consortium study. AB - A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in cases of pediatric recurrent ependymoma (EPN) to estimate sustained objective response rate and progression-free survival (PFS). Eligible patients received 2 doses of single-agent BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion-weighted and T1 dynamic contrast enhanced permeability imaging and tumor immunohistochemistry for vascular endothelial growth factor (VEGF)-A and -B, hypoxia inducible factor-2alpha, VEGF receptor (R)-2, and carbonic anhydrase (CA) 9. Thirteen evaluable patients received a median of 3 courses (range, 2-12) of BVZ + CPT-11. No sustained response was observed in any patient. Median time to progression in 10 patients was 2.2 months (range, 1.9-6.3). Two patients had stable disease for 10 months and 12 months, respectively. Six-month PFS was 25.7% (SE = 11.1%). Grades I-III toxicities related to BVZ treatment included fatigue in 4 patients, systemic hypertension in 2, epistaxis in 1, headache in 1, and avascular necrosis of bone in 1. Although there was a decrease in the mean diffusion ratio following 2 doses of BVZ, it did not correlate with PFS. BVZ + CPT-11 was well tolerated but had minimal efficacy in cases of recurrent EPN. PMID- 23019235 TI - Rare ADH variant constellations are specific for alcohol dependence. AB - AIMS: Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B*2, ADH1B*3 and ADH1C*2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF) <0.05] and alcohol dependence, with several other neuropsychiatric and neurological disorders as reference. METHODS: A total of 49,358 subjects in 22 independent cohorts with 11 different neuropsychiatric and neurological disorders were analyzed, including 3 cohorts with alcohol dependence. The entire ADH gene cluster (ADH7-ADH1C-ADH1B-ADH1A-ADH6-ADH4-ADH5 at Chr4) was imputed in all samples using the same reference panels that included whole-genome sequencing data. We stringently cleaned the phenotype and genotype data to obtain a total of 870 single nucleotide polymorphisms with 0< MAF <0.05 for association analysis. RESULTS: We found that a rare variant constellation across the entire ADH gene cluster was significantly associated with alcohol dependence in European-Americans (Fp1: simulated global P = 0.045), European Australians (Fp5: global P = 0.027; collapsing: P = 0.038) and African-Americans (Fp5: global P = 0.050; collapsing: P = 0.038), but not with any other neuropsychiatric disease. Association signals in this region came principally from ADH6, ADH7, ADH1B and ADH1C. In particular, a rare ADH6 variant constellation showed a replicable association with alcohol dependence across these three independent cohorts. No individual rare variants were statistically significantly associated with any disease examined after group- and region-wide correction for multiple comparisons. CONCLUSION: We conclude that rare ADH variants are specific for alcohol dependence. The ADH gene cluster may harbor a causal variant(s) for alcohol dependence. PMID- 23019236 TI - Understanding cultural issues in the diabetes self-management behaviors of Korean immigrants. AB - PURPOSE: The purpose of this study was to explore potential factors affecting the self-management behaviors of Korean immigrants with type 2 diabetes mellitus (KIT2Ds). METHODS: A qualitative descriptive design guided this study. Semistructured interviews lasting 45 to 60 minutes were conducted with 20 KIT2Ds in the participants' preferred language; in all cases, this was Korean. Each interview was audiotaped, transcribed, and analyzed using conventional content analysis. Data analysis was performed in two steps. The data written in Korean were initially analyzed by 3 bilingual researchers. A qualitative researcher then participated in the analysis to refine the findings for presentation to an English-speaking audience while staying true to the data and preserving the nuanced Korean meanings. RESULTS: The mean age of the sample was 64. 5 +/- 11.6 years (9 men and 11 women). The mean years of staying in the United States and age at diabetes mellitus diagnosis were 23.6 +/- 9.7 years and 52.5 +/- 12.3 years, respectively. Three major ideas were identified: (1) issues on treatment regimen related to medications and diet, (2) resources that helped or hindered ability to manage diabetes, and (3) the physician-patient relationship. CONCLUSIONS: Important cultural nuances need to be addressed to better prepare KIT2Ds to manage their diabetes more effectively. A culture-specific program should extend beyond a diabetes self-management education delivered in Korean language. Rather, content and education methods need to consider acculturation effects on diabetes management behaviors. PMID- 23019237 TI - Families United/Familias Unidas: development and implementation of a family-based group office visit model for the primary prevention of type 2 diabetes. AB - PURPOSE: The purpose of this study is to describe the development and implementation of a new diabetes prevention intervention that combines the benefits of family support with the group office model. Intensive lifestyle modification can effectively delay the onset of type 2 diabetes, yet health providers are challenged in translating these results to their patients. The group outpatient visit model can provide a means to address prevention issues in a financially sustainable manner. METHODS: Materials from the Diabetes Prevention Program and a previously developed group office visit program were combined to create the Families United/Familias Unidas curriculum. The session content utilized a multiculturally tailored approach designed to help participants decrease portion size, decrease carbohydrate intake, increase physical activity, and increase resiliency. Adults aged 18 to 70 were recruited who had any diabetes risk factors but did not have diabetes. Eligible participants enlisted a support person, aged 14 to 70, to join them in the 6-month group office visit intervention. RESULTS: Twenty-nine pairs (n = 58) of primary participants plus support persons were recruited. Participants' average age was 45; 74% were female; 56.9% identified themselves as white and 37.9% as Hispanic/Latino. Over one-third had 4 or more diabetes risk factors. Twelve family group office visits were delivered over 6 months. The attendance rate for those who attended at least one session was 72%. CONCLUSIONS: Group office visits can provide a new sustainable model for diabetes prevention and are a natural fit for primary care physicians in collaboration with other health care professionals, such as dieticians or diabetes educators. PMID- 23019238 TI - Risk for cervical intraepithelial neoplasia grade 3 or worse in relation to smoking among women with persistent human papillomavirus infection. AB - BACKGROUND: Smoking has been associated with cervical cancer. We examined whether smoking increases the risk for high-grade cervical lesions in women with high risk human papillomavirus (HPV) infection. METHODS: In a population-based cohort study, 8,656 women underwent a structured interview, and subsequently cervical cells were obtained for HPV DNA testing. Women with high-risk HPV infection and no prevalent cervical disease at baseline (n = 1,353) were followed through the Pathology Data Bank for cervical lesions for up to 13 years. Separate analyses of women with persistent high-risk HPV infection (n = 312) were also conducted. HRs for a diagnosis of cervical intraepithelial neoplasia grade 3 or worse/high-grade squamous intraepithelial lesions or worse (CIN3+) and the corresponding 95% confidence intervals (CI) were calculated in the two groups. RESULTS: Among high risk HPV-positive women, an increased risk for CIN3+ was associated with long term smoking (>=10 years) and heavy smoking (>=20 cigarettes/d). In the subgroup of women with persistent HPV infection, heavy smoking was also associated with a statistically significantly higher risk for CIN3+ than never smoking (HR, 1.85; 95% CI, 1.05-3.22, adjusted for length of schooling, parity, and HPV type at baseline). The average number of cervical cytology screening tests per year during follow-up did not explain the differences in risk in relation to smoking (P = 0.4). CONCLUSIONS: Smoking is associated with an increased risk for subsequent high-grade cervical lesions in women with persistent high-risk HPV infection. IMPACT: Our study adds to the understanding of the role of smoking in the natural history of HPV and cervical carcinogenesis. PMID- 23019239 TI - Assessing the process of designing and implementing electronic health records in a statewide public health system: the case of Colima, Mexico. AB - The findings of a case study assessing the design and implementation of an electronic health record (EHR) in the public health system of Colima, Mexico, its perceived benefits and limitations, and recommendations for improving the implementation process are presented. In-depth interviews and focus group discussions were used to examine the experience of the actors and stakeholders participating in the design and implementation of EHRs. Results indicate that the main driving force behind the use of EHRs was to improve reporting to the two of the main government health and social development programs. Significant challenges to the success of the EHR include resistance by physicians to use the ICD-10 to code diagnoses, insufficient attention to recurrent resources needed to maintain the system, and pressure from federal programs to establish parallel information systems. Operating funds and more importantly political commitment are required to ensure sustainability of the EHRs in Colimaima. PMID- 23019240 TI - Modeling temporal relationships in large scale clinical associations. AB - OBJECTIVE: We describe an approach for modeling temporal relationships in a large scale association analysis of electronic health record data. The addition of temporal information can inform hypothesis generation and help to explain the relationships. We applied this approach on a dataset containing 41.2 million time stamped International Classification of Diseases, Ninth Revision (ICD-9) codes from 1.6 million patients. METHODS: We performed two independent analyses including a pairwise association analysis using a chi(2) test and a temporal analysis using a binomial test. Data were visualized using network diagrams and reviewed for clinical significance. RESULTS: We found nearly 400 000 highly associated pairs of ICD-9 codes with varying numbers of strong temporal associations ranging from >=1 day to >=10 years apart. Most of the findings were not considered clinically novel, although some, such as an association between Helicobacter pylori infection and diabetes, have recently been reported in the literature. The temporal analysis in our large cohort, however, revealed that diabetes usually preceded the diagnoses of H pylori, raising questions about possible cause and effect. DISCUSSION: Such analyses have significant limitations, some of which are due to known problems with ICD-9 codes and others to potentially incomplete data even at a health system level. Nevertheless, large scale association analyses with temporal modeling can help provide a mechanism for novel discovery in support of hypothesis generation. CONCLUSIONS: Temporal relationships can provide an additional layer of meaning in identifying and interpreting clinical associations. PMID- 23019241 TI - ccML, a new mark-up language to improve ISO/EN 13606-based electronic health record extracts practical edition. AB - OBJECTIVE: The objective of this paper is to introduce a new language called ccML, designed to provide convenient pragmatic information to applications using the ISO/EN13606 reference model (RM), such as electronic health record (EHR) extracts editors. EHR extracts are presently built using the syntactic and semantic information provided in the RM and constrained by archetypes. The ccML extra information enables the automation of the medico-legal context information edition, which is over 70% of the total in an extract, without modifying the RM information. MATERIALS AND METHODS: ccML is defined using a W3C XML schema file. Valid ccML files complement the RM with additional pragmatics information. The ccML language grammar is defined using formal language theory as a single-type tree grammar. The new language is tested using an EHR extracts editor application as proof-of-concept system. RESULTS: Seven ccML PVCodes (predefined value codes) are introduced in this grammar to cope with different realistic EHR edition situations. These seven PVCodes have different interpretation strategies, from direct look up in the ccML file itself, to more complex searches in archetypes or system precomputation. DISCUSSION: The possibility to declare generic types in ccML gives rise to ambiguity during interpretation. The criterion used to overcome ambiguity is that specificity should prevail over generality. The opposite would make the individual specific element declarations useless. CONCLUSION: A new mark-up language ccML is introduced that opens up the possibility of providing applications using the ISO/EN13606 RM with the necessary pragmatics information to be practical and realistic. PMID- 23019242 TI - MEDLINE clinical queries are robust when searching in recent publishing years. AB - OBJECTIVE: To determine if the PubMed and Ovid MEDLINE clinical queries (which were developed in the publishing year 2000, for the purpose categories therapy, diagnosis, prognosis, etiology, and clinical prediction guides) perform as well when searching in current publishing years. METHODS: A gold standard database of recently published research literature was created using the McMaster health knowledge refinery (http://hiru.mcmaster.ca/hiru/HIRU_McMaster_HKR.aspx) and its continuously updated database, McMaster PLUS (http://hiru.mcmaster.ca/hiru/HIRU_McMaster_PLUS_projects.aspx). This database contains articles from over 120 clinical journals that are tagged for meeting or not meeting criteria for scientific merit and clinical relevance. The clinical queries sensitive ('broad') and specific ('narrow') search filters were tested in this gold standard database, and sensitivity and specificity were calculated and compared with those originally reported for the clinical queries. RESULTS: In all cases, the sensitivity of the highly sensitive search filters and the specificity of the highly specific search filters did not differ substantively when comparing results derived in 2000 with those derived in a more current database. In addition, in all cases, the specificities for the highly sensitive search filters and the sensitivities for the highly specific search filters remained above 50% when testing them in the current database. DISCUSSION: These results are reassuring for modern-day searchers. The clinical queries that were derived in the year 2000 perform equally well a decade later. CONCLUSION: The PubMed and Ovid MEDLINE clinical queries have been revalidated and remain a useful public resource for searching the world's medical literature for research that is most relevant to clinical care. PMID- 23019243 TI - Evaluation of serum cobalamin concentrations in dogs of 164 dog breeds (2006 2010). AB - Altered serum cobalamin concentrations have been observed in dogs with gastrointestinal disorders such as exocrine pancreatic insufficiency (EPI) or gastrointestinal inflammation. The aims of the current study were 1) to identify breeds with a higher proportion of dogs with a decreased serum cobalamin concentration, 2) to determine whether dogs with such decreased concentrations tend to have serum canine trypsin-like immunoreactivity (cTLI) concentrations diagnostic for EPI, and 3) to compare the number of submissions for serum cobalamin analysis by breed to the American Kennel Club (AKC) breed ranking list of 2009. In this retrospective study, results of 28,675 cobalamin tests were reviewed. Akitas, Chinese Shar-Peis, German Shepherd Dogs, Greyhounds, and Labrador Retrievers had increased proportions of serum cobalamin concentrations below the lower limit of the reference interval (<251 ng/l; all P < 0.0001). Akitas, Chinese Shar-Peis, German Shepherd Dogs, and Border Collies had increased proportions of serum cobalamin concentrations below the detection limit of the assay (<150 ng/l; all P < 0.0001). Akitas, Border Collies, and German Shepherd Dogs with serum cobalamin concentrations <150 ng/l were more likely to have a serum cTLI concentration considered diagnostic for EPI (<=2.5 ug/l; all P <= 0.001). The breed with the highest proportion of samples submitted for serum cobalamin analysis in comparison with the AKC ranking list was the Greyhound (odds ratio: 84.6; P < 0.0001). In Akitas and Border Collies, further investigations are warranted to clarify if a potentially breed-specific gastrointestinal disorder is responsible for the increased frequency of decreased serum cobalamin and cTLI concentrations. PMID- 23019244 TI - The occurrence of Bovine viral diarrhea virus in hunter-harvested white-tailed deer (Odocoileus virginianus) in the state of Georgia, southeastern United States. AB - The prevalence of Bovine viral diarrhea virus (BVDV) in free-ranging white-tailed deer (WTD, Odocoileus virginianus) in the state of Georgia was evaluated using ear notches collected from hunter-harvested deer during the hunting season of 2010-2011. From September to December 2010, 367 ear samples from WTD were collected from 37 counties in Georgia. The samples were from 178 (48.5%) female deer, 187 (51%) male deer, and 2 (0.5%) of unknown sex. The age of the animals varied from 6 months to 6.5 years. The age was not recorded in 34 animals (9.3%). Of the animals with known ages, 42% were under 2 years. Screening of 367 samples for BVDV using an antigen-capture enzyme-linked immunosorbent assay (AgELISA) resulted in 364 negative samples and 3 suspect samples. The 3 suspect samples were negative for BVDV reverse transcription polymerase chain reaction (RT-PCR), virus isolation, and immunohistochemistry. A subpopulation of samples (n = 89) selected from various geographical regions also tested negative for BVDV RT-PCR. In conclusion, although a few of the samples were suspect for the presence of BVDV by AgELISA, the presence of the virus within the deer population studied could not be confirmed further. PMID- 23019245 TI - Social perception in autism spectrum disorders: impaired category selectivity for dynamic but not static images in ventral temporal cortex. AB - Studies of autism spectrum disorders (ASDs) reveal dysfunction in the neural systems mediating object processing (particularly faces) and social cognition, but few investigations have systematically assessed the specificity of the dysfunction. We compared cortical responses in typically developing adolescents and those with ASD to stimuli from distinct conceptual domains known to elicit category-related activity in separate neural systems. In Experiment 1, subjects made category decisions to photographs, videos, and point-light displays of people and tools. In Experiment 2, subjects interpreted displays of simple, geometric shapes in motion depicting social or mechanical interactions. In both experiments, we found a selective deficit in the ASD subjects for dynamic social stimuli (videos and point-light displays of people, moving geometric shapes), but not static images, in the functionally localized lateral region of the right fusiform gyrus, including the fusiform face area. In contrast, no group differences were found in response to either static images or dynamic stimuli in other brain regions associated with face and social processing (e.g. posterior superior temporal sulcus, amygdala), suggesting disordered connectivity between these regions and the fusiform gyrus in ASD. This possibility was confirmed by functional connectivity analysis. PMID- 23019247 TI - In vivo imaging of neurovascular remodeling after stroke. PMID- 23019246 TI - Functional heterogeneity in posterior parietal cortex across attention and episodic memory retrieval. AB - While attention is critical for event memory, debate has arisen regarding the extent to which posterior parietal cortex (PPC) activation during episodic retrieval reflects engagement of PPC-mediated mechanisms of attention. Here, we directly examined the relationship between attention and memory, within and across subjects, using functional magnetic resonance imaging attention-mapping and episodic retrieval paradigms. During retrieval, 4 functionally dissociable PPC regions were identified. Specifically, 2 PPC regions positively tracked retrieval outcomes: lateral intraparietal sulcus (latIPS) indexed graded item memory strength, whereas angular gyrus (AnG) tracked recollection. By contrast, 2 other PPC regions demonstrated nonmonotonic relationships with retrieval: superior parietal lobule (SPL) tracked retrieval reaction time, consistent with a graded engagement of top-down attention, whereas temporoparietal junction displayed a complex pattern of below-baseline retrieval activity, perhaps reflecting disengagement of bottom-up attention. Analyses of retrieval effects in PPC topographic spatial attention maps (IPS0-IPS5; SPL1) revealed that IPS5 and SPL1 exhibited a nonmonotonic relationship with retrieval outcomes resembling that in the SPL region, further suggesting that SPL activation during retrieval reflects top-down attention. While demands on PPC attention mechanisms vary during retrieval attempts, the present functional parcellation of PPC indicates that 2 additional mechanisms (mediated by latIPS and AnG) positively track retrieval outcomes. PMID- 23019248 TI - Continuous positive airway pressure for treatment of obstructive sleep apnea in stroke survivors: what do we really know? PMID- 23019249 TI - Simultaneous analysis of SbIII, SbV and TMSb by high performance liquid chromatography-inductively coupled plasma-mass spectrometry detection: application to antimony speciation in soil samples. AB - This study was conducted to develop a method for the simultaneous separation and detection of antimonite (Sb(III)), antimonate (Sb(V)) and trimethyl antinmony (TMSb) species in soils, using ultrasonic-aided citric acid extraction and high performance liquid chromatography-inductively coupled plasma-mass spectrometry separation and detection. The extractions were performed using various chemical solutions. The separation was conducted on a PRP-X100 anion exchange column (25 cm * 4.1 mm i.d., 10 um) using an isocratic elution program. The various factors of the elution procedure, e.g., pH, elution concentration and retention time, were optimized for the best separation of the three Sb species. It was found that two consecutive extractions using 100 mmol/L citric acid at pH 2.03 resulted in the highest extraction efficiency, 53%. The optimal elution procedure was obtained by using 200 mmol/L ammonium tartrate with 4% methanol as the mobile phase at pH 5.0. Under these conditions, the retention times for Sb(III), Sb(V) and TMSb species were 3.8, 2.1 and 6.8 min with detection limits of 0.03, 0.02 and 0.05 ug/L, respectively. Spiked recoveries for Sb(III), Sb(V) and TMSb ranged from 88 to 118%. The proposed method is reliable for antimony speciation in soil samples. PMID- 23019250 TI - Quantifying glenoid bone loss in anterior shoulder instability: reliability and accuracy of 2-dimensional and 3-dimensional computed tomography measurement techniques. AB - BACKGROUND: Glenoid support is critical for stability of the glenohumeral joint. An accepted noninvasive method of quantifying glenoid bone loss does not exist. PURPOSE: To perform independent evaluations of the reliability and accuracy of standard 2-dimensional (2-D) and 3-dimensional (3-D) computed tomography (CT) measurements of glenoid bone deficiency. STUDY DESIGN: Descriptive laboratory study. METHODS: Two sawbone models were used; one served as a model for 2 anterior glenoid defects and the other for 2 anteroinferior defects. For each scapular model, predefect and defect data were collected for a total of 6 data sets. Each sample underwent 3-D laser scanning followed by CT scanning. Six physicians measured linear indicators of bone loss (defect length and width-to length ratio) on both 2-D and 3-D CT and quantified bone loss using the glenoid index method on 2-D CT and using the glenoid index, ratio, and Pico methods on 3 D CT. The intraclass correlation coefficient (ICC) was used to assess agreement, and percentage error was used to compare radiographic and true measurements. RESULTS: With use of 2-D CT, the glenoid index and defect length measurements had the least percentage error (-4.13% and 7.68%, respectively); agreement was very good (ICC, .81) for defect length only. With use of 3-D CT, defect length (0.29%) and the Pico(1) method (4.93%) had the least percentage error. Agreement was very good for all linear indicators of bone loss (range, .85-.90) and for the ratio linear and Pico surface area methods used to quantify bone loss (range, .84-.98). Overall, 3-D CT results demonstrated better agreement and accuracy compared to 2 D CT. CONCLUSION: None of the methods assessed in this study using 2-D CT was found to be valid, and therefore, 2-D CT is not recommended for these methods. However, the length of glenoid defects can be reliably and accurately measured on 3-D CT. The Pico and ratio techniques are most reliable; however, the Pico(1) method accurately quantifies glenoid bone loss in both the anterior and anteroinferior locations. Future work is required to implement valid imaging techniques of glenoid bone loss into clinical practice. CLINICAL RELEVANCE: This is one of the only studies to date that has investigated both the reliability and accuracy of multiple indicators and quantification methods that evaluate glenoid bone loss in anterior glenohumeral instability. These data are critical to ensure valid methods are used for preoperative assessment and to determine when a glenoid bone augmentation procedure is indicated. PMID- 23019251 TI - Shoulder range of motion deficits in baseball players with an ulnar collateral ligament tear. AB - BACKGROUND: Shoulder range of motion (ROM) deficits are associated with elbow injury in baseball players. PURPOSE: To compare the ROM characteristics of baseball players with a diagnosed ulnar collateral ligament (UCL) tear with those of a group of age-, activity-, and position-matched healthy controls. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Sixty male competitive high school and collegiate baseball players participated. Thirty athletes (age [mean +/- standard deviation], 18.20 +/- 1.56 years) with a diagnosed UCL tear were compared with 30 (age, 18.57 +/- 0.86 years) age-, activity-, and position-matched players without a UCL injury. Of the 60 participants, there were 44 pitchers, 4 catchers, 5 infielders, and 7 outfielders. Participants were measured for shoulder internal rotation (IR), external rotation (ER), and horizontal adduction (HA) at 90 degrees of shoulder elevation. Participants were also measured for elbow extension in a seated position. Group comparisons were made between participants with and without a UCL injury using independent t tests with an alpha level set at P < .05. All measurements were taken bilaterally, and the differences (involved to uninvolved) were used to calculate means for all variables, including glenohumeral internal rotation deficit (GIRD), total rotational motion (TRM), HA, and elbow extension. RESULTS: Baseball players with a UCL tear (UCLInj) exhibited significantly greater deficits in TRM compared with the control group of healthy baseball players (NUCLInj) (UCLInj = -6.67 degrees +/- 11.82 degrees , NUCLInj = 0.93 degrees +/- 9.91 degrees ; P = .009). No group differences were present for GIRD (UCLInj = -12.53 degrees +/- 5.98 degrees , NUCLInj = -13.63 degrees +/- 5.90 degrees ; P = .476), HA (UCLInj = -3.00 degrees +/- 5.01 degrees , NUCLInj = 3.23 degrees +/- 5.15 degrees ; P = .860), or elbow extension (UCLInj = -2.63 degrees +/- 7.86 degrees , NUCLInj = -1.17 degrees +/- 2.76 degrees ; P = .339). Pitchers with a UCL tear had significantly greater deficits in TRM (UCLInjPitch = -6.96 degrees +/- 11.20 degrees , NUCLInjPitch = 1.29 degrees +/ 8.33 degrees ; P = .0087) and dominant shoulder ER (UCLInjPitch = 112.04 degrees +/- 14.35 degrees , NUCLInjPitch = 121.85 degrees +/- 9.46 degrees ; P = .011) than pitchers without a UCL tear. CONCLUSION: A deficit in TRM is associated with a UCL tear in baseball players. Although GIRD may be prevalent in throwers, it may not be associated with a UCL injury. When examining ROM in baseball players, it is important to assess both TRM and GIRD. PMID- 23019252 TI - Magnetic resonance imaging after arthroscopic microfracture of capitellar osteochondritis dissecans. AB - BACKGROUND: Osteochondritis dissecans (OCD) of the capitellum affects young athletes involved in elbow load-bearing activities. Unstable lesions are best managed surgically, although debate remains regarding the optimal method. Arthroscopic treatment allows rapid recovery, but the effect on the articular surface is undetermined. HYPOTHESIS: The clinical outcome after arthroscopic microfracture of stage III/IV capitellum OCD would be successful in terms of return to sport and restoration of function, and there would be some evidence of articular restoration or repair. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We reviewed records of 10 consecutive adolescent patients (age <=18 years) with stage III or IV OCD lesions of the capitellum managed with arthroscopic microfracture. The mean age at the time of surgery was 13.9 years (range, 10.8-18.5 years); 7 patients were skeletally immature and 3 were skeletally mature. Pre- and postoperative functional assessment included active range of motion, Mayo Elbow Performance Score (MEPS), and Timmerman/Andrews elbow score. All patients underwent plain radiographic and magnetic resonance imaging (MRI) evaluation at a minimum of 12 months (mean, 27 months; range, 12-49 months) and clinical evaluation at a minimum of 24 months (mean, 42 months; range, 27-54 months) after surgery. RESULTS: The mean range of motion improved in both flexion (135.8 degrees ->140.7 degrees , P = .112) and extension (20.4 degrees ->-2.2 degrees , P = .005). The mean MEPS (70.5->97, P = .007) and Timmerman/Andrews elbow scores (116.4->193.0, P = .008) improved significantly. magnetic resonance imaging (MRI) evaluation demonstrated an improvement in overall joint congruence and the formation of a reparative articular surface in 8 of 10 (80%) patients. No reoperations or major complications were encountered. Six of 8 patients involved in competitive athletics returned to the same level of participation at an average of 5.1 months. CONCLUSION: Arthroscopic OCD fragment excision and capitellar microfracture demonstrates good to excellent functional results in short-term follow-up. Follow-up MRI suggests potential for a reparative fibrocartilaginous articular surface. Longer term follow-up is necessary to determine durability of the technique. PMID- 23019253 TI - Failure with continuity in rotator cuff repair "healing". AB - BACKGROUND: Ten to seventy percent of rotator cuff repairs form a recurrent defect after surgery. The relationship between retraction of the repaired tendon and formation of a recurrent defect is not well defined. PURPOSE/ HYPOTHESES: To measure the prevalence, timing, and magnitude of tendon retraction after rotator cuff repair and correlate these outcomes with formation of a full-thickness recurrent tendon defect on magnetic resonance imaging, as well as clinical outcomes. We hypothesized that (1) tendon retraction is a common phenomenon, although not always associated with a recurrent defect; (2) formation of a recurrent tendon defect correlates with the timing of tendon retraction; and (3) clinical outcome correlates with the magnitude of tendon retraction at 52 weeks and the formation of a recurrent tendon defect. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Fourteen patients underwent arthroscopic rotator cuff repair. Tantalum markers placed within the repaired tendons were used to assess tendon retraction by computed tomography scan at 6, 12, 26, and 52 weeks after operation. Magnetic resonance imaging was performed to assess for recurrent tendon defects. Shoulder function was evaluated using the Penn score, visual analog scale (VAS) score for pain, and isometric scapular-plane abduction strength. RESULTS: All rotator cuff repairs retracted away from their position of initial fixation during the first year after surgery (mean [standard deviation], 16.1 [5.3] mm; range, 5.7-23.2 mm), yet only 30% of patients formed a recurrent defect. Patients who formed a recurrent defect tended to have more tendon retraction during the first 6 weeks after surgery (9.7 [6.0] mm) than those who did not form a defect (4.1 [2.2] mm) (P = .08), but the total magnitude of tendon retraction was not significantly different between patient groups at 52 weeks. There was no significant correlation between the magnitude of tendon retraction and the Penn score (r = 0.01, P = .97) or normalized scapular abduction strength (r = -0.21, P = .58). However, patients who formed a recurrent defect tended to have lower Penn scores at 52 weeks (P = .1). CONCLUSION: Early tendon retraction, but not the total magnitude, correlates with formation of a recurrent tendon defect and worse clinical outcomes. "Failure with continuity" (tendon retraction without a recurrent defect) appears to be a common phenomenon after rotator cuff repair. These data suggest that repairs should be protected in the early postoperative period and repair strategies should endeavor to mechanically and biologically augment the repair during this critical early period. PMID- 23019254 TI - The president speaks: prevention is best: lessons from protecting the ozone layer. AB - The Montreal Protocol was signed 25 years ago. As a result, the irreversible destruction of the ozone layer was prevented. However, stratospheric ozone will not recover completely until 2060 and the consequent epidemic in skin cancer cases will persist until 2100. Many millions of patients with asthma and chronic obstructive pulmonary disease have safely switched from chlorofluorocarbon (CFC) powered metered-dose inhalers (MDIs) to either hydrofluorocarbon (HFC) or DPIs. China will be the last country to phase out CFCs by 2016. HFCs are global warming gases which will be controlled in the near future. HFCs in MDIs may be phased out over the next 10-20 years. PMID- 23019255 TI - Ethnicity and mycobacterial lineage as determinants of tuberculosis disease phenotype. AB - BACKGROUND: Emerging evidence suggests that Mycobacterium tuberculosis (Mtb) lineage and host ethnicity can determine tuberculosis (TB) clinical disease patterns but their relative importance and interaction are unknown. METHODS: We evaluated prospectively collected TB surveillance and Mtb strain typing data in an ethnically heterogeneous UK population. Lineage assignment was denoted using 15-loci mycobacterial interspersed repetitive units containing variable numbers of tandem repeats (MIRU-VNTR) and MIRU-VNTRplus. Geographical and ethnic associations of the six global Mtb lineages were identified and the influence of lineage and demographic factors on clinical phenotype were assessed using multivariate logistic regression. RESULTS: Data were available for 1070 individuals with active TB which was pulmonary only, extrapulmonary only and concurrent pulmonary-extrapulmonary in 52.1%, 36.9% and 11.0% respectively. The most prevalent lineages were Euro-American (43.7%), East African Indian (30.2%), Indo-Oceanic (13.6%) and East Asian (12.2%) and were geo-ethnically restricted with, for example, Indian subcontinent ethnicity inversely associated with Euro American lineage (OR 0.23; 95% CI 0.14 to 0.39) and positively associated with the East African-Indian lineage (OR 4.04; 95% CI 2.19 to 7.45). Disease phenotype was most strongly associated with ethnicity (OR for extrathoracic disease 21.14 (95% CI 6.08 to 73.48) for Indian subcontinent and 14.05 (3.97 to 49.65) for Afro Caribbean), after adjusting for lineage. With East Asian lineage as the reference category, the Euro-American (OR 0.54; 95% CI 0.32 to 0.91) and East-African Indian (OR 0.50; 95% CI 0.29 to 0.86) lineages were negatively associated with extrathoracic disease, compared with pulmonary disease, after adjusting for ethnicity. CONCLUSIONS: Ethnicity is a powerful determinant of clinical TB phenotype independently of mycobacterial lineage and the role of ethnicity associated factors in pathogenesis warrants investigation. PMID- 23019256 TI - Lower prevalence of tuberculosis infection in BCG vaccinees: a cross-sectional study in adult prison inmates. AB - OBJECTIVES: To address whether the effect of BCG vaccination against tuberculosis (TB) infection lasts to adulthood. METHODS: A cross-sectional study on the prevalence of latent TB infection (LTBI) among HIV-negative men, using QuantiFERON-TB Gold In-tube (QFT-IT), was conducted at a prison in northern Taiwan with >3000 inmates. A QFT-IT >=0.35 IU/ml was defined as LTBI. A QFT-IT >=0.7 IU/ml was defined as recent LTBI. The association between the number of BCG scars and LTBI stratified by age was analysed. The study procedure was approved by the institutional review board, and all participants gave written informed consent before receiving screening tests. RESULTS: Among the 2385 participants, 25% had a QFT-IT >=0.35 IU/ml. Increasing LTBI (14%, 32% and 50%) was observed with increased age (18-34 years, 35-54 years and >=55 years) (p<0.001 by the Cochran-Armitage Trend Test). The number of BCG scars were found to be inversely correlated with QFT-IT results for both LTBI and recent LTBI in all three age groups (p<0.001 by Cochran-Mantel-Haenszel statistics). CONCLUSIONS: Our results suggest that BCG vaccine seems to have a protective effect in adults decades after vaccination according to the number of recent infections (QFT-IT >=0.7 IU/ml). This finding has important implications for national policy of BCG vaccination. Further prospective cohort studies on the protective effect of BCG vaccination against TB infection in adults are warranted. PMID- 23019257 TI - Forced vital capacity as a primary end point in idiopathic pulmonary fibrosis treatment trials: making a silk purse from a sow's ear. PMID- 23019258 TI - Correlation of cognitive impairment and thalamic atrophy in MS: for men only? PMID- 23019259 TI - Injury markers predict time to dementia in subjects with MCI and amyloid pathology. AB - OBJECTIVES: Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology. METHODS: We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of beta-amyloid(1-42) (Abeta(1-42)) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models. RESULTS: We included 110 subjects with MCI with abnormal CSF Abeta(1-42) and a mean MMSE score of 26.3 +/- 2.8. During a mean follow-up of 2.2 +/- 1.0 (range 0.4-5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1-4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3-9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1-5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0-55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score. CONCLUSIONS: In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline. PMID- 23019260 TI - Bid signal pathway components are identified in the temporal cortex with Parkinson disease. AB - OBJECTIVE: Parkinson disease (PD), a devastating neurodegenerative disorder, affects motor abilities and cognition as well. It is not clear whether the proapoptotic protein, Bid, is involved in tumor necrosis factor death receptor I (TNFRI)-mediated destructive signal transduction pathways such as cell dysfunction or neurodegeneration in the temporal cortex of patients with PD. METHODS: Molecular and biochemical approaches were used to dissect mitochondrial related components of the destructive signaling pathway in the temporal cortex from rapidly autopsied brains (postmortem interval mean 2.6 hours). Brains from patients with PD (n = 15) had an average age of 81.4 years, compared to the average age of 84.36 years in age-matched control patient brains (n = 15). RESULTS: TNFRI and its adaptor protein, TRADD, were not only present in the cytoplasm of the temporal cortex, but were significantly elevated (42.3% and 136.1%, respectively) in PD brains compared to age-matched control brains. Bid in the PD temporal cortex could be further cleaved into tBid in the cytosol, which is translocated into the mitochondria, where cytochrome c is then released and caspase-3 is subsequently activated. CONCLUSION: Patients with PD have an activated Bid-mediated destructive signal pathway via TNFRI in the temporal cortex. Such deficits are pervasive, suggesting that they might contribute to cortex degeneration as PD manifests. PMID- 23019261 TI - Molecular mechanisms of cortical degeneration in Parkinson disease. PMID- 23019262 TI - Incidence of mild cognitive impairment in the Pittsburgh Cardiovascular Health Study-Cognition Study. AB - OBJECTIVES AND METHODS: The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 years) in the Cardiovascular Health Study-Cognition Study from 1998-1999 to 2010-2011. RESULTS: Two hundred (70%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95% confidence interval, 88.13-142.95) per 1,000 person-years. A total of 107 (53.5%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 +/- 1.8 years. Forty (20%) of the incident MCI cases had an "unstable" course: 19 (9.5%) converted to MCI and later returned to normal; 10 (5%) converted to MCI, to normal, and later back to MCI; 7 (3.5%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years). CONCLUSIONS: The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts. PMID- 23019263 TI - Ocular hyperintense acute reperfusion marker. PMID- 23019264 TI - Reversion from mild cognitive impairment to normal or near-normal cognition: risk factors and prognosis. AB - OBJECTIVES: We sought to identify characteristics of individuals with mild cognitive impairment (MCI) that are associated with a relatively high probability of reverting back to normal cognition, and to estimate the risk of future cognitive decline among those who revert. METHODS: We first studied 3,020 individuals diagnosed with MCI on at least 1 visit to an Alzheimer's Disease Center in the United States. All underwent standardized Uniform Data Set evaluations at their first visit with an MCI diagnosis and on a subsequent visit, about 1 year later, at which cognitive status was reassessed. Multiple logistic regression was used to identify predictors of reverting from MCI back to normal cognition. We then estimated the risk of developing MCI or dementia over the next 3 years among those who had reverted, compared with individuals who had not had a study visit with MCI. RESULTS: About 16% of subjects diagnosed with MCI reverted back to normal or near-normal cognition approximately 1 year later. Five characteristics assessed at the first MCI visit contributed significantly to a model predicting a return to normal cognition: Mini-Mental State Examination (MMSE) score, Clinical Dementia Rating (CDR) score, MCI type, Functional Activities Questionnaire (FAQ) score, and APOE epsilon4 status. Survival analysis showed that the risk of retransitioning to MCI or dementia over the next 3 years was sharply elevated among those who had MCI and then improved, compared with individuals with no history of MCI. CONCLUSIONS: Even in a cohort of patients seen at dementia research centers, reversion from MCI was fairly common. Nonetheless, those who reverted remained at increased risk for future cognitive decline. PMID- 23019265 TI - Subcortical atrophy and cognition: sex effects in multiple sclerosis. AB - OBJECTIVES: Gray matter (GM) atrophy is common in multiple sclerosis (MS), as is cognitive dysfunction. Understanding the exact relationship between atrophy and cognition requires further investigation. The aim of this study was to investigate the relationship between subcortical GM atrophy and cognition in early relapsing onset MS. METHODS: Structural MRI and neuropsychological evaluations were performed in 120 patients (80 women) and 50 controls (30 women), part of an early inception cohort, 6 years postdiagnosis. Deep GM volumes were segmented automatically. Cognition was assessed in 7 domains. Stepwise linear regression was used to predict average cognition in the patient group. RESULTS: Most deep GM volumes were reduced in patients, with larger effects on average in men (-11%) than in women (-6.3%). Only the bilateral hippocampus, amygdala, and right nucleus accumbens in men, and right hippocampus and nucleus accumbens, bilateral amygdala, and putamen in women, showed no atrophy compared to controls. All cognitive domains except visuospatial memory were affected in men; none were significantly affected in women. In the MS group, average cognition was best predicted by thalamic volume, sex, and education (adjusted R(2) = 0.31), while lesion volume was not a significant predictor in the model. CONCLUSIONS: Six years postdiagnosis, almost all subcortical structures were affected by MS, especially in men. Cognition was most severely affected in male patients. Thalamic volume, sex, and education best predicted average cognition. These results underline the relevance of specific subcortical structures to cognition, as well as the relevance of (sex-specific) atrophy in MS. PMID- 23019266 TI - Vestibular migraine: long-term follow-up of clinical symptoms and vestibulo cochlear findings. AB - OBJECTIVE: The aim of the study was to assess the evolution of clinical symptoms and vestibulo-cochlear function in patients with definite vestibular migraine (dVM). METHODS: We reassessed 61 patients (54 women, 7 men, aged 24-76 years) with dVM according to validated diagnostic criteria after a median follow-up time of 9 years (range, 5.5-11). Assessment comprised a clinical interview and neurotologic examination, including pure-tone audiometry and caloric testing. RESULTS: The majority of patients (87%) had recurrent vertigo at follow-up. Frequency of vertigo was reduced in 56%, increased in 29%, and unchanged in 16%. Impact of vertigo was severe in 21%, moderate in 43%, and mild in 36%. Eighteen percent reported mild persistent unsteadiness. Interictal ocular motor abnormalities had increased from 16% initially to 41% of patients at follow-up. The most frequent finding was positional nystagmus (PN), in 28%, including definite central-type PN in 18%. However, only 1 of 9 patients with ocular motor abnormalities at initial presentation showed similar findings on follow-up. Concomitant cochlear symptoms with vertigo had increased from 15% initially to 49%. Eleven patients (18%) had developed mild bilateral sensorineural hearing loss, which also involved the low-frequency range. CONCLUSIONS: The majority of patients continue to have recurrent vertigo in the long-term evolution of VM, and the impact of vertigo may remain severe. Whereas interictal ocular motor abnormalities may show some variation over time, vestibulo-cochlear dysfunction progresses slowly in some patients with VM. Interictal central-type PN may help distinguish VM from peripheral vestibular disorders such as Meniere disease. PMID- 23019267 TI - Past exposure to neuroleptic drugs and risk of Parkinson disease in an elderly cohort. AB - OBJECTIVE: Neuroleptics and neuroleptic-like drugs are known to induce parkinsonism, which may reveal underlying Parkinson disease (PD) in some cases. We assessed the long-term risk of developing PD after past exposure to these drugs, in a 15-year prospective population-based elderly cohort study. METHODS: We used the Cox proportional hazards model to assess the relation between past exposure to neuroleptics and the risk of developing incident PD. All incident cases of parkinsonism were identified by standardized procedure and validated by a committee of experts. RESULTS: Of 2,991 subjects followed, 117 developed parkinsonism and 43 developed probable PD during follow-up, of whom 22.2% and 32.6%, respectively, had been exposed to neuroleptics, compared to 16.6% for subjects without parkinsonism. About a third of subjects presented transient parkinsonism during drug exposure. After adjustment for gender and past occupation, past exposure to neuroleptics was associated with incident PD (relative risk, 3.16; 95% confidence interval [CI], 1.65-6.04). The relative risk was 3.65 (95% CI, 1.41-9.45) for benzamides and 2.59 (95% CI, 1.23-5.43) for phenothiazines. The population-attributable fraction of the risk for developing PD was 8.2% for benzamides and 12.2% for phenothiazines. CONCLUSIONS: In a French elderly cohort, the risk of probable PD was increased by 3.2-fold after exposure to neuroleptics. This finding suggests the necessity of limiting the use of such drugs in elderly people. PMID- 23019268 TI - Quality of life in children with new-onset epilepsy: a 2-year prospective cohort study. AB - OBJECTIVES: To assess health-related quality of life (HRQL) over 2 years in children 4-12 years old with new-onset epilepsy and risk factors. METHODS: Data are from a multicenter prospective cohort study, the Health-Related Quality of Life Study in Children with Epilepsy Study (HERQULES). Parents reported on children's HRQL and family factors and neurologists on clinical characteristics 4 times. Mean subscale and summary scores were computed for HRQL. Individual growth curve models identified trajectories of change in HRQL scores. Multiple regression identified baseline risk factors for HRQL 2 years later. RESULTS: A total of 374 (82) questionnaires were returned postdiagnosis and 283 (62%) of eligible parents completed all 4. Growth rates for HRQL summary scores were most rapid during the first 6 months and then stabilized. About one-half experienced clinically meaningful improvements in HRQL, one-third maintained their same level, and one-fifth declined. Compared with the general population, at 2 years our sample scored significantly lower on one-third of CHQ subscales and the psychosocial summary. After controlling for baseline HRQL, cognitive problems, poor family functioning, and high family demands were risk factors for poor HRQL 2 years later. CONCLUSIONS: On average, HRQL was relatively good but with highly variable individual trajectories. At least one-half did not experience clinically meaningful improvements or declined over 2 years. Cognitive problems were the strongest risk factor for compromised HRQL 2 years after diagnosis and may be largely responsible for declines in the HRQL of children newly diagnosed with epilepsy. PMID- 23019269 TI - Auditory threshold, phonologic demand, and incident dementia. AB - OBJECTIVE: This study was undertaken to investigate the association of auditory threshold with cognitive decline and dementia. METHODS: The 1,057 surviving men of the Caerphilly cohort with audiometric data at baseline were followed for 17 years for cognitive outcomes. Pure-tone unaided audiometric threshold was assessed at 0.5, 1, 2, and 4 KHz at baseline and after 9 years. Incident dementia was assessed according to DSM-IV criteria, including standard criteria for vascular dementia and for Alzheimer disease. Cognitive decline was assessed by repeat administration of a cognitive test battery. RESULTS: Mean age-adjusted auditory threshold across both time points was associated with incident dementia and cognitive decline. After adjustment for premorbid cognitive function, the association with dementia was retained (odds ratio(0.5 KHz) = 2.67; 95% confidence interval, 1.38-5.18; p = 0.004). Stronger associations with cognitive decline were found for tests administered by interview than for those administered by computer. CONCLUSIONS: This study has found an association of auditory threshold with dementia and cognitive decline over a 17-year period. The mechanisms underlying this association are unclear and may include a prodromal effect of dementia on auditory threshold, an effect of auditory threshold on cognitive assessment, an effect of auditory threshold on cognitive loss, or a shared etiologic pathway between both. PMID- 23019270 TI - Multiple origins of the determinate growth habit in domesticated common bean (Phaseolus vulgaris). AB - BACKGROUND AND AIMS: The actual number of domestications of a crop is one of the key questions in domestication studies. Answers to this question have generally been based on relationships between wild progenitors and domesticated descendants determined with anonymous molecular markers. In this study, this question was investigated by determining the number of instances a domestication phenotype had been selected in a crop species. One of the traits that appeared during domestication of common bean (Phaseolus vulgaris) is determinacy, in which stems end with a terminal inflorescence. It has been shown earlier that a homologue of the arabidopsis TFL1 gene - PvTFL1y - controls determinacy in a naturally occurring variation of common bean. METHODS: Sequence variation was analysed for PvTFL1y in a sample of 46 wild and domesticated accessions that included determinate and indeterminate accessions. KEY RESULTS: Indeterminate types - wild and domesticated - showed only synonymous nucleotide substitutions. Determinate types - observed only among domesticated accessions - showed, in addition to synonymous substitutions, non-synonymous substitutions, indels, a putative intron splicing failure, a retrotransposon insertion and a deletion of the entire locus. The retrotransposon insertion was observed in 70 % of determinate cultivars, in the Americas and elsewhere. Other determinate mutants had a more restricted distribution in the Americas only, either in the Andean or in the Mesoamerican gene pool of common bean. CONCLUSIONS: Although each of the determinacy haplotypes probably does not represent distinct domestication events, they are consistent with the multiple (seven) domestication pattern in the genus Phaseolus. The predominance of determinacy in the Andean gene pool may reflect domestication of common bean prior to maize introduction in the Andes. PMID- 23019272 TI - Editorial commentary. Viva no difference! PMID- 23019271 TI - Improvement in the health of HIV-infected persons in care: reducing disparities. AB - BACKGROUND: Despite advances in human immunodeficiency virus (HIV) treatment, major challenges remain in achieving access, retention, and adherence. Our inner city HIV clinical practice in Baltimore has a diverse patient population with high rates of poverty, black race, and injection drug use (IDU), providing us the opportunity to compare health process and outcomes. METHODS: Using data collected in a clinical HIV cohort in Baltimore, we compared receipt of combination antiretroviral therapy (ART), HIV type 1 (HIV-1) RNA, CD4, incidence of opportunistic illness, and mortality from 1995 to 2010. Comparisons were made of these outcomes by HIV risk group, sex, and race (black, white). RESULTS: From 1995 to 2010, we followed 6366 patients comprising 27 941 person-years (PY) of follow-up. By 2010, 87% of patients were receiving ART; median HIV-1 RNA was <200 copies/mL, median CD4 was 475 cells/mm(3), opportunistic illness rates were 2.4 per 100 PY, and mortality rates were 2.1 per 100 PY, with no differences by demographic or HIV risk group. The only differences were that the IDU risk group had a median CD4 that was 79 cells/mm(3) lower and HIV-1 RNA 0.16 log(10 )copies/mL higher compared with other risk groups (P < .01). In 2009 a 28-year old HIV-infected person was estimated to have 45.4 years of life remaining, which did not differ by demographic or behavioral risk group. DISCUSSION: Our results emphasize that advances in HIV treatment have had a positive impact on all affected demographic and behavioral risk groups in an HIV clinical setting, with an expected longevity for HIV-infected patients that is now 73 years. PMID- 23019274 TI - Novel assays for detection of urinary KIM-1 in mouse models of kidney injury. AB - Kidney injury molecule-1 (KIM-1) has been qualified by the Food and Drug Administration and European Medicines Agency as a urinary biomarker to monitor preclinical nephrotoxicity in rats and on a case-by-case basis for the translation of potentially nephrotoxic drugs into first-in human studies. Although mouse models are widely employed in preclinical studies, few urinary biomarker studies have been performed in mice due to limited urine availability and lack of sensitive assays. Here, we report the development and validation of two different assays for quantitative assessment of mouse urinary KIM-1 (uKIM-1) and compare the sensitivity of KIM-1 relative to other standard markers in ischemia reperfusion and aristolochic acid (AA)-induced kidney injury in mice. A sensitive, reproducible, and quantitative microbead-based KIM-1 ELISA was established, which requires only 10 MUl urine for triplicate determination with an assay range of 12.21 pg/ml to 50 ng/ml. The second assay is a laminar flow dipstick assay, which has an assay range of 195 pg/ml to 50 ng/ml and provides quantitative assessment of KIM-1 in 15 min. uKIM-1 levels increased with increasing time of ischemia or time after AA administration. After only 10-min ischemia followed by 24-h reperfusion, uKIM-1 was significantly elevated by 13 fold, whereas serum creatinine (sCr), blood urea nitrogen, N-acetyl-beta glucosaminidase (NAG), and proteinuria levels did not change. After AA administration, uKIM-1 levels were significantly upregulated by greater than threefold within 12 h, whereas sCr and NAG levels were unchanged. Mouse KIM-1 was stable for multiple freeze-thaw cycles, for up to 5 days at room temperature and up to at least an year when stored at -80 degrees C. PMID- 23019275 TI - Demonstration of blood pressure-independent noninfarct myocardial fibrosis in primary aldosteronism: a cardiac magnetic resonance imaging study. AB - BACKGROUND: Primary aldosteronism (PA) is common and associates with excess cardiovascular morbidity independent of blood pressure. Exposure to aldosterone and sodium leads to cardiac fibrosis and hypertrophy in humans and animals possibly mediated by inflammation and oxidative stress. We aimed to clarify the effects of aldosterone excess on myocardial structure and composition in human subjects with PA and essential hypertension using contrast-enhanced cardiac magnetic resonance imaging as well as explore the mechanistic basis for any observed differences. METHODS AND RESULTS: Twenty-seven subjects with recently diagnosed PA and 54 essential hypertension controls were recruited. Subjects underwent gadolinium-enhanced cardiac magnetic resonance; noninfarct related myocardial fibrosis was identified by a diffuse pattern of late gadolinium enhancement. Patients also underwent assessment of pulse wave velocity, measurement of circulating superoxide anion and C-reactive protein, as well as blood pressure and biochemical assessment. Subjects were well matched with no difference in severity or duration of hypertension. There was a significant increase in the frequency of noninfarct late gadolinium enhancement in PA (70%) when compared with essential hypertension subjects (13%; P<0.0001) with no difference in left ventricular mass. Pulse wave velocity, superoxide, and C reactive protein were significantly higher in subjects with PA. CONCLUSIONS: These data illustrate that patients with PA exhibit frequent myocardial fibrosis as demonstrated by late gadolinium enhancement using cardiac magnetic resonance imaging; this finding is independent of blood pressure. This may be mediated partly through inflammation and oxidative stress. This study highlights the importance of specific targeting of aldosterone excess as well as blood pressure reduction to minimize cardiac morbidity in PA. PMID- 23019276 TI - Goserelin with chemotherapy to preserve ovarian function in pre-menopausal women with early breast cancer: menstruation and pregnancy outcomes. AB - BACKGROUND: Premature ovarian failure and infertility following chemotherapy in early breast cancer (EBC) are major concerns for young women. The role of gonadotrophin-releasing hormone (GnRH) agonists with chemotherapy in EBC in reducing the incidence of chemotherapy-induced early menopause remains uncertain, and long-term data on the recovery of fertility are sparse. We report an audit of our experience with the GnRH agonist, goserelin (Zoladex(r)), used with chemotherapy to preserve ovarian function and maintain fertility. PATIENTS AND METHODS: Pre-menopausal women were given goserelin subcutaneously every 28 days during chemotherapy, starting 0-14 days before treatment. The main clinical end point was recovery of menstruation after chemotherapy. The other end points were rate of successful conception and median time to recovery of menses. RESULTS: About 84% of 125 women recovered menstruation with the median time to recovery of 6 months (1-43 months), including 76% of 71 patients aged over 35. Of the 42 patients who attempted pregnancy, 71% (n=30) managed to achieve pregnancies. At the time of analysis, there were 42 pregnancies and 30 healthy deliveries. CONCLUSIONS: The GnRH agonist, goserelin, given with chemotherapy for EBC is associated with a low risk of long-term chemotherapy-induced amenorrhoea and a high chance of pregnancy. Further randomised trials are needed. PMID- 23019273 TI - A cross-country comparison of secondhand smoke exposure among adults: findings from the Global Adult Tobacco Survey (GATS). AB - OBJECTIVE: Exposure to secondhand smoke (SHS) from burning tobacco products causes disease and premature death among non-smoking adults and children. The objective of this study was to determine the nature, extent and demographic correlates of SHS exposure among adults in low- and middle-income countries with a high burden of tobacco use. METHODS: Data were obtained from the Global Adult Tobacco Survey (GATS), a nationally representative household survey of individuals 15 years of age or older. Interviews were conducted during 2008-2010 in Bangladesh, Brazil, China, Egypt, India, Mexico, the Philippines, Poland, Russia, Thailand, Turkey, Ukraine, Uruguay and Vietnam. Descriptive statistics were used to determine the prevalence and correlates of SHS exposure in homes, workplaces, government buildings, restaurants, public transportation and healthcare facilities. RESULTS: Exposure to SHS in the home ranged from 17.3% (Mexico) to 73.1% (Vietnam). Among those who work in an indoor area outside the home, SHS exposure in the workplace ranged from 16.5% (Uruguay) to 63.3% (China). Exposure to SHS ranged from 6.9% (Uruguay) to 72.7% (Egypt) in government buildings, 4.4% (Uruguay) to 88.5% (China) in restaurants, 5.4% (Uruguay) to 79.6% (Egypt) on public transportation, and 3.8% (Uruguay) to 49.2% (Egypt) in healthcare facilities. CONCLUSIONS: A large proportion of adults living in low- and middle-income countries are exposed to SHS in their homes, workplaces, and other public places. Countries can enact and enforce legislation requiring 100% smoke-free public places and workplaces, and can also conduct educational initiatives to reduce SHS exposure in homes. PMID- 23019277 TI - Patient-doctor agreement on recall of clinical trial discussion across cultures. AB - BACKGROUND: The purpose was to investigate patient-doctor agreement on clinical trial discussion cross-culturally. METHODS: In the International Breast Cancer Study Group Trial 33-03 on shared decision-making for early breast cancer in Australian/New Zealand (ANZ) and Swiss/German/Austrian (SGA) centers, doctor and patient characteristics plus doctor stress and burnout were assessed. Within 2 weeks post-consultation about treatment options, the doctor and patient reported independently, whether a trial was discussed. Odds ratios of agreement for covariables were estimated by generalized estimating equations for each language cohort, with doctor as a random effect. RESULTS: In ANZ, 21 doctors and 339 patients were eligible; in SGA, 41 doctors and 427 patients. In cases where the doctor indicated 'no trial discussed', 82% of both ANZ and SGA patients agreed; if the doctor indicated 'trial discussed', 50% of ANZ and 38% of SGA patients agreed, respectively. Factors associated with higher agreement were: low tumor grade and fewer patients recruited into clinical trials in SGA; public institution, patient born in ANZ (versus other), higher doctor depersonalization and personal accomplishment in ANZ. CONCLUSION: There is discordance between oncologists and their patients regarding clinical trial discussion, particularly when the doctor indicates that a trial was discussed. Factors contributing to this agreement vary by culture. PMID- 23019279 TI - Early intervention for psychosis in Asia. PMID- 23019278 TI - Does the body mass index reflect cardiovascular risk factors in Brazilian children? AB - This cross-sectional study aimed to: (i) investigate whether obesity and overweight defined according to body mass index (BMI) are good predictors of body fat excess, abdominal adiposity and hypertension in 769 Brazilian children aged 6 11 years, (ii) assess the relationship between overweight/obesity and cardiovascular risk factors. Overweight and obesity were estimated using cut-off points corresponding to World Health Organization 1 and 2 SD (standard deviation) scores. Based on the results of a multiple logistic regression analysis, overweight and obesity were significantly associated with body fat excess, abdominal adiposity and hypertension. The prevalence of obesity (10.7%), overweight (18.7%), abdominal adiposity (17.6%) and systolic (10.1%) and diastolic hypertension (9.3%) was high in this population of Brazilian children. The cardiovascular risk factors increased significantly according to the BMI SD scores, indicating that in epidemiologic studies, BMI may be a good indicator of risk for cardiovascular diseases. PMID- 23019280 TI - Early psychosis declaration for Asia by the Asian Network of Early Psychosis. AB - In line with the Early Psychosis Declaration issued by the World Health Organization and the International Early Psychosis Association, as well as the International Clinical Practice Guidelines for early psychosis by the latter in 2005, increasing interest in early intervention programmes is evident throughout Asia. Experience sharing and close collaboration that take into account the unique Asian context are needed to facilitate development of early psychosis services, education, and research in the region. The Asian Network of Early Psychosis has defined a set of Asian-specific principles to guide best practice in mental health care delivery for psychotic disorders in Asia. These principles are outlined in this paper. PMID- 23019281 TI - Early intervention for first-episode psychosis in India. AB - OBJECTIVE: There have been very few studies of first-episode psychoses or early intervention programmes in India. This paper describes a pilot intervention programme for first-episode psychosis at the Schizophrenia Research Foundation, India. METHODS: A total of 47 patients with the first episode of psychosis were followed up for 2 years. Based on the Positive and Negative Syndrome Scale for schizophrenia and Global Assessment of Functioning Scale scores, the data from 2 groups of patients, those who had remission and those who did not, were identified and compared. Assessments done at 3, 6, 12 and 24 months after recruitment enabled computation of time to achieve remission. RESULTS: Complete data were available for 38 patients (28 patients in remission group and 10 patients in non-remission group) at 2 years. Baseline scores were not significantly different between the groups. In the remission group, more than 50% attained maximal improvement at 3 months, another 30% at 1 year, and the remaining 20% at 2 years. Maximal reduction in the mean Positive and Negative Syndrome Scale score was seen between 3 and 6 months after recruitment. CONCLUSIONS: With regular treatment, most patients with early psychosis achieve remission within 2 years. Negative symptoms persisting for longer than 6 months could be an indicator of long-term outcome. Early intervention is feasible and effective in developing countries. PMID- 23019282 TI - Developments in early intervention for psychosis in Hong Kong. AB - The year 2011 marked the 10-year milestone of early intervention for psychosis in Hong Kong. Since 2001, the landscape of early psychosis services has changed markedly in Hong Kong. Substantial progress has been made in the areas of early intervention service implementation, knowledge generation, and public awareness promotion. Favourable outcomes attributable to the early intervention service are supported by solid evidence from local clinical research studies; early intervention service users showed improved functioning, ameliorated symptoms, and decreased hospitalisation and suicide rates. Continued development of early intervention in Hong Kong over the decade includes the introduction and maturation of several key platforms, such as the Hospital Authority Early Assessment Service for Young People with Psychosis programme, the Psychosis Studies and Intervention Unit by the University of Hong Kong, the Hong Kong Early Psychosis Intervention Society, the Jockey Club Early Psychosis Project, and the postgraduate Psychological Medicine (Psychosis Studies) programme. In this paper, we reviewed some of the major milestones in local service development with reference to features of the Hong Kong mental health system. We describe chronologically the implementation and consolidation of public early intervention services as well as recent progresses in public awareness work that are tied in with knowledge generation and transfer, and outline the prospects for early intervention in the next decade and those that follow. PMID- 23019283 TI - Development of an early psychosis intervention system in Korea: focus on the continuing care system for first-episode psychosis treatment in Seoul. AB - Providing intensive psychosocial intervention within the 5-year critical period following the first psychotic episode is important for both symptomatic and functional recovery. Recently, community mental health centres in Korea have begun to shift their main roles from care of those with chronic schizophrenia to early detection of and interventions for those with first-episode psychosis. This pioneering approach was initiated by the Seoul Mental Health Center, which established a community network, formed a clinical consortium with hospitals and clinics, and developed guidelines for early psychosis detection and management and for the Social Treatment for Early Psychosis (STEP) programme. The One-STEP programme, provided during hospitalisation, has been especially efficient in obtaining a high acceptance rate for community services. Several key issues are discussed with regard to the successful establishment of the close partnership between community mental health centres and hospitals / clinics. PMID- 23019284 TI - Clinical practice at a multi-dimensional treatment centre for individuals with early psychosis in Japan. AB - Early intervention for psychosis in Japan has lagged behind that in western countries, but has rapidly begun to attract attention in recent years. As part of a worldwide trend, a multi-dimensional treatment centre for early psychosis consisting of a Youth Clinic, which specialises in young individuals with an at risk mental state for psychosis, and Il Bosco, a special day-care service for individuals with early psychosis, was initiated at the Toho University Omori Medical Center in Japan in 2007. The treatment centre aims to provide early intervention to prevent the development of full-blown psychosis in patients with an at-risk mental state and intensive rehabilitation to enable first-episode schizophrenia patients to return to the community. We presently provide the same programmes for both groups at Il Bosco. However, different approaches may need to be considered for patients with an at-risk mental state and for those with first episode schizophrenia. More phase-specific and need-specific services will be indispensable for early psychiatric interventions in the future. PMID- 23019285 TI - Evolution of early psychosis intervention services in Singapore. AB - The alarmingly long duration of untreated psychosis in Singapore and probable severe consequences were the impetus for establishing the Early Psychosis Intervention Programme in 2001. In 2007, the Early Psychosis Intervention Programme became a part of the National Mental Health Blueprint. This study analysed the Early Psychosis Intervention Programme's key outcomes according to the case management model, and shows how the programme has evolved and expanded into indicated prevention by establishment of the Support for Wellness Achievement Programme focusing on at-risk mental state. The Early Psychosis Intervention Programme has incorporated an evaluation component into the clinical programme by administering regular structured assessments and generating operational statistics from the hospital's data systems. Based on data analysis from a study on consecutive patients accepted into the Early Psychosis Intervention Programme over a 4-year period, we found that at the end of 2 years of follow-up, majority of patients (85%) scored >= 61 on Global Assessment of Functioning (GAF) disability scale, while two-thirds (66%) met criteria for functional remission, which was defined as having a GAF disability score of >= 61 with engagement in age-appropriate vocation (gainfully employed or studying). There was also a significant decrease in the Positive and Negative Syndrome Scale for schizophrenia (t = 27.7, p < 0.05) and increase in GAF (t = 33.7, p < 0.05) mean scores from baseline at 2 years. As a national programme, the Early Psychosis Intervention Programme has articulated processes and outcome indicators to the stakeholders, and a periodic report card on these outcomes ensures accountability to the funders, patients, and their families. PMID- 23019286 TI - Identification of vulnerability among first-degree relatives of patients with schizophrenia. AB - OBJECTIVES: To evaluate the status of schizotypy, neurological soft signs, and cognitive functions as vulnerability markers for schizophrenia and to investigate the potential value of their combination for early identification of people at high risk for schizophrenia. METHODS: A cross-sectional study was conducted. Subjects were drawn from first-degree relatives of inpatients and outpatients with schizophrenia (n = 50). Controls (n = 30) were recruited by word-of-mouth from hospital staff and attendants of hospitalised patients. Subjects who met inclusion criteria on screening were subjected to selected measures for assessment, including Schizotypal Personality Questionnaire-Brief Version, the Cambridge Neurological Inventory, digit span test, paired associate learning test, and visuospatial working memory matrix. Statistical analysis was completed using the independent t test and significance (p value), as well as calculation of effect size (Cohen's d). Discriminant function analysis was used to determine the effect of combining assessment measures. RESULTS: First-degree relatives showed higher schizotypy scores (Cohen's d = 0.88) and neurological soft signs (Cohen's d = 1.55). They scored significantly worse on all neurocognitive measures (Cohen's d = -1.27). Discriminant function analysis showed that Schizotypal Personality Questionnaire-Brief Version, neurological soft signs, and total cognitive index (the sum of weighted scores on individual cognitive scales) in combination better discriminated between the first-degree relative and control groups (Wilks' lambda = 0.54). CONCLUSION: Use of multiple vulnerability markers could enhance the specificity of measures used to determine risk for schizophrenia. PMID- 23019288 TI - Medical students' specialty choices. PMID- 23019287 TI - Schizophrenia and suicide. AB - OBJECTIVE: Schizophrenia is characterised by distorted thinking and perception and tends to run a chronic course. The World Health Organization reported that suicide accounts for almost 2% of the world's deaths. There is a close relationship between schizophrenia and suicide. Patients with schizophrenia experience personal distress and socio-occupational dysfunction and reduced life expectancy as a group. The current article presents a review of suicide in schizophrenia. DATA SOURCES: The literature search included MEDLINE, CINHAL, EMBASE, and Cochrane Controlled Trials Register databases. STUDY SELECTION: Search terms used included 'schizophrenia', 'suicide', 'positive symptoms', 'negative symptoms', 'self-harm', 'anti-psychotics', 'risk factors' in different combinations. DATA EXTRACTION: We included epidemiological findings, socio demographical variables, symptom profiles, biological underpinnings, risk factors, and management issues. No publication year limits were applied but the search was restricted to articles in English. The abstracts of articles retrieved in the search were manually scanned. DATA SYNTHESIS: Male gender and being unmarried are associated with an increased risk of suicide among individuals with schizophrenia. The presence of depression and depressive features is associated with an increased risk of suicidality. An association between insight into the illness, a consequent feeling of hopelessness, and increased risk of suicide has also been a consistent finding. In contrast the role of schizophrenia subtype in suicidal risk remains controversial. CONCLUSIONS: To date, the impact of specific pharmacotherapeutic agents and non-pharmacological interventions on the suicidal behaviour of individuals with schizophrenia is also yet to be fully explored by robust research. PMID- 23019289 TI - Safely ruling out inflammatory bowel disease in children and teenagers without referral for endoscopy. AB - BACKGROUND: Up to 70% of children and teenagers referred to a paediatric gastroenterology centre with suspected inflammatory bowel disease (IBD) do not have the disease. OBJECTIVE: To evaluate whether faecal calprotectin as an 'add on test' improves the specificity of the clinical case definition for suspected IBD in a general paediatric practice. DESIGN: A prospective diagnostic accuracy study. SETTING: Six outpatient clinics for general paediatrics and one tertiary care hospital in the Netherlands. PATIENTS: 117 children and teenagers with a clinical suspicion of IBD. DIAGNOSTIC TESTS: Faecal calprotectin was measured (index test) in all patients. Patients with a high index of suspicion on the basis of the paediatrician's global assessment, physical examination and blood results were referred for endoscopy (reference standard). Children and teenagers who were not selected for endoscopy initially were followed for half a year for the appearance of possible additional symptoms (delayed type reference standard). PRIMARY OUTCOME: The proportion of referred patients with confirmed IBD. RESULTS: The mean age of patients was 14 years (range 6-18). A total of 42 (36%) had confirmed IBD. The paediatricians, who were blinded to the faecal calprotectin result, referred 68 children and teenagers for endoscopy. If they had referred only those patients with a positive faecal calprotectin result (>50 MUg/g), 54 patients would have undergone endoscopy. LIMITATION: The study relied on clinical follow-up to detect missed IBD. CONCLUSIONS: A diagnostic strategy in general paediatric practice of using a simple clinical case definition for suspected IBD in combination with a positive faecal calprotectin result increases the specificity to detect IBD and reduces the need for referral to a paediatric gastroenterology centre with a very low risk of missing cases. PMID- 23019290 TI - Interferon-gamma release assays for the diagnosis of tuberculosis in children. PMID- 23019291 TI - Targeted sarcoplasmic reticulum Ca2+ ATPase 2a gene delivery to restore electrical stability in the failing heart. AB - BACKGROUND: Recently, we reported that sarcoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a), the pump responsible for reuptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with impaired myocardial calcium handling, deficient SERCA2a, and increased susceptibility to cardiac alternans. Therefore, we hypothesized that restoring deficient SERCA2a by gene transfer will significantly reduce arrhythmogenic cardiac alternans in the failing heart. METHODS AND RESULTS: Adult guinea pigs were divided into 3 groups: control, HF, and HF+AAV9.SERCA2a gene transfer. HF resulted in a decrease in left ventricular fractional shortening compared with controls (P<0.001). As expected, isolated HF myocytes demonstrated slower sarcoplasmic reticulum calcium uptake, decreased Ca(2+) release, and increased diastolic Ca(2+) (P<0.05) compared with controls. Moreover, SERCA2a, cardiac ryanodine receptor 2, and sodium-calcium exchanger protein expression was decreased in HF compared with control (P<0.05). As predicted, HF increased susceptibility to cardiac alternans, as evidenced by decreased heart rate thresholds for both V(m) alternans and Ca alternans compared with controls (P<0.01). Interestingly, in vivo gene transfer of AAV9.SERCA2a in the failing heart improved left ventricular contractile function (P<0.01), suppressed cardiac alternans (P<0.01), and reduced ryanodine receptor 2 P(o) secondary to reduction of ryanodine receptor 2-P(S2814) (P<0.01). This ultimately resulted in a decreased incidence of inducible ventricular arrhythmias (P=0.05). CONCLUSIONS: These data show that SERCA2a gene transfer in the failing heart not only improves contractile function but also directly restores electric stability through the amelioration of key arrhythmogenic substrate (ie, cardiac alternans) and triggers (ie, sarcoplasmic reticulum Ca(2+) leak). PMID- 23019292 TI - SERCA2a gene therapy for the prevention of sudden cardiac death: a future theranostic for heart failure? PMID- 23019293 TI - Outcomes of Medicare beneficiaries undergoing catheter ablation for atrial fibrillation. AB - BACKGROUND: Atrial fibrillation is common among older persons. Catheter ablation is increasingly used in patients for whom medical therapy has failed. METHODS AND RESULTS: We conducted a retrospective cohort study of all fee-for-service Medicare beneficiaries >=65 years of age who underwent catheter ablation for atrial fibrillation between July 1, 2007, and December 31, 2009. The main outcome measures were major complications within 30 days and mortality, heart failure, stroke, hospitalization, and repeat ablation within 1 year. A total of 15 423 patients underwent catheter ablation for atrial fibrillation. Mean age was 72 years; 41% were women; and >95% were white. For every 1000 procedures, there were 17 cases of hemopericardium requiring intervention, 8 cases of stroke, and 8 deaths within 30 days. More than 40% of patients required hospitalization within 1 year; however, atrial fibrillation or flutter was the primary discharge diagnosis in only 38.4% of cases. Eleven percent of patients underwent repeat ablation within 1 year. Renal impairment (hazard ratio, 2.07; 95% confidence interval, 1.66-2.58), age >=80 years (hazard ratio, 3.09; 95% confidence interval, 2.32-4.11), and heart failure (hazard ratio, 2.54; 95% confidence interval, 2.07-3.13) were major risk factors for 1-year mortality. Advanced age was a major risk factor for all adverse outcomes. CONCLUSIONS: Major complications after catheter ablation for atrial fibrillation were associated with advanced age but were fairly infrequent. Few patients underwent repeat ablation. Randomized trials are needed to inform risk-benefit calculations for older persons with drug-refractory, symptomatic atrial fibrillation. PMID- 23019295 TI - Adverse cardiac remodeling: phosphoinositide 3-kinase, another unique factor in a multifactorial condition. PMID- 23019294 TI - Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. AB - BACKGROUND: Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum- and glucocorticoid regulated kinase-1 (SGK1), in heart failure and its complications. METHODS AND RESULTS: We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart by using cardiac-specific expression of constitutively active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The proarrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations. CONCLUSIONS: SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease. PMID- 23019296 TI - A prospective randomized multicentre study comparing vaginal progesterone gel and vaginal micronized progesterone tablets for luteal support after in vitro fertilization/intracytoplasmic sperm injection. AB - SUMMARY QUESTION: Is vaginal progesterone gel equivalent to vaginal micronized progesterone tablets concerning ongoing pregnancy rate and superior concerning patient convenience when used for luteal support after IVF/ICSI? SUMMARY ANSWER: Equivalence of treatments in terms of ongoing live intrauterine pregnancy rate has not been demonstrated; the 95% confidence interval (CI) for the difference in ongoing pregnancy rate (-8.2 to 0.1%) did not lie entirely within the pre specified equivalence interval -7 to 7%. WHAT IS KNOWN ALREADY: No significant differences in clinical pregnancy rates have been observed between vaginal progesterone gel and other vaginal progesterone products in earlier studies. However, all previous studies included a limited number of patients. STUDY DESIGN, SIZE AND DURATION: This was a randomized, multicentre, controlled, assessor-blinded equivalence trial in 18 fertility centres in Denmark and Sweden between March 2006 and January 2010. A web-based randomization program was used with concealed allocation of patients. Patients were randomized to one of two groups: vaginal progesterone gel or vaginal micronized progesterone tablets. There was no blinding of patients. PARTICIPANTS AND SETTING: A total of 2057 women <= 40 years of age were included and down-regulated, using the long agonist protocol and rFSH for stimulation. Luteal support was given for 19 days after embryo transfer or until a negative pregnancy test Day 14 after embryo transfer. Patient convenience was assessed using questionnaires to be filled in 14 days after embryo transfer, before pregnancy test. MAIN RESULTS AND THE ROLE OF CHANCE: Ongoing intrauterine pregnancy rates were 299/991 (30.2%) (95% CI 27.3 33.0%) in the progesterone gel group and 324/992 (32.7%) (29.7-35.6%) in the micronized progesterone tablet group. The difference in ongoing pregnancy rates between the groups was -4.1% (-8.2 to 0.1%) and the difference in live birth rates was -3.4% (-7.4 to 0.7%), both calculated after correction for significant confounders. Patient convenience and ease of use (1 = very convenient, 10 = very inconvenient) was in favour of progesterone gel, as the overall score was 2.9 (2.7-3.0) for progesterone gel and 4.8 (4.7-5.0; P < 0.0001) for micronized progesterone tablets. This large equivalence trial shows that, even though equality could not be demonstrated, there is no substantial difference in ongoing pregnancy rate between vaginal progesterone gel and vaginal micronized progesterone tablets. It also shows that progesterone gel is considered more convenient by the patients. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: Blinding of patients was not possible in this study, but since the outcome (pregnancy) is robust, blinding would have been unlikely to affect the results. Unfortunately, owing to an error in the randomization, the intended age distribution allocated older women to the micronized progesterone tablet group. In the analysis of results, adjustments were made for age and number of embryos transferred. GENERALIZABILITY TO OTHER POPULATIONS: The results can be generalized to other women >= 18 and <= 40 years of age undergoing IVF/ICSI who have regular menstrual cycles (25-35 days), both ovaries present and no more than two previous failed IVF attempts. STUDY FUNDING/COMPETING INTEREST: Merck Serono supported the study but had no influence on the design of the study and was not involved in the analysis of the results or preparation of the manuscript. TRIAL REGISTRATION NUMBER: The trial was issued with the EudraCT number 2005-001248-22 with the Protocol code number 95576471. PMID- 23019297 TI - The follicular hormonal profile in low-responder patients undergoing unstimulated cycles: Is it hypoandrogenic? AB - STUDY QUESTION: What is the final hormonal milieu of pre-ovulatory follicles of low-responder (LR) patients undergoing unstimulated cycles? SUMMARY ANSWER: Neither androgen secretion nor LH was impaired in pre-ovulatory follicles of LR women. WHAT IS KNOWN ALREADY: Therapies currently used to improve ovarian response in LR women have an impact on the final hormonal follicular milieu, and these changes are believed to be partially responsible for determining the success rate in these women. Surprisingly, as far as we know, there is no report of the final hormonal profile of LR women undergoing unstimulated cycles or evidence that follicular androgen secretion in LR women is impaired. STUDY DESIGN, SIZE AND DURATION: A prospective case-control study including 94 women, 36 normal controls and 58 LR patients (19 Young <= 35 years LR and 39 Aged >35 years LR) from 2009 to 2011. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Fifty eight LR women were divided into two groups: Young LR (age <= 35; n = 19) and Aged LR (ALR; age >35; n = 39). The control group (group C) comprised 36 egg donors undergoing an unstimulated cycle in our IVF unit. Serum and follicular fluid hormonal concentrations for estradiol (E2), progesterone, testosterone and androstendione were measured. The spindle parameters of metaphase II oocytes generated from these groups were also analysed. MAIN RESULTS AND THE ROLE OF CHANCE: Pre-ovulatory follicles from LR patients had similar androgenic and LH concentrations to those observed in the control group. However, higher intrafollicular concentrations of FSH and progesterone were observed in ALR. Moreover, no differences were found for the spindle evaluation of oocytes between groups by the Oosight technology. LIMITATIONS, REASONS FOR CAUTION: The controls were younger and had a lower BMI than the LR women. The sample size available restricted statistical power. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that the problem with LR women is not the final pre-ovulatory follicular androgen concentration since this is similar to normal responders, but in the ability to respond to controlled ovarian stimulation protocols. Therefore, efforts should be focused on long-interval androgen priming to potentially increase the recruitment of small antral follicles rather than increasing the intraovarian androgen levels within the current cycle. STUDY FUNDING/COMPETING INTEREST: The present project has been supported by the R+D programme from the Generalitat Valenciana (Regional Valencian Government) IMPIVA MIDTF/2010/95. The authors have no conflict of interest to declare. PMID- 23019298 TI - The impact of social relations among men and women in fertility treatment on the decision to terminate treatment. AB - STUDY QUESTION: Do social support and social strain from social relations have an impact on the decision to terminate fertility treatment among men and women after 1 year of unsuccessful treatment? SUMMARY ANSWER: Several functional aspects of social relations show an impact on the probability to terminate treatment; social support from family significantly decreases the probability to terminate and experience of conflicts or problematic communication with the partner significantly increases the probability to terminate treatment. WHAT IS KNOWN ALREADY: Fertility patients can experience psychological, physical and economical strain as consequences of infertility and fertility treatment, and previous studies have shown that these pressures increase the probability of deciding to terminate treatment before the treatment options are exhausted. Some studies have indicated that social relations can also have an effect. STUDY DESIGN, SIZE, DURATION: This study is part of the prospective Infertility Cohort from the Copenhagen Multi-centre Psychosocial Infertility Research Programme. Baseline data were collected during January 2000-August 2001 among patients recruited at five Danish fertility clinics during their initial visit and follow-up data were collected after 1 year. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study group (n = 777; 427 women, 350 men) consisted of patients who did not achieve a live birth or an ongoing pregnancy during follow-up. Social support and strain from the patients' partner, family, family-in-law, friends and colleagues were measured at baseline and the decision to terminate treatment while treatment options were not yet exhausted was measured as the outcome at the 1-year follow up. MAIN RESULTS AND THE ROLE OF CHANCE: At the 1-year follow-up, 23% of the study group had decided to terminate treatment. For women, low levels of family support, specifically with regard to infertility, were associated with the termination of treatment after 1 year [odds ratio (OR) 6.1, 95% confidence interval (CI) 2.2-16.8] and, for men, low levels of general family support had a similar impact (OR 2.6, 95% CI 1.0-7.0). For men, difficulties in communicating with their partner about the infertility increased the probability of terminating the treatment (OR 2.3, 95% CI 1.2-4.1) and, for women, frequent conflicts with their partner increased the probability of terminating the treatment (OR 12.4, 95% CI 2.9-54.1). For women, conflicts with friends were also a predictor of treatment termination (OR 2.2, 95% CI 1.2-4.2). WIDER IMPLICATIONS OF THE FINDINGS: Functional aspects of social relations have an impact on the decision to terminate fertility treatment among men and women. The findings in this study provide new insights into how the close social environment can have implications for men and women going through fertility treatment. FUNDING: This study has received support from the Danish Health Insurance Fund (J.nr. 11/097-97), the Else and Mogens Wedell-Wedellsborgs Fund, the manager E. Danielsens and Wife's Fund, the merchant L.F. Foghts Fund, the Jacob Madsen and Wife Olga Madsen's Fund, and the Engineer K.A. Rohde and Wife's Fund. The authors have no conflicts of interest to declare. PMID- 23019299 TI - Reproducibility of AMH. PMID- 23019300 TI - Semen apoptotic M540 body levels correlate with testis abnormalities: a study in a cohort of infertile subjects. AB - STUDY QUESTION: What are the associations between semen apoptotic M540 bodies and other parameters of semen quality and sonographic alterations of the male genital tract in a cohort of infertile subjects? SUMMARY ANSWER: In infertile subjects, semen M450 bodies are highly correlated with ultrasound and clinical signs of testis abnormalities but not with alterations of other parts of the male genital tract, suggesting a testicular origin of M540 bodies. WHAT IS KNOWN ALREADY: We have reported the presence in semen of round anucleate elements, named 'M540 bodies', resembling apoptotic bodies as they contain several apoptotic markers. STUDY DESIGN AND SIZE: A consecutive series of 130 males with couple infertility were evaluated, during the same day session, for clinical, scrotal and transrectal color-Doppler ultrasound characteristics, and hormonal and semen parameters, including interleukin 8 (sIL-8) and M540 body levels. PARTICIPANTS/MATERIALS, SETTING METHODS: Semen parameters were analyzed by WHO recommended procedures. CDU was performed using the ultrasonographic console Hitachi H21. sIL-8 and serum hormones were evaluated by ELISA methods. MAIN RESULTS AND THE ROLE OF CHANCE: The average percentage value of M540 bodies was 24.6 +/- 18.3. After adjusting for possible confounders (age, waist, calculated free testosterone and smoking habit), M450 body levels negatively correlated with sperm number/ejaculate, progressive motility, normal morphology and sIL-8 levels (adj.r = -0.455, P < 0.0001; adj.r = -0.464, P < 0.0001; adj.r = -0.430, P < 0.001; adj.r = -0.236, P < 0.05, respectively). In a subset of patients with a history of cryptorchidism (n = 8), M540 bodies were higher than in non cryptorchid men (40.5 +/- 14.8 versus 23.6 +/- 18.2%; P < 0.02). A negative correlation was found between M540 and ultrasound testis volume (adj.r = -0.241, P < 0.05), whereas a positive association was found with testis inhomogeneity [HR = 1.06 (1.02-1.09); P = 0.002], hypoechogenicity [HR = 1.05 (1.01-1.08); P < 0.02] and FSH levels (adj.r = 0.309, P < 0.01). No relationships were found with CDU characteristic of the prostate, seminal vesicles, epididymis and vas deferens. In a multivariate model, testis inhomogeneity and history of cryptorchidism were independently associated with M540 body levels (adj.r = 0.355, P < 0.01 and adj.r = 0.223, P < 0.05, respectively). Receiver operating characteristic analysis demonstrated that at the threshold of 27%, M540 bodies discriminate subjects with testis inhomogeneity with a sensitivity of 72% and specificity of 73%. LIMITATIONS, REASONS FOR CAUTION: The increased M540 body semen levels in men with a history of cryptorchidism should be confirmed in a larger number of patients. WIDER IMPLICATIONS OF THE FINDINGS: M540 bodies may be considered a semen marker of altered testis function and thus their evaluation may be helpful in the diagnosis of male infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from Ministry of University and Scientific Research (Prin project to E.B. and FIRB project to S.M.) and Regione Toscana (to G.F.). PMID- 23019301 TI - CD4+ CD25+ FOXP3+ regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis. AB - STUDY QUESTION: Is endometriosis associated with changes in CD4+ CD25+ FOXP3+ regulatory T cells (Treg cells)? SUMMARY ANSWER: Endometriosis is associated with disturbed compartmentalization of CD25(high) FOXP3+ Treg cells. WHAT IS KNOWN ALREADY: Endometriosis is associated with an abrogated immune response and displays some features of an autoimmune disorder. Treg cells play a part in the development of autoimmune reactions; however, their role in pathogenesis of endometriosis is still poorly recognized. STUDY DESIGN, SIZE AND DURATION: Case control study comparing 17 women with laparoscopically and histopathologically confirmed ovarian endometriosis with 15 control women without visible endometriosis foci, pelvic inflammation or related pathology who were subjected to laparoscopic surgery between 2010 and 2011. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Peripheral blood and peritoneal fluid were collected during laparoscopy and T cell subpopulations were analysed by flow cytometry using specific monoclonal antibodies recognizing CD4+, CD25+ and FOXP3+ markers. MAIN RESULTS: The percentage of CD25(high) FOXP3+ Treg cells was significantly decreased in the peripheral blood of women with ovarian endometriosis compared with control women. On the other hand, the proportion of these cells was significantly increased in the peritoneal fluid of women with endometriosis. LIMITATIONS, REASONS FOR CAUTION: The present study is limited to patients with ovarian endometrioma and further investigations are needed, including patients with lower grade of endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: The present results suggest that Treg cells may play a part in immunopathogenesis of endometriosis being responsible for abrogated local cellular immune responses and facilitation and development of autoimmune reactions. Treg cells may be thus a potential target in the treatment of endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by 1M15/N/2011 and NK1W grants from the I Faculty of Medicine, Warsaw Medical University. None of the authors has any competing interests to declare. PMID- 23019302 TI - BMI-related metabolic composition of the follicular fluid of women undergoing assisted reproductive treatment and the consequences for oocyte and embryo quality. AB - STUDY QUESTION: Is the metabolic composition of the follicular fluid of women undergoing assisted reproductive treatment (ART) related to serum composition and BMI and is it associated with oocyte and embryo quality? SUMMARY ANSWER: We showed that metabolic alterations in the serum are reflected in the follicular fluid and that some of these alterations may affect oocyte quality, irrespective of BMI. WHAT IS KNOWN ALREADY: Many studies have focused on the effect of metabolic disorders, such as obesity and type 2 diabetes, on assisted reproduction outcomes. There are, however, only few studies focusing on the importance of the correlation between serum and follicular fluid compositions and the composition of the follicular fluid as the oocyte's micro-environment, affecting its development and subsequent embryo quality. DESIGN, PARTICIPANTS AND SETTING: In this prospective cohort study, patient information, fertility treatment outcome data, follicular fluid and serum were obtained from women undergoing ART. Patients were categorized according to their BMI (kg/m(2)) as normal (n = 60), overweight (n = 26) or obese (n = 20). Serum and follicular fluid samples were analyzed for urea, total protein, albumin, cholesterol, high density lipoprotein cholesterol, triglycerides, non-esterified fatty acids, apolipoprotein A1, apolipoprotein B, glucose, lactate, C-reactive protein, insulin-like growth factor -1 (IGF-1), IGF-binding protein 3 (only in follicular fluid), free carnitine and total carnitine. Metabolite concentrations in serum and follicular fluid samples were correlated and were associated with BMI and fertility treatment outcome. MAIN RESULTS: Most serum metabolite differences between patients were reflected in the follicular fluid (P < 0.05). Follicular fluid apolipoprotein A1 and follicular fluid total protein concentrations negatively affected oocyte quality parameters (P < 0.05). However, overall BMI related associations were poor. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: In this study, we included every patient willing to participate. Within this cohort, women with a BMI transcending 35 kg/m(2) were scarce (n = 2), because extremely overweight women are mostly advised to lose weight before starting ART. Furthermore, the number of patients in each BMI group was different, possibly masking associations between the metabolic composition of serum and follicular fluid and oocyte quality parameters. GENERALIZABILITY TO OTHER POPULATIONS: There were significant associations indicating that metabolic changes in the serum are reflected in the follicular fluid, potentially affecting oocyte quality, irrespective of the patient's BMI. For ethical reasons, this study only focused on women already in need of artificial reproductive treatment. From a metabolic point of view, we consider this cohort as a representative sample of all women of reproductive age. STUDY FUNDING: This study was funded by the special research fund, university of Antwerp (BOF UA). None of the authors has any conflict of interest to declare. PMID- 23019303 TI - Integrity of the blood-testis barrier in healthy men after suppression of spermatogenesis with testosterone and levonorgestrel. AB - STUDY QUESTION: Do exogenous male hormonal contraceptives that suppress intratesticular testosterone and spermatogenesis interfere with the blood-testis barrier integrity in men? SUMMARY ANSWER: When spermatogenesis was suppressed by testosterone alone or combined with levonorgestrel (LNG) treatment in men, the structural appearance of Sertoli cell tight junctions remained intact in the human testis. WHAT IS ALREADY KNOWN: Testosterone promotes the integrity of the blood-testis barrier. Intratesticular androgen deprivation induced by exogenous testosterone plus a progestin to suppress spermatogenesis in a contraceptive regimen may disturb the structural and functional integrity of the blood-testis barrier. STUDY DESIGN, SIZE AND DURATION: Testicular biopsies were obtained from a sub-study of a randomized clinical trial of 36 healthy Chinese men who were treated for 18 weeks and followed for at least a 12-week recovery period. PARTICIPANTS/MATERIAL, SETTING, METHODS: Healthy Chinese male volunteers (27-48 years) were randomized to two treatment groups (n = 18/group) for 18 weeks: (1) testosterone undecanoate (TU) 1000 mg i.m. injection followed by a 500 mg injection every 6 weeks and (2) TU + LNG 250 MUg orally daily. Blood samples were obtained from all participants before and during treatment and at the end of the recovery phase. Open testicular biopsies for this study were obtained from four men before treatment and from four men in each of the TU and TU + LNG groups at 2 and 9 weeks of treatment. The presence of antisperm antibodies was checked in the archived serum samples of the subjects at baseline, during treatment and at the end of the recovery period. Stored testicular biopsy samples from cynomolgus monkeys treated with either sub-cutaneous testosterone or placebo for 12 weeks were used for additional protein expression studies. MAIN RESULTS AND ROLE OF THE CHANCE: Expression of blood-testis barrier associated proteins quantified by immunohistochemistry (claudin 3, claudin 11, junctional adhesion molecule-A, zonula occludens-1) remained unchanged despite a significant decrease in the numbers of pachytene spermatocytes and round spermatids in the seminiferous tubules at 9 weeks in the TU + LNG group. This was confirmed by immunoblots showing a lack of quantitative change in these tight junction proteins in monkeys after testosterone treatment. There were no increases in serum antisperm antibodies in the volunteers during the study. LIMITATIONS/REASONS FOR CAUTION: The duration of the study was short and the long-term effects of male hormonal contraceptive treatments on the integrity of the blood-testis barrier remain to be determined. WIDER IMPLICATIONS OF THE FINDINGS: This study supports the safety of male hormonal contraceptive treatment and does not corroborate the previous findings of disturbed immunological integrity of the blood-testis barrier from animal studies such as androgen receptor knockout mice and exogenous hormonal treatment in rats. STUDY FUNDING/COMPETING INTEREST: The study was supported by grants from the Contraceptive Research and Development Program and the Mellon Foundation (MFG-02-64, MFG-03-67), Endocrine, Metabolism and Nutrition Training Grant (T32 DK007571), the Clinical and Translational Science Institute at Los Angeles Biomedical and Harbor-UCLA Medical Center (UL1RR033176 and UL1TR000124) and the Los Angeles Biomedical Research Institute Summer High School Student Program. PMID- 23019304 TI - MR-guided focus ultrasound (MRgFUS) for symptomatic uterine fibroids: predictors of treatment success. AB - STUDY QUESTION: What are the factors associated with long-term success in patients with symptomatic uterine fibroids treated by magnetic resonance-guided focus ultrasound (MRgFUS) and can they be employed to create a clinically useful index that predicts long-term efficacy? SUMMARY ANSWER: Hypo-intense fibroids on T2-weighted magnetic resonance imaging (MRI) and older age were associated with higher success rates and can be used to predict success rates on the basis of their presence or absence as pre-treatment parameters. WHAT IS KNOWN ALREADY: The signal intensity of baseline T2-weighted MRI images and non-perfused volume at the end of the treatment can be correlated with MRgFUS outcome. STUDY DESIGN, SIZE AND DURATION: This was a retrospective analysis of 81 patients who were treated by MRgFUS for symptomatic uterine fibroids, in an academic affiliated center between 2003 and 2008. PARTICIPANTS/MATERIALS, SETTING AND METHODS: There was a post-treatment phone interview >6 months following MRgFUS for symptomatic uterine fibroids. MAIN RESULTS AND THE ROLE OF CHANCE: The eighty-one patients completed a successful MRgFUS treatment during this period, of whom 74 were included in the final analysis (1 was post-menopausal at treatment and 5 were lost for follow-up). The mean time for the phone interview was 33.0 +/- 15.1 months (range: 6-53 months) after the MRgFUS treatment. Fifty-five patients (69%) did not need any additional alternative treatment following MRgFUS. Nineteen patients (24%) underwent other surgical interventions. Hypo-intense fibroids were associated with a higher chance of success than hyper-intense fibroids [odds ratio = 2.96 (1.01-8.71); P = 0.04] for surgery in hyper-intense fibroids). Women with long-term treatment success were significantly older at the time of treatment [46.3 +/- 3.8 (range: 37-53) years versus 43.6 +/- 4.4 (range: 36-51) years, respectively; P = 0.02]. LIMITATIONS AND REASONS FOR CAUTION: Retrospective non-comparative studies are suboptimal and might overemphasize favorable outcomes. WIDER IMPLICATIONS OF THE FINDINGS: This paper can contribute to selection of suitable candidates for the MRgFUS treatment for patients with uterine fibroids' and can serve as a guide for gynecologists for a better patient selection. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A. PMID- 23019305 TI - Molecular pathways: the metabolic regulator estrogen-related receptor alpha as a therapeutic target in cancer. AB - The estrogen-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor superfamily of transcription factors whose activity is regulated by the expression level and/or activity of its obligate coregulators, peroxisome proliferator-activated receptor gamma coactivator-1 alpha and beta (PGC-1alpha or PGC-1beta). Under normal physiologic conditions, and in responding to different environmental stimuli, the ERRalpha/PGC-1 complex is involved in regulating metabolic homeostasis under conditions of high energy demand in brown adipocytes, proliferating T cells, and muscle. Interestingly, increased expression and activity of the ERRalpha/PGC-1 axis has also been shown to correlate with unfavorable clinical outcomes in both breast and ovarian tumors. The observation that ERRalpha activity is manifest in all breast tumor subtypes with particularly high activity being evident in ERalpha-negative, HER2-positive, and triple negative breast cancers has raised significant interest in targeting this receptor for the treatment of those breast cancers for which therapeutic options are limited. PMID- 23019306 TI - Model T muscle CARs can treat brain tumors. AB - Despite standard treatment with resection, radiation, and chemotherapy, glioblastoma remains a deadly disease with a dismal prognosis. Redirecting patient T cells to target the glioblastoma-associated antigen, IL13Ralpha2, offers a promising translational immunotherapy with the potential to make a meaningful impact for patients with this disease. PMID- 23019307 TI - The long journey of cancer biomarkers from the bench to the clinic. AB - BACKGROUND: Protein cancer biomarkers serve multiple clinical purposes, both early and late, during disease progression. The search for new and better biomarkers has become an integral component of contemporary cancer research. However, the number of new biomarkers cleared by the US Food and Drug Administration has declined substantially over the last 10 years, raising concerns regarding the efficiency of the biomarker-development pipeline. CONTENT: We describe different clinical uses of cancer biomarkers and their performance requirements. We also present examples of protein cancer biomarkers currently in clinical use and their limitations. The major barriers that candidate biomarkers need to overcome to reach the clinic are addressed. Finally, the long and arduous journey of a protein cancer biomarker from the bench to the clinic is outlined with an example. SUMMARY: The journey of a protein biomarker from the bench to the clinic is long and challenging. Every step needs to be meticulously planned and executed to succeed. The history of clinically useful biomarkers suggests that at least a decade is required for the transition of a marker from the bench to the bedside. Therefore, it may be too early to expect that the new technological advances will catalyze the anticipated biomarker revolution any time soon. PMID- 23019308 TI - Longitudinal studies of cardiac troponin I in a large cohort of healthy children. AB - BACKGROUND: There is little information available on cardiac troponin concentrations in healthy young children. METHODS: Using a precommercial high sensitivity assay from Abbott Diagnostics, we measured cardiac troponin I (cTnI) in longitudinal blood samples collected at ages 8, 10, and 12 years from a cohort of healthy, community-dwelling children. The 99th percentile values were calculated and estimates of the long-term biological variation were made. RESULTS: cTnI concentrations were above the limit of detection in 87%, 90%, and 98% of the children at ages 8, 10, and 12 years. The 99th percentiles were lower compared to a healthy adult population in both male and female children at all ages studied. At the 3 periods of study assessment, different children had cTnI concentrations above the 99th percentile. The calculated 99th percentile varied markedly depending upon whether the lowest or highest cTnI measurement for an individual child was included in the calculation. Biological variation varied markedly between 0% and 136%, the index of individuality was low at 0.36, and the reference change value was an increase of 147% or a decrease of 59%. CONCLUSIONS: In this longitudinal study of cTnI concentrations in healthy children as determined by a high-sensitivity assay, different children had concentrations of cTnI above the 99th percentile at the 3 episodes of assessment. These results suggest that in children the 99th percentile may not be a reliable index of silent cardiac disease, but rather may be indicating low-grade intercurrent illness. PMID- 23019309 TI - Associations of alternative markers of glycemia with hemoglobin A(1c) and fasting glucose. AB - BACKGROUND: 1,5-Anhydroglucitol (1,5-AG), fructosamine, and glycated albumin are of increasing interest as alternative measures of hyperglycemia. We characterize the associations of these nontraditional glycemic markers with hemoglobin A(1c) (Hb A(1c)) and fasting glucose and assess their ability to identify people with diabetes. METHODS: We conducted a cross-sectional comparison of 1,5-AG, fructosamine, and glycated albumin with Hb A(1c) and fasting glucose measurements in 1719 participants from the Atherosclerosis Risk in Communities Study. We evaluated nonlinear relationships using R(2) and F-statistics. Performance for identification of cases of diabetes was determined using the area under the curve (AUC). Diabetes was defined by Hb A(1c) >=6.5%, fasting glucose >=126 mg/dL (>=6.99 mmol/L), and/or a self-reported history of diagnosed diabetes. RESULTS: Median values of Hb A(1c) and fasting glucose were 5.8% and 109 mg/dL (6.05 mmol/L), respectively; 17.3% of the study population had diagnosed diabetes. Glycated albumin, fructosamine, and 1,5-AG were more strongly correlated with Hb A(1c) compared with fasting glucose (all P values <0.05). Nonlinear models provided the best fit for describing the relationships of the alternative markers to Hb A(1c). When diabetes was defined by an Hb A(1c) >=6.5%, fructosamine (AUC 0.83; 95% CI, 0.79-0.87) and glycated albumin (AUC 0.87; 95% CI, 0.83-0.90) performed comparably to fasting glucose (AUC 0.83; 95% CI, 0.79-0.87), while 1,5 AG performed worse (AUC 0.74; 95% CI, 0.69-0.78) for identifying cases of undiagnosed diabetes. CONCLUSIONS: Fructosamine and glycated albumin may be useful adjuncts to Hb A(1c) and fasting glucose. Future studies should examine these markers in situations in which fasting glucose or Hb A(1c) measurements are invalid or not available. PMID- 23019310 TI - Sustained high-altitude hypoxia increases cerebral oxygen metabolism. AB - Acute mountain sickness (AMS) is a common condition occurring within hours of rapid exposure to high altitude. Despite its frequent occurrence, the pathophysiological mechanisms that underlie the condition remain poorly understood. We investigated the role of cerebral oxygen metabolism (CMR(O(2))) in AMS. The purpose of this study was to test 1) if CMR(O(2)) changes in response to hypoxia, and 2) if there is a difference in how individuals adapt to oxygen metabolic changes that may determine who develops AMS and who does not. Twenty six normal human subjects were recruited into two groups based on Lake Louise AMS score (LLS): those with no AMS (LLS <= 2), and those with unambiguous AMS (LLS >= 5). [Subjects with intermediate scores (LLS 3-4) were not included.] CMR(O(2)) was calculated from cerebral blood flow and arterial-venous difference in O(2) content. Cerebral blood flow was measured using arterial spin labeling MRI; venous O(2) saturation was calculated from the MRI of transverse relaxation in the superior sagittal sinus. Arterial O(2) saturation was measured via pulse oximeter. Measurements were made during normoxia and after 2-day high-altitude exposure at 3,800 m. In all subjects, CMR(O(2)) increased with sustained high altitude hypoxia [1.54 (0.37) to 1.82 (0.49) MUmol.g(-1).min(-1), n = 26, P = 0.045]. There was no significant difference in CMR(O(2)) between AMS and no-AMS groups. End-tidal Pco(2) was significantly reduced during hypoxia. Low arterial Pco(2) is known to increase neural excitability, and we hypothesize that the low arterial Pco(2) resulting from ventilatory acclimatization causes the observed increase in CMR(O(2)). PMID- 23019311 TI - Characterization of the effects of exercise training on hematopoietic stem cell quantity and function. AB - The effect of exercise training on hematopoietic stem cells (HSC) is largely unknown. The aim of the present investigation was to determine whether exercise training could expand the bone marrow HSC pool and influence various aspects of HSC function. Mice were either exercise trained (EX; 1 h/day, 3 days/wk, for 8 wk) or remained sedentary (SED). Bone marrow (BM) from SED or EX mice was extracted from different HSC niches for cell cycle analysis, HSC (lineage(-), Sca 1(+), c-Kit(+)) quantification, and differentiation along various hematopoietic lineages via flow cytometry. Serum was collected for evaluation of cytokines known to regulate HSC. To determine HSC function, BM from EX and SED mice was transplanted into primary and secondary recipients in a BM transplant assay. EX increased HSC quantity in the vascular BM niche 20% vs. SED (P < 0.05) and increased the proportion of whole BM cells in G(2)/M phase of cell cycle (P < 0.05). The number of spleen colonies was 48% greater (P < 0.05) in recipients transplanted with BM from EX. Serum IL-6 levels were decreased 38% in EX, and differentiation along the lineage trended to increase (16%, P = 0.053 and 16%, P = 0.061, respectively). Short- or long-term engraftment and homing in primary recipients were not altered in EX. HSC self-renewal as analyzed by hematopoietic regeneration in secondary recipients was also unaffected by EX. Here we demonstrate that HSC quantity is increased in the BM niche associated with more activated, differentiated HSC, and that this expansion does not improve or impair HSC function. PMID- 23019312 TI - Effects of endurance exercise training, metformin, and their combination on adipose tissue leptin and IL-10 secretion in OLETF rats. AB - Adipose tissue inflammation plays a role in cardiovascular (CV) and metabolic diseases associated with obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). The interactive effects of exercise training and metformin, two first-line T2DM treatments, on adipose tissue inflammation are not known. Using the hyperphagic, obese, insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rat model, we tested the hypothesis that treadmill training, metformin, or a combination of these reduces the secretion of proinflammatory cytokines from adipose tissue. Compared with Long-Evans Tokushima Otsuka (LETO) control rats (L Sed), sedentary OLETF (O-Sed) animals secreted significantly greater amounts of leptin from retroperitoneal adipose tissue. Conversely, secretion of interleukin (IL)-10 by O-Sed adipose tissue was lower than that in L-Sed animals. Examination of leptin and IL-10 secretion from adipose tissue in OLETF groups treated with endurance exercise training (O-EndEx), metformin treatment (O-Met), and a combination of these (O-E+M) from 20 to 32 wk of age indicated that 1) leptin secretion from adipose tissue was reduced in O-Met and O-E+M, but not O-EndEx animals; 2) adipose tissue IL-10 secretion was increased in O-EndEx and O-E+M but not in O-Met animals; and 3) only the combined treatment (O-E+M) displayed both a reduction in leptin secretion and an increase in IL-10 secretion. Leptin and IL 10 concentrations in adipose tissue-conditioned buffers were correlated with their plasma concentrations, adipocyte diameters, and total adiposity. Overall, this study indicates that exercise training and metformin have additive influences on adipose tissue secretion and plasma concentrations of leptin and IL 10. PMID- 23019313 TI - Respiratory timing and variability during sleep in children with sleep-disordered breathing. AB - Sleep-disordered breathing (SDB) in children is assessed by quantification of hypopnea and apnea events. Little is known, however, about respiratory timing and breath-to-breath variability during sleep. The aim of this study was to investigate respiratory parameters across sleep stages in children with SDB before and after treatment compared with healthy children. Overnight polysomnography (PSG) was conducted in 40 children with SDB prior to and 6 mo following adenotonsillectomy. For comparison, a control group of 40 healthy sex- and age-matched children underwent two PSGs at equivalent time points but without intervention. The following variables were measured breath by breath during obstruction-free periods in stage 2 nonrapid eye movement (NREM), stage 4 NREM, and REM sleep: inspiratory time (Ti), expiratory time (Te), total time (Ttotal), inspiratory duty cycle (DC; =Ti/Ttotal), respiratory frequency (fR), and SD of the parameters Ti, Te, fR, and DC. Variability in waveform morphology was also computed using the residue of respiratory patterns. The severity of SDB was relatively mild in the study cohort (obstructive apnea hypopnea index: baseline, 5.1 +/- 9.4 vs. 0.1 +/- 0.2, P < 0.001; follow-up, 0.3 +/- 0.3 vs. 0.8 +/- 1.0, P < 0.01). Compared with healthy controls, children with SDB showed significantly longer Ti and Te and a lower fR at the baseline study. These differences were not significant after adenotonsillectomy. Sleep stages were associated with significant differences in all of the respiratory measures in both groups of children. In conclusion, children with relatively mild SDB showed prolonged inspiration and expiration indicative of chronic narrowing of the upper airway. Treatment of SDB normalizes respiratory timing. Documentation of these parameters may aid in both understanding and management of children with SDB. PMID- 23019314 TI - The mechanisms of cachexia underlying muscle dysfunction in COPD. AB - Pulmonary cachexia is a prevalent, debilitating, and well-recognized feature of COPD associated with increased mortality and loss of peripheral and respiratory muscle function. The exact cause and underlying mechanisms of cachexia in COPD are still poorly understood. Increasing evidence, however, shows that pathological changes in intracellular mechanisms of muscle mass maintenance (i.e., protein turnover and myonuclear turnover) are likely involved. Potential factors triggering alterations in these mechanisms in COPD include oxidative stress, myostatin, and inflammation. In addition to muscle wasting, peripheral muscle in COPD is characterized by a fiber-type shift toward a more type II, glycolytic phenotype and an impaired oxidative capacity (collectively referred to as an impaired oxidative phenotype). Atrophied diaphragm muscle in COPD, however, displays an enhanced oxidative phenotype. Interestingly, intrinsic abnormalities in (lower limb) peripheral muscle seem more pronounced in either cachectic patients or weight loss-susceptible emphysema patients, suggesting that muscle wasting and intrinsic changes in peripheral muscle's oxidative phenotype are somehow intertwined. In this manuscript, we will review alterations in mechanisms of muscle mass maintenance in COPD and discuss the involvement of oxidative stress, inflammation, and myostatin as potential triggers of cachexia. Moreover, we postulate that an impaired muscle oxidative phenotype in COPD can accelerate the process of cachexia, as it renders muscle in COPD less energy efficient, thereby contributing to an energy deficit and weight loss when not dietary compensated. Furthermore, loss of peripheral muscle oxidative phenotype may increase the muscle's susceptibility to inflammation- and oxidative stress induced muscle damage and wasting. PMID- 23019315 TI - Validity of combining heart rate and uniaxial acceleration to measure free-living physical activity energy expenditure in young men. AB - Combining accelerometry (ACC) with heart rate (HR) monitoring is thought to improve activity energy expenditure (AEE) estimations compared with ACC alone to evaluate the validity of ACC and HR used alone or combined. The purpose of this study was to estimate AEE in free-living conditions compared with doubly labeled water (DLW). Ten-day free-living AEE was measured by a DLW protocol in 35 18- to 55-yr-old men (11 lean active; 12 lean sedentary; 12 overweight sedentary) wearing an Actiheart (combining ACC and HR) and a RT3 accelerometer. AEE was estimated using group or individual calibration of the HR/AEE relationship, based on an exercise-tolerance test. In a subset (n = 21), AEE changes (DeltaAEE) were measured after 1 mo of detraining (active subjects) or an 8-wk training (sedentary subjects). Actiheart-combined ACC/HR estimates were more accurate than estimates from HR or ACC alone. Accuracy of the Actiheart group-calibrated ACC/HR estimates was modest [intraclass correlation coefficient (ICC) = 0.62], with no bias but high root mean square error (RMSE) and limits of agreement (LOA). The mean bias of the estimates was reduced by one-third, like RMSE and LOA, by individual calibration (ICC = 0.81). Contrasting with group-calibrated estimates, the Actiheart individual-calibrated ACC/HR estimates explained 40% of the variance of the DLW-DeltaAEE (ICC = 0.63). This study supports a good level of agreement between the Actiheart ACC/HR estimates and DLW-measured AEE in lean and overweight men with varying fitness levels. Individual calibration of the HR/AEE relationship is necessary for AEE estimations at an individual level rather than at group scale and for DeltaAEE evaluation. PMID- 23019317 TI - The effects of phosphate and acidosis on regulated thin-filament velocity in an in vitro motility assay. AB - Muscle fatigue from intense contractile activity is thought to result, in large part, from the accumulation of inorganic phosphate (P(i)) and hydrogen ions (H(+)) acting to directly inhibit the function of the contractile proteins; however, the molecular basis of this process remain unclear. We used an in vitro motility assay and determined the effects of elevated H(+) and P(i) on the ability of myosin to bind to and translocate regulated actin filaments (RTF) to gain novel insights into the molecular basis of fatigue. At saturating Ca(++), acidosis depressed regulated filament velocity (V(RTF)) by ~ 90% (6.2 +/- 0.3 vs. 0.5 +/- 0.2 MUm/s at pH 7.4 and 6.5, respectively). However, the addition of 30 mM P(i) caused V(RTF) to increase fivefold, from 0.5 +/- 0.2 to 2.6 +/- 0.3 MUm/s at pH 6.5. Similarly, at all subsaturating Ca(++) levels, acidosis slowed V(RTF), but the addition of P(i) significantly attenuated this effect. We also manipulated the [ADP] in addition to the [P(i)] to probe which specific step(s) of cross-bridge cycle of myosin is affected by elevated H(+). The findings are consistent with acidosis slowing the isomerization step between two actomyosin ADP-bound states. Because the state before this isomerization is most vulnerable to P(i) rebinding, and the associated detachment from actin, this finding may also explain the P(i)-induced enhancement of V(RTF) at low pH. These results therefore may provide a molecular basis for a significant portion of the loss of shortening velocity and possibly muscular power during fatigue. PMID- 23019316 TI - Effects of aerobic and/or resistance training on body mass and fat mass in overweight or obese adults. AB - Recent guidelines on exercise for weight loss and weight maintenance include resistance training as part of the exercise prescription. Yet few studies have compared the effects of similar amounts of aerobic and resistance training on body mass and fat mass in overweight adults. STRRIDE AT/RT, a randomized trial, compared aerobic training, resistance training, and a combination of the two to determine the optimal mode of exercise for obesity reduction. Participants were 119 sedentary, overweight or obese adults who were randomized to one of three 8 mo exercise protocols: 1) RT: resistance training, 2) AT: aerobic training, and 3) AT/RT: aerobic and resistance training (combination of AT and RT). Primary outcomes included total body mass, fat mass, and lean body mass. The AT and AT/RT groups reduced total body mass and fat mass more than RT (P < 0.05), but they were not different from each other. RT and AT/RT increased lean body mass more than AT (P < 0.05). While requiring double the time commitment, a program of combined AT and RT did not result in significantly more fat mass or body mass reductions over AT alone. Balancing time commitments against health benefits, it appears that AT is the optimal mode of exercise for reducing fat mass and body mass, while a program including RT is needed for increasing lean mass in middle aged, overweight/obese individuals. PMID- 23019318 TI - A phenomenological model of muscle fatigue and the power-endurance relationship. AB - The relationship between power output and the time that it can be sustained during exercise (i.e., endurance) at high intensities is curvilinear. Although fatigue is implicit in this relationship, there is little evidence pertaining to it. To address this, we developed a phenomenological model that predicts the temporal response of muscle power during submaximal and maximal exercise and which was based on the type, contractile properties (e.g., fatiguability), and recruitment of motor units (MUs) during exercise. The model was first used to predict power outputs during all-out exercise when fatigue is clearly manifest and for several distributions of MU type. The model was then used to predict times that different submaximal power outputs could be sustained for several MU distributions, from which several power-endurance curves were obtained. The model was simultaneously fitted to two sets of human data pertaining to all-out exercise (power-time profile) and submaximal exercise (power-endurance relationship), yielding a high goodness of fit (R(2) = 0.96-0.97). This suggested that this simple model provides an accurate description of human power output during submaximal and maximal exercise and that fatigue-related processes inherent in it account for the curvilinearity of the power-endurance relationship. PMID- 23019319 TI - Activation of cholera toxin production by anaerobic respiration of trimethylamine N-oxide in Vibrio cholerae. AB - Vibrio cholerae is a gram-negative bacterium that causes cholera. Although the pathogenesis caused by this deadly pathogen takes place in the intestine, commonly thought to be anaerobic, anaerobiosis-induced virulence regulations are not fully elucidated. Anerobic growth of the V. cholerae strain, N16961, was promoted when trimethylamine N-oxide (TMAO) was used as an alternative electron acceptor. Strikingly, cholera toxin (CT) production was markedly induced during anaerobic TMAO respiration. N16961 mutants unable to metabolize TMAO were incapable of producing CT, suggesting a mechanistic link between anaerobic TMAO respiration and CT production. TMAO reductase is transported to the periplasm via the twin arginine transport (TAT) system. A similar defect in both anaerobic TMAO respiration and CT production was also observed in a N16961 TAT mutant. In contrast, the abilities to grow on TMAO and to produce CT were not affected in a mutant of the general secretion pathway. This suggests that V. cholerae may utilize the TAT system to secrete CT during TMAO respiration. During anaerobic growth with TMAO, N16961 cells exhibit green fluorescence when stained with 2',7' dichlorofluorescein diacetate, a specific dye for reactive oxygen species (ROS). Furthermore, CT production was decreased in the presence of an ROS scavenger suggesting a positive role of ROS in regulating CT production. When TMAO was co administered to infant mice infected with N16961, the mice exhibited more severe pathogenic symptoms. Together, our results reveal a novel anaerobic growth condition that stimulates V. cholerae to produce its major virulence factor. PMID- 23019320 TI - Aberrant gene expression profiles in pluripotent stem cells induced from fibroblasts of a Klinefelter syndrome patient. AB - Klinefelter syndrome (KS) is the most common male chromosome aneuploidy. Its pathophysiology is largely unexplained due to the lack of adequate models. Here, we report the derivation of induced pluripotent stem cell (iPSCs) lines from a KS patient with a karyotype of 47, XXY. Derived KS-iPSCs meet all criteria of normal iPSCs with the potential for germ cell differentiation. Although X chromosome inactivation occurs in all KS-iPSCs, genome-wide transcriptome analysis identifies aberrantly expressed genes associated with the clinical features of KS. Our KS-iPSCs can serve as a cellular model for KS research. Identified genes may become biomarkers for early diagnosis or potential therapeutic targets for KS and significantly accelerate the understanding, diagnosis, and treatment of Klinefelter syndrome. PMID- 23019321 TI - Mycobacterium paratuberculosis CobT activates dendritic cells via engagement of Toll-like receptor 4 resulting in Th1 cell expansion. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne disease in animals and MAP involvement in human Crohn disease has been recently emphasized. Evidence from M. tuberculosis studies suggests mycobacterial proteins activate dendritic cells (DCs) via Toll-like receptor (TLR) 4, eventually determining the fate of immune responses. Here, we investigated whether MAP CobT contributes to the development of T cell immunity through the activation of DCs. MAP CobT recognizes TLR4, and induces DC maturation and activation via the MyD88 and TRIF signaling cascades, which are followed by MAP kinases and NF-kappaB. We further found that MAP CobT-treated DCs activated naive T cells, effectively polarized CD4(+) and CD8(+) T cells to secrete IFN-gamma and IL-2, but not IL-4 and IL-10, and induced T cell proliferation. These data indicate that MAP CobT contributes to T helper (Th) 1 polarization of the immune response. MAP CobT treated DCs specifically induced the expansion of CD4(+)/CD8(+)CD44(high)CD62L(low) memory T cells in the mesenteric lymph node of MAP-infected mice in a TLR4-dependent manner. Our results indicate that MAP CobT is a novel DC maturation-inducing antigen that drives Th1 polarized-naive/memory T cell expansion in a TLR4-dependent cascade, suggesting that MAP CobT potentially links innate and adaptive immunity against MAP. PMID- 23019322 TI - Modulation of inositol 1,4,5-trisphosphate receptor type 2 channel activity by Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated phosphorylation. AB - InsP(3)-mediated calcium release through the type 2 inositol 1,4,5-trisphosphate receptor (InsP(3)R2) in cardiac myocytes results in the activation of associated CaMKII, thus enabling the kinase to act on downstream targets, such as histone deacetylases 4 and 5 (HDAC4 and HDAC5). The CaMKII activity also feedback modulates InsP(3)R2 function by direct phosphorylation and results in a dramatic decrease in the receptor-channel open probability (P(o)). We have identified S150 in the InsP(3)R2 core suppressor domain (amino acids 1-225) as the specific residue that is phosphorylated by CaMKII. Site-directed mutagenesis reveals that S150 is the CaMKII phosphorylation site responsible for modulation of channel activity. Nonphosphorylatable (S150A) and phosphomimetic (S150E) mutations were studied in planar lipid bilayers. The InsP(3)R2 S150A channel showed no decrease in activity when treated with CaMKII. Conversely, the phosphomimetic (S150E) channel displayed a very low P(o) under normal recording conditions in the absence of CaMKII (2 MUM InsP(3) and 250 nM [Ca(2+)](FREE)) and mimicked a WT channel that has been phosphorylated by CaMKII. Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIdelta. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability. PMID- 23019323 TI - The neck region of the C-type lectin DC-SIGN regulates its surface spatiotemporal organization and virus-binding capacity on antigen-presenting cells. AB - The C-type lectin DC-SIGN expressed on dendritic cells (DCs) facilitates capture and internalization of a plethora of different pathogens. Although it is known that DC-SIGN organizes in nanoclusters at the surface of DCs, the molecular mechanisms responsible for this well defined nanopatterning and role in viral binding remain enigmatic. By combining biochemical and advanced biophysical techniques, including optical superresolution and single particle tracking, we demonstrate that DC-SIGN intrinsic nanoclustering strictly depends on its molecular structure. DC-SIGN nanoclusters exhibited free, Brownian diffusion on the cell membrane. Truncation of the extracellular neck region, known to abrogate tetramerization, significantly reduced nanoclustering and concomitantly increased lateral diffusion. Importantly, DC-SIGN nanocluster dissolution exclusively compromised binding to nanoscale size pathogens. Monte Carlo simulations revealed that heterogeneity on nanocluster density and spatial distribution confers broader binding capabilities to DC-SIGN. As such, our results underscore a direct relationship between spatial nanopatterning, driven by intermolecular interactions between the neck regions, and receptor diffusion to provide DC-SIGN with the exquisite ability to dock pathogens at the virus length scale. Insight into how virus receptors are organized prior to virus binding and how they assemble into functional platforms for virus docking is helpful to develop novel strategies to prevent virus entry and infection. PMID- 23019324 TI - Single-cell characterization of autotransporter-mediated Escherichia coli surface display of disulfide bond-containing proteins. AB - Autotransporters (ATs) are a family of bacterial proteins containing a C-terminal beta-barrel-forming domain that facilitates the translocation of N-terminal passenger domain whose functions range from adhesion to proteolysis. Genetic replacement of the native passenger domain with heterologous proteins is an attractive strategy not only for applications such as biocatalysis, live-cell vaccines, and protein engineering but also for gaining mechanistic insights toward understanding AT translocation. The ability of ATs to efficiently display functional recombinant proteins containing multiple disulfides has remained largely controversial. By employing high-throughput single-cell flow cytometry, we have systematically investigated the ability of the Escherichia coli AT Antigen 43 (Ag43) to display two different recombinant reporter proteins, a single-chain antibody (M18 scFv) that contains two disulfides and chymotrypsin that contains four disulfides, by varying the signal peptide and deleting the different domains of the native protein. Our results indicate that only the C terminal beta-barrel and the threaded alpha-helix are essential for efficient surface display of functional recombinant proteins containing multiple disulfides. These results imply that there are no inherent constraints for functional translocation and display of disulfide bond-containing proteins mediated by the AT system and should open new avenues for protein display and engineering. PMID- 23019325 TI - Generation of a drug-inducible reporter system to study cell reprogramming in human cells. AB - BACKGROUND: Strategies on the basis of doxycycline-inducible lentiviruses in mouse cells allowed the examination of mechanisms governing somatic cell reprogramming. RESULTS: Using a doxycycline-inducible human reprogramming system, we identified unreported miRs enhancing reprogramming efficiency. CONCLUSION: We generated a drug-inducible human reprogramming reporter system as an invaluable tool for genetic or chemical screenings. SIGNIFICANCE: These cellular systems provide a tool to enable the advancement of reprogramming technologies in human cells. Reprogramming of somatic cells into induced pluripotent stem cells is achieved by the expression of defined transcription factors. In the last few years, reprogramming strategies on the basis of doxycycline-inducible lentiviruses in mouse cells became highly powerful for screening purposes when the expression of a GFP gene, driven by the reactivation of endogenous stem cell specific promoters, was used as a reprogramming reporter signal. However, similar reporter systems in human cells have not been generated. Here, we describe the derivation of drug-inducible human fibroblast-like cell lines that express different subsets of reprogramming factors containing a GFP gene under the expression of the endogenous OCT4 promoter. These cell lines can be used to screen functional substitutes for reprogramming factors or modifiers of reprogramming efficiency. As a proof of principle of this system, we performed a screening of a library of pluripotent-enriched microRNAs and identified hsa-miR 519a as a novel inducer of reprogramming efficiency. PMID- 23019326 TI - Membrane protein Rim21 plays a central role in sensing ambient pH in Saccharomyces cerevisiae. AB - External alkalization activates the Rim101 pathway in Saccharomyces cerevisiae. In this pathway, three integral membrane proteins, Rim21, Dfg16, and Rim9, are considered to be the components of the pH sensor machinery. However, how these proteins are involved in pH sensing is totally unknown. In this work, we investigated the localization, physical interaction, and interrelationship of Rim21, Dfg16, and Rim9. These proteins were found to form a complex and to localize to the plasma membrane in a patchy and mutually dependent manner. Their cellular level was also mutually dependent. In particular, the Rim21 level was significantly decreased in dfg16Delta and rim9Delta cells. Upon external alkalization, the proteins were internalized and degraded. We also demonstrate that the transient degradation of Rim21 completely suppressed the Rim101 pathway but that the degradation of Dfg16 or Rim9 did not. This finding strongly suggests that Rim21 is the pH sensor protein and that Dfg16 and Rim9 play auxiliary functions through maintaining the level of Rim21 and assisting in its plasma membrane localization. Even without external alkalization, the Rim101 pathway was activated in a Rim21-dependent manner by either protonophore treatment or depletion of phosphatidylserine in the inner leaflet of the plasma membrane, both of which caused plasma membrane depolarization like the external alkalization. Therefore, plasma membrane depolarization seems to be one of the key signals for the pH sensor molecule Rim21. PMID- 23019327 TI - Targeting and import mechanism of coiled-coil helix coiled-coil helix domain containing protein 3 (ChChd3) into the mitochondrial intermembrane space. AB - Coiled-coil helix coiled-coil helix domain-containing protein 3 (ChChd3) is a mitochondrial inner membrane (IM) protein facing toward the intermembrane space (IMS). In the IMS, ChChd3 complexes with multiple proteins at the crista junctions and contact sites and plays a key role in maintaining crista integrity. ChChd3 is myristoylated at the N terminus and has a CHCH domain with twin CX(9)C motifs at its C terminus. The CHCH domain proteins are traditionally imported and trapped in the IMS by using a disulfide relay system mediated by Mia40 and Erv1. In this study, we systematically analyzed the role of the myristoylation and the CHCH domain in the import and mitochondrial localization of ChChd3. Based on our results, we predict that myristoylation promotes binding of ChChd3 to the outer membrane and that the CHCH domain translocates the protein across the outer membrane. By analysis of the CHCH domain cysteine mutants, we further show that they have distinct roles in binding to Mia40 in the IMS and proper folding of the protein. The transient disulfide-bonded intermediate with Mia40 is formed preferentially between the second cysteine in helix 1, Cys(193), and the active site cysteine in Mia40, Cys(55). Although each of the four cysteines is essential for folding of the protein and binding to mitofilin and Sam50, they are not involved in import. Together our results indicate that both the myristoylation and the CHCH domain are essential for the import and mitochondrial localization of ChChd3. Once imported, ChChd3 binds to Mia40 for further folding and assembly into macromolecular complexes. PMID- 23019329 TI - The potassium channel interacting protein 3 (DREAM/KChIP3) heterodimerizes with and regulates calmodulin function. AB - Downstream regulatory element antagonistic modulator (DREAM/KChIP3), a neuronal EF-hand protein, modulates pain, potassium channel activity, and binds presenilin 1. Using affinity capture of neuronal proteins by immobilized DREAM/KChIP3 in the presence and absence of calcium (Ca(2+)) followed by mass spectroscopic identification of interacting proteins, we demonstrate that in the presence of Ca(2+), DREAM/KChIP3 interacts with the EF-hand protein, calmodulin (CaM). The interaction of DREAM/KChIP3 with CaM does not occur in the absence of Ca(2+). In the absence of Ca(2+), DREAM/KChIP3 binds the EF-hand protein, calcineurin subunit-B. Ca(2+)-bound DREAM/KChIP3 binds CaM with a dissociation constant of ~3 MUM as assessed by changes in DREAM/KChIP3 intrinsic protein fluorescence in the presence of CaM. Two-dimensional (1)H,(15)N heteronuclear single quantum coherence spectra reveal changes in chemical shifts and line broadening upon the addition of CaM to (15)N DREAM/KChIP3. The amino-terminal portion of DREAM/KChIP3 is required for its binding to CaM because a construct of DREAM/KChIP3 lacking the first 94 amino-terminal residues fails to bind CaM as assessed by fluorescence spectroscopy. The addition of Ca(2+)-bound DREAM/KChIP3 increases the activation of calcineurin (CN) by calcium CaM. A DREAM/KChIP3 mutant incapable of binding Ca(2+) also stimulates calmodulin-dependent CN activity. The shortened form of DREAM/KChIP3 lacking the NH(2)-terminal amino acids fails to activate CN in the presence of calcium CaM. Our data demonstrate the interaction of DREAM/KChIP3 with the important EF-hand protein, CaM, and show that the interaction alters CN activity. PMID- 23019328 TI - CD36 protein influences myocardial Ca2+ homeostasis and phospholipid metabolism: conduction anomalies in CD36-deficient mice during fasting. AB - Sarcolemmal CD36 facilitates myocardial fatty acid (FA) uptake, which is markedly reduced in CD36-deficient rodents and humans. CD36 also mediates signal transduction events involving a number of cellular pathways. In taste cells and macrophages, CD36 signaling was recently shown to regulate store-responsive Ca(2+) flux and activation of Ca(2+)-dependent phospholipases A(2) that cycle polyunsaturated FA into phospholipids. It is unknown whether CD36 deficiency influences myocardial Ca(2+) handling and phospholipid metabolism, which could compromise the heart, typically during stresses. Myocardial function was examined in fed or fasted (18-22 h) CD36(-/-) and WT mice. Echocardiography and telemetry identified conduction anomalies that were associated with the incidence of sudden death in fasted CD36(-/-) mice. No anomalies or death occurred in WT mice during fasting. Optical imaging of perfused hearts from fasted CD36(-/-) mice documented prolongation of Ca(2+) transients. Consistent with this, knockdown of CD36 in cardiomyocytes delayed clearance of cytosolic Ca(2+). Hearts of CD36(-/-) mice (fed or fasted) had 3-fold higher SERCA2a and 40% lower phospholamban levels. Phospholamban phosphorylation by protein kinase A (PKA) was enhanced after fasting reflecting increased PKA activity and cAMP levels in CD36(-/-) hearts. Abnormal Ca(2+) homeostasis in the CD36(-/-) myocardium associated with increased lysophospholipid content and a higher proportion of 22:6 FA in phospholipids suggests altered phospholipase A(2) activity and changes in membrane dynamics. The data support the role of CD36 in coordinating Ca(2+) homeostasis and lipid metabolism and the importance of this role during myocardial adaptation to fasting. Potential relevance of the findings to CD36-deficient humans would need to be determined. PMID- 23019330 TI - The simultaneous abolition of three starch hydrolases blocks transient starch breakdown in Arabidopsis. AB - In this study, we investigated which enzymes are involved in debranching amylopectin during transient starch degradation. Previous studies identified two debranching enzymes, isoamylase 3 (ISA3) and limit dextrinase (LDA), involved in this process. However, plants lacking both enzymes still degrade substantial amounts of starch. Thus, other enzymes/mechanisms must contribute to starch breakdown. We show that the chloroplastic alpha-amylase 3 (AMY3) also participates in starch degradation and provide evidence that all three enzymes can act directly at the starch granule surface. The isa3 mutant has a starch excess phenotype, reflecting impaired starch breakdown. In contrast, removal of AMY3, LDA, or both enzymes together has no impact on starch degradation. However, removal of AMY3 or LDA in addition to ISA3 enhances the starch excess phenotype. In plants lacking all three enzymes, starch breakdown is effectively blocked, and starch accumulates to the highest levels observed so far. This provides indirect evidence that the heteromultimeric debranching enzyme ISA1-ISA2 is not involved in starch breakdown. However, we illustrate that ISA1-ISA2 can hydrolyze small soluble branched glucans that accumulate when ISA3 and LDA are missing, albeit at a slow rate. Starch accumulation in the mutants correlates inversely with plant growth. PMID- 23019331 TI - Blood vessel epicardial substance (Bves) regulates epidermal tight junction integrity through atypical protein kinase C. AB - Bves is widely observed in the cell junction of the skin, epicardium, intestine, and cornea of both developmental embryos and mature adults. However, it is not clear how Bves confers its role in intercellular adhesion. Here, we identified the zebrafish bves (zBves) and found that the epidermal barrier function could be disrupted after knockdown of Bves, and these zBves morphants were sensitive to osmotic stress. A loss of zBves would affect the partitioning defective protein (PAR) junctional complex identified by the rescue experiment with tjp-2/ZO-2 or the PAR complex (par-3, par-6, and prkci/atypical (a)PKC) mRNAs, in which the survival rate of embryos increased 11, 24, 25, and 28%, respectively, after injection with junctional components; the tjp-2 and aPKC mRNA-rescued embryos also had 24 and 45% decreases in the defective rate. Immunofluorescent studies demonstrated that the aggregation of aPKC around the cell junctions had disintegrated in zBves morphants. However, the expression and assembly of zBves were not influenced by aPKC-MO. These results indicate that a loss of zBves affects the proteins involved in the pathway of the PAR junctional complex, especially aPKC, and both aPKC and Bves are indispensable to claudin expression. PMID- 23019332 TI - A universal scaffold for synthesis of the Fe(CN)2(CO) moiety of [NiFe] hydrogenase. AB - Hydrogen-cycling [NiFe] hydrogenases harbor a dinuclear catalytic center composed of nickel and iron ions, which are coordinated by four cysteine residues. Three unusual diatomic ligands in the form of two cyanides (CN(-)) and one carbon monoxide (CO) are bound to the iron and apparently account for the complexity of the cofactor assembly process, which involves the function of at least six auxiliary proteins, designated HypA, -B, -C, -D, -E, and -F. It has been demonstrated previously that the HypC, -D, -E, and -F proteins participate in cyanide synthesis and transfer. Here, we show by infrared spectroscopic analysis that the purified HypCD complexes from Ralstonia eutropha and Escherichia coli carry in addition to both cyanides the CO ligand. We present experimental evidence that in vivo the attachment of the CN(-) ligands is a prerequisite for subsequent CO binding. With the aid of genetic engineering and subsequent mutant analysis, the functional role of conserved cysteine residues in HypD from R. eutropha was investigated. Our results demonstrate that the HypCD complex serves as a scaffold for the assembly of the Fe(CN)(2)(CO) entity of [NiFe] hydrogenase. PMID- 23019333 TI - ADAMTS-12 metalloprotease is necessary for normal inflammatory response. AB - ADAMTSs (a disintegrin and metalloprotease with thrombospondin domains) are a family of enzymes with both proteolytic and protein interaction functions, which have been implicated in distinct pathologies. In this work, we have investigated the putative role of ADAMTS-12 in inflammation by using a mouse model deficient in this metalloprotease. Control and mutant mice were subjected to different experimental conditions to induce colitis, endotoxic sepsis, and pancreatitis. We have observed that Adamts12-deficient mice exhibit more severe inflammation and a delayed recovery from these challenges compared with their wild-type littermates. These changes are accompanied by an increase in inflammatory markers including several cytokines, as assessed by microarray expression analysis and proteomic based approaches. Interestingly, the clinical symptoms observed in Adamts12 deficient mice are also concomitant with an elevation in the number of neutrophils in affected tissues. Finally, isolation and in vitro culture of human neutrophils demonstrate that the presence of ADAMTS-12 induces neutrophil apoptosis. On the basis of these results, we propose that ADAMTS-12 is implicated in the inflammatory response by modulating normal neutrophil apoptosis. PMID- 23019334 TI - Metabolic inhibition of sialyl-Lewis X biosynthesis by 5-thiofucose remodels the cell surface and impairs selectin-mediated cell adhesion. AB - Sialyl-Lewis X (sLe(X)) is a tetrasaccharide that serves as a ligand for the set of cell adhesion proteins known as selectins. This interaction enables adhesion of leukocytes and cancer cells to endothelial cells within capillaries, resulting in their extravasation into tissues. The last step in sLe(X) biosynthesis is the alpha1,3-fucosyltrasferase (FUT)-catalyzed transfer of an L-fucose residue to carbohydrate acceptors. Impairing FUT activity compromises leukocyte homing to sites of inflammation and renders cancer cells less malignant. Inhibition of FUTs is, consequently, of great interest, but efforts to generate glycosyltransferase inhibitors, including FUT inhibitors, has proven challenging. Here we describe a metabolic engineering strategy to inhibit the biosynthesis of sLe(X) in cancer cells using peracetylated 5-thio-L-fucose (5T-Fuc). We show that 5T-Fuc is taken up by cancer cells and then converted into a sugar nucleotide analog, GDP-5T-Fuc, that blocks FUT activity and limits sLe(X) presentation on HepG2 cells with an EC(50) in the low micromolar range. GDP-5T-Fuc itself does not get transferred by either FUT3 or FUT7 at a measurable rate. We further demonstrate that treatment of cells with 5T-Fuc impaired their adhesive properties to immobilized adhesion molecules and human endothelial cells. 5T-Fuc, therefore, is a useful probe that can be used to modulate sLe(X) levels in cells to evaluate the consequences of inhibiting FUT-mediated sLe(X) formation. These data also reveal the utility of using sugar analogues that lead to formation of donor substrate analogues within cells as a general approach to blocking glycosyltransferases in cells. PMID- 23019335 TI - Activation of autoreactive B cells by endogenous TLR7 and TLR3 RNA ligands. AB - The key step in the activation of autoreactive B cells is the internalization of nucleic acid containing ligands and delivery of these ligands to the Toll-like Receptor (TLR) containing endolysosomal compartment. Ribonucleoproteins represent a large fraction of autoantigens in systemic autoimmune diseases. Here we demonstrate that many uridine-rich mammalian RNA sequences associated with common autoantigens effectively activate autoreactive B cells. Priming with type I IFN increased the magnitude of activation, and the range of which RNAs were stimulatory. A subset of RNAs that contain a high degree of self-complementarity also activated B cells through TLR3. For the RNA sequences that activated predominantly through TLR7, the activation is proportional to uridine-content, and more precisely defined by the frequency of specific uridine-containing motifs. These results identify parameters that define specific mammalian RNAs as ligands for TLRs. PMID- 23019336 TI - The first mammalian aldehyde oxidase crystal structure: insights into substrate specificity. AB - BACKGROUND: Aldehyde oxidases have pharmacological relevance, and AOX3 is the major drug-metabolizing enzyme in rodents. RESULTS: The crystal structure of mouse AOX3 with kinetics and molecular docking studies provides insights into its enzymatic characteristics. CONCLUSION: Differences in substrate and inhibitor specificities can be rationalized by comparing the AOX3 and xanthine oxidase structures. SIGNIFICANCE: The first aldehyde oxidase structure represents a major advance for drug design and mechanistic studies. Aldehyde oxidases (AOXs) are homodimeric proteins belonging to the xanthine oxidase family of molybdenum containing enzymes. Each 150-kDa monomer contains a FAD redox cofactor, two spectroscopically distinct [2Fe-2S] clusters, and a molybdenum cofactor located within the protein active site. AOXs are characterized by broad range substrate specificity, oxidizing different aldehydes and aromatic N-heterocycles. Despite increasing recognition of its role in the metabolism of drugs and xenobiotics, the physiological function of the protein is still largely unknown. We have crystallized and solved the crystal structure of mouse liver aldehyde oxidase 3 to 2.9 A. This is the first mammalian AOX whose structure has been solved. The structure provides important insights into the protein active center and further evidence on the catalytic differences characterizing AOX and xanthine oxidoreductase. The mouse liver aldehyde oxidase 3 three-dimensional structure combined with kinetic, mutagenesis data, molecular docking, and molecular dynamics studies make a decisive contribution to understand the molecular basis of its rather broad substrate specificity. PMID- 23019337 TI - A limited 4 A radial displacement of the S4-S5 linker is sufficient for internal gate closing in Kv channels. AB - Voltage-gated ion channels are responsible for the generation of action potentials in our nervous system. Conformational rearrangements in their voltage sensor domains in response to changes of the membrane potential control pore opening and thus ion conduction. Crystal structures of the open channel in combination with a wealth of biophysical data and molecular dynamics simulations led to a consensus on the voltage sensor movement. However, the coupling between voltage sensor movement and pore opening, the electromechanical coupling, occurs at the cytosolic face of the channel, from where no structural information is available yet. In particular, the question how far the cytosolic pore gate has to close to prevent ion conduction remains controversial. In cells, spectroscopic methods are hindered because labeling of internal sites remains difficult, whereas liposomes or detergent solutions containing purified ion channels lack voltage control. Here, to overcome these problems, we controlled the state of the channel by varying the lipid environment. This way, we directly measured the position of the S4-S5 linker in both the open and the closed state of a prokaryotic Kv channel (KvAP) in a lipid environment using Lanthanide-based resonance energy transfer. We were able to reconstruct the movement of the covalent link between the voltage sensor and the pore domain and used this information as restraints for molecular dynamics simulations of the closed state structure. We found that a small decrease of the pore radius of about 3-4 A is sufficient to prevent ion permeation through the pore. PMID- 23019338 TI - Proteasomal degradation of Nod2 protein mediates tolerance to bacterial cell wall components. AB - The innate immune system serves as the first line of defense by detecting microbes and initiating inflammatory responses. Although both Toll-like receptor (TLR) and nucleotide binding domain and leucine-rich repeat (NLR) proteins are important for this process, their excessive activation is hazardous to hosts; thus, tight regulation is required. Endotoxin tolerance is refractory to repeated lipopolysaccharide (LPS) stimulation and serves as a host defense mechanism against septic shock caused by an excessive TLR4 response during gram-negative bacterial infection. Gram-positive bacteria as well as their cell wall components also induce shock. However, the mechanism underlying tolerance is not understood. Here, we show that activation of Nod2 by its ligand, muramyl dipeptide (MDP) in the bacterial cell wall, induces rapid degradation of Nod2, which confers MDP tolerance in vitro and in vivo. Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. Upon MDP stimulation, Hsp90 rapidly dissociates from Nod2, which subsequently undergoes ubiquitination and proteasomal degradation. The SOCS 3 protein induced by Nod2 activation further facilitates this degradation process. Therefore, Nod2 protein stability is a key factor in determining responsiveness to MDP stimulation. This indicates that TLRs and NLRs induce a tolerant state through distinct molecular mechanisms that protect the host from septic shock. PMID- 23019339 TI - Tau protein diffuses along the microtubule lattice. AB - Current models for the intracellular transport of Tau protein suggest motor protein-dependent co-transport with microtubule fragments and diffusion of Tau in the cytoplasm, whereas Tau is believed to be stationary while bound to microtubules and in equilibrium with free diffusion in the cytosol. Observations that members of the microtubule-dependent kinesin family show Brownian motion along microtubules led us to hypothesize that diffusion along microtubules could also be relevant in the case of Tau. We used single-molecule total internal reflection fluorescence microscopy to probe for diffusion of individual fluorescently labeled Tau molecules along microtubules. This allowed us to avoid the problem that microtubule-dependent diffusion could be masked by excess of labeled Tau in solution that might occur in in vivo overexpression experiments. We found that approximately half of the individually detected Tau molecules moved bidirectionally along microtubules over distances up to several micrometers. Diffusion parameters such as diffusion coefficient, interaction time, and scanned microtubule length did not change with Tau concentration. Tau binding and diffusion along the microtubule lattice, however, were sensitive to ionic strength and pH and drastically reduced upon enzymatic removal of the negatively charged C termini of tubulin. We propose one-dimensional Tau diffusion guided by the microtubule lattice as one possible additional mechanism for Tau distribution. By such one-dimensional microtubule lattice diffusion, Tau could be guided to both microtubule ends, i.e. the sites where Tau is needed during microtubule polymerization, independently of directed motor-dependent transport. This could be important in conditions where active transport along microtubules might be compromised. PMID- 23019340 TI - Vitronectin induces phosphorylation of ezrin/radixin/moesin actin-binding proteins through binding to its novel neuronal receptor telencephalin. AB - Vitronectin (VN) is an extracellular matrix protein abundantly present in blood and a wide variety of tissues and plays important roles in a number of biological phenomena mainly through its binding to alphaV integrins. However, its definite function in the brain remains largely unknown. Here we report the identification of telencephalin (TLCN/ICAM-5) as a novel VN receptor on neuronal dendrites. VN strongly binds to TLCN, a unique neuronal member of the ICAM family, which is specifically expressed on dendrites of spiny neurons in the mammalian telencephalon. VN-coated microbeads induce the formation of phagocytic cup-like plasma membrane protrusions on dendrites of cultured hippocampal neurons and trigger the activation of TLCN-dependent intracellular signaling cascade including the phosphorylation of ezrin/radixin/moesin actin-binding proteins and recruitment of F-actin and phosphatidylinositol 4,5-bisphosphate for morphological transformation of the dendritic protrusions. These results suggest that the extracellular matrix molecule VN and its neuronal receptor TLCN play a pivotal role in the phosphorylation of ezrin/radixin/moesin proteins and the formation of phagocytic cup-like structures on neuronal dendrites. PMID- 23019341 TI - The PmrAB system-inducing conditions control both lipid A remodeling and O antigen length distribution, influencing the Salmonella Typhimurium-host interactions. AB - The Salmonella enterica serovar Typhimurium lipopolysaccharide consisting of covalently linked lipid A, non-repeating core oligosaccharide, and the O-antigen polysaccharide is the most exposed component of the cell envelope. Previous studies demonstrated that all of these regions act against the host immunity barrier. The aim of this study was to define the role and interaction of PmrAB dependent gene products required for the lipopolysaccharide component synthesis or modification mainly during the Salmonella infection. The PmrAB two-component system activation promotes a remodeling of lipid A and the core region by addition of 4-aminoarabinose and/or phosphoethanolamine. These PmrA-dependent activities are produced by activation of ugd, pbgPE, pmrC, cpta, and pmrG transcription. In addition, under PmrA regulator activation, the expression of wzz(fepE) and wzz(st) genes is induced, and their products are required to determine the O-antigen chain length. Here we report for the first time that Wzz(st) protein is necessary to maintain the balance of 4-aminoarabinose and phosphoethanolamine lipid A modifications. Moreover, we demonstrate that the interaction of the PmrA-dependent pbgE(2) and pbgE(3) gene products is important for the formation of the short O-antigen region. Our results establish that PmrAB is the global regulatory system that controls lipopolysaccharide modification, leading to a coordinate regulation of 4-aminoarabinose incorporation and O antigen chain length to respond against the host defense mechanisms. PMID- 23019342 TI - Matrix metalloproteinase 9 (MMP-9)-dependent processing of betaig-h3 protein regulates cell migration, invasion, and adhesion. AB - Cell migration is critically involved in inflammation, cancer, and development. In this study, transforming growth factor-beta-induced protein (betaig-h3) was identified as a substrate of matrix metalloproteinase-9 (MMP-9) by site-directed mutagenesis. betaig-h3 has two cleavage sites with the consensus sequence Pro-Xaa Xaa-Hy-(Ser/Thr) (Hy is a hydrophobic amino acid) (PGSFT beginning at amino acid 135 and PPMGT beginning at amino acid 501). Using recombinant human betaig-h3 and MMP-9, betaig-h3 from betaig-h3-transfected HEK293F cells, and MMP-9 from MMP-9 transfected HEK293F cells, human macrophages, and neutrophils, we found that MMP 9 proteolytically cleaves betaig-h3. Cleavage leads to the loss of its adhesive property and its release from extracellular matrix proteins, collagen IV, and fibronectin. Spheroids formed by increased cell-cell interactions were observed in betaig-h3-transfected HEK293F cells but not in vehicle-transfected HEK293F cells. In human glioma U87MG cells, MMP-9 constitutive overexpression resulted in endogenous betaig-h3 cleavage. betaig-h3 cleavage by MMP-9 led to increased cell invasion, and betaig-h3 knockdown also resulted in increased cell invasion. The betaig-h3 fragment cleaved by MMP-9 could bind to the surface of macrophages, and it may play a role as a peptide chemoattractant by inducing macrophage migration via focal adhesion kinase/Src-mediated signal activation. Thus, intact betaig-h3 is responsible for cell migration inhibition, cell-cell contact, and cell extracellular matrix interaction. Experimental evidence indicates that MMP-9 cleaved betaig-h3 plays a role in MMP-9-mediated tumor cell and macrophage migration. PMID- 23019343 TI - Diversification of the structural determinants of fibroblast growth factor heparin interactions: implications for binding specificity. AB - The functions of a large number (>435) of extracellular regulatory proteins are controlled by their interactions with heparan sulfate (HS). In the case of fibroblast growth factors (FGFs), HS binding determines their transport between cells and is required for the assembly of high affinity signaling complexes with their cognate FGF receptor. However, the specificity of the interaction of FGFs with HS is still debated. Here, we use a panel of FGFs (FGF-1, FGF-2, FGF-7, FGF 9, FGF-18, and FGF-21) spanning five FGF subfamilies to probe their specificities for HS at different levels as follows: binding parameters, identification of heparin-binding sites (HBSs) in the FGFs, changes in their secondary structure caused by heparin binding and structures in the sugar required for binding. For interaction with heparin, the FGFs exhibit K(D) values varying between 38 nM (FGF 18) and 620 nM (FGF-9) and association rate constants spanning over 20-fold (FGF 1, 2,900,000 M(-1) s(-1) and FGF-9, 130,000 M(-1) s(-1)). The canonical HBS in FGF-1, FGF-2, FGF-7, FGF-9, and FGF-18 differs in its size, and these FGFs have a different complement of secondary HBS, ranging from none (FGF-9) to two (FGF-1). Differential scanning fluorimetry identified clear preferences in these FGFs for distinct structural features in the polysaccharide. These data suggest that the differences in heparin-binding sites in both the protein and the sugar are greatest between subfamilies and may be more restricted within a FGF subfamily in accord with the known conservation of function within FGF subfamilies. PMID- 23019344 TI - Overcoming transcription activator-like effector (TALE) DNA binding domain sensitivity to cytosine methylation. AB - Within the past 2 years, transcription activator-like effector (TALE) DNA binding domains have emerged as the new generation of engineerable platform for production of custom DNA binding domains. However, their recently described sensitivity to cytosine methylation represents a major bottleneck for genome engineering applications. Using a combination of biochemical, structural, and cellular approaches, we were able to identify the molecular basis of such sensitivity and propose a simple, drug-free, and universal method to overcome it. PMID- 23019346 TI - A newly identified enhancer element responsible for type II collagen gene expression. AB - Type II collagen is a major component of cartilage where it is present at a high concentration, which is essential for the functional maintenance of the tissue. Therefore, any fundamental understanding of the physiology of cartilage tissue must include an understanding of the mechanism that allows the high level of expression of type II collagen gene, Col2a1, by chondrocytes. To this end, we developed a new reporter assay system based on the co-transfection of candidate enhancer elements and reporter construct into Swarm rat chondrosarcoma chondrocytes that allowed their stable expression. Using this system, we screened more than 70 kb of the Col2a1 gene and found an enhancer domain that is responsible for the regulation of its expression level. The domain is localized in intron 7, and consists of an 800-bp region that contains within it a previously unidentified domain, ~140 bp in size. PMID- 23019345 TI - Peroxiredoxin I null mice exhibits reduced acute lung inflammation following ozone exposure. AB - Acute ozone (O(3)) exposure causes oxidative stress leading inflammation in the lung. However, its precise mechanisms are not fully elucidated. Here, we examined the role of peroxiredoxin I (PrxI) in O(3)-induced pulmonary inflammation using PrxI null (PrxI(-/-)) and wild-type (WT) mice. PrxI is known as an antioxidant and also emerged as a potent proinflammatory factor that activates toll-like receptor 4/nuclear factor-kappa B signalling. Both mice were exposed to 2 ppm O(3) for 6 h and their responses to oxidative stress and acute inflammation in the lung were evaluated after 18 h. The O(3) inhalation activated the transcription factor nuclear factor-erythroid 2-related factor 2 and upregulated heme oxygenase-1 mRNA, the typical makers of oxidative stress, to similar extent in both lungs observed after 0 and 4 h, respectively. O(3) exposure induced significantly less pulmonary inflammation in PrxI(-/-) than in WT mice judging from the reduced infiltrations of neutrophils into the lung and the suppressed production of proinflammatory mediators, such as interleukin-6 and keratinocyte chemoattractant in the bronchoalveolar lavage fluids. Our results suggest that PrxI is not an effective protector against O(3)-induced oxidative damages reportedly caused by harmful lipid metabolites but plays a positive role in the initiation of lung inflammation following O(3) exposure. PMID- 23019347 TI - Correlation between the number of lymph node metastases and lung metastasis in papillary thyroid cancer. AB - CONTEXT: A prognostic classification system based on aggregate numbers of lymph node metastases may better estimate the risk of distant metastasis. OBJECTIVE: This investigation sought to evaluate a papillary thyroid cancer (PTC) patient's risk of distant metastasis. DESIGN: This was a retrospective analysis. SETTING: The setting was a tertiary referral center. PATIENTS: Included were 972 PTC patients. INTERVENTION: The intervention was compartment-oriented surgery. MAIN OUTCOME MEASURE: The main outcome measure was lung, bone, and liver metastasis. RESULTS: Eighty-seven (9.0%) of the 972 PTC patients had distant metastases to lung (79 patients), bone (16 patients), liver (two patients), brain and skin (one patient each). For distant metastasis, more than 20 lymph node metastases had a specificity of 90.8% and a negative predictive value of 92.7%, whereas sensitivity and positive predictive value were low (27.6 and 22.9%). On multivariate logistic regression, 1-5, 6-10, and 11-20 involved nodes denoted a moderate risk of lung metastasis [odds ratio (OR), 9.9, 10.6, and 13.8; P <= 0.004], whereas more than 20 involved nodes indicated a high risk of lung metastasis (OR, 25.0; P < 0.001). Mediastinal lymph node metastasis carried a moderate risk of lung metastasis (OR, 7.5; P = 0.001). When these numeric categories of lymph node metastases were exchanged for current tumor node metastasis (TNM) N categories, the OR decreased from 25.0 (for > 20 lymph node metastases) to 16.4 (N1b), and from 9.9-13.8 (for 1-20 lymph node metastases) to 4.7 (N1a). CONCLUSION: In PTC, categories of 0, 1-20, and more than 20 lymph node metastases correlate better with lung metastasis than current TNM N categories N0, N1a, and N1b. PMID- 23019349 TI - Thyroid nodules treated with percutaneous radiofrequency thermal ablation: a comparative study. AB - PURPOSE: Percutaneous radiofrequency thermal ablation (RTA) was reported as an effective tool for the management of thyroid nodules (TNs). The aim of this study was to investigate the effects of RTA and to establish whether they were treatment-related by comparison with a matched, untreated control group. PATIENTS AND METHODS: The study population included 40 patients with compressive TNs: 22 had nontoxic TNs, and 18 had toxic TNs and were treated with methimazole. In all patients, a fine-needle aspiration cytology was performed to exclude a thyroid malignancy. STUDY DESIGN: Twenty patients were treated with RTA (group A), and 20 others did not receive any treatment (group B). At baseline, age, gender, and TN features did not differ significantly between groups. All patients were clinically, biochemically, and morphologically evaluated at baseline and after 1, 3, 6, and 12 months. RESULTS: TN volume significantly decreased in group A (1.8 +/- 0.3 ml at 12 months vs. 13.3 +/- 1.8 ml at baseline; P < 0.0001) and remained stable in group B [11.7 +/- 1.5 ml at 12 months vs. 11.2 +/- 1.5 ml at baseline; P = not significant (NS)]. At 3-, 6-, and 12-month evaluations, TN volume was significantly lower in group A than in group B (P < 0.005). At the end of the follow-up, pressure symptoms were improved in all patients in group A but persisted unchanged in group B. In group A, hyperthyroidism completely recovered in 40% and improved in 40% of patients with toxic TNs, whereas it persisted in all patients with toxic TNs in group B. RTA was safe and well tolerated in all patients. CONCLUSIONS: RTA induced a marked TN volume shrinkage resulting in parallel improvement of pressure symptoms. In most patients with toxic TNs, hyperthyroidism significantly improved as well. RTA may represent a valid therapeutic approach in patients with TNs not receiving conventional treatments. PMID- 23019348 TI - Update in TSH receptor agonists and antagonists. AB - The physiological role of the TSH receptor (TSHR) as a major regulator of thyroid function is well understood, but TSHRs are also expressed in multiple normal extrathyroidal tissues, and the physiological roles of TSHRs in these tissues are unclear. Moreover, TSHRs play a major role in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Small molecule, "drug-like" TSHR agonists, neutral antagonists, and inverse agonists may be useful as probes of TSHR function in extrathyroidal tissues and as leads to develop drugs for several diseases of the thyroid. In this Update, we review the most recent findings regarding the development and use of these small molecule TSHR ligands. PMID- 23019350 TI - Sex differences in the neurokinin B system in the human infundibular nucleus. AB - CONTEXT: The recent report that loss-of-function mutations in either the gene encoding neurokinin B (NKB) or its receptor (NK3R) produce gonadotropin deficiencies in humans strongly points to NKB as a key regulator of GnRH release. OBJECTIVES: We used NKB immunohistochemistry on postmortem human brain tissue to determine: 1) whether the human NKB system in the infundibular nucleus (INF) is sexually dimorphic; 2) at what stage in development the infundibular NKB system would diverge between men and women; 3) whether this putative structural difference is reversed in male-to-female (MtF) transsexual people; and 4) whether menopause is accompanied by changes in infundibular NKB immunoreactivity. METHODS: NKB immunohistochemical staining was performed on postmortem hypothalamus material of both sexes from the infant/pubertal period into the elderly period and from MtF transsexuals. RESULTS: Quantitative analysis demonstrated that the human NKB system exhibits a robust female-dominant sexual dimorphism in the INF. During the first years after birth, both sexes displayed a moderate and equivalent level of NKB immunoreactivity in the INF. The adult features emerged progressively around puberty until adulthood, where the female dominant sex difference appeared and continued into old age. In MtF transsexuals, a female-typical NKB immunoreactivity was observed. Finally, in postmenopausal women, there was a significant increase in NKB immunoreactivity compared to premenopausal women. CONCLUSION: Our results indicate that certain sex differences do not emerge until adulthood when activated by sex steroid hormones and the likely involvement of the human infundibular NKB system in the negative and positive feedback of estrogen on GnRH secretion. PMID- 23019351 TI - Bone marrow localisation of metastatic melanoma and synchronous leukaemic evolution of low-risk myelodysplastic syndrome. PMID- 23019353 TI - Saturation wind power potential and its implications for wind energy. AB - Wind turbines convert kinetic to electrical energy, which returns to the atmosphere as heat to regenerate some potential and kinetic energy. As the number of wind turbines increases over large geographic regions, power extraction first increases linearly, but then converges to a saturation potential not identified previously from physical principles or turbine properties. These saturation potentials are >250 terawatts (TW) at 100 m globally, approximately 80 TW at 100 m over land plus coastal ocean outside Antarctica, and approximately 380 TW at 10 km in the jet streams. Thus, there is no fundamental barrier to obtaining half (approximately 5.75 TW) or several times the world's all-purpose power from wind in a 2030 clean-energy economy. PMID- 23019352 TI - Chemical approaches to artificial photosynthesis. PMID- 23019354 TI - Experimental results from a preclinical X-ray phase-contrast CT scanner. AB - To explore the future clinical potential of improved soft-tissue visibility with grating-based X-ray phase contrast (PC), we have developed a first preclinical computed tomography (CT) scanner featuring a rotating gantry. The main challenge in the transition from previous bench-top systems to a preclinical scanner are phase artifacts that are caused by minimal changes in the grating alignment during gantry rotation. In this paper, we present the first experimental results from the system together with an adaptive phase recovery method that corrects for these phase artifacts. Using this method, we show that the scanner can recover quantitatively accurate Hounsfield units in attenuation and phase. Moreover, we present a first tomography scan of biological tissue with complementary information in attenuation and phase contrast. The present study hence demonstrates the feasibility of grating-based phase contrast with a rotating gantry for the first time and paves the way for future in vivo studies on small animal disease models (in the mid-term future) and human diagnostics applications (in the long-term future). PMID- 23019355 TI - Pointillist structural color in Pollia fruit. AB - Biological communication by means of structural color has existed for at least 500 million years. Structural color is commonly observed in the animal kingdom, but has been little studied in plants. We present a striking example of multilayer-based strong iridescent coloration in plants, in the fruit of Pollia condensata. The color is caused by Bragg reflection of helicoidally stacked cellulose microfibrils that form multilayers in the cell walls of the epicarp. We demonstrate that animals and plants have convergently evolved multilayer-based photonic structures to generate colors using entirely distinct materials. The bright blue coloration of this fruit is more intense than that of any previously described biological material. Uniquely in nature, the reflected color differs from cell to cell, as the layer thicknesses in the multilayer stack vary, giving the fruit a striking pixelated or pointillist appearance. Because the multilayers form with both helicoidicities, optical characterization reveals that the reflected light from every epidermal cell is polarized circularly either to the left or to the right, a feature that has never previously been observed in a single tissue. PMID- 23019356 TI - Folate binding site of flavin-dependent thymidylate synthase. AB - The DNA nucleotide thymidylate is synthesized by the enzyme thymidylate synthase, which catalyzes the reductive methylation of deoxyuridylate using the cofactor methylene-tetrahydrofolate (CH(2)H(4)folate). Most organisms, including humans, rely on the thyA- or TYMS-encoded classic thymidylate synthase, whereas, certain microorganisms, including all Rickettsia and other pathogens, use an alternative thyX-encoded flavin-dependent thymidylate synthase (FDTS). Although several crystal structures of FDTSs have been reported, the absence of a structure with folates limits understanding of the molecular mechanism and the scope of drug design for these enzymes. Here we present X-ray crystal structures of FDTS with several folate derivatives, which together with mutagenesis, kinetic analysis, and computer modeling shed light on the cofactor binding and function. The unique structural data will likely facilitate further elucidation of FDTSs' mechanism and the design of structure-based inhibitors as potential leads to new antimicrobial drugs. PMID- 23019357 TI - Selection of antibodies that regulate phenotype from intracellular combinatorial antibody libraries. AB - A method is presented that uses combinatorial antibody libraries to endow cells with new binding energy landscapes for the purpose of regulating their phenotypes. Antibodies that are expressed in cells infected with a lentiviral combinatorial antibody library are selected directly for function rather than only for binding. The potential diversity space can be very large because more than one lentivirus can infect a single cell. Thus, the initial combinatorial diversity of ~1.0 * 10(11) members generated by the random association of antibody heavy and light chains is greatly increased by the reassortment of the antibody Fv domains themselves inside cells. The power of the system is illustrated by its ability to select unusual antibodies. Here, the selected antibodies are potent erythropoietin agonists whose ontogeny depends on recombination at the protein level of pairs of antibodies expressed in the same cell to generate heterodimeric bispecific antibodies. The obligate synergy between the different binding specificities of the antibody's monomeric subunits appears to replicate the asymmetric binding mechanism of authentic erythropoietin. PMID- 23019358 TI - Reversible cycling between cysteine persulfide-ligated [2Fe-2S] and cysteine ligated [4Fe-4S] clusters in the FNR regulatory protein. AB - Fumarate and nitrate reduction (FNR) regulatory proteins are O(2)-sensing bacterial transcription factors that control the switch between aerobic and anaerobic metabolism. Under anaerobic conditions [4Fe-4S](2+)-FNR exists as a DNA binding homodimer. In response to elevated oxygen levels, the [4Fe-4S](2+) cluster undergoes a rapid conversion to a [2Fe-2S](2+) cluster, resulting in a dimer-to-monomer transition and loss of site-specific DNA binding. In this work, resonance Raman and UV-visible absorption/CD spectroscopies and MS were used to characterize the interconversion between [4Fe-4S](2+) and [2Fe-2S](2+) clusters in Escherichia coli FNR. Selective (34)S labeling of the bridging sulfides in the [4Fe-4S](2+) cluster-bound form of FNR facilitated identification of resonantly enhanced Cys(32)S-(34)S stretching modes in the resonance Raman spectrum of the O(2)-exposed [2Fe-2S](2+) cluster-bound form of FNR. This result indicates O(2) induced oxidation and retention of bridging sulfides in the form of [2Fe-2S](2+) cluster-bound cysteine persulfides. MS also demonstrates that multiple cysteine persulfides are formed on O(2) exposure of [4Fe-4S](2+)-FNR. The [4Fe-4S](2+) cluster in FNR can also be regenerated from the cysteine persulfide-coordinated [2Fe-2S](2+) cluster by anaerobic incubation with DTT and Fe(2+) ion in the absence of exogenous sulfide. Resonance Raman data indicate that this type of cluster conversion involving sulfide oxidation is not unique to FNR, because it also occurs in O(2)-exposed forms of O(2)-sensitive [4Fe-4S] clusters in radical S-adenosylmethionine enzymes. The results provide fresh insight into the molecular mechanism of O(2) sensing by FNR and iron-sulfur cluster conversion reactions in general, and suggest unique mechanisms for the assembly or repair of biological [4Fe-4S] clusters. PMID- 23019359 TI - Topography of funneled landscapes determines the thermodynamics and kinetics of protein folding. AB - The energy landscape approach has played a fundamental role in advancing our understanding of protein folding. Here, we quantify protein folding energy landscapes by exploring the underlying density of states. We identify three quantities essential for characterizing landscape topography: the stabilizing energy gap between the native and nonnative ensembles deltaE, the energetic roughness DeltaE, and the scale of landscape measured by the entropy S. We show that the dimensionless ratio between the gap, roughness, and entropy of the system Lambda=deltaE/(DeltaE?(2S)) accurately predicts the thermodynamics, as well as the kinetics of folding. Large Lambda implies that the energy gap (or landscape slope towards the native state) is dominant, leading to more funneled landscapes. We investigate the role of topological and energetic roughness for proteins of different sizes and for proteins of the same size, but with different structural topologies. The landscape topography ratio Lambda is shown to be monotonically correlated with the thermodynamic stability against trapping, as characterized by the ratio of folding temperature versus trapping temperature. Furthermore, Lambda also monotonically correlates with the folding kinetic rates. These results provide the quantitative bridge between the landscape topography and experimental folding measurements. PMID- 23019360 TI - Evidence that viral RNAs have evolved for efficient, two-stage packaging. AB - Genome packaging is an essential step in virus replication and a potential drug target. Single-stranded RNA viruses have been thought to encapsidate their genomes by gradual co-assembly with capsid subunits. In contrast, using a single molecule fluorescence assay to monitor RNA conformation and virus assembly in real time, with two viruses from differing structural families, we have discovered that packaging is a two-stage process. Initially, the genomic RNAs undergo rapid and dramatic (approximately 20-30%) collapse of their solution conformations upon addition of cognate coat proteins. The collapse occurs with a substoichiometric ratio of coat protein subunits and is followed by a gradual increase in particle size, consistent with the recruitment of additional subunits to complete a growing capsid. Equivalently sized nonviral RNAs, including high copy potential in vivo competitor mRNAs, do not collapse. They do support particle assembly, however, but yield many aberrant structures in contrast to viral RNAs that make only capsids of the correct size. The collapse is specific to viral RNA fragments, implying that it depends on a series of specific RNA protein interactions. For bacteriophage MS2, we have shown that collapse is driven by subsequent protein-protein interactions, consistent with the RNA protein contacts occurring in defined spatial locations. Conformational collapse appears to be a distinct feature of viral RNA that has evolved to facilitate assembly. Aspects of this process mimic those seen in ribosome assembly. PMID- 23019361 TI - Supertertiary structure of the synaptic MAGuK scaffold proteins is conserved. AB - Scaffold proteins form a framework to organize signal transduction by binding multiple partners within a signaling pathway. This shapes the output of signal responses as well as providing specificity and localization. The Membrane Associated Guanylate Kinases (MAGuKs) are scaffold proteins at cellular junctions that localize cell surface receptors and link them to downstream signaling enzymes. Scaffold proteins often contain protein-binding domains that are connected in series by disordered linkers. The tertiary structure of the folded domains is well understood, but describing the dynamic inter-domain interactions (the superteritary structure) of such multidomain proteins remains a challenge to structural biology. We used 65 distance restraints from single-molecule fluorescence resonance energy transfer (smFRET) to describe the superteritary structure of the canonical MAGuK scaffold protein PSD-95. By combining multiple fluorescence techniques, the conformational dynamics of PSD-95 could be characterized across the biologically relevant timescales for protein domain motions. Relying only on a qualitative interpretation of FRET data, we were able to distinguish stable interdomain interactions from freely orienting domains. This revealed that the five domains in PSD-95 partitioned into two independent supramodules: PDZ1-PDZ2 and PDZ3-SH3-GuK. We used our smFRET data for hybrid structural refinement to model the PDZ3-SH3-GuK supramodule and include explicit dye simulations to provide complete characterization of potential uncertainties inherent to quantitative interpretation of FRET as distance. Comparative structural analysis of synaptic MAGuK homologues showed a conservation of this supertertiary structure. Our approach represents a general solution to describing the supertertiary structure of multidomain proteins. PMID- 23019362 TI - TBC1D16 is a Rab4A GTPase activating protein that regulates receptor recycling and EGF receptor signaling. AB - Rab4A is a master regulator of receptor recycling from endocytic compartments to the plasma membrane. The protein TBC1D16 is up-regulated in melanoma, and TBC1D16 overexpressing melanoma cells are dependent on TBC1D16. We show here that TBC1D16 enhances the intrinsic rate of GTP hydrolysis by Rab4A. TBC1D16 is both cytosolic and membrane associated; the membrane-associated pool colocalizes with transferrin and EGF receptors (EGFRs) and early endosome antigen 1, but not with LAMP1 protein. Expression of two TBC1D16 isoforms, but not the inactive R494A mutant, reduces transferrin receptor recycling but has no effect on transferrin receptor internalization. Expression of TBC1D16 alters GFP-Rab4A membrane localization. In HeLa cells, overexpression of TBC1D16 enhances EGF-stimulated EGFR degradation, concomitant with decreased EGFR levels and signaling. Thus, TBC1D16 is a GTPase activating protein for Rab4A that regulates transferrin receptor recycling and EGFR trafficking and signaling. PMID- 23019364 TI - Dual modes of motility at the leading edge of migrating epithelial cell sheets. AB - Purse-string healing is driven by contraction of actin/myosin cables that span cells at wound edges, and it is the predominant mode of closing small round wounds in embryonic and some adult epithelia. Wounds can also heal by cell crawling, and my colleagues and I have shown previously that the presence of unconstrained, straight edges in sheets of epithelial cells is a sufficient signal to induce healing by crawling. Here, it is reported that the presence of highly concave edges, which are free or physically constrained by an inert material (agarose), is sufficient to induce formation of purse strings. It was determined that neither of the two types of healing required cell damage or other potential stimuli by using the particularly gentle procedure of introducing gaps by digesting agarose blocks imbedded in the cell sheets. Movement by crawling depends on signaling by the EGF receptor (EGFR); however, this was not required for purse-string contraction. A migrating epithelial cell sheet usually produces finger-like projections of crawling cells. The cells between fingers contain continuous actin cables, which were also determined to contain myosin IIA and exhibit additional characteristics of purse strings. When crawling was blocked by inhibition of EGFR signaling, the concave regions continued to move, suggesting that both mechanisms contribute to propel the sheets forward. Wounding epithelial cell sheets causes activation of the EGFR, which triggers movement by crawling. The EGFR was found to be activated only at straight and convex edges, which explains how both types of movement can coexist at leading epithelial edges. PMID- 23019365 TI - cAMP response element-binding protein promotes gliomagenesis by modulating the expression of oncogenic microRNA-23a. AB - Gliomas are the most common and deadly type of primary brain tumor. In this study, we showed that cAMP response element-binding protein (CREB), a proto oncogenic transcription factor that is overexpressed in gliomas, can promote gliomagenesis by modulating the expression of oncogenic microRNA-23a (mir-23a). First, we found that CREB is highly expressed in glioma tissues and cell lines. CREB is also essential for glioma cell growth and cell survival in vitro and is critical for gliomagenesis in vivo. Second, microRNA microarray, ChIP-chip, ChIP quantitative PCR, and luciferase reporter assays showed that CREB directly binds to the regulatory sequences of mir-23a and enhance the expression of mir-23a. Moreover, mir-23a was confirmed as a functional downstream target of CREB in glioma cell growth and cell survival. Finally, using computational prediction followed by experimental confirmation, we identified PTEN, which is frequently silenced in gliomas, as a downstream target of mir-23a. Taken together, we propose that CREB promotes gliomagenesis and acts as a modulator of oncogenic mir 23a, which represses the tumor suppressor PTEN. PMID- 23019366 TI - Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi. AB - In the adult intestine, an organized array of finger-like projections, called villi, provide an enormous epithelial surface area for absorptive function. Villi first emerge at embryonic day (E) 14.5 from a previously flat luminal surface. Here, we analyze the cell biology of villus formation and examine the role of paracrine epithelial Hedgehog (Hh) signals in this process. We find that, before villus emergence, tight clusters of Hh-responsive mesenchymal cells form just beneath the epithelium. Cluster formation is dynamic; clusters first form dorsally and anteriorly and spread circumferentially and posteriorly. Statistical analysis of cluster distribution reveals a patterned array; with time, new clusters form in spaces between existing clusters, promoting approximately four rounds of villus emergence by E18.5. Cells within mesenchymal clusters express Patched1 and Gli1, as well as Pdgfralpha, a receptor previously shown to participate in villus development. BrdU-labeling experiments show that clusters form by migration and aggregation of Hh-responsive cells. Inhibition of Hh signaling prevents cluster formation and villus development, but does not prevent emergence of villi in areas where clusters have already formed. Conversely, increasing Hh signaling increases the size of villus clusters and results in exceptionally wide villi. We conclude that Hh signals dictate the initial aspects of the formation of each villus by controlling mesenchymal cluster aggregation and regulating cluster size. PMID- 23019367 TI - Allometric scaling of population variance with mean body size is predicted from Taylor's law and density-mass allometry. AB - Two widely tested empirical patterns in ecology are combined here to predict how the variation of population density relates to the average body size of organisms. Taylor's law (TL) asserts that the variance of the population density of a set of populations is a power-law function of the mean population density. Density-mass allometry (DMA) asserts that the mean population density of a set of populations is a power-law function of the mean individual body mass. Combined, DMA and TL predict that the variance of the population density is a power-law function of mean individual body mass. We call this relationship "variance-mass allometry" (VMA). We confirmed the theoretically predicted power-law form and the theoretically predicted parameters of VMA, using detailed data on individual oak trees (Quercus spp.) of Black Rock Forest, Cornwall, New York. These results connect the variability of population density to the mean body mass of individuals. PMID- 23019368 TI - Position-dependent correlations between DNA methylation and the evolutionary rates of mammalian coding exons. AB - DNA cytosine methylation is a central epigenetic marker that is usually mutagenic and may increase the level of sequence divergence. However, methylated genes have been reported to evolve more slowly than unmethylated genes. Hence, there is a controversy on whether DNA methylation is correlated with increased or decreased protein evolutionary rates. We hypothesize that this controversy has resulted from the differential correlations between DNA methylation and the evolutionary rates of coding exons in different genic positions. To test this hypothesis, we compare human-mouse and human-macaque exonic evolutionary rates against experimentally determined single-base resolution DNA methylation data derived from multiple human cell types. We show that DNA methylation is significantly related to within-gene variations in evolutionary rates. First, DNA methylation level is more strongly correlated with C-to-T mutations at CpG dinucleotides in the first coding exons than in the internal and last exons, although it is positively correlated with the synonymous substitution rate in all exon positions. Second, for the first exons, DNA methylation level is negatively correlated with exonic expression level, but positively correlated with both nonsynonymous substitution rate and the sample specificity of DNA methylation level. For the internal and last exons, however, we observe the opposite correlations. Our results imply that DNA methylation level is differentially correlated with the biological (and evolutionary) features of coding exons in different genic positions. The first exons appear more prone to the mutagenic effects, whereas the other exons are more influenced by the regulatory effects of DNA methylation. PMID- 23019363 TI - Dinoflagellate tandem array gene transcripts are highly conserved and not polycistronic. AB - Dinoflagellates are an important component of the marine biota, but a large genome with high-copy number (up to 5,000) tandem gene arrays has made genomic sequencing problematic. More importantly, little is known about the expression and conservation of these unusual gene arrays. We assembled de novo a gene catalog of 74,655 contigs for the dinoflagellate Lingulodinium polyedrum from RNA Seq (Illumina) reads. The catalog contains 93% of a Lingulodinium EST dataset deposited in GenBank and 94% of the enzymes in 16 primary metabolic KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, indicating it is a good representation of the transcriptome. Analysis of the catalog shows a marked underrepresentation of DNA-binding proteins and DNA-binding domains compared with other algae. Despite this, we found no evidence to support the proposal of polycistronic transcription, including a marked underrepresentation of sequences corresponding to the intergenic spacers of two tandem array genes. We also have used RNA-Seq to assess the degree of sequence conservation in tandem array genes and found their transcripts to be highly conserved. Interestingly, some of the sequences in the catalog have only bacterial homologs and are potential candidates for horizontal gene transfer. These presumably were transferred as single-copy genes, and because they are now all GC-rich, any derived from AT-rich contexts must have experienced extensive mutation. Our study not only has provided the most complete dinoflagellate gene catalog known to date, it has also exploited RNA-Seq to address fundamental issues in basic transcription mechanisms and sequence conservation in these algae. PMID- 23019369 TI - Genetic composition of yield heterosis in an elite rice hybrid. AB - Heterosis refers to the superior performance of hybrids relative to the parents. Utilization of heterosis has contributed tremendously to the increased productivity in many crops for decades. Although there have been a range of studies on various aspects of heterosis, the key to understanding the biological mechanisms of heterotic performance in crop hybrids is the genetic basis, much of which is still uncharacterized. In this study, we dissected the genetic composition of yield and yield component traits using data of replicated field trials of an "immortalized F(2)" population derived from an elite rice hybrid. On the basis of an ultrahigh-density SNP bin map constructed with population sequencing, we calculated single-locus and epistatic genetic effects in the whole genome and identified components pertaining to heterosis of the hybrid. The results showed that the relative contributions of the genetic components varied with traits. Overdominance/pseudo-overdominance is the most important contributor to heterosis of yield, number of grains per panicle, and grain weight. Dominance * dominance interaction is important for heterosis of tillers per plant and grain weight and has roles in yield and grain number. Single-locus dominance has relatively small contributions in all of the traits. The results suggest that cumulative effects of these components may adequately explain the genetic basis of heterosis in the hybrid. PMID- 23019370 TI - p21-activated kinase interacts with Wnt signaling to regulate tissue polarity and gene expression. AB - Wnt signaling is mediated by three classes of receptors, Frizzled, Ryk, and Ror. In Caenorhabditis elegans, Wnt signaling regulates the anterior/posterior polarity of the P7.p vulval lineage, and mutations in lin-17/Frizzled cause loss or reversal of P7.p lineage polarity. We found that pak-1/Pak (p21-activated kinase), along with putative activators of Pak, nck-1/Nck, and ced-10/Rac, regulates P7.p polarity. Mutations in these genes suppress the polarity defect of lin-17 mutants. Furthermore, mutations in pak-1, nck-1, and ced-10 cause constitutive dauer formation at 27 degrees C, a phenotype also observed in egl 20/Wnt and cam-1/Ror mutants. In HEK293T cells, Pak1 can antagonize canonical Wnt signaling. Moreover, overexpression of Ror2 leads to phosphorylation of Pak1. Together, these results indicate that Pak interacts with Wnt signaling to regulate tissue polarity and gene expression. PMID- 23019371 TI - A mouse model for HIV-1 entry. AB - Passive transfer of neutralizing antibodies against HIV-1 can prevent infection in macaques and seems to delay HIV-1 rebound in humans. Anti-HIV antibodies are therefore of great interest for vaccine design. However, the basis for their in vivo activity has been difficult to evaluate systematically because of a paucity of small animal models for HIV infection. Here we report a genetically humanized mouse model that incorporates a luciferase reporter for rapid quantitation of HIV entry. An antibody's ability to block viral entry in this in vivo model is a function of its bioavailability, direct neutralizing activity, and effector functions. PMID- 23019372 TI - Single-cell analysis of early B-lymphocyte development suggests independent regulation of lineage specification and commitment in vivo. AB - To better understand the process of B-lymphocyte lineage restriction, we have investigated molecular and functional properties in early B-lineage cells from Pax-5-deficient animals crossed to a B-lineage-restricted reporter mouse, allowing us to identify B-lineage-specified progenitors independently of conventional surface markers. Pax-5 deficiency resulted in a dramatic increase in the frequency of specified progenitor B-cells marked by expression of a lambda5 (Igll1) promoter-controlled reporter gene. Gene expression analysis of ex vivo isolated progenitor cells revealed that Pax-5 deficiency has a minor impact on B cell specification. However, single-cell in vitro differentiation analysis of ex vivo isolated cells revealed that specified B-lineage progenitors still displayed a high degree of plasticity for development into NK or T lineage cells. In contrast, we were unable to detect any major changes in myeloid lineage potential in specified Pax-5-deficient cells. By comparison of gene expression patterns in ex vivo isolated Pax-5- and Ebf-1-deficient progenitors, it was possible to identify a set of B-cell-restricted genes dependent on Ebf-1 but not Pax-5, supporting the idea that B-cell specification and commitment is controlled by distinct regulatory networks. PMID- 23019373 TI - T cells engineered with a T cell receptor against the prostate antigen TARP specifically kill HLA-A2+ prostate and breast cancer cells. AB - To produce genetically engineered T cells directed against prostate and breast cancer cells, we have cloned the T-cell receptor recognizing the HLA-A2 restricted T-cell receptor gamma-chain alternate reading-frame protein (TARP)(4 13) epitope. TARP is a protein exclusively expressed in normal prostate epithelium and in adenocarcinomas of the prostate and breast. Peripheral blood T cells transduced with a lentiviral vector encoding the TARP-TCR proliferated well when exposed to peptide-specific stimuli. These cells exerted peptide-specific IFN-gamma production and cytotoxic activity. Importantly, HLA-A2(+) prostate and breast cancer cells expressing TARP were also killed, demonstrating that the TARP(4-13) epitope is a physiologically relevant target for T-cell therapy of prostate and breast cancer. In conclusion, we present the cloning of a T cell receptor (TCR) directed against a physiologically relevant HLA-A2 epitope of TARP. To our knowledge this report on engineering of T cells with a TCR directed against an antigen specifically expressed by prostate cells is unique. PMID- 23019374 TI - Virulence and transmissibility of H1N2 influenza virus in ferrets imply the continuing threat of triple-reassortant swine viruses. AB - Efficient worldwide swine surveillance for influenza A viruses is urgently needed; the emergence of a novel reassortant pandemic H1N1 (pH1N1) virus in 2009 demonstrated that swine can be the direct source of pandemic influenza and that the pandemic potential of viruses prevalent in swine populations must be monitored. We used the ferret model to assess the pathogenicity and transmissibility of predominant Korean triple-reassortant swine (TRSw) H1N2 and H3N2 influenza viruses genetically related to North American strains. Although most of the TRSw viruses were moderately pathogenic, one [A/Swine/Korea/1204/2009; Sw/1204 (H1N2)] was virulent in ferrets, causing death within 10 d of inoculation, and was efficiently transmitted to naive contact ferrets via respiratory droplets. Although molecular analysis did not reveal known virulence markers, the Sw/1204 virus acquired mutations in hemagglutinin (HA) (Asp-225-Gly) and neuraminidase (NA) (Ser-315-Asn) proteins during the single ferret passage. The contact-Sw/1204 virus became more virulent in mice, replicated efficiently in vitro, extensively infected human lung tissues ex vivo, and maintained its ability to replicate and transmit in swine. Reverse-genetics studies further indicated that the HA(225G) and NA(315N) substitutions contributed substantially in altering virulence and transmissibility. These findings support the continuing threat of some field TRSw viruses to human and animal health, reviving concerns on the capacity of pigs to create future pandemic viruses. Apart from warranting continued and enhanced global surveillance, this study also provides evidence on the emerging roles of HA(225G) and NA(315N) as potential virulence markers in mammals. PMID- 23019375 TI - Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease. AB - DJ-1 mutations cause autosomal recessive early-onset Parkinson disease (PD). We report a model of PD pathology: the DJ1-C57 mouse. A subset of DJ-1-nullizygous mice, when fully backcrossed to a C57BL/6 [corrected] background, display dramatic early-onset unilateral loss of dopaminergic (DA) neurons in their substantia nigra pars compacta, progressing to bilateral degeneration of the nigrostriatal axis with aging. In addition, these mice exhibit age-dependent bilateral degeneration at the locus ceruleus nucleus and display mild motor behavior deficits at aged time points. These findings effectively recapitulate the early stages of PD. Therefore, the DJ1-C57 mouse provides a tool to study the preclinical aspects of neurodegeneration. Importantly, by exome sequencing, we identify candidate modifying genes that segregate with the phenotype, providing potentially critical clues into how certain genes may influence the penetrance of DJ-1-related degeneration in mice. PMID- 23019376 TI - Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses. AB - Formation of specific neuronal connections often involves competition between adjacent axons, leading to stabilization of the active terminal, while retraction of the less active ones. The underlying molecular mechanisms remain unknown. We show that activity-dependent conversion of pro-brain-derived neurotrophic factor (proBDNF) to mature (m)BDNF mediates synaptic competition. Stimulation of motoneurons triggers proteolytic conversion of proBDNF to mBDNF at nerve terminals. In Xenopus nerve-muscle cocultures, in which two motoneurons innervate one myocyte, proBDNF-p75(NTR) signaling promotes retraction of the less active terminal, whereas mBDNF-tyrosine-related kinase B (TrkB) p75NTR (p75 neurotrophin receptor) facilitates stabilization of the active one. Thus, proBDNF and mBDNF may serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, and activity-dependent conversion of proBDNF to mBDNF may regulate synapse elimination. PMID- 23019377 TI - Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis. AB - Toxoplasma gondii is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show that the endochin like quinolone (ELQ) class of compounds contains extremely potent inhibitors of T. gondii growth in vitro and is effective against acute and latent toxoplasmosis in mice. We screened 50 ELQs against T. gondii and selected two lead compounds, ELQ-271 and ELQ-316, for evaluation. ELQ-271 and ELQ-316, have in vitro IC(50) values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED(50) values of 0.14 mg/kg and 0.08 mg/kg when administered orally to mice with acute toxoplasmosis. Moreover, ELQ-271 and ELQ-316 are highly active against the cyst form of T. gondii in mice at low doses, reducing cyst burden by 76-88% after 16 d of treatment. To investigate the ELQ mechanism of action against T. gondii, we demonstrate that endochin and ELQ-271 inhibit cytochrome c reduction by the T. gondii cytochrome bc(1) complex at 8 nM and 31 nM, respectively. We also show that ELQ-271 inhibits the Saccharomyces cerevisiae cytochrome bc(1) complex, and an M221Q amino acid substitution in the Q(i) site of the protein leads to >100 fold resistance. We conclude that ELQ-271 and ELQ-316 are orally bioavailable drugs that are effective against acute and latent toxoplasmosis, likely acting as inhibitors of the Q(i) site of the T. gondii cytochrome bc(1) complex. PMID- 23019378 TI - Degradation of the antiviral component ARGONAUTE1 by the autophagy pathway. AB - Posttranscriptional gene silencing (PTGS) mediated by siRNAs is an evolutionarily conserved antiviral defense mechanism in higher plants and invertebrates. In this mechanism, viral-derived siRNAs are incorporated into the RNA-induced silencing complex (RISC) to guide degradation of the corresponding viral RNAs. In Arabidopsis, a key component of RISC is ARGONAUTE1 (AGO1), which not only binds to siRNAs but also carries the RNA slicer activity. At present little is known about posttranslational mechanisms regulating AGO1 turnover. Here we report that the viral suppressor of RNA silencing protein P0 triggers AGO1 degradation by the autophagy pathway. Using a P0-inducible transgenic line, we observed that AGO1 degradation is blocked by inhibition of autophagy. The engineering of a functional AGO1 fluorescent reporter protein further indicated that AGO1 colocalizes with autophagy-related (ATG) protein 8a (ATG8a) positive bodies when degradation is impaired. Moreover, this pathway also degrades AGO1 in a nonviral context, especially when the production of miRNAs is impaired. Our results demonstrate that a selective process such as ubiquitylation can lead to the degradation of a key regulatory protein such as AGO1 by a degradation process generally believed to be unspecific. We anticipate that this mechanism will not only lead to degradation of AGO1 but also of its associated proteins and eventually small RNAs. PMID- 23019379 TI - Auditory perception at the root of language learning. AB - Learning a spoken language presupposes efficient auditory functions. In the present event-related potential study, we tested whether and how basic auditory processes are related to online learning of a linguistic rule in infants and adults. Participants listened to frequent standard stimuli, which were interspersed with infrequent pitch deviants and rule deviants, violating a nonadjacent dependency between two syllables. Only infants who showed the more mature mismatch response for the pitch deviants (i.e., a negativity) showed a mismatch response to the rule deviants. Concordantly, the small group of adults who showed evidence of rule learning showed larger mismatch effects for pitch processing. We conclude that the ability to extract linguistic rules develops in early infancy and is tightly linked to functional aspects of basic auditory mechanisms. PMID- 23019381 TI - Anisotropic conductivity of magnetic carbon nanotubes embedded in epoxy matrices. AB - Maghemite (gamma-Fe(2)O(3))/multi-walled carbon nanotubes (MWCNTs) hybrid materials were synthesized and their anisotropic electrical conductivities as a result of their alignment in a polymer matrix under an external magnetic field were investigated. The tethering of gamma-Fe(2)O(3) nanoparticles on the surface of MWCNT was achieved by a modified sol-gel reaction, where sodium dodecylbenzene sulfonate (NaDDBS) was used in order to inhibit the formation of a 3D iron oxide gel. These hybrid-materials, specifically, magnetized multi-walled carbon nanotubes (m-MWCNTs) were readily aligned parallel to the direction of a magnetic field even when using a relatively weak magnetic field. The conductivity of the epoxy composites formed in this manner increased with increasing m-MWCNT mass fraction in the polymer matrix. Furthermore, the conductivities parallel to the direction of magnetic field were higher than those in the perpendicular direction, indicating that the alignment of the m-MWCNT contributed to the enhancement of the anisotropic electrical properties of the composites in the direction of alignment. PMID- 23019380 TI - Nonconscious activation of placebo and nocebo pain responses. AB - The dominant theories of human placebo effects rely on a notion that consciously perceptible cues, such as verbal information or distinct stimuli in classical conditioning, provide signals that activate placebo effects. However, growing evidence suggest that behavior can be triggered by stimuli presented outside of conscious awareness. Here, we performed two experiments in which the responses to thermal pain stimuli were assessed. The first experiment assessed whether a conditioning paradigm, using clearly visible cues for high and low pain, could induce placebo and nocebo responses. The second experiment, in a separate group of subjects, assessed whether conditioned placebo and nocebo responses could be triggered in response to nonconscious (masked) exposures to the same cues. A total of 40 healthy volunteers (24 female, mean age 23 y) were investigated in a laboratory setting. Participants rated each pain stimulus on a numeric response scale, ranging from 0 = no pain to 100 = worst imaginable pain. Significant placebo and nocebo effects were found in both experiment 1 (using clearly visible stimuli) and experiment 2 (using nonconscious stimuli), indicating that the mechanisms responsible for placebo and nocebo effects can operate without conscious awareness of the triggering cues. This is a unique experimental verification of the influence of nonconscious conditioned stimuli on placebo/nocebo effects and the results challenge the exclusive role of awareness and conscious cognitions in placebo responses. PMID- 23019382 TI - Web-Enhanced Preservice Training for Prospective Resource Parents: A Randomized Trial of Effectiveness and User Satisfaction. AB - Traditionally, prospective resource parents must attend all preservice training in person. While live sessions are necessary for activities such as screening applicants, instructional portions of training could be enhanced by web-based sessions. This pilot study compares the effectiveness of online and classroom versions of one session from a widely used preservice training program. Ninety two individuals who volunteered to complete the program in two states were randomly assigned to a treatment group that viewed an online version of the class on child abuse and neglect or a comparison group that took the same class in person. Written questionnaires were completed before and after the class. Significant group differences on knowledge of child maltreatment and empathy toward birth parents, plus high user satisfaction, were hypothesized. ANCOVA results showed the online training was more effective than the live training at increasing knowledge. MANCOVA findings on empathy were not significant but trended toward greater empathy for the online group. Feedback indicated high satisfaction with the online course. If supported by future research, the finding that online instruction is more effective than live has positive implications for practice, because web-based training offers advantages like standardizing instruction, cutting agency and trainee costs, and providing greater flexibility. PMID- 23019383 TI - Partner Choice Patterns Among the Descendants of Turkish Immigrants in Europe. AB - We examine the partner choice patterns of second-generation Turks in 13 European cities in seven countries. We not only compare intermarriage versus endogamous marriage, but also explicitly include the choice of a second-generation partner of the same origin and of a partner of other migrant origin as important alternatives. In Europe, populations are made up increasingly of migrants and their descendants resulting in new alternative partner options not open before. Findings suggest that second-generation Turks who choose a second-generation partner seem to be located between the partner choice of a first-generation and native partner in terms of family values and contact to non-coethnic peers. The choice of a partner of other migrant origin hardly differs in these characteristics from the choice of a native partner. Context variables such as group size and type of integration policies seem to play a role for the likelihood of having a first-generation versus a second-generation partner of Turkish origin but not for the likelihood of exogamous partner choice. A second generation partner is the most popular choice in Germany but represents a minor option in the other countries. Furthermore, a partner of other migrant origin is more common among men but is in some countries more popular than a native partner among Turkish second-generation men and women. PMID- 23019385 TI - Finding Seeds for Segmentation Using Statistical Fusion. AB - Image labeling is an essential step for quantitative analysis of medical images. Many image labeling algorithms require seed identification in order to initialize segmentation algorithms such as region growing, graph cuts, and the random walker. Seeds are usually placed manually by human raters, which makes these algorithms semi-automatic and can be prohibitive for very large datasets. In this paper an automatic algorithm for placing seeds using multi-atlas registration and statistical fusion is proposed. Atlases containing the centers of mass of a collection of neuroanatomical objects are deformably registered in a training set to determine where these centers of mass go after labels transformed by registration. The biases of these transformations are determined and incorporated in a continuous form of Simultaneous Truth And Performance Level Estimation (STAPLE) fusion, thereby improving the estimates (on average) over a single registration strategy that does not incorporate bias or fusion. We evaluate this technique using real 3D brain MR image atlases and demonstrate its efficacy on correcting the data bias and reducing the fusion error. PMID- 23019387 TI - Echocardiography in transcatheter aortic valve implantation and mitral valve clip. AB - Transcatheter aortic valve implantation and transcatheter mitral valve repair (MitraClip) procedures have been performed worldwide. In this paper, we review the use of two-dimensional and three-dimensional transesophageal echo for guiding transcatheter aortic valve replacement and mitral valve repair. PMID- 23019386 TI - Amyotrophic lateral sclerosis: update and new developments. AB - Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. It is typically characterized by adult-onset degeneration of the upper and lower motor neurons, and is usually fatal within a few years of onset. A subset of ALS patients has an inherited form of the disease, and a few of the known mutant genes identified in familial cases have also been found in sporadic forms of ALS. Precisely how the diverse ALS-linked gene products dictate the course of the disease, resulting in compromised voluntary muscular ability, is not entirely known. This review addresses the major advances that are being made in our understanding of the molecular mechanisms giving rise to the disease, which may eventually translate into new treatment options. PMID- 23019389 TI - Photodynamic therapy: establishing its role in palliation of advanced esophageal cancer. PMID- 23019388 TI - Practical treatments for constipation in Korea. AB - Constipation is a digestive symptom that is frequently seen in clinical practice. Its prevalence has been reported to be 2% to 20%, depending on geographical region. Despite the rapid development of medical science, systematic studies on constipation have been rarely conducted in Korea. Recently, guidelines on the diagnosis and treatment of functional gastrointestinal disorders, including constipation, were proposed by The Korean Society of Neurogastroenterology and Motility. These guidelines are expected to reflect the current situation regarding treatment of constipation in Korea. In this paper, practical constipation treatment methods that are in current use will be reviewed with reference to these recent guidelines. PMID- 23019384 TI - Guidelines for diagnosis and management of community- and hospital-acquired pneumonia in adults: Joint ICS/NCCP(I) recommendations. PMID- 23019390 TI - Low hemoglobin concentration is associated with several diabetic profiles. PMID- 23019391 TI - Validation study of the Oxford classification for IgA nephropathy in Korean adults. PMID- 23019392 TI - Role of photodynamic therapy in the palliation of obstructing esophageal cancer. AB - BACKGROUND/AIMS: The aim of this non-randomized study was to determine the role of photodynamic therapy (PDT) in a multimodal approach for the palliation of advanced esophageal carcinoma. METHODS: Twenty consecutive patients with obstructing esophageal cancer were enrolled in this study. Each subject had dysphagia, and nine could not swallow fluid. External beam radiotherapy or a self expandable metal stent was used following PDT for dysphagia due to recurrence of the malignancy. RESULTS: At 4 weeks post-PDT, a significant improvement in the dysphagia score was observed in 90% of patients, from 2.75 +/- 0.91 to 1.05 +/- 0.83 (p < 0.05). Patients with recurrent dysphagia underwent stent insertion at an average of 63 days (range, 37 to 90). The rate of major complications was 10%. Two esophageal strictures occurred, which were treated by placement of a modified expandable stent across the stricture. The median survival in these cases was 7.0 +/- 0.6 months. One patient that was treated with PDT and radiotherapy is alive and showed a complete tumor response. CONCLUSIONS: PDT as a multimodality treatment is safe and effective for relieving malignant esophageal obstruction with minimal complications. PMID- 23019393 TI - Associations between hemoglobin concentrations and the clinical characteristics of patients with type 2 diabetes. AB - BACKGROUND/AIMS: Many studies have demonstrated an association between hemoglobin levels and cardiovascular disease in diabetic patients. The aim of this study was to determine whether there is an association between hemoglobin concentrations and various clinical parameters, including metabolic factors, plasma C-peptide response after a meal tolerance test, and microvascular complications, in Korean patients with type 2 diabetes. METHODS: In total, 337 male patients with type 2 diabetes were recruited. All subjects were subjected to a meal tolerance test and underwent assessment of hemoglobin levels, fasting and postprandial beta-cell responsiveness, and microvascular complications. RESULTS: Patients with lower hemoglobin concentrations had a longer duration of diabetes, a lower body mass index, and lower concentrations of total cholesterol, triglycerides, and low density lipoprotein cholesterol. They also had lower levels of postprandial C peptide, Delta C-peptide, and postprandial beta-cell responsiveness. They had a higher prevalence of retinopathy and nephropathy. In multivariate analyses, there was a significant association between nephropathy and hemoglobin concentration. Also, hemoglobin concentrations were independently associated with Delta C peptide levels and postprandial beta-cell responsiveness. CONCLUSIONS: Hemoglobin concentrations are associated with postprandial C-peptide responses and diabetic nephropathy in patients with type 2 diabetes. PMID- 23019394 TI - Validation of the Oxford classification of IgA nephropathy: a single-center study in Korean adults. AB - BACKGROUND/AIMS: The recently published Oxford classification of IgA nephropathy (IgAN) proposed a split system for histological grading, based on prognostic pathological features. This new classification system must be validated in a variety of cohorts. We investigated whether these pathological features were applicable to an adult Korean population. METHODS: In total, 69 adult Korean patients with IgAN were analyzed using the Oxford classification system at Soonchunhyang University Hospital, Seoul, Korea. All cases were categorized according to Lee's classification. Renal biopsies from all patients were scored by a pathologist who was blinded to the clinical data for pathological variables. Inclusion criteria were age greater than 18 years and at least 36 months of follow-up. We excluded cases with secondary IgAN, diabetic nephropathy combined other glomerulopathies, less than 36 months of follow-up, and those that progressed rapidly. RESULTS: The median age of the patients was 34 years (range, 27 to 45). Mean arterial blood pressure was 97 +/- 10 mmHg at the time of biopsy. The median follow-up period was 85 months (range, 60 to 114). Kaplan-Meier analysis showed significant prognostic predictions for M, E, and T lesions. A Cox proportional hazard regression analysis also revealed prognostic predictions for E and T lesions. CONCLUSIONS: Using the Oxford classification in IgAN, E, and T lesions predicted renal outcome in Korean adults after taking clinical variables into account. PMID- 23019395 TI - Plasma N-terminal pro-B-type natriuretic peptide is predictive of perioperative cardiac events in patients undergoing vascular surgery. AB - BACKGROUND/AIMS: Identification of patients at high risk for perioperative cardiac events (POCE) is clinically important. This study aimed to determine whether preoperative measurement of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) could predict POCE, and compared its predictive value with that of conventional cardiac risk factors and stress thallium scans in patients undergoing vascular surgery. METHODS: Patients scheduled for non-cardiac vascular surgery were prospectively enrolled. Clinical risk factors were identified, and NT-proBNP levels and stress thallium scans were obtained. POCE was the composite of acute myocardial infarction, congestive heart failure including acute pulmonary edema, and primary cardiac death within 5 days after surgery. A modified Revised Cardiac Risk Index (RCRI) was proposed and compared with NT proBNP; a positive result for ischemia and a significant perfusion defect (>= 3 walls, moderate to severely decreased, reversible perfusion defect) on the thallium scan were added to the RCRI. RESULTS: A total of 365 patients (91% males) with a mean age of 67 years had a median NT-proBNP level of 105.1 pg/mL (range of quartile, 50.9 to 301.9). POCE occurred in 49 (13.4%) patients. After adjustment for confounders, an NT-proBNP level of > 302 pg/mL (odds ratio [OR], 5.7; 95% confidence interval [CI], 3.1 to 10.3; p < 0.001) and a high risk by the modified RCRI (OR, 3.9; 95% CI, 1.6 to 9.3; p = 0.002) were independent predictors for POCE. Comparison of the area under the curves for predicting POCE showed no statistical differences between NT-proBNP and RCRI. CONCLUSIONS: Preoperative measurement of NT-proBNP provides information useful for prediction of POCE as a single parameter in high-risk patients undergoing noncardiac vascular surgery. PMID- 23019396 TI - Clinical features of patients on home oxygen therapy due to chronic respiratory failure at one university hospital. AB - BACKGROUND/AIMS: Home oxygen therapy (HOT) costs a great deal every year and demand for the service is growing. In Korea, health insurance has covered HOT since November 1, 2006. The objective of this study was to evaluate clinical features of patients who used long-term HOT due to chronic respiratory failure and to determine the appropriateness of oxygen prescriptions. METHODS: Between November 2006 and April 2010, patients prescribed long-term HOT were enrolled in the study at a tertiary university referral hospital and their medical records and telephone survey information were evaluated. In total, 340 patients were evaluated retrospectively. RESULTS: Regarding the initial indications for HOT, their mean PaO(2) was 49.8 mmHg and mean SpO(2) was 82.2%. Underlying diseases included chronic obstructive pulmonary disease (COPD, 19.8%), lung cancer (12.6%), and interstitial lung disease (11.2%). The admission rate within 1 year was 53.4% and the average number of admissions was 1.64/patient. Other underlying diseases for which oxygen was prescribed, despite not meeting the insurance coverage criteria, were lung cancer (36.6%) and interstitial pneumonia (16.6%). CONCLUSIONS: Home oxygen prescriptions have increased since health insurance coverage was extended. However, cases of oxygen prescriptions frequently do not meet the coverage criteria. It is important to discuss extending the coverage criteria to other disease groups, such as interstitial lung disease and lung cancer, in terms of cost-effectiveness. Further, physicians prescribing oxygen therapy should be educated regarding the criteria. PMID- 23019397 TI - Characteristics of subjects with very low serum low-density lipoprotein cholesterol and the risk for intracerebral hemorrhage. AB - BACKGROUND/AIMS: The clinical implications of hypocholesterolemia have not been well studied, although some studies have revealed an association between hypocholesterolemia and intracerebral hemorrhage (ICH). We evaluated the clinical characteristics of subjects with very low-density lipoprotein cholesterol (LDL-C) and compared the risk for ICH using various clinical parameters. METHODS: Using hospital records, we evaluated the clinical characteristics of subjects with LDL C levels <= 40 mg/dL (very low LDL-C group). We also evaluated the risk for ICH in this very low LDL-C group and in subjects with low LDL-C <= 70 mg/dL (low LDL C group). RESULTS: Among 34,415 subjects who presented at the laboratory for serum LDL-C measurements, 250 subjects had a very low serum LDL-C level (<= 40 mg/dL). About half of the subjects were statin users; the very low LDL levels in the other subjects were likely attributable to alcohol consumption or a various chronic illness such as liver disease or end-stage renal disease (ESRD). ICH occurred in three subjects with very low LDL-C, all of whom had no history of statin use. ESRD tended to be associated with ICH in subjects with serum LDL-C <= 70 mg/dL. CONCLUSIONS: About 1% of the subjects whose LDL-C was measured in the hospital had a LDL-C level <= 40 mg/dL, and about half of these subjects had no history of hypolipidemic therapy. ICH incidence was not related to LDL-C level or statin use. PMID- 23019398 TI - Interleukin-6 -634 C/G and -174 G/C polymorphisms in Korean patients undergoing hemodialysis. AB - BACKGROUND/AIMS: Chronic inflammatory status is a possible risk factor for vascular access dysfunction in hemodialysis (HD) patients, but susceptibility differences appear among individuals. Interleukin (IL)-6 is a well-known inflammatory cytokine with various polymorphisms. We examined whether IL-6 polymorphisms are associated with vascular access dysfunction in HD patients. METHODS: A total of 80 HD patients (including 42 diabetic patients) were enrolled. Polymorphisms in the IL-6 gene promoter (-634 C/G and -174 G/C) were studied using restriction length polymorphism polymerase chain reaction analysis. Vascular access patency was compared between the patient groups with respect to IL-6 polymorphisms. An additional 89 healthy individuals were enrolled in the control group. Plasma IL-6 levels were determined by enzyme-linked immunosorbent assay. RESULTS: The GG genotype and G allele at position -634 in the IL-6 promoter were more frequently observed in HD patients than in controls. Furthermore, the distribution of the -634 polymorphism differed according to vascular access patency in non-diabetic HD patients. However, the G allele was not a significant risk factor for early access failure. No significant association appeared between the IL-6 -634 C/G polymorphism and plasma IL-6 levels. The C allele of the IL-6 -174 G/C polymorphism was not detected in our study population. CONCLUSIONS: The IL-6 -634 G allele appears with greater frequently in patients with end-stage renal disease and may be associated with vascular access dysfunction in non-diabetic HD patients. PMID- 23019399 TI - Simultaneous xanthogranulomatous cholecystitis and gallbladder cancer in a patient with a large abdominal aortic aneurysm. AB - There have been reports of the coexistence of abdominal aortic aneurysm (AAA) with intra-abdominal malignancy including gastric, colonic, pancreatic, and renal. We herein report a case of a previously undiagnosed AAA and a presenting complaint consistent with acute cholecystitis. Following cholecystectomy, this was noted to be a rare form of chronic cholecystitis: xanthogranulomatous cholecystitis. There is a known possible association of this uncommon condition with gallbladder cancer. The management of concomitant pathologies can present a real challenge to the multidisciplinary team, especially with large aneurysms. PMID- 23019400 TI - A case of severe coronary spasm associated with 5-fluorouracil chemotherapy. AB - Cardiotoxicity associated with 5-fluorouracil (FU) is an uncommon, but potentially lethal, condition. The case of an 83-year-old man with colon cancer who developed chest pain during 5-FU infusion is presented. The electrocardiogram (ECG) showed pronounced ST elevation in the lateral leads, and the chest pain was resolved after infusion of nitroglycerin. A coronary angiogram (CAG) revealed that the patient had significant atherosclerosis in the proximal left circumflex artery. Coronary artery spasm with fixed stenosis was considered, and a drug eluting stent was implanted. After 8 hours, the patient complained of recurring chest pain, paralleled by ST elevation on the ECG. The chest pain subsided after administration of intravenous nitroglycerin followed by sublingual nifedipine. Repeated CAG showed patency of the previous stent. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, indicating that a calcium channel blocker may be effective in the prevention or treatment of 5-FU cardiotoxicity. PMID- 23019401 TI - A case of idiopathic granulomatous hypophysitis. AB - Granulomatous hypophysitis is a rare pituitary condition that commonly presents with enlargement of the pituitary gland. A 31-year-old woman was admitted to the hospital with a severe headache and bitemporal hemianopsia. Magnetic resonance imaging (MRI) showed an 18 * 10-mm sellar mass with suprasellar extension and compression of the optic chiasm. Interestingly, brain MRI had shown no abnormal finding 4 months previously. On hormonal examination, hypopituitarism with mild hyperprolactinemia was noted. The biopsy revealed granulomatous changes with multinucleated giant cells. We herein report this rare case and discuss the relevant literature. PMID- 23019402 TI - Spontaneous cerebrospinal fluid rhinorrhea with pneumocephalus: an unusual manifestation of nasal tuberculosis. AB - An unusual case of spontaneous cerebrospinal fluid (CSF) rhinorrhea with a pneumocephalus is described in a middle-aged woman who presented with a watery nasal discharge for 1 week and headache, vomiting, and fever for 1 day. The neurological examination revealed meningeal signs and bilateral papilledema. The CSF picture suggested pyogenic meningitis, and computed tomography of the brain revealed pneumocephalus. Diagnostic nasal endoscopy showed outpouching of the dura from the left olfactory cleft with a CSF leak and granular nasal mucosa. The defect was repaired surgically, and a biopsy of that area revealed granulomatous changes suggestive of tuberculosis. The patient recovered completely with standard four-drug antitubercular therapy. To our knowledge spontaneous CSF rhinorrhea with pneumocephalus occurring secondary to nasal tuberculosis has not been previously reported. PMID- 23019403 TI - Isolated bowel endometriosis resembling a myogenic tumor on endoscopic ultrasonography. PMID- 23019404 TI - Concurrent parathyroid carcinoma and hyperplasia in hyperparathyroidism. PMID- 23019405 TI - Ozone exposure suppresses proliferative response in mice skin. PMID- 23019406 TI - Strangulated small bowel obstruction following endoscopic retrograde cholangiopancreatography. PMID- 23019407 TI - Bilateral emphysematous pyelonephritis. PMID- 23019408 TI - An overlooked cause of impaired consciousness in a hemodialysis patient. PMID- 23019409 TI - Inhibition of pancreatic intraepithelial neoplasia progression to carcinoma by nitric oxide-releasing aspirin in p48(Cre/+)-LSL-Kras(G12D/+) mice. AB - Nitric oxide-releasing aspirin (NO-aspirin) represents a novel class of promising chemopreventive agents. Unlike conventional nonsteroidal anti-inflammatory drugs, NO-aspirin seems to be free of adverse effects while retaining the beneficial activities of its parent compound. The effect of NO-aspirin on pancreatic carcinogenesis was investigated by assessing the development of precursor pancreatic lesions and adenocarcinomas in Kras(G12D/+) transgenic mice that recapitulate human pancreatic cancer progression. Six-week-old male p48(Cre/+) LSL-Kras(G12D/+) transgenic mice (20 per group) were fed diets containing 0, 1000, or 2000 ppm NO-aspirin. The development of pancreatic tumors was monitored by positron emission tomography imaging. All mice were killed at the age of 41 weeks and assessed for pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) and for molecular changes in the tumors. Our results reveal that NO-aspirin at 1000 and 2000 ppm significantly suppressed pancreatic tumor weights, PDAC incidence, and carcinoma in situ (PanIN-3 lesions). The degree of inhibition of PanIN-3 and carcinoma was more pronounced with NO-aspirin at 1000 ppm (58.8% and 48%, respectively) than with 2000 ppm (47% and 20%, respectively). NO-aspirin at 1000 ppm significantly inhibited the spread of carcinoma in the pancreas (~97%; P < .0001). Decreased expression of cyclooxygenase (COX; with ~42% inhibition of total COX activity), inducible nitric oxide synthase, proliferating cell nuclear antigen, Bcl-2, cyclin D1, and beta-catenin was observed, with induction of p21, p38, and p53 in the pancreas of NO-aspirin-treated mice. These results suggest that low-dose NO-aspirin possesses inhibitory activity against pancreatic carcinogenesis by modulating multiple molecular targets. PMID- 23019410 TI - High-resolution whole-genome analysis of skull base chordomas implicates FHIT loss in chordoma pathogenesis. AB - Chordoma is a rare tumor arising in the sacrum, clivus, or vertebrae. It is often not completely resectable and shows a high incidence of recurrence and progression with shortened patient survival and impaired quality of life. Chemotherapeutic options are limited to investigational therapies at present. Therefore, adjuvant therapy for control of tumor recurrence and progression is of great interest, especially in skull base lesions where complete tumor resection is often not possible because of the proximity of cranial nerves. To understand the extent of genetic instability and associated chromosomal and gene losses or gains in skull base chordoma, we undertook whole-genome single-nucleotide polymorphism microarray analysis of flash frozen surgical chordoma specimens, 21 from the clivus and 1 from C1 to C2 vertebrae. We confirm the presence of a deletion at 9p involving CDKN2A, CDKN2B, and MTAP but at a much lower rate (22%) than previously reported for sacral chordoma. At a similar frequency (21%), we found aneuploidy of chromosome 3. Tissue microarray immunohistochemistry demonstrated absent or reduced fragile histidine triad (FHIT) protein expression in 98% of sacral chordomas and 67%of skull base chordomas. Our data suggest that chromosome 3 aneuploidy and epigenetic regulation of FHIT contribute to loss of the FHIT tumor suppressor in chordoma. The finding that FHIT is lost in a majority of chordomas provides new insight into chordoma pathogenesis and points to a potential new therapeutic target for this challenging neoplasm. PMID- 23019411 TI - CAND1 promotes PLK4-mediated centriole overduplication and is frequently disrupted in prostate cancer. AB - Centrosomes play a crucial role in the maintenance of genome stability by orchestrating bipolar mitotic spindle formation. The centrosome normally duplicates precisely once before mitosis in a process that is extensively regulated by protein degradation including SKP1-Cullin 1 (CUL1)-F-box (SCF) E3 ubiquitin ligase activity. The core SCF component CUL1 has recently been found to be required to suppress the formation of supernumerary centrosomes and centrioles, the core-forming units of centrosomes. Here, we identify the CUL1 interacting protein cullin-associated and neddylation-dissociated 1 (CAND1) as a novel centrosomal protein with a role in centriole duplication control. CAND1 was found to synergize with Polo-like kinase 4 (PLK4), a master regulator of centriole biogenesis, in the induction of centriole overduplication. We provide evidence that CAND1 functions in this process by increasing PLK4 protein stability. Furthermore, mutants of CUL1 that lack the ability to interact with CAND1 and are unable to assemble functional E3 ubiquitin ligase complexes were impaired in their ability to restrain aberrant daughter centriole synthesis. To corroborate a role of CAND1 in human carcinogenesis, we analyzed a series of prostate adenocarcinomas and found altered expression of CAND1 on the mRNA or protein level in 52.9% and 40.8%, respectively, of the tumor samples analyzed. These results highlight the role of altered SCF components in cancer in general and encourage further studies to explore the SCF-CAND1 axis for the development of novel predictive biomarkers and therapeutic approaches in prostate cancer. PMID- 23019412 TI - Retained heterodisomy is associated with high gene expression in hyperhaploid inflammatory leiomyosarcoma. AB - Inflammatory leiomyosarcoma (ILMS) is a soft tissue tumor that morphologically resembles conventional leiomyosarcoma (LMS) admixed with a prominent inflammatory infiltrate. Genetic data on ILMS are still limited but have suggested that this entity is characterized by hyperhaploidy (24-34 chromosomes). This low chromosome number is otherwise uncommon in neoplasia and has been found only in 0.2% to 0.3% of cytogenetically investigated tumors. Here, three ILMS were investigated using cytogenetic, single-nucleotide polymorphism (SNP) array, and global gene expression analyses. All cases displayed a hyperhaploid origin. Combined with previously reported cases, hyperhaploidy has been found in six of seven cytogenetically investigated ILMS. The copy number distribution of individual chromosomes is clearly nonrandom; the hyperhaploid clones of all six cases displayed disomy for chromosomes 5 and 20, and two copies of chromosomes 18, 21, and 22 were also common. All chromosomes identified as disomic showed a biparental origin by SNP array analysis; whether this is of pathogenetic importance is not known. Compared with conventional LMS, ILMS had a distinct gene expression signature. Furthermore, the number of chromosome copies correlated well with gene expression levels; disomic chromosomes showed higher gene expression levels than monosomic chromosomes, a finding that has not previously been reported for hyperhaploid tumors. Taken together, our findings suggest that disomy for some chromosomes, notably 5 and 20, as well as distorted gene expression achieved through massive loss of other chromosomes are essential features of ILMS. PMID- 23019413 TI - Alterations of phosphoproteins in NCI-H526 small cell lung cancer cells involved in cytotoxicity of cisplatin and titanocene Y. AB - First-line treatment of small cell lung cancer (SCLC) with combination chemotherapy consisting of cis-diamminedichloroplatinum(II) (cisplatin) and etoposide is frequently followed by early relapses and a dismal prognosis. Survival of a fraction of tumor cells and development of chemoresistance may be influenced by an initial cellular stress response against the administered xenobiotics. Therefore, we compared the short-term effects of cisplatin and non cross-resistant bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) on phosphorylation of 46 sites of a total of 38 signaling proteins in tumor suppressor protein 53 (p53)-wild-type NCI-H526 SCLC cells. The functional significance of selected kinases for the cytotoxicity of both drugs was tested using specific inhibitors and an activator. The cisplatin-induced cellular stress response involved activation of p38alpha mitogen-activated protein kinase, whereas Titanocene Y-triggered signaling affected c-Jun N terminal kinase. Phosphorylation of adenosine monophosphate (AMP)-activated protein kinase alpha1 (AMPKalpha1) was increased by both drugs, which promoted cell survival, as indicated by results obtained using AMPK inhibitor compound C and AMPK activator 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside. This is in good agreement with previous reports, where AMPKalpha1 was demonstrated to represent an important factor for the sensitivity to cisplatin in colon and ovarian cancers, most likely by induction of autophagy. Thus, AMPKalpha1 constitutes a potential target to be exploited for chemotherapeutic treatment of SCLC to circumvent resistance to metal-based compounds. PMID- 23019414 TI - High genomic instability predicts survival in metastatic high-risk neuroblastoma. AB - We aimed to identify novel molecular prognostic markers to better predict relapse risk estimate for children with high-risk (HR) metastatic neuroblastoma (NB). We performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR NBs. Children older than 1 year of age were categorized as "short survivors" (dead of disease within 5 years from diagnosis) and "long survivors" (alive with an overall survival time >= 5 years). We reported that patients with less than three segmental copy number aberrations in their tumor represent a molecularly defined subgroup with a high survival probability within the current HR group of patients. The complex genomic pattern is a prognostic marker independent of NB associated chromosomal aberrations, i.e., MYCN amplification, 1p and 11q losses, and 17q gain. Integrative analysis of genomic and expression signatures demonstrated that fatal outcome is mainly associated with loss of cell cycle control and deregulation of Rho guanosine triphosphates (GTPases) functioning in neuritogenesis. Tumors with MYCN amplification show a lower chromosome instability compared to MYCN single-copy NBs (P = .0008), dominated by 17q gain and 1p loss. Moreover, our results suggest that the MYCN amplification mainly drives disruption of neuronal differentiation and reduction of cell adhesion process involved in tumor invasion and metastasis. Further validation studies are warranted to establish this as a risk stratification for patients. PMID- 23019415 TI - Metronomic ceramide analogs inhibit angiogenesis in pancreatic cancer through up regulation of caveolin-1 and thrombospondin-1 and down-regulation of cyclin D1. AB - AIMS: To evaluate the antitumor and antiangiogenic activity of metronomic ceramide analogs and their relevant molecular mechanisms. METHODS: Human endothelial cells [human dermal microvascular endothelial cells and human umbilical vascular endothelial cell (HUVEC)] and pancreatic cancer cells (Capan-1 and MIA PaCa-2) were treated with the ceramide analogs (C2, AL6, C6, and C8), at low concentrations for 144 hours to evaluate any antiproliferative and proapoptotic effects and inhibition of migration and to measure the expression of caveolin-1 (CAV-1) and thrombospondin-1 (TSP-1) mRNAs by real-time reverse transcription-polymerase chain reaction. Assessment of extracellular signal regulated kinases 1 and 2 (ERK1/2) and Akt phosphorylation and of CAV-1 and cyclin D1 protein expression was performed by ELISA. Maximum tolerated dose (MTD) gemcitabine was compared against metronomic doses of the ceramide analogs by evaluating the inhibition of MIA PaCa-2 subcutaneous tumor growth in nude mice. RESULTS: Metronomic ceramide analogs preferentially inhibited cell proliferation and enhanced apoptosis in endothelial cells. Low concentrations of AL6 and C2 caused a significant inhibition of HUVEC migration. ERK1/2 and Akt phosphorylation were significantly decreased after metronomic ceramide analog treatment. Such treatment caused the overexpression of CAV-1 and TSP-1 mRNAs and proteins in endothelial cells, whereas cyclin D1 protein levels were reduced. The antiangiogenic and antitumor impact in vivo of metronomic C2 and AL6 regimens was similar to that caused by MTD gemcitabine. CONCLUSIONS: Metronomic C2 and AL6 analogs have antitumor and antiangiogenic activity, determining the up-regulation of CAV-1 and TSP-1 and the suppression of cyclin D1. PMID- 23019417 TI - Apicidin and docetaxel combination treatment drives CTCFL expression and HMGB1 release acting as potential antitumor immune response inducers in metastatic breast cancer cells. AB - Currently approved combination regimens available for the treatment of metastatic tumors, such as breast cancer, have been shown to increase response rates, often at the cost of a substantial increase in toxicity. An ideal combination strategy may consist of agents with different mechanisms of action leading to complementary antitumor activities and safety profiles. In the present study, we investigated the effects of the epigenetic modulator apicidin in combination with the cytotoxic agent docetaxel in tumor breast cell lines characterized by different grades of invasiveness. We report that combined treatment of apicidin and docetaxel, at low toxicity doses, stimulates in metastatic breast cancer cells the expression of CTCF-like protein and other cancer antigens, thus potentially favoring an antitumor immune response. In addition, apicidin and docetaxel co-treatment specifically stimulates apoptosis, characterized by an increased Bax/Bcl-2 ratio and caspase-8 activation. Importantly, following combined exposure to these agents, metastatic cells were also found to induce signals of immunogenic apoptosis such as cell surface expression of calreticulin and release of considerable amounts of high-mobility group box 1 protein, thus potentially promoting the translation of induced cell death into antitumor immune response. Altogether, our results indicate that the combined use of apicidin and docetaxel, at a low toxicity profile, may represent a potential innovative strategy able to activate complementary antitumor pathways in metastatic breast cancer cells, associated with a potential control of metastatic growth and possible induction of antitumor immunity. PMID- 23019416 TI - Inhibition of SIRT2 potentiates the anti-motility activity of taxanes: implications for antineoplastic combination therapies. AB - Taxanes are potent inhibitors of cell motility, a property implicated in their antiangiogenic and antimetastatic activity and unrelated to their antiproliferative effect. The molecular mechanism of this anti-motility activity is poorly understood. In this study, we found that paclitaxel induced tubulin acetylation in endothelial and tumor cells, at concentrations that affected cell motility but not proliferation (10(-8) to 10(-9) M, for 4 hours). Induction of tubulin acetylation correlated with inhibition of motility but not proliferation based on a comparison of highly and poorly cytotoxic taxanes (paclitaxel and IDN5390) and tumor cell lines sensitive and resistant to paclitaxel (1A9 and 1A9 PTX22). Consistent with the hypothesis that tubulin deacetylase activity might affect cell response to the anti-motility activity of taxanes, we found that overexpression of the tubulin deacetylase SIRT2 increased cell motility and reduced cell response to the anti-motility activity of paclitaxel. Conversely, the SIRT2 inhibitor splitomicin reduced cell motility and potentiated the anti motility activity of paclitaxel. The inhibitory effect was further potentiated by the addition of the HDAC6 inhibitor trichostatin A. Paclitaxel and splitomicin promoted translocation into the nucleus--and hence activation--of FOXO3a, a negative regulator of cell motility. This study indicates a role for SIRT2 in the regulation of cell motility and suggests that therapies combining sirtuin inhibitors and taxanes could be used to treat cell motility-based pathologic processes such as tumor angiogenesis, invasion, and metastasis. PMID- 23019418 TI - MiR-9, -31, and -182 deregulation promote proliferation and tumor cell survival in colon cancer. AB - Several microRNAs (miRNAs) are known to be deregulated in colon cancer, but the mechanisms behind their potential involvement on proliferation and tumor cell survival are unclear. The present study aimed to identify miRNAs with functional implications for development of colon cancer. The cell proliferation and apoptosis were examined following perturbations of miRNA levels by employing a comprehensive miRNA library screen. miRNAs nominated for relevance to colon cancer were validated on expression and functional levels. By integrating the effect of miRNA up-regulation with the endogenous miRNA expression levels within the HT29, HCT116, and SW480 colon cancer cell lines, we identified miRNAs controlling cell proliferation (n = 53) and apoptosis (n = 93). From these functionally nominated miRNAs, we narrowed the list to 10 oncogene- and 20 tumor suppressor-like miRNAs that were also differentially expressed between colon cancer (n = 80) and normal colonic mucosa (n = 20). The differential expressions of miR-9, miR-31, and miR-182 were successfully validated in a series of colon carcinomas (n = 30) and polyps (n = 10) versus normal colonic mucosa (n = 10), whereas the functional effect was confirmed in an in-depth validation using different cell viability and apoptotic markers. Several transcription factors and genes regulating cell proliferation were identified as putative target genes by integrative miRNA/mRNA expression analysis obtained from the same colon cancer patient samples. This study suggests that deregulated expression of miR-9, miR 31, and miR-182 during carcinogenesis plays a significant role in the development of colon cancer by promoting proliferation and tumor cell survival. PMID- 23019419 TI - Shake, Rattle, and ... One or Two Objects? Young Infants' Use of Auditory Information to Individuate Objects. AB - Most research on object individuation in infants has focused on the visual domain. Yet the problem of object individuation is not unique to the visual system, but shared by other sensory modalities. This research examined 4.5-month old infants' capacity to use auditory information to individuate objects. Infants were presented with events in which they heard 2 distinct sounds, separated by a temporal gap, emanate from behind a wide screen; the screen was then lowered to reveal 1 or 2 objects. Longer looking to the 1- than 2-object display was taken as evidence that the infants (a) interpreted the auditory event as involving 2 objects and (b) found the presence of only 1 object when the screen was lowered unexpected. The results indicated that the infants used sounds produced by rattles, but not sounds produced by an electronic keyboard, as the basis for object individuation (Experiments 1 and 2). Data collected with adult participants revealed that adults are also more sensitive to rattle sounds than electronic tones. A final experiment assessed conditions under which young infants attend to rattle sounds (Experiment 3). Collectively, the outcomes of these experiments suggest that infants and adults are more likely to use some sounds than others as the basis for individuating objects. We propose that these results reflect a processing bias to attend to sounds that reveal something about the physical properties of an object-sounds that are obviously linked to object structure-when determining object identity. PMID- 23019420 TI - Epigenetic control of reprogramming and cellular differentiation. PMID- 23019421 TI - The use of regenerative medicine in the management of invasive bladder cancer. AB - Muscle invasive and recurrent nonmuscle invasive bladder cancers have been traditionally treated with a radical cystectomy and urinary diversion. The urinary diversion is generally accomplished through the creation of an incontinent ileal conduit, continent catheterizable reservoir, or orthotopic neobladder utilizing small or large intestine. While radical extirpation of the bladder is often successful from an oncological perspective, there is a significant morbidity associated with enteric interposition within the genitourinary tract. Therefore, there is a great opportunity to decrease the morbidity of the surgical management of bladder cancer through utilization of novel technologies for creating a urinary diversion without the use of intestine. Clinical trials using neourinary conduits (NUC) seeded with autologous smooth muscle cells are currently in progress and may represent a significant surgical advance, potentially eliminating the complications associated with the use of gastrointestinal segments in the urinary reconstruction, simplifying the surgical procedure, and greatly facilitating recovery from cystectomy. PMID- 23019422 TI - Monitoring Detrusor Oxygenation and Hemodynamics Noninvasively during Dysfunctional Voiding. AB - The current literature indicates that lower urinary tract symptoms (LUTSs) related to benign prostatic hyperplasia (BPH) have a heterogeneous pathophysiology. Pressure flow studies (UDSs) remain the gold standard evaluation methodology for such patients. However, as the function of the detrusor muscle depends on its vasculature and perfusion, the underlying causes of LUTS likely include abnormalities of detrusor oxygenation and hemodynamics, and available treatment options include agents thought to act on the detrusor smooth muscle and/or vasculature. Hence, near infrared spectroscopy (NIRS), an established optical methodology for monitoring changes in tissue oxygenation and hemodynamics, has relevance as a means of expanding knowledge related to the pathophysiology of BPH and potential treatment options. This methodological report describes how to conduct simultaneous NIRS monitoring of detrusor oxygenation and hemodynamics during UDS, outlines the clinical implications and practical applications of NIRS, explains the principles of physiologic interpretation of NIRS voiding data, and proposes an exploratory hypothesis that the pathophysiological causes underlying LUTS include detrusor dysfunction due to an abnormal hemodynamic response or the onset of oxygen debt during voiding. PMID- 23019423 TI - Pain management techniques and practice: new approaches, modifications of techniques, and future directions. PMID- 23019425 TI - Relaxation estimation of RMSD in molecular dynamics immunosimulations. AB - Molecular dynamics simulations have to be sufficiently long to draw reliable conclusions. However, no method exists to prove that a simulation has converged. We suggest the method of "lagged RMSD-analysis" as a tool to judge if an MD simulation has not yet run long enough. The analysis is based on RMSD values between pairs of configurations separated by variable time intervals Deltat. Unless RMSD(Deltat) has reached a stationary shape, the simulation has not yet converged. PMID- 23019424 TI - Glutamine randomized studies in early life: the unsolved riddle of experimental and clinical studies. AB - Glutamine may have benefits during immaturity or critical illness in early life but its effects on outcome end hardpoints are controversial. Our aim was to review randomized studies on glutamine supplementation in pups, infants, and children examining whether glutamine affects outcome. Experimental work has proposed various mechanisms of glutamine action but none of the randomized studies in early life showed any effect on mortality and only a few showed some effect on inflammatory response, organ function, and a trend for infection control. Although apparently safe in animal models (pups), premature infants, and critically ill children, glutamine supplementation does not reduce mortality or late onset sepsis, and its routine use cannot be recommended in these sensitive populations. Large prospectively stratified trials are needed to better define the crucial interrelations of "glutamine-heat shock proteins-stress response" in critical illness and to identify the specific subgroups of premature neonates and critically ill infants or children who may have a greater need for glutamine and who may eventually benefit from its supplementation. The methodological problems noted in the reviewed randomized experimental and clinical trials should be seriously considered in any future well-designed large blinded randomized controlled trial involving glutamine supplementation in critical illness. PMID- 23019426 TI - Expanding the chemical diversity of spirooxindoles via alkylative pyridine dearomatization. AB - A mild and practical synthesis of spirooxindole [1,3]oxazino derivatives from N substituted isatins and 1,3-dicarbonyl compounds with pyridine derivatives is reported. The reactions provided good to excellent yields. Further exploration of the molecular diversity of these compounds is demonstrated through Diels-Alder reactions. PMID- 23019427 TI - Hybrid super electron donors - preparation and reactivity. AB - Neutral organic electron donors, featuring pyridinylidene-imidazolylidene, pyridinylidene-benzimidazolylidene and imidazolylidene-benzimidazolylidene linkages are reported. The pyridinylidene-benzimidazolylidene and imidazolylidene benzimidazolylidene hybrid systems were designed to be the first super electron donors to convert iodoarenes to aryl radicals at room temperature, and indeed both show evidence for significant aryl radical formation at room temperature. The stronger pyridinylidene-imidazolylidene donor converts iodoarenes to aryl anions efficiently under appropriate conditions (3 equiv of donor). The presence of excess sodium hydride base has a very important and selective effect on some of these electron-transfer reactions, and a rationale for this is proposed. PMID- 23019429 TI - The effect of the formyl group position upon asymmetric isomeric diarylethenes bearing a naphthalene moiety. AB - Three new isomeric asymmetric diarylethenes with a naphthyl moiety and a formyl group at the para, meta or ortho position of the terminal benzene ring were synthesized. Their photochromism, fluorescent-switch, and electrochemical properties were investigated. Among these diarylethenes, the one with a formyl group at the ortho position of benzene displayed the largest molar absorption coefficients and fluorescence quantum yield. The cyclization quantum yields of these compounds increased in the order of para < ortho < meta, whereas their cycloreversion quantum yields decreased in the order of meta > para > ortho. Additionally, all of these diarylethenes functioned as effective fluorescent switches in both solution and PMMA films. Cyclic voltammograms proved that the formyl group and its position could effectively modulate the electrochemical behaviors of these diarylethene derivatives. PMID- 23019428 TI - Recent advances towards azobenzene-based light-driven real-time information transmitting materials. AB - Photochromic switches that are able to transmit information in a quick fashion have attracted a growing interest within materials science during the last few decades. Although very fast photochromic switching materials working within hundreds of nanoseconds based on other chromophores, such as spiropyranes, have been successfully achieved, reaching such fast relaxation times for azobenzene based photochromic molecular switches is still a challenge. This review focuses on the most recent achievements on azobenzene-based light-driven real-time information-transmitting systems. Besides, the main relationships between the structural features of the azo-chromophore and the thermal cis-to-trans isomerisation, the kinetics and mechanism are also discussed as a key point for reaching azoderivatives endowed with fast thermal back-isomerisation kinetics. PMID- 23019430 TI - Parallel solid-phase synthesis of diaryltriazoles. AB - A series of substituted diaryltriazoles was prepared by a solid-phase-synthesis protocol using a modified Wang resin. The copper(I)- or ruthenium(II)-catalyzed 1,3-cycloaddition on the polymer bead allowed a rapid synthesis of the target compounds in a parallel fashion with in many cases good to excellent yields. Substituted diaryltriazoles resemble a molecular structure similar to established terphenyl-alpha-helix peptide mimics and have therefore the potential to act as selective inhibitors for protein-protein interactions. PMID- 23019431 TI - Synthesis of new pyrrole-pyridine-based ligands using an in situ Suzuki coupling method. AB - The compounds 6-(pyrrol-2-yl)-2,2'-bipyridine, 2-(pyrrol-2-yl)-1,10 phenanthroline and 2-(2-(N-methylbenz[d,e]imidazole)-6-(pyrrol-2-yl)-pyridine were synthesized by using an in situ generated boronic acid for the Suzuki coupling. Crystals of the products could be grown and exhibited interesting structures by X-ray analysis, one of them showing a chain-like network with the adjacent molecules linked to each other via intermolecular N-H(...)N hydrogen bonds. PMID- 23019432 TI - Synthesis and in silico screening of a library of beta-carboline-containing compounds. AB - The synthesis of a library of tetrahydro-beta-carboline-containing compounds in milligram quantities is described. Among the unique heterocyclic frameworks are twelve tetrahydroindolizinoindoles, six tetrahydrocyclobutanindoloquinolizinones and three tetrahydrocyclopentenoneindolizinoindolones. These compounds were selected from a virtual combinatorial library of 11,478 compounds. Physical chemical properties were calculated and most of them are in accordance with Lipinski's rules. Virtual docking and ligand-based target evaluations were performed for the beta-carboline library compounds and selected synthetic intermediates to assess the therapeutic potential of these small organic molecules. These compounds have been deposited into the NIH Molecular Repository (MLSMR) and may target proteins such as histone deacetylase 4, endothelial nitric oxide synthase, 5-hydroxytryptamine receptor 6 and mitogen-activated protein kinase 1. These in silico screening results aim to add value to the beta carboline library of compounds for those interested in probes of these targets. PMID- 23019433 TI - Synthesis and structure of tricarbonyl(eta(6)-arene)chromium complexes of phenyl and benzyl D-glycopyranosides. AB - A series of 15 glycoside-derived tricarbonyl(eta(6)-arene)chromium complexes were prepared in 19-87% yield by heating fully acetylated or methylated aryl O-, S-, N and C-glycosides of D-glucopyranose and D-mannopyranose with hexacarbonylchromium. All tricarbonylchromium complexes were fully characterized. The structures of nine crystalline complexes were determined by X-ray diffraction, revealing unusual intra- and intermolecular nonclassical hydrogen bonds. PMID- 23019434 TI - Control over molecular motion using the cis-trans photoisomerization of the azo group. AB - Control over molecular motion represents an important objective in modern chemistry. Aromatic azobenzenes are excellent candidates as molecular switches since they can exist in two forms, namely the cis (Z) and trans (E) isomers, which can interconvert both photochemically and thermally. This transformation induces a molecular movement and a significant geometric change, therefore the azobenzene unit is an excellent candidate to build dynamic molecular devices. We describe selected examples of systems containing an azobenzene moiety and their motions and geometrical changes caused by external stimuli. PMID- 23019435 TI - Synthesis of a library of tricyclic azepinoisoindolinones. AB - Hydrozirconation of 1-hexyne, the addition to in situ prepared N-acyliminium species, and ring-closing metathesis (RCM) were key steps in the preparation of a tricyclic isoindolinone scaffold. An unusual alkene isomerization process during the RCM was identified and studied in some detail. Chemical diversification for library synthesis was achieved by a subsequent alkene epoxidation and zinc mediated aminolysis reaction. The resulting library products provided selective hits among a large number of high-throughput screens reported in PubChem, thus illustrating the utility of the novel scaffold. PMID- 23019436 TI - Chiral multifunctional thiourea-phosphine catalyzed asymmetric [3 + 2] annulation of Morita-Baylis-Hillman carbonates with maleimides. AB - We have developed a multifunctional thiourea-phosphine catalyzed asymmetric [3 + 2] annulation of Morita-Baylis-Hillman (MBH) carbonates with maleimides, which can efficiently construct functionalized cyclopentenes bearing three contiguous stereocenters in moderate to excellent yields and excellent diastereo- and enantioselectivities. A plausible mechanism has been also proposed on the basis of control experiments and previous literature. PMID- 23019437 TI - Screening of ligands for the Ullmann synthesis of electron-rich diaryl ethers. AB - In the search for new ligands for the Ullmann diaryl ether synthesis, permitting the coupling of electron-rich aryl bromides at relatively low temperatures, 56 structurally diverse multidentate ligands were screened in a model system that uses copper iodide in acetonitrile with potassium phosphate as the base. The ligands differed largely in their performance, but no privileged structural class could be identified. PMID- 23019438 TI - Asymmetric total synthesis of smyrindiol employing an organocatalytic aldol key step. AB - The first organocatalytic asymmetric synthesis of smyrindiol, by using an (S) proline catalyzed enantioselective intramolecular aldol reaction as the key step, is described. Smyrindiol was synthesized from commercially available 2,4 dihydroxybenzaldehyde in 15 steps, with excellent stereoselectivity (de = 99%, ee = 99%). In the course of this total synthesis a new and mild coumarin assembly was developed. PMID- 23019439 TI - Formation of smectic phases in binary liquid crystal mixtures with a huge length ratio. AB - A system of two liquid-crystalline phenylpyrimidines differing strongly in molecular length was studied. The phase diagram of these two chemically similar mesogens, with a length ratio of 2, was investigated, and detailed X-ray diffraction and electrooptical measurements were performed. The phase diagram revealed a destabilization of the nematic phase, which is present in the pure short compound, while the smectic state was stabilized. The short compound forms smectic A and smectic C phases, whereas the longer compound forms a broad smectic C phase and a narrow higher-ordered smectic phase. Nevertheless, in the mixtures, the smectic C phase is destabilized and disappears rapidly, whereas smectic A is the only stable phase observed over a broad concentration range. In addition, the smectic translational order parameters as well as the tilt angles of the mixtures are reduced. The higher-ordered smectic phase of the longer mesogen was identified as a smectic F phase. PMID- 23019440 TI - Combined bead polymerization and Cinchona organocatalyst immobilization by thiol ene addition. AB - In this work, we report an unusually concise immobilization of Cinchona organocatalysts using thiol-ene chemistry, in which catalyst immobilization and bead polymerization is combined in a single step. A solution of azo initiator, polyfunctional thiol, polyfunctional alkene and an unmodified Cinchona-derived organocatalyst in a solvent is suspended in water and copolymerized on heating by thiol-ene additions. The resultant spherical and gel-type polymer beads have been evaluated as organocatalysts in catalytic asymmetric transformations. PMID- 23019441 TI - Synthesis of 4" manipulated Lewis X trisaccharide analogues. AB - Three analogues of the Le(x) trisaccharide antigen (beta-D-Galp(1->4)[alpha-L Fucp(1->3)]-D-GlcNAcp) in which the galactosyl residue is modified at O-4 as a methyloxy, deoxychloro or deoxyfluoro, were synthesized. We first report the preparation of the modified 4-OMe, 4-Cl and 4-F trichloroacetimidate galactosyl donors and then report their use in the glycosylation of an N-acetylglucosamine glycosyl acceptor. Thus, we observed that the reactivity of these donors towards the BF(3).OEt(2)-promoted glycosylation at O-4 of the N-acetylglucosamine glycosyl acceptors followed the ranking 4-F > 4-OAc ~ 4-OMe > 4-Cl. The resulting disaccharides were deprotected at O-3 of the glucosamine residue and fucosylated, giving access to the desired protected Le(x) analogues. One-step global deprotection (Na/NH(3)) of the protected 4"-methoxy analogue, and two-step deprotections (removal of a p-methoxybenzyl with DDQ, then Zemplen deacylation) of the 4"-deoxychloro and 4"-deoxyfluoro protected Le(x) analogues gave the desired compounds in good yields. PMID- 23019442 TI - Antibiotic and cytotoxic peptides. PMID- 23019443 TI - Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics. AB - The chemical similarity of antibacterial cyclic peptides and peptidomimetics was studied in order to identify new promising cyclic scaffolds. A large descriptor space coupled with cluster analysis was employed to digitize known antibacterial structures and to gauge the potential of new peptidomimetic macrocycles, which were conveniently synthesized by acylbenzotriazole methodology. Some of the synthesized compounds were tested against an array of microorganisms and showed antibacterial activity against Bordetella bronchistepica, Micrococcus luteus, and Salmonella typhimurium. PMID- 23019444 TI - Partial thioamide scan on the lipopeptaibiotic trichogin GA IV. Effects on folding and bioactivity. AB - Backbone modification is a common chemical tool to control the conformation of linear peptides and to explore potentially useful effects on their biochemical and biophysical properties. The thioamide, psi[CS-NH], group is a nearly isosteric structural mimic of the amide (peptide) functionality. In this paper, we describe the solution synthesis, chemical characterization, preferred conformation, and membrane and biological activities of three, carefully selected, peptide analogues of the lipopeptaibiotic [Leu(11)-OMe] trichogin GA IV. In each analogue, a single thioamide replacement was incorporated. Sequence positions near the N-terminus, at the center, and near the C-terminus were investigated. Our results indicate that (i) a thioamide linkage is well tolerated in the overall helical conformation of the [Leu(11)-OMe] lipopeptide analogue and (ii) this backbone modification is compatible with the preservation of its typical membrane leakage and antibiotic properties, although somewhat attenuated. PMID- 23019446 TI - Highly selective synthesis of (E)-alkenyl-(pentafluorosulfanyl)benzenes through Horner-Wadsworth-Emmons reaction. AB - Diethyl 2-nitro-(pentafluorosulfanyl)benzylphosphonates, available by the vicarious nucleophilic substitution reaction of meta- and para-nitro (pentafluorosulfanyl)benzenes and diethyl chloromethylphosphonate, undergo Horner Wadsworth-Emmons reaction with aldehydes in the presence of potassium hydroxide in acetonitrile at ambient temperature to give (E)-2-nitro-1-alkenyl (pentafluorosulfanyl)benzenes in good yields and high stereoselectivities. Follow up transformations of the primary products provided (E)-1-alkenyl (pentafluorosulfanyl)benzenes and 2-(2-arylethyl)-(pentafluorosulfanyl)anilines. PMID- 23019445 TI - Design of a novel tryptophan-rich membrane-active antimicrobial peptide from the membrane-proximal region of the HIV glycoprotein, gp41. AB - A number of physicochemical characteristics have been described which contribute to the biological activity of antimicrobial peptides. This information was used to design a novel antimicrobial peptide sequence by using an intrinsically inactive membrane-associated peptide derived from the HIV glycoprotein, gp41, as a starting scaffold. This peptide corresponds to the tryptophan-rich membrane proximal region of gp41, which is known to interact at the interfacial region of the viral membrane and adopts a helical structure in the presence of lipids. Three synthetic peptides were designed to increase the net positive charge and amphipathicity of this 19-residue peptide. Ultimately, the peptide with the greatest degree of amphipathicity and largest positive charge proved to be the most potent antimicrobial, and this peptide could be further modified to improve the antimicrobial activity. However, the other two peptides were relatively ineffective antimicrobials and instead proved to be extremely hemolytic. This work demonstrates a novel approach for the design of unexplored antimicrobial peptide sequences but it also reveals that the biological and cytotoxic activities of these polypeptides depend on a number of interrelated factors. PMID- 23019447 TI - Synthesis of diverse indole libraries on polystyrene resin - Scope and limitations of an organometallic reaction on solid supports. AB - The synthesis of diverse substituted indole structures on solid supports is described. The immobilization of nitrobenzoic acid onto Merrifield resin and the subsequent treatment with alkenyl Grignard reagents delivered indole carboxylates bound to solid supports. In contrast to results in the liquid phase, ortho,ortho unsubstituted nitroarenes also delivered indole moieties in good yields. Subsequent palladium-catalyzed reactions (Suzuki, Heck, Sonogashira, Stille) delivered, after cleavage, the desired molecules in moderate to good yields over four steps. The scope and limitations are presented. PMID- 23019448 TI - Palladium-catalyzed substitution of (coumarinyl)methyl acetates with C-, N-, and S-nucleophiles. AB - The palladium-catalyzed nucleophilic substitution of (coumarinyl)methyl acetates is described. The reaction proceeds though a palladium pi-benzyl-like complex and allows for many different types of C-, N-, and S-nucleophiles to be regioselectively added to the biologically active coumarin motif. This new method was utilized to prepare a 128-membered library of aminated coumarins for biological screening. PMID- 23019449 TI - Photoreactions of cyclic sulfite esters: Evidence for diradical intermediates. AB - The photochemistry of a phenyl and 1,2-diphenyl substituted sulfite ester is reported. The performance of photoreactions under relatively mild reaction conditions enables the detection of products that have not been observed in previous studies. It is concluded that, complementary to the initially proposed carbene intermediates, diradicals may also be considered. PMID- 23019450 TI - Photochemistry with laser radiation in condensed phase using miniaturized photoreactors. AB - Miniaturized microreactors enable photochemistry with laser irradiation in flow mode to convert azidobiphenyl into carbazole with high efficiency. PMID- 23019451 TI - Studies on the substrate specificity of a GDP-mannose pyrophosphorylase from Salmonella enterica. AB - A series of methoxy and deoxy derivatives of mannopyranose-1-phosphate (Manp-1P) were chemically synthesized, and their ability to be converted into the corresponding guanosine diphosphate mannopyranose (GDP-Manp) analogues by a pyrophosphorylase (GDP-ManPP) from Salmonella enterica was studied. Evaluation of methoxy analogues demonstrated that GDP-ManPP is intolerant of bulky substituents at the C-2, C-3, and C-4 positions, in turn suggesting that these positions are buried inside the enzyme active site. Additionally, both the 6-methoxy and 6 deoxy Manp-1P derivatives are good or moderate substrates for GDP-ManPP, thus indicating that the C-6 hydroxy group of the Manp-1P substrate is not required for binding to the enzyme. When taken into consideration with other previously published work, it appears that this enzyme has potential utility for the chemoenzymatic synthesis of GDP-Manp analogues, which are useful probes for studying enzymes that employ this sugar nucleotide as a substrate. PMID- 23019452 TI - Conformational analysis, stereoelectronic interactions and NMR properties of 2 fluorobicyclo[2.2.1]heptan-7-ols. AB - Four diastereoisomers of 2-fluorobicyclo[2.2.1]heptan-7-ols were computationally investigated by using quantum-chemical calculations, and their relative energies were analyzed on the basis of stereoelectronic interactions, particularly the presence or otherwise of the F???HO intramolecular hydrogen bond in the syn-exo isomer. It was found through NBO and AIM analyses that such an interaction contributes to structural stabilization and that the (1h)J(F,H(O)) coupling constant in the syn-exo isomer is modulated by the n(F)->sigma*(OH) interaction, i.e., the quantum nature of the F???HO hydrogen bond. PMID- 23019453 TI - Recyclable fluorous cinchona alkaloid ester as a chiral promoter for asymmetric fluorination of beta-ketoesters. AB - A fluorous cinchona alkaloid ester has been developed as a chiral promoter for the asymmetric fluorination of beta-ketoesters. It has comparable reactivity and selectivity to the nonfluorous versions of cinchona alkaloids and can be easily recovered from the reaction mixture by simple fluorous solid-phase extraction (F SPE) and used for the next round of reaction without further purification. PMID- 23019454 TI - Organocatalytic asymmetric allylic amination of Morita-Baylis-Hillman carbonates of isatins. AB - The investigation of a Lewis base catalyzed asymmetric allylic amination of Morita-Baylis-Hillman carbonates derived from isatins afforded an electrophilic pathway to access multifunctional oxindoles bearing a C3-quaternary stereocenter, provided with good to excellent enantioselectivity (up to 94% ee) and in high yields (up to 97%). PMID- 23019455 TI - Stereoselective synthesis of trans-fused iridoid lactones and their identification in the parasitoid wasp Alloxysta victrix, Part I: Dihydronepetalactones. AB - Starting from the enantiomers of limonene, all eight stereoisomers of trans-fused dihydronepetalactones were synthesized. Key compounds were pure stereoisomers of 1-acetoxymethyl-2-methyl-5-(2-hydroxy-1-methylethyl)-1-cyclopentene. The stereogenic center of limonene was retained at position 4a of the target compounds and used to stereoselectively control the introduction of the other chiral centers during the synthesis. Basically, this approach could also be used for the synthesis of enantiomerically pure trans-fused iridomyrmecins. Using synthetic reference samples, the combination of enantioselective gas chromatography and mass spectrometry revealed that volatiles released by the endohyperparasitoid wasp Alloxysta victrix contain the enantiomerically pure trans-fused (4R,4aR,7R,7aS)-dihydronepetalactone as a minor component, showing an unusual (R)-configured stereogenic center at position 7. PMID- 23019456 TI - Stereoselective synthesis of trans-fused iridoid lactones and their identification in the parasitoid wasp Alloxysta victrix, Part II: Iridomyrmecins. AB - Following our earlier approach to the synthesis of dihydronepetalactones, all eight stereoisomers of trans-fused iridomyrmecins were synthesized starting from the enantiomers of limonene. Combined gas chromatography and mass spectrometry including enantioselective gas chromatography revealed that volatiles released by the endohyperparasitoid wasp Alloxysta victrix contain (4S,4aR,7S,7aR) iridomyrmecin of 95-97% ee and stereochemically pure (4S,4aS,7R,7aS) iridomyrmecin as a minor component. PMID- 23019457 TI - Binaphthyl-anchored antibacterial tripeptide derivatives with hydrophobic C terminal amino acid variations. AB - The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobic group variations in the C-terminal amino acid component, is described. Moderate to good activity was seen against Gram-positive bacteria in vitro. One cyclohexyl-substituted compound 2c was tested more widely and showed good potency (MIC values ranging from 2-4 MUg/mL) against antibiotic-resistant strains of Staphylococcus aureus and Enterococci (VRE, VSE), and against Staphylococcus epidermidis. PMID- 23019458 TI - The preferred conformation of erythro- and threo-1,2-difluorocyclododecanes. AB - Cyclododecane adopts a square-like structure with corner and edge CH(2) groups. In this study erythro- and threo-1,2-difluorocyclododecanes were prepared to explore whether the two vicinal C-F bonds, with different relative configurations, preferably locate at corner/edge or edge/edge locations. Conformational analysis comparing the diastereoisomers was explored by using a combination of (19)F{(1)H} NMR spectroscopy, computational studies and, in the case of the threo isomer, X-ray structural analysis. In the lowest energy conformers for both diastereoisomers the vicinal C-F bonds are located corner/edge, rather than edge/edge. These structures avoid placing a C-F bond endo into the ring, and appear to benefit from C-CHF-C angle widening, which relaxes 1,4-H,H transannular interactions. PMID- 23019459 TI - Asymmetric organocatalytic decarboxylative Mannich reaction using beta-keto acids: A new protocol for the synthesis of chiral beta-amino ketones. AB - The first decarboxylative Mannich reaction employing beta-keto acids, catalyzed by cinchonine-derived bifunctional thiourea catalyst has been described. The desired beta-amino ketones were obtained in excellent yields and with moderate to good enantioselectivities. PMID- 23019460 TI - Beilstein Journal of Organic Chemistry: Open Access comes of age in Organic Chemistry. PMID- 23019461 TI - On the proposed structures and stereocontrolled synthesis of the cephalosporolides. AB - The synthesis of four candidate stereoisomers of cephalosporolide H is described, made possible by a zinc-chelation strategy for controlling the stereochemistry of oxygenated 5,5-spiroketals. The same strategy likewise enables the first stereocontrolled synthesis of cephalosporolide E, which is typically isolated and prepared admixed with its spiroketal epimer, cephalosporolide F. PMID- 23019463 TI - Superstructures with cyclodextrins: Chemistry and applications. PMID- 23019462 TI - Exploring chemical diversity via a modular reaction pairing strategy. AB - The efficient synthesis of an 80-member library of unique benzoxathiazocine 1,1 dioxides by a microwave-assisted, intermolecular nucleophilic aromatic substitution (S(N)Ar) diversification pathway is reported. Eight benzofused sultam cores were generated by means of a sulfonylation/S(N)Ar/Mitsunobu reaction pairing protocol, and subsequently diversified by intermolecular S(N)Ar with ten chiral, non-racemic amine/amino alcohol building blocks. Computational analyses were employed to explore and evaluate the chemical diversity of the library. PMID- 23019464 TI - Cyclodextrin nanosponge-sensitized enantiodifferentiating photoisomerization of cyclooctene and 1,3-cyclooctadiene. AB - Enantiodifferentiating geometrical photoisomerizations of (Z)-cyclooctene and (Z,Z)-1,3-cyclooctadiene were performed by using the pyromellitate-linked cyclodextrin network polymer, termed "cyclodextrin nanosponge (CDNS)", as a supramolecular sensitizing host. The photochirogenic behavior of the nanosponges incorporating beta- or gamma-cyclodextrin was significantly different from that reported for the conventional sensitizer-appended monomeric cyclodextrins, affording chiral (E)-cyclooctene and (E,Z)-cyclooctadiene in enantiomeric excesses critically dependent on the solution pH and solvent composition employed, revealing the active roles of chiral void spaces of CDNS in the photochirogenic reaction. PMID- 23019465 TI - Interaction of cyclodextrins with pyrene-modified polyacrylamide in a mixed solvent of water and dimethyl sulfoxide as studied by steady-state fluorescence. AB - The interaction of beta- and gamma-cyclodextrins (beta-CD and gamma-CD, respectively) with polyacrylamide modified with pyrenyl (Py) residues (pAAmPy) was investigated in a mixed solvent of water and dimethyl sulfoxide (DMSO) by steady-state fluorescence. In the absence of CD, the fluorescence spectra indicated that the formation of Py dimers became less favorable with increasing volume fraction of DMSO (x(DMSO)). The fluorescence spectra at varying x(DMSO) and CD concentrations indicated that beta-CD and gamma-CD included monomeric and dimeric Py residues, respectively. Using the fluorescence spectra, equilibrium constants of the formation of Py dimers and the complexation of beta-CD and gamma CD with Py residues were roughly estimated based on simplified equilibrium schemes. PMID- 23019466 TI - Restructuring polymers via nanoconfinement and subsequent release. AB - During the past several years my students and I have been utilizing certain small molecule hosts to create nanostructured polymers. This is accomplished by first forming noncovalently bonded inclusion complexes (ICs) between these small molecule hosts and guest polymers, followed by the careful removal of the host crystalline lattice to obtain a coalesced bulk polymer. We have repeatedly observed that such coalesced polymer samples behave distinctly from those produced from their solutions or melts. Coalesced amorphous homopolymers exhibit higher glass-transition temperatures, while crystallizable homopolymers coalesced from their ICs display higher melting and crystallization temperatures, and sometimes different crystalline polymorphs. When ICs are formed with block copolymers or with two or more different homopolymers, the resulting coalesced samples can exhibit intimate mixing between the copolymer blocks, or between entire homopolymer chains. Each of the distinct behaviors observed for polymers coalesced from their ICs is a consequence of the structural organization of the polymer-host-ICs. Polymer chains in host-IC crystals are confined to occupy narrow channels (diameter ~0.5-1.0 nm) formed by the small-molecule hosts around the included guest polymers during IC crystallization. This results in the separation and high extension of the included guest polymer chains, which leads, following the careful removal of the host molecule lattice, to unique behaviors for the bulk coalesced polymer samples. Apparently, substantial degrees of the extended and unentangled natures of the IC-included chains are retained upon coalescence. In this review we summarize the behaviors and uses of coalesced polymers, and attempt to draw conclusions on the relationship between their behavior and the organization/structures/conformations of the constituent polymer chains achieved upon coalescence from their ICs. PMID- 23019467 TI - Asymmetric one-pot sequential Friedel-Crafts-type alkylation and alpha oxyamination catalyzed by a peptide and an enzyme. AB - In the presence of a peptide catalyst and the oxidative enzyme laccase, a one-pot sequential reaction including a Friedel-Crafts-type alkylation of alpha,beta unsaturated aldehydes followed by an alpha-oxyamination was realized. The reaction in aqueous solvent to promote the enzymatic oxidation, and the use of a peptide catalyst compatible with such conditions, were essential. The present sequential reaction afforded oxygen-functionalized indole or pyrrole derivatives in a highly enantioselective manner. PMID- 23019468 TI - Synthesis of a novel chemotype via sequential metal-catalyzed cycloisomerizations. AB - Sequential cycloisomerizations of diynyl o-benzaldehyde substrates to access novel polycyclic cyclopropanes are reported. The reaction sequence involves initial Cu(I)-mediated cycloisomerization/nucleophilic addition to an isochromene followed by diastereoselective Pt(II)-catalyzed enyne cycloisomerization. PMID- 23019469 TI - A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues. AB - The cyclic peptide core of the antifungal and antibiotic cyclic depsipeptide LI F04a was synthesised by using a modified Yamaguchi macrolactonization approach. Alternative methods of macrolactonization (e.g., Corey-Nicolaou) resulted in significant epimerization of the C-terminal amino acid during the cyclization reaction. The D-stereochemistry of the alanine residue in the naturally occurring cyclic peptide may be required for the antifungal activity of this natural product. PMID- 23019470 TI - A simple and efficient dual optical signaling chemodosimeter for toxic Hg(II). AB - 10-Methylthioacridone, designated as acrithion, has been employed as an easily accessible chemodosimeter for the optical targeting of toxic Hg(2+) in buffered aqueous DMSO. The Hg(2+)-mediated desulfurization of the probe is translated into selective dual signaling of Hg(2+) by means of color bleaching and fluorescence amplification while several other metal ions, including potentially competing Ag(+), Cu(2+) and Pb(2+), afford no significant interferences even in excess concentrations. PMID- 23019471 TI - Organocatalysis. PMID- 23019472 TI - Organocatalytic asymmetric Michael addition of unprotected 3-substituted oxindoles to 1,4-naphthoquinone. AB - We reported the first example of organocatalytic Michael addition of unprotected 3-prochiral oxindoles 1 to 1,4-naphthoquinone. Quinidine derivative (DHQD)(2)PYR was found to be able to catalyze this reaction in up to 83% ee, with moderate to excellent yields. This method could be used for the synthesis of enantioenriched 3,3-diaryloxindoles, and the catalytic synthesis of which was unprecedented. PMID- 23019473 TI - A novel asymmetric synthesis of cinacalcet hydrochloride. AB - A novel route to asymmetric synthesis of cinacalcet hydrochloride by the application of (R)-tert-butanesulfinamide and regioselective N-alkylation of the naphthyl ethyl sulfinamide intermediate is described. PMID- 23019474 TI - Organocatalytic C-H activation reactions. AB - Organocatalytic C-H activation reactions have recently been developed besides the traditional metal-catalysed C-H activation reactions. The recent non-asymmetric and asymmetric C-H activation reactions mediated by organocatalysts are discussed in this review. PMID- 23019475 TI - Highly enantioselective access to cannabinoid-type tricyles by organocatalytic Diels-Alder reactions. AB - After prosperous domino reactions towards benzopyrans, the products were used as the starting material in Lewis acid catalyzed and organocatalytic Diels-Alder reactions to build up a tricyclic system. Herein, an asymmetric induction up to 96% enantiomeric excess was obtained by the use of imidazolidinone catalysts. This approach can be utilized to construct the tricyclic system in numerous natural products, in particular the scaffold of tetrahydrocannabinol (THC) being the most representative one. Compared with other published methods, condensation with a preexisting cyclohexane moiety in the precursor is needed to gain the heterogenic tricycle systems, whereas we present a novel strategy towards cannabinoid derivatives based on a flexible modular synthesis. PMID- 23019476 TI - Approaches to alpha-amino acids via rearrangement to electron-deficient nitrogen: Beckmann and Hofmann rearrangements of appropriate carboxyl-protected substrates. AB - The titled approaches were effected with various 2-substituted benzoylacetic acid oximes 3 (Beckmann) and 2-substituted malonamic acids 9 (Hofmann), their carboxyl groups being masked as a 2,4,10-trioxaadamantane unit (an orthoacetate). The oxime mesylates have been rearranged with basic Al(2)O(3) in refluxing CHCl(3), and the malonamic acids with phenyliodoso acetate and KOH/MeOH. Both routes are characterized by excellent overall yields. Structure confirmation of final products was conducted with X-ray diffraction in selected cases. The final N benzoyl and N-(methoxycarbonyl) products are alpha-amino acids with both carboxyl and amino protection; hence, they are of great interest in peptide synthesis. PMID- 23019477 TI - Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide. AB - Eletriptan hydrobromide (1) is a selective serotonin (5-HT(1)) agonist, used for the acute treatment of the headache phase of migraine attacks. During the manufacture of eletriptan hydrobromide the formation of various impurities were observed and identified by LC-MS. To control the formation of these impurities during the preparation of active pharmaceutical ingredients, the structure of the impurities must be known. Major impurities of the eletriptan hydrobromide synthesis were prepared and characterized by using various spectroscopic techniques, i.e., mass spectroscopy, FTIR , (1)H NMR, (13)C NMR/DEPT, and further confirmed by co-injection in HPLC. The present study will be of great help in the synthesis of highly pure eletriptan hydrobromide related compounds. PMID- 23019478 TI - Cation affinity numbers of Lewis bases. AB - Using selected theoretical methods the affinity of a large range of Lewis bases towards model cations has been quantified. The range of model cations includes the methyl cation as the smallest carbon-centered electrophile, the benzhydryl and trityl cations as models for electrophilic substrates encountered in Lewis base-catalyzed synthetic procedures, and the acetyl cation as a substrate model for acyl-transfer reactions. Affinities towards these cationic electrophiles are complemented by data for Lewis-base addition to Michael acceptors as prototypical neutral electrophiles. PMID- 23019479 TI - Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis. AB - For the first time, chiral sulfoximine derivatives have been applied as asymmetric organocatalysts. In combination with a thiourea-type backbone the sulfonimidoyl moiety leads to organocatalysts showing good reactivity in the catalytic desymmetrization of a cyclic meso-anhydride and moderate enantioselectivity in the catalytic asymmetric Biginelli reaction. Straightforward synthetic routes provide the newly designed thiourea-sulfoximine catalysts in high overall yields without affecting the stereohomogeneity of the sulfur-containing core fragment. PMID- 23019480 TI - Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones. AB - The organocatalytic Michael addition of malonates to symmetric unsaturated 1,4 diketones catalyzed by thiourea and squaramide derivatives with Cinchona alkaloids afforded the formation of a new C-C bond in high yields (up to 98%) and enantiomeric purities (up to 93%). The absolute configuration of the product was suggested from comparison of the experimental and calculated VCD spectra of the reaction product 3a. PMID- 23019482 TI - Impact of cyclodextrins on the behavior of amphiphilic ligands in aqueous organometallic catalysis. AB - In this study, we showed that the addition of randomly modified beta-cyclodextrin (RAME-beta-CD) in aqueous medium could have a beneficial impact on the catalytic performances of phosphane-based aggregates in the Pd-catalyzed cleavage of allyl carbonates (Tsuji-Trost reaction). The RAME-beta-CD/phosphane supramolecular interactions helped explain the catalytic results. The presence of RAME-beta-CD in the aqueous compartment improved the phosphane-based aggregate dynamics. The exchanges between the hydrophobic substrate-containing aggregate core and the catalyst-containing aqueous phase were then greatly favored, resulting in an increase in the catalytic performances. PMID- 23019481 TI - A quantitative approach to nucleophilic organocatalysis. AB - The key steps in most organocatalytic cyclizations are the reactions of electrophiles with nucleophiles. Their rates can be calculated by the linear free energy relationship log k(20 degrees C) = s(N)(E + N), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by the solvent-dependent nucleophilicity (N) and sensitivity (s(N)) parameters.Electrophilicity parameters in the range -10 < E < -5 were determined for iminium ions derived from cinnamaldehyde and common organocatalysts, such as pyrrolidines and imidazolidinones, by studying the rates of their reactions with reference nucleophiles. Iminium activated reactions of alpha,beta-unsaturated aldehydes can, therefore, be expected to proceed with nucleophiles of 2 < N < 14, because such nucleophiles are strong enough to react with iminium ions but weak enough not to react with their precursor aldehydes. With the N parameters of enamines derived from phenylacetaldehyde and MacMillan's imidazolidinones one can rationalize why only strong electrophiles, such as stabilized carbenium ions (-8 < E < -2) or hexachlorocyclohexadienone (E = -6.75), are suitable electrophiles for enamine activated reactions with imidazolidinones. Several mechanistic controversies concerning iminium and enamine activated reactions could thus be settled by studying the reactivities of independently synthesized intermediates.Kinetic investigations of the reactions of N-heterocyclic carbenes (NHCs) with benzhydrylium ions showed that they have similar nucleophilicities to common organocatalysts (e.g., PPh(3), DMAP, DABCO) but are much stronger (100-200 kJ mol(-1)) Lewis bases. While structurally analogous imidazolylidenes and imidazolidinylidenes have comparable nucleophilicities and Lewis basicities, the corresponding deoxy Breslow intermediates differ dramatically in reactivity. The thousand-fold higher nucleophilicity of 2-benzylidene-imidazoline relative to 2 benzylidene-imidazolidine is explained by the gain of aromaticity during electrophilic additions to the imidazoline derivatives. O-Methylated Breslow intermediates are a hundred-fold less nucleophilic than deoxy Breslow intermediates. PMID- 23019484 TI - N-Heterocyclic carbene-catalyzed direct cross-aza-benzoin reaction: Efficient synthesis of alpha-amino-beta-keto esters. AB - An efficient catalytic synthesis of alpha-amino-beta-keto esters has been newly developed. Cross-coupling of various aldehydes with alpha-imino ester, catalyzed by N-heterocyclic carbene, leads chemoselectively to alpha-amino-beta-keto esters in moderate to good yields with high atom efficiency. The reaction mechanism is discussed, and it is proposed that the alpha-amino-beta-keto esters are formed under thermodynamic control. PMID- 23019483 TI - Synthesis and evaluation of new guanidine-thiourea organocatalyst for the nitro Michael reaction: Theoretical studies on mechanism and enantioselectivity. AB - A new guanidine-thiourea organocatalyst has been developed and applied as bifunctional organocatalyst in the Michael addition reaction of diethyl malonate to trans-beta-nitrostyrene. Extensive DFT calculations, including solvent effects and dispersion corrections, as well as ab initio calculations provide a plausible description of the reaction mechanism. PMID- 23019485 TI - Synthesis and characterization of low-molecular-weight pi-conjugated polymers covered by persilylated beta-cyclodextrin. AB - The paper reports the preparation of a poly[2,7-(9,9-dioctylfluorene)-alt-5,5' bithiophene/PS-betaCD] (PDOF-BTc) polyrotaxane copolymer, through a Suzuki coupling reaction between the 5,5(')-dibromo-2,2'-bithiophene (BT) inclusion complex with persilylated beta-cyclodextrin (PS-betaCD), and 9,9-dioctylfluorene 2,7-bis(trimethylene borate) (DOF) as the blocking group. The chemical structure and the thermal and morphological properties of the resulting polyrotaxane were investigated by using NMR and FT-IR spectroscopy, TGA, DSC and AFM analysis. The encapsulation of BT inside the PS-betaCD cavity results in improvements in the solubility, as well as in different surface morphology and thermal properties of the PDOF-BTc rotaxane copolymer compared to its noncomplexed PDOF-BT homologue. In contrast, the number-average molecular weight (M(n)) of PDOF-BTc rotaxane copolymer indicated lower values suggesting that the condensation reaction is subjected to steric effects of the bulkier silylated groups, affecting the ability of the diborate groups from the DOF molecule to partially penetrate the PS-betaCD cavity. PMID- 23019486 TI - Reactions of nitroxides XIII: Synthesis of the Morita-Baylis-Hillman adducts bearing a nitroxyl moiety using 4-acryloyloxy-2,2,6,6-tetramethylpiperidine-1 oxyl as a starting compound, and DABCO and quinuclidine as catalysts. AB - The Morita-Baylis-Hillman adducts bearing a nitroxyl moiety were synthesized from 4-acryloyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl and aliphatic, aryl and heterocyclic aldehydes. PMID- 23019487 TI - The crystal structure of the Dess-Martin periodinane. AB - We report the elusive X-ray structure of the Dess-Martin periodinane (DMP), a hypervalent iodine reagent popular amongst synthetic chemists. In the solid state, the highly crystalline compound forms an intricate coordination polymer held together by intermolecular halogen and hydrogen bonds. PMID- 23019488 TI - Influence of cyclodextrin on the solubility of a classically prepared 2 vinylcyclopropane macromonomer in aqueous solution. AB - A macromonomer 5 consisting of a polymerizable vinylcyclopropane end group and a poly(N-isopropylacrylamide) (poly(NiPAAm)) chain was obtained from amidation of 1 ethoxycarbonyl-2-vinylcyclopropane-1-carboxylic acid (4) with an amino-terminated poly(NiPAAm) 3 as an example. This macromonomer 5 showed an LCST effect after complexation of the vinyl end group with beta-cyclodextrin in water. Via radical ring-opening copolymerization of 5 and NiPAAm a graft copolymer 8 with a clouding point of 32 degrees C was synthesized. The branched unsaturated polymer was treated with ozone to cleave the double bonds of the main chain. PMID- 23019489 TI - C2-Alkylation of N-pyrimidylindole with vinylsilane via cobalt-catalyzed C-H bond activation. AB - Direct C2-alkylation of an indole bearing a readily removable N-pyrimidyl group with a vinylsilane was achieved by using a cobalt catalyst generated in situ from CoBr(2), bathocuproine, and cyclohexylmagnesium bromide. The reaction allows coupling between a series of N-pyrimidylindoles and vinylsilanes at a mild reaction temperature of 60 degrees C, affording the corresponding alkylated indoles in moderate to good yields. PMID- 23019490 TI - Celebrating serotonin. PMID- 23019491 TI - Exploring chemical space for drug discovery using the chemical universe database. AB - Herein we review our recent efforts in searching for bioactive ligands by enumeration and virtual screening of the unknown chemical space of small molecules. Enumeration from first principles shows that almost all small molecules (>99.9%) have never been synthesized and are still available to be prepared and tested. We discuss open access sources of molecules, the classification and representation of chemical space using molecular quantum numbers (MQN), its exhaustive enumeration in form of the chemical universe generated databases (GDB), and examples of using these databases for prospective drug discovery. MQN-searchable GDB, PubChem, and DrugBank are freely accessible at www.gdb.unibe.ch. PMID- 23019492 TI - Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets. AB - The synthesis of phidianidines A and B, the first 1,2,4-oxadiazole-containing alkaloid, from the marine opisthobranch mollusk Phidiana militaris is reported. The synthesis proceeds in six steps from known indole acetic acids in 39.9% (phidianidine A) and 21% (phidianidine B) overall yields from commercially available materials. Biological characterization found that phidianidines A and B are selective inhibitors of DAT (versus SERT and NET) and a selective, potent ligand and partial agonist of the MU opioid receptor (versus delta- and kappa opioid receptors). Moreover, neither phidianidines A and B are cytotoxic, and thus represent an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries and prepared a diverse series of unnatural analogs. PMID- 23019493 TI - Differentiating enantioselective actions of GABOB: a possible role for threonine 244 in the binding site of GABA(C) rho(1) receptors. AB - Designing potent and subtype-selective ligands with therapeutic value requires knowledge about how endogenous ligands interact with their binding site. 4-Amino 3-hydroxybutanoic acid (GABOB) is an endogenous ligand found in the central nervous system in mammals. It is a metabolic product of GABA, the major inhibitory neurotransmitter. Homology modeling of the GABA(C) rho(1) receptor revealed a potential H-bond interaction between the hydroxyl group of GABOB and threonine 244 (T244) located on loop C of the ligand binding site of the rho(1) subunit. Using site-directed mutagenesis, we examined the effect of mutating T244 on the efficacy and pharmacology of GABOB and various ligands. It was found that mutating T244 to amino acids that lacked a hydroxyl group in their side chains produced GABA insensitive receptors. Only by mutating rho(1)T244 to serine (rho(1)T244S) produced a GABA responsive receptor, albeit 39-fold less sensitive to GABA than rho(1)wild-type. We also observed changes in the activities of the GABA(C) receptor partial agonists, muscimol and imidazole-4-acetic acid (I4AA). At the concentrations we tested, the partial agonists antagonized GABA-induced currents at rho(1)T244S mutant receptors (Muscimol: rho(1)wild-type, EC(50) = 1.4 MUM; rho(1)T244S, IC(50) = 32.8 MUM. I4AA: rho(1)wild-type, EC(50) = 8.6 MUM; rho(1)T244S, IC(50) = 21.4 MUM). This indicates that T244 is predominantly involved in channel gating. R-(-)-GABOB and S-(+)-GABOB are full agonists at rho(1)wild-type receptors. In contrast, R-(-)-GABOB was a weak partial agonist at rho(1)T244S (1 mM activates 26% of the current produced by GABA EC(50) versus rho(1)wild-type, EC(50) = 19 MUM; I(max) 100%), and S-(+)-GABOB was a competitive antagonist at rho(1)T244S receptors (rho(1)wild-type, EC(50) = 45 MUM versus rho(1)T244S, IC(50) = 417.4 MUM, K(B) = 204 MUM). This highlights that the interaction of GABOB with T244 is enantioselective. In contrast, the potencies of a range of antagonists tested, 3-aminopropyl(methyl)phosphinic acid (3-APMPA), 3 aminopropylphosphonic acid (3-APA), S- and R-(3-amino-2 hydroxypropyl)methylphosphinic acid (S-(-)-CGP44532 and R-(+)-CGP44533), were not altered. This suggests that T244 is not critical for antagonist binding. Receptor gating is dynamic, and this study highlights the role of loop C in agonist-evoked receptor activation, coupling agonist binding to channel gating. PMID- 23019494 TI - Toxicity in rat primary neurons through the cellular oxidative stress induced by the turn formation at positions 22 and 23 of Abeta42. AB - The 42-mer amyloid beta-protein (Abeta42) aggregates to form soluble oligomers that cause memory loss and synaptotoxicity in Alzheimer's disease (AD). Oxidative stress is closely related to the pathogenesis of AD. We previously identified the toxic conformer of Abeta42 with a turn at positions 22 and 23 ("toxic turn") by solid-state NMR and demonstrated that a monoclonal antibody (11A1) against the toxic turn in Abeta42 mainly detected the oligomer in the brains of AD patients. Our recent study suggested that oxidative stress is a key factor of the oligomerization and cognitive impairment induced by Abeta overproduction in vivo. However, the involvement of the toxic conformer in Abeta42-induced oxidative damage remains unclear. To investigate this mechanism, we examined the levels of intracellular reactive oxygen species (ROS) and neurotoxicity in rat primary neurons using E22P-Abeta42, a mutant that induces a turn at positions 22 and 23, and E22V-Abeta42, a turn-preventing mutant. E22P-Abeta42, but not E22V-Abeta42, induced greater ROS production than Wt-Abeta42 in addition to potent neurotoxicity. Interestingly, the formation of the toxic conformer in both E22P Abeta42 and Wt-Abeta42 probed by the 11A1 antibody preceded Abeta42-induced neurotoxicity. Trolox (a radical scavenger) and Congo red (an aggregation inhibitor) significantly prevented the neurotoxicity and intracellular ROS induced by E22P-Abeta42 and Wt-Abeta42, respectively. These results suggest that Abeta42-mediated toxicity is caused by the turn that favors toxic oligomers, which increase generation of ROS. PMID- 23019495 TI - Defining the putative inhibitory site for a selective negative allosteric modulator of human alpha4beta2 neuronal nicotinic receptors. AB - Neuronal nicotinic receptors (nAChRs) have been implicated in several diseases and disorders such as autism spectrum disorders, Alzheimer's disease, Parkinson's disease, epilepsy, and nicotine addiction. To understand the role of nAChRs in these conditions, it would be beneficial to have selective molecules that target specific nAChRs in vitro and in vivo. Our laboratory has previously identified a novel allosteric site on human alpha4beta2 nAChRs using a series of computational and in vitro approaches. At this site, we have identified negative allosteric modulators that selectively inhibit human alpha4beta2 nAChRs, a subtype implicated in nicotine addiction. This study characterizes the allosteric site via site-directed mutagenesis. Three amino acids (Phe118, Glu60, and Thr58) on the beta2 subunit were shown to participate in the inhibitory properties of the selective antagonist KAB-18 and provided insights into its antagonism of human alpha4beta2 nAChRs. SAR studies with KAB-18 analogues and various mutant alpha4beta2 nAChRs also provided information concerning how different physiochemical features influence the inhibition of nAChRs through this allosteric site. Together, these studies identify the amino acids that contribute to the selective antagonism of human alpha4beta2 nAChRs at this allosteric site. Finally, these studies define the physiochemical features of ligands that influence interaction with specific amino acids in this allosteric site. PMID- 23019496 TI - Binding of the amphetamine-like 1-phenyl-piperazine to monoamine transporters. AB - The human serotonin transporter (hSERT), the human dopamine transporter (hDAT), and the human norepinephrine transporter (hNET) facilitate the active uptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Drugs of abuse such as MDMA (streetname "ecstasy") and certain 1-phenyl piperazine (PP) analogs such as 1-(3-chlorophenyl)-piperazine (mCPP) elicit their stimulatory effect by elevating the synaptic concentration of serotonin by blocking or reversing the normal transport activity of hSERT. Recent data suggest that certain analogs of PP may be able to counteract the addictive effect of cocaine. Little is still known about the precise mechanism by which MDMA and PP analogs function at hSERT, hDAT, and hNET and even less is known about the specific protein-ligand interactions. In this study, we provide a comprehensive biochemical examination of a repertoire of PP analogs in hSERT, hDAT, and hNET. Combined with induced fit docking models and molecular dynamics simulations of PP and 1-(3-hydroxyphenyl)-piperazine (3-OH-PP) bound to hSERT and hDAT, we present detailed molecular insight into the promiscuous binding of PP analogs in the monoamine transporters. We find that PP analogs inhibit uptake as well as induce release in all three monoamine transporters. We also find that the selectivity of the PP analogs can be adjusted by carefully selecting substituents on the PP skeleton. PMID- 23019499 TI - Comparison of the influence of two flap designs on periodontal healing after surgical extraction of impacted third molars. AB - BACKGROUND AND AIMS: Impacted lower third molar is found in 90% of the general population. Impacted lower third molar surgery may result in periodontal complications on the distal surface of the adjacent second molar. The aim of this study was to evaluate the effect of flap design on the periodontal status of the second molar after lower third molar surgery. MATERIALS AND METHODS: Twenty patients, with an age range of 18-26 years, participated in the present study. The inclusion criteria consisted of the presence of bilateral symmetrical impacted third molars on panoramic radiographs. The subjects were randomly divided into two groups. The impactions on the left and right sides were operated by Szmyd and triangular flaps, respectively. Postoperative management and medications were similar for both groups. The subjects were evaluated at two week, one-month, and six-month postoperative intervals by a surgeon who was blind to the results. Data was analyzed by t-test using SPSS 11 software. RESULTS: There were no significant differences in clinical attachment loss, pocket depth, bone level, plaque index, and free gingival margin between the two flaps (p>0.05). CONCLUSION: The results of the present study did not show any differences in pocket depth, clinical attachment level, bone level and FGM (free gingival margin) between the two flap designs under study. PMID- 23019497 TI - Kisspeptin prevention of amyloid-beta peptide neurotoxicity in vitro. AB - Alzheimer's disease (AD) onset is associated with changes in hypothalamic pituitary-gonadal (HPG) function. The 54 amino acid kisspeptin (KP) peptide regulates the HPG axis and alters antioxidant enzyme expression. The Alzheimer's amyloid-beta (Abeta) is neurotoxic, and this action can be prevented by the antioxidant enzyme catalase. Here, we examined the effects of KP peptides on the neurotoxicity of Abeta, prion protein (PrP), and amylin (IAPP) peptides. The Abeta, PrP, and IAPP peptides stimulated the release of KP and KP 45-54. The KP peptides inhibited the neurotoxicity of Abeta, PrP, and IAPP peptides, via an action that could not be blocked by kisspeptin-receptor (GPR-54) or neuropeptide FF (NPFF) receptor antagonists. Knockdown of KiSS-1 gene, which encodes the KP peptides, in human neuronal SH-SY5Y cells with siRNA enhanced the toxicity of amyloid peptides, while KiSS-1 overexpression was neuroprotective. A comparison of the catalase and KP sequences identified a similarity between KP residues 42 51 and the region of catalase that binds Abeta. The KP peptides containing residues 45-50 bound Abeta, PrP, and IAPP, inhibited Congo red binding, and were neuroprotective. These results suggest that KP peptides are neuroprotective against Abeta, IAPP, and PrP peptides via a receptor independent action involving direct binding to the amyloid peptides. PMID- 23019498 TI - Clinically employed opioid analgesics produce antinociception via MU-delta opioid receptor heteromers in Rhesus monkeys. AB - Morphine and related drugs are widely employed as analgesics despite the side effects associated with their use. Although morphine is thought to mediate analgesia through mu opioid receptors, delta opioid receptors have been implicated in mediating some side effects such as tolerance and dependence. Here we present evidence in rhesus monkeys that morphine, fentanyl, and possibly methadone selectively activate mu-delta heteromers to produce antinociception that is potently antagonized by the delta opioid receptor antagonist, naltrindole (NTI). Studies with HEK293 cells expressing mu-delta heteromeric opioid receptors exhibit a similar antagonism profile of receptor activation in the presence of NTI. In mice, morphine was potently inhibited by naltrindole when administered intrathecally, but not intracerebroventricularly, suggesting the possible involvement of mu-delta heteromers in the spinal cord of rodents. Taken together, these results strongly suggest that, in primates, mu-delta heteromers are allosterically coupled and mediate the antinociceptive effects of three clinically employed opioid analgesics that have been traditionally viewed as mu selective. Given the known involvement of delta receptors in morphine tolerance and dependence, our results implicate mu-delta heteromers in mediating both antinociception and these side effects in primates. These results open the door for further investigation in humans. PMID- 23019500 TI - Efficacy of hydrophobic layer on sealing ability of dentin adhesive systems in class v composite resin restorations. AB - BACKGROUND AND AIMS: Adhesive permeability is hindered by application of an additional layer of hydrophobic resin, which increases its concentration within the hydrophilic layer, reduces its affinity to water, and enhances its physical prop-erties. The aim of the present study was to evaluate the effect of a hydrophobic layer on the microleakage of class V composite restorations using different adhesives. MATERIALS AND METHODS: The adhesives including total-etch Scotchbond MP and Single Bond, and the self-etch Clearfil SE Bond and Clearfil S3 Bond were applied to 80 class V cavities in vitro on the buccal surface in CEJ and then were fol-lowed by hydrophobic resin (Margin Bond) in half of the cavities in each group (n=10). After restoration with microhybrid composite, Z100 and immersion in fuchsine, the degree of microleakage was assessed. Data were analyzed using the Krus-kal-Wallis, Man-Whitney, and Wilcoxon tests. RESULTS: The hydrophobic layer significantly reduced the microleakage of Clearfil SE Bond and Clearfil S3 Bond only in dentin (p<0.05). There was no significant difference between enamel and dentinal margins in Clearfil S3 Bond, Clearfil SE Bond plus Margin Bond, and Clearfil S3 Bond plus Margin Bond (p>0.05). CONCLUSION: Within the limitation of this study, only Clearfil S3 Bond could demonstrate the identical values of microle-akage in enamel and dentinal margins. PMID- 23019501 TI - Association between Periodontopathogens and CRP Levels in Patients with Periodontitis in Serbia. AB - BACKGROUND AND AIMS: Recent epidemiological studies have shown that individuals with periodontitis have a significantly higher risk of developing coronary heart disease, which might be attributed to the complex microbiota in the dental plaque. Periodontopathogens have been reported as risk factors for cardiovascular disease. This study evaluated association of chronic periodontitis and periodontopathogens with CRP in systemically healthy Serbian adults. MATERIALS AND METHODS: Serum C-reactive protein levels were measured in 24 patients with moderate periodontitis, 26 patients with severe periodontitis, and 25 periodontally healthy subjects. Periodontal health indicators included gingival bleeding on probing and periodontal disease status. Patients with moderate periodontitis had low attachment loss and pocket depths of <4 mm. Patients with severe periodontitis had high AL and pocket depth of >5 mm. The control group with healthy gingiva had gingival sulcus of <2 mm and no attachment loss. Presence of periodontopathogens in subgingival plaque samples was analyzed by polymerase chain reaction. RESULTS: The periodontal parameters and CRP levels were significantly higher in the patients with periodontitis. Patients who had both severe and moderate periodontitis had higher mean CRP levels. The percentage of subjects with elevated CRP leves of >5 mol/L was greater in the higher clinical AL group compared to the group with less attachment loss. Presence of periodontopathogens was also associated with elevated CRP levels and poor periodontal status. CONCLUSION: PD and subgingival periodontopathogens are associated with increased CRP levels. These findings suggest that periodontal infection may contribute to systemic inflammatory burden in otherwise healthy individuals. PMID- 23019502 TI - Application of crestal anesthesia for treatment of class I caries in posterior mandibular teeth. AB - BACKGROUND AND AIMS: Current infiltration techniques for achieving anesthesia in dental procedures are not applicable in posterior mandibular region because of its dense cortical bone. The aim of this study was to evaluate the efficacy of a specific infiltration anesthesia in posterior mandibular teeth instead of inferior alveolar nerve block for restorative procedures. MATERIALS AND METHODS: Crestal anesthesia (CA) was assessed both clinically and by computed tomography scan for its efficacy and side effects. A combination of an opaque material (Ultravist) and 2% lidocaine was used to trace the anesthetic solution. The combination was primarily injected in the gingival tissue of rabbit and was followed-up regularly for two weeks to assess any possible injury. After confirming its safety, a combination of these materials was injected to volunteers to assess efficacy and diffusion route. A total of 154 patients (77 female, 77 male) with matched bilateral posterior teeth in mandible were selected randomly and an IANB and CA were performed randomly and separately in different sessions for the contra lateral teeth. The onset of anesthesia, anesthesia duration, pain, blood pressure, pulse rate, and consumed volume of anesthetic solution was recorded for each technique. Data were analyzed using paired t-test. RESULTS: There were no significant differences in clinical attachment loss, pocket depth, bone level, plaque index, and free gingival margin between the two flaps (p>0.05). CONCLUSION: CA could be considered as a reliable and safe primary injection in posterior mandibular teeth for restorative treatments. PMID- 23019503 TI - Evaluation of Genetic Pattern of Gentamicin-resistant Enterococci Isolated from Clinical Samples. AB - BACKGROUND AND AIMS: Enterococci are among resistant microorganisms to antibiotics and are responsible for some of acute gingival infections. This study aimed at molecular evaluation of gentamicin-resistant enterococcus species and determining the resistance genes. MATERIALS AND METHODS: Clinical samples were cultured on BHI medium and enterococci were isolated by specific methods and antibiograms were prepared. DNA was derived from gentamicin-resistant species by alkaline lysis method and replicated by PCR method. Four gentamicin-resistant genes were evaluated by electrophoresis method on agarose gel. RESULTS: From 105 Enterococcus faecalis isolates, 36.2% and from 38 Enterococcus faecium isolates, 78.2% were resistant to gentamicin. 60% of these species bore aac (6')- le - aph(2")- la gene. ph(2")- Ib,Ic,Id genes were not seen in any of the evaluated species. CONCLUSION: In gentamicin-resistant species of E. faecalis and E. faecium, the aac (6')- le - aph(2")- la gene was identified as the main cause of resistance. PMID- 23019504 TI - Desmoplastic ameloblastoma: a case report. AB - Desmoplastic ameloblastoma is a rare variant of ameloblastoma. Up until now, less than 150 patients have been reported in the literature. We report a case of desmoplastic ameloblastoma in a 45-year-old female with a painless swelling in the left anterior maxillary region. Fine needle aspiration yielded no fluid. Periapical and panoramic radiographs as well as computer tomography scan showed a mixed lesion with multilocular appearance. The present case deserves special importance be-cause of its unfamiliar appearance, potentially aggressive nature and high chances of misdiagnosis. Moreover, the radio-graphic features of this lesion rarely point towards ameloblastoma. A partial maxillectomy for tumor resection was per-formed and the involved teeth were removed. This report is an attempt to help the dental community in developing familiarity with the clinical presentation and at the same time advocating to develop a high index of suspicion in recognizing such cases. PMID- 23019505 TI - Erupted compound odontomas: a case report. AB - The tumors in which odontogenic differentiation is fully expressed are the odontomas. Odontomas are considered as hamartomas rather than a true neoplasm. These tumors are composed of enamel, dentine, cementum and pulp tissue. It is most commonly associated with the eruption of the teeth. They are usually discovered on routine radiographic examination. In exceptional cases, the odontoma erupts in to the mouth. Nine cases of erupted compound odontomas are reported in the English literature, and the present paper reports another case of an erupted compound odontoma in a 22-year-old female patient. PMID- 23019506 TI - Talon cusps in mandibular incisors: an unusual presentation in a child patient. AB - Talon cusp is a dental anomaly also known as an eagle's talon. It is an extra cusp on an anterior tooth which arises as a result of evagination on the surface of a crown before calcification has occurred. The exact etiology is unknown. The inci-dence of talon cusp is less than 6%. Commonly involved teeth are maxillary incisors, usually unilateral but in some instanc-es bilateral. The classical radiographical feature of talon cusp is double teeth appearance. The anomaly has been reported to be unusual in the mandibular dentition. This article reports an unusual case of talon cusp of permanent mandibular central incisors. PMID- 23019507 TI - Comparison of chamfer and deep chamfer preparation designs on the fracture resistance of zirconia core restorations. AB - BACKGROUND AND AIMS: One of the major problems of all-ceramic restorations is their probable fracture under occlusal force. The aim of the present in vitro study was to compare the effect of two marginal designs (chamfer and deep chamfer) on the fracture resistance of all-ceramic restorations, CERCON. MATERIALS AND METHODS: This in vitro study was carried out with single-blind experimental technique. One stainless steel die with 50' chamfer finish line design (0.8 mm deep) was prepared using a milling machine. Ten epoxy resin dies were prepared. The same die was retrieved and 50' chamfer was converted into a deep chamfer design (1 mm). Again ten epoxy resin dies were prepared from the deep chamfer die. Zirconia cores with 0.4 mm thickness and 35 um cement space were fabricated on the epoxy resin dies (10 chamfer and 10 deep chamfer samples). The zirconia cores were cemented on the epoxy resin dies and underwent a fracture test with a universal testing machine and the samples were investigated from the point of view of the origin of the failure. RESULTS: The mean values of fracture resistance for deep chamfer and chamfer samples were 1426.10+/-182.60 and 991.75+/-112.00 N, respectively. Student's t-test revealed statistically significant differences between the groups. CONCLUSION: The results indicated a relationship between the marginal design of zirconia cores and their fracture re sistance. A deep chamfer margin improved the biomechanical performance of posterior single zirconia crown restorations, which might be attributed to greater thickness and rounded internal angles in deep chamfer margins. PMID- 23019508 TI - Frequency of Traumatic Ulcerations and Post-insertion Adjustment Recall Visits in Complete Denture Patients in an Iranian Faculty of Dentistry. AB - BACKGROUND AND AIMS: The first few days following the insertion of complete dentures are critical for the patients since they are struggling to adapt to their new dentures. This study aimed to evaluate the most common locations of traumatic ulcerations, their frequency and also the duration and number of adjustment visits required to achieve patient comfort fol-lowing placement of complete dentures. MATERIALS AND METHODS: Sixty patients were selected from edentulous patients referring to a removable prosthodontics department. Complete dentures were fabricated for the patients. After placement of dentures, all the patients were evaluated from the day after placement until patient comfort was achieved. Descriptive analysis was performed and chi-squared test was used to evaluate the associations between lesions, post-insertion visits and gender. RESULTS: A total of 85.8% of patients required denture adjustment because of mucosal injuries during their first visit fol-lowing denture placement. Maxillary and mandibular dentures did not require further adjustments after fourth and sixth visits, respectively. No significant differences were detected between males and females in the number of mucosal injuries in the anatomical areas evaluated in the maxilla and mandible using Fisher's exact test (P > 0.05). Furthermore, the number of mandibular dentures requiring adjustments was significantly higher than maxillary dentures in all the post-insertion ap pointments (P < 0.001). CONCLUSION: Since most mucosal injuries are located in the vestibule, adequate extension of denture flanges, especially during border molding, and use of pressure indicators that reveal over-extended borders, play an important role in decreas-ing mucosal injuries and improving patient comfort following complete denture placement. PMID- 23019509 TI - Sexual dimorphism in human mandibular canines: a radiomorphometric study in South Indian population. AB - BACKGROUND AND AIMS: The aim of this study was to determine whether variations in the mesiodistal dimensions of mandibular canines had any role in sex determination. MATERIALS AND METHODS: The study comprised of patients in the 19 24-year age group (20 males and 20 females). Mesiodistal dimensions of mandibular canines was measured at the maximum mesiodistal width, first intraorally, then on plaster models of the same patient, followed by intraoral periapical radiograph of the same patient. The values were subjected to statistical analysis using t test. RESULTS: It might be concluded from the results that there exists a definite statistically significant difference in the mesi-odistal width of mandibular canines when measured for males and females. Moreover, the left mandibular canine showed a greater sexual dimorphism (9.7%) when compared to the right mandibular canine (7.4%). CONCLUSION: The present study establishes a statistically significant sexual dimorphism in mandibular canines. It can be concluded that the standard mandibular canine index is a quick and easy method for determining sex and in identification of an unknown individual. PMID- 23019510 TI - Periodontal reasons for tooth extraction in a group of greek army personnel. AB - BACKGROUND AND AIMS: The aim of this study was to investigate the prevalence of permanent teeth extracted due to periodontal disease and its relation to age, military rank, and type of extracted teeth due to periodontal and non-periodontal reasons among a group of Greek Army personnel attending a military dental practice. MATERIALS AND METHODS: Study population consisted of 509 officers, non commissioned officers and soldiers, aged 18 to 44 years from a military dental hospital in Greece. The reasons for extractions of teeth for a period of two years were obtained, including aspects such as age, military rank and the type of teeth extracted due to periodontal and non-periodontal reasons. Data were analyzed using chi-squared test. RESULTS: The total number of extracted teeth was 1,231, of which 34.4% were extracted because of periodontal reasons, 32.2% for dental caries and 33.4% for other reasons. The average number of extracted teeth due to periodontal disease showed an increase with age. Maxillary and mandibular first and second molars were the most frequently extracted teeth due to periodontal reasons; however, the anterior teeth of both jaws with mobility (grade III), the same teeth with attach-ment loss (>=5.0 mm) and the posterior teeth of both jaws with furcation involvement (grade IV) were the most frequently extracted teeth due to periodontal reasons. CONCLUSION: Although the goal of the WHO regarding the reduction of dental caries was accomplished, periodontal dis ease was still the main cause of tooth extraction and showed an increase with age. PMID- 23019511 TI - Knowledge and Antibiotics Prescription Pattern among Ugandan Oral Health Care Providers: A Cross-sectional Survey. AB - BACKGROUND AND AIMS: Irrational prescription of antibiotics by clinicians might lead to drug resistance. Clinicians do prescribe antibiotics for either prophylactic or therapeutic reasons. The decision of when and what to prescribe leaves room for misuse and therefore it is imperative to continuously monitor knowledge and pattern of prescription. The aim of the present study was to determine the knowledge of antibiotic use and the prescription pattern among dental health care practitioners in Uganda. MATERIALS AND METHODS: A structured and pretested questionnaire was sent to 350 dental health care practitioners by post or physical delivery. All the questionnaires were sent with self-addressed and prepaid postage envelopes to enable re-spondents to mail back the filled questionnaires. Chi-squared test was used to test for any significant differences between groups of respondents based on qualitative variables. RESULTS: The response rate was 40.3% (n=140). Of these 52.9 % were public health dental officers (PHDOs) and 47.1% were dental surgeons. The males constituted 74.3% of the respondents. There were statistically significant differences be-tween dental surgeons and (PHDOs) in knowledge on prophylactic antibiotic use (P = 0.001) and patient influence on pre-scription (P = 0.001). Amoxicillin, in combination with metronidazole, was the most common combination of antibiotics used followed by co trimoxazole with metronidazole. CONCLUSION: The knowledge of dental health care practitioners in antibiotic use in this study was generally low. A combi-nation of amoxicillin with metronidazole was the most commonly prescribed antibiotics subsequent to different dental pro-cedures. PMID- 23019512 TI - Diagnostic Dental Radiation Risk during Pregnancy: Awareness among General Dentists in Tabriz. AB - BACKGROUND AND AIMS: Pregnant women often do not receive proper dental care in emergency visits due to a lack of awareness of the effect of radiation doses and the involved risks for the fetus. The aim of the present study was to assess the awareness of general dentists practicing in Tabriz, Iran, of the risks involved during exposure to diagnostic dental radiation in pregnant women. MATERIALS AND METHODS: In this descriptive/cross-sectional study, 250 general dentists, who had attended continuing education courses under the supervision of the Faculty of Dentistry, filled out questionnaires on their awareness of radiation risks. Data was analyzed by Spearman's correlation coefficient test. RESULTS: The mean of correct answers was 6.47+/-1.66, with the least and highest correct answers of 2 and 10, respectively. The highest and the lowest levels of awareness were related to the use of a lead apron (92%) and a long rectangular collimator (3.2%), respectively. There was a statistically significant correlation between the age of practitioners and awareness of radiation risks (P=0.02). However, no statistically significant correlation was observed between job experience (P=0.25) and the number of continuing education courses attended (P=0.16) and awareness of radiation risks. CONCLUSION: The studied population of dentists does not seem to have the sufficient knowledge regarding the diagnostic dental radiation risk during pregnancy. Further educational courses and pamphlets are recommended for increasing their awareness of this subject. PMID- 23019513 TI - A simple method for prosthodontic rehabilitation of edentulous patient with epidermolysis bullosa: a clinical case report. AB - An abnormally small oral orifice is defined as microstomia. Microstomia may result from epidermolysis bullosa (EB), which consists of a group of disorders characterized by the presence of mechanical fragility of the skin with recurrent de-velopment of blisters and vesicles, resulting from minor mechanical friction or trauma. Since such patients have a small oral aperture, it may be impossible to take impression and fabricate dentures using conventional methods. In this article, a simple method for taking preliminary impressions from upper and lower edentulous ridges in one patient with limited mouth opening and then preparing the complete denture with custom denture teeth in a single unit was described. PMID- 23019514 TI - Dentigerous cyst associated with a mesiodens: a case report. AB - Dentigerous cysts are the second most common odontogenic cysts after radicular cysts and are most commonly seen in association with third molars and maxillary canines. Only 5% of dentigerous cysts involve supernumerary teeth, of which mesiodens is the most frequent type. This paper presents a case of dentigerous cyst associated with a mesiodens that caused a painless swelling in the upper lip of an 18-year-old female. The patient was treated surgically by enucleation of total cyst and surgical extraction of mesiodens under local anesthesia. PMID- 23019515 TI - A Simple Method for Causal Analysis of Return on IT Investment. AB - This paper proposes a method for examining the causal relationship among investment in information technology (IT) and the organization's productivity. In this method, first a strong relationship among (1) investment in IT, (2) use of IT and (3) organization's productivity is verified using correlations. Second, the assumption that IT investment preceded improved productivity is tested using partial correlation. Finally, the assumption of what may have happened in the absence of IT investment, the so called counterfactual, is tested through forecasting productivity at different levels of investment. The paper applies the proposed method to investment in the Veterans Health Information Systems and Technology Architecture (VISTA) system. Result show that the causal analysis can be done, even with limited data. Furthermore, because the procedure relies on overall organization's productivity, it might be more objective than when the analyst picks and chooses which costs and benefits should be included in the analysis. PMID- 23019516 TI - GTP binding and intramolecular regulation by the ROC domain of Death Associated Protein Kinase 1. AB - The ROCO proteins are a family of large, multidomain proteins characterised by the presence of a Ras of complex proteins (ROC) domain followed by a COR, or C terminal of ROC, domain. It has previously been shown that the ROC domain of the human ROCO protein Leucine Rich Repeat Kinase 2 (LRRK2) controls its kinase activity. Here, the ability of the ROC domain of another human ROCO protein, Death Associated Protein Kinase 1 (DAPK1), to bind GTP and control its kinase activity has been evaluated. In contrast to LRRK2, loss of GTP binding by DAPK1 does not result in loss of kinase activity, instead acting to modulate this activity. These data highlight the ROC domain of DAPK1 as a target for modifiers of this proteins function, and casts light on the role of ROC domains as intramolecular regulators in complex proteins with implications for a broad range of human diseases. PMID- 23019517 TI - Genomes of surface isolates of Alteromonas macleodii: the life of a widespread marine opportunistic copiotroph. AB - Alteromonas macleodii is a marine gammaproteobacterium with widespread distribution in temperate or tropical waters. We describe three genomes of isolates from surface waters around Europe (Atlantic, Mediterranean and Black Sea) and compare them with a previously described deep Mediterranean isolate (AltDE) that belongs to a widely divergent clade. The surface isolates are quite similar, the most divergent being the Black Sea (BS11) isolate. The genomes contain several genomic islands with different gene content. The recruitment of very similar genomic fragments from metagenomes in different locations indicates that the surface clade is globally abundant with little effect of geography, even the AltDE and the BS11 genomes recruiting from surface samples in open ocean locations. The finding of CRISPR protospacers of AltDE in a lysogenic phage in the Atlantic (English Channel) isolate illustrates a flow of genetic material among these clades and a remarkably wide distribution of this phage. PMID- 23019518 TI - The hematopoietic cytokine granulocyte-macrophage colony stimulating factor is important for cognitive functions. AB - We recently reported expression of hematopoietic growth factor GM-CSF and its receptor (GM-CSFR) in CNS neurons. Here we evaluated this system in learning and memory formation using GM-CSF deficient mice. In complementation, GM-CSF signalling was manipulated specifically in adult murine hippocampus by adeno associated virus (AAV)-mediated GM-CSFR alpha overexpression or knock-down. GM CSF ablation caused various hippocampus and amygdala-dependent deficits in spatial and fear memory while rendering intact basic parameters like motor function, inherent anxiety, and pain threshold levels. Corroborating these data, spatial memory of AAV-injected mice was positively correlated with GM-CSFRalpha expression levels. Hippocampal neurons of knock-out mice showed markedly pruned dendritic trees, reduced spine densities, and lower percentages of mature spines. Despite such morphological alterations, long-term potentiation (LTP) was unimpaired in the knock-out hippocampus. Collectively, these results suggest that GM-CSF signalling plays a major role in structural plasticity relevant to learning and memory. PMID- 23019519 TI - Synthesis of one-molecule-thick single-crystalline nanosheets of energetic material for high-sensitive force sensor. AB - Energetic material is a reactive substance that contains a great amount of potential energy, which is extremely sensitive to external stimuli like force. In this work, one-molecule-thick single-crystalline nanosheets of energetic material were synthesized. Very small force applied on the nanosheet proves to lead to the rotation of the tilted nitro groups, and subsequently change of current of the nanosheet. We apply this principle to design high-sensitive force sensor. A theoretical model of force-current dependence was established based on the nanosheets' molecular packing structure model that was well supported with the high resolution XPS, AFM analysis results. An ultra-low-force with range of several picoNewton to several nanoNewton can be measured by determination of corresponding current value. PMID- 23019520 TI - Supercurrent enhancement in Bloch domain walls. AB - Conventional spin-singlet Cooper pairs convert into spin-triplet pairs in ferromagnetic Josephson junctions in which the superconductor/ferromagnet interfaces (S/F) are magnetically inhomogeneous. Although much of the theoretical work describing this triplet proximity effect has considered ideal junctions with magnetic domain walls (DW) at the interfaces, in practice it is not easily possible to isolate a DW and propagate a supercurrent through it. The rare-earth magnet Gd can form a field-tuneable in-plane Bloch DW if grown between non-co linearly aligned ferromagnets. Here we report supercurrents through magnetic Ni Gd-Ni nanopillars: by field annealing at room temperature, we are able to modify the low temperature DW-state in Gd and this result has a striking effect on the junction supercurrent at 4.2 K. We argue that this result can only be explained in terms of the interconversion of triplet and singlet pairs, the efficiency of which depends on the magnetic helicity of the structure. PMID- 23019521 TI - Morbidity and Mortality Patterns of Hospitalised Adult HIV/AIDS Patients in the Era of Highly Active Antiretroviral Therapy: A 4-year Retrospective Review from Zaria, Northern Nigeria. AB - Background. This study, undertaken in major tertiary hospital in northern Nigeria, examined the morbidity and mortality patterns of hospitalised adult HIV/AIDS patients in the HAART era. Methods. Between January 2006 and December 2009, admission records and causes of deaths of hospitalised medical HIV-infected patients were retrieved and analysed according to antiretroviral (ART) status. Results. Of the 207 HIV/AIDS patients reviewed, majority were newly diagnosed (73.4%), and most were hospitalised and died from various AIDS-defining illnesses, mainly disseminated tuberculosis and sepsis. Immune-inflammatory reconstitution-syndrome, ART-toxicity and ART-failure, contributed to morbidity and mortality in patients receiving ART. Sixty six (31.9%) patients died, with higher mortality in males and in those with lower CD4-cell count, lower PCV, and shorter hospital stay. However, hospital stay <=3 days and severe anaemia (PCV < 24%) were independent predictors of mortality. Conclusion. In the current HAART era, late presentation and tuberculosis continue to fuel the HIV/AIDS pandemic in Africa, with emerging challenges due to ART-related complications. PMID- 23019522 TI - beta-Thalassemia: New Therapeutic Modalities, Genetics, Complications, and Quality of Life. PMID- 23019523 TI - Monitoring in the intensive care unit: its past, present, and future. PMID- 23019524 TI - Goal-directed mechanical ventilation: are we aiming at the right goals? A proposal for an alternative approach aiming at optimal lung compliance, guided by esophageal pressure in acute respiratory failure. AB - Patients with acute respiratory failure and decreased respiratory system compliance due to ARDS frequently present a formidable challenge. These patients are often subjected to high inspiratory pressure, and in severe cases in order to improve oxygenation and preserve life, we may need to resort to unconventional measures. The currently accepted ARDSNet guidelines are characterized by a generalized approach in which an algorithm for PEEP application and limited plateau pressure are applied to all mechanically ventilated patients. These guidelines do not make any distinction between patients, who may have different chest wall mechanics with diverse pathologies and different mechanical properties of their respiratory system. The ability of assessing pleural pressure by measuring esophageal pressure allows us to partition the respiratory system into its main components of lungs and chest wall. Thus, identifying the dominant factor affecting respiratory system may better direct and optimize mechanical ventilation. Instead of limiting inspiratory pressure by plateau pressure, PEEP and inspiratory pressure adjustment would be individualized specifically for each patient's lung compliance as indicated by transpulmonary pressure. The main goal of this approach is to specifically target transpulmonary pressure instead of plateau pressure, and therefore achieve the best lung compliance with the least transpulmonary pressure possible. PMID- 23019526 TI - Anterior and posterior meniscofemoral ligaments: MRI evaluation. AB - Although meniscofemoral ligaments are distinct anatomic units, their anatomy and function are controversial from an anatomic and radiologic point of view. Five hundred knee MR examinations were retrospectively studied in an effort to demonstrate the incidence and variations regarding sex and age distribution, as well as the anatomy of the meniscofemoral ligament at magnetic resonance imaging. Patients were mostly men, three hundred and twelve, in contrast with women who were fewer, one hundred eighty-eight patients. The mean age of the patients who were included in this study was 46 years. More than half of them were between 20 and 40 years old; one hundred thirty-three patients among 20 to 30 years old and one hundred and one patients among 31 and 40 years old, in total two hundred thirty-four patients. PMID- 23019525 TI - Potential role of peptidylarginine deiminase enzymes and protein citrullination in cancer pathogenesis. AB - The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein bound arginine and methylarginine residues to the uncharged, nonstandard amino acid citrulline. This enzymatic activity is referred to as citrullination or, alternatively, deimination. Citrullination can significantly affect biochemical pathways by altering the structure and function of target proteins. Five mammalian PAD family members (PADs 1-4 and 6) have been described and show tissue specific distribution. Recent reviews on PADs have focused on their role in autoimmune diseases. Here, we will discuss the potential role of PADs in tumor progression and tumor-associated inflammation. In the context of cancer, increasing clinical evidence suggests that PAD4 (and possibly PAD2) has important roles in tumor progression. The link between PADs and cancer is strengthened by recent findings showing that treatment of cell lines and mice with PAD inhibitors significantly suppresses tumor growth and, interestingly, inflammatory symptoms. At the molecular level, transcription factors, coregulators, and histones are functional targets for citrullination by PADs, and citrullination of these targets can affect gene expression in multiple tumor cell lines. Next generation isozyme-specific PAD inhibitors may have therapeutic potential to regulate both the inflammatory tumor microenvironment and tumor cell growth. PMID- 23019527 TI - Pertussis Epidemiology in Greece and Emerging Risk Groups during the Vaccination Era (1980-2008). AB - To study the epidemiology of pertussis in Greece and epidemiologic changes throughout a period of twenty-nine years, we conducted a retrospective analysis of available data of pertussis cases for the past twenty-nine years (1980-2008) and a prospective analysis of hospitalized pertussis cases from a children's hospital in Athens for eight years (2001-2008). From 1980 through 2008, the incidence of pertussis in Greece declined from 11.2 to 0.05 cases per 100,000. Epidemic cycles occurring every 3 to 5 years were observed. Since pertussis circulation cannot be fully controlled by present immunization programs, efforts should be made to vaccinate infants at the recommended age, early diagnose, treatment as well as contact tracing of pertussis cases. Control of pertussis in social susceptible populations is necessary. A national program with adolescent and adult booster could decrease the circulation of B. pertussis. Despite an overall decrease for pertussis cases, pertussis is still a present and future challenge of public health service in Greece. PMID- 23019528 TI - Roles of Participatory Action-oriented Programs in Promoting Safety and Health at Work. AB - Reflecting the current international trends toward proactive risk assessment and control at work with practical procedures, participatory action-oriented approaches are gaining importance in various sectors. The roles of these approaches in promoting the safety and health at work are discussed based on their recent experiences in preventing work-related risks and improving the quality of work life, particularly in small-scale workplaces. The emphasis placed on the primary prevention at the initiative of workers and managers is commonly notable. Participatory steps, built on local good practices, can lead to many workplace improvements when the focus is on locally feasible low-cost options in multiple aspects. The design and use of locally adjusted action toolkits play a key role in facilitating these improvements in each local situation. The effectiveness of participatory approaches relying on these toolkits is demonstrated by their spread to many sectors and by various intervention studies. In the local context, networks of trainers are essential in sustaining the improvement activities. With the adequate support of networks of trainers trained in the use of these toolkits, participatory approaches will continue to be the key factor for proactive risk management in various work settings. PMID- 23019529 TI - Malignant tumors of the female reproductive system. AB - This review summarizes the epidemiology of cancer of the female reproductive system and associated lifestyle factors. It also assesses the available evidence for occupational factors associated with these cancers. Cervical, endometrial, and ovarian cancers are relatively common, and cause significant cancer morbidity and mortality worldwide, whereas vulvar, vaginal, fallopian tube cancers, and choriocarcinomas are very rare. As several lifestyle factors are known to play a major role in the etiology of these cancers, very few published studies have investigated possible relationships with occupational factors. Some occupational exposures have been associated with increased risks of these cancers, but apart from the available evidence on the relationships between asbestos fibers and ovarian cancer, and tetrachloroethylene and cervical cancer, the data is rather scarce. Given the multifactorial nature of cancers of the female reproductive system, it is of the utmost importance to conduct occupational studies that will gather detailed data on potential individual confounding factors, in particular reproductive history and other factors that influence the body's hormonal environment, together with information on socio-economic status and lifestyle factors, including physical activity from multiple sources. Studies on the mechanisms of carcinogenesis in the female reproductive organs are also needed in order to elucidate the possible role of chemical exposures in the development of these cancers. PMID- 23019530 TI - A model for design of tailored working environment intervention programmes for small enterprises. AB - OBJECTIVES: Small enterprises have higher exposure to occupational hazards compared to larger enterprises and further, they have fewer resources to control the risks. In order to improve the working environment, development of efficient measures is therefore a major challenge for regulators and other stakeholders. The aim of this paper is to develop a systematic model for the design of tailored intervention programmes meeting the needs of small enterprises. METHODS: An important challenge for the design process is the transfer of knowledge from one context to another. The concept of realist analysis can provide insight into mechanisms by which intervention knowledge can be transferred from one context to another. We use this theoretical approach to develop a design model. RESULTS: THE MODEL CONSIST OF FIVE STEPS: 1) Defining occupational health and safety challenges of the target group, 2) selecting methods to improve the working environment, 3) developing theories about mechanisms which motivate the target group, 4) analysing the specific context of the target group for small enterprise programmes including owner-management role, social relations, and the perception of the working environment, and 5) designing the intervention based on the preceding steps. We demonstrate how the design model can be applied in practice by the development of an intervention programme for small enterprises in the construction industry. CONCLUSION: The model provides a useful tool for a systematic design process. The model makes it transparent for both researchers and practitioners as to how existing knowledge can be used in the design of new intervention programmes. PMID- 23019531 TI - Fall risk assessments based on postural and dynamic stability using inertial measurement unit. AB - OBJECTIVES: Slip and fall accidents in the workplace are one of the top causes of work related fatalities and injuries. Previous studies have indicated that fall risk was related to postural and dynamic stability. However, the usage of this theoretical relationship was limited by laboratory based measuring instruments. The current study proposed a new method for stability assessment by use of inertial measurement units (IMUs). METHODS: Accelerations at different body parts were recorded by the IMUs. Postural and local dynamic stability was assessed from these measures and compared with that computed from the traditional method. RESULTS: THE RESULTS DEMONSTRATED: 1) significant differences between fall prone and healthy groups in IMU assessed dynamic stability; and 2) better power of discrimination with multi stability index assessed by IMUs. CONCLUSION: The findings can be utilized in the design of a portable screening or monitoring tool for fall risk assessment in various industrial settings. PMID- 23019532 TI - EBM E-learning: Feasible and Effective for Occupational Physicians in Different Countries. AB - OBJECTIVES: Although evidence-based medicine (EBM) is a useful method for integrating evidence into the decision-making process of occupational physicians, occupational physicians lack EBM knowledge and skills, and do not have the time to learn the EBM method. In order to enable them to educate themselves at the time and place they prefer, we designed an electronic EBM course. We studied the feasibility and utility of the course as well as its effectiveness in increasing EBM knowledge, skills, and behaviour. METHODS: Occupational physicians from various countries were included in a within-subjects study. Measurements were conducted on participants' EBM knowledge, skills, behaviour, and determinants of behaviour at baseline, directly after finishing the course and 2 months later (n = 36). The feasibility and utility of the course were evaluated directly after the course (n = 42). RESULTS: The course is applicable as an introductory course on EBM for occupational physicians in various countries. The course is effective in enhancing EBM knowledge and self-efficacy in practising EBM. No significant effect was found on EBM skills, behaviour, and determinants of behaviour. After the course, more occupational physicians use the international journals to solve a case. CONCLUSION: An electronic introductory EBM course is suitable for occupational physicians. Although it is an effective method for increasing EBM knowledge, it does not seem effective in improving skills and behaviour. We recommend integrating e-learning courses with blended learning, where it can be used side by side with other educational methods that are effective in changing behaviour. PMID- 23019533 TI - Blood and body fluid exposure related knowledge, attitude and practices of hospital based health care providers in United arab emirates. AB - OBJECTIVES: Knowledge, attitudes, and practices of healthcare providers related to occupational exposure to bloodborne pathogens were assessed in a tertiary-care hospital in Middle East. METHODS: A cross-sectional study was undertaken using a self-administered questionnaire based on 3 paired (infectivity known vs. not known-suspected) case studies. Only 17 out of 230 respondents had an exposure in the 12 months prior to the survey and of these, only 2 had complied fully with the hospital's exposure reporting policy. RESULTS: In the paired case studies, the theoretical responses of participating health professionals showed a greater preference for initiating self-directed treatment with antivirals or immunisation rather than complying with the hospital protocol, when the patient was known to be infected. The differences in practice when exposed to a patient with suspected blood pathogens compared to patient known to be infected was statistically significant (p < 0.001) in all 3 paired cases. Failure to test an infected patient's blood meant that an adequate risk assessment and appropriate secondary prevention could not be performed, and reflected the unwillingness to report the occupational exposure. CONCLUSION: Therefore, the study demonstrated that healthcare providers opted to treat themselves when exposed to patient with infectious disease, rather than comply with the hospital reporting and assessment protocol. PMID- 23019534 TI - An examination of blood lead levels in thai nielloware workers. AB - OBJECTIVES: The objectives of this study were to determine the lead levels in blood samples from nielloware workers, to determine airborne lead levels, to describe the workers' hygiene behaviors, and to ascertain and describe any correlations between lead levels in blood samples and lead levels in airborne samples. METHODS: Blood samples and airborne samples from 45 nielloware workers were collected from nielloware workplaces in Nakhon Sri Thammarat Province, Thailand. Lead levels were determined by flame atomic absorption spectrometry (FAAS), at a wavelength of 283.3 nm. FAAS was used especially adequate for metals at relatively high concentration levels. RESULTS: The geometric mean of the 45 airborne lead levels was 81.14 ug/m(3) (range 9.0-677.2 ug/m(3)). The geometric mean blood lead level of the 45 workers was 16.25 ug/dL (range 4.59-39.33 ug/dL). No worker had a blood lead level > 60 ug/dL. A statistically significantly positive correlation was found between airborne lead level and blood lead levels (r = 0.747, p < 0.01). It was observed that personal hygiene was poor; workers smoked and did not wash their hands before drinking or eating. It was concluded that these behaviors had a significant correlation with blood lead levels (p < 0.001). CONCLUSION: Improvements in working conditions and occupational health education are required due to the correlation found between blood leads and airborne lead levels. PMID- 23019535 TI - Subchronic Inhalation Toxicity Study of n-pentane in Rats. AB - OBJECTIVES: This study was conducted in order to obtain information concerning the health hazards that may result from a 13 week inhalation exposure of n pentane in Sprague-Dawley rats. METHODS: This study was conducted in accordance with the Organization for Economic Co-operation and Development (OECD) guidelines for the testing of chemicals No. 413 'Subchronic inhalation toxicity: 90-day study (as revised in 2009)'. The rats were divided into 4 groups (10 male and 10 female rats in each group), and were exposed to 0, 340, 1,530, and 6,885 ppm n pentane in each exposure chamber for 6 hour/day, 5 days/week, for 13 weeks. All of the rats were sacrificed at the end of the treatment period. During the test period, clinical signs, mortality, body weights, food consumption, ophthalmoscopy, locomotion activity, urinalysis, hematology, serum biochemistry, gross findings, organ weights, and histopathology were assessed. RESULTS: During the period of testing, there were no treatment related effects on the clinical findings, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, relative organ weight, and histopathological findings. CONCLUSION: The no-observable-adverse-effect level (NOAEL) of n-pentane is evaluated as being more than 6,885 ppm (20.3 mg/L) in both male and female rats. n-pentane was not a classified specific target organ toxicity in the globally harmonized classification system (GHS). PMID- 23019536 TI - Asbestos Exposure among Mitering Workers. AB - The objectives are to compare the airborne asbestos concentrations resulted from mitering of abestos cement roof sheets by a high-speed motor and a hand saw, and to monitor whether other workers near the test sites are vulnerable to the fibers exceeding the occupational exposure limit. Four test cases were carried out and altogether 7 personal and 4 area air samples were collected. The NIOSH method 7400 was employed for the air samplings and analysis. Using the phase contrast microscopy, fiber counting was conducted under Rule A. The study showed that the fiber concentration medians for personal air samples gathered from the two tools were 4.11 fibers/cc (ranged: 1.33-12.41 fibers/cc) and 0.13 fibers/cc (ranged: 0.01-5.00 fibers/cc) respectively. The median for the area samples was 0.59 fibers/cc (ranged: 0.14-3.32 fibers/cc). Comparing each study case, the concentration level caused by the high-speed motor saw was more than twice that of the hand saw. According to the area samples, the workers nearby the test site are at risk from high exposure to asbestos. PMID- 23019537 TI - Comparing Peripheral Blood Mononuclear Cell DNA and Circulating Plasma viral RNA pol Genotypes of Subtype C HIV-1. AB - INTRODUCTION: Drug resistance mutations (DRM) in viral RNA are important in defining to provide effective antiretroviral therapy (ART) in HIV-1 infected patients. Detection of DRM in peripheral blood mononuclear cell (PBMC) DNA is another source of information, although the clinical significance of DRMs in proviral DNA is less clear. MATERIALS AND METHODS: From 25 patients receiving ART at a center in Zimbabwe, 32 blood samples were collected. Dideoxy-sequencing of gag-pol identified subtype and resistance mutations from plasma viral RNA and proviral DNA. Drug resistance was estimated using the calibrated population resistance tool on www.hivdb.stanford.edu database. Numerical resistance scores were calculated for all antiretroviral drugs and for the subjects' reported regimen. Phylogenetic analysis as maximum likelihood was performed to determine the evolutionary distance between sequences. RESULTS: Of the 25 patients, 4 patients (2 of which had given 2 blood samples) were not known to be on ART (NA) and had exclusively wild-type virus, 17 had received Protease inhibitors (PI), 18, non-nucleoside reverse transcriptase inhibitors (NNRTI) and 19, two or more nucleoside reverse transcriptase inhibitors (NRTI). Of the 17 with history of PI, 10 had PI mutations, 5 had minor differences between mutations in RNA and DNA. Eighteen samples had NNRTI mutations, six of which demonstrated some discordance between DNA and RNA mutations. Although NRTI resistance mutations were frequently different between analyses, mutations resulted in very similar estimated phenotypes as measured by resistance scores. The numerical resistance scores from RNA and DNA for PIs differed between 2/10, for NNRTIs between 8/18, and for NRTIs between 17/32 pairs. When calculated resistance scores were collapsed, 3 pairs showed discordance between RNA and DNA for at least one PI, 6 were discordant for at least one NNRTI and 11 for at least one NRTI. Regarding phylogenetic evolutionary analysis, all RNA and DNA sequence pairs clustered closely in a maximum likelihood tree. CONCLUSION: PBMC DNA could be useful for testing drug resistance in conjunction with plasma RNA where the results of each yielded complementary information about drug resistance. Identification of DRM, archived in proviral DNA, could be used to provide for sustainable public health surveillance among subtype C infected patients. PMID- 23019538 TI - Anisotropic Diffusion of Polyelectrolyte Chains within Multilayer Films. AB - We have found diffusion of polyelectrolyte chains within multilayer films to be highly anisotropic, with the preferential chain motion parallel to the substrate. The degree of anisotropy was quantified by a combination of fluorescence recovery after photobleaching and neutron reflectometry, probing chain diffusion in directions parallel and perpendicular to the substrate, respectively. Chain mobility was controlled by ionic strength of annealing solutions and steric hindrance to ionic pairing of interacting polyelectrolytes. PMID- 23019539 TI - Covalently tethered transforming growth factor beta in PEG hydrogels promotes chondrogenic differentiation of encapsulated human mesenchymal stem cells. AB - Methods to precisely control growth factor presentation in a local and sustained fashion are of increasing interest for a number of complex tissue engineering applications. The cytokine transforming growth factor beta (TGFbeta) plays a key role in promoting the chondrogenic differentiation of human mesenchymal stem cells (hMSCs). Traditional chondrogenic approaches utilize soluble delivery, an approach with limited application for clinical translation. In this work, we introduce a reactive thiol onto TGFbeta and covalently tether the growth factor into poly(ethylene glycol) (PEG) hydrogels using a photoinitiated thiol-acrylate polymerization mechanism. We demonstrate the bioactivity of thiolated TGFbeta, before and after polymerization, using a SMAD2 reporter cell line. hMSCs were encapsulated in PEG hydrogels with and without tethered TGFbeta, and subsequently assayed for glycosaminoglycan and collagen II production as indicators of chondrogenesis. Over a 21-day time course, tethered TGFbeta promoted chondrogenesis at levels similar to a positive control using solubly dosed growth factor. These results provide evidence that tethered TGFbeta materials can be successfully used to promote chondrogenic differentiation of MSCs. PMID- 23019540 TI - Mapping mechanical properties of organic thin films by force-modulation microscopy in aqueous media. AB - The mechanical properties of organic and biomolecular thin films on surfaces play an important role in a broad range of applications. Although force-modulation microscopy (FMM) is used to map the apparent elastic properties of such films with high lateral resolution in air, it has rarely been applied in aqueous media. In this letter we describe the use of FMM to map the apparent elastic properties of self-assembled monolayers and end-tethered protein thin films in aqueous media. Furthermore, we describe a simple analysis of the contact mechanics that enables the selection of FMM imaging parameters and thus yields a reliable interpretation of the FMM image contrast. PMID- 23019541 TI - Macromolecular shape and interactions in layer-by-layer assemblies within cylindrical nanopores. AB - Layer-by-layer (LbL) deposition of polyelectrolytes and proteins within the cylindrical nanopores of anodic aluminum oxide (AAO) membranes was studied by optical waveguide spectroscopy (OWS). AAO has aligned cylindrical, nonintersecting pores with a defined pore diameter d(0) and functions as a planar optical waveguide so as to monitor, in situ, the LbL process by OWS. The LbL deposition of globular proteins, i.e., avidin and biotinylated bovine serum albumin was compared with that of linear polyelectrolytes (linear-PEs), both species being of similar molecular weight. LbL deposition within the cylindrical AAO geometry for different pore diameters (d(0) = 25-80 nm) for the various macromolecular species, showed that the multilayer film growth was inhibited at different maximum numbers of LbL steps (n(max)). The value of n(max) was greatest for linear-PEs, while proteins had a lower value. The cylindrical pore geometry imposes a physical limit to LbL growth such that n(max) is strongly dependent on the overall internal structure of the LbL film. For all macromolecular species, deposition was inhibited in native AAO, having pores of d(0) = 25-30 nm. Both, OWS and scanning electron microscopy showed that LbL growth in larger AAO pores (d(0) > 25-30 nm) became inhibited when approaching a pore diameter of d(eff,n_max) = 25-35 nm, a similar size to that of native AAO pores, with d(0) = 25-30 nm. For a reasonable estimation of d(eff,n_max), the actual volume occupied by a macromolecular assembly must be taken into consideration. The results clearly show that electrostatic LbL allowed for compact macromolecular layers, whereas proteins formed loosely packed multilayers. PMID- 23019542 TI - FTIR nanobiosensors for Escherichia coli detection. AB - Infections due to enterohaemorrhagic E. coli (Escherichia coli) have a low incidence but can have severe and sometimes fatal health consequences, and thus represent some of the most serious diseases due to the contamination of water and food. New, fast and simple devices that monitor these pathogens are necessary to improve the safety of our food supply chain. In this work we report on mesoporous titania thin-film substrates as sensors to detect E. coli O157:H7. Titania films treated with APTES ((3-aminopropyl)triethoxysilane) and GA (glutaraldehyde) were functionalized with specific antibodies and the absorption properties monitored. The film-based biosensors showed a detection limit for E. coli of 1 * 10(2) CFU/mL, constituting a simple and selective method for the effective screening of water samples. PMID- 23019543 TI - P-wave Cooper pair splitting. AB - BACKGROUND: Splitting of Cooper pairs has recently been realized experimentally for s-wave Cooper pairs. A split Cooper pair represents an entangled two-electron pair state, which has possible application in on-chip quantum computation. Likewise the spin-activity of interfaces in nanoscale tunnel junctions has been investigated theoretically and experimentally in recent years. However, the possible implications of spin-active interfaces in Cooper pair splitters so far have not been investigated. RESULTS: We analyze the current and the cross correlation of currents in a superconductor-ferromagnet beam splitter, including spin-active scattering. Using the Hamiltonian formalism, we calculate the cumulant-generating function of charge transfer. As a first step, we discuss characteristics of the conductance for crossed Andreev reflection in superconductor-ferromagnet beam splitters with s-wave and p-wave superconductors and no spin-active scattering. In a second step, we consider spin-active scattering and show how to realize p-wave splitting using only an s-wave superconductor, through the process of spin-flipped crossed Andreev reflection. We present results for the conductance and cross correlations. CONCLUSION: Spin activity of interfaces in Cooper pair splitters allows for new features in ordinary s-wave Cooper pair splitters, that can otherwise only be realized by using p-wave superconductors. In particular, it provides access to Bell states that are different from the typical spin singlet state. PMID- 23019544 TI - Channeling in helium ion microscopy: Mapping of crystal orientation. AB - BACKGROUND: The unique surface sensitivity and the high resolution that can be achieved with helium ion microscopy make it a competitive technique for modern materials characterization. As in other techniques that make use of a charged particle beam, channeling through the crystal structure of the bulk of the material can occur. RESULTS: Here, we demonstrate how this bulk phenomenon affects secondary electron images that predominantly contain surface information. In addition, we will show how it can be used to obtain crystallographic information. We will discuss the origin of channeling contrast in secondary electron images, illustrate this with experiments, and develop a simple geometric model to predict channeling maxima. CONCLUSION: Channeling plays an important role in helium ion microscopy and has to be taken into account when trying to achieve maximum image quality in backscattered helium images as well as secondary electron images. Secondary electron images can be used to extract crystallographic information from bulk samples as well as from thin surface layers, in a straightforward manner. PMID- 23019545 TI - Imaging ultra thin layers with helium ion microscopy: Utilizing the channeling contrast mechanism. AB - BACKGROUND: Helium ion microscopy is a new high-performance alternative to classical scanning electron microscopy. It provides superior resolution and high surface sensitivity by using secondary electrons. RESULTS: We report on a new contrast mechanism that extends the high surface sensitivity that is usually achieved in secondary electron images, to backscattered helium images. We demonstrate how thin organic and inorganic layers as well as self-assembled monolayers can be visualized on heavier element substrates by changes in the backscatter yield. Thin layers of light elements on heavy substrates should have a negligible direct influence on backscatter yields. However, using simple geometric calculations of the opaque crystal fraction, the contrast that is observed in the images can be interpreted in terms of changes in the channeling probability. CONCLUSION: The suppression of ion channeling into crystalline matter by adsorbed thin films provides a new contrast mechanism for HIM. This dechanneling contrast is particularly well suited for the visualization of ultrathin layers of light elements on heavier substrates. Our results also highlight the importance of proper vacuum conditions for channeling-based experimental methods. PMID- 23019546 TI - A facile approach to nanoarchitectured three-dimensional graphene-based Li-Mn-O composite as high-power cathodes for Li-ion batteries. AB - We report a facile method to prepare a nanoarchitectured lithium manganate/graphene (LMO/G) hybrid as a positive electrode for Li-ion batteries. The Mn(2)O(3)/graphene hybrid is synthesized by exfoliation of graphene sheets and deposition of Mn(2)O(3) in a one-step electrochemical process, which is followed by lithiation in a molten salt reaction. There are several advantages of using the LMO/G as cathodes in Li-ion batteries: (1) the LMO/G electrode shows high specific capacities at high gravimetric current densities with excellent cycling stability, e.g., 84 mAh.g(-1) during the 500th cycle at a discharge current density of 5625 mA.g(-1) (~38.01 C capacity rating) in the voltage window of 3-4.5 V; (2) the LMO/G hybrid can buffer the Jahn-Teller effect, which depicts excellent Li storage properties at high current densities within a wider voltage window of 2-4.5 V, e.g., 93 mAh.g(-1) during the 300th cycle at a discharge current density of 5625 mA.g(-1) (~38.01 C). The wider operation voltage window can lead to increased theoretical capacity, e.g., 148 mAh.g(-1) between 3 and 4.5 V and 296 mAh.g(-1) between 2 and 4.5 V; (3) more importantly, it is found that the attachment of LMO onto graphene can help to reduce the dissolution of Mn(2+) into the electrolyte, as indicated by the inductively coupled plasma (ICP) measurements, and which is mainly attributed to the large specific surface area of the graphene sheets. PMID- 23019547 TI - Low-temperature synthesis of carbon nanotubes on indium tin oxide electrodes for organic solar cells. AB - The electrical performance of indium tin oxide (ITO) coated glass was improved by including a controlled layer of carbon nanotubes directly on top of the ITO film. Multiwall carbon nanotubes (MWCNTs) were synthesized by chemical vapor deposition, using ultrathin Fe layers as catalyst. The process parameters (temperature, gas flow and duration) were carefully refined to obtain the appropriate size and density of MWCNTs with a minimum decrease of the light harvesting in the cell. When used as anodes for organic solar cells based on poly(3-hexylthiophene) (P3HT) and phenyl-C61-butyric acid methyl ester (PCBM), the MWCNT-enhanced electrodes are found to improve the charge-carrier extraction from the photoactive blend, thanks to the additional percolation paths provided by the CNTs. The work function of as-modified ITO surfaces was measured by the Kelvin probe method to be 4.95 eV, resulting in an improved matching to the highest occupied molecular orbital level of the P3HT. This is in turn expected to increase the hole transport and collection at the anode, contributing to the significant increase of current density and open-circuit voltage observed in test cells created with such MWCNT-enhanced electrodes. PMID- 23019548 TI - Radiation-induced nanostructures: Formation processes and applications. PMID- 23019549 TI - Directed deposition of silicon nanowires using neopentasilane as precursor and gold as catalyst. AB - In this work the applicability of neopentasilane (Si(SiH(3))(4)) as a precursor for the formation of silicon nanowires by using gold nanoparticles as a catalyst has been explored. The growth proceeds via the formation of liquid gold/silicon alloy droplets, which excrete the silicon nanowires upon continued decomposition of the precursor. This mechanism determines the diameter of the Si nanowires. Different sources for the gold nanoparticles have been tested: the spontaneous dewetting of gold films, thermally annealed gold films, deposition of preformed gold nanoparticles, and the use of "liquid bright gold", a material historically used for the gilding of porcelain and glass. The latter does not only form gold nanoparticles when deposited as a thin film and thermally annealed, but can also be patterned by using UV irradiation, providing access to laterally structured layers of silicon nanowires. PMID- 23019550 TI - Spontaneous dissociation of Co(2)(CO)(8) and autocatalytic growth of Co on SiO(2): A combined experimental and theoretical investigation. AB - We present experimental results and theoretical simulations of the adsorption behavior of the metal-organic precursor Co(2)(CO)(8) on SiO(2) surfaces after application of two different pretreatment steps, namely by air plasma cleaning or a focused electron beam pre-irradiation. We observe a spontaneous dissociation of the precursor molecules as well as autodeposition of cobalt on the pretreated SiO(2) surfaces. We also find that the differences in metal content and relative stability of these deposits depend on the pretreatment conditions of the substrate. Transport measurements of these deposits are also presented. We are led to assume that the degree of passivation of the SiO(2) surface by hydroxyl groups is an important controlling factor in the dissociation process. Our calculations of various slab settings, using dispersion-corrected density functional theory, support this assumption. We observe physisorption of the precursor molecule on a fully hydroxylated SiO(2) surface (untreated surface) and chemisorption on a partially hydroxylated SiO(2) surface (pretreated surface) with a spontaneous dissociation of the precursor molecule. In view of these calculations, we discuss the origin of this dissociation and the subsequent autocatalysis. PMID- 23019551 TI - Nanolesions induced by heavy ions in human tissues: Experimental and theoretical studies. AB - The biological effects of energetic heavy ions are attracting increasing interest for their applications in cancer therapy and protection against space radiation. The cascade of events leading to cell death or late effects starts from stochastic energy deposition on the nanometer scale and the corresponding lesions in biological molecules, primarily DNA. We have developed experimental techniques to visualize DNA nanolesions induced by heavy ions. Nanolesions appear in cells as "streaks" which can be visualized by using different DNA repair markers. We have studied the kinetics of repair of these "streaks" also with respect to the chromatin conformation. Initial steps in the modeling of the energy deposition patterns at the micrometer and nanometer scale were made with MCHIT and TRAX models, respectively. PMID- 23019552 TI - Synthesis and electrical characterization of intrinsic and in situ doped Si nanowires using a novel precursor. AB - Perchlorinated polysilanes were synthesized by polymerization of tetrachlorosilane under cold plasma conditions with hydrogen as a reducing agent. Subsequent selective cleavage of the resulting polymer yielded oligochlorosilanes Si(n)Cl(2) (n) (+2) (n = 2, 3) from which the octachlorotrisilane (n = 3, Cl(8)Si(3), OCTS) was used as a novel precursor for the synthesis of single crystalline Si nanowires (NW) by the well-established vapor-liquid-solid (VLS) mechanism. By adding doping agents, specifically BBr(3) and PCl(3), we achieved highly p- and n-type doped Si-NWs by means of atmospheric-pressure chemical vapor deposition (APCVD). These as grown NWs were investigated by means of scanning electron microscopy (SEM) and transmission electron microscopy (TEM), as well as electrical measurements of the NWs integrated in four-terminal and back-gated MOSFET modules. The intrinsic NWs appeared to be highly crystalline, with a preferred growth direction of [111] and a specific resistivity of rho = 6 kOmega.cm. The doped NWs appeared to be [112] oriented with a specific resistivity of rho = 198 mOmega.cm for p-type Si-NWs and rho = 2.7 mOmega.cm for n-doped Si-NWs, revealing excellent dopant activation. PMID- 23019553 TI - The oriented and patterned growth of fluorescent metal-organic frameworks onto functionalized surfaces. AB - A metal-organic framework (MOF) material, [Zn(2)(adc)(2)(dabco)] (adc = anthracene-9,10-dicarboxylate, dabco = 1,4-diazabicyclo[2.2.2]-octane), the fluorescence of which depends on the loading of its nanopores, was synthesized in two forms: as free-flowing nanocrystals with different shapes and as surface attached MOFs (SURMOFs). For the latter, we used self-assembled monolayers (SAMs) bearing functional groups, such as carboxylate and pyridyl groups, capable of coordinating to the constituents of the MOF. It could be demonstrated that this directed coordination also orients the nanocrystals deposited at the surface. Using two different patterning methods, i.e., microcontact printing and electron beam lithography, the lateral distribution of the functional groups could be determined in such a way that the highly localized deposition of the SURMOF films became possible. PMID- 23019554 TI - Nano-structuring, surface and bulk modification with a focused helium ion beam. AB - We investigate the ability of a focused helium ion beam to selectively modify and mill materials. The sub nanometer probe size of the helium ion microscope used provides lateral control not previously available for helium ion irradiation experiments. At high incidence angles the helium ions were found to remove surface material from a silicon lamella leaving the subsurface structure intact for further analysis. Surface roughness and contaminants were both reduced by the irradiation process. Fabrication is also realized with a high level of patterning acuity. Implantation of helium beneath the surface of the sample is visualized in cross section allowing direct observation of the extended effects of high dose irradiation. The effect of the irradiation on the crystal structure of the material is presented. Applications of the sample modification process are presented and further prospects discussed. PMID- 23019555 TI - Nanotribology at high temperatures. AB - Recent molecular dynamics simulation results have increased conceptual understanding of the grazing and the ploughing friction at elevated temperatures, particularly near the substrate's melting point. In this commentary we address a major constraint concerning its experimental verification. PMID- 23019556 TI - Strong spin-filtering and spin-valve effects in a molecular V-C(60)-V contact. AB - Motivated by the recent achievements in the manipulation of C(60) molecules in STM experiments, we study theoretically the structure and electronic properties of a C(60) molecule in an STM tunneljunction with a magnetic tip and magnetic adatom on a Cu(111) surface using first-principles calculations. For the case of a vanadium tip/adatom, we demonstrate how spin coupling between the magnetic V atoms, mediated by the C(60), can be observed in the electronic transport, which display a strong spin-filtering effect, allowing mainly majority-spin electrons to pass (>95%). Moreover, we find a significant change in the conductance between parallel and anti-parallel spin polarizations in the junction (86%) which suggests that STM experiments should be able to characterize the magnetism and spin coupling for these systems. PMID- 23019557 TI - Focused electron beam induced deposition: A perspective. AB - BACKGROUND: Focused electron beam induced deposition (FEBID) is a direct-writing technique with nanometer resolution, which has received strongly increasing attention within the last decade. In FEBID a precursor previously adsorbed on a substrate surface is dissociated in the focus of an electron beam. After 20 years of continuous development FEBID has reached a stage at which this technique is now particularly attractive for several areas in both, basic and applied research. The present topical review addresses selected examples that highlight this development in the areas of charge-transport regimes in nanogranular metals close to an insulator-to-metal transition, the use of these materials for strain- and magnetic-field sensing, and the prospect of extending FEBID to multicomponent systems, such as binary alloys and intermetallic compounds with cooperative ground states. RESULTS: After a brief introduction to the technique, recent work concerning FEBID of Pt-Si alloys and (hard-magnetic) Co-Pt intermetallic compounds on the nanometer scale is reviewed. The growth process in the presence of two precursors, whose flux is independently controlled, is analyzed within a continuum model of FEBID that employs rate equations. Predictions are made for the tunability of the composition of the Co-Pt system by simply changing the dwell time of the electron beam during the writing process. The charge-transport regimes of nanogranular metals are reviewed next with a focus on recent theoretical advancements in the field. As a case study the transport properties of Pt-C nanogranular FEBID structures are discussed. It is shown that by means of a post-growth electron-irradiation treatment the electronic intergrain-coupling strength can be continuously tuned over a wide range. This provides unique access to the transport properties of this material close to the insulator-to-metal transition. In the last part of the review, recent developments in mechanical strain-sensing and the detection of small, inhomogeneous magnetic fields by employing nanogranular FEBID structures are highlighted. CONCLUSION: FEBID has now reached a state of maturity that allows a shift of the focus towards the development of new application fields, be it in basic research or applied. This is shown for selected examples in the present review. At the same time, when seen from a broader perspective, FEBID still has to live up to the original idea of providing a tool for electron-controlled chemistry on the nanometer scale. This has to be understood in the sense that, by providing a suitable environment during the FEBID process, the outcome of the electron-induced reactions can be steered in a controlled way towards yielding the desired composition of the products. The development of a FEBID-specialized surface chemistry is mostly still in its infancy. Next to application development, it is this aspect that will likely be a guiding light for the future development of the field of focused electron beam induced deposition. PMID- 23019558 TI - Polymer blend lithography: A versatile method to fabricate nanopatterned self assembled monolayers. AB - A rapid and cost-effective lithographic method, polymer blend lithography (PBL), is reported to produce patterned self-assembled monolayers (SAM) on solid substrates featuring two or three different chemical functionalities. For the pattern generation we use the phase separation of two immiscible polymers in a blend solution during a spin-coating process. By controlling the spin-coating parameters and conditions, including the ambient atmosphere (humidity), the molar mass of the polystyrene (PS) and poly(methyl methacrylate) (PMMA), and the mass ratio between the two polymers in the blend solution, the formation of a purely lateral morphology (PS islands standing on the substrate while isolated in the PMMA matrix) can be reproducibly induced. Either of the formed phases (PS or PMMA) can be selectively dissolved afterwards, and the remaining phase can be used as a lift-off mask for the formation of a nanopatterned functional silane monolayer. This "monolayer copy" of the polymer phase morphology has a topographic contrast of about 1.3 nm. A demonstration of tuning of the PS island diameter is given by changing the molar mass of PS. Moreover, polymer blend lithography can provide the possibility of fabricating a surface with three different chemical components: This is demonstrated by inducing breath figures (evaporated condensed entity) at higher humidity during the spin-coating process. Here we demonstrate the formation of a lateral pattern consisting of regions covered with 1H,1H,2H,2H-perfluorodecyltrichlorosilane (FDTS) and (3 aminopropyl)triethoxysilane (APTES), and at the same time featuring regions of bare SiO(x). The patterning process could be applied even on meter-sized substrates with various functional SAM molecules, making this process suitable for the rapid preparation of quasi two-dimensional nanopatterned functional substrates, e.g., for the template-controlled growth of ZnO nanostructures [1]. PMID- 23019559 TI - Horizontal versus vertical charge and energy transfer in hybrid assemblies of semiconductor nanoparticles. AB - We studied the photoluminescence and time-resolved photoluminescence from self assembled bilayers of donor and acceptor nanoparticles (NPs) adsorbed on a quartz substrate through organic linkers. Charge and energy transfer processes within the assemblies were investigated as a function of the length of the dithiolated linker (DT) between the donors and acceptors. We found an unusual linker-length dependency in the emission of the donors. This dependency may be explained by charge and energy transfer processes in the vertical direction (from the donors to the acceptors) that depend strongly on charge transfer processes occurring in the horizontal plane (within the monolayer of the acceptor), namely, parallel to the substrate. PMID- 23019560 TI - Probing three-dimensional surface force fields with atomic resolution: Measurement strategies, limitations, and artifact reduction. AB - Noncontact atomic force microscopy (NC-AFM) is being increasingly used to measure the interaction force between an atomically sharp probe tip and surfaces of interest, as a function of the three spatial dimensions, with picometer and piconewton accuracy. Since the results of such measurements may be affected by piezo nonlinearities, thermal and electronic drift, tip asymmetries, and elastic deformation of the tip apex, these effects need to be considered during image interpretation.In this paper, we analyze their impact on the acquired data, compare different methods to record atomic-resolution surface force fields, and determine the approaches that suffer the least from the associated artifacts. The related discussion underscores the idea that since force fields recorded by using NC-AFM always reflect the properties of both the sample and the probe tip, efforts to reduce unwanted effects of the tip on recorded data are indispensable for the extraction of detailed information about the atomic-scale properties of the surface. PMID- 23019561 TI - Ordered arrays of nanoporous gold nanoparticles. AB - A combination of a "top-down" approach (substrate-conformal imprint lithography) and two "bottom-up" approaches (dewetting and dealloying) enables fabrication of perfectly ordered 2-dimensional arrays of nanoporous gold nanoparticles. The dewetting of Au/Ag bilayers on the periodically prepatterned substrates leads to the interdiffusion of Au and Ag and the formation of an array of Au-Ag alloy nanoparticles. The array of alloy nanoparticles is transformed into an array of nanoporous gold nanoparticles by a following dealloying step. Large areas of this new type of material arrangement can be realized with this technique. In addition, this technique allows for the control of particle size, particle spacing, and ligament size (or pore size) by varying the period of the structure, total metal layer thickness, and the thickness ratio of the as-deposited bilayers. PMID- 23019562 TI - Dimer/tetramer motifs determine amphiphilic hydrazine fibril structures on graphite. AB - Fibril structures are produced at a solvent-graphite interface by self-assembly of custom-designed symmetric and asymmetric amphiphilic benzamide derivatives bearing C(10) aliphatic chains. Scanning tunnelling microscopy (STM) studies reveal geometry-dependent internal structures for the elementary fibrils of the two molecules that are distinctly different from known mesophase bulk structures. The structures are described by building-block models based on hydrogen-bonded dimer and tetramer precursors of hydrazines. The closure and growth in length of building units into fibrils takes place through van der Waals forces acting between the dangling alkyl chains. The nanoscale morphology is a consequence of the basic molecular geometry, where it follows that a closure to form a fibril is not always likely for the doubly substituted hydrazine. Therefore, we also observe crystallite formation. PMID- 23019563 TI - Explaining reduction of pedestrian-motor vehicle crashes in Arkhangelsk, Russia, in 2005-2010. AB - OBJECTIVE: To explain a reduction in pedestrian-motor vehicle crashes in Arkhangelsk, Russia, in 2005-2010. STUDY DESIGN: Retrospective ecological study. METHODS: For 2005-2010, police data on pedestrian-motor vehicle crashes, traffic violations, and total motor vehicles (MVs) were combined with data on changes in national road traffic legislation and municipal road infrastructure. Negative binomial regression was used to investigate trends in monthly rates of pedestrian motor vehicle crashes per total MVs and estimate changes in these rates per unit changes in the safety measures. RESULTS: During the 6 years, the police registered 2,565 pedestrian-motor vehicle crashes: 1,597 (62%) outside crosswalks, 766 (30%) on non-signalized crosswalks, and 202 (8%) on signalized crosswalks. Crash rates outside crosswalks and on signalized crosswalks decreased on average by 1.1% per month, whereas the crash rate on non-signalized crosswalks remained unchanged. Numbers of signalized and non-signalized crosswalks increased by 14 and 19%, respectively. Also, 10% of non-signalized crosswalks were combined with speed humps, and 4% with light-reflecting vertical signs. Pedestrian penalties for traffic violations increased 4-fold. Driver penalties for ignoring prohibiting signal and failure to give way to pedestrian on non-signalized crosswalk increased 7- and 8-fold, respectively. The rate of total registered drivers' traffic violations per total MVs decreased on average by 0.3% per month. All studied infrastructure and legislative measures had inverse associations with the rate of crashes outside crosswalks. The rate of crashes on signalized crosswalks showed inverse associations with related monetary penalties. CONCLUSIONS: The introduction of infrastructure and legislative measures is the most probable explanation of the reduction of pedestrian-motor vehicle crashes in Arkhangelsk. The overall reduction is due to decreases in rates of crashes outside crosswalks and on signalized crosswalks. No change was observed in the rate of crashes on non-signalized crosswalks. PMID- 23019564 TI - Forging a new legacy of trust in research with Alaska Native college students using CBPR. AB - OBJECTIVES: Disparities in the rates of matriculation and graduation are of concern to Alaska Native (AN) students and the universities committed to their academic success. Efforts to reduce attrition require a keen understanding of the factors that impact quality of life (QOL) at college. Yet, a long-standing legacy of mistrust towards research poses challenges to conducting inquiry among AN students. We introduced a partnership between the University of Alaska Fairbank's Rural Student Services (RSS) and the Center for Alaska Native Health Research (CANHR) within which we conducted the "What makes life good?" study aimed towards developing a QOL measure for AN students. Equally important was building a legacy of research trust among AN partners. STUDY DESIGN: We describe Phase I of a 2 phase study that employed a sequential mixed methods approach. Discussed are facilitators, challenges and lessons learned while striving to adhere to the principles of community-based participatory research (CBPR). METHODS: Phase I included formative focus groups and QOL measurement development. The research involved the interplay among activities that were co-developed with the goal of enhancing trust and research capacity. Emphasis was placed on ensuring that data collection and analyses were student driven. CONCLUSIONS: All partners resided at the same university. However, trust and collaboration could not be assumed. Working within a collaborative framework, our partnership achieved the aim of developing a culturally informed QOL measure, while also creating an empowering experience for all partners who became co-investigators in a process that might normally be regarded with mistrust. PMID- 23019565 TI - Mask Functions for the Symbolic Modeling of Epistasis Using Genetic Programming. AB - The study of common, complex multifactorial diseases in genetic epidemiology is complicated by nonlinearity in the genotype-to-phenotype mapping relationship that is due, in part, to epistasis or gene-gene interactions. Symobolic discriminant analysis (SDA) is a flexible modeling approach which uses genetic programming (GP) to evolve an optimal predictive model using a predefined collection of mathematical functions, constants, and attributes. This has been shown to be an effective strategy for modeling epistasis. In the present study, we introduce the genetic "mask" as a novel building block which exploits expert knowledge in the form of a pre-constructed relationship between two attributes. The goal of this study was to determine whether the availability of "mask" building blocks improves SDA performance. The results of this study support the idea that pre-processing data improves GP performance. PMID- 23019566 TI - Selective determination of cholesterol based on cholesterol oxidase-alkaline phosphatase bienzyme electrode. AB - A bienzyme electrode for the determination of cholesterol was prepared by the co immobilization of cholesterol oxidase and alkaline phosphatase (ALP) on the carbon nanotubes modified electrode surface. The parameters influenced the performance of the bienzyme electrode such as the pH of the base solution; the concentration of DPP and the incubation time, were optimized. A linear calibration graph in the 0.05-2.0 mM concentration range with the sensitivity of 4.65 MUA mM(-1) was obtained. In addition, this work provides a new interferent depleted method and universal protocol for the design of multi-enzyme biosensors. PMID- 23019567 TI - An efficient Ag-ionomer interface for hydroxide exchange membrane fuel cells. AB - An efficient Ag-phosphonium ionomer interface is discovered in HEMFCs, helping enhance oxygen reduction and improve mass transports simultaneously. As a result, a completely-precious-metal-free HEMFC has been fabricated, which shows a cost normalized power much higher than that of a Pt-based PEMFC benchmark (117 vs. 7.7 W US$(-1)). PMID- 23019568 TI - A structural study of DPP-based sensitizers for DSC applications. AB - Four D-pi-A sensitizers comprising a thienyl-diketopyrrolopyrrole (ThDPP) bridge were synthesized and tested in iodide/triiodide liquid electrolyte DSC devices. The dye series was strategically designed to develop a structure-property relationship. The best performing sensitizer utilized a phenyl-based anchor and triphenylamine donor (eta = 5.03%). PMID- 23019569 TI - Sub-oxide-to-metallic, uniformly-nanoporous crystalline nanowires by plasma oxidation and electron reduction. AB - Sub-oxide-to-metallic highly-crystalline nanowires with uniformly distributed nanopores in the 3 nm range have been synthesized by a unique combination of the plasma oxidation, re-deposition and electron-beam reduction. Electron beam exposure-controlled oxide -> sub-oxide -> metal transition is explained using a non-equilibrium model. PMID- 23019570 TI - Bisarylindenols: fixation of conformation leads to exceptional properties of photochromism based on 6pi-electrocyclization. AB - Thermally irreversible photochromic 1-tert-butyl-substituted 2,3 bisthiazolylindenol has been synthesized. It showed perfect diastereoselectivity and high ring-closing quantum yield with high conversion ratio to the closed form. The collaborative interaction of two intramolecular hydrogen bonds and the steric restriction fixed the conformation in favour of cyclization in a highly diastereoselective manner. PMID- 23019571 TI - A novel electrolyte system without a Grignard reagent for rechargeable magnesium batteries. AB - A new phenolate-based magnesium ion conducting electrolyte is prepared. The electrolyte exhibits air insensitive character and excellent electrochemical performances which make it highly promising for advanced rechargeable Mg battery systems. PMID- 23019572 TI - Heteroaromatic imidazo[1,2-a]pyridines synthesis from C-H/N-H oxidative cross coupling/cyclization. AB - A novel silver-mediated highly selective C-H/N-H oxidative cross coupling/cyclization between 2-aminopyridines and terminal alkynes has been demonstrated. This approach provided a simple way to construct heteroaromatic imidazo[1,2-a]pyridines. By using this protocol, the marketed drug zolimidine (antiulcer) could be synthesized easily. PMID- 23019573 TI - Organocatalysis: a web collection. PMID- 23019574 TI - Optimal control theory--closing the gap between theory and experiment. AB - Optimal control theory and optimal control experiments are state-of-the-art tools to control quantum systems. Both methods have been demonstrated successfully for numerous applications in molecular physics, chemistry and biology. Modulated light pulses could be realized, driving these various control processes. Next to the control efficiency, a key issue is the understanding of the control mechanism. An obvious way is to seek support from theory. However, the underlying search strategies in theory and experiment towards the optimal laser field differ. While the optimal control theory operates in the time domain, optimal control experiments optimize the laser fields in the frequency domain. This also implies that both search procedures experience a different bias and follow different pathways on the search landscape. In this perspective we review our recent developments in optimal control theory and their applications. Especially, we focus on approaches, which close the gap between theory and experiment. To this extent we followed two ways. One uses sophisticated optimization algorithms, which enhance the capabilities of optimal control experiments. The other is to extend and modify the optimal control theory formalism in order to mimic the experimental conditions. PMID- 23019575 TI - Dynamics of the reactions of muonium and deuterium atoms with vibrationally excited hydrogen molecules: tunneling and vibrational adiabaticity. AB - Quantum mechanical (QM) and quasiclassical trajectory (QCT) calculations have been carried out for the exchange reactions of D and Mu (Mu = muonium) with hydrogen molecules in their ground and first vibrational states. In all the cases considered, the QM rate coefficients, k(T), are in very good agreement with the available experimental results. In particular, QM calculations on the most accurate potential energy surfaces (PESs) predict a rate coefficient for the Mu + H(2) (nu = 1) reaction which is very close to the preliminary estimate of its experimental value at 300 K. In contrast to the D + H(2) (nu = 0,1) and the Mu + H(2) (nu = 0) reactions, the QCT calculations for Mu + H(2) (nu = 1) predict a much smaller k(T) than that obtained with the accurate QM method. This behaviour is indicative of tunneling. The QM reaction probabilities and total reactive cross sections show that the total energy thresholds for the reactions of Mu with H(2) in nu = 0 and nu = 1 are very similar, whereas for the corresponding reaction with D the nu = 0 total energy threshold is about 0.3 eV lower than that for nu = 1. The results just mentioned can be explained by considering the vibrational adiabatic potentials along the minimum energy path. The threshold for the reaction of Mu with H(2) in both nu = 0 and nu = 1 states is the same and is given by the height of the ground vibrational adiabatic collinear potential, whereas for the D + H(2) reaction the adiabaticity is preserved and the threshold for the reaction in nu = 1 is very close to the height of the nu = 1 adiabatic collinear barrier. For Mu + H(2) (nu = 1) the reaction takes place by crossing from the nu = 1 to the nu = 0 adiabat, since the exit channel leading to MuH (nu = 1) is not energetically accessible. At the lowest possible energies, the non adiabatic vibrational crossing implies a strong tunneling effect through the nu = 1 adiabatic barrier. Absence of tunneling in the classical calculations results in a threshold that coincides with the height of the nu = 1 adiabatic barrier. Most interestingly, the expected tunneling effect in the reaction of Mu with hydrogen molecules occurs for H(2) (nu = 1) but not for H(2) (nu = 0) where zero point-energy effects clearly dominate. PMID- 23019576 TI - Water structure and charge transfer phenomena at the liquid-graphene interface. AB - Physicochemical properties of the graphene-water interface have been investigated to scrutinize the perturbations with respect to the graphene-air interface, in terms of changes in optical and vibrational spectra, as well as in the 3D network of water. Experimental investigations were carried out using Raman spectroscopy and laser scanning confocal microscopy, and integrated with density functional theory (DFT) calculations. Results evidence a substantial orientation of the hydrogen-bonded water molecules at the interfacial region, which, in turn, induces disorder in the water clusters and interfacial charge transfer phenomena. PMID- 23019577 TI - Defect-related luminescent materials: synthesis, emission properties and applications. AB - Luminescent materials have found a wide variety of applications, including information displays, lighting, X-ray intensification and scintillation, and so on. Therefore, much effort has been devoted to exploring novel luminescent materials so far. In the past decade, defect-related luminescent materials have inspired intensive research efforts in their own right. This kind of luminescent material can be basically classified into silica-based materials, phosphate systems, metal oxides, BCNO phosphors, and carbon-based materials. These materials combine several favourable attributes of traditional commercially available phosphors, which are stable, efficient, and less toxic, being free of the burdens of intrinsic toxicity or elemental scarcity and the need for stringent, intricate, tedious, costly, or inefficient preparation steps. Defect related luminescent materials can be produced inexpensively and on a large scale by many approaches, such as sol-gel process, hydro(solvo)thermal reaction, hydrolysis methods, and electrochemical methods. This review article highlights the recent advances in the chemical synthesis and luminescent properties of the defect-related materials, together with their control and tuning, and emission mechanisms (solid state physics). We also speculate on their future and discuss potential developments for their applications in lighting and biomedical fields. PMID- 23019579 TI - Structural evolution of the membrane-coating module of the nuclear pore complex. AB - The coatomer module of the nuclear pore complex borders the cylinder-like nuclear pore-membrane domain of the nuclear envelope. In evolution, a single coatomer module increases in size from hetero-heptamer (Saccharomyces cerevisiae) to hetero-octamer (Schizosaccharomyces pombe) to hetero-nonamer (Metazoa). Notably, the heptamer-octamer transition proceeds through the acquisition of the nucleoporin Nup37. How Nup37 contacts the heptamer remained unknown. Using recombinant nucleoporins, we show that Sp-Nup37 specifically binds the Sp-Nup120 member of the hetero-heptamer but does not bind an Sc-Nup120 homolog. To elucidate the Nup37-Nup120 interaction at the atomic level, we carried out crystallographic analyses of Sp-Nup37 alone and in a complex with an N-terminal, ~110-kDa fragment of Sp-Nup120 comprising residues 1-950. Corroborating structural predictions, we determined that Nup37 folds into a seven-bladed beta propeller. Several disordered surface regions of the Nup37 beta-propeller assume structure when bound to Sp-Nup120. The N-terminal domain of Sp-Nup120(1-950) also folds into a seven-bladed propeller with a markedly protruding 6D-7A insert and is followed by a contorted helical domain. Conspicuously, this 6D-7A insert contains an extension of 50 residues which also is highly conserved in Metazoa but is absent in Sc-Nup120. Strikingly, numerous contacts with the Nup37 beta propeller are located on this extension of the 6D-7A insert. Another contact region is situated toward the end of the helical region of Sp-Nup120(1-950). Our findings provide information about the evolution and the assembly of the coatomer module of the nuclear pore complex. PMID- 23019580 TI - cAMP response element modulator alpha controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus. AB - Appropriate expression of IL-2 plays a central role during the priming and differentiation of T cells. A tight balance between IL-2 and the effector cytokine IL-17A is essential for immune homeostasis. Epigenetic mechanisms have been documented as a key component of cytokine regulation during lineage commitment. The molecular mechanisms that induce chromatin remodeling are less well understood. We investigated epigenetic regulators that mediate the diametric expression of IL-2 and IL-17A in naive, central memory, and effector memory CD4(+) T cells. We demonstrate that cAMP response modulator (CREM)alpha contributes to epigenetic remodeling of IL2 in effector memory T cells through the recruitment of DNMT3a. CREMalpha also reduces CpG-DNA methylation of the IL17A promoter. CREMalpha expression is regulated at the epigenetic level by CpG DNA methylation, which allows increased CREMalpha expression in effector memory CD4(+) T cells. T cells from patients with systemic lupus erythematosus (SLE) express increased levels of CREMalpha and exhibit a phenotype that is similar to effector memory CD4(+) T cells with epigenetically predetermined expression patterns of IL-2 and IL-17A. We conclude that CREMalpha mediates epigenetic remodeling of the IL2 and IL17A gene during T-cell differentiation in favor of effector memory T cells in health and disease. PMID- 23019582 TI - Static and dynamic friction in sliding colloidal monolayers. AB - In a pioneer experiment, Bohlein et al. realized the controlled sliding of two dimensional colloidal crystals over laser-generated periodic or quasi-periodic potentials. Here we present realistic simulations and arguments that besides reproducing the main experimentally observed features give a first theoretical demonstration of the potential impact of colloid sliding in nanotribology. The free motion of solitons and antisolitons in the sliding of hard incommensurate crystals is contrasted with the soliton-antisoliton pair nucleation at the large static friction threshold F(s) when the two lattices are commensurate and pinned. The frictional work directly extracted from particles' velocities can be analyzed as a function of classic tribological parameters, including speed, spacing, and amplitude of the periodic potential (representing, respectively, the mismatch of the sliding interface and the corrugation, or "load"). These and other features suggestive of further experiments and insights promote colloid sliding to a unique friction study instrument. PMID- 23019581 TI - DBL-1, a TGF-beta, is essential for Caenorhabditis elegans aversive olfactory learning. AB - The TGF-beta superfamily is conserved throughout metazoan, and its members play essential roles in development and disease. TGF-beta has also been implicated in adult neural plasticity. However, the underlying mechanisms are not well understood. Here we report that DBL-1, a Caenorhabditis elegans TGF-beta homolog known to control body morphology and immunity, is essential for aversive olfactory learning of potentially harmful bacteria food. We show that DBL-1 generated by the AVA command interneurons, which are critical for sensorimotor responses, regulates aversive olfactory learning, and that the activity of the type I TGF-beta receptor SMA-6 in the hypodermis is needed during adulthood to generate olfactory plasticity. These spatial and temporal mechanisms are critical for the DBL-1 signaling to achieve its diverse functions in development and adult neural plasticity. Interestingly, aversive training decreases AVA calcium response, leading to an increase in the DBL-1 signal secreted from AVA, revealing an experience-dependent change that can underlie the role of TGF-beta signaling in mediating plasticity. PMID- 23019583 TI - Tetrameric assembly of KvLm K+ channels with defined numbers of voltage sensors. AB - Voltage-gated K(+) (Kv) channels are tetrameric assemblies in which each modular subunit consists of a voltage sensor and a pore domain. KvLm, the voltage-gated K(+) channel from Listeria monocytogenes, differs from other Kv channels in that its voltage sensor contains only three out of the eight charged residues previously implicated in voltage gating. Here, we ask how many sensors are required to produce a functional Kv channel by investigating heterotetramers comprising combinations of full-length KvLm (FL) and its sensorless pore module. KvLm heterotetramers were produced by cell-free expression, purified by electrophoresis, and shown to yield functional channels after reconstitution in droplet interface bilayers. We studied the properties of KvLm channels with zero, one, two, three, and four voltage sensors. Three sensors suffice to promote channel opening with FL(4)-like voltage dependence at depolarizing potentials, but all four sensors are required to keep the channel closed during membrane hyperpolarization. PMID- 23019584 TI - Rocking the foundations of molecular genetics. PMID- 23019585 TI - Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. AB - Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, gamma-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G(2)/M cell cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant. PMID- 23019587 TI - Global climate policy impacts on livestock, land use, livelihoods, and food security. AB - Recent research has shed light on the cost-effective contribution that agriculture can make to global greenhouse gas abatement; however, the resulting impacts on agricultural production, producer livelihoods, and food security remain largely unexplored. This paper provides an integrated assessment of the linkages between land-based climate policies, development, and food security, with a particular emphasis on abatement opportunities and impacts in the livestock sector. Targeting Annex I countries and exempting non-Annex I countries from land-based carbon policies on equity or food security grounds may result in significant leakage rates for livestock production and agriculture as a whole. We find that such leakage can be eliminated by supplying forest carbon sequestration incentives to non-Annex I countries. Furthermore, substantial additional global agricultural abatement can be attained by extending a greenhouse gas emissions tax to non-Annex I agricultural producers, while compensating them for their additional tax expenses. Because of their relatively large emissions intensities and limited abatement possibilities, ruminant meat producers face the greatest market adjustments to land-based climate policies. We also evaluate the impacts of climate policies on livelihoods and food consumption in developing countries. In the absence of non-Annex I abatement policies, these impacts are modest. However, strong income and food consumption impacts surface because of higher food costs after forest carbon sequestration is promoted at a global scale. Food consumption among unskilled labor households falls but rises for the representative farm households, because global agricultural supplies are restricted and farm prices rise sharply in the face of inelastic food demands. PMID- 23019586 TI - Epidermal growth factor receptor is a preferred target for treating amyloid-beta induced memory loss. AB - Current understanding of amyloid-beta (Abeta) metabolism and toxicity provides an extensive list of potential targets for developing drugs for treating Alzheimer's disease. We took two independent approaches, including synaptic-plasticity-based analysis and behavioral screening of synthetic compounds, for identifying single compounds that are capable of rescuing the Abeta-induced memory loss in both transgenic fruit fly and transgenic mouse models. Two clinically available drugs and three synthetic compounds not only showed positive effects in behavioral tests but also antagonized the Abeta oligomers-induced activation of the epidermal growth factor receptor (EGFR). Such surprising converging outcomes from two parallel approaches lead us to conclude that EGFR is a preferred target for treating Abeta-induced memory loss. PMID- 23019588 TI - Competency-based training: who benefits? AB - Competency based training describes progression through training referenced to the demonstrated ability to perform certain tasks. In recent years, this has become the dominant curriculum model. We seek to examine who benefits from a competency based approach to medical education. For the regulators and service, the apparent advantage is in terms of apparent measurable accountability and flexibility. For assessors, the promise of competence based assessments in the workplace to provide a reliable and objective measurement of a trainee's performance has not been demonstrated in practice. For the doctor in training, there is very little evidence to show benefit from competency based training. Competency based training places emphasis on individual skills rather than overall learning experience thus risks diminishing the role of the trainee in the workplace. Any form of medical education that devalues workplace based learning will ultimately harm the profession and, in turn, patient care. PMID- 23019589 TI - Unplanned alcohol withdrawal: a survey of consecutive admissions to an acute medical unit in 2010 and 2011. AB - BACKGROUND: Alcohol-related presentations to hospital have been increasing in the UK in recent years, including the occurrence of acute withdrawal. This study sought to better characterize the clinical features, patterns of treatment and outcomes in this patient group. METHODS: Patients admitted to the Acute Medical Unit of York Hospital due to acute alcohol withdrawal are normally treated according to a protocol that involves both fixed-dose and symptom-triggered drug administration. Admissions between 2010 and 2011 inclusive were studied. RESULTS: There were 211 admission episodes solely due to acute alcohol withdrawal, involving 127 patients (97 men, 76.4%) with median age of 45 years (interquartile range: 39-52 years). There was a high prevalence of depression (34%), alcoholic liver disease (22%) and drug misuse (12%). Total dose of chlordiazepoxide varied between 0 and 610 mg and tapered rapidly after the first day of admission. Vitamin supplements were administered to >90% of patients, including parenteral and oral in 74%, parenteral alone in 9% and oral alone in 9%. A specialist alcohol nurse reviewed patients while in hospital in 40% of cases. Approximately one-third of patients had multiple admissions for alcohol withdrawal during the study period. CONCLUSION: A high prevalence of physical and mental health disorders was observed. The local policy permitted high initial chlordiazepoxide doses and prompt downward titration, with a broad range of doses between individuals. Approximately 10% required no specific therapy, and there may be opportunities for developing alternative pathways for delivery of care in an ambulatory setting for these patients. PMID- 23019590 TI - Eight-weekly intravenous antibiotics is beneficial in severe bronchiectasis. AB - AIM: The aim of our study was to assess the impact of 8-weekly intravenous (IV) antibiotics on exacerbation frequency and health-related quality of life in bronchiectasis. METHODS: Patients were recruited prospectively from June 2008 to December 2010. Patients with recurrent exacerbations (five or more exacerbations per year) and subjectively reporting ill health between antibiotic courses were recruited. Eight-weekly IV antibiotics (for 14 days) were initiated. Patients were followed up for 1 year. Main outcome was reduction in exacerbation frequency and improvement in health-related quality of life (HRQoL) at 1 year after starting intravenous antibiotic therapy. Other outcomes recorded were forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), incremental shuttle walk test (ISWT), 24-h sputum volume, sputum microbiology, body mass index (BMI), markers of inflammation--white cell count (WCC), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). RESULTS: In total, 19 patients were recruited. Mean age was 64.1 years and 52.6% were female. With 8-weekly antibiotics, there was a significant reduction in the number of exacerbations [mean (SE): 9.3 (0.5) in the year before vs. 8.0 (0.4) in the year after; P = 0.02]. In 63.2%, Leicester Cough Questionnaire (LCQ) improved by >=1.3 U (P = 0.006)] and in 42.1% St. George's Respiratory Questionnaire (SGRQ) improved by >=4 U (P = 0.03). Exercise capacity increased by 58.7 m (P = 0.004). There was no improvement in the other end points. CONCLUSION: Treatment with 8-weekly intravenous antibiotics in severe bronchiectasis reduced exacerbation frequency and improved exercise tolerance and health-related quality of life. PMID- 23019591 TI - Stroke rehabilitation: recent advances and future therapies. AB - Despite advances in the acute management of stroke, a large proportion of stroke patients are left with significant impairments. Over the coming decades the prevalence of stroke-related disability is expected to increase worldwide and this will impact greatly on families, healthcare systems and economies. Effective neuro-rehabilitation is a key factor in reducing disability after stroke. In this review, we discuss the effects of stroke, principles of stroke rehabilitative care and predictors of recovery. We also discuss novel therapies in stroke rehabilitation, including non-invasive brain stimulation, robotics and pharmacological augmentation. Many trials are currently underway, which, in time, may impact on future rehabilitative practice. PMID- 23019592 TI - Does base-pairing strength play a role in microRNA repression? AB - MicroRNAs (miRNAs) are short, single-stranded RNAs that silence gene expression by either degrading mRNA or repressing translation. Each miRNA regulates a specific set of mRNA "targets" by binding to complementary sequences in their 3' untranslated region. In this study, we examined the importance of the base pairing strength of the miRNA-target duplex to repression. We hypothesized that if base-pairing strength affects the functionality of miRNA repression, organisms with higher body temperature or that live at higher temperatures will have miRNAs with higher G/C content so that the miRNA-target complex will remain stable. In the nine model organisms examined, we found a significant correlation between the average G/C content of miRNAs and physiological temperature, supporting our hypothesis. Next, for each organism examined, we compared the average G/C content of miRNAs that are conserved among distant organisms and that of miRNAs that are evolutionarily recent. We found that the average G/C content of ancient miRNAs is lower than recent miRNAs in homeotherms, whereas the trend was inversed in poikilotherms, suggesting that G/C content is associated with temperature, thus further supporting our hypothesis. In the organisms examined, the average G/C content of miRNA "seed" sequences was higher than that of mature miRNAs, which was higher than pre-miRNA loops, suggesting an association between the degree of functionality of the sequence and its average G/C content. Our analyses show a possible association between the base-pairing strength of miRNA-targets and the temperature of an organism, suggesting that base-pairing strength plays a role in repression by miRNAs. PMID- 23019593 TI - Biological role of the two overlapping poly(A)-binding protein interacting motifs 2 (PAM2) of eukaryotic releasing factor eRF3 in mRNA decay. AB - Eukaryotic releasing factor GSPT/eRF3 mediates translation termination-coupled mRNA decay via interaction with a cytosolic poly(A)-binding protein (PABPC1). A region of eRF3 containing two overlapping PAM2 (PABPC1-interacting motif 2) motifs is assumed to bind to the PABC domain of PABPC1, on the poly(A) tail of mRNA. PAM2 motifs are also found in the major deadenylases Caf1-Ccr4 and Pan2 Pan3, whose activities are enhanced upon PABPC1 binding to these motifs. Their deadenylase activities are regulated by eRF3, in which two overlapping PAM2 motifs competitively prevent interaction with PABPC1. However, it is unclear how these overlapping motifs recognize PABC and regulate deadenylase activity in a translation termination-coupled manner. We used a dominant-negative approach to demonstrate that the N-terminal PAM2 motif is critical for eRF3 binding to PABPC1 and that both motifs are required for function. Isothermal titration calorimetry (ITC) and NMR analyses revealed that the interaction is in equilibrium between the two PAM2-PABC complexes, where only one of the two overlapping PAM2 motifs is PABC-bound and the other is PABC-unbound and partially accessible to the other PABC. Based on these results, we proposed a biological role for the overlapping PAM2 motifs in the regulation of deadenylase accessibility to PABPC1 at the 3' end of poly(A). PMID- 23019595 TI - Neutron-gamma discrimination with UGAB scintillator using zero-crossing method. AB - The new-type scintillator, Ultima Gold Alpha-Beta (UGAB), was studied for its neutron-gamma discrimination capability. The figure-of-merit and peak-to-valley values for the neutron-gamma discrimination spectra of UGAB scintillator when exposed to (241)Am-Be neutron source were presented. The results show that this new-type scintillator can efficiently be used in neutron-gamma discrimination experiments. PMID- 23019594 TI - Alternative RISC assembly: binding and repression of microRNA-mRNA duplexes by human Ago proteins. AB - MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate protein output from the majority of human mRNAs. In contrast to the consensus view that all miRNAs are associated with Argonaute (Ago) proteins, we determine that miRNAs are expressed in a 13-fold excess relative to Agos in HeLa cells and that miRNAs are bound to mRNAs in a sevenfold excess relative to Agos, implying the existence of miRNA-mRNA duplexes not stoichiometrically bound by Agos. We show that all four human Agos can repress miRNA-mRNA duplexes, but only Ago2 can cleave small interfering RNA-mRNA duplexes in vitro. We visualize direct Ago binding to miRNA-mRNA duplexes in live cells using fluorescence lifetime imaging microscopy. In contrast to the consensus view that Agos bind miRNA duplexes, these data demonstrate that Agos can bind and repress miRNA-mRNA duplexes and support a model of catalytic Ago function in translational repression. PMID- 23019596 TI - Organ dose and effective dose estimation in paediatric chest radiographic examinations by using pin silicon photodiode dosemeters. AB - Organ and effective doses during paediatric chest radiographic examination were investigated for various tube voltages between 60 and 110 kV at a constant milliampere-second value and focus-to-film distance by using an in-phantom dose measuring system and a Monte Carlo (MC) simulation software (PCXMC), where the former was composed of 32 photodiode dosemeters embedded in various tissue and organ sites within a 6-y-old child anthropomorphic phantom. Lung doses obtained ranged from 0.010 to 0.066 mGy and effective doses from 0.004 to 0.025 mSv, where these doses varied by a factor of 6 with the change in the tube voltage. Effective doses obtained using the MC simulation software agreed with those obtained using the dose measuring system within 23 %, revealing the usefulness of PCXMC software for evaluating effective doses. The present study would provide helpful dose data for the selection of technical parameters in paediatric chest radiography in Japan. PMID- 23019597 TI - On rethinking occupancy factors. PMID- 23019598 TI - Neutron spectrometry and dosimetry study at two research nuclear reactors using Bonner sphere spectrometer (BSS), rotational spectrometer (ROSPEC) and cylindrical nested neutron spectrometer (NNS). AB - Neutron spectrometry and subsequent dosimetry measurements were undertaken at the McMaster Nuclear Reactor (MNR) and AECL Chalk River National Research Universal (NRU) Reactor. The instruments used were a Bonner sphere spectrometer (BSS), a cylindrical nested neutron spectrometer (NNS) and a commercially available rotational proton recoil spectrometer. The purposes of these measurements were to: (1) compare the results obtained by three different neutron measuring instruments and (2) quantify neutron fields of interest. The results showed vastly different neutron spectral shapes for the two different reactors. This is not surprising, considering the type of the reactors and the locations where the measurements were performed. MNR is a heavily shielded light water moderated reactor, while NRU is a heavy water moderated reactor. The measurements at MNR were taken at the base of the reactor pool, where a large amount of water and concrete shielding is present, while measurements at NRU were taken at the top of the reactor (TOR) plate, where there is only heavy water and steel between the reactor core and the measuring instrument. As a result, a large component of the thermal neutron fluence was measured at MNR, while a negligible amount of thermal neutrons was measured at NRU. The neutron ambient dose rates at NRU TOR were measured to be between 0.03 and 0.06 mSv h-1, while at MNR, these values were between 0.07 and 2.8 mSv h-1 inside the beam port and <0.2 mSv h-1 between two operating beam ports. The conservative uncertainty of these values is 15 %. The conservative uncertainty of the measured integral neutron fluence is 5 %. It was also found that BSS over-responded slightly due to a non-calibrated response matrix. PMID- 23019599 TI - Ulexite-galena intermediate-weight concrete as a novel design for overcoming space and weight limitations in the construction of efficient shields against neutrons and photons. AB - Recently, due to space and weight limitations, scientists have tried to design and produce concrete shields with increased attenuation of radiation but not increased mass density. Over the past years, the authors' had focused on the production of heavy concrete for radiation shielding, but this is the first experience of producing intermediate-weight concrete. In this study, ulexite (hydrated sodium calcium borate hydroxide) and galena (lead ore) have been used for the production of a special intermediate-weight concrete. Shielding properties of this intermediate-weight concrete against photons have been investigated by exposing the samples to narrow and broad beams of gamma rays emitted from a 60Co radiotherapy unit. Densities of the intermediate-weight concrete samples ranged 3.64-3.90 g cm-3, based on the proportion of the ulexite in the mix design. The narrow-beam half-value layer (HVL) of the ulexite-galena concrete samples for 1.25 MeV 60Co gamma rays was 2.84 cm, much less than that of ordinary concrete (6.0 cm). The Monte Carlo (MC) code MCNP4C was also used to model the attenuation of 60Co gamma-ray photons and Am-Be neutrons of the ulexite galena concrete with different thicknesses. The 60Co HVL calculated by MCNP simulation was 2.87 cm, indicating a good agreement between experimental measurements and MC simulation. Furthermore, MC-calculated results showed that thick ulexite-galena concrete shields (60-cm thickness) had a 7.22 times (722 %) greater neutron attenuation compared with ordinary concrete. The intermediate weight ulexite-galena concrete manufactured in this study may have many important applications in the construction of radiation shields with weight limitations such as the swing or sliding doors that are currently used for radiotherapy treatment rooms. PMID- 23019600 TI - Systematic review on the association between F2-isoprostanes and cardiovascular disease. AB - BACKGROUND: Oxidative stress may play an aetiological role in the development and progression of cardiovascular disease (CVD). However, evidence on its biochemical markers has been controversial. This article aimed to assess the role of F2 isoprostanes, a marker for measuring in vivo lipid oxidation, as a biomarker for CVD, including coronary artery disease, stroke and peripheral artery disease. METHODS: A literature search was performed using PubMed and EMBASE (from 1966 to February 2012). Studies that investigated the association between F2-isoprostanes and CVD were eligible. RESULTS: Of the 22 eligible studies retrieved, 20 studies showed a significant association between F2-isoprostanes and CVD. However, to date, there have been only four population-based studies, with one study reporting null association. Although data from prospective studies are ideal to examine a role of such biomarkers in predicting future CVD events, only two studies were prospective. In addition, differences in population characteristics, sample handling/storage and assays, coupled with a lack of confounding adjustment, may all contribute to the enormous variation in previous studies. CONCLUSIONS: High levels of F2-isoprostanes in urine or blood may be a non specific indicator of CVD. However, further population-based studies are needed. In addition, multivariable analyses are required for future studies to control confounding and improve classification accuracy. PMID- 23019601 TI - Investigation of cholesterol bias due to a matrix effect of external quality assurance samples: how true is your cholesterol method? AB - BACKGROUND: Comparability of cholesterol measurement is clinically required and external quality assurance (EQA) programmes are important to verify the trueness of routine methods. METHODS: We developed a gas chromatography-isotope dilution mass spectrometry (GC-IDMS) total cholesterol assay to investigate the cause of a suspected matrix-related negative bias with the Beckman Coulter enzymatic method discovered in an EQA programme. The GC-IDMS method was calibrated with certified reference material and verified against a secondary reference method. Bias between the GC-IDMS and Beckman Coulter methods was estimated according to Clinical and Laboratory Standards Institute (CLSI) protocol EP9-A2 with 40 clinical samples. RESULTS: At clinically important decision levels, no significant bias was demonstrated on patients' samples (all results within a +/ 3% limit). A matrix effect confined to the EQA material that affected the Beckman Coulter total cholesterol method was confirmed. CONCLUSIONS: The GC-IDMS method is suitable as a higher order total cholesterol method in a routine clinical laboratory. Matrix effects defeat the objectives of EQA schemes by preventing the verification of trueness. Given the importance of obtaining a true cholesterol result without systematic error, we recommend that EQA material without matrix effects should be used. PMID- 23019602 TI - A liquid chromatography tandem mass spectrometry assay for plasma renin activity using online solid-phase extraction. AB - BACKGROUND: The plasma renin activity (PRA) assay measures the ability of renin to generate angiotensin I (AngI) from angiotensinogen. It is used to monitor mineralocorticoid therapy and to screen hypertensive individuals for primary aldosteronism (PA). METHODS: Samples were incubated in the presence of protease inhibitors for 6.5 and 24 h. The reaction was stopped by the addition of 2% ammonium hydroxide. AngI was then quantified by liquid chromatography tandem mass spectrometry using online solid-phase extraction (XLC-MS/MS). RESULTS: This method requires a sample volume of 50 MUL and has an inter-assay precision <14% across the working range. A 6.5-h incubation gave a lower limit of quantification (LLOQ) of 0.3 nmol/L/h and this can be reduced to 0.08 nmol/L/h using a 24-h incubation. Comparison to a radioimmunoassay revealed excellent correlation (r(2) = 0.98), but a 37% negative bias. We also found that renin is stable in whole blood for up to 24 h at room temperature. In contrast, storage at 4 degrees C should be avoided as prorenin cryoactivation can affect the PRA result in some patient groups. CONCLUSIONS: We have developed and fully validated a semi automated XLC-MS/MS method for the measurement of PRA. In addition, a reference range specific to this assay has been defined. We have also demonstrated that renin is stable for up to 24 h at room temperature. This will enable this assay to be extended to samples taken in primary care, potentially increasing the number of hypertensive patients who can be screened for PA. PMID- 23019603 TI - Quantitative study on the hygroscopic expansion of spurr resin to obtain a high resolution atlas of the mouse brain. AB - Ultra-thin section-based microscopic imaging is considered one of the most realistic techniques for determining fine architectures of a brain-wide neural network. In this kind of method, the sample is usually embedded in resin and then immersed in water for sectioning and imaging. The effect of resin hygroscopic expansion on data accuracy and integrity is important as it may lead to inconsistent image qualities or degeneration of sectioning properties. But few studies have been conducted on this issue. Here, we have used surface profile measurements combined with sectioning and imaging by micro-optical sectioning tomography (MOST) to quantitatively study the sectioned surface expansion of spurr resin blocks as a result of water immersion for a short time period. The expansion effect on MOST imaging is also presented. The results revealed significant differences in the surface expansion of pure resin blocks with different immersion time durations (P < 0.001). During an eight-minute immersion, the surface expansion of the experimental specimens exhibited an approximately linear increase with immersion duration, while MOST images suffered a correlated decrease in brightness. Expansion was restricted to the submicron level with immersion duration of four minutes or less, and the mean and standard deviation of the expansion measurements both reached a maximum at eight minutes. When the immersion duration exceeded eight minutes, the expansion value decreased, which was most likely related to the degeneration of mechanical properties of the resin material on the block surface. This study indicates that it is necessary to select a specific sectioning mode according to the hygroscopic expansion properties of resin materials for maintaining the accuracy and integrity of whole brain atlas data. PMID- 23019604 TI - The effect of doxycycline on alcohol consumption and sensitivity: consideration for inducible transgenic mouse models. AB - Neuroinflammation is known to elicit numerous changes in brain physiology and is associated with various pathologies, including neurodegenerative diseases, and behaviors, such as sleep and acute illness. In addition, there is accumulating evidence that the behavioral response to alcohol is affected by perturbations to the neuroimmune system. Recent studies have shown that administration of proinflammatory mediators increases alcohol consumption, while anti-inflammatory drugs, such as minocycline, decrease consumption. Doxycycline is an anti inflammatory mediator and a tetracycline derivative, and is commonly used in the tetracycline regulatory system, a transgenic approach widely accredited for its inducible and reversible nature. Given the established link between anti inflammatory agents and response to and consumption of alcohol, and because the tetracycline regulatory system is becoming increasingly employed for genetic manipulations and behavioral phenotyping, we investigated the effect of doxycycline administration on alcohol sensitivity and consumption. Two independent transgenic lines containing a tetracycline transactivator transgene or the tetracycline operator promoter insertion, along with wild-type littermate mice (C57Bl/6J), were used to measure changes in alcohol consumption, alcohol induced motor impairment and sedation, and blood alcohol concentration with doxycycline administration (40 mg/kg in chow). Using repeated sessions of the drinking-in-the-dark paradigm, we found that doxycycline consistently reduced consumption of 20% alcohol during two- and four-hour access. Doxycycline also increased sensitivity to the motor-impairing effects of alcohol (2 g/kg), and the duration of loss of righting reflex after ethanol injection (3.5 g/kg), without causing a significant alteration in blood alcohol levels. Despite the many advantages of using a tetracycline-regulated transgenic approach, it is important to consider the effects of doxycycline administration in behaviors that may be influenced by neuroinflammation, including alcohol behaviors. PMID- 23019605 TI - A systematic review of the mediating role of knowledge, self-efficacy and self care behaviour in telehealth patients with heart failure. AB - We conducted a systematic review of controlled trials and pre-post studies to examine whether the putative benefits of telehealth, notably, improvements in clinical outcomes and quality of life, are mediated by increases in knowledge, self-efficacy and self-care behaviour in patients with heart failure. Telehealth was defined as any system of home-based self-monitoring of signs or symptoms of heart failure that transferred data for remote assessment by healthcare providers. Seven electronic databases were searched for studies that assessed any of six pathways in a proposed model. Data were independently extracted by two reviewers. Twelve studies met the inclusion criteria and provided evidence for or against one or more of the six pathways. Although all of the pathways in the model can be theoretically justified and three of the six relationships have been established in heart failure samples outside the context of telehealth, none of the pathways in the model were supported by the telehealth studies reviewed. Failure to replicate previously established relationships emphasizes the weakness of the telehealth literature, which impedes our ability to address questions such as how telehealth might achieve beneficial outcomes. PMID- 23019606 TI - Crossover ilio-iliac bypass and removal of femoro-femoral graft as first treatment for the infection of crossover bypass in aorto-uni-iliac endovascular aneurysm repair. AB - The crossover femoro-femoral bypass, classically used for the treatment of unilateral iliac arterial obstruction, has recently become an integral part of aorto-uni-iliac endovascular aneurysm repair. We therefore, reconsider the therapeutic problems related to thrombosis and in particular to infection of the femoro-femoral prosthesis, when many attempts have been made to preserve the bypass and treat the infection. Showing a case treated and well eight months later, we put forward the old technique of crossover ilio-iliac bypass, followed by the removal of the infected femoro-femoral graft. In our opinion, this technique circumvents the need for autologous tissue and allows for the use of prosthetics in a new, sterile, uncontaminated field. As this approach for these cases has so far not been reported in the literature, further cases and long-term follow-up are needed. PMID- 23019607 TI - Cardiovascular disease: primary prevention, disease modulation and regenerative therapy. AB - Cardiovascular primary prevention and regeneration programs are the contemporary frontiers in functional metabolic vascular medicine. This novel science perspective harnesses our inherent ability to modulate the interface between specialized gene receptors and bioavailable nutrients in what is labeled as the nutrient-gene interaction. By mimicking a natural process through the conveyance of highly absorbable receptor specific nutrients, it is feasible to accelerate cell repair and optimize mitochondrial function, thereby achieving cardiovascular cure. We performed a comprehensive review of PubMed, EMBASE and Cochrane Review databases for articles relating to cardiovascular regenerative medicine, nutrigenomics and primary prevention, with the aim of harmonizing their roles within contemporary clinical practice. We searched in particular for large-scale randomized controlled trials on contemporary cardiovascular pharmacotherapies and their specific adverse effects on metabolic pathways which feature prominently in cardiovascular regenerative programs, such as nitric oxide and glucose metabolism. Scientific research on 'cardiovascular-free' centenarians delineated that low sugar and low insulin are consistent findings. As we age, our insulin level increases. Those who can decelerate the rapidity of this process are prompting their cardiovascular rejuvenation. It is beginning to dawn on some clinicians that contemporary treatments are not only failing to impact on our most prevalent diseases, but they may be causing more damage than good. Primary prevention programs are crucial elements for a better outcome. Cardiovascular primary prevention and regeneration programs have enhanced clinical efficacy and quality of life and complement our conventional endovascular practice. PMID- 23019608 TI - Limb salvage in a child with severely injured mangled lower extremity and muscle rigor. AB - Most surgeons make their decision to amputate or perform limb salvage of a mangled extremity based on scoring systems and grading of acute ischemic limb. We report on a child in whom limb salvage was achieved in spite of a clinical picture of irreversible ischemia with high mangled severity scores. Attempts to revascularize the mangled extremity of children are recommended, regardless of their severity scores and condition of the foot. PMID- 23019610 TI - The APC/C inhibitor XErp1/Emi2 is essential for Xenopus early embryonic divisions. AB - Mitotic divisions result from the oscillating activity of cyclin-dependent kinase 1 (Cdk1). Cdk1 activity is terminated by the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets cyclin B for destruction. In somatic divisions, the early mitotic inhibitor 1 (Emi1) and the spindle assembly checkpoint (SAC) regulate cell cycle progression by inhibiting the APC/C. Early embryonic divisions lack these APC/C-inhibitory components, which raises the question of how those cycles are controlled. We found that the APC/C-inhibitory activity of XErp1 (also known as Emi2) was essential for early divisions in Xenopus embryos. Loss of XErp1 resulted in untimely destruction of APC/C substrates and embryonic lethality. XErp1's APC/C-inhibitory function was negatively regulated by Cdk1 and positively by protein phosphatase 2A (PP2A). Thus, Cdk1 and PP2A operate at the core of early mitotic cell cycles by antagonistically controlling XErp1 activity, which results in oscillating APC/C activity. PMID- 23019609 TI - Gene loops enhance transcriptional directionality. AB - Eukaryotic genomes are extensively transcribed, forming both messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). ncRNAs made by RNA polymerase II often initiate from bidirectional promoters (nucleosome-depleted chromatin) that synthesize mRNA and ncRNA in opposite directions. We demonstrate that, by adopting a gene-loop conformation, actively transcribed mRNA encoding genes restrict divergent transcription of ncRNAs. Because gene-loop formation depends on a protein factor (Ssu72) that coassociates with both the promoter and the terminator, the inactivation of Ssu72 leads to increased synthesis of promoter associated divergent ncRNAs, referred to as Ssu72-restricted transcripts (SRTs). Similarly, inactivation of individual gene loops by gene mutation enhances SRT synthesis. We demonstrate that gene-loop conformation enforces transcriptional directionality on otherwise bidirectional promoters. PMID- 23019611 TI - Jet-launching structure resolved near the supermassive black hole in M87. AB - Approximately 10% of active galactic nuclei exhibit relativistic jets, which are powered by the accretion of matter onto supermassive black holes. Although the measured width profiles of such jets on large scales agree with theories of magnetic collimation, the predicted structure on accretion disk scales at the jet launch point has not been detected. We report radio interferometry observations, at a wavelength of 1.3 millimeters, of the elliptical galaxy M87 that spatially resolve the base of the jet in this source. The derived size of 5.5 +/- 0.4 Schwarzschild radii is significantly smaller than the innermost edge of a retrograde accretion disk, suggesting that the M87 jet is powered by an accretion disk in a prograde orbit around a spinning black hole. PMID- 23019613 TI - Status and solutions for the world's unassessed fisheries. AB - Recent reports suggest that many well-assessed fisheries in developed countries are moving toward sustainability. We examined whether the same conclusion holds for fisheries lacking formal assessment, which comprise >80% of global catch. We developed a method using species' life-history, catch, and fishery development data to estimate the status of thousands of unassessed fisheries worldwide. We found that small unassessed fisheries are in substantially worse condition than assessed fisheries, but that large unassessed fisheries may be performing nearly as well as their assessed counterparts. Both small and large stocks, however, continue to decline; 64% of unassessed stocks could provide increased sustainable harvest if rebuilt. Our results suggest that global fishery recovery would simultaneously create increases in abundance (56%) and fishery yields (8 to 40%). PMID- 23019612 TI - Coagulation factor X activates innate immunity to human species C adenovirus. AB - Although coagulation factors play a role in host defense for "living fossils" such as horseshoe crabs, the role of the coagulation system in immunity in higher organisms remains unclear. We modeled the interface of human species C adenovirus (HAdv) interaction with coagulation factor X (FX) and introduced a mutation that abrogated formation of the HAdv-FX complex. In vivo genome-wide transcriptional profiling revealed that FX-binding-ablated virus failed to activate a distinct network of nuclear factor kappaB-dependent early-response genes that are activated by HAdv-FX complex downstream of TLR4/MyD88/TRIF/TRAF6 signaling. Our study implicates host factor "decoration" of the virus as a mechanism to trigger an innate immune sensor that responds to a misplacement of coagulation FX from the blood into intracellular macrophage compartments upon virus entry into the cell. PMID- 23019619 TI - Climate change. Ice-free Arctic sea may be years, not decades, away. PMID- 23019614 TI - The end of "small science"? PMID- 23019620 TI - Scientific community. U.S. study shows unconscious gender bias in academic science. PMID- 23019621 TI - Anthropology. Turning from war to peace in Papua New Guinea. PMID- 23019622 TI - Medicine. Drug trial offers uncertain start in race to save children with progeria. PMID- 23019623 TI - Paleoclimatology. Roots of empire. PMID- 23019624 TI - Paleoclimatology. Where Asia's monsoons go to die. PMID- 23019625 TI - Global research universities. Satellite labs extend science. PMID- 23019626 TI - Global research universities. How to go global. PMID- 23019627 TI - Curiosity and contamination. PMID- 23019628 TI - Religiously protecting Myanmar's environment. PMID- 23019629 TI - U.S. basic research: delayed drug development. PMID- 23019630 TI - U.S. basic research: still number one? PMID- 23019632 TI - Comment on "The geometric structure of the brain fiber pathways". AB - Wedeen et al. (Reports, 30 March 2012, p. 1628) proposed a geometrical grid pattern in the brain that could help the understanding of the brain's organization and connectivity. We show that whole-brain fiber crossing quantification does not support their theory. Our results suggest that the grid pattern is most likely an artifact attributable to the limitations of their method. PMID- 23019633 TI - Response to comment on "the geometric structure of the brain fiber pathways". AB - In response to Catani et al., we show that corticospinal pathways adhere via sharp turns to two local grid orientations; that our studies have three times the diffusion resolution of those compared; and that the noted technical concerns, including crossing angles, do not challenge the evidence of mathematically specific geometric structure. Thus, the geometric thesis gives the best account of the available evidence. PMID- 23019634 TI - Science and law. When scientific research and legal practice collide. PMID- 23019635 TI - Evolution. Suppression of sleep for mating. PMID- 23019636 TI - Astronomy. How oblate is the Sun? PMID- 23019637 TI - Ecology. Insecticide resistance after Silent spring. PMID- 23019638 TI - Ecology. Life in a contaminated world. PMID- 23019639 TI - Cancer. Immune surveillance from chromosomal chaos? PMID- 23019640 TI - Biochemistry. A radical route for nitrogenase carbide insertion. PMID- 23019641 TI - Retrospective. R. Duncan Luce (1925-2012). PMID- 23019642 TI - IBI* series winner. Personal plants: making botany meaningful by experimentation. PMID- 23019643 TI - Scientific thinking in young children: theoretical advances, empirical research, and policy implications. AB - New theoretical ideas and empirical research show that very young children's learning and thinking are strikingly similar to much learning and thinking in science. Preschoolers test hypotheses against data and make causal inferences; they learn from statistics and informal experimentation, and from watching and listening to others. The mathematical framework of probabilistic models and Bayesian inference can describe this learning in precise ways. These discoveries have implications for early childhood education and policy. In particular, they suggest both that early childhood experience is extremely important and that the trend toward more structured and academic early childhood programs is misguided. PMID- 23019644 TI - Out of the tropics: the Pacific, Great Basin lakes, and late Pleistocene water cycle in the western United States. AB - The water cycle in the western United States changed dramatically over glacial cycles. In the past 20,000 years, higher precipitation caused desert lakes to form which have since dried out. Higher glacial precipitation has been hypothesized to result from a southward shift of Pacific winter storm tracks. We compared Pacific Ocean data to lake levels from the interior west and found that Great Basin lake high stands are older than coastal wet periods at the same latitude. Westerly storms were not the source of high precipitation. Instead, air masses from the tropical Pacific were transported northward, bringing more precipitation into the Great Basin when coastal California was still dry. The changing climate during the deglaciation altered precipitation source regions and strongly affected the regional water cycle. PMID- 23019645 TI - Parallel molecular evolution in an herbivore community. AB - Numerous insects have independently evolved the ability to feed on plants that produce toxic secondary compounds called cardenolides and can sequester these compounds for use in their defense. We surveyed the protein target for cardenolides, the alpha subunit of the sodium pump, Na(+),K(+)-ATPase (ATPalpha), in 14 species that feed on cardenolide-producing plants and 15 outgroups spanning three insect orders. Despite the large number of potential targets for modulating cardenolide sensitivity, amino acid substitutions associated with host-plant specialization are highly clustered, with many parallel substitutions. Additionally, we document four independent duplications of ATPalpha with convergent tissue-specific expression patterns. We find that unique substitutions are disproportionately associated with recent duplications relative to parallel substitutions. Together, these findings support the hypothesis that adaptation tends to take evolutionary paths that minimize negative pleiotropy. PMID- 23019646 TI - A physically transient form of silicon electronics. AB - A remarkable feature of modern silicon electronics is its ability to remain physically invariant, almost indefinitely for practical purposes. Although this characteristic is a hallmark of applications of integrated circuits that exist today, there might be opportunities for systems that offer the opposite behavior, such as implantable devices that function for medically useful time frames but then completely disappear via resorption by the body. We report a set of materials, manufacturing schemes, device components, and theoretical design tools for a silicon-based complementary metal oxide semiconductor (CMOS) technology that has this type of transient behavior, together with integrated sensors, actuators, power supply systems, and wireless control strategies. An implantable transient device that acts as a programmable nonantibiotic bacteriocide provides a system-level example. PMID- 23019647 TI - Gold-catalyzed direct arylation. AB - Biaryls (two directly connected aromatic rings, Ar(1)-Ar(2)) are common motifs in pharmaceuticals, agrochemicals, and organic materials. Current methods for establishing the Ar(1)-Ar(2) bond are dominated by the cross-coupling of aryl halides (Ar(1)-X) with aryl metallics (Ar(2)-M). We report that, in the presence of 1 to 2 mole percent of a gold catalyst and a mild oxidant, a wide range of arenes (Ar(1)-H) undergo site-selective arylation by arylsilanes (Ar(2)-SiMe(3)) to generate biaryls (Ar(1)-Ar(2)), with little or no homocoupling (Ar(1) Ar(1)/Ar(2)-Ar(2)). Catalysis proceeds at room temperature and tolerates a broad range of functional groups, including those incompatible with cross-coupling. These features expedite biaryl preparation, as demonstrated by synthesis of the nonsteroidal anti-inflammatory diflunisal. PMID- 23019648 TI - Toward peace: foreign arms and indigenous institutions in a Papua New Guinea society. AB - In 1990, shotguns and M-16s were adopted into Enga warfare, setting off some 15 years of devastation as youths (~17 to 28) took charge of interclan warfare. In response, people called on elder leaders to adapt customary institutions to restore peace; subsequently, war deaths and the frequency of war declined radically. Data from precolonial warfare, 501 recent wars, and 129 customary court sessions allow us to consider (i) the principles and values behind customary institutions for peace, (ii) their effectiveness, (iii) how they interact with and compare to state institutions of today, and (iv) how such institutions might have shaped our human behavioral repertoire to make life in state societies possible. PMID- 23019650 TI - Fermentation, hydrogen, and sulfur metabolism in multiple uncultivated bacterial phyla. AB - BD1-5, OP11, and OD1 bacteria have been widely detected in anaerobic environments, but their metabolisms remain unclear owing to lack of cultivated representatives and minimal genomic sampling. We uncovered metabolic characteristics for members of these phyla, and a new lineage, PER, via cultivation-independent recovery of 49 partial to near-complete genomes from an acetate-amended aquifer. All organisms were nonrespiring anaerobes predicted to ferment. Three augment fermentation with archaeal-like hybrid type II/III ribulose-1,5-bisphosphate carboxylase-oxygenase (RuBisCO) that couples adenosine monophosphate salvage with CO(2) fixation, a pathway not previously described in Bacteria. Members of OD1 reduce sulfur and may pump protons using archaeal-type hydrogenases. For six organisms, the UGA stop codon is translated as tryptophan. All bacteria studied here may play previously unrecognized roles in hydrogen production, sulfur cycling, and fermentation of refractory sedimentary carbon. PMID- 23019651 TI - Sedlin controls the ER export of procollagen by regulating the Sar1 cycle. AB - Newly synthesized proteins exit the endoplasmic reticulum (ER) via coat protein complex II (COPII) vesicles. Procollagen (PC), however, forms prefibrils that are too large to fit into typical COPII vesicles; PC thus needs large transport carriers, which we term megacarriers. TANGO1 assists PC packing, but its role in promoting the growth of megacarriers is not known. We found that TANGO1 recruited Sedlin, a TRAPP component that is defective in spondyloepiphyseal dysplasia tarda (SEDT), and that Sedlin was required for the ER export of PC. Sedlin bound and promoted efficient cycling of Sar1, a guanosine triphosphatase that can constrict membranes, and thus allowed nascent carriers to grow and incorporate PC prefibrils. This joint action of TANGO1 and Sedlin sustained the ER export of PC, and its derangement may explain the defective chondrogenesis underlying SEDT. PMID- 23019649 TI - Mutations in the neverland gene turned Drosophila pachea into an obligate specialist species. AB - Most living species exploit a limited range of resources. However, little is known about how tight associations build up during evolution between such specialist species and the hosts they use. We examined the dependence of Drosophila pachea on its single host, the senita cactus. Several amino acid changes in the Neverland oxygenase rendered D. pachea unable to transform cholesterol into 7-dehydrocholesterol (the first reaction in the steroid hormone biosynthetic pathway in insects) and thus made D. pachea dependent on the uncommon sterols of its host plant. The neverland mutations increase survival on the cactus's unusual sterols and are in a genomic region that faced recent positive selection. This study illustrates how relatively few genetic changes in a single gene may restrict the ecological niche of a species. PMID- 23019652 TI - Radical SAM-dependent carbon insertion into the nitrogenase M-cluster. AB - The active site of nitrogenase, the M-cluster, is a metal-sulfur cluster containing a carbide at its core. Using radiolabeling experiments, we show that this carbide originates from the methyl group of S-adenosylmethionine (SAM) and that it is inserted into the M-cluster by the assembly protein NifB. Our SAM cleavage and deuterium substitution analyses suggest a similarity between the mechanism of carbon insertion by NifB and the proposed mechanism of RNA methylation by the radical SAM enzymes RlmN and Cfr, which involves methyl transfer from one SAM equivalent, followed by hydrogen atom abstraction from the methyl group by a 5'-deoxyadenosyl radical generated from a second SAM equivalent. This work is an initial step toward unraveling the importance of the interstitial carbide and providing insights into the nitrogenase mechanism. PMID- 23019653 TI - An immunosurveillance mechanism controls cancer cell ploidy. AB - Cancer cells accommodate multiple genetic and epigenetic alterations that initially activate intrinsic (cell-autonomous) and extrinsic (immune-mediated) oncosuppressive mechanisms. Only once these barriers to oncogenesis have been overcome can malignant growth proceed unrestrained. Tetraploidization can contribute to oncogenesis because hyperploid cells are genomically unstable. We report that hyperploid cancer cells become immunogenic because of a constitutive endoplasmic reticulum stress response resulting in the aberrant cell surface exposure of calreticulin. Hyperploid, calreticulin-exposing cancer cells readily proliferated in immunodeficient mice and conserved their increased DNA content. In contrast, hyperploid cells injected into immunocompetent mice generated tumors only after a delay, and such tumors exhibited reduced DNA content, endoplasmic reticulum stress, and calreticulin exposure. Our results unveil an immunosurveillance system that imposes immunoselection against hyperploidy in carcinogen- and oncogene-induced cancers. PMID- 23019654 TI - Pharmacogenomics and patient care: one size does not fit all. AB - The time is ripe to assess whether pharmacogenomics research--the study of the genetic basis for variation in drug response--has provided important insights into a personalized approach to prescribing and dosing medications. Here, we describe the status of the field and approaches for addressing some of the open questions in pharmacogenomics research and use of genetic testing in guiding drug therapy. PMID- 23019655 TI - Quantitative analysis of the human airway microbial ecology reveals a pervasive signature for cystic fibrosis. AB - Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the CF transmembrane conductance regulator. Disruption of electrolyte homeostasis at mucosal surfaces leads to severe lung, pancreatic, intestinal, hepatic, and reproductive abnormalities. Loss of lung function as a result of chronic lung disease is the primary cause of death from CF. Using high throughput sequencing to survey microbes in the sputum of 16 CF patients and 9 control individuals, we identified diverse microbial communities in the healthy samples, contravening conventional wisdom that healthy airways are not significantly colonized. Comparing these communities with those from the CF patients revealed significant differences in microbial ecology, including differential representation of uncultivated phylotypes. Despite patient-specific differences, our analysis revealed a focal microbial profile characteristic of CF. The profile differentiated case and control groups even when classically recognized CF pathogens were excluded. As a control, lung explant tissues were also processed from a group of patients with pulmonary disease. The findings in lung tissue corroborated the presence of taxa identified in the sputum samples. Comparing the sequencing results with clinical data indicated that diminished microbial diversity is associated with severity of pulmonary inflammation within our adult CF cohort. PMID- 23019656 TI - An RNA profile identifies two subsets of multiple sclerosis patients differing in disease activity. AB - The multiple sclerosis (MS) patient population is highly heterogeneous in terms of disease course and treatment response. We used a transcriptional profile generated from peripheral blood mononuclear cells to define the structure of an MS patient population. Two subsets of MS subjects (MS(A) and MS(B)) were found among 141 untreated subjects. We replicated this structure in two additional groups of MS subjects treated with one of the two first-line disease-modifying treatments in MS: glatiramer acetate (GA) (n = 94) and interferon-beta (IFN-beta) (n = 128). One of the two subsets of subjects (MS(A)) was distinguished by higher expression of molecules involved in lymphocyte signaling pathways. Further, subjects in this MS(A) subset were more likely to have a new inflammatory event while on treatment with either GA or IFN-beta (P = 0.0077). We thus report a transcriptional signature that differentiates subjects with MS into two classes with different levels of disease activity. PMID- 23019657 TI - Vascular catheters with a nonleaching poly-sulfobetaine surface modification reduce thrombus formation and microbial attachment. AB - Adherence of proteins, cells, and microorganisms to the surface of venous catheters contributes to catheter occlusion, venous thrombosis, thrombotic embolism, and infections. These complications lengthen hospital stays and increase patient morbidity and mortality. Current technologies for inhibiting these complications are limited in duration of efficacy and may induce adverse side effects. To prevent complications over the life span of a device without using active drugs, we modified a catheter with the nonleaching polymeric sulfobetaine (polySB), which coordinates water molecules to the catheter surface. The modified surface effectively reduced protein, mammalian cell, and microbial attachment in vitro and in vivo. Relative to commercial catheters, polySB modified catheters exposed to human blood in vitro had a >98% reduction in the attachment and a significant reduction in activation of platelets, lymphocytes, monocytes, and neutrophils. Additionally, the accumulation of thrombotic material on the catheter surface was reduced by >99% even after catheters were exposed to serum in vitro for 60 days. In vivo, in a highly thrombogenic canine model, device- and vessel-associated thrombus was reduced by 99%. In vitro adherence of a broad spectrum of microorganisms was reduced on both the external and the internal surfaces of polySB-modified catheters compared to unmodified catheters. When unmodified and polySB-modified catheters were exposed to the same bacterial challenge and implanted into animals, 50% less inflammation and fewer bacteria were associated with polySB-modified catheters. This nonleaching, polySB-modified catheter could have a major impact on reducing thrombosis and infection, thus improving patient health. PMID- 23019658 TI - Biomaterial-associated infection: locating the finish line in the race for the surface. AB - Biomaterial-associated infections occur on both permanent implants and temporary devices for restoration or support of human functions. Despite increasing use of biomaterials in an aging society, comparatively few biomaterials have been designed that effectively reduce the incidence of biomaterial-associated infections. This review provides design guidelines for infection-reducing strategies based on the concept that the fate of biomaterial implants or devices is a competition between host tissue cell integration and bacterial colonization at their surfaces. PMID- 23019660 TI - Attitudes of medical oncologists in Qatar toward palliative care. AB - OBJECTIVES: The first and only palliative care (PC) unit in Qatar was established in 2008 to serve adult patients with cancer. As PC was only recently introduced to oncology practice in Qatar and the region, raising awareness among physicians is crucial. This survey study is designed to outline the level of awareness and knowledge of oncologists in Qatar toward PC. METHODS: In this cross-sectional survey study, copies of a self-constructed questionnaire were distributed to 49 physicians at the National Center for Cancer Care and Research in Qatar during January 2012 and collected for data analysis. RESULTS: The physician response rate was 100%. Less than half of the responders (36.7%) had official training in PC, but the majority (89.8%) showed interest in the field. Only 57.8% of the physicians reported self-competence in providing good PC to the dying patient. On the other hand, up to 69.4% are aware of the guidelines for pain relief and 58.7% apply them in their clinical practice. The concept of PC hospice was familiar to 77.1% of participants. On one hand, 85.7% of the physicians advocated that every medical center should have PC service, while up to 70.8% preferred that patients with short survival expectancy die in the community, rather than in a hospital setting. CONCLUSIONS: There is relatively good awareness and knowledge among health care providers specialized in cancer treatment in our hospital, despite the lack of formal training. Further training and informative sessions are required to raise awareness among oncologists and encourage utilization of PC services and thus optimize patient accessibility to PC. PMID- 23019659 TI - The role of physical examination in diagnosing common causes of vaginitis: a prospective study. AB - OBJECTIVE: We evaluated agreement in diagnoses for bacterial vaginosis (BV), Trichomonas vaginalis (TV) and vulvovaginal candidiasis (VVC) between clinicians examining the patient and performing diagnostic tests versus a clinician with access only to the patient's history and diagnostic findings from self-obtained vaginal swabs (SOVS). DESIGN: Women presenting with vaginal discharge to a sexually transmitted infections clinic provided SOVS for evaluation and completed the study and qualitative questionnaires. A clinician then obtained a history and performed speculum and bimanual examinations. Participants' history and diagnostic test results from SOVS were provided to a masked non-examining clinician who rendered independent diagnoses. Overall agreement in diagnoses and kappa statistics was calculated. RESULTS: The prevalence of infections among the 197 participants was 63.4% (BV), 19% (TV) and 14% (VVC). The per cent agreement between the examining and non-examining clinician for the diagnoses of BV was 68.5%, 90.9% for TV and 91.9% for VVC. Of the 105 women diagnosed with BV by the examining clinician, 34 (32%) were missed by the non-examining clinician. The non examining clinician missed 13 (48%) of 27 women and 12 (34%) of 35 women treated for VVC and TV, respectively. Four women who all presented with abdominal pain were diagnosed with pelvic inflammatory disease. CONCLUSIONS: Tests from SOVS and history alone cannot be used to adequately diagnose BV, TV and VVC in women presenting with symptomatic vaginal discharge. Cost benefits from eliminating the speculum examination and using only tests from SOVS may be negated by long-term costs of mistreatment. PMID- 23019661 TI - Fetal yawning. PMID- 23019662 TI - Perspectives on neuroscience and behavior. PMID- 23019664 TI - Proceedings of the 6th International Conference on Electron Tomography, May 2011, Heidelberg, Germany. PMID- 23019663 TI - [Robert Killick-Kendrick (1929-2011)- in memoriam]. PMID- 23019665 TI - Proceedings of the 4th International Workshop on Recent Advances in Monte Carlo Techniques for Radiation Therapy, June 8-10, 2011, 2012, Montreal, Canada. PMID- 23019666 TI - A special issue in honor of Ira B. Black. PMID- 23019667 TI - [Proceedings and abstracts of the 65th Congress of the French National Society of Internal Medicine, June 13-15, 2012, Clermont-Ferrand, France]. PMID- 23019668 TI - Gut feelings: the potential of oral administration of therapeutic peptides to the brain. PMID- 23019669 TI - Good things come in ultrasmall packages. AB - Recent study shows that ultrasmall gold nanoparticles have enhanced localization and penetration of cancer cells and tumors. PMID- 23019670 TI - Fighting the resistance: rejuvenating anticancer platinum-based drugs. AB - A platinum prodrug encapsulated within a gold nanorod-based delivery system has shown potential to overcome cisplatin resistance in cancer cells. PMID- 23019671 TI - Synergizing radiation therapy with drug-loaded nanovectors. PMID- 23019672 TI - Enhancing the cell uptake of nanoparticles within tumors. PMID- 23019673 TI - Targeted and drug-loaded micelles. PMID- 23019674 TI - Emergency department noninvasive (NICOM) cardiac outputs are associated with trauma activation, patient injury severity and host conditions and mortality. AB - BACKGROUND: Anoninvasive cardiac output (CO) monitor (NICOM), using Bioreactance technology, has been validated in several nontrauma patient studies. We hypothesized that NICOM CO would have more significant associations with clinical conditions than would systolic blood pressure (sBP). METHODS: This is a prospective observational study of consecutive trauma activation patients during the first 10 to 60 minutes after emergency department arrival. RESULTS: Analysis includes 270 consecutive trauma activation patients with 1,568 observations. CO was decreased (p <= 0.002) with major blood loss, hypotension, red blood cell transfusion, Injury Severity Score (ISS) higher than 20, low PetCO2, abnormal pupils, elderly, preexisting conditions, low body surface area level, females, hypothermia, and death. CO was increased (p < 0.0001) with base deficit, ethanol positivity, and illicit drug positivity. The sBP was decreased (p <= 0.0005) with major blood loss, red blood cell transfusion, low PetCO2, low body surface area level, and illicit drug positivity. The sBP was increased (p e 0.01) with ISS higher than 20, elderly, and preexisting conditions. Total significant condition associations were CO 83% (15 of 18 patients) and sBP 47% (8 of 17 patients; p = 0.03). In hypotensive patients, CO was lower with major blood loss (3.3 +/- 2.1 L/ min) than without (6.0 +/- 2.2 L/min; p < 0.0001). Of survivors with ISS 15 or higher, NICOM patients experienced a shorter hospital length of stay (10.5 days) when compared with 2009 and 2010 patients (14.0 days; p = 0.03). CONCLUSION: The multiple associations of CO with patient conditions imply that NICOM provides an objective and clinically valid, relevant, and discriminate measure of cardiac function in acutely injured trauma activation patients. NICOM use may be associated with a shorter length of stay in surviving patients with complex injuries. PMID- 23019675 TI - Hypothermia in massive transfusion: have we been paying enough attention to it? AB - OBJECTIVE: The development of acidosis, coagulopathy, and hypothermia has been shown to adversely affect survival after injury. Significant attention has focused on the correction of the early coagulopathy in those requiring massive transfusion (MT). We sought to characterize the importance of temperature as a risk factor for poor outcome relative to the changes in MT resuscitation that have occurred. METHODS: Data were obtained from a multicenter prospective cohort study of adults with blunt injury with hemorrhagic shock. MT was defined as 10 U or more of packed red blood cell (PRBC) during 24 hours. The lowest 24-hour temperature was categorized into groups (<34.0 degrees C, 34.1-35.0 degrees C, 35.1-36.0 degrees C, and >36 degrees C). A Kaplan-Meier analysis and a multivariate logistic regression were used to analyze temperature survival differences over time and independent risks of mortality after controlling for all important confounders. RESULTS: In the MT cohort (n = 604), as temperature decreased, shock parameters, early coagulopathy, injury severity, and blood component transfusion requirements significantly increased. A Kaplan-Meier comparison revealed a dose-response relationship with a temperature lower than 34 degrees C resulting in the greatest mortality. Logistic regression analysis demonstrated that a temperature lower than 34 degrees C was associated with a greater independent risk of mortality of more than 80% after controlling for differences in shock, coagulopathy, injury severity, and transfusion requirements (odds ratio, 1.87; 95% confidence interval, 1.18-3.0; p = 0.007). When the cohort was stratified into high or low plasma to red blood cell transfusion ratio groups (high fresh frozen plasma [FFP]/PRBC, >=1:2 vs. low FFP/PRBC, <1:2), regression modeling demonstrated that a temperature lower than 34 degrees C was associated with a twofold higher independent risk of mortality, only in the low FFP/PRBC transfusion group. CONCLUSION: A temperature of 34 degrees C seems to define a clinically significant hypothermia in MT. The independent risks of mortality were greatest in those who received a low FFP/PRBC transfusion ratio. These data suggest that the prevention of hypothermia may be as important as addressing early coagulopathy. Further research is required to verify if the prevention or correction of hypothermia improves the outcome of patients requiring MT. PMID- 23019676 TI - The impact of antiplatelet drugs on trauma outcomes. AB - BACKGROUND: Antiplatelet drugs (APDs) are among the most commonly prescribed medications.We wondered whether patients with trauma receiving preinjury APD have worse outcomes. METHODS: We interrogated our institutional database during a 5 year period to evaluate preoperative risks and trauma outcomes in patients taking APDs before traumatic injury. We used propensity balancing scores to adjust for preoperative risks in assessing outcomes in APD-treated patients. RESULTS: During a 5-year period, 1,327 (11.7%) of 11,374 adult patients with trauma took APDs before injury. The yearly use of APD in patients with trauma increased nearly threefold during the study period. Cardiac, pulmonary, and renal comorbidities were significantly more common in APD-treated patients. Multivariate regression indicated that preinjury APDs predicted significantly worse composite morbidity and mortality. After propensity adjustment for preinjury risk factors, APD treated patients demonstrated significantly increased composite morbidity (39.0 vs. 24.6%, p = 0.037) and cardiac complications (23.0 vs. 17.3%, p = 0.017) compared with patients without APDs. The type and intensity of APD conferred an incremental risk, with patients taking dual APDs having a significantly worse multivariate risk of adverse outcomes compared with patients taking a single APD. CONCLUSION: APD-treated patients with trauma have significantly more comorbidities compared with those not taking APDs. After adjusting for preoperative risks, APD-treated patients have significantly worse trauma outcomes. Dual APD treatment confers an incremental risk of adverse outcomes compared with single APD preinjury treatment. The number of patients with trauma taking APDs increased during the 5-year study period, so we speculate that trauma management of patients taking APDs will occur more commonly in the future. PMID- 23019677 TI - Clinical clearance of the cervical spine in patients with distracting injuries: It is time to dispel the myth. AB - OBJECTIVE: The purpose of this study was to prospectively assess the sensitivity and efficacy of clinical examination for screening of cervical spine (c-spine) injury in awake and alert blunt trauma patients with concomitant "distracting injuries." METHODS: During the 24-month period from December 2009 to December 2011, all blunt trauma patients older than 13 years were prospectively evaluated with a standard cervical spine examination protocol by the trauma surgery team at a Level 1 trauma center. Awake and alert patients with a Glasgow Coma Score (GCS) >=14 underwent clinical examination of the cervical spine. Clinical examination was performed regardless of "distracting injuries." Patients without complaints of pain or tenderness on physical exam had their cervical collar removed, and the c-spine was considered clinically cleared of injury. All awake and alert patients with "distracting injuries," including those clinically cleared and those with complaints of c-spine pain or tenderness underwent computerized tomographic (CT) scanning of the entire c-spine. "Distracting injuries" were categorized into three anatomic regions: head injuries, torso injuries and long bone fractures. Patients with minor distracting injuries were not considered to have a "distracting injury." RESULTS: During the 24-month study period, 761 blunt trauma patients with GCS >=14 and at least one "distracting injury" had been entered into the study protocol. Two-hundred ninety-six (39%) of the patients with "distracting injuries" had a positive c-spine clinical examination, 85 (29%) of whom were diagnosed with c-spine injury. Four hundred sixty-four (61%) of the patients with "distracting injuries"' were initially clinically cleared, with one patient (0.2%) diagnosed with a c-spine injury. This yielded an overall sensitivity of 99% (85/86) and negative predictive value greater than 99% (463/464) for cervical spine clinical examination in awake and alert blunt trauma patients with "distracting injuries." CONCLUSIONS: In the awake and alert blunt trauma patient with "distracting injuries," clinical examination is a sensitive screening method for cervical spine injury. Radiological assessment is unnecessary for safe clearance of the asymptomatic cervical spine in awake and alert blunt trauma patients with "distracting injuries." These findings suggest the concept of "distracting injury" in the context of cervical spine clinical examination is invalid. Expanding the utility of cervical spine clinical examination to patients with "distracting injuries" allows for significant reduction of both healthcare cost and radiation exposure. PMID- 23019678 TI - Inhaled epoprostenol improves oxygenation in severe hypoxemia. AB - BACKGROUND: Epoprostenol (Flolan), an inhalational epoprostenol vasodilator, increases pulmonary arterial flow and decreases pulmonary pressures, thereby improving gas exchange and arterial oxygenation. We evaluated the benefits of inhaled epoprostenol as a less expensive alternative to nitric oxide in ventilated surgical intensive care patients with severe hypoxemia. METHODS: After institutional review board approval was obtained, the records of mechanically ventilated surgical intensive care unit patients who received epoprostenol as a therapy for severe hypoxia (SaO2 < 90%) in a tertiary care referral center were retrospectively reviewed. Initial PaO2/FIO2 (P/F) ratio and oxygen saturation were compared with values at 12 and 48 hours after the administration of epoprostenol. One-way repeated-measures analysis of variance compared improvements in oxygenation. Further subgroup analyses evaluated differences among trauma, nontrauma patient subgroups, time to initiation of epoprostenol, and age. RESULTS: During a 20 month-interval beginning February 2009, 36 patients (23 trauma and 13 nontrauma; age, 15-80 years) were treated. Epoprostenol significantly improved both P/F ratio and oxygen saturation in both trauma and nontrauma patients. Therewas no difference between subgroups. Larger improvements in P/F ratiowere seen when epoprostenolwas started within 7 days. Response between age groups did not differ significantly. Subgroup analysis of mortality (trauma, 60.9% vs. nontrauma, 61.5%) failed to show any differences. CONCLUSION: Treatment with inhaled epoprostenol improved gas exchange in severely hypoxemic surgical patients. Earlier intervention (within 7 days of intubation) was more efficacious at improving oxygenation. PMID- 23019679 TI - Compared to conventional ventilation, airway pressure release ventilation may increase ventilator days in trauma patients. AB - BACKGROUND: Airway pressure release ventilation (APRV) is used both as a rescue therapy for patients with acute lung injury and as a primary mode of ventilation. Unlike assist-control volume (ACV) ventilation that uses spontaneous breathing trials, APRV weaning consists of gradual decreases in supporting pressure. We hypothesized that the APRV weaning process increases total ventilator days compared with those of spontaneous breathing trials-based weaning. METHODS: A retrospective review of a Level I trauma center's database identified trauma admissions from January 1, 2007, to December 31, 2010, which required mechanical ventilation for more than 24 hours and survived. Demographics, injuries, in hospital complications, ventilation mode(s), and total ventilator days were abstracted. RESULTS: A total of 362 patients fulfilled study entry criteria; 53 patients with more than one ventilator mode change were excluded. Seventy-five patients were successfully liberated from mechanical ventilation on APRV and 234 on ACV. The APRV and ACV groups, respectively, were similar in age (46.1 vs. 44.6 years) and sex (72% vs. 73% male) but differed in Injury Severity Score (20.8 vs. 17.5; p = 0.03). Patients on APRV had higher rates of abdominal compartment syndrome (6.7% vs. 0.8%, p = 0.003) and were more likely to have a higher chest Abbreviated Injury Scale (AIS) score >=3 (57.3% vs. 30.8%, p < 0.001). Ventilator days were significantly greater in the APRV group (19.6 vs. 10.7 days, p < 0.001). Multiple regression was performed to adjust for the clinical differences between the two groups, identifying APRV as an independent predictor for increased number of ventilator days (B = 6.2 +/- 1.5, p < 0.001) in addition to male sex, abdomen AIS score of 3 or higher, spine AIS score of 3 or higher, acute renal failure, and sepsis. CONCLUSION: APRV is frequently used for patients who are more severely injured or who develop in-hospital complications such as pneumonia. However, after controlling for potential confounding factors in a multiple regression model, the APRV mode itself seems to increase ventilator days. PMID- 23019680 TI - Determining venous thromboembolic risk assessment for patients with trauma: the Trauma Embolic Scoring System. AB - BACKGROUND: This study aimed to determine the relative "weight" of risk factors known to be associated with venous thromboembolism (VTE) for patients with trauma based on injuries and comorbidities. METHODS: A retrospective review of 16,608 consecutive admissions to a trauma center was performed. Patients were separated into those who developed VTE (n = 141) versus those who did not (16,467). Univariate analysis was performed for each risk factor reported in the trauma literature. Risk factors that were shown to be significant (p < 0.05) by univariate analysis underwent multivariate analysis to develop odds ratios for VTE. The Trauma Embolic Scoring System (TESS) was derived from the multivariate coefficients. The resulting TESS was compared with a data set from the National Trauma Data Bank (2002-2006) to determine its ability to predict VTE. RESULTS: The multivariate analysis demonstrated that age, Injury Severity Score, obesity, ventilator use for more than 3 days, and lower-extremity trauma were significant predictors of VTE in our patient population. The TESS was from 0 to 14, with the best prediction for those patients with a score of more than 6 (sensitivity, 81.6%; specificity, 84%). Overall, the model had excellent discrimination in predicting VTE with a receiver operating characteristic curve of 0.89. The VTE rates for TESS in the National Trauma Data Bank data set were similar for all integers except for 3 and 4, in which the VTE rates were significantly higher (3, 0.2% vs. 0.6%; 4, 0.4% vs. 1.0%). CONCLUSION: The TESS provides an objective measure of classifying VTE risk for patients with trauma. The TESS could allow informed decision making regarding prophylaxis strategies in patients with trauma. PMID- 23019681 TI - Regional variations in cost of trauma care in the United States: who is paying more? AB - BACKGROUND: The study of regional variations in costs of care has been used to identify areas of savings for several diseases and conditions. This study investigates similar potential regional differences in the cost of adult trauma care using an all-payer, nationally representative sample. METHODS: Trauma patients aged 18 to 64 years in the 2006-2008 Nationwide Inpatient Sample were identified using International Classification of Diseases, 9th Revision, Clinical Modification codes. Those with isolated diagnoses for five index conditions (ICs): blunt splenic injury, liver injury, tibia fracture, moderate traumatic brain injury, and pneumothorax/hemothorax were selected. Cost was estimated from charges using a cost-to-charge ratio. Generalized linear modeling was used to compare the mean cost for treating these ICs between US regions (Northeast, South, Midwest, and West), adjusting for hospital factors (size, teaching status, and location), patient demographics, injury severity, length of stay, Charlson comorbidity index, local wage index, and payer. Relative mean cost (RC) was calculated using Northeast as the reference, and sampling weights were applied to obtain regional estimates. Differences in adjusted mortality between regions were also assessed. RESULTS: Adjusted relative costs were estimated for 62,678 patients (South: 28,536; West: 12,975; Midwest: 11,450; and Northeast: 9,717). Mean costs for liver injury were 22%higher in the Midwest compared with the Northeast (RC: 1.22; 95%confidence interval [CI]: 1.10-1.35). Similarly higher costs were seen with other regions and ICs (RC for blunt splenic injury in the South: 1.18; 95% CI: 1.07-1.31; RC for pneumothorax/hemothorax in the West: 1.31; 95% CI: 1.22-1.41). No differences in adjusted mortality by region were noted overall. CONCLUSION: Even after controlling for factors known to influence medical care cost, as well as controlling for geographic differences in pricing, significant regional differences exist in the cost of trauma care. Exploring these variations may assist in identifying potential areas for cost savings. PMID- 23019682 TI - Alternative methods in Europe. Editorial. PMID- 23019683 TI - In praise of referees. PMID- 23019684 TI - The author file: Gustavo Stolovitzky. PMID- 23019685 TI - Points of view: Mapping quantitative data to color. PMID- 23019686 TI - Writing the histone code. PMID- 23019687 TI - Reproductive and developmental toxicity testing: from in vivo to in vitro. PMID- 23019688 TI - Bacteria and Candida yeasts in inflammations of the oral mucosa in children with secondary immunodeficiency. AB - BACKGROUND: Oral microbial flora and a damaged oral mucosa may increase the risk of bacteriemia, fungemia and complications in immunocompromised patients. AIM OF THE STUDY: Assessment of presence: bacteria and Candida spp. in different oral lesions, and the incidence of bacteremia in the case of a damaged mucosa in transplant recipients and patients receiving anti-tumour chemotherapy. MATERIAL AND METHOD: Forty-five patients - 18 months to 18 years of life, were included (20 - organ recipients, 14- anti-tumour chemotherapy, 11 - control group). Clinical, oral mucosa examination focused on the type, severity and site of lesions, and microbiology assessed the presence of bacteria and fungi in the material from lesions. Blood cultures were performed in ten immunocompromised patients with manifestations of systemic infection. The control material consisted of blood cultures made prior to the onset of oral lesions and after 4-6 weeks following their remission in a diagnosed bacteremia. The statistical analysis was performed. RESULTS: In the subjects with secondary immunodeficiency, among other coagulase-negative Staphylococcus (CoNS), Candidia spp. were more frequent. In cancer patients, mucositis was associated with Candida spp., Streptococcus spp. Organ recipients with stomatitis exhibited the presence of CoNS, Streptococcus viridians and other. Oral lesions in the control group contained Haemophilus parainfluenzae, Neisseria spp. and Staphylococcus aureus. In 30% of immunocompromised patients, oral lesions were accompanied by bacteremia. CONCLUSIONS: A correlation has been found between oral lesions and the presence of S. aureus in patients without secondary immunodeficiency, and of CoNS, Enterococcus spp., Candida spp. in immunocompromised patients. PMID- 23019689 TI - Upgrades for the AFM. PMID- 23019690 TI - A blood-brain barrier in a dish. PMID- 23019691 TI - Ribosomes, start your engines. PMID- 23019692 TI - (Protein) timing is everything. PMID- 23019693 TI - Living longer, staying healthy. PMID- 23019694 TI - Don't let your workplace define you. PMID- 23019695 TI - Look beyond your hospital walls to prevent readmissions. AB - Instead of limiting their efforts to what happens while patients are in the hospital, case managers need to reach out to community providers and make sure patients have everything they need to prevent a readmission. Next month, CMS begins penalizing hospitals for excess readmissions. It takes collaboration with downstream providers to ensure a successful transition to the community. Communication between levels of care is essential in preventing readmissions. Start by taking a hard look at your discharge process and collaborating within the hospital to make improvements. PMID- 23019696 TI - Improving discharges starts within the hospital. PMID- 23019697 TI - Meetings help improve patient transitions. AB - It took a while to get started, but UConn Health Center/John Dempsey Hospital in Farmington, CT, is now meeting monthly with dozens of post-acute providers to work on improving transitions. Providers exchange ideas for better patient care. Educational materials have been standardized throughout the continuum. Based on input from other providers, the hospital is improving the discharge materials. PMID- 23019698 TI - Community collaboration helps cut readmits. AB - Charles Cole Memorial Hospital in Coudersport, PA, slashed its readmission rate by 15.9% by collaborating with post-acute providers and making internal improvements. Community transition team members educate each other on what happens at each level of care. Team worked together to standardize educational materials and improve communication between providers. Internal measures include revising educational process and improving medication reconciliation. Eligible patients are referred to Pennsylvania Area Agencies on Aging for follow-up after discharge. PMID- 23019699 TI - Nine hospitals collaborate to prevent readmissions. AB - The Rio Grande Valley Readmission Coalition, which includes nine hospitals and the Agency on Aging is collaborating to prevent readmissions for at-risk patients. Program is funded through the Community-Based Care Transition Project administered by the Centers for Medicare & Medicaid Services. Hospital case managers refer appropriate patients to the program and check for eligibility using a Web-based data exchange program that includes criteria for eligibility. Agency on Aging health coaches visit patients in the hospital and follow up for 30 days after discharge. PMID- 23019700 TI - Hospital, nurses team up to prevent readmissions. AB - University Hospital in Newark, NJ, and the Visiting Nurses Association Health Group are working together to provide intensive case management to Medicare and Medicaid beneficiaries and uninsured patients with multiple chronic conditions. Hospital case managers identify patient eligible for the program. Patient navigators employed by the VNA and funded by the hospital provide education while patients are in the hospital. Navigators visit the patients every day in the hospital and link them with primary care providers for follow up. PMID- 23019701 TI - How mobility can shorten stay, improve outcomes. PMID- 23019702 TI - Are hospitals safer now? PMID- 23019703 TI - Facility cuts falls 88% and med errors 30%. PMID- 23019704 TI - SC hospitals taking on mislabeled specimens. PMID- 23019705 TI - How a hospital brought VAP rates to zero. PMID- 23019706 TI - Hospitals honored by Quest prize for quality. PMID- 23019707 TI - Are you flu-shot ready? PMID- 23019708 TI - Vascular health vital to optimal heart and brain function. Treating hypertension and atherosclerosis may help prevent stroke and dementia. PMID- 23019709 TI - Innovative device may reduce stroke risk for AFib patients. Watchman(r) may offer an alternative to long-term anti-coagulant use. PMID- 23019710 TI - Stick with your aspirin therapy to reduce heart attack risks. New research shows that discontinuation of aspirin can raise the risk of non-fatal heart attack by 60 percent. PMID- 23019711 TI - New warnings emerge for estrogen plus progesterone. Two studies confirm major cardiovascular risks outweigh minor health benefits for postmenopausal women. PMID- 23019712 TI - Five ways to prevent unhealthy weight gain and help your heart. Keeping an eye on the scale in the kitchen can help prevent unwelcome surprises on the other scale in your home. PMID- 23019713 TI - Chronic constipation may signify higher risk of heart disease. If you suffer from chronic constipation, see your cardiologist. PMID- 23019714 TI - Niacin: its value in raising HDL cholesterol is being questioned. PMID- 23019715 TI - My paternal grandfather had coronary bypass surgery at age 63. My father had it at age 58. They were both active and not overweight. I am concerned I have inherited a big risk of heart disease. I take baby aspirin, flaxseed and fish oil daily with a multivitamin. I eat well and try to exercise. Is there anything else I can do to prevent this from happening to me? PMID- 23019716 TI - I went to the hospital with back and chest pain, and the tests showed I have a 50 60 percent blockage in the three main arteries. Now they want to do a stress test. Do you think I will need stents? PMID- 23019717 TI - My mother was not prescribed cardiac rehab after her heart attack. When is cardiac rehab not recommended? PMID- 23019718 TI - I am a 60-year-old woman with CAD. My LDL is 64 and my HDL is 72 on Zocor, but my doctor thinks Crestor may be better for me. He says it is more potent and could reduce my numbers even more. I would have to pay for this drug out-of pocket. Do you think the additional cost would be worth it? PMID- 23019719 TI - I recently had a physical. My doctor took an EKG and said it looks like I have some damage to my heart. He scheduled me for a stress echo. Is it possible to have heart damage without knowing it? I feel fine, but am maybe a little tired? PMID- 23019720 TI - My legs ache. I originally thought it was due to my statin. My doctor told me to stop taking it. I am watching my diet carefully. One ankle seems swollen. I am 59 years old and about 40 pounds overweight. I can't exercise because I have no cartilage in my knees? PMID- 23019721 TI - My perfectly healthy, athletic brother died at age 38 in his sleep from mitral valve prolapse, which caused sudden cardiac death. My sister and I are worried it could be hereditary. PMID- 23019722 TI - I have mild left ventricular hypertrophy that was discovered on a stress test. Will a repeat test show if my heart has increased in size? PMID- 23019723 TI - Mitral valve regurgitation can often be a hidden condition. The leaky valve is frequently discovered during a routine exam when a doctor picks up a murmur while listening to the heart. PMID- 23019724 TI - Stay active and protect yourself against PAD and CHD. Recent studies show a strong association between physical activity and risks of peripheral artery disease and coronary heart disease. PMID- 23019725 TI - I take three different blood pressure medications-six pills total-every day. They are isosorbide mononitrate, amlodipine, and atenolol. They seem to do a good job bringing down my blood pressure, but before my 6 p.m. atenolol and then later before my 10 p.m. amlodipine, my blood pressure shoots up. I'm worried about carrying an elevated blood pressure for much of the evening. I know ift goes up in the early hours before I wake up, too. What can you tell me about how these fluctuations are affecting my health? My doctor says I shouldn't worry. And is it possible to keep the blood pressure under control 24 hours a day? PMID- 23019726 TI - I have atrial flutter. I read a lot about atrial fibrillation, but how is atrial flutter different? Also, I find myself laboring to breathe at times, with or without physical activity. Could that be related to the flutter? Do the symptoms of atrial flutter tend to get worse? PMID- 23019727 TI - [The protective effects of inhibition of c-Jun N-terminal kinase signal pathway on the intestinal barrier in rats with endotoxemia]. AB - OBJECTIVE: To examine the protective effects of inhibition of c-jun N-terminal kinase (JNK) stress signal pathway on the injured barrier in endotoxemic rats. METHODS: Twenty-four male Sprague Dwaley (SD) rats were randomly divided into control group, endotoxemia model group and JNK inhibitor group (n=8 each) to receive administration of: 1 normal saline 2 ml/kg + PPCES 2.5 ml/kg [vehicle of JNK inhibitor (SP600125), control group]; 2 lipopolysaccharide (LPS) 10 mg/kg + PPCES 2.5 ml/kg (endotoxemia model group); 3 LPS 10 mg/kg + JNK inhibitor (SP600125) 10 mg/kg (JNK inhibitor group). The activity and survival rate of the rats were recorded. Ileum tissue samples were collected 12 hours after drug administration for pathological examination. Blood samples were collected at the same time for determination of concentration of D-lactate by enzyme linked immunosorbent assay (ELISA). RESULTS: Rats in control group were active normally, and there was no death. Pathological examination showed there was edema of ileal mucosa, and shortening of villus and inflammatory cell infiltration in model group as compared with control group. JNK inhibitor greatly ameliorated the lesions compared with model group. The concentration of D-lactate (ug/L) in model group was significantly higher than that in control group. (943.8 +/- 439.6 vs 227.9 +/- 130.0, P<.05). JNK inhibitor could decrease the plasma D-lactate concentration (637.4 +/- 114.4 vs 943.8 +/- 439.6, P<.05). CONCLUSION: Inhibition of the JNK stress signal pathway could attenuate the intestinal barrier injury in endotoxemic rats. PMID- 23019728 TI - [Effect of rhubarb and Glauber's salt cathartic intervention on acute organophosphorus pesticide poisoning]. AB - OBJECTIVE: To investigate the effect of nasal tube feeding of rhubarb solution and umbilical compress of Glauber's salt for purgation in the treatment of patients with severe acute organophosphorus pesticide poisoning (AOPP). METHODS: A retrospective study was conducted. Eighty patients with severe AOPP were divided into two groups according to different treatment, with 40 patients in each group. A thorough gastric lavage was done, followed by cholinesterase complex agent and atropine were given for all the patients. On the base of this treatment, one group of patients were given nasogastric feeding of rhubarb solution (200 ml) and Glauber's salt solution ( 100 g) for umbilical compress (rhubarb plus Glauber group),and another group of patients were fed with 20% mannitol (200 ml)as a control group (mannitol group).The time of first defecation, number of passing stools, the time of normalization of cholinesterase (ChE) activity, time of atropinization, dosage of atropinization, and total amount of atropine given, incidence of adverse reactions, and hospital stay in two groups were observed, a statistical analysis of the data was conducted. RESULTS: In rhubarb plus Glauber group, all the conditions were improved better than those of mannitol group [first defecation time (minutes):134.13 +/- 31.31 vs.154.35 +/- 34.78,the number of stools (times/d):2.60 +/- 0.81 vs.2.14 +/- 0.63,time of ChE activity returned to normal (days):9.65 +/- 1.42 vs.10.66 +/- 1.74,atropinization time ( hours ):3.00 +/- 0.73 vs.3.56 +/- 1.02,dosage of atropinization (mg):51.43 +/- 7.03 vs. 57.65 +/- 7.74,the total amount of atropine given (mg):229.78 +/- 28.96 vs. 248.41 +/- 31.45, the incidence of adverse reactions: abdominal pain 0 vs. 17.5%,abdominal distention 0 vs. 20.0%,hospital stay (days):10.43 +/- 1.68 vs.11.59 +/- 2.121,and all the differences were statistically significant (all P<0.01). CONCLUSION: Combination usage with aqueous rhubarb solution and Glauber's salt in AOPP patients could yield quick clearance of toxin, reduced adverse effects, and lower length of hospital stay. PMID- 23019729 TI - [Clinical study of effect of penehyclidine hydrochloride and atropine sequential therapy in the treatment of severe acute organophosphorus pesticide poisoning]. AB - OBJECTIVE: To investigate the clinical efficacy of penehyclidine hydrochloride sequential to atropine in severe acute organophosphorus pesticide poisoning (AOPP). METHODS: A retrospective analysis of the clinical data of 180 patients with severe AOPP admitted to the Emergency Center of Wuwei City People's Hospital from January 2007 to August 2011 was conducted. The patients were divided into penehyclidine hydrochloride sequential to atropine group, atropine group and penehyclidine hydrochloride group according to difference of anti-choline drugs using, with 60 cases in each group. The complication rate, time of recovery of cholinesterase (ChE) activity to 70%, hospital stay time and cost, the cure rate, mortality rate in three groups were analyzed. RESULTS: In penehyclidine hydrochloride sequential to atropine group, except for 1 case of cancer of gastric cardia with poisoning after operation showing intermediate syndrome of poisoning, the remaining patients did not have any complication, and the incidence of complications was 1.67%.No death occurred in all the patients, and the cure rate was 100.00%.Time of recovery from ChE activity to 70% was (4.0 +/- 1.1 ) days; hospital stay was (7.0 + 2.2) days; hospital expenses were (6268 +/- 238 ) yuan. In atropine group, 3 patients were found to have atropine resistance, 3 patients showed intermediate syndrome, rebound was observed in 2 cases, atropine poisoning in 2 patients, and the incidence of complications was 16.67%.Three patients died of respiratory or circulatory failure, and the mortality rate was 5.00%.Fifty-seven patients were cured, the cure rate was 95.00%.The time of ChE activity recovery to 70% was (8.0 +/- 0.9) days. Hospital stay was (12.0 +/- 2.1) days. Hospital expenses were (7160 +/- 110) yuan. In penehyclidine hydrochloride group, 1 patient was found to have respiratory failure, 1 case suffered from pulmonary edema, and the complication rate was 3.33%.Two patients died, the mortality rate wan 3.33%.Fifty-eight patients were cured, the cure rate was 96.67%.The time of ChE activity recovery to 70% was (6.0 +/- 0.7) days, hospital stay was (9.0 +/- 1.5) days, and hospital expenses were (7921 +/- 230) yuan. Compared with atropine group, penehyclidine hydrochloride sequential to atropine group had a low death rate, high cure rate, less complications, ChE activity recover fast, short hospital days, and the hospitalization expenses were lower than that of the single use of atropine or single use of penehyclidine hydrochloride group, and the differences were statistically significant (all P<0.01). CONCLUSIONS: In treatment of severe AOPP by penehyclidine hydrochloride sequential to atropine, curative effect was more significant, with fewer adverse reactions, short hospital stay, and lower cost. PMID- 23019731 TI - [On "a case of idiopathic intussusception in an adult having undergone ileocecal excision, Shokakibyo Gakkai Zasshi, 108; 1540-1545: 2011" by Wataru Izumo, et al]. PMID- 23019730 TI - Introducing generally physiological. PMID- 23019732 TI - [Q & A. Gall bladder lesion with a high CA19-9 blood level]. PMID- 23019733 TI - Bosch osteotomy. PMID- 23019734 TI - [Protective effects of Xuebijing effervescent tablet on vital organs in rats with toxic injury induced by endotoxin]. PMID- 23019735 TI - [Dexmedetomidine for sedation of post liver transplantation patients]. PMID- 23019736 TI - [Progress in the research of post-operative gastro-intestinal tract dysfunction]. PMID- 23019737 TI - Sonography: the veritable punching bag. PMID- 23019738 TI - Accuracy of medical certification of the cause of death in a rural non-teaching hospital in Delhi. PMID- 23019739 TI - Co-curricular activities in medical education. PMID- 23019740 TI - Is vasovagal syncope really a diagnostic problem? PMID- 23019741 TI - First cousin marriages: genetic concerns versus value judgement. PMID- 23019742 TI - Height velocity in children with nephrotic syndrome. PMID- 23019743 TI - Retraction. Funneled landscape leads to robustness of cellular networks: MAPK signal transduction. Biophys. J. 91:L54-L56, 2006. PMID- 23019744 TI - IL-22 as key factor of thymic regeneration. PMID- 23019745 TI - Graft-versus-host disease is ameliorated by blocking of IL-21 signaling. PMID- 23019746 TI - Utilizing voice recognition as diagnostician. PMID- 23019747 TI - HIEs: beyond controversy. How health information exchanges are connecting the healthcare space. PMID- 23019748 TI - Why your lab needs an HIE. PMID- 23019749 TI - What private organizations should know when building HIEs. Lessons can be learned from public health. PMID- 23019750 TI - What health insurers should know to get an NCQA rating. PMID- 23019751 TI - Clinical integration sets the stage for positive change. Goal is to promote higher-quality, more cost-efficient patient services by better coordinating care across a continuum of conditions, providers, settings and time. PMID- 23019752 TI - Painless compliance. PMID- 23019753 TI - How to use pen and paper to achieve MU with an EHR. PMID- 23019754 TI - How mobile technology helps meet MU. PMID- 23019755 TI - 'EHR within an EHR' accelerates workflows. As it transitioned to an electronic environment, St. Vincent Healthcare's outpatient gastroenterology center had to identify solutions that addressed its unique workflow needs. PMID- 23019756 TI - Achieving operational excellence through best practices. PMID- 23019757 TI - Powerful stuff. When it comes to getting optimal use from carts, Philadelphia's Main Line Health finds it's all about battery lifespan and charge time. PMID- 23019758 TI - Integrate your security measures. From medical records to video surveillance equipment, technology utilized across healthcare institutions is rapidly migrating to a centralized network. PMID- 23019759 TI - [Positive sputum smear results after two consecutive negative smears during treatment of pulmonary tuberculosis]. AB - OBJECTIVES: During treatment of pulmonary tuberculosis, sputum smear may turn positive after 2 consecutive negative results. In the present study, we analyzed the infectivity in such cases. SUBJECTS AND METHODS: The study involved 201 patients with sputum smear positive pulmonary tuberculosis who were admitted to our hospital between January 2004 and June 2009. Chart review was performed on the bacterial culture results and clinical course of patients in whom the sputum smear test turned to positive after 2 consecutive negative smears. RESULTS: There were 37 such cases (42 events). The event occurred after the treatment of 2 weeks or longer and less than 1 month in 6 cases (7 events). The culture examination of the smear-positive sputum was negative in only 1 of these cases. There were 9 cases who turned smear positive after the treatment period of 1 month or longer and less than 2 months, and 6 of these cases showed negative results in the bacterial culture of the smear positive sputum. In these cases, the grade of smear positivity was generally low and subsequent tests yielded negative results. There were 22 cases (26 events) in which this phenomenon was observed after treatment for 2 months or longer. Subsequent bacterial culture yielded negative results in all but 1 of these cases. DISCUSSION AND CONCLUSION: In patients whose sputum smears gave positive results after 2 consecutive negative smear tests, the bacterial load of the sputum decreased or disappeared after treatment for 1 month or longer, and bacterial discharge was almost completely absent after treatment for 2 months or longer. If the clinical condition is favorable in such cases, we may judge that they are no longer infectious. PMID- 23019760 TI - [The association between smoking and sputum smear-positive pulmonary tuberculosis in Osaka City]. AB - PURPOSE: This study aimed to analyze and evaluate the association between tuberculosis (TB) and smoking in order to obtain basic information for the control of smoking. METHODS: Of the 637 patients with sputum smear-positive pulmonary tuberculosis who were newly registered in Osaka City in 2009, 581 patients whose smoking status was identified were selected as study subjects. Data on the following were collected: patient characteristics, presence or absence of underlying conditions, patient's delay and doctor's delay in the diagnosis of TB, presence or absence of cavities, and degree of smear positivity. The patients were divided into the following three groups according to their smoking status: (1) never smokers (those who have never smoked), (2) former smokers (those who had smoked, but quitted), and (3) current smokers (those who smoke currently). RESULTS: (1) PATIENT CHARACTERISTICS: The subjects consisted of 413 males and 168 females, with mean ages of 65.7, 55.4, and 70.2 years for never smokers, current smokers, and former smokers, respectively. (2) Comparison with the national adult smoking rate (National health and nutrition survey 2009, Ministry of Health, Labour and Welfare): The prevalence of current smoking among male patients with sputum smear-positive pulmonary TB in Osaka was 62.4-82.4% among men in their 20s to 60s, and 27.5% among men in their 70s, which is higher than the national average. For female patients, the prevalence of current smoking was 46.2% among women in their 20s and 45.5% among women in their 30s, which is clearly higher than the national average. This was also true for those aged 40 years or older. (3) Severity of TB disease and smoking status: The presence of a cavity was significantly associated with being a male patient, being a current smoker, and longer patient's delay. Sputum smear grades (2+) and (3 +) were significantly correlated with being under 59 years old, being a current smoker, and longer patient's delay. CONCLUSION: The prevalence of current smokers was significantly higher among sputum smear-positive pulmonary TB patients in Osaka than the national average. More smokers had cavitary lesions and a high degree of smear positivity, which may lead to poorer treatment outcomes, and may also expose more surrounding people to infection. PMID- 23019761 TI - Poor sleep challenging the health of a Nation. AB - Sleep is integral to the health and well-being of all people. Sleep disorders are on the rise and affect millions of people in America. Misconceptions about sleep are prevalent, and the negative effects of poor sleep on society are underrepresented. The goal of this study is to investigate and report the effects of poor sleep on society. Information is obtained through a systematic review of current literature, including journal articles, books, and reports. Multiple themes emerged from the literature review relative to poor sleep and societal impacts. These themes include major disasters related to insufficient sleep, performance and productivity, stress, drowsy driving, substance use and abuse, mortality and morbidity, overall health and wellbeing, effects on healthcare systems, and economic costs. Poor sleep decreases human productivity and performance, and increases mortality and morbidity. The National Sleep Foundation estimates that poor sleep costs America billions of dollars each year and greatly compromises public safety and health. Possible solutions to the Nation's sleep problem may begin with promoting education and awareness of sleep disorders and their negative societal impact, research in sleep medicine, as well as public education about healthy sleep. The beginnings of these solutions lie in the hands of healthcare workers and educational institutions. Interventions in the form of questionnaires have been validated as effective in determining a person's risk of sleep apnea. The STOP-BANG questionnaire is one such intervention that may be useful by allied health professionals to assist in patient screening of sleep apnea. PMID- 23019762 TI - The importance of cardiac monitoring in the epilepsy monitoring unit: a case presentation of ictal asystole. AB - Ictal asystole may be a potent marker for epilepsy patients at high risk for sudden unexpected death in epilepsy (SUDEP). The use of inpatient long-term video electroencephalographic (VEEG) monitoring coupled with simultaneous continuous cardiac telemetry is an important tool to detect ictal asystole as well as other significant ictal cardiac arrhythmias. In this paper a case of ictal asystole detected during VEEG is presented. Routine 12-lead EKG was normal upon admission. After antiepileptic medication was tapered, the patient had a typical complex partial seizure with oral automatisms at onset followed by secondary generalization. Ictal onset was noted in left temporal lobe with subsequent spread to the right temporal region. A 20 second period of asystole began just prior to the secondary generalization. During this admission the patient underwent a potentially life-saving pacemaker implantation. The use of cardiac telemetry and baseline EKG are suggested for patients admitted into epilepsy monitoring units as part of the standard epilepsy monitoring protocol. PMID- 23019763 TI - Evolution of Ohtahara syndrome to continuous spikes and waves during slow sleep in an infant. AB - Encephalopathy with electrical status epilepticus in sleep (ESES) is defined as an age-related and self-limited electroclinical syndrome whose etiology is unknown and characterized by continuous spikes and waves during slow sleep (CSWS). Typical CSWS starts at an age of 4 to 5 years and ends by an average of 11 years. We report on an unexpected finding of CSWS in an 18-month-old male whose previous EEG at age 45 days was grossly abnormal with the presence of a burst suppression pattern during wakefulness and sleep. The patient had clinical seizures beginning day 1 of life leading to the suspicion of Ohtahara syndrome (the earliest form of epileptic encephalopathy). Patients with ESES usually have normal EEGs and functional development prior to the onset of CSWS pattern. To our knowledge, this presentation of a neonate with a history of neonatal seizures and developmental delay with an evolution to CSWS has not been described. A sleep record is strongly advised in children with epilepsy (despite the recording of awake EEG abnormalities), especially in patients with behavior or cognitive regression, to rule out the presence of CSWS. PMID- 23019764 TI - Piezoelectric belts as a method for measuring chest and abdominal movement for obstructive sleep apnea diagnosis. AB - Distinguishing obstructive sleep apnea from central apnea depends upon accurate measure of chest and abdominal movement. American Academy of Sleep Medicine (AASM) polysomnography guidelines recommend the use of respiratory inductive plethysmography (RIP) belts but not piezoelectrode (PE) belts for measuring chest and abdominal movements. To compare these two sensors, we measured the signal amplitude for 10 RIP belts and 10 PE belts stretched by mechanical distraction across six distances (2.5 to 15.0 centimeters) and replicated 10 times for each belt. Amplitudes were measured using the Stellate Harmonie (Stellate Systems, Inc., Natus Medical, Inc., San Carlos, California, USA) recording system. A Pearson Product Moment Correlation coefficient was calculated. All RIP belts performed well at all distraction lengths and demonstrated linear performance. Eight of 10 PE belts performed well through all measures whereas, two showed nonlinear increase in signal on stretch of greater than 12.5 centimeters. Signals from PE belts highly correlated with the distance of distraction (r = 0.96 to 0.99) and the RIP belts (r = 0.98 to 0.99). These results suggest that PE belts perform similarly to RIP belts at distraction distances up to 10.0 centimeters. Further testing on biological models is needed to determine if PE belts are a suitable alternative for RIP belts in polysomnography. PMID- 23019765 TI - Cross section of stat (emergent) EEG use. Who orders them? What do we find? What indications best predict finding seizures? AB - Stat electroencephalograms (sEEG) recorded over a one year period were analyzed to determine the rate of seizure or status epilepticus (SE) detection and the best predictors based on: ordering physician, clinical indication for study, and clinical history. All consecutive sEEG reports done over a year period at our institution were retrospectively reviewed. The following data were evaluated: sEEG findings, clinical history, clinical indication for study, requesting physician, location of patient, and demographics. Univariate analysis followed by a multivariate regression model analysis was performed. Of the 3,471 inpatient EEGs performed during the review period, 778 (22.4%) were sEEGs. 3.5% (n = 27) nonconvulsive status epilepticus (NCSE), 0.4% (n = 3) convulsive status epilepticus (CSE), and 1.1% (n = 9) had discrete electrographic seizures giving a total yield of 5.0% (39/778) patients with seizures or SE. A multivariate logistic retrospective model looking at ordering physician, clinical indication, and clinical history found that only clinical indications (overt continuous seizures/movements and witnessed seizure without return to baseline) were significant in the overall model. In our tertiary care institution sample, the rate of detecting status epilepticus or seizures among sEEG is low compared to prior studies. The best clinical predictors of finding SE or discrete seizures were overt continuous seizures/movements or witnessed seizure without return to baseline. PMID- 23019766 TI - Electrophysiological contribution of both sensory branches of the superficial peroneal nerve in the diagnosis of peripheral neuropathy. AB - The aim of this study is to evaluate the simultaneous recording of the medial dorsal cutaneous nerve (MDCN) and the intermediate dorsal cutaneous nerve (IDCN) in the investigation of peripheral neuropathy. We obtained MDCN and IDCN recordings in 35 patients with peripheral neuropathy and in 41 healthy subjects to determine the specificity of the sensory nerve action potential (SNAP) amplitude of each branch separately and of both simultaneously by using the maximal amplitude of either branch. The patients with peripheral neuropathy had low MDCN and IDCN SNAP amplitude in 60% and 14.3% respectively. Though, when recording both MDCN and IDCN simultaneously, the maximum peroneal SNAP amplitude was abnormally low in 68.6%. All the healthy individuals had normal IDCN SNAP amplitude; whereas in 9.7% the MDCN SNAP amplitude was lower than normal. In case of simultaneous recording of both branches the maximum SNAP amplitude was normal in all healthy subjects. Conclusively, the simultaneous amplitude recording of the terminal sensory peroneal branches can better detect abnormal responses in patients with peripheral neuropathy. PMID- 23019767 TI - Initial University of Otago oral health graduates' employment pathways and preparedness for work. AB - OBJECTIVES: To examine University of Otago BOH graduates' post-graduation pathways and employment experiences; and graduate, employer and host therapist perspectives of the new BOH programme and student/ graduate preparedness for work. DESIGN: A survey-based qualitative research project. SETTING: Private and public oral healthcare settings. PARTICIPANTS AND METHODS: Open-ended questionnaires were used to conduct a 2010 survey of 2009 BOH graduates and consenting graduates' employers, and a 2011 survey of dental therapists who had hosted BOH students on clinical placement since 2009. Data were analysed inductively using a thematic content and analysis approach. MAIN OUTCOME MEASURES: 18 (60%) of the 30,2009 BOH graduates completed the online graduate questionnaire with 10 providing employer information. Six employers completed the 'graduate attribute' questionnaire, and 30 (45%) of the 66 eligible host therapists, the 'student attribute' questionnaire. Clear themes emerged from the three participant groups. RESULTS: Of the 18 graduate participants, 10 were working in dental therapy and dental hygiene, with the remaining eight working in only one area. Graduates' primary concern was with maintaining both scopes of practice. Graduates and host therapists stressed a need for students' exposure to complex cases, while employers indicated that graduates' clinical confidence had developed over time. CONCLUSION: Recommendations for improving BOH graduates' transition outcomes included (1) increasing students' exposure to complex clinical and placement experience; (2) improving continuing education opportunities for new graduates; and (3) promoting interaction between BOH and dental students with a view to improving (future) dentists' knowledge of BOH graduate skills and attributes. PMID- 23019768 TI - Self-reported oral health and dental service-use of rangatahi within the rohe of Tainui. AB - OBJECTIVES: To investigate the self-reported oral health and use of oral health services by rangatahi (teenagers) residing within the Waikato rohe (region) of the Waikato-Tainui tribal area. METHODS: A cross-sectional study of self-reported oral health and use of dental services by Maori teenagers. The 14-item short-form Oral Health Impact Profile (OHIP-14) was used to collect data on oral-health related quality of life (OHRQoL). RESULTS: Just over half of the 238 survey participants (who were aged 16 to 18 years old) were male. Most brushed at least once daily. One-quarter reported hiding their smile, and just over one-fifth reported suffering from bad breath. Awareness of their current entitlement to free dental care was high, but it was lower among males. Just over one-third of participants had experienced one or more OHIP-14 impacts; that was higher among females than males, with the largest difference being apparent with the physical disability subscale, where the prevalence of impacts among females was twice that among males. The prevalence of OHIP impacts was higher among those who reported experiencing bad breath often, and significant differences were observed in all seven OHIP domains (as well as in the mean overall OHIP-14 score and in the mean number of different impacts experienced often). CONCLUSIONS: The data provide some important insghts into the oral health perceptions and concerns of young Maori. PMID- 23019769 TI - A review of attention-deficit/hyperactivity disorder from the dental perspective. PMID- 23019770 TI - Intra-oral malignant melanoma--a case report and review of the literature. AB - Malignant melanomas represent one of the most life-threatening forms of cancer. Arising from melanocyte precursors, they have the ability to invade or readily metastasise to any organ. Intra-oral melanomas represent 1-2% of all oral malignancies, and 0.2-8% of all melanomas. Prognoses and eight-year survival rates for intra-oral malignant melanomas are poorer than for cutaneous malignant melanomas (20% and 60% survival, respectively) because of: the absence of symptoms in the early stage of the disease delaying diagnosis; difficulty in determining the width of the radical surgical excision due to anatomic limitations; and the rich blood supply to the region, which may facilitate haematogenic propagation. We report a case of a 65-year-old man with malignant melanoma of the anterior maxillary gingiva. Considering the poor prognosis associated with oral melanomas, it also emphasises the fact that suspicious pigmented lesions should be surgically removed and investigated further. PMID- 23019771 TI - Bilateral radicular cysts of mandibular deciduous teeth: a case report. AB - While common in adult teeth, radicular cysts are uncommon in deciduous teeth. When they do occur, they are associated with non-vital teeth and typically present 6 months to 5 years after vitality is lost. They cause swelling, bone loss and permanent tooth bud displacement. Often, they are incidental findings. A case involving radicular cysts on the left and right sides of the mandible is presented. If non-vital deciduous teeth receive pulp therapy, regular post- operative reviews are recommended. PMID- 23019772 TI - Single-bone fixation of paediatric diaphyseal both-bone forearm fractures: a systematic review. AB - Unstable paediatric diaphyseal both-bone forearm fractures that fail conservative management are usually treated with fixation of both radius and ulna. This systematic review aimed to establish if single-bone fixation achieves results comparable to both-bone fixation and which bone should be fixed and by what method. A systematic review of the published literature was performed, searching Medline for English language studies that reported functional or radiographic outcome following single-bone fixation of either bone by any method. Eight studies met the inclusion criteria (Level of Evidence III or IV). Three studies compared single- with both-bone fixation, showing comparable functional and radiographic outcomes. Redisplacement of the radius fracture is common following fixation of the ulna, particularly with intramedullary K-wires. Flexible nails achieve better results than K-wires in intramedullary stabilisations. Outcome is good following radius fixation with plating or nailing. Plating achieves good results in either bone. Few complications are seen when the second bone was left unfixed only if reduced and stable. Single-bone fixation achieves results comparable to both-bone fixation. Fixing the radius rather than the ulna provides better outcome, regardless of the method. The second bone should only be left unfixed if reduced and stable intra-operatively. PMID- 23019773 TI - Retrograde cement arteriovenogram of nutrient vessels following hemiarthroplasty of the hip. AB - Retrograde cement extrusion into the nutrient vessels of the femur is a rare phenomenon in uncomplicated cemented hemiarthroplasty of the hip; this is a report on three cases. Routine postoperative radiographs showed a continuous dense linear opacity arising from the posterior medial region of the femur. Computed tomography (CT) scans revealed no evidence of a cortical break in the femur and confirmed our suspicion of retrograde cement extrusion into the nutrient vessels of the femur. Post-operative recovery was uneventful with no complications of cement thromboembolism. Our findings in three cases suggest that cement retrograde extrusion into nutrient vessels following hemiarthroplasty is a benign complication of modern cementing techniques involving pressurisation. The site of cement extrusion into the nutrient foramina displays a constant topography. We recommend that a CT scan of the femur be done on detection of a radio-opaque density on postoperative radiographs to differentiate an extraosseous breach from an intra-vascular extrusion of cement. The theoretical complications of cement embolism and thrombosis should be kept in mind and looked for clinically. PMID- 23019774 TI - Trapezius tendon transfer according to Saha after neglected complete axillary nerve injury. AB - Traumatic axillary nerve injury represents less than 1% of all nerve injuries.It is often subclinical because it is masked by the pain due to a shoulder fracture or dislocation, so that treatment is neglected for a long period. When nerve repair and physiotherapy are unsuccessful, trapezius tendon transfer may be considered. Between March 2008 and May 2009, 10 patients with neglected deltoid paralysis were treated by trapezius tendon transfer at Mansoura University hospital and in a private hospital. All patients were males. Their mean age was 27.8 years (range: 17-35). The mean follow-up period was 30 months (range: 24 to 36 months). The operations were performed according to the method described by Saha in 1967, involving transfer of the lateral extremity of the clavicle, the acromioclavicular joint and the acromion, with the insertion of the trapezius, to the proximal humerus. The authors retrospectively assessed the results according to the 5 items (a-e) of the Rowe and Zarins score: all 10 patients had (a) improved shoulder function with (e) a more stable shoulder. The mean active abduction (b) was 76 degrees (range: 50-100 degrees) and the mean active flexion (c) 78 degrees (range: 45-110 degrees). However, most authors report lower values: from 34 to 76 degrees of abduction, and from 30 to 78 degrees of flexion. Arthrodesis results in 59 to 71.43 degrees of abduction. The abduction power (d) was improved: it reached grade 3 in 7 cases and grade 4 in 3 cases. In this study, trapezius tendon transfer provided satisfactory functional improvement for paralysis of shoulder abduction after neglected complete axillary nerve injury, with improvement in shoulder stability, power and range of motion. PMID- 23019775 TI - Mid-term outcome of reverse shoulder prostheses in complex proximal humeral fractures. AB - The functional outcome of hemiarthroplasty in displaced proximal humeral 3- and 4 part fractures or fracture dislocations in elderly patients is frequently unpredictable and depends on the position of the prosthesis and tuberosity fixation. Reverse shoulder arthroplasty represents an alternative in elderly patients. The purpose of this study was to report the results of a retrospective series of 30 reverse shoulder prostheses in trauma indications. We also compared the results of a less medialized reverse shoulder prosthesis (Arrow) with those reported for the traditional (Delta III) reverse prosthesis. Twenty seven cases were available for analysis. The mean follow-up was 22.5 months. The mean absolute Constant score was 54.9, the score for pain was 13.5, for activities 14, for strength 4.59. The mean active anterior elevation was 112 degrees, abduction 97 degrees, external rotation with the arm at the side: 12.7 degrees, in abduction: 55 degrees. Radiographs revealed no loosening, no glenoid notching. Reverse shoulder prosthesis may be a good alternative for displaced three- and four-part proximal humeral fractures in selected patients. The functional results are more predictable than with hemiarthroplasty in elderly patients. PMID- 23019776 TI - Reconstruction of the proximal humerus for bone neoplasm using an anatomic prosthesis-bone graft composite. AB - This study assesses function after limb sparing bone tumour resections of the proximal humerus. Twenty-seven patients had an intraarticular resection with reconstruction using an anatomic prosthesis-bone graft composite with average clinical follow-up of 63 years (range: 13-15.8 years). Pain relief was achieved for 22 shoulders (81%); 19 of 25 patients responding (76%) were satisfied. Active elevation averaged 62 degrees, external rotation 25 degrees, and internal rotation to L-4. Complications included instability in 7, nonunion in 4, implant loosening in 3 of these and tumour recurrence in 1. There were 7 reoperations. Using the Neer rating, 19 primary operations (70%) were successful. The Musculoskeletal Tumor Society Score averaged 18.5 (62%), the American Shoulder and Elbow Surgeons functional score 18.4 (37%) with a total score of 51 (51%), and on the Simple Shoulder Test 5.4 of 12 questions were answered affirmatively. This procedure is oncologically safe. There are structural complications, notably shoulder instability. Function ratings are one-third to one-half normal. PMID- 23019777 TI - Multi slice computed tomography approach in the assessment of supracondylar humeral fractures in children. AB - The purpose of this study was to assess the impact of Multi Slice Computed Tomography (MSCT) on the understanding of the spatial displacement of supracondylar humeral (SCH) fractures, their classification and their management. A prospective study was conducted on 63 children with SCH fractures Gartland II or Lagrange 2 and 3, over a period of 30 months. The patients were 42 boys and 21 girls, aged between 3 and 14. All patients were imaged using conventional radiography. Thirty-two patients underwent MSCT and 3-dimensional reconstructions. According to the Lagrange classification system, 16 patients had type 2 fractures and 47 had type 3 fractures. In type 2, the posterior cortices of both medial and lateral columns were bent on CT (n = 6). In type 3, CT-scan made it possible to distinguish two subgroups. In the first subgroup (n = 12) there was fracture of both anterior and posterior cortices of the lateral column; however, the posterior cortical surface of the medial column was preserved. In the second subgroup (n = 14), there was no cortical surface contact in the medial column, but the continuity of the posterior cortical surface of the lateral column was preserved. Based on a new concept of column stability, the use of CT scan has allowed for a better understanding of supracondylar fractures in children. PMID- 23019778 TI - Linked total elbow arthroplasty as treatment of distal humerus fractures. AB - Treatment of distal humerus fractures may be challenging, especially in the elderly patient. Total elbow replacement has been proposed as an option in selected patients. We present the results of a linked elbow replacement in 16 patients with a comminuted fracture of the distal humerus which was not considered amenable to reliable open reduction and internal fixation. At a mean follow-up of 57 months, average range of motion was from 28 degrees to 117 degrees of flexion-extension. Five patients with moderate to severe pain (31%) were not satisfied with the results of the operation. Three patients had an infection which resulted in implant removal in one patient. Eight patients had symptoms of sensory ulnar nerve neuropathy. Our results show that elbow replacement may be an optimal solution for highly comminuted osteoporotic fractures, if there are no associated complications. However, the rate of significant and minor complications such as infection or postoperative ulnar nerve symptoms is probably higher than reported. Appropriate selection of ideal candidates for this procedure and meticulous surgical technique are of paramount importance in reducing the risk of complications. PMID- 23019779 TI - Treatment of fractures of the proximal phalanx of long fingers with an isometric traction splint. AB - Treatment of fractures of the proximal phalanx of the long fingers remains difficult and challenging ; several options have been used. We report our experience with an isometric traction splint, modified from the Southampton design. A cohort of 32 patients with displaced fractures of a proximal phalanx was treated and assessed retrospectively after a short term (9 weeks after splint application). Traction splint was applied to realign the fracture and to control rotation. This construct was used for approximatively 5 weeks (mean: 36 days; range: 21-44 days), considering the usual progression of fracture healing in closed phalangeal fractures and patient tolerance to the splint. Three weeks after splint removal, almost full range of motion was regained in the metacarpophalangeal and interphalangeal joints in all patients, except in 3 cases. Two of these three patients had a displaced fracture of the proximal phalanx as a result of a compression trauma. The combination of the trauma type with static traction splint led to a tenodesis effect with a severe active flexion deficit in the metacarpophalangeal and interphalangeal joints. Our results suggest that isometric traction splint is a valid treatment option for displaced fractures of the proximal phalanx, however compression type fractures should be excluded. PMID- 23019780 TI - Hunter's technique without Hunter's rod. AB - Silicon rods initially advocated by Hunter have been widely used in two-stage flexor tendon reconstruction. Two-stage tendoplasty is an expensive procedure; with the addition of the high cost of rods, it is still more expensive. An experimental study investigated cheaper alternatives to silicon rods, but no clinical studies seem to have been reported so far. This study involved 17 patients undergoing two stage flexor tendon grafting. In all fingers, silicon urinary catheters were used as tendon prosthesis. The Wehbe et al modification of the Boyes and Stark classification was used for preoperative classification and Strickland formulation and Buck-Gramcko criteria for postoperative analysis. This clinical study showed that comparable clinical results and proper pseudosheaths for tendon grafting with similar histological and physical features can be obtained using a silicon urinary catheter which is fifty times less costly than Hunter's rod. PMID- 23019781 TI - Hip resurfacing requires larger acetabular cups than conventional hip replacement: a comparative analysis of 100 hips, based on radiographic templating. AB - Acetabular bone loss is a matter for concern in hip resurfacing arthroplasty (HRA), as preservation of the femoral head and neck might demand a larger acetabular cup than in total hip arthroplasty (THA). Using radiographic templating, the cup size required for either THA or HRA was calculated on 100 pelvic films. First, the cup size was determined based on the dimensions of the acetabulum. Then, the cup size for HRA was evaluated taking into account the dimensions of the femoral head/neck. The average cup size required for HRA was larger than for THA (delta + 1.1 mm). The cup size for HRA and THA was similar in 49% of hips; in 51% of the hips the cup required for HRA was larger: one size larger in 31%, two sizes larger in 18% and three sizes larger in 2% of the cases. The greatest difference and highest bone loss were observed for the large sizes (between 52 and 56 mm) and thus predominantly in men (delta + 15 mm male, delta + 0.7 mm female). This study shows that HRA requires a larger acetabular cup in more than 50% of the cases compared to THA. When planning HRA surgeons should remember that cup size is determined by the size of the matching femoral component and that size difference with THA increases with increasing hip sizes. PMID- 23019782 TI - Distal femur non-union after interlocked intramedullary nailing. Successful augmentation with wave plate and strut graft. AB - Eleven patients with aseptic non-union of a distal metaphyseo-diaphyseal femoral fracture after intramedullary interlocked nailing were treated by wave plate fixation and an interposed tricortical iliac strut graft with the nail in situ. Complete clinical and radiological union occurred in all cases in a mean period of 7.5 months (range: 7-10). Augmentative wave plate fixation with a tricortical iliac strut graft is a biological and simple solution for non-union of the distal diaphyseo-metaphyseal femoral shaft fracture following an intramedullary locked nail fixation. No special instrumentation is required. In spite of early weight bearing, it led to bony union in a reasonable delay in all the patients reported. PMID- 23019783 TI - Early results with a patient specific interpositional knee device. AB - The iForma ConforMIS Interpositional knee device is a recently developed patient specific implant used for the treatment of mild to moderate uni-compartmental osteoarthritis. The benefits over traditional methods of surgical management are: it is less invasive, can be performed as a day procedure and does not limit future options. Bespoke implants are produced from data extracted from MRIs. Twenty-six patients with the iForma ConforMIS interpositional knee implant from November 2007 were retrospectively reviewed. The average age was 54.7 years, The average pre-operative WOMAC score was 37.8 improving to 67.6 post-operatively. Five patients required revision. No dislocations were reported. Our early experience suggests this device is a viable and safe treatment option. However, patient selection plays an important role in the outcome following surgery and long term results should be awaited. PMID- 23019784 TI - Safety of retransfusing shed blood after local infiltration analgesia in total knee arthroplasty. AB - We investigated the safety of LIA (local infiltration analgesia) combined with retransfusion of drained blood. Total knee arthroplasty patients received two peri-articular injections during surgery followed by continuous infusion, both with ropivacaine (567 mg). Ropivacaine plasma concentrations were determined in blood samples taken at 0, 3, 6 and 24 hours postoperatively. The collected shed blood was not retransfused, instead retransfusion was modelled by estimating the cumulative plasma concentrations at 6 hours postoperative. Total and unbound ropivacaine plasma concentrations ranged respectively from 0.08 to 1.9 mg/L and 0.003 to 0.11 mg/L. An average of 13.1 +/- 3.7 mg unbound ropivacaine would have been returned to the patient. The estimated cumulative ropivacaine plasma levels showed that instant retransfusion would have led to plasma levels below 0.26 mg/L. It appears to be safe to transfuse autologous blood in combination with LIA. However, before drawing definite conclusions formal measurement of actual concentrations is required. PMID- 23019785 TI - Complications of vertebroplasty and kyphoplasty in the treatment of vertebral fractures: results of a questionnaire study. AB - Percutaneous vertebroplasty (VP) and balloon kyphoplasty (BKP) are minimally invasive procedures performed to stabilize vertebral fractures. With continuing expansion in clinical use, a broad spectrum of complications has been reported for both interventions. The goal of the current study was to compare the safety of these procedures using a questionnaire completed by practitioners. A questionnaire was developed with multiple choice and open questions. General data as well as information regarding complications which occurred during the year 2007 were requested. The incidence and odds ratios (OR) of complications for both procedures were analysed. One hundred and sixteen questionnaires detailing 3216 VP and 5139 BKP procedures were included for evaluation. The risk of cement extrusion from the vertebra (OR 2.64, p <0.01) and into the spinal canal (OR 435, p <0.01) was markedly increased for VP. The odds ratio for neurologic complications (OR 2.56, p = 0.1) and secondary fracture (OR = 0.99, p = 0.96) did not indicate significant predisposition for either procedure. Secondary fracture occurred in 5% of VP and 5.1% of BKP procedures. Overall, 80% of practitioners subjectively considered BKP the safer procedure. Overall, BKP appears safer than VP. Symptomatic complications are rare with both procedures. Additional prospective data is necessary to reach more definitive conclusions. PMID- 23019786 TI - Percutaneous iliosacral screw placement using a radiolucent drive. AB - Percutaneous iliosacral screw placement is a standard stabilisation technique for pelvic fractures. It is a demanding operative technique. Various methods of guidance are currently available. We present a quick and simple fluoroscopy guided technique using a radiolucent drive designed for distal locking of intramedullary nails. From January 2008 to December 2009, 27 screws were inserted using this technique in 21 patients with a pelvic fracture. The rate of incorrect placement was 11%. This technique does not require highly specialised equipment and is precise in determining both the entry point and drill track. PMID- 23019787 TI - Preoperative radiofrequency ablation in painful osteolytic long bone metastases. AB - This study aimed to determine whether Radiofrequency Ablation (RFA) followed by prophylactic internal fixation produces better palliation in terms of pain and reduces the need for blood transfusion more than radiotherapy and surgical stabilization (RT-SS). Patients with solitary long bone metastases and a pain score of 5 or more on the VAS scale were selected. Fifteen patients were treated with RFA and surgical stabilization (RFA-SS) and were compared with a matched group (15 subjects) treated by radiotherapy and surgical stabilization (RT-SS). A complete response in terms of pain relief at 12 weeks was documented in 20% (3/15) and 533% (8/15) of the subjects treated by RT-SS or RFA-SS, respectively (p = 0.027). The overall response rate at 12 weeks was 93.3% (14 patients) in the group treated by RFA-SS and 59.9% (9 patients) in the group treated by RT-SS (p = 0.048). Although recurrent pain was documented more frequently after RT-SS (26.6%) than after RFA-SS (6.7%) the difference did not reach statistical significance. The morbidity related to RT-SS did not significantly differ when the treatment was associated with RFA. We observed a reduction in blood transfusion, as 3 patients in the RT-SS group required a blood transfusion, versus none in the RFA-SS group. Our results suggest that RFA-SS is safe and is more effective than RT-SS; furthermore, RFA may become an option for patients with metastases of the long bones to prevent tumour dissemination and reduce intraoperative blood loss. The findings described here should serve as a framework around which to design future clinical trials. PMID- 23019788 TI - Hand dominance in orthopaedic surgeons. AB - Handedness is perhaps the most studied human asymmetry. Laterality is the preference shown for one side and it has been studied in many aspects of medicine. Studies have shown that some orthopaedic procedures had poorer outcomes and identified laterality as a contributing factor. We developed a questionnaire to assess laterality in orthopaedic surgery and compared this to an established scoring system. Sixty-two orthopaedic surgeons surveyed with the validated Waterloo Handedness Questionnaire (WHQ) were compared with the self developed Orthopaedic Handedness Questionnaire (OHQ). Fifty-eight were found to be right hand dominant (RHD) and 4 left hand dominant (LHD). In RHD surgeons, the average WHQ score was 44.9% and OHQ 15%. For LHD surgeons the WHQ score was 30.2% and OHQ 9.4%. This represents a significant amount of time using the non dominant hand but does not necessarily determine satisfactory or successful dexterity transferable to the operating room. Training may be required for the non dominant side. PMID- 23019789 TI - 3D-corrective osteotomy using surgical guides for posttraumatic distal humeral deformity. AB - An original technique was developed to correct distal humerus malunion using a three-dimensional computer-assisted planning and a custom-made surgical guide. The technique was used in three cases (two with cubitus varus and one with cubitus valgus).A CT-scan of the distal humerus was obtained. The correction was simulated by software. A three-dimensional model of the patient's affected humerus was created by rapid prototyping, allowing creation of a surgical guide and premoulding of the osteosynthesis plate. At the time of surgery, the sterilised guide was placed on the surface of the bone to guide the saw blade. Osteosynthesis was performed using the moulded plate. At the latest follow-up, all three patients were asymptomatic and had regained full elbow mobility. Satisfying correction was obtained in all three cases. One complication was encountered: a postoperative infection that healed with plate removal and systemic antibiotic administration. Using an osteotomy guide facilitates three dimensional humeral correction. This technique presents several benefits: it decreases the operating time and minimizes the surgical incision. Fluoroscopy is unnecessary during the procedure and accuracy is increased. Disadvantages are the time for planning and guide confection, the need of a CT-scanner and the increased cost. PMID- 23019790 TI - Reduction of treatment time in external ring fixation using the monofix device. AB - One of the disadvantages of the Ilizarov method is the long treatment time needed for extensive lengthening or complex deformity correction. To minimize the discomfort of the circular frame the authors have introduced a 'frame reduction' technique in which the ring frame is converted towards a unilateral fixator, the 'Monofix'. Both its efficacy and patient satisfaction encouraged the authors to apply this method on a routine basis since 1998 for lower and upper limb corrections. The technique is demonstrated, its indications and potential problems are discussed. PMID- 23019791 TI - Gluteal compartment syndrome following bone marrow biopsy: a case report. AB - Compartment syndrome is a well described limb-threatening and potentially life threatening condition. Compartment syndromes of the upper and lower limbs are well documented in the literature. The gluteal region, however, is often not considered as a compartment despite having three osseofascial boundaries. We report a case of gluteal compartment syndrome which resulted from a bone marrow biopsy. The patient was anticoagulated at the time. The outcome was residual right sided foot drop due to sciatic nerve palsy. This case describes an unusual presentation of a rare condition. Gluteal compartment syndrome is a potential complication of bone marrow biopsy. PMID- 23019792 TI - Failure of the titanium trochanteric gamma nail in ununited metastatic fractures. AB - Metastatic lesions often occur in the trochanteric region of the femur with a risk for pathologic fractures, requiring aggressive surgical treatment. We present two cases of mechanical failure of the Titanium Gamma 3 Nail 180 used for treatment of impending pertrochanteric pathologic fractures. Metallurgic and low power optical examination findings are presented. Treatment with intramedullary nailing devices has proven its efficacy. However in cases of delayed union or non union, a fatigue fracture due to dynamic overload should be expected sooner of later. If there is no evidence of healing within six months postoperatively a hardware exchange or another therapeutic option should be considered. PMID- 23019793 TI - Management of periprosthetic fractures in patients treated with a megaprosthesis for malignant bone tumours around the knee. AB - Early and late infection as well as loosening and mechanical failure are among the postoperative complications most often reported following reconstruction with a tumour prosthesis in patients with a sarcoma around the knee. Scarce instances of periprosthetic fractures have been reported. The literature includes the description of two patients with such a complication, however no treatment recommendation was detailed in those articles. We recorded in our experience two patients with a traumatic fracture following a massive prosthetic bone and joint replacement after major resection for a bone sarcoma. The surgical treatment was open reduction and internal fixation using a cable and plate system, allowing preservation of the prosthesis and providing stable fracture fixation and excellent fracture healing. PMID- 23019794 TI - Pulmonary embolism following an ankle fracture in a 9-year-old boy: a case report. AB - Venous thromboembolism following trauma is an uncommon event in childhood and associated pulmonary embolus after routine lower extremity fracture is exceedingly rare. We present a case report of postoperative pulmonary embolus following an open reduction and internal fixation of a Salter-Harris IV medial malleolus fracture in a 9-year-old boy. Four days after open reduction and percutaneous pin fixation of the ankle fracture, the child began to experience chest pain and shortness of breath. Computed tomographic angiography demonstrated a pulmonary embolus, and he was started on anticoagulation therapy. The child had no medical history, family history, nor known risk factors for venous thromboembolism other than the fracture, and a thrombophilic work-up revealed no coagulopathies or other blood disorders. He was treated with Coumadin for three months. His orthopedic course was uneventful; the fracture healed and he returned to normal function. This appears to be the first case reported in the literature of a significant pulmonary embolus after a routine ankle fracture in a child. While insufficient to warrant deep venous thrombosis prophylaxis in all children, this case report suggests that a venous thromboembolic event can occur even in uncomplicated fractures in children. PMID- 23019795 TI - Do we need CPR/AED programmes or only CPR education for the nursing staff in our hospital? PMID- 23019796 TI - Community associated methicillin-resistant Staphylococcus aureus. AB - Community associated methicillin resistant Staphylococcus aureus (CA-MRSA) is an emergent infectious pathogen that might become an important public-health problem. Indeed, unique strains of S. aureus that combine specific virulence factors with resistance against frequently used antibiotics have been associated with severe community acquired infections in otherwise healthy and often younger people. This is especially the case in the USA, were these strains now represent a major part of staphylococcal infections in the outpatient setting. But, severe infections with CA-MRSA strains have already been reported in Belgium as well. This article summarizes the current knowledge on CA-MRSA as an emergent pathogen and discusses its clinical management. PMID- 23019797 TI - Should we use automated external defibrillators in hospital wards? AB - Automated external defibrillators (AEDs) have shown to improve survival after cardiopulmonary arrest (CPA) in many, but not all clinical settings. A recent study reported that the use of AEDs in-hospital did not improve survival. The current retrospective study reports the results of an in-hospital AED programme in a university hospital, and focuses on the quality of AED use. At Ghent University Hospital 30 AEDs were placed in non-monitored hospital wards and outpatient clinics treating patients with non-cardiac problems. Nurses were trained to use these devices. From November 2006 until March 2011, the AEDs were used in 23 of 39 CPA cases, in only one patient the presenting heart rhythm was ventricular fibrillation and this patient survived. Pulseless electrical activity was present in 14 patients (four survived) and asystole in eight patients (one survived). AEDs were attached to eight patients without CPA, and in 16 patients with CPA AED was not used. The quality of AED use was often suboptimal as illustrated by external artifacts during the first rhythm analysis by the AED in 30% (7/23) and more than 20 seconds delay before restart of chest compressions after the AED rhythm analysis in 50% (9/18). The literature data, supported by our results, indicate that in-hospital AED programmes are unlikely to improve survival after CPA. Moreover, their use is often suboptimal. Therefore, if AEDs are introduced in a hospital, initial training, frequent retraining and close follow-up are essential. PMID- 23019798 TI - A comparison between Moroccan and Belgian type-2 diabetic patients. AB - The aim of this study was to compare diabetes parameters and complications among Moroccan and Belgian type 2 diabetic patients living in Belgium. In two general practices 62 Belgian and 95 Moroccan diabetic patients aged between 40 and 70 were included. The mean fasting plasma glucose (FPG) was 31% higher in the Moroccan group (186 mg/dL) than in the Belgian group (142 mg/dL) (p < 0.001). Compared with 7.6% in the Belgian group, mean HbA1c was also significantly higher in the Moroccan group (8.7%) (p < 0.001). In the Moroccan group 43% showed at least one of the four major diabetic complications compared to 33% in the Belgian group (p = 0.21). Among Moroccan patients retinopathy occurred in 15%, nephropathy in 32%, neuropathy in 21% and foot problems in 18%. PMID- 23019799 TI - Glycemic control and weight changes in patients with type 2 diabetes intensified to three insulin regimens after therapeutic failure to exenatide. AB - The aim of this multicentre and observational study was to evaluate in a real life setting glycated haemoglobin A1(c), (HbA1c) as well as body weight outcomes in patients with type 2 diabetes in whom insulin was initiated after unsatisfactory response to exenatide, combined with maximal dosages of metformin and a sulfonylurea. We included 81 patients. In 56 patients, data were available after 6-8 and in 42 after 9-12 month's follow-up. Age and duration of diabetes were 57 +/- 11 and 11 +/- 6 years, respectively. Body mass index (BMI) was 32.4 +/- 6.9 kg/m2. Insulin was initiated with a basal insulin injection (22%), premixed insulin injections (48%) or a basal prandial scheme (30%). In the 6-8 and 9-12 month's cohorts, HbA(1c) decreased from 9.3 +/- 1.4 to 8.2 +/- 1.2% and from 9.3 +/- 1.3 to 8 +/- 1.1%, respectively (p < 0.0001). However, only 9 and 12% of subjects reached a target HbA(1c) of less than 7.0%, respectively. About half of the patients had HbA(1c) levels equal or higher than 8.0%. Insulin doses were progressively increased during the follow-up period. Insulin treatment was associated with a significant body weight increase (5-7 kg) (p < 0.0001). In conclusion, a high proportion of patients remained above the HbA(1c) targets after 6-12 month's treatment, despite a progressive increase in insulin dosages. Insulin treatment was associated with a marked weight gain. PMID- 23019800 TI - Gestational diabetes: overview of the new consensus screening strategy and diagnostic criteria. AB - Gestational diabetes (GDM) is a frequent medical condition during pregnancy. GDM is associated with an increased risk of complications for both the mother and the baby during pregnancy and birth. Women with GDM also have an increased risk of developing type 2 diabetes later in life. Two large randomised intervention trials demonstrated improvement in perinatal outcomes in the group that received treatment of mild glucose intolerance during pregnancy. However, there is lack of international uniformity in the approach to ascertainment and diagnosis of GDM. The HAPO trial studied for the first time on a very large scale the relationship between glucose tolerance of the mother and the risk for complications for both mother and child. The 'International Association of Diabetes and Pregnancy Study Groups (IADPSG)' subsequently published a new consensus for a screening strategy and diagnosis of GDM which has now been adopted by the American Diabetes Association (ADA). This remains controversial as the American College of Obstetricians and Gynecologists (ACOG) advices to continue with the two-step screening strategy, while other associations have not yet reached a consensus. The discussion now focuses on two issues: an improved detection of pregestational diabetes and an improved detection of GDM. The new screening strategy and the more stringent diagnostic criteria for GDM will probably lead to an important increase in the prevalence of GDM in Belgium and might lead to logistical problems to organise an universal screening with the 2-hour 75 g oral glucose tolerance test (OGTT). We performed an audit on the current two-step screening strategy for GDM in the university hospital Leuven. Diagnosis of GDM seems sub optimal as only two thirds of abnormal glucose challenge tests were appropriately followed by an OGTT. When the new criteria for GDM are used, the prevalence for GDM increases significantly from 3.3% to 5.7%. We feel that more data are necessary on the cost-effectiveness of an universal screening strategy using an OGTT with more stringent diagnostic criteria for GDM, especially in a population with a low background prevalence of GDM. PMID- 23019801 TI - Suppressed increase in blood endothelial progenitor cell content as result of single exhaustive exercise bout in male revascularised coronary artery disease patients. AB - Endothelial progenitor cells (EPCs) significantly affect endothelial repair capacity and, hence, cardiovascular disease incidence. In healthy subjects, blood EPC content increases significantly as result of a single maximal exercise test, hereby stimulating endothelial repair capacity. It remains to be shown whether a single exercise positively affects blood EPCs in revascularised coronary artery disease (CAD) patients. From male revascularised CAD patients (n = 60) and healthy volunteers (n = 25) blood samples were collected before and immediately after a maximal cardiopulmonary exercise test. Blood samples were analyzed by optimised flow cytometry methodology for EPC content (CD34+, CD34+ CD133+, CD34+VEGFR2+, CD34+CD133+VEGFR2+, and CD34+CD133-VEGFR2+ cells) and compared between groups. CFU-Hill colonies were additionally assessed. As a result of a maximal exercise test, blood CD34+, CD34+VEGFR2+ (all EPCs), CD34+CD133+, and CD34+ CD133-VEGFR2+ (mature EPCs) cells increased significantly in CAD patients (p < 0.05), but less than in healthy subjects (p < 0.05, and p = 0.06 for CD34+VEGFR2+). CD34+CD133+VEGFR2+ cells (immature EPCs) did not change as result of exercise (p > 0.05). No changes in CFU-Hill colonies as result of exercise were observed. This study shows that blood mature EPCs (CD34+CD133-VEGFR2+) increase significantly as result of a single exercise bout in revascularised CAD patients, but with smaller magnitude compared to healthy subjects. Blood immature EPCs (CD34+CD133+VEGFR2+) did not change significantly as result of exercise. PMID- 23019803 TI - Fever in HIV-infected patients: less frequent but still complex. AB - Fever was a common symptom in patients with Human Immunodeficiency Virus (HIV) infection in the early phases of the epidemic. Fever of Unknown Origin (FUO) was frequent in HIV-patients and conditions causing FUO were often opportunistic conditions. The HIV-epidemic continues to expand, but access to effective antiretroviral therapy is also expanding, resulting in a growing number of HIV infected patients less likely to be severely immunocompromised and less likely to present opportunistic conditions. Yet part of newly diagnosed patients continue to present with advanced HIV-infection and are still at high risk of opportunistic conditions. This epidemiological evolution strongly influences the spectrum of conditions causing fever and FUO in HIV-patients. While some patients with HIV-associated fever and FUO may still be suffering from opportunistic conditions classically associated with HIV-related FUO, many others will have causes of fever that are similar to the non-HIV-infected population or to classical FUO. Strategies for diagnosis and treatment of fever and its causes in HIV-infected patients need to take into account this evolution. PMID- 23019802 TI - Screening and early diagnosis of prostate cancer: an update. AB - Screening for prostate cancer has become a main controversial topic. First the currently used screening tools, PSA (Prostate Specific Antigen) and DRE (Digital Rectal Examination) have a low accuracy in the prediction of prostate cancer. Second, the benefit of screening in reducing the prostate cancer related mortality was not uniformly shown in older screening studies and there was concern about the risk of overdiagnosis and over-treatment of insignificant prostate cancers. Very recently, 3 major prospective, randomized screening studies have been published. This paper aims to provide an overview how the performance of the current screening tools can be ameliorated and evaluates the recently published screening studies with practical considerations for future screening protocols. PMID- 23019804 TI - External validation of the bacterial meningitis score in children hospitalized with meningitis. AB - The Bacterial Meningitis Score (BMS) is considered as the rule with the highest sensitivity to safely distinguish between aseptic and bacterial meningitis (BM). OBJECTIVE: The objective of our study was to evaluate the performance of the score and its usefulness for the clinician. METHOD: Retrospective analysis of two Belgian academic hospitals-based cohort studies. All consecutive children aged 29 days to 18 years admitted for acute meningitis between January 1996 and December 2008 was eligible. The BMS (risk of bacterial meningitis if seizure, positive cerebrospinal fluid (CSF) Gram staining, CSF protein level (3) 80 mg/dl, CSF neutrophil count 1,000/ mm3 or blood neutrophil count > or = 10,000/mm3) was applied to all patients with meningitis defined by CSF pleocytosis > 8 WBC/mm3. RESULTS: 174 patients were included in the final analysis of whom 26 (15%) had BM. Of the 93 patients categorized as having with no risk for BM (BMS score = 0), 2 patients had BM, one of which had petechial rash (negative predictive value 97.8%). BMS had a sensitivity of 92.3%. Risk of BM was significantly related to the BMS score: 6/147 (4%) patients with BMS < or = 1 had BM compared to 20/27 (74%) patients with BMS > 1. CONCLUSIONS: Our study reports a lower sensitivity of the BMS than observed in previous validation studies. We suggest to include the BMS in a decision tree aiming to optimize the ordering of laboratory investigations including viral and bacterial PCR testing in any child with CSF pleocytosis. PMID- 23019805 TI - Clinical, virological and epidemiological assessment of 2009 influenza A (H1N1) pandemic in a Belgian university hospital. AB - BACKGROUND: Recommendations were applied before and during the Belgian pandemic (2009) H1N1 influenza wave at a university hospital (420 beds), for optimizing isolation processes and therapeutic management of possible and confirmed infected cases. METHODS: All patients presenting to the Emergency Department (ED) between August 1st and December 31st 2009 were screened for ILI symptoms, and were isolated for clinical assessment in case of positive screening. Patients categorized as possible influenza cases and who required hospitalization were isolated in dedicated wards. Specific diagnostic algorithms were implemented. Medical charts were retrospectively reviewed and matched with results of the microbiology laboratory. Patient's characteristics were analyzed, the contribution of laboratory diagnosis on therapy and lengh of stay (LOS) in isolation was also assessed. RESULTS: 310 patients out of 6068 had a positive screening for ILI, of these, 265 were retained as possible influenza cases and 139 required hospitalization. Twenty-eight children (8 requiring hospitalization) and 20 hospitalized adult patients had confirmed influenza infection. Five adult patients were admitted to the intensive care unit (ICU), 3 requiring extracorporeal membrane oxygenation (ECMO). There was no death related to the new influenza strain. The majority of confirmed patients were diagnosed during the Belgian epidemic wave, with a sensitivity of antigen detection of 50% in children and 35% in adults comparatively to real-time PCR (RT-PCR). CONCLUSIONS: The impact of (2009) H1N1 pandemic influenza remained limited, except for ICU patients requiring ECMO. Implementation of screening, isolation, and virological diagnosis processes led to significant improvement of patient management. PMID- 23019806 TI - Brain abscesses with Peptostreptococcus: not unusual after oesophageal dilatation. AB - A case of a brain abscess following oesophageal dilatation for caustic stenosis in a 67-year old woman is reported. Previously reported cases of brain abscess development after oesophageal dilatation are reviewed. Following oesophageal dilatation, bacteraemia and fever are common but the occurrence of metastatic brain abscesses is rare. The clinical presentation is non-specific, with high fever and neurological findings as most reported signs. The isolated organisms belong to the normal oropharyngeal bacterial flora. Prognosis is satisfactory after early diagnosis and correct management. As a result, clinicians dealing with oesophageal strictures should keep in mind that brain abscess formation is a potential complication of oesophageal dilatation. PMID- 23019807 TI - Acute cholecystitis with Listeria monocytogenes. AB - Listeriosis, an opportunistic food-borne disease caused by Listeria monocytogenes, is infrequent and occurs preferentially in patients at the extremes of age, during pregnancy or in immunocompromised hosts. Most common manifestations are maternofoetal and neonatal infections, severe invasive presentations such as bacteraemia with or without central nervous system symptoms occuring preferentially in immunosuppressed patients and self-limited gastro enteritis affecting healthy individuals. Exceptionally, focal infections such as cholecystitis are described. We report here a case of acute cholecystitis caused by Listeria monocytogenes in an 82-year-old woman. Thanks to a successful treatment: cholecystectomy and antimicrobial therapy (amoxicillin plus clavulanic acid), the patient soon recovered. This case-report provides an opportunity to review the current literature concerning the association of Listeria monocytogenes and cholecystitis. PMID- 23019808 TI - Multiple magnet ingestion: a real challenge for the paediatric surgeon. AB - The paediatric population aged 1-3 years represents about 80% of patients presenting with foreign body ingestion. Only 10 to 20% of ingested foreign bodies will fail to pass through the entire gastrointestinal tract. The decision to remove them is based on location, size and nature of the foreign body. In particular, ingestion of multiple magnets or magnets and other metallic objects require a more aggressive management. PMID- 23019809 TI - Late hypersensitivity to omeprazole and other proton pump inhibitors. AB - A 63 year-old woman presented with a persistent, red, papular, itching skin eruption localised on the face, right shoulder and the right upper member. The evolution was longer than ten years with a permanent progressive diffuse facial burning sensation and unaesthetic aspect despite topical antibiotic and anti inflammatory treatments. The clinical and the histological diagnosis corresponded to prurigo. She was treated by omeprazole for gastric reflux since more than ten years, and she had a viral C hepatitis. The relationship between prurigo and omeprazole was evidenced by the complete resolution of symptoms after the drug's interruption and the recurrence after the omeprazole re-introduction. The immediate and late skin tests were negative for the tested drugs. Clinical cross reactivity was observed with pantoprazole and lansoprazole; this suggested a late hypersensitivity to drugs of the proton pump inhibitors class. To our knowledge, it is the first case of prurigo induced by these drugs. PMID- 23019810 TI - Thymoma--an important differential diagnosis of mediastinal tumours. AB - A 69-year-old man with slight dyspnoea underwent routine X-ray examination by his primary care physician. The X-ray and the CT showed a homogenous mass at the right side of the anterior mediastinum. The benignity and the origin of the tissue were still unknown. Therefore, we performed a CT-guided fine needle aspiration biopsy of the mediastinal mass. Histopathological examination finds out a spindle-cell or type A thymoma. Based on these findings we decide for a thoracoscopic resection of the thymoma. After the surgical intervention the patient was completely asymptomatic. In conclusion, because thymomas are prone to ectopic occurrence, they should be considered in the differential diagnosis of mediastinal tumors. PMID- 23019811 TI - Two unusual cases of Graves' hyperthyroidism with unilaterally increased 99mTc uptake. PMID- 23019812 TI - A reanalysis of fine particulate matter air pollution versus life expectancy in the United States. AB - A reduction in population exposure to fine particulate matter air pollution (PM2.5) has been associated with improvements in life expectancy. This article presents a reanalysis of this relationship and comments on the results from a study on the reduction of ambient air PM2.5 concentrations versus life expectancy in metropolitan areas of the United States. The results of the reanalysis show that the statistical significance of the correlation is lost after removing one of the metropolitan areas from the regression analysis, suggesting that the results may not be suitable for a meaningful and reliable inference. IMPLICATIONS: The observed loss of statistical significance in the correlation between the reduction of ambient air PM2.5 concentrations and life expectancy in metropolitan areas of the United States, after removing one of the metropolitan areas from the regression analysis, may raise concern for the policymakers in decisions regarding further reductions in permitted levels of air pollution emissions. PMID- 23019813 TI - Compositions and greenhouse gas emission factors of flared and vented gas in the Western Canadian Sedimentary Basin. AB - A significant obstacle in evaluating mitigation strategies for flaring and venting in the upstream oil and gas industry is the lack of publicly available data on the chemical composition of the gas. This information is required to determine the economic value of the gas, infrastructure and processing requirements, and potential emissions or emissions credits, all of which have significant impact on the economics of such strategies. This paper describes a method for estimating the composition of solution gas being flared and vented at individual facilities, and presents results derived for Alberta, Canada, which sits at the heart of the Western Canadian Sedimentary Basin. Using large amounts of raw data obtained through the Alberta Energy Resources Conservation Board, a relational database was created and specialized queries were developed to link production stream data, raw gas samples, and geography to create production linked gas composition profiles for approximately half of the currently active facilities. These were used to create composition maps for the entire region, to which the remaining facilities with unknown compositions were geographically linked. The derived data were used to compute a range of solution gas composition profiles and greenhouse gas emission factors, providing new insight into flaring and venting in the region and enabling informed analysis of future management and mitigation strategies. IMPLICATIONS: Accurate and transparent determination of environmental impacts of flaring and venting of gas associated with oil production, and potential benefits of mitigation, is severely hampered by the lack of publicly available gas composition data. In jurisdictions within the Western Canadian Sedimentary Basin, frameworks exist for regulating and trading carbon offset credits but current potential for mitigation is limited by a lack of standardized methods for calculating CO2 equivalent emissions. The composition and emission factor data derived in this paper will be useful to industry, regulators, policy researchers, and entrepreneurs seeking statistically significant and openly available data necessary to manage and mitigate upstream flaring and venting activity and estimate greenhouse gas impacts. PMID- 23019814 TI - Temporal and spatial variations of polycyclic aromatic hydrocarbon concentrations around a coke oven plant. AB - From 1995 to 2004, in Genoa, Italy, daily concentrations of twelve polycyclic aromatic hydrocarbons (PAHs) were measured in particulate phase (PM10), around a coke oven plant in operation from the 1950s and closed in 2002. The study permitted to identify the coke oven as the main PAH source in Genoa, causing constant exceeding of benzo(a)pyrene (BaP) air quality target (1.0 ng/m3) in the urban area till 1,900 meters distance downwind the plant. For this reason the plant was closed. Distance and daily hours downwind the coke plant were the main sources of variability of toxic BaP equivalent (BaPeq) concentrations and equations that best fitted these variables were experimentally obtained. During full plant activity, annual average BaPeq concentrations, measured in the three sampling sites aligned downwind to the summer prevalent winds, were: 85 ng/m3 at 40 m (site 2, industrial area), 13.2 ng/m3 at 300 m (site 3, residential area) and 5.6 ng/m3 at 575 m (site 4, residential area). Soon after the coke oven's closure (February 2002) BaPeq concentrations (annual average) measured in residential area, decreased drastically: 0.2 ng/m3 at site 3, 0.4 ng/m3 at site 4. Comparing 1998 and 2003 data, BaPeq concentrations decreased 97.6% in site 3 and 92.8% in site 4. Samples collected at site 3, during the longest downwind conditions, provided a reliable PAH profile of fugitive coke oven emissions. This profile was significantly different from the PAH profile, contemporary found at site 5, near the traffic flow. This study demonstrates that risk assessment based only on distance of residences from a coke plant can be heavily inaccurate and confirmed that seasonal variability of BaPeq concentrations and high variability of fugitive emissions of PAHs during coke oven activities require at least one year of frequent and constant monitoring (10-15 samples each month). IMPLICATIONS: Around a coking plant, polycyclic aromatic hydrocarbons (PAHs), concentrations depend mainly on downwind hours and distance. Equations that best fit these variables were experimentally calculated. Fugitive emissions of an old coke oven did not comply with the threshold BAP air concentration proposed by the World Health Organization (WHO), up to 1,900 m distance. The study identified the PAH profile of fugitive emissions of a coke oven, statistically different from the profile of traffic emissions. During its activity, in the Genoa residential area, 575 m away from the plant, 92.8% of found PAHs was due to coke oven emission only. PMID- 23019815 TI - Experimental study on removals of SO2 and NO(x) using adsorption of activated carbon/microwave desorption. AB - Experimental studies on desulfurization and denitrification were carried out using activated carbon irradiated by microwave. The influences of the concentrations of nitric oxide (NO) and sulfur dioxide (SO2), the flue gas coexisting compositions, on adsorption properties of activated carbon and efficiencies of desulfurization and denitrification were investigated. The results show that adsorption capacity and removal efficiency of NO decrease with the increasing of SO2 concentrations in flue gas; adsorption capacity of NO increases slightly first and drops to 12.79 mg/g, and desulfurization efficiency descends with the increasing SO2 concentrations. Adsorption capacity of SO2 declines with the increasing of O2 content in flue gas, but adsorption capacity of NO increases, and removal efficiencies of NO and SO2 could be larger than 99%. Adsorption capacity of NO declines with the increase of moisture in the flue gas, but adsorption capacity of SO2 increases and removal efficiencies of NO and SO2 would be relatively stable. Adsorption capacities of both NO and SO2 decrease with the increasing of CO2 content; efficiencies of desulfurization and denitrification augment at the beginning stage, then start to fall when CO2 content exceeds 12.4%. The mechanisms of this process are also discussed. IMPLICATIONS: The prominent SO2 and NOx treatment techniques in power plants are wet flue gas desulfurization (FGD) and the catalytic decomposition method like selective catalytic reduction (SCR) or nonselective catalytic reduction (NSCR). However, these processes would have some difficulties in commercial application due to their high investment, requirement of expensive catalysts and large-scale equipment, and so on. A simple SO2 and NOx reduction utilizing decomposition by microwave energy method can be used. The pollutants control of flue gas in the power plants by the method of microwave-induced decomposition using adsorption of activated carbon/microwave desorption can meet the requirements of environmental protection, which will be stricter in the future. PMID- 23019816 TI - Prediction of daily fine particulate matter concentrations using aerosol optical depth retrievals from the Geostationary Operational Environmental Satellite (GOES). AB - Although ground-level PM2.5 (particulate matter with aerodynamic diameter < 2.5 microm) monitoring sites provide accurate measurements, their spatial coverage within a given region is limited and thus often insufficient for exposure and epidemiological studies. Satellite data expand spatial coverage, enhancing our ability to estimate location- and/or subject-specific exposures to PM2.5. In this study, the authors apply a mixed-effects model approach to aerosol optical depth (AOD) retrievals from the Geostationary Operational Environmental Satellite (GOES) to predict PM2.5 concentrations within the New England area of the United States. With this approach, it is possible to control for the inherent day-to-day variability in the AOD-PM2.5 relationship, which depends on time-varying parameters such as particle optical properties, vertical and diurnal concentration profiles, and ground surface reflectance. The model-predicted PM2.5 mass concentration are highly correlated with the actual observations, R2 = 0.92. Therefore, adjustment for the daily variability in AOD-PM2.5 relationship allows obtaining spatially resolved PM2.5 concentration data that can be of great value to future exposure assessment and epidemiological studies. IMPLICATIONS: The authors demonstrated how AOD can be used reliably to predict daily PM2.5 mass concentrations, providing determination of their spatial and temporal variability. Promising results are found by adjusting for daily variability in the AOD-PM2.5 relationship, without the need to account for a wide variety of individual additional parameters. This approach is of a great potential to investigate the associations between subject-specific exposures to PM2.5 and their health effects. Higher 4 x 4-km resolution GOES AOD retrievals comparing with the conventional MODerate resolution Imaging Spectroradiometer (MODIS) 10-km product has the potential to capture PM2.5 variability within the urban domain. PMID- 23019817 TI - Application of ultraviolet light-emitting diode photocatalysis to remove volatile organic compounds from indoor air. AB - Photocatalytic oxidation (PCO) is a promising technology for indoor air purification due to low operating cost, potentially long service life, and low maintenance. Ultraviolet light-emitting diode (UVLED) is a new concept in the field of PCO, which has several advantages over conventional UV light sources. Limited research has been conducted using UVLED PCO for air treatment. This study demonstrated the potential application of UVLED for the removal of volatile organic compounds (VOCs; toluene and xylene) from indoor air under different operating conditions including flow rate (25-117 cubic feet per minute [cfm]), types of catalysts (Degussa P25, sol-gel TiO2, nitrogen-doped TiO2, clay TiO2, and Bi2O3), LED intensity, and humidity in a continuous reactor. About 7-32% VOC removal occurred depending on the experimental conditions. The results show that UVLED can activate different types of photocatalysts effectively. IMPLICATIONS: This study demonstrates the effectiveness of UVLED in photocatalytic oxidation applied for indoor air cleaning. Several TiO2 catalysts (Degussa P25, sol-gel TiO2, nitrogen-doped TiO2, clay TiO2, and Bi2O3) were used in the reactor to characterize the removal performance of indoor air pollutants, for example, VOCs. This is one of the very few studies that have, to date, examined toluene and xylene removal from indoor air using these catalysts with UVLED in a continuous reactor. The intent is to develop an energy-efficient continuous reaction system to remove VOCs from indoor air. The performance of the system was characterized with respect to air flow rate, humidity, types of catalysts, and light intensity. PMID- 23019818 TI - Effect of biogas generation on radon emissions from landfills receiving radium bearing waste from shale gas development. AB - Dramatic increases in the development of oil and natural gas from shale formations will result in large quantities of drill cuttings, flowback water, and produced water. These organic-rich shale gas formations often contain elevated concentrations of naturally occurring radioactive materials (NORM), such as uranium, thorium, and radium. Production of oil and gas from these formations will also lead to the development of technologically enhanced NORM (TENORM) in production equipment. Disposal of these potentially radium-bearing materials in municipal solid waste (MSW) landfills could release radon to the atmosphere. Risk analyses of disposal of radium-bearing TENORM in MSW landfills sponsored by the Department of Energy did not consider the effect of landfill gas (LFG) generation or LFG control systems on radon emissions. Simulation of radon emissions from landfills with LFG generation indicates that LFG generation can significantly increase radon emissions relative to emissions without LFG generation, where the radon emissions are largely controlled by vapor-phase diffusion. Although the operation of LFG control systems at landfills with radon source materials can result in point-source atmospheric radon plumes, the LFG control systems tend to reduce overall radon emissions by reducing advective gas flow through the landfill surface, and increasing the radon residence time in the subsurface, thus allowing more time for radon to decay. In some of the disposal scenarios considered, the radon flux from the landfill and off-site atmospheric activities exceed levels that would be allowed for radon emissions from uranium mill tailings. IMPLICATIONS: Increased development of hydrocarbons from organic-rich shale formations has raised public concern that wastes from these activities containing naturally occurring radioactive materials, particularly radium, may be disposed in municipal solid waste landfills and endanger public health by releasing radon to the atmosphere. This paper analyses the processes by which radon may be emitted from a landfill to the atmosphere. The analyses indicate that landfill gas generation can significantly increase radon emissions, but that the actual level of radon emissions depend on the place of the waste, construction of the landfill cover, and nature of the landfill gas control system. PMID- 23019819 TI - A 2009 Mobile Source Carbon Dioxide Emissions Inventory for the University of Central Florida. AB - A mobile source carbon dioxide (CO2) emissions inventory for the University of Central Florida (UCF) has been completed. Fora large urban university, more than 50% of the CO2 emissions can come from mobile sources, and the vast majority of mobile source emissions come from on-road sources: personal vehicles and campus shuttles carrying students, faculty, staff and administrators to and from the university as well as on university business trips. In addition to emissions from on-road vehicles, emissions from airplane-based business travel are significant, along with emissions from nonroad equipment such as lawnmowers, leaf blowers, and small maintenance vehicles utilized on campus. UCF has recently become one of the largest universities in the nation (with over 58,000 students enrolled in the fall 2011 semester) and emits a substantial amount of CO2 in the Central Florida area. For this inventory, students, faculty, staff and administrators were first surveyed to determine their commuting distances and frequencies. Information was also gathered on vehicle type and age distribution of the personal vehicles of students, faculty, administrators, and staff as well as their bus, car-pool, and alternate transportation usage. The latest US. Environmental Protection Agency (EPA)-approved mobile source emissions model, Motor Vehicle Emissions Simulator (MOVES2010a), was used to calculate the emissions from on-road vehicles, and UCF fleet gasoline consumption records were used to calculate the emissions from nonroad equipment and from on-campus UCF fleet vehicles. The results of this UCF mobile source emissions inventory were compared with those for another large U.S. university. IMPLICATIONS: With the growing awareness of global climate change, a number of colleges/universities and other organizations are completing greenhouse gas emission inventories. Assumptions often are made in order to calculate mobile source emissions, but without field data or valid reasoning, the accuracy of those assumptions may be questioned. This paper presents a method that involves a survey, the use of the MOVES model, and emission factors to produce a mobile source emissions inventory. The results show that UCF mobile source CO2 emissions are larger than most other universities, and make up about 2% of all the mobile source emissions in Orange County, Florida. PMID- 23019820 TI - Evaluating the effects of climate change on summertime ozone using a relative response factor approach for policymakers. AB - The impact of climate change on surface-level ozone is examined through a multiscale modeling effort that linked global and regional climate models to drive air quality model simulations. Results are quantified in terms of the relative response factor (RRF(E)), which estimates the relative change in peak ozone concentration for a given change in pollutant emissions (the subscript E is added to RRF to remind the reader that the RRF is due to emission changes only). A matrix of model simulations was conducted to examine the individual and combined effects offuture anthropogenic emissions, biogenic emissions, and climate on the RRF(E). For each member in the matrix of simulations the warmest and coolest summers were modeled for the present-day (1995-2004) and future (2045 2054) decades. A climate adjustment factor (CAF(C) or CAF(CB) when biogenic emissions are allowed to change with the future climate) was defined as the ratio of the average daily maximum 8-hr ozone simulated under a future climate to that simulated under the present-day climate, and a climate-adjusted RRF(EC) was calculated (RRF(EC) = RRF(E) x CAF(C)). In general, RRF(EC) > RRF(E), which suggests additional emission controls will be required to achieve the same reduction in ozone that would have been achieved in the absence of climate change. Changes in biogenic emissions generally have a smaller impact on the RRF(E) than does future climate change itself The direction of the biogenic effect appears closely linked to organic-nitrate chemistry and whether ozone formation is limited by volatile organic compounds (VOC) or oxides of nitrogen (NO(x) = NO + NO2). Regions that are generally NO(x) limited show a decrease in ozone and RRF(EC), while VOC-limited regions show an increase in ozone and RRF(EC). Comparing results to a previous study using different climate assumptions and models showed large variability in the CAF(CB). IMPLICATIONS: We present a methodology for adjusting the RRF to account for the influence of climate change on ozone. The findings of this work suggest that in some geographic regions, climate change has the potential to negate decreases in surface ozone concentrations that would otherwise be achieved through ozone mitigation strategies. In regions of high biogenic VOC emissions relative to anthropogenic NO(x) emissions, the impact of climate change is somewhat reduced, while the opposite is true in regions of high anthropogenic NO(x) emissions relative to biogenic VOC emissions. Further, different future climate realizations are shown to impact ozone in different ways. PMID- 23019821 TI - Emissions of p-dichlorobenzene and naphthalene from consumer products. AB - p-Dichlorobenzene (p-DCB) and naphthalene are classified as hazardous air pollutants and rank highly among chronic chemical hazards in US. residences. Sources of p-DCB and naphthalene include moth repellents and deodorizers typically used in closets, garment bags, and toilet bowls. Nearly pure concentrations of p-DCB and naphthalene are found in these products. p-DCB and naphthalene mass emission rates were determined for four different products placed in well-ventilated laboratory chambers as well as closets in a test house and in a garment bag. Concentrations were measured in bedrooms adjacent to closets where products were used. Emission rates varied considerably between products that contain p-DCB, primarily due to product packaging, and were generally suppressed when the product was used in closed closet or garments bags relative to products placed in well-ventilated chambers. This reduction appears to be due to lower air speeds in closets and garment bags as opposed to chemical accumulation. Variations in air temperature within typical ranges observed in homes can significantly influence emission rates of p-DCB and naphthalene. Concentrations of p-DCB and naphthalene in bedrooms adjacent to closets where moth repellents are used can exceed or approach odor thresholds. For this study, the concentrations exceeded or were within the upper few percentiles of those previously reported in residential indoor air. Based on a comparison of whole house emission rates derived in a previous study, it appears that somewhere between 2% and 12% of homes in that study had active sources of p-DCB and between 5% and 15% had active sources of naphthalene. IMPLICATIONS: Inhalation of p-DCB and naphthalene has been linked to several health effects. Several off-the-shelf consumer products are nearly pure p-DCB or naphthalene, thus leading to potential for high emission rates and gas-phase concentrations in indoor environments where such products are used. Knowledge of p-DCB and naphthalene emission rates and variability in emissions with environmental conditions should provide for improvements in predictions of indoor concentrations of these compounds, which are in turn needed to complete exposure and inhalation risk assessments. PMID- 23019822 TI - Effect of the Mn oxidation state and lattice oxygen in Mn-based TiO2 catalysts on the low-temperature selective catalytic reduction of NO by NH3. AB - TiO2-supported manganese oxide catalysts formed using different calcination temperatures were prepared by using the wet-impregnation method and were investigated for their activity in the low-temperature selective catalytic reduction (SCR) of NO by NH3 with respect to the Mn valence and lattice oxygen behavior. The surface and bulk properties of these catalysts were examined using Brunauer-Emmett-Teller (BET) surface area, X-ray diffraction (XRD), temperature programmed reduction (TPR), and temperature-programmed desorption (TPD). Catalysts prepared using lower calcination temperatures, which contained Mn4+ displayed high SCR activity at low temperatures and possessed several acid sites and active oxygen. The TPD analysis determined that the Bronsted and Lewis acid sites in the Mn/TiO2 catalysts were important for the low-temperature SCR at 80 160 and 200-350 degrees C, respectively. In addition, the available lattice oxygen was important for attaining high NO to NO2 oxidation at low temperatures. IMPLICATIONS: Recently, various Mn catalysts have been evaluated as SCR catalysts. However, there have been no studies on the relationship of adsorption and desorption properties and behavior of lattice oxygen according to the valence state for manganese oxides (MnO(x)). Therefore, in this study, the catalysts were prepared by the wet-impregnation method at different calcination temperatures in order to show the difference of manganese oxidation state. These catalysts were then characterized using various physicochemical techniques, including BET, XRD, TPR, and TPD, to understand the structure, oxidation state, redox properties, and adsorption and desorption properties of the Mn/TiO2 catalysts. PMID- 23019823 TI - Demonstration of fuel switching on oceangoing vessels in the Gulf of Mexico. AB - Switching fuels from high-sulfur heavy fuel oils (HFO) to lower sulfur marine gas oils (MGO) on an oceangoing vessel (OGV) can substantially reduce both PM and SO(x) ship stack emissions, potentially resulting in significant human health and environmental benefits in Gulf of Mexico port communities. The International Maritime Organization (IMO) established an emission control area (ECA) within 200 nautical miles of the US. and Canadian coastlines and French territories off the coast of Canada with lower fuel sulfur standards effective beginning August 2012, where OGVs will need to switch from HFO to MGO. However some operators and other stakeholders, particularly in the Gulf of Mexico, may be unfamiliar with the benefits and requirements and ship operators may be concerned over potential implications for cost and operations. This first-ever US. Environmental Protection Agency (EPA)-sponsored fuel switching demonstration in the Gulf of Mexico was initiated to showcase the environmental and health benefits of as well as operational issues associated with, fuel switching through the following activities: (1) Fuel switching was conducted on typical container ships operating the Gulf of Mexico, as routine fuel switching has been demonstrated in California in recent years. Two vessels were employed in the demonstration: the Maersk Roubaix, which switched fuels entering Port of Houston, TX, and the Port of Progreso, Mexico, and the Hamburg Sud vessel Cap San Lorenzo, which switched fuels entering the Port of Houston and the Mexican Ports of Veracruz and Altamira. Operational and cost aspects were also noted. (2) Emissions reductions were quantified through both a calculation approach based on fuel use of the Maersk Line vessel Roubaix and in-stack monitoring of emissions from the Hamburg Sud Cap San Lorenzo. Pollutant emissions including PM, SO(x), NO(x), and PM component speciation were sampled during use of both fuels. These observations showed reductions (1-6%) in NO(x) and substantial reductions in PM (50-70%) and SO(x) (> 99%) depending on engine and load. (3) Emission inventories at three ports were calculated. (4) Potential health and environmental benefits to communities and ecosystems in the Gulf of Mexico were estimated through screening level modeling of air dispersion and atmospheric deposition of ship emissions at the Port of Veracruz to indicate the substantial reductions available through fuel switching. IMPLICATIONS: The United States and Canada have recently adopted a North American Emission Control Area that will require a shift from high-sulfur to low-sulfur fuels in the marine transportation sector. Cleaner fuels are expected to reduce sulfur and particulate emissions. This paper verifies the feasibility of such switching operations, the potential to reduce emissions if extended to the Gulf of Mexico, and the associated environmental impacts of these emission reductions inland and to sensitive ecosystems. PMID- 23019824 TI - Sensitivity and linearity analysis of ozone in East Asia: the effects of domestic emission and intercontinental transport. AB - In this study, ozone (O3) sensitivity and linearity over East Asia (EA) and seven urban areas are examined with an integrated air quality modeling system under two categories of scenarios: (1) The effects of domestic emission are estimated under local emission reduction scenarios, as anthropogenic NO(x) and volatile organic compounds (VOC) emissions are reduced by 20%, 50%, and 100%, respectively and independently; and (2) the influence of intercontinental transport is evaluated under Task Force on Hemispheric Transport of Air Pollution (TF HTAP) emission reduction scenarios, as anthropogenic NO(x) emission is reduced by 20% in Europe (EU), North America (NA), and South Asia (SA), respectively. Simulations are conducted for January and July 2001 to examine seasonal variation. Through the domestic O3 sensitivity investigation, we find O3 sensitivity varies dynamically depending on both time and location: North EA is VOC limited in January and NO(x) limited in July, except for the urban areas Beijing, Shanghai, Tokyo, and Seoul, which are VOC limited in both months; south EA is NO(x) limited in both January and July, except for the urban areas Taipei, which is VOC-limited in both months, and Pearl River Delta, which is VOC limited in January. Surface O3 change is found to be affected more by NO(x) than by VOC over EA in both January and July. We also find different O3 linearity characteristics among urban areas in EA: O3 at Beijing, Tokyo, and Seoul shows a strong negative linear response to NO(x) emission in January; O3 at Shanghai, Pearl River Delta, and Taipei shows a strong positive response to VOC emission in both January and July. Through the long range transport investigation, monthly O3 changes over EA resulting from different source regions indicate the largest source contribution comes from NA (0.23 ppb), followed by SA (0.11 ppb) and EU (0.10 ppb). All of the three regions show higher impacts in January than in July. IMPLICATIONS: This study examine O3 sensitivities and linear response of NO(x) and VOC emission over EA and seven urban areas based on regional air quality modeling system MM5/CMAQ. We also quantify the intercontinental transport effect from EU, SA, and NA over EA. The result provide a theoretical basis for emission control strategy design in EA, and also reveal the O3 special nonlinearity features for further related studies that are applicable to other continents. The HTAP multimodel experiments need to examine the potential impacts on ground-level O3 of changes in meteorology and transport patterns expected as a result of the regional scale. PMID- 23019825 TI - "Ketamine vs midazolam for sedation in oral procedures" is only part of the story. PMID- 23019826 TI - Multifunctional Ribbond--a versatile tool. AB - Pediatric dentists come across a variety of cases in their day to day practice that requires quick intervention in order to enhance or restore children's smile and functions in the oral cavity. Ribbond is one such material, which has occupied an important place in the dentist's repertoire. Ribbond can be used as an alternative to conventional treatment in pediatric dentistry. This case report demonstrates usage of Ribbond as a space maintainer a fixed partial denture with an acrylic tooth pontic, an endodontic post and a splint material in children. Ribbond combines high-strength fibers with enhanced bondability and patented crosslink lock-stitch leno weave. Ribbond's strength, esthetics, and bondability make it useful for multiple applications in clinical pediatric dentistry. PMID- 23019827 TI - The autotransplantation and orthodontic treatment of multiple congenitally missing and impacted teeth. AB - Congenitally missing teeth are one of the most common dental anomalies. When permanent teeth are absent, various problems can occur It is important to consider the facial profile, position of the incisor teeth, skeletal and dental development, and available dental space before planning treatment. Possible treatment methods include preserving and retaining the deciduous tooth, replacing the missing tooth with prosthesis, placing an implant, or performing a transplant after extracting the deciduous tooth. Among these possibilities, autotransplantation combined with orthodontic treatment corrects both function and esthetics. This report describes the case of a 7-year-old girl with multiple congenitally missing teeth and an impacted right mandibular second premolar. Timely autotransplantation of the impacted mandibular tooth to the region of the congenitally missing right maxillary second premolar produced favorable results. PMID- 23019828 TI - Nigella sativa oil as a pulp medicament for pulpotomized teeth: a histopathological evaluation. AB - PURPOSE: Concerns about the safety of formocresol (FC) as a pulpotomy agent in Pediatric Dentistry have lead to the search of new capping medicaments. Indigenous plant medicines such as Nigella Sativa (NS) have been the focus of many researches. Therefore the purpose of this study was to investigate histo pathologically the pulp response to NS oil and FC in dogs. METHOD: Forty teeth in 4 male dogs of undefined breed aging 12-14 months were used in this study. Coronal access cavities were performed on the upper and lower premolars so that both medicaments were tested in the same animal in alternate sides of the mouth. Four weeks after treatment the animals were sacrificed, paraffin sections were prepared for histological, histochemical and immuno-histochemical staining. RESULTS: Specimens in the NS group showed mild to moderate vasodilatation. Few specimens showed scattered inflammatory cell infiltration and the odontoblastic layer was continuous. While the FC group showed moderate to severe vasodilatation with high inflammatory cell infiltrate and degenerative changes. CONCLUSIONS: NS possesses an anti-inflammatory effect and the pulp maintains its vitality after its application, which could qualify its use as a pulp medicament for pulpotomized teeth in clinical practice. PMID- 23019829 TI - Caries-preventive effect of fissure sealant containing surface reaction-type pre reacted glass ionomer filler and bonded by self-etching primer. AB - OBJECTIVE: We aimed to evaluate the caries-preventive effect of a fissure sealant containing surface reaction-type pre-reacted glass ionomer (S-PRG) filler and bonded by self-etching primer versus those of 2 conventional resin-based sealants bonded by acid etching in terms of its impact on enamel demineralization and remineralization, enamel bond strength, and integrity of debonded enamel surfaces. MATERIALS AND METHOD: Demineralization, remineralization, and bond strength on untreated enamel and enamel subsurface lesions of bovine incisors were assessed among the sealants by polarizing microscopy and microradiography; debonded enamel surfaces were examined by scanning electron microscopy. RESULTS: The conventional resin-based sealants bonded by acid etching caused surface defects on the enamel subsurface lesions and significantly increased the lesion depth (p = 0.014), indicative of enamel demineralization. However the S-PRG filler-containing sealant bonded by self-etching primer maintained the enamel surface integrity and inhibited enamel demineralization. No difference in bond strength on both untreated enamel and enamel subsurface lesions was noted among the sealants. CONCLUSIONS: An S-PRG filler-containing fissure sealant bonded by self-etching primer can prevent enamel demineralization, microleakage, and gaps without the tags created by acid etching regardless of the enamel condition. Such sealants are suitable for protecting the pits and fissures of immature permanent teeth. PMID- 23019830 TI - Anxiety in children during occlusal ART restorations in primary molars placed in school environment and hospital dental setup. AB - OBJECTIVE: To evaluate the anxiety in children during occlusal atraumatic restorative treatment (ART) in the primary molars of children; and compare the anxiety for ART procedure performed in school environment and in hospital dental setup. STUDY DESIGN: A randomized controlled trial where one dentist placed 120 ART restorations in 60 five- to seven year-olds who had bilateral matched pairs of occlusal carious primary molars. A split-mouth design was used to place restorations in school and in hospital dental setup, which were assigned randomly to contralateral sides. Anxiety was evaluated by Modified Venhem score and the heart rate of the children at five fixed moments during dental treatment. RESULTS: At the entrance of the children into the treatment room, statistically significant difference between treatment in school environment and treatment in hospital dental setup for venham score and heart rate could be found (P = 0.023 and P = 0.037 respectively). At the start of the treatment procedure higher venham score and heart rate was observed in children treated in hospital dental setup in comparison with the children treated in school environment, finding was statistically significant (P = 0.011 and P = 0.029 respectively). During all other three points of treatment, the Venham scores of the children treated in school were lower than those of the children treated in hospital dental setup but statistically not significant (P > 0.05). Positive co-relation between Venham scores and Heart rate was established. No statistically significant relation could be established between boys and girls. CONCLUSIONS: Overall anxiety in children for ART treatment was found to be less and the procedure was well accepted irrespective of environment where treatment was performed Hospital dental setup by itself made children anxious during entrance and starting of the treatment when compared to children treated in school environment. PMID- 23019831 TI - Incipient enamel lesions remineralization using casein phosphopeptide amorphous calcium phosphate cream with and without fluoride: a laser fluorescence study. AB - The aim of this in vitro investigation was to evaluate and compare the incipient enamel lesions remineralized by topical application of casein phospho peptide amorphous calcium phosphate (CPP-ACP) cream with and without fluoride. METHOD: Sixty caries free teeth were used in the study. They were divided into four groups as positive control negative control and two experimental groups. The samples were demineralized and then remineralized using a CPP-ACP Cream with and without fluoride. The remineralization was evaluated at 7, 14 and 21 days using laser fluorescence. Results of this study showed that the laser fluorescence readings of test samples for remineralization were very highly significant at 14 and 21 days (p < 0.001). CONCLUSIONS: The degree of remineralization achieved between CPP-ACP and CPP-ACP with fluoride was statistically significant (p = 0.040) at 21 days. PMID- 23019832 TI - Cariogenic potential of pediatric liquid medicaments--an in vitro study. AB - Pediatric liquid medicaments (PLM) are popular and are easily accepted by both parents and children. They are widely prescribed and easily available. However the sugar content and properties of these preparations determines their cariogenic potential. AIMS AND OBJECTIVES: This study assessed the pH and viscosity of pediatric liquid medicaments, type and concentration of sugars present in them and their effect on the growth of Streptococcus mutans. METHODOLOGY: PLM included two each of the most commonly prescribed analgesics, antibiotics, nutritional supplements, antitussive and antiepileptic preparations. The endogenous pH was measured using a digital pH meter and the viscosity was measured using a digital Brookefield viscometer. Analysis of sugars (sucrose, glucose and sorbitol) was performed using High Performance Liquid Chromatography. The effect of PLM on Streptococcus mutans was done by ditch plate method. RESULTS: The pH of PLM ranged from 3.70 to 7.04 and viscosity varied from 307.33cP to 2408.33cP. Fifty percent of the PLM contained sucrose, glucose and sorbitol, and sucrose was present in nine of the PLM. The antibiotic preparations showed zones of inhibition against growth of Streptococcus mutans. CONCLUSIONS: The physical properties of Pediatric Liquid Medicaments as well as the type and concentration of sugars present in them can be indicative of their cariogenic potential. PMID- 23019833 TI - Dentin microhardness of primary teeth undergoing partial carious removal. AB - AIM: To evaluate the dentin microhardness of primary teeth undergoing indirect pulp capping (IPC) after partial caries removal. MATERIALS: Primary molars were treated with IPC, restored with self-etching primer (Clearfil SE Bond; CSE), and filled with composite resin (Filtek Z250) with (n = 10) or without (n = 7) a calcium hydroxide base liner (Dycal; Dy). After tooth exfoliation, the microhardness of the demineralized dentin remaining under the restoration (n = 17) was analyzed and compared with that of sound and carious primary dentin (n = 20). Microhardness measurements were obtained from the deepest portion of the cavity until the roof of the pulp chamber. Data were analyzed by Kruskal-Wallis test (p < 0.05). RESULTS: There was no difference in microhardness values at all depths between the treated groups (DY and CSE), but when the exfoliated carious teeth were included, the CSE had significantly higher values at 35-microm depth. This difference was only detected in the DY group after a depth of 200 microm. At 700 microm, there was no difference in microhardness values between all 4 groups. CONCLUSIONS: Primary teeth that underwent IPC showed the same microhardness, regardless of the capping material used. PMID- 23019834 TI - Effect of zinc sulfate on human primary enamel microhardness: an in vitro study. AB - OBJECTIVE: The aim of this study was to assess the effect of zinc sulfate on microhardness of human primary enamel. METHOD: Sixteen sound primary molars were sectioned mesiodistally. For each sample one of the sections was randomly immersed in artificial saliva (Biotene, USA) and the other was immersed in artificial saliva which was charged with 10 mg/5 mL concentration of zinc sulfate supplement (Razak Company, Iran) daily. After 24 days (the expected time to use up one 120-mL bottle) the surface microhardness of enamel was measured by knoop hardness test (KH) with Knoop diamond under a 50-gram load for 10 seconds. RESULTS: The mean (+/- SD) microhardness values (KHV) for the tested groups were 320 +/- 49.45 and 357 +/- 36.35, respectively. There were statistically significant differences between the groups as exhibited by independent t-test (P = 0.023). CONCLUSION: Primary teeth immersed in a zinc sulfate rich solution for 24 days showed higher microhardness values in comparison with the control group. PMID- 23019835 TI - Ghost cell odontogenic tumor associated with odontoma--report of two rare cases. AB - The ghost cell odontogenic tumor (GCOT) is a neoplastic/cystic lesion with a diverse histopathological and clinical behavior It was formerly known as calcified odontogenic cyst, but in 2005 the World Health Organization categorized this lesion as an odontogenic, benign tumor rather than a cyst; nominating this neoplasm as calcifying cystic odontogenic tumor. A later comprehensive classification named it ghost cell odontogenic tumor because the most remarkable histopathologic characteristic is the presence of a mass of ghost cells embedded in the epithelium. We report two cases of a rare variant of a ghost cell odontogenic tumor associated with odontoma; to our knowledge, one is the youngest patient (four month old) reported in the English literature. PMID- 23019836 TI - Monostotic Langerhans' cell histiocytosis in a child with central diabetes insipidus. AB - Langerhans'cell histiocytosis (LCH) comprises a rare group of reticuloendothelial system disorders that can produce focal or systemic manifestations. Diabetes insipidus is considered to be an important indicator of serious underlying diseases in children, including LCH. We report the case of a young patient with monostotic LCH confined to the mandibular ramus, who was diagnosed with the disease after presenting symptoms of central diabetes insipidus and was satisfactorily treated with multi-agent chemotherapy. Additionally, we discuss the clinical, radiographic, histological and immunohistochemical findings, as well as the multidisciplinary approach of this important disease, which should receive attention by dental practitioners, especially when it occurs in children. PMID- 23019837 TI - Sedative effects of oral midazolam, intravenous midazolam and oral diazepam. AB - OBJECTIVES: To evaluate and compare the behavioral changes and effect of sedative techniques in pediatric dental patients using Oral Midazolam, Intravenous Midazolam and Oral Diazepam as sedative agents. MATERIALS AND METHODS: Triple blind randomized control trial with 40 patients aged between 2-10 years, exhibiting definitely negative behavior was considered Patients were randomly assigned to one of the four treatment groups. Group I received midazolam 0.5 mg/kg orally, Group II received 0.5 mg/kg diazepam orally, Group III received 0.06 mg/kg midazolam intravenously and Group IV received oral placebo. Behavioral changes (sleep, crying, movement, and overall behavior) and effect of sedative techniques on pediatric patients were assessed. RESULTS: All the patients in group 3 were significantly better in post administrative behavior viz. sleep, crying and movement. Over all behavior scores for group 3 patients were significantly better than other three groups (p < 0.001). Positive behavior of patients in group 2 and 3 did not show significant difference but positive behavior in group 3 was significantly (p < 0.05) more than group 2. Placebo group showed the highest negative behavior. CONCLUSION: Sedative effects of oral midazolam and oral diazepam were comparable, where as intravenous midazolam produced more sedation. Anxiolysis was found to be more in both the midazolam groups than the diazepam group. Most number of positive changes were observed in midazolam groups as compared to diazepam group. PMID- 23019838 TI - Premedication intake behavior--does it predict behavior during dental treatment? AB - OBJECTIVES: To investigate whether behavior during hydroxyzine administration predicts children's behavior during dental treatment and whether behavior during treatment is affected by the complexity of treatment. MATERIALS AND METHOD: 118 children aged 2 to 6.5 years old were treated under conscious sedation with oral premedication (3.7 mg/kg of hydroxyzine in a concentration of 50 mg/5 cc. hydroxyzine) and 50% nitrous oxide/oxygen sedation. Children were divided in two age groups: aged 2 to < or = 4 years old, and aged 4 > to 6 years old. Behavior during first examination; cooperation during premedication administration, cooperation during nitrous oxide nose-mask placement, behavior during dental treatment, treatment duration and complexity of treatment were recorded. RESULTS: More children in the older group took the premedication willingly (p = 0.026). Significant correlation (p = 0.002) between behavior during examination and nitrous oxide mask acceptance was found in the older age group. No correlation was found regarding the cooperation during premedication intake and behavior during treatment within and between age groups. No statistical differences within the groups and between the groups were found between complexity of treatment and behavior during treatment. CONCLUSIONS: Premedication intake is not a reliable predictive tool for behavior during treatment in children aged 2-6.5 years. Complexity of treatment does not influence behavior during treatment in children aged 2-6.5 years. PMID- 23019839 TI - Craniofacial and dental characteristics of Kabuki syndrome: nine years cephalometric follow-up. AB - OBJECTIVE: Kabuki syndrome is a rare autosomal dominant trait with variable clinical expression. Common dental manifestations of Kabuki syndrome are high arched palate, micrognathia, malocclusion, microdontia, small dental arches, hypodontia, severe maxillary recession and mid-facial hypoplasia. STUDY DESIGN: This report includes the oral manifestations of a Turkish patient with Kabuki syndrome with consideration of the long-term craniofacial prognosis for this patient based on the physical, clinical and radiological findings in 9 years follow-up period. General appearance of the patient was characterized by postnatal growth retardation, moderate mental retardation, peculiar face characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids, prominent and cup-shaped ears, broad and depressed nasal tips, short fifth fingers, psychomotor retardation and dermatologic abnormalities. RESULTS AND CONCLUSION: Cephalometric analysis revealed skeletal open bite; periapical and panoramic radiographic examinations showed agenesis permanent teeth. A patient with Kabuki syndrome, who may lead to a better understanding of the abnormalities, playing an important role in clinical diagnosis, planning and dental management is presented. PMID- 23019840 TI - Orofacial findings and dental management of Williams-Beuren syndrome. AB - Williams-Beuren syndrome is a rare congenital disorder involving the cardiovascular system, mental retardation, distinctive facial features, and tooth anomalies. The aim of the present report is to show a 10-year-old girl with Williams-Beuren syndrome, her general and orofacial clinical characteristics and the dental management. PMID- 23019841 TI - Palatal soft tissue thickness at different ages using an ultrasonic device. AB - OBJECTIVE: To evaluate the palatal soft tissue thickness among placement sites of temporary anchorage devices (TADs) in late mixed, early permanent and permanent dentition. MATERIALS AND METHOD: The sample consisted of three groups; 42 late mixed dentition (mean age = 11.0 years), 41 early permanent dentition (mean age = 13.8 years), and 38 permanent dentition (mean age = 23.1 years). Soft tissue thickness was measured intraorally with an ultrasonic device using a grid of 27, 4 x 4 mm2 squares to delineate the measurement points. Repeated measures analysis of variance was performed to analyze the data. RESULTS: There was a significant difference in soft tissue thickness among dentition groups with the permanent dentition group showing the highest values (P < 0.001). In each group, the thickness significantly increased from median to lateral and from anterior to posterior sites. Furthermore, the thickness showed a significant difference according to the arch form and gender (P < 0.05). However, there were no significant differences according to irregularity index and Angle classification. CONCLUSIONS: The soft tissue thickness of the palate increases from the late mixed to permanent dentition. These findings may be helpful for clinicians to enhance their successful application of TADs in the palate. PMID- 23019842 TI - Knowledge of care providers regarding the oral health of visually impaired children. AB - OBJECTIVE: To assess the awareness of care providers of visually impaired children regarding their oral hygiene. METHOD: A simple pre-structured questionnaire was given to the care providers and the awareness regarding their oral health was assessed. RESULTS: There was a general lack of awareness among the care providers of these children regarding dental diseases and its prevention. Furthermore, the importance of oral hygiene was found to be very low. CONCLUSION: The results obtained showed that most of the caretakers were unaware of the difficulties faced by these children in the maintenance of their oral health. PMID- 23019843 TI - Aggregatibacter actinomycetemcomitans in Down's syndrome children. AB - OBJECTIVES: To investigate the presence of Aggregatibacter actinomycetemcomitans (Aa) in Down's syndrome (DS) children in comparison with age-matched normal children and to determine if Aa was acquired during childhood in DS individuals. STUDY DESIGN: 60 DS children and 60 healthy children participated in this cross sectional study. Both groups were matched regarding gender and age and were equally selected from public schools/non-fee paying centers and private schools. Subgingival plaque sample were obtained and analyzed for Aggregatibacter actinomycetemcomitans (Aa). Traditional cultivation method was used on a selective medium "modified malachite green vancomycin agar " RESULTS: A significantly higher percentage ofDS children had Aa in their subgingival plaque compared to their healthy counterparts (Chi square = 8.78, p = 0.003). Although Aa was acquired by children as early as 5 years of age in both groups, no association was found between the occurrence of Aa and age. CONCLUSIONS: Higher proportion ofDS children acquired Aa compared to their healthy controls and Aa is acquired by children as early as 5 years of age. PMID- 23019844 TI - Striking a balance. PMID- 23019845 TI - How to get social media results in your practice. PMID- 23019846 TI - Semantics undermine the oral-systemic disease message. PMID- 23019847 TI - Focus on: lasers. PMID- 23019848 TI - Saving lives: toothbrushes trump seat belts. PMID- 23019849 TI - Impacted maxillary canines: diagnosis and management. AB - Canine impaction is a relatively frequent clinical presentation in dentistry, with challenges that should be resolved. A good understanding by the clinician of the situation and treatment options can have a significant impact on the treatment outcome. Therefore, clinicians should be competent to perform the proper investigation, provide a correct diagnosis, develop an optimum treatment plan, and render appropriate treatment for each individual patient so each patient realizes the best outcome possible. PMID- 23019850 TI - Technology: today, tomorrow, and beyond! Interview by Damon Adams. PMID- 23019852 TI - Laser removal of porcelain veneers. PMID- 23019851 TI - Are you treating planned cases or treating teeth to stay busy? AB - Responsible aesthetics and comprehensive care requires a thorough patient examination and evaluation of risk factors that help to prevent and curtail re restoration and more aggressive tooth preparation. Managing identified risks that could potentially lead to otherwise piecemeal dental procedures keeps dentists treating comprehensively planned cases, not just teeth. Dentistry that is comprehensive, desired, and evidence-based is a valuable service to patients and a satisfying endeavor for dentists and their teams. By choosing between the sure thing of a quick fix and discussing what the patient wants, dentists can embrace a MI, responsible aesthetic approach to treatment planning, case acceptance, and most importantly, patient oral care. PMID- 23019853 TI - An evidence-based concept of implant dentistry. Utilization of short and narrow platform implants. AB - As a profession, we must remember that tooth replacement is not a luxury; it is often a necessity for health reasons. Although bone augmentation and CBCT and expensive surgical guides are often indicated for complex cases, they are being overused. Simple or straightforward implant cases, when there is sufficient natural bone for narrow or shorter implant, can be predictable performed by well trained GPs and other trained specialists. Complex cases requiring bone augmentation and other complexities as described herein, should be referred to a surgical specialist. Implant courses and curricula have to be based on the level of complexity of implant surgery that each clinician wishes to provide to his or her patients. Using a "logical approach" to implant dentistry keeps cases simple or straightforward, and more accessible to patients by the correct use of narrow and shorter implants. PMID- 23019854 TI - Everything's changed except the anatomy! PMID- 23019855 TI - Making contact just got easier. Making Class II composite restorations more predictable. PMID- 23019856 TI - Difficult case types: Part 2. A discussion of adult short-term orthodontics. PMID- 23019857 TI - Upgrading from a removable to a fixed prosthesis. PMID- 23019858 TI - Prerequisites for trouble-free fully functional dentures. PMID- 23019859 TI - [Methodology for preclinical assay of pseudoallergy of injectable drugs (I)- mouse model for assay of pseudoallergy induced by injections]. AB - OBJECTIVE: To develop animal models and methodologies for assay of pseudoallergy induced by injectable drugs. METHOD: Mouse anaphylactoid reaction model was developed by intravenous injection of test substance solutions containing Evans blue (EB). Scores of ear blue staining and quantitation of ear EB exudation were the parameters for the pseudoallergy reaction. RESULT: Mouse anaphylactoid reaction was characterized as vascular hyperpermeability which was detectable in ears by quantitation of blue staining score and EB exudation. Compound 48/80 and histamine caused severe ear bluing and EB exudation by inducing obvious vascular hyperpermeability which indicated that they can induce mouse pseudoallergy. Intravenous injection of either normal saline or 5% glucose injection showed no ear bluing. The mouse pseudoallergy model was validated by intravenous injections of western drugs and Chinese medicine. CONCLUSION: Mice could be developed into pseudoallergy model for preclinical safety evaluation of injectable drugs. The pseudoallergy reaction in this model is of high clinic consistency, sensitivity, reproducibility, and maneuverability. The model is suitable for the evaluation for pseudoallergy induced by injectable products prepared from Chinese materia medica This model can also be used for safety assay and quality control in manufacturing process, spot checking of marketed products, screening of allergen as well as studying of pseudoallergy mechanism. PMID- 23019860 TI - [Methodology for preclinical assay of pseudoallergy of injectable drugs (II) rat model for assay of cutaneous pseudoallergy induced by injections]. AB - OBJECTIVE: To develop animal models and methodologies for assay of pseudoallergy induced by injectable drugs. METHOD: Rats cutaneous anaphylactoid reaction model was developed by intravenous injection of 0. 6% Evans blue(EB) followed by intracutaneous injection of test substance solutions 50 microL. Diameters of subcutaneous blue spots and EB exudation were assayed. RESULT: Rat anaphylactoid reaction was characterized as vascular hyperpermeability which was measured by diameters of blue spots inside the skin and the EB exudation of the blue spots. Compound 48/80 caused severe bluing and EB exudation in the skin by inducing obvious vascular hyperpermeability which indicated that it can induce rat skin pseudoallergy. Normal saline or 5% glucose injection showed no obvious reactions. The rat pseudoallergy model was validated by intracutaneous injections of western drug injections and Chinese medicine. CONCLUSION: Rats could be developed into skin pseudoallergy model for preclinical safety evaluation of injectable drugs. The pseudoallergy reaction in this model is of high clinic consistency, sensitivity, reproducibility, and maneuverability. The model is suitable for the evaluation for pseudoallergy induced by injectable products prepared from Chinese materia medica This model can also be used for safety assay and quality control in manufacturing process, spot checking of marketed products, screening of allergen as well as studying of pseudoallergy mechanism. PMID- 23019861 TI - [Comparative study on pseudoanaphylactoid reactions induced by pulse-activating injection before and after improving technology]. AB - OBJECTIVE: To investigate a possibility to improve the security of pulse activating injection by comparing the difference of pseudoanaphylactoid reactions (PR) induced by pulse-activating injection before and after improving technology. METHOD: The analysis of vascular permeability of the mice's ears: ICR mouse were divided into different test groups, and intravenously injected with solutions of different concentration of pulse-activating injection before and after improving technology, positive control Compound 48/80 and 5% glucose injection. All test substances were mixed with 0. 4% Evans blue. The reaction and vascular permeability of the ears were observed and measured 30 min after injection. The vascular permeability of the rat's skin: the rats were intravenous injected with 0. 6% Evans blue normal saline solution first, 10 minutes later, the same test substances were intradermal injected into the back of rats, there are 16 injected spots in the back of rat. The rats were sacrificed and the diameter of locus ceruleus and the content of Evans blue leaked out were measured 20 min after injection. RESULT: Pulse-activating injection before improving technology with dose of 16.7 mL x kg(-1) ( in 1.67 times the clinical dose ) caused obvious vascular hyperpermeability in ICR mice. In the group of pulse-activating injection before improving technology with dose of 10 mL x kg(-1) (in clinic equivalent dose), no obvious vascular hyperpermeability in the ears were observed. The degrees of vascular hyperpermeability in the group of pulse activating injection after improving technology with dose of 16.7 mL x kg(-1) were more lessen than the same dose of injection before improving technology. Pulse-activating injection before improving technology caused obvious exudation, oedema locus ceruleus in the injection site of rat's back, and it showed a certain dose-effect relation. Pulse-activating injection after improving technology caused locus ceruleus in the injection site too, but the diameters of the locus ceruleus were shorter than the diameters in the group of pulse activating injection before improving technology, and the contents of leaked out Evans blue were fewer. All of these showed that PR of skin induced by pulse activating injection after improving technology is alleviated. CONCLUSION: Pulse activating injection before improving technology cause obvious vascular hyperpermeability, but the same dose of pulse-activating injection after improving technology can't cause obvious vascular hyperpermeability. The result indicated that the pulse-activating injection before improving technology can cause PR, improving technology can lessen the degree of PR induced by the injection. PMID- 23019862 TI - [Experimental study on anaphylactoid reactions induced by different components of shengmai injection (new production process) on Beagle dogs]. AB - OBJECTIVE: To evaluate the sensitization effect of different components of Shengmai injection (new production process) on Beagle dogs. METHOD: Beagle dogs were randomly divided into 7 groups, 3 in each group. Each group was respectively injected with 5% glucose injection, Ginseng Radix et Rhizoma Rubra extract, Ophiopogonis Radix extract, Schisandrae Chinensis Fructus extract, Schisandrae Chinersis Fructus distillate, Shengmaifang, 0.2% tween 80. The changes of each dog were observed from injection before until 24 hours after injection, and the response level was determined according to the severity of the symptoms. Blood samples were collected before injection and at 10 min after injection for measuring histamine content in plasma by ELISA. Sensitization of the injection was comprehensively determined by combined the response level of symptoms and the histamine level. RESULT: One dog of Ginseng Radix et Rhizoma Rubra extract group showed untypical symptoms of anaphylactoid reactions, and serum histamine of two dogs increased more than doubled. The Beagle dogs administrated with 0.2% tween 80 showed typical symptoms of anaphylactoid reactions, while there was no significant increase of serum histamine. Other groups were observed with no typical anaphylactoid reactions. CONCLUSION: The sensitization effect of Shengmai injection (new production process) may be associated with Ginseng Radix et Rhizoma Rubra extract and 0.2% tween 80. PMID- 23019863 TI - [Experimental study on anaphylactoid reactions induced by shengmai injection (new production process) on Cynomolgus monkey]. AB - OBJECTIVE: To compare the anaphylactoid effect of old Shengmai injection and new Shengmai injection on Cynomolgus monkey. METHOD: Cynomolgus monkeys were randomly divided into 4 groups, and were respectively injected with 5% glucose injection, old Shengmai injection, new Shengmai injection, positive control drug. The changes of each monkey were observed from injection before until 24 hours after injection, and the response level was determined according to the severity of the symptoms. Blood samples were collected before injection and at 10 min after injection for measuring histamine content in plasma. Blood pressure and heart rates were detected before injection and at 10 min after injection. Sensitization of the injection was comprehensively determined by combined the response level of symptoms and the histamine level. RESULT: The Cynomolgus monkeys administrated with old Shengmai injection showed typical symptoms of anaphylactoid reactions and the content of serum histamine is not more than doubled. The Cynomolgus monkeys administrated with new Shengmai injection showed untypical symptoms of anaphylactoid reactions and the content of serum histamine did not rise. CONCLUSION: The old Shengmai injection can induce typical anaphylactoid reactions on Cynomolgus monkeys, and the sensitization ability is strong. The symptoms of anaphylactoid reactions induced by the new Shengmai injection appeared later and showed lesser degree with the sensitization lower. PMID- 23019864 TI - [Comparative study on pseudoanaphylactoid reactions induced by medicinal tween 80 and injectable tween 80]. AB - OBJECTIVE: To investigate the safety of different level of tween 80 by comparing the degree of pseudoanaphylactoid reactions (PR) induced by medicinal tween 80 and injectable tween 80. METHOD: The analysis of vascular permeability of the mice ears: ICR mouse were divided into different test groups, the mice were intravenously injected with solutions of medicinal tween 80 and injectable tween 80 with 0.2%, 1% and 5% concentration, positive control Compound 48/80 and 5% glucose injection. All test substances were mixed with 0.4% Evans blue. The reaction and vascular permeability of the ears were observed and measured 30 min after injection. The analysis of vascular permeability of the rat's skin: the rats were intravenous injected with 0. 6% Evans blue normal saline solution first, 10 minutes later, the same substances were intradermal administrated into the back of rats. The rats were sacrificed and the diameter of locus ceruleus and the content of Evans blue leak out were measured 20 min after injection. RESULT: Medicinal tween 80 and injectable tween 80 with 5% concentration caused obvious vascular hyper permeability in ICR mice, but the degree of vascular hyperpermeability caused by injectable tween 80 was lighter than by medicinal tween 80. Other tween 80 didn't cause obvious vascular hyper permeability in the ears of mouse. The solution of different concentration of tween 80 caused obvious locus ceruleus reaction in rat's back. As for the content Evans blue leak out, there was no statistical significance between each group except positive control Compound 48/80 group. CONCLUSION: Tween 80 can cause obvious vascular hyper permeability and the effect is dose dependent, which indicated that tween 80 can cause PR. On the other hand, injectable tween 80 is more security than medicinal tween 80, the dosage of tween 80 should be still controlled strictly so that to decrease the incidence of PR. PMID- 23019865 TI - [Experimental study on anaphylactoid reactions of guinea pig induced by danshen injection and its components]. AB - OBJECTIVE: To compare the anaphylactoid effect of Danshen injection and its components on guinea pig. METHOD: Applying active systemic anaphylaxis (ASA) tests, the corresponding experimental injections were administrated to guinea pigs to sensitized, and allergen with double doses was injected to stimulate in the 11 days after the last sensitized. The anaphylaxis situation of guinea pigs was observed. RESULT: Danshen injection and its components are suspicion on guinea pigs, while negative reaction was observed on guinea pigs which injected by the liquid excipients of Danshen injection. CONCLUSION: Danshen injection using the ultrafiltration method still have some antigenic impurities which cannot be removed completely, and this may be one of the reasons for anaphylactic reaction. PMID- 23019866 TI - [Relationship between specific immunocyte and pseudoanaphylactoid reactions induced by Shuanghuanglian injection]. AB - OBJECTIVE: To investigate the relationship between specific immunocyte and pseudoanaphylactoid reactions (PR) induced by Shuanghuanglian injection (SHLI). METHOD: ICR mice, SCID mice and BALB/C athymic mouse were divided into different test groups, the mice were intravenously injected with solutions of different concentration of SHLI, positive control Compound 48/80 and normal sodium. All test substances were mixed with 0. 4% Evans blue. The reaction and vascular permeability of the ears were observed and measured 30 min after SHLI injected. RESULT: SHLI of 300, 600 mg x kg(-1) caused obvious vascular hyperpermeability in ICR mice, but the same dose of SHLI didn't cause vascular hyperpermeability in SCID mice and BALB/C athymic mouse. CONCLUSION: SHLI in equivalent and 2 times the clinical dose can cause PR in ICR mice, but the same dose of SHLI can't cause PR in SCID mice and BALB/C athymic mouse, so specific immunocyte maybe take part in the SHLI-induced PR. PMID- 23019867 TI - [Advance of studies on bioactivity of flavonoid-metal complexes]. AB - The flavonoid-metal complexes showed obviously stronger bioactivities such as antibiosis, antivirus, anti-inflammatory, anti-tumor and anti-free-radical, possibly because of the stronger binding force caused by the change in complex structure and accessibility to target spots, or the synergy effect between flavonoids and metallic ions. This essay summarizes studies on bioactivity and mechanism of flavonoid-metal complexes, in order to provide reference for in depth study and development on effective constituents contained in flavonoid traditional Chinese medicines. PMID- 23019869 TI - [Analysis of genetic diversity and genetic relationships of Lonicera macranthoides cultivars]. AB - OBJECTIVE: To study genetic diversity and genetic relationships among Lonicera macranthoides cultivars. METHOD: Five cultivars were estimated by ISSR and SRAP. The data of amplified bands were analyzed by Treeconw software. The system diagram of genetic relationship was built by UPGMA. RESULT: Twenty ISSR primers amplified 186 bands with 103 (54.63%) polymorphic bands and 58 SRAP primer combinations amplified 591 bands with 347(55.46%) polymorphic bands. Genetic distance ranges were 0.058 4-0.230 8 (by ISSRs) and 0.1071-0.2611 (by SRAPs). Both ISSR and SRAP analyses revealed a middle level of genetic diversity in L. macranthoides cultivars. The dendrograms based on SRAP and ISSR markers were not all the same. CONCLUSION: The genetic diversity of L. macranthoides cultivars is middle. ISSR and SRAP markers can be effectively applied to genetic analysis in L. macranthoides cultivars. PMID- 23019868 TI - [Effects of balanced fertilization and soil amendment on growth and yield of sanqi in continuous cropping]. AB - OBJECTIVE: To explore the solution of continuous cropping obstacle of Panax notoginseng. METHOD: The effects of balanced fertilization and soil amendment on the emergence rate, survival rate, growth and yield of P. notoginseng were studied with a pot culture experiment in 3-year-interval continuous cropping soil. RESULT: The result showed that the content of total N, total P, available N, available P and other available components in continuous cropping soil were higher than those in fresh soil while available K and the rate of K/N were declined, and available Cu and some other micro elements were lack. The way of balanced fertilization "low N + fused calcium-magnesium-phosphate fertilizer + high K + lime + micro elements" would significantly enhance the rate of survival, biomass and yield. It also promoted the growth of P. notoginseng in continuous cropping. The bagasse could relieve the continuous cropping obstacle obviously, the survival rate was improved for 31.6% and the yield of medicinal materials was 19.5%. The fly ash had also some effect in relieving the continuous cropping obstacle. CONCLUSION: The overall results suggested that the adequate fertilization plan is the applying lime, reducing N, applying calcium-magnesium phosphate fertilizer, improving K and supplying mircoelement as well as applying bagasse to resolve the problem of continuous cropping obstacle of P. notoginseng. PMID- 23019870 TI - [Variation of icariin and total flavonoid of Epimedium acuminatum in different parts and habitats]. AB - OBJECTIVE: Through comparative study on contents of icariin and total flavonoid of Epimedium acuminatum in different habitats and parts, the distribution and correlation of the two components were observed. METHOD: Twenty-four sample spots in four habitats were set up, and the whole plant of these samples was divided as following: leaf, root, stem and rhizome. Total flavonoid and icariin of samples were determined by using the UV method and the HPLC, respectively. The data was analyzed by SPSS 17.0. RESULT: The distribution of icariin in different parts had the pattern: leaf > root > stem > rhizome, the total flavonoid content was higher in leaf, but it showed no difference in other parts. Habitat had certain effect on icariin accumulation in E. acuminatum. The significant differences of total flavonoid content in E. acuminatum from different parts were not observed. CONCLUSION: The distribution of icariin from different parts and habitats has high selectivity. Metabolism and accumulation of flavonoid content in each part have no difference. Flavonoid content is less affected by environment. Considering the distribution of icariin and flavonoid content in every part and the growth strategy in different habitats comprehensively, it is reasonable to harvest the aerial part for the sustainable utilization of E. acuminatum. PMID- 23019871 TI - [Relationship between seedling grade and plant growth, yield and quality of medicinal Chrysanthemum morifolium]. AB - OBJECTIVE: To provide the basis for standardization cultivation of medicinal Chrysanthemum morifolium, the relationship between the seedling grading and plant growth, yield and quality were studied. METHOD: The morphological index of the seedlings was measured and the method of principal component and correlation analysis were used to determine the grading index, and step-wise cluster analysis was applied for clustering analysis. Pot experiments were used to measure the indicators of plant growth and development, yield and quality. RESULT: The height and ground diameter were determined for the quality indicators of the seedlings grading, and the standard quality grading of seedlings of Ch. morifolium was initially set up. The ground diameter of the class I and II were larger than that of the class III, and the number of branches of class I and II was more than that of the class III, on the contrary, the plant height of the class III was higher than that of the class I and II. The shape and appearance of the plant had no effect on the intrinsic quality. Flower center diameter and tubular floret number of the class I and II were significantly larger than those of the class III, so as the yield. The seedling grading had no obvious effect on the internal quality of medicinal material. CONCLUSION: Seedlings of the class I and class II were suitable for transplanting. PMID- 23019872 TI - [Identification of microorganism from traditional Chinese medicine Massa Medicata Fermentata]. AB - OBJECTIVE: To identify the yeast strains isolated from Massa Medicata Fermentata samples that sold in markets. METHOD: The strains were identified through conventional classification methods including colony characteristics, cell morphology, physiological and biochemical properties, as well as 26S rDNA sequence analysis. RESULT: The isolated strains Y1, Y3, Y4, Y5 were Cryptococcus albidus, Saccharomyces cerevisiae, Pichia kudriavzevii, Endomyces fibuliger, respectively. CONCLUSION: After fermentation the Massa Medicata Fermentata samples contained a variety of yeast species. Yeasts were the main contribution microorganism of the fermentation process. PMID- 23019873 TI - [Effects of different harvest times and processing methods on quality of Gardeniae Fructus]. AB - OBJECTIVE: To study effects of different harvest times and processing methods on the quality of Gardeniae Fructus. METHOD: The content of asminoidin and the similarity of the fingerprint of Gardeniae Fructus were determined and applied for assessment of the quality. RESULT: Gardeniae Fructus harvested in October with yellow-green appearance was the better time point for harvest. Drying in the sun and boiling in the water is the better processing method for Gardeniae Fructus. CONCLUSION: Different harvest times and processing methods can affect the quality of Gardeniae Fructus. PMID- 23019874 TI - [Multistage multivariate statistic quality control (MMSQC) for monitoring production process of traditional Chinese medicines]. AB - OBJECTIVE: To establish a method for monitoring the quality of intermediates generated in each working procedure during the production process of traditional Chinese medicine (TCM) , in order to ensure the batch-to-batch quality consistency of TCM products. METHOD: The multistage multivariate statistic quality control (MMSQC) was proposed to monitor production quality of TCMs based on multivariate data analysis technique. Hotelling T2 and SPE were adopted for monitoring the quality of intermediates generated in each working procedure. Danshen injection was taken as the example to introduce the application method of MMSQC. RESULT: MMSQC can monitor the quality of intermediates generated in multiple working procedures, which is simpler and more accurate compared with single-indicator monitoring method. CONCLUSION: MMSQC can be popularized to monitor quality of multistage production of TCMs. PMID- 23019875 TI - [Effect of different solvents on extraction of effective components from Ligusticum chuanxiong]. AB - OBJECTIVE: To compare the effect of different solvents such as water, ethanol, methanol, ethyl acetate and petroleum ether on extraction of 10 effective components from Ligusticum chuanxiong and component characteristics of corresponding extracts. METHOD: Ultrasonic assisted solvent extraction and high performance liquid chromatography quantitative analysis were adopted to determine effective components. CAPCELL PAK C18 column (4.6 mm x 150 mm, 5 microm) was adopted. The mobile phase was methanol-0. 5% HAc for gradient elute. The detection wavelength was 280 nm. The column temperature was 30 degrees C. The flow rate was 0. 7 mL x min(-1). The sample size was 10 microL. RESULT: Methanol or ethanol showed no significant difference in extraction of ferulic acid, hydroxyphthalide, alkylphthalide and diligustilide. Ethyl acetate displayed relatively low extraction ratios in hydroxyphthalide and ferulic acid. Water and petroleum ether showed relatively low extraction ratios in all four effective components, and water extracts showed different component characteristics. CONCLUSION: Ethanol and methanol are the most suitable solvents to extract four effective components from L. chuanxiong. PMID- 23019876 TI - [Boiling extraction of oleuropein at low temperature and reduced pressure]. AB - OBJECTIVE: To look for optimum extraction techniques for oleuropein by boiling olive leaves at low temperature and reduced pressure. METHOD: According to single factor experiment (SFE) design, the effects of seven factors, the impact of seven factors, type of solvent, temperature, time, ratio of material to liquid, ethanol concentration, vacuum degree and extraction times, on extraction yield of oleuropein were investigated. Based on the results of SFE, four more important factors, temperature, time, ratio of material to liquid and ethanol concentration, were selected in L9 (3(4)) orthogonal experiment (OE) to compare with those extracted with traditional methods. RESULT: The optimum conditions for boiling extraction of oleuropein at low temperature and reduced pressure were as follows: temperature 60 degrees C, time 20 min, ratio of material to liquid 1:30 and ethanol concentration 85%. The conditions presented an extraction yield of 5.90%. CONCLUSION: Compared with traditional extraction methods and the ultrasound assisted extraction method, boiling extraction techniques at low temperature and reduced pressure were so quick and efficient that it has a good application prospect. PMID- 23019877 TI - [Chemical and structural analysis of Nengchi Bajin ashes in refining of Tibetan medicine gTSo thal]. AB - OBJECTIVE: To investigate the chemical components and microstructure of Nengchi Bajin ashes which are adjuvant material in the refining of Tibetan medicine gTSo thal, in order to explore the material basis of the refining of gTSo thal. METHOD: Scanning electron microscope-energy dispersive spectrometer (SEM-EDX) and X-ray diffraction (XRD) were used to measure the Nengchi Bajin ashes. RESULT: SEM EDX analysis show that except of themselves elements of Nengchi Bajin ashes, Nengchi Bajin ashes contain the major elements, such as S, O, C and so on, also contain small amount other elements. XRD analysis show that the structures are AuPb2, PbO (tetragonal and orthorhombic) and Pb in gold ash, Ag2S and PbO in silver ash, Cu1.98 (Zn0.73 Fe0.29)Sn0.99 S4, CuS, SiO2, NaCu2S2 and Ca (Fe(+2), Mg) (CO3)2 in bronze ash, Cu7S4 (orthorhombic and monoclinic) and CuO in red copper ash, Cu7 S4, PbS, ZnS, CaCO3and NaCu2S2 in brass ash, FeS, Fe+2 Fe(2+3)O4 and SiO2 in iron ash, SnS and SiO2 tin ash, PbS, PbSO4 and SnS2 in lead ash. CONCLUSION: We have acquired the datum of elements and microstructure of Nengchi Bajin ashes by SEM-EDX and XRD techniques, and that is benefit to explore the material basis of refining gTSo thal. PMID- 23019878 TI - [Study on in vitro antioxidant activity of flavonoids contained in Hebei balmy chrysanthemum and structure-activity relationship]. AB - OBJECTIVE: To study the antioxidant activity in vitro of five flavonoids contained Hebei balmy chrysanthemum, luteolin, apigenin, acacetin, acacetin-7-O beta-D-glucoside and acacetin-7-O-beta-D-glucoside and discuss the antioxidant mechanism of Hebei balmy chrysanthemum as well as the structure-activity relationship of antioxidant activity of flavonoids. METHOD: UV-visible spectrophotometric method was used to determine the DPPH scavenging rate and anti hemolysis activity of the five flavonoids. The inhibitions on lipid peroxidation in rat brain homogenate were evaluated by measuring the content of MDA, and detected by the TBA method. The effect on glutathione peroxidase (GSH-Px) in rat plasma was detected by GSH-Px kit. RESULT: The flavonoids from Hebei balmy chrysanthemum showed better activity in scavenging DPPH radical, protecting RBC from hemolysis, inhibiting lipid peroxidation in rat brain homogenate, and increasing the activity of GSH-Px in rat plasma. The order of antioxidant efficacy was as follows: luteolin > luteolin-7-O-beta-D-glucoside > apigenin > acacetin > acacetin-7-O-beta-D-glucoside. CONCLUSION: The antioxidant activity of Hebei balmy chrysanthemum is related to the effect of flavonoids in scavenging radical, inhibiting lipid peroxidation and increasing the activity of GSH-Px. And the antioxidant activity of flavonoids is related to the number and position of hydroxide radicals and the steric hindrance of glucoside. PMID- 23019879 TI - [Chemical constituents contained in Aeschynanthus moningeriae]. AB - OBJECTIVE: To study chemical constituents contained in Aeschynanthus moningeriae. METHOD: The chemical constituents were separated and purified by column chromatographic methods such as Diaion HP-20, Toyopearl HW-40, Sephadex LH-20, MCI-Gel CHP-20, RP18 and normal phase silica gel. Their structures were identified on the basis of physiochemical property and spectral techniques (1H, 13C-NMR, DEPT, 1H-1H COSY, HSQC, HMBC, HR-MS). RESULT: Twelve compounds were separated and identified as 5,7-dihydroxy-8-C-beta-D-glucosyl-chromone (1), 5 hydroxyl-7,4'-dimethoxyl-flavone (2), 2,3,19, 24-tetrahydroxy-urs12-en-28-oic acid (3), 2,3,19, 24-tetrahydroxy-urs-12-en-28-oic acid ester-28-O-beta-D gucoside (4), 5-hydroxyl-6,4'-dimethoxyl-7-O-[alpha-L-rhamnosyl-(1-->6)]-beta-D glucopyranosyl-flavone (5), 5,7,3',4'-tetrahydroxy-6-C-beta-D-glucosyl-flavonol (6), 5,7-dihydroxy-6-C-beta-D-glucosyl-flavonones (7), 5,7, 3',4'-tetrahydroxy-6 C-beta-D-glucosyl-dihydroflavonol (8), daucosterol (9), stigmasterol (10), beta sitosterol (11), and 3-O-beta-D-glucosyl-stigmasterol (12). CONCLUSION: Compound 1 is a new compound, while other compounds were separated from this plant for the first time. PMID- 23019880 TI - [Lignans from Sinocalamus affinis]. AB - Fifteen compounds were isolated from the stem (with skin removed) of Sinocalamus affinis by a combination of various chromatographic techniques including silica gel, macroporous adsorbent resin, Sephadex LH-20, and preparative HPLC. Their structures were elucidated by spectroscopic data as ( + )-(1S, 2R)-1, 2-bis (4 hydroxy- 3-methoxyphenyl)-1, 3-propanediol (1), threo-guaiacylglycerol-beta-O-4' coniferyl ether(2), erythro-guaiacylglycerol-beta-O-4'-coniferyl ether(3), ( + ) (7S, 8R, 8'R)-5'-methoxylariciresinol(4), ( + )-(7S, 8R, 8'R)-5, 5' dimethoxylariciresinol (5), ( +/- )-glaberide I (6), ( - )-syringaresinol (7), ( )-medioresinol(8), ( - )-(8R, 8R')-4, 4'-dihydroxy-3, 3', 5, 5' tetramethoxyligna-9, 9'-diol(9), ( - )-secoisolariciresinol-9, 9'-acetonide (10), and ( + )-lyoniresinol (11); a new natural product 2, 6-dimethoxypyran4-one (12), and beta-sitosterol, 4-hydroxycinnamic acid, and 2, 6-dimethoxy-p-benzoquinone. These compounds were isolated from the genus Sinocalamus for the first time, compound 10 should be an artifact. PMID- 23019881 TI - [Sesquiterpenes and monoterpene from Aquilaria sinensis]. AB - The column chromatography on silica gel, semi-preparative HPLC were used to separate and purify the compounds from the petroleum ether and ethanol extract of Aquilaria sinensis. Nine compounds were isolated. On the basis of their spectroscopic data, the structures were identified as 3, 3, 7 trimethyltricycloundecan-8-one (1), longifolene (2), norlongilactone (3), caryophyllenol-II (4), humulene diepoxide A (5), kobusone (6), (-)-bornyl ferulate (7), (24R) -24-ethylcholesta-4, 22-dien-3-one (8), (24R)-24-3-ono-4-en sitosterone (9). Compounds 2-9 were isolated from this plant for the first time. compounds 1-6 are sesquiterpenes, compound 7 is a monoterpene derivative, compound 8 and 9 are steroids. PMID- 23019882 TI - [Chemical constituents contained in Macropanax rosthornii]. AB - OBJECTIVE: To study active constituents of Macropanax rosthornii in treating rheumatoid arthritis. METHOD: Silica gel column chromatography, preparative HPLC and modern spectrum techniques were applied for a systematic study on chemical constituents contained in M. rosthornii. RESULT: Twelve compounds were separated from M. rosthornii and identified as serratagenic acid (1), serjanic acid (2), betulinic acid (3), 6beta-hydroxy-3-oxo-olean-12-en-28-oic acid (4), 3-O-alpha-L arabinopyranosyl serratagenic acid (5), 3-O-alpha-L-arabinopyranosyl serratagenic acid-29-methyl ester (6) , 3-O-alpha-L-arabinopyranosyl serratagenic acid-28-O beta-D-glucopyranosyl ester (7), scopoletin (8), beta-sitosterol (9), daucosterol (10), 3,4-dihydroxybenzoic acid (11), and stearic acid (12). CONCLUSION: Above compounds are separated from M. rosthornii for the first time. PMID- 23019883 TI - [Chemical constituents contained in roots of Pterospermum heterophyllum]. AB - OBJECTIVE: To study chemical constituents of contained in roots of Pterospermum heterophyllum. METHOD: The chemical constituents of P. heterophyllum were separated and purified by silica gel, sephadex LH-20, ODS column chromatography and preparative HPLC. Their structures were identified by spectroscopic techniques. RESULT: Ten compounds were separated and identified as asperglaucide (1), 2-methoxy4-hydroxyphenol-1-O-beta-D-apiofuranosyl (1-->6)-O-beta-D glucopyranoside (2), 5, 5'-dimethoxy-9-beta-D-xylopyranosyl-(-) isolariciresinol(3), (-)-epicatechin (4), eriodictyol (5), taxifolin (6), 3beta hydroxy-12-en-28-ursolic acid (7), 2beta, 3beta-dihydroxy-12-en-28-oleanolic acid (8), quercetin (9), cholest-4-en-3-one (10). CONCLUSION: Compounds 1-10 were separated from this plant for the first time. PMID- 23019884 TI - [Chemical constituents contained in Salvia castanea]. AB - OBJECTIVE: To investigate chemical constituents contained in Salvia castanea. METHOD: The compounds were separated and purified by silica gel, macroporous resin, RP-C18 and Sephadex LH-20 column chromatography. The structures were identified on the basis of physicochemical property and spectral data. RESULT: Nineteen compounds were separated and identified as tanshinone II(A) (1) , tanshinone II(B) (2), hydroxytanshinone II(A) (3), tanshinone I(4), dihydrotanshinone I(5), cryptotanshinone (6) , neotanshinone A(7) , neotanshinone B(8) , tanshinoldehyde(9), przewaquinone A(10), przewaquinone B(11), sugiol(12), caffeic acid(13), rosmarinci acid(14), ethylrosmarinate(15), lithospermic acid(16), pro-lithospermic acid ( 17) , protocatechualdehyde (18), and danshensu(19). CONCLUSION: Compounds 2, 3, 7-13 and 15-19 were separated from S. castanea for the first time. PMID- 23019885 TI - [Study on water-soluble constituents of Fritillaria unibracteata by HPLC fingerprints]. AB - OBJECTIVE: To establish a HPLC fingerprint of water-soluble constituents of Fritillaria unibracteata. METHOD: Zorbax SB Aq C18 chromatographic column (4. 6 mm x 250 mm, 5 microm) was adopted for gradient elute with the mobile phase consisting of methanol and water. The flow rate was 1.0 mL x min(-1); the detection wavelength was 260 nm, and the temperature of sample manager was set at 25 degrees C. Similarity Evaluation System for Chromatographic Fingerprint of traditional Chinese medicine (version 2.0) published by the State Pharmacopeia Committee of China was adopted for the fingerprint analysis on the 11 batches of F. unibracteata herbs. RESULT: The 11 batches of F. unibracteata herbs had 14 common peaks, nine of which were identified with good separating degrees. The similarities of the 11 batches were more than 0. 970, with good quality homogeneity. CONCLUSION: The method is so accurate, highly reproducible and stable that it is suitable for the comprehensive quality evaluation of F. unibracteata herbs. PMID- 23019886 TI - [Simultaneous determination of contents of five major bioactive components contained in Polygoni Cuspidati Rhizoma et Radix by microwave extraction-ultra performance liquid chromatography]. AB - OBJECTIVE: To establish a microwave extraction and UPLC method for simultaneous determination of polydatin, resveratrol, anthraglycoside B, emodin and physicion contained in Polygoni Cuspidati Rhizoma et Radix, in order to provide scientific basis for improving quality standards of Polygoni Cuspidati Rhizoma et Radix. METHOD: The test solutions were prepared in a MDS-8 closed microwave system at 160 degrees C with methanol as the solvent. The UPLC analysis was performed in a Waters Acquity UPLC system. A BEH C18 column (2. 1 mm x 100 mm, 1.7 microm) was adopted for gradient elution with acetonitrile and water as the mobile phase. The temperature of column was 30 degrees C, and the detection wavelength was 226 nm. RESULT: The five active components can be completely extracted in 10 minutes and separated completely in 12 minutes according to UPLC analysis, with a good linearity (r > or = 0. 999 6) within the linear ranges. The average recovery rate was 97.00%-103.7% with RSD < or = 2. 2%. Despite a large difference in content among tested components from Polygoni Cuspidati Rhizoma et Radix, the total content of the five major constituents was relatiely stable (3.683 3%-7.1031%). CONCLUSION: The microwave extraction-ultra performance liquid chromatography method in simultaneous determination for contents of five major bioactive components contained in polygoni cuspidati rhizoma et radix is so rapid and highly reproducible that it can be used for quality control and assessment of Polygoni Cuspidati Rhizoma et Radix. PMID- 23019887 TI - [Study on proteomics of Hela cell apoptosis in bufalin-induced human cervical carcinoma]. AB - OBJECTIVE: To seek possible effect targets of bufalin in HeLa cells by studying the impact of bufalin on cell protein expression profile after treatment on human cervical carcinoma cell lines HeLa. METHOD: Bufalin's ICs0was measured by MTr assay. The apoptosis of cells was observed by FCM (flow cytometry) and Hoechst 33342 staining assay. Differentiated expression protein spots were founded and identified using proteomic techniques, which could induce HeLa cell apoptosis. RESULT: Bufalin showed remarkable cytotoxic effect on HeLa cells. IC50 (154 +/- 21.5) nmol X L(-1) indicated the possibility of inducing cell apoptosis. The protein expression profile showed 11 differentiated expression protein spots. Among the 11 proteins, nudix-type motif 5, vimentin, hnRNP C1/hnRNP C2 variant, HNRPK, HNRPK isoform a variant (two spots are the same protein), heat shock protein 27, macrophage-capping protein, SELENBP1 protein were down-regulated, while ribosomal protein, large, P0 and S-adenosylmethionine synthetase 2 were up regulated by bufalin treatment. They may be effect targets of bufalin in HeLa cells. Western blotting showed consistent results in heat shock protein 27, vimentin and HNRPK between expression after treatment with bufalin and two dimensional electrophoresis. CONCLUSION: Bufa-Lin can induce apoptosis in human cervical carcinoma cells HeLa and the effect of bufalin may be related to the joint intervention with multiple protein targets. PMID- 23019888 TI - [Study on absorption ingredients of yuanhuzhitong pill by everted intestinal sac method]. AB - OBJECTIVE: To establish an everted intestinal sac method for determining absorption ingredients of yuanhuzhitong pill and study absorption characteristics of major chemical constituents of yuanhuzhitong pill. METHOD: The everted intestinal sac model was adopted. Intestinal sac fluid samples at different time points after administration of three concentrations of Yuanhuzhitong pill were collected and determined by HPLC. The accumulative absorbed doses of active constituents were calculated, while the proportion between samples of yuanhuzhitong pill and absorption ingredients was compared. RESULT: Eight ingredients of Yuanhuzhitong pill can be detected in intestinal sac, they are protopine, palmatine, coptisine, imperatorin, berberine, byakangelicin, alpha allocryptopine and tetrahydropalmatine. The absorption rate constants (Ka) of eight constituents increased in jejunum and ileum with the increase in concentration of Yuanhuzhitong pill extracts (P < 0. 05), indicating a passive absorption. CONCLUSION: As ingredients are selectively absorbed in intestinal sac, the everted intestinal sac method is selected to assess the intestinal absorption characteristics of ingredients of Yuanhuzhitong prescription. PMID- 23019889 TI - [Multi-channel analysis and comparison on absorption difference between paeoniflorin and Paeonia lactiflora extracts]. AB - OBJECTIVE: To compare the difference of the absorption difference between paeoniflorin monomer and Paeonia lactiflora extracts in rat intestinal canals by multi-channels. METHOD: The rat intestinal perfusion model was established. The intestinal perfusate, bile and plasma samples were collected, in combination of the intestinal enzymes incubation test and the partition coefficient determination, to conduct a multi-channel analysis and comparison on absorption difference between paeoniflorin and P. lactiflora extracts. RESULT: In the same concentration, permeability coefficient P(eff)* of paeoniflorin in the different intestinal segments of P. lactiflora extract higher than the monomer of paeoniflorin, especially in the jejunum and ileum intestinal segments (P < 0. 05). However, both paeoniflorin monomer and P. lactiflora extracts showed less P(eff)* in four intestinal segments, with the former ranging between 0. 209-0.290 and the latter 0.252-0.333. No paeoniflorin and its metabolin was determined in bile samples, plasma samples and intestinal enzymes incubation samples of paeoniflorin monomer and P. lactiflora extracts. CONCLUSION: Compared with the paeoniflorin monomer, P. lactiflora extract showed significantly increase in P(eff)*, which indicated that other ingredients in the extract can improve the absorption of paeoniflorin. However, due to the poor absorption of paeoniflorin, this effect fails to increase the concentration of paeoniflorin in bile and plasma within short period of time. PMID- 23019890 TI - [Study on HPLC characteristic fingerprint of active components of dachuanxiong fang in plasma and cerebrospinal fluid]. AB - OBJECTIVE: To establish an accurate and simple qualitative analytical method in vivo in the study on HPLC characteristic fingerprint of active components of dachuanxiong fang in plasma and cerebrospinal fluid, in order to lay a foundation for studies on components found in plasma and cerebrospinal fluid and provide basis for compatible regularity of initiators. METHOD: HPLC characteristic fingerprint of active components of dachuanxiong fang in plasma and cerebrospinal fluid was established. RESULT: The similarity of fingerprints of all of six batches of samples was above 0.85, RSD of their relative retention times in common peaks was less than 2. 0%. CONCLUSION: The fingerprints of active components of dachuanxiong fang in plasma and cerebrospinal fluid were stable and accurate that they can be used in qualitative analysis on in vivo components. PMID- 23019891 TI - [Meta-analysis on treatment of non-small cell lung cancer with brucea javanica oil emulsion in combination with platinum-contained first-line chemotherapy]. AB - OBJECTIVE: To study the efficacy and safety of brucea javanica oil emulsion (BJOE) combining platinum-contained first-line chemotherapy in treating non small cell lung cancer (NSCLC). METHOD: Cochrane library, PubMed, EMBASE, VIP, CBM and CNKI were searched through computers. The search was finished in February, 2011. Randomized controlled trials (RCTs) of BJOE combining platinum-contained first line chemotherapy were included. Two researchers extracted data and assess literature quality separately,and made a meta-analyses by RevMan 5.1.2 software. RESULT: Totally 22 RCTs involving 1512 patients were included. The Meta-analysis showed that compared with the pure application of platinum-contained first-line chemotherapy,the combination of BJOE and chemotherapy can enhance the near-term curative effect (RR = 1. 31, 95% CI: 1.18-1.45, P < 0. 000 01), improve the quality of life (RR = 1.78, 95% CI: 1.51-2. 09, P < 0.00001) and reduce the suppression of bone marrow (OR = 0.37, 95% CI: 0. 27-0. 51, P < 0.00001) and the gastrointestinal reactions (OR = 0.59, 95% CI: 0.44-0.80, P = 0.0007) ,with an improvement in organism immunity. CONCLUSION: The current evidence indicates that BJOE can enhance the chemotherapeutic effect on NSCLC patients, improve the quality of life and reduce adverse effect of platinum-contained chemotherapeutics and thus it is worth referring in clinic. PMID- 23019892 TI - [Study on quality evaluation of Panax ginseng based on effects for replenishing qi and preventing exhaustion]. AB - Based on the effect for replenishing Qi and preventing exhaustion, this essay provides a method to rebuild the quality evaluation system of Panax ginseng. As an independent medical system, the traditional Chinese medicine (TCM) science lacks enough credible evidences to support its theory and thereby wants more relevant studies. Current, it is a misunderstanding for experimental studies on TCM to prove TCM drugs from the angle of western medicine. Therefore, following study modes are recommended to researchers focusing on either the theory of the unique importance of class origin or the theory of the unique importance of techniques. Under the guidance of TCM theories, a new TCM assessment mode, consisting of clinical efficacy, pharmacological effect and effective components, is established in line with clinical application of TCMs. Studies on Chemical fingerprint or active ingredient are made on effective components. In-depth studies are worth to the viewpoint to rebuild the TCM quality reassessment system. On the basis of analysis on ancient herbal literatures and experience in clinical application of TCMs, the author proves the irreplaceable effect of P. ginseng. (pure ginseng decoction) is to replenish Qi and prevent exhaustion. Based on the major effect, a pharmacological model is established in combination with modern clinical efficacy to screen effective components of ginseng herbs and make a quality assessment on safety and efficiency of clinical application of P. ginseng, in order to provide theoretical and experimental basis for cultivation, development and utilization of P. ginseng resources on Changbai mountain. PMID- 23019893 TI - [Thermal energy utilization analysis and energy conservation measures of fluidized bed dryer]. AB - OBJECTIVE: To propose measures for enhancing thermal energy utilization by analyzing drying process and operation principle of fluidized bed dryers,in order to guide optimization and upgrade of fluidized bed drying equipment. METHOD: Through a systematic analysis on drying process and operation principle of fluidized beds,the energy conservation law was adopted to calculate thermal energy of dryers. The thermal energy of fluidized bed dryers is mainly used to make up for thermal consumption of water evaporation (Qw), hot air from outlet equipment (Qe), thermal consumption for heating and drying wet materials (Qm) and heat dissipation to surroundings through hot air pipelines and cyclone separators. RESULT: Effective measures and major approaches to enhance thermal energy utilization of fluidized bed dryers were to reduce exhaust gas out by the loss of heat Qe, recycle dryer export air quantity of heat, preserve heat for dry towers, hot air pipes and cyclone separators, dehumidify clean air in inlets and reasonably control drying time and air temperature. CONCLUSION: Such technical parameters such air supply rate, air inlet temperature and humidity, material temperature and outlet temperature and humidity are set and controlled to effectively save energy during the drying process and reduce the production cost. PMID- 23019894 TI - [Study on prediction model of Angelicae sinensis yield per unit in Min County]. AB - OBJECTIVE: To establish a prediction model of Angelicae sinensis yield per unit in Min County, and the forecasting information can be provided to correlated department and organization. METHODS: With the basis of the Angelicae sinensis yield statistics in Min County from 1995 to 2009 and weather data of development phase of each ten days, polynomial forecasting modeling was used and the stimulation forecasting of Angelicae sinensis yield in Min County was carried out. RESULTS: The results showed that the average accuracy of prediction model was reached to 97.2%, which basically met the demand for yield prediction. CONCLUSION: The prediction model of Angelicae sinensis yield per unit in Min County has good accuracy and relatively correct forecasting information about Angelicae sinensis yield, which provides methodology and important references for dynamic forecasting in the progress of Chinese medicinal materials production. PMID- 23019895 TI - [Regulation effect of scorpio and scolopendra on CD4 + CD25 + FoxP3 + Treg cell in peripheral blood from rats with collagen-induced arthritis (CIA)]. AB - OBJECTIVE: To study the regulation effect of Scorpio and Scolopendra on CD4 + CD25 + FoxP3 + Treg Cell in peripheral blood from rats with collagen-induced arthritis. METHODS: Sixty female Wistar rats were randomly divided into 6 groups, normal control group, model control group, low-dose, middle-dose and high-dose Scorpio and Scolopendra group,and the type II collagen group. Rats' arthritis was induced by collagen. The number of CD4 + CD25 + FoxP3 + Treg cell in peripheral blood was tested by flow cytometry, and the level of IL-2 in serum was detected by enzyme linked immunosorbent assay. RESULTS: Compared with the model groups,the levels of CD4 + CD25 + Treg cell and CD4 + CD25 + FoxP3 + Treg cell were increased obviously in the high and low dose of Scorpio and Scolopendra groups (P < 0.05 or P < 0.01), while the level of IL-2 in serum was decreased remarkably in the middle and low dose of Scorpio and Scolopendra groups (P < 0.05 or P < 0.01). CONCLUSION: It is realized that Scorpio and Scolopendra effectively treat RA by regulating the level of CD4 + CD25 + FoxP3 + Treg cell to restore immunological tolerance. PMID- 23019896 TI - [Study on the spatial and temporal expression of beta-AS gene of Glycyrriza uralensis]. AB - OBJECTIVE: To reveal the temporal and spatial specificity of the expression of beta-AS gene of Glycyrriza uralensis. METHODS: Used PCR to obtain the cDNA of beta-AS gene of Glycyrriza uralensis at different time and from different part and Gel-Pro to carry out the densitometric analysis of the electrophoretic band, then calculate the relative expression. RESULTS: The spatial specificity experiment showed that beta-AS gene didn't express in the overground part of Glycyrriza uralensis,while in the underground part,the expression of beta-AS in root tip was higher than that of rootstock. And the temporal specificity experiment showed that the expression of beta-AS gene of Glycyrriza uralensis could be divided into 4 stages. From December to February, the expression of beta AS gene was under the detection limit. From March to May, beta-AS gene began to express. From May to September,the expression of beta-AS gene kept at a high level. And in October and November the expression of beta-AS gene began to decrease. CONCLUSION: When the beta-AS gene of Glycyrriza uralensis is researched, the root tip is the suitable plant material and May, June, August and September are the right acquisition time. PMID- 23019897 TI - [Analysis of cadmium in Cortex Ilicis Rotundae]. AB - OBJECTIVE: To study the contents of cadmium in Cortex Ilicis Rotundae and provide evidence for establishing the detection limit of cadmium in its quality standard. METHODS: ICP-MS was used to determine the contents of cadmium in 18 batches of Ilex L. RESULTS: The contents of cadmium in 10 batches of Cortex Ilex Rotunda ranged from 3.4 to 10.4 mg/kg,and the contents of cadmium in Ilex asprella and Ilex pubescents were more than 0.3 mg/kg. CONCLUSION: The contents of cadmium of Cortex Ilicis Rotundae, Ilex asprella and Ilex pubescents have particular characterise, and this study provides a basic for the analysis of cadmium in Cortex Ilicis Rotundace and other plants of this genus. PMID- 23019898 TI - [Effects of different processing on active components in fructus polygoni orientalis by HPLC analysis]. AB - OBJECTIVE: To study the effects of different processing on taxifolin and quercetin in Fructus Polygoni Orientalis. METHODS: The analysis was performed on a Agilent column (4. 6 mm x 150 mm, 5 microm) eluted with a gradient elution of methanol-water containing 0. 1% phosphoric acid. The flow rate was 1 mL/min, the detection wave length was 270 nm and the column temperature was set at 25 degrees C. The content changes of taxifolin and quercetin processed by different methods was compared. RESULTS: The contents of active ingredients in Fructus Polygoni Orientalis that processed by the method of therm-high pressure (the pressure was 14Pa) was obvious higher than those of other methods. CONCLUSION: Active ingredients of Fructus Polygoni Orientalis may be promoted by therm-high pressure processed. There is significant difference for the major components by different processing methods. The method of therm-high pressure to processing is used for the first time in the Fruit Polygoni Orientalis. The method appears to be simple, easy and can be used as quantitative determination method for quality control of the Fructus Polygoni Orientalis. PMID- 23019899 TI - [Molecular authentication of Fallopia multiflora by PCR-RFLP based on the trnL trnF analysis]. AB - OBJECTIVE: To establish a method for the molecular authentication of Fallopia multiflora. METHODS: The trnL-trnF regions of Fallopia multiflora and its closely related species and/or adulterants were sequenced and analyzed. RESULTS: It was found that the trnL-trnF sequence divergences between Fallopia multiflora and its closely related species and/or adulterants were 2.1%-22%. While the intra-species trnL-trnF divergences of Fallopia multiflora were 0%-1.5%. Based on the trnL-trnF regional variations, an endonuclease Xba I (T CTAGA) restriction site specific to Fallopia multiflora was detected. The Fallopia multiflora trnL-F polymerase chain reaction product could be cleaved by Xba I into two pieces, 804-819 bp and 256 bp each, whereas the restriction endonuclease could not digest the trnL-trnF polymerase chain reaction product of its closely related species or adulterants. The restriction patterns analyzed for restriction enzyme Xba I were found to be identical in all Fallopia multiflora individuals from different geographical regions in China. CONCLUSION: The assay based on polymerase chain reaction amplification of the trnL-trnF fragment of chloroplast DNA and subsequent restriction fragment length polymorphism can be used as a general test to identify Fallopia multiflora. PMID- 23019900 TI - [Study on the HPCE fingerprint of Rehmannia glutinosa]. AB - OBJECTIVE: To establish the analytical method for the fingerprint of Rehmannia glutinosa by HPCE and compare the fingerprints of Rehmannia glutinosa and its processed products. METHODS: Based on the mode of high performance capillary electrophoresis, 60 mmol/L sodium borate was used as buffer solution (5% MeOH, pH 9.5). The separation voltage was 20 kV and the detection wavelength was set at 210 nm. Catalpol was used as a reference standard, the chromatographic fingerprint were determined. The data were analyzed by fuzzy cluster and fingerprint similarity evaluation software was used to compare the similarity of samples. RESULTS: HPCE fingerprints with 7 common peaks of Rehmannia glutinosa were established preliminarily. It was discovered that a small number of samples differed from others. Regarding to the fingerprints of Rehmannia glutinosa and its processed products, there were obvious differences in the relative areas of common peaks. CONCLUSION: The method is reliable, accurate and can be used for quality control of Rehmannia glutinosa. PMID- 23019901 TI - [Identification of Dens Draconis and Os Draconis by XRD method]. AB - OBJECTIVE: To establish an XRD method for evaluating the quality of Os Draconis and Dens Draconis and applying in judgement of the counterfeit. METHODS: Dens Draconis, Os Draconis and the counterfeit of Os Draconis were analyzed by XRD. Their diffraction patterns were clustered analysis and evaluated their similarity degree. RESULTS: Established the analytical method of Dens Draconis and Os Draconis basing the features fingerprint information of the 10 common peaks by XRD pattern. Obtained the XRD pattern of the counterfeit of Os Draconis. The similarity degree of separate sources of Dens Draconis was high,while the similarity degree of separate sources of Os Draconis was significant different from each other. CONCLUSION: This method can be used for identification and evaluation of Os Draconis and Dens Draconis. It also can be used for identification the counterfeit of Os Draconis effectively. PMID- 23019902 TI - [Study on the chemical constituents from Gnaphalium hypoleucum]. AB - OBJECTIVE: To research the chemical constituents from Gnaphalium hypoleucum. METHODS: Compounds were separated by using silica gel, ODS, Sephadex LH-20 chromatography and their structures were elucidated by means of spectral data analysis. RESULTS: Ten compounds were isolated and identified as tetracosanoic acid (1), 5-hydroxy-3,6,7,8-tetramethoxyflavone (2), beta-sitosterol (3), 5 hydroxy-3,6,7,8,4'-pentamethoxyflavone (4), 5-hydroxy-3,6, 7,8,3',4' hexamethoxyflavone (5), apigenin (6), luteolin (7), quercetin (8), luteolin4'-O beta-D-glucoside (9), quercetin-4'-O-beta-D-glucoside (10). CONCLUSION: All of these compounds are isolated from this plant for the first time. Compound 5 is isolated from the genus for the first time. PMID- 23019903 TI - [Study on the chemical constituents from Cyathea spinulosa]. AB - OBJECTIVE: To study the chemical constituents from Cyathea spinulosa. METHODS: Compounds were isolated by chromatographic techniques. Their structures were elucidated by spectral methods. RESULTS: Eight compounds were isolated from the ethanol extract of Cyathea spinulosa and identified as stigmast-4-ene-3,6-dione (1), stigmast-3,6-dione (2), ergosterol (3), protocatechuic aldehyde (4), 1-O beta-D-glucopyranosyl-(2S,3R,4E,8Z)-2-[(2-hydroxyoctadecanoyl) amido]-4,8- octadecadiene-1,3-diol (5), (2S,3S, 4R)-2-[(2'R) -2'-hydroxytetracosanoylamino] 1,3,4-octadecanetriol (6), beta-sitosterol (7), daucosterol (8). CONCLUSION: Compounds 1-6 are isolated from this plant for the first time. PMID- 23019904 TI - [Study on phenolic constituents of Amomum villosum]. AB - OBJECTIVE: To study the chemical constituents of Amomum villosum. METHODS: Compounds were isolated from the alcoholic extract using polyamide, silica gel, Sephadex LH-20, ODS open column chromatography and other means. Their structures were elucidated according to spectral data and physiochemical properties. RESULTS: Five compounds were isolated from Amomum villosum. They were identified as: 3-ethoxy-hydroxy benzoic acid (1), vanillic acid-1-beta-D-glucopyranosyl ester (2), isorhamnetin-3-beta-D-glucoside (3), flavanocoumarin (4), isoflavanocoumarin (5). CONCLUSION: Compounds 1-5 are isolated from this plant for the first time. PMID- 23019905 TI - [Analysis of volatile compounds of inflorescence by GC-MS from Cistanche deserticola]. AB - OBJECTIVE: To study the volatile compounds from inflorescence of Cistanche deserticola and provide basis for its utilization and seed breeding. METHODS: The volatile compounds were collected by dynamic headspace adsorption and analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: Forty volatile components were identified in inflorescence of Cistanche deserticola from squaring period to full-bloom period. The main components in buds of Cistanche deserticola were hydrocarbons and green leaf volatiles in squaring period. Some components were characteristic in buds and disappeared or decreased in flowers. The relative contents of some components gradually increased with the buds blooming. And some components only emerged in flowers of Cistanche deserticola. The higher content of esters and aromatics were found in flowers, which were significantly increased in comparison with the volatile compounds from buds. CONCLUSION: The volatile compounds from inflorescence of Cistanche deserticola were complex, consisting of various compositions and significantly different with buds blooming. PMID- 23019906 TI - [Study on chemical constituents of volatile oil from rhizomes and leaves of Pileostegia viburnoides var. glabrescens by GC-MS]. AB - OBJECTIVE: To analyze the chemical constituents of volatile oil from the rhizomes and leaves of Pileostegia viburnoides var. glabrescens by GC-MS. METHODS: The volatile oil was extracted from the rhizomes and leaves of Pileostegia viburnoides var. glabrescens by steam distillation. The constituents of volatile oil were identified by GC-MS technology. RESULTS: 37 compounds were identified from the oil of rhizomes. 36 compounds were identified from the oil of leaves. The rhizomes and leaves volatile oil had 18 compounds in common. CONCLUSION: This study is the first one to report the volatile components of Pileostegia viburnoides var. glabrescens. It can provide a scientific basis for rational use of the rhizomes and leaves of Pileostegia viburnoides var. glabrescens. PMID- 23019907 TI - [Effects of Xinjierkang on two kidney one clip-induced hypertension and target organ injury in rats]. AB - OBJECTIVE: To investigate the effects of Xinjierkang on two kidney one clip induced hypertension and target organ injury in rats. METHODS: Two kidney one clip-induced hypertension rats model was established. Rats were divided into control group, model group, Xinjierkang group, and fosinopril group. At the end of 8th w, the hemodynamics indexes were recorded. The cardiac hypertrophy index was expressed as heart weight/body weight (HW/BW), the histological changes of heart, aorta and kidney were investigated by HE and/or Van Gieson stain. RESULTS: Compared with control group, the heart systolic and diastolic function were impaired, the heart weight index, cardiomyocytes cross section area (CSA), cardiac collagen deposition, vascular remodeling index and glomerulus area were increased markedly in model group rats. Administration of Xinjierkang and fosinopril markedly ameliorated hemodynamic indexes, inhibited the elevation of HW/BW ratio, CSA of cardiomyocytes, vascular remodeling index and glomerulus hypertrophy, decreased collagen deposition in heart. CONCLUSION: Xinjierkang has protective effects against two kidney one clip-induced hemodynamic impairment, cardiovascular remodeling and glomerulus hypertrophy in rats. PMID- 23019908 TI - [The role of hypercholesterolemia in the outbreak of Alzheimer's disease and the treatment effect of Sibraea angustata extract]. AB - OBJECTIVE: To observe the role of hypercholesterolemia in the outbreak of Alzheimer's disease (AD) and the treatment effect of Sibraea angustata extract. METHODS: Divided rats into four groups randomly: normal controls for group I ,Alzheimer's disease model for group II, hypercholesterolemia involved in Alzheimer's disease model for group III, and treatment by Sibraea angustata model for group IV. Then observed the general reaction of each group;The content of cholesterol in the blood and brain tissue was detected; The neurofibrillary tangles, beta amyloidal protein deposits and loss of midbrain neurons of hippocampus and cortex tissue were observed. In time fluorescence quantitative method was used to detect the hippocampus and cortex tissue metabolism of cholesterol key genes CYP46a1 and APOE expression. The tau expression was determined by Western-blot. RESULTS: Compared with the normal group, group II, III turned to be listless, poor appetite, fur rough, especially group III, group IV after the treatment of Sibraea angustata extract, the animals turned to be spirit better,increased appetite,fur smooth; Group II's cholesterol content did not differ significantly compared with the normal group. While Group II was obviously higher than that of group II (P < 0.05), and group IV was lower than those of all the others after the treatment of Sibraea angustata. Actually the content of cholesterol of group II, III increased obviously, especially group III, while decreases in group IV after the treatment. Compared with group I :the expression of APOE mRNA RMFI both increased in group II & III (P < 0.01), and group III was higher than group II (P < 0.01), but group IV decreased dramatically. The expression of CYP46al RMFI decreased of group II & III (P < 0.01), while that of group IV increased;The expression of tau protein phosphorylation was down-regulated in group II, III, especially group III, that of group IV was down-regulated. CONCLUSION: Hypercholesterolemia can promote the happening of the AD. The extract of Sibraea angustata can not only reduce the content of cholesterol in the AD animal effectively but also improve brain tissue pathology. It is possible that adjusting the brain key enzyme cholesterol metabolism in gene or protein level may be one of the mechanisms. PMID- 23019909 TI - [Protection and mechanism of Fagopyrum cymosum on lung injury in rats with Klebsiella pneumonia]. AB - OBJECTIVE: To study the mechanism of protective effect of Fagopyrum cymosum on lung injury induced by Klebsiella pneumonia in rats. METHODS: The model of rats with Klebsiella pneumonia was established. The male SD rats were randomly divided into control group, model group, Fagopyrum cymosum (6, 3, 1.5 g/kg) three groups, levofloxacin (25 mg/kg) group. The pathological change of lung was observed. The content of IL-1beta, IL-6, IL-8, TNF-alpha, ICAM-1, INF-gamma in serum were measured by radioimmunoassay and Elisa. TNF-alpha, ICAM-1, NF-kappaB p65 protein expressions were measured by immunohistochemistry. MIP-2mRNA expression was detected by in situ hybridization. RESULTS: The rats of model group had obvious lung injury, but those of Fagopyrum cymosum and levofloxacin groups had less injury. The contents of IL-1beta, IL-6, IL-,8, TNF-alpha, ICAM-1 and INF-gamma in serum and the expressions of TNF-a, ICAM-1, NF-kappaB p65 and MIP--2mRNA of model group were significantly higher than those of the control group (P < 0.05 or P < 0.01), while the indexes of Fagopyrum cymosum and levofloxacin groups were significantly lower than those of model group (P < 0.05 or P < 0.01). CONCLUSION: The lung injury induced by Klebsiella pneumonia is related to TNF-alpha, ICAM-1, NF-kappaB p65 and MIP-2mRNA. To decrease the excessive expression of TNF-alpha, ICAM-1, NF-kappaB p65 and MIP-2mRNA might be the main mechanism of protective effect of Fagopyrum cymosum on lung injury. PMID- 23019910 TI - [Effect of artemisinin on the expressions of GRalpha mRNA, GRbeta mRNA and P300/CBP protein in lupus nephritis mice]. AB - OBJECTIVE: To investigate the effects of Artemisinin on the expressions of GRalpha mRNA, GRbeta mRNA and P300/CBP protein in lupus nephritis mice. METHODS: Forty hybrid female mice were randomly and equally divided into four groups with the method of random number table: control group, model group, prednisone group administrated with 6.45 mg/kg Artemisinin (Art) suspension. A mice model of LN was established by injection with living lymph cell suspension. The expressions of GC receptor alpha (GRalpha) mRNA, GC receptor beta (GRbeta) mRNA in peripheral blood mononuclear cells (PBMCs), and transcriptional coactivator P300/CBP protein in renal tissue were respectively measured by the technique of RT - PCR and immunohistochemical assay. RESULTS: Compared with the model group. The expression of transcriptional coactivator P300/CBP protein in renal tissue and GRa mRNA in PBMCs of treatment groups was increased significantly, GRbeta mRNA expression was significantly decreased (P < 0.05 or P < 0.01). And the Art group had a better effect on the expression of GRalpha mRNA and transcriptional coactivator P300/CBP protein than that of the prednisone group (P < 0.01). CONCLUSION: The underlying therapeutic mechanism may be correlated with the regulation of Art on the expressions of GRalpha mRNA, GRbeta mRNA in PBMC and transcriptional coactivator P300/CBP protein in renal tissue. PMID- 23019911 TI - [Optimization on ultrasonic extraction technology of total coumarines in cortex fraxini]. AB - OBJECTIVE: To optimize the ultrasonic extraction technology of total coumarins in Cortex Fraxini. METHODS: The effects of ethanol concentration, ratio of solid to liquid, extraction temperature, ultrasonic frequency and extraction time in extraction procedure on the extraction rate of total coumarins in Cortex Fraxini was researched by single factor experiment, the optimal extraction technology was determined by orthogonal experiment. RESULTS: The optimal extraction technology of total coumarins in Cortex Fraxini was:mixing the material with 60% ethanol according to ratio of solid to liquid 1:10 (W/V), ultrasonic frequency 175 W and extracting 40 min at 50 degrees C. The extraction rate of total coumarins reached 6.283% with the optimal extraction technology. CONCLUSION: Compares with the classic Soxhlet extraction, ultrasound is a less time-comsuming, low energy and great efficiency tool for the fast extraction of coumarins from Cortex Fraxini. PMID- 23019912 TI - [Optimization of extraction on flavonoids from leaves of Heritiera littoralis]. AB - OBJECTIVE: To optimize the preparation procedure for extraction of flavonoids from leaves of Heritiera littoralis. METHODS: Comparing microwave extraction and ultrasonic extraction, The content of total flavonoids was measure by UV spectrophometry and the wavelength set at 510 nm. The effects of treatment time, extraction power, ethanol concentration and solid-liquid ratio were studied. The orthogonal test of four factors and three levels were studied to obtain the extraction technology of flavonoids from leaves of Heritiera littoralis. RESULTS: The optimal technical conditions were mixing leaves of Heritiera littoralis with 70% ethanol on the ratio of 1 g: 30 mL, when microwave treatment time was 8 min and micro-wave power was 400 W. Under this condition, the extraction rate reached 6.15%. CONCLUSION: This study explores a practical extraction method for flavonoids from leaves of Heritiera littoralis, and lay a good foundation for mangrove medical research in future. PMID- 23019913 TI - [Study on the extraction technology of its flavonoids parts from Tricyrtis maculata growing in Shaanxi Province]. AB - OBJECTIVE: To optimize the extraction technology of total flavonoids from Tricyrtis maculata. METHODS: With UV spectrophotometry as detection method and the content of total flavonoids as index,using single factor experiment and L9 (3(4)) orthogonal test, the optimal condition was deterined. RESULTS: The best extraction technology was as follows:soaked the medicinal materials for 15 minutes, water-decoted for 3 times, the solid-water ratio was 1:45, 1:40, 1:40 and the decotion time was 1, 0.5, 0.5 h respectively. CONCLUSION: The optimal extraction technology is reasonable and provides a basis for its further study. PMID- 23019914 TI - [The quality standard study on Hugan qingzhi tablets]. AB - OBJECTIVE: To develop a method of quality control for Hugan qingzhi tablets. METHODS: Fructus Crataegi, Rhizoma Alismatis and Radix Notoginseng were identified by TLC. HPLC was used for the determination of ursolic acid in Hugan qingzhi tablets. RESULTS: The chromatographic spots were identified without the interference of negative control. Ursolic acid had a good linearity over the concentration range of 40-200 microg/mL (r = 1.000). The average recoveries was 99.05% with relatively standard deviations of 1.3%. CONCLUSION: This method is reliable, accurate and specific and can be used for the quality control of Hugan qingzhi tablets. PMID- 23019915 TI - [Optimum extraction technology of total triterpenoids from Hypodematium sinense]. AB - OBJECTIVE: To optimize the extraction technology of total triterpenoids from Hypodematium sinense. METHODS: With 5% vanillin-glacial acetic acid solution and 72% sulfuric acid as chromogenic agent and the content of total tripenoids as index,using single factor experiment and orthogonal test,the optimal extraction condition was determined. RESULTS: The optimal conditions were solid-liquid ratio 1:12, 60% ethanol concentration, and ultrasonic extraction time of 60 min at 60 degrees C. CONCLUSION: The extraction technology is feasible and can be used as extraction process of total triterpenoids from Hypodematium sinense. PMID- 23019916 TI - [Reminiscences of biochemical science in Beijing Medical College]. PMID- 23019917 TI - [Recent advance in DNA epigenetic modifications-the sixth base in the genome]. AB - Recently, 5-hydroxymethyl cytosine (5-hmC) has been discovered as a naturally existed component of normal mammalian genomic DNAs, and it is generally accepted as the sixth base in the genome. This review will introduce the recent advances in the researches on 5-hmC of its formation, tissue-specific distribution, the roles in cell differentiation and gene expression regulation, and the connections as a epigenetic marker with diseases, such as various cancers. We also summarized the current development of the methodologies to detect methylated or hydroxymetholated cytosines of cells at the genomic levels. PMID- 23019918 TI - [Progress in understanding the pathogenesis of Sjogren's syndrome in non-obese diabetic mice]. AB - Sjogren's syndrome is a chronic autoimmune disease, the pathogenesis of which still remains to be explored. Non-obese diabetic (NOD) mouse, presenting impairment of secretory function as well as the development of sialoadenitis, which is in common with human Sjogren's syndrome, is considered as one of the appropriate animal models for the study of Sjogren's syndrome. With regard to genetic factors, apoptosis, autoantibodies and cytokines, this paper reviewed the progress in understanding the pathogenesis of Sjogren's syndrome in NOD mice. PMID- 23019919 TI - [Regulatory mechanism of bradykinin receptor in signal transduction and cardiovascular diseases]. AB - Bradykinin receptors are an important member of the G protein-coupled receptors family. Bradykinin receptor-mediated signal transductions play a significant role in maintaining cardiovascular homeostasis, regulating pain and inflammation. In recent years, the introduction of fluorescence resonance energy transfer, bioluminescence resonance energy transfer and their extended technologies, confirmed that bradykinin receptors can exist in the formation of dimerizations or even high-order oligomers. Compared with the monomer, its signal transduction and pathological features have changed accordingly. In this paper, we overview how bradykinin receptor monomeric and dimers regulate physiological and pathological processes as well as the latest research techniques. PMID- 23019920 TI - [Gap junction communication: alternative pattern of signal exchange in glia and neuron]. AB - Gap junction is a direct communication between the cells as the channel, which exists widely in the central nervous system involving in transporting the electronic and chemical messages between neurons and glias. It plays roles in regulation of metabolism, ion buffer, "calcium wave" as well ATP receptor signal. Gap junction also has been complicated in the nerve growth and development. Switching the gap junction participates in pathological process and maintainning the local metabolites concentration. Calcium wave is the prominently regulated by gap junction. In the central nervous system, it is remain to be elucidated whether the gap junction play roles in embryonic development and pathophysiological processes. PMID- 23019921 TI - [Recent research progresses of transferrin receptor 1 in central nervous system]. AB - Transferrin receptor 1 exists widely in central nervous system (CNS). It is responsible for iron transport in vivo and mediates the endocytosis of transferring-iron complex, regulating the cell growth. TfR1 transports other metal ions as well, such as Mn, Al and Cu. It is proved that TfR1 can help macromolecular drugs to pass through the blood-brain barrier and emerges as a potential therapeutic target of neurological diseases in CNS. This review summarizes recent findings in distribution, function, and modulatory mechanisms of TfR1 as well as its applications as therapeutic targets in clinical medicine. The investigations on these issues can not only provide new ideas for the research about the mechanism and function of TfR1, but also have profound significance in the understanding of neuroscience. PMID- 23019922 TI - [Research progress of tight junction in salivary epithelium]. PMID- 23019923 TI - [The role of neutrophil gelatinase-associated lipocalin (NGAL) in the glycolipid metabolism and inflammation]. PMID- 23019924 TI - [Research progress on intestinal amino acid and amino acid transporters]. PMID- 23019925 TI - [Pericytes: markers, physiological function and diseases]. PMID- 23019926 TI - [The phenotypes of APPswe/PS1dE9 double transgenic mice]. PMID- 23019927 TI - [Current research progress on steroid receptor coactivator-1 expression and function in brain]. PMID- 23019928 TI - [Neural stem cells and stroke induced-neurogenesis]. PMID- 23019929 TI - [The post-translational modification of estrogen receptor alpha in breast cancer]. PMID- 23019930 TI - [Progress of aquaporin 5 on tumor development and metastasis]. PMID- 23019931 TI - [HFOs's origins, positioning and significance]. PMID- 23019933 TI - [Critical care medicine has the breakthrough for the advantages of integrative medicine]. PMID- 23019932 TI - [Investigations of modulations of GSK3 on the development of neural stem cells and oligodendrocyte precursor cells]. PMID- 23019934 TI - [Reporting specification of systematic reviews on Chinese medicine and methodological evaluation]. AB - Currently, the number of systematic reviews on Chinese medicine (CM) increases gradually. However, the quality of the reviews varied, which resulted in great limitations in guiding clinical practice. This article refers to the Cochrane Handbook and PRISMA Statement to introduce the reporting specification of the systematic review, including asking a research question, review methods, presentation of the results, discussion and conclusion. We analyzed the methodology issues in the published systematic reviews on CM in order to improve the quality of future reviews. PMID- 23019936 TI - [Prof. YUE Mei-zhong, a great master for classical prescriptions]. PMID- 23019935 TI - [Learning from Prof. YUE Mei-zhong's academic thought of combining a specific prescription for a specific disease and syndrome typing]. PMID- 23019937 TI - [Prof. YUE Mei-zhong's clinical experience in treating common diseases by disease identification and syndrome typing]. PMID- 23019938 TI - [Clinical observation on combination of compound xuanju capsule and clomiphene citrate in treating ovulatory dysfunctional infertility patients of Shen-yang deficiency]. AB - OBJECTIVE: To explore the therapeutic efficacy of combination of Compound Xuanju Capsule (CXC) and clomiphene citrate (CC) for ovulatory dysfunctional infertility (001) patients of Shen-yang deficiency syndrome (SYDS). METHODS: Totally 87 001 patients of SYDS were randomly assigned to 2 groups, the treatment group (44 cases, treated with CXC and CC) and the control group (43 cases, treated with CC alone). The post-treatment clinical symptoms, the cervical mucus, the endometrial thickness, the quality of follicles, the ovulation, and the pregnancy rate, and so on were observed. RESULTS: In aspect of improving the patients' SYDS, the effective rate was 86.4% (38/44) in the treatment group and 25.6% (11/43) in the control group. It was better in the treatment group (P < 0.01). After treatment better effects on the cervical mucus, the endometrial thickness, and the pregnancy rate were obtained in the treatment group, showing statistical difference when compared with the control group (P < 0.05). There was no statistical difference in the rate of ovulation and mature follicular numbers between the two groups (P > 0.05). CONCLUSION: CXC combined CC could ameliorate hypoestrinemia-like effects on the endometrium, increase the endometrial thickness, and be favorable to the pregnancy in treating ODI patients of SYDS. PMID- 23019939 TI - [Efficacy and safety of patient-controlled sedation with transcutaneous electrical stimulation of auricular Shenmen (TF4) in cesarean section]. AB - OBJECTIVE: To study the efficacy and safety of patient-controlled sedation with transcutaneous electrical stimulation of auricular Shenmen (TF4) in cesarean section. METHODS: A randomized controlled clinical trail was conducted on 180 singleton primiparas (SAS > 30) undergoing selective cesarean section. They were randomly assigned to three groups, i. e., the patient-controlled sedation with transcutaneous electrical stimulation of auricular Shenmen (TF4) group (Group A, 60 cases), the patient-controlled sedation with transcutaneous electrical stimulation of auricular eye point group (Group B, 60 cases), and the control group (Group C, 60 cases). Patients in Group A received patient-controlled sedation with transcutaneous electrical stimulation of auricular Shenmen (TF4) in the operating room. The strength was controlled by patients themselves. The stimulation lasted for 30 min before the epidural puncture till ending the surgery. Patients in Group B received stimulation of auricular eye point. Patients in Group C received pressurization with the same connected line as Group A, but without electric stimulation. The following indices were observed: (1) the bispectral index (BIS), heart rate (HR), mean arterial pressure (MAP), Ramsay sedation score when the women entered the operating room (T0), 30 min after stimulation (T1), at the time after removing the fetus (T2), and by the end of surgery (T3); (2) the concentrations of plasma angiotensin II (AngII) and cortisone (Cor) at the aforesaid time points; (3) the use rates of oxytocin, atropine, and ephedrine; the hemorrhage amount, and the neonatal Apgar score. RESULTS: Compared with Group A, the BIS, the plasma concentrations of AngII and Cor increased at T1, T2, and T3 (P < 0.05), and the Ramsay sedation score decreased (P < 0.05). The HR and MAP increased at T1 (P < 0.05) in Group B and Group C. Compared with T0, the BIS, HR, MAP, and Ramsay sedation score, the plasma concentrations of AnglI and Cor were lowered in Group A at T1 (P < 0.05). There was no statistical difference in the use rates of oxytocin, atropine, and ephedrine; the hemorrhage amount, and the neonatal Apgar score (P > 0.05). CONCLUSIONS: Patient-controlled sedation with transcutaneous electrical stimulation of auricular Shenmen (TF4) in cesarean section had obvious sedative effects. It had no adverse effects on puerperal or neonates. PMID- 23019940 TI - [Clinical observation of Compound Zhebei Granule in improving the survival time of refractory acute leukemia patients]. AB - OBJECTIVE: To observe the effects of Compound Zhebei Granule (CZG) as the main intervention and treatment protocol on the sustained remission time, the median survival time, the relapse rate, and the mortality rate of refractory acute leukemia (RAL) patients. METHODS: The RAL subjects, who were completely released after one standard chemotherapeutic course of the National Support Scheme (Chinese medicine interventions and standard chemotherapy of Western medicine in the peri-chemotherapy) were followed-up to get knowledge of the sustained remission time, the survival time, the relapse rate, and the morbidity. RESULTS: Totally 41 patients were finally accounted into the statistics, 20 in the treatment group and 21 in the control group. The sustained remission time was 172 days in the treatment group and 115 days in the control group, the median survival time was 363 days and 201 days respectively. The relapse rate of the treatment group within 3 months, 6 months,1 year, and the total relapse rate was 30.0%, 50.0%, 70.0%, and 90.0%, respectively, lower than that of the control group (being 42.8%, 76.2%, 90.5%, 90.5%, respectively). The mortality rate of the treatment group was 80.0%, 5.7% lower than that of the control group (85.7%). CONCLUSION: CZG could lengthen the sustained remission time for RAL patients, elevate their survival time, and reduce the relapse rate and the mortality rate. PMID- 23019941 TI - [Adjunctive therapy of hypopharyngeal carcinoma by Qingliu Lianghou Recipe]. AB - OBJECTIVE: To study the adjunctive roles of Qingliu Lianghou Recipe (QLR) in treatment of hypopharyngeal carcinoma. METHODS: A total of 156 patients with hypopharyngeal squamous cell carcinoma were recruited, including 21 cases of stage I, 34 in stage II, 55 in stage III, and 46 in stage IV. Of them, 31 patients (Group A) were managed with operation and post-operative radiotherapy, 40 patients (Group B) with operation, post-operative radiotherapy, and QLR, 45 patients (Group C) were managed with concomitant chemoradiotherapy, 40 patients (Group D)with concomitant chemoradiation and QLR. QLR was given for 12 weeks. The radio- and chemotoxic reactions, quality of life (KPS score), and long-term efficacy (the recurrence time and the survival time) were observed. RESULTS: The toxicity levels were significantly lower in Group B than in Group A, manifested as radioactive dermatitis, mucositis, dysphagia, changes in body weight, and lymphatic edema (P < 0.05, P < 0.01). The toxicity levels were significantly lower in Group D than in Group C, manifested as radioactive dermatitis, mucositis, dysphagia, marrow depression, changes in body weight, and gastrointestinal reactions (P < 0.05, P < 0.01). After treatment the KPS scores of all patients obviously decreased (P < 0.05, P < 0.01). But the KPS scores were significantly higher in Group B than in Group A (P < 0.05), and they were significantly higher in Group D than in Group C (P < 0.05). The 3-year recurrence rate of patients in Group A was 41.94%, 20.00% in Group B, 60.00% in Group C, and 37.50% in Group D (P < 0.05). The 5-year survival rate of patients in Group A was 38.71%, 62.50% in Group B, 22.22% in Group C, and 42.50% in Group D (P < 0.05). CONCLUSIONS: QLR could effectively prevent and reduce the toxicity response caused by operation, radiotherapy and chemotherapy. The combination therapy of integrative medicine could postpone the recurrence and prolong the lifespan of patients. Therefore, we must not neglect the adjunctive therapy of QLR in treating hypopharyngeal carcinoma. PMID- 23019942 TI - [Study on the correlation between the inflammatory factors in the serum and the induced sputum and the hypothalamic-pituitary-adrenal axis function in advanced lung adenocarcinoma of different syndromes]. AB - OBJECTIVE: To study the correlation between the inflammatory factors in the serum and the induced sputum and the hypothalamic-pituitary-adrenal (HPA) axis function in advanced lung adenocarcinoma patients of different syndromes. METHODS: Totally 71 patients with advanced lung adenocarcinoma were assigned to three groups according to syndrome differentiation, i.e., Shen-yang deficiency (SYD) group (28 cases), Fei-qi deficiency (FQD) group (23 cases), and yin deficiency fire excess (YDFE) group (20 cases). Another 41 healthy subjects were enrolled as the normal control group. Sputum was induced and blood samples were collected for measurement of cytokines including tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interleukin-6 (IL-6), and interferon gamma (INF-gamma). The cytokine assay was performed using Bio-Plex Pro multi assay technology. 24-h collection of urine was performed and salivary samples of the diurnal rhythm profiles [including urinary free cortisol (UFC), urinary 17 hydroxycorticosteroids (17-OH), urinary 17-ketosteroid (17-KS), and cortisol in the serum and saliva] were obtained for assessment of the HPA axis activity. RESULTS: A higher level of serum IL-6 and a lower level of 24-h UFC and 17-OH were found in the SYD group (P < 0.05). The urinary 17-KS was obviously lower in the SYD group than in the normal control group and the YDEE group (P < 0.05). Compared with the FQD group and the normal control group, a higher serum level of TNF-alpha and a lower level of IFN-gamma were found in the SYD group and the YDFE group (P < 0.05). The TNF-alpha and TGF-beta levels in the induced sputum obviously increased in the SYD group (P < 0.05). The IFN-gamma level in the induced sputum obviously decreased in the YDFE group (P < 0.05). The serum and salivary cortisol obviously decreased from 8: 00 am to 8:00 am the next morning in the SYD group (P < 0.05). The serum cortisol level was negatively correlated with serum TNF-alpha (r = -0.26, P = 0.03) and serum IL-6 (r = -0.25, P = 0.03). The salivary cortisol level was negatively correlated with IL-6 in the induced sputum (r = -0.29, P = 0.02). The serum IFN-gamma was positively correlated with urinary 17-OH (r = 0.21, P = 0.03). CONCLUSIONS: The inflammatory factors of advanced lung adenocarcinoma patients of SYD syndrome were up-regulated, with the most obvious decreased or disarranged HPA axis functions. The levels of IL-6, TNF alpha, and IFN-gamma were closely correlated with the HPA axis functions. The transformation from qi deficiency, yin deficiency to Shen-yang deficiency existed in lung adenocarcinoma patients. The levels of IL-6, TNF-alpha, and IFN-gamma in the serum and the induced sputum, as well as the HPA axis functions are important indices for microscopic syndrome typing of lung adenocarcinoma. PMID- 23019943 TI - [Curative effect of 3D-CRT combined with gemcitabine concurrently with addition of Kanglaite Injection in treatment of locally advanced pancreatic]. AB - OBJECTIVE: To explore the efficacy of concurrent chemoradiotherapy combined with Kanglaite Injection (KI) for locally advanced pancreatic carcinoma patients. METHODS: Totally 50 patients unsuitable for surgery were randomly assigned to the treatment group and the control group, 25 in each group. Patients in the control group were treated with gemcitabine and concurrent 3D-CRT, while those in the treatment group were also treated with intravenous injection of KI (at 100 mL/d) for 21 successive days, 28 days as one cycle, two cycles with one week interval. The short-term curative effect, the survival time, the improvement of symptoms, the tumor markers, and adverse reactions were respectively observed for two years. RESULTS: The short-term curative effective rate (CR + PR) was 52.17% (12/23), and the disease control rate (CR + PR + SD) was 95.65% (22/23) in the treatment group. The short-term curative effective rate (CR + PR) was 41.67% (10/24), and the disease control rate (CR + PR + SD) was 87.50% (21/24) in the control group. There was no statistical difference between the two groups (P > 0.05). The 2-year survival rate was 34.78% (8/23) in the treatment group, better than that in the control group (25.00%, 6/24). The median survival time was 17.2 months in the treatment group and 12.4 months in the control group with statistical difference (P < 0.05). The response rate of pain relief and weight gain were 75.00% and 82.61% in the treatment group respectively, and they were 50.00% and 54.67% in the control group respectively, showing statistical difference between the two groups (P < 0.05). After treatment, the levels of CA19 9 (U/mL) and CEA (ng/mL) were respectively reduced to 118. 00 +/- 78.89 and 7.41 +/- 2.37 respectively in the treatment group, showing statistical difference when compared with those of the control group (being 216.00 +/- 153.23 and 12.25 +/- 7.53 respectively, P < 0.05). CONCLUSION: The concurrent chemoradiotherapy com- bined with KI for locally advanced pancreatic carcinoma patients obtained better results. PMID- 23019944 TI - [Effects of Maixuekang Capsule on the platelet aggregation rate and its long-term prognosis of patients with acute coronary syndrome under percutaneous coronary intervention]. AB - OBJECTIVE: To study the changes of adenosine diphosphate (ADP)-induced platelet aggregation rate, and evaluate the effects of Maixuekang Capsule (MC) on the platelet aggregation rate, high-sensitive C-reactive protein (hs-CRP) and the long-term prognosis in patients with acute coronary syndrome under percutaneous coronary intervention (PCI). METHODS: Totally 236 inpatients with acute coronary syndrome under PCI, who successively received PCI from July 2008 to June 2010, were randomly assigned to the routine treatment group (RTT, 120 cases) and the MC treatment group (MKT, 116 cases). Besides routine medication, patients in the MKT group additionally took MC, 12 capsules daily for 12 successive months. The ADP induced platelet aggregation rate and hs-CRP concentration were determined before PCI, 12 h and 30 days after PCI. In the meantime, the incidence of adverse cardio /cerebrovascular events was recorded during the twelve-month clinical follow-up. Results Compared with before PCI, ADP-induced platelet aggregation rate and the serum hs-CRP concentration were significantly higher 12 h after PCI (P < 0.05). They were significantly reduced after 30-day treatment of MC, showing statistical difference when compared with those in the RTT group (P < 0.05). In the 12-month follow-up, the incidence of adverse cardio-/cerebrovascular events was significantly lower in the MKT group than in the RTT group (6.9% vs 12.5%, P < 0.01). CONCLUSIONS: ADP-induced platelet aggregation function was significantly elevated after PCI, which was a predictive factor of poor coronary events. MC improved the long-term prognosis of patients with acute coronary syndrome possibly through inhibiting the platelet aggregation rate and the hs-CRP concentration. PMID- 23019945 TI - [Clinical study of Jiangtang Xiaozhi Capsule in treating type 2 diabetes mellitus patients]. AB - OBJECTIVE: To evaluate the efficacy and safety of Jiangtang Xiaozhi Capsule (JTXZC) in treating type 2 diabetes mellitus (T2DM) patients of qi-yin deficiency and inter-obstruction between phlegm and stasis. METHODS: Adopting prospective, randomized, controlled trial design, 73 T2DM patients of qi-yin deficiency and inter-obstruction between phlegm and stasis syndrome, were randomly assigned to two groups, the pioglitazone tablet group (36 cases) and the JTXZC group (37 cases). The therapeutic course for all was 8 weeks. The body weight, height, body mass index (BMI), waistline (WC), hipline, waist-to-hip ratio (WHR), and scoring for Chinese medicine (CM) symptoms assessment were observed. The fasting blood glucose (FBG), 2-h postprandial blood glucose (PBG), glycated hemoglobin (HbA1c), plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), plasma insulin (FINS) were detected. The HOMA-IR was also calculated. The safety indices such as liver and renal functions, adverse reactions were also observed. RESULTS: The levels of HbA1c were lowered after treatment in the two groups after 8 weeks of treatment, showing statistical difference when compared with before treatment ( 0.59% +/- 1.99% and -0.27% +/- 2.73%, P < 0.05). The PBG level also decreased with statistical difference (-1.71 +/- 2.52 mmol/L and -0.72 +/- 4.17 mmol/L, P < 0.05), but there was no statistical difference between the two groups. The body weight, BMI, TG obviously decreased (P < 0.05). The CM symptoms efficacy and CM symptom scoring were significantly reduced in the two groups (P < 0.01). Besides, better effects were shown in the JTXZC group (P < 0.05). No severe adverse event occurred in either group during the therapeutic course. There was no statistical difference in the incidence of adverse events (P > 0.05). CONCLUSIONS: JTXZC showed similar therapeutic effects to pioglitazone. They both could effectively im- prove clinical symptoms with no severe adverse reaction. PMID- 23019946 TI - [Correlation between Chinese medicine syndromes and the NPHS1 gene and NPHS2 gene polymorphism as well as corticosteroid sensitivity in patients with minimal change disease]. AB - OBJECTIVE: To explore the correlation between Chinese medicine (CM) syndromes and the NPHS1 gene and NPHS2 gene polymorphism as well as corticosteroid sensitivity in patients with minimal change disease (MCD). METHODS: A total of 94 MCD patients were recruited, including 58 steroid-sensitive nephritic syndrome (SSNS) patients and 36 steroid-resistant nephritic syndrome (SRNS) patients. Genomic DNA was obtained from peripheral blood lymphocytes and sequence analysis of single nucleotide polymorphisms (SNPs) in the genes was performed. RESULTS: (1) The SNPs of G349A-3 in NPHS1 gene was found in MCD, but the SNPs of G686A-5 and C695T-5 in NPHS2 gene were not discovered in MCD. (2) When comparing the frequency of genotype AA and allele A in NPHS1 gene (G349A-3), genotype AA and allele A were higher in the SRNS group than in the SSNS group (P < 0.05). (3) When compared with the SRNS group, qi yang deficiency syndrome had a higher incidence in the SSNS group, and yin deficiency syndrome and qi-yin deficiency syndrome had a less incidence in the SSNS, but with no statistical difference (P > 0.05). The rheumatism syndrome had a higher incidence in the SSNS group (P < 0.05). The blood stasis syndrome had a lower incidence in the SSNS with statistical difference (P < 0.05). (4) There was no statistical difference in the correlation between GG, AA, GA and CM syndromes (P > 0.05). CONCLUSIONS: Homozygous mutations of AA and allele A in NPHS1 gene were correlated to SRNS patients of MCD. Rheumatism syndrome patients were prone to be sensitive to corticosteroids, while patients of blood stasis syndrome were prone to be insensitive to corticosteroids. We didn't discover the correlation between NPHS1 gene polymorphism and CM syndrome distribution. PMID- 23019947 TI - [Clinical research on Sanmiao powder combined fibrinogenase for injection in treatment of acute deep venous thrombosis of lower limbs]. AB - OBJECTIVE: To observe the clinical effectiveness of Sanmiao Powder (SP) combined fibrinogenase for injection in treatment of acute deep venous thrombosis (ADVT) of lower limbs. METHODS: Eighty patients with ADVT were randomly assigned to two groups according to the disease course (within 7 days or 7-28 days), 40 in each group. Every time phase was also divided into two groups, i. e., one group treated with fibrinogenase for injection alone (Group A and C) and another group treated with fibrinogenase for injection + SP administration (Group B and D) , 20 in each group. The clinical effectiveness was observed after 2-week treatment. RESULTS: The fibrinogenase for injection + SP administration showed better effects in alleviating the swelling of limbs, relieving pain, and lowering fibrinogen. Better effects were obtained in the group with the disease course less than 7 days. CONCLUSION: Better effect on ADVT was obtained by integrative medicine. PMID- 23019948 TI - [Effects of tuina manipulation on the three-dimensional space of cervical vertebral segments of cervical spondylosis patients]. AB - OBJECTIVE: To study the mechanisms of tuina manipulation for treating the dislocation of bone in cervical spondylosis (CS) patients by observing the effects of tuina manipulation on the three-dimensional (3D) angles. METHODS: From August to December 2009 20 CS patients were assigned to Group 1 (10 cases, treated with relaxing manipulation) and Group 2 (10 cases, treated with relaxing manipulation and joint regulation). Besides, 10 healthy subjects were recruited as the normal group (treated with relaxing manipulation). Before and after manipulation intervention, all of them were scanned from the base of the skull to the first thoracic vertebra using Philips 64 spiral CT under equal conditions, thus obtaining the volume data. The 0.625 mm thickness was reconstructed using ITK reconstruction software provided by the digital medical laboratory, Software College of Shanghai Jiaotong University. The reconstruction of each cervical skeleton was finished referring to CT data. Changes of the 3D angles were compared among the three groups. RESULTS: The regulation of the 3D C2 vertebra: Results of Group 2 were significantly larger than those of the normal group at X , Y-, and Z-axis (P < 0.05). Results of Group 2 were significantly larger than those of Group 1 at X- and Z-axis (P < 0.05). But results of Group 1 were significantly larger than those of the normal group at Z-axis (P < 0.05). The regulation of the 3D C3 vertebra: Results of Group 2 were significantly larger than those of the normal group at X- and Y-axis (P < 0.05). Results of Group 2 were significantly larger than those of Group 1 at X-axis (P < 0.05). But results of Group 1 were significantly larger than those of the normal group at X-axis (P < 0.05). The regulation of the 3D C4 vertebra: Results of Group 2 were significantly larger than those of the normal group at X- and Y-axis (P < 0.05). Results of Group 2 were significantly larger than those of Group 1 at X- and Z axis (P < 0.05). There were no significant difference among the three groups in the 3D spaces of C1, C5, C6, and C7. The larger 3D space was shown in Group 2 than in Group 1 and the normal group. CONCLUSIONS: The relaxing manipulation combined with joint regulation significantly improved the 3D angles of C2, C3, and C4 in CS patients. The mechanism of tuina manipulation for treating the dislocation of bone in CS patients might lie in adjusting the 3D space of the cervical spine, and improving its functions. PMID- 23019949 TI - [Effects of Jing'an Oral Liquid on the central neurotransmitter of multiple tics children]. AB - OBJECTIVE: To study the effects of Jing'an Oral Liquid (JOL) on the central neurotransmitters of multiple tics (MT) children. METHODS: Sixty MT children patients were randomly assigned to the treatment group and the control group, 30 cases in each group. Another 30 healthy children were recruited as the health group. JOL and Tiapride Tablet (TT) was respectively given to patients in the treatment group and the control group. The treatment course was 2 months. The levels of central neurotransmitters [dopamine (DA), homovanillic acid (HVA), 5 hydroxytryptamine (5-HT), norepinephrine (NE), glutamic acid (GLU), aspartate (ASP), gamma-aminobutyric acid (GABA)] were measured using high performance liquid chromatography (HPLC) before and after treatment, and compared with the health group. RESULTS: Compared with the health group, the levels of 5-HT, HVA, GLU, and ASP significantly increased in the treatment group and the control group before treatment (P < 0.05), GABA significantly decreased (P < 0.05). Compared with before treatment in the same group, the levels 5-HT, HVA, and GLU significantly decreased in the treatment group (P < 0.05), while the levels of NE and GABA significantly increased (P < 0.05). The levels of DA, 5-HT, GLU, and ASP significantly decreased, while the levels of NE ang GABA significantly increased in the control group, showing statistical difference (P < 0.05). There was no statistical difference in each index between the treatment group and the control group before and after treatment (P > 0.05). CONCLUSIONS: (1) The imbalance of a variety of monoamines and amino acid neurotransmitters can lead to MT, especially in the changes of 5-HT, HVA, GLU, ASP, and GABA. (2) JOL can significantly reduce the levels of 5-HT, HVA, and GLU, and significantly increase the levels of NE and GABA, which might be its pharmacodynamic mechanisms for treating MT. PMID- 23019950 TI - [Effects of Tanshinone II A on the myocardial apoptosis and the miR-133 levels in rats with heart failure]. AB - OBJECTIVE: To explore the effects of Tanshinone II A (Tan II A) on the myocardial apoptosis in rats with heart failure and its mechanisms for regulating the miR- 133 levels. METHODS: The heart failure rat model was established by thoracic aorta constriction (TAC). Tan II A Injection was applied for 12 successive weeks. Meanwhile, partial heart failure rats were subcutaneously implanted with osmotic pump of antagonist to observe its inhibition on the miR-133 level. Twelve weeks later, the hemodynamic conditions, the myocardial apoptosis (using TUENL method), myocardial pro-apoptotic genes (Bax and Caspase-3), and the expressions of anti apoptosis genes (Bcl-2) (using Western blot and RT-PCR method) were analyzed. RESULTS: Compared with the sham-operation group, TAC operation could deteriorate the heart function (except the mean arterial pressure), elevate the myocardial apoptosis level, increase the protein and mRNA levels of Bax and Caspase-3, and down-regulate the protein and mRNA levels of miR-133 and Bcl-2. TAC rats treated by Tan II A could significantly improve all indices with statistical difference except the heart rate. Subcutaneously pumping of antagonist could partially abolish the anti-apoptosis effect of Tan II A. CONCLUSION: Tan II A could decrease the myocardial apoptosis level of heart failure rats, which was possibly realized by up-regulating the miR-133 level. PMID- 23019951 TI - [Effects of Sini decoction on the expressions of Smad2 and Smad7 in isoproterenol induced myocardial fibrosis rats]. AB - OBJECTIVE: To explore the effects of Sini Decoction (SD) on the expressions of Samd2 and Smad7 isoproterenol (Iso) induced myocardial fibrosis rats. METHODS: Totally 19 Wistar rats were randomly divided into 3 groups, i.e., the control group, the model group, and the SD group. Iso was injected to rats in the model group and the SD group, while normal saline was injected to rats in the control group. SD was given to rats in the SD group by gastrogavage, while normal saline was administered to rats in the control group and the model group by gastrogavage. Four weeks later Masson staining and electron microscopic analysis were performed in each group. The protein and mRNA expressions of Smad2 and Smad7 were detected using immunohistochemical assay and RT-PCR. RESULTS: Masson staining showed the IOD value of the myocardial collagen fiber was 9 303 in the model group, 2 459 in the SD group, and 4 224 in the control group, indicating the myocardial fibrosis was more obvious in the model group than in the SD group and the control group. The IOD value of Smad2 protein was 20 275 and the mRNA IOD of Smad2 protein was 0. 919 in the model group, while they were respectively 9 949 and 0. 561 in the SD group, indicating the protein and mRNA expressions of Smad2 were obviously higher in the model group than in the SD group (P < 0.05). The IOD value of Smad7 protein was 25 667 and the mRNA IOD of Smad7 protein was 0.222 in the model group, while they were respectively 93 147 and 0. 412 in the SD group, indicating the protein and mRNA expressions of Smad7 was obviously lower in the model group than in the SD group (P < 0.05). CONCLUSION: SD could effectively inhibit Iso induced myocardial fibrosis, and its mechanism may be associated with down-regulating the expression of Smad2 and up-regulating the expression of Smad7. PMID- 23019952 TI - [Experimental study on attenuating ischemic injury of acute myocardial infarction rats by Huoxue Anxin Recipe]. AB - OBJECTIVE: To study the protection effects and the mechanisms of Huoxue Anxin Recipe (HAR) on acute myocardial infarction (AMI) rats. METHODS: The AMI Wistar rat model was prepared by ligating the left anterior descending coronary artery. By taking elantan long as the positive control drug, HAR was extracted from Chinese herbs by modern pharmacological methods and composed according to theories of Chinese medicine (CM). The medication time started from the day of modeling to the 21st day of the modeling. The heart function, the morphological changes of the heart, changes in the mRNA and protein levels of toll like receptor 4 nuclear factor kappa B tumor necrosis factor alpha (TLR4-NFkappaB TNFalpha) pathway were observed. RESULTS: Compared with the sham-operation group, the ejection fraction (EF) and left ventricular fractional shortening (FS) significantly decreased (P < 0.01), the left ventricular intemal dimension end diastolic (LVIDd) and left ventricular internal dimension end-systolic (LVIDs) significantly increased (P < 0.01), the mRNA and protein levels of TLR4-NFkappaB TNFalpha channel significantly increased in the model group (P < 0.01). The infarction in the front wall of the left ventricle was obviously seen, accompanied with severe inflammatory cell infiltration and collagen deposition in model group. Compared with the model group, the EF and FS significantly increased, LVIDd and LVIDs significantly decreased in the positive control group, the high and low dose HAR groups (P < 0.05, P < 0.01). The infracted area of the front wall of the left ventricle was obviously contracted. The inflammatory cell infiltration and collagen deposition were obviously alleviated. In the high and low dose HAR groups, the mRNA and protein expression levels of TLR4-NFkappaB TNFalpha significantly decreased (P < 0.05, P < 0.01), but no inhibition was found in the positive control group. CONCLUSIONS: HAR could significantly improve the morphological structures and functional abnormality induced by myocardial ischemia in AMI rats. Its effects was correlated with inhibiting TLR4-NFkappaB TNFalpha pathway. PMID- 23019953 TI - [Effects of glycyrrhetinic acid on sodium ion channel currents of rats' ventricular myocardial cells]. AB - OBJECTIVE: To study the effects of glycyrrhetinic acid (GA) on the sodium ion channel currents (I(Na)) of rats' ventricular myocardial cells, and to explore its anti-arrhythmic mechanisms at the ion channel level. METHODS: Single ventricular myocardial cells was isolated from SD rats. The whole cell patch clamp was used to record the effects of GA on I(Na) of rats' ventricular myocardial cells. RESULTS: GA could inhibit I(Na) of rats' ventricular myocardial cells dose-dependently. GA at 1, 5, and 10 micromol/L decreased I(Na) of rats' ventricular myocardial cells from (-4.26 +/- 0.15) nA to (-3.54 +/- 0.10) nA, ( 2.19 +/- 0.09) nA, and (-1.25 +/- 0.08) nA, respectively. GA at 1, 5, and 10 micromol/L inhibited I(Na) by 16.08% +/- 2.3%, 50.82% +/- 3.56%, and 75.98% +/- 5.12%, showing statistical difference when compared with the control group (P < 0.05). GA at 10 micromol/L shifted I(Na) current-voltage curve more positively, but the activation potential and the peak potential were not changed. CONCLUSION: GA inhibited the I(Na) of rats' ventricular myocardial cells dose-dependently, which was possibly associated with its antiarrhythmia effects. PMID- 23019954 TI - [Study on improving the speed and quality of making rat myocardial infarction model by coronary artery ligation]. AB - OBJECTIVE: To establish the methods for improving the speed and quality of making rat myocardial infarction model by coronary artery ligation. METHODS: With the precondition of having no effect on rat myocardial infarction size: (1) To compare the thoracotomy time, the ligation time of the way of coronary artery ligation by tying one knot with the way by tying two knots. (2) To compare the survival rate of making model, the onset time of anesthesia, the awakening time, the effect on myocardial infarction size between using hydration chlorine aldehyde and using sodium pentobarbital. RESULTS: In case of having no significant effect on the myocardial infarction size (P > 0.05), the way of tying one knot could significantly shorten the thoracotomy time and the ligation time (P < 0.01). There was no statistical difference in the onset time of anesthesia or the myocardial infarction size between the model made by sodium pentobarbital and that made by hydration chlorine aldehyde (P > 0.05). But the awakening time of the model made by sodium pentobarbital was obviously shortened (P < 0.01). The clarity rate of myocardial infarction size was improved. CONCLUSIONS: The way of tying one knot could improve the speed of model making. Sodium pentobarbital as the anesthetic for in vivo rat myocardial infarction model could improve the clarity rate of myocardial infarction area. PMID- 23019955 TI - [Protective effects of Ginkgo biloba extract on the lung injury of dogs undergoing hypothermic cardiopulmonary bypass]. AB - OBJECTIVE: To study the protective effects of Ginkgo biloba extract (EGb) on the lung injury of dogs undergoing hypothermic cardiopulmonary bypass (CPB). METHODS: Fourteen healthy hybrid dogs were randomly divided into the control group and the EGb group, 7 in each group. EGb (8 mg/kg) was intravenously dripped to dogs in the EGb group before thoracotomy after anesthesia, while equal volume of normal saline was intravenously dripped to those in the control group. The lung tissue was collected after 60-min CPB and 120-min recovery of heart beat. The lung tissues were collected to detect the wet weight-dry weight ratio and the permeability. The contents of malondialdehyde (MDA), the activities of myeloperoxidase (MPO) and total superoxide dismutase (T-SOD) in the lung tissues were detected by biochemical assay. The levels of IL-1beta, IL-8, tumor necrosis factor alpha (TNF-alpha), platelet activating factor (PAF) in the lung tissue were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with the control group, the wet weight-dry weight ratio was reduced and the permeability of the lung tissue decreased (P < 0.05), the MDA content was reduced, the activity of MPO decreased, and the activity of T-SOD increased (P < 0.05), and the levels of IL-1beta, IL-8, and PAF obviously decreased (P < 0.05). CONCLUSIONS: EGb showed better protective effects on the lung injury of dogs undergoing hypothermic CPB. Its possible mechanisms might be associated with alleviating ischemia-reperfusion injury of in vitro circulation and systemic inflammatory response. PMID- 23019956 TI - [Effects of huatan jiangqi capsule on the levels of multi-drug resistance associated protein 1 in the bronchial epithelial cells of model rats with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To observe the effects of huatan jiangqi capsule (HJC) on the expression levels and functions of multi-drug resistance-associated protein 1 (MRP1) in the bronchial epithelial cells of chronic obstructive pulmonary disease (COPD) model rats, and to explore the mechanism of HJC for treating COPD. METHODS: Twenty-four male wistar rats were randomly divided into the normal control group, the model group, and HJC group. Except the normal control group, the COPD rat model was established in the rest groups using quantitative stimulation with tobacco, SO2, and caroid aerosol rebreathing method. The indices of the post-treatment lung functions, the cell counts of bronchoalveolar lavage fluid (BALF), the pathological features of the lung tissue were observed. The concentration of LTC, in lung tissues was also examined by ELISA. The expression of MRP1 of the pulmonary tracheal epithelium was detected using immunohistochemical assay. RESULTS: (1) The pulmonary compliance, the forced expiratory volume at 0. 3 second (FEV 0.3%)/the forced vital capacity (FVC), the peak expiratory flow, the maximum mid expiratory flow decreased more significantly in the model group than in the normal control group (P < 0.05). The aforesaid pulmonary function indices obviously increased in the HJC group when compared with the model group (P < 0.05). (2) The air inflammation was aggravated with obvious emphysema in the model group. The inflammation and emphysema occurred in the HJC group in a milder degree. (3) Compared with the normal control group, the levels of LTC4 significantly increased in the lung tissue of the model group and HJC group (P < 0.01). Compared with the model group, the levels of LTC4 significantly decreased in the lung tissues of the HJC group (P < 0.05). (4) Compared with the normal control group, the protein expression of the bronchial epithelial MRP1 significantly decreased in the model group (P < 0.01). Compared with the model group, the protein expression of the bronchial epithelial MRP1 were significantly enhanced in the HJC group (P < 0.05). CONCLUSION: HJC could effectively alleviate the lung inflammation, postpone the occurrence and development of COPD possibly through effecting the functions and expressions of MRP1 in COPD rats. PMID- 23019957 TI - [Effects of Chinese materia medica of qi benefiting, yin nourishing, stasis removing, and collaterals dredging and their dissembled recipes on nephrin of diabetes mellitus model rats]. AB - OBJECTIVE: To observe the effects of Chinese materia medica (CMM) of qi benefiting, yin nourishing, stasis removing, and collaterals dredging (QBYNSRCD) and their dissembled recipes on nephrin of diabetes mellitus (DM) model rats. METHODS: The DM model was induced by high fat diet combined with low dose STZ. Rats in the normal control group (abbreviated as Group N) and the model group (abbreviated as Group M) were administered with ultrapure water at corresponding volume by gastrogavage. Rats in the CMM of QBYNSRCD treatment group (abbreviated as Group YHT) were administered with CMM of QBYNSRCD, composed of milkvetch root, rehmannia root, danshen root, chuanxiong (2 packages each), solomonseal, earth worm, leech, and scorpion (1 package each), which was administered at 1.0 g/kg. Rats in the CMM of qi benefiting, yin nourishing, and stasis removing (QBYNSR) treatment group (abbreviated as Group YT) were administered with CMM of QBYNSR, composed of milkvetch root, rehmannia root, danshen root, chuanxiong (2 packages each), and solomonseal (1 package each), which was administered at 0. 92 g/kg. Rats in the CMM of qi benefiting, yin nourishing, and collaterals dredging (QBYNCD) treatment group (abbreviated as Group YT) were administered with CMM of QBYNCD, composed of milkvetch root, rehmannia root (2 packages each), solomonseal, earth worm, leech, and scorpion (1 package each), which was administered at 0.79 g/kg. The volume was set to 1 mL/100 g, once daily by gastrogavage, for total 32 weeks. Rats' body weight was measured. By the end of medication, urinary creatinine (UCr), 24-h urinary albumin (U-alb), and urinary nephrin (U-nephrin), fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), serum creatinine (SCr), and nephrin of kidney tissues homogenate (K nephrin) were detected. The renal tissue sections were stained with Masson. The pathomorphological changes were observed. RESULTS: The body weight of rats in Group N increased gradually. After modeling, the body weight of rats in Group M and all medicated groups obviously decreased. Compared with Group M, the decreased body weight was not obvious in all medicated groups, still showing statistical difference (P < 0.01). Compared with Group N, U-alb and U-nephrin in Group M significantly increased (P < 0.01) in a positive linear correlation (r = 0.941, P = 0.017). K-nephrin significantly decreased, and K-nephrin had a negative linear correlation with U-alb (r = -0. 987, P = 0.002). FBG, CCr, and HbA1c significantly increased (P < 0.01). Glomeruli were obviously enlarged under light microscope, with obviously increased extracellular matrix accumulation. Compared with Group M, corresponding indices were obviously improved ( P < 0.01) except FBG and HbA1c in Group YT. As for inter-group comparison among all medicated groups, the improvement of CCr was the best in Group YHT with statistical difference shown (P < 0.01). There was no statistical difference for the rest indices (P > 0.05). When compared with Group M, the hypertrophy of glomerulus was not so obvious in all medicated groups. Neither was extracellular matrix accumulation. CONCLUSIONS: CMM of QBYNSRCD and dissembled recipes showed renal protection on DM model rats. One of its action pathways might be reducing the loss of nephrin, thus reducing U-alb. PMID- 23019958 TI - [Effects of tanshinone IIA on Wnt/beta-catenin signaling pathway of high glucose induced renal tubular epithelial cell transdifferentiation]. AB - OBJECTIVE: To observe the expressions of Wnt/beta-catenin and the effects of tanshinone IIA (TII A) on Wnt/beta-catenin signaling pathway in high glucose induced renal tubular epithelial cell transdifferentiation. METHODS: Human kidney proximal tubular epithelial cells (HK-2) were divided into three groups, i. e., the normal glucose group, the high glucose group, and the high glucose plus tanshinone IIA group. The expression of beta-catenin was observed using immunocytochemical staining. The protein expression of beta-catenin, E-cadherin, and alpha-smooth muscle actin (alpha-SMA) were detected by Western blot. The mRNA levels of beta-catenin and E-cadherin were detected by RT-PCR. RESULTS: Compared with the normal glucose group, both the protein and the mRNA expressions of beta catenin were significantly enhanced (P < 0.01), the expression of E-cadherin significantly decreased (P < 0.01), the expression of beta-catenin increased in the cytoplasm and nucleus in the high glucose group. TIIA at the final concentration of 100 micromol/L significantly reduced the ectopic expression of beta-catenin. At that concentration, the protein and mRNA expressions of beta catenin in the nucleus significantly decreased, while the protein and mRNA expressions of E-cadherin were up-regulated. Meanwhile, the expression of alpha SMA obviously decreased. CONCLUSIONS: Wnt/beta-catenin signaling pathway participated in the high glucose induced renal tubular epithelial cell transdifferentiation. TIIA inhibited the transdifferentiation process possibly through down-regulating the activities of Wnt/beta-catenin signaling pathway, thus further playing a role in renal protection. PMID- 23019959 TI - [Anti-angiogenic effects of zengmian YiIiu granule on ovarian carcinoma xenograft]. AB - OBJECTIVE: To investigate the anti-angiogenic effects and mechanisms of Zengmian Yiliu Granule (ZMYLG) on ovarian carcinoma xenograft. METHODS: The SKOV3 ovarian carcinoma bearing mouse model was established. The tumor-bearing mice were randomly divided into the control group, the paclitaxel group, the high, medium, and low dose ZMYLG group, 8 in each group. The medication was lasted for ten days. The microvessel density (MVD) in the xenograft was calculated by the method of using cell membrane differentiation antigen 34 (CD34) antibody marking new vascular endothelial cells. The protein and mRNA expressions of vascular endothelial growth factor (VEGF) and its receptor fetal liver kinase-1 (FLK-1), hypoxia inducible factor-1alpha (HIF-1alpha) in the tumor were determined using immunohistochemical assay and RT-PCR. RESULTS: The MVD of ovarian carcinoma xenografts in the paclitaxel group, the high, medium, and low dose ZMYLG group obviously decreased, showing statistical difference when compared with the control group (P < 0.01, P < 0.05). Each ZMYLG dose group could down-regulate the protein and mRNA expressions of VEGF, FLK-1, and HIF-1alpha (P < 0.01, P < 0.05). CONCLUSIONS: ZMYLG could inhibit neogenesis of tumor vessels. Its mechanisms might be associated with down-regulating the expression of HIF-1alpha, modifying the hypoxic state, inhibiting the expressions of VEGF and FLK-1, and exerting its anti-angiogenic effects. PMID- 23019960 TI - [Experimental study of ginsenoside Rb1 on herpes simplex virus-1 infection for protecting nerves]. AB - OBJECTIVE: To explore the action mechanism of ginsenoside Rb1 (GRb1) on protecting herpes simplex virus-1 (HSV-1) infected nerves by studying its inhibitory effects on abnormal changes of apoptosis and nerve growth factor (NGF) mRNA expression in HSV-1 infected human glioma cells U251. METHODS: The inhibitory effects of GRb1 on HSV-1 induced abnormal apoptosis of U251 cells were detected using MTT colorimetry and flow cytometry. The NGF mRNA expressions in different treatment groups were detected using semiquantitative RT-PCR. RESULTS: (1) In 400 microg/mL GRb1 + HSV-1 group, MTT value was higher than HSV-1 group at 24, 36, and 48 h after infection (P < 0.05). (2) Cytopathic effects (CPE) were observed in HSV-1 group at 36 h after infection. In 400 microg/mL GRb1 + HSV-1 group merges increased at 36 h after infection, but most cells were in normal shapes. (3) Results of flow cytometry showed that the cell apoptosis rate was lower in 400 microg/mL GRb1 + HSV-1 group than in the HSV-1 group at24 and 36 h after infection (P < 0.05). (4) Results of RT-PCR showed that in 400 microg/mL GRb1 + HSV-1 group, NGF mRNA expressions decreased at 6-12 h after infection (P < 0.05), but it increased at 24, 36, and 48 h after infection, and was obviously higher than that in the HSV-1 group (P < 0.05). CONCLUSIONS: GRb1 at an appropriate concentration could inhibit abnormal cell apoptosis and changes of NGF mRNA expressions in HSV-1 infection. Therefore, we inferred that GRb1 could protect nerves possibly through up-regulating NGF mRNA expressions and inhibiting apoptosis. PMID- 23019961 TI - [Effects of musk ketone at different concentrations on in vivo migration of exogenous rat bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To study the effects of musk ketone at different concentrations on in vivo migration of exogenous rat bone marrow mesenchymal stem cells (rBMSCs), thus screening out the optimal therapeutic dose. METHODS: Forty SD rats were randomly divided into 4 groups, 10 in each group. The rat model of skull defect was established using dental surgery. The primary rBMSCs were cultured by adherence screening method. The third passage cells were labeled by 10 micromol/L BrdU, and the labeled cells were injected into skull defect rats from the tail vein. Rats were administered with musk ketone at high, moderate and low concentration, respectively by gastrogavage, while equal volume of normal saline was administered to those in the blank control group by gastrogavage. Their skulls were taken out 14 days later, fixed, and decalcified. BrdU positive cells were counted under fluorescence microscope. RESULTS: After immunohistochemical processing, the gray scale analysis was preformed. There was statistical difference in the BrdU positive cell number between the blank control group and the low and moderate concentration musk ketone groups (P < 0.01). There was no statistical difference in the BrdU positive cell number between the blank control group and the high concentration musk ketone group (P > 0.05). CONCLUSION: Musk ketone could accelerate the in vivo migration of exogenous stem cells, with the optimal effects obtained at moderate and low concentrations. PMID- 23019962 TI - [The correlation between adrenal corticosteroids and cytokines expressions in mice of different syndromes]. AB - OBJECTIVE: To study the cytokines expressions in the adrenal gland and its correlation with serum adrenal corticosteroids in mice of different syndromes. METHODS: Using the quantitative four diagnosis and syndrome differentiation methods, 60 normal mice and 190 H22 liver cancer bearing mice were syndrome typed. Serum corticosterone and aldosterone were tested by ELISA, and mRNA expressions of cytokines in the adrenal gland were detected using Real-time PCR. RESULTS: Mice of different syndromes were obtained, such as normal mice of no syndrome, normal mice of vigorous qi syndrome, normal mice of qi deficiency syndrome, liver cancer bearing mice of excessive evil toxic syndrome, liver cancer bearing mice of evil lying in the middle syndrome, liver cancer bearing mice of weak evil toxic syndrome, and liver cancer bearing mice of poisonous pathogenic factors and qi deficiency syndrome. The serum corticosteroids were significantly higher in the liver cancer bearing mice than in the normal mice (P < 0.05). The cortex hormones increased most significantly in the liver cancer bearing mice of excessive evil toxic syndrome (P < 0.05). Compared with the normal mice, IL-1beta, IL-2, IL-6, IL-10, IL-12alpha, IL-12beta, and TNF-alpha gene expressions increased in the liver cancer bearing mice, while only expressions of IL-1alpha and IL-5 decreased. But the expressions of IL-13 and transforming growth factor beta1 (TGF-beta1) showed no regularity. The expressions of IL-4 and INF-alpha were not detected in all mice. It is notable that the more severe degree of poisonous pathogenic factors, the higher the expressions of serum corticosterone and aldosterone levels as well as IL-6, the lower expressions of IL-1beta, IL-2, IL-5, IL-12alpha, IL-12beta, and TNF-alpha. CONCLUSIONS: The increased serum corticosteroid level in liver cancer bearing mice could possibly be induced by chronic tumor stress, partial cytokines were involved in the synthesis and secretion of the adrenal hormone. Of them, IL-6 might positively regulate the secretion of corticosteroids, while IL-1beta, IL-2, IL-5, IL-12alpha, IL-12beta, and TNF-alpha might negatively regulate their secretions. PMID- 23019963 TI - [Proteomics is the important technology platform of Chinese medicine pathogenesis research]. AB - Pathogenesis is the core of the theoretical system in Chinese medicine (CM). Pathogenesis research is the breakthrough of the innovation and development of CM theories. Proteomics and CM pathogenesis were amazingly similar in aspects of integrity, dynamics, space, and complexity. It is of great significance using proteomics methods in studying CM pathogenesis essence and evolution laws, exploring the mechanisms of classical prescriptions or recipes with therapeutic efficacy, and promoting the modernization of CM. PMID- 23019965 TI - [Progress of treating hormonal avascular necrosis of the femoral head by Chinese medicine and transplant of human bone marrow mesenchymal stem cells]. PMID- 23019964 TI - [Discussing the safety application of Chinese materia medics in patients with cardiovascular diseases]. AB - Along with the development of Chinese medicine and pharmacy (CMP), Chinese materia medica (CMM) has been used more and more widely at home and abroad. But we have to confront worsening problems such as lack of safety evidence, immature self -formulation technologies, lack of knowledge about their toxicities, and public misunderstanding, especially for patients with cardiovascular disease (CVD). Therefore, we cardiovascular physicians are requested improve knowledge for CMM preparations and their effects and side effects, supervise and identify the interactions between CMM and Westem medicine. Meanwhile, the researchers are also requested to assess the safety and efficacy of CMM through rigorous experimental designs, further improve the quality, safety, and efficacy of CMM, strictly formulate the specification of CMM products, guide the rational use of CMM by clinicians and the general public. PMID- 23019966 TI - [Obstructive sleep apnea syndrome in patients with chronic obstructive pulmonary disorder]. AB - Sleep obstructive apnea syndrome (SOAS) is a life-threatening respiratory disorder. Its combination with COPD further deteriorates respiratory distress and accelerates the development of pulmonary hypertension (crossover syndrome). Systemic inflammation with concomitant oxidative stress in patients with SOAS and COPD suggests their influence on the development of circulatory disorders. Night time cyclic hypoxia in patients with SOAS triggers systemic inflammation, oxidative stress, and atherogenesis which accounts for the frequent complications more severe in combination of SOAS and COPD than in either of these diseases. Intermittent hypoxia in patients with SOAS is associated with hypoventilation resulting from COPD, deteriorates clinical conditions of the patients, and requires the choice of specific methods of respiratory support. PMID- 23019967 TI - [Cardiorenal syndrome: currents views of relationships between renal and cardiovascular diseases]. AB - Current concepts of the development and pathogenesis of cardiorenal syndrome are considered. Special emphasis is laid on the data concerning chronic renal diseases (CRD) as risk factors of cardiovascular disorders (CVD), pathophysiological features of CVD concomitant with CRD, and relationships between CRD and traditional risk factors of CVD. The development of renal dysfunction is regarded as a complication of the heart failure. PMID- 23019968 TI - [Disorders of vitamin D metabolism in clinical practice]. AB - Results of recent studies give evidence of a pandemic of vitamin D deficiency due largely to insufficient exposure to sunlight. Epidemiological surveys demonstrated that vitamin B deficiency corresponding to blood calcidiol levels below 75 nmol/l or 30 ng/ml has negative effect on human health, increases the risk of cardiovascular disorders, malignant neoplasm, autoimmune and infectious diseases in proportion to the severity of deficit. Patients with extreme deficiency (calcidiol levels below 25 nmol/l or 10 ng/ ml) suffer osteomalation/rickets, diffuse muscular pain, myodystrophy, and enhanced risk of osteoporosis. Vitamin D replenishment reduces the risk of bone fracture, neoplastic growth, diabetes of both types, infectious, cardiovascular and autoimmune diseases. Being devoid of toxicity, vitamin D may be prescribed in a wide range of doses to patients from a variety of populations. PMID- 23019969 TI - [Peculiarities of endovascular myocardial revascularization in patients with coronary heart disease and multivascular lesions in the coronary bed]. AB - This study included 171 patients with multivascular lesions in the coronary bed treated endovascularly for myocardial revascularization. The patients divided into 3 groups underwent complete, functionally adequate, and incomplete revascularization respectively. Analysis of clinical, anamnestic and angiographic characteristics of the patients revealed possible risk factors hampering the necessary extent of revascularization in case of multivascular lesions in the coronary bed such as chronic coronary occlusion, occlusion of more than 20 mm of the coronary artery, high risk of percutaneous coronary intervention based on the SYNTAX Score scale, and calcinosis of the effected segment. PMID- 23019970 TI - [Predictors of hemodynamically significant coronary stenoses in patients with disturbed myocardial perfusion based on the results of single-photon emission computed tomography]. AB - Patients with positive results of single-photon emission CT (SPECT) were examined to identify parameters indicative of hemodynamically significant coronary stenosis (HSCS) prior to coronaroangiography (CAG). 47 of the 84 patients (mean age 49.1 +/- 8.7 yr, 71% men) had positive results of SPECT. Patients with HSCS more frequently experienced acute myocardial infarction (37.1% vs 6.5%. p = 0.005) and circulatory failure (II-IV functional class NYHA) (92.3% vs 51.6%, p = 0.026). Also, they had higher blood glucose levels (6.9 +/- 2.5 vs 5.3 +/- 0.8 mmol/l, p = 0.007). The echocardiographic study more frequently revealed the 50% impairment of left ventricular function in these patients (17.4 vs 7.4%, p = 0.001), reduced ejection fraction (59.6 +/- 8.9 vs 48.9 +/- 10.5%), greater LV size and asynergia (20.8 +/- 18.0 vs 2.0 +/- 5.5% and 1.4 +/- 0.3 vs 1.0 +/- 0.1%), more pronounced mitral insufficiency (81.3 +/- 59.4%, p = 0.026). Only these patients had post-infarctional changes in myocardium (31.3%. p = 0.001). Discrimination analysis revealed independent association of HSCS with LV asynergia and mitral regurgitation. These echocardiographic parameters may be regarded as predictors of HSCS in patients with suspected CHD and positive results of SPECT. PMID- 23019971 TI - [The role of lipid-protein interplay in the development of atherogenesis during coronary heart disease and metabolic syndrome]. AB - Lipid-protein relationships were studied in 155 men and women (mean age 48/9 +/ 0.6 years) with CHD (stable angina of effort) and MS. The frequency of concomitant arterial hypertension in men/women was 100%, aortic atherosclerosis 49.7/24.5%, athersclerosis of lower leg arteries 14.8/0%, chronic obstructive pulmonary disease 27.7/5.2%, locomotor disorders 25.8/14.8%, hepato-biliary diseases 24.5/17.4%, gastro-duodenal disorders 16.8/3.2%, hepatic problems 10.5/26.7%. Heterogeneity of lipid-protein homeostasis was documented. Evaluation of dysproteinemia, besides dyslipidemia, is crucial for estimating activity of inflammation as acute or chronic. Patients with CHD and MS need therapy not only of these conditions but also of concomitant diseases taking into account their phases (exacerbation, remission) and results of dynamic observation. Such approach ensures prevention of progression of combined pathology and improvement of patients' quality of life. PMID- 23019972 TI - [Diurnal profile of arterial pressure during sleep deprivation in patients with hypertensive disease receiving antihypertensive therapy]. AB - Diurnal profile of arterial pressure during sleep deprivation was studied by 24 hr AP monitoring in 40 patients with grade I-II AH (hypertensive disease) and slightly or moderately elevated AP. Group 1 included 10 patients who did not receive antihypertensive therapy. Group 2 (n = 30) was treated with 10 mg/d lisinopril either in the morning or in the evening. Patients of group 3 (n = 10) were given b-blocker metoprolol (35 mg at 22.00). AP monitoring was performed in duplicate (with night sleep deprivation and without it). Sleep deprivation resulted in the inverted AP profile (mean night-time AP higher than the mean daytime value) whether the patients were treated with long-acting lisinopril or with short-acting metoprolol given immediately before sleep deprivation. Mean daily AP in case of night deprivation was higher than under normal conditions. PMID- 23019973 TI - [Lipoprotein-associated phospholipase A2 in subjects at low and moderate risk estimated by the SCORE scale]. AB - The aim of the work was to elucidate the relationship between PLA2 content and results of the tests of abnormal lipid transfer in lipoproteins (LP) in subjects at low and moderate risk estimated by the SCORE scale. Another aim was to estimate the diagnostic value of plasma PLA2 content that was determined in 378 subjects (285 women and 93 men) aged 30-64 yr at low and moderate risk (SCORE scale). The patients were divided into groups depending on the age, the number of atheroscleroic plaques (ACP) in carotid arteries (0ACP 1 ACP, more than 1 ACP), enhanced and normal PLA2 levels. PLA2 was measured using PLAC Test Elisa Kits (DiaDexus, USA), with the upper normal limit assumed to be 200 ng/ml. In women, PLA2 levels positively correlated with apoA-1 (main HDLP apoprotein) content (r = 0.51, p < 0.03); in men, PLA2 negatively correlated with TG (r = -0.38, p < 0.01); in subjects with homogeneous ACP PLA2 positively correlated with LP(a) (r = -.38, p < 0.03). Simultaneous rise in PLA2 and LP(a) levels may be a significant risk factor of atherosclerosis and atherothromhosis. Enhanced levels of TG, PLA2, and LP(a) may be the biochemical triad of "soft" plaque formation in the intima. PMID- 23019975 TI - [Microbiocenosis and activity of the inflammatory process in the colon of the patients with chronic cardiac failure]. AB - The aim of this work was to study colonic microbiocenosis, endotoxin level, intensity of systemic inflammation and the state of matrix metalloproteinase (MMP) system and MMP tissue inhibitors (TIMP) in 75 patients with post-infarction cardiosclerosis at different stages of chronic cardiac failure (CCF). The patients were examined by clinical, echocardiographic and laboratory methods including bacteriological analysis of feces and measurement of amino-terminal brain natriuruetic peptide, endotoxin, TNF-alpha, MMP-9, and TIMP-4. The progress of CCF was shown to be associated with increasing colonic dysbiosis, endotoxin and TNF-alpha levels, disbalance in the MMO and TIMP systems. PMID- 23019974 TI - [Polymorphism of GSTT1 and GSNM1 glutathione transferase genes in smokers and patients at the early stages of chronic obstructive pulmonary disease]. AB - We studied the distribution of deletion polymorphisms of GSTT1 and GSTM1 glutathione transferase genes by PCR in patients with stage I and II chronic obstructive pulmonary disease (COPD) and in smokers without COPD. The significance of the differences in allele and genotype distribution between the groups was estimated by the X2 test and BIOSTAT software package. The study revealed a significant rise in the frequency of deletion polymorphisms of GSTT1 transferase genes in patients with stage I COPD compared with controls. The odd ratio between the groups was 0.6 which suggests a two-fold decrease in the risk of COPD. Simultaneous increase in the frequency of "zero" GSTT1 genotype in patients with stage 2 COPD is indicative of rapid progress of the disease in the presence of homozygous deletion of GSTT1. The difference between the frequency of homozygous deletion of GSTM1 was insignificant. The "zero" GSTT1 genotype in heavy smokers was associated with a decreased risk of COPD and may be regarded as a marker of the diminished impact of smoking on the pulmonary function. The homozygous deletion of GSTT1 in patients at the early stages of COPD suggests the risk of its rapid progress. Deletion polymorphism of GSTT1 glutathione transferase gene is recommended to use as a marker for predictive diagnostics of development and progress of COPD. PMID- 23019976 TI - [Bacterial endotoxinemia and risk of hemorrhage from oesophageal varicose veins in patients with liver cirrhosis]. AB - This work was designed to substantiate the necessity of estimating serum bacterial endotoxin levels in patients with liver cirrhosis (LC) for the prognostication of the risk of bleeding from oesophageal varices. The prospective cohort study included 90 patients with LC and clinical signs of portal hypertension. Total endotoxin of Gram-negative bacteria was measured by the activated particle method. The intensity of endotoxemia was estimated using the end-point turbidimetric test (variant of LAL test). Pronounced endotoxemia was associated with acute bleeding from oesophageal varices. Its severity in the patients with the history of hemorrhage was higher than in the absence of this complication. The endotoxin level in the range from 0 to 4 ng/ml suggested low probability of hemorrhage; its risk increased significantly at the endotoxin level in excess of 4.1 ng/ ml. It is concluded that the severity of endotoxemia in LC patients correlates with the degree of oesophageal vein dilation and hemorrhage, the endotoxin level of 4 ng/ml being a reliable diagnostic criterion for the associated risks. PMID- 23019977 TI - [Cutaneous-visceral interplay in patients with systemic lupus erythematosus]. AB - Systemic lupus erythematosus (SLE) remains a challenging medical problem. The integral approach to the analysis of underlying pathogenetic processes allows identifying main symptom complexes of SLE and establishing relationship between skin lesions and activity of the disease. We examined 84 patients with SLE (84% women), their mean age was 42.3 +/- 2.3 yr duration of SLE 6.5 +/- 1.2 yr. The subacute and chronic SLE variants were diagnosed in 30 (36%) and 54 (64%) patients respectively. Grade 1 and 2-3 inflammatory process occurred in 53 (63%) and 31 (37%) patients respectively. Symptom complexes "systemic inflammation", "butterfly rash", "wrist petechiae", "enanthema of the oral mucous membrane", and other lesions were regarded as the markers of SLE activity. The relationship of lupus-cheilitis and facial erythema with polyserositis and pericarditis ("visceral pathology-cardiovascular lesions") requires instrumental examination of pericardium, pleural and abdominal cavities in the patients with the above skin symptoms for diagnostics of polyserositis. At the same time, the presence of teleangiectasia on the wrists (symptom complex "visceral pathology renoparenchymatous lesions") requires thorough examination of the renal function. The presence of erythema at the major joints, mesh livedo, and Raynaud's syndrome (symptom complex "musculoskeletal disorders") implies specialized examination of the locomotor apparatus. PMID- 23019978 TI - [The use of cytoflavin in sports nutrition]. AB - Sports nutrition for 35 athletes was supplemented by the metabolic preparation cytoflavin 1 month before a pre-competition training camp. Their physical status was estimated using a specialized Omega-C hardware-software complex. It was shown that cytoflavin promotes physical fitness of the athletes by improving energy supply, psychoemotional conditions, and competition form. It is recommended to use cytoflavin for the training of athletes in the pre-competition period. PMID- 23019979 TI - [Diagnostics of cavitary processes in the lungs]. AB - The paper concerns CT-semiotics of cavitary processes in the lungs. Their major forms are discussed with reference to underlying pathological changes. The most common manifestations of the diseases associated with the cavitary processes are described. CT is a highly informative method for the visualization of pulmonary cavitation and the surrounding chest structures; this method improves diagnostics of pulmonary pathology. PMID- 23019980 TI - [Anaphylactic shock following administration of lidocaine after negative skin test]. AB - A rare case of sudden fatal anaphylactic shock is described in a 50 year-old woman after secondary lidocaine blockade to relieve lumbar pain (the first blockade was performed 4 days before by the same physician after the negative skin test). The patient had the history of multiple allergic reactions to drugs, pollen, home dust, and citrus fruits (repeated Quincke's oedema). In the preceding period, lidocaine was several time administered without side effects during out-patient visits to a surgeon and dentist. The signs of anaphylactic shock appeared within 2 min after injection of 4 ml of 2% lidocaine solution (no other injections were made between the two blockades). Comprehensive emergency measures had no effect. The diagnosis was confirmed at autopsy; microscopic study of soft tissues revealed mast cell degranulation and characteristic changes in internal organs. A literature review of anaphylactic shock symptoms is presented. The fulminant development of this condition after lidocaine administration may be regarded as a fatal coincidence of circumstances that could not be foreseen by the physician. Caution is needed when prescribing medications to polyallergic patients. PMID- 23019981 TI - [Splenic cyst]. AB - True non-parasitic splenic cysts are a rare pathology represented by some 800 cases recorded worldwide. The method of choice for the treatment of this condition is surgical intervention. To-day, open surgery is substituted by low invasive methods, such as laparoscopic splenectomy. A clinical case is described illustrating approaches to diagnostics and stages of surgical management of this pathology. PMID- 23019982 TI - [A case of lymphogranulomatosis in a patient with type 1 neurofibromatosis]. AB - Neurofibromatosis is a common monogenic disease in man; its incidence is at least 1:3000-1:4000 population. It is inherited in the autosomal dominant mode with high penetrance and variable expression. A patient presenting with type 1 neurofibromatosis since the age of 3 mo who developed lymphogranulomatosis is reported. The patient 1 life prognosis is presently determined by the competing pathology. It is emphasized that neurofibromatosis is associated with different forms of lung lesions and creates a risk of neoplastic (including malignant) growth. PMID- 23019983 TI - [Physician humanists, contemporaries of F.P]. PMID- 23019984 TI - Hernias of the greater omentum through the antero-superior abdominal wall: an extensive pictorial MDCT review with emphasis on typical anatomic landmarks. A pictorial essay. AB - Thanks to its very high performances in term of spatial resolution, table speed and multiplanar reconstructions (MPR), 64-row MDCT today produces unrivalled high quality images of the entire abdominal wall (AW) during a single short breath hold. It appears thus particularly useful for the evaluation of AW hernias, allowing accurate identification of their contents, differentiation from other abdominal masses, planning of optimal surgical repair and detection of pre- or post-operative complications. The greater omentum (GO) is another structure that can also be clearly identified, localized and characterized with 64-row MDCT. The identification of its numerous vessels, which predominantly have a vertical course, is the essential key for its delineation. AW hernias implicating the GO are therefore exquisite situations that can also be optimally diagnosed by MDCT. The very high contrast provided by the mostly predominant fatty content of the GO offers a unique opportunity to clearly illustrate the classical anatomic landmarks of almost nearly each type of hernia of the antero-superior AW. The cases presented in this extensive pictorial review were collected in our department during a 5-year-period. PMID- 23019985 TI - The relation between pelvic varicose veins and lower extremity venous insufficiency in women with chronic pelvic pain. AB - PURPOSE: To determine the relation between pelvic varicose veins and lower extremity venous insufficiency in women with chronic pelvic pain. METHODS AND MATERIALS: This study was done in Yuzuncu Yil University Faculty of Medicine, Department of Radiology, with patients who were referred for abdominal and pelvic imaging between January 2007 and April 2008. A total of 1029 women with pelvic imaging study were included in the study. The presence of venous dilatations (diameter > 5 mm) in parauterine and paraovarian localizations were accepted as pelvic varicose veins. In all patients, endometrial thickness was measured and lower extremity venous system was examined with Doppler ultrasonography to assess possible associated venous insufficiency. All patients were undergone questionnaire for frequency of delivery, age, and chronic pelvic pain. RESULTS: Pelvic varicose veins were discovered with transabdominal ultrasound and computerized tomography in 56 of 1029 patients. Various degrees of associated lower extremity venous insufficiency were also discovered in 44 of 56 patients (78,6%) with pelvic venous dilatation. Of the 44 patients with lower extremity venous insufficiency, 21 were bilateral, 9 were right-sided, and 14 were left sided. Endometrial thickness was significantly increased in patients with pelvic venous dilatation. CONCLUSION: The presence of pelvic varicose veins is significantly associated with lower extremity venous insufficiency. Since the diagnosis of lower extremity venous insufficiency plays an important role in deciding the course of treatment, lower extremity Doppler ultrasonography examination would be useful to include in the evaluation of pelvic varicose veins. PMID- 23019987 TI - Left vein of Labbe thrombosis associated with ipsilateral dural sinus thrombosis: non-enhanced CT and contrast-enhanced CT (CTV) findings. AB - A rare case of aseptic thrombosis of the left vein of Labbe in a young woman is reported. Cerebral venous thrombosis was suggested by computed tomography and confirmed after intravenous administration of contrast by computed tomography venography. The combination of the clinical setting with the findings on the non enhanced CT may favour the diagnosis of vein of Labbe thrombosis. The diagnosis can be confirmed on computed tomography venography. PMID- 23019986 TI - Intramyocardial paravalvular abscess after aortic valve replacement. AB - Myocardial abscess is a rare but life-threatening disease with various clinical presentations. We describe the case of a paravalvular abscess distending intramurally 7 years post surgery for aortic valve replacement. Early detection and urgent surgical intervention is essential for this otherwise fatal disease entity. PMID- 23019988 TI - The association of intramammarian arterial calcifications detected on mammography with coronary artery disease and its risk factors. AB - AIM OF THE STUDY: To evaluate the association of intramammarian arterial calcifications seen on mammography with coronary artery disease and its risk factors and to discuss intramammarian arterial calcifications value as a predictor of coronary artery disease. MATERIAL AND METHODS: Mammography was performed on 55 women over 40 years of age who have undergone coronary angiography and have not had a mammography in the past year. Coronary angiography results, coronary artery disease risk factors and intramammarian arterial calcifications are evaluated. RESULTS: The prevalance of intramammarian arterial calcifications was 41.8%. A significant relationship between intramammarian arterial calcifications and coronary artery disease was indicated (OR 10,8, 95% Cl 3,02-38,59). The positive predictive value and negative predictive value of intramammarian arterial calcifications for coronary artery disease was 78.3% and 75% respectively. Also advancing age was found relevant with these calcifications (OR 1,15, 95% Cl 1,05-1,25). CONCLUSION: The results support the present literature and suggest that mammography, already widely in use as a screening tool among women over 40, may be used simultaneously in coronary artery disease risk assessment. These results should be confirmed by further larger group controlled studies. PMID- 23019989 TI - Granular cell tumor of the breast. AB - Granular cell tumor is a rare benign soft-tissue neoplasm, usually appearing in the tongue, the oral cavity and subcutaneous tissue. Examples of granular cell tumor of breast are encountered in 30-50-year-old women. Herein, we report ultrasonographic and mammographic imaging findings of a 59 years old woman presented with a painless palpable mass, which was diagnosed as granular cell tumor on histopathological analysis. PMID- 23019990 TI - Gastrointestinal tract wall visualization and distention during abdominal and pelvic multidetector CT with a neutral barium sulphate suspension: comparison with positive barium sulphate suspension and with water. AB - OBJECTIVE: When examining patients with contrast-enhanced multidetector-row CT, we determined if the stomach and small bowel were visualized and distended better with a neutral barium sulphate suspension than with positive barium sulphate suspension or water. MATERIALS AND METHODS: After obtaining approval from our institutional review board, 156 patients (women: 84; mean age: 54 yrs) with no history of gastrointestinal tract disease were randomized prospectively to receive orally either 900 ml of neutral (0.1% w/v) barium sulphate suspension (n = 53), 900 ml of positive (2.1% w/v) barium sulphate suspension (n = 53), or 900 ml of water (n = 50), prior to undergoing contrast-enhanced abdominal and pelvic multidetector-row CT. Two independent radiologists evaluated the stomach, and small bowel, for luminal distension and wall visualization, using a five point scale. Results were compared using Kruskal-Wallis and Mann-Whitney U tests. RESULTS: The walls of the stomach, and small bowel were visualized better in patients who were administered neutral barium sulphate suspension than those who were administered either positive barium sulphate suspension (p < 0.01) or water (p < 0.01). In patients who received neutral barium sulphate suspension, the stomach and small bowel were distended better compared to patients administered water (p < 0.01); the stomach, duodenum, and ileum were distended better compared to patients administered positive barium sulphate suspension (p < 0.05). CONCLUSIONS: When examining patients with intravenous contrast-enhanced abdominal and pelvic multidetector-row CT, orally administered neutral barium sulphate suspension allows the gastrointestinal tract to be visualized and distended better than either positive barium sulphate suspension, or water. PMID- 23019991 TI - Milwaukee shoulder syndrome. AB - Milwaukee shoulder syndrome or rapid destructive arthropathy of the shoulder is a rare form of arthropathy that mainly affects elderly women. It is characterized by a rapid destruction of the glenohumeral joint and the rotator cuff and by an important noninflammatory joint effusion containing hydroxyapatite crystals. Radiography plays an important role in the evaluation of patients with articular disease. However, magnetic resonance imaging is the method of choice for assessing the full extent of osseous, chondral, and soft-tissue involvement. PMID- 23019992 TI - Erdheim-Chester disease detected with 99mTc MDP bone SPECT/CT. AB - Erdheim-Chester disease (ECD) is a rare non-Langerhans' cell histiocytosis. Mild but permanent juxta-articular bone pain in mainly knees and ankles is the most frequent associated symptom. Despite the pathognomonic radiographic findings, most cases are still diagnosed by the pathologist.The lesions consist of lipid storing CD 68 +/CD 1a--non-Langerhans' cell histiocytes, most frequently localized in bone but also involving multiple organ systems in the body. We present a case report in which the diagnosis of ECD was established with 99mTc MDP bone SPECT/CT. PMID- 23019993 TI - Single left coronary artery with the right coronary artery arising from the mid portion of the left anterior descending artery. Diagnosis with MDCT. AB - Single coronary artery is a very rare entity. We describe a very unusual subtype of this anomaly in which the right coronary artery arises from the mid-portion of the left anterior descending artery. MDCT allowed diagnosis of this non pathogenic variant and excluded any significant coronary stenosis. PMID- 23019994 TI - Double contrast percutaneous transhepatic cholangiographic CT in patients with obstructive jaundice: an initial experience of seven cases. AB - PURPOSE: To explore the technical feasibility of double contrast percutaneous transhepatic cholangiographic CT (DC-PCT-CT) in patients with bile duct obstruction. METHODS: Seven patients with bile duct obstructive diseases were studied, including 5 males and 3 females, ranging in age from 24 yrs to 74 yrs (average: 47.7 yrs). There were 5 cases of hilar cholangiocarcinoma, 1 case of sclerosing cholangitis, and 1 case of malignant transformation of adenoma at the distal end of the common bile duct. PTC was carried out initially, involving injection of 30 ml 4.5-6.0 mgl iohexol. After the bile duct system was filled, CT scan was performed, and further followed by enhanced CT with intravenous injection of 300 mgl/ml contrast agent. Arterial phase, venous phase, and parenchymal phase acquisitions were obtained. Raw CT images were viewed and multiplanar reconstruction (MPR), maximum intensity projection (MIP), and volume rendering (VR) image post-processing were performed. RESULTS: DC-PCT-CT was performed successfully and bile duct drainage was carried out. Mild lesion enhancement was demonstrated in three cases in arterial phase, while all seven cases demonstrated enhancement of various degrees in venous phase.The lesions lead to track-like, asymmetrical or irregular bile duct obstructive narrowing, and in one case intra-luminal filling defect. Reliable diagnosis was suggested in all cases. MPR, MIP and VR images were useful in demonstrating precise lesion location and for surgical planning. CONCLUSION: In patients with bile duct obstruction, DC-PTC-CT is a feasible technique offering both important diagnostic value and drainage application. PMID- 23019995 TI - Combination of partial situs inversus, polysplenia and annular pancreas with duodenal obstruction and intestinal malrotation. AB - Situs inversus is a challenge to the physician, both for the diagnostic and for the therapeutic. A combination of partial situs inversus, annular pancreas and polysplenia with bowel malrotation has been reported in a newborn who presented as duodenal obstruction. Situs inversus is rare especially without heart malformation. All the abnormalities in this combination can be explained on the basis of multiple organ malrotation. It also demonstrates the necessity of meticulous investigation and precise description of the anomaly as far as the management of this case is concerned. PMID- 23019996 TI - Managing coronary artery vein bypass graft stump pseudoaneurysm: a novel approach. AB - We present a case of a pseudoaneurysm of the saphenous vein graft stump, which was managed with percutaneous thrombin injection. Aneurysms of a saphenous vein coronary bypass graft are rare and aneurysms of a bypass graft stump are even rarer. To our knowledge this is the first reported case of a pseudoaneurysm of a graft stump with the use of thrombin to treat a saphenous vein graft pseudoaneurysm. PMID- 23019997 TI - Chronic recurrent multifocal osteomyelitis mimicking osteoid osteoma. AB - In this article we illustrate an unusual case of chronic recurrent multifocal osteomyelitis (CRMO) in a 9 year old girl who presented with right thigh pain. The initial plain radiographs were normal. The white cell count was normal and there was a mild rise in C-reactive protein. Cross sectional imaging of the right femur showed a lesion with features suggestive of osteoid osteoma. However, when the lesion was excised, the appearances on histopathological examination were non specific showing chronic inflammatory cells and the microbiological testing revealed no organisms. Six months later, this child presented with right shoulder pain and the subsequent imaging demonstrated bilateral clavicular lesions. At this stage, the diagnosis of CRMO was made based on the combination of the clinical, radiological, histopathological and microbiological features. This case demonstrates that the cross sectional imaging features of the bony lesion in CRMO can mimic osteoid osteoma. PMID- 23019998 TI - Inflammatory myofibroblastic tumor of the pancreatic head. AB - Inflammatory myofibroblastic tumors are rare, especially in the pancreas. It is sometimes difficult to obtain a definitive diagnosis with radiological imaging and there is not yet consensus about treatment. We report a case of a 56-year-old man with recurrent abdominal pain particularly in the right upper quadrant without other symptoms. The imaging results showed a pancreatic hypovascularized mass with stenosis of the main pancreatic duct and the common bile duct without metastasis. The FDG PET scanner showed two hypermetabolic foci in the head of the pancreas. The biopsies of the mass were not diagnostic. The therapy adopted was Whipple's pancreaticoduodenectomy with a histological diagnosis of the inflammatory myofibroblastic tumor. PMID- 23019999 TI - MRI of myelitis. PMID- 23020000 TI - [Protecting children, supporting parents]. PMID- 23020001 TI - [Protection of the child is the first priority]. PMID- 23020002 TI - ["Noticing instead of looking away" (interview by Urs Luti)]. PMID- 23020003 TI - [Patient positioning care with more focus on the patient]. PMID- 23020004 TI - [Spitex in New York - large, modern, innovative]. PMID- 23020005 TI - [Skin and mucosal care in systemic sclerosis]. PMID- 23020006 TI - [Eliminating pain, but not autonomy]. PMID- 23020007 TI - [With a snail's tempo to advanced specialty examinations]. PMID- 23020008 TI - [Interventions for improving adherence]. PMID- 23020009 TI - [Internet learning, video, internet forum and blog]. PMID- 23020010 TI - [Audacity, a coveted asset]. PMID- 23020011 TI - [The challenges of reporting]. PMID- 23020012 TI - [Viewpoints]. PMID- 23020013 TI - [The nurse's role and practical interventions]. PMID- 23020014 TI - ["Nurses should be indignant, dare, go beyond the frame" (interview by Brigitte Longerich)]. PMID- 23020015 TI - [Implantable venous access port]. PMID- 23020016 TI - [From indignation to audacity]. PMID- 23020017 TI - [Self caring - for better dying?]. PMID- 23020018 TI - [The unspoken words]. PMID- 23020019 TI - Studies and measurements of physical activity of the society. PMID- 23020020 TI - Weight training and appropriate nutrient supplementation as an alternative method to pharmacological treatment in rehabilitation of post-myocardial infarction patients. AB - The article describes the impact of weight training, micro-elements and vitamins on rehabilitation in post-myocardial infarction patients. Cardiac rehabilitation is a multi-disciplinary and multi-faceted intervention aimed at restoring well being and retarding disease progression in patients with heart disease. It has been shown that exercise-based cardiac rehabilitation is effective in reducing total and cardiovascular mortality. Intake of vitamins and other diet supplements was reported to exert beneficial effects. Pharmacological medication is associated with an increased risk of severe arrhythmia, and many adverse outcomes. Therefore, since conventional medicine only relieves the symptoms, cellular nutrition should be used in order to improve the quality of life in post myocardial infarction patients. These elements prevent another infarction. The following nutrients are reported to have beneficial effects on general and cardiovascular health: amino acids, vitamins, coenzyme Q10, pycnogenol, inositol, omega-3 fatty acids, macromineral elements, and trace mineral elements. In conclusion, the review indicates that appropriate weight training and diet supplementation ensure full recovery and elimination of risk factors for cardiovascular diseases. PMID- 23020021 TI - An assessment of dietary intake and state of nutritional in hypertensive patients from rural and urban areas of Greater Poland. AB - The aim of this study was to determine the nutritional factors connected with the prevalence of hypertension in rural and urban areas of Greater Poland. The study consisted of 308 people aged 35-62, with essential hypertension but without any other coexisting disorders. The studied group consisted of 154 residents of Poznan (79 women and 75 men) and 152 inhabitants of rural areas in Greater Poland (78 women and 74 men). Participants were randomly assigned to the study. Nutritional state assessment was based on Body Mass Index (BMI) and body fat percentage. Dietary intake were assessed with a 24-hour nutritional survey from 3 consecutive days. Analysis of anthropometric examination results showed a large prevalence of obesity in the studied group. Moreover people living in rural areas had a significantly higher BMI and body fat percentage than those living in a city. It has been proved that the patients with hypertension consume food with an excess of fat and a shortage of fibre, antioxidant vitamins, potassium, calcium and magnesium. The total food rations of rural dwellers consisted of larger amounts of fat, cholesterol and vitamin A compared to those of city dwellers. Present studies have shown incorrect dietary intake among patients with hypertension, often related to the coexistence of overweight and obesity. Obtained results indicate significantly worse eating habits and state of nutrition among rural inhabitants. PMID- 23020022 TI - An attempt to assess knowledge about tobacco dependence among students at the Medical University in Wroclaw. AB - INTRODUCTION: Tobacco smoking is still one of the greatest, avoidable, singular causes of death. Although students of medical faculties are expected to have solid knowledge about smoking hazards, a significant number of them still smoke. AIM: The aim of the study was to assess knowledge on tobacco dependence in a sample of students at the Medical University in Wroclaw. MATERIAL AND METHODS: Between 2009-2011, non-compulsory lectures on the diagnosis and treatment of tobacco dependence were provided for 3(rd) to 6(th) year students of medicine at the Medical University in Wroclaw (170 students). The questionnaire contained 10 questions about smoking-related diseases and medicines used in tobacco dependence treatment. RESULTS: 21% of students smoked cigarettes and 79% were never smokers. 36% of the study group was exposed to passive smoking at the university. Nearly 80% of survey respondents agreed with the statement that cigarette smoking can lead to psychological addiction as strong as drug addiction, but more than 12% of the respondents perceived smoking just as a strong habit. Only 6 out of 10 surveyed students recognised tobacco dependence as an illness classified in an international classification of diseases and health problems (ICD-10). The correct amount of the chemical substances to be found in tobacco smoke was known by 67.1% of all surveyed students. The vast majority of the surveyed students indicated correctly 2 brands of nicotine replacement therapy, but none of them could name even one chemical and corresponding trade name of the pharmaceutical with central effect. CONCLUSIONS: The level of knowledge about the diagnosis and treatment of tobacco dependence among the students of the Medical Faculty in Wroclaw Medical University is low, and requires improvement through educational activities at both facultative and compulsory study level. Special attention should be paid to pharmaceutical treatment of the tobacco dependence syndrome. PMID- 23020023 TI - Occurrence of neurotic and anxiety disorders in rural schoolchildren and the role of physical exercise as a method to support their treatment. AB - INTRODUCTION: School anxiety has become a common problem in children and adolescents. Despite numerous studies, it is difficult to definitely identify the cause of neurotic disorders in school-age children. The objective of the presented study was to assess the prevalence of neurotic disorders in rural schoolchildren and the role of physical activity as a method to support their treatment. MATERIAL AND METHODS: The study consisted of 123 girls and 117 boys living in rural areas of Wielkopolska. A questionnaire was provided evaluating family status, family relationships, school situation, somatic symptoms related to being at school, and the frequency of physical activity. RESULTS: It was found that over the 50% of children considered the relations with siblings as correct, but also acknowledged that there were a conflict situations in their relationship. Nearly 25% of children indicated an emotional irrelevance with their parents. About 20% of the young people did not like going to school or were afraid to stay there. Over the 50% of children declared somato-emotional problems associated with the being at school. The symptoms of neurotic disorders were more strongly expressed and more common in girls. Analysis of physical activity indicated that only a small group of young people practiced sport regularly, and an even smaller percentage of children exercised with their parents and/or peers. CONCLUSIONS: The development of somatic and emotional disturbances in children may be associated with irregular family and school relationships and low physical activity. It was found that gender had a significant influence on most of the studied parameters. PMID- 23020024 TI - Determining the scale of designer drugs (DD) abuse and risk to public health in Poland through an epidemiological study in adolescents. AB - Since 2008, it has been recognised by most health authorities worldwide that the abuse of newly-emerging psychoactive drugs, ('designer drugs'/'legal highs'; DD), in youth is a rapidly increasing problem, especially in the EU, threatening to offset gains made in tackling established and illegal drugs which they are intended to mimic; DD diversity is continually increasing to circumvent laws. The aim of the study was to determine the scale of DD abuse/availability amongst Polish youth. The surveyed test population was randomly selected from a representative group of adolescents attending high schools, secondary schools and universities throughout Poland. Questionnaires were completed by 14,511 subjects (10,083 school pupils and 4,428 students). Few persons from each group admitted using DDs; 453 school pupils (4.49%) vs. 81 students (1.83%). More males (4.74%) took DDs than females (2.77%). The tendency to take DDs in the company of friends was high in both DD-taking groups (>80%). DDs were consumed mostly in open spaces (34.15%), discos/pubs (21.13%) and boarding school/friend's house (20.57). Most frequently, DDs came from shops (57.68%), friends (31.46%) or dealers (10.11%). Ensuing symptoms included; happy/euphoric mood (58.80%), talkativeness (42.51%) and hallucinations (22.85%). Over 74% of DD-takers in both groups experienced adverse reactions, and those requiring help sought it from: friends/colleagues (6.74%), doctors (5.06%), and hospitals (4.87%), but most rarely from parents/guardians (2.62%). Urgent action is being taken, especially in youth education, to prevent DDs becoming the serious menace seen with conventional drugs. PMID- 23020025 TI - Alcohol-related Developmental Origin of Adult Health--population studies in Poland among mothers and newborns (2010-2012). AB - Alcohol related harm is a global problem for public health where frequent consumption of large amounts of alcohol constitutes a serious health risk, particularly to vulnerable groups such as adolescents, pregnant women and newborns. The epidemiological study on health-lifestyle behaviour, especially alcohol consumption, was performed on a randomised group of post-partum women's health behaviour during pregnancy, covering drinking habits, was undertaken in 2010, 2011 and 2012, (n=8,237) according to the PRAMS model including effects on the foetus and newborn; women being selected from obstetric and gynaecological wards. In this Polish study, only 14% of women did not consume alcohol before becoming pregnant while 15% of women drank alcohol throughout the entire period of pregnancy. In addition, awareness of the harmful effects of alcohol consumed, especially of small amounts, before and during pregnancy is low among Polish women. It is also alarming that more than 55% of physicians who provide care for pregnant women do not discuss with them the harmful effect of alcohol on the organism of the mother and foetus, whereas over 2% of doctors even recommend the consumption of alcohol in pregnancy. With reference to the Barker's Foetal Origin of Diseases Hypothesis, the authors suggest such alcohol drinking behaviour of women during their reproductive ages and while pregnant may exert negative health effects on offspring, mainly in the form of susceptibility to contracting chronic diseases. Such findings pose a risk to future generations in Poland and require remedial/educational action targeted on health care professionals and public like. PMID- 23020026 TI - Life style and risk of development of breast and ovarian cancer. AB - INTRODUCTION: Many risk factors may be monitored, and individual decisions concerning life style exert an effect on most factors associated with the development of cancer. It is estimated that the majority of malignant cancers, as much as 70%, are the result of the harmful effect of factors related with diet, life style, or those present in the surrounding environment. OBJECTIVE: The objective of the study was analysis of selected factors related with life style and their effect on the risk of development of breast and ovarian cancer. METHODOLOGY: The study covered healthy women, without the diagnosis of focal lesions in the breast and ovaries, and women with the diagnosis of breast or ovarian cancer. The study was conducted during the period September 2007-November 2011, and covered a total of 1,484 women aged 18-80. Odds ratio was calculated for individual risk factors. Statistical analysis was performed by means of the statistical packages STATISTICA v8, GrafPad Instat v 3.00, Analyse-it v. 2.2, and Cytel Studio StatXact-8. Statistical hypothesis were verified on the level of significance p <= 0.05. RESULTS: Health-promoting life style related with physical activity and other health promoting behaviours, such as mode of nutrition, reduction or elimination of alcohol consumption and discontinuation of smoking considerably decrease the risk of development of malignant breast and ovarian cancer. The number and variety of factors which affect the risk of occurrence of cancerous diseases indicate that there is a need for monitoring of the hazard. CONCLUSION: It is necessary to carry out preventive actions which would cover the health education of women, concerning life style-related risk factors and methods of their modification. PMID- 23020027 TI - Past obstetric history and risk of ovarian cancer. AB - INTRODUCTION: Early age at menarche and late age at last menstrual period, as well as other reproductive factors, may be the cause of development of some types of cancer concerning the female reproductive organs. It has been estimated that late menopause may be responsible for the occurrence of even 16% of cases of ovarian cancer in the population. The incidence of ovarian cancer is also higher among nulliparous women, and among those who rarely become pregnant. OBJECTIVE: The objective of the study was analysis of the effect of reproductive factors on the risk of ovarian cancer. METHODOLOGY: The study covered healthy women, without the diagnosis of focal lesions in the ovaries, and women with the diagnosis of ovarian cancer. The study was conducted during the period from September 2007 November 2011, and covered a total number of 1,346 women. Odds ratio was calculated for individual risk factors. Statistical analysis was performed by means of the statistical packages STATISTICA v8, GrafPad Instat v 3.00, Analyse it v. 2.2, and Cytel Studio StatXact-8. Statistical hypothesis were verified on the level of significance p <= 0.05. RESULTS: Among females who began menstruating by the age of 11, the risk of ovarian cancer was 1.6 higher than among those in whom the first period occurred at the age of over 13. Similarly, among women who menstruated at the age of over 55 the risk of development of ovarian cancer was 1.4 times higher. The age at which a woman delivered her first live baby is also of importance. In the group of women who gave birth at the age of over 35, the risk was elevated and remained on the level of OR=1.7; 95%CI 0.66 4.5, compared to those who bore the first baby under the age of 25. If the pregnancy was terminated with miscarriage, the risk of contracting ovarian cancer decreases, and was on the level of OR=0.8; 95%CI 0.53-1.28, compared to the women who have never been pregnant. Among patients who did not breastfeed their babies, ovarian cancer risk was 1.7 times higher, compared to those breastfeeding. CONCLUSION: Reproductive factors exert a significant effect of the risk of development of ovarian cancer. PMID- 23020028 TI - Dietary intake and adipose tissue level of specific fatty acids in a selected group from the Lower Silesia population. AB - PURPOSE: The aim of the study was to assess the content of specific fatty acids in the diet and adipose tissue in a selected group of inhabitants of Lower Silesia in Poland. METHODS: The study group consisted of 95 inhabitants of Wroclaw and surrounding villages (22 men and 23 women from the urban area, 23 men and 27 women from the rural area). Fatty acid content in subcutaneous fat samples was assessed by gas-chromatography. Dietary assessment was carried out using food frequency questionnaire. Dietary intake was analyzed using computer programme The Food Processor SQL 10.5.2 produced by ESHA Research USA, with a Polish database. RESULTS: Mean daily energy and fatty acids intake was significantly higher among rural than urban inhabitants. Intake of alpha-linolenic acid (ALA), mainly from rapeseed oil, in urban inhabitants was 1.5 g/day in men and 1.6 g/day in women, and in rural inhabitants 2.6 g/day and 2.1 g/day, respectively. Dietary n-6 to n 3 ratio was higher among urban compared to rural inhabitants (6.7 vs. 5.5 among men and 6.4 vs. 5.5 among women, respectively). Content of ALA in adipose tissue was higher in rural women than in urban men (1.08% vs. 0.92% of total fat). Content of eicosapentaenoic acid (EPA) in adipose tissue in rural men (0.04% of total fat) and women (0.05% of total fat) was higher than in urban men (0.01% of total fat). The positive correlation (r=0.43) between the level of EPA in adipose tissue and percentage of energy from dietary EPA was observed among rural men. Overall, positive correlations were found between saturated (SFA) and polyunsaturated (PUFA) n-3 level in adipose tissue and percentage of energy from these fatty acids in a diet (r=0.20 and r=0.22, respectively). CONCLUSIONS: Mean daily n-3 fatty acid intake in urban inhabitants was lower than the recommended daily consumption in Poland. The positive correlation between fatty acids level in adipose tissue and dietary fatty acid intake was observed only for EPA among rural men, and in the all-study population for SFA and PUFA n-3. A high n-6 to n 3 ratio in the study group was observed. PMID- 23020029 TI - Managing water safety in healthcare. Part 1--Strategies and approaches for waterborne pathogen control. AB - Summaries in 2 parts are presented from a conference held in London at the Royal Society for Public Health on 16-17 May 2012, on the latest developments in dealing with waterborne hospital-acquired infections (nosocomial), from the UK perspective. Also included were some views from continental Europe. The first part, focuses on management strategies and plans that are either in use or recommended by domestic/international guidelines, such as the WHO, for prevention, control and risk assessment of disease outbreaks resulting from the presence of these pathogenic microorganisms in water appliances/supplies. Various solutions are discussed, some more effective than others, but all require a comprehensive strategy and technical expertise run by properly trained and dedicated professionals. PMID- 23020030 TI - A model to account for variations in holm-oak (Quercus ilex subsp. ballota) acorn production in southern Spain. AB - One of the characteristics of holm-oak acorn production is its high variability among individuals and years. To examine the main causes of this fact, a study was conducted from 1998-2010 in a natural area of holm-oak in southern Spain, where floral phenology, fruit production, fruit size, airborne pollen emission and meteorology factors were analyzed with the ultimate aim of developing a model for forecasting holm-oak yield. Pollen emission during flowering season was the main factor determining the final acorn harvest, but also some meteorological variables played an important role in explaining acorn crop variations, especially humidity and temperature during the months of April and September. The reliability of the proposed model was externally validated using data not included in its construction; validation yielded acceptable results, with a minimum error of estimation. Our results appear to be very useful for planning cropping and pig feeding strategies. Further research could extend the use of airborne pollen counts in forest studies relating to anemophilous species, in order to optimize agricultural policies. PMID- 23020031 TI - Aeromonas hydrophila subsp. dhakensis--a causative agent of gastroenteritis imported into the Czech Republic. AB - Out of the twenty-one A. hydrophila complex isolates obtained during a routine examination of human diarrhoeal faeces, two A. hydrophila subsp. dhakensis isolates (P1097 = CCM 7329 and P1165) were successfully identified by ribotyping. The correct taxonomic position of the A. hydrophila subsp. dhakensis CCM 7329 was verified by cpn60 sequencing (GeneBank accession number HM536193). The remaining A. hydrophila complex isolates were identified as A. hydrophila subsp. hydrophila. The ability of biochemical tests and fatty acid methyl ester analysis to reliably discern both A. hydrophila subsp. dhakensis and A. hydrophila subsp. hydrophila was limited. In contrast to the A. hydrophila subsp. hydrophila, the faecal isolates of A. hydrophila subsp. dhakensis did not produce acid from arbutin. When compared in a two-dimensional plot, the A. hydrophila subsp. dhakensis faecal isolates contained higher amounts of the two minor fatty acids C(13:0) and C(17:1) omega8c than the A. hydrophila subsp. hydrophila reference strain. This is the first detected occurrence of the less frequent A. hydrophila subsp. dhakensis in our region and ribotyping was proved as a suitable method for the identification of A. hydrophila subsp. dhakensis. PMID- 23020032 TI - Analysis of high allergenicity airborne pollen dispersion: common ragweed study case in Lithuania. AB - The appearance of ragweed pollen in the air became more frequent in northerly countries. Attention of allergologists and aerobiologists in these countries is focused on the phenomenon that Ambrosia plants found relatively sporadic but the amount of pollen is high in particular days. Over the latter decade, a matter of particular concern has been Ambrosia pollen, whose appearance in the air is determined by the plants dispersing it and meteorological processes that alter pollen release, dissemination, transport or deposition on surfaces. Pollen data used in this study were collected in three pollen-trapping sites in Lithuania. The data corresponding to 2006-2011 years of pollen monitoring were documented graphically and evaluated statistically. Analysis of the pollen data suggests that although the number of ragweed plants identified has not increased over the latter decade, the total pollen count has been on the increase during the recent period. The highest atmospheric pollen load is established on the last days of August and first days of September. The estimated effect of meteorological parameters on pollen dispersal in the air showed that in Lithuania ragweed pollen is recorded when the relative air humidity is about 70%, and the minimal air temperature is not less than 12 degrees C. Analysis of wind change effect on pollen count indicates that pollen is most often recorded in the air when the changes in wind speed are low (1-2 m/s). We have established a regularity exhibiting an increase in ragweed pollen count conditioned by south-eastern winds in Lithuania. PMID- 23020033 TI - Contamination of vegetables, fruits and soil with geohelmints eggs on organic farms in Poland. AB - The objective of this study was to evaluate the contamination of vegetables, fruits and soil with zoonotic parasite eggs on organic and conventional farms in south-eastern Poland. To evaluate the contamination with eggs of zoonotic parasites, examinations were conducted on 8 conventional and 11 organic farms in south-eastern Poland from May-October in 2008 and 2009. The following fruit and vegetables were selected for the experiment: strawberry, leek, onion, carrot, zucchini, beetroot, parsley, potatoes, celery, rhubarb, lettuce, cabbage, broccoli, pumpkin, young beetroot leaves, cauliflower, French beans, turnip, fennel and sorrel. A total of 187 samples of vegetables, fruits and soil were examined by means of a modified flotation method according to Quinn et al. (1980). Contamination with Ascaris, Trichuris and Toxocara eggs was found, with a higher number of positive samples revealed on conventional (34.7%), compared to organic farms (18.9%). The level of contamination in soil samples from conventional farms was higher (88.5% positive samples), than of those from organic farms (32.8%). Of the 15 geohelmints eggs, positive samples were found in vegetables: 9 Toxocara eggs, 4 Ascaris eggs and 2 Trichuris eggs. No geohelmints eggs were observed in the strawberry samples. The consumption of vegetables and fruits contaminated with the eggs of parasites may be the cause of parasitoses in humans. Stricter sanitary standards on farms of all types may limit the incidence of parasitic zoonoses. PMID- 23020034 TI - Sanitization efficacy of anaerobic digestion and aeration of slurry from the aspect of limiting emission of Salmonella into the environment. AB - The aim of this study was to estimate the usefulness of mesophilic anaerobic digestion and aeration for sanitization of slurry from the aspect of limiting transmission of Salmonella into the environment. Material for the study was fresh pig slurry. Collected samples were subjected to anaerobic digestion at 35 degrees C and aeration with an initial temperature of 35 degrees C. The efficacy of both methods was examined based on determination of the elimination rate and theoretical time of survival of Salmonella Senftenberg W(775), Salmonella Enteritidis and Salmonella Typhimurium introduced into slurry in carriers of type Filter-Sandwich. Samples for the study were collected every 24 hours and the number of bacilli was determined with the MPN (Most Probably Number) method. The study indicated that fermentation is a more effective method for slurry sanitization. A higher rate of elimination and shorter time of survival of all the tested bacteria was observed, compared with the use of aeration. The experiment allowed us to prove the high sanitization efficacy of both examined methods. They ensure the full elimination of the tested serotypes of Salmonella in only slightly more than 10 days. The use of fermentation or aeration as a way of slurry treatment for agricultural purposes makes it possible to obtain a fertilizer which is valuable and safe for humans and the environment. PMID- 23020035 TI - Influence of temperature, chlorine residual and heavy metals on the presence of Legionella pneumophila in hot water distribution systems. AB - The microbiological colonisation of buildings and man-made structures often occurs on the walls of plumbing systems; therefore, monitoring of opportunistic pathogens such as Legionella pneumophila (L. pneumophila), both in water distribution mains and in consumers' plumbing systems, is an important issue according to the international and national guidelines that regulate the quality of drinking water. This paper investigates the presence of L. pneumophila in the Dalmatian County of Croatia and the relationship between L. pneumophila presence and heavy metals concentrations, free residual chlorine and water temperature in hot water distribution systems (WDS). Investigations were performed on a large number of hot water samples taken from taps in kitchens and bathrooms in hotels and homes for the elderly and disabled in the Split region. Of the 127 hot water samples examined, 12 (9.4%) were positive for Legionella spp. with median values concentration of 450 cfu * L(-1). Among positive isolates, 10 (83.3%) were L. pneumophila sg 1, and two of them (16.6%) belonged to the genera L. pneumophila sg 2-14. The positive correlation between the water temperature, iron and manganese concentrations, and L. pneumophila contamination was proved by statistical analysis of the experimental data. On the contrary, zinc and free residual chlorine had no observed influence on the presence of L. pneumophila. The presence of heavy metals in water samples confirms the corrosion of distribution system pipes and fittings, and suggests that metal plumbing components and associated corrosion products are important factors in the survival and growth of L. pneumophila in WDS. PMID- 23020036 TI - Sequence based typing and pre-absorption test in retrospective analysis of a pseudo-outbreak of Legionella infections differentiates true cases of legionellosis. AB - The aim of this study was elimination of false positive results obtained by the Chlamylege kit. Two serological kits (IgM ELISA L. pneumophila sgs1-7; ImmuView(TM) L. pneumophila sg1/sg3) and pre-absorption tests (with L. pneumophila sg1 and sg3 reference strains antigens) were used. 153 sera (79 patients) were examined. The high correlations were found between the results by both tests. Positive results by ELISA (sgs1-7) were found in 19/79 patients; by ImmuView(TM) (sg1+sg3) in 16/63. In 8 patients, the dynamics of the IgM in pairs of sera was high (ratio >=2). In 5/8 of those patients seroconversion was determined. Selected pre-absorbed sera (15 pairs) were tested simultaneously by the same tests. In 8/15 pairs of sera, the reduction of IgM levels in pre absorbed sera was higher than 10. The reduction of IgM differed in sg1 and sg3 tests. The probability of infections due to L. pneumophila sg3 (7 patients) and L. pneumophila sg1 (5 patients) was based on the results of pre-absorption tests. The correlation between ELISA and ImmuView(TM) tests of pre-absorbed sera was statistically significant (Po=0.0389). Moreover, genotyping of L. pneumophila (SBT) directly in the sera of selected 15 patients (high IgM reduction) was carried out. Completed 7 alleles profile (ST36) was determined in one patient. However, a second patient had the same profile of 5 alleles, and similar reactions in pre-absorption tests. At least 4 sources of infections were suggested on the base of genotyping and pre-absorption results. CONCLUSIONS: Positive results obtained by molecular techniques (eg.PCR) in the diagnosis of Legionella infections should be supplemented by other tests for confirmation of legionellosis. The sequence based typing carried out directly in clinical specimens seems to be a promising method. PMID- 23020037 TI - Human dirofilariosis in Poland: the first cases of autochthonous infections with Dirofilaria repens. AB - Dirofilaria (Nochtiella) repens Railliet et Henry, 1911 (Nematoda: Onchocercidae) is a subcutaneous parasite of dogs and other carnivorous animals, with human acting as incidental hosts. D. repens occurs endemically in warm climates on various continents, in Europe mainly in Mediterranean countries. The aim of this study was to summarize information on human dirofilariosis in Poland, taking into consideration parasitological and epidemiological data. Between April 2009 December 2011, in the parasitological laboratories of Medical University in Warsaw and the National Institute of Public Health/National Institute of Hygiene, fragments of affected human tissues and parasite specimens were examined microscopically. Molecular methods were used to confirm the results from eight microscopic investigations. A literature review to summarize all data on dirofilarial infections in humans in Poland was conducted. In these investigations, autochthonous dirofilariosis was found in humans for the first time in Poland. During the last 3 years, 12 new cases of human D. repens dirofilariosis were recognized. Since 2007, a total of 18 D. repens infection have been found in humans in Poland. Parasitic changes were located in various parts of the body, in the form of subcutaneous nodules containing single nematodes surrounded by granulation tissue (15 cases). In 3 cases, a subconjuctival localization was found. Seventeen of the 18 described cases were noted in central Poland where dirofilariosis occured in dogs. In this area, autochtonous infection was identified in 3 women who had never left Poland in their lives; the others were probably infected outside the country while staying in endemic regions. Data on human and canine infection collected from central Poland during the last 5 years indicates that Dirofilaria repens has been introduced into our country, and that the infection is successfully spreading, with the border of the endemic area currently on 52 degrees N, 21 degrees E. To control the epidemiological situation it is necessary to identify D. repens hosts within local mosquito populations, and to monitor dogs. Because of the increasing number of cases of human infections, whether introduced or local, physicians should take dirofilariosis into consideration in differential diagnosis of skin and eye diseases. PMID- 23020038 TI - Molecular screening for Bartonella henselae and Borrelia burgdorferi sensu lato co-existence within Ixodes ricinus populations in central and eastern parts of Poland. AB - The presented study aimed at establishing the prevalence and co-infection rates of Bartonella henselae and Borrelia burgdorferi sensu lato in Ixodes ricinus ticks collected from the central and eastern parts of Poland. The common tick individuals were gathered in the years 2008-2009. Questing ticks were sampled by dragging a white woollen flag over lower vegetation at 17 localities within diverse types of habitats: urban recreational green areas (city parks and squares), suburban forests and rural woodlands throughout the investigated regions of Poland. Detection of B. henselae in tested tick specimens was based on PCR amplification of the citrate synthase (gltA) gene, while screening for the presence of B. burgdorferi s.l. DNA was carried out by analyzing fragments of two genes: the flagellin (fla) and outer surface protein A (ospA). A total number of 1,571 I. ricinus ticks were sampled: 865 (55.1%) nymphs, 377 females (24.0%) and 329 males (20.9%). The application of PCR assays revealed that 76 (4.8%) tick samples were B. henselae-positive, B. burgdorferi s.l. DNA was detected in 194 specimens (12.3%), whereas the co-existence of these pathogens was evidenced in 22 tested ticks (1.4%). Furthermore, the occurrence of bartonellae and co circulation of analysed microorganisms in I. ricinus was affirmed only within adult individuals, while presence of the screened spirochetes was ascertained in both nymphal and adult ticks. It should be stressed that the suburban woods of Warsaw and rural forests in Warsaw County characterized the highest prevalence levels of dual infection with investigated tick-borne pathogens, whereas the lowest co-infection rates were recorded in tick populations inhabiting rural forests in Plock County and forested areas in Korczew-Mogielnica (within the Nadbuzanski Landscape Park). PMID- 23020039 TI - National monitoring study on microbial contamination of food-contact surfaces in hospital kitchens in Poland. AB - INTRODUCTION AND OBJECTIVE: The risk of food-borne infections in hospitalized patients with compromised immune systems is much higher and can also lead to more serious health consequences than among other population groups. Therefore, food hygiene within the hospital setting, should be handled in an appropriate manner. In 2008, there were 732 hospitals in Poland. It was estimated that 7.2 million hospitalized patients, with an average hospital stay of 5.9 days, benefited from hospital meals. On average, nearly half of the hospitals (ranging from 30%-50%, depending on the province) outsourced the preparation and delivery of meals to external service providers. The objective of this study was to survey the bacteriological contamination of selected food production and processing areas in hospital kitchens in Poland. MATERIALS AND METHODS: The nationwide microbiological examination of food contact surfaces was performed in 10% of randomly selected hospital kitchens in all 16 provinces in Poland. A total of 3,277 samples were scientifically examined for hygiene indicator micro-organisms; namely, for Total Viable Count (TVC), Enterobacteriaceae count and coliforms, as well as for the presence of coagulase-positive staphylococci. The environmental samples were collected and examined according to European and Polish standards. All analyses were performed using Statistica version 6 software. RESULTS: The results revealed that food hygiene within the test sample was poor. Of the total samples taken for testing, 25.5% failed. The most common failures were related to excess TVC in swabs. CONCLUSION: Testing shows that there is a need to improve the standard of hygiene in food handling areas of Polish hospitals. PMID- 23020040 TI - Risk of Lyme disease at various sites and workplaces of forestry workers in eastern Poland. AB - Knowledge about the seasonal activity of various stages of the Ixodes ricinus tick is of great importance while developing models of the circulation of pathogens transmitted by ticks in a given environment, as well as while evaluating the risk of infection with these pathogens among individuals performing work in this environment. The objectives of the study was determination of the relative activity of Ixodes ricinus ticks occurring at 4 different workplaces of workers employed in one randomly selected forestry inspectorate, and the comparison of this activity to the Borrelia burgdorferi prevalence in ticks collected from the above-mentioned working stands. Ticks were collected by dragging a woollen flag over lower vegetation and litter along the paths and edges of a forest in July and September 2011 at the following sites and workplaces: acquisition of timber, growing of forest, forest cultivation and forest protection. The relative activity (density) of ticks was determined by means of a combined method of single sample and area sampling. A forest area of approximately 100 m(2) was brushed with a flag. The isolates obtained from Ixodes ricinus ticks were examined for the presence of Borrelia burgdorferi sensu lato DNA by polymerase chain reaction, using primers FLA1 and FLA2 specific for the fragment of fla gene sequence. In the statistical analysis, the Mann-Whitney test, chi(2) test and Spearman test were applied. The differences between Ixodes ricinus activity at individual places of work where various biotopes were observed, were not statistically significant. A statistically significant variation in the tick infection rate, depending on work stands, was found for all the tick stages, i.e. for nymphs (chi(2)=76.516, p<0.000001), females (chi(2)=18.832, p<0.000292) and males (chi(2)=69.257, p=0.000001). Nevertheless, the statistical analysis showed the significant difference in total infection rates only between timber acquisition and growing of forest sites (p=0.049), and between growing of forest and forest cultivation sites (p=0.049). The study showed also the lack of relationship between the ticks' activity and Borrelia burgdorferi infection of ticks at individual places and sites of work of forestry workers. In conclusion, forestry workers employed at such stands of work as timber acquisition, growing of forest, forest cultivation and forest protection are nearly at the same risk of Borrelia burgdorferi infection. PMID- 23020041 TI - Risk of tick-borne diseases in various categories of employment among forestry workers in eastern Poland. AB - Among the zoonotic agents causing occupational diseases, those transmitted by ticks are very important, in particular the spirochetes Borrelia burgdorferi which are the common cause of occupational Lyme borreliosis in forestry and agricultural workers. The objective of this study was an evaluation of the exposure of forestry workers employed at individual workplaces to infection with tick-borne pathogens (especially Borrelia burgdorferi spirochetes), based on epidemiological investigation and serologic tests. Epidemiological studies covered 111 forestry employees from eastern Poland employed in 4 randomly selected forest inspectorates which replied to questions in the area of epidemiology and prophylaxis of diseases transmitted by ticks. Eighty-two forestry workers employed in one forest inspectorate were examined for the presence of specific anti-Borrelia burgdorferi antibodies. The correlation between individual items of the questionnaire was assessed by Spearman's test. Results of serological tests were assessed by Mann-Whitney test. Statistical analysis of the results indicated that the workers performing manual jobs in the forest are at the greatest risk of tick bite and contraction of tick-borne disease. They are aware of the risk, but use the improper method of removal of ticks with the fingers. Comparisons of the relationship between job category and the results of serologic study, expressed in BBU/ml, revealed that the serologic response was significantly greater in manual workers than in administrative workers (p=0.019). All other comparisons did not produce significant results. Therefore, providing a simple tweezer-like device to forest inspectorates seems to be an effective mean of protection against Lyme borreliosis and other tick borne diseases. PMID- 23020042 TI - Environmental factors and allergic diseases. AB - An objective of this article is a review of contemporary knowledge on various environmental factors, that influence prevalence and course of allergic diseases, like asthma, allergic rhinitis, atopic dermatitis and also contact dermatitis. Surrounding climate may directly influence each patient, but also determines type of flora and fauna within particular geographical regions and thus affects sources of airborne and food allergens. Epidemiological studies suggest that there is a strong relationship between air pollution and development and exacerbation of asthma and other allergic diseases--main attention has been concentrated on gaseous materials such as ozone (O(3)) and nitrogen dioxide (NO(2)), as well as particulate matter (PM), generated by car traffic and industry. Diesel exhaust particulate (DEP) has the ability to bind proteins and may serve as a potential carrier of allergens, penetrating deep into respiratory tract. Among the most extensively studied environmental factors influencing allergy are airborne allergens: dust mites, pollens, fungi and animal dander. Foods may elicit both true IgE-mediated allergy and also various non immunological reactions, associated with direct release of mediators or toxic activity. It has been estimated, that over 85,000 chemicals are recognized in the human environment and they may act as contact allergens or irritants, causing allergic or non-allergic contact dermatitis. Among them metals, fragrances, preservatives, botanicals and paraphenylenediamine are considered as the most significant. Infections have always been associated with etiopathogenesis of allergic diseases and they may contribute to exacerbation of their course. PMID- 23020043 TI - Influence of chlorpyrifos on the profile of subpopulations of immunoactive cells and their phagocytic activity in an experimental in vivo model. AB - Many environmental factors, including pesticides, cause immunological system disorders by inducing changes in humoral and cellular response. They may stimulate or trigger immunological autoaggression, hypersensitivity and allergy, as well as lead to immunosuppression, thus increasing the incidence of infectious diseases and cancers. Such activity is also attributed to organophosphorus compounds used in agriculture as insecticides, and commonly in households as biocides. The aim of the study was to define possible mechanisms of the immunotoxic activity of the chlorpyrifos (an organophosphorus compound) on experimental animals following their exposure to the compound via the oral route. The present study attempts to define the influence of chlorpyrifos on the profile of subpopulations of immunoactive cells: B, T, CD4+, CD8+, and NK, and on their phagocytic activity in an experimental in vivo model. For this purpose, the Wistar rats, were exposed orally to increasing doses of chlorpyrifos: 0.1 LD(50), 0.15 LD(50), 0.2 LD(50), 0.3 LD(50) and 0.4 LD(50) for 28 days. In the study animals, we failed to demonstrate a statistically significant decrease in the phagocytic activity of the granulocyte. PMID- 23020045 TI - Epigenetic regulation in drug addiction. AB - The interaction between environmental signals and genes has now taken on a clear molecular form as demonstrated by stable changes in chromatin structure. These changes occur through activation or repression of specific gene programmes by a combination of chromatin remodelling, activation and enzymatic modification of DNA and histones as well as nucleosomal subunit exchange. Recent research investigating the molecular mechanisms controlling drug-induced transcriptional, behavioural and synaptic activity has shown a direct role for chromatin remodelling--termed as epigenetic regulation--of neuronal gene programmes and subsequent addictive behaviour arising from it. Recent data suggest that repeated exposure to certain drugs promotes changes in levels of histone acetylation, phosphorylation and methylation, together with alterations in DNA methylation levels in the neurons of the brain reward centre, localised in the Nucleus Accumbens (NAc) region of the limbic system. The combination of acetylating, phosphorylating and methylating H3 and H4 histone tails alter chromatin compaction thereby promoting altered levels of cellular gene expression. Histone modifications, which weaken histone interaction with DNA or that promote recruitment of transcriptional activating complexes, correlate with permissive gene expression. Histone deacetylation, (which strengthen histone: DNA contacts), or histone methylation, (which recruits repressive complexes to chromatin), promote a state of transcriptional repression. Using animal models, acute cocaine treatment increases H4 acetylation at acutely regulated gene promoters, whereas H3 acetylation appears to predominate at chronically induced promoters. Chronic cocaine and alcohol treatment activate and repress many genes such as FosB, Cdk5, and Bdnf, where their dysregulation, at the chromatin level, contribute to the development and maintenance of addiction. Following drug exposure, it is still unknown, howver, how long these changes in chromatin structure persist in affecting neuronal function, but some do so for life. PMID- 23020046 TI - Why and how to include anthropological perspective into multidisciplinary research in the Polish health system. AB - The article focuses on ways in which anthropological knowledge, incorporated into multidisciplinary and multilevel research projects, can be applied for understanding health- and illness-related behaviours and functioning of the health system in Poland. It selectively presents potential theoretical and methodological contributions of the anthropological discipline to the field of applied health research, and briefly reviews selected ethnographic theories and methods for researching and interpreting socio-cultural conditioning of healing, health and illness related practices. The review focuses on the following approaches: Critical Medical Anthropology, Cultural Interpretive Theory, phenomenology, narrative analysis, and the biography of pharmaceuticals. The author highlights the need for team work and use of a holistic perspective while analyzing the health system in Poland, and underlines the need for serious attention and financial support to be given to multidisciplinary research projects of which anthropology is a part. PMID- 23020044 TI - Effects of fluoxetine on the anticonvulsant action of valproate and ethosuximide in mouse model of myoclonic convulsions. AB - Depression is becoming a growing problem in rural areas. This psychiatric disorder often accompanies epilepsy. The aim of this study was to assess the influence of fluoxetine (FXT), a commonly used antidepressant, on the protective action of two conventional antiepileptic drugs: ethosuximide (ETX) and valproate (VPA), against pentylenetetrazole (PTZ)-induced convulsions in mice. Motor coordination and long-term memory deficits induced by FXT, antiepileptic drugs alone and in combinations with FXT were assessed in the chimney test and passive avoidance task, respectively. Brain concentrations of ETX and VPA were measured by immunofluorescence. Obtained results indicate that FXT at the dose of 15 mg/kg (i.p., 30 min before the test) significantly increased the threshold for clonic convulsions. The antidepressant drug at lower doses remained ineffective in this respect. Moreover, FXT at the highest subprotective dose (10 mg/kg, i.p.) markedly enhanced the anticonvulsant effects of VPA, but not of ETX, against PTZ induced seizures. The interaction between FXT and VPA seems to be pharmacodynamic because the antidepressant drug did not alter the brain concentration of VPA. With regard to adverse effects, FXT, VPA, ETX, and the combinations of FXT with antiepileptic drugs, did not impair motor coordination and long-term memory in mice. In conclusion, the combination of FXT with VPA may be advantageous in the treatment of myoclonic epilepsy, and therefore it should be recommended for further study in clinical conditions. PMID- 23020047 TI - Physicians' religiosity and attitudes towards patients. AB - BACKGROUND: Many religions underline the value of merciful acts, especially the care of the sick. The aim of the survey was to verify the hypothesis that a higher religiosity correlates with a more desirable ethical attitude towards patients. METHOD: An anonymous questionnaire consisting of standardized tools: Scale of Attitudes towards the Patient (SAtP) (four dimensions: respect for autonomy, altruism, empathy and holistic approach to a patient), the Scale of Religious Attitudes (SReAt) evaluating the religiosity, and some questions related to the role of religious beliefs in respondents' professional lives. The research was carried out on a group of 528 Polish physicians, 324 of whom returned the questionnaire (return = 61%); 51% women, 49% men; average work experience: 17.03 years; 93% Catholics. RESULTS: Religiosity correlates positively with altruism (r=0.12; p<0.05), holistic approach (r=0.18; p<0.01) and empathy (r=0.20; p<0.01), but not with respect for autonomy. For the majority of physicians, religious faith is an important supportive factor, especially in making difficult decisions. Surgeons are less religious (M=5.32; SD=1.06) than non-surgeons (M=5.61; SD=0.93); (t= -2.59, p<0.05). CONCLUSION: Physicians' religiosity is an essential factor shaping their attitude towards patients. The majority of physicians declared that their religious faith influences their professional decisions, especially in difficult situations. The religiosity variable explains physicians' moral attitude better than the denomination (religious affiliation) variable. Physician-patient relation frameworks should take into account not only patients' but also physicians' cultural and religious beliefs. PMID- 23020048 TI - Psychosocial aspect of quality of life of Polish women with breast cancer. AB - INTRODUCTION AND OBJECTIVE: Breast cancer is one of the most frequently occurring malignant tumours among women in Poland. The highest incidence of the disease is registered among women aged 50 and more. Cancer imposes a considerable psychological strain on a woman. It causes a sense of uncertainty about one's health and further life, as well as frequent problems with accepting the image of one's own body. It often results in low self-esteem and a feeling of embarrassment, accompanied by symptoms of apathy and detachment. The aim of the study was to determine mental and social life quality of Polish women treated for breast cancer. MATERIALS AND METHODS: The research encompassed 107 women aged between 45 and 65 (SD=6.11) undergoing treatment for breast cancer. The WHOQOL Bref scale was applied in the research. RESULTS: The social field was better evaluated in comparison with the mental sphere. There was a statistical correlation between place of residence and social sphere of quality of life (p=,036), with higher ratings assigned by respondents residing in rural areas (M=15.36) compared with residents of towns (M=14.15). CONCLUSIONS: Given the fact that respondents were coping with cancer or its consequences, paradoxically, perception of the overall quality of life and examined areas was generally good, especially among women with higher education, those who were single and those living in rural areas. Along with age, there decreases at the respondents the experienced quality of life, however a rise of evaluations of the mental sphere is accompanying the rise in the education level. PMID- 23020049 TI - Socio-economic conditionings of families with children treated due to scoliosis in Eastern Poland. AB - INTRODUCTION AND OBJECTIVE: Scoliosis is a serious clinical problem which requires a systematic physical therapy and control of body balance--treatment from the moment of achieving skeletal maturity by a child. In the situation of neglect of such a management, the deformation of the spine often requires surgical intervention. The role of parents in the process of treatment of a child is undeniable. The study concerned the determination of socio-economic conditions and the engagement of parents with children treated due to scoliosis in Eastern Poland. MATERIAL AND METHODS: The study was conducted by means of a diagnostic survey. The study group consisted of 193 parents (148 females (76.7%) and 45 males (23.3%))--a randomly selected sample of the parents of children who participated in scoliosis rehabilitation courses in rehabilitation centres in Eastern Poland. The significance of the relationships between variables was investigated by means of chi-square test for independence. The differences between the empirical and theoretical sample distribution was examined by means of chi-square goodness-of-fit test. The significance level was set at p=0.05. RESULTS: The study group covered 47.7% of inhabitants of the rural areas and small towns, and 52.3% of inhabitants of medium-size and large cities. Respondents with a higher economic status were more engaged in the treatment of their child with scoliosis. A greater number of parents with university education level reported to a specialist; however the frequency of these visits, similar to incomplete families, was the lowest. CONCLUSIONS: The accessibility to specialists is lower in the rural than urban areas. 1. There is a relationship between the economic standard of the family and engagement in the treatment of a child with scoliosis. 2. There is a need to develop a system of education of parents concerning scoliosis and the consequences of neglecting treatment. 3. The system of public health services is insufficient for satisfying health demands of patients with the diagnosis of scoliosis. PMID- 23020050 TI - Injuries caused by sharp instruments among healthcare workers--international and Polish perspectives. AB - Health care workers (HCW) worldwide are especially exposed to injury by sharp instruments in the course of their duty. The most often executed procedures with injury risk are: intramuscular or subcutaneous injection (22%), taking blood samples, or during intravenous cannulation (20%), and repeatedly replacing the cap on an already used needle (30%). Even a minor sharp injury with only a small loss of blood carries the risk of transfer of over 20 pathogens: Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), HIV/AIDS virus, malaria, syphilis, tuberculosis, brucellosis, herpes virus and diphtheria. The World Health Organization (WHO) estimates that more than two million health care workers experience the stressful event of a percutaneous injury with a contaminated sharp object each year (25-90% of them, however, remain unreported). These exposures result in about 16,000 infections with HCV, 66,000 with HBV and about 1,000 (200 5000) with HIV, which lead to about 1,100 deaths or significant disability. Exposures to sharp injuries and their consequences are highly preventable through simple interventions, such as HBV vaccination, education and providing containers for sharp instruments. Specific guidelines, similar to the American Occupational Safety and Health Administration (OSHA) regulations that have lowered by up to 88% of needle stabbing incidents, should be introduced by the European Union (EU) and other countries. The results of a review of reports leads to the following conclusions: 1) elaboration and implementation of new State regulations, especially in EU countries and in countries where such regulations do not exist; 2) the training of health care personnel should always be undertaken for new employees, and periodically for those already employed; 3) periodical control by appointed inspectors of knowledge of procedures for the prevention of injuries by sharp instruments among health care workers; 4) introducing and training in the use of equipment, which can prevent the sharp injuries; 5) an advanced monitoring system of sharp injuries sustained by worker should also be introduced. Successful implementation of these prevention measures will result in progress for public health and HCW's health and safety. PMID- 23020051 TI - Oral hygiene in children suffering from acute lymphoblastic leukemia living in rural and urban regions. AB - INTRODUCTION AND OBJECTIVE: During acute lymphoblastic leukemia treatment, oral mucositis is a hugely important dental problem. In order to lower the risk of such complications, patients should take special care of their oral hygiene. The aim of this study was to assess the oral hygiene status in children with ALL during anti-cancer treatment protocols. MATERIALS AND METHODS: 78 children with ALL who were examined in 3 stages, and 78 generally healthy children, who constituted the control group, participated in the study. In the group of patients were 55 children from the rural environment and 23 children living in towns. Oral hygiene status was assessed with the use of the Oral Hygiene Simplified Index, Plaque Index, and Gingival Index. RESULTS: The average value of OHI-S index in children with ALL before the chemotherapy was 0.64 +/- 0.85, the value of the Pl.I index was 0.59 +/- 0.74, GI index value was 0.08 +/- 0.34. In the period from 0.5-1.5 years, the anti-cancer therapy value indicators of oral hygiene in children with ALL developed as follows: OHI-S--0.49 +/- 0.69, Pl.I- 0.49 +/- 0.67, GI--0.02 +/- 0.13. CONCLUSIONS: Oral hygiene was significantly better in children with ALL than in children in the control group. The better condition of oral hygiene in children with ALL than children in the control group is the result of the oral hygiene regime that the children were following during cancer treatment protocols. Significantly higher GI in children with ALL, compared to children from the control group, was observed despite the better oral hygiene. PMID- 23020052 TI - Relationships between biochemical bone metabolism indices and morphometric, densitometric and mechanical properties of mandible in 6-month-old pigs. AB - INTRODUCTION AND OBJECTIVE: Mandible is used as a bone model for monitoring bone tissue responses to various factors influencing skeletal homeostasis. Considering the lack of experimental data on interrelationships between bone metabolism indices and morphometric, densitometric and mechanical properties of mandible, the aim of this study was to perform such an evaluation in 6-month-old pigs. MATERIALS AND METHODS: Quantitative computed tomography was used to determine bone volume, mean volumetric bone mineral density, cortical bone density and cortical bone area. Using dual-energy X-ray absorptiometry, bone mineral density and bone mineral content were measured for ramus, body and whole jaw. In the three-point bending test, maximum elastic strength and ultimate strength of jaw was determined. Assessment of calcium (Ca), phosphorus (P), magnesium (Mg), parathormone (PTH), growth hormone (GH), insulin-like growth factor-1 (IGF-1), alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BAP), osteocalcin (OC) and C-terminal telopeptide of collagen type-I (CTX) in blood was performed. RESULTS: Statistically significant correlations in relation to the investigated traits of the jaw were found in the case of ALP, OC, CTX, GH and IGF-1. Significant correlations of ALP activity, OC and IGF-1 concentrations with final body weight were stated (p<0.05). CONCLUSIONS: This study shows the highest predictive value of ALP activity determination in relation to assessment of morphological, densitometric and biomechanical properties of mandible. Evaluation of Ca, P, Mg, BAP and PTH has not confirmed its significance for morphological, densitometric and biomechanical properties prediction in the jaw of pigs. ALP activity, OC and IGF-1 concentrations would be prognostic for body weight prediction. PMID- 23020053 TI - Evaluation of prognostic parameters of E-cadherin status in breast cancer treatment. AB - INTRODUCTION AND OBJECTIVE: Breast cancer is one of the most frequent malignancies in women. Axillary lymph node involvement, tumour size, receptor status, and level of malignancy are the most significant prognostic factors in breast cancer, but insufficient to date. More factors are needed for establishing the prognosis and treatment in these patients. The aim of the presented study was evaluation of E-cadherin expression and its prognostic value among 89 specimens of breast cancer. MATERIALS AND METHODS: 89 formalin-fixed and paraffin-embedded breast cancer specimens were studied for expression of E-cadherin detected by immunohistochemistry. During 10-year observation overall/OS/and disease-free survival/DFS/of patients were assessed. RESULTS: Average of OS and DFS were shorter among patients without expression of E-cadherin in comparison to survival time of patients with expression of E-cadherin. The lack of E-cadherin expression was present more often among patients with distant metastasis. No essential changes were noticed in the level of E-cadherin depending on the size of the tumour, G, presence of metastasis into the lymph nodes, ER, PR and HER-2, hormonal condition and presence of cancerous tissues in lymphatic vessels and the infiltration of lymph nodes capsules. CONCLUSIONS: E-cadherin may play an important role in the prognosis of breast cancer patients. PMID- 23020054 TI - Passive smoking as an environmental health risk factor. AB - Initially, tobacco was considered as a decorative plant and only later began to be treated as a herb with special therapeutic properties. With time, it was found that tobacco had strong insecticidal and addictive properties. There also occurred reports about the negative influence of tobacco on human health. The World Health Organization (WHO) classifies smoking as a chronic, progressive disease which is also 'contagious'. It is also considered to be a neurobiotic addiction. Nicotine addiction does not cause changes in the behaviour or functioning of a smoker; however, it adversely affects his or her general health status and the health status of people within their environment. Passive smoking (so-called ETS--Environmental Tobacco Smoke), which means accompanying smokers negatively influences the health of passive smokers. Environmental tobacco smoke, on the one hand, is the result of spontaneous cigarette burning and, on the other hand, the result of the side-stream of cigarette smoke, as well as the smoke exhaled by active smokers. Health personnel should clearly and convincingly present the data concerning the adverse results of smoking, as well as the dangers of exposure to environmental tobacco smoke, thereby making their patients aware that breaking their addiction will not only be beneficial for their own health, but will also protect non-smokers in their environment from the adverse effects of exposure to environmental tobacco smoke. PMID- 23020055 TI - Prevalence of metabolic syndrome among 40- and 50-year-old inhabitants of Wroclaw, Poland. AB - INTRODUCTION AND OBJECTIVE: The metabolic syndrome (MetS) has been discussed for many years, but there is no doubt that those who have confirmed the presence of risk factors comprising the MetS had a higher risk of cardiovascular disease. The aim of this study was to evaluate the prevalence of MetS among 40- and 50-year old (y.o.) inhabitants of Wroclaw, Poland. MATERIALS AND METHODS: The study group included Wroclaw inhabitants who were recruited between 2001-2004 into the Cardiovascular Disease Prevention Programme. The study group consisted of 18,583 participants (females: 40 y.o.--5,248 and 50 y.o.--5,329; males: 40 y.o.--4,229 and 50 y.o.--3,777). The MetS was defined by IDF/NHLBI/AHA (2009) criteria. RESULTS: MetS was found in 12.7% of 40 y.o. and in 33.1% of 50 y.o. females, while in males, respectively, in 30.4% and 42.1%. Overall, MetS occurred in 28.5% of the study group. MetS occurred significantly more frequent among the older than the younger groups, both in females and males. MetS was found significantly more frequent among males than females from Wroclaw, in both 40- and in 50 y.o. participants. Among those females with MetS, the most frequently (more than 90% in both age groups) occurred excessive waist circumference (WC), followed by elevated blood pressure-BP (72.1% of 40 y.o., 86.8% of 50 y.o.). Excessive WC, elevated BP and triglycerides-TG was found in more than 80% of males aged 40 and with diagnosed MetS. Among the older group of males with MetS, the most frequently occurred elevated BP (90.4%), followed by excessive WC (87%) and elevated TG (78.5%). CONCLUSION: MetS was diagnosed more frequent in males than females of Wroclaw. Prevalence of MetS increased with age. The most significant impact on reducing the prevalence of MetS in the study group would be the lowering of BP and WC to recommended values. PMID- 23020056 TI - Lifestyle as an important factor in control of overweight and obesity among schoolchildren from the rural environment. AB - INTRODUCTION: Lifestyle of an individual is responsible for sixty percent of his/her state of health. Many studies of this problem indicate that in the style of life of schoolchildren, anti-health behaviours dominate over health promoting behaviours. OBJECTIVE: The objective of the presented study was recognition of the lifestyle of the rural adolescents with overweight and obesity. MATERIAL AND METHODS: The study covered adolescents aged 15-19, living in the rural environments of the West Pomeranian Region. Finally, the analysis covered 2,165 schoolchildren, and was performed with the use of a self-designed questionnaire form and the BMI was applied. RESULTS: The study showed that overweight occurred more often in the group of examined girls than boys, while obesity was twice as frequent among boys than among girls. Overweight schoolchildren (35.1%) had an adequate diet, while those obese--inadequate (78.3%). In the group of schoolchildren with overweight, passive leisure prevailed over active forms of leisure, 83.8% and 16.2%, respectively. Passive leisure was also dominant among obese respondents. Among as many as 81.8% of schoolchildren with overweight, physical activity was mediocre, while only 8.1% of them were active. The highest percentage of respondents with obesity were totally inactive physically. Obese schoolchildren relatively often experienced stressful situations. It is an alarming fact that both overweight and obese schoolchildren relatively often used psychoactive substances. CONCLUSIONS: A considerable number of respondents with overweight and obesity applied an adequate diet, preferred passive forms of leisure, experienced stressful situations, were characterized by low physical activity, and systematically used psychoactive substances. PMID- 23020057 TI - Is the advancement of diabetic angiopathy evaluated as ankle-brachial index directly associated with current glycaemic control? AB - INTRODUCTION AND OBJECTIVE: Diabetic patients are at high risk for peripheral arterial disease (PAD) characterized by symptoms of intermittent claudication or critical limb ischemia. Measurement of ankle-brachial index (ABI) has emerged as the diagnostic tool of choice, because it is relatively simple, non-invasive and inexpensive. It is also an independent marker of increased morbidity and mortality from cardiovascular diseases. The aim of the presented study was to assess the relationship between current glycemic control defined by glycated hemoglobin (HbA(1c)) level, and quantitative changes in the arteries of the lower limbs in patients with type 2 diabetes. MATERIALS AND METHODS: 175 patients with type 2 diabetes hospitalized in the Diabetology Ward were studied. VENO Doppler and a sphygmomanometer were used to assess blood flow. RESULTS: The average level of HbA(1c) was assessed at 8.48%. Although the average level of ABI indicator was 1.20 (normal), only 45% of evaluated patients had their individual index within the normal range. Signs of ischemia were found in 17.7% of examined subjects. There was no conclusive correlation between ABI and HbA(1c) levels. CONCLUSIONS: The current level of glycemic control evaluated as HbA(1c) has no direct impact on the advancement of diabetic angiopathy evaluated as ABI. PMID- 23020058 TI - Replacement therapy of secondary hypothyroidism in children born with low body weight improves mental development. AB - BACKGROUND: Secondary hypothyroidism is observed in children after brain damage. The aim of the study was evaluation of the mental development in preterm-born children during replacement therapy with l-thyroxin because of secondary hypothyroidism. MATERIALS AND METHODS: The motor and mental development of preterm newborns with secondary hypothyroidism treated with l-thyroxin since the second week of life were compared with the development of preterm newborns with secondary hypothyroidism treated since the fourth week, or later. Motor development was evaluated, and the mental development and IQ assessed by the Wechsler Intelligence Scale for Children in the seventh year of life. RESULTS: Earlier achievement of the milestones of motor development, i.e. sitting, standing, and walking, was observed in children from the group who received early treatment with modest doses of l-thyroxin. In this group, all infants acquired the motor functions statistically significantly earlier in comparison to the infants from group with delayed treatment. In the seventh year of life, the IQs were significantly higher in group I treated since the second week of life, compared to group II. CONCLUSIONS: The early replacement therapy with l-thyroxin initiated in the second week of life may improve long-term mental development in children. PMID- 23020059 TI - Efficacy and safety of insulin pump treatment in adult T1DM patients--influence of age and social environment. AB - INTRODUCTION AND OBJECTIVE: Continuous subcutaneous insulin infusion (CSII) via personal insulin pump is a valuable therapeutic tool in T1DM patients. However, adherence to recommended CSII-related behaviours may be of concern to young adults with intensive, variable daily activities (students, young professionals). The aim of this observational study was to estimate treatment outcomes in young adult patients with T1DM, and compare them with older individuals. MATERIALS AND METHODS: Overall, 140 adults with T1DM on CSII were examined, divided into 2 subgroups: 77 patients younger than 26 years of age (mean 20.6 years) and 63 older subjects (mean 39.0). We compared the glycaemic control in both groups of T1DM subjects and analyzed treatment attitudes to identify potentially modifiable behaviours influencing the efficacy of the treatment. RESULTS: The younger individuals were characterized by significantly worse treatment outcomes, compared to the older ones: the mean HbA1c levels were 7.6 +/- 1.3% and 6.9+/ 1.3% (p=0.00001), while the mean glucose levels based on glucometer downloads were 161+/-33.6 mg/dL and 136+/-21.8 mg/dL (p=0.00001), respectively. The frequency of self-monitoring of blood glucose (SMBG) was lower in younger individuals (5.3+/-2.1 vs. 7.0+/-2.8 daily, p=0.0005, respectively); they were also less frequently used advanced pump functions, e.g. the bolus calculator (48% vs. 67% users, p=0.0014, respectively). CONCLUSIONS: The efficacy of CSII treatment observed in young T1DM adults was worse than in older patients. The reason for this phenomenon remains unclear, it may be due simply to age-dependend behaviours, to social environment, or both. PMID- 23020060 TI - Determinants of favourable neonatal outcome after premature rupture of membranes (PROM) before 24 weeks of pregnancy--review of the literature and a case report. AB - OBJECTIVES: Premature rupture of the membranes (PROM) in pregnancy refers to rupture of membranes of the amniotic sac and chorion. The aim of the study was to review the literature and analyze the course of pregnancy (primipara) complicated by the premature rupture of the membranes, and consequent loss of amniotic fluid after 19 weeks of gestation. STUDY DESIGN: A 27-year old primiparous patient was admitted to the Gynaecology and Obstetrics University Hospital in Poznan on 9 December 2010, due to suspected premature rupture of the membranes. On presentation, foetal development was at 19 weeks gestation. Standard clinical investigations included ultrasonography, amniotic fluid index measurements and laboratory blood tests. RESULTS: Ultrasonography confirmed the size of the foetus to be normal for the gestational age. However, no amniotic fluid pockets were visible and the amniotic fluid index was 0 cm. The patient was hospitalized on multiple occasions and as a result a decision was made to end the pregnancy prematurely by means of a caesarean section at 32 weeks of gestation. Longer-term observation of the newborn indicated that one year following delivery, the development of the baby was normal, and thus far no neurological injuries or complications have been observed. CONCLUSION: The pregnancy was ultimately successfully completed with the delivery of a healthy newborn at 32 weeks of gestation. A regime involving rigorous bed rest and antibiotic administration can positively extend the duration of pregnancies complicated by premature rupture of the membranes. PMID- 23020061 TI - Three most important etiological factors of occurrence of stress urinary incontinence in nulliparous pre- and postmenopausal Polish women. AB - INTRODUCTION: Stress urinary incontinence (SUI) is a chronic disease which occurs in 50% of women with urinary incontinence. It is estimated that in association with a longer life span and ageing of the population, this disorder will become even more prevalent and will exert an increasingly stronger effect on the deterioration of the quality of life. OBJECTIVE: The objective of the study is analysis of the factors affecting the occurrence of SUI. METHODOLOGY: The analysis covered 260 patients aged 27-82. The criterion of enrolment into the study was: diagnosis of SUI without disorders of pelvi-genital statics, and negative obstetric history (nulliparous and non-pregnant women). The investigations covered, among other things, the effect surgeries in the area of the lesser pelvis, body mass index (BMI), cigarette smoking, concomitant internal diseases, and hormonal therapy, with consideration of the division into two groups: women before and after menopause. Statistical analysis was performed by means of chi 2 Pearson, t-Student test, and Fisher-Freeman-Halton test for p<0.05. RESULTS: The results of the analysis unequivocally indicate that the age of patients (p=0.0001), body mass index (BMI) (p=0.0001), and surgical procedure for the removal of the uterus by laparotomy (p=0.0001) exert the greatest effect on the occurrence of SUI in pre- and postmenopausal women. The effect of the remaining etiologic factors is rather controversial. CONCLUSION: A comprehensive analysis of risk factors may contribute to the improvement of the results of treatment and quality of life of pre- and postmenopausal patients. PMID- 23020062 TI - Sexual initiation of youths in selected European countries compared with their sexual and contraceptive knowledge. AB - The problem of educating youths entering adult life is as old as the history of mankind. The data shown in the introduction indicate that the methods of education depend on culture, religion, climatic zone, and a whole chain of events characteristic for the place where the young man grows up. Research data, however, show that adolescents of the former Eastern Bloc use contraceptives significantly less often and have a more traditional approach to the relationships between a man and a woman. They are, however, more likely to engage in random sexual contacts and accompanied dangerous sexual behaviours. Polish youths have a more liberal approach to the norms concerning sexual activity. The age of sexual initiation lowers gradually, but not as radically as over the western border. These changes occur at a slower rate than in other European countries. Sexual education, which is supposed to prepare the young man, responsible and fully aware of his actions, for adult life, also develops at a slower rate. PMID- 23020063 TI - Principles of social security and health insurance for farmers in Poland and Germany--a comparative assessment. AB - INTRODUCTION AND OBJECTIVE: As landowners occupied with agricultural production comprise a sizeable part of the populations in mid- and western European countries, it seemed reasonable to assess the organization of health care systems concerning farmers and their families in Poland and Germany. Both countries have similar geographical conditions and rural environments. It so happens that in Poland the principles of the system of agricultural insurance (KRUS) is based on the experiences of Germany and France. STATE OF KNOWLEDGE: Basically, both in Poland and Germany, the agricultural health insurance companies provide the same insurance cover as other health insurance companies. In both countries, under certain conditions, in the case of illness, the insured farmers receive instead of sickness benefit operational assistance and home help. In spite of the similarities that characterize both administrations, many particular differences are to be noted, e.g. the farmers' social insurance in Poland is subject to only one ministry, in contrast to Germany where two ministries are responsible for farmers' social insurance. In Poland, KRUS is a monopolistic organization, whereas in Germany, nine similar independent structures fulfil the task of a health insurance company. Needless to say, many more funds are available for prevention, treatment and rehabilitation in Germany than in Poland, due to obvious differences in the overall national income. PMID- 23020064 TI - Professional communication competences of nurses. AB - INTRODUCTION: Dissonance between the high 'technical' professionalism of nurses and the relatively low level of patient satisfaction with care received is a phenomenon observed in many countries. Many studies show that it occurs in the case of an inadequate interpersonal communication between nurses and patients. METHODS: Three basic scopes of communication competences were involved in the research process: a) motivation, b) knowledge, c) skills, and the following three methods were used: 1) documentation analysis (standards, plans and educational programmes); 2) diagnostic survey concerning professional communication competences of nurses in nursing care--a questionnaire form designed by the authors; 3) self-reported communication skills in nursing care--adjective check list. The study group covered a total number of 108 respondents in the following subgroups: 1) professional nurses who, as a rule, were not trained in interpersonal communication (42 respondents); students of nursing covered by a standard educational programme (46 respondents); 3) students of nursing who, in addition to a standard educational programme, attended extra courses in professional interpersonal communications nursing (20 respondents). The data obtained were subjected to statistical analysis with the use of descriptive statistics and hypothesis testing. RESULTS: The results of studies indicate poor efficacy of shaping communication competences of nurses based on education in the area of general psychology and general interpersonal communication. Communication competences acquired during undergraduate nursing education, are subject to regression during occupational activity. DISCUSSION: Methods of evaluating communication competences are useful in constructing group and individual programmes focused on specific communication competences rather than on general communication skills. PMID- 23020065 TI - Alcohol-containing mouthwash and oral cancer--can epidemiology prove the absence of risk? PMID- 23020066 TI - Absolute rate coefficient and mechanism of gas phase reaction of ketenyl radical and SO2. AB - The kinetics of the gas phase reaction of the ketenyl radical with SO(2) was investigated over the temperature range 296-568 K using a laser photofragment/laser-induced fluorescence technique (LP/LIF). The reactor pressure was 10 Torr N(2) or He. Pulsed photolysis of ketene (CH(2)CO) at 193 nm was used as the source of HCCO radicals. The rate coefficient for the title reaction was determined to be described by k(T) = (1.05 +/- 0.33) * 10(-12) exp[(690 +/- 98)K/T] cm(3) s(-1) molecule(-1) (2sigma error). We applied the coupled cluster and density functional theory to explore the mechanism of the title reaction. The dominant reaction pathway begins with a barrierless association of the C of the CH group of HCCO and the O atom of SO(2). PMID- 23020067 TI - Commercial 'ready-to-feed' infant foods in the UK: macro-nutrient content and composition. AB - Quantitative analyses of the macronutrient content of eight popular commercial 'ready-to-feed' baby meals for 6-9-month old infants in the UK market have been undertaken in order to ascertain their nutritional suitability in relation to the total daily dietary intake as well as nutritional profiling of the products. The chemical analyses conducted included Kjeldhal for protein, acid hydrolysis and extraction for fat, phenol sulphuric acid for carbohydrate and Association of Official Analytical Chemists 985.29 for fibre. The only difference found between different varieties (meat- and vegetable-based) was with respect to the protein content (P=0.04) per 100 g of food. The experimentally determined concentrations of macronutrients (g/100 kcal) were compared with the declared values provided by the manufacturers on the product labels and, despite some variations, the values obtained comply with regulatory requirements (Commission Directive 2006/125/EC). The total daily intake of fat (27.0 g per day) - based on the menu composed from commercial complementary food - is suggested to exceed the daily recommended values for fat (31%), if the intake of snacks and desserts are incorporated. These findings imply that the formulation of recipes, based on a standard commercial menu, is an important consideration in relation to the nutritional quality of the diet of infants. PMID- 23020068 TI - Associations among patient characteristics, health-related quality of life, and spiritual well-being among Arab Muslim cancer patients. AB - BACKGROUND: Despite Islam being the world's second largest religion and despite the fact that there are 22 Arabic-speaking nations representing North Africa and the Middle East, little is known about the relationship between spiritual well being and health-related quality of life (HrQoL) for Arabic-speaking Muslims in treatment for cancer. AIM: The study's aim was to determine whether spiritual well-being is correlated with HrQoL and whether participants' age, sex, marital status, site of cancer, and stage of disease are related to spiritual well-being. DESIGN: Using a cross-sectional design, a total of 159 Arabic-speaking, study eligible cancer patients who were in treatment at the King Hussein Cancer Center (KHCC), Amman, Jordan, completed three questionnaires: a demographic questionnaire; the Functional Assessment in Cancer Therapy-General (FACT-G), which assesses the physical, social, functional, and emotional domains of HrQoL; and the Functional Assessment in Chronic Illness Therapy-Spiritual Well-being (FACIT-Sp). RESULTS: Physical well-being was negatively correlated with the FACIT Sp for men, divorced, and stage IV disease. Social Well-being was positively correlated with the FACIT-Sp for ages 18-34 and 35-49 years; both sexes; married, never married, and divorced; breast, bone/sarcoma, and gastrointestinal cancers; and stages II-IV. Emotional Well-being was negatively correlated with the FACIT Sp for ages 35-49; males; never married; and stages III and IV. Functional Well being was positively correlated with the FACIT-Sp for ages 35-49 and 50-64; both sexes; married or never married; and stages II and III. Age and cancer site showed a positive relationship with spiritual well-being. CONCLUSIONS: The FACIT Sp distinguishes between domains of HrQoL and patient characteristics. Further study on the unique contribution of the FACIT-Sp's Peace and Meaning subscales to HrQoL is needed. PMID- 23020069 TI - Altered plasma and brain disposition of isopropylidene shikimic acid liposome in rats and the brain protection in cerebral ischemia-reperfusion. AB - CONTEXT: Cerebral ischemia-reperfusion (I/R) injury is a secondary injury caused by oxidative stresses and inflammatory responses after recovery from cerebral ischemia. Brain protective drugs were used to reduce the injury. In order to improve the distribution in brain and enhance the brain-protective efficacy, some pharmaceutical technologies were used to achieve brain targeting delivery. OBJECTIVE: To investigate the physiological disposition of ISA liposome, and provide references for the further study about high-efficacy brain-protective preparations for I/R injury. MATERIALS AND METHODS: Comparative studies were carried out. The pharmacodynamics in t-MCAO model rats were studied first, and then the pharmacokinetics and brain distribution of the two preparations were determined. RESULTS: At the same dose, the efficacy of ISA liposome was better (P < 0.05). The efficacy was dose dependent, with significant difference of 20 mg/kg (P < 0.01) and indistinctive difference of 10 mg/kg (P = 0.22), compared with vehicle-treated rats. The parameters, T(1/2beta), MRT and AUC were different significantly between the two preparations. The enhancement of brain distribution for ISA in the liposome was obvious, with the maximum concentration 7.18 MUg/g, while close to zero for the solution group. DISCUSSION AND CONCLUSION: ISA liposome could increase the distribution in brain and enhance the efficacy significantly. The results revealed that the liposomal DDS was potential as a novel strategy for the treatment of cerebral I/R injury. In addition, further targeted modification, such as PEG-modified liposomes, which possess a long circulating property in the bloodstream, would further improve the targeting delivery to the brain and lead to more significant efficacy. PMID- 23020070 TI - 'Things you can't learn from books': teaching recovery from a lived experience perspective. AB - Mental health policy in Australia is committed to the development of recovery focused services and facilitating consumer participation in all aspects of mental health service delivery. Negative attitudes of mental health professionals have been identified as a major barrier to achieving these goals. Although the education of health professionals has been identified as a major strategy, there is limited evidence to suggest that consumers are actively involved in this education process. The aim of this qualitative study was to evaluate students' views and opinions at having been taught 'recovery in mental health nursing' by a person with a lived experience of significant mental health challenges. In-depth interviews were held with 12 students. Two main themes were identified: (i) 'looking through fresh eyes' - what it means to have a mental illness; and (ii) 'it's all about the teaching'. The experience was perceived positively; students referred to the impact made on their attitudes and self-awareness, and their ability to appreciate the impact of mental illness on the individual person. Being taught by a person with lived experience was considered integral to the process. This innovative approach could enhance consumer participation and recovery-focused care. PMID- 23020072 TI - Topical administration of the pan-Src kinase inhibitors, dasatinib and LCB 03 0110, prevents allergic contact dermatitis in mice. AB - BACKGROUND: Allergic contact dermatitis (ACD) is a delayed type of T cell mediated cutaneous inflammatory response, in which multiple cell types are involved. Dasatinib and LCB 03-0110 are small molecule multityrosine kinase inhibitors, and they share remarkably similar target kinases such as the c-Src family, Btk and Syk, which play key roles in the cell signalling of T cells and other inflammatory cells. OBJECTIVES: To test the anti-ACD activity of dasatinib and LCB 03-0110 and compare it with that of tacrolimus (FK506) and triamcinolone acetonide (a glucocorticoid), which are widely used for topical treatment of ACD, and to examine the two compounds for their capacity to induce skin atrophy, a side-effect. METHODS: ACD was induced on the ears of mice by repeated topical application of oxazolone. Each test compound was then topically applied on the ear. Ear swelling, epidermal thickness and levels of inflammatory cytokines were measured. The skin atrophy induced by the compounds was tested during prolonged application on the dorsal skin of hairless mice, followed by haematoxylin and eosin staining. RESULTS: Dasatinib and LCB 03-0110 suppressed the symptoms of ACD such as ear swelling, increase in epidermal thickness and synthesis of inflammatory cytokines (i.e. interleukin-1beta, tumour necrosis factor-alpha and interferon-gamma) in a dose-dependent manner. The two compounds showed near-equal potency to tacrolimus; however, their potency was lower than that of triamcinolone acetonide. Prolonged treatment with the two compounds did not induce any skin atrophy, whereas use of steroidal agents induced severe atrophy. CONCLUSIONS: Dasatinib and LCB 03-0110 could be used as effective agents for the treatment of ACD without the adverse side-effect of skin atrophy. PMID- 23020071 TI - Global multi-method analysis of affinities and cooperativity in complex systems of macromolecular interactions. AB - Cooperativity, multisite, and multicomponent interactions are hallmarks of biological systems of interacting macromolecules. Their thermodynamic characterization is often very challenging due to the notoriously low information content of binding isotherms. We introduce a strategy for the global multimethod analysis of data from multiple techniques (GMMA) that exploits enhanced information content emerging from the mutual constraints of the simultaneous modeling of orthogonal observables from calorimetric, spectroscopic, hydrodynamic, biosensing, or other thermodynamic binding experiments. We describe new approaches to address statistical problems that arise in the analysis of dissimilar data sets. The GMMA approach can significantly increase the complexity of interacting systems that can be accurately thermodynamically characterized. PMID- 23020073 TI - Insufflation of hydrogen gas restrains the inflammatory response of cardiopulmonary bypass in a rat model. AB - Systemic inflammatory responses in patients receiving cardiac surgery with the use of the cardiopulmonary bypass (CPB) significantly contribute to CPB associated morbidity and mortality. We hypothesized that insufflated hydrogen gas (H2) would provide systemic anti-inflammatory and anti-apoptotic effects during CPB, therefore reducing proinflammatory cytokine levels. In this study, we examined the protective effect of H2 on a rat CPB model. Rats were divided into three groups: the sham operation (SHAM) group, received sternotomy only; the CPB group, which was initiated and maintained for 60 min; and the CPB + H2 group in which H2 was given via an oxygenator during CPB for 60 min. We collected blood samples before, 20 min, and 60 min after the initiation of CPB. We measured the serum cytokine levels of (tumor necrosis factor-alpha, interleukin-6, and interleukin-10) and biochemical markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). We also measured the wet-to-dry weight (W/D) ratio of the left lung 60 min after the initiation of CPB. In the CPB group, the cytokine and biochemical marker levels significantly increased 20 min after the CPB initiation and further increased 60 min after the CPB initiation as compared with the SHAM group. In the CPB + H2 group, however, such increases were significantly suppressed at 60 min after the CPB initiation. Although the W/D ratio in the CPB group significantly increased as compared with that in the SHAM group, such an increase was also suppressed significantly in the CPB + H2 group. We suggest that H2 insufflation is a possible new potential therapy for counteracting CPB-induced systemic inflammation. PMID- 23020075 TI - Crystal structure and superconducting properties of hexagonal lithium-niobium oxynitride. AB - A hexagonal oxynitride (Li(0.88)?(0.12))Nb(3.0)(O(0.13)N(0.87))(4) was synthesized through ammonia nitridation of LiNb(3)O(8). The structural analysis revealed that this oxynitride consists of alternate stacking of octahedral and prismatic layers with different Li/Nb ratios: significant amounts of Li and Nb atoms (Li/Nb = 43/57) coexist in the octahedral layer, while the prismatic site is preferentially occupied by Nb (Li/Nb = 3/97). A metallic behavior was accompanied by an abrupt drop of electrical resistivity at about 3 K. Furthermore, large diamagnetism and specific-heat anomaly were observed below this temperature, suggesting the appearance of superconductivity in the Li-Nb oxynitride. PMID- 23020074 TI - Variation in dengue virus plaque reduction neutralization testing: systematic review and pooled analysis. AB - BACKGROUND: The plaque reduction neutralization test (PRNT) remains the gold standard for the detection of serologic immune responses to dengue virus (DENV). While the basic concept of the PRNT remains constant, this test has evolved in multiple laboratories, introducing variation in materials and methods. Despite the importance of laboratory-to-laboratory comparability in DENV vaccine development, the effects of differing PRNT techniques on assay results, particularly the use of different dengue strains within a serotype, have not been fully characterized. METHODS: We conducted a systematic review and pooled analysis of published literature reporting individual-level PRNT titers to identify factors associated with heterogeneity in PRNT results and compared variation between strains within DENV serotypes and between articles using hierarchical models. RESULTS: The literature search and selection criteria identified 8 vaccine trials and 25 natural exposure studies reporting 4,411 titers from 605 individuals using 4 different neutralization percentages, 3 cell lines, 12 virus concentrations and 51 strains. Of 1,057 titers from primary DENV exposure, titers to the exposure serotype were consistently higher than titers to non-exposure serotypes. In contrast, titers from secondary DENV exposures (n = 628) demonstrated high titers to exposure and non-exposure serotypes. Additionally, PRNT titers from different strains within a serotype varied substantially. A pooled analysis of 1,689 titers demonstrated strain choice accounted for 8.04% (90% credible interval [CrI]: 3.05%, 15.7%) of between-titer variation after adjusting for secondary exposure, time since DENV exposure, vaccination and neutralization percentage. Differences between articles (a proxy for inter-laboratory differences) accounted for 50.7% (90% CrI: 30.8%, 71.6%) of between-titer variance. CONCLUSIONS: As promising vaccine candidates arise, the lack of standardized assays among diagnostic and research laboratories make unbiased inferences about vaccine-induced protection difficult. Clearly defined, widely accessible reference reagents, proficiency testing or algorithms to adjust for protocol differences would be a useful first step in improving dengue PRNT comparability and quality assurance. PMID- 23020076 TI - Nanoparticulate nonviral agent for the effective delivery of pDNA and siRNA to differentiated cells and primary human T lymphocytes. AB - Delivery of polynucleotides such as plasmid DNA (pDNA) and siRNA to nondividing and primary cells by nonviral vectors presents a considerable challenge. In this contribution, we introduce a novel type of PDMAEMA-based star-shaped nanoparticles that (i) are efficient transfection agents in clinically relevant and difficult-to-transfect human cells (Jurkat T cells, primary T lymphocytes) and (ii) can efficiently deliver siRNA to human primary T lymphocytes resulting to more than 40% silencing of the targeted gene. Transfection efficiencies achieved by the new vectors in serum-free medium are generally high and only slightly reduced in the presence of serum, while cytotoxicity and cell membrane disruptive potential at physiological pH are low. Therefore, these novel agents are expected to be promising carriers for nonviral gene transfer. Moreover, we propose a general design principle for the construction of polycationic nanoparticles capable of delivering nucleic acids to the above-mentioned cells. PMID- 23020077 TI - Application of faecal metabonomics on an experimental model of tubulointerstitial fibrosis by ultra performance liquid chromatography/high-sensitivity mass spectrometry with MS(E) data collection technique. AB - Chronic renal failure (CRF) is a major challenge for the public healthcare problem. A novel UPLC Q-TOF/MS method with MS(E) data collection mode was developed as a very effective biochemical analytical tool for precise identification of important biomarkers in the adenine-induced CRF rats. Nine endogenous metabolites were identified by using metabonomic method combined with multivariate data analysis, the accurate mass, isotopic pattern, MS(E) fragments information and MassLynx i-FIT algorithm. The identified metabolites indicated the perturbations of bile acid and phospholipid metabolism are related to CRF rats. This work shows that metabonomics method is a valuable tool in CRF mechanism study. PMID- 23020078 TI - Evidence for complex selection on four-fold degenerate sites in Drosophila melanogaster. AB - We considered genome-wide four-fold degenerate sites from an African Drosophila melanogaster population and compared them to short introns. To include divergence and to polarize the data, we used its close relatives Drosophila simulans, Drosophila sechellia, Drosophila erecta and Drosophila yakuba as outgroups. In D. melanogaster, the GC content at four-fold degenerate sites is higher than in short introns; compared to its relatives, more AT than GC is fixed. The former has been explained by codon usage bias (CUB) favouring GC; the latter by decreased intensity of directional selection or by increased mutation bias towards AT. With a biallelic equilibrium model, evidence for directional selection comes mostly from the GC-rich ancestral base composition. Together with a slight mutation bias, it leads to an asymmetry of the unpolarized allele frequency spectrum, from which directional selection is inferred. Using a quasi equilibrium model and polarized spectra, however, only purifying and no directional selection is detected. Furthermore, polarized spectra are proportional to those of the presumably unselected short introns. As we have no evidence for a decrease in effective population size, relaxed CUB must be due to a reduction in the selection coefficient. Going beyond the biallelic model and considering all four bases, signs of directional selection are stronger. In contrast to short introns, complementary bases show strand specificity and allele frequency spectra depend on mutation directions. Hence, the traditional biallelic model to describe the evolution of four-fold degenerate sites should be replaced by more complex models assuming only quasi-equilibrium and accounting for all four bases. PMID- 23020079 TI - Effects of different dietary protein levels and DL-methionine supplementation on hair growth and pelt quality in mink (Neovision vision). AB - The effect of different dietary protein levels and DL-methionine (Met) supplementation on hair growth and the resulting pelt quality in mink was studied. Four groups of male mink were fed with four isocaloric diets containing 32% (P32), 24% (P24), 16% (P16) or P24+Met (0.8%) crude protein of dry matter (DM) from September to December. Skin biopsies were taken at the pelting. Histological techniques and computer-assisted light microscopy were used to determine the ratio of activity (ROA) of under hairs and guard hairs respectively. The results showed that when the dietary protein level reduced from 32% to 16%, body length, number and diameter of under hairs and guard hairs of minks declined, and pelt length and pelt weight of minks decreased significantly (p < 0.05). These parameters were similar between P32 and P24 with Met supplementation (p > 0.05). The hair follicle density of the winter coat was not influenced by the dietary protein levels and Met supplementation (p > 0.05). Low protein diets content led to a reduction of hair follicle developing to next phase. It was documented that 24% crude protein of DM with Met supplementation during growing-furring period was sufficient for minks to express their genetic capacity to develop hair follicles and achieve the prime fur characteristics. Overall this study demonstrated that hair growth and hair properties in pelts are very dependent on the dietary protein and Met supply in the growing-furring period of minks. PMID- 23020080 TI - Uptake of titanium from TiO2 nanoparticle exposure in the isolated perfused intestine of rainbow trout: nystatin, vanadate and novel CO2-sensitive components. AB - Nanoparticle (NP) uptake across the gut is poorly understood. In vitro gut sac preparations and isolated perfused intestines were used to investigate the absorption mechanism(s). Exposure of whole gut sacs to 1 mg/l TiO2 NPs for 4 h caused total Ti metal concentrations to increase in the intestine, with 80% or more of the Ti in the mucosa. Perfused intestines showed a saturable time dependent accumulation of total Ti, which increased when the CO2 in the gas mixture was lowered to 0.5%. Adding cyanide did not stop Ti uptake, and 100 umol/l vanadate (ATPase inhibitor) caused a 2.8-fold reduction in the net uptake rate of Ti for TiO2 NP exposure. Luminal additions of nystatin (endocytosis inhibitor), blocked the uptake of Ti from both bulk and TiO2 NP treatments. The data demonstrate Ti uptake across the intestine from TiO2 NP exposures, involving CO2-dependent and nystatin-sensitive mechanisms. PMID- 23020081 TI - Ipilimumab induces simultaneous regression of melanocytic naevi and melanoma metastases. AB - Ipilimumab blocks cytotoxic T-lymphocyte-associated antigen (CTLA)-4, potentiating the antimelanoma T-cell host response. Ipilimumab has been shown to improve overall survival in patients with previously treated metastatic melanoma. CTLA-4 antibodies generate immune responses to the melanoma-associated antigens Melan-A, NY-ESO-1 and glycoprotein (gp)100 in metastatic melanoma. Digital epiluminescence microscopy (DELM) is a noninvasive method permitting the monitoring of the morphology of melanocytic lesions over time. A 50-year-old man with metastatic melanoma received four ipilimumab injections after failure of dacarbazine chemotherapy. Positron emission tomography revealed regression of pulmonary metastases, and simultaneously, DELM showed regression of several melanocytic naevi. On histological examination of the regressing naevi, prominent CD8+, CD4+ and CD45R0 lichenoid lymphohistiocytic infiltrates were seen, whereas nonregressing naevi were almost free of inflammatory infiltrate. Expression of melanoma-associated antigens in benign melanocytic naevi may explain the induction of naevus regression by ipilimumab. DELM could represent a valuable noninvasive method to monitor ipilimumab efficacy. PMID- 23020082 TI - Melatonin ameliorates low-grade inflammation and oxidative stress in young Zucker diabetic fatty rats. AB - The aim of this study was to investigate the effects of melatonin on low-grade inflammation and oxidative stress in young male Zucker diabetic fatty (ZDF) rats, an experimental model of metabolic syndrome and type 2 diabetes mellitus (T2DM). ZDF rats (n = 30) and lean littermates (ZL) (n = 30) were used. At 6 wk of age, both lean and fatty animals were subdivided into three groups, each composed of 10 rats: naive (N), vehicle treated (V), and melatonin treated (M) (10 mg/kg/day) for 6 wk. Vehicle and melatonin were added to the drinking water. Pro inflammatory state was evaluated by plasma levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP). Also, oxidative stress was assessed by plasma lipid peroxidation (LPO), both basal and after Fe(2+)/H2O2 inducement. ZDF rats exhibited higher levels of IL-6 (112.4 +/- 1.5 pg/mL), TNF-alpha (11.0 +/- 0.1 pg/mL) and CRP (828 +/- 16.0 ug/mL) compared with lean rats (IL-6, 89.9 +/- 1.0, P < 0.01; TNF-alpha, 9.7 +/- 0.4, P < 0.01; CRP, 508 +/- 21.5, P < 0.001). Melatonin lowered IL-6 (10%, P < 0.05), TNF-alpha (10%, P < 0.05), and CRP (21%, P < 0.01). Basal and Fe(2+)/H2O2-induced LPO, expressed as malondialdehyde equivalents (umol/L), were higher in ZDF rats (basal, 3.2 +/- 0.1 versus 2.5 +/- 0.1 in ZL, P < 0.01; Fe(2+)/H2O2-induced, 8.7 +/- 0.2 versus 5.5 +/- 0.3 in ZL; P < 0.001). Melatonin improved basal LPO (15%, P < 0.05) in ZDF rats, and Fe(2+)/H2O2- induced LPO in both ZL (15.2%, P < 0.01) and ZDF rats (39%, P < 0.001). These results demonstrated that oral melatonin administration ameliorates the pro-inflammatory state and oxidative stress, which underlie the development of insulin resistance and their consequences, metabolic syndrome, diabetes, and cardiovascular disease. PMID- 23020083 TI - Association of KCNE1 genetic polymorphisms with atrial fibrillation in a Chinese Han population. AB - OBJECTIVE: The purpose of this study was to investigate the association of the polymorphisms of the KCNE1 gene with atrial fibrillation (AF) in a Chinese Han population. METHODS: Three hundred seven AF patients and 330 age- and sex-matched controls were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method for two single-nucleotide polymorphisms (rs1805127 and rs1892593) of the human KCNE1 gene. RESULTS: The frequencies of the AA, AG, and GG genotypes of rs1805127 were 11.7%, 50.0%, and 43.3%, respectively, in the AF group, whereas the ones in the control group had frequencies of 19.4%, 44.9%, and 35.8%, respectively. There were significant differences in frequencies of these three genotypes (chi(2)=7.820, p=0.016) and G allele (65.8% vs. 58.2%; chi(2)=8.266, p=0.005). The frequencies of AA, AG, and GG of rs1892593 were 38.4%, 47.9%, and 13.7% in the AF group, whereas the ones in the control group had frequencies of 37.8%, 48.5%, and 14.0%, respectively. There was no difference in distributions of frequencies of these three genotypes and allele (chi(2)=0.051, p=0.978; chi(2)=1.024, p=0.837, respectively) between AF patients and control subjects. We also found that rs1805127 was associated with left atrial diameter and left ventricular end diastolic diameter in AF patients (chi(2)=24.883, p<0.001; chi(2)=34.901, p<0.001, respectively). Logistic regression analysis showed that rs1805127 was an independent risk factor of AF in a Chinese Han population (odds ratio [OR]=1.66, 95% confidence interval [CI]: 1.02-2.68 for AG; OR=2.03, 95% CI: 1.24-3.31 for GG). CONCLUSION: The genetic polymorphism of KCNE1 was associated with increased risk of AF in a Chinese Han population. PMID- 23020084 TI - Association between four resistin polymorphisms, obesity, and metabolic syndrome parameters in Tunisian volunteers. AB - Resistin is an adipocyte-secreted cytokine recently discovered and has been proposed as a link between obesity and diabetes. Many resistin gene polymorphisms were described and their implication in obesity and metabolic syndrome (MetS) was controversial. Our aim was to study the relationship between four resistin polymorphisms (420C/G, 44G/A, 62G/A, and 394C/G), MetS parameters, and the risk of obesity in Tunisian volunteers. We recruited 169 nonobese (sex ratio=0.594; mean age=43.25+/-13.12 years; mean body mass index [BMI]=24.73+/-3.50 kg/m(2)) and 160 obese subjects (sex ratio=0.221; mean age=48.41+/-10.92 years; mean BMI=36.6+/-4.8 kg/m(2)). Genotyping was performed using polymerase chain reaction restriction fragment length polymorphism. Anthropometric parameters, lipid levels, glycemia, and insulinemia were measured. BMI was calculated and insulin resistance was evaluated with the homeostasis model assessment insulin resistance (HOMA-IR). Statistical analyses were performed by SPSS 17.0. The 420C/G seems to contribute to obesity. In fact adjusted odds ratio (OR) of obesity associated to mutated genotypes was 2.17 and 95% confidence interval was 1.28-3.68 (p=0.004). Mutated genotypes at 420C/G were associated with higher waist circumference and BMI. In addition, 44G/A polymorphism was associated with increased total cholesterol and low-density lipoprotein-cholesterol levels. The other genotypes showed no association with MetS parameters. Concerning association between single nucleotide polymorphisms and MetS risk, only mutated genotypes at 44G/A increase the risk of MetS after adjustment to confounding parameters (OR=1.93, p=0.023). In conclusion, resistin gene polymorphisms 420C/G and 44G/A were associated with obesity and MetS parameters in Tunisian volunteers. PMID- 23020085 TI - Suppression of endogenous hydrogen sulfide contributes to the radiation-induced bystander effects on hypoxic HepG2 cells. AB - Radiation-induced bystander effects may have important implications in radiotherapy, but it is still not well known if radiation-induced bystander effects can be triggered in hypoxic tumor cells and what are the related bystander signals. Using human hepatoma cells of HepG2, the present study found that micronuclei (MN) could be induced in the nonirradiated cells after treatment with conditioned medium (CM) harvested from irradiated cells under hypoxic conditions. Bystander effects were diminished when the irradiated cells were pretreated with sodium hydrosulfide (NaHS, an exogenous H(2)S donor) (<=100 MUM). However, the bystander effects were increased when the irradiated cells were pretreated with an inhibitor of cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), the synthases of endogenous hydrogen sulfide (H(2)S). Western blotting showed that the expressions of CSE and CBS were increased in the irradiated hypoxic cells, but were reduced in the CM treated bystander cells. The ratio of Bcl-2/Bax, a molecular marker of apoptosis, decreased with CM treatment time. However, the activity of caspase-3 increased in the hypoxic bystander cells, and this could be regulated by both NaHS and the inhibitor of endogenous H(2)S. These results demonstrate that under hypoxic conditions irradiated hepatoma cells induce bystander responses by depressing the generation of endogenous H(2)S and altering Bcl-2/Bax ratios as well as caspase-3 dependent damage in the bystander cells. PMID- 23020086 TI - Early-onset absence epilepsy: SLC2A1 gene analysis and treatment evolution. AB - BACKGROUND AND PURPOSES: To determine the prevalence of SLC2A1 mutations in children with early-onset absence epilepsy (EOAE) and to investigate whether there were differences in demographic and electroclinical data between patients who became seizure-free with anti-epileptic drug (AED) monotherapy (group I) and those who needed add-on treatment of a second AED (group II). METHODS: We reviewed children with EOAE attending different Italian epilepsy centers. All participants had onset of absence seizures within the first 3 years of life but otherwise conformed to a strict definition of childhood absence epilepsy. Mutation analysis of SLC2A1 was performed in each patient. RESULTS: Eighty-four children (57 in group I, 27 in group II) fulfilled the inclusion criteria. No mutation in SLC2A1 was found. There were no statistical differences between the two groups with regard to F/M ratio, age at onset of EOAE, early history of febrile seizures, first-degree family history for genetic generalized epilepsy, duration of AED therapy at 3 years after enrollment, use of AEDs at 3 years, failed withdrawals at 3 years, terminal remission of EOAE at 3 years, and 6-month follow-up EEG data. Mean duration of seizures/active epilepsy was significantly shorter in group I than in group II (P = 0.008). CONCLUSIONS: We demonstrate that in a large series of children with rigorous diagnosis of EOAE, no mutations in SLC2A1 gene are detected. Except for duration of seizures/active epilepsy, no significant differences in demographic and electroclinical aspects are observed between children with EOAE who responded well to AED monotherapy and those who became seizure-free with add-on treatment of a second AED. PMID- 23020087 TI - Nicotine hair concentrations in dogs exposed to environmental tobacco smoke: a pilot study. AB - OBJECTIVES: To investigate the association between dog hair nicotine concentration and owner-reported exposure to environmental tobacco smoke to establish whether dogs are exposed to significant, detectable amounts of environmental tobacco smoke in the home. METHODS: Hair was collected from 23 dogs exposed to environmental tobacco smoke and from 15 dogs reportedly not exposed to environmental tobacco smoke. Hair was washed to remove adhered nicotine, digested in 1 M NaOH and extracted using solid phase extraction. Nicotine concentration was measured by high-resolution mass spectrometry. Results were analysed using a Kruskall-Wallis test and post hoc pair-wise comparisons using a Mann-Whitney test to assess significance between exposure groups. RESULTS: The different exposure groups were significantly different (P < 0.001) for both hair and surface nicotine. Pair-wise comparisons were significant at P < 0.05 for all categories except unexposed and occasionally exposed groups (P = 0.076). CLINICAL SIGNIFICANCE: Dog hair nicotine concentration appears to be strongly associated with reported exposure to environmental tobacco smoke. The range and median of hair nicotine concentration in dogs exposed to environmental tobacco smoke was similar to those reported in children. This suggests that dog hair could provide a useful method of determining the amount of environmental tobacco smoke exposure in all environments common to pets and children. PMID- 23020088 TI - A chloroplast-derived Toxoplasma gondii GRA4 antigen used as an oral vaccine protects against toxoplasmosis in mice. AB - The parasitic protozoan Toxoplasma gondii, the causal agent of toxoplasmosis, can infect most mammals and birds. In human medicine, T. gondii can cause complications in pregnant women and immunodeficient individuals, while in veterinary medicine, T. gondii infection has economic importance due to abortion and neonatal loss in livestock. Thus, the development of an effective anti Toxoplasma vaccine would be of great value. In this study, we analysed the expression of T. gondii GRA4 antigen by chloroplast transformation (chlGRA4) in tobacco plants and evaluated the humoral and cellular responses and the grade of protection after oral administration of chlGRA4 in a murine model. The Western blot analysis revealed a specific 34-kDa band mainly present in the insoluble fractions. The chlGRA4 accumulation levels were approximately 6 MUg/g of fresh weight (equivalent to 0.2% of total protein). Oral immunization with chlGRA4 resulted in a decrease of 59% in the brain cyst load of mice compared to control mice. ChlGRA4 immunization elicited both a mucosal immune response characterized by the production of specific IgA, and IFN-gamma, IL-4 and IL-10 secretion by mesenteric lymph node cells, and a systemic response in terms of GRA4-specific serum antibodies and secretion of IFN-gamma, IL-4 and IL-10 by splenocytes. Our results indicate that oral administration of chlGRA4 promotes the elicitation of both mucosal and systemic balanced Th1/Th2 responses that control Toxoplasma infection, reducing parasite loads. PMID- 23020090 TI - Transmission, host specificity, and seasonal occurrence of Cyrtosomum penneri (Nematoda: Atractidae) in lizards from Florida. AB - Experimental infections and field-collected lizards were used to investigate issues of transmission, host specificity, and seasonal occurrence in the nematode Cyrtosomum penneri (Cosmocercoidea: Atractidae). Anolis sagrei (87 males, 42 females) were captured from the Florida Southern College campus, Polk County, Florida, from October 2010 to September 2011, and 8,803 C. penneri were collected from their intestines. During the breeding season all sexually mature (SVL >= 34 mm) A. sagrei were infected, whereas juvenile lizards (SVL <34 mm) were never infected. Experimental infections, using A. sagrei , found that worms were transferred to new hosts venereally, but not during oral exposures. Mating trials confirmed that worms were consistently transferred between hosts during copulation under natural conditions. Experimental exposures found that land snails and crickets do not serve as transport or intermediate hosts, which supports the idea that C. penneri is transferred only during host copulation. Experimental infections to test host specificity in C. penneri successfully infected A. sagrei , Hemidactylus turcicus , and Sceloporus undulatus , but not Anolis carolinensis or Plestiodon inexpectatus. Overall, this is the first study to fully elucidate the life cycle of any atractid nematode, and we suggest a venereal route of transmission for all atractid worms that infect reptilian hosts. Our findings also have implications for the host's reproductive and behavioral biology, e.g., support for covert or satellite males in the A. sagrei mating system. PMID- 23020089 TI - Hearing dysfunction in heterozygous Mitf(Mi-wh) /+ mice, a model for Waardenburg syndrome type 2 and Tietz syndrome. AB - The human deafness-pigmentation syndromes, Waardenburg syndrome (WS) type 2a, and Tietz syndrome are characterized by profound deafness but only partial cutaneous pigmentary abnormalities. Both syndromes are caused by mutations in MITF. To illuminate differences between cutaneous and otic melanocytes in these syndromes, their development and survival in heterozygous Microphthalmia-White (Mitf(Mi-wh) /+) mice were studied and hearing function of these mice characterized. Mitf(Mi wh) /+ mice have a profound hearing deficit, characterized by elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emissions, absent endocochlear potential, loss of outer hair cells, and stria vascularis abnormalities. Mitf(Mi-wh) /+ embryos have fewer melanoblasts during embryonic development than their wild-type littermates. Although cochlear melanocytes are present at birth, they disappear from the Mitf(Mi-wh) /+ cochlea between P1 and P7. These findings may provide insight into the mechanism of melanocyte and hearing loss in human deafness-pigmentation syndromes such as WS and Tietz syndrome and illustrate differences between otic and follicular melanocytes. PMID- 23020091 TI - Enhancement by sodium caprate and sodium deoxycholate of the gastrointestinal absorption of berberine chloride in rats. AB - The aim of the investigation was to compare the effectiveness of two absorption enhancers, sodium caprate (C10) and sodium deoxycholate (SDC), in increasing the bioavailability of a poorly absorbed paracellar flux drug, berberine chloride, across the intestinal mucosae of rats in vivo, together with examination of their effects on mucosal damage. In addition, all four intestinal segments were collected after administration of the enhancers and sodium saline. The results of the bioavailability experiments showed the oral absorption of berberine chloride was poor and both C10 and SDC could significantly improve the very poor absorption of berberine chloride. After co-administration, the area under the plasma concentration-time curve of berberine chloride was increased 41.1-fold by C10 (100 mg/kg) and 35.3-fold by SDC (100 mg/kg) compared with that in the absence of C10 and SDC, respectively. Local toxicity experiment indicated that both enhancers caused no specific damage to the intact intestine. This study demonstrates that C10 and SDC could significantly promote the absorption of berberine chloride from the gastrointestinal tract with few toxic effects, which might be due mainly to relaxing the absorption limitation while inhibiting the efflux transporter of berberine chloride by the enhancers. Besides, this could lead to the development of new drug-enhancers. PMID- 23020092 TI - Pediatric reference intervals for muscle coenzyme Q(10). AB - Coenzyme Q(10) (CoQ(10)) is present in humans in both the reduced (ubiquinol, CoQ(10)H(2)) and oxidized (ubiquinone, CoQ(10)) forms. CoQ(10) is an essential cofactor in mitochondrial oxidative phosphorylation, and is necessary for ATP production. Total, reduced and oxidized CoQ(10) levels in skeletal muscle of 148 children were determined by HPLC coupled with electrochemical detection, and we established three level thresholds for total CoQ(10) in muscle. We defined as "severe deficiency", CoQ(10) levels falling in the range between 0.82 and 4.88 MUmol/g tissue; as "intermediate deficiency", those ranging between 5.40 and 9.80 MUmol/g tissue, and as "mild deficiency", the amount of CoQ(10) included between 10.21 and 19.10 MUmol/g tissue. Early identification of CoQ(10) deficiency has important implications in children, not only for those with primary CoQ(10) defect, but also for patients with neurodegenerative disorders, in order to encourage earlier supplementation with this agent also in mild and intermediate deficiency. PMID- 23020093 TI - Cell cooperation and role of the P2X7 receptor in pulmonary inflammation induced by nanoparticles. AB - Macrophages and alveolar epithelial cells are the first targets of inhaled nanoparticles (NPs) reaching the alveoli. Mono- or co-cultures of lung epithelial (A549 or NCI-H441) and macrophage (THP-1) cell lines were used to study the cell cooperation and the involvement of the P2X7 cell death receptor during the inflammation caused by SiO2 and TiO2 NPs. Here we show that, secretion of pro inflammatory cytokines (IL-1beta, IL-6 and IL-8) in response to NPs exposure was higher in co-cultures than in mono-cultures. A functional P2X7 receptor was found in all the cell lines studied. Its involvement in IL-1beta secretion in co cultures was demonstrated using a specific antagonist, the brilliant blue G. Furthermore, mono and co-cultures exhibited distinct secretion patterns of pro inflammatory cytokines in response to NPs exposure, and we provide the first evidence that the P2X7 receptor is involved in the inflammation triggered by SiO2 and TiO2 NPs, by increasing IL-1beta secretion, and likely through the inflammasome pathway. Altogether, our data indicate that cell co-cultures used in this study represent valid models to study the inflammatory mechanisms of NPs within the alveoli. PMID- 23020095 TI - Interview with Laura Fortunato, winner of the 2011 Gabriel W. Lasker Prize. Interview by Evelyne Heyer. PMID- 23020094 TI - Short-term treatment with a SOD/catalase mimetic, EUK-207, mitigates pneumonitis and fibrosis after single-dose total-body or whole-thoracic irradiation. AB - In the event of a radiological accident or terrorist attack, whole- or partial body exposure can injure the lungs. To simulate such an incident, we used a single fraction of total-body irradiation (TBI) or whole-thoracic irradiation to induce pneumonitis or pulmonary fibrosis, respectively, in a rat model. The superoxide dismutase and catalase mimetic EUK-207 was given by subcutaneous injection (20 mg/kg/day, 5 days per week, once daily) starting at 7 days after irradiation and stopping before pneumonitis developed. After TBI, morbidity and the increase in breathing rates associated with pneumonitis were significantly improved in rats treated with EUK-207 compared to rats receiving irradiation alone. At 42 days after TBI (the peak of pneumonitis) changes in vascular end points including pulmonary hemodynamics ex vivo and relative arterial density in lungs were also mitigated by EUK-207. At 7 months after whole-thoracic irradiation, EUK-207 reduced synthesis of collagen as assessed by the Sircol collagen assay and Masson's trichrome staining. Our results demonstrate promise for EUK-207 as a mitigator of radiation pneumonitis and fibrosis. We also demonstrate for the first time mitigation of multiple vascular injuries in the irradiated lung in vivo by EUK-207. PMID- 23020096 TI - General method to unravel ancient population structures through surnames, final validation on Italian data. AB - We analyze the geographic location of 77,451 different Italian surnames (17,579,891 individuals) obtained from the lists of telephone subscribers of the year 1993. By using a specific neural network analysis (Self-Organizing Maps, SOMs), we automatically identify the geographic origin of 49,117 different surnames. To validate the methodology, we compare the results to a study, previously conducted, on the same database, with accurate supervised methods. By comparing the results, we find an overlap of 97%, meaning that the SOMs methodology is highly reliable and well traces back the geographic origin of surnames at the time of their introduction (Late Middle Ages/Renaissance in Italy). SOMs results enables one to distinguish monophyletic surnames from polyphyletic ones, that is surnames having had a single geographic and historic origin from those that started to be in use, with an identical spelling, in different locations (respectively, 76.06% and 21.05% of the total). As we are interested in geographic origins, polyphyletic surnames are excluded from further analyses. By comparing the present location of each monophyletic surname to its inferred geographic origin in late Middle Ages/Renaissance, we measure the extent of the migrations having occurred in Italy since that time. We find that the percentage of individuals presently living in the very area where their surname started to be in use centuries ago is extremely variable (ranging from 22.77% to 77.86% according to the province), thus meaning that self-assessed regional identities seldom correspond to the "autochthony" they imply. For example the upper part of the Thyrennian coast (Northern Latium, Tuscany) has a strong identity but few "autochthonous" inhabitants (~28%) having been a passageway from the North to the South of Italy. PMID- 23020097 TI - A new mitochondrial C1 lineage from the prehistory of Uruguay: population genocide, ethnocide, and continuity. AB - Uruguayan population has been considered as of European descent, as its Native populations victims of genocide apparently disappeared in the 19th century. Contradicting this national belief, genetic studies have shown a substantial Native contribution. However, the continuity between prehistoric, historic, and present populations remains unproved. With the aim of adding elements to prove a possible population continuity, we studied a mitochondrial lineage, part of haplogroup C1, analyzing the complete genome of a modern Uruguayan individual and the hypervariable region I (HVRI) in prehistoric, historic, and contemporary individuals. Several individuals carried the mutations that characterize this lineage: two from an archaeological mound located in the east of the country, the Charrua Indian chief Vaimaca Peru and five individuals from the present population. The lineage was initially characterized by its HVRI sequence, having the four typical C1 mutations and adding 16051G and 16288C; other mutations were also found: 16140C was found in all but the oldest individual, dated 1,610 years BP, while 16209C, 16422C, and 16519C were found only in some individuals. Hypervariable region II showed the typical C1 mutations and 194T. The coding region, analyzed in modern individuals, was characterized by 12378T, while other mutations found were not common to all of them. In summary, we have found and described a new lineage that shows continuity from prehistoric mound builders to the present population, through a representative of the extinct Charrua Indians. The lineage appeared at least 1,600 years ago and is carried by approximately 0.7% of the modern Uruguayan population. The continuity of the lineage supports alternative perspectives about Uruguayan national identity and the meaning of the genocide, best labeled as ethnocide because of its consequences. It also contributes to the discussion about who the prehistoric mound builders were, and to the origin, at least in the maternal line, of a Charrua Indian. From a more general perspective, we can conclude that the characteristics, evolution, and expansion of founder haplogroup C in America have not yet been elucidated. PMID- 23020098 TI - A note on the dependence of heritability on variances of genetic and environmental components. PMID- 23020101 TI - A program for sustained improvement in preventing ventilator associated pneumonia in an intensive care setting. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a common infection in the intensive care unit (ICU) and associated with a high mortality. METHODS: A quasi experimental study was conducted in a medical-surgical ICU. Multiple interventions to optimize VAP prevention were performed from October 2008 to December 2010. All of these processes, including the Institute for Healthcare Improvement's (IHI) ventilator bundle plus oral decontamination with chlorhexidine and continuous aspiration of subglottic secretions (CASS), were adopted for patients undergoing mechanical ventilation. RESULTS: We evaluated a total of 21,984 patient-days, and a total of 6,052 ventilator-days (ventilator utilization rate of 0.27). We found VAP rates of 1.3 and 2.0 per 1,000 ventilator days respectively in 2009 and 2010, achieving zero incidence of VAP several times during 12 months, whenever VAP bundle compliance was over 90%. CONCLUSION: These results suggest that it is possible to reduce VAP rates to near zero and sustain these rates, but it requires a complex process involving multiple performance measures and interventions that must be permanently monitored. PMID- 23020102 TI - Effectiveness of an educational intervention to improve child feeding practices and growth in rural China: updated results at 18 months of age. AB - Inappropriate complementary feeding practices have led to, in part, significant disparities in growth and nutritional status between rural and urban children in China. A cluster-randomised, controlled trial was implemented in Laishui, China to assess the effectiveness of an educational intervention on caregivers' feeding practices and children's growth. Eight townships were randomly assigned to the intervention or control. Five hundred ninety-nine healthy infants were enrolled at 2-4 months old, and were followed up at ages 6, 9, 12, 15 and 18 months. The intervention group received information on enhanced home-prepared recipes and food preparation and hygiene through group training, counselling and home visit. Key outcomes were children's physical growth, caregivers' knowledge and behaviours on complementary feeding, and the infant and child feeding index (ICFI). Analysis was by intention to treat. The intervention group achieved better knowledge and practices related to complementary feeding, and significantly higher ICFI scores at each follow-up point. Children in the intervention group achieved higher z-scores for weight-for-age (WAZ) and weight for-height (WHZ) than the control (0.18 vs. 0.01 and 0.49 vs. 0.19, respectively) at 18 months old, and were less likely to have stunted growth (odds ratio = 0.71, 95% confidence interval: 0.53-0.94). Mixed model showed that the intervention group achieved significantly better linear growth over time, including WAZ (P = 0.016), WHZ (P = 0.030) and HAZ (P = 0.078). These results indicated that an educational intervention delivered through local health services can enhance caregivers' knowledge and practices of complementary feeding and ultimately improve children's growth. PMID- 23020104 TI - Large geographic range size reflects a patchwork of divergent lineages in the long-toed salamander (Ambystoma macrodactylum). AB - For northern taxa, persistence in multiple vs. single Pleistocene refugia may have been an important determinant of contemporary range size, with larger ranges achieved by species that colonized the north from several glacial refugia. Under this hypothesis, widespread species are expected to demonstrate marked phylogeographic structure in previously glaciated regions. We use a genome-wide survey to characterize genetic structure and evaluate this hypothesis in the most widely distributed salamander in the Pacific Northwest, the long-toed salamander (Ambystoma macrodactylum). Patterns of variation based on 751 amplified fragment length polymorphism (AFLP) loci and mitochondrial sequence data were concordant and support the recognition of at least four distinct lineages of long-toed salamander. The distributions of these lineages indicate that multiple refugia contributed to the species' large contemporary range. At the same time, with up to 133 AFLP bands differing between lineages and levels of sequence divergence ranging from 2.5 to 5.8%, these lineages would be considered separate species by some definitions. Such splitting would partition the large geographic range of the long-toed salamander into several relatively restricted ranges. Our results thus also underscore the potential for estimates of geographic range size to vary considerably depending on the taxonomic treatment of cryptic lineages. PMID- 23020103 TI - Conserved functional connectivity but impaired effective connectivity of thalamocortical circuitry in schizophrenia. AB - Schizophrenia is a severe mental illness with neurobiological bases that remain elusive. One hypothesis emphasizes disordered thalamic function. We previously used concurrent single pulse transcranial magnetic stimulation (spTMS) and functional magnetic resonance imaging (fMRI) to show that individuals with schizophrenia have a decreased spTMS-evoked response in the thalamus, and decreased effective connectivity between thalamus and insula and thalamus and superior frontal gyrus. To better understand the factors that may accompany or account for these findings, we investigated, in the same participants, resting state functional connectivity, white matter structural connectivity, and grey matter integrity. Patients with schizophrenia did not differ from healthy control subjects in resting state functional- or white matter structural connectivity, although they did show decreased measures of grey matter integrity in the insula. However, in this region, the spTMS-evoked response did not differ between groups. In a region of the thalamus that also had grey matter intensity abnormalities, although not at a level that survived correction for multiple comparisons, the spTMS-evoked response in patients was deficient. These results suggest that measures of structure and function are not necessarily complementary. Further, given its sensitivity for identifying deficits not evident with traditional imaging methods, these results highlight the utility of spTMS-fMRI, a method that directly and causally probes effective connectivity, as a tool for studying brain based disorders. PMID- 23020105 TI - Mental health nurses working in primary care: Perceptions of general practitioners. AB - The Mental Health Nurse Incentive Program (MHNIP) was established across Australia during 2007. Under the guidelines for the program, mental health nurses work in partnership with general practitioners (GPs) to assist in the assessment and treatment of those with more severe mental health problems. This paper provides insights, from the perspective of GPs, on the qualities required of mental health nurses seeking employment in the primary care setting. A descriptive, exploratory approach was employed to isolate relevant themes. Discussion groups were conducted with 25 GPs involved with the Mental Health Nurse Incentive Program. These discussion groups were audio-taped, transcribed, and analyzed using content analysis. Five overarching thematic clusters emerged from the data: (i) 'fitting in'; (ii) knowledge; (iii) skills; (iv) supporting GPs; and (v) educating GPs. While GPs recognize the valuable contribution that mental health nurses can make in the treatment of those with mental health problems, this appears to be dependent on the knowledge and skills of the nurses involved and their ability to engage with GPs. Ongoing education and other practical interventions are required to ensure that GPs are better informed about the initiative. PMID- 23020106 TI - Point-process principal components analysis via geometric optimization. AB - There has been a fast-growing demand for analysis tools for multivariate point process data driven by work in neural coding and, more recently, high-frequency finance. Here we develop a true or exact (as opposed to one based on time binning) principal components analysis for preliminary processing of multivariate point processes. We provide a maximum likelihood estimator, an algorithm for maximization involving steepest ascent on two Stiefel manifolds, and novel constrained asymptotic analysis. The method is illustrated with a simulation and compared with a binning approach. PMID- 23020107 TI - Stochastic Hodgkin-Huxley equations with colored noise terms in the conductances. AB - The excitability of cells is facilitated by voltage-gated ion channels. These channels accommodate a multiple number of gates individually. The possible impact of that gate multiplicity on the cell's function, specifically when the membrane area is of limited size, was investigated in the author's prior work (Guler, 2011 ). There, it was found that a nontrivially persistent correlation takes place between the transmembrane voltage fluctuations (also between the fluctuations in the gating variables) and the component of open channel fluctuations attributed to the gate multiplicity. This nontrivial phenomenon was found to be playing a major augmentative role for the elevation of excitability and spontaneous firing in small cells. In addition, the same phenomenon was found to be enhancing spike coherence significantly. Here we extend Fox and Lu's ( 1994 ) stochastic Hodgkin-Huxley equations by incorporating colored noise terms into the conductances there to obtain a formalism capable of capturing the addressed cross-correlations. Statistics of spike generation, spike coherence, firing efficiency, latency, and jitter from the articulated set of equations are found to be highly accurate in comparison with the corresponding statistics from the exact microscopic Markov simulations. This way, it is demonstrated vividly that our formulation overcomes the inherent inadequacy of the Fox and Lu equations. Finally, a recently proposed diffusion approximation method (Linaro, Storace, & Giugliano, 2011 ) is taken into consideration, and a discussion on its character is pursued. PMID- 23020108 TI - Dynamics of feature categorization. AB - In visual and auditory scenes, we are able to identify shared features among sensory objects and group them according to their similarity. This grouping is preattentive and fast and is thought of as an elementary form of categorization by which objects sharing similar features are clustered in some abstract perceptual space. It is unclear what neuronal mechanisms underlie this fast categorization. Here we propose a neuromechanistic model of fast feature categorization based on the framework of continuous attractor networks. The mechanism for category formation does not rely on learning and is based on biologically plausible assumptions, for example, the existence of populations of neurons tuned to feature values, feature-specific interactions, and subthreshold evoked responses upon the presentation of single objects. When the network is presented with a sequence of stimuli characterized by some feature, the network sums the evoked responses and provides a running estimate of the distribution of features in the input stream. If the distribution of features is structured into different components or peaks (i.e., is multimodal), recurrent excitation amplifies the response of activated neurons, and categories are singled out as emerging localized patterns of elevated neuronal activity (bumps), centered at the centroid of each cluster. The emergence of bump states through sequential, subthreshold activation and the dependence on input statistics is a novel application of attractor networks. We show that the extraction and representation of multiple categories are facilitated by the rich attractor structure of the network, which can sustain multiple stable activity patterns for a robust range of connectivity parameters compatible with cortical physiology. PMID- 23020109 TI - Multilayer perceptron classification of unknown volatile chemicals from the firing rates of insect olfactory sensory neurons and its application to biosensor design. AB - In this letter, we use the firing rates from an array of olfactory sensory neurons (OSNs) of the fruit fly, Drosophila melanogaster, to train an artificial neural network (ANN) to distinguish different chemical classes of volatile odorants. Bootstrapping is implemented for the optimized networks, providing an accurate estimate of a network's predicted values. Initially a simple linear predictor was used to assess the complexity of the data and was found to provide low prediction performance. A nonlinear ANN in the form of a single multilayer perceptron (MLP) was also used, providing a significant increase in prediction performance. The effect of the number of hidden layers and hidden neurons of the MLP was investigated and found to be effective in enhancing network performance with both a single and a double hidden layer investigated separately. A hybrid array of MLPs was investigated and compared against the single MLP architecture. The hybrid MLPs were found to classify all vectors of the validation set, presenting the highest degree of prediction accuracy. Adjustment of the number of hidden neurons was investigated, providing further performance gain. In addition, noise injection was investigated, proving successful for certain network designs. It was found that the best-performing MLP was that of the double-hidden-layer hybrid MLP network without the use of noise injection. Furthermore, the level of performance was examined when different numbers of OSNs used were varied from the maximum of 24 to only 5 OSNs. Finally, the ideal OSNs were identified that optimized network performance. The results obtained from this study provide strong evidence of the usefulness of ANNs in the field of olfaction for the future realization of a signal processing back end for an artificial olfactory biosensor. PMID- 23020110 TI - Computing sparse representations of multidimensional signals using Kronecker bases. AB - Recently there has been great interest in sparse representations of signals under the assumption that signals (data sets) can be well approximated by a linear combination of few elements of a known basis (dictionary). Many algorithms have been developed to find such representations for one-dimensional signals (vectors), which requires finding the sparsest solution of an underdetermined linear system of algebraic equations. In this letter, we generalize the theory of sparse representations of vectors to multiway arrays (tensors)--signals with a multidimensional structure--by using the Tucker model. Thus, the problem is reduced to solving a large-scale underdetermined linear system of equations possessing a Kronecker structure, for which we have developed a greedy algorithm, Kronecker-OMP, as a generalization of the classical orthogonal matching pursuit (OMP) algorithm for vectors. We also introduce the concept of multiway block sparse representation of N-way arrays and develop a new greedy algorithm that exploits not only the Kronecker structure but also block sparsity. This allows us to derive a very fast and memory-efficient algorithm called N-BOMP (N-way block OMP). We theoretically demonstrate that under the block-sparsity assumption, our N-BOMP algorithm not only has a considerably lower complexity but is also more precise than the classic OMP algorithm. Moreover, our algorithms can be used for very large-scale problems, which are intractable using standard approaches. We provide several simulations illustrating our results and comparing our algorithms to classical algorithms such as OMP and BP (basis pursuit) algorithms. We also apply the N-BOMP algorithm as a fast solution for the compressed sensing (CS) problem with large-scale data sets, in particular, for 2D compressive imaging (CI) and 3D hyperspectral CI, and we show examples with real-world multidimensional signals. PMID- 23020111 TI - A model of the differential representation of signal novelty in the local field potentials and spiking activity of the ventrolateral prefrontal cortex. AB - Local field potentials (LFPs) and spiking activity reflect different types of information procssing. For example, neurophysiological studies indicate that signal novelty in the ventrolateral prefrontal cortex is differentially represented by LFPs and spiking activity: LFPs habituate to repeated stimulus presentations, whereas spiking activity does not. The neural mechanisms that allow for this differential representation between LFPs and spiking activity are not clear. Here, we model and simulate LFPs and spiking activity of neurons in the ventrolateral prefrontal cortex in order to elucidate potential mechanisms underlying this differential representation. We demonstrate that dynamic negative feedback loops cause LFPs to habituate in response to repeated presentations of the same stimulus while spiking activity is maintained. This disassociation between LFPs and spiking activity may be a mechanism by which LFPs code stimulus novelty, whereas spiking activity carries abstract information, such as category membership and decision-related activity. PMID- 23020113 TI - Home advantage in judo: a study of the world ranking list. AB - In 2009, the International Judo Federation established a ranking system (RS) to classify athletes and to distribute the competitor quotas of the Olympic Games. However, the RS does not consider the home advantage. This issue has not been studied in judo, and its implications for the RS have not been determined. The objective was to verify the home advantage in judo in terms of winning a medal or the number of matches won. Therefore, 25 competitions that computed points for the RS in 2009 were analysed. Logistic regression analysis and the Poisson generalised linear model were used for the analyses, which included the relative quality of the athletes. The sample was composed only of athletes who had competed both at home and away. The odds ratio for winning medals was higher for athletes who competed at home for both males and females. The association between the number of matches won and competing at home was significant only for the male athletes. The home advantage was observed in the competitions that used the judo RS. Thus, it is likely that athletes from countries that host competitions using the RS have an advantage in terms of obtaining their Olympic classification. PMID- 23020112 TI - A spiking neural model for stable reinforcement of synapses based on multiple distal rewards. AB - In this letter, a novel critic-like algorithm was developed to extend the synaptic plasticity rule described in Florian (2007) and Izhikevich (2007) in order to solve the problem of learning multiple distal rewards simultaneously. The system is augmented with short-term plasticity (STP) to stabilize the learning dynamics, thereby increasing the system's learning capacity. A theoretical threshold is estimated for the number of distal rewards that this system can learn. The validity of the novel algorithm was verified by computer simulations. PMID- 23020114 TI - Hydrothermal derived LaOF:Ln3+ (Ln = Eu, Tb, Sm, Dy, Tm, and/or Ho) nanocrystals with multicolor-tunable emission properties. AB - A series of LaOF:Ln(3+) (Ln = Eu, Tb, Sm, Dy, Tm, and/or Ho) nanocrystals with good dispersion have been successfully prepared by the hydrothermal method followed a heat-treatment process. Under ultraviolet radiation and low-voltage electron beam excitation, the LaOF:Ln(3+) nanocrystals show the characteristic f f emissions of Ln(3+) (Ln = Eu, Tb, Sm, Dy, Tm, or Ho) and give red, blue-green, orange, yellow, blue, and green emission, respectively. Moreover, there exists simultaneous luminescence of Tb(3+), Eu(3+), Sm(3+), Dy(3+), Tm(3+), or Ho(3+) individually when codoping them in the single-phase LaOF host (for example, LaOF:Tb(3+), Eu(3+)/Sm(3+); LaOF:Tm(3+), Dy(3+)/Ho(3+); LaOF:Tm(3+), Ho(3+), Eu(3+) systems), which is beneficial to tune the emission colors. Under low voltage electron beam excitation, a variety of colors can be efficiently adjusted by varying the doping ions and the doping concentration, making these materials have potential applications in field-emission display devices. More importantly, the energy transfer from Tm(3+) to Ho(3+) in the LaOF:Tm(3+), Ho(3+) samples under UV excitation was first investigated and has been demonstrated to be a resonant type via a quadrupole-quadrupole mechanism. The critical distance (R(Tm Ho)) is calculated to be 28.4 A. In addition, the LaOF:Tb(3+) and LaOF:Tm(3+) phosphors exhibit green and blue luminescence with better chromaticity coordinates, color purity, and higher intensity compared with the commercial green phosphor ZnO:Zn and blue phosphor Y(2)SiO(5):Ce(3+) to some extent under low-voltage electron beam excitation. PMID- 23020115 TI - Density functional theory study on subtriazaporphyrin derivatives: dipolar/octupolar contribution to the second-order nonlinear optical activity. AB - Density functional theory calculations have been carried out on the subtriazaporphyrin skeletons, an excellent prototype for investigating the dipolar/octupolar contribution to the second-order nonlinear optical (second order NLO) activity, revealing the size effect and clarifying the nature of the limit when expanding the conjugated system is employed to improve the hyper Rayleigh scattering response coefficient (beta(HRS)). The octupolar and dipolar contributions are theoretically separated, rendering it possible to control the dipolar/octupolar second-order NLO contribution ratio by changing the number and orientation of the peripheral fused benzene moieties. In addition, both the dispersion and solvent effect were also revealed to lead to the enhancement of beta(HRS). PMID- 23020116 TI - Metal ions: driving the orderly assembly of polyelectrolytes at a hydrophobic surface. AB - The accumulation of polyelectrolytes at the interface between water and nonpolar fluids is an important process in both environmental and biological systems. For instance, polyelectrolytes such as humic acids are highly charged molecules that play a role in the remediation of water contaminated by oil, and the adsorption of other polyelectrolytes such as proteins and DNA to cellular surfaces is essential in biological processes. The properties of these naturally occurring polyelectrolytes are highly tunable and depend strongly on the binding of metal ions commonly found in environmental and biological systems. While the metal complexation behaviors of many polyelectrolytes and biomolecules are well characterized in bulk solution, this work shows in molecular detail that the behavior of a common polyelectrolyte in the presence of metal ions can be quite different when it adsorbs to a hydrophobic-aqueous liquid interface. In these studies, vibrational sum frequency spectroscopy and interfacial tension measurements conducted on poly(acrylic acid) (PAA) at a model oil-water interface show how small amounts of monovalent and divalent cations significantly alter the interfacial conformation of PAA at the interface and act to enhance its interfacial adsorption. The results provide important new insights that have direct relevance for understanding the effect of metal ions on the adsorption of charged macromolecules to a hydrophobic-aqueous boundary layer, specifically in biological and environmental systems. PMID- 23020117 TI - Association of Chr17q25 with cerebral white matter hyperintensities and cognitive impairment: the J-SHIPP study. AB - BACKGROUND AND PURPOSE: A recent genome-wide association study has successfully identified several genetic variations in the Chr17q25 locus as susceptible genotypes for white matter hyperintensities. We report the first replication study in subjects of non-European origin. We also investigated possible associations with other asymptomatic cerebrovascular diseases and cognitive function. METHODS: Study subjects were 1190 general Japanese persons (66.0 +/- 8.9 years old). Asymptomatic cerebrovascular damage, including lacunar infarctions, microbleeds, periventricular hyperintensity and deep and subcortical white matter hyperintensity (DSWMH), was evaluated by brain magnetic resonance imaging. RESULTS: A polymorphism rs3744028 was significantly associated with DSWMH grade (P = 0.015) but not periventricular hyperintensity, lacunar infarction, and microbleeds. Although age, hypertension, insulin resistance, B type natriuretic peptide, and carotid atherosclerosis were also correlated with DSWMH, association of the genotype was independent of these environmental risk factors. In contrast, the risk allele had a protective effect against reduced cognitive function. CONCLUSION: Susceptibility of the 17q25 locus may be conserved beyond ethnic differences. Genetic variants may have bipolar effects on brain histological and functional changes. PMID- 23020118 TI - Novel GATA6 mutations associated with congenital ventricular septal defect or tetralogy of fallot. AB - Congenital heart disease (CHD) is the most common form of developmental malformation and is the leading noninfectious cause of infant mortality. Emerging evidence indicates that genetic defects are involved in the pathogenesis of CHD. Nevertheless, CHD is genetically heterogeneous, and the molecular basis for CHD in a majority of patients remains unknown. In this study, the whole coding region of GATA6, a gene encoding a zinc-finger transcription factor crucial for normal cardiogenesis, was sequenced in 380 unrelated patients with CHD. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional effect of the mutations was characterized using a luciferase reporter assay system. As a result, two novel heterozygous GATA6 mutations, p.D404Y and p.E460X, were identified in two families with ventricular septal defect and tetralogy of Fallot, respectively. The mutations co-segregated with CHD in the families with complete penetrance, and were absent in 400 control chromosomes. Functional analysis demonstrated that the mutated GATA6 proteins were associated with significantly decreased transactivational activity in comparison with their wild-type counterpart. These findings provide novel insight into the molecular mechanism implicated in CHD, suggesting potential implications for the early prophylaxis and personalized treatment of CHD. PMID- 23020119 TI - Protective effects of L-dopa and carbidopa combined treatments on human catecholaminergic cells. AB - Parkinson's disease (PD) is one of the most common neurodegenerative disorders characterized by decreased levels of the neurotransmitter dopamine (DA) in the striatum of the brain, as a result of degeneration of DA neurons. Levodopa (L Dopa) crosses the blood-brain barrier and its administration replenishes the loss of DA in dopaminergic neurons in PD patients. Despite the evident beneficial effects, L-Dopa use may cause side effects and its toxicity found in in vitro assays has been attributed to the generation of reactive oxygen species (ROS): L Dopa is converted to DA and its metabolism and autoxidation gives rise to quinones, semiquinones, and hydrogen peroxide. Despite this evidence, L-Dopa in some in vivo and in vitro experiments showed no toxic effects, or even antioxidant effects. Two major peripheral L-Dopa metabolic pathways, driven by the enzymes Aromatic L-amino acid decarboxylase (AADC) and catechol-O-methyl transferase (COMT), significantly deplete the amount of L-Dopa reaching the brain. The low bioavailability of L-Dopa may cause a wide variation in clinical response between patients. Strategies addressing to improve the bioavailability of L-Dopa include coadministering L-Dopa with carbidopa, a decarboxylase inhibitor, as multiple daily doses. We utilized catecholaminergic human neuroblastoma cells to study DNA damage and ROS production after L-Dopa and carbidopa treatments. Our data lead us to confirm that L-Dopa may have a protective effect on dopaminergic cells especially at certain concentrations, in particular, toward the production of ROS and their toxic effects on DNA. Furthermore in the combined treatment, with induction of ROS following administration of H(2)O(2), carbidopa is effective in reducing the damage caused by reactive oxygen intermediates both alone and in combination with L-Dopa. PMID- 23020121 TI - Cobalt-mediated synthesis of the tricyclo[5.2.1.0(1,6)]decene framework in solanoeclepin A. AB - The stereocontrolled synthesis of the highly strained, tricyclo[5.2.1.0(1,6)]decene skeleton (C) of solanoeclepin A has been achieved through two key transformations: a [2,3]-Wittig rearrangement of allylpropargyl ether (A) to propargyl alcohol (B) having a trans-fused perhydroindane framework and the formation of the cyclobutane via a cobalt-mediated Hosomi-Sakurai type cyclization of an acetylene dicobalthexacarbonyl complex. PMID- 23020122 TI - Embolised mesothelial cells in a tracheobronchial lymph node associated with idiopathic chylopericardium in a dog. AB - A 5.5-year-old male castrated Bernese mountain dog presented with respiratory difficulties and was diagnosed with haemorrhagic pericardial effusion which transformed into chylopericardium. Thoracic duct ligation and subtotal pericardiectomy in combination with biopsy of an enlarged tracheobronchial lymph node were performed. Multiple clusters of mesothelial cell emboli were observed in the subcapsular sinus of the lymph node. No causative agent for the pericardial effusion could be identified, suggesting that this is a case of mesothelial cell embolisation associated with idiopathic -chylopericardium in a dog. PMID- 23020124 TI - Suitability of live yeast addition to alleviate the adverse effects due to the restriction of the time of access to feed in sheep fed only pasture. AB - The effect of yeast addition on intake and digestive utilization of pasture was studied in ovines under restricted time of access to forage. Eighteen wethers housed in metabolic cages and fed fresh forage (predominantly Lotus corniculatus) were randomly assigned to three treatments: forage available all day (AD); forage available only 6 h/day (R) and forage available only 6 h/day plus live Saccharomyces cerevisiae yeast (RY). Feed intake and digestibility, feeding behaviour, kinetics of passage, ruminal pH and ammonia concentration, nitrogen balance and microbial nitrogen synthesis (MNS) were determined in vivo, and ruminal liquor activity of animals was evaluated in vitro. Restricted animals consumed less than those fed all day but achieved more than 75% of the intake and spent less time ruminating (p = 0.014). Although animals without restriction consumed more feed, they had a lower rate of passage (p = 0.030). The addition of yeast did affect neither intake nor feeding behaviour, but increased digestibility. Organic matter digestibility tended to increase 11% by yeast addition (p = 0.051), mainly by a rise in NDF (27%, p = 0.032) and ADF digestibility (37%, p = 0.051). Ingested and retained N was lower in restricted animals, as MNS (p <= 0.045). The use of yeasts did not significantly change the N balance or MNS, but retained N tended to be higher in supplemented animals (p = 0.090). Neither ruminal pH nor ammonia concentrations were affected by the restriction, but restricted animals had a lower ruminal activity evidenced by a lower volume of gas (p = 0.020). The addition of yeast overcame this limitation, noted by a higher volume of gas of inocula from supplemented animals (p = 0.015). Yeast addition emerged as a useful tool to improve digestibility of forage cell walls in ovines under restricted time of access to forage. PMID- 23020123 TI - Controlling mesenchymal stem cell gene expression using polymer-mediated delivery of siRNA. AB - siRNA treatment has great promise to specifically control gene expression and select cell behaviors but has delivery challenges limiting its use. Particularly for applications in regenerative medicine, uniform and consistent delivery of siRNA to control gene expression and subsequent stem cell functions, such as differentiation, is paramount. Therefore, a diblock copolymer was examined for its ability to effectively deliver siRNA to mesenchymal stem cells (MSCs). The diblock copolymers, which are composed of cationic blocks for siRNA complexation, protection, and uptake and pH-responsive blocks for endosomal escape, were shown to facilitate nearly 100% MSC uptake of siRNA. This is vastly superior to a commercially available control, DharmaFECT, which resulted in only ~60% siRNA positive MSCs. Moreover, the diblock copolymer, at conditions that result in excellent knockdown (down to ~10% of control gene expression), was cytocompatible, causing no negative effects on MSC survivability. In contrast, DharmaFECT/siRNA treatment resulted in only ~60% survivability of MSCs. Longitudinal knockdown after siRNA treatment was examined and protein knockdown persists for ~6 days regardless of delivery system (diblock copolymer or DharmaFECT). Finally, MSC phenotype and differentiation capacity was examined after treatment with control siRNA. There was no statistically significant differences on cell surface markers of diblock copolymer/siRNA or DharmaFECT/siRNA-treated or cells measured 2 weeks after siRNA delivery compared to untreated cells. Upon differentiation with typical media/culture conditions to adipogenic, chondrogenic, and osteogenic lineages and examination of histological staining markers, there was no discernible differences between treated and untreated cells, regardless of delivery mechanism. Thus, diblock copolymers examined herein facilitated uniform siRNA treatment of MSCs, inducing siRNA specific gene and protein knockdown without adversely affecting MSC survival or differentiation capacity and therefore show great promise for use within regenerative medicine applications. PMID- 23020125 TI - Quantitative dynamics of phosphoproteome: the devil is in the details. AB - Recent advances in peptide-based (bottom-up) quantitative proteomics and bioinformatics have opened unprecedented opportunities for extensive investigation of cellular proteomes and their dynamics. Here we discuss two approaches currently used to investigate the global dynamics of phosphorylation based on the isolation of phosphorylated proteins or peptides. We evaluate the accuracy of these methodologies to grasp the global dynamics of phosphorylation, and we raise awareness on ambiguities inherent to these analyses. We conclude that further development of targeted approaches should prevent inaccurate conclusions about the nature of biological regulations and in particular kinase substrate networks. PMID- 23020126 TI - Combined effect of longevity-associated mitochondrial DNA 5178 c/a polymorphism and green tea consumption on risk of hypertension in middle-aged Japanese men. AB - Mitochondrial DNA 5178 cytosine/adenine (Mt5178C/A) polymorphism is reported to be associated with longevity and to modify the effects of alcohol consumption or coffee consumption on the risk of hypertension in the Japanese population. The objective of this study was to investigate whether Mt5178C/A polymorphism modifies the effects of green tea consumption on blood pressure or risk of hypertension in middle-aged Japanese men. A total of 394 male subjects (age, 53.9+/-7.9 years; mean+/-SD) was selected among individuals visiting the hospital for regular medical check-ups. Hypertension was defined as systolic blood pressure (SBP)>=140 mmHg, diastolic blood pressure (DBP)>=90 mmHg, and/or undergoing antihypertensive drug treatment. After adjustment, irrespective of antihypertensive drug treatment, the association between Mt5178C genotype and hypertension was dependent on green tea consumption (P for trend=0.043 and P for trend=0.011, respectively). In particular, among subjects>=50 years old with Mt5178C, excluding those taking antihypertensive drugs, a significant association between green tea consumption and risk of hypertension was observed (P for trend=0.019), and the odds ratio for hypertension was significantly lower in those who consumed>=6 cups of green tea per day than in those who consumed<=1 cup per day (odds ratio=0.167, 95% confidence interval: 0.033-0.832). On the other hand, the association between Mt5178A genotype and hypertension did not depend on green tea consumption. No consistent association between green tea consumption and blood pressure was observed in either genotype. The present results suggest a joint effect for Mt5178C/A polymorphism and green tea consumption on the risk of hypertension in middle-aged Japanese men. PMID- 23020127 TI - Effects of sodium alginate bead encapsulation on the storage stability of durum wheat (Triticum durum Desf.) bran oil extracted by supercritical CO2. AB - The aim of this study was to investigate the influence of encapsulation on the storage stability of oil extracted by supercritical carbon dioxide from a micronized durum wheat bran fraction. Wheat bran oil was encapsulated in 2% (w/v) sodium alginate beads. Encapsulated and unencapsulated oil samples were stored at 4 or 25 degrees C, in daylight or darkness, over 90 days, and, at defined time points, subjected to stability evaluation based on fatty acid hydroperoxide production and tocopherol (alpha, beta, and gamma forms), tocotrienol (alpha, beta, and gamma forms) and carotenoid (lutein, zeaxanthin, and beta-carotene) degradation. The encapsulation of the oil into alginate beads significantly increased stability, optimally when stored at 4 degrees C, maintaining high levels of isoprenoids and low content of fatty acid hydroperoxides over 30 days of storage. PMID- 23020128 TI - The miR-146a rs2910164 C/G polymorphism is associated with telangiectasia in systemic sclerosis. PMID- 23020129 TI - The impact of transition metals on bacterial plant disease. AB - Metals play essential roles in many biological processes but are toxic when present in excess. This makes their transport and homoeostatic control of particular importance to living organisms. Within the context of plant-pathogen interactions the availability and toxicity of transition metals can have a substantial impact on disease development. Metals are essential for defensive generation of reactive oxygen species and other plant defences and can be used directly to limit pathogen growth. Metal-based antimicrobials are used in agriculture to control plant disease, and there is increasing evidence that metal hyperaccumulating plants use accumulated metal to limit pathogen growth. Pathogens and hosts compete for available metals, with plants possessing mechanisms to withhold essential metals from invading microbes. Pathogens, meanwhile, use low-metal conditions as a signal to recognise and respond to the host environment. Consequently, metal-sensing systems such as fur (iron) and zur (zinc) regulate the expression of pathogenicity and virulence genes; and pathogens have developed sophisticated strategies to acquire metal during growth in plant tissues, including the production of multiple siderophores. This review explores the impact of transition metals on the processes that determine the outcome of bacterial infection in plants, with a particular emphasis on zinc, iron and copper. PMID- 23020130 TI - Erratum: Clinical features and treatment of World Health Organization Grade II and III meningiomas in childhood: report of 23 cases. PMID- 23020131 TI - Identification of unique sensitizing targets for anti-inflammatory CDDO-Me in metastatic melanoma by a large-scale synthetic lethal RNAi screening. AB - CDDO-Me has been shown to exert potent anti-inflammatory activity for chronic kidney disease and antitumor activity for several tumors, including melanoma, in early clinical trials. To improve CDDO-Me response in melanoma, we utilized a large-scale synthetic lethal RNAi screen targeting 6000 human druggable genes to identify targets that would sensitize melanoma cells to CDDO-Me. Based on screening results, five unique genes (GNPAT, SUMO1, SPINT2, FLI1, and SSX1) significantly potentiated the growth inhibitory effects of CDDO-Me and induced apoptosis in A375, a BRAF mutated melanoma line (P < 0.001). These five genes were then individually validated as targets to potentiate CDDO-Me activity, and related downstream signaling pathways of these genes were analyzed. In addition, the levels of phosphorylated Erk1/2, Akt, GSK-2, and PRAS40 were dramatically decreased by downregulating each of these five genes separately, suggesting a set of common mediators. Our findings indicate that GNPAT, SUMO1, SPINT2, FLI1, and SSX1 play critical roles in synergy with inflammation pathways in modulating melanoma cell survival and could serve as sensitizing targets to enhance CDDO-Me efficacy in melanoma growth control. PMID- 23020133 TI - Platelets of patients with chronic kidney disease demonstrate deficient platelet reactivity in vitro. AB - BACKGROUND: In patients with chronic kidney disease studies focusing on platelet function and properties often are non-conclusive whereas only few studies use functional platelet tests. In this study we evaluated a recently developed functional flow cytometry based assay for the analysis of platelet function in chronic kidney disease. METHODS: Platelet reactivity was measured using flow cytometric analysis. Platelets in whole blood were triggered with different concentrations of agonists (TRAP, ADP, CRP). Platelet activation was quantified with staining for P-selectin, measuring the mean fluorescence intensity. Area under the curve and the concentration of half-maximal response were determined. RESULTS: We studied 23 patients with chronic kidney disease (9 patients with cardiorenal failure and 14 patients with end stage renal disease) and 19 healthy controls. Expression of P-selectin on the platelet surface measured as mean fluorescence intensity was significantly less in chronic kidney disease patients compared to controls after maximal stimulation with TRAP (9.7 (7.9-10.8) vs. 11.4 (9.2-12.2), P=0.032), ADP (1.6 (1.2-2.1) vs. 2.6 (1.9-3.5), P=0.002) and CRP (9.2 (8.5-10.8) vs. 11.5 (9.5-12.9), P=0.004). Also the area under the curve was significantly different. There was no significant difference in half-maximal response between both groups. CONCLUSION: In this study we found that patients with chronic kidney disease show reduced platelet reactivity in response of ADP, TRAP and CRP compared to controls. These results contribute to our understanding of the aberrant platelet function observed in patients with chronic kidney disease and emphasize the significance of using functional whole blood platelet activation assays. PMID- 23020134 TI - The effects of competition on the strength and softness of selection. AB - Deleterious alleles are constantly introduced into populations due to mutation. In subdivided populations, the impact of these mutations depends on the strength of selection as well as the softness of selection, that is, the extent to which fitness is governed by local rather than global competition. It is widely appreciated that the intensity and type of competition will affect selection on deleterious mutations but most empirical work has focused solely on the effects of competition on selection strength. However, competition has rarely been studied in the context of selection 'softness' even though competition is at the conceptual root of soft selection. All other things being equal, theory predicts that inter- and intraspecific competitions have opposing effects on the softness of selection. Using Drosophila melanogaster, we estimated the strength and softness of selection in a 'baseline' competitive environment as well as two additional competitive environments characterized by either additional intra- or interspecific competitors. We found that competitive environment had little effect on the average strength of selection. While the softness of selection was affected by the type of competition, the direction of change varied across tests of different genes, contrary to expectation. Although the 'hard/soft' selection paradigm implicitly assumes that all individuals are equally sensitive to the local competitive environment, we found this not to be the case. Wild-type individuals were more sensitive to changes in the genetic quality of their local competitors than mutant individuals. PMID- 23020132 TI - Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. AB - BACKGROUND: Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. METHODS: In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. RESULTS: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03). CONCLUSIONS: Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.). PMID- 23020135 TI - Early growth velocities and weight gain plasticity improve linear growth in Peruvian infants. AB - Growth velocity patterns have the potential to signal unhealthy responses to environmental insults with long-term consequences. We aimed to investigate velocities in Peruvian infants (n = 259) in relation to attained anthropometric outcomes at 12 months and to identify determinants of velocities during critical periods of infancy. From 1995 to 1997, a randomised controlled trial of maternal zinc supplementation was conducted in a peri-urban slum area of Lima. Infants were followed monthly through 1 year on a range of anthropometric measures. Three types of velocity variables were studied: (1) incremental velocity (1 months and 3 months); (2) proportional changes (% of total size gained/month); and (3) individual velocity variability [standard deviation (SD) of individual child incremental velocities]. Mean individual child SD of weight velocity was 417 g (+/-126). In multivariate ordinary least squares regression analyses, growth velocities in month 1 and individual weight velocity variability positively predicted attained length and weight by 12 months. Panel regression by generalised least-squares with random effects of length and weight velocities confirmed the exponentially decelerating pace of growth through infancy and the importance of birth size in driving this trajectory. This study contributes evidence to support the importance of early growth velocities and greater degrees of weight gain plasticity for attained length and weight. PMID- 23020136 TI - Serostatus disclosure to sexual partners among people living with HIV: examining the roles of partner characteristics and stigma. AB - HIV serostatus disclosure among people living with HIV/AIDS (PLWHA) is an important component of preventing HIV transmission to sexual partners. Due to barriers like stigma, however, many PLWHA do not disclose their serostatus to all sexual partners. This study explored differences in HIV serostatus disclosure based on sexual behavior subgroup (men who have sex with men [MSM]; heterosexual men; and women), characteristics of the sexual relationship (relationship type and HIV serostatus of partner), and perceived stigma. We examined disclosure in a sample of 341 PLWHA: 138 MSM, 87 heterosexual men, and 116 heterosexual women who were enrolled in SafeTalk, a randomized, controlled trial of a safer sex intervention. We found that, overall, 79% of participants disclosed their HIV status to all sexual partners in the past 3 months. However, we found important differences in disclosure by subgroup and relationship characteristics. Heterosexual men and women were more likely to disclose their HIV status than MSM (86%, 85%, and 69%, respectively). Additionally, disclosure was more likely among participants with only primary partners than those with only casual or both casual and primary partners (92%, 54%, and 62%, respectively). Participants with only HIV-positive partners were also more likely to disclose than those with only HIV-negative partners, unknown serostatus partners, or partners of mixed serostatus (96%, 85%, 40%, and 60%, respectively). Finally, people who perceived more HIV-related stigma were less likely to disclose their HIV serostatus to partners, regardless of subgroup or relationship characteristics. These findings suggest that interventions to help PLWHA disclose, particularly to serodiscordant casual partners, are needed and will likely benefit from inclusion of stigma reduction components. PMID- 23020137 TI - Efficacy of low dose radiotherapy for primary orbital marginal zone lymphoma. AB - Marginal zone lymphoma (MZL) is a radiosensitive tumor, with high local control (LC) rates with moderate dose radiotherapy (RT). This retrospective study, performed at the Peter MacCallum Cancer Centre, evaluated the efficacy and toxicity of patients with orbital MZL treated to 24-25 Gy. Twenty-four patients (27 orbits) were identified, with median follow-up of 41 months. Disease was conjunctival in 16 orbits (59%), lacrimal in seven (26%), in the eyelid in one (4%) and elsewhere in three (11%). All patients attained a complete response. Three patients had treatment failures: one local relapse, one contralateral and one distant relapse. Freedom from local failure, freedom from progression, progression-free survival and overall survival were 100%, 90%, 90% and 100% at 2 years and 92%, 81%, 81% and 100% at 5 years, respectively. Aside from cataractogenesis, there was no significant late toxicity. Our study shows that RT doses of 24-25 Gy provide high rates of LC for orbital MZL with acceptable morbidity. PMID- 23020138 TI - The first uranyl arsonates featuring heterometallic cation-cation interactions with U(VI)?O-Zn(II) bonding. AB - Two new uranyl arsonates, Zn(UO(2))(PhAsO(3))(2)L.H(2)O [L = 1,10-phenanthroline (1) and 2,2'-bipyridine (2)], have been synthesized by hydrothermal reactions of phenylarsonic acid, L, and ZnUO(2)(OAc)(4).7H(2)O. Single-crystal X-ray analyses demonstrate that these two compounds are isostructural and exhibit one dimensional chains in which U(VI) and Zn(II) cations are directly connected by the yl oxygen atoms and additionally bridged by arsonate groups. Both compounds represent the first examples of uranyl arsonates with heterometallic cation cation interactions. PMID- 23020139 TI - Molecular model of the ring-opening and ring-closure reaction of a fluorinated indolylfulgide. AB - A combination of experimental and theoretical techniques is used to study the photoinduced ring-opening/closure of a trifluoromethyl-indolylfulgide. Time resolved UV/vis pump and IR probe measurements are performed in the subpicosecond to 50 ps time range. Probing in the mid-IR between 1200 and 1900 cm(-1) provides mode-specific dynamics and reveals photochemical reaction dynamics as well as the presence of a noncyclizable conformer. Ring-opening occurs with about 3 ps. Experiments on the open isomer confirm that the ring-closure occurs on the subpicosecond time scale. They also show a 10 ps transient that can be assigned to internal conversion of a noncyclizable conformer. Quantum chemical calculations with multireference methods are used to explore the complex potential energy landscape in the excited electronic state showing paths for ring opening and closure reactions as well as for competing side-reactions. The calculations reveal that photoexcitation induces a charge transfer from the indole to the anhydride. The same charge transfer drives the system toward a low energy conical intersection seam spreading from the closed to the open ring side and is responsible for the ultrafast relaxation to the ground state. The ultrafast photoreactivity comes at the expense of selectivity. PMID- 23020140 TI - Experimental and computational studies reveal an alternative supramolecular structure for fmoc-dipeptide self-assembly. AB - We have investigated the self-assembly of fluorenylmethoxycarbonyl-conjugated dialanine (Fmoc-AA) molecules using combined computational and experimental approaches. Fmoc-AA gels were characterized using transmission electron microscopy (TEM), circular dichroism (CD), Fourier transform infrared (FTIR), and wide-angle X-ray scattering (WAXS). Computationally, we simulated the assembly of Fmoc-AA using molecular dynamics techniques. All simulations converged to a condensed fibril structure in which the Fmoc groups stack mostly within in the center of the fibril. However, the Fmoc groups are partially exposed to water, creating an amphiphilic surface, which may be responsible for the aggregation of fibrils into nanoscale fibers observed in TEM. From the fibril models, radial distribution calculations agree with d-spacings observed in WAXS for the fibril diameter and pi-stacking interactions. Our analyses show that dialanine, despite its short length, adopts a mainly extended polyproline II conformation. In contrast to previous hypotheses, these results indicate that beta-sheet-like hydrogen bonding is not prevalent. Rather, stacking of Fmoc groups, inter-residue hydrogen bonding, and hydrogen bonding with water play the important roles in stabilizing the fibril structure of supramolecular assemblies of short conjugated peptides. PMID- 23020141 TI - The changing characteristics of talented soccer players--a decade of work in Groningen. AB - Talent development programmes for professional soccer clubs aim to guide players towards professional level performance. We identify whether the intermittent endurance capacity of these players may have changed over time. Since the 2000/2001 competition season, the intermittent endurance capacity of players in the talent development programmes of two professional soccer clubs was measured annually. A total of 492 players participated, divided across seven age categories (under 13 (U13), U14, U15, U16, U17, U18, U19) and resulting in 953 measurements. Analyses of variance showed an improvement in intermittent endurance capacity from the 2000/2001 season to 2009/2010 of around 50% in all age groups (P < 0.05). A possible explanation is the increased quantity and quality of training over the years. When identifying, developing and selecting young players, scouts, trainers and coaches have to be aware that the current level of soccer and its underlying performance characteristics--such as intermittent endurance capacity--are improving over time. This factor may have consequences for current young players aiming to make it to the top 10 years from now. PMID- 23020142 TI - Dynamic swelling of tunable full-color block copolymer photonic gels via counterion exchange. AB - One-dimensionally periodic block copolymer photonic lamellar gels with full-color tunability as a result of a direct exchange of counteranions were fabricated via a two-step procedure comprising the self-assembly of a hydrophobic block hydrophilic polyelectrolyte block copolymer, polystyrene-b-poly(2-vinyl pyridine) (PS-b-P2VP), followed by sequential quaternization of the P2VP layers in 1 bromoethane solution. Depending on the hydration characteristics of each counteranion, the selective swelling of the block copolymer lamellar structures leads to large tunability of the photonic stop band from blue to red wavelengths. More extensive quaternization of the P2VP block allows the photonic lamellar gels to swell more and red shift to longer wavelength. Here, we investigate the dynamic swelling behavior in the photonic gel films through time-resolved in situ measurement of UV-vis transmission. We model the swelling behavior using the transfer matrix method based on the experimentally observed reflectivity data with substitution of appropriate counterions. These tunable structural color materials may be attractive for numerous applications such as high-contrast displays without using a backlight, color filters, and optical mirrors for flexible lasing. PMID- 23020143 TI - In vitro and in vivo chemical labeling of ribosomal proteins: a quantitative comparison. AB - Thioimidates have emerged as reagents for probing the protein structure, folding, and interactions under physiological conditions. The same properties that give thioimidates biological relevance make these molecules ideal candidates for use in vivo. Through labeling of ribosomal proteins, we have quantified the in vivo and in vitro reactivity of two thioimidates: S-methylthioacetimidate (SMTA) and a novel, charge-carrying analogue, S-sulfethylthioacetimidate (SSETA). In vitro experiments demonstrate that both amidinating reagents can probe the protein structure. Under comparable in vivo conditions, SMTA is found to be membrane permeable while SSETA is not. The use of mass spectrometry with permeant and impermeant thioimidates promises insights into the membrane topology and protein structure in the native environment. PMID- 23020144 TI - Polymorphisms in interleukin-10 and interleukin-28B genes in Egyptian patients with chronic hepatitis C virus genotype 4 and their effect on the response to pegylated interferon/ribavirin-therapy. AB - BACKGROUND AND AIM: Recently, it has been suggested that single nucleotide polymorphisms (SNPs) in some cytokine genes may influence the production of the associated cytokines that affect the host immune response to pegylated interferon alpha (Peg-IFN-alpha) with ribavirin (RBV) in hepatitis C virus (HCV) patients. The aim of the present study was to investigate the possible role of the SNPs of IL-10 and Il-28B and their serum levels in predicting the response to treatment of HCV-4. METHODS: Egyptian patients were treated with Peg-IFN-alpha/RBV. A total of 100 HCV genotype 4-infected patients and 80 healthy control subjects were included in the present study. SNPs in the IL-10 (-592 A/C and -819 T/C) and IL 28B (rs8099917 T/G and rs12979860 C/T) genes and their serum levels were assessed. The IL-10-592-CC, IL-28-rs8099917-TT and IL-28-rs12979860-CC genotypes were significantly higher in responders than in non-responders. RESULTS: Interestingly, the serum levels of IL-10 were significantly increased; in contrast, the serum levels of Il-28B were significantly decreased in HCV patients compared with normal patients. Polymorphisms in IL-28B are more sensitive (P < 0.001) than those in IL-10-592 (P = 0.03). However, the serum level of IL-10 is higher than that of IL-28, and this difference can serve as a prognostic marker using a receiver operator characteristic (ROC) analysis. CONCLUSIONS: It can be concluded that SNPs in IL-28B and the serum levels of Il-10 and IL-28 may be promising predictors for HCV therapy. PMID- 23020146 TI - Social learning theory parenting intervention promotes attachment-based caregiving in young children: randomized clinical trial. AB - Parenting programs for school-aged children are typically based on behavioral principles as applied in social learning theory. It is not yet clear if the benefits of these interventions extend beyond aspects of the parent-child relationship quality conceptualized by social learning theory. The current study examined the extent to which a social learning theory-based treatment promoted change in qualities of parent-child relationship derived from attachment theory. A randomized clinical trial of 174 four- to six-year-olds selected from a high need urban area and stratified by conduct problems were assigned to a parenting program plus a reading intervention (n = 88) or nonintervention condition (n = 86). In-home observations of parent-child interactions were assessed in three tasks: (a) free play, (b) challenge task, and (c) tidy up. Parenting behavior was coded according to behavior theory using standard count measures of positive and negative parenting, and for attachment theory using measures of sensitive responding and mutuality; children's attachment narratives were also assessed. Compared to the parents in the nonintervention group, parents allocated to the intervention showed increases in the positive behavioral counts and sensitive responding; change in behavioral count measures overlapped modestly with change in attachment-based changes. There was no reliable change in children's attachment narratives associated with the intervention. The findings demonstrate that standard social learning theory-based parenting interventions can change broader aspects of parent-child relationship quality and raise clinical and conceptual questions about the distinctiveness of existing treatment models in parenting research. PMID- 23020147 TI - Synthesis of the pentacyclic skeleton of the indole alkaloid arboflorine. AB - An effective synthesis of the pentacyclic core of the unusual Kopsia alkaloid arboflorine is reported. The success of the synthetic route rested on the use of a borylative C-H functionalization reaction, a convergent Suzuki cross-coupling to a C(2) halogenated indole, and an unprecedented transannular dehydrogenative C N bond forming reaction. PMID- 23020145 TI - Molecular events in matrix protein metabolism in the aging kidney. AB - We explored molecular events associated with aging-induced matrix changes in the kidney. C57BL6 mice were studied in youth, middle age, and old age. Albuminuria and serum cystatin C level (an index of glomerular filtration) increased with aging. Renal hypertrophy was evident in middle-aged and old mice and was associated with glomerulomegaly and increase in mesangial fraction occupied by extracellular matrix. Content of collagen types I and III and fibronectin was increased with aging; increment in their mRNA varied with the phase of aging. The content of ZEB1 and ZEB2, collagen type I transcription inhibitors, and their binding to the collagen type Ialpha2 promoter by ChIP assay also showed age-phase specific changes. Lack of increase in mRNA and data from polysome assay suggested decreased degradation as a potential mechanism for kidney collagen type I accumulation in the middle-aged mice. These changes occurred with increment in TGFbeta mRNA and protein and activation of its SMAD3 pathway; SMAD3 binding to the collagen type Ialpha2 promoter was also increased. TGFbeta-regulated microRNAs (miRs) exhibited selective regulation. The renal cortical content of miR-21 and miR-200c, but not miR-192, miR-200a, or miR-200b, was increased with aging. Increased miR-21 and miR-200c contents were associated with reduced expression of their targets, Sprouty-1 and ZEB2, respectively. These data show that aging is associated with complex molecular events in the kidney that are already evident in the middle age and progress to old age. Age-phase-specific regulation of matrix protein synthesis occurs and involves matrix protein specific transcriptional and post-transcriptional mechanisms. PMID- 23020148 TI - Migration of a retained surgical swab into the jejunum in a dog. AB - A two-year-old spayed female shih-tzu was referred with a 10-month history of lethargy, chronic diarrhoea and weight loss. On presentation, a partial response to antibiotics was noted. Physical examination revealed an abdominal mass, and serum biochemistry and haematology revealed a mature neutrophilia, hypoalbuminaemia and a non-regenerative anaemia. Contrast radiography and abdominal ultrasound were suggestive of an intraluminal foreign body. Exploratory laparotomy revealed a surgical swab in the lumen of the jejunum that was associated with severe adhesions. Histopathology showed evidence of transmural migration of the swab from the peritoneal cavity to the lumen of the jejunum. PMID- 23020149 TI - Thermally stable N2-intercalated WO3 photoanodes for water oxidation. AB - We describe stable intercalation compounds of the composition xN(2).WO(3) (x = 0.034-0.039), formed by trapping N(2) in WO(3). The incorporation of N(2) significantly reduced the absorption threshold of WO(3); notably, 0.039N(2).WO(3) anodes exhibited photocurrent under illumination at wavelengths <=640 nm with a faradaic efficiency for O(2) evolution in 1.0 M HClO(4)(aq) of nearly unity. Spectroscopic and computational results indicated that deformation of the WO(3) host lattice, as well as weak electronic interactions between trapped N(2) and the WO(3) matrix, contributed to the observed red shift in optical absorption. Noble-gas-intercalated WO(3) materials similar to xN(2).WO(3) are predicted to function as photoanodes that are responsive to visible light. PMID- 23020150 TI - Escherichia coli adapts to tetracycline resistance plasmid (pBR322) by mutating endogenous potassium transport: in silico hypothesis testing. AB - Antibiotic resistance exerts a metabolic cost on bacteria and presumably a fitness disadvantage in the absence of antibiotics. However, several studies have shown that bacteria can evolve to eliminate this cost. Escherichia coli can adapt to the plasmid pBR322 carrying the tetA tetracycline-resistance gene (codes for the TetA efflux pump) by a chromosome mutation, which requires an intact tetA gene on the plasmid. The TetA pump can mediate potassium uptake. Here, the hypothesis that TetA replaces the endogenous K(+) uptake system Trk is explored using a multi-level modeling approach that explicitly resolves relevant intracellular processes (e.g., metabolism and K(+) uptake) and simulates individual bacteria in competition. The general behavior of the model is consistent with observations from the literature (e.g., growth rate and K(+) limitation). In competition experiments without tetracycline, the model correctly predicts the fitness advantage of naive susceptible over naive resistant, evolved resistant over naive resistant and evolved resistant over evolved susceptible strains. Trk takes up about 10 times the K(+) required, which costs energy. TetA takes up less K(+) , which is more efficient and leads to the evolution of the Trk mutant. The evolved Trk mutant relies on TetA to take up K(+) , and thus, carrying the plasmid is advantageous even in the absence of the antibiotic. PMID- 23020151 TI - Methods to improve international comparability of census and survey measures of disability. AB - PURPOSE: To describe the methods used by the Washington Group on Disability Statistics (WG) to develop internationally comparable questions on disability that can be used worldwide. METHOD: The WG approach to developing disability measures included careful consideration of the theoretical and conceptual issues associated with disability, translating disability concepts into measurement tools, and mixed-method evaluations of the proposed questions using both cognitive and field interviewing methodologies. RESULTS: Disability is a complex construct the measurement of which presents considerable challenges for survey methodologists. The Washington Group on Disability Statistics (WG), a UN Statistical Commission sponsored city group, was established to address the methodological and measurement challenges that have characterized disability statistics and to develop questions for use worldwide that will provide comparable, valid and reliable disability statistics. The WG used a variety of methods to meet these objectives and has finalized a short set disability measure for use in censuses worldwide. CONCLUSIONS: The methodologies adopted by the WG have resulted in question sets that greatly improve the international comparability of disability statistics and will advance our understanding of disability worldwide. PMID- 23020152 TI - Genetic variation at KIT locus may predispose to melanoma. AB - As loss of KIT frequently occurs in melanoma progression, we hypothesized that KIT is implicated in predisposition to melanoma (MM). Thus, we sequenced the KIT coding region in 112 familial MM cases and 143 matched controls and genotyped tag single-nucleotide polymorphisms (SNPs) in two cohorts of melanoma patients and matched controls. Five rare KIT substitutions, all predicted possibly or probably deleterious, were identified in five patients, but none in controls [RR = 2.26 (1.26-2.26)]. Expressed in melanocyte lines, three substitutions inhibited KIT signaling. Comparison with exomes database (7020 alleles) confirmed a significant excess of rare deleterious KIT substitutions in patients. Additionally, a common SNP, rs2237028, was associated with MM risk, and 6 KIT variants were associated with nevus count. Our data strongly suggest that rare KIT substitutions predispose to melanoma and that common variants at KIT locus may also impact nevus count and melanoma risk. PMID- 23020153 TI - Association between multiple cutaneous melanoma and other primary neoplasms. AB - BACKGROUND: The risk of a subsequent cancer is an important issue for patients with melanoma. The development of a second primary cancer in patients with a solitary melanoma has been discussed in several studies. However, to our knowledge, the incidence of second primary cancer (SPC) in patients with multiple primary melanoma (MPM) has not been thoroughly investigated. AIM: To quantify the incidence of SPC in patients with MPM, with the aim of possibly developing further preventive measures. METHODS: In a retrospective study, 76 patients with MPM were identified from 2155 patients being followed up at our unit. RESULTS: Of the 76 patients, 12 (16%) developed another neoplasm, with 59% of them having nonmelanoma skin cancer (NMSC), and 41% other noncutaneous cancers. By contrast, only 8% of those with single primary melanoma had other neoplasms (21% of whom had NMSC). CONCLUSIONS: Patients with MPM, especially men with skin phototype II, have a significantly increased incidence of developing SPC, particularly NMSC. Thus, careful monitoring is essential not only to detect recurrence of the original cancer or development of another primary melanoma, but also development of new malignancies of different types, particularly NMSC. PMID- 23020154 TI - Management of pediatric intracranial gunshot wounds: predictors of favorable clinical outcome and a new proposed treatment paradigm. AB - OBJECT: There has been an increase in civilian gun violence since the late 1980s, with a disproportionately high increase occurring within the pediatric population. To date, no definite treatment paradigm exists for the management of these patients, nor is there a full understanding of the predictors of favorable clinical outcome in this population. METHODS: The authors completed a retrospective review of all victims of intracranial gunshot injury from birth to age 18 years at a major metropolitan Level 1 trauma center (n = 48) from 2002 to 2011. The predictive values of widely accepted adult clinical and radiographic factors for poor prognosis were investigated. RESULTS: Eight statistically significant factors (p < 0.05) for favorable outcome were identified. These factors include single hemispheric involvement, absence of a transventricular trajectory, < 3 lobes involved, >= 1 reactive pupil on arrival, systolic blood pressure > 100 mm Hg on arrival, absence of deep nuclei and/or third ventricular involvement, initial ICP < 30 mm Hg when monitored, and absence of midline shift. Of these 8 factors, 5 were strong predictors of favorable clinical outcome as defined by Glasgow Outcome Scale score of 4 or 5. These predictive factors included absence of a transventricular trajectory, < 3 lobes involved, >= 1 reactive pupil on arrival, absence of deep nuclei and/or third ventricular involvement, and initial ICP < 30 mm Hg. These findings form the basis of the St. Louis Scale for Pediatric Gunshot Wounds to the Head, a novel metric to inform treatment decisions for pediatric patients who sustain these devastating injuries. CONCLUSIONS: The pediatric population tends to demonstrate more favorable outcomes following intracranial gunshot injury when compared with the adult population; therefore some patients may benefit from more aggressive treatment than is considered for adults. The St. Louis Scale for Pediatric Gunshot Wounds to the Head may provide critical data toward evidence-based guidelines for clinical decision making. PMID- 23020155 TI - Adult day services: a service platform for delivering mental health care. AB - OBJECTIVES: The purpose of this study was to understand the degree to which mental health services targeting anxiety and depression disorders are offered by adult day services (ADS) centers in the US. In addition, researchers wanted to determine whether staffing and organizational characteristics are associated with the provision of medication management, individual counseling, and group counseling for participants with anxiety or depression. METHOD: Data were drawn from the MetLife National Study of ADS. Hierarchical logistic regression analyses were conducted to determine which staffing and organizational factors were associated with the provision of services to treat anxiety and depression. RESULTS: Approximately, three in four adult day programs provided medication management for the treatment of anxiety and depression while 38% provided individual counseling and almost 30% group counseling. Programs offering medication management were more likely to have more registered nurse (RN) service hours available per shift and higher costs. Programs that provided individual and group counseling for participants with anxiety or depression were more likely to have more hours of RN and social work services available and a lower percentage of participants who pay privately for services. CONCLUSION: The results suggest that ADS are well positioned to act as a platform for delivering mental health care to older persons with anxiety or depression. PMID- 23020156 TI - Identification and quantitation of carotenoids and tocopherols in seed oils recovered from different Rosaceae species. AB - Seed oils recovered from Rosaceae species such as dessert and cider apples (Malus domestica Borkh.), quince (Cydonia oblonga Mill.), and rose hip (Rosa canina L.) were analyzed for their tocopherol and carotenoid contents using HPLC-DAD-MS(n) following saponification. Qualitative and quantitative tocopherol and carotenoid compositions significantly differed, not only among the different genera but also among cultivars of one species. In particular, seed oils of cider apples were shown to contain higher amounts of both antioxidant classes than that of dessert apples. Total contents of tocopherols of the investigated Rosaceous seed oils ranged from 597.7 to 1099.9 mg/kg oil, while total carotenoid contents varied between 0.48 and 39.15 mg/kg oil. Thus, these seed oils were found to contain appreciable amounts of lipohilic antioxidants having health beneficial potential. The results of the present study contribute to a more economical and exhaustive exploitation of seed byproducts arising from the processing of these Rosaceous fruits. PMID- 23020157 TI - Identifying between-person and within-person factors to enhance understanding of observed score profiles. AB - This study aims to reparameterize ordinary factors into between- and within person factor effects and utilize an array of the within-person factor loadings as a latent profile which encapsulates all score responses of individuals in a population. To illustrate, the Woodcock-Johnson III (WJ-III) tests of cognitive abilities were analysed and one between- and two within-person factors were identified. The scoring patterns of individuals in the WJ-III sample were interpreted according to the within-person factor patterns. Regression analyses were performed to examine how much the within-person factors accounted for the person scoring patterns and criterion variables. Finally, the importance and applications of the between- and within-person factors are discussed. PMID- 23020158 TI - Assessment of self-esteem levels of Turkish patients with severe haemophilia A: Ankara Hospital experience. PMID- 23020159 TI - Focus on invasive mucormycosis in paediatric haematology oncology patients: a series of 11 cases. AB - Mucormycosis has emerged as an increasingly important infection in oncology centres with high mortality, especially in severely immunocompromised patients. We carried out a retrospective study of 11 children with mucormycosis treated in seven French oncology-haematology paediatric wards during the period from 1991 to 2011. Lichtheimia corymbifera and Mucor spp. were the predominant pathogens. Treatment regimens included antifungal therapy, reversal of underlying predisposing risk factors and surgical debridement. Although mucormycosis is associated with high mortality, this infection could be cured in eight of our cases of severely immunocompromised paediatric cancer patients. PMID- 23020160 TI - Evolution of dispersal in metacommunities of interacting species. AB - Theoretical studies on the evolution of dispersal in metacommunities are rare despite empirical evidence suggesting that interspecific interactions can modify dispersal behaviour of organisms. To understand the role of species interactions for dispersal evolution, we utilize an individual-based model of a metacommunity where local population dynamics follows a stochastic version of the Nicholson Bailey model and dispersal probability is an evolving trait. Our results show that in comparison with a neutral system (commensalism), parasitism promotes dispersal of hosts and parasites, while mutualism tends to reduce dispersal in both partners. Search efficiency of guests (only in the case of parasitism), dispersal mortality and external extinction risk can influence the evolution of dispersal of all partners. In systems composed of two host and two guest species, lower dispersal probabilities evolve under parasitism as well as mutualism than in one host and one guest species systems. This is because of frequency-dependent modulations of dispersal benefits emerging in such systems for all partners. PMID- 23020161 TI - Born-Oppenheimer and non-Born-Oppenheimer, atomic and molecular calculations with explicitly correlated Gaussians. PMID- 23020163 TI - Ba3LnInS6 (Ln = Pr, Sm, Gd, Yb) and Ba2LnGaS5 (Ln = Pr, Nd): syntheses, structures, and magnetic and optical properties. AB - Six new quaternary rare-earth sulfides Ba(3)LnInS(6) (Ln = Pr, Sm, Gd, Yb) and Ba(2)LnGaS(5) (Ln = Pr, Nd) have been synthesized for the first time. Ba(3)LnInS(6) (Ln = Pr, Sm, Gd, Yb) belong to the centrosymmetric space group R3[overline]c of the trigonal system. The structures contain infinite one dimensional anionic chains (1)(infinity)[LnInS(6)](6-), which are built from face sharing LnS(6) distorted triangular prisms and InS(6) octahedra. Ba(2)LnGaS(5) (Ln = Pr, Nd) crystallize in the centrosymmetric space group I4/mcm of the tetragonal system. Their structures consist of (BaLn)S layers built from (BaLn)S(8) bicapped trigonal prisms. These layers are stacked perpendicular to the c axis and further connected by GaS(4) tetrahedra to form a three-dimensional framework with channels occupied by Ba(2+) cations. As deduced from magnetic susceptibility measurements on Ba(2)NdGaS(5), it is paramagnetic and obeys the Curie-Weiss law. Besides, the band gap of Ba(2)NdGaS(5) is determined to be about 2.12(2) eV. PMID- 23020162 TI - Trastuzumab emtansine for HER2-positive advanced breast cancer. AB - BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. METHODS: We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. RESULTS: Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. CONCLUSIONS: T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.). PMID- 23020164 TI - Trichlorophenyl formate: highly reactive and easily accessible crystalline CO surrogate for palladium-catalyzed carbonylation of aryl/alkenyl halides and triflates. AB - The high utility of 2,4,6-trichlorophenyl formate, a highly reactive and easily accessible crystalline CO surrogate, is demonstrated. The decarbonylation with NEt(3) to generate CO proceeded rapidly at rt, thereby allowing external-CO-free Pd-catalyzed carbonylation of aryl/alkenyl halides and triflates. The high reactivity of the CO surrogate enabled carbonylation at rt and significantly reduced the quantities of formate to near-stoichiometric levels. The obtained trichlorophenyl esters can be readily converted to a variety of carboxylic acid derivatives in high yields. PMID- 23020165 TI - Editorial: biomedical engineering imaging. PMID- 23020166 TI - Picking transplant glomerulopathy out of the CAN: evidence from a clinico pathological evaluation. AB - BACKGROUND: Since the term chronic allograft nephropathy (CAN) was removed from the Banff scheme in 2005, transplant glomerulopathy (TG) has been regarded as a clinicopathological entity that is one of the major causes of graft loss. To assess the distinction between CAN and TG, we performed a comprehensive evaluation comparing TG with traditional CAN. METHODS: We compared the clinicopathological features of 43 cases of TG with 43 matched cases of non-TG CAN (non-TG group) after renal transplantation. TG was diagnosed by light microscopy based on the double contours of the glomerular basement membranes, and the Banff 97 classification system was used to score TG severity (cg0-3). RESULTS: Compared to the control group, we found a significantly higher incidence of positivity for human leukocyte antigen class-I and II antibodies, a higher incidence of hepatitis C virus (HCV) infection, and poorer graft survival in TG patients. Clinically, TG was associated with a higher prevalence of proteinuria, hematuria, anaemia and hypoalbuminemia. Histologically, TG strongly correlated with antibody related microcirculatory injuries, including glomerulitis, peritubular capillaritis and peritubular capillary (PTC) C4d deposition. Interestingly, the TG patients showed a significantly higher incidence of IgA deposition than the control patients. C4d-positive TG was correlated with higher TG and PTC scores, and PTC C4d deposition was correlated with a more rapid progression to graft dysfunction. TG accompanied by HCV infection was associated with heavier proteinuria, higher TG and C4d scores, and poorer graft survival. CONCLUSIONS: TG presents clinicopathological features that are distinct from non TG cases and leads to poorer outcomes. PTC C4d deposition is related to a more rapid progression to graft loss, suggesting ongoing antibody reactivity. HCV positive TG is a more severe sub-entity, that requires further investigation. PMID- 23020167 TI - A rapid microfluidic mixer for high-viscosity fluids to track ultrafast early folding kinetics of G-quadruplex under molecular crowding conditions. AB - Tracking the folding kinetics of macromolecules under molecular crowding conditions represents a tremendous challenge due to the high viscosity of the solution. In this paper, we report a unique T-type microfluidic mixer with seven consecutive omega-shaped baffles for fast mixing of high-viscosity fluids. Numerical simulations and experimental characterizations proved that the micromixer could achieve a mixing time of 579.4 MUs for solutions with viscosities about 33.6 times that of pure water. Over a 1000-fold improvement in mixing dead time was accomplished in comparison to those reported previously. We further used this highly efficient micromixer to track the early folding kinetics of human telomere G-quadruplex under molecular crowding conditions. Results indicated an exponential process in the initial folding phase of G-quadruplex, and the G-quadruplex formed a more compact structure under higher degrees of molecular crowding conditions. PMID- 23020169 TI - Enabling advanced cell therapies (EnACT): invitation to an online forum on resolving barriers to clinical translation. PMID- 23020168 TI - Mycoplasma haemocanis--the canine hemoplasma and its feline counterpart in the genomic era. AB - Mycoplasma haemocanis is a hemotrophic mycoplasma (hemoplasma), blood pathogen that may cause acute disease in immunosuppressed or splenectomized dogs. The genome of the strain Illinois, isolated from blood of a naturally infected dog, has been entirely sequenced and annotated to gain a better understanding of the biology of M. haemocanis. Its single circular chromosome has 919 992 bp and a low G + C content (35%), representing a typical mycoplasmal genome. A gene-by-gene comparison against its feline counterpart, M. haemofelis, reveals a very similar composition and architecture with most of the genes having conserved synteny extending over their entire chromosomes and differing only by a small set of unique protein coding sequences. As in M. haemofelis, M. haemocanis metabolic pathways are reduced and apparently rely heavily on the nutrients afforded by its host environment. The presence of a major percentage of its genome dedicated to paralogous genes (63.7%) suggests that this bacterium might use antigenic variation as a mechanism to evade the host's immune system as also observed in M. haemofelis genome. Phylogenomic comparisons based on average nucleotide identity (ANI) and tetranucleotide signature suggest that these two pathogens are different species of mycoplasmas, with M. haemocanis infecting dogs and M. haemofelis infecting cats. PMID- 23020170 TI - TEASIng apart alien species risk assessments: a framework for best practices. AB - Some alien species cause substantial impacts, yet most are innocuous. Given limited resources, forecasting risks from alien species will help prioritise management. Given that risk assessment (RA) approaches vary widely, a synthesis is timely to highlight best practices. We reviewed quantitative and scoring RAs, integrating > 300 publications into arguably the most rigorous quantitative RA framework currently existing, and mapping each study onto our framework, which combines Transport, Establishment, Abundance, Spread and Impact (TEASI). Quantitative models generally measured single risk components (78% of studies), often focusing on Establishment alone (79%). Although dominant in academia, quantitative RAs are underused in policy, and should be made more accessible. Accommodating heterogeneous limited data, combining across risk components, and developing generalised RAs across species, space and time without requiring new models for each species may increase attractiveness for policy applications. Comparatively, scoring approaches covered more risk components (50% examined > 3 components), with Impact being the most common component (87%), and have been widely applied in policy (> 57%), but primarily employed expert opinion. Our framework provides guidance for questions asked, combining scores and other improvements. Our risk framework need not be completely parameterised to be informative, but instead identifies opportunities for improvement in alien species RA. PMID- 23020171 TI - Delayed intracranial hematoma following stereoelectroencephalography for intractable epilepsy: case report. AB - Intracranial bleeding following stereoelectroencephalography (sEEG) is rare and commonly occurs early after electrode implantation. The authors report the case of a delayed intracranial hematoma following sEEG. This 10-year-old boy was referred to the authors' department to undergo an sEEG study for intractable epilepsy, with the hypothesis of a single localized epileptic zone in the left precentral region. To perform the exploration, 14 depth electrodes were implanted under stereotactic conditions. The results of a postoperative CT scan performed routinely at the end of the surgical procedure were normal. Eight days later, following an epileptic seizure, the child's condition worsened. The neurological examination revealed a left hemiparesis, agitation, and coma due to a right subdural hematoma with intraparenchymal bleeding. Despite a surgical evacuation followed by a decompressive craniectomy, the curative treatments were stopped 1 week later due to severe diffuse ischemic lesions found on MRI studies. This is the first observation of a delayed hematoma following an sEEG procedure. The mechanism underlying this complication remains unclear, but the rupture of a growing pseudoaneurysm caused by the electrode's implantation or the tearing of a neighboring vessel by an electrode were suspected. In consequence, physicians must remain vigilant during the entire sEEG recording period and probably also several days after electrode removal. PMID- 23020172 TI - Congenital mesoblastic nephroma in a young basset hound dog. AB - An 18-month-old male basset hound was presented with vomiting, diarrhoea and depression. Abdominal ultrasonography revealed a mass in the left kidney. An ultrasound-guided core-biopsy indicated aggregates of spindle cells, but did not allow a definitive diagnosis. Nephrectomy was performed after a period of six months, when ultrasound examination revealed a slight increase in mass dimensions. Histologically the mass was composed of neoplastic spindle cells forming interlacing fascicles, bundles and whorls, within a loose myxoid to dense collagenous stroma. Immunohistochemically neoplastic cells were positive for vimentin and smooth muscle actin. Based on these findings the tumour was diagnosed as a congenital mesoblastic nephroma, classical variant. After a two and-a-half-year follow-up the dog was clinically healthy, indicating a benign behaviour. To the authors' knowledge, this report describes the first case of canine congenital mesoblastic nephroma successfully treated surgically, with a reasonable postsurgical follow-up. PMID- 23020173 TI - Formation of active sites for oxygen reduction reactions by transformation of nitrogen functionalities in nitrogen-doped carbon nanotubes. AB - Heat treating nitrogen-doped multiwalled carbon nanotubes containing up to six different types of nitrogen functionalities transforms particular nitrogen functionalities into other types which are more catalytically active toward oxygen reduction reactions (ORR). In the first stage, the unstable pyrrolic functionalities transform into pyridinic functionalities followed by an immediate transition into quaternary center and valley nitrogen functionalities. By measuring the electrocatalytic oxidation reduction current for the different samples, we achieve information on the catalytic activity connected to each type of nitrogen functionality. Through this, we conclude that quaternary nitrogen valley sites, N-Q(valley), are the most active sites for ORR in N-CNTs. The number of electrons transferred in the ORR is determined from ring disk electrode and rotating ring disk electrode measurements. Our measurements indicate that the ORR processes proceed by a direct four-electron pathway for the N-Q(valley) and the pyridinic sites while it proceeds by an indirect two-electron pathway via hydrogen peroxide at the N-Q(center) sites. Our study gives both insights on the mechanism of ORR on different nitrogen functionalities in nitrogen-doped carbon nanostructures and it proposes how to treat samples to maximize the catalytic efficiency of such samples. PMID- 23020174 TI - Synthesis and photophysics of fully pi-conjugated heterobis-functionalized polymeric molecular wires via Suzuki chain-growth polymerization. AB - We present a fast and efficient in situ synthetic approach to obtain fully pi conjugated polymers with degrees of polymerization up to 23 and near quantitative (>95%) heterobis-functionalization. The synthesis relies on the key advantages of controlled Suzuki chain-growth polymerization: control over molecular weight, narrow polydispersity, and ability to define polymer end groups. The first end group is introduced through the initiator metal complex tBu(3)PPd(X)Br, while the second end group is added by quenching of the chain-growth polymerization with the desired boronic esters. In all cases, polymers obtained at 50% conversion showed excellent end group fidelity and high purity following a simple workup procedure, as determined by MALDI-TOF, GPC, and (1)H and 2D NMR. End group functionalization altered the optoelectronic properties of the bridge polymer. Building on a common fluorene backbone, and guided by DFT calculations, we introduced donor and acceptor end groups to create polymeric molecular wires exhibiting charge transfer and energy transfer as characterized by fluorescence, absorption, and transient absorption spectroscopy as well as by fluorescence lifetime measurements. PMID- 23020175 TI - Borderline personality features and implicit shame-prone self-concept in middle childhood and early adolescence. AB - This study tested if children and adolescents with high levels of borderline personality features (BPF) exhibit the same shame-prone self-concept previously found to characterize adults with borderline personality disorder (Rusch et al., 2007 ). Self-concept was indexed using the Implicit Association Test, in a community sample of children/adolescents aged 10 to 14 years (48% female; M age = 12.04 years). Common domains of child and adolescent psychopathology and core components of BPF were assessed using self-reports on the Strengths and Difficulties Questionnaire and the Borderline Personality Features Scale for Children. The identity problems component of BPF was found to significantly predict implicit levels of shame-prone self-concept, but only among girls. This effect was independent of the key dimensions of child and adolescent psychopathology that overlap with BPF-including features hyperactivity/inattention, disruptive behavior problems, and anxiety/depression none of which were associated with shame-prone self-concept at the bivariate level or otherwise. The current findings provide preliminary evidence that self schemas related to shame are uniquely associated with a core component of BPF in middle childhood and early adolescence and suggest that this correlate may apply uniquely to female individuals. These findings point to the identity problems component of BPF as a priority for future clinical and developmental research into mechanisms associated with BPF across childhood and adolescence. PMID- 23020176 TI - Comparison of the 2002 and 2010 TNM classification systems regarding outcome prediction in clear cell and papillary renal cell carcinoma. AB - AIMS: A novel version of the tumour-node-metastasis (TNM) classification system for renal cell carcinoma (RCC) was introduced in 2010, although the prognostic significance with regard to different histological subtypes has not been explored. Therefore, the aim of our study was to compare the predictive ability of the 2002 and 2010 versions of the TNM classification system for clear cell and papillary RCC. METHODS AND RESULTS: Data from 2263 consecutive clear cell and 309 papillary RCC patients, operated at a single tertiary academic centre, were evaluated. According to TNM 2010, statistically significant differences for cancer-specific survival (CSS) were observed for pT1a versus pT1b (P < 0.001) and pT3a versus pT3b (P < 0.004) in clear cell RCC; and pT1b versus pT2a (P = 0.002) and pT3b versus pT3c (P = 0.046) in papillary RCC. The c-index for CSS in clear cell RCC was 0.74 and 0.73, and in papillary RCC 0.79 and 0.78, for the 2002 and 2010 versions of the TNM classification system, respectively. CONCLUSIONS: According to our data, the predictive ability of the 2010 version of the TNM classification system regarding CSS is not superior to the 2002 version, either in clear cell or in papillary RCC. PMID- 23020177 TI - Should we clean up the reputation of "dirty drugs"? PMID- 23020179 TI - Conceptualizing belonging. AB - PURPOSE: To develop a transdisciplinary conceptualization of social belonging that could be used to guide measurement approaches aimed at evaluating the effectiveness of community-based programs for people with disabilities. METHOD: We conducted a narrative, scoping review of peer reviewed English language literature published between 1990 and July 2011 using multiple databases, with "sense of belonging" as a key search term. The search engine ranked articles for relevance to the search strategy. Articles were searched in order until theoretical saturation was reached. We augmented this search strategy by reviewing reference lists of relevant papers. RESULTS: Theoretical saturation was reached after 40 articles; 22 of which were qualitative accounts. We identified five intersecting themes: subjectivity; groundedness to an external referent; reciprocity; dynamism and self-determination. CONCLUSION: We define a sense of belonging as a subjective feeling of value and respect derived from a reciprocal relationship to an external referent that is built on a foundation of shared experiences, beliefs or personal characteristics. These feelings of external connectedness are grounded to the context or referent group, to whom one chooses, wants and feels permission to belong. This dynamic phenomenon may be either hindered or promoted by complex interactions between environmental and personal factors. PMID- 23020178 TI - Tyr682 in the Abeta-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. AB - Processing of Abeta-precursor protein (APP) plays an important role in Alzheimer's disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the 682YENPTY687 motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y682 to Gly (APP(YG/YG) mice). This mutation alters the processing of APP and TrkA signaling and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APP(YG/YG) mice. Here, we show that APP(YG/YG) mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone, and TrkA levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and TrkA signaling deficit, and cognitive and neuromuscular decline in APP(YG/YG) mice. The profound deficits caused by the Y682 mutation underscore the biological importance of APP and indicate that APP(YG/YG) are a valuable mouse model to study APP functions in physiological and pathological processes. PMID- 23020180 TI - An assay to screen bacterial adhesion to mucus biomolecules. AB - AIMS: To develop an assay for rapid screening of bacterial adhesion to various groups of biomolecules present in fish mucus. METHODS AND RESULTS: A novel assay was developed for investigation of bacterial adhesion to various groups of mucus biomolecules from fish. Lipid-, protein-, carbohydrate- and nucleic acid-rich constituents of mucus were separated using isopycnic density gradient centrifugation techniques. Separated mucus fractions were assayed for bacterial adhesion using a blotting apparatus. The assay was validated using Vibrio vulnificus and skin mucus from hybrid tilapia. CONCLUSIONS: A novel assay was developed for the screening of bacterial adhesion to major groups of mucus biomolecules. Adhesion of V. vulnificus MLT403 positively correlated with lipid- and protein-rich mucus constituents and negatively correlated with carbohydrate rich mucus constituents. SIGNIFICANCE AND IMPACT OF THE STUDY: The assay can be used as an initial approach in a systematic identification of mucus constituent(s) exhibiting the most favourable adhesion properties for bacteria. PMID- 23020181 TI - Refining the conditions for sympatric ecological speciation. AB - Can speciation occur in a single population when different types of resources are available, in the absence of any geographical isolation, or any spatial or temporal variation in selection? The controversial topics of sympatric speciation and ecological speciation have already stimulated many theoretical studies, most of them agreeing on the fact that mechanisms generating disruptive selection, some level of assortment, and enough heterogeneity in the available resources, are critical for sympatric speciation to occur. Few studies, however, have combined the three factors and investigated their interactions. In this article, I analytically derive conditions for sympatric speciation in a general model where the distribution of resources can be uni- or bimodal, and where a parameter controls the range of resources that an individual can exploit. This approach bridges the gap between models of a unimodal continuum of resources and Levene type models with discrete resources. I then test these conditions against simulation results from a recently published article (Thibert-Plante & Hendry, 2011, J. Evol. Biol. 24: 2186-2196) and confirm that sympatric ecological speciation is favoured when (i) selection is disruptive (i.e. individuals with an intermediate trait are at a local fitness minimum), (ii) resources are differentiated enough and (iii) mating is assortative. I also discuss the role of mating preference functions and the need (or lack thereof) for bimodality in resource distributions for diversification. PMID- 23020182 TI - Efficient synthesis and characterization of lactulosucrose by Leuconostoc mesenteroides B-512F dextransucrase. AB - This work describes an efficient enzymatic synthesis and NMR structural characterization of the trisaccharide beta-D-galactopyranosyl-(1->4)-beta-D fructofuranosyl-(2->1)-alpha-D-glucopyranoside, also termed as lactulosucrose. This oligosaccharide was formed by the Leuconostoc mesenteroides B-512F dextransucrase-catalyzed transfer of the glucosyl residue from sucrose to the 2 hydroxyl group of the reducing unit of lactulose. The enzymatic reaction was carried out under optimal conditions, i.e., at 30 degrees C in 20 mM sodium acetate buffer with 0.34 mM CaCl(2) at pH 5.2, and the effect of factors such as reaction time (0-48 h), enzyme charge (0.8, 1.6, and 2.4 U mL(-1)), and sucrose:lactulose concentration ratios (20:40, 30:30, and 40:20, expressed in g/100 mL) on the formation of transfer products were studied. The highest formation in lactulosucrose was attained at 8 and 24-32 h by using 20%:40% and 30%:30% sucrose:lactulose mixtures, respectively, with 1.6 or 2.4 U mL(-1) dextransucrase, leading to lactulosucrose yields of 27-35% in weight respect to the initial amount of lactulose. Furthermore, minor tetra- and pentasaccharide, both probably derived from lactulose, were also detected and quantified. Likewise, the capacity of lactulosucrose to act as D-glucosyl donor once the sucrose was consumed, could explain its decrease from 16 to 24 h when the highest charge of dextransucrase was used. Considering the chemical structure of the synthesized oligosaccharides, lactulosucrose and its derivatives could potentially be excellent candidates for an emerging prebiotic ingredient. PMID- 23020183 TI - Innovative TiO2/Cu nanosurfaces inactivating bacteria in the minute range under low-intensity actinic light. AB - The bacterial inactivation of E. coli by cotton TiO(2)/Cu DC-magnetron sputtered thin films was investigated in the dark and under low-intensity actinic light. The TiO(2)/Cu sputtered layers revealed to be sensitive to actinic light showing the spectral characteristics of Cu/CuO. This indicates that Cu does not substitute Ti(4+) in the crystal lattice. Under diffuse actinic light (4 mW/cm(2)), the hybrid composite TiO(2)/Cu sample lead to fast bacterial inactivation times <5 min. This study presents evidence for a direct relation between the film optical absorption obtained by diffuse reflectance spectroscopy (DRS) and the bacterial inactivation kinetics by the TiO(2)/Cu samples. The Cu ions inactivating the bacteria were followed in solution by inductively plasma coupled spectroscopy (ICPS). The amounts of Cu-ions detected by ICPS provide the evidence for an oligodynamic antibacterial effect. The changes in the oxidation state of Cu during bacterial inactivation were followed by XPS. The E. coli cell viability was detected by standard coliform counting CFU methods. The TiO(2)/Cu thickness layer was determined by profilometry and the film microstructure by XPS, TEM, AFM, XRD, XRF and contact angle (CA). A mechanism of bacterial inactivation by TiO(2)/Cu samples is suggested in terms of interfacial charge transfer (IFCT) involving charge transfer between TiO(2) and Cu. PMID- 23020184 TI - Caregiver experiences of discrimination and african american adolescents' psychological health over time. AB - The present study examined the effect of caregivers' experiences of racial discrimination on their adolescent children's psychological functioning among a sample of 264 African American dyads. Potential relations between caregiver discrimination experiences and a number of indicators of adolescents' (aged 12 17) psychological functioning over time were examined. It was found that caregiver discrimination experiences were positively related to adolescents' symptoms of depression and negatively related to their psychological well-being. Additional analysis revealed interactions between the effects of caregiver discrimination experiences and family income on all 3 outcomes. Greater caregiver discrimination experiences and lower family income were risk factors for the youth in the sample. These findings underscore the deleterious consequence of caregivers' discrimination experiences on African American youth's psychological health. PMID- 23020185 TI - Impact of parathyroidectomy on allograft outcomes in kidney transplantation. AB - We performed retrospective, multi-center study of the impacts of parathyroidectomy (PTX) after or before kidney transplantation on allograft outcomes. A total of 63 patients who underwent PTX after kidney transplantation were identified. Deterioration in eGFR by more than 25% at 1 month after PTX occurred in 20% of the patients. The baseline eGFR was significantly lower in impairment group than nonimpairment group [adjusted odds ratio (OR) 0.87, 95% confidence interval (CI) 0.77-0.99, P = 0.033]. Low iPTH concentration after PTX was also a significant risk factor for the renal impairment (OR 0.96, CI 0.94 0.99, P = 0.009). A total of 37 patients who underwent PTX before transplantation were identified. Thirty-six percent of the patients had persistent hyperparathyroidism by 1 year after transplantation. A high iPTH level before PTX was a significant risk factor for persistent post-transplant hyperparathyroidism (adjusted OR 1.002, CI 1.000-1.005, P = 0.039). Finally, eGFR values during the first 5 years after transplantation were significantly lower in the patients who underwent PTX at less than 1 year after transplantation, than the pretransplant PTX patients (P = 0.032). As PTX after kidney transplantation has a risk of deterioration of allograft function, pretransplant PTX should be considered for patients with severe hyperparathyroidism, who could undergo post-transplant PTX. PMID- 23020186 TI - Syntheses and structures of closely related copper(I) complexes of tridentate (2 pyridylmethyl)imine and (2-pyridylmethyl)amine ligands and their use in mediating atom transfer radical polymerizations. AB - A series of five copper(I) bromide complexes of tridentate (N,N,L) pyridine-imine and pyridine-amine ligands with a third amine, ether, or thioether neutral donor was synthesized and utilized in the atom transfer radical polymerization of styrene. The ligand design illustrated a systematic approach to the development of copper complexes for use in ATRP. Variations in the nature of the ligand impacted the solid state structures of the complexes. A mononuclear [CuBr(L)] complex was observed for L = pyridine-amine-amine, whereas complexes of L = pyridine-imine-amine and -thioether formed dinuclear [CuBr(L)](2) structures with a central 10-membered ring. A doubly-bromide-bridged dimer was revealed for the [CuBr(L)] complex of L = pyridine-imine-ether and a polymeric species for [CuBr(L)], where L = pyridine-imine-amine and the imine-amine spacer was extended from two to three carbon atoms. In the application of these complexes to the ATRP of styrene, the redox potentials of the complexes were found to be one indicator of ATRP efficiency. Of the series presented, two complexes in particular provided fast polymerization rates and good to excellent molecular weight control. In both of these complexes, the ligand contained all nitrogen-based donor moieties. PMID- 23020187 TI - Human very small embryonic-like cells generate skeletal structures, in vivo. AB - Human very small embryonic-like (hVSEL) cells are a resident population of multipotent stem cells in the bone marrow involved in the turnover and regeneration of tissues. The levels of VSEL cells in blood are greatly increased in response to injury, and they have been shown to repair injured tissues. Adult hVSEL cells, SSEA-4(+)/CD133(+)/CXCR4(+)/Lin(-)/CD45(-), express the pluripotency markers (Oct-4 and Nanog) and may be able to differentiate into cells from all 3 germ lineages. hVSEL cells isolated from blood by apheresis following granulocyte colony-stimulating factor mobilization were fractionated and enriched by elutriation and fluorescence activated cell sorting. Collagen sponge scaffolds containing 2,000-30,000 hVSEL cells were implanted into cranial defects generated in SCID mice. Analysis by microcomputed tomography showed that a cell population containing VSEL cells produced mineralized tissue within the cranial defects compared with controls at 3 months. Histologic studies showed significant bone formation and cellular organization within the defects compared with cellular or scaffold controls alone. Antibodies to human leukocyte antigens demonstrated that the newly generated tissues were of human origin. Moreover, human osteocalcin was identified circulating in the peripheral blood. There was evidence that some level of hVSEL cells migrated away from the defect site, using quantitative real time polymerase chain reaction to detect for human-specific Alu sequences. This study demonstrates that hVSEL cells are able to generate human bone tissue in a mouse model of skeletal repair. These studies lay the foundation for future cell based regenerative therapies for osseous and connective tissue disorders, including trauma and degenerative conditions, such as osteoporosis, fracture repair, and neoplastic repair. PMID- 23020188 TI - gamma-secretase inhibitors prevent overgrowth of transplanted neural progenitors derived from human-induced pluripotent stem cells. AB - Although transplanted pluripotent stem cell-derived neurons can contribute to functional recovery in animal models of Parkinson's disease, the risk of tumor formation hinders clinical applications of this approach. Removing undifferentiated cells from the donor population is critical to reduce tumorigenesis. Moreover, immature neural progenitors in transplants can proliferate unpredictably, resulting in neural overgrowth and long-term risks of compressing the surrounding host tissue. Because Notch signaling plays a role in maintaining the multipotency and proliferative capacity of neural progenitors, we used gamma-secretase inhibitors (GSIs) to dampen Notch signaling in human-induced pluripotent stem cell-derived neural progenitors before transplantation and examined the effects on the growth of proliferative grafts. We observed a marked reduction in the percentage of dividing cells and increased neuronal maturation in GSI-treated samples in vitro. Next, grafts were transplanted into the striata of nonobese diabetic/severe combined immune deficiency mice. Histological analyses performed 8 weeks after the operation showed that grafts pretreated with GSIs--N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester or compound E--were significantly smaller than control samples. Immunohistologic analyses revealed that briefly treating the donor population with GSIs not only reduced the graft volume, but also altered the composition of the graft; control grafts showed neural overgrowth with numerous PAX6+ and Ki67+ neural rosettes, whereas GSI-treated samples developed into mature neuronal grafts containing primarily Tubbeta3+ cells. These results suggest that pretreating potentially proliferative progenitors with GSIs may improve the safety of cell replacement therapies using pluripotent stem cells. PMID- 23020189 TI - Multiplexed detection of mRNA using porosity-tuned hydrogel microparticles. AB - Transcriptional profiling, which is directly or indirectly associated with expressed protein levels, has been used in various applications including clinical prognosis and pharmaceutical investigation of drug activities. Although the widely used reverse transcription polymerase chain reaction (RT-PCR) allows for the quantification of absolute amounts of mRNA (mRNA) from inputs as small as a single cell, it is an indirect detection method that requires the amplification of cDNA copies of target mRNAs. Here, we report the quantification of unmodified full-length transcripts, using poly(ethylene) glycol diacrylate (PEGDA) hydrogel microparticles synthesized via stop flow lithography (SFL). We show that PEG600 serves as an effective porogen to allow for the capture of large (~1000-3700 nt long) mRNAs. Our relatively simple hydrogel-based mRNA detection scheme uses a multibiotinylated universal label probe and provides assay performance (limit of detection of ~6 amol of an in-vitro-transcribed model target) comparable to an existing commercial bead-based technology that uses branched DNA (bDNA) signal amplification. We also demonstrate a 3-plex mRNA detection, without cross reactivity, using shape-encoded "intraplex" hydrogel microparticles. Our ability to tune the porosity of encoded hydrogel microparticles expands the utility of this platform to now quantify biomacromolecules ranging in size from large mRNAs to small miRNAs. PMID- 23020191 TI - Palladium-catalyzed regioselective [3 + 2] annulation of internal alkynes and iodo-pyranoquinolines with concomitant ring opening. AB - A regioselective tandem synthesis of highly functionalized pyrrolo[1,2 a]quinolines has been developed through a novel strategy by palladium-catalyzed [3 + 2] annulation of iodo-pyranoquinolines and internal alkynes with subsequent ring opening. Pyranoquinoline with n-alkyl substitution at the 3-position leads to the formation of pyrrolo-acridones via [3 + 2] annulations/ring opening and successive intramolecular cross-aldol condensation. PMID- 23020194 TI - Plant diversity controls arthropod biomass and temporal stability. AB - Understanding the linkages among species diversity, biomass production and stability underlies effective predictions for conservation, agriculture and fisheries. Although these relationships have been well studied for plants and, to a lesser extent, consumers, relationships among plant and consumer diversity, productivity, and temporal stability remain relatively unexplored. We used structural equation models to examine these relationships in a long-term experiment manipulating plant diversity and enumerating the arthropod community response. We found remarkably similar strength and direction of interrelationships among diversity, productivity and temporal stability of consumers and plants. Further, our results suggest that the frequently observed relationships between plant and consumer diversity occur primarily via changes in plant production leading to changed consumer production rather than via plant diversity directly controlling consumer diversity. Our results demonstrate that extinction or invasion of plant species can resonate via biomass and energy flux to control diversity, production and stability of both plant and consumer communities. PMID- 23020192 TI - Patients with chronic kidney disease are at an elevated risk of dementia: a population-based cohort study in Taiwan. AB - BACKGROUND: Chronic kidney disease (CKD) is more prevalent in Taiwan than in most countries. This population-based cohort study evaluated the dementia risk associated with CKD. METHODS: Using claims data of 1,000,000 insured residents covered in the universal health insurance of Taiwan, we selected 37049 adults with CKD newly diagnosed from 2000-2006 as the CKD cohort. We also randomly selected 74098 persons free from CKD and other kidney diseases, frequency matched with age, sex and the date of CKD diagnosed. Incidence and hazard ratios (HRs) of dementia were evaluated by the end of 2009. RESULTS: Subjects in the CKD cohort were more prevalent with comorbidities than those in the non-CKD cohort (p <0.0001). The dementia incidence was higher in the CKD cohort than in the non-CKD cohort (9.30 vs. 5.55 per 1,000 person-years), with an overall HR of 1.41 (95% confidence interval (CI), 1.32-1.50), controlling for sex, age, comorbidities and medicaitions. The risk was similar in men and women but increased sharply with age to an HR of 133 (95% CI, 68.9-256) for the elderly. However, the age-specific CKD cohort to non-CKD cohort incidence rate ratio decreased with age, with the highest ratio of 16.0 (95% CI, 2.00-128) in the youngest group. Among comorbidities and medications, alcoholism and taking benzodiazepines were also associated with dementia with elevated adjusted HRs of 3.05 (95% CI 2.17-4.28) and 1.23 (95% CI 1.14-1.32), respectively. CONCLUSIONS: Patients with CKD could have an elevated dementia risk. CKD patients with comorbidity deserve attention to prevent dementia. PMID- 23020195 TI - Direct imaging of complex nano- to microscale interfaces involving solid, liquid, and gas phases. AB - Surfaces with special wetting properties not only can efficiently repel or attract liquids such as water and oils but also can prevent formation of biofilms, ice, and clathrate hydrates. Predicting the wetting properties of these special surfaces requires detailed knowledge of the composition and geometry of the interfacial region between the droplet and the underlying substrate. In this work we introduce a 3D quantitative method for direct nanoscale visualization of such interfaces. Specifically, we demonstrate direct nano- to microscale imaging of complex fluidic interfaces using cryostabilization in combination with cryogenic focused ion beam milling and SEM imaging. We show that application of this method yields quantitative information about the interfacial geometry of water condensate on superhydrophilic, superhydrophobic, and lubricant-impregnated surfaces with previously unattainable nanoscale resolution. This type of information is crucial to a fundamental understanding as well as the design of surfaces with special wetting properties. PMID- 23020190 TI - Traumatic brain injury-associated coagulopathy. AB - Traumatic injury is a common cause of coagulopathy, primarily due to blood loss and hemodilution secondary to fluid resuscitation. Traumatic injury-associated coagulopathy often follows a course of transition from hyper- to hypocoagulable state exemplified in disseminated intravascular coagulation. The incidence of coagulopathy is significantly higher in patients with traumatic brain injury (TBI), especially those with penetrating trauma compared to injury to the trunk and limbs. This occurs despite the fact that patients with isolated TBI bleed less and receive restricted volume load of fluids. TBI-associated coagulopathy is extensively documented to associate with poor clinical outcomes, but its pathophysiology remains poorly understood. Studies in the past have shown that brain tissue is highly enriched in key procoagulant molecules. This review focuses on the biochemical and cellular characteristics of these molecules and pathways that could make brain uniquely procoagulant and prone to coagulopathy. Understanding this unique procoagulant environment will help to identify new therapeutic targets that could reverse a state of coagulopathy with minimal impacts on hemostasis, a critical requirement for neurosurgical treatments of TBI. PMID- 23020196 TI - Tuning the reactivity of difluoromethyl sulfoximines from electrophilic to nucleophilic: stereoselective nucleophilic difluoromethylation of aryl ketones. AB - A stereoselective synthesis of enantiomerically enriched difluoromethyl tertiary alcohols by tuning the reactivity of difluoromethyl sulfoximines from electrophilic to nucleophilic difluoromethylating agents is reported. The key feature of this chemistry is the diastereoselective addition of the difluoromethyl sulfoximine to the prochiral carbon of the ketone. The present method was used to prepare enantiomerically enriched difluoromethyl secondary alcohols and difluorinated analogues of the natural products gossonorol and boivinian B, demonstrating the potency of the method. PMID- 23020197 TI - Multifocal meningioangiomatosis in a 3-year-old patient. AB - Meningioangiomatosis consists of benign hamartomatous lesions of the brain and the leptomeninges, which typically present with seizure. Management is predicated on resection and control of seizures with medication. Lesions are typically solitary. Multifocal meningioangiomatosis is extremely rare, with only 2 cases reported in adults and none in children. The authors report the first case, to their knowledge, of multifocal meningioangiomatosis in a child. This unique case highlights therapeutic challenges associated with these lesions and demonstrates that multifocality is possible in the pediatric population. This finding has implications for diagnosis and follow-up for children afflicted with these tumors. PMID- 23020198 TI - Hyperascorbaemia in dogs admitted to a teaching hospital intensive care unit. AB - OBJECTIVE: To determine whether or not dogs develop a deficiency of ascorbic acid during hospitalisation in an intensive care unit. METHODS: Blood samples were collected daily for up to three days from dogs hospitalised in an intensive care unit for 36 to 72 hours (n = 16) or e72 hours (n = 20) and from healthy dogs (n = 13). Plasma total ascorbic acid concentrations were measured using a colorimetric method involving a reaction between ascorbic acid, 2,6 dichlorophenol-indophenol, thiourea and dinitrophenyl hydrazine. Additionally, clinical data were recorded for each patient. RESULTS: Dogs hospitalised for e72 hours had significantly greater plasma ascorbic acid concentrations on day 3 compared to days 1 and 2. There was no difference in plasma ascorbic acid concentrations between days 1 and 2 for dogs hospitalised for 36 to 72 hours. Plasma ascorbic acid concentrations were significantly greater for each day of sampling for the hospitalised dogs compared to the control dogs. CLINICAL SIGNIFICANCE: Plasma ascorbic acid concentrations appear to increase during hospitalisation, and supplementation may not be indicated in dogs hospitalised in an intensive care unit. PMID- 23020199 TI - One-year follow-up of combined parent and child intervention for young children with ADHD. AB - Efficacies of the Incredible Years (IY) interventions are well-established in children with oppositional defiant disorder (ODD) but not among those with a primary diagnosis of attention-deficit/hyperactivity disorder (ADHD). We sought to evaluate 1-year follow-up outcomes among young children with ADHD who were treated with the IY interventions. Four- to 6-year-olds with ADHD (n = 49, 73% male) participated in 6 months of treatment using the IY parent and child interventions. Immediate posttreatment results indicated improvements in parenting, children's externalizing and attention problems, and social contact at school. At 1-year follow up, 22 of 27 variables that showed significant posttreatment effects demonstrated maintenance to 1-year follow up. Children with higher ODD symptoms at baseline showed more improvement in oppositionality and total behavior problems, and their mothers showed more improvement on harsh discipline scores. Approximately 70 to 75% of children were reported by their parents and teachers to fall below clinical cutoffs on measures of externalizing symptoms at the 1-year follow up (compared to 50% at baseline), and more than 50% fell below clinical cutoffs on measures of hyperactivity and inattentiveness (all were in the clinical range at baseline). Children with ADHD who were treated with the IY parent and child treatment programs showed maintenance of treatment effects 1 year after treatment. PMID- 23020200 TI - Diffuse CK7, CAM5.2 and BerEP4 positivity in pagetoid squamous cell carcinoma in situ (pagetoid Bowen's disease) of the perianal region: a mimic of extramammary Paget's disease. PMID- 23020201 TI - Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white adipose tissue. AB - Insulin sensitivity deteriorates with age, but mechanisms remain unclear. Age related changes in the function of subcutaneous white adipose tissue (sWAT) are less characterized than those in visceral WAT. We hypothesized that metabolic alterations in sWAT, which in contrast to epididymal WAT, harbors a subpopulation of energy-dissipating UCP1+ brown adipocytes, promote age-dependent progression toward insulin resistance. Indeed, we show that a predominant consequence of aging in murine sWAT is loss of 'browning'. sWAT from young mice is histologically similar to brown adipose tissue (multilocular, UCP1+), but becomes morphologically white by 12 months of age. Correspondingly, sWAT expression of ucp1 precipitously declines (~300-fold) between 3 and 12 months. Loss continues into old age (24 months) and is inversely correlated with the development of insulin resistance. Additional age-dependent changes in sWAT include lower expression of adbr3 and higher expression of maoa, suggesting reduced local adrenergic tone as a potential mechanism. Indeed, treatment with a beta3 adrenergic agonist to compensate for reduced tone rescues the aged sWAT phenotype. Age-related changes in sWAT are not explained by the differences in body weight; mice subjected to 40% caloric restriction for 12 months are of body weight similar to 3-month-old ad lib fed mice, but display sWAT resembling that of age-matched ad lib fed mice (devoid of brown adipose-like morphology). Overall, findings identify the loss of 'browning' in sWAT as a new aging phenomenon and provide insight into the pathogenesis of age-associated metabolic disease by revealing novel molecular changes tied to systemic metabolic dysfunction. PMID- 23020202 TI - Cellular therapy promotes endogenous stem cell repair. AB - Cellular transplantation for cardiac repair has emerged as an exciting treatment option for patients with myocardial infarction (MI) and heart failure. Animal models of post-infarction left ventricular remodeling have demonstrated an improvement in left ventricular (LV) function, decrease in scar size, and amelioration of adverse cardiac remodeling after stem cell transplantation. These beneficial effects occur despite minimal engraftment and negligible differentiation of transplanted cells. Evidence of the heart capability to self renew continues to mount; however, the extent to which this occurs is still unclear. Although there is a specific population of cardiac stem cells capable of differentiating into cardiomyocytes, they alone are not capable of fully regenerating tissue damaged by MI. Therefore, paracrine mechanisms may be responsible for activating endogenous stem cells to promote regeneration and prevent apoptosis. These structural beneficial effects may reduce regional wall stresses, consequently leading to long-term host myocardium gene/protein expression changes, which may subsequently result in improvement in LV function. PMID- 23020203 TI - Gases and volatile compounds associated with micro-organisms in blown pack spoilage of Brazilian vacuum-packed beef. AB - This study correlated the composition of the spoilage bacterial flora with the main gaseous and volatile organic compounds (VOCs) found in the package headspace of spoiled, chilled, vacuum-packed meat. Fifteen chilled, vacuum-packed beef samples, suffering from blown pack spoilage, were studied using 16S rRNA clone sequencing. More than 50% of the bacteria were identified as lactic acid bacteria (LAB), followed by clostridia and enterobacteria. Fifty-one volatile compounds were detected in the spoiled samples. Although the major spoilage compounds were identified as alcohols and aldehydes, CO2 was identified as the major gas in the spoiled samples by headspace technique. Different species of bacteria contribute to different volatile compounds during meat spoilage. LAB played an important role in blown pack deterioration of the Brazilian beef studied. SIGNIFICANCE AND IMPACT OF THE STUDY: The data generated by this study provided useful information to correlate the microbial contamination of Enterobacteriaceae, lactic acid bacteria and Clostridium with the VOC and gaseous compound production to define, in a faster manner, not only the type of contamination, but also to prevent it. PMID- 23020204 TI - Effect of Fructose and glucose on glycation of beta-lactoglobulin in an intermediate-moisture food model system: analysis by liquid chromatography-mass spectrometry (LC-MS) and data-independent acquisition LC-MS (LC-MS(E)). AB - To evaluate the effect of glucose and fructose on the glycation of beta lactoglobulin (beta-Lg) in intermediate-moisture food (IMF), model systems consisting of beta-Lg, glucose/fructose/sorbitol, glycerol, and water were established. All systems were stored at 25 and 35 degrees C for 2 months. The progress of the Maillard reaction and the mass change of beta-Lg were investigated by the browning assay and gel electrophoresis, respectively. Meanwhile, liquid chromatography-mass spectrometry (LC-MS) and data-independent acquisition LC-MS (LC-MS(E)) were used to monitor the glycation extent and the glycated sites of beta-Lg. The results indicated that glucose had a higher reaction activity of glycation than fructose, but both sugars had similar preference on the glycation site for beta-Lg. The ranking order from high to low for the 9 detected glycated sites was L 1, K 91 > K 47 > K 70, K 77, K 83, K 100 > K 75 > K 135 for both sugars. PMID- 23020205 TI - Electrochemiluminescence of the [Ru(bpy)3]2+ complex: the coreactant effect of PAMAM dendrimers in an aqueous medium. AB - Electrogenerated chemiluminescence (ECL) from aqueous solutions of tris(2,2' bipyridine)ruthenium(II), [Ru(bpy)(3)](2+), in the presence of PAMAM G1.5 and G4.5 dendrimers, was observed without the addition of coreactants. The ECL efficiency, Phi(ECL), was enhanced with the addition of increasing amounts of G1.5 dendrimer. Indeed, the ECL efficiency for the [Ru(bpy)(3)](2+)/G1.5 dendrimer became about 10 times higher than that for the [Ru(bpy)(3)](2+)/ oxalate anion system. However, the ECL efficiency in the presence of the G4.5 dendrimer was smaller than that for the G1.5 dendrimer at concentrations similar to those for G1.5 with identical medium conditions. Besides, the addition of NaCl at a given concentration of G1.5 dendrimer decreased the ECL efficiency. The results of Phi(ECL) were interpreted by taking into account the coreactant effect and the electrostatic (long-range and short-range) interactions between the ruthenium(II) complex and the electric field of the dendrimer surface. Standard formal potentials of the [Ru(bpy)(3)](3+/2+) couple in the presence of G1.5 and G4.5 dendrimers were also determined. PMID- 23020206 TI - Wafer-scale pattern transfer of metal nanostructures on polydimethylsiloxane (PDMS) substrates via holographic nanopatterns. AB - In this paper, we report on a cost-effective and simple, nondestructive pattern transfer method that allows the fabrication of metallic nanostructures on a polydimethylsiloxane (PDMS) substrate on a wafer scale. The key idea is to use holographic nanopatterns of a photoresist (PR) layer as template structures, where a metal film is directly deposited in order to replicate the nanopatterns of the PR template layer. Then, the PDMS elastomer is molded onto the metal film and the metal/PDMS composite layer is directly peeled off from the PR surface. Many metallic materials including Ti, Al, and Ag were successfully nanopatterned on PDMS substrates by the pattern transfer process with no use of any adhesion promoter layer or coating. In case of Au that has poor adhesion to PDMS material, a salinization of the metal surface with 3-(aminopropyl)-triethoxysilane (APTES) monolayer promoted the adhesion and led to successful pattern transfer. A series of adhesion tests confirmed the good adhesion of the transferred metal films onto the molded PDMS substrates, including scotch-tape and wet immersion tests. The inexpensive and robust pattern transfer approach of metallic nanostructures onto transparent and flexible PDMS substrates will open the new door for many scientific and engineering applications such as micro-/nanofluidics, optofluidics, nanophotonics, and nanoelectronics. PMID- 23020207 TI - MRI findings in 232 horses with lameness localized to the metacarpo(tarso)phalangeal region and without a radiographic diagnosis. AB - Two hundred and thirty-two horses with lameness localized to the metacarpo(tarso)phalangeal (MCP/MTP) region without a radiographic diagnosis were evaluated. All horses had high-field magnetic resonance (MR) imaging of the MCP/MTP region performed for the lame limb and the contralateral limb for comparison. There were 46 horses that had bilateral abnormalities in the forelimbs; 27 of these horses were not lame in the contralateral limb at the time of examination. Bilateral hind limb abnormalities were observed in 37 horses; 22 horses were not lame in the contralateral limb. Soft tissue abnormalities alone were observed in 218 limbs (162 horses). Subchondral bone and articular cartilage abnormalities alone were observed in 43 limbs (34 horses). A combination of soft tissue, subchondral bone, and cartilage abnormalities were observed in 64 limbs (36 horses). The distribution of primary abnormalities was as follows; oblique distal sesamoidean ligament desmitis (73 limbs in 56 horses), straight distal sesamoidean ligament desmitis (44 limbs in 38 horses), chronic subchondral bone injuries (15 limbs in 12 horses), suspensory ligament branch desmitis (14 limbs in 12 horses), collateral ligament desmitis (12 limbs in 12 horses), tendonitis of the superficial and deep digital flexor tendons (10 limbs in 10 horses), osteochondral defects greater than 1 cm (nine limbs in six horses), osteochondral defects less than 1 cm (eight limbs in seven horses), bone marrow lesions (six limbs in five horses), intersesamoidean ligament desmitis (five limbs in four horses). MR imaging is useful in diagnosing bone and soft tissue injuries when radiographs and ultrasound fail to yield a diagnosis. PMID- 23020208 TI - Single-fraction stereotactic body radiotherapy for spinal metastases from renal cell carcinoma. AB - OBJECT: Stereotactic body radiotherapy (SBRT) has emerged as an important treatment option for spinal metastases from renal cell carcinoma (RCC) as a means to overcome RCC's inherent radioresistance. The authors reviewed the outcomes of SBRT for the treatment of RCC metastases to the spine at their institution, and they identified factors associated with treatment failure. METHODS: Fifty-seven patients (88 treatment sites) with RCC metastases to the spine received single fraction SBRT. Pain relief was based on the Brief Pain Inventory and was adjusted for narcotic use according to the Radiation Therapy Oncology Group protocol 0631. Toxicity was scored according to Common Toxicity Criteria for Adverse Events version 4.0. Radiographic failure was defined as infield or adjacent (within 1 vertebral body [VB]) failure on follow-up MRI. Multivariate analyses were performed to correlate outcomes with the following variables: epidural, paraspinal, single-level, or multilevel disease (2-5 sites); neural foramen involvement; and VB fracture prior to SBRT. Kaplan-Meier analysis and Cox proportional hazards modeling were used for statistical analysis. RESULTS: The median follow-up and survival periods were 5.4 months (range 0.3-38 months) and 8.3 months (range 1.5-38 months), respectively. The median time to radiographic failure and unadjusted pain progression were 26.5 and 26.0 months, respectively. The median time to pain relief (from date of simulation) and duration of pain relief (from date of treatment) were 0.9 months (range 0.1-4.4 months) and 5.4 months (range 0.1-37.4 months), respectively. Multivariate analyses demonstrated that multilevel disease (hazard ratio [HR] 3.5, p = 0.02) and neural foramen involvement (HR 3.4, p = 0.02) were correlated with radiographic failure; multilevel disease (HR 2.3, p = 0.056) and VB fracture (HR 2.4, p = 0.046) were correlated with unadjusted pain progression. One patient experienced Grade 3 nausea and vomiting; no other Grade 3 or 4 toxicities were observed. Twelve treatment sites (14%) were complicated by subsequent vertebral fractures. CONCLUSIONS: Stereotactic body radiotherapy for RCC metastases to the spine offers fast and durable pain relief with minimal toxicity. Stereotactic body radiotherapy seems optimal for patients who have solitary or few spinal metastases. Patients with neural foramen involvement are at an increased risk for failure. PMID- 23020209 TI - Independent predictors of survival and the impact of repeat surgery in patients undergoing surgical treatment of spinal metastasis. AB - OBJECT: Surgery for spinal metastasis is considered palliative, and postoperative survival is often less than a year. Recurrence of metastatic lesions is quite common, and it remains unclear whether repeat surgery is effective. In this study, the authors assessed independent predictors for survival at 6 months, 1 year, and 2 years after surgery, and examined whether repeat surgery for recurrence of spinal metastasis influenced survival rates. METHODS: Retrospective review of the electronic medical records was performed to identify a consecutive population of adult patients who underwent surgery for spinal metastasis during the period 2005-2011. Utilizing a Cox proportional hazard regression model, the authors assessed independent predictors and risk factors for survival at 6 months, 1 year, and 2 years after surgery. In addition, the impact of repeat surgery on survival was specifically assessed via multivariable analysis. RESULTS: A total of 99 patients were included in the final analysis. The overall mean postoperative duration of survival was 9.6 months. In addition to previously identified predictors of survival (preoperative ambulation, Karnofsky Performance Status [KPS], radiotherapy, primary cancer type, presence of extraspinal metastasis, and number of spinal segments with metastasis), pain on presentation and body mass index (BMI) of 25-30 were both independently associated with survival. Patients with recurrence who underwent repeat surgery had longer mean survival times than patients with recurrence who did not undergo repeat surgery (19.6 months vs 12.8 months, respectively). Repeat surgery was also independently associated with higher survival rates on multivariate analysis. Follow-up KPS was significantly higher in patients who underwent repeat surgery as well. CONCLUSIONS: In addition to confirming previously identified predictors of survival following surgery for spinal metastasis, the authors identified BMI and pain on presentation as independent predictors of survival. They also found that repeat surgery may be a viable option in patients with metastatic recurrence and may offer prolonged survival, likely due to improved functionality, mitigating complications associated with immobility. PMID- 23020210 TI - Tumors at the lateral portion of the C1-2 interlaminar space compressing the spinal cord by rotation of the atlantoaxial joint: new aspects of spinal cord compression. AB - The authors describe 2 patients with C-2 nerve root tumors in whom the lesions were located bilaterally in the lateral portions of the C1-2 interlaminar space and compressed the spinal cord when the atlantoaxial joint was rotated. The patients were adult men with neurofibromatosis. Each presented with clumsiness of both hands and motor weakness of the extremities accompanied by spastic gait. Magnetic resonance imaging of the cervical spine performed with the neck in the neutral position showed tumors at the bilateral lateral portion of the C1-2 interlaminar space without direct compression of the spinal cord. The spinal cord exhibited an I-shaped deformity at the same level as the tumors in one case and a trapezoidal deformity at the same level as the tumors in the other case. Computed tomography myelography and MRI on rotation of the cervical spine revealed bilateral intracanal protrusion of the tumors compressing the spinal cord from the lateral side. The tumors were successfully excised and occipitocervical fusion was performed. The tumors were pushed out into the spinal canal from the bilateral lateral portion of the interlaminar spaces due to rotation of the atlantoaxial joint. This was caused by a combination of posteromedial displacement of the lateral mass on the rotational side of the atlas and narrowing of the lateral portion of the interlaminar space on the contralateral side due to the coupling motion of the lateral bending and extension of the atlas. The spinal cord underwent compression from both lateral sides in a one-way rotation. Without sustained spinal cord compression, intermittent long-term dynamic spinal cord compression from both lateral sides should induce a pathognomonic spinal cord deformity and the onset of paralysis. To the authors' knowledge, there have been no reports of the present conditions-that is, the bilateral protrusion of tumors from the bilateral lateral portion of the C1-2 interlaminar spaces into the spinal canal due to atlantoaxial rotation. PMID- 23020211 TI - Anterior longitudinal ligament release using the minimally invasive lateral retroperitoneal transpsoas approach: a cadaveric feasibility study and report of 4 clinical cases. AB - OBJECT: Traditional procedures for correction of sagittal imbalance via shortening of the posterior column include the Smith-Petersen osteotomy, pedicle subtraction osteotomy, and vertebral column resection. These procedures require wide exposure of the spinal column posteriorly, and may be associated with significant morbidity. Anterior longitudinal ligament (ALL) release using the minimally invasive lateral retroperitoneal approach with a resultant net lengthening of the anterior column has been performed as an alternative to increase lordosis. The objective of this study was to demonstrate the feasibility and early clinical experience of ALL release through a minimally invasive lateral retroperitoneal transpsoas approach, as well as to describe its surgical anatomy in the lumbar spine. METHODS: Forty-eight lumbar levels were dissected in 12 fresh-frozen cadaveric specimens to study the anatomy of the ALL as well as its surrounding structures, and to determine the feasibility of the technique. The lumbar disc spaces and ALL were accessed via the lateral transpsoas approach and confirmed with fluoroscopy in each specimen. As an adjunct, 4 clinical cases of ALL release through the minimally invasive lateral retroperitoneal transpsoas approach were reviewed. Operative technique, results, complications, and early outcomes were assessed. RESULTS: In the cadaveric study, sectioning of the ALL proved to be feasible from the minimally invasive lateral retroperitoneal transpsoas approach. The structures at most immediate risk during this procedure were the aorta, inferior vena cava, iliac vessels, and sympathetic plexus. The mean increase in segmental lumbar lordosis per level of ALL release was 10.2 degrees , while global lumbar lordosis improved by 25 degrees . Each level of ALL release took 56 minutes and produced 40 ml of blood loss on average. Visual analog scale and Oswestry Disability Index scores improved by 9 and 35 points, respectively. There were no cases of hardware failure, and as of yet no complications to report. CONCLUSIONS: This initial experience suggests that ALL release through the minimally invasive lateral retroperitoneal transpsoas approach may be feasible, allows for improvement of lumbar lordosis without the need of an open laparotomy/thoracotomy, and minimizes the tissue disruption and morbidity associated with posterior osteotomies. PMID- 23020212 TI - Qualities of life design measures with chronic illness or disability. AB - PURPOSE: Rehabilitation assessment data influence decisions for the design of preferred lifestyles with a chronic illness or disability (CID). As a result, careful consideration of the source, type and scope of these data is needed in selecting appropriate procedures for their collection and use. This article proposes three essential qualities of data to assess in life design counselling with CID. METHOD: A narrative analytical review approach is applied to synthesize findings from the research on person-oriented approaches to rehabilitation assessments. In addition, illustrative life design data on preferred community living solutions with CID for rehabilitation clients (n = 68) are presented. The concept of life design foregrounds the narrative analytical review on essential qualities of rehabilitation assessments to support life choices with disability. RESULTS: The evidence from a narrative synthesis of the person-oriented assessment literature and community living study suggests that effective life design with CID is enhanced with person-centric, resource enabling and participation focused data. Data that prioritizes personal values for participation enable persons with a disability jurisdiction in their life design choices. CONCLUSION: Life design is a robust concept to understand the purposes for which rehabilitation assessment data are gathered, and the essential qualities for those data. When life design measures have person-centric qualities, people with CID are empowered to construct their own lives. PMID- 23020213 TI - Grb14 mRNA levels during follicular deviation in cattle are higher in granulosa cells of subordinate compared to dominant follicles. AB - The growth factor receptor-bound protein 14 (Grb14) is a cellular adapter protein belonging to the Grb7 family of proteins. Studies with human and rodent cells have demonstrated that Grb14 acts as a negative regulator of tyrosine kinase receptor signalling through the MAPK and PI3K pathways. In cattle, tyrosine kinase receptors are activated during follicular development but the role of Grb14 in this process has not yet been investigated. Therefore, the aim of the present study was to characterize Grb14 mRNA expression in ovarian somatic cells during follicular growth and deviation in cattle. We found Grb14 mRNA expressed in both granulosa and theca cells derived from follicles at different stages of development (3-5 , 6-8, >8 mm in diameter). The abundance of mRNA for Grb14 was higher in granulosa cells of subordinate compared with those from dominant follicles at days 3 and 4 of the follicular wave (p < 0.05). Further, there was a negative correlation between the abundance of mRNA for Grb14 and P450Arom in granulosa cells (R(2) = 0.367; p < 0.05) and between the abundance of mRNA for Grb14 in granulosa cells and concentration of oestradiol in follicular fluid (R(2) = 0.545; p < 0.05). In theca cells, the expression of Grb14 mRNA did not differ between dominant and subordinate follicles (p > 0.05). These findings suggest that Grb14 may play a regulatory role in granulosa cells during follicular deviation in cattle. PMID- 23020214 TI - Application of chromosomal microarray in the evaluation of abnormal prenatal findings. AB - We performed karyotype and array comparative genomic hybridization (aCGH) analyses on 177 prenatal samples, including 162 (92%) samples from fetuses with sonographic anomalies. Overall 12 fetuses (6.8%) had abnormal karyotype and 42 (23.7%) fetuses had abnormal microarray results: 20 (11.3%) with pathogenic copy number variations (CNVs), 16 with CNVs of uncertain clinical significance, 4 with CNVs establishing carrier status for recessive, X-linked, or susceptibility to late onset dominant disease, and two CNVs with pseudomosaicism due to in vitro cultural artifacts. For 23 pregnancies (13%), aCGH contributed important new information. Our results highlight the interpretation challenges associated with CNVs of unclear significance, incidental findings, as well as technical aspects. Array CGH analysis significantly improved the detection of genomic imbalances in prenatal diagnosis of pregnancies with structural birth defects. PMID- 23020215 TI - The Process-Interaction-Model: a common representation of rule-based and logical models allows studying signal transduction on different levels of detail. AB - BACKGROUND: Signaling systems typically involve large, structured molecules each consisting of a large number of subunits called molecule domains. In modeling such systems these domains can be considered as the main players. In order to handle the resulting combinatorial complexity, rule-based modeling has been established as the tool of choice. In contrast to the detailed quantitative rule based modeling, qualitative modeling approaches like logical modeling rely solely on the network structure and are particularly useful for analyzing structural and functional properties of signaling systems. RESULTS: We introduce the Process Interaction-Model (PIM) concept. It defines a common representation (or basis) of rule-based models and site-specific logical models, and, furthermore, includes methods to derive models of both types from a given PIM. A PIM is based on directed graphs with nodes representing processes like post-translational modifications or binding processes and edges representing the interactions among processes. The applicability of the concept has been demonstrated by applying it to a model describing EGF insulin crosstalk. A prototypic implementation of the PIM concept has been integrated in the modeling software ProMoT. CONCLUSIONS: The PIM concept provides a common basis for two modeling formalisms tailored to the study of signaling systems: a quantitative (rule-based) and a qualitative (logical) modeling formalism. Every PIM is a compact specification of a rule based model and facilitates the systematic set-up of a rule-based model, while at the same time facilitating the automatic generation of a site-specific logical model. Consequently, modifications can be made on the underlying basis and then be propagated into the different model specifications - ensuring consistency of all models, regardless of the modeling formalism. This facilitates the analysis of a system on different levels of detail as it guarantees the application of established simulation and analysis methods to consistent descriptions (rule based and logical) of a particular signaling system. PMID- 23020217 TI - Four tandem C-H activations: a sequential C-C and C-O bond making via a Pd catalyzed cross dehydrogenative coupling (CDC) approach. AB - An unprecedented aroylation at the ortho C-H bond with respect to a directing group has been accomplished via a Pd(II)-catalyzed cross dehydrogenative coupling approach using alkylbenzene as the synthetic equivalent of an aroyl moiety. The reaction proceeds through sequential C-C and C-O bond making at the expense of four consecutive C-H bond cleavages (three sp(3) benzylic C-H's and one sp(2) arene C-H) to selectively install an aroyl functionality at the proximal site of substrates containing various directing groups. PMID- 23020216 TI - Searching for clarity in therapy-related myelodysplastic syndrome/acute myeloid leukemia prognostication. PMID- 23020218 TI - The expression of alpha-SMA in the painful traumatic neuroma: potential role in the pathobiology of neuropathic pain. AB - The exact mechanism of neuroma-associated pain is not yet fully understood, thus contributing to the substantial challenge faced in managing patients with painful neuromas. We aimed to observe the expression of alpha smooth muscle actin (alpha SMA) in the painful traumatic neuroma and to investigate its possible roles in the cause of neuroma-associated pain. Its expression is considered to be a useful phenotypic marker for myofibroblast, and may contribute to its increased contractile activity. We collected peripheral neuroma specimens prospectively and subsequently divided them into two groups: painful (n=21) and non-painful (n=27) based on blinded preoperative visual analogue scale (VAS) pain scores. We also harvested normal nerve specimens from the discarded limbs as a control group (n=8). We performed immunohistological studies to observe the expression of alpha SMA in each group, and calculated the expression level by a high-resolution pathological image analysis system. There was no positive staining of alpha-SMA observed in the control group, slight positive staining in the non-painful group, and obviously positive staining in the painful group. Pearson correlation analysis demonstrated that VAS scores were significantly associated with the expression intensity of alpha-SMA (R=0.831; p<0.001). Linear regression analysis indicated that the expression intensity of alpha-SMA was positively related to the scale of VAS (R(2)=0.691, p<0.001). These findings suggest that: 1) expression of alpha-SMA may play certain roles in painful traumatic neuroma, either as a direct cause of neuroma-associated pain or as an indirect marker of local mechanical stimuli, and 2) the presence of alpha-SMA in the painful group may provide rationale for transpositional procedures in the management of traumatic neuroma. The persistent existence of alpha-SMA in the painful group and the correlation with VAS scores may provide insight into the development of new therapeutic strategies. PMID- 23020219 TI - Patchy nanocapsules of poly(vinylferrocene)-based block copolymers for redox responsive release. AB - Nanocapsules composed of a poly(vinylferrocene)-block-poly(methyl methacrylate) shell and a hydrophobic liquid core are prepared in water. The nanocapsule shells display a patchy structure with poly(vinylferrocene) patches with sizes of 25 +/- 3 nm surrounded by poly(methyl methacrylate). The functional nanopatches can be selectively oxidized, thereby influencing the colloidal morphology and introducing polar domains in the nanocapsule shell. The hydrophobic to hydrophilic transition in the redox-responsive nanopatches can be advantageously used to release a hydrophobic payload encapsulated in the core by an oxidation reaction. PMID- 23020220 TI - Comparative phytochemical analysis and antibacterial efficacy of in vitro and in vivo extracts from East Indian sandalwood tree (Santalum album L.). AB - Sandalwood oil has been found in numerous therapeutic applications in traditional medicines such as Chinese traditional medicine and Ayurveda. However, there are no comparative accounts available in the literature that focused on in vitro and in vivo tree sample-derived extracts. Combined dichloromethane and methanol extracts were obtained from in vitro samples, that is, callus, somatic embryo and seedlings, and in vivo from leaves of non-oil-yielding young and oil-yielding matured trees. Phytochemical evaluation of the extracts reveals that the tree is rich in terpenoids, saponin, phenolics and tannins. The antibacterial properties of the five extracts were compared with sandalwood oil by screening against nine Gram-negative and five Gram-positive bacterial strains by disc diffusion, agar spot and TLC bioautography methods. Minimum inhibitory concentration (MIC) for sandalwood oil was determined to be in the range of 0.078-5 MUg ml(-1) for most of the test micro-organisms screened. Bioautography results indicated the presence of potential antimicrobial constituents in somatic embryo extracts and sandalwood oil. Among the extracts screened, the somatic embryo extracts showed the strongest antibacterial activity comparable only with sandalwood oil and matured tree leaves' extract. The findings presented here also suggest that apart from sandalwood oil, other parts of this tree across developmental stages are also enriched with antibacterial principles. SIGNIFICANCE AND IMPACT OF STUDY: This study constitutes the first systematic investigation on phytochemical composition and antimicrobial efficacy of sandalwood tree across in vitro and in vivo developmental stages screened against thirteen bacterial strains by four methods. Using a battery of antimicrobial assay techniques, it is possible to follow the differential bioactive metabolic richness of plant parts, to decipher, for example comparable efficacy of somatic embryo extracts and sandalwood oil. PMID- 23020221 TI - Pitfall in the use of terminal deoxynucleotidyl transferase (TdT) in the cytological diagnosis of lymphoma. PMID- 23020222 TI - Analysis of conifer FLOWERING LOCUS T/TERMINAL FLOWER1-like genes provides evidence for dramatic biochemical evolution in the angiosperm FT lineage. AB - In flowering plants, homologs of the Arabidopsis phosphatidylethanolamine-binding protein (PEBP) FLOWERING LOCUS T (FT) are key components in controlling flowering time. We show here that, although FT homologs are found in all angiosperms with completed genome sequences, there is no evidence to date that FT-like genes exist in other groups of plants. Through phylogeny reconstructions and heterologous expression, we examined the biochemical function of the Picea (spruces) and Pinus (pines) PEBP families - two gymnosperm taxa phylogenetically distant from the angiosperms. We have defined a lineage of gymnosperm PEBP genes, termed the FT/TERMINAL FLOWER1 (TFL1)-like genes, that share sequence characteristics with both the angiosperm FT- and TFL1-like clades. When expressed in Arabidopsis, FT/TFL1-like genes repressed flowering, indicating that the proteins are biochemically more similar to the angiosperm TFL1-like proteins than to the FT like proteins. This suggests that the regulation of the vegetative-to reproductive switch might differ in gymnosperms compared with angiosperms. Molecular evolution studies suggest that plasticity at exon 4 contributes to the divergence of FT-like function in floral promotion. In addition, the presence of FT-like genes in basal angiosperms indicates that the FT-like function emerged at an early stage during the evolution of flowering plants as a means to regulate flowering time. PMID- 23020223 TI - Comparative analysis of volatiles in traditionally cured Bourbon and Ugandan vanilla bean ( Vanilla planifolia ) extracts. AB - Traditionally cured vanilla beans ( Vanilla planifolia ) from Madagascar and Uganda were extracted with organic solvents, and the volatiles were separated from the nonvolatile fraction using the solvent assisted flavor evaporation (SAFE) technique. Concentrated vanilla bean extracts were analyzed using GC-MS and GC-O. Two hundred and forty-six volatile compounds were identified using the Automated Mass Spectral Deconvolution and Identification System (AMDIS) software, of which 13 were confirmed with authentic compounds from commercial sources and the others were tentatively identified on the basis of calibrated linear retention indices and the comparison of deconvoluted mass spectra with the in house and/or NIST spectra databases. Vanillin was the most abundant constituent followed by guaiacol. The total concentration of the volatile compounds, excluding vanillin, was 301 mg/kg for Bourbon and 398 mg/kg for Ugandan vanilla bean extracts. Analytical comparison between the two vanilla bean extracts was discussed. Seventy-eight compounds were identified as odor-active compounds in the vanilla bean extracts with 10 confirmed with authentic references. It was found that there were substantial analytical differences in the odor-active compounds of the two extracts. PMID- 23020224 TI - Common genetic variants of the beta2-adrenergic receptor affect its translational efficiency and are associated with human longevity. AB - beta-adrenoceptors are the common pharmacological targets for the treatment of cardiovascular diseases and asthma. Genetic modifications of beta-adrenergic system in engineered mice affect their lifespan. Here, we tested whether genes encoding for key components of the beta-adrenergic signaling pathway are associated with human longevity. We performed a 10-year follow-up study of the Chinese longitudinal healthy longevity survey. The Han Chinese population in this study consisted of 963 long-lived and 1028 geography-matched young individuals. Sixteen SNPs from ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 were selected and genotyped. Two SNPs, rs1042718 (C/A) and rs1042719 (G/C), of ADRB2 in linkage disequilibrium (D' = 1.0; r2 = 0.67) were found to be associated with enhanced longevity in men in two geographically isolated populations. Bonferroni-corrected P-values in a combined analysis were 0.00053-0.010. Men with haplotype A-C showed an increased probability to become centenarians (the frequency of A-C in long lived and young individuals are 0.332 and 0.250, respectively, OR = 1.49, CI 95% = 1.17-1.88, P = 0.0007), in contrast to those with haplotype C-G (the frequency of C-G in long-lived and young individuals are 0.523 and 0.635, respectively, OR = 0.63, CI 95% = 0.51-0.78, P = 0.000018). The permuted P-values were 0.00005 and 0.0009, respectively. ADRB2 encodes the beta2-adrenergic receptor; the haplotype A-C markedly reduced its translational efficiency compared with C-G (P = 0.002) in transfected HEK293 cells. Thus, our data indicate that enhanced production of beta2-adrenergic receptors caused by genetic variants is inversely associated with human lifespan. PMID- 23020226 TI - Nuclear magnetic resonance of hyperpolarized fluorine for characterization of protein-ligand interactions. AB - Fluorine NMR spectroscopy is widely used for detection of protein-ligand interactions in drug discovery because of the simplicity of fluorine spectra combined with a relatively high likelihood for a drug molecule to include at least one fluorine atom. In general, an important limitation of NMR spectroscopy in drug discovery is its sensitivity, which results in the need for unphysiologically high protein concentrations and large ligand:protein ratios. An enhancement in the (19)F signal of several thousand fold by dynamic nuclear polarization allows for the detection of submicromolar concentrations of fluorinated small molecules. Techniques for exploiting this gain in signal to detect ligands in the strong-, intermediate-, and weak-binding regimes are presented. Similar to conventional NMR analysis, dissociation constants are determined. However, the ability to use a low ligand concentration permits the detection of ligands in slow exchange that are not easily amenable to drug screening by traditional NMR methods. The relative speed and additional information gained may make the hyperpolarization-based approach an interesting alternative for use in drug discovery. PMID- 23020225 TI - Recurrent aseptic meningitis in association with Kikuchi-Fujimoto disease: case report and literature review. AB - BACKGROUND: Kikuchi Fujimoto disease (KFD), or histiocytic necrotising lymphadenitis, is a benign and self-limiting condition characterised by primarily affecting the cervical lymph nodes. Recurrent aseptic meningitis in association with KFD is extremely rare and remains a diagnostic challenge. CASE PRESENTATION: We report a 28-year-old man who presented 7 episodes of aseptic meningitis associated with KFD over the course of 7 years. Histopathological findings of enlarged lymph nodes led to the diagnosis of KFD. The patient's headache and lymphadenopathy spontaneously resolved without any sequelae. CONCLUSIONS: A diagnosis of KFD should be considered when enlarged cervical lymph nodes are observed in patients with recurrent aseptic meningitis. A long-term prognosis remains uncertain, and careful follow-up is preferred. PMID- 23020227 TI - Early deterioration of cerebrospinal fluid dynamics in a neonatal piglet model of intraventricular hemorrhage and posthemorrhagic ventricular dilation. AB - OBJECT: The optimal management of neonatal intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilation is challenging. The importance of early treatment has been demonstrated in a recent randomized study, involving early ventricular irrigation and drainage, which showed significant cognitive improvement at 2 years. The objective of this study was to define the changes in CSF absorption capacity over time in a neonatal piglet model of IVH. METHODS: Ten piglets (postnatal age 9-22 hours) underwent intraventricular injection of homologous blood. A ventricular access device was inserted 7-10 days later. Ventricular dilation was measured by ultrasonography. Serial constant flow infusion studies were performed through the access device from Week 2 to Week 8. RESULTS: Seven piglets survived long term, 43-60 days, and developed ventricular dilation; this reached a maximum by Week 6. There was no significant difference in baseline intracranial pressure throughout this period. The resistance to CSF outflow, R(out), increased from 63.5 mm Hg/ml/min in Week 2 to 118 mm Hg/ml/min in Week 4. Although R(out) decreased after Week 5, the ventriculomegaly persisted. CONCLUSIONS: In this neonatal piglet model, reduction in CSF absorptive capacity occurs early after IVH and accompanies progressive and irreversible ventriculomegaly. This suggests that early treatment of premature neonates with IVH is desirable. PMID- 23020228 TI - Cochinchina momordica seed extract induces apoptosis and cell cycle arrest in human gastric cancer cells via PARP and p53 signal pathways. AB - Cochinchina momordica seed is the dried ripe seed of Momordica cochinchinensis (Lour.) Spreng, which is a kind of fruit and consumed for dietary as well as medicinal uses. In this study, using the human SGC7901 and MKN-28 gastric cancer cell lines, we explored the anticancer activity of the extract from cochinchina momordica seed (ECMS). ECMS inhibited significantly the survival rates of SGC7901 and MKN-28 cells in concentration- and time-dependent manners by MTT assay. The typical apoptotic morphological changes were observed by Hoechst 33258 dye assay after SGC7901 and MKN-28 cells were treated with ECMS for 48 h. Flow cytometry analysis revealed that ECMS-treatment blocked the cells at the S phase of cell cycle. Furthermore, the protein expression levels of poly (ADP-ribose) polymerase (PARP) and Bcl-2 were downregulated notably by ECMS-treatment, whereas those of Fas/Fas-associated death domain, p53, and Bax were upregulated in SGC7901 cells. ECMS dramatically enhanced the enzymatic activities of caspase-3 and caspase-9 whilst slightly increased caspase-8 activity. Taken together, this study demonstrated that ECMS exerted cytotoxic activities via PARP and p53 signal pathways in the human gastric cancer cells. PMID- 23020229 TI - Smoking, von Willebrand factor and ADAMTS-13 in healthy males. AB - While von Willebrand factor (vWF) has been reported to be elevated in smokers, there are no reports on the effects of smoking on its cleaving protease ADAMTS 13, particularly in subjects of Arab ethnicity. This study was conducted to determine the effects of smoking on vWF and ADAMTS-13 antigen and activity levels in Arab males. Venous blood samples from 80 smoking (at rest) and 80 non-smoking healthy males were collected after asking subjects to fast and refrain from smoking for 8 hours. Similar sampling was done for 40 smokers (acute smokers), who were asked to smoke one cigarette immediately before blood collection. Plasma was used to measure ADAMTS-13 antigen and activity levels, as well as vWF antigen and collagen binding activity levels using commercial ELISA kits. Compared to non smokers, ADAMTS-13 and vWF activities were significantly lower in smokers at rest (p < 0.05). Acute smokers had significantly higher levels of vWF activity and ADAMTS-13 antigen and activity levels (p < 0.01), compared to smokers at rest. Our results suggest that high vWF activity is accompanied by an increase in ADAMTS-13 activity as a natural physiological mechanism to degrade the elevated vWF molecules. If not followed by a subsequent smoke, the activities of both proteins subside. It is possible that the repeated increase in vWF and constant degradation by ADAMTS-13 results in lower overall levels of both proteins in smokers (at rest) compared to nonsmokers who do not experience a similar (repeated) injury to the endothelium. PMID- 23020230 TI - Fibrinogen and d-dimer in contrasting relation with measures of wave reflection and arterial stiffness. AB - INTRODUCTION: The relationship between the results of coagulation tests and measures of arterial stiffness or wave reflection has been investigated in different diseases. This exploratory study aimed at the evaluation of similar associations in healthy individuals. MATERIAL AND METHODS: Pulse wave analysis of reconstructed aortic pressure waveform for the central augmentation index, augmentation pressure and pulse pressure, and digital volume pulse for the stiffness index were measured at supine rest in 91 healthy volunteers (54.1 +/- 8.5 years; 56 female). Standard coagulation tests for the d-dimer and fibrinogen concentrations were performed in fasting venous blood. RESULTS: In univariate linear regression d-dimer and fibrinogen concentrations were significantly and positively, although weakly, associated with measures related to pulse wave analysis. Multivariate linear regression adjusted to subjects' age, resting pulse rate and mean blood pressure showed that the d-dimer concentration was significantly related to central augmentation index (p = 0.014), augmentation pressure (p = 0.003) and pulse pressure (p = 0.029) whereas fibrinogen was linked to the stiffness index (p = 0.04). Higher concentrations of d-dimers and fibrinogen are associated with increased arterial stiffness and faster pulse wave propagation in healthy people and the observed associations are independent of typical determinants of the shapes of pulse pressure waveforms like age, pulse rate and mean blood pressure. CONCLUSIONS: The independent relationships between the results of the coagulation tests and pulse wave analysis suggest that the existence of such associations may indicate a biologically plausible phenomenon. PMID- 23020231 TI - Serum retinol binding protein-4 and neutrophil gelatinase-associated lipocalin are interrelated in pancreatic cancer patients. AB - OBJECTIVES: Pancreatic cancer has an extremely dismal clinical course and high fatality rate. Knowing that, adipokines could regulate insulin resistance, inflammation, immunity and carcinogenesis. Accordingly, an understanding of adipokines in relation to pancreatic cancer could be useful to improve disease outcome. We aimed to determine serum retinol binding protein-4 (RBP-4) and neutophil gelatinase-associated lipocalin (NGAL) levels in pancreatic cancer patients. Moreover, we assessed their association with tumor severity and with each other. METHODS: A total of 23 pancreatic cancer patients and 20 healthy controls were enrolled. Fifteen of the pancreatic cancer patients underwent Whipple resection and were examined before and after operation. Serum glucose, insulin, lipid profile, CA19-9, RBP-4 and NGAL were estimated by ELISA. RESULTS: Significant elevation in serum concentrations of RBP-4 (64.4 +/- 5.6 ng/ml) and NGAL (142(80-235) ng/ml) at p < 0.001 was found in pancreatic cancer patients. Both RBP-4 and NGAL were significantly lower after operation than before operation. Moreover, NGAL was elevated in advanced pathological T stage. Interestingly, RBP-4 and NGAL levels were positively correlated (r = 0.484, p = 0.05) and they are associated with some of the lipid profile parameters. CONCLUSIONS: Elevated serum RBP-4 and NGAL are associated with pancreatic cancer. They were positively interrelated; highlighting the possible interplay between them in pancreatic cancer. PMID- 23020232 TI - CSF and serum AFP in patients without gestational or neoplastic AFP-secretion. AB - BACKGROUND: The measurement of alpha-fetoprotein (AFP) in cerebrospinal fluid (CSF) is important for the diagnosis of intracranial or intraspinal trophoblastic tumors. The current study was performed to establish reference values for AFP in CSF and to explore the relationship of CSF AFP and serum AFP in patients. MATERIAL AND METHODS: CSF samples were obtained from 351 inpatients admitted because of various neurological diseases, excluding those who were pregnant, had active liver disease, or who had trophoblastic or other malignant tumors. In 256 of the 351 patients, paired samples of CSF and serum were obtained. Both CSF AFP and serum AFP were measured. The 97.5th percentile and maximum value of CSF AFP were obtained. The CSF AFP and serum AFP concentrations in each of the 256 paired samples were compared. RESULTS: The 97.5th percentile and maximum value of CSF AFP concentration for overall participants were 1.042 and 1.950 g/L, respectively. The CSF AFP concentration was found to be higher than the simultaneous serum AFP concentration only in 1.6% (4/256) of participants. CONCLUSIONS: The reference value determined in this study for CSF AFP is significantly lower than that usually used in clinical practice. A CSF AFP concentration higher than the simultaneous serum AFP concentration but lower than the upper reference limit does not necessarily suggest abnormal intrathecal AFP secretion. PMID- 23020234 TI - What does coping mean to the worker with pain-related disability? A qualitative study. AB - PURPOSE: Pain coping is important in health outcomes. In the current literature, pain coping usually means those goal-directed strategies to manage pain. The study goal was to explore what personal meaning "coping" has for work-disabled individuals in pain. METHOD: Qualitative, in depth interviews with follow-up verification interviews were conducted with 13 volunteers who were off work and in rehabilitation for chronic pain from a musculoskeletal injury. The two main questions were: (1) How did participants understand the term "coping with pain"; and (2) how did they come to this understanding of coping. The theoretical approach was social phenomenology and data were analyzed using thematic analysis. RESULTS: The dominant theme was that pain coping is an intrinsic and life defining attitude and belief. This understanding primarily arose through early modeling by parents and significant others. Secondary theme was that coping is practical strategies to manage or eliminate pain. This arose through more current interactions with health care providers and others in the social network. CONCLUSIONS: Researchers' and clinicians' view of coping may not always match the views held by individuals with chronic pain. This might impact on the effectiveness of interventions designed to modify coping behaviors, and alternative ways of intervening may be needed. PMID- 23020235 TI - Gold nanostructures on flexible substrates as electrochemical dopamine sensors. AB - In this study, we fabricated Au nanowires (NWs), nanoslices (NSs), and nanocorals (NCs) on flexible polyethylene terephthalate (PET) substrates via direct current electrochemical depositions. Without any surface modification, the Au nanostructures were used as the electrodes for dopamine (DA) sensing. Among them, the Au NW electrode performed exceptionally well. The determined linear range for DA detection was 0.2-600 MUM (N = 3) and the sensitivity was 178 nA/MUM cm(2), while the detection limit was 26 nM (S/N = 3). After 10 repeated measurements, 95% of the original anodic current values were maintained for the nanostructured electrodes. Sequential additions of citric acid (CA, 1 mM), uric acid (UA, saturated), and ascorbic acid (AA, 1 MUM) did not interfere the amperometric response from the addition of DA (0.1 MUM). PMID- 23020233 TI - The revised classification of eukaryotes. AB - This revision of the classification of eukaryotes, which updates that of Adl et al. [J. Eukaryot. Microbiol. 52 (2005) 399], retains an emphasis on the protists and incorporates changes since 2005 that have resolved nodes and branches in phylogenetic trees. Whereas the previous revision was successful in re introducing name stability to the classification, this revision provides a classification for lineages that were then still unresolved. The supergroups have withstood phylogenetic hypothesis testing with some modifications, but despite some progress, problematic nodes at the base of the eukaryotic tree still remain to be statistically resolved. Looking forward, subsequent transformations to our understanding of the diversity of life will be from the discovery of novel lineages in previously under-sampled areas and from environmental genomic information. PMID- 23020236 TI - Integrating next-generation sequencing into the diagnostic testing of inherited cancer predisposition. AB - The clinical application of next-generation sequencing (NGS) as a diagnostic tool has become increasingly evident. The coupling of NGS technologies with new genomic sequence enrichment methods has made the sequencing of panels of target genes technically feasible, at the same time as making such an approach cost effective for diagnostic applications. In this article, we discuss recent studies that have applied NGS in the diagnostic setting in relation to hereditary cancer. PMID- 23020237 TI - Piezo-phototronic effect enhanced visible and ultraviolet photodetection using a ZnO-CdS core-shell micro/nanowire. AB - The piezo-phototronic effect is about the use of the piezoelectric potential created inside some materials for enhancing the charge carrier generation or separation at the metal-semiconductor contact or pn junction. In this paper, we demonstrate the impact of the piezo-phototronic effect on the photon sensitivity for a ZnO-CdS core-shell micro/nanowire based visible and UV sensor. CdS nanowire arrays were grown on the surface of a ZnO micro/nanowire to form a ZnO-CdS core shell nanostructure by a facile hydrothermal method. With the two ends of a ZnO CdS wire bonded on a polymer substrate, a flexible photodetector was fabricated, which is sensitive simultaneously to both green light (548 nm) and UV light (372 nm). Furthermore, the performance of the photon sensor is much enhanced by the strain-induced piezopotential in the ZnO core through modulation of the Schottky barrier heights at the source and drain contacts. This work demonstrates a new application of the piezotronic effect in photon detectors. PMID- 23020238 TI - Alpha activity marking word boundaries mediates speech segmentation. AB - This study examined the neurophysiological mechanisms of speech segmentation, the process of parsing the continuous speech signal into isolated words. Individuals listened to sequences of two monosyllabic words (e.g. gas source) and non-words (e.g. nas sorf). When these phrases are spoken, talkers usually produce one continuous s-sound, not two distinct s-sounds, making it unclear where one word ends and the next one begins. This ambiguity in the signal can also result in perceptual ambiguity, causing the sequence to be heard as one word (failed to segment) or two words (segmented). We compared listeners' electroencephalogram activity when they reported hearing one word or two words, and found that bursts of fronto-central alpha activity (9-14 Hz), following the onset of the physical /s/ and end of phrase, indexed speech segmentation. Left-lateralized beta activity (14-18 Hz) following the end of phrase distinguished word from non-word segmentation. A hallmark of enhanced alpha activity is that it reflects inhibition of task-irrelevant neural populations. Thus, the current results suggest that disengagement of neural processes that become irrelevant as the words unfold marks word boundaries in continuous speech, leading to segmentation. Beta activity is likely associated with unifying word representations into coherent phrases. PMID- 23020239 TI - Anti-breast cancer agents from Chinese herbal medicines. AB - Chinese Herbal Medicines (CHM) have been used in disease prevention and treatment for centuries in China. A number of anti-breast cancer agents isolated from CHM recently, showed very interesting structures, although some of the mechanism of action is not quite clear. These unique chemical structures could be an important information resource for new anti-breast cancer drugs' design and discovery. This review summarizes these findings on anti-breast cancer agents from CHM. PMID- 23020240 TI - Histopathological study of lymph node lesions in the acute phase of Kawasaki disease. AB - AIMS: To review the histopathological features of cervical LNs, and to clarify the changes in extracervical LNs, in acute Kawasaki disease (KD). METHODS AND RESULTS: The samples were obtained from 33 patients with acute-phase KD. We divided the LNs into those in the neck (n = 23) and those located elsewhere (n = 26), and investigated them histologically. Changes occur not only in the cervical region, but also in LNs throughout the body. Most lymphadenopathy is non specific, caused by sinus expansion and paracortical zone enlargement, but there are also necrotic lesions of various sizes that can be surmised to result from ischaemic changes in some LNs. Necrotic foci start to develop immediately below the capsule, and are accompanied by fibrin thrombi in the small vessels and perivascular nuclear debris. Especially in the case of cervical LNs with necrosis, a high degree of non-purulent inflammation develops in the LN capsule and surrounding connective tissue. CONCLUSIONS: In addition to lymphadenopathy with necrosis, KD should be suspected if there is non-purulent inflammation of the LN capsule and/or surrounding connective tissue featuring mainly monocytes/macrophages. PMID- 23020241 TI - Occurrence and distribution of Naegleria species from thermal spring environments in Taiwan. AB - Naegleria spp. is a free-living amoeba that can be found in the natural environment. A number of Naegleria spp. can cause fatal infections in the central nervous system in humans and animals, and the most important source of infection is through direct water contact. In this study, water samples from various thermal springs were taken from four thermal spring areas. Naegleria spp. was detected via culture confirmation and molecular taxonomic identification. Among the 60 samples obtained, Naegleria spp. was identified in 26 (43.3%) samples. The identified species included Naegleria australiensis, Naegleria gruberi, Naegleria lovaniensis and Naegleria mexicana. The presence of living Naegleria spp. was significantly associated with elevated pH value in the water sample. SIGNIFICANCE AND IMPACT OF STUDY: In this study, we examined the presence of living Naegleria spp. in thermal spring waters in south-eastern Taiwan. Naegleria spp. was isolated and culture-confirmed from thermal spring water. Naegleria fowleri was not found in all water samples, and Naegleria australiensis was the most common Naegleria genotype. PMID- 23020242 TI - Affective communication deficits associated with cerebellar degeneration. AB - The cerebellum has extensive connections with the frontal lobes. Cerebellar injury has been reported to induce frontal-executive cognitive dysfunction and blunting of affect. We examined a patient with idiopathic cerebellar degeneration with impaired family relationships attributed to an "emotional disconnection." Examination revealed ataxia, dysmetria, and adiadochokinesia more severe on the left and frontal-executive dysfunction; memory and cognitive functions were otherwise normal. Testing of emotional communication included assessments of emotional semantic knowledge, emotional prosody, and emotional facial expressions. Comprehension was normal but expression was severely impaired. Cerebellar dysfunction can cause a defect in facial and prosodic emotional communication. PMID- 23020243 TI - QUAliFiER: an automated pipeline for quality assessment of gated flow cytometry data. AB - BACKGROUND: Effective quality assessment is an important part of any high throughput flow cytometry data analysis pipeline, especially when considering the complex designs of the typical flow experiments applied in clinical trials. Technical issues like instrument variation, problematic antibody staining, or reagent lot changes can lead to biases in the extracted cell subpopulation statistics. These biases can manifest themselves in non-obvious ways that can be difficult to detect without leveraging information about the study design or other experimental metadata. Consequently, a systematic and integrated approach to quality assessment of flow cytometry data is necessary to effectively identify technical errors that impact multiple samples over time. Gated cell populations and their statistics must be monitored within the context of the experimental run, assay, and the overall study. RESULTS: We have developed two new packages, flowWorkspace and QUAliFiER to construct a pipeline for quality assessment of gated flow cytometry data. flowWorkspace makes manually gated data accessible to BioConductor's computational flow tools by importing pre-processed and gated data from the widely used manual gating tool, FlowJo (Tree Star Inc, Ashland OR). The QUAliFiER package takes advantage of the manual gates to perform an extensive series of statistical quality assessment checks on the gated cell sub-populations while taking into account the structure of the data and the study design to monitor the consistency of population statistics across staining panels, subject, aliquots, channels, or other experimental variables. QUAliFiER implements SVG based interactive visualization methods, allowing investigators to examine quality assessment results across different views of the data, and it has a flexible interface allowing users to tailor quality checks and outlier detection routines to suit their data analysis needs. CONCLUSION: We present a pipeline constructed from two new R packages for importing manually gated flow cytometry data and performing flexible and robust quality assessment checks. The pipeline addresses the increasing demand for tools capable of performing quality checks on large flow data sets generated in typical clinical trials. The QUAliFiER tool objectively, efficiently, and reproducibly identifies outlier samples in an automated manner by monitoring cell population statistics from gated or ungated flow data conditioned on experiment-level metadata. PMID- 23020245 TI - Influence of the degree of roasting on the antioxidant capacity and genoprotective effect of instant coffee: contribution of the melanoidin fraction. AB - The roasting process induces chemical changes in coffee beans that strongly affect the antioxidant activity of coffee. In this study, the polyphenol and melanoidin contents and the antioxidant activity of three instant coffees with different roasting degrees (light, medium, and dark) were assessed. Coffee brews were separated into fractions, and the potential biological activity of the melanoidins was evaluated by simulating their gastrointestinal digestion. Total antioxidant capacity, hydroxyl radical scavenger activity, lipid peroxidation inhibition capacity, and protection against DNA oxidative damage (in vitro and ex vivo genoprotective effects) were determined. We report that instant coffee has a high total antioxidant capacity and protective effect against certain oxidative stress biomarkers (lipids and DNA), although this capacity decreases with the roasting degree. Our study confirms the hypothesis that several of the polyphenols present in coffee may become part of the melanoidins generated during roasting. Furthermore, the elevated genoprotective effect of melanoidin-digested fractions is noteworthy. PMID- 23020244 TI - Common mechanisms for calorie restriction and adenylyl cyclase type 5 knockout models of longevity. AB - Adenylyl cyclase type 5 knockout mice (AC5 KO) live longer and are stress resistant, similar to calorie restriction (CR). AC5 KO mice eat more, but actually weigh less and accumulate less fat compared with WT mice. CR applied to AC5 KO results in rapid decrease in body weight, metabolic deterioration, and death. These data suggest that despite restricted food intake in CR, but augmented food intake in AC5 KO, the two models affect longevity and metabolism similarly. To determine shared molecular mechanisms, mRNA expression was examined genome-wide for brain, heart, skeletal muscle, and liver. Significantly more genes were regulated commonly rather than oppositely in all the tissues in both models, indicating commonality between AC5 KO and CR. Gene ontology analysis identified many significantly regulated, tissue-specific pathways shared by the two models, including sensory perception in heart and brain, muscle function in skeletal muscle, and lipid metabolism in liver. Moreover, when comparing gene expression changes in the heart under stress, the glutathione regulatory pathway was consistently upregulated in the longevity models but downregulated with stress. In addition, AC5 and CR shared changes in genes and proteins involved in the regulation of longevity and stress resistance, including Sirt1, ApoD, and olfactory receptors in both young- and intermediate-age mice. Thus, the similarly regulated genes and pathways in AC5 KO and CR mice, particularly related to the metabolic phenotype, suggest a unified theory for longevity and stress resistance. PMID- 23020247 TI - Multicomponent approach in the synthesis of 2,2,6-trisubstituted morpholine derivatives. AB - An efficient synthesis of 2,2,6-trisubstituted morpholine is described which involves a multicomponent process by simply mixing epichlorohydrin, N bromosuccinimide, nosyl amide, and an olefin. The products contain chloride handles which are suitable for further modification. PMID- 23020246 TI - Pramipexole use and the risk of pneumonia. AB - BACKGROUND: Patients with Parkinson's disease have an elevated risk of pneumonia and randomized trials suggest that this risk may be increased with the dopamine agonist pramipexole. It is uncertain whether pramipexole or other dopamine agonists increase the risk of pneumonia. METHODS: We used the United Kingdom's General Practice Research Database (GPRD) to identify users of anti-parkinsonian drugs, 40-89 years of age, between 1997 and 2009. Using a nested case-control approach, all incident cases hospitalised for pneumonia were matched with up to ten controls selected among the cohort members. Rate ratios (RR) and 95% confidence intervals (CI) of pneumonia associated with current use of dopamine agonists were estimated using conditional logistic regression, adjusted for covariates. RESULTS: The cohort included 13,183 users of anti-parkinsonian drugs, with 1,835 newly diagnosed with pneumonia during follow-up (rate 40.9 per 1,000 per year). The rate of pneumonia was not increased with the current use of pramipexole (RR 0.76; 95% CI: 0.57-1.02), compared with no use. The use of pramipexole was not associated with an increased rate of pneumonia when compared with all other dopamine agonists collectively (RR 0.85; 95% CI: 0.62-1.17). CONCLUSIONS: The use of pramipexole does not appear to increase the risk of pneumonia. PMID- 23020248 TI - Oxygen vacancy-assisted coupling and enolization of acetaldehyde on CeO2(111). AB - The temperature-dependent adsorption and reaction of acetaldehyde (CH(3)CHO) on a fully oxidized and a highly reduced thin-film CeO(2)(111) surface have been investigated using a combination of reflection-absorption infrared spectroscopy (RAIRS) and periodic density functional theory (DFT+U) calculations. On the fully oxidized surface, acetaldehyde adsorbs weakly through its carbonyl O interacting with a lattice Ce(4+) cation in the eta(1)-O configuration. This state desorbs at 210 K without reaction. On the highly reduced surface, new vibrational signatures appear below 220 K. They are identified by RAIRS and DFT as a dimer state formed from the coupling of the carbonyl O and the acyl C of two acetaldehyde molecules. This dimer state remains up to 400 K before decomposing to produce another distinct set of vibrational signatures, which are identified as the enolate form of acetaldehyde (CH(2)CHO-). Furthermore, the calculated activation barriers for the coupling of acetaldehyde, the decomposition of the dimer state, and the recombinative desorption of enolate and H as acetaldehyde are in good agreement with previously reported TPD results for acetaldehyde adsorbed on reduced CeO(2)(111) [Chen et al. J. Phys. Chem. C 2011, 115, 3385]. The present findings demonstrate that surface oxygen vacancies alter the reactivity of the CeO(2)(111) surface and play a crucial role in stabilizing and activating acetaldehyde for coupling reactions. PMID- 23020249 TI - Upregulated ataxia-telangiectasia group D complementing gene correlates with poor prognosis in patients with esophageal squamous cell carcinoma. AB - The ataxia-telangiectasia group D complementing gene (ATDC) plays significant roles in various human cancers. However, the clinical significance of ATDC in esophageal squamous cell carcinoma (ESCC) has not been investigated. The ATDC messenger RNA level of 40 paired ESCC and nonneoplastic tissues were evaluated using quantitative real-time polymerase chain reaction, 10 pairs of which were also used for Western blot analysis. In addition, immunohistochemical staining was performed to detect the ATDC expression in 118 paraffin-embedded cancerous and matched nonneoplastic tissues, and the correlation of ATDC expression with the clinicopathological parameters and prognosis of the ESCC patients was analyzed. The quantitative real-time polymerase chain reaction, immunohistochemical staining, and Western blot results demonstrated that the expression level of ATDC was significantly higher in ESCC tissue than in matched noncancerous tissues. Both ATDC messenger RNA and protein expression in the ESCC tissue were significantly correlated with tumor differentiation, stage, and lymph node metastasis. However, there was no significant difference in ATDC expression based on patient age or gender. Moreover, the results of both univariate and multivariate analyses showed that increased ATDC expression was correlated with a shorter 5-year survival time for ESCC patients after surgery. We concluded that increased ATDC expression is associated with poor clinical outcomes and that this marker might be a useful indicator for prognosis and a promising target for therapy in ESCC patients. PMID- 23020250 TI - Secondary health conditions and spinal cord injury: an uphill battle in the journey of care. AB - PURPOSE: To understand the journey of care in the prevention and management of secondary health conditions (SHCs) following spinal cord injury (SCI). METHOD: This was a case study design with 'Ontario' as the case. The Network Episode Model was used as the conceptual framework. Data sources included in depth interviews with persons with SCI, care providers, and policy and decision makers. Document analysis was also conducted on relevant materials and policies. Key informants were selected by purposeful sampling as well as snowball sampling to provide maximum variation. Data analysis was an iterative process and involved descriptive and interpretive analyses. A coding structure was developed based on the conceptual framework which allowed for free nodes when emerging ideas or themes were identified. RESULTS: Twenty-eight individuals were interviewed (14 persons with SCI and 14 persons representing care providers, community advocacy organization representatives, system service delivery administrators and policy makers). A major over-arching domain that emerged from the data was the concept of 'fighting'. Eleven themes were identified: at the micro-individual level: (i) social isolation and system abandonment, (ii) funding and equitable care, (iii) bounded freedom and self-management; at the meso care provider level: (iv) gender and caregiving strain, (v) help versus disempowerment, (vi) holistic care thinking outside the box, (vii) poor communication and coordination of care; and at the macro health system level: (viii) fight for access and availability, (ix) models of care tensions, (x) private versus public tensions and (xi) rigid rules and policies. CONCLUSIONS: Findings suggest that the journey is challenging and a persistent uphill struggle for persons with SCI, care providers, and community based advocates. If we are to make significant gains in minimizing the incidence and severity of SHCs, we need to tailor efforts at the health system level. IMPLICATIONS FOR REHABILITATION: * Secondary health conditions are problematic for individuals with a spinal cord injury (SCI). * This study aimed to understand the journey of care in the prevention and management of secondary health conditions (SHCs) following SCI. * Findings suggest that the journey is challenging and a persistent uphill struggle for persons with SCI, care providers, and community-based advocates. * All stakeholders involved recognized the disparities in access to care and resources that exist within the system. We recommend that if we are to make significant gains in minimizing the incidence and severity of SHCs, we need to tailor efforts at the health system level. PMID- 23020252 TI - A review of the pharmacokinetic profile of transmucosal fentanyl formulations. AB - BACKGROUND AND OBJECTIVES: Breakthrough pain (BTP) is a transitory flare of moderate-to-severe pain that occurs in patients with stable, controlled persistent pain. Management of BTP episodes is difficult because frequency, time to-peak intensity, and duration of episodes vary both within and between individuals. Formulations of fentanyl that use a buccal, sublingual, or nasal transmucosal route of administration have been developed for the treatment of BTP in opioid-tolerant patients with cancer. These formulations allow rapid passage into the bloodstream and avoid first-pass metabolism and, therefore, are more likely to match the time-course of BTP episodes than are oral formulations. The purposes of this analysis were to identify and review published data describing the pharmacokinetic properties of rapid-onset fentanyl formulations and to evaluate these properties in view of the temporal dynamic characteristics of BTP in order to help guide medical practice. METHODS: Relevant publications were searched in the PubMed database from 1998. The plasma drug concentration-time profile of each formulation obtained from the identified studies was adjusted to a consistent scale for comparison. RESULTS: The data revealed that the various transmucosal formulations resulted in three typical plasma fentanyl concentration profiles: (1) type 1: a very rapid rise and short duration; (2) type 2: a rapid increase and sustained intensity; and (3) type 3: a slower onset and longer duration. CONCLUSIONS: Given the substantial variability of BTP episodes experienced by patients, these pharmacokinetic differences may provide useful information for a physician who is selecting a rapid-onset opioid medication for a patient. PMID- 23020251 TI - Recombinant fibronectin matrix mimetics specify integrin adhesion and extracellular matrix assembly. AB - Tissue engineering seeks to create functional tissues and organs by integrating natural or synthetic scaffolds with bioactive factors and cells. Creating biologically active scaffolds that support key aspects of tissue regeneration, including the re-establishment of a functional extracellular matrix (ECM), is a challenge currently facing this field. During tissue repair, fibronectin is converted from an inactive soluble form into biologically active ECM fibrils through a cell-dependent process. ECM fibronectin promotes cell processes critical to tissue regeneration and regulates the deposition and organization of other ECM proteins. We previously developed biomimetics of ECM fibronectin by directly coupling the heparin-binding fragment of the first type III repeat of fibronectin (FNIII1H) to the integrin-binding repeats (FNIII8-10). As adhesive substrates, fibronectin matrix mimetics promote cell growth, migration, and contractility through a FNIII1H-dependent mechanism. Here, we analyzed fibronectin matrix mimetic variants designed to include all or part of the integrin-binding domain for their ability to support new ECM assembly. We found that specific modifications of the integrin-binding domain produced adhesive substrates that selectively engage different integrin receptors to, in turn, regulate the amount of fibronectin and collagen deposited into the ECM. The ability of fibronectin matrix mimetics to direct cell-substrate interactions and regulate ECM assembly makes them promising candidates for use as bioactive surfaces, where precise control over integrin-binding specificity and ECM deposition are required. PMID- 23020253 TI - Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT study. AB - OBJECTIVE: The PROMPT study compared efficacy and tolerability of two treatment intensification strategies: adding saxagliptin or uptitrating metformin monotherapy, in patients with type 2 diabetes (T2D) and inadequate glycaemic control on a sub-maximal metformin dose. RESEARCH DESIGN AND METHODS: In this double-blind, 24-week study, metformin-tolerant patients with T2D on metformin monotherapy were randomised to receive fixed-dose metformin 1500 mg/day, plus either add-on saxagliptin 5 mg/day (SAXA-MET) or a two-step metformin uptitration (MET-UP) to a maximum dose (2500 mg/day). CLINICAL TRIAL REGISTRATION: NCT01006590. MAIN OUTCOME MEASURES: Primary: absolute change from baseline in glycated haemoglobin A(1c) (HbA(1c)) (Week 24). Secondary: proportion of patients achieving a therapeutic glycaemic response (Week 24); change from baseline in fasting plasma glucose (Week 24); safety and tolerability. Exploratory analyses comprised three patient-related questionnaires, including the validated 5 dimension Digestive Health Status Index (DHSI). RESULTS: A total of 286 patients were randomised: (SAXA-MET: 147; MET-UP: 139). Baseline mean (SD) HbA(1c): 7.71 (0.85; SAXA-MET); 7.80 (0.82; MET-UP). Adjusted mean reductions from baseline in HbA(1c) (Week 24): -0.47% (SAXA-MET); -0.38% (MET-UP); mean (95% CI) difference in treatment effect, -0.10% (-0.26, 0.07); p = 0.260. The proportion of patients (95% CI) achieving a therapeutic glycaemic response (HbA(1c) < 7%): 43.8% (34.8, 49.6) (SAXA-MET) vs. 35.0% (29.0, 43.8) (MET-UP). Of the five DHSI domains, mean (95% CI) differences were observed for diarrhoea-predominant score (+0.8 [-2.5, 4.0] vs. +7.9 [4.6, 11.2]) and dysmotility score (-0.5 [-2.0, 1.0] vs. +1.9 [0.3, 3.4]), (SAXA-MET and MET-UP, respectively). The most common adverse event was diarrhoea: 6.1% (SAXA-MET) vs. 12.2% (MET-UP). CONCLUSIONS: In metformin-tolerant patients with T2D (inadequately controlled on sub-maximal metformin monotherapy), saxagliptin was well tolerated. Although HbA(1c) reduction was not significantly different between treatment groups, the lower occurrence of gastrointestinal symptoms in the SAXA-MET group suggests that saxagliptin add-on treatment may be a suitable alternative treatment strategy to metformin uptitration. PMID- 23020254 TI - Stoichiometric effect on electrical, optical, and structural properties of composition-tunable In(x)Ga(1-x)As nanowires. AB - Ternary InGaAs nanowires have recently attracted extensive attention due to their superior electron mobility as well as the ability to tune the band gap for technological applications ranging from high-performance electronics to high efficiency photovoltaics. However, due to the difficulties in synthesis, there are still considerable challenges to assess the correlation among electrical, optical, and structural properties of this material system across the entire range of compositions. Here, utilizing a simple two-step growth method, we demonstrate the successful synthesis of composition and band gap tunable In(x)Ga(1-x)As alloy nanowires (average diameter = 25-30 nm) by manipulating the source powder mixture ratio and growth parameters. The lattice constants of each NW composition have been well correlated with the chemical stoichiometry and confirmed by high-resolution transmission electron microscopy and X-ray diffraction. Importantly, the as-grown NWs exhibit well-controlled surface morphology and low defect concentration without any phase segregation in all stoichiometric compositions. Moreover, it is found that the electrical nanowire device performances such as the turn-off and I(ON)/I(OFF) ratios are improved when the In concentration decreases at a cost of mobility degradation. More generally, this work suggests that a careful stoichiometric design is required for achieving optimal nanowire device performances. PMID- 23020255 TI - Entrapment of subtilisin in ceramic sol-gel coating for antifouling applications. AB - Enzymes with antifouling properties are of great interest in developing nontoxic antifouling coatings. A bottleneck in developing enzyme-based antifouling coatings is to immobilize the enzyme in a suitable coating matrix without compromising its activity and stability. Entrapment of enzymes in ceramics using the sol-gel method is known to have several advantages over other immobilization methods. The sol-gel method can be used to make robust coatings, and the aim of this study was to explore if sol-gel technology can be used to develop robust coatings harboring active enzymes for antifouling applications. We successfully entrapped a protease, subtilisin (Savinase, Novozymes), in a ceramic coating using a sol-gel method. The sol-gel formulation, when coated on a stainless steel surface, adhered strongly and cured at room temperature in less than 8 h. The resultant coating was smoother and less hydrophobic than stainless steel. Changes in the coating's surface structure, thickness and chemistry indicate that the coating undergoes gradual erosion in aqueous medium, which results in release of subtilisin. Subtilisin activity in the coating increased initially, and then gradually decreased. After 9 months, 13% of the initial enzyme activity remained. Compared to stainless steel, the sol-gel-coated surfaces with active subtilisin were able to reduce bacterial attachment of both Gram positive and Gram negative bacteria by 2 orders of magnitude. Together, our results demonstrate that the sol gel method is a promising coating technology for entrapping active enzymes, presenting an interesting avenue for enzyme-based antifouling solutions. PMID- 23020256 TI - The value of immunophenotyping hepatocellular adenomas: consecutive resections at one UK centre. AB - AIMS: To determine the utility of immunophenotyping for classification of hepatocellular adenomas resected at one Scottish centre. METHODS AND RESULTS: This study comprised a retrospective review and immunophenotyping of consecutive resected benign hepatocellular tumours. Fifty-five patients (seven men) had 64 adenomas and 26 focal nodular hyperplasias (FNHs) resected. Map-like glutamine synthetase (GS) staining was specific for FNH. Immunophenotyping changed the morphological typing for three adenomas and resolved 16 of 18 unclassified or equivocal cases, revealing GS positivity in these (seven) and four others. Steatotic/liver fatty acid binding protein-deficient adenomas were the commonest type in women (12/29 women, 41%) but were absent from men. Where one of multiple adenomas was morphologically unclassified, there was still a shared immunophenotype. Diffuse CD34 positivity correlated with GS positivity or unclassified status (P < 0.0001). Supervised cluster analysis identified morphological discriminants for FNH and predictors of adenoma type and their insensitivity in predicting GS status. Forty per cent of men and 7% of women with adenomas had a specific adenoma risk, including danazol and portal venopathies. Inflammatory adenomas were associated with metabolic syndrome, steatosis, or alcohol (P = 0.053). Four patients showed carcinoma ex-adenoma. CONCLUSIONS: The distribution of adenoma types in this population matches that in others, and immunoprofiling is required for accurate typing. Carcinoma ex-adenoma is uncommon and fits the published risk profile (large size and GS-positive). PMID- 23020257 TI - The baric probe: a novel long-term implantable intracranial pressure monitor with ultrasound-based interrogation. AB - OBJECT: Prompt diagnosis of shunt malfunction is critical in preventing neurological morbidity and death in individuals with hydrocephalus; however, diagnostic methods for this condition remain limited. For several decades, investigators have sought a long-term, implantable intracranial pressure (ICP) monitor to assist in the diagnosis of shunt malfunction, but efforts have been impeded by device complexity, marked measurement drift, and limited instrumentation lifespan. In the current report, the authors introduce an entirely novel, simple, compressible gas design that addresses each of these problems. METHODS: The device described herein, termed the "baric probe," consists of a subdural fluid bladder and multichannel indicator that monitors the position of an air-fluid interface (AFI). A handheld ultrasound probe is used to interrogate the baric probe in vivo, permitting noninvasive ICP determination. To assess the function of device prototypes, ex vivo experiments were conducted using a water column, and short- and long-term in vivo experiments were performed using a porcine model with concurrent measurements of ICP via a fiberoptic monitor. RESULTS: Following a toe region of approximately 2 cm H(2)O, the baric probe's AFI demonstrated a predictable linear relationship to ICP in both ex vivo and in vivo models. After a 2-week implantation of the device, this linear relationship remained robust and reproducible. Further, changes in ICP were observed with the baric probe, on average, 3 seconds in advance of the fiberoptic ICP monitor reading. CONCLUSIONS: The authors demonstrate "proof-of-concept" and feasibility for the baric probe, a long-term implantable ICP monitor designed to facilitate the prompt and accurate diagnosis of shunt malfunction. The baric probe showed a consistent linear relationship between ICP and the device's AFI in ex vivo and short- and long-term in vivo models. With a low per-unit cost, a reduced need for radiography or CT, and an indicator that can be read with a handheld ultrasound probe that interfaces with any smart phone, the baric probe promises to simplify the care of patients with shunt-treated hydrocephalus throughout both the developed and the developing world. PMID- 23020259 TI - Risk of developmental delay increases exponentially as gestational age of preterm infants decreases: a cohort study at age 4 years. AB - AIM: The aim of the study was to assess the influence of decreasing gestational age on the risk of developmental delay in various domains at age 4 years among children born at a wide range of gestational ages. METHOD: In a community-based cohort, the parents of 1439 preterm-born children (24 0/7 to 35 6/7 wks) and 544 term-born children (38 0/7 to 41 6/7 wks') born in 2002 and 2003 completed the Ages and Stages Questionnaire (ASQ) when their child was 3 years 7 months to 4 years 1 month old. The prevalence rates of abnormal scores on the ASQ-total problems scale were compared in preterm and term-born children and the resulting odds ratios for gestational age groups were calculated and adjusted for social and biological covariates. RESULTS: The prevalence rates of abnormal scores on the ASQ-total problems scale increased with decreasing gestational age: from 4.2% among term-born children to 37.5% among children born at 24-25 weeks' gestation (p<0.001). The risk of an abnormal ASQ-total score increased exponentially with decreasing gestational age compared with children born at term (odds ratio per week of gestation 1.14, 95% confidence interval 1.09-1.19). A similar exponential pattern was seen on all underlying ASQ domains, both before and after adjustment. INTERPRETATION: The risk of developmental delay increases exponentially with decreasing gestational age below 36 weeks' gestation on all developmental domains of the ASQ. Adjustment for covariates did not alter the pattern of exponential increase in developmental risk with decreasing gestational age. We speculate that both direct perinatal cerebral injuries and tropic and maturational brain disturbances are involved. PMID- 23020260 TI - A multiplex RT-PCR for rapid and simultaneous detection of viruses and viroids in chrysanthemum. AB - Chrysanthemum plants are subject to serious virus diseases, so detection and identification of virus pathogens is important to prevent the virus spread. A reliable one-step multiplex RT-PCR was developed to simultaneously detect two viruses and two viriods: chrysanthemum virus B, tomato Aspermy virus, chrysanthemum stunt viroid and chrysanthemum chlorotic mottle viroid. In addition, we investigated the detection limit and the efficiency of single and multiplex RT-PCR assays. The results showed that the multiplex RT-PCR assay proved to be as sensitive as the single one. In conclusion, this technique is potentially useful in routine diagnosis of chrysanthemum viruses and viroids. SIGNIFICANCE AND IMPACT OF STUDY: The multiplex RT-PCR assay described in this study is the first report of simultaneous detection of virus and viroid in chrysanthemum, which provides a fast, convenient, cost-saving way to detect the virus and viroid mixed infections in plants. PMID- 23020258 TI - Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 and the intravascular processing of triglyceride-rich lipoproteins. AB - Lipoprotein lipase (LPL) is produced by parenchymal cells, mainly adipocytes and myocytes, but is involved in hydrolysing triglycerides in plasma lipoproteins at the capillary lumen. For decades, the mechanism by which LPL reaches its site of action in capillaries was unclear, but this mystery was recently solved. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells, 'picks up' LPL from the interstitial spaces and shuttles it across endothelial cells to the capillary lumen. When GPIHBP1 is absent, LPL is mislocalized to the interstitial spaces, leading to severe hypertriglyceridaemia. Some cases of hypertriglyceridaemia in humans are caused by GPIHBP1 mutations that interfere with the ability of GPIHBP1 to bind to LPL, and some are caused by LPL mutations that impair the ability of LPL to bind to GPIHBP1. Here, we review recent progress in understanding the role of GPIHBP1 in health and disease and discuss some of the remaining unresolved issues regarding the processing of triglyceride-rich lipoproteins. PMID- 23020261 TI - Practice effects: a unique cognitive variable. AB - Practice effects are improvements in cognitive test performance due to repeated evaluation with the same or similar test materials. Prior studies have reported that these improvements can vary with age, education/intellect, and disease status. However, additional information is needed about variables that influence practice effects. The current study prospectively quantified short-term practice effects in 268 community-dwelling older adults and compared these practice effects to demographic variables, global cognition, premorbid intellect, depression, and individual cognitive domains. Overall, practice effects were not significantly related to most demographic and clinical characteristics or individual cognitive domains, which was contrary to our hypotheses. However, since practice effects appear to be uninfluenced by many variables that typically affect cognitive scores, they may be a unique and valuable tool that could be applied in a number of diverse patient groups. PMID- 23020262 TI - Influence of cultivar and harvest time on the amounts of isoalliin and methiin in leek (Allium ampeloprasum var. porrum). AB - Extracts of 31 leek cultivars were analyzed using liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to determine the distribution of the two most abundant S-alk(en)yl-l-cysteine sulfoxides (ACSOs) in leek, that is, isoalliin and methiin. The isoalliin concentration of the white shaft and green leaves of the 31 leek cultivars varied from 15 to 53 mg/g dry weight (dw) and from 9 to 45 mg/g dw, respectively, whereas the methiin concentration varied from 3 to 16 mg/g dw and from 1 to 10 mg/g dw, respectively. Leek cultivar and tissue had an effect on the ACSO amounts. Cultivars Artico and Apollo F1 rated highest for the mean isoalliin and methiin concentration, respectively. In general, the whole leek plant of the winter leek cultivars contained a significantly higher ACSO amount than the summer and autumn cultivars. To determine whether this difference was attributed to the cultivar background or time of harvest, ACSOs were also quantitated in nine leek hybrids at four different stages during the next growth season. The amounts of ACSO changed significantly during the growth season, indicating the importance of harvest at specific time moments, although there was still an effect of cultivar on the ACSO amounts. PMID- 23020264 TI - Effectiveness of intravenous dexamethasone versus propofol for pain relief in the migraine headache: a prospective double blind randomized clinical trial. AB - BACKGROUND: There are many drugs recommended for pain relief in patients with migraine headache. METHODS: In a prospective double blind randomized clinical trial, 90 patients (age >= 18) presenting to Emergency medicine Department with Migraine headache were enrolled in two equal groups. We used intravenous propofol (10 mg every 5-10 minutes to a maximum of 80 mg, slowly) and intravenous dexamethasone (0.15 mg/kg to a maximum of 16 mg, slowly), in group I and II, respectively. Pain explained by patients, based on VAS (Visual Analogue Scale) was recorded at the time of entrance to ED, and after injection. Data were analyzed by paired samples t test, using SPSS 16. P < 0.05 was considered to be statistically significant. RESULTS: The mean of reported pain (VAS) was 8 +/- 1.52 in propofol group and 8.11 +/- 1.31 in dexamethasone group at presenting time (P > 0.05). The VAS in propofol group was obviously decreased to 3.08 +/- 1.7, 1.87 +/- 1.28 and 1.44 +/- 1.63 after 10, 20 and 30 minutes of drug injection, respectively. The VAS in dexamethasone group was 5.13 +/- 1.47, 3.73 +/- 1.81 and 3.06 +/- 2 after 10, 20 and 30 minutes of drug injection, respectively. The mean of reported VAS in propofol group was less than dexamethasone group at the above mentioned times (P < 0.05). The reduction of headache in propofol group, also, was very faster than dexamethasone group (P < 0.05). There were no adverse side effects due to administration of both drugs. CONCLUSIONS: Intravenous propofol is an efficacious and safe treatment for patients presenting with Migraine headache to the emergency department. TRIAL REGISTRATION: Clinical Trials IRCT201008122496N4. PMID- 23020263 TI - G-NEST: a gene neighborhood scoring tool to identify co-conserved, co-expressed genes. AB - BACKGROUND: In previous studies, gene neighborhoods-spatial clusters of co expressed genes in the genome-have been defined using arbitrary rules such as requiring adjacency, a minimum number of genes, a fixed window size, or a minimum expression level. In the current study, we developed a Gene Neighborhood Scoring Tool (G-NEST) which combines genomic location, gene expression, and evolutionary sequence conservation data to score putative gene neighborhoods across all possible window sizes simultaneously. RESULTS: Using G-NEST on atlases of mouse and human tissue expression data, we found that large neighborhoods of ten or more genes are extremely rare in mammalian genomes. When they do occur, neighborhoods are typically composed of families of related genes. Both the highest scoring and the largest neighborhoods in mammalian genomes are formed by tandem gene duplication. Mammalian gene neighborhoods contain highly and variably expressed genes. Co-localized noisy gene pairs exhibit lower evolutionary conservation of their adjacent genome locations, suggesting that their shared transcriptional background may be disadvantageous. Genes that are essential to mammalian survival and reproduction are less likely to occur in neighborhoods, although neighborhoods are enriched with genes that function in mitosis. We also found that gene orientation and protein-protein interactions are partially responsible for maintenance of gene neighborhoods. CONCLUSIONS: Our experiments using G-NEST confirm that tandem gene duplication is the primary driver of non random gene order in mammalian genomes. Non-essentiality, co-functionality, gene orientation, and protein-protein interactions are additional forces that maintain gene neighborhoods, especially those formed by tandem duplicates. We expect G NEST to be useful for other applications such as the identification of core regulatory modules, common transcriptional backgrounds, and chromatin domains. The software is available at http://docpollard.org/software.html. PMID- 23020266 TI - The prevalence of gastroesophageal reflux disease among hospital employees. AB - Quantitative estimate of the actual prevalence of the gastroesophageal reflux disease (GERD) is difficult to obtain because most of the patients with heartburn have intermittent symptoms. The aim of this study was to assess the frequency of typical and atypical symptoms suggesting GERD to investigate the association of habits and social conditions reported to lead to reflux in the employees of hospital. A total of 2037 collected forms were assessed. The prevalence of GERD was found to be 21.7% (442). The prevalence of symptoms other than heartburn in employees with and without GERD symptoms were 6.6% versus 3.4% (P < 0.05) for asthma, 27.6% versus 8.3% (P < 0.001) for night cough, 50% versus 19.5% (P < 0.001) for noncardiac chest pain. Dyspeptic complaints were found to be significantly higher among GERD patients (P < 0.001). By multiple logistic regression analysis, female gender (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.03-1.60, P = 0.027), non-steroidal anti-inflammatory drug medication (OR 1.29, 95% CI 1.03-1.60, P = 0.021) and body mass index over 30 (OR 2.26, 95% CI 1.60-3.18, P < 0.001) were independent risk factors associated with GERD symptoms. GERD is a common health problem in Turkey, and its prevalence is similar to that of Western populations with different symptom profiles. Female gender, non-steroidal anti-inflammatory drug, and body mass index >30 kg/m(2) were independent risk factors associated with GERD symptoms. Age, alcohol, coffee, tea, and tobacco smoking do not seem to be risk factors for reflux. PMID- 23020265 TI - Positive association between a glutathione-S-transferase polymorphism and lymphoma in dogs. AB - Glutathione-S-transferase enzymes (GSTs) play an important role in the detoxification of environmental carcinogens. Defective GST genotypes are over represented in human cancers; in particular, low activity GSTT1 genotypes are risk factors for non-Hodgkin lymphoma. We hypothesized that defective GSTT1 genotypes would be associated with lymphoma risk in dogs. To address this, we resequenced the exons, splice junctions, and 3'-UTR of canine GSTT1 in dogs with lymphoma (n = 93) and age-matched unaffected dogs (n = 86). Of 27 canine GSTT1 variants identified, the I2+28 G>A was significantly associated with lymphoma [odds ratio (OR) 6.26, 95% confidence interval (CI), 1.77-22.2], with the AA genotype found in 18.3% of affected dogs but only 3.5% of controls (P = 0.002). This intronic variant was predicted to perturb GSTT1 mRNA splicing, and may increase lymphoma risk by impairing detoxification of environmental chemicals. Confirmation of this finding in a larger population of dogs may support the inclusion of GSTT1 genotyping in epidemiologic studies of canine lymphoma risk. PMID- 23020267 TI - Research design. AB - The development of a good research design permits us to obtain the best research data possible. From the experimental question to the research hypothesis and data collection variables, we can begin to consider the optimal research design. Details pertaining to the selection of the research design are considered within and very much in relation with the knowledge of the researcher and the support of his research group. PMID- 23020268 TI - Leonardo da Vinci's foot: historical evidence of concept. AB - INTRODUCTION: Leonardo da Vinci (1452-1519), world-renowned Italian renaissance master, is known for his contributions to, and broad interests in science and art. The objective of this work is to demonstrate the extent of his science by applying the use of his concepts to current models of foot and ankle mechanics. METHODS: The art and science of Leonardo Da Vinci were extensively analyzed by reviewing his original drawings and hand written notebooks as well as their English translation. Current medical journals including the topics of foot, ankle, and biomechanics were reviewed for modern evidence and application of his concepts. The library of Michigan State University and the electronic library of the Royal Library at Windsor Castle were extensively utilized. RESULTS: From the depths of Santa Maria Nuova Hospital in Florence and Santo Spirito Hospital in Rome, through his commentary and anatomical drawings of around 30 cadaver dissections he performed, Leonardo da Vinci expressed his concept of foot and ankle anatomy and mechanics. He laid forth concepts, which vary little from current theories including those of proportion, statics and joint stability, sesamoid biomechanics, and structural support of the foot. DISCUSSION: Leonardo da Vinci, by combining an interest in anatomy and a gift of genius and artistic ability laid a foundation of foot and ankle anatomy and mechanics that have been applied in modern clinical sciences. Leonardo in this way made important contributions to the practice of foot and ankle orthopedics. PMID- 23020269 TI - Serum D-dimer as a prognostic marker in patients undergoing radiofrequency ablation of colorectal liver metastasis. AB - BACKGROUND: Although traditionally used for coagulation disorders, there has been a recent interest in serum D-dimer as a tumor marker. The aim of this prospective study is to determine its value as a tumor marker in patients with colorectal liver metastasis. PATIENTS AND METHODS: Between January 2000 and October 2007, 242 patients undergoing laparoscopic radiofrequency ablation (RFA) of colorectal liver metastasis were evaluated prospectively. The relationship of D-dimer levels to pre-ablation parameters, recurrence, and survival was prospectively assessed. All data are expressed as mean +/- SEM. RESULTS: Preoperative D-dimer levels correlated with liver tumor volume (p = .04) and CEA (p = .003). D-dimer levels increased by a mean of 11.4 +/- 1.5 folds after RFA on POD#7 and returned to preoperative values in three months. The rate of the elevation of D-dimer values after RFA was related to tumor volume ablated. The median overall survival was six months for patients with preoperative D-dimer > 1,000 ng/ml vs. 32 months for patients with D-dimer < 1,000 ng/ml (p = .02). On multivariate analysis preoperative serum D-dimer was an independent predictor of overall survival along with CEA and liver tumor burden. CONCLUSION: Serum D-dimer levels reflect liver tumor burden and independently predict survival in patients with colorectal liver metastasis undergoing RFA. PMID- 23020270 TI - Effects of caffeic acid phenethyl ester on anastomotic healing in secondary peritonitis. AB - PURPOSE: We aimed to investigate the effects of caffeic acid phenethyl ester (CAPE) on wound healing in left colonic anastomoses in the presence of intraperitoneal sepsis induced by cecal ligation and puncture (CLP) in a rodent model. METHODS: This experimental study was conducted on 48 male Wistar albino rats. The animals were randomly allocated into four groups and a left colonic anastomosis was performed on the day following sham operation or CLP in all rats: (i) sham-operated control group, laparatomy plus cecal mobilization (n = 12) (Group 1), (ii) sham + CAPE group, identical to Group 1 except for CAPE treatment (10 MUmol/kg, intraperitoneally, 30 min before construction of the colonic anastomosis) (n = 12) (Group 2), (iii) CLP group, cecal ligation and puncture (n = 12) (Group 3), and (iv) CLP + CAPE-treated group, 10 MUmol/kg, intraperitoneally, 30 min before the construction of colonic anastomosis (n = 12) (Group 4). On the postoperative day 7, the animals were subjected to relaparotomy for in-vivo measurement of the colonic anastomotic bursting pressure. A colonic segment including the anastomotic site was resected for histopathological evaluation and biochemical analyses of hydroxyproline (Hyp) contents, myeloperoxidase (MPO) acivity, malondialdehyde (MDA) levels, reduced glutathione (GSH) levels, and superoxide dismutase (SOD) activity. Body weight changes were examined. RESULTS: CAPE treatment significantly increased colonic anastomotic bursting pressures (p < .05), colonic anastomotic tissue Hyp contents, and enzymatic and nonenzymatic antioxidant markers (p < .05), and significantly decreased oxidative stress parameters in colonic anastomotic tissues (p < .05). Histopathological scores were significantly better by CAPE administration (p < .05). CONCLUSION: This study clearly showed that CAPE treatment prevented the detrimental effects of intraperitoneal sepsis on colonic anastomotic wound healing. Further clinical studies are required to determine whether CAPE has a useful role in the enhancement of gastrointestinal anastomotic wound healing during particular surgeries in which sepsis-induced organ injury occurs. PMID- 23020271 TI - Limited use of antiseptics in septic surgery. AB - In septic joint surgery, treatment with antiseptics is a standard procedure. Postinfectious degeneration of cartilage often results in early arthritis that necessitates joint replacement, even in young patients. It is still unclear whether antiseptics have only a toxic effect on chondrocytes or also induce late cell death through apoptosis. We hypothesized that commonly used antiseptics (polyhexanide, hydrogen peroxide, and chlorhexidine) induce different stages of apoptosis on human chondrocytes. Human chondrocytes were isolated and cultured. Polyhexanide, hydrogen peroxide, and chlorhexidine were added to the monolayer cultures. Early and late apoptotic cells were analyzed using flow cytometric detection of Annexin V, active caspases, and 7AAD, and fluorescence microscopy using Annexin V and propidium iodide staining. Flow cytometric analysis revealed an increase of Annexin V and active caspases expression of human chondrocytes after incubation with polyhexanide, hydrogen peroxide, and chlorhexidine. Fluorescence microscopy demonstrated a high number of apoptotic cells. Our data show that polyhexanide and chlorhexidine only promote the early stages of apoptosis without any differences in toxicity. Conversely, hydrogen peroxide induces early and later stages of apoptosis on primary human chondrocytes in vitro. PMID- 23020272 TI - Single-stitch telescopic bilioenterostomy in an animal model. AB - BACKGROUND/AIMS: An end-to-side biliodigestive anastomosis is the most common procedure performed in hepato-pancreato-biliary surgery, and this procedure may become technically demanding. A telescopic ureterovesical anastomosis is frequently used in transplant surgery. The aim of this study was to investigate the feasibility of constructing a telescopic biliodigestive anastomosis. METHODOLOGY: The technique-standardization (n = 8) and main study (n = 3) groups were formed from 11 pigs. A single-stitch telescopic anastomosis with a self disposable internal stent was performed in the main study group. The animals were sacrificed at the end of the 4-week follow-up period, and cholangiograms and tissue samples were obtained. Repeated biological, hematological, and biochemical data were recorded. RESULTS: No bilomas or functional biliary strictures were identified in any of the main study group animals. Light microscopy revealed intestinal metaplasia of the biliary epithelium in the portion of the bile duct telescoped inside the intestinal lumen. CONCLUSIONS: Telescopic bilioenterostomy with a single pull-through stitch and a self-disposable stent is quick and reproducible in animal models, and it appears to be free of complications. Further experiments with longer follow-up periods are required to confirm that this anastomotic technique does not lead to episodes of delayed cholangitis or development of adenocarcinoma. PMID- 23020274 TI - Multipole surface plasmon resonances in conductively coupled metal nanowire dimers. AB - We report on the experimental and the theoretical investigation of multipole surface plasmon resonances in metal nanowires conductively connected by small junctions. The influence of a conductive junction on the resonance energies of nanowire dimers was simulated using the finite element method based software CST Microwave Studio and experimentally measured by electron energy-loss spectroscopy in a transmission electron microscope. We extend the analysis of conductively connected structures to higher order multipole modes up to third order, including dark modes. Our results reveal that an increase in junction size does not shift significantly the antibonding modes, but causes a strong blue shift of the bonding modes, leading to an energetic rearrangement of the modes compared to those of a capacitively coupled dimer with similar dimensions. PMID- 23020275 TI - A general chelate-assisted co-assembly to metallic nanoparticles-incorporated ordered mesoporous carbon catalysts for Fischer-Tropsch synthesis. AB - The organization of different nano objects with tunable sizes, morphologies, and functions into integrated nanostructures is critical to the development of novel nanosystems that display high performances in sensing, catalysis, and so on. Herein, using acetylacetone as a chelating agent, phenolic resol as a carbon source, metal nitrates as metal sources, and amphiphilic copolymers as a template, we demonstrate a chelate-assisted multicomponent coassembly method to synthesize ordered mesoporous carbon with uniform metal-containing nanoparticles. The obtained nanocomposites have a 2-D hexagonally arranged pore structure, uniform pore size (~4.0 nm), high surface area (~500 m(2)/g), moderate pore volume (~0.30 cm(3)/g), uniform and highly dispersed Fe(2)O(3) nanoparticles, and constant Fe(2)O(3) contents around 10 wt %. By adjusting acetylacetone amount, the size of Fe(2)O(3) nanoparticles is readily tunable from 8.3 to 22.1 nm. More importantly, it is found that the metal-containing nanoparticles are partially embedded in the carbon framework with the remaining part exposed in the mesopore channels. This unique semiexposure structure not only provides an excellent confinement effect and exposed surface for catalysis but also helps to tightly trap the nanoparticles and prevent aggregating during catalysis. Fischer-Tropsch synthesis results show that as the size of iron nanoparticles decreases, the mesoporous Fe-carbon nanocomposites exhibit significantly improved catalytic performances with C(5+) selectivity up to 68%, much better than any reported promoter-free Fe-based catalysts due to the unique semiexposure morphology of metal-containing nanoparticles confined in the mesoporous carbon matrix. PMID- 23020276 TI - Macroscopic and microscopic study of 1-ethyl-3-methyl-imidazolium acetate-water mixtures. AB - Mixtures of 1-ethyl-3-methyl-imidazolium acetate ([C2mim][OAc]) and water across the entire composition range, from pure [C2mim][OAc] to pure water, have been investigated using density, viscosity, and NMR spectroscopy, relaxometry, and diffusion measurements. These results have been compared to ideal mixing laws for the microscopic data obtained from the NMR results and macroscopic data through the viscosity and density. It was also found that the mixing of the two fluids is exothermal. The proton spectra indicate though that [C2mim][OAc] and water are interacting without the formation of new compounds. The maximal deviations of experimental data from theoretical mixing rules were all found to occur within the range 0.74 +/- 0.06 mol fraction of water, corresponding to approximately three water molecules per [C2mim][OAc] molecule. PMID- 23020277 TI - Alginic acid nanoparticles prepared through counterion complexation method as a drug delivery system. AB - In this paper, a kind of novel alginic acid nanoparticles was successfully prepared by a non-solvent-aided counterion complexation between anionic alginic acid and cationic 2,2'-(ethylenedioxy)diethylamine in aqueous solution followed by cross-linking alginic acid moiety using Ca(2+). It was found that these alginic acid nanoparticles have a spherical morphology with the diameter of about 100 nm, and negatively charged surface with the zeta potential of about -30 mV. Compared to the desintegrity of un-cross-linked nanoparticles, the Ca(2+)-cross linked nanoparticles maintained their integrity in the aqueous medium with the physiological pH value. Doxorubicin, a model antitumor drug, was successfully loaded into the alginic acid nanoparticles, and their in vitro and in vivo antitumor activities were evaluated. It was found that these negatively charged nanoparticles could be taken up by the cancer cells through an endocytosis mechanism. In vivo near-infrared (NIR) fluorescence imaging and biodistribution examinations showed that the alginic acid nanoparticles could be well-accumulated in the tumor site by the enhanced permeability and retention effect. In vivo antitumor examination showed that the drug-loaded nanoparticles have superior efficacy in impeding tumor growth and prolonging the lifetime of H22 tumor bearing mice than free drug. PMID- 23020279 TI - Guadial A and psiguadials C and D, three unusual meroterpenoids from Psidium guajava. AB - The first monoterpene-based meroterpenoid (1) and two novel sesquiterpene-based ones (2 and 3) with unprecedented skeletons were isolated from the leaves of Psidium guajava. Their structures with absolute configuration were elucidated by extensive spectroscopic studies. A plausible biosynthetic pathway for all meroterpenoids from the title plant is also proposed. Compounds 2 and 3 showed significant cytotoxicity toward HepG2 and HepG2/ADM cells. PMID- 23020280 TI - Using the ICF to develop the capability-oriented database of persons with disabilities: a case study in Nakornpanom province, Thailand. AB - PURPOSE: This study aims to determine functioning information, rehabilitation needs, and environmental barriers of persons with disabilities (PWDs) using a developed ICF-based questionnaire with community survey approach in Thailand. METHOD: A systematic review of the use of ICF and disability surveys from January 2000- June 2010 was undertaken. A questionnaire was then developed and tested in two pilot studies before using in a face-to-face interview conducted with legally registered PWDs in Nakornpanom province. Forty-six ICF codes were used in the questionnaire; two second-level codes in body functions, 18 second-level and six third-level codes in activities & participation and 14 second-level and six third level codes in environmental factors. Each code had 2-6 qualifiers. RESULTS: One thousand and seven PWDs (56.6% male, mean age = 48.4 +/- 0.64 years) were interviewed by 16 trained-interviewers. Interview duration was approximately 17 min. The functioning profile could be revealed for both individual and population. These reflected the need for rehabilitation. Several cut-off points to identify "disabled persons" were offered. Regarding participation, PWDs were concerned more about environmental barriers. One-fourth of PWDs needed home environment adaptation, almost 13% were uneducated and 23% had limited chance to participate in social activities. CONCLUSIONS: ICF framework and codes can be used to develop a questionnaire to measure population functioning profile and rehabilitation needs of PWDs by community survey. Results can be used to develop a capability-oriented disability database to identify prevalence of disabilities and rehabilitation needs. Policy makers may use this database to plan, monitor and evaluate rehabilitation service programs and removal of environmental barriers. PMID- 23020281 TI - Abnormal neurological exam findings in individuals with mild traumatic brain injury (mTBI) versus psychiatric and healthy controls. AB - In those with a history of mild traumatic brain injury (mTBI), cognitive and emotional disturbances are often misattributed to that preexisting injury. However, causal determinations of current symptoms cannot be conclusively determined because symptoms are often nonspecific to etiology and offer virtually no differential diagnostic value in postacute or chronic phases. This population based study examined whether the presence of abnormalities during neurological examination would distinguish between mTBI (in the chronic phase), healthy controls, and selected psychiatric conditions. Retrospective analysis of data from 4462 community-dwelling Army veterans was conducted. Diagnostically unique groups were compared on examination of cranial nerve function and other neurological signs. Results demonstrated that individuals with mTBI were no more likely than those with a major depressive disorder, generalized anxiety disorder, posttraumatic stress disorder, or somatoform disorder to show any abnormality. Thus, like self-reported cognitive and emotional symptoms, the presence of cranial nerve or other neurological abnormalities offers no differential diagnostic value. Clinical implications and study limitations are presented. PMID- 23020282 TI - Predictive biomarkers in breast cancer: their value in neoadjuvant chemotherapy. AB - Neoadjuvant chemotherapy (NCT) of breast cancer enabled improved outcomes especially in patients with advanced and inflammatory diseases. Biological heterogeneity of these tumors, however, requires better molecular characterization of the malignant tissue with consequent individualization in the selection of appropriate agents. To date, numerous molecular markers have been identified, and some of them (e.g., measurement of hormonal or growth factors receptors) are already routinely used for breast cancer classification before NCT. In the present article, we summarize current knowledge about established as well as promising biomarkers which have demonstrated prognostic or predictive value in NCT of breast cancer. PMID- 23020284 TI - Relationship of interleukin-1beta levels and gastroesophageal reflux disease in Korea. AB - BACKGROUND AND AIM: Gastric mucosal expression of interleukin (IL)-1beta may alter acid secretion and influence the development of gastroesophageal reflux disease (GERD). The relationship of gastric mucosal IL-1beta level and GERD was evaluated in the Korean population. METHODS: Genotypes of IL-1B-511 and IL-1RN VNTR polymorphism and clinical characteristics were analyzed in 44 patients with erosive esophagitis (EE), 32 patients with minimal change lesions (MCL), 54 patients with non-erosive reflux disease (NERD) and 113 controls. Gastric mucosal IL-1beta levels were measured by enzyme linked immunosorbent assay. RESULTS: Significant differences were found between the EE and the control group with respect to sex, body mass index, and Helicobacter pylori infection. On the other hand, the MCL and the NERD group showed similar characteristics to that of the control group. IL-1B-511 genetic polymorphism showed relationship with gastric mucosal IL-1beta levels. That is, T/T group (112.4 +/- 14.3 pg/mg) had higher IL 1beta level than C/C group (59.5 +/- 11.6, P = 0.011). T carriers (92.8 +/- 7.6 pg/mg) showed higher level than T non-carrier group (P = 0.050). In addition, mucosal IL-1beta level of the EE group (52.3 +/- 9.9 pg/mg) was lower than that of the control (107.8 +/- 12.6 pg/mg, P = 0.001), the MCL (103.1 +/- 13.5 pg/mg, P = 0.004), and the NERD group (83.8 +/- 14.5 pg/mg, P = 0.079). However, genetic polymorphisms of IL-1B-511 and IL-1RN VNTR did not reach statistical significance among four groups. CONCLUSION: Gastric mucosal IL-1beta level might be one factor in the development of GERD. PMID- 23020285 TI - Diagnostic value of fine needle aspirates processed by ThinPrep(r) for the assessment of axillary lymph node status in patients with invasive carcinoma of the breast. AB - OBJECTIVE: To evaluate the utility of ThinPrep(r) as an optional specimen processing method for the detection of axillary lymph node metastasis of invasive breast carcinoma. METHODS: A computer SNOMED search from the file at our institution between January 2003 and August 2011 retrieved a total of 209 fine needle aspiration (FNA) specimens of axillary lymph nodes prepared by ThinPrep and followed by axillary lymph node biopsy and/or dissection. Original cytological diagnoses and corresponding histological diagnoses were documented. Using the histological diagnoses as the gold standard, the diagnostic parameters including sensitivity, specificity, positive (PPV) and negative predictive values (NPV) and diagnostic accuracy were calculated. Both cytology and histology slides from cyto-histologically discrepant cases were reviewed. RESULTS: Out of a total of 209 specimens, 193 (92%) had adequate diagnostic material while the remaining 16 specimens (8%) were inadequate for cytological assessment. The diagnostic specimens included 168 invasive ductal carcinomas (IDC), 15 invasive lobular carcinomas (ILC) and 10 mixed carcinomas (IDC and ILC). Excluding 19 cases with malignant cells on FNA in which no residual tumour was found in fibrotic lymph nodes after neoadjuvant therapy (cytology and histology confirmed on review) ThinPrep detected nodal metastasis with an overall sensitivity of 77.5%, specificity of 100%, PPV of 100% and NPV of 53.7%. Diagnostic accuracy was 82.2%. There was no difference in Bloom-Richardson grade or the number or size of metastases between tumours with true-positive and false-negative cytology. Sampling error was the sole factor contributing to cyto-histological discrepancy. CONCLUSIONS: ThinPrep is a good alternative to the conventional smear for cytological assessment of axillary lymph node status in patients with invasive breast carcinoma, particularly when specimens are collected at remote sites or when cytologists are not available for assistance during FNA. PMID- 23020283 TI - The relationship between the hierarchical position of proteins in the human signal transduction network and their rate of evolution. AB - BACKGROUND: Proteins evolve at disparate rates, as a result of the action of different types and strengths of evolutionary forces. An open question in evolutionary biology is what factors are responsible for this variability. In general, proteins whose function has a great impact on organisms' fitness are expected to evolve under stronger selective pressures. In biosynthetic pathways, upstream genes usually evolve under higher levels of selective constraint than those acting at the downstream part, as a result of their higher hierarchical position. Similar observations have been made in transcriptional regulatory networks, whose upstream elements appear to be more essential and subject to selection. Less well understood is, however, how selective pressures distribute along signal transduction pathways. RESULTS: Here, I combine comparative genomics and directed protein interaction data to study the distribution of evolutionary forces across the human signal transduction network. Surprisingly, no evidence was found for higher levels of selective constraint at the upstream network genes (those occupying more hierarchical positions). On the contrary, purifying selection was found to act more strongly on genes acting at the downstream part of the network, which seems to be due to downstream genes being more highly and broadly expressed, performing certain functions and, in particular, encoding proteins that are more highly connected in the protein-protein interaction network. When the effect of these confounding factors is discounted, upstream and downstream genes evolve at similar rates. The trends found in the overall signaling network are exemplified by analysis of the distribution of purifying selection along the mammalian Ras signaling pathway, showing that upstream and downstream genes evolve at similar rates. CONCLUSIONS: These results indicate that the upstream/downstream position of proteins in the signal transduction network has, in general, no direct effect on their rates of evolution, suggesting that upstream and downstream genes are similarly important for the function of the network. This implies that natural selection differently distributes across signal transduction networks and across biosynthetic and transcriptional regulatory networks, which might reflect fundamental differences in their function and organization. PMID- 23020286 TI - Electronic nose to detect volatile compound profile and quality changes in 'spring Belle' peach (Prunus persica L.) during cold storage in relation to fruit optical properties measured by time-resolved reflectance spectroscopy. AB - The aim of this research was to study the relationships between electronic nose (E-nose) pattern, maturity class of peaches assessed at harvest by means of absorption coefficient at 670 nm (MU(a)670) measured in fruit pulp by time resolved reflectance spectroscopy (TRS), and quality evolution during a 4 week cold storage. 'Spring Belle' peaches were measured for MU(a)670 by TRS, ranked according to decreasing MU(a)670 value, divided into three TRS maturity classes (less (LeM), medium (MeM), and more (MoM) mature), and randomized into 9 samples of 30 fruit each, so that fruits from the whole MU(a)670 range were present in each sample. At harvest and after 1, 2, 3, and 4 weeks of storage at 0 and 4 degrees C, fruits of each sample were evaluated for firmness, expressible juice, MU(a)670, and ethylene production. LeM and MoM peaches of each sample were analyzed for aroma pattern by a commercial electronic nose and by static HS-GC and for sugar (glucose, fructose, sucrose, and sorbitol) and organic acid (quinic, malic, and citric acids) compositions by HPLC. Principal component analysis (PCA) of electronic nose data emphasized the ability of the E-nose to assess the ripening stage of fruit associated with maturity class, storage time, and storage temperature. The sensors having the highest influence on the pattern were W5S in PC-1, W1S in PC-2, and W2S in PC-3. From linear correlation analysis between PCs and firmness, flavor, and volatile compounds, it was found that PC-1 was related to ethylene production and volatile compounds (mainly acetate esters and ethanol); the highest PC-1 scores were found for fruit belonging to the MoM class after 2 weeks of storage at 4 degrees C, which showed the rise in ethylene production coupled with the highest total volatile production and sugar and acid composition of ripe peach fruits. PC-2 correlated with hexanal, ethyl acetate, and sugar composition, and PC-3 was mainly related to flavor compounds; both functions significantly changed with cold storage time in different ways according to storage temperature and maturity class. PMID- 23020287 TI - Clinical outcomes after tricuspid valve annuloplasty in addition to mitral valve surgery. AB - Current guidelines recommend tricuspid valve annuloplasty (TVP) together with mitral valve surgery in cases of tricuspid annulus dilation (>=40 mm) or functional tricuspid valve regurgitation >2/4. Baseline clinical and echocardiographic data of patients undergoing mitral valve surgery in a single tertiary care hospital between 2007 and 2010 were analyzed. Mortality and heart failure hospitalization data were collected and groups with or without TVP were compared. Patients with TVP (n=89) had similar baseline characteristics compared with patients without (n=86), except for lower right ventricular fractional area change and more concomitant aortic valve surgery. Mortality was higher in the TVP group at 30 days (14% vs 5%; P=.04), but the difference was no longer significant at the end of follow-up. More patients were hospitalized for heart failure in the TVP group (31% vs 17%; hazard ratio, 2.1; 95% confidence interval, 1.1-4.0; P=.05). Right ventricular sphericity index was the only preoperative parameter predicting death or heart failure hospitalizations. In conclusion, patients undergoing TVP in addition to mitral valve surgery are at high risk for early death or subsequent heart failure hospitalizations, which might be partly explained by more complex heart disease. The extent of preoperative right ventricular remodeling may be predictive of adverse outcomes. PMID- 23020288 TI - Mitochondrial analysis sheds light on the origin of hair sheep. AB - A total of 180 mtDNA sequences from hair Caribbean (93), West African (73) and Canarian-wooled (14) sheep were analysed to shed light on the origin of hair sheep. A comparison of 360 Iberian sheep sequences retrieved from GenBank was performed to assess a possible European origin of the Caribbean hair sheep. These 180 sequences gave 48 different haplotypes (16 in Caribbean sheep). All Caribbean and Canarian-wooled sequences and 91.8% of the West African samples belonged to haplogroup B. The sheep analysed showed wide haplotypic identity. Caribbean sheep shared roughly two-thirds of their samples with Canarian-wooled and West African samples, respectively. Principal component analysis showed that the Caribbean and the Canarian-wooled sheep clustered together. Additional analyses showed that hair and Iberian sheep had wide genetic identity. It was not possible to ascertain a single Canarian, African or European origin of the Caribbean hair sheep using mtDNA markers only. European, African and Caribbean hair sheep maternal genetic backgrounds likely result from related domestication events. PMID- 23020290 TI - Iron insertion and hematite segregation on Fe-doped TiO2 nanoparticles obtained from sol-gel and hydrothermal methods. AB - Iron-doped TiO(2) (Fe:TiO(2)) nanoparticles were synthesized by the sol-gel method (with Fe/Ti molar ratio corresponding to 1, 3, and 5%), followed by hydrothermal treatment, drying, and annealing. A similar methodology was used to synthesize TiO(2) and alpha-Fe(2)O(3) nanoparticles. For comparison, a mixture hematite/titania, with Fe/Ti = 4% was also investigated. Characterization of the samples using Rietveld refinement of X-ray diffraction data revealed that TiO(2) consisted of 82% anatase and 18% brookite; for Fe:TiO(2), brookite increased to 30% and hematite was also identified (0.5, 1.0, and 1.2 wt % for samples prepared with 1, 3, and 5% of Fe/Ti). For hematite/titania mixture, Fe/Ti was estimated as 4.4%, indicating the Rietveld method reliability for estimation of phase composition. Because the band gap energy, estimated as 3.2 eV for TiO(2), gradually ranged from 3.0 to 2.7 eV with increasing Fe content at Fe:TiO(2), it can be assumed that a Fe fraction was also inserted as dopant in the TiO(2) lattice. Extended X-ray absorption fine structure spectra obtained for the Ti K edge and Fe K-edge indicated that absorbing Fe occupied a Ti site in the TiO(2) lattice, but hematite features were not observed. Hematite particles also could not be identified in the images obtained by transmission electron microscopy, in spite of iron identification by elemental mapping, suggesting that hematite can be segregated at the grain boundaries of Fe:TiO(2). PMID- 23020289 TI - Well-differentiated and dedifferentiated liposarcomas with prominent myxoid stroma: analysis of 56 cases. AB - AIMS: Occasional cases of well-differentiated and dedifferentiated liposarcoma (LPS) contain myxoid stroma, leading to confusion with other sarcomas. The aim of this study was to analyse the clinicopathological and genetic features of well differentiated/dedifferentiated LPS with prominent myxoid stroma. METHODS AND RESULTS: Fifty-six cases of LPS (22 well-differentiated; 34 dedifferentiated) with prominent myxoid stroma were evaluated. Most arose in the retroperitoneum, abdominal cavity, or spermatic cord. The mean size was 170 mm. Myxoid LPS-like plexiform vessels were conspicuous in 11 cases of well-differentiated LPS. In 22 cases of dedifferentiated LPS, myxofibrosarcoma-like curvilinear vessels were prominent. In other cases, the myxoid component had variably bland or pleomorphic morphology. By immunohistochemistry, staining for MDM2 was positive in 95% of cases, and CDK4 in 78%. Cytogenetics in 13 cases showed ring and giant marker chromosomes. Fluorescence in-situ hybridization showed amplification of 12q13-15 in six cases evaluated. Of 30 patients with follow-up, all but one had local recurrences (up to four), but only one has so far had distant metastases. CONCLUSIONS: Well-differentiated/dedifferentiated LPS with prominent myxoid stroma can closely resemble other sarcoma types, especially myxoid LPS and myxofibrosarcoma. The clinical presentation (large retroperitoneal or abdominal tumour) is a clue to the correct diagnosis; the degree of nuclear atypia helps to exclude myxoid LPS. Immunohistochemistry for MDM2 and CDK4 and genetic analysis can be useful to confirm the diagnosis. PMID- 23020291 TI - Cyclin D1 G870A polymorphism is a risk factor for esophageal cancer among Asians. AB - Investigations concerning the association of Cyclin D1 (CCND1) G870A polymorphism with esophageal cancer risk have generated conflicting results. Thus, meta analyses were conducted. The overall data suggest that CCND1 G870A variation might have an association with increased esophageal cancer susceptibility. In subgroup analyses on ethnicity, homozygous AA alleles might elevate esophageal cancer risk among Asians but not Caucasians. In subgroup analysis on histological types, no association was found in either the adenocarcinoma or the squamous cell carcinoma subgroup. Collectively, results suggest that CCND1 G870A polymorphism might be a low-penetrant risk factor for esophageal carcinoma, particularly among Asians. PMID- 23020292 TI - Incorporation of cis- and trans-4,5-difluoromethanoprolines into polypeptides. AB - Substituted prolines exert diverse effects on the backbone conformation of proteins. Novel difluoro-analogues were obtained by adding difluorocarbene to N Boc-4,5-dehydroproline methyl ester, which gave the trans-adduct as the sole product with 71% yield. Upon cleavage of the N-protection group the free amino acid decomposed rapidly. Its incorporation into the proline-rich cell-penetrating "sweet arrow peptide" was thus accomplished using a dipeptide strategy. Two building blocks, containing either cis- or trans-4,5-difluoromethanoproline, were obtained by difluorocyclopropanation of the aminoacyl derivatives of 4,5 dehydroproline. The resulting dipeptides were stable under standard conditions of Fmoc solid phase peptide synthesis and, thus, suitable to study conformational effects. PMID- 23020293 TI - G protein-coupled receptor deorphanizations. AB - G protein-coupled receptors (GPCRs) are major regulators of intercellular interactions. They initiate these actions by being activated by a wide variety of natural ligands. Historically, ligands were discovered first, but the advent of molecular biology reversed this trend. Most GPCRs are identified on the basis of their DNA sequences and thus are initially unmatched to known natural ligands. They are termed orphan GPCRs. Discovering their ligands-i.e., "deorphanizing" the GPCRs-gave birth to the field of reverse pharmacology. This review discusses the present status of GPCR deorphanization, presents a few examples of successes and surprises, and highlights difficulties encountered in these efforts. PMID- 23020294 TI - Pharmacology of iron transport. AB - Elucidating the molecular basis for the regulation of iron uptake, storage, and distribution is necessary to understand iron homeostasis. Pharmacological tools are emerging to identify and distinguish among different iron transport pathways. Stimulatory or inhibitory small molecules with effects on iron uptake can help characterize the mechanistic elements of iron transport and the roles of the transporters involved in these processes. In particular, iron chelators can serve as potential pharmacological tools to alleviate diseases of iron overload. This review focuses on the pharmacology of iron transport, introducing iron transport membrane proteins and known inhibitors. PMID- 23020295 TI - Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health. AB - The presence of epoxyeicosatrienoic acids (EETs) in tissues and their metabolism by soluble epoxide hydrolase (sEH) to 1,2-diols were first reported 30 years ago. However, appreciation of their importance in cell biology and physiology has greatly accelerated over the past decade with the discovery of metabolically stable inhibitors of sEH, the commercial availability of EETs, and the development of analytical methods for the quantification of EETs and their diols. Numerous roles of EETs in regulatory biology now are clear, and the value of sEH inhibition in various animal models of disease has been demonstrated. Here, we review these results and discuss how the pharmacological stabilization of EETs and other natural epoxy-fatty acids could lead to possible disease therapies. PMID- 23020297 TI - Impact of modern chemotherapy on the survival of women presenting with de novo metastatic breast cancer. AB - BACKGROUND: Data that directly associate utilization of novel systemic therapies with survival trends in metastatic breast cancer (MBC) are limited. In the setting of de novo MBC, large registry analyses cite positive temporal trends in survival, but the extent to which advances in systemic therapy have contributed to these gains is not clear. METHODS: The City of Hope Cancer Registry was used to identify a consecutive series of patients with de novo MBC who received their first line of therapy between 1985 and 2004. Comprehensive clinicopathologic and treatment-related data were collected for each patient. Univariate analyses were conducted via Cox regression to identify factors associated with improved survival. Multivariate analysis was also conducted via Cox regression and the stepwise procedure was used to identify independent predictors of survival. RESULTS: A total of 324 patients with de novo MBC were identified. After application of exclusion criteria, including the sole presence of supraclavicular node metastasis, 274 patients were retained in the analysis. The treatment related characteristics associated with improved survival included: use of endocrine therapy (hazard ratio [HR] 0.60, 95%CI 0.47-0.77; P<0.0001), and addition of bisphosphonates (HR 0.70, 95%CI 0.52-0.96; P=0.02). However, recipients of novel cytotoxic agents (defined as drugs approved for MBC since 1994) had no improvement in survival relative to patients treated with older cytotoxic agents. On multivariate analysis, age (< 50), receipt of aromatase inhibitors, and receipt of zoledronic acid were independent predictors of survival. CONCLUSIONS: The overall survival of women with de novo metastatic breast cancer has improved over the past 20 years. However, the contribution of conventional cytotoxic agents to this improvement is minimal. PMID- 23020298 TI - Neurovascular screening in hereditary haemorrhagic telangiectasia: dilemmas for the paediatric neuroscience community. PMID- 23020299 TI - Rebamipide ameliorates indomethacin-induced small intestinal injury in rats via the inhibition of matrix metalloproteinases activity. AB - BACKGROUND AND AIM: The pathogenesis of non-steroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal lesions remains unclear, although it is considered to be quite different from that of upper gastrointestinal tract ulcers due to the absence of acid and the presence of bacteria and bile in the small intestine. The aim of this study was to characterize specific gene expression profiles of intestinal mucosa in indomethacin-induced small intestinal injury, and to investigate the effects of rebamipide on the expression of these genes. METHODS: Intestinal injury was induced in male Wistar rats by subcutaneous administration of indomethacin. Total RNA of the intestinal mucosa was extracted 24 h after indomethacin administration, gene expression was investigated using microarray analysis, and the identified genes were confirmed by real-time polymerase chain reaction (PCR). In addition, we investigated whether the treatment with rebamipide altered the expression of these identified genes. RESULTS: The administration of indomethacin induced small intestine injuries, and these lesions were significantly inhibited by the treatment with rebamipide. Microarray analysis showed that the genes for several matrix metalloproteinases (MMPs) and several chemokine-related genes were significantly upregulated, and metallothionein 1a (MT1a) was downregulated in the intestinal mucosa after administration of indomethacin. The expressions of these genes were reversed by the treatment with rebamipide. CONCLUSION: These data suggest that MMPs, chemokines, and MT1a may play an important role in the intestinal mucosal injury induced by indomethacin. In particular, the inhibition of MMP genes and chemokine related genes by rebamipide may be important for the therapeutic effect against NSAIDs-induced small intestinal injury. PMID- 23020296 TI - Epigenetic mechanisms of depression and antidepressant action. AB - Epigenetic mechanisms, which control chromatin structure and function, mediate changes in gene expression that occur in response to diverse stimuli. Recent research has established that environmental events and behavioral experience induce epigenetic changes at particular gene loci and that these changes help shape neuronal plasticity and function and hence behavior. Some of these changes can be stable and can even persist for a lifetime. Increasing evidence supports the hypothesis that aberrations in chromatin remodeling and subsequent effects on gene expression within limbic brain regions contribute to the pathogenesis of depression and other stress-related disorders such as post-traumatic stress disorder and other anxiety syndromes. Likewise, the gradually developing but persistent therapeutic effects of antidepressant medications may be achieved in part via epigenetic mechanisms. This review discusses recent advances in our understanding of the epigenetic regulation of stress-related disorders and focuses on three distinct aspects of stress-induced epigenetic pathology: the effects of stress and antidepressant treatment during adulthood, the lifelong effects of early-life stress on subsequent stress vulnerability, and the possible transgenerational transmission of stress-induced abnormalities. PMID- 23020300 TI - Intraoperative recurrent laryngeal nerve monitoring: a useful method for patients with esophageal cancer. AB - It is well accepted that recurrent laryngeal nerve paralysis is a severe complication of esophagectomy or lymphadenectomy performed adjacent to the recurrent laryngeal nerves. Herein, determination of the effectiveness of implementing continuous recurrent laryngeal nerve monitoring to reduce the incidence of recurrent laryngeal nerve paralysis after esophagectomy was sought. A total of 115 patients diagnosed with esophageal cancer were enrolled in the thoracic section of the Tangdu Hospital of the Fourth Military Medical University from April 2008 to April 2009. Clinical parameters of patients, the morbidity, and the mortality following esophageal resection were recorded and compared. After the surgery, a 2-year follow up was completed. It was found that recurrent laryngeal nerve paralysis and postoperative pneumonia were more frequently diagnosed in the patients that did not receive continuous recurrent laryngeal nerve monitoring (6/61 vs. 0/54). Furthermore, positive mediastinal lymph nodes (P = 0.015), total mediastinal lymph nodes (P < 0.001), positive total lymph nodes (P = 0.027), and total lymph nodes (P < 0.001) were more often surgically removed in the patients with continuous recurrent laryngeal nerve monitoring. These patients also had a higher 2-year survival rate (P = 0.038) after surgery. It was concluded that continuous intraoperative recurrent laryngeal nerve monitoring is technically safe and effectively identifies the recurrent laryngeal nerves. This may be a helpful method for decreasing the incidence of recurrent laryngeal nerve paralysis and postoperative pneumonia, and for improving the efficiency of lymphadenectomy. PMID- 23020301 TI - Environmental improvements brought by the legal interventions in the homes of poorly controlled inner-city adult asthmatic patients: a proof-of-concept study. AB - OBJECTIVES: Domestic contamination with mold, cockroaches, rodents, and dust worsens asthma severity. This violates warranty of habitability laws in most of the states, but patients often find it beyond their means to remedy their housing situation. We aimed to study the effect of a medical-legal collaborative intervention to force landlords into providing better living conditions for patients with poorly controlled asthma. METHODS: We retrospectively studied charts of adult patients aged 18 years or older with poorly controlled asthma (moderate or severe persistent) despite maximum medical therapy. Additionally, patients had self-reported domestic allergen exposures such as mold, cockroaches, mice or rats, and dust. The patients received legal assistance to improve their domestic environments, including fixing leaks, exterminating pests, or providing a different apartment. Post-intervention change in peak expiratory flow rate (PEFR), asthma severity class, medications, emergency department (ED) visits, hospitalizations, and requirement for systemic steroids for symptom control was assessed. RESULTS: Data were available for 12 patients (9-12 months pre intervention and 6-12 months post-intervention). Analysis of paired data revealed that mean PEFR rose by 38.6 LPM (95% CI: 9.9-67.3; p = .014). The number of ED visits and hospital admissions declined from 22 ED visits and 11 admissions to 2 ED visits and 1 admission (91% reduction), respectively. Of the 11 patients requiring systemic steroids, only three required these post-intervention. All patients had reductions in the dose and/or number of medications. During post intervention, 11 (91.7%) patients dropped >=2 classes in asthma severity. CONCLUSIONS: Medical-legal collaboration is highly effective in improving the control of inner-city asthmatics by effecting improvements in the domestic environment. PMID- 23020302 TI - Two distinct phases of bilayer graphene films on Ru(0001). AB - By combining angle-resolved photoemission spectroscopy and scanning tunneling microscopy we reveal the structural and electronic properties of multilayer graphene on Ru(0001). We prove that large ethylene exposure allows the synthesis of two distinct phases of bilayer graphene with different properties. The first phase has Bernal AB stacking with respect to the first graphene layer and displays weak vertical interaction and electron doping. The long-range ordered moire pattern modulates the crystal potential and induces replicas of the Dirac cone and minigaps. The second phase has an AA stacking sequence with respect to the first layer and displays weak structural and electronic modulation and p doping. The linearly dispersing Dirac state reveals the nearly freestanding character of this novel second-layer phase. PMID- 23020303 TI - Bacterial contamination of blood products at the Croatian Institute of Transfusion Medicine: results of eleven-year monitoring. AB - OBJECTIVES: The aim of this study is to present the results and experiences of the Croatian Institute of Transfusion Medicine (CITM) in blood product testing for the presence of bacterial contamination. This is the first study analysing the results of bacterial testing of blood products in Croatia. METHODS: Results of monitoring blood products for the presence of bacterial contamination during an 11-year period (2000-2010) were retrospectively analysed. As universal screening of platelet concentrates for bacterial contamination is not mandatory in Croatia, the results presented refer to the products tested within the frame of statistical process control. RESULTS: A total of 23,130 blood products were tested during the study period. There were 122 (0.53%) initially positive and 41 (0.18%) confirmed positive blood products, whereas suspicion of bacterial contamination could be neither confirmed nor ruled out in 8 (0.03%) blood products. While the frequency of bacterial contamination of plasma products was very low (0.03%), there was no statistically significant difference between bacterial contamination of platelet concentrates (0.26%) and RBC concentrates (0.20%). There were 73 (0.32%) false-positive blood products, with nearly equal proportion of causes related to laboratory contamination (n = 34; 0.15%) and those related to the testing system (n = 39; 0.17%). CONCLUSION: The results obtained in the study did not differ significantly from literature data. A number of measures to reduce the risk of bacterial contamination of blood products have been implemented at CITM. The introduction of universal screening of platelet concentrates for the presence of bacterial contamination should be taken into consideration. PMID- 23020304 TI - Intermolecular vibration coupling between libration of water and nu2-SOH for Clusters HSO4(-)(H2O)n. AB - The hydrated bisulfate ion clusters (HSO(4)(-)(H(2)O)(n), n = 1-10) were optimized at the M06/6-311++G(d,p) level. The factors affecting nu(2)-SOH of the clusters involved vibration coupling between nu(2)-SOH and the water wagging libration mode (W-H(2)O) and hydrogen bonding effect. In order to understand the vibration coupling between W-H(2)O and nu(2)-SOH for the bisulfate clusters, D(2)O instead of H(2)O and Se instead of S were used to estimate the uncoupling frequency of nu(2)-SOH and W-H(2)O, respectively. For HSO(4)(-).H(2)O-I, the uncoupling frequencies of nu(2)-SOH and W-H(2)O were obtained at 752.0 and 753.4 cm(-1). After coupling, the frequencies appeared at 782.2 and 732.6 cm(-1). H(2)S and NH(4)(+) instead of D(2)O in HSO(4)(-).D(2)O-II were compared to analyze the effect of hydrogen bond. The sequence of hydrogen bond strength was found to be HSO(4)(-).H(2)S-II < HSO(4)(-).D(2)O-II < HSO(4)(-).NH(4)(+)-II with the respective nu(2)-SOH at 736.7, 740.5, and 802.2 cm(-1) increasing in the same order. In HSO(4)(-).(H(2)O)(n), coupling appeared when n was from 1 to 8. For HSO(4)(-).(D(2)O)(n), no coupling between nu(2)-SOH and D(2)O librations made it possible to understand the hydrogen bonding effect on the nu(2)-SOH. The frequencies of nu(2)-SOH for clusters HSO(4)(-)(D(2)O)(n) almost linearly decreased from 752.0 to 854.6 cm(-1) with n from 1 to 10. PMID- 23020306 TI - Stability of steviol glycosides in several food matrices. AB - As steviol glycosides are now allowed as a food additive in the European market, it is important to assess the stability of these steviol glycosides after they have been added to different food matrices. We analyzed and tested the stability of steviol glycosides in semiskimmed milk, soy drink, fermented milk drink, ice cream, full-fat and skimmed set yogurt, dry biscuits, and jam. The fat was removed by centrifugation from the dairy and soy drink samples. Proteins were precipitated by the addition of acetonitrile and also removed by centrifugation. Samples of jam were extracted with water. Dry biscuits were extracted with ethanol. The resulting samples were concentrated with solid-phase extraction and analyzed by high-performance liquid chromatography on a C18 stationary phase and a gradient of acetonitrile/aqueous 25 mM phosphoric acid. The accuracy was checked using a standard addition on some samples. For assessing the stability of the steviol glycosides, samples were stored in conditions relevant to each food matrix and analyzed periodically. The results indicate that steviol glycosides can be analyzed with good precision and accuracy in these food categories. The recovery was between 96 and 103%. The method was also validated by standard addition, which showed excellent agreement with the external calibration curve. No sign of decomposition of steviol glycosides was found in any of the samples. PMID- 23020305 TI - Massive expansion of the calpain gene family in unicellular eukaryotes. AB - BACKGROUND: Calpains are Ca2+-dependent cysteine proteases that participate in a range of crucial cellular processes. Dysfunction of these enzymes may cause, for instance, life-threatening diseases in humans, the loss of sex determination in nematodes and embryo lethality in plants. Although the calpain family is well characterized in animal and plant model organisms, there is a great lack of knowledge about these genes in unicellular eukaryote species (i.e. protists). Here, we study the distribution and evolution of calpain genes in a wide range of eukaryote genomes from major branches in the tree of life. RESULTS: Our investigations reveal 24 types of protein domains that are combined with the calpain-specific catalytic domain CysPc. In total we identify 41 different calpain domain architectures, 28 of these domain combinations have not been previously described. Based on our phylogenetic inferences, we propose that at least four calpain variants were established in the early evolution of eukaryotes, most likely before the radiation of all the major supergroups of eukaryotes. Many domains associated with eukaryotic calpain genes can be found among eubacteria or archaebacteria but never in combination with the CysPc domain. CONCLUSIONS: The analyses presented here show that ancient modules present in prokaryotes, and a few de novo eukaryote domains, have been assembled into many novel domain combinations along the evolutionary history of eukaryotes. Some of the new calpain genes show a narrow distribution in a few branches in the tree of life, likely representing lineage-specific innovations. Hence, the functionally important classical calpain genes found among humans and vertebrates make up only a tiny fraction of the calpain family. In fact, a massive expansion of the calpain family occurred by domain shuffling among unicellular eukaryotes and contributed to a wealth of functionally different genes. PMID- 23020307 TI - Exploiting microRNA regulation for genetic engineering. AB - RNA interference (RNAi) has been a landmark discovery in science. A typical application is to knock down the expression of endogenous genes by delivering small interfering RNA (siRNA) into cells triggering the degradation of complementary mRNA. However, RNAi can also be exploited the other way round: making use of the huge diversity of endogenous microRNAs (miRNA), the expression of exogenously introduced genes tagged with artificial miRNA target sequences can be negatively regulated according to the activity of a given miRNA which can be tissue-, lineage-, activation- or differentiation stage specific. This has significantly expanded the regulatory potential of gene transfer vectors and will benefit both basic science and therapeutic applications. This review briefly introduces the reader to the technical basis for exploiting miRNA regulation, followed by a discussion of specific applications for miRNA-regulated vectors/viruses in basic research, gene- and virotherapy. PMID- 23020308 TI - The HLA-B gene and Hashimoto disease in Han Chinese children: a case-control and family-based study. AB - Hashimoto disease (HD) is an autoimmune thyroid disease resulting from complex interactions between genetic and environmental factors. The human leukocyte antigen (HLA) gene has been established to be involved in the susceptibility to HD. We aim to investigate the associations between HLA-B alleles and Han Chinese children with HD by both case-control and family-based studies. A total of 108 unrelated children with HD, 380 unrelated healthy controls, 58 trios of affected patients and their parents, and 75 trios of unaffected siblings and their parents were recruited. HLA-B genotyping was performed by polymerase chain reaction and detected with a sequence-specific oligonucleotide probes system. We found that B*46:01 allele (OR = 2.31, 95% CI 1.60-3.34, P(c) = 9.99 * 10(-5)) and carrier (OR = 3.28, 95% CI 2.10-5.11, P(c) = 1.35 * 10(-6)) were associated with HD risk. Transmission/disequilibrium test further confirmed an overtransmission of the B*46:01 (OR 2.55, 95% CI 1.36-6.10, P = 6.5 * 10(-3)). The findings were similar in females when stratified by gender. In conclusion, our results clearly identify that HLA-B*46:01 confers susceptibility to HD in Han Chinese children. Further studies with larger children cohort are required to confirm the role of B*46:01 in the development of HD. PMID- 23020309 TI - Distinct HLA allele and haplotype distributions in four ethnic groups of China. AB - Distinct human leukocyte antigen (HLA) allele and haplotype distributions occur in the northern and southern Han populations of China. However, different ethnic groups in China show limited regional distributions for many HLA alleles and haplotypes. Therefore, it is necessary and meaningful to study the differences in HLA allele and haplotype distribution for northern and southern ethnic groups of China. A total of 428 unrelated individuals from the Lisu, Nu, Tu and Yugur ethnic populations were genotyped for HLA-A, -B, -C and -DRB1 alleles using the PCR-Luminex typing method. The frequencies of HLA alleles and statistically inferred haplotypes were calculated. A total of 29 HLA-A, 54 HLA-B, 27 HLA-C and 41 HLA-DRB1 alleles were spread throughout these four populations with distinct allele and deduced haplotype frequencies between populations. Some alleles and deduced haplotypes exhibited significantly different distributions between northern (Tu and Yugur) and southern groups (Lisu and Nu). A phylogenetic tree and principal component analysis were used to compare the HLA polymorphism between our dataset and 19 other eastern and southeastern Asian populations. This analysis showed that Lisu and Nu belong to a cluster of southern ethnic groups, while Tu and Yugur are most closely related to other northern groups. Thus, distinct ethnic population histories were revealed by analyzing HLA allelic polymorphisms with the HLA profiles of the Lisu and Nu southern Chinese ethnic groups clearly different from the Tu and Yugur northern ethnic groups. The results will be useful for future association studies of infectious disease and contribute toward a more efficient search of organ/tissue matches for transplantation. PMID- 23020310 TI - First description of an uterine perforation potentially imputable to treatment with bevacizumab. PMID- 23020311 TI - Perceived risk and benefit of nuclear waste repositories: four opinion clusters. AB - Local public resistance can block the site-selection process, construction, and operation of nuclear waste repositories. Social science has established that the perception of risks and benefits, trust in authorities, and opinion on nuclear energy play important roles in acceptance. In particular, risk and benefit evaluations seem critical for opinion formation. However, risks and benefits have rarely been studied independently and, most often, the focus has been on the two most salient groups of proponents and opponents. The aim of this exploratory study is to examine the often-neglected majority of people holding ambivalent or indifferent opinions. We used cluster analysis to examine the sample (N = 500, mailed survey in German-speaking Switzerland) in terms of patterns of risk and benefit perception. We reveal four significantly different and plausible clusters: one cluster with high-benefit ratings in favor of a repository and one cluster with high-risk ratings opposing it; a third cluster shows ambivalence, with high ratings on both risk and benefit scales and moderate opposition, whereas a fourth cluster seems indifferent, rating risks and benefits only moderately compared to the ambivalent cluster. We conclude that a closer look at the often neglected but considerable number of people with ambivalent or indifferent opinions is necessary. Although the extreme factions of the public will most probably not change their opinion, we do not yet know how the opinion of the ambivalent and indifferent clusters might develop over time. PMID- 23020312 TI - Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma according to Child-Pugh classification. AB - BACKGROUND AND AIM: We compared the treatment response, survival, and safety to hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) according to Child-Pugh (CP) score. METHODS: The study subjects were 249 patients with advanced HCC and CP class A and B who had been treated with HAIC. Patients were grouped according to CP score (5/6, 7 and 8/9) and their tumor response, tolerance, and survival were assessed. RESULTS: The median survival time (MST) was 8.2, 9.7, 6.3, and 3.9 months for the whole group, patients with CP 5/6, 7 and 8/9, respectively (P < 0.0001). Complete response (CR) and partial response (PR) were seen in 11 and 57 patients, respectively, with an overall response rate of 27.3%. The response rate was higher in patients with CP score 5/6 and 7, than CP 8/9 (30.5%, 28.2%, 13.8%). The dropout rate was significantly higher in patients with CP score 8/9 than the other two (8.0%, 12.8%, 33.3%, respectively). The survival rate was significantly better in patients who achieved CR/PR than the others with CP score 5/6, 7. CP score 8/9 was an independent negative factor for response and survival. CONCLUSION: Advanced HCC patients with CP score of 5/6 and 7 showed a better response to HAIC and better prognosis than those with CP score 8/9. PMID- 23020313 TI - Nanoporous gold catalyst for highly selective semihydrogenation of alkynes: remarkable effect of amine additives. AB - We report for the first time the highly selective semihydrogenation of alkynes using the unsupported nanoporous gold (AuNPore) as a catalyst and organosilanes with water as a hydrogen source. Under the optimized reaction conditions, the present semihydrogenation of various terminal- and internal-alkynes affords the corresponding alkenes in high chemical yields and excellent Z-selectivity without any over-reduced alkanes. The use of DMF as solvent, which generates amines in situ, or pyridine as an additive is crucial to suppress the association of hydrogen atoms on AuNPore to form H(2) gas, which is unable to reduce alkynes on the unsupported gold catalysts. The AuNPore catalyst can be readily recovered and reused without any loss of catalytic activity. In addition, the SEM and TEM characterization of nanoporosity show that the AuNPore catalyst has a bicontinuous 3D structure and a high density of atomic steps and kinks on ligament surfaces, which should be one of the important origins of catalytic activity. PMID- 23020314 TI - Benign mesenchymal tumours and tumour-like lesions in end-stage renal disease. AB - AIMS: Mesenchymal neoplasms of the kidney are rare, and most represent sporadic angiomyolipomas. A few haemangiomas have been reported in end-stage renal disease (ESRD) but, to date, no study has focused on the frequency and morphological spectrum of mesenchymal lesions in ESRD. METHODS AND RESULTS: We evaluated retrospectively 90 nephrectomy specimens with ESRD. Haemangiomas were detected in eight cases (8.8%; six males and two females; mean age: 55 years); four were multifocal and four had concurrent renal epithelial neoplasms. Lesions involved the medulla (three), cortex (two) or both (three), and the size range was 1-25 mm (mean 4.8 mm). Histologically, all were capillary haemangiomas with an at least focally detectable spleen-like anastomosing pattern. All tumours stained positively for CD31 and FLI-1, but none expressed pankeratin (KL-1), podoplanin/D2-40, HHV8 or GLUT-1. Minute angiomyolipomas (mean size 2.3 mm) were detected in four patients (mean age 49.5 years). Tumour-like smooth muscle proliferations were seen surrounding muscular arteries (eight), occasionally admixed with fat extending from the renal sinus mimicking angiomyolipoma. No similar tumours were found in 105 control kidneys. CONCLUSIONS: Benign haemangiomas are not uncommon in ESRD, but may be under-recognized. They display distinctive morphology and should be distinguished from angiosarcomas and capillary-rich renal cell carcinomas. PMID- 23020315 TI - von Willebrand factor: the old, the new and the unknown. AB - von Willebrand factor (VWF) is a protein best known from its critical role in hemostasis. Indeed, any dysfunction of VWF is associated with a severe bleeding tendency known as von Willebrand disease (VWD). Since the first description of the disease by Erich von Willebrand in 1926, remarkable progress has been made with regard to our understanding of the pathogenesis of this disease. The cloning of the gene encoding VWF has allowed numerous breakthroughs, and our knowledge of the epidemiology, genetics and molecular basis of VWD has been rapidly expanding since then. These studies have taught us that VWF is rather unique in terms of its multimeric structure and the unusual mechanisms regulating its participation in the hemostatic process. Moreover, it has become increasingly clear that VWF is a more all-round protein than originally thought, given its involvement in several pathologic processes beyond hemostasis. These include angiogenesis, cell proliferation, inflammation, and tumor cell survival. In the present article, an overview of advances concerning the various structural and functional aspects of VWF will be provided. PMID- 23020316 TI - Gibberellin indirectly promotes chloroplast biogenesis as a means to maintain the chloroplast population of expanded cells. AB - Chloroplast biogenesis needs to be well coordinated with cell division and cell expansion during plant growth and development to achieve optimal photosynthesis rates. Previous studies showed that gibberellins (GAs) regulate many important plant developmental processes, including cell division and cell expansion. However, the relationship between chloroplast biogenesis with cell division and cell expansion, and how GA coordinately regulates these processes, remains poorly understood. In this study, we showed that chloroplast division was significantly reduced in the GA-deficient mutants of Arabidopsis (ga1-3) and Oryza sativa (d18 AD), accompanied by the reduced expression of several chloroplast division related genes. However, the chloroplasts of both mutants exhibited increased grana stacking compared with their respective wild-type plants, suggesting that there might be a compensation mechanism linking chloroplast division and grana stacking. A time-course analysis showed that cell expansion-related genes tended to be upregulated earlier and more significantly than the genes related to chloroplast division and cell division in GA-treated ga1-3 leaves, suggesting the possibility that GA may promote chloroplast division indirectly through impacting leaf mesophyll cell expansion. Furthermore, our cellular and molecular analysis of the GA-response signaling mutants suggest that RGA and GAI are the major repressors regulating GA-induced chloroplast division, but other DELLA proteins (RGL1, RGL2 and RGL3) also play a role in repressing chloroplast division in Arabidopsis. Taken together, our data show that GA plays a critical role in controlling and coordinating cell division, cell expansion and chloroplast biogenesis through influencing the DELLA protein family in both dicot and monocot plant species. PMID- 23020317 TI - Perspective: Advances and challenges in treating van der Waals dispersion forces in density functional theory. AB - Electron dispersion forces play a crucial role in determining the structure and properties of biomolecules, molecular crystals, and many other systems. However, an accurate description of dispersion is highly challenging, with the most widely used electronic structure technique, density functional theory (DFT), failing to describe them with standard approximations. Therefore, applications of DFT to systems where dispersion is important have traditionally been of questionable accuracy. However, the last decade has seen a surge of enthusiasm in the DFT community to tackle this problem and in so-doing to extend the applicability of DFT-based methods. Here we discuss, classify, and evaluate some of the promising schemes to emerge in recent years. A brief perspective on the outstanding issues that remain to be resolved and some directions for future research are also provided. PMID- 23020318 TI - Affine-response model of molecular solvation of ions: Accurate predictions of asymmetric charging free energies. AB - Two mechanisms have been proposed to drive asymmetric solvent response to a solute charge: a static potential contribution similar to the liquid-vapor potential, and a steric contribution associated with a water molecule's structure and charge distribution. In this work, we use free-energy perturbation molecular dynamics calculations in explicit water to show that these mechanisms act in complementary regimes; the large static potential (~44 kJ/mol/e) dominates asymmetric response for deeply buried charges, and the steric contribution dominates for charges near the solute-solvent interface. Therefore, both mechanisms must be included in order to fully account for asymmetric solvation in general. Our calculations suggest that the steric contribution leads to a remarkable deviation from the popular "linear response" model in which the reaction potential changes linearly as a function of charge. In fact, the potential varies in a piecewise-linear fashion, i.e., with different proportionality constants depending on the sign of the charge. This discrepancy is significant even when the charge is completely buried, and holds for solutes larger than single atoms. Together, these mechanisms suggest that implicit solvent models can be improved using a combination of affine response (an offset due to the static potential) and piecewise-linear response (due to the steric contribution). PMID- 23020319 TI - The effect of the Perdew-Zunger self-interaction correction to density functionals on the energetics of small molecules. AB - Self-consistent calculations using the Perdew-Zunger self-interaction correction (PZ-SIC) to local density and gradient dependent energy functionals are presented for the binding energy and equilibrium geometry of small molecules as well as energy barriers of reactions. The effect of the correction is to reduce binding energy and bond lengths and increase activation energy barriers when bond breaking is involved. The accuracy of the corrected functionals varies strongly, the correction to the binding energy being too weak for the local density approximation but too strong for the gradient dependent functionals considered. For the Perdew, Burke, and Ernzerhof (PBE) functional, a scaling of the PZ-SIC by one half gives improved results on average for both binding energy and bond lengths. The PZ-SIC does not necessarily give more accurate total energy, but it can result in a better cancellation of errors. An essential aspect of these calculations is the use of complex orbitals. A restriction to real orbitals leads to less accurate results as was recently shown for atoms [S. Klupfel, P. Klupfel, and H. Jonsson, Phys. Rev. A 84, 050501 (2011)]. The molecular geometry of radicals can be strongly affected by PZ-SIC. An incorrect, non-linear structure of the C(2)H radical predicted by PBE is corrected by PZ-SIC. The CH(3) radical is correctly predicted to be planar when complex orbitals are used, while it is non-planar when the PZ-SIC calculation is restricted to real orbitals. PMID- 23020320 TI - Electron scattering cross sections from HCN over a broad energy range (0.1-10,000 eV): Influence of the permanent dipole moment on the scattering process. AB - We report theoretical integral and differential cross sections for electron scattering from hydrogen cyanide derived from two ab initio scattering potential methods. For low energies (0.1-100 eV), we have used the symmetry adapted-single centre expansion method using a multichannel scattering formulation of the problem. For intermediate and high energies (10-10,000 eV), we have applied an optical potential method based on a screening corrected independent atom representation. Since HCN is a strong polar molecule, further dipole-induced excitations have been calculated in the framework of the first Born approximation and employing a transformation to a space-fixed reference frame of the calculated K-matrix elements. Results are compared with experimental data available in the literature and a complete set of recommended integral elastic, inelastic, and total scattering cross sections is provided from 0.1 to 10,000 eV. PMID- 23020321 TI - Mean first-passage time for random walks in general graphs with a deep trap. AB - We provide an explicit formula for the global mean first-passage time (GMFPT) for random walks in a general graph with a perfect trap fixed at an arbitrary node, where GMFPT is the average of mean first-passage time to the trap over all starting nodes in the whole graph. The formula is expressed in terms of eigenvalues and eigenvectors of Laplacian matrix for the graph. We then use the formula to deduce a tight lower bound for the GMFPT in terms of only the numbers of nodes and edges, as well as the degree of the trap, which can be achieved in both complete graphs and star graphs. We show that for a large sparse graph, the leading scaling for this lower bound is proportional to the system size and the reciprocal of the degree for the trap node. Particularly, we demonstrate that for a scale-free graph of size N with a degree distribution P(d) ~ d(-gamma) characterized by gamma, when the trap is placed on a most connected node, the dominating scaling of the lower bound becomes N(1-1/gamma), which can be reached in some scale-free graphs. Finally, we prove that the leading behavior of upper bounds for GMFPT on any graph is at most N(3) that can be reached in the bar-bell graphs. This work provides a comprehensive understanding of previous results about trapping in various special graphs with a trap located at a specific location. PMID- 23020322 TI - Time-dependent importance sampling in semiclassical initial value representation calculations for time correlation functions. II. A simplified implementation. AB - An efficient time-dependent (TD) Monte Carlo (MC) importance sampling method has recently been developed [G. Tao and W. H. Miller, J. Chem. Phys. 135, 024104 (2011)] for the evaluation of time correlation functions using the semiclassical (SC) initial value representation (IVR) methodology. In this TD-SC-IVR method, the MC sampling uses information from both time-evolved phase points as well as their initial values, and only the "important" trajectories are sampled frequently. Even though the TD-SC-IVR was shown in some benchmark examples to be much more efficient than the traditional time-independent sampling method (which uses only initial conditions), the calculation of the SC prefactor-which is computationally expensive, especially for large systems-is still required for accepted trajectories. In the present work, we present an approximate implementation of the TD-SC-IVR method that is completely prefactor-free; it gives the time correlation function as a classical-like magnitude function multiplied by a phase function. Application of this approach to flux-flux correlation functions (which yield reaction rate constants) for the benchmark H + H(2) system shows very good agreement with exact quantum results. Limitations of the approximate approach are also discussed. PMID- 23020323 TI - Extension of local response dispersion method to excited-state calculation based on time-dependent density functional theory. AB - We report the extension of the local response dispersion (LRD) method to the excited-state calculation based on time-dependent density functional theory. The difference density matrix, which is usually used for excited-state response properties, enables a state-specific dispersion correction. The numerical assessment proves that interaction energies of exciton-localized molecular complexes and their shifts from the ground state are accurately reproduced by the LRD method. Furthermore, we find that the dispersion correction is important in reproducing binding energies of aromatic excimers, despite the existence of other attractive forces such as exciton delocalization and charge-transfer interaction. PMID- 23020324 TI - On the stability of ion water clusters at atmospheric conditions: Open system Monte Carlo simulation. AB - The formation of water clusters on Li(+), Na(+), K(+), Cl(-), and I(-) ions from water vapor at atmospheric conditions have been studied using Monte Carlo simulations. The extended simple point charge model has been employed for water molecules. The polarization of ions in the field of molecules and the polarization of molecules in the field of ions have been considered explicitly in the total Hamiltonian of the molecular system. The cluster formation work and the Gibbs free energy and enthalpy of attachment reactions of one water molecule to the cluster have been calculated via the bicanonical ensemble method. Our results reveal the formation of stable clusters in equilibrium with the moist atmosphere in a wide range of vapor pressure values, with largest clusters are formed around cations. Decreasing the temperature, from 293 K to 253 K, leads to the formation of larger equilibrium clusters, and enhances the stability of systems as whole. According to clusters' molecular structures, negative ions are expected to be more active in atmospheric processes, including chemical reactions and cloud formation, than positive ones. PMID- 23020325 TI - Interaction between coinage metal cations M(II) and Xe: CCSD(T) study of MXen 2+(M = Cu, Ag, and Au, n = 1-6). AB - Quantum chemical calculations of the structures, stabilities, and interactions of the title series at the coupled-cluster single double triple theoretical level are performed. The n = 2 systems are more stable than its neighbors. Topological analysis of the Laplacian, electron density deformation, electron localization function, bond critical point properties, and reduced density gradient analysis are performed to explore the nature of the interaction. The results show that a covalent contribution occurs in the Xe-M(2+) intermediate interaction. PMID- 23020326 TI - Electronic transitions of platinum monoboride. AB - The electronic transition spectrum of platinum monoboride (PtB) radical has been observed for the first time. Using laser vaporization/reaction free jet expansion and laser induced fluorescence spectroscopy, the optical spectrum of PtB in the visible region between 455 and 520 nm has been studied. Gas-phase PtB molecule was produced by the reaction of diborane (B(2)H(6)) seeded in argon and laser ablated platinum atom. Seven vibrational bands of the Pt(11)B radical have been recorded and analyzed. The observation of Pt isotopic molecules and the Pt(10)B isotope confirmed the carrier of the bands. Two different transition systems, namely: the [20.2]3/2-X(2)Sigma(+) and the [21.2]1/2-X(2)Sigma(+) systems were identified. PtB was determined to have an X(2)Sigma(+) ground state and the bond length, r(e), was determined to be 1.741 A. PMID- 23020327 TI - Assessment of density functional theory for iron(II) molecules across the spin crossover transition. AB - Octahedral Fe(2+) molecules are particularly interesting as they often exhibit a spin-crossover transition. In spite of the many efforts aimed at assessing the performances of density functional theory for such systems, an exchange correlation functional able to account accurately for the energetic of the various possible spin-states has not been identified yet. Here, we critically discuss the issues related to the theoretical description of this class of molecules from first principles. In particular, we present a comparison between different density functionals for four ions, namely, [Fe(H(2)O)(6)](2+), [Fe(NH(3))(6)](2+), [Fe(NCH)(6)](2+), and [Fe(CO)(6)](2+). These are characterized by different ligand-field splittings and ground state spin multiplicities. Since no experimental data are available for the gas phase, the density functional theory results are benchmarked against those obtained with diffusion Monte Carlo, one of the most accurate methods available to compute ground state total energies of quantum systems. On the one hand, we show that most of the functionals considered provide a good description of the geometry and of the shape of the potential energy surfaces. On the other hand, the same functionals fail badly in predicting the energy differences between the various spin states. In the case of [Fe(H(2)O)(6)](2+), [Fe(NH(3))(6)](2+), [Fe(NCH)(6)](2+), this failure is related to the drastic underestimation of the exchange energy. Therefore, quite accurate results can be achieved with hybrid functionals including about 50% of Hartree-Fock exchange. In contrast, in the case of [Fe(CO)(6)](2+), the failure is likely to be caused by the multiconfigurational character of the ground state wave-function and no suitable exchange and correlation functional has been identified. PMID- 23020328 TI - Experimental and theoretical studies of ammonia generation: Reactions of H2 with neutral cobalt nitride clusters. AB - Ammonia generation through reaction of H(2) with neutral cobalt nitride clusters in a fast flow reactor is investigated both experimentally and theoretically. Single photon ionization at 193 nm is used to detect neutral cluster distributions through time-of-flight mass spectrometry. Co(m)N(n) clusters are generated through laser ablation of Co foil into N(2)/He expansion gas. Mass peaks Co(m)NH(2) (m = 6, 10) and Co(m)NH(3) (m = 7, 8, 9) are observed for reactions of H(2) with the Co(m)N(n) clusters. Observation of these products indicates that clusters Co(m)N (m = 7, 8, 9) have high reactivity with H(2) for ammonia generation. Density functional theory (DFT) calculations are performed to explore the potential energy surface for the reaction Co(7)N + 3/2H(2) -> Co(7)NH(3), and a barrierless, thermodynamically favorable pathway is obtained. An odd number of hydrogen atoms in Co(m)NH(3) (m = 7, 8, 9) probably come from the hydrogen molecule dissociation on two active cobalt nitride clusters based on the DFT calculations. Both experimental observations and theoretical calculations suggest that hydrogen dissociation on two active cobalt nitride clusters is the key step to form NH(3) in a gas phase reaction. A catalytic cycle for ammonia generation from N(2) and H(2) on a cobalt metal catalyst surface is proposed based on our experimental and theoretical investigations. PMID- 23020329 TI - On the relationship between bond-length alternation and many-electron self interaction error. AB - Predicting accurate bond-length alternations (BLAs) in long conjugated molecular chains has been a major challenge for electronic-structure theory for many decades. While Hartree-Fock (HF) overestimates BLA significantly, second-order perturbation theory and commonly used density functional theory (DFT) approaches typically underestimate it. Here, we discuss how this failure is related to the many-electron self-interaction error (MSIE), which is inherent to both HF and DFT approaches. We use tuned long-range corrected hybrids to minimize the MSIE for a series of polyenes. The key result is that the minimization of the MSIE alone does not yield accurate BLAs. On the other hand, if the range-separation parameter is tuned to yield accurate BLAs, we obtain a significant MSIE that grows with chain length. Our findings demonstrate that reducing the MSIE is one but not the only important aspect necessary to obtain accurate BLAs from density functional theory. PMID- 23020330 TI - Symmetry interplay in Brownian photomotors: From a single-molecule device to ensemble transport. AB - Unlike most of Brownian motor models in which the state of a point particle is described by a single scalar fluctuating parameter, we consider light-induced dichotomic fluctuations of electron density distributions in an extended molecule moving in the electrostatic periodic potential of a polar substrate. This model implies that the potential energy profiles of two motor states differ substantially and their symmetry is dictated by the interplay between the symmetries of the substrate potential and of molecular electronic states. As shown, a necessary condition for the occurrence of directed motion, the asymmetry of the potential energy profiles, is satisfied for (i) symmetric electron density distributions in molecules on asymmetric substrates and (ii) asymmetric electron density distributions in molecules on symmetric substrates. In the former case, the average velocity of directed motion is independent of molecular orientations and the ensemble of molecules moves as a whole, whereas in the latter case, oppositely oriented molecules move counterdirectionally thus causing the ensemble to diffuse. Using quantum chemical data for a specific organic-based photomotor as an example, we demonstrate that the behavior of molecular ensembles is controllable by switching on/off resonance laser radiation: they can be transported as a whole or separated into differently oriented molecules depending on the ratio of symmetric and antisymmetric contributions to the substrate electrostatic potential and to the molecular electron density distributions. PMID- 23020331 TI - First principle evaluation of the chiroptical activity of the di-phenyl-diazene derivatives. AB - Azobenzene (di-phenyl-diazene) is well-known as a photoisomerisable molecule and has been widely studied as a molecular photoswitcher. Molecular rods, where di phenyl arms are bound to the diazene moiety, have been also synthesized. In this article we explore by first principle density functional theory calculations the chiroptical properties (electronic circular dichroism spectra, ECD) of azobenzene and its homologues with polyphenyl arms. In particular, we demonstrate that for molecules in the cis configuration the intrinsic chirality of the distorted cis diazene group dominates the ECD response, while for trans species the non planarity of the polyphenyl arms induces peaks in the ECD spectrum. Finally, the possibility of obtaining a light-controlled chiral switch by proper functionalization is also speculated. PMID- 23020332 TI - Competitive fragmentation pathways of acetic acid dimer explored by synchrotron VUV photoionization mass spectrometry and electronic structure calculations. AB - In present study, photoionization and dissociation of acetic acid dimers have been studied with the synchrotron vacuum ultraviolet photoionization mass spectrometry and theoretical calculations. Besides the intense signal corresponding to protonated cluster ions (CH(3)COOH)(n).H(+), the feature related to the fragment ions (CH(3)COOH)H(+).COO (105 amu) via beta-carbon-carbon bond cleavage is observed. By scanning photoionization efficiency spectra, appearance energies of the fragments (CH(3)COOH).H(+) and (CH(3)COOH)H(+).COO are obtained. With the aid of theoretical calculations, seven fragmentation channels of acetic acid dimer cations were discussed, where five cation isomers of acetic acid dimer are involved. While four of them are found to generate the protonated species, only one of them can dissociate into a C-C bond cleavage product (CH(3)COOH)H(+).COO. After surmounting the methyl hydrogen-transfer barrier 10.84 +/- 0.05 eV, the opening of dissociative channel to produce ions (CH(3)COOH)(+) becomes the most competitive path. When photon energy increases to 12.4 eV, we also found dimer cations can be fragmented and generate new cations (CH(3)COOH).CH(3)CO(+). Kinetics, thermodynamics, and entropy factors for these competitive dissociation pathways are discussed. The present report provides a clear picture of the photoionization and dissociation processes of the acetic acid dimer in the range of the photon energy 9-15 eV. PMID- 23020333 TI - Short- and long-range binding of Be with Mg in the X1Sigma+ ground state and in the A1Pi excited state. AB - We present results of configuration-interaction (CI) computations of wavefunctions and of properties of the first two singlet states, X(1)Sigma(+) and A(1)Pi, of the, as yet unobserved, BeMg polar molecule, for internuclear distances in the range [2.5-1000] A. The X(1)Sigma(+) state is very weakly bound, (D(e) = 469.4 cm(-1) at R(e) = 3.241 A), whereas the A(1)Pi state, which correlates with the excited dissociation channel [Mg KL3s3p(1)P(o) + Be 1s(2)2s(2) (1)S], is bound rather strongly (D(e) = 19 394 cm(-1) (55.5 kcal/mol) at R(e) = 2.385 A). The X(1)Sigma(+) state supports 12 vibrational levels, for which vibrationally averaged dipole moments, (upsilon), were obtained, while 71 vibrational levels were found for A(1)Pi. For the level (X(1)Sigma(+)), (0) = 0.213 D. The upsilon(") = 7 and 8 X(1)Sigma(+) vibrational levels are found to have the highest probability to be reached via emission from the lowest lying vibrational levels of A(1)Pi. The work had a dual outcome: First, it explored consequences of different choices of the state-specific reference "Fermi sea" space ("active" space), which is required for the construction and execution of the multiconfigurational "complete active space self-consistent field" calculations and the subsequent multi-reference CI calculations. In this context, comparisons with results on the weakly bound ground states of the homonuclear Be(2) and Mg(2) molecules were made. Second, it produced reliable data for the short- as well as the long-range parts of the potential energy curve (PEC). Such information is relevant to analyses concerning cold and ultra-cold Physics and Chemistry. For example, accurate fits to the X(1)Sigma(+) PEC, which was computed to nano-Hartree accuracy, with account for basis-set-superposition error, produced the C(6) and C(8) dispersion coefficients as 364.3 +/- 1.1 a.u. and 28 000 +/- 500 a.u., respectively. The result for C(6) is in excellent agreement with that of Derevianko et al. [At. Data Nucl. Data Tables 96, 323 (2010)], (364 +/- 4 a.u.), that was obtained in the framework of the theory of long-range interactions and many-body calculations on the constituent atoms. On the other hand, our result for C(8) differs from that of Standard and Certain [J. Chem. Phys. 83, 3002 (1985)] by about 7000 a.u. PMID- 23020334 TI - The vibrationally mediated photodissociation of Cl2. AB - The photodissociation of vibrationally excited Cl(2)(v = 1) has been investigated experimentally using the velocity mapped ion imaging technique. The experimental measurements presented here are compared with the results of time-dependent wavepacket calculations performed on a set of ab initio potential energy curves. The high level calculations allow prediction of all the dynamical information regarding the dissociation, including electronic polarization effects. Using a combination of theory and experiment it was found that there was negligible cooling of the vibrational degree of freedom of the parent molecule in the molecular beam. The results presented are compared with those following the photodissociation of Cl(2)(v = 0). Although the same electronic states are found to be important for Cl(2)(v = 1) as for Cl(2)(v = 0), significant differences were found regarding many of the observables. The overall level of agreement between theory and experiment was found to be reasonable and confirms previous assignments of the photodissociation mechanism. PMID- 23020336 TI - Properties of the B+-H2 and B+-D2 complexes: A theoretical and spectroscopic study. AB - The rotationally resolved infrared spectrum of the B(+)-D(2) ion-neutral complex is recorded in the D-D stretch vibration region (2805-2875 cm(-1)) by detecting B(+) photofragments. Analysis of the spectrum confirms a T-shaped equilibrium geometry for the B(+)-D(2) complex with a vibrationally averaged intermolecular bond length of 2.247 A, around 0.02 A shorter than for the previously characterised B(+)-H(2) complex [V. Dryza, B. L. J. Poad, and E. J. Bieske, J. Am. Chem. Soc. 130, 12986 (2008)]. The D-D stretch band centre occurs at 2839.76 +/- 0.10 cm(-1), representing a -153.8 cm(-1) shift from the Q(1)(0) transition of the free D(2) molecule. A new three dimensional ab initio potential energy surface for the B(+)+H(2) interaction is calculated using the coupled cluster RCCSD(T) method and is used in variational calculations for the rovibrational energies of B(+)-H(2) and B(+)-D(2). The calculations predict dissociation energies of 1254 cm(-1) for B(+)-H(2) with respect to the B(+)+H(2) (j = 0) limit, and 1313 cm(-1) for B(+)-D(2) with respect to the B(+)+D(2) (j = 0) limit. The theoretical approach reproduces the rotational and centrifugal constants of the B(+)-H(2) and B(+)-D(2) complexes to within 3%, and the magnitude of the contraction of the intermolecular bond accompanying excitation of the H(2) or D(2) sub-unit, but underestimates the H-H and D-D vibrational band shifts by 7%-8%. Combining the theoretical and experimental results allows a new, more accurate estimation for the B(+)-H(2) band origin (3939.64 +/- 0.10 cm( 1)). PMID- 23020335 TI - A GGA+U approach to effective electronic correlations in thiolate-ligated iron oxo (IV) porphyrin. AB - High-valent oxo-metal complexes exhibit correlated electronic behavior on dense, low-lying electronic state manifolds, presenting challenging systems for electronic structure methods. Among these species, the iron-oxo (IV) porphyrin denoted Compound I occupies a privileged position, serving a broad spectrum of catalytic roles. The most reactive members of this family bear a thiolate axial ligand, exhibiting high activity toward molecular oxygen activation and substrate oxidation. The default approach to such systems has entailed the use of hybrid density functionals or multi-configurational/multireference methods to treat electronic correlation. An alternative approach is presented based on the GGA+U approximation to density functional theory, in which a generalized gradient approximation (GGA) functional is supplemented with a localization correction to treat on-site correlation as inspired by the Hubbard model. The electronic structure of thiolate-ligated iron-oxo (IV) porphyrin and corresponding Coulomb repulsion U are determined both empirically and self-consistently, yielding spin distributions, state level splittings, and electronic densities of states consistent with prior hybrid functional calculations. Comparison of this detailed electronic structure with model Hamiltonian calculations suggests that the localized 3d iron moments induce correlation in the surrounding electron gas, strengthening local moment formation. This behavior is analogous to strongly correlated electronic systems such as Mott insulators, in which the GGA+U scheme serves as an effective single-particle representation for the full, correlated many-body problem. PMID- 23020337 TI - Dielectric and structural properties of aqueous nonpolar solute mixtures. AB - The dielectric properties and molecular structure of water mixtures with different nonpolar solutes (methane and noble gases) are studied using molecular dynamics. The water-water, water-solute, and solute-solute interactions are calculated using the combination of a polarizable potential [J. Li, Z. Zhou, and R. J. Sadus, J. Chem. Phys. 127, 154509 (2007)] for water plus the Lennard-Jones potential. The effect of solute size and concentration on the solubility of the system, hydrogen bonding, dielectric constant, and dipole moment are investigated over a temperature range of 278-750 K and solute percentage mole fractions up to 30%. Solute particles affect the structure of water, resulting in the compression of oxygen-oxygen and oxygen-hydrogen radial distribution functions. The influence of the solute extends both to relatively low concentrations and high temperatures. The coordination numbers of aqueous solutions of the nonpolar solutes appear to be proportional to the size of the solute particles. Our study shows the destructive influence of the nonpolar solute on both the tetrahedral water structure and hydrogen bond formation at solute concentrations greater than 30%. The presence of nonpolar particles typically decreases both the dielectric constant and dipole moment. The decrease of dielectric constant and water dipole moment is directly proportional to the solute concentration and temperature. PMID- 23020338 TI - Ca2+ solvation as a function of p, T, and pH from ab initio simulation. AB - First principles molecular dynamics simulations have been carried out at various temperatures and pressures starting with either Ca(2+) or CaO in a reactive volume of 63 H(2)O molecules. In the case of aqueous Ca(2+), the ion is surrounded by six H(2)O molecules in the first hydration shell at 300 K/0.3 GPa, with rare exchange between first and second hydrations shells. At 900 K/0.9 GPa, the coordination number in the first hydration shell fluctuates between six and eight, the average being 7.0. CaO immediately reacts with the surrounding H(2)O molecules to form Ca(2+) + 2OH(-). The hydroxyl ions form transient Ca(OH)(+) and Ca(OH)(2) complexes and have a mean residence time in the first coordination shell of Ca(2+) of 6 +/- 4 ps at 500 K and 3 +/- 3 ps at 900 K, respectively. At 500 K/0.5 GPa, the time-averaged relative concentrations of the transient Ca(2+), Ca(OH)(+), and Ca(OH)(2) species are 14%, 55%, and 29%, while at 900 K/0.9 GPa, they are 2%, 34%, and 63%. PMID- 23020339 TI - Partial molar quantity of an intensive mother function. AB - A new formal definition is given to the partial molar quantity of a component i for an intensive mother function. We perturb the entire system by increasing the amount of the target component by deltan(i) keeping others constant and measure the response of the system in terms of an intensive mother function, Phi, deltaPhi. We then define its partial molar quantity of the ith component, phi(i), as phi(i) = [deltaPhi/{deltan(i)/(N + deltan(i))]] in the limit of deltan(i) -> 0. Thus, the physical meaning of phi(i) is the effect of the ith component (only) on Phi of the system, just as the partial molar quantity for an extensive mother function. This new formal definition could serve as a starting point for statistical mechanics development of a microscopic connection to the third derivatives of G. We show a number of examples such as an enthalpic inter-solute interaction, a partial molar S-V cross fluctuation density of solute, their analogues, and an excess partial molar absorptivity of solute. These examples were used for studying the nature of aqueous solutions without realizing their formal definition and were instrumental in advancing our understandings. PMID- 23020340 TI - Mechanism of mutarotation in supercooled liquid phase: Studies on L-sorbose. AB - We have studied mutarotation in anhydrous supercooled L-sorbose by means of dielectric spectroscopy. The phenomenon observed in L-sorbose is much faster than in the structurally similar D-fructose. The kinetics of this process has been determined by applying 1st order kinetics model. Activation energy equal to 68 kJ/mol was obtained from temperature dependence of rate constants. To understand differences in mutarotation rate between D-fructose and L-sorbose, quantum mechanical calculations were performed to study mechanism of this phenomenon. The possible impact of water absorbed from air on the mutarotation in supercooled liquid state has been checked. It turned out that the process is probably intermolecular and the water molecules or other carbohydrate molecules assist in the proton transfer process. Finally we have shown that the rate constant can be alternatively determined from frequency of the maximum of peak, obtained by performing Fourier transform of kinetic curve. PMID- 23020341 TI - Progressive transformations of silica glass upon densification. AB - The elastic and plastic behaviors of silica glasses densified at various maximum pressure reached (12 GPa, 15 GPa, 19 GPa, and 22 GPa), were analyzed using in situ Raman and Brillouin spectroscopies. The elastic anomaly was observed to progressively vanish up to a maximum pressure reached of 12 GPa, beyond which it is completely suppressed. Above the elastic anomaly the mechanical behavior of silica glass, as derived from Brillouin measurements, is interpreted in terms of pressure induced transformation of low density amorphous silica into high density amorphous silica. PMID- 23020342 TI - Free minimization of the fundamental measure theory functional: Freezing of parallel hard squares and cubes. AB - Due to remarkable advances in colloid synthesis techniques, systems of squares and cubes, once an academic abstraction for theorists and simulators, are nowadays an experimental reality. By means of a free minimization of the free energy functional, we apply fundamental measure theory to analyze the phase behavior of parallel hard squares and hard cubes. We compare our results with those obtained by the traditional approach based on the Gaussian parameterization, finding small deviations and good overall agreement between the two methods. For hard squares, our predictions feature at intermediate packing fraction a smectic phase, which is however expected to be unstable due to thermal fluctuations. Due to this inconsistency, we cannot determine unambiguously the prediction of the theory for the expected fluid-to-crystal transition of parallel hard squares, but we deduce two alternative scenarios: (i) a second-order transition with a coexisting vacancy-rich crystal or (ii) a higher-density first order transition with a coexisting crystal characterized by a lower vacancy concentration. In accordance with previous studies, a second-order transition with a high vacancy concentration is predicted for hard cubes. PMID- 23020343 TI - NMR and conductivity studies of the mixed glass former effect in lithium borophosphate glasses. AB - Alkali ion charge transport has been studied in a series of mixed glass former lithium borophosphate glasses of composition 0.33Li(2)O + 0.67[xB(2)O(3) + (1 - x)P(2)O(5)]. The entire concentration range, 0.0 <= x <= 1.0, from pure glassy Li(2)P(4)O(11) to pure glassy Li(2)B(4)O(7) has been examined while keeping the molar fraction of Li(2)O constant. Electrical conductivity measurements and nuclear magnetic resonance techniques such as spin relaxometry, line shape analysis, and stimulated-echo spectroscopy were used to examine the temperature and frequency dependence of the Li(+) ion motion over wide ranges of time scale and temperature. By accurately determining motional time scales and activation energies over the entire composition range the ion dynamics and the charge transport are found to be fastest if the borate and the phosphate fractions are similar. The nonlinear variation of the charge conduction, the most notable feature of the mixed glass former effect, is discussed in terms of the composition dependence of network former units which determine the local glass structure. PMID- 23020344 TI - Charge carrier dynamics and interactions in electric force microscopy. AB - In electric force microscopy, a charged atomic force microscope tip in vacuum senses a fluctuating electrical force generated by the sample. Such measurements can in principle probe electrical noise generated by moving charge carriers in an organic semiconductor. We present a theory of cantilever frequency fluctuations in electric force microscopy, driven by coupled charge carrier dynamics and dielectric fluctuations. The connection between observable frequency fluctuations in electric force microscopy and the Casimir-Lifshitz force is described. This classical electrodynamic calculation is based on Maxwell's equations coupled to diffusive carrier transport. The effects of carrier transport and inter-carrier interactions on the spectrum of cantilever frequency noise are elucidated. We find that a simplified model of freely diffusing carriers can overestimate cantilever frequency noise by several orders of magnitude because of the neglect of interactions. Electric force microscopy measurements on an organic field effect transistor are reported and qualitatively interpreted in terms of the suppression of electrical noise from charge carriers by Coulomb interactions. PMID- 23020345 TI - Water nucleation: A comparison between some phenomenological theories and experiment. AB - The predictions of several homogeneous nucleation theories are compared with experimental results for water for a range of temperatures and vapor supersaturations, S. The theoretical models considered are: classical theory (including the 1/S correction factor), the Gibbs p-form, mean-field kinetic nucleation theory (MKNT), the extended modified liquid drop model-dynamical nucleation theory, and two forms of density functional theory, one without and one with a contribution due to association. The theoretical expressions for the logarithm of the nucleation rate are expanded in a series in powers of the logarithm of S. The residual dependence (once the classical dependence has been factored out) of the experimental results shows a stronger decrease with increasing temperature than all the theories except MKNT. The residual S dependence of the experimental results decreases with increasing supersaturation whereas all the theories except the Gibbs p-form predict an increase. The first correction term to classical theory involves both the liquid compressibility and curvature correction to the surface tension (Tolman length) so the experimental results suggest that the Tolman length is zero (as assumed in the Gibbs p-form) or positive whereas the other theories predict a negative Tolman length. The effect of including a term proportional to ln(lnS) in the series expansion is also discussed. PMID- 23020346 TI - Position-displacement correlations in QELSS spectra of non-dilute colloids. AB - This paper examines relationships between the quasielastic light scattering spectrum S(q, t) and the distribution functions for particle displacements over various times. For dilute probes in a complex, non-scattering fluid, S(q, t) is determined by the even moments of the one-particle displacement distribution function P(X, t). For concentrated scattering particles, S(q, t) is not determined by P(X, t). Instead, S(q, t) is determined in part by P(X, t) and in part by a spatial Fourier transform of the two particle displacement distribution function P(2)(X, t, R(12)). Here, X is the displacement of particle 1 during t, and R(12) is the component (at t = 0), parallel to the scattering vector q, of the vector from particle 1 to a second particle 2. PMID- 23020347 TI - Mechanical properties and local mobility of atactic-polystyrene films under constant-shear deformation. AB - We have performed molecular-dynamics simulations of atactic polystyrene thin films to study the effect of shear rate, pressure, and temperature on the stress strain behaviour, the relevant energetic contributions and non-affine displacements of polymer chains during constant-shear deformation. Under this deformation sliding motion is observed at high shear rates between the top substrate and top polymer layer, which disappears when the shear rate decreases. At low shear rates stick-slip motion of the whole film with respect to the bottom substrate takes place. We found that at low shear rates the yield stress logarithmically depends on the shear rate; this behaviour can be explained in terms of the Eyring model. It was also observed that an increase in the normal pressure leads to an increase in the yield stress in agreement with experiments. The contributions to the total shear stress and energy are mainly given by the excluded-volume interactions. It corresponds to a local translational dynamics under constant shear in which particles are forced to leave their original cages much earlier as compared to the case of the isotropic, non-sheared film. Moreover, it was observed that under constant-shear deformation the polymer glass is deformed non-affinely. As a result, the middle part of the film is much more deformed than the layers close to the supporting substrates, meaning that the well-known effect of shear-banding occurs. PMID- 23020348 TI - Conformational transitions in semiflexible dendrimers induced by bond orientations. AB - We theoretically investigate the conformational properties of semiflexible dendrimers where the semiflexibility is implemented by topologically restricting the bond directions and orientations of the respective bond vectors. Molecular size (radius of gyration, R(g) and Wiener index, W), shape factor rho, configurational free energy F, and the static structure factor, S(q) of semiflexible dendrimers are analyzed as a function of the bond orientation angle, phi. The size of the lower generation dendrimers decreases with increasing phi throughout the entire range of phi, phi ? (0, pi). The higher generation dendrimers show a non-uniform behavior, for compressed conformations the size decreases with increasing phi, while for the expanded ones it increases with the increase in phi. A conformational transition occurs for the higher generation dendrimers from the limiting value of the hard sphere to an ideal chain with the change in phi. This conformational transition at phi = pi/2 is also reflected in the configurational free energy. The configurational free energy exhibits a discontinuous behavior with the variation of phi, and this discontinuity occurs at phi = pi/2. However, no such conformational transition is observed with the variation of the bond direction angle, theta, generation, G and functionality, f of the semiflexible dendrimers. The flexible dendrimer, i.e., at phi = pi/2 is flanked between the compressed and expanded conformations of the semiflexible dendrimers resembling a hard sphere. The Kratky plot of the structure factor of all conformations quantitatively match with the results obtained from experiments and simulations in the low q-region in respect to the position of the major Kratky peak. For higher wave numbers, the Kratky plots for all conformations of semiflexible dendrimers agree with earlier theoretical results of model dendrimers [R. La Ferla, J. Chem. Phys. 106, 688 (1997); F. Ganazzoli, R. La Ferla, and G. Raffaini, Macromolecules 34, 4222 (2001)] but are in sharp contrast to the experimental [S. Rathgeber et al., J. Chem. Phys. 117, 4047 (2002); S. Rathgeber, T. Pakula, and V. Urban, J. Chem. Phys. 121, 3840 (2004)] and simulated [M. L. Mansfield and L. I. Klushin, Macromolecules 26, 4262 (1993)] scattering curves for the higher generation dendrimers. All compressed conformations (0 < phi < pi/2) behave as compact hard spheres, while the expanded conformations (pi/2 < phi < pi) are relatively more open, partially decongesting the steric crowding among the monomers with increasing phi. PMID- 23020349 TI - Two-dimensional electronic spectroscopy of bacteriochlorophyll a in solution: Elucidating the coherence dynamics of the Fenna-Matthews-Olson complex using its chromophore as a control. AB - Following the observation of long-lived coherences in the two-dimensional (2D) electronic spectra of the Fenna-Matthews-Olson (FMO) complex, many theoretical works suggest that coherences between excitons may play a role in the efficient energy transfer that occurs in photosynthetic antennae. This interpretation of the dynamics depends on the assignment of quantum beating signals to superpositions of excitons, which is complicated by the possibility of observing both electronic and vibrational coherences in 2D spectra. Here, we explore 2D spectra of bacteriochlorophyll a (BChla) in solution in an attempt to isolate vibrational beating signals in the absence of excitonic signals to identify the origin of the quantum beats in 2D spectra of FMO. Even at high laser power, our BChla spectra show strong beating only from the nonresonant response of the solvent. The beating signals that we can conclusively assign to vibrational modes of BChla are only slightly above the noise and at higher frequencies than those previously observed in spectra of FMO. Our results suggest that the beating observed in spectra of FMO is of a radically different character than the signals observed here and can therefore be attributed to electronic coherences or intermolecular degrees of freedom. PMID- 23020350 TI - Counting statistics for genetic switches based on effective interaction approximation. AB - Applicability of counting statistics for a system with an infinite number of states is investigated. The counting statistics has been studied a lot for a system with a finite number of states. While it is possible to use the scheme in order to count specific transitions in a system with an infinite number of states in principle, we have non-closed equations in general. A simple genetic switch can be described by a master equation with an infinite number of states, and we use the counting statistics in order to count the number of transitions from inactive to active states in the gene. To avoid having the non-closed equations, an effective interaction approximation is employed. As a result, it is shown that the switching problem can be treated as a simple two-state model approximately, which immediately indicates that the switching obeys non-Poisson statistics. PMID- 23020351 TI - Enhanced sampling molecular dynamics simulation captures experimentally suggested intermediate and unfolded states in the folding pathway of Trp-cage miniprotein. AB - The ability of molecular dynamics simulation to capturing the transient states within the folding pathway of protein is important to the understanding of protein folding mechanism. In the present study, the integrated-tempering sampling molecular dynamics (ITS-MD) simulation was performed to investigate the transient states including intermediate and unfolded ones in the folding pathway of a miniprotein, Trp-cage. Three force fields (FF03, FF99SB, and FF96) were tested, and both intermediate and unfolded states with their characteristics in good agreement with experiments were observed during the simulations, which supports the hypothesis that observable intermediates might present in the folding pathway of small polypeptides. In addition, it was demonstrated that FF03 force field as combined with ITS-MD is in overall a more proper force field than the others in reproducing experimentally recorded properties in UVRS, ECD, and NMR, Photo-CIDNP NMR, and IR T-jump experiments, and the folding/unfolding thermodynamics parameters, such as DeltaG(U), DeltaC(p), and DeltaH(U) (T(m)). In summary, the present study showed that using suitable force field and energy sampling method, molecular dynamics simulation could capture the transient states within the folding pathway of protein which are consistent with the experimental measurements, and thus provide information of protein folding mechanism and thermodynamics. PMID- 23020352 TI - Comment on "Soret motion in non-ionic binary molecular mixtures" [J. Chem. Phys. 135, 054102 (2011)]. AB - The material transport equations derived in the article by Leroyer and Wurger [J. Chem. Phys. 135, 054102 (2011)] do not adequately provide a description of material transport in liquid binary systems. An alternate approach based on non equilibrium thermodynamics is presented. PMID- 23020355 TI - Invited review article: physics and Monte Carlo techniques as relevant to cryogenic, phonon, and ionization readout of Cryogenic Dark Matter Search radiation detectors. AB - This review discusses detector physics and Monte Carlo techniques for cryogenic, radiation detectors that utilize combined phonon and ionization readout. A general review of cryogenic phonon and charge transport is provided along with specific details of the Cryogenic Dark Matter Search detector instrumentation. In particular, this review covers quasidiffusive phonon transport, which includes phonon focusing, anharmonic decay, and isotope scattering. The interaction of phonons in the detector surface is discussed along with the downconversion of phonons in superconducting films. The charge transport physics include a mass tensor which results from the crystal band structure and is modeled with a Herring-Vogt transformation. Charge scattering processes involve the creation of Neganov-Luke phonons. Transition-edge-sensor (TES) simulations include a full electric circuit description and all thermal processes including Joule heating, cooling to the substrate, and thermal diffusion within the TES, the latter of which is necessary to model normal-superconducting phase separation. Relevant numerical constants are provided for these physical processes in germanium, silicon, aluminum, and tungsten. Random number sampling methods including inverse cumulative distribution function (CDF) and rejection techniques are reviewed. To improve the efficiency of charge transport modeling, an additional second order inverse CDF method is developed here along with an efficient barycentric coordinate sampling method of electric fields. Results are provided in a manner that is convenient for use in Monte Carlo and references are provided for validation of these models. PMID- 23020356 TI - Laser Doppler velocimetry based on the optoacoustic effect in a RF-excited CO2 laser. AB - We present a compact optoacoustic laser Doppler velocimetry method that utilizes the self-mixing effect in a RF-excited CO(2) laser. A portion of a Doppler shifted laser beam, produced by irradiating a single wavelength laser beam on a moving object, is mixed with an originally existing laser beam inside a laser cavity. The fine change of pressure in the laser cavity modulated by the Doppler shifted frequency is detected by a condenser microphone in the laser tube. In our studies, the frequency of the Doppler signal due to the optoacoustic effect was detected as high as 50 kHz. Our measurements also confirmed that the signal varied linearly with the velocity of the external scatterer (the moving object) and the cosine of the angle between the laser beam and the velocity vector of the object. PMID- 23020358 TI - Velocity map photoelectron-photoion coincidence imaging on a single detector. AB - Here we report on a new simplified setup for velocity map photoelectron-photoion coincidence imaging using only a single particle detector. We show that both photoelectrons and photoions can be extracted toward the same micro-channel-plate delay line detector by fast switching of the high voltages on the ion optics. This single detector setup retains essentially all the features of a standard two detector coincidence imaging setup, viz., the high spatial resolution for electron and ion imaging, while only slightly decreasing the ion time-of-flight mass resolution. The new setup paves the way to a significant cost reduction in building a coincidence imaging setup for experiments aiming to obtain the complete correlated three-dimensional momentum distribution of electrons and ions. PMID- 23020357 TI - Effect of photodiode angular response on surface plasmon resonance measurements in the Kretschmann-Raether configuration. AB - We study the effect of photodiode angular response on the measurement of surface plasmon resonance (SPR) in metallic thin films using the Kretschmann-Raether configuration. The photodiode signal depends not only on the light intensity but also on the incidence angle. This implies that the photodiode sensitivity changes along the SPR curve. Consequently, the measured SPR spectrum is distorted, thus affecting fits and numerical analyses of SPR curves. We analyze the magnitude of this change, determine when it is significant, and develop a calibration method of the experimental setup which corrects for this type of spectral shape distortions. PMID- 23020359 TI - A digital optical phase-locked loop for diode lasers based on field programmable gate array. AB - We have designed and implemented a highly digital optical phase-locked loop (OPLL) for diode lasers in atom interferometry. The three parts of controlling circuit in this OPLL, including phase and frequency detector (PFD), loop filter and proportional integral derivative (PID) controller, are implemented in a single field programmable gate array chip. A structure type compatible with the model MAX9382/MCH12140 is chosen for PFD and pipeline and parallelism technology have been adapted in PID controller. Especially, high speed clock and twisted ring counter have been integrated in the most crucial part, the loop filter. This OPLL has the narrow beat note line width below 1 Hz, residual mean-square phase error of 0.14 rad(2) and transition time of 100 MUs under 10 MHz frequency step. A main innovation of this design is the completely digitalization of the whole controlling circuit in OPLL for diode lasers. PMID- 23020360 TI - Femtosecond pump/supercontinuum-probe setup with 20 kHz repetition rate. AB - We developed a fast multichannel detection system for pump-probe spectroscopy, capable of detecting single shot super-continuum spectra at the repetition rate (10-50 kHz) of an amplified femtosecond laser system. By tandem pumping the amplifier with three pump lasers we obtain very low noise operation, with less than 0.1% rms intensity fluctuations at the output of the amplifier. We also propose an alternative way of chopping the pump beam. With a synchronized scanning mirror two spots in the sample are illuminated by the train of pump pulses in an alternating fashion, such that when both spots are interrogated by the probe pulse, the duty cycle of the experiment is doubled. PMID- 23020361 TI - Multiangle static and dynamic light scattering in the intermediate scattering angle range. AB - We describe a light scattering apparatus based on a novel optical scheme covering the scattering angle range 0.5 degrees <= theta <= 25 degrees , an intermediate regime at the frontier between wide angle and small angle setups that is difficult to access by existing instruments. Our apparatus uses standard, readily available optomechanical components. Thanks to the use of a charge-coupled device detector, both static and dynamic light scattering can be performed simultaneously at several scattering angles. We demonstrate the capabilities of our apparatus by measuring the scattering profile of a variety of samples and the Brownian dynamics of a dilute colloidal suspension. PMID- 23020362 TI - The resolution estimation of wedge and strip anodes. AB - A new resolution estimation method for wedge and strip anode based on the single photon imaging configuration is provided. The limiting resolution estimation equation is deduced theoretically according to the threshold principle. The relation between the charge cloud and the covered electrodes is discussed, and the equivalent diameter number is calculated. The resolution equation for the position deviation amplitude or FWHM is provided if noise exists. The relation between the position deviation amplitude and the total charge deviation amplitudes is discussed. The constancy of the position deviation amplitudes versus positions is provided. The results calculated from these equations are discussed. According to the equations, it is indicated that the spatial resolution is affected by the detection system configuration and noise. These conclusions may be useful for the designing and performance improvement of future photon imagers. PMID- 23020363 TI - Performance of the NIST goniocolorimeter with a broad-band source and multichannel charged coupled device based spectrometer. AB - The authors describe the NIST high-efficiency instrument for measurements of bidirectional reflectance distribution function of colored materials, including gonioapparent materials such as metallic and pearlescent coatings. The five-axis goniospectrometer measures the spectral reflectance of samples over a wide range of illumination and viewing angles. The implementation of a broad-band source and a multichannel CCD spectrometer corrected for stray light significantly increased the efficiency of the goniometer. In the extended range of 380 nm to 1050 nm, a reduction of measurement time from a few hours to a few minutes was obtained. Shorter measurement time reduces the load on the precise mechanical assembly ensuring high angular accuracy over time. We describe the application of matrix based correction of stray light and the extension of effective dynamic range of measured fluxes to the values of 10(6) to 10(7) needed for the absolute characterization of samples. The measurement uncertainty was determined to be 0.7% (k = 2), which is comparable with similar instruments operating in a single channel configuration. Several examples of reflectance data obtained with the improved instrument indicate a 0.3% agreement compared to data collected with the single channel configuration. PMID- 23020364 TI - A versatile detector for total fluorescence and electron yield experiments. AB - The combination of a non-coated silicon photodiode with electron repelling meshes makes a versatile detector for total fluorescence yield and electron yield techniques highly suitable for x-ray absorption spectroscopy. In particular, a copper mesh with a bias voltage allows to suppress or transmit the electron yield signal. The performance of this detection scheme has been characterized by near edge x-ray absorption fine structure studies of thermal oxidized silicon and sapphire. The results show that the new detector probes both electron yield and for a bias voltage exceeding the maximum photon energy the total fluorescence yield. PMID- 23020365 TI - Frequency comb assisted mid-infrared spectroscopy of cold molecular ions. AB - A mid-infrared spectrometer consisting of a high power optical parametric oscillator, a frequency comb, and a cold ion trap is described and characterized. The idler frequency at 3 MUm is measured accurately by analyzing the pump and signal beat frequencies with the comb. This is done via two spectrum analyzers, allowing for a wide and continuous scanning ideal for spectroscopy of cold molecules with unknown spectra. The potential of this approach is demonstrated by measuring a ro-vibrational line of CH(5)(+) in a 22-pole ion trap via action spectroscopy of only several thousand cold ions. The current setup limits the precision of the line center frequency determination to some 100 kHz with ample room for future improvements. Following this approach, ground state combination differences of molecular ions can be predicted in order to identify them in astronomical objects. PMID- 23020366 TI - Quasi-bichromatic laser for a lin[perpendicular]lin coherent population trapping clock produced by vertical-cavity surface-emitting lasers. AB - With two vertical-cavity surface-emitting lasers working under the master-slave sideband injection-locking configuration, we have realized a quasi-bichromatic laser beam with residual phase noise Deltaphi(2) < 0.282 rad(2). The two wanted frequency components share more than 96% power of the beam. With the realized beam, we have carried out coherent population trapping (CPT) resonance experiment with (87)Rb in the lin[perpendicular]lin CPT scheme, and recorded CPT resonance signal with contrast of 60%. Such laser system is promising to realize a lin[perpendicular]lin CPT clock with high performance and low power consumption. PMID- 23020367 TI - Angle-resolved environmental X-ray photoelectron spectroscopy: a new laboratory setup for photoemission studies at pressures up to 0.4 Torr. AB - The paper presents the development and demonstrates the capabilities of a new laboratory-based environmental X-ray photoelectron spectroscopy system incorporating an electrostatic lens and able to acquire spectra up to 0.4 Torr. The incorporation of a two-dimensional detector provides imaging capabilities and allows the acquisition of angle-resolved data in parallel mode over an angular range of 14 degrees without tilting the sample. The sensitivity and energy resolution of the spectrometer have been investigated by analyzing a standard Ag foil both under high vacuum (10(-8) Torr) conditions and at elevated pressures of N(2) (0.4 Torr). The possibility of acquiring angle-resolved data at different pressures has been demonstrated by analyzing a silicon/silicon dioxide (Si/SiO(2)) sample. The collected angle-resolved spectra could be effectively used for the determination of the thickness of the native silicon oxide layer. PMID- 23020368 TI - A high resolution gamma-ray spectrometer based on superconducting microcalorimeters. AB - Improvements in superconductor device fabrication, detector hybridization techniques, and superconducting quantum interference device readout have made square-centimeter-sized arrays of gamma-ray microcalorimeters, based on transition-edge sensors (TESs), possible. At these collecting areas, gamma microcalorimeters can utilize their unprecedented energy resolution to perform spectroscopy in a number of applications that are limited by closely-spaced spectral peaks, for example, the nondestructive analysis of nuclear materials. We have built a 256 pixel spectrometer with an average full-width-at-half-maximum energy resolution of 53 eV at 97 keV, a useable dynamic range above 400 keV, and a collecting area of 5 cm(2). We have demonstrated multiplexed readout of the full 256 pixel array with 236 of the pixels (91%) giving spectroscopic data. This is the largest multiplexed array of TES microcalorimeters to date. This paper will review the spectrometer, highlighting the instrument design, detector fabrication, readout, operation of the instrument, and data processing. Further, we describe the characterization and performance of the newest 256 pixel array. PMID- 23020369 TI - Optical transition radiation used in the diagnostic of low energy and low current electron beams in particle accelerators. AB - Optical transition radiation (OTR) plays an important role in beam diagnostics for high energy particle accelerators. Its linear intensity with beam current is a great advantage as compared to fluorescent screens, which are subject to saturation. Moreover, the measurement of the angular distribution of the emitted radiation enables the determination of many beam parameters in a single observation point. However, few works deals with the application of OTR to monitor low energy beams. In this work we describe the design of an OTR based beam monitor used to measure the transverse beam charge distribution of the 1.9 MeV electron beam of the linac injector of the IFUSP microtron using a standard vision machine camera. The average beam current in pulsed operation mode is of the order of tens of nano-Amps. Low energy and low beam current make OTR observation difficult. To improve sensitivity, the beam incidence angle on the target was chosen to maximize the photon flux in the camera field-of-view. Measurements that assess OTR observation (linearity with beam current, polarization, and spectrum shape) are presented, as well as a typical 1.9-MeV electron beam charge distribution obtained from OTR. Some aspects of emittance measurement using this device are also discussed. PMID- 23020370 TI - A new method to calculate the beam charge for an integrating current transformer. AB - The integrating current transformer (ICT) is a magnetic sensor widely used to precisely measure the charge of an ultra-short-pulse charged particle beam generated by traditional accelerators and new laser-plasma particle accelerators. In this paper, we present a new method to calculate the beam charge in an ICT based on circuit analysis. The output transfer function shows an invariable signal profile for an ultra-short electron bunch, so the function can be used to evaluate the signal quality and calculate the beam charge through signal fitting. We obtain a set of parameters in the output function from a standard signal generated by an ultra-short electron bunch (about 1 ps in duration) at a radio frequency linear electron accelerator at Tsinghua University. These parameters can be used to obtain the beam charge by signal fitting with excellent accuracy. PMID- 23020371 TI - Influence of high temperature on solid state nuclear track detector parameters. AB - This work concerns the influence of high temperatures on tracks induced in solid state nuclear track detectors of the CR-39/PM-355 type. In order to investigate this effect some samples of the detectors were irradiated with energetic protons and alpha particles and subsequently heated under controlled temperatures for different periods of time. After heating the samples were etched and the track evolution was analyzed using an optical microscope. The bulk etch rate V(B) of the PM-355 material was also determined as a function of heating temperature. The track etch rate V(T) values were estimated for craters induced by protons and alpha particles from track diameter measurement as a function of heating temperature. PMID- 23020372 TI - Estimation of radon diffusion coefficients in soil using an updated experimental system. AB - Radon diffusion through soil is strongly affected by the degree of water saturation of the soil pores. Methods have been developed by many researchers to measure radon diffusion coefficient. We developed an updated experimental system to estimate radon diffusion coefficients for typical types of soil in Japan and applied it to a typical loam with different water saturation levels (0-0.82). The system consists of a passive-type scintillation cell, soil column, accumulation tank, and radon source. The radon concentration in the accumulation tank is kept stable, and radon diffused through the soil column is continuously measured with the passive-type scintillation cell. We found the radon diffusion coefficients vary from 9.60 * 10(-6) m(2) s(-1) to 1.27 * 10(-7) m(2) s(-1) for the loam samples. Generally, the diffusion coefficients are almost constant for a water saturation range of 0-0.4 and decrease with increasing water saturation from 0.4 to 0.82. PMID- 23020373 TI - Revisiting plasma hysteresis with an electronically compensated Langmuir probe. AB - The measurement of electron temperature in plasma by Langmuir probes, using ramped bias voltage, is seriously affected by the capacitive current of capacitance of the cable between the probe tip and data acquisition system. In earlier works a dummy cable was used to balance the capacitive currents. Under these conditions, the measured capacitive current was kept less than a few mA. Such probes are suitable for measurements in plasma where measured ion saturation current is of the order of hundreds of mA. This paper reports that controlled balancing of capacitive current can be minimized to less than 20 MUA, allowing plasma measurements to be done with ion saturation current of the order of hundreds of MUA. The electron temperature measurement made by using probe compensation technique becomes independent of sweep frequency. A correction of <=45% is observed in measured electron temperature values when compared with uncompensated probe. This also enhances accuracy in the measurement of fluctuation in electron temperature as deltaT(pk-pk) changes by ~30%. The developed technique with swept rate <=100 kHz is found accurate enough to measure both the electron temperature and its fluctuating counterpart. This shows its usefulness in measuring accurately the temperature fluctuations because of electron temperature gradient in large volume plasma device plasma with frequency ordering <=50 kHz. PMID- 23020374 TI - Synchronized operation by field programmable gate array based signal controller for the Thomson scattering diagnostic system in KSTAR. AB - The Thomson scattering diagnostic system is successfully installed in the Korea Superconducting Tokamak Advanced Research (KSTAR) facility. We got the electron temperature and electron density data for the first time in 2011, 4th campaign using a field programmable gate array (FPGA) based signal control board. It operates as a signal generator, a detector, a controller, and a time measuring device. This board produces two configurable trigger pulses to operate Nd:YAG laser system and receives a laser beam detection signal from a photodiode detector. It allows a trigger pulse to be delivered to a time delay module to make a scattered signal measurement, measuring an asynchronous time value between the KSTAR timing board and the laser system injection signal. All functions are controlled by the embedded processor running on operating system within a single FPGA. It provides Ethernet communication interface and is configured with standard middleware to integrate with KSTAR. This controller has operated for two experimental campaigns including commissioning and performed the reconfiguration of logic designs to accommodate varying experimental situation without hardware rebuilding. PMID- 23020375 TI - Imaging spectroscopy diagnosis of internal electron temperature and density distributions of plasma cloud surrounding hydrogen pellet in the Large Helical Device. AB - To investigate the behavior of hydrogen pellet ablation, a novel method of high speed imaging spectroscopy has been used in the Large Helical Device (LHD) for identifying the internal distribution of the electron density and temperature of the plasma cloud surrounding the pellet. This spectroscopic system consists of a five-branch fiberscope and a fast camera, with each objective lens having a different narrow-band optical filter for the hydrogen Balmer lines and the background continuum radiation. The electron density and temperature in the plasma cloud are obtained, with a spatial resolution of about 6 mm and a temporal resolution of 5 * 10(-5) s, from the intensity ratio measured through these filters. To verify the imaging, the average electron density and temperature also have been measured from the total emission by using a photodiode, showing that both density and temperature increase with time during the pellet ablation. The electron density distribution ranging from 10(22) to 10(24) m(-3) and the temperature distribution around 1 eV have been observed via imaging. The electron density and temperature of a 0.1 m plasma cloud are distributed along the magnetic field lines and a significant electron pressure forms in the plasma cloud for typical experimental conditions of the LHD. PMID- 23020376 TI - Digital discrimination of neutrons and gamma-rays in organic scintillation detectors using moment analysis. AB - Digital discrimination of neutron and gamma-ray events in an organic scintillator has been investigated by moment analysis. Signals induced by an americium beryllium (Am/Be) isotropic neutron source in a stilbene crystal detector have been sampled with a flash analogue-to-digital converter (ADC) of 1 GSamples/s sampling rate and 10-bit vertical resolution. Neutrons and gamma-rays have been successfully discriminated with a threshold corresponding to gamma-ray energy about 217 keV. Moment analysis has also been verified against the results assessed by a time-of-flight (TOF) measurement. It is shown that the classification of neutrons and gamma-rays afforded by moment analysis is consistent with that achieved by digital TOF measurement. This method has been applied to analyze the data acquired from the stilbene crystal detector in mixed radiation field of the HL-2A tokamak deuterium plasma discharges and the results are described. PMID- 23020377 TI - How are the behaviors of piezoelectric inertial sliders interpreted? AB - We report on the effect of different driving signal waveforms on the positioning response of piezoelectric inertial sliders. Surprisingly, a delayed retraction waveform is found to perform better than the more widely adopted undelayed retraction, which is opposite to the expected behavior because the former has a less sharp turning point with lower inertial force. This is confirmed in both piezoelectric tube driven and shear piezo stack driven inertial sliders. We explain that this effect is owing to the creeping property of piezoelectric materials, as indicated by our simulated response including the creeping effect. PMID- 23020378 TI - Depth profiling and imaging capabilities of an ultrashort pulse laser ablation time of flight mass spectrometer. AB - An ultrafast laser ablation time-of-flight mass spectrometer (AToF-MS) and associated data acquisition software that permits imaging at micron-scale resolution and sub-micron-scale depth profiling are described. The ion funnel based source of this instrument can be operated at pressures ranging from 10(-8) to ~0.3 mbar. Mass spectra may be collected and stored at a rate of 1 kHz by the data acquisition system, allowing the instrument to be coupled with standard commercial Ti:sapphire lasers. The capabilities of the AToF-MS instrument are demonstrated on metal foils and semiconductor wafers using a Ti:sapphire laser emitting 800 nm, ~75 fs pulses at 1 kHz. Results show that elemental quantification and depth profiling are feasible with this instrument. PMID- 23020379 TI - Coupling scanning tunneling microscope and supersonic molecular beams: a unique tool for in situ investigation of the morphology of activated systems. AB - We report here on a new experimental apparatus combining a commercial low temperature scanning tunneling microscope with a supersonic molecular beam. This setup provides a unique tool for the in situ investigation of the topography of activated adsorption systems and opens thus new interesting perspectives. It has been tested towards the formation of the O/Ag(110) added rows reconstruction and of their hydroxylation, comparing data recorded upon O(2) exposure at thermal and hyperthermal energies. PMID- 23020380 TI - Fast microtomography using bright monochromatic x-rays. AB - A fast microtomography system for high-resolution high-speed imaging has been developed using bright monochromatic x-rays at the BL29XU beamline of SPring-8. The shortest scan time for microtomography we attained was 0.25 s in 1.25 MUm effective pixel size by combining the bright monochromatic x-rays, a fast rotating sample stage, and a high performance x-ray imaging detector. The feasibility of the tomography system was successfully demonstrated by visualization of rising bubbles in a viscous liquid, an interesting issue in multiphase flow physics. This system also provides a high spatial (a measurable feature size of 300 nm) or a very high temporal (9.8 MUs) resolution in radiographs. PMID- 23020381 TI - Spectrally resolved fluorescence lifetime imaging microscope using tunable bandpass filters. AB - A simple structure of spectral fluorescence lifetime imaging microscope (SLIM) is designed with the use of tunable bandpass filter, a kind of Fabry-perot filter that transmission wavelength is varying according to incident angle of light. Feasibility tests of this angle-tuned bandpass filter (ATBF) are performed and it shows high transmission and constant spectral bandwidth (20 nm) with respect to angle of incidence. Furthermore, using two ATBFs in series, spectral bandwidth can be adjustable down to 4 nm. In this paper, dual ATBFs are implemented to the detection part of fluorescence lifetime imaging microscope (FLIM) system so that we obtained spectrally resolved FLIM images. We compare these SLIM images with an original FLIM image and confirm that the former case provides high accuracy to analyze lifetime distribution as well as high contrast of images. The proposed SLIM microscope with good wavelength selectivity has many opportunities to utilize to other applications such as FLIM-Foster resonant energy transfer and autofluorescence imaging. PMID- 23020382 TI - Reflection-mode, confocal, tip-enhanced Raman spectroscopy system for scanning chemical microscopy of surfaces. AB - A reflection-mode, confocal, tip-enhanced Raman spectroscopy system for nanoscale chemical imaging of surfaces is presented. The instrument is based on a beam bounce atomic force microscope with a side-on Raman microscope with true confocal light illumination and collection. Localized vibrational (Raman) spectroscopy is demonstrated at length scales down to 20 nm on opaque samples. The design and validation of the instrument are discussed with quantitative emphasis on confocal microscope operation, plasmonic properties of the tip, point spectroscopy, and Raman imaging of SiGe nanowires. PMID- 23020383 TI - Feasibility study for mega-electron-volt electron beam tomography. AB - Electron beam tomography is a promising imaging modality for the study of fast technical processes. But for many technical objects of interest x rays of several hundreds of keV energy are required to achieve sufficient material penetration. In this article we report on a feasibility study for fast electron beam computed tomography with a 1 MeV electron beam. The experimental setup comprises an electrostatic accelerator with beam optics, transmission target, and a single x ray detector. We employed an inverse fan-beam tomography approach with radiographic projections being generated from the linearly moving x-ray source. Angular projections were obtained by rotating the object. PMID- 23020385 TI - Stability enhancement of an atomic force microscope for long-term force measurement including cantilever modification for whole cell deformation. AB - Atomic force microscopy (AFM) is widely used in the study of both morphology and mechanical properties of living cells under physiologically relevant conditions. However, quantitative experiments on timescales of minutes to hours are generally limited by thermal drift in the instrument, particularly in the vertical (z) direction. In addition, we demonstrate the necessity to remove all air-liquid interfaces within the system for measurements in liquid environments, which may otherwise result in perturbations in the measured deflection. These effects severely limit the use of AFM as a practical tool for the study of long-term cell behavior, where precise knowledge of the tip-sample distance is a crucial requirement. Here we present a readily implementable, cost effective method of minimizing z-drift and liquid instabilities by utilizing active temperature control combined with a customized fluid cell system. Long-term whole cell mechanical measurements were performed using this stabilized AFM by attaching a large sphere to a cantilever in order to approximate a parallel plate system. An extensive examination of the effects of sphere attachment on AFM data is presented. Profiling of cantilever bending during substrate indentation revealed that the optical lever assumption of free ended cantilevering is inappropriate when sphere constraining occurs, which applies an additional torque to the cantilevers "free" end. Here we present the steps required to accurately determine force-indentation measurements for such a scenario. Combining these readily implementable modifications, we demonstrate the ability to investigate long-term whole cell mechanics by performing strain controlled cyclic deformation of single osteoblasts. PMID- 23020384 TI - Combined versatile high-resolution optical tweezers and single-molecule fluorescence microscopy. AB - Optical trapping and single-molecule fluorescence are two major single-molecule approaches. Their combination has begun to show greater capability to study more complex systems than either method alone, but met many fundamental and technical challenges. We built an instrument that combines base-pair resolution dual-trap optical tweezers with single-molecule fluorescence microscopy. The instrument has complementary design and functionalities compared with similar microscopes previously described. The optical tweezers can be operated in constant force mode for easy data interpretation or in variable force mode for maximum spatiotemporal resolution. The single-molecule fluorescence detection can be implemented in either wide-field or confocal imaging configuration. To demonstrate the capabilities of the new instrument, we imaged a single stretched lambda DNA molecule and investigated the dynamics of a DNA hairpin molecule in the presence of fluorophore-labeled complementary oligonucleotide. We simultaneously observed changes in the fluorescence signal and pauses in fast extension hopping of the hairpin due to association and dissociation of individual oligonucleotides. The combined versatile microscopy allows for greater flexibility to study molecular machines or assemblies at a single-molecule level. PMID- 23020386 TI - Sensitivity maximized near-field scanning optical microscope with dithering sample stage. AB - We developed a new scheme for a higher sensitivity near-field scanning optical microscope (NSOM) by using a dithering sample stage rather than a dithering probe for the constant gap control between probe and sample. In a conventional NSOM, which use tip dithering feedback mechanism, the Q factor drastically decreases from 7783 to 1000 (13%) or even to 100 (1%) because harmonic oscillating characteristic is deteriorated owing to the large change of stiffness and mass of one prong of tuning fork when a probe is attached to it. In our proposed scheme, on the other hand, we use sample dithering feedback mechanism, where the probe is not attached to the tuning fork and the sample is loaded directly onto the surface of dithering tuning fork. Thus, the Q factor does not decrease significantly, from only 7783 to 7480 (96%), because the loaded sample hardly changes the stiffness and mass of tuning fork. Accordingly, gap control between the immobile fiber probe and the dithering sample is performed precisely by detecting the shear force with high sensitivity. Consequently, the extremely high Q factor enables clear observation of graphene sheets with sub-nanometer vertical resolution, which is not possible with a conventional NSOM setup. PMID- 23020387 TI - Rapid preparation of electron beam induced deposition Co magnetic force microscopy tips with 10 nm spatial resolution. AB - Magnetic force microscope Co spike tips with lateral magnetic resolution of 10 nm have been prepared. The Co spikes are grown by electron beam induced deposition of Co from Co(2)(CO)(8) gas precursor. The high resolution Co spikes are fabricated at the spot of a tightly focused electron beam on the tip of commercial atomic force microscope cantilevers. Qualitative investigations indicate that a spike grown on a planar base of Co improves the signal to noise. PMID- 23020388 TI - A two-axis goniometer for low-temperature nuclear magnetic resonance measurements on single crystals. AB - We report on the construction of a two-axis goniometer intended for low temperature, single-crystal nuclear magnetic resonance (NMR) measurements. With the use of home-made and commercially available parts, our simple probe-head design achieves good sensitivity, while maintaining a high angular precision and the ability to orient samples also when cooled to liquid helium temperatures. The probe with the goniometer is adapted to be inserted into a commercial (4)He-flow cryostat, which fits into a wide-bore superconducting solenoid magnet. Selected examples of NMR measurements illustrate the operation of the device. PMID- 23020389 TI - Strength analysis and optimisation of double-toroidal anvils for high-pressure research. AB - We used the finite element method for stress and deformation analysis of the large sample volume double-toroidal anvil and gasket assembly used with the Paris Edinburgh press for neutron scattering, in order to investigate the failure of this assembly observed repeatedly in experiments at a load of approximately 240 tonnes. The analysis is based on a new approach to modelling an opposed anvil device working under extreme stress conditions. The method relies on use of experimental data to validate the simulation in the absence of the material property data available for high pressure conditions. Using this method we analysed the stress distribution on the surface and in the bulk of the double toroidal anvils, and we conclude that the failure occurs on the surface of the anvil and that it is caused by the tensile stress. We also use the model to show possible ways of optimising the anvil design in order to extend its operational pressure range. PMID- 23020390 TI - Measurement setup for the simultaneous determination of diffusivity and Seebeck coefficient in a multi-anvil apparatus. AB - In this paper, a high pressure setup is presented for performing simultaneous measurements of Seebeck coefficient and thermal diffusivity in multianvil apparatus for the purpose of enhancing the study of transport phenomena. Procedures for the derivation of Seebeck coefficient and thermal diffusivity/conductivity, as well as their associated sources of errors, are presented in detail, using results obtained on the filled skutterudite, Ce(0.8)Fe(3)CoSb(12,) up to 12 GPa at ambient temperature. Together with recent resistivity and sound velocity measurements in the same apparatus, these developments not only provide the necessary data for a self-consistent and complete characterization of the figure of merit of thermoelectric materials under pressure, but also serve as an important tool for furthering our knowledge of the dynamics and interplay between these transport phenomena. PMID- 23020391 TI - Insertable system for fast turnaround time microwave experiments in a dilution refrigerator. AB - Microwave experiments in dilution refrigerators are a central tool in the field of superconducting quantum circuits and other research areas. This type of experiments relied so far on attaching a device to the mixing chamber of a dilution refrigerator. The minimum turnaround time in this case is a few days as required by cooling down and warming up the entire refrigerator. We developed a new approach, in which a suitable sample holder is attached to a cold-insertable probe and brought in contact with transmission lines permanently mounted inside the cryostat. The total turnaround time is 8 h if the target temperature is 80 mK. The lowest attainable temperature is 30 mK. Our system can accommodate up to six transmission lines, with a measurement bandwidth tested from zero frequency to 12 GHz. This bandwidth is limited by low-pass components in the setup; we expect the intrinsic bandwidth to be at least 18 GHz. We present our setup, discuss the experimental procedure, and give examples of experiments enabled by this system. This new measurement method will have a major impact on systematic ultra-low temperature studies using microwave signals, including those requiring quantum coherence. PMID- 23020392 TI - Measurement of the high-temperature Seebeck coefficient of thin films by means of an epitaxially regrown thermometric reference material. AB - The Seebeck coefficient of a typical thermoelectric material, silicon-doped InGaAs lattice-matched to InP, is measured over a temperature range from 300 K to 550 K. By depositing and patterning a thermometric reference bar of silicon-doped InP adjacent to a bar of the material under test, temperature differences are measured directly. This is in contrast to conventional two-thermocouple techniques that subtract two large temperatures to yield a small temperature difference, a procedure prone to errors. The proposed technique retains the simple instrumentation of two-thermocouple techniques while eliminating the critical dependence of the latter on good thermal contact. The repeatability of the proposed technique is demonstrated to be +/-2.6% over three temperature sweeps, while the repeatability of two-thermocouple measurements is about +/-5%. The improved repeatability is significant for reliable reporting of the ZT figure of merit, which is proportional to the square of the Seebeck coefficient. The accuracy of the proposed technique depends on the accuracy with which the high temperature Seebeck coefficient of the reference material may be computed or measured. In this work, the Seebeck coefficient of the reference material, n+ InP, is computed by rigorous solution of the Boltzmann transport equation. The accuracy and repeatability of the proposed technique can be systematically improved by scaling, and the method is easily extensible to other material systems currently being investigated for high thermoelectric energy conversion efficiency. PMID- 23020393 TI - Design and implementation of an integral wall-mounted quartz crystal microbalance for atomic layer deposition. AB - Quartz crystal microbalance (QCM) measurements have played a vital role in understanding and expediting new atomic layer deposition (ALD) processes; however, significant barriers remain to their routine use and accurate execution. In order to turn this exclusively in situ technique into a routine characterization method, an integral QCM fixture was developed. This new design is easily implemented on a variety of chemical vapor deposition (CVD) tools, allows rapid sample exchange, prevents backside deposition, and minimizes both the footprint and flow disturbance. Unlike previous QCM designs, the fast thermal equilibration enables tasks such as temperature-dependent studies and ex situ sample exchange, further highlighting the utility of this QCM design for day-to day use. Finally, the in situ mapping of thin film growth rates across the ALD reactor was demonstrated in a popular commercial tool operating in both continuous and quasi-static ALD modes. PMID- 23020394 TI - A low noise single-transistor transimpedance preamplifier for Fourier-transform mass spectrometry using a T feedback network. AB - A novel single-transistor transimpedance preamplifier has been introduced for improving performance in Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry. A low noise junction field-effect transistor (JFET), BF862, is used as the main amplification stage of this trans-impedance preamplifier, and a T shaped feedback network is introduced as both the feedback and the gate biasing solutions. The T feedback network has been studied using an operational amplifier (Op Amp), AD8099. Such a feedback system allows ~100-fold less feedback resistance at a given transimpedance, hence preserving bandwidth, which is beneficial to applications demanding high gain. The single-transistor preamplifier yields a tested transimpedance of ~10(4) Omega (80 dBOmega) in the frequency range between 1 kHz and 1 MHz (mass-to-charge ratio, m/z, of around 180 180k for a 12-T FT-ICR system), with a low power consumption of ~6 mW, which implies that this preamplifier is well suited to a 12-T FT-ICR mass spectrometer. In trading noise performance for higher trans-impedance, an alternative preamplifier design, an AD8099 preamplifier with the T feedback network, has also been studied with a capability of ~10(6) Omega (120 dBOmega) transimpedance in the same frequency range. The resistive components in the T feedback network reported here can be replaced by complex impedances, which allows adaptation of this feedback system to other frequency, transimpedance, and noise characteristics for applications not only in other mass spectrometers, such as Orbitrap, time-of-flight (TOF), and ion trap systems, but also in other charge/current detecting systems such as spectroscopy systems, microscopy systems, optical communication systems, or charge-coupled devices (CCDs). PMID- 23020395 TI - A fast neuronal signal-sensitive continuous-wave near-infrared imaging system. AB - We have developed a continuous-wave near-infrared imaging system to measure fast neuronal signals. We used a simultaneous sampling method with a separate high speed analog-to-digital converter for each input channel, which provides a much larger point sample in a digital lock-in algorithm, higher temporal resolution, and lower crosstalk among detected channels. Without any analog filter, digital lock-in detection with a large point sample suppresses noise excellently, making the system less complex and offering better flexibility. In addition, using a custom-made collimator, more photons can reach the brain tissue due to the smaller divergence angle. Performance analysis shows high detection sensitivity (on the order of 0.1 pW) and high temporal resolution (~50 Hz, 48 channels). Simulation experiments show that intensity changes on the order of 0.01% can be resolved by our instrument when averaging over approximately 500 stimuli. In vivo experiments over the motor cortex show that our instrument can detect fast neuronal signals in the human brain. PMID- 23020396 TI - Micro glass ball embedded gels to study cell mechanobiological responses to substrate curvatures. AB - The effects of substrate stiffness on cell behaviors have been extensively studied; however, the effects of substrate curvature are not well documented. The curvature of the surface to which cells adhere can have profound effects on cell behaviors. To reveal these cell mechanobiological responses to substrate curvatures, here we introduce a novel, unique, simple, and flexible class of substrates, polyacrylamide gels embedded with micro glass balls ranging in diameter from 5 MUm to 2 mm, to culture cells. NIH-3T3 fibroblasts were cultured on these glass ball embedded gels. Morphologies of cells growing on glass balls were analyzed by using an optical microscope and a 3D confocal laser scanning microscope. The cell behaviors on micro cylindrical glass tubes having similar diameters to the glass balls were also compared. It is observed that the fibroblasts were sensitive to the curvatures of the glass balls. Significant differences in cell attachment rate, migration speed, and morphology were noted for cells cultured on glass balls of diameters at or below 500 MUm, compared to those on glass balls of larger diameters. Cell spread area increased as a function of the ball diameter with three different slopes in the three distinct regions depending on the ball diameter. To the best of our knowledge, this is the first experimental attempt to study cell responses to spherically shaped substrates. These cell culture experiments imply that this class of substrates, micro glass ball embedded gels, can be useful tools to study cell mechanobiological responses to substrate curvatures, related cell and tissue engineering researches, and biomedical applications. PMID- 23020397 TI - The tracking control system of the VLT Survey Telescope. AB - The VLT survey telescope is the latest telescope installed at European Southern Observatory's Paranal observatory that is considered one of the best sites for optical astronomy for the excellent seeing conditions. The exceptional quality of the site imposes tight requirements for the telescope tracking system that shall perform very well to fully exploit the extreme sharpness of the Chilean sky. We describe the specific solutions adopted for pointing, servo and guiding systems and the results obtained during the commissioning of the telescope. The hardware implementation relies on industry components and the control solutions privilege both the performance and the future maintainability of the system. PMID- 23020398 TI - Development of a new laser heating system for thin film growth by chemical vapor deposition. AB - We have developed a new laser heating system for thin film growth by chemical vapor deposition (CVD). A collimated beam from a high-power continuous-wave 808 nm semiconductor laser was directly introduced into a CVD growth chamber without an optical fiber. The light path of the heating laser inside the chamber was isolated mechanically from the growth area by bellows to protect the optics from film coating. Three types of heat absorbers, (10 * 10 * 2 mm(3)) consisting of SiC, Ni/NiO(x), or pyrolytic graphite covered with pyrolytic BN (PG/PBN), located at the backside of the substrate, were tested for heating performance. It was confirmed that the substrate temperature could reach higher than 1500 degrees C in vacuum when a PG/PBN absorber was used. A wide-range temperature response between 400 degrees C and 1000 degrees C was achieved at high heating and cooling rates. Although the thermal energy loss increased in a H(2) gas ambient due to the higher thermal conductivity, temperatures up to 1000 degrees C were achieved even in 200 Torr H(2). We have demonstrated the capabilities of this laser heating system by growing ZnO films by metalorganic chemical vapor deposition. The growth mode of ZnO films was changed from columnar to lateral growth by repeated temperature modulation in this laser heating system, and consequently atomically smooth epitaxial ZnO films were successfully grown on an a-plane sapphire substrate. PMID- 23020399 TI - Investigation of a high power electromagnetic pulse source. AB - A high power electromagnetic pulse source with a resonant antenna driven by a compact power supply was investigated in this paper. To match the impedance of the resonant antenna and initial power source, a compact power conditioning circuit based on electro exploding opening switch (EEOS) and pulsed transformer was adopted. In the preliminary experiments, an impulse capacitor was used to drive the system. With the opening of the EEOS at the current of 15 kA flowing trough the primary of the transformer, the resonant antenna was rapidly charged to about -370 kV within a time of about 100 ns. When the switch in the resonant antenna closed at the charging voltage of about -202 kV, the peak intensity of the detected electric field at a distance of about 10 m from the center of the source was 7.2 kV/m. The corresponding peak power of the radiated electromagnetic field reached 76 MW, while the total radiated electromagnetic energy was about 0.65 J. The total energy efficiency of the resonant antenna was about 22% which can be improved by increasing the closing rapidity of the switch in the antenna. PMID- 23020400 TI - Design and analysis of a radio frequency extractor in an S-band relativistic klystron amplifier. AB - A radio frequency (RF) extractor converts the energy of a strongly modulated intense relativistic electron beam (IREB) into the energy of high power microwave in relativistic klystron amplifier (RKA). In the aim of efficiently extracting the energy of the modulated IREB, a RF extractor with all round coupling structure is proposed. Due to the all round structure, the operating transverse magnetic mode can be established easily and its resonant property can be investigated with an approach of group delay time. Furthermore, the external quality factor can be low enough. The design and analysis of the extractor applied in an S-band RKA are carried out, and the performance of the extractor is validated with three-dimensional (3D) particle-in-cell simulations. The extraction efficiency reaches 27% in the simulation with a totally 3D model of the whole RKA. The primary experiments are also carried out and the results show that the RF extractor with the external quality factor of 7.9 extracted 22% of the beam power and transformed it into the high power microwave. Better results are expected after the parasitic mode between the input and middle cavities is suppressed. PMID- 23020401 TI - Quasi-monochromatic field-emission x-ray source. AB - By favoring the L-peak emission over the bremsstrahlung part, direct quasi monochromatic soft x-ray emission has been obtained with a field emission (FE) x ray source. The electron impact x-ray setup uses an arrayed cathode of carbon nanopearl FE tips as a stable cold electron source within a vacuum of 10(-6)-10( 7) Torr. The high brightness of the FE e-beam coupled with the array structure of the cold cathode allows a smoother control of the x-ray emission intensity. The wavelength of the x-ray source can be modified by the choice of target materials. Using Mo as the target material, the x-ray emission shows a peak centered at 2.45 keV with a monochromaticity between 75% and 55% and a FWHM in the range of 450 eV. PMID- 23020402 TI - Comparison of photo detectors and operating conditions for decay time determination in phosphor thermometry. AB - This work compares the extent of linear response regions from standard time resolving optical detectors for phosphor thermometry. Different types of photomultipliers (ordinary and time-gated) as well as an avalanche photodiode were tested and compared using the phosphorescence decay time of cadmium tungstate (CdWO(4)). Effects originating from incipient detector saturation are revealed as a change in evaluated phosphorescence decay time, which was found to be a more sensitive measure for saturation than the conventional signal strength comparison between in- and output. Since the decay time of thermographic phosphors is used for temperature determination systematic temperature errors in the order of several tens of Kelvins may be introduced. Saturation from the initial intensity is isolated from temporally developed saturation by varying the CdWO(4) decay time over the microsecond to nanosecond range, resultant of varying the temperature from 290 to 580 K. A detector mapping procedure is developed in order to identify linear response regions where the decay-to-temperature evaluations are unbiased. In addition, this mapping procedure generates a library of the degree of distortion for operating points outside of linear response regions. Signals collected in the partly saturated regime can thus be corrected to their unbiased value using this library, extending the usable detector operating range significantly. PMID- 23020403 TI - Quantitative evaluation of hidden defects in cast iron components using ultrasound activated lock-in vibrothermography. AB - This paper reports one of the first experimental results on the application of ultrasound activated lock-in vibrothermography for quantitative assessment of buried flaws in complex cast parts. The use of amplitude modulated ultrasonic heat generation allowed selective response of defective areas within the part, as the defect itself is turned into a local thermal wave emitter. Quantitative evaluation of hidden damages was accomplished by estimating independently both the area and the depth extension of the buried flaws, while x-ray 3D computed tomography was used as reference for sizing accuracy assessment. To retrieve flaw's area, a simple yet effective histogram-based phase image segmentation algorithm with automatic pixels classification has been developed. A clear correlation was found between the thermal (phase) signature measured by the infrared camera on the target surface and the actual mean cross-section area of the flaw. Due to the very fast cycle time (<30 s/part), the method could potentially be applied for 100% quality control of casting components. PMID- 23020404 TI - Spherical-sapphire-based whispering gallery mode resonator thermometer. AB - A novel microwave whispering gallery mode (WGM) resonator based on a spherical sapphire crystal was developed at INRIM and its use as a thermometer was tested. The temperature dependence of the WGM frequencies was studied and the most promising resonance near to 13.6 GHz, with a loaded quality factor as large as 82 000, was carefully investigated. Its potential use in thermometry was evaluated through a study of its main metrological characteristics, such as the temperature sensitivity, the frequency stability, the repeatability, and the resolution at several temperatures over the temperature range -40 degrees C to 85 degrees C. Finally, the INRIM spherical sapphire thermometer was compared with the NIST SWGT, a dielectric thermometer based on a cylindrical sapphire resonator [V. B. Braginsky, V. S. Ilchenko, and Kh. S. Bagdassarov, Phys. Lett. A 120(3), 300 (1987)]. PMID- 23020405 TI - Investigating and understanding fouling in a planar setup using ultrasonic methods. AB - Fouling is an unwanted deposit on heat transfer surfaces and occurs regularly in foodstuff heat exchangers. Fouling causes high costs because cleaning of heat exchangers has to be carried out and cleaning success cannot easily be monitored. Thus, used cleaning cycles in foodstuff industry are usually too long leading to high costs. In this paper, a setup is described with which it is possible, first, to produce dairy protein fouling similar to the one found in industrial heat exchangers and, second, to detect the presence and absence of such fouling using an ultrasonic based measuring method. The developed setup resembles a planar heat exchanger in which fouling can be made and cleaned reproducible. Fouling presence, absence, and cleaning progress can be monitored by using an ultrasonic detection unit. The setup is described theoretically based on electrical and mechanical lumped circuits to derive the wave equation and the transfer function to perform a sensitivity analysis. Sensitivity analysis was done to determine influencing quantities and showed that fouling is measurable. Also, first experimental results are compared with results from sensitivity analysis. PMID- 23020406 TI - Broadband ultrasonic linear array using ternary PIN-PMN-PT single crystal. AB - Ternary Pb(In(1/2)Nb(1/2))O(3)-Pb(Mg(1/3)Nb(2/3))O(3)-PbTiO(3) (PIN-PMN-PT) single crystal was investigated for potential application in ultrasonic linear array. Orientation and temperature dependences of height extensional electromechanical coupling coefficient k'(33) for PIN-PMN-PT single crystal were studied. It was found that the [001] poled PIN-PMN-PT diced along the [100] direction would achieve a maximum k'(33) (~87%) and the service temperature was up to 110 degrees C. Ultrasonic linear arrays using PIN-PMN-PT single crystal and PZT ceramic were fabricated and compared. The bandwidth at -6 dB, two-way insertion loss and pulse length of the PIN-PMN-PT array were 98.6%, -45.1 dB, and 0.28 MUs, respectively, which were about 25% broader, 3.7dB higher, and 0.08 MUs shorter than those of the PZT array. The experimental results agreed well with the theoretical simulation. These superior performances were attributable to the excellent piezoelectric properties of PIN-PMN-PT single crystal. PMID- 23020407 TI - High resolution space quartz-flexure accelerometer based on capacitive sensing and electrostatic control technology. AB - High precision accelerometer plays an important role in space scientific and technical applications. A quartz-flexure accelerometer operating in low frequency range, having a resolution of better than 1 ng/Hz(1/2), has been designed based on advanced capacitive sensing and electrostatic control technologies. A high precision capacitance displacement transducer with a resolution of better than 2 * 10(-6) pF/Hz(1/2) above 0.1 Hz, is used to measure the motion of the proof mass, and the mechanical stiffness of the spring oscillator is compensated by adjusting the voltage between the proof mass and the electrodes to induce a proper negative electrostatic stiffness, which increases the mechanical sensitivity and also suppresses the position measurement noise down to 3 * 10( 10) g/Hz(1/2) at 0.1 Hz. A high resolution analog-to-digital converter is used to directly readout the feedback voltage applied on the electrodes in order to suppress the action noise to 4 * 10(-10) g/Hz(1/2) at 0.1 Hz. A prototype of the quartz-flexure accelerometer has been developed and tested, and the preliminary experimental result shows that its resolution comes to about 8 ng/Hz(1/2) at 0.1 Hz, which is mainly limited by its mechanical thermal noise due to low quality factor. PMID- 23020408 TI - Polymer microfabrication by scanning based microstereolithography: optical design and material functionality. AB - Several research groups have attempted to optimize photopolymerization parameters to increase the throughput of scanning based microstereolithography (MSL) systems through modified beam scanning techniques. Efforts in reducing the curing line width have been implemented through high numerical aperture (NA) optical setups. However, the intensity contour symmetry and the depth of field of focus have led to grossly non-vertical and non-uniform curing profiles. This work tries to review the photopolymerization process in a scanning based MSL system from the aspect of material functionality and optical design. The focus has been to exploit the rich potential of photoreactor scanning system in achieving desired fabrication modalities (minimum curing width, uniform depth profile, and vertical curing profile) even with a reduced NA optical setup and a single movable stage. The present study tries to manipulate to its advantage the effect of optimized lower [c] (photoinitiator (PI) concentration) in reducing the minimum curing width to ~10-20 MUm even with a higher spot size (~21.36 MUm) through a judiciously chosen "monomer-PI" system. Optimization on grounds of increasing E(max) (maximum laser exposure energy at surface) by optimizing the scan rate provides enough time for the monomer or resin to get cured across the entire resist thickness (surface to substrate ~10-100 MUm), leading to uniform depth profiles along the entire scan lengths. PMID- 23020409 TI - Measurement of resonant mode of piezoelectric thin plate using speckle interferometry and frequency-sweeping function. AB - This study proposes a frequency-sweeping function of electronic speckle pattern interferometry, based on standard deviation in the temporal domain. The proposed method facilities the measurement of resonant vibration, and provides stable and clear interference fringes. This study investigated the third in-plane eigenmode of a thin piezoelectric plate, using the finite element method and an impedance analyzer to verify the dynamic response obtained using the proposed method. We analyzed the vibration amplitude of interference fringes to obtain quantitative results on the sub-micron scale. The close agreement between the experimental results demonstrates the effectiveness of using the frequency-sweeping function to obtain the resonant states and provides an accurate prediction of resonance. Furthermore, statistical analysis of interference fringes obtained using the subtractive, mean, and the standard deviation method is performed. The result shows that the standard deviation method provides higher quality and stability of fringe pattern. PMID- 23020410 TI - Instrument for layer-by-layer deposition of catalyst layers directly on proton exchange membrane for direct methanol fuel cell. AB - A catalyst layer (CL) layer-by-layer (LbL) deposition instrument, consisting of an electrohydrodynamic atomization (EHDA) device and a proton exchange membrane (PEM) fixing device, has been developed. It has been used to deposit anode CL on Nafion membrane under different working distances of 4, 5, and 6 mm. The incorporation of EHDA LbL deposition allowed the generation of the CLs with different structures, where the higher working distance produced more porous CL structure. A catalyst-coated membrane (CCM) was also produced using this EHDA LbL deposition and PEM fixing device. It was observed that the catalyst has been uniformly coated on the Nafion membrane and the CCM presents an uniform surface feature. The performance of a single direct methanol fuel cell (DMFC) assembled with the deposited CCM at different working temperatures was analysed. The cell performance increased when the temperature rose. This instrument has the potential of being developed into a powerful device for controlling the deposition of CL of desired structures directly on PEM for DMFCs. PMID- 23020411 TI - Spatial angular positioning device with three-dimensional magnetoelectric sensors. AB - This paper reports on the development of a novel simple three-dimensional geomagnetic device for sensing the spatial azimuth and pitch positions by using three one-dimensional magnetoelectric sensors assembled along three orthogonal axes. This sensing device combines piezoelectric transducer plates and elongated high-performance Ni-based Metglas ribbons. It allows the simultaneous detection of all three orthogonal components of the terrestrial magnetic field. Output signals from the device components are provided in form of sine and/or cosine functions of both the rotation azimuth and the pitch angles, from which the total intensity as well as the inclination angle of the Earth's magnetic field is determined in an overall field resolution of better than 10(-4) Oe and an angle precision of +/-0.1 degrees , respectively. This simple and low-cost geomagnetic field device is promising for the automatic determination and control of the mobile transceiver antenna's orientation with respect to the position of the related geostationary satellite. PMID- 23020412 TI - Frequency analysis of a step dynamic pressure calibrator. AB - A dynamic high pressure standard is becoming more essential in the fields of mobile engines, space science, and especially the area of defense such as long range missile development. However, a complication arises when a dynamic high pressure sensor is compared with a reference dynamic pressure gauge calibrated in static mode. Also, it is difficult to determine a reference dynamic pressure signal from the calibrator because a dynamic high pressure calibrator generates unnecessary oscillations in a positive-going pressure step method. A dynamic high pressure calibrator, using a quick-opening ball valve, generates a fast step pressure change within 1 ms; however, the calibrator also generates a big impulse force that can lead to a short life-time of the system and to oscillating characteristics in response to the dynamic sensor to be calibrated. In this paper, unnecessary additional resonant frequencies besides those of the step function are characterized using frequency analysis. Accordingly, the main sources of resonance are described. In order to remove unnecessary frequencies, the post processing results, obtained by a filter, are given; also, a method for the modification of the dynamic calibration system is proposed. PMID- 23020413 TI - Particle size and density of a slurry from ultrasonic backscattering measurements at a solid interface. AB - The pivotal experiment was performed with a setup in which a plastic cylinder was mounted on the top of a horizontal Rexolite plate and a transducer mounted directly below the cylinder; a single layer of stationary 1588-MUm acrylic spheres was placed in the cylinder filled with water. Two well-separated signals were received by the transducer operating in the pulse-echo mode: (1) a signal due to the reflection from water at the interface and (2) a time-delayed signal resulting from the backscattering from the spheres of diameter D. The important observation was that the time delay was equal to 2 D/c using standard notation. A method was developed to use the FFT phase difference between the incident and scattered signals at the interface to determine the time-delay as a function of frequency, the backscattering coefficient M versus frequency, a particle size distribution, and an average value of the diameter. Experimental average diameter results are shown in the square brackets for nominal particle sizes: (1) 1588-MUm acrylic spheres [1564 MUm], (2) polystyrene spheres for diameters from 200 MUm to 500 MUm [260 MUm-536 MUm], (3) suspended slurry of 250-300 MUm polystyrene spheres at 2.25 MHz [253 MUm], (4) 794 MUm [759 MUm] and 1588-MUm [1623 MUm] Teflon spheres, (5) 1588-MUm stainless steel spheres [1674 MUm], and (6) suspended slurry of 250-300 MUm polystyrene spheres [275 MUm] at 3.5 MHz for seven volume fractions. Density and particle size measurements were obtained for the latter. For the density measurement, the FFT amplitude of the scattered signal was summed from 2 to 4 MHz for each slurry. A plot of the square root of the FFT-amplitude-sum versus the volume fraction yields a straight line, passing through the origin. A calibration of the experimental setup is obtained by fitting a straight line through the data with error bars. Thus, the volume fraction for a slurry of unknown concentration can be determined by measuring the FFT-amplitude-sum. The density of the slurry is obtained from the volume fraction. These results make it feasible to develop an online and real-time pipeline sensor to measure particle size and slurry density. PMID- 23020414 TI - A compact and miniaturized high resolution capacitance dilatometer for measuring thermal expansion and magnetostriction. AB - We describe the design, construction, calibration, and two different applications of a miniature capacitance dilatometer. The device is suitable for thermal expansion and magnetostriction measurements from 300 K down to about 25 mK, with a resolution of 0.02 A at low temperatures. The main body of the dilatometer is fabricated from a single block of a Be-Cu alloy by electrical discharge milling. This creates an extremely compact high-resolution measuring cell. We have successfully tested and operated dilatometers of this new type with the commonly used physical property measurement system by quantum design, as well as with several other cryogenic refrigeration systems down to 25 mK and in magnetic fields up to 20 T. Here, the capacitance is measured with a commercially available capacitance bridge. Using a piezoelectric rotator from Attocube Systems, the cell can be rotated at T = 25 mK inside of an inner vacuum chamber of 40 mm diameter. The miniaturized design for the one-axis rotation setup allows a rotation of 360 degrees . PMID- 23020415 TI - Development of nondestructive non-contact acousto-thermal evaluation technique for damage detection in materials. AB - This paper presents the development of a new non-contact acousto-thermal signature (NCATS) nondestructive evaluation technique. The physical basis of the method is the measurement of the efficiency of the material to convert acoustic energy into heat, and a theoretical model has been used to evaluate this. The increase in temperature due to conversion of acoustic energy injected into the material without direct contact was found to depend on the thermal and elastic properties of the material. In addition, it depends on the experimental parameters of the acoustic source power, the distance between sample and acoustic source, and the period of acoustic excitation. Systematic experimental approaches to optimize each of the experimental variables to maximize the observed temperature changes are described. The potential of the NCATS technique to detect microstructural-level changes in materials is demonstrated by evaluating accumulated damage due to plasticity in Ti-6Al-4V and low level thermal damage in polymer matrix composites. The ability of the technique for macroscopic applications in nondestructive evaluation is demonstrated by imaging a crack in an aluminum test sample. PMID- 23020416 TI - Manufacturing of diamond windows for synchrotron radiation. AB - A new diamond window construction is presented and explicit manufacturing details are given. This window will increase the power dissipation by about a factor of 4 over present day state of the art windows to absorb 600 W of power. This power will be generated by in-vacuum undulators with the storage ring ALBA operating at a design current of 400 mA. Extensive finite element (FE) calculations are included to predict the windows behavior accompanied by explanations for the chosen boundary conditions. A simple linear model was used to cross-check the FE calculations. PMID- 23020417 TI - A novel apparatus for in situ compression of submicron structures and particles in a high resolution SEM. AB - We report on the development and characterization of a novel in situ manipulation device to perform stressing experiments on the submicron scale inside a high resolution field emission scanning electron microscope. The instrument comprises two main assembly groups: an upper part for positioning and moving a mounted probe and a force sensor as well as a specimen support as lower part. The upper part consists of a closed loop tripod piezoelectric scanner mounted on a self locking coarse positioning stage. Two interlocked steel springs and a linear variable differential transformer measuring the springs' deflections compose the lower part of the instrument. This arrangement acts as force-sensor and sample support. In comparison to already well-established concepts a wide measuring range is covered by adjusting the spring constant between 30 N/m and 50000 N/m. Moreover, the new device offers striking advantages with respect to force calibration and sample deformation measurements. Force calibration is performed using the eigenfrequency of the force detection system directly inside the SEM. Deformation data are obtained with high accuracy by simultaneously recording displacements above and below the specimen. The detrimental apparatus compliance is determined, and the influence on measured data subsequently minimized: an easy to validate two-springs-in-series model is used for data correction. A force resolution in normal direction of 100 nN accompanied by a sample deformation resolution of 5 nm can be achieved with the instrument using an appropriate load cell stiffness. The capabilities and versatility of this instrument are exemplified by compression experiments performed on submicron amorphous silica particles. PMID- 23020418 TI - Critical analysis of uncertainties during particle filtration. AB - Using the law of propagation of uncertainties we show how equipment- and measurement-related uncertainties contribute to the overall combined standard uncertainties (CSU) in filter permeability and in modelling the results for polystyrene latex microspheres filtration through a borosilicate glass filter at various injection velocities. Standard uncertainties in dynamic viscosity and volumetric flowrate of microspheres suspension have the greatest influence on the overall CSU in filter permeability which excellently agrees with results obtained from Monte Carlo simulations. Two model parameters "maximum critical retention concentration" and "minimum injection velocity" and their uncertainties were calculated by fitting two quadratic mathematical models to the experimental data using a weighted least squares approximation. Uncertainty in the internal cake porosity has the highest impact on modelling uncertainties in critical retention concentration. The model with the internal cake porosity reproduces experimental "critical retention concentration vs velocity"-data better than the second model which contains the total electrostatic force whose value and uncertainty have not been reliably calculated due to the lack of experimental dielectric data. PMID- 23020419 TI - New beam line for time-of-flight medium energy ion scattering with large area position sensitive detector. AB - A new beam line for medium energy ion mass scattering (MEIS) has been designed and set up at the Angstrom laboratory, Uppsala University, Sweden. This MEIS system is based on a time-of-flight (ToF) concept and the electronics for beam chopping relies on a 4 MHz function generator. Repetition rates can be varied between 1 MHz and 63 kHz and pulse widths below 1 ns are typically obtained by including beam bunching. A 6-axis goniometer is used at the target station. Scattering angle and energy of backscattered ions are extracted from a time resolved and position-sensitive detector. Examples of the performance are given for three kinds of probing ions, (1)H(+), (4)He(+), and (11)B(+). Depth resolution is in the nanometer range and 1 and 2 nm thick Pt layers can easily be resolved. Mass resolution between nearby isotopes can be obtained as illustrated by Ga isotopes in GaAs. Taking advantage of the large size detector, a direct imaging (blocking pattern) of crystal channels are shown for hexagonal, 4H-SiC. The ToF-MEIS system described in this paper is intended for use in semiconductor and thin film areas. For example, depth profiling in the sub nanometer range for device development of contacts and dielectric interfaces. In addition to applied projects, fundamental studies of stopping cross sections in this medium energy range will also be conducted. PMID- 23020420 TI - Modeling and analysis of a negative stiffness magnetic suspension vibration isolator with experimental investigations. AB - This paper presents a negative stiffness magnetic suspension vibration isolator (NSMSVI) using magnetic spring and rubber ligaments. The positive stiffness is obtained by repulsive magnetic spring while the negative stiffness is gained by rubber ligaments. In order to study the vibration isolation performance of the NSMSVI, an analytical expression of the vertical stretch force of the rubber ligament is constructed. Experiments are carried out, which demonstrates that the analytical expression is effective. Then an analytical expression of the vertical stiffness of the rubber ligament is deduced by the derivative of the stretch force of the rubber ligament with respect to the displacement of the inner magnetic ring. Furthermore, the parametric study of the magnetic spring and rubber ligament are carried out. As a case study, the size dimensions of the magnetic spring and rubber ligament are determined. Finally, an NSMSVI table was built to verify the vibration isolation performance of the NSMSVI. The transmissibility curves of the NSMSVI are subsequently calculated and tested by instruments. The experimental results reveal that there is a good consistency between the measured transmissibility and the calculated ones, which proves that the proposed NSMSVI is effective and can realize low-frequency vibration isolation. PMID- 23020421 TI - A portable optical emission spectroscopy-cavity ringdown spectroscopy dual-mode plasma spectrometer for measurements of environmentally important trace heavy metals: initial test with elemental Hg. AB - A portable optical emission spectroscopy-cavity ringdown spectroscopy (OES-CRDS) dual-mode plasma spectrometer is described. A compact, low-power, atmospheric argon microwave plasma torch (MPT) is utilized as the emission source when the spectrometer is operating in the OES mode. The same MPT serves as the atomization source for ringdown measurements in the CRDS mode. Initial demonstration of the instrument is carried out by observing OES of multiple elements including mercury (Hg) in the OES mode and by measuring absolute concentrations of Hg in the metastable state 6s6p (3)P(0) in the CRDS mode, in which a palm-size diode laser operating at a single wavelength 405 nm is incorporated in the spectrometer as the light source. In the OES mode, the detection limit for Hg is determined to be 44 parts per 10(9) (ppb). A strong radiation trapping effect on emission measurements of Hg at 254 nm is observed when the Hg solution concentration is higher than 50 parts per 10(6) (ppm). The radiation trapping effect suggests that two different transition lines of Hg at 253.65 nm and 365.01 nm be selected for emission measurements in lower (<50 ppm) and higher concentration ranges (>50 ppm), respectively. In the CRDS mode, the detection limit of Hg in the metastable state 6s6p (3)P(0) is achieved to be 2.24 parts per 10(12) (ppt) when the plasma is operating at 150 W with sample gas flow rate of 480 mL min(-1); the detection limit corresponds to 50 ppm in Hg sample solution. Advantage of this novel spectrometer has two-fold, it has a large measurement dynamic range, from a few ppt to hundreds ppm and the CRDS mode can serve as calibration for the OES mode as well as high sensitivity measurements. Measurements of seven other elements, As, Cd, Mn, Ni, P, Pb, and Sr, using the OES mode are also carried out with detection limits of 1100, 33, 30, 144, 576, 94, and 2 ppb, respectively. Matrix effect in the presence of other elements on Hg measurements has been found to increase the detection limit to 131 ppb. These elements in lower concentrations can also be measured in the CRDS mode when a compact laser source is available to be integrated into the spectrometer in the future. This exploratory study demonstrates a new instrument platform using an OES-CRDS dual-mode technique for potential field applications. PMID- 23020422 TI - Fundamental limits on the digital phase measurement method based on cross correlation analysis. AB - Ultra-precision phase measurement is a key technology for state-of-the-art laser interferometry. In this paper we present a fully digital phase measurement method based on cross-correlation analysis, and analyze the measurement errors caused by sampling quantization, intrinsic white noise and non-integral-cycle sampling. The last error source results in a cyclic error that has not been reported ever. We used a high-performance data acquisition system to carry out the cross correlation-based phase measurement, and obtained a noise level of 1.2 * 10(-6) rad/Hz(1/2)[commercial at]1 Hz. Moreover, the cyclic phase error of about 10(-2) rad/Hz(1/2), caused by non-integral-cycle sampling, had been observed. In order to demonstrate the application of this precision phase measurement method, an ultra-precision heterodyne laser interferometer, consisting of digital phase measurement system and ultra-stable optical bench, was constructed for displacement measurement. The experimental results showed that a measurement resolution of 63 pm had been achieved. PMID- 23020423 TI - Performance improvement of a measurement station for superconducting cable test. AB - A fully digital system, improving measurements flexibility, integrator drift, and current control of superconducting transformers for cable test, is proposed. The system is based on a high-performance integration of Rogowski coil signal and a flexible direct control of the current into the secondary windings. This allows state-of-the-art performance to be overcome by means of out-of-the-shelf components: on a full-scale of 32 kA, current measurement resolution of 1 A, stability below 0.25 A min(-1), and controller ripple less than +/-50 ppm. The system effectiveness has been demonstrated experimentally on the superconducting transformer of the Facility for the Research of Superconducting Cables at the European Organization for Nuclear Research (CERN). PMID- 23020424 TI - A simple technique to measure the magnetic susceptibility of liquids. AB - A novel technique for measuring the magnetic susceptibility of liquids with modest applied magnetic fields (order of 0.25 T) is presented. The deformation of the liquid surface by a magnetic field is determined by a laser bounce or optical lever technique. The energy balance between the magnetic energy and the gravitational potential of the diamagnetic or paramagnetic liquid interaction is used to determine the susceptibility. The energy due to the surface tension energy is about 10% of the gravitational energy and can be neglected for fast measurements. PMID- 23020425 TI - Adaptable infrared surface plasmon resonance spectroscopy accessory. AB - A second generation prototype enabling surface plasmon resonance spectroscopic measurements in the infrared (IR) range is described. The new design (v2) uses the optical train (optics and detector) within conventional FT-IR spectrometers by confining dimensions of the accessory to space available within the sample compartment of the spectrometer. The v2 accessory builds upon knowledge gained from a previous version that was based on a modified commercial variable angle spectroscopic accessory and addresses observed limitations of the original design improved temporal stability and measurement acquisition speed, crucial to biomolecular binding studies, as well as optical flexibility, a requirement for investigations of novel plasmon-supporting materials. Different aspects of the accessory, including temporal stability, mechanical resilience, and sensitivity to changes in refractive index of a sample were evaluated and presented in this contribution. PMID- 23020426 TI - Synchrotron-based coherent scatter x-ray projection imaging using an array of monoenergetic pencil beams. AB - Traditional projection x-ray imaging utilizes only the information from the primary photons. Low-angle coherent scatter images can be acquired simultaneous to the primary images and provide additional information. In medical applications scatter imaging can improve x-ray contrast or reduce dose using information that is currently discarded in radiological images to augment the transmitted radiation information. Other applications include non-destructive testing and security. A system at the Canadian Light Source synchrotron was configured which utilizes multiple pencil beams (up to five) to create both primary and coherent scatter projection images, simultaneously. The sample was scanned through the beams using an automated step-and-shoot setup. Pixels were acquired in a hexagonal lattice to maximize packing efficiency. The typical pitch was between 1.0 and 1.6 mm. A Maximum Likelihood-Expectation Maximization-based iterative method was used to disentangle the overlapping information from the flat panel digital x-ray detector. The pixel value of the coherent scatter image was generated by integrating the radial profile (scatter intensity versus scattering angle) over an angular range. Different angular ranges maximize the contrast between different materials of interest. A five-beam primary and scatter image set (which had a pixel beam time of 990 ms and total scan time of 56 min) of a porcine phantom is included. For comparison a single-beam coherent scatter image of the same phantom is included. The muscle-fat contrast was 0.10 +/- 0.01 and 1.16 +/- 0.03 for the five-beam primary and scatter images, respectively. The air kerma was measured free in air using aluminum oxide optically stimulated luminescent dosimeters. The total area-averaged air kerma for the scan was measured to be 7.2 +/- 0.4 cGy although due to difficulties in small-beam dosimetry this number could be inaccurate. PMID- 23020427 TI - Development of miniaturized, portable magnetic resonance relaxometry system for point-of-care medical diagnosis. AB - A novel, compact-sized (19 cm * 16 cm) and portable (500 g) magnetic resonance relaxometry system is designed and developed. We overcame several key engineering barriers so that magnetic resonance technology can be potentially used for disease diagnosis-monitoring in point-of-care settings, directly on biological cells and tissues. The whole system consists of a coin-sized permanent magnet (0.76 T), miniaturized radio-frequency microcoil probe, compact lumped-circuit duplexer, and single board 1-W power amplifier, in which a field programmable gate array -based spectrometer is used for pulse excitation, signal acquisition, and data processing. We show that by measuring the proton transverse relaxation rates from a large pool of natural abundance proton-nuclei presence in less than 1 MUL of red blood cells, one can indirectly deduce the relative magnetic susceptibility of the bulk cells within a few minutes of signal acquisition time. Such rapid and sensitive blood screening system can be used to monitor the fluctuation of the bulk magnetic susceptibility of the biological cells (e.g., human blood cells), where unusual state of the bulk magnetic susceptibility is related to a number of diseases. PMID- 23020428 TI - Auto- and cross-power spectral analysis of dual trap optical tweezer experiments using Bayesian inference. AB - The thermal fluctuations of micron-sized beads in dual trap optical tweezer experiments contain complete dynamic information about the viscoelastic properties of the embedding medium and-if present-macromolecular constructs connecting the two beads. To quantitatively interpret the spectral properties of the measured signals, a detailed understanding of the instrumental characteristics is required. To this end, we present a theoretical description of the signal processing in a typical dual trap optical tweezer experiment accounting for polarization crosstalk and instrumental noise and discuss the effect of finite statistics. To infer the unknown parameters from experimental data, a maximum likelihood method based on the statistical properties of the stochastic signals is derived. In a first step, the method can be used for calibration purposes: We propose a scheme involving three consecutive measurements (both traps empty, first one occupied and second empty, and vice versa), by which all instrumental and physical parameters of the setup are determined. We test our approach for a simple model system, namely a pair of unconnected, but hydrodynamically interacting spheres. The comparison to theoretical predictions based on instantaneous as well as retarded hydrodynamics emphasizes the importance of hydrodynamic retardation effects due to vorticity diffusion in the fluid. For more complex experimental scenarios, where macromolecular constructs are tethered between the two beads, the same maximum likelihood method in conjunction with dynamic deconvolution theory will in a second step allow one to determine the viscoelastic properties of the tethered element connecting the two beads. PMID- 23020429 TI - Note: a versatile, stable, high-resolution readout system for RTD and thermistor sensors. AB - A readout system for resistance temperature detectors and thermistors is described featuring temperature resolution better than 1 mK and capability to fit sensors having different resistance or requiring different excitation current. For instance, with a sensor equivalent to an ideal 100 Omega Pt, an excitation current of 0.7 mA, and reading @ 1Hz, the system resolution corresponds to 0.38 mK and its temperature coefficient (TC) to 0.26 mK/K. The system, however, can control its own temperature accurately enough to make its TC negligible. When thermostated, the overall stability of the system was better than 10 ppm for 230 h. PMID- 23020430 TI - Note: radio frequency inductance-capacitance band-stop filter circuit to perform contactless conductivity measurements in pulsed magnetic fields. AB - We present a new technique to perform radio frequency (rf) contactless conductivity measurements in pulsed magnetic fields to probe different ground states in condensed matter physics. The new method utilizes a simple analog band stop filter circuit implemented in a radio frequency transmission setup to perform contactless conductivity measurements. The new method is more sensitive than the other methods (e.g., the tunnel diode oscillator and the proximity detector oscillator) due to more sensitive dependence of the circuit resonance frequency on the tank circuit inductance (not the transmission line). More important, the new method is more robust than other methods when used to perform measurements in very high magnetic fields, works for a wide range of temperatures (i.e., 300 K-1.4 K) and is less sensitive to noise and mechanical vibrations during pulse magnet operation. The new technique was successfully applied to measure the Shubnikov-de Haas effect in Bi(2)Se(3) in pulsed magnetic fields of up to 60 T. PMID- 23020431 TI - Note: digital optical zoom by selection of polarization. AB - The combination of a liquid crystal cell with a polarizing beam splitter is used to select one of the two paths through an optical imaging system. The paths both focus the same image on a CCD detector, but one has 4 times the magnification of the other. PMID- 23020432 TI - Note: automatic laser-to-optical-fiber coupling system based on monitoring of Raman scattering signal. AB - We developed an automatic laser-to-optical-fiber coupling (ALOC) system that is based on the difference in the Raman scattering signals of the core and cladding of the optical fiber. This system can be easily applied to all fields of fiber optics since it can perform automatic optical coupling within a few seconds regardless of the core size or the condition of the output end of the optical fiber. The coupling time for a commercial single-mode fiber for a wavelength of 632.8 nm (core diameter: 9 MUm, cladding diameter: 125 MUm) is ~1.5 s. The ALOC system was successfully applied to single-mode-fiber Raman endoscopy for the measurement of the Raman spectrum of carbon nanotubes. PMID- 23020433 TI - Note: a 4 ns hardware photon correlator based on a general-purpose field programmable gate array development board implemented in a compact setup for fluorescence correlation spectroscopy. AB - We present a fast hardware photon correlator implemented in a field-programmable gate array (FPGA) combined with a compact confocal fluorescence setup. The correlator has two independent units with a time resolution of 4 ns while utilizing less than 15% of a low-end FPGA. The device directly accepts transistor transistor logic (TTL) signals from two photon counting detectors and calculates two auto- or cross-correlation curves in real time. Test measurements demonstrate that the performance of our correlator is comparable with the current generation of commercial devices. The sensitivity of the optical setup is identical or even superior to current commercial devices. The FPGA design and the optical setup both allow for a straightforward extension to multi-color applications. This inexpensive and compact solution with a very good performance can serve as a versatile platform for uses in education, applied sciences, and basic research. PMID- 23020434 TI - Note: micro-cantilevers with AlN actuators and PtSi tips for multi-frequency atomic force microscopy. AB - We report the design, fabrication, and characterization of cantilevers with integrated AlN actuators and conductive PtSi tips for multi-frequency atomic force microscopy. These cantilevers also possess a stepped-rectangular geometry. The excellent dynamic behavior of these cantilevers is investigated using both finite-element simulations and experimental methods. Several imaging experiments are presented to illustrate the efficacy and versatility of these cantilevers. PMID- 23020435 TI - Comment on "A nanopositioner for scanning probe microscopy: the KoalaDrive" [Rev. Sci. Instrum. 83, 023703 (2012)]. AB - In a recent paper, Cherepanov et al. [Rev. Sci. Instrum. 83, 023703 (2012)] present two types of piezoelectric nanopositioners: Type I consists of two piezoelectric tubes coaxially mounted in series. At the ends and between the two piezo tubes, three springs are mounted and hold a central tube; Type II nanopositioner (called "a variant of Type I" by the authors) is similar to Type I except that the two tube piezo elements are mounted in parallel with one being coaxially inserted in the other. They both work via concerted axial deformations of the two piezo tubes such that each spring is in turn sliding on the shaft in the same direction while the other two springs hold the shaft by static friction. In this comment, we would like to clarify that both Type I and II nanopositioners are closely related to the one disclosed in our year 2009 paper [Rev. Sci. Instrum. 80, 085104 (2009)] which should therefore be cited. PMID- 23020436 TI - Comment on "Transferring cold atoms in double magneto-optical trap by a continuous-wave transfer laser beam with large red detuning" [Rev. Sci. Instrum. 79, 123116 (2008)]. AB - To calculate the transfer efficiency correctly in the study of Wang et al. [Rev. Sci. Instrum. 79, 123116 (2008)], an additional experimental value is needed. PMID- 23020437 TI - Comment on "The long range voice coil atomic force microscope" [Rev. Sci. Instrum. 83, 023705 (2012)]. AB - In a recent article Barnard et al. described the use of voice coil actuators to realize a large range scanner for probe microscopy. The results reported are interesting, but the idea is not new. In two preceding papers [1998, 1991] we had described a large coverage, wide dynamic range scanner based on homemade voice coil actuators, while Garcia Cantu and Huerta Garnica [1986] had already used inductive scanners for tunneling microscopy. Lamentably, none of these articles was cited by Barnard et al. PMID- 23020440 TI - Depinning, front motion, and phase slips. AB - Pinning and depinning of fronts bounding spatially localized structures in the forced complex Ginzburg-Landau equation describing the 1:1 resonance is studied in one spatial dimension, focusing on regimes in which the structure grows via roll insertion instead of roll nucleation at either edge. The motion of the fronts is nonlocal but can be analyzed quantitatively near the depinning transition. PMID- 23020441 TI - Estimating the largest Lyapunov exponent and noise level from chaotic time series. AB - A novel method for estimating simultaneously the largest Lyapunov exponent (LLE) and noise level (NL) from a noisy chaotic time series is presented in this paper. We research the influence of noise on the average distance of different pairs of points in an embedding phase space and provide a rescaled formula for calculating the LLE when the time series is contaminated with noise. Our algorithm is proposed based on this formula and the invariant of the LLE in different dimensional embedding phase spaces. With numerical simulation, we find that the proposed method provides a reasonable estimate of the LLE and NL when the NL is less than 10% of the signal content. The comparison with Kantz algorithm shows that our method gives more accurate results of the LLE for the noisy time series. Furthermore, our method is not sensitive to the distribution of the noise. PMID- 23020442 TI - Phantom instabilities in adiabatically driven systems: dynamical sensitivity to computational precision. AB - We study the robustness of dynamical phenomena in adiabatically driven nonlinear mappings with skew-product structure. Deviations from true orbits are observed when computations are performed with inadequate numerical precision for monotone, periodic, or quasiperiodic driving. The effect of slow modulation is to "freeze" orbits in long intervals of purely contracting or purely expanding dynamics in the phase space. When computations are carried out with low precision, numerical errors build up phantom instabilities which ultimately force trajectories to depart from the true motion. Thus, the dynamics observed with finite precision computation shows sensitivity to numerical precision: the minimum accuracy required to obtain "true" trajectories is proportional to an internal timescale that can be defined for the adiabatic system. PMID- 23020443 TI - Analysis of noise-induced transitions from regular to chaotic oscillations in the Chen system. AB - The stochastically perturbed Chen system is studied within the parameter region which permits both regular and chaotic oscillations. As noise intensity increases and passes some threshold value, noise-induced hopping between close portions of the stochastic cycle can be observed. Through these transitions, the stochastic cycle is deformed to be a stochastic attractor that looks like chaotic. In this paper for investigation of these transitions, a constructive method based on the stochastic sensitivity function technique with confidence ellipses is suggested and discussed in detail. Analyzing a mutual arrangement of these ellipses, we estimate the threshold noise intensity corresponding to chaotization of the stochastic attractor. Capabilities of this geometric method for detailed analysis of the noise-induced hopping which generates chaos are demonstrated on the stochastic Chen system. PMID- 23020444 TI - Effects of hybrid synapses on the vibrational resonance in small-world neuronal networks. AB - We investigate the effect of vibrational resonance in small-world neuronal networks with hybrid chemical and electrical synapses. It is shown that, irrespective of the probability of chemical synapses, an optimal amplitude of high-frequency component of the signal can optimize the dynamical response of neuron populations to the low-frequency component, which encodes the information. This effect of vibrational resonance of neuronal systems depends extensively on the network structure and parameters, which determine the ability of neuronal networks to enhance the outreach of localized subthreshold low-frequency signal. In particular, chemical synaptic coupling is more efficient than the electrical coupling for the transmission of local input signal due to its selective coupling. Moreover, there exists an optimal small-world topology characterized by an optimal value of rewiring probability, warranting the largest peak value of the system response. Considering that two-frequency signals are ubiquity in brain dynamics, we expect the presented results could have important implications for signal processing in neuronal systems. PMID- 23020445 TI - Short-term prediction of dynamical behavior of flame front instability induced by radiative heat loss. AB - We apply nonlinear forecasting to the time series of the flame front instability induced by radiative heat loss to test for the short-term predictability and long term unpredictability characteristic of deterministic chaos in flame front instability. Our results indicate that the flame front instability represents high-dimensional chaos generated via the period-doubling cascade process reported in our previous study [H. Gotoda, K. Michigami, K. Ikeda, and T. Miyano, Combust Theory Modell. 14, 479 (2010)], while its short-term behavior is predictable using a local nonlinear predictor based on the Sugihara-May method [H. Gotoda, H. Nikimoto, T. Miyano, and S. Tachibana, Chaos 20, 013124 (2011); G. Sugihara and R. M. May, Nature 344, 734 (1990)] as well as a generalized radial basis function network as a global nonlinear predictor. The feasibility of a new approach based on short-term prediction is also discussed in this work from the practical viewpoint of combustion systems. PMID- 23020446 TI - Small-world topology of functional connectivity in randomly connected dynamical systems. AB - Characterization of real-world complex systems increasingly involves the study of their topological structure using graph theory. Among global network properties, small-world property, consisting in existence of relatively short paths together with high clustering of the network, is one of the most discussed and studied. When dealing with coupled dynamical systems, links among units of the system are commonly quantified by a measure of pairwise statistical dependence of observed time series (functional connectivity). We argue that the functional connectivity approach leads to upwardly biased estimates of small-world characteristics (with respect to commonly used random graph models) due to partial transitivity of the accepted functional connectivity measures such as the correlation coefficient. In particular, this may lead to observation of small-world characteristics in connectivity graphs estimated from generic randomly connected dynamical systems. The ubiquity and robustness of the phenomenon are documented by an extensive parameter study of its manifestation in a multivariate linear autoregressive process, with discussion of the potential relevance for nonlinear processes and measures. PMID- 23020447 TI - Semiconductor lasers driven by self-sustained chaotic electronic oscillators and applications to optical chaos cryptography. AB - In this work, we numerically study the dynamics of vertical cavity surface emitting laser (VCSEL) firstly when it is driven by Chua's oscillator, secondly in case where it is driven by a broad frequency spectral bandwidth chaotic oscillator developed by Nana et al. [Commun. Nonlinear Sci. Numer. Simul. 14, 2266 (2009)]. We demonstrated that the VCSEL generated robust chaotic dynamics compared to the ones found in VCSEL subject to a sinusoidally modulated current and therefore it is more suitable for chaos encryption techniques. The synchronization characteristics and the communication performances of unidirectional coupled VCSEL driven by the broad frequency spectral bandwidth chaotic oscillators are investigated numerically. The results show that high quality synchronization and transmission of messages can be realized for suitable system parameters. Chaos shift keying method is successfully applied to encrypt a message at a high bitrate. PMID- 23020448 TI - Different routes from a matter wavepacket to spatiotemporal chaos. AB - We investigate the dynamics of a quasi-one-dimensional Bose-Einstein condensate confined in a double-well potential with spatiotemporally modulated interaction. A variety of phenomena is identified in different frequency regimes, including the self-compression, splitting, breathing-like, and near-fidelity of the matter wavepacket, which are associated with different routes for the onset of spatiotemporal chaos. The results also reveal that chaos can retain space inversion symmetry of the system. PMID- 23020449 TI - Filippov systems and quasi-synchronization control for switched networks. AB - This paper is concerned with the quasi-synchronization issue of linearly coupled networks with discontinuous nonlinear functions in each isolated node. Under the framework of Filippov systems, the existence and boundedness of solutions for such complex networks can be guaranteed by the matrix measure approach. A design method is presented for the synchronization controllers of coupled networks with non-identical discontinuous systems. Moreover, a sufficient condition is derived to ensure the quasi-synchronization of switched coupled complex networks with discontinuous isolated nodes, which could be controlled by some designed linear controllers. The obtained results extend the previous work on the synchronization issue of coupled complex networks with Lipschitz continuous conditions. Numerical simulations on the coupled chaotic systems are given to demonstrate the effectiveness of the theoretical results. PMID- 23020450 TI - Design of coupling for synchronization in time-delayed systems. AB - We report a design of delay coupling for targeting desired synchronization in delay dynamical systems. We target synchronization, antisynchronization, lag-and antilag-synchronization, amplitude death (or oscillation death), and generalized synchronization in mismatched oscillators. A scaling of the size of an attractor is made possible in different synchronization regimes. We realize a type of mixed synchronization where synchronization and antisynchronization coexist in different pairs of state variables of the coupled system. We establish the stability condition of synchronization using the Krasovskii-Lyapunov function theory and the Hurwitz matrix criterion. We present numerical examples using the Mackey-Glass system and a delay Rossler system. PMID- 23020451 TI - On the use of Fourier averages to compute the global isochrons of (quasi)periodic dynamics. AB - The concept of isochrons is crucial for the analysis of asymptotically periodic systems. Roughly, isochrons are sets of points that partition the basin of attraction of a limit cycle according to the asymptotic behavior of the trajectories. The computation of global isochrons (in the whole basin of attraction) is however difficult, and the existing methods are inefficient in high-dimensional spaces. In this context, we present a novel (forward integration) algorithm for computing the global isochrons of high-dimensional dynamics, which is based on the notion of Fourier time averages evaluated along the trajectories. Such Fourier averages in fact produce eigenfunctions of the Koopman semigroup associated with the system, and isochrons are obtained as level sets of those eigenfunctions. The method is supported by theoretical results and validated by several examples of increasing complexity, including the 4 dimensional Hodgkin-Huxley model. In addition, the framework is naturally extended to the study of quasiperiodic systems and motivates the definition of generalized isochrons of the torus. This situation is illustrated in the case of two coupled Van der Pol oscillators. PMID- 23020452 TI - Generating self-organizing collective behavior using separation dynamics from experimental data. AB - Mathematical models for systems of interacting agents using simple local rules have been proposed and shown to exhibit emergent swarming behavior. Most of these models are constructed by intuition or manual observations of real phenomena, and later tuned or verified to simulate desired dynamics. In contrast to this approach, we propose using a model that attempts to follow an averaged rule of the essential distance-dependent collective behavior of real pigeon flocks, which was abstracted from experimental data. By using a simple model to follow the behavioral tendencies of real data, we show that our model can exhibit a wide range of emergent self-organizing dynamics such as flocking, pattern formation, and counter-rotating vortices. PMID- 23020453 TI - Collision of invariant bundles of quasi-periodic attractors in the dissipative standard map. AB - We perform a numerical study of the breakdown of hyperbolicity of quasi-periodic attractors in the dissipative standard map. In this study, we compute the quasi periodic attractors together with their stable and tangent bundles. We observe that the loss of normal hyperbolicity comes from the collision of the stable and tangent bundles of the quasi-periodic attractor. We provide numerical evidence that, close to the breakdown, the angle between the invariant bundles has a linear behavior with respect to the perturbing parameter. This linear behavior agrees with the universal asymptotics of the general framework of breakdown of hyperbolic quasi-periodic tori in skew product systems. PMID- 23020454 TI - Transient chaotic rotating waves in a ring of unidirectionally coupled symmetric Bonhoeffer-van der Pol oscillators near a codimension-two bifurcation point. AB - Propagating waves in a ring of unidirectionally coupled symmetric Bonhoeffer-van der Pol (BVP) oscillators were studied. The parameter values of the BVP oscillators were near a codimension-two bifurcation point around which oscillatory, monostable, and bistable states coexist. Bifurcations of periodic, quasiperiodic, and chaotic rotating waves were found in a ring of three oscillators. In rings of large numbers of oscillators with small coupling strength, transient chaotic waves were found and their duration increased exponentially with the number of oscillators. These exponential chaotic transients could be described by a coupled map model derived from the Poincare map of a ring of three oscillators. The quasiperiodic rotating waves due to the mode interaction near the codimension-two bifurcation point were evidently responsible for the emergence of the transient chaotic rotating waves. PMID- 23020455 TI - Fermi acceleration and adiabatic invariants for non-autonomous billiards. AB - Recent results concerned with the energy growth of particles inside a container with slowly moving walls are summarized, augmented, and discussed. For breathing bounded domains with smooth boundaries, it is proved that for all initial conditions the acceleration is at most exponential. Anosov-Kasuga averaging theory is reviewed in the application to the non-autonomous billiards, and the results are corroborated by numerical simulations. A stochastic description is proposed which implies that for periodically perturbed ergodic and mixing billiards averaged particle energy grows quadratically in time (e.g., exponential acceleration has zero probability). Then, a proof that in non-integrable breathing billiards some trajectories do accelerate exponentially is reviewed. Finally, a unified view on the recently constructed families of non-ergodic billiards that robustly admit a large set of exponentially accelerating particles is presented. PMID- 23020456 TI - On the asymptotics of the Hopf characteristic function. AB - We study the asymptotic behavior of the Hopf characteristic function of fractals and chaotic dynamical systems in the limit of large argument. The small argument behavior is determined by the moments, since the characteristic function is defined as their generating function. Less well known is that the large argument behavior is related to the fractal dimension. While this relation has been discussed in the literature, there has been very little in the way of explicit calculation. We attempt to fill this gap, with explicit calculations for the generalized Cantor set and the Lorenz attractor. In the case of the generalized Cantor set, we define a parameter characterizing the asymptotics which we show corresponds exactly to the known fractal dimension. The Hopf characteristic function of the Lorenz attractor is computed numerically, obtaining results which are consistent with Hausdorff or correlation dimension, albeit too crude to distinguish between them. PMID- 23020457 TI - Isospectral compression and other useful isospectral transformations of dynamical networks. AB - It is common knowledge that a key dynamical characteristic of a network is its spectrum (the collection of all eigenvalues of the network's weighted adjacency matrix). We demonstrated that it is possible to reduce a network, considered as a graph, to a smaller network with fewer vertices and edges while preserving the spectrum (or spectral information) of the original network [L. A. Bunimovich and B. Z. Webb, Nonlinearity 25, 211-254 (2012)]. This procedure allows for the introduction of new equivalence relations between networks, where two networks are spectrally equivalent if they can be reduced to the same network. Additionally, using this theory it is possible to establish whether a network, modeled as a dynamical system, has a globally attracting fixed point (is strongly synchronizing). In this paper, we further develop this theory of isospectral network transformations and demonstrate that our procedures are applicable to families of parameterized networks and networks of arbitrary size. PMID- 23020458 TI - Forecasting the future: is it possible for adiabatically time-varying nonlinear dynamical systems? AB - Nonlinear dynamical systems in reality are often under environmental influences that are time-dependent. To assess whether such a system can perform as desired or as designed and is sustainable requires forecasting its future states and attractors based solely on time series. We propose a viable solution to this challenging problem by resorting to the compressive-sensing paradigm. In particular, we demonstrate that, for a dynamical system whose equations are unknown, a series expansion in both dynamical and time variables allows the forecasting problem to be formulated and solved in the framework of compressive sensing using only a few measurements. We expect our method to be useful in addressing issues of significant current concern such as the sustainability of various natural and man-made systems. PMID- 23020459 TI - Edge state and crisis in the Pierce diode. AB - We study the chaotic dynamics of the Pierce diode, a simple spatially extended system for collisionless bounded plasmas, focusing on the concept of edge of chaos, the boundary that separates transient from asymptotic dynamics. We fully characterize an interior crisis at the end of a periodic window, thereby showing direct evidence of the collision between a chaotic attractor, a chaotic saddle, and the edge of chaos, formed by a period-3 unstable periodic orbit and its stable manifold. The edge of chaos persists after the interior crisis, when the global attractor of the system increases its size in the phase space. PMID- 23020460 TI - Attractors generated from switching unstable dissipative systems. AB - In this paper, we present a class of 3-D unstable dissipative systems, which are stable in two components but unstable in the other one. This class of systems is motivated by whirls, comprised of switching subsystems, which yield strange attractors from the combination of two unstable "one-spiral" trajectories by means of a switching rule. Each one of these trajectories moves around two hyperbolic saddle equilibrium points. Both theoretical and numerical results are provided for verification and demonstration. PMID- 23020461 TI - Time-dependent resilience assessment and improvement of urban infrastructure systems. AB - This paper introduces an approach to assess and improve the time-dependent resilience of urban infrastructure systems, where resilience is defined as the systems' ability to resist various possible hazards, absorb the initial damage from hazards, and recover to normal operation one or multiple times during a time period T. For different values of T and its position relative to current time, there are three forms of resilience: previous resilience, current potential resilience, and future potential resilience. This paper mainly discusses the third form that takes into account the systems' future evolving processes. Taking the power transmission grid in Harris County, Texas, USA as an example, the time dependent features of resilience and the effectiveness of some resilience inspired strategies, including enhancement of situational awareness, management of consumer demand, and integration of distributed generators, are all simulated and discussed. Results show a nonlinear nature of resilience as a function of T, which may exhibit a transition from an increasing function to a decreasing function at either a threshold of post-blackout improvement rate, a threshold of load profile with consumer demand management, or a threshold number of integrated distributed generators. These results are further confirmed by studying a typical benchmark system such as the IEEE RTS-96. Such common trends indicate that some resilience strategies may enhance infrastructure system resilience in the short term, but if not managed well, they may compromise practical utility system resilience in the long run. PMID- 23020462 TI - Adaptive lag synchronization of chaotic Cohen-Grossberg neural networks with discrete delays. AB - A class of Cohen-Grossberg neural networks with discrete delays are investigated in this paper. By using the suitable Lyapunov function, sufficient conditions for adaptive lag synchronization of such systems are obtained. Finally, a numerical example is given to demonstrate the main results. PMID- 23020463 TI - Transition from order to chaos, and density limit, in magnetized plasmas. AB - It is known that a plasma in a magnetic field, conceived microscopically as a system of point charges, can exist in a magnetized state, and thus remain confined, inasmuch as it is in an ordered state of motion, with the charged particles performing gyrational motions transverse to the field. Here, we give an estimate of a threshold, beyond which transverse motions become chaotic, the electrons being unable to perform even one gyration, so that a breakdown should occur, with complete loss of confinement. The estimate is obtained by the methods of perturbation theory, taking as perturbing force acting on each electron that due to the so-called microfield, i.e., the electric field produced by all the other charges. We first obtain a general relation for the threshold, which involves the fluctuations of the microfield. Then, taking for such fluctuations, the formula given by Iglesias, Lebowitz, and MacGowan for the model of a one component plasma with neutralizing background, we obtain a definite formula for the threshold, which corresponds to a density limit increasing as the square of the imposed magnetic field. Such a theoretical density limit is found to fit pretty well the empirical data for collapses of fusion machines. PMID- 23020464 TI - Multiple current reversals and diffusion enhancement in a symmetrical periodic potential. AB - Transport and diffusion of Brownian particles in a symmetrical periodic potential were investigated for both overdamped and underdamped cases, where the ratchet potential is driven by an external unbiased time periodic force and correlation between thermal and potential fluctuations. It is shown that the correlation between two noises breaks the symmetry of the potential to generate motion of the Brownian particles in particular direction, and the current can reverse its direction by changing the sign of the noise correlation. For the overdamped case, the systemic parameters only induce the directed current, and the noise correlation suppresses the diffusion of the overdamped Brownian particles. However for the underdamped case, the current reverses its direction multiple times with increasing the systemic parameters, i.e., the multiple current reversal is observed, and the noise negative correlation suppresses the diffusion of the underdamped Brownian particles, while the noise positive correlation enhances it. PMID- 23020465 TI - Analysis of stable periodic orbits in the one dimensional linear piecewise-smooth discontinuous map. AB - In this paper, we consider one dimensional linear piecewise-smooth discontinuous maps. It is well known that stable periodic orbits exist for such maps, in some parameter region. It is also known that the corresponding bifurcation phenomena (termed as period adding bifurcation) exhibit a special structure. In the last couple of years, several authors have analyzed this structure using border collision bifurcation curves and given the characterization for various parameter regions. In this paper, we have analyzed a specific parameter range employing a different approach. We show that this approach enables one to pose some interesting questions like: what is the number of distinct periodic orbits of any given cardinality? We prove that there are precisely phi(n) distinct orbits of period n, where phi is the Euler's totient function. We propose an algorithm which calculates the location of fixed points of all these phi(n) distinct orbits and gives the precise range of existence of these orbits with respect to the parameters. Further, we show how the amount of computations required to find these ranges of existence can be optimized. PMID- 23020466 TI - The architecture of dynamic reservoir in the echo state network. AB - Echo state network (ESN) has recently attracted increasing interests because of its superior capability in modeling nonlinear dynamic systems. In the conventional echo state network model, its dynamic reservoir (DR) has a random and sparse topology, which is far from the real biological neural networks from both structural and functional perspectives. We hereby propose three novel types of echo state networks with new dynamic reservoir topologies based on complex network theory, i.e., with a small-world topology, a scale-free topology, and a mixture of small-world and scale-free topologies, respectively. We then analyze the relationship between the dynamic reservoir structure and its prediction capability. We utilize two commonly used time series to evaluate the prediction performance of the three proposed echo state networks and compare them to the conventional model. We also use independent and identically distributed time series to analyze the short-term memory and prediction precision of these echo state networks. Furthermore, we study the ratio of scale-free topology and the small-world topology in the mixed-topology network, and examine its influence on the performance of the echo state networks. Our simulation results show that the proposed echo state network models have better prediction capabilities, a wider spectral radius, but retain almost the same short-term memory capacity as compared to the conventional echo state network model. We also find that the smaller the ratio of the scale-free topology over the small-world topology, the better the memory capacities. PMID- 23020467 TI - Synchronization-based approach for detecting functional activation of brain. AB - In this paper, we investigate a synchronization-based, data-driven clustering approach for the analysis of functional magnetic resonance imaging (fMRI) data, and specifically for detecting functional activation from fMRI data. We first define a new measure of similarity between all pairs of data points (i.e., time series of voxels) integrating both complete phase synchronization and amplitude correlation. These pairwise similarities are taken as the coupling between a set of Kuramoto oscillators, which in turn evolve according to a nearest-neighbor rule. As the network evolves, similar data points naturally synchronize with each other, and distinct clusters will emerge. The clustering behavior of the interaction network of the coupled oscillators, therefore, mirrors the clustering property of the original multiple time series. The clustered regions whose cross correlation coefficients are much greater than other regions are considered as the functionally activated brain regions. The analysis of fMRI data in auditory and visual areas shows that the recognized brain functional activations are in complete correspondence with those from the general linear model of statistical parametric mapping, but with a significantly lower time complexity. We further compare our results with those from traditional K-means approach, and find that our new clustering approach can distinguish between different response patterns more accurately and efficiently than the K-means approach, and therefore more suitable in detecting functional activation from event-related experimental fMRI data. PMID- 23020468 TI - A network function-based definition of communities in complex networks. AB - We consider an alternate definition of community structure that is functionally motivated. We define network community structure based on the function the network system is intended to perform. In particular, as a specific example of this approach, we consider communities whose function is enhanced by the ability to synchronize and/or by resilience to node failures. Previous work has shown that, in many cases, the largest eigenvalue of the network's adjacency matrix controls the onset of both synchronization and percolation processes. Thus, for networks whose functional performance is dependent on these processes, we propose a method that divides a given network into communities based on maximizing a function of the largest eigenvalues of the adjacency matrices of the resulting communities. We also explore the differences between the partitions obtained by our method and the modularity approach (which is based solely on consideration of network structure). We do this for several different classes of networks. We find that, in many cases, modularity-based partitions do almost as well as our function-based method in finding functional communities, even though modularity does not specifically incorporate consideration of function. PMID- 23020469 TI - Phase coherence and attractor geometry of chaotic electrochemical oscillators. AB - Chaotic attractors are known to often exhibit not only complex dynamics but also a complex geometry in phase space. In this work, we provide a detailed characterization of chaotic electrochemical oscillations obtained experimentally as well as numerically from a corresponding mathematical model. Power spectral density and recurrence time distributions reveal a considerable increase of dynamic complexity with increasing temperature of the system, resulting in a larger relative spread of the attractor in phase space. By allowing for feasible coordinate transformations, we demonstrate that the system, however, remains phase-coherent over the whole considered parameter range. This finding motivates a critical review of existing definitions of phase coherence that are exclusively based on dynamical characteristics and are thus potentially sensitive to projection effects in phase space. In contrast, referring to the attractor geometry, the gradual changes in some fundamental properties of the system commonly related to its phase coherence can be alternatively studied from a purely structural point of view. As a prospective example for a corresponding framework, recurrence network analysis widely avoids undesired projection effects that otherwise can lead to ambiguous results of some existing approaches to studying phase coherence. Our corresponding results demonstrate that since temperature increase induces more complex chaotic chemical reactions, the recurrence network properties describing attractor geometry also change gradually: the bimodality of the distribution of local clustering coefficients due to the attractor's band structure disappears, and the corresponding asymmetry of the distribution as well as the average path length increase. PMID- 23020470 TI - Reverse engineering of complex dynamical networks in the presence of time-delayed interactions based on noisy time series. AB - Reverse engineering of complex dynamical networks is important for a variety of fields where uncovering the full topology of unknown networks and estimating parameters characterizing the network structure and dynamical processes are of interest. We consider complex oscillator networks with time-delayed interactions in a noisy environment, and develop an effective method to infer the full topology of the network and evaluate the amount of time delay based solely on noise-contaminated time series. In particular, we develop an analytic theory establishing that the dynamical correlation matrix, which can be constructed purely from time series, can be manipulated to yield both the network topology and the amount of time delay simultaneously. Extensive numerical support is provided to validate the method. While our method provides a viable solution to the network inverse problem, significant difficulties, limitations, and challenges still remain, and these are discussed thoroughly. PMID- 23020471 TI - Pacemaker interactions induce reentrant wave dynamics in engineered cardiac culture. AB - Pacemaker interactions can lead to complex wave dynamics seen in certain types of cardiac arrhythmias. We use experimental and mathematical models of pacemakers in heterogeneous excitable media to investigate how pacemaker interactions can be a mechanism for wave break and reentrant wave dynamics. Embryonic chick ventricular cells are cultured in vitro so as to create a dominant central pacemaker site that entrains other pacemakers in the medium. Exposure of those cultures to a potassium channel blocker, E-4031, leads to emergence of peripheral pacemakers that compete with each other and with the central pacemaker. Waves emitted by faster pacemakers break up over the slower pacemaker to form reentrant waves. Similar dynamics are observed in a modified FitzHugh-Nagumo model of heterogeneous excitable media with two distinct sites of pacemaking. These findings elucidate a mechanism of pacemaker-induced reentry in excitable media. PMID- 23020472 TI - Fully synchronous solutions and the synchronization phase transition for the finite-N Kuramoto model. AB - We present a detailed analysis of the stability of phase-locked solutions to the Kuramoto system of oscillators. We derive an analytical expression counting the dimension of the unstable manifold associated to a given stationary solution. From this we are able to derive a number of consequences, including analytic expressions for the first and last frequency vectors to phase-lock, upper and lower bounds on the probability that a randomly chosen frequency vector will phase-lock, and very sharp results on the large N limit of this model. One of the surprises in this calculation is that for frequencies that are Gaussian distributed, the correct scaling for full synchrony is not the one commonly studied in the literature; rather, there is a logarithmic correction to the scaling which is related to the extremal value statistics of the random frequency vector. PMID- 23020473 TI - Topological field theory of dynamical systems. AB - Here, it is shown that the path-integral representation of any stochastic or deterministic continuous-time dynamical model is a cohomological or Witten-type topological field theory, i.e., a model with global topological supersymmetry (Q symmetry). As many other supersymmetries, Q-symmetry must be perturbatively stable due to what is generically known as non-renormalization theorems. As a result, all (equilibrium) dynamical models are divided into three major categories: Markovian models with unbroken Q-symmetry, chaotic models with Q symmetry spontaneously broken on the mean-field level by, e.g., fractal invariant sets (e.g., strange attractors), and intermittent or self-organized critical (SOC) models with Q-symmetry dynamically broken by the condensation of instanton antiinstanton configurations (earthquakes, avalanches, etc.) SOC is a full dimensional phase separating chaos and Markovian dynamics. In the deterministic limit, however, antiinstantons disappear and SOC collapses into the "edge of chaos." Goldstone theorem stands behind spatio-temporal self-similarity of Q broken phases known under such names as algebraic statistics of avalanches, 1/f noise, sensitivity to initial conditions, etc. Other fundamental differences of Q broken phases is that they can be effectively viewed as quantum dynamics and that they must also have time-reversal symmetry spontaneously broken. Q-symmetry breaking in non-equilibrium situations (quenches, Barkhausen effect, etc.) is also briefly discussed. PMID- 23020474 TI - Global stability analysis of discrete-time coupled systems on networks and its applications. AB - This paper is concerned with the global stability for a general discrete-time coupled system on network (DTCSN). A systematic method of constructing global Lyapunov function for the DTCSN is provided by combining graph theory and the Lyapunov method. Consequently, some novel global stability principles, which have close relation to the topology property of the network, are given. They have important leading significance in the design and applications for the globally stable DTCSNs. In addition, to present the effectiveness and applicability of the results, the proposed theory is used to analyze the global stability for some practical models and numerical methods. PMID- 23020475 TI - Nonstationarity signatures in the dynamics of global nonlinear models. AB - The aim of this paper is to learn how to recognize a posteriori signatures that nonstationarity leaves on global models obtained from data. To this end the effects of nonstationarity on the dynamics of such models are reported for two benchmarks. Parameters of the Rossler and Lorenz models are varied to produce nonstationary data. It is shown that not only the rate of change of the varying parameter but also which recorded variable is used to estimate global models may have visible effects on the results, which are system-dependent and therefore difficult to generalize. Although the effects of nonstationarity are not necessarily obvious from the phase portraits, the first-return map to a Poincare section is a much more adequate tool to recognize such effects. Three examples of models previously obtained from experimental data are analyzed in the light of the concepts discussed in this paper. PMID- 23020476 TI - Characterizing the dynamics of higher dimensional nonintegrable conservative systems. AB - The phase space dynamics of higher dimensional nonintegrable conservative systems is characterized via the effect of "sticky" motion on the finite time Lyapunov exponents (FTLEs) distribution. Since a chaotic trajectory suffers the sticky effect when chaotic motion is mixed to the regular one, it offers a way to separate the mixed from the totally chaotic regimes. To detect stickiness, four different measures are used, related to the distributions of the positive FTLEs, and provide conditions to characterize the dynamics. Conservative maps are systematically studied from the uncoupled two-dimensional case up to coupled maps of dimension 20. Sticky motion is detected in all unstable directions above a threshold K(d) of the nonlinearity parameter K for the high dimensional cases d = 10, 20. Moreover, as K increases we can clearly identify the transition from mixed to totally chaotic motion which occurs simultaneously in all unstable directions. Results show that all four statistical measures sensitively characterize the motion in high dimensional systems. PMID- 23020477 TI - Clocking convergence to a stable limit cycle of a periodically driven nonlinear pendulum. AB - Convergence to a stable limit cycle of a periodically driven nonlinear pendulum is analyzed in this paper. The concept of the H-rank of a scalar sequence is used for the assessment of transient processes of the system. The circle map is used to illustrate the complex structure of the manifold of non-asymptotic convergence to a fixed point. It is demonstrated that the manifold of non-asymptotic convergence to a stable limit cycle also exists in the stroboscopic representation of the transient data of the periodically driven nonlinear pendulum. A simple method based on a short external impulse is proposed for the control of transient processes when the transition time to stable limit cycles must be minimized. PMID- 23020478 TI - Complex network classification using partially self-avoiding deterministic walks. AB - Complex networks have attracted increasing interest from various fields of science. It has been demonstrated that each complex network model presents specific topological structures which characterize its connectivity and dynamics. Complex network classification relies on the use of representative measurements that describe topological structures. Although there are a large number of measurements, most of them are correlated. To overcome this limitation, this paper presents a new measurement for complex network classification based on partially self-avoiding walks. We validate the measurement on a data set composed by 40000 complex networks of four well-known models. Our results indicate that the proposed measurement improves correct classification of networks compared to the traditional ones. PMID- 23020479 TI - Chaotic dynamics in cardiac aggregates induced by potassium channel block. AB - Chaotic rhythms in deterministic models can arise as a consequence of changes in model parameters. We carried out experimental studies in which we induced a variety of complex rhythms in aggregates of embryonic chick cardiac cells using E 4031 (1.0-2.5 MUM), a drug that blocks the hERG potassium channel. Following the addition of the drug, the regular rhythm evolved to display a spectrum of complex dynamics: irregular rhythms, bursting oscillations, doublets, and accelerated rhythms. The interbeat intervals of the irregular rhythms can be described by one dimensional return maps consistent with chaotic dynamics. A Hodgkin-Huxley-style cardiac ionic model captured the different types of complex dynamics following blockage of the hERG mediated potassium current. PMID- 23020480 TI - Delay induced bifurcation of dominant transition pathways. AB - We investigate delay effects on dominant transition pathways (DTP) between metastable states of stochastic systems. A modified version of the Maier-Stein model with linear delayed feedback is considered as an example. By a stability analysis of the "on-axis" DTP in trajectory space, we find that a bifurcation of DTPs will be induced when time delay tau is large enough. This finding is soon verified by numerically derived DTPs which are calculated by employing a recently developed minimum action method extended to delayed stochastic systems. Further simulation shows that the delay-induced bifurcation of DTPs also results in a nontrivial dependence of the transition rate constant on the delay time. Finally, the bifurcation diagram is given on the tau-beta plane, where beta measures the non-conservation of the original Maier-Stein model. PMID- 23020481 TI - Secondary nontwist phenomena in area-preserving maps. AB - Phenomena as reconnection scenarios, periodic-orbit collisions, and primary shearless tori have been recognized as features of nontwist maps. Recently, these phenomena and secondary shearless tori were analytically predicted for generic maps in the neighborhood of the tripling bifurcation of an elliptic fixed point. In this paper, we apply a numerical procedure to find internal rotation number profiles that highlight the creation of periodic orbits within islands of stability by a saddle-center bifurcation that emerges out a secondary shearless torus. In addition to the analytical predictions, our numerical procedure applied to the twist and nontwist standard maps reveals that the atypical secondary shearless torus occurs not only near a tripling bifurcation of the fixed point but also near a quadrupling bifurcation. PMID- 23020482 TI - How synaptic weights determine stability of synchrony in networks of pulse coupled excitatory and inhibitory oscillators. AB - Under which conditions can a network of pulse-coupled oscillators sustain stable collective activity states? Previously, it was shown that stability of the simplest pattern conceivable, i.e., global synchrony, in networks of symmetrically pulse-coupled oscillators can be decided in a rigorous mathematical fashion, if interactions either all advance or all retard oscillation phases ("mono-interaction network"). Yet, many real-world networks-for example neuronal circuits-are asymmetric and moreover crucially feature both types of interactions. Here, we study complex networks of excitatory (phase-advancing) and inhibitory (phase-retarding) leaky integrate-and-fire (LIF) oscillators. We show that for small coupling strength, previous results for mono-interaction networks also apply here: pulse time perturbations eventually decay if they are smaller than a transmission delay and if all eigenvalues of the linear stability operator have absolute value smaller or equal to one. In this case, the level of inhibition must typically be significantly stronger than that of excitation to ensure local stability of synchrony. For stronger coupling, however, network synchrony eventually becomes unstable to any finite perturbation, even if inhibition is strong and all eigenvalues of the stability operator are at most unity. This new type of instability occurs when any oscillator, inspite of receiving inhibitory input from the network on average, can by chance receive sufficient excitatory input to fire a pulse before all other pulses in the system are delivered, thus breaking the near-synchronous perturbation pattern. PMID- 23020483 TI - Inhomogeneous stationary and oscillatory regimes in coupled chaotic oscillators. AB - The dynamics of linearly coupled identical Lorenz and Pikovsky-Rabinovich oscillators are explored numerically and theoretically. We concentrate on the study of inhomogeneous stable steady states ("oscillation death (OD)" phenomenon) and accompanying periodic and chaotic regimes that emerge at an appropriate choice of the coupling matrix. The parameters, for which OD occurs, are determined by stability analysis of the chosen steady state. Three model-specific types of transitions to and from OD are observed: (1) a sharp transition to OD from a nonsymmetric chaotic attractor containing random intervals of synchronous chaos; (2) transition to OD from the symmetry-breaking chaotic regime created by negative coupling; (3) supercritical bifurcation of OD into inhomogeneous limit cycles and further evolution of the system to inhomogeneous chaotic regimes that coexist with complete synchronous chaos. These results may fill a gap in the understanding of the mechanism of OD in coupled chaotic systems. PMID- 23020484 TI - Symmetry breaking in linearly coupled Korteweg-de Vries systems. AB - We consider solitons in a system of linearly coupled Korteweg-de Vries (KdV) equations, which model two-layer settings in various physical media. We demonstrate that traveling symmetric solitons with identical components are stable at velocities lower than a certain threshold value. Above the threshold, which is found exactly, the symmetric modes are unstable against spontaneous symmetry breaking, which gives rise to stable asymmetric solitons. The shape of the asymmetric solitons is found by means of a variational approximation and in the numerical form. Simulations of the evolution of an unstable symmetric soliton sometimes produce its breakup into two different asymmetric modes. Collisions between moving stable solitons, symmetric and asymmetric ones, are studied numerically, featuring noteworthy features. In particular, collisions between asymmetric solitons with identical polarities are always elastic, while in the case of opposite polarities the collision leads to a switch of the polarities of both solitons. Three-soliton collisions are studied too, featuring quite complex interaction scenarios. PMID- 23020485 TI - An analytic criterion for generalized synchronization in unidirectionally coupled systems based on the auxiliary system approach. AB - An analytic criterion is developed to investigate generalized synchronization (GS) in unidirectionally coupled systems based on the auxiliary system approach. The criterion is derived by transforming the existence problem of generalized synchronization into an eigenvalue problem. Numerical simulations show that the analytic criterion is almost as accurate as the response Lyapunov exponents method, and may provide an estimation of the threshold of strong generalized synchronization. A significant result can be deduced from our analysis that the more the number of equilibria of the unidirectionally coupled systems, the greater the chance of generalized synchronization, but the harder it may be for strong generalized synchronization to occur. PMID- 23020486 TI - Cluster synchronization of spiking induced by noise and interaction delays in homogenous neuronal ensembles. AB - Properties of spontaneously formed clusters of synchronous dynamics in a structureless network of noisy excitable neurons connected via delayed diffusive couplings are studied in detail. Several tools have been applied to characterize the synchronization clusters and to study their dependence on the neuronal and the synaptic parameters. Qualitative explanation of the cluster formation is discussed. The interplay between the noise, the interaction time-delay and the excitable character of the neuronal dynamics is shown to be necessary and sufficient for the occurrence of the synchronization clusters. We have found the two-cluster partitions where neurons are firmly bound to their subsets, as well as the three-cluster ones, which are dynamical by nature. The former turn out to be stable under small disparity of the intrinsic neuronal parameters and the heterogeneity in the synaptic connectivity patterns. PMID- 23020487 TI - A pseudo-matched filter for chaos. AB - A matched filter maximizes the signal-to-noise ratio of a signal. In the recent work of Corron et al. [Chaos 20, 023123 (2010)], a matched filter is derived for the chaotic waveforms produced by a piecewise-linear system. This system produces a readily available binary symbolic dynamics that can be used to perform correlations in the presence of large amounts of noise using the matched filter. Motivated by these results, we describe a pseudo-matched filter, which operates similarly to the original matched filter. It consists of a notch filter followed by a first-order, low-pass filter. We compare quantitatively the matched filter's performance to that of our pseudo-matched filter using correlation functions. On average, the pseudo-matched filter performs with a correlation signal-to-noise ratio that is 2.0 dB below that of the matched filter. Our pseudo-matched filter, though somewhat inferior in comparison to the matched filter, is easily realizable at high speed (>1 GHz) for potential radar applications. PMID- 23020488 TI - Dynamical regimes due to technological change in a microeconomical model of production. AB - We develop a microeconomical model to investigate the impact of technological change onto production decisions of suppliers-modeling an effective feedback mechanism of the market. An important property-the time horizon of production planning-is related to the Kolmogorov entropy of the one-dimensional maps describing price dynamics. We simulate this price dynamics in an ensemble representing the whole macroeconomy. We show how this model can be used to support ongoing research in economic growth and incorporate the obtained microeconomic findings into the discussion about appropriate macroeconomic quantities such as the production function-thus effectively underpinning macroeconomics with microeconomical dynamics. From there we can show that the model exhibits different dynamical regimes (suggesting "phase transitions") with respect to an order parameter. The non-linear feedback under technological change was found to be the crucial mechanism. The implications of the obtained regimes are finally discussed. PMID- 23020489 TI - Predicting the outcome of roulette. AB - There have been several popular reports of various groups exploiting the deterministic nature of the game of roulette for profit. Moreover, through its history, the inherent determinism in the game of roulette has attracted the attention of many luminaries of chaos theory. In this paper, we provide a short review of that history and then set out to determine to what extent that determinism can really be exploited for profit. To do this, we provide a very simple model for the motion of a roulette wheel and ball and demonstrate that knowledge of initial position, velocity, and acceleration is sufficient to predict the outcome with adequate certainty to achieve a positive expected return. We describe two physically realizable systems to obtain this knowledge both incognito and in situ. The first system relies only on a mechanical count of rotation of the ball and the wheel to measure the relevant parameters. By applying these techniques to a standard casino-grade European roulette wheel, we demonstrate an expected return of at least 18%, well above the -2.7% expected of a random bet. With a more sophisticated, albeit more intrusive, system (mounting a digital camera above the wheel), we demonstrate a range of systematic and statistically significant biases which can be exploited to provide an improved guess of the outcome. Finally, our analysis demonstrates that even a very slight slant in the roulette table leads to a very pronounced bias which could be further exploited to substantially enhance returns. PMID- 23020490 TI - Adaptive node-to-node pinning synchronization control of complex networks. AB - In this work, we propose an adaptive node-to-node pinning control strategy. In this approach, both the coupling strength among nodes and the pinning control gains are adaptively changed according to well chosen adaptation laws that take into account the specificities of the oscillators and the network topology. Proof of stability and performance comparison is also shown in this paper. PMID- 23020491 TI - On the formulation and solution of the isochronal synchronization stability problem in delay-coupled complex networks. AB - We present a new framework to the formulation of the problem of isochronal synchronization for networks of delay-coupled oscillators. Using a linear transformation to change coordinates of the network state vector, this method allows straightforward definition of the error system, which is a critical step in the formulation of the synchronization problem. The synchronization problem is then solved on the basis of Lyapunov-Krasovskii theorem. Following this approach, we show how the error system can be defined such that its dimension can be the same as (or smaller than) that of the network state vector. PMID- 23020492 TI - Introduction to the focus issue: chemo-hydrodynamic patterns and instabilities. AB - Pattern forming instabilities are often encountered in a wide variety of natural phenomena and technological applications, from self-organization in biological and chemical systems to oceanic or atmospheric circulation and heat and mass transport processes in engineering systems. Spatio-temporal structures are ubiquitous in hydrodynamics where numerous different convective instabilities generate pattern formation and complex spatiotemporal dynamics, which have been much studied both theoretically and experimentally. In parallel, reaction diffusion processes provide another large family of pattern forming instabilities and spatio-temporal structures which have been analyzed for several decades. At the intersection of these two fields, "chemo-hydrodynamic patterns and instabilities" resulting from the coupling of hydrodynamic and reaction-diffusion processes have been less studied. The exploration of the new instability and symmetry-breaking scenarios emerging from the interplay between chemical reactions, diffusion and convective motions is a burgeoning field in which numerous exciting problems have emerged during the last few years. These problems range from fingering instabilities of chemical fronts and reactive fluid-fluid interfaces to the dynamics of reaction-diffusion systems in the presence of chaotic mixing. The questions to be addressed are at the interface of hydrodynamics, chemistry, engineering or environmental sciences to name a few and, as a consequence, they have started to draw the attention of several communities including both the nonlinear chemical dynamics and hydrodynamics communities. The collection of papers gathered in this Focus Issue sheds new light on a wide range of phenomena in the general area of chemo-hydrodynamic patterns and instabilities. It also serves as an overview of the current research and state-of-the-art in the field. PMID- 23020493 TI - Stirring effects in models of oceanic plankton populations. AB - We present an overview and extend previous results on the effects of large scale oceanic transport processes on plankton population dynamics, considering different types of ecosystem models. We find that increasing stirring rate in an environment where the carrying capacity is non-uniformly distributed leads to an overall decrease of the effective carrying capacity of the system. This may lead to sharp regime shifts induced by stirring in systems with multiple steady states. In prey-predator type systems, stirring leads to resonant response of the population dynamics to fluctuations enhancing the spatial variability-patchiness in a certain range of stirring rates. Oscillatory population models produce strongly heterogeneous patchy distribution of plankton blooms when the stirring is weak, while strong stirring may either synchronise the oscillatory dynamics, when the inhomogeneity is relatively weak, or suppress oscillations completely (oscillator death) by reducing the effective carrying capacity below the bifurcation point. PMID- 23020494 TI - Barriers to front propagation in ordered and disordered vortex flows. AB - We present experiments on reactive front propagation in a two-dimensional (2D) vortex chain flow (both time-independent and time-periodic) and a 2D spatially disordered (time-independent) vortex-dominated flow. The flows are generated using magnetohydrodynamic forcing techniques, and the fronts are produced using the excitable, ferroin-catalyzed Belousov-Zhabotinsky chemical reaction. In both of these flows, front propagation is dominated by the presence of burning invariant manifolds (BIMs) that act as barriers, similar to invariant manifolds that dominate the transport of passive impurities. Convergence of the fronts onto these BIMs is shown experimentally for all of the flows studied. The BIMs are also shown to collapse onto the invariant manifolds for passive transport in the limit of large flow velocities. For the disordered flow, the measured BIMs are compared to those predicted using a measured velocity field and a three dimensional set of ordinary differential equations that describe the dynamics of front propagation in advection-reaction-diffusion systems. PMID- 23020495 TI - Invariant manifolds and the geometry of front propagation in fluid flows. AB - Recent theoretical and experimental work has demonstrated the existence of one sided, invariant barriers to the propagation of reaction-diffusion fronts in quasi-two-dimensional periodically driven fluid flows. These barriers were called burning invariant manifolds (BIMs). We provide a detailed theoretical analysis of BIMs, providing criteria for their existence, a classification of their stability, a formalization of their barrier property, and mechanisms by which the barriers can be circumvented. This analysis assumes the sharp front limit and negligible feedback of the front on the fluid velocity. A low-dimensional dynamical systems analysis provides the core of our results. PMID- 23020496 TI - Horizontally propagating three-dimensional chemo-hydrodynamic patterns in the chlorite-tetrathionate reaction. AB - Planar reaction fronts resulting from the coupling of exothermic autocatalytic reactions and transport processes can be deformed by convection in the presence of gravity field. We have experimentally investigated how buoyancy affects the spatiotemporal pattern formation at various solution thicknesses in three dimensional medium. In the chlorite-tetrathionate reaction, a stable structure propagating horizontally with constant velocity and geometry develops when appropriately thick solutions are studied. Both the horizontal and the vertical projections of the resulting three-dimensional structures are quantitatively characterized: the smooth leading edge of the front is independent of the solution thickness and the structured trailing edge ends in a center cusp with a constant angle. PMID- 23020497 TI - Marangoni-driven convection around exothermic autocatalytic chemical fronts in free-surface solution layers. AB - Gradients of concentration and temperature across exothermic chemical fronts propagating in free-surface solution layers can initiate Marangoni-driven convection. We investigate here the dynamics arising from such a coupling between exothermic autocatalytic reactions, diffusion, and Marangoni-driven flows. To this end, we numerically integrate the incompressible Navier-Stokes equations coupled through the tangential stress balance to evolution equations for the concentration of the autocatalytic product and for the temperature. A solutal and a thermal Marangoni numbers measure the coupling between reaction-diffusion processes and surface-driven convection. In the case of an isothermal system, the asymptotic dynamics is characterized by a steady fluid vortex traveling at a constant speed with the front, deforming and accelerating it [L. Rongy and A. De Wit, J. Chem. Phys. 124, 164705 (2006)]. We analyze here the influence of the reaction exothermicity on the dynamics of the system in both cases of cooperative and competitive solutal and thermal effects. We show that exothermic fronts can exhibit new unsteady spatio-temporal dynamics when the solutal and thermal effects are antagonistic. The influence of the solutal and thermal Marangoni numbers, of the Lewis number (ratio of thermal diffusivity over molecular diffusivity), and of the height of the liquid layer on the spatio-temporal front evolution are investigated. PMID- 23020498 TI - Influence of temperature on linear stability in buoyancy-driven fingering of reaction-diffusion fronts. AB - A vertical Hele-Shaw cell was used to study the influence of temperature on Rayleigh-Taylor instabilities on reaction-diffusion fronts. The propagation of the chemical front can thus be observed, and experimental results can be obtained via image treatment. A chemical front produced by the coupling between molecular diffusion and the auto-catalysis of the chlorite-tetrathionate reaction, descends through the cell, consuming the reactants below while the product is formed above. Buoyancy-driven instabilities are formed due to the density difference between reactants and products, and the front takes a fingering pattern, whose growth rate has temperature dependence. In this study, the effect of temperature on the linear regime of the instability (that is, when the effects of such instability start to appear) was analyzed. To measure the instability, Fourier transform analysis is performed, in order to obtain the different wave numbers and their power as a function of time. Thus, the growth rate for each wave number and the most unstable wave number is obtained for each of the temperatures under study. Based on repeated experiments, a decrease in the growth rate for the most unstable wave number can be observed with the increase of temperature. PMID- 23020499 TI - CHEMO-hydrodynamic coupling between forced advection in porous media and self sustained chemical waves. AB - Autocatalytic reaction fronts between two reacting species in the absence of fluid flow, propagate as solitary waves. The coupling between autocatalytic reaction front and forced simple hydrodynamic flows leads to stationary fronts whose velocity and shape depend on the underlying flow field. We address the issue of the chemico-hydrodynamic coupling between forced advection in porous media and self-sustained chemical waves. Towards that purpose, we perform experiments over a wide range of flow velocities with the well characterized iodate arsenious acid and chlorite-tetrathionate autocatalytic reactions in transparent packed beads porous media. The characteristics of these porous media such as their porosity, tortuosity, and hydrodynamics dispersion are determined. In a pack of beads, the characteristic pore size and the velocity field correlation length are of the order of the bead size. In order to address these two length scales separately, we perform lattice Boltzmann numerical simulations in a stochastic porous medium, which takes into account the log-normal permeability distribution and the spatial correlation of the permeability field. In both experiments and numerical simulations, we observe stationary fronts propagating at a constant velocity with an almost constant front width. Experiments without flow in packed bead porous media with different bead sizes show that the front propagation depends on the tortuous nature of diffusion in the pore space. We observe microscopic effects when the pores are of the size of the chemical front width. We address both supportive co-current and adverse flows with respect to the direction of propagation of the chemical reaction. For supportive flows, experiments and simulations allow observation of two flow regimes. For adverse flow, we observe upstream and downstream front motion as well as static front behaviors over a wide range of flow rates. In order to understand better these observed static state fronts, flow experiments around a single obstacle were used to delineate the range of steady state behavior. A model using the "eikonal thin front limit" explains the observed steady states. PMID- 23020500 TI - Segmented waves in a reaction-diffusion-convection system. AB - The interaction of traveling waves, with both Marangoni and buoyancy driven flows, can generate an extraordinary rich array of patterns ranging from stationary structures to chaotic waves. However, the inherent complexity of reaction-diffusion-convection (RDC) systems makes the explanation of the patterning mechanisms very difficult, both numerically and experimentally. In this paper, we describe the appearance of segmented waves in a shallow layer of an excitable Belousov-Zhabotinsky solution. The segmentation process was found to be dependent both on the depth of the solution and on the excitability of the reaction. We caught the essential features of the system through a RDC model, where the chemical waves were coupled both with surface and bulk fluid motions and we found that by varying the excitability of the reaction, and in turn the wavelength of the chemical fronts, it is possible to create a sort of hydrodynamic resonance structures (corridors), which are responsible for the segmentation process. PMID- 23020501 TI - The heads and tails of buoyant autocatalytic balls. AB - Buoyancy produced by autocatalytic reaction fronts can produce fluid flows that advect the front position, giving rise to interesting feedback between chemical and hydrodynamic effects. In this paper, we numerically investigate the evolution of autocatalytic iodate-arsenous acid reaction fronts initialized in spherical configurations. Deformation of these "autocatalytic balls" is driven by buoyancy produced by the reaction. In our simulations, we have found that depending on the initial ball radius, the reaction front will develop in one of three different ways. In an intermediate range of ball size, the flow can evolve much like an autocatalytic plume: the ball develops a reacting head and tail that is akin to the head and conduit of an autocatalytic plume. In the limit of large autocatalytic balls, however, growth of a reacting tail is suppressed and the resemblance to plumes disappears. Conversely, very small balls of product solution fail to initiate sustained fronts and eventually disappear. PMID- 23020502 TI - Ion-selective Marangoni instability--chemical sensing of specific cation for macroscopic movement. AB - Spontaneous motion and tension oscillation of an oil/water interface responding to specific cation Ca(2+) or Fe(3+) were observed when the oil phase containing the anionic surfactant bis(2-ethylhexyl) phosphate came in contact with the cation-containing water. Both the dynamics were the results of Marangoni instability. Complex formation between the anionic surfactant and cation caused the instability. The results showing the level of cation extraction and degree of interfacial tension revealed that the surfactant-cation combination forms an oil soluble complex with reduced surface activity. Brewster angle microscopy indicated that molecules of the complex tend to aggregate at the interface. This aggregation affected the desorption rate of the complex. We were able to generate ion-selective instability by imposing mechanical and electrochemical perturbations to the interface at equilibrium. The results from these efforts suggested that the aggregation is a type of thermodynamic transition and is required for the onset of instability: Desorption probably occurs as an exfoliation of the aggregated complex, which generates the gradient of interfacial tension. For the standard experiment of biphasic contact, two neighboring interfacial flows compress the local interface between them. We considered that this compression provides mechanical work to the local interface, resulting in desorption of the aggregates and occurrence of instability. Both complex formation and aggregation are possible in the presence of the specific cation. The interface detects the cation via the chemical and thermodynamic processes in order to develop the macroscopic movement, a form of biomimetic motion of the oil/water interface. PMID- 23020503 TI - Chemo-Marangoni convection driven by an interfacial reaction: pattern formation and kinetics. AB - A combined study devoted to chemo-Marangoni convection and the underlying kinetics is presented for a biphasic system in which surfactants are produced in situ by an interfacial reaction. The pattern formation studied in a Hele-Shaw cell in both microgravity and terrestrial environments initially shows an ensemble of chemo-Marangoni cells along a nearly planar interface. Soon, a crossover occurs to periodic large-scale interfacial deformations which coexist with the Marangoni cells. This crossover can be correlated with the autocatalytic nature of the interfacial reaction identified in the kinetic studies. The drastic increase in the product concentration is associated with an enhanced aggregate assisted transfer after the critical micellar concentration is approached. In this context, it was possible to conclusively explain the changes in the periodicity of the interfacial deformations depending on the reactant concentration ratio. PMID- 23020504 TI - Convection and reaction in a diffusive boundary layer in a porous medium: nonlinear dynamics. AB - We study numerically the nonlinear interactions between chemical reaction and convective fingering in a diffusive boundary layer in a porous medium. The reaction enhances stability by consuming a solute that is unstably distributed in a gravitational field. We show that chemical reaction profoundly changes the dynamics of the system, by introducing a steady state, shortening the evolution time, and altering the spatial patterns of velocity and concentration of solute. In the presence of weak reaction, finger growth and merger occur effectively, driving strong convective currents in a thick layer of solute. However, as the reaction becomes stronger, finger growth is inhibited, tip-splitting is enhanced and the layer of solute becomes much thinner. Convection enhances the mass flux of solute consumed by reaction in the boundary layer but has a diminishing effect as reaction strength increases. This nonlinear behavior has striking differences to the density fingering of traveling reaction fronts, for which stronger chemical kinetics result in more effective finger merger owing to an increase in the speed of the front. In a boundary layer, a strong stabilizing effect of reaction can maintain a long-term state of convection in isolated fingers of wavelength comparable to that at onset of instability. PMID- 23020505 TI - CO2 sequestration in a radial Hele-Shaw cell via an interfacial chemical reaction. AB - In this manuscript, experimental data for the displacement of a finite volume of aqueous Ca(OH)(2) using CO(2) gas in a radial Hele-Shaw cell will be presented. This chemical reaction is known to generate CaCO(3) precipitate along the gas liquid interface and we seek to understand the influence of the reactive process on fluid displacement. The reactive experiment is compared with the non-reactive case to determine if there are any measurable differences between the two in the range of parameters: CO(2) pressures (1%-10% of an atmosphere measured in gage pressure), liquid volumes (either 50 or 70 MUl), and Ca(OH)(2) concentrations (0, 10, or 20 mM) studied. Analysis is performed by measuring the displacing fluid area A(gas) and total fluid area A(tot) to determine several quantities (gas expansion rate, quasi-equilibrium film rate and value, and presence of fingering instability) used to distinguish the experiments. In general there appears to be little effect of the chemical reaction on most of the measured quantities. PMID- 23020506 TI - Comment on "Generalized projective synchronization in time-delayed systems: nonlinear observer approach" [Chaos 19, 013102 (2009); 20, 029902 (2010)]. AB - In Chaos 19, 013102 (2009), the author proposed generalized projective synchronization for time delay systems using nonlinear observer and obtained sufficient condition to ensure projective synchronization for modulated time varying delay. There are concerns with the obtained conditions as the result was applicable only to trivial case of time varying delay tau[over dot](1)(t)=dtau(1)(t)/dt<1. In this paper, we note the drawbacks of the proposed sufficient condition. The new improved sufficient condition for ensuring the projective synchronization of time varying delayed systems is presented. The proposed new criteria have been verified by adopting the Ikeda system. PMID- 23020508 TI - Porphyrin-containing electrospun nanofibers: positional control of porphyrin molecules in nanofibers and their catalytic application. AB - Polyacrylonitrile nanofibers containing a series of porphyrin molecules were prepared by an electrospinning method. We first succeeded in controlling the position of porphyrin molecules in the nanofibers by considering porphyrin characteristics and the electrospinning conditions. It was concluded that positive charge of cationic porphyrin, TMPyP, and higher applied voltages were effective to locate the porphyrin molecules on the polymer nanofiber surfaces because of the electrostatic repulsion among the molecules during the electrospinning process. The polymer nanofibers with cationic manganese-porphyrin (Mn-TMPyP) on their surface repeatedly showed superoxide dismutase (SOD) activity, which is a catalytic activity to work as antioxidant in various biochemical fields. The positional control of functional molecules in nanofibers demonstrated a new possibility of nanofiber applications. PMID- 23020509 TI - Dysplasia detection rate of confirmatory EGD in nondysplastic Barrett's esophagus. AB - Current guidelines for endoscopic surveillance of Barrett's esophagus (BE) recommend that patients with newly diagnosed BE undergo confirmatory esophagogastroduodenoscopy (EGD) to exclude the presence of dysplasia. The extent to which confirmatory endoscopy alters management and detects missed dysplasia in newly diagnosed BE has not been reported. The frequency with which confirmatory endoscopy changed surveillance management in patients with newly diagnosed BE was assessed. A two center cohort analysis was conducted on patients newly diagnosed with BE. The rate of dysplasia on confirmatory endoscopy for patients who had nondysplastic BE was obtained. Demographic and endoscopic variables were assessed for association with dysplasia detection using Firth logistic regression model. Out of the 146 patients newly diagnosed with BE and initially determined to be without dysplasia, 12 had dysplasia on the confirmatory second EGD (8.2%). Eleven of 12 cases with dysplasia on confirmatory endoscopy had long-segment BE (LSBE). Among all the LSBE cases in our cohort, 11 had newly diagnosed dysplasia on confirmatory EGD, 29.7% (11/37). The average number of biopsies obtained from the 11 LSBE cases with dysplasia was comparable with the rest of the LSBE cases without dysplasia (6.73 and 5.42, respectively, P-value 0.205). The rate of dysplasia detection in short-segment BE (SSBE) was much lower, 0.95% (1 out of 105). There were no cases of high-grade dysplasia (HGD) or cancer detected in any SSBE case. HGD was detected on confirmatory EGD in two cases, both were LSBE. Segment length was the only statistically significant factor to predict the presence of dysplasia on confirmatory endoscopy (odds ratio 9.158, P. 0.008). Confirmatory EGD in newly diagnosed LSBE had significant rate of dysplasia detection (29.7%) in this cohort. Among patients with SSBE, there was a low rate of dysplasia detection with confirmatory EGD, less than 1% of cases. No additional cases of HGD or esophageal carcinoma in SSBE cases were detected. This suggests that the yield of confirmatory EGD is greater in patients with LSBE. PMID- 23020511 TI - Cation dynamics in the pyridinium based ionic liquid 1-N-butylpyridinium bis((trifluoromethyl)sulfonyl) as seen by quasielastic neutron scattering. AB - Quasielastic neutron scattering (QENS) has been used to study the cation dynamics in the pyridinium based ionic liquid (IL) 1-N-butylpyridinium bis((trifluoromethyl)sulfonyl)imide (BuPy-Tf(2)N). This IL allows for a detailed investigation of the dynamics of the cations only, due to the huge incoherent scattering cross section of the cation (sigma(inc)(cation) >> sigma(inc)(anion)). The measured spectra can be decomposed into two Lorentzian lines, indicative of two distinct dynamic processes. The slower of these two processes is diffusive in nature, whereas the faster one can be attributed to localized motions. The temperature dependence of the diffusion coefficient of the slow process follows an Arrhenius law, with an activation energy of E(A) = 14.8 +/- 0.3 kJ/mol. Furthermore, we present here results from experiments with polarized neutrons. These experiments clearly show that the slower of the two observed processes is coherent, while the faster one is incoherent in nature. PMID- 23020510 TI - Molecule-dependent plasmonic enhancement of fluorescence and Raman scattering near realistic nanostructures. AB - The enhancement of fluorescence and Raman scattering by plasmonic nanostructures is studied theoretically with special focus on the effects of the observed molecule's properties and the realistic geometry of the plasmonic nanostructure. Numerical experiments show that the enhancement factor may vary by many orders of magnitude depending on a fluorophore's transition rates or intrinsic quantum yield. For different molecules, boosting fluorescence enhancement means optimizing different factors, leading to a different ideal geometric and spectral configuration. This framework, coupled with powerful new simulation tools, will facilitate the design and characterization of fluorescence-enhancing plasmonic nanostructures as well as yield experimental access to the intrinsic properties of the molecules under study. PMID- 23020512 TI - Factors influencing outcome and incidence of late complications in children who underwent allogeneic hematopoietic stem cell transplantation for hemoglobinopathy. AB - BACKGROUND: Hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment for severe hemoglobinopathy (HGP). Late complications (LCs) are all events occurring beyond two years post-HSCT. We retrospectively analyzed prevalence, factors influencing occurrence, and prognosis of LCs post-HSCT for HGP. PATIENTS AND METHODS: Between 2000 and 2011, 47 patients (21 males, 26 females; 43 with beta thalassemia major, four with sickle cell disease) who had survived more than two years post-HSCT for HGP were retrospectively reviewed. Mean age at HSCT was 7.7 years (1.1-32 years); mean follow-up was 7.1 years (2-11.6 years); 11 patients were splenectomized; mean ferritin level was 3022 ng/mL (350-10900); and seven patients underwent a second HSCT. RESULTS: Endocrinological complications were observed with primary gonadal failure in 16/20 mature females and 4/11 mature males, in five patients with primary hypothyroidism and in four with insulin-dependent diabetes mellitus (DM). Skeletal complications were observed in 10 with secondary osteoporosis; 22 patients had elevated transaminase levels; two had hepatitis B reactivation. Neurological, cardiac and ocular manifestations were relatively rare. A higher incidence of LCs was observed in splenectomized than in nonsplenectomized patients: cGVHD -64% versus 13% (P = .003); endocrine abnormalities -91% versus 30.5%, (P = .001); elevated transaminase levels -73% versus 33% (P = .043); mortality -18% versus 2.7% (NS). CONCLUSIONS: LCs post-HSCT for HGP are common and heterogeneous. Etiology is multifactorial with iron overload (IO), class, splenectomy, age, chronic GVHD, and corticosteroid (CS) treatment. Our data may help build follow-up guidelines to limit, detect, and treat any LCs and improve quality of life. PMID- 23020513 TI - Bisphenol analogues in sediments from industrialized areas in the United States, Japan, and Korea: spatial and temporal distributions. AB - Bisphenol analogues are used in the production of polycarbonate plastics and epoxy resins. Despite the widespread use of bisphenols, few studies have reported the occurrence of compounds other than bisphenol A (BPA) in sediment. In this study, concentrations and profiles of eight bisphenol analogues were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS) in sediments collected from several industrialized areas in the United States (U.S.), Japan, and Korea. The total concentrations of bisphenols (SigmaBPs; sum of eight bisphenols) in sediment ranged from below the limit of quantitation (LOQ) to 25,300 ng/g dry weight (dw), with a mean value of 201 ng/g dw. Sediment samples from Lake Shihwa, Korea, contained the highest concentrations of both individual and total bisphenols. Among individual bisphenols, BPA and bisphenol F (BPF) were the predominant compounds, accounting for 64% and 30% of the total bisphenol concentrations in sediment. We also examined vertical profiles of concentrations of bisphenol analogues in sediment cores from the U.S. and Japan. Sediment cores from the U.S. showed a gradual decline in the concentrations of bisphenols as compared to the past decade. BPA concentrations were found to decline in a sediment core from Tokyo Bay, but bisphenol S (BPS) was more frequently detected in core sections that represent the most recent decade, which is consistent with the replacement of BPA with BPS in some applications since 2001 in Japan. PMID- 23020514 TI - Evidence for different mechanisms of 'unhooking' for melphalan and cisplatin induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples. AB - BACKGROUND: DNA interstrand cross-links (ICLs) are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma) and solid tumours (ovarian cancer) that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the 'unhooking' step is common to all ICLs. METHODS: Using a modification of the single cell gel electrophoresis (Comet) assay we measured the formation and unhooking of melphalan and cisplatin induced ICLs in cell lines and clinical samples. DNA damage response in the form of gamma-H2AX foci formation and the formation of RAD51 foci as a marker of homologous recombination were also determined. Real-time PCR of 84 genes involved in DNA damage signalling pathways was also examined pre- and post-treatment. RESULTS: Plasma cells from multiple myeloma patients known to be clinically resistant to melphalan showed significant unhooking of melphalan-induced ICLs at 48 hours, but did not unhook cisplatin-induced ICLs. In ovarian cancer cells obtained from patients following platinum-based chemotherapy, unhooking of cisplatin-induced ICLs was observed at 48 hours, but no unhooking of melphalan induced ICLs. In vitro, A549 cells were proficient at unhooking both melphalan and cisplatin-induced ICLs. gamma-H2AX foci formation closely followed the formation of ICLs for both drugs, and rapidly declined following the peak of formation. RPMI8226 cells unhooked melphalan, but not cisplatin-induced ICLs. In these cells, although cross-links form with cisplatin, the gamma-H2AX response is weak. In A549 cells, addition of 3nM gemcitabine resulted in complete inhibition of cisplatin-induced ICL unhooking but no effect on repair of melphalan ICLs. The RAD51 foci response was both drug and cell line specific. Real time PCR studies highlighted differences in the damage response to melphalan and cisplatin following equi-ICL forming doses. CONCLUSIONS: These data suggest that the mechanisms by which melphalan and cisplatin-induced ICLs are 'unhooked' in vitro are distinct, and the mechanisms of clinical acquired resistance involving repair of ICLs, are drug specific. PMID- 23020515 TI - Exploiting 4-sulphate N-acetyl galactosamine decorated gelatin nanoparticles for effective targeting to professional phagocytes in vitro and in vivo. AB - The present study was focused on the development of surface modified gelatin nanoparticles (SGNPs) using novel ligand 4-sulfated N-acetyl galactosamine (4 SO(4)GalNAc) for specific targeting to macrophages. The gelatin has been modified with the potential targeting moiety 4-SO(4)GalNAc, which was further used for the preparation of modified nanoparticles. The nanoparticles have been prepared by two step desolvation method. The SGNPs and unmodified gelatin nanoparticles (GNPs) were loaded with doxorubicin (DxR) and its targeting potential was compared. Developed DxR-loaded SGNPs (DxR-SGNPs) were found to have negative zeta potential (-19.8 +/- 0.22 mV) whereas DxR-loaded GNPs (DxR-GNPs) have the positive zeta potential of around +12.2 +/- 0.36 mV. The mean particle size of DxR-SGNPs and DxR-GNPs was found to be 283 +/- 7 and 134 +/- 5 nm, respectively. Flow cytometric data confirmed the enhanced uptake of DxR-SGNPs in J774A.1 and PBMC when compared with DxR-GNPs. Intracellular localization studies indicate that the fluorescence intensity of DxR-SGNPs was significantly higher when compared to DxR-GNPs. DxR-SGNPs rendered significantly higher localization of DxR in liver and spleen as compared to DxR-GNPs after i.v. administration. The study stipulates that 4-SO(4)GalNAc assures for targeting resident macrophages. PMID- 23020516 TI - Enantioselective Baeyer-Villiger oxidation: desymmetrization of meso cyclic ketones and kinetic resolution of racemic 2-arylcyclohexanones. AB - Catalytic enantioselective Baeyer-Villiger (BV) oxidations of racemic and meso cyclic ketones were achieved in the presence of chiral N,N'-dioxide-Sc(III) complex catalysts. The BV oxidations of prochiral cyclohexanones and cyclobutanones afforded series of optically active epsilon- and gamma-lactones, respectively, in up to 99% yield and 95% ee. Meanwhile, the kinetic resolution of racemic 2-arylcyclohexanones was also realized via an abnormal BV oxidation. Enantioenriched 3-aryloxepan-2-ones, whose formation is counter to the migratory aptitude, were obtained preferentially. Both the lactones and the unreacted ketones were obtained with high ee values. PMID- 23020517 TI - Environmental and individual drivers of animal movement patterns across a wide geographical gradient. AB - Within the rapidly developing field of movement ecology, much attention has been given to studying the movement of individuals within a subset of their population's occupied range. Our understanding of the effects of landscape heterogeneity on animal movement is still fairly limited as it requires studying the movement of multiple individuals across a variety of environmental conditions. Gaining deeper understanding of the environmental drivers of movement is a crucial component of predictive models of population spread and habitat selection and may help inform management and conservation. In Ontario, woodland caribou (Rangifer tarandus caribou) occur along a wide geographical gradient ranging from the boreal forest to the Hudson Bay floodplains. We used high resolution GPS data, collected from 114 individuals across a 450000 km(2) area in northern Ontario, to link movement behaviour to underlying local environmental variables associated with habitat permeability, predation risk and forage availability. We show that a great deal of observed variability in movement patterns across space and time can be attributed to local environmental conditions, with residual individual differences that may reflect spatial population structure. We discuss our results in the context of current knowledge of movement and caribou ecology and highlight potential applications of our approach to the study of wide-ranging animals. PMID- 23020518 TI - Perceptions of the characteristics of the Alberta Nutrition Guidelines for Children and Youth by child care providers may influence early adoption of nutrition guidelines in child care centres. AB - In 2008, the Alberta government released the Alberta Nutrition Guidelines for Children and Youth (ANGCY) as a resource for child care facilities to translate nutrition recommendations into practical food choices. Using a multiple case study method, early adoption of the guidelines was examined in two child care centres in Alberta, Canada. Key constructs from the Diffusion of Innovations framework were used to develop an interview protocol based on the perceived characteristics of the guidelines (relative advantage, compatibility, complexity, trialability and observability) by child care providers. Analysis of the ANGCY was conducted by a trained qualitative researcher and validated by an external qualitative researcher. This entailed reviewing guideline content, layout, organisation, presentation, format, comprehensiveness and dissemination to understand whether characteristics of the guidelines affect the adoption process. Data were collected through direct observation, key informant interviews and documentation of field notes. Qualitative data were analysed using content analysis. Overall, the guidelines were perceived positively by child care providers. Child care providers found the guidelines to have a high relative advantage, be compatible with current practice, have a low level of complexity, easy to try and easy to observe changes. It is valuable to understand how child care providers perceive characteristics of guidelines as this is the first step in identifying the needs of child care providers with respect to early adoption and identifying potential educational strategies important for dissemination. PMID- 23020519 TI - Mini test dose of intravenous busulfan (busulfex((r))) in allogeneic non myeloablative stem cell transplantation, followed by liquid chromatography tandem mass spectrometry. PMID- 23020520 TI - Multiexciton dynamics in infrared-emitting colloidal nanostructures probed by a superconducting nanowire single-photon detector. AB - Carrier multiplication (CM) is the process in which absorption of a single photon produces multiple electron-hole pairs. Here, we evaluate the effect of particle shape on CM efficiency by conducting a comparative study of spherical nanocrystal quantum dots (NQDs) and elongated nanorods (NRs) of PbSe using a time-resolved technique that is based on photon counting in the infrared using a superconducting nanowire single-photon photodetector (SNSPD). Due to its high sensitivity and low noise levels, this technique allows for accurate determination of CM yields, even with the small excitation intensities required for quantitative measurements, and the fairly low emission quantum yields of elongated NR samples. Our measurements indicate an up to ~60% increase in multiexciton yields in NRs versus NQDs, which is attributed primarily to a decrease in the electron-hole pair creation energy. These findings suggest that shape control is a promising approach for enhancing the CM process. Further, our work demonstrates the effectiveness of the SNSPD technique for the rapid screening of CM performance in infrared nanomaterials. PMID- 23020521 TI - Tumour budding and the expression of cancer stem cell marker aldehyde dehydrogenase 1 in nasopharyngeal carcinoma. AB - AIMS: To detect the prognostic significance of tumour budding and its expression of aldehyde dehydrogenase 1 (ALDH1) in nasopharyngeal carcinoma (NPC). METHODS AND RESULTS: Tumour budding was investigated in 105 patients with NPC by immunohistochemistry for pan-cytokeratin (AE1/AE3). The intensity of budding correlated strongly with T classification (P=0.008), lymphatic invasion (P<0.001), vascular invasion (P=0.029), lymph node metastasis (P < 0.001), and clinical stage (P=0.010). Univariate analysis revealed that patients with high budding grade had poorer survival than those with low grade (P=0.002). Multivariate analysis showed that tumour budding was an independent predictor of survival (P=0.001). Furthermore, budding cells showed high-level expression of the cancer stem cell (CSC) marker ALDH1. Budding cells with high-level ALDH1 expression contributed to several aggressive behaviours and poor survival (P=0.000). CONCLUSIONS: We describe, for the first time, the presence of tumour budding and its correlation with aggressive tumour behaviour and poor patient survival in NPC. The degree of tumour budding could be a valuable predictive factor in NPC. In addition, we show, also for the first time, that budding cells in NPC might possess the invasive and metastatic properties of CSCs. PMID- 23020522 TI - Outcome and determinants of mortality in 269 patients with combination anti tuberculosis drug-induced liver injury. AB - BACKGROUND AND AIM: Worldwide anti-tuberculosis (TB) drug-induced liver disease (DILI) is an important cause of hepatotoxicity, and drug-induced acute liver failure (ALF). Reported series on anti-TB DILI are limited by a mix of cases with mild transaminase elevation or adaptation. Our aim was to analyze the clinical features, laboratory characteristics, outcome, and determine predictors of 90-day mortality. METHODS: Single center analysis of consecutive cases of anti-TB DILI following combination anti-TB drugs exposure from 1997-2011. RESULTS: Of the 269 patients, 191 (71%) experienced jaundice and 69 (25.7%) accounted for ALF. The mean age and treatment duration was 41.3 years and 1.9 months, respectively; males constituted 55.7%. DILI occurred throughout the course of treatment; three quarters occurred within the first 2 months. HIV infection was present in 21 (7.8%). The 90-day mortality was 22.7%. DILI accompanied by jaundice (n = 191), encephalopathy (n = 69) or ascites (n = 69) resulted in mortality in 30%, 69.6% and 50.7%, respectively (P < 0.001). Age, gender, transaminase levels, HIV or hepatitis B surface antigen (HBsAg) status did not influence survival. Treatment duration, encephalopathy, ascites, bilirubin, serum albumin, international normalized ratio (INR), serum creatinine and leukocyte count were associated with mortality (P < 0.001). Multivariate logistic regression model for mortality, incorporating encephalopathy, albumin, bilirubin, INR, and creatinine yielded a C statistic of 97%. CONCLUSIONS: Anti-TB DILI occurs throughout treatment duration progressing to ALF in a quarter of patients. The overall mortality is 22.7%, which is higher when accompanied by jaundice, ascites or encephalopathy. An anti TB DILI model, incorporating bilirubin, INR, encephalopathy, serum creatinine and albumin predicted mortality with C-statistic of 97%. PMID- 23020524 TI - Glucan adsorption on mesoporous carbon nanoparticles: effect of chain length and internal surface. AB - The adsorption of cellulose-derived long-chain (longer than ten glucose repeat units on size) glucans onto carbon-based acid catalysts for hydrolysis has long been hypothesized; however, to date, there is no information on whether such adsorption can occur and how glucan chain length influences adsorption. Herein, in this manuscript, we first describe how glucan chain length influences adsorption energetics, and use this to understand the adsorption of long-chain glucans onto mesoporous carbon nanoparticles (MCN) from a concentrated acid solution, and the effect of mesoporosity on this process. Our results conclusively demonstrate that mesoporous carbon nanoparticle (MCN) materials adsorb long-chain glucans from concentrated acid hydrolyzate in amounts of up to 30% by mass (303 mg/g of MCN), in a manner that causes preferential adsorption of longer-chain glucans of up to 40 glucose repeat units and, quite unexpectedly, fast adsorption equilibration times of less than 4 min. In contrast, graphite type carbon nanopowders (CNP) that lack internal mesoporosity adsorb glucans in amounts less than 1% by mass (7.7 mg/g of CNP), under similar conditions. This inefficiency of glucan adsorption on CNP might be attributed to the lack of internal mesoporosity, since the CNP actually possesses greater external surface area relative to MCN. A systematic study of adsorption of glucans in the series glucose to cellotetraose on MCN shows a monotonically decreasing free energy of adsorption upon increasing the glucan chain length. The free energy of adsorption decreases by at least 0.4 kcal/mol with each additional glucose unit in this series, and these energetics are consistent with CH-pi interactions providing a significant energetic contribution for adsorption, similar to previous observations in glycoproteins. HPLC of hydrolyzed fragments in solution, (13)C Bloch decay NMR spectroscopy, and GPC provide material balance closure of adsorbed glucan coverages on MCN materials. The latter and MALDI-TOF-MS provide direct evidence for adsorption of long-chain glucans on the MCN surface, which have a radius of gyration larger than the pore radius of the MCN material. PMID- 23020523 TI - Comparative phylogeography and demographic history of European shads (Alosa alosa and A. fallax) inferred from mitochondrial DNA. AB - BACKGROUND: Comparative broad-scale phylogeographic studies of aquatic organisms provide insights on biotic responses to the paleohydrological dynamics associated with climatic oscillations. These insights can be used to formulate a framework for understanding the evolutionary history of a species or closely related taxa as well as aid in predictive modeling of further responses to climate change. Anadromous fishes constitute interesting models for understanding the relative importance of environmental versus biological factors in shaping intraspecific genetic substructure on the interface between marine and freshwater realms. European shads, Alosa alosa and A. fallax are anadromous species that have persisted through historical large-scale environmental perturbations and now additionally face an array of anthropogenic challenges. A comprehensive phylogeographic investigation of these species is needed to provide insights on both the historical processes that have shaped their extant genetic structure and diversity, and the prospects for their future management and conservation. RESULTS: Despite introgressive hybridization, A. alosa and A. fallax are genetically divergent, congruent with previous studies. Three similarly divergent mtDNA clades were recognized within both A. fallax and A. alosa, most likely originating during common periods of isolation during the Pleistocene among the studied oceanographic regions. Periods of basin isolation apparently extended to the Black Sea as additional Alosa clades occur there. The present day geographic distribution of genetic diversity within European Alosa sp. suggests the existence of a strong but permeable barrier between the Atlantic and Mediterranean seas, as shown for a number of other aquatic species. Overall mtDNA diversity is considerably lower for A. alosa compared to A. fallax, suggesting that the former species is more sensitive to climatic as well as anthropogenic changes. For A. fallax, migration from the Mediterranean to the Atlantic was detected but not in the opposite direction, with colonization of the North Atlantic probably occurring after last glacial maximum. CONCLUSION: The similar haplotype network topologies between the two species support a common intraspecific history of isolation. Despite these similarities, A. alosa and A. fallax have clearly responded differently to the hydrological dynamics of the Pleistocene, as reflected in their distinct demographic histories. As the species additionally occupy different ecological niches it should not be surprising that they differ in resilience to natural or human-mediated climatic changes. For A. fallax, it is further clear that its demographic response to large-scale hydrological events is not synchronized between the Atlantic and Mediterranean basins. These regional and species-specific differences should be incorporated into future predictive modeling of biological response to climate change as well as current management concepts. PMID- 23020525 TI - CHD1L protein is overexpressed in human ovarian carcinomas and is a novel predictive biomarker for patients survival. AB - BACKGROUND: Our recent studies suggested that the chromodomain helicase DNA binding protein 1-like (CHD1L) gene plays an oncogenic role in human hepatocellular carcinoma. However, the status of CHD1L protein expression in ovarian cancer and its clinical/prognostic significance are obscure. METHODS: In this study, immunohistochemistry (IHC) for CHD1L was performed on a tissue microarray (TMA) containing 102 primary ovarian carcinomas and 44 metastatic lesions (omental metastasis). Receiver-operator curve (ROC) analysis was used to evaluate patients' survival status. RESULTS: There is an augmented tendency of CHD1L expression in ovarian carcinoma metastasis than in primary lesions (P<0.05). A significant association was found between positive expression of CHD1L and tumors histological type (P <0.05). By univariate survival analysis of the ovarian carcinoma cohorts, positive expression of CHD1L was significantly correlated with shortened patient survival (mean 66.7 months versus 97.4 months, P<0.05). Moreover, CHD1L expression was evaluated to be a significant and independent prognostic factor in multivariate analysis (P<0.05). CONCLUSIONS: These findings provide evidence that positive expression of CHD1L protein is significantly correlated with the metastasis proceeding of ovarian carcinoma, and CHD1L protein expression, as examined by IHC, may act as a novel prognostic biomarker for patients with ovarian carcinoma. PMID- 23020526 TI - Peritoneal macrophages mediated delivery of chitosan/siRNA nanoparticle to the lesion site in a murine radiation-induced fibrosis model. AB - BACKGROUND: Radiation-induced fibrosis (RIF) is a dose-limiting complication of cancer radiotherapy and causes serious problems, i.e. restricted tissue flexibility, pain, ulceration or necrosis. Recently, we have successfully treated RIF in a mouse model by intraperitoneal administration of chitosan/siRNA nanoparticles directed towards silencing TNF alpha in local macrophage populations, but the mechanism for the therapeutic effect at the lesion site remains unclear. METHODS: Using the same murine RIF model we utilized an optical imaging technique and fluorescence microscopy to investigate the uptake of chitosan/fluorescently labeled siRNA nanoparticles by peritoneal macrophages and their subsequent migration to the inflamed tissue in the RIF model. RESULTS: We observed strong accumulation of the fluorescent signal in the lesion site of the irradiated leg up to 24 hours using the optical imaging system. We further confirm by immunohistochemical staining that Cy3 labeled siRNA resides in macrophages of the irradiated leg. CONCLUSION: We provide a proof-of-concept for host macrophage trafficking towards the inflamed region in a murine RIF model, which thereby suggests that the chitosan/siRNA nanoparticle may constitute a general treatment for inflammatory diseases using the natural homing potential of macrophages to inflammatory sites. PMID- 23020527 TI - Pathologic complete response in poorly differentiated adenocarcinomas of the appendix: a case series. PMID- 23020528 TI - Non-steroidal anti-inflammatory treatment in cancer cachexia: a systematic literature review. AB - BACKGROUND: There are no established treatments for cachexia. Recently it has been suggested that the evidence for non-steroidal anti-inflammatory (NSAID) treatment is sufficient to support its regular clinical use. Primary objective in this systematic review was to assess efficacy and safety of NSAID treatment in improving body weight and muscle mass in patients with cancer cachexia. Secondary objectives were to assess whether this treatment could improve other cachexia domains such as anorexia and food intake, catabolic drive and function. MATERIAL AND METHODS: A systematic literature review of PubMed, EMBASE and Cochrane Central register of controlled trials database was carried out using both text words and MeSH/EMTREE terms. RESULTS: Thirteen studies were included; all but two trials showed either improvement or stabilization in weight or lean body mass. Seven studies were without a comparator. Studies are generally small and a few are methodologically flawed, often due to multiple outcomes with excess risk of false positives. CONCLUSION: NSAIDs may improve weight in cancer patients with cachexia, and there is some evidence on effect on physical performance, self reported quality of life and inflammatory parameters. Evidence is too frail to recommend NSAID for cachexia outside clinical trials. This is supported by the known side effects of NSAIDs, even though the reviewed literature report almost negligible toxicity. PMID- 23020529 TI - Potential of marine lactic acid bacteria to ferment Sargassum sp. for enhanced anticoagulant and antioxidant properties. AB - AIM: To evaluate the suitability of marine lactic acid bacteria (LAB) as starter cultures for Sargassum sp. fermentation to enhance its antioxidant and anticoagulation activity. METHODS AND RESULTS: LAB isolated from marine source were characterized for their ability to utilize seaweed as a sole carbon source and applied to Sargassum fermentation. Fermentation period was optimized by monitoring the fermented sample at regular interval for a period of 18 days. Results revealed that a fermentation period of 12 days was effective with maximum culture viability and other desirable characteristics such as pH, total titratable acidity, total and reducing sugars. Under optimum fermentation period, the sample fermented with P1-2CB-w1 (Enterococcus faecium) exhibited maximum anticoagulation activity and antioxidant activity. CONCLUSIONS: The study reveals a novel well-defined starter culture from marine origin intended for seaweed fermentation for recovery of bioactive molecules. SIGNIFICANCE AND IMPACT OF THE STUDY: The study provides information for the enhancement of bioactive molecules in an eco-friendly manner and also paves a way towards the development of wide range of seaweed functional foods. PMID- 23020530 TI - HLA-A*02:335 and HLA-A*02:370 were identified by polymerase chain reaction sequence-based typing in Chinese individuals. AB - HLA-A*02:335 shows one nucleotide different from HLA-A*02:07:01 at position 173T>A and HLA-A*02:370 has a single nucleotide polymorphism at position 886 C>G compared with HLA-A*02:03:01. PMID- 23020531 TI - Ensuring the quality of occupational safety risk assessment. AB - In work environments, the main aim of occupational safety risk assessment (OSRA) is to improve the safety level of an installation or site by either preventing accidents and injuries or minimizing their consequences. To this end, it is of paramount importance to identify all sources of hazards and assess their potential to cause problems in the respective context. If the OSRA process is inadequate and/or not applied effectively, it results in an ineffective safety prevention program and inefficient use of resources. An appropriate OSRA is an essential component of the occupational safety risk management process in industries. In this article, we performed a survey to elicit the relative importance for identified OSRA tasks to enable an in-depth evaluation of the quality of risk assessments related to occupational safety aspects on industrial sites. The survey involved defining a questionnaire with the most important elements (tasks) for OSRA quality assessment, which was then presented to safety experts in the mining, electrical power production, transportation, and petrochemical industries. With this work, we expect to contribute to the main question of OSRA in industries: "What constitutes a good occupational safety risk assessment?" The results obtained from the questionnaire showed that experts agree with the proposed OSRA process decomposition in steps and tasks (taxonomy) and also with the importance of assigning weights to obtain knowledge about OSRA task relevance. The knowledge gained will enable us, in the near future, to build a framework to evaluate OSRA quality for industrial sites. PMID- 23020532 TI - The completeness of medical records to assess quality of hospital care: the case of acute myocardial infarction in a district-level general hospital in Iran. AB - BACKGROUND: Quantifying the quality of care in high-cost and fatal conditions such as acute myocardial infarction (AMI) is a crucial step toward improving clinical outcomes in these patients. The main objective of this pilot study is to show whether abstraction of medical charts would be a useful method to systematically assess quality of care in patients hospitalized for AMI in a general hospital that has no interventional cardiac technology. METHODS: A general physician and a cardiologist working with Shahid Gholipour Hospital in Bukan, Northwest Iran, retrospectively abstracted medical records of all patients with verified diagnoses of myocardial infarction who were hospitalized between April 1, 2010 and March 31, 2011. The targeted outcome variables were risk adjusted mortality and risk-adjusted length of hospital stay. Process quality indicators were selected from those developed by the National Quality Forum (NQF) of the United States. We reported completeness of selected variables used to build and calculate quality indicators in this study. RESULTS: For most variables, missing values were negligible. However, missing data on fields related to contraindications for prescribed medications were common. CONCLUSIONS: Medical chart abstractions provide useful first steps in assessing differences in the quality of hospital care for patients with AMI. Extension of our pilot study is highly recommended and may help trigger policy decisions to promote hospital quality in Iran. PMID- 23020533 TI - Late-onset multiple sclerosis in Isfahan, Iran. AB - BACKGROUND: Multiple sclerosis (MS) typically affects young adults; however, the first symptoms can occur after age 50 and is classified as late-onset MS (LOMS). METHODS: In this retrospective study, we extracted the records of 3522 MS patients (2716 females and 806 males) registered in the Isfahan MS Society (IMSS) from 2003 to 2010. Next, we searched for LOMS cases. We aimed to compare these cases with 1698 non-LOMS subjects also extracted from the IMSS database. RESULTS: We found 48 LOMS patients (28 females and 20 males), which gave a crude frequency of 1.36%. The frequency by sex of LOMS in males (2.4%) was significantly greater than in females (1.0%, P = 0.002). The mean age at onset was 55.1 +/- 4.3 years. The female to male ratio of 1.4:1 in these patients was significantly lower than in non-LOMS subjects (3.37:1, P = 0.003). The leading pattern of MS was relapsing remitting (RR) in 62.5%, followed by primary progressive (PP) in 27.1%, and secondary progressive (SP) in 10.4%. Predominant presenting symptoms and signs were motor disturbances (35.4%), followed by brainstem (25%), optic neuritis (22.9%), and sensory related deficits (18.7%). The mean progression index (PI) in LOMS patients (0.88 +/- 0.48) was significantly higher than in non-LOMS cases, 0.37 +/- 0.17 (P < 0.0001). DISCUSSION: In comparing LOMS patients with the non LOMS cohort, there was a higher frequency of the PP pattern and a higher PI in the LOMS group. In comparing other high-risk populations with the Isfahan cohort, LOMS formed a lower percentage of the total Isfahan MS population. PMID- 23020534 TI - The association between diet quality indices and obesity: Tehran Lipid and Glucose Study. AB - BACKGROUND: The aim of this study was to investigate the ability of diet quality indices in predicting obesity and abdominal obesity in a population in nutrition transition. METHODS: This study explored the association of the Mediterranean Diet Scale (MDS), Healthy Eating Index-2005 (HEI-2005), and Diet Quality Index International (DQI-I) with body mass index (BMI) and waist circumference (WC) in a cross-sectional study after 6.7 years of follow-up in the Tehran Lipid and Glucose Study (TLGS) population. RESULTS: Out of 192 subjects who had BMI < 25kg/m(2) and of 283 subjects who were free of abdominal obesity at baseline, 39.6% developed overweight and obesity and 43.1% developed abdominal obesity, respectively during 6.7 years of follow-up in the study population. In cross sectional analysis, after adjusting for age, sex, energy intake, physical activity and smoking status, multivariate analysis of covariance did not show any significant results regarding the relation of the diet quality indices, BMI and WC. According to follow-up analysis, none of the indices had significant associations with BMI and WC after adjustments for confounders and baseline values of BMI and WC. CONCLUSION: Adherence to MDS, HEI-2005, and DQI-I could not predict BMI and WC in Iranian participants after 6.7 years of follow-up. PMID- 23020535 TI - Diagnostic values of metabolic syndrome definitions for detection of insulin resistance: Tehran Lipid and Glucose Study (TLGS). AB - BACKGROUND: This study examines the characteristics and agreement between different definitions of metabolic syndrome (MetS) and insulin resistance (IR). METHODS: A total of 347 non-diabetic individuals who were >= 20 years of age were selected from the Tehran Lipid and Glucose Study (TLGS). Subjects were categorized as having MetS by the Adult Treatment Panel III (ATP III) and the Joint Interim Statement (JIS). IR was estimated by using the homeostasis model assessment (HOMA-IR). RESULTS: According to ATP III and JIS criteria 38.9% and 38.2% of subjects had MetS respectively. The sensitivity of ATP III was 52.3% and specificity was 65%; for JIS the sensitivity was 52.3%, with a specificity of 66.5%. Kappa between ATP III or JIS and HOMA-IR was 0.14 and 0.16, respectively. Based on receiver operating characteristic (ROC) analysis, the use of waist circumference (WC) and fasting plasma glucose (FPG) for the diagnosis of IR in women showed a diagnostic accuracy equal to or instead of counting MetS components using modified ATP III or JIS. WC optimal cut points for prediction of IR were 93.5 cm for men and 92.5 cm for women. CONCLUSIONS: ATP III and JIS definitions have low sensitivities and specificities for detecting IR. There is poor agreement between these criteria and IR. PMID- 23020536 TI - The relationship between serum adiponectin levels with the presence and severity of coronary artery disease. AB - BACKGROUND: Adiponectin plays important roles in the endocrine and cardiovascular systems, in fat and carbohydrate metabolism, and inflammation. In this study the relationship between adiponectin levels with the presence and severity of coronary artery disease (CAD) is evaluated. METHODS: This was a cross-sectional study that enrolled 213 persons who referred for coronary angiography. One cardiologist reported the results of each coronary angiography by using two scoring systems [number of vessel disease (usual method) and Gensini scoring system]. Then, the relationship between adiponectin levels with the presence and severity of CAD as well as predictive factors for CAD were evaluated. RESULTS: There was a significant negative association between mean serum adiponectin levels and presence of CAD (P = 0.04) after adjustment for all conventional risk factors for CAD. Also there was a significant negative correlation between serum adiponectin levels and severity of CAD based on the usual method for reporting coronary angiograms (P = 0.01). After adjustment for all conventional risk factors for CAD the serum adiponectin level tended to be inversely associated with the Gensini score (P = 0.09). Logistic regression analysis showed that a higher serum adiponectin level was negatively and independently associated with CAD (odds ratio: 0.94; 95% confidence interval: 0.88-1.00; P < 0.05). The variables predictive of serum adiponectin levels were determined as follows: HDL cholesterol (P = 0.001); age (P = 0.002); insulin resistance (P = 0.005) and triglycerides (P = 0.036). CONCLUSIONS: This cross-sectional study showed a significant negative association between serum adiponectin levels to the presence and severity of CAD. PMID- 23020537 TI - The effect of cholestasis on rewarding and exploratory behaviors induced by opioidergic and dopaminergic agents in mice. AB - BACKGROUND: Several investigations have indicated that cholestasis decreases opioid receptor expression in the brain following increased opioidergic neurotransmission. The opioidergic system plays an important role in regulation of reward circuits that may be produced via dopamine-dependent mechanisms. It has been suggested that the dopaminergic system of the nucleus accumbens is necessary in conditioned place preference (CPP). The aim of this study is, therefore, to test if cholestasis can alter the reward system and the involvement of opioidergic and dopaminergic systems in this phenomenon. METHODS: We used CPP and hole-board paradigms to measure the reward effect and exploratory behaviors, respectively, in mice. Cholestasis was induced by ligation of the main bile duct, using two ligatures and transecting the duct between them (BDL mice). RESULTS: The data showed that morphine (1 and 2 mg/kg), sulpiride (80 mg/kg) and SKF38393 (20 mg/kg) produced CPP, while naloxone (1 mg/kg) and SCH23390 (1mg/kg) produced conditioned place aversion (CPA), whereas quinpirole had no effect in sham operated mice. However, morphine (2 mg/kg, i.p.), sulpiride (40 mg/kg) and? SKF38393 (10 mg/kg) induced CPP in BDL mice compared to sham-operated mice. Naloxone- or SCH23390-induced CPA was reduced in BDL mice compared with the respective sham-operated mice. Quinpirole tended to induce aversion in BDL mice which was, however, not significant. In addition, quinpirole 1 mg/kg) and SCH23390 (1 mg/kg) increased head-dip exploratory behavior, whereas naloxone (2 mg/kg) caused a decrease in head-dip exploratory behavior in sham-operated mice. Morphine (2 mg/kg), SCH23390 (1 mg/kg) and quinpirole (0.25 and 0.5 mg/kg) induced anxiogenic-like behavior in BDL mice. CONCLUSION: It can be concluded that cholestasis differentially alters the reward effects of opioidergic and dopaminergic agents. PMID- 23020538 TI - Association between serum levels of MASP-2 and neutropenic febrile attacks in children with leukemia. AB - BACKGROUND: Infectious complications are a major etiology of morbidity and mortality in febrile neutropenic patients. Low serum mannose-binding lectin (MBL) associated serine protease-2 (MASP-2) concentration may represent a risk factor for infection in leukemia patients receiving chemotherapy. This study evaluates the relationship between serum levels of MASP-2 with neutropenic febrile attacks in children with leukemia. METHOD: This prospective cohort study conducted between 2009-2010, we measured baseline serum MASP-2 levels by enzyme-linked immunosorbent assay (ELISA) prior to chemotherapy in leukemia patients less than 14 years of age. The relationship of febrile neutropenia (FN) episodes and duration of hospitalization with MASP-2 concentration was analyzed. RESULTS: We evaluated 75 children [38 girls (51%), 37 boys (49%); mean age, 61.6 +/- 43.7 months]. There were 8 (10.7%) children with MASP-2 deficiency (< 200 ng/mL). Mean MASP-2 was 673.2 +/- 288.7 ng/mL (range: 116-1112). Eight patients had no FN episodes. Of the 129 FN episodes recorded, 19 (average 2.4 times) were from the MASP-2deficient group and 110 (average 1.6 times) were in the normal group. There was a significant difference between the mean MASP-2 concentration and FN episodes (P = 0.043). There was an inverse relationship between FN episodes (r = 0.332, P = 0.004) and the duration of hospitalization (r = -0.334, P = 0.005) with MASP-2 concentration. MASP-2 deficient patients were hospitalized longer than the normal group, which was strongly significant (P < 0.001). CONCLUSION: Our study confirmed the results of several previous studies. MASP-2 deficiency in leukemic children treated with chemotherapy was associated with an increased risk of FN episodes, prolonged cumulative duration of hospitalization, and intravenous antimicrobial therapy. PMID- 23020539 TI - Percutaneous transvenous mitral commissurotomy: significance of echocardiographic assessment in prediction of immediate result. AB - BACKGROUND: The current study aims to identify demographic, clinical characteristics, echocardiographic and/or mitral valve morphological parameters that may predict the successful result of percutaneous transvenous mitral commissurotomy (PTMC). METHODS: The medical records of 196 patients (48 males, mean age: 42.7 +/- 11.5 years) who underwent PTMC were reviewed. Prior to PTMC, a combination of transthoracic and transesophageal echocardiography were used to investigate substantial mitral valve morphological subcomponents (thickening, mobility, calcification, and subvalvular thickness) and suitability for PTMC. The second transthoracic echocardiographic assessment was performed within six weeks after PTMC. Patients were divided into two categories of successful or unsuccessful according to PTMC results. Successful PTMC was defined as: final mitral valve area (MVA) >=1.5 cm2 without a post-procedure mitral regurgitation (MR) grade >2. The significant predictor of the result was identified by comparing demographic data, initial echocardiographic assessments and mitral valve morphological scores within both groups. RESULTS: The mean MVA increased from 1.0 +/- 0.2 cm2 to 1.7 +/- 0.4 cm2, and mitral valve mean gradient (MVMG) decreased from 11.5 +/- 5.2 to 5.2 +/- 3.3 mmHg (P < 0.001 for both). Successful results were obtained in 139 (70.9%) patients compared to unsuccessful results in 57 (29.1%). Unsuccessful results were due to suboptimal secondary MVA < 1.5 cm2 in 50 (25.5%) patients and post-procedure MR grade >2 in 7 (3.6%). Multiple logistic regression analysis indicated that young age, lower size of the left atrium (LA), and smaller degree of mitral valve thickness were the predictors of successful result. CONCLUSION: Pre-procedure echocardiographic assessment appears to be helpful in predicting PTMC results. Successful PTMC is influenced by the patients' age, LA size, and mitral valve thickness. PMID- 23020540 TI - Medical management of diabetic retinopathy: an overview. AB - Diabetes mellitus is a global health problem affecting 366 million people worldwide and its prevalence is growing rapidly. Diabetic eye disease is present in up to 25% of diabetic subjects. Diabetic retinopathy is a chronic complication of diabetes that can result in blindness. Generally, there are two stages of diabetic retinopathy, non-proliferative and proliferative. The longer a person has diabetes and the poorer metabolic control, the higher the chance of developing diabetic retinopathy. The majority of people with type 2 diabetes will ultimately develop diabetic retinopathy. Multifactorial therapy targeted to lifestyle modification and optional glycemic control reduces the risk. However, diabetic retinopathy develops or progresses with time. Primary (preventive) strategies include glycemic, lipid, and blood pressure control. Glycemic control effectively reduces the incidence of diabetic retinopathy. In additional, its effect on progression of diabetic retinopathy has been demonstrated in randomized clinical trials. Furthermore, tight control of blood pressure significantly reduces the progression of retinopathy and visual loss. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study Group has shown that intensive blood pressure control has no beneficial effect on reducing the rate of diabetic retinopathy in subjects with type 2 diabetes. Elevated serum lipids and dyslipidemias are associated with a higher risk of diabetic retinopathy. The beneficial effects of lipid-lowering agents on the progression of retinopathy have been reported. Intensive combination therapy for dyslipidemia has been shown to effectively reduce the rate of progression of diabetic retinopathy in type 2 diabetes. Secondary strategies are focused on various pathophysiologic approaches such as blockade of the renin angiotensin system (RAS), anti-vascular endothelial growth factor agents, somatostatin analogues, protein kinase inhibitors, and anti-inflammatory agents. The purpose of the current overview is to look into the medical management of diabetic retinopathy, and to explore the primary (preventive) measures as well as secondary strategies proposed to be effective in its medical management. PMID- 23020541 TI - Causality in epidemiology. AB - This article provides an introduction to the meaning of causality in epidemiology and methods that epidemiologists use to distinguish causal associations from non causal ones. Alternatives to causal association are discussed in detail. Hill's guidelines, set forth approximately 50 years ago, and more recent developments are reviewed. The role of religious and philosophic views in our understanding of causality is briefly discussed. PMID- 23020542 TI - Quantity and quality of carbohydrate intake in Iran: a target for nutritional intervention. PMID- 23020543 TI - Pseudoaneurysm of the brachial artery in a four-month-old boy: diagnosis and treatment. AB - Pseudoaneurysms arise from a disruption in the arterial wall and blood dissecting into the tissues around the damaged artery creating a perfused sac that communicates with the arterial lumen. Trauma to the wall of the artery may lead to the development of a pseudoaneurysm. Post-traumatic pseudoaneurysm development is very rare in the peripheral artery and often is a consequence of venipuncture. We have reported the case of the four-month-old boy who developed a pseudoaneurysm following an accidental arterial puncture. In the antecubital area we noticed a pulsative mass and palpable thrill. The patient underwent a Doppler ultrasound examination and CT with contrast. Surgery was indicated. Following excision of the pseudoaneurysm, an end-to-end anastomosis was performed. Follow up for four years revealed palpable peripheral pulsation at the wrist level. In the postoperative period, all ultrasound findings were normal. End-to-end anastomosis is preferable if it can be performed without tension or damage to the major collateral vessels. PMID- 23020544 TI - Sudden suffocation with cancer of unknown primary: a case report and review of diagnostic approach. AB - A case of a 31-year-old woman with sudden respiratory distress is presented. Preliminary evaluations and imaging studies did not reveal the underlying cause. Workup during hospital stay showed advanced metastatic cancer of unknown primary origin. This is an unusual presentation of cancer of an unknown primary involving the thyroid with sudden suffocation. It suggests that malignancies involving the thyroid gland should be considered in patients with abrupt onset of respiratory distress. Also, this case shows the application of fine needle aspiration in diffuse thyroid enlargements mimicking thyroiditis without nodules. Diagnostic approach to cancer of unknown primary origin (CUP) is reviewed in further detail. PMID- 23020545 TI - Photoclinic. PMID- 23020546 TI - The life and career of professor Parviz Dabiri (1921-2012). PMID- 23020547 TI - Engineering copper hyperaccumulation in plants by expressing a prokaryotic copC gene. AB - In this work, engineering Cu-hyperaccumulation in plants was approached. First, the copC gene from Pseudomonas sp. Az13, encoding a periplasmic Cu-binding protein, was expressed in Arabidopsis thaliana driven by the CaMV35S promoter (transgenic lines 35S-copC). 35S-copC lines showed up to 5-fold increased Cu accumulation in roots (up to 2000 MUg Cu. g(-1)) and shoots (up to 400 MUg Cu. g( 1)), compared to untransformed plants, over the limits established for Cu hyperaccumulators. 35S lines showed enhanced Cu sensitivity. Second, copC was engineered under the control of the cab1 (chlorophyll a/b binding protein 1) promoter, in order to drive copC expression to the shoots (transgenic lines cab1 copC). cab1-copC lines showed increased Cu translocation factors (twice that of wild-type plants) and also displayed enhanced Cu sensitivity. Finally, subcellular targeting the CopC protein to plant vacuoles was addressed by expressing a modified copC gene containing specific vacuole sorting determinants (transgenic lines 35S-copC-V). Unexpectedly, increased Cu-accumulation was not achieved-neither in roots nor in shoots-when compared to 35S-copC lines. Conversely, 35S-copC-V lines did display greatly enhanced Cu-hypersensitivity. Our results demonstrate the feasibility of obtaining Cu-hyperaccumulators by engineering a prokaryotic Cu-binding protein, but they highlight the difficulty of altering the exquisite Cu homeostasis in plants. PMID- 23020549 TI - A high proportion of blue light increases the photosynthesis capacity and leaf formation rate of Rosa * hybrida but does not affect time to flower opening. AB - Alterations in light quality affect plant morphogenesis and photosynthetic responses but the effects vary significantly between species. Roses exhibit an irradiance-dependent flowering control but knowledge on light quality responses is scarce. In this study we analyzed, the responses in morphology, photosynthesis and flowering of Rosa * hybrida to different blue (B) light proportions provided by light-emitting diodes (LED, high B 20%) and high pressure sodium (HPS, low B 5%) lamps. There was a strong morphological and growth effect of the light sources but no significant difference in total dry matter production and flowering. HPS-grown plants had significantly higher leaf area and plant height, yet a higher dry weight proportion was allocated to leaves than stems under LED. LED plants showed 20% higher photosynthetic capacity (Amax ) and higher levels of soluble carbohydrates. The increase in Amax correlated with an increase in leaf mass per unit leaf area, higher stomata conductance and CO2 exchange, total chlorophyll (Chl) content per area and Chl a/b ratio. LED-grown leaves also displayed a more sun-type leaf anatomy with more and longer palisade cells and a higher stomata frequency. Although floral initiation occurred at a higher leaf number in LED, the time to open flowers was the same under both light conditions. Thereby the study shows that a higher portion of B light is efficient in increasing photosynthesis performance per unit leaf area, enhancing growth and morphological changes in roses but does not affect the total Dry Matter (DM) production or time to open flower. PMID- 23020550 TI - Facile method for modulating the profiles and periods of self-ordered three dimensional alumina taper-nanopores. AB - We report a facile nanofabrication method, one-step hard anodizing and etching peeling (OS-HA-EP) of aluminum foils followed by multistep mild anodizing and etching pore-widening (MS-MA-EW), for the controllable tailoring of hexagonally packed three-dimensional alumina taper-nanopores. Their profiles can be precisely tailored by the synergistic control of anodizing time, etching time and cyclic times at the MS-MA-EW stage, exemplified by linear cones, whorl-embedded cones, funnels, pencils, parabolas, and trumpets. Meantime, their periods can also be modulated in the range of 70-370 nm by choosing matched anodizing electrolytes (e.g., H(2)C(2)O(4), H(2)SO(4), H(2)C(2)O(4)-H(2)SO(4), and H(2)C(2)O(4) C(2)H(5)OH mixture) and anodizing voltages at the OS-HA-EP stage. We also demonstrated that the long-range ordering of nanopits and the peak voltage of stable self-ordered HA, which are unachievable in a single H(2)C(2)O(4) electrolyte system, can be effectively tuned by simply adding tiny quantity of H(2)SO(4) and C(2)H(5)OH to keep an appropriate HA current density, respectively. This method of using the combination of simple pure chemical nanofabrication technologies is very facile and efficient in realizing the controllable tailoring of large-area alumina membranes containing self-ordered taper-nanopores. Our work opens a door for exploring the novel physical and chemical properties of different materials of nanotaper arrays. PMID- 23020548 TI - Chloroperoxidase-catalyzed epoxidation of cis-beta-methylstyrene: distal pocket flexibility tunes catalytic reactivity. AB - Chloroperoxidase, the most versatile heme protein, has a hybrid active site pocket that shares structural features with peroxidases and cytochrome P450s. The simulation studies presented here show that the enzyme possesses a remarkable ability to efficiently utilize its hybrid structure, assuming structurally different peroxidase-like and P450-like distal pocket faces and thereby enhancing the inherent catalytic capability of the active center. We find that, during epoxidation of cis-beta-methylstyrene (CBMS), the native peroxidase-like aspect of the distal pocket is diminished as the polar Glu183 side chain is displaced away from the active center and the distal pocket takes on a more hydrophobic, P450-like, aspect. The P450-like distal pocket provides a significant enthalpic stabilization of ~4 kcal/mol of the 14 kcal/mol reaction barrier for gas-phase epoxidation of CMBS by an oxyferryl heme-thiolate species. This stabilization comes from breathing of the distal pocket. As until recently the active site of chloroperoxidase was postulated to be inflexible, these results suggest a new conceptual understanding of the enzyme's versatility: catalytic reactivity is tuned by flexibility of the distal pocket. PMID- 23020551 TI - 3D tissue-engineered construct analysis via conventional high-resolution microcomputed tomography without X-ray contrast. AB - As the field of tissue engineering develops, researchers are faced with a large number of degrees of freedom regarding the choice of material, architecture, seeding, and culturing. To evaluate the effectiveness of a tissue-engineered strategy, histology is typically done by physically slicing and staining a construct (crude, time-consuming, and unreliable). However, due to recent advances in high-resolution biomedical imaging, microcomputed tomography (MUCT) has arisen as a quick and effective way to evaluate samples, while preserving their structure in the original state. However, a major barrier for using MUCT to do histology has been its inability to differentiate between materials with similar X-ray attenuation. Various contrasting strategies (hardware and chemical staining agents) have been proposed to address this problem, but at a cost of additional complexity and limited access. Instead, here we suggest a strategy for how virtual 3D histology in silico can be conducted using conventional MUCT, and we provide an illustrative example from bone tissue engineering. The key to our methodology is an implementation of scaffold surface architecture that is ordered in relation to cells and tissue, in concert with straightforward image-processing techniques, to minimize the reliance on contrasting for material segmentation. In the case study reported, MUCT was used to image and segment porous poly(lactic acid) nonwoven fiber mesh scaffolds that were seeded dynamically with mesenchymal stem cells and cultured to produce soft tissue and mineralized tissue in a flow perfusion bioreactor using an osteogenic medium. The methodology presented herein paves a new way for tissue engineers to identify and distinguish components of cell/tissue/scaffold constructs to easily and effectively evaluate the tissue engineering strategies that generate them. PMID- 23020552 TI - Difference between parental perception and actual weight status of children: a systematic review. AB - An increasing number of children worldwide are overweight, and the first step in treating obesity is to identify overweight. However, do parents recognise overweight in their child and which factors influence parental perception? The aim of the present review is to systematically study differences between parental perception and the actual weight status of children. Medline, EMbase, CINAHL and PsychINFO were searched. After screening 2497 abstracts and 106 full texts, two reviewers independently scored the methodological quality of 51 articles (covering 35 103 children), which fulfilled the inclusion criteria. The primary outcome parameters were sensitivity and specificity of parental perception for actual weight status of their child. The methodological quality of the studies ranged from poor to excellent. Pooled results showed that according to objective criteria 11 530 children were overweight; of these, 7191 (62.4%) were incorrectly perceived as having normal weight by their parents. The misperception of overweight children is higher in parents with children aged 2-6 years compared with parents of older children. Sensitivity (correct perception of overweight) of the studies ranged from 0.04 to 0.89, while specificity (correct perception of normal weight) ranged from 0.86 to 1.00. There were no significant differences in sensitivity or specificity for different cut-off points for overweight, or between newer and older studies. Therefore we can conclude that parents are likely to misperceive the weight status of their overweight child, especially in children aged 2-6 years. Because appropriate treatment starts with the correct perception of overweight, health care professionals should be aware of the frequent parental misperception of the overweight status of their children. PMID- 23020553 TI - Complex carriers of affibody-displaying bio-nanocapsules and composition-varied liposomes for HER2-expressing breast cancer cell-specific protein delivery. AB - A bio-nanocapsule (BNC), a hollow particle composed of hepatitis B virus (HBV) surface antigen (HBsAg), and liposome (LP) conjugation method (BNC/LP) has been recently developed by Jung et al. (2008) . The BNC/LP complex carrier could successfully deliver fluorescence-labeled beads (100 nm) into liver cells. In this study, we report the promising delivery of proteins incorporated in the complex carriers, which were prepared by the BNC/LP conjugation method with specificity-altered BNC and composition-varied LPs. The specificity-altered BNC, Z(HER2)-BNC was developed by replacing the hepatocyte recognition site of BNC with Z(HER2) binding to HER2 receptor specifically. Using green fluorescent protein (GFP; 27 kDa) and cellular cytotoxic protein (exotoxin A; 66 kDa) for the delivery, we herein present the impact of different charges attributed to the composition of the LP on specific cell targeting and cellular uptake of the complex carriers. In addition, we demonstrate that the mixture prepared by mixing LPs with helper lipid possessing endosomal escaping ability boosts the functional expression of the cellular cytotoxic exotoxin A activity specifically. Finally, we further show the blending ratio of the LP mixture and Z(HER2)-BNC is a critical factor in determining the highly-efficient expression of the cytotoxic activity of exotoxin A. PMID- 23020554 TI - The future of glycoprotein VI as an antithrombotic target. AB - The treatment of acute coronary syndromes has been considerably improved in recent years with the introduction of highly efficient antiplatelet drugs. However, there are still significant limitations: the recurrence of adverse vascular events remains a problem, and the improvement in efficacy is counterbalanced by an increased risk of bleeding, which is of particular importance in patients at risk of stroke. One of the most attractive targets for the development of new molecules with potential antithrombotic activity is platelet glycoprotein (GP)VI, because its blockade appears to ideally combine efficacy and safety. This review summarizes current knowledge on GPVI regarding its structure, its function, and its role in physiologic hemostasis and thrombosis. Strategies for inhibiting GPVI are presented, and evidence of the antithrombotic efficacy and safety of GPVI antagonists is provided. PMID- 23020555 TI - Identification of stock components using morphological markers. AB - This study investigated the development of a quantitative method for distinguishing stock components of Icelandic cod Gadus morhua based on visual examination of morphology. The stock is known to be structured into genetically distinct geographic components (north and south of Iceland) and behavioural types that spawn sympatrically. Differences in morphology were tested between locations, genotypes (a proxy for behaviour) and sexes. Results show morphological markers on the head, fins and body of G. morhua that are correlated with the sex, genotype of the fish at the pantophysin (pan-I) locus and the location at which the fish were caught. Females were found to have relatively deep bodies, and the pan-I(BB) genotype (associated with deep-water feeding behaviour) have greater gaps between their fins. Overall, morphology is more useful for distinguishing sympatric genotypes but less powerful at identifying genetically distinct geographic sub-populations, perhaps because counter-gradient evolution reduces phenotypic differences even with an underlying genetic cause. PMID- 23020556 TI - Effects of temperature, salinity and body size on routine metabolism of coastal largemouth bass Micropterus salmoides. AB - Routine metabolism (i.e. standard metabolism plus a low level of activity) of coastal largemouth bass Micropterus salmoides from Mobile-Tensaw Delta, AL, U.S.A. was examined as a function of temperature (15, 20, 25 and 30 degrees C), salinity (0, 4, 8 and 12) and body mass (range 24-886 g) using flow-through respirometry. Functionally, a cubic relationship best described the effect of salinity on respiration; the magnitude of these effects increased with temperature and body mass. The best model predicted that specific respiration (mg O(2) g(-1) h(-1)) at temperatures >20 degrees C was lowest at salinities of 0.0 and 9.7, and elevated at 3.2 and 12.0; salinity had little to no effect at temperatures <=20 degrees C. Respiration increased exponentially with temperature, but when compared with previously published respiration rates for M. salmoides from northern latitudes, predicted respiration was higher at cool temperatures and lower at high temperatures. The reduced energetic cost near the isosmotic level (i.e. c. 9) may be an adaptive mechanism to tolerate periods of moderate salinity levels and may help explain why M. salmoides do not flee an area in response to increased salinity. Further, these results suggest that salinity has high energetic costs for coastal populations of M. salmoides and may contribute to the observed slow growth and small maximum size within coastal systems relative to inland freshwater populations. PMID- 23020557 TI - Phylogenetic status of brown trout Salmo trutta populations in five rivers from the southern Caspian Sea and two inland lake basins, Iran: a morphogenetic approach. AB - Interrelationships, origin and phylogenetic affinities of brown trout Salmo trutta populations from the southern Caspian Sea basin, Orumieh and Namak Lake basins in Iran were analysed from complete mtDNA control region sequences, 12 microsatellite loci and morphological characters. Among 129 specimens from six populations, seven haplotypes were observed. Based on mtDNA haplotype data, the Orumieh and southern Caspian populations did not differ significantly, but the Namak basin-Karaj population presented a unique haplotype closely related to the haplotypes of the other populations (0.1% Kimura two-parameter, K2P divergence). All Iranian haplotypes clustered as a distinct group within the Danube phylogenetic grouping, with an average K2P distance of 0.41% relative to other Danubian haplotypes. The Karaj haplotype in the Namak basin was related to a haplotype (Da26) formerly identified in the Tigris basin in Turkey, to a Salmo trutta oxianus haplotype from the Aral Sea basin, and to haplotype Da1a with two mutational steps, as well as to other Iranian haplotypes with one to two mutational steps, which may indicate a centre of origin in the Caspian basin. In contrast to results of the mtDNA analysis, more pronounced differentiation was observed among the populations studied in the morphological and microsatellite DNA data, except for the two populations from the Orumieh basin, which were similar, possibly due to anthropogenic causes. PMID- 23020558 TI - Effects of temperature and food supply on the growth of whitefish Coregonus lavaretus larvae in an oligotrophic peri-alpine lake. AB - The relative roles of temperature and food availability on the seasonal and daily growth of whitefish Coregonus lavaretus larvae were investigated in the oligotrophic peri-alpine Lake Annecy, France. During the spring from 2004 to 2007, surface water temperature and density of potential zooplankton prey were monitored, and 2688 larvae were caught and measured. In addition, the daily growth of 130 larvae was estimated retrospectively by investigating the microstructure of their otoliths. Temperature played the predominant role in controlling both seasonal and daily growth of early larvae. In contrast, the abundance of Mesocyclops leuckarti and larval density was only slightly correlated to larval growth, suggesting no food limitation nor strong interindividual competition over the study period. Overall, these findings run counter to concerns about potential food limitation, but sound a warning about the potential impact of climate change on fish ecology and fisheries management. PMID- 23020559 TI - Gambusia quadruncus (Cyprinodontiformes: Poeciliidae): a new species of mosquitofish from east-central Mexico. AB - Gambusia quadruncus n. sp., the llanos mosquitofish, is described from east central Mexico. The region inhabited by the species represents a hotspot of diversity of Gambusia, and G. quadruncus sometimes coexists with at least three congeners. The species differs from its closest relative, Gambusia affinis, in several characteristics with plausible effects on reproductive isolation, e.g. body size, body and fin morphology, male genital morphology (distal tip of gonopodium) and female anal spot morphology (colouration near the urogenital sinus). Moreover, combined analysis of mitochondrial and nuclear gene sequence data (c. 2158 total base pairs) indicates reciprocal monophyly of G. quadruncus and its sister species G. affinis, with levels of genetic divergence suggesting the two species diverged from one another over a million years ago. The origin of G. quadruncus may reflect a vicariant event associated with Pliocene orogenesis in the Tamaulipas Arch and a frontal section of the Sierra Madre Oriental (Lleran Mesas). Gambusia quadruncus inhabits a variety of freshwater habitats across several river drainages, with its range spanning at least 350 km from north to south, covering over 25 000 km(2). A key to aid identification of the species is provided. PMID- 23020560 TI - Characterizing the biological traits and life history of Acanthopagrus (Sparidae) hybrid complexes: implications for conservation and management. AB - This study examined the spatio-temporal reproductive patterns, population structure, maturity and growth of Acanthopagrus hybrid complexes, which comprise mainly black bream Acanthopagrus butcheri and the hybrids they form with yellowfin bream Acanthopagrus australis, in two Australian estuaries (Coila and Brou Lakes, NSW). There were no differences between pure A. butcheri and hybrids in terms of their population structure, growth and maturity, suggesting that these two breeds have similar life histories and may therefore be managed as single, naturally cohesive units. Sexual variation in size structure was only observed for the complex in Coila Lake. Although there was significant variation in age structure between estuaries, both complexes exhibited dominance of only a few year classes indicating episodic recruitment and high fishing mortality. Acanthopagrus eggs occurred in higher numbers within upstream creek habitats compared to lake habitats, thereby highlighting the need to protect these spawning habitats. Although maturity in the complexes was not influenced by gender or estuary, differences in growth were detected between the genders and estuaries. PMID- 23020562 TI - Ontogenetic dietary shifts and feeding ecology of the rasptail skate Raja velezi and the brown smoothhound shark Mustelus henlei along the Pacific coast of Costa Rica, Central America. AB - Stomachs from 511 Raja velezi and 340 Mustelus henlei captured as by-catch in the commercial trawling fishery (2010-2012) were analysed to examine diet composition, ontogenetic shifts and degree of dietary overlap between species life stages in the Pacific Ocean of Costa Rica. Shrimps were the most important prey categories in the diet of R. velezi, while teleosts and cephalopods dominated the diet of M. henlei. Diet comparisons between different stages of R. velezi and M. henlei revealed clear ontogenetic dietary shifts: crustaceans (mainly shrimps, crabs and stomatopods) dominated the diet of immature individuals, and adults had a higher proportion of teleosts. The results suggest that R. velezi is an epibenthic predator that specializes in shrimps during early life stages, and to a lesser extent, teleosts as it matures, while M. henlei is an opportunistic predator with a highly diverse diet consisting of teleosts, cephalopods, shrimps and stomatopods. This study also found little evidence of dietary overlap between species or life stages and suggests that intra- and interspecific competition between R. velezi and M. henlei may be reduced by: (1) diet specialization in immature stages of R. velezi, (2) ontogenetic dietary shifts between immature and mature individuals, (3) prey-size selectivity in larger individuals of R. velezi and (4) differences in depth utilization in overlapping geographical regions. PMID- 23020561 TI - Nuclear and mitochondrial phylogenetic analysis of big-scale sand smelt Atherina boyeri complex in Greece. AB - Genetic differentiation and phylogenetic relationships of big-scale sand smelt Atherina boyeri specimens from 23 sampling sites in Greece and one from a lake in Turkey were investigated. A total of 2180 base pairs (bp) corresponding to the partial sequence of the mitochondrial gene cytochrome oxidase I (coI), cytochrome b (cytb) and control region, as well as of the nuclear protein-coding gene rhodopsin (rh), were determined for the 143 specimens studied. Phylogenetic analysis of each gene segment separately and of the combined dataset revealed the existence of three different and well divergent lineages in Greece. The first corresponds to the lagoon form, in which a clear distinction between the Aegean and Ionian Sea was observed. The other two correspond to the punctuated and non punctuated marine forms that have been previously reported. The fact that in the present study a population without black spots on the flanks is clustered with the punctuated form and vice versa, however, suggests that differences in colour pattern do not seem to be a sufficient marker to discriminate the two marine forms. In contrast, the presence of a different length insertion between transfer RNA (tRNA) glutamic acid (tRNA(glu)) and cytb genes in the lagoon and in one of the two forms of marine populations, and its absence from the rest marine-form specimens confirms that this character is conserved and capable to be used for distinguishing the different forms. Even though the divergence values among the different forms were high, their phylogenetic relationships were not able to be resolved. PMID- 23020563 TI - The effect of familiarity on aggregation and social behaviour in juvenile small spotted catsharks Scyliorhinus canicula. AB - This study was designed to address whether juvenile small spotted catsharks Scyliorhinus canicula aggregate and to determine whether potential aggregation is underpinned by social preferences for conspecifics. Using controlled and replicated experiments, the role of familiarity as a potential mechanism driving aggregation and social behaviour in this species was considered. Observed S. canicula association data compared to null model simulations of random distributions revealed differences in aggregation under different social contexts. Only familiar juvenile S. canicula aggregated more than would be expected from random distribution across their habitat. Familiarity increased the mean number of groups but did not significantly affect mean group size. Significant preference and avoidance behaviour across all groups were also observed. Furthermore, the strength of social attraction, quantified by the mean association index, was significantly higher in groups containing familiar individuals. Mixed familiar and unfamiliar treatments were also conducted to test for within- and between-group effects, finding high variation across replicates with some groups assorting by familiarity and others not. It is believed that this study is the first to examine experimentally the influence of conspecific familiarity on aggregation behaviour in sharks. These results not only imply a functional benefit to aggregation, but also suggest that persistent social affiliation is likely to influence dispersal following hatching in this small benthic elasmobranch. PMID- 23020564 TI - Investigating the behavioural responses of trapped fishes using underwater video surveillance. AB - An underwater video surveillance system known as TrapCam was used to continuously record (15 *c. 24 h periods) fish behaviour within and immediately surrounding an experimental fish trap situated in a coral reef ecosystem in the United States Virgin Islands. Of the 100 fishes (18 species, 12 families) trapped, surgeonfishes (Acanthuridae) and snappers (Lutjanidae) were most common. Thirteen distinctively identifiable behaviours were observed for trapped fishes. Species did not differ significantly in the proportion of time allocated to different behaviours (ANOSIM, R = 0.142). Doctorfish Acanthurus chirurgus and grey angelfish Pomacanthus arcuatus allocated the largest proportion of their recorded time to enter and exit the trap. Fishes spent an average of 15 min in the trap before escaping. Sixty-seven per cent of trap approaches consisted of an individual of the same species as one already trapped suggesting that conspecific attraction may have occurred. Fifteen per cent of trapped species were observed with abrasions to the head and 70% were observed approaching the trap corners. The results of this study provide a greater understanding of the behavioural interactions between fishes and traps that can help explain patterns of catch composition, the physical condition of fishes in traps and inform design of gear modifications to optimize by-catch reduction in the trap fishery. PMID- 23020565 TI - Estuarine survival and migratory behaviour of Atlantic salmon Salmo salar smolts. AB - To estimate mortality rates, assess the spatio-temporal dynamics of natural mortality and examine migratory behaviour during the fresh to saltwater transition, 185 wild Atlantic salmon Salmo salar smolts were implanted with coded acoustic transmitters. Seaward migration of tagged S. salar from four river systems in an area of Nova Scotia, Canada known as the Southern Upland was monitored using fixed receivers and active telemetry over 3 years. Cumulative survival through the river, inner estuary, outer estuary and bay habitats averaged 59.6% (range = 39.4-73.5%). When standardized to distance travelled, survival rates followed two patterns: (1) constant rates of survival independent of habitat or (2) low survival most frequently associated with inner estuary habitats. In rivers where survival was independent of habitat, residency periods were also independent of habitat, post-smolts exhibited few upstream movements, took a more direct route to the ocean and reached the ocean rapidly. Alternatively, in rivers where survival was habitat specific, residency was also habitat specific with overall increased residency, more frequent upstream movements and delayed arrival to the open ocean. The sudden disappearance of most (75-100%) smolts and post-smolts assumed dead during the course of this study warrants further examination into the role of avian predators as a mortality vector. PMID- 23020566 TI - Detection of low-frequency tones and whale predator sounds by the American sand lance Ammodytes americanus. AB - Auditory evoked potentials (AEP) were used to measure the hearing range and auditory sensitivity of the American sand lance Ammodytes americanus. Responses to amplitude-modulated tone pips indicated that the hearing range extended from 50 to 400 Hz. Sound pressure thresholds were lowest between 200 and 400 Hz. Particle acceleration thresholds showed an improved sensitivity notch at 200 Hz but not substantial differences between frequencies and only a slight improvement in hearing abilities at lower frequencies. The hearing range was similar to Pacific sand lance Ammodytes personatus and variations between species may be due to differences in threshold evaluation methods. AEPs were also recorded in response to pulsed sounds simulating humpback whale Megaptera novaeangliae foraging vocalizations termed megapclicks. Responses were generated with pulses containing significant energy below 400 Hz. No responses were recorded using pulses with peak energy above 400 Hz. These results show that A. americanus can detect the particle motion component of low-frequency tones and pulse sounds, including those similar to the low-frequency components of megapclicks. Ammodytes americanus hearing may be used to detect environmental cues and the pulsed signals of mysticete predators. PMID- 23020567 TI - Age, growth and hatch dates of ingressing larvae and surviving juveniles of Atlantic menhaden Brevoortia tyrannus. AB - Ages, growth and hatch dates of ingressing Brevoortia tyrannus larvae were determined in a 3 year sampling survey at the mouth of the Chesapeake Bay, U.S.A. To determine if otolith-aged cohorts had variable relative survival, hatch dates of summer-caught young-of-the-year (YOY) juveniles collected throughout the Chesapeake Bay were compared with hatch dates of ingressing larvae. Modal total length of ingressing larvae was similar among years: 28 mm in 2005-2006 and 2007 2008, and 30 mm in 2006-2007. Ages of ingressing larvae ranged from 9 to 96 days post hatch (dph); mean ages were similar among years, but significantly older in 2006-2007 (50 dph) than in 2005-2006 (44 dph) and 2007-2008 (46 dph). Larval growth rates differed among years. Earliest growth, when larvae were offshore (0 20 dph), was faster in 2006-2007 (0.62 mm day(-1)), than in 2005-2006 and 2007 2008 (0.55 mm day(-1) in these years). Subsequently, from 30 to 80 dph, growth was slowest in 2006-2007. Hatch dates of ingressing larvae occurred from September to March and 90% (2007-2008) to 98% (2006-2007) had hatched prior to 31 December. In contrast, most surviving YOY juvenile B. tyrannus had hatched in January to February, suggesting selective mortality of early-hatched individuals, apparently during the overwinter, larval to juvenile transition period. PMID- 23020568 TI - The role of hyperiid parasites as a trophic link between jellyfish and fishes. AB - The trophic interactions between the scyphozoan medusa Chrysaora plocamia and the palm ruff Seriolella violacea were investigated off northern Chile and showed that large numbers of hyperiid amphipods parasitizing the medusa may channel energy back to the fishes, which feed on the parasites. The biomass of hyperiids eaten by the fish was a function of the biomass of hyperiids parasitizing the medusa. This temporally available food supply may enhance fish recruitment. The large number of hyperiids parasitizing diverse jellyfish species represents a missing trophic link in current efforts to understand the effects of jellyfish blooms on marine food webs. PMID- 23020569 TI - Parasites and parallel divergence of the number of individual MHC alleles between sympatric three-spined stickleback Gasterosteus aculeatus morphs in Iceland. AB - Two pairs of sympatric three-spined stickleback Gasterosteus aculeatus morphs and two single morph populations inhabiting mud and lava or rocky benthic habitats in four Icelandic lakes were screened for parasites and genotyped for MHC class IIB diversity. Parasitic infection differed consistently between G. aculeatus from different benthic habitats. Gasterosteus aculeatus from the lava or rocky habitats were more heavily infected in all lakes. A parallel pattern was also found in individual MHC allelic variation with lava G. aculeatus morphs exhibiting lower levels of variation than the mud morphs. Evidence for selective divergence in MHC allele number is ambiguous but supported by two findings in addition to the parallel pattern observed. MHC allele diversity was not consistent with diversity reported at neutral markers (microsatellites) and in Pingvallavatn the most common number of alleles in each morph was associated with lower infection levels. In the Pingvallavatn lava morph, lower infection levels by the two most common parasites, Schistocephalus solidus and Diplostomum baeri, were associated with different MHC allele numbers. PMID- 23020570 TI - Asteriscus v. lapillus: comparing the chemistry of two otolith types and their ability to delineate riverine populations of common carp Cyprinus carpio. AB - The chemical composition of common carp Cyprinus carpio asteriscus (vaterite) and lapillus (aragonite) otoliths from the same individual and reflecting the same growth period was measured to (1) determine whether there are differences in the uptake of trace metals (Mg:Ca, Mn:Ca, Sr:Ca and Ba:Ca ) and Sr isotope ratios ((87)Sr:(86)Sr) in co-precipitating lapilli and asterisci and (2) compare the ability of multi-element and isotopic signatures from lapilli, asterisci and both otolith types combined to discriminate C. carpio populations over a large spatial scale within a river basin. Depth profile analyses at the otolith edge using laser-ablation inductively coupled plasma mass spectrometry showed that asterisci were enriched in Mg and Mn and depleted in Sr and Ba relative to lapilli, whilst (87)Sr:(86)Sr values were nearly identical in both otolith types. Significant spatial differences among capture locations were found when all trace element and Sr isotope ratio data were aggregated into a multi-element and isotopic signature, regardless of which otolith type was used or if they were used in combination. Discriminatory power was enhanced, however, when data for both otolith types were combined, suggesting that analysis of multiple otolith types may be useful for studies attempting to delineate C. carpio populations at finer spatial or temporal scales. PMID- 23020571 TI - The effect of stocking with 0+ year age-class Atlantic salmon Salmo salar fry: a case study from the River Bush, Northern Ireland. AB - An enhancement programme based on stocking 0+ year age-class Atlantic salmon Salmo salar, conducted in the River Bush, Northern Ireland, U.K. over the period 1996-2005, was reviewed with reference to the performance and biological characteristics of wild fish. Wild ova to 0+ year fry (summer) survival was c. 8% with subsequent wild 0+ year fry-to-smolt survival c. 9%. Stocked unfed 0+ year juveniles gave c. 1% survival to smolt whilst fed 0+ year S. salar stocked in late summer exhibited survival at c. 5%. Stocking with unfed and fed fry contributed to increased smolt production and helped attain local management objectives between 2001 and 2005. Significant differences in biological characteristics were observed between wild and stocked-origin fish. Wild-smolt cohorts were dominated by 2+ year age-class fish on the River Bush whilst smolts originating from fed fry mostly comprised younger 1+ year individuals. The mean mass of 1+ year smolts derived from stocked fed fry was significantly lower than that of wild 1+ year smolts, although these differences were not evident between older age classes. Differences in run timing between wild smolts and smolts derived from stocked fry were also apparent with the stocked-origin fish tending to run earlier than wild fish. Although the stocking exercise was useful in terms of maximizing freshwater production, concerns over the quality of stocked-origin recruits and the long term consequences for productivity are highlighted. PMID- 23020572 TI - Genetic differentiation between two sympatric morphs of the blind Iran cave barb Iranocypris typhlops. AB - The phylogenetic relationship between two sympatric morphotypes of the Iran cave barb Iranocypris typhlops, and Garra rufa, was investigated by sequencing the cytochrome c oxidase I (coI) region (788 bp) providing the first molecular evidence of their phylogeny. Consistent with their morphological differences, the mean genetic distance between the two forms of I. typhlops was significantly higher than generally reported for intraspecific divergence in freshwater fishes. They were phylogenetically closer to G. rufa than to any other species. PMID- 23020573 TI - Comparison of isogenic lines provides evidence that phenotypic plasticity is under genetic control in rainbow trout Oncorhynchus mykiss. AB - Comparison of nine isogenic lines of rainbow trout Oncorhynchus mykiss kept in the same environment showed significant genetic determinism of phenotypic plasticity assessed through body mass measurements. Ranking of lines differed between two tested environments. PMID- 23020574 TI - Population structure in Chilean hake Merluccius gayi as revealed by mitochondrial DNA sequences. AB - Genetic variation and divergence among samples of Chilean hake Merluccius gayi, from three localities off the coast of Chile and one locality off the coast of northern Peru, were assessed using sequences from the control region of mitochondrial DNA. Homogeneity tests revealed occurrence of at least three distinct genetic stocks of M. gayi within the region sampled. Factors potentially contributing to genetic divergence among M. gayi probably include hydrodynamics and behaviour. PMID- 23020575 TI - Comparison of remote video and diver's direct observations to quantify reef fishes feeding on benthos in coral and rocky reefs. AB - This study compared remote underwater video and traditional direct diver observations to assess reef fish feeding impact on benthos across multiple functional groups within different trophic categories (e.g. herbivores, zoobenthivores and omnivores) and in two distinct reef systems: a subtropical rocky reef and a tropical coral reef. The two techniques were roughly equivalent, both detecting the species with higher feeding impact and recording similar bite rates, suggesting that reef fish feeding behaviour at the study areas are not strongly affected by the diver's presence. PMID- 23020576 TI - Development and characterization of 11 novel microsatellite loci for the roundscale spearfish Tetrapturus georgii and their cross-species amplification among other istiophorid species. AB - Eleven novel polymorphic microsatellite loci were developed and characterized for the recently validated roundscale spearfish Tetrapturus georgii. Characterization of these markers, based on 35 roundscale spearfish from the western North Atlantic, revealed two to 21 alleles per locus with an average expected heterozygosity (H(E) ) of 0.09-0.94, and all loci conformed to Hardy-Weinberg expectations. Cross-amplification of these 11 loci against all other eight known istiophorid species indicates promising prospects for the utility of these markers for istiophorids in general. PMID- 23020577 TI - Studies on catalytic enantioselective total synthesis of caprazamycin B: construction of the western zone. AB - We describe a simple and convenient synthesis of the western zone of caprazamycin B using two catalytic asymmetric reactions as key elements of our approach. Desymmetrization of 3-methylglutaric anhydride with the (S)-Ni(2)-(Schiff base) complex as a catalyst furnished the chiral hemiester, and a thioamide-aldol reaction with mesitylcopper, (R,R)-Ph-BPE, and 2,2,5,7,8-pentamethylchromanol as a catalyst furnished the beta-hydroxy thioamide in good yield and enantioselectivity. On further transformation, the thioamide functionality was converted to the corresponding beta-hydroxy ester. Finally, a convergent synthesis of the western zone of caprazamycin B was achieved by connecting the hemiester, the beta-hydroxy ester, and the 2,3,4-tri-O-methyl-l-rhamnose fragments. PMID- 23020578 TI - An unusual chemoselective hydrogenation of quinoline compounds using supported gold catalysts. AB - The pursuit of modern sustainable chemistry has stimulated the development of innovative catalytic processes that enable chemical transformations to be performed under mild and clean conditions with high efficiency. Herein, we report that gold nanoparticles supported on TiO(2) catalyze the chemoselective hydrogenation of functionalized quinolines with H(2) under mild reaction conditions. Our results point toward an unexpected role for quinolines in gold mediated hydrogenation reactions, namely that of promoter; this is in stark contrast to what prevails in the traditional noble metal Pd-, Pt-, and Ru-based catalyst systems, in which quinolines and their derivatives typically act as poisons. As a result of the remarkable promotional effect of quinoline molecules to H(2) activation over supported gold, the transformation can proceed smoothly under very mild conditions (even at temperatures as low as 25 degrees C). Of practical significance is that various synthetically useful functional groups including halogens, ketone, and olefin remain intact during the hydrogenation of quinolines. Moreover, the protocol also shows promise for the regiospecific hydrogenation of the heterocyclic ring of a variety of other biologically important heteroaromatic nitrogen compounds, such as isoquinoline, acridine, and 7,8-benzoquinoline, in a facile manner. Apart from its importance in catalytic hydrogenation, we believe that this intriguing self-promoted effect by reactant molecules may have fundamental implications for the broad field of gold catalysis and form the basis for development of new catalytic procedures for other key transformations. PMID- 23020580 TI - Coping with endoplasmic reticulum stress in the cardiovascular system. AB - The endoplasmic reticulum (ER) is a multifunctional intracellular organelle, a component of the cellular reticular network that allows cells to adjust to a wide variety of conditions. The cardiomyocyte reticular network is the ideal location of sensors for both intrinsic and extrinsic factors that disrupt energy and/or nutrient homeostasis and lead to ER stress, a disturbance in ER function. ER stress has been linked to both physiological and pathological states in the cardiovascular system; such states include myocardial infarction, oxygen starvation (hypoxia) and fuel starvation, ischemia, pressure overload, dilated cardiomyopathy, hypertrophy, and heart failure. The ER stress coping response (e.g., the unfolded protein response) is composed of discrete pathways that are controlled by a collection of common regulatory components that may function as a single entity involved in reacting to ER stress. These corrective strategies allow the cardiomyocyte reticular network to restore energy and/or nutrient homeostasis and to avoid cell death. Therefore, the identities of the ER stress corrective strategies are important targets for the development of therapeutic approaches for cardiovascular and other acquired disorders. PMID- 23020581 TI - Methylthioadenosine phosphorylase inactivation depends on gene deletion in laryngeal squamous cell carcinoma. AB - AIMS: Methylthioadenosine phosphorylase (MTAP) is an essential enzyme for the methionine and adenosine salvage pathway in normal cells, frequently inactivated in many different human cancers. MTAP status could be important for tumour cell sensitivity to adjuvant chemotherapy. To our knowledge, there have been no reports to date on MTAP status in laryngeal carcinoma. METHODS AND RESULTS: A series of 31 laryngeal squamous cell carcinomas was investigated for MTAP mRNA expression using reverse transcription and quantitative polymerase chain reaction (qPCR), as well as for MTAP gene deletion and/or promoter hypermethylation using qPCR and methylation-specific PCR, respectively. Low MTAP mRNA expression was found in 32% of cases, and was associated with MTAP gene deletion (in 70%; P<0.001) but not with MTAP promoter hypermethylation, indicating that, in this tumour, gene deletion is the main mechanism for MTAP inactivation. Neither low mRNA expression nor gene deletion was associated with any of the clinicopathological parameters investigated. CONCLUSION: Given the significance of MTAP status for cell sensitivity to different chemotherapeutic regimens, our results suggest that determination of MTAP inactivation should be taken into consideration in managing laryngeal squamous cell carcinomas. PMID- 23020579 TI - TRPA1: A gatekeeper for inflammation. AB - Tissue damage evokes an inflammatory response that promotes the removal of harmful stimuli, tissue repair, and protective behaviors to prevent further damage and encourage healing. However, inflammation may outlive its usefulness and become chronic. Chronic inflammation can lead to a host of diseases, including asthma, itch, rheumatoid arthritis, and colitis. Primary afferent sensory neurons that innervate target organs release inflammatory neuropeptides in the local area of tissue damage to promote vascular leakage, the recruitment of immune cells, and hypersensitivity to mechanical and thermal stimuli. TRPA1 channels are required for neuronal excitation, the release of inflammatory neuropeptides, and subsequent pain hypersensitivity. TRPA1 is also activated by the release of inflammatory agents from nonneuronal cells in the area of tissue injury or disease. This dual function of TRPA1 as a detector and instigator of inflammatory agents makes TRPA1 a gatekeeper of chronic inflammatory disorders of the skin, airways, and gastrointestinal tract. PMID- 23020582 TI - Angiogenic factors and acute-phase proteins in serum samples of preeclampsia and HELLP patients: a matched-pair analysis. AB - OBJECTIVES: To investigate the serum level distribution of angiogenic markers (PlGF, endoglin, sFlt-1) and acute-phase proteins (SAA, CRP) in patients with HELLP syndrome or preeclampsia (PE) including matched controls. METHODS: The matching procedure revealed 46 controls for 23 HELLP cases, and 81 controls for 42 preeclamptic patients. Maternal serum concentrations were determined by immunoassays. RESULTS: SAA and CRP levels were significantly higher in HELLP patients compared with controls. This finding was not observed in preeclamptic subgroup. Pro-angiogenic PlGF is significantly lower in PE and HELLP syndrome. Anti-angiogenic endoglin is significantly higher in PE and HELLP syndrome. The sFlt-1 analysis supports the anti-angiogenic shift in HELLP and preeclamptic patients, but with smaller differences between subgroups. The SAA/PlGF ratio showed the highest ROC value of all tested parameters in discrimination between HELLP and HELLP controls. CONCLUSIONS: These findings support the concept that patients with HELLP syndrome have both an anti-angiogenic state and a pronounced inflammatory response, while patients with PE are characterized only by an anti angiogenic shift. PMID- 23020583 TI - The effect of metastatic site and decade of diagnosis on the individual burden of metastatic melanoma: contemporary estimates of average years of life lost. AB - OBJECTIVES: Metastatic melanoma (MM) is a leading cause of years of life lost due to malignancy. This study aimed to identify the average years of life lost (AYLL) in MM patients. METHODS: MM patients were identified from a prospectively maintained database, and a linear model predicting AYLL was developed. RESULTS: Between 1970 and 1999, 4,774 patients diagnosed with MM died. The AYLL was 23.2 years. AYLL remained stable across three decades. CONCLUSIONS: AYLL for MM is greater than 20 years, and has not improved. This burden underscores the need for continued research and access to funding for this disease. PMID- 23020585 TI - Dependence of transport rate on area of lithography and pretreatment of tip in dip-pen nanolithography. AB - This study examines the lithographic capacity of tips in dip-pen nanolithography (DPN). The dependence of the transport rate (R) decay on the area of lithography (A(lith)), the dependence of A(lith) on the lithographic time (t), and the effect of piranha cleaning on the lithographic capacity are considered herein. The dependencies in the line-drawing lithography process are studied using 16 mercaptohexadecanoic acid (MHA) ink. On the basis of the linear decay dependence discovered in the R-A(lith) dependence, piranha treatment can increase the lithographic capacity by up to 35.5-fold, an improvement that may originate from a change in the tip's surface chemistry. Moreover, a theoretical model is derived to describe the A(lith)-t dependence accurately and to predict the tips' lifetime. Furthermore, an experiment involving DPN-based nanostructure fabrication demonstrates the importance of monitoring the tips' transport rate and lifetime. In addition to shedding light on the physical and chemical principles behind DPN, this study provides a comprehensive model for a quantitative analysis of the tips' behavior. PMID- 23020584 TI - Skin toxicity and quality of life in patients with metastatic colorectal cancer during first-line panitumumab plus FOLFIRI treatment in a single-arm phase II study. AB - BACKGROUND: Integument-related toxicities are common during epidermal growth factor receptor (EGFR)-targeted therapy. Panitumumab is a fully human monoclonal antibody targeting the EGFR that significantly improves progression-free survival when added to chemotherapy in patients with metastatic colorectal cancer who have wild-type (WT) KRAS tumours. Primary efficacy and tolerability results from a phase II single-arm study of first-line panitumumab plus FOLFIRI in patients with metastatic colorectal cancer have been reported. Here we report additional descriptive tolerability and quality of life data from this trial. METHODS: Integument-related toxicities and quality of life were analysed; toxicities were graded using modified National Cancer Institute Common Toxicity Criteria. Kaplan Meier estimates of time to and duration of first integument-related toxicity were prepared. Quality of life was measured using EuroQoL EQ-5D and EORTC QLQ-C30. Best overall response was analysed by skin toxicity grade and baseline quality of life. Change in quality of life was analysed by skin toxicity severity. RESULTS: 154 patients were enrolled (WT KRAS n = 86; mutant KRAS n = 59); most (98%) experienced integument-related toxicities (most commonly rash [42%], dry skin [40%] and acne [36%]). Median time to first integument-related toxicity was 8 days; median duration was 334 days. Overall, proportionally more patients with grade 2+ skin toxicity responded (56%) compared with those with grade 0/1 (29%). Mean overall EQ-5D health state index scores (0.81 vs. 0.78), health rating scores (72.5 vs. 71.0) and QLQ-C30 global health status scores (65.8 vs. 66.7) were comparable at baseline vs. safety follow-up (8 weeks after completion), respectively and appeared unaffected by skin toxicity severity. CONCLUSIONS: First-line panitumumab plus FOLFIRI has acceptable tolerability and appears to have little impact on quality of life, despite the high incidence of integument related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov NCT00508404. PMID- 23020587 TI - Quantifying resistances across nanoscale low- and high-angle interspherulite boundaries in solution-processed organic semiconductor thin films. AB - The nanoscale boundaries formed when neighboring spherulites impinge in polycrystalline, solution-processed organic semiconductor thin films act as bottlenecks to charge transport, significantly reducing organic thin-film transistor mobility in devices comprising spherulitic thin films as the active layers. These interspherulite boundaries (ISBs) are structurally complex, with varying angles of molecular orientation mismatch along their lengths. We have successfully engineered exclusively low- and exclusively high-angle ISBs to elucidate how the angle of molecular orientation mismatch at ISBs affects their resistivities in triethylsilylethynyl anthradithiophene thin films. Conductive AFM and four-probe measurements reveal that current flow is unaffected by the presence of low-angle ISBs, whereas current flow is significantly disrupted across high-angle ISBs. In the latter case, we estimate the resistivity to be 22 MOmegaMUm(2)/width of the ISB, only less than a quarter of the resistivity measured across low-angle grain boundaries in thermally evaporated sexithiophene thin films. This discrepancy in resistivities across ISBs in solution-processed organic semiconductor thin films and grain boundaries in thermally evaporated organic semiconductor thin films likely arises from inherent differences in the nature of film formation in the respective systems. PMID- 23020586 TI - Eukaryotic genomes may exhibit up to 10 generic classes of gene promoters. AB - BACKGROUND: The main function of gene promoters appears to be the integration of different gene products in their biological pathways in order to maintain homeostasis. Generally, promoters have been classified in two major classes, namely TATA and CpG. Nevertheless, many genes using the same combinatorial formation of transcription factors have different gene expression patterns. Accordingly, we tried to ask ourselves some fundamental questions: Why certain genes have an overall predisposition for higher gene expression levels than others? What causes such a predisposition? Is there a structural relationship of these sequences in different tissues? Is there a strong phylogenetic relationship between promoters of closely related species? RESULTS: In order to gain valuable insights into different promoter regions, we obtained a series of image-based patterns which allowed us to identify 10 generic classes of promoters. A comprehensive analysis was undertaken for promoter sequences from Arabidopsis thaliana, Drosophila melanogaster, Homo sapiens and Oryza sativa, and a more extensive analysis of tissue-specific promoters in humans. We observed a clear preference for these species to use certain classes of promoters for specific biological processes. Moreover, in humans, we found that different tissues use distinct classes of promoters, reflecting an emerging promoter network. Depending on the tissue type, comparisons made between these classes of promoters reveal a complementarity between their patterns whereas some other classes of promoters have been observed to occur in competition. Furthermore, we also noticed the existence of some transitional states between these classes of promoters that may explain certain evolutionary mechanisms, which suggest a possible predisposition for specific levels of gene expression and perhaps for a different number of factors responsible for triggering gene expression. Our conclusions are based on comprehensive data from three different databases and a new computer model whose core is using Kappa index of coincidence. CONCLUSIONS: To fully understand the connections between gene promoters and gene expression, we analyzed thousands of promoter sequences using our Kappa Index of Coincidence method and a specialized Optical Character Recognition (OCR) neural network. Under our criteria, 10 classes of promoters were detected. In addition, the existence of "transitional" promoters suggests that there is an evolutionary weighted continuum between classes, depending perhaps upon changes in their gene products. PMID- 23020588 TI - Types of cell death and methods of their detection in yeast Saccharomyces cerevisiae. AB - The occurrence of programmed cell death in unicellular organisms is a subject that arouses great interest of theoreticians and experimental scientists. Already found evolutionarily conserved genes and metabolic pathways confirmed its existence in yeast, protozoa and even bacteria. In the yeast Saccharomyces cerevisiae, at least three main types of death are distinguished: apoptosis, necrosis and autophagy. Their classification suggested by the Nomenclature Committee on Cell Death initially based on the morphological characteristics has now been extended to include the measurable biochemical characteristics. Several laboratory methods previously used to detect the types of cell death of higher eucaryotes and later developed and successfully used for the analysis of yeast cells are here critically reviewed. Their advantages and limitations are described. PMID- 23020589 TI - Characterization of the novel HLA-DPB1*140:01 allele identified by sequence-based typing. AB - The novel HLA-DPB1*140:01 variant allele differs from the closest allele DPB1*05:01:01 by single nucleotide change at genomic nt 4898G>C in exon 2. PMID- 23020591 TI - Experimental and theoretical observation of different intramolecular H-bonds in lysine conformations. AB - Due to the importance of the structure of amino acids for the folding and functionality of proteins, the conformational behavior of lysine has been investigated. Experimental matrix-isolation FT-IR spectra have been recorded. These spectra were interpreted using an extended theoretical DFT and MP2 study. Theoretically, 28 (DFT) and 18 (MP2) conformations were found with DeltaE < 10 kJ mol(-1). Incorporation of the entropy term changed the relative order of the stability because of the large unfavorable effect of this term for the conformations with one or two intramolecular H-bonds. As a matter of fact, the predicted abundances are strongly temperature dependent. The abundant conformations of lysine at sublimation temperature can be characterized by the type of amino acid backbone and the eventual additional H-bond in four groups. These groups are predicted to be detectable in the matrix, as their abundances are all larger than 5%. The theoretical spectral data of the most abundant conformation of a particular group are used to represent the group. In the matrix isolation FT-IR spectrum all the important, H-bonded involved modes (nu(OH), nu(NH(2)), nu(C?O), gamma(OH), delta(OH) and gamma(NH(2))) of the four conformational groups were observed. A linear correlation between the stretching frequency shift nu(XH) and the elongation of the XH distance Deltar(XH) in different conformations of lysine and other amino acids has been observed. The experimental frequencies are in good relationship with the theoretically obtained data, which is proven by a mean frequency deviation for the most abundant conformation is 12.6 cm(-1). PMID- 23020592 TI - Fuzzy-logic-based safety verification framework for nuclear power plants. AB - This article presents a practical implementation of a safety verification framework for nuclear power plants (NPPs) based on fuzzy logic where hazard scenarios are identified in view of safety and control limits in different plant process values. Risk is estimated quantitatively and compared with safety limits in real time so that safety verification can be achieved. Fuzzy logic is used to define safety rules that map hazard condition with required safety protection in view of risk estimate. Case studies are analyzed from NPP to realize the proposed real-time safety verification framework. An automated system is developed to demonstrate the safety limit for different hazard scenarios. PMID- 23020593 TI - Weighing worth against uncertain work: the interplay of exhaustion, ambiguity, hope and disappointment in mothers breastfeeding late preterm infants. AB - Poor breastfeeding outcomes among late preterm infants (LPIs) have been attributed to inadequate breast milk transfer stemming from physiological immaturities. However, breastfeeding is more than a biological phenomenon, and it is unclear how mothers of LPIs manage other factors that may also impact the breastfeeding course. Using grounded theory methods and incorporating serial post partum interviews with several novel data collection techniques, we examined breastfeeding establishment over a 6-8-week-period among 10 late preterm mother infant dyads recruited from a maternity hospital in Pittsburgh, Pennsylvania, USA. We found that breastfeeding in the LPI population was a fluctuating, cascade like progression of trial and error, influenced by a host of contextual factors and events and culminating with breastfeeding continuation (with or without future caveats for duration or exclusivity of breastfeeding) or cessation. The trajectory was explained by the basic psychosocial process Weighing Worth against Uncertain Work, which encompassed the tension among breastfeeding motivation, the intensity of breastfeeding work and the ambiguity surrounding infant behaviour and feeding cues. Several sub-processes were also identified: Playing the Game, Letting Him Be the Judge vs. Accommodating Both of Us and Questioning Worth vs. Holding out Hope. If valid, our theoretical model indicates a need for earlier, more extensive and more qualified breastfeeding support for mothers of LPIs that emphasizes the connection between prematurity and observed feeding behaviours. PMID- 23020594 TI - Hepatitis B virus reactivation associated with anti-neoplastic therapy. AB - Reactivation of hepatitis B virus (HBV) infection is a known complication during and after anti-cancer therapy. This condition can affect two patient populations: it is most commonly seen in patients who are seropositive for hepatitis B surface antigen (HBsAg), but it is also being increasingly reported among patients who are HBsAg-negative but who have prior infection, as evident by seropositive status for antibody to hepatitis B core antigen (anti-HBc), irrespective of their anti-HBs (antibody to HBsAg) status. The clinical course can vary from asymptomatic hepatitis to fulminant hepatic failure that can be potentially fatal. With the increasing use of biological agents in addition to potent cytotoxic chemotherapy in the armamentarium of anti-cancer treatments, reactivation of hepatitis B has become a common clinical situation that is faced by both oncologists and hepatologists especially in HBV endemic areas. In this review, we discuss the clinical course of reactivation in the two HBV-infected sub-populations, and the role of anti-virals in the prevention and management of HBV reactivation in association with cytotoxic chemotherapy and biological therapies. PMID- 23020595 TI - Origin of Swedish hemophilia A mutations. AB - BACKGROUND: Hemophilia A (HA) has a high level of variation within the disease class, with more than 1000 mutations being listed in the HAMSTeRS database. At the same time a number of F8 mutations are present in specific populations at high frequencies. OBJECTIVES: The simultaneous presence of large numbers of rare mutations and a small number of high-frequency mutations raises questions about the origins of HA mutations. The present study was aimed at describing the origins of HA mutations in the complete Swedish population. The primary issue was to determine what proportion of identical mutations are identical by descent (IBD) and what proportion are attributable to recurrent mutation events. The age of IBD mutations was also determined. PATIENTS/METHODS: In Sweden, the care of HA is centralized, and the Swedish HA population consists of ~ 750 patients from > 300 families (35% severe, 15% moderate, and 50% mild). Identical haplotypes were defined by single-nucleotide polymorphism and microsatellite haplotyping, and the ages of the mutations were estimated with estiage. RESULTS: Among 212 presumably unrelated patients with substitution mutations, 97 (46%) had mutations in common with other patients. Haplotyping of the 97 patients showed that 47 had IBD mutations (22%) with estimated ages of between two and 35 generations. The frequency of mild disease increased with an increasing number of patients sharing the mutations. CONCLUSIONS: A majority of the IBD mutations are mild and have age estimates of a few hundred years, but some could date back to the Middle Ages. PMID- 23020596 TI - Characterization of mercury binding onto a novel brominated biomass ash sorbent by X-ray absorption spectroscopy. AB - Recent laboratory and field-scale experiments demonstrated the potential for brominated industrial solid waste from biomass combustion (Br-Ash) to be an efficient, cost-effective alternative to activated carbon for capturing mercury from coal-fired power plants. To develop this attractive alternative technology to a commercially sustainable level, a better understanding of mercury capture mechanisms by Br-Ash is required. For this purpose, X-ray absorption fine structure (XAFS) spectra of Br-Ash were collected at the Hg L(III)-edge, Br K edge and S K-edge, and analyzed to determine the local bonding environment of mercury atoms. The coordination environment of Hg was compared with that on a commercial brominated activated carbon. Our results indicate that the mercury was captured by chemisorption on both the commercial and biomass ash sorbents; however, the mercury binding environment was different for each sorbent. Mercury was found to bind to the reduced sulfur by the commercial brominated activated carbon, in contrast to mercury binding with carbon and bromine on the brominated biomass ash. Based on the results obtained, a mechanism of Hg capture involving oxidation of elemental Hg followed by binding of the oxidized mercury on the surface of the sorbent near Br was proposed for the brominated biomass ash. PMID- 23020597 TI - Formulation and evaluation of carnosic acid nanoparticulate system for upregulation of neurotrophins in the brain upon intranasal administration. AB - To develop formulations of carnosic acid nanoparticles and to assess their in vivo efficacy to enhance the expression of neurotrophins in rat model. Carnosic acid loaded chitosan nanoparticles were prepared by ionotropic gelation technique using central composite design. Response surface methodology was used to assess the effect of three factors namely chitosan concentration (0.1-1% w/v), tri-poly phosphate concentration (0.1-1% w/v) and sonication time (2-10 min) on the response variables such as particle size, zeta potential, drug encapsulation efficiency and drug release. The neurotrophins level in the rat brain upon intranasal administration of optimized batch of carnosic acid nanoparticles was determined. The experimental values for the formulation were in good agreement with those predicted by the mathematical models. A single intranasal administration of the optimized formulation of carnosic acid nanoparticles was sufficient to result in comparable levels of endogenous neurotrophins level in the brain that was almost on par with four, once a day intranasal administration of solution in rats. The results clearly demonstrated the fact that nanoparticulate drug delivery system for intranasal administration of carnosic acid would require less number of administrations to elicit the required pharmacological activity owing to its ability to localize on the olfactory mucosal region and provide controlled delivery of carnosic acid for prolonged time periods. PMID- 23020598 TI - Antibody-linked spherical nucleic acids for cellular targeting. AB - Spherical nucleic acid (SNA) constructs are promising new single entity gene regulation materials capable of both cellular transfection and gene knockdown, but thus far are promiscuous structures, exhibiting excellent genetic but little cellular selectivity. In this communication, we describe a strategy to impart targeting capabilities to these constructs through noncovalent functionalization with a complementary antibody-DNA conjugate. As a proof-of-concept, we designed HER2-targeting SNAs and demonstrated that such structures exhibit cell type selectivity in terms of their uptake, and significantly greater gene knockdown in cells overexpressing the target antigen as compared to the analogous antibody free and off-target materials. PMID- 23020599 TI - Does growth under elevated CO2 moderate photoacclimation in rice? AB - Acclimation of plant photosynthesis to light irradiance (photoacclimation) involves adjustments in levels of pigments and proteins and larger scale changes in leaf morphology. To investigate the impact of rising atmospheric CO2 on crop physiology, we hypothesize that elevated CO2 interacts with photoacclimation in rice (Oryza sativa). Rice was grown under high light (HL: 700 umol m-2 s-1), low light (LL: 200 umol m-2 s-1), ambient CO2 (400 ul l-1) and elevated CO2 (1000 ul l-1). Leaf six was measured throughout. Obscuring meristem tissue during development did not alter leaf thickness indicating that mature leaves are responsible for sensing light during photoacclimation. Elevated CO2 raised growth chamber photosynthesis and increased tiller formation at both light levels, while it increased leaf length under LL but not under HL. Elevated CO2 always resulted in increased leaf growth rate and tiller production. Changes in leaf thickness, leaf area, Rubisco content, stem and leaf starch, sucrose and fructose content were all dominated by irradiance and unaffected by CO2. However, stomata responded differently; they were significantly smaller in LL grown plants compared to HL but this effect was significantly suppressed under elevated CO2. Stomatal density was lower under LL, but this required elevated CO2 and the magnitude was adaxial or abaxial surface-dependent. We conclude that photoacclimation in rice involves a systemic signal. Furthermore, extra carbohydrate produced under elevated CO2 is utilized in enhancing leaf and tiller growth and does not enhance or inhibit any feature of photoacclimation with the exception of stomatal morphology. PMID- 23020600 TI - Fatty acid esters of monochloropropanediol (MCPD) and glycidol in refined edible oils. AB - Recently, fatty acid esters of monochloropropanediol (MCPD) and that of glycidol have been reported in refined edible oils. Since then a wealth of research has been published on the factors influencing the formation of these contaminants in foods. It can be noted that the predominant precursors in a given matrix will not necessarily be the same as in other matrices. Further, proven relationships in the past between precursors responsible for free MCPD or free glycidol formation will not necessarily be valid for their fatty acid-esterified counterparts. This review attempts to summarise the current status of the literature as it pertains to the reasons surrounding the manifestation of MCPD esters and glycidyl esters in oils and fats. Recent efforts to mitigate the levels of these contaminants were highlighted and put into the context of their respective reaction matrices. As more accurate occurrence data for MCPD esters and glycidyl esters in other foods are collected, more targeted mitigation experiments can be formulated with respect to the reaction matrices under investigation. PMID- 23020601 TI - beta-catenin (CTNNB1) mutations and clinicopathological features of mesenteric desmoid-type fibromatosis. AB - AIMS AND METHODS: Desmoid-type fibromatosis (desmoid) is a fibroblastic tumour that shows locally aggressive growth. Mesenteric desmoid is a rare lesion that shares morphological and biological features with fibromatoses occurring in the abdominal wall or in extraabdominal sites, but differs in terms of gross appearance and clinical presentation. We report on a series of 56 cases of mesenteric desmoids from our consultation files and compare them with cases of non-mesenteric desmoids and retroperitoneal fibrosis. RESULTS: Primary diagnosis of desmoid-type fibromatosis was correct in 42%, and gastrointestinal stromal tumour was a common misdiagnosis. Nuclear expression of beta-catenin was detected in 91.6% of all desmoids. Mutational analysis of exon 3 of the beta catenin gene (CTNNB1) revealed that mesenteric desmoids carried mutations significantly more often (51/56, 91.1%) than non-mesenteric tumours (20/28; 71.4%; P = 0.027). p.T41A occurred significantly more frequently in mesenteric fibromatoses (80.4%) than in abdominal wall and extra-abdominal fibromatoses (46.4%; P = 0.002). Two novel mutations (p.S45C and p.D32G) were found. In retroperitoneal fibrosis, mutations and nuclear beta-catenin expression were absent. beta-Catenin-negative desmoids either carried a CTNNB1 mutation or were associated with Gardner syndrome. CONCLUSIONS: Our study provides evidence that some clinical and genetic features of mesenteric desmoids differ from those of non-mesenteric fibromatosis, and corroborates the usefulness of mutational analysis, especially in diagnosing beta-catenin-negative mesenteric desmoids. PMID- 23020602 TI - General anesthesia for intussusception reduction by enema. AB - OBJECTIVES: Intussusception is the most frequent cause of bowel obstruction in children. Although enema is usually used as the initial treatment, surgery may be required in more than 50% of patients. General anesthesia (GA) has been suggested to increase the rate of enema success. The purpose of this study was to evaluate whether GA increases the success rate of reduction by air enema. METHODS: In this retrospective single-center study from 1989 to the end of June 2008, patients receiving air enema for intussusception reduction were studied. Multivariable analysis using propensity score was performed to compare the success rate between patients receiving sedation or GA. RESULTS: The success rate of air enema increased from 72% in 1989 to the current rate of 90%. When time elapsed between first symptoms and enema was >12 h, the success rate decreased significantly (Odds Ratio 0.67 [0.56-0.81], P < 0.0001). When patients were matched by propensity score, GA significantly increased the likelihood of success (OR 5.66 [2.85-12.89], P = 0.013). CONCLUSIONS: Air enema performed under GA allows intussusception reduction in more than 90% of patients. PMID- 23020603 TI - French version validation of the psychotic symptom rating scales (PSYRATS) for outpatients with persistent psychotic symptoms. AB - BACKGROUND: Most scales that assess the presence and severity of psychotic symptoms often measure a broad range of experiences and behaviours, something that restricts the detailed measurement of specific symptoms such as delusions or hallucinations. The Psychotic Symptom Rating Scales (PSYRATS) is a clinical assessment tool that focuses on the detailed measurement of these core symptoms. The goal of this study was to examine the psychometric properties of the French version of the PSYRATS. METHODS: A sample of 103 outpatients suffering from schizophrenia or schizoaffective disorders and presenting persistent psychotic symptoms over the previous three months was assessed using the PSYRATS. Seventy five sample participants were also assessed with the Positive And Negative Syndrome Scale (PANSS). RESULTS: ICCs were superior to .90 for all items of the PSYRATS. Factor analysis replicated the factorial structure of the original version of the delusions scale. Similar to previous replications, the factor structure of the hallucinations scale was partially replicated. Convergent validity indicated that some specific PSYRATS items do not correlate with the PANSS delusions or hallucinations. The distress items of the PSYRATS are negatively correlated with the grandiosity scale of the PANSS. CONCLUSIONS: The results of this study are limited by the relatively small sample size as well as the selection of participants with persistent symptoms. The French version of the PSYRATS partially replicates previously published results. Differences in factor structure of the hallucinations scale might be explained by greater variability of its elements. The future development of the scale should take into account the presence of grandiosity in order to better capture details of the psychotic experience. PMID- 23020604 TI - A comparison between adolescent mothers and adult mothers in terms of maternal and infant outcomes at follow-ups. AB - OBJECTIVE: To determine the risk factors of adolescent pregnancies and to ascertain the effects of this condition on the maternal and infant outcomes. METHODS: The study was carried out on 100 adolescent mothers less than 20 years of age and on a same number of adult mothers between 22 and 32 years of age and their infants. A socio-demographic attributes questionnaire form, a pregnancy follow-up and birth history form, and a mother and infant follow-up form were used. RESULTS: The mean age of the adolescent mothers was 17.8 +/- 0.7 years and that of the adult mothers was 26 +/- 0.3 years. Income level of 83% of the families of adolescent mothers and 69% of the families of adult mothers was below the poverty line (p < 0.05). Dropout rate (i.e. rate of those not attending any school) was 36% in the adolescent group and 21% in the adult group. Rate of exclusively breastfeeding during the first 2 months was 40% in adolescents and 62% in adults (p < 0.01). Higher rates of adolescent mothers felt themselves inadequate infant care and with 7% of them experiencing problems in accessing a healthcare institution. CONCLUSIONS: Properly following up adolescent pregnancies during prenatal and postnatal periods may be helpful for preventing the negative impacts on mother and infant health. PMID- 23020605 TI - Prognostic significance of hypoxia inducible factor-1alpha and vascular endothelial growth factor expression in patients with diffuse large B-cell lymphoma treated with rituximab. AB - We evaluated hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) expression and their prognostic significance in diffuse large B-cell lymphoma (DLBCL). Expression of HIF-1alpha and VEGF was studied in 78 patients and results correlated with clinicopathological and prognostic data. HIF-1alpha and VEGF were expressed in 67% and 84% of patients, respectively, and a significant correlation was demonstrated between them (p < 0.001). Outcome was analyzed according to treatment. HIF-1alpha positive patients given rituximab demonstrated improved outcome, with 5-year overall survival of 72% for those receiving rituximab versus 65% for those not receiving rituximab, and 5-year progression-free survival (PFS) 76% versus 57%. No correlation was demonstrated between HIF-1alpha and other prognostic biomarkers including BCL6, CD10 and MUM-1. We demonstrated significantly improved PFS (p = 0.003) in patients receiving rituximab and showing BCL6 overexpression. The results confirm the significant association between HIF-1alpha and VEGF expression and suggest that HIF-1alpha expression is a favorable prognostic factor in patients with DLBCL treated with rituximab. PMID- 23020606 TI - Genetic polymorphism of PRKCDBP is associated with an increased risk of endometrial cancer. AB - PRKCDBP is a putative tumor suppressor located at 11p15.4, where frequent genomic loss has been observed in human cancers. We explored the possible association between an intra-exonic single nucleotide polymorphism (SNP), rs1051992, that results in a Leu to Pro substitution, and risk for endometrial carcinogenesis. We assessed the genotype of rs1051992 in endometrial cancer tissues from 147 patients and normal endometrial tissue from 191 healthy individuals by restriction endonuclease PvuII-based genotyping. Allele frequencies in the cancer specimens were compared with those in the healthy controls. We also evaluated the association between polymorphisms at this locus and histopathological features of endometrial cancer. PMID- 23020607 TI - BAT1, a putative acyltransferase, modulates brassinosteroid levels in Arabidopsis. AB - Brassinosteroids (BRs) are essential for various aspects of plant development. Cellular BR homeostasis is critical for proper growth and development of plants; however, its regulatory mechanism remains largely unknown. BAT1 (BR-related acyltransferase 1), a gene encoding a putative acyltransferase, was found to be involved in vascular bundle development in a full-length cDNA over-expressor (FOX) screen. Over-expression of BAT1 resulted in typical BR-deficient phenotypes, which were rescued by exogenously applied castasterone and brassinolide. Analyses of BR profiles demonstrated that BAT1 alters levels of several brassinolide biosynthetic intermediates, including 6-deoxotyphasterol, typhasterol and 6-deoxocastasterone. BAT1 is mainly localized in the endoplasmic reticulum. BAT1 is highly expressed in young tissues and vascular bundles, and its expression is induced by auxin. These data suggest that BAT1 is involved in BR homeostasis, probably by conversion of brassinolide intermediates into acylated BR conjugates. PMID- 23020608 TI - Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin. AB - AIMS: We compared metformin with insulin as treatment of gestational diabetes mellitus (GDM). Furthermore, we aimed to characterize metformin-treated patients needing additional insulin to achieve prespecified glucose targets. METHODS: We conducted a single centre randomized controlled study with non-inferiority design comparing metformin and insulin in the treatment of 217 GDM patients having birth weight as primary outcome variable. RESULTS: There were no significant differences in mean birth weight expressed in grams [+15 (90% confidence interval (CI): -121 to 89)] or SD units [+0.04 (90% CI: -0.27 to 0.18)] between the metformin and insulin groups. There were no significant differences in neonatal or maternal data between the groups. Only 23 (20.9%) of the 110 patients in the metformin group needed additional insulin. Compared with the patients on metformin only, those needing additional insulin were older (p = 0.04), their oral glucose tolerance test had been performed earlier and diabetes therapy started earlier in gestation (p = 0.01 and p = 0.004, respectively). The risk for additional insulin was 4.6-fold in women with baseline serum fructosamine concentration above median compared with those below median. CONCLUSIONS: Metformin is an effective alternative to insulin in the treatment of GDM patients. Serum fructosamine may help in predicting the adequacy of metformin treatment alone. PMID- 23020609 TI - Biomimetic synthesis of the apoptosis-inducing thiazinoquinone thiaplidiaquinone A. AB - A concise total synthesis of the apoptosis-inducing, marine metabolite thiaplidiaquinone A is described. The key ring forming steps are both based on biosynthetic considerations and involve the construction of the central benzo[c]chromene quinone unit by an extremely facile oxa-6pi-electrocyclic ring closure reaction of an ortho-quinone intermediate, derived by tautomerization of a bis-benzoquinone, readily accessed from two simple phenolic precursors. This is followed by the installation of the 1,4-thiazine-dioxide ring by reaction of the benzo[c]chromene quinone with hypotaurine. PMID- 23020610 TI - Effects of spiritual healing for women undergoing long-term hormone therapy for breast cancer: a qualitative investigation. AB - BACKGROUND: Spiritual Healing is widely available and used, but is a neglected area for research and its biologic and psychologic mechanisms are not understood. The side-effects of long-term hormonal therapy for breast cancer are onerous and have been reported to lead to "drug holidays" that could diminish the long-term treatment benefits. It was investigated whether Spiritual Healing could support patients with breast cancer undergoing this treatment. METHODS: The qualitative observation study took place in a specialist research facility in a general hospital. Spiritual Healing was provided by 4 healers registered with the National Federation of Spiritual Healers. Twelve (12) patients with breast cancer undergoing long-term hormone treatment and who found the effects onerous, self referred themselves and were given ten weekly sessions of approximately 40 minutes each. Data collected included participant's daily records, direct observations noted by healers, the researcher's field diary and a one-to-one semi structured interview. FINDINGS: The positive effects of Spiritual Healing included alleviation of the physical side-effects of their treatment, increased energy levels, enhanced well-being, emotional relaxation, and re-engagement with precancer activities. Although 1 participant admitted considering a drug holiday prior to joining the study, none of the participants felt tempted to stop their hormonal treatments while receiving Spiritual Healing. CONCLUSIONS: These qualitative findings indicate that Spiritual Healing has the potential to support patients with breast cancer in the maintenance of their long-term orthodox treatments. Further research is needed to test Spiritual Healing as a cost effective complementary therapy, for those undergoing long-term cancer treatments. PMID- 23020611 TI - DoD-NCCAM/NIH workshop on acupuncture for treatment of acute pain. AB - The Department of Defense (DoD) and the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) cosponsored a workshop that explored the possible benefits of acupuncture treatment for acute pain. One goal of the workshop was to establish a roadmap to building an evidence base on that would indicate whether acupuncture is helpful for treating active-duty military personnel experiencing acute pain. The workshop highlighted brief presentations on the most current research on acupuncture and acute pain mechanisms. The impact of various modifiers (stress, genetics, population, phenotypes, etc.) on acute pain pathways and response to acupuncture treatment was discussed. Additional presentations focused on common neural mechanisms, an overview of real-world experience with using acupuncture to treat traumatic acute pain, and best tools and methods specific for acupuncture studies. Three breakout groups addressed the gaps, opportunities, and barriers to acupuncture use for acute pain in military and trauma settings. Different models of effectiveness research and optimal research designs for conducting trials in acute traumatic pain were also discussed. PMID- 23020612 TI - Raw starch-degrading alpha-amylase from Bacillus aquimaris MKSC 6.2: isolation and expression of the gene, bioinformatics and biochemical characterization of the recombinant enzyme. AB - AIMS: The aims were to isolate a raw starch-degrading alpha-amylase gene baqA from Bacillus aquimaris MKSC 6.2, and to characterize the gene product through in silico study and its expression in Escherichia coli. METHODS AND RESULTS: A 1539 complete open reading frame of a starch-degrading alpha-amylase gene baqA from B. aquimaris MKSC 6.2 has been determined by employing PCR and inverse PCR techniques. Bioinformatics analysis revealed that B. aquimaris MKSC 6.2 alpha amylase (BaqA) has no starch-binding domain, and together with a few putative alpha-amylases from bacilli may establish a novel GH13 subfamily most closely related to GH13_1. Two consecutive tryptophans (Trp201 and Trp202, BaqA numbering) were identified as a sequence fingerprint of this novel GH13 subfamily. Escherichia coli cells produced the recombinant BaqA protein as inclusion bodies. The refolded recombinant BaqA protein degraded raw cassava and corn starches, but exhibited no activity with soluble starch. CONCLUSIONS: A novel raw starch-degrading B. aquimaris MKSC 6.2 alpha-amylase BaqA is proposed to be a member of new GH13 subfamily. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has contributed to the overall knowledge and understanding of amylolytic enzymes that are able to bind and digest raw starch directly. PMID- 23020613 TI - Congenital defects of platelet function. AB - Congenital abnormalities of platelet function disorder (PFD) are associated with the heightened risk for bleeding. Typically, patients with PFDs have mucocutaneous bleeding of variable severity and excessive hemorrhage after surgery or trauma. The diagnostic laboratory assessment appropriate for the evaluation of suspected inherited PFD should be based on a two-step diagnostic strategy: the first step, based on screening tests, helps raising a diagnostic hypothesis, which should then be tested in the second step, which is based on the use of specific tests. The first step should include: complete blood cell count, examination of the peripheral blood smear, and assessment of platelet aggregation. Although light transmission aggregometry (LTA) is the most widely used platelet function test, it is relatively insensitive to defects of platelet secretion; for this reason, laboratory tests that measure platelet aggregation and secretion simultaneously, such as lumi-aggregometry, should be preferred to traditional LTA. The second step includes specific tests (e.g., flow cytometry, Western blotting, DNA analysis). Platelet transfusions should be used only to treat severe bleeding episodes. Recombinant Factor VIIa can be used in patients with severe bleeding episodes who do not respond to platelet transfusion because of alloimmunization. Fibrinolytic inhibitors or the vasopressin analogue desmopressin (DDAVP) should be used in all other circumstances. PMID- 23020614 TI - Identification of a novel allele, HLA-B*37:04:02, from a registered donor of the China Marrow Donor Program. AB - B*37:04:02 has 1 nt change from B*37:04:01 at nt 618 where G->A (codon 206 GCG >GCA) resulting in no coding change. PMID- 23020615 TI - Neural mechanisms of reward in insects. AB - Reward seeking is a major motivator and organizer of behavior, and animals readily learn to modify their behavior to more easily obtain reward, or to respond to stimuli that are predictive of reward. Here, we compare what is known of reward processing mechanisms in insects with the well-studied vertebrate reward systems. In insects almost all of what is known of reward processing is derived from studies of reward learning. This is localized to the mushroom bodies and antennal lobes and organized by a network of hierarchically arranged modulatory circuits, especially those involving octopamine and dopamine. Neurogenetic studies with Drosophila have identified distinct circuit elements for reward learning, "wanting," and possibly "liking" in Drosophila, suggesting a modular structure to the insect reward processing system, which broadly parallels that of the mammals in terms of functional organization. PMID- 23020616 TI - Potential of insects as food and feed in assuring food security. AB - With a growing world population and increasingly demanding consumers, the production of sufficient protein from livestock, poultry, and fish represents a serious challenge for the future. Approximately 1,900 insect species are eaten worldwide, mainly in developing countries. They constitute quality food and feed, have high feed conversion ratios, and emit low levels of greenhouse gases. Some insect species can be grown on organic side streams, reducing environmental contamination and transforming waste into high-protein feed that can replace increasingly more expensive compound feed ingredients, such as fish meal. This requires the development of cost-effective, automated mass-rearing facilities that provide a reliable, stable, and safe product. In the tropics, sustainable harvesting needs to be assured and rearing practices promoted, and in general, the food resource needs to be revalorized. In the Western world, consumer acceptability will relate to pricing, perceived environmental benefits, and the development of tasty insect-derived protein products. PMID- 23020617 TI - Diamondback moth ecology and management: problems, progress, and prospects. AB - Agricultural intensification and greater production of Brassica vegetable and oilseed crops over the past two decades have increased the pest status of the diamondback moth (DBM), Plutella xylostella L., and it is now estimated to cost the world economy US$4-5 billion annually. Our understanding of some fundamental aspects of DBM biology and ecology, particularly host plant relationships, tritrophic interactions, and migration, has improved considerably but knowledge of other aspects, e.g., its global distribution and relative abundance, remains surprisingly limited. Biological control still focuses almost exclusively on a few species of hymenopteran parasitoids. Although these can be remarkably effective, insecticides continue to form the basis of management; their inappropriate use disrupts parasitoids and has resulted in field resistance to all available products. Improved ecological understanding and the availability of a series of highly effective selective insecticides throughout the 1990s provided the basis for sustainable and economically viable integrated pest management (IPM) approaches. However, repeated reversion to scheduled insecticide applications has resulted in resistance to these and more recently introduced compounds and the breakdown of IPM programs. Proven technologies for the sustainable management of DBM currently exist, but overcoming the barriers to their sustained adoption remains an enormous challenge. PMID- 23020618 TI - Spider-venom peptides: structure, pharmacology, and potential for control of insect pests. AB - Spider venoms are an incredibly rich source of disulfide-rich insecticidal peptides that have been tuned over millions of years to target a wide range of receptors and ion channels in the insect nervous system. These peptides can act individually, or as part of larger toxin cabals, to rapidly immobilize envenomated prey owing to their debilitating effects on nervous system function. Most of these peptides contain a unique arrangement of disulfide bonds that provides them with extreme resistance to proteases. As a result, these peptides are highly stable in the insect gut and hemolymph and many of them are orally active. Thus, spider-venom peptides can be used as stand-alone bioinsecticides, or transgenes encoding these peptides can be used to engineer insect-resistant crops or enhanced entomopathogens. We critically review the potential of spider venom peptides to control insect pests and highlight their advantages and disadvantages compared with conventional chemical insecticides. PMID- 23020619 TI - Host preferences of blood-feeding mosquitoes. AB - Mosquitoes use plant sugars and vertebrate blood as nutritional resources. When searching for blood hosts, some mosquitoes express preferential behavior for selected species. Here, we review the available knowledge on host preference, as this is expected to affect the life history and transmission of infectious pathogens. Host preference is affected by myriad extrinsic and intrinsic factors. Inherent factors are determined by genetic selection, which appears to be controlled by adaptive advantages that result from feeding on certain host species. Host preference of mosquitoes, although having a genetic basis, is characterized by high plasticity mediated by the density of host species, which by their abundance form a readily accessible source of blood. Host-selection behavior in mosquitoes is an exception rather than the rule. Those species that express strong and inherent host-selection behavior belong to the most important vectors of infectious diseases, which suggests that this behavioral trait may have evolved in parallel with parasite-host evolution. PMID- 23020620 TI - Biology of invasive termites: a worldwide review. AB - The number of recognized invasive termite species has increased from 17 in 1969 to 28 today. Fourteen species have been added to the list in the past 44 years; 10 have larger distributions and 4 have no reported change in distribution, and 3 species are no longer considered invasive. Although most research has focused on invasive termites in urban areas, molecular identification methods have answered questions about certain species and found that at least six species have invaded natural forest habitats. All invasive species share three characteristics that together increase the probability of creating viable propagules: they eat wood, nest in food, and easily generate secondary reproductives. These characteristics are most common in two families, the Kalotermitidae and Rhinotermitidae (which make up 21 species on the invasive termite list), particularly in three genera, Cryptotermes, Heterotermes, and Coptotermes (which together make up 16 species). Although it is the largest termite family, the Termitidae (comprising 70% of all termite species) have only two invasive species, because relatively few species have these characteristics. Islands have double the number of invasive species that continents do, with islands in the South Pacific the most invaded geographical region. Most invasive species originate from Southeast Asia. The standard control methods normally used against native pest termites are also employed against invasive termites; only two eradication attempts, in South Africa and New Zealand, appear to have been successful, both against Coptotermes species. PMID- 23020621 TI - Vision in Drosophila: seeing the world through a model's eyes. AB - The fruit fly, Drosophila melanogaster, has been used for decades as a genetic model for unraveling mechanisms of development and behavior. In order to efficiently assign gene functions to cellular and behavioral processes, early measures were often necessarily simple. Much of what is known of developmental pathways was based on disrupting highly regular structures, such as patterns of cells in the eye. Similarly, reliable visual behaviors such as phototaxis and motion responses provided a solid foundation for dissecting vision. Researchers have recently begun to examine how this model organism responds to more complex or naturalistic stimuli by designing novel paradigms that more closely mimic visual behavior in the wild. Alongside these advances, the development of brain recording strategies allied with novel genetic tools has brought about a new era of Drosophila vision research where neuronal activity can be related to behavior in the natural world. PMID- 23020622 TI - Odorant reception in insects: roles of receptors, binding proteins, and degrading enzymes. AB - Our knowledge of the molecular basis of odorant reception in insects has grown exponentially over the past decade. Odorant receptors (ORs) from moths, fruit flies, mosquitoes, and the honey bees have been deorphanized, odorant-degrading enzymes (ODEs) have been isolated, and the functions of odorant-binding proteins (OBPs) have been unveiled. OBPs contribute to the sensitivity of the olfactory system by transporting odorants through the sensillar lymph, but there are competing hypotheses on how they act at the end of the journey. A few ODEs that have been demonstrated to degrade odorants rapidly may act in signal inactivation alone or in combination with other molecular traps. Although ORs in Drosophila melanogaster respond to multiple odorants and seem to work in combinatorial code involving both periphery and antennal lobes, reception of sex pheromones by moth ORs suggests that their labeled lines rely heavily on selectivity at the periphery. PMID- 23020623 TI - Responsive emulsions stabilized by stimuli-sensitive microgels: emulsions with special non-Pickering properties. AB - Recent studies revealing the unique properties of microgel-stabilized responsive emulsions are discussed, and microgels are compared to classical rigid-particle Pickering stabilizers. Microgels are strongly swollen, lyophilic particles that become deformed at the oil-water interface and protrude only a little into the oil phase. Temperature- and pH-sensitive microgels allow us to prepare temperature- and pH-sensitive emulsions and thus enable us to prepare and break emulsions on demand. Although such emulsions are sensitive to pH, the stabilization of droplets is not due to electrostatic repulsion, instead the viscoelastic properties of the interface seem to dominate droplet stability. Being soft and porous, microgels behave distinctly differently from rigid particles at the interface: they are deformed and strongly flattened especially in the case of oil-in-water emulsions. The microgels are located mainly on the water side of the interface for both oil-in-water and water-in-oil emulsions. In contrast to rigid, solid particles, the behavior of microgels at oil-water interfaces does not depend only on the interfacial tension but also on the balance among the interfacial tension, swelling, elasticity, and deformability of the microgel, which needs to be considered. It is obvious that microgels as soft, porous particles are significantly different from classical rigid colloidal stabilizers in Pickering emulsions and we suggest avoiding the term Pickering emulsion when swollen microgels are employed. Microgel-stabilized emulsions require the development of new theoretical models to understand their properties. They open the door to new sophisticated applications. PMID- 23020626 TI - Autonomous water sampling for long-term monitoring of trace metals in remote environments. AB - A remotely controlled autonomous method for long-term high-frequency sampling of environmental waters in remote locations is described. The method which preserves sample integrity of dissolved trace metals and major ions for month-long periods employs a gravitational filtration system (GFS) that separates dissolved and particulate phases as samples are collected. The key elements of GFS are (1) a modified "air-outlet" filter holder to maximize filtration rate and thus minimize filtration artifacts; and (2) the direct delivery of filtrate to dedicated bottle sets for specific analytes. Depth and screen filter types were evaluated with depth filters showing best performance. GFS performance is validated using ground, stream, and estuary waters. Over 30 days of storage, samples with GFS treatment had average recoveries of 95 +/- 19% and 105 +/- 7% of Fe and Mn, respectively; without GFS treatment, average recoveries were only 16% and 18%. Dissolved major cations K, Mg, and Na were stable independent of collection methodology, whereas Ca in some groundwater samples decreased up to 42% without GFS due to CaCO(3) precipitation. In-field performance of GFS equipped autosamplers is demonstrated using ground and streamwater samples collected at the Angelo Coast Range Reserve, California from October 3 to November 4 2011. PMID- 23020625 TI - A duck RH panel and its potential for assisting NGS genome assembly. AB - BACKGROUND: Owing to the low cost of the high throughput Next Generation Sequencing (NGS) technology, more and more species have been and will be sequenced. However, de novo assemblies of large eukaryotic genomes thus produced are composed of a large number of contigs and scaffolds of medium to small size, having no chromosomal assignment. Radiation hybrid (RH) mapping is a powerful tool for building whole genome maps and has been used for several animal species, to help assign sequence scaffolds to chromosomes and determining their order. RESULTS: We report here a duck whole genome RH panel obtained by fusing female duck embryonic fibroblasts irradiated at a dose of 6,000 rads, with HPRT deficient Wg3hCl2 hamster cells. The ninety best hybrids, having an average retention of 23.6% of the duck genome, were selected for the final panel. To allow the genotyping of large numbers of markers, as required for whole genome mapping, without having to cultivate the hybrid clones on a large scale, three different methods involving Whole Genome Amplification (WGA) and/or scaling down PCR volumes by using the Fluidigm BioMark(TM) Integrated Fluidic Circuits (IFC) Dynamic Array(TM) for genotyping were tested. RH maps of APL12 and APL22 were built, allowing the detection of intrachromosomal rearrangements when compared to chicken. Finally, the panel proved useful for checking the assembly of sequence scaffolds and for mapping EST located on one of the smallest microchromosomes. CONCLUSION: The Fluidigm BioMark(TM) Integrated Fluidic Circuits (IFC) Dynamic Array(TM) genotyping by quantitative PCR provides a rapid and cost-effective method for building RH linkage groups. Although the vast majority of genotyped markers exhibited a picture coherent with their associated scaffolds, a few of them were discordant, pinpointing potential assembly errors. Comparative mapping with chicken chromosomes GGA21 and GGA11 allowed the detection of the first chromosome rearrangements on microchromosomes between duck and chicken. As in chicken, the smallest duck microchromosomes appear missing in the assembly and more EST data will be needed for mapping them. Altogether, this underlines the added value of RH mapping to improve genome assemblies. PMID- 23020627 TI - Immune protection function of multipotent mesenchymal stromal cells: role of transforming growth factor-beta1. AB - The immunosuppressive functions of multipotent mesenchymal stromal cells (MSCs) may give cancer cells a survival advantage. This study tests the hypothesis that MSCs protect leukemia cells from immune clearance. Our results demonstrate that MSCs are capable of inhibiting peripheral blood mononuclear cells (PBMNCs) proliferation and their migration toward leukemic cells by the reduction of CCL5 and CXCL12. In addition, we find that MSCs can inhibit the cytolytic functions of NK-cells and CTLs. TGF-beta1 secreted by MSCs is responsible for impaired CTLs and NK function by down-modulating surface NKG2D expression. These inhibitory functions of MSCs have negative effects on the CTLs or NK-mediated graft-versus leukemia (GVL), particularly in the allogeneic hematopoietic stem cells transplantation setting. PMID- 23020628 TI - Analytical approaches for MCPD esters and glycidyl esters in food and biological samples: a review and future perspectives. AB - Esters of 2 - and 3-monochloropropane-1,2-diol (MCPD) and glycidol esters are important contaminants of processed edible oils used as foods or food ingredients. This review describes the occurrence and analysis of MCPD esters and glycidol esters in vegetable oils and some other foods. The focus is on the analytical methods based on both direct and indirect methods. Methods of analysis applied to oils and lipid extracts of foods have been based on transesterification to free MCPD and determination by gas chromatography-mass spectrometry (indirect methods) and by high-performance liquid chromatography mass spectrometry (direct methods). The evolution and performance of the different methods is described and their advantages and disadvantages are discussed. The application of direct and indirect methods to the analysis of foods and to research studies is described. The metabolism and fate of MCPD esters and glycidol esters in biological systems and the methods used to study these in body tissues studies are described. A clear understanding of the chemistry of the methods is important when choosing those suitable for the desired application, and will contribute to the mitigation of these contaminants. PMID- 23020629 TI - Prevalence of paroxysmal nocturnal hemoglobinuria in Chinese patients with Budd Chiari syndrome or portal vein thrombosis. AB - BACKGROUND AND AIM: Routine screening for paroxysmal nocturnal hemoglobinuria (PNH) in patients with Budd-Chiari syndrome (BCS) or portal vein thrombosis (PVT) has been recommended in Western countries. However, little is known about whether the routine screening test should be necessary in Chinese patients with BCS or PVT. We conducted a prospective observational study to examine the prevalence of PNH in these patients. METHODS: Patients with primary BCS or non-malignant PVT who were consecutively admitted to our department or regularly followed up between September 2009 and December 2011 were eligible for the study and detected the expression of CD55 and CD59 on erythrocytes and granulocytes. The CD55 or CD59 deficiency was considered as the proportion of erythrocytes or granulocytes with normal expression of CD55 or CD59 was less than 90%. PNH was diagnosed by both CD55 and CD59 deficient clone at flow cytometry of peripheral blood cells. RESULTS: CD55 and/or CD59 deficiencies were found in 1.6% (2/127) of patients with primary BCS, 1.0% (1/100) of non-malignant and non-cirrhotic patients with PVT, and 4.7% (4/85) of cirrhotic patients with PVT. Only one patient had both CD55 and CD59 deficiencies on granulocytes. But he had been diagnosed with PNH before BCS. CONCLUSIONS: Paroxysmal nocturnal hemoglobinuria was very rare in Chinese patients with BCS or PVT, suggesting that routine screening for PNH should not be indiscriminately performed in such patients. PMID- 23020630 TI - ZmGA3ox2, a candidate gene for a major QTL, qPH3.1, for plant height in maize. AB - Maize plant height is closely associated with biomass, lodging resistance and grain yield. Determining the genetic basis of plant height by characterizing and cloning plant height genes will guide the genetic improvement of crops. In this study, a quantitative trait locus (QTL) for plant height, qPH3.1, was identified on chromosome 3 using populations derived from a cross between Zong3 and its chromosome segment substitution line, SL15. The plant height of the two lines was obviously different, and application of exogenous gibberellin A(3) removed this difference. QTL mapping placed qPH3.1 within a 4.0 cM interval, explaining 32.3% of the phenotypic variance. Furthermore, eight homozygous segmental isolines (SILs) developed from two larger F(2) populations further narrowed down qPH3.1 to within a 12.6 kb interval. ZmGA3ox2, an ortholog of OsGA3ox2, which encodes a GA3 beta-hydroxylase, was positionally cloned. Association mapping identified two polymorphisms in ZmGA3ox2 that were significantly associated with plant height across two experiments. Quantitative RT-PCR showed that SL15 had higher ZmGA3ox2 expression relative to Zong3. The resultant higher GA(1) accumulation led to longer internodes in SL15 because of increased cell lengths. Moreover, a large deletion in the coding region of ZmGA3ox2 is responsible for the dwarf mutant d1 6016. The successfully isolated qPH3.1 enriches our knowledge on the genetic basis of plant height in maize, and provides an opportunity for improvement of plant architecture in maize breeding. PMID- 23020631 TI - Improving oral hygiene in the long-term care of the elderly--a RCT. AB - BACKGROUND: Oral hygiene and health of the institutionalized elderly are frequently described as inadequate. OBJECTIVES: This randomized and single blinded (outcome evaluation) study compared three types of intervention for improving oral hygiene with a control. The purpose was to investigate whether there were any significant differences between the intervention and control groups. METHODS: One hundred and six participants living in long-term care homes in South-West Germany were recruited and randomly divided into four groups-three therapy groups and one control group. For all three therapy groups, teeth and dentures were cleaned professionally and individual instruction was given. One of these groups was also re-instructed and remotivated by a dentist (n = 27). One also received help from, and was remotivation by, staff educated in dental hygiene (n = 26). The third therapy group was not remotivated after professional cleaning of teeth and dentures (n = 26). For the control group, there was no intervention (n = 23). The main target clinical data were mean plaque (plaque control record, O'Leary), gingival bleeding (Ainamo/Bay), and denture hygiene indices. For assessment of the difference between being in an intervention group and in a control group, mixed-model analysis for repeated measurements was performed for each main target variable. In addition, target clinical data were evaluated in long-term follow-up after 3 years. RESULTS: Compared with controls, denture hygiene, plaque, and gingival bleeding indices were significantly lower in the intervention groups over a twelve-week period (mixed model for repeated measurements; P < 0.023). Estimates of effects between control and each treatment group were comparable among the three therapy groups; however, even though two of the groups received further help and instruction. Long-term follow-up showed that all indices were significantly worse than at the last study recall (P < 0.001). CONCLUSIONS: Professional cleaning of teeth and dentures, with individual instruction, can be recommended to improve oral hygiene. However, the effect decreases over time and renewal of the intervention is necessary. PMID- 23020632 TI - Preanalytic variables of thrombin generation: towards a standard procedure and validation of the method. AB - BACKGROUND: Thrombin generation assays are sensitive methods for assessment of the overall clotting potential of plasma, but, despite their common use in thrombosis research, standardization of preanalytic conditions is lacking. In order to set up a standardized protocol, we analyzed different preanalytic variables and validated the calibrated automated thrombogram method. METHODS AND RESULTS: Thrombin generation was assessed with 0, 1 and 5 pm tissue factor (TF). Variations in thrombin generation were mostly attributable to the type of collection tube, mainly because of variations in contact activation. The collection tube also determined the influence of other preanalytic variables on thrombin generation, e.g. the need for a discard tube, the storage of whole blood, and the centrifugation method. Regarding the collection system, blood drawn through intravenous catheters or butterfly needles showed significantly more hemolysis than blood obtained with venipuncture using conventional needles. The results showed that a discard tube is still needed for thrombin generation measurements. After blood collection, whole blood is best centrifuged immediately, to prevent activation or degradation of coagulation proteins, and a second centrifugation step at 10,000 * g is recommended. After thawing, plasma is best analyzed immediately, as storage resulted in thrombin generation results outside the 10% range of the reference sample. On the basis of these results, we set up an in-house standardized protocol, which was used for validation, resulting in coefficients of variations of < 15% for all derived parameters with both the 1 and 5 pm TF triggers. CONCLUSION: Thrombin generation was greatly influenced by preanalytic conditions, demonstrating the need for an international standardized protocol. PMID- 23020633 TI - Crystal structure of the redox-active cofactor dibromothymoquinone bound to circadian clock protein KaiA and structural basis for dibromothymoquinone's ability to prevent stimulation of KaiC phosphorylation by KaiA. AB - KaiA protein that stimulates KaiC phosphorylation in the cyanobacterial circadian clock was recently shown to be destabilized by dibromothymoquinone (DBMIB), thus revealing KaiA as a sensor of the plastoquinone (PQ) redox state and suggesting an indirect control of the clock by light through PQ redox changes. Here we show using X-ray crystallography that several DBMIBs are bound to KaiA dimer. Some binding modes are consistent with oligomerization of N-terminal KaiA pseudoreceiver domains and/or reduced interdomain flexibility. DBMIB bound to the C-terminal KaiA (C-KaiA) domain and limited stimulation of KaiC kinase activity by C-KaiA in the presence of DBMIB demonstrate that the cofactor may weakly inhibit KaiA-KaiC binding. PMID- 23020634 TI - Evaluation of viral co-infections in hospitalized and non-hospitalized children with respiratory infections using microarrays. AB - The impact of viral co-infections and recently discovered viruses on the epidemiology of respiratory infections in children is still unclear. To simultaneously detect viruses that are involved in the aetiology of respiratory infections, we used a DNA/RNA microarray assay that identifies 17 different viruses or viral subtypes. Rhinopharyngeal washes were taken from 611 children (aged 1 month to 14 years) who presented in the emergency department with respiratory infections from June 2010 to June 2011 and were treated as outpatients (299, 48.9%) or hospitalized (312, 51.1%). Lower respiratory tract infection was diagnosed more often in hospitalized children (68% versus 36%, p 0.001). Of 397 children in which microarrays detected viral infection (70.1%), a single virus was found in 228 (57.4%) and two or more viruses in 169 (42.5%). The most prevalent viruses among children with positive samples were respiratory syncytial virus (RSV) in 225 (56.6%), parainfluenza virus (PIV) in 118 (29.7%), rhinovirus (RV) in 73 (18.4%), followed by influenza in 56 (14.1%), adenoviruses in 31 (7.8%), bocavirus in 25 (6.3%), human metapneumovirus in 15 (3.7%) and enteroviruses in 12 (3%). Most common viral co-infections were RSVA-RSVB in 46 children (27.2%), RSV-Influenza in 20 (11.8%), RSV-RV in 18 (10.6%) and PIV-RV in 13 (7.7%). Multiple logistic regression analysis revealed that viral co infections were associated with increased probability for hospitalization (OR 1.52, 95% CI 1.01-2.29, p 0.04), and previous pneumococcal vaccination was associated with decreased probability for hospitalization (OR 0.52, 95% CI 0.33 0.81, p 0.004). We conclude that viral co-infections are involved in a significant proportion of children with an acute respiratory infection and may increase the severity of clinical presentation and the risk for hospitalization. PMID- 23020635 TI - Synthesis of 1-acetyl-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives and evaluation of their anticancer activity. AB - In the present study, 1-acetyl-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives (1 6) were synthesized via the ring closure reaction of 1-(2-thienyl)-3-aryl-2 propen-1-ones with hydrazine hydrate in acetic acid. The chemical structures of the compounds were elucidated by IR, (1)H-NMR, (13)C-NMR and mass spectral data and elemental analyses. MTT assay, analysis of DNA synthesis and caspase-3 activation assay were carried out to determine anticancer effects of the compounds on A549 and C6 cancer cell lines. They exhibited dose-dependent anticancer activity against A549 and C6 cancer cell lines. Anticancer activity screening results revealed that compounds 1, 2 and 4 were the most potent derivatives among these compounds. But anticancer effects of these compounds may result from different death mechanisms in A549 and C6 cell lines. PMID- 23020636 TI - Reducing cardiovascular disease risk in type 2 diabetes: is the focus on glycaemia warranted? AB - Cardiovascular disease remains a major source of morbidity and mortality in type 2 diabetes mellitus. This article examines the recent evidence from trials and related meta-analyses on the effects of glycaemic control on cardiovascular disease (and, to a lesser extent, microvascular outcomes) in diabetes, and compares this with evidence accrued from blood pressure and statin trials. On the basis of such evidence, as well as pragmatic considerations, it is clear that clinicians should place stronger emphasis on lipid and blood pressure management to lessen cardiovascular risks. At the same time, cardiovascular disease benefits of glycaemia reduction appear less pronounced, with patient characteristics critically influencing risk to benefit ratio. Recent guidelines now reflect recent observations on glycaemic control (with relaxed targets in specific patient groups), whereas future guidelines should encourage physicians to prioritize lipid-lowering and blood pressure management in patients with diabetes. PMID- 23020637 TI - Solid-phase synthesis of phenylalanine containing peptides using a traceless triazene linker. AB - The use of a triazene function to anchor phenylalanine to a polymeric support through its side chain is reported. To prove the usefulness of this strategy in solid-phase peptide synthesis, several bioactive peptides have been prepared including cyclic, C-modified, and protected peptides. The triazene linkage is formed by coupling the diazonium salt of Fmoc-Phe(pNH(2))-OAllyl to a MBHA polystyrene resin previously functionalized with isonipecotic acid (90%). Further assembly of the peptide chain, cleavage from the resin using 2-5% TFA in DCM, and reduction of the resulting diazonium salt of the peptide with FeSO(4).7H(2)O in DMF afforded the desired products in high purities (73-94%). PMID- 23020638 TI - Comprehensive review of caprock-sealing mechanisms for geologic carbon sequestration. AB - CO(2) capture and geologic sequestration is one of the most promising options for reducing atmospheric emissions of CO(2). Its viability and long-term safety, which depends on the caprock's sealing capacity and integrity, is crucial for implementing CO(2) geologic storage on a commercial scale. In terms of risk, CO(2) leakage mechanisms are classified as follows: diffusive loss of dissolved gas through the caprock, leakage through the pore spaces after breakthrough pressure has been exceeded, leakage through faults or fractures, and well leakage. An overview is presented in which the problems relating to CO(2) leakage are defined, dominant factors are considered, and the main results are given for these mechanisms, with the exception of well leakage. The overview includes the properties of the CO(2)-water/brine system, and the hydromechanics, geophysics, and geochemistry of the caprock-fluid system. In regard to leakage processes, leakage through faults or fracture networks can be rapid and catastrophic, whereas diffusive loss is usually low. The review identifies major research gaps and areas in need of additional study in regard to the mechanisms for geologic carbon sequestration and the effects of complicated processes on sealing capacity of caprock under reservoir conditions. PMID- 23020639 TI - Self-regulated learning: beliefs, techniques, and illusions. AB - Knowing how to manage one's own learning has become increasingly important in recent years, as both the need and the opportunities for individuals to learn on their own outside of formal classroom settings have grown. During that same period, however, research on learning, memory, and metacognitive processes has provided evidence that people often have a faulty mental model of how they learn and remember, making them prone to both misassessing and mismanaging their own learning. After a discussion of what learners need to understand in order to become effective stewards of their own learning, we first review research on what people believe about how they learn and then review research on how people's ongoing assessments of their own learning are influenced by current performance and the subjective sense of fluency. We conclude with a discussion of societal assumptions and attitudes that can be counterproductive in terms of individuals becoming maximally effective learners. PMID- 23020640 TI - The antecedents and consequences of human behavioral mimicry. AB - Behavioral mimicry--the automatic imitation of gestures, postures, mannerisms, and other motor movements--is pervasive in human interactions. The current review focuses on two recent themes in the mimicry literature. First, an analysis of the moderators of mimicry uncovers the various motivational, social, emotional, and personality factors that lead to more or less mimicry of an interaction partner in a given situation. Second, a significant amount of recent research has identified important downstream consequences of mimicking or being mimicked by another person. These include not only increased prosociality between interactants, but also unexpected effects on the individual, such as cognitive processing style, attitudes, consumer preferences, self-regulatory ability, and academic performance. Behavioral mimicry is also placed in its broader context: a form of interpersonal coordination. It is compared to interactional synchrony and other social contagion effects, including verbal, goal, and emotional contagion and attitudinal convergence. PMID- 23020642 TI - Visual aesthetics and human preference. AB - Human aesthetic preference in the visual domain is reviewed from definitional, methodological, empirical, and theoretical perspectives. Aesthetic science is distinguished from the perception of art and from philosophical treatments of aesthetics. The strengths and weaknesses of important behavioral techniques are presented and discussed, including two-alternative forced-choice, rank order, subjective rating, production/adjustment, indirect, and other tasks. Major findings are reviewed about preferences for colors (single colors, color combinations, and color harmony), spatial structure (low-level spatial properties, shape properties, and spatial composition within a frame), and individual differences in both color and spatial structure. Major theoretical accounts of aesthetic response are outlined and evaluated, including explanations in terms of mere exposure effects, arousal dynamics, categorical prototypes, ecological factors, perceptual and conceptual fluency, and the interaction of multiple components. The results of the review support the conclusion that aesthetic response can be studied rigorously and meaningfully within the framework of scientific psychology. PMID- 23020643 TI - S-adenosyl-L-methionine usage during climacteric ripening of tomato in relation to ethylene and polyamine biosynthesis and transmethylation capacity. AB - S-adenosyl-L-methionine (SAM) is the major methyl donor in cells and it is also used for the biosynthesis of polyamines and the plant hormone ethylene. During climacteric ripening of tomato (Solanum lycopersicum 'Bonaparte'), ethylene production rises considerably which makes it an ideal object to study SAM involvement. We examined in ripening fruit how a 1-MCP treatment affects SAM usage by the three major SAM-associated pathways. The 1-MCP treatment inhibited autocatalytic ethylene production but did not affect SAM levels. We also observed that 1-(malonylamino)cyclopropane-1-carboxylic acid formation during ripening is ethylene dependent. SAM decarboxylase expression was also found to be upregulated by ethylene. Nonetheless polyamine content was higher in 1-MCP-treated fruit. This leads to the conclusion that the ethylene and polyamine pathway can operate simultaneously. We also observed a higher methylation capacity in 1-MCP-treated fruit. During fruit ripening substantial methylation reactions occur which are gradually inhibited by the methylation product S-adenosyl-L-homocysteine (SAH). SAH accumulation is caused by a drop in adenosine kinase expression, which is not observed in 1-MCP-treated fruit. We can conclude that tomato fruit possesses the capability to simultaneously consume SAM during ripening to ensure a high rate of ethylene and polyamine production and transmethylation reactions. SAM usage during ripening requires a complex cellular regulation mechanism in order to control SAM levels. PMID- 23020641 TI - Executive functions. AB - Executive functions (EFs) make possible mentally playing with ideas; taking the time to think before acting; meeting novel, unanticipated challenges; resisting temptations; and staying focused. Core EFs are inhibition [response inhibition (self-control--resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking "outside the box," seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances). The developmental progression and representative measures of each are discussed. Controversies are addressed (e.g., the relation between EFs and fluid intelligence, self-regulation, executive attention, and effortful control, and the relation between working memory and inhibition and attention). The importance of social, emotional, and physical health for cognitive health is discussed because stress, lack of sleep, loneliness, or lack of exercise each impair EFs. That EFs are trainable and can be improved with practice is addressed, including diverse methods tried thus far. PMID- 23020644 TI - Interaction between lactobacilli, bacterial vaginosis-associated bacteria, and HIV Type 1 RNA and DNA Genital shedding in U.S. and Kenyan women. AB - Bacterial vaginosis has been associated with genital HIV-1 shedding; however, the effect of specific vaginal bacterial species has not been assessed. We tested cervicovaginal lavage from HIV-1-seropositive women for common Lactobacillus species: L. crispatus, L. jensenii, and seven BV-associated species: BVAB1, BVAB2, BVAB3, Leptotrichia, Sneathia, Megasphaera, and Atopobium spp. using quantitative PCR. We used linear and Poisson regression to evaluate associations between vaginal bacteria and genital HIV-1 RNA and DNA. Specimens from 54 U.S. (310 visits) and 50 Kenyan women (137 visits) were evaluated. Controlling for plasma viral load, U.S. and Kenyan women had similar rates of HIV-1 RNA (19% of visits vs. 24%; IRR=0.95; 95% CI 0.61, 1.49) and DNA shedding (79% vs. 76%; IRR=0.90; 0.78, 1.05). At visits during antiretroviral therapy (ART), the likelihood of detection of HIV-1 RNA shedding was greater with BVAB3 (IRR=3.16; 95% CI 1.36, 7.32), Leptotrichia, or Sneathia (IRR=2.13; 1.02, 4.72), and less with L. jensenii (IRR=0.39; 0.18, 0.84). At visits without ART, only L. crispatus was associated with a lower likelihood of HIV-1 RNA detection (IRR=0.6; 0.40, 0.91). Vaginal Lactobacillus species were associated with lower risk of genital HIV-1 shedding, while the presence of certain BV-associated species may increase that risk. PMID- 23020645 TI - Biocontrol potential of phylloplane bacterium Ochrobactrum anthropi BMO-111 against blister blight disease of tea. AB - AIMS: The present study was carried out to screen the phylloplane bacteria from tea for antagonism against grey blight caused by Pestalotiopsis theae and blister bight caused by Exobasidium vexans and to further evaluate the efficient isolates for disease control potential under field condition. METHODS AND RESULTS: A total of 316 morphologically different phylloplane bacteria were isolated. Among the antagonists, the isolates designated as BMO-075, BMO-111 and BMO-147 exhibited maximum inhibitory activity against both the pathogens under in vitro conditions and hence were selected for further evaluation under microplot field trial. Foliar application of 36-h-old culture of BMO-111 (1 * 10(8) colony-forming units ml(-1) ) significantly reduced the blister blight disease incidence than the other isolates. The culture of BMO-111 as well as its culture filtrate effectively inhibited the mycelial growth of various fungal plant pathogens. The isolate BMO-111 was identified as Ochrobactrum anthropi based on the morphological and 16S rDNA sequence analyses. CONCLUSIONS: It could be concluded that the biocontrol agent O. anthropi BMO-111 was effective against blister blight disease of tea. SIGNIFICANCE AND IMPACT OF THE STUDY: Further study is required to demonstrate the mechanism of its action and formulation for the biocontrol potential against blister blight disease of tea. PMID- 23020646 TI - Umbilical artery pH may be a possible confounder for neonatal adverse outcomes in preterm infants exposed to antenatal magnesium. AB - OBJECTIVES: To determine the normal range of ionized magnesium (IMg) levels in cord blood during preterm gestation and to investigate whether antenatal Mg administration affects neonatal intraventricular hemorrhage (IVH) or patent ductus arteriosus (PDA). METHODS: In this retrospective case-control study, we reviewed 118 pregnant women with antenatal Mg administration and their infants after they gave birth at one tertiary care center between January 2006 and December 2010. Thirty-seven cases with IVH and/or PDA were compared to 81 controls by multiple logistic regression analysis. The normal range of IMg levels was determined by another 79 subjects without any tocolytic agents and possible confounders. Perinatal and neonatal characteristics were then compared between three groups divided by the IMg levels in cord serum. RESULTS: The normal range of IMg levels in cord blood was determined to be 0.47 +/- 0.07 mmol/L, regardless of gestational weeks. IMg level in cord serum could not be a risk factor for IVH or PDA. Elevation of IMg level in cord blood resulted in an increased incidence of IVH and a decreased incidence of PDA, but not significantly. IMg level in cord blood was inversely correlated with umbilical artery pH (p = 0.067). CONCLUSIONS: There was no significant relationship between the IMg levels in cord serum and neonatal IVH and PDA. Umbilical artery pH may be a possible confounder. PMID- 23020647 TI - Cost-utility analysis of a telerehabilitation program: a case study of COPD patients. AB - OBJECTIVE: The present study seeks to conduct cost-utility analysis (CUA) of the Danish TELEKAT (Telehomecare, Chronic Patients and the Integrated Healthcare System) project. The TELEKAT project seeks to test and develop a preventive home monitoring concept across sectors for chronic obstructive pulmonary disease (COPD) patients. The concept of the TELEKAT project is to reduce admissions by enabling the COPD patients to conduct self-monitoring and maintain rehabilitation activities in their own home. COPD patients with severe and very severe COPD were included in the study. SUBJECTS AND METHODS: This economic evaluation follows international guidelines for the conduction of a CUA alongside a clinical randomized controlled trial. The analysis is based on a health sector perspective. RESULTS: The mean incremental cost efficiency ratio, located in the southeast quadrant, shows that telerehabilitation is less costly and more effective than the rehabilitation given to the control group. The telerehabilitation program produces more value for money and generates savings on healthcare budgets. CONCLUSIONS: The telerehabilitation program appears to be more cost-effective than the conventional rehabilitation program for COPD patients. Further studies of cost-effectiveness with a focus on large-scale studies are needed. PMID- 23020648 TI - Enantiospecific desorption of R- and S-propylene oxide from D- or L-lysine modified Cu(100) surfaces. AB - The enantiospecific desorption kinetics of R- and S-propylene oxide (PO) from a Cu(100) surface modified by enantiomerically pure D- or L-lysine have been studied using temperature programmed desorption. These experiments have used R- or S-PO as the chiral probe for study of enantiospecific adsorption on Cu(100) surfaces modified with D- or L-lysine. This chiral probe/modifier/Cu system manifests a significant diastereomeric effect in the R- and S-PO peak desorption temperatures and, hence, true enantiospecific behavior. The enantiospecificity in the PO desorption kinetics is observed only over a narrow range of lysine modifier coverage with a maximum at a lysine coverage leaving an empty site density of theta(O) ~ 0.25. The observation of enantiospecific behavior in the PO/lysine/Cu(100) system is in contrast with the failed results of prior attempts to observe enantiospecific desorption from chirally modified Cu surfaces. The potential for hydrogen-bonding interactions between the chiral probe and chiral modifier, which can depend on the coverage and configuration of the adsorbed modifier, may play a crucial role in enantiospecific adsorption on lysine modified Cu surfaces. PMID- 23020649 TI - Update on the molecular pathogenesis and clinical treatment of mantle cell lymphoma: report of the 11th annual conference of the European Mantle Cell Lymphoma Network. AB - Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL displays an aggressive course, with a continuous relapse pattern and a median survival of only 3-7 years. However, a subset of up to 15% long-term survivors has recently been identified with a rather indolent clinical course. In general, conventional chemotherapy is only palliative and the median duration of remissions is only 1-2 years. In 2000, the European MCL Network (http://www.european-mcl.net) was founded, which consists of 15 national lymphoma study groups supplemented by experts in hematopathology, cytogenetics and molecular genetics. During the last decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide. In the current study generation, the addition of high dose cytosine arabinoside (Ara-C) to an R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival. Similarly, in elderly patients, rituximab maintenance until progression led to a marked prolongation of remission duration. Emerging strategies include proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and others, all based on the dysregulated cell cycle machinery and impairment of several signaling transduction and apoptotic pathways. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the annual conference in Lisbon, recent results of molecular pathogenesis, analyses of current clinical trials and new study concepts were discussed. PMID- 23020650 TI - Efficacy of indacaterol 75 MUg once-daily on dyspnea and health status: results of two double-blind, placebo-controlled 12-week studies. AB - Indacaterol is an inhaled, once-daily, long-acting (r)(2)-agonist for the treatment of COPD. Most previous studies were conducted with doses of 150 and/or 300 MUg once-daily, and data with the 75 MUg dose are limited. Two identically designed studies were, therefore, conducted to evaluate the efficacy and safety of the 75 MUg once-daily dose. In two double-blind studies conducted in the USA, patients with moderate-to-severe COPD were randomized to treatment with indacaterol 75 MUg once-daily (n = 163 and 159) or matching placebo (n = 160 and 159) for 12 weeks. The primary variable was forced expiratory volume in 1 s measured 24 h post-dose after 12 weeks (reported elsewhere). This report describes secondary efficacy endpoints, including transition dyspnea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores, and the percentages of patients with improvements of or above the minimal clinically important difference (MCID; >=1 in TDI score and >=4 in SGRQ score). Differences between indacaterol and placebo for TDI total score at week 12 were 1.23 (p < 0.001) and 0.45 (p = 0.16), with odds ratios for achieving the MCID of 2.19 (p = 0.002) and 1.58 (p = 0.065). SGRQ total score decreased (improved) from baseline by 5.8 and 4.9 units with indacaterol at week 12 (2.0 and 0.9 with placebo), with odds ratios for achieving the MCID of 1.80 (p = 0.024) and 1.71 (p = 0.031). Patients receiving indacaterol had statistically significant or numerical improvements in diary-derived symptom variables compared with placebo. Treatment with indacaterol 75 MUg may provide useful improvements in patient-reported outcomes in patients with moderate-to-severe COPD. PMID- 23020651 TI - Predictive factors for pancreatitis and cholecystitis in endoscopic covered metal stenting for distal malignant biliary obstruction. AB - BACKGROUND AND AIM: Pancreatitis and cholecystitis are major complications after self-expandable metal stent (SEMS) placement in distal malignant biliary obstruction. We aimed to clarify predictive factors for pancreatitis and cholecystitis after covered SEMS placement. METHODS: We retrospectively reviewed 74 consecutive patients with distal malignant biliary obstruction who underwent initial endoscopic drainage using covered SEMS. Predictive factors for pancreatitis and cholecystitis were evaluated in the 74 patients described above and in 66 patients who had not undergone cholecystectomy. RESULTS: The incidences of pancreatitis and cholecystitis were 10.8% (8/74) and 6.1% (4/66), respectively. Univariate analysis revealed that non-pancreatic cancer (P = 0.018) and contrast injection into the pancreatic duct (P = 0.030) were significant predictive factors for pancreatitis. Multivariate analysis revealed that non pancreatic cancer (odds ratio [OR], 4.21; 95% confidence interval [CI], 1.63 14.18; P = 0.007) and contrast injection into the pancreatic duct (OR, 3.34; 95% CI, 1.33-9.60; P = 0.016) were significant independent predictive factors for pancreatitis. On the other hand, univariate and multivariate analyses revealed that tumor involvement to the orifice of the cystic duct (OCD) was a significant independent predictive factor for cholecystitis (OR, 5.85; 95% CI, 1.91-27.74; P = 0.005). CONCLUSIONS: Non-pancreatic cancer and contrast injection into the pancreatic duct were predictive factors for pancreatitis, and tumor involvement to the OCD was a positive predictive factor for cholecystitis after endoscopic covered SEMS placement for distal malignant biliary obstruction. PMID- 23020652 TI - A comparative analysis of the intestinal metagenomes present in guinea pigs (Cavia porcellus) and humans (Homo sapiens). AB - BACKGROUND: Guinea pig (Cavia porcellus) is an important model for human intestinal research. We have characterized the faecal microbiota of 60 guinea pigs using Illumina shotgun metagenomics, and used this data to compile a gene catalogue of its prevalent microbiota. Subsequently, we compared the guinea pig microbiome to existing human gut metagenome data from the MetaHIT project. RESULTS: We found that the bacterial richness obtained for human samples was lower than for guinea pig samples. The intestinal microbiotas of both species were dominated by the two phyla Bacteroidetes and Firmicutes, but at genus level, the majority of identified genera (320 of 376) were differently abundant in the two hosts. For example, the guinea pig contained considerably more of the mucin degrading Akkermansia, as well as of the methanogenic archaea Methanobrevibacter than found in humans. Most microbiome functional categories were less abundant in guinea pigs than in humans. Exceptions included functional categories possibly reflecting dehydration/rehydration stress in the guinea pig intestine. Finally, we showed that microbiological databases have serious anthropocentric biases, which impacts model organism research. CONCLUSIONS: The results lay the foundation for future gastrointestinal research applying guinea pigs as models for humans. PMID- 23020653 TI - Closed-loop double-vasopressor automated system to treat hypotension during spinal anaesthesia for caesarean section: a preliminary study. AB - Hypotension occurs in most caesarean sections under spinal anaesthesia, necessitating vasopressor administration. However, the optimal dosing regimen remains unclear. We have developed a novel vasopressor delivery system that automatically administers phenylephrine or ephedrine based on continuous non invasive blood pressure monitoring. This prospective cohort study recruited 55 healthy women under standardised spinal anaesthesia with 2.2 ml hyperbaric bupivacaine 0.5%, 15 MUg fentanyl and 100 MUg morphine. A 50-MUg phenylephrine bolus was given at 1-min intervals when systolic blood pressure fell below 90% of baseline, and a 4-mg ephedrine bolus was given when hypotension developed with bradycardia (heart rate <60 beats.min(-1) ). Systolic blood pressure was within 20% of baseline in 88% of all measurements. Six patients (11%) had one or more measurements above 120% of baseline (1% of all measurements), whereas 36 (65%) had at least one reading below 80% of baseline (11% of total measurements). The system maintained systolic blood pressure at a mean (SD) of -9.1 (7.0)% below baseline, with 5.4 (2.5)% fluctuation. Two patients (4%) experienced pre-delivery nausea. All 5-min Apgar scores were 9. PMID- 23020654 TI - The generation of fullerenes. AB - We describe an efficient new algorithm for the generation of fullerenes. Our implementation of this algorithm is more than 3.5 times faster than the previously fastest generator for fullerenes - fullgen - and the first program since fullgen to be useful for more than 100 vertices. We also note a programming error in fullgen that caused problems for 136 or more vertices. We tabulate the numbers of fullerenes and IPR fullerenes up to 400 vertices. We also check up to 316 vertices a conjecture of Barnette that cubic planar graphs with maximum face size 6 are Hamiltonian and verify that the smallest counterexample to the spiral conjecture has 380 vertices. PMID- 23020655 TI - Ionic liquid as soluble support for synthesis of 1,2,3-thiadiazoles and 1,2,3 selenadiazoles. AB - A convenient synthesis of 1,2,3-thiadiazoles and 1,2,3-selenadiazoles was achieved using an ionic liquid as a novel soluble support. Ionic liquid-supported sulfonyl hydrazine was synthesized and reacted with a number of ketones to afford the corresponding ionic liquid-supported hydrazones that were converted to 1,2,3 thiadiazoles in the presence of thionyl chloride. The reaction of ionic liquid supported hydrazones with selenium dioxide in acetonitrile afforded 1,2,3 selenadiazoles. The advantages of this methodology were the ease of workup, simple reaction conditions, and high purity. PMID- 23020656 TI - The uric acid metabolism pathway as a therapeutic target in hyperuricemia related to metabolic syndrome. AB - INTRODUCTION: Uric acid (UA) increase is considered an important risk factor for the development of cardiovascular disease (CVD) favoring oxidative stress and endothelial dysfunction and is also involved in metabolic syndrome (MS) pathophysiology. AREAS COVERED: Insulin has a physiological action on renal tubules, causing a reduction in UA clearance, what could explain the hyperuricemia found in MS. On the other hand, it was also hypothesized a causal role of UA in fructose-induced MS. Moreover, it has been suggested that higher UA levels predict the development of MS. MS subjects present a redox imbalance and UA participates in this process. UA can contribute to oxidative stress present in MS; however, it has also an important role in the antioxidant defense system. Although UA may have a protective effect due to its antioxidant properties, it is clear that the dominant effect of UA in MS is deleterious. All-cause mortality and CVD have been shown to be increased with higher UA levels. EXPERT OPINION: It is extremely important to prescribe drugs which concomitantly decrease hyperuricemia and improve co-morbidities associated with hyperuricemia. Long-term studies to verify the consequences of decreasing UA concentration below current recommendations in asymptomatic patients are needed. PMID- 23020657 TI - Circulation of West Nile virus lineage 1 and 2 during an outbreak in Italy. AB - In 2011, from 26 September to 16 October, a small outbreak of West Nile virus (WNV) disease occurred on the island of Sardinia (Italy). According to the national case definition, six cases with acute neurological disease were confirmed in hospitalized patients, and four of them died; one of these was only 34 years old. In two case, WNV RNA was detected in urine, suggesting renal involvement. Sequence analysis showed lineage 1 and 2 circulation. PMID- 23020658 TI - Biochemical characterization of selective inhibitors of human group IIA secreted phospholipase A(2) and hyaluronic acid-linked inhibitor conjugates. AB - We explored the inhibition mode of group IIA secreted phospholipase A(2) (GIIA sPLA(2)) selective inhibitors and tested their ability to inhibit GIIA sPLA(2) activity as chemical conjugates with hyaluronic acid (HA). Analogues of a benzo fused indole sPLA(2) inhibitor were developed in which the carboxylate group on the inhibitor scaffold, which has been shown to coordinate to a Ca(2+) ligand in the enzyme active site, was replaced with other functionality. Replacing the carboxylate group with amine, amide, or hydroxyl groups had no effect on human GIIA (hGIIA) sPLA(2) inhibition potency but dramatically lowered inhibition potency against hGV and hGX sPLA(2)s. An alkylation protection assay was used to probe active site binding of carboxylate and noncarboxylate inhibitors in the presence and absence of Ca(2+) and/or lipid vesicles. We observed that carboxylate-containing inhibitors bind the hGIIA sPLA(2) active site with low nanomolar affinity, but only when Ca(2+) is present. Noncarboxylate, GIIA sPLA(2) selective inhibitors also bind the hGIIA sPLA(2) active site in the nanomolar range. However, binding for GIIA sPLA(2) selective inhibitors was dependent on the presence of a lipid membrane and not Ca(2+). These results indicate that GIIA sPLA(2) selective inhibitors exert their inhibitory effects by binding to the hGIIA sPLA(2) active site. An HA-linked GIIA inhibitor conjugate was developed using peptide coupling conditions and found to be less potent and selective against hGIIA sPLA(2) than the unconjugated inhibitor. Compounds reported in this study are some of the most potent and selective GIIA sPLA(2) active site binding inhibitors reported to date. PMID- 23020659 TI - Treatment of peri-implantitis using multiple applications of chlorhexidine chips: a double-blind, randomized multi-centre clinical trial. AB - BACKGROUND: Universal strategies for managing peri-implantitis are yet to be adopted. The aim of this study is to examine a protocol of intensive application of chlorhexidine containing chips in sites with peri-implantitis. MATERIALS AND METHODS: This multi-centre, randomized, double-blind, parallel, two-arm clinical trial included 60 patients (77 implants) with probing depth (PD) 6-10 mm and bone loss >=2 mm around 1-2 implants. One to two weeks following SRP, baseline measurements were made followed by implants' debridement. Patients were randomized to receive matrix chips (MatrixC) or chlorhexidine Chips (PerioC). Measurements and chips placement were repeated at weeks 2, 4, 6, 8, 12 and 18. At 6 months, patients returned for final examination. RESULTS: Probing depth reduction was greater in the PerioC (2.19 +/- 0.24 mm) compared with MatrixC (1.59 +/- 0.23 mm), p = 0.07. Seventy percentage of the implants in the PerioC and 54% in the MatrixC had PD reduction >= 2 mm. Likewise, 40% of the sites (PerioC) and 24% (MatrixC) had PD reduction >= 3 mm. Clinical attachment level gains for both groups were significant; however, the changes in the PerioC group were significantly greater than in MatrixC [2.21 +/- 0.23 mm. and 1.56 +/- 0.25 mm respectively, p = 0.05]. Bleeding on probing was reduced by half in both groups. CONCLUSION: Frequent placement of PerioC and MatrixC together with implants debridement resulted in a substantial improvement in sites with peri implantitis. Further studies will be required to fully appreciate the mechanism of this treatment. PMID- 23020660 TI - Gas bubble formation in the cytoplasm of a fermenting yeast. AB - Current paradigms assume that gas bubbles cannot be formed within yeasts although these workhorses of the baking and brewing industries vigorously produce and release CO(2) gas. We show that yeasts produce gas bubbles that fill a significant part of the cell. The missing link between intracellular CO(2) production by glycolysis and eventual CO(2) release from cells has therefore been resolved. Yeasts may serve as model to study CO(2) behavior under pressurized conditions that may impact on fermentation biotechnology. PMID- 23020662 TI - Energy component analysis of pi interactions. AB - Fundamental features of biomolecules, such as their structure, solvation, and crystal packing and even the docking of drugs, rely on noncovalent interactions. Theory can help elucidate the nature of these interactions, and energy component analysis reveals the contributions from the various intermolecular forces: electrostatics, London dispersion terms, induction (polarization), and short range exchange-repulsion. Symmetry-adapted perturbation theory (SAPT) provides one method for this type of analysis. In this Account, we show several examples of how SAPT provides insight into the nature of noncovalent pi-interactions. In cation-pi interactions, the cation strongly polarizes electrons in pi-orbitals, leading to substantially attractive induction terms. This polarization is so important that a cation and a benzene attract each other when placed in the same plane, even though a consideration of the electrostatic interactions alone would suggest otherwise. SAPT analysis can also support an understanding of substituent effects in pi-pi interactions. Trends in face-to-face sandwich benzene dimers cannot be understood solely in terms of electrostatic effects, especially for multiply substituted dimers, but SAPT analysis demonstrates the importance of London dispersion forces. Moreover, detailed SAPT studies also reveal the critical importance of charge penetration effects in pi-stacking interactions. These effects arise in cases with substantial orbital overlap, such as in pi stacking in DNA or in crystal structures of pi-conjugated materials. These charge penetration effects lead to attractive electrostatic terms where a simpler analysis based on atom-centered charges, electrostatic potential plots, or even distributed multipole analysis would incorrectly predict repulsive electrostatics. SAPT analysis of sandwich benzene, benzene-pyridine, and pyridine dimers indicates that dipole/induced-dipole terms present in benzene-pyridine but not in benzene dimer are relatively unimportant. In general, a nitrogen heteroatom contracts the electron density, reducing the magnitude of both the London dispersion and the exchange-repulsion terms, but with an overall net increase in attraction. Finally, using recent advances in SAPT algorithms, researchers can now perform SAPT computations on systems with 200 atoms or more. We discuss a recent study of the intercalation complex of proflavine with a trinucleotide duplex of DNA. Here, London dispersion forces are the strongest contributors to binding, as is typical for pi-pi interactions. However, the electrostatic terms are larger than usual on a fractional basis, which likely results from the positive charge on the intercalator and its location between two electron-rich base pairs. These cation-pi interactions also increase the induction term beyond those of typical noncovalent pi-interactions. PMID- 23020663 TI - Sarcopenia negatively affects preoperative total functional liver volume in patients undergoing liver resection. AB - OBJECTIVES: Sarcopenia may negatively affect short-term outcomes after liver resection. The present study aimed to explore whether total functional liver volume (TFLV) is related to sarcopenia in patients undergoing partial liver resection. METHODS: Analysis of total liver volume and tumour volume and measurements of muscle surface were performed in patients undergoing liver resection using OsiriX((r)) and preoperative computed tomography. The ratio of TFLV to bodyweight was calculated as: [TFLV (ml)/bodyweight (g)]*100%. The L3 muscle index (cm(2) /m(2) ) was then calculated by normalizing muscle areas (at the third lumbar vertebral level) for height. RESULTS: Of 40 patients, 27 (67.5%) were classified as sarcopenic. There was a significant correlation between the L3 skeletal muscle index and TFLV (r= 0.64, P < 0.001). Median TFLV was significantly lower in the sarcopenia group than in the non-sarcopenia group [1396 ml (range: 1129-2625 ml) and 1840 ml (range: 867-2404 ml), respectively; P < 0.05]. Median TFLV : bodyweight ratio was significantly lower in the sarcopenia group than in the non-sarcopenia group [2.0% (range: 1.4-2.5%) and 2.3% (range: 1.5-2.5%), respectively; P < 0.05]. CONCLUSIONS: Sarcopenic patients had a disproportionally small preoperative TFLV compared with non-sarcopenic patients undergoing liver resection. The preoperative hepatic physiologic reserve may therefore be smaller in sarcopenic patients. PMID- 23020664 TI - Amyotrophic lateral sclerosis mimic syndrome due to neurosyphilis. PMID- 23020665 TI - Effect of gamma irradiation on metallothionein protein expression in Plantago ovata Forsk. AB - PURPOSE: The effect of gamma rays on metallothionein (MT) expression was studied using the medicinal plant Plantago ovata as the test system. MATERIALS AND METHODS: Western blotting and Matrix-assisted laser desorption ionization time-of flight mass spectrometry (MALDI-TOF MS) were used for this purpose. RESULTS: Western blot analysis showed significant induction of metallothionein protein following gamma exposure and that induction was highest at 20 Gy gamma dose. At higher gamma doses (100 Gy) MT expression level declined due to degeneration of cells. MALDI-TOF MS analysis indicated the presence of low molecular weight (7-8 kD) MT molecules following the lower radiation doses. CONCLUSION: It was concluded from the MALDI-TOF MS result that low gamma exposure leads to expression of MT-like protein. At high doses of gamma ray, MT homologues or MT like protein were not identified, possibly because they might have precipitated due to uncontrolled cross-linking and non-specific aggregation. PMID- 23020666 TI - High interleukin-16 concentrations in the early second trimester amniotic fluid: an independent predictive marker for preterm birth. AB - OBJECTIVE: Infection is believed to be one of frequent and important causes of preterm labor. We attempted to evaluate whether the level of inflammatory markers, e.g. interleukin-16 (IL-16), interleukin-18 (IL-18), and ferritin, in amniotic fluid at early second trimester can predict preterm birth. METHODS: Amniotic fluid (AF) samples were collected from 350 pregnant women who had trans abdominal amniocentesis for genetic indications at 16 to 20 weeks of gestation. AF levels of IL-16, IL-18 and ferritin levels were measured by immunoassay and were correlated with pregnancy outcomes. RESULTS: Among the 350 pregnant women, 58 (16.6%) had preterm birth (<37 weeks gestation). AF levels of IL-16, IL-18, and ferritin were significantly higher in pregnant women with subsequent preterm birth. Multivariate analyses showed that a quartile higher of AF IL-16 level was significantly associated with preterm birth (OR: 3.09, 95% CI 1.52-6.27, p = 0.002). A receiver operating characteristic analysis revealed that an IL-16 cutoff value of 105 pg/ml was a reliable predictor of preterm birth (sensitivity, 90.2%; specificity, 52.7%; negative predictive value, 84.3%). CONCLUSION: It is feasible to predict preterm birth by measuring the AF levels of IL-16 especially for the pregnant women requiring genetic amniocentesis during early second trimester. PMID- 23020667 TI - Insight into the role of dissolved organic matter in sorption of sulfapyridine by semiarid soils. AB - Sorption-desorption behavior of sulfapyridine was studied with three distinct soil types low in organic carbon with or without the introduction of exogenous dissolved organic matter (DOM). Experiments with bulk soils yielded sorption coefficients equivalent to those obtained with soils richer in organic matter, indicating an important sorptive role for soil mineral matrices. Cointroduction of sulfapyridine with DOM significantly reduced sulfapyridine sorption. However, decreasing solution pH from ~9 to ~6 limited the effect of DOM and revealed the effect of ionic speciation of sulfapyridine on the sorption potential. Sulfapyridine sorption to soils precoated with DOM exhibited contrasting trends. Two of the coated soils exhibited decreased sorption of sulfapyridine probably due to blockage of sorption sites by DOM. Conversely, the third soil demonstrated cumulative adsorption of sulfapyridine. Precoating also enhanced sulfapyridine desorption, suggesting that sorption of sulfapyridine to mineral surfaces involves stronger chemisorptive binding as compared with interactions with sorbed DOM. The capacity of soil to sorb DOM as well as the chemical fractionation of DOM during sorption were found to significantly affect binding of sulfapyridine. Competition between preferentially sorbed DOM moieties (e.g., carboxyl, phenol) and sulfapyridine for sorption sites is proposed. This study suggests that the chemical nature of DOM can significantly affect the fate of sulfonamide compounds in soils. PMID- 23020668 TI - Health promotion messages in entertainment media: crime drama viewership and intentions to intervene in a sexual assault situation. AB - Popular crime dramas have tackled sensitive issues such as sexual assault with increasing frequency over the past 20 years. These popular programs increasingly demonstrate the emotional and physical effect of sexual assault on its victims, and in some instances they depict individuals being rewarded for intervening to prevent or stop an assault in progress. It is possible that this content could affect attitudes related to sexual assault prevention. However, no previous research has examined this possibility. In the fall 2008 semester, 508 undergraduates at a large northwestern university completed a questionnaire about media use and bystander intervention in a sexual assault situation. Results from hierarchical regressions lend support for the integrative model of behavioral prediction in that instrumentality, rape myth acceptance, perceived social norms, perceived efficacy related to intervening, and exposure to primetime crime dramas were associated with participants' intentions to intervene in a sexual assault. The results suggest that crime dramas may be a useful venue for prevention messages as exposure to crime dramas uniquely contributed to intentions to intervene in a sexual assault. PMID- 23020669 TI - Effect of polymer molecular weight and solution pH on the surface properties of sodium dodecylsulfate-poly(ethyleneimine) mixtures. AB - The effect of polymer molecular weight and solution pH on the surface properties of the anionic surfactant sodium dodecylsulfate, SDS, and a range of small linear poly(ethyleneimine), PEI, polyelectrolytes of different molecular weights has been studied by surface tension, ST, and neutron reflectivity, NR, at the air solution interface. The strong SDS-PEI interaction gives rise to a complex pattern of ST behavior which depends significantly on solution pH and PEI molecular weight. The ST data correlate broadly with the more direct determination of the surface adsorption and surface structure obtained using NR. At pH 3, 7, and 10, the strong SDS-PEI interaction results in a pronounced SDS adsorption at relatively low SDS and PEI concentrations, and is largely independent of pH and PEI molecular weight (for PEI molecular weights on the order of 320, 640, and 2000 Da). At pH 7 and 10, there are combinations of SDS and PEI concentrations for which surface multilayer structures form. For the PEI molecular weights of 320 and 640 Da, these surface multilayer structures are most well-developed at pH 10 and less so at pH 7. At the molecular weight of 2000 Da, they are poorly developed at both pH 7 and 10. This evolution in the surface structure with molecular weight is consistent with previous studies, (1) where for a molecular weight of 25,000 Da no multilayer structures were observed for the linear PEI. The results show the importance with increasing polymer molecular weight of the entropic contribution due to the polymer flexibility in control of the surface multilayer formation. PMID- 23020670 TI - Effects of spatially extensive control of invasive rats on abundance of native invertebrates in mainland New Zealand forests. AB - Predation on native fauna by non-native invasive mammals is widely documented, but effects of predation at the population level are rarely measured. Eradication of invasive mammals from islands has led to recovery of native biota, but the benefits of controlling invasive mammal populations in settings where eradication is not feasible are less understood. We used various combinations of aerially delivered toxic bait and control measures on the ground to reduce abundances of invasive rats (Rattus rattus) to low levels over large areas on mainland New Zealand and then monitored the abundance of invertebrates on replicated treatment sites to compare with abundances on similar nontreatment sites. We also assessed rat diet by examining stomach contents. Abundance of the rats' most-consumed invertebrate prey item, the large-bodied Auckland tree weta (Hemideina thoracica), increased 3-fold on treatment sites where we maintained rats at <4/ha for approximately 3 years, compared with the nontreatment sites. Auckland tree weta also increased in abundance on sites where rats were controlled with a single aerial-poisoning operation, but rat abundance subsequently increased on these sites and tree weta abundance then declined. Nevertheless, our data suggest that biennial reduction of rat abundances may be sufficient to allow increases in tree weta populations. Other invertebrates that were consumed less often (cave weta [Rhaphidophoridae], spiders [Araneae], and cockroaches [Blattodea]) showed no systematic changes in abundance following rat control. Our results suggest that the significant threat to recruitment and individual survival that predation by rats poses for tree weta can be mitigated by wide-scale aerial pest control. PMID- 23020672 TI - N-heterocyclic carbene-palladium(II)-1-methylimidazole complex catalyzed amination between aryl chlorides and amides. AB - We report herein that amides are excellent N-sources in the NHC-Pd(II)-Im complex 1 catalyzed amination of aryl chlorides. In the presence of KO(t)Bu, various aryl chlorides and amides can react smoothly to give the corresponding aminated products in moderate to almost quantitative yields at room temperature within 6 h. PMID- 23020673 TI - Mechanism of the antitumoral activity of deferasirox, an iron chelation agent, on mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) characterized by the t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression, is one of the most challenging lymphomas to treat. Iron chelators, such as deferasirox, have previously been shown to exhibit anti-proliferative properties; however, their effect on MCL cells has never been investigated. We showed that deferasirox exhibited antitumoral activity against the MCL cell lines HBL-2, Granta-519 and Jeko-1, with 50% inhibitory concentration (IC(50)) values of 7.99 +/- 2.46 MUM, 8.93 +/- 2.25 MUM and 31.86 +/- 7.26 MUM, respectively. Deferasirox induced apoptosis mediated through caspase-3 activation and decreased cyclin D1 protein levels resulting from increased proteasomal degradation. We also demonstrated down-regulation of phosphor-RB (Ser780) expression, which resulted in increasing levels of the E2F/RB complex and G(1)/S arrest. Finally, we showed that deferasirox activity was dependent on its iron chelating ability. The present data indicate that deferasirox, by down-regulating cyclin D1 and inhibiting its related signals, may constitute a promising adjuvant therapeutic molecule in the strategy for MCL treatment. PMID- 23020674 TI - Changes in the photoplethysmogram with tracheal intubation and remifentanil concentration. AB - Autonomic sympathetic activation, for instance following noxious stimuli, decreases the size and flattens the shape of the photoplethysmographic peripheral pulse waveform. We report a simple measure of the waveform shape, the ratio of mean-to-peak wave amplitude, for measuring nociception level during general anaesthesia. Fifty participants, anaesthetised with propofol and remifentanil, were randomly allocated to one of three different remifentanil effect-site concentrations (1, 3 and 5 ng.ml(-1) ). Tracheal intubation increased the mean (SD) plethysmographic ratio from 0.38 (0.06) to 0.48 (0.04), p = 2.6 * 10(-16) . The mean (SD) ratios following intubation at remifentanil effect-site concentrations of 1 ng.ml(-1) , 3 ng.ml(-1) and 5 ng.ml(-1) , were 0.49 (0.03), 0.48 (0.03) and 0.45 (0.04), respectively. Remifentanil therefore suppressed changes in the mean-to-peak ratio caused by tracheal intubation (p = 0.006). The ratio of the mean-to-peak plethysmographic amplitude may represent a simple measure of the balance of autonomic sympathetic and parasympathetic activity under general anaesthesia, and its performance following intubation was significantly different from peak amplitude (p = 0.046). PMID- 23020671 TI - Microtubule stabilizing agents as potential treatment for Alzheimer's disease and related neurodegenerative tauopathies. AB - The microtubule (MT) associated protein tau, which is highly expressed in the axons of neurons, is an endogenous MT-stabilizing agent that plays an important role in axonal transport. Loss of MT-stabilizing tau function, caused by misfolding, hyperphosphorylation, and sequestration of tau into insoluble aggregates, leads to axonal transport deficits with neuropathological consequences. Several in vitro and preclinical in vivo studies have shown that MT stabilizing drugs can be utilized to compensate for the loss of tau function and to maintain/restore effective axonal transport. These findings indicate that MT stabilizing compounds hold considerable promise for the treatment of Alzheimer disease and related tauopathies. The present article provides a synopsis of the key findings demonstrating the therapeutic potential of MT-stabilizing drugs in the context of neurodegenerative tauopathies, as well as an overview of the different classes of MT-stabilizing compounds. PMID- 23020675 TI - Interferon-gamma release assay: use and misuse. PMID- 23020676 TI - Immunolocalization of collagens (I and III) and cartilage oligomeric matrix protein in the normal and injured equine superficial digital flexor tendon. AB - This is a descriptive study of tendon pathology with different structural appearances of repair tissue correlated to immunolocalization of cartilage oligomeric matrix protein (COMP) and type I and III collagens and expression of COMP mRNA. The material consists of nine tendons from seven horses (5-25 years old; mean age of 10 years) with clinical tendinopathy and three normal tendons from horses (3, 3, and 13 years old) euthanized for non-orthopedic reasons. The injured tendons displayed different repair-tissue appearances with organized and disorganized fibroblastic regions as well as areas of necrosis. The normal tendons presented distinct immunoreactivity for COMP and expression of COMP mRNA and type I collagen in the normal aligned fiber structures, but no immunolabeling of type III collagen. However, immunoreactivity for type III collagen was present in the endotenon surrounding the fiber bundles, where no expression of COMP could be seen. Immunostaining for type I and III collagens was present in all of the pathologic regions indicating repair tissue. Interestingly, the granulation tissues showed immunostaining for COMP and expression of COMP mRNA, indicating a role for COMP in repair and remodeling of the tendon after fiber degeneration and rupture. The present results suggest that not only type III collagen but also COMP is involved in the repair and remodeling processes of the tendon. PMID- 23020677 TI - Seven cysteine-deficient mutants depict the interplay between thermal and chemical stabilities of individual cysteine residues in mitogen-activated protein kinase c-Jun N-terminal kinase 1. AB - Intracellular proteins can have free cysteines that may contribute to their structure, function, and stability; however, free cysteines can lead to chemical instabilities in solution because of oxidation-driven aggregation. The MAP kinase, c-Jun N-terminal kinase 1 (JNK1), possesses seven free cysteines and is an important drug target for autoimmune diseases, cancers, and apoptosis-related diseases. To characterize the role of cysteine residues in the structure, function, and stability of JNK1, we prepared and evaluated wild-type JNK1 and seven cysteine-deficient JNK1 proteins. The nonreduced sodium dodecyl sulfate polyacrylamide gel electrophoresis experiments showed that the chemical stability of JNK1 increased as the number of cysteines decreased. The contribution of each cysteine residue to biological function and thermal stability was highly susceptible to the environment surrounding the particular cysteine mutation. The mutations of solvent-exposed cysteine to serine did not influence biological function and increased the thermal stability. The mutation of the accessible cysteine involved in the hydrophobic pocket did not affect biological function, although a moderate thermal destabilization was observed. Cysteines in the loosely assembled hydrophobic environment moderately contributed to thermal stability, and the mutations of these cysteines had a negligible effect on enzyme activity. The other cysteines are involved in the tightly filled hydrophobic core, and mutation of these residues was found to correlate with thermal stability and enzyme activity. These findings about the role of cysteine residues should allow us to obtain a stable JNK1 and thus promote the discovery of potent JNK1 inhibitors. PMID- 23020678 TI - Variation in the genomic locations and sequence conservation of STAR elements among staphylococcal species provides insight into DNA repeat evolution. AB - BACKGROUND: Staphylococcus aureus Repeat (STAR) elements are a type of interspersed intergenic direct repeat. In this study the conservation and variation in these elements was explored by bioinformatic analyses of published staphylococcal genome sequences and through sequencing of specific STAR element loci from a large set of S. aureus isolates. RESULTS: Using bioinformatic analyses, we found that the STAR elements were located in different genomic loci within each staphylococcal species. There was no correlation between the number of STAR elements in each genome and the evolutionary relatedness of staphylococcal species, however higher levels of repeats were observed in both S. aureus and S. lugdunensis compared to other staphylococcal species. Unexpectedly, sequencing of the internal spacer sequences of individual repeat elements from multiple isolates showed conservation at the sequence level within deep evolutionary lineages of S. aureus. Whilst individual STAR element loci were demonstrated to expand and contract, the sequences associated with each locus were stable and distinct from one another. CONCLUSIONS: The high degree of lineage and locus-specific conservation of these intergenic repeat regions suggests that STAR elements are maintained due to selective or molecular forces with some of these elements having an important role in cell physiology. The high prevalence in two of the more virulent staphylococcal species is indicative of a potential role for STAR elements in pathogenesis. PMID- 23020679 TI - Supramolecular sensing with phosphonate cavitands. AB - Molecular recognition is a recurrent theme in chemical sensing because of the importance of selectivity for sensor performances. The popularity of molecular recognition in chemical sensing has resulted from the progress made in mastering weak interactions, which has enabled the design of synthetic receptors according to the analyte to be detected. However, the availability of a large pool of modular synthetic receptors so far has not had a significant impact on sensors used in the real world. This technological gap has emerged because of the difficulties in transferring the intrinsic molecular recognition properties of a given receptor from solution to interfaces and in finding high fidelity transduction modes for the recognition event. This Account focuses on the ways to overcome these two bottlenecks, and we recount our recent efforts to produce highly selective supramolecular sensors using phosphonate cavitands as receptors. Through two examples, we present an overview of the different operating strategies that are implemented depending on whether the interface is vapor-solid or liquid-solid. First we describe the selective detection of short chain aliphatic alcohols in the vapor phase. In this example, we solved a key issue common to all sensors for organic vapors: the dissection of the specific interaction (between cavitand and the alcohol) from ubiquitous nonspecific dispersion interactions (between the analytes and interferents in the solid layer). We removed responses resulting from the nonspecific interactions of the analytes with interferents by directly connecting the recognition event at the interface to the transduction mechanism (photoinduced charge transfer). The second example addresses the specific detection of sarcosine in urine. Recent research has suggested that sarcosine can serve as reliable biomarker of the aggressive forms of prostate cancer. Tetraphosphonate cavitands can complex N methyl ammonium salts with impressive selectivity in solution, and we used this property as a starting point. The sensor implementation requires that we first graft the cavitand onto silicon and gold surfaces as monolayers. The exclusive recognition of sarcosine by these supramolecular sensors originates from their operation in aqueous environments, where synergistic multiple interactions with the phosphonate cavitand are possible only for N-methyl ammonium derivatives. We couple that selectivity with detection modes that probe the strength of the complexation either directly (microcantilever) or via exchange with molecules that have comparable affinity for the cavity (fluorescence dye displacement). PMID- 23020680 TI - Attendance at iron deficiency anaemia clinic: audit of outcomes 5 years on. AB - AIM: To determine the long-term outcomes of patients in whom no initial cause for their anaemia is established. METHOD: Six hundred and thirty-nine patients presenting to an iron deficiency anaemia pathway were prospectively entered onto a database. Initial assessment included haematological review, coeliac screen, oesophagogastroduodenoscopy and colonic imaging as per British Society of Gastroenterology guidelines. A 5-year audit of outcomes was undertaken using patient medical records and hospital laboratory databases. RESULTS: A diagnosis was found initially in 266 (42%) patients, with 124 (19%) having a gastrointestinal (GI) luminal neoplasm, 54 (8%) of which were malignant. Twelve patients had a nonluminal or non-GI malignancy. Eighty-eight (14%) had benign upper GI bleeding and 23 (4%) had coeliac disease. One hundred and forty-three (22%) did not have confirmed iron deficiency anaemia on review of haematinics. Complete records were available for 595 (93%) patients at 5 years. Of the 373 patients in whom a cause was not initially diagnosed, 6 (2%) were ultimately diagnosed with a GI luminal malignancy and 18 (5%) with a nonluminal or non-GI malignancy. There was no difference in the incidence of malignancies between those with or without confirmed iron deficiency. CONCLUSIONS: Most patients in whom no cause was found at initial investigation resolve on oral iron supplements. Patients with normal ferritin values had as high an incidence of GI malignancies as those with low values and should be investigated. In the over 50s if the anaemia remains after a course of iron further investigation is recommended as there is a significant incidence of both GI and non-GI pathology. PMID- 23020682 TI - Early-life sex-dependent vulnerability to oxidative stress: the natural twining model. AB - OBJECTIVES: Twins represent a unique natural model for studying fetal adaptation to a suboptimal supply of nutrients in utero, the most likely cause of reduced fetal growth, which has been associated with cardiovascular risk. The proposed developmental origin of cardiovascular diseases may offer new venues for investigating the molecular basis of the well-known gender disparity in cardiovascular disease pathogenesis and progression. Early sex differences in oxidative stress, a mechanism of injury associated with both reduced fetal growth and cardiovascular diseases, have been so far poorly investigated. Thus, we aimed at evaluating oxidative stress in newborn twins by measuring oxidative stress biomarkers in cord blood. METHODS: Blood samples were collected from umbilical cord of 80 premature twins. The oxidative stress biomarker15-F(2t)-isoprostane and the total antioxidant capacity (tAOC) were measured in cord plasma. RESULTS: Males had higher levels of plasma 15-F(2t)-isoprostane than females. 15-F(2t) isoprostane values remained greater in males than in females when considering like-sex or unlike sex pairs. No difference was found in tAOC levels. CONCLUSIONS: Our data suggest that sex-based differences in oxidant injury vulnerability occurring early in life could represent a biological mechanism contributing to gender disparity later in life. PMID- 23020683 TI - Customer interest in and experience with various types of pharmacy counselling - a qualitative study. AB - BACKGROUND: Despite pharmacists' extensive knowledge in the optimization of patients' medical treatments, community pharmacies are still fighting to earn patients' trust with respect to medicinal counselling at the counter. OBJECTIVE: The aim was to investigate how patients perceive pharmacy counselling at the present time, in order to develop the patient-pharmacy relationship for the benefit of both patients and pharmacies. DESIGN: Short semi-structured interviews were carried out with pharmacy customers by pharmacy internship students. SETTING AND PARTICIPANTS: One hundred and eight customers in 35 independent pharmacies across Denmark were interviewed during the spring of 2011. MAIN VARIABLES STUDIED: Customers were interviewed about their expectations of pharmacies in general and their experiences with medical counselling in particular. RESULTS: Customers perceive community pharmacies very differently in terms of both expectations of and positive experiences with counselling. They appear to be in favour of pharmacy counselling with respect to over-the-counter medicine and first-time prescription medicine in contrast to refills. Customers find it difficult to express the health-care role of pharmacies even when experiencing and appreciating it. DISCUSSION: Lack of appreciation of pharmacy counselling for refill prescription medicine and the difficulty in defining the role of pharmacies might stem from the difficulties that customers have in understanding medicine and thus the role of counselling services with respect to medicine. The pharmacy staff does not seem to realize these barriers. CONCLUSIONS: For pharmacies to encourage customer interest in pharmacy counselling, the staff should start taking the identified barriers into account when planning communication strategies. PMID- 23020684 TI - Class II subdivision treatment with the Herbst appliance. AB - OBJECTIVE: To assess the effectiveness of Class II subdivision Herbst nonextraction treatment and its short-term stability retrospectively. MATERIALS AND METHODS: Twenty-two Class II subdivision (SUB: right-left molar difference >=0.75 cusp width) and 22 symmetric Class II patients (SYM: >=0.75 cusp width bilaterally) were matched according to gender and pretreatment handwrist radiographic stage. The mean treatment duration of the Herbst and subsequent multibracket phase was 8 months and 14 months, respectively. The mean retention period amounted to 36 months. Dental casts from before treatment (T1), after Herbst treatment (T2), after Multibracket treatment (T3), and after retention (T4) were evaluated. RESULTS: A bilateral Class I or super Class I molar relationship was seen in 72.7% (SUB) and 77.3% (SYM) at T3. The corresponding values at T4 were 63.7% (SUB) and 72.7% (SYM). A unilateral or bilateral Class III molar relationship was more frequent in the SUB group (T3: +4.6%; T4: +13.6%). For overjet, similar mean values were seen in both groups after treatment (T3: SUB, 2.7 mm; SYM, 2.3 mm) and after retention (T4: SUB, 3.0 mm; SYM, 3.4 mm). This was also true for the midline shift (T3: SUB, -0.4 mm; SYM, 0.0 mm; T4: SUB, -0.3 mm; SYM, 0.0 mm). CONCLUSION: Class II subdivision Herbst treatment was successful similarly to symmetric Class II Herbst treatment. However, a slight overcompensation of the molar relationship (Class III tendency) was more frequent in the subdivision patients (original Class I side). PMID- 23020685 TI - Electrophysiological, biochemical and ultrastructural effects of radiotherapy on normal rat sciatic nerve. AB - Abstract Purpose: The aim of the present study was to evaluate the electrophysiological, biochemical and ultrastructural changes on the rat sciatic nerve after radiotherapy. MATERIAL AND METHODS: Thirty male Wistar albino rats were divided into three groups as: Control group (n = 10), Group I: 3 months after radiotherapy (n = 10), and Group II: 6 months after radiotherapy (n = 10). Groups I and II were irradiated with a (60)Co gamma source. A dose of 20 Gy in 10 fractions was applied to Groups I and II. Compound motor action potentials (CMAP) were recorded in all groups. Superoxide dismutase (SOD) and catalase (CAT) activities and malondialdehyde (MDA) levels were measured in the sciatic nerve of rats using the biochemical methods. Ultrastructural changes were determined by electron microscopy. RESULTS: In Groups I and II, the amplitude of CMAP was significantly lower and the latency was significantly higher than that of the control group. There were no significant differences between Groups I and II regarding the CMAP amplitude and latency. The MDA levels were significantly increased, whereas the SOD and CAT activities were significantly decreased in experimental groups when compared with the control group. However, there were no significant changes in these parameters between Groups I and II. Degeneration in myelinated nerve fibers was observed ultrastructurally only in the experimental groups. Significant changes were observed between the control group and experimental groups in terms of ultrastructural myelin grading score and axonal damage score. No significant differences were found between Groups I and II. CONCLUSIONS: These findings indicated that the dose of 20 Gy in 10 fractions radiotherapy caused neuropathic damages in normal rat sciatic nerve 3 and 6 months after irradiation. PMID- 23020686 TI - The impact of coal combustion residue effluent on water resources: a North Carolina example. AB - The combustion of coal to generate electricity produces about 130 million tons of coal combustion residues (CCRs) each year in the United States; yet their environmental implications are not well constrained. This study systematically documents the quality of effluents discharged from CCR settling ponds or cooling water at ten sites and the impact on associated waterways in North Carolina, compared to a reference lake. We measured the concentrations of major and trace elements in over 300 samples from CCR effluents, surface water from lakes and rivers at different downstream and upstream points, and pore water extracted from lake sediments. The data show that CCR effluents contain high levels of contaminants that in several cases exceed the U.S. EPA guidelines for drinking water and ecological effects. This investigation demonstrates the quality of receiving waters in North Carolina depends on (1) the ratio between effluent flux and freshwater resource volumes and (2) recycling of trace elements through adsorption on suspended particles and release to deep surface water or pore water in bottom sediments during periods of thermal water stratification and anoxic conditions. The impact of CCRs is long-term, which influences contaminant accumulation and the health of aquatic life in water associated with coal-fired power plants. PMID- 23020687 TI - Exploring optimistic bias and the integrative model of behavioral prediction in the context of a campus influenza outbreak. AB - This study aims to determine the utility of constructs from the Integrative Model of Behavioral Prediction in predicting behaviors associated with flu prevention in a college campus. Building on previous studies that document substantial optimistic bias among college students, this study explores possible roles for optimistic bias in the Integrative Model of Behavioral Prediction. The authors conducted an online survey among a stratified random sample (N = 429) of undergraduate students in a university that experienced a large H1N1 influenza outbreak in the fall of 2009. The authors offer 3 major findings: (a) the 3 primary components in the Integrative Model of Behavioral Prediction predicted the intention to perform hand washing and sanitizing, with self-efficacy being the strongest predictor; (b) unrealistic optimists had significantly lower intentions to perform hand hygiene practices compared with realists or unrealistic pessimists; and (c) comparative optimism was a significant moderator of the relation between self-efficacy and behavioral intention, controlling for perceived risk. Theoretical and practical implications of these findings are discussed. PMID- 23020688 TI - 2-Acylamino- and 2,4-bis(acylamino)pyrimidines as supramolecular synthons analyzed by multiple noncovalent interactions. DFT, X-ray diffraction, and NMR spectral studies. AB - Intermolecular interactions of ten 2-acylamino and 2,4-bis(acylamino)pyrimidines (7 of which are previously unknown) have been investigated by X-ray structural, quantum chemical (DFT), and NMR spectral methods. Especially the concentration dependencies of the (1)H NMR chemical shifts and titrations with other molecules capable of multiple hydrogen bonding provided useful information regarding their association via triple or quadruple hydrogen bonding, which is controlled by the conformational preferences of 2-acylamino- and 2,4-bis(acylamino)pyrimidines. On comparison of the properties of 2-acylamino- and 2,4-bis(acylamino)pyrimidines with the corresponding pyridines, an additional nitrogen in the heterocyclic ring is the crucial factor in explaining the stability of various conformers and dimers of pyrimidines. Computational modeling of their dimerization (self association) and heteroassociation supports the experimental findings. The substituent effects in 2-acylamino- and 2,4-bis(acylamino)pyrimidines are discussed via inter- and intramolecular terms. The subtle balance between several structural factors and their influence on the aggregation of studied pyrimidines was confirmed also by variable-temperature NMR and NOE experiments. X-ray structures of 2-methyl- and 2-adamantyl-CONH-pyrimidines revealed very different intermolecular interactions, showing the importance of the substituent size on the self-assembly process. As a whole NMR spectral, X-ray structural, and computational data of 2-acylamino- and 2,4-bis(acylamino)pyrimidines can be interpreted in terms of multiple intra-/intermolecular interactions. PMID- 23020689 TI - Quantum dot impregnated-chitosan film for heavy metal ion sensing and removal. AB - We report the use of biopolymer-stabilized ZnS quantum dots (Q-dots) for cation exchange reaction-based easy sensing and removal of heavy metal ions such as Hg(2+), Ag(+), and Pb(2+) in water. Chitosan-stabilized ZnS Q-dots were synthesized in aqueous medium and were observed to have been converted to HgS, Ag(2)S, and PbS Q-dots in the presence of corresponding ions. The transformed Q dots showed characteristic color development, with Hg(2+) being exceptionally identifiable due to the visible bright yellow color formation, while brown coloration was observed in other metal ions. The cation exchange was driven by the difference in the solubility product of the reactant and the product Q-dots. The cation exchanged Q-dots preserved the morphology of the reactant Q-dots and displayed volume increase based on the bulk crystal lattice parameters. The band gap of the transformed Q-dots showed a major increase from the corresponding bulk band gap of the material, demonstrating the role of quantum confinement. Next, we fabricated ZnS Q-dot impregnated chitosan film which was used to remove heavy metal ions from contaminated water as measured using atomic absorption spectroscopy (AAS). The present system could suitably be used as a simple dipstick for elimination of heavy metal ion contamination in water. PMID- 23020691 TI - Trade practices are main factors involved in the transmission of viral haemorrhagic septicaemia. AB - Viral haemorrhagic septicaemia (VHS), caused by the novirhabdovirus viral haemorrhagic septicaemia virus (VHSV), causes significant economic problems to European rainbow trout, Oncorhynchus mykiss (Walbaum), production. The virus isolates can be divided into four distinct genotypes with additional subgroups. The main source of outbreaks in European rainbow trout farming is sublineage Ia isolates. Recently, this group of isolates has been further subdivided in to two subclades of which the Ia-2 consists of isolates occurring mainly in Continental Europe outside of Denmark. In this study, we sequenced the full-length G-gene sequences of 24 VHSV isolates that caused VHS outbreaks in Polish trout farms between 2005 and 2009. All these isolates were identified as genotype Ia-2; they divided however into two genetically distinct subgroups, that we name Pol I and Pol II. The Pol I isolates mainly caused outbreaks in the southern part of Poland, while Pol II isolates predominantly were sampled in the north of Poland, although it seems that they have been transmitted to other parts of the country. Molecular epidemiology was used for characterization of transmission pathways. This study shows that a main cause of virus transmission appears to be movement of fish. At least in Polish circumstances trading practices appear to have significant impact on spreading of VHSV infection. PMID- 23020692 TI - Successful treatment of first and second recurrence of acute lymphoblastic leukemia after related allogeneic bone marrow transplant at unusual sites using single-dose vincristine followed by interferon-alpha2b and granulocyte-macrophage colony-stimulating factor. PMID- 23020693 TI - Effectiveness of pre-surgical infant orthopedic treatment for cleft lip and palate patients: a systematic review and meta-analysis. AB - The objective of the study was to systematically summarize current evidence on the effectiveness of pre-surgical infant orthopedics (PSIO) in cleft lip and palate (CLP) patients. Electronic and manual searches were conducted, and using specific inclusion and exclusion criteria, data extraction and analysis was performed by two independent investigators. When possible, overall pooled estimates with 95% confidence intervals were obtained using the random-effects model. Twenty-four of 885 original studies met the inclusion criteria and were included in the qualitative synthesis, whereas 10 of them were included in the quantitative synthesis (meta-analysis). Except for the variable M-T-C(5) assessing maxillary arch form, which presented an increase at 48 months of follow up, all other variables concerning craniofacial and dentoalveolar changes demonstrated no significant differences, indicating that PSIO treatment has no effect on CLP patients. The limited evidence derived from this study does not seem to support the short- or long-term effectiveness of PSIO in CLP patients. PMID- 23020694 TI - Assessment of facial asymmetry in growing subjects with a three-dimensional laser scanning system. AB - OBJECTIVES: To evaluate facial asymmetry in growing subjects with no malocclusion on three-dimensional laser facial scans. SETTING AND SAMPLE POPULATION: Twenty seven healthy Caucasian children (15 boys and 12 girls, aged 5.4 +/- 0.3 years) in the primary dentition without malocclusion were randomly selected from a local kindergarten in Slovenia. MATERIAL AND METHODS: Surface facial images were obtained using a three-dimensional laser scanning system at baseline and at 18, 30, 42 and 54 months of follow-up. Facial asymmetry was assessed quantitatively by measuring the average distance between facial image and mirrored image. Further, the percentage of asymmetry was calculated as the percentage of image to mirrored image not coinciding within 0.5 mm. Qualitative assessment was performed on colour deviation maps by recording the predominant side of the face for the upper, middle and lower parts of the face separately. Nonparametric tests were used for data analysis. RESULTS: No face was perfectly symmetric. The average distance between the mirrored images for the whole face ranged 0.22-0.85 mm and the percentage of asymmetry 7.8-66.9. There were no significant gender differences (p > 0.05), and no significant change was found over the observed period. The upper part of the face was the least asymmetric, while the lower and middle parts showed similar degrees of asymmetry. CONCLUSION: Facial asymmetry is already present at an early developmental stage and does not show any tendency to increase or decrease with growth in the pre-pubertal period. PMID- 23020695 TI - Visual pathway-related horizontal reference plane for three-dimensional craniofacial analysis. AB - OBJECTIVES: To construct three-dimensional (3D) horizontal reference planes based on visual pathway and to determine their stability and reliability by analyzing the structural patterns of normal and dysmorphology for 3D craniofacial analysis. SETTING AND SAMPLE POPULATION: Thirty-six subjects with maxillofacial dysmorphology and malocclusion, and eight normal controls. MATERIALS AND METHODS POPULATION: On the 3D computed tomographic images of the subjects, the visual pathway-based planes, including the orbital axis plane (OAP), visual axis plane (VAP), and the optical axis plane (OpAP), were constructed and evaluated. RESULTS: The OAP, but not the VAP and OpAP, showed the ideal relationship between the midsagittal and posterior maxillary plane, and properly described the different patterns of maxillofacial dysmorphology with craniofacial plane 1 of Delaire's analysis and the occlusal plane. CONCLUSIONS: The proposed visual pathway-related horizontal reference planes, and in particular the OAP, seem to correctly express the visual axis and the position of the head in natural head position and can be used as a horizontal reference plane for the 3D analysis of craniofacial dysmorphology and anthropology. PMID- 23020696 TI - Torque capabilities of self-ligating and conventional brackets under the effect of bracket width and free wire length. AB - OBJECTIVES: To numerically investigate the torque capacity of conventional and self-ligating brackets under the effect of varying bracket width and free wire length. MATERIAL AND METHODS: Finite element models of three kinds of orthodontic brackets in the 0.022-inch slot size were investigated: Discovery, Damon 3MX, Speed. Additionally, finite element (FE) models of Speed and Damon brackets were generated with the same width as the Discovery. From the left upper incisor to the right upper canine, four brackets each were modelled. The total wire length at the upper right incisor was kept constant at 12 mm for all brackets types. For the Discovery brackets, the wire length was increased from 12 to 16 mm in 2-mm steps. A torque of 20 degrees was applied to the upper right incisor with 0.46 * 0.64 mm(2) (0.018" * 0.025") and 0.48 * 0.64 mm(2) (0.019" * 0.025") wires. Wires made of stainless steel, titanium molybdenum and nickel titanium were studied. Torque angle/moment characteristics were recorded. RESULTS: Wider brackets showed more torque control capability (e.g. Discovery: 10.6 Nmm, Damon: 9.2 Nmm, Speed: 4.0 Nmm for the NiTi wire). Even with the same width as the Discovery bracket, Damon and Speed brackets showed lower torque capability than the Discovery bracket. Increasing the free wire length decreased the torsional stiffness of the wire and thus decreased the torque capability. CONCLUSION: The results showed that the bracket design has less influence on the torquing moment than other parameters, such as bracket width, free wire length, wire/slot play or misalignment. PMID- 23020697 TI - Size-selective fractionation and visual mapping of allergen protein chemistry in Arachis hypogaea. AB - Peanuts (Arachis hypogaea) in addition to milk, eggs, fish, crustaceans, wheat, tree nuts, and soybean are commonly referred to as the "big eight" foods that contribute to the majority of food allergies worldwide. Despite the severity of allergic reactions and growing prevalence in children and adults, there is no cure for peanut allergy, leaving avoidance as the primary mode of treatment. To improve analytical methods for peanut allergen detection, researchers must overcome obstacles involved in handling complex food matrices while attempting to decipher the chemistry that underlies allergen protein interactions. To address such challenges, we conducted a global proteome characterization of raw peanuts using a sophisticated GELFrEE-PAGE-LC-MS/MS platform consisting of gel-based protein fractionation followed by mass spectrometric identification. The in solution mass-selective protein fractionation: (1) enhances the number of unique peptide identifications, (2) provides a visual map of protein isoforms, and (3) aids in the identification of disulfide-linked protein complexes. GELFrEE-PAGE-LC MS/MS not only overcomes many of the challenges involved in the study of plant proteomics, but enriches the understanding of peanut protein chemistry, which is typically unattainable in a traditional bottom-up proteomic analysis. A global understanding of protein chemistry in Arachis hypogaea ultimately will aid the development of improved methods for allergen detection in food. PMID- 23020698 TI - Early intraarticular injection of hyaluronic acid attenuates osteoarthritis progression in anterior cruciate ligament-transected rats. AB - SUBJECT: Hyaluronic acid (HA) is widely used to relieve the symptoms of osteoarthritis (OA). An association of reduction of glutamate content with the synovial fluid of OA rats was reported previously. DESIGN: Anterior cruciate ligament transaction (ACLT) was performed on one knee in male Wistar rats, the other knee was assigned to sham control and HA or saline was injected intraarticularly into the ACLT knee from week 3 to week 7. Knee dialysate was collected for amino acid measurement at week 20. Morphology and histopathology of the femoral medial condyles and synovium were examined and evaluated using Mankin and synovitis scores. RESULTS: HA injection provided better cartilage (3.38 +/- 0.03 vs. 5.45 +/- 0.0.02) and synovial condition (3 +/- 0.02 vs. 6.03 +/- 0.02) than saline controls. Moreover, HA injection reduced the concentration of glutamates in knee dialysates compared to saline controls (1.11 +/- 0.14-folds and 2.21 +/- 0.19-folds of the sham-operated knee, respectively). Cystine/glutamate antiporter system [Formula: see text] expression was significantly downregulated in the saline group, but not in the HA group (0.32 +/ 0.08-folds and 0.71 +/- 0.10-folds of the sham-operated knee, respectively). CONCLUSION: Early intraarticular injection of HA attenuates the progression of cartilage destruction in the ACLT knee, and the downregulation of the cystine/glutamate antiporter system [Formula: see text] was accompanied by the progression of OA. PMID- 23020699 TI - A randomised crossover trial comparing a single-use polyvinyl chloride laryngeal mask airway with a single-use silicone laryngeal mask airway. AB - We compared insertion rates of single-use polyvinyl chloride laryngeal mask airways (LMAs) vs single-use silicone LMAs in 72 anaesthetised patients. Both airways were produced by Flexicare Medical. Laryngeal mask airway insertion was successful on the first attempt in 68/72 (94%) polyvinyl chloride LMAs vs 64/72 (89%) silicone LMAs (p = 0.39). Overall insertion rates were 72/72 (100%) for the polyvinyl chloride LMAs and 71/72 (99%) for the silicone LMAs (p = 1.0). Mean (SD) insertion times were similar for polyvinyl chloride and silicone LMAs: 24.3 (5.1)s vs 24.8 (7.8)s (p = 0.64). Laryngeal mask airway position, as assessed using a fibrescope, was not different (p = 0.077). The median (IQR [range]) leak pressure was 16 (12-20 [6-30]) cmH(2) O for the polyvinyl LMA and 18 (13-22 [6 30]) cmH(2) O or the silicone LMA (p = 0.037). In conclusion, we did not find any important differences between polyvinyl chloride and silicone laryngeal mask airways. PMID- 23020700 TI - An interview with Roger Kirby, MA, MD, FRCS (Urol), FEBU. Interview by John Fitzpatrick. PMID- 23020701 TI - A novel technique to limit renal warm ischaemia time during laparoscopic partial nephrectomy. PMID- 23020702 TI - Apples and oranges: comparison of treatment methods for prostate cancer using biochemical recurrence as an endpoint. PMID- 23020703 TI - Management of severe blunt renal trauma in adult patients: a 10-year retrospective review from an emergency hospital. PMID- 23020704 TI - Another virtual issue available online. PMID- 23020706 TI - Virulence of the Pseudomonas fluorescens clinical strain MFN1032 towards Dictyostelium discoideum and macrophages in relation with type III secretion system. AB - BACKGROUND: Pseudomonas fluorescens biovar I MFN1032 is a clinical isolate able to grow at 37 degrees C. This strain displays secretion-mediated hemolytic activity involving phospholipase C and cyclolipopeptides, and a cell-associated hemolytic activity distinct from the secreted hemolytic activity. Cell-associated hemolysis is independent of biosurfactant production and remains in a gacA mutant. Disruption of the hrpU-like operon (the basal part of type III secretion system from rhizospheric strains) suppresses this activity. We hypothesized that this phenotype could reflect evolution of an ancestral mechanism involved in the survival of this species in its natural niche. In this study, we evaluated the hrpU-like operon's contribution to other virulence mechanisms using a panel of Pseudomonas strains from various sources. RESULTS: We found that MFN1032 inhibited the growth of the amoebae Dictyostelium discoideum and that this inhibition involved the hrpU-like operon and was absent in a gacA mutant. MFN1032 was capable of causing macrophage lysis, if the hrpU-like operon was intact, and this cytotoxicity remained in a gacA mutant. Cell-associated hemolytic activity and macrophage necrosis were found in other P. fluorescens clinical isolates, but not in biocontrol P. fluorescens strains harbouring hrpU-like operon. The growth of Dictyostelium discoideum was inhibited to a different extent by P. fluorescens strains without correlation between this inhibition and hrpU-like operon sequences. CONCLUSIONS: In P. fluorescens MFN1032, the basal part of type III secretion system plays a role in D. discoideum growth inhibition and macrophage necrosis. The inhibition of D. discoideum growth is dependent on the GacS/GacA system, while cell-associated hemolytic activity and macrophage lysis are not. Virulence against eukaryotic cells based on the hrpU-like operon may be more than just a stochastic evolution of a conserved system dedicated to survival in competition with natural predators such as amoebae. It may also mean that there are some important modifications of other type III secretion system components, which remain unknown. Cell-associated hemolysis might be a good indicator of the virulence of Pseudomonas fluorescens strain. PMID- 23020707 TI - Discordance between anaplastic lymphoma kinase status in primary non-small-cell lung cancers and their corresponding metastases. AB - AIMS: The anaplastic lymphoma kinase gene (ALK) has attracted considerable attention as a potential molecular target in non-small-cell lung cancer (NSCLC). However, it is unclear whether ALK alterations are acquired during the metastatic progression of NSCLC. METHODS AND RESULTS: ALK status and ALK expression were evaluated in a series of 67 primary NSCLCs and their corresponding metastatic lesions using fluorescence in-situ hybridization and immunohistochemistry. ALK rearrangement was detected in 7.5% (5/67) of the primary tumours and in 9.0% (6/67) of the metastases (P < 0.001). ALK copy number gain (CNG) was detected in 1.5% (1/67) of the primary tumours and in 35.8% (24/67) of the metastases. Whereas ALK rearrangement was detected only in adenocarcinomas, CNG was identified in various histological subtypes of NSCLC. ALK expression was detected in 11.9% (8/67) of the primary tumours and in 25.4% (17/67) of the metastatic lesions. CONCLUSIONS: ALK alteration and ALK expression can be acquired during metastatic progression in NSCLC, and ALK CNG is associated with ALK expression. PMID- 23020708 TI - Recurrent perianal red plaque with superficial erosions and pustular exudate in a 16-month-old boy. PMID- 23020709 TI - Atmospheric concentrations of polycyclic aromatic hydrocarbons in the watershed of Lake Victoria, East Africa. AB - In the first study of its kind in Africa, PAHs were measured in high volume (24 h) air samples collected from two sampling stations, at Kakira and Entebbe (KAK and EBB, respectively) within the Lake Victoria watershed in Uganda, to assess source contributions and generate a baseline reference data set for future studies in the East African region. Sampling was conducted over two periods [2000 2004 (KAK and EBB1) and 2008-2010 (EBB2)]. The samples were extracted by accelerated solvent extraction and analyzed for 30 PAHs by GC-MS. The mean total PAH concentrations (ng/m(3)) were found to be 74.3 (range; 19.3-311, N = 39) for KAK, 56.8 (range; 13.3-126, N = 22) for EBB1 and 33.1 (range; 4.91-108, N = 56) for EBB2. The 3-ringed PAHs were the most predominant group with mean concentrations of 35.9 ng/m(3)(EBB1), 30.5 ng/m(3)(KAK) and 23.2 ng/m(3)(EBB2). Naphthalene had an exceptionally high mean concentration (21.9 ng/m(3)) for KAK compared to 0.44 and 0.39 ng/m(3) in EBB1 and EBB2 respectively, likely due to intensive agricultural operations nearby KAK. Principal component and diagnostic ratio analyses showed that the measured levels of PAHs were associated with mixed sources, combustion of petroleum, and biomass being the major sources. PMID- 23020710 TI - Cost-of-illness of leg ulcers in the community. AB - Leg ulcer management is complex, time-consuming and of high socio-economic importance. Data on cost-of-illness in leg ulcer care are sparse. The objective of this study was to evaluate the cost-of-illness in leg ulcer treatment in the metropolitan area of Hamburg. About 147 institutions involved in wound care participated in a cross-sectional study. Patients consecutively recruited underwent a standardised interview and clinical examination. Main economic outcomes were direct, indirect and intangible costs from a societal perspective. Five hundred and two patients with a mean age of 71 years and mean wound duration of 9 years were enrolled. Annual total costs summed up to a mean of 9060? /patient/year (8288? direct, 772? indirect costs). Direct costs carried by statutory health insurances amounted to 7680? , patients themselves paid on average 607?. Leg ulcer is associated with high costs for health insurances, patients and the society. Exploratory predictor analyses suggest that early, interprofessional disease-management could lower treatment costs. PMID- 23020711 TI - Quetiapine fumarate augmentation for patients with a primary anxiety disorder or a mood disorder: a pilot study. AB - BACKGROUND: Comorbid anxiety symptoms,in patients with a primary anxiety disorder or a mood disorder, leads to poor patient outcomes and burdens the healthcare system. This pilot study evaluated the feasibility of extended-release quetiapine fumarate (quetiapine XR) for the treatment of patients with either a primary anxiety disorder or a mood disorder with comorbid anxiety symptoms compared to a placebo, as an adjunct to antidepressant therapy. METHODS: Thirty-nine patients with a diagnosis of a primary anxiety disorder or a mood disorder with comorbid anxiety symptoms were enrolled in this study. Patients with a stable dose of antidepressant therapy were randomized according to a 2:1 probability of receiving either quetiapine XR or a placebo adjunctive treatment for 8 weeks. The efficacy was assessed by the Hamilton Anxiety Rating Scale (HAM-A) and the Clinical Global Impression of severity (CGI-S) score at baseline, week 1, 4, and 8. RESULTS: A total of 35 patients were included in this intention-to treat (ITT) population for the efficacy analysis (quetiapine XR: 22 patients; placebo: 13 patients). At week 4, statistically significant differences were observed on both the HAM-A score (p = 0.003) and the CGI-S score (p = 0.025), favouring the quetiapine XR (-13.00 +/- 4.14) compared to placebo (-6.63 +/- 5.42). However, no statistically significant difference was observed between the two groups with regard to changes from the baseline to week 8 on the HAM-A score (p = 0.332) or the CGI-S score (p = 0.833). CONCLUSIONS: Augmentation of antidepressant treatment with quetiapine XR did not result in clinical improvement according to the outcome measure of anxiety using the HAM-A and CGI-S scores at week 8, among the patients with either a primary anxiety disorder or a mood disorder with comorbid anxiety symptoms. However, treatment with quetiapine XR as an adjunct to antidepressant therapy appeared to provide a short-term benefit at 4 weeks. Further study is needed with a larger sample size, randomized controlled design and control of the dosage prescribed. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00912535. PMID- 23020712 TI - Diagnostic utility of urine protein-to-creatinine ratio for identifying proteinuria in pregnancy. AB - OBJECTIVE: To evaluate urine protein-to-creatinine ratio (UPC) alone and with uric acid and clinical factors to predict or exclude significant proteinuria in preeclampsia evaluations. METHODS: Retrospective cohort study patients undergoing evaluation for preeclampsia. Greater than 300 mg of protein in a 24-h collection was the gold standard defining proteinuria against which UPC performance was measured. Bivariable, multivariable, and Receiver Operating Characteristic Curve (ROC) analyses were performed. Sensitivity, specificity, predictive values, and likelihood ratios were calculated for multiple cut-points of UPC alone and with uric acid. RESULTS: In a cohort of 356 patients, the area under the curve for UPC in the diagnosis of proteinuria was 0.81. No single cut-point of UPC was diagnostic of preeclampsia. UPC values <=0.08 or >=1.19 have useful negative or positive predictive values of 86% and 96%. Uric acid and clinical factors did not improve the detection of significant proteinuria. CONCLUSION: Extreme values of UPC ratio <=0.08 or >=1.19 have favorable predictive values, which could enable the rapid diagnosis of preeclampsia without a 24-h urine collection. PMID- 23020714 TI - Cigarette smoking and impulsivity in bipolar disorder. AB - OBJECTIVES: There is a high prevalence of smoking among individuals with bipolar disorder, yet there have been few efforts to identify potential contributing factors as a means of improving prevention and treatment approaches. The goal of this study was to examine the association between impulsivity and the initiation or maintenance of smoking in bipolar disorder. METHODS: Participants comprised 97 adolescents and adults, ages 16-50, with bipolar I disorder who were experiencing a mixed or manic episode at the time of study enrollment. Participants completed the Barratt Impulsiveness Scale-11 (BIS-11) as a self-report indicator of trait impulsivity, and the Logan Stop-Signal Task (SST), Delayed Reward Task (DRT), and Degraded Stimulus Continuous Performance Task (DSCPT) as behavioral measures of impulsivity. RESULTS: Current smokers (34%) and former smokers (23%) generally reported higher trait impulsivity on the BIS-11 than never smokers (43%), with minimal evidence for differences among the two ever-smoking groups. No differences in impulsivity by smoking status emerged on the behavioral measures. CONCLUSIONS: Trait impulsivity is associated with the initiation, but not necessarily the maintenance, of cigarette smoking in adolescents and adults with bipolar disorder. Our findings provide no evidence that smoking is associated with impulsive responding on cognitive tasks during a symptomatic period during which impulsivity is elevated. PMID- 23020716 TI - Detection of silicone in lung tissue. PMID- 23020718 TI - Tertium non datur? Legitimacy of a third diagnostic category in melanocytic lesions. PMID- 23020719 TI - The transformation of pathology: proceedings of the Houston Lung Symposium. PMID- 23020720 TI - Precision medicine for lung cancer: role of the surgical pathologist. AB - Precision medicine is altering the traditional role of the surgical pathologist in caring for patients with lung cancer. Diagnosing specific cell type is now a foundation for selecting lung cancers for predictive-biomarker testing by molecular techniques. Using conventional techniques and familiar equipment, the surgical pathologist's role goes beyond this important step and will include screening for, and possibly diagnosis of, predictive biomarkers as we illustrate for one predictive biomarker. Pathologists should embrace the innovations described at the Houston Lung Symposium but must recognize that their traditional expertise will be an important component of precision medicine for the foreseeable future. PMID- 23020721 TI - Classification of lung cancer: proposals for change? AB - Clinical need and developments in pathology and molecular biology require our cancer classifications to be constantly updated to keep them relevant and useful. A review of lung cancer classification is due and has been initiated with new proposals on classification of lung adenocarcinoma. Other major lung cancer types also deserve a similar consideration. As well as addressing the categories of tumor, as signed out in surgical resection specimens, recent proposals on small diagnostic-sample reporting would be an important addition to any new classification. The huge increase in data on the molecular biology of lung cancer has improved our understanding of these diseases, has driven improved therapy for some patients, and must be reflected in the way lung cancer is classified. PMID- 23020722 TI - Dilemmas in lung cancer staging. AB - The TNM staging system is the most important prognostic factor for lung cancer. The most encountered difficulties in pathologic staging of lung cancer include assessment of pleural invasion, synchronous tumor nodules, and lymph node sampling. PMID- 23020723 TI - Molecular diagnostics of lung cancers at the Brigham and Women's Hospital and Dana-Farber Cancer Institute: technology in rapid evolution. AB - The past 9 years have seen a remarkable shift in the diagnostic and therapeutic approach to lung carcinomas, beginning with the discovery of EGFR mutations and their role in directing management with targeted tyrosine kinase inhibitors. This special review recounts the experiences at one molecular diagnostic testing center, the Brigham and Women's Hospital/Dana-Farber Cancer Institute, from the initial research observations in 2003 to the development of multigene next generation sequencing in 2012. Throughout this time, the activities in the molecular diagnostics laboratory have been in a state of rapid flux, responding to changes in clinical needs and scientific discoveries. PMID- 23020724 TI - Treatment of ALK-positive non-small cell lung cancer. AB - Crizotinib (Xalkori), the first inhibitor of both anaplastic lymphoma kinase (ALK) and c-Met receptor kinases, has been approved in the United States, Korea, and other countries for the treatment of ALK-positive non-small cell lung cancer (NSCLC). This approval came within just 4 years of the discovery of rearrangements in the ALK gene in a subset of patients with NSCLC. Oral crizotinib 250 mg twice daily showed excellent efficacy in patients with advanced ALK-positive NSCLC, with objective response rates of 61% and 51% in ongoing phase I and II studies, respectively. Objective response rates of current standard, single-agent, second-line therapies are less than 10%. Median progression-free survival was 10 months (95% confidence interval, 8.2-14.7) in the phase I study expanded cohort and has yet to be reached in the phase II study; progression-free survival with current therapies is less than 3 months. Crizotinib was well tolerated; grade 1/2 gastrointestinal toxicity and visual disturbances were the most common adverse events. Patients in the phase II study reported improvements in fatigue, dyspnea, and cough, based on quality of life assessments. Phase III studies investigating crizotinib for the first- and second-line treatment of advanced ALK-positive NSCLC, versus current standards of care, are ongoing. Crizotinib represents a new standard of care for patients with ALK-positive NSCLC and highlights the importance of the role of the pathologist, as molecular profiling becomes a part of initial workups for newly diagnosed patients with NSCLC. This approach will ensure effective individualized treatment for patients with NSCLC. PMID- 23020725 TI - Strategies for overcoming acquired resistance to epidermal growth factor receptor: targeted therapies in lung cancer. AB - Acquired resistance to targeted therapy in epidermal growth factor receptor (EGFR)-mutant lung cancer represents a valuable model for considering strategies of overcoming different types of cellular resistance mechanisms. Using existing data on resistance in EGFR-mutant lung cancer, this review will discuss 3 basic approaches for overcoming resistance to EGFR-targeted therapies: intensification of EGFR inhibition, combination of EGFR inhibitors with other targeted therapies, and changing to anticancer therapies acting via alternate pathways. PMID- 23020726 TI - Advancing personalized cancer medicine in lung cancer. AB - Although improvements in genomic technologies during the past decade have greatly advanced our understanding of the genomic alterations that contribute to lung cancer, and the disease has (to a degree) become a paradigm for individualized cancer treatment in solid tumors, additional challenges must be addressed before the goal of personalized cancer therapy can become a reality for lung cancer patients. PMID- 23020727 TI - The separation of benign and malignant mesothelial proliferations. AB - CONTEXT: The separation of benign from malignant mesothelial proliferations is crucial to patient management but is often a difficult problem for the pathologist. OBJECTIVE: To review the pathologic features that allow separation of benign from malignant mesothelioma proliferations, with an emphasis on new findings. DATA SOURCES: Literature review and experience of the authors. CONCLUSIONS: Invasion is still the most reliable indicator of malignancy. The distribution and amount of proliferating mesothelial cells are important in separating benignity from malignancy, and keratin stains can be valuable because they highlight the distribution of mesothelial cells. Hematoxylin-eosin examination remains the gold standard, and the role of immunochemistry is extremely controversial; we believe that at present there is no reliable immunohistochemical marker of malignancy in this setting. Mesothelioma in situ is a diagnosis that currently cannot be accurately made by any type of histologic examination. Desmoplastic mesotheliomas are characterized by downward growth of keratin-positive spindled cells between S100-positive fat cells; some cases of organizing pleuritis can mimic involvement of fat, but these fat-like spaces are really S100-negative artifacts aligned parallel to the pleural surface. Fluorescence in situ hybridization on tissue sections to look for homozygous p16 gene deletions is occasionally useful, but many mesotheliomas do not show homozygous p16 deletions. Equivocal biopsy specimens should be diagnosed as atypical mesothelial hyperplasia and another biopsy requested if the clinicians believe the process is malignant. PMID- 23020728 TI - Neoplastic and nonneoplastic benign mass lesions of the lung. AB - While most lung neoplasms are malignant, a subset of true neoplasms are benign, the most common of which are pulmonary hamartomas. In addition, a substantial proportion of lung mass lesions are nonneoplastic; granulomas are among the commonly encountered nonneoplastic masses. There is also a group of relatively rare, mainly inflammatory and fibrous tumor-like lesions that are encountered on core biopsy and excisions of lung tissue. PMID- 23020729 TI - Update for pathologists on idiopathic interstitial pneumonias. AB - CONTEXT: Idiopathic interstitial pneumonias are a subset of diffuse pulmonary interstitial diseases classified by international consensus in 2002 as idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonia, and lymphoid interstitial pneumonia. Each is associated with a characteristic histopathologic pattern. In 2011, updated consensus guidelines were released for diagnosis and management of idiopathic pulmonary fibrosis. The entire group of idiopathic interstitial pneumonias is currently undergoing refinement, with updates expected in a forthcoming consensus classification. Many of these recent and anticipated changes are relevant to pathologists. OBJECTIVES: To review international consensus guidelines for diagnosis of idiopathic pulmonary fibrosis and other idiopathic interstitial pneumonias and to discuss recent and expected future classification updates. DATA SOURCES: Published peer-reviewed literature and personal experience of the authors. CONCLUSIONS: Diagnosis of idiopathic interstitial pneumonias by multidisciplinary discussion among clinicians, radiologists, and pathologists is now strongly encouraged. Diagnosis of idiopathic pulmonary fibrosis no longer requires surgical lung biopsy; high resolution computed tomography is an acceptable surrogate. In the context of clinical trials, pathologists are being asked to assign levels of confidence for histologic diagnosis of usual interstitial pneumonia in patients with idiopathic pulmonary fibrosis. Acute exacerbation of idiopathic pulmonary fibrosis is now accepted and should be considered when acute lung injury is superimposed on a background of usual interstitial pneumonia. The updated classification of idiopathic interstitial pneumonias will include a separate category for rare entities, including lymphoid interstitial pneumonia and idiopathic pleuroparenchymal fibroelastosis. PMID- 23020730 TI - Pleuropulmonary pathology in patients with rheumatic disease. AB - Thoracic manifestations of rheumatic disease (RD) are increasingly recognized as a significant cause of morbidity and mortality worldwide. Rheumatologic underpinnings have been identified in a significant proportion of patients with interstitial lung disease. The 5 RDs most frequently associated with pleuropulmonary disease are (1) rheumatoid arthritis, (2) systemic lupus erythematosus, (3) progressive systemic sclerosis, (4) polymyositis/dermatomyositis, and (5) Sjogren syndrome. The onset of thoracic involvement in these diseases is variable. In some patients, it precedes the systemic disease or is its only manifestation. Moreover, there is a wide spectrum of clinical presentation ranging from subclinical abnormalities to acute respiratory failure. Histopathologically, the hallmark features of thoracic involvement by RD are inflammatory, targeting one or more lung compartments. The reactions range from acute to chronic, with remodeling by fibrosis being a common result. Although the inflammatory findings are often nonspecific, certain reactions or anatomic distributions may favor one RD over another, and occasionally, a distinctive histopathology may be present (eg, rheumatoid nodules). Three diagnostic dilemmas are encountered in patients with RD who develop diffuse lung disease: 1) opportunistic infection in the immunocompromised host, 2) drug toxicity related to the medications used to treat the systemic disease, and 3) manifestations of the patient's known systemic disease in lung and pleura. To confidently address the latter, the 5 major RDs are presented here, with their most common pleuropulmonary pathologic manifestations, accompanied by brief clinical and radiologic correlations. PMID- 23020731 TI - Pathologic quantification of connective tissue disease-associated versus idiopathic usual interstitial pneumonia. AB - CONTEXT: Usual interstitial pneumonia (UIP) is a common chronic interstitial pneumonitis. It can occur idiopathically (I-UIP) or in the setting of systemic connective tissue disease (CTD-UIP). Some studies suggest that CTD-UIP has a better prognosis than I-UIP. The histologic differences between CTD-UIP and I-UIP are not clearly defined. OBJECTIVE: The purpose of this study was to evaluate histologic criteria that may differentiate CTD-UIP from I-UIP, including fibroblastic foci (FFs), lymphoid aggregates (LAs), and the presence of nonspecific interstitial pneumonia pattern. DESIGN: Thirty-five patients with histologic diagnoses of UIP were identified (27 biopsies [77%]; 8 explants [23%]). Biopsy slides were scanned and analyzed quantitatively for FF size, FF area, LA size, and LA area. Biopsy and explant slides were examined qualitatively for the presence of a nonspecific interstitial pneumonia pattern in areas away from UIP fibrosis. Results.-Of 27 biopsies, the number and size of FFs in CTD-UIP were smaller than they were in I-UIP. The number and size of LAs were larger in patients with rheumatoid arthritis than they were in patients with I-UIP. There was no interobserver variability among 3 pathologists using this quantitative system. Of 35 biopsies and explants, there was a higher prevalence of the nonspecific interstitial pneumonia pattern among patients with CTD-UIP than there was among patients with I-UIP (P = .005). CONCLUSIONS: Patients with CTD-UIP had fewer, smaller FFs than did patients with I-UIP, and patients with rheumatoid arthritis-UIP had more, larger LAs than did patients with I-UIP. Of importance, the coexistence of UIP and the nonspecific interstitial pneumonia patterns was one of the most salient features in distinguishing CTD-UIP from I-UIP because CTD UIP demonstrated an increased prevalence of multilobar, cellular, nonspecific interstitial pneumonia patterns in areas away from the UIP fibrosis. PMID- 23020732 TI - Negative loop electrosurgical cone biopsy finding following a biopsy diagnosis of high-grade squamous intraepithelial lesion: frequency and clinical significance. AB - CONTEXT: Loop electrosurgical excision procedure (LEEP) is a therapeutic option following biopsy diagnosis of high-grade squamous intraepithelial lesion (HSIL). Most LEEPs will confirm the HSIL biopsy diagnosis but a number of them will not. Such negative findings suggest the possibility of an incorrect biopsy diagnosis, removal of the lesion by biopsy, or insufficient LEEP sampling. OBJECTIVE: To determine the frequency of negative LEEP findings following HSIL biopsies and better understand the clinical significance of negative LEEP findings. DESIGN: The Department of Pathology's records were searched for all patients undergoing LEEP excision who had prior cervical biopsies and subsequent clinical follow-up. RESULTS: Three hundred seventy-eight women were found who had index biopsies, subsequent LEEPs, and clinical follow-up averaging 25.8 months. Three hundred six women had HSIL on biopsy with 223 (73%) showing HSIL on LEEP. Seventy-three (24%) LEEPs in women with HSIL index biopsy results yielded negative findings or disclosed low-grade squamous intraepithelial lesion (LSIL). Twenty-nine of 223 patients (13%) with an HSIL result both on biopsies and LEEPs had HSIL on biopsy and/or excisional clinical follow-up. Seven of 73 patients (10%) with positive (HSIL) biopsy results but negative LEEP findings or LSIL had HSIL on biopsy and/or excisional follow-up. CONCLUSIONS: Twenty-four percent of patients with HSIL on biopsy had negative findings or LSIL on LEEP. There is no statistical difference in development of HSIL after LEEP for those with positive biopsy and positive LEEP results (13%) versus positive biopsy and negative LEEP results (10%). The occurrence of a negative LEEP finding following a positive biopsy finding was frequent (24%) and does not portend a different clinical follow-up from a positive biopsy and positive LEEP result. PMID- 23020733 TI - Potassium but not lactate dehydrogenase elevation due to in vitro hemolysis is higher in capillary than in venous blood samples. AB - CONTEXT: Elevated potassium concentrations due to in vitro hemolysis can lead to errors in diagnoses and treatment. Recently, we observed that potassium elevation in capillary samples appeared higher than expected, based on hemolytic index (H index). OBJECTIVE: To investigate the relation between potassium increase and H index for capillary samples. As a control, the same analysis was performed for lactate dehydrogenase (LDH). DESIGN: Potassium results of 332 760 venous and 2620 capillary samples were selected. For LDH, 135 974 venous and 999 capillary samples were included. Venous and capillary samples were differentiated by using patient age, as we perform mostly capillary blood sampling in children and venous sampling in adults. Results were obtained with Beckman-Coulter DxC800 analyzers. RESULTS: The increase in potassium with increasing H-index was considerably higher for capillary samples than venous samples. Linear regression revealed a potassium increase of 0.38 mEq/L per increment in H-index for capillary samples, whereas a 0.17 mEq/L increase was found for venous samples. For LDH, no differences were found between venous and capillary samples. CONCLUSIONS: At identical H-index, capillary samples showed higher potassium elevations than venous samples. A possible explanation is that capillary sampling causes increased leakage of ions, such as potassium, from erythrocytes, compared with proteins such as hemoglobin and LDH. These results are especially important considering the increasing use of whole blood point-of-care analyzers, where the H-index is often not determined. Potassium results should therefore be interpreted with caution to avoid severe misdiagnosis of hypokalemia and hyperkalemia. PMID- 23020734 TI - Solid papillary carcinoma of the breast: a pathologically and clinically distinct breast tumor. AB - Solid papillary carcinomas are tumors morphologically characterized by round, well-defined nodules composed of low-grade ductal cells separated by fibrovascular cores. These tumors are rare and affect predominantly older women. Although they are considered in situ carcinomas, debate and uncertainty still exist regarding their true nature, because immunohistochemistry for myoepithelial cells has shown absence of myoepithelial cell layer along the epithelial-stromal interface of the tumor in many cases. Clinically, these tumors present as a palpable, centrally located mass or as bloody nipple discharge. Pathologically, solid papillary carcinomas exhibit low-grade features, and often the tumors display neuroendocrine and mucinous differentiation. In the majority of cases an associated invasive carcinoma is present, with colloid and neuroendocrine carcinomas being the most common. The pathologic differential diagnosis is broad and ranges from benign to malignant lesions. The treatment for solid papillary carcinomas is surgical excision. When invasive carcinoma is not present, the prognosis is excellent. PMID- 23020735 TI - Cell death pathways in directly irradiated cells and cells exposed to medium from irradiated cells. AB - PURPOSE: The aim of this study was to compare levels of apoptosis, necrosis, mitotic cell death and senescence after treatment with both direct radiation and irradiated cell conditioned medium. MATERIALS AND METHODS: Human keratinocytes (HaCaT cell line) were irradiated (0.005, 0.05 and 0.5 Gy) using a cobalt 60 teletherapy unit. For bystander experiments, the medium was harvested from donor HaCaT cells 1 hour after irradiation and transferred to recipient HaCaT cells. Clonogenic assay, apoptosis, necrosis, mitotic cell death, senescence and cell cycle analysis were measured in both directly irradiated cells and bystander cells RESULTS: A reduction in cell survival was observed for both directly irradiated cells and irradiated cell conditioned medium (ICCM)-treated cells. Early apoptosis and necrosis was observed predominantly after direct irradiation. An increase in the number of cells in G2/M phase was observed at 6 and 12 h which led to mitotic cell death after 72 h following direct irradiation and ICCM treatment. No senescence was observed in the HaCaT cell line following either direct irradiation or treatment with ICCM. CONCLUSION: This study has shown that directly irradiated cells undergo apoptosis, necrosis and mitotic cell death whereas ICCM-treated cells predominantly undergo mitotic cell death. PMID- 23020736 TI - Radiological and micro-computed tomography analysis of the bone at dental implants inserted 2, 3 and 4 mm apart in a minipig model with platform switching incorporated. AB - BACKGROUND: The purpose of this study was to assess the effect of inter-implant distance on interproximal bone utilizing platform switching. Analysis of interproximal bone usually depends on traditional two-dimensional radiographic assessment. Although there has been increased reliability of current techniques, there has been an inability to track bone level changes over time and in three dimensions. Micro-CT has provided three-dimensional imaging that can be used in conjunction with traditional two-dimensional radiographic techniques. METHODS: This study was performed on 24 female minipigs. Twelve animals received three implants with an inter-implant distance of 3 mm on one side of the mandible and another three implants on the contra-lateral side, where the implants were placed 2 mm apart creating a split mouth design. Twelve other animals received three implants with an inter-implant distance of 3 mm on one side of the mandible and another three implants on the contra-lateral side, where the implants were placed 4 mm apart creating a split mouth design too. The quantitative evaluation was performed comparatively on radiographs taken at t 0 (immediately after implantation) and at t 8 weeks (after termination). The samples were scanned by micro-computed tomography (MUCT) to quantify the first bone to implant contact (fBIC) and bone volume/total volume (BV/TV). Mixed model regressions using the nonparametric Brunner-Langer method were used to determine the effect of inter implant distance on the measured outcomes. RESULTS: The change in bone level was determined using radiography and its mean was 0.05 mm for an inter-implant distance of 3 and 0.00 mm for a 2 mm distance (P = 0.7268). The mean of this outcome was 0.18 mm for the 3 mm and for 4 mm inter-implant distance (P = 0.9500). Micro-computed tomography showed that the fBIC was always located above the reference, 0.27 and 0.20 mm for the comparison of 2-3 mm (P = 0.4622) and 0.49 and 0.34 mm for the inter-implant distance of 3 and 4 mm (P = 0.1699). BV/TV inside the defined parallelepipedic masks reached 82.38% for the 2 mm inter implant distance and 85.00% for 3 mm, P = 0.8432. For the comparison of the 3-4 mm inter-implant distance, the means were 84.69% and 84.38%, respectively, P = 0.8401. Non-inferiority tests for the smaller inter-implant distances for both comparisons showed similar differences and similar tolerance ranges. CONCLUSION: The effect of a smaller interproximal distances between implants on bone level, fBIC and BV/TV assessed by two convergent investigation methods, radiology and MUCT, was similar to that of larger distances. Implants can potentially be placed 2 mm apart instead of 3 mm and 3 mm apart instead of 4 mm when platform switching is utilized. Further research with a conventional platform is warranted. PMID- 23020737 TI - Leidenfrost point reduction on micropatterned metallic surfaces. AB - Droplets are able to levitate when deposited over a hot surface exceeding a critical temperature. This is known as the Leidenfrost effect. This phenomenon occurs when the surface is heated above the so-called Leidenfrost point (LFP), above which the vapor film between the droplet and hot surface is able to levitate the droplet. Such a critical temperature depends on several factors. One of the most studied parameters has been the surface roughness. Almost all of the experimental studies in the literature have concluded that the LFP increases with the roughness. According to these results, it seems that the roughness is detrimental for the stability of the vapor film. In contrast with these results, we present here a micropatterned surface that significantly reduces the LFP. The temperature increase, relative to the boiling point, required to reach the LFP is 70% lower than that on the flat surface. The reasons for such an effect are qualitatively and quantitatively discussed with a simple semiempirical model. This result can be relevant to save energy in applications that take advantage of the Leidenfrost effect for drop control or drag reduction. PMID- 23020738 TI - Deep proteome profiling of circulating granulocytes reveals bactericidal/permeability-increasing protein as a biomarker for severe atherosclerotic coronary stenosis. AB - Coronary atherosclerosis represents the major cause of death in Western societies. As atherosclerosis typically progresses over years without giving rise to clinical symptoms, biomarkers are urgently needed to identify patients at risk. Over the past decade, evidence has accumulated suggesting cross-talk between the diseased vasculature and cells of the innate immune system. We therefore employed proteomics to search for biomarkers associated with severe atherosclerotic coronary lumen stenosis in circulating leukocytes. In a two-phase approach, we first performed in-depth quantitative profiling of the granulocyte proteome on a small pooled cohort of patients suffering from chronic (sub)total coronary occlusion and matched control patients using stable isotope peptide labeling, two-dimensional LC-MS/MS and data-dependent decision tree fragmentation. Over 3000 proteins were quantified, among which 57 candidate biomarker proteins remained after stringent filtering. The most promising biomarker candidates were subsequently verified in the individual samples of the discovery cohort using label-free, single-run LC-MS/MS analysis, as well as in an independent verification cohort of 25 patients with total coronary occlusion (CTO) and 19 matched controls. Our data reveal bactericidal/permeability increasing protein (BPI) as a promising biomarker for severe atherosclerotic coronary stenosis, being down-regulated in circulating granulocytes of CTO patients. PMID- 23020740 TI - Synthesis and evaluation of a photochromic surfactant for organic reactions in aqueous media. AB - A novel photochromic azobenzene-based surfactant was described for organic chemistry in water. The molecule 4-butylazobenzyl-4'-triazologlucuronic acid sodium salt thus synthesized can be isomerized from its trans to its cis form reversibly in solution by simple light irradiation. That property allowed the recyclability of a model acetylation reaction performed in the surfactant media, compared to the well-known, commercially available sodium dodecyl sulfate surfactant media. PMID- 23020739 TI - Apolipoprotein E acts at pre-synaptic sites...among others. PMID- 23020741 TI - Exploring audience segmentation: investigating adopter categories to diffuse an innovation to prevent famine in rural Mozambique. AB - Audience segmentation is a useful tool for designing effective campaigns. Further, the efficiency promised in diffusion science rests to some degree on the existence of adopter categories that can be identified and used to strategically disseminate prevention innovations. This study investigates the potential to identify adopter categories in potential recipients (n = 127) of an innovation to prevent food shortages in Mozambique. A 5-class model was found using latent class analysis, but it showed important differences from existing descriptions of adopter categories. Implications for theory and practice are discussed. PMID- 23020742 TI - Measuring and analyzing the causes of problematic Internet use. AB - Since Internet surfing became a daily activity, people have changed their behavior. This research analyzes the causes of problematic Internet use through an online survey, where 1,094 samples were collected. Based on the results of structural equation modeling analysis, the following conclusions are reached: First, novelty, security, and efficiency increase users' online trust. Second, information and efficiency enhance users' sharing and anonymity online. Third, greater trust in Internet environments leads to an increase in a user's cognitive bias toward online behavioral responsibility and Internet addiction. Fourth, a user's attitude toward online sharing further increases the cognitive bias toward online copyright. Fifth, a user's attitude toward anonymity increases cognitive bias toward online copyright, online behavioral responsibility, and deepens Internet addiction. PMID- 23020743 TI - News and the overloaded consumer: factors influencing information overload among news consumers. AB - News producers continue to increase their volume of production and delivery platforms in an effort to reach and maintain news consumers. However, consumers may not necessarily find more news desirable. Previous studies have suggested that information surplus can lead to negative outcomes for consumers, but research of outcomes related to news production and consumption has been scant. This study explores novel areas of news surplus and overload, empirically examining factors associated with the degree of perceived overload across a broad spectrum of news delivery platforms. The findings reveal that the majority of today's news consumers feel overloaded with the amount of news they are confronted with. Gender, news interest, and the use of specific news platforms and outlets predict the degree of that overload. News access through platforms and outlets such as computers, e-readers, and Facebook is positively associated with overload, whereas other platforms such as television and the iPhone are negatively associated with overload. Implications for media psychology and news consumption are discussed. PMID- 23020744 TI - Facebook, stress, and incidence of upper respiratory infection in undergraduate college students. AB - Having a large social network is generally beneficial to health. However, it is unclear how Internet-based social networks might influence health. Chronic stress can have negative health consequences, and some data suggest that Facebook could be a new source of psychological stress. Thus, we examined undergraduate college student perceptions of Facebook use and incidence of upper respiratory infections (URIs). We hypothesized that subjects with more diverse networks (i.e., more friends on Facebook) would have fewer URIs than their less diverse counterparts; that subjects reporting Facebook-induced stress would be more susceptible to URIs; and that subjects with more diverse networks who report Facebook-induced stress would be less susceptible to URIs than subjects with less diverse social networks who reported Facebook-induced stress. In this prospective study, healthy college students completed online questionnaires that assessed use and perceptions of Facebook and technology, and then were interviewed weekly for 10 weeks to track incidence of URI. URI episodes were defined by a symptom-based criterion. The social network size was significantly related to the rate of URI, such that, the larger the social network, the greater the incidence rate of URI. Most (85.7 percent) respondents experienced some degree of Facebook-induced stress. The effects of Facebook-induced stress on incidence of URI varied across the social network size, such that, the impact of stress on the URI incidence rate increased with the size of the social network. These results are largely in contrast to our hypotheses, but clearly suggest an association between Facebook use, psychological stress, and health. PMID- 23020745 TI - The female player does not exist: gender identity relates to differences in player motivations and play styles. AB - This study addresses the female player of massively multiplayer online (role playing) games and investigates how gender identity (GI), indicating a person's identification with characteristics that are traditionally defined as masculine or feminine, can be used to explain playing patterns within the female gender group. Results from an online survey (n=466) show that females' player motivations and play styles vary as a function of their GI, indicating that it is a relevant and additional predictor of play behavior and confirming that female play behavior cannot be generalized based on stereotypical male/female conceptions. PMID- 23020746 TI - Social network games uncovered: motivations and their attitudinal and behavioral outcomes. AB - This study explores motivations for playing games on social network sites as well as attitudinal and behavioral outcomes of those motivations. A total of 324 college students in the United States participated in an online survey. Found were the six motivations for playing social network games (SNG): social interaction, self-presentation, fantasy/role playing, passing time/escapism, entertainment, and challenge/competition. Further, the findings demonstrated that different types of motivations influenced attitudes toward playing SNG and intentions to engage in different social network gaming activities differentially. PMID- 23020747 TI - Pfizer Global Virtual Library (PGVL): a chemistry design tool powered by experimentally validated parallel synthesis information. AB - An unprecedented amount of parallel synthesis information was accumulated within Pfizer over the past 12 years. This information was captured by an informatics tool known as PGVL (Pfizer Global Virtual Library). PGVL was used for many aspects of drug discovery including automated reactant mining and reaction product formation to build a synthetically feasible virtual compound collection. In this report, PGVL is discussed in detail. The chemistry information within PGVL has been used to extract synthesis and design information using an intuitive desktop Graphic User Interface, PGVL Hub. Several real-case examples of PGVL are also presented. PMID- 23020748 TI - Effort and contribution of T-DNA Insertion mutant library for rice functional genomics research in China: review and perspective. AB - With the completion of the rice (Oryza sativa L.) genome-sequencing project, the rice research community proposed to characterize the function of every predicted gene in rice by 2020. One of the most effective and high-throughput strategies for studying gene function is to employ genetic mutations induced by insertion elements such as T-DNA or transposons. Since 1999, with support from the Ministry of Science and Technology of China for Rice Functional Genomics Programs, large scale T-DNA insertion mutant populations have been generated in Huazhong Agricultural University, the Chinese Academy of Sciences and the Chinese Academy of Agricultural Sciences. Currently, a total of 372,346 mutant lines have been generated, and 58,226 T-DNA or Tos17 flanking sequence tags have been isolated. Using these mutant resources, more than 40 genes with potential applications in rice breeding have already been identified. These include genes involved in biotic or abiotic stress responses, nutrient metabolism, pollen development, and plant architecture. The functional analysis of these genes will not only deepen our understanding of the fundamental biological questions in rice, but will also offer valuable gene resources for developing Green Super Rice that is high yielding with few inputs even under the poor growth conditions of many regions of Africa and Asia. PMID- 23020749 TI - Cochlin expression in the rat perilymph during postnatal development. AB - CONCLUSIONS: The changes in the cochlin isoforms in the perilymph may provide important insights to the understanding of cochlin function and the pathogenesis of related inner ear diseases. OBJECTIVES: Cochlin is involved in various pathologies of the inner ear. Altered levels of cochlin isoforms in developing inner ear tissue were reported previously. The purpose of this study was to elucidate the cochlin isoform expression in the perilymph of rats during postnatal development in relation to Coch gene mRNA expression. METHODS: We studied the cochlin isoforms in the rat perilymph during postnatal development by Western blot analysis. Real-time PCR was also performed to elucidate the expression level of Coch mRNA in the developing inner ear of rats. RESULTS: Western blot analysis showed that the expression of p63s in the perilymph was highest on the 12th day after birth (DAB12), the earliest age at which we could identify the perilymphatic space microscopically, and it decreased gradually as the cochlea developed. On the other hand, the expression of Cochlin-tomoprotein (CTP)was lowest on DAB12 and increased gradually up to DAB24. COCH mRNA was detected from DAB3 and gradually increased to DAB15, and then gradually decreased to DAB70. PMID- 23020750 TI - Gross generalized molluscum contagiosum in a patient with autosomal recessive hyper-IgE syndrome, which resolved spontaneously after haematopoietic stem-cell transplantation. PMID- 23020751 TI - Ethnicity, body mass index and risk of pre-eclampsia in a multiethnic New Zealand population. AB - BACKGROUND: Pre-eclampsia rates are reported to vary by ethnicity; however, few studies include body mass index (BMI). Increasing BMI has a dose-dependent relationship with pre-eclampsia, and rates of overweight and obesity as well as ratios of body fat to muscle mass differ between ethnicities. We hypothesised that after adjusting for confounders, including ethnic-specific BMI, ethnicity would not be an independent risk factor for pre-eclampsia. AIM: To assess independent pre-eclampsia risk factors in a multiethnic New Zealand population. METHODS: We performed a retrospective cohort analysis of prospectively recorded maternity data from 2006 to 2009 at National Women's Health, Auckland, New Zealand. After exclusion of infants with congenital anomalies and missing data, our final study population was 26 254 singleton pregnancies. Multivariable logistic regression analysis adjusted for ethnicity, BMI, maternal age, parity, smoking, social deprivation, diabetes, chronic hypertension and relevant pre existing medical conditions was performed. RESULTS: Independent associations with pre-eclampsia were observed in Chinese (adjusted odds ratio (aOR) 0.56, [95% CI 0.41-0.76]) and Maori (aOR 1.51, [1.16-1.96]) compared with European women. Other independent risk factors for pre-eclampsia were overweight and obesity, nulliparity, type 1 diabetes, chronic hypertension and pre-existing medical conditions. CONCLUSIONS: Contrary to our hypothesis, we report an independent reduced risk of pre-eclampsia in Chinese and increased risk of pre-eclampsia in Maori women. Prospective studies are required to further explore these relationships. Other independent risk factors are consistent with international literature. Our findings may assist clinicians to stratify risk of pre-eclampsia in clinical practice. PMID- 23020752 TI - Online preconcentration-IC-ICP-MS for selenium quantification and speciation at ultratraces. AB - Selenium (Se) is of key importance to human health with a very narrow concentration range of optimal dietary intake. Due to the inherent analytical challenge linked with the low natural abundance, information on precise and accurate Se speciation in deficient environments is hardly existent. This study presents a novel approach to determine Se species-specifically at ultratraces, by online coupling of a preconcentration (trap) column to an ion chromatography inductively coupled plasma mass spectrometry (IC-ICP-MS) system. It is demonstrated that with this robust and work/time efficient method, the predominant selenium oxyanions, selenite (Se(IV)) and selenate (Se(VI)), can be quantified down to 7.3 and 8.3 picogram total Se, respectively, in an overall analytical time of 420 s, only. The applicability for environmental samples was proven on pristine volcanic ashes collected from seven different volcanoes. The high sensitivity of the novel approach allowed to determine speciation in samples that were strongly depleted in total selenium (<0.05 mg kg(-1) Se) with only minor fractions of Se mobilized (i.e., less than 10% of the total selenium was leached in 10 out of 12 samples). The studied samples showed considerate differences in selenium speciation, with selenite and selenate co-occurring in most samples. The fact that the studied sample leachates had a wide range of pH (3.78-9.55) and major anion/cation composition underlines the versatility and wide potential application range of the method presented. PMID- 23020753 TI - Tannin derived materials can block swarming motility and enhance biofilm formation in Pseudomonas aeruginosa. AB - Surface-associated swarming motility is implicated in enhanced bacterial spreading and virulence, hence it follows that anti-swarming effectors could have clinical benefits. When investigating potential applications of anti-swarming materials it is important to consider whether the lack of swarming corresponds with an enhanced sessile biofilm lifestyle and resistance to antibiotics. In this study, well-defined tannins present in multiple plant materials (tannic acid (TA) and epigallocathecin gallate (EGCG)) and undefined cranberry powder (CP) were found to block swarming motility and enhance biofilm formation and resistance to tobramycin in Pseudomonas aeruginosa. In contrast, gallic acid (GA) did not completely block swarming motility and did not affect biofilm formation or tobramycin resistance. These data support the theory that nutritional conditions can elicit an inverse relationship between swarming motility and biofilm formation capacities. Although anti-swarmers exhibit the potential to yield clinical benefits, it is important to be aware of possible implications regarding biofilm formation and antibiotic resistance. PMID- 23020754 TI - Lymph node infarction: role of underlying malignancy, tumour proliferation fraction and vascular compromise--a study of 35 cases and a comprehensive review of the literature. AB - AIMS: To determine the roles of the presence of malignancy, tumour proliferation fraction, vascular compromise and therapeutic and diagnostic manipulations in lymph node infarction (LNI). METHODS AND RESULTS: Thirty-five cases of LNI were identified over a 20-year period. Of the 35 patients, 31 (89%) had an underlying malignancy: 27 of the 31 (87%) were haematologic malignancies, the rest being metastatic carcinoma (two), melanoma, and seminoma. Of the four patients without evidence of malignancy, two were diagnosed with viral infection, one had LNI adjacent to a thrombosed pancreas graft, and one was lost to follow up. Ki67 immunostaining in viable tumour demonstrated a range (5-60%) of proliferation fractions. A history of fine needle aspiration alone was present in seven of the 35 patients (20%), a history of chemotherapy alone in 11 (31%), and a history of both in two (5.7%). Factor VIII immunostaining highlighted thrombosed and recanalized vessels next to the infarction. CONCLUSIONS: Infarction of lymph nodes is associated with previous, concurrent or subsequent diagnosis of malignancy in the vast majority of cases. Chemotherapy or previous fine needle aspiration can precipitate infarction in some cases, but infarction may occur without such intervention, possibly because of an underlying subacute or chronic vascular compromise produced by vascular thrombosis. PMID- 23020755 TI - The anatomic impact of sequential, additional, ostial radiofrequency ablation following pulmonary vein cryo-isolation. AB - BACKGROUND: Although pulmonary vein (PV) stenosis is a serious complication of radiofrequency PV isolation, the anatomical impact of a combination of two energy sources on PV diameter has not been evaluated. The aim of this study was to evaluate the impact of supplementary point-by-point radiofrequency applications (following PV cryoablation) on the PV orifice diameter. METHODS: Forty-nine patients having undergone PV isolation for drug-refractory atrial fibrillation were included. All had undergone cardiac computed tomography before ablation and again at least 3 months afterwards. When isolation with the cryoballoon was not complete, a conventional irrigated-tip radiofrequency catheter was used for point by-point applications. RESULTS: Of the 189 target PVs, 117 were isolated with cryotherapy alone (cryo PVs) and 72 required additional radiofrequency (hybrid PVs). The second scan (performed an average of 11.4 +/- 5.4 months after) showed a decrease in diameter for all the hybrid PVs (17.2 +/- 2.6 to 16.3 +/- 3.4 mm; P = 0.037) but no change for the cryo PVs. This change was associated with a decrease in left superior pulmonary vein (LSPV) diameter (19.2 +/- 3.0 to 17.8 +/ 4.9 mm, P = 0.014). There were no changes in other veins. A subgroup analysis for the LSPV revealed a decrease for the hybrid PVs (18.8 +/- 3.6 to 15.9 +/- 7.1 mm, P = 0.046) but not for the cryo PVs. Significant PV stenosis was observed in three hybrid PVs (two severe stenosis of the LSPV and one moderate stenosis of the right inferior pulmonary vein) but not in cryo PVs (4.1% vs 0%, respectively; P = 0.023). CONCLUSIONS: Cryoballoon ablation of the PV with adjunct, focal, irrigated ostial RF applications may be associated with a higher risk of PV stenosis. PMID- 23020756 TI - Implication of 14-3-3epsilon and 14-3-3theta/tau in proteasome inhibition-induced apoptosis of glioma cells. AB - Proteasome inhibitors represent a novel class of anticancer agents that are used in the treatment of hematologic malignancies and various solid tumors. However, mechanisms underlying their anticancer actions were not fully understood. It has been reported that strong 14-3-3 protein expression is observed and associated with tumor genesis and progression of astrocytoma. In addition, global inhibition of 14-3-3 functions with a general 14-3-3 antagonist difopein induces apoptosis of human astrocytoma cells, validating 14-3-3 as a potential molecular target for anticancer therapeutic management. In the current study, for the first time we demonstrated that proteasome inhibitors downregulated 14-3-3epsilon and 14-3 3theta/tau in U87 and SF295 glioma cells. Overexpression of 14-3-3epsilon and 14 3-3theta/tau significantly suppressed apoptosis of human glioma cells induced by proteasome inhibitors. We also demonstrated that MG132 activated ASK1 and siASK1 compromised the MG132-induced apoptosis of glioma cells. Furthermore, overexpression of 14-3-3epsilon and 14-3-3theta/tau markedly suppressed activation of ASK1. Collectively, the current study supported that proteasome inhibitors, at least in part, caused cytotoxicity of glioma cells via downregulation of 14-3-3epsilon and 14-3-3theta/tau and subsequent activation of ASK1. PMID- 23020757 TI - Adenylate kinase 2 (AK2) promotes cell proliferation in insect development. AB - BACKGROUND: Adenylate kinase 2 (AK2) is a phosphotransferase that catalyzes the reversible reaction 2ADP(GDP) <-> ATP(GTP) + AMP and influences cellular energy homeostasis. However, the role of AK2 in regulating cell proliferation remains unclear because AK2 has been reported to be involved in either cell proliferation or cell apoptosis in different cell types of various organisms. RESULTS: This study reports AK2 promotion of cell proliferation using the lepidopteran insect Helicoverpa armigera and its epidermal cell line HaEpi as models. Western blot analysis indicates that AK2 constitutively expresses in various tissues during larval development. Immunocytochemistry analysis indicates that AK2 localizes in the mitochondria. The recombinant expressed AK2 in E. coli promotes cell growth and viability of HaEpi cell line by 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay. AK2 knockdown in larvae by RNA interference causes larval growth defects, including body weight decrease and development delay. AK2 knockdown in larvae also decreases the number of circulating haemocytes. The mechanism for such effects might be the suppression of gene transcription involved in insect development caused by AK2 knockdown. CONCLUSION: These results show that AK2 regulates cell growth, viability, and proliferation in insect growth and development. PMID- 23020758 TI - Patients' perceptions of podoconiosis causes, prevention and consequences in East and West Gojam, Northern Ethiopia. AB - BACKGROUND: Podoconiosis is a form of non-filarial elephantiasis that affects barefoot individuals in highland tropical areas. The disease presents with bilateral, asymmetric swelling of the legs, usually confined to below the knee. This study aimed to assess podoconiosis patients' perceptions of prevention, control, causes and familial clustering of the disease, and to document physical, social and economic impairments associated with the disease, with the ultimate aim of enabling development of tailored interventions in this region. METHODS: This descriptive study is part of the largest cross-sectional community-based household survey yet conducted on podoconiosis. It was completed in November and December, 2011, in Debre Eliyas and Dembecha Woredas of East and West Gojam Zones, northern Ethiopia, and consisted of a house-to-house census by community health workers followed by interviews of identified patients using a structured questionnaire. RESULTS: In the 17,553 households surveyed, 1,319 patients were identified. More male as compared to female patients were married (84.6% vs. 53.6%, chi(2) = 157.1, p < 0.0001) while more female as compared to male patients were divorced (22.5% vs. 3.6%, chi(2) = 102.3, p < 0.0001). Less than half of the study subjects believed podoconiosis could be prevented (37.5%) or controlled (40.4%) and many (41.3%) did not know the cause of podoconiosis. Two-fifths of the study subjects had a relative affected with podoconiosis. Approximately 13% of the respondents had experienced one or more forms of social stigmatization. The coping strategies adopted by patients to mitigate the physical impairments caused by podoconiosis were: working only occasionally (44.9%), avoiding physically demanding tasks (32.4%), working fewer hours (21.9%) or completely stopping work (8%). Most study subjects (96.4%) had noticed a decline in their income following the development of podoconiosis, and 78% said they were poorer than their healthy neighbours. CONCLUSION: This study shows that podoconiosis has strong psychosocial, physical and economic impacts on patients in East and West Gojam Zones of northern Ethiopia. Concerns related to familial clustering, poor understanding of the causes and prevention of podoconiosis all add to the physical burden imposed by the disease. Strategies that may ease the impact of podoconiosis include delivery of tailored health education on the causes and prevention of disease, involving patients in intervention activities, and development of alternative income-generating activities for treated patients. PMID- 23020759 TI - A budget impact analysis comparing a Hydrofiber(r) ; dressing to an alginate dressing in managing exuding venous leg ulcers in France. AB - An Excel model was developed to compare total costs (including primary and secondary dressings only) of Hydrofiber((r)) ; dressing (2010 branded price) versus an alginate dressing (generic or branded price) in managing exuding venous leg ulcers considering mean wear time and mean duration of exudate management phase, from the French Social Security perspective over 5 years (2011-2015). Budget impact (based on prevalence of venous leg ulcers in France) was estimated as the difference between scenario 1 (Hydrofiber((r)) ; versus alginate dressing usage proportion increasing slightly per year) and Scenario2 (proportion remaining at 2010 levels). Annual costs and net savings per patient for the dressings were calculated in analyses 1 and 2. Analysis 1 (28-day mean exudate management phase for both Hydrofiber((r)) ; and alginate dressing groups): total costs 66.82? Hydrofiber((r)) ;, 70.08? generic alginate, 77.0? branded alginate; net savings 3.26? and 10.18? for Hydrofiber((r)) ; versus generic and branded alginate. Analysis 2 (mean exudate management phase of 22.2 versus 28 days for Hydrofiber((r)) ; versus alginate): total costs 52.92?, 70.08? and 77.0?, and net savings 17.10? and 24.02?, accordingly. Total cost savings (budget impact scenario 1 minus scenario 2): Analysis 1 - 223 107? and 696 304? for Hydrofiber((r)) ; versus generic and branded alginate dressings, respectively; Analysis 2 - 1 169 845? and 1 643 042? accordingly. Sensitivity analyses indicated that results are reliable. This conservative analysis shows that effective exudate management using Hydrofiber((r)) ; dressing can produce sizeable cost savings. PMID- 23020760 TI - Influence of nitrate supplementation on VO2 kinetics and endurance of elite cyclists. AB - The present study examined if an elevated nitrate intake would improve VO(2) kinetics, endurance, and repeated sprint capacity in elite endurance athletes. Ten highly trained cyclists (72 +/- 4 mL O(2) /kg/min, mean +/- standard deviation) underwent testing for VO(2) kinetics (3 * 6 min at 298 +/- 28 W), endurance (120 min preload followed by a 400-kcal time trial), and repeated sprint capacity (6 * 20 s sprints, recovery 100 s) during two 6-day periods in randomized order with a daily ingestion of either 0.5 L beetroot (BR) juice to increase nitrate levels or a 0.5 L placebo (PLA) drink with blackcurrant juice. Plasma NOx (nitrate + nitrite) levels were higher (P < 0.01) in BR (147 +/- 102 and 159 +/- 103 MUM after 4 and 6 days of beverage intake, respectively) compared with PLA (41 +/- 10 and 40 +/- 7 MUM). VO(2) kinetics and exercise economy were the same in BR and PLA. Time-trial performance was similar with an average completion time of 18:20 and 18:37 min:s in BR and PLA, respectively, with average power outputs of 290 +/- 43 W in BR and 285 +/- 44 W in PLA. Peak and mean power during repeated sprinting were similar in BR and PLA. In contrast to observations in moderately trained subjects intake of BR juice had no effect on VO(2) kinetics and performance in elite cyclists. PMID- 23020761 TI - Clonal heterogeneity in patients with cytogenetically normal acute myeloid leukemia with NPM1 mutations. AB - The nucleophosmin 1 (NPM1) gene is one of the most commonly mutated genes in acute myeloid leukemia (AML), occurring in approximately 60% of adult cytogenetically normal AML (CN-AML). To date, these mutations have only been detected in cells of the myeloid lineage, whereas the potential clonal involvement of the lymphoid lineage is controversial. In our study, NPM1 mutations were analyzed using the highly sensitive real-time quantitative polymerase chain reaction (RQ-PCR) method on fluorescence-activated cell-sorted (FACS) purified different circulating mature cell populations in patients with NPM1-mutated CN-AML. As expected, NPM1 mutations were found in myeloid blood cells, including CD14(+) monocytes and CD66b(+) granulocytes. However, we were also able to detect NPM1 mutations in CD19(+) B cells and CD3(-)14(-)16(+)56(+) natural killer (NK) cells, albeit at lower levels. Surprisingly, mutations were also detected in CD3(+) T cells from all analyzed patients. Our data demonstrate that NPM1-mutated CN-AML originates in an early stem cell with both lymphoid and myeloid differentiation potential. PMID- 23020762 TI - The teen years. PMID- 23020763 TI - Picking up the pace: changes in method and frame for the health information national trends survey (2011-2014). AB - Health communication and health information technology influence the ways in which health care professionals and the public seek, use, and comprehend health information. The Health Information National Trends Survey (HINTS) program was developed to assess the effect of health communication and health information technology on health-related attitudes, knowledge, and behavior. HINTS has fielded 3 national data collections with the fourth (HINTS 4) currently underway. Throughout this time, the Journal of Health Communication has been a dedicated partner in disseminating research based on HINTS data. Thus, the authors thought it the perfect venue to provide an historical overview of the HINTS program and to introduce the most recent HINTS data collection effort. This commentary describes the rationale for and structure of HINTS 4, summarizes the methodological approach applied in Cycle 1 of HINTS 4, describes the timeline for the HINTS 4 data collection, and identifies priorities for research using HINTS 4 data. PMID- 23020764 TI - Using collaborative web technology to construct the health information national trends survey. AB - Scientists are taking advantage of web-based technology to work in new collaborative environments, a phenomenon known as Science 2.0. The National Cancer Institute created a web-based tool called HINTS-GEM, which allows a diverse group of stakeholders to collaborate in a virtual environment by providing input on content for the Health Information National Trends Survey (HINTS). This involved stakeholders providing new suggested content and commenting and rating on existing content. HINTS is a nationally representative survey of the US noninstitutionalized adult population. This article describes the conceptual development of HINTS-GEM and provides results of its use by stakeholders in creating an improved survey instrument. PMID- 23020765 TI - The value of serial plasma and cerebrospinal fluid nuclear and mitochondrial deoxyribonucleic acid levels in aneurysmal subarachnoid hemorrhage. AB - OBJECT: Increased plasma nuclear and mitochondrial DNA levels have been reported in critically ill patients, and extracellular DNA may originate from damaged tissues having undergone necrosis. This study tested the hypothesis that nuclear and mitochondrial DNA levels in CSF and plasma are substantially increased in patients with acute spontaneous aneurysmal subarachnoid hemorrhage (SAH) and decrease thereafter, such that nuclear and mitochondrial DNA levels may be predictive of treatment outcomes. METHODS: Serial nuclear and mitochondrial DNA levels in CSF and plasma from 21 adult patients with spontaneous aneurysmal SAH and 39 healthy volunteers who received myelography examinations during the study period were evaluated. RESULTS: Data showed that circulating plasma nuclear DNA concentrations and both nuclear and mitochondrial DNA levels in CSF significantly increased in patients with aneurysmal SAH on admission compared with the volunteers. In patients with poor outcome, the CSF nuclear and mitochondrial DNA levels were significantly higher on Days 1 and 4, and plasma nuclear DNA levels were significantly higher from Day 8 to Day 14. Higher CSF nuclear (> 85.1 ng/ml) and mitochondrial DNA levels (> 31.4 ng/ml) on presentation were associated with worse outcome in patients with aneurysmal SAH. CONCLUSIONS: Higher CSF DNA levels on presentation, rather than plasma DNA levels, are associated with worse outcomes in patients with acute spontaneous aneurysmal SAH. More prospective multicenter investigations are needed to confirm the predictive value of CSF and plasma DNA levels on outcome. PMID- 23020766 TI - Letters to the editor: Stenting and idiopathic intracranial hypertension. PMID- 23020767 TI - Letters to the editor: Esthesioneuroblastoma. PMID- 23020768 TI - Ocular neuromyotonia treated by microvascular decompression: usefulness of preoperative 3D imaging: case report. AB - Ocular neuromyotonia is a rare ocular motility disorder characterized by involuntary contraction of extraocular muscles resulting in paroxysmal diplopia. Although ocular neuromyotonia is reported as a rare complication after radiation therapy, there are a few cases of ocular neuromyotonia in the absence of irradiation. In the reported cases the possibility of vascular compression has been suggested on radiological imaging. The authors report a case of ocular neuromyotonia treated by microvascular decompression of the third cranial nerve, supporting the hypothesis that neurovascular compression may play a role in its pathogenesis. The usefulness of preoperative 3D imaging for microvascular decompression is also discussed. PMID- 23020769 TI - Neurotoxicity of Nigerian bonny light crude oil in rats. AB - Biometal accumulation may contribute to organ toxicity in individuals using the Nigerian bonny light crude oil (BLCO) for ailment management. We assessed the levels of biometals, antioxidant status, along with histomorphometric analysis to investigate the effect of BLCO, commonly use in folklore medicine, on the brain. Adult male Wistar rats were dosed by gavage with BLCO at 0, 200, and 800 mg/kg( 1) of BLCO for 7 days. Results showed the accumulation of iron, zinc, nickel and lead, in contrast to copper, in BLCO-treated rats. Administration of BLCO disrupted the brain's antioxidant system and significantly increased levels of hydrogen peroxide and lipid peroxidation. Although the Purkinje layer and maximum width of Purkinje cells were not affected, BLCO treatment significantly decreased molecular layer, granular layer, and density of Purkinje cells of the cerebellum. The neurotoxicity of BLCO may be the result of oxidative stress resulting from loss of biometal homeostasis as well as toxicant injury from other constituents of BLCO. PMID- 23020770 TI - Asp664 cleavage of amyloid precursor protein induces tau phosphorylation by decreasing protein phosphatase 2A activity. AB - Caspase cleavage of amyloid precursor protein (APP) has been reported to be important in amyloid beta protein (Abeta)-mediated neurotoxicity. However, the underlying mechanisms are not clearly understood. In this study, we explored the effect of caspase cleavage of APP on tau phosphorylation in relation to Abeta. We found that Asp664 cleavage of APP increased tau phosphorylation at Thr212 and Ser262 in N2A cells and primary cultured hippocampal neurons. Compared with wild type APP, protein phosphatase 2A (PP2A) activity was significantly increased when Asp664 cleavage was blocked by the D664A point mutation. Furthermore, we found that over-expression of C31 reduced PP2A activity. C31 binds directly to the PP2A catalytic subunit, through the asparagine, proline, threonine, tyrosine (NPTY) motif, which is essential for C31-induced tau hyperphosphorylation. However, it appears that the other fragment produced by Asp664 cleavage, Jcasp, modulates neither PP2A activity nor tau hyperphosphorylation. Asp664 cleavage and accompanying tau hyperphosphorylation were remarkably diminished by blockage of Abeta production using a gamma-secretase inhibitor. Taken together, our results suggest that Asp664 cleavage of APP leads to tau hyperphosphorylation at specific epitopes by modulating PP2A activity as a downstream of Abeta. Direct binding of C31 to PP2A through the C31-NPTY domain was identified as a mechanism underlying this effect. PMID- 23020771 TI - Controlled release using a polymer stereocomplex capsule through the selective extraction and incorporation of one capsule shell component. AB - Isotactic poly(methyl methacrylate) (it-PMMA)/syndiotactic poly(methacrylic acid) (st-PMAA) stereocomplex hollow capsules were fabricated by the deposition of stereocomplex films of it-PMMA and st-PMAA on silica particles by alternate layer by-layer assembly and the subsequent removal of the silica particles with aqueous HF. The selective extraction of st-PMAA from the it-PMMA/st-PMAA stereocomplex capsule shells was successfully carried out by immersion in a pH 6-9 aqueous solution. The incorporation of st-PMAA into the resulting porous capsule shells was performed by immersion in an acetonitrile/water (1/1) solution of st-PMAA. The controlled release of an encapsulated dye from the it-PMMA/st-PMAA hollow capsules was achieved by combining the selective extraction of st-PMAA from the capsule shells and the incorporation of st-PMAA into the resulting porous shells. PMID- 23020772 TI - Two new species of dicyemid (Dicyemida: Dicyemidae) from two Australian cephalopod species: Sepioteuthis australis (Mollusca: Cephalopoda: Loliginidae) and Sepioloidea lineolata (Mollusca: Cephalopoda: Sepiadariidae). AB - Two new species of dicyemid parasites from Dicyema are described from 2 species of Australian cephalopods, i.e., Dicyema calamaroceum n. sp. from Sepioteuthis australis Quoy and Gaimard, 1832 (southern calamary) collected from Spencer Gulf (SG) and Gulf St Vincent (GSV), South Australia (SA), Australia, and Dicyema pyjamaceum n. sp. from Sepioloidea lineolata Quoy and Gaimard, 1832 (striped pyjama squid), collected from SG, SA, Australia. Dicyema calamaroceum is a medium sized species that reaches approximately 2,400 MUm in length. The vermiform stages are characterized by having 31-34 peripheral cells, a conical calotte, and an axial cell that extends to the propolar cells. An anterior abortive axial cell is absent in vermiform embryos, and verruciform cells were not observed in nematogens and rhombogens. Infusoriform embryos consist of 39 cells; 2 nuclei are present in each urn cell, and the refringent bodies are solid. Dicyema pyjamaceum is smaller than D. calamaroceum, with a body length that reaches approximately 1,950 MUm. The vermiform stages are characterized by having 20-23 peripheral cells, a cap-shaped calotte that forms a cephalic swelling together with the parapolar cells, and an axial cell that extends to the propolar cells. An anterior abortive axial cell is absent in vermiform embryos. Verruciform cells and granules in propolar cells were observed in nematogens and rhombogens. Infusoriform embryos consist of 37 cells; 2 nuclei are present in each urn cell, and the refringent bodies are solid. This represents the first description of dicyemid parasites from Australia. PMID- 23020773 TI - Social cognition in bipolar disorder versus schizophrenia: comparability in mental state decoding deficits. AB - OBJECTIVES: Neuropsychological studies comparing patients with bipolar disorder (BD) to patients with schizophrenia (SZ) suggest milder cognitive deficits in BD patients and across a smaller range of functions. The present study investigated whether this pattern is also true for social cognition - a range of socially relevant abilities, including emotion perception and recognition, theory of mind, and social attributions - by comparing performance on measures of social cognition in patients with BD, SZ, and healthy participants. METHODS: One hundred and two patients with BD, 208 patients with SZ, and 132 healthy participants were assessed using a battery of tasks measuring basic neuropsychological and social cognition. RESULTS: We observed significant differences between patients with BD and healthy participants in a test of mental state decoding ('eyes task') that was at a level comparable to deficits seen in patients with SZ. By comparison, BD patients showed more subtle deficits in mental state reasoning ('hinting task') than those shown by patients with SZ. CONCLUSIONS: Mental state decoding difficulties are significant in BD. An important direction for further research will be to establish to what extent these deficits affect social and occupational functioning as a potential target for therapeutic intervention. PMID- 23020774 TI - Phase I trial of OTS11101, an anti-angiogenic vaccine targeting vascular endothelial growth factor receptor 1 in solid tumor. AB - OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.0, 2.0, or 3.0 mg of OTS11101 subcutaneously, once a week in a 28-day cycle. Three patients experienced grade 1 injection site reactions, which were the most frequent adverse events. Grade 2 proteinuria and hypertension each occurred in one patient. As other toxicities were generally mild, the maximum tolerated dose was not reached. Furthermore, we explored the induction of specific activated CTLs, and biomarkers related to angiogenesis. A pharmacodynamics study revealed that induction of specific CTLs was observed for a dose of 2.0 and 3.0 mg. The serum concentrations of soluble VEGF receptor 1 and 2 after vaccination increased significantly compared with baseline. A microarray was performed to give a comprehensive analysis of gene expression, suggesting that OTS11101 vaccination resulted in T cell activation in a clinical setting. In conclusion, OTS11101 was well tolerated in patients up to 3.0 mg once weekly and our biomarker analysis suggested that this anti angiogenesis vaccine is biologically active. PMID- 23020775 TI - Robust Gaussian graphical modeling via l1 penalization. AB - Gaussian graphical models have been widely used as an effective method for studying the conditional independency structure among genes and for constructing genetic networks. However, gene expression data typically have heavier tails or more outlying observations than the standard Gaussian distribution. Such outliers in gene expression data can lead to wrong inference on the dependency structure among the genes. We propose a l(1) penalized estimation procedure for the sparse Gaussian graphical models that is robustified against possible outliers. The likelihood function is weighted according to how the observation is deviated, where the deviation of the observation is measured based on its own likelihood. An efficient computational algorithm based on the coordinate gradient descent method is developed to obtain the minimizer of the negative penalized robustified likelihood, where nonzero elements of the concentration matrix represents the graphical links among the genes. After the graphical structure is obtained, we re estimate the positive definite concentration matrix using an iterative proportional fitting algorithm. Through simulations, we demonstrate that the proposed robust method performs much better than the graphical Lasso for the Gaussian graphical models in terms of both graph structure selection and estimation when outliers are present. We apply the robust estimation procedure to an analysis of yeast gene expression data and show that the resulting graph has better biological interpretation than that obtained from the graphical Lasso. PMID- 23020776 TI - Engineering vascularized bone graft with osteogenic and angiogenic lineage differentiated bone marrow mesenchymal stem cells. AB - Tissue-engineered bone provides a promising method for the rehabilitation of acquired bone defects and congenital deformities. However, generating a vascular supply to the engineered graft remains a major challenge. We report a novel strategy to engineer vascularized bone grafts with osteogenic and angiogenic lineage differentiated marrow mesenchymal stem cells (MSCs). MSCs were expanded to form an osteogenic cell sheet using a continuous culture method and a scraping technique under osteogenic culture conditions. Another portion of MSCs was directed to differentiate into highly proliferative endothelial progenitor cells (EPCs), which were then seeded onto the cell sheets. Cell sheet-EPC complexes were implanted subcutaneously in nude mice. Cell sheets without EPCs were also implanted as a control. The mice were sacrificed, and the samples were harvested for evaluation consisting of micro-CT scanning, histological analysis and scanning electronic microscopy 4 and 8 weeks after implantation. The results showed that cell sheets were composed of viable cells and extracellular matrix and showed apparent mineralization. The obtained EPCs could express the specific antigen marker of CD31 and form capillary-like structures in vitro. The osteogenic cell sheet-EPC complexes yielded well-vascularized bone grafts 4 and 8 weeks after implantation. Both bone density and vascular density were significantly higher in the cell sheet-EPC complex group than in the control group. The results demonstrated that the introduction of EPCs could not only generate a vascular network but also increase bone formation for cell sheet-based bone engineering. These findings suggest that the strategy of engineering bone grafts with osteogenic and angiogenic lineage differentiated MSCs has great potential for clinical applications to repair large bone defects. PMID- 23020777 TI - Brassinosteroid signaling network and regulation of photomorphogenesis. AB - In plants, the steroidal hormone brassinosteroid (BR) regulates numerous developmental processes, including photomorphogenesis. Genetic, proteomic, and genomic studies in Arabidopsis have illustrated a fully connected BR signal transduction pathway from the cell surface receptor kinase BRI1 to the BZR1 family of transcription factors. Genome-wide analyses of protein-DNA interactions have identified thousands of BZR1 target genes that link BR signaling to various cellular, metabolic, and developmental processes, as well as other signaling pathways. In controlling photomorphogenesis, BR signaling is highly integrated with the light, gibberellin, and auxin pathways through both direct interactions between signaling proteins and transcriptional regulation of key components of these pathways. BR signaling also cross talks with other receptor kinase pathways to modulate stomata development and innate immunity. The molecular connections in the BR signaling network demonstrate a robust steroid signaling system that has evolved in plants to orchestrate signal transduction, genome expression, metabolism, defense, and development. PMID- 23020778 TI - DNA repair and replication proteins as prognostic markers in melanoma. AB - AIMS: Elevated expression of DNA repair and replication genes has been reported in thick, non-fixed primary melanomas that subsequently went on to metastasize, when compared to non-recurrent primary tumours. This increased expression could contribute to the extreme resistance shown by melanoma to DNA-damaging chemotherapeutics. We have investigated the hypothesis that levels of key DNA repair and replication proteins are prognostic biomarkers in melanoma. METHODS AND RESULTS: We used a tissue microarray containing samples from all stages of melanomagenesis to investigate the hypothesis that levels of key DNA repair and replication proteins are prognostic biomarkers in a larger, more representative and readily available set of fixed primary melanomas. High expression of topoisomerase IIalpha (TOP2A), that relieves torsional stress during DNA replication, and XRCC5 (Ku80), required for DNA double-strand break repair, were associated with significantly worse survival. CONCLUSIONS: Two (XRCC5 and TOP2A) of seven DNA repair and replication proteins studied were prognostic for melanoma. PMID- 23020779 TI - Factors associated with presenting >12 hours after symptom onset of acute myocardial infarction among Veteran men. AB - BACKGROUND: Approximately 2/3 of Veterans admitting to Veterans Health Administration (VHA) facilities present >12 hours after symptom onset of acute myocardial infarction (AMI) ("late presenters"). Veterans admitted to VHA facilities with AMI may delay hospital presentation for different reasons compared to their general population counter parts. Despite the large descriptive literature on factors associated with delayed presentation in the general population, the literature describing these factors among the Veteran AMI population is limited. The purpose of this analysis is to identify predictors of late presentation in the Veteran population presenting with AMI to VHA facilities. Identifying predictors will help inform and target interventions for Veterans at a high risk of late presentation. METHODS: In our cross-sectional study, we analyzed a cohort of 335 male Veterans from nine VHA facilities with physician diagnosed AMI between April 2005 and December 2006. We compared demographics, presentation characteristics, medical history, perceptions of health, and access to health care between early and late presenting Veterans. We used standard descriptive statistics for bivariate comparisons and multivariate logistic regression to identify independent predictors of late presentation. RESULTS: Our cohort was an average of 64 +/- 10 years old and was 88% white. Sixty-eight percent of our cohort were late presenters. Bivariate comparisons found that fewer late presenters had attended at least some college or vocational school (late 53% vs. early 66%, p = 0.02). Multivariate analysis showed that presentation with ST-elevation myocardial infarction (STEMI) was associated with early presentation (OR = 0.4 95%CI [0.2, 0.9]) and >=2 angina episodes in the prior 24 hours (versus 0-1 episode) was associated with late presentation (OR = 7.5 95%CI [3.6,15.6]). CONCLUSIONS: A significant majority of Veterans presenting to VHA facilities with AMI were late presenters. We found few differences between early and late presenters. Having a STEMI was independently associated with early presentation and reporting >=2 angina episodes in the 24 hours prior to hospital admission was independently associated with late presentation. These independent predictors of early and late presentation are similar to what has been reported for the general population. Despite these similarities to the general population, there may be untapped opportunities for patient education within the VHA to decrease late presentation. PMID- 23020780 TI - A case-control study to examine the association between breastfeeding during late pregnancy and risk of a small-for-gestational-age birth in Lima, Peru. AB - Excessive demands on maternal nutritional status may be a risk factor for poor birth outcomes. This study examined the association between breastfeeding during late pregnancy (>= 28 weeks) and the risk of having a small-for-gestational-age (SGA) newborn, using a matched case-control design (78 SGA cases: birthweight <10th percentile for gestational age; 150 non-SGA controls: 50th percentile 300 fold higher than abiraterone exposure in plasma. The majority of TR resided in the plasma compartment of blood. 3. Main circulating metabolites were abiraterone sulfate and N-oxide abiraterone sulfate. The main metabolite excreted in urine was N-oxide abiraterone sulfate (4.22% of TR). Major components of TR in faeces were unchanged AA (55.3% of TR) and abiraterone (22.3% of TR). Mean recovery of TR in faeces was 87.9%, indicating faeces as primary route of excretion. PMID- 23020790 TI - Study of the oxygen vacancy influence on magnetic properties of Fe- and Co-doped SnO2 diluted alloys. AB - Transition-metal (TM)-doped diluted magnetic oxides (DMOs) have attracted attention from both experimental and theoretical points of view due to their potential use in spintronics towards new nanostructured devices and new technologies. In the present work, we study the magnetic properties of Sn0.96TM0.04O2 and Sn0.96TM0.04O1.98(VO)0.02, where TM = Fe and Co, focusing in particular in the role played by the presence of O vacancies nearby the TM. The calculated total energy as a function of the total magnetic moment per cell shows a magnetic metastability, corresponding to a ground state, respectively, with 2 and 1 MUB/cell, for Fe and Co. Two metastable states, with 0 and 4 MUB/cell were found for Fe, and a single value, 3 MUB/cell, for Co. The spin-crossover energies (ES) were calculated. The values are ES0/2 = 107 meV and ES4/2 = 25 meV for Fe. For Co, ES3/1 = 36 meV. By creating O vacancies close to the TM site, we show that the metastablity and ES change. For iron, a new state appears, and the state with zero magnetic moment disappears. The ground state is 4 MUB/cell instead of 2 MUB/cell, and the energy ES2/4 is 30 meV. For cobalt, the ground state is then found with 3 MUB/cell and the metastable state with 1 MUB/cell. The spin crossover energy ES1/3 is 21 meV. Our results suggest that these materials may be used in devices for spintronic applications that require different magnetization states. PMID- 23020789 TI - Characterizing sexual histories of women before formal sex-work in south India from a cross-sectional survey: implications for HIV/STI prevention. AB - BACKGROUND: Interventions designed to prevent HIV and STIs in female sex-workers (FSWs) reach women after they formally enter the sex-trade. We aimed to characterize the pattern of sexual behaviour among FSWs from first-sex to when they identify as sex-workers (transition period) in a region with traditional (historically characterized by dedication into sex-work at first-sex) and non traditional forms of sex-work. METHODS: We conducted a cross-sectional survey of 246 traditional and 765 non-traditional FSWs across three districts in Karnataka, India. We performed univariate and multivariate logistic regression to profile FSWs most likely to engage in a commercial first-sex before identifying as a sex worker. Sexual life-course patterns were distinguished using univariate and multivariate linear regression based on key events associated with length of transition period. RESULTS: Overall, 266 FSWs experienced a commercial first-sex, of whom 45.9% (95% CI: 38.2,53.7) continued a long-term relationship with the first partner. In adjusted analysis, traditional FSWs were more likely to experience a commercial first-sex (AOR 52.5, 95% CI: 27.4,100.7). The average transition time was 8.8 years (SD 3.9), but there was considerable variability between respondents. Among women who experienced a commercial first-sex, a slower transition was independently associated with non-traditional sex-work, the presence of long-term partnerships during the transition period, and ongoing partnerships at time of entry into sex-work. In the absence of a commercial first sex, a faster transition was associated with traditional sex-work and the dissolution of long-term partnerships, while a slower transition was associated with the presence of long-term partnerships and widowhood. Only 18.5% (95% CI: 12.7,26.2) and 47.3% (95% CI: 32.7,62.3) of women reported 'always' condom use with their long-term and occasional partners during the transition period, respectively. CONCLUSIONS: FSWs identify as sex-workers several years after becoming sexually active, even when the first-sex is commercial in nature. Long term partnerships are common after a commercial first-sex, and are associated with a delay in formally entering the sex-trade. The findings call for a better understanding of HIV/STI risk before FSWs identify as sex-workers, and an adaptive programme to reach this period of vulnerability. PMID- 23020791 TI - Multistructural variational transition state theory: kinetics of the hydrogen abstraction from carbon-2 of 2-methyl-1-propanol by hydroperoxyl radical including all structures and torsional anharmonicity. AB - We calculated the forward and reverse rate constants of the hydrogen abstraction reaction from carbon-2 of 2-methyl-1-propanol by hydroperoxyl radical over the temperature range 250-2400 K by using multistructural canonical variational transition state theory (MS-CVT) including both multiple-structure and torsional potential anharmonicity effects by the multistructural torsional anharmonicity (MS-T) method. In these calculations, multidimensional tunneling (MT) probabilities used to compute the tunneling transmission coefficients were evaluated by the small-curvature tunneling (SCT) approximation. Comparison with the rate constants obtained by the single-structural harmonic oscillator (SS-HO) approximation shows that multistructural anharmonicity increases the forward rate constants for all temperatures, but the reverse rate constants are reduced for temperatures lower than 430 K and increased for higher temperatures. The neglect of multistructural torsional anharmonicity would lead to errors of factors of 1.5, 8.8, and 13 at 300, 1000, and 2400 K, respectively, for the forward reaction, and would lead to errors of factors of 0.76, 3.0, and 6.0, respectively, at these temperatures for the reverse reaction. PMID- 23020792 TI - Gray Hausdorff distance measure for medical image comparison in dermatology: Evaluation of treatment effectiveness by image similarity. AB - INTRODUCTION: In clinical dermatology, the stabilization of the overall skin condition can be in many cases the earliest qualitative measure of the effectiveness of the therapeutic intervention. Subjective image comparisons, that offer empirical 'qualitative' judgments of degrees of image similarities, are traditionally employed by the involved physicians. OBJECTIVES: To quantify, by means of an image similarity metric, the degree of stabilization of an expanding skin disease, and to identify the situation of 'no further change' of the skin condition of the patient, providing thus the physician with an early, objective measure of the efficacy of the used therapy. METHODS: For treatment assessment, a variant of gray Hausdorff distance metric was employed to compare images of lesional skin segments of a patient, taken at different time points during a therapeutic course. Prior to image comparison, an effective preprocessing scheme was adapted to constrain wide pose and light variations. The proposed similarity algorithm was tested on raw clinical image data sets of patients diagnosed with toxic epidermal necrolysis, a life-threatening condition with rapid evolution. Fine tuning of algorithm's parameters was optimized using Precision-Recall curves. RESULTS: Proposed image comparison method resulted in a high-degree of image similarity (about 96%) between pictures taken at second and fifth day of hospitalization. Current similarity results substantiate a significant agreement between the computer-treatment assessment, by means of image comparison, and the corresponding clinical experts' review of skin condition. CONCLUSION: Objective evidence of 'no further change' situation may provide (a) intuitive clinical decision support to dermatologists in assessing aggressive skin conditions, where the timely evaluation of treatment response is of vital importance and (b) a versatile end-point measure for corresponding therapeutic clinical trials. PMID- 23020793 TI - Mechanistic studies on histone catalyzed cleavage of apyrimidinic/apurinic sites in nucleosome core particles. AB - Duplex DNA containing an apurinic/apyrimidinic (AP) lesion undergoes cleavage significantly more rapidly in nucleosome core particles (NCPs) than it does when free. The mechanism of AP cleavage within NCPs was studied through independently generating lesions within them. AP mediated DNA cleavage within NCPs is initiated by DNA-protein cross-link (DPC(un)) formation followed by beta-elimination to give DPCs containing cleaved DNA (DPC(cl)). Hydrolysis of DPC(cl) produces a DNA single strand break (SSB). C2-dideuteration of AP showed that deprotonation from this position is involved in the rate-determining step. Experiments utilizing NCPs containing mutated histone H4 proteins indicated that lysine residues in the amino terminal tail are involved in both DPC formation and beta-elimination steps. Lysines 16 and 20 seem to play a greater role in reacting with AP at superhelical location 1.5, but other amino acids (e.g., lysines 5, 8, and 12) compensate in their absence. The mechanism of rapid double strand breaks in bistranded, clustered AP lesions was studied by independently preparing reaction intermediates within model NCPs. A single strand break on one strand enhances the cleavage of a proximal AP on the opposite strand. PMID- 23020795 TI - Improved conversion rates in drug screening applications using miniaturized electrochemical cells with frit channels. AB - This paper reports a novel design of a miniaturized three-electrode electrochemical cell, the purpose of which is aimed at generating drug metabolites with a high conversion efficiency. The working electrode and the counter electrode are placed in two separate channels to isolate the reaction products generated at both electrodes. The novel design includes connecting channels between these two electrode channels to provide a uniform distribution of the current density over the entire working electrode. In addition, the effect of ohmic drop is decreased. Moreover, two flow resistors are included to ensure an equal flow of analyte through both electrode channels. Total conversion of fast reacting ions is achieved at flow rates up to at least 8 MUL/min, while the internal chip volume is only 175 nL. Using this electrochemical chip, the metabolism of mitoxantrone is studied by microchip electrospray ionization-mass spectrometry. At an oxidation potential of 700 mV, all known metabolites from direct oxidation are observed. The electrochemical chip performs equally well, compared to a commercially available cell, but at a 30-fold lower flow of reagents. PMID- 23020794 TI - Clinical, epidemiological, and spatial characteristics of Vibrio parahaemolyticus diarrhea and cholera in the urban slums of Kolkata, India. AB - BACKGROUND: There is not much information on the differences in clinical, epidemiological and spatial characteristics of diarrhea due to V. cholerae and V. parahaemolyticus from non-coastal areas. We investigated the differences in clinical, epidemiological and spatial characteristics of the two Vibrio species in the urban slums of Kolkata, India. METHODS: The data of a cluster randomized cholera vaccine trial were used. We restricted the analysis to clusters assigned to placebo. Survival analysis of the time to the first episode was used to analyze risk factors for V. parahaemolyticus diarrhea or cholera. A spatial scan test was used to identify high risk areas for cholera and for V. parahaemolyticus diarrhea. RESULTS: In total, 54,519 people from the placebo clusters were assembled. The incidence of cholera (1.30/1000/year) was significantly higher than that of V. parahaemolyticus diarrhea (0.63/1000/year). Cholera incidence was inversely related to age, whereas the risk of V. parahaemolyticus diarrhea was age-independent. The seasonality of diarrhea due to the two Vibrio species was similar. Cholera was distinguished by a higher frequency of severe dehydration, and V. parahaemolyticus diarrhea was by abdominal pain. Hindus and those who live in household not using boiled or treated water were more likely to have V. parahaemolyticus diarrhea. Young age, low socioeconomic status, and living closer to a project healthcare facility were associated with an increased risk for cholera. The high risk area for cholera differed from the high risk area for V. parahaemolyticus diarrhea. CONCLUSION: We report coexistence of the two vibrios in the slums of Kolkata. The two etiologies of diarrhea had a similar seasonality but had distinguishing clinical features. The risk factors and the high risk areas for the two diseases differ from one another suggesting different modes of transmission of these two pathogens. PMID- 23020796 TI - Apical myosin XI anticipates F-actin during polarized growth of Physcomitrella patens cells. AB - Tip growth is essential for land colonization by bryophytes, plant sexual reproduction and water and nutrient uptake. Because this specialized form of polarized cell growth requires both a dynamic actin cytoskeleton and active secretion, it has been proposed that the F-actin-associated motor myosin XI is essential for this process. Nevertheless, a spatial and temporal relationship between myosin XI and F-actin during tip growth is not known in any plant cell. Here, we use the highly polarized cells of the moss Physcomitrella patens to show that myosin XI and F-actin localize, in vivo, at the same apical domain and that both signals fluctuate. Surprisingly, phase analysis shows that increase in myosin XI anticipates that of F-actin; in contrast, myosin XI levels at the tip fluctuate in identical phase with a vesicle marker. Pharmacological analysis using a low concentration of the actin polymerization inhibitor latrunculin B showed that the F-actin at the tip can be significantly diminished while myosin XI remains elevated in this region, suggesting that a mechanism exists to cluster myosin XI-associated structures at the cell's apex. In addition, this approach uncovered a mechanism for actin polymerization-dependent motility in the moss cytoplasm, where myosin XI-associated structures seem to anticipate and organize the actin polymerization machinery. From our results, we inferred a model where the interaction between myosin XI-associated vesicular structures and F-actin polymerization-driven motility function at the cell's apex to maintain polarized cell growth. We hypothesize this is a general mechanism for the participation of myosin XI and F-actin in tip growing cells. PMID- 23020797 TI - Transcriptional suppression of the neuronal PAS domain 4 (Npas4) gene by stress via the binding of agonist-bound glucocorticoid receptor to its promoter. AB - Neuronal PAS domain 4 (NPAS4), a brain-specific helix-loop-helix transcription factor, has recently been shown to regulate the development of GABAergic inhibitory neurons. We previously reported that Npas4 mRNA expression levels were reduced in the hippocampus of mice exposed to social isolation or restraint stress, which was accompanied by impairment of memory, emotional behavior, and hippocampal neurogenesis. Therefore, the reduction of NPAS4 expression may play a role in stress-induced brain dysfunction. In this study, to investigate the transcriptional regulation of Npas4 by stress, we focused on the effect of glucocorticoids (GCs) upon Npas4 transcription. Corticosterone treatment reduced Npas4 expression in the frontal cortex and hippocampus, whereas adrenalectomy caused an increase in expression. GC receptor (GR) antagonist, mifepristone, inhibited the stress-induced reduction of Npas4 expression. Putative negative glucocorticoid response elements (GREs) were found -2000 to -1000 upstream of the Npas4 transcription initiation site. Npas4 promoter activity was increased by mifepristone or by mutation of the negative GRE sequences. A chromatin immunoprecipitation assay revealed that restraint stress increased the binding of GR to Npas4 promoter region in the hippocampus. These results suggest that transcription of Npas4 is down-regulated by stress via the binding of agonist bound GR to its promoter. PMID- 23020799 TI - The val66met polymorphism of brain-derived neurotrophic factor is associated with human esophageal hypersensitivity. AB - BACKGROUND: Recent evidence implicates brain-derived neurotrophic factor (BDNF) in visceral hypersensitivity and pain in functional gastrointestinal disorders. We hypothesized that presence of the val66met polymorphism in the BDNF gene would be linked to increased esophageal sensitivity to electrical stimulation. METHODS: A total of 39 healthy volunteers (20 males, mean age 30) compliant with inclusion criteria after screening procedures were genotyped for BDNF polymorphisms and completed an Hospital Anxiety and Depression Scale (HADS) questionnaire. Sensory (ST) and pain (PT) thresholds in the proximal (PE) and distal (DE) esophagus were determined using electrical stimuli to a swallowed intraluminal catheter with bipolar electrodes by an investigator blinded to the subjects' genotype. For comparison, somatic ST and PT (hand and foot) were also tested. HADS scores together with esophageal and somatic thresholds were then correlated with BDNF polymorphism status. KEY RESULTS: Eleven of 39 (28%) volunteers had at least one Met allele (Met carriers). When compared with Val/Val, Met carriers had lower esophageal PT (Median PT [mA]: Val/Val vs Met carriers, PE; 49.4 vs 44.3, P = 0.033, DE: 63.8 vs 55.4, P = 0.045) with higher proportion of Val/Val subjects in the upper quartile for PT in both PE (P = 0.021) and DE (P = 0.033), yet similar somatic PT (Median PT [mA] Hand; 33.6 vs 38.0, P = 0.22, Foot; 44.7 vs 44.0, P = 0.48). Sensitivity results were independent of anxiety (P = 0.66) and depression (P = 0.33) scores. CONCLUSIONS & INFERENCES: val66met BDNF polymorphisms are associated with increased esophageal sensitivity to experimental electrical stimulation. Thus, BDNF genotype may be a useful biomarker for electrical sensitivity in the healthy human esophagus. PMID- 23020798 TI - Polymorphisms in ERCC1, GSTs, TS and MTHFR predict clinical outcomes of gastric cancer patients treated with platinum/5-Fu-based chemotherapy: a systematic review. AB - BACKGROUND: Despite genetic polymorphism in response to platinum/5-Fu chemotherapy in gastric cancer (GC) has been studied, data reported so far are conflicting and critical consideration is needed before translation to the treatment of GC. METHODS: We performed a meta-analysis by using 20 eligible studies to examine polymorphisms of ERCC1, GSTs, TS and MTHFR in predicting clinical outcomes (response rate, overall survival and toxicity) of GC patients treated with platinum/5-Fu-based chemotherapy. The association was measured using random/fixed effect odds ratios (ORs) or hazard ratios (HRs) combined with their 95% confidence intervals (CIs) according to the studies' heterogeneity. Statistical analysis was performed with the software STATA 9.0 package. RESULTS: No significant association was found between response rate and genetic polymorphism in TS, MTHFR, ERCC1, GSTM1 and GSTP1. However, response rate was higher in GSTT1 (+) genotype compared with GSTT1 (-) genotype (T-/T+: OR=0.67, 95% CI: 0.47-0.97). With regard to long term outcomes, we could observe a significant longer overall survival in TS 3R/3R [(2R2R+2R3R)/3R3R: HR=1.29, 95% CI: 1.02-1.64] and GSTP1 GG/GA [(GG+AG)/AA: HR=0.51, 95% CI: (0.39, 0.67)] genotypes. In addition, significant association was demonstrated between toxicity and genetic polymorphism in TS, MTHFR and GSTP1 in included studies. CONCLUSION: Polymorphisms of ERCC1, GSTs, TS and MTHFR were closely associated with clinical outcomes of GC patients treated with platinum/5-Fu-based chemotherapy. Studies with large sample size using the method of multi-variant analyses may help us to give more persuasive data on the putative association in future. PMID- 23020800 TI - Cell type-specific termination of transcription by transposable element sequences. AB - BACKGROUND: Transposable elements (TEs) encode sequences necessary for their own transposition, including signals required for the termination of transcription. TE sequences within the introns of human genes show an antisense orientation bias, which has been proposed to reflect selection against TE sequences in the sense orientation owing to their ability to terminate the transcription of host gene transcripts. While there is evidence in support of this model for some elements, the extent to which TE sequences actually terminate transcription of human gene across the genome remains an open question. RESULTS: Using high throughput sequencing data, we have characterized over 9,000 distinct TE-derived sequences that provide transcription termination sites for 5,747 human genes across eight different cell types. Rarefaction curve analysis suggests that there may be twice as many TE-derived termination sites (TE-TTS) genome-wide among all human cell types. The local chromatin environment for these TE-TTS is similar to that seen for 3' UTR canonical TTS and distinct from the chromatin environment of other intragenic TE sequences. However, those TE-TTS located within the introns of human genes were found to be far more cell type-specific than the canonical TTS. TE-TTS were much more likely to be found in the sense orientation than other intragenic TE sequences of the same TE family and TE-TTS in the sense orientation terminate transcription more efficiently than those found in the antisense orientation. Alu sequences were found to provide a large number of relatively weak TTS, whereas LTR elements provided a smaller number of much stronger TTS. CONCLUSIONS: TE sequences provide numerous termination sites to human genes, and TE-derived TTS are particularly cell type-specific. Thus, TE sequences provide a powerful mechanism for the diversification of transcriptional profiles between cell types and among evolutionary lineages, since most TE-TTS are evolutionarily young. The extent of transcription termination by TEs seen here, along with the preference for sense-oriented TE insertions to provide TTS, is consistent with the observed antisense orientation bias of human TEs. PMID- 23020801 TI - On testing an unspecified function through a linear mixed effects model with multiple variance components. AB - We examine a generalized F-test of a nonparametric function through penalized splines and a linear mixed effects model representation. With a mixed effects model representation of penalized splines, we imbed the test of an unspecified function into a test of some fixed effects and a variance component in a linear mixed effects model with nuisance variance components under the null. The procedure can be used to test a nonparametric function or varying-coefficient with clustered data, compare two spline functions, test the significance of an unspecified function in an additive model with multiple components, and test a row or a column effect in a two-way analysis of variance model. Through a spectral decomposition of the residual sum of squares, we provide a fast algorithm for computing the null distribution of the test, which significantly improves the computational efficiency over bootstrap. The spectral representation reveals a connection between the likelihood ratio test (LRT) in a multiple variance components model and a single component model. We examine our methods through simulations, where we show that the power of the generalized F-test may be higher than the LRT, depending on the hypothesis of interest and the true model under the alternative. We apply these methods to compute the genome-wide critical value and p-value of a genetic association test in a genome-wide association study (GWAS), where the usual bootstrap is computationally intensive (up to 10(8) simulations) and asymptotic approximation may be unreliable and conservative. PMID- 23020802 TI - Modified and derived ethanol injection toward liposomes: development of the process. AB - A modified and derived ethanol injection (MDEI) process was developed to produce liposomes. The aim of the present study was to more efficiently control the vesicle diameter than with the conventional ethanol injection method. A hot ethanolic solution of lipids (60 degrees C) was injected into a hot aqueous buffer (70 degrees C). Then, ethanol was removed by rotary evaporation under reduced pressure. The size of the liposomes could be controlled by the ratio of ethanol to hydroalcoholic solution before evaporation. The concentration of lipids, the charge of lipids, and the type of aqueous phase had little effect on the vesicle diameter when the process involved a ratio of 33% (v/v) ethanol. In addition, it was possible to obtain lipid concentrations 10- to 30-fold higher that the conventional ethanol injection method. The encapsulation of a hydrophilic compound was feasible with this MDEI process. The observation by cryogenic transmission electron microscopy revealed that these liposomes were predominantly unilamellar at a ratio as high as 33 or 50% (v/v) ethanol. Thus, the results showed that MDEI is an appropriate alternative for the manufacture of liposomes with respect to the ethanol injection process. PMID- 23020803 TI - Effects of vitamin D on antigen-specific and non-antigen-specific immune modulation: relevance for type 1 diabetes. AB - Vitamin D is a fat-soluble precursor of the circulating 25-hydroxyvitamin D3 (25(OH)D3)which can be converted by the 1alpha-hydroxylase (1alpha(OH)ase) enzyme into the bioactive hormonal metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), generally known to promote bone mineralization through its ability to enhance calcium absorption from the gut. Importantly, in humans, vitamin D is mainly derived from endogenous production of vitamin D3 from ultraviolet (UV) radiation exposure to the skin while a small part (<10%) is obtained via dietary intake of dairy products and fatty fish (1). Taking these factors into account, geographic distribution and seasonality, skin pigmentation, age, and lifestyle may predispose certain populations to be at a higher risk of developing vitamin D insufficiency or deficiency (2). The first valid reports correlating the importance of an adequate vitamin D status to optimal human health originate from the early part of the 20th century, when vitamin D was described to prevent and treat the bone disease rickets. Since then, the findings that vitamin D receptors (VDR) are present in many body tissues and that vitamin D metabolizing enzymes can be found in various cells outside the kidney, including the intestine, prostate, immune cells, and within the skin itself (reviewed in reference 3), have revolutionized the vitamin D business. In this review, we will mainly focus on vitamin D as a component of immune regulation and on the role of vitamin D in antigen-specific and non-specific therapies with potential relevance for type 1 diabetes (T1D). PMID- 23020804 TI - Two new species of Rhabdias (Nematoda: Rhabditida: Rhabdiasidae) in anuran hosts from Dehradun (Uttarakhand), India. AB - Rhabdias himalayanus n. sp. from the lungs of Duttaphrynus himalayanus and Rhabdias dehradunensis n. sp. from the lungs of Nanorana minica from Dehradun, India are described and figured. Of the 3 previously described Indian species, Rhabdias himalayanus n. sp. is most similar to Rhabdias shortii in having a cylindrical corpus, inflated cuticle, and conical tail; it differs from R. shortii in having greater body measurements, longer esophagus, larger eggs, and a different pattern of cuticle inflation at the vulva and tail region. Rhabdias dehradunensis n. sp. is most similar to Rhabdias bulbicauda in that both possess a swollen posterior end; it differs from R. bulbicauda by having a subterminal anus, a prominent tail, and a postequatorial vulva. PMID- 23020805 TI - Enhancement of hemocompatibility of the MERA monopivot centrifugal pump: toward medium-term use. AB - The MERA monopivot centrifugal pump has been developed for use in open-heart surgery, circulatory support, and bridge-to-decision for up to 4 weeks. The pump has a closed-type, 50-mm diameter impeller with four straight paths. The impeller is supported by a monopivot bearing and is driven by a radial-flux magnet coupling motor. Because flow visualization experiments have clarified sufficient pivot wash and stagnation at the sharp corner of the pivot support was suggested, sharp corners were removed in the design stage. The index of hemolysis of the pump operating at more than 200 mm Hg was found to be lower than that of a commercial pump. Four-week animal tests were then conducted two times; improvement of thrombus formation was seen in the female pivot through modification of female pivot geometry. Overall antithrombogenicity was also recorded. Finally, to assure mid-term use, an additional 4-week durability test revealed that the rate of the axial pivot wear was as small as 1.1 um/day. The present in vitro and in vivo studies revealed that the MERA monopivot centrifugal pump has sufficient hemocompatibility and durability for up to 4 weeks. PMID- 23020806 TI - Influence of early life factors on body mass index trajectory during childhood: a population-based longitudinal analysis in the Western Brazilian Amazon. AB - Low- to middle-income countries may experience the occurrence of a dual burden of under and overnutrition. To better understand the overall progression of body mass index (BMI) during childhood, we estimated average BMI-for-age z-score (BAZ) growth curves in a population-based longitudinal study of 255 children living in the Brazilian Amazon. Children were aged 0.1-5.5 years at recruitment (2003). We collected data on socio-economic and maternal characteristics, children's birthweight and infant feeding practices. Child anthropometric measurements were taken in 2003, 2007 and 2009. BAZ differences among categories of exposure variables were calculated at 6 and 12 months, and 2, 7 and 10 years. At baseline, the mean (standard deviation) age was 2.6 (1.4) years; 12.9% were overweight and 3.9% thin. After adjustment, mean BAZ estimates were mostly negative. Boys were close to the median value for BAZ until 12 months, whereas girls were below the median (P=0.05). Children from households above the wealth median were 0.36 z- and 0.49 z-less underweight than poorer children at 7 and 10 years, respectively (P<0.01). Maternal BMI was positively associated with children's BAZ since 12 months old; BAZ in children from overweight mothers was higher by 0.69 compared with their counterparts at 10 years (P<0.01). Birthweight was positively related to BAZ up until 2 years (P=0.01). Socio-economic background and maternal nutritional status are important predictors of BAZ throughout childhood. Although excessive weight gain is a public health concern, it is critical to restrict inequities, while promoting healthier growth in developing countries. PMID- 23020807 TI - Actinic granuloma: a history of photoexacerbation and the importance of a radial 'three-zone' biopsy. PMID- 23020808 TI - Radiation-associated changes in the length of telomeres in peripheral leukocytes from inpatients with cancer. AB - PURPOSE: The telomere length of somatic cells shortens with age and with other endogenous and exogenous pathogenic factors. However, the effects of radiation therapy on telomere DNA of non-cancer tissue have not been thoroughly investigated. This study analyzed the telomere length of inpatients with cancer treated with radiation therapy to see whether the telomere lengths change in response to therapeutic radiation. MATERIALS AND METHODS: Twenty-five patients were enrolled in the study. The patients had lung cancer, prostate cancer, thyroid cancer, hepatoma, or rectal cancer. They received radiation therapy with a dose range of 15-74 Gy. The telomere lengths and telomere length distribution in peripheral leukocytes were analyzed by using a Southern blot-based method. RESULTS: The telomere length and the telomere length distribution of the peripheral leukocytes did not change after radiation therapy. However, there was a significant proportional decrease in the short telomere fraction (< 4.4 kb) per day and per Gy. CONCLUSIONS: This observation suggested that the telomere length distribution of peripheral leukocytes could be affected by radiation therapy, and that the effect of radiation tends to appear in cells with short telomeres. Radiation therapy-associated somatic telomere length change within a short range of time, about three months or shorter, can be detected by analyzing the mean telomere length and telomere length distribution. PMID- 23020809 TI - Expression of DNA methyltransferase genes in four-cell bovine embryos cultured in the presence of oviductal fluid. AB - The possible epigenomic effect of oviductal fluid on expression of DNA methyltransferase (DNMT) genes was examined in early bovine embryos (4-cell stage). Real-time quantitative PCR was performed to determine the relative expression of DNMT1, DNMT3a and DNMT3b transcripts in embryos cultured in vitro in the presence or absence of oviductal fluid. Expression of DNMT1 significantly increased when cultured with oviductal fluid, whereas DNMT3a and DNMT3b transcripts were unaffected by the addition of oviductal fluid. These results may help reveal the role of oviductal factors in the regulation of DNMT expression. PMID- 23020810 TI - Alternate coupling mechanism for dynamical quorum sensing. AB - Dynamical quorum sensing transition in a system, is the sudden change in its dynamics at a critical population size. We propose a novel coupling mechanism, the "dominating surrounding effect", that can lead to the dynamical quorum sensing transitions. This coupling mechanism has been implemented in both globally and locally coupled systems and found to be independent of the choice of the coupled variables (instantaneous or delayed). Because no local coupling scheme has been proposed so far that can illustrate dynamical quorum sensing in locally coupled systems, our local coupling scenario is a novel contribution. Although global coupling schemes for dynamical quorum sensing have been previously proposed, our global coupling scenario is different, as discussed in the text below. This coupling mechanism has been tested using a two-dimensional electrochemical model and a four dimensional biological model (Hodgkin-Huxley's neuronal model). Two types of dynamical quorum sensing transitions, the emergence and the extinction of global oscillations in an ensemble of globally (all to all) and locally (1-D array with no flux boundary conditions) coupled oscillators, have been studied. Furthermore, the provoked spikes in the neuronal ensemble exhibit zero lag synchronization in the case of time delay and lag synchronization in the case of no-delay (instantaneous). In contrast, the induced oscillations are phase synchronized in the coupled electrochemical oscillators for both delay and no delay. PMID- 23020811 TI - Ocular penetration of topically applied 1% daptomycin in a rabbit model. AB - PURPOSE: To evaluate the ocular penetration of daptomycin, a new antibiotic agent targeted against Gram-positive organisms. METHODS: Thirty-two New Zealand white rabbits were divided into 4 equal groups. One drop of 50 MUL 1% daptomycin was administered to group 1. In group 2, 1 drop of 1% daptomycin was administered after the corneal epithelium was scraped. In group 3, 1 drop of 1% daptomycin was administered every 15 min for 1 h (keratitis protocol). In group 4, the keratitis protocol was applied after the corneal epithelium was scraped. In groups 1 and 2, aqueous humor samples were collected 30 min, 1 h, and 2 h after the single drop under general anesthesia. All the animals in groups 3 and 4 were humanely killed. Cornea, aqueous humor, and vitreous samples were collected 1 and 2 h after the last drop. Daptomycin concentrations were measured by high-performance liquid chromatography. RESULTS: Each group comprised 8 rabbits. Daptomycin was not detected in the aqueous humor in groups 1 and 2. In group 3, the mean values at 1 h in the aqueous humor and cornea, respectively, were 1.90+/-0.15 MUg/mL and 3.93+/-0.67 MUg/g, and at 2 h were 1.71+/-0.42 MUg/mL and 4.13+/-0.46 MUg/g. In group 4, the mean values at 1 h were 5.19+/-0.50 MUg/mL and 7.10+/-0.35 MUg/g, and at 2 h were 4.96+/-0.47 MUg/mL and 7.22+/-0.34 MUg/g. Daptomycin was not detected in vitreous samples in groups 3 and 4. CONCLUSIONS: Single-drop administration does not yield a detectable daptomycin concentration in aqueous humor in neither nonscraped nor scraped group. In the multiple-drop regimen, daptomycin seems to penetrate well into the aqueous humor and cornea both in nonscraped and scraped groups. However, this concentration may not cover the minimum inhibitory concentration (MIC) of organisms such as Enterococcus fecalis. PMID- 23020812 TI - ARS turns fifteen: la quinceanera bonita. AB - ARS was aimed at advancing the erstwhile niche field of redox biology to a more central position in research. Currently, ARS ranks first (impact factor: 8.456) in the field of redox biology. Of 8336 journals listed in Journal Citation Reports, ARS ranks 205th. The next journal in redox biology ranks 449th. ARS ranks 169th of 8336 in immediacy index. The next journal in redox biology ranks 923rd. Thus, ARS is the primary source of hot papers in redox sciences and healthcare. To grow footprint and overall impact, ARS has nearly doubled the annual publication volume from roughly 200 to 400 in one year. Because the manuscript volume represents the denominator of the impact factor calculation, such a sharp increase in volume would be predicted to a proportionally lower impact factor. Because of the robust current upward momentum, ARS will be affected less than that predicted by simple arithmetic and will maintain its top position even after such aggressive volume expansion. As another year passes, the additional manuscripts will get more time to be cited, and therefore the impact factor is expected to bounce back resulting in a much stronger journal with a substantially enhanced overall presence. ARS currently publishes 36 issues annually as two series: ARS-Discoveries, and ARS-Therapeutics. Redox biology does have the potential of major health impact. ARS-Therapeutics is the first and only forum dedicated to highlight that strength. I am grateful to the global redox village for their unreserved support to raise ARS and this fascinating field of redox research and healthcare. Antioxid. Redox Signal. 18, 1-4. PMID- 23020813 TI - Global trends in exclusive breastfeeding. AB - BACKGROUND: Infant and young child feeding is critical for child health and survival. Proportion of infants 0-5 months who are fed exclusively with breast milk is a common indicator used for monitoring and evaluating infant and young child feeding in a given country and region. Despite progress made since 1990, a previous review in 2006 of global and regional trends found improvement to be modest. The current study provides an update in global and regional trends in exclusive breastfeeding from 1995 to 2010, taking advantage of the wealth of data from recent household surveys. METHODS: Using the global database of infant and young child feeding maintained by the United Nations Children's Fund, the authors examined estimates from 440 household surveys in 140 countries over the period between 1995 and 2010 and calculated global and regional averages of the rate of exclusive breastfeeding among infants 0-5 months for the two time points to assess the trends. RESULTS: Trend data suggest the prevalence of exclusive breastfeeding among infants younger than six months in developing countries increased from 33% in 1995 to 39% in 2010. The prevalence increased in almost all regions in the developing world, with the biggest improvement seen in West and Central Africa. CONCLUSIONS: In spite of the well-recognized importance of exclusive breastfeeding, the practice is not widespread in the developing world and increase on the global level is still very modest with much room for improvement. Child nutrition programmes worldwide continue to require investments and commitments to improve infant feeding practices in order to have maximum impact on children's lives. PMID- 23020815 TI - Antibacterial performance of Ag nanoparticles and AgGO nanocomposites prepared via rapid microwave-assisted synthesis method. AB - Silver nanoparticles and silver-graphene oxide nanocomposites were fabricated using a rapid and green microwave irradiation synthesis method. Silver nanoparticles with narrow size distribution were formed under microwave irradiation for both samples. The silver nanoparticles were distributed randomly on the surface of graphene oxide. The Fourier transform infrared and thermogravimetry analysis results showed that the graphene oxide for the AgNP graphene oxide (AgGO) sample was partially reduced during the in situ synthesis of silver nanoparticles. Both silver nanoparticles and AgGO nanocomposites exhibited stronger antibacterial properties against Gram-negative bacteria (Salmonella typhi and Escherichia coli) than against Gram-positive bacteria (Staphyloccocus aureus and Staphyloccocus epidermidis). The AgGO nanocomposites consisting of approximately 40 wt.% silver can achieve antibacterial performance comparable to that of neat silver nanoparticles. PMID- 23020814 TI - Experiences with surgical treatment of chronic lower limb ulcers at a tertiary hospital in northwestern Tanzania: a prospective review of 300 cases. AB - BACKGROUND: Chronic lower limb ulcers constitute a major public health problem of great important all over the world and contribute significantly to high morbidity and long-term disabilities. There is paucity of information regarding chronic lower limb ulcers in our setting; therefore it was necessary to conduct this study to establish the patterns and outcome of chronic lower limb ulcers and to identify predictors of outcome in our local setting. METHODS: This was a descriptive prospective study of patients with chronic lower limb ulcers conducted at Bugando Medical Centre between November 2010 and April 2012. Ethical approval to conduct the study was sought from relevant authorities. Statistical data analysis was done using SPSS version 17.0 and STATA version 11.0. RESULTS: A total of 300 patients were studied. Their ages ranged from 3 months to 85 years (median 32 years). The male to female ratio was 2:1. The median duration of illness was 44 days. Traumatic ulcer was the most frequent type of ulcer accounting for 60.3% of patients. The median duration of illness was 44 days. The leg was commonly affected in 33.7% of cases and the right side (48.7%) was frequently involved. Out of 300 patients, 212 (70.7%) had positive aerobic bacterial growth within 48 hours of incubation. Pseudomonas aeruginosa (25.5%) was the most frequent gram negative bacteria isolated, whereas gram positive bacteria commonly isolated was Staphylococcus aureus (13.7%). Twenty (6.7%) patients were HIV positive with a median CD4+ count of 350 cells/MUl. Mycological investigation was not performed. Bony involvement was radiologically reported in 83.0% of cases. Histopathological examination performed in 56 patients revealed malignancy in 20 (35.7%) patients, of which malignant melanoma (45.0%) was the most common histopathological type. The vast majority of patients, 270 (90.0%) were treated surgically, and surgical debridement was the most common surgical procedure performed in 24.1% of cases. Limb amputation rate was 8.7%. Postoperative complication rate was 58.3% of which surgical site infection (77.5%) was the most common post-operative complications. The median length of hospital stay was 23 days. Mortality rate was 4.3%. Out of the two hundred and eighty-seven (95.7%) survivors, 253 (91.6%) were treated successfully and discharged well (healed). After discharge, only 35.5% of cases were available for follow up at the end of study period. CONCLUSION: Chronic lower limb ulcers remain a major public health problem in this part of Tanzania. The majority of patients in our environment present late when the disease is already in advanced stages. Early recognition and aggressive treatment of the acute phase of chronic lower limb ulcers at the peripheral hospitals and close follow-up are urgently needed to improve outcomes of these patients in our environment. PMID- 23020816 TI - Sector expansion and elliptical modeling of blue-gray ovoids for basal cell carcinoma discrimination in dermoscopy images. AB - BACKGROUND: Blue-gray ovoids (B-GOs), a critical dermoscopic structure for basal cell carcinoma (BCC), offer an opportunity for automatic detection of BCC. Due to variation in size and color, B-GOs can be easily mistaken for similar structures in benign lesions. Analysis of these structures could afford accurate characterization and automatic recognition of B-GOs, furthering the goal of automatic BCC detection. This study utilizes a novel segmentation method to discriminate B-GOs from their benign mimics. METHODS: Contact dermoscopy images of 68 confirmed BCCs with B-GOs were obtained. Another set of 131 contact dermoscopic images of benign lesions possessing B-GO mimics provided a benign competitive set. A total of 22 B-GO features were analyzed for all structures: 21 color features and one size feature. Regarding segmentation, this study utilized a novel sector-based, non-recursive segmentation method to expand the masks applied to the B-GOs and mimicking structures. RESULTS: Logistic regression analysis determined that blue chromaticity was the best feature for discriminating true B-GOs in BCC from benign, mimicking structures. Discrimination of malignant structures was optimal when the final B-GO border was approximated by a best-fit ellipse. Using this optimal configuration, logistic regression analysis discriminated the expanded and fitted malignant structures from similar benign structures with a classification rate as high as 96.5%. CONCLUSIONS: Experimental results show that color features allow accurate expansion and localization of structures from seed areas. Modeling these structures as ellipses allows high discrimination of B-GOs in BCCs from similar structures in benign images. PMID- 23020817 TI - Modification of plant Rac/Rop GTPase signalling using bacterial toxin transgenes. AB - Bacterial protein toxins which modify Rho GTPase are useful for the analysis of Rho signalling in animal cells, but these toxins cannot be taken up by plant cells. We demonstrate in vitro deamidation of Arabidopsis Rop4 by Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1) and glucosylation by Clostridium difficile toxin B. Expression of the catalytic domain of CNF1 caused modification and activation of co-expressed Arabidopsis Rop4 GTPase in tobacco leaves, resulting in hypersensitive-like cell death. By contrast, the catalytic domain of toxin B modified and inactivated co-expressed constitutively active Rop4, blocking the hypersensitive response caused by over-expression of active Rops. In transgenic Arabidopsis, both CNF1 and toxin B inhibited Rop-dependent polar morphogenesis of leaf epidermal cells. Toxin B expression also inhibited Rop dependent morphogenesis of root hairs and trichome branching, and resulted in root meristem enlargement and dwarf growth. Our results show that CNF1 and toxin B transgenes are effective tools in Rop GTPase signalling studies. PMID- 23020818 TI - Ten-year trends in HIV prevalence among visitors to public health centers under the National HIV Surveillance System in Korea, 2000 to 2009. AB - BACKGROUND: Korea saw a sharp increase in HIV diagnosis from 2000. This serious public health concern must be monitored diligently. We identified the characteristics and trends in HIV prevalence among visitors to public health centers (PHCs) from 2000 to 2009. METHODS: We retrieved ten-year data of HIV tests from 253 PHCs. The HIV prevalence was analyzed by gender, age, nationality, region, and reason for HIV testing. Data were analyzed using logistic regression and score test for trend. RESULTS: HIV prevalence among PHCs' visitors has rapidly increased for six years since 2000, decreased from 2006, and then remained stable. Approximately 50% of total HIV tests were performed for sexually transmitted infection risk group (STI RG), who were tested 1.4 times within a year. Women and the 20s comprised approximately 70% and 40% of PHCs' visitors, respectively. The prevalence of voluntary test takers was the highest and showed most rapid increase (P = 0.007), but that of prisoners declined (P = 0.003). The prevalence of STI RG was lower than those of the other groups and remained stable throughout the ten-year period (P = 0.606). Percentage of anonymous tests was 2 3% of a total HIV tests, but overall HIV-positive rate showed a rapid increase (P < 0.001). CONCLUSIONS: As voluntary or anonymous testing groups are actively engaged in learning their status of HIV, these groups showed the highest in HIV infection. Groups in the population with these characteristics should be located and encouraged to be tested, and offered anonymity. This study suggests that it is important to ascertain the characteristics of people choosing to take voluntary testing. PMID- 23020819 TI - Effect of Lactobacillus rhamnosus LGG(r) and Bifidobacterium animalis ssp. lactis BB-12(r) on health-related quality of life in college students affected by upper respiratory infections. AB - College students are susceptible to upper respiratory infections (URI) due to inadequate sleep, stress and close living quarters. Certain probiotic strains modulate immune function and may improve health-related quality of life (HRQL) during URI. The present study recruited apparently healthy college students and assessed the effect of probiotics on HRQL outcomes (i.e. self-reported duration, symptom severity and functional impairment of URI) in those who developed URI. Missed school and work days due to URI were also considered. Subjects (n 231) were apparently healthy college students living on campus in residence halls at the Framingham State University (Framingham, MA, USA), and were randomised to receive placebo (n 117) or probiotic-containing powder (daily dose of minimum 1 billion colony-forming units of each Lactobacillus rhamnosus LGG(r) (LGG(r)) and Bifidobacterium animalis ssp. lactis BB-12(r) (BB-12(r)); n 114) for 12 weeks. Subjects completed The Wisconsin Upper Respiratory Symptom Survey-21 to assess HRQL during URI. The final analyses included 198 subjects (placebo, n 97 and probiotics, n 101). The median duration of URI was significantly shorter by 2 d and median severity score was significantly lower by 34% with probiotics v. placebo (P,0.001), indicating a higher HRQL during URI. Number of missed work days was not different between groups (P=0.429); however, the probiotics group missed significantly fewer school days (mean difference = 0.2 d) compared to the placebo group (P=0.002). LGG(r) and BB-12(r) may be beneficial among college students with URI for mitigating decrements in HRQL. More research is warranted regarding mechanisms of action associated with these findings and the cost benefit of prophylactic supplementation. PMID- 23020820 TI - Transverse myelitis secondary to melioidosis: a case report. AB - BACKGROUND: Melioidosis has become an emerging infection in Sri Lanka; a country which is considered non endemic for it. Paraplegia due to Burkholderia pseudomallei is a very rare entity encountered even in countries where the disease is endemic. There are no reported cases of transverse myelitis due to melioidosis in Sri Lankan population thus we report the first case. CASE PRESENTATION: A 21 year old farmer presented with sudden onset bi lateral lower limb weakness, numbness and urine retention. Examination revealed flaccid areflexic lower limbs with a sensory loss of all modalities and a sensory level at T10 together with sphincter involvement. MRI of the thoracolumbar spine showed extensive myelitis of the thoracic spine complicating left psoas abscess without definite extension to the spinal cord or cord compression. Burkholderia pseudomallei was isolated from the psoas abscess pus cultures and the diagnosis of melioidosis was confirmed with high titers of Burkholderia pseudomallei antibodies and positive PCR. He was treated with high doses of IV ceftazidime and oral cotrimoxazole for one month with a plan to continue cotrimoxazole and doxycycline till one year. Patient's general condition improved but the residual neurological problems persisted. CONCLUSION: The exact pathogenesis of spinal cord melioidosis is not quite certain except in the cases where there is direct microbial invasion, which does not appear to be the case in our patient. We postulate our patient's presentation could be due to ischemia of the spinal cord following septic embolisation or thrombosis of spinal artery due to the abscess nearby. A neurotrophic exotoxin causing myelitis or post infectious immunological demyelination is yet another possibility. This emphasizes the necessity of further studies to elucidate the exact pathogenesis in this type of presentations.Health care professionals in Sri Lanka, where this is an emerging infection, need to improve their knowledge regarding this disease and should have high degree of suspicion to make a correct and a timely diagnosis to reduce the morbidity and mortality due to Burkholderia pseudomallei infection. It is highly likely that this infection is under diagnosed in developing countries where diagnostic facilities are minimal. Therefore strategies to improve the awareness and upgrade the diagnostic facilities need to be implemented in near future. PMID- 23020821 TI - Mitogen- and stress-activated kinases regulate progenitor cell proliferation and neuron development in the adult dentate gyrus. AB - The neurogenic niche within the subgranular zone (SGZ) of the dentate gyrus is a source of new neurons throughout life. Interestingly, SGZ proliferative capacity is regulated by both physiological and pathophysiological conditions. One outstanding question involves the molecular mechanisms that regulate both basal and inducible adult neurogenesis. Here, we examined the role of the MAPK regulated kinases, mitogen- and stress-activated kinase (MSK)1 and MSK2. as regulators of dentate gyrus SGZ progenitor cell proliferation and neurogenesis. Under basal conditions, MSK1/2 null mice exhibited significantly reduced progenitor cell proliferation capacity and a corollary reduction in the number of doublecortin (DCX)-positive immature neurons. Strikingly, seizure-induced progenitor proliferation was totally blocked in MSK1/2 null mice. This blunting of cell proliferation in MSK1/2 null mice was partially reversed by forskolin infusion, indicating that the inducible proliferative capacity of the progenitor cell population was intact. Furthermore, in MSK1/2 null mice, DCX-positive immature neurons exhibited reduced neurite arborization. Together, these data reveal a critical role for MSK1/2 as regulators of both basal and activity dependent progenitor cell proliferation and morphological maturation in the SGZ. PMID- 23020826 TI - Refractory neuro-Behcet treated by tocilizumab: a case report. AB - A patient with central nervous system involvement of Behcet's disease was refractory to conventional immunosuppressive therapy and showed secondary failure of the anti-TNF agent infliximab. This presented as a progressive weakness of the legs and reduction in walking distance. The cerebrospinal fluid showed signs of inflammation including a vastly elevated IL-6 concentration. Given this result, the anti-IL-6 receptor antibody tocilizumab was administered and a good improvement of inflammatory parameters and a satisfactory increase of the walking distance were achieved. PMID- 23020828 TI - Reflective practice groups for nurses: a consultation liaison psychiatry nursing initiative: part 2--the evaluation. AB - This paper outlines an evaluation of reflective practice groups (RPG) involving nurses and midwives from three clinical nursing specialties at Redcliffe and Caboolture Hospitals, Queensland, Australia. The groups were facilitated by the consultation liaison psychiatry nurse and author using a process-focused, whole of-group approach to explore clinical narrative in a supportive group setting. This was a preliminary evaluation utilizing a recently-developed tool, the Clinical Supervision Evaluation Questionnaire, along with externally-facilitated focus groups. Nurses and midwives responded favourably to RPG, reporting a positive impact on clinical practice, self-awareness, and resilience. The majority of participants considered RPG had positive implications for team functioning. The focus groups identified the importance of facilitation style and the need to address aspects of workplace culture to enable group development and enhance the capacity for reflection. Evaluation of the data indicates this style of RPG can improve reflective thinking, promote team cohesion, and provide support for nurses and midwives working in clinical settings. Following on from this study, a second phase of research has commenced, providing more detailed, longitudinal evaluation across a larger, more diverse group of nurses. PMID- 23020827 TI - A note on Using regression models to analyze randomized trials: asymptotically valid hypothesis tests despite incorrectly specified models. AB - In the context of randomized trials, Rosenblum and van der Laan (2009, Biometrics 63, 937-945) considered the null hypothesis of no treatment effect on the mean outcome within strata of baseline variables. They showed that hypothesis tests based on linear regression models and generalized linear regression models are guaranteed to have asymptotically correct Type I error regardless of the actual data generating distribution, assuming the treatment assignment is independent of covariates. We consider another important outcome in randomized trials, the time from randomization until failure, and the null hypothesis of no treatment effect on the survivor function conditional on a set of baseline variables. By a direct application of arguments in Rosenblum and van der Laan (2009), we show that hypothesis tests based on multiplicative hazards models with an exponential link, i.e., proportional hazards models, and multiplicative hazards models with linear link functions where the baseline hazard is parameterized, are asymptotically valid under model misspecification provided that the censoring distribution is independent of the treatment assignment given the covariates. In the case of the Cox model and linear link model with unspecified baseline hazard function, the arguments in Rosenblum and van der Laan (2009) cannot be applied to show the robustness of a misspecified model. Instead, we adopt an approach used in previous literature (Struthers and Kalbfleisch, 1986, Biometrika 73, 363-369) to show that hypothesis tests based on these models, including models with interaction terms, have correct type I error. PMID- 23020829 TI - A pragmatic randomised controlled trial on routine iron prophylaxis during pregnancy in Maputo, Mozambique (PROFEG): rationale, design, and success. AB - The effects of prophylactic iron during pregnancy on maternal and child health in developing settings with endemic malaria and high prevalence of HIV remain unclear. This paper describes the rationale, implementation and success of a pragmatic randomised controlled trial comparing routine iron supplementation vs. screening and treatment for anaemia during pregnancy. The setting was two health centres in Maputo, Mozambique. Pregnant women (>= 12-week gestation; >= 18 years old; and not with a high-risk pregnancy, n=4326) were recruited. The main outcomes are preterm delivery and low birthweight. The women were randomly assigned to one of two iron administration policies: a routine iron group (n=2184) received 60 mg of ferrous sulphate plus 400 MUg of folic acid daily while a selective iron group (n=2142) had screening and treatment for anaemia and a daily intake of 1 mg of folic acid. The recruitment, follow-up, and collection of follow-up data were successful; both groups were similar to each other in all the trial stages. Collection of delivery data was challenging and data on about 40% of births is missing. These are currently being traced through different hospitals and health centres. The compliance of the study personnel and the women with regard to regular measurement of haemoglobin and intake of the iron and folic acid tablets was high and similar in both trial arms. Taking into account the various constraints encountered, the stages of the present trial prior to delivery were carried out well. PMID- 23020830 TI - Clonal relations of atypical enteropathogenic Escherichia coli O157:H16 strains isolated from various sources from several countries. AB - Atypical enteropathogenic Escherichia coli (aEPEC) is comprised of a large heterogeneous group of strains and serotypes that carry the intimin gene (eae) but no other EPEC virulence factors. In a previous study, we examined a few aEPEC strains of O157:H16 serotype from the U.S. and France and found these to be nearly homologous, and speculated that the same strain had been disseminated or perhaps they are part of a large clonal group that exists worldwide. To test that hypothesis, we examined additional 45 strains isolated from various sources from 4 other countries and determined that although there are a few eae-negative O157:H16 strains, most are aEPEC that carried eae and specifically, the epsilon eae allele. Analysis by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing showed that as a whole, O157:H16 strains are phylogenetically diverse and have different sequence types and PFGE profiles. But the aEPEC strains within the O157:H16 serotype, regardless of the eae allele carried, are a highly conserved and homologous group of sequence type (ST)-171 strains that shared similar PFGE profiles. These aEPEC strains of O157:H16 serotype are not closely related to any of the major EPEC and enterohemorrhagic E. coli clonal lineages and appear to be part of a large clonal group that are prevalent worldwide. PMID- 23020831 TI - A decrease in the percentage of CD3+ cells is correlated with clinical improvement during plasmapheresis in patients with myasthenia gravis. AB - Plasmapheresis not only removes circulating antibodies but also modulates cellular immunity, including lymphocyte subsets. To investigate the effect of double-filtration plasmapheresis (DFPP) on the ratio of lymphocyte subsets in patients with myasthenia gravis (MG), we examined the percentages of B-cells, T cells, T helper (Th) cells, T suppressor (Ts) cells, natural killer (NK) cells, NKT cells, and Th/Ts ratio before and after a single DFPP session and after a course of DFPP. A total of 26 patients were recruited; their peripheral blood lymphocyte subsets were assayed using flow cytometry. After a single session of DFPP treatment, the percentages of T-cells (P = 0.0200), Th cells (P = 0.0178), and the Th/Ts ratio (P = 0.0309) decreased significantly, whereas the percentage of NK cells (P = 0.0007) increased significantly. More importantly, after one course of DFPP treatment, the reduced clinical quantitative MG (QMG) score was correlated with the decrease of the percentage of T-cells (r = 0.5005, P = 0.0092). Fourteen thymectomized MG patients had decreased percentages of T-cells (P = 0.0304) and Th cells (P = 0.0444), whereas they had increased NK cells (P = 0.0197) after a single DFPP session. Here, transiently decreased percentages of T cells after the full DFPP course could enhance the effectiveness of plasmapheresis for MG patients. PMID- 23020832 TI - The use of FEIBA(r) in the correction of coagulation abnormalities induced by dabigatran. AB - INTRODUCTION: Studies have shown dabigatran to be an effective anticoagulant with an acceptable bleeding profile. None the less, these patients do suffer from bleeding complications. Unfortunately, there are currently no direct reversal agents to dabigatran or established guidelines on the management of bleeding in these circumstances. METHODS: We examined the effects on thrombin generation parameters, after ex-vivo spiking the plasma of patients on dabigatran (n = 8) with FEIBA((r)). These parameters were measured using the calibrated automated thrombography (CAT) machine. RESULTS: In our study, we showed the ability of FEIBA((r)) to improve the abnormal thrombin generation parameters caused by dabigatran in these patients. CONCLUSION: This provides evidence, lacking in the literature, that this agent may be able to provide haemostatic support in situations where dabigatran induced coagulopathy exists. PMID- 23020833 TI - Early breastfeeding experiences of adolescent mothers: a qualitative prospective study. AB - BACKGROUND: Teen mothers face many challenges to successful breastfeeding and are less likely to breastfeed than any other population group in the U.S. Few studies have investigated this population; all prior studies are cross-sectional and collect breastfeeding data retrospectively. The purpose of our qualitative prospective study was to understand the factors that contribute to the breastfeeding decisions and practices of teen mothers. METHODS: This prospective study took place from January through December 2009 in Greensboro, North Carolina in the U.S. We followed the cohort from pregnancy until two weeks after they ceased all breastfeeding and milk expression. We conducted semi-structured interviews at baseline and follow-up, and tracked infant feeding weekly by phone. We analyzed the data to create individual life and breastfeeding journeys and then identified themes that cut across the individual journeys. RESULTS: Four of the five teenagers breastfed at the breast for nine days: in contrast, one teen breastfed exclusively for five months. Milk expression by pumping was associated with significantly longer provision of human milk. Breastfeeding practices and cessation were closely connected with their experiences as new mothers in the context of ongoing multiple roles, complex living situations, youth and dependency, and poor knowledge of the fundamentals of breastfeeding and infant development. Breastfeeding cessation was influenced by inadequate breastfeeding skill, physically unpleasant and painful early experiences they were unprepared to manage, and inadequate health care response to real problems. CONCLUSIONS: Continued breastfeeding depends on a complex interplay of multiple factors, including having made an informed choice and having the skills, support and experiences needed to sustain the belief that breastfeeding is the best choice for them and their baby given their life situation. Teenagers in the US context need to have a positive early breastfeeding experience, be able to identify and claim a reliable support system supportive of breastfeeding, and gain through their experience, a belief in their own agency and competency as mothers. PMID- 23020834 TI - Dose-dependent effects of gamma radiation on lettuce (Lactuca sativa var. capitata) seedlings. AB - Abstract Purpose: The objectives of this study were to determine the effects of gamma radiation on lettuce growth and development, as well as on the content of photosynthetic pigments in 28 days lettuce leaf. MATERIALS AND METHODS: Lettuce dry seeds were exposed to a (60)Co [Cobalt-60] gamma source at doses ranging from 2-70 Gray (Gy). The photosynthetic pigment content was determined spectrophotometrically. RESULTS: Our results showed that an irradiation dose between of 2-30 Gy enhanced the growth parameters (final germination percentage, germination index, root and hypocotyl length) as compared to untreated plants. Seed germination test revealed that 30 Gy irradiation dose induced the highest increase of growth parameters, while at 70 Gy a significant decrease of plant vegetative growth was recorded. The results indicated that exposing the seeds at doses ranging from 2-30 Gy enhanced the photosynthetic pigments (chlorophyll a, chlorophyll b, carotenoids) content, while at higher doses (70 Gy)) the decrease of the assimilatory pigments was noticed. CONCLUSION: The present results suggested that seed treatment with gamma radiations (0-30 Gy) was effective in stimulating plant growth and development, as well as the content of assimilatory pigments. At a higher dose of 70 Gy, there was a drastic reduction in the length of shoots and roots and also in the total chlorophyll content. These observations confirm that ionizing radiation stimulates physiological parameters up to certain low doses, and then it inhibits these parameters at higher doses. PMID- 23020835 TI - [Not Available]. PMID- 23020836 TI - [Not Available]. PMID- 23020837 TI - [Not Available]. PMID- 23020838 TI - Temperature variation of ultralow frequency modes and mean square displacements in solid lasamide (diuretic drug) studied by 35Cl-NQR, X-ray and DFT/QTAIM. AB - The application of combined (35)Cl-NQR/X-ray/DFT/QTAIM methods to study the temperature variation of anisotropic displacement parameters and ultralow frequency modes of anharmonic torsional vibrations in the solid state is illustrated on the example of 2,4-dichloro-5-sulfamolybenzoic acid (lasamide, DSBA) which is a diuretic and an intermediate in the synthesis of furosemide and thus its common impurity. The crystallographic structure of lasamide is solved by X-ray diffraction and refined to a final R-factor of 3.06% at room temperature. Lasamide is found to crystallize in the triclinic space group P-1, with two equivalent molecules in the unit cell a = 7.5984(3) A, b = 8.3158(3) A, c = 8.6892(3) A; alpha = 81.212(3) degrees , beta = 73.799(3) degrees , gamma = 67.599(3) degrees . Its molecules form symmetric dimers linked by two short and linear intermolecular hydrogen bonds O-H...O (O-H...O = 2.648 A and ?OHO = 171.5 degrees ), which are further linked by weaker and longer intermolecular hydrogen bonds N-H...O (N-H...O = 2.965 A and ?NHO = 166.4 degrees ). Two (35)Cl-NQR resonance frequencies, 36.899 and 37.129 MHz, revealed at room temperature are assigned to chlorine sites at the ortho and para positions, relative to the carboxyl functional group, respectively. The difference in C-Cl(1) and C-Cl(2) bond lengths only slightly affects the value of (35)Cl-NQR frequencies, which results mainly from chemical inequivalence of chlorine atoms but also involvement in different intermolecular interactions pattern. The smooth decrease in both (35)Cl-NQR frequencies with increasing temperature in the range of 77-300 K testifies to the averaging of EFG tensor at each chlorine site due to anharmonic torsional vibrations. Lasamide is thermally stable; no temperature-induced release of chlorine or decomposition of this compound is detected. The temperature dependence of ultralow frequency modes of anharmonic small-angle internal torsional vibrations averaging EFG tensor and mean square angle displacements at both chlorine sites is derived from the (35)Cl-NQR temperature dependence. The frequencies of torsional vibrations higher for the para site than the ortho site are in good agreement with those obtained from thermal parameters obtained from X-ray studies. The mean square angle displacements are in good agreement with those estimated from X-ray data with the use of the TLS model. The detailed DFT/QTAIM analysis suggests that the interplay between different hydrogen bonds in adjacent molecules forming dimers is responsible for the differences in flexibility of the carboxyl and sulphonamide substituents as well as both C-Cl(1) and C-Cl(2) bonds. Three ultralow wavenumber modes of internal vibrations in Raman and IR spectra obtained at the B3LYP/6-311++G(d,p) level close to those obtained within the TLS model suggest that internal and external modes of vibrations are not well separated. PMID- 23020839 TI - A rare case of gamma knife-induced smoking cessation in a patient with a vestibular schwannoma. AB - OBJECTIVE: We report a rare case of a patient with a vestibular schwanomma who underwent gamma knife irradiation and subsequently lost unilateral taste sensation. As a result, the patient ceased smoking. PMID- 23020840 TI - Aggressive continuous passive motion exercise does not improve knee range of motion after total knee arthroplasty. AB - AIMS AND OBJECTIVES: The aim of this study was to evaluate the effects of continuous passive motion on the range of motion, postoperative pain and life quality of patients undergoing total knee arthroplasty within six months after the operation. BACKGROUND: Total knee arthroplasty reduces pain and improves range of motion of the osteoarthritic knee joint. Continuous passive motion increases postoperative movement, but there is some controversy regarding whether aggressive continuous passive motion can improve range of motion or life quality, and whether it induces more pain. DESIGN: A prospective controlled study was conducted in a medical centre in Taiwan from January to December 2006. METHODS: One hundred and seven patients were recruited. The patients underwent the basic rehabilitation protocols (the control group) or the basic rehabilitation protocols and additional daily use of continuous passive motion for more than six hours per day (the experimental group). The range of motion, modified Short Form 36 (SF-36) and semi-quantitative visual analogue scale were recorded. Results. Range of motion increased from 109 degrees preoperatively to 125 degrees at six months postoperatively in the treatment group and from 111 degrees preoperatively to 125 degrees at six months postoperatively in the control group. Visual analogue scale decreased from 7.78 preoperatively to 0.37 at six months postoperatively in the treatment group and from 7.92 preoperatively to 0.21 at six months postoperatively in the control group. The SF-36 improved from 3.76 preoperatively to 1.77 at six months postoperatively in the treatment group and from 3.68 preoperatively to 1.83 at six months postoperatively in the control group. There was no significant difference in range of motion, visual analogue scale and SF-36 between groups at each visit. CONCLUSION: With the advances in total knee arthroplasty surgical technique, aggressive continuous passive motion does not provide obvious benefits. RELEVANCE TO CLINICAL PRACTICE: Total knee arthroplasty can alleviate pain and improve range of motion, but aggressive continuous passive motion does not provide additional benefits. PMID- 23020841 TI - Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorder (ASD) is highly heritable, but the genetic risk factors for it remain largely unknown. Although structural variants with large effect sizes may explain up to 15% ASD, genome-wide association studies have failed to uncover common single nucleotide variants with large effects on phenotype. The focus within ASD genetics is now shifting to the examination of rare sequence variants of modest effect, which is most often achieved via exome selection and sequencing. This strategy has indeed identified some rare candidate variants; however, the approach does not capture the full spectrum of genetic variation that might contribute to the phenotype. METHODS: We surveyed two loci with known rare variants that contribute to ASD, the X-linked neuroligin genes by performing massively parallel Illumina sequencing of the coding and noncoding regions from these genes in males from families with multiplex autism. We annotated all variant sites and functionally tested a subset to identify other rare mutations contributing to ASD susceptibility. RESULTS: We found seven rare variants at evolutionary conserved sites in our study population. Functional analyses of the three 3' UTR variants did not show statistically significant effects on the expression of NLGN3 and NLGN4X. In addition, we identified two NLGN3 intronic variants located within conserved transcription factor binding sites that could potentially affect gene regulation. CONCLUSIONS: These data demonstrate the power of massively parallel, targeted sequencing studies of affected individuals for identifying rare, potentially disease-contributing variation. However, they also point out the challenges and limitations of current methods of direct functional testing of rare variants and the difficulties of identifying alleles with modest effects. PMID- 23020844 TI - Antioxidant, antiglycation and cytotoxicity evaluation of selected medicinal plants of the Mascarene Islands. AB - BACKGROUND: Many indigenous plants of Mascarene Islands have been used in folkloric medicine to manage diabetes but few species have received scientific attention. Selected traditional medicinal plants (Antidesma madagascariense Lam. Euphorbiaceae (AM), Erythroxylum macrocarpum O.E.Schulz -Erythroxylaceae (EM), Pittosporum senacia Putterl -Pittosporaceae (PS), Faujasiopsis flexuosa Lam. C.Jeffrey -Asteraceae (FF), Momordica charantia Linn -Cucurbitaceae (MC) and Ocimum tenuiflorum L -Lamiaceae (OT) were evaluated for their antioxidant, antiglycation and cytotoxic potential in vitro. METHODS: Graded concentrations (1.25-100 MUg/mL) of the crude methanolic and water extracts and fractions (dichloromethane, ethyl-acetate, n-butanol and water) were evaluated for abilities to scavenge 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH), nitric oxide (NO), superoxide (SO) radicals and to inhibit lipoxygenase and formation of advanced glycation endproduct (AGE) in vitro. The MTT (3-(4, 5-dimethylthazol-2 yl)-2,5-diphenyl tetrazonium bromide) cytotoxicity test was performed on 3T3 cell line. RESULTS: Only IC50 for DPPH, SO, NO and lipoxygenase for AM, FF and OT crude extracts and fractions were comparable to ascorbic acid and quercetin activity. Crude aqueous extracts of AM and FF showed IC50 of 4.08 and 3.89 MUg/mL respectively for lipoxygenase which was significantly lower (p < 0.05) than quercetin (10.86 +/- 0.68 MUg/mL). The three crude aqueous extracts of these plants and their n-butanol fractions also showed antiglycation activities (p < 0.05) comparable to aminoguanidine. Increasing concentrations (250-2000 MUg/mL) of the six crude extracts (Methanol and water) and their fractions did not inhibit mitochondrial respiration as measured by MTT cytotoxicity assay. CONCLUSION: AM, FF and OT crude extracts and fractions have potent antioxidant and antiglycation properties with no apparent cytotoxicity and might have prophylactic and therapeutic potentials in the management of diabetes and related complications. Our study tends to validate the traditional use of these medicinal herbs and food plants as complementary and alternative medicines. PMID- 23020843 TI - Interferon regulatory factor 8/interferon consensus sequence binding protein is a critical transcription factor for the physiological phenotype of microglia. AB - BACKGROUND: Recent fate-mapping studies establish that microglia, the resident mononuclear phagocytes of the CNS, are distinct in origin from the bone marrow derived myeloid lineage. Interferon regulatory factor 8 (IRF8, also known as interferon consensus sequence binding protein) plays essential roles in development and function of the bone marrow-derived myeloid lineage. However, little is known about its roles in microglia. METHODS: The CNS tissues of IRF8 deficient mice were immunohistochemically analyzed. Pure microglia isolated from wild-type and IRF8-deficient mice were studied in vitro by proliferation, immunocytochemical and phagocytosis assays. Microglial response in vivo was compared between wild-type and IRF8-deficient mice in the cuprizon-induced demyelination model. RESULTS: Our analysis of IRF8-deficient mice revealed that, in contrast to compromised development of IRF8-deficient bone marrow myeloid lineage cells, development and colonization of microglia are not obviously affected by loss of IRF8. However, IRF8-deficient microglia demonstrate several defective phenotypes. In vivo, IRF8-deficient microglia have fewer elaborated processes with reduced expression of IBA1/AIF1 compared with wild-type microglia, suggesting a defective phenotype. IRF8-deficient microglia are significantly less proliferative in mixed glial cultures than wild-type microglia. Unlike IRF8 deficient bone marrow myeloid progenitors, exogenous macrophage colony stimulating factor (colony stimulating factor 1) (M-CSF (CSF1)) restores their proliferation in mixed glial cultures. In addition, IRF8-deficient microglia exhibit an exaggerated growth response to exogenous granulocyte-macrophage colony stimulating factor (colony stimulating factor 2) (GM-CSF (CSF2)) in the presence of other glial cells. IRF8-deficient microglia also demonstrate altered cytokine expressions in response to interferon-gamma and lipopolysaccharide in vitro. Moreover, the maximum phagocytic capacity of IRF8-deficient microglia is reduced, although their engulfment of zymosan particles is not overtly impaired. Defective scavenging activity of IRF8-deficient microglia was further confirmed in vivo in the cuprizone-induced demyelination model in mice. CONCLUSIONS: This study is the first to demonstrate the essential contribution of IRF8-mediated transcription to a broad range of microglial phenotype. Microglia are distinct from the bone marrow myeloid lineage with respect to their dependence on IRF8-mediated transcription. PMID- 23020845 TI - Are the infrared thermography findings skin temperature-dependent? a study on neck pain patients. AB - BACKGROUND: Skin temperature (Tsk) disorders have been proposed as sign of impaired innervation in several conditions, but the influence of different factors on the infrared thermography (IRT) findings remains unclear. METHODS: The relations between the Tsk and deltaT (side-to-side temperature difference) values, and influence of age, gender, anthropometric characteristics and pain intensity on those values were analysed in non-specific neck pain (NP) patients (n = 91) using mixed model analysis. IRT findings were also compared in subgroups of NP patients: with cold (CHNPP, n = 21) or warm hands (WHNPP, n = 56) and healthy controls, with cold (CHC, n = 11) or warm hands (WHC, n = 19). Also, the stability of deltaT values in CHNPP was examined. RESULTS: Only the area of measurement and the actual Tsk influenced the deltaT values. CHNPP demonstrated higher deltaT values in distal parts, compared with WHNPP and controls, but those values vanished when their hands turned warm. deltaT values in CHNPP were related to the pain intensity. The findings of WHNPP and WHC did not differ. CONCLUSION: Our results suggest that the deltaT values as signs of impaired Tsk regulation are dynamic and better detectable in cold skin. The results underline the need of caution in interpretation of IRT findings. PMID- 23020846 TI - Neuroprotective actions of glucagon-like peptide-1 in differentiated human neuroprogenitor cells. AB - Glucagon-like peptide-1 (GLP-1)-based therapies are currently available for the treatment of type 2 diabetes, based on their actions on pancreatic beta cells. GLP-1 is also known to exert neuroprotective actions. To determine its mechanism of action, we developed a neuron-rich cell culture system by differentiating human neuroprogenitor cells in the presence of a combination of neurotrophins and retinoic acid. The neuronal nature of these cells was characterized by neurogenesis pathway-specific array. GLP-1 receptor expression was seen mainly in the neuronal population. Culture of neurons in the presence of Abeta oligomers resulted in the induction of apoptosis as shown by the activation of caspase-3 and caspase-6. Exendin-4, a long-acting analog of GLP-1, protected the neurons from apoptosis induced by Abeta oligomers. Exendin-4 stimulated cyclic AMP response element binding protein phosphorylation, a regulatory step in its activation. A transient transfection assay showed induction of a reporter linked to CRE site-containing human brain-derived neurotrophic factor promoter IV, by the growth factor through multiple signaling pathways. The anti-apoptotic action of exendin-4 was lost following down-regulation of cAMP response element binding protein. Withdrawal of neurotrophins resulted in the loss of neuronal phenotype of differentiated neuroprogenitor cells, which was prevented by incubation in the presence of exendin-4. Diabetes is a risk factor in the pathogenesis of Alzheimer's disease. Our findings suggest that GLP-1-based therapies can decrease the incidence of Alzheimer's disease among aging diabetic population. PMID- 23020847 TI - Oral availability and brain penetration of the B-RAFV600E inhibitor vemurafenib can be enhanced by the P-GLYCOprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. AB - Vemurafenib (PLX4032) is a novel tyrosine kinase inhibitor that has clinical efficacy against metastatic melanoma harboring a BRAF(V600E) mutation. We aimed to establish whether oral availability and brain penetration of vemurafenib could be restricted by the multidrug efflux transporters P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), as these might limit therapeutic efficacy, especially against brain metastases. In vitro, vemurafenib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse Abcg2, but not by mouse Abcc2. Upon oral administration of vemurafenib (5 mg/kg), Abcb1a/1b(-/-) mice had a 1.6-fold increased, Abcg2(-/-) mice a 2.3 fold increased, and Abcb1a/1b(-/-);Abcg2(-/-) mice a 6.6-fold increased plasma AUC, respectively, compared to wild-type (WT) mice, indicating a marked and additive role of these transporters in limiting vemurafenib oral availability. Brain-to-plasma ratios of vemurafenib (oral, 25 mg/kg) were not increased in Abcg2(-/-) mice, only 1.7-fold in Abcb1a/1b(-/-) mice, but 21.4-fold in Abcb1a/1b(-/-);Abcg2(-/-) mice, indicating pronounced overlapping functions of these transporters in reducing vemurafenib brain accumulation. Oral coadministration of the dual ABCB1 and ABCG2 inhibitor elacridar almost completely eliminated the roles of Abcb1 and Abcg2 in restricting oral availability and brain accumulation of vemurafenib. As predicted by previously described pharmacokinetic modeling, halving the amount of active efflux transport at the WT blood-brain barrier by testing heterozygous Abcb1a/1b(+/-);Abcg2(+/-) mice had little impact on vemurafenib brain accumulation. Our data suggest that elacridar coadministration may be considered to improve the therapeutic efficacy of vemurafenib, especially for brain metastases located behind a functional blood brain barrier. PMID- 23020848 TI - Positioning mental health nursing practice within a positive health paradigm. AB - Mental health service provision has traditionally been dominated by biomedical models of illness and disorder, a problem-based orientation, and the assessment and management of risk. While psychotherapeutic approaches are numerous and have been widely utilized, psychotropic medications, either as monotherapy or in conjunction with psychological therapies, remain the mainstay for the 'treatment' of mental health problems. This is despite growing uncertainty over the effectiveness of psychotropic medications (particularly antidepressants), as well as their potential for enduring and debilitating side-effects. This discussion paper outlines the emerging field of positive health, which eschews a psychiatric disorder and illness focus, and is instead oriented towards the identification of strengths, abilities, hopes, and the individual's preferred future. The shift in positive health, from illness towards wellness, aims to build health literacy and the capacity of individuals to make decisions conducive to health, and thereby make more effective the use of health-care services. A positioning of mental health nursing practice within a positive health paradigm is promoted. By illustration, a number of solution-focused mental health assessment questions are tabled to contrast the current format for mental health assessment, which rather than being 'comprehensive', is predominantly concerned only with problem and risk identification, and the search for pathology in the individual. PMID- 23020849 TI - Thiamin status of premature infants assessed by measurement of thiamin diphosphate in whole blood. AB - Premature infants constitute a risk group for thiamin deficiency but only little is known about their thiamin status. The aim of the present study was to investigate the thiamin status of premature infants by determination of thiamin diphosphate (TDP) and to identify risk factors for low TDP concentrations. In a prospective, longitudinal study TDP was determined by HPLC in whole blood in the first days of life and approximately every 2 weeks. Demographical data, weight gain, type of nutrition and thiamin intake were recorded. A total of 111 premature infants were included at the Children's Hospital of the University of Cologne, Germany from May 2009 until December 2010 and 222 blood samples were analysed. TDP concentrations showed an age-dependent decline (age 0-10 d, mean TDP = 110.6 ng/ml; age 11-20 d, mean TDP = 95.4 ng/ml; age 21-103 d, mean TDP = 33.6 ng/ml). There was no significant difference between males and females. Young gestational age and low birth weight were associated with low TDP concentrations. No infant was diagnosed with thiamin deficiency. The current nutritional regimen in our hospital did not lead to thiamin deficiency in the study cohort. Further research is required to evaluate how TDP concentrations are regulated in premature infants. PMID- 23020852 TI - Mitochondria and telomeres: the promiscuous roles of TIN2. AB - Telomeric proteins are best known for their role in maintenance of telomere function. In this issue, Chen et al. (2012) demonstrate that the telomeric protein TIN2 can specifically localize to the mitochondria, where it can regulate metabolism and ROS production. PMID- 23020850 TI - Effectiveness of dance in patients with fibromyalgia: a randomized, single-blind, controlled study. AB - OBJECTIVES: The aim of the present study was to assess the effectiveness of belly dance as a treatment option for patients with fibromyalgia. METHODS: Eighty female patients with fibromyalgia between 18 to 65 years were randomly allocated to a dance group (n=40) and control group (n=40). Patients in the dance group underwent 16 weeks of belly dance twice a week, while the patients in the control group remained on a waiting list. The patients were evaluated with regard to pain (VAS), function (6MWT), quality of life (FIQ and SF-36), depression (Beck Inventory), anxiety (STAI) and self-image (BDDE). Evaluations were carried out at baseline, 16 weeks and 32 weeks by a blinded assessor. RESULTS: The dance group achieved significant improvements in VAS for pain (p<0.001), six-minute walk test (p<0.001), FIQ (p=0.003), BDDE (p<0.009) as well as the pain (p<0.001), emotional aspects (p<0.003) and mental health (p<0.021) subscales on the SF-36. CONCLUSIONS: Belly dance can be used in the treatment of fibromyalgia to reduce pain and improve functional capacity, quality of life and self-image. PMID- 23020853 TI - RNase E finds some sRNAs stimulating. AB - In this issue of Molecular Cell, Bandyra et al. (2012) describe how a bacterial sRNA can lead to degradation of an mRNA by pairing within the coding region of the mRNA; the 5' monophosphate end of the sRNA activates RNase E, leading to rapid cleavage of the paired mRNA. PMID- 23020855 TI - Family members' perceptions of the nursing bedside handover. AB - AIMS AND OBJECTIVES: To explore families' perceptions of shift-to-shift bedside handover. BACKGROUND: The potential role families can play in bedside handover is unknown. Understanding family members' perceptions can provide a foundation for nurses to tailor their bedside handover to family members' perceptions, encouraging their involvement and potentially improving patient care. DESIGN: Qualitative study, using case study methodology. METHODS: The study was conducted with eight family members in one rehabilitation ward in Queensland, Australia, in 2009. Data included observations of bedside handover, field notes and in-depth interviews. Thematic analysis of data was conducted to identify unique and common themes indicative of family perceptions. RESULTS: Three major themes emerged. The first, understanding the situation, consisted of three subthemes: feeling informed, understanding the patient's condition and understanding patient's treatment. The second theme was interacting with nursing staff, with five subthemes, including sharing information, clarifying information, assisting in care, asking questions and interpreting for the patient. The final subtheme was finding value, which contained five subthemes: feeling at ease, feeling included, valuing individualisation, preparing for the future and maintaining patient privacy. CONCLUSIONS: Bedside handover provides an opportunity to involve family members in patient care and promote family-centred care core concepts. Family members value the chance to participate and can ultimately improve the accuracy of handover communication. RELEVANCE TO CLINICAL PRACTICE: Bedside handover is beneficial for nurses, patients and family members and embodies patient and family-centred care. Managers should consider its implementation in hospitals, developing strategies such as standard operating protocols for a more family inclusive approach to communication. Nurses may require further training to best undertake bedside handover and involve family members in care. The study suggests expansion of research into this important area of family-centred care. PMID- 23020856 TI - The culture of care within psychiatric services: tackling inequalities and improving clinical and organisational capabilities. AB - INTRODUCTION: Cultural Consultation is a clinical process that emerged from anthropological critiques of mental healthcare. It includes attention to therapeutic communication, research observations and research methods that capture cultural practices and narratives in mental healthcare. This essay describes the work of a Cultural Consultation Service (ToCCS) that improves service user outcomes by offering cultural consultation to mental health practitioners. The setting is a psychiatric service with complex and challenging work located in an ethnically diverse inner city urban area. Following a period of 18 months of cultural consultation, we gather the dominant narratives that emerged during our evaluation of our service. RESULTS: These narratives highlight how culture is conceptualized and acted upon in the day-to-day practices of individual health and social care professionals, specialist psychiatric teams and in care systems. The findings reveal common narratives and themes about culture, ethnicity, race and their perceived place and meaningfulness in clinical care. These narratives express underlying assumptions and covert rules for managing, and sometimes negating, dilemmas and difficulties when considering "culture" in the presentation and expression of mental distress. The narratives reveal an overall "culture of understanding cultural issues" and specific "cultures of care". These emerged as necessary foci of intervention to improve service user outcomes. CONCLUSION: Understanding the cultures of care showed that clinical and managerial over-structuring of care prioritises organisational proficiency, but it leads to inflexibility. Consequently, the care provided is less personalised and less accommodating of cultural issues, therefore, professionals are unable to see or consider cultural influences in recovery. PMID- 23020854 TI - Molecular roadblocks for cellular reprogramming. AB - During development, diverse cellular identities are established and maintained in the embryo. Although remarkably robust in vivo, cellular identities can be manipulated using experimental techniques. Lineage reprogramming is an emerging field at the intersection of developmental and stem cell biology in which a somatic cell is stably reprogrammed into a distinct cell type by forced expression of lineage-determining factors. Lineage reprogramming enables the direct conversion of readily available cells from patients (such as skin fibroblasts) into disease-relevant cell types (such as neurons and cardiomyocytes) or into induced pluripotent stem cells. Although remarkable progress has been made in developing novel reprogramming methods, the efficiency and fidelity of reprogramming need to be improved in order increase the experimental and translational utility of reprogrammed cells. Studying the mechanisms that prevent successful reprogramming should allow for improvements in reprogramming methods, which could have significant implications for regenerative medicine and the study of human disease. Furthermore, lineage reprogramming has the potential to become a powerful system for dissecting the mechanisms that underlie cell fate establishment and terminal differentiation processes. In this review, we will discuss how transcription factors interface with the genome and induce changes in cellular identity in the context of development and reprogramming. PMID- 23020857 TI - Genomic view on the peopling of India. AB - India is known for its vast human diversity, consisting of more than four and a half thousand anthropologically well-defined populations. Each population differs in terms of language, culture, physical features and, most importantly, genetic architecture. The size of populations varies from a few hundred to millions. Based on the social structure, Indians are classified into various caste, tribe and religious groups. These social classifications are very rigid and have remained undisturbed by emerging urbanisation and cultural changes. The variable social customs, strict endogamy marriage practices, long-term isolation and evolutionary forces have added immensely to the diversification of the Indian populations. These factors have also led to these populations acquiring a set of Indian-specific genetic variations responsible for various diseases in India. Interestingly, most of these variations are absent outside the Indian subcontinent. Thus, this review is focused on the peopling of India, the caste system, marriage practice and the resulting health and forensic implications. PMID- 23020858 TI - Compromised hematopoiesis and increased DNA damage following non-lethal ionizing radiation of a human hematopoietic system reconstituted in immunodeficient mice. AB - PURPOSE: Precise understanding of radiation effects is critical to development of new modalities for the prevention and treatment of radiation-induced damage. In this study, we evaluated the effects of non-lethal doses of X-ray irradiation on human hematopoietic stem and progenitor cells (HSPC) reconstituted in NOD/Shi scid, IL2Rgamma(null) (NOG) immunodeficient mice. MATERIALS AND METHODS: We transplanted cord blood CD34(+) HSPC into NOG mice irradiated with 2.0 Gy via tail veins. At the 12th week after transplantation, the NOG mice were irradiated with 0, 0.5, 1.0, 2.0, or 4.0 Gy, and the radiation effects on human HSPC in vivo were evaluated. RESULTS: Although a majority of the mice irradiated with 2.0 Gy or more died in 12 weeks after irradiation, the mice that were exposed to 0.5 or 1.0 Gy of irradiation survived and were subjected to analysis. The chimerism of human CD45(+) hematopoietic cells in peripheral blood and bone marrow (BM) of the recipient mice was reduced in an X-ray dose-dependent manner after irradiation. Percentages of human CD34(+) HSPC as well as human (CD34+CD38-) HSC in BM similarly declined. (CD34+CD38-) HSC purified from the humanized mice at the 12th week after irradiation showed significantly increased numbers of phosphorylated H2AX (gammaH2AX) foci, a marker of DNA breaks, in an X-ray dose- dependent manner. Expression of p16INK4A, a hallmark of aging of HSC, was also detected only in HSPC from irradiated mice. CONCLUSIONS: With further refinement, the humanized mouse model might be effectively used to study the biological effects of non-lethal radiation in vivo. PMID- 23020859 TI - Effect of minimized perfusion circuit on brain injury markers carnosinase and brain-type fatty binding protein in coronary artery bypass grafting patients. AB - A minimized perfusion circuit (MPC) has proven to be superior to the conventional circulatory perfusion bypass (CCPB) as it reduces the blood-material interaction and hemodilution. Until now not much is known about impact these different perfusion systems have on the brain. The objective of this study is to determine carnosinase and brain-type fatty binding protein (BFABP) activity as novel specific biomarkers for ischemic brain tissue damage and how their activity differs during and after MPC and CCPB as well as to compare the inflammatory response of both perfusion systems. In a prospective pilot study, 28 patients undergoing coronary artery bypass grafting were randomly divided into an MPC group (n = 14) and a CCPB group (n = 14). Blood samples were taken before, during, and after operation until the fifth postoperative day. The brain biomarker carnosinase was determined by measuring the rate of histidine production from the substrate homocarnosine, whereas BFABP and interleukin-6 were determined by enzyme-linked immunosorbent assay (ELISA). C-reactive protein (CRP) and endothelin-1 were determined by enzyme immunoassay. The mean serum carnosinase activity was significantly higher in MPC (0.57 +/- 0.34 nM histidine/mL/min) as compared with the CCPB group (0.36 +/- 0.13 nM histidine/mL/min) at the end of operation (P = 0.02). The BFABP did not show any difference between the two groups in the immediate postoperative period until the second postoperative day. From that time point onward, it showed a steep increase in the CCPB group (581.3 +/- 157.11 pg/mL) as compared with the concentrations in the MPC group (384.6 +/- 39 pg/mL) (P = 0.04). The inflammation markers interleukin-6 and CRP showed a similar pattern in both groups without significant difference. In contrast, the leukocyte count on operation day and endothelin-1 on the first postoperative day were significantly higher in the CCPB group (P = 0.01, P = 0.03, respectively). MPC showed a significant higher and stable serum carnosinase activity during extracorporeal circulation as compared with the CCPB due to less hemodilution and a better preserved oxygen capacity. As a consequence, the antioxidant stress during MPC is limited as compared with CCPB, which means less brain tissue damage reflected by a lower BFABP release. Except endothelin-1 and leukocyte count, the inflammatory response of the MPC and CCPB was equal. PMID- 23020860 TI - Intravenous multipotent adult progenitor cell therapy after traumatic brain injury: modulation of the resident microglia population. AB - INTRODUCTION: We have demonstrated previously that the intravenous delivery of multipotent adult progenitor cells (MAPC) after traumatic brain injury affords neuroprotection via interaction with splenocytes, leading to an increase in systemic anti-inflammatory cytokines. We hypothesize that the observed modulation of the systemic inflammatory milieu is related to T regulatory cells and a subsequent increase in the locoregional neuroprotective M2 macrophage population. METHODS: C57B6 mice were injected with intravenous MAPC 2 and 24 hours after controlled cortical impact injury. Animals were euthanized 24, 48, 72, and 120 hours after injury. In vivo, the proportion of CD4(+)/CD25(+)/FOXP3(+) T regulatory cells were measured in the splenocyte population and plasma. In addition, the brain CD86(+) M1 and CD206(+) M2 macrophage populations were quantified. A series of in vitro co-cultures were completed to investigate the need for direct MAPC:splenocyte contact as well as the effect of MAPC therapy on M1 and M2 macrophage subtype apoptosis and proliferation. RESULTS: Significant increases in the splenocyte and plasma T regulatory cell populations were observed with MAPC therapy at 24 and 48 hours, respectively. In addition, MAPC therapy was associated with an increase in the brain M2/M1 macrophage ratio at 24, 48 and 120 hours after cortical injury. In vitro cultures of activated microglia with supernatant derived from MAPC:splenocyte co-cultures also demonstrated an increase in the M2/M1 ratio. The observed changes were secondary to an increase in M1 macrophage apoptosis. CONCLUSIONS: The data show that the intravenous delivery of MAPC after cortical injury results in increases in T regulatory cells in splenocytes and plasma with a concordant increase in the locoregional M2/M1 macrophage ratio. Direct contact between the MAPC and splenocytes is required to modulate activated microglia, adding further evidence to the central role of the spleen in MAPC-mediated neuroprotection. PMID- 23020861 TI - Influence of architecture of high molecular weight linear and branched polyglycerols on their biocompatibility and biodistribution. AB - The availability of long circulating, multifunctional polymers is critical to the development of drug delivery systems and bioconjugates. The ease of synthesis and functionalization make linear polymers attractive but their rapid clearance from circulation compared to their branched or cyclic counterparts, and their high solution viscosities restrict their applications in certain settings. Herein, we report the unusual compact nature of high molecular weight (HMW) linear polyglycerols (LPGs) (LPG - 100; M(n) - 104 kg mol(-1), M(w)/M(n) - 1.15) in aqueous solutions and its impact on its solution properties, blood compatibility, cell compatibility, in vivo circulation, biodistribution and renal clearance. The properties of LPG have been compared with hyperbranched polyglycerol (HPG) (HPG 100), linear polyethylene glycol (PEG) with similar MWs. The hydrodynamic size and the intrinsic viscosity of LPG-100 in water were considerably lower compared to PEG. The Mark-Houwink parameter of LPG was almost 10-fold lower than that of PEG. LPG and HPG demonstrated excellent blood and cell compatibilities. Unlike LPG and HPG, HMW PEG showed dose dependent activation of blood coagulation, platelets and complement system, severe red blood cell aggregation and hemolysis, and cell toxicity. The long blood circulation of LPG-100 (t(1/2beta,) 31.8 +/- 4 h) was demonstrated in mice; however, it was shorter compared to HPG-100 (t(1/2beta,) 39.2 +/- 8 h). The shorter circulation half life of LPG-100 was correlated with its higher renal clearance and deformability. Relatively lower organ accumulation was observed for LPG-100 and HPG-100 with some influence of on the architecture of the polymers. Since LPG showed better biocompatibility profiles, longer in vivo circulation time compared to PEG and other linear drug carrier polymers, and has multiple functionalities for conjugation, makes it a potential candidate for developing long circulating multifunctional drug delivery systems similar to HPG. PMID- 23020862 TI - Broilers as a source of quinolone-resistant and extraintestinal pathogenic Escherichia coli in the Czech Republic. AB - Extraintestinal Escherichia coli infections are associated with extraintestinal pathogenic E. coli (ExPEC) strains. A total of 114 E. coli isolates were characterized regarding their antimicrobial resistance in a prospective study of 319 broilers from 12 slaughterhouses in the Czech Republic, a European Union member, during 2008. PCR-based assays to define ExPEC-associated traits were performed in resistant strains. Consumption of antimicrobial drugs by poultry in the Czech Republic was also analyzed. Antibiotic resistance was detected in 82% of isolates. Resistance to nalidixic acid and ciprofloxacin was predominant. Plasmid-mediated quinolone resistance genes, qnrB19 and qnrS1, were detected in 1 and 3 of 93 resistant isolates, respectively. Twenty-three percent of resistant isolates were considered as ExPEC. In total, 972 kg of flumequine, enrofloxacin, and difloxacin were used in poultry in the Czech Republic during 2008. High prevalence of broilers with ciprofloxacin-resistant E. coli isolates was linked to consumption of quinolones in poultry. Broilers may comprise an important vehicle for community-wide dissemination of fluoroquinolone-resistant E. coli and ExPEC. Withdrawal of fluoroquinolones from use in chicken production should be seriously considered in the Czech Republic and the European Union as well. PMID- 23020863 TI - Acceptance of virtual dental implant planning software in an undergraduate curriculum: a pilot study. AB - BACKGROUND: Advances in healthcare such as virtual dental implant planning have the capacity to result in greater accuracy, speed, and efficiencies leading to improvement in patient care. It has been suggested that the acceptance of new technology is influenced by a variety of factors including individual differences, social and situational influences, user beliefs, and user attitudes. Despite the large volume of work in this area, only limited research has been conducted in the field of dental education. Therefore, the present study aimed at assessing the acceptance of virtual dental implant planning software by undergraduate students. METHODS: Forty-three third-year dental students of the University of Erlangen-Nuremberg, Germany, were included in the study. They filled in a questionnaire based on a combination of the technology acceptance model and the theory of planned behavior (C-TAM-TPB). Cronbach's alpha, Pearson product moment correlation coefficients, and squared multiple correlations (R2) were calculated. RESULTS: Cronbach's alpha exceeded .7 for all constructs. Pearson correlations were significant for the pairs perceived usefulness/behavioral intention, perceived usefulness/attitude, and attitude/behavioral intention. Perceived ease of use explained .09% of the variance of perceived usefulness (R2 = .09). Perceived ease of use and perceived usefulness accounted for 31% of the variance of attitude (R2 = .31). Perceived usefulness, attitude, subjective norm, and perceived behavioral control explain 37% of the variance of behavioral intention (R2 = .37). CONCLUSIONS: Virtual dental implant planning software seems to be accepted by dental students especially because of its usefulness and the students' attitude towards this technology. On the other hand, perceived ease of use does not play a major role. As a consequence, the implementation of virtual dental implant planning software in a dental undergraduate curriculum should be supported by highlighting the usefulness by the supervisors, who should also strengthen the attitude of the students towards this technology. PMID- 23020864 TI - Weight status at age 18 influences marriage prospects. A population-based study of Swedish men. AB - BACKGROUND: In a longitudinal population-based study of the relationship between body mass index (BMI) in early adulthood and marital status at 40 years of age, obese men were half as likely to be married compared with men of normal weight. Significant associations between obesity and marital status among men in a longitudinal setting are novel findings. METHODS: The study cohort comprised Swedish men born from 1951 to 1961. Height and weight at age 18 was gathered from the Military Service Conscription Register and information on marital status at 40 years of age was obtained from population registers by record-linkage using the unique personal identification number. The odds ratio (OR) for being married was calculated by polytomous logistic regression analysis adjusting for birth year, intellectual performance, education, country of birth, residential area, socioeconomic position in childhood and adulthood, parental education and muscle strength. RESULTS: Our study included 486 599 Swedish men. Young men who were obese (BMI >= 30.0) at 18 years of age had an OR of 0.49 (95% CI: 0.46-0.52) for being married at 40 years of age compared to normal weight men (BMI: 18.5-24.9). Underweight men (BMI <= 18.5) had an OR of 0.84 (0.82-0.86) and overweight men (BMI: 25.0-29.9) had an OR of 0.83 (0.80-0.85) for being married at 40 years of age. CONCLUSION: Underweight, overweight and obese men were less likely to be married than their normal weight counterparts. Obese men had the lowest likelihood of being married. Stigmatization and discrimination may partly explain these findings, but further research is needed before firm conclusions can be drawn. PMID- 23020865 TI - Influenza A (H1N1): a rare cause of deafness in two children. AB - OBJECTIVE: We report deafness occurring as an extremely rare complication of influenza A caused by the H1N1 virus ('swine flu'), in two children. METHODS: Case reports and review of the literature concerning influenza A (H1N1) and acquired viral infection causing deafness. RESULTS: Two children with normal hearing developed bilateral deafness following influenza A (H1N1). The diagnosis was confirmed using polymerase chain reaction. Both patients were treated with oseltamivir. CONCLUSION: Following a review of the literature, these two patients appear to be the first reported cases of bilateral deafness following influenza A (H1N1). PMID- 23020866 TI - A multicentre study on high-frequency ultrasound evaluation of the skin and joints in patients with psoriatic arthritis treated with infliximab. AB - OBJECTIVES: Our objective was to describe the ultrasound features of patients with PsA in joints and skin and their changes after treatment with infliximab. METHODS: Eight hospitals recruited PsA active patients. Clinical (joint count for pain, TJC, and swelling, SJC, pain VAS, ESR, C-reactive protein and PASI) and US variables (plaque thickness, PD signal of dermal lesions, synovitis, erosions, and PD signal, assessed by 4-category ordinal scales) were independently recorded at baseline and 4, 12 and 24-week after starting treatment with infliximab. The results were analysed with paired T, Wilcoxon test, ANOVA and marginal homogeneity test. RESULTS: Changes in 24 patients from baseline to last available data were significant for clinical variables, pain VAS, TJC and SJC as well as for ESR, CRP (all p<0.0005). Dermatological PASI changed from 14.6+/-14.9 to 2.1+/-4.1 and plaque thickness from 3.34+/-1.75 mm to 1.74+/-0.96 mm (both p<0.0005); synovitis and PD signal improved (both p<0.0005). Psoriatic plaque PD improved across the study (p<0.0005) with no signal increasing from 36.4% to 88.9% and positive PD signal decreasing from 63.6% to 11.1% of the plaques. CONCLUSIONS: Treatment with anti-TNF-alpha infliximab improves the symptoms of patients with PsA at joint and psoriatic skin levels from a clinical and ultrasonographic perspective. PMID- 23020867 TI - Another brick in the wall. Validation of the sigma1 receptor 3D model by computer assisted design, synthesis, and activity of new sigma1 ligands. AB - Originally considered an enigmatic polypeptide, the sigma(1) receptor has recently been identified as a unique ligand-regulated protein. Many studies have shown the potential of sigma(1) receptor ligands for the treatment of various diseases of the central nervous system (CNS); nevertheless, almost no information about the 3D structure of the receptor and/or the possible modes of interaction of the sigma(1) protein with its ligands have been unveiled so far. With the present work we validated our sigma(1) 3D homology model and assessed its reliability as a platform for sigma(1) ligand structure-based drug design. To this purpose, the 3D sigma(1) model was exploited in the design of 33 new sigma(1) ligands and in their ranking for receptor affinity by extensive molecular dynamics simulation-based free energy calculations. Also, the main interactions involved in receptor/ligand binding were analyzed by applying a per residue free energy deconvolution and in silico alanine scanning mutagenesis calculations. Subsequently, all compounds were synthesized in our laboratory and tested for sigma(1) binding activity in vitro. The agreement between in silico and in vitro results confirms the reliability of the proposed sigma(1) 3D model in the a priori prediction of the affinity of new sigma(1) ligands. Moreover, it also supports and corroborates the currently available biochemical data concerning the sigma(1) protein residues considered essential for sigma(1) ligand binding and activity. PMID- 23020868 TI - Intra-articular injection of tranexamic acid via a drain plus drain-clamping to reduce blood loss in cementless total knee arthroplasty. AB - BACKGROUND: Patients undergoing cementless total knee arthroplasty (TKA) sometimes suffer large blood loss. In a retrospective study, we explored whether postoperative intra-articular retrograde injection of tranexamic acid (TA) and leaving a drain clamp in place for 1 h reduced blood loss. PATIENTS AND METHODS: Patients (n = 140) treated with unilateral primary cementless TKA (posterior cruciate ligament retained) were divided into two groups: those who had an intra articular injection of TA (1000 mg) and drain clamping for 1 h postoperatively (study group, n = 70) and those who were not given TA and did not undergo clamping of their drains (control group, n = 70). Postoperative total blood loss, volume of drainage, hemoglobin level, transfusion amounts and rates, D-dimer level at postoperative day (POD) 7, and complications were recorded. RESULTS: Total blood loss, total drainage, mean transfusion volume, and transfusion rates were lower in the study group than in controls (P < 0.001). Hemoglobin levels on PODs 1 and 14 were similar in the groups, but on POD 7 the hemoglobin level was higher in the study group than in controls (P < 0.001). D-dimer level on POD 7 was lower in the study group than in controls (P < 0.05). There were no complications in either group. CONCLUSIONS: Immediately postoperative intra articular retrograde injection of TA and 1 h of drain-clamping effectively reduced blood loss and blood transfusion after cementless TKA. We believe that this method is simple, easy, and suitable for these patients. PMID- 23020869 TI - Re: Grubb et al., Breath alcohol analysis incorporating standardization to water vapour is as precise as blood alcohol analysis. Forensic Sci. Int. 216 (2012) 88 91. PMID- 23020870 TI - Correlation of metabolic syndrome with urinary stone composition. AB - OBJECTIVE: To determine the correlation between metabolic syndrome and the distribution of stone components in patients with urolithiasis. METHODS: Between January 2007 and December 2010, renal or ureteral stones were collected from 712 patients (432 males, 280 females) who underwent surgical intervention at three hospitals in South Korea. Metabolic syndrome was defined according to the latest definition of the International Diabetes Federation, using ethnicity- and sex specific cut-off values for central obesity. Patients were assessed by factors used in metabolic syndrome. All urinary stones were analyzed using infrared spectrophotometry and categorized according to their main component. RESULTS: The patients' mean age was 55.9 years (range 19-93 years). Of the 712 patients, 347 (48.7%; 205 males, 142 females) had a diagnosis of metabolic syndrome. Calcium oxalate (71.5%), uric acid (15.3%), carbonate apatite (8.0%) and struvite (4.1%) calculi were found as the main stone components. Overall, the proportion of uric acid calculi was markedly higher in patients with rather than without metabolic syndrome (19.6 vs 11.2%; P=0.002). However, the proportion of calcium oxalate, carbonate apatite and struvite calculi did not differ between the two groups. The multivariable-adjusted odds ratio for uric acid calculi according to the metabolic syndrome components indicated that the presence of metabolic syndrome was associated with a 93% increased odds ratio of uric acid calculi compared with the absence of metabolic syndrome. Impaired fasting glucose and hypertriglyceridemia were independent risk factors for uric acid calculi. CONCLUSIONS: Metabolic syndrome is associated with a significantly increased risk of uric acid calculi development, especially those with impaired fasting glucose and hypertriglyceridemia. PMID- 23020871 TI - Impaired Notch signalling: the unifying mechanism explaining the pathogenesis of hidradenitis suppurativa (acne inversa). PMID- 23020872 TI - Sources older people draw on to nurture, strengthen and improve self-efficacy in managing home rehabilitation following orthopaedic surgery. AB - AIMS AND OBJECTIVES: To explore how older people maintained and improved their self-efficacy in managing home rehabilitation and their adherence to rehabilitation exercise programmes following orthopaedic surgery. BACKGROUND: Successful postoperative orthopaedic rehabilitation for older people depends on building their confidence about adherence to exercise programmes designed to improve their functional performance. Many older people, however, do not reach a satisfactory level of functional ability before discharge and some fail to adhere to their rehabilitation exercise programme at home. This contributes to a reduced quality of life. Although many studies report the influences of self-efficacy, little is known about the factors that help rebuild self-efficacy beliefs towards postdischarge exercise following orthopaedic surgery. DESIGN: A descriptive exploratory qualitative study. METHODS: Semi-structured interviews were used with 15 older people who had returned to their homes following orthopaedic surgery. RESULTS: Findings emphasise the importance of social support from family, friends and community to nurture self-efficacy. Accessing personal beliefs and attitudes, adaptive strategies and goal setting were all sources and ways participants rebuilt their confidence and motivation in regard to adhering to a rehabilitation programme. CONCLUSION: Facilitating self-efficacy assists older people to manage home rehabilitation and planning care with family and friends to create a support system in early discharge planning allows a safer and smoother recovery. RELEVANCE TO CLINICAL PRACTICE: Rehabilitation programmes and education should encourage an understanding of self-efficacy as a means to improve individual functional performance. PMID- 23020873 TI - Conservation and evolutionary divergence in the activity of receptor-regulated smads. AB - BACKGROUND: Activity of the Transforming growth factor-beta (TGFbeta) pathway is essential to the establishment of body axes and tissue differentiation in bilaterians. Orthologs for core pathway members have been found in all metazoans, but uncertain homology of the body axes and tissues patterned by these signals raises questions about the activities of these molecules across the metazoan tree. We focus on the principal canonical transduction proteins (R-Smads) of the TGFbeta pathway, which instruct both axial patterning and tissue differentiation in the developing embryo. We compare the activity of R-Smads from a cnidarian (Nematostella vectensis), an arthropod (Drosophila melanogaster), and a vertebrate (Xenopus laevis) in Xenopus embryonic assays. RESULTS: Overexpressing NvSmad1/5 ventralized Xenopus embryos when expressed in dorsal blastomeres, similar to the effects of Xenopus Smad1. However, NvSmad1/5 was less potent than XSmad1 in its ability to activate downstream target genes in Xenopus animal cap assays. NvSmad2/3 strongly induced general mesendodermal marker genes, but weakly induced ones involved in specifying the Spemann organizer. NvSmad2/3 was unable to induce a secondary trunk axis in Xenopus embryos, whereas the orthologs from Xenopus (XSmad2 and XSmad3) and Drosophila (dSmad2) were capable of doing so. Replacement of the NvSmad2/3 MH2 domain with the Xenopus XSmad2 MH2 slightly increased its inductive capability, but did not confer an ability to generate a secondary body axis. CONCLUSIONS: Vertebrate and cnidarian Smad1/5 have similar axial patterning and induction activities, although NvSmad1/5 is less efficient than the vertebrate gene. We conclude that the activities of Smad1/5 orthologs have been largely conserved across Metazoa. NvSmad2/3 efficiently activates general mesendoderm markers, but is unable to induce vertebrate organizer specific genes or to produce a secondary body axis in Xenopus. Orthologs dSmad2 and XSmad3 generate a secondary body axis, but activate only low expression of organizer-specific genes that are strongly induced by XSmad2. We suggest that in the vertebrate lineage, Smad2 has evolved a specialized role in the induction of the embryonic organizer. Given the high level of sequence identity between Smad orthologs, this work underscores the functional importance of the emergence and fixation of a few divergent amino acids among orthologs during evolution. PMID- 23020875 TI - Host genetics of HIV acquisition and viral control. AB - Since the discovery of HIV as the cause of AIDS, numerous insights have been gained from studies of its natural history and epidemiology. It has become clear that there are substantial interindividual differences in the risk of HIV acquisition and course of disease. Meanwhile, the field of human genetics has undergone a series of rapid transitions that have fundamentally altered the approach to studying HIV host genetics. We aim to describe the field as it has transitioned from the era of candidate-gene studies and the era of genome-wide association studies (GWAS) to its current state in the infancy of comprehensive sequencing. In some ways the field has come full circle, having evolved from being driven almost exclusively by our knowledge of immunology, to a bias-free GWAS approach, to a point where our ability to catalogue human variation far outstrips our ability to biologically interpret it. PMID- 23020876 TI - Abiraterone and novel antiandrogens: overcoming castration resistance in prostate cancer. AB - Suppression of gonadal androgens by medical or surgical castration remains the mainstay of treatment for patients with advanced prostate cancer. However, the response to treatment is not durable, and transition to a "castration-resistant" state is invariable. Recent advances in our understanding of the androgen receptor signaling pathway have led to the development of therapeutic strategies to overcome castration resistance. This article reviews current concepts and challenges behind targeting continued androgen receptor signaling in castration resistant prostate cancer and provides an overview of recently completed and ongoing clinical trials of novel hormonal agents, with a focus on abiraterone acetate and enzalutamide (MDV3100). PMID- 23020877 TI - The role of anti-inflammatory drugs in colorectal cancer. AB - A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet, and lifestyle are key risk factors for colorectal cancer (CRC). Prevention of CRC has long been considered a plausible approach for the population and individuals at high risk for developing this disease. A significant effort has been made in the development of novel drugs for both prevention and treatment over the past two decades. This review highlights recent advances in our understanding of the role of nonsteroidal anti-inflammatory drugs in CRC prevention and adjuvant treatment. Moreover, we focus on the molecular mechanisms underlying the antitumor effects of these drugs in CRC. The knowledge of how anti-inflammatory agents inhibit cancer formation and progression may provide a rationale for the development of more effective chemopreventive and chemotherapeutic agents with less toxicity. PMID- 23020878 TI - Molecular mechanisms in progressive idiopathic pulmonary fibrosis. AB - There is clear evidence that environmental exposures and genetic predisposition contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoking increases the risk of developing IPF several-fold, as do other exposures such as metal-fume and wood-dust exposure. Occupations that increase the risk of IPF are agricultural work, hairdressing, and stone polishing, supporting the role of environmental exposure in disease pathogenesis. Genetic predisposition to IPF is evident from its familial aggregation and the fact that pulmonary fibrosis develops in several rare genetic disorders. Mutations in surfactant proteins lead to pulmonary fibrosis and are associated with endoplasmic reticulum stress in alveolar type II epithelial cells. Mutations in telomerase have been found in several families with IPF, and shortened telomeres are found in sporadic cases of IPF. A common variant in mucin 5B predisposes to both familial and sporadic IPF and is present in the majority of cases, indicating sporadic IPF occurs in those with genetic predisposition. PMID- 23020879 TI - Genetic basis of intellectual disability. AB - In the past decade, we have witnessed a flood of reports about mutations that cause or contribute to intellectual disability (ID). This rapid progress has been driven in large part by the implementation of chromosomal microarray analysis and next-generation sequencing methods. The findings have revealed extensive genetic heterogeneity for ID, as well as examples of a common genetic etiology for ID and other neurobehavioral/psychiatric phenotypes. Clinical diagnostic application of these new findings is already well under way, despite incomplete understanding of non-Mendelian transmission patterns that are sometimes observed. PMID- 23020880 TI - Update on typical and atypical antipsychotic drugs. AB - Antipsychotic drugs (APDs) are best classified as typical or atypical. The distinction is based solely on their ability to cause extrapyramidal side effects (EPS), including tardive dyskinesia (TD). The two classes differ in mechanism of action, with atypical APDs providing important modulation of serotonergic neurotransmission. TD increases the death rate and can be minimized by limiting use of typical APDs. Clozapine is unique among the atypical APDs in its efficacy for ameliorating psychosis in patients with treatment-resistant schizophrenia (TRS), for reduction of suicide, and for improving longevity. The typical and atypical APDs do not differ in improving psychopathology in non-TRS. The atypicals vary in metabolic side effects: some have little burden. Cognitive benefits of the atypical APDs may be superior for some domains of cognition and require less use of anticholinergic drugs, which impair memory, for treatment of EPS. Overall, choosing among the atypical APDs as first-line treatment represents the best course for schizophrenia and most likely other disorders for which APDs are used. PMID- 23020881 TI - The need for lymph node dissection in nonmetastatic breast cancer. AB - Determining whether cancer has spread to locoregional lymph nodes is a critical step in the initial staging of breast cancer patients. Although axillary dissection reliably identifies nodal metastases and prevents the recurrence of cancer in the axilla, there is a significant incidence of long-term side effects, notably lymphedema, and the procedure is of no therapeutic benefit in women without axillary metastases. With the advent of sentinel lymph node biopsy, the axilla can be accurately staged in patients with T1-T3, clinically node-negative breast cancers while avoiding the morbidity of axillary lymph node dissection if the nodes do not contain cancer. Recent clinical trials suggest that for women with metastases to 1 or 2 sentinel nodes, the radiation and systemic therapy that are part of modern multimodality breast cancer treatment can replace axillary dissection when breast-conserving therapy is undertaken. For those with greater disease burden or those undergoing mastectomy, axillary dissection remains standard management. PMID- 23020883 TI - Systemic and topical drugs for the prevention of HIV infection: antiretroviral pre-exposure prophylaxis. AB - Pre-exposure prophylaxis (PrEP), in which HIV-uninfected persons use oral or topical antiretroviral medications to protect against HIV acquisition, is a promising new HIV prevention strategy. The biologic rationale for evaluation of PrEP for sexual HIV prevention included nonhuman primate models and the efficacy of antiretroviral prophylaxis for HIV-exposed infants. Proof-of-concept that PrEP protects against sexual HIV acquisition has been demonstrated in four clinical trials, which used the antiretroviral medication tenofovir, either as a vaginal gel or as daily oral tenofovir disoproxil fumarate, alone or coformulated with emtricitabine. Importantly, however, two trials failed to demonstrate HIV protection with PrEP; low adherence to daily use of PrEP is the leading hypothesis to account for the lack of efficacy. Next steps in the field include rigorous evaluation of uptake and adherence to PrEP in implementation settings and research into next-generation PrEP agents with longer half-life and less user dependence. PMID- 23020882 TI - Mechanisms of premature atherosclerosis in rheumatoid arthritis and lupus. AB - Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), the two most common systemic autoimmune disorders, have both unique and overlapping manifestations. One feature they share is a significantly enhanced risk of atherosclerotic cardiovascular (CV) disease that significantly contributes to morbidity and mortality. The primary mechanisms that drive CV damage in these diseases remain to be fully characterized, but recent discoveries indicate that distinct inflammatory pathways and immune dysregulation characteristic of RA and SLE likely play prominent roles. This review focuses on analyzing the major mechanisms and pathways potentially implicated in the acceleration of atherothrombosis and CV risk in SLE and RA, as well as in the identification of putative preventive strategies that may mitigate vascular complications in systemic autoimmunity. PMID- 23020884 TI - Left atrial decompression during venoarterial extracorporeal membrane oxygenation for left ventricular failure in children: current strategy and clinical outcomes. AB - From 2005 to 2011, 23 of 178 (12.9%) patients with venoarterial (VA) extracorporeal membrane oxygenation (ECMO) had left atrial (LA) decompression to help improve left ventricular (LV) function, LA/LV dilatation, and/or lung edema. LA decompression was achieved with LA cannulation (n = 16), surgically created adjustable atrial septal defect (n = 3), or balloon atrial septostomy (n = 4). Sixteen (70%) patients had LA decompression at the time of ECMO initiation and all had LA decompression within 12 hours of ECMO initiation. ECMO duration was 5.9 +/- 4.5 days and 16 (70%) patients were successfully decannulated. Subsequent intensive care unit and hospital survival was achieved in 13 (57%) and 12 (52%) patients, respectively. Earlier timing of LA decompression appeared to be associated with a high probability of weaning from ECMO and reasonable LV functional recovery. PMID- 23020885 TI - Assessing fitness-to-practice of overseas-trained health practitioners by Australian registration & accreditation bodies. AB - BACKGROUND: Assessment of fitness-to-practice of health professionals trained overseas and who wish to practice in Australia is undertaken by a range of organisations. These organisations conduct assessments using a range of methods. However there is very little published about how these organisations conduct their assessments. The purpose of the current paper is to investigate the methods of assessment used by these organisations and the issues associated with conducting these assessments. METHODS: A series of semi-structured interviews was undertaken with a variety of organisations who undertake assessments of overseas trained health professionals who wish to practice in Australia. Content analysis of the interviews was used to identify themes and patterns. RESULTS: Four themes were generated from the content analysis of the interviews: (1) assessing; (2) process; (3) examiners; and (4) cost-efficiency. The themes were interconnected and each theme also had a number of sub-themes. CONCLUSIONS: The organisations who participated in the present study used a range of assessment methods to assess overseas trained health professionals. These organisations also highlighted a number of issues, particularly related to examiners and process issues, pre- and post-assessment. Organisations demonstrated an appreciation for ongoing review of their assessment processes and incorporating evidence from the literature to inform their processes and assessment development. PMID- 23020887 TI - External auditory canal paraganglioma: an atypical presentation. AB - OBJECTIVE: We present the first published description of a painful paraganglioma of the external auditory canal. Atypical histopathology made the diagnosis difficult. We discuss the potential pitfalls of clinical diagnosis and treatment of such a case. CLINICAL PRESENTATION: A 49-year-old woman presented with left sided otalgia, hearing loss and tinnitus. Physical examination revealed a firm swelling arising from the superior portion of the left external auditory canal. A clinical diagnosis of otitis externa was made. INTERVENTION: There was minimal response to medical treatment. The swelling was aspirated, leading to brisk bleeding. A tumour was suspected from the computed tomography scan, and confirmed by a biopsy. The patient underwent excision of the paraganglioma. The histopathology was atypical, making diagnosis difficult. CONCLUSION: Such unusual masses of the external ear should always be borne in mind, especially when dealing with atypical presentations of commonly encountered diseases. Clinicians should have a low threshold for early intervention with imaging and biopsy. PMID- 23020886 TI - From promoting to inhibiting: diverse roles of helicases in HIV-1 Replication. AB - Helicases hydrolyze nucleotide triphosphates (NTPs) and use the energy to modify the structures of nucleic acids. They are key players in every cellular process involving RNA or DNA. Human immunodeficiency virus type 1 (HIV-1) does not encode a helicase, thus it has to exploit cellular helicases in order to efficiently replicate its RNA genome. Indeed, several helicases have been found to specifically associate with HIV-1 and promote viral replication. However, studies have also revealed a couple of helicases that inhibit HIV-1 replication; these findings suggest that HIV-1 can either benefit from the function of cellular helicases or become curtailed by these enzymes. In this review, we focus on what is known about how a specific helicase associates with HIV-1 and how a distinct step of HIV-1 replication is affected. Despite many helicases having demonstrated roles in HIV-1 replication and dozens of other helicase candidates awaiting to be tested, a deeper appreciation of their involvement in the HIV-1 life cycle is hindered by our limited knowledge at the enzymatic and molecular levels regarding how helicases shape the conformation and structure of viral RNA-protein complexes and how these conformational changes are translated into functional outcomes in the context of viral replication. PMID- 23020888 TI - Dose reduction does not affect detection of bone marrow lesions with dual-energy CT virtual noncalcium technique. AB - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate if a dose reduced, dose-neutral dual-energy computed tomographic (CT) virtual noncalcium technique can equally detect posttraumatic bone marrow lesions (BMLs) of the knee. MATERIALS AND METHODS: Fifty patients underwent DE CT imaging with either a standard dose (group A) or a dose equal to that of a single-energy CT scan (group B) (28% dose reduction) and magnetic resonance imaging for knee trauma workup. Calcium was virtually subtracted from the images. Two radiologists rated the presence of abnormal soft tissue-like attenuation in the bone marrow in a total of 12 femoral and tibial regions and performed Hounsfield unit measurements thereafter. Receiver-operating characteristic curve analysis was used for four point rating scores and Hounsfield unit measurements. Fractures were classified. RESULTS: Magnetic resonance imaging depicted 170 BMLs (35 femoral, 135 tibial). Mean age, number of fractures, attenuation values and number of regions with BMLs were not significantly different between the groups. Visual rating revealed overall areas under the curves of 0.983 and 0.979 for observers 1 and 2, respectively. Visual judgment was superior to attenuation measurements for femoral regions regardless of the dose applied. Analysis of variance of all CT values revealed a significant influence for the presence of edema (P < .001) but no differences for the radiation dose used (P = .424). Interobserver agreement was excellent (kappa = 0.944). CONCLUSIONS: Dose reduction does not affect the detectability of posttraumatic BMLs with a dual-energy CT virtual noncalcium technique, thereby providing potential additional information compared with single-energy CT imaging without additional radiation dose. PMID- 23020889 TI - Value of a short four-joint ultrasound test for gout diagnosis: a pilot study. AB - OBJECTIVES: The goal of this study was to investigate the usefulness of a short ultrasound (US) assessment in gout. METHODS: Patients with gout, confirmed by urate crystal identification, and having at least one symptomatic flare in the last three months were included. Standardised US examinations of sixteen joints and eight tendons in the lower limbs were carried out. Six lesions were studied: hyperechoic spots in the synovial fluid, hyperechoic cloudy areas (HCA), bright stippled aggregates (BSA), the double contour sign (DCS), erosions and the Doppler signal. For reliability, inter-reader analyses were performed by five rheumatologists. With the results, a short US assessment was created. RESULTS: Twenty-nine consecutive patients were included (93% men). The Doppler signal, HCAs and BSAs appeared in 100%, 97% and 93% of the patients, respectively. The DCS was found in 69% of patients. The locations that were most affected were the first metatarsophalangeal joint (MTP) and the knee joints, both of which are in 93% of patients. Reliability analyses showed consistent results for erosions, the Doppler signal, HCAs and the DCS in the 1st MTP (k=0.818, k=0.958, k=0.739 and k= 0.697, respectively) and for the DCS in the knees (k=0.779). A six-minute US examination of four joints (knees and the 1st MTPs) detected HCAs or DCS in 97% of cases. CONCLUSIONS: A US examination of four joints for two elemental lesions (the DCS and HCAs) is feasible, reliable and has face and content validity as a diagnostic test in patients with crystal-proven gout. PMID- 23020890 TI - Resilience in families with a member with chronic pain: a mixed methods study. AB - AIMS AND OBJECTIVE: To measure and explore between 2007-2010 measure and explore the nature of family resilience in the context of families with a member with chronic pain. BACKGROUND: Chronic pain impacts on the entire family. The literature suggests that it is possible to strengthen resilience in individuals with chronic conditions, but little is known about the impact of chronic pain on family resilience. DESIGN: A explanatory sequential mixed method study was undertaken. METHODS: In the initial quantitative phase, assessment measures were administered using the Connor-Davidson Resilience Scale, Family Impact of Pain Scale, Medical Outcomes Study Short Form 36 and Medical Outcomes Study Social Support Survey. Data were collected and analysed from 31 family cases (n = 67 participants). In the second, qualitative phase, follow-up semi-structured interviews were undertaken with 10 families to help explain the quantitative results. RESULTS: The impact of pain on the family was high overall, but the perceived impact was greater for the person with pain. Resilience scores were above average for both the person with pain and other family members. However, the person with pain scored lower on the resilience scale than other members of the family. The families scored high for social support overall, while the person with pain perceived they had greater support than their family members. CONCLUSIONS: Identifying the strengths or resilient properties inherent in families and using those strengths in the planning and implementation of care, especially of chronic conditions such as chronic pain, is pivotal to quality health outcomes. RELEVANCE TO CLINICAL PRACTICE: It is important that nurses and healthcare professionals include family members when planning and delivering care for persons with chronic pain. Identification of strengths within families can help tailor nursing interventions to meet family needs. PMID- 23020891 TI - Antibodies against conserved amidated neuropeptide epitopes enrich the comparative neurobiology toolbox. AB - BACKGROUND: Neuronal antibodies that show immunoreactivity across a broad range of species are important tools for comparative neuroanatomy. Nonetheless, the current antibody repertoire for non-model invertebrates is limited. Currently, only antibodies against the neuropeptide RFamide and the monoamine transmitter serotonin are extensively used. These antibodies label respective neuron populations and their axons and dendrites in a large number of species across various animal phyla. RESULTS: Several other neuropeptides also have a broad phyletic distribution among invertebrates, including DLamides, FVamides, FLamides, GWamides and RYamides. These neuropeptides show strong conservation of the two carboxy-terminal amino acids and are alpha-amidated at their C-termini. We generated and affinity-purified specific polyclonal antibodies against each of these conserved amidated dipeptide motifs. We thoroughly tested antibody reactivity and specificity both by peptide pre-incubation experiments and by showing a close correlation between the immunostaining signals and mRNA expression patterns of the respective precursor genes in the annelid Platynereis. We also demonstrated the usefulness of these antibodies by performing immunostainings on a broad range of invertebrate species, including cnidarians, annelids, molluscs, a bryozoan, and a crustacean. In all species, the antibodies label distinct neuronal populations and their axonal projections. In the ciliated larvae of cnidarians, annelids, molluscs and bryozoans, a subset of antibodies reveal peptidergic innervation of locomotor cilia. CONCLUSIONS: We developed five specific cross-species-reactive antibodies recognizing conserved two-amino-acid amidated neuropeptide epitopes. These antibodies allow specific labelling of peptidergic neurons and their projections in a broad range of invertebrates. Our comparative survey across several marine phyla demonstrates a broad occurrence of peptidergic innervation of larval ciliary bands, suggesting a general role of these neuropeptides in the regulation of ciliary swimming. PMID- 23020892 TI - Mitral valve repair and redo repair for mitral regurgitation in a heart transplant recipient. AB - A 37-year-old man with end-stage idiopathic dilated cardiomyopathy underwent an orthotopic heart transplant followed by a reoperation with mitral annuloplasty for severe mitral regurgitation. Shortly thereafter, he developed severe tricuspid regurgitation and severe recurrent mitral regurgitation due to annuloplasty ring dehiscence. The dehisced annuloplasty ring was refixated, followed by tricuspid annuloplasty through a right anterolateral thoracotomy. After four years of follow-up, there are no signs of recurrent mitral or tricupid regurgitation and the patient remains in NYHA class II. Pushing the envelope on conventional surgical procedures in marginal donor hearts (both before and after transplantation) may not only improve the patient's functional status and reduce the need for retransplantation, but it may ultimately alleviate the chronic shortage of donor hearts. PMID- 23020893 TI - Prognostic prediction following radical prostatectomy for prostate cancer using conventional as well as molecular biological approaches. AB - Although radical prostatectomy has been the mainstay of treatment for men with clinically organ-confined prostate cancer, a certain proportion of men undergoing radical prostatectomy fail to achieve a complete cure of this disease; that is, postoperative biochemical recurrence develops in approximately 30% of men, some of whom will ultimately die of disease progression. A number of studies, therefore, have been carried out to identify factors reflecting prognostic outcomes following radical prostatectomy, which would be potentially helpful for properly counseling individual patients undergoing this surgery. Furthermore, various types of model systems using multiple clinicopathological parameters, such as the nomogram, look-up table and artificial neural network, have been shown to have better performance in postoperative prognostic prediction than the opinions of expert clinicians. However, there have not been any standard models uniformly applied to postoperative prognostic prediction, which could be explained, at least in part, by the use of conventional clinicopathological parameters alone, suggesting the need for the additional evaluation of molecular markers simultaneously considering the unique biological features of prostate cancer. In this review, a search of the literature was carried out focusing on the significance of prognostic models following radical prostatectomy, and it is suggested that these models could be promising tools to provide accurate information on the postoperative clinical course of prostate cancer patients. To widely introduce such models into clinical practice, it is necessary to further improve currently available models and develop more reliable, flexible, simple and easily accessible tools by incorporating conventional clinicopathological factors as well as molecular biomarkers. PMID- 23020894 TI - Microbial cocktail for bioconversion of green waste to reducing sugars. AB - Green waste has been identified as a sustainable resource to convert into reducing sugars and subsequently for production of ethanol. In this study, enhancement of reducing sugar production from green waste by the different combination of pure strains was investigated. The best-defined microbial cocktail for high reducing sugars production, consisting of one fungus (Pseudallescheria sp. D42) and three bacteria (Microbacterium sp. F28, Tsukamurella sp. C35, and Bacillus sp. F4), was successfully constructed. The maximum reducing sugars yield by this fungal-bacterial cocktail was 165.2 mg/g-green waste within 24 h, which is approximate 10 times higher than the selected individual microbial strains. Without extraction and purification of specific enzymes, whole-cell-bioconversion by a defined microbial cocktail is proven as a potential alternative process for lignocellulose hydrolysis and reducing sugars production. PMID- 23020895 TI - Adverse effects of smoking in ulcerative colitis. PMID- 23020896 TI - Improving teaching on an inpatient pediatrics service: a retrospective analysis of a program change. AB - BACKGROUND: The traditional role of the faculty inpatient attending providing clinical care and effectively teaching residents and medical students is threatened by increasing documentation requirements, pressures to increase clinical productivity, and insufficient funding available for medical education. In order to sustain and improve clinical education on a general pediatric inpatient service, we instituted a comprehensive program change. Our program consisted of creating detailed job descriptions, setting clear expectations, and providing salary support for faculty inpatient attending physicians serving in clinical and educational roles. This study was aimed at assessing the impact of this program change on the learners' perceptions of their faculty attending physicians and learners' experiences on the inpatient rotations. METHODS: We analyzed resident and medical student electronic evaluations of both clinical and teaching faculty attending physician characteristics, as well as resident evaluations of an inpatient rotation experience. We compared the proportions of "superior" ratings versus all other ratings prior to the educational intervention (2005-2006, baseline) with the two subsequent years post intervention (2006-2007, year 1; 2007-2008, year 2). We also compared medical student scores on a comprehensive National Board of Medical Examiners clinical subject examination pre and post intervention. RESULTS: When compared to the baseline year, pediatric residents were more likely to rate as superior the quality of didactic teaching (OR=1.7 [1.0-2.8] year 1; OR=2.0 [1.1-3.5] year 2) and attendings' appeal as a role model (OR=1.9 [1.1-3.3] year 2). Residents were also more likely to rate as superior the quality of feedback and evaluation they received from the attending (OR=2.1 [1.2-3.7] year 1; OR=3.9 [2.2-7.1] year 2). Similar improvements were also noted in medical student evaluations of faculty attendings. Most notably, medical students were significantly more likely to rate feedback on their data gathering and physical examination skills as superior (OR=4.2 [2.0-8.6] year 1; OR=6.4 [3.0-13.6] year 2). CONCLUSIONS: A comprehensive program which includes clear role descriptions along with faculty expectations, as well as salary support for faculty in clinical and educational roles, can improve resident and medical student experiences on a general pediatric inpatient service. The authors provide sufficient detail to replicate this program to other settings. PMID- 23020897 TI - Knowledge and attitudes of female genital mutilation among midwives in Eastern Sudan. AB - BACKGROUND: Female Genital Mutilation (FGM) or cutting caries legal and bioethical debates and it is practiced in many developing countries. METHODS: Random selection of 154 midwives was used for the study during June 2012 and through July 2012 aiming to assess knowledge and attitudes of the midwives towards FGM in Eastern Sudan. RESULTS: A total of 157 midwives enrolled in this study. They had been practicing for 3-44 years (mean SD 19.2+/-10.3). More than two third of them experienced practicing FGM sometime in their life (127/157, 80.9%). There was low level of awareness of types of FGM practice since only 7% (11/157) identified the four types correctly. 53.5% (84/157) identified type 1 correctly while 18.5% (29/157), 17.8% (28/157) and 15.9% (25/157) identified type 2, 3 and 4 as correct respectively. While 30 (19.1%) of the midwives claimed that all types of FGM are harmful, 76.4% (120/157) were of the opinion that some forms are not harmful and 7 (4.5%) reported that all types of FGM are not harmful. Likewise while 74.5% (117/157) of the interviewed midwives mentioned that the FGM is a legal practice only 25.5% (40/117) were of the opinion that FGM is illegal practice. The vast majority of the respondents (64.3%, 101/157) have an opinion that FGM decreases the sexual pleasure. More than half (53.5%, 84/157) of the participants affirmed that FGM does not increase the risk of HIV transmission. High proportion of the respondents (71.3%, 112/157) did not know whether or not infertility could complicate FGM. CONCLUSIONS: Thus a substantial effort should be made to discourage the continuation of FGM practice among midwives in Sudan. This might be achieved by improving knowledge and awareness among the midwives and the community. PMID- 23020898 TI - Periorbital cellulitis, subgaleal abscess and superior sagittal sinus thrombosis: a rare combination of complications arising from unilateral frontal sinusitis. AB - BACKGROUND: Subclinical infection of the sinuses can result in delayed diagnosis and unusual presenting complications. CASE REPORT: This paper describes the case of a 14-year-old boy with a rare combination of periorbital cellulitis, subgaleal abscess and superior sagittal sinus thrombosis following a late presentation of unilateral frontal sinusitis. RESULTS: Following multiple surgical procedures, and antimicrobial and anticoagulation therapy, the patient made a full recovery. CONCLUSION: Serious sinusitis complications still occur, and can do so in unusual combinations with minimal clinical signs. Systemic anticoagulation therapy is considered safe practice in the management of cerebral venous sinus thrombosis and may reduce morbidity and mortality. PMID- 23020900 TI - Repetitive transcranial magnetic stimulation of the supplementary motor area induces echophenomena. AB - Apart from tics, echopraxia or echophenomena (EP), i.e., automatic imitation of observed movements, are common in patients with Gilles de la Tourette syndrome (TS). The supplementary motor area (SMA) has been shown to be overactive before the onset of tics in these patients, and it is possible that this area might also play a key role in the generation of echopraxia. We wondered whether EP can also be evoked in healthy controls (HC) by modifying neural activity of this cortical region. To this end, we modulated activity of the SMA in 30 HC by repetitive transcranial magnetic stimulation (rTMS) in an attempt to induce EP. We used both 5 Hz (which can temporarily increase neural activity) and 1 Hz (which disrupts or reduces cortical activity) rTMS. Video clips were presented to 30 HC before and after stimulation. Each clip showed one single movement, either a tic of a TS patient or a spontaneous movement of a HC. During the whole presentation, participants were videotaped in order to detect EP. Video films of participants' responses were rated by two independent raters with respect to EP frequency. Our results reveal an increase of EP following 5 Hz stimulation but no effect following 1 Hz stimulation. This finding implies that the SMA is a relay mediating EP. PMID- 23020899 TI - Reduced neural activation during an inhibition task is associated with impaired fear inhibition in a traumatized civilian sample. AB - INTRODUCTION: Impaired inhibition of fear in the presence of safety cues and a deficiency in the extinction of fear cues are increasingly thought to be important biological markers of Posttraumatic stress disorder (PTSD). Other studies have suggested that there may be altered neural activation during behavioral inhibition tasks in subjects with PTSD. The current study aimed to see whether neural activation during inhibition was reduced in a highly traumatized civilian population, and whether atypical activation was associated with impaired fear inhibition. METHODS: The participants were 41 traumatized women (20 PTSD+, 21 PTSD-) recruited from Grady Memorial Hospital in Atlanta, GA. We used a Go/NoGo procedure with functional magnetic resonance imaging (fMRI) in a high resolution 3T scanner. Participants were instructed to press a button whenever an "X" or "O" appeared on the screen, but not if a red square appeared behind the letter. Participants were assessed for trauma history and PTSD diagnosis, and completed a fear-potentiated startle and extinction paradigm. RESULTS: We found stronger activation in the ventromedial prefrontal cortex (vmPFC) in traumatized subjects without PTSD compared to those with PTSD in the NoGo greater than Go contrast condition. Activation in the vmPFC was negatively correlated with fear potentiated startle responses during safety signal learning (p = .02) and fear extinction (p = .0002). CONCLUSIONS: These results contribute to understanding of how the neural circuitry involved in inhibitory processes may be deficient in PTSD. Furthermore, the same circuits involved in behavioral inhibition appear to be involved in fear inhibition processes during differential fear conditioning and extinction. PMID- 23020901 TI - Proteomic evidence of a paedomorphic evolutionary process within a marine snail species: a strategy for adapting to extreme ecological conditions? AB - The exposed and sheltered ecotypes of the marine snail Littorina saxatilis from European rocky shores are considered a key model system to study adaptation and ecological speciation. Previous studies showed that two ecotypes (RB and SU) of this species in NW Spain have adapted differently to different shore levels and microhabitats. In order to understand how this divergent adaptive process has been accomplished, we followed a quantitative proteomic approach to investigate the proteome variation in a number of different biological factors, that is, ecotype, ontogeny and their interactions. This approach allowed testing the hypothesis that one of the ecotypes has evolved by paedomorphosis, and also whether or not the molecular mechanisms related to ecotype differentiation are set up in early developmental stages. Additionally, the identification of some candidate proteins using mass spectrometry provides some functional insights into these evolutionary processes. Results from this study provided evidence of higher ontogenetic differentiation at proteome level in the RB (metamorphic) than in SU (paedomorphic) ecotype that point to the possibility of juvenile stage retention in this latter ecotype. The level of protein expression (proteome) differences between ecotypes maintained nearly constant from late embryonic stages to adulthood, although some proteins involved in these changes considerably differed in embryonic compared to other ontogenetic stages. Paedomorphosis may be the evolutionary response of the SU ecotype of solving the trade-off during sexually immaturity that is caused by the evolution of small size arising from adaptation to the wave-exposed habitat. Some potential candidate genes of adaptation related to energetic metabolism have been identified, providing a promising baseline for future functional analyses. PMID- 23020902 TI - Classification and characterisation of peripheral neuropathies in 102 patients with primary Sjogren's syndrome. AB - OBJECTIVES: This paper aims to analyse the etiology, characterisation and outcomes of the different types of peripheral neuropathy in patients with primary Sjogren's syndrome (SS) and their association with clinical and immunological disease expression. METHODS: A total of 563 consecutive patients diagnosed with primary SS were evaluated. We retrospectively assessed the results of nerve conduction studies carried out in patients with suspected peripheral nervous system involvement. Peripheral neuropathies were classified into mononeuropathy, mononeuropathy multiplex, polyneuropathy and neuronopathy according to the patterns evidenced by electrodiagnostic studies. RESULTS: Nerve conduction studies were carried out in 158/563 (28%) SS patients. The results were normal in 49 and abnormal in 109 patients, in whom peripheral neuropathy was diagnosed in 102. After excluding patients with neuropathy associated with other diseases and patients with entrapment mononeuropathies, 55/563 (10%) patients were classified as having SS-related peripheral neuropathy, including axonal sensorimotor polyneuropathy (n=24), pure sensory neuronopathy (n=15), mononeuropathy multiplex (n=15) and demyelinating polyradiculoneuropathy (n=1). In spite of therapy, clinical progression measured by the MOHS scale was observed in 12% of patients with axonal polyneuropathy, 13% of those with mononeuropathy multiplex and 47% of those with neuronopathy. Survival was significantly reduced in patients with peripheral neuropathy (especially in those with mononeuropathy multiplex and axonal polyneuropathy) in comparison with the control group (log rank =0.001). CONCLUSIONS: We found a prevalence of SS-related peripheral neuropathy of 10%. Classification of neuropathy according to the clinical presentation and electrodiagnostic tests may be useful in determining the functional outcome, therapeutic response and survival. PMID- 23020903 TI - Developmental and evolutionary origins of the pharyngeal apparatus. AB - The vertebrate pharyngeal apparatus, serving the dual functions of feeding and respiration, has its embryonic origin in a series of bulges found on the lateral surface of the head, the pharyngeal arches. Developmental studies have been able to discern how these structures are constructed and this has opened the way for an analysis of how the pharyngeal apparatus was assembled and modified during evolution. For many years, the role of the neural crest in organizing pharyngeal development was emphasized and, as this was believed to be a uniquely vertebrate cell type, it was suggested that the development of the pharyngeal apparatus of vertebrates was distinct from that of other chordates. However, it has now been established that a key event in vertebrate pharyngeal development is the outpocketing of the endoderm to form the pharyngeal pouches. Significantly, outpocketing of the pharyngeal endoderm is a basal deuterostome character and the regulatory network that mediates this process is conserved. Thus, the framework around which the vertebrate pharyngeal apparatus is built is ancient. The pharyngeal arches of vertebrates are, however, more complex and this can be ascribed to these structures being populated by neural crest cells, which form the skeletal support of the pharynx, and mesoderm, which will give rise to the musculature and the arch arteries. Within the vertebrates, as development progresses beyond the phylotypic stage, the pharyngeal apparatus has also been extensively remodelled and this has seemingly involved radical alterations to the developmental programme. Recent studies, however, have shown that these alterations were not as dramatic as previously believed. Thus, while the evolution of amniotes was believed to have involved the loss of gills and their covering, the operculum, it is now apparent that neither of these structures was completely lost. Rather, the gills were transformed into the parathyroid glands and the operculum still exists as an embryonic entity and is still required for the internalization of the posterior pharyngeal arches. Thus, the key steps in our phylogenetic history are laid out during the development of our pharyngeal apparatus. PMID- 23020904 TI - Comparative pulmonary functional recovery after Nuss and Ravitch procedures for pectus excavatum repair: a meta-analysis. AB - BACKGROUND: Pectus excavatum (PE) is a common chest wall malformation, with surgery being the only method known to correct the defect. Although the Nuss and Ravitch procedures are commonly used, there is no consensus as to whether surgical repair improves pulmonary function. We therefore investigated whether pulmonary function recovers after surgical repair, and if recovery is dependent on the type of procedure or time after surgery. METHODS: Literature searches were performed using PubMed, EMBASE, Health Periodicals Database, and CNKI (Chinese National Knowledge Index) from January 1990 to December 2007. The following keywords were used: pectus excavatum, chest wall deformity, funnel chest, pulmonary function, respiratory, lung function, and pectus severity index. The primary outcome of interest was possible changes in pulmonary function following surgical repair. RESULTS: Meta-analysis of 23 studies showed that, although there was evidence of statistically significant heterogeneity among studies (Chi square, 17.11, p < 0.05), changes in pulmonary functional indices, including forced expiratory volume over 1 s (FEV1), forced vital capacity (FVC), vital capacity (VC), and total lung capacity (TLC), were similar 1 year after the Ravitch and Nuss procedures. Several years after surgery and bar removal, however, the changes in pulmonary functional indices significantly favored the Nuss procedure. CONCLUSIONS: Pulmonary function tends to improve after the surgical correction of pectus excavatum. Although the Nuss procedure was not significantly better 1 year after surgery, long-term postoperative pulmonary function improvement was significantly better after bar removal. PMID- 23020905 TI - Food transit time, nutrient digestibility and nitrogen retention in farmed and feral American mink (Neovison vison)--a comparative analysis. AB - The aim of this study was to determine whether farming leads to changes in gastrointestinal function and nitrogen metabolism in farmed mink (FA), as compared with their wild-living counterparts. Three digestibility and balance trials were carried out. Experiment I was performed in May, and experiments II and III were conducted in September 2011. Farmed mink with the standard coat colour were purchased from a production farm in south-eastern Poland. Feral mink were harvested using cages in the hunting grounds of the Polish Hunting Association, Branch in Olsztyn. The experimental materials comprised of the following: trial I - adult males (eight animals per group), trial II - young females (six animals per group), trial III-young animals (five males and five females per group). Food transit time was measured during digestibility trials, on 10 consecutive days. The coefficients of nutrient and energy digestibility and daily nitrogen balance values were compared between groups in each experiment. It was found that farming contributed to changes in gastrointestinal function and nitrogen metabolism in mink. Farmed animals were characterized by a longer bowel transit time, a tendency towards higher nutrient digestibility and higher nitrogen retention, which resulted from selection for higher productivity. PMID- 23020906 TI - Managing patient deterioration: a protocol for enhancing undergraduate nursing students' competence through web-based simulation and feedback techniques. AB - AIMS: To describe a funded proposal for the development of an on-line evidence based educational program for the management of deteriorating patients. BACKGROUND: There are international concerns regarding the management of deteriorating patients with issues around the 'failure to rescue'. The primary response to these issues has been the development of medical emergency teams with little focus on the education of primary first responders. DESIGN/METHODS: A mixed methods triangulated convergent design.In this four phase proposal we plan to 1. examine nursing student team ability to manage deteriorating patients and based upon these findings 2. develop web based educational material, including interactive scenarios. This educational material will be tested and refined in the third Phase 3, prior to evaluation and dissemination in the final phase. CONCLUSION: This project aims to enhance knowledge development for the management of deteriorating patients through rigorous assessment of team performance and to produce a contemporary evidence-based online training program. PMID- 23020907 TI - Stereological assessment of placental morphology in intrahepatic cholestasis of pregnancy. AB - OBJECTIVE: To apply stereology for the detection of possibly morphological abnormalities in placentas of women with intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN: Prospective case-control study of placentas from untreated and UDCA-treated ICP, respectively, and normal pregnancies, examined for morphological differences by systematic random sampling generated by computerized stereology methodology. MAIN OUTCOME MEASURES: Volume of placenta, surface area of terminal villi and capillaries, volume fraction of collagen, number of syncytial knots, and chorangiosis. RESULTS: Surface area of terminal villi and capillaries, and number of syncytial knots were higher in placentas from all ICP, as compared to controls (p < 0.01). A reduction of collagen was found in placentas from UDCA-treated ICP, both in comparison to placentas from untreated ICP and controls (p < 0.05). CONCLUSION: ICP affects the placenta morphologically as shown by increased terminal villous and capillary surface area, and number of syncytial knots. PMID- 23020908 TI - David L. Healy, M.D., Ph.D., 1948-2012. PMID- 23020910 TI - Fertility, pregnancy, and medical management of Turner syndrome in the reproductive years. AB - Turner syndrome results in infertility in most cases. Fertility preservation through the cryopreservation of oocytes or ovarian tissue may be an option for some girls with Turner syndrome. Oocyte donation results in high pregnancy rates (PR). Those women who plan to pursue pregnancy need comprehensive screening and counseling before and after conception. Pregnancies conceived with either autologous or donated oocytes are at high risk of maternal death from aortic dissection/rupture and are at high risk of serious hypertensive disorders. Reproductive age women with Turner syndrome require ongoing screening for associated medical conditions unrelated to reproduction. PMID- 23020909 TI - Genetic considerations in the patient with Turner syndrome--45,X with or without mosaicism. AB - Turner syndrome (TS) is a complex developmental disorder in individuals with short stature who possess a 45,X cell line, with or without mosaicism. Because the single X chromosome is maternally derived in 80% of patients, the genesis of the 45,X karyotype is due to instability of the Y chromosome leading to its loss during meiosis. Phenotypic features vary depending on the mode of ascertainment, with postnatal presentation usually generating a more severe phenotype than a prenatal one. Although patients with pure 45,X present with delayed puberty more often than those with mosaicism for 46,XX or 47,XXX cell lines, the chromosomal complement cannot reliably predict the clinical presentation. Most living TS patients are mosaics, whereas nearly all first-trimester TS fetuses have a single 45,X cell line. Exclusion of a Y cell line, the presence of which increases the risk of gonadoblastomas and subsequent gonadal germ cell tumors, is best accomplished by karyotype, fluorescence in situ hybridization, and DNA analysis if necessary. The precise genetic etiology of TS has not been elucidated, but it does appear that deletion of the short arm of the X chromosome is sufficient to result in the TS phenotype, thereby implicating haploinsufficiency of multiple genes, including SHOX. PMID- 23020911 TI - Reproductive medicine and Turner syndrome: ethical issues. AB - This article discusses the ethical issues raised by the medical responses to Turner syndrome (TS). It explores the issues and challenges faced by women with Turner, and by prospective parents of a child with Turner. It focuses on four issues: the use of GH to increase height; the use of third-party oocytes to enable women with Turner to become pregnant; the parental decision to remove and cryopreserve ovarian tissue from a child with Turner; and the termination of fetuses diagnosed with Turner. Many of the challenges associated with TS are directly or indirectly related to social attitudes and practices, from harsh teasing in school to health professionals' assumption that a woman will abort a fetus diagnosed with Turner. All the interventions designed to alleviate the difficulties faced by women with TS should be employed with caution, in part because they raise significant concerns about risk and consent; in part because they offer a medical response to problems that are to some extent social. PMID- 23020912 TI - Indonesian infertility patients' health seeking behaviour and patterns of access to biomedical infertility care: an interviewer administered survey conducted in three clinics. AB - BACKGROUND: Indonesia has high levels of biological need for infertility treatment, great sociological and psychological demand for children, and yet existing infertility services are underutilized. Access to adequate comprehensive reproductive health services, including infertility care, is a basic reproductive right regardless of the economic circumstances in which individuals are born into. Thus, identifying and implementing strategies to improve access to assisted reproductive technology (ART) in Indonesia is imperative. The principle objectives of this article are to improve our understanding of infertility patients' patterns of health seeking behaviour and their patterns of access to infertility treatment in Indonesia, in order to highlight the possibilities for improving access. METHODS: An interviewer-administered survey was conducted with 212 female infertility patients recruited through three Indonesian infertility clinics between July and September 2011. Participants were self-selected and data was subject to descriptive statistical analysis. RESULTS: Patients identified a number of barriers to access, including: low confidence in infertility treatment and high rates of switching between providers due to perceived treatment failure; the number and location of clinics; the lack of a well established referral system; the cost of treatment; and patients also experienced fear of receiving a diagnosis of sterility, of vaginal examinations and of embarrassment. Women's age of marriage and the timing of their initial presentation to gynaecologists were not found to be barriers to timely access to infertility care. CONCLUSIONS: The findings based on the responses of 212 female infertility patients indicated four key areas of opportunity for improving access to infertility care. Firstly, greater patient education about the nature and progression of infertility care was required among this group of women. Secondly, increased resources in terms of the number and distribution of infertility clinics would reduce the substantial travel required to access infertility care. Thirdly, improvements in the financial accessibility of infertility care would have promoted ease of access to care in this sample. Finally, the expansion of poorly developed referral systems would also have enhanced the efficiency with which this group of patients were able to access appropriate care. PMID- 23020913 TI - Zinc alpha2-glycoprotein as a potential novel urine biomarker for the early diagnosis of prostate cancer. AB - What's known on the subject? and What does the study add? The use of biomarkers to detect a cancer early, especially prostate cancer, is not a new idea and PSA has been proved to be the best biomarker for the early diagnosis of prostate cancer. Since the introduction and wide use of PSA various efforts have been made to find novel biomarkers in both serum and urine of individuals at high risk for prostate cancer. The best example of a biomarker detected in the urine after a vigorous digital rectal examination is PCA3, which is used mainly in the subgroup of patients with PSA 4-10 ng/mL whose prostate biopsy was repeatedly negative for prostate cancer in order to decide the performance or not of a new biopsy. Proteomics is a state of the art new biotechnology used to identify the proteome of a certain tissue meaning the whole group of proteins related to the anatomy and biochemistry of the tissue. Using proteomics can effectively and more specifically identify proteins that can be used as potential biomarkers for the early diagnosis of prostate cancer. Zinc alpha2-glycoprotein has been studied in the past as a protein related to cancer cachexia and it has been measured in both prostate tissue and serum in patients with prostate cancer. Zinc alpha2 glycoprotein has also been recently identified by proteomics in prostate tissue showing different values in patients with prostate cancer and benign prostate hyperplasia. It is the first time that zinc alpha2-glycoprotein has been systematically measured and studied in an easily obtained biological fluid such as urine showing a very optimistic potential both as a novel solo biomarker and as an adjunct to PSA for the early diagnosis of prostate cancer. PSA has revolutionized the way we approximate prostate cancer diagnosis. Even though PSA is still the best biomarker for the diagnosis of prostate cancer it constitutes an organ-specific and not a disease-specific biomarker and diagnostic dilemmas are often raised concerning the performance or not of a prostate biopsy. Thus novel biomarkers are required in order to improve the diagnostic ability of PSA. Increasingly in the literature it is stated that the future of prostate cancer diagnosis could be not a single biomarker but a band of different biomarkers that as a total could give the possibility of an individual having prostate cancer. By detecting and measuring zinc alpha2-glycoprotein in the urine we believe that interesting conclusions can be made: first that proteomics is the way to detect with accuracy proteins that could be proved to be valuable novel biomarkers; second that zinc alpha2-glycoprotein detected in the urine could be used both as a solo biomarker and as an adjunct to PSA for the early diagnosis of prostate cancer. OBJECTIVE: * To examine the potential utility as a novel biomarker in the urine of zinc alpha2-glygoprotein (ZAG) for the early diagnosis of prostate cancer. PATIENTS AND METHODS: * The urine of 127 consecutive candidates for a transrectal ultrasound prostatic biopsy with a mean age of 65.7 +/- 8.7 years and mean PSA 9.1 +/- 5.3 ng/mL was collected. * Western blot analysis and immunohistochemistry for ZAG were performed. * Receiver operating characteristic curves and logistic regression models were used to estimate the predictive ability of ZAG and to determine the optimal sensitivity and specificity by using various cut-off values for the prediction of prostate cancer. RESULTS: * In all, 42 patients had prostate cancer, 29 showed high grade prostatic intraepithelial neoplasia and 56 were negative. * Receiver operating characteristic curve analysis showed a significant predictive ability of ZAG for prostate cancer. The area under the curve (AUC) for the prediction of prostate cancer was 0.68 (95% CI 0.59-0.78). * The combination of ZAG with PSA showed a significant improvement in the predictive ability (P= 0.010), with AUC equal to 0.75 (95% CI 0.66-0.85). Separate analysis in patients with PSA levels of 4-10 ng/mL (70.1%) showed that ZAG had a discriminative power with AUC equal to 0.68. * The optimal cut-off was 1.13 for ZAG, which corresponded to 6.88 times greater odds for prostate cancer. CONCLUSIONS: * Urine detected ZAG showed promising results in the prediction of prostate cancer. * Further validation is required to establish ZAG as a novel biomarker. PMID- 23020914 TI - [The scientific fraud in the medical domain]. PMID- 23020915 TI - Stability of the ready-to-use solutions of eribulin for intravenous infusion. AB - A simple HPLC-UV method was developed to determine the stability of ready-to-use eribulin solutions under different storage conditions. The developed method was validated with respect to linearity, accuracy, precision and ruggedness. The following admixtures were prepared: 3-mL polypropylene syringes at concentration of 440 MUg/mL and multilayer laminate polyolefin containers containing 0.9% sodium chloride (50 mL) at concentrations of 15.4 and 43.3 MUg/mL. The open-vial stability of eribulin was also evaluated. The following storage conditions were tested: 4 degrees C in the refrigerator; 20 degrees C under room light exposure; and 20 degrees C with light-protection. The drug was also subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. The retention time of eribulin was 4.9 min. Admixtures of eribulin solutions in vials, syringes or polyolefin bags at clinically relevant concentrations were physically compatible and chemically stable for at least 14 days at 4 degrees C in the refrigerator and at 20 degrees C with or without any protection against light. Degradation was only found to occur under oxidation conditions. PMID- 23020916 TI - Fresh aromatic herbs containing methylchavicol did not exhibit the pro-oxidative effects of pure methylchavicol on a human hepatoma cell line, HepG2. AB - Methylchavicol (CH(3)-CV), an important aromatic constituent of different plants like tarragon and basils, has been shown to be carcinogenic by a mechanism yet unclear, although it has been reported that carcinogenicity of CH(3)-CV in rodent might be linked to its metabolic conversion into a genotoxic electrophilic metabolite generated through a two steps bioactivation pathway catalyzed by cytochrome P450 enzymes and sulfotransferases. The induction of carcinogenesis by certain agents has been associated with the generation of oxidative stress. The aim of the present study was to determine whether pure methylchavicol applied on a human hepatoma cell line, HepG2, could promote oxidative stress and might alter the expression of procarcinogenic biomarkers such as the drug-metabolizing enzyme (CYP2E1), the inducible form of nitric oxide synthase (iNOS) and might induce the expression of Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and Mn-SOD that control the redox equilibrium of the cells. CH(3)-CV was shown to cause a significant induction of oxidative stress, as revealed by luminol-dependent chemiluminescence (LDCL) and to alter dramatically the expression of CYP2E1, iNOS and Mn-SOD, indicating that the toxic effect of CH(3)-CV could be mediated through a nitric oxide dependent mechanism. Under similar experimental conditions, the extracts from tarragon, chervil and basil did not induce such biological changes. These results provide evidence that the generation of an oxidative stress may be a significant event occurring during CH(3)-CV-induced toxicity. It also suggests that natural extracts containing different amounts of CH(3)-CV (tarragon, chervil and basil) did not elicit such toxicity and might contain compounds able to counteract this detrimental property. PMID- 23020917 TI - [A programme to support clinical evaluation of medical devices: pilot experiment in the Rhone-Alpes region]. AB - INTRODUCTION: The drug and medical devices Committee of the University Hospital of Lyon faces the weakness of clinical data available to justify medical devices purchase. The Hospital of Lyon has worked with several organisms of the Rhone Alpes region to set up a pilot programme aimed at encouraging small and medium enterprises (SMEs) to realise clinical studies for the evaluation of their medical device. We report the results of this experiment which took place from 2007 to 2010. METHODS: Eligible projects were selected on the basis of their scientific interest. A specific structure for regulatory and methodological support was set up. RESULTS: Twenty companies applied, seventeen were selected. Eight research protocols were written; four clinical studies were implemented. These studies were performed by micro-companies for medical devices that could be considered as innovative device or substantial novelty. Two draft protocols were started but deferred by choice of the company. For projects that did not lead to a research protocol or study, the main causes were: a longer than expected development phase (n = 3); a problem linked to methodological feasibility (n = 1); the unsuccessful search for a principal investigator (n = 2); or the company's choice (n = 5). DISCUSSION AND CONCLUSION: This pilot experience in France has supported and trained regional SMEs in clinical research. Its continuation could encourage manufacturers to conduct clinical trials of good quality. PMID- 23020918 TI - [Depyrogenation test regarding inox and glass containers in the preparation of parenteral nutrition mixtures]. AB - INTRODUCTION: The preparation of parenteral nutrition mixture (PNM) in an open chamber requires the use of intermediate containers sterile and non-pyrogenic. A sterilization of containers by moist heat in large autoclaves is the suitable method. However, sterilization by moist heat is not a depyrogenation method. In our study, we report the validation of a sterilization and depyrogenation method for containers by dry heat using a convection oven. MATERIALS AND METHODS: Sterilization and depyrogenation of material by dry heat have been audited by the reduction of at least three logarithms of original endotoxin rate. The containers were initially artificially contaminated with a suspension of endotoxin for 16 hours. Contaminated containers were placed in an oven with revolving heat at 250 degrees C for 1 hour. After treatment with dry heat, the residual endotoxin levels in the containers were determined by a kinetic chromogenic method. RESULTS: After treatment with dry heat, the average log reductions of endotoxin levels were respectively, for glass and steel containers, 4.78 +/- 0.07 and 4.87 +/- 0.03. DISCUSSION AND CONCLUSION: The present validation study confirms the effectiveness of treatment with dry heat for sterilization and depyrogenation of glass and steel containers. This method of sterilization and depyrogenation meets the microbiological quality requirements for the preparation of MNP. PMID- 23020919 TI - [Computerized prescription for medical devices: examples, interest and limits]. AB - INTRODUCTION: Related to the good practice contract implemented in hospitals, the prescription dedicated to medical devices, such as pharmaceuticals, could promote safety and good practice. MATERIAL AND METHOD: We attempted to implement a computerized prescription for medical devices. In order to illustrate the method, two examples were selected: the Negative Pressure Wound Therapy (NPWT) and the Drug Eluting Stents (DES). RESULTS: In partnership with the medical teams was elaborated a computerized protocol which included all the needed items for the good use of NPWT. For DES, a pre-existing questionnaire was used. We updated it in order to integrate new items such as the prescriber's name, the patient's name, the characteristics of the wound, the DES references and the indications. DISCUSSION AND CONCLUSION: Computerized prescriptions for high-risk and expensive medical devices seem to be an interesting approach to guarantee the patient care safety and to reduce the budget impacts. In order to monitor the indications funded as fee-for-service medical devices, a prescription will emerge as a gold standard in the future in France. Eventually, this study highlights a new activity of clinical pharmacy for hospital pharmacists dealing with medical devices. PMID- 23020920 TI - [Evaluation of the prescription of long-term systemic steroid-therapy associated measures]. AB - INTRODUCTION: To prevent the occurrence of corticosteroid's side effects, adjuvant measures are prescribed in a very different way depending on the practitioner's experience. The aim of this study was to assess the physicians' practices regarding the prescription of long-term corticosteroid therapy. METHODS: In May 2010, we realized a cross-sectional study among physicians in Ibn Sina University Hospital in Rabat. With a data collection form, we assessed the principal indications for prescribing steroids and the frequency of prescription of measures sometimes associated with systemic corticosteroid. RESULTS: Fifty nine out of eighty physicians completed the data collection form (response rate: 69.4%). Calcium-vitamin D supplementation was recommended by most of the physicians. Half of them were prescribing biphosphonate therapy. Most of them propose a low-sodium, a low-fat and a low-carbohydrate dietary regimen. Regular physical exercise was recommended by 35% of physicians. Gastric protection was indicating by 54.4% of practicians and potassium supplementation by 42.1% of them. Finally, the recommendation for influenza vaccination, hydrocortisone prescription and Synacthen((r)) test, varied between physicians. CONCLUSION: The prescription of adjuvant measures with a long-term corticosteroid therapy was very heterogeneous. There is no consensus regarding most of the measures. PMID- 23020921 TI - [Audits of good practice: implantable medical devices are also concerned]. AB - INTRODUCTION: Within the framework of a good practices agreement, French hospitals must perform clinical audits of costly molecules and implantable medical devices (IMD) to justify their medical costs. We present two examples of clinical audits of IMD: hip arthroplasties and cardiac stimulators. PATIENTS AND METHODS: The clinical audits were managed by the pharmacy with the support of the medical teams. Retrospective evaluation of patient files was performed by a pharmaceutical team using evaluation grids developed from official references from the French National Authority for Health and French National Health Insurance. RESULTS: The audit of hip arthroplasty procedures, including a retrospective and prospective study, showed that 95.4% and 96.9% of the surgical procedures followed guidelines. The audit of cardiac stimulators showed 100% agreement with guidelines. The audit of traceability showed that 97% of the files were complete. DISCUSSION: These audits show that the cost increases of the IMD are linked to following guidelines. It is important for these audits of pertinent use to be performed by both physicians and pharmacists. CONCLUSION: There is very little information in the literature or from authorities to help implement these audits. It would be interesting to propose common prospective and retrospective methods to evaluate the pertinent use of IMD. PMID- 23020922 TI - Low DWI-ASPECTS is associated with atrial fibrillation in acute stroke with the middle cerebral artery trunk occlusion. AB - BACKGROUND AND PURPOSE: For optimal acute stroke management and secondary prevention, discrimination of stroke etiology is crucial. We hypothesized that a low Alberta Stroke Program Early CT Score (ASPECTS) on diffusion-weighted imaging (DWI) immediately after stroke onset was associated with the presence of atrial fibrillation (AF). METHODS: Consecutive patients admitted within 24h from stroke onset with an occlusion at the horizontal segment of the middle cerebral artery (M1) on initial MRA were retrospectively enrolled. AF was diagnosed based on continuous electrocardiogram monitoring during acute hospitalization or its confirmed history. RESULTS: Of the 206 patients (95 women, median age 77 [IQR 69 85] years, NIHSS score 18 [13-23]) enrolled, AF was identified in 138 patients (AF group): chronic AF in 89, known paroxysmal AF (pAF) in 13, and masked pAF on admission in 36. The ASPECTS score on the initial DWI, performed a median of 2.5h after onset, was lower in the AF group than in the others (4 [2-6] vs. 7 [4-8], p<0.001). With the optimal cut-off value of <= 6 (sensitivity, 78%; specificity, 57%; area under the ROC curve, 0.682), DWI-ASPECTS was independently associated with the presence of any AF (OR 5.05, 95%CI 2.36 to 10.8), as well as the presence of any pAF (OR 8.64, 95%CI 3.00 to 24.9) and that of masked pAF on admission (OR 10.0, 95%CI 3.06 to 32.9). CONCLUSION: Extensive early ischemic change assessed by DWI-ASPECTS predicts the presence of AF, even initially masked pAF, in acute stroke patients with M1 occlusion. PMID- 23020923 TI - Cannabis affects people differently: inter-subject variation in the psychotogenic effects of Delta9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers. AB - BACKGROUND: Cannabis can induce transient psychotic symptoms, but not all users experience these adverse effects. We compared the neural response to Delta9 tetrahydrocannabinol (THC) in healthy volunteers in whom the drug did or did not induce acute psychotic symptoms. Method In a double-blind, placebo-controlled, pseudorandomized design, 21 healthy men with minimal experience of cannabis were given either 10 mg THC or placebo, orally. Behavioural and functional magnetic resonance imaging measures were then recorded whilst they performed a go/no-go task. RESULTS: The sample was subdivided on the basis of the Positive and Negative Syndrome Scale positive score following administration of THC into transiently psychotic (TP; n = 11) and non-psychotic (NP; n = 10) groups. During the THC condition, TP subjects made more frequent inhibition errors than the NP group and showed differential activation relative to the NP group in the left parahippocampal gyrus, the left and right middle temporal gyri and in the right cerebellum. In these regions, THC had opposite effects on activation relative to placebo in the two groups. The TP group also showed less activation than the NP group in the right middle temporal gyrus and cerebellum, independent of the effects of THC. CONCLUSIONS: In this first demonstration of inter-subject variability in sensitivity to the psychotogenic effects of THC, we found that the presence of acute psychotic symptoms was associated with a differential effect of THC on activation in the ventral and medial temporal cortex and cerebellum, suggesting that these regions mediate the effects of the drug on psychotic symptoms. PMID- 23020924 TI - Early life trauma predicts self-reported levels of depressive and anxiety symptoms in nonclinical community adults: relative contributions of early life stressor types and adult trauma exposure. AB - Exposure to early life trauma is a known risk factor for depression and anxiety disorders in adulthood. This study aimed to evaluate the relative contributions of early life versus adult trauma in predicting levels of depressive and anxiety symptoms in nonclinical community adults. 1209 nonclinical community adults (18 70 years; 45% male) were assessed for mental health status, early life stressors, lifetime trauma exposure, and self-reported levels of depressive and anxiety symptoms. A subset of the full sample subjected to group comparisons (n = 1088) indicated that early life stressor exposure primarily accounted for significantly higher depressive and anxiety symptom scores when compared against adults reporting to be free of childhood stressor or adult trauma exposure. Subsequent hierarchical multiple regression analyses of this subset using five distinct early life stressor types, namely 'Interpersonal violation', 'Family breakup', 'Disasters/war', 'Familial health trauma/death' and 'Personal health trauma' derived from principal component analysis of a wide range of self-reported early stressor events in the full sample, showed childhood 'Interpersonal violation' differentially predicted higher self-reported depressive and anxiety symptom scores in both males and females. Adult trauma exposure did not significantly predict these symptom scores. These findings underline the relative importance of exposure to 'interpersonal violation' relative to other types of early life stressors and adult trauma in the risk of depressive and anxiety symptoms in nonclinical community adults. PMID- 23020926 TI - Effect of metabolic syndrome on pathologic features of prostate cancer. AB - OBJECTIVE: The prevalence of metabolic syndrome has been increasing worldwide, however its association with prostate cancer (CaP) is unclear. We reviewed patients undergoing robot assisted radical prostatectomy (RARP) to evaluate if those with metabolic syndrome had more aggressive disease. MATERIALS AND METHODS: A prospective database of patients undergoing RARP between January 2005 and December 2008 (n = 2756) was queried for components of metabolic syndrome (BMI >= 30 and >= 2 of the following: hypertension, diabetes or elevated blood glucose, and dyslipidemia; n = 357). Patients with no components of metabolic syndrome were used as controls (n = 694). Biopsy and final pathology were compared between the 2 groups using all controls, and using best-matched controls (n = 357) based on greedy matching by propensity score. RESULTS: Compared with unmatched controls, metabolic syndrome patients had higher pathology Gleason grade (>= 7: 78% vs. 64%, P < 0.001) and higher pathologic stage (>= T3 disease: 43% vs. 31%, P < 0.001). After controlling for confounders, those with metabolic syndrome when compared with best-matched controls had maintained the greater pathology Gleason grade (>= 7: 78% vs. 64%, P < 0.001) and pathologic stage (>= T3 disease: 43% vs. 32%, P < 0.001). They also had significantly greater pathologic upgrading of Gleason grade 6 adenocarcinoma found on biopsy compared with best-matched controls (63% vs. 45%, P < 0.001). On pathology, a 2-fold increase in Gleason 8 and greater was noted between patients with metabolic syndrome and best-matched controls (15% vs. 8%). CONCLUSIONS: After controlling for confounders, patients with metabolic syndrome were found to have higher Gleason grade and tumor stage on final pathology and were more likely to have upgrading. PMID- 23020927 TI - Environmental analysis of a construction and demolition waste recycling plant in Portugal--Part II: Environmental sensitivity analysis. AB - Part I of this study deals with the primary energy consumption and CO(2)eq emissions of a 350 tonnes/h construction and demolition waste (CDW) recycling facility, taking into account incorporated, operation and transportation impacts. It concludes that the generated impacts are mostly concentrated in operation and transportation, and that the impacts prevented through material recycling can be up to one order of magnitude greater than those generated. However, the conditions considered for the plant's operation and related transportation system may, and very likely will, vary in the near future, which will affect its environmental performance. This performance is particularly affected by the plant's installed capacity, transportation fuel and input CDW mass. In spite of the variations in overall primary energy and CO(2)eq balances, the prevented impacts are always higher than the generated impacts, at least by a factor of three and maybe even as high as 16 times in particular conditions. The analysis indicates environmental performance for variations in single parameters, except for the plant's capacity, which was considered to vary simultaneously with all the others. Extreme best and worst scenarios were also generated to fit the results into extreme limits. PMID- 23020928 TI - ["Veille sanitaire": tools, functions, process of healthcare monitoring in France]. AB - In France, the term "veille sanitaire" is widely used to designate healthcare monitoring. It contains, however, a set of concepts that are not shared equally by the entire scientific community. The same is true for activities that are part of it, even if some (surveillance for example) are already well defined. Concepts such as "observation", "vigilance", "alert" for example are not always clear. Furthermore, the use of these words in everyday language maintains this ambiguity. Thus, it seemed necessary to recall these definitions as already used in the literature or legislation texts and to make alternative suggestions. This formalization cannot be carried out without thinking about the structure of "veille sanitaire" and its components. Proposals are provided bringing out concepts of formated "veille" (monitoring) and non-formatted "veille" (monitoring). Definitions, functions, (methods and tools, processes) of these two components are outlined here as well as the cooperative relationship they sustain. The authors have attempted to provide the scientific community with a reference framework useful for exchanging information to promote research and methodological development dedicated to this public health application of epidemiology. PMID- 23020925 TI - TBX2 expression is regulated by PAX3 in the melanocyte lineage. AB - The paired box homeotic gene 3 (PAX3) is a crucial regulator for the maintenance of melanocytic progenitor cells and has a poorly defined role in melanoma. To understand how PAX3 affects melanocyte and melanoma proliferation, we identified potential PAX3 downstream targets through gene expression profiling. Here, we identify T-box 2 (TBX2), a key developmental regulator of cell identity and an antisenescence factor in melanoma, as a directly regulated PAX3 target. We also found that TBX2 is involved in the survival of melanoma cells and is overexpressed in some melanoma specimens. The identification of TBX2 as a target for PAX3 provides a key insight into how PAX3 may contribute to melanoma evolution and may provide opportunities for prosenescence therapeutic intervention aimed at disrupting the ability of PAX3 to regulate TBX2. PMID- 23020929 TI - Estimating the burden of mucormycosis infections in France (2005-2007) through a capture-recapture method on laboratory and administrative data. AB - BACKGROUND: Mucormycoses are rare but severe fungal infections whose incidence is increasing, particularly in immunosuppressed and diabetic patients. Following a retrospective study on the characteristics and outcomes of cases who were identified through two sources of information, we carried out a capture-recapture method to estimate the actual burden of the disease in France, 2005-2007. METHODS: An administrative dataset from the national hospital discharge system and a laboratory dataset from the National Reference Centre for Mycoses and Antifungals were combined to identify patients from 2005 to 2007. We applied capture-recapture equations to estimate the number of cases missed by both sources and to assess the advantages of each dataset, especially in terms of sensitivity. RESULTS: There were 94 mucormycosis cases included in the study: 30 and 31 in each respective source and 33 common to both. Capture-recapture showed that 28 cases were missed (expected total: 122 cases, CI95: 102-142). Each dataset had a sensitivity value below 53%. The merged set yielded a 77% sensitivity (66%-92%). CONCLUSION: This study highlights the importance of combining available sources when analysing rare infectious diseases. The proportion of 23% missed cases might seem acceptable given the scarcity of the disease, for which further knowledge is needed. However this proportion could decrease in the future, through the sensitization of clinicians, pathologists and mycologists together with the improving quality of discharge datasets. PMID- 23020930 TI - Outcomes and lessons from the PROactive study. AB - Beyond improvement of glucose control, thiazolidinediones exert pleiotropic effects, which may contribute to some cardiovascular protection. PROactive ("PROspective pioglitAzone Clinical Trial In macroVascular Events") has provided valuable, although controversial, information on the impact of pioglitazone on cardiovascular outcomes in a high-risk population of patients with type 2 diabetes and established macrovascular disease. Since 2005, there has been much debate on the relative value of the statistically non-significant 10% reduction in the quite challenging primary composite endpoint (combining cardiovascular disease-driven and procedural events in all vascular beds) versus the statistically significant 16% decrease in the more robust and conventional main secondary endpoint (all-cause mortality, myocardial infarction, and stroke) observed with pioglitazone. Revisiting PROactive deserves much interest following the report of inconclusive results on cardiovascular efficacy and safety of rosiglitazone in RECORD, the withdrawal (limitation) of rosiglitazone because of cardiovascular safety concern, the recent publication of a statement positioning pioglitazone in type 2 diabetes and the near availability of cheaper generics of pioglitazone. Although subanalyses may have more limited value from a statistical viewpoint, they nonetheless can provide valuable information on the drug efficacy/safety profile and clinical insights into which patients might benefit most (in terms of cardiovascular outcomes) from pioglitazone therapy. PMID- 23020931 TI - Treatment options for diabetes: potential role of stem cells. AB - There are diseases and injuries in which a patient's cells or tissues are destroyed that can only be adequately corrected by tissue or organ transplants. Stem cells may be able to generate new tissue and even cure diseases for which there is no adequate therapy. Type 1 diabetes (T1DM), an insulin-dependent diabetes, is a chronic disease affecting genetically predisposed individuals, in which insulin-secreting beta (beta)-cells within pancreatic islets of Langerhans are selectively and irreversibly destroyed by autoimmune assault. Type 2 diabetes (T2DM) is characterized by a gradual decrease in insulin sensitivity in peripheral tissues and the liver (insulin resistance), followed by a gradual decline in beta-cell function and insulin secretion. Successful replacing of damaged beta-cells has shown considerable potential in treating T1DM, but lack of adequate donors is a barrier. The literature suggests that embryonic and adult stem cells are promising alternatives in long-term treatment of diabetes. However, any successful strategy should address both the need for beta-cell replacement and controlling the autoimmune response to cells that express insulin. This review summarizes the current knowledge of options and the potential of stem cell transplantation in diabetes treatment. PMID- 23020932 TI - High prevalence of advanced retinopathy in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study. AB - AIMS: The natural history of diabetic complications, including diabetic retinopathy (DR), is changing due to improved care. This study aimed at assessing prevalence of advanced DR and its correlation with risk factors and complications in subjects with type 2 diabetes from the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study. METHODS: This study enrolled 15,773 patients visiting consecutively 19 Diabetes Clinics in years 2007-2008. DR was assessed by dilated fundoscopy and classified according to the Global Diabetic Retinopathy Project Group. RESULTS: Advanced DR was observed in 9.8% of patients (4.2% pre-proliferative, 4.2% proliferative, 1.3% maculopathy, 0.1% blindness). Advanced DR was independently associated with hemoglobin (Hb) A(1c), diabetes duration and treatment, particularly with insulin, hypertension, previous cardiovascular disease (CVD), albuminuria and, inversely, age, age at diabetes diagnosis, smoking and estimated glomerular filtration rate. Maculopathy alone was associated with female gender, but not HbA(1c), hypertension and age. CONCLUSIONS: We found an alarming high prevalence of advanced DR in subjects with type 2 diabetes from the RIACE cohort, suggesting that the expected favorable effect of improved diabetes management has not emerged yet. Independent correlates of advanced DR were indexes of glycemic exposure, hypertension, CVD, albuminuria and, inversely, age at diagnosis and smoking. PMID- 23020933 TI - The alteration in Cu/Zn superoxide dismutase and adhesion molecules concentrations in diabetic patients with chronic kidney disease: the effect of dialysis treatment. AB - AIMS: The study investigated the effect of chronic kidney disease (CKD) and renal replacement therapy on diabetes mellitus-mediated alterations in antioxidative defence and in soluble adhesion molecules (sCAMs). METHODS: We assessed plasma Cu/Zn superoxide dismutase (Cu/Zn SOD) and sCAMs (sICAM-1, sVCAM-1) concentrations by ELISA in diabetic and non-diabetic patients on hemodialysis (HD), continuous ambulatory peritoneal dialysis (CAPD) and on conservative treatment. RESULTS: All studied parameters were higher in diabetic patients when compared to non-diabetics CKD patients. Cu/Zn SOD and sVCAM-1 were lower in diabetic patients on HD and on CAPD relative to their non-diabetic counterparts. In contrary, sICAM-1 level was grown up in dialyzed diabetic patients relative to the non-diabetic patients. The positive association was between Cu/Zn SOD and sVCAM-1 in each studied group. The inverse relationship was between glycemia and these parameters in CAPD, whereas the positive correlation was observed between glycemia and sICAM-1. CONCLUSIONS: The coexistence of diabetes mellitus is the important factor for the elevation both antioxidant defence as well as sCAMs in CKD patients. The inception of dialysis treatment can affect Cu/Zn SOD and sVCAM 1 but not sICAM-1 levels in diabetics. Moreover, these data suggest that both antioxidative defence and sCAMs could be regulated in different ways by glycemia. PMID- 23020934 TI - Cardiovascular safety and glycemic control of glucagon-like peptide-1 receptor agonists for type 2 diabetes mellitus: a pairwise and network meta-analysis. AB - AIMS: Integrating evidence from all randomized controlled trials (RCTs) of glucagon-like peptide-1 receptor agonists (GLP-1s) to assess the safety of cardiovascular disease (CVD) and efficacy of glycemic control. METHODS: Besides performing pairwise meta-analysis, network meta-analysis of all RCTs was used to combine direct and indirect estimates of the effect of GLP-1 with placebo, active comparator drugs (ACD), or another GLP-1 agent with treatment duration >=8 weeks in T2DM patients, 15,883 for CVD safety from 45 RCTs and 14,136 for glycemic control from 36 RCTs. RESULTS: For CVD safety, both of the results from pairwise and network meta-analysis failed to demonstrate significant difference between any two comparators. For glycemic control, the effect of any GLP-1 was better than placebo, but no difference was found between GLP-1s. We also found that liraglutide was the only GLP-1 drug shown to be more effective on improving glycemic control than ACD and exenatide. The results based on direct or indirect estimates were similar for two outcomes. CONCLUSION: Our network meta-analysis provides a complete picture of the associations between GLP-1s, ACD and placebo on CVD safety and glycemic control. The GLP-1s are promising candidates for the treatment of T2DM, but more long-term trials are needed to confirm potential CVD safety. PMID- 23020935 TI - Child, family and environmental correlates of children's motor skill proficiency. AB - OBJECTIVES: To identify factors associated with children's motor skills. DESIGN: Cross-sectional. METHODS: Australian preschool-aged children were recruited in 2009 as part of a larger study. Parent proxy-report of child factors (age, sex, parent perception of child skill, participation in unstructured and structured activity), self-report of parent factors (confidence in their own skills to support child's activity, parent-child physical activity interaction, parent physical activity) and perceived environmental factors (play space visits, equipment at home) were collected. Moderate to vigorous physical activity (MVPA) (ActiGraph GT1M accelerometer) and motor skills (Test of Gross Motor Development 2) were also assessed. After age adjustment, variables were checked for association with raw object control and locomotor scores. Variables with associations of p<0.20 were entered into two multiple regression models with locomotor/object control as respective outcome variables. RESULTS: Motor skills were assessed for 76 children (42 female), mean [SD] age=4.1 [0.68]; 71 completed parent proxy-report and 53 had valid MVPA data. Child age, swimming lessons, and home equipment were positively associated explaining 20% of locomotor skill variance, but only age was significant (beta=0.36, p=0.002). Child age and sex, unstructured activity participation, MVPA%, parent confidence, home equipment (all positively associated), and dance participation (inversely associated) explained 32% object control variance. But only age (beta=0.67, p<0.0001), MVPA% (beta=0.37, p=0.038) and no dance (beta=-0.34, p=0.028) were significant. CONCLUSION: Motor skill correlates differ according to skill category and are context specific with child level correlates appearing more important. PMID- 23020936 TI - New mutations and sporadic intellectual disability. PMID- 23020937 TI - Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. AB - BACKGROUND: The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability. METHODS: In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls. FINDINGS: We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1.71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1.2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0.022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity. INTERPRETATION: After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions. FUNDING: German Ministry of Education and Research, European Commission 7th Framework Program, and Swiss National Science Foundation. PMID- 23020938 TI - Discrimination between incomplete and atypical Kawasaki syndrome versus other febrile diseases in childhood: results from an international registry-based study. AB - OBJECTIVES: Kawasaki syndrome (KS) is an acute systemic vasculitis of unknown origin predominantly affecting young children. Early diagnosis is crucial to prevent cardiac complications. However, the differential diagnosis of patients with the incomplete or atypical form of the disease poses a heavy challenge for the paediatrician. Our aim was to evaluate the prevalence of incomplete and atypical cases among children with KS and to identify clinical and laboratory variables that may help differentiate incomplete and atypical KS from other febrile diseases at this age. METHODS: We established an international registry to recruit patients with KS, including those with incomplete and atypical forms. The control group included age-matched febrile children admitted to the hospital with a variety of diseases mimicking KS. The aim was to define clinical or laboratory clues to help in the discrimination of incomplete and atypical KS patients from others. RESULTS: Two hundred and twenty-eight patients with incomplete KS (78%) and atypical KS (22%) were compared to 71 children with other febrile diseases. Patients with incomplete and atypical KS presented a statistically significant higher frequency of mucosal changes, conjunctivitis, extremity abnormalities and perineal desquamation compared to the group of other febrile diseases. In addition, C-reactive protein and platelet counts were significantly higher in incomplete and atypical KS compared to the other group. CONCLUSIONS: This is the largest series of incomplete and atypical KS patients of non East-Asian ancestry: we suggest that in patients with the aforementioned clinical features and laboratory evidence of systemic inflammation in terms of increased C-reactive protein and platelet counts an echocardiogram should be performed and diagnosis of KS considered. PMID- 23020939 TI - Intravenous flurbiprofen for post-thymectomy pain relief in patients with myasthenia gravis. AB - BACKGROUND: Post-thymectomy pain in myasthenia gravis (MG) patients can inhibit breathing and coughing. Inappropriate usage of analgesics may exacerbate respiratory inhibition and even cause myasthenic crisis. Flurbiprofen is a non steroidal anti-inflammatory drug (NSAID) that is commonly used to control moderate postoperative pain and is not associated with respiratory inhibition. We hypothesized that flurbiprofen may provide post-thymectomy pain relief without increasing the risk of complications in MG patients. METHODS: Two hundred MG patients underwent extended thymectomy from March 2006 to December 2010 and were randomly allocated to a flurbiprofen group (110 patients, 50 mg intravenous flurbiprofen axetil) or a control group (90 patients, 100 mg intramuscular tramadol) as postoperative analgesia. Visual analog scale (VAS) pain score, heart rate, blood pressure, respiratory rate, pulse oximetry (SpO2), and adverse effects were recorded before and up to 24 h after drug administration. RESULTS: There were no significant differences in the preoperative clinical characteristics of the flurbiprofen and control (tramadol) groups. Both flurbiprofen and tramadol significantly alleviated post-thymectomy pain (p<0.05 for both), but patients in flurbiprofen group had significantly lower VAS pain scores at 0.5 h, 2 h, 4 h, and 8 h after surgery (p<0.05 for all times). There were no significant post-thymectomy changes of heart rate, respiratory rate, mean arterial blood pressure, or SpO2 in either group at all time points. CONCLUSIONS: Post-thymectomy intravenous administration of flurbiprofen axetil provides safe and effective analgesia for MG patients. PMID- 23020940 TI - Short sleep duration and type 2 diabetes enhance the risk of cardiovascular events in hypertensive patients. AB - AIMS: We tested the hypothesis that short sleep duration is not only a risk factor for diabetes, but that the two conditions in combination would be associated with the risk of incident cardiovascular disease (CVD). METHODS: We analyzed 1255 hypertensive patients (mean age: 70.4+/-9.9 years) with (N=299) and without diabetes (N=956). Short sleep duration was defined as a sleep time <7.5 h. A Hard CVD event was defined as either myocardial infarction, stroke, or sudden cardiac death; and All CVD events as Hard CVD events plus angina, heart failure and end-stage renal disease. RESULTS: When the patients were divided into 4 categories by diabetes (present or absent) and sleep duration (short or long), the diabetes+short sleep group had a significantly higher incidence of both Hard CVD events (HR=2.27, 95% CI=1.17-4.42, P=0.015) and All CVD events (HR=2.47, 95% CI=1.37-4.43, P=0.003) compared with the non-diabetes+long sleep group, independent of significant covariates. There were significant interactions between sleep duration and glycemic control on CVD events. CONCLUSIONS: The combination of both diabetes and short duration of sleep was associated with higher risk of incident CVD compared with those with only one or neither condition. Altered glycemic control and short sleep duration could act synergistically to pose a risk for future CVD. PMID- 23020941 TI - Temporal expression analysis of angiogenesis-related genes in brain development. AB - BACKGROUND: The current knowledge on molecular pathogenesis of cerebral vascular malformations (CVM), which are believed to arise during development, is very limited. To unravel the molecular mechanisms involved in CVMs, a detailed understanding of the brain vascular development at molecular level is crucial. In this study, we aimed to explore the temporal and comparative expression profile of angiogenesis-related genes in the establishment of brain vasculature. METHODS: Expression of a total of 113 angiogenesis-related genes during murine brain development has been analyzed using low-density array systems designed for angiogenesis-related genes. Bai1 (brain specific angiogenesis inhibitor-1), a recently identified novel anti-angiogenic gene, has been selected for further characterization. RESULTS: We found that 62 out of 113 analyzed genes have expression in brain development at varying levels. Nineteen of these were differentially expressed between embryonic and postnatal stages (>1.5 fold). Bai1 is strongly expressed on growing blood vessels of cerebral cortex and hippocampus, partially expressed in the lateral regions of striatum, but mostly absent on the thalamus. CONCLUSION: By showing the comparative expression analysis of angiogenesis-related genes throughout brain development, the data presented here will be a crucial addition to further functional studies on cerebrovascular research. PMID- 23020942 TI - Comorbidities of bladder pain syndrome/interstitial cystitis: a population-based study. AB - Study Type--System prevalence (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Compared with the general population, patients with BPS/IC often experience difficulties in performing normal activities owing to physical limitations, decreased energy, greater pain and impaired social functioning With the exception of metastatic cancer, separate conditional logistic regression analyses in this study suggested that subjects with BPS/IC were consistently more likely than subjects without BPS/IC to have all the medical comorbidities investigated. When compared with subjects without BPS/IC, subjects with BPS/IC had particularly higher odds of comorbid neurological diseases, rheumatological diseases and mental illnesses. OBJECTIVE: * To explore the comorbid medical conditions of patients with bladder pain syndrome/interstitial cystitis (BPS/IC) in Taiwan using a cross-sectional study design and a population-based administrative database. SUBJECTS AND METHODS: * The study included 9269 subjects with BPS/IC and 46,345 randomly selected comparison subjects. * Conditional logistic regression analyses were performed to calculate the odds ratio for each of the 32 medical comorbidities (hypertension, congestive heart failure, cardiac arrhythmias, blood loss anaemia, peripheral vascular disorders, stroke, ischaemic heart disease, hyperlipidaemia, hepatitis B or C, migraines, headaches, Parkinson's disease, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, pulmonary circulation disorders, chronic pulmonary disease, diabetes, hypothyroidism, renal failure, fluid and electrolyte disorders, liver diseases, peptic ulcers, deficiency anaemias, depressive disorder, psychoses, metastatic cancer, solid tumour without metastasis, alcohol abuse, drug abuse and asthma) between subjects with and without BPS/IC. RESULTS: * With the exception of metastatic cancer, the subjects with BPS/IC had a significantly higher prevalence of all the medical comorbidities analysed than subjects without BPS/IC. * With the exception of metastatic cancer, separate conditional logistic regression analyses suggested that subjects with BPS/IC were consistently more likely than subjects without BPS/IC to have any of the medical comorbidities investigated in this study. * When compared with subjects without BPS/IC, subjects with BPS/IC had particularly higher odds of comorbid neurological diseases, rheumatological diseases and mental illnesses. CONCLUSION: * Our results indicated that subjects with BPS/IC had an increased prevalence of multiple comorbidities. PMID- 23020944 TI - Neoplastic severe central airways obstruction, interventional bronchoscopy: a decision-making analysis. AB - OBJECTIVE: Cancer can involve the airways, causing various degrees of obstruction. Usually, after days or months of mild to moderate undervalued symptoms, severe dyspnea arises abruptly, imposing an immediate attempt to restore the airflow regardless of the etiology. This study focuses on the development of a predictive preintervention model that is useful when deciding whether to perform therapeutic interventional bronchoscopy in patients with severe central airway obstruction. METHODS: A total of 804 patients who underwent rigid bronchoscopy under general anesthesia to treat severe neoplastic central airway obstruction from 1990 to 2009 were studied. Electronic records for patients who underwent bronchoscopy were analyzed. The patients were primarily male (n = 618, 76.9%) and the median age was 62 years. Lung cancer was the most frequent cause of neoplastic airway obstruction (n = 645, 81.65%). An estimate of the probability of individual endoscopic success was made. RESULTS: Of the 804 patients with severe neoplastic airway obstruction, 681 (84.7%) achieved luminal clearance, and the procedure was considered an endoscopic success. Tracheal involvement (rate ratio, 1.21; range, 1.16-1.27) endoluminal mass (rate ratio, 1.13; range, 1.06-1.12), and extrinsic compression (rate ratio, 1.17; 1.11-1.17) were associated significantly with a favorable endoscopic outcome. Tumor location and any kind of mucosal infiltration were the main determinants of the predictive preoperative model of intervention success. CONCLUSIONS: Endoscopic characteristics and location of the neoplastic lesions are the major determinants of patients' endoscopic outcome. The preintervention model adds to the clinical evaluation an important contribution to the decision-making process on performing therapeutic interventional bronchoscopy in a critical setting. PMID- 23020943 TI - Understanding and benchmarking health service achievement of policy goals for chronic disease. AB - BACKGROUND: Key challenges in benchmarking health service achievement of policy goals in areas such as chronic disease are: 1) developing indicators and understanding how policy goals might work as indicators of service performance; 2) developing methods for economically collecting and reporting stakeholder perceptions; 3) combining and sharing data about the performance of organizations; 4) interpreting outcome measures; 5) obtaining actionable benchmarking information. This study aimed to explore how a new Boolean-based small-N method from the social sciences-Qualitative Comparative Analysis or QCA could contribute to meeting these internationally shared challenges. METHODS: A 'multi-value QCA' (MVQCA) analysis was conducted of data from 24 senior staff at 17 randomly selected services for chronic disease, who provided perceptions of 1) whether government health services were improving their achievement of a set of statewide policy goals for chronic disease and 2) the efficacy of state health office actions in influencing this improvement. The analysis produced summaries of configurations of perceived service improvements. RESULTS: Most respondents observed improvements in most areas but uniformly good improvements across services were not perceived as happening (regardless of whether respondents identified a state health office contribution to that improvement). The sentinel policy goal of using evidence to develop service practice was not achieved at all in four services and appears to be reliant on other kinds of service improvements happening. CONCLUSIONS: The QCA method suggested theoretically plausible findings and an approach that with further development could help meet the five benchmarking challenges. In particular, it suggests that achievement of one policy goal may be reliant on achievement of another goal in complex ways that the literature has not yet fully accommodated but which could help prioritize policy goals. The weaknesses of QCA can be found wherever traditional big-N statistical methods are needed and possible, and in its more complex and therefore difficult to empirically validate findings. It should be considered a potentially valuable adjunct method for benchmarking complex health policy goals such as those for chronic disease. PMID- 23020945 TI - Use of cryopreserved saphenous vein grafts in congenital heart surgery. PMID- 23020946 TI - Newly created animal model of human postoperative junctional ectopic tachycardia. AB - OBJECTIVE: Junctional ectopic tachycardia complicates the postoperative recovery from open heart surgery in children. The reported risk factors include younger age, prolonged cardiopulmonary bypass times, and administration of inotropic agents. Junctional ectopic tachycardia occurs early after open heart surgery, in the setting of relative postoperative sinus node dysfunction, and exhibits QRS morphology consistent with an origin from the atrioventricular node or proximal conduction system. Our goal was to develop a reproducible animal model for postoperative junctional ectopic tachycardia. METHODS: Eleven pigs, aged 2 to 4 months, underwent open heart surgery after induction of general anesthesia. Electrodes were sewn to the left atrium and right ventricle. RESULTS: Sinus node dysfunction was created using clamp crushing without or with radiofrequency ablation (successful in 1 of 5 pigs) or sinus node removal (successful in 4 of 4). After prolonged cardiopulmonary bypass (>120 minutes) alone and with isoproterenol infusion, no spontaneous junctional ectopic tachycardia developed. Junctional ectopic tachycardia or fascicular tachycardia could be initiated after either slow atrioventricular nodal pathway ablation and/or digoxin administration. Junctional ectopic tachycardia occurred in 8 of 9 pigs (mean ventricular rate, 171 +/- 32 bpm), and fascicular tachycardia occurred in 9 of 9 pigs (mean ventricular rate, 187 +/- 39 bpm). His and right bundle recordings confirmed the conduction system origin. CONCLUSIONS: Experimental junctional ectopic tachycardia or fascicular tachycardia can occur in the intraoperative setting of sinus node dysfunction, prolonged cardiopulmonary bypass, and enhanced conduction system automaticity. Conduction system automaticity occurred after either physical injury (ablation or tricuspid valve stretch) or measures to augment the transient inward current of the conduction system (isoproterenol and digoxin). This animal model can serve as the basis to assess new treatments of postoperative junctional ectopic tachycardia. PMID- 23020947 TI - [Not Available]. PMID- 23020948 TI - [Not Available]. PMID- 23020949 TI - [Not Available]. PMID- 23020950 TI - [Not Available]. PMID- 23020951 TI - Vagal afferents sense meal-associated gastrointestinal and pancreatic hormones: mechanism and physiological role. AB - Some gastrointestinal and pancreatic hormones are potently secreted by meal intake and reduce food intake, therefore these hormones play a role in the meal evoked satiety peptides. Previous reports have demonstrated that peripheral administration of these gastrointestinal or pancreatic hormones decrease feeding and the anorectic effects are abolished by lesions of vagal afferent nerves using surgical or chemical protocols, indicative of the involvement of the vagal afferents. Vagal afferent nerves link between several peripheral organs and the nucleus tractus solitarius of the brainstem. The present review focuses on cholecystokinin, peptide YY(3-36), pancreatic polypeptide, and nesfatin-1 released from endocrine cells of the gut and pancreas. These hormonal peptides directly act on and increase cytosolic Ca(2+) in vagal afferent nodose ganglion neurons and finally suppress food intake via vagal afferents. Therefore, peripheral terminals of vagal afferents could sense gastrointestinal and pancreatic hormones and regulate food intake. Here, we review how the vagal afferent neurons sense a variety of gastrointestinal and pancreatic hormones and discuss its physiological significance in regulation of feeding. PMID- 23020954 TI - Detection of lung cancer tissue by attenuated total reflection-Fourier transform infrared spectroscopy-a pilot study of 60 samples. AB - BACKGROUND: Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy could serve as a diagnostic tool for detecting and discriminating different diseases. The aim of this preliminary study was to distinguish malignant and nonmalignant lung tissues with ATR-FTIR spectroscopy. METHODS: Sixty lung tissue samples were obtained from 30 patients who underwent pulmonary lobectomy. Samples were examined with ATR-FTIR spectroscopy before histologic diagnosis. Peak positions, intensities, and full width at half maximum of each absorbent band were measured, and the relative intensity ratios were calculated. Canonical discriminant analysis was performed to discriminate malignant and nonmalignant groups. RESULTS: Twenty-two parameters were significantly different between malignant and nonmalignant groups. Peak intensity at 1546/cm, intensity ratio at 1120/cm, and full width at half maximum at 1303 and 1240/cm were selected as independent factors to form discriminant functions. The sensitivity and specificity of the discriminants were all 96.7%. CONCLUSIONS: ATR-FTIR spectroscopy is a promising method for the detection of malignant lung tissue and could be proved useful in lung tumor surgery. PMID- 23020955 TI - Oxidative stress-associated hypertension in surgically induced brain injury patients: effects of beta-blocker and angiotensin-converting enzyme inhibitor. AB - BACKGROUND: Postoperative hypertension is a common problem in patients undergoing surgical procedures, and the modification of this response could result in improved surgical outcome. Although it is recognized that the incidence of postoperative hypertension is higher in neurosurgical procedures, mechanisms behind this are not well understood. Oxidative stress is an important component of brain injury, and free radicals can influence blood pressure by a number of mechanisms. This study examined the effect of pretreatment with antihypertensive agents on postoperative hypertension in patients undergoing neurosurgery for supratentorial brain tumors and the role of oxidative stress in the process. METHODS: Forty-nine consecutive patients who underwent surgery for supratentorial brain tumors were divided in to three groups (control, Tab. Glucose; atenolol; and lisinopril groups). Blood was drawn at three time points (1 d before the surgery, at the time of dura opening, and at the time of extubation). Hemodynamic parameters in all three groups and levels of malondialdehyde, protein carbonyl content, nitrate, and alpha-tocopherol in serum at various time points were analyzed. RESULTS: The results showed that perioperative hemodynamic changes were highly associated with oxidative stress parameters in all the three groups. It was seen that atenolol and lisinopril significantly decreased levels of malondialdehyde, protein carbonyl content, and nitrate in the intraoperative period (P < 0.05), an effect which continued postoperatively. CONCLUSIONS: The results demonstrate that pretreatment with beta-receptor blocker (atenolol) or angiotensin-converting enzyme inhibitor (lisinopril) reduces postoperative hypertension in patients undergoing neurosurgery, and inhibition of oxidative stress may be a potential mechanism for this effect. PMID- 23020956 TI - The role of negative emotionality and impulsivity in depressive/anxiety disorders and alcohol dependence. AB - BACKGROUND: Much is still unclear about the role of personality in the structure of common psychiatric disorders such as depressive/anxiety disorders and alcohol dependence. This study will therefore examine whether various traits of negative emotionality and impulsivity showed shared or specific associations with these disorders. Method Cross-sectional data were used from the Netherlands Study of Depression and Anxiety (NESDA), including individuals with no DSM-IV psychiatric disorder (n = 460), depressive/anxiety disorder only (i.e. depressive and/or anxiety disorder; n = 1398), alcohol dependence only (n = 32) and co-morbid depressive/anxiety disorder plus alcohol dependence (n = 358). Aspects of negative emotionality were neuroticism, hopelessness, rumination, worry and anxiety sensitivity, whereas aspects of impulsivity included disinhibition, thrill/adventure seeking, experience seeking and boredom susceptibility. RESULTS: Aspects of negative emotionality formed a homogeneous dimension, which was unrelated to the more heterogeneous construct of impulsivity. Although all aspects of negative emotionality were associated with alcohol dependence only, associations were much stronger for depressive/anxiety disorder only and co morbid depressive/anxiety disorder with alcohol dependence. The results for impulsivity traits were less profound and more variable, with disinhibition and boredom susceptibility showing modest associations with both depressive/anxiety disorder and alcohol dependence, whereas low thrill/adventure seeking and high disinhibition were more strongly related with the first and the latter, respectively. CONCLUSIONS: Our results suggest that depressive/anxiety disorder and alcohol dependence result from shared as well as specific aetiological pathways as they showed the same associations with all aspects of negative emotionality, disinhibition and boredom susceptibility as well as specific associations with thrill/adventure seeking and disinhibition. PMID- 23020962 TI - Should highly active antiretroviral therapy be prescribed in critically ill HIV infected patients during the ICU stay? A retrospective cohort study. AB - BACKGROUND: The impact of highly active antiretroviral therapy (HAART) in HIV infected patients admitted to the intensive care unit (ICU) remains controversial. We evaluate impact of HAART prescription in HIV-infected patients admitted to the ICU of Tourcoing Hospital from January 2000 to December 2009. RESULTS: There were 91 admissions concerning 85 HIV-infected patients. Reasons for ICU admission were an AIDS-related diagnosis in 46 cases (51%). Fifty two patients (57%) were on HAART at the time of ICU admission, leading to 21 immunovirologic successes (23%). During the ICU stay, HAART was continued in 29 patients (32%), and started in 3 patients (3%). Only one patient experienced an adverse event related to HAART. Mortality rate in ICU and 6 months after ICU admission were respectively 19% and 27%. Kaplan-Meier estimates of the cumulative unajusted survival probability over 6 months were higher in patients treated with HAART during the ICU stay (Log rank: p = 0.04). No benefit of HAART in ICU was seen in the adjusted survival proportion at 6 months or during ICU stay. Prescription of HAART during ICU was associated with a trend to lower incidence of new AIDS-related events at 6 months (respectively 17% and 34% with and without HAART, p = 0.07), and with higher incidence of antiretroviral resistance after ICU stay (respectively 25% and 7% with and without HAART, p = 0.02). CONCLUSIONS: Our results suggest a lower death rate over 6 months in critically ill HIV infected patients taking HAART during ICU stay. The optimal time to prescribe HAART in critically ill patients needs to be better defined. PMID- 23020963 TI - The best conditions for parallel stenting during EVAR: an in vitro study. AB - OBJECTIVES: The aim of this study is to identify which endograft, and to what degree of oversizing, in combination with what type of parallel stent, may result in the most adequate fit in a juxtarenal abdominal aneurysmal neck when using a parallel-stent technique. MATERIALS/METHODS: In-vitro silicon aneurysmal neck models of different diameters, with one side-branch, were constructed. Two different endografts (Medtronic-Endurant Abdominal Stent Graft and Gore-Excluder abdominal aortic aneurysm Endoprosthesis; three diameters each), and two stents (self-expanding Gore Viabahn Endoprosthesis and balloon-expandable Atrium Advanta V12; 6-mm diameter) were tested, applying three endograft-oversizing degrees (15%, 30% and 40%). After remodelling using the kissing-balloon technique at 37 degrees C, the 36 endograft-stent-oversizing combinations were scanned by computed tomography (CT). The size of the results in gutters, parallel-stent compression and main stent-graft infolding were recorded. RESULTS: Increasing oversizing (15%, 30% and 40%) significantly decreased gutter areas (11.5, 6.2, 4.3 mm(2), P < 0.001); nevertheless, main endograft infolding of most 40% oversized stent grafts was detected, particularly with Excluder devices. Lower stent compression, but wider gutters, were observed with the Excluder when compared to Endurant stent grafts, and with V12 when compared to Viabahn parallel stents. The Endurant-Viabahn combination resulted in maximum stent compression (35%). CONCLUSIONS: Better endograft-stent apposition was achieved when using 30% endograft oversizing. Lower stent compression, but wider gutters, were observed with the Excluder stent-graft and V12 parallel stent, achieving maximum stent compression with the Endurant-Viabahn combination. PMID- 23020964 TI - Re: Use of colour duplex ultrasound as a first line surveillance to following EVAR is associated with a reduction in cost without compromising accuracy. PMID- 23020965 TI - The significance of upper arm cephalic vein disease in vascular access creation. PMID- 23020966 TI - Transcriptome analysis using next-generation sequencing. AB - Up to date research in biology, biotechnology, and medicine requires fast genome and transcriptome analysis technologies for the investigation of cellular state, physiology, and activity. Here, microarray technology and next generation sequencing of transcripts (RNA-Seq) are state of the art. Since microarray technology is limited towards the amount of RNA, the quantification of transcript levels and the sequence information, RNA-Seq provides nearly unlimited possibilities in modern bioanalysis. This chapter presents a detailed description of next-generation sequencing (NGS), describes the impact of this technology on transcriptome analysis and explains its possibilities to explore the modern RNA world. PMID- 23020967 TI - As of 2012, what are the key predictive risk factors for pressure ulcers? Developing French guidelines for clinical practice. AB - INTRODUCTION: An evaluation of predictive risk factors for pressure ulcers is essential in development of a preventive strategy on admission to hospitals and/or nursing homes. OBJECTIVES: Identification of the predictive factors for pressure ulcers as of 2012. METHOD: Systematic review of the literature querying the databases PASCAL Biomed, Cochrane Library and PubMed from 2000 through 2010. RESULTS: Immobility should be considered as a predictive risk factor for pressure ulcers (grade B). Undernutrition/malnutrition may also be a predictive risk factor for pressure ulcers (grade C). DISCUSSION: Even if the level of evidence is low, once these risk factors have been detected, management is essential. Sensitizing and mobilizing health care teams requires training in ways of tracking and screening. According to the experts, risk scales should be used. As decision aids, they should always be balanced and complemented by the clinical judgment of the treatment team. CONCLUSION: According to experts, it is important to know and predictively evaluate risk of pressure ulcers at the time of hospital admission. The predictive risk factors found in this study are identical to those highlighted at the 2001 consensus conference of which was PERSE was the promoter. PMID- 23020968 TI - Detection of suspected placental invasion by MRI: do the results depend on observer' experience? AB - PURPOSE: To evaluate the diagnostic value of previously described MR features used for detecting suspected placental invasion according to observers' experience. MATERIALS AND METHODS: Our population included 25 pregnant women (mean age 35.16) investigated by prenatal MRI (1.5T, T1- and T2-weighted MR sequences without i.v. contrast), among them 12 with histopathologically proven placental invasion and 13 women (52%) without placental invasion used as control group. Two senior and two junior radiologists blindly and independently reviewed MR-examinations in view of 6 previously defined MR-features indicating presence and degree of placental invasion (placenta increta, accreta or percreta). For each reader the sensibility, specificity, and receiver operating curve (ROC) were calculated. Interobserver agreements between senior and junior readers were determined. Stepwise logistic regression was performed including the 6 MR features predictive of placental invasion. RESULTS: Demographics between both groups were statistically equivalent. Overall sensitivity and specificity for placental invasion was 90.9% and 75.0% for seniors and 81.8% and 61.8% for juniors, respectively. The best single MR-feature indicating placental invasion was T2-hypointense placental bands (r(2)=0.28), followed by focally interrupted myometrial border, infiltration of pelvic organs and tenting of the bladder (r(2)=0.36). Interobserver agreement for detecting placental invasion was 0.64 for seniors and 0.41 for juniors, thus substantial and moderate, respectively. Seniors detected placental invasion and depth of infiltration with significantly higher diagnostic certitude than juniors (p=0.0002 and p=0.0282, respectively). CONCLUSION: MRI can be a reliable and reproducible tool for the detection of suspected placental invasion, but the diagnostic value significantly depends on observers' experience. PMID- 23020969 TI - Drugs commonly associated with weight change: umbrella systematic review and meta analysis (Protocol). AB - BACKGROUND: Many drugs and treatments given to patients for various reasons affect their weight. This side effect is of great importance to patients and is also a concern for the treating physician because weight change may lead to the emergence or worsening of other health conditions. OBJECTIVE: The aim of this study is to summarize the evidence about commonly prescribed drugs and their association with weight change. METHODS/DESIGN: Umbrella systematic review and meta-analysis of randomized controlled trials.We will use an umbrella approach to identify eligible randomized controlled trials (RCTs). We will search for systematic reviews of RCTs that compare any of the drugs that have been associated with weight gain (obesogenic) or weight loss (leptogenic); these have been summarized by our experts' panel in a predefined list. Two reviewers will independently determine RCT eligibility. Disagreement will be solved by consensus and arbitrated by a third reviewer. We will extract descriptive, methodological, and efficacy data in duplicate. Our primary continuous outcomes will be weight loss or gain expressed as a mean difference (MD) for weight (kg) or BMI (kg/m2). We will calculate the MD considering the mean difference in weight or BMI between baseline and the last available follow-up in both study arms (drugs and placebo). Our primary dichotomous outcome, presented as a relative risk, will compare the ratio of the incidence of weight change in each trial arm. When possible, results will be pooled using classic random-effects meta-analyses and a summary estimate with 95% confidence interval will provided. We will use the I2 statistic and Cochran's Q test to assess heterogeneity. The risk of bias will be assessed using the Cochrane risk of bias tool. Publication bias, if appropriate, will be evaluated, as well as overall strength of the evidence. DISCUSSION: This systematic review will offer the opportunity to generate a ranking of commonly prescribed drugs in terms of their effect on weight, allowing guideline developers and patient-physician dyad to choose between available therapies. PMID- 23020970 TI - Determinants of generic entry in the regulated Taiwanese prescription drug market. AB - OBJECTIVES: This paper investigates the determinants of generic entry in the regulated Taiwanese prescription drug market, where physicians both prescribe and dispense drugs. METHODS: Using a sample of 29 ingredients and a population claim data set from 1997-2007, we employ the negative binomial regression to empirically examine the determinants of generic entry in Taiwan. RESULTS: This study finds that the lagged number of competitors, market size, and market share of large-scale medical providers affect generic entry. CONCLUSIONS: The negative effect of large buyers on generic entry implies that rent-seeking behavior appears to create a barrier for generic manufacturers to enter into the Taiwanese prescription drug market. PMID- 23020972 TI - Automatic detection of lung nodules in CT datasets based on stable 3D mass-spring models. AB - We propose a computer-aided detection (CAD) system which can detect small-sized (from 3mm) pulmonary nodules in spiral CT scans. A pulmonary nodule is a small lesion in the lungs, round-shaped (parenchymal nodule) or worm-shaped (juxtapleural nodule). Both kinds of lesions have a radio-density greater than lung parenchyma, thus appearing white on the images. Lung nodules might indicate a lung cancer and their early stage detection arguably improves the patient survival rate. CT is considered to be the most accurate imaging modality for nodule detection. However, the large amount of data per examination makes the full analysis difficult, leading to omission of nodules by the radiologist. We developed an advanced computerized method for the automatic detection of internal and juxtapleural nodules on low-dose and thin-slice lung CT scan. This method consists of an initial selection of nodule candidates list, the segmentation of each candidate nodule and the classification of the features computed for each segmented nodule candidate.The presented CAD system is aimed to reduce the number of omissions and to decrease the radiologist scan examination time. Our system locates with the same scheme both internal and juxtapleural nodules. For a correct volume segmentation of the lung parenchyma, the system uses a Region Growing (RG) algorithm and an opening process for including the juxtapleural nodules. The segmentation and the extraction of the suspected nodular lesions from CT images by a lung CAD system constitutes a hard task. In order to solve this key problem, we use a new Stable 3D Mass-Spring Model (MSM) combined with a spline curves reconstruction process. Our model represents concurrently the characteristic gray value range, the directed contour information as well as shape knowledge, which leads to a much more robust and efficient segmentation process. For distinguishing the real nodules among nodule candidates, an additional classification step is applied; furthermore, a neural network is applied to reduce the false positives (FPs) after a double-threshold cut. The system performance was tested on a set of 84 scans made available by the Lung Image Database Consortium (LIDC) annotated by four expert radiologists. The detection rate of the system is 97% with 6.1 FPs/CT. A reduction to 2.5 FPs/CT is achieved at 88% sensitivity. We presented a new 3D segmentation technique for lung nodules in CT datasets, using deformable MSMs. The result is a efficient segmentation process able to converge, identifying the shape of the generic ROI, after a few iterations. Our suitable results show that the use of the 3D AC model and the feature analysis based FPs reduction process constitutes an accurate approach to the segmentation and the classification of lung nodules. PMID- 23020971 TI - PfCRT and its role in antimalarial drug resistance. AB - Plasmodium falciparum resistance to chloroquine, the former gold standard antimalarial drug, is mediated primarily by mutant forms of the chloroquine resistance transporter (PfCRT). These mutations impart upon PfCRT the ability to efflux chloroquine from the intracellular digestive vacuole, the site of drug action. Recent studies reveal that PfCRT variants can also affect parasite fitness, protect immature gametocytes against chloroquine action, and alter P. falciparum susceptibility to current first-line therapies. These results highlight the need to be vigilant in screening for the appearance of novel pfcrt alleles that could contribute to new multi-drug resistance phenotypes. PMID- 23020974 TI - The anterograde transport of the human neuropeptide Y2 receptor is regulated by a subtype specific mechanism mediated by the C-terminus. AB - The export of newly synthesized proteins, including G protein-coupled receptors (GPCR), from the endoplasmic reticulum (ER) and further transport to the plasma membrane is a tightly regulated process. ER export and subsequent cell surface targeting of GPCR is initially mediated through COPII-coated vesicles. It is governed by specific amino acid sequences located in extracellular as well as intracellular receptor domains, for example in the C-terminus (CT) of the receptor. Herein, we determined the role of the CT in the anterograde transport of the human neuropeptide Y receptor (hYR) type 2. We identified a short sequence motif in the membrane proximal CT: Y(x)(3)F(x)(3)F in the region of the putative 8th helix has a critical functional relevance for the anterograde transport of hY(2)R, since its deletion leads to accumulation of the receptor in the ER. It is sequence and position specific. Furthermore we identified a distinct role of C terminal sequences in hY(1)R, hY(2)R, hY(4)R and hY(5)R. Regulation of hY(5)R export is regulated by a different mechanism as compared to hY(2)R. Different sequence elements with respect to function and localization are involved as demonstrated by the construction of a hY(2)/hY(5) receptor chimera and a noneffective deletion in the region of helix eight in the hY(5)R. In contrast to hY(2)R, deletion of the corresponding helical segment F(x)(3)L(x)(3)F has no influence on anterograde transport of hY(1)R, whereas deletion of F(x)(3)I(x)(3)V in hY(4)R restrains the receptor to the Golgi apparatus. Interestingly this pattern is not mirrored by repression of COPII vesicle transport by Sar1[H79G] overexpression. Whereas the 8th helix is involved before or at the level of Sar1 dependent export pathways in the ER for the hY(2)R, in hY(4)R helix eight is involved at later stages of anterograde transport. PMID- 23020973 TI - Effect of vitamin D deficiency and replacement on endothelial functions in Behcet's disease. AB - OBJECTIVES: Endothelial dysfunction is previously demonstrated in Behcet's disease (BD) and vitamin D is implicated to affect endothelial functions. We aimed to evaluate the status of serum 25(OH)Vit D3 levels and its association with disease activity, endothelial function and carotis intima media thickness (CIMT) in patients with BD. METHODS: Thirty-six BD (F/M: 22/14, mean age: 39.6 years) patients and 51 healthy controls (F/M: 28/23, mean age: 34.5 years) were studied. Rheumatoid arthritis (RA) (n=33) patients (F/M: 26/7, mean age: 50.82 years) were also enrolled, as a disease control group. Endothelial function was evaluated by brachial artery flow mediated dilatation (FMD) and CIMT with B-Mode ultrasound. The vitamin D-deficient BD patients received 1000 IU Vitamin D3 daily for 3 months. RESULTS: Less than 50 nmol/L levels of 25(OH) Vit D3 were present in 61.1% (n=22) of BD and 35.3% (n=18) of HC (serum 25(OH)Vit D3 levels: BD: 44.5 (9-112) vs HC: 56 (14-125) nmol/lt, p=0.01). CIMT and FMD were also significantly different between BD and HC [0.56 (0.35-9.26) vs. 0.39 (0-0.52) and 5.20 (0.56 30.58) vs. 9.04 (-6.9-34.17), p=0.001 and p=0.02, respectively]. However, no correlation was observed between 25(OH)VitD3 levels and CIMT or FMD (r=0.6, p=0.7 and r=0.03, p=0.8, respectively) at baseline. CIMT measurements improved after replacement therapy (0.56 vs. 0.49, p=0.02), FMD measurements also improved, but not reaching statistical significance (5.2 vs. 8.28, p=0.06). CONCLUSIONS: A high presence of vitamin D deficiency was observed in BD patients from Turkey and replacement of vitamin D had favourable effects on endothelial function. PMID- 23020978 TI - Prevalencia de fibrilacion auricular y uso de farmacos antitromboticos en el paciente hipertenso >= 65 anos. El registro FAPRES. AB - INTRODUCTION AND OBJECTIVES: Age and arterial hypertension are two of the main factors associated with atrial fibrillation and an increased risk of embolism. The objective of this study was to determine the prevalence of atrial fibrillation and the extent of antithrombotic use in hypertensive patients aged >=65 years in the Spanish region of Valencia. METHODS: Each study investigator enrolled the first three hypertensive patients aged >=65 years who came for a consultation on the first day of each week for 5 weeks. Each patient's risk factors, history of cardiovascular disease, CHADS(2) score and medical treatment were noted and an ECG was recorded. Data were analyzed centrally. A patient was regarded as having atrial fibrillation if it was observable on the ECG or reported in medical records. RESULTS: The study included 1,028 hypertensive patients with a mean age of 72.8 years. Overall, 10.3% had atrial fibrillation: in 6.7%, it was observable on the ECG while 3.6% were in sinus rhythm but had a history of the condition. Factors associated with atrial fibrillation were age, alcohol intake, structural heart disease and glomerular filtration rate. In total, 76.2% of patients with ECG evidence of atrial fibrillation and a CHADS(2) score >1 were taking anticoagulants compared with 41.7% of those who had a history of the condition but were currently in sinus rhythm. CONCLUSIONS: The prevalence of atrial fibrillation in our group of hypertensives was 10.3%; in 1.7%, it was previously undiagnosed. Antithrombotic use was high in patients with current atrial fibrillation, but lower in those who had experienced an episode previously. PMID- 23020979 TI - [Not Available]. PMID- 23020980 TI - [Not Available]. PMID- 23020981 TI - [Not Available]. PMID- 23020982 TI - [Not Available]. PMID- 23020986 TI - Seasonal variation of bioaccumulation in Engraulis encrasicolus (Linneaus, 1758) and related biomarkers of exposure. AB - In the last years, the development of new techniques and the increase of sophisticated assays has improved the environmental monitoring programs by using fish as bioindicators of marine ecosystems, applying a multibiomarkers approach. The aim of this study was to assess the contamination level of the Catania Gulf through bioaccumulation and contaminant exposure response in Engraulis encrasicolus (Linnaeus, 1758). Heavy metals, polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) were analyzed in muscle tissue of the species. Furthermore we evaluated biomarkers of exposure to such contaminants: the metallothioneins (MTs), the ethoxyresorufin-O-deethylase (EROD) and stress protein or "heat shock proteins" (HSP70). In total, three sampling of 30 specimens each were performed during 2011. Comparison between classes of contaminants was performed using Student's t-test for paired samples Data showed that: the populations of E. encrasicolus accumulated a certain amount of metals, PAHs and organochlorine compounds in their tissues, that, however, did not exceed the legal limits set by Regulation 1881/2006 for contaminants in fish muscle; essential metals accumulate more during the reproductive periods of the species; the accumulation of heavy metals and PAHs are more closely related to natural and anthropogenic events; the presence of PCBs, although in traces, is the confirmation that banned compounds persist in the environment for several years; the levels of contaminants found in the tissues of the species do not seem to be likely to cause toxic effects both in the studied fish species. In conclusion, environmental risk assessment came out in this study for the Catania Gulf, showed a positive picture, although the contaminants detected are related to a certain degree of anthropic impact, and should be constantly monitored to ensure quality standards of the studied area. PMID- 23020987 TI - Multiple pollution biomarker application on tissues of Eobania vermiculata during two periods characterized by augmented and reduced snail activity. AB - In the present study a package of biomarkers was applied on land snails E. vermiculata collected from polluted areas, as well as from an unpolluted reference one. Snail collection was performed during two different sampling periods characterized by reduced and augmented organism activity, October and May, respectively. The biomarkers applied were lysosomal membrane stability on digestive cells (LMS), neutral red lysosomal retention assay on haemocytes (NRR), morphometric changes of the lysosomal system (VDL, NDL), morphometric alterations of the neutral lipids (VDLP, NDLP), acetylcholinesterase activity on digestive gland and hemolymph (AChE), metallothionein content on digestive gland (MTs) and cyclic AMP content on digestive gland (cAMP). The results revealed significant differences in biomarker values between the two sampling periods. Significant differences were also detected among the sampling groups. The fluctuation of the parameters applied indicated that spring is a more suitable period for sampling conduction compared to autumn and that biomonitoring studies should be performed with special attention during the last mentioned period. PMID- 23020988 TI - Arsenic and selenium interactive effect on alga Desmodesmus quadricauda. AB - Substances known to be toxic in one-component solutions often exhibit unexpected effects when present in mixtures. Only a few efforts have been made to assess the effect of As-Se mixture in algae or plants in general. Due to the lack of information on this topic, the aim of this study was to examine the As-Se interactive effect in the alga species Desmodesmus quadricauda. The initial density of algal cells was 1.9*10(4), cultures were permanently illuminated (70MUEm(-2)s(-1)) and As and Se adverse effect was expressed as EC (effective concentration) value. For all experiments three EC (EC(10), EC(20), EC(50)) values for both metalloids were used: for As 26.20, 29.05, 35.38mg L(-1) and for Se 1.93, 3.65, 12.24mg L(-1), respectively. During this study algal biomass growth, lipid peroxidation and protein-bound thiol content parameters were used to assess the As-Se interactions. The reciprocal effect of the elements on their uptake by the alga was also determined. The As-treated algae supplemented with Se exhibited impaired growth indicating a synergistic interaction between the two elements. In samples treated with As-Se mixture, the total algal As content showed marked increase depending on the Se concentration in the mixture. Se uptake was also positively affected by rising As concentrations in the mixture. Consequently, the As-Se-treated algae experienced greater damage to membranes, evidenced by marked elevation of the TBARS (thiobarbituric acid reactive substances) content. The TBARS content increased to a maximum level by 29.05mg L( 1) of As and 3.65mg L(-1) of Se, which was around 70 percent higher than that of the control. The thiol content was very close to that of the control treatment over the entire concentration range and for all As and Se combinations tested. Possible explanation for the synergism observed in D. quadricauda, is that the elevated uptake of As and Se upon their interaction and impaired antioxidant system, has added to the toxicity of the elements. PMID- 23020989 TI - Intermittent hypoglossal nerve palsy caused by a calcified persistent hypoglossal artery: an uncommon neurovascular compression syndrome. AB - Neurovascular compression is assumed to cause symptoms like trigeminal neuralgia, hemifacial spasm and vestibular paroxysmia. We present a patient with recurrent episodes of transient dysarthria due to isolated right hypoglossal nerve (HN) palsy. We describe the first case of a calcified persistent hypoglossal artery (PHA) as the putative cause of a hypoglossal neurovascular compression syndrome. Our patient received a daily low-dose medication of carbamazepine resulting in complete relief of symptoms. In conclusion, PHA is not only an anatomic variation but also a possible cause of a neurovascular compression syndrome leading to intermittent HN palsy. PMID- 23020990 TI - Breast cancer molecular subtypes--modern therapeutic concepts for targeted therapy of a heterogeneous entity. AB - Within the last decade, breast cancer is increasingly understood as a heterogeneous disease comprising distinct entities that vary significantly with regard to molecular biology and clinical features. Despite impressive advances in the treatment of patients with breast cancer, not all patients derive equal benefits from current therapeutic options and a significant number of patients still experience disease recurrence. Whereas for patients with hormone receptor positive and/or HER2/neu-positive breast cancer overcoming resistance against endocrine and/or anti-HER2/neu-targeted therapy is of particular importance, patients with triple negative breast cancer suffer from a lack of sufficient targeted therapeutic options at all. In this review we give a summary of the most important targeted agents recently or currently being developed for patients with breast cancer. PMID- 23020991 TI - Fertility after breast cancer. AB - Breast cancer is the most common tumor in childbearing women. In the last decades, considerable improvement in breast cancer-related death has been achieved with adjuvant therapies (chemotherapy, endocrine and targeted therapies, radiotherapy) but at cost of significant long-term sequels, including infertility. Reproductive issues are of great importance to young women, in particular for those who did not complete their families before breast cancer diagnosis: patients should be adequately informed at the time of diagnosis about the risk of infertility and the available methods for fertility preservation. This review will focus on incidence and impact of infertility secondary to breast cancer treatment, the available options for ovarian function preservation, including embryo and oocyte cryopreservation, ovarian tissue cryopreservation, and ovarian suppression with gonadotropin-releasing hormone agonists. We will also discuss the optimal time of subsequent pregnancy, the potential risks for the mother and the fetus, and the impact of therapies on breastfeeding. PMID- 23020992 TI - Alanine aminotransferase/aspartate aminotransferase ratio is the best surrogate marker for insulin resistance in non-obese Japanese adults. AB - BACKGROUND: The aim of the present study was to examine how liver markers are associated with insulin resistance in Japanese community-dwelling adults. METHODS: This cross-sectional study included 587 men aged 58 +/- 14 (mean +/- standard deviation; range, 20-89) years and 755 women aged 60 +/- 12 (range, 21 88) years. The study sample consisted of 998 (74.4%) non-obese [body mass index (BMI) <25.0 kg/m2] and 344 (25.6%) overweight (BMI >= 25 kg/m2) subjects. Insulin resistance was defined by homeostasis model assessment of insulin resistance (HOMA-IR) of at least 2.5, and HOMA-IR and potential confounders were compared between the groups. Areas under the curve (AUC) of the receiver operating characteristic curves (ROC) were used to compare the power of these serum markers. RESULTS: In non-obese subjects, the best marker of insulin resistance was alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio of 0.70 (95% confidence interval (CI), 0.63-0.77). In overweight subjects, AUC values for the ALT/AST ratio and ALT were 0.66 (0.59-0.72) and 0.66 (0.59-0.72), respectively. Multiple linear regression analyses for HOMA-IR showed that ALT/AST ratios were independently and significantly associated with HOMA-IR as well as other confounding factors in both non-obese and overweight subjects. The optimal cut-off point to identifying insulin resistance for these markers yielded the following values: ALT/AST ratio of >= 0.82 in non-obese subjects and >= 1.02 in overweight subjects. In non-obese subjects, the positive likelihood ratio was greatest for ALT/AST ratio. CONCLUSIONS: In non-obese Japanese adults, ALT/AST ratio may be the best reliable marker of insulin resistance. PMID- 23020994 TI - Prefrontal cortex function in remitted major depressive disorder. AB - BACKGROUND: Recent models of major depressive disorder (MDD) have proposed the rostral anterior cingulate (rACC) and dorsomedial prefrontal cortex (dmPFC) as nexus sites in the dysfunctional regulation of cognitive-affective state. Limited evidence from remitted-state MDD supports these theories by suggesting that aberrant neural activity proximal to the rACC and the dmPFC may play a role in vulnerability to recurrence/relapse within this disorder. Here we present a targeted analysis assessing functional activity within these two regions of interest (ROIs) for groups with identified vulnerability to MDD: first, remitted, high predicted recurrence-risk patients; and second, patients suffering observed 1-year recurrence. Method Baseline T2* images sensitive to blood oxygen level dependent (BOLD) contrast were acquired from patients and controls during a Go/No Go (GNG) task incorporating negative feedback, with 1-year patient follow-up to identify recurrence. BOLD contrast data for error commission (EC) and visual negative feedback (VNF) were used in an ROI analysis based on rACC and dmPFC coordinates from the literature, comparing patients versus controls and recurrence versus non-recurrence versus control groups. RESULTS: Analysis of patients (n = 20) versus controls (n = 20) showed significant right dmPFC [Brodmann area (BA) 9] hypoactivity within the patient group, co-localized during EC and VNF, with additional significant rACC (BA 32) hypoactivity during EC. The results from the follow-up analysis were undermined by small groups and potential confounders but suggested persistent right dmPFC (BA 9) hypoactivity associated with 1-year recurrence. CONCLUSIONS: Convergent hypoactive right dmPFC (BA 9) processing of VNF and EC, possibly impairing adaptive reappraisal of negative experience, was associated most clearly with clinically predicted vulnerability to MDD. PMID- 23020995 TI - Fetal cardiac function after labetalol or pindolol for maternal hypertension in a sheep model of increased placental vascular resistance. AB - OBJECTIVE: We hypothesized that labetalol and pindolol have no detrimental effects on fetal cardiac function and pulmonary hemodynamics when administered for norepinephrine-induced maternal hypertension in a chronic sheep model of increased placental vascular resistance. Specifically, we investigated the effects of labetalol and pindolol on fetal cardiopulmonary responses to acute hypoxemia. STUDY DESIGN: Twenty chronically instrumented near-term ewes with increased placental vascular resistance after placental embolization were anesthetized and randomized to receive labetalol or pindolol for norepinephrine induced hypertension. Thereafter, maternal inspiratory oxygen fraction was decreased to induce fetal hypoxemia. At the end of each phase, fetal hemodynamics were assessed by Doppler ultrasonography. The data were analyzed using repeated measures ANOVA. RESULTS: Maternal administration of norepinephrine had no effect on fetal hemodynamics. Pindolol decreased fetal heart rate and weight-indexed left ventricular cardiac output and increased pulmonary vascular impedances, while labetalol had no effect on these parameters. During hypoxemia, fetal heart rate increased to baseline in the pindolol group and pulmonary vascular impedances increased in the labetalol group, with no changes in fetal cardiac outputs. CONCLUSION: Pindolol decreased fetal left ventricular cardiac output and induced vasoconstriction in the pulmonary vasculature, but neither pindolol nor labetalol significantly modified fetal cardiopulmonary responses to acute hypoxemia. PMID- 23020996 TI - GnRH antagonist versus long GnRH agonist protocol in poor IVF responders: a randomized clinical trial. AB - OBJECTIVE: To compare the efficacy of the long GnRH agonist and the fixed GnRH antagonist protocols in IVF poor responders. STUDY DESIGN: This was a randomized controlled trial performed in the Iakentro IVF centre, Thessaloniki, from January 2007 to December 2011, concerning women characterised as poor responders after having 0-4 oocytes retrieved at a previous IVF cycle. They were assigned at random, using sealed envelopes, to either a long GnRH agonist protocol (group I) or a GnRH antagonist protocol (group II). RESULTS: Overall 364 women fulfilled the inclusion criteria and were allocated to the two groups: finally 330 participated in our trial. Of these, 162 were treated with the long GnRH agonist protocol (group I), and 168 with the fixed GnRH antagonist protocol (group II). Numbers of embryos transferred and implantation rates were similar between the two groups (P=NS). The overall cancellation rate was higher in the antagonist group compared to the agonist group, but the difference was not significant (22.15% vs. 15.2%, P=NS). Although clinical pregnancy rates per transfer cycle were not different between the two groups (42.3% vs. 33.1%, P=NS), the clinical pregnancy rate per cycle initiated was significantly higher in the agonist compared to the antagonist group (35.8% vs. 25.6%, P=0.03). CONCLUSIONS: Although long GnRH agonist and fixed GnRH antagonist protocols seem to have comparable pregnancy rates per transfer in poor responders undergoing IVF, the higher cancellation rate observed in the antagonist group suggests the long GnRH agonist protocol as the first choice for ovarian stimulation in these patients. PMID- 23020997 TI - Paratesticular cystadenomas with ovarian stroma, metaplastic serous Mullerian epithelium, and male adnexal tumor of probable wolffian origin: A series of 5 hitherto poorly recognized testicular tumors. AB - We present 5 paratesticular tumors, which manifested ovarian-type stroma and various serous mullerian epithelial structures including serous fallopian-like epithelium and proliferations closely mimicking cystic serous borderline tumors of the ovary. In addition, 3 of the tumors in our series revealed a solid epithelial component, which was morphologically and immunohistochemically similar to so called "female adnexal tumor of probable wolffian origin," which is a rare neoplasm described so far only in the female genital tract, retroperitoneum, and the pelvic cavity. In analogy with mixed epithelial and stromal tumors of the kidney, which are renal neoplasms producing ovarian-type stroma, we suggest to designate the above paratesticular tumors containing ovarian-type stroma as "mixed epithelial and stromal tumors of the paratestis with features of cystic serous borderline tumor" (cases 1 and 2) and "mixed epithelial and stromal tumors of the paratestis with male adnexal tumor of probable wolffian origin" (cases 3 5). PMID- 23020998 TI - Xanthomatous hyperplastic polyps of the stomach: clinicopathologic study of 5 patients with polypoid gastric lesions showing combined features of gastric xanthelasma and hyperplastic polyp. AB - Gastric xanthelasmas are uncommon benign lesions that are macroscopically well demarcated yellow or yellow-white plaques and are microscopically formed by collections of foamy macrophages. Because gastric hyperplastic polyps may rarely be associated with xanthelasma, we aimed to report 5 cases of combined lesions showing features of gastric xanthelasma and hyperplastic polyps observed over the past 3 years at our institution among 4497 patients who underwent gastric endoscopy. The patients were 3 men and 2 women aged 45 to 78 years. The lesions were located in oxyntic mucosa, except one in the antrum, and measured 2 to 6 mm. Three patients showed associated chronic gastritis; none showed evidence of Helicobacter pylori infection. Combined lesions of hyperplastic polyp with xanthelasma appear to have an association with chronic gastritis, and the lipid accumulation may be the cause of hyperplasia in the overlying mucosa. PMID- 23020999 TI - Preliminary study of an intestinal bio-robot system based on nerve stimulation. AB - BACKGROUND: Wireless capsule endoscopes for diagnosis and treatment in the gastrointestinal tract face the common problem of active actuation. To tackle this difficulty, a non-invasive intestinal bio-robot system with active actuation based on nerve stimulation was developed. METHODS: This intestinal inspection system utilized a natural organism--the mud eel--to serve as the locomotion mechanism, and it was controlled by a LabVIEW-programmed pulse generator. The exterior control unit was able to actively drive and remotely control the navigation and site-specific anchoring of the organism. RESULTS: Through in vitro stimulation experiments, a method of controlling the organism's forward motion was obtained: when the organism was stimulated at the tail, it moved forward at a relatively fast speed and with high repeatability. The stimulator parameters were as follows: amplitude 1.85 MUA, frequency 2 Hz, pulse duration 500 MUs. CONCLUSIONS: Since this is a preliminary study, considerable work remains to be done. However, the results could provide a solid theoretical basis for further research toward producing a practical intestinal bio-robot for the diagnosis and treatment of the gastrointestinal tract. PMID- 23021000 TI - Ectopic pyriform sinus parathyroid adenoma. AB - OBJECTIVE: To describe the diagnosis and treatment of ectopic pyriform sinus parathyroid adenoma. MATERIAL AND METHODS: A 44-year-old woman presented with persistent primary hyperparathyroidism after previous failed cervical exploratory surgery. RESULTS: Diagnosis of ectopic pyriform sinus parathyroid adenoma was suggested by computed tomography and technetium-99m sestamibi scintigraphy (99mTc MIBI SPECT/CT). A submucosal tumor was identified under laryngoscopy and resected by endoscopic CO2 laser. Histopathology confirmed the diagnosis of parathyroid adenoma. CONCLUSIONS: Ectopic pyriform sinus locations are rare in parathyroid adenoma. 99mTc-MIBI SPECT/CT facilitates diagnosis, especially in case of previous failed neck exploration. Endoscopic CO2 laser resection is the treatment of choice. PMID- 23021001 TI - Abecedarium: Who am I? G'.... PMID- 23021002 TI - Intraparotid Kimura disease. AB - INTRODUCTION: Intraparotid locations are extremely rare in Kimura disease, especially in Europe. CASE REPORT: A 31-year-old man presented with intraparotid Kimura disease, managed by parotidectomy. DISCUSSION/CONCLUSION: The case was analyzed in the light of a review of the literature, focusing on the diagnostic and anatomopathologic problems encountered, and the physiopathology and treatment of this pathology. Any parotid mass found in a patient of Far-Eastern origin showing hypereosinophilia should suggest a diagnosis of intraparotid Kimura disease. PMID- 23021003 TI - Abecedarium: who am I? F'... PMID- 23021005 TI - Quality evaluation of Polygonum multiflorum in China based on HPLC analysis of hydrophilic bioactive compounds and chemometrics. AB - Polygonum multiflorum is one of the most commonly used Chinese medicines. In this study, an effective pressurized water extraction and HPLC method was developed for first simultaneous determination of 8 hydrophilic compounds, including gallic acid, Hypaphorine, Catechin, Proanthocyanidin B1, Epicatechin, Proanthocyanidin B2, Emodin-8-O-beta-d-glucopyranoside, stilbene glycosides, in P. multiflorum. The analysis was performed on a Zorbax SB-AQ column with gradient elution of 0.05% phosphoric acid aqueous solution and acetonitrile in 45 min. All calibration curves showed good linearity (R(2)>0.9994) within test ranges. The LOD and LOQ were lower than 0.2 and 1.0 MUg/mL on column, respectively. RSD for intra- and inter-day of 8 analytes were less than 4.1% and 4.0%, respectively, and the overall recovery was 96.0-100.7%. The validated method was successfully applied to quantification of 8 hydrophilic compounds in samples of P. multiflorum from different locations of China. Chemometrics such as principal component analysis (PCA) and hierarchical clustering analysis (HCA) were used to evaluate homogeneity of P. multiflorum in China, which suggested that their quality homogeneity was good. PMID- 23021004 TI - Time-resolved structural studies at synchrotrons and X-ray free electron lasers: opportunities and challenges. AB - X-ray free electron lasers (XFELs) are potentially revolutionary X-ray sources because of their very short pulse duration, extreme peak brilliance and high spatial coherence, features that distinguish them from today's synchrotron sources. We review recent time-resolved Laue diffraction and time-resolved wide angle X-ray scattering (WAXS) studies at synchrotron sources, and initial static studies at XFELs. XFELs have the potential to transform the field of time resolved structural biology, yet many challenges arise in devising and adapting hardware, experimental design and data analysis strategies to exploit their unusual properties. Despite these challenges, we are confident that XFEL sources are poised to shed new light on ultrafast protein reaction dynamics. PMID- 23021006 TI - Novel insight into qualitative standardization of Polygoni avicularis herba (Ph. Eur.). AB - Polygonum aviculare L. (Common Knotrgrass) (Polygonaceae Juss.) is an annual from which pharmacopoeial (Ph. Eur.) plant material Polygoni avicularis herba is obtained. Although its main active constituents are flavonoids and its standardization is based on their total content, no profound qualitative analysis has been performed, yet. The use of hyphenated analytical methods: UHPLC-DAD coupled with ion trap or time of flight mass detectors together with acidic hydrolysis products analysis allowed for a comprehensive determination of flavonoid composition. Among dominating compounds, myricetin, kaempferol, isorhamnetin and kaempferide glucuronides, which were not previously reported in P. avicularis herba, were discovered. The developed method can be used as a suitable tool for a more insightful, metabolome-based standardization of flavonoid rich pharmacopoeial plant material -P. avicularis herba. PMID- 23021007 TI - Efficacy of infliximab in a patient with refractory idiopathic retroperitoneal fibrosis. AB - Glucocorticoids are the mainstay of treatment of idiopathic retroperitoneal fibrosis (IRF). However, relapses are frequent upon tapering of the glucocorticoid dose. A variety of traditional immunosuppressants have been proposed as steroid-sparing agents, but some patients fail to adequately respond to combined glucocorticoid and immunosuppressive therapy. We report a patient with IRF refractory to combined glucocorticoid and methotrexate therapy treated with the anti-TNF-alpha monoclonal antibody infliximab. Infliximab was administered at 5 mg/kg/bodyweight at week 0, 2, 6 and 8-weekly thereafter for 3 consecutive years. Drug efficacy and safety were assessed clinically and by laboratory tests at treatment onset and subsequently before each infusion. In addition, 18FFluorodeoxyglucose (FDG) positron emission computerised tomography (PET/CT) and abdominal CT scans were used to monitor disease activity and response to treatment. Infliximab therapy resulted in a satisfactory clinical and laboratory response paralleled by an improvement in imaging findings. No serious adverse events were noted. Infliximab may be an effective and safe treatment for refractory IRF. A controlled study is required to confirm our findings. PMID- 23021008 TI - [Spontaneous carotid dissection presenting as painful Horner syndrome]. PMID- 23021009 TI - Low rates of hepatotoxicity among Asian patients with paracetamol overdose: a review of 1024 cases. AB - BACKGROUND: The metabolism of paracetamol in Asians is thought to differ from Westerners. Detailed clinical features of paracetamol -induced hepatotoxicity among Asians remains largely unreported. METHODS: A retrospective review of adult cases with paracetamol overdose over a five-year duration was performed in two of the largest public institutions in this country. Prevalence and predictive factors for hepatotoxicity were determined. RESULTS: Data on 1024 patients (median age 23 years, 82.0% female, ethnic groups: Malays 40.8%, Chinese 20.9% , Indian 33.2%) were obtained from January 2005 to December 2009. The median amount of paracetamol ingestion was 10.0 (IQR 5.0 - 15.0) g and the median serum paracetamol level was 274.80 (IQR 70.0 - 640.0) MUmol/L at presentation. 75 (7.3%) patients developed hepatotoxicity. 23/ 55 (41.8%) patients who had ingested > 10 g of paracetamol and had a delayed (> 24 hour) administration of N acetyl cystine (NAC) developed hepatotoxicity. No patients developed acute liver failure nor suffered any mortality (0%). Independent predictors for hepatotoxicity were identified as Malay (OR 2.22, 95% CI = 1.13-4.37) and Chinese (OR 3.26, 95% CI = 1.55-6.84) ethnicity, paracetamol dose > 10 g (OR 2.61, 95% CI = 1.53-4.46), prolonged duration of time from paracetamol ingestion to hospital presentation (> 24 hours OR 10.71, 95% CI = 3.46-33.15) and prolonged duration of time from paracetamol ingestion to NAC administration (> 24 hours OR 9.02, 95% CI = 2.97-27.45). CONCLUSIONS: Paracetamol-induced hepatotoxicity rates in a multi ethnic Asian population was low at 7.3%. Mortality and morbidity were non existent despite high doses of paracetamol ingestion and delayed presentations to hospital. PMID- 23021010 TI - Model of practical skill performance as an instrument for supervision and formative assessment. AB - There are still weaknesses in the practical skills of newly graduated nurses. There is also an escalating pressure on existing clinical placements due to increasing student numbers and structural changes in health services. Innovative educational practices and the use of tools that might support learning are sparsely researched in the field of clinical education for nursing students. This paper reports on an action research study that promoted and investigated use of The Model of Practical Skill Performance as a learning tool during nursing students' clinical placement. Clinical supervisors and two cohorts of nursing students placed in a hospital setting shared their experiences on the use of the model in six focus group interviews. Data was also generated through the supervisors' reflective logs. The model was viewed as highly applicable in the planning of learning situations as well as during practice, performance and formative assessment of practical skills learning. It provided a common language about practical skills and enhanced the participants' understanding of professionalism in practical nursing skill. In conclusion, the model helped to highlight the complexity in mastering practical skills, afforded help in sequencing a learning process that supported the novice, and contributed to a more nuanced feedback by supervisors. PMID- 23021011 TI - Reasons for using contraception: perspectives of US women seeking care at specialized family planning clinics. AB - BACKGROUND: The availability and use of contraception to prevent unintended pregnancy has had profound and positive impacts on the lives of American women. This study looks beyond the aggregate benefits of contraceptive use to examine the individual-level benefits and reasons for using contraception reported by women themselves. STUDY DESIGN: We surveyed 2,094 women receiving services from 22 family planning clinics located throughout the United States. RESULTS: A majority of respondents reported that birth control use had allowed them to take better care of themselves or their families (63%), support themselves financially (56%), complete their education (51%), or keep or get a job (50%). Young women, unmarried women and those without children reported more reasons for using contraception than others. Not being able to afford a baby, not being ready for children, feeling that having a baby would interrupt their goals and wanting to maintain control in their lives were the most commonly reported very important reasons for using birth control. CONCLUSIONS: Women value the ability to plan their childbearing and need continued access to contraception and contraceptive services, allowing them to realize the benefits that accrue when unintended pregnancies are avoided. PMID- 23021013 TI - Whole egg consumption improves lipoprotein profiles and insulin sensitivity to a greater extent than yolk-free egg substitute in individuals with metabolic syndrome. AB - OBJECTIVE: We investigated if daily egg feeding, along with carbohydrate restriction, would alter lipoprotein metabolism and influence atherogenic lipoprotein profiles and insulin resistance in men and women with metabolic syndrome (MetS). METHODS: In a randomized, single-blind, parallel design, participants consumed either 3 whole eggs/day (EGG, n=20) or the equivalent amount of yolk-free egg substitute (SUB, n=17), as part of a moderately carbohydrate-restricted diet (25%-30% energy) for 12 weeks. Plasma lipids, apolipoproteins (apos), oxidized LDL (oxLDL), cholesteryl ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT) activities were assessed at baseline and week 12. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy. RESULTS: Atherogenic dyslipidemia improved for all individuals as evidenced by reductions in plasma triglycerides, apoC-III, apoE, oxLDL, VLDL particle diameter, large VDL, total IDL, small LDL, and medium LDL particles (P<0.05). Furthermore, there were increases in HDL-cholesterol, large LDL and large HDL particles (P<0.05) for all individuals. However, there were greater increases in HDL-cholesterol and large HDL particles, and reductions in total VLDL and medium VLDL particles for those consuming EGG compared to SUB (P<0.05). Plasma insulin and insulin resistance (HOMA-IR) were reduced, while LCAT activity, and both HDL and LDL diameters increased over time in the EGG group only (P<0.05). CONCLUSIONS: Incorporating daily whole egg intake into a moderately carbohydrate-restricted diet provides further improvements in the atherogenic lipoprotein profile and in insulin resistance in individuals with MetS. PMID- 23021014 TI - The neuropsychological profile of children at high risk of developing an eating disorder. AB - BACKGROUND: There is a large body of evidence indicating that eating disorders (EDs) are characterized by particular neuropsychological profiles. We aimed to further explore whether impairments in neuropsychological functioning previously found in ED groups are present prior to onset, or are secondary to the disorder. Method This is the first study to explore neuropsychological functioning in children born to a mother with a lifetime ED, who are therefore at high risk of developing an ED, in a large cohort sample. We investigated intelligence and attention at age 8 years (n = 6201) and working memory (WM) and inhibition at age 10 years (6192) in children who are at high risk of developing an ED, compared to children who are not. RESULTS: The children of women with lifetime anorexia nervosa (AN) showed high full-scale and performance IQ, increased WM capacity, better visuo-spatial functioning, and decreased attentional control. The children of women with lifetime bulimia nervosa (BN) showed comparatively poor visuo spatial functioning. CONCLUSIONS: Our findings suggest that high intelligence, increased WM capacity and impaired attentional control might be intermediate phenotypes on the pathway between genetic vulnerability and the development of an ED. PMID- 23021015 TI - A study of Iranian immigrants' experiences of accessing Canadian health care services: a grounded theory. AB - BACKGROUND: Immigration is not a new phenomenon but, rather, has deep roots in human history. Documents from every era detail individuals who left their homelands and struggled to reestablish their lives in other countries. The aim of this study was to explore and understand the experience of Iranian immigrants who accessed Canadian health care services. Research with immigrants is useful for learning about strategies that newcomers develop to access health care services. METHODS: The research question guiding this study was, "What are the processes by which Iranian immigrants learn to access health care services in Canada?" To answer the question, a constructivist grounded theory approach was applied. Initially, unstructured interviews were conducted with 17 participants (11 women and six men) who were adults (at least 18 years old) and had immigrated to Canada within the past 15 years. Eight participants took part in a second interview, and four participants took part in a third interview. RESULTS: Using a constructivist grounded theory approach, "tackling the stumbling blocks of access" emerged as the core category. The basic social process (BSP), becoming self-sufficient, was a transitional process and had five stages: becoming a stranger; feeling helpless; navigating/seeking information; employing strategies; and becoming integrated and self-sufficient. We found that "tackling the stumbling blocks of access" was the main struggle throughout this journey. Some of the immigrants were able to overcome these challenges and became proficient in accessing health care services, but others were unable to make the necessary changes and thus stayed in earlier stages/phases of transition, and sometimes returned to their country of origin. CONCLUSION: During the course of this journey a substantive grounded theory was developed that revealed the challenges and issues confronted by this particular group of immigrants. This process explains why some Iranian immigrants are able to access Canadian health care effectively while others cannot. Many elements, including language proficiency, cultural differences, education, previous experiences, financial status, age, knowledge of the host country's health care services, and insider and outsider resources work synergistically in helping immigrants to access health care services effectively and appropriately. PMID- 23021019 TI - [Not Available]. PMID- 23021020 TI - [Not Available]. PMID- 23021021 TI - The emerging role of exercise and health counseling in patients with acute leukemia undergoing chemotherapy during outpatient management. AB - This study investigates the feasibility, safety and benefits of a 6-week exercise and health counseling intervention in patients with acute leukemia undergoing consolidation chemotherapy during outpatient management. Seventeen of twenty patients completed study requirements (85%), adherence to exercise was 73% and for health counseling 92%. There were improvements in the 6-min-walk-distance (p=0.0013), sit-to-stand test (p=0.0062), the right and left biceps arm-curl tests p=0.0002 and p=0.0002, respectively; health-related quality of life (p=0.0209) (FACT-An), vitality (p=0.0015), mental health (p=0.0471) and physical component scale (p=0.0295) (SF36). Significant reduction in the symptom burden (p=0.0021) and symptom interference on daily life activities (p=0.0069) (MDASI). No adverse reactions were observed. PMID- 23021022 TI - Teosinte as a model system for population and ecological genomics. AB - As the cost of next-generation sequencing diminishes and genomic resources improve, crop wild relatives are well positioned to make major contributions to the field of ecological genomics via full-genome resequencing and reference assisted de novo assembly of genomes of plants from natural populations. The wild relatives of maize, collectively known as teosinte, are a more varied and representative study system than many other model flowering plants. In this review of the population and ecological genomics of the teosintes we highlight recent advances in the study of maize domestication, introgressive hybridization, and local adaptation, and discuss future prospects for applying the genomic resources of maize to this intriguing group of species. The maize/teosinte study system is an excellent example of how crops and their wild relatives can bridge the model/non-model gap. PMID- 23021023 TI - Accuracy of the Historical, Clinical and Risk Management Scales (HCR-20) in predicting violence and other offenses in forensic psychiatric patients in Brazil. AB - BACKGROUND: Assessing the risk of violence is a complex task. In Latin America it is often based on clinical criteria that are not very objective or structured. HCR-20 has been used to increase the accuracy of this exam. AIMS: The aim of this study was to examine the predictive validity of the Historical, Clinical and Risk Management Scales (HCR-20) violence risk assessment scale on a sample of Brazilian male forensic psychiatric inpatients. METHOD: A concurrent prospective cohort design was used. The cohort was selected among the population of inpatients in Unit D (N=68) at Instituto Psiquiatrico Forense Mauricio Cardoso (IPF), Brazil. For the baseline assessment the following instruments: HCR-20 Assessing Risk for Violence, Version 2, and Hare Psychopathy Checklist, Revised (PCL-R) were used. During the one-year follow up, episodes of violent and/or anti social behavior were assessed, and recorded on the Yudofsky's Overt Aggression Scale (OAS) and Tengstrom et al.'s Follow-Up Questionnaire. The accuracy of HCR 20 and PCL-R to predict violent and/or anti-social behavior was assessed. RESULTS AND CONCLUSIONS: For the whole cohort, the mean total score of PCL-R was 13.54 and of HCR-20 it was 23.32. The rate of recidivism in the twelve month follow up was 73.5%. Outstanding among the risk factors explored for their predictive efficacy are scale HCR-20 and subscale H for any event, and scale HCR-20 for a violent event. The predictive efficacy of scales HCR-20 and PCL-R was greater for any antisocial event than for a violent event. By taking into account the possibility of recidivism and the probability of recidivism accumulated over time, instruments HCR-20 and PCL-R behaved as expected. In all these explorations, the instruments significantly differentiated the group of the sample that recidivated earlier. PMID- 23021025 TI - Migraine and proctitis: what is the link? PMID- 23021026 TI - Cell-free fetal DNA and adverse outcome in low risk pregnancies. AB - OBJECTIVE: To analyze in a large prospective cohort study of low risk pregnancies whether cell-free fetal (cff) DNA in maternal plasma of the second trimester might be associated with the development of preeclampsia, preterm delivery, and small for gestational age. STUDY DESIGN: A subset of a large prospective cohort study in serological RhD negative pregnant women with RHD positive fetuses was used. Cff DNA was determined through the detection of RHD specific sequences with real-time PCR. RESULTS: In 611 pregnancies, rates of 7.2% preeclampsia, 1.6% preterm birth <=32, 2.9% <=34, and 12.4% <=37 weeks of gestation, 5.7% of small for gestational age <5th percentile, and 8.2% <10th percentile were observed. For none of these risk groups an association with cff DNA could be established. CONCLUSION: Cff DNA in maternal plasma of the second trimester was not found to be a marker for an adverse pregnancy outcome in low risk pregnancies. PMID- 23021027 TI - Commentary: Dysphagia after anterior cervical discectomy and fusion. PMID- 23021024 TI - IL-2 immunotherapy in chronically SIV-infected Rhesus macaques. AB - BACKGROUND: Despite inducing a sustained increase in CD4+ T cell counts, intermittent recombinant IL-2 (rIL-2) therapy did not confer a better clinical outcome in HIV-infected patients enrolled in large phase III clinical trials ESPRIT and SILCAAT. Several hypotheses were evoked to explain these discrepancies. Here, we investigated the impact of low and high doses of IL-2 in Rhesus macaques of Chinese origin infected with SIVmac251 in the absence of antiretroviral therapy (ART). RESULTS: We demonstrated that rIL-2 induced a dose dependent expansion of CD4+ and CD8+ T cells without affecting viral load. rIL-2 increased CD4 and CD8 Treg cells as defined by the expression of CD25(high)FoxP3(+)CD127(low). We also showed that rIL-2 modulated spontaneous and Fas-mediated CD4(+) and CD8(+) T cell apoptosis. The higher dose exhibited a dramatic pro-apoptotic effect on both CD4(+) and CD8(+) T cell populations. Finally, all the animals treated with rIL-2 developed a wasting syndrome in the month following treatment simultaneously to a dramatic decrease of circulating effector T cells. CONCLUSION: These data contribute to the understanding of the homeostatic and dosage effects of IL-2 in the context of SIV/HIV infection. PMID- 23021028 TI - Commentary: Postoperative analgesia after lumbar laminectomy: is there a role for single-shot epidural fentanyl? PMID- 23021029 TI - Commentary: Anterior atlantoaxial transarticular screws: should this be the preferred atlantoaxial fixation technique? PMID- 23021030 TI - Commentary: Do no harm: the potential negative effects of injectates used in spinal intervention. PMID- 23021031 TI - Commentary: Implications and limitations of cost-utility analysis. PMID- 23021032 TI - Commentary: Total disc arthroplasty and the bearing surface debate. PMID- 23021033 TI - Commentary: Total disc arthroplasty: careful follow-up is necessary. PMID- 23021034 TI - Spine surgery research: on and beyond current strategies. AB - BACKGROUND CONTEXT: Systematic reviews of the literature are powerful tools in evidence-based medicine. However, the design and report of systematic reviews in spinal surgery contain many aspects amenable to improvement. PURPOSE: To discuss the issues especially relevant for systematic reviews in spinal surgery. METHODS: From our experience of systematic reviews and meta-analyses of clinical trials in spinal surgery, we infer guidance for the design and execution of systematic literature reviews. RESULTS: There are many difficulties associated with the design as well as conduct of clinical trials and consequently appraising evidence in spinal surgery. New treatments should be compared with the gold standard before other comparisons are investigated. Studies should present data as thoroughly as possible regarding all subgroups and follow-up moments, possibly in supplementary material. To provide the highest level of evidence, systematic reviews should be as rigorously designed as possible. CONCLUSIONS: Gathering information on clinical effectiveness in spinal surgery can be improved both at the clinical study level and at the systematic review level. Alternatives to randomized controlled trials such as comparative studies can be valuable tools on the clinical effectiveness of treatments in spinal surgery. The experience reflected in this article can support the scientific efforts in this field. PMID- 23021035 TI - Intraoperative anaphylaxis to gelatin in topical hemostatic agents during anterior spinal fusion: a case report. AB - BACKGROUND CONTEXT: The use of topical hemostatic agents is widespread and has been shown to reduce bleeding during a wide variety of surgical procedures. Nonetheless, as biologically active agents, there is potential for allergic reactions to these products. PURPOSE: This is a report of intraoperative anaphylaxis to gelatin associated with the use of two topical hemostatic agents. STUDY DESIGN: Case report. There is no outside funding or potential conflict of interest. PATIENT SAMPLE: A patient with anaphylaxis during anterior spinal fusion. OUTCOME MEASURES: Laboratory assays for tryptase, gelatin-specific immunoglobulin E (IgE), and total IgE. METHODS: A 14-year-old male with myelomeningocele and scoliosis was treated with anterior spinal fusion from T12 to L3. Gelfoam sponges were applied during the preparation of the disc spaces. Approximately 1 hour later, Floseal hemostatic matrix was applied to a briskly bleeding screw hole in the L3 vertebral body, and the patient experienced an abrupt onset of hypotension and ventilatory difficulty. Epinephrine, dexamethasone, and blood products were administered for hemodynamic support while the surgical site was closed. Removal of the drapes revealed a widespread erythematous rash, and the patient was then transferred to the intensive care unit. When stable 3 days later, he returned to the operating room for completion of the spinal fusion. RESULTS: Postoperative laboratory assays were sent that revealed elevated levels of tryptase, total IgE, porcine, and bovine gelatin specific IgE. The patient was counseled to avoid gelatin-containing products. At 6-month follow-up, his instrumented spine was radiographically fused and he reported no further allergic issues. CONCLUSIONS: Anaphylaxis may occur because of animal gelatin components of topical hemostatic agents. Previous reports have focused on the thrombin components. Care should be taken in the administration of these products, particularly in the atopic individual. PMID- 23021036 TI - Spinal metastasis from acinic cell carcinoma of the parotid gland: a case report. AB - BACKGROUND CONTEXT: Acinic cell carcinoma is the fourth most common tumor of the parotid gland, and spinal metastases are thought to be exceedingly rare. Only two other reported presentations are found in the literature, both presumably secondary to incomplete surgical resections. PURPOSE: To present the first known case of metastasis to the lumbar spine causing vertebral body involvement, after complete resection of the parotid gland. STUDY DESIGN: Case report. METHODS: A case of a patient who presented with low back pain and had imaging studies showing an expansive destructive lesion of the L4 vertebral body. The patient underwent a radical parotidectomy and radiation therapy for dedifferentiated, high-grade acinic cell carcinoma 2 years prior. RESULTS: The patient underwent anterior L4 corpectomy and strut cage placement and posterior pedicle screw fixation from L2 to L5 on the same day, followed by radiation and oral chemotherapy 3 weeks later. Histopathologic examination confirmed metastatic dedifferentiated acinic cell carcinoma, present in the L4 vertebral body and overlying psoas muscle. CONCLUSIONS: This case report underscores the importance of careful evaluation of patients presenting with back pain with a history of malignancy. It also calls into question the traditional low-grade classification ascribed to these tumors, given their ability to metastasize after complete excision and adjuvant therapy. PMID- 23021037 TI - Role of genomics on the path to personalized medicine. AB - Technology continues to lead the field of personalized medicine as the interpretation of the human genome is progressing. The cost and duration of genomic sequencing continue to decrease sharply and there is intensive research aimed at understanding how the changes that occur within the genome can alter its function and the genomic variations that constitute individual susceptibility to diseases and responses to therapy. The overlay of a personal genome with the personal medical record of patients has a potential to improve prediction and prevention and to allow a more pro-active therapeutic strategy. It is evident that pharmacogenomics and individualized drug therapy are the building blocks of personalized medicine. A growing number of drugs are now used for the treatment of cancer in subjects selected by a companion genetic test. Personalized medicine while based upon genomic knowledge of the individual requires equally essential personalised environmental information as well as the understanding of every subject's capacity for health-promoting behaviour. PMID- 23021038 TI - Preclinical sporadic Alzheimer's disease: target for personalized diagnosis and preventive intervention. AB - The most opportune time for preventive intervention in sporadic Alzheimer's disease (spAD) is early in its preclinical stage (pcAD), when the odds of preventing or minimizing later disabling neurodegeneration are most favorable. The efficacy of promising preventive interventions should be assessed in patients in the earliest discernible phase of pcAD. This will require application of personalized medicine techniques, with use of suitable biomarkers to detect pcAD in individuals believed to be spAD-prone. This review focuses on the genetic biomarker, apolipoprotein E (apoE) epsilon4, and on certain neuroimaging biomarkers, such as structural MRI (sMRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), and PET-amyloid tracers capable of delineating the extent and distribution of amyloid-beta (Abeta) deposits in the brain, that can be useful in identifying cognitively normal people who are at enhanced risk of developing spAD. Many years before AD symptoms appear, such neuroimaging procedures can disclose signature abnormalities of brain structure, function, and amyloid levels in cognitively normal apoE epsilon4 allele carriers and/or individuals with a family history of spAD. Although no effective treatment for spAD is yet available, there is evidence that, by taking a proactive personalized medicine approach, the practicing physician may be able to reduce risk in AD prone patients by attending to such modifiable AD risk factors as hypertension, obesity, type 2 diabetes, insulin resistance, hypercholesterolemia, sedentary lifestyle, and current cigarette smoking. Young patients who are epsilon4 positive should be advised to avoid participation in contact sports or other activities that expose them to risk of traumatic brain injury. PMID- 23021039 TI - Advances in adipokines. PMID- 23021041 TI - The detection of occult HBV infection in patients with HBsAg negative pattern by real-time PCR method. AB - AIM: Diagnostic problems may be encountered in Hepatitis B virus (HBV) infections by serological tests and HBV DNA can be detectable in plasma and liver tissue while the HBsAg test is negative. This situation can be defined as occult or isolated Anti-HBc infections. Occult HBV infections may be divided into two categories by using hepatitis markers. One of them being that all hepatitis markers are negative and the other situation is having Anti-HBc +/- and Anti HBs+patterns. These situations can be seen in isolated Anti-HBc cases. METHOD: In this study, we aimed to detect the ratio of occult HBV infections by investigating HBV DNA in four different groups. These groups are: (1) 20 isolated Anti-HBc positive individuals, (2) 23 individuals naturally immune to HBV infection, (3) 20 individuals with seronegative hepatitis markers and high ALT levels, and (4) 23 vaccinated individuals against HBV. In order to detect HBV DNA the real-time PCR kit (QIAGEN, Artus HBV RG PCR Kit, Germany) with high analytical sensitivity (<=3.8IU/ml) was used. RESULTS: The reliability of the molecular methods was assessed by increasing the quantitation standards of internal, external and also positive controls. No HBV DNA was detected in any of the 86 individuals consisting of four study groups. CONCLUSION: In conclusion, we did not detect occult HBV infection in our four study groups by using a high sensitivity real-time (RT) PCR method, while occult HBV infections with various frequencies were detected in other large, serial international studies in which highly sensitive analytical molecular methods were used. Although we also used a high standard molecular kit to detect occult HBV infections, we suggest that the reason for the absence of detection of occult HBV infections may be due to the small number of cases included in this study. However, it was assumed that the use of a nucleic acid amplification technology (NAT) with high analytical sensitivity in blood banks to prevent HBV transmission by blood transfusion is controversial due to both costs and diagnostic efficacy and for this reason we suggest that it will be useful to perform large serial studies regarding occult HBV infections in the future. PMID- 23021040 TI - Personalized medicine in major depressive disorder -- opportunities and pitfalls. AB - The sequencing of the human genome in the early days of this millennium was greeted with great fanfare as this accomplishment was expected to revolutionize medicine and result in individualized treatments based on the genetic make-up of the patient. The ultimate promise of personalized medicine would be fulfilled with the identification of disease biomarkers that would be widely available for use in diagnosis and treatment. Progress, however, has been slow in providing disease biomarkers or approved diagnostic tests. This is true for major depressive disorder (MDD), despite its prevalence in the general population and the widespread acceptance of its biological basis. Studies using strategies like genome-wide association and candidate gene analyses have identified a number of possible biomarkers of MDD, including serum levels of neurotrophic factors, inflammatory cytokines and HPA axis hormones, but none have proven sufficiently powerful for clinical use. The lack of biologically based tests available for use in identifying patients with MDD is a significant impediment to personalized and more effective treatment, because it means diagnosis continues to be driven by subjective symptoms. While genetic studies of MDD have not yet led to diagnostic and treatment biomarkers, progress in determining the role of the genome in drug metabolism heralds the first effort in personalized prescribing for the antidepressants. The FDA suggested and approved genotyping tests for common variants of drug metabolism genes, such as the cytochrome p450s. By using these tests a physician can select an appropriate antidepressant for a given patient, as differences in clearance, half-life, and peak blood concentrations are controlled by genetic variability in drug metabolism. Personalization in drug choice can be achieved because these tests: (1) identify responders and non responders; (2) provide alerts to possible adverse drug events; and (3) help optimize dose. Improved ways of diagnosing and prescribing effective treatments for MDD are needed, as the available methods are inadequate and symptom based. In the foreseeable future, further interrogation of the genome may serve as the basis for development of new personalized medicine strategies for diagnosis and treatment of MDD. PMID- 23021042 TI - Glia: an emerging target for neurological disease therapy. AB - Therapeutic strategies using stem cells for treating neurological diseases are receiving more attention as the scientific community appreciates cell-autonomous contributions to several diseases of the central nervous system. The transplantation of stem cells from various sources is now being employed for both neuronal and glial replacement. This review provides an assessment of glial contributions to some of the central nervous system diseases and the advancements in cellular replacement approaches. The rationale for glial replacement in individual diseases and the potential hurdles for cell-replacement strategies are also emphasized. The significant progress in the field of stem cell biology with the advent of tools such as induced pluripotent stem cells and imaging techniques holds promise for the clinical application of cell therapeutics. PMID- 23021043 TI - Genetics of Behcet's disease in Sardinia: two distinct extended HLA haplotypes harbour the B*51 allele in the normal population and in patients. AB - OBJECTIVES: To define the contribution of HLA genes and extended HLA haplotypes to the susceptibility to Behcet's disease (BD) in Sardinia. METHODS: Forty-five unrelated Sardinian patients with BD, diagnosed according to the ISG criteria, 45 HLA-B*51 positive and 185 unselected healthy controls were enrolled in the study. DNA samples were typed for HLA class I and class II alleles and genotyped for microsatellites (MICA-TM) and single-nucleotide polymorphisms (rs1264457 HLA-E; rs2281820 motilin; rs1799724 at -857, rs361525 at -238 TNF-alpha) spanning the HLA region. RESULTS: HLA-B*5101 was confirmed as conferring susceptibility to BD (pc=0.0042; OR=4.4; 95% CI=2.0 to 9.6). It is noteworthy that in Sardinia this allele was found more frequently within a haplotype (HLA-A2; -Cw2; -B*5101; DRB1*11; -DQA1*05; - DQB1*03) that reached its highest frequency in patients with BD. Linkage disequilibrium analysis showed the existence of an additional B*51 haplotype (HLA-A2; -Cw2; -B*5101; -DRB1*04; -DQA1*03; -DQB1*03) not associated with susceptibility to the disease. CONCLUSIONS: In Sardinia, the BD-associated HLA-B*5101 allele is inherited as part of two distinctive haplotypes differently distributed in patients and controls. These findings can be interpreted as suggestive of the presence of additional genes within the MHC region conferring susceptibility to BD. The hypothesis that an environmental pressure could have contributed to the preservation of the BD-associated HLA haplotype in Sardinia is also discussed. PMID- 23021044 TI - Analysis of "dry" mesothelioma with ultrasound guided biopsies. AB - BACKGROUND: Image-guided sampling of the thickened pleura is a sensitive approach in patients with malignant pleural mesothelioma with pleural effusion. Malignant pleural mesothelioma presenting without effusion however is more of a diagnostic challenge. In this study we report the diagnostic yield and complications of ultrasound-guided cutting needle biopsies in this particular category of patients. METHODS: A retrospective database analysis from September 2007 until January 2012 was performed in 56 patients with malignant pleural mesothelioma. Clinical characteristics and results of diagnostic evaluations were analysed. RESULTS: Of the 56 patients with malignant pleural mesothelioma, 20 patients presented without pleural effusion of with locular effusion. Ultrasound-guided cutting needle biopsy was performed in 14/20 patients with a diagnostic accuracy of 80%. Only 1 patient had mild haemoptysis immediately following biopsies. CONCLUSION: Diagnosing patients with pleural thickenings suspect for malignant mesothelioma without pleural effusion or with loculated pleural effusion is effective and safe with ultrasound-guided cutting needle biopsies. PMID- 23021046 TI - Update on immunohistochemistry in melanocytic lesions. AB - This article is an up-to-date overview of the potential uses and limitations of immunohistochemistry (IHC) in melanocytic lesions. The information is intended to assist dermatopathologists and dermatologists who read slides to appropriately use IHC in this setting. In addition, dermatologists who do not review microscopic slides will better understand the rationale of the pathologist when reading and interpreting the pathology report. PMID- 23021045 TI - Cytogenetic and mutational analyses of melanocytic tumors. AB - Analyses of genetic and genomic alterations of melanocytic tumors have not only led to a better understanding of the pathogenesis of melanocytic tumors but also created new opportunities for improvements in diagnostic accuracy in distinguishing nevus from melanoma, and more effective treatments for patients affected by melanoma. Cytogenetic tests have emerged as a promising ancillary method for the workup of diagnostically problematic melanocytic tumors with ambiguous light microscopic features. Mutation analysis not only is important in treatment decision making but also can be used for improved diagnostic accuracy, staging, and prognosis. PMID- 23021047 TI - Melanoma staging: where are we now? AB - The seventh version of the American Joint Committee on Cancer (AJCC) Melanoma Staging guidelines, published in 2009, has significant revisions compared with the previous version. The current schema was based on the largest melanoma patient cohort analyzed to date and is the result of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7972 patients with stage IV melanoma. This article summarizes the findings and the new definitions included in the 2009 AJCC Melanoma Staging and Classification. The TNM categories and the stage groupings are defined. Changes in the melanoma staging system are summarized. PMID- 23021048 TI - Medicolegal issues with regard to melanoma and pigmented lesions in dermatopathology. AB - Understanding malpractice risk and practicing risk management strategies results in better care and a less stressful environment of practice. Errors in diagnosis are most commonly related to melanoma and neoplasms of the skin. To offset the threat of malpractice litigation, malpractice data can be used to focus safety efforts on common diagnostic errors. Recognition of sources of error in the analysis of pigmented lesions by dermatopathologists, and the development of new immunohistochemical or genotypic techniques for the recognition and distinction of malignant disease from benign pigmented lesions, will also provide important improvements in care and diagnosis in the future. PMID- 23021049 TI - Dermatopathology updates on melanocytic lesions. AB - This article provides an update on histopathologic studies of different types of melanocytic lesions, such as site-specific nevi, "Spark's" nevi, nevi during pregnancy, and atypical dermal melanocytic proliferation, including pigmented epithelioid melanocytoma, proliferating nodules, and atypical Spitzoid tumor. Special-site nevi, such as those appearing on the breast and genital region, generally have more cytologic and architectural atypia. Melanocytic proliferations generally do not change during pregnancy, contrary to earlier observations. Atypical dermal melanocytic proliferations are difficult to diagnose and usually have a better outcome after adequate treatment, including wide local skin excision with or without sentinel lymph node resection. PMID- 23021050 TI - Dermatology clinics: what's new in dermatopathology: news in nonmelanocytic neoplasia. AB - This article reviews the recent dermatopathology literature involving nonmelanocytic neoplasia, with a focus on important work done over the last 5 years. The discussion includes advances in the understanding of Merkel cell carcinoma pathogenesis and prognosis; changes in the seventh edition of the American Joint Committee of Cancer staging manual in reference to staging of squamous cell carcinoma and Merkel cell carcinoma; newly described or rare histopathologic patterns and entities including squamoid eccrine ductal carcinoma, rippled-pattern adnexal neoplasms, onychomatricoma, spindle cell predominant trichodiscoma/neurofollicular hamartoma, and myoepithelioma; and microsatellite instability in sebaceous neoplasms of Muir-Torre syndrome and other tumors. PMID- 23021051 TI - Fibrous and fibrohistiocytic neoplasms: an update. AB - Important advances in fibroblastic and fibrohistiocytic tumors relevant to dermatologists and dermatopathologists include (1) recognition that myxofibrosarcoma is a distinct entity that frequently arises in skin; (2) CD10 is sensitive but not specific atypical fibroxanthoma; (3) neurothekeomas lacking S100 expression are probably fibrohistiocytic/fibroblastic tumors, whereas S100+ myxoid variants are better classified as nerve sheath myxomas; (4) the recognition of a primary cutaneous variant of solitary fibrous tumor; (5) thelimitations of b-catenin immunohistochemistry in desmoid tumors; and (6) the prognostic utility of clinical and histopathologic variables in dermatofibrosarcoma protuberans, and the effects of imatinib mesylate therapy. PMID- 23021052 TI - Update on vascular neoplasms. AB - This article provides an update on vascular neoplasms. New immunohistochemical markers for the diagnosis of vascular neoplasms tumor 1, infantile hemangiomas, myopericytomas, perivascular epithelial cell tumors, acquired elastotic hemangiomas, vascular proliferations in radiated skin, and new histopathologic variants of AIDS-related Kaposi sarcoma are explored. PMID- 23021053 TI - Current knowledge in inflammatory dermatopathology. AB - The complex and fascinating spectrum of inflammatory skin disease, and the comprehension of it, is ever expanding and evolving. During the first decade of the 21st century, numerous advances in the understanding of inflammatory disease mechanisms have occurred, particularly in psoriasis and atopic dermatitis. Continuation of this trend will assure a future in which molecular tests for biomarkers of immediate clinical relevance are used in routine patient care, not only for diagnosis but also for prognosis and management. This article focuses on selected recent or noteworthy developments that are clinically relevant for the histologic diagnosis of inflammatory skin diseases. PMID- 23021054 TI - What's new in the histologic evaluation of alopecia and hair-related disorders? AB - The diagnosis of alopecia and other hair-related disorders can be challenging. An appreciation of the newest diagnostic techniques and newly described entities can help clinicians to provide the best care for patients. This article focuses on advances in the histologic evaluation of alopecia. Also discussed are recent advances in the understanding of hair-related disorders that do not result in alopecia. Advances in the understanding of disease mechanisms can help in treating hair disorders that proved refractory in the past. PMID- 23021055 TI - Emerging adverse cutaneous drug reactions. AB - The past several decades have seen the advent and rapidly expanding use of biological agents in the treatment of chronic disease states. As increasingly large pools of patients have been enrolled in treatment protocols using these agents, physicians have become acquainted with both desired and adverse events associated with their use. Dermatologists frequently encounter patients affected by cutaneous drug reactions associated with the use of biological agents, thereby becoming familiar with the full range of side effects reported in the literature. This review discusses these adverse cutaneous effects, their underlying mechanisms, and efforts to predict and minimize their occurrence. PMID- 23021056 TI - Histopathologic patterns associated with external agents. AB - A large number of foreign substances may penetrate the skin for both voluntary and involuntary reasons. The voluntary group includes the particulate materials used in tattoos and cosmetic fillers, whereas the involuntary group is almost always caused by accidental inclusion of external substances secondary to cutaneous trauma. This article focuses on the histopathologic findings seen in cutaneous reactions to exogenous agents, with special emphasis on the microscopic morphology of the external particles in recognizing specifically the involved substance (something that is becoming increasingly important in the event of litigation). PMID- 23021057 TI - Current understanding of cutaneous lymphoma: selected topics. AB - Recent epidemiology studies have identified a steady increase in the incidence of cutaneous lymphomas over the past few decades. Although possible explanations for this increased incidence include heightened awareness of these conditions as well as a more refined diagnostic acuity by dermatologists and pathologists, an increase secondary to environmental factors cannot be discounted. Our understanding of cutaneous lymphomas keeps evolving. Consequently, our knowledge and understanding of cutaneous lymphomas requires reconsideration of past dogma and critical revision of the new proposals. In this article, some hot topics and important new findings in the field are reviewed. PMID- 23021058 TI - Direct immunofluorescence testing in the diagnosis of immunobullous disease, collagen vascular disease, and vascular injury syndromes. AB - Direct and indirect immunofluorescence (IF) plays a role in the evaluation of immunobullous diseases and their mimics, and in the investigation of vascular injury syndromes and autoimmune connective tissue disease (CTD). IF mapping may be an important adjunct in the assessment of congenital epidermolysis bullosa syndromes and in Alport disease, in which antibodies are directed at certain components of the basement membrane zone to assay for their deficiency. In many cases of immunobullous and autoimmune CTDs, correlation with direct IF results is useful and often decisive in lesional evaluation and thus in patient management. PMID- 23021059 TI - New directions in dermatopathology: in vivo confocal microscopy in clinical practice. AB - In vivo confocal microscopy represents a new device that generates a virtual skin biopsy at cytologic resolution. This article describes the most relevant confocal findings and their histopathologic correlates in skin oncology and inflammatory diseases. The light and dark of confocal microscopy are briefly discussed in relation with its clinical applications. PMID- 23021060 TI - Dermatopathology education: an update. AB - Dermatopathology (DP) education is critical to the comprehensive training of dermatology and pathology residents and to the accurate diagnosis and management of cutaneous disease. DP has seen tremendous growth, and its success depends on our ability to effectively educate future leaders, teachers, and researchers who will continue to advance the field. This article focuses on DP education in the United States, although specific components, such as assessment of medical education and the future of DP education, are relevant to the larger DP community. It is hoped that this review will aid in discussions of direction and collaboration. PMID- 23021061 TI - Update in dermatopathology. Preface. PMID- 23021062 TI - A practical approach to improve safety and management in chemotherapy units based on the PROCHE - programme for optimisation of the chemotherapy network monitoring program. AB - The PROCHE (PRogramme d'Optimisation du circuit CHimiothErapie [Programme for optimisation of the chemotherapy network]) initiative is an innovative oncology monitoring program designed to reduce patient waiting time and chemotherapy wastage, ultimately improving patient care. Laboratory test results and side effects data were collected for patients in the PROCHE monitoring program group 2d prior to scheduled chemotherapy visits, allowing oncologists to confirm or delay each patient's chemotherapy. Data from 1037 patients entered in the PROCHE program were compared with 513 control patients, who had been treated according to previous typical hospital procedures. Results demonstrated significant reductions in mean hospital stay i.e. decreased it by 66 min and drug wastage decreased from 6% to 2% (95% CI (confidence interval) 0.21-0.59, P<0.0001), and a significant increase in bed occupancy rates with the PROCHE initiative (all P<0.0001 vs. controls). The incidence of pain and severity of fatigue were also reduced. In conclusion, the PROCHE initiative resulted in improved patient quality of care and reduced chemotherapy toxicities, and improved hospital and pharmacy productivity. These encouraging preliminary results warrant further study. PMID- 23021063 TI - Molecular characteristics of community-associated methicillin-resistant Staphylococcus aureus colonizing surgical patients in Greece. AB - Fifty-one of 925 patients screened for methicillin-resistant Staphylococcus aureus (MRSA) upon admission to a surgical unit were MRSA carriers; 15 were classified as community- and 36 as hospital-associated-MRSA. Fourteen of 22 isolates typed by molecular methods belonged to the European clone ST80-IVc, 3 of which exhibited resistance to >=3 non-beta-lactam antibiotics. PMID- 23021064 TI - Virulence gene profiling and molecular characterization of hospital-acquired Staphylococcus aureus isolates associated with bloodstream infection. AB - A better understanding of virulence gene profiling and molecular characterization of Staphylococcus aureus isolates associated with bloodstream infection (BSI) may provide further insights related to clinical outcomes with these infections. We analyzed 89 S. aureus isolates including 37 MRSA isolates (41.6%) recovered from 89 adult patients with BSI from 4 hospitals in Zhejiang province, eastern China. Thirty-five (94.6%) of MRSA isolates and 4 (7.7%) of methicillin-sensitive S. aureus (MSSA) isolates were resistant to multiple antimicrobials. All isolates harbored at least 2 of 22 possible virulence genes, including sdrC (92.1%), icaA (89.9%), hla (80.9%), clf (69.7%), sea (68.5%), sdrD (67.4%), hlb (67.4%), sdrE (65.2%), sei (51.7%), seg (50.6%), and cna (50.6%). Forty-four (49.4%) of all S. aureus BSI isolates, including 23 (62.2%) of MRSA isolates, harbored >=10 of the virulence genes evaluated in this study. Sixteen (43.2%) MRSA isolates and 5 (9.6%) MSSA isolates harbored the gene encoding Panton-Valentine leukocidin (PVL). Collective genes for pvl, sdrE, sed, seg, and sei among MRSA isolates were significantly more frequent relative to MSSA isolates (P < 0.05). A total of 22 sequence types (STs), including novel ST2184, ST2199, and ST2200, and 33 spa types, including novel spa types t9530 and t9532, were identified among S. aureus BSI isolates, among which ST188 (15.7%) and ST7 (15.7%), and t091 (12.4%) and t189 (12.4%), seldom noted for Chinese isolates previously, were major STs and spa types, respectively. In contrast to previous reports, no predominant clones were found in the present study. Among the MRSA isolates, although ST239-MRSA SCCmecIII, predominant clone in China, still represented the most common clone, it only accounted for 18.9%. However, ST188-MRSA- SCCmecIV seldom reported before accounted for 10.8%. Among the MSSA isolates, ST7-MSSA represented the most common clone (23.1%), followed by ST188-MSSA and ST630-MSSA (9.6% each). In conclusion, simultaneous carriage of multiple virulence genes and genetically considerable diversity were common among S. aureus BSI isolates. Furthermore, MRSA isolates exhibited more frequent carriage of superantigen genes and pvl relative to MSSA isolates. Taken together, there are distinctive virulence gene profiling and molecular characteristic among S. aureus isolates associated with bloodstream infection in China. PMID- 23021068 TI - Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. AB - Pyruvate dehydrogenase complex (PDC) deficiency is a relatively common mitochondrial disorder that primarily presents with neurological manifestations and lactic acidemia. We analyzed the clinical outcomes and neurological features of 59 consented symptomatic subjects (27 M, 32 F), who were confirmed to have PDC deficiency with defined mutations in one of the genes of PDC (PDHA1, n = 53; PDHB, n = 4; DLAT, n = 2), including 47 different mutations, of which 22 were novel, and for whom clinical records and/or structured interviews were obtained. 39% of these subjects (23/59) have died. Of these, 91% (21/23) died before age 4 years, 61% (14/23) before 1 year, and 43% (10/23) before 3 months. 56% of males died compared with 25% of females. Causes of death included severe lactic acidosis, respiratory failure, and infection. In subjects surviving past 6 months, a broad range of intellectual outcomes was observed. Of 42 subjects whose intellectual abilities were professionally evaluated, 19% had normal or borderline intellectual ability (CQ/IQ >= 70), 10% had mild intellectual disability (ID) (CQ/IQ 55-69), 17% had moderate ID (CQ/IQ 40-54), 24% had severe ID (CQ/IQ 25-39) and 33% had profound ID (CQ/IQ<25). Assessment by parents was comparable. Of 10 subjects who reached age 12 years, 9 had had professional IQ assessments, and only 4 had IQs >= 70 (only 2 of these 4 had assessments after age 12 years). The average outcome for females was severe-to-profound ID, whereas that of males was mild-to-moderate ID. Of subjects for whom specific neurological data were available, the majority had hypotonia (89%), and hypertonia or mixed hyper-/hypotonia (49%) were common. Seizures (57%), microcephaly (49%), and structural brain abnormalities including ventriculomegaly (67%) and agenesis, dysgenesis, or hypoplasia of the corpus callosum (55%) were common. Leigh syndrome was found in only 35%. Structural brain abnormalities were more common in females, and Leigh syndrome was more common in males. In a subgroup of 16 ambulatory subjects >3.5 years in whom balance was evaluated, ataxia was found in 13. Peripheral neuropathy was documented in 2 cases but not objectively evaluated in most subjects. Outcomes of this population with genetically confirmed PDC deficiency are heterogeneous and not distinctive. Correlations between specific genotypes and outcomes were not established. Although more females survive, related to the prevalence of X-linked PDHA1 mutations, symptomatic surviving females are generally more severely impaired cognitively and have a different pattern of neurological impairment compared to males. Neonatal or infant onset of symptoms was associated with poor outcomes. Males with PDHA1 mutations and low fibroblast PDC activity were less likely to survive beyond infancy. Recurrence rate in siblings of subjects with PDHA1 mutation was less than 5%. Paradoxically, in this retrospective review, potential factors considered possibly relevant to development, such as in vitro PDC activity, specific mutations, use of ketogenic diets, supplements, or medications, were generally not confirmed to be significantly correlated with objective outcomes of survival or neuro-cognitive function. Therefore, the basis of variability of these outcomes remains largely undetermined. PMID- 23021069 TI - Language proficiency modulates the engagement of cognitive control areas in multilinguals. AB - Language proficiency should modulate the regions involved in language control in predictable ways during language switching. However, prior studies reveal inconsistent effects on the regions involved in language monitoring [pre Supplementary Motor Area/Anterior Cingulate Cortex (pre-SMA/ACC)] and language selection (left caudate) conceivably because variations in relative proficiency are confounded with other between-group differences. We circumvented this problem in an fMRI (functional Magnetic Resonance Imaging) study of overt picture naming in trilingual participants. In this case, the difference between a high proficient and a low-proficient further language can be assessed within subjects with no between-group confound. We also used a monolingual group to assess the neural correlates of switching between two categories of response within the same language. We report a novel result: relative language proficiency dissociates response of the pre-SMA/ACC and left caudate during language switching. Switching between languages increased pre-SMA/ACC response regardless of proficiency differences. By contrast, left caudate response did vary with proficiency differences. Switching from the most to the least proficient language increased the response. Within-language switching, as contrasted with between-language switching, elicited a comparable increase in pre-SMA/ACC response but a decrease in left caudate response. Taken together, our data support a wider role of pre SMA/ACC in task monitoring and establish the critical role of the left caudate in the selection of the less proficient language in language switching. PMID- 23021070 TI - Neural correlates of priming and adaptation in familiar face perception. AB - Priming (PR) and adaptation-related aftereffects (AEs) are two phenomena when recent perceptual experiences alter face perception. While AEs are often reflected in contrastive perceptual biases, PR typically leads to behavioural facilitation. Previous research suggests that both phenomena modulate broadly similar components of the event-related potentials (ERPs). To disentangle the underlying neural mechanisms of PR and AE, we induced both effects within the same subjects and paradigm. We presented pairs of stimuli, where the first (S1) was a famous face (identity A, B or C), a morph between two famous faces (50/50% A/B), or a Fourier phase randomized face (as a control stimulus matched for low level visual information) and the second (S2) was a face drawn from morph continua between identity A and B. Participants' performance in matching S2s to either A or B revealed contrastive aftereffects for ambiguous S2 faces, which were more likely perceived as identity B following the presentation of A and vice versa. Unambiguous S2 faces, however, showed PR, with significantly shorter response times, as well as higher classification performance, for identity congruent than for incongruent S1-S2 pairs. Analyses of the simultaneously recorded ERPs revealed clear categorical adaptation at around 155-205 msec post stimulus onset. We also found amplitude modulations for unambiguous S2 faces following identity-congruent S1 faces, related to PR, starting at 90 msec and being the most pronounced at around 205-255 msec. For ambiguous S2 faces, we also observed an ERP effect at around 205-255 msec that was correlated with behavioural AEs. Our results show that face PR and AEs are present simultaneously within a single paradigm, depending on the ambiguity of S2 faces and/or on the similarity of S1 and S2, and suggest that exclusive mechanisms might underlie both PR and AEs and that object-category and identity processing might run in parallel during face processing. PMID- 23021071 TI - Temporal coupling due to illusory movements in bimanual actions: evidence from anosognosia for hemiplegia. AB - In anosognosia for hemiplegia, patients may claim having performed willed actions with the paralyzed limb despite unambiguous evidence to the contrary. Does this false belief of having moved reflect the functioning of the same mechanisms that govern normal motor performance? Here, we examined whether anosognosics show the same temporal constraints known to exist during bimanual movements in healthy subjects. In these paradigms, when participants simultaneously reach for two targets of different difficulties, the motor programs of one hand affect the execution of the other. In detail, the movement time of the hand going to an easy target (i.e., near and large), while the other is going to a difficult target (i.e., far and small), is slowed with respect to unimanual movements (temporal coupling effect). One right-brain-damaged patient with left hemiplegia and anosognosia, six right-brain-damaged patients with left hemiplegia without anosognosia, and twenty healthy subjects were administered such a bimanual task. We recorded the movement times for easy and difficult targets, both in unimanual (one target) and bimanual (two targets) conditions. We found that, as healthy subjects, the anosognosic patient showed coupling effect. In bimanual asymmetric conditions (when one hand went to the easy target and the other went to the difficult target), the movement time of the non-paralyzed hand going to the easy target was slowed by the 'pretended' movement of the paralyzed hand going to the difficult target. This effect was not present in patients without anosognosia. We concluded that in anosognosic patients, the illusory movements of the paralyzed hand impose to the non-paralyzed hand the same motor constraints that emerge during the actual movements. Our data also support the view that coupling relies on central operations (i.e., activation of intention/programming system), rather than on online information from the periphery. PMID- 23021075 TI - Children's referential understanding of novel words and parent labeling behaviors: similarities across children with and without autism spectrum disorders. AB - This study examined two facets of the use of social cues for early word learning in parent-child dyads, where children had an Autism Spectrum Disorder (ASD) or were typically developing. In Experiment 1, we investigated word learning and generalization by children with ASD (age range: 3;01-6;02) and typically developing children (age range: 1;02-4;09) who were matched on language ability. In Experiment 2, we examined verbal and non-verbal parental labeling behaviors. First, we found that both groups were similarly able to learn a novel label using social cues alone, and to generalize this label to other representations of the object. Children who utilized social cues for word learning had higher language levels. Second, we found that parental cues used to introduce object labels were strikingly similar across groups. Moreover, parents in both groups adapted labeling behavior to their child's language level, though this surfaced in different ways across groups. PMID- 23021076 TI - Lactic acid production by Enteroccocus faecium in liquefied sago starch. AB - Enterococcus faecium No. 78 (PNCM-BIOTECH 10375) isolated from puto, a type of fermented rice in the Philippines was used to produce lactic acid in repeated batch fermentation mode. Enzymatically liquefied sago starch was used as the sole carbon source, since sago (Metroxylon spp) is a sustainable crop for industrial exploitation. Liquefied sago starch was inoculated with E. faecium to perform the saccharification and fermentation processes simultaneously. Results demonstrated that E. faecium was reused for 11 fermentation cycles with an average lactic acid yield of 36.3 +/- 4.71 g/l. The lactic acid production was superior to that of simple batch mode and continuous fermentation in terms of lactic acid concentration. An un-dissociated lactic acid concentration of 1.15 mM affected the productivity of the cells. Work is in progress to maintain and increase the usability of the cells over higher fermentation cycles. PMID- 23021077 TI - Endovascular treatment of internal carotid-posterior communicating artery wide necked aneurysm using 2 Enterprise stents in Y-configuration. PMID- 23021078 TI - Vanishing lesion associated with cauda equina ependymoma. PMID- 23021079 TI - A case of cavernous angioma in the septum pellucidum. PMID- 23021080 TI - Clinical characteristics and outcomes of neurogenic stress cadiomyopathy in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is an often devastating form of stroke. Aside from the initial hemorrhage, cardiac complications can occur resulting in neurogenic stress cardiomyopathy (NCM), leading to impaired cardiac function. We investigated whether aSAH patients with NCM had poorer long term functional outcomes than patients without NCM. Mortality, vasospasm, and delayed ischemic complications were also evaluated. METHODS: A retrospective study of all patients admitted for aneurysmal subarachnoid hemorrhage (aSAH) from January 2006 to June 2011 (n=299) was conducted. Those patients who underwent an echocardiogram were identified (n=120) and were assigned to the NCM (n=49) category based on echocardiographic findings defined by a depressed ejection fraction (EF%) along with a regional wall motion abnormality (RWMA) in a non vascular pattern. Primary outcome measures included in-hospital mortality and functional outcomes as measured by the Modified Barthel Index (mBI) at 3 months and one year. Secondary analysis determined if there was an association between NCM, cerebral vasospasm and delayed cerebral ischemia. RESULTS: 16% of aSAH patients developed NCM. Mortality was higher (p<.001) in the NCM group (n=23[46.9%]) than in the non-CM group (n=28[11.2%]). Patients with NCM had poorer functional outcomes as measured by the mBI at both 3 months (p=.002) and 12 months (p=.014). The Hunt-Hess score was predictive of functional outcome as measured by the mBI at both 3 months (p=.002) as well as at 1 year (p=.014). NCM was associated with both death (p=.047 CI, 1.012-7.288) and vasospasm (p=.008 CI, 1.34-6.66) after correction for Hunt-Hess grade. Tobacco use (p<.001) and a history of diabetes mellitus (p<.009) were also associated with vasospasm. NCM was associated with higher in-hospital mortality (p=.047) in multivariate analysis. CONCLUSION: NCM is seen in a substantial number of aSAH patients and when present, it is associated with higher mortality and poorer long-term functional outcomes. This finding may guide further prospective studies in order to determine if early recognition of NCM as well as optimization of cardiac output would improve mortality. PMID- 23021081 TI - [Not Available]. PMID- 23021082 TI - US Food and Drug Administration international collaborations for cellular therapy product regulation. AB - Cellular therapy products are an emerging medical product class undergoing rapid scientific and clinical innovation worldwide. These products pose unique regulatory challenges both for countries with existing regulatory frameworks and for countries where regulatory frameworks for cellular therapy products are under development. The United States Food and Drug Administration (US FDA) has a history of productive working relationships with international regulatory authorities, and seeks to extend this to the cellular therapy field. The US FDA and its global regulatory counterparts are engaged in collaborations focused on the convergence of scientific and regulatory approaches, and the education of scientists, clinicians, regulators, and the public at large on the development of cellular therapies. PMID- 23021083 TI - Focal overexpression of CEACAM6 contributes to enhanced tumourigenesis in head and neck cancer via suppression of apoptosis. AB - BACKGROUND: Overexpression of CEACAM6 has been reported for a number of malignancies. However, the mechanism of how CEACAM6 contributes to cancer formation and its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, we examined the role of CEACAM6 in head and neck squamous cell carcinoma (HNSCC). METHODS: CEACAM6 expression was examined in normal squamous epithelia as well as a number of patient HNSCC samples and tumours derived from HNSCC cell lines injected into NOD/SCID mice. CEACAM6 expression was manipulated in HNSCC cell lines by shRNA-mediated CEACAM6 knockdown or virally delivered overexpression of CEACAM6. The role of CEACAM6 in tumour growth and chemotherapeutic sensitivity was then assessed in vivo and in vitro respectively. RESULTS: CEACAM6 expression was significantly increased in highly tumourigenic HNSCC cell lines when compared to poorly tumourigenic HNSCC cell lines. Moreover, HNSCC patient tumours demonstrated focal expression of CEACAM6. Functional investigation of CEACAM6, involving over-expression and knock down studies, demonstrated that CEACAM6 over-expression could enhance tumour initiating activity and tumour growth via activation of AKT and suppression of caspase-3 mediated cell death. CONCLUSION: We report that CEACAM6 is focally overexpressed in a large fraction of human HNSCCs in situ. We also show that over-expression of CEACAM6 increases tumour growth and tumour initiating activity by suppressing PI3K/AKT-dependent apoptosis of HNSCC in a xenotransplant model of HNSCC. Finally, our studies indicate that foci of CEACAM6 expressing cells are selectively ablated by treatment of xenotransplant tumours with pharmacological inhibitors of PI3K/AKT in vivo. PMID- 23021084 TI - [Role of the pathologist in the diagnosis of palpebral keratoacanthoma: case report and literature review]. AB - We report the case of a keratoacanthoma of the lower lid in a 14-year-old girl posing diagnostic difficulty with differentiating the lesion from a verrucous squamous cell carcinoma on histologic examination of an incisional biopsy. It was only upon complete excision of the tumor that the diagnosis of keratoacanthoma could be made and that of malignancy ruled out. We discuss the clinical and histologic diagnostic criteria for keratoacanthoma and assert that wide biopsy is essential for adequate morphologic study to enable better therapeutic management. PMID- 23021085 TI - Vivid visual hallucinations manifested as the initial symptom in a patient with neurosyphilis. PMID- 23021086 TI - A neuropsychiatric perspective of phenylketonuria II: needs assessment for a psychiatric presence. AB - BACKGROUND: Phenylketonuria (PKU) is a neuropsychiatric disease with a genetically transmitted metabolic etiology. A large percentage of untreated, early-treated, and continuously treated patients with PKU suffer from neurocognitive and neuropsychiatric sequelae. To our knowledge, this is the first survey of the mental health needs of persons with PKU and availability of referral and treatment for this population. METHODS: A targeted, web-based survey was sent to 100 PKU clinics across the United States. Follow-up e-mails were sent to nonresponders. RESULTS: Thirty-four clinics responded; 56% of responding clinics reported that cognitive issues impaired patients' ability to obtain regular treatment and that screening for cognitive impairment at the clinics varied in scope and format. Clinic screening for cognitive and psychiatric issues are reported, as well as referral practices. DISCUSSION: The authors propose an integrated model for both medical and mental health care of the patients, analyze perceived barriers to screening and referral for cognitive impairment, and discuss the limitations of the survey results. PMID- 23021087 TI - Discontinuation rates and timing of antimalarial drugs in primary Sjogren's syndrome. PMID- 23021088 TI - Re: Meelan Bul, Xiaoye Zhu, Antti Rannikko, et al. Radical prostatectomy for low risk prostate cancer following initial active surveillance: results from a prospective observational study. Eur Urol 2012;62:195-200. PMID- 23021089 TI - Re: Renzo Colombo, Lorenzo Rocchini, Nazareno Suardi, et al. Neoadjuvant short term intensive intravesical mitomycin C regimen compared with weekly schedule for low-grade recurrent non-muscle-invasive bladder cancer: preliminary results of a randomised phase 2 study. Eur Urol 2012;62:797-802. PMID- 23021090 TI - Postchemotherapy laparoscopic retroperitoneal lymph node dissection for low volume, stage II, nonseminomatous germ cell tumor: first 100 patients. AB - BACKGROUND: Retroperitoneal lymph node dissection (RPLND) is indicated after chemotherapy in case of radiologic incomplete remission or teratomatous elements in orchiectomy specimens. Open RPLND is associated with considerable morbidity, but technical difficulty of postchemotherapy laparoscopic RPLND (L-RPLND) can be significant; therefore, literature concerning pc L-RPLND is sparse. OBJECTIVE: To evaluate feasibility and long-term oncologic outcome of postchemotherapy L-RPLND for clinical stage II disease at a single institution. DESIGN, SETTING, AND PARTICIPANTS: Records of patients with nonseminomatous germ cell tumor who underwent postchemotherapy L-RPLND between 1993 and 2010 were retrospectively reviewed. Unilateral template resection was used until a bilateral nerve-sparing approach was introduced in 2004. Follow-up investigations were performed at 3-mo intervals for the first 3 yr, every 6 mo for the next 2 yr, and annually thereafter. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: This was a descriptive analysis. RESULTS AND LIMITATIONS: The study cohort comprised 100 patients with stage II retroperitoneal disease (stage IIC: n=16; IIB: n=68; IIA with persisting tumor marker: n=16). Mean diameter of retroperitoneal masses before and after chemotherapy was 3.5 cm and 1.4 cm, respectively. Unilateral and bilateral templates were resected in 71 and 29 patients, respectively. Surgery was successfully completed in all but one patient, whose procedure was converted to open surgery due to bleeding. Mean operation time for unilateral and bilateral resection was 241 and 343 min, respectively. Mean blood loss was 84 ml. Postoperative complications were a large lymphocele in one patient and chylous ascites in another. Mean postoperative hospital stay was 3.9 d. L-RPLND specimens showed teratoma in 38 patients and active tumor in 2 patients. During a mean follow-up of 74 mo, one patient recurred. No recurrence was observed inside the applied surgical field. No patient died of tumor progression. After bilateral nerve-sparing postchemotherapy L-RPLND, 95.2% of patients reported antegrade ejaculation. CONCLUSIONS: Postchemotherapy L-RPLND performed by experienced hands is feasible and associated with low morbidity and high oncologic efficacy. PMID- 23021091 TI - Utilization of integrated Michaelis-Menten equations for enzyme inhibition diagnosis and determination of kinetic constants using Solver supplement of Microsoft Office Excel. AB - Enzyme kinetic parameters are usually determined from initial rates nevertheless, laboratory instruments only measure substrate or product concentration versus reaction time (progress curves). To overcome this problem we present a methodology which uses integrated models based on Michaelis-Menten equation. The most severe practical limitation of progress curve analysis occurs when the enzyme shows a loss of activity under the chosen assay conditions. To avoid this problem it is possible to work with the same experimental points utilized for initial rates determination. This methodology is illustrated by the use of integrated kinetic equations with the well-known reaction catalyzed by alkaline phosphatase enzyme. In this work nonlinear regression was performed with the Solver supplement (Microsoft Office Excel). It is easy to work with and track graphically the convergence of SSE (sum of square errors). The diagnosis of enzyme inhibition was performed according to Akaike information criterion. PMID- 23021092 TI - Chronic epileptic encephalopathy in adult patients with bilaterally synchronous frequent and/or prolonged subclinical epileptiform discharges. AB - We followed four patients with infrequent convulsive seizures for four to 10 years, with periodic EEGs and neuropsychological tests. All four had bursts of frontally predominant, bilaterally synchronous 1.5-3-Hz spike or polyspike and slow-wave discharges (SWDs) that initially comprised 15% to 88% but were reduced to 5% or less of total EEG time with appropriate antiepileptic drugs. Case 1 showed a 30-point improvement in his verbal WAIS-R score and Case 4 a 21-point improvement in his performance WAIS-R score, over nine- and five-year periods, respectively, with normalization of frontal executive function. Cases 2 and 3 showed no improvement in frontal executive dysfunction despite being free of SWDs for nine and five years, respectively. These patients had variable degrees of epileptic encephalopathy and subclinical SWDs. They illustrate the importance of minimizing the occurrence of SWDs with appropriate antiepileptic drugs and long term monitoring with neuropsychological tests because chronic cognitive deficits are potentially reversible. PMID- 23021093 TI - The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age related macular degeneration. AB - OBJECTIVE: To evaluate long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular age-related macular degeneration (nAMD). DESIGN: Twenty four-month, open-label, multicenter, phase IV extension study. PARTICIPANTS: Two hundred thirty-four patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. METHODS: Ranibizumab 0.5 mg administered at the investigator's discretion as per the European summary of product characteristics 2007 (SmPC, i.e., ranibizumab was administered if a patient experienced a best corrected visual acuity [BCVA] loss of >5 Early Treatment Diabetic Retinopathy Study letters measured against the highest visual acuity [VA] value obtained in SECURE or previous studies [EXCITE and SUSTAIN], attributable to the presence or progression of active nAMD in the investigator's opinion). MAIN OUTCOME MEASURES: Incidence of ocular or nonocular adverse events (AEs) and serious AEs, mean change in BCVA from baseline over time, and the number of injections. RESULTS: Of 234 enrolled patients, 210 (89.7%) completed the study. Patients received 6.1 (mean) ranibizumab injections over 24 months. Approximately 42% of patients had 7 or more visits at which ranibizumab was not administered, although they had experienced a VA loss of more than 5 letters, indicating either an undertreatment or that factors other than VA loss were considered for retreatment decision by the investigator. The most frequent ocular AEs (study eye) were retinal hemorrhage (12.8%; 1 event related to study drug), cataract (11.5%; 1 event related to treatment procedure), and increased intraocular pressure (6.4%; 1 event related to study drug). Cataract reported as serious due to hospitalization for cataract surgery occurred in 2.6% of patients; none was suspected to be related to study drug or procedure. Main nonocular AEs were hypertension and nasopharyngitis (9.0% each). Arterial thromboembolic events were reported in 5.6% of the patients. Five (2.1%) deaths occurred during the study, none related to the study drug or procedure. At month 24, mean BCVA declined by 4.3 letters from the SECURE baseline. CONCLUSIONS: The SECURE study showed that ranibizumab administered as per a VA-guided flexible dosing regimen recommended in the European ranibizumab SmPC at the investigator's discretion was well tolerated over 2 years. No new safety signals were identified in patients who received ranibizumab for a total of 3 years. On average, patients lost BCVA from the SECURE study baseline, which may be the result of disease progression or possible undertreatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23021097 TI - Factors associated with mortality among heroin users after seeking treatment with methadone: a population-based cohort study in Taiwan. AB - Data concerning factors associated with mortality among heroin users under methadone maintenance treatment (MMT) in the Han Chinese population are limited. This study examined mortality risk among heroin users after seeking treatment with methadone in a catchment area using a cohort of 1616 Taiwanese heroin users between October 2006 and December 2008. During the study period, 26 (1.6%) people died, with an all-cause mortality rate per 100 person years of 3.42. The primary cause of death among our patients was accidents, followed by suicide and drug overdose. Older age, HIV infection, psychiatric treatment history, and alcohol abuse/dependence were risk factors for all-cause mortality; remaining on MMT was protective for survival. Our findings suggest that although mortality is mainly associated with medical and psychiatric comorbidities, continuing with the MMT program is still an important predictor for survival. PMID- 23021094 TI - HSV-1 latent rabbits shed viral DNA into their saliva. AB - BACKGROUND: Rabbits latent with HSV-1 strain McKrae spontaneously shed infectious virus and viral DNA into their tears and develop recurrent herpetic-specific corneal lesions. The rabbit eye model has been used for many years to assess acute ocular infections and pathogenesis, antiviral efficacy, as well as latency, reactivation, and recurrent eye diseases. This study used real-time PCR to quantify HSV-1 DNA in the saliva and tears of rabbits latent with HSV-1 McKrae. METHODS: New Zealand white rabbits used were latent with HSV-1 strain McKrae and had no ocular or oral pathology. Scarified corneas were topically inoculated with HSV-1. Eye swabs and saliva were taken from post inoculation (PI) days 28 through 49 (22 consecutive days). Saliva samples were taken four times each day from each rabbit and the DNA extracted was pooled for each rabbit for each day; one swab was taken daily from each eye and DNA extracted. Real-time PCR was done on the purified DNA samples for quantification of HSV-1 DNA copy numbers. Data are presented as copy numbers for each individual sample, plus all the copy numbers designated as positive, for comparison between left eye (OS), right eye (OD), and saliva. RESULTS: The saliva and tears were taken from 9 rabbits and from 18 eyes and all tested positive at least once. Saliva was positive for HSV-1 DNA at 43.4% (86/198) and tears were positive at 28.0% (111/396). The saliva positives had 48 episodes and the tears had 75 episodes. The mean copy numbers +/- the SEM for HSV 1 DNA in saliva were 3773 +/- 2019 and 2294 +/- 869 for tears (no statistical difference). CONCLUSION: Rabbits latent with strain McKrae shed HSV-1 DNA into their saliva and tears. HSV-1 DNA shedding into the saliva was similar to humans. This is the first evidence that documents HSV-1 DNA in the saliva of latent rabbits. PMID- 23021098 TI - Development of a scale to measure practitioner adherence to a brief intervention in the emergency department. AB - Brief intervention (BI) can reduce harmful and hazardous drinking among emergency department patients. However, no psychometrically-validated instrument for evaluating the extent to which practitioners correctly implement BIs in clinical practice (e.g., adherence) exists. We developed and subsequently examined the psychometric properties of a scale that measures practitioner adherence to a BI, namely the Brief Negotiation Interview (BNI). Ratings of 342 audiotaped BIs in the emergency department demonstrated that the BNI Adherence Scale (BAS) has: (1) excellent internal consistency and discriminant validity; (2) good to excellent inter-rater reliability, and (3) good construct validity, with an eight-item, two factor structure accounting for 62% of the variance, but (4) no predictive validity in this study. The BAS provides practitioners with a brief, objective method to evaluate their BNI skills and give feedback to them about their performance. PMID- 23021099 TI - Predictors of outcome after short-term stabilization with buprenorphine. AB - Using buprenorphine as a medication to treat opioid dependence is becoming more prevalent as illicit opiate use increases. Identifying the characteristics of opiate dependent individuals best suited to benefit from buprenorphine would improve guidelines for its administration. This study evaluates baseline and treatment participation variables for predicting positive response to short-term stabilization with buprenorphine. Data include demographic, drug use, and other variables collected from participants undergoing stabilization over a 4-week period before being tapered off buprenorphine in a short-term detoxification process. Outcome variables include opioid use and retention. Logistic regression results indicate several characteristics associated with opioid use at the end of the stabilization period. These include being older, having no criminal history, and less opiate use. Criminal activity and opioid use in the last 30 days were significantly associated with shorter treatment stays. The benefits of identifying individual characteristics that may predict treatment response are discussed. PMID- 23021100 TI - Inorganic impurity removal from waste oil and wash-down water by Acinetobacter johnsonii. AB - The removal of the abundant inorganic impurities in waste oil has been one of the most significant issues in waste oil reclamation. Acinetobacter johnsonii isolated from waste oil in aerobic process was employed to remove the inorganic impurities in waste oil and wash-down water. The biological process was developed through the primary mechanism research on the impurity removal and the optimization of the various parameters, such as inoculum type, inoculum volume and disposal temperature and time. The results showed that waste oil and wash down water were effectively cleansed under the optimized conditions, with inorganic impurity and turbidity below 0.5% and 100 NTU from the initial values of 2% and 300 NTU, respectively. Sulfide, the main hazardous matter during waste oil reclamation, was also reduced within 1mg/L. After the biotreatment, the oil water interface was clear in favor of its separation to benefit the smooth reclamation of waste oil and wash-down water. PMID- 23021101 TI - Enhanced effect of water vapor on complete oxidation of formaldehyde in air with ozone over MnOx catalysts at room temperature. AB - At room temperature, the enhanced effect of water vapor on ozone catalytic oxidation (OZCO) of formaldehyde to CO2 over MnOx catalysts and the reaction stability was reported. In a dry air stream, only below 20% of formaldehyde could be oxidized into CO2 by O3. In humid air streams (RH>=55%), ~100% of formaldehyde were oxidized into CO2 by O3 and the reaction stability was significantly enhanced. Meanwhile, in situ Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectra of OZCO of HCHO demonstrate that the amount of both monodentate and bidentate carbonate species on MnOx, in the dry stream, increased gradually with time on stream (TOS). However, in the humid stream, almost no accumulation of carbonate species on the catalysts was observed. To clarify the enhanced mechanism, formaldehyde surface reactions and CO2 adsorption/desorption on the fresh, O3 and O3+H2O treated MnOx catalysts were examined comparatively. PMID- 23021102 TI - N-doped P25 TiO2-amorphous Al2O3 composites: one-step solution combustion preparation and enhanced visible-light photocatalytic activity. AB - Nitrogen-doped Degussa P25 TiO2-amorphous Al2O3 composites were prepared via facile solution combustion. The composites were characterised using X-ray diffraction, high-resolution transmission microscopy, scanning electron microscopy, nitrogen adsorption-desorption measurements, X-ray photoelectron spectroscopy, UV-vis light-diffusion reflectance spectrometry (DRS), zeta potential measurements, and photoluminescence spectroscopy. The DRS results showed that TiO2 and amorphous Al2O3 exhibited absorption in the UV region. However, the Al2O3/TiO2 composite exhibited visible-light absorption, which was attributed to N-doping during high-temperature combustion and to alterations in the electronic structure of Ti species induced by the addition of Al. The optimal molar ratio of TiO2 to Al2O3 was 1.5:1, and this composite exhibited a large specific surface area of 152 m2/g, surface positive charges, and enhanced photocatalytic activity. These characteristics enhanced the degradation rate of anionic methylene orange, which was 43.6 times greater than that of pure P25 TiO2. The high visible-light photocatalytic activity was attributed to synthetic effects between amorphous Al2O3 and TiO2, low recombination efficiency of photo excited electrons and holes, N-doping, and a large specific surface area. Experiments that involved radical scavengers indicated that OH and O2- were the main reactive species. A potential photocatalytic mechanism was also proposed. PMID- 23021103 TI - Development of support networks in informal dementia care: guided, organic, and chance routes through support. AB - Increasing knowledge about factors that shape the development of care networks for people with dementia is imperative in countries with aging populations that are relying increasingly on informal care. This study used a qualitative approach to identify the complex routes through support taken by informal caregivers for people with dementia in the development of their care networks. Interview data were collected from 13 caregivers. Three routes through support were identified: guided routes, organic routes, and chance routes. This article's principal argument is that these routes are the outcomes not only of the resources that caregivers draw upon, but also of their varying expectations regarding the role of the informal caregiver. The identification of the three routes through support provides a potentially valuable framework for examining the experiences of caregivers for individuals with other long-term health conditions. PMID- 23021104 TI - Cyclic tetrapeptides with thioacetate tails or intramolecular disulfide bridge as potent inhibitors of histone deacetylases. AB - Two thioacetate tails were introduced to the chlamydocin- and CHAP31-related cyclic tetrapeptides. An intramolecular disulfide bridge could be formed in the CHAP31-related cyclic peptides. Both the thioacetate-tailed and disulfide-bridged peptides were potent histone deacetylase inhibitors in the presence of sulfhydryl compound. Potent p21 promoter inducing activity was also observed in vivo. PMID- 23021105 TI - Biologic TNF inhibiting agents for treatment of inflammatory rheumatic diseases: dosing patterns and related costs in Switzerland from a payers perspective. AB - BACKGROUND: To obtain detailed real-life data on costs and dosing patterns in the utilisation of the TNF inhibitors adalimumab, etanercept, and infliximab in patients treated in Switzerland. METHODS: Administrative claims processed by a major Swiss health insurer between 2005 and 2008 were analysed. Patients with inflammatory rheumatic diseases (IRDs) with at least one prescription for adalimumab, etanercept, or infliximab were identified. All-cause and disease specific costs, as well as daily costs of treatment, were calculated. Dosing patterns and discontinuation rates were analysed. RESULTS: A total of 555 IRD patients were identified. All-cause costs during the 12 months after the index event were 20,555CHF in the etanercept group, 24,152CHF in the adalimumab group, and 27,614CHF in the infliximab group. The most important cost driver was mean TNF inhibitor drug cost, which was 15,613CHF in the etanercept group, 19,166CHF in the adalimumab group, and 21,313CHF in the infliximab group. Discontinuation rates during the first year after the index event were 46.8% in etanercept, 41.3% in adalimumab, and 51.2% in the infliximab group. Rates of dosage increase were 13.3% in the etanercept group, 13.0% in the adalimumab group, and 14.1% in the infliximab group. When time on treatment was considered, daily costs of treatment were similar for etanercept and adalimumab, but were higher for infliximab. CONCLUSIONS: Marked differences in costs between subcutaneous and intravenous therapies were observed. Among the three groups of patients defined by TNF inhibitor treatment, costs for the infliximab group were highest during the year after the index event. PMID- 23021106 TI - Lycopersicon esculentum submitted to Cd-stressful conditions in nutrition solution: Nutrient contents and translocation. AB - The increasing number of cases on soil contamination by heavy metals has affected crop yields, besides representing an imminent risk to food. Some of these contaminants, such as cadmium, are very similar to micronutrients and thus more easily absorbed by the plants. This study assessed the effect of increasing amounts of cadmium on the content and translocation of micro and macronutrients in tomato. Tomatoes were grown in Clark's nutrient solution and subjected to increasing levels of Cd: 0, 0.025, 0.1, 0.5 and 1.0mg L(-1). The plants contaminated by cadmium had a maximum reduction in the aerial part compared to the control of: 2.25g kg(-1), 2.80g kg(-1), 18.93mg kg(-1) and 14.15mg kg(-1) for K, Ca, Mn and Zn, respectively. In other parts of the tomato were reduced from 2.3g kg(-1) K in fruits and 280.5mg kg(-1) of Mn in the roots. In addition to changes in the levels of some nutrients, the restricted Cd translocation in 1.15 percent P and 2.8 percent Cu to shoots compared to control, but did not affect the translocation of K, Ca, Mg and Zn. PMID- 23021107 TI - Type II DeBakey dissection with complete aortic rupture visualized by unenhanced postmortem imaging. AB - We present postmortem computed tomography (pmCT) as well as postmortem magnetic resonance (pmMR) imaging findings in a case of type II DeBakey aortic dissection with a complete rupture of the ascending aorta compared to the findings obtained at forensic autopsy. PmCT only allowed a presumptive diagnosis of aortic dissection based on an anterior mediastinal enlargement. However, at pmMR the dissection including the aortic rupture was clearly visible. Visualization was realized in an unenhanced manner without the need for postmortem angiography. PMID- 23021108 TI - Variation of the proximal insertion of the abductor digiti minimi muscle: correlation with Guyon's canal syndrome? Case report and literature review. AB - We describe the case of an original insertion and course of the abductor digiti minimi muscle on the medial part of the palmaris longus tendon. The anomalous muscle was only present on the left side. Various studies have reported the frequency of anomalous muscles in approximately 22 to 35% of hands and it was in majority an anomalous abductor digiti minimi muscle. The knowledge of this original insertion is important because it can sometimes be correlated with ulnar nerve compression at Guyon's canal. But Guyon's canal syndrome is less common than carpal tunnel syndrome, and the incidence of ulnar nerve compression in relation with anomalous muscle is approximately 2.9% of cases. It is possible to diagnose the anomalous muscle through ultrasound or MRI. This variation should be taken into consideration by surgeons during surgical procedures for ulnar nerve decompression at Guyon's canal and when performing anteromedial approach to the wrist between flexors tendons and ulnar bundle. PMID- 23021109 TI - Accelerated muscle and adipose tissue loss may predict survival in pancreatic cancer patients: the relationship with diabetes and anaemia. AB - Weight loss leading to cachexia is associated with poor treatment response and reduced survival in pancreatic cancer patients. We aim to identify indicators that allow for early detection that will advance our understanding of cachexia and will support targeted anti-cachexia therapies. A total of fifty pancreatic cancer patients were analysed for skeletal muscle and visceral adipose tissue (VAT) changes using computed tomography (CT) scans. These changes were related to physical characteristics, secondary disease states and treatment parameters. Overall, patients lost 1.72 (SD 3.29) kg of muscle and 1.04 (SD 1.08) kg of VAT during the disease trajectory (413 (SD 213) d). After sorting patients into tertiles by rate of VAT and muscle loss, patients losing VAT at > -0.40 kg/100 d had poorer survival outcomes compared with patients with < -0.10 kg/100 d of VAT loss (P= 0.020). Patients presenting with diabetes at diagnosis demonstrated significantly more and accelerated VAT loss compared with non-diabetic patients. In contrast, patients who were anaemic at the first CT scan lost significantly more muscle tissue and at accelerated rates compared with non-anaemic patients. Accelerated rates of VAT loss are associated with reduced survival. Identifying associated features of cachexia, such as diabetes and anaemia, is essential for the early detection of cachexia and may facilitate the attenuation of complications associated with cachexia. PMID- 23021110 TI - Comparative analysis of hemolymph proteome maps in diapausing and non-diapausing larvae of Sesamia nonagrioides. AB - BACKGROUND: Sesamia nonagrioides is a noctuid that feeds on maize, sugar cane and sorghum in North Africa and Southern Europe. Larvae reared under long day conditions pupate after 5 or 6 larval instars, whereas larvae reared under short day conditions enter diapause and undergo up to 12 molts before dying or pupating. To better understand the mechanism of larval development and diapause, we identified proteins with different expressions in the sixth instar of diapausing and non-diapausing larvae. RESULTS: A total of 52 differentially regulated proteins were detected in the hemolymph of the diapausing or non diapausing larvae at the beginning or end of the sixth instar. From these proteins, 11 were identified by mass spectrometry (MALDI-TOF MS or MALDI-TOF/TOF MS/MS): 5 were upregulated in the hemolymph of non-diapausing larvae and 6 in the hemolymph of the diapausing larvae. Interestingly, some proteins were expressed only in non-diapausing larvae but none was expressed only in the hemolymph of diapausing larvae. The possible functions of some of these proteins related to diapause maintenance or to larval-pupal metamorphosis are discussed. CONCLUSIONS: The 2-DE proteomic map of S. nonagrioides hemolymph shows differential protein expression in diapausing and non-diapausing larvae. Some proteins that showed higher expression in the diapausing larvae at the end of the sixth instar could be involved in JH level maintenance thus in the diapause status maintenance. On the contrary, other proteins that showed the highest expression or that were expressed only in the non-diapausing larvae could be involved in larval-pupal metamorphosis. PMID- 23021111 TI - Progress in Orthodontics closer to internationalization. PMID- 23021112 TI - A prospective study on the clinical effectiveness of the stainless steel crown Herbst appliance. AB - OBJECTIVES: To evaluate the clinical performance of the stainless steel crown Herbst (cHerbst) used as a single appliance for a single phase therapy. MATERIALS AND METHODS: A total of 180 consecutive Class II patients were treated with cHerbst for one year and followed up one year after the end of treatment. RESULTS: Class I relationship was achieved in all 175 patients who finished the functional phase of treatment, 58 patients continued treatment with fixed appliances while 21 patients (12%) showed relapse. Seventy two patients (41.1%) obtained and maintained stable Class I relationship one year after treatment with the cHerbst appliance used as a single appliance. Altogether 46 episodes of appliance breakages were observed and most of them could be repaired at the chair side. Patients' questionnaire revealed that in general the appliance was easy to tolerate and did not cause esthetic or functional problems. CONCLUSIONS: The crown Herbst appliance is a viable therapeutical option in patients with Class II malocclusions and it is characterized by low complication rate along with good patient compliance. PMID- 23021113 TI - Tissue response during self-ligating treatment. AB - INTRODUCTION: Orthodontic tooth movement is characterized by tissue reactions, which consist in an inflammatory response in periodontal ligament, depending on the forces applied. Self-ligating brackets are able to minimize the sliding resistance and to reduce the forces necessary to move a tooth, with a better tissue response. OBJECTIVES: The purpose of this study was to evaluate the activity of the lactate dehydrogenase (LDH) in gingival crevicular fluid (GCF) during orthodontic tooth movement using self-ligating brackets. MATERIALS AND METHODS: Forty patients were selected and treated with two kinds of self-ligating brackets, Quick 2.0 and Smart Clip, and superelastic or thermoactive archwires. Patients' lower arches were bonded and GCF was collected at one side for each tooth at baseline, one hour after bonding and on the 7(th), 28(th) and 42(nd) day. Test teeth were 4.1, 4.3 and 4.5. Control teeth were 1.1, 1.3 and 1.5. Samples were analyzed with a specific assay for LDH activity. RESULTS: The statistical analysis showed no significant differences in the LDH activity between test and control teeth in the selected groups. CONCLUSIONS: There are no significant differences, in terms of tissue response, between superelastic and thermoactive archwires. PMID- 23021114 TI - Anchorage loss during canine retraction using intermittent versus continuous force distractions; a split mouth randomized clinical trial. AB - OBJECTIVES: The aim of this study was to evaluate the anchorage loss, amount and time of canine retraction, and canine tipping concomitant with periodontal ligament distraction (PLD) using intermittent and continuous forces. MATERIALS AND METHODS: This was a split mouth randomized clinical trial involving 30 patients in need of first premolar extraction. For each patient, one side was randomly allocated to receive a screw-based dental distractor, and the other side a continuous force coil spring distractor. Molar and canine movements were recorded on study casts using the rugae as reference. Changes in the long axis of the canines were evaluated from pre- and post distraction panoramic radiographs. RESULTS: On the screw side, molars moved mesially 2.5+/-0.9 mm. The canine tipped distally a mean of 10.5 degrees +/-3.1 degrees . The average time needed for canine retraction was 5.3+/-1.3 weeks. In the coil side, the molar mesial movement was not statistically different from the screw group (2.8+/-1.5 mm). The canine moved bodily with a mean distal tip of 0.27 degrees +/-1.75 degrees in a period of 27.8+/-6.6 weeks. CONCLUSIONS: Anchorage loss occurs with dental distraction using either intermittent or continuous force. No significant difference in anchorage loss was found with either type of force. The surgical intervention did not shorten the time needed for canine retraction using the continuous force. Continuous force leads to slow bodily retraction of the canine unlike the intermittent force which leads to rapid tipping of the canine. PMID- 23021115 TI - Bone age estimation by cervical vertebral dimensions in lateral cephalometry. AB - OBJECTIVES: A critical issue in contemporary orthodontics is bone age estimation. The most reliable method for skeletal age evaluation is hand-wrist radiography; but it requires further radiation. There is an increasing attention for evaluating cervical vertebrae to reduce the radiation to the patients. The aim of this study was to estimate bone age by measuring 3rd and 4th cervical vertebrae (C3, C4) dimensions. MATERIALS AND METHODS: We conducted a correlational study on 91 Iranian individuals aged 8-18 years. After taking lateral cephalometry and hand-wrist radiographs, C3 and C4 were measured using Vixwin 2000 software. Hand wrist bone age, determined on Greulich Atlas, was the reference test. Stepwise multiple linear regression model demonstrated the correlation between the two measurements. RESULTS: Anterior height of the fourth cervical vertebrae (AH4) had the strongest simple correlation with hand-wrist bone age (r=0.831, P<0.001) and was the only variable that remained in stepwise multivariate regression model. The regression model was: Bone age=0.989*AH4+3.308. Adjusted R2 was 0.686 (p<0.001). CONCLUSIONS: Lateral cephalometric radiographs are useful for bone age estimation, and might be an alternative for hand-wrist radiography, with the advantage of radiation reduction. PMID- 23021116 TI - Accuracy of landmark identification on postero-anterior cephalograms. AB - OBJECTIVES: The aim of this study was to examine accuracy in landmark identification on digital postero-anterior cephalograms, (PAC) assessing the intra-observer and the inter-observer repeatability in determining these landmarks. MATERIALS AND METHODS: Twenty postero-anterior digital cephalometric radiographs were randomly selected from data files of patients aged between 11 to 15 years and were used in this study. Thirty-four commonly used PAC landmarks were included in this investigation and each observer performed the determination of all landmarks on every PAC cephalograms twice (T1 and T2). Mean positions located by the three observers in the first recording session both on the x and y axes, were calculated and defined as the "best estimate" for every landmarks. Systematic differences between the two records at T1 and T2 of the same observer were evaluated using the paired t-test with P<0.05. In order to test the hypothesis of equal mean of the vectors of differences to the "best estimate" for the three raters, a one-way ANOVA test was performed. RESULTS: Most landmarks showed a good reproducibility between the two recording sessions, except for some landmarks located in the zygomatic arch, mandible and dentition. As regards inter observer reliability, there were statistically significant differences (P<0.05) in both x and y axis. CONCLUSIONS: Each landmark has its own margin of error and there is a clear difference in the localization accuracy between the x and y coordinates. Since condylar points (CDr-CDl), coronoid points (CORr-CORl) and mental foramen points (MFr-MFl) showed to have a questionable localization accuracy, PAC cannot be strictly recommended for accurate evaluation of any asymmetry. Some dental landmarks seem to be poorly reproducible; therefore the usefulness of postero-anterior cephalometric analysis to evaluate dental discrepancies or maxillo-mandibular molar relationship is questioned. PMID- 23021117 TI - The ability of orthodontists and laypeople to discriminate mandibular stepwise advancements in a Class II retrognathic mandible. AB - OBJECTIVES: This study analysed the ability of orthodontists and laypeople to discriminate mandibular stepwise advancements. MATERIALS AND METHODS: Four pictures (in duplicate) were taken of a male patient with Class II malocclusion and mandibular deficiency with the mandible positioned in habitual maximum intercuspation (HMI) and with stepwise advancements of 2mm, 4mm and 6mm. These images were examined by orthodontists (n=30) and laypeople (n=30). The Wilcoxon signed-rank test was used to evaluate intra-examiner agreement. Intra-examiner ability to discriminate stepwise mandibular advancements was examined by Friedman's test. A Mann-Whitney's test was carried out to analyse score difference between orthodontists and laypeople. Type I error (alpha) was set as 5% for all statistical tests. RESULTS: We observed a satisfactory to excellent level of methodological reliability. While laypeople were able to notice mandibular advancements >=4 mm (p<0.05), orthodontists were able to observe mandibular advancements >=2 mm (p<0.05). The orthodontists were more critical than laypeople with regard to the facial profile evaluation when facial convexity increased (p<0.001), but no significant difference was observed when the sagittal maxillo-mandibular relationship approached normality (p<0.05). CONCLUSIONS: Considering that the mean sagittal mandibular growth due to the use of functional orthopaedic appliances is reported in the literature as 2mm, it seems that laypeople may not able to discriminate this amount of change in facial-profile attractiveness. PMID- 23021118 TI - Sliding resistance of polycarbonate self-ligating brackets and stainless steel esthetic archwires. AB - OBJECTIVES: To compare the sliding resistance forces produced by polycarbonate self-ligating brackets with esthetic archwires. MATERIALS AND METHODS: Samples of Opal, Oyster and conventional Blonde brackets were tested each one with 30 segments of .018x.025-in wires. The archwires were slipped at 8mm/min for 40 seconds with an universal testing machine. Two way ANOVA with Bonferroni correction were used. RESULTS: Blonde brackets presented the highest sliding resistance, followed in decreasing order by Oyster and Opal. The TP Shiny Bright Wire produced the highest surface friction, while the lowest was observed for Imagination archwires (except for Opal brackets where the TP Pearltone Wire achieved the best performance). CONCLUSIONS: Self-ligating system is more effective to reduce the sliding force resistance than conventional brackets. Esthetic stainless steel archwires produce less friction resistance than those without surface treatment. Polycarbonate self-ligating brackets are more effective to reduce the frictional forces than esthetic archwires with surface treatment. PMID- 23021119 TI - Three-dimensional finite-element analysis of a central lower incisor under labial and lingual loads. AB - INTRODUCTION: The aim was to evaluate the differences between labial and lingual application of an orthodontic force. This was achieved using a three-dimensional CAD design software model of a real lower incisor surrounded by a prismatic representation of the mandibular bone. This model was subjected to various loading conditions, with finite-element analysis. MATERIALS AND METHODS: Cone beam computed tomography scanning was used to create a three-dimensional geometric model of a lower incisor, together with its simulated periodontal ligament. This model was then meshed and analysed with commercial finite-element code. Various single and combined forces and moments were applied to each side of the simulated lower incisor at the centre of the clinical crown. To evaluate the effects of the various forces considered, the instantaneous displacement and stress generated in the bone and the periodontal ligament were measured, as a comparison of the labial and lingual loading sites. RESULTS: Dental movement was only influenced by the side of the force application when an intrusive component was present. The simulations showed larger displacement when a vertical force was present at the lingual surface. In general, this movement was of the tipping type when the combined forces were applied, while there was greater intrusion upon application of combined forces and an anticlockwise moment to the labial surface. CONCLUSIONS: Application of an intrusive lingual force to a lower incisor appears to generate bodily movement, while the same intrusive labial force appears to lead to labial tipping. Subject to further study, this should be taken into consideration when devising treatment plans for fixed appliances. PMID- 23021120 TI - Prevalence of malocclusions and orthodontic treatment need in 8- to 12-year-old schoolchildren in Casablanca, Morocco. AB - OBJECTIVES: The purpose of this work was to evaluate the prevalence of malocclusions and orthodontic treatment need among schoolchildren in Casablanca, Morocco. MATERIALS AND METHODS: A sample of 1000 children aged between 8 and 12 years, with no history of orthodontic treatment, was chosen at random in state schools in different administrative areas of the city of Casablanca. Data was registered using the method of Bjork et al. (1964). Orthodontic treatment need was assessed with the index used by the Swedish National Board of Health (SweNBH). RESULTS: We found Angle Class I malocclusions in 61.4%, Class II in 24%, Class III in 10% and an indeterminate molar class with one or more missing molars in 4.6% of the children. Overjet was 1-4mm in 63.8%, 4-6 mm in 17.2% and >6 mm in 10%. Bite was normal in 65.4%, 23.6% presented an overbite greater than 4 mm, 1.7% an anterior open bite <=3 mm, 1.2% an anterior open bite >3 mm and 0.2% a bilateral open bite. Half of the sample presented anterior crowding, while only 2.5% presented posterior crowding. In all, 84.2% of the subjects needed some orthodontic treatment, and 15.8% needed no treatment. No statistically significant difference was found between sex or age and orthodontic treatment need (P>0.05). CONCLUSIONS: This study found a strong need for orthodontic treatment, confirming the utility of implementing a programme of bucco-dental prevention and screening for malocclusion. PMID- 23021121 TI - Non-compliance maxillary molar distalizing appliances: an overview of the last decade. AB - OBJECTIVES: To perform a literature review focusing on the use of non-compliance intraoral appliances for molar distalization therapy. MATERIALS AND METHODS: A literature search ranged from January 1999 to December 2009 in order to describe dento-alveolar changes and skeletal vertical modifications following the use of conventional anchorage intraoral distalizing appliances. The quality of the retrieved studies was ranked on a 12-points scale, from low to high quality. RESULTS: A total of 214 articles were found and only 24 were considered eligible for the critical examination. Maxillary first molar distalization ranged from 6.4mm to 0.5mm with a concomitant distal tipping from 18.5 degrees to bodily distalization. A smaller amount of distal movement and a greater amount of crown tipping can be noted at second molars. Premolar anchorage loss and incisor proclination represent an unavoidable side-effect and ranged from 4.33 mm to 0.73 mm and from 13.7 degrees to 0.6 degrees respectively. Skeletal vertical modifications were noted. Increase in vertical facial dimension ranged from 1.5 degrees to -1.8 degrees and lower anterior facial height ranged from an increase of 3.2 to a decrease of 0.6 mm. The assessment of study quality showed that 19 studies were of low quality, 3 of medium quality and 2 of medium-high quality. CONCLUSIONS: Maxillary molar distalization can be effectively performed with the use of noncompliance intraoral appliances. As a consequence, premolar anchorage loss, incisor proclination and a slight increase in vertical facial dimension can occur. Because of the lack of high-quality studies the findings of this review should be carefully interpreted. PMID- 23021122 TI - Interceptive therapy for maxillary constriction: a cast-metal-type splint expander. AB - A new cast-metal-type splint expander was used to treat severe maxillary constriction. This new appliance has the same advantages of a rapid expander on acrylic splints, compared to a Haas or to a banded expander. Furthermore, it is characterized by greater respect for the gingival tissue, both during the therapy and immediately after the removal of the expander. It is also more comfortable for the patient, so that it is possible to maintain the expander in the mouth for several months without gingival suffering. This appliance is very versatile and well indicated for permanent, mixed and deciduous dentitions. PMID- 23021123 TI - A modified thermoplastic retainer. AB - The aim of this article is to describe a method for fabricating a new esthetic maxillary retainer. To fabricate this retainer it is necessary to fit a segment of orthodontic wire in the maxillary molar and premolar region, followed by plasticization of the model. In order to allow occlusal finishing the occlusal and incisal surfaces of the plate are removed. The described retainer can be a useful alternative to the orthodontist for esthetic orthodontic retention. PMID- 23021124 TI - Protein carbonyls and traditional biomarkers in pigs exposed to low-dose gamma radiation. AB - Response of pigs to irradiation manifested by production of protein carbonyls and adaptable enzymes was studied in two experiments. In one experiment, 10 mixed-sex pigs were exposed to 0.5 Gy whole body (60)Co irradiation. In the other experiment, another batch of 10 pigs was exposed to 1.0 Gy half-body irradiation. Unlike those exposed to half-body irradiation, the pigs exposed to whole-body irradiation showed significant increase in protein carbonyls by 73%, and a decrease in cholesterol by 25.7%, compared to the control group. In both cases of dose-dependent irradiation exposure, pigs showed a decrease in alanine aminotransferase activity compared with the control group. At the dose of 1 Gy, ALT activity decreased significantly by 27.7%. Aspartate aminotransferase activity in pigs after half-body irradiation decreased significantly by 65.5%. Although low doses of ionizing radiation were applied, monitoring of the above biochemical parameters helped define the pigs' biological response. PMID- 23021125 TI - Polymorphism of the FAM13A, ABCG2, OPN, LAP3, HCAP-G, PPARGC1A genes and somatic cell count of Jersey cows--preliminary study. AB - The aim of this study was to investigate association between genotypes/combined genotypes of selected genes located on BTA6 (FAM13A, ABCG2, OPN, LAP3, HCAP-G, PPARGC1A) and somatic cell count (SCC) in milk. The study included 181 Jersey, all of which were genotyped. Allele frequencies were also determined. Genotypes were identified by the PCR-RFLP method and the results showed statistically significant (P<=0.05, P<=0.01, P<=0.001) differences between mean values of SCC in analysed cows with different genotypes of FAM13A1 G85A and combined genotypes OPN and FAM13A1. Data resulting from the present studies may be useful in further analysis in order to define the role of analysed genes (FAM13A, ABCG2, OPN, LAP3, HCAP-G, PPARGC1A) in relation to mastitis. PMID- 23021126 TI - Perioperative chemotherapy with or without bevacizumab in patients with metastatic colorectal cancer undergoing liver resection. AB - The impact of adding bevacizumab to perioperative chemotherapy in patients with colorectal cancer (CRC) undergoing liver resection is yet to be defined. A retrospective review of our patient records showed that the addition of bevacizumab did not increase morbidity or mortality related to liver resection. Pathologic complete response (CR) is associated with prolonged survival. BACKGROUND: Patients with colorectal cancer (CRC) and liver metastases benefit from perioperative chemotherapy and liver resection. The potential benefit of adding bevacizumab is yet to be defined. The impact of bevacizumab on liver resection complications has been explored in a small number of retrospective studies. METHODS: The records of patients with CRC and liver metastases who underwent liver resection and had received perioperative chemotherapy were reviewed. Complications were reported separately for 2 groups (chemotherapy alone vs chemotherapy and bevacizumab). Survival outcomes (progression-free survival [PFS] and overall survival [OS]) for responders and nonresponders were estimated using the Kaplan-Meier method. RESULTS: Fifty-two patients received chemotherapy alone and 42 patients received chemotherapy and bevacizumab. The median time from the end of systemic treatment to liver resection was 59 days (33-181 days) for the chemotherapy group and 62 days (44-127 days) for the chemotherapy and bevacizumab group. Postoperative complications developed in 54% of the chemotherapy group and in 48% of the chemotherapy and bevacizumab group. Severe complications (grade III-V) occurred in only 13% and 12%, respectively (P = .822). Pathologic complete response (CR) was seen in 11/94 patients. Poor performance status (PS) before starting chemotherapy was associated with higher rates of complications (P = .002), and severe complications led to prolonged hospital admission (P = .001). Patients with pathologic CR had longer OS (P = .0275), but there was no difference in OS between responders and nonresponders (P = .778). CONCLUSION: The addition of bevacizumab to chemotherapy does not increase liver resection complication rates. Pathologic CR is associated with prolonged survival. PMID- 23021127 TI - Rituximab for the first-line treatment of stage III-IV follicular lymphoma (review of Technology Appraisal No. 110): a systematic review and economic evaluation. AB - BACKGROUND: Follicular lymphoma (FL) is a non-Hodgkin's lymphoma which typically presents when the disease is at an advanced stage. The majority of patients receive first-line therapy of rituximab in combination with chemotherapy, with two-thirds receiving cyclophosphamide, vincristine and prednisolone. The clinical and cost-effectiveness of other chemotherapies in combination with rituximab in first-line therapy is not known. OBJECTIVE: To systematically evaluate and appraise the clinical effectiveness and cost-effectiveness of rituximab (MabThera((r)), Roche Products) in combination with chemotherapy, compared with chemotherapy alone, for the first-line treatment of symptomatic stage III-IV FL. DATA SOURCES: A systematic review of literature and an economic evaluation were carried out. Key databases [including MEDLINE In-Process & Other Non-Indexed Citations; Cumulative Index to Nursing and Allied Health Literature (CINAHL); EMBASE; The Cochrane Library, including the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED) and Health Technology Assessment (HTA) databases; Science Citation Index (SCI); and BIOSIS], plus research registers and conference proceedings, were searched for relevant studies from inception up to October 2010. REVIEW METHODS: One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. The quality of included studies was assessed by one reviewer and checked by a second. A patient-level simulation model was developed to estimate the costs and quality-adjusted life-year (QALY) gains from the perspective of the UK NHS and Personal Social Services, with costs and benefits discounted at 3.5% annually. RESULTS: Four randomised controlled trials comparing rituximab plus chemotherapy (R-chemotherapy) with chemotherapy alone in untreated, symptomatic patients with stage III-IV FL were identified. R chemotherapy compared with chemotherapy alone increased the likelihood of a response to treatment in all four trials, with no additional toxicity of clinical relevance. Overall response rates were significantly improved in all four trials, with a difference between the R-chemotherapy and chemotherapy arms of between 5% and 24%, respectively. Complete response rates were also improved, with a difference between the R-chemotherapy and chemotherapy arms of between 2% and 25%, respectively. Exploratory meta-analyses were conducted; the level of statistical heterogeneity was very high and thus we believe the response rates from the individual trials to be a more robust estimator of the efficacy of the specific R-chemotherapy regimens. Over a follow-up period of 4-5 years, R chemotherapy significantly increased the overall survival rate compared with chemotherapy alone in three trials, although data for two trials were compromised owing to the use of additional treatments. The incremental cost-effectiveness ratio (ICER) for the addition of rituximab to CVP (cyclophosphamide, vincristine and prednisolone), CHOP (cyclophosphamide, doxorubicin/adriamycin, vincristine and prednisolone) and MCP [mitoxantrone, chlorambucil (Leukeran((r)), Aspen) and prednisolone] was L7720, L10,834 and L9316 per QALY gained, respectively, when it was assumed that first-line rituximab maintenance was not used. A scenario analysis is also presented, assuming that responders to R-chemotherapy in first line induction receive maintenance with rituximab, increasing the ICER to L14,959, L21,687 and L20,493 per QALY gained, respectively. LIMITATIONS: These relate to the sources of data used for the effectiveness in first and second line and the assumed utility values; there is uncertainty about the effect of salvage treatment on patients who had been previously treated with an anthracycline regimen. There is uncertainty whether or not rituximab is as effective in second line treatment when patients have been previously treated with rituximab. CONCLUSIONS: The results from four randomised trials comparing R-chemotherapy with chemotherapy alone showed an improvement in clinical effectiveness outcomes, with minimal clinically relevant additional adverse events or toxicity. The cost per QALY gained is estimated to be < L25,000 for all three comparisons under our base-case assumption and is considerably lower if first-line rituximab maintenance is not assumed. More data on patients pre-treated with rituximab and on the effect of first-line maintenance with rituximab is required for future work. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 23021129 TI - The burden of Clostridium difficile-associated disease following digestive tract surgery in Japan. AB - BACKGROUND: Although surgery is considered a risk for Clostridium difficile associated disease (CDAD), large-scale data on outcomes of postsurgical CDAD are rare. AIM: Using the Japanese Diagnosis Procedure Combination inpatient database, we analysed factors affecting the occurrence of CDAD and the outcomes of CDAD following digestive tract surgery. METHODS: We identified patients postoperatively diagnosed with CDAD among patients undergoing oesophagectomy, gastrectomy, and colorectal resection for cancer from 2007 to 2010. We performed logistic regression analyses for the occurrence of CDAD and in-hospital mortality, and multiple linear regressions and one-to-one propensity-matched analyses for postoperative length of stay and total costs, with adjustment for patient backgrounds and hospital factors. FINDINGS: Of 143,652 patients undergoing digestive tract surgery, 409 (0.28%) CDAD patients were identified. Higher Charlson comorbidity index, longer preoperative length of stay and non academic hospitals were significantly associated with higher occurrence of CDAD. In-hospital mortality was higher in the CDAD patients compared with non-CDAD patients [3.4% vs 1.6%; odds ratio: 1.83; 95% confidence interval (CI): 1.07 3.13; P = 0.027]. Attributable postoperative length of stay and total costs related to CDAD were 12.4 days (95% CI: 9.7-15.0; P < 0.001) and US$6,576 (3,753 9,398; P < 0.001) in the linear regressions and 9 days (P < 0.001) and US$6,724 (P < 0.001) in the propensity-matched paired analyses. CONCLUSIONS: High mortality, long hospital stay and high costs were associated with postsurgical CDAD. The results indicate the necessity of further CDAD control measures for patients undergoing digestive tract surgery. PMID- 23021128 TI - Nuclear domain 10-associated proteins recognize and segregate intranuclear DNA/protein complexes to negate gene expression. AB - BACKGROUND: DNA viruses, such as herpes simplex virus type 1 (HSV-1), Simian virus 40 (SV40), and Cytomegaloviruses (CMV), start their replicative processes and transcription at specific nuclear domains known as ND10 (nuclear domain 10, also called PML bodies). It has been previously determined that for HSV-1 and SV40, a short DNA sequence and its binding protein are required and sufficient for cell localization of viral DNA replication and gene transcription. RESULTS: Our recent observations provide evidence that a foreign (not endogenous) DNA/protein complex in the nucleus recruits ND10 proteins. First, the complexes formed from the bacterial lac operator DNA and its binding protein (lac repressor), or from HPV11 (human papillomavirus 11) origin DNA and its binding protein (E2), co-localized with different ND10 proteins. Second, the HSV-1 amplicon without inserted lac operator DNA repeats distributed in the nucleus randomly, whereas the amplicon with lac operator DNA repeats associated with ND10, suggesting that DNA-binding proteins are required to localize at ND10. The cellular intrinsic DNA/protein complex (as detected for U2 DNA) showed no association with ND10. Furthermore, our examination of PML-/-, Daxx-/-, and Sp100 negative cells led to our discovering that DNA/protein complexes recruit ND10 protein independently. Using the GFP-LacI/Operator system, we were able to direct the transfected DNA to ND10 and found that gene expression was significantly repressed when the transfected DNA was directed to ND10. CONCLUSION: Taken together, the results suggest that cells recognize DNA/protein complexes through a mechanism that involves interaction with the ND10-associated proteins. PMID- 23021130 TI - Validity of intraoperative evaluation of myometrial invasion and preoperative grading in endometrial cancer. PMID- 23021131 TI - Human papillomavirus: what every provider should know. AB - Persistence of human papillomavirus (HPV) infection is necessary for the development of cervical cancer. Additionally, infection with HPV is implicated in the majority of cases of other genital tract malignancies including vulvar, penile, and vaginal cancer. HPV testing and vaccination are a routine part of obstetrical/gynecological clinical practice. With an enhanced public awareness of HPV infections, many patients turn to their obstetricians/gynecologists with questions about transmission, testing, and prevention. In this review, we will discuss the biology of HPV, epidemiology of disease, methods and indications for testing, and vaccination strategies. PMID- 23021133 TI - Evaluation of a novel laparoscopic simulation laboratory curriculum. AB - BACKGROUND: Simulation training may be an invaluable tool in training and assessing surgeons. Questions remain regarding its true impact on acquisition of laparoscopic skills and their transferability to the operating room. METHODS: Twenty general surgery residents completed 5 exercises: bean drop/rope drill, foam cutting/endoloop, checkerboard, endostitch, and suturing/intracorporeal knot. After baseline scoring, residents had 3 weeks to practice before re testing. Statistical analysis of objective and subjective scores included the signed rank test or paired t-test, the Kruskal-Walis test, the McNemar test, and the Global Operative Assessment of Laparoscopic Skills (GOALS). P < .05 was considered significant. RESULTS: Five postgraduate year (PGY) 4 and 15 PGY 1-3 residents completed the curriculum. When compared with baseline, overall scores improved (P < .05) in all categories except for the bean drop/rope drill, which improved on objectively measured tasks only (dropped beads and beads threaded). The foam cutting/endoloop task was mastered by a majority of trainees at baseline leaving no room for improvement. CONCLUSION: The results of this study reinforce that simulation leads to improvement in laparoscopic skills and that our curriculum is a valid educational tool. Further studies are needed to validate whether this results in improved skills in the operating room. PMID- 23021132 TI - Procedure-specific venous thromboembolism prophylaxis: a paradigm from colectomy surgery. AB - BACKGROUND: Colectomy patients are at high-risk for venous thromboembolism (VTE), but associated risk factors and best prophylaxis in this defined population are only generalized. METHODS: Fifteen hospitals prospectively collected pre-, peri-, and postoperative variables related to VTE and prophylaxis, in addition to the variables defined by the National Surgical Quality Improvement Program between 2008 and 2009 concerning open and laparoscopic colectomy patients with 30-day outcomes. Symptomatic VTE was the primary outcome, and risk factors were tested for association with VTE using multiple logistic regression. RESULTS: The cohort included 3,464 patients with a mean age of 65; 53% were female. Overall, the 30d incidence of VTE was 2.2%. VTE prophylaxis included sequential compression devices (SCDs, 11%) alone; pharmacologic prophylaxis alone (15%); and both SCDs and pharmacologic prophylaxis (combined prophylaxis, 74%). VTE was associated with each additional year of age (OR, 1.05; 95% CI 1.02-1.06, P < .001); increased body mass index (OR 1.03; CI 1.01-1.05; P = .02); preoperative anemia (OR 2.4; CI 1.2-4.8; P = .011); contaminated wound (OR 3.4; CI 1.6-7.3; P < .01); postoperative surgical site infection (OR 2.5; CI 1.2-5.2; P < .011); and postoperative sepsis/pneumonia (OR 3.6;CI 1.9-6.7; P < .01). Postoperative factors alone accounted for 32% of VTE risk. When controlling for all other factors, only combination prophylaxis was protective against VTE (OR 0.48; CI 0.27-0.9; P = .02). Operative time, presence of disseminated malignancy, anastomotic leak, transfusion, urinary tract infection, and laparoscopic procedure were not significantly associated with VTE. Propensity matching showed that unfractionated heparin was equivalent to low molecular weight heparin, and the transfusion rate was not increased with pharmacologic prophylaxis compared to SCDs alone. CONCLUSION: Regardless of preoperative factors, VTE prophylaxis using a combination of SCDs and chemoprophylaxis was associated with significant reduction in VTE and should be standard care for patients after colectomy. PMID- 23021134 TI - Persistent elevation in serum parathyroid hormone levels in normocalcemic patients after parathyroidectomy: does it matter? AB - BACKGROUND: The clinical importance of elevated serum parathyroid hormone (PTH) levels in patients with normocalcemia after curative parathyroidectomy (PTX) for primary hyperparathyroidism (pHPT) is unclear. This study sought to determine whether these patients, when compared with those with normal PTH levels, differ in preoperative and pathologic factors and are at increased risk of recurrent pHPT. METHODS: A chart review was performed of sporadic pHPT patients who underwent PTX between December 1999 and July 2011. RESULTS: Of 1,037 patients who underwent PTX, 310 had 6-month serum calcium, vitamin D, and PTH levels evaluated. PTX was curative (normocalcemia at >=6 months) in 97%. At 6 months, 62 (21%) had elevated serum PTH levels. Compared with patients with normal postoperative PTH levels, patients with elevated PTH levels had greater BMI (P < .0001), greater PTH levels (P < .0001), and lesser vitamin D levels (P = .014) preoperatively and lesser vitamin D levels at 6 months (P = .05). At >=1 year follow-up, 38 (61%) patients had calcium levels checked; all remained normocalcemic. PTH levels were available for 32 patients; 17 had persistently increased PTH levels. CONCLUSION: Patients with elevated PTH levels after curative PTX do not have greater rates of recurrence than patients with normal PTH levels. The greater PTH levels and lesser vitamin D levels support postoperative vitamin D supplementation in these patients. PMID- 23021135 TI - Surgeon beware: many patients referred for parathyroidectomy are misdiagnosed with primary hyperparathyroidism. AB - PURPOSE: We hypothesized that patients referred for the evaluation and management of primary hyperparathyroidism (pHPT) often do not have pHPT and that they may be harmed by unwarranted parathyroidectomy (PTX). METHODS: We reviewed all patients who were referred to our endocrine surgery practice between 2008 and 2011 with International Classification of Diseases, Ninth Revision codes for HPT (252.00), benign or malignant parathyroid tumors (227.1, 194.1, respectively), or hypercalcemia (275.42). Patients with renal failure were excluded. Clinical parameters for investigation included age, sex, presentation, laboratories, imaging studies, and referring physician. RESULTS: Three hundred twenty-four patients were referred for pHPT. The diagnosis was confirmed in 265 (82%), of whom 211 (80%) underwent PTX. Misdiagnoses occurred in 60 of 324 patients (19%). Of these, 54 (90%) had secondary HPT and 6 (10%) had hypercalcemia but no pHPT. Before referral, 70% of misdiagnosed patients underwent localizing studies, 57% of which suggested a positive finding. CONCLUSION: Considerable confusion exists regarding the differentiation of primary and secondary HPT. Surgeons should be cautioned that patients who are referred for parathyroidectomy, even those with complete laboratory and radiographic evaluations, might not have pHPT at all. PMID- 23021136 TI - Defining geriatric trauma: when does age make a difference? AB - BACKGROUND: Injured elderly patients experience high rates of undertriage to trauma centers (TCs) whereas debate continues regarding the age defining a geriatric trauma patient. We sought to identify when mortality risk increases in injured patients as the result of age alone to determine whether TC care was associated with improved outcomes for these patients and to estimate the added admissions burden to TCs using an age threshold for triage. METHODS: We performed a retrospective cohort study of injured patients treated at TCs and non-TCs in Pennsylvania from April 1, 2001, to March 31, 2005. Patients were included if they were between 19 and 100 years of age and had sustained minimal injury (Injury Severity Score < 9). The primary outcome was in-hospital mortality. We analyzed age as a predictor of mortality by using the fractional polynomial method. RESULTS: A total of 104,015 patients were included. Mortality risk significantly increased at 57 years (odds ratio 5.58; 95% confidence interval 1.07-29.0; P = .04) relative to 19-year-old patients. TC care was associated with a decreased mortality risk compared with non-TC care (odds ratio 0.83; 95% confidence interval 0.69-0.99; P = .04). Using an age of 70 as a threshold for mandatory triage, we estimated TCs could expect an annual increase of approximately one additional admission per day. CONCLUSION: Age is a significant risk factor for mortality in trauma patients, and TC care improves outcomes even in older, minimally injured patients. An age threshold should be considered as a criterion for TC triage. Use of the clinically relevant age of 70 as this threshold would not impose a substantial increase on annual TC admissions. PMID- 23021137 TI - Preoperative factors predict mortality after major lower-extremity amputation. AB - BACKGROUND: The objective was to develop a preoperative mortality risk stratification tool for patients facing major amputation. METHODS: Patients who underwent above-knee (AKA) or below-knee amputation (BKA) from 2005 to 2010 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Univariate and multivariate analyses were performed to determine the association of preoperative factors with 30-day mortality. Multivariable models were used to create a computerized prediction tool. RESULTS: Of 9,368 patients, 4,032 underwent AKA and 5,336 BKA. The 30-day mortality rate after AKA was 12.8%, almost double that of BKA (6.5%, P < .001). The complication rate was statistically greater after AKA although numerically similar (28.5% vs 26.6%, P = .020), whereas the rate of reoperation was substantially greater after BKA (22.7% vs 11.7%, P < .001). Preoperative factors that predicted mortality after both procedures included older age, dependent functional status, dialysis, steroid use, preoperative sepsis, delirium, thrombocytopenia, increased international normalized ratio, and azotemia. Prediction tools were developed and validated, and their concordance indices were 0.75 for AKA and 0.81 for BKA, indicating good predictive accuracy. CONCLUSION: Preoperative factors predict mortality after major amputation, and the risk calculator that we have developed may facilitate informed decision-making and provide realistic expectations for surgeons and patients faced with limb threatening disease. PMID- 23021138 TI - Impact of business infrastructure on financial metrics in departments of surgery. AB - BACKGROUND: In the current environment, pressure is ever increasing to maximize financial performance in surgery departments. Factors such as physician extenders, billing and collection, payor mix, contracting, incentives from the Centers for Medicare and Medicaid Services, and administrative incentives may greatly influence financial performance. However, despite a plethora of information from the University HealthSystem Consortium and the Association of American Medical Colleges, best-practice information for business infrastructure is lacking. To obtain a sampling of current practices, we conducted a survey of departments of surgery. METHODS: An anonymous 30-question survey addressing demographics, productivity, revenue and expense profile, payor mix, physician extender and staff personnel, billing and collections methodology, and financial performance was distributed among members of the Society of Surgical Chairs via SurveyMonkey. This was approved by the Loyola Institutional Research Board. Multivariate linear regression analyses and t tests/rank-sum tests were performed, as appropriate. Data are presented as mean +/- SEM. RESULTS: A total of 25 (19%) departments responded; 14 were integrated with the hospital/health system, and 11 were integrated with the medical school. In 60% (n = 15), the main hospital had 500 to 1,000 beds; 48% (n = 12) had >4 hospitals in their system. For FY10, MD clinical full-time equivalents (FTEs) were 49 +/- 10; total work relative value units (wRVUs) were 320 +/- 8 k; and total billed cases were 43 +/- 16 k. A total of 23 of 25 used physician-extenders with an average of 18 +/- 5 per department and in 22 of 23, the physician extenders billed. On average, there were 18 +/- 6 clinical-support staff, 25 +/- 11 front-office staff, and 13 +/- 3 back-office support staff FTEs. Among these FTEs, there were 16 +/- 5 devoted to business operations (billing, coding, denial/claims management, financial oversight). Collections/wRVUs were $60 +/- 3 (range, 39-80). Regression modeling demonstrated that total wRVUs were determined by the number of MD FTEs (P = .01), number of physician extenders (P = .01), number of front-office staff (P = .01), number of back-office staff (P = .02), and number of total business staff (P = .01). Collections/wRVUs were predicted by number of hospitals (P = .04), number of MD FTEs (P = .03), number of physician extenders (P = .01), and number of cases/total business staff (P = .02). Interestingly, wRVUs/MD was predicted by number of MD FTEs (P = .01) but were not greatly impacted by numbers of clinical or business support staff. In 4 of 25, the billing and coding staff were incentivized and had a Collections/wRVU = 64 +/- 5 whereas nonincentivized staff had collections/wRVU = 59 +/- 3. (P = NS) Also, %Accounts receivable >90 days (15% vs 25%) were not substantially different. Only 48% (12/25) have departments have recouped Centers for Medicare and Medicaid dollars for Physician Quality Reporting Initiative, Meaningful Use, Patient-Centered Medical Homes, or other Accountable Care-like programs. One-half (13) of the departments had both an inpatient and outpatient electronic medical record. Finally, on a scale of 1-10 (10 = highest), the average level of satisfaction with billing and collections processes was 6. CONCLUSION: Our results indicate that the physician extender, clinical support staff, and business staff environment can impact surgeon productivity, and there is opportunity for improvement. Determining best practices for ratios of support staff/MD and optimizing the role of electronic medical record in workflow and billing/collections are critical in the current environment. Our pilot study requires extension across more institutions for validation. PMID- 23021139 TI - Haploinsufficiency of retinaldehyde dehydrogenase 2 decreases the severity and incidence of duodenal atresia in the fibroblast growth factor receptor 2IIIb-/- mouse model. AB - BACKGROUND: Homozygous null mutation of the fibroblast growth factor receptor 2IIIb (Fgfr2IIIb) gene in mice results in 42% of embryos developing duodenal atresias. Retinaldehyde dehydrogenase 2 (Raldh2, a gene critical for the generation of retinoic acid) is expressed in the mouse duodenum during the temporal window when duodenal atresias form. Raldh2 is critical for the normal development of the pancreatoduodenal region; therefore, we were interested in the effect of a Raldh2 mutation on duodenal atresia formation. To test this, we rendered Fgfr2IIIb(-/-) embryos haploinsufficient for the Raldh2 and examined these embryos for the incidence and severity of duodenal atresia. METHODS: Control embryos, Fgfr2IIIb(-/-) mutants, and Fgfr2IIIb(-/-); Raldh2(+/-) mutants were harvested at embryonic day 18.5, genotyped, and fixed overnight. Intestinal tracts were isolated. The type and severity of duodenal atresia was documented. RESULTS: A total of 97 Fgfr2IIIb(-/-) embryos were studied; 44 had duodenal atresias, and 41 of these presented as type III. In the 70 Fgfr2IIIb(-/-); Raldh2(+/-) embryos studied, a lesser incidence of duodenal atresia was seen (15 of 70; P = .0017; Fisher exact test). Atresia severity was also decreased; there were 12 embryos with type I atresias, 3 with type II atresias, and 0 with type III atresias (P < 2.81E-013; Fisher exact test). CONCLUSION: Haploinsufficiency of Raldh2 decreases the incidence and severity of duodenal atresia in the Fgfr2IIIb(-/-) model. The ability to alter defect severity through manipulation of a single gene in a specific genetic background has potentially important implications for understanding the mechanisms by which intestinal atresias arise. PMID- 23021141 TI - Science from a black box. PMID- 23021142 TI - The myth of hypoallergenic dogs (and cats). PMID- 23021143 TI - Influenza enhances caspase-1 in bronchial epithelial cells from asthmatic volunteers and is associated with pathogenesis. AB - BACKGROUND: The leading cause of asthma exacerbation is respiratory viral infection. Innate antiviral defense pathways are altered in the asthmatic epithelium, yet involvement of inflammasome signaling in virus-induced asthma exacerbation is not known. OBJECTIVE: This study compared influenza-induced activation of inflammasome and innate immune signaling in human bronchial epithelial cells from volunteers with and without asthma and investigated the role of caspase-1 in epithelial cell antiviral defense. METHODS: Differentiated primary human bronchial epithelial cells from volunteers with and without asthma were infected with influenza A virus. An inflammasome-specific quantitative real time polymerase chain reaction array was used to compare baseline and influenza induced gene expression profiles. Cytokine secretion, innate immune gene expression, and viral replication were compared between human bronchial epithelial cells from volunteers with and without asthma. Immunofluorescence microscopy was used to evaluate caspase-1 and PYCARD colocalization. Tracheal epithelial cells from caspase-1-deficient or wild-type mice were infected with influenza and assessed for antiviral gene expression and viral replication. RESULTS: Human bronchial epithelial cells from asthmatic volunteers had altered influenza-induced expression of inflammasome-related and innate immune signaling components, which correlated with enhanced production of IL-1beta, IL-6, and TNF alpha. Specifically, influenza-induced caspase-1 expression was enhanced and localization differed in human bronchial epithelial cells from asthmatic volunteers compared to volunteers without asthma. Influenza-infected tracheal epithelial cells from caspase-1-deficient mice had reduced expression of antiviral genes and viral replication. CONCLUSION: Caspase-1 plays an important role in the airway epithelial cell response to influenza infection, which is enhanced in asthmatic volunteers, and may contribute to the enhanced influenza related pathogenesis observed in vivo. PMID- 23021146 TI - Reply: Selection of contrast media in patients with delayed reactions should be based on challenge test results. PMID- 23021144 TI - Topical inhaled ciclesonide for treatment of eosinophilic esophagitis. PMID- 23021147 TI - Evaluation and management of a patient with chronic pruritus. PMID- 23021148 TI - Patients' interactions in an intensive care unit and their memories of intensive care: a mixed method study. AB - AIM: The aim of this study was to describe the interaction between intensive care patients and the intensive care unit (ICU) environment from the perspective of the hospital bed and patients' memories of the ICU. METHODS: Four adult patients in an intensive care unit were each recorded on DVD over a 24 hour period. The patients were also interviewed three months and six months after discharge from hospital. The data generated regarding their interactions with the ICU environment were then analysed using qualitative and quantitative content analysis. RESULTS: The ICU patient has short, direct and indirect contacts during treatment. In addition, the patient reacts to events in the ICU environment that do not include contact. Patients' memories were divided into two main categories: internal and external. Internal memories included physical and mental memories, which were experienced as surreal, unpleasant feelings or physical symptoms such as pain or the experience of being cold or thirsty. External experiences included events that the patient experienced through participation or observation, for example during nursing routines, or through hearing or observing other people, communication and the surroundings. CONCLUSION: The patient's day in ICU is occupied with episodes of brief contact with nursing staff in an environment that the patient experiences as confusing or incomprehensible. The day and night rhythm is disturbed while the patient's opportunities for rest or concentration are limited. Most interactions affect the patient and it is important for staff to be aware of the impact of potentially unsettling events. PMID- 23021149 TI - DNA fragmentation, transgene expression and embryo development after intracytoplasmic injection of DNA-liposome complexes in IVF bovine zygotes. AB - Summary This study was designed to evaluate the quality and viability of bovine embryos produced by in vitro fertilization (IVF), after intracytoplasmic injection of pCX-EGFP-liposome complexes or pBCKIP2.8-liposome complexes (plasmids that codify the human insulin gene). Cleavage, blastocysts and expanded blastocysts rates of these both groups were not different from that of controls (IVF or IVF embryos injected with liposomes alone; IVF-L). The percentage of EGFP positive (EGFP+) blastocysts was 41.8%. In Experiment 2, the blastocysts obtained after injection of pCX-EGFP-liposome complexes that did or did not express the transgene, were analyzed by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labelling) assay at days 6, 7 and 8 of culture in vitro(Bd6, Bd7 and Bd8), in order to evaluate DNA fragmentation. The EGFP+ blastocysts showed different proportions of TUNEL-positive cells (T+) at Bd6, Bd7 and Bd8 (91, 73.7 and 99.5%, respectively) while blastocysts without EGFP expression (EGFP-) showed statistically lower numbers of fragmented nuclei (0, 44.6 and 85%, respectively; P < 0.05). There was no evidence of DNA fragmentation in either Bd6 or Bd7 IVF and IVF-L control blastocysts, but T+ nuclei were detected at Bd8 in both groups (66.4 and 85.8% respectively). Finally, IVF blastocysts (n = 21) injected with insulin-liposome complexes, cultured for 6, 7 and 8 days, were transferred to recipient cows. Pregnancy rates of 18.2% (2/11) and 40% (2/5) resulted from the transfer of Bd6 and Bd7 cells, respectively. Two pregnancies developed to term but they were not transgenic for the insulin gene. In conclusion, EGFP expression affects DNA integrity but not embryo development. Moreover, additional transfers are required in order to overcome the drawbacks generated by in vitro culture length and transgene expression. PMID- 23021151 TI - Phenotypic characterisation of the monocyte subpopulations in healthy adult pigs and Salmonella-infected piglets by seven-colour flow cytometry. AB - The present study describes the distinct bone marrow (BM) and peripheral blood (PB) monocyte subpopulations detected by seven-colour flow cytometry. Mononuclear phagocytes were identified as viable CD172a(+) SWC8(-) CD203a(-) mononuclear leukocytes. After that, monocyte subpopulations were differentiated by using CD14, CD163 and SLA-DR markers. Four distinct monocyte subpopulations were found in the BM and PB. Based on the discovered populations two possible maturation pathways have been proposed. The first pathway was characterised by release of CD14(hi) CD163(-) SLA-DR(-) BM monocytes into the PB where they matured into CD14(low) CD163(+) SLA-DR(+) monocytes. In the alternative pathway the monocytes finalised their phenotypical maturation in the BM and then they were released into the PB as CD14(low) CD163(+) SLA-DR(+) cells. In Salmonella-infected piglets, the population of CD14(low) CD163(+) SLA-DR(+) monocytes was elevated in the BM and mesenteric lymph nodes (MLN), suggesting the role of this population in pathogenesis of Salmonella infection in pigs. PMID- 23021150 TI - Peripheral nerve injury produces a sustained shift in the balance between glutamate release and uptake in the dorsal horn of the spinal cord. AB - Peripheral nerve injury provokes heightened excitability of primary sensory afferents including nociceptors, and elicits ectopic activity in lesioned and neighboring intact nerve fibers. The major transmitter released by sensory afferents in the superficial dorsal horn of the spinal cord is glutamate. Glutamate is critically involved in nociceptive signaling and the development of neuropathic pain. We recorded miniature excitatory postsynaptic currents (mEPSCs) from neurons in lamina II of the rat dorsal horn to assess spontaneous synaptic activity after spared nerve injury (SNI), a model of chronic neuropathic pain. Following SNI, the frequency of mEPSCs doubled, indicating heightened glutamate release from primary afferents or spinal interneurons. Consistent with this finding, glutamate concentrations in the cerebrospinal fluid were elevated at 1 and 4 weeks after SNI. Transmitter uptake was insufficient to prevent the rise in extracellular glutamate as the expression of glutamate transporters remained unchanged or decreased. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride, an antagonist of metabotropic glutamate receptor 5 (mGluR5), reduced the frequency of mEPSCs to its preinjury level, suggesting a positive feedback mechanism that involves facilitation of transmitter release by mGluR5 activation in the presence of high extracellular glutamate. Treatment with the beta-lactam antibiotic ceftriaxone increased the expression of glutamate transporter 1 (Glt1) in the dorsal horn after SNI, raised transmitter uptake, and lowered extracellular glutamate. Improving glutamate clearance prevented the facilitation of transmitter release by mGluR5 and attenuated neuropathic pain-like behavior. Balancing glutamate release and uptake after nerve injury should be an important target in the management of chronic neuropathic pain. PMID- 23021152 TI - Seroprevalence and risk factors of Trypanosoma evansi infection in horses in Peninsular Malaysia. AB - A cross-sectional study was designed to assess the seroprevalence and risk factors associated with Trypanosoma evansi infection among horses, using a total of 527 blood samples obtained from eight states in Peninsular Malaysia. A structured questionnaire was used to collect data on risk factors associated with T. evansi seroprevalence. The overall seroprevalence detected by card agglutination test for T. evansi (CATT/T. evansi) was 13.90% (73/527, CI: 11.2 17.1%). Female and exogenous horses showed a higher risk in association with the disease seroprevalence compared to other groups. The majority of the horse owners were not familiar with surra (85.30%). However, most of them were very cautious with the health of their animals. In conclusion, this study showed that T. evansi occurred in low frequency among horses in Peninsular Malaysia, and the good management system adopted by horse owners was probably responsible for the low T. evansi occurrence. PMID- 23021153 TI - Characterization of the capsid protein VP2 gene of a virulent strain NE/09 of porcine parvovirus isolated in China. AB - A virulent strain NE/09 of porcine parvovirus (PPV) was isolated from mummified swine fetus samples in China and its capsid protein VP2 gene was analyzed. The data showed that the VP2 gene encompassed an open reading frame of 1713 nucleotides with a composition of 684 adenine (39.9%), 387 cytosine (22.6%), 268 guanine (15.7%), and 374 thymine (21.8%). The VP2 gene encoded a 570aa-long protein which could be recognized by anti-PPV-VP2 monoclonal antibody 3C9. Sequence analysis revealed that the VP2 gene of PPV-NE/09 had close sequence similarity with the VP2 gene of other PPV strains. However, a 27 nucleotide region that encodes a glycine-rich domain at the N-terminal region of VP2 was deleted in the PPV-NE/09 strain. The PPV-NE/09 virions were purified by 1.39 g/ml CsCl density centrifugation and subjected to SDS-PAGE analysis. The results showed that only two major polypeptides VP1 and VP2 with molecular weights of 83 and 64kDa, respectively were observed, whereas VP3 with a molecular weight of 60 kDa was not present, in contrast to the PPV-NADL-2 strain. According to the phylogenetic relationship of the VP2 gene of PPV-NE/09, the isolate was a new mutant strain of PPV prevailing in China. PMID- 23021154 TI - Diagnostic and therapeutic impact of SPECT/CT in patients with unspecific pain of the hand and wrist. AB - BACKGROUND: Unspecific pain of the hand/wrist is a diagnostic challenge. Radiographs and planar bone scan are useful diagnostic tools in patients with unspecific wrist pain. Both modalities are deficient, either by not presenting metabolic disorders or due to inadequate anatomical resolution. Single photon emission computed tomography/computed tomography (SPECT/CT) claims to fuse both features. METHODS: Fifty-one patients with persisting wrist pain were referred for evaluation by SPECT/CT. All patients received X-ray and early-phase/late phase SPECT/CT imaging. SPECT/CT results were compared with X-ray alone and X-ray combined with planar bone scan. The therapeutic impact was evaluated in consensus with the referring hand surgeon. RESULTS: A total of 48 lesions were detected on plain radiographs, 117 on planar bone scan, and 142 on SPECT/CT. SPECT/CT detected significantly more lesions than the other imaging modalities. In 30 out of 51 patients (61%), a positive concordance between the clinical diagnosis and SPECT/CT findings was found. In 19 out of 51 patients (37%), SPECT/CT findings had significant impact on consecutive therapy. CONCLUSIONS: SPECT/CT showed higher lesion detection rates compared to standard X-rays and planar bone scan. Significant impact on patient management could be demonstrated. SPECT/CT might be added to the workup of such a specific patient population when standard imaging fails to detect the patient's main pathology. PMID- 23021155 TI - Acute effects of mustard, horseradish, black pepper and ginger on energy expenditure, appetite, ad libitum energy intake and energy balance in human subjects. AB - Chilli peppers have been shown to enhance diet-induced thermogenesis (DIT) and reduce energy intake (EI) in some studies, but there are few data on other pungent spices. The primary aim of the present study was to test the acute effects of black pepper (pepper), ginger, horseradish and mustard in a meal on 4 h postprandial DIT. The secondary aim was to examine the effects on subjective appetite measures, ad libitum EI and energy balance. In a five-way placebo controlled, single-blind, cross-over trial, twenty-two young (age 24.9 (SD 4.6) years), normal-weight (BMI 21.8 (SD 2.1) kg/m2) males were randomly assigned to receive a brunch meal with either pepper (1.3 g), ginger (20 g), horseradish (8.3 g), mustard (21 g) or no spices (placebo). The amounts of spices were chosen from pre-testing to make the meal spicy but palatable. No significant treatment effects were observed on DIT, but mustard produced DIT, which tended to be larger than that of placebo (14 %, 59 (SE 3) v. 52 (SE 2) kJ/h, respectively, P=0.08). No other spice induced thermogenic effects approaching statistical significance. Subjective measures of appetite (P>0.85), ad libitum EI (P=0.63) and energy balance (P=0.67) also did not differ between the treatments. Finally, horseradish decreased heart rate (P=0.048) and increased diastolic blood pressure (P= 0.049) compared with placebo. In conclusion, no reliable treatment effects on appetite, EI or energy balance were observed, although mustard tended to be thermogenic at this dose. Further studies should explore the possible strength and mechanisms of the potential thermogenic effect of mustard actives, and potential enhancement by, for example, combinations with other food components. PMID- 23021156 TI - Personal preferences and discordant prostate cancer treatment choice in an intervention trial of men newly diagnosed with localized prostate cancer. AB - BACKGROUND: Men diagnosed with localized prostate cancer (LPC) can choose from multiple treatment regimens and are faced with a decision in which medical factors and personal preferences are important. The Personal Patient Profile Prostate (P3P) is a computerized decision aid for men with LPC that focuses on personal preferences. We determined whether the P3P intervention improved the concordance of treatment choice with self-reported influential side-effects compared with a control group. METHODS: English/Spanish-speaking men diagnosed with LPC (2007-2009) from four US cities were enrolled into a randomized trial and followed through 6-months via mailed or online questionnaire. Men were randomized to receive the P3P intervention or standard education plus links to reputable websites. We classified choice as concordant if men were concerned with (a) sexual function and chose external beam radiotherapy or brachytherapy, (b) bowel function and chose prostatectomy, (c) sex, bowel, and/or bladder function and chose active surveillance, or (d) not concerned with any side effect and chose any treatment. Using logistic regression, we calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between the P3P intervention and concordance. RESULTS: Of 448 men, most were <65 years, non Hispanic white, had multiple physician consultations prior to enrollment, and chose a treatment discordant with concerns about potential side effects. There was no significant difference in concordance between the intervention (45%) and control (50%) group (OR = 0.82; 95%CI = 0.56, 1.2). CONCLUSIONS: The P3P intervention did not improve concordance between potential side effects and treatment choice. Information and/or physician consultation immediately after diagnosis was likely to influence decisions despite concerns about side effects. The intervention may be more effective before the first treatment options consultation. TRIAL REGISTRATION: NCT00692653 http://clinicaltrials.gov/ct2/show/NCT00692653. PMID- 23021157 TI - Prevalence of calcium pyrophosphate and monosodium urate crystals in synovial fluid of patients with previously diagnosed joint diseases. AB - OBJECTIVE: The main aim of this study was to investigate the frequency of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in synovial fluid (SF) obtained from patients with previously diagnosed joint diseases. METHODS: We reviewed the results of SF analysis of 5020 samples identifying those collected from patients with a previously definite diagnosis (2370 samples). SF analysis results, age, sex, diagnosis and disease duration were recorded from computerized records of patients' archives. RESULTS: The prevalence of CPP crystals in SF was 22.28% in osteoarthritis (OA), 8.28% in rheumatoid arthritis (RA), 3.82% in psoriatic arthritis (PsA), 2.79% in other spondyloarthropathies (SpA), 10% in septic arthritis (SeA), 0.66% in gout and 9.18% in the miscellanea of joint diseases, respectively. The prevalence of MSU crystals in SF was 0.30% in RA, 3.34% in PsA, 0.70% in other SpA, 0.80% in acute CPP crystal arthritis (CPP-CA), 0% in OA, reactive arthritis (ReA), SeA, juvenile idiopathic arthritis (JIA) and miscellanea. In OA group, we observed that age and SF inflammatory indices were higher in SF positive to CPP crystals with respect to those without crystals (P<0.0001). In RA, we found that the group of patients with CPP crystals was significantly older (P=0.001) and had a SF less inflammatory (P=0.022) with respect to that without crystals but with a higher disease duration than those without crystals. CONCLUSION: Crystals can be detected more frequently than expected in SF from joint diseases with a previous established diagnosis. This highlights the importance of SF analysis for the diagnosis of possible comorbidities linked to the presence of crystals. PMID- 23021158 TI - Efficacy of anti-TNF in patients with spondyloarthritis in absence of any imaging sign. AB - OBJECTIVE: Some clinical pictures satisfy spondyloarthritis criteria without any detected imaging signs and the question sometimes arises in clinical daily practice if biologics should be started. Our aim was to evaluate anti-TNF efficacy in patients with clinical but not imaging (radiographic, CT-scan, MRI) signs of spondyloarthritis. METHODS: This retrospective study concerned patients with axial spondyloarthritis fulfilling European Spondyloarthritis Study Group (ESSG) criteria, treated with anti-TNF after failure of conventional therapies. Therapeutic responses, rated according to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)-50% or 20 mm and ASAS-20 or -40 definitions, were evaluated after 12 months. Factors associated with those responses were also sought. Propensity score was used to check thereafter whether there were interactions with some baseline variables. RESULTS: Among 385 patients included, 257 with imaging signs had significantly more frequent therapeutic responses (P=0.0005). About 40% of the spondyloarthritis patients without imaging signs responded to anti-TNF. The response rate was significantly higher in HLA-B27 carriers with initial imaging signs (P=0.028). Furthermore, responders were younger at biotherapy onset, with lower Bath Ankylosing Spondylitis Functional Index (BASFI) and pain visual analog scale score, and higher C-reactive protein (CRP), compared to non-responders. After weighted calculation, the prediction of response to TNF-blockers was quite similar in both groups. CONCLUSION: The percentage of patients with exclusively clinical signs who responded to anti-TNF was far from negligible. Regardless the HLA-B27 status, having imaging signs of spondyloarthritis does not provide a superiority of response to anti-TNF compared to the absence of imaging sign. The absence of any imaging sign in patients with spondyloarthritis should therefore not lead to the exclusion of anti-TNF therapy. PMID- 23021159 TI - Effect of vitamin D3 treatment on bone density in neurofibromatosis 1 patients: a retrospective clinical study. AB - OBJECTIVES: We have previously demonstrated reduced bone density and an increased incidence of 25-hydroxy vitamin D3 (25-OH D3) deficiency in adults with neurofibromatosis 1 (NF1) compared to healthy controls. Vitamin D3 is a cheap, safe, and effective supplement in the general population, but its value in NF1 patients has not been demonstrated. This study investigates the therapeutic potential of oral vitamin D3 on bone mineral density (BMD) in NF1 patients with vitamin D3 deficiency. METHODS: We measured serum 25-OH D3, parathyroid hormone, calcium, and bone alkaline phosphatase concentrations, urinary deoxypyridinoline concentrations, and BMD in 35 adults with NF1. Nineteen patients received vitamin D3 supplementation for 2 years, six patients received supplementation for 1 year and 10 patients received no supplementation. Supplementation was administered in a dose that maintained the serum 25-OH D3 level above 30 MUg/l. BMD was measured again at 1 and 2 years, and biochemical assessments of bone metabolism were measured at least every half year during therapy. RESULTS: Treated subjects had significantly reduced loss of BMD, as measured by T score at the hip (p=0.011) and lumbar spine (p=0.022). The effect on hip BMD was apparent at 1 year in comparison to baseline (p=0.02) and was greater at 2 years in comparison to measurements at 1 year (p=0.02). CONCLUSIONS: Vitamin D3 supplementation improves BMD in adult NF1 patients. Further studies are needed to elucidate the mechanisms responsible for reduced BMD in NF1 patients. PMID- 23021160 TI - Feasibility and safety of EUS-guided cryothermal ablation in patients with locally advanced pancreatic cancer. AB - BACKGROUND: New therapies are needed for pancreatic cancer. OBJECTIVE: To determine the feasibility and safety of a new endoscopic treatment. Secondary endpoints were to determine effects on tumor growth measured with CT scan and to find the overall survival. DESIGN: A cohort study of patients with local progression of advanced pancreatic adenocarcinoma after neoadjuvant therapy. The cryotherm probe (CTP), a flexible bipolar device that combines radiofrequency with cryogenic cooling, was used under EUS guidance. SETTING: San Raffaele Hospital, Milan, Italy; University Medical Center, Hamburg-Eppendorf, Germany. PATIENTS: A total of 22 patients (male/female 11/11; mean age 61.9 years) were enrolled from September 2009 to May 2011. INTERVENTION: Radiofrequency heating: 18 W; pressure for cooling: 650 psi (Pounds per Square Inch); application time: depending on tumor size. MAIN OUTCOME MEASUREMENTS: Feasibility was evaluated during the procedure. A clinical and radiologic follow-up was planned. RESULTS: The CTP was successfully applied in 16 patients (72.8%); in 6 it was not possible because of stiffness of the GI wall and of the tumor. Amylase arose in 3 of 16 patients; none had clinical signs of pancreatitis. Late complications arose in 4 cases: 3 were mostly related to tumor progression. Median postablation survival time was 6 months. A CT scan was performed in all patients, but only in 6 of 16 was it possible to clearly define the tumor margins after ablation. In these patients, the tumor appeared smaller compared with the initial mass (P = .07). LIMITATIONS: Small sample of patients, difficulty of objectifying the size of the ablated zone by CT scan. CONCLUSION: EUS-guided CTP ablation is feasible and safe. Further investigations are needed to demonstrate progression-free survival and local control. PMID- 23021161 TI - EUS-guided transmural drainage of postoperative collections. PMID- 23021162 TI - Location in the ascending colon is a predictor of refractory colonic diverticular hemorrhage after endoscopic clipping. AB - BACKGROUND: Predictors of refractory colonic diverticular hemorrhage after endoscopic clipping (EC) remain unclear. OBJECTIVE: To elucidate the predictors of uncontrolled bleeding after EC. DESIGN: Retrospective study. SETTING: Two tertiary referral centers. PATIENTS: Eighty-nine patients with colonic diverticular hemorrhage who underwent EC as a first-line treatment were included. INTERVENTIONS: If bleeding remained uncontrolled after 1 or 2 EC sessions, other interventions (transcatheter arterial embolization, endoscopic band ligation, or surgery) were performed. Patients were divided into EC-controlled and EC uncontrolled groups; the characteristics of each group were compared. MAIN OUTCOME MEASUREMENTS: Comorbidities, location of bleeding diverticula, and EC technique (direct vs indirect placement). RESULTS: Initial treatment with EC was successful in 87 patients. Early rebleeding (primary failure) occurred in 30 of 87 patients (34%). Secondary failure occurred in 6 of 22 patients treated with reclipping (27%). Cumulatively, 78 patients were successfully managed with EC. Non-EC treatments were required in 11 patients. Location in the right side of the colon, particularly in the ascending colon, was significantly more common in the EC-uncontrolled group than in the EC-controlled group (P = .017 and P = .0029, respectively). Although the difference was not significant, bleeding was successfully managed in all 13 patients treated with direct placement. Bleeding remained uncontrolled after EC in 11 of 52 ascending cases (21%) treated with indirect placement. Diverticular hemorrhage in other locations was managed regardless of EC technique. LIMITATIONS: Retrospective study. CONCLUSIONS: Location in the ascending colon is a significant predictor of refractory colonic diverticular hemorrhage after EC. Indirect placement of hemoclips in ascending lesions is ineffective. PMID- 23021163 TI - Endoscopic balloon dilation to facilitate treatment of intraductal extension of ampullary adenomas (with video). PMID- 23021164 TI - Bloc biopsy by using submucosal endoscopy with a mucosal flap method for gastric subepithelial tumor tissue sampling (with video). PMID- 23021165 TI - Gastric mucosal longitudinal tears after drowning. PMID- 23021166 TI - Subjective and objective data on esophageal manometry and impedance pH monitoring 1 year after endoscopic full-thickness plication for the treatment of GERD by using multiple plication implants. AB - BACKGROUND: Subjective and especially objective data after endoluminal full thickness gastroplication are scarce. OBJECTIVE: To evaluate symptoms and reflux activity 12 months after gastroplication by using multichannel intraluminal impedance monitoring. DESIGN: Open-label, prospective, single-center study. SETTING: Tertiary referral hospital in Zell am See, Austria. PATIENTS: Subjects without hiatal hernias with documented GERD and persistent or recurrent symptoms despite treatment with a proton pump inhibitor. INTERVENTIONS: A total of 36 patients underwent endoscopic full-thickness gastroplication with 1 or more Plicator implants. MAIN OUTCOME MEASUREMENTS: Mean Gastrointestinal Quality of Life Index and reflux-specific symptom scores significantly improved on follow-up (P < .01). Atypical reflux, gas/bloating, and bowel dysfunction-specific symptom scores as well as belching and dysphagia scores improved. Twenty-two patients returned for esophageal manometry and multichannel intraluminal impedance testing 1 year after surgery. DeMeester scores decreased from 20 to 10 (P < .029). The median numbers of total, acid, proximal, upright, and recumbent reflux episodes were all significantly reduced (P < .05). Manometric data were virtually unchanged. The percentage of patients taking proton pump inhibitors on daily basis after the procedure was 11.5%. There was only 1 postprocedure incident (bleeding) that required intervention. Three of 36 patients (8.3%) were considered treatment failures because of persistent symptoms and were assigned to undergo laparoscopic fundoplication. LIMITATIONS: No randomized comparison with a sham procedure or laparoscopic fundoplication; follow-up interval. CONCLUSIONS: Endoscopic plication is safe and improves objective and subjective parameters at 1-year follow-up, without side effects seen after laparoscopic fundoplication. Further studies on the clinical merit of this procedure in specific patient populations are warranted. PMID- 23021167 TI - Initial experience with EUS-guided cholangiopancreatography for biliary and pancreatic duct drainage: a Spanish national survey. AB - BACKGROUND: EUS-guided cholangiopancreatography (ESCP) allows transmural access to biliopancreatic ducts when ERCP fails. Data regarding technical details, safety, and outcomes of ESCP are still unknown. OBJECTIVE: To evaluate outcomes of ESCP in community and referral centers at the initial development phase of this procedure, to identify the ESCP stages with higher risk of failure, and to evaluate the influence on outcomes of factors related to the endoscopist. DESIGN: Multicenter retrospective study. SETTING: Public health system hospitals with experience in ESCP in Spain. PATIENTS: A total of 125 patients underwent ESCP in 19 hospitals, with an experience of <20 procedures. INTERVENTION: ESCP. MAIN OUTCOME MEASUREMENTS: Technical success and complication rates in the initial phase of implantation of ESCP are described. The influence of technical characteristics and endoscopist features on outcomes was analyzed. RESULTS: A total of 125 patients from 19 hospitals were included. Biliary ESCP was performed in 106 patients and pancreatic ESCP was performed in 19. Technical success was achieved in 84 patients (67.2%) followed by clinical success in 79 (63.2%). Complications occurred in 29 patients (23.2%). Unsuccessful manipulation of the guidewire was responsible for 68.2% of technical failures, and 58.6% of complications were related to problems with the transmural fistula. LIMITATIONS: Retrospective study. CONCLUSION: Outcomes of ESCP during its implantation stage reached a technical success rate of 67.2%, with a complication rate of 23.2%. Intraductal manipulation of the guidewire seems to be the most difficult stage of the procedure. PMID- 23021168 TI - Warm water infusion during sedated colonoscopy does not decrease amount of sedation medication used. AB - BACKGROUND: Water infusion versus air insufflation during colonoscope insertion has been suggested to reduce patient discomfort and decrease sedation medication requirements. Warm water is thought to further facilitate colonoscopy perhaps by decreasing colon spasm. OBJECTIVE: To compare the utility of warm (35 degrees -38 degrees C) versus cool (20 degrees -23 degrees C) water infused during colonoscopic insertion by measuring patient sedation medication use and discomfort scores between the warm and cool water groups. DESIGN: Randomized, controlled, double-blinded study. SETTING: Outpatient endoscopy unit at an academic medical center. PATIENTS: A total of 175 adults. INTERVENTION: Elective outpatient sedated screening colonoscopies. MAIN OUTCOME MEASUREMENTS: Sedation medication used, pain scores, cecal intubation rate, endoscopy times, satisfaction scores, and patient willingness to repeat procedures. RESULTS: There was no significant difference in sedation medication requirement during colonoscopy with the use of warm or cool water (fentanyl 83.6 +/- 29.0 MUg vs 87.6 +/- 39.6 MUg; P = .45; midazolam 3.3 +/- 1.2 mg vs 3.3 +/- 1.3 mg; P = .91). There was no significant difference in patient pain scores or satisfaction scores. Cecal intubation rates (100%) were similar. There was no significant difference in cecal intubation times (6 minutes 40 seconds +/- 4 minutes 9 seconds vs 7 minutes 49 seconds +/- 4 minutes 0 seconds; P = .06) between the warm and cool water groups. All patients were willing to repeat the colonoscopy by using the same method in both groups. LIMITATIONS: Limited generalizability to patients undergoing screening sedated colonoscopies with good to excellent bowel preparation. CONCLUSION: Water does not need to be warmed before infusion in patients undergoing sedated colonoscopies. PMID- 23021169 TI - Cap-assisted EMR of large, sporadic, nonampullary duodenal polyps. AB - BACKGROUND: EMR is an effective alternative to surgery for the removal of nonampullary duodenal polyps (NADPs). Cap-assisted EMR (EMR-C) has been rarely performed in the duodenum because of the risk of perforation. OBJECTIVE: To evaluate the safety and effectiveness of EMR-C for the removal of large (>= 15 mm) NADPs. DESIGN: Retrospective study. SETTING: Tertiary-care referral center. PATIENTS: Between 2000 and 2010, 26 consecutive patients with sporadic NADPs underwent EMR-C. INTERVENTION: EMR with the cap technique. MAIN OUTCOME MEASUREMENTS: Complete eradication of polyps, complications, and recurrence. RESULTS: A total of 14 sessile polyps (53.8%), 7 lateral spreading type nongranular tumors (26.9%), and 5 lateral spreading type granular tumors (19.2%) were treated. The median size of lesions was 15 mm. Five lesions involved one half of the luminal circumference. Post-EMR histologic assessment showed low grade dysplasia in 5 patients (19.2%) and high-grade dysplasia in 18 patients (69.2%). Three patients (11.5%) had well-differentiated endocrine tumors. Complete eradication was obtained in 25 of 26 (96%) patients. No perforations occurred. Three cases of intraprocedural bleeding were managed endoscopically. Median follow-up was 6 years (range 1-10 years). Residual adenomatous tissue was observed in 3 patients in lesions of 50 mm. In one of these cases, an adenocarcinoma occurred after 8 months, which was managed surgically. LIMITATIONS: Retrospective design, single center. CONCLUSION: This study supports the efficacy and safety of EMR-C for removing NADPs. Regular follow-up is mandatory because of the high risk of residual or recurrent adenomatous tissue and even cancer. PMID- 23021170 TI - Commentary on core competencies in fellowship training. PMID- 23021171 TI - Use of bioabsorbable nerve conduits as an adjunct to brachial plexus neurorrhaphy. AB - PURPOSE: The use of bioabsorbable conduits in digital nerve repair has demonstrated increased efficacy compared to direct repair (for gaps <= 4mm) and nerve grafting (for gaps >= 8 mm) for sensory recovery in a level 1 human trial. Although nonhuman primate studies on mixed motor-sensory nerves have documented comparable efficacy of the bioabsorbable nerve conduits when compared to nerve repair or grafting, there is minimal human clinical data on motor recovery following bioabsorbable nerve conduit repair. This study investigates the outcomes of bioabsorbable nerve conduits in pure motor nerve reconstruction for adult traumatic brachial plexus injuries. METHODS: Over a 3-year period, 21 adult patients had 1 or more nerve-to-nerve transfers for traumatic brachial plexus palsy performed using the operative microscope. Ten nerve transfers were performed by advancing the nerve ends into a semi-permeable type I collagen conduit stabilized with 8-0 nylon sutures (conduit-assisted neurorrhaphy). Twenty eight concurrent nerve transfers were performed using standard end-to-end neurorrhaphy and 8-0 or 9-0 nylon sutures. Clinical evaluation using the Medical Research Council grading system (MRC) was performed at 1 and 2 years postoperatively. Postoperative electromyographic studies were performed in 28 of 38 transfers at final follow-up. RESULTS: Thirty transfers (17 patients) were available for 2-year follow-up evaluation. All 10 transfers performed with nerve conduits demonstrated clinical recovery and electromyographic reinnervation at 2 years. Eighteen of 20 transfers performed without conduits demonstrated clinical recovery. CONCLUSIONS: Although no statistical difference in functional recovery was seen in nerve transfers performed with collagen nerve conduits or by traditional neurorrhaphy, this pilot series demonstrated clinical and electromyographic recovery in 10 of 10 motor nerve repairs performed using conduits. These findings warrant continued investigation into the efficacy of conduit-assisted repair for motor nerves, especially in regards to operative time, precision of repair, and speed of nerve recovery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23021172 TI - Transfer of median and ulnar nerve fascicles for lesions of the posterior cord in infraclavicular brachial plexus injury: report of 2 cases. AB - In infraclavicular lesions of brachial plexus, severe lesions of the posterior cord often occur when medial and lateral cord function is preserved to a greater or lesser extent. In these cases, shoulder function may be preserved by activity of the muscles innervated by the suprascapular nerve, but complete paralysis exists in the deltoid, triceps, and brachioradialis, and all wrist and finger extensors. Classical reconstruction procedures consist of nerve grafts, but their results in adults are disappointing. We report an approach transferring: (1) an ulnar nerve fascicle to the motor branch of the long portion of the triceps brachii muscle, (2) a median nerve branch from the pronator teres to the motor branch of the extensor carpi radialis longus, and (3) a median nerve branch from the flexor carpi radialis to the posterior interosseous nerve. We describe the procedure and report 2 clinical cases showing the effectiveness of this technique for restoring extension of the elbow, wrist, and fingers in the common infraclavicular lesions of the brachial plexus affecting the posterior cord. PMID- 23021173 TI - Treatment of carpal tunnel syndrome by members of the American Society for Surgery of the Hand: a 25-year perspective. AB - PURPOSE: In 1987, Duncan et al.(1) reported on a survey of the members of the American Society for the Surgery of the Hand (ASSH) about their practices in treating carpal tunnel syndrome (CTS). To better understand changes in the treatment of CTS over the past 25 years, we repeated the survey while incorporating present-day controversies. METHODS: With the approval of the ASSH, an Internet-based survey was e-mailed to all members of the Society. This included 33 primary questions focusing on 4 areas of study: surgeon demographic information, nonoperative treatment, surgical technique, and postoperative care. A total of 1,463 surveys were delivered and 707 surveys were completed and returned, for a response rate of 48%. Responses were compared with the responses from Duncan et al. published 25 years ago.(1) RESULTS: In contrast to the practice patterns identified 25 years ago, this survey identified several changes in current clinical practices including the following statistically significant findings: Preoperatively, surgeons have increased the use of splints and corticosteroid injections, treat nonoperatively longer, and have narrowed their surgical indications. Regarding surgical technique, surgeons now are using tourniquets less, infiltrate the carpal tunnel with corticosteroids less, and place deep sutures less often. Furthermore, performing concomitant procedures along with release of the transverse carpal ligament has decreased. Orthotic use and duration postoperatively also decreased. CONCLUSIONS: Although significant differences are evident between management of CTS between 1987 and 2011, no consensus has emerged. PMID- 23021174 TI - Recurrence of radial bowing after soft tissue distraction and subsequent radialization for radial longitudinal deficiency. AB - PURPOSE: Centralization and radialization are the most widely reported surgical treatments for Bayne and Klug Type III and IV radial longitudinal deficiency. Prior soft tissue distraction has been introduced to improve reducibility of the deformity without skeletal resection. Satisfying long-term effects have been reported with centralization but are still unclear with radialization. METHODS: This is a retrospective study of 8 consecutive children with Bayne and Klug Type III or IV radial longitudinal deficiency treated with preliminary soft tissue distraction followed by radialization between 2003 and 2008. All children underwent the same surgical protocol. End points of the study were clinical appearance, the hand-forearm angle, and mean angular correction at last follow up. RESULTS: The mean preoperative hand-forearm angle was 61 degrees (26 degrees -91 degrees ). The average duration of distraction was 1.9 month (1-3 mo). The initial postoperative angle averaged 12 degrees (-14 degrees -40 degrees ). There were 3 postoperative complications: 2 cases of pin loosening and 1 case of fracture of the base of the small finger metacarpal. Mean follow-up duration was 2.6 years (1-4 y). At last follow-up, 7 of the 8 patients had visible recurrence of the deformity, the hand-forearm angle had deteriorated to 44 degrees (20 degrees -69 degrees ), and the mean angular correction was 18 degrees (-43 degrees -59 degrees ). CONCLUSIONS: Preoperative distraction allows a gradual realignment of the hand on the forearm without skeletal resection, but the recurrence rate after radialization is high. Tendon transfers and soft tissue tensioning were unable to maintain hand-forearm alignment following soft tissue distraction. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23021175 TI - Dupuytren diathesis and genetic risk. AB - PURPOSE: Dupuytren disease (DD) is a benign fibrosing disorder of the hand and fingers. Recently, we identified 9 single nucleotide polymorphisms (SNPs) associated with DD in a genome-wide association study. These SNPs can be used to calculate a genetic risk score for DD. The aim of this study was to test whether certain clinical characteristics (including the DD diathesis features) of patients with DD are associated with a high genetic risk score. METHODS: Between 2007 and 2010, we prospectively invited all DD patients (1,120 in total) to participate. Clinical characteristics were noted using patient- and doctor completed questionnaires, and blood was obtained for DNA analysis. We analyzed a total of 933 subjects with genetic and clinical data. The 9 previously identified DD SNPs were used to calculate a weighted genetic risk score. Patients were categorized into high and low genetic risk score groups, according to their weighted genetic risk score. Logistic regression was performed to study the association of clinical characteristics with a high genetic risk score. RESULTS: In a univariate regression model, patients with an age of onset of DD younger than 50 years, a family history positive for DD, knuckle pads, and Ledderhose disease were statistically significantly associated with a high genetic risk score. In an additional analysis using high and low genetic risk groups that deviate further from the median, Ledderhose disease was no longer significantly associated with DD. CONCLUSIONS: Patients with DD who present with these diathesis features, and predominantly patients with knuckle pads, are more likely to carry more risk alleles for the discovered DD SNPs than patients without these diathesis features. CLINICAL RELEVANCE: These markers may prove useful in predicting disease progression or recurrence. PMID- 23021176 TI - Stress shielding around radial head prostheses. AB - PURPOSE: Stress shielding is known to occur around rigidly fixed implants. We hypothesized that stress shielding around radial head prostheses is common but nonprogressive. In this study, we present a classification scheme to support our radiographic observations. METHODS: We reviewed charts and radiographs of 86 cases from 79 patients with radial head implants from both primary and revision surgeries between 1999 and 2009. Exclusion criteria included infection, loosening, or follow-up of less than 12 months. We classified stress shielding as: I, cortical thinning; II, partially (IIa) or circumferentially (IIb) exposed stem; and III, impending mechanical failure. RESULTS: Of 26 well-fixed stems, 17 (63%) demonstrated stress shielding: I = 2, II = 15 (IIa = 12, IIb = 3), and III = 0. We saw stress shielding with all stem types: cemented or noncemented; long or short; and straight, curved, or tapered. The only significant difference was that stems implanted into the radial shaft had less stress shielding than stems implanted into the neck or tuberosity (P = .03). The average follow-up was 33 months (range, 13-70 mo). Stress shielding was detectable by an average of 11 months (range, 1-15 mo). The pattern of bone loss was similar in 16 of 17 cases (94%), starting on the outer periosteal cortex. The 3 cases with circumferential exposure of the stem (stage IIb) averaged 2.6 mm (range, 1-4 mm) of exposed stem. Stress shielding never extended to the bicipital tuberosity, and there were no cases of impending mechanical failure. CONCLUSIONS: Stress shielding around radial head prostheses is common, regardless of stem design. However, it is typically minor, nonprogressive, and of questionable clinical consequence. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23021177 TI - Supercharged end-to-side anterior interosseous to ulnar motor nerve transfer for intrinsic musculature reinnervation. AB - Functional motor recovery after peripheral nerve injury is predominantly determined by the time to motor end plate reinnervation and the absolute number of regenerated motor axons that reach target. Experimental models have shown that axonal regeneration occurs across a supercharged end-to-side (SETS) nerve coaptation. In patients with a recovering proximal ulnar nerve injury, a SETS nerve transfer conceptually is useful to protect and preserve distal motor end plates until the native axons fully regenerate. In addition, for nerve injuries in which incomplete regeneration is anticipated, a SETS nerve transfer may be useful to augment the regenerating nerve with additional axons and to more quickly reinnervate target muscle. We describe our technique for a SETS nerve transfer of the terminal anterior interosseous nerve (AIN) to the pronator quadratus muscle (PQ) end-to-side to the deep motor fascicle of the ulnar nerve in the distal forearm. In addition, we describe our postoperative therapy regimen for these transfers and an evaluation tool for monitoring progressive muscle reinnervation. Although the AIN-to-ulnar motor group SETS nerve transfer was specifically designed for ulnar nerve injuries, we believe that the SETS procedure might have broad clinical utility for second- and third-degree axonotmetic nerve injuries, to augment partial recovery and/or "babysit" motor end plates until the native parent axons regenerate to target. We would consider all donor nerves currently utilized in end-to-end nerve transfers for neurotmetic injuries as candidates for this SETS technique. PMID- 23021178 TI - Scapholunate instability: current concepts in diagnosis and management. AB - Injuries to the scapholunate joint are the most frequent cause of carpal instability and account for a considerable degree of wrist dysfunction, lost time from work, and interference with activities. Although it is insufficient to cause abnormal carpal posture or collapse on static radiographs, an isolated injury to the scapholunate interosseous ligament may be the harbinger of a relentless progression to abnormal joint mechanics, cartilage wear, and degenerative changes. Intervention for scapholunate instability is aimed at arresting the degenerative process by restoring ligament continuity and normalizing carpal kinematics. In this review, we discuss the anatomy, kinematics, and biomechanical properties of the scapholunate articulation and provide a foundation for understanding the spectrum of scapholunate ligament instability. We propose an algorithm for treatment based on the stage of injury and the degree of secondary ligamentous damage and arthritic change. PMID- 23021179 TI - Letter regarding "salvage of complete degloved digits with reversed vascularized pedicled forearm flap: a new technique". PMID- 23021180 TI - Letter regarding "effect of platelet-rich plasma with fibrin matrix on healing of intrasynovial flexor tendons". PMID- 23021181 TI - Palmaris profundus tendon as possible cause for median nerve compression. PMID- 23021182 TI - Optimizing the effect of local anesthetic infiltration after trapeziectomy. PMID- 23021183 TI - Ultrasound and MRI in carpal tunnel syndrome: the dilemma of simplifying the approach to a complex disease or making complex assessments of a simple problem. PMID- 23021185 TI - Letter regarding "microsurgical arterialization of degloving injuries of the upper limb". PMID- 23021188 TI - The effect of suture coated with mesenchymal stem cells and bioactive substrate on tendon repair strength in a rat model: a complementary mechanism. PMID- 23021189 TI - Letter regarding "community-acquired methicillin-resistant Staphylococcus aureus hand infections in the pediatric population". PMID- 23021190 TI - [Subarachnoid hemorrhage induced by cerebral venous thrombosis]. AB - Nontraumatic subarachnoid hemorrhage is a relatively rare disease, typically secondary to a ruptured aneurysm. We report the case of a 23-year-old patient who developed a subarachnoid hemorrhage caused by extensive cerebral venous thrombosis due to a factor V Leiden mutation. Cerebral venous thrombosis is an uncommon etiology of subarachnoid hemorrhage. This raises diagnostic difficulties and a therapeutic dilemma regarding the use of anticoagulants. PMID- 23021191 TI - Qualitative interviewing with vulnerable populations: individuals' experiences of participating in suicide and self-harm based research. AB - BACKGROUND: Concern exists that involving vulnerable individuals as participants in research into suicide and self-harm may cause distress and increase suicidal feelings. Actual understanding of participants' experiences is however limited, especially in relation to in-depth qualitative research. METHODS: Data were collected from four separate studies focused on self-harm or suicide. These included people with varying levels of past distress, including some who had made nearly lethal suicide attempts. Each involved semi-structured qualitative interviewing. Participants (n=63) were asked to complete a visual analogue scale measuring current emotional state before and after their interview and then comment on how they had experienced the interview, reflecting on any score change. RESULTS: Most participants experienced a change in well-being. Between 50% and 70% across studies reported improvement, many describing the cathartic value of talking. A much smaller group in each study (18-27%) reported lowering of mood as they were reminded of difficult times or forced to focus on current issues. However, most anticipated that their distress would be transient and it was outweighed by a desire to contribute to research. An increase in distress did not therefore necessarily indicate a negative experience. LIMITATIONS: There was no follow-up so the long-term effects of participation are unknown. Scores and post interview reflections were collected from participants by the researcher who had conducted the interview, which may have inhibited reporting of negative effects. CONCLUSIONS: These findings suggest individuals are more likely to derive benefit from participation than experience harm. Overprotective gate keeping could prevent some individuals from gaining these benefits. PMID- 23021192 TI - Comparing the Beck Depression Inventory-II (BDI-II) and Patient Health Questionnaire (PHQ-9) depression measures in an integrated mood disorders practice. AB - BACKGROUND: Patient self-assessment instruments are useful in screening, tracking, and documenting the course of depressive symptoms with minimal clinician time. Two popular instruments are the Beck Depression Inventory (BDI II) and the Patient Health Questionnaire (PHQ-9). We compared the performance of these two instruments in a mood disorders setting. METHODS: A retrospective study of 625 patients who completed a PHQ-9 and BDI-II as part of routine clinical care (1) during initial outpatient evaluation between 2008 and 2009, and (2) on admission to an inpatient mood disorders unit between 2006 and 2009. Pearson correlation coefficients for total PHQ-9 and BDI-II scores were calculated for all patients, the outpatients, and the inpatients. RESULTS: Overall r=0.77, indicating strong correlation, more in the outpatients (n=287, r=0.81) than the inpatients (n=338, r=0.67). Mean PHQ-9 and BDI-II scores for the outpatients were 15.1 (SD 7.4) and 27.8 (SD 14.1) corresponding to "moderately severe" and "moderate" categories respectively; for inpatients, 18.9 (SD 5.7) and 33.8 (SD 11.5) corresponding to "moderately severe" and "severe." LIMITATIONS: Retrospective design and no monitoring of which instrument was completed first in case that influenced patient response to the second instrument CONCLUSIONS: PHQ-9 and BDI-II scores, as continuous but not categorical variables, in a mood disorders subspeciality setting are closely correlated and essentially interchangeable. There are practical applications to our findings, as the PHQ-9 is shorter and free. PMID- 23021193 TI - A magnetic resonance imaging study of hippocampal, amygdala and subgenual prefrontal cortex volumes in major depression subtypes: melancholic versus psychotic depression. AB - BACKGROUND: Volumetric studies examining brain structure in depression subtypes are limited and inconclusive. The aim of the current study was to compare the volumes of brain regions previously implicated in depression among patients with melancholic major depressive disorder (MDD), patients with psychotic MDD and normal controls. METHODS: Twenty two patients with melancholic MDD, 17 with psychotic MDD and 18 normal controls were included in the study. Hippocampal (HV), amygdala (AV), anterior (ASCV) and posterior (PSCV) subgenual cortex volumes were measured on magnetic resonance volumetric images. RESULTS: There were no volumetric differences between patients with melancholic and psychotic subgroups. We identified larger AVs and smaller left ASCVs in both patient groups compared to controls with medium to large effect sizes. Regression analysis revealed that AVs were predicted by the presence of depression, late depression onset, insomnia and left hippocampal tail volume in patients, but not in controls. There were no differences in HVs, right ASCVs and PSCVs across the 3 groups. LIMITATIONS: Small sample size, a possible inclusion of paracingulate gyrus in ASCV and PSCV tracings, significant differences in education level and medication status are discussed as limitations. CONCLUSIONS: Diagnostically delineated melancholic and psychotic MDD patients do not differ in medial temporal and cingulate volumes. However, significant volumetric differences were detected between both patient-groups and controls. PMID- 23021194 TI - Complementary and alternative medicines usage in bipolar patients from Argentina and Colombia: associations with satisfaction and adherence to treatment. AB - BACKGROUND: The use of Complementary and Alternative Medicines (CAM) has been reported by around half the patients undergoing medical treatment for chronic conditions. CAM use could be higher in people affected by bipolar disorders (BD). Some questions about CAM use in BD have not been investigated enough. We report here the results of an anonymous survey on CAM-use conducted among BD outpatients of two centers located in Argentina and Colombia. METHODS: an anonymous self survey was administrated to bipolar euthymic outpatients treated at each center. The survey included a self-report measure of adherence to psychiatric treatment and a modified version of CGI to asses satisfaction with the current treatment. RESULTS: 200 patients completed the survey. Although samples differ in socio economic profile, they do not differ in their reported CAM-usage (more than 40%). CAM-usage did not modify the adherence or satisfaction with the psychiatric treatment reported level. Thirty eight percent of those who were still resorting to CAM failed to inform it to their clinician. CAM-usage was rated as "useful" or "very useful" by 52% of patients. LIMITS: adherence to current medical treatment and satisfaction with current treatment were investigated by a self-reported instrument. DISCUSSION: the prevalence of CAM usage found is similar to that of other studies. CAM usage seems to be ubiquitous, which takes to posit that a subgroup of patients may be in need of treatment with greater magical-religious components. Half of these patients were reluctant to disclose CAM use. Clinicians may need to consider coexistence between "traditional" treatments and CAM for these patients. PMID- 23021195 TI - Improved outcomes of incarcerated femoral hernia: a multivariate analysis of predictive factors of bowel ischemia and potential impact on postoperative complications. AB - BACKGROUND: Although much of the literature focuses on risk factors for intestinal resection in groin hernias, little is known specifically for the femoral type. This study identifies clinical and analytic parameters associated with intestinal ischemia in patients with an incarcerated femoral hernia. METHODS: Eighty-six patients with an incarcerated femoral hernia were included in an analytic, longitudinal, observational, retrospective cohort study. Clinical presentation, the duration of symptoms, analytic and radiologic studies, complications, and mortality rates were analyzed. RESULTS: Eight (9.3%) patients underwent intestinal resection. Factors related to intestinal ischemia were oral anticoagulants intake (odds ratio = 9.6) and a duration of symptoms longer than 3 days (odds ratio = 2.1). There was no relationship between leukocytosis (P = .02) or radiographic signs of intestinal obstruction (P = .28) and bowel resection. CONCLUSIONS: Patients with a duration of symptoms longer than 3 days and, interestingly, those having oral anticoagulant therapy appeared to be at a higher risk for developing intestinal ischemia. A remarkable reduction in morbimortality can be achieved through an earlier referral to the hospital, quick preoperative workup, and urgent operation. PMID- 23021196 TI - Colonoscopy is superior to neostigmine in the treatment of Ogilvie's syndrome. AB - BACKGROUND: Colonic pseudo-obstruction in critically ill patients may lead to devastating colonic perforation. Neostigmine is often the first-line intervention, because colonoscopy is more invasive and labor intensive. METHODS: A retrospective 10-year review at a tertiary medical center identified 100 patients with Ogilvie's syndrome, in whom treatment course and clinical and radiographic response were evaluated. RESULTS: Colonoscopy was significantly more successful than neostigmine (defined as no further therapy) after 1 or 2 interventions (75.0% vs 35.5%, P = .0002, and 84.6% vs 55.6%, P = .0031, respectively). One colonoscopy was more effective than 2 neostigmine administrations (75.0% vs 55.6%, P = .044). Clinical response (poor, fair, or good) was significantly better after colonoscopy than neostigmine after 1 or 2 interventions (P = .0028 and P = .00079). Cecal diameters decreased significantly more after colonoscopy than neostigmine (from 10.2 +/- .5 cm to 7.1 +/- .4 cm vs from 10.5 +/- .5 cm to 8.8 +/- .5 cm, P = .026). Neostigmine administration before colonoscopy did not affect outcomes. There were 3 perforations (3.7%): 1 each after colonoscopy, neostigmine, and no intervention. Neostigmine dose or repetition did not affect radiographic (P = .41) or clinical (P = .31) response. CONCLUSIONS: Colonoscopy is superior to neostigmine for Ogilvie's syndrome and should be considered first-line therapy, although neostigmine is useful in select patients and repeat interventions. PMID- 23021197 TI - Competing commitments in psychiatric research: an examination of psychiatric researchers' perspectives. AB - Clinician-researchers have responsibilities both to seek the best interests of the people they treat and to advance scientific knowledge. The purpose of this study was to examine researchers' beliefs and behaviors regarding areas of tension between their clinical and scientific roles. We conducted and analyzed 19 in-depth interviews with psychiatric clinical researchers to explore these issues. Responses usually indicated that researchers recognize limits on their abilities to be helpful to patients, since they cannot know in advance whether a specific research intervention will help and whether participation is in the patient's best interest. Hence, most researchers did not make special efforts to recruit patients doing poorly in standard care, although they occasionally tolerated minor deviations from recruitment and treatment protocols when they might be in participants' interests. Often respondents asked the IRB to approve these deviations or change the protocol for all subjects, though it was unclear how often they may have acted without this approval. Despite researchers' high regard for following the research protocol, clinical judgment remained the ultimate guide if patients were not doing well and needed alternative care. Hence, respondents expressed a strong commitment both to protecting patients' interests and to advancing science. In cases of direct conflict between the two, many of the researchers tended to promote patients' best interests even at some cost to scientific research. PMID- 23021198 TI - The adequacy of single-incisional thoracoscopic surgery as a first-line endoscopic approach for the management of recurrent primary spontaneous pneumothorax: a retrospective study. AB - BACKGROUND: Thoracoscopic surgery is a commonly used endoscopic surgical treatment approach in patients with primary spontaneous pneumothorax. The conventional thoracoscopic approach utilizes three or more small wounds for surgery. Currently, a single port approach is a potential alternative procedure in general thoracoscopic surgery. We investigated whether a single-port approach is suitable as a first-line endoscopic approach for all patients with primary spontaneous pneumothorax requiring surgery. METHODS: From July 1st, 2008 to Dec 31, 2009, a total of 62 patients was included in this study. All the patients were admitted to our ward because they had surgical indications for surgery. Twenty-six patients underwent conventional three-port thoracoscopic surgery and thirty-six underwent single-port thoracoscopic surgery. All of the clinical data were analyzed retrospectively. Variables were compared and analyzed to determine the outcomes of the different surgical approaches. RESULTS: The mean age of the 62 patients was 27.2 years. Forty-nine patients were men and thirteen patients were women. The mean time required for the operation was 61.6 minutes. There was one patient who had a recurrence in single-port group and 2 patients had a recurrence in three-port group during the period of follow-up. The average pain scores at 24 and 48 hrs after the operation were similar, but the pain scores at 72 hrs in the single-port group were better than the three-port group. There was no case that required conversion from a single-port to multiple wound approach in this study. There was no immediate postoperative recurrence. The follow-up duration was greater than 12 months. CONCLUSION: This study showed that single port thoracoscopic surgery is a feasible and reasonable first-line endoscopic approach in the surgical treatment of primary spontaneous pneumothorax. PMID- 23021199 TI - Multidisciplinary care: experience of patients with complex needs. AB - The rapidly increasing prevalence of diabetes with its high morbidity and mortality raises the need for an integrated multidisciplinary service from health care providers across health sectors. The aim of this study was to explore the diabetic patients' experience of multidisciplinary care, in particular their perceptions, perceived barriers and facilitators. Thirteen patients with type-2 diabetes admitted to the emergency department of a local hospital in NSW were interviewed and completed a demographic questionnaire. Results showed that patients found it inconvenient to be referred to many health professionals because of multiple physical and psychosocial barriers. Separate sets of instructions from different health professionals were overwhelming, confusing and conflicting. Lack of a dedicated coordinator of care, follow up and support for self-management from health professionals were factors that contributed to patients' challenges in being actively involved in their care. The presence of multiple co-morbidities made it more difficult for patients to juggle priorities and 'commitments' to many health professionals. In addition, complex socioeconomic and cultural issues, such as financial difficulties, lack of transport and language barriers, intensified the challenge for these patients to navigate the health system independently. Few patients felt that having many health professionals involved in their care improved their diabetes control. Communication among the multidisciplinary care team was fragmented and had a negative effect on the coordination of care. The patients' perspective is important to identify the problems they experience and to formulate strategies for improving multidisciplinary care for patients with diabetes. PMID- 23021200 TI - Distribution of tubulointerstitial nephritis antigen-like 1 and structural matrix proteins in mouse embryos during preimplantation development in vivo and in vitro. AB - Summary Tubulointerstitial nephritis antigen-like 1 (TINAGL1) is a novel matricellular protein that interacts with structural matrix proteins and promotes cell adhesion and spreading. We have previously reported unique localization of TINAGL1 to the trophectoderm (TE) of mouse blastocysts. TINAGL1 was found to be upregulated in implantation-competent blastocysts after estrogen treatment using progesterone-treated delayed-implantation models. Moreover, colocalization of TINAGL1 and extracellular matrix (ECM) protein laminin 1 was detected in the Reichert membrane on embryonic days 6.5 and 7.5. Although these data suggested a role for TINAGL1 in the embryo development at postimplantation, its relevance to other ECM proteins during preimplantation development is not clear. In this study, we examined the expression of TINAGL1 and its relevance to other ECM proteins fibronectin (FN) and collagen type IV (ColIV) during in vivo development of preimplantation embryos, particularly at blastocyst stage in detail. Localizations of TINAGL1, FN, and ColIV were similar. In 1-cell to 8-cell embryos, they were expressed in cytoplasm of blastomeres, and in morulae they were localized in the outer cells. FN and ColIV were expressed primarily on outer surface of the cells. In blastocysts, FN and ColIV were distributed in the cytoplasm of TE, but, just prior to implantation, they became localized uniquely to the blastocoelic surface of TE. In in vitro fertilized (IVF) blastocysts, expression levels of TINAGL1 and FN were lower than in in vivo blastocysts. These results suggest that, during preimplantation development, TINAGL1 may be involved in roles of structural matrix proteins, whose expression in blastocysts may be affected by in vitro culture. PMID- 23021201 TI - Trajectory of fatigue severity in natalizumab treated multiple sclerosis patients. AB - Fatigue is one of the most debilitating symptoms in multiple sclerosis (MS). The aim of this study was to observe the severity of MS associated fatigue in a community-based sample of natalizumab (ntz) treated patients over one year. In 48 relapsing remitting MS patients (mean age=38.3 years) fatigue was longitudinally measured with the Modified Fatigue Impact Scale (MFIS) at two time points. The primary analysis of differences in MFIS was performed using non-parametric Wilcoxon test for dependent variables. Mean total MFIS Score increased significantly from 32.6+/-20.9 to 49.1+/-20.0 over the observation period of 12 months (p<0.001). 83% of patients remained clinically disease activity free (no relapse, no progression in the Expanded Disability Status Scale, EDSS) over the observation period of one year. Age, gender, disease duration, spinal involvement, Gd-enhancement, depressive symptoms and EDSS had no influence on fatigue levels as measured with MFIS. Severity of fatigue symptoms during ntz treatment might increase despite very low disease activity. PMID- 23021202 TI - Endovascular recanalisation therapy for prolonged basilar artery occlusion based on clinical-diffusion MRI mismatch. AB - OBJECTIVES: Clinical-diffusion magnetic resonance imaging (MRI) mismatch (CDM) in patients with anterior circulation occlusions is an optional method used to select patients for recanalisation outside the 3-h time window. A similar concept has not been reported with posterior circulation occlusions. METHODS: CDM was defined as a Glasgow Coma Scale (GCS) score <8 with DWI lesions not located in the dorsal pons, midbrain or thalamus at the time of admission. Eligible patients were treated with endovascular recanalisation therapy (ERT). The treatment included intra-arterial rt-PA thrombolysis and angioplasty and stenting performed separately or combined. The recanalisation result was assessed by angiography immediately after the treatment according to the trial reports in the Thrombolysis in Myocardial Infarction Criteria (TIMI). The complications and outcome 3 months later were recorded. RESULTS: Nine patients with a mean age of 66.6 years were included in the study (7 men and 2 women). The median durations of clinical presentation and coma were 31 h (range 25-53 h) and 6 h (range 2-13 h). The median GCS score at admission was 6 (range 4-7). Occlusions were located in the proximal basilar artery (BA) (n=2) and the middle BA (n=7). ERT was successful in 8 patients (TIMI 2, n=2 and TIMI 3, n=6) but failed in 1 patient because recanalisation was not possible (TIMI 0). No intracranial haemorrhage or dissections occurred during treatment. The recanalised patients recovered consciousness within 9-27 h after treatment. The median GCS score upon discharge was 14 (range 3-15). Three months later, 6 patients had a good outcome (modified Rankin Score (mRS) 0-2), and 2 patients had a moderate outcome (mRS 3). The patient who did not undergo recanalisation died in the rehabilitation hospital 21 days later. CONCLUSIONS: CDM may be a valid method for selecting patients with prolonged basilar artery occlusion (BAO) who are eligible for recanalisation treatment. ERT was feasible for patients with BAO. A good clinical outcome was achieved with successful recanalisation. PMID- 23021203 TI - Frequency of subtype B and F1 dual infection in HIV-1 positive, Brazilian men who have sex with men. AB - BACKGROUND: Because various HIV vaccination studies are in progress, it is important to understand how often inter- and intra-subtype co/superinfection occurs in different HIV-infected high-risk groups. This knowledge would aid in the development of future prevention programs. In this cross-sectional study, we report the frequency of subtype B and F1 co-infection in a clinical group of 41 recently HIV-1 infected men who have sex with men (MSM) in Sao Paulo, Brazil. METHODOLOGY: Proviral HIV-1 DNA was isolated from subject's peripheral blood polymorphonuclear leukocytes that were obtained at the time of enrollment. Each subject was known to be infected with a subtype B virus as determined in a previous study. A small fragment of the integrase gene (nucleotide 4255-4478 of HXB2) was amplified by nested polymerase chain reaction (PCR) using subclade F1 specific primers. The PCR results were further confirmed by phylogenetic analysis. Viral load (VL) data were extrapolated from the medical records of each patient. RESULTS: For the 41 samples from MSM who were recently infected with subtype B virus, it was possible to detect subclade F1 proviral DNA in five patients, which represents a co-infection rate of 12.2%. In subjects with dual infection, the median VL was 5.3 * 10(4) copies/ML, whereas in MSM that were infected with only subtype B virus the median VL was 3.8 * 10(4) copies/ML (p > 0.8). CONCLUSIONS: This study indicated that subtype B and F1 co-infection occurs frequently within the HIV-positive MSM population as suggested by large number of BF1 recombinant viruses reported in Brazil. This finding will help us track the epidemic and provide support for the development of immunization strategies against the HIV. PMID- 23021204 TI - Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. AB - BACKGROUND: This phase II randomized, placebo-controlled study was conducted to evaluate efficacy and safety of radium-223 in patients with castration-resistant prostate cancer (CRPC) and painful bone metastases. Twelve- and 18-month survival results were reported previously. Here we report 24-month overall survival (OS) and safety data from the period 12 to 24 months after the first injection of study medication. METHODS: Patients with CRPC and bone pain were randomized 1:1 to receive 4 injections of radium-223 (50 kBq/kg [n = 33]) or placebo (n = 31) after external-beam radiotherapy; each injection was given every 4 weeks. Endpoints for this report were 24-month OS, long-term safety, and treatment related adverse events (AEs) occurring in the 12- to 24-month period. RESULTS: After 24 months, 10 (30%) patients were alive in the radium-223 group compared with 4 patients (13%) in the placebo group. Patients who received at least 1 dose of study medication had a median OS of 65 weeks in the radium-223 group vs. 46 weeks in the placebo group (log-rank P = .056). The hazard ratio (HR) for OS, adjusted for baseline covariates, was 0.476 (95% confidence interval [CI], 0.258 0.877; Cox regression P = .017). The most frequent cause of death for both arms was disease progression. There were no reports of treatment-related AEs or long term hematologic toxicity during the 12- to 24-month follow-up. CONCLUSION: Radium-223 had a highly favorable safety profile, with no evidence of second malignancies at 24-month follow-up. The significant improvement in OS observed in patients receiving radium-223 vs. placebo suggests that treatment of bone disease with radium-223 has survival benefits. PMID- 23021205 TI - Effects of lifestyle intervention and meal replacement on glycaemic and body weight control in Chinese subjects with impaired glucose regulation: a 1-year randomised controlled trial. AB - The purpose of the present study was to evaluate the impact of a lifestyle intervention programme, combined with a daily low-glycaemic index meal replacement, on body-weight and glycaemic control in subjects with impaired glucose regulation (IGR). Subjects with IGR were randomly assigned to an intervention group (n 46) and a control group (n 42). Both groups received health counselling at baseline. The intervention group also received a daily meal replacement and intensive lifestyle intervention to promote healthy eating habits during the first 3 months of the study, and follow-up visits performed monthly until the end of the 1-year study. Outcome measurements included changes in plasma glucose, glycated Hb (HbA1c), plasma lipids, body weight, blood pressure and body composition (such as body fat mass and visceral fat area). The results showed that body-weight loss after 1 year was significant in the intervention group compared with the control group (-1.8 (SEM 0.35) v. -0.6 (SEM 0.40) 2.5 kg, P<0.05). The 2 h plasma glucose concentration decreased 1.24 mmol/l in the intervention group and increased 0.85 mmol/l in the control group (P<0.05) compared with their baseline, respectively. A 5 kg body-weight loss at 1 year was associated with a decrease of 1.49 mmol/l in 2 h plasma glucose (P<0.01). The incidence of normal glucose regulation (NGR) in the two groups was significantly different (P=0.001). In conclusion, the combination of regular contact, lifestyle advice and meal replacement is beneficial in promoting IGR to NGR. PMID- 23021206 TI - Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent. AB - BACKGROUND: Sigma receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with a high affinity for sigma receptors and prepared radioiodinated (+)-pIV. As a result, (+)-[125I]pIV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+) pIV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2 hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH). METHODS: (+) [125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[125I]IV-OH and (+)-[131I]pIV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice. RESULTS: The hydrophilicity of (+)-[125I]IV-OH was much higher than that of (+)-[125I]pIV. In biodistribution experiments, (+)-[125I]IV-OH and (+)-[131I]pIV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[131I]pIV tended to be retained in most tissues, (+)-[125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[125I]IV-OH was significantly lower at all time points compared to those of (+)-[131I]pIV. In the blocking studies, co injection of an excess amount of sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[125I]IV-OH. CONCLUSIONS: The results indicate that radioiodinated (+)-IV-OH holds a potential as a sigma receptor imaging agent. PMID- 23021207 TI - Neutral risk of lung cancer in adults with celiac disease--nationwide cohort study. AB - BACKGROUND: Data on celiac disease (CD) and the risk of lung cancer are contradictory, with several studies suggesting a protective effect of CD. We investigated the future risk of lung cancer in individuals with biopsy-verified CD. METHODS: In this cohort study we used biopsy reports from 28 Swedish pathology departments to identify adults with CD who had been diagnosed between 1969 and 2008 (Marsh 3: villous atrophy). Each patient with CD (n=18,365) was matched with up to five reference individuals (n=90,962) from the general population matched for age, sex, calendar year and county. Lung cancer events were identified through the Swedish Cancer Register. Using Cox regression, we then calculated hazard ratios (HRs) for lung cancer. RESULTS: During follow-up there were 109 cases of lung cancer in patients with CD, and 470 among reference individuals. This corresponded to a HR of 1.07 (95% CI=0.87-1.32). The absolute risk of future lung cancer in patients with CD was 57/100,000 person-years (excess risk=4/100,000 person-years). In the first year after CD diagnosis, the HR for lung cancer was 2.01 (95% CI=1.08-3.76), decreasing to a HR of 1.00 beyond the first year of follow-up (95% CI=0.80-1.25). There was no difference in men or women with CD, and age at CD onset did not influence the risk of lung cancer. CONCLUSION: In a Swedish setting, patients with CD were at a similar risk of lung cancer to reference individuals from the general population. PMID- 23021208 TI - Potential anti-tumor effect of IFN-lambda2 (IL-28A) against human lung cancer cells. AB - Interferon (IFN)-lambdas (IL-28A/IL-28B/IL-29) classified as type III IFNs, are the latest members identified of the interferon family. As with type I IFNs such as IFN-alpha, type III IFNs share antiviral and antitumor activity and may have fewer side effects due to a more selective receptor distribution. Therefore, type III IFNs may be clinically useful for human viral and malignant diseases. Here we demonstrate the potential anti-tumor effect of IFN-lambda2 (IL-28A) against human lung cancer cells. All lung cancer cell lines that we examined expressed both IFN lambda receptors (IL-28R1 and IL-10R2). Lung cancer cells with epidermal growth factor receptor (EGFR) mutations were more sensitive to IFN-lambda2 treatment compared with cells with KRAS mutations. HCC827 cells with an EGFR mutation treated with IFN-lambda2 underwent growth suppression and apoptotic cell death by STAT1 phosphorylation. Administration of neutralizing antibodies to IFN-lambda inhibited caspase-3/7 activity induced by IFN-lambda2. Finally, in vivo luminescent imaging also demonstrated the anti-tumor effect of IFN-lambda2 in a cancer cell transplant animal model. Taken together, IFN-lambda2 would be a new therapeutic agent for clinical lung cancers with EGFR mutations. PMID- 23021209 TI - Predicting necrosis in residual mass analysis after retroperitoneal lymph node dissection: a retrospective study. AB - BACKGROUND: Recent studies have demonstrated that pathological analysis of retroperitoneal residual masses of patients with testicular germ cell tumors revealed findings of necrotic debris or fibrosis in up to 50% of patients. We aimed at pursuing a clinical and pathological review of patients undergoing post chemotherapy retroperitoneal lymph node dissection (PC-RPLND) in order to identify variables that may help predict necrosis in the retroperitoneum. METHODS: We performed a retrospective analysis of all patients who underwent PC RPLND at the University Hospital of the University of Sao Paulo and Cancer Institute of Sao Paulo between January 2005 and September 2011. Clinical and pathological data were obtained and consisted basically of: measures of retroperitoneal masses, histology of the orchiectomy specimen, serum tumor marker and retroperitoneal nodal size before and after chemotherapy. RESULTS: We gathered a total of 32 patients with a mean age of 29.7; pathological analysis in our series demonstrated that 15 (47%) had necrosis in residual retroperitoneal masses, 15 had teratoma (47%) and 2 (6.4%) had viable germ cell tumors (GCT). The mean size of the retroperitoneal mass was 4.94 cm in our sample, without a difference between the groups (P = 0.176). From all studied variables, relative changes in retroperitoneal lymph node size (P = 0.04), the absence of teratoma in the orchiectomy specimen (P = 0.03) and the presence of choriocarcinoma in the testicular analysis after orchiectomy (P = 0.03) were statistically significant predictors of the presence of necrosis. A reduction level of 35% was therefore suggested to be the best cutoff for predicting the absence of tumor in the retroperitoneum with a sensitivity of 73.3% and specificity of 82.4%. CONCLUSIONS: Even though retroperitoneal lymph node dissection remains the gold standard for patients with residual masses, those without teratoma in the primary tumor and a shrinkage of 35% or more in retroperitoneal mass have a considerably smaller chance of having viable GCT or teratoma in the retroperitoneum and a surveillance program could be considered. PMID- 23021210 TI - A molecular link tethering neuronal responses with the past. AB - Neurons need to alter their response to a given stimulus over time in order for the animal to modify its behavior within a changing environment. Chen et al. now demonstrate that neuronal structure and function are altered coordinately by the history of the cell's activity through an unexpected molecular pathway. PMID- 23021211 TI - All things to all people. AB - Myc is an enigma wrapped in a mystery. Attempts to identify Myc target genes, particularly in cancer, have been fraught with dead ends and context-specific functions. Lin et al. and Nie et al. address this conundrum by showing that Myc acts to amplify the output of existing transcriptionally active genes. PMID- 23021212 TI - Restructuring G-protein- coupled receptor activation. AB - G-protein-coupled receptors serve as key signal transduction conduits, linking extracellular inputs with diverse cellular responses. These receptors eluded structural characterization for decades following their identification. A landmark structure of rhodopsin provided a basis for structure-function studies and homology modeling, but advances in receptor biology suffered from a lack of receptor-specific structural insights. The recent explosion in GPCR structures confirms some features predicted by rhodopsin-based models, and more importantly, it reveals unexpected ligand-binding modes and critical aspects of the receptor activation process. The new structures also promise to foster studies testing emerging models for GPCR function such as receptor dimerization and ligand-biased signaling. PMID- 23021213 TI - TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. AB - Astrocytes release glutamate upon activation of various GPCRs to exert important roles in synaptic functions. However, the molecular mechanism of release has been controversial. Here, we report two kinetically distinct modes of nonvesicular, channel-mediated glutamate release. The fast mode requires activation of G(alphai), dissociation of G(betagamma), and subsequent opening of glutamate permeable, two-pore domain potassium channel TREK-1 through direct interaction between G(betagamma) and N terminus of TREK-1. The slow mode is Ca(2+) dependent and requires G(alphaq) activation and opening of glutamate-permeable, Ca(2+) activated anion channel Best1. Ultrastructural analyses demonstrate that TREK-1 is preferentially localized at cell body and processes, whereas Best1 is mostly found in microdomains of astrocytes near synapses. Diffusion modeling predicts that the fast mode can target neuronal mGluR with peak glutamate concentration of 100 MUM, whereas slow mode targets neuronal NMDA receptors at around 1 MUM. Our results reveal two distinct sources of astrocytic glutamate that can differentially influence neighboring neurons. PMID- 23021214 TI - The transcription factor MEF2 directs developmental visually driven functional and structural metaplasticity. AB - Natural sensory input shapes both structure and function of developing neurons, but how early experience-driven morphological and physiological plasticity are interrelated remains unclear. Using rapid time-lapse two-photon calcium imaging of network activity and single-neuron growth within the unanesthetized developing brain, we demonstrate that visual stimulation induces coordinated changes to neuronal responses and dendritogenesis. Further, we identify the transcription factor MEF2A/2D as a major regulator of neuronal response to plasticity-inducing stimuli directing both structural and functional changes. Unpatterned sensory stimuli that change plasticity thresholds induce rapid degradation of MEF2A/2D through a classical apoptotic pathway requiring NMDA receptors and caspases-9 and -3/7. Knockdown of MEF2A/2D alone is sufficient to induce a metaplastic shift in threshold of both functional and morphological plasticity. These findings demonstrate how sensory experience acting through altered levels of the transcription factor MEF2 fine-tunes the plasticity thresholds of brain neurons during neural circuit formation. PMID- 23021215 TI - Transcriptional amplification in tumor cells with elevated c-Myc. AB - Elevated expression of the c-Myc transcription factor occurs frequently in human cancers and is associated with tumor aggression and poor clinical outcome. The effect of high levels of c-Myc on global gene regulation is poorly understood but is widely thought to involve newly activated or repressed "Myc target genes." We report here that in tumor cells expressing high levels of c-Myc the transcription factor accumulates in the promoter regions of active genes and causes transcriptional amplification, producing increased levels of transcripts within the cell's gene expression program. Thus, rather than binding and regulating a new set of genes, c-Myc amplifies the output of the existing gene expression program. These results provide an explanation for the diverse effects of oncogenic c-Myc on gene expression in different tumor cells and suggest that transcriptional amplification reduces rate-limiting constraints for tumor cell growth and proliferation. PMID- 23021216 TI - c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. AB - The c-Myc HLH-bZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism, and differentiation at the cellular, tissue, or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc's targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II, and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a nonlinear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature. PMID- 23021217 TI - Protein modularity, cooperative binding, and hybrid regulatory states underlie transcriptional network diversification. AB - We examine how different transcriptional network structures can evolve from an ancestral network. By characterizing how the ancestral mode of gene regulation for genes specific to a-type cells in yeast species evolved from an activating paradigm to a repressing one, we show that regulatory protein modularity, conversion of one cis-regulatory sequence to another, distribution of binding energy among protein-protein and protein-DNA interactions, and exploitation of ancestral network features all contribute to the evolution of a novel regulatory mode. The formation of this derived mode of regulation did not disrupt the ancestral mode and thereby created a hybrid regulatory state where both means of transcription regulation (ancestral and derived) contribute to the conserved expression pattern of the network. Finally, we show how this hybrid regulatory state has resolved in different ways in different lineages to generate the diversity of regulatory network structures observed in modern species. PMID- 23021218 TI - TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. AB - PGC1alpha is a key transcriptional coregulator of oxidative metabolism and thermogenesis. Through a high-throughput chemical screen, we found that molecules antagonizing the TRPVs (transient receptor potential vanilloid), a family of ion channels, induced PGC1alpha expression in adipocytes. In particular, TRPV4 negatively regulated the expression of PGC1alpha, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. Mice with a null mutation for TRPV4 or wild-type mice treated with a TRPV4 antagonist showed elevated thermogenesis in adipose tissues and were protected from diet-induced obesity, adipose inflammation, and insulin resistance. This role of TRPV4 as a cell-autonomous mediator for both the thermogenic and proinflammatory programs in adipocytes could offer a target for treating obesity and related metabolic diseases. PMID- 23021219 TI - TMEM16F forms a Ca2+-activated cation channel required for lipid scrambling in platelets during blood coagulation. AB - Collapse of membrane lipid asymmetry is a hallmark of blood coagulation. TMEM16F of the TMEM16 family that includes TMEM16A/B Ca(2+)-activated Cl(-) channels (CaCCs) is linked to Scott syndrome with deficient Ca(2+)-dependent lipid scrambling. We generated TMEM16F knockout mice that exhibit bleeding defects and protection in an arterial thrombosis model associated with platelet deficiency in Ca(2+)-dependent phosphatidylserine exposure and procoagulant activity and lack a Ca(2+)-activated cation current in the platelet precursor megakaryocytes. Heterologous expression of TMEM16F generates a small-conductance Ca(2+)-activated nonselective cation (SCAN) current with subpicosiemens single-channel conductance rather than a CaCC. TMEM16F-SCAN channels permeate both monovalent and divalent cations, including Ca(2+), and exhibit synergistic gating by Ca(2+) and voltage. We further pinpointed a residue in the putative pore region important for the cation versus anion selectivity of TMEM16F-SCAN and TMEM16A-CaCC channels. This study thus identifies a Ca(2+)-activated channel permeable to Ca(2+) and critical for Ca(2+)-dependent scramblase activity during blood coagulation. PAPERFLICK: PMID- 23021220 TI - Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. AB - In Drosophila, the fat body (FB), a functional analog of the vertebrate adipose tissue, is the nutrient sensor that conveys the nutrient status to the insulin producing cells (IPCs) in the fly brain to release Drosophila insulin-like peptides (Dilps). Dilp secretion in turn regulates energy balance and promotes systemic growth. We identify Unpaired 2 (Upd2), a protein with similarities to type I cytokines, as a secreted factor produced by the FB in the fed state. When upd2 function is perturbed specifically in the FB, it results in a systemic reduction in growth and alters energy metabolism. Upd2 activates JAK/STAT signaling in a population of GABAergic neurons that project onto the IPCs. This activation relieves the inhibitory tone of the GABAergic neurons on the IPCs, resulting in the secretion of Dilps. Strikingly, we find that human Leptin can rescue the upd2 mutant phenotypes, suggesting that Upd2 is the functional homolog of Leptin. PMID- 23021221 TI - Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. AB - Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes, observed in macrophage foam cells. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol. PMID- 23021222 TI - Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. AB - Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to preaccessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers lacking in Foxp3(-) CD4(+) cells became accessible upon T cell receptor activation prior to Foxp3 expression, and only a small subset associated with several functionally important genes were exclusively Treg cell specific. Thus, in a late cellular differentiation process, Foxp3 defines Treg cell functionality in an "opportunistic" manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape. PMID- 23021223 TI - Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants. AB - DNA methylation and histone modification exert epigenetic control over gene expression. CHG methylation by CHROMOMETHYLASE3 (CMT3) depends on histone H3K9 dimethylation (H3K9me2), but the mechanism underlying this relationship is poorly understood. Here, we report multiple lines of evidence that CMT3 interacts with H3K9me2-containing nucleosomes. CMT3 genome locations nearly perfectly correlated with H3K9me2, and CMT3 stably associated with H3K9me2-containing nucleosomes. Crystal structures of maize CMT3 homolog ZMET2, in complex with H3K9me2 peptides, showed that ZMET2 binds H3K9me2 via both bromo adjacent homology (BAH) and chromo domains. The structures reveal an aromatic cage within both BAH and chromo domains as interaction interfaces that capture H3K9me2. Mutations that abolish either interaction disrupt CMT3 binding to nucleosomes and show a complete loss of CMT3 activity in vivo. Our study establishes dual recognition of H3K9me2 marks by BAH and chromo domains and reveals a distinct mechanism of interplay between DNA methylation and histone modification. PMID- 23021225 TI - SnapShot: Mammalian Rab proteins in endocytic trafficking. PMID- 23021224 TI - Asymmetrically modified nucleosomes. AB - Mononucleosomes, the basic building blocks of chromatin, contain two copies of each core histone. The associated posttranslational modifications regulate essential chromatin-dependent processes, yet whether each histone copy is identically modified in vivo is unclear. We demonstrate that nucleosomes in embryonic stem cells, fibroblasts, and cancer cells exist in both symmetrically and asymmetrically modified populations for histone H3 lysine 27 di/trimethylation (H3K27me2/3) and H4K20me1. Further, we obtained direct physical evidence for bivalent nucleosomes carrying H3K4me3 or H3K36me3 along with H3K27me3, albeit on opposite H3 tails. Bivalency at target genes was resolved upon differentiation of ES cells. Polycomb repressive complex 2-mediated methylation of H3K27 was inhibited when nucleosomes contain symmetrically, but not asymmetrically, placed H3K4me3 or H3K36me3. These findings uncover a potential mechanism for the incorporation of bivalent features into nucleosomes and demonstrate how asymmetry might set the stage to diversify functional nucleosome states. PMID- 23021226 TI - Familial congenital heart disease: data collection and preliminary analysis. AB - The aim of this study was to explore genetic mechanisms of congenital heart disease by analysing family data. Families with two or more affected members were studied, and information on family history and risk factors was collected. A total of 25 families with congenital heart disease were identified, and among them the condition was confirmed in 57. The prevalence of congenital heart disease in first-degree relatives was 43.0%, that is 46 out of 107, significantly higher than that in second-degree relatives, that is, 4.4%, 11 out of 252) (chi2 = 83.897, P < 0.01). The prevalence difference between twins (90%) and siblings (62.2%) (chi2 = 4.983, P < 0.05) was also significant among first-degree relatives. Eleven families were found to have the same phenotype (44%), including ventricular septal defect in six families, atrial septal defect in two families, conotruncal defects in two families, and hypoplastic left heart syndrome in one family. Both twins were diagnosed with congenital heart disease in 8 out of 10 twin families - all eight twins were monozygotic. The cardiac phenotype of the twins was consistent in three families (37.5%). The cardiac phenotype of first- and second-degree relatives was not fully consistent with their probands. There was an increased incidence of threatened abortion in early pregnancy in patients with familial congenital heart disease when compared with sporadic congenital heart disease (chi2 = 8.704, P < 0.05). Morbidity in relatives was related to blood relationship, with a closer relationship increasing the risk of congenital heart disease. Genetic factors appear to play an important role in congenital heart disease. PMID- 23021227 TI - Application of electrophysiological tests in the study of neurological diseases with visual involvement. PMID- 23021228 TI - [Assessment of intra-operative techniques to prevent visual axis opacification in congenital cataract surgery]. AB - OBJECTIVE: To evaluate the effectiveness of various surgical procedures in the management of posterior capsule and anterior vitreous on the prevention of visual axis opacification. SUBJECTS, MATERIAL AND METHODS: We retrospectively reviewed 120 eyes operated for unilateral congenital cataracts, with a median age at the time of cataract surgery of 21 months (interquartile range, 6-52 months). The eyes were divided into 3 groups: group 1 (eyes with intact posterior capsule, n=39), group 2 (eyes with posterior continuous curvilinear capsulorhexis, n=38), group 3 (eyes with posterior continuous curvilinear capsulorhexis and anterior vitrectomy, n=43). RESULTS: To determine the effect of posterior continuous curvilinear capsulorhexis on visual axis opacification we compared group 2 with group 1 (chi-square Pearson test, P=.281), therefore in this study the implementation of the posterior continuous curvilinear capsulorhexis did not show any decreases in the incidence of visual axis opacification. To study the effect of posterior continuous curvilinear capsulorhexis associated anterior vitrectomy, we compared group 3 with group 1 (chi-square Pearson test, P=.014), demonstrating that the combination of both techniques (posterior continuous curvilinear capsulorhexis and anterior vitrectomy) decreases the incidence of visual axis opacification. CONCLUSION: Posterior continuous curvilinear capsulorhexis as a single technique did not show any decrease in the incidence of visual axis opacification. Posterior continuous curvilinear capsulorhexis together with anterior vitrectomy are required to prevent visual axis opacification and to decrease reoperation rate. PMID- 23021229 TI - [Triamcinolone acetonide without solvents]. AB - OBJECTIVE: The purification of commercially prepared triamcinolone acetonide is important in order to avoid the potential toxic side-effects of the solvent benzyl alcohol. We present a new technique for preparation of pure triamcinolone acetonide by dissolving the powder in sterile distilled water with no additional solvents. As the triamcinolone powder is relatively insoluble in water, we describe the sterile method used for the preparation and control of this suspension. MATERIALS AND METHODS: The triamcinolone acetonide is prepared in our hospital pharmacy, under optimum sterile conditions, and then packaged in a primary vial, sealed and sterilized in an autoclave at 121 degrees C. This vial contains an individual dose of 4mg/0.1ml. RESULTS: A final dose for an intravitreal administration of 3.77mg/0.1ml triamcinolone acetonide was obtained using high pressure liquid chromatography (HPLC). The chemical, physical and microbiological stability allows the solution to be kept at a temperature of 2-8 degrees C for 6 months. CONCLUSIONS: A rapid method is presented for preparing triamcinolone acetonide in pure state without preservatives in a concentration near the standard dose and under optimum sterile conditions. PMID- 23021231 TI - [Use of botulinum toxin in a patient with pendular congenital nystagmus]. AB - CASE REPORT: We report the case of a 5 month-old male diagnosed with congenital nystagmus and oculocutaneous albinism. The initial examination showed pendular horizontal nystagmus with high amplitude and without blocking position or foveal fixation periods. A 2.5 IU injection of botulinum toxin was administered in the horizontal rectus muscles of both eyes in two sessions separated by 6 weeks. This led to a decrease in amplitude of nystagmus and early development of binocular visual acuity of 4.8cycles/cm. CONCLUSION: Faced with diagnosis of horizontal nystagmus in the early stages of development, and in order to avoid periods of foveal fixation, the use of botulinum toxin leads to a temporary reduction in its amplitude and an improvement in visual acuity with low complication rates. Given the possibility of spontaneous improvement described in these patients, studies are needed with longer follow-up to establish the advantage of long term treatment. PMID- 23021230 TI - [Central nervous system demyelinating disease-associated uveitis]. AB - OBJECTIVE: To describe the epidemiology, clinical features and visual prognosis in uveitis associated with demyelinating disease (DD) of the CNS. METHODS: A clinical, retrospective, and descriptive study was performed. Data regarding age at presentation, gender, time from onset was recorded, as well as, type of uveitis, complications, treatment and initial and final visual acuity (BCVA) on all patients with DD-associated uveitis diagnosed in our Unit between January 2009 and June 2011. RESULTS: Five women and 4 men were finally included (1.3% of 697 with uveitis). There was associated multiple sclerosis in 78% of cases. Mean age at presentation was 36.6 years for uveitis and 40 years for DD. The uveitis preceded the DD in 3 cases (33%). Typically, uveitis was bilateral (89%), chronic (89%), intermediate (89%), and associated with previous inflammation (29%), with synechiae (65%), and granulomatous (44%). The most frequent complications were cataract (71%) and macular oedema (53%). Besides local treatment, uveitis was managed with systemic steroids (78%), immunosuppressants (44%), and surgery (41% of eyes). After a mean follow up of 5 years, 47% of the eyes had a worse BCVA, among which, 12% lost >= 3 Snellen lines. The only patient treated with interferon (IFN), remained stable without treatment for the last 7 years. CONCLUSIONS: DD-associated uveitis typically affected young adult women with intermediate-anterior uveitis of chronic, bilateral and synechiae type. Complications are common and there is a risk of visual loss, despite treatment. IFN therapy may be an effective alternative to be investigated. PMID- 23021232 TI - [Best's vitelliform macular dystrophy associated with choroidal neovascularization]. AB - CASE REPORT: We report the case of a child with a sudden loss of vision of the left eye. Ophthalmoscopic examination revealed vitelliform lesions in both foveal centers, as well as an adjacent hemorrhage in his left eye. Fluorescein angiography confirmed the presence of a neovascular membrane in his left eye. The electrooculogram showed disease. According to complementary studies the patient was diagnosed with Best's disease associated with choroidal neovascularization. DISCUSSION: The diagnosis of Best's vitelliform macular dystrophy is often a casual finding as visual acuity tends to remain stable for long periods of time. A sudden deterioration in vision may suggest complications, such as choroidal neovascularization. PMID- 23021233 TI - [High-altitude retinopathy]. AB - CASE REPORT: This case report presents a 36 year-old male with a sudden loss of vision while taking part in an expedition in the Daulaghiri (8,167 metres high peak located in the Himalayan Mountain Range). DISCUSSION: High altitude retinal haemorrhage is a common condition in those mountaineers who reach altitudes over 5,500m. Depending on its location it may not present any symptoms and the condition improves with no further complications. However, in case of macular involvement the vision decreases dramatically and the consequences are uncertain. PMID- 23021236 TI - Hepatoprotective activities of a sesquiterpene-rich fraction from the aerial part of Cichorium glandulosum. AB - BACKGROUND: Cichorium glandulosum Boiss. et Huet is used for treatment of liver disorders, and its effects are attributed to sesquiterpenes. This study aims to investigate the hepatoprotective effects of a sesquiterpene-rich fraction (SRF) from the aerial part of C. glandulosum on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in mice, and on priming with Bacillus Calmette-Guerin (BCG) followed by lipopolysaccharide (LPS)-induced immunological liver injury in mice. METHODS: SRF was suspended in water and administered to mice at 0.05, 0.10 and 0.20 g/kg body weight for 7 consecutive days. An active control drug (bifendate pills) was suspended in distilled water and administered to mice at 0.40 g/kg body weight for 7 consecutive days. Hepatotoxicity was induced by intraperitoneal injection of 0.1% CCl4 (0.2 mL/mouse) at 13 h before the last drug administration, or by tail intravenous injection of BCG (0.2 mL/mouse) before the first drug administration and LPS (0.2 mL/mouse; 8 MUg) at 15 h before the last drug administration. Blood samples and the livers were collected for evaluation of the biochemical parameters of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (TBIL). RESULTS: SRF significantly reduced the impact of CCl4 toxicity. The highest dose of SRF (0.20 g/kg) was the most effective, reflected by significant reductions in the levels of AST (P = 0.001), ALT (P = 0.000) and TBIL (P = 0.009). The serum enzymatic levels induced by BCG and subsequent LPS injection were significantly and dose-dependently restored by SRF, reflected by significant reductions in the levels of AST (P = 0.003), ALT (P = 0.003) and TBIL (P = 0.007) for the highest dose of SRF (0.20 g/kg). CONCLUSION: SRF is hepatoprotective in animal models of chemical and immunological acute liver injury. PMID- 23021237 TI - Effects of diagnostic ultrasound-targeted microbubble destruction on permeability of normal liver in rats. AB - This work investigated the effect of diagnostic ultrasound-targeted microbubble destruction (UTMD) on the permeability of normal liver tissue and the safety of this technique. One hundred and four rats were divided into four groups: the control group, the microbubble-only (MB) group, the ultrasound-only (US) group, and the ultrasound-targeted microbubble destruction group (UTMD). The permeabilities of capillaries and cell membranes were determined using Evans blue and lanthanum nitrate as tracers, respectively. The amount of Evans blue was approximately fourfold higher in the UTMD group than in the control, MB-only, and US-only groups (all P<0.01). Evans blue extravasation, visualized as red fluorescence, was detectable by laser confocal scanning microscopy in the parenchyma only in the UTMD group. Lanthanum nitrate-tracing transmission electron microscopy examination indicated that intracellular lanthanum was detectable in the cytoplasm only in the UTMD group. Blood chemical analysis indicated that the effect of diagnostic ultrasound-targeted microbubble destruction on the rats' serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels was transient and recoverable and that this technique had no obvious effect on renal function. Cellular swelling was observed in liver cells in the UTMD group at 0.5 h, but this swelling was no longer apparent after 1 week. These results suggest that diagnostic ultrasound-targeted microbubble destruction can increase the capillary and cell membrane permeabilities in normal liver tissue without a significant increase in hepatic and renal toxicity. PMID- 23021238 TI - Improved fabrication of focused single element P(VDF-TrFE) transducer for high frequency ultrasound applications. AB - We present an improved fabrication technique for the focused single element poly (vinylidene fluoride-trifluoroethylene) P(VDF-TrFE) transducer. In this work, a conductive epoxy for a backing layer was directly bonded to the 25MUm thick P(VDF TrFE) film and thus made it easy to conform the aperture of the P(VDF-TrFE) transducer. Two prototype focused P(VDF-TrFE) transducers with disk- and ring type aperture were fabricated and their performance was evaluated using the UBM (Ultrasound Biomicroscopy) system with a wire phantom. All transducers had a spherically focused aperture with a low f-number (focal depth/aperture size=1). The center frequency of the disk-type P(VDF-TrFE) transducer was 23MHz and-6dB bandwidth was 102%. The ring-type P(VDF-TrFE) transducer had 20MHz center frequency and-6dB bandwidth of 103%. The measured pulse echo signal had reduced reverberation due to no additional adhesive layer between the P(VDF-TrFE) film and the backing layer. Hence, the proposed method is promising to fabricate a single element transducer using P(VDF-TrFE) film for high frequency applications. PMID- 23021239 TI - [Effects of a cardiac rehabilitation programme in coronary patient according to age]. AB - BACKGROUND: Benefits of cardiac rehabilitation (CR) are well established in coronary heart disease. The effects according to age are less known, especially in France. AIM OF THE STUDY: Evaluation at 6 months of a CR programme in three groups of patients with different age. PATIENTS AND METHODS: Two hundred and two coronary patients were included in the CR department in Machecoul between 2007 and 2009. They attended the CR programme and were examined at six months. Patients were divided into three groups: group 1, n=103 (<65 years), group 2, n=71 (65 to 75 years) and group 3, n=28 (>75 years). We analysed the exercise capacity (exercise stress testing and six minutes walk-test or 6MWT), two questionnaires (dietary and physical activity) and bio-clinical data. RESULTS: Exercise capacity improved respectively by 24, 27 and 18% (P<0.004 between G2 and G3). The 6MWT improved by 19, 22 and 25% (P<0.01 between G1 and G3). At 6 months, the 6MWT remain stable, the dietary and physical activity scales improved in the three groups, the body mass index (BMI) was unchanged, HDL cholesterol increased, smoking prevalence was respectively 16, 0 and 0% and medical treatment were optimal in 90, 82 and 79% (NS). CONCLUSION: If the impact of CR was almost similar in the three groups, a more prolonged physical training seems desirable in patients over 75 years. PMID- 23021242 TI - Chapter three--Syrian hamster as an animal model to study oncolytic adenoviruses and to evaluate the efficacy of antiviral compounds. AB - The Syrian (golden) hamster (Mesocricetus auratus) has served as a useful model for different aspects of biology for at least 50 years, and its use has been expanding recently. In earlier years, among other things, it was a model for cancer development. More recently, it has become a model for many different infectious diseases. It has also become an alternative model for the study of oncolytic adenovirus vectors for cancer gene therapy. Among several other human pathogens, the hamster is permissive for the replication of human species C adenoviruses, which are the parental virus for the majority of adenovirus vectors in use today. These vectors replicate in some of the established hamster tumor cell lines that can be used to generate tumors in vivo, that is, one can study oncolytic (replication competent) adenoviruses in a permissive, immunocompetent model. This has afforded the opportunity to study the effect of the host immune system on the vector-infected tumor and has allowed the use of a more relevant animal model to determine the safety and biodistribution of replication-competent adenoviruses. The hamster has also been used to evaluate antiviral compounds and vaccines against many viruses, including adenoviruses, flaviviruses, alphaviruses, arenaviruses, bunyaviruses, and paramyxoviruses. PMID- 23021243 TI - Chapter four--Design of improved oncolytic adenoviruses. AB - During the last decade adenovirus has lost its appeal in gene therapy due to a high immunogenicity that leads to a transient gene expression. However, adenovirus has gained attention as replication-competent vector to treat cancer. Designed for virotherapy, adenovirus has been successfully modified to replicate selectively in tumor cells. After the initial clinical trials with tumor selective adenoviruses, it has become clear that further improvements on tumor targeting, intratumoral dissemination, and modulation of antiviral and antitumor immune responses are needed to effectively treat cancer. The non-viral delivery of infectious DNA encoding an oncolytic adenovirus armed with extracellular matrix-degrading genes and with genes that regulate the immune system to favor antitumor instead of antiviral immunity are key in the design oncolytic adenovirus. PMID- 23021240 TI - Chapter One---Cancer terminator viruses and approaches for enhancing therapeutic outcomes. AB - No single or combinatorial therapeutic approach has proven effective in decreasing morbidity or engendering a cure of metastatic cancer. In principle, conditionally replication-competent adenoviruses that induce tumor oncolysis through cancer-specific replication hold promise for cancer therapy. However, a single-agent approach may not be adequate to completely eradicate cancer in a patient because most cancers arise from abnormalities in multiple genetic and signal transduction pathways and targeting disseminated metastases is difficult to achieve. Based on these considerations, a novel class of cancer destroying adenoviruses have been produced, cancer terminator viruses (CTVs), in which cancer-specific replication is controlled by the progression-elevated gene-3 promoter and replicating viruses produce a second transgene encoding an apoptosis inducing and immunomodulatory cytokine, either melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) or interferon-gamma. This review focuses on these viruses and ways to improve their delivery systemically and enhance their therapeutic efficacy. PMID- 23021244 TI - Chapter five--The development of transcription-regulated adenoviral vectors with high cancer-selective imaging capabilities. AB - A clear benefit of molecular imaging is to enable noninvasive, repetitive monitoring of intrinsic signals within tumor cells as a means to identify the lesions as malignant or to assess the ability of treatment to perturb key pathways within the tumor cells. Due to the promising utility of molecular imaging in oncology, preclinical research to refine molecular imaging techniques in small animals is a blossoming field. We will first discuss the several imaging modalities such as fluorescent imaging, bioluminescence imaging, and positron emission tomography that are now commonly used in small animal settings. The indirect imaging approach, which can be adapted to a wide range of imaging reporter genes, is a useful platform to develop molecular imaging. In particular, reporter gene-based imaging is well suited for transcriptional-targeted imaging that can be delivered by recombinant adenoviral vectors. In this review, we will summarize transcription-regulated strategies used in adenoviral-mediated molecular imaging to visualize metastasis and monitor oncolytic therapy in preclinical models. PMID- 23021241 TI - Chapter two--Adenovirus strategies for tissue-specific targeting. AB - Cancer gene therapy approaches have benefited greatly from the utilization of molecular-based therapeutics. Of these, adenovirus-based interventions hold much promise as a platform for targeted therapeutic delivery to tumors. However, a barrier to this progression is the lack of native adenovirus receptor expression on a variety of cancer types. As such, any adenovirus-based cancer therapy must take into consideration retargeting the vector to nonnative cellular surface receptors. Predicated upon the knowledge gained in native adenovirus biology, several strategies to transductionally retarget adenovirus have emerged. Herein, we describe the biological hurdles as well as strategies utilized in adenovirus transductional targeting, covering the progress of both adapter-based and genetic manipulation-based targeting. Additionally, we discuss recent translation of these targeting strategies into a clinical setting. PMID- 23021245 TI - Chapter six--Adenovirus-based immunotherapy of cancer: promises to keep. AB - Progress in vector design and an increased knowledge of mechanisms underlying tumor-induced immune suppression have led to a new and promising generation of Adenovirus (Ad)-based immunotherapies, which are discussed in this review. As vaccine vehicles Ad vectors (AdVs) have been clinically evaluated and proven safe, but a major limitation of the commonly used Ad5 serotype is neutralization by preexistent or rapidly induced immune responses. Genetic modifications in the Ad capsid can reduce intrinsic immunogenicity and facilitate escape from antibody mediated neutralization. Further modification of the Ad hexon and fiber allows for liver and scavenger detargeting and selective targeting of, for example, dendritic cells. These next-generation Ad vaccines with enhanced efficacy are now becoming available for testing as tumor vaccines. In addition, AdVs encoding immune-modulating products may be used to convert the tumor microenvironment from immune-suppressive and proinvasive to proinflammatory, thus facilitating cell mediated effector functions that can keep tumor growth and invasion in check. Oncolytic AdVs, that selectively replicate in tumor cells and induce an immunogenic form of cell death, can also be armed with immune-activating transgenes to amplify primed antitumor immune responses. These novel immunotherapy strategies, employing highly efficacious AdVs in optimized configurations, show great promise and warrant clinical exploration. PMID- 23021247 TI - Chapter eight--Oncolytic adenoviruses for cancer immunotherapy: data from mice, hamsters, and humans. AB - Adenovirus is one of the most commonly used vectors for gene therapy and two products have already been approved for treatment of cancer in China (Gendicine(R) and Oncorine(R)). An intriguing aspect of oncolytic adenoviruses is that by their very nature they potently stimulate multiple arms of the immune system. Thus, combined tumor killing via oncolysis and inherent immunostimulatory properties in fact make these viruses in situ tumor vaccines. When further engineered to express cytokines, chemokines, tumor-associated antigens, or other immunomodulatory elements, they have been shown in various preclinical models to induce antigen-specific effector and memory responses, resulting both in full therapeutic cures and even induction of life-long tumor immunity. Here, we review the state of the art of oncolytic adenovirus, in the context of their capability to stimulate innate and adaptive arms of the immune system and finally how we can modify these viruses to direct the immune response toward cancer. PMID- 23021248 TI - [A comparative study of a disposable non-prismatic cone versus the biprismatic cone over 100 IOP measurements]. AB - INTRODUCTION: In 2009, we developed a non-prismatic cone in accordance with Goldmann tonometer standards. We undertook a prospective comparative clinical study of the non-prismatic cone versus the traditional biprismatic cone. MATERIALS AND METHODS: The disposable non-prismatic Plexiglas cone contains, on the inner side of its applanating end, a raised circular pattern 3.06 mm in diameter. Patient recruitment was performed in the setting of diurnal intraocular pressure (IOP) measurement for all comers including medically treated glaucoma patients. Two operators clinically tested the non-prismatic cone, with each operator measuring his or her own series of 50 eyes, for a total of 100 IOP measurements. RESULTS: For the first operator, the mean IOP measurement with the non-prismatic cone was 17.92 mmHg, range 13 to 26 mmHg; the mean IOP measurement with the biprismatic cone was 17.40 mmHg; the difference between mean IOP measurements was 0.52 mmHg, with a correlation coefficient of 0.98. For the second operator, with a series ranging from 10 to 19 mmHg, similar results were observed. DISCUSSION: Disposable cones, including the non-prismatic cone, adapted for the Goldmann tonometer are superior to other strategies for infection prophylaxis, such as chemical disinfection or condoms. CONCLUSION: This study demonstrates the reliability of the disposable non-prismatic cone adapted for the Goldmann tonometer. Other features unique to the non-prismatic cone are evoked at the end of this paper. PMID- 23021250 TI - Advanced brain dopamine transporter imaging in mice using small-animal SPECT/CT. AB - BACKGROUND: Iodine-123-beta-CIT, a single-photon emission computed tomography (SPECT) ligand for dopamine transporters (DATs), has been used for in vivo studies in humans, monkeys, and rats but has not yet been used extensively in mice. To validate the imaging and analysis methods for preclinical DAT imaging, wild-type healthy mice were scanned using 123I-beta-CIT. METHODS: The pharmacokinetics and reliability of 123I-beta-CIT in mice (n = 8) were studied with a multipinhole SPECT/CT camera after intravenous injection of 123I-beta-CIT (38 +/- 3 MBq). Kinetic imaging of three mice was continued for 7 h postinjection to obtain the time-activity curves in the striatum and cerebellum volumes. Five mice had repeated measures 4 h post-123I-beta-CIT injection to provide an indication of test-retest reliability. The same five mice served as a basis for a healthy mean SPECT template. RESULTS: Specific binding of 123I-beta-CIT within the mouse striatum could be clearly visualized with SPECT. The kinetics of 123I beta-CIT was similar to that in previously published autoradiography studies. Binding potential mean values of the test-retest studies were 6.6 +/- 15.7% and 6.6 +/- 4.6%, respectively, and the variability was 9%. The SPECT template was aggregated from the first and second imaging of the test-retest animals. No significant difference between the templates (P > 0.05) was found. From the test template, a striatal volume of 22.3 mm3 was defined. CONCLUSIONS: This study demonstrates that high-resolution SPECT/CT is capable of accurate, repeatable, and semiquantitative measurement of 123I-beta-CIT DAT binding in the mouse brain. This methodology will enable further studies on DAT density and neuroprotective properties of drugs in mice. PMID- 23021249 TI - Dietary folate does not significantly affect the intestinal microbiome, inflammation or tumorigenesis in azoxymethane-dextran sodium sulphate-treated mice. AB - Inflammatory bowel disease (IBD) is a risk factor for the development of colon cancer. Environmental factors including diet and the microflora influence disease outcome. Folate and homocysteine have been associated with IBD-mediated colon cancer but their roles remain unclear. We used a model of chemically induced ulcerative colitis (dextran sodium sulphate (DSS)) with or without the colon carcinogen azoxymethane (AOM) to determine the impact of dietary folic acid (FA) on colonic microflora and the development of colon tumours. Male mice (n 15 per group) were fed a FA-deficient (0 mg/kg), control (2 mg/kg) or FA-supplemented (8 mg/kg) diet for 12 weeks. Folate status was dependent on the diet (P< 0.001) and colitis-induced treatment (P= 0.04) such that mice with colitis had lower circulating folate. FA had a minimal effect on tumour initiation, growth and progression, although FA-containing diets tended to be associated with a higher tumour prevalence in DSS-treated mice (7-20 v. 0%, P= 0.08) and the development of more tumours in the distal colon of AOM-treated mice (13-83% increase, P= 0.09). Folate deficiency was associated with hyperhomocysteinaemia (P< 0.001) but homocysteine negatively correlated with tumour number (r - 0.58, P= 0.02) and load (r - 0.57, P= 0.02). FA had no effect on the intestinal microflora. The present data indicate that FA intake has no or little effect on IBD or IBD mediated colon cancer in this model and that hyperhomocysteinaemia is a biomarker of dietary status and malabsorption rather than a cause of IBD-mediated colon cancer. PMID- 23021246 TI - Chapter seven--Cancer treatment with gene therapy and radiation therapy. AB - Radiation therapy methods have evolved remarkably in recent years which have resulted in more effective local tumor control with negligible toxicity of surrounding normal tissues. However, local recurrence and distant metastasis often occur following radiation therapy mostly due to the development of radioresistance through the deregulation of the cell cycle, apoptosis, and inhibition of DNA damage repair mechanisms. Over the last decade, extensive progress in radiotherapy and gene therapy combinatorial approaches has been achieved to overcome resistance of tumor cells to radiation. In this review, we summarize the results from experimental cancer therapy studies on the combination of radiation therapy and gene therapy. PMID- 23021251 TI - Granular cell tumors: a report of six cases. AB - Granular cell tumor is a soft tissue neoplasm that originates in the nervous system and arises at virtually any body site, but is mainly found in the skin, oral cavity or digestive tract. Most are benign and reportedly malignant cases are rare, occurring in only 1% or 2% of cases. We report on our findings in six patients who developed granular cell tumor in the mammary gland, esophagus, subcutaneous tissue and muscle. Of six patients, two had granular cell tumor located in the breast, two in the submucosa of the esophagus, and the other two under the skin of the left axillary cavity and in the right latissimus dorsi muscle, respectively. One of the two patients with tumor in the submucosa of the esophagus also had esophageal cancer. Patients' age ranged from 41 to 70 years (average, 59.1 years). Two patients with tumor in the submucosa of the esophagus were men, and the others were women. All of them were given a diagnosis of granular cell tumor by tissue biopsy and examination of excised specimens, but no evidence of malignancy was found. No recurrence has been noted in the patients who underwent surgical tumor removal. PMID- 23021252 TI - Attenuation of an adult T-cell leukemia skin lesion after treatment of a concomitant herpes simplex infection: a case study. AB - We report the development and treatment of eczema herpeticum in a 51-year-old male suffering from adult T-cell leukemia (ATL). Lesions of eczema herpeticum coexisted with the skin lesions of ATL. Treatment of eczema herpeticum resulted in a concomitant improvement in the symptoms of ATL, including a reduction in the size of the ATL plaques, for over 2 months before relapse. PMID- 23021253 TI - Nonconscious priming of elderly or youthful stereotypes influences walking velocity in healthy undergraduates. AB - Psychological studies of "priming" effects document that covertly presented stimuli can influence behavior without participant awareness. We examined whether nonconscious priming can influence walking velocity on an instrumented walkway. Fifty-nine healthy participants were randomly assigned to unscramble sentences and answer self-concept questions containing words related to either the concepts elderly/passive or youthful/active. Walking velocity was measured before and after this priming manipulation. An ANOVA revealed a significant Group*Time interaction; the elderly/passive group showed a decrease in walking velocity over time while the youthful/active group showed an increase. None of the participants expressed any awareness of the study purpose and the experimenter was blind to group assignment. These results suggest that spoken or written material received by patients prior to gait assessments (such as casual conversations or written health inventories) might influence walking performance outside of client or clinician awareness. PMID- 23021254 TI - Knee and hip internal moments and upper-body kinematics in the frontal plane in unilateral transtibial amputees. AB - OBJECTIVE: The aim of this study was to quantify the motor adaptations in the frontal plane made by unilateral transtibial amputees (UTAs), with special regard to: (1) abduction/adduction moment at the hip and knee valgus moment in the frontal plane; (2) pelvic and thorax obliquity; and (3) stride length and gait speed. METHODS: 15 Males with unilateral transtibial amputation comprised the subject group and 15 non-disabled individuals served as control group. Gait analysis was performed using the VICON MOTION SYSTEM((r)) (Oxford Metrics, Oxford, UK). RESULTS: In this study, UTAs walked with a reduced hip abductor moment during the stance phase. At the knee joint, the valgus moment was reduced in the prosthetic limb compared to the sound and the control limb. The thorax range of motion in the frontal plane was increased on the prosthetic side, compared with the non amputee subjects. CONCLUSION: Our findings suggest that unilateral transtibial amputation patients walk with different motor control strategies in the frontal plane compared with the non-disabled subjects. These results suggest the need for specific training for this group of UTAs, focusing on exercises to stabilize and strengthen the proximal muscles as well as practicing balance and coordination in the coronal plane. PMID- 23021255 TI - An increase in milk IgA correlates with both pIgR expression and IgA plasma cell accumulation in the lactating mammary gland of PRM/Alf mice. AB - In mice, during late pregnancy and lactation, maternal precursors of IgA containing cells (cIgA-cells) are primed in the gut and home to the mammary gland where they secrete IgA. In turn, the ensuing increase in milk IgA mediates immune protection of the newborn gastrointestinal tract. PRM/Alf is an inbred mouse strain which exhibits a substantial post-natal intestinal lengthening which develops throughout the neonatal suckling period, suggesting that the availability of cIg-A cells and the level of protective IgA in milk might also be increased. We confirmed that PRM/Alf milk contains higher amounts of IgA than C57BL/6J throughout lactation, concomitantly with an increase of pIgR on epithelial cells and a higher density of cIgA-cells in the PRM/Alf mammary gland. Furthermore, a search for variations in cellular and humoral factors implicated in regulating cIgA-cell migration towards the mammary gland, including the vascular addressins MAdCAM-1 (mucosal addressin cell adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) as well as the mucosal epithelial chemokine CCL28, did not reveal any quantitative differences in expression between PRM/Alf and C57BL/6J mice strains. Thus our results indicate that these factors are not limiting in the recruitment of cIgA-cells released from the elongated gut of PRM/Alf mice. In the context of intestinal lengthening, these findings strengthen the notion of an entero-mammary gland link, where the neonatal gut is protected by the maternal gut through the immune function of the mammary gland. PMID- 23021256 TI - Absence of viruses in amniotic fluid of women with PPROM: a case series. AB - Preterm premature rupture of membranes (PPROM) and preterm birth are strongly linked to intrauterine inflammation. Bacterial infection is often not identified as the cause. The objective was to examine the amniotic fluid of women with PPROM for viral genomic content, and to correlate with the presence of bacterial infection and markers of intrauterine inflammation. A case series of 13 women with PPROM is presented. Amniocentesis was performed in each of these women. DNA/RNA isolated from amniotic fluid was tested using polymerase chain reaction (PCR) for the presence of herpes simplex virus (HSV)-1 and -2, adenovirus, adeno associated virus-2 (AAV-2), cytomegalovirus (CMV), parvovirus B19, human papilloma viruses (HPV), and enteroviruses. Maternal and neonatal hospital course and laboratory information, including results of amniotic fluid inflammatory marker testing and bacterial culture, were determined from the medical record. All amniotic fluid samples were negative for HSV-1 and HSV-2, adenovirus, AAV-2, CMV, parvovirus B19, HPV, and enteroviruses. Six of the 13 fluid samples (46%) had positive bacterial cultures, including culture for atypical organisms. In a small series of women, viral infection as assessed by the presence of viral genomic content in the amniotic fluid was not associated with PPROM. PMID- 23021257 TI - Amniotic fluid and maternal race influence responsiveness of fetal membranes to bacteria. AB - Spontaneous preterm birth (PTB) and preterm prelabor rupture of membranes (pPROM) occur more frequently in African-American women than in other racial groups. This may be due to an enhanced inflammatory response to pathogens associated with the condition. It is also possible that amniotic fluid (AF) has different immunomodulatory properties in African-American women that increase their risk of PTB and pPROM. To test this, we cultured fetal membranes from European-American and African-American women with sterile medium (control), Escherichia coli, Gardnerella vaginalis, Group B streptococci (GBS), Polyporphorans gingivalis, Mycoplasma hominis, Ureaplasma urealyticum or Ureaplasma parvum in the presence and absence of 50% autologous AF. Cytokine concentrations were quantified in the conditioned medium. All bacterial species increased IL-8 production. IL-1beta and TNF-alpha production were stimulated by LPS, E. coli, and G. vaginalis compared with control, but responses to Group B streptococci and P. gingivalis were limited to IL-1beta and TNF-alpha respectively. Genital mycoplasmas stimulated TNF-alpha and IL-10 but had no effect on IL-1beta production. African-Americans had twice the IL-1beta response to E. coli as European-Americans (P=0.031). Conversely, European-Americans produced more IL-8 in response to LPS than African Americans (P=0.026). AF had both pro- and anti-inflammatory properties that varied between races and pathogens. These results suggest that the host response to fetal membrane infections is complex and not generalizable. Interventions to prevent PTB and pPROM may need to be customized based on a patient's race, type of bacterial infection and factors in her AF. PMID- 23021258 TI - Poly(vinylidene fluoride) membranes by an ultrasound assisted phase inversion method. AB - Poly(vinylidene fluoride) (PVDF) membranes were prepared by an ultrasound assisted phase inversion process. The effect of ultrasonic intensity on the evolution of membrane morphology with and without the addition of pore former LiCl during precipitation process was comprehensively investigated. Besides the inter-diffusion between the solvent and nonsolvent, the ultrasonic cavitation was thought to have significant influences on phase inversion and the resultant membrane morphology. The mutual diffusion between water and solvent during the ultrasound assisted phase inversion process was measured. The crystalline structure was detected by wide angle X-ray diffractometer (WAXD). The thermal behavior was studied by differential scanning calorimeter (DSC). The mechanical strength, forward and reverse water flux, rejection to bovine serum albumin (BSA) and pepsin were also investigated. By the ultrasound assisted phase inversion method, ultra-filtration membrane was successfully prepared, which exhibited more preferable morphology, better mechanical property and more favorable permeability without sacrificing the rejection and thermal stability. PMID- 23021259 TI - Effects of FSH on the expression of receptors for oocyte-secreted factors and members of the EGF-like family during in vitro maturation in cattle. AB - FSH induces expansion of bovine cumulus-oocyte complexes (COCs) in cattle, which can be enhanced by oocyte-secreted factors (OSFs). In this study it was hypothesised that FSH stimulates COC expansion in part from direct stimulation of the epidermal growth factor (EGF)-like ligands amphiregulin (AREG), epiregulin (EREG) and betacellulin (BTC), but also in part through regulation of OSFs or their receptors in cumulus cells. Bovine COCs were cultured in defined medium with graded doses of FSH. In the absence of FSH, COCs did not expand. FSH caused cumulus expansion, and increased the abundance of AREG and EREG mRNA in a time- and dose-dependent manner, but decreased BTC mRNA levels. FSH had modest stimulatory effects on the levels of mRNA encoding the bone morphogenetic protein 15 (BMP15) receptor, BMPR1B, in cumulus cells, but did not alter mRNA expression of the growth and differentiation factor 9 (GDF9) receptor, TGFBR1. More interestingly, FSH dramatically stimulated levels of mRNA encoding two receptors for fibroblast growth factors (FGF), FGFR2C and FGFR3C, in cumulus cells. FSH also stimulated mRNA expression of FGFR1B, but not of FGFR2B in cumulus cells. Based on dose-response studies, FGFR3C was the receptor most sensitive to the influence of FSH. This study demonstrates that FSH stimulates the expression of EGF-like factors in bovine cumulus cells, and provides evidence that FSH differently regulates the expression of distinct receptors for OSFs in cumulus cells. PMID- 23021260 TI - Identification of the major proteins of an immune modulating fraction from adult Fasciola hepatica released by Nonidet P40. AB - Fasciola hepatica NP-40 released protein extract (FhNPE) exhibits potent Th1 immunosuppressive properties in vitro and in vivo. However, the protein composition of this active fraction, responsible for Th1 immune modulatory activity, has yet to be resolved. Therefore, FhNPE, a Nonidet P-40 extract, was subjected to a proteomic analysis in order to identify individual protein components. This was performed using an in house F. hepatica EST database following 2D electrophoresis combined with de novo sequencing based mass spectrometry. The identified proteins, a mixture of excretory/secretory and membrane-associated proteins, are associated with stress response and chaperoning, energy metabolism and cytoskeletal components. The immune modulatory properties of these identified protein(s) are discussed and HSP70 from F. hepatica is highlighted as a potential host immune modulator for future study. PMID- 23021261 TI - Performance of commercially available serological diagnostic tests to detect Leishmania infantum infection on experimentally infected dogs. AB - Leishmania infantum (syn. Leishmania chagasi) is the etiological agent of a widespread serious zoonotic disease that affects both humans and dogs. Prevalence and incidence of the canine infection are important parameters to determine the risk and the ways to control this reemergent zoonosis. Unfortunately, there is not a gold standard test for Leishmania infection. Our aim was to assess the operative validity of commercial tests used to detect antibodies to Leishmania in serum samples from experimental infections. Three ELISA tests (LEISCAN((r)) Leishmania ELISA Test, INGEZIM((r)) LEISHMANIA, and INGEZIM((r)) LEISHMANIA VET), three immunochromatographic tests (INGEZIM((r)) LEISHMACROM, SNAP((r)) Leishmania, and WITNESS((r)) Leishmania), and one IFAT were evaluated. LEISCAN((r)) Leishmania ELISA test achieved the highest sensitivity and accuracy (both 0.98). Specificity was 1 for all tests except for IFAT. All tests but IFAT obtained a positive predictive value of 1, while the maximum negative predictive value was achieved by LEISCAN((r)) Leishmania ELISA Test (0.93). The best positive likelihood ratio was obtained by INGEZIM((r)) LEISHMANIA VET (30.26), while the best negative likelihood ratio was obtained by LEISCAN((r)) Leishmania ELISA Test (0.02). The highest diagnostic odds ratio was achieved by LEISCAN((r)) Leishmania ELISA Test (729.00). The largest area under the ROC curve was obtained by LEISCAN((r)) Leishmania ELISA Test (0.981). Quantitative ELISA based tests performmed better than qualitative tests ("Rapid Tests"), and the test best suited to detect Leishmania in infected dogs and to provide clinically useful information was LEISCAN((r)) Leishmania ELISA Test. This and other results point also to the need of revising the status of IFAT as a gold standard for the diagnosis of leishmaniasis. PMID- 23021262 TI - Assessment of owner-administered monthly treatments with oral spinosad or topical spot-on fipronil/(S)-methoprene in controlling fleas and associated pruritus in dogs. AB - Monitoring of the performance of flea control products under conditions of natural challenge is valuable in assessing continued effectiveness and determining the ongoing relevance of laboratory studies. A multi-clinic, investigator-blinded study was undertaken in client-owned dogs to investigate and compare the flea control provided by 3 consecutive monthly treatments of oral spinosad (SPN) or fipronil/(S)-methoprene topical (FSM) spot-on. The first household dog meeting enrollment criteria and with at least 10 fleas (whole-body flea count) served as the index dog in a household against which primary objectives were set. Stratification was based on pruritus scores at the enrollment visit and on single or multiple pet household. Index pets were randomized to treatment with either SPN or FSM, dispensed on day 0 for at-home administration by owners. All other household dogs and cats, maximum 4 pets per household, were dispensed the same treatment as the index dog (spinetoram was dispensed for cats in SPN households). Subsequent treatments were dispensed when index dogs were returned for whole-body flea counts and pruritus-scoring at visits on days 30 and 60, with final assessments on day 90 (+/-5 days on each occasion). Primary endpoints were the number of flea-free index dogs in each group one month after the final treatment, the reduction in owner-reported pruritus, and the reduction from baseline mean flea counts. One hundred twenty eight index dogs were enrolled (65 in the SPN arm; 63 in the FSM arm) at 10 clinics in FL (6), NC (2), LA (1), and TX (1). On day 0, geometric mean flea counts were 57.7 (range: 10-1469) and 44.8 (10-717) for the SPN and FSM groups, respectively. On Day 90, 55 of 58 (95%) and 21 of 55 (38%) index dogs completing the study were flea-free in SPN and FSM groups, respectively; mean SPN pruritus scores declined to 0.92 (6.67 on day 0), and to 3.83 (6.33 on day 0) for FSM; geometric mean flea counts (% control) were 0.08 (99.9%) and 5.19 (88.4%), for SPN and FSM groups, respectively. Between-treatment differences were highly statistically significant (p<0.0001). In conclusion, SPN provided reliable flea control in client-owned dogs, regardless of challenge level. PMID- 23021263 TI - Evidence of intracellular stages in Trypanosoma (Megatrypanum) theileri in non phagocytic mammalian cells. AB - Trypanosoma (subgenus Megatrypanum) theileri was first identified over one hundred years ago, and is a widespread parasite in cattle. Its life cycle within the mammalian host has rarely been reported. Whether there is an intracellular stage in tissues is unknown and such a stage has not been demonstrated experimentally. Intriguingly, using Giemsa staining with light microscopy and transmission electron microscopy examination, we found that the parasite was able not only to attach to cells but also to invade several phagocytic and non phagocytic mammalian cells. Based on these findings, we conducted further investigations using a special antibody in immunofluorescence confocal images. Moreover, we examined a series of possible events of cell invasion in T. theileri. The results revealed that GM1, a marker of membrane rafts, was implicated in the mechanism of entry by this parasite. After incubation with tissue culture trypomastigotes, the gelatinolytic activity was significantly increased and accumulated at the attachment sites. Using ultrastructural localization detection by CytoTracker live imaging and confocal immunofluorescence microscopy, we found that lysosome fusion and the autophagy pathway were engaged in invaginating processes. T. theileri amastigotes also invaded cells and were enclosed by the lysosomes. Furthermore, tissue-cultured trypomastigotes were found to be capable of triggering intracellular free Ca(2+) transients and TGF-beta-signaling. Our findings that intracellular amastigote stages exist in mammalian cells infected with T. theileri and that the invasion processes involved various host cell components and cell signalings were extremely surprising and warrant further investigation. PMID- 23021266 TI - Wanted: a global campaign against epilepsy. PMID- 23021265 TI - In vitro inhibition of Eimeria tenella invasion of epithelial cells by phytochemicals. AB - Resistance to coccidiostats and possible future restrictions on their use raise the need for alternative methods of reducing coccidiosis in poultry. The aim of this study was to evaluate the effect of selected phytochemicals on Eimeria tenella sporozoite invasion in vitro. Four phytochemicals were selected on the basis that they reduce the virulence of Eimeria spp. and/or provide immune modulatory benefits to host cells: betaine, carvacrol, curcumin and Echinacea purpurea extract (EP). Madin-Darby bovine kidney (MDBK) cells were covered by medium containing phytochemicals at the highest concentration which was non-toxic to the cells. Salinomycin 50 MUg/ml was positive control; negative control was medium only. E. tenella (Houghton strain) sporozoites were added to wells and after incubation for 2, 4 or 20 h at 37 degrees C, cells were fixed and stained with hematoxylin-eosin. Ten evenly spaced fields per well were photographed and the percentage of cells invaded by sporozoites was calculated and normalized to the control. At 2h, carvacrol, curcumin and EP showed a significantly lower percentage of sporozoite invasion than the untreated control; in contrast, betaine treatment represented a significantly higher invasion percentage. Combining carvacrol with EP inhibited E. tenella invasion more effectively than applying the compounds individually, but the further addition of curcumin did not reduce invasion further. In conclusion, this study shows that invasion of MDBK epithelial cells by E. tenella sporozoites is inhibited in the presence of carvacrol, curcumin, or EP and enhanced by betaine. There may be potential for developing these phytochemicals as anti-coccidial feed or water additives for poultry. PMID- 23021264 TI - Cryptosporidium scrofarum n. sp. (Apicomplexa: Cryptosporidiidae) in domestic pigs (Sus scrofa). AB - We describe the morphological, biological, and molecular characteristics of Cryptosporidium pig genotype II and propose the species name Cryptosporidium scrofarum n. sp. to reflect its prevalence in adult pigs worldwide. Oocysts of C. scrofarum are morphologically indistinguishable from C. parvum, measuring 4.81 5.96 MUm (mean=5.16)*4.23-5.29 MUm (mean=4.83) with a length to width ratio of 1.07+/-0.06 (n=400). Oocysts of C. scrofarum obtained from a naturally infected pig were infectious for 8-week-old pigs but not 4-week-old pigs. The prepatent period in 8-week-old Cryptosporidium-naive pigs was 4-6 days and the patent period was longer than 30 days. The infection intensity of C. scrofarum in pigs was generally low, in the range 250-4000 oocysts per gram of feces. Infected pigs showed no clinical signs of cryptosporidiosis and no pathology was detected. Cryptosporidium scrofarum was not infectious for adult SCID mice, adult BALB/c mice, Mongolian gerbils (Meriones unguiculatus), southern multimammate mice (Mastomys coucha), yellow-necked mice (Apodemus flavicollis), or guinea pigs (Cavia porcellus). Phylogenetic analyses based on small subunit rRNA, actin, and heat shock protein 70 gene sequences revealed that C. scrofarum is genetically distinct from all known Cryptosporidium species. PMID- 23021267 TI - Domestic abuse in the UK. PMID- 23021268 TI - Superheart to the rescue. PMID- 23021269 TI - Women's and children's health: no time for complacency. PMID- 23021270 TI - Challenges of epilepsy in elderly people. PMID- 23021271 TI - Africa's changing mosquito dynamics. PMID- 23021274 TI - Charles Newton: changing perceptions of neurodisability in Africa. PMID- 23021275 TI - Zinc for probable serious bacterial infection in infants. PMID- 23021276 TI - Zinc for probable serious bacterial infection in infants. PMID- 23021277 TI - Zinc for probable serious bacterial infection in infants. PMID- 23021278 TI - Reducing preterm births in China. PMID- 23021280 TI - Reducing the global burden of congenital rubella syndrome. PMID- 23021282 TI - Health and the built environment. PMID- 23021283 TI - Controlled cord traction in active management of the third stage of labour. PMID- 23021284 TI - The Lancet: the real media and the true voice of doctors. PMID- 23021285 TI - Family planning, health systems, and the health workforce. PMID- 23021286 TI - World Rabies Day: evidence of rise in paediatric rabies cases in Malawi. PMID- 23021288 TI - Epilepsy in poor regions of the world. AB - Epilepsy is a common disorder, particularly in poor areas of the world, and can have a devastating effect on people with the disorder and their families. The burden of epilepsy in low-income countries is more than twice that found in high income countries, probably because the incidence of risk factors is higher. Many of these risk factors can be prevented with inexpensive interventions, but there are only a few studies that have assessed the effect of reducing risk factors on the burden of epilepsy. The mortality associated with epilepsy in low-income countries is substantially higher than in less impoverished countries and most deaths seem to be related to untreated epilepsy (eg, as a result of falls or status epilepticus), but the risk factors for death have not been adequately examined. Epilepsy is associated with substantial stigma in low-income countries, which acts as a barrier to patients accessing biomedical treatment and becoming integrated within society. Seizures can be controlled by inexpensive antiepileptic drugs, but the supply and quality of these drugs can be erratic in poor areas. The treatment gap for epilepsy is high (>60%) in deprived areas, but this could be reduced with low-cost interventions. The substantial burden of epilepsy in poor regions of the world can be reduced by preventing the risk factors, reducing stigma, improving access to biomedical diagnosis and treatment, and ensuring that there is a continuous supply of good quality antiepileptic drugs. PMID- 23021289 TI - Appendiceal intussusception caused by endometriosis. PMID- 23021290 TI - Traditional preparations used as uterotonics in Sub-Saharan Africa and their pharmacologic effects. AB - BACKGROUND: Little is known about the use of traditional preparations for uterotonic effects at or near delivery in Sub-Saharan Africa. OBJECTIVE: To describe (1) use of traditional preparations in Sub-Saharan Africa intended to have uterotonic effects at or near birth; and (2) results of pharmacologic investigations of the uterotonic properties of such preparations. SEARCH STRATEGY: Structured review of 13 databases. SELECTION CRITERIA: Articles describing use of traditional preparations in Sub-Saharan Africa with primary data, published in English between January 1, 1980 and June 30, 2010. DATA COLLECTION AND ANALYSIS: Full-text review using standard spreadsheet templates. MAIN RESULTS: Objective 1 analysis identified 208 plant species used for uterotonic effects at or near delivery. The most common use was labor induction/augmentation (n=185). Other uses were to expel the placenta, shorten the third stage of labor, manage retained placenta (n=61), and prevent/manage postpartum hemorrhage (n=20). Objective 2 analysis identified 82 species with uterotonic activity confirmed through pharmacologic evaluation. Studies also identified potentiating/inhibiting effects of extracts on pharmaceutical uterotonics. CONCLUSION: Numerous plants are used for uterotonic effects in Sub Saharan Africa; uterotonic activity has been confirmed in many through pharmacologic evaluation. Such use may increase the risk of adverse outcomes. Further research is needed on the uterotonic efficacy of traditional preparations and on interventions to address use during labor. PMID- 23021287 TI - Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. AB - Epilepsy is a common neurological disorder that is complicated by psychiatric, cognitive, and social comorbidities that have become a major target of concern and investigation in view of their adverse effect on the course and quality of life. In this report we define the specific psychiatric, cognitive, and social comorbidities of paediatric and adult epilepsy, their epidemiology, and real life effects; examine the relation between epilepsy syndromes and the risk of neurobehavioural comorbidities; address the lifespan effect of epilepsy on brain neurodevelopment and brain ageing and the risk of neurobehavioural comorbidities; consider the overarching effect of broader brain disorders on both epilepsy and neurobehavioural comorbidities; examine directions of causality and the contribution of selected epilepsy-related characteristics; and outline clinic friendly screening approaches for these problems and recommended pharmacological, behavioural, and educational interventions. PMID- 23021291 TI - Evolving food retail environments in Thailand and implications for the health and nutrition transition. AB - OBJECTIVE: To investigate evolving food retail systems in Thailand. DESIGN: Rapid assessment procedures based on qualitative research methods including interviews, focus groups discussions and site visits. SETTING: Seven fresh markets located in the four main regions of Thailand. SUBJECTS: Managers, food specialists, vendors and shoppers from seven fresh markets who participated in interviews and focus group discussions. RESULTS: Fresh markets are under economic pressure and are declining in number. They are attempting to resist the competition from supermarkets by improving convenience, food diversity, quality and safety. CONCLUSIONS: Obesity has increased in Thailand at the same time as rapid growth of modern food retail formats has occurred. As fresh markets are overtaken by supermarkets there is a likely loss of fresh, healthy, affordable food for poorer Thais, and a diminution of regional culinary culture, women's jobs and social capital, with implications for the health and nutrition transition in Thailand. PMID- 23021292 TI - Mental Health Research in Spain: a bit more than green shoots. PMID- 23021293 TI - Hearing voices--the significance of psychotic symptoms among young people. PMID- 23021294 TI - Secondary effects of antipsychotic treatment in naive or quasi-naive children and adolescents: design of a follow-up protocol and baseline results. AB - INTRODUCTION: The prescribing of anti-psychotic drugs has become a normal clinical practice. METHODS: This article presents a longitudinal, multicentre study of 12 months conducted on 266 children and adolescents who were prescribed a first or second generation antipsychotic drug for the first time, and the baseline results of the study. The follow-up protocol had as its purpose to detect the possible appearance of metabolic, cardiological, and motor changes. RESULTS: When the presence of side effects was evaluated using the UKU (clinical side-effects scale) statistically significant differences were found between naive (patients who had never taken an anti-psychotic drug) and quasi-naive patients (those who have taken anti-psychotic drugs for a period of less than 30 days), with a greater number of the latter showing symptoms of: anxiety/laxity/tiredness (P=.0049), drowsiness/sedation (P<.001), increase in dream duration (P<.001), increase in dreams (P=.0199), emotional indifference (P=.0194), hypokinesia/akinesia (P=.0224), paresthesias (P=.0049), accommodation disorder (P=.0254), increase in salivation (P<.001), polyuria/polydipsia (P=.0076), increase in sweating (P=.0076), increase in sexual desire (P=.0117), decrease in sexual desire (P=.0053), tension headaches (P=.0405). When the presence of extrapyramidal symptoms was assessed using the MPRC-IMS (Maryland Psychiatry Research Center-Involuntary Movements) Scale, it was observed that the quasi-naive patients had a statistically higher number of dyskinesia (P=.002), Parkinsonism (P=.0004) and akathisia (P=.0437) symptoms compared to the naive patients. CONCLUSIONS: These results show that, in the childhood-adolescent population, the presence of secondary effects begins to be observed from the first dose of the antipsychotic drug. PMID- 23021295 TI - Criterion and concurrent validity of Conners Adult ADHD Diagnostic Interview for DSM-IV (CAADID) Spanish version. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in adulthood. Its diagnosis requires a retrospective evaluation of ADHD symptoms in childhood, the continuity of these symptoms in adulthood, and a differential diagnosis. For these reasons, diagnosis of ADHD in adults is a complex process which needs effective diagnostic tools. AIM: To analyse the criterion validity of the CAADID semi-structured interview, Spanish version, and the concurrent validity compared with other ADHD severity scales. METHODS: An observational case-control study was conducted on 691 patients with ADHD. They were out-patients treated in a program for adults with ADHD in a hospital. RESULTS: A sensitivity of 98.86%, specificity 67.68%, positive predictive value 90.77% and a negative predictive value 94.87% were observed. Diagnostic precision was 91.46%. The kappa index concordance between the clinical diagnostic interview and the CAADID was 0.88. Good concurrent validity was obtained, the CAADID correlated significantly with WURS scale (r=0.522, P<.01), ADHD Rating Scale (r=0.670, P<.0.1) and CAARS (self-rating version; r=0.656, P<.01 and observer-report r=0.514, P<.01). CONCLUSION: CAADID is a valid and useful tool for the diagnosis of ADHD in adults for clinical, as well as for research purposes. PMID- 23021296 TI - Adherence to lifestyle recommendations by patients with depression. AB - INTRODUCTION: There is an increasing amount of evidence showing that physical activity and sun exposure are effective coadjuvant treatments for patients with mild to moderate depression. However, there is a lack of information regarding patient's adherence to these recommendations in daily clinical practice. METHODS: We conducted a study including 15 depressive patients who had been under antidepressant treatment for at least one month. They wore a wrist-watch-like actimetry sensor to measure physical activity and sun exposure 24 hours a day. After one week of baseline assessment, patients were randomised into one of the two arms of the study. Patients in the experimental group received a brief note in which they were explicitly asked to increase both their physical activity level and time of sun exposure, while control group patients did not receive these explicit recommendations. RESULTS: One week after recommendations were delivered, only patients in the experimental group had increased time of sun exposure and physical activity (25.8% and 14.3%, respectively). CONCLUSIONS: Depressive patients are able to follow prescribed lifestyle recommendations in the short-term. PMID- 23021297 TI - Effectiveness and pattern of use of continuation and maintenance electroconvulsive therapy. AB - Patients with major depressive disorder (MDD) who require an acute course of electroconvulsive therapy (ECT) have high relapse rates. Therefore, an effective maintenance treatment strategy needs to be established. Continuation and maintenance ECT (C/M-ECT) could be an adequate treatment option, although the lack of controlled studies has led to its usefulness being questioned. This review includes a detailed description of studies on the effectiveness/efficacy of ECT in MDD. Despite their methodological limitations, the results appear to support the idea that C/M-ECT would be a safe and effective alternative, especially in patients with severe and recurrent disease. Nevertheless, more controlled studies are needed to provide new evidence and allow a more accurate assessment of the efficacy, safety and pattern of use of C/M-ECT. PMID- 23021298 TI - Severe hypernatraemia associated with lithium treatment. PMID- 23021299 TI - Structure and stability of warfarin-sodium inclusion complexes formed with permethylated monoamino-beta-cyclodextrin. AB - Inclusion complexes of warfarin enantiomers with permethylated monoamino-beta cyclodextrin (PMMABCD) were characterized using CE and (1)H NMR spectroscopy in aqueous solution. These techniques gave complementary information on the stability and the structure of the diastereomeric host-guest inclusion complexes. The stability constants were determined from CE experiments in a wide pH range. Change in the migration order on the variation of the pH was observed. (1)H NMR assignments have been established for the seven non-equivalent carbohydrate units of the host in the complex at pH 7-9. Specific H-H distance restraints were obtained from NOESY experiments and were introduced into molecular modeling to establish the geometry of the inclusion complexes. It was found that the open side chain warfarin enters the cavity from the primary side of the CD. The orientation of the coumarin ring within the cavity has the same preference for the two warfarin enantiomers owing to an ionic interaction with the amino group of the CD. Accordingly, enantioselectivity at pH 8.5 arises from the difference in the CH/pi interactions between warfarin aromatics and the manifold of CH groups of the CD. PMID- 23021300 TI - Antibiotic resistance patterns of Acinetobacter calcoaceticus-A. baumannii complex species from Colombian hospitals. AB - INTRODUCTION: Only automated phenotypic methods are currently used in Colombian hospitals for identifying isolates of the Acinetobacter calcoaceticus-A. baumannii complex (ACB). The phenotypical similarities in these species mean that they cannot be differentiated by manual or automated methods, thereby leading to their identification as A. baumannii, or ACB complex in clinical settings. Our objective was to identify to the species level 60 isolates, from four hospitals, evaluate their antibiotic susceptibility, and detect resistance-related genes. METHODS: 16S-23S rRNA internal transcribed spacer (ITS) region and rpoB gene partial sequences were amplified. Resistance genes for cephalosporin, carbapenem and aminoglycoside were detected by PCR. Possible mutations in the quinolone resistance-determining region (QRDR) were evaluated. The association of ISAba-1 with blaOXA and blaADC genes was determined by PCR. Amplification products of ITS region, rpoB gene and some resistance genes were sequenced and compared using the BLAST tool. RESULTS: 16S-23S rRNA ITS region and partial rpoB gene sequence analysis allowed 51isolates to be identified as A. baumannii, 8 as A. nosocomialis, and 1 isolate as A. pitti. A. baumannii isolates were highly resistant to all antibiotics tested, while the others were susceptible to ciprofloxacin and ampicillin/sulbactam. Quinolone resistance, found only in A. baumannii, was associated with mutations in the QRDR region of gyrA and parC genes. CONCLUSION: This is the first investigation in Colombia that has identified ACB complex species using molecular methods, and determined differences in antibiotic resistance and resistance genes among the species. It is of the highest importance to identify isolates to the species level for future resistance and epidemiology studies in our region. PMID- 23021301 TI - Sequence and comparative analysis of the genome of HSV-1 strain McKrae. AB - Ocular infection by HSV-1 strain McKrae is neurovirulent in both mice and rabbits and causes fatal encephalitis in approximately 50% of animals. In addition, it spontaneously reactivates with high frequency relative to other HSV-1 strains in rabbits. We sequenced the McKrae strain genome and compared its coding protein sequences with those of six other HSV-1 strains. Most of the 74 predicted protein sequences are conserved; only eleven are less than 98% conserved. Eight proteins were identified to be unique for McKrae based on sequence homology bit score ratio (BSR). These include five proteins showing significant variations (RL1, RS1, UL49A, US7 and US11), two truncated proteins (UL36 and UL56) and one (US10) containing an extended open reading frame. The McKrae strain also has unique features in its 'a' sequence and non-coding sequences, such as LAT and miRNA. These data are indicative of strain variation but need further work to connect observed differences with phenotype effects. PMID- 23021302 TI - Management of high-risk patients with aortic stenosis and coronary artery disease. AB - BACKGROUND: Aortic valve replacement with coronary artery bypass graft surgery is currently the standard therapy for patients with aortic stenosis and concomitant coronary artery disease. We sought to determine whether transcatheter aortic valve implantation combined with percutaneous coronary intervention might be an equivalent strategy. METHODS: A total of 243 high-risk patients (Society of Thoracic Surgeons [STS] score >10% and/or European System for Cardiac Operative Risk Evaluation [EuroSCORE] >15%) presenting with aortic stenosis with concomitant coronary artery disease were studied. Patients were treated either by surgical aortic valve replacement combined with coronary artery bypass graft (group 1, n = 184) or by percutaneous coronary intervention within 12 months before transapical or transfemoral transcatheter aortic valve implantation (group 2, n = 59). A propensity score adjusted regression analysis was used to compare 30-day mortality as the primary study endpoint between the groups. RESULTS: Group 1 mean age (75 +/- 6 years), EuroSCORE (18.1% +/- 13.8%), and STS score (13.1% +/ 8.7%) were significantly different from group 2 (mean age 80 +/- 6 years, EuroSCORE 27.5% +/- 16.3%, and STS score 16.7% +/- 10.5%; p < 0.001). Thirty-day mortality was 12.5% in group 1 compared with 11.9% in group 2 (odds ratio 0.94, 95% confidence interval: 0.38 to 2.32, p = 0.89). Univariate analysis revealed left ventricular ejection fraction, pulmonary hypertension, renal insufficiency, STS score, EuroSCORE, and previous cardiac surgery as predictors for 30-day mortality (p < 0.05). Risk-adjusted multivariate regression analysis showed only left ventricular ejection fraction to be strongly associated with 30-day mortality and confirmed no significant difference between the groups (p = 0.44). To further control for study bias, a 10-layer propensity score model based on the univariate analysis again indicated equivalence regarding the primary endpoint (p = 0.33). CONCLUSIONS: The present study demonstrates that transcatheter aortic valve implantation in combination with prior percutaneous coronary intervention within 12 months produces similar results in a propensity score matched high-risk patient population. PMID- 23021303 TI - Functional investigation of Fas ligand expressions in human non-small cell lung cancer cells and its clinical implications. AB - BACKGROUND: The purpose of this study is to investigate whether Fas ligand is functionally expressed in human lung cancer cells and to verify our hypothesis that specific inhibition of cancer-expressed FasL can improve the cellular immunity against cancer cells. METHODS: The primary lung cancer cells (PLCCs) and autologous tumor-infiltrating lymphocytes (TILs) were separated from the surgical tissue samples. Western blot and immunofluorescence flow cytometry were used to detect the expressions of FasL. The FasL-specific small interfering (si)RNA was used to downregulate the expression of FasL, and a neutralizing mAb was used to block the ligation between FasL and Fas. Cancer cells and immune cells were alternatively selected as the effector cells or the target cells according to the different purposes. Cytotoxicity and apoptosis assays were used to detect the growth inhibition and apoptosis. The A549 cells and Jurkat T cells were co cultured to study whether there is a counterattack against T cells. The PLCCs were co-cultured with autologous TILs to study whether specific blockage of cancer-expressed FasL can improve the TILs' cytotoxicity. RESULTS: The FasL is functionally expressed in human lung cells and can facilitate cancer cells to counterattack immune cells. Activated immune cells are more vulnerable to counterattack. Targeting A549-expressed FasL by siRNA could significantly abrogate counterattack while blockade of PLCCs-expressed FasL by a neutralizing mAb could enhance TILs' cytotoxicity. CONCLUSIONS: The improvement of cellular immunity against lung cancer depends on both activation and protection of immune cells. The specific inhibition of cancer-expressed FasL is effective in protecting immune cells, thus making FasL a new therapeutic target for cancer treatment. PMID- 23021304 TI - Associations between nosocomial meticillin-resistant Staphylococcus aureus and nosocomial Clostridium difficile-associated diarrhoea in 89 German hospitals. AB - BACKGROUND: Clostridium difficile is mainly considered as a hospital-acquired pathogen causing diarrhoea in healthcare settings. AIM: To quantify and compare the incidence density of hospital-acquired meticillin-resistant Staphylococcus aureus (MRSA) and C. difficile-associated infection (CDI) in a network of German hospitals; also to assess whether there is an association between nosocomial MRSA and nosocomial CDI. METHODS: Acute hospitals reported data on the number of patients, patient-days and MRSA and/or CDI cases to the German nosocomial infection surveillance system (KISS). Cases were classified as nosocomial or imported. Nosocomial incidences and incidence densities (per 1000 patient-days) of MRSA and CDI were calculated by Spearman correlation index. RESULTS: In 2010, a total of 89 hospitals reported hospital-wide MRSA and CDI cases. The analysis included 1,536,031 patients, 11,138,496 patient-days, 5183 nosocomial CDI cases and 2233 nosocomial MRSA cases. The pooled incidence density of nosocomial CDI was 0.47, more than two-fold higher than that of nosocomial MRSA (0.20). Correlation of nosocomial incidences of MRSA and CDI was statistically significant [correlation coefficient (CC) of 0.515]. Correlation of incidence densities was likewise significant with a CC of 0.484. CONCLUSIONS: The incidence of nosocomial CDI was twice as high as nosocomial MRSA incidence among our database and with the definitions used. High nosocomial MRSA or CDI cases might be indicators for deficits in infection control and/or selection pressure of antibiotics. PMID- 23021305 TI - Breast vibro-acoustography: initial results show promise. AB - INTRODUCTION: Vibro-acoustography (VA) is a recently developed imaging modality that is sensitive to the dynamic characteristics of tissue. It detects low frequency harmonic vibrations in tissue that are induced by the radiation force of ultrasound. Here, we have investigated applications of VA for in vivo breast imaging. METHODS: A recently developed combined mammography-VA system for in vivo breast imaging was tested on female volunteers, aged 25 years or older, with suspected breast lesions on their clinical examination. After mammography, a set of VA scans was acquired by the experimental device. In a masked assessment, VA images were evaluated independently by 3 reviewers who identified mass lesions and calcifications. The diagnostic accuracy of this imaging method was determined by comparing the reviewers' responses with clinical data. RESULTS: We collected images from 57 participants: 7 were used for training and 48 for evaluation of diagnostic accuracy (images from 2 participants were excluded because of unexpected imaging artifacts). In total, 16 malignant and 32 benign lesions were examined. Specificity for diagnostic accuracy was 94% or higher for all 3 reviewers, but sensitivity varied (69% to 100%). All reviewers were able to detect 97% of masses, but sensitivity for detection of calcification was lower (<= 72% for all reviewers). CONCLUSIONS: VA can be used to detect various breast abnormalities, including calcifications and benign and malignant masses, with relatively high specificity. VA technology may lead to a new clinical tool for breast imaging applications. PMID- 23021306 TI - Commentary: extensive cortical involvement in leptomeningeal carcinomatosis. PMID- 23021307 TI - Validation of a Mexican food photograph album as a tool to visually estimate food amounts in adolescents. AB - The aim of the present study was to validate a food photograph album (FPA) as a tool to visually estimate food amounts, and to compare this estimation with that attained through the use of measuring cups (MC) and food models (FM). We tested 163 foods over fifteen sessions (thirty subjects/session; 10-12 foods presented in two portion sizes, 20-24 plates/session). In each session, subjects estimated food amounts with the assistance of FPA, MC and FM. We compared (by portion and method) the mean estimated weight and the mean real weight. We also compared the percentage error estimation for each portion, and the mean food percentage error estimation between methods. In addition, we determined the percentage error estimation of each method. We included 463 adolescents from three public high schools (mean age 17.1 (sd 1.2) years, 61.8 % females). All foods were assessed using FPA, 53.4 % of foods were assessed using MC, and FM was used for 18.4 % of foods. The mean estimated weight with all methods was statistically different compared with the mean real weight for almost all foods. However, a lower percentage error estimation was observed using FPA (2.3 v. 56.9 % for MC and 325 % for FM, P< 0.001). Also, when analysing error rate ranges between methods, there were more observations (P< 0.001) with estimation errors higher than 40 % with the MC (56.1 %), than with the FPA (27.5 %) and FM (44.9 %). In conclusion, although differences between estimated and real weight were statistically significant for almost all foods, comparisons between methods showed FPA to be the most accurate tool for estimating food amounts. PMID- 23021309 TI - V-shaped lymph node dissection in laparoscopic distal gastrectomy; new technique of intra-abdominal dissection and surgical outcomes. AB - BACKGROUND: Recently, laparoscopic-assisted distal gastrectomy (LADG) has become popular for the treatment of early gastric cancer. Furthermore, the use of totally laparoscopic gastrectomy (TLG), a more difficult procedure than LADG, has been increasing in Japan. Laparoscopic-assisted distal gastrectomy is currently performed more frequently than laparoscopic distal gastrectomy (LDG) in hospitals in Japan. METHOD: Reconstruction after LDG is commonly performed extra abdominally and lymph node dissection of the lesser curvature is performed at the same time. We have developed a new method of intra-abdominal lymph node dissection for the lesser curvature. RESULTS: Our technique showed positive results, is easy to perform, and is reasonable in terms of general oncology theory. CONCLUSION: In oncological therapy, this technique could be a valuable surgical option for totally laparoscopic surgery. PMID- 23021308 TI - Toxicological properties of emission particles from heavy duty engines powered by conventional and bio-based diesel fuels and compressed natural gas. AB - BACKGROUND: One of the major areas for increasing the use of renewable energy is in traffic fuels e.g. bio-based fuels in diesel engines especially in commuter traffic. Exhaust emissions from fossil diesel fuelled engines are known to cause adverse effects on human health, but there is very limited information available on how the new renewable fuels may change the harmfulness of the emissions, especially particles (PM). We evaluated the PM emissions from a heavy-duty EURO IV diesel engine powered by three different fuels; the toxicological properties of the emitted PM were investigated. Conventional diesel fuel (EN590) and two biodiesels were used - rapeseed methyl ester (RME, EN14214) and hydrotreated vegetable oil (HVO) either as such or as 30% blends with EN590. EN590 and 100% HVO were also operated with or without an oxidative catalyst (DOC + POC). A bus powered by compressed natural gas (CNG) was included for comparison with the liquid fuels. However, the results from CNG powered bus cannot be directly compared to the other situations in this study. RESULTS: High volume PM samples were collected on PTFE filters from a constant volume dilution tunnel. The PM mass emission with HVO was smaller and with RME larger than that with EN590, but both biofuels produced lower PAH contents in emission PM. The DOC + POC catalyst greatly reduced the PM emission and PAH content in PM with both HVO and EN590. Dose-dependent TNFalpha and MIP-2 responses to all PM samples were mostly at the low or moderate level after 24-hour exposure in a mouse macrophage cell line RAW 264.7. Emission PM from situations with the smallest mass emissions (HVO + cat and CNG) displayed the strongest potency in MIP-2 production. The catalyst slightly decreased the PM-induced TNFalpha responses and somewhat increased the MIP-2 responses with HVO fuel. Emission PM with EN590 and with 30% HVO blended in EN590 induced the strongest genotoxic responses, which were significantly greater than those with EN590 + cat or 100% HVO. The emission PM sample from the CNG bus possessed the weakest genotoxic potency but had the strongest oxidative potency of all the fuel and catalyst combinations. The use of 100% HVO fuel had slightly weaker and 100% RME somewhat stronger emission PM induced ROS production, when compared to EN590. CONCLUSIONS: The harmfulness of the exhaust emissions from vehicle engines cannot be determined merely on basis of the emitted PM mass. The study conditions and the engine type significantly affect the toxicity of the emitted particles. The selected fuels and DOC + POC catalyst affected the PM emission from the heavy EURO IV engine both qualitative and quantitative ways, which influenced their toxicological characteristics. The plain HVO fuel performed very well in emission reduction and in lowering the overall toxicity of emitted PM, but the 30% blend of HVO in EN590 was no better in this respect than the plain EN590. The HVO with a DOC + POC catalyst in the EURO IV engine, performed best with regard to changes in exhaust emissions. However some of the toxicological parameters were significantly increased even with these low emissions. PMID- 23021310 TI - Can subject-specific single-fibre electrically evoked auditory brainstem response data be predicted from a model? AB - This article investigates whether prediction of subject-specific physiological data is viable through an individualised computational model of a cochlear implant. Subject-specific predictions could be particularly useful to assess and quantify the peripheral factors that cause inter-subject variations in perception. The results of such model predictions could potentially be translated to clinical application through optimisation of mapping parameters for individual users, since parameters that affect perception would be reflected in the model structure and parameters. A method to create a subject-specific computational model of a guinea pig with a cochlear implant is presented. The objectives of the study are to develop a method to construct subject-specific models considering translation of the method to in vivo human models and to assess the effectiveness of subject-specific models to predict peripheral neural excitation on subject level. Neural excitation patterns predicted by the model are compared with single fibre electrically evoked auditory brainstem responses obtained from the inferior colliculus in the same animal. Results indicate that the model can predict threshold frequency location, spatial spread of bipolar and tripolar stimulation and electrode thresholds relative to one another where electrodes are located in different cochlear structures. Absolute thresholds and spatial spread using monopolar stimulation are not predicted accurately. Improvements to the model should address this. PMID- 23021311 TI - Biotransformation of oral contraceptive ethynodiol diacetate with microbial and plant cell cultures. AB - BACKGROUND: Biotransformation by using microbial and plant cell cultures has been applied effectively for the production of fine chemicals on large scale. Inspired by the wealth of literature available on the biotransformation of steroids, we decided to investigate the biotransformation of ethynodiol diacetate (1) by using plant and microbial cultures. RESULTS: The biotransformation of ethynodiol diacetate (1) with Cunninghamella elegans and plant cell suspension cultures of Ocimum basilicum and Azadirachta indica is being reported here for the first time. Biotransformation of 1 with Cunninghamella elegans yielded three new hydroxylated compounds, characterized as 17alpha-ethynylestr-4-en 3beta,17beta-diacetoxy-6alpha-ol (2), 17alpha-ethynylestr-4-en-3beta,17beta diacetoxy-6beta-ol (3), and 17alpha-ethynylestr-4-en-3beta,17beta-diacetoxy 10beta-ol (4) and a known metabolite, 17alpha-ethynyl-17beta-acetoxyestr-4-en-3 one (5). The biotransformation of 1 with Ocimum basilicum included hydrolysis of the ester group, oxidation of alcohol into ketone, and rearrangement of the hydroxyl group. Thus four major known metabolites were characterized as 17alpha ethynyl-17beta-acetoxyestr-4-en-3-one (5), 17alpha-ethynyl-17beta-hydroxyestr-4 en-3-one (6), 17alpha-ethynyl-3 beta-hydroxy-17beta-acetoxyestr-4-ene (7) and 17alpha-ethynyl-5alpha,17beta-dihydroxyestr-3-ene (8). Biotransformation of 1 with Azadirachta indica culture yielded compounds 5 and 6. Spectroscopic data of compound 8 is being reported for the first time. Structure of compound 6 was unambiguously deduced through single-crystal x-ray diffraction studies. CONCLUSION: Biotransformation of an oral contraceptive, ethynodiol diacetate (1), by using microbial and plant cell cultures provides an efficient route to the synthesis of a library of new steroids with potential contraceptive properties. These methods can be employed in the production of such compounds with high stereoselectivity. PMID- 23021312 TI - Burn-injured adults with long term functional impairments demonstrate the same response to resistance training as uninjured controls. AB - OBJECTIVE: The catabolic response associated with major burn injuries results in loss of lean body mass (LBM) and prolonged muscle weakness. Exercise training improves LBM and muscle strength in burn-injured children in the acute post injury phase, yet it is unknown whether adults will experience the same benefits when exercise training is implemented at least two years post injury. PROCEDURES: Nine burn-injured participants (%TBSA=42+/-18.38; time since injury=6.56+/-3.68 years) and 9 matched controls participated in a 12-week interval training and resistance exercise programme. Muscle strength was assessed via isokinetic dynamometry and LBM was determined via dual energy X-ray absorptiometry. Both measures were administered prior to and following the exercise programme. RESULTS: There was no significant difference in LBM or strength between the two groups at baseline. Following the exercise programme, both groups displayed significant improvements in LBM and in hip, shoulder and elbow muscle strength. There was no significant difference in muscle strength or LBM, between the groups, following the exercise training. CONCLUSION: A combined exercise training programme was able to improve muscle strength and lean body mass in adults with burn injury. There was no difference between the two groups in their response to the exercise programme, therefore general exercise prescription principles may be applied directly to the burns population. PMID- 23021313 TI - Use of food supplements and determinants of usage in a sample Italian adult population. AB - OBJECTIVE: The aims were to collect data on consumption of different food supplements in a sample of the adult Italian population and to characterize users by demographic, physical and health-related characteristics, lifestyle and behaviour. DESIGN: Cross-sectional survey. SETTING: The study was conducted in 2008 in ten towns of Italy (two towns from each of the five macro-areas: Northwest, Northeast, Centre, South and Islands). SUBJECTS: Adults (n 10 000) aged >=18 years were randomly selected and asked to fill in a self-administered questionnaire regarding their use of food supplements and the above variables. The effect of these variables on food supplement use was evaluated by univariate and multivariate logistic regression. RESULTS: Of the 1723 individuals who returned the questionnaire, 49% were users of food supplements. A large proportion (54%) of users used more than one category of food supplement: vitamin and/or mineral supplements were the most used (61%), followed by supplements with botanicals and botanical extracts (28%). The results obtained by logistic regression showed that gender, town size, education level, sports practice, regular use of wholemeal cereal-based foods and presence of a low stress level were determinants for the use of food supplements in the examined population. However, these determinants were not shared by all categories of supplements. CONCLUSIONS: The results of this preliminary study highlight that associations between demographic, dietary and lifestyle factors and use of different categories of food supplements differ according to products, and cannot be accounted for simply by dichotomizing individuals as users or non-users. PMID- 23021314 TI - Gibberellic acid alleviates cadmium toxicity by reducing nitric oxide accumulation and expression of IRT1 in Arabidopsis thaliana. AB - Gibberellic acid (GA) is involved in not only plant growth and development but also plant responses to abiotic stresses. Here it was found that treating the plants with GA concentrations from 0.1 to 5 MUM for 24 h had no obvious effect on root elongation in the absence of cadmium (Cd), whereas in the presence of Cd2+, GA at 5 MUM improved root growth, reduced Cd content and lipid peroxidation in the roots, indicating that GA can partially alleviate Cd toxicity. Cd2+ increased nitric oxide (NO) accumulation in the roots, but GA remarkably reduced it, and suppressed the up-regulation of the expression of IRT1. In contrary, the beneficial effect of GA on alleviating Cd toxicity was not observed in an IRT1 knock-out mutant irt1, suggesting the involvement of IRT1 in Cd2+ absorption. Furthermore, the GA-induced reduction of NO and Cd content can also be partially reversed by the application of a NO donor (S-nitrosoglutathione [GSNO]). Taken all these together, the results showed that GA-alleviated Cd toxicity is mediated through the reduction of the Cd-dependent NO accumulation and expression of Cd2+ uptake related gene-IRT1 in Arabidopsis. PMID- 23021315 TI - Polycyclic aromatic hydrocarbons in PM2.5 in Guangzhou, southern China: spatiotemporal patterns and emission sources. AB - Fine particulate samples were simultaneously collected at six sites in Guangzhou in November-December 2009. Eighteen polycyclic aromatic hydrocarbons (PAHs) and tracers, i.e. hopanes, elemental carbon, picene and levoglucosan were measured. Three high level episodes were observed during the sampling period, likely due to accumulation effects. Back trajectory analysis revealed that the air masses for the three episodes were from eastern inland Pearl River Delta (PRD) region. There was no obvious concentration gradient for total and 5-6 ring PAHs such as benzo[g,h,i]perylene (BghiP) from urban to rural sites. However, 4-ring PAHs such as pyrene (Pyr) exhibited significantly higher levels at rural site than that at urban/suburban sites (p<0.01). BghiP correlated well with hopanes, elemental carbon and picene, indicating vehicular emissions and coal combustion were the sources of 5-6 ring PAHs, which were further confirmed by comparing the four tracers/BghiP ratios and IcdP/BghiP ratios in ambient samples with those from source profiles. Results indicated that vehicular emissions were no longer the dominant sources in winter season in Guangzhou. PMID- 23021316 TI - The impacts of silver nanoparticles and silver ions on wastewater biological phosphorous removal and the mechanisms. AB - The effects of AgNPs and Ag+ (0-5 mg/L) on wastewater enhanced biological phosphorus removal (EBPR) were investigated. The phosphorus removal efficiency was maintained at 99% no matter what the concentrations of AgNPs were, but it was decreased to 48.8% at Ag+ of 1 mg/L, and no net phosphorus was removed at Ag+ greater than 2 mg/L in the batch tests. The uptake of wastewater carbon source and the anaerobic and aerobic transformations of phosphorus, polyhydoxyalkanoates and glycogen were inhibited by Ag+ other than AgNPs. Ag+ showed stronger toxicity on polyphosphate accumulating organisms (PAOs) than glycogen accumulating organisms (GAOs). Further investigation revealed that the decrease in anaerobic phosphorus release by Ag+ was caused by the inhibition on the activities of adenylate kinase and expolyphosphatase, whereas the decrease in aerobic phosphorus uptake was due to the suppression in energy generation for phosphorus uptake. However, the presence of either AgNPs or Ag+ did not lead to cell leakage and membrane damage. PMID- 23021317 TI - Reuse of sewage sludge as a catalyst in ozonation--efficiency for the removal of oxalic acid and the control of bromate formation. AB - Sewage derived sludge is produced with an annual amount increase of 2% all over the world and it is an urgent issue to be addressed by human being. In the present study, sludge was converted into sludge-based catalyst (SBC) with ZnCl2 as activation agent and characterized by several methods (e.g., scanning electron microscope, X-ray photoelectron spectroscope and Fourier transform infrared spectroscope). Then it was used as a catalyst to enhance the removal of refractory organic matter, oxalic acid, and to control the formation of bromate (BrO3-) in bench semi-continuous ozonation experiments. The effects of various operating parameters on the control of BrO3- formation were investigated. Furthermore, the mechanism for the enhancement of organic matter removal and the control of BrO3- formation was discussed as well. Results indicate that the combination of SBC with ozone shows a strong synergistic effect, resulting in a notable improvement on oxalic acid removal. A crucial surface reaction mechanism for the enhancement of organic matter removal is proposed on the basis of negative effect of higher pH and no inhibition effect of tert-butanol. The control for BrO3- formation was demonstrated and the reason for its control in the process of O3/SBC is the combined effect of SBC reductive properties, ozone exposure decrease and hydrogen peroxide concentration increase. PMID- 23021319 TI - Clinical characteristics associated with different strengths of loudness dependence of auditory evoked potentials (LDAEP) in major depressive disorder. AB - Loudness dependence of auditory evoked potentials (LDAEP), also called as intensity dependence of auditory evoked potentials (IDAP), has been proposed as a potential marker for central serotonergic tone and has been noticed for its possible clinical implications in depression. However, its distributions in major depressive disorder (MDD) and factors affecting it are largely unknown. In this study, we examined its distribution and relationships with various demographic and clinical variables in MDD patients. In 143 MDD patients, the LDAEP was measured using five intensities of auditory stimulus. The influences of ten independent variables (age, gender, education years, marital status, psychiatric family history, age of onset, suicide attempt history, depression severity, later augmentation of mood stabilizer, and smoking status) on the LDAEP strength were examined using univariate analyses and data mining method. The mean (+/-S.D.) LDAEP was 0.90 (+/-0.73)MUV/10dB (-0.78-3.83MUV/10dB). Female gender, smoking, and being married were consistently associated with a weaker LDAEP. In the pathway model, sequential combination of being male, living alone, and older age predicted the strongest LDAEP, whereas female gender, older age, and smoking predicted the weakest LDAEP. These variables need to be considered when interpreting the LDAEP. PMID- 23021318 TI - Impact of a nurse-directed, coordinated school health program to enhance physical activity behaviors and reduce body mass index among minority children: a parallel group, randomized control trial. AB - BACKGROUND: Underserved children, particularly girls and those in urban communities, do not meet the recommended physical activity guidelines (>60min of daily physical activity), and this behavior can lead to obesity. The school years are known to be a critical period in the life course for shaping attitudes and behaviors. Children look to schools for much of their access to physical activity. Thus, through the provision of appropriate physical activity programs, schools have the power to influence apt physical activity choices, especially for underserved children where disparities in obesity-related outcomes exist. OBJECTIVES: To evaluate the impact of a nurse directed, coordinated, culturally sensitive, school-based, family-centered lifestyle program on activity behaviors and body mass index. DESIGN, SETTINGS AND PARTICIPANTS: This was a parallel group, randomized controlled trial utilizing a community-based participatory research approach, through a partnership with a University and 5 community schools. Participants included 251 children ages 8-12 from elementary schools in urban, low-income neighborhoods in Los Angeles, USA. METHODS: The intervention included Kids N Fitness((c)), a 6-week program which met weekly to provide 45min of structured physical activity and a 45min nutrition education class for parents and children. Intervention sites also participated in school-wide wellness activities, including health and counseling services, staff professional development in health promotion, parental education newsletters, and wellness policies for the provision of healthy foods at the school. The Child and Adolescent Trial for Cardiovascular Health School Physical Activity and Nutrition Student Questionnaire measured physical activity behavior, including: daily physical activity, participation in team sports, attending physical education class, and TV viewing/computer game playing. Anthropometric measures included height, weight, body mass index, resting blood pressure, and waist circumference. Measures were collected at baseline, completion of the intervention phase (4 months), and 12 months post-intervention. RESULTS: Significant results for students in the intervention, included for boys decreases in TV viewing; and girls increases in daily physical activity, physical education class attendance, and decreases in body mass index z-scores from baseline to the 12 month follow up. CONCLUSIONS: Our study shows the value of utilizing nurses to implement a culturally sensitive, coordinated, intervention to decrease disparities in activity and TV viewing among underserved girls and boys. PMID- 23021320 TI - Left dorsolateral prefrontal transcranial magnetic stimulation (TMS): sleep factor changes during treatment in patients with pharmacoresistant major depressive disorder. AB - As they alleviate major depressive disorder, antidepressant therapies may improve associated sleep disturbances, but may also have inherent sedating or activating properties. We examined sleep changes during a multicenter, sham-controlled, trial of transcranial magnetic stimulation (TMS) therapy for pharmacoresistant MDD. Medication-free outpatients (N=301) were randomized to receive active (N=155) or sham (N=146) TMS for 6 weeks. Depression severity was rated with the Montgomery-Asberg Depression Rating Scale, the 24-item Hamilton Depression Scale (HAMD), and the Inventory of Depressive Symptoms-Self Report (IDS-SR). Assessments were performed at baseline, 2, 4, and 6 week time points. Sleep was assessed using the HAMD and IDS-SR sleep factors; comparison between treatment groups employed ANCOVA model. No significant differences were identified between the active and sham treatment groups in either the HAMD or IDS-SR sleep factor scores at any time during treatment. Sleep difficulty as an adverse event over the length of the study did not differ between active and sham treatment. Stratified by end of acute treatment responder status, there was a statistically significant improvement in both the HAMD sleep factor score and the IDS-SR sleep factor during acute treatment in both the active and sham treatment conditions. TMS exerts no intrinsic effect upon sleep in patients with MDD. PMID- 23021321 TI - Assessing expressed emotion during pregnancy. AB - We assessed expressed emotion (EE) with an adapted version of the five-minute speech sample in 847 pregnant women. The prevalence of high EE was 6%. High EE was significantly associated with having a first child, low income, maternal childhood trauma and lack of parental emotional warmth during childhood. PMID- 23021322 TI - Vascular contributions to early ovarian development: potential roles of VEGFA isoforms. AB - Vascularisation is an essential component of ovarian morphogenesis; however, little is known regarding factors regulating the establishment of vasculature in the ovary. Angiogenesis involving extensive endothelial cell migration is a critical component of vessel formation in the embryonic testis but vasculogenic mechanisms appear to play a prominent role in ovarian vascularisation. Vasculature has a strong influence on the formation of ovarian structures, and the early developmental processes of ovigerous cord formation, primordial follicle assembly and follicle activation are all initiated in regions of the ovary that are in close association with the highly vascular medulla. The principal angiogenic factor, vascular endothelial growth factor A (VEGFA), has an important role in both endothelial cell differentiation and vascular pattern development. Expression of VEGFA has been localised to ovigerous cords and follicles in developing ovaries and an increased expression of pro-angiogenic Vegfa isoform mRNA in relation to anti-angiogenic isoform mRNA occurs at the same time-point as the peak of primordial follicle assembly in perinatal rats. Elucidation of specific genes that affect vascular development within the ovary may be critical for determining not only the normal mechanisms of ovarian morphogenesis, but also for understanding certain ovarian reproductive disorders. PMID- 23021323 TI - A clinical study on the effectiveness of implant supported dental restoration in patients with chronic periodontal diseases. AB - This study evaluated the efficacy of implant supported dental restorations in patients with chronic periodontal diseases at various stages within 2 years of completing treatment. 30 patients with periodontal diseases and 30 patients without periodontal diseases were studied. Total counts of 276 implant bodies were divided into group A (patients with periodontal diseases; a total of 149 implants) and group B (patients with healthy periodontium; a total of 127 implants). In group A subjects, periodontitis was treated prior to implant placement. The study focused on patients' modified sulcus bleeding index, modified plaque index, implant mobility index, periodontal probing depth and implant success rate 12 and 24 months after the completion of the treatment. The result show: there were no significant differences in implant success rate between groups A and B; modified sulcus bleeding index scores showed differences between the groups 24 months after treatment; there were no significant differences in other clinical indexes during the study between the groups; there were no significant differences in periodontal probing depth between the groups; modified plaque index and modified sulcus bleeding index were positively correlated in implant supported dental restoration patients with chronic periodontal diseases. PMID- 23021324 TI - The usefulness of brain natriuretic peptide in complex congenital heart disease: a systematic review. AB - Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT proBNP) are well-established markers for heart failure in the general population. However, the value of BNP as a diagnostic and prognostic marker for patients with structural congenital heart disease (CHD) is still unclear. Therefore, the purpose of this study was to evaluate the clinical utility of BNP in patients with CHD. We executed a PubMed literature search and included 49 articles that focused on complex congenital heart defects such as tetralogy of Fallot, systemic right ventricle, and univentricular hearts. Data on BNP measurements and cardiac function parameters were extracted. In all patients after correction for tetralogy of Fallot, BNP levels were elevated and correlated significantly with right ventricular end-diastolic dimensions and severity of pulmonary valve regurgitation. Patients with a systemic right ventricle had elevated BNP levels, and positive correlations between BNP and right ventricular function were seen. In patients with a univentricular heart, elevated BNP levels were observed before completion of the Fontan circulation or when patients were symptomatic; a clear association between BNP and New York Heart Association functional class was demonstrated. In conclusion, this review shows an overall increase in BNP values in complex CHD, although differences between types of congenital heart anomaly are present. As BNP values differ widely, conclusions for individual patients should be drawn with caution. Further investigation with sequential BNP measurement in a large, prospective study is warranted to elucidate the prognostic value of BNP assessment in patients with CHD. PMID- 23021325 TI - Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery. AB - OBJECTIVES: This study investigated the differences in specific causes of post coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial. BACKGROUND: In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality. METHODS: In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death. RESULTS: Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively). CONCLUSIONS: The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications. (Platelet Inhibition and Patient Outcomes [PLATO]; NCT00391872). PMID- 23021326 TI - Left ventricular midwall fibrosis as a predictor of mortality and morbidity after cardiac resynchronization therapy in patients with nonischemic cardiomyopathy. AB - OBJECTIVES: The aim of this study was to determine whether left ventricular (LV) midwall fibrosis, detected by midwall hyperenhancement (MWHE) on late gadolinium enhancement cardiovascular magnetic resonance (CMR) imaging, predicts mortality and morbidity in patients with dilated cardiomyopathy (DCM) undergoing cardiac resynchronization therapy (CRT). BACKGROUND: Midwall fibrosis predicts mortality and morbidity in patients with DCM. METHODS: Patients with DCM with (+) or without (-) MWHE (n = 20 and n = 77, respectively) as well as 161 patients with ischemic cardiomyopathy (ICM) undergoing CRT (n = 258) were followed up for a maximum of 8.7 years. RESULTS: Among patients with DCM, +MWHE predicted cardiovascular mortality (hazard ratio [HR]: 18.6; 95% confidence intervals [CI]: 3.51 to 98.5; p = 0.0008), total mortality or hospitalization for major adverse cardiovascular events (HR: 7.57; 95% CI: 2.71 to 21.2; p < 0.0001), and cardiovascular mortality or heart failure hospitalizations (HR: 9.56; 95% CI: 2.72 to 33.6; p = 0.0004), independent of New York Heart Association class, QRS duration, atrial fibrillation, LV volumes, LV ejection fraction, and a CMR derived measure of dyssynchrony. Among patients with DCM and ICM, the risk of cardiovascular mortality for DCM +MWHE (adjusted HR: 18.5; 95% CI: 3.93 to 87.3; p = 0.0002) was similar to that for ICM (adjusted HR: 21.0; 95% CI: 5.06 to 87.2; p < 0.0001). Both DCM +MWHE and ICM were predictors of pump failure death as well as sudden cardiac death. LV reverse remodeling was observed in DCM -MWHE and in ICM but not in DCM +MWHE. CONCLUSIONS: Midwall fibrosis is an independent predictor of mortality and morbidity in patients with DCM undergoing CRT. The outcome of DCM with midwall fibrosis is similar to that of ICM. This relationship is mediated by both pump failure and sudden cardiac death. PMID- 23021327 TI - The population burden of heart failure attributable to modifiable risk factors: the ARIC (Atherosclerosis Risk in Communities) study. AB - OBJECTIVES: The goal of this study was to estimate the population burden of heart failure and the influence of modifiable risk factors. BACKGROUND: Heart failure is a common, costly, and fatal disorder, yet few studies have evaluated the population-level influence of modifiable risk factors. METHODS: From 14,709 ARIC (Atherosclerosis Risk in Communities) study participants, we estimated incidence rate differences (IRD) for the association between 5 modifiable risk factors (cigarette smoking, diabetes, elevated low-density lipoproteins, hypertension, and obesity) and heart failure. Potential impact fractions were used to measure expected changes in the heart failure incidence assuming achievement of a 5% proportional decrement in the prevalence of each risk factor. RESULTS: Over an average of 17.6 years of follow-up, 1 in 3 African American and 1 in 4 Caucasian participants were hospitalized with heart failure, defined as the first hospitalization with International Classification of Diseases, Ninth Revision discharge codes of 428.x. Of the 5 modifiable risk factors, the largest IRD was observed for diabetes, which was associated with 1,058 (95% confidence interval [CI]: 787 to 1,329) and 660 (95% CI: 514 to 805) incident hospitalizations of heart failure/100,000 person-years among African-American and Caucasian participants, respectively. A 5% proportional reduction in the prevalence of diabetes would result in approximately 53 and 33 fewer incident heart failure hospitalizations per 100,000 person-years in African-American and Caucasian ARIC participants, respectively. When applied to U.S. populations, this reduction may prevent approximately 30,000 incident cases of heart failure annually. CONCLUSIONS: Modest decrements in the prevalence of modifiable heart failure risk factors such as diabetes may substantially decrease the incidence of this major disease. PMID- 23021328 TI - Mechanical valve thrombosis with dabigatran. PMID- 23021329 TI - Left main percutaneous coronary intervention. AB - The introduction of drug-eluting stents and advances in catheter techniques have led to increasing acceptance of percutaneous coronary intervention (PCI) as a viable alternative to coronary artery bypass graft (CABG) for unprotected left main disease. Current guidelines state that it is reasonable to consider unprotected left main PCI in patients with low to intermediate anatomic complexity who are at increased surgical risk. Data from randomized trials involving patients who are candidates for either treatment strategy provide novel insight into the relative safety and efficacy of PCI for this lesion subset. Herein, we review the current data comparing PCI with CABG for left main disease, summarize recent guideline recommendations, and provide an update on technical considerations that may optimize clinical outcomes in left main PCI. PMID- 23021330 TI - A diagnosis of the metabolic syndrome in youth that resolves by adult life is associated with a normalization of high carotid intima-media thickness and type 2 diabetes mellitus risk: the Bogalusa heart and cardiovascular risk in young Finns studies. AB - OBJECTIVES: The aim of this study was to examine the effect of resolution from metabolic syndrome (MetS) between youth and adulthood on carotid artery intima media thickness (IMT) and type 2 diabetes mellitus (T2DM). BACKGROUND: Published findings demonstrate that youth with MetS are at increased risk of cardio metabolic outcomes in adulthood. It is not known whether this risk is attenuated in those who resolve their MetS status. METHODS: Participants (n = 1,757) from 2 prospective cohort studies were examined as youth (when 9 to 18 years of age) and re-examined 14 to 27 years later. The presence of any 3 components (low high density lipoprotein cholesterol, high triglycerides, high glucose, high blood pressure, or high body mass index) previously shown to predict adult outcomes defined youth MetS; the harmonized MetS criteria defined adulthood MetS. Participants were classified according to their MetS status at baseline and follow-up and examined for risk of high IMT and T2DM. RESULTS: Those with MetS in youth and adulthood were at 3.4 times the risk (95% confidence interval: 2.4 to 4.9) of high IMT and 12.2 times the risk (95% confidence interval: 6.3 to 23.9) of T2DM in adulthood compared with those that did not have MetS at either time point, whereas those that had resolved their youth MetS status by adulthood showed similar risk to those that did not have MetS at either time-point (p > 0.20 for all comparisons). CONCLUSIONS: Although youth with MetS are at increased risk of adult high IMT and T2DM, these data indicate that the resolution of youth MetS by adulthood can go some way to normalize this risk to levels seen in those who have never had MetS. PMID- 23021331 TI - Prediction of mortality in clinical practice for medicare patients undergoing defibrillator implantation for primary prevention of sudden cardiac death. AB - OBJECTIVES: The aim of this study was to derive and validate a practical risk model to predict death within 4 years of primary prevention implantable cardioverter-defibrillator (ICD) implantation. BACKGROUND: ICDs for the primary prevention of sudden cardiac death improve survival, but recent data suggest that a patient subset with high mortality and minimal ICD benefit may be identified. METHODS: Data from a development cohort (n = 17,991) and validation cohort (n = 27,893) of Medicare beneficiaries receiving primary prevention ICDs from 2005 to 2007 were merged with outcomes data through mid-2010 to construct and validate complete and abbreviated risk models for all-cause mortality using Cox proportional hazards regression. RESULTS: Over a median follow-up period of 4 years, 6,741 (37.5%) development and 8,595 (30.8%) validation cohort patients died. The abbreviated model was based on 7 clinically relevant predictors of mortality identified from complete model results, referred to as the "SHOCKED" predictors: 75 years of age or older (hazard ratio [HR]: 1.70; 95% confidence interval [CI]: 1.62 to 1.79), heart failure (New York Heart Association functional class III) (HR: 1.35; 95% CI: 1.29 to 1.42), out of rhythm because of atrial fibrillation (HR: 1.26; 95% CI: 1.19 to 1.33), chronic obstructive pulmonary disease (HR: 1.70; 95% CI: 1.61 to 1.80), kidney disease (chronic) (HR: 2.33; 95% CI: 2.20 to 2.47), ejection fraction (left ventricular) <= 20% (HR: 1.26; 95% CI: 1.20 to 1.33), and diabetes mellitus (HR: 1.43; 95% CI: 1.36 to 1.50). This model had C-statistics of 0.75 (95% CI: 0.75 to 0.76) and 0.74 (95% CI: 0.74 to 0.75) in the development and validation cohorts, respectively. Validation patients in the highest risk decile on the basis of the SHOCKED predictors had a 65% 3-year mortality rate. A nomogram is provided for survival probabilities 1 to 4 years after ICD implantation. CONCLUSIONS: This useful model, based on more than 45,000 primary prevention ICD patients, accurately identifies patients at highest risk for death after device implantation and may significantly influence clinical decision making. PMID- 23021332 TI - Implantable cardioverter-defibrillators for primary prevention of sudden death: the quest to identify patients most likely to benefit. PMID- 23021334 TI - Multimarker strategy for short-term risk assessment in patients with dyspnea in the emergency department: the MARKED (Multi mARKer Emergency Dyspnea)-risk score. AB - OBJECTIVES: The study aim was to determine the prognostic value of a multimarker strategy for risk-assessment in patients presenting to the emergency department (ED) with dyspnea. BACKGROUND: Combining biomarkers with different pathophysiological backgrounds may improve risk stratification in dyspneic patients in the ED. METHODS: The study prospectively investigated the prognostic value of the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), Cystatin-C (Cys-C), high sensitivity C-reactive protein (hs-CRP), and Galectin-3 (Gal-3) for 90-day mortality in 603 patients presenting to the ED with dyspnea as primary complaint. RESULTS: hs-CRP, hs-cTnT, Cyst-C, and NT-proBNP were independent predictors of 90 day mortality. The number of elevated biomarkers was highly associated with outcome (odds ratio: 2.94 per biomarker, 95% confidence interval [CI]: 2.29 to 3.78, p < 0.001). A multimarker approach had incremental value beyond a single marker approach. Our multimarker emergency dyspnea-risk score (MARKED-risk score) incorporating age >=75 years, systolic blood pressure <110 mm Hg, history of heart failure, dyspnea New York Heart Association functional class IV, hs-cTnT >=0.04 MUg/l, hs-CRP >=25 mg/l, and Cys-C >=1.125 mg/l had excellent prognostic performance (area under the curve: 0.85, 95% CI: 0.81 to 0.89), was robust in internal validation analyses and could identify patients with very low (<3 points), intermediate (>=3, <5 points), and high risk (>=5 points) of 90-day mortality (2%, 14%, and 44% respectively; p < 0.001). CONCLUSIONS: A multimarker strategy provided superior risk stratification beyond any single-marker approach. The MARKED-risk score that incorporates hs-cTnT, hs-CRP, and Cys-C along with clinical risk factors accurately identifies patients with very low, intermediate, and high risk. PMID- 23021333 TI - Neuropeptide Y (NPY): genetic variation in the human promoter alters glucocorticoid signaling, yielding increased NPY secretion and stress responses. AB - OBJECTIVES: This study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells. BACKGROUND: The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15. METHODS: Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population. RESULTS: Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ? 880Delta (2-bp TG/-, Ins/Del, rs3037354) minor/Delta allele was associated with several heritable (h(2)) stress traits: higher NPY secretion (h(2) = 73 +/- 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ?-880Delta and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele -880Delta to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter -880Delta interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same -880Delta allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes. CONCLUSIONS: We conclude that common genetic variation at the NPY locus, especially in proximal promoter ?-880Delta, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states. PMID- 23021335 TI - Detection of antecedent myocardial ischemia with multiselectin molecular imaging. AB - OBJECTIVES: Our aim was to develop an echocardiographic molecular imaging approach for detecting recent myocardial ischemia by using recombinant P-selectin glycoprotein ligand (PSGL)-1 as a targeting ligand, which is a feasible approach for human use. BACKGROUND: Ischemic memory imaging using human PSGL-1 as a targeting moiety may extend the time window for postischemic detection by targeting the early (P-selectin) and late (E-selectin) endothelial ischemic response. METHODS: Lipid microbubbles bearing recombinant human PSGL-1 (MB(YSPSL)) or P-selectin antibody (MB(Ab)) were prepared. Targeted attachment was evaluated by using flow chamber and intravital microscopy. In vivo ultrasound molecular imaging was first performed in the hindlimb in wild-type and P-selectin deficient (P(-/-)) mice 45 to 360 min after brief ischemia-reperfusion injury. Myocardial contrast echocardiography molecular imaging was performed 1.5, 3, 6, and 18 h after brief left anterior descending coronary artery ischemia reperfusion. RESULTS: Microbubble attachment to P-selectin-immunoglobulin G fusion protein in flow chamber experiments (shear stress 0.5 to 8.0 dyne/cm(2)) and to activated venular endothelium on intravital microscopy were similar for MB(Ab) and MB(YSPSL). Intense enhancement was seen for MB(Ab) and MB(YSPSL) in postischemic muscle and was more stable over time for MB(YSPSL). On myocardial contrast echocardiography, both MB(YSPSL) and MB(Ab) produced similar signal enhancement at 90 min and 3 h after ischemia, which spatially correlated with the postischemic risk area. Signal significantly decreased but was still present at 6 to 18 h. CONCLUSIONS: Echocardiographic molecular imaging with a human multi selectin-targeted contrast agent bearing recombinant human PSGL-1 can detect myocardial ischemia hours after resolution. This approach may potentially be used for rapid bedside evaluation of patients with recent chest pain. PMID- 23021337 TI - Multi-criteria analyses of wastewater treatment bio-processes under an uncertainty and a multiplicity of steady states. AB - This paper presents a multi-criteria evaluation methodology for determining the operating strategies for bio-chemical, wastewater treatment plants based on a model analysis under an uncertainty that can present multiple steady states. The method is based on Monte Carlo (MC) simulations and the expected utility theory in order to deal with the analysis of choices among risky operating strategies with multi-dimensional outcomes. The motivation is given by a case study using an anaerobic digestion model (ADM) adapted for multiple co-substrates. It is shown how the multi-criteria analyses' computational complexity can be reduced within an approximation based on Gaussian-process regression and how a reliability map can be built for a bio-process model under uncertainty and multiplicity. In our uncertainty-analyses case study, the reliability map shows the probability of a biogas-production collapse for a given set of substrates mixture input loads. PMID- 23021336 TI - Angiogenic factors and their soluble receptors predict organ dysfunction and mortality in post-cardiac arrest syndrome. AB - INTRODUCTION: Post-cardiac arrest syndrome (PCAS) often leads to multiple organ dysfunction syndrome (MODS) with a poor prognosis. Endothelial and leukocyte activation after whole-body ischemia/reperfusion following resuscitation from cardiac arrest is a critical step in endothelial injury and related organ damage. Angiogenic factors, including vascular endothelial growth factor (VEGF) and angiopoietin (Ang), and their receptors play crucial roles in endothelial growth, survival signals, pathological angiogenesis and microvascular permeability. The aim of this study was to confirm the efficacy of angiogenic factors and their soluble receptors in predicting organ dysfunction and mortality in patients with PCAS. METHODS: A total of 52 resuscitated patients were divided into two subgroups: 23 survivors and 29 non-survivors. The serum levels of VEGF, soluble VEGF receptor (sVEGFR)1, sVEGFR2, Ang1, Ang2 and soluble Tie2 (sTie2) were measured at the time of admission (Day 1) and on Day 3 and Day 5. The ratio of Ang2 to Ang1 (Ang2/Ang1) was also calculated. This study compared the levels of angiogenic factors and their soluble receptors between survivors and non survivors, and evaluated the predictive value of these factors for organ dysfunction and 28-day mortality. RESULTS: The non-survivors demonstrated more severe degrees of organ dysfunction and a higher prevalence of MODS. Non survivors showed significant increases in the Ang2 levels and the Ang2/Ang1 ratios compared to survivors. A stepwise logistic regression analysis demonstrated that the Ang2 levels or the Ang2/Ang1 ratios on Day 1 independently predicted the 28-day mortality. The receiver operating characteristic curves of the Ang2 levels, and the Ang2/Ang1 ratios on Day 1 were good predictors of 28-day mortality. The Ang2 levels also independently predicted increases in the Sequential Organ Failure Assessment (SOFA) scores. CONCLUSIONS: We observed a marked imbalance between Ang1 and Ang2 in favor of Ang2 in PCAS patients, and the effect was more prominent in non-survivors. Angiogenic factors and their soluble receptors, particularly Ang2 and Ang2/Ang1, are considered to be valuable predictive biomarkers in the development of organ dysfunction and poor outcomes in PCAS patients. PMID- 23021338 TI - HuBac and nifH source tracking markers display a relationship to land use but not rainfall. AB - Identification of the source of fecal pollution is becoming a priority for states and territories in the U.S. in order to meet water quality standards and to develop and implement total maximum daily loads. The goal of this research was to relate microbial source tracking (MST) assay concentrations to land use and levels of impervious surfaces in order to gauge how increasing development is associated with human fecal contamination in inland watersheds. The concentrations of two proposed MST markers, targeting nifH of Methanobrevibacter smithii and HuBac of Bacteroides sp., were positively correlated with increasing anthropogenic development and impervious surfaces. Higher concentrations of these MST markers in more urbanized watersheds suggest that increasing development negatively affects water quality. Neither MST marker concentration was correlated with antecedent rainfall levels, and detection of markers did not differ between dry weather and rain events. Water samples were also analyzed for norovirus and enterovirus, but these enteric viruses were rarely detected. These MST results differ from previous studies that have found correlations between traditional fecal indicator bacteria (FIB) and antecedent rainfall. This difference suggests that the MST markers used in this study may be more specific for recent, land based contamination events as opposed to resuspension of particle-associated organisms in waterways. HuBac was detected in 98% of samples, correlating with fecal coliform and Escherichia coli concentrations. The ubiquity of the HuBac marker in our samples suggests that this marker does not provide sufficiently different or additional information than FIB, and it is likely this marker was amplifying non-human targets. The nifH marker was detected in 30% of samples. Less than half of the nifH-positive samples contained levels of fecal coliforms or E. coli above regulatory thresholds, suggesting that nifH would be more useful when utilized simultaneously with FIB than in a tiered monitoring strategy. The results of this research suggests that land use factors play an important role in characterizing and mitigating fecal contamination in watersheds. PMID- 23021342 TI - Improving the affinity of naphthalene diimide ligand to telomeric DNA by incorporating Zn2+ ions into its dipicolylamine groups. AB - N,N'-bis[3-[3-(2,2'-dipicolyl)methylaminopropyl]-methylaminopropyl]naphthalene 1,4,5,8-tetracarboxylic acid diimide, 1, and its complex with zinc ions, 2, were investigated against telomeric sequences, [TAGGG(TTAGGG)(3)] and [AGGG(TTAGGG)(3)], which reveal different G-quadruplex structures depending on the conditions. Spectrophotometric, SPR, and CD techniques revealed that both ligands showed large binding constants to hybrid-type G-quadruplexes formed in the presence of K(+) ions. Moreover, 2 revealed higher affinity to investigated oligonucleotides suggesting that complex of naphthalene diimide derivative with Zn(2+), comparing to 1, provided additional electrostatic or coordination interactions between positively charged zinc ions and condensed negative charged phosphate anions from G4 DNA. PMID- 23021343 TI - [Acute myocarditis and inflammatory bowel diseases: a case series of two patients]. AB - INTRODUCTION: Acute myocarditis is one of the less common extra-intestinal manifestations of inflammatory bowel diseases (IBD). It may reveal IBD or occur during the follow-up. CASE REPORTS: We report two patients who presented an acute myocarditis associated with ulcerative colitis that reveal the disease in one of them. Clinical features at presentation were non specific and both patients presented with chest pain. Diagnosis was obtained with cardiac MRI. Outcome was favourable in the two patients. CONCLUSION: Etiologies of myocarditis are various and the diagnosis of extra-intestinal manifestations related to IBD remains a diagnosis of exclusion. Cardiac MRI is an important diagnostic tool. Colchicine and acetylsalicylic acid are commonly prescribed in a first therapeutic approach. PMID- 23021344 TI - Improvement of Catalytic Efficiency, Thermo-stability and Dye Decolorization Capability of Pleurotus ostreatus IBL-02 laccase by Hydrophobic Sol Gel Entrapment. AB - BACKGROUND: In serious consideration of the worldwide environmental issues associated with the extensive use of the textile dyes and effluents generated thereof, the scientists across the world are in search for potential treatment technologies for their treatment. In such scenario the ligninolytic enzymes provide a potential alternative because they are cost effective, eco-friendly and can be applied to wide range of dye containing industrial effluents. RESULTS: Laccase produced from Pleurotus ostreatus IBL-02 during decolorization of the reactive textile dye Drimarene brilliant red K-4BL (DBR K-4BL) was purified and immobilized by hydrophobic gel entrapment. The crude laccase was 4.2-fold purified with specific activity of 573.52 U/mg after passing through the DEAE Sepharose ion exchange and Sephadex-G-100 chromatography columns. P. ostreatus IBL-02 laccase was found to be a homogenous monomeric protein as evident by single band corresponding to 67 kDa on native and sodium dodesylsulfate polyacrylamide gel electrophoresis (PAGE). The laccase was immobilized by entrapment in Sol-gel matrix of trimethoxysilane (T) and proplytetramethoxysilane (P) prepared using different T:P molar ratios. The free and immobilized laccases were compared to investigate the effect of immobilization on catalytic efficiency and thermo-stability features. Laccase immobilized in the Sol-gel of 1:5 T:P ratio was optimally active and thermo-stable fraction at pH 5, 60 degrees C with half-life of 3 h and 50 min. Laccases immobilized in 1:2 and 1:5 T:P ratio gels had significantly higher Km (83 and100mM) and Vmax (1000 and 1111 mM/mg) values as compared to free laccase. After 5 h reaction time varying decolorization percentages with a maximum of 100% were achieved for different dyes and effluents. CONCLUSIONS: In summary, P. ostreatus IBL-02 laccase was immobilized by entrapping in a Sol-gel matrix with an objective to enhance its catalytic and stability properties. Sol-gel entrapped laccase presented potential efficiency as a biocatalyst when applied for decolorization of different dyes and effluents. The main benefits of the Sol-gel matrix immobilization processes are the eco friendly approach, chemical free and energy saving reaction conditions. PMID- 23021345 TI - Gene-diet interactions on plasma lipid levels in the Inuit population. AB - The Inuit population is often described as being protected against CVD due to their traditional dietary patterns and their unique genetic background. The objective of the present study was to examine gene-diet interaction effects on plasma lipid levels in the Inuit population. Data from the Qanuippitaa Nunavik Health Survey (n 553) were analysed via regression models which included the following: genotypes for thirty-five known polymorphisms (SNP) from twenty genes related to lipid metabolism; dietary fat intake including total fat (TotFat) and saturated fat (SatFat) estimated from a FFQ; plasma lipid levels, namely total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and TAG. The results demonstrate that allele frequencies were different in the Inuit population compared with the Caucasian population. Further, seven SNP (APOA1 - 75G/A (rs670), APOB XbAI (rs693), AGT M235T (rs699), LIPC 480C/T (rs1800588), APOA1 84T/C (rs5070), PPARG2 - 618C/G (rs10865710) and APOE 219G/T (rs405509)) in interaction with TotFat and SatFat were significantly associated with one or two plasma lipid parameters. Another four SNP (APOC3 3238C>G (rs5128), CETP I405V (rs5882), CYP1A1 A4889G (rs1048943) and ABCA1 Arg219Lys (rs2230806)) in interaction with either TotFat or SatFat intake were significantly associated with one plasma lipid variable. Further, an additive effect of these SNP in interaction with TotFat or SatFat intake was significantly associated with higher TC, LDL-C or TAG levels, as well as with lower HDL-C levels. In conclusion, the present study supports the notion that gene-diet interactions play an important role in modifying plasma lipid levels in the Inuit population. PMID- 23021346 TI - Public health interventions in the emergency department: one resident's perspective. PMID- 23021348 TI - Nationwide improvement of door-to-balloon times in patients with acute ST-segment elevation myocardial infarction requiring primary percutaneous coronary intervention with out-of-hospital 12-lead ECG recording and transmission. AB - STUDY OBJECTIVE: Reducing door-to-balloon times for acute ST-segment elevation myocardial infarction (STEMI) patients has been shown to improve long-term survival. We aim to reduce door-to-balloon time for STEMI patients requiring primary percutaneous coronary intervention by adoption of out-of-hospital 12-lead ECG transmission by Singapore's national ambulance service. METHODS: This was a nationwide, before-after study of STEMI patients who presented to the emergency departments (ED) and required percutaneous coronary intervention. In the before phase, chest pain patients received 12-lead ECGs in the ED. In the after phase, 12-lead ECGs were performed by ambulance crews and transmitted from the field to the ED. Patients whose ECG showed greater than or equal to 2 mm ST-segment elevation in anterior or greater than or equal to 1 mm ST-segment elevation in inferior leads for 2 or more contiguous leads and symptom onset of less than 12 hours' duration were eligible for percutaneous coronary intervention activation before arrival. RESULTS: ECGs (2,653) were transmitted by the ambulance service; 180 (7%) were suspected STEMI. One hundred twenty-seven patients from the before and 156 from the after phase met inclusion criteria for analysis. Median door-to balloon time was 75 minutes in the before and 51 minutes in the after phase (median difference=23 minutes; 95% confidence interval 18 to 27 minutes). Median door-to-balloon times were significantly reduced regardless of presentation hours. Overall, there was significant reduction in door-to-activation, door-to ECG, and door-to-cardiovascular laboratory times. No significant difference was found pertaining to adverse events. CONCLUSION: This study describes a nationwide implementation of out-of-hospital ECG transmission resulting in reduced door-to balloon times, regardless of presentation hours. Out-of-hospital ECG transmission should be adopted as best practice for management of chest pain. PMID- 23021347 TI - Variability of ICU use in adult patients with minor traumatic intracranial hemorrhage. AB - STUDY OBJECTIVE: Patients with minor traumatic intracranial hemorrhage are frequently admitted to the ICU, although many never require critical care interventions. To describe ICU resource use in minor traumatic intracranial hemorrhage, we assess (1) the variability of ICU use in a cohort of patients with minor traumatic intracranial hemorrhage across multiple trauma centers, and (2) the proportion of adult patients with traumatic intracranial hemorrhage who are admitted to the ICU and never receive a critical care intervention during hospitalization. In addition, we evaluate the association between ICU admission and key independent variables. METHODS: A structured, historical cohort study of adult patients (aged 18 years and older) with minor traumatic intracranial hemorrhage was conducted within a consortium of 8 Level I trauma centers in the western United States from January 2005 to June 2010. The study population included patients with minor traumatic intracranial hemorrhage, defined as an emergency department (ED) Glasgow Coma Scale (GCS) score of 15 (normal mental status) and an Injury Severity Score less than 16 (no other major organ injury). The primary outcome measure was initial ICU admission. The secondary outcome measure was a critical care intervention during hospitalization. Critical care interventions included mechanical ventilation, neurosurgical intervention, transfusion of blood products, vasopressor or inotrope administration, and invasive hemodynamic monitoring. ED disposition and the proportion of ICU patients not receiving a critical care intervention were compared across sites with descriptive statistics. The association between ICU admission and predetermined independent variables was analyzed with multivariable regression. RESULTS: Among 11,240 adult patients with traumatic intracranial hemorrhage, 1,412 (13%) had minor traumatic intracranial hemorrhage and complete ED disposition data (mean age 48 years; SD 20 years). ICU use within this cohort across sites ranged from 50% to 97%. Overall, 847 of 888 patients (95%) with minor traumatic intracranial hemorrhage who were admitted to the ICU did not receive a critical care intervention during hospitalization (range between sites 80% to 100%). Three of 524 (0.6%) patients discharged home or admitted to the observation unit or ward received a critical care intervention. After controlling for severity of injury (age, blood pressure, and Injury Severity Score), study site was independently associated with ICU admission (odds ratios ranged from 1.5 to 30; overall effect P<.001). CONCLUSION: Across a consortium of trauma centers in the western United States, there was wide variability in ICU use within a cohort of patients with minor traumatic intracranial hemorrhage. Moreover, a large proportion of patients admitted to the ICU never required a critical care intervention, indicating the potential to improve use of critical care resources in patients with minor traumatic intracranial hemorrhage. PMID- 23021349 TI - Sibling composition during childhood and adult blood pressure among native Amazonians in Bolivia. AB - Sibling configuration, including birth order, or the number, age, and sex of siblings is associated with parental resource allocation between children and is thus associated with a person's well-being. Little is known about the association between specific types of siblings and adult health outcomes. Here we test several hypotheses about sibling composition (number of older brothers, older sisters, younger sisters, younger brothers) and adult blood pressure in a foraging-farming society of native Amazonians in Bolivia (Tsimane'). We collected data in 2007 from 374 adults (16-60years of age) from 196 households in 13 villages. Household random-effects multiple regressions were run using systolic (SBP) or diastolic blood pressure (DBP) as outcomes; covariates included the four sibling categories and control variables (e.g., sex, age, education, body mass index [BMI]). Mean SBP and DBP were 114 (SD=14) and 66 (SD=11)mmHg. The prevalence of hypertension was 5.08%. Having an additional younger brother bore a small (3.3-5.9%) positive association with both SBP and DBP, with the effect weakening as people aged. Having an additional younger sister was associated with a small (3.8%) increase in SBP among women, with the magnitude shrinking as people aged. In a large family, the number of younger brothers may exert an impact on an individual's blood pressure. PMID- 23021350 TI - Zinc chloride exposure increases heme oxygenase-1 expression in MDPC-23 odontoblast-like cells. AB - OBJECTIVE: The aim of this study is to clarify the effects of zinc chloride (ZnCl2) exposure on the induction of heme oxygenase-1 (HO-1) expression and its regulatory mechanisms in MDPC-23 mouse odontoblast-like cells. METHODS: MDPC-23 cells were incubated with ZnCl2, and the levels of HO-1 protein, phosphorylated forms of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38, and phosphorylated forms of amino kinase terminal (Akt) and nuclear factor-kappaB (NF-kappaB) p65 were determined with western immunoblotting. The level of HO-1 mRNA was determined with RT-PCR analysis. After pretreatment with inhibitors of ERK, JNK, p38, phosphoinositide-3 kinase (PI3K), and NF-kappaB, HO-1 protein level was determined in MDPC-23 cells exposed to ZnCl2. RESULTS: Following exposure to 500MUM ZnCl2, the levels of both HO-1 mRNA and protein were markedly increased. The phosphorylated forms of ERK, JNK, and p38 increased after ZnCl2 exposure. Furthermore, the expression of HO-1 was markedly suppressed by treatment with the p38 inhibitor, SB203580, and mildly suppressed by the MAPK/ERK kinase inhibitor, U0126. However, treatment with the JNK inhibitor, SP600125, did not suppress ZnCl2-induced HO-1 expression. In addition, the phosphorylated forms of Akt, a downstream kinase of PI3K, and NF-kappaB p65 increased after ZnCl2 exposure. Treatment with the PI3K inhibitor, LY294002, and the NF-kappaB inhibitor, Bay11-7082, suppressed ZnCl2-induced HO-1 expression. CONCLUSION: These results suggest that ZnCl2 exposure induces HO-1 expression via multiple intracellular signalling pathways, including p38, ERK, PI3K/Akt, and NF-kappaB, in this odontoblast-like cell line. PMID- 23021351 TI - Chronic Cough in Musculoskeletal disorders: Using high resolution oesophageal manometry in search of an Aetiology. AB - Chronic cough is a common symptom carrying significant morbidity which can occur as a result of oesophageal dysmotility. Here we report 2 patients with musculoskeletal disease presenting with chronic cough to our tertiary cough clinic. Prior to referral both patients had been extensively investigated to determine the basis of their cough, with no cause found. Oesophageal studies, using high resolution oesophageal manometry, demonstrated oesophageal dysmotility with consequent airway reflux. Anti-reflux therapy resulted in a good response in both patients. These are the first reports of the recently developed technique of high resolution manometry aiding the diagnosis of chronic cough. This technique may provide important clues into aetiological mechanism in patients with conditions predisposing to reflux into the airways. PMID- 23021352 TI - Down-regulation of NOD1 in neutrophils of periparturient dairy cows. AB - Increased susceptibility of periparturient dairy cows to infectious diseases has been linked to neutrophil dysfunction. Cytoplasmic nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) mediate numerous aspects of innate immunity in humans and experimental animals. The authors hypothesized that neutrophils in periparturient cows have reduced NLR expression, resulting in declined immune responses to NLR activation. In this study, blood neutrophils from periparturient and mid-lactating cows were isolated and assessed for mRNA and protein expression of NOD1 and NOD2. Neutrophil phagocytosis and oxidative burst activity following NLR agonist-induced activation were also investigated. Periparturient cows demonstrated weak-to-absent NOD1 mRNA expression along with a significant reduction in NOD1 protein in their neutrophils. However, no difference in NOD2 protein expression was observed between groups although NOD2 mRNA abundance in periparturient cows was significantly reduced. Phagocytosis and oxidative burst activity measured by production of reactive oxygen species (ROS) were diminished in periparturient cows. NOD1 activation enhanced phagocytosis and ROS production in both isolated cell populations, regardless of the lactation stage. Nevertheless, NOD1-activated neutrophils showed reduced phagocytosis and ROS generation in periparturient cows with respect to mid-lactating subjects. Collectively, our findings suggest that NOD1 down-regulation in neutrophils may be a mechanism involved in periparturient neutrophil dysregulation. PMID- 23021353 TI - Interleukin-15 activated bovine natural killer cells express CD69 and produce interferon-gamma. AB - Interleukin (IL)-15 is an essential cytokine in natural killer (NK) cell development and survival. In humans, IL-15 shows overlapping properties with IL-2 due to partly shared receptors and signal transduction and both cytokines synergize equally well with IL-12 in the induction of interferon (IFN)-gamma production from NK cells. Bovine NK cells however, have been reported to produce less IFN-gamma after in vitro IL-12 stimulation when exposed to human IL-15 in comparison to bovine IL-2. We therefore wanted to determine if homologous IL-15 is needed for adequate stimulation of bovine NK cells. Biologically active recombinant bovine IL-15 (rbIL-15) produced in mammalian cells by the use of a modified expression vector stimulated NK cells to a dose-dependent IFN-gamma production in the presence of IL-12. In contrast to earlier findings, we also detected potent IFN-gamma production from bovine NK cells stimulated by human IL 15 and IL-12. Finally, we describe a monoclonal antibody recognizing bovine CD69 and show the expression of this early activation marker on bovine NK cells ex vivo and following rbIL-15 stimulation. PMID- 23021354 TI - Detection of antibody responses against Mycobacterium avium subsp. paratuberculosis stress-associated proteins within 30 weeks after infection in cattle. AB - In this study, humoral immune responses in cattle against Mycobacterium avium subsp. paratuberculosis (MAP) stress-associated recombinant proteins were assessed longitudinally by ELISA during the first 30 weeks after MAP infection. A total of 11 MAP genes previously identified by proteomic analysis were selected for cloning and expression. These included possible general stress-associated proteins of MAP and proteins expressed in vivo in MAP-infected sheep at an early stage of infection. An increase in the antibody levels against 5 recombinant antigen preparations (MAP1027c, MAP1339, MAP1588c, MAP1589c and MAP2411) was seen in MAP-infected calves (n=16) but not in control calves (n=3) over the time examined. Antibody responses were recorded as early as two weeks post inoculation, and 87.5% of the inoculated cattle responded to at least one of the five immunogenic antigen preparations within the first 30 weeks of infection, suggesting that these proteins identified in the in vitro models of stress were also expressed in vivo in MAP-infected cattle at a relatively early stage after infection and therefore stimulate the host's immune system. It has been assumed that the sensitivity of antibody ELISA tests is dependent on the stage of infection and the age of the animals. However, we have provided some evidence that humoral immunity occurs at an early stage of paratuberculosis and can be detected using appropriate antigens such as MAP stress-associated proteins. PMID- 23021355 TI - [Monitor of ECG signal and heart rate using a mobile phone with Bluetooth communication protocol]. AB - OBJECTIVE: To develop a portable signal monitoring equipment for electrocardiography (ECG) and heart rate (HR), communicated with a mobile phone using the Bluetooth (BT) communication protocol for display of the signal on screen. METHODS: A monitoring system was designed in which the electronic section performs the ECG signal acquisition, as well as amplification, filtering, analog to digital conversion and transmission of the ECG and HR using BT. Two programs were developed for the system. The first one calculates HR through QRS identification and sends the ECG signals and HR to the mobile, and the second program is an application to acquire and display them on the mobile screen. RESULTS: We developed a portable electronic system powered by a 9 volt battery, with amplification and bandwidth meeting the international standards for ECG monitoring. The QRS complex identification was performed using the second derivative algorithm, while the programs allow sending and receiving information from the ECG and HR via BT, and viewing it on the mobile screen. The monitoring is feasible within distances of 15 m and it has been tested in various mobiles telephones of brands Nokia(r), Sony Ericsson(r) and Samsung(r). CONCLUSIONS: This system shows an alternative for mobile monitoring using BT and Java 2 Micro Edition (J2ME) programming. It allows the register of the ECG trace and HR, and it can be implemented in different phones. PMID- 23021356 TI - Autoimmunity as a possible predisposing factor for Stenotrophomonas maltophilia endocarditis. AB - Only 40 cases of Stenotrophomonas maltophilia (S. maltophilia) endocarditis have been reported to date, and there is no description in patients with underlying autoimmunity. A 23-year-old woman with systemic lupus erythematosus (SLE) overlapping rheumatoid arthritis (RA) and no risk factors for endocarditis was admitted in our hospital because of community-acquired tricuspid valve endocarditis. During hospitalization, she was complicated with pulmonary thromboembolism and pneumonia. Laboratory showed autoimmune diathesis featured by anti-cyclic citrullinated peptide (anti-CCP), anti-Sm, anti-Ro/SSA, anti cardiolipin, anti-beta2 glycoprotein 1, and antinuclear antibodies, rheumatoid factor (RF), low complement, lymphopenia and C-reactive protein (CRP) of 425mg/L. S. maltophilia grew in serial blood culture sets. Empirical broad-spectrum antimicrobials were ineffective until trimethoprim/sulfamethoxazole (TMP/SMX) was added to therapy. One month after admission, the patient underwent successful surgical replacement of the tricuspid valve and the subsequent course was satisfactory, allowing her to be discharged 14 days after. Nowadays, she remains free of complaints and her cardiac, renal and pulmonary functioning is stable. Noteworthy is that all auto-antibodies have been persistently raised over time. Here, we present a compilation of the available information about S. maltophilia endocarditis, and suggest that autoimmunity could be included as a novel predisposing factor for S. maltophilia endocarditis. PMID- 23021357 TI - The MHC2TA gene polymorphisms are not associated with restenosis after coronary stenting in Mexican patients. AB - OBJECTIVE: The aim of this study was to test for association between MHC2TA gene polymorphisms and risk for restenosis after coronary stent placement in a group of Mexican patients. METHODS: The MHC2TA-168A>G (rs3087456), 1614C>G (rs4774), and 2536G>A (rs2229320) single nucleotide polymorphisms were genotyped using 5' exonuclease TaqMan genotyping assays in a group of 202 patients, who underwent coronary artery stenting. Basal and procedure coronary angiography were analyzed, looking for angiographic predictors of restenosis and follow-up angiography was performed to screen for binary restenosis. RESULTS: The results obtained in this study showed that the frequency of the three polymorphisms studied was similar in patients with and without restenosis. Univariate analysis showed that the use of drug-eluting stent (DES) reduces the risk of developing restenosis (p<0.001, OR=0.26). In contrast, the diameter<2.5mm of the stent and bifurcations increased the risk of developing restenosis (p=0.049, OR=1.74 and p=0.041, OR=1.8). CONCLUSION: The present study suggests that the MHC2TA polymorphisms are not involved in the risk of developing restenosis after coronary stent placement. PMID- 23021358 TI - Systolic heart murmur as first manifestation of high output heart failure due to the vein of galen malformation. AB - The vein of Galen aneurysmal malformation (VGAM) is an extremely rare arterio venous malformation. The VGAM clinical manifestations vary depending on the magnitude of vascular compromise and the age at initial presentation. Neonates typically present with severe congestive heart failure. Here we present a case in which a systolic heart murmur was the first manifestation of high output heart failure due to a VGAM. PMID- 23021359 TI - [Cell therapy for ischemic heart disease]. AB - Ischemic heart disease is the leading cause of death and heart failure worldwide. That is why it is important to develop new therapeutic modalities to decrease mortality and long-term complications in these patients. One of the main lines of research worldwide is myocardial regeneration, using progenitor cells in order to improve systolic and diastolic function in patients with ischemic heart disease, as well as to increase their survival. There have been carried out, with great enthusiasm worldwide, human and animal studies to define the usefulness of stem cells in the management of patients with ischemic heart disease. Today, regenerative therapy in ischemic heart disease is considered a novel therapeutic tool, with substantial theoretical benefits and few side effects. Here we present the scientific principles that support the use of this therapy, discuss the current clinical evidence available; and point out the controversial issues still not clarified on its use and usefulness in the short and long term. PMID- 23021360 TI - [Totally subcutaneous defibrillator]. AB - The implantable cardioverter-defibrillators (ICD) is a therapy for the prevention of sudden cardiac death. Complications with implant have been associated mainly with transvenous lead insertion. Difficulties in achieving venous access can occasionally result in failed ICD implantation. Lead failures remains a major limitation and often require removal. This procedure is associated with important morbidity and mortality. To eliminate the need for venous access, Bardy et al. designed an entirely subcutaneous ICD system. The subcutaneous ICD consists of a 3-mm tripolar parasternal electrode positioned parallel to the left of the sternal midline and guided exclusively by anatomical landmarks without fluoroscopy. The pulse generator is positioned over the sixth rib between the midaxillary line and the anterior axillary line. The device delivers a maximum of only 80-J shocks. Ventricular fibrillation was converted twice in 58 of 59 patients (98%) with the delivery of 65-J shocks in two tests to ensure a margin of safety. A demand pacing at 50 beats per minute is available for 30 seconds after a shock. These studies are preliminary but the system will need to be employ in a long-term, randomized, prospective, multicenter clinical trials. PMID- 23021361 TI - [Current status of cardiac resynchronization therapy]. AB - The present document reviews various aspects of the current status of cardiac resynchronization therapy: mechanisms of action, current indications and implantation technique. PMID- 23021362 TI - [Long QT syndrome: a brief review of the electrocardiographical diagnosis including Viskin's test]. AB - The QT interval measures both repolarization and depolarization. Learning to measure the QT interval and know how to correct (QTc) for heart rate (HR) is essential for the diagnosis of long QT syndrome (LQTS). The QTc interval changes in duration and even morphology depending on the time of the day and on a day-to day basis. A diminished adaptive response of the QTc interval to changes in HR is known as QT hysteresis. Viskin has introduced a very simple clinical test to confirm the diagnosis of LQTS based on the "hypoadaptation" of the QT when standing. This phenomenon gives the appearance of a "stretching of the QT" on the surface ECG. Likewise, he has coined the term "QT stunning" to refer to the phenomenon that the QTc interval does not return to baseline despite recovery of baseline HR after standing. This article shows some examples of the Viskin's test. PMID- 23021363 TI - [Should we add antiplatelet therapy to oral anticoagulation in patients with atrial fibrillation and vascular disease? Review of available evidence]. AB - Current recommendation is to add antiplatelet drug to oral anticoagulation in patients with atrial fibrillation (AF) and vascular disease. However, it is debatable to join both antithrombotic drugs in stable vascular disease. PMID- 23021364 TI - How electricity was discovered and how it is related to cardiology. AB - We relate the fundamental stages of the long road leading to the discovery of electricity and its uses in cardiology. The first observations on the electromagnetic phenomena were registered in ancient texts; many Greek and Roman writers referred to them, although they provided no explanations. The first extant treatise dates back to the XIII century and was written by Pierre de Maricourt during the siege of Lucera, Italy, by the army of Charles of Anjou, French king of Naples. There were no significant advances in the field of magnetism between the appearance of this treatise and the publication of the study De magnete magneticisque corporibus (1600) by the English physician William Gilbert. Scientists became increasingly interested in electromagnetic phenomena occurring in certain fish, i.e., the so-called electric ray that lived in the South American seas and the Torpedo fish that roamed the Mediterranean Sea. This interest increased in the 18th century, when condenser devices such as the Leyden jar were explored. It was subsequently demonstrated that the discharges produced by "electric fish" were of the same nature as those produced in this device. The famous "controversy" relating to animal electricity or electricity inherent to an animal's body also arose in the second half of the 18th century. The school of thought of the physicist Volta sustained the principle of a single electrical action generated by metallic contact. This led Volta to invent his electric pile, considered as the first wet cell battery. Toward the middle of the XIX century, the disciples of the physiologist Galvani were able to demonstrate the existence of animal electricity through experiments exploring the so-called current of injury. On the path of Volta's approach, many characteristics of electricity were detailed, which ultimately led to their usage in the industrial field. The route followed by Galvani-Nobili-Matteucci led to the successes of Waller, Einthoven, etcetera, enabling the modern conquests of electro-vectorcardiography. PMID- 23021365 TI - [The arbitrariness of the cut off points. A reflection since the perspective of predisease]. PMID- 23021366 TI - [Pre-illness and cutting -points, terms begins questioned]. PMID- 23021367 TI - 12-month generic health status and psychological distress outcomes following an Australian natural disaster experience: 2009 Black Saturday Wildfires. AB - OBJECTIVE: To describe the generic health status, health-related quality of life and psychological distress over a 12-month period of burns patients affected by the 2009 Black Saturday Wildfires. DESIGN SETTING AND PARTICIPANTS: Cohort study with retrospective assessment of pre-injury status and prospective assessment of physical and psychosocial functioning in the Black Saturday Wildfires burns patients across time. Generic health status and burn specific quality of life using the 36-item Short Form Health Survey (SF-36) and Burn Specific Health Scale (BSHS) were collected at three, six and twelve months post-burn injury. In addition, similar time points were used to measure level of psychological distress and the presence of pain using the Kessler-10 questionnaire (K-10) and the McGill Pain Questionnaire. RESULTS: At 12 months post-injury, patients reported a mean 16.4 (standard error, SE: 3.2) reduction in physical health and a 5.3 (SE 2.5) reduction in mental health scores of the SF-36 as compared to their pre-injury scores, with significant decreases observed in the "bodily pain", "physical functioning", "role physical" and "vitality" subscales. High levels of psychological distress and persistent pain were experienced, with no significant changes during the study period to the overall burns specific quality of life. CONCLUSIONS: Even 12 months post-burn injury, patients affected by the 2009 Victorian Wildfires still experienced a significant reduction in generic health, increased psychological distress and persistent pain. The need for early and ongoing identification of physical and psychosocial impairments during hospital admission and upon discharge could be helpful to establish systematic interdisciplinary goals for long-term rehabilitation after severe burn injury. PMID- 23021368 TI - Reduction in trauma mortality in Israel during the last decade (2000-2010): the impact of changes in the trauma system. AB - HYPOTHESIS: Following the introduction of changes to the trauma system there would be a period of time during which the impact on mortality would be minimal. A decrease in mortality rates would be noted as the TS matured and would continue over time. DESIGN: A retrospective cohort study of all severely injured patients (injury severity score >= 16) recorded in the Israeli National Trauma Registry at six level I trauma centres in Israel from 2000 to 2010. Inpatient death rates were examined overall and by sub groups. SETTING: The National Trauma Registry contains hospitalized patients, transfer patients to or from other hospitals and those who died in the emergency department. It excludes patients who were dead on arrival, discharged following treatment in the emergency department, and patients whose injuries by definition are not classified as trauma. MAIN OUTCOME MEASURES: In-hospital mortality RESULTS: Data included 23,143 severe trauma patients available for analysis. Inpatient mortality rates decreased significantly from 16% in 2000 to 11% in 2010. The odds ratio for mortality in 2010 vs. 2000, adjusted for year, age, sex, mechanism of injury, traumatic brain injury, penetrating injury, and severity of injury (ISS >= 25), was 0.53, confirming a downward trend. CONCLUSIONS: A steady significant reduction in the inpatient mortality rate for severe trauma patients hospitalized at all level I trauma centres in Israel between 2000 and 2010 was observed. Although a single factor that explains the reduction was not identified, evidently the establishment of the trauma system brought about a significant decrease in hospital mortality. Integrated cooperation between components of the national trauma system in Israel over the years may explain the reduction. PMID- 23021369 TI - Meta-analysis of plasma to red blood cell ratios and mortality in massive blood transfusions for trauma. AB - BACKGROUND: The current military paradigm for blood transfusion in major trauma favours high plasma:RBC ratios. This study aimed determine whether high plasma:red blood cell (RBC) ratios during massive transfusion for trauma decrease mortality, using meta-analysis of contemporaneous groups matched for injury severity score. METHODS: A systemic review of the published literature for massive blood transfusions in trauma was performed. Patients were categorised into groups based on plasma:RBC transfusion ratios. Meta-analysis was only performed when there were no significant differences in Injury Severity Score (ISS) between ratio groups within studies. The main endpoint was 30-day mortality. RESULTS: Six observational studies reporting outcomes for 1885 patients were included in this meta-analysis. Five studies were from civilian environments and one from a military setting. Ratio cut-offs at 1:2 were the most commonly reported, demonstrating a survival advantage with higher ratios (OR 0.49, 95% CI 0.31-0.80, p=0.004). Ratios>=1:2 showed a significant reduction in mortality compared to lower ratios (OR 0.56, 95% CI 0.40-0.78, p<0.001). Reducing the cut-off level was still protective (ratios between 1:2.5 and 1:4, OR 0.41), although the confidence interval was wide (0.16-1.00, p=0.05) and data heterogenous (I(2)=78%). Ratios of 1:1 were not proven to confer additional benefit beyond ratios of 1:2 (OR 0.50, 95% CI 0.37-0.68, p<0.001). CONCLUSIONS: In groups matched for ISS, there was a survival benefit with high plasma:RBC resuscitation ratios. No additional benefits of 1:1 over 1:2 ratios were identified. PMID- 23021370 TI - Advances in immunotherapy for food allergy. AB - Food allergy is a life-threatening allergic disease that is increasing in prevalence with no approved curative therapy. Standard treatment of food allergy is limited to avoidance of the allergen and supportive management of allergic symptoms and anaphylaxis. Current research, however, has been focused on developing therapy that can modify the allergic immune response in both allergen specific and non-specific methods. This review will provide an overview of these methods including oral immunotherapy, sublingual immunotherapy, epicutaneous immunotherapy, modified food protein vaccines, anti-IgE monoclonal antibody adjuvant therapy, Chinese herbs, and helminth therapy. PMID- 23021371 TI - Revertant mosaicism in heritable skin diseases: mechanisms of natural gene therapy. AB - Revertant mosaicism (RM) refers to the co-existence of cells carrying disease causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous event. It has been discovered in an increasing number of heritable skin diseases: ichthyosis with confetti and different subtypes of epidermolysis bullosa. This "natural gene therapy" phenomenon manifests as normal appearing skin areas surrounded by affected skin. Although initially thought to be rare, RM is now considered relatively common in genetic skin diseases. To address the issues relevant to RM, we here discuss the following questions: 1) What is the incidence of RM in heritable skin diseases? 2) What are the repair mechanisms in RM? 3) When do the revertant mutations occur? 4) How do you recognize revertant skin? 5) Do the areas of RM change in size? The answers to these questions allow us to acquire knowledge on these reverted cells, the mechanisms of RM, and utility of the reverted cells to the advantage of the patient. The revertant skin could potentially be used to treat the patient's own affected skin. PMID- 23021372 TI - Evaluating a new marker for risk prediction: decision analysis to the rescue. AB - In many areas of medicine risk prediction models are used to identify high-risk persons to receive treatment, with the goal of maximizing the ratio of benefits to harms. Thus there is considerable interest in evaluating markers to improve risk prediction. Many measures to evaluate a new marker for risk prediction are based solely on predictive accuracy including the odds ratio, change in the area under the receiver operating characteristic curve, and net reclassification improvement. However, predictive accuracy measures do not capture important clinical implications. Decision analysis comes to the rescue by including the ratio of the anticipated harm ("cost") of a false positive to the anticipated benefit of a true positive, which is transformed into a risk threshold (T) of indifference between treatment and no treatment. A decision-analytic measure of the "value" of a new marker is the number needed to test at a particular risk threshold, denoted NNTest(T), the minimum number of marker tests per true positive needed for risk prediction to be worthwhile. If NNTest(T) is acceptable given the invasiveness and adverse consequences of the test for the new marker, the new marker is recommended for inclusion in risk prediction. We provide a simple review of the derivation and computation of NNTest(T) from risk stratification tables and compare the minimum of NNTest(T), over risk thresholds, with measures of predictive accuracy in six studies. The results illustrate the advantages of this decision-analytic approach for evaluating a new marker for risk prediction. PMID- 23021373 TI - Natural compounds that modulate BACE1-processing of amyloid-beta precursor protein in Alzheimer's disease. AB - Alzheimer's disease (AD) is a fatal neurodegenerative disorder and the primary cause of dementia, with no cure presently available. The pathogenesis of AD is believed to be primarily driven by amyloid-beta (Abeta), the principal component of senile plaques in the AD brain. Abeta is generated through a sequential proteolytic process initiated by BACE1, or beta-secretase, from the amyloid-beta precursor protein (APP). BACE1-cleavage of APP is the rate-limiting step in producing Abeta; therefore, much of the effort has focused on identifying BACE1 inhibitors. More recently, an AD clinical trial using a BACE1 inhibitor was halted due to adverse effects outside of the brain in animal models. This raised questions with respect to the physiological roles of BACE1 and the approach in identifying lead compounds to inhibit BACE1 with desirable safety profiles. Natural products, particularly those utilized in traditional Chinese medicine (TCM), have an advantage in their safety profiles because they have already been utilized in humans for a long time. This article will discuss the background of AD and the biological aspects of BACE1, and then discuss the effects of several natural products that modulate BACE1-processing of APP. PMID- 23021374 TI - Nongenomic regulation by thyroid hormone of plasma membrane ion and small molecule pumps. AB - The sodium/proton (Na/H) exchanger, Na,K-ATPase, and Ca2+-ATPase are membrane ion pumps whose basal activities may be regulated by local nongenomic actions of thyroid hormone and hormone analogues via a hormone receptor on plasma membrane integrin alphavbeta3. System A amino acid transport and the activity of P glycoprotein (P-gp; ABCB1), a multidrug efflux pump, are also modulated by thyroid hormone and alphavbeta3. Where signal transduction has been studied, the presence of the hormone at the receptor is transduced by mitogen-activated protein kinase (MAPK) isoforms (ERK1/2; p38) or phosphatidylinositol 3-kinase into local actions. The existence of the cell surface receptor offers opportunities to pharmacologically modify actions of these important transport functions with nanoparticulate formulations of T4 and T3 that do not enter the cell. Such formulations may reverse complex intracellular accumulations of H+, Na+, and Ca2+ that occur in clinical settings such as ischemia. In addition, nanoparticulate tetraiodothyroacetic acid (tetrac), a thyroid hormone analogue that inhibits binding of T4 and T3 to integrin alphavbeta3 as well as certain other functions of the integrin, may reverse P-gp-dependent resistance to anti cancer drugs in tumor cells. PMID- 23021375 TI - EGFR and downstream genetic alterations in KRAS/BRAF and PI3K/AKT pathways in colorectal cancer: implications for targeted therapy. AB - The promise of individualized treatment is gradually being fulfilled, and targeted therapy is becoming a powerful strategy to treat selected patients based on their molecular profile. For metastatic colorectal cancer (mCRC) patients anti EGFR (epidermal growth factor receptor) targeted therapy has markedly improved disease control and survival. However, only a subgroup of patients with mCRC respond to anti-EGFR treatment, and selecting the patients with a positive effect from treatment is important for both the patient and the society. Patients with mutations in the KRAS gene are known as non-responders to anti-EGFR treatment and, consequently, KRAS testing has been employed in routine clinical practice for patient selection. However, a large number of the KRAS wildtype patients do not respond to this treatment. The molecular mechanism underlying response is not fully understood, and other members of the KRAS-BRAF pathway and PI3K-AKT pathway are investigated as predictive biomarkers. Furthermore, concordance of mutation status of primary tumors and their corresponding hepatic or pulmonary metastases, as well as treatment-induced mutations, possess another challenge for properly tailoring the appropriate therapy to this patient group. In this review, molecular biomarkers involved in prediction of response to anti-EGFR treatment are discussed. PMID- 23021376 TI - Catch it before it kills: progesterone, obesity, and the prevention of endometrial cancer. AB - The lifetime risk for developing endometrial cancer, the fourth most common malignancy in women, is approximately 3%. Endometrial cancer is a hormone-driven cancer, with approximately 80% of endometrial cancers arising attributable to either an excess of estrogen or a lack of progesterone. In the normal endometrium, the proliferative effects of estrogen are normally countered by progesterone, but the absence of progesterone allows estrogen to induce oncogenesis, an effect that is amplified in situations of excess estrogen. One of the major emerging causes of the estrogen/progesterone imbalance is obesity. Obesity is associated with several hormonal derangements as well as dysregulation of insulin/insulin-like growth factor activity, which collectively contribute to hyperplasia and carcinogenesis in the endometrium. In this article, we provide an in-depth description of how obesity mechanistically promotes this hormone and growth factor imbalance. Given that endometrial cancer is clearly associated with obesity, we put forth the hypothesis that a large portion of these cancers might be prevented by treatment with progesterone. PMID- 23021379 TI - Does the level of education influence completed suicide? A nationwide register study. AB - OBJECTIVE: To evaluate whether education attainment was associated with completed suicide, a topic only marginally investigated in the literature. METHODS: Data for the years between 2006 and 2008 were extracted from the Italian Mortality Database to include all deaths by suicide and natural causes and to obtain information on their education attainment. RESULTS: We found significant differences in education attainment between suicide victims and individuals deceased by natural causes, stratified by sex and broken down by age bands. Of both males and females from 15 to 64 years old, suicide victims were significantly more often to have a higher education attainment compared with the same sex and age counterparts died from natural causes. Persons with higher school attainment, compared with those with a maximum primary school degree, had significantly increased odds ratios of dying from a suicide rather than a natural cause. For persons aged 65-74 years or above, however, the differences were not so much obvious. These observations remained almost the same after adjustment for marital status, region of residence and age. CONCLUSIONS: Individual with higher educational achievement may be more prone to suicide risk when facing failures, public shame, and high premorbid functioning. PMID- 23021377 TI - Manic symptoms in youth with bipolar disorder: factor analysis by age of symptom onset and current age. AB - BACKGROUND: Factor analysis has been used to identify potential clinical subtypes of mania in pediatric bipolar disorder. Results vary in the number of factors retained. The present study used a formal diagnostic instrument to examine how symptoms of mania in young people are expressed, depending on age of symptom onset and current age. METHODS: Trained clinicians completed the Schedule of Affective Disorders and Schizophrenia for School-Age Children (K-SADS) Mania Rating Scale (MRS) with parents of 163 children with child-onset of symptoms (before age 12), 94 adolescents with child-onset of symptoms, and 90 adolescents with adolescent-onset of symptoms (after age 12). Factor analysis of symptom ratings during the most severe lifetime manic episode was performed for each age group. RESULTS: Symptom factor structures were established for each age group. Two factors were evident for children with child-onset of symptoms ("activated/pleasure seeking" and "labile/disorganized"), one factor was present for adolescents with child-onset of symptoms ("activated/pleasure seeking/disorganized") and two factors were evident for adolescents with adolescent-onset of symptoms ("activated/pleasure seeking" and "disorganized/psychotic"). The factor structures for children with child-onset and adolescents with adolescent-onset of symptoms were highly similar, with the latter factor structure including psychotic symptoms. LIMITATIONS: Limitations include reliance on retrospective parent report and potential issues with generalizability. CONCLUSIONS: Findings suggest mania symptomatology is largely similar when examined by both age of onset and current age, with some notable differences. Specifically, psychotic symptoms begin emerging as a distinct factor in adolescents with adolescent-onset of symptoms. PMID- 23021378 TI - People with bipolar I disorder report avoiding rewarding activities and dampening positive emotion. AB - BACKGROUND: Researchers have linked bipolar disorder to elevations in reward sensitivity and positive affect. Little is known, however, about how people with bipolar disorder respond to rewards and positive affect and how these tendencies relate to functioning or quality of life. METHODS: Persons diagnosed with bipolar I disorder and matched controls completed the Responses to Positive Affect (RPA) measure and the Brief Quality of Life in Bipolar Disorder scale. Bipolar participants also completed the Reward Responses Inventory, which we designed to assess the extent to which participants avoid rewarding activities to prevent mania. A subsample of participants with bipolar disorder completed a positive mood induction procedure to examine the validity of the Response to Positive Affect scale. RESULTS: The majority of bipolar participants reported avoiding at least one rewarding activity as a means of preventing mania. In addition, people with bipolar I disorder reported more dampening responses to positive affect than did control participants. Dampening positive emotions was related to lower quality of life. LIMITATIONS: This study does not address whether responses to affect and reward are related to the longitudinal course of symptoms. CONCLUSIONS: These findings suggest that people with bipolar I disorder seem to be aware of the potential of goal achievements to trigger mania, and many people with bipolar disorder seem to take steps to avoid positive emotion and reward. PMID- 23021380 TI - Strong effects of environmental factors on prevalence and course of major depressive disorder are not moderated by 5-HTTLPR polymorphisms in a large Dutch sample. AB - BACKGROUND: There is ongoing interest in the possible interaction of the serotonin-transporter-linked polymorphic region (5-HTTLPR) with environmental factors in determining Major Depressive Disorder (MDD). The current study contributes to this research area by comprehensively examining the interaction effects and direct-effects of 5-HTTLPR and five environmental factors on MDD prevalence and course in a well-characterized longitudinal sample. METHODS: The sample consisted of 1625 patients with a CIDI-confirmed diagnosis of MDD and 1698 screened controls from the Netherlands. Four MDD outcomes were studied as dependent variables: one main MDD prevalence-outcome (all MDD), two more severe MDD prevalence-outcomes (suicidal and chronic MDD), and one MDD course outcome (chronic versus non-chronic MDD). Because SNP rs25531 modifies the effect of 5 HTTLPR, haplotypes of 5-HTTLPR and rs25531 were measured. For the four MDD outcome measures, we examined the direct effects of 5-HTTLPR/rs25531-haplotypes, five environmental factors (lifetime and recent stressful life-events, sexual abuse, low educational attainment, and childhood trauma) and their interaction in logistic regression models. RESULTS: The environmental factors had large and consistent effects on all four MDD outcomes, including course of MDD. The 5 HTTLPR/rs25531-haplotype had a suggestive effect on course of MDD, but not on presence of MDD. Gene-by-environment interaction was significant (<0.05) for one of the 20 tests performed, which is not more than expected by chance. LIMITATIONS: Environmental factors were not assessed before the onset of MDD. CONCLUSIONS: Environmental factors had a strong impact on the presence and course of MDD, but no evidence for gene-by-environment interaction was found. PMID- 23021381 TI - Isolated febrile seizures are not associated with structural abnormalities of the limbic system. AB - The nature of the relationship between childhood febrile seizures (CFSs) and temporal lobe epilepsy (TLE) remains unknown. The purpose of this study was to perform a comprehensive analysis of measures of structural changes of the hippocampus and limbic white matter to determine whether structural abnormalities previously demonstrated in TLE were present in adults with isolated CFS. Twenty three adults with past CFS but no history of nonfebrile seizures and 21 controls underwent research MRI for measurement of volume, T2 and mean diffusivity of the hippocampus and fractional anisotropy of the fornix and cingulum. No significant group differences were found in any of the measured parameters. These findings suggest that structural abnormalities of the hippocampus and limbic white matter that have been demonstrated in TLE are not associated with isolated CFS. PMID- 23021382 TI - Why should patients and clinicians talk about emotion? PMID- 23021384 TI - Simple in situ functionalizing magnetite nanoparticles by reactive blue-19 and their application to the effective removal of Pb2+ ions from water samples. AB - An in situ method for direct attachment of reactive blue-19 onto the surface of magnetite nanoparticles to prepare an efficient adsorbent for removal of Pb(2+) ion from water samples was proposed. The produced modified magnetite nanoparticles (MMNP) were characterized by X-ray diffraction (XRD) analysis, scanning electron microscopy (SEM) and infrared spectroscopy. The synthesized MMNP showed high adsorption capacity to removal of Pb(2+) from wastewater samples. Lead ion adsorption process has been thoroughly studied from both kinetic and equilibrium points of view for adsorbent. The adsorption isotherms were analyzed using the five different isotherm models and correlation coefficients were determined for each isotherm. It was found that the Langmuir isotherm showed better correlation with the experimental data than other isotherms. The adsorption kinetics was tested for the pseudo-first order and pseudo-second order kinetic models at different experimental conditions. The kinetic data showed that the process is very fast and the adsorption process follows pseudo second order kinetic models for modified magnetite adsorbents. Thus, the new nanoparticles are favorable and useful for the removal of this metal ion, and the high adsorption capacity makes them good promising candidate materials for Pb(2+) ion removal from water samples. PMID- 23021383 TI - Mercury bioaccumulation in the aquatic plant Elodea nuttallii in the field and in microcosm: accumulation in shoots from the water might involve copper transporters. AB - Previous studies suggest that macrophytes might participate in bioaccumulation and biomagnification of toxic mercury (Hg) in aquatic environment. Hg bioaccumulation and uptake mechanisms in macrophytes need therefore to be studied. Amongst several macrophytes collected in an Hg contaminated reservoir in Romania, Elodea nuttallii showed a high organic and inorganic Hg accumulation and was then further studied in the laboratory. Tolerance and accumulation of Hg of this plant was also high in the microcosm. Basipetal transport of inorganic Hg was predominant, whereas acropetal transport of methyl-Hg was observed with apparently negligible methylation or demethylation in planta. Hg concentrations were higher in roots>leaves>stems and in top>middle>bottom of shoots. In shoots, more than 60% Hg was found intracellularly where it is believed to be highly available to predators. Accumulation in shoots was highly reduced by cold, death and by competition with Cu(+). Hg in E. nuttallii shoots seems to mainly originate from the water column, but methyl-Hg could also be remobilized from the sediments and might drive in part its entry in the food web. At the cellular level, uptake of Hg into the cell sap of shoots seems linked to the metabolism and to copper transporters. The present work highlights an important breakthrough in our understanding of Hg accumulation and biomagnifications: the remobilization of methyl-Hg from sediments to aquatic plants and differences in uptake mechanisms of inorganic and methyl-Hg in a macrophyte. PMID- 23021385 TI - Hydrogeo-chemical impacts of air sparging remediation on a semi-confined aquifer: evidences from field monitoring and modeling. AB - Air sparging (AS) was explored for remediation of a petroleum contaminated semi confined groundwater system in NE China. Physical, hydro-chemical and hydraulic behaviors in subsurface environment during AS were investigated with support of modeling to understand the hydrogeo-chemical impacts of AS on the aquifer. The responses of groundwater, dissolved oxygen and temperature indicated that the radius of influence of AS was up to 8-9 m, and a 3D boundary of the zone of influence (ZOI) was accordingly obtained with volume of 362 m(3). Water mounding unlike normal observations was featured by continuous up-lift and blocked dissipation. AS induced water displacement was calculated showing no obvious spreading of contaminant plume under this AS condition. Slug tests were employed before and after AS to reveal that the physical perturbation led to sharp increase in permeability and porosity. Modeling indicated that the regional groundwater flow field was not affected by AS except the physical perturbation in ZOI. Hydro-chemically increase of pH and Eh, and reduction of TDS, electrical conductivity and bicarbonate were observed in ZOI during AS. PHREEQC modeling inferred that these chemical phenomena were induced by the inorganic carbon transfer during air mixing. PMID- 23021386 TI - Performance of two swine manure treatment systems on chemical composition and on the reduction of pathogens. AB - Swine effluents must be correctly handled to avoid negative environmental impacts. In this study, the profiles of two swine manure treatment systems were evaluated: a solid-liquid separation step, followed by an anaerobic reactor, and an aerobic step (System 1); and a biodigester followed by serial lagoons (System 2). Both systems were described by the assessment of chemical, bacterial and viral parameters. The results showed that in System 1, there was reduction of chemicals (COD, phosphorus, total Kjeldhal nitrogen - TKN - and NH(3)), total coliforms and Escherichia coli; however, the same reduction was not observed for Salmonella sp. Viral particles were significantly reduced but not totally eliminated from the effluent. In System 2, there was a reduction of chemicals, bacteria and viruses with no detection of Salmonella sp., circovirus, parvovirus, and torque teno virus in the effluent. The chemical results indicate that the treated effluent can be reused for cleaning swine facilities. However, the microbiological results show a need of additional treatment to achieve a complete inactivation for cases when direct contact with animals is required. PMID- 23021387 TI - Ultrasonic wave's interaction at fluid-porous piezoelectric layered interface. AB - The complete description of acoustic propagation in a multilayered system is of great interest in a variety of applications such as non-destructive evaluation and acoustic design and there is need for a flexible model that can describe the reflection and transmission of ultrasonic waves in these media. The reflection and transmission of ultrasonic waves from a fluid loaded porous piezoelectric layered structure is studied analytically. The layered structure is considered to be consisting of n number of layers of porous piezoelectric materials. Transfer matrix technique is used to study the layered materials. The analytical expressions for the reflected, transmitted, interaction energy ratios and surface impedance are obtained. The effects of frequency, porosity, angle of incidence, layer thickness and number of layers on the energy ratios and surface impedance are studied for different configurations of the layered materials. The results obtained are deduced for the poro-elastic and fluid loaded porous piezoelectric half space case, which are in agreement with earlier established results. A comparison of the results, obtained by alternate numerical techniques, is made. PMID- 23021388 TI - Advanced HER2-positive gastric cancer: current and future targeted therapies. AB - The prognostic value of human epidermal growth factor receptor 2 (HER2) in gastric cancer is controversial. Consensus guidelines have standardized the testing of HER2 status in gastric cancer. Overexpression of this receptor occurs in approximately 20% of gastric and gastro-esophageal junction adenocarcinomas, predominantly those of the intestinal type. Recently, trastuzumab has emerged as the first targeted drug to improve overall survival when combined with chemotherapy in advanced HER2-positive gastric cancer. Primary and secondary resistance to trastuzumab has become a major problem and new strategies to overcome this resistance are needed. A high percentage of advanced HER2-positive gastric cancer patients who progress on trastuzumab therapy are candidates for second-line therapy. New families of targeted drugs, including tyrosine kinase inhibitors (TKIs) such as lapatinib and PF-00299804, mammalian target of rapamycin (mTOR) pathway inhibitors such as everolimus, heat-shock protein 90 (HSP90) inhibitors such as AUY922, HER dimerization inhibitors such as pertuzumab, and antibody-chemotherapy conjugates such as trastuzumab-emtansine (T DM1), could offer alternative second-line treatments when trastuzumab-based first line therapy fails. PMID- 23021392 TI - The nature of third molars: are third molars different than other teeth? PMID- 23021393 TI - Evaluation of third molars: clinical examination and imaging techniques. PMID- 23021394 TI - The management of the asymptomatic, disease-free wisdom tooth: removal versus retention. PMID- 23021395 TI - Complications of retention: pathology associated with retained third molars. PMID- 23021396 TI - Surgical management of third molars. PMID- 23021397 TI - Perioperative strategies for third molar surgery. PMID- 23021398 TI - Complications of third molar surgery and their management. AB - The frequency and severity of untoward events associated with surgical procedures are influenced by multiple factors that may be related to the procedure, patient, and/or surgeon. Not every third molar needs to be removed. Full bony impacted lower third molars well below the cervical margin of the second molar crowns should be considered for retention. Certain deviations from normal healing should be considered to be complications. Risk factors associated with third molar removal should be carefully established and explained to the patient. Third molar surgery has a predictable postsoperative course for the average patient. PMID- 23021399 TI - Controversy, evidence, and third molar management. PMID- 23021400 TI - Contemporary management of third molars. PMID- 23021402 TI - Manual vacuum aspiration in the emergency department for management of early pregnancy failure. PMID- 23021403 TI - Molecular and cellular effects of cardiac mechanotransduction during cardiopulmonary resuscitation and postresuscitation period: another piece in the puzzle. PMID- 23021401 TI - CMR of microvascular obstruction and hemorrhage in myocardial infarction. AB - Microvascular obstruction (MO) or no-reflow phenomenon is an established complication of coronary reperfusion therapy for acute myocardial infarction. It is increasingly recognized as a poor prognostic indicator and marker of subsequent adverse LV remodeling. Although MO can be assessed using various imaging modalities including electrocardiography, myocardial contrast echocardiography, nuclear scintigraphy, and coronary angiography, evaluation by cardiovascular magnetic resonance (CMR) is particularly useful in enhancing its detection, diagnosis, and quantification, as well as following its subsequent effects on infarct evolution and healing. MO assessment has become a routine component of the CMR evaluation of acute myocardial infarction and will increasingly play a role in clinical trials of adjunctive reperfusion agents and strategies. This review will summarize the pathophysiology of MO, current CMR approaches to diagnosis, clinical implications, and future directions needed for improving our understanding of this common clinical problem. PMID- 23021404 TI - Health care students' personal experiences and coping with bullying in clinical training. AB - Previous studies show that health care students have experienced bullying by nursing staff in clinical training. Although these studies provide plenty of information considering the manifestation and consequences of bullying on students, there is a gap of knowledge on how health care students' cope with bullying. In addition, previous studies seem to have focused only on the experiences of nursing and midwifery students. This paper presents the results of a qualitative study exploring the bullying experiences of Finnish health care students (n=41) representing two Universities of Applied Sciences. In order to provide information for faculties of health care on bullying intervention and prevention strategies, this study aimed at describing health care students' experiences and coping with bullying in clinical training. Based on previous study findings, an electronic semi-structured questionnaire was developed for the data collection. The qualitative data was analysed using inductive content analysis. The results show that the students experienced verbal and non-verbal bullying in clinical training. In addition to psychological and physical symptoms, bullying also decreased the students' learning, their studying motivation and their professional engagement. One reason why some students did not share their bullying experiences with their teachers and clinical instructors was their idea that sharing their experiences would be useless. On the other hand, students who did share their experiences with a teacher or a clinical instructor usually received emotional support, information, and help in the form of bullying intervention. The results of this study suggest that faculties of health care need to develop action plans against bullying in co-operation with clinical training sites in order to ensure students' learning and professional engagement. In the future, it is suggested that research is focused on factors preventing and contributing to bullying towards health care students. PMID- 23021405 TI - Endoscopic ultrasound with double-balloon endoscopy for the diagnosis of inverted Meckel's diverticulum: a case report. AB - INTRODUCTION: Inverted Meckel's diverticulum has usually been misdiagnosed in the cases based on computed tomography images presented in the literature. The final diagnosis was made intra-operatively or by pathology reports after surgery. Despite this, preoperative diagnosis could be made successfully by using endoscopic ultrasound with double-balloon endoscopy prior to surgery. CASE PRESENTATION: A 60-year-old Japanese woman with severe anemia complained of several episodes of black stool over the preceding 2 years. Abdominal computed tomography showed a 3.0-cm low-density tumor in the ileum, suggesting a diagnosis of intestinal lipoma. Examination of the tumor by endoscopic ultrasound with double-balloon endoscopy revealed a hypo-echoic layer corresponding to the muscularis propria, and a hyper-echoic layer corresponding to the fat tissue. These findings, which suggested that the tumor included areas outside the intestinal serosa, are not typical for a lipoma, despite the existence of a hyper echoic layer corresponding to fatty tissue. We then considered a diagnosis of inverted Meckel's diverticulum. CONCLUSION: Lipoma and inverted Meckel's diverticulum are difficult to differentially diagnose by computed tomography. Polypectomy is the preferred therapeutic approach when a lipoma is present; however, polypectomy in a patient with Meckel's diverticulum requires full thickness resection. Situations where polypectomy is performed without preparing for full-thickness resection can be avoided by first making a precise diagnosis using double-balloon endoscopy and endoscopic ultrasound. PMID- 23021406 TI - Increased endogenous erythropoietin concentrations after cardiac surgery: another useful biomarker to be validated. PMID- 23021407 TI - Relation between proteinuria and acute kidney injury in patients with severe burns. AB - INTRODUCTION: Proteinuria in burn patients is common, and may be associated with acute kidney injury (AKI) and adverse outcomes. We evaluated the incidences, outcomes, characteristics and determinants of proteinuria and its influence on AKI and outcomes in burn patients. METHODS: This retrospective study was carried out in a hospital's burn department. The study population consisted of patients with burn injuries admitted during a five-year period. Positive urine dipstick readings were defined as mild (+/- or 1+) or heavy (>= 2+) proteinuria, and AKI was diagnosed and staged according to the Risk, Injury, Failure, Loss, End Stage (RIFLE) classification system. Patient characteristics, management and outcomes were evaluated for associations with proteinuria using nonparametric tests, chi square (chi(2)) tests and binary logistic regression. RESULTS: Of the patients admitted to the burn unit during the study period (n = 2,497), 865 (34.64%) were classified as having proteinuria. In the patients whose total burn surface areas (TBSA) were > 30% (n = 396), 271 patients (68.43%) had proteinuria and 152 of these patients (56.09%) met AKI criteria. No patients without proteinuria developed AKI. Intensive care unit (ICU) mortality rates were 0.8%, 16.67% and 30.77% (P < 0.001) in the groups with no, mild and heavy proteinuria, respectively. Logistic regression analysis identified proteinuria (OR 4.48; 95% CI, 2.824 to 7.108; P < 0.001) and sequential organ failure assessment (OR 1.383; 95% CI, 1.267 to 1.509; P < 0.001) as risk factors for AKI. CONCLUSIONS: We observed a high prevalence of proteinuria in patients with severe burns (> 30% TBSA). Severely burned patients with proteinuria had a high risk of developing AKI and a poor prognosis for survival. This suggests that proteinuria should be used for identifying burn patients at risk of developing AKI. PMID- 23021408 TI - Detection of a novel genotype of Cryptosporidium in Antarctic pinnipeds. AB - A study was conducted to investigate the presence of Cryptosporidium and Giardia in Antarctic marine mammals. A total of 270 faecal samples from different species of pinnipeds from different locations in the South Shetland Islands and Antarctic Peninsula were analysed by immunofluorescence microscopy and PCR. Cryptosporidium was detected by PCR in three samples from Southern elephant seals (Mirounga leonina) and 2 Weddell seals (Leptonychotes weddellii). However, no oocysts were observed in any of the samples by immunofluorescence microscopy. Molecular characterisation of the isolates, using the 18S rDNA, the HSP70 and the COWP loci, revealed the presence of a Cryptosporidium sp., previously reported from an Antarctic Southern elephant seal, in the elephant seals and a novel genotype in Weddell seals. Giardia could not be detected in any of the samples analysed. PMID- 23021409 TI - Polymorphic variations in the FANCA gene in high-risk non-BRCA1/2 breast cancer individuals from the French Canadian population. AB - The majority of genes associated with breast cancer susceptibility, including BRCA1 and BRCA2 genes, are involved in DNA repair mechanisms. Moreover, among the genes recently associated with an increased susceptibility to breast cancer, four are Fanconi Anemia (FA) genes: FANCD1/BRCA2, FANCJ/BACH1/BRIP1, FANCN/PALB2 and FANCO/RAD51C. FANCA is implicated in DNA repair and has been shown to interact directly with BRCA1. It has been proposed that the formation of FANCA/G (dependent upon the phosphorylation of FANCA) and FANCB/L sub-complexes altogether with FANCM, represent the initial step for DNA repair activation and subsequent formation of other sub-complexes leading to ubiquitination of FANCD2 and FANCI. As only approximately 25% of inherited breast cancers are attributable to BRCA1/2 mutations, FANCA therefore becomes an attractive candidate for breast cancer susceptibility. We thus analyzed FANCA gene in 97 high-risk French Canadian non-BRCA1/2 breast cancer individuals by direct sequencing as well as in 95 healthy control individuals from the same population. Among a total of 85 sequence variants found in either or both series, 28 are coding variants and 19 of them are missense variations leading to amino acid change. Three of the amino acid changes, namely Thr561Met, Cys625Ser and particularly Ser1088Phe, which has been previously reported to be associated with FA, are predicted to be damaging by the SIFT and PolyPhen softwares. cDNA amplification revealed significant expression of 4 alternative splicing events (insertion of an intronic portion of intron 10, and the skipping of exons 11, 30 and 31). In silico analyzes of relevant genomic variants have been performed in order to identify potential variations involved in the expression of these spliced transcripts. Sequence variants in FANCA could therefore be potential spoilers of the Fanconi-BRCA pathway and as a result, they could in turn have an impact in non-BRCA1/2 breast cancer families. PMID- 23021411 TI - Awareness, recognition, and celebration for infection prevention. PMID- 23021410 TI - An approach for diagnosing plasma cell myeloma by three-color flow cytometry based on kappa/lambda ratios of CD38-gated CD138(+) cells. AB - BACKGROUND: World Health Organization (WHO) criteria are commonly used to diagnose plasma cell myeloma (PCM); however, these criteria are complex and require several laboratory parameters. For differentiating reactive plasmacytosis from clonal plasma cell (PC) neoplasms such as PCM, it is important to accurately determine the expression of cytoplasmic immunoglobulin light chains. METHODS: We retrospectively analyzed the records of 27 selected patients with PCM who underwent bone biopsies for confirmative diagnosis according to WHO criteria. Twenty-three controls were also investigated. In the present study, all the samples were analyzed using flow cytometry (FC) in the side scatter vs. CD38 histogram mode, and the CD38-gated PC population was identified. Bivariate histograms of CD138/kappa and CD138/lambda were assessed, and the ratios of dual positive cells to the CD138(+) PC population were calculated. The kappa/lambda ratio was defined as the ratio of CD138/kappa to CD138/lambda. RESULTS: PCM cells were distinguished from normal PCs using cutoff levels between 0.76 and 1.5, at a sensitivity of 96.3% and specificity of 95.7%. CONCLUSIONS: Three-color FC analysis is simple to perform and inexpensive, with clinically relevant data obtained soon after the completion of FC measurements. The detection of the cytoplasmic kappa/lambda ratio of CD38-gated CD138(+) PCs may be a useful tool in the diagnosis of PCM. To the best of our knowledge, this report represents the first diagnostic assessment of the cytoplasmic kappa/lambda ratio in CD38-gated CD138+ PCs using FC analysis. This method may help in more simple, efficient, rapid, and accurate diagnosis of PCM. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1568085959771735. PMID- 23021412 TI - Surveillance: challenges and direction. PMID- 23021414 TI - Assessing the quality of the peer review process: author and editorial board member perspectives. AB - BACKGROUND: Because peer review is central to the publication of rigorous research, periodic assessment of the process's effectiveness is clearly warranted. METHODS: Two online surveys, one for authors (n = 102) and the other for Editorial Board members (n = 20), were conducted to assess their perspectives on the quality and timeliness of peer review. The chi(2) or Fisher exact test was used to analyze differences between authors and Board member responses. RESULTS: Authors of accepted manuscripts were significantly more likely to rate the review as the same or better than other peer reviews they had received when compared with authors of rejected manuscripts (93.3% vs 47.4%, respectively, P = .001). In general, perceptions of review quality among Board members and authors were similar, but Board members were significantly more likely to rate reviewers as fair and unbiased (91.4% and 70%, respectively, P = .04). Approximately one fourth (23.5%) of authors reported that length of time between manuscript submission and receipt of decision was 0 to 4 weeks, 38.2% indicated 5 to 7 weeks, 18.6% took 8 to 10 weeks, and 19.6% of authors reported that the decision required more than 10 weeks. CONCLUSION: This survey of authors and Board members provided important insights into perceptions of the peer review process and identified areas for improvement. PMID- 23021415 TI - Sample size and power. AB - A quick review of the basics of sample size and power is presented. Readers can participate in an online exercise that introduces them to a power calculator that can be used in their practice, and illustrates the concepts discussed in the article. PMID- 23021413 TI - Wide variation in adoption of screening and infection control interventions for multidrug-resistant organisms: a national study. AB - BACKGROUND: We performed a survey of National Healthcare Safety Network hospitals in 2008 to describe adoption of screening and infection control policies aimed at multidrug-resistant organisms (MDRO) in intensive care units (ICUs) and identify predictors of their presence, monitoring, and implementation. METHODS: Four hundred forty-one infection control directors were surveyed using a modified Dillman technique. To explore differences in screening and infection control policies by setting characteristics, bivariate and multivariable logistic regression models were constructed. RESULTS: In total, 250 hospitals participated (57% response rate). Study ICUs (n = 413) routinely screened for methicillin resistant Staphylococcus aureus (59%); vancomycin-resistant Enterococcus (22%); multidrug-resistant, gram-negative rods (12%); and Clostridium difficile (11%). Directors reported ICU policies to screen all admissions for any MDRO (40%), screen periodically (27%), utilize presumptive isolation/contact precautions pending a screen (31%), and cohort colonized patients (42%). Several independent predictors of the presence and implementation of different interventions including mandatory reporting and teaching status were identified. CONCLUSION: This study found wide variation in adoption of MDRO screening and infection control interventions, which may reflect differences in published recommendations or their interpretation. Further research is needed to provide additional insight on effective strategies and how best to promote compliance. PMID- 23021416 TI - Validation and comparison of three adenosine triphosphate luminometers for monitoring hospital surface sanitization: a Rosetta Stone for adenosine triphosphate testing. AB - BACKGROUND: The application of adenosine triphosphate (ATP) luminometry for monitoring sanitized hospital surfaces is an evolving infection control practice. The goal of this study is to validate and compare 3 commercially available ATP luminometry, swab, rapid-test systems for use in hospital surface sanitization testing. Regulatory agencies may consider this a point-of-care laboratory test; it is therefore imperative that validation criteria are established. METHODS: The ability of instruments to measure long-term stability of ATP dried on surfaces was determined. Dilutions of 3 species of microorganisms and a blood sample were dried onto a surface and tested. The performance characteristics of instruments were compared side-by-side for their ability to recover microorganism-derived ATP from surfaces. RESULTS: Timed studies showed that surface biologic-ATP remained detectable for 10 days. Instrument clinical sensitivity, precision, detection range, limit of detection, and linearity were determined. Swab recovery of microorganisms from surfaces varied by instrument and organism. All 3 systems detected microorganisms in the presence of disinfectants. CONCLUSION: All instruments were validated, but only 1 was verified, because of variations in performance for each system. These studies indicate that careful consideration of the technologic application and instrument performance are important criteria for the selection of an ATP monitoring system. PMID- 23021417 TI - Exercise enhancement of hepatic insulin-sensitising substance-mediated glucose uptake in diet-induced prediabetic rats. AB - The sensitisation of insulin action in response to a meal (i.e. meal-induced insulin sensitisation, MIS) represents one of the major means of increased glucose disposal in peripheral tissues during the postprandial state. MIS occurs when the release of hepatic insulin-sensitising substance (HISS) stimulates skeletal muscle glucose uptake. Our previous study had demonstrated that the HISS pathway is impaired in age-associated insulin resistance, and in the rats which were part of that study, voluntary exercise improved the response to insulin by restoring HISS action. The present study tests the hypothesis that voluntary exercise would reverse insulin resistance in diet-induced models of insulin resistance, and that the benefits are attributed through the improvement in HISS action. In this study, two experimental diets, a high-fat diet (for 4 weeks) and 35 % sucrose solution (for 9 and 16 weeks), were used to induce insulin resistance in rats. These rats were assigned to the exercise/no-exercise intervention. The effect of 7 d voluntary running-wheel exercise was determined by measuring insulin- and HISS action in the exercised rats and comparing them with the non-exercised controls. Voluntary exercise reversed insulin resistance, caused by dietary manipulation, through restoration of the HISS action. The direct insulin action was not changed by either diet or exercise. The metabolic improvements and reduced adiposity correlated with the extent of reversal of HISS action induced by exercise. Exercise improves insulin sensitivity in diet-induced insulin resistance primarily by restoration of HISS-mediated glucose uptake. PMID- 23021418 TI - A study on neuroinflammation and NMDA receptor function in STZ (ICV) induced memory impaired rats. AB - Present study was designed to investigate the status of neuroinflammation and NMDA receptor function in STZ (ICV) induced memory impaired rats. STZ produced significant increase in proinflammatory cytokines (TNF-alpha and IL-1beta), ROS, nitrite and mRNA and protein expression of iNOS and nNOS indicating a state of neuroinflammation in rat brain which was significantly prevented by Memantine and Ibuprofen treatment. STZ also significantly altered NMDA subunits, NR2A and NR2B protein and mRNA expression which were restored by Memantine only. The results suggest that neuroinflammatory markers might be involved in memory impairment via modulating the NMDA receptor in STZ induced memory impaired rats. PMID- 23021419 TI - Extracting decision rules from police accident reports through decision trees. AB - Given the current number of road accidents, the aim of many road safety analysts is to identify the main factors that contribute to crash severity. To pinpoint those factors, this paper shows an application that applies some of the methods most commonly used to build decision trees (DTs), which have not been applied to the road safety field before. An analysis of accidents on rural highways in the province of Granada (Spain) between 2003 and 2009 (both inclusive) showed that the methods used to build DTs serve our purpose and may even be complementary. Applying these methods has enabled potentially useful decision rules to be extracted that could be used by road safety analysts. For instance, some of the rules may indicate that women, contrary to men, increase their risk of severity under bad lighting conditions. The rules could be used in road safety campaigns to mitigate specific problems. This would enable managers to implement priority actions based on a classification of accidents by types (depending on their severity). However, the primary importance of this proposal is that other databases not used here (i.e. other infrastructure, roads and countries) could be used to identify unconventional problems in a manner easy for road safety managers to understand, as decision rules. PMID- 23021420 TI - Cyclists and drivers in road interactions: A comparison of perceived crash risk. AB - Today's increase in the number of cyclists has triggered a change in the interactions to be handled by road users. However, few studies have investigated crash risk perceived by cyclists interacting with other users, and few have compared cyclists' and drivers' perceptions of crash risk in bike-car interactions, the most dangerous situation for cyclists. Our aims here are to study perceived crash risk (no matter the seriousness of the crash) in six common road situations during which cyclist crashes are frequent and also to study cyclists' and drivers' perceived risk in bike-car interactions, in comparison to other interaction types (cyclist vs. cyclist and driver vs. driver). We predicted that perceived risk of being involved in a crash during a particular interaction would be greater when in interaction with a car than with a bike, and that drivers would perceive more risk than cyclists would. We also predicted that perceived risk would decrease with drivers' and cyclists' experience of their transportation mode and their perceived control over the interaction situation. We ran an online survey on two samples, experienced cyclists (N=336) and non cyclist car drivers (N=92). Participants evaluated their personal risk - as cyclists or as drivers - of being involved in a road crash if they were in an interaction with a bike or a car for each of six risky road situations. Experience was measured in terms of years of vehicle driving and driven km; perceived control was measured in terms of perceived skill and responsibility for the risky behavior. The results validated our hypotheses: perceived risk was higher for car drivers than for cyclists and for interacting with a car than with a bike. The implications of these results for interventions to improve road safety for both cyclists and car drivers are discussed. PMID- 23021421 TI - When two motivations race: The effects of time-saving bias and sensation-seeking on driving speed choices. AB - Time-saving bias-people's biased judgments in estimating the time saved when increasing speed-has been found to strongly impact driving speed choices. However, this bias may be relevant only when the driver's motivation for increasing speed is to arrive sooner. If, on the other hand, the driver is motivated by the desire to experience thrill and sensation, a driver's level of sensation-seeking might better explain choices of speed. In this study, participants were asked to estimate the journey time when increasing speed and to estimate the speed required to arrive on time. They also indicated the speed they would personally choose in such a situation. Next, participants filled out Zuckerman's (1994) Sensation Seeking Scale. Results showed that both time-saving estimations and the Disinhibition scale of Sensation Seeking (as well as drivers' gender) contributed independently and additively to drivers' choice of speed and that time-saving bias' role was somewhat stronger than sensation-seeking. PMID- 23021423 TI - Psychometric evaluation of the Subjective Well-being Under Neuroleptic Treatment Scale (SWN) in patients with schizophrenia, their relatives and controls. AB - The objective of this study was to evaluate the psychometric properties of the 20 item version of the Subjective Well-being Under Neuroleptic Treatment Scale (SWN) in patients, their siblings and parents and in healthy controls. In order to study heritability of subjective well-being, assessment in unaffected relatives and healthy controls is necessary. Data were obtained from the Dutch GROUP study (Genetic Risk and Outcome of Psychosis), a large cohort study on non-affective psychotic disorders incorporating patients, their relatives and healthy controls. The SWN scale and other relevant assessments were completed by 545 schizophrenia patients, 541 siblings, 75 parents, and 280 healthy controls. Reliability within the four groups ranged between Cronbach's alpha 0.88 and 0.92. Factor analysis indicated a single factor structure of the SWN scale, which makes only SWN total scores relevant.The WHO-Quality of Life psychological domain correlated highly with SWN total scores in all groups. Subclinical psychotic experiences were found to be associated with SWN total scores in relatives and healthy controls, supporting the psychosis continuum concept. The 20-item SWN scale is a reliable measure for subjective well-being that can also be used in relatives and healthy controls to investigate genetic and psychological dispositions of subjective well being. PMID- 23021422 TI - Enhanced cancer cell killing by truncated E2F-1 used in combination with oncolytic adenovirus. AB - Adenovirus-mediated gene transfer into a tumor mass can be improved by combining it with conditionally-replicating adenovirus (CRAd) when both vectors co-infect the same cancer cell. We investigated the efficiency of enhancing transgene expression and effectiveness of cancer killing of two advenoviruses (Ads), one expressing E2F-1 (AdE2F-1) and another expressing a truncated form of E2F-1 that lacks the transactivation domain (AdE2Ftr), when combined with oncolytic Adhz60. We found that AdE2F-1 with Adhz60 actually decreased E2F-1 expression and viral replication through a mechanism apparently involving repression of the cyclin-E promoter and decreased expression of early and late structural proteins necessary for viral replication. In contrast, AdE2Ftr with Adhz60 resulted in increased E2Ftr expression, AdE2Ftr replication, and cancer cell death both in vitro and in vivo. These results indicate that AdE2Ftr coupled with a CRAd enhances AdE2Ftr mediated cancer cell death. PMID- 23021424 TI - Can behaviour during immunisation be used to identify attachment patterns? A feasibility study. AB - BACKGROUND: Infant attachment is a strong predictor of mental health, and current measures involve placing children into a stressful situation in order to observe how the child uses their primary caregiver to assuage their distress. OBJECTIVES: This study aimed to explore observational correlates of attachment patterns during immunisation. PARTICIPANTS AND SETTING: 18 parent-child pairs were included in the study. They were all recruited through a single general medical practice. METHODS: Infant immunisation videos were observed and coded for parenting behaviours as well as pain promoting and pain reducing strategies. Results were compared between different attachment groups, as measured with the Manchester Child Attachment Story Task. RESULTS: Parents of securely attached children scored higher on positive Mellow Parenting Observational System behaviours, but not at a statistically significant level. Parents of securely attached children were also significantly more likely to engage in pain reducing behaviours (p<0.01) than parents of insecurely attached children. CONCLUSIONS: Robust composite measures for attachment informative behaviours in the immunisation situation should be developed and tested in a fully powered study. PMID- 23021425 TI - Prevalence of antibodies to Toxoplasma gondii in patients with schizophrenia and mood disorders. PMID- 23021429 TI - A process evaluation using a Self Determination Theory measure of the co-delivery of self management training by clinicians and by lay tutors. AB - OBJECTIVE: To evaluate the co-delivery style of lay and clinician co-tutors of courses for patients, and courses for clinicians to support their patients' self management skills. METHODS: Motivational style of course delivery was assessed in 37 patient course sessions and 14 clinician workshops by independent observers using four Self Determination Theory rating scales and ethnographic notes. Forty five tutors and 35 attendees were interviewed about their experience of co delivered courses. RESULTS: Lay and clinician tutors had similar motivational styles, with significant differences between the four motivational style scales; patient courses (F(3, 216)=3.437, p=.018); and clinician courses (F(3, 78)=3.37, p=.025). The courses were experienced as co productive in style as suggested during interviews, but adherence to manuals limited the tutors' contributions. Lay and clinician tutors scored higher on providing structure and engaging participants than they scored on supporting autonomous decision making and involvement. CONCLUSION: Co-delivery was a successful model, affording opportunities to demonstrate co-production skills. PRACTICE IMPLICATIONS: There is more scope to enable lay and clinician tutors to use their respective expertise in supporting self-management, and for tutor training to encourage a less didactic delivery style. PMID- 23021430 TI - Association between cytokine removal by polymyxin B hemoperfusion and improved pulmonary oxygenation in patients with acute exacerbation of idiopathic pulmonary fibrosis. AB - Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is characterized by severe worsening dyspnea of unknown etiology and high mortality without effective treatment. Recently, direct hemoperfusion with polymyxin B (PMX)-immobilized fiber cartridge (PMX-DHP) has been reported to improve pulmonary oxygenation and survival in patients with AE-IPF although its mechanism of action remains unknown. To gain insights into the pathobiology of AE-IPF through the beneficial effects of PMX-DHP, we analyzed the profile of cytokines adsorbed onto PMX-fibers used in 9 AE-IPF patients. In addition, the sera of these AE-IPF patients collected immediately before and after PMX-DHP, 9 stable IPF patients and 8 healthy individuals were also analyzed. The serum levels of cytokines including IL-9, IL-12, IL-17, PDGF and VEGF were significantly decreased immediately after PMX-DHP (P<0.02), and VEGF and IL-12 were most prominently reduced. In addition to PDGF and VEGF, IL-1beta, IL-1ra, IL-8, IL-23, FGF basic, GM-CSF, IP-10, RANTES and TGF-beta were eluted from used PMX-fibers. Interestingly, improved pulmonary oxygenation after PMX-DHP was correlated well with the quantities of eluted VEGF. These results suggest that adsorption of proinflammatory, profibrotic and proangiogenic cytokines onto PMX-fibers is one of the mechanisms of action of PMX DHP in AE-IPF. Notably, removal of VEGF by PMX-DHP may contribute to the rapid improvement in oxygenation by suppressing vascular permeability in the lung. PMID- 23021431 TI - Signals from fat after injury: plasma adipokines and ghrelin concentrations in the severely burned. AB - INTRODUCTION: Hypermetabolism is universal in the severely burned and is characterized by catabolism of lean mass and body fat with associated insulin resistance. Adipokines are likely to play a role in these changes but have not been identified to date in burn patients. METHODS: From a single burn ICU, 17 burn patients with an expected stay>14 days were studied. Study period began within 14 days of admission. Over 7 days, plasma samples were collected for measurement of leptin, adiponectin, resistin, ghrelin, insulin, and cortisol by ELISA. For comparison, samples from 15 healthy controls of similar age, BMI, and blood glucose were obtained. RESULTS: Mean age was 33+/-17 years and BMI 26+/ 3.4. Average burn size was 45+/-20% TBSA and ISS 32+/-10 with 72% having inhalation injury; in-hospital mortality was 29%. Estimated energy needs were 3626+/-710 kcal, of which 84+/-21% were met by enteral feeding with intensive insulin treatment (glucose 80-110 mg/ml). Using the homeostasis model assessment of insulin resistance, burned subjects were more resistant than controls (17+/ 11.3 and 8+/-10.0). Insulin levels were elevated (57+/-35.6 MUU/ml in burned subject vs. 26+/-31.1 MUU/ml in controls), and cortisol concentrations increased (50+/-41.2 MUg/dl vs. 12+/-3.9 MUg/dl). These traditional hormone changes were associated with increased resistin (16.6+/-5.5 ng/ml vs. 3.8+/-0.9 ng/ml) and decreased leptin (8.8+/-8.9 ng/ml vs. 19.4+/-23.5 ng/ml), adiponectin (9+/-3.5 ng/ml vs. 17+/-10.2 ng/ml), and ghrelin (0.37+/-0.14 ng/ml vs.0.56+/-0.26 ng/ml). CONCLUSION: Patients with burns, who are characteristically hypermetabolic with hypercortisolism and insulin resistant, have significant changes in adipokine levels that appear independent of the magnitude of initial injury or metabolic derangement. In addition, suppression of ghrelin in the presence of decreased leptin and adiponectin levels in combination with increased insulin and resistin levels represent unexpected changes in the metabolic milieu of the injured patient possibly due to dramatic activation of inflammatory pathways, indicating strategies for treatment. PMID- 23021433 TI - Effect of glutamine on glucose metabolism in children with Duchenne muscular dystrophy. AB - BACKGROUND & AIMS: Glutamine is a potent gluconeogenic precursor and stimulates insulin secretion. Glutamine's effect on glucose metabolism in Duchenne muscular dystrophy (DMD) has never been studied. To determine plasma glucose and insulin concentrations measured during and after glutamine administration in DMD boys. We hypothesized that glutamine can modulate whole body glutamine-glucose metabolism in DMD, a genetically determined disease. METHODS: As secondary endpoints of a randomized crossover trial in 30 prepubertal DMD boys, we measured fasting blood glucose, insulin and the Homeostasis Model Assessment (HOMA) index after daily oral glutamine (0.5 g kg(-1) d(-1)) for 4 months versus placebo. In a separate time series trial in 6 prepubertal DMD boys, we measured the same endpoints as well as plasma glutamine and whole body glucose turnover (Ra,glc) (primed continuous i.v. infusion of d-[6,6-(2)D]glucose), while participants received acute oral glutamine (0.5 g kg(-1) d(-1)) continuously for 5 h. RESULTS: In the randomized trial, baseline measurements of HOMA correlated with age (r = 0,51, p = 0.007) and percent fat estimated by bioelectrical impedance analysis (BIA) (r = 0.39, p = 0.047). After 4 months glutamine supplementation, we observed no treatment or order effect on HOMA or insulin. During acute glutamine for 5 h (time series trial), plasma glutamine doubled and was associated with increased plasma insulin concentration (10.42 +/- 2.54 vs 7.32 +/- 1.86, p = 0.05) with no effect on plasma glucose, HOMA or Ra,glc. CONCLUSIONS: Acute glutamine transiently stimulates insulin secretion in DMD boys, which could be mediated by plasma glutamine concentrations. Fasting insulin concentration and HOMA might provide quantifiable indices of disease progression. PMID- 23021432 TI - Genome-wide analysis of intracellular pH reveals quantitative control of cell division rate by pH(c) in Saccharomyces cerevisiae. AB - BACKGROUND: Because protonation affects the properties of almost all molecules in cells, cytosolic pH (pH(c)) is usually assumed to be constant. In the model organism yeast, however, pH(c) changes in response to the presence of nutrients and varies during growth. Since small changes in pH(c) can lead to major changes in metabolism, signal transduction, and phenotype, we decided to analyze pH(c) control. RESULTS: Introducing a pH-sensitive reporter protein into the yeast deletion collection allowed quantitative genome-wide analysis of pH(c) in live, growing yeast cultures. pH(c) is robust towards gene deletion; no single gene mutation led to a pH(c) of more than 0.3 units lower than that of wild type. Correct pH(c) control required not only vacuolar proton pumps, but also strongly relied on mitochondrial function. Additionally, we identified a striking relationship between pH(c) and growth rate. Careful dissection of cause and consequence revealed that pH(c) quantitatively controls growth rate. Detailed analysis of the genetic basis of this control revealed that the adequate signaling of pH(c) depended on inositol polyphosphates, a set of relatively unknown signaling molecules with exquisitely pH sensitive properties. CONCLUSIONS: While pH(c) is a very dynamic parameter in the normal life of yeast, genetically it is a tightly controlled cellular parameter. The coupling of pH(c) to growth rate is even more robust to genetic alteration. Changes in pH(c) control cell division rate in yeast, possibly as a signal. Such a signaling role of pH(c) is probable, and may be central in development and tumorigenesis. PMID- 23021434 TI - Evaluation of peak cough flow in Brazilian healthy adults. AB - INTRODUCTION: In this study we aimed to evaluate the peak cough flow (PCF) in healthy Brazilian subjects. METHODS: We evaluated 484 healthy subjects between 18 and 40 years old. Subjects were seated and oriented were asked to perform a maximal inspiration followed by a quick, short and explosive expiration on the peak flow meter. Three measures were carried out and recorded the average of the three results for each individual. RESULTS: The PCF values ranged between 240 and 500 L/min. The PCF values were lower in females than in males. The PCF was inversely proportional to age. CONCLUSION: The values for Brazilian adult healthy subjects regarding PCF were between 240 and 500 L/min. PMID- 23021435 TI - Validation of normal tissue complication probability predictions in individual patient: late rectal toxicity. AB - PURPOSE: To perform validation of risk predictions for late rectal toxicity (LRT) in prostate cancer obtained using a new approach to synthesize published normal tissue complication data. METHODS AND MATERIALS: A published study survey was performed to identify the dose-response relationships for LRT derived from nonoverlapping patient populations. To avoid mixing models based on different symptoms, the emphasis was placed on rectal bleeding. The selected models were used to compute the risk estimates of grade 2+ and grade 3+ LRT for an independent validation cohort composed of 269 prostate cancer patients with known toxicity outcomes. Risk estimates from single studies were combined to produce consolidated risk estimates. An agreement between the actuarial toxicity incidence 3 years after radiation therapy completion and single-study or consolidated risk estimates was evaluated using the concordance correlation coefficient. Goodness of fit for the consolidated risk estimates was assessed using the Hosmer-Lemeshow test. RESULTS: A total of 16 studies of grade 2+ and 5 studies of grade 3+ LRT met the inclusion criteria. The consolidated risk estimates of grade 2+ and 3+ LRT were constructed using 3 studies each. For grade 2+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.537 compared with 0.431 for the best-fit single study. For grade 3+ LRT, the concordance correlation coefficient for the consolidated risk estimates was 0.477 compared with 0.448 for the best-fit single study. No evidence was found for a lack of fit for the consolidated risk estimates using the Hosmer-Lemeshow test (P=.531 and P=.397 for grade 2+ and 3+ LRT, respectively). CONCLUSIONS: In a large cohort of prostate cancer patients, selected sets of consolidated risk estimates were found to be more accurate predictors of LRT than risk estimates derived from any single study. PMID- 23021436 TI - Survival advantage with the addition of radiation therapy to chemotherapy in early stage peripheral T-cell lymphoma, not otherwise specified. AB - PURPOSE: Early stage peripheral T-cell lymphoma, not otherwise specified (PTCL NOS) is rare. The purpose of this study was to evaluate the outcome of treatment as well as the potential role of radiation therapy in PTCL-NOS. METHODS AND MATERIALS: Thirty-five patients with early stage PTCL-NOS were included. There were 13 patients with stage I disease and 22 with stage II. All patients except 1 received doxorubicin-based chemotherapy alone (n=13) or a combination of chemotherapy and radiation therapy (CMT) (n=21). RESULTS: The 3-year overall survival (OS) and progression-free survival (PFS) rates for the entire group were 41.3% and 25.7%, respectively. The addition of radiation therapy to chemotherapy significantly improved OS and PFS in early stage PTCL-NOS. The 3-year OS and PFS rates were 49.7% and 33.3% for CMT, compared with 23.1% (P=.042) and 15.4% (P=.035) for chemotherapy alone, respectively. The prognosis for patients who achieved a complete response (CR) was significantly better than that observed in those who did not achieve a CR. CONCLUSIONS: Despite the aggressive clinical course of early stage PTCL-NOS, additional radiation therapy has a significant impact on outcome. The integration of local radiation therapy into more effective systemic therapies may further improve survival. PMID- 23021437 TI - Parameningeal rhabdomyosarcoma: outcomes and opportunities. AB - PURPOSE: To examine patterns of failure in patients with parameningeal rhabdomyosarcoma (PM-RMS) treated with intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: Forty-seven patients with PM-RMS received chemotherapy and IMRT for definitive treatment. The median age was 9 years (range, 0.5-35 years). The high-risk features were as follows: 40% alveolar histology, 72% group III and 26% group IV disease, 57% either intracranial extension (ICE) (n=25) or cranial neuropathy (n=21). The median time to RT from the start of chemotherapy was 15 weeks (range, 2-54 weeks). Patients received 50.4 Gy in 1.8-Gy fractions to the primary tumor by use of IMRT. Thirteen patients aged>=14 years with alveolar histology received 36 Gy prophylactic nodal irradiation (PNI) to bilateral cervical nodes. Events were defined as local, regional (nodal), central nervous system (CNS), or distant failures. RESULTS: With a median follow-up time of 3.3 years (range, 0.5-12.8 years), 18 patients experienced failure: 5 local, 2 regional, 6 distant, and 7 CNS. The 5-year local failure-free survival was 86%. Age, histology, and time to RT did not influence the risk of local failure. The 5-year regional failure-free survival was 92%: 100% for embryonal and 74% for alveolar (P=.03). However, there were no lymph node failures in patients with alveolar histology who were given PNI. The 5-year CNS failure-free survival was 83%: 100% without and 70% with ICE (P=.01); 95% without and 69% with cranial neuropathy (P=.02). The estimated 5-year event-free survival and overall survival were 61% for group III and 58% for group IV patients. CONCLUSIONS: Distant failure was the most common type of failure among group IV patients. Patients with alveolar histology seem to benefit from PNI. The presence of ICE or cranial neuropathy portends a high risk of CNS failure, the most common pattern of failure among non-group IV patients. These patients may benefit from the addition of novel CNS-directed therapy. PMID- 23021438 TI - Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation. AB - PURPOSE: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. METHODS AND MATERIALS: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 MUg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. RESULTS: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 MUg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. CONCLUSIONS: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells. PMID- 23021440 TI - Inelastic light scattering by 2D electron system with SO interaction. AB - Inelastic light scattering by electrons of a two-dimensional system taking into account the Rashba spin-orbit interaction (SOI) in the conduction band is theoretically investigated. The case of resonance scattering (frequencies of incident and scattered light are close to the effective distance between conduction and spin-split-off bands of the AIIIBV-type semiconductor) is considered. As opposed to the case of SOI absence, the plasmon peak in the scattering occurs even at strictly perpendicular polarizations of the incident and scattered waves. Under definite geometry, one can observe the spectrum features conditioned by only single-particle transitions. In the general case of elliptically polarized incident and scattered light, the amplitude of the plasmon peak turns out to be sensitive to the sign of the SOI coupling. PMID- 23021439 TI - Adaptive radiation therapy for postprostatectomy patients using real-time electromagnetic target motion tracking during external beam radiation therapy. AB - PURPOSE: Using real-time electromagnetic (EM) transponder tracking data recorded by the Calypso 4D Localization System, we report inter- and intrafractional target motion of the prostate bed, describe a strategy to evaluate treatment adequacy in postprostatectomy patients receiving intensity modulated radiation therapy (IMRT), and propose an adaptive workflow. METHODS AND MATERIALS: Tracking data recorded by Calypso EM transponders was analyzed for postprostatectomy patients that underwent step-and-shoot IMRT. Rigid target motion parameters during beam delivery were calculated from recorded transponder positions in 16 patients with rigid transponder geometry. The delivered doses to the clinical target volume (CTV) were estimated from the planned dose matrix and the target motion for the first 3, 5, 10, and all fractions. Treatment adequacy was determined by comparing the delivered minimum dose (Dmin) with the planned Dmin to the CTV. Treatments were considered adequate if the delivered CTV Dmin is at least 95% of the planned CTV Dmin. RESULTS: Translational target motion was minimal for all 16 patients (mean: 0.02 cm; range: -0.12 cm to 0.07 cm). Rotational motion was patient-specific, and maximum pitch, yaw, and roll were 12.2, 4.1, and 10.5 degrees , respectively. We observed inadequate treatments in 5 patients. In these treatments, we observed greater target rotations along with large distances between the CTV centroid and transponder centroid. The treatment adequacy from the initial 10 fractions successfully predicted the overall adequacy in 4 of 5 inadequate treatments and 10 of 11 adequate treatments. CONCLUSION: Target rotational motion could cause underdosage to partial volume of the postprostatectomy targets. Our adaptive treatment strategy is applicable to post-prostatectomy patients receiving IMRT to evaluate and improve radiation therapy delivery. PMID- 23021441 TI - Obstructive sleep apnea: a focus on best practice. PMID- 23021442 TI - An introduction to the ASPAN obstructive sleep apnea in the adult patient evidence-based practice recommendation. PMID- 23021443 TI - The ASPAN obstructive sleep apnea in the adult patient evidence-based practice recommendation. PMID- 23021444 TI - An evidence-based checklist for the postoperative management of obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) can present significant challenges in providing postoperative care. OSA policies have been developed and are in place within many facilities; however, a standard OSA protocol ensuring the safe delivery of postoperative care has not been universally accepted into practice. A synthesis of current OSA literature led to the development of a comprehensive evidence based checklist to improve patient safety and direct the management of postoperative care for diagnosed or suspected OSA patients throughout their hospitalization. The checklist describes interventions for providing care in the immediate postoperative phase and sleep-specific interventions. These interventions include guidelines for postoperative assessment, continuous monitoring, extubation readiness, pain management, sleep positioning, respiratory monitoring, and continuous positive airway pressure therapy. The implementation of this checklist with the synergistic effect of the combined interventions may lead to a greater improvement in the care, safety, satisfaction, and clinical outcomes of OSA patients. PMID- 23021445 TI - Obstructive sleep apnea: a standard of care that works. AB - Examining the care of patients with obstructive sleep apnea (OSA) is forefront in perianesthesia nursing. The issue of how to effectively manage patients with OSA emerges as the patient presents for surgery. Evaluation of current practice demonstrates a gap in the consistency of care provided to patients with OSA. The development and implementation of a nursing standard of care has proven highly effective in improving the perioperative management of patients with OSA. With the introduction of preoperative screening, we can more readily identify and facilitate communication of the presence of OSA. Staff education and an increase in postoperative monitoring time help to ensure that all patients with OSA receive safe, consistent, quality care while recovering from anesthesia. PMID- 23021446 TI - Caring for the patient with obstructive sleep apnea: implications for health care providers in postanesthesia care. AB - Obstructive sleep apnea (OSA) is a sleep disorder affecting 18 million Americans. The prevalence of OSA is increasing due to an epidemic rise in obesity, which is a major contributing factor. The primary treatment for OSA is continuous positive airway pressure, designed to maintain a patent airway for unobstructed breathing. OSA patients may experience postoperative hypoventilation due to residual anesthetic, analgesic requirements, and other comorbidities. Postoperative health care providers must be prepared to assess for hypoventilation and intervene using evidence-based interventions to improve outcomes. It is incumbent that the PACU nurse be aware of and implement evidence-based clinical guidelines for patients with OSA. Therefore, the purpose of this manuscript is to (1) describe the physiology, comorbidities, diagnosis, and treatment of OSA; (2) identify the effects of anesthesia in persons with OSA; (3) discuss clinical guidelines; and (4) describe implications for care in an effort to improve health outcomes in persons with OSA during the perianesthesia period. PMID- 23021447 TI - Support surfaces for pressure ulcer prevention. PMID- 23021448 TI - Evidence into practice: using research findings to create practice recommendations. PMID- 23021449 TI - Social media and web 2.0 for the perianesthesia nurse. PMID- 23021450 TI - Research news: ageism. PMID- 23021451 TI - Developing a better understanding of handoffs. PMID- 23021452 TI - Evidence-based clinical practice and standardization. PMID- 23021462 TI - Effects of nitrogen application rate and a nitrification inhibitor dicyandiamide on ammonia oxidizers and N2O emissions in a grazed pasture soil. AB - Ammonia oxidizers, including ammonia oxidizing bacteria (AOB) and ammonia oxidizing archaea (AOA) are important drivers of a key step of the nitrogen cycle - nitrification, which affects the production of the potent greenhouse gas, nitrous oxide (N2O). A field experiment was conducted to determine the effect of nitrogen application rates and the nitrification inhibitor dicyandiamide (DCD) on the abundance of AOB and AOA and on N2O emissions in a grazed pasture soil. Nitrogen (N) was applied at four different rates, with urea applied at 50 and 100 kg N ha(-1) and animal urine at 300 and 600 kg N ha(-1). DCD was applied to some of the N treatments at 10 kg ha(-1). The results showed that the AOB amoA gene copy numbers were greater than those of AOA. The highest ratio of the AOB to AOA amoA gene copy numbers was 106.6 which occurred in the urine-N 600 treatment. The AOB amoA gene copy numbers increased with increasing nitrogen application rates. DCD had a significant impact in reducing the AOB amoA gene copy numbers especially in the high nitrogen application rates. N2O emissions increased with the N application rates. DCD had the most significant effect in reducing the daily and total N2O emissions in the highest nitrogen application rate. The greatest reduction of total N2O emissions by DCD was 69% in the urine-N 600 treatment. The reduction in the N2O emission factor by DCD ranged from 58% to 83%. The N2O flux and NO3(-)-N concentrations were significantly correlated to the growth of AOB, rather than AOA. This study confirms the importance of AOB in nitrification and the effect of DCD in inhibiting AOB growth and in decreasing N2O emissions in grazed pasture soils under field conditions. PMID- 23021463 TI - The role of HRCT and three-dimensional VR CT findings in patients of congenital atresia combined with microtia. AB - OBJECTIVE: To determine the anatomic differences in patients of atresia by using high-resolution computed tomography (HRCT) and 3D volume rendered (VR) CT. METHODS: High-resolution computed tomography (HRCT) was performed in 43 atresia patients including 34 unilateral atresia patients (n=34, 26 males, 8 females, mean age 13.82 years, range 8-19 years) and 9 bilateral atresia patients (6 males, 3 females, mean age 13.2 years, range 9-19 years). HRCT and 3D VR findings were compared with those in 43 normal ears of the unilateral atresia patients with normal PTA results (n=34, 26 males, 8 females, mean age 13.82 years, range 8 19 years) and 11 patients with sensorineural hearing loss but with no associated aplasia of the middle and inner ear (n=22, 7 males and 4 females, range 8-20.8 years, median age of 13.4 years) by using the independent one sample T test. RESULTS: On the HRCT images, the angle between the basic line and the tympanic segment of the facial nerve is more acute. And the area of the malleus-incus joint or the malleus-incus-complex in the diseased ears is smaller than that in the control subjects (P<0.05). The tympanic segment is shorter and the area of the tympanic cavity is smaller in the atresia group, while the diameter of the oval window is also smaller in atresia group than that in the control group (P<0.05). The morphologic differences of the small ossicles and the entire length of the tympanic and mastoid segments can be depicted on a single 3D VR CT image. CONCLUSIONS: The facial nerve demonstrates abnormal lateral and anterior displacement in the CAA patients and the area of the Malleus-incus-joint and the tympanic cavity are significantly smaller, and the oval window is much narrower in the control group. HRCT and 3D VR CT provide valuable information about preoperative planning of patients with CAA. Measurements of all the angles and length serve as useful adjunct measurements in determining surgical candidacy. PMID- 23021464 TI - Radiofrequency ablation of pediatric vallecular cysts. AB - OBJECTIVE: Pediatric congenital vallecular cysts are an infrequent cause of infantile airway obstruction that can cause difficulty breathing or feeding, and lead to failure to thrive or death. There have been many different techniques proposed for effective treatment. We present three cases of congenital vallecular cyst, all excised utilizing a bipolar radiofrequency plasma ablation (RFA) device. The bipolar RFA device provides excellent hemostasis without the risk of airway fire. We offer a review of literature and a discussion of the potential advantages of this modality in treating neonatal/infantile vallecular cysts. METHODS: Retrospective case series of three infants all between 2 and 3 months old who presented with failure to thrive due to partially obstructive vallecular cysts. The cysts were removed surgically utilizing a bipolar RFA device. Patients were followed by complications and signs of recurrence for periods ranging from 9 to 20months. RESULTS: All cysts were excised completely in a single operation. All children are feeding well and without stridor or evidence of recurrence between 9 and 20 months postoperatively. CONCLUSIONS: RFA appears to be an effective and safe modality for removing vallecular cysts. We were able to demonstrate complete removal of lesions in our patients. This provides an alternative to other ablative modalities in treating cystic lesions of the vallecula and larynx. PMID- 23021465 TI - Effect of tonsillar fossa closure on postoperative pain and bleeding risk after tonsillectomy. AB - OBJECTIVE: To determine if closing the tonsil fossa after tonsillectomy leads to less pain and bleeding. STUDY DESIGN: Interventional, Randomized, Single Blind, Active Control, Single Group Assignment, Safety/Efficacy Study. FOLLOW-UP: 2 months. METHODS: Generalized Estimating Equations (GEE) analyzed effects of tonsillar pillar closure, surgeon experience and interaction on outcomes. SETTING: Primarily academic tertiary care referral center, institutional practice, primarily children, both ambulatory and hospitalized care. SUBJECTS: 763 subjects (age 8-264 months) undergoing tonsillectomy. EXCLUSIONS: suspected malignancy or active peritonsillar abscess. At the discretion of the attending surgeon, patients undergoing tonsillectomy during the 4 year study period were offered participation. A computer selected the side closed. 131 subjects withdrew (complete lack of follow-up information) after the first 72 h. INTERVENTION: 3-0 chromic sutures on tapered needles to close one tonsillar fossa. The subject was not told which side was closed. MAIN OUTCOME MEASURES: postoperative bleeding (at any time) and pain reported was sought on days 1, 7, 14, 21, and 28. RESULTS: Closure of the tonsillar fossa did not change the risk of bleeding. Closing the tonsillar fossa had a 40% increase in the odds ratio of postoperative pain. In the tonsillar fossa sides left open, greater surgeon experience decreased the risk of bleeding. In closed sides, enriched surgeon experience increased the risk of bleeding (p<.0.05). CONCLUSIONS: Suture closure of the tonsillar fossa after tonsillectomy does not reduce the risk of bleeding. Additionally, closing the tonsillar fossa increased postoperative pain. LEVEL OF EVIDENCE: 1b (individual randomized controlled trial). PMID- 23021466 TI - Left main bronchus obstruction after patent ductus arteriosus ligation: an unusual complication. AB - This report discusses a premature complex newborn with persistent pulmonary difficulties following the clipping of the PDA. Bronchoscopy was critical in revealing a metallic clip obstructing the bronchus. Thoracothomy revealed that the clip had been placed across the bronchus. This case illustrates the importance of bronchoscopy in the face of persistent unexplained pulmonary symptoms as well as having clear intraoperative exposure of the anatomy in this region to assure accurate placement of PDA metallic clips. PMID- 23021467 TI - Methicillin-resistant Staphylococcus aureus (MRSA) pediatric tympanostomy tube otorrhea. AB - OBJECTIVES: To describe our experience and clinical outcomes with the management of pediatric tympanostomy tube otorrhea secondary to methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Retrospective review of pediatric patients (age <18) diagnosed with culture-positive MRSA tympanostomy tube otorrhea. RESULTS: MRSA positive ear cultures in the presence of tympanostomy tubes were identified in 41 patients (6.3%). The average age was 2.9 years old. In all cases, culture results indicated sensitivity to trimethoprim/sulfamethoxazole and gentamicin; resistance to fluoroquinolones and clindamycin occurred in 87.8% and 61.0% of cases, respectively. Fluoroquinolone and sulfacetamide ototopical medications were found to be associated with successful otorrhea resolution (p=0.005 and 0.009, respectively). Adjunctive therapy with oral antibiotics, bactrim and clindamycin (p=0.172 and 0.877, respectively), did not improve resolution rates with medical treatment. Tympanostomy tube removal was more successful than medical therapy alone (p<0.0001). CONCLUSION: Appropriately treated recurrent or recalcitrant tympanostomy tube-related otorrhea should raise the suspicion for MRSA-related tympanostomy tube otorrhea. Fluoroquinolone ototopical medication should be considered for initial therapy. Sulfacetamide ototopical medication can be considered for failures. The adjunctive use of oral antibiotics, bactrim and clindamycin, and aminoglycoside ototopical medications did not improve clinical outcomes for medical therapy alone. We believe that some consideration be given to removal of the tympanostomy tube with or without replacement, after an initial treatment period with fluoroquinolone and/or sulfacetamide otopical medications. Our findings seem to suggest an improved rate with tympanostomy tube removal over medical therapy alone (p<0.0001). No standard management guidelines currently exist. PMID- 23021468 TI - Incidental intraoperative discovery of a pancreatic neuroendocrine tumor associated with chronic pancreatitis. AB - Pancreatic neuroendocrine tumors are a rare entity with an incidence between 2 per million to 5 per 100,000. Association with pancreatitis (acute or chronic) is rare and is considered to be determined by the tumoral obstruction of pancreatic ducts, but sometimes occurs without any apparent relationship between them. Non functional neuroendocrine pancreatic tumors are usually diagnosed when either very large or metastatic. Small ones are occasionally diagnosed when imagery is performed for other diagnostic reasons. Intraoperative discovery is even rarer and poses problems of differential diagnosis with other pancreatic tumors. Association with chronic pancreatitis is rare and usually due to pancreatic duct obstruction by the tumor. We describe the case of a patient with a small non functioning neuroendocrine tumor in the pancreatic tail accidentally discovered during surgery for delayed traumatic splenic rupture associated with chronic alcoholic pancreatitis. The tumor of 1.5 cm size was well differentiated and confined to the pancreas, and was resected by a distal splenopancreatectomy. CONCLUSIONS: Surgeons should be well aware of the rare possibility of a non functional neuroendocrine tumor in the pancreas, associated with chronic pancreatitis, surgical resection being the optimal treatment for cure. Histopathology is of utmost importance to establish the correct diagnosis, grade of differentiation, malignancy and prognosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2114470176676003. PMID- 23021471 TI - Abstract thinking: do aggressive kids grow up to be troubled adults? PMID- 23021470 TI - [Renal juxtaglomerular cell tumor]. PMID- 23021469 TI - Type of milk feeding in infancy and health behaviours in adult life: findings from the Hertfordshire Cohort Study. AB - A number of studies suggest that breast-feeding has beneficial effects on an individual's cardiovascular risk factors in adulthood, although the mechanisms involved are unknown. One possible explanation is that adults who were breastfed differ in their health behaviours. In a historical cohort, adult health behaviours were examined in relation to type of milk feeding in infancy. From 1931 to 1939, records were kept on all infants born in Hertfordshire, UK. Their type of milk feeding was summarised as breastfed only, breast and bottle-fed, or bottle-fed only. Information about adult health behaviours was collected from 3217 of these men and women when they were aged 59-73 years. Diet was assessed using an administered FFQ; the key dietary pattern was a 'prudent' pattern that described compliance with 'healthy' eating recommendations. Of the study population, 60 % of the men and women were breastfed, 31 % were breast and bottle fed, and 9 % were bottle-fed. Type of milk feeding did not differ according to social class at birth, and was not related to social class attained in adult life. There were no differences in smoking status, alcohol intake or reported physical activity according to type of milk feeding, but there were differences in the participants' dietary patterns. In a multivariate model that included sex and infant weight gain, there were independent associations between type of feeding and prudent diet scores in adult life (P= 0.009), such that higher scores were associated with having been breastfed. These data support experimental findings which suggest that early dietary exposures can have lifelong influences on food choice. PMID- 23021472 TI - Retiring gracefully. PMID- 23021473 TI - Integrating mental health care into pediatric primary care settings. PMID- 23021474 TI - Translations and clinical perspectives: toward a more perfect union. PMID- 23021475 TI - Estimating the costs of attention-deficit/hyperactivity disorder. PMID- 23021476 TI - Economic impact of childhood and adult attention-deficit/hyperactivity disorder in the United States. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent mental disorders in children in the United States and often persists into adulthood with associated symptomatology and impairments. This article comprehensively reviews studies reporting ADHD-related incremental (excess) costs for children/adolescents and adults and presents estimates of annual national incremental costs of ADHD. METHOD: A systematic search for primary United States based studies published from January 1, 1990 through June 30, 2011 on costs of children/adolescents and adults with ADHD and their family members was conducted. Only studies in which mean annual incremental costs per individual with ADHD above non-ADHD controls were reported or could be derived were included. Per person incremental costs were adjusted to 2010 U.S. dollars and converted to annual national incremental costs of ADHD based on 2010 U.S. Census population estimates, ADHD prevalence rates, number of household members, and employment rates by age group. RESULTS: Nineteen studies met the inclusion criteria. Overall national annual incremental costs of ADHD ranged from $143 to $266 billion (B). Most of these costs were incurred by adults ($105 B-$194 B) compared with children/adolescents ($38 B-$72 B). For adults, the largest cost category was productivity and income losses ($87 B-$138 B). For children, the largest cost categories were health care ($21 B-$44 B) and education ($15 B-$25 B). Spillover costs borne by the family members of individuals with ADHD were also substantial ($33 B-$43 B). CONCLUSION: Despite a wide range in the magnitude of the cost estimates, this study indicates that ADHD has a substantial economic impact in the United States. Implications of these findings and future directions for research are discussed. PMID- 23021477 TI - Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses. AB - OBJECTIVE: To determine whether peripheral biochemical markers (biomarkers) might differentiate patients with attention-deficit/hyperactivity disorder (ADHD) from non-ADHD individuals. METHOD: We conducted a systematic search and a series of meta-analyses of case-control studies comprising studies from 1969 to 2011. RESULTS: We identified 210 studies in the following categories: 71 studies of the main metabolites and metabolism enzymes of monoaminergic neurotransmission pathway; 87 studies of environmental risk factors divided into heavy metals (18 studies), substance/chemical exposures (16 studies), and nutritional factors (trace elements: 29 studies; essential fatty acids: 24 studies); 22 studies of the hypothalamic-pituitary-adrenal axis (HPA) pathway; 31 studies indicated with "other". After screening for the availability for meta-analyses of drug naive/free case-control studies and Bonferroni correction, five comparisons were statistically significant (Norepinephrine [NE], 3-Methoxy-4-hydroxyphenylethylene glycol [MHPG], monoamine oxidase [MAO], Zinc [Zn], cortisol), five of the significant findings found support in studies of response to ADHD medications (NE, MHPG, MAO, b-phenylethylamine [PEA], cortisol), six in studies of symptoms severity (NE, MHPG, MAO, ferritin, Zn, cortisol) and three in studies of neurophysiological or cognitive functioning (lead-ferritin-Zn). No evidence of publication bias was found, whereas significant heterogeneity of effect sizes across studies was found for three of the five biomarkers that differentiated ADHD from control subjects. Suggestive associations were evidenced for neuropeptide Y (NPY), manganese, and dehydroepiandrosterone (DHEA). CONCLUSIONS: This study provides evidence for several peripheral biomarkers as being associated with ADHD both in diagnosis and in treatment efficacy. Further studies are warranted to replicate these findings, to assess their specificity for ADHD, and to quantify the degree to which they are sufficiently precise to be useful in clinical settings. PMID- 23021478 TI - The TRacking Adolescents' Individual Lives Survey (TRAILS): design, current status, and selected findings. AB - OBJECTIVES: The objectives of this study were as follows: to present a concise overview of the sample, outcomes, determinants, non-response and attrition of the ongoing TRacking Adolescents' Individual Lives Survey (TRAILS), which started in 2001; to summarize a selection of recent findings on continuity, discontinuity, risk, and protective factors of mental health problems; and to document the development of psychopathology during adolescence, focusing on whether the increase of problem behavior often seen in adolescence is a general phenomenon or more prevalent in vulnerable teens, thereby giving rise to diverging developmental pathways. METHOD: The first and second objectives were achieved using descriptive statistics and selective review of previous TRAILS publications; and the third objective by analyzing longitudinal data on internalizing and externalizing problems using Linear Mixed Models (LMM). RESULTS: The LMM analyses supported the notion of diverging pathways for rule breaking behaviors but not for anxiety, depression, or aggression. Overall, rule breaking (in both genders) and withdrawn/depressed behavior (in girls) increased, whereas aggression and anxious/depressed behavior decreased during adolescence. CONCLUSIONS: TRAILS has produced a wealth of data and has contributed substantially to our understanding of mental health problems and social development during adolescence. Future waves will expand this database into adulthood. The typical development of problem behaviors in adolescence differs considerably across both problem dimensions and gender. Developmental pathways during adolescence suggest accumulation of risk (i.e., diverging pathways) for rule-breaking behavior. However, those of anxiety, depression and aggression slightly converge, suggesting the influence of counter-forces and changes in risk unrelated to initial problem levels and underlying vulnerability. PMID- 23021479 TI - Developmental trajectories of physical and indirect aggression from late childhood to adolescence: sex differences and outcomes in emerging adulthood. AB - OBJECTIVE: Two common subtypes of aggression (physical and indirect) have been shown to develop concurrently throughout childhood and to uniquely predict maladjustment. However, nothing is known about psychiatric outcomes of joint trajectories of physical aggression (PA) and indirect aggression (IA) in emerging adulthood. METHOD: Trajectories of PA and IA across ages 10 to 15 were modeled using 2,338 youth drawn from the National Longitudinal Study of Children and Youth. The identified trajectories were then used to predict delinquency problems, depressive symptoms, and emotional intelligence in emerging adulthood. RESULTS: Three groups of children with distinct developmental trajectories of PA (no PA, 32.5%; moderate-declining PA 52.2%; and high-increasing PA, 15.3%) and three distinct developmental trajectories of IA (low-declining IA, 29.9%; moderate-declining IA, 65.5%; and high IA, 4.6%) were identified. Joint trajectories indicate that the largest group of children (41.6%) followed a moderate-declining IA trajectory and moderate-declining PA trajectory. Virtually no children were high on one type and low on the other. The proportion of boys was higher in the low IA-moderate declining PA and moderate IA-high increasing PA groups, whereas girls were more likely to be in the low IA-low PA and moderate IA low PA groups. Individuals who followed elevated trajectories of IA and PA had significantly more depressive and delinquency symptoms and lower emotional quotient scores in emerging adulthood compared with those with lower trajectories. CONCLUSIONS: These results suggest that some children have high PA and IA trajectories from childhood to adolescence and that these trajectories are associated with an increased risk for maladjustment. PMID- 23021480 TI - Effects of a brief Early Start Denver model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: a randomized controlled trial. AB - OBJECTIVE: This study was carried out to examine the efficacy of a 12-week, low intensity (1-hour/wk of therapist contact), parent-delivered intervention for toddlers at risk for autism spectrum disorders (ASD) aged 14 to 24 months and their families. METHOD: A randomized controlled trial involving 98 children and families was carried out in three different sites investigating the efficacy of a parent delivery of the Early Start Denver model (P-ESDM), which fosters parental use of a child-centered responsive interaction style that embeds many teaching opportunities into play, compared to community treatment as usual. Assessments were completed at baseline and 12 weeks later, immediately after the end of parent coaching sessions. RESULTS: There was no effect of group assignment on parent-child interaction characteristics or on any child outcomes. Both groups of parents improved interaction skills, and both groups of children demonstrated progress. Parents receiving P-ESDM demonstrated significantly stronger working alliances with their therapists than did the community group. Children in the community group received significantly more intervention hours than those in the P-ESDM group. For the group as a whole, both younger child age at the start of intervention and a greater number of intervention hours were positively related to the degree of improvement in children's behavior for most variables. CONCLUSIONS: Parent-implemented intervention studies for early ASD thus far have not demonstrated the large effects seen in intensive-treatment studies. Evidence that both younger age and more intervention hours positively affect developmental rates has implications for clinical practice, service delivery, and public policy. PMID- 23021481 TI - Behavioral inhibition and risk for developing social anxiety disorder: a meta analytic study. AB - OBJECTIVE: Behavioral inhibition (BI) has been associated with increased risk for developing social anxiety disorder (SAD); however, the degree of risk associated with BI has yet to be systematically examined and quantified. The goal of the present study was to quantify the association between childhood BI and risk for developing SAD. METHOD: A comprehensive literature search was conducted to identify studies that assessed both BI and SAD. Meta-analyses were performed to estimate the odds ratio (OR) of the association between BI and SAD in children. RESULTS: Seven studies met inclusion criteria. BI was associated with a greater than sevenfold increase in risk for developing SAD (odds ratio = 7.59, p < .00002). This association remained significant even after considering study differences in temperament assessment, control group, parental risk, age at temperament assessment, and age at anxiety diagnosis. CONCLUSIONS: Identifying early developmental risk factors is critical for preventing psychiatric illness. Given that 15% of all children show extreme BI, and that almost half of these inhibited children will eventually develop SAD, we propose that BI is one of the largest single risk factors for developing SAD. PMID- 23021482 TI - Schizophrenia spectrum and attention-deficit/hyperactivity disorder symptoms in autism spectrum disorder and controls. AB - OBJECTIVE: This study compared the differential severity of specific symptoms of schizophrenia spectrum disorder (SSD) in children with autism spectrum disorder (ASD) and child psychiatry outpatient referrals (controls). Each group was further subdivided into subgroups with and without co-occurring attention deficit/hyperactivity disorder (ADHD). METHOD: Children with ASD (n = 147) and controls (n = 335) were evaluated with parent and teacher versions of a psychometrically established DSM-IV-referenced rating scale. RESULTS: The two ASD groups (with and without ADHD) had a larger number of more severe SSD symptoms than their respective control groups (with and without ADHD), extending the observation of an association between ASD and SSD to subgroups with and without co-occurring ADHD. The ASD groups exhibited more severe schizoid personality symptoms than controls, but findings for schizophrenia symptoms were mixed. The ASD + ADHD group generally had more severe disorganized thought, disorganized behavior, and negative schizophrenia symptoms than controls (with and without ADHD); nevertheless, findings varied according to ADHD status (present versus absent), individual symptom (symptom specificity), and informant (informant specificity). Ratings of hallucinations and delusions indicated mild severity and few group differences. Negative symptoms such as inappropriate emotional reactions evidenced considerable group divergence. CONCLUSION: Findings provide additional support for an interrelation between ASD and SSD symptoms and the differential influence of neurobehavioral syndromes on co-occurring symptom severity, underscore the multidimensionality of SSD in children with ASD, and suggest how symptom phenotypes may contribute to a better understanding of the etiology, nosology, and possibly clinical management. PMID- 23021483 TI - Family functioning, social impairment, and symptoms among adolescents with bipolar disorder. AB - OBJECTIVE: Impaired social functioning is common among youth with bipolar disorder (BD), emerges in multiple settings, and persists over time. However, little is known about factors associated with poor peer and family functioning in the early-onset form of BD. Using a sample of adolescents with BD I or II, we examined which symptoms of BD, including nonspecific symptoms such as inattention, aggression, and anxiety/depression, were associated with family functioning (adaptability, cohesion, and conflict) and peer relationship quality. METHOD: Adolescents (N = 115; 46% male) with BD I and II and their parents were evaluated before participation in a multi-site randomized controlled trial. Adolescents had experienced an episode of depression, mania, or hypomania within the previous 3 months and were not in full remission. Adolescents' problem behaviors were assessed using the parent-rated Child Behavior Checklist (CBCL). Family functioning was assessed via child- and parent-report questionnaires. RESULTS: Depressive symptoms were associated with lower child-ratings of family functioning. Contrary to hypotheses, moderate mania was associated with better parent-reported family conflict, adaptability, and cohesion. Aggression was associated with poorer family functioning across reporters and measures, even when controlling for the effects of depression, mania, and inattention. None of these symptom clusters were associated with peer functioning. CONCLUSIONS: Aggression was the strongest correlate of family functioning in pediatric BD in this cross-sectional study. Findings speak to the potential value of addressing aggression and family dysfunction in the treatment of youth with BD. Clinical trial registration information-Effectiveness of Family-Focused Treatment Plus Pharmacotherapy for Bipolar Disorder in Adolescents; http://clinicaltrials.gov/; NCT00332098. PMID- 23021488 TI - Association between -308 G/A polymorphism in TNF-alpha gene and lichen planus: a meta-analysis. AB - BACKGROUND: Different studies have conflicting opinions on the association between the -308 G/A polymorphism in TNF-alpha gene and genetic risk of lichen planus (LP). OBJECTIVE: The purpose of this meta-analysis is to comprehensively evaluate interactions on this polymorphism and LP risk. METHODS: A meta-analysis was employed to assess genetic risk of -308 G/A polymorphism in TNF-alpha gene for lichen planus. Odds ratios (ORs) with 95% confidence intervals (CIs) were also included. RESULTS: Five studies including 8 comparisons were involved in this meta-analysis. The result showed that no association was found between this polymorphism and LP risk in combined analyses (OR=1.42 and 95% CI=0.85-2.37, P=0.180 for AA+GA vs. GG model). In the subgroup analysis by subtypes of LP (cutaneous LP and OLP) and OLP (eOLP, neOLP and mixed), no significant connections of risks were obtained from the two groups for AA+GA vs. GG comparison. In the subgroup analysis by ethnicity, significant increased OLP risks were found among population with mixed ethnicity (OR=3.26, 95%CI=1.46-7.26, P=0.004), but not in Asians (OR=1.19, 95%CI=0.69-2.05, P=0.528) and Caucasians (OR=1.32, 95%CI=0.41-4.27, P=0.645) for AA+GA vs. GG comparison. For the population presence or absence of hepatitis C virus (HCV) infection, significant increased risk of OLP was found among patients without HCV infection (OR=2.16, 95%CI=1.05-4.43, P=0.037), but not in LP-HCV +ve patients (OR=0.48, 95%CI=0.13 1.69, P=0.251) and mixed HCV status LP patient (OR=1.24, 95%CI=0.62-2.50, P=0.546). However, the negative results could have been biased because some included papers were lack of some information, which mainly related to HCV-status and clinical variety. That is the limitation of this meta-analysis. CONCLUSIONS: The -308 G/A polymorphism may be a risk factor for OLP patients without HCV infection and those with mixed ethnicity. More studies are needed to validate these associations. PMID- 23021485 TI - Chronic social stress impairs virus specific adaptive immunity during acute Theiler's virus infection. AB - Prior exposure to social disruption (SDR) stress exacerbates Theiler's murine encephalomyelitis virus (TMEV) infection, a model of multiple sclerosis. Here we examined the impact of SDR on T cell responses to TMEV infection in SJL mice. SDR impaired viral clearance and exacerbated acute disease. Moreover, TMEV infection alone increased CD4 and CD8 mRNA expression in brain and spleen while SDR impaired this response. SDR decreased both CD4(+) and CD8(+) virus-specific T cells in CNS, but not spleen. These findings suggest that SDR-induced suppression of virus-specific T cell responses contributes to impairments in viral clearance and exacerbation of acute disease. PMID- 23021489 TI - Candidate gene association study in pediatric acute lymphoblastic leukemia evaluated by Bayesian network based Bayesian multilevel analysis of relevance. AB - BACKGROUND: We carried out a candidate gene association study in pediatric acute lymphoblastic leukemia (ALL) to identify possible genetic risk factors in a Hungarian population. METHODS: The results were evaluated with traditional statistical methods and with our newly developed Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method. We collected genomic DNA and clinical data from 543 children, who underwent chemotherapy due to ALL, and 529 healthy controls. Altogether 66 single nucleotide polymorphisms (SNPs) in 19 candidate genes were genotyped. RESULTS: With logistic regression, we identified 6 SNPs in the ARID5B and IKZF1 genes associated with increased risk to B-cell ALL, and two SNPs in the STAT3 gene, which decreased the risk to hyperdiploid ALL. Because the associated SNPs were in linkage in each gene, these associations corresponded to one signal per gene. The odds ratio (OR) associated with the tag SNPs were: OR = 1.69, P = 2.22x10(-7) for rs4132601 (IKZF1), OR = 1.53, P = 1.95x10(-5) for rs10821936 (ARID5B) and OR = 0.64, P = 2.32x10(-4) for rs12949918 (STAT3). With the BN-BMLA we confirmed the findings of the frequentist-based method and received additional information about the nature of the relations between the SNPs and the disease. E.g. the rs10821936 in ARID5B and rs17405722 in STAT3 showed a weak interaction, and in case of T-cell lineage sample group, the gender showed a weak interaction with three SNPs in three genes. In the hyperdiploid patient group the BN-BMLA detected a strong interaction among SNPs in the NOTCH1, STAT1, STAT3 and BCL2 genes. Evaluating the survival rate of the patients with ALL, the BN-BMLA showed that besides risk groups and subtypes, genetic variations in the BAX and CEBPA genes might also influence the probability of survival of the patients. CONCLUSIONS: In the present study we confirmed the roles of genetic variations in ARID5B and IKZF1 in the susceptibility to B-cell ALL. With the newly developed BN-BMLA method several gene-gene, gene-phenotype and phenotype-phenotype connections were revealed. We showed several advantageous features of the new method, and suggested that in gene association studies the BN-BMLA might be a useful supplementary to the traditional frequentist-based statistical method. PMID- 23021490 TI - In vitro functional characterization of missense mutations in the LDLR gene. AB - BACKGROUND: Mutations in the LDL receptor gene are the major cause of familial hypercholesterolaemia (FH) but it has been previously shown that the simple finding of a variation in the coding sequence of the LDLR does not confirm that it is the actual cause of FH. The pathogenicity of five missense alterations in the LDLR gene coding sequence found in a previous epidemiologic study was investigated. METHODS: The effects of the different sequence variants on LDLR expression and activity were analysed in vitro stably transfected CHO-ldlA7 cells by immunobloting of cell extracts, by uptake and degradation rates of (125)I labelled LDL and immunofluorescence microscopy of whole cells. Analysis in silico was also performed. RESULTS: LDLR functional assays showed that variants p.V429L, p.W490R and p.S648P of the LDLR coding sequence severely impaired receptor function, while variant p.P685S had a milder effect and cells carrying p.V859M variant had LDL clearance rates comparable to cells expressing normal LDLR. In silico analysis failed to predict correctly the effect of 4/5 alterations. CONCLUSION: Assessing the pathogenicity of the different variants found in patients with clinical diagnosis of FH is of great importance to distinguish pathogenic mutations from rare silent variants and has clinical implications for determining the associated cardiovascular risk. PMID- 23021491 TI - Correlation of proteome-wide changes with social immunity behaviors provides insight into resistance to the parasitic mite, Varroa destructor, in the honey bee (Apis mellifera). AB - BACKGROUND: Disease is a major factor driving the evolution of many organisms. In honey bees, selection for social behavioral responses is the primary adaptive process facilitating disease resistance. One such process, hygienic behavior, enables bees to resist multiple diseases, including the damaging parasitic mite Varroa destructor. The genetic elements and biochemical factors that drive the expression of these adaptations are currently unknown. Proteomics provides a tool to identify proteins that control behavioral processes, and these proteins can be used as biomarkers to aid identification of disease tolerant colonies. RESULTS: We sampled a large cohort of commercial queen lineages, recording overall mite infestation, hygiene, and the specific hygienic response to V. destructor. We performed proteome-wide correlation analyses in larval integument and adult antennae, identifying several proteins highly predictive of behavior and reduced hive infestation. In the larva, response to wounding was identified as a key adaptive process leading to reduced infestation, and chitin biosynthesis and immune responses appear to represent important disease resistant adaptations. The speed of hygienic behavior may be underpinned by changes in the antenna proteome, and chemosensory and neurological processes could also provide specificity for detection of V. destructor in antennae. CONCLUSIONS: Our results provide, for the first time, some insight into how complex behavioural adaptations manifest in the proteome of honey bees. The most important biochemical correlations provide clues as to the underlying molecular mechanisms of social and innate immunity of honey bees. Such changes are indicative of potential divergence in processes controlling the hive-worker maturation. PMID- 23021492 TI - Immunotoxicity of surface waters contaminated by municipal effluents to the snail Lymnaea stagnalis. AB - The immunotoxic effects of surface waters contaminated by a municipal effluent dispersion plume were examined in the snail Lymnaea stagnalis. Snails were exposed to surface waters where changes in hemocyte counts, viability, levels of reactive oxygen species (ROS), reduced thiols and phagocytic activity were tracked following exposure periods of 3h and 3 and 7d. Changes in mRNA expression of some genes in the hemocytes were also assessed after 7d of exposure, as follows: genes coding for catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GSR), selenium-dependent glutathione peroxidase (SeGPX), two isoforms of the nitric oxide synthetase (NOS1 and NOS2), molluscan defensive molecule (MDM), toll-like receptor 4 (TLR4), allograft inflammatory factor-1 (AIF), and heat-shock protein 70 (HSP70). At the sites closest to the discharge point, exposure led to impaired hemocyte viability and intracellular thiol levels and also an increase of hemocyte count, ROS levels and phagocytosis. Phagocytosis and ROS levels in hemocytes were correlated with heterotrophic bacterial counts in snails. We found four genes with increased mRNA expression as a response to exposure of municipal wastewaters: TLR4 (6-fold), HSP70 (2-fold), SeGPx (4-fold) and CAT (2-fold). Immunocompetence responses were analyzed by canonical analysis to seek out relationships with mRNA expression of the genes involved in stress, pattern recognition, cellular and humoral responses. The data revealed that genes involved in oxidative stress were strongly involved with immunocompetence and that the resulting immune responses were influenced both by the bacterial and pollutant loadings of the effluent. PMID- 23021493 TI - Acute cholecystitis in end-stage renal disease patients: a nation-wide longitudinal study. AB - BACKGROUND: The objective of this study was to evaluate the risks of acute cholecystitis among end-stage renal disease patients and compare the incidence between two dialysis modality. STUDY DESIGN: In this retrospective cohort study, records of fifty thousand end-stage renal disease patients older than 20 years of age from 1998 to 2007 and an age, gender, Charlson's score, diabetes, and dyslipidemia matched control cohort were retrieved from Taiwan National Health Insurance Research Database. Hospitalizations for acute cholecystitis were retrieved using ICD-9-CM diagnosis codes and ICD-9-CM operation codes from in patient claims. RESULTS: The incidence rates were 5.8 per 1000 patient-years in the end-stage renal disease patients and 0.92 per 1000 patient-years in the control group. End-stage renal disease was an independent risk factor for acute cholecystitis. In the end-stage renal disease patients, independent risk factors were old age, higher Charlson's score, diabetes, severe liver disease, atrial fibrillation, and haemodialysis (all p<0.05). However, the peritoneal dialysis patients had a higher mortality rate after developing acute cholecystitis. CONCLUSION: Acute cholecystitis is not uncommon in end-stage renal disease patients. The independent risk factors were older age, higher Charlson's score, atrial fibrillation, severe liver disease, diabetes, and dialysis modality. Haemodialysis patients had a higher risk of acute cholecystitis than PD patients. PMID- 23021494 TI - Examining access to addiction treatment: scheduling processes and barriers. AB - This paper reports on the phone scheduling systems that patients encounter when seeking addiction treatment. Researchers made a series of 28 monthly calls to 192 addiction treatment clinics to inquire about the clinics' first available appointment for an assessment. Each month, the date of each clinic's first available appointment and the date the appointment was made were recorded. During a 4-month baseline data collection period, the average waiting time from contact with the clinic to the first available appointment was 7.2 days. Clinics engaged in a 15-month quality improvement intervention in which average waiting time was reduced to 5.8 days. During the course of the study, researchers noted difficulty in contacting clinics and began recording the date of each additional attempt required to secure an appointment. On average, 0.47 callbacks were required to establish contact with clinics and schedule an appointment. Based on these findings, aspects of quality in phone scheduling processes are discussed. Most people with addiction seek help by calling a local addiction treatment clinic, and the reception they get matters. The results highlight variation in access to addiction treatment and suggest opportunities to improve phone scheduling processes. PMID- 23021495 TI - Clinician attitudes, social norms and intentions to use a computer-assisted intervention. AB - The National Drug Abuse Treatment Clinical Trials Network (CTN) works to bridge the gap between research and practice and tested a Web-delivered psychosocial intervention (the Therapeutic Education System, TES) in 10 community treatment centers. Computer-assisted therapies, such as Web-delivered interventions, may improve the consistency and efficiency of treatment for alcohol and drug use disorders. Prior to the start of the study, we surveyed counselors (N=96) in participating treatment centers and assessed counselor attitudes, perceived social norms and intentions to use a Web-delivered intervention. Analysis of the intention to adopt a Web-delivered intervention assessed the influence of attitudes and perceived social norms. Perceived social norms were a significant contributor to clinician intention to adopt Web-based interventions while attitude was not. To promote successful implementation, it may be helpful to create social norms supportive of computer-assisted therapies. PMID- 23021497 TI - Donor impurity-related linear and nonlinear intraband optical absorption coefficients in quantum ring: effects of applied electric field and hydrostatic pressure. AB - : The linear and nonlinear intraband optical absorption coefficients in GaAs three-dimensional single quantum rings are investigated. Taking into account the combined effects of hydrostatic pressure and electric field, applied along the growth direction of the heterostructure, the energies of the ground and first excited states of a donor impurity have been found using the effective mass approximation and a variational method. The energies of these states are examined as functions of the dimensions of the structure, electric field, and hydrostatic pressure. We have also investigated the dependencies of the linear, nonlinear, and total optical absorption coefficients as a function of incident photon energy for several configurations of the system. It is found that the variation of distinct sizes of the structure leads to either a redshift and/or a blueshift of the resonant peaks of the intraband optical spectrum. In addition, we have found that the application of an electric field leads to a redshift, whereas the influence of hydrostatic pressure leads to a blueshift (in the case of on-ring center donor impurity position) of the resonant peaks of the intraband optical spectrum. PMID- 23021496 TI - HIV rapid testing in drug treatment: comparison across treatment modalities. AB - Despite high rates of risky behavior among patients, many drug abuse treatment programs do not provide on-site HIV testing. This secondary analysis examined differences in outcome by program modality from a multi-site trial in which 1281 HIV-negative patients in three methadone programs, seven non-methadone outpatient programs, and three residential programs were randomly assigned to: (1) off-site referral for HIV risk reduction counseling and testing; or on-site rapid testing (2) with or (3) without risk reduction counseling. The parent study using generalized estimating equations with site as a cluster variable found significantly higher rates of HIV testing and feedback of results by 1 month post enrollment for the combined on-site conditions compared to the offsite condition [RR=4.52, 97.5% CI (3.57, 5.72)]. Utilizing the same statistical approach, we found neither significant treatment modality nor significant treatment modality by testing condition interaction effects either for receipt of HIV test results at 1 month or for sexual or drug use HIV-risk behaviors at 6-month follow-up. On site HIV testing is effective across treatment modalities for achieving high rates of testing and results feedback. All programs should be encouraged to adopt or expand this service. PMID- 23021498 TI - Twenty-five years of research on the behavioural malaise associated with influenza and the common cold. AB - Minor illnesses such as the common cold and influenza are frequent and widespread. As well as specific symptoms such as nasal problems and fever, these illnesses are associated with a behavioural malaise. One feature of this malaise is reduced alertness and this has been confirmed using subjective reports and objective measures of performance. Such effects have been obtained with both experimentally induced infections and in studies of naturally occurring illnesses. The mechanisms underlying the effects are unclear but possibly reflect effects of cytokines on the CNS which result in changes in neurotransmitter functioning that lead to reduced alertness. The malaise induced by these illnesses has many real-life consequences and activities such as driving and safety at work may be at risk. These illnesses not only have direct effects on performance and mood but also make the person more sensitive to effects of other negative influences such as noise, alcohol and prolonged work. Countermeasures include ingestion of caffeine and other drugs known to increase alertness. PMID- 23021499 TI - Plasminogen activator inhibitor-1 promotes the proliferation and inhibits the apoptosis of pulmonary fibroblasts by Ca(2+) signaling. AB - AIM: Our previous investigation demonstrated that plasminogen activator inhibitor 1 (PAI-1) siRNA ameliorated bleomycin (BLM)-induced rat lung fibrosis. The present study was undertaken to explore the effect and the mechanism of PAI-1 siRNA and plasmid pcDNA on the proliferation and apoptosis of cultured fibroblasts from BLM-induced fibrotic lung tissues. MATERIALS AND METHODS: The fibroblasts from BLM-induced fibrotic lung tissue were isolated and transfected using PAI-1 siRNA and plasmid pcDNA-PAI-1. The techniques of real time RT-PCR and/or western blot were used to determine the expression of PAI-1, alpha-smooth muscle actin (alpha-SMA) (real time RT-PCR only), collagen type-1 and type-3 (real time RT-PCR only), and the levels of caspase-3, ERK and AKT signal molecules. The proliferation of fibroblasts was measured by cell cycle with flow cytometry. The intracellular concentration of Ca(2+) was examined by confocal laser microscopy. RESULTS: PAI-1 siRNA downregulated the PAI-1 mRNA expression by 70%+/-7% at 24h and protein expression by 73.5%+/-10% and 42%+/-3% at 48h and 72h compared to Non-specific siRNA group. Flow cytometry showed that the fibroblasts at the G(2)M+S phase were significantly reduced by 20.56+/-1.03% after transfecting PAI-1 siRNA and were significantly increased by 43.8+/-1.21% after transfecting plasmid pcDNA-PAI-1. The mRNA expressions of alpha-SMA, collagen type-1and type-3 were downregulated after transfecting the PAI-1 siRNA, while upregulated after the transfection of pcDNA-PAI-1. PAI-1 siRNA increased the level of caspase-3, inhibited the expressions of p-ERK and p-AKT protein molecules, while the pcDNA-PAI-1 transfection showed a reversal effect on these expressions. Intracellular Ca(2+) concentration was decreased after transfecting PAI-1 siRNA, whereas increased after transfecting pcDNA-PAI-1. CONCLUSION: PAI-1 promotes the proliferation, transforming into myofibroblasts, collagen synthesis, and inhibits apoptosis of pulmonary fibroblasts by activating Ca(2+), ERK and AKT signaling pathway. Decreasing PAI-1 expression is an available strategy in inhibiting the progression of pulmonary fibrosis. PMID- 23021500 TI - Human hepatoma cell line HuH-7 is an effective cellular system to produce recombinant factor IX with improved post-translational modifications. AB - Recombinant factor IX (rFIX) is increasingly used to treat patients with hemophilia B. CHO (Chinese Hamster Ovary) cells are commonly used for the production of rFIX but they have a limited capacity for introducing post translational modifications (PTM) leading to incomplete gamma-carboxylation, low phosphorylation and sulfation profiles as compared with plasma-derived preparations. Imperfect PTM might have an impact on the activity of Factor IX molecule. Several studies in animal models as well as clinical trials have previously reported a lower recovery of rFIX compared to plasma-derived FIX concentrates. In the present study, we aimed to produce a rFIX having a profile of PTM similar to plasma-derived FIX, using human hepatoma cell line HuH-7. We showed that rFIX produced by HuH-7 cells followed the classical intracellular pathway before secretion. In addition, improved PTM were associated with fully active molecule compared to plasma-derived and recombinant control FIX molecules. Secreted rFIX presented as a single band at the correct molecular weight. HuH-7 cellular clones were obtained and they secreted a biologically active human FIX. FIX was then purified for a detailed evaluation of PTM. Glycosylation and sialylation profiles were similar to plasma-derived and rFIX and mass spectrometry analysis demonstrated the presence of phosphorylated and sulfated forms of rFIX. These data strongly support that HuH-7 cells may represent an effective cellular system for production of rFIX exhibiting PTM similar to plasma derived FIX. PMID- 23021501 TI - Global transmission of multiple-drug resistant Neisseria gonorrhoeae strains refractive to cephalosporin treatment. PMID- 23021502 TI - CD4(+)FoxP3(+) regulatory T-cells in human systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of immune tolerance to self antigens and by the persistent production of pathogenic autoantibodies. Recent studies have suggested a dysregulation of regulatory T-cells (Tregs), particularly CD4(+)CD25(high)FoxP3(+) (forkhead box P3) Tregs, as one of the major factors conferring the risk for expression of human autoimmune diseases, including SLE. However, detailed studies of CD4(+)FoxP3(+) T-cells in patients with SLE remain limited. We attempt here to integrate the current experimental evidence to delineate the role of CD4(+)CD25(high) and other subsets of CD4(+)FoxP3(+) T-cells in human SLE. PMID- 23021503 TI - Tension-compression viscoelastic behaviors of the periodontal ligament. AB - BACKGROUND/PURPOSE: Although exhaustively studied, the mechanism responsible for tooth support and the mechanical properties of the periodontal ligament (PDL) remain a subject of considerable controversy. In the past, various experimental techniques and theoretical analyses have been employed to tackle this intricate problem. The aim of this study was to investigate the viscoelastic behaviors of the PDL using three-dimensional finite element analysis. METHODS: Three dentoalveolar complex models were established to simulate the tissue behaviors of the PDL: (1) deviatoric viscoelastic model; (2) volumetric viscoelastic model; and (3) tension-compression volumetric viscoelastic model. These modified models took into consideration the presence of tension and compression along the PDL during both loading and unloading. The inverse parameter identification process was developed to determine the mechanical properties of the PDL from the results of previously reported in vitro and in vivo experiments. RESULTS: The results suggest that the tension-compression volumetric viscoelastic model is a good approximation of normal PDL behavior during the loading-unloading process, and the deviatoric viscoelastic model is a good representation of how a damaged PDL behaves under loading conditions. Moreover, fluid appears to be the main creep source in the PDL. CONCLUSION: We believe that the biomechanical properties of the PDL established via retrograde calculation in this study can lead to the construction of more accurate extra-oral models and a comprehensive understanding of the biomechanical behavior of the PDL. PMID- 23021504 TI - Less-invasive MR indices of clinically evident esophageal variceal bleeding in biliary atresia patients. AB - BACKGROUND/PURPOSE: Esophageal variceal hemorrhaging is potentially life threatening for long-term survivors of biliary atresia. We evaluated the feasibility of less-invasive parameters for predicting the presence of clinically significant esophageal variceal bleeding in biliary atresia patients. METHODS: A total of 30 patients aged 108-5314 days (median = 285 days) with biliary atresia underwent a magnetic resonance examination with fast spin-echo T2-weighted imaging and spin-echo, T1-weighted images with fat saturation after use of a contrast medium on a 1.5-tesla scanner. The splenic length-platelet ratio was divided by the each patient's body height (m) to produce the corrected splenic length-platelet ratios. In addition, the splenic volume index-to-platelet count ratio was divided by the patient's body weight (kg) to produce a corrected ratio. RESULTS: The corrected splenic length-platelet ratio was more significantly increased in 21 patients with esophageal variceal bleeding (Group A) than in nine patients without variceal bleeding [(Group B) 0.98 +/- 0.64 vs. 0.44 +/- 0.18, p < 0.01]. The splenic volume index-to-platelet count ratio corrected by body weight was significantly larger in Group A (510.7 +/- 536.2) than in Group B (148.1 +/- 88.9, p < 0.01). CONCLUSION: Less-invasive indices, including the corrected splenic length platelet ratio and the splenic volume index-to-platelet count ratio, may be valuable predictors of esophageal variceal bleeding in patients with biliary atresia. PMID- 23021505 TI - Prognosis of symptomatic patients with the A3243G mutation of mitochondrial DNA. AB - BACKGROUND/PURPOSE: The clinical analyses and prognoses of mitochondrial diseases with A3243G mutation are rarely documented in Taiwan. Our study investigated the clinical phenotypes and the outcomes of patients with mitochondrial disease and the A3243G mutation of mtDNA in a Taiwanese population, and compared these with previous reports. METHODS: We retrospectively studied 22 consecutive patients with mitochondrial disease and the A3243G mutation of mtDNA in Chang Gung Memorial Hospital between 1988 and 2009. All patients underwent a detailed demographic registration, neurological examinations, a muscle biopsy, and mitochondrial DNA analysis. Modified Rankin scale, the presence of recurrent strokes or seizures, critical medical complications, and death were monitored during the follow-up period. RESULTS: Of the 22 patients, seizures and stroke like episodes were found in 12 (55%). Visceral involvement, including cardiomyopathy, nephropathy, and pulmonary hypertension, were noted in five patients (23%). Patients with seizures had a high frequency of status epilepticus (92%) and a younger age of onset (21.3+/-7.2 years). Both the Kaplan-Meier survival analysis and the Cox-regression model showed a marked deterioration in patients with seizures after 7 years of follow-up. CONCLUSION: Our study found that seizures and status epilepticus are the most important predictive values for a poor outcome in patients with the mtA3243G mutation of mtDNA. Age of onset and visceral organ involvement had no prominent influence on the prognosis. Some medical complications could be well controlled or even reversed after management. PMID- 23021506 TI - Immunogenicity and safety of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered with routine childhood vaccines in Taiwan. AB - BACKGROUND/PURPOSE: The immunogenicity and safety of the 10-valent pneumococcal nontypeable Haemophilus influenzae (H. Influenzae) protein D conjugate vaccine (PHiD-CV), co-administered with routine childhood vaccines, were assessed in Taiwanese infants. METHODS: In this open study, 230 healthy infants were primed with three doses of PHiD-CV (Synflorix) and diphtheria, tetanus, acellular pertussis, hepatitis B (HBV), inactivated poliomyelitis and Haemophilus influenzae type b (Hib) conjugate vaccine (DTPa-HBV-IPV/Hib vaccine) at 1.5, 3 and 6 months of age and two doses of oral human rotavirus vaccine at 1.5 and 3 months. Pneumococcal immune responses were assessed 1 month post-dose three, by 22F-inhibition ELISA and opsonophagocytic activity (OPA) assay. Local and general solicited/unsolicited symptoms and serious adverse events (SAEs) were recorded. RESULTS: At least 95.4% of participants had an antibody concentration >= 0.2 MUg/mL against each vaccine serotype. At least 96.1% of participants had an OPA titer >= 8 against each vaccine serotype except 6B (87.3%). All infants, but one, were seropositive for antibodies against nontypeable H. influenzae protein D. Immune responses to the co-administered vaccines were good and in line with previous reports. PHiD-CV was well tolerated, with low (<= 6.3%) incidences of grade 3 solicited local symptoms. The frequencies of general symptoms were in line with other pneumococcal conjugate vaccine studies. There were no systematic increases in incidences of solicited general or local symptoms with successive doses. There were no reports of grade 3 fever (rectal temperature > 40 degrees C) or SAEs considered to be causally related to vaccination. CONCLUSION: PHiD-CV co-administered with routine childhood vaccines within the first 6 months of life, was highly immunogenic, and well tolerated in Taiwanese infants. PMID- 23021507 TI - Readmission to the intensive care unit: a population-based approach. AB - BACKGROUND/PURPOSE: Readmission to the intensive care unit (ICU) results in increased consumption of medical resources and costs, and has been proposed as a marker for quality of care. ICU readmission rates have been estimated at 4-14% and different risk factors have been proposed by various studies. METHODS: Every admission event to the ICU was recorded and readmission episodes were analyzed using a population-based database from the Taiwan National Health Insurance Research Database (NHIRD) for the period from January 1, 2006 to December 31, 2006. RESULTS: The average follow-up time was 206.35 days. From the database of 192,201 patients admitted to the ICU, 25,263 patients were re-admitted, with a readmission rate of 13.13%. The leading etiologies for readmission were identified. Using multivariate analysis, age > 39 years old, female gender, ischemic heart disease, lung related disorders, pneumonia, cerebrovascular disease, sepsis, heart failure, chronic liver disease, diabetes mellitus, and chronic obstructive pulmonary disease were identified as significant risk factors for readmission to the ICU. CONCLUSION: This study uses a novel approach to assess risk factors for readmission to the ICU. Higher risk patients should be assessed more carefully before discharge or transfer from the ICU to prevent readmission episodes. PMID- 23021508 TI - The influence on liver function after transcatheter arterial chemoembolization combined with percutaneous radiofrequency ablation in patients with hepatocellular carcinoma. AB - OBJECTIVES: Our aim was to investigate how transcatheter arterial chemoembolization (TACE) combined with percutaneous radiofrequency ablation (RFA) affected liver parenchymal function in patients with hepatocellular carcinoma (HCC), and to evaluate the significant risk factors for post-procedural deterioration of liver function. METHODS: Changes in liver laboratory tests and development of complications were monitored in 53 patients with unresectable hepatocellular carcinoma from January 2007 to January 2009. Cox proportional hazard regression model was performed to evaluate risk factors for deterioration of liver function after the procedure. RESULTS: Plasma total bilirubin (TB) increased from pre-procedural 22.1 +/- 12.4 MUmol/L to 34.1 +/- 21.8 MUmol/L on post-procedural day three (P = 0.017). Alanine aminotransferase (ALT) also increased greatly from 65 +/- 58 IU/L to 285 +/- 182 IU/L post-procedurally (P = 0.006). Albumin (ALB) dropped from 42.5 +/- 4.5 g/L to 34.6 +/- 5.4 g/L (P = 0.019) and the Child-Pugh score increased from 5.2 +/- 1.3 to 7.1 +/- 1.5 three days after treatment (P = 0.021). Most of these parameters returned to normal range within 3-4 weeks. Thirty-three out of 53 patients developed complications in our study. Cox proportional hazards regression univariate analysis demonstrated that a Child-Pugh score >= 9 points and age >= 60 years were risk factors for deterioration of liver function after the procedure. Furthermore, a Child-Pugh score >= 9 points was found to be the only risk factor for post procedural deterioration of liver function identified by stepwise multivariate analysis. CONCLUSION: Liver function parameters such as plasma total bilirubin, ALT, serum ALB and Child-Pugh score could be transiently deteriorated by TACE combined with RFA in patients with Child-Pugh grades B or C. Therefore, patients with a Child-Pugh score >= 9 points were not appropriate candidates for TACE combined with RFA. PMID- 23021509 TI - Primary gastric synovial sarcoma. AB - Synovial sarcoma is a malignant soft tissue neoplasm that may arise from a variety of sites in the human body. It is typically characterized by its biphasic histological pattern, but a monophasic type composed entirely of spindle cells also exists. The diagnosis of monophasic synovial sarcoma can be very challenging and often requires molecular diagnostic techniques, especially for tumors arising in rare locations such as the gastrointestinal tract. We report here the case of a 38-year-old woman with a primary gastric monophasic synovial sarcoma confirmed by reverse transcriptase polymerase chain reaction that revealed t(X;18) (SYT SSX1) translocation. To our knowledge, only 11 synovial sarcomas arising in the stomach have previously been reported. The pathologic features, differential diagnoses, and clinical manifestations are discussed. PMID- 23021510 TI - Successful thrombolytic therapy in a patient with infective endocarditis-related stroke. PMID- 23021511 TI - Toluene intoxication-atrioventricular block due to hypokalemia? PMID- 23021513 TI - Role of baseline echocardiography in the preoperative management of liver transplant candidates. AB - Liver transplantation (LT) has not traditionally been offered to patients with intracardiac shunts (ICSs) or pulmonary hypertension (PH). There is a paucity of data regarding cardiac structural characteristics in LT candidates. We examined echocardiographic characteristics and their role in managing LT candidates diagnosed with ICS and PH. We identified 502 consecutive patients (318 men, mean age 55 +/- 11 years) who underwent LT and had preoperative echocardiogram. Demographics, cardiovascular risk factors, and echocardiographic variables were recorded and data were analyzed for end-stage liver disease diagnosis. ICSs were diagnosed with contrast echocardiography and PH was defined as estimated pulmonary artery systolic pressure >40 mm Hg. Primary end points included short term (30-day) and long-term (mean 41-month) mortalities and the correlation between pre- and perioperative stroke. In our studied population >50% had >2 cardiovascular risk factors and with increasing frequency ICSs were diagnosed in 16%, PH in 25%, and intrapulmonary shunts in 41% of LT candidates. There was no correlation between short- and long-term mortality and ICS (p = 0.71 and 0.76, respectively) or PH (p = 0.79 and 0.71). Importantly, in those with ICS, no strokes occurred. In conclusion, structural differences exist between various end stage liver disease diagnoses. ICSs diagnosed by echocardiography are not associated with an increased risk of perioperative stroke or increased mortality. A diagnosis of mild or moderate PH on baseline echocardiogram is not associated with worse outcomes and requires further assessment. Based on these findings, patients should not be excluded from consideration for LT based solely on the presence of an ICS or PH. PMID- 23021514 TI - Continuation of statin therapy and primary prevention of nonfatal cardiovascular events. AB - Although the beneficial effect of statins in secondary prevention of cardiac events is well established, their effectiveness in primary prevention is questionable when most evidence derives from randomized controlled trials and not "real-life" data. To evaluate the association between persistent use of statins and risk of acute nonfatal cardiovascular events in primary prevention patients in community settings, we retrospectively analyzed a cohort of 171,535 adults 45 to 75 years old with no indication of cardiovascular disease who began statin therapy from 1998 to 2009 in a large health maintenance organization in Israel. Persistence with statins was measured by the proportion of days covered with dispensed prescriptions of statins during the follow-up period. Main outcome measurements were occurrence of myocardial infarction or performance of a cardiac revascularization procedure. Incidence of acute cardiovascular events during the follow-up period (993,519 person-years) was 10.22 per 1,000 person-years. Persistence with statins was associated with a lower risk of incident cardiac events (p for trend <0.01). The most persistent users (covered with statins for >=80% of their follow-up time) had a hazard ratio of 0.58 (95% confidence interval 0.55 to 0.62) compared to nonpersistent users (proportion of days covered <20%). Similar results were found when analyses were limited to patients with >5 years of follow-up. Treatment with high efficacy statins was associated with a lower risk of cardiac events. In conclusion, our large and unselected community-based study supports the results of randomized controlled trials regarding the beneficial effect of statins in the primary prevention of acute cardiac events. PMID- 23021515 TI - Relationship between sex hormones and cognitive performance in men with substance use. AB - BACKGROUND: Hypogonadism is common with opiate-like drug use and may contribute to cognitive abnormalities. With the increasing epidemic of HIV and substance use (SU) worldwide, it is important to understand the impact of these conditions on cognition, which may affect quality of life and possibly decrease adherence to treatment. We hypothesized that men with SU, by virtue of hypogonadism secondary to HIV and/or SU, may demonstrate impaired cognition. METHODS: We recruited men aged 18-50 from a population of low income, inner-city individuals. Details of HIV and SU status, serum blood levels of total testosterone (TT), free testosterone (FT) and estradiol (E2) were assessed. All subjects were administered ten neuropsychological tests. RESULTS: Our sample consisted of 68 men (mean age: 43.2 years (SD 5.8), African Americans: 86.6%). The recruited population was primarily from low socioeconomic status and unemployed. The mean level of TT was 553.9 ng/dL (SD 262.0), the mean level of FT was 69.5 pg/mL (SD 34.8), mean E2 was 3.2 pg/mL (SD 4.4). We found that 30.9% were hypogonadal and it was associated with higher SU. We observed some relationships between sex hormones and cognitive domains, however, after adjustment for age, drug use category, education, depression, HIV, there was no statistically significant correlation between cognitive performance and sex hormone levels. CONCLUSIONS: In this cross-sectional study of men with a high prevalence of SU and hypogonadism, endogenous levels of TT, FT or E2 were not related to cognitive performance. Other factors need to be identified which may contribute to poor cognitive function in the setting of SU. PMID- 23021516 TI - n-3 Long-chain PUFA reduce allergy-related mediator release by human mast cells in vitro via inhibition of reactive oxygen species. AB - Increased n-6 and reduced n-3 long-chain PUFA (LC-PUFA) intake in Western diets may contribute to the increased prevalence of allergic diseases. Key effector cells in allergy are mast cells (MC). The aim of the present study was to investigate the effects of n-6 v. n-3 LC-PUFA on MC phenotype. Human MC lines (LAD2 and HMC-1) were incubated for 24 h with either arachidonic acid (AA, n-6 LC PUFA) or the n-3 LC-PUFA EPA or DHA. The effects of these three LC-PUFA on degranulation, mediator secretion and reactive oxygen species (ROS) generation were assessed. ROS, mitogen-activated protein kinase (MAPK) or NF-kappaB inhibitors were used to unravel signalling pathways involved in cytokine secretion. AA, EPA or DHA did not reduce IgE-mediated degranulation by LAD2 cells. However, AA increased PGD2 and TNF-alpha secretion by ionomycin/phorbol 12 myristate 13-acetate-stimulated HMC-1, whereas EPA and DHA more prominently inhibited IL-4 and IL-13 secretion. Suppression of IL-4 and IL-13 release by LC PUFA correlated with reduced ROS generation. IL-4 and IL-13 release by activated HMC-1 was abrogated using ROS inhibitors. Inhibition of MAPK signalling, but not NF-kappaB, downstream of ROS reduced IL-13 secretion by activated HMC-1. Combined incubation of EPA or DHA with MAPK inhibitors further suppressed IL-13 secretion. In conclusion, the n-6 LC-PUFA AA enhanced pro-inflammatory mediator production by MC, while the n-3 LC-PUFA EPA as well as DHA more effectively suppressed ROS generation and IL-4 and IL-13 release. This suggests that dietary supplementation with EPA and/or DHA may alter the MC phenotype, contributing to a reduced susceptibility to develop and sustain allergic disease. PMID- 23021517 TI - An in vitro study of osteoblast vitality influenced by the vitamins C and E. AB - Vitamin C and vitamin E are known as important cellular antioxidants and are involved in several other non-antioxidant processes. Generally vitamin C and vitamin E are not synthesized by humans and therefore have to be applied by nutrition. The absence or deficiency of the vitamins can lead to several dysfunctions and even diseases (e.g. scurvy). The main interest in this study is that vitamin C and E are known to influence bone formation, e.g. vitamin C plays the key role in the synthesis of collagen, the major component of the extracellular bone matrix.In the present study we evaluate the effect of ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) on the proliferation and differentiation of primary bovine osteoblasts in vitro. Starting from standard growth medium we minimized the foetal calf serum to reduce their stimulatory effect on proliferation.An improved growth and an increased synthesis of the extracellular matrix proteins collagen type I, osteonectin and osteocalcin was observed while increasing the ascorbic acid concentration up to 200 MUg/ml. Furthermore the effects of alpha-tocopherol on cell growth and cell differentiation were examined, whereby neither improved growth nor increased synthesis of the extracellular matrix proteins collagen type I, osteonectin and osteocalcin were detected.Further investigations are necessary to target at better supportive effect of vitamins on bone regeneration, and healing. PMID- 23021518 TI - Characterization of nonpoint source microbial contamination in an urbanizing watershed serving as a municipal water supply. AB - Inland watersheds in the southeastern United States are transitioning from agricultural and forested land uses to urban and exurban uses at a rate greater than the national average. This study sampled creeks representing a variety of land use factors in a rapidly urbanizing watershed that also serves as a drinking water supply. Samples were collected bimonthly under dry-weather conditions and four times during each of three storm events and assessed for microbial indicators of water quality. Concentrations of fecal indicator bacteria (FIB) including fecal coliforms and Escherichia coli were measured using standard membrane filtration techniques. Results showed that FIB concentrations varied between 10(0) and 10(4) colony forming units (CFU) per 100 mL. An analysis of variance (ANOVA) showed that FIB were generally higher in more developed watersheds (p < 0.01). Concentrations were also significantly greater during storm events than during dry-weather conditions (p < 0.02), although concentrations demonstrated both intra and inter-storm variability. These results indicate that the magnitude of microbial contamination is influenced by intensity of watershed development, streamflow and antecedent precipitation. Dry-weather FIB loads showed considerable seasonal variation, but the average storm event delivered contaminant loads equivalent to months of dry-weather loading. Analysis of intra-storm loading patterns provided little evidence to support "first-flush" loading of either FIB, results that are consistent with environmental reservoirs of FIB. These findings demonstrate that single sampling monitoring efforts are inadequate to capture the variability of microbial contaminants in a watershed, particularly if sampling is conducted during dry weather. This study also helps to identify timing and conditions for public health vulnerabilities, and for effective management interventions. PMID- 23021519 TI - Modeling complexity in simulating pesticide fate in a rice paddy. AB - Modeling approaches for pesticide regulation are required to provide generic and conservative evaluations on pesticide fate and exposure based on limited data. This study investigates the modeling approach for pesticide simulation in a rice paddy, by developing a component-based modeling system and characterizing the dependence of pesticide concentrations on individual fate processes. The developed system covers the modeling complexity from a "base model" which considers only the essential processes of water management, water-sediment exchange, and aquatic dissipation, to a "full model" for all commonly simulated processes. Model capability and performance were demonstrated by case studies with 5 pesticides in 13 rice fields of the California's Sacramento Valley. With registrant-submitted dissipation half-lives, the base model conservatively estimated dissolved pesticide concentrations within one order of magnitude of measured data. The full model simulations were calibrated to characterize the key model parameters and processes varying with chemical properties and field conditions. Metabolism in water was identified as an important process in predicting pesticide fate in all tested rice fields. Relative contributions of metabolism, hydrolysis, direct aquatic photolysis, and volatilization to the overall pesticide dissipation were significantly correlated to the model sensitivities to the corresponding physicochemical properties and half-lives. While modeling results were sensitive to metabolism half-lives in water for all fields, significances of metabolism in sediment and water-sediment exchange were only observed for pesticides with pre-flooding applications or with rapid dissipation in sediment. Results suggest that, in addition to the development of regional modeling scenarios for rice production, the registrant-submitted maximum values for the aquatic dissipation half-lives could be used for evaluating pesticide for regulatory purposes. PMID- 23021520 TI - A novel bioelectrochemical BOD sensor operating with voltage input. AB - Biochemical oxygen demand (BOD) is a measure of biodegradable compounds in water and is, for example, a common parameter to design and assess the performance of wastewater treatment plants. The conventional method to measure BOD is time consuming (5 or 7 days) and requires trained personnel. Bioelectrochemical BOD sensors designed as microbial fuel cells (MFCs), which are systems where bacteria convert organic matter into an electrical current, have emerged as an alternative to the conventional technique. In this study, a new type of bioelectrochemical BOD sensor with features that overcome some of the limitations of current MFC type designs was developed: (1) An external voltage was applied to overcome internal resistances and allow bacteria to generate current at their full capacity, and (2) the ion exchange membrane was omitted to avoid pH shifts that would otherwise limit the applicability of the sensor for wastewaters with low alkalinity. The sensor was calibrated with an aerated nutrient medium containing acetate as the BOD source. Linear correlation (R(2) = 0.97) with charge was obtained for BOD concentrations ranging from 32 to 1280 mg/L in a reaction time of 20 h. Lowering the reaction time to 5 h resulted in lowering the measurable BOD concentration range to 320 mg/L (R(2) = 0.99). Propionate, glucose, and ethanol could also be analyzed by the sensor that was acclimated to acetate. The study demonstrates a way to design more robust and simple bioelectrochemical BOD sensors that do not suffer from the usual limitations of MFCs (high internal resistance and pH shifts). PMID- 23021521 TI - Membrane bioreactor fouling behaviour assessment through principal component analysis and fuzzy clustering. AB - Adequate membrane bioreactor operation requires frequent evaluation of the membrane state. A data-driven approach based on principal component analysis (PCA) and fuzzy clustering extracting the necessary monitoring information solely out of transmembrane pressure data was investigated for this purpose. Out of three tested PCA techniques the two functional methods proved useful to cope with noise and outliers as opposed to the common standard PCA, while all of them presented similar capabilities for revealing data trends and patterns. The expert functional PCA approach enabled linking the two major trends in the data to reversible fouling and irreversible fouling. The B-splines approach provided a more objective way for functional representation of the data set but its complexity did not appear justified by better results. The fuzzy clustering algorithm, applied after PCA, was successful in recognizing the data trends and placing the cluster centres in meaningful positions, as such supporting data analysis. However, the algorithm did not allow a correct classification of all data. Factor analysis was used instead, exploiting the linearity of the observed two dimensional trends, to completely split the reversible and irreversible fouling effects and classify the data in a more pragmatic approach. Overall, the tested techniques appeared useful and can serve as the basis for automatic membrane fouling monitoring and control. PMID- 23021522 TI - Quantitative assessment of the efficacy of spiral-wound membrane cleaning procedures to remove biofilms. AB - Cleaning of high pressure RO/NF membranes is an important operational tool to control biofouling. Quantitative information on the efficacy of cleaning agents and protocols to remove biomass is scarce. Therefore, a laboratory cleaning test to assess the efficiency of cleaning procedures to remove attached biomass was developed. The major components of the test are (i) production of uniform biofilm samples, (ii) the quantification of the biomass concentrations with robust parameters and (iii) a simple test procedure with optimal exposure of the biofilm samples to the chemicals. The results showed that PVC-P is a suitable substratum for the production of uniform biofilm samples. ATP and carbohydrates (CH) as major components of the biofilm matrix for nucleotides (living bacterial cells) and extracellular polymeric substances EPS, respectively, were selected as robust biomass parameters. The removal of ATP and CH with the NaOH/Sodium Dodecyl Sulfate (SDS) mixture, selected as a standard treatment at pH 12.0, was reproducible. The resistance of the EPS matrix against chemical cleaning was demonstrated by a low CH removal (32.8 +/- 6.0%) compared to the ATP removal (70.5 +/- 15.1%). The inverse relationship of biomass removal with the CH to ATP ratio (MUg/ng) of the biofilms demonstrated the influence of the biomass characteristics on cleaning. None of the 27 chemicals tested (analytical-grade and commercial brands) in single step or in double-step treatments were significantly more effective than NaOH/SDS. Oxidizing agents NaOCl and H(2)O(2), the latter in combination with SDS, both tested as common agents in biofilm control, showed a significantly higher efficiency (70%) to remove biofilms. In the test, simultaneously, the efficiency of agents to remove precipitated minerals such as Fe can be assessed. Validation tests with Cleaning in Place (CIP) in 8 and 2.5-inch RO membrane pilot plant experiments showed similar ranking of the cleaning efficiency of cleaning protocols as determined in the laboratory tests. Further studies with the laboratory test are required to study the effect of cleaning conditions such as duration, temperature, shear forces as well as chemical conditions (concentrations, alternative agents or mixtures and sequence of application) on the efficiency to remove attached biomass. PMID- 23021523 TI - Water disinfection using photo-Fenton: Effect of temperature on Enterococcus faecalis survival. AB - The photo-Fenton process is a promising alternative to classical water disinfection treatments, although information in this regard is scarce due to its operational limitations. The effect of temperature (10, 20, 30 and 40 degrees C) was studied on water disinfection using the photo-Fenton reaction at initial near neutral pH with resorcinol as a model of natural organic matter (NOM). Enterococcus faecalis, a Gram-positive microorganism, was selected as an indicator of wastewater faecal contamination. The individual effects of different variables involved in this process (mechanical stress, UVA, H(2)O(2), Fe(2+), H(2)O(2)/Fe(2+), UVA/Fe(2+), UVA/H(2)O(2) and UVA/H(2)O(2)/Fe(2+)) were determined. UVA and H(2)O(2) led to a 2.5-log decrease individually and the combined effect of both variables managed to disinfect up to the detection limit (i.e. from a 5.5 to a 6-log reduction) over the same treatment time. Only by adding 10 mg L(-1) of Fe(2+), the inactivation time was reduced from 120 min (H(2)O(2)/UVA) to 80 min (H(2)O(2)/UVA/Fe(2+); photo-Fenton) with 120 mg L(-1) of H(2)O(2). A higher disinfection result for E. faecalis was observed by increasing temperature according to the Arrhenius equation in the photo-Fenton process. The detection limit was not reached at 10 degrees C and, to achieve the detection limit at 20, 30 and 40 degrees C, 80, 65 and 40 min were needed, respectively. The decrease in treatment time is a key factor in applying the photo-Fenton disinfection process to a wastewater treatment plant. PMID- 23021524 TI - [Will we have to change the diagnostic criteria of respiratory distress syndrome?]. PMID- 23021525 TI - [Inadequate multiple implantable automatic defibrillator (iad) discharges due to electrocatheter malpositioning. A report of two cases]. PMID- 23021526 TI - Middle ear fluid characteristics in pediatric otitis media with effusion. AB - OBJECTIVE: Persistent otitis media with effusion is caused by poor clearance of middle ear fluid usually following an episode of acute otitis media. This fluid is thought to be viscous and poorly transportable by cilia. Because a subset of children require multiple myringotomy and tube placements for recurrent disease, we hypothesized that children requiring repeated procedures would have effusion fluid that was more viscous and less transportable than those having their first procedure. DESIGN: Prospective clinical study. SETTING: Tertiary care center. PATIENTS AND INTERVENTIONS: Middle ear secretions were collected at the time of myringotomy and tube insertion in 36 children accrued sequentially. Twenty-six of these children were having their first procedure and 10 had previously undergone myringotomy and tube placement. MAIN OUTCOME MEASURES: The secretions were evaluated for in vitro mucociliary transportability, and dynamic rheology in a magnetic microrheometer. RESULTS: Children with the need for repeated procedures had effusions with lower mucociliary transportability, and overall higher mean measures of surface mechanical impedance/frictional adhesion, but these did not reach statistical significance. Mucopurulent effusions had significantly greater transportability than both the mucoid and serous effusions in both groups. CONCLUSIONS: Persistent or recurrent otitis media with effusion is associated with poorly transportable middle ear fluid, which may have higher frictional adhesion. The best mucociliary transportability was measured in mucopurulent effusions. PMID- 23021527 TI - Effect of ginkgo biloba extract on recovery after facial nerve crush injury in the rat. AB - BACKGROUND AND OBJECTIVE: Many pharmacological agents have shown successful results in experimental crush injury of the peripheral nerve. To date, therapeutic effect of ginkgo biloba extract (GBE) on the peripheral nerve crush injury of rats has been rarely reported, moreover, neuroprotective effect on the facial nerve crush injury has not been reported. MATERIALS AND METHODS: Prospective functional recovery, using a vibrissae movement and electrophysiological analysis of recovery 4 weeks after the facial nerve crush in adult rats, and comparison with randomized intraperitoneal injection of either GBE or control phosphate buffered saline. RESULTS: Relative to the control group (26 days post operation), administration of GBE significantly accelerated the recovery of vibrissae orientation to 11.7 days post the operation. A significant functional recovery was observed by postoperative 2nd week in the experimental group. The recovery of threshold and conduction velocity, postoperative 4th week in the experimental group, showed statistically significant difference compared to that of the control group. CONCLUSION: From this result, intraperitoneal injection of GBE has been found effective in promoting the regeneration of the nerve in an experimental facial nerve crush rat model. Further studies, including morphological and molecular analyses, are necessary to clarify the mechanisms of GBE on the facial nerve crush. PMID- 23021528 TI - Comparison of ropivacaine, bupivacaine and lidocaine in the management of post tonsillectomy pain. AB - OBJECTIVES: To compare the efficacy of preoperative peritonsillar injection of ropivacaine, bupivacaine and lidocaine for pediatric tonsillectomy. PATIENTS AND METHODS: Between March 2009 and April 2012, 120 patients (66 males and 54 females) between ages of 4 and 13 years were included to the study. After informed consent was obtained from the parents, the patients were randomized into four groups. In Group 1 (31 patients, mean age 8.40 +/- 4.05 years) received topical lidocaine hydrochloride with 1:100,000 epinephrine was applied to surgical bed following tonsillectomy. Group 2 (29 patients, mean age 8.15 +/- 4.20 years) and group 3 (31 patients, mean age 7.75 +/- 3.95 years) were administered 0.25% bupivacaine hydrochloride with 1:200,000 epinephrine and 0.5% ropivacaine respectively. In Group 4 (29 patients, mean age 8.15 +/- 4.20 years) topical 0.9% saline was used. The operation time, postoperative pain, amount of intraoperative blood loss, postoperative hemorrhage and complications were assessed. The intensity of pain was scored on a visual analogue scale. The patients were followed up for 3 weeks after surgery. RESULTS: The difference between mean operative time of the three groups against saline injected group was statistically significant (p<0.001). The difference between mean intraoperative blood loss of the lidocaine group against three groups was statistically significant (p<0.001). None of the patients in four groups experienced primary and secondary hemorrhage. The difference between mean pain score between ropovacaine and bupivacaine groups was not statistically significant (p>0.001). The difference between mean pain score of the two groups against lidocaine and saline groups was statistically significant (p<0.001). CONCLUSION: Ropivacaine infiltration is as effective as bupivacaine for post-tonsillectomy pain management in children. In view of potential side effects of bupivacaine epinephrin combination, ropivacaine is a safer choice, for post-tonsillectomy pain relief. PMID- 23021529 TI - Relationship between adenoid size and severity of obstructive sleep apnea in preschool children. AB - OBJECTIVE: To investigate the contributions of adenoid and tonsil sizes to obstructive sleep apnea syndrome (OSAS) in normal-weight children in two age categories: preschool and schoolchildren. METHODS: Fifty-eight normal-weight (body mass index z-score<2) symptomatic children with OSAS (apnea-hypopnea index >= 2) were evaluated. The patients were divided into two age categories: preschool (age<6; n=33) and schoolchildren (age >= 6; n=25). Polysomnographic findings and adenoid and tonsil sizes were compared. The relative contributions of body mass index and adenoid and tonsil sizes were also investigated with a regression analysis. RESULTS: Adenoid grade and apnea index correlated significantly in preschool children (r=0.45, p<0.01). On regression analysis, adenoid grade was a significant predictor of the apnea index in preschool children. The influence of adenoid hypertrophy decreased from preschool to schoolchildren. Tonsil size had little influence on the apnea index in either group. CONCLUSION: Adenoid hypertrophy was a major contributor to OSAS in normal weight preschool children. The upper airway morphology of younger children with OSAS differed from that of older children with OSAS. PMID- 23021533 TI - Cortisol response to social stress in parentally bereaved youth. AB - BACKGROUND: Parental bereavement is associated with increased risk for psychiatric illness and functional impairment in youth. Dysregulated hypothalamic pituitary-adrenal (HPA) axis functioning may be one pathway through which bereaved children experience increased risk for poor outcomes. However, few studies have prospectively examined the association between parental bereavement and cortisol response while accounting for psychiatric disorders in both youth and their caregivers. METHODS: One-hundred and eighty-one bereaved and nonbereaved offspring and their caregivers were assessed at multiple time points over a 5-year period after parental death. Offspring participated in an adaptation of the Trier Social Stress Task (TSST), and salivary cortisol samples were collected before and after exposure to social stressors. Mixed models for repeated measures were used to analyze the effects of bereavement status, psychiatric disorder in both offspring and caregiver, and demographic indices on trajectories of cortisol response. RESULTS: After controlling for demographic variables and offspring depression, bereaved offspring demonstrated significantly different trajectories of cortisol response compared with nonbereaved offspring, characterized by higher total cortisol output and an absence of cortisol reactivity to acute social stress. Within the bereaved group, offspring of parents who died by sudden natural death demonstrated significant cortisol reactivity to social stress compared with offspring whose parents died by suicide, who demonstrated more blunted trajectory of cortisol response. CONCLUSIONS: Parentally bereaved youth demonstrate higher cortisol output than nonbereaved youth but are less able to mount an acute response in the face of social stressors. PMID- 23021540 TI - Photoconductivity and photoluminescence under bias in GaInNAs/GaAs MQW p-i-n structures. AB - The low temperature photoluminescence under bias (PLb) and the photoconductivity (PC) of a p-i-n GaInNAs/GaAs multiple quantum well sample have been investigated. Under optical excitation with photons of energy greater than the GaAs bandgap, PC and PLb results show a number of step-like increases when the sample is reverse biased. The nature of these steps, which depends upon the temperature, exciting wavelength and intensity and the number of quantum wells (QWs) in the device, is explained in terms of thermionic emission and negative charge accumulation due to the low confinement of holes in GaInNAs QWs. At high temperature, thermal escape from the wells becomes much more dominant and the steps smear out. PMID- 23021534 TI - Young adults at risk for stimulant dependence show reward dysfunction during reinforcement-based decision making. AB - BACKGROUND: While stimulant-dependent individuals continue to make risky decisions, in spite of poor outcomes, much less is known about decision-making characteristics of occasional stimulant users (OSU) at risk for developing stimulant dependence. This study examines whether OSU exhibit inefficient learning and execution of reinforced decision-outcome contingencies. METHODS: Occasional stimulant users (n = 161) and stimulant-naive comparison subjects (CTL) (n = 48) performed a Paper Scissors Rock task during functional magnetic resonance imaging. Selecting a particular option was associated with a predetermined probability of winning, which was altered repeatedly to examine neural and behavioral characteristics of reinforced contingencies. RESULTS: Occasional stimulant users displayed greater anterior insula, inferior frontal gyrus, and dorsal striatum activation than CTL during late trials when contingencies were familiar (as opposed to being learned) in the presence of comparable behavioral performance in both groups. Follow-up analyses demonstrated that during late trials: 1) OSU with high cannabis use displayed greater activation in these brain regions than CTL, whereas OSU with low cannabis use did not differ from the other two groups; and 2) OSU preferring cocaine exhibited greater anterior insula, inferior frontal gyrus, and dorsal striatum activation than CTL and also displayed higher activation in the former two regions than OSU who preferred prescription stimulants. CONCLUSIONS: Occasional stimulant users exhibit inefficient resource allocation during the execution of reinforced contingencies that may be a result of additive effects of cocaine and cannabis use. A critical next step is to establish whether this inefficiency predicts transition to stimulant dependence. PMID- 23021541 TI - The tiny zebrafish keep swimming fast in the developmental biology pond. PMID- 23021542 TI - Reverse genetic approaches in zebrafish. AB - Zebrafish (Danio rerio) is a well-established vertebrate animal model. A comprehensive collection of reverse genetics tools has been developed for studying gene function in this useful organism. Morpholino is the most widely used reagent to knock down target gene expression post-transcriptionally. For a long time, targeted genome modification has been heavily relied on large-scale traditional forward genetic screens, such as ENU (N-ethyl-N-nitrosourea) mutagenesis derived TILLING (Targeting Induced Local Lesions IN Genomes) strategy and pseudo-typed retrovirus mediated insertional mutagenesis. Recently, engineered endonucleases, including ZFNs (zinc finger nucleases) and TALENs (transcription activator-like effector nucleases), provide new and efficient strategies to directly generate site-specific indel mutations by inducing double strand breaks in target genes. Here we summarize the major reverse genetic approaches for loss-of-function studies used and emerging in zebrafish, including strategies based on genome-wide mutagenesis and methods for site-specific gene targeting. Future directions and expectations will also be discussed. PMID- 23021543 TI - Myelopoiesis during zebrafish early development. AB - Myelopoiesis is the process of producing all types of myeloid cells including monocytes/macrophages and granulocytes. Myeloid cells are known to manifest a wide spectrum of activities such as immune surveillance and tissue remodeling. Irregularities in myeloid cell development and their function are known to associate with the onset and the progression of a variety of human disorders such as leukemia. In the past decades, extensive studies have been carried out in various model organisms to elucidate the molecular mechanisms underlying myelopoiesis with the hope that these efforts will yield knowledge translatable into therapies for related diseases. Zebrafish has recently emerged as a prominent animal model for studying myelopoiesis, especially during early embryogenesis, largely owing to its unique properties such as transparent embryonic body and external development. This review introduces the methodologies used in zebrafish research and focuses on the recent research progresses of zebrafish myelopoiesis. PMID- 23021544 TI - Overlapping cardiac programs in heart development and regeneration. AB - Gaining cellular and molecular insights into heart development and regeneration will likely provide new therapeutic targets and opportunities for cardiac regenerative medicine, one of the most urgent clinical needs for heart failure. Here we present a review on zebrafish heart development and regeneration, with a particular focus on early cardiac progenitor development and their contribution to building embryonic heart, as well as cellular and molecular programs in adult zebrafish heart regeneration. We attempt to emphasize that the signaling pathways shaping cardiac progenitors in heart development may also be redeployed during the progress of adult heart regeneration. A brief perspective highlights several important and promising research areas in this exciting field. PMID- 23021545 TI - Ribosome biogenesis factor Bms1-like is essential for liver development in zebrafish. AB - Ribosome biogenesis in the nucleolus requires numerous nucleolar proteins and small non-coding RNAs. Among them is ribosome biogenesis factor Bms1, which is highly conserved from yeast to human. In yeast, Bms1 initiates ribosome biogenesis through recruiting Rcl1 to pre-ribosomes. However, little is known about the biological function of Bms1 in vertebrates. Here we report that Bms1 plays an essential role in zebrafish liver development. We identified a zebrafish bms1l(sq163) mutant which carries a T to A mutation in the gene bms1-like (bms1l). This mutation results in L(152) to Q(152) substitution in a GTPase motif in Bms1l. Surprisingly, bms1l(sq163) mutation confers hypoplasia specifically in the liver, exocrine pancreas and intestine after 3 days post-fertilization (dpf). Consistent with the bms1l(sq163) mutant phenotypes, whole-mount in situ hybridization (WISH) on wild type embryos showed that bms1l transcripts are abundant in the entire digestive tract and its accessory organs. Immunostaining for phospho-Histone 3 (P-H3) and TUNEL assay revealed that impairment of hepatoblast proliferation rather than cell apoptosis is one of the consequences of bms1l(sq163) giving rise to an under-developed liver. Therefore, our findings demonstrate that Bms1l is necessary for zebrafish liver development. PMID- 23021546 TI - Kzp regulates the transcription of gata2 and pu.1 during primitive hematopoiesis in zebrafish embryos. AB - Kaiso zinc finger-containing protein (Kzp), a maternally-derived transcription factor, controls dorsoventral patterning during zebrafish gastrulation. Here, we uncovered a new function for Kzp in zebrafish embryonic primitive hematopoiesis. The depletion of kzp led to defects in primitive hematopoiesis including the development of the erythroid and myeloid lineages. On the other hand, overexpression of kzp caused the ectopic expression of gata1, gata2, and pu.1. Chromosome immunoprecipitation assays revealed that Kzp protein directly binds to gata1, gata2, and pu.1 promoters. Interestingly, the ectopic expression of gata2 was able to rescue the erythroid, but not the myeloid lineage in kzp-depleted zebrafish embryos. gata1 expression controlled by Kzp was dependent on gata2 during primitive erythropoiesis. Our results indicate that Kzp is a critical transcriptional factor for the expression of gata2 and pu.1 to modulate primitive hematopoiesis. PMID- 23021547 TI - Large-scale forward genetic screening analysis of development of hematopoiesis in zebrafish. AB - Zebrafish is a powerful model for the investigation of hematopoiesis. In order to isolate novel mutants with hematopoietic defects, large-scale mutagenesis screening of zebrafish was performed. By scoring specific hematopoietic markers, 52 mutants were identified and then classified into four types based on specific phenotypic traits. Each mutant represented a putative mutation of a gene regulating the relevant aspect of hematopoiesis, including early macrophage development, early granulopoiesis, embryonic myelopoiesis, and definitive erythropoiesis/lymphopoiesis. Our method should be applicable for other types of genetic screening in zebrafish. In addition, further study of the mutants we identified may help to unveil the molecular basis of hematopoiesis. PMID- 23021548 TI - A surgery protocol for adult zebrafish spinal cord injury. AB - Adult zebrafish has a remarkable capability to recover from spinal cord injury, providing an excellent model for studying neuroregeneration. Here we list equipment and reagents, and give a detailed protocol for complete transection of the adult zebrafish spinal cord. In this protocol, potential problems and their solutions are described so that the zebrafish spinal cord injury model can be more easily and reproducibly performed. In addition, two assessments are introduced to monitor the success of the surgery and functional recovery: one test to assess free swimming capability and the other test to assess extent of neuroregeneration by in vivo anterograde axonal tracing. In the swimming behavior test, successful complete spinal cord transection is monitored by the inability of zebrafish to swim freely for 1 week after spinal cord injury, followed by the gradual reacquisition of full locomotor ability within 6 weeks after injury. As a morphometric correlate, anterograde axonal tracing allows the investigator to monitor the ability of regenerated axons to cross the lesion site and increasingly extend into the gray and white matter with time after injury, confirming functional recovery. This zebrafish model provides a paradigm for recovery from spinal cord injury, enabling the identification of pathways and components of neuroregeneration. PMID- 23021549 TI - Development of novel visual-plus quantitative analysis systems for studying DNA double-strand break repairs in zebrafish. AB - The use of reporter systems to analyze DNA double-strand break (DSB) repairs, based on the enhanced green fluorescent protein (EGFP) and meganuclease such as I Sce I, is usually carried out with cell lines. In this study, we developed three visual-plus quantitative assay systems for homologous recombination (HR), non homologous end joining (NHEJ) and single-strand annealing (SSA) DSB repair pathways at the organismal level in zebrafish embryos. To initiate DNA DSB repair, we used two I-Sce I recognition sites in opposite orientation rather than the usual single site. The NHEJ, HR and SSA repair pathways were separately triggered by the injection of three corresponding I-Sce I-cut constructions, and the repair of DNA lesion caused by I-Sce I could be tracked by EGFP expression in the embryos. Apart from monitoring the intensity of green fluorescence, the repair frequencies could also be precisely measured by quantitative real-time polymerase chain reaction (qPCR). Analysis of DNA sequences at the DSB sites showed that NHEJ was predominant among these three repair pathways in zebrafish embryos. Furthermore, while HR and SSA reporter systems could be effectively decreased by the knockdown of rad51 and rad52, respectively, NHEJ could only be impaired by the knockdown of ligaseIV (lig4) when the NHEJ construct was cut by I Sce I in vivo. More interestingly, blocking NHEJ with lig4-MO increased the frequency of HR, but decreased the frequency of SSA. Our studies demonstrate that the major mechanisms used to repair DNA DSBs are conserved from zebrafish to mammal, and zebrafish provides an excellent model for studying and manipulating DNA DSB repair at the organismal level. PMID- 23021550 TI - Effective expression-independent gene trapping and mutagenesis mediated by Sleeping Beauty transposon. AB - Expression-independent gene or polyadenylation [poly(A)] trapping is a powerful tool for genome-wide mutagenesis regardless of whether a targeted gene is expressed. Although a number of poly(A)-trap vectors have been developed for the capture and mutation of genes across a vertebrate genome, further efforts are needed to avoid the 3'-terminal insertion bias and the splice donor (SD) read through, and to improve the mutagenicity. Here, we present a Sleeping Beauty (SB) transposon-based vector that can overcome these limitations through the inclusion of three functional cassettes required for gene-finding, gene-breaking and large scale mutagenesis, respectively. The functional cassette contained a reporter/selective marker gene driven by a constitutive promoter in front of a strong SD signal and an AU-rich RNA-destabilizing element (ARE), which greatly reduced the SD read-through events, except that the internal ribosomal entry site (IRES) element was introduced in front of the SD signal to overcome the phenomenon of 3'-bias gene trapping. The breaking cassette consisting of an enhanced splicing acceptor (SA), a poly(A) signal coupled with a transcriptional terminator (TT) effectively disrupted the transcription of trapped genes. Moreover, the Hsp70 promoter from tilapia genome was employed to drive the inducible expression of SB11, which allows the conditional remobilization of a trap insert from a non-coding region. The combination of three cassettes led to effective capture and disruption of endogenous genes in HeLa cells. In addition, the Cre/LoxP system was introduced to delete the Hsp70-SB11 cassette for stabilization of trapped gene interruption and biosafety. Thus, this poly(A)-trap vector is an alternative and effective tool for identification and mutation of endogenous genes in cells and animals. PMID- 23021551 TI - Establishment of multi-site infection model in zebrafish larvae for studying Staphylococcus aureus infectious disease. AB - Zebrafish (Danio rerio) is an ideal model for studying the mechanism of infectious disease and the interaction between host and pathogen. As a teleost, zebrafish has developed a complete immune system which is similar to mammals. Moreover, the easy acquirement of large amounts of transparent embryos makes it a good candidate for gene manipulation and drug screening. In a zebrafish infection model, all of the site, timing, and dose of the bacteria microinjection into the embryo are important factors that determine the bacterial infection of host. Here, we established a multi-site infection model in zebrafish larvae of 36 hours post-fertilization (hpf) by microinjecting wild-type or GFP-expressing Staphylococcus aereus (S. aureus) with gradient burdens into different embryo sites including the pericardial cavity (PC), eye, the fourth hindbrain ventricle (4V), yolk circulation valley (YCV), caudal vein (CV), yolk body (YB), and Duct of Cuvier (DC) to resemble human infectious disease. With the combination of GFP expressing S. aureus and transgenic zebrafish Tg (coro1a: eGFP; lyz: Dsred) and Tg (lyz: Dsred) lines whose macrophages or neutrophils are fluorescent labeled, we observed the dynamic process of bacterial infection by in vivo multicolored confocal fluorescence imaging. Analyses of zebrafish embryo survival, bacterial proliferation and myeloid cells phagocytosis show that the site- and dose dependent differences exist in infection of different bacterial entry routes. This work provides a consideration for the future study of pathogenesis and host resistance through selection of multi-site infection model. More interaction mechanisms between pathogenic bacteria virulence factors and the immune responses of zebrafish could be determined through zebrafish multi-site infection model. PMID- 23021552 TI - Inferring novel gene-disease associations using Medical Subject Heading Over representation Profiles. AB - BACKGROUND: MEDLINE((r))/PubMed((r)) currently indexes over 18 million biomedical articles, providing unprecedented opportunities and challenges for text analysis. Using Medical Subject Heading Over-representation Profiles (MeSHOPs), an entity of interest can be robustly summarized, quantitatively identifying associated biomedical terms and predicting novel indirect associations. METHODS: A procedure is introduced for quantitative comparison of MeSHOPs derived from a group of MEDLINE((r)) articles for a biomedical topic (for example, articles for a specific gene or disease). Similarity scores are computed to compare MeSHOPs of genes and diseases. RESULTS: Similarity scores successfully infer novel associations between diseases and genes. The number of papers addressing a gene or disease has a strong influence on predicted associations, revealing an important bias for gene-disease relationship prediction. Predictions derived from comparisons of MeSHOPs achieves a mean 8% AUC improvement in the identification of gene-disease relationships compared to gene-independent baseline properties. CONCLUSIONS: MeSHOP comparisons are demonstrated to provide predictive capacity for novel relationships between genes and human diseases. We demonstrate the impact of literature bias on the performance of gene-disease prediction methods. MeSHOPs provide a rich source of annotation to facilitate relationship discovery in biomedical informatics. PMID- 23021553 TI - The stress response of three-spined sticklebacks is modified in proportion to effluent exposure downstream of wastewater treatment works. AB - This study was conducted to investigate whether exposure to wastewater treatment works (WWTW) effluent affects the adaptive stress axis of fish resident within the receiving water. Three-spined sticklebacks (Gasterosteus aculeatus) were sampled from sites downstream of ten WWTWs in north-west England, selected to represent a range of human population equivalents between 1000 and 125,000. Following capture, indices of stress (whole-body cortisol and glucose concentrations) were measured both prior to, and following, the imposition of a standardised stressor to establish both baseline and stress-induced concentrations of cortisol and glucose. There was considerable between-site variation in size, and to a lesser extent condition, of the fish. Pre- and post stress cortisol and glucose concentrations also varied significantly between sites. A large proportion of the variation in both the somatic data and the stress response was explained by variation in the proportion of effluent contributing to total river flow at the study sites. Mass (r(2)=0.35, P<0.001) and length (r(2)=0.37, P<0.001) of the fish, and cortisol (r(2)=0.26, P<0.001) and glucose (r(2)=0.12, P<0.01) concentrations in unstressed sticklebacks, were positively related to the concentration of effluent across the sample sites. However, in stressed fish, cortisol (r(2)=0.32, P<0.001) and glucose (r(2)=0.14, P<0.001) concentrations exhibited a negative trend in relation to the effluent concentrations across sites. Individual variation in fish size did not account for the variation in either cortisol or glucose levels. These data provide the first indication that modulation of the stress axis in fish by anthropogenic factors might be widespread and of greater significance than hitherto assumed. PMID- 23021554 TI - Plagiarism. PMID- 23021555 TI - Overview. PMID- 23021556 TI - Physical activity and urologic cancers. AB - Despite convincing evidence that physical activity protects against colon and breast cancers, the association of physical activity with urologic cancers is less well explored. Expert panels have previously found a probably protective benefit for prostate cancer, but insufficient evidence for other urologic cancers. We review the evidence for testicular, kidney/renal, bladder, and prostate cancers, including whether benefits may exist within subgroups. While the limited evidence base does not support an association of physical activity with either testicular or bladder cancers, a growing body of research suggests that physical activity results in a modest risk reduction for kidney cancer. A large number (>30) of studies suggests a probable small decrease in prostate cancer risk among those who are physically active, which is likely driven by the effect on advanced/aggressive tumors. The role of physical activity in decreasing urologic cancer risk is thus likely limited to advanced prostate and possibly kidney cancers with no association in testicular or bladder cancers. PMID- 23021557 TI - Why are diabetics at reduced risk for prostate cancer? A review of the epidemiologic evidence. AB - A large body of epidemiologic evidence provides strong support for the notion that type-2 diabetics are at decreased risk for prostate cancer. In this review article, we summarize the epidemiologic literature that explores the role of diabetes mellitus and related biomarkers in prostate cancer risk and detection, in order to create a better understanding of the potential mechanisms that underlie this inverse association. The bulk of the data supporting this association comes from the USA, as evidence for this association is less consistent in many other regions of the world. The relationship between diabetes and prostate cancer is suspected to be causal due to evidence of decreasing prostate cancer risk with increasing diabetes duration and lack of evidence for any confounding of this association. Hypothesized mechanisms for decreased prostate cancer risk among diabetics include (1) decreased levels of hormones and other cancer-related growth factors among diabetics, (2) the impact of diabetes on detection-related factors, such as prostate size, circulating prostate specific antigen (PSA), and health-care seeking behaviors, (3) protective effects of diabetes medications, and (4) a protective effect of diabetes-induced vascular damage in the prostate. The evidence for screening-related factors is compelling, as diabetics appear to have reduced PSA and lower levels of health-care seeking behavior compared with nondiabetics. Furthermore, the inverse association between diabetes and prostate cancer is much less apparent in populations that do not perform biopsies based on PSA levels and in studies restricted to biopsied individuals. The inverse association appears to be stronger for low-grade disease, as compared with high-grade (Gleason >7), which is consistent with the observation that among patients receiving biopsy or prostate cancer treatment, diabetics are more likely to have high-grade disease as compared to nondiabetics, potentially resulting in worse outcomes for diabetics. Epidemiological research has reveals a great deal regarding the relationship between diabetes and prostate cancer risk, but additional research is needed to further clarify the mechanisms underlying this inverse association. PMID- 23021558 TI - Commentary on "surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen suppression therapy in men with localized or locally advanced prostate cancer: an analysis of 2 randomized trials." A.V. D'Amico, M.H. Chen, M. de Castro, M. Loffredo, D.S. Lamb, A. Steigler, P.W. Kantoff, J.W. Denham, Department of Radiation Oncology, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA, USA: Lancet Oncol 2012;13:189-95 [Epub;2011, November 21]. PMID- 23021559 TI - Commentary on "association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials." Nguyen PL, Je Y, Schutz FA, Hoffman KE, Hu JC, Parekh A, Beckman JA, Choueiri TK, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA: JAMA 2011;306(21):2359-66. PMID- 23021560 TI - Commentary on "duration of short-course androgen suppression therapy and the risk of death as a result of prostate cancer." A.V. D'Amico, M.H. Chen, J. Crook, J.G. Armstrong, S. Malone, A. Steigler, M. Dunne, P.W. Kantoff, J.W. Denham, Brigham and Women's Hospital, Boston, MA. 02115, USA.: J Clin Oncol 2011;29:4682-7. PMID- 23021561 TI - Commentary on "denosumab and bone-metastasis-free survival in men with castration resistant prostate cancer: results of a phase 3, randomized, placebo-controlled trial." M.R. Smith, F. Saad, R. Coleman, N. Shore, K. Fizazi, B. Tombal, K. Miller, P. Sieber, L. Karsh, R. Damiao, T.L. Tammela, B. Egerdie, H. Van Poppel, J. Chin, J. Morote, F. Gomez-Veiga, T. Borkowski, Z. Ye, A. Kupic, R. Dansey, C. Goessl, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.: Lancet 2012;379:39-46 [Epub;2011, November 15]. PMID- 23021562 TI - Commentary on "comparative effectiveness of axitinib vs. sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial." B.I. Rini, B. Escudier, P. Tomczak, A. Kaprin, C. Szczylik, T.E. Hutson, M.D. Michaelson, V.A. Gorbunova, M.E. Gore, I.G. Rusakov, S. Negrier, Y.C. Ou, D. Castellano, H.Y. Lim, H. Uemura, J. Tarazi, D. Cella, C. Chen, B. Rosbrook, S. Kim, R.J. Motzer: Lancet 2011;378:1931-9 [Epub;2011, November 4]. PMID- 23021563 TI - A review of trauma and trauma-related papers published in the British Journal of Oral and Maxillofacial Surgery in 2010-2011. AB - This review summarises all trauma and related papers published in the British Journal of Oral and Maxillofacial Surgery (BJOMS) from January 2010 to December 2011. In total 45 articles were published, of which 42% (19) were full-length articles. These articles primarily focused on the management of mandibular condyle and orbital fractures, with several papers discussing maxillofacial surgery by the British military. There were no articles discussing midfacial fractures or massive facial trauma. The remaining papers included short communications, technical notes, and letters; and provided discussion of interesting cases, new surgical techniques and fracture classifications. The number of trauma papers published in BJOMS appears to be less than other sub specialties such as head and neck oncology. The number of prospective and randomised studies remains low, highlighting a need to foster further research within maxillofacial trauma. PMID- 23021564 TI - Nursing student's perceptions and understanding of intimate partner violence. AB - Intimate partner violence (IPV) is a significant health issue in the Australian population and nurses have a role in assessment, intervention and support of families. World Health Organization Statistics indicate that as many as 61% of women, under the age of 50 have been physically abused by their partners. As nurses are in a unique position to identify, assist and support women living with IPV a greater understanding of student nurse's knowledge and attitudes may assist undergraduate programs to ensure better preparation of nurses for this role. A nurse's readiness to manage IPV may be influenced by their knowledge, attitudes, beliefs and behaviors, largely related to their self-efficacy in identifying these women (i.e. via screening procedures) and providing effective interventions. Students from all levels of the undergraduate program of an Australian regional university were invited to participate in focus groups and a subsequent survey that explored their perceptions, attitudes and knowledge of IPV. The results showed students had limited and stereotypical beliefs regarding what constitutes IPV and who perpetrates it. They indicated that they were under prepared to deal with IPV situations in clinical practice but did identify communication as a core skill required. Nursing students may not understand the significance of the issues of IPV nor fully understand the social, economic and health impacts at an individual and societal level. This may result in further under detection of the problem. The results of this study indicate a number of important implications for undergraduate nursing education curricula. PMID- 23021565 TI - Vascular profiling: should manual therapists take blood pressure? AB - Risk assessment of the cervical spine prior to manual therapy interventions is currently a contentious topic, highlighted by recent suggestions in the medical press (http://www.bmj.com/content/344/bmj.e3679), that manipulative therapy should be abandoned because of the perceived risk. This paper addresses the issue of manual therapists using blood pressure measurement as an aid to clinical reasoning and decision making. The authors' use a case series of three neuromusculoskeletal presentations, which support the contention that blood pressure recording can prove to be an appropriate objective test for assessment prior to manual therapy interventions. Furthermore, it is suggested that blood pressure testing may provide direction for risk assessment and/or the management of patients across all populations and age groups as part of a holistic 'vascular profiling' approach to clinical reasoning and decision making. PMID- 23021566 TI - Psychiatrists' decision making between branded and generic drugs. AB - To study psychiatrists' decision making between generic and branded antipsychotics or antidepressants a hypothetical decision scenario involving decisions between branded and generic drugs was presented to a sample of German psychiatrists. Factors influencing this decision were identified using a regression analysis. n=410 Psychiatrists participated in the survey. Psychiatrists were more likely to choose branded drugs when imagining choosing the drug for themselves (vs. recommending a drug to a patient). In addition, psychiatrists were more likely to choose generic antidepressants than generic antipsychotics. Additional predictors for choosing a generic drug were a higher share of outpatients, less negative attitudes toward generics and higher uncertainty tolerance. In conclusion, psychiatrists' decision making in choosing between branded or generic antidepressants or antipsychotics is to a large extent influenced by vague attitudes towards properties of generics and branded drugs as well as by "non-evidence based" factors such as uncertainty tolerance. PMID- 23021567 TI - Brain-derived neurotrophic factor serum levels in cocaine-dependent patients during early abstinence. AB - Preclinical studies indicate that brain-derived neurotrophic factor (BDNF) is involved in neuroplastic changes underlying enduring cocaine-seeking following withdrawal. However, little is known about temporal changes in serum BDNF levels or the involvement of BDNF in craving and abstinence in early-abstinent cocaine dependent patients. Twenty-three cocaine-dependent individuals (aged 33.65 +/- 6.85 years) completed a two-week detoxification program at an inpatient facility. Two serum samples were collected for each patient at baseline and at the end of the protocol. Serum samples were also collected for 46 healthy controls (aged 35.52 +/- 9.37 years). Demographic, consumption and clinical data were recorded for all patients. Significantly lower serum BDNF levels (p<.0001) were observed for cocaine-dependent patients at baseline compared to healthy controls. Serum BDNF levels increased significantly across 12 days of early abstinence (p=.030). Baseline BDNF levels correlated with craving (p=.034). Post-detoxification BDNF levels correlated with craving (p=.018), loss of control (p<.000), abstinence measures (p=0.031), depression (p=0.036), and anxiety (p=0.036). Post detoxification BDNF levels also had predictive value for the loss of control measure of craving. Chronic cocaine use is associated with decreased serum BDNF. A progressive increase in serum BDNF levels during early abstinence correlates with cocaine craving and abstinence symptoms and may reflect increasing BDNF levels in different brain regions. These findings suggest that serum BDNF may be a biomarker for cocaine addiction. PMID- 23021568 TI - Ubiquinol decreases monocytic expression and DNA methylation of the pro inflammatory chemokine ligand 2 gene in humans. AB - BACKGROUND: Coenzyme Q10 is an essential cofactor in the respiratory chain and serves in its reduced form, ubiquinol, as a potent antioxidant. Studies in vitro and in vivo provide evidence that ubiquinol reduces inflammatory processes via gene expression. Here we investigate the putative link between expression and DNA methylation of ubiquinol sensitive genes in monocytes obtained from human volunteers supplemented with 150 mg/ day ubiquinol for 14 days. FINDINGS: Ubiquinol decreases the expression of the pro-inflammatory chemokine (C-X-C motif) ligand 2 gene (CXCL2) more than 10-fold. Bisulfite-/ MALDI-TOF-based analysis of regulatory regions of the CXCL2 gene identified six adjacent CpG islands which showed a 3.4-fold decrease of methylation status after ubiquinol supplementation. This effect seems to be rather gene specific, because ubiquinol reduced the expression of two other pro-inflammatory genes (PMAIP1, MMD) without changing the methylation pattern of the respective gene. CONCLUSION: In conclusion, ubiquinol decreases monocytic expression and DNA methylation of the pro-inflammatory CXCL2 gene in humans. Current Controlled Trials ISRCTN26780329. PMID- 23021569 TI - The importance of controlling for the acute-phase response in the population based assessment of vitamin A status: a study in children of pre-school age in Uganda. AB - OBJECTIVE: To improve estimates of vitamin A deficiency in children of pre-school age in the 2006 Uganda Demographic and Health Survey (UDHS 2006). DESIGN: A cross sectional study in which dried blood spot samples were analysed for C-reactive protein (CRP). Retinol-binding protein (RBP) had previously been analysed using a commercial enzyme immunoassay. SETTING: A population-based study in Uganda. SUBJECTS: A systematically selected subset of the dried blood spot samples collected from children aged 6-59 months for UDHS 2006. Children were categorized into 'normal CRP' (Group A) and 'raised CRP' (Group B) using a CRP cut-off of 5mg/l. A correction factor was calculated to adjust the Group B RBP values for the influence of the acute-phase response. RESULTS: Geometric mean CRP was 6.2 (95% CI 5.5, 7.0) mg/l, 1.6 (95% CI 1.5, 1.8) mg/l and 17.9 (95% CI 16.4, 19.6) mg/l in all children, in Group A and in Group B, respectively. Geometric mean RBP in all children, in Group A and in Group B was 1.18 (95% CI 1.14, 1.22)mmol/l, 1.26 (95% CI 1.20, 1.33)mmol/l and 1.12 (95% CI 1.07, 1.17)mmol/l, respectively, before correction. Correction increased mean RBP in Group B to 1.26 (95% CI 1.21, 1.31)mmol/l. The prevalence of vitamin A deficiency (RBP,0.825mmol/l) reduced from 18.4% (95% CI 17.2, 23.0%) to 13.9% (95% CI 11.3, 16.5%). CONCLUSIONS: Correcting for the acute-phase response significantly reduced the prevalence of vitamin A deficiency; thus, the acute-phase response should be considered when vitamin A status is assessed using RBP in order to improve population-level estimates of vitamin A deficiency. PMID- 23021570 TI - Left subclavian artery coverage during thoracic endovascular aortic aneurysm repair does not mandate revascularization. AB - OBJECTIVE: This study assessed the risk of left subclavian artery (LSA) coverage and the role of revascularization in a large population of patients undergoing thoracic endovascular aortic aneurysm repair. METHODS: A retrospective multicenter review of 1189 patient records from 2000 to 2010 was performed. Major adverse events evaluated included cerebrovascular accident (CVA) and spinal cord ischemia (SCI). Subgroup analysis was performed for noncovered LSA (group A), covered LSA (group B), and covered/revascularized LSA (group C). RESULTS: Of 1189 patients, 394 had LSA coverage (33.1%), and 180 of these patients (46%) underwent LSA revascularization. In all patients, emergency operations (9.5% vs 4.3%; P=.001), renal failure (12.7% vs 5.3%; P=.001), hypertension (7% vs 2.3%; P=.01), and number of stents placed (1=3.7%, 2=7.4%, >=3=10%; P=.005) were predictors of SCI. History of cerebrovascular disease (9.6% vs 3.5%; P=.002), chronic obstructive pulmonary disease (9.5% vs 5.4%; P=.01), coronary artery disease (8.5% vs 5.3%; P=.03), smoking (8.9% vs 4.2%) and female gender (5.3% men vs 8.2% women; P=.05) were predictors of CVA. Subgroup analysis showed no significant difference between groups B and C (SCI, 6.3% vs 6.1%; CVA, 6.7% vs 6.1%). LSA revascularization was not protective for SCI (7.5% vs 4.1%; P=.3) or CVA (6.1% vs 6.4%; P=.9). Women who underwent revascularization had an increased incidence of CVA event compared with all other subgroups (group A: 5.6% men, 8.4% women, P=.16; group B: 6.6% men, 5.3% women, P=.9; group C: 2.8% men, 11.9% women, P=.03). CONCLUSIONS: LSA coverage does not appear to result in an increased incidence of SCI or CVA event when a strategy of selective revascularization is adopted. Selective LSA revascularization results in similar outcomes among the three cohorts studied. Revascularization in women carries an increased risk of a CVA event and should be reserved for select cases. PMID- 23021571 TI - Pathophysiology of regression of synovial cysts of the lumbar spine: the 'anti inflammatory hypothesis'. AB - The term 'synovial cysts' of the lumbar spine refers to cysts that arise from the zygapophyseal joint capsule of the lumbar spine. Although several cases of regression of lumbar spine synovial cysts after oral anti-inflammatory therapy as well as local steroid injection have already been reported in the literature, no study up to now has addressed the role of 'inflammation suppression' in the regression of such lesions. In fact most of the previous studies have regarded 'spontaneous rupture' as well as 'instability resolution' as the most probable explanations for such phenomenon. In this article the authors review the current experimental data about the role of cytokines and inflammation in the development of synovial cysts of the lumbar spine. Additionally with basis on both our clinical experience of regression of a synovial cyst after conservative treatment with a non-steroidal anti-inflammatory drug (Cox-2 inhibitor) as well as on the experimental data supporting the multi-factorial effects of such drugs on the lumbar facet joints, the authors hypothesize that inhibition of inflammation might play a significant role in the pathophysiology of lumbar spine synovial cysts' regression. PMID- 23021572 TI - A biochemical rationale for the interaction between gastrointestinal yeast and autism. AB - Autism is a disorder characterized by difficulty with social interactions, difficulty expressing empathy and intimacy and, in many cases, mild to severe language and learning deficits. Current estimates suggest autism now affects approximately one in 88 children, with rates increasing rapidly, making autism one of the most common and devastating developmental disorders. This trend is especially alarming considering that a cause for this disorder has yet to be discovered, nor are there successful biological treatments. Here a possible biochemical etiology is proposed for a certain spectrum of autism based on a reaction between propionic acid and ammonia released by Candida albicans in the gastrointestinal tract. A reaction between ammonia and propionic acid should result in the production of beta-alanine, a chemical similar in composition to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter which has been shown to be present in higher quantities in autistic patients. Assuming beta alanine is able to cross the blood-brain barrier, beta-alanine would be used in the brain as a partial antagonist, blocking the receptor sites for GABA, thus facilitating the production of more GABA to achieve equilibrium. An excess of GABA has been proposed as a possible contributor to autism. Further research should be conducted with this hypothesis to determine whether the chemical reaction in the human body between propionic acid and ammonia does in fact produce a chemical structurally and functionally similar to beta-alanine, as well as how this product affects the brain. Positive conclusions from this follow-on research could result in a preventative screening test for sensitivity to propionic acid and gastrointestinal yeast, thus slowing the progression of this type of autism. A more targeted treatment for children already diagnosed with autism could also result. PMID- 23021573 TI - [SEMERGEN-Medicina de Familia indexed in Medline(r): great news for our society]. PMID- 23021574 TI - [Perception of rare diseases by the primary care physicians]. AB - OBJECTIVES: Identify the elements that lead to the perception that primary health care physicians (PHCP) have as regards rare diseases (RD) as a whole, and to analyse the characteristics of these patients with rare diseases. METHODS: Descriptive cross-sectional study. Surveys completed by PHCP during the years 2008-2010 were used to explore socio-demographic data, health care facilities, manpower, and services, knowledge level, expectations, means of obtaining available information, and training-support preferences of RD. RESULTS: A total of 260 questionnaires were analysed. The average level of knowledge was 3.68 (SD 1.93), of interest 7.34 (SD 2.02), and of importance 7.51 (SD 1.69). Less than one quarter (20.4%) of responders had done some training activity. Care at home (6.38, SD 2.07) is the most valued long term care option, emphasising the need of primary prevention (7.63 SD 1.5). Over one-third (35%) applied for some aid, mainly economic (37.4%). Internet is their main source of information (71.2%), and an average of 7.85 (SD 2.38) perceived the need for specific continuing training. By registered lists, each professional attends a mean of 2.45 (SD 3.69) patients with RD, 1.604% having temporary work disability, 1.479% having some disability and 1.62% with a dependence situation. The follow up of RD patients was: at Hospital level 55.72%, by special reference units 44.34%, by specialists 39.75%, and exclusively at PHCP level 14.46%. CONCLUSIONS: PHCP have a low level of knowledge of RD, although a high interest, with emphasis on primary prevention, the importance of the family environment, genetic counselling and health education. They rarely request medical resources for RD. Internet is their main source of information, and prefer specific continuing education courses. PMID- 23021575 TI - [Life-style and self-rated health status, and the use of health services by an immigrant population from Paraguay and Bolivia in city of Elche (Alicante, Spain)]. AB - OBJECTIVE: To study the lifestyle, use of health services, self-perceived health status and health services evaluations of immigrants from Paraguay and Bolivia in the city of Elche, and to establish and/or adapt prevention health services strategies to the needs of this population. METHODS: A cross-sectional study, using a health questionnaire, was conducted between November 2009 and April 2010, using a convenience sample selected from the Paraguay and Bolivia Citizens Association. RESULTS: A total of 49 Paraguayans and 35 Bolivians over 15 years old were interviewed of whom 42 (50%) were male; 33% of respondents did not perform any physical activity, and 14.3% were smokers (males [23.8%] vs female [4.8%], P=.03). The assessment of health was good or very good in 59.5% (Paraguayans [71.4%] vs Bolivians [42.9%]), P=.02). The use of health services was 85.4% (males [75%] vs women [95.2%], P=02) and 51% went to an emergency department. Consultation with a dentist was reported in 43.9% (Paraguayans [56.2%] vs Bolivians [26.5%], P=.007); 65.9% considered the Spanish public health system as being excellent, very good or good. CONCLUSION: The lifestyle, the use of private resources and the assessment of health status are different in both groups studied. The assessment of the Spanish public health system was good in both. Strategies are needed to improve lifestyle, counselling for smoking cessation, alcohol use and control of dyslipidaemia. PMID- 23021576 TI - [Study of sociodemographic and psychopathological risk factors in suicide attempts. 2008-2010]. AB - OBJECTIVE: The aim of this study is to determine the sociodemographic and psychopathological features and risk factors associated with suicide attempts. DESIGN: A descriptive cross-sectional study based on medical records. Emergency Primary Care Centres (Jumilla, Yecla) and Hospital Emergency Departments (Yecla, Murcia, Spain). RESULTS: The suicide attempt rate increases in younger people (average of 36.4 years old). Suicide attempts are higher among women (67%). In terms of psychopathological data, suicide attempts were characterised by a higher prevalence of depression and anxiety disorder (30%), and substance abuse (13%). The percentage of patients who had made a previous suicide attempt was 37%. Self poisoning was the most recurrent method of suicide attempt, present in at least 80% of the cases. Gender was a significant factor in the cause of suicide attempt (P=.042) and psychopathology (P=.011). The geographic origin of the patient is significantly associated with the suicide method used (P=.000). CONCLUSIONS: Suicide treatment protocols and suicide prevention programs must be developed, as well as recording the risk factors in the patient history. PMID- 23021577 TI - [Why and when to begin pharmacological treatment with dual-therapy]. AB - Hypertension is a syndrome in which, in addition to the elevation of blood pressure, there is micro-, macrovascular and kidney disease. Several mechanisms are interrelated in the physiopathology of hypertension, such as, the volume, renin-angiotensin system, and the sympathetic nervous system. These factors make it difficult to achieve blood pressure control with only a single drug. The vast majority of patients will require the combination of 2 or 3 drugs acting synergistically to increase the rate of response rate to treatment, and improve blood pressure control. Recent studies show that this blood pressure control must be achieved as soon as possible, with dual therapy being the first choice, particularly in high cardiovascular risk patients, and in patients who need greater reductions in blood pressure to achieve the goal. PMID- 23021578 TI - [Consensus on integrated care of acute exacerbations of chronic obstructive pulmonary disease (ATINA-EPOC). Part III]. PMID- 23021579 TI - [Extrinsic allergic alveolitis: An initial form of presentation as a fever of unknown origin]. AB - Extrinsic allergic alveolitis is characterised by an inflammatory immune process with pulmonary impairment caused by inhalation of organic dust. It is considered an occupational disease and is a very significant cause of temporary and permanent disability that can be prevented. The diagnosis is not often easy, but it is important to make it in the early stages, when the disease is still reversible. PMID- 23021580 TI - [Aortic dissection: 2 cases of atypical presentation]. AB - Aortic dissection is an uncommon disease with high mortality. The typical clinical picture is characterised by sudden pain in the retrosternal or interscapular region radiating to the back and abdomen. There can be several signs, depending on the arterial branches involved (stroke, renal or mesenteric ischaemia), and even the absence of pain. Two cases with unusual presentations are discussed; one with sudden paresis and ischaemia of both legs with involvement of spinal and iliac branches, and the other began as a syncope and right hemiparesis with carotid involvement. PMID- 23021581 TI - [Unilateral hip arthrosis: expression of joint haemochromatosis]. AB - Hereditary haemochromatosis is the most common genetic disorder in the Caucasian population, with an estimated prevalence of 1/200-1/400 (homozygous) and 1/8-1/10 in carriers (heterozygous). The transmission is recessive and linked to HLA. The clinical expression of disease appears only in homozygous and will depend on the time of diagnosis and the degree of organ involvement. The clinical case presented below describes the process of differential diagnosis made in a young patient with unilateral coxarthrosis and clinical suspicion of hemochromatosis. Early diagnosis of hereditary hemochromatosis in primary care can reduce morbidity and mortality of this disease by detecting homozygous at younger ages. PMID- 23021582 TI - [Iatrogenic adrenal insufficiency]. AB - Adrenal insufficiency is a disease caused by the deficit in production and/or secretion of glucocorticoids. The aetiology of Adrenal Insufficiency (AI) can be classified into primary and secondary, and it should be taken that the incidence and prevalence of the secondary formare much higher than the primary form. One of the main causes of AI is due to prescription of exogenous steroids. It can be taken orally, which is more common, or topically. The latter is more uncommon but it should not be a a reason for ruling it out. We have to be aware when giving a topical treatment and to monitor the frequency our patients ask for the prescription. PMID- 23021583 TI - [RS3PE Syndrome: Remitting Seronegative Symmetrical Synovitis with Pitting Edema: A presentation of 3 cases]. AB - RS3PE (Remitting Seronegative Symmetrical Synovitis with Pitting Edema) is a relatively rare rheumatological disease, which predominantly affects the elderly. Its importance lies in the need for a differential diagnosis with other more serious diseases, given its usual good response to treatment with oral corticosteroids. PMID- 23021584 TI - [Acute pancreatitis associated with Epstein-Barr virus infection]. PMID- 23021585 TI - [Allergies in occupational health]. PMID- 23021586 TI - [Reply from the authors]. PMID- 23021587 TI - [Immunoglobulin M positive for cytomegalovirus and Epstein-Barr virus in a patient with infectious mononucleosis. As we interpret it?]. PMID- 23021588 TI - Forensic culture as epistemic culture: the sociology of forensic science. AB - This paper explores whether we can interpret the notion of 'forensic culture' as something akin to what Knorr-Cetina called an 'epistemic culture'. Can we speak of a 'forensic culture', and, if so, how is it similar to, or different from, other epistemic cultures that exist in what is conventionally called 'science'? This question has important policy implications given the National Academy Science's (NAS) recent identification of 'culture' as one of the problems at the root of what it identified as 'serious deficiencies' in U.S. forensic science and 'scientific culture' as an antidote to those problems. Finding the NAS's characterisation of 'scientific culture' overly general and naive, this paper offers a preliminary exploration of what might be called a 'forensic culture'. Specifically, the paper explores the way in which few of the empirical findings accumulated by sociologists of science about research science seem to apply to forensic science. Instead, forensic science seems to have developed a distinct culture for which a sociological analysis will require new explanatory tools. Faithful sociological analysis of 'forensic culture' will be a necessary prerequisite for the kind of culture change prescribed by external reformist bodies like the NAS. PMID- 23021589 TI - [Clinical outcome of the hyperacute form of acute disseminated encephalomyelitis]. AB - INTRODUCTION: Acute disseminated encephalomyelitis (ADEM) is an inflammatory disease that damages the white matter of the central nervous system. Its clinical course is monophasic and multifocal. The outcome is usually favourable. We report our experience in the management of the hyperacute form of ADEM. PATIENTS AND METHODS: A retrospective chart review was performed on five patients admitted in coma with a diagnosis of ADEM in the Paediatric Intensive Care Unit (PICU). We describe their epidemiological, clinical, microbiological, magnetic resonance imaging features and their treatment and outcomes. RESULTS: The mean age was 5.2 years and all were male. None of them fulfilled radiologic criteria for acute haemorrhagic leukoencephalitis. At admission all patients were in a coma, and all were on controlled mechanical ventilation support. Before their admission all patients had fever. In all cases the time between the first neurological symptom and coma was <= 24hours. The cerebrospinal fluid examination was abnormal in three patients, and in one case, oligoclonal bands were detected. The first brain magnetic resonance imaging (MRI) showed white matter and basal ganglia lesions in all patients, and in three cases the spinal medulla was affected by demyelination. All patients were treated with a course of high-dose methylprednisolone. Four patients were also treated with high-dose immunoglobulins, and one of them received plasmapheresis. Two patients died, and one patient had severe sequelae at discharge from the PICU. At discharge the lesions in the white matter were still present in the MRI. After nine months the three survivors had a Glasgow Outcome Scale score of five and no one relapsed. CONCLUSIONS: There is a hyperacute clinical form of ADEM which has a high mortality rate. In the short term, the clinical improvement of hyperacute ADEM is not accompanied by a decrease of severity of the brain MRI. PMID- 23021590 TI - [MRI enterography in the assessment of paediatric Crohn's disease]. AB - OBJECTIVE: To determine the usefulness of MRI enterography for assessing the extension and activity of paediatric Crohn's disease. MRI findings were compared with clinical, biological, endoscopic and other imaging data. PATIENTS AND METHODS: Studies of MRI enterography use in patients younger than 18 years of age were reviewed. Patients received 500-1000mL of polyethylene glycol one hour before examination (1.5-TMR). T2 HASTE sequences with or without fat saturation, T2 true-FISP, T1 with fat saturation, pre- and post gadolinium-enhanced VIBE sequences, and dynamic and diffusion HASTE were acquired. Thickening of the bowel wall, mucosal enhancement, and extra-luminal complications were evaluated. Five MRI patterns (normal, fibrosis, mild, moderate, and severe transmural activity) were defined. Findings were compared with PCDAI scores, inflammatory parameters, and endoscopic and histological results. RESULTS: Twenty-two studies were reviewed. Optimal intestinal distension was present in 82% of the cases. Mild side effects were observed in 12% of patients. There was a significant relationship between MRI patterns and PCDAI scores (P=.002), sedimentation rate (P=.006) and serum PCR levels (P=.047) and a non-significant relationship with the histology (P=.571). MRI enterography correctly assessed the ileal (80%) and colonic (66%) extension. Extra-luminal complications unrelated to MRI classification (P=.274) were reported in 86.4% of studies. CONCLUSIONS: There was a significant relationship between MRI patterns and PCR, sedimentation rate, and PCDAI scores. MRI enterography showed excellent agreement with ileoscopies, and allowed endoscopically non-accessible areas to be assessed, as well as the diagnosis of extra-luminal complications without irradiation. PMID- 23021591 TI - [Contribution of 64-slice cardiac tomodensitometry for non-invasive diagnosis of acute myocarditis]. AB - BACKGROUND: The association of acute chest pain, elevation of the cardiac enzymes and biological markers of inflammation suggests the diagnosis of myocarditis. The aim of the present study is to evaluate the diagnostic value of the multidetectors cardiac tomodensitometry (MDCT) for the confirmation of this diagnosis. PATIENTS AND METHODS: From October 2005 to April 2011, 39 patients aged 15.4 to 75.7years (mean 43.3+/-15.1) underwent a MDCT for suspected acute myocarditis (chest pain, elevation of troponin I, systemic inflammation). The electrocardiogram highlighted repolarization disorders in 27 (69%) patients (negative T waves, elevation of ST segment). The MDCT consisted in a first acquisition phase (imaging of coronary arteries) followed 7minutes later by a late acquisition, with thicker slices (imaging of the myocardium). When the MDCT was performed after a coronary angiography, only the late acquisition was performed. Sixteen patients then underwent a cardiac MRI. RESULTS: No significant coronary stenoses were found in all patients. The MDCT showed homogeneous myocardial enhancement on the early acquisition. A subepicardial late enhancement was found in 30 (76.9%) patients. The subepicardial enhancement was mainly found in the lateral myocardium. In patients who underwent cardiac MRI and MDCT (n=16), there was a good correlation between the enhanced segments. MDCT found differential diagnosis in 11 patients (myocardial infarction, Tako-Tsubo). CONCLUSION: The ECG-gated MDCT is a non-invasive and reliable diagnostic tool in patient with suspected myocarditis. It allows at the same time to rule out a significant coronary disease, when no coronary angiography was performed, and to show subepicardial enhancement confirming the diagnosis of myocarditis. While cardiac MRI remains the gold standard, MDCT could prove useful when there is no access to or contraindication for an MRI, studying both the coronary arteries and the myocardium. PMID- 23021592 TI - Electromechanical deformation of mammalian cells in suspension depends on their cortical actin thicknesses. AB - The mechanical properties of mammalian cells are largely determined by their cytoskeletons (CSKs), which comprise several distinct but interacting cytoplasmic molecular networks. To examine the influence of the CSK on cell mechanical properties, we deformed several mammalian cell-types (L929, CHO, HEK293, and U937) in suspension using time-varying non-uniform electric fields. Confocal fluorescent microscopy was also used to visualize and semi-quantitatively analyze CSK dimensions. We found mechanical properties of individually deformed cells to depend on cortical actin (CA) thickness. U937 and HEK293 cells with thin CA were more easily deformed than CHO and L929 cells, which bore thicker CA. In additional experiments, we treated U937 cells with latrunculin-A (Lat-A) and acrylamide (ACR), drugs that disrupt microfilaments (MF) and intermediate filaments (IF), respectively, in order to assess their effects on the CSK and on the cell mechanical properties. We fit strain data using either a power-law or a viscoelasticity model of compliance. Our results demonstrated that maximal strain values observed under identical loading conditions were determined by the structural integrity and thickness of CA in suspended cells. Young's modulus values of individually deformed cells that were estimated using a power-law model showed a linear dependence on cortical actin thickness. PMID- 23021593 TI - Quantitative assessment of the anisotropy of vocal fold tissue using shear rheometry and traction testing. AB - The human vocal folds are layered structures with intrinsically anisotropic elastic properties. Most testing methods assume isotropic behavior. Biaxial testing of vocal folds is strictly difficult because the very soft tissue tends to delaminate under transverse traction loads. In the present study, a linear transversely isotropic model was used to characterize the tissue in-vitro. Shear rheometry was used in conjunction with traction testing to quantify the elasticity of porcine vocal fold tissue. Uniaxial traction testing along with optical measurements were used to obtain the longitudinal modulus. The alternate vocal fold of each animal was subjected to a test-specific sample preparation and concurrently tested using dynamic shear rheometry. The stiffness ratio (i.e., the ratio of the longitudinal modulus and the transverse modulus) varied between ~5 and ~7 at low frequencies. The proposed methodology can be applied to other soft tissues. PMID- 23021594 TI - Nuclear quadrupole resonance characterization of carbamazepine cocrystals. AB - Nuclear quadrupole resonance (NQR) is used as a method for the characterization of cocrystals and crystal polymorphs. (14)N NQR spectra of several cocrystals of carbamazepine have been measured together with the (14)N NQR spectra of cocrystal formers. The results show that the (14)N NQR spectrum of a cocrystal and the (14)N NQR spectra of cocrystal formers differ well outside the experimental resolution. It is further described how the NQDR techniques, that have been used to measure the (14)N NQR frequencies, can be used to check the homogeneity of a polycrystalline sample and to monitor the stability of a metastable crystal polymorph. PMID- 23021597 TI - Detection of acute aortic dissection by extremely high soluble lectin-like oxidized LDL receptor-1 (sLOX-1) and low troponin T levels in blood. PMID- 23021595 TI - Short time administration of antirheumatic drugs - methotrexate as a strong inhibitor of osteoblast's proliferation in vitro. AB - INTRODUCTION: Due to increasing use of disease modifying antirheumatic drugs (DMARDs) as first line therapy in rheumatic diseases, dental and maxillofacial practitioner should be aware of drug related adverse events. Especially effects on bone-metabolism and its cells are discussed controversially. Therefore we investigate the in vitro effect of short time administration of low dose methotrexate (MTX) on osteoblasts as essential part of bone remodelling cells. METHODS: Primary bovine osteoblasts (OBs) were incubated with various concentrations of MTX, related to tissue concentrations, over a period of fourteen days by using a previously established standard protocol. The effect on cell proliferation as well as mitochondrial activity was assessed by using 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay, imaging and counting of living cells. Additionally, immunostaining of extracellular matrix proteins was used to survey osteogenic differentiation. RESULTS: All methods indicate a strong inhibition of osteoblast's proliferation by short time administration of low dose MTX within therapeutically relevant concentrations of 1 to 1000 nM, without affecting cell differentiation of middle-stage differentiated OBs in general. More over a significant decrease of cell numbers and mitochondrial activity was found at these MTX concentrations. The most sensitive method seems to be the MTT-assay. MTX-concentration of 0,01 nM and concentrations below had no inhibitory effects anymore. CONCLUSION: Even low dose methotrexate acts as a potent inhibitor of osteoblast's proliferation and mitochondrial metabolism in vitro, without affecting main differentiation of pre differentiated osteoblasts. These results suggest possible negative effects of DMARDs concerning bone healing and for example osseointegration of dental implants. Especially the specifics of the jaw bone with its high vascularisation and physiological high tissue metabolism, suggests possible negative effects of DMARD therapy concerning oral and cranio-maxillofacial bone surgery as could be seen in a similar way in bisphosphonate related osteonecrosis of the jaw. PMID- 23021598 TI - Cardiac hybrid imaging guides revascularization prior to non-cardiac surgery. PMID- 23021599 TI - Cardiac functional benefits of ivabradine therapy in patients with severe heart failure. PMID- 23021600 TI - Tuberculous endocarditis. AB - Mycobacterium tuberculosis (TB) is a major cause of death globally. TB is capable of infecting every organ in the body, and the heart is no exception. Tuberculous endocarditis (TBE) was first reported in 1892 and subsequently many other cases have been described, highlighting the significant morbidity and mortality associated with this manifestation of TB. TBE usually presents with miliary tuberculosis and most early cases were diagnosed on autopsy. With increasing application of prosthetic valve replacements in the treatment of infective endocarditis (IE), TB infections have begun to affect these as well as native valves. With the introduction of TB culture methods and drug therapy, the prognosis has improved. HIV and drug resistance are likely to make the management of TBE more difficult in the future. Large scale studies, both prospective and retrospective, are required to ascertain the true incidence of TBE whilst development of novel anti-TB therapy is also required to combat resistance. We present the first extensive literature review on TBE in over 75 years. PMID- 23021601 TI - Comparison of effectiveness and safety of transcatheter aortic valve implantation in patients aged >=90 years versus <90 years. AB - In a fraction of patients aged >=90 years, less-invasive transcatheter aortic valve implantation (TAVI) has been considered a therapeutic option for aortic stenosis under careful clinical screening. However, the safety and effectiveness using TAVI in such a population has not been fully elucidated. The aim of the present study was to investigate the feasibility of TAVI in nonagenarians. We prospectively enrolled 136 consecutive patients with severe aortic stenosis who were referred for TAVI. The procedural, early, and midterm clinical outcomes were compared between patients aged <90 years (n = 110, average age 82.3 +/- 8.3 years) and >=90 years (n = 26; average age 91.6 +/- 1.9 years). A comparison of the baseline characteristics revealed that among patients aged >=90 years, the prevalence of women (50% vs 81%, p <0.001) and the mean aortic valve gradient (45.5 +/- 15.4 vs 56.3 +/- 23.4 mm Hg, p = 0.005) were greater than those in patients aged <90 years. Major vascular complications occurred more frequently in patients >=90 years (5% vs 19%, p = 0.022), although the rate of procedural success and 30-day and 6-month mortality were not different between the 2 age groups (96% vs 100%, p = 0.58; 6% vs 15%, p = 0.22; and 14% vs 27%, p = 0.14, respectively). The mortality rates were greater among patients aged >=90 years. At 6 months, both groups of survivors were similar in symptom status, with a New York Heart Association classification less than class II (89% vs 84%, p = 0.68). The cumulative survival (median 13.4 +/- 8.0 months of follow-up) was not significantly different between the 2 age groups (p = 0.22, log-rank test). In conclusion, even very elderly nonagenarians can experience acceptable clinical results and benefits after TAVI. PMID- 23021602 TI - Mechanisms that influence accuracy of the soccer kick. AB - Goal scoring represents the ultimate purpose of soccer and this is achieved when players perform accurate kicks. The purpose of the present study was to compare accurate and inaccurate soccer kicks aiming to top and bottom targets. Twenty-one soccer players performed consecutive kicks against top and bottom targets (0.5m(2)) placed in the center of the goal. The kicking trials were categorized as accurate or inaccurate. The activation of tibialis anterior (TA), rectus femoris (RF), biceps femoris (BF) and gastrocnemius muscle (GAS) of the swinging leg and the ground reaction forces (GRFs) of the support leg were analyzed. The GRFs did not differ between kicking conditions (P > 0.05). There was significantly higher TA and BF and lower GAS EMG activity during accurate kicks to the top target (P < 0.05) compared with inaccurate kicks. Furthermore, there was a significantly lower TA and RF activation during accurate kicks against the bottom target (P < 0.05) compared with inaccurate kicks. Enhancing muscle activation of the TA and BF and reducing GAS activation may assist players to kick accurately against top targets. In contrast, players who display higher TA and RF activation may be less accurate against a bottom target. It was concluded that muscle activation of the kicking leg represents a significant mechanism which largely contributes to soccer kick accuracy. PMID- 23021604 TI - Effect of a personal weight transfer device on muscle activities and joint flexions in the stooped posture. AB - Repetitive work in the stooped posture is a known risk factor for developing low back disorders (LBDs); regardless, the stooped posture is widespread throughout the world in the agriculture, construction, and mining industries. An on-body weight transfer device was tested as a possible intervention for reducing the risk of developing LBDs. Eighteen subjects (11 male and 7 female), with no history of LBDs, performed stooped posture tasks in the laboratory. Surface electromyograms of the erector spinae, rectus abdominis, biceps femoris, and tibialis anterior muscles were recorded. Bodily joint flexions were measured with a combination of inclinometers and electrogoniometers. When wearing the device in the stooped posture, biceps femoris activity and lumbar flexion were significantly reduced. Subjects who did not experience flexion-relaxation had a significant reduction in lumbar erector spinae activity. By reducing back muscle activity, and by limiting lumbar flexion, the device could reduce the risk of developing LBDs for those who work while adopting the stooped posture. The device may also be beneficial for those with existing LBDs. Follow up field studies are needed to confirm the long-term potential benefits of such an intervention approach. PMID- 23021603 TI - Neuromuscular responses to different resistance loading protocols using pneumatic and weight stack devices. AB - The purpose of this study was to examine single repetition characteristics and acute neuromuscular responses to typical hypertrophic (HL), maximal strength (MSL), and power (PL) loadings performed with two of the most common resistance modes; pneumatic and weight stack. Acute responses were assessed by measuring maximal voluntary contraction (MVC), corresponding quadriceps-EMG and resting and superimposed twitch torques. Activation level was calculated from the twitch torques. Decreases in MVC were greater during HL and MSL than during PL. During HL, resting twitch force decreased 8% (P < 0.05) more on the weight stack than on the pneumatic device. Furthermore, loading using the weight stack caused reduced resting twitch force, activation level, and EMG-amplitude after MSL and PL (P < 0.05-0.01). PL on the pneumatic device decreased MVC and rapid force production, while the respective PL on the weight stack device was specific to decreased rapid force production only. However, mean angular velocities and power of the repetitions were higher on the pneumatic device when using light loads. The present study showed that, at least in untrained subjects, the weight stack device induced greater levels of peripheral fatigue during HL. It also led to large central fatigue during MSL and PL. On the other hand, on the pneumatic device contraction velocity with low loads was higher compared to the weight stack device. Therefore, it is recommended that the resistance mode should be chosen according to the specific training goal. PMID- 23021605 TI - Subject-specific, whole-body models of the stooped posture with a personal weight transfer device. AB - A prior laboratory study found that when wearing a weight transfer device in the stooped posture, trunk flexions were reduced, and subjects who did not experience flexion-relaxation of the erector spinae had reduced back muscle activity. Whole body musculoskeletal models, which included individual passive torso stiffness and anthropometry, were implemented to predict loads in the passive tissues of the back and the leg joints. Results predicted that when wearing the device in the stooped posture, compression and shear forces at the L5-S1 level were reduced by 13% and 12% respectively. Internal loads in the leg joints were reduced between 10% and 31%. Much of the reduction in joint loads may be a result of the device's ability to limit torso flexion during stoop, rather than a transferring of load. While these results show possible benefit in the short-term, further study is needed on the long-term effects to determine if the device is an effective intervention for those who use the stooped posture routinely. PMID- 23021606 TI - Outcome models in clinical studies: implications for designing and evaluating trials in clinical nutrition. AB - BACKGROUND & AIMS: The selection of appropriate outcome variables in clinical nutrition is particularly challenging, since nutrition is an adjunct therapy in most cases. Therefore, its effect may be confounded with the primary therapy, and classic biomedical outcomes may not reflect the effect of the nutritional intervention. This paper scrutinizes different alternatives to the biomedical perspective. RESULTS: Five different outcome models are proposed and analyzed for their suitability in clinical nutrition studies: biomedical, patient-centered/ reported, health economic, decision-making, and integration of classical and patient-reported endpoints. Most published studies in the field of clinical nutrition make use of biomedical endpoints, but the growing importance of patient centered/-reported and health economic outcomes is recognized. We recommend avoiding to focus solely on biomedical endpoints in clinical nutrition studies. The availability and value of a broader set of outcome-models should be acknowledged. CONCLUSION: Patient-centered/-reported, health economic or combined endpoints are particularly useful to assess the effect of nutritional therapies, especially when applied in conjunction with a primary therapy. The proposed outcome models can also contribute to refine clinical nutrition guidelines in assessing the clinical relevance of the study results. PMID- 23021607 TI - Improved prediction of rat cortical bone mechanical behavior using composite beam theory to integrate tissue level properties. AB - Tissue level characteristics of bone can be measured by nanoindentation and microspectroscopy, but are challenging to translate to whole bone mechanical behavior in this hierarchically structured material. The current study calculated weighted section moduli from microCT attenuation values based on tissue level relationships (Z(lin,a) and Z(lin,b)) between mineralization and material properties to predict whole bone mechanical behavior. Z(lin,a) was determined using the equation of the best fit linear regression between indentation modulus from nanoindentation and mineral:matrix ratio from Raman spectroscopy. To better represent the modulus of unmineralized tissue, a second linear regression with the intercept fixed at 0 was used to calculate Z(lin,b). The predictive capability of the weighted section moduli calculated using a tissue level relationship was compared with average tissue level properties and weighted section moduli calculated using an apparent level relationship (Z(exp)) between Young's Modulus and mineralization. A range of bone mineralization was created using vitamin D deficiency in growing rats. After 10 weeks, left femurs were scanned using microCT and tested to failure in 3 point bending. Contralateral limbs were used for co-localized tissue level mechanical properties by nanoindentation and compositional measurements by Raman microspectroscopy. Vitamin D deficiency reduced whole bone stiffness and strength by ~35% and ~30%, respectively, but only reduced tissue mineral density by ~10% compared with Controls. Average tissue level properties did not correlate with whole bone mechanical behavior while Z(lin,a), Z(lin,b), and Z(exp) predicted 54%, 66%, and 80% of the failure moment respectively. This study demonstrated that in a model for varying mineralization, the composite beam model in this paper is an improved method to extrapolate tissue level data to macro-scale mechanical behavior. PMID- 23021608 TI - On the role of modeling choices in estimation of cerebral aneurysm wall tension. AB - OBJECTIVE: To assess various approaches to estimating pressure-induced wall tension in intracranial aneurysms (IA) and their effect on the stratification of subjects in a study population. METHODS: Three-dimensional models of 26 IAs (9 ruptured and 17 unruptured) were segmented from Computed Tomography Angiography (CTA) images. Wall tension distributions in these patient-specific geometric models were estimated based on various approaches such as differences in morphological detail utilized or modeling choices made. For all subjects in the study population, the peak wall tension was estimated using all investigated approaches and were compared to a reference approach-nonlinear finite element (FE) analysis using the Fung anisotropic model with regionally varying material fiber directions. Comparisons between approaches were focused toward assessing the similarity in stratification of IAs within the population based on peak wall tension. RESULTS: The stratification of IAs tension deviated to some extent from the reference approach as less geometric detail was incorporated. Interestingly, the size of the cerebral aneurysm as captured by a single size measure was the predominant determinant of peak wall tension-based stratification. Within FE approaches, simplifications to isotropy, material linearity and geometric linearity caused a gradual deviation from the reference estimates, but it was minimal and resulted in little to no impact on stratifications of IAs. CONCLUSION: Differences in modeling choices made without patient-specificity in parameters of such models had little impact on tension-based IA stratification in this population. Increasing morphological detail did impact the estimated peak wall tension, but size was the predominant determinant. PMID- 23021609 TI - Gait strategy changes with acceleration to accommodate the biomechanical constraint on push-off propulsion. AB - To maintain steady and level walking, push-off propulsion during the double support phase compensates for the energy loss through heel strike collisions in an energetically optimal manner. However, a large portion of daily gait activities also contains transient gait responses, such as acceleration or deceleration, during which the observed dominance of the push-off work or the energy optimality may not hold. In this study, we examined whether the push-off propulsion during the double support phase served as a major energy source for gait acceleration, and we also studied the energetic optimality of accelerated gait using a simple bipedal walking model. Seven healthy young subjects participated in the over-ground walking experiments. The subjects walked at four different constant gait speeds ranging from a self-selected speed to a maximum gait speed, and then they accelerated their gait from zero to the maximum gait speed using a self-selected acceleration ratio. We measured the ground reaction force (GRF) of three consecutive steps and the corresponding leg configuration using force platforms and an optical marker system, respectively, and we compared the mechanical work performed by the GRF during each single and double support phase. In contrast to the model prediction of an increase in the push-off propulsion that is proportional to the acceleration and minimizes the mechanical energy cost, the push-off propulsion was slightly increased, and a significant increase in the mechanical work during the single support phase was observed. The results suggest that gait acceleration occurs while accommodating a feasible push off propulsion constraint. PMID- 23021611 TI - Automatic prediction of tongue muscle activations using a finite element model. AB - Computational modeling has improved our understanding of how muscle forces are coordinated to generate movement in musculoskeletal systems. Muscular-hydrostat systems, such as the human tongue, involve very different biomechanics than musculoskeletal systems, and modeling efforts to date have been limited by the high computational complexity of representing continuum-mechanics. In this study, we developed a computationally efficient tracking-based algorithm for prediction of muscle activations during dynamic 3D finite element simulations. The formulation uses a local quadratic-programming problem at each simulation time step to find a set of muscle activations that generated target deformations and movements in finite element muscular-hydrostat models. We applied the technique to a 3D finite element tongue model for protrusive and bending movements. Predicted muscle activations were consistent with experimental recordings of tongue strain and electromyography. Upward tongue bending was achieved by recruitment of the superior longitudinal sheath muscle, which is consistent with muscular-hydrostat theory. Lateral tongue bending, however, required recruitment of contralateral transverse and vertical muscles in addition to the ipsilateral margins of the superior longitudinal muscle, which is a new proposition for tongue muscle coordination. Our simulation framework provides a new computational tool for systematic analysis of muscle forces in continuum-mechanics models that is complementary to experimental data and shows promise for eliciting a deeper understanding of human tongue function. PMID- 23021610 TI - Accuracy of a contour-based biplane fluoroscopy technique for tracking knee joint kinematics of different speeds. AB - While measuring knee motion in all six degrees of freedom is important for understanding and treating orthopaedic knee pathologies, traditional motion capture techniques lack the required accuracy. A variety of model-based biplane fluoroscopy techniques have been developed with sub-millimeter accuracy. However, no studies have statistically evaluated the consistency of the accuracy across motions of varying intensity or between degrees of freedom. Therefore, this study evaluated the bias and precision of a contour-based tracking technique by comparing it to a marker-based method (gold standard) during three movements with increasing intensity. Six cadaveric knees with implanted tantalum markers were used to simulate knee extension, walking and drop landings, while motion was recorded by a custom biplane fluoroscopy system. The 3D geometries of the bones were reconstructed from CT scans and anatomical coordinate systems were assigned. The position and orientation of the bone and marker models were determined for an average of 27 frames for each trial and knee joint kinematics were compared. The average bias and precision was 0.01 +/- 0.65 degrees for rotations and 0.01 +/- 0.59 mm for joint translations. Rotational precision was affected by motion (p=0.04) and depended on the axis of rotation (p=0.02). However, the difference in average precision among motions or axes was small (<= 0.13 degrees ) and not likely of consequence for kinematic measurements. No other differences were found. The contour-based technique demonstrated sub-millimeter and sub-degree accuracy, indicating it is a highly accurate tool for measuring complex three dimensional knee movements of any intensity. PMID- 23021612 TI - River water contaminated with perfluorinated compounds potentially posing the greatest risk to young children. AB - Although, humans are exposed to perflourinated compounds (PFCs) from various media, water consumption could be an important source for the residents living near to contaminated areas. Since comprehensive multimedia exposure model has not been developed for PFCs, assessment of the potential risk due to exposure to PFCs through direct water consumption could be a conservative estimate. The human health risks derived from the exposure to PFCs through water consumption were assessed for different age groups of general population in Taiwan using probabilistic approach. Based on available data on concentrations of PFCs in river water, exposure to PFOS, PFOA and PFDA via water consumption for different age groups were calculated using deterministic and probabilistic risk assessment methods. The oral non-cancer risks from PFOS, PFOA and their combination, expressed as a Hazard Index (HI), was determined by comparing oral exposure dose (through water intake) with the oral Reference Dose (RfD). The average exposure to PFOS, PFOA and PFDA via water consumption for adults ranged from 0.16 to 220.15, 0.43 to 12.5 and 0.43 to 2.36 ng kg-bw(-1) d(-1) and for children 0.13 354.3, 0.35-20.17 and 0.35-3.79 ng kg-bw(-1) d(-1), respectively. Probabilistic values of total HIs for all age groups reside near to Keya River exceed the RfD 2.4-4.8 times, corresponding mainly to PFOS with a percentage of 97%. In conclusions, children aged 1-3 years old and the residents reside near to Keya River are at the highest risk of exposure to PFCs via water consumption. PMID- 23021613 TI - Zero valent iron reduces toxicity and concentrations of organophosphate pesticides in contaminated groundwater. AB - The potential of zero valent iron (ZVI) for remediation of contaminated groundwater from an abandoned chemical disposal site was examined through batch and column experiments. The key contaminants were organophosphate pesticides but the chemical analysis also comprised additional 22 compounds including synthesis intermediates and degradation products of organophosphates. The ZVI treatment showed that all the contaminants were degraded with the exception of two diesters (phosphorothioates). The most rapid reduction was found for methyl parathion, ethyl parathion and malathion, which had first-order degradation rate constants on the order of 10(-3) min(-1). In the study, acute toxicity towards freshwater crustaceans (Daphnia magna) was included to evaluate the overall efficiency of ZVI treatment of the complex mixture. The acute toxicity tests with D. magna showed that the untreated groundwater was highly toxic. Thus, 50% of the daphnids were unable to swim upon 24h exposure to groundwater diluted 770 times. ZVI facilitated degradation resulted in a complete toxicity removal for the first four pore volumes, where after a three times dilution caused 50% inhibition of the mobility of the daphnids. The rapid degradation of the highly toxic organophosphates combined with the significant decrease in the ecotoxicological potential shows a promising potential for site remediation of organophosphates with ZVI technologies. PMID- 23021614 TI - Chemical characterization of organic microcontaminant sources and biological effects in riverine sediments impacted by urban sewage and pulp mill discharges. AB - The Biobio River basin is highly impacted by a variety of anthropogenic activities such as pulp mills and urban wastewaters subjected to different treatment processes. This work assesses for the first time, the contamination source and biological effects (estrogenic and dioxin-like activities) in the river basin by the determination of 45 organic microcontaminants in seven sediment samples. Pressurized solvent extraction combined with two-dimensional comprehensive gas chromatography coupled to time of flight mass spectrometry was employed for this purpose. The organic microcontaminants identified comprise monoterpenes, sesquiterpenes, diterpenes, ionones, lineal alkyl benzenes, polycyclic aromatic hydrocarbons, musk fragrances, sterols and phathalate esters. The presence of pine and eucalyptus pulp mill effluents increased the abundance of resin-derived neutral compounds and monoterpenes respectively. A principal component analysis showed that the Biobio River basin was impacted by domestic wastewater treatment plants (WWTPs), pine or eucalyptus Kraft pulp mills and pyrolytic and pyrogenic processes. Finally, the recombinant yeast assays showed that the presence of estrogenic and dioxin-like activity was mostly located in sediments impacted by domestic WWTP effluents. PMID- 23021616 TI - Human spastic Gracilis muscle isometric forces measured intraoperatively as a function of knee angle show no abnormal muscular mechanics. AB - BACKGROUND: To show whether mechanics of activated spastic muscle are representative of the functional deficiencies clearly apparent in the joints, our goal was to test the following hypotheses: (1) The muscle's joint range of force exertion is narrow, and (2) high muscle forces are available at low muscle length. METHODS: During remedial surgery, we measured the forces of the Gracilis muscle of spastic cerebral palsy patients (n=7, 10 limbs tested) as a function of knee joint angle from flexion (120 degrees ) to full extension (0 degrees ). FINDINGS: The spastic Gracilis exerted non-zero forces for the entire knee angles studied. For four limbs, the peak force was exerted at the highest length. For the remainder limbs, the closest knee angle of peak force exertion to 120 degrees was 66 degrees . Maximally 79.1%, and for most limbs only a much lower percentage (minimally 22.4%) of peak Gracilis force (mean 41.59N (SD 41.76N)) was available at 120 degrees knee flexion. Moreover, a clinical metric was obtained showing that the occurrence of a contracture was not correlated significantly with key determinants of knee angle-Gracilis force characteristics. INTERPRETATION: Our hypotheses are rejected: the spastic Gracilis has no narrow operational joint range of force exertion and no supreme active resistance capacity to stretch at low length. We conclude that if activated alone, spastic muscle shows no abnormal mechanics representative of joint movement disorder. Simultaneous stimulation of other muscles as in daily activities may change this situation. PMID- 23021617 TI - Editor's perspectives--ASiT abstracts. PMID- 23021615 TI - Post-traumatic stress symptoms correlate with smaller subgenual cingulate, caudate, and insula volumes in unmedicated combat veterans. AB - Prior studies have examined differences in brain volume between patients with post-traumatic stress disorder (PTSD) and control subjects. Convergent findings include smaller hippocampus and medial prefrontal cortex volumes in PTSD. However, post-traumatic stress symptoms (PTSS) exist on a spectrum, and neural changes may occur beyond the diagnostic threshold of PTSD. We examined the relationship between PTSS and gray matter among combat-exposed U.S. military veterans. Structural brain magnetic resonance imaging (MRI) was obtained on 28 combat veterans from Operations Enduring and Iraqi Freedom. PTSS were assessed using the Clinician-Administered PTSD Scale (CAPS). Thirteen subjects met criteria for PTSD. Subjects were unmedicated, and free of major comorbid psychiatric disorders. Images were analyzed using voxel-based morphometry, and regressed against the total CAPS score and trauma load. Images were subsequently analyzed by diagnosis of PTSD vs. non-PTSD. CAPS scores were inversely correlated with volumes of the subgenual cingulate (sgACC), caudate, hypothalamus, insula, and left middle temporal gyrus (MTG). Group contrast revealed smaller sgACC, caudate, hypothalamus, left insula, left MTG, and right MFG in the PTSD group. PTSS are associated with abnormalities in limbic structures that may underlie the pathophysiology of PTSD. These abnormalities exist on a continuum with PTSS, beyond a diagnosis of PTSD. PMID- 23021618 TI - [About safety parameters for patient-controlled analgesia (PCA) devices]. AB - During the course of preparation of an opioid prescription, the nurse in charge became aware that the patient-controlled analgesia (PCA) syringe driver did not permit programming for the delivery as required: a maximum bolus number (Bmax) was indicated but only a maximum cumulative dose (Dcmax) could be programmed. The prescription dose criteria were consistent with the guidelines of the French societies of palliative care, anesthesiology, and reanimation (Societe francaise d'accompagnement et de soins palliatifs [Sfap] and Societe francaise d'anesthesie reanimation [Sfar]). A Dcmax dose simulation was programmed and used in order to test this problem. This highlighted the following four defects: bolus delivery is not controlled, leading to potential overdose. When Dcmax is reached, the continuous flow stops, triggering an end dose failure and a new programming step is needed to restart infusion, increasing the risk of programming errors. Human intervention is required to stop the alarm, identify and solve the problem. Finally, Dcmax leads to random dose delivery in place of the predictability of dose delivery expected for opioid administration. On the other hand, Bmax is a limited dose, administered only as a bolus and regulated by the lockout interval. When the Bmax dose is reached, no alarm is triggered, the basal flow continues, but no additional doses can be delivered. Bmax and Dcmax systems are not interchangeable. No comparative study between Bmax and Dcmax could be found, and Sfap and Sfar guidelines are not precise and did not take into consideration the safety aspects of dose delivery however some facts tend to prefer that Bmax. Most of the syringe driver devices are configured for the Dcmax, but not all of them, and the physician is often forced to use the parameter of the available device restricting the choice between Bmax and Dcmax. This is not justified, whether by scientific evidence, industrial, manufacturing or commercial standards. It becomes only a technical option that does not promote standardization of dose delivery and compromises the main safety feature of PCA. PMID- 23021619 TI - [Late rupture of a mycotic aneurysm occurring after an appropriate antibiotic therapy of Streptococcus mitis mitral endocarditis]. PMID- 23021620 TI - Prevalence and incrimination of Anopheles fluviatilis species S (Diptera: Culicidae) in a malaria endemic forest area of Chhattisgarh state, central India. AB - BACKGROUND: Chhattisgarh state in central India is highly endemic for malaria and contributes about 13% of annually reported malaria cases in the country with predominance of P. falciparum. Entomological investigations were carried out in a tribal forested area of district Bastar located in the southern part of Chhattisgarh state to record the prevalence of sibling species of Anopheles fluviatilis and An. culicifacies complexes. The vector species complexes were investigated at sibling species level for their biology in terms of resting and feeding behavior and malaria transmission potential. METHODS: Indoor resting vector mosquitoes collected during 2010-2011 were identified to sibling species by cytotaxonomy and polymerase chain reaction (PCR) assay. The blood meal source analysis and incrimination studies were done at sibling species level by counter current immunoelectrophoresis and enzyme linked immunosorbent assay (ELISA) respectively. RESULTS: Analysis of sibling species composition revealed predominance of An. fluviatilis species S in the study area, which was found to be highly anthropophagic and rested in human dwellings whereas the sympatric species T was primarily zoophagic. Incrimination studies showed high sporozoite rate in species S, thereby confirming its vectorial efficiency. An. culicifacies was encountered in low numbers and comprised species B and C in almost equal proportion. Both these species were found to be exclusively zoophagic. CONCLUSION: The observations made strongly suggest that species S of Fluviatilis Complex is the principal vector of malaria in certain forest areas of district Bastar, Chhattisgarh state and should be the target species for vector control operation. Vector control strategies based on biological characteristics of Fluviatilis S will lead to substantial decline in malaria incidence in such areas. PMID- 23021621 TI - White matter imaging changes in subjective and mild cognitive impairment. AB - BACKGROUND: To determine whether white matter (WM) memory network changes accompany early cognitive impairment and whether these changes represent early, pathologically independent axonal affection, we combined WM diffusion tensor imaging and cortical morphometric measurements of normal control subjects, patients with only subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). METHODS: We included 66 patients with SCI or MCI and 21 control subjects from a university-hospital-based memory clinic in a cross-sectional study. Morphometric analysis was performed in FreeSurfer, and Tract-Based Spatial Statistics was used for analysis of diffusion tensor imaging-derived WM fractional anisotropy, radial diffusivity (DR), and mean diffusivity (MD). Relationships between WM measures and stage were assessed with whole-brain voxelwise statistics and on a region-of-interest basis, with subsequent correction for cortical atrophy. RESULTS: In SCI patients, as compared with control subjects, there were widespread changes in DR and MD. No significant differences in thickness could be demonstrated. In MCI patients, as compared with control subjects, there were widespread changes in DR, MD, and fractional anisotropy; the precuneal and inferior parietal cortices were thinner; and the hippocampus was smaller. Multiple logistic regression analysis eliminated morphometry as an explanatory variable in favor of DR/MD for all regions of interest, except in the precuneus, where both thickness and DR/MD were significant explanatory variables. CONCLUSIONS: WM tract degeneration is prominent in SCI and MCI patients, and is at least in part independent of overlying gray matter atrophy. PMID- 23021622 TI - Ischemic axonopathy: the missing link between cardiocerebral hypotension, white matter loss, and Alzheimer's disease. PMID- 23021623 TI - Vascular diseases: one pathway toward new conceptual models of dementia. PMID- 23021624 TI - Cerebral white matter disease is associated with Alzheimer pathology in a prospective cohort. AB - BACKGROUND: Although magnetic resonance imaging (MRI)-detected white matter disease has been correlated with cognitive decline in the elderly individuals, it is unclear whether white matter disease is primarily responsible for the cognitive deterioration or whether another process is common to both white matter disease and dementia. METHODS: We examined the relationship between Alzheimer type brain pathology at autopsy and MRI-detected cerebral white matter disease in 50 participants from the Baltimore Longitudinal Study of Aging Autopsy Program, a prospective study of aging that includes detailed cognitive assessments. RESULTS: White matter disease was quantitated in pre- and postmortem MRI scans using the Cardiovascular Health Study (CHS) criteria in a blinded manner. We found that several measures of Alzheimer's disease (AD) pathology, including the Consortium to Establish a Registry for Alzheimer's Disease score, Braak score, and a composite AD pathology score, along with hypertension, were significantly associated with CHS white matter score using univariate and multivariate ordinal regression. In contrast, amyloid angiopathy was not independently associated with CHS score. Although a clinical diagnosis of dementia was associated with CHS score in univariate analysis, the association disappeared after accounting for AD pathology. CONCLUSION: AD pathology at autopsy is associated with MRI-detected cerebral white matter disease. This relationship may explain, in part, the association between cerebral white matter disease and cognitive decline in the elderly individuals. PMID- 23021625 TI - White matter atrophy in Alzheimer's disease variants. AB - BACKGROUND: In comparison with late-onset Alzheimer's disease (LOAD, onset, >65 years), early-age-of-onset Alzheimer's disease (EOAD, onset, <65 years) more often presents with language, visuospatial, and/or executive impairment, often occurring earlier than a progressive memory deficit. The logopenic variant of primary progressive aphasia (lv-PPA) and posterior cortical atrophy (PCA) have recently been described as possible atypical variants of EOAD. Lv-PPA is characterized by isolated language deficit, whereas PCA is characterized by predominant visuospatial deficits. Severe hemispheric gray matter (GM) atrophy associated with EOAD, lv-PPA, and PCA has been described, but regional patterns of white matter (WM) damage are still poorly understood. METHODS: Using structural magnetic resonance imaging and voxel-based morphometry, we investigated WM damage in patients with EOAD (n = 16), PCA (n = 13), lv-PPA (n = 10), and LOAD (n = 14) at presentation and 72 age-matched control subjects. RESULTS: In patients with EOAD, PCA, and lv-PPA, WM atrophy was centered on the lateral temporal and parietal regions, including the cingulum and posterior corpus callosum. Compared with control subjects, patients with lv-PPA showed more severe left parietal damage, and patients with PCA showed more severe occipital atrophy. Moreover, patients with EOAD had greater cingulum atrophy compared with those with LOAD. LOAD showed WM damage in the medial temporal regions and less extensive hemispheric involvement. CONCLUSION: Patterns of WM damage in EOAD, lv PPA, and PCA are consistent with the clinical syndromes and GM atrophy patterns. WM injury in AD atypical variants may contribute to symptoms and disease pathogenesis. PMID- 23021627 TI - Effects of chilling methods and hot-boning on quality parameters of M. longissimus lumborum from Bos indicus Nelore steer. AB - To study the effects of chilling methods and hot-boning on quality parameters of M. longissimus lumborum (LL) of Nelore steers, sixteen left-carcass sides were electrically stimulated and the LL muscles were hot-boned and chilled at -20 degrees C (HBVFC) or 0 degrees C (HBO). Eight control left-carcass sides were cold-boned (AT). All muscles were vacuum-packaged and aged at 0 degrees C for 14 d. Shear force and tenderness of the AT-treated muscles were not different from HBO-treated muscles. The shear force values of the HBVFC muscles were higher after 7 and 14 d post-mortem (pm) compared to those of the AT muscles, but there was no difference from the HBO muscles. Aging did not reduce the shear force values of the HBVFC muscles. The purge losses of the HBVFC muscles were higher than those of the HBO and AT muscles. The HBVFC muscles were less tender than the HBO and AT muscles at 14 d pm. PMID- 23021626 TI - Associations of intake of antioxidant vitamins and fatty acids with asthma in pre school children. AB - OBJECTIVE: Increasing childhood asthma rates may be due to changing dietary lifestyle. We investigated the association of dietary intake of antioxidant vitamins and fatty acids with asthma in Japanese pre-school children. DESIGN: Cross-sectional study. SETTING: School-based survey on lifestyle/diet and health status in children in Japan. SUBJECTS: Parents of 452 children aged 3-6 years completed a questionnaire on the children's and parents' lifestyle and demographics. Children were classified into asthma cases and non-asthma cases in accordance with the ATS-DLD(American Thoracic Society and Division of Lung Diseases of the National Heart, Lung, and Blood Institute) questionnaire. Children's diet was assessed using a 3 d dietary record completed by parents. Children's age, sex, BMI, history of food allergy, maternal age, parental history of allergy, maternal education,family size and second-hand smoking were included as covariates. Logistic regression models were used to examine the association between children's diet and asthma. RESULTS: Compared with children with the lowest intake tertile for vitamin C and vitamin E, those in the highest were significantly inversely associated with asthma; adjusted OR (95% CI) were 0?35 (0?14, 0?88) and 0?32 (0?12, 0?85),respectively. A statistically significant trend was also observed. Fruit intake showed an inverse but insignificant association with asthma. There were no associations of any type of fatty acids with asthma. CONCLUSIONS: These data suggest that children with high intakes of vitamins C and E may be associated with a reduced prevalence of asthma. PMID- 23021628 TI - The effects of high salt and low pH on the water-holding of meat. AB - The study investigated the water-holding (WH) in meat in the pH-NaCl (ionic strength) combinations that prevail in dry sausages during fermentation and drying. WH in raw beef homogenates, with 230% added water, was determined by centrifugation at pH values of 5.47-4.60, and ionic strengths (MU) 0.50-1.50. The minimum WH in relation to pH was at pH 4.8, but at higher pH values, the WH optimum was at 1.0-1.5 MU; at lower pH-values (<5.0) the optimum was more pronounced at 1.0 MU. The WH reducing effect by pH decrease was stronger than the effect of MU. At lower pH values, the relative effect of MU on WH was higher compared to that of pH than at higher pH values. The pH-salt combinations prevailing in fermented sausage in the beginning of the ripening produced a high WH, which decreased, first with pH decrease and then in the last period of ripening mainly due to the increase of ionic strength. PMID- 23021629 TI - [Management of monoarthritis in children]. AB - Joint swelling is common in childhood. The pattern of presentation, the duration and the location may reveal sometimes monoarthritis. A detailed clinical history, thorough clinical examination, and sometimes complementary tests are needed to reach the correct diagnosis. The single most important investigation in a child with acute monoarthritis is joint aspiration to rule out septic arthritis that may destroy the joint within few hours. Serum inflammatory markers, antinuclear antibody, tuberculosis testing, and imaging (in specific cases) play an important role in making the diagnosis. This article presents the clinical approach to the diagnosis of monoarthritis as well as the different causes of monoarthritis in children. PMID- 23021630 TI - Touch screen performance by individuals with and without motor control disabilities. AB - Touch technology is becoming more prevalent as functionality improves and cost decreases. Therefore, it is important that this technology is accessible to users with diverse abilities. The objective of this study was to investigate the effects of button and gap size on performance by individuals with varied motor abilities. Participants with (n = 38) and without (n = 15) a motor control disability completed a digit entry task. Button size ranged from 10 to 30 mm and gap size was either 1 or 3 mm. Results indicated that as button size increased, there was a decrease in misses, errors, and time to complete tasks. Performance for the non-disabled group plateaued at button size 20 mm, with minimal, if any gains observed with larger button sizes. In comparison, the disabled group's performance continued to improve as button size increased. Gap size did not affect user performance. These results may help to improve accessibility of touch technology. PMID- 23021631 TI - The effect of carrying a portable respiratory gas analysis system on energy expenditure during incremental running. AB - This study aimed to assess the effect of portable gas analysis system carriage on energy expenditure (EE) during incremental treadmill running. Eight males (Mean +/- SD) age 25.0 +/- 9.47 y, body mass 78.5 +/- 8.39 kg, completed an experimental trial (PT) during which they wore the system in a chest harness and a control trial (CT) when the system was externally supported. Each protocol consisted of 4 min stages at speeds of 0, 4, 7, 10, 12, 14 km h(-1). Increments continued until volitional exhaustion. The EE was greater (3.95 and 7.02% at 7 and 14 km h(-1) respectively) during PT (p < 0.05) but no significant differences were observed during standing, walking or VO(2max.) (4.10 +/- 0.53, and 4.28 +/- 0.75 l min(-1) for CT and PT respectively), HR or RPE. Portable gas analysis systems therefore only increase EE when running sub-maximally, but VO(2max) is unaffected, suggesting that using portable gas analysis systems in field-based situations is appropriate for maximal aerobic capacity measurement, but the effects of prolonged use on EE remains unclear. PMID- 23021632 TI - A laboratory validation study of comfort and limit temperatures of four sleeping bags defined according to EN 13537 (2002). AB - In this study, we validated comfort and limit temperatures of four sleeping bags with different levels of insulation defined according to EN 13537. Six male subjects and four female subjects underwent totally 20 two-hour exposures in four sleeping bags at four intended testing temperatures: 11.2, 3.8, 2.1 and -9.0 degrees C. The subjective perceptions and physiological responses of these subjects were reported and analyzed. It was found that the EN 13537 defined comfort temperature and limit temperature were underestimated for sleeping bags MA3, HAG and MAM. The predictions are so conservative that further revision may be required to meet the requirements of both manufacturers and consumers. In contrast, for the sleeping bag MA0 with a low level of insulation, the limit temperature defined by EN 13537 was slightly overestimated. In addition, two individual case studies (-28.0 and -32.0 degrees C) demonstrated that low toe temperatures were widely observed among the male and female subjects, although the mean skin temperatures were almost within the thermoneutrality range (32.0 34.0 degrees C). It seems that the IREQ model (ISO 11079) overestimated both the comfort and limit temperatures of the sleeping bags. Finally, traditional sleeping bags may be required to be re-designed to provide consumers both whole body comfort as well as local thermal comfort at feet/toes or users need to be made aware of the higher need for their insulation. PMID- 23021633 TI - Potential protective effect of taurine against dibromoacetonitrile-induced neurotoxicity in rats. AB - Dibromoacetonitrile (DBAN) is a disinfection by-product of water chlorination. Epidemiological studies indicate that it might present a potential hazard to human health. The present study aimed to investigate the possible neurotoxicity of DBAN in rats and possible protection by taurine. Based on initial dose response experiment, DBAN (60 mg/kg) was administrated orally for 7 days. DBAN administration significantly impaired behavior of rats. Further, DBAN produced significant decrease of monoamines, gamma-aminobutyric acid (GABA), glutamate contents, acetylcholinestrase (AChE) and aspartate aminotransferase (AST) activities, in rat brain. On the other hand, a significant increase in malondialdehyde (MDA), nitric oxide (NO) contents and lactic dehydrogenase (LDH) activity was observed. Co-administration of taurine (200mg/kg, i.p.) with DBAN mitigated most tested parameters. In conclusion, the present study indicates that DBAN has the propensity to cause significant oxidative damage in rat brain. However, taurine has a promising role in attenuating the obtained hazardous effects of DBAN. PMID- 23021634 TI - Comprehensive analysis of commercial willow bark extracts by new technology platform: combined use of metabolomics, high-performance liquid chromatography solid-phase extraction-nuclear magnetic resonance spectroscopy and high resolution radical scavenging assay. AB - Here, proof-of-concept of a new analytical platform used for the comprehensive analysis of a small set of commercial willow bark products is presented, and compared with a traditional standardization solely based on analysis of salicin and salicin derivatives. The platform combines principal component analysis (PCA) of two chemical fingerprints, i.e., HPLC and (1)H NMR data, and a pharmacological fingerprint, i.e., high-resolution 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonate) radical cation (ABTS(+)) reduction profile, with targeted identification of constituents of interest by hyphenated HPLC-solid-phase extraction-tube transfer NMR, i.e., HPLC-SPE-ttNMR. Score plots from PCA of HPLC and (1)H NMR fingerprints showed the same distinct grouping of preparations formulated as capsules of Salix alba bark and separation of S. alba cortex. Loading plots revealed this to be due to high amount of salicin in capsules and ampelopsin, taxifolin, 7-O-methyltaxifolin-3'-O-glucoside, and 7-O methyltaxifolin in S. alba cortex, respectively. PCA of high-resolution radical scavenging profiles revealed clear separation of preparations along principal component 1 due to the major radical scavengers (+)-catechin and ampelopsin. The new analytical platform allowed identification of 16 compounds in commercial willow bark extracts, and identification of ampelopsin, taxifolin, 7-O methyltaxifolin-3'-O-glucoside, and 7-O-methyltaxifolin in S. alba bark extract is reported for the first time. The detection of the novel compound, ethyl 1 hydroxy-6-oxocyclohex-2-enecarboxylate, is also described. PMID- 23021635 TI - Preparative enantioseparation of beta-blocker drugs by counter-current chromatography using dialkyl L-tartrate as chiral selector based on borate coordination complex. AB - Counter-current chromatography (CCC) was applied for preparative enantioseparation of three beta-blocker drugs, including propranolol, pindolol and alprenolol. The two-phase solvent system was composed of chloroform-0.05 mol L(-1) acetate buffer containing 0.10 mol L(-1) boric acid (1:1, v/v), in which 0.10 mol L(-1) di-n-hexyl L-tartrate was added in the organic phase as chiral selector. Influence factors in the enantioseparation of propranolol were investigated. The chromatographic retention mechanism based on borate coordination complex was proposed. 116 mg of racemic propranolol was completely enantioseparated using conventional high speed CCC in a single run, yielding 48 mg of (+)-propranolol with HPLC purity of 98.9% and 47 mg of (-)-propranolol with HPLC purity of 96.3%. Recovery for propranolol enantiomers from CCC fractions was in the range of 75-82%. pH-zone-refining CCC was also successfully applied in enantioseparation of propanolol and it was found that 356 mg of racemic propranolol could be completely enantioseparated. 145 mg of (+)-enantiomer with HPLC purity of 95.6% and 148 mg of (-)-enantiomer with HPLC purity of 98.2% were recovered from pH-zone-refining mode. Separation mechanism about chiral separation by pH-zone-refining CCC was discussed. PMID- 23021636 TI - Tumor vascular responses to antivascular and antiangiogenic strategies: looking for suitable models. AB - Antiangiogenic and vascular disrupting agents are in the current cancer therapeutic armamentarium. A better understanding of the intricate mechanisms ruling neovessel survival within tumors during or after treatment is needed. Refinement of imaging and a growing knowledge of molecular biology of tumor vascularization provide new insights. It is necessary to define suitable methods for monitoring tumor response and appropriate tools to analyze data. This review compares most commonly used preclinical models, considering their recent improvements, and describes promising new approaches such as microfluidics, real time electrical impedance based technique and noninvasive imaging techniques. The advantages and limitations of the in vitro, ex vivo and in vivo models are discussed. This review also provides a critical summary of emerging approaches using mathematical modeling. PMID- 23021637 TI - Predicting drive for muscularity behavioural engagement from body image attitudes and emotions. AB - We examined the potential moderating effects of appearance investment, body image disturbance, and situational body image dysphoria on the drive for muscularity attitude-behaviour relationship. Participants (339 British college men, M(AGE)=20.00 years, SD=2.59) completed drive for muscularity attitude and behaviour, appearance investment, body image disturbance, and situational body image dysphoria measures. Results indicated higher levels of appearance investment, body image disturbance, and situational body image dysphoria were associated with increases in the drive for muscularity attitude's relationship with physique-enhancing behavioural engagement. Results help extend recent research that has moved beyond identifying correlates to examining ways that groups of variables interact to predict drive for muscularity behavioural engagement and may contribute to theory development. PMID- 23021639 TI - Full length articles published in BJOMS during 2010-11--an analysis by sub specialty and study type. AB - Full length articles such as prospective and retrospective studies, case series, laboratory-based research and reviews form the majority of papers published in the British Journal of Oral and Maxillofacial Surgery (BJOMS). We were interested to evaluate the breakdown of these types of articles both by sub-specialty and the type of study as well as the proportion that are written by UK colleagues compared to overseas authors over a 2 year period (2010-11). A total of 191 full length articles across all sub-specialties of our discipline were published, with 107 papers (56%) coming from UK authors. There were proportionately more oncology papers arising from the UK than overseas (60 and 30% of total respectively) while the opposite was found for cleft/deformity studies (10% and 22%). There was only one laboratory-based study published from the UK compared with 27 papers from overseas. The number of quality papers being submitted to the Journal continues to increase, and the type of article being published between UK and overseas probably reflects different practices and case-loads amongst colleagues. The relatively few UK laboratory based studies published in BJOMS compared to overseas authors are most likely due to authors seeking the most prestigious journals possible for their work. PMID- 23021638 TI - Systematics and species-specific response to pH of Oxytricha acidotolerans sp. nov. and Urosomoida sp. (Ciliophora, Hypotricha) from acid mining lakes. AB - We investigated the morphology, phylogeny of the 18S rDNA, and pH response of Oxytricha acidotolerans sp. nov. and Urosomoida sp. (Ciliophora, Hypotricha) isolated from two chemically similar acid mining lakes (pH~2.6) located at Langau, Austria, and in Lusatia, Germany. Oxytricha acidotolerans sp. nov. from Langau has 18 frontal-ventral-transverse cirri but a very indistinct kinety 3 fragmentation so that the assignment to Oxytricha is uncertain. The somewhat smaller species from Lusatia has a highly variable cirral pattern and the dorsal kineties arranged in the Urosomoida pattern and is, therefore, preliminary designated as Urosomoida sp. The pH response was measured as ciliate growth rates in laboratory experiments at pH ranging from 2.5 to 7.0. Our hypothesis was that the shape of the pH reaction norm would not differ between these closely related (3% difference in their SSU rDNA) species. Results revealed a broad pH niche for O. acidotolerans, with growth rates peaking at moderately acidic conditions (pH 5.2). Cyst formation was positively and linearly related to pH. Urosomoida sp. was more sensitive to pH and did not survive at circumneutral pH. Accordingly, we reject our hypothesis that similar habitats would harbour ciliate species with virtually identical pH reaction norm. PMID- 23021640 TI - Neutrophil extracellular traps (NETs) and infection-related vascular dysfunction. AB - The innate immune system orchestrated by leukocytes primarily neutrophils, serves to remove dead and dying host cells and to provide protection against invasion by pathogens. Failure of this system results in the onset of sepsis leading to grave consequences for the host. Together with mechanical methods to physically isolate and remove the pathogen, neutrophils also release an important set of proinflammatory biological modulators that mediate recruitment of additional cells to a site of infection and amplify the innate protective response. Additionally, neutrophils release highly charged mixtures of DNA and nuclear proteins named neutrophil extracellular traps (NETs). These electrostatically charged adhesive networks trigger intrinsic coagulation, limit dispersion and entrap the pathogens. NETs also contain the neutrophil secretary granule-derived serine proteases, neutrophil elastase and cathepsin G, known to regulate the reactivity of both neutrophils and platelets. Since the characterization of NETs in 2004, new studies of their functional effect in vivo continue to expand upon unexpected extracellular roles for DNA, and in doing so renew attention to the haemostatic role of the leukocyte. This review will provide a basic description of NETs and examine current knowledge of this important system of defense, including recent work illustrating a role for NETs in activation of thrombosis. PMID- 23021641 TI - Does age of fracture affect the outcome of vertebroplasty? Results from data from a prospective multicenter FDA IDE study. AB - PURPOSE: To evaluate whether the age of a fracture is a variable that can identify patients for whom vertebroplasty would be most beneficial. MATERIALS AND METHODS: Data from 256 patients with painful osteoporotic vertebral compression fractures (VCFs) who underwent vertebroplasty were examined to assess the effect of fracture age on outcomes. Patients ranged in age from 34-76 years, and the age of fractures ranged from 6 weeks or less (n = 117) to more than 52 weeks (n = 3). Most patients had a fracture age of 12 weeks or less (n = 207), with only 17% having a fracture age greater than 12 weeks. The duration of back pain was used as a surrogate for fracture age and was confirmed by edema on magnetic resonance (MR) imaging, abnormal bone scans, and the presence of central pain over the spinous process The primary outcome was pain reduction as determined by the change in the visual analog scale (VAS) pain score from baseline and at 1, 3, 6, and 24 months after vertebroplasty. RESULTS: A fracture age of 12 weeks or less versus greater than 12 weeks did not affect outcomes, with patients in both groups achieving equivalent benefit after vertebroplasty. Patients with a fracture age of 6 weeks or less had a slightly improved benefit at 3 months after vertebroplasty compared with those having a fracture age of greater than 6 weeks, but the benefit beyond 3 months was the same. CONCLUSIONS: Results of the study showed that the age of a fracture does not independently affect the outcomes of vertebroplasty. PMID- 23021642 TI - A novel fibronectin-binding protein of Streptococcus suis serotype 2 contributes to epithelial cell invasion and in vivo dissemination. AB - Streptococcus suis serotype 2 (SS2) is an important pathogen with zoonotic potential. In this study, a novel in vivo induced protein Ssa, encoded by the functionally unknown gene SSU05_1311, was identified as a surface anchored fibronectin-binding protein. The recombinant Ssa as well as its truncated proteins harboring the N-terminal domain (residues 33-153) could bind to human fibronectin with high-affinity. Isogenic knockout of ssa in SS2 led to decrease of bacterial binding to immobilized fibronectin. SS2 Deltassa mutant showed reduced adherence and invasion of human pharyngeal epithelial (HEp-2) cells compared to the wild type strain. Heterologous surface display of Ssa fibronectin binding domain in Escherichia coli enhanced the bacterial attachment and entry to HEp-2 cells. Less SS2 Deltassa mutants than the wild type strain were recovered from the blood and brains of the Balb/c mice infected intranasally. But there was no significant difference between the wild type and the mutant on phagocytosis by macrophages (RAW264.7) and bacterial killing by murine PMNs under opsonizing condition. Our data suggest that Ssa is an important virulence factor for SS2 crossing the mucosal epithelia to disseminate in vivo. PMID- 23021643 TI - Retrospective genetic characterisation of Encephalomyocarditis viruses from African elephant and swine recovers two distinct lineages in South Africa. AB - Encephalomyocarditis virus (EMCV) outbreaks are rare in southern Africa. Only two have been reported to date from South Africa, both coinciding with rodent irruptions. The first outbreak manifested as acute myocarditis in pigs in 1979, whilst the second, occurring from 1993 to 1994, was linked to the deaths of 64 free-ranging adult African elephants (Loxodonta africana). The P1 genome region, inclusive of the flanking leader (L) and 2A genes, of three South African isolates, one from swine and two from elephants, was characterised by PCR amplification and sequencing of up to 11 overlapping fragments. In addition to the resulting 3329 nucleotide dataset, the 3D region that is widely used in molecular epidemiology studies, was characterised, and three datasets (P1, VP1/3 and 3D), complemented with available homologous EMCV data, were compiled for analyses. Phylogenetic inferences revealed the near-identical elephant outbreak strains to be most closely related to a mengovirus from rhesus macaques (Macaca mulatta) in Uganda, differing from the latter by between 11% (3D) and 15% (VP3/1). The South African pig isolate differed by 4% (3D) and 11% (VP3/1) from available European and Asian pig virus sequences. This study confirms the presence of two genetically distinct EMCV lineages recovered from sporadic outbreaks in wild and domestic hosts in southern Africa, and provides valuable baseline data for future outbreak eventualities in the sub-region. PMID- 23021645 TI - Oriented covalent immobilization of antibodies onto heterofunctional agarose supports: a highly efficient immuno-affinity chromatography platform. AB - The development of new bioconjugates formed by one antibody optimally bound (through its Fc region) to fairly inert solid surfaces is of primary relevance in immuno-affinity chromatography. Immunoglobulins G (IgG) have a Fc region very rich in histidine (His) residues. In this way, immobilization of IgGs on heterofunctional metal chelate-glyoxyl supports (Ag-Me(2+)/G) takes place in two steps: firstly the antibodies are conjugated to the support via His-metal coordination bonds. Secondly, their incubation under alkaline condition promotes an intramolecular covalent attachment between lysine residues at the Fc region and glyoxyl groups on the support surface. The IgG that recognizes as antigen the HRP (antiHRP-IgG) has been conjugated to Ag-Me(2+)/G supports. The resulting bioconjugate is highly inert and able to specifically bind the antigen (HRP) without significant unspecific binding of any other proteins, resulting in an excellent HRP purification platform. The binding activity of this bioconjugate has been optimized by controlling the antibody distribution throughout the bead's surface in order to avoid high antibody densities that led to a low binding activity of the antibodies. The optimal antibody distribution has been achieved when these proteins were slowly immobilized on Ag-Cu(2+)/G in presence of imidazole. This bioconjugate was able to bind up to 1.5 moles of antigen per mole of antibody, only 1.3-fold less than the antibody in solution. Hence, we have been able to develop an optimal protocol to prepare bioconjugated composites in an oriented and irreversible fashion which results in highly efficient and specific surfaces for the exclusive biological recognition. PMID- 23021646 TI - Agarose film liquid phase microextraction combined with gas chromatography-mass spectrometry for the determination of polycyclic aromatic hydrocarbons in water. AB - Agarose film liquid phase microextraction (AF-LPME) procedure for the extraction and preconcentration of polycyclic aromatic hydrocarbons (PAHs) in water has been investigated. Agarose film was used for the first time as an interface between donor and acceptor phases in liquid phase microextraction which allowed for selective extraction of the analytes prior to gas chromatography-mass spectrometry. Using 1-octanol as acceptor phase, high enrichment factors in the range of 57-106 for the targeted analytes (fluorene, phenanthrene, fluoranthene and pyrene) were achieved. Under the optimum extraction conditions, the method showed good linearity in the range of 0.1-200 MUgL(-1), good correlation coefficients in the range of 0.9963-0.9999, acceptable reproducibility (RSD 6.1 9.2%, n=3), low limits of detection (0.01-0.04 MUgL(-1)) and satisfactory relative recoveries (92.9-104.7%). As the AF-LPME device was non-expensive, reuse or recycle of the film was not required, thus eliminating the possibility of analytes carry-over between runs. The AF-LPME technique is environment-friendly and compatible with the green chemistry concept as agarose is biodegradable polysaccharide extracted from seaweed and the procedure requires small volume of organic solvent and generates little waste. The validated method was successfully applied to the analysis of the four analytes in river water samples. PMID- 23021647 TI - Fast, extraction-free analysis of chlorinated phenols in well water by high performance liquid chromatography-tandem mass spectrometry. AB - A fast and sensitive analytical method was developed for the chlorinated phenols included in the Canadian Drinking Water Guidelines without the need for costly, time-consuming sample extraction and concentration. Sensitivity and specificity were achieved by derivatization with dansyl chloride and detection via liquid chromatography-tandem mass spectrometry. The dansyl-modified analytes displayed method detection limits in the range of 0.01-1.0 MUg/L, enabling the direct determination of chlorophenols from well water without sample enrichment. Recoveries (n=4 days) ranged from 91 to 101% and accuracies were between 79 and 116% (n=4). This method significantly increases sample throughput compared to the current EPA method for phenols in finished drinking water. PMID- 23021648 TI - Antimicrobial effects of ozonated water on the sanitization of dental instruments contaminated with E. coli, S. aureus, C. albicans, or the spores of B. atrophaeus. AB - OBJECTIVES: Ozone has been used as an alternative method for the decontamination of water, food, equipment and instruments. The objective of this study was to evaluate the antimicrobial effects of ozonated water on the sanitization of dental instruments that were contaminated by Escherichia coli, Staphylococcus aureus, Candida albicans and the spores of Bacillus atrophaeus. METHODS: A total of one hundred and twenty standardized samples of diamond dental burs were experimentally contaminated with E. coli (ATCC 25922), S. aureus (ATCC 6538) and C. albicans (ATCC 18804) and the spores of B. atrophaeus (ATCC 6633) for 30 min. After the contamination, the samples were exposed to ozonated water (10mg/L O(3)) for 10 or 30min. The control group was composed of samples that were exposed to distilled water for 30 min. After the exposure to the ozonated water, 0.1 mL aliquots were seeded onto BHI agar to count the colony-forming units per milliliter (CFU/mL) of E. coli, S. aureus, and B. atrophaeus. Sabouraud dextrose agar was used to count the CFU/mL of C. albicans. The results were subjected to an analysis of variance and the Tukey test. RESULTS: For all of the microorganisms studied, the ozonated water reduced the number of CFU/mL after 10 and 30 min of sanitization, and this microbial reduction was dependent on the duration of the exposure to the ozonated water. E. coli exhibited the greatest reduction in CFU/mL (2.72-3.78 log) followed by S. aureus (2.14-3.19 log), C. albicans (1.44-2.14 log) and the spores of B. atrophaeus (1.01-1.98 log). CONCLUSION: The ozonated water was effective in reducing the CFU of E. coli, S. aureus, C. albicans and B. atrophaeus spores, suggesting that ozonated water can be used for the sanitization of dental instruments. PMID- 23021649 TI - Household transmission of 2009 H1N1 influenza virus in Yazd, Iran. AB - OBJECTIVES: The 2009 pandemic influenza A (H1N1) virus is a public health challenge. Notably, laboratory-confirmed cases do not represent the age group most susceptible to infection. To characterize the age distribution of all cases of H1N1 influenza, we studied the personal contacts of confirmed cases to identify the age group at the highest risk. METHODS: We investigated the family members of 162 laboratory-confirmed cases of 2009 H1N1 in Yazd, Iran. Family members were retrospectively asked whether they had >=2 respiratory symptoms within 7days of the last contact with the associated index cases. The ages and symptoms of the patients as well as the interval between diagnosis and the onset of symptoms among household contacts were determined using a questionnaire. RESULTS: We identified 596 family members of index cases, 83 (13.9%) of whom developed acute respiratory illness. No acute respiratory illness was found in 104 families (64%); however, there were 2 cases in 15 families (9.3%) and >=3 cases in 4 families (24%). Household contacts from 5 to 18years old were more susceptible to acute respiratory illness than those who were >=51years old (RR=3.174, 95% CI 1.313-7.675 P-value=0.01). CONCLUSION: Individuals <=18years old were most susceptible to infection by the H1N1 virus. Therefore, in low income populations, prevention of the spread of H1N1 to this age group should be emphasized. PMID- 23021650 TI - Primary anti-tuberculous drugs resistance of pulmonary tuberculosis in Southwestern Saudi Arabia. AB - The emergence of drug-resistant tuberculosis (TB) is an increasing problem which adversely affects patient care and public health. This study aimed to determine the rates and patterns of primary anti-TB drugs resistance in Najran, Southwestern Saudi Arabia. The study included 80 smear-positive new pulmonary TB patients. Sputum samples were cultured on Lowenstein-Jensen and Middle-Brook 7H10 media. Mycobacterium tuberculosis susceptibility testing was done by the conventional agar proportion method for isoniazide (INH), rifampicin (RIF), streptomycin (SPM) and ethambutol (EMB). Out of the 68 M. tuberculosis isolates, 42 (61.8%) were sensitive to all 4 drugs and 26 (38.2%) were resistant to one or more drugs. The most common resistance was found to INH (33.8%), followed by RIF (23.5%), SPM (13.2%) and EMB (2.9%). Eight (11.8%) isolates were resistant to one drug, 14 (20.6%) were resistant to 2 drugs, 3 (4.4%) were resistant to 3 drugs and one (1.5%) was resistant to 4 drugs. Multi-drug resistant (MDR) isolates were found in 14 (20.6%) cases. In conclusion, the primary resistance rate to four first-line anti-tuberculous drugs and MDR-TB rate are worryingly high, representing an alarming situation in Najran. Further studies are necessary for continuous surveillance of M. tuberculosis resistance patterns. PMID- 23021651 TI - Did pandemic preparedness aid the response to pandemic (H1N1) 2009? A qualitative analysis in seven countries within the WHO European Region. AB - BACKGROUND: Although the 2009-2010 influenza A (H1N1) pandemic was of low severity compared with other pandemics of the 20th century, this pandemic was the first opportunity for countries to implement a real-life pandemic response. The aim of the project was to review the extent to which these plans and planning activities proved useful and to identify areas of pandemic planning that require further strengthening. METHODS: We randomly selected seven countries within the WHO European Region to participate in a comprehensive, qualitative study to evaluate the pandemic preparedness activities undertaken prior to March 2009 compared with the subsequent pandemic responses mounted from May 2009 onwards. Research teams visited each country and interviewed stakeholders from health and civil response ministries, national public health authorities, regional authorities and family and hospital doctors. RESULTS: The following six consistent themes were identified as essential elements of successful pandemic preparedness activities: communication, coordination, capacity building, adaptability/flexibility, leadership and mutual support. Regarding future pandemic preparedness activities, an emphasis on these areas should be retained and planning for the following activities should be improved: communication (i.e., with the public and health professionals); coordination of vaccine procurement and logistics; flexibility of response and hospital surveillance. CONCLUSIONS: Pandemic preparedness activities were successfully undertaken in the WHO European Region prior to the 2009 pandemic. These activities proved to be effective and were generally appropriate for the response provided in 2009. Nevertheless, consistent themes also emerged regarding specific areas of under planning that were common to most of the surveyed countries. PMID- 23021652 TI - Impact of infection control educational activities on rates and frequencies of percutaneous injuries (PIs) at a tertiary care hospital in Saudi Arabia. AB - OBJECTIVE: To study the impact of educational activities on the rates and frequencies of percutaneous injuries (PIs) at a tertiary care hospital in Saudi Arabia. METHODS: PI surveillance is a routine activity in King Abdulaziz Medical City (a 900-bed teaching tertiary health care hospital) in Riyadh using the Exposure Prevention Information Network (EPINet) data collection tool. From 2001 through 2003, educational activities were conducted for health care workers (HCWs) to prevent PIs. The education included lectures on the risk of unsafe practices that may lead to PIs and how to avoid them. Data from before (1997 2000) and after (2004-2008) the intervention were imported from our surveillance system and statistically analyzed. RESULTS: The total overall rate of PIs per 1000 HCWs was significantly lower in the post-intervention period than in the pre intervention period (14 vs. 32.8/1000 HCWs, respectively). The rates of PIs among nurses and housekeepers showed a significant decrease (15 vs. 37.6/1000 HCWs and 10 vs. 34.5/1000 HCWs, respectively). The frequency of PIs in the emergency department (ED) and intensive care units (ICUs) showed a significant decrease (3.4% for both vs. 12.4% and 13.7%, respectively). PIs associated with devices, such as needles on IV lines, IV catheters, lancets and suture needles, showed a significant decrease. PIs occurring during device disassembly and from inappropriately discarded devices also decreased significantly. CONCLUSION: The educational program reduced some categories of PIs, including the overall rate, the rate among nurses and housekeepers, the frequency in the ED and ICUs and the frequency among needles on IV lines, IV catheters, lancets and suture needles. Other PI categories did not change significantly. PMID- 23021653 TI - Acanthamoeba contamination of hemodialysis and dental units in Alexandria, Egypt: a neglected potential source of infection. AB - Ubiquitous free-living amoebae of the genus Acanthamoeba can be pathogenic and can serve as carriers of other pathogenic organisms. These amoebae are potentially dangerous when they contaminate health facilities, and these organisms may act as a source of infection for medical personnel and those seeking medical care. The purpose of the present study was to evaluate the extent to which Acanthamoeba species contaminate hemodialysis and dental units in Alexandria, Egypt. Seventy samples were collected aseptically from these systems and cultivated on non-nutrient agar at room temperature, followed by morphological confirmation of the identity of Acanthamoeba using trichrome stained smears. This study revealed that 42.9% of water samples from the hydraulic systems of both hemodialysis and dental units were positive for Acanthamoeba, with no statistically significant difference between the two unit types or between pre- and post-disinfection samples for each type of unit. The surgical category of dental clinics had the highest contamination rate (72.7%), whereas no contamination was observed for water samples from pediatric dentistry clinics. In conclusion, the hydraulic systems of hemodialysis and dental units in Alexandria are contaminated with Acanthamoeba species, and to minimize the risk of human infections, there is an urgent need to implement effective preventative measures, such as the installation of water filtration units. PMID- 23021654 TI - Methicillin-resistant Staphylococcus aureus transmission in a low-prevalence healthcare setting. AB - BACKGROUND: The aim of this study was to assess the nosocomial transmission of methicillin-resistant Staphylococcus aureus (MRSA) and the predictive role of colonization pressure (CP) in a low-prevalence healthcare setting. METHODS: A retrospective analysis of MRSA infection rates from 2004 to 2009 at the Saudi Aramco Dhahran Health Center, Saudi Arabia, was performed. MRSA patient-days, susceptible patient-days, nosocomial incidence and CP were calculated for each month from January 2008 to December 2009. RESULTS: During the study period, 878 cases of MRSA colonization/infection were identified. Of these cases, 777 (88.4%) and 101 (11.5%) were community-acquired MRSA (CA-MRSA) and healthcare-associated MRSA (HA-MRSA) cases, respectively. A decrease in the number of HA-MRSA cases and an increase in the number of CA-MRSA cases were observed during the study period. The incidence of nosocomial infection per 1000 susceptible patient-days was 1.17 in 2008 and 0.7 in 2009. The monthly colonization pressure ranged from 0.1 to 1.62 throughout the 2-year period. Nosocomial transmission was observed in 13 months of the 24-month study period. No association between the CP of the preceding month and the incidence of nosocomial transmission in the subsequent month was observed. CONCLUSION: In a setting of low MRSA prevalence, CP does not appear to be a useful predictor of nosocomial transmission or incidence. PMID- 23021655 TI - Plasmodium vivax malaria: is it actually benign? PMID- 23021656 TI - [Addiction to cocaine and other stimulants]. AB - Due to many available forms (powder, pasta base, freebase and crack...) and because of multiple routes of administration (intranasal, intravenous, or smoked), cocaine has become in 30 years one of the most consumed illegal drugs worldwide, after cannabis. While the frequency of consumption decreases in North America, it continues to rise in Europe, and in some countries in South America, including Brazil, despite a growing knowledge of its specific effects, physical complications and psychiatric consequences. Elsewhere (notably in Asia and Indian Ocean), amphetamine and other stimulants (including methamphetamine), whose properties and patterns of use are very similar to those of cocaine, tend to replace it. Another amphetamine derivative, MDMA or ecstasy, is also consumed by many young people of less than 25 years, in Europe and North America, in a festive setting, with specific consequences and special procedures of care. Although there is currently no consensus for a specific medication, the most appropriate therapeutic approach seems to involve a psychosocial treatment associated with an anticraving medication, which will reduce compulsive desire to consume, in order to facilitate the psychotherapeutic and social care. However, pharmacological research remains very active, and many options are explored (GABAergic or dopaminergic agonists, amphetamine derivatives with long half-life, vaccine...), whether to treat addiction to cocaine or to methamphetamine. PMID- 23021657 TI - [New recommendations for the diagnosis and the treatment of Helicobacter pylori infection]. AB - Management of Helicobacter pylori infection is evolving. New data concern the role of the bacterium in various clinical conditions, the indications of H. pylori testing, diagnosis procedures and eradication treatment regimens. H. pylori should be sought and eradicated before starting NSAIDs treatment, in aspirin users with a history of gastroduodenal ulcer, and in patients presenting with chronic dyspepsia, high risk factors of gastric cancer, unexplained iron deficiency anaemia, vitamin B12 deficiency, or immune (idiopathic) thrombocytopenic purpura. The Urea Breath Test remains the best test to diagnose H. pylori infection, whereas serology is the only test, which is not affected by local changes in the stomach. Molecular tests can be used to detect H. pylori and clarithromycin and/or fluoroquinolone resistance in gastric biopsies without necessitating culture. In regions of high clarithromycin resistance, such as France, sequential treatment or bismuth-containing quadruple therapies are replacing standard triple therapies for the first-line empirical treatment. PMID- 23021658 TI - [Herpes encephalo-polyneuropathy]. PMID- 23021659 TI - [Treatment of chronic hepatitis viral C: new associations]. AB - The current treatment of patients with chronic HCV infection since ten years is pegylated interferon combined with ribavirin. This association allows a virological eradication in 55% of patients, all genotype and 40% of those infected with genotype 1, the most prevalent. Two protease inhibitors (telaprevir and boceprevir) were approved in 2011, in combination with pegylated interferon and ribavirin in both naive and non-responder patients infected with HCV genotype 1. These new drugs allow obtaining a viral eradication in 70% of cases. Other direct acting antiviral drugs are also currently being tested and likely to radically change treatment strategies for patients with chronic hepatitis due to HCV. PMID- 23021660 TI - [Autonomic peripheral neuropathy]. AB - The mechanisms of dysautonomic disturbances are varied and mostly acquired. They can result from lesions of sympathetic or parasympathetic vegetative fibers located in the peripheral contingent, or in the somatic contingent by demyelination or axonal loss; or more rarely by cellular bodies in the sympathetic or parasympathetic ganglia. Several chronic peripheral neuropathies can be associated with dysautonomia. Only some causes need to be known because they can be clinically significant. Dysautonomia may be seen during chronic acquired neuropathies but also acute or subacute ones. The most frequent cause in the world is the dysautonomia of the diabetes; it affects all the systems; the cardiovascular dysfunction has an impact on the prognosis for survival when it is severe. Hereditary autonomic neuropathies are rare; they can declare themselves very early during the Riley-Day syndrome or very late during amyloid polyneuropathies due to transthyretin gene mutation. The diagnosis can be confirmed by molecular biology. The dysautonomia is frequent and often severe. These neuropathies justify symptomatic treatment to improve quality of life. For some of them, a specific treatment can be proposed to treat the causal affection to try to stop the progression of the disease. PMID- 23021661 TI - [Cryofibrinogenemia revealed by digital ischemia with stroke]. PMID- 23021662 TI - Effects of angiogenesis inhibition by spironolactone on isolated vas deferens contractility in an experimental varicocele model in rats. AB - OBJECTIVE: To investigate the effect of spironolactone, as an angiogenesis inhibitor, on the isometric contractile responses in isolated vas deferens strips from left varicocele-induced rats. METHODS: Twenty-four adult (12-14 months) male Wistar albino rats were randomly assigned to 4 groups (n = 6 in each): (1) Control group, (2) sham-operated group, (3) experimental left varicocele group, and (4) Spironolactone (20 mg/kg/d)-treated experimental left varicocele group. Histopathologic and immunohistochemical (CD31 staining) findings in the rat testis and functional findings in the rat isolated vas deferens were investigated. RESULTS: Angiogenesis increased in the varicocele group and the spironolactone inhibited angiogenesis in the spironolactone-treated group. Spironolactone seemed to change phenylephrine and serotonin responses in the left vas deferens. CONCLUSION: It is possible that by inhibiting angiogenesis, spironolactone treatment negatively impairs testicular morphology and functional (vas deferens) pathways. Varicocele formation seems to elicit an increase to 5-HT sensitivity in rat vas deferens, and this process is prevented by spironolactone pretreatment. PMID- 23021663 TI - Effect of smoking on sperm vitality, DNA integrity, seminal oxidative stress, zinc in fertile men. AB - OBJECTIVE: To assess the effect of smoking on sperm vitality, sperm DNA integrity, semen reactive oxygen species, and zinc levels in fertile men. METHODS: One-hundred sixty men were investigated. They were divided into 2 equal groups: healthy fertile nonsmokers and healthy fertile smokers. They were subjected to history taking, clinical examination, and semen analysis. In their semen, sperm hypo-osmotic swelling test, sperm DNA fragmentation test, seminal reactive oxygen species, and zinc were assessed. RESULTS: Compared with fertile nonsmokers, fertile smokers were significantly associated with lower hypo-osmotic swelling test and seminal zinc levels and significantly associated with higher sperm DNA fragmentation percent and seminal reactive oxygen species levels. CONCLUSION: Smoking (cigarettes/day and duration) has detrimental effects on sperm motility, viability, DNA fragmentation, seminal zinc levels, and semen reactive oxygen species levels, even in fertile men, and it is directly correlated with cigarette quantity and smoking duration. PMID- 23021664 TI - Robotic partial nephrectomy: imperative vs elective indications. AB - OBJECTIVE: To assess the impact of imperative or elective indications on the perioperative outcomes of patients undergoing robotic partial nephrectomy. MATERIALS AND METHODS: Between January 2008 and August 2011, 381 consecutive robotic partial nephrectomies were retrospectively included. Two groups of patients were identified: those who underwent the procedure for an imperative indication (n = 98) and those who underwent the procedure for an elective indication (n = 283). Perioperative and renal function outcomes were compared between the 2 groups. Multivariate analysis was performed to determine whether imperative indications were predictors of complications, chronic kidney disease stage upstaging, postoperative estimated glomerular filtration rate, and percentage of estimated glomerular filtration rate decrease. RESULTS: There were no differences between the 2 groups with respect to RENAL score and tumor size. Patients in the imperative group were more likely to have a higher Charlson Comorbidity Index score (6 vs 4, P < .001), higher chronic kidney disease stage (P < .001), and lower estimated glomerular filtration rate (61.9 vs 88.6 mL/min/1.73 m(2), P < .001). Perioperative outcomes were similar with respect to warm ischemia time, estimated blood loss, operative time, transfusion rate, positive surgical margin rate, and length of stay. Imperative indications were associated with higher major complication rate (7.22% vs 2.47%, P = .032), but not with overall (31.6% vs 26%, P = .62) and intraoperative complications (6.1% vs 3.2%, P = .22). In multivariate analysis, imperative indication was an independent predictor of postoperative estimated glomerular filtration rate but was not a predictor of percentage of estimated glomerular filtration rate decrease and chronic kidney disease upstaging. CONCLUSION: Patients undergoing robotic partial nephrectomy for an imperative indication have similar functional outcomes than those with an elective indication. However, they are at higher risk of major complications. PMID- 23021665 TI - Robotic partial nephrectomy for small renal masses in patients with pre-existing chronic kidney disease. AB - OBJECTIVE: To assess the outcomes of robotic partial nephrectomy in patients with pre-existing chronic kidney disease (CKD). MATERIALS AND METHODS: Patients who underwent robotic partial nephrectomy for renal tumors between 2007 and 2011 were identified from our prospectively maintained institutional database. Perioperative as well as short-term oncological and functional outcomes were assessed. A comparative analysis was performed between patients with pre-existing CKD (estimated glomerular filtration rate [eGFR] 15-60 mL/min, group 1, n = 52) and patients with eGFR >60 mL/min (group 2, n = 303). RESULTS: Group 1 patients were older (median 68 vs 57 years, P < .001), with higher American Society of Anesthesiology (ASA) score (3 vs 2, P < .001) and a higher Charlson comorbidity index (7 vs 4, P < .001). Warm ischemia time (WIT) was similar in both groups (18 vs 18 minutes, P = .52). Group 1 had a higher postoperative complication rate (40.4% vs 21.1%, P = .003). Pathologic and oncological data were similar. After a median follow-up of 3 months (interquartile: 1-10), deterioration of eGFR was lower in group 1 patients (-5% vs -12%, P = .004). No endstage renal disease was noted in either group. There was significantly less CKD upstaging in group 1 than in group 2 (11.5% vs 33.9%, P = .001). After multivariate analysis, preoperative eGFR and WIT were independent predictors of latest eGFR. Less than 15% of patients with normal baseline renal function developed CKD stage III or higher. CONCLUSION: Despite a high risk of surgical complications, robotic partial nephrectomy only marginally affects renal function in patients with pre-existing CKD. PMID- 23021666 TI - Psychosocial difficulties in children referred to pediatric urology: a closer look. AB - OBJECTIVE: To assess rates of psychosocial difficulties in children seen in a pediatric urology clinic to determine whether all patients should be screened for psychosocial problems, and to use standardized measures to determine whether the severity of voiding dysfunction and/or enuresis in children is related to their degree of psychosocial difficulties. METHODS: A retrospective chart review was conducted to collect the Pediatric Symptom Checklist from all children referred to an outpatient urology clinic over a 6-month period. In addition, scores from the child's Dysfunctional Voiding Scoring System were collected for patients referred for voiding dysfunction and/or enuresis. RESULTS: Caregivers of 600 children completed the Pediatric Symptom Checklist as part of their child's outpatient clinic paperwork. Overall, 15.2% of the patients met the clinical cut off for significant psychosocial difficulties. However, children with voiding dysfunction and/or enuresis were at increased risk for these problems, with the severity of their psychosocial difficulties being related to the severity of their urologic condition. CONCLUSION: It is unnecessary to screen all pediatric urology patients, although those referred for voiding dysfunction and/or enuresis should be screened for psychosocial difficulties. Children at greatest risk for psychosocial problems were those who were male, had a high body mass index, had nocturnal enuresis, had an elevated Dysfunctional Voiding Scoring System score, and/or reported frequent episodes of wetting or soaking their underwear when they wet. Importantly, children appear to be most concerned with "wetness." PMID- 23021667 TI - Editorial comment. PMID- 23021669 TI - Re: Zekey et al.: evaluation of the impact of shock wave lithotripsy on kidneys using a new marker: how do neutrophil gelatinase-associated lypocalin values changes after shock wave lithotripsy? (Urology 2012;80:267-272). PMID- 23021670 TI - Re: Bozkurt et al.: relationship between mean platelet volume and varicocele: a preliminary study (urology 2012;79:1048-1051). PMID- 23021672 TI - Re: Penbegul et al.: safety and efficacy of ultrasound-guided percutaneous nephrolithotomy of urinary stone disease in children (urology 2012;79:1015-1019). PMID- 23021673 TI - Re: Hepner et al.: suicidal ideation among patients with bladder pain syndrome/interstitial cystitis. (Urology 2012;80:280-285). PMID- 23021674 TI - Re: El-Nahas et al.: factors affecting stone-free rate and complications of percutaneous nephrolithotomy for treatment of staghorn stone (urology 2012;79:1236-1241). PMID- 23021677 TI - Re: Welk et al.: the augmented nontransected anastomotic urethroplasty for the treatment of bulbar urethral stricture (urology 2012;79:917-921). PMID- 23021678 TI - Re: Elkoushy et al.: pulsed fluoroscopy in ureteroscopy and percutaneous nephrolithotomy (urology 2012;79:1230-1235). PMID- 23021679 TI - Re: El-Nahas et al.: factors affecting stone-free rate and complications of percutaneous nephrolithotomy for treatment of staghorn stone (urology 2012;79:1236-1241). PMID- 23021683 TI - Re: Bozkurt et al.: relationship between mean platelet volume and varicocele: a preliminary study (urology 2012;79:1048-1051). PMID- 23021684 TI - Obstetric ultrasound for estimated fetal weight: is the information more harm than benefit? PMID- 23021685 TI - Another question for the list. PMID- 23021687 TI - Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. AB - OBJECTIVE: The objective of the study was to evaluate the regression, relapse, and live birth rates of early-stage endometrial cancer (EC) and atypical complex hyperplasia (ACH) with fertility-sparing treatment. STUDY DESIGN: This was a metaanalysis of the proportions from observational studies with a random-effects model and a meta-regression to explore for heterogeneity. RESULTS: Thirty-four observational studies, evaluating the regression, relapse, and live birth rates of early-stage EC (408 women) and ACH (151 women) with fertility-sparing treatment. Fertility-sparing treatment for EC achieved a pooled regression rate of 76.2%, a relapse rate of 40.6%, and a live birth rate of 28%. For ACH the pooled regression rate was 85.6%, a relapse rate of 26%, and a live birth rate of 26.3%. Twenty women were diagnosed with ovarian cancer (concurrent or metastatic) during follow-up (3.6%) and 10 progressed to higher than stage I EC (1.9%) from which 2 women died. CONCLUSION: Fertility-sparing treatment of EC and ACH is feasible and selected women can satisfy their reproductive wishes. PMID- 23021688 TI - Trends in the rate of invasive procedures after the addition of the intrauterine tamponade test to a protocol for management of severe postpartum hemorrhage. AB - OBJECTIVE: The purpose of this study was to investigate changes in invasive procedure rates after the addition of intrauterine balloon tamponade as an initial second-line therapy to our protocol for the management of severe postpartum hemorrhage. STUDY DESIGN: We compared the outcomes of all patients with postpartum hemorrhage that was unresponsive to prostaglandin during 2 equal periods, before (first period) and after (second period) the introduction of a balloon tamponade protocol. RESULTS: During the second period, 43 women had uterine tamponade with a Bakri balloon as their initial second-line therapy (after vaginal delivery, 31; after caesarean delivery, 12). The global success rate was 86% (37/43 women). Among patients who delivered vaginally, the rates of arterial embolization (8.2% vs 2.3% in the first and second period; P = .006; odds ratio, 0.26; 95% confidence interval, 0.09-0.72) and conservative surgical procedures (5.1% vs 1.4%, in the first and second period; P = .029; odds ratio, 0.26; 95% confidence interval, 0.07-0.95) were significantly lower after the uterine tamponade test was added to our protocol. CONCLUSION: Intrauterine balloon tamponade is an attractive adjunctive strategy for the achievement of hemostasis in intractable hemorrhages and prevention of the need for invasive procedures. PMID- 23021689 TI - A system-based intervention to improve postpartum diabetes screening among women with gestational diabetes. AB - OBJECTIVE: We sought to determine whether our process improvement program led to increased postpartum diabetes screening rates among women with gestational diabetes mellitus (GDM). STUDY DESIGN: In early 2009, we conducted obstetrics department staff education sessions, revised GDM patient care protocols, and developed an electronic system to trigger reminder calls to patients who had not completed diabetes mellitus screening by 3 months postpartum. We then evaluated the rates of postpartum glucose test order entry and completion for women with GDM delivering from July 2009 through June 2010 (n = 179) and July 2007 through June 2008 (n = 200). RESULTS: After the program's implementation, the proportion of women receiving an order for a postpartum glucose test within 3 months of delivery increased from 77.5-88.8% (P = .004), and test completion increased from 59.5-71.5% (hazard ratio, 1.37; 95% confidence interval, 1.07-1.75). CONCLUSION: Rates of postpartum diabetes testing can be improved with system changes and reminders. PMID- 23021690 TI - Factors associated with adverse perinatal outcomes for term breech fetuses with planned vaginal delivery. AB - OBJECTIVE: We sought to identify factors associated with adverse perinatal outcomes (APO) among term breech neonates with planned vaginal deliveries. STUDY DESIGN: We conducted univariable and multilevel multivariable analysis of the data collected in the multicenter prospective observational study PREsentation et MODe d'Accouchement (PREMODA) in women with planned vaginal delivery giving birth to singleton term breech babies. The end point was a composite set of APO. RESULTS: Of 2502 women with planned vaginal delivery recruited in the 174 participating centers, 1772 (71%) delivered vaginally. Adverse outcomes were observed in 165 cases (6.59%). After adjustment, the factors associated with them were geographic origin, gestational age <39 weeks at birth, birthweight <10th percentile, and annual number of maternity unit births <1500. CONCLUSION: When strict conditions governed the selection of delivery route and management of labor was rigorous, APO were not associated with any prenatal or peripartum obstetric factors. PMID- 23021691 TI - Pneumonia and pregnancy outcomes: a nationwide population-based study. AB - OBJECTIVE: Using 2 nationwide population-based datasets, this study aimed to assess the risk of adverse pregnancy outcomes, including low birthweight (LBW), preterm birth, small for gestational age (SGA), cesarean section (CS), lower Apgar score, and preeclampsia/eclampsia, between women with and without pneumonia. STUDY DESIGN: This study included 1462 women who had been hospitalized with pneumonia during pregnancy and used 7310 matched women without pneumonia as a comparison group. RESULTS: Compared to women without pneumonia, conditional logistic regression analyses showed that the adjusted odds ratios for LBW, preterm birth, SGA, CS, Apgar scores <7 at 5 minutes, and preeclampsia/eclampsia in women with pneumonia were 1.73 (95% confidence interval [CI], 1.41-2.12), 1.71 (95% CI, 1.42-2.05), 1.35 (95% CI, 1.17-1.56), 1.77 (95% CI, 1.58-1.98), 3.86 (95% CI, 1.64-9.06), and 3.05 (95% CI, 2.01-4.63), respectively. CONCLUSION: Women with pneumonia during pregnancy had significantly higher risk of LBW, preterm birth, SGA, low Apgar scores infants, CS, and preeclampsia/eclampsia, compared to unaffected women. PMID- 23021692 TI - A multicenter, randomized, prospective, controlled study comparing sacrospinous fixation and transvaginal mesh in the treatment of posthysterectomy vaginal vault prolapse. AB - OBJECTIVE: The objective of the study was to compare recurrence and complication rates for sacrospinous fixation (SSF) and prolene mesh techniques for the primary treatment of posthysterectomy vaginal vault prolapse. STUDY DESIGN: Patients undergoing surgery for vault prolapse were included in a multicenter, randomized, controlled study comparing SSF or total mesh (Prolift; Gynecare/Ethicon, Somerville, NJ). The examination included pelvic organ prolapse quantification, urodynamics, ultrasound, and quality-of-life (QoL) questionnaires before and 3 and 12 months after surgery. RESULTS: Of 168 randomized patients, 83 underwent SSF and 85 mesh repair. Prolapse recurrence after 12 months occurred in 39.4% of the SSF group and in 16.9% of the mesh group (P = .003). The mesh exposure rate was 20.8%. No difference in QoL improvement as well as of de novo stress urinary incontinence and overactive bladder onset was found. CONCLUSION: Mesh exposure occurrence was balanced against a lower prolapse recurrence rate in the patients undergoing mesh surgery compared with those undergoing SSF. PMID- 23021693 TI - Risk of surgically managed pelvic floor dysfunction in relation to age at first delivery. AB - OBJECTIVE: The purpose of this study was to compare the risk of surgically treated stress urinary incontinence (SUI) and pelvic organ prolapse (POP) in relation to mode of delivery and age at first childbirth. STUDY DESIGN: This was a cohort study. Data from the Swedish Medical Birth Register on women with only cesarean delivery (n = 30,880 women) or only vaginal delivery (n = 59,585 women) were compared with the Swedish Patient Register to calculate incidence rates and hazard ratios (95% confidence interval [CI]) for SUI and POP surgery. RESULTS: In analyses that were stratified by age, vaginal delivery consistently increased the risks of SUI and POP surgery. Among vaginally delivered women who were >= 30 years old, incidence rates of POP surgery were 13.8 (95% CI, 12.7-15.1), and for younger women were 6.4 (95% CI, 6.0-6.8) per 10,000 person-years. Exclusion of instrumental vaginal delivery did not alter the conclusions. CONCLUSION: Increasing age at first delivery increased the risk of subsequent SUI and POP surgery after both vaginal and cesarean delivery. PMID- 23021694 TI - Nonstress testing at <= 32.0 weeks' gestation: a randomized trial comparing different assessment criteria. AB - OBJECTIVE: Comparison of time and outcomes of National Institutes of Child Health and Human Development defined fetal heart rate acceleration criteria at <= 32 weeks (>= 10 beats/min, >= 10 seconds) compared with standard criteria (>= 15 beats/min, >= 15 seconds). STUDY DESIGN: Singleton high-risk pregnancies that were referred for nonstress testing at <= 32 weeks' gestation were randomly assigned to 15 * 15 or 10 * 10 criteria. Data included nonstress test information, maternal data, and outcomes. RESULTS: One hundred forty-three women were randomly assigned to 15 * 15 (n = 71) or 10 * 10 (n = 72). The groups were similar in maternal and pregnancy characteristics. Median time to reactive nonstress testing was shorter in the 10 * 10 group (37.3 minutes) than the 15 * 15 group (41.3 minutes; P = .04). There were no serious adverse events. CONCLUSION: The time to attain a reactive nonstress testing at <= 32 weeks' gestation was 4 minutes shorter when the 10 * 10 criteria were used. There were no adverse events related to use of 10 * 10 nonstress testing criteria. PMID- 23021695 TI - PreImplantation Factor (PIF) orchestrates systemic antiinflammatory response by immune cells: effect on peripheral blood mononuclear cells. AB - OBJECTIVE: Embryo-derived PreImplantation Factor (PIF) is essential for pregnancy immune modulation and synthetic PIF (sPIF), reverses neuroinflammation, and prevents diabetes mellitus through its immune modulatory properties. Herein, we explore sPIF's systemic effects on peripheral blood mononuclear cells (PBMCs). STUDY DESIGN: sPIF's effects on PBMCs and subset populations from nonpregnant patients (n = 7) and male patients were evaluated by the assessment of binding characteristics, mixed lymphocyte reaction, proliferation, cytokine secretion, and associated gene expression. Data analysis was by analysis of variance (P < .05). RESULTS: Fluorescein isothiocyanate-sPIF bound all myelomonocytic cells; binding was 30-fold up-regulated in mitogen-activated T and B cells (P < .05). sPIF decreased mixed lymphocyte reaction by 70% and blocked anti-CD3 antibody stimulated-PBMC proliferation by approximately 80% (P < .05). In naive PBMCs, sPIF reduced interleukin (IL)-10 and -2; in activated PBMCs, sPIF increased IL-4, -5, -10, and -2, tumor necrosis factor-alpha, interferon-gamma, and granulocyte macrophage colony-stimulating factor (P < .05). CONCLUSION: Physiologic concentrations of PIF exert potent systemic antiinflammatory effects on nonpregnant activated immune cells. PMID- 23021696 TI - Single-nucleotide polymorphisms in genes involved in placental function and unexplained stillbirth. AB - OBJECTIVE: The purpose of this study was to evaluate the association between unexplained stillbirth (SB) and single-nucleotide polymorphisms (SNPs) in genes involved in placental function using a well-characterized cohort. STUDY DESIGN: Placentas were obtained from 50 unexplained SB and 46 live birth controls. Classification of stillbirth was by Wigglesworth criteria. SBs were stratified by weight: appropriate (AGA-SB) and small for gestational age (SGA-SB, less than the 10th percentile) and gestational age: before 32 and after 32 weeks. Placental DNA was extracted and various SNPs in the endothelial nitric oxide synthase (eNOS), Klotho, hypoxic inducible factor-1alpha, and and tumor necrosis factor-alpha genes were evaluated. RESULTS: None of the SNPs were associated with SB overall. Significantly different genotype distribution emerged for eNOS-SNP rs1800783 when comparing AGA-SB with SGA-SB and control (P = .004). Its allele-A was more frequent in AGA-SB compared with both controls (P = .03) and SGA-SB (P = .001). No differences were seen accordingly to gestational age. CONCLUSION: Unexplained stillbirth in the setting of adequate growth is associated with carrier of allele A of rs1800783 eNOS gene in the placenta. PMID- 23021697 TI - The risk of intrauterine fetal death in the small-for-gestational-age fetus. AB - OBJECTIVE: We sought to evaluate the risk of intrauterine fetal death (IUFD) in small-for-gestational-age (SGA) fetuses. STUDY DESIGN: We analyzed a retrospective cohort of all births in the United States in 2005, as recorded in a national database. We calculated the risk of IUFD within 3 sets of SGA threshold categories as well as within non-SGA pregnancies using the number of at-risk fetuses as the denominator. RESULTS: The risk of IUFD increased with gestational age and was inversely proportional to percentile of birthweight for gestational age. The risk for IUFD in those <3rd percentile was as high as 58.0 IUFDs per 10,000 at-risk fetuses, 43.9 for <5th percentile, and 26.3 for <10th percentile compared to 5.1 for non-SGA gestations. CONCLUSION: There is an increase in the risk of IUFD in SGA fetuses compared to non-SGA fetuses at all gestational ages with the greatest risk demonstrated in the lowest percentile cohort evaluated. PMID- 23021698 TI - Prevalence and risk factors of cerebral lesions in neonates after laser surgery for twin-twin transfusion syndrome. AB - OBJECTIVE: To identify risk factors for cerebral lesions among survivors of twin twin transfusion syndrome treated with laser surgery. STUDY DESIGN: A multilevel regression analysis examined risk factors for neonatal cerebral lesions identified by imaging. Imaging was routine in "high-risk survivors," defined as those delivered at <32 weeks' gestation, and by clinical indications if born later. Severe lesions were defined as: intraventricular hemorrhage grade III-IV, cystic periventricular leukomalacia, ventriculomegaly and/or hydrocephalus, microcephaly, infarctions, porencephalic/Dandy-Walker cysts, or bilateral other cysts. RESULTS: For 262 consecutive laser-treated twin-twin transfusion syndrome patients, 18 neonates had severe lesions identified among 427 individual survivors (4.2%) and 242 "high-risk survivors" (7.4%). Forty-six newborns had any cerebral lesion, resulting in lesion rates of 10.8%-19.0%. Delivery <32 weeks' (odds ratio, 4.95; P < .001) and <28 weeks' (odds ratio, 6.25; P < .001) gestation were associated with increased likelihood of any cerebral lesion. CONCLUSION: This cohort showed low rates (4-7%) of severe neonatal cerebral lesions, with prematurity being the primary risk factor. PMID- 23021699 TI - Insulin pump dosing across gestation in women with well-controlled type 1 diabetes mellitus. AB - OBJECTIVE: We hypothesized that bolus and basal insulin doses in women with type 1 diabetes mellitus who use insulin pumps would increase 2-fold to maintain hemoglobin A1c <6.5% across gestation. STUDY DESIGN: This was a retrospective study of 9 women with type 1 diabetes mellitus with preconceptional hemoglobin A1c <= 7.4% using insulin pumps. The primary outcome was absolute and percentage change of basal and bolus insulin from preconception to delivery. RESULTS: Total daily dose of insulin increased from 33.3 +/- 7.8 U/d before conception to 93.5 +/- 27.9 U/d at delivery. Basal rates rose modestly (50% increase, from 16.2 +/- 6.5 U/d to 24.0 +/- 9 U/d); bolus insulin doses quadrupled from 17.1 +/- 6.1 U/d to 69.5 +/- 29.6 U/d (P = .0001). Bolus insulin increased from approximately 50% of total daily dose of insulin before conception to 75% of total daily dose of insulin at 36 weeks' gestation. CONCLUSION: In well-controlled type 1 diabetes mellitus, insulin requirements increased 3-fold from before conception to 36 weeks' gestation. Most of this requirement was attributed to an increase in bolus rates that are required for control with meals. PMID- 23021700 TI - Epidural-associated hypotension is more common among severely preeclamptic patients in labor. AB - OBJECTIVE: To determine whether severe preeclampsia is associated with increased maternal hypotension or fetal heart rate abnormalities after epidural anesthesia placement during labor. STUDY DESIGN: Retrospective cohort study of 100 women with severe preeclampsia and 100 normotensive controls who underwent epidural anesthesia during labor from May 2008 to July 2011. Blood pressures during 2 minute time intervals for 20 minutes postepidural were compared with baseline measurements. Fetal heart rate abnormalities and related interventions were evaluated according to study group. RESULTS: Severe preeclampsia was associated with a greater percent decrease in blood pressure across all intervals and more episodes of systolic and diastolic hypotension after dosing. Severely preeclamptic women received more intravenous pressor support and developed more Category II fetal heart rate tracings, minimal variability, and late decelerations after dosing. CONCLUSION: Severe preeclampsia is associated with more frequent hypotension, need for pressor support, and fetal heart rate abnormalities after epidural anesthesia placement during labor. PMID- 23021702 TI - Discussion: 'ultrasound screening for fetal spina bifida,' by Bernard et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Bernard J-P, Cuckle HS, Stirnemann JJ, et al. Screening for fetal spina bifida by ultrasound examination in the first trimester of pregnancy using fetal biparietal diameter. Am J Obstet Gynecol 2012;207:306.e1-2. PMID- 23021701 TI - Systemic inflammatory stimulation by microparticles derived from hypoxic trophoblast as a model for inflammatory response in preeclampsia. AB - OBJECTIVE: To determine whether trophoblast-derived microparticles can induce different inflammatory responses of the peripheral blood mononuclear cells depending upon the state of trophoblast when the microparticles are generated. STUDY DESIGN: A trophoblast-derived cell line (ATCC no. CRL-1584) was cultured under normal or hypoxic conditions. Microparticles were isolated from the cell culture supernatants (microparticles from normal trophoblast; microparticles from hypoxic trophoblast). Peripheral blood mononuclear cells were cultured alone or cocultured with either microparticles from normal trophoblast or microparticles from hypoxic trophoblast. RESULTS: After 48 hours, the peripheral blood mononuclear cells cocultured with microparticles from normal trophoblast released higher concentrations of interleukin-6 than peripheral blood mononuclear cells cultured alone. The peripheral blood mononuclear cells cocultured with microparticles from hypoxic trophoblast showed higher concentration of interleukin-6 and tumor necrosis factor alpha than peripheral blood mononuclear cells cocultured with microparticles from normal trophoblast, after 24 hours and 48 hours. CONCLUSION: More intense and rapid inflammatory response of peripheral blood mononuclear cells was observed with microparticles from hypoxic trophoblast than with microparticles from normal trophoblast. This difference might explain the exaggerated systemic inflammatory response as a result of placental hypoxia in preeclampsia. PMID- 23021704 TI - Solid deformation induced by the adsorption of methane and methanol under sub- and supercritical conditions. AB - Carbonaceous materials with some degree of flexibility in their physical structure can expand or contract under the influence of the forces exerted by adsorbed molecules. To gain insight into how adsorption of non-polar and polar fluids could deform a carbon solid, we present GCMC simulations of sub- and supercritical adsorption of methane and methanol in slit-shaped pores whose walls are made of graphene layers. Our extensive simulation study shows that there is a strong correlation between solvation pressure and solid deformation, and that the expansion or contraction of the pore strongly depends on adsorbate loading, temperature and pore size. PMID- 23021703 TI - Enhancement of the photostability and photoactivity of metallo-meso-5,10,15,20 tetrakis-(4-sulfonatophenyl)porphyrins by polymeric micelles. AB - Metallo-meso-5,10,15,20-tetrakis-(4-sulfonatophenyl)porphyrins (metallo-TPPSs), such as ZnTPPS, have been widely used as photosensitizers. However, their vulnerability to photodegradation significantly limits their applications. In this contribution, we demonstrate a method to enhance the photostability of metallo-TPPSs while retaining photoactivity via encapsulation inside cores of complex micelles. Poly(ethylene glycol)-b-poly(4-vinylpyridine) (PEG-b-P4VP) and metallo-TPPSs can form complex micelles in acidic solution through electrostatic interactions and then undergo axial coordination with the pyridine moieties of PEG-b-P4VP when the pH is adjusted to 7.4. In this way, metallo-TPPSs are entrapped in the hydrophobic, compact micellar cores, which effectively prevents photodegradation of the metallo-TPPSs that would otherwise occur in aqueous solution. In addition, the photodebromination of 2,3-dibromo-3-phenylpropionic acid (DPP) sensitized with ZnTPPS has been used as a model reaction to study the photosensitive activity of ZnTPPS entrapped in complex micelles. The entrapped ZnTPPSs exhibit pronounced activity and have much higher efficiency and faster photosensitive reaction rates than free ZnTPPS. PMID- 23021705 TI - Superhydrophobic polyethylcyanoacrylate coatings. Contact area with water measured by Raman spectral images, contact angle and Cassie-Baxter model. AB - Apolar fibers wired into a mesh-like microstructure forming a coating with a contact angle larger than 160 degrees and fabricated by polycyanoacrylate polymerization are described. Interconnected fibers with diameters measuring approximately 5 MUm are formed by texturized linear or folded nanowires. The structure forming the deposited film occupies ~1.5% of the coating's top geometric area. This value agrees with the water/coating contact area given by the Cassie-Baxter contact-angle model (~1.5%). The spatial distribution of the surface in contact with water was determined by Raman spectral imaging (~1.5%) using the polycyanoacrylate lines and by scanning electron microscopy (~2.0%). PMID- 23021706 TI - Detection of Leishmania parasites in the testis of a dog affected by orchitis: case report. AB - BACKGROUND: Transmission of canine leishmaniasis (CanL), a severe infection caused by L. infantum, usually occurs through the sand fly bite to the vertebrate host. A venereal route of transmission has also been suggested, but this issue is still controversial. FINDINGS: Here, we report a case of a dog affected by orchitis showing a clinical profile of L. infantum infection. By exploiting a real-time PCR assay, we detected a significantly higher DNA load of the parasite in the lymph node and testis than in blood and urine samples collected from the dog. CONCLUSIONS: Our results suggest that: 1) L. infantum infection can be associated with testicular lesions in naturally infected dogs; 2) genital involvement could result in shedding of the parasites in the semen, favoring venereal transmission of the disease. PMID- 23021707 TI - Twins, tissue, and time: an assessment of SNPs and CNVs. AB - With the desire to assess genetic variation across the lifespan in large-scale collaborative projects, one question is whether inference of copy number (CN) is sensitive to the source of material for deoxyribonucleic acid (DNA) analysis (e.g., blood and buccal) and another question is whether CN is stable as individual sage. Here, we address these questions by applying Affymetrix 6.0 single nucleotide polymorphism (SNP)micro-arrays to 1,472 DNA samples from 710 individuals from the Netherlands Twin Register, including twin and non-twin individuals (372 with buccal and blood derived DNA and 388 with longitudinal data).Similar concordance for CN and genotype inference between samples from the same individual [or from the monozygotic (MZ) co-twins] was found for blood and buccal tissues. There was a small but statistically significant decrease in across-tissue concordance compared with concordance of samples from the same tissue type. No temporal effect was seen on CN variation from the 388 individuals sampled at two time points ranging from 1 to 12 years apart. The majority of our individuals were sampled at age younger than 20 years. Genotype concordance was very high (~ > 99%) between co-twins from 43 MZ pairs. For75 dizygotic (DZ) pairs, ~was ~65%. CN estimates were highly consistent between co-twins from MZ pairs for both deletions (f?2 ~ 90%) and duplications (~ ~ 86%). For DZ, these were similar for within-individual comparisons, but naturally lower between co twins (~ ~ 50-60%). These results suggest that DNA from buccal samples perform as well as DNA from blood samples on the current generation of micro-array technologies. PMID- 23021708 TI - A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer. AB - PURPOSE: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. METHODS AND MATERIALS: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. RESULTS: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1*10(-5) to 6.2*10(-4)). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value=1.7*10(-29)). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value=2.1*10(-19)). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. CONCLUSIONS: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort. PMID- 23021709 TI - Is there a dose-response relationship for heart disease with low-dose radiation therapy? AB - PURPOSE: To quantify cardiac radiation therapy (RT) exposure using sensitive measures of cardiac dysfunction; and to correlate dysfunction with heart doses, in the setting of adjuvant RT for left-sided breast cancer. METHODS AND MATERIALS: On a randomized trial, 32 women with node-positive left-sided breast cancer underwent pre-RT stress single photon emission computed tomography (SPECT CT) myocardial perfusion scans. Patients received RT to the breast/chest wall and regional lymph nodes to doses of 50 to 52.2 Gy. Repeat SPECT-CT scans were performed 1 year after RT. Perfusion defects (PD), summed stress defects scores (SSS), and ejection fractions (EF) were evaluated. Doses to the heart and coronary arteries were quantified. RESULTS: The mean difference in pre- and post RT PD was -0.38% +/- 3.20% (P=.68), with no clinically significant defects. To assess for subclinical effects, PD were also examined using a 1.5-SD below the normal mean threshold, with a mean difference of 2.53% +/- 12.57% (P=.38). The mean differences in SSS and EF before and after RT were 0.78% +/- 2.50% (P=.08) and 1.75% +/- 7.29% (P=.39), respectively. The average heart Dmean and D95 were 2.82 Gy (range, 1.11-6.06 Gy) and 0.90 Gy (range, 0.13-2.17 Gy), respectively. The average Dmean and D95 to the left anterior descending artery were 7.22 Gy (range, 2.58-18.05 Gy) and 3.22 Gy (range, 1.23-6.86 Gy), respectively. No correlations were found between cardiac doses and changes in PD, SSS, and EF. CONCLUSIONS: Using sensitive measures of cardiac function, no clinically significant defects were found after RT, with the average heart Dmean <5 Gy. Although a dose response may exist for measures of cardiac dysfunction at higher doses, no correlation was found in the present study for low doses delivered to cardiac structures and perfusion, SSS, or EF. PMID- 23021710 TI - Higher regular fat dairy consumption is associated with lower incidence of metabolic syndrome but not type 2 diabetes. AB - BACKGROUND AND AIMS: Limited evidence suggests habitual dairy consumption to be protective against metabolic syndrome (MetSyn) and type 2 diabetes among older adults. We assessed the association of baseline consumption of dairy products with the incidence of MetSyn and type 2 diabetes among a cohort of Australian adults aged 49 years and over. METHODS AND RESULTS: A validated 145-item semi quantitative food frequency questionnaire was used to assess food and nutrient intake at baseline. Ten-year incidence of MetSyn and type 2 diabetes were obtained from 1807 and 1824 subjects respectively. Odds ratios (OR) were calculated by discrete time logistic regression modelling. Compared with subjects in the lowest intake quartile of regular fat dairy products, those in the highest quartile had a 59% lower risk of MetSyn (multivariate adjusted OR: 0.41; 95% CI: 0.23-0.71; p(trend) = 0.004), after adjustment for risk factors. Among obese subjects, an association between a high intake of regular fat dairy foods and reduced risk of type 2 diabetes was also found (age and sex adjusted OR 0.37; 95% CI: 0.16-0.88; p(trend) = 0.030), but the association did not persist after adjustment for additional confounders. There was no association between total dairy consumption and risk of MetSyn or type 2 diabetes. CONCLUSIONS: We found an inverse association between regular fat dairy consumption and risk of MetSyn among Australian older adults. Further studies are warranted to examine the association between weight status, dairy consumption and risk of type 2 diabetes. PMID- 23021711 TI - Synthesis of multifunctional fluorescent magnetic graphene oxide hybrid materials. AB - Fluorescent magnetic graphene oxide hybrid materials have been fabricated by a multistep method. X-ray diffraction, transmission and scanning electron microscopy, fluorescence spectroscopy, Fourier transform infrared spectroscopy, vibration sample magnetometry, and energy dispersive spectroscopy were used to characterize the resulting material. The results showed that the materials have a saturation magnetization value of 22.0 emu/g at room temperature and exhibit a symmetrical and narrow emission peak at 544 nm. The resultant materials are able to carry an anti-cancer drug, 5-fluorouracil, with a load capacity of 0.24 mg/mg. PMID- 23021713 TI - Patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, and role of laparoscopy in diagnosis, staging, and treatment. AB - The indications for peritonectomy + hyperthermic intraperitoneal chemotherapy (HIPEC) are based on careful assessment of disease extent, but no imaging procedure is accurate enough to identify lesions smaller than 5 mm or extensively diffuse. Video-laparoscopy allows, with minimal surgical trauma, correct staging with a reliable prediction of expected cytoreduction index. Operative laparoscopy is indicated for palliation of neoplastic ascites with chemotherapy, offering encouraging results. Minimally invasive surgery in the treatment of minimal peritoneal carcinomatosis is not yet validated from wide international experience; the procedure is technically possible with strict indications, and combination with intraoperative hyperthermic chemotherapy is strongly recommended. PMID- 23021712 TI - Evidence-based guideline recommendations on the use of positron emission tomography imaging in head and neck cancer. AB - AIMS: To provide evidence-based practice guideline recommendations on the use of fluoro-2-deoxy-D-glucose positron emission tomography (PET) for diagnosis, staging and assessing treatment response, restaging or recurrence of head and neck cancer. MATERIALS AND METHODS: A systematic review by Facey et al. (Health Technology Assessment 2007;11(44):iii-iv, xi-267) was used as the evidence base for recommendation development. As the review was limited to August 2005, the evidence base was updated to July 2011 using the same search strategies for MEDLINE and EMBASE used in the original review. The authors of the current systematic review drafted recommendations, which were reviewed, adapted and accepted by consensus by the Ontario provincial Head and Neck Disease Site Group and a special meeting of clinical experts. RESULTS: The results of the Facey et al. review for head and neck cancer included five other systematic reviews and 31 primary studies. The 2005 to 2011 update search included four additional systematic reviews and 53 primary studies. Recommendations were developed based on this evidence and accepted by consensus. CONCLUSIONS: PET is recommended in the M and bilateral nodal staging of all patients with head and neck squamous cell carcinoma where conventional imaging is equivocal, or where treatment may be significantly modified. PET is recommended in all patients after conventional imaging and in addition to, or prior to, diagnostic panendoscopy where the primary site is unknown. PET is recommended for the staging and assessment of recurrence of patients with nasopharyngeal carcinoma if conventional imaging is equivocal. PET is recommended for restaging patients who are being considered for major salvage treatment, including neck dissection. PMID- 23021714 TI - Anesthesia considerations during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - This article outlines the anesthetic management of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. This includes a discussion of preoperative evaluation, hemodynamic monitoring, fluid and electrolyte therapy, and temperature management. An understanding of the unique physiologic consequences of this procedure is essential to ensure good outcomes and avoid patient injuries. PMID- 23021715 TI - Hyperthermic intraperitoneal chemotherapy: methodology and safety considerations. AB - Several methods of delivering hyperthermic intraperitoneal chemotherapy (HIPEC) during the course of cytoreductive surgery have been described, but no significant differences in treatment results have been found among them. HIPEC is a safe treatment for the patient and for healthcare workers involved in the procedure provided standard protective and environmental measures are used. This article describes the different techniques in use and the technology available for the administration of HIPEC. Also reviewed are the safety features that must be taken into consideration when performing this procedure. Recommended guidelines to prevent associated occupational hazards are provided. PMID- 23021716 TI - The importance of the learning curve and surveillance of surgical performance in peritoneal surface malignancy programs. AB - Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are complex procedures with a very steep a learning curve (LC). This study evaluates the LC of CRS and HIPEC in a single-center experience of peritoneal surface malignancies (PSMs). Approximately 140 to 150 cases were necessary for the acquisition of competence in CRS and HIPEC with adequate radicality and acceptable safety. Eighty to 100 cases were necessary to assure short-term prognostic gains in rare PSMs. This article highlights how LC and continuous monitoring of surgical performance is critical in evaluating the credibility of emerging and already established PSM centers. PMID- 23021717 TI - Pharmacology of perioperative intraperitoneal and intravenous chemotherapy in patients with peritoneal surface malignancy. AB - Peritoneal surface malignancy is a common manifestation of intra-abdominal malignancies. Systemic chemotherapy offers no long-term survival and poor quality of life for these patients in their terminal stages of disease. By contrast, cytoreductive surgery combined with perioperative intraperitoneal and intravenous chemotherapy has resulted in encouraging clinical results. Further improvements should come from both clinical phase II/III studies and pharmacologic research. This article reviews the current pharmacologic data and controversies regarding the perioperative intraperitoneal and intravenous application of chemotherapy. PMID- 23021718 TI - Current status and future directions in appendiceal cancer with peritoneal dissemination. AB - This article focuses on the use of intraperitoneal hyperthermic chemotherapy for the treatment of peritoneal dissemination from appendiceal primary tumors. The first part of the article details patient selection criteria used at the Wake Forest University School of Medicine and the use of preoperative imaging and endoscopic evaluation in the management of this cohort of patients. The second part of the article focuses on clinical outcomes for patients undergoing hyperthermic intraperitoneal perfusion for peritoneal dissemination from appendiceal tumors. Finally, future challenges for the use of hyperthermic intraperitoneal perfusion for appendiceal primary tumors are explored. PMID- 23021719 TI - Current status and future directions in the treatment of peritoneal dissemination from colorectal carcinoma. AB - Peritoneal carcinomatosis (PC) carries a worse prognosis than other sites of colorectal metastases. If incomplete resection of PC affords no benefit to patients, complete resection of PC is beneficial in selected patients. The combination of complete cytoreductive surgery to treat the visible PC and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat the nonvisible PC is on the verge of becoming the gold standard. The prognostic impact of a complete resection is high, but that of HIPEC per se is more hypothetical. The presence of a few resectable liver metastases associated with PC is not a contraindication to surgery plus HIPEC. PMID- 23021720 TI - Current status and future directions in gastric cancer with peritoneal dissemination. AB - Peritoneal carcinomatosis arising from gastric cancer is mostly associated with poor prognosis. Despite the improvement of survival with modern polychemotherapy, the results are still unsatisfactory. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy might provide an additional therapeutic option for highly selected patients with gastric cancer and peritoneal metastasis leading to improved prognosis. Considering the increased rate of perioperative morbidity and the crucial prognostic role of complete macroscopic cytoreduction, adequate preoperative diagnostics and patient selection are strongly recommended. Further prospective randomized trials are needed to determine the roles of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as part of an interdisciplinary treatment concept. PMID- 23021721 TI - Peritoneal mesothelioma: current status and future directions. AB - Peritoneal mesothelioma is a rare malignancy where life expectancy with systemic chemotherapy remains poor. Most patients with this disease are diagnosed late with extensive peritoneal disease burden leading to nausea, pain, and abdominal distention as a result of ascites and a partial bowel obstruction. A newly proposed staging system comprising elements of the tumor burden measured by the peritoneal cancer index, abdominal nodal status, and extra-abdominal metastases has been demonstrated to reliably stratify patient outcomes based on staging subgroups after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. This new staging system may form the basis of selecting patients for radical surgery and improve survival outcomes. PMID- 23021722 TI - Current status and future directions of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of ovarian cancer. AB - Epithelial ovarian cancer is a peritoneal surface malignancy that most often presents with spread of disease within the peritoneal cavity. Overall 5-year survival is around 50% and progress in improving outcomes is slow. Among other areas of research, hyperthermic intraperitoneal chemotherapy (HIPEC) provides a promising option. This article reviews the current status of treatment of epithelial ovarian cancer, experience with HIPEC to date, and future directions. PMID- 23021723 TI - Randomized clinical trials for colorectal cancer peritoneal surface malignancy. AB - Upwards of 40% of patient with colorectal cancer develop peritoneal carcinomatosis (CRCPC). Of the 2500 patients reported in the literature, 1000 underwent cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), resulting in median survival of 22 to 63 months. However, level I data from prospective randomized trials are limited. Further trials are indicated to identify peritoneal carcinomatosis in at-risk patients early in the natural history of the disease and confirm the efficacy of multimodality therapy (CRS/HIPEC/systemic therapy) in those with CRCPC amenable to CRS in the modern era of novel targeted and cytotoxic systemic therapy. PMID- 23021724 TI - Early intervention for treatment and prevention of colorectal carcinomatosis: a plan for individualized care. AB - The benefits that are reported in patients who have carcinomatosis from colorectal cancer increase as the extent of disease within the abdomen and pelvis decreases. To optimize treatments that involve cytoreductive surgery and perioperative chemotherapy, early intervention is necessary. Strategies to improve the results of carcinomatosis treatments include second-look surgery and hyperthermic intraperitoneal chemotherapy in patients at high risk for recurrence. Alternatively, the use of hyperthermic intraperitoneal chemotherapy can be used to treat or prevent carcinomatosis at the time of primary colorectal cancer resection in selected patients. PMID- 23021725 TI - Treatment of peritoneal surface malignancies. PMID- 23021726 TI - Treatment of peritoneal surface malignancies. PMID- 23021727 TI - Do the biomechanical properties of the ankle-foot complex influence postural control for people with Type 2 diabetes? AB - BACKGROUND: The ankle-foot complex plays an important role in the mechanics of postural control. The objectives of this study were to compare the biomechanical properties of the ankle-foot complex of people with diabetes who had or did not have peripheral neuropathy with those healthy individuals; and to examine its correlation with postural control. METHODS: A total of 64 individuals participated in this study: 9 people with diabetic peripheral neuropathy, 23 diabetes without neuropathy, and 32 healthy controls. A hand-held ultrasound indentation system was used to assess the soft tissue biomechanical properties of the ankle-foot complex. The Sensory Organization test was performed using The Smart EquiTest system to assess postural control. FINDINGS: The soft tissue of the Achilles tendon was significantly thickened in all individuals with diabetes (P<0.001), and was associated with the vestibular ratio (r=0.40; P<0.05). The Young's modulus of the plantar soft tissue was significantly increased in the diabetic neuropathy group (all P<0.05). Also, the Young's modulus of the plantar soft tissue at the first metatarsal head was positively correlated with the somatosensory ratio (r=0.46; P<0.05) and visual ratio (r=0.39; P<0.05). INTERPRETATION: Diabetic patients with or without neuropathy had a thicker Achilles tendon and stiffer plantar soft tissue than the healthy control. Changes in the biomechanical properties of the ankle-foot complex were correlated with the use of vestibular, somatosensory or visual inputs to maintain balance in individuals with diabetes. PMID- 23021728 TI - Comparative morphological and morphometric description of the hominin calvaria from Bukuran (Sangiran, Central Java, Indonesia). AB - We describe the hominin skull (called here "Bukuran") discovered in the lower Kabuh (or "Bapang") series near Sendangbusik, from the Bukuran area in the Sangiran dome. The fossil, heavily mineralized, consists of the parieto-occipital and the left temporal, and the frontal bones. When combined, those two cranial parts represent a rather complete and well-preserved calvaria. Its stratigraphic position was established after the discovery. A detailed description is presented of the morphological and metric features of the Bukuran calvaria, and comparisons are made with Asian Homo erectus from Indonesia and China. The estimated cranial capacity of Bukuran, the general shape of its cranial vault, its ectocranial structures, and its morphological and metrical characters are in the range of Asian Homo erectus, and show clear affinities with other Indonesian members of the species. We discuss the evolutionary status of the Bukuran calvaria and its implication for hominin history on Java. PMID- 23021729 TI - Clinical outcomes and patterns of failure after intensity-modulated radiotherapy for T4 nasopharyngeal carcinoma. AB - The goal of this study is to study and report the clinical outcomes and patterns of failure after intensity-modulated radiotherapy (IMRT) for T4 nasopharyngeal carcinoma (NPC). A total of 70 patients treated with IMRT between 2004 and 2009 were eligible for study inclusion. According to the staging system of 2010 AJCC, all the primary tumors were attributed to T4 stage, while the distribution of disease by N stage was N0 in 2, N1 in 23, N2 in 39, N3a in 1, and N3b in 5. The location and extent of locoregional failures were transferred to the pretreatment planning computed tomography for dosimetry analysis. The median follow-up period was 26.8 (range, 4-78) months. The overall 2-year local failure-free survival, regional failure-free survival, distant failure-free survival, and overall survival rate was 82.1%, 92.3%, 73.8%, and 82.5%, respectively. Thirty-three patients had developed treatment failure. Of the 33 patients, 11, 2, and 15 had developed local failure, regional failure, and distant metastasis, respectively, 2 had developed locoregional failure, 1 had developed distant metastasis and failure at the primary, and 2 had developed distant metastasis and failure at the primary and nodal site. Eight of the locoregional failures were marginal. The results of treating T4 NPC with IMRT were excellent. Advanced T4 disease remained difficult to treat. One possible strategy is to lessen the dose constraint criteria of selected neurologic structures. Distant metastasis remains the most difficult treatment challenge for patients with T4 NPC at present, and more effective systemic chemotherapy should be explored. PMID- 23021730 TI - Crime risk associated with disability. PMID- 23021731 TI - Assessing quality of life in relation to physical activity participation in persons with spinal cord injury: a systematic review. AB - BACKGROUND: Physical activity (PA) participation in persons with spinal cord injury (SCI) holds a number of benefits for quality of life (QOL) but there is a need to better understand conceptual and measurement issues. OBJECTIVE: To evaluate the appropriateness of outcome measurement tools to assess QOL in relation to PA in persons with SCI. METHODS: A systematic literature review was conducted using PubMed and CINAHL databases to identify studies that used a QOL measurement tool and assessed PA or employed a PA intervention to determine a relationship between PA and QOL. RESULTS: Thirteen articles met the inclusion criteria. Within the 13 articles, 9 different QOL outcome measurement tools were used; two objective measures (Short Form-36 [SF-36] and Quality of Well-being [QWB]) and 7 subjective measures (Perceived QOL [PQoL], Satisfaction with Life Scale [SWLS], QOL Index SCI Version III, Life Satisfaction [LISAT], QOL Feedback, QOL Profile: Physical and Sensory Disabilities Version [QOLP-PSD] and Subjective QOL [SQOL]). The PQoL was the most commonly used tool (4 studies) and was used in 2 of the 3 randomized controlled trials. Twelve of the studies demonstrated a positive effect of PA on QOL. CONCLUSIONS: Outcome measurement tool selection should be guided by the specific purpose of the data collection activity as well as the context under which the tool will be used (e.g., setting, population, etc.). Therefore, different tools may rightfully be selected to assess the same construct when considering different circumstances-however, these considerations should be balanced by the evidence and demonstrated prior utility of potential tools. PMID- 23021732 TI - A systematic scoping review of measures of participation in disability and rehabilitation research: a preliminary report of findings. AB - PURPOSE/OBJECTIVE: The concept of participation is emerging as a gold-standard of outcome measurement in disability and rehabilitation. We aimed to assess the status of methods to measure this new concept. METHOD/DESIGN: We conducted a scoping review and a content analysis to assess the literature on participation. RESULTS: We identified 586 articles addressing participation. Seventy-two articles passed all exclusion criteria. Twenty-four articles cited the International Classification of Function as their conceptual foundation. Most studies included individuals with a broad range of impairments (cross disability). Most instruments relied on self-report in a cross-sectional design. We noted three levels of measurement (static, interactional, and dynamic). Few studies reported collecting data on the environment along with participation. Subjective aspects of participation emerged as an important consideration but few articles reported measuring it. CONCLUSIONS: The concept of participation represents more than a "shift from negative to more positive language." It represents a transformational concept that requires new, dynamic measures collected in context. PMID- 23021733 TI - "I'm healthy": construction of health in disability. AB - BACKGROUND: The bio-mechanical view of medicine being disabled, implies unhealthiness because these states are not included in the physical and mental medical norms. This study is to show how people with physical disabilities define health and being healthy within a social framework and to demonstrate the impact of social environments on people with physical disabilities given their application of the social model and their process of social construction. OBJECTIVE: This study is to demonstrate that the meaning of health and the definition of oneself as healthy take place in a social-construction process involving an interaction between people and society. METHODS: To attain this goal, a qualitative technique was applied, and qualitative data were obtained. Terms were formed by encoding the data, and themes were formed using the terms. Analysis and interpretation were made based on 5 themes that emerged from the encoding of the research. RESULTS: The qualitative data obtained in the research indicate that being healthy is equal to not being ill, that a disability does not imply unhealthiness for people with disabilities, and that people with physical disabilities interpret their physical adequacy and body images positively. CONCLUSIONS: The results show that people with physical disabilities socially construct their states of being healthy and their states of health and interpret themselves as "healthy" despite the medical model's definition of health. The positive impact of this positive social construction of physical adequacy and body image is evident in their interpretations of themselves as healthy. PMID- 23021734 TI - Child and adult disability in the 2000 Census: disability is a household affair. AB - BACKGROUND: Survey data indicate that individuals with disabilities in the United States often experience less advantageous economic and social resources than individuals without disabilities. Furthermore, they often reside with other individuals with disabilities in the same household. However, less is known about resource availability when multiple child and adult household members have a disability. OBJECTIVE: We use child-level data from the 2000 Census to examine the relationship between aggregation of disability in households with children and education, labor force participation, poverty level, and inadequate housing. METHODS: We utilize tabular analysis and Kruskal-Wallis tests to examine how resources in education, employment, income, and housing adequacy compare for children with disabilities who are the only member of their household with a disability, children with disabilities who live in a household with at least one other member with a disability, children without disabilities who live in a household where no other member has a disability, and children without disabilities who live in a household where at least one other member has a disability. RESULTS: Among children without a disability, 86% live in a household in which no other member has a disability. Among children with a disability, 53% live in a household in which no other adult or child has a disability. Poverty, inadequate housing, and low adult education were more than two times more likely and adult unemployment over five times more likely - in households with multiple members with disability versus households without disability. CONCLUSION: There is a high prevalence of aggregation of adults and children with disability in households of children with disability. These households have substantially fewer resources than households who do not have children or adults with disabilities. PMID- 23021735 TI - Influence of adapted sports on quality of life and life satisfaction in sport participants and non-sport participants with physical disabilities. AB - BACKGROUND: The lack of controlled trials in the relationship between participation in adapted sports, and quality of life (QoL) and life satisfaction in people with physical disabilities encouraged us to consider conducting this study. OBJECTIVE: The aim of this study was to compare the QoL and life satisfaction scores between people with physical disabilities who participated in adapted sports and those who did not participate in any adapted sports. METHODS: This cross-sectional controlled study included 60 individuals with physical disabilities (paraplegia and amputee). Participants were divided into two groups based on sports participation and non-sports participation. Group one included 30 disabled elite athletes who participated in adapted sports. The control group included 30 disabled individuals not involved in any adapted sports. We compared scores on the World Health Organization Quality-of-Life Scale (WHOQoL-BREF) and the Satisfaction With Life Scale (SWLS) between the two groups. Participation in the community and QoL was examined as a reflection of participant's priority on sports participation. RESULTS: We found that WHOQoL-BREF physical, psychological, and social domain scores were significantly higher in group one than in the control group (p < 0.05), whereas environment domain scores were similar (p = 0.13). Moreover, SWLS scores were significantly higher in group one than in the control group (p < 0.05). CONCLUSIONS: These results showed that people with physical disabilities who participated in adapted sports had significantly higher QoL and life satisfaction scores compared to people with physical disabilities not involved in any adapted sports. PMID- 23021736 TI - Perceived benefits and barriers to exercise among persons with physical disabilities or chronic health conditions within action or maintenance stages of exercise. AB - BACKGROUND: Information regarding factors that affect the initial step to exercise behavior change among persons with physical disabilities or chronic health conditions is available in the literature but much less is known regarding perceived benefits and barriers to exercise among those who are regularly active. OBJECTIVE: The purpose of this study was to examine the perceived benefits and barriers to exercise among persons with physical disabilities or chronic health conditions within action or maintenance stages of exercise. METHODS: Participants (n = 152) completed the Exercise Benefits and Barriers Scale (EBBS). For data analyses, disabilities and health conditions were grouped as neuromuscular, orthopedic, cardiovascular/pulmonary, or multiple conditions. Multivariate analysis of variance (MANOVA) was conducted to determine if mean differences on EBBS benefits and barriers scores existed among disability types, between sexes, among age groups, and between physical activity levels. Sum scores were computed to determine the strongest benefit and barrier responses. RESULTS: No significant mean differences in EBBS scores were found between disability types, sexes, age groups, or physical activity levels (p > 0.05). Strongest benefit responses varied by group. Strongest barrier responses were the same for all demographic groups: "Exercise tires me," "Exercise is hard work for me," and "I am fatigued by exercise." CONCLUSIONS: EBBS scores were similar across disability/health condition, sex, age, and physical activity level. Primary benefits reported were in the areas of improved physical performance and psychological outlook whereas the primary barriers were in the area of physical exertion. PMID- 23021737 TI - Health beliefs and physical activity behavior in adults with multiple sclerosis. AB - BACKGROUND: Understanding how health beliefs intersect with physical activity in people with multiple sclerosis (MS) is an important step in developing effective activity promotion programs. OBJECTIVE: The purpose of the study was to employ the Health Belief Model (HBM) to assess the health beliefs of adults with MS and examine the relationship between health beliefs and physical activity behavior. METHOD: Participants with MS (N = 384) completed a web-based survey assessing the following HBM constructs: perceived susceptibility and seriousness of negative health outcomes, perceived benefits and barriers to physical activity, cues to action, and self-efficacy. Self-reported physical activity was also surveyed. RESULTS: Participant perceptions of susceptibility to negative health outcomes were focused more on physical conditioning and functioning rather than on general health conditions. The most important HBM predictors of physical activity were self-efficacy and perceived benefits of exercise. Even when controlling for the significant effects of disability level on physical activity, self-efficacy and perceived benefits remained robust exercise predictors. CONCLUSION: Individuals with MS believe they can benefit from physical activity and remain healthy even in the context of their disease. They also acknowledge the fact that their disability levels limit their exercise capabilities. Given that self-efficacy and perceived benefits of activity are important determinants of physical activity, health promotion efforts should be directed at these modifiable factors. PMID- 23021738 TI - Physical activity and depression in middle and older-aged adults with multiple sclerosis. AB - BACKGROUND: Depression is common among people with multiple sclerosis (MS), and research shows that individuals, including individuals with MS, who are more physically active report lower rates of depression. However, little is known about the relative importance of level of physical activity (e.g., moderate versus vigorous) in relationship to depression, or the role that age might play in this relationship among people with MS. The current study sought to (1) clarify the associations between moderate and vigorous physical activity and depression in a sample of individuals with MS, (2) determine the associations between age and physical activity, and (3) test for the potential moderating influence of age on the associations between physical activity and depression. OBJECTIVE/HYPOTHESIS: Cross-sectional survey. METHODS: 112 individuals with MS completed a survey assessing demographic variables, amount of moderate and vigorous physical activity, and depression. RESULTS: There was a gradual decrease in the amount of moderate and vigorous physical activity as age increased, but this decrease was not statistically significant. Moderate physical activity was significantly (negatively) associated with depression across all age cohorts. Time spent in vigorous physical activity was significantly (negatively) associated with depression among the middle-aged but not younger or older participants who are physically active. CONCLUSIONS: The findings support a link between moderate physical activity and depression and, for middle-aged individuals, vigorous physical activity and depression in persons with MS. The findings indicate that research examining the impact of activity enhancing treatments on depression in individuals with MS is warranted. PMID- 23021739 TI - Effects of pain and fatigue on physical functioning and depression in persons with muscular dystrophy. AB - BACKGROUND: Pain and fatigue are common symptoms experienced by persons with muscular dystrophy (MD). However, it is unclear from previous studies whether pain and fatigue have independent effects on physical functioning and depression, and whether age moderates the relationship of pain and fatigue with physical functioning and depression. OBJECTIVE: This cross-sectional study aimed to describe the relationship of pain and fatigue to physical functioning and depression in persons 20-89 years old with MD. METHOD: A convenience sample of 332 individuals with MD completed a questionnaire that included measures of physical functioning (PROMIS item bank items), depression (PHQ-9), pain intensity (0-10 NRS), and fatigue (0-10 NRS). RESULTS: Pain and fatigue were each independently associated with physical functioning and depression. Depressive symptoms were most severe among middle-aged participants (45-64 years old) relative to older and younger participants. Physical functioning had a negative relationship with chronological age. CONCLUSIONS: Symptoms of pain and fatigue are significantly and independently related to physical functioning and depression in persons with MD. Research is needed to determine if treatments that target both pain and fatigue in patients with MD have more beneficial effects than treatments that target only one of these symptoms. PMID- 23021740 TI - Correlates of nutritional behavior in individuals with multiple sclerosis. AB - BACKGROUND: Adults with multiple sclerosis (MS) have many health problems that can interfere with healthy nutritional behaviors. Self-management activities (e.g., strategies used to manage emotions and functional limitations) may help facilitate engagement in healthy nutritional behaviors. However, few studies have documented such relationships. OBJECTIVE: Identify predictors of nutritional behaviors from among a set of variables (i.e., personal characteristics, health status indicators, and self-management activities) linked to the International Classification of Function. METHODS: Data were obtained from an online survey of 292 individuals with MS. Significant bivariate correlates were entered into a logistic regression analysis using backward and forward selection methods to identify predictors of healthy nutritional behaviors (i.e., endorsing 4 out of 5 questions about frequently making good food choices, limiting fat intake, consuming 5 servings of fruits and vegetables, reading food labels, and eating regularly). RESULTS: Sex, nutritional self-efficacy, optimism/pessimism, body mass index, physical activity, emotional self-management, and communication with physician were used in the logistic analysis. Nutritional self-efficacy (beta = 0.69, p < 0.001) was the strongest predictor of nutritional behaviors, followed by physician communication (beta = 0.08, p = 0.029) and physical activity (beta = 0.01, p = 0.035). Neither impairments nor activity limitations were significantly associated with nutritional behaviors. CONCLUSIONS: This study provides preliminary evidence that self-efficacy and self-management activities are correlates of nutritional behaviors in individuals with MS. Supporting the development of self-management skills and increasing self-efficacy might be methods for improving engagement in healthy nutritional behaviors among adults with MS. PMID- 23021741 TI - Construction and validation of the Outpatient Health Care Usability Profile (OHCUP). AB - BACKGROUND: The Americans with Disabilities Act (ADA) requires health care facilities to provide equal access to patents with disabilities. Yet, people with disabilities experience many access barriers. OBJECTIVE/HYPOTHESIS: To develop a valid, reliable, and user-friendly tool that measures the physical and environmental features of outpatient health care facilities. Instead of addressing full compliance with the ADA, the tool measures the essential features of an outpatient health care facility. METHODS: The project included an online survey of people with disabilities (reported elsewhere), work groups of people with disabilities prioritizing ADA administrative guidelines (ADAAG), ADA expert review, measure development, pilot testing and re-testing. ADA experts' ratings were summarized as Content Validity Ratios (CVR). Retained ADAAG items were organized into a survey instrument and tested by raters at outpatient health clinics. Inter-rater reliability was assessed using Cohen's Kappa coefficient and Gwet's AC1 statistic. Refinement and re-testing of the instrument was conducted. RESULTS: The work groups narrowed the ADAG items from over 400 to 154 items. CVR ratings from ADA subject-matter experts reduced the items to 129. Inter-rater reliability for the pilot version was 0.61 (Kappa) and 0.88 (AC1). After refinement, inter-rater reliability was 0.77 (Kappa) and 0.90 (AC1). The items with the lowest reliability scores were re-examined, revised, and re-tested. Inter-rater reliability for the final version of the OHCUP was 0.89 (Kappa) and 0.97 (AC1). CONCLUSIONS: The OHCUP is a valid and reliable tool for measuring the usability of health care facilities. PMID- 23021742 TI - Parent perceptions of autism severity: exploring the social ecological context. AB - BACKGROUND: Health professionals incorporate parent reports into the diagnosis and treatment of children with an autism spectrum disorder (ASD). Yet little is known about the contextual forces that may shape parents' perceptions of their child. OBJECTIVES: The current study seeks to: 1) compare the social ecological contexts of parents of children with ASD and parents of non-autistic children, and 2) explore the social ecological influences on parents' perception of their child's ASD severity. METHODS: This study employed a cross-sectional analysis of data from the 2007-2008 National Survey of Children's Health (NSCH) in the United States. Social ecological factors of interest included variables depicting family physical environment, family social environment, and individual parent characteristics. RESULTS: Results indicate that parents of children with ASD had increased odds of reporting poor neighborhood social capital, greater aggravation, more difficulty coping, and lower levels of relationship satisfaction and mental health. Parents' perceptions of their child's ASD severity were associated with several factors of their social ecological context. More severe parent-reported ASD was associated with aspects of the physical environment (rundown housing and garbage on the street), the social environment (parent relationship satisfaction) and individual parent characteristics (parent aggravation and mental health). CONCLUSIONS: Results suggest ways that professionals can contextualize parent reports to aid in the diagnosis and treatment of children with ASD. Findings also highlight a need for longitudinal research using well-characterized measures to determine the nature and direction of relationships between contextual factors and parents' perceptions. PMID- 23021744 TI - A novel technique for harvesting autologous fat prior to its transfer. PMID- 23021743 TI - Evaluation of a multi-component group exercise program for adults with arthritis: Fitness and Exercise for People with Arthritis (FEPA). AB - BACKGROUND: Research supports the favorable effects of exercise on physical and psychosocial outcomes in those with arthritis. Few easily disseminated, multi component, arthritis-specific programs have been evaluated using both physical function and psychosocial measures. Fitness and Exercise for People with Arthritis (FEPA) is a new community-based, 3-month, instructor supervised multi component exercise program for individuals with arthritis designed to increase strength, flexibility, balance, and aerobic conditioning, while emphasizing joint protection and proper biomechanics. PURPOSE: To conduct a preliminary evaluation of the effects of the FEPA program on physical function and arthritis-related outcomes in individuals with arthritis. METHOD: Middle-aged (n = 31, M(age) = 54.8 +/- 7.2) and older (n = 79, M(age) = 76.0 +/- 6.6) adults with arthritis completed the instructor led FEPA program in community senior centers, churches, and adult education settings. Changes in physical function, measured using the arm curl, back-scratch test, 8-foot up-and-go, and 6 min walk and self-reported arthritis-related pain, perceived physical function, affect, and self-efficacy for symptom management were assessed using RM ANOVA. RESULTS: Significant improvements (ps < .05) in all physical function measures were found in the older group. In the middle-aged group, significant improvements (ps < .05) were found in the 8-foot up-and-go and 6 min walk. Self-reported physical function, pain perceptions, and self-efficacy for pain management significantly improved (ps < .05) in middle-aged participants, while only self-reported pain perceptions significantly improved in the older group. CONCLUSIONS: FEPA shows promise for improving health-related outcomes in those with arthritis, and has potential for sustainability in community settings. PMID- 23021745 TI - Can long-term ventricular assist devices be safely implanted in low-volume, non heart transplant centres? AB - BACKGROUND: Mechanical circulatory support (MCS) using long-term ventricular assist devices (VADs) is an established therapy in select patients with advanced heart failure. Studies have suggested that outcomes after VAD implantation may be dependent on institutional procedural volume, and outcome data from non transplant centres are lacking. This study reviews the outcomes of patients who received a long-term VAD at our centre to determine if these devices can be safely implanted at tertiary care, low-volume, non-transplant centres. METHODS: We conducted a single-centre retrospective cohort study, examining the clinical outcomes of consecutive patients who received a long-term VAD over a 42-month period. RESULTS: During the study period 73 patients required MCS, of whom 16 received a long-term VAD. This select group had a mean Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile of 1.6 (0.9) and before implantation 94% required at least 1 inotropic medication, 69% had suffered a cardiac arrest, 63% required an intra-aortic balloon pump, 69% required mechanical ventilation, and 44% required short-term MCS. The primary outcome of survival to transplant or ongoing MCS at 1 year was achieved in 75% of patients. Operating room, intensive care unit, and hospital survival were 100%, 88%, and 81%, respectively. CONCLUSIONS: Long-term VADs can be implanted at low volume, nontransplant centres with survival rates comparable with contemporary clinical trials. Availability of a specialty trained multidisciplinary team with expertise in short-term and long-term MCS options facilitates appropriate patient selection and might be more important than institutional volume in determining outcomes after implantation. PMID- 23021748 TI - Short communication: Recovery of viable Mycobacterium avium subspecies paratuberculosis from retail pasteurized whole milk in Brazil. AB - Mycobacterium avium ssp. paratuberculosis (MAP) is the etiological agent of paratuberculosis, a chronic granulomatous enteritis that affects all ruminants worldwide. Some researchers have indicated a possible role of MAP in Crohn's disease. Despite extensive research and large and important advances in the past few decades, the etiology of Crohn's disease remains indefinite. The most probable transmission route of MAP from animals to humans is milk and dairy products. Mycobacterium avium ssp. paratuberculosis has already been detected in milk samples worldwide, and some studies have reported that MAP is resistant to pasteurization. In Brazil, MAP has been reported in raw milk samples; however, Brazilian retail pasteurized milk has not yet been tested for viable MAP. The aim of this study was to investigate MAP in pasteurized milk in the region of Vicosa (Minas Gerais, Brazil). Thirty-seven samples were collected and processed for culture of MAP. One colony similar to MAP was observed and confirmed by IS900 nested PCR and sequencing. Analysis revealed 97 to 99% identity with the MAP K-10 strain. This study is the first report of the presence of MAP in retail pasteurized whole milk in Brazil. PMID- 23021747 TI - Reduced glutathione and Trolox (vitamin E) as extender supplements in cryopreservation of red deer epididymal spermatozoa. AB - The use of assisted reproductive techniques in cervids is increasing as the commercial use of these species increase. We have tested the suitability of the antioxidants Trolox and reduced glutathione (GSH) for freezing red deer epididymal spermatozoa, aiming at improving post-thawing quality. Samples from 19 stags were frozen in a TES-Tris-fructose extender (20% egg yolk, 8% glycerol), with 1 or 5 mM of antioxidant. Motility (CASA), lipoperoxidation (malondialdehyde -MDA- production), membrane status, mitochondrial activity, acrosomal status (flow cytometry) and chromatin status (SCSA: %DFI and %HDS; flow cytometry) were assessed after thawing and after 6 h at 39 degrees C. There were few differences between treatments after thawing, with Trolox reducing MDA production in a dose response manner. After the incubation, sperm quality decreased and %DFI increased moderately, with no change for MDA. GSH improved motility, kinematic parameters and mitochondrial status, with a slight increase in %HDS. GSH 5 mM also increased moderately MDA production and %DFI, possibly due to enhanced metabolic activity and reducing power. Trolox maintained MDA low, but was detrimental to sperm quality. Trolox might not be appropriate for the cryopreservation of red deer epididymal spermatozoa, at least at the millimolar range. GSH results are promising, especially regarding motility improvement after the post-thawing incubation, and should be selected for future fertility trials. PMID- 23021749 TI - Relationship between bacteriological findings in the second and fourth weeks postpartum and uterine infection in dairy cows considering bacteriological results. AB - The uterine lumen in early postpartum dairy cows is contaminated with different bacteria. The most relevant uterine pathogens are Escherichia coli and Trueperella pyogenes. Prevalence of alpha-hemolytic streptococci and coagulase negative staphylococci (CNS) is also high; however, these pathogens are considered opportunistic. The overall objective of this study was to investigate effects of the intrauterine presence of E. coli, T. pyogenes, alpha-hemolytic streptococci, or CNS at 10+/-1 d in milk (DIM) on the type of bacteria 2 wk later and their influence on uterine infections and subsequent reproductive performance. Furthermore, we set out to quantify 2 relevant methodological factors (i.e., laboratory and sampling instrument). Bacteriological samples were collected at 10+/-1 and 24+/-1 DIM from the uterine lumen using a cytobrush (CB). Vaginal mucus was classified by vaginoscopy. In a subsample, bacteriological results of 3 different laboratories and of CB and cotton swabs (CS) were compared. Samples of uterine discharge were collected at 10+/-1 DIM and bacteriological samples were taken using CB and CS. Bacteria were identified and bacterial growth quantified on a 4-point scale. Animals infected with E. coli or T. pyogenes at 10+/-1 DIM had a higher risk for an infection with the same bacterial species at 24+/-1 DIM [E. coli relative risk (RR)=3.7 and T. pyogenes RR=2.9]. Moreover, the risk of being diagnosed with abnormal vaginal discharge at 24+/-1 DIM increased in cows with E. coli (RR=1.7) or T. pyogenes (RR=1.7) at 10+/-1 DIM. Uterine infection with alpha-hemolytic streptococci or CNS did not increase the risk of an infection with T. pyogenes or E. coli or abnormal vaginal discharge 2 wk later. Cows with E. coli at 10+/-1 DIM or T. pyogenes at 24+/-1 DIM had greater days to first artificial insemination than cows positive for the 3 remaining bacterial species. Cows with T. pyogenes at 10+/-1 DIM had more days to pregnancy and more cows were culled when positive for E. coli at 10+/-1 DIM. Agreement of bacteriological results of 3 different laboratories were significant for laboratory A + B and A + C for the CB and CS. The highest agreement considering the bacterial species was for E. coli. All results for laboratory A + B and A + C for the CB and CS were significant. The results generated from samples collected with CB agreed nicely with those from CS from each laboratory (laboratory A: 250/272; laboratory B: 264/272; laboratory C: 253/272). PMID- 23021750 TI - Presynchronization with Double-Ovsynch improves fertility at first postpartum artificial insemination in lactating dairy cows. AB - The objective of this study was to compare circulating progesterone (P4) profiles and pregnancies per AI (P/AI) in lactating dairy cows bred by timed artificial insemination (TAI) following Ovsynch-56 after 2 different presynchronization protocols: Double-Ovsynch (DO) or Presynch-Ovsynch (PS). Our main hypothesis was that DO would increase fertility in primiparous cows, but not in multiparous cows. Within each herd (n=3), lactating dairy cows (n=1,687; 778 primiparous, 909 multiparous) were randomly assigned to DO [n=837; GnRH-7d-PGF(2alpha)-3d-GnRH-7d Ovsynch-56 (GnRH-7d-PGF(2alpha)-56h-GnRH-16hTAI)] or PS (n=850; PGF(2alpha)-14d PGF(2alpha)-12d-Ovsynch-56). In 1 herd, concentrations of P4 were determined at the first GnRH (GnRH1) of Ovsynch-56 and at d 11 after TAI (n=739). In all herds, pregnancy was diagnosed by palpation per rectum at 39 d. In 1 herd, the incidence of late embryo loss was determined at 74d, and data were available on P/AI at the subsequent second service. Presynchronization with DO reduced the percentage of animals with low P4 concentrations (<0.50 ng/mL) at GnRH1 of Ovsynch-56 (5.4 vs. 25.3%, DO vs. PS). A lesser percentage of both primiparous and multiparous cows treated with DO had low P4 concentrations at GnRH1 of Ovsynch-56 (3.3 vs. 19.7%, DO vs. PS primiparous; and 8.8 vs. 31.9%, DO vs. PS multiparous). Presynchronization with DO improved P/AI at the first postpartum service (46.3 vs. 38.2%, DO vs. PS). Statistically, a fertility improvement could be detected for primiparous cows treated with DO (52.5 vs. 42.3%, DO vs. PS, primiparous), but only a tendency could be detected in multiparous cows (40.3 vs. 34.3%, DO vs. PS, multiparous), consistent with our original hypothesis. Presynchronization treatment had no effect on the incidence of late embryo loss after first service (8.5 vs. 5.5%, DO vs. PS). A lower body condition score increased the percentage of cows with low P4 at GnRH1 of Ovsynch-56 and reduced fertility to the TAI. In addition, P4 concentration at d 11 after TAI was reduced by DO. The method of presynchronization at first service had no effect on P/AI at the subsequent second service (34.7 vs. 36.5%, DO vs. PS). Thus, presynchronization with DO induced cyclicity in most anovular cows and improved fertility compared with PS, suggesting that DO could be a useful reproductive management protocol for synchronizing first service in commercial dairy herds. PMID- 23021751 TI - Effect of late-gestation maternal heat stress on growth and immune function of dairy calves. AB - Heat stress during the dry period affects the cow's mammary gland development, metabolism, and immunity during the transition period. However, the effect of late-gestation heat stress on calf performance and immune status is unknown. Our objective was to evaluate the effect of heat stress during the final ~45 d of gestation on growth and immune function of calves. Calves (17/treatment) were born to cows that were exposed to cooling (CL) or heat stress (HT) during the dry period. Only heifer calves (CL, n=12; HT, n=9) were used in measurements of growth and immune status after birth. Heifer calves were managed under identical conditions. All were fed 3.78 L of colostrum from their respective dams within 4 h of birth and were weaned at 2 mo of age (MOA). Body weight (BW) was obtained at weaning and then monthly until 7 MOA. Withers height (WH) was measured monthly from 3 to 7 MOA. Hematocrit and plasma total protein were assessed at birth, 1, 4, 7, 11, 14, 18, 21, 25, and 28 d of age. Total serum IgG was evaluated at 1, 4, 7, 11, 14, 18, 21, 25, and 28 d of age, and apparent efficiency of absorption was calculated. Peripheral blood mononuclear cells were isolated at 7, 28, 42, and 56 d of age, and proliferation rate was measured by (3)H-thymidine incorporation in vitro. Blood cortisol concentration was measured in the dams during the dry period and in calves in the preweaning period. Gestation length was 4d shorter for HT cows compared with CL cows. Calves from CL cows had greater BW than calves from HT cows at birth (42.5 vs. 36.5 kg). Compared with CL heifers, HT heifers had decreased weaning BW (78.5 vs. 65.9 kg) but similar BW (154.6 vs. 146.4 kg) and WH (104.8 vs. 103.4 cm) from 3 to 7 MOA. Compared with CL, heifers from HT cows had less total plasma protein (6.3 vs. 5.9 g/dL), total serum IgG (1,577.3 vs. 1,057.8 mg/dL), and apparent efficiency of absorption (33.6 vs. 19.2%), and tended to have decreased hematocrit (33 vs. 30%). Additionally, CL heifers had greater peripheral blood mononuclear cell proliferation relative to HT heifers (23.8 vs. 14.1 fold). Compared with CL, late-gestation HT did not affect the blood cortisol concentration of dams during the dry period or that of the calves in the preweaning period, but CL calves tended to have increased circulating cortisol at birth (7.6 vs. 5.7 ug/dL). We conclude that heat stress of the dam during the dry period compromises the fetal growth and immune function of offspring from birth through weaning. PMID- 23021752 TI - Invited review: Genetics and modeling of milk coagulation properties. AB - Milk coagulation properties (MCP) are conventionally measured using computerized renneting meters, mechanical or optical devices that record curd firmness over time (CF(t)). The traditional MCP are rennet coagulation time (RCT, min), curd firmness (a(30), mm), and curd-firming time (k(20), min). The milk of different ruminant species varies in terms of CF(t) pattern. Milk from Holstein-Friesian and some Scandinavian cattle breeds yields higher proportions of noncoagulating samples, samples with longer RCT and lower a(30), and samples for which k(20) is not estimable, than does milk from Brown Swiss, Simmental, and other local Alpine breeds. The amount, proportion, and genetic variants (especially kappa-casein) of milk protein fractions strongly influence MCP and explain variable proportions of the observed differences among breeds and among individuals of the same breed. In addition, other major genes have been shown to affect MCP. Individual repeatability of MCP is high, whereas any herd effect is low; thus, the improvement of MCP should be based principally on selection. Exploitable additive genetic variation in MCP exists and has been assessed using different breeds in various countries. Several models have been formulated that either handle noncoagulating samples or not. The heritability of MCP is similar to that of other milk quality traits and is higher than the heritability of milk yield. Rennet coagulation time and a(30) are highly correlated, both phenotypically and genetically. This means that the use of a(30) data does not add valuable information to that obtainable from RCT; both traits are genetically correlated mainly with milk acidity. Moreover, a(30) is correlated with casein content. The major limitations of traditional MCP can be overcome by prolonging the observation period and by using a novel CF(t) modeling, which uses all available information provided by computerized renneting meters and allows the estimation of RCT, the potential asymptotic curd firmness, the curd-firming rate, and the syneresis rate. Direct measurements of RCT obtained from both mechanical and optical devices show similar heritabilities and exhibit high phenotypic and genetic correlations. Moreover, mid-infrared reflectance spectroscopy can predict MCP. The heritabilities of predicted MCP are higher than those of measured MCP, and the 2 sets of values are strongly correlated. Therefore, mid-infrared reflectance spectroscopy is a reliable and cheap method whereby MCP can be improved at the population level; this is because such spectra are already routinely acquired from the milk of cows enrolled in milk recording schemes. PMID- 23021753 TI - Test accuracy of metabolic indicators in predicting decreased fertility in dairy cows. AB - Negative energy balance is a known risk factor for decreased fertility in dairy cows. This study evaluated the accuracy of plasma concentrations of nonesterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), and insulin-like growth factor 1 (IGF-1)-factors related to negative energy balance-in predicting decreased fertility. One plasma sample per cow was collected from 480 cows in 12 herds during the period from d 4 to 21 in milk and analyzed for NEFA, BHBA, and IGF-1. For each cow, data on breed, parity, calving date, gynecological examinations, and insemination dates were obtained. Milk samples from 241 cows in 7 of the participating herds were analyzed for progesterone concentration to define the first day of luteal activity. The diagnostic sensitivity (Se) and specificity (Sp) at different cut-off concentrations of NEFA, BHBA, or IGF-1 were calculated and related to individual cow fertility status, measured as anestrus (ANEST), delayed first artificial insemination (DFAI), or delayed conception. Positive and negative predictive values (PV+; PV-) were calculated considering different levels of (within-herd) prevalence. Strata (i.e., subgroup)-specific Se and Sp and associations between test results and fertility parameters were investigated using logistic regression. The NEFA and BHBA tests for ANEST and DFAI had the highest combined Se and Sp and were thus evaluated further. Cut-off values with Sp around 80% were used in this step to provide a reasonable number of test positive cows, representing a practical situation. This corresponded to a cut-off value for the NEFA test of 400 uEq/L (Se 0.27-0.45) and for the BHBA test of 1.8mM (Se 0.15-0.30) across all cows included in the study. The estimated Sp was generally higher than the original 80%, but the corresponding Se was further decreased when the test was used in heifers compared with older cows. The true prevalence of ANEST in the study population was 27%, which gave a PV+ of 0.36 to 0.45 and a PV- of 0.76 to 0.79. With 35% true prevalence of DFAI, PV+ was 0.29 to 0.38 and PV- was 0.64 to 0.66. Thus, overall test performance was low when metabolic indicators measured as single values in early lactation were used to predict fertility in dairy cows, but accuracy was influenced by cow-level factors such as parity. The prevalence of the target condition (in this case, decreased fertility) also influences test usefulness and should be considered when planning test systems and interpreting test results. PMID- 23021754 TI - Comparing technical efficiency of farms with an automatic milking system and a conventional milking system. AB - Changing from a conventional milking system (CMS) to an automatic milking system (AMS) necessitates a new management approach and a corresponding change in labor tasks. Together with labor savings, AMS farms have been found to have higher capital costs, primarily because of higher maintenance costs and depreciation. Therefore, it is hypothesized that AMS farms differ from CMS farms in capital:labor ratio and possibly their technical efficiency, at least during a transition learning period. The current study used actual farm accounting data from dairy farms in the Netherlands with an AMS and a CMS to investigate the empirical substitution of capital for labor in the AMS farms and to determine if the technical efficiency of the AMS farms differed from the CMS farms. The technical efficiency estimates were obtained with data envelopment analysis. The 63 AMS farms and the 337 CMS farms in the data set did not differ in general farm characteristics such as the number of cows, number of hectares, and the amount of milk quota. Farms with AMS have significantly higher capital costs (?12.71 per 100 kg of milk) than CMS farms (?10.10 per 100 kg of milk). Total labor costs and net outputs were not significantly different between AMS and CMS farms. A clear substitution of capital for labor with the adoption of an AMS could not be observed. Although the AMS farms have a slightly lower technical efficiency (0.76) than the CMS farms (0.78), a significant difference in these estimates was not observed. This indicates that the farms were not different in their ability to use inputs (capital, labor, cows, and land) to produce outputs (total farm revenues). The technical efficiency of farms invested in an AMS in 2008 or earlier was not different from the farms invested in 2009 or 2010, indicating that a learning effect during the transition period was not observed. The results indicate that the economic performance of AMS and CMS farms are similar. What these results show is that other than higher capital costs, the use of AMS rather than a CMS does not affect farm efficiency and that the learning costs to use an AMS are not present as measured by any fall in technical efficiency. PMID- 23021755 TI - Evaluation of peripartal calcium status, energetic profile, and neutrophil function in dairy cows at low or high risk of developing uterine disease. AB - In this prospective cohort study, Holstein cows considered to be at high risk of developing metritis (dystocia, twins, stillbirth, retained placenta, or their combination) were matched with herdmates at low risk of developing metritis (normal calving) and monitored daily for rectal temperature and uterine discharge during the first 12 d in milk (DIM). Blood was sampled on d 0, 1, and 3 postpartum for assessment of neutrophil phagocytic and oxidative burst activities. Blood was also sampled at 0, 1, 2, 3, 4, 7, and 12 DIM for determination of serum concentrations of Ca, K, Mg, nonesterified fatty acids, beta-hydroxybutyrate, and glucose. On the basis of receiver operator characteristic curves, subclinical hypocalcemia (SCH) was defined as a serum Ca concentration <=8.59 mg/dL in at least 1 sample in the first 3 DIM. The overall incidences of metritis and puerperal metritis were 47.3 and 30%, respectively. Concentration in blood and percentages of neutrophils undergoing phagocytosis and oxidative burst were all reduced in cows with SCH compared with normocalcemic cows. Cows with SCH were at a greater risk of developing fever, metritis, and puerperal metritis compared with normocalcemic cows. Among cows at low risk of developing metritis, those with SCH had a greater incidence of metritis (40.7%) compared with normocalcemic cows (14.3%). Similarly, among cows at high risk of developing metritis, cows with SCH had a greater incidence of metritis (77.8%) compared with normocalcemic cows (20.0%). Cows with SCH had elevated concentrations of nonesterified fatty acids and beta-hydroxybutyrate compared with normocalcemic cows. The relative risk of developing metritis decreased by 22% for every 1mg/dL increase in serum Ca. Neither metritis nor SCH influenced the resumption of estrous cyclicity by 38 DIM, but cows with SCH had a reduced pregnancy rate and a longer interval to pregnancy compared with normocalcemic cows. Finally, the population risk to develop uterine diseases attributable to SCH was 66.6% for metritis and 91.3% for puerperal metritis in the present study. PMID- 23021756 TI - Emissions of ammonia, nitrous oxide, methane, and carbon dioxide during storage of dairy cow manure as affected by dietary forage-to-concentrate ratio and crust formation. AB - Sixteen 200-L barrels were used to determine the effects of dietary forage-to concentrate (F:C) ratio on the rate of NH(3)-N, N(2)O, CH(4), and CO(2) emissions from dairy manure during a 77-d storage period. Manure was obtained from a companion study where cows were assigned to total mixed rations that included the following F:C ratio: 47:53, 54:46, 61:39, and 68:32 (diet dry matter basis) and housed in air-flow-controlled chambers constructed in a modified tiestall barn. On d 0 of this study, deposited manure and bedding from each emission chamber was thoroughly mixed, diluted with water (1.9 to 1 manure-to-water ratio) and loaded in barrels. In addition, on d 0, 7, 14, 28, 35, 49, 56, 63, 70, and 77 of storage, the rate of NH(3)-N, N(2)O, CH(4), and CO(2) emissions from each barrel were measured with a dynamic chamber and gas concentration measured with a photo acoustic multi-gas monitor. Data were analyzed as a randomized complete block with 4 replications. Dietary F:C ratio had no effect on manure dry matter, total N and total ammoniacal-N (NH(3)-N + NH(4)(+)-N), or pH at the time of storage (mean +/- SD: 10.6+/-0.6%, 3.0+/-0.2%, 93.1+/-18.1 mg/dL, and 7.8+/-0.5, respectively). No treatment differences were observed in the overall rate of manure NH(3)-N, N(2)O, CH(4), and CO(2) emissions (mean +/- SD over the 77-d storage period; 117+/-25, 30+/-7, 299+/-62, and 15,396+/-753 mg/hr per m(2), respectively). The presence of straw bedding in manure promoted the formation of a surface crust that became air dried after about 1 mo of storage, and was associated with an altered pattern in NH(3)-N and N(2)O emissions in particular. Whereas NH(3)-N emission rate was highest on d 0 and gradually decreased until reaching negligible levels on d 35, N(2)O emission rate was almost zero the first 2 wk of storage, increased sharply to peak on d 35, and decreased subsequently. The emission rate of CH(4) and CO(2) peaked simultaneously on d 7, but decreased subsequently until the end of the storage period. In this study, C:N ratio of gaseous losses was 32:1, reflecting higher volatile C loss than volatile N loss during storage. On a CO(2)-equivalent basis, the most important source of non CO(2) greenhouse gas emitted was CH(4) until formation of an air-dried crust, but N(2)O thereafter. Taken together, these results suggested that the formation of an air-dried crust resulting from the straw bedding present in the manure reduced drastically NH(3)-N, and CH(4) emissions, but was conducive of N(2)O production and emission. PMID- 23021757 TI - Stability of free and encapsulated Lactobacillus acidophilus ATCC 4356 in yogurt and in an artificial human gastric digestion system. AB - The objective of this study was to determine the effect of encapsulation on survival of probiotic Lactobacillus acidophilus ATCC 4356 (ATCC 4356) in yogurt and during artificial gastric digestion. Strain ATCC 4356 was added to yogurt either encapsulated in calcium alginate or in free form (unencapsulated) at levels of 8.26 and 9.47 log cfu/g, respectively, and the influence of alginate capsules (1.5 to 2.5mm) on the sensorial characteristics of yogurts was investigated. The ATCC 4356 strain was introduced into an artificial gastric solution consisting of 0.08 N HCl (pH 1.5) containing 0.2% NaCl or into artificial bile juice consisting of 1.2% bile salts in de Man, Rogosa, and Sharpe broth to determine the stability of the probiotic bacteria. When incubated for 2h in artificial gastric juice, the free ATCC 4356 did not survive (reduction of >7 log cfu/g). We observed, however, greater survival of encapsulated ATCC 4356, with a reduction of only 3 log cfu/g. Incubation in artificial bile juice (6 h) did not significantly affect the viability of free or encapsulated ATCC 4356. Moreover, statistically significant reductions (~1 log cfu/g) of both free and encapsulated ATCC 4356 were observed during 4-wk refrigerated storage of yogurts. The addition of probiotic cultures in free or alginate-encapsulated form did not significantly affect appearance/color or flavor/odor of the yogurts. However, significant deficiencies were found in body/texture of yogurts containing encapsulated ATCC 4356. We concluded that incorporation of free and encapsulated probiotic bacteria did not substantially change the overall sensory properties of yogurts, and encapsulation in alginate using the extrusion method greatly enhanced the survival of probiotic bacteria against an artificial human gastric digestive system. PMID- 23021758 TI - The effect of milk fat globules on adherence and internalization of Salmonella Enteritidis to HT-29 cells. AB - Milk fat globules were extracted from bovine and goat milk and incubated with HT 29 human adenocarcinoma cells to assess the attachment and internalization of Salmonella Enteritidis. Because the expression of bacterial adhesins is highly affected by the presence of antibiotic, the attachment was studied with and without antibiotic in the cell growth medium. Although no inhibitory effect of the fat globules was observed in the presence of the antibiotic, milk fat globules significantly inhibited the binding and internalization of Salmonella in medium free of antibiotic. The fat globules from both bovine and goat milk markedly reduced bacterial binding and invasion compared with controls, and the cells treated with goat milk-derived fat globules demonstrated greater protective properties than those derived from bovine milk. The effect of heat treatment on bovine fat globules was also investigated, and it was shown that the fat globules from heated milk had a higher degree of inhibition than those from unheated milk. PMID- 23021759 TI - Effects of presynchronization with gonadotropin-releasing hormone-prostaglandin F2alpha or progesterone before Ovsynch in noncyclic dairy cows. AB - The aim of this study was to evaluate the efficiency of presynchronization with GnRH and PGF(2alpha) or with progesterone on overall Ovsynch (OVS) outcomes in noncyclic dairy cows. Cows were scanned 7 d apart with ultrasonography to determine cyclicity. Noncyclic cows (n=281; no corpus luteum on ovaries at both examinations) were randomly divided into 3 groups. In the GP group (n=108), the cows received GnRH and PGF(2alpha) (PGF) administrations 7 d apart, and OVS was started 11 d after PGF (GnRH-7 d-PGF-11 d-OVS). In the P4 group (n=90), the cows were treated for 7d with an intravaginal progesterone (P4) implant (PRID), and then OVS was started 11 d after removal of the implant (7d PRID-11 d-OVS). The control group (CON, n=83) did not receive any presynchronization, and OVS was started at the same time as in the other groups (18 d-OVS). The percentage of cows that became cyclic at the beginning of OVS was lower in the CON group (38.6%; 32/83) than in the presynchronization groups (66.7%, 72/108 in GP; 71.1%, 64/90 in P4). The response to the first GnRH of OVS did not differ among groups (63.9%, 53/83 in CON; 67.6%, 73/108 in GP; 63.3%; 57/90 in P4), and synchronization rates were similar among the groups (74-82%). The cows that responded to presynchronization treatments (GP or P4) had higher pregnancy per artificial insemination (P/AI) than did nonresponding cows. Pregnancy per AI at 31 d did not differ between groups (30.1%, 25/83 in CON; 43.5%, 47/108 in GP; and 35.6%, 32/90 in P4). However, CON cows (24.1%, 20/83) had lower P/AI at 62 d than GP cows (41.7%, 45/108). Embryonic loss was higher in CON (20%, 5/25) compared with the P4 group (3%, 1/32). The administration of GnRH followed by PGF or exogenous progesterone (PRID) similarly increased the percentage of cows that became cyclic before Ovsynch in noncyclic cows, but fertility did not improve. However, the cows that responded to presynchronization had higher fertility rates than the nonresponding cows. PMID- 23021760 TI - Short communication: Genetic parameters for mastitis and its predictors in Canadian Holsteins. AB - The objective of this study was to estimate genetic parameters for mastitis and its predictors [mean somatic cell score (SCS) in early lactation, standard deviation of SCS, excessive test-day somatic cell count (SCC), udder depth (UD), fore udder attachment (FUA), and body condition score (BCS)]. Mastitis data recorded by producers were available from the national dairy cattle health system in Canada. Mastitis was defined as a binary variable based on whether or not the cow had at least 1 mastitis case in the period from calving to 305 d after calving. A Bayesian analysis using Gibbs sampling was applied. Threshold liability models were applied for binary traits (mastitis and excessive test-day SCC), and linear models were used for other normally distributed traits. For mastitis, a heritability of 0.07 was obtained. Heritability estimates for mean SCS in early lactation, standard deviation of SCS, excessive test-day SCC, UD, FUA, and BCS were 0.10, 0.04, 0.06, 0.41, 0.21, and 0.18, respectively. Mastitis was highly correlated with mean SCS in early lactation (0.63), standard deviation of SCS (0.74), and excessive test-day SCC (0.76). Moderate genetic correlations of -0.36, -0.24, and -0.28 were found between mastitis and UD, FUA, and BCS, respectively. As much as 72% of the genetic variation in mastitis resistance was explained by all the indirect predictor traits, whereas the most commonly used indirect measures of mastitis resistance (SCS in early lactation, UD, and FUA) explained together only 46% of the genetic variation in mastitis resistance. A combination of mean and standard deviation of SCS seem to be more successful in improving udder health than the traditional indirect measures. The results of the present study highlight that although routine cow SCC is the best measurement to monitor udder health, it cannot explain all the genetic variation in mastitis resistance and, therefore, direct information on mastitis resistance can be expected to yield to a more accurate genetic evaluation for this trait. PMID- 23021761 TI - Brain integration: from networks to the cellular-molecular level. PMID- 23021762 TI - Unique case of giant Kommerell diverticulum with aberrant left subclavian artery arising from the left aortic arch associated with situs inversus. PMID- 23021763 TI - Endothelial dysfunction measured by peripheral arterial tonometry predicts prognosis in patients with heart failure with preserved ejection fraction. AB - BACKGROUND: There is need for risk stratification of adverse events in patients with heart failure with HFpEF as the number of patients is increasing and prognosis of this population is poor. This study was performed to determine whether endothelial dysfunction measured by peripheral artery tonometry (PAT) can predict prognosis of patients with heart failure with preserved ejection fraction (HFpEF). METHODS: We included 159 patients with HFpEF, and log-transformed reactive hyperemia index (L_RHI) was measured. Patients were followed-up for HF related events, which including HF-related death and re-hospitalization due to congestive heart failure for 300 days. RESULTS: A total of 32 HF-related events occurred during follow-up, including 4 deaths due to HF and 28 cases of re hospitalization due to acute decompensated HF. Cox regression analysis indicated that L_RHI (HR 0.56, 95% CI: 0.39-0.80 for an increase of 0.1) was an independent predictor of HF-related events. Receiver operating characteristic analysis was performed for L_RHI, and the area under the curve was 0.73 (95% CI: 0.62-0.83). Moreover, a value of 0.49 was suggested as the optimal cut-off value for prediction of adverse events in this population. CONCLUSION: L_RHI measured by non-invasive PAT is a predictor of poor prognosis in patients with HFpEF. PMID- 23021764 TI - Frequency of Brugada type ECG pattern in male subjects with fever. PMID- 23021765 TI - Why do we need an official journal in English? PMID- 23021766 TI - Recent findings in chronic obstructive pulmonary disease by using quantitative computed tomography. AB - Chronic obstructive pulmonary disease (COPD) is characterized by an incompletely reversible airflow limitation that results from a combination of airway wall remodeling and emphysematous lung destruction. Forced expiratory volume in 1s (FEV(1)) has been considered the gold standard for diagnosis, classification, and follow-up in patients with COPD, but it has certain limitations and it is still necessary to find other noninvasive modalities to complement FEV(1) to evaluate the effect of therapeutic interventions and the pathogenesis of COPD. Quantitative computed tomography (CT) has partly met this demand. The extent of emphysema and airway dimensions measured using quantitative CT are associated with morphological and functional changes and clinical symptoms in patients with COPD. Phenotyping COPD based on quantitative CT has facilitated interventional and genotypic studies. Recent advances in COPD findings with quantitative CT are discussed in this review. PMID- 23021767 TI - Rapid decrease in forced vital capacity in patients with idiopathic pulmonary upper lobe fibrosis. AB - BACKGROUND: We are occasionally presented with patients with unclassifiable interstitial pneumonia of unknown etiology. Idiopathic pulmonary upper lobe fibrosis (IPUF) does not fit any of the currently defined subsets of idiopathic interstitial pneumonias (IIPs). This study was performed to examine clinical, functional, and pathological characteristics of IPUF. METHODS: We present 9 cases of histologically confirmed IPUF. The clinical and histological characteristics of the 9 patients were evaluated. The baseline respiratory function of all patients was measured. There were 7 patients whose forced vital capacity (FVC) had been monitored for at least a year who were selected to quantify the yearly decline in FVC. RESULTS: All patients were slender, with a body mass index of 16.0-19.8 kg/m(2). Seven patients had a history of pneumothorax. Six patients died 1.8 to 5.7 years after the onset of the first symptoms. Fundamental histological features were intraalveolar collagen deposition and densely packed elastic fibers in the subpleural areas. These findings are the same as those seen in pleuroparenchymal fibroelastosis. However, the visceral pleura was thickened with dense collagen in only 2 patients, and pleural thickening was localized, if present, in the remaining 7 patients. Ventilatory impairment was also a characteristic. The time course decline of FVC was rapid and almost linear. The median yearly decline in FVC was -20.3% (range, -7.7% to -26.5%), which was more rapid than that reported for chronic fibrosing interstitial pneumonias such as idiopathic pulmonary fibrosis. CONCLUSIONS: IPUF is a unique pulmonary fibrosis that results in rapid deterioration of ventilatory function and poor prognosis. PMID- 23021768 TI - Long-term management of chronic obstructive pulmonary disease: a survey of collaboration among physicians involved in pulmonary rehabilitation in Japan. AB - BACKGROUND: This study evaluated the implementation of pulmonary rehabilitation (PR), and the extent of the collaboration between primary care and chest physicians involved in the management of chronic obstructive pulmonary disease (COPD) in Japan. METHODS: The survey was conducted in 2006 via post and facsimile and included all medical institutions approved by the Japan Respiratory Society. RESULTS: In total, 176 institutions responded (response rate, 27%); a PR program was conducted at 55.1% of these institutions throughout Japan, but with regional differences. The mean duration of each session in an outpatient setting was 30 min with 2 sessions per week, and the mean length of hospitalization was 2-3 weeks. Although 33% of the hospitals adopted PR programs, on a scale from none (0) to maximum achievement (100), the accomplishment score was 48. Similarly, the mean satisfaction level score for collaboration was 44. The main problem arising with regards to chest physicians' referral to general physicians was the reluctance of patients or family members (88%). Chest physicians believed that general physicians should perform early screening of patients and manage early exacerbations, including educating patients of the need to discontinue smoking. CONCLUSIONS: Most chest physicians in Japan were not satisfied with the status of long-term COPD management. PR for COPD patients and collaboration between primary care physicians and specialists remain problematic in Japan. Moreover, there are widespread regional differences in terms of implementation. Sharing and implementing appropriate clinical information with primary care physicians according to current clinical guidelines should be emphasized. PMID- 23021769 TI - Th1 and Th17 immune responses to viable Propionibacterium acnes in patients with sarcoidosis. AB - BACKGROUND: Propionibacterium acnes and Mycobacterium tuberculosis have emerged as probable candidates responsible for sarcoidosis. This study was conducted to investigate the Th1/Th17 responses elicited by these pathogens in sarcoidosis and to clarify the causative role of these pathogens. METHODS: Peripheral blood mononuclear cells (PBMCs) obtained from patients with sarcoidosis and from healthy volunteers were, respectively, co-cultured with viable P. acnes, with Bacille de Calmette et Guerin (BCG) as a viable M. tuberculosis complex, and with the early secretory antigenic target (ESAT)-6. Th1 cytokine production was measured using RT-PCR and enzyme-linked immunospot (ELISPOT) assays, and interleukin (IL)-17 mRNA expression was measured by RT-PCR. RESULTS: IL-2 secretion from PBMCs after stimulation with P. acnes was significantly higher in patients with sarcoidosis than in the controls. Similarly, IL-2 and IL-12 mRNA expression after stimulation with P. acnes was significantly higher in PBMCs from patients with sarcoidosis than in PBMCs from controls. In contrast, IL-17 mRNA expression was significantly lower in PBMCs from patients with sarcoidosis than in PBMCs from controls. No significant differences between the groups were observed in the responses to stimulation with BCG or ESAT-6. CONCLUSION: Sarcoidosis may arise from an imbalance of Th1/Th17 immune responses against viable P. acnes, but not M. tuberculosis complex. PMID- 23021770 TI - Analysis of gene expression profiles in alveolar epithelial type II-like cells differentiated from human alveolar epithelial progenitor cells. AB - BACKGROUND: Damage to lung epithelial cells through chronic injury and abnormal repair and remodeling lead to lung destruction and fibrosis. We isolated lung progenitor cells that could potentially contribute to lung diseases. The progenitor cells can differentiate into alveolar type II (ATII)-like cells in vitro, and are increased in number and localized within the region of alveolar epithelial cell proliferation that is involved in the reparative response to injury. However, global gene expression patterns in the ATII-like cells derived from the progenitor cells and in mature ATII cells isolated from lung tissue have not yet been evaluated. METHODS: We performed gene expression array and directly compared the gene expression patterns in ATII-like cells derived from the progenitor cells with those in mature ATII cells isolated from human lung tissues. RESULTS: ATII-like cells and mature ATII cells expressed certain common genes, such as CEPBD and FOXP1, which determine the phenotypes of ATII cells. However, many genes were differentially expressed between the 2 cell types. As compared to mature ATII cells, ATII-like cells showed decreased expression of the genes associated with surfactant protein production and epithelial phenotypes. Pathway analysis indicated changes in several pathways, including those involved in epithelial-to-mesenchymal transition and receptor tyrosine kinase signaling, which could contribute to the observed differences in gene expression patterns. CONCLUSIONS: In this study, we identified genes commonly or differentially expressed by ATII-like cells differentiated from progenitor cells and mature ATII cells isolated from human lung tissues. PMID- 23021771 TI - Miliary brain metastases in 2 cases with advanced non-small cell lung cancer harboring EGFR mutation during gefitinib treatment. AB - Here we report 2 cases of non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) gene mutation that developed miliary brain metastases characterized by dementia and disorientation during gefitinib therapy. One patient's therapy was switched from gefitinib to chemotherapy followed by whole brain radiotherapy (WBRT), which resulted in disease progression with coma. Gefitinib reinitiation improved the patient's symptoms. The other patient continued gefitinib during WBRT and achieved complete remission of the miliary metastases and lived 18 months longer. These results suggest that gefitinib concomitant with WBRT is an optional strategy for the treatment of patients with EGFR-mutated NSCLC with miliary metastases to prevent disease flare. PMID- 23021772 TI - An integrated data analysis approach to investigating measurement equivalence of DSM nicotine dependence symptoms. AB - INTRODUCTION: Research identifying nicotine dependence (ND) symptoms most appropriate for measurement of adolescent ND and invariant across the range of smoking exposure is hampered by limited sample size and variability of smoking behavior within independent studies. Integrative data analysis, the process of pooling and analyzing data from multiple studies, produces larger and more heterogeneous samples with which to evaluate measurement equivalence across the full continuum of smoking quantity and frequency. METHODS: Data from two studies were pooled to obtain a large sample of adolescent and young adult smokers with considerable variability in smoking. We used moderated nonlinear factor analysis, which produces study equivalent ND scores, to simultaneously evaluate whether 14 DSM ND symptoms had equivalent psychometric properties (1) at different levels of smoking frequency and (2) across a continuous range of smoking quantity, after accounting for study differences. RESULTS: Nine of 14 symptoms were equivalent across levels of smoking frequency and quantity in probability of endorsement at different levels of ND and in ability to discriminate between levels of ND severity. A more precise ND factor score accounted for study and smoking related differences in symptom psychometric properties. CONCLUSIONS: DSM-IV symptoms may be used to reliably assess ND in young populations across a wide range of smoking quantity and frequency and within both nationally representative and geographically restricted samples with different study designs. Symptoms shared across studies produced an equivalently scaled ND factor score, demonstrating that integrating data for the purpose of studying ND in young smokers is viable. PMID- 23021773 TI - Atypical neural activity during inhibitory processing in substance-naive youth who later experience alcohol-induced blackouts. AB - BACKGROUND: Alcohol-induced blackouts are associated with the development of alcohol abuse and dependence, so it is important to consider potential neurobiological risk factors for experiencing this problem prior to the onset of substance use. This study examines whether neural activity during inhibitory processing might be atypical in substance-naive youth who later experience alcohol-induced blackouts. METHODS: We examined inhibitory processing during fMRI with a go/no-go task that requires withholding a prepotent response in substance naive youth who would later transition into heavy drinking (n=40) and youth who remain abstinent (n=20). After approximately 5 years of annual follow-up assessments, youth were classified as nondrinkers (n=20), and heavy drinking youth were classified as having experienced an alcohol-induced blackout (blackout+; n=20) or not (blackout-; n=20). Groups were matched on demographic variables, and youth who experienced blackouts were matched on follow-up substance use. RESULTS: Prior to initiating substance use, blackout+ youth showed greater activation during inhibitory processing than nondrinkers and blackout- youth in frontal and cerebellar brain regions. Mean activation during correct inhibitory responses relative to go responses in the left and right middle frontal gyri at baseline predicted future blackout experience, after controlling for follow-up externalizing behaviors and lifetime alcohol consumption. CONCLUSIONS: Substance-naive adolescents who later experience alcohol-induced blackouts show increased neural effort during inhibitory processing, as compared to adolescents who go on to drink at similar levels but do not experience blackouts and healthy, nondrinking controls, suggesting a neurobiological vulnerability to alcohol-induced memory impairments. PMID- 23021774 TI - KB-R7943 restores endothelium-dependent relaxation induced by advanced glycosylation end products in rat aorta. AB - OBJECTIVES: The aims of this study were to examine the effects of KB-R7943, an inhibitor of Na(+)/Ca(2+) exchanger, on impaired endothelium-dependent relaxation (EDR) induced by advanced glycosylation end products (AGE) in isolated rat aorta. METHODS: Both acetylcholine (ACh)-induced EDR and sodium nitroprusside (SNP) induced endothelium-independent relaxation (EIR) were measured after the rings were exposed to AGE in the absence and presence of KB-R7943. RESULTS: Co incubation of aortic rings with AGE (0.1 g/L) for 24 h resulted in a significant inhibition of EDR, but had no effects on EIR. After incubation of the rings in the co-presence of KB-R7943 (0.1-10 MUM) with AGE for 24 h, KB-R7943 (10 MUM) significantly attenuated impaired EDR. Superoxide dismutase (200 U/mL) and l arginine (3mM) could ameliorate the impairment of EDR caused by AGE, whereas d arginine (3mM) had no effect on EDR. Similarly, AGE decreased superoxide dismutase (SOD) activity and the release of nitric oxide (NO), and increased superoxide anion (O(2)(.-)) production in aortic tissue. KB-R7943 (10 MUM) significantly decreased O(2)(.-) production and increased SOD activity and the NO release. CONCLUSIONS: These results suggest that KB-R7943 attenuated the impairment of EDR elicited by AGE partially through scavenging oxygen free radicals. PMID- 23021775 TI - Effect of age on atherogenicity of LDL and inflammatory markers in healthy women. AB - BACKGROUND AND AIM: Since using LDL level alone is insufficient as a method to identify individuals with incident coronary artery disease (CAD), other factors may be implicated in the pathogenesis of CAD. Additionally, controversy still remains regarding whether there is an age-related increase in circulating cytokines in healthy individuals. We investigated the influence of age on atherogenicity of LDL and inflammatory markers in healthy women. METHODS AND RESULTS: Two thousand nine hundred forty four healthy women form 30-79 years old (23.3 +/- 0.05 kg/m2) were categorized into 5 age groups: 30-39, 40-49, 50-59, 60 69 and 70-79 years. BMI, smoking, drinking, and metabolic syndrome prevalence adjusted mean values of total-cholesterol progressively increased from the group age 30-39 years to the group age 40-49 and 50-59 years and thereafter decreased in the group age 60-69 and 70-79 years. Serum concentrations of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were higher in women aged 60-79 years than women aged 30-59 years. Plasma ox-LDL levels increased in the group age 50-59 years compared with the group age 30-39 and 40-49 years and further increased in the group age 60-69 and 70-79 years. Mean values of LDL particle size were smaller in women aged 60-79 years than those in women aged 30-59 years. After adjustment for BMI, smoking, drinking, and metabolic syndrome status, age was positively correlated with LDL-cholesterol (r = 0.095, P < 0.001), oxidized LDL (r = 0.305, P < 0.001), hs-CRP (r = 0.150, P < 0.001), TNF-alpha (r = 0.171, P < 0.001) and IL-6 (r = 0.294, P < 0.001) and negatively with LDL particle size (r = -0.239, P < 0.001). CONCLUSION: Our results indicate that LDL atherogenicity and inflammatory mediators can be better markers of CAD risk than known risk factors such as elevated concentrations of total- and LDL-cholesterol, decreased HDL-cholesterol levels and smoking in old healthy women. PMID- 23021776 TI - Automatic segmentation of lung nodules with growing neural gas and support vector machine. AB - Lung cancer is distinguished by presenting one of the highest incidences and one of the highest rates of mortality among all other types of cancer. Unfortunately, this disease is often diagnosed late, affecting the treatment outcome. In order to help specialists in the search and identification of lung nodules in tomographic images, many research centers have developed computer-aided detection systems (CAD systems) to automate procedures. This work seeks to develop a methodology for automatic detection of lung nodules. The proposed method consists of the acquisition of computerized tomography images of the lung, the reduction of the volume of interest through techniques for the extraction of the thorax, extraction of the lung, and reconstruction of the original shape of the parenchyma. After that, growing neural gas (GNG) is applied to constrain even more the structures that are denser than the pulmonary parenchyma (nodules, blood vessels, bronchi, etc.). The next stage is the separation of the structures resembling lung nodules from other structures, such as vessels and bronchi. Finally, the structures are classified as either nodule or non-nodule, through shape and texture measurements together with support vector machine. The methodology ensures that nodules of reasonable size be found with 86% sensitivity and 91% specificity. This results in a mean accuracy of 91% for 10 experiments of training and testing in a sample of 48 nodules occurring in 29 exams. The rate of false positives per exam was of 0.138, for the 29 exams analyzed. PMID- 23021778 TI - Postoperative use of drain in thyroid lobectomy - a randomized clinical trial conducted at Civil Hospital, Karachi, Pakistan. AB - BACKGROUND: Thyroidectomy is a common surgical procedure, after which drains are placed routinely. This study aims to assess the benefits of placing postoperative drains, its complications and affects on postoperative stay, in thyroid lobectomy. METHODOLOGY: Randomized Clinical Trial of 60 goitre patients undergoing lobectomy was conducted at Civil Hospital Karachi, during July'11 December'11. Patients were randomly assigned into drain and non drain groups. Patient demographics, labs and complications were noted. Ultrasound of neck was performed on both groups. For drain group, the amount of fluid present in the surgical bed and redivac drain was added to calculate fluid collection while in non drain group it was calculated by ultrasound of neck on first and second post op days. Data was entered and analyzed on SPSS v16 using Independent T tests. RESULT: The mean total drain output for 2 days in non-drain group was significantly lower 10.67 (+/-9.072) ml while in drain group was 30.97 (+/ 42.812) ml (p = 0.014). The mean postoperative stay of drain group (79.2 +/-15.63 hours) was significantly higher, as compared to mean postoperative stay of non drain group (50.4 +/-7.32 hours). Mean Visual Analogue Score (VAS) for pain day 1 (6.2 +/-0.997) and day 2 (4.17 +/-0.95) in drain group were significantly higher compared to day 1 (2.6 +/-1.163) and day 2 (1.3 +/-0.877 ) of non drain group. From drain group, 2 patients complained of stridor, dyspnea on Day 1 which subsided by Day 2 and 1 case of voice change, with no such complains in non drain group. No patients from both groups developed seroma, wound infection or hematoma. CONCLUSION: In uncomplicated surgeries especially for lobectomy, use of drain can be omitted. PMID- 23021779 TI - Perspectives in atopic dermatitis-optimizing outcomes: introduction. PMID- 23021777 TI - A validated regulatory network for Th17 cell specification. AB - Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORgammat working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage specifying TF RORgammat, which plays a focal deterministic role at key loci. Integration of multiple data sets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease. PMID- 23021780 TI - Treatment strategies for atopic dermatitis: optimizing the available therapeutic options. AB - Bathing and moisturization to control dryness, applications of topical anti inflammatory agents (including corticosteroids and calcineurin inhibitors [TCIs]) to control flares, minimization of the risk for infection, and relief of pruritus are the cornerstones of effective therapy for atopic dermatitis. Education of parents and patients is crucial to enhance adherence. Strategies for reduced Staphylococcus aureus colonization may help control re-emergence of flares following cessation of antimicrobial treatment for infection; these include dilute bleach baths and minimizing the risk for contamination of topical agents. In severe, refractory cases, more aggressive therapy with systemic immunosuppressants may be considered, but appropriate laboratory testing must be included as part of patient monitoring during treatment. The value of adjuvant therapy with wet wraps to "cool down" particularly erythematous and pruritic flares is becoming increasingly recognized. PMID- 23021781 TI - Understanding and managing atopic dermatitis in adult patients. AB - Atopic dermatitis (AD) in adults is an important dermatologic disease. Even in patients in whom the clinical presentation is mild, the burden of disease can be considerable. Relatively little has been published on adult AD compared to the body of literature devoted to AD in children, although adults with severe AD are greatly affected by the disease. Even when AD is a mild clinical disease in adults, the psychosocial and economic burden of the disease can be profound. Patients are likely to find it useful if these nondermatologic comorbidities of AD are addressed by health care providers in clinical encounters. The treatment options for AD in adults are the same as those for children with AD, with some modifications. PMID- 23021782 TI - Improving the patient-clinician and parent-clinician partnership in atopic dermatitis management. AB - Long-term adherence to carefully developed, individualized strategies is necessary for the optimum treatment outcomes in patients with atopic dermatitis (AD). However, the parents of children with AD frequently lack sufficient information about the disease and its treatment, hold incorrect and sometimes harmful beliefs about these issues, and too often do not follow through consistently with the treatment plan. The health care provider is the primary source of such education, so an effective provider relationship is fundamental to adherence. In addition to the provision of correct information and the correction of misinformation, clinicians must be aware of and must address barriers to adherence with AD therapy, especially parent anxiety about the safety of topical medications (corticosteroids and topical calcineurin inhibitors). PMID- 23021783 TI - Atopic dermatitis: epidemiology and pathogenesis update. AB - The prevalence of atopic dermatitis (AD) has increased markedly in the United States over the past 5 decades, with current reports varying from 10% to 20% prevalence in US children, and new diagnoses are estimated at almost 11% per year. Recent research in AD pathophysiology and pathogenesis has demonstrated that AD is associated with epidermal barrier dysfunction and that mutations in the filaggrin gene are implicated in barrier defects. These discoveries hold promise for future breakthroughs in the diagnosis and management of AD. PMID- 23021784 TI - Current issues in atopic comorbidities and preventing the atopic march. AB - The individual, family, and public health burden of atopic dermatitis (AD) is considerable. The prevalence of AD is high, the signs and symptoms of the disease adversely affect quality of life for patients and their families, and the comorbid conditions associated with AD can increase considerably the negative impact of the disease. These comorbid conditions patients with AD are susceptible to include skin infectious, IgE-mediated diseases, and mental health disorders. New research identifies the skin barrier as not only an important initiator of atopic dermatitis but may even be a site for allergic sensitization to protein antigens. The skin barrier represents a potential new target for novel atopic prevention strategies. PMID- 23021785 TI - The effect of bilingual exposure versus language impairment on nonword repetition and sentence imitation scores. AB - PURPOSE: Nonword repetition (NWR) and sentence imitation (SI) are increasingly used as diagnostic tools for the identification of Primary Language Impairment (PLI). They may be particularly promising diagnostic tools for bilingual children if performance on them is not highly affected by bilingual exposure. Two studies were conducted which examined (1) the effect of amount of bilingual exposure on performance on French and English nonword repetition and sentence imitation in 5 year-old French-English bilingual children and (2) the diagnostic accuracy of the French versions of these measures and of receptive vocabulary in 5-year-old monolingual French-speakers and bilingual speakers with and without PLI, carefully matched on language exposure. METHOD: Study 1 included 84 5-year-olds acquiring French and English simultaneously, differing in their amount of exposure to the two languages but equated on age, nonverbal cognition and socio economic status. Children were administered French and English tests of NWR and SI. In Study 2, monolingual and bilingual children with and without PLI (four groups, n=14 per group) were assessed for NWR, SI, and receptive vocabulary in French to determine diagnostic accuracy. RESULTS: Study 1: Both processing measures, but in particular NWR, were less affected by previous exposure than vocabulary measures. Bilingual children with varying levels of exposure were unaffected by the length of nonwords. Study 2: In contrast to receptive vocabulary, NWR and SI correctly distinguished children with PLI from children with typical development (TD) regardless of bilingualism. Sensitivity levels were acceptable, but specificity was lower. CONCLUSIONS: Bilingual children perform differently than children with PLI on NWR and SI. In contrast to children with PLI, bilingual children with a large range of previous exposure levels achieve high NWR scores and are unaffected by the length of the nonwords. LEARNING OUTCOMES: Readers will recognize the effect of language input on the rate of language development, focusing specifically on how bilingual exposure affects the language learning of each language of bilingual children. PMID- 23021786 TI - Open guide suture technique for distal fingertip replantation. PMID- 23021787 TI - A propeller flap based on the thoracoacromial artery for reconstruction of a skin defect in the cervical region: a case report. AB - A propeller flap is useful for coverage of an adjacent skin defect without dissection back to source vessels and harvesting muscle tissues. The thoracoacromial artery is one of the vascular pedicles of the flaps for reconstruction in the cervical region. Use of a propeller flap based on the thoracoacromial artery has not previously been reported for reconstruction in the cervical region. We report a case in which a propeller flap based on the thoracoacromial artery was used for skin coverage after tumour resection in the cervical region together with an anatomical investigation. The propeller flap based on the thoracoacromial artery was harvested in the supine position, requiring no change in position after tumour resection. The skin defect was successfully reconstructed using the propeller flap based on the thoracoacromial artery with linear closure of the donor site. The propeller flap based on the thoracoacromial artery offers an alternative for reconstruction in the cervical region. PMID- 23021788 TI - Reconstruction of the sacral region using the lumbo-gluteal sensory flap. AB - PURPOSE: Local skin flaps are used for reconstruction of sacral decubitus ulcers because of their structural endurance against the patient's weight. However, a major concern is associated with decubitus recurrence after repair. Sensory flaps are one choice to prevent recurrence. Thus, we reconstructed sacral decubitus ulcers using Nakajima's lumbo-gluteal flap as a sensory flap. PATIENTS AND METHODS: Two patients with unstable sacral scars caused by decubitus ulcers were treated operatively. Neither had spinal cord injury, and buttock sensation thus remained. The flap's proximal end was designed on the posterior iliac crest and included the lateral dorsal cutaneous branch of the fourth lumbar artery as examined preoperatively with a Doppler stethoscope. The distal end was beyond the gluteal fold in case 1, but not in case 2. We subcutaneously dissected the vascular pedicle and the superior cluneal nerve located at the proximal portion of the flap after resection of the unstable scar. We then elevated the flap beneath the fascia of the gluteus maximus of the right buttock, preserving the nerve, artery and subcutaneous tissue as one pedicle, and transferred the flap to the defect. RESULTS: In case 1, 2 cm of the distal end of the flap was lost. The sensation of the proximal two-thirds of the flap was identical to that of the contralateral buttock. However, the distal one-third of the flap, which was elevated from the area caudal to the gluteal fold, had insufficient sensation. Case 2 had complete flap survival and sufficient sensation in all areas of the flap. Decubitus recurrence has not occurred in 7 years in case 1 and in 9 months in case 2. CONCLUSION: This flap is useful for reconstruction of sacral decubitus ulcers if sensory function of the buttock remains and may be best designed as not extending beyond the gluteal fold. PMID- 23021789 TI - Performing the Union: the Prum Decision and the European dream. AB - In 2005, seven European countries signed the so-called Prum Treaty to increase transnational collaboration in combating international crime, terrorism and illegal immigration. Three years later, the Treaty was adopted into EU law. EU member countries were now obliged to have systems in place to allow authorities of other member states access to nationally held data on DNA, fingerprints, and vehicles by August 2011. In this paper, we discuss the conditions of possibility for the Prum network to emerge, and argue that rather than a linear ascent towards technological and political convergence and harmonisation, the (hi)story of Prum is heterogeneous and halting. This is reflected also in the early stages of implementing the Prum Decision which has proven to be more challenging than it was hoped by the drivers of the Prum process. In this sense, the Prum network sits uncomfortably with success stories of forensic science (many of which served the goal of justifying the expansion of technological and surveillance systems). Instead of telling a story of heroic science, the story of Prum articulates the European dream: one in which goods, services, and people live and travel freely and securely. PMID- 23021790 TI - The impact of medication reconciliation program at admission in an internal medicine department. AB - BACKGROUND: Medication reconciliation process has proved to be an effective tool to improve the safety of drug use. The objective of this study was to assess the impact of an intervention aimed to decrease unintended discrepancies between patient's usual treatment and medications prescribed on admission to the Department of Internal Medicine. METHODS: A quasi-experimental study was carried out from June 2009 to May 2010, analyzing discrepancies between home medication and drugs prescribed in a tertiary care hospital, before (first phase) and after (second phase) an electronic reconciliation tool was introduced at admission. This tool connected patients' usual medication with the electronic prescription program. The research team was made up of two hospital pharmacists, two nurses and three physicians from the Internal and Preventive Medicine Departments. RESULTS: During the two phases of the study, 162 patients were included with a total of 1,959 medicines reconciled. The incidence of unintended discrepancies decreased from 3.5% to 1.8% after the intervention (p value 0.03). The proportion of patients with at least one unintended discrepancy was 23.7% in the first phase and 14.6% in the second phase (p value 0.20). Omission was the most common unintended discrepancy. Asthmatic patients showed 6 times higher risk of being affected by an unintended discrepancy (OR 6.37, 95%CI 1.6-25.5; p value 0.009). CONCLUSIONS: Implementing a computerized tool integrated into the electronic prescribing program could be very helpful to develop a medication reconciliation process. It is essential to involve all hospital staff in this process. PMID- 23021791 TI - Lipoprotein (a) is independently correlated with coronary artery calcification. AB - INTRODUCTION: Lipoprotein a (Lp(a)) has been recognized as a risk factor for both coronary heart diseases and for cardiovascular events. Coronary artery calcification (CAC) is a well proven marker for coronary artery disease and risk factor for cardiovascular events. Still there are conflicting data regarding the relationship of Lp(a) and CAC. We therefore wanted to evaluate the influence of Lp(a) on CAC. METHODS: 1560 European patients (1123 men, age 59.3 +/- 20.8 years) with typical or atypical chest pain underwent CAC scoring by a multi-slice CT scanner, using a standard protocol. Blood samples were evaluated the same day using an automated particle enhanced immunoturbidimetric assay to determine Lp(a) serum levels. RESULTS: There was a positive correlation between CAC score, age, and common cardiovascular risk factors. Lp(a) serum levels were not associated with age but a positive correlation between Lp(a) serum levels and CAC was found. In the multivariate analysis age, diabetes, statin therapy, and Lp(a) could be identified as independent risk factors for CAC. (p<0.001). BMI, smoking, hypertension and LDL-C were not independently associated with CAC. CONCLUSION: Lp (a) could be identified as an independent predictor of CAC, a marker of coronary atherosclerosis. Further a positive correlation between increasing Lp (a) levels and CAC scores was found. PMID- 23021792 TI - Risk assessment on the presence of pharmaceuticals in sediments, soils and waters of the Pego-Oliva Marshlands (Valencia, eastern Spain). AB - This study is focused on the occurrence of 17 pharmaceuticals in waters (34 samples), sediments (16 samples) and soils (23 samples, at two different depths) in a typical Mediterranean coastal wetland (Pego-Oliva marsh, Spain). Soil and sediment samples were extracted by pressurized liquid extraction (PLE). Aqueous extracts from PLE and water samples were concentrated by solid-phase extraction (SPE) and determined by liquid-chromatography tandem mass spectrometry (LC MS/MS). Pharmaceuticals were detected in concentrations up to 112 ng/L in water samples, up to 15.1 ng/g sediments and up to 8.4 ng/g in soil. In surface waters, ibuprofen and codeine were the compounds more frequently detected (up to 59 ng/L and 63 ng/L, respectively). Ground and tap water samples analyzed were also contaminated with pharmaceuticals. The 94% of sediments and the 80% of agricultural soils were polluted (mostly by carbamazepine and acetaminophen). Diffusion of codeine and fluoroquinolones to deeper soil horizons was observed. Possible relationships between variables were established by Pearson correlations and principal components analysis (PCA). An environmental risk assessment based on the available long-term data was performed. Results showed actual risk for the lowest trophic level, and for fishes, due to the presence of fluoroquinolones and ibuprofen. Nevertheless, the presence of pharmaceuticals in the environment is not limited only to an ecological problem since contamination also affects drinking water, being a potential risk to human health. PMID- 23021793 TI - Radiation-induced enteropathy: molecular basis of pentoxifylline-vitamin E anti fibrotic effect involved TGF-beta1 cascade inhibition. AB - BACKGROUND: Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline-vitamin E has proven effective and safe in clinical trials in the treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored. METHODS: Ten patients suffering from radiation induced enteropathy were treated with pentoxifylline-vitamin E combination with SOMA score as the primary endpoint. In parallel, primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy were incubated with pentoxifylline, trolox (vit. E hydrophilic analogous) or their combination. Activation of the TGF-beta1/Smad and Rho/ROCK pathways was subsequently investigated using Q-RT-PCR, gene reporter, Western-blot, ELISA and immunohistochemistry. RESULTS: Pentoxifylline-vitamin E combination induces regression of symptoms (SOMA) by -41% and -80% at 6 and 18months. In vitro, pentoxifylline and trolox synergize to inhibit TGF-beta1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-beta1/Smad targets (Col Ialpha1, FN1, PAI 1, CTGF), while it has no effect on the Rho/ROCK pathway. CONCLUSIONS: The anti fibrotic effect of combined pentoxifylline-vitamin E is at least in part mediated by inhibition of the TGF-beta1 cascade. It strengthens previous clinical data showing pentoxifylline-vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis. PMID- 23021794 TI - Re: The "safe" triangle, contrast material, and particulate steroids in lumbar transforaminal injections: what are the right things to do? PMID- 23021795 TI - Preoperative imaging evaluation of head and neck cancer: comparison of 2D spin echo and 3D THRIVE MRI techniques with resected tumours. AB - AIM: To evaluate the usefulness of contrast-enhanced three-dimensional (3D) T1 weighted high-resolution isotropic volume examination (THRIVE) for the preoperative assessment of head and neck cancer, by comparison with spin-echo (SE) T1-weighted sequences and the pathology specimen. MATERIALS AND METHODS: Thirty-seven consecutive patients who were diagnosed with oral cavity, oropharyngeal, and hypopharyngeal cancer and received surgical excision with preoperative magnetic resonance imaging (MRI) using both SE and 3D THRIVE sequences after gadolinium injection were studied. Tumour conspicuity, motion- and flow-related artefacts were evaluated, and the tumour size was measured based on both sequences, which were correlated with the surgical specimen. The population correlation coefficient (r(g)(2)) and Bland-Altman plots were used to assess measurement agreement. RESULTS: There was no statistical difference between SE and THRIVE in terms of tumour conspicuity and motion-related artefacts, however, flow-related artefacts significantly decreased with THRIVE. The measurement agreement of tumour size estimated on both SE and THRIVE was good (r(g)(2) = 0.87 for SE and 0.93 for THRIVE), and the difference was statistically significant. CONCLUSION: The 3D THRIVE sequence provided satisfactory image quality for the accurate measurement of tumour size with fewer artefacts and could be an acceptable alternative for SE T1-weighted images for preoperative staging in patients with head and neck cancer. PMID- 23021796 TI - Calpain-10 gene polymorphisms in type 2 diabetes and its micro- and macrovascular complications. AB - Genetic variations in the calpain 10 gene (CAPN10) were previously implicated with increased risk of type 2 diabetes (T2DM). We studied the association of single nucleotide polymorphisms in the CAPN10 gene, SNP -43, SNP -19 and SNP -63, with T2DM and its complications. Overall, we examined 1440 individuals: 880 patients with diabetes and 560 healthy subjects, all Caucasians of Polish origin. All subjects were genotyped for the CAPN10 SNPs by polymerase chain reaction (PCR). The frequencies of alleles, genotypes and haplotypes at three studied loci were similar between the groups. However, the -43 SNP was significantly more frequent in T2DM patients with coexisting cardiovascular disease (CVD) than in patients without CVD (p=0.001). The -43 SNP was still significantly associated with the risk of CVD after adjusting for potential risk factors including male gender, age, BMI, dyslipidemia and hypertension. The odds ratio for G allele for CVD+ versus CVD- patients was 1.89, 95% CI 1.52-2.35. None of the studied SNPs was significantly associated with microvascular diabetic complications. There was a tendency to increased frequency of SNP -43 1/1 homozygotes in patients with diabetic retinopathy (p=0.057). The homozygous haplotype combination 121/121 was more frequent in T2DM patients than in non-diabetic controls (18.4% vs 10.5%, p=0.019). In conclusion, the results of our study suggest the significant association of SNP -43 with the risk of CVD coexisting with T2DM. We also observed that 121/121 haplotype was associated with T2DM in the studied population. PMID- 23021797 TI - The effect of hydrochloride pioglitazone on urinary 8-hydroxy -deoxyguanosine excretion in type 2 diabetics. AB - OBJECTIVE: To observe the effects of hydrochloride pioglitazone on urinary 8 hydroxy-deoxyguanosine (8OHdG) excretion in type 2 diabetics and explore its possible reno-protective mechanisms. METHODS: Ninety-eight uncontrolled type 2 diabetics were assigned randomly into group DP (pioglitazone add-on) and group DS (sulfonylureas add-on). At the basal and after 12 weeks treatment, FBG, HbA1c, urinary 8-OHdG, urinary albumin(ALB) and urinary creatinine (Cr) were determined, respectively. RESULTS: Compared with pre-treatment, FBG, HbA1c and urinary 8-OHdG /Cr ratio(U8CR) were all obviously decreased in both therapy groups; urinary albumin/urinary creatinine ratio(UACR) markedly decreased in group DP (P<0.01), while slightly decreased in group DS (P>0.05) after twelve weeks of observation. After 12-week treatment, UACR and U8CR in group DP were significantly lower than those in group DS (both P<0.05) without no marked difference in FBG and HbA1c between group DP and group DS. Meanwhile, U8CR had positive correlation with UACR (r=0.755, P<0.01). CONCLUSION: Pioglitazone can decrease urinary 8-OHdG excretion and lighten oxidative stress in vivo in type 2 diabetics, which may play a protective role for the kidney damage. PMID- 23021798 TI - The association between glutathione S-transferase T1 and M1 gene polymorphisms and cardiovascular autonomic neuropathy in Slovak adolescents with type 1 diabetes mellitus. AB - Glutathione S-transferase (GST), as antioxidant enzyme, protects tissue from oxidative damage typical for many pathologic conditions as type 1 diabetes (T1D) and its chronic complications. The aim of the study was to compare the prevalence of GST T1/M1 gene polymorphisms between diabetic adolescents with (CAN+) and without (CAN-) cardiovascular autonomic neuropathy. Forty-six subjects with T1D at the age 15-19 years were enrolled. CAN was diagnosed in 19 patients (41.3%) based on standard cardiovascular tests. GST M1 null genotype was more prevalent in CAN+subjects but this was not statistically significant (OR=1.889, 0.61-6.55, p>0.05). GST T1 wild genotype nearly 5-fold increased the risk of CAN (OR=4.952, 1.13-21.739, p<0.05). Regarding genotype combination, GST T1/M1 wild/null genotype was significantly more frequent in CAN+compared to the CAN- subjects (OR=3.96, 1.024-15.302, p<0.05). No significant difference was found in any biochemical parameters between CAN+and CAN- subgroups. Multivariable logistic regression showed that none of the biochemical parameters estimated was considered a risk factor for CAN, however GST T1 wild and GST T1/M1 wild/null represented a risk factor for CAN development (OR=2.227, 1.079-4.587, p<0.05 and OR=1.990, 1.026-3.859, p<0.05, respectively). GST T1 wild allele and GST T1/M1 wild/null genotype can be considered as risk factors for CAN in Slovak adolescents with T1D. PMID- 23021799 TI - Emerging analytical techniques for comparative effectiveness research. PMID- 23021800 TI - Sitting time increases the overweight and obesity risk independently of walking time in elderly people from Spain. AB - INTRODUCTION: Obesity, defined as an excess of total body fat, is a matter of concern all over the world, and its prevalence is still increasing among elderly people. OBJECTIVES: To examine whether sedentary behaviour (hours sitting per day) is associated with higher risk of central obesity, overweight-obesity and overfat in a representative sample of non-institutionalized Spanish elderly population and if so, whether hours walking per day modified this association. STUDY DESIGN: A cross-sectional study in a sample of 3136 people >=65 years of age. MAIN OUTCOMES MEASURES: Anthropometric measurements were obtained using standardized techniques and equipment. Active and sedentary behaviours were recorded by questionnaire. RESULTS: For both men and women, the higher prevalence of overweight-obesity, central obesity and overfat was found in those who spent sitting more than 4h per day and walk less than 1h, compared with those who spent sitting less than 4h per day and walk more than 1h (all p<0.001, except for central obesity in women). In men, more than 4h sitting per day was associated with 1.7-fold higher odds of having central obesity compared with those sitting less than 4h per day (p<0.01). In women, this sedentary behaviour increased the risk of overweight-obesity and overfat by 1.5 and 1.4, respectively (p<0.01). Age or time spent walking did not significantly change these results. CONCLUSION: Sitting time increases the risk of overweight-obesity and overfat in women and the risk of central obesity in men, independently of walking time. PMID- 23021801 TI - Preparation of molecularly imprinted polymers for organophosphates and their application to the recognition of organophosphorus compounds and phosphopeptides. AB - Monodisperse molecularly imprinted polymers (MIPs) for diphenyl phosphate (DPP) and 1-naphthyl phosphate (1-NapP) have been prepared by a multi-step swelling and polymerization method using 4-vinylpyridine as a functional monomer, glycerol dimethacrylate as a crosslinker and cyclohexanol or 1-hexanol as a porogen. The retention and molecular-recognition properties of these MIPs for organophosphorus compounds were evaluated by HPLC using a mixture of phosphate buffer and acetonitrile as an eluent. In addition to shape recognition, hydrogen bonding and hydrophobic interactions could play an important role in the retention and molecular recognition of DPP and 1-NapP. Furthermore, the MIPs were applied to the separation of adenosine and adenosine phosphates (AMP, ADP and ATP). These phosphates were retained on the MIPs according to the number of phosphate groups in the molecule and were well separated from one another. Hydrogen bonding and hydrophobic interactions seemed to affect the retention and recognition of adenosine phosphates in low acetonitrile content, while hydrophilic interactions affected these properties in high acetonitrile content. Finally, the MIPs were applied to the trapping of phosphopeptides. The MIPs non-selectively trapped phosphopeptides, which have phosphorylated tyrosine, serine or threonine in the sequences, and successfully trapped four phosphopeptides in tryptic digests of bovine alpha-casein. PMID- 23021803 TI - Determination of eight fluoroquinolones in groundwater samples with ultrasound assisted ionic liquid dispersive liquid-liquid microextraction prior to high performance liquid chromatography and fluorescence detection. AB - An ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction (US IL-DLLME) procedure was developed for the extraction of eight fluoroquinolones (marbofloxacin, norfloxacin, ciprofloxacin, lomefloxacin, danofloxacin, enrofloxacin, oxolinic acid and nalidixic acid) in groundwater, using high performance liquid chromatography with fluorescence detection (HPLC-FD). The ultrasound-assisted process was applied to accelerate the formation of the fine cloudy solution using a small volume of disperser solvent (0.4 mL of methanol), which increased the extraction efficiency and reduced the equilibrium time. For the DLLME procedure, the IL 1-octyl-3-methylimidazolium hexafluorophosphate ([C(8)MIM] [PF(6)]) and methanol (MeOH) were used as extraction and disperser solvent, respectively. By comparing [C(8)MIM] [PF(6)] with 1-hexyl-3 methylimidazolium hexafluorophosphate ([C(6)MIM] [PF(6)]) and 1-butyl-3 methylimidazolium hexafluorophosphate ([C(4)MIM] [PF(6)]) as extraction solvents, it was observed that when using [C(8)MIM] [PF(6)] the cloudy solution was formed more readily than when using [C(6)MIM] [PF(6)] or [C(4)MIM] [PF(6)]. The factors affecting the extraction efficiency, such as the type and volume of ionic liquid, type and volume of disperser solvent, cooling in ice-water, sonication time, centrifuging time, sample pH and ionic strength, were optimised. A slight increase in the recoveries of fluoroquinolones was observed when an ice-water bath extraction step was included in the analytical procedure (85-107%) compared to those obtained without this step (83-96%). Under the optimum conditions, linearity of the method was observed over the range 10-300 ng L(-1) with correlation coefficient >0.9981. The proposed method has been found to have excellent sensitivity with limit of detection between 0.8 and 13 ng L(-1) and precision with relative standard deviation values between 4.8 and 9.4% (RSD, n=5). Good enrichment factors (122-205) and recoveries (85-107%) were obtained for the extraction of the target analytes in groundwater samples. This simple and economic method has been successfully applied to analyse real groundwater samples with satisfactory results. PMID- 23021802 TI - Application of semi-permeable membrane dialysis/ion trap mass spectrometry technique to determine polybrominated diphenyl ethers and polychlorinated biphenyls in milk fat. AB - Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are hazardous food contaminants, their maximum legally allowable levels in food and environment are in the low pgg(-1) range. Therefore some highly selective and sensitive analytical methods must be used to determine them. The 96/23/EC Directive implemented by EC Decision of 12 August 2002 requires recovery rate of an analyte at a concentration below 1 ng g(-1) within the 50-120% range at relative standard deviation (RSD) as low as possible. A method to determine low level PCBs and PBDEs in milk fat based on the semi-permeable membrane dialysis/ion trap GC MS technique was developed. Validation experiments proved that the method performance was within bounds set by the currently standing UE regulations. Recovery rates calculated on the basis of labeled internal standards for majority of the studied indicator PCB congeners and PBDE congeners were close to 100% at RSD below 20%. Also, dioxin-like PCBs recovery rates were compatible with the 1883/2006 EC Regulation (80-120%, RSD below 15%). The developed method turned out to be linear within a far broader concentration range than the studied 0.0025-10 pg MUL(-1) range entirely sufficient for analyses of PCB and PBDE in milk fat. Within that range coefficient of linear correlation (R(2)) of calibration curves exceeded 0.98. PMID- 23021804 TI - A new HPLC-DAD-MS/MS method for the simultaneous determination of major compounds in the crude extract of Lychnophora salicifolia Mart. (Brazilian arnicao) leaves: application to chemical variability evaluation. AB - Lychnophora salicifolia Mart., which occurs in the Brazilian Cerrado in the states of Bahia and Minas Gerais as well as in the southeast of the state of Goias, is the most widely distributed and also the most polymorphic species of the genus. This plant is popularly known to have anti-inflammatory and analgesic activities. In this work, we have studied the variation in terms of polar metabolites of ninety-three Lychnophora salicifolia Mart. specimens collected from different regions of the Brazilian Cerrado. Identification of the constituents of this mixture was carried out by analysis of the UV spectra and MS data after chromatographic separation. Twenty substances were identified, including chlorogenic acid derivatives, a flavonoid C-glucoside, and other sesquiterpenes. The analytical method was validated, and the reliability and credibility of the results was ensured for the purposes of this study. The concentration range required for analysis of content variability within the analyzed group of specimens was covered with appropriate values of limits of detection and quantitation, as well as satisfactory precision and recovery. A quantitative variability was observed among specimens collected from the same location, but on average they were similar from a chemical viewpoint. In relation to the study involving specimens from different locations, there were both qualitative and quantitative differences among plants collected from different regions of Brazil. Statistical analysis revealed that there is a correlation between geographical localization and polar metabolites profile for specimens collected from different locations. This is evidence that the pattern of metabolites concentration depends on the geographical distribution of the specimens. PMID- 23021805 TI - Characterizing uranium oxide reference particles for isotopic abundances and uranium mass by single particle isotope dilution mass spectrometry. AB - Uranium and plutonium particulate test materials are becoming increasingly important as the reliability of measurement results has to be demonstrated to regulatory bodies responsible for maintaining effective nuclear safeguards. In order to address this issue, the Institute for Reference Materials and Measurements (IRMM) in collaboration with the Institute for Transuranium Elements (ITU) has initiated a study to investigate the feasibility of preparing and characterizing a uranium particle reference material for nuclear safeguards, which is finally certified for isotopic abundances and for the uranium mass per particle. Such control particles are specifically required to evaluate responses of instruments based on mass spectrometric detection (e.g. SIMS, TIMS, LA-ICPMS) and to help ensuring the reliability and comparability of measurement results worldwide. In this paper, a methodology is described which allows quantifying the uranium mass in single micron particles by isotope dilution thermal ionization mass spectrometry (ID-TIMS). This methodology is characterized by substantial improvements recently achieved at IRMM in terms of sensitivity and measurement accuracy in the field of uranium particle analysis by TIMS. The use of monodisperse uranium oxide particles prepared using an aerosol generation technique developed at ITU, which is capable of producing particles of well characterized size and isotopic composition was exploited. The evidence of a straightforward correlation between the particle volume and the mass of uranium was demonstrated in this study. Experimental results have shown that the uranium mass per particle can be measured via the ID-TIMS method to a relative expanded uncertainty of about 10% (coverage factor k=2). The availability of reliable and validated methods for the characterization of uranium particles is considered to be essential for the establishment of SI-traceable measurement results. It is therefore expected that the method developed in this study is valuable for the certification of particulate materials in which the isotopic composition and the content of uranium must be accurately known. PMID- 23021806 TI - A mass spectrometric method to determine activities of enzymes involved in polyamine catabolism. AB - An analytical method for the determination of three polyamines (putrescine, spermidine, and spermine) and five acetylpolyamines [N(1)-acetylspermidine (N(1)AcSpd), N(8)-acetylspermidine (N(8)AcSpd), N(1)-acetylspermine, N(1),N(8) diacetylspermidine, and N(1),N(12)-diacetylspermine] involved in the polyamine catabolic pathway has been developed using a hybrid tandem mass spectrometer. Heptafluorobutyryl (HFB) derivatives of these compounds and respective internal standards labeled with stable isotopes were analyzed simultaneously by TOF MS, based on peak areas appearing at appropriate m/z values. The isomers, N(1)AcSpd and N(8)AcSpd were determined from their fragment ions, the acetylamidopropyl and acetylamidobutyl groups, respectively, using MS/MS with (13)C(2)-N(1)AcSpd and (13)C(2)-N(8)AcSpd which have the (13)C(2)-acetyl group as an internal standard. The TOF MS method was successfully applied to measure the activity of enzymes involved in polyamine catabolic pathways, namely N(1)-acetylpolyamine oxidase (APAO), spermine oxidase (SMO), and spermidine/spermine N(1)-acetyltransferase (SSAT). The following natural substrates and products labeled with stable isotopes considering the application to biological samples were identified; for APAO, [4,9,12-(15)N(3)]-N(1)-acetylspermine and [1,4,8-(15)N(3)]spermidine ((15)N(3)-Spd), respectively; for SMO, [1,4,8,12-(15)N(4)]spermine and (15)N(3) Spd, respectively; and for SSAT, (15)N(3)-Spd and [1,4,8-(15)N(3)]-N(1) acetylspermidine, respectively. PMID- 23021807 TI - Direct quantification of creatinine in human urine by using isotope dilution extractive electrospray ionization tandem mass spectrometry. AB - Urinary creatinine (CRE) is an important biomarker of renal function. Fast and accurate quantification of CRE in human urine is required by clinical research. By using isotope dilution extractive electrospray ionization tandem mass spectrometry (EESI-MS/MS) a high throughput method for direct and accurate quantification of urinary CRE was developed in this study. Under optimized conditions, the method detection limit was lower than 50 MUg L(-1). Over the concentration range investigated (0.05-10 mg L(-1)), the calibration curve was obtained with satisfactory linearity (R(2)=0.9861), and the relative standard deviation (RSD) values for CRE and isotope-labeled CRE (CRE-d3) were 7.1-11.8% (n=6) and 4.1-11.3% (n=6), respectively. The isotope dilution EESI-MS/MS method was validated by analyzing six human urine samples, and the results were comparable with the conventional spectrophotometric method (based on the Jaffe reaction). Recoveries for individual urine samples were 85-111% and less than 0.3 min was taken for each measurement, indicating that the present isotope dilution EESI-MS/MS method is a promising strategy for the fast and accurate quantification of urinary CRE in clinical laboratories. PMID- 23021808 TI - Use of temperature dependent Raman spectra to improve accuracy for analysis of complex oil-based samples: lube base oils and adulterated olive oils. AB - A simple and effective strategy to improve accuracy for Raman spectroscopic analysis of complex mixture samples by probing a measurement temperature yielding enhanced spectral selectivity has been demonstrated. For the evaluation, the determination of Kinematic Viscosity at 40 degrees C (KV@40) of lube base oil (LBO) samples was initially attempted. Partial least squares (PLS) was used to determine the KV@40 using Raman spectra of the samples collected at 8 different temperatures from 20 to 90 degrees C with 10 degrees C increments. Interestingly, the distinct temperature-induced spectral variation among the samples occurred at 50 degrees C, thereby resulting in the improved accuracy for determination of KV@40. Two-dimensional (2D) correlation analysis was also performed to find an additional supportive rationale for the improved accuracy. The strategy was further evaluated for the identification of soybean oil adulterated olive oils using linear discriminant analysis (LDA). Similarly, the discrimination accuracy was improved around 80-90 degrees C due to the enhanced spectral selectivity between olive and soybean oils. In overall, these two results successfully demonstrate analytical effectiveness of the strategy. PMID- 23021809 TI - In vitro selection and characterization of deoxyribonucleic acid aptamers for digoxin. AB - The low therapeutic index of digoxin necessitates careful monitoring of its serum levels. Most of digoxin immunoassays suffer from interferences with digoxin-like immunoreactive substances. Since aptamers have been shown to be highly specific for their targets, the aim of this study was to develop DNA aptamers for this widely used cardiac glycoside. Digoxin was coated onto the surface of streptavidin magnetic beads. DNA aptamers against digoxin were designed using Systematic Evolution of Ligands by Exponential enrichment method (SELEX) by 11 iterative rounds of incubation of digoxin-coated streptavidin magnetic beads with synthetic DNA library, DNA elution, electrophoresis and PCR amplification. The PCR product was cloned and sequenced. Binding affinity was determined using digoxin-BSA conjugate, coated onto ELISA plate. Inhibitory effect of anti-digoxin aptamer was conducted using isolated guinea-pig atrium. Three aptamers (D1, D2 and D3) were identified. Binding studies of fluorescein-labeled truncated (without primer binding region) D1 and D2 and full length D1 anti-digoxin aptamers were performed and their corresponding dissociation constants values were 8.2*10(-9), 44.0*10(-9) and 17.8*10(-9) M, respectively. This is comparable to what other workers have obtained for interaction of monoclonal antibodies raised against digoxin. There was little difference in binding affinity between full length and truncated anti-digoxin D1 aptamer. D1 anti-digoxin aptamer also inhibited the effects of digoxin on the isolated guinea-pig atrium. D1 anti digoxin aptamer distinguished between digoxin and ouabain in both tissue study and binding experiments. Our finding indicated that D1 anti-digoxin aptamer can selectively bind to digoxin. Further studies might show its suitability for use in digoxin assays and as a therapeutic agent in life-threatening digoxin toxicity. PMID- 23021810 TI - Highly sensitive and ultrafast response surface acoustic wave humidity sensor based on electrospun polyaniline/poly(vinyl butyral) nanofibers. AB - Polyaniline (PANi) composite nanofibers were deposited on surface acoustic wave (SAW) resonator with a central frequency of 433 MHz to construct humidity sensors. Electrospun nanofibers of poly(methyl methacrylate), poly(vinyl pyrrolidone), poly(ethylene oxide), poly(vinylidene fluoride), poly(vinyl butyral) (PVB) were characterized by scanning electron microscopy, and humidity response of corresponding SAW humidity sensors were investigated. The results indicated that PVB was suitable as a matrix to form nanofibers with PANi by electrospinning (ES). Electrospun PANi/PVB nanofibers exhibited a core-sheath structure as revealed by transmittance electron microscopy. Effects of ES collection time on humidity response of SAW sensor based on PANi/PVB nanofibers were examined at room temperature. The composite nanofiber sensor exhibited very high sensitivity of ~75kHz/%RH from 20 to 90%RH, ultrafast response (1s and 2s for humidification and desiccation, respectively) and good sensing linearity. Furthermore, the sensor could detect humidity as low as 0.5%RH, suggesting its potentials for low humidity detection. Attempts were done to explain the attractive humidity sensing performance of the sensor by considering conductivity, hydrophilicity, viscoelasticity and morphology of the polymer composite nanofibers. PMID- 23021811 TI - A rational design of the multiwalled carbon nanotube-7,7,8,8 tetracyanoquinodimethan sensor for sensitive detection of acetylcholinesterase inhibitors. AB - A new, simple and effective amperometric acetylcholinesterase biosensor was developed using screen-printed carbon electrodes modified with carbon nanotubes (MWCNTs)-7,7,8,8-tetracyanoquinodimethane (TCNQ). The design of the biosensor was based on the supramolecular arrangement resulted from the interaction of MWCNTs and TCNQ. This arrangement was confirmed by spectroscopic and electrochemical techniques. Two different supramolecular arrangements were proposed based on different MWCNTs:TCNQ ratios. The synergistic effect of MWCNTs and TCNQ was, for the first time, exploited for detection of thiocholine at low potential with high sensitivity. The biosensor developed by immobilization of acetylcholinesterase (AChE) in sol-gel allowed the detection of two reference AChE inhibitors, paraoxon-methyl and chlorpyrifos with detection limits of 30 pM (7 ppt) and 0.4 nM (0.1 ppb), respectively. Efficient enzyme reactivation was obtained by using obidoxime. PMID- 23021812 TI - Ultrasensitive and facile electrochemical deoxyribonucleic acid biosensor based on the conformational change of the recognition interface. AB - An ultrasensitive electrochemical impedance spectroscopic deoxyribonucleic acid biosensor has been developed based on the conformational change of the deoxyribonucleic acid recognition interface with lodging probes. Pairing process leads to desorption of deoxyribonucleic acid bases from the gold surface, leading to a significant change of the interfacial conformation and the charge transfer resistance. Remarkably low detection limits down to 40 fM are thus obtained without any additional amplification step. PMID- 23021813 TI - Optimization of an immunoassay of 2,6-dichlorobenzamide (BAM) and development of regenerative surfaces by immunosorbent modification with newly synthesised BAM hapten library. AB - Dichlobenil is an extensively used herbicide worldwide which is transformed to the mobile 2,6-dichlorobenzamide (BAM) in soil. BAM has been found in many European groundwater resources that are exploited for drinking water. Currently, immunoassay based monitoring technique (plate based ELISA) is being employed to quantitatively detect BAM in water samples. In this work, as a starting step of developing immunoassay based on-site monitoring systems for pesticide analysis, the heterogeneous BAM immunoassay is optimised in terms of surface (polymer) regeneration. We have synthesised a small library of BAM haptens which are slightly different in chemical structures, immobilised them on surfaces and compared the affinity constants of the monoclonal antibody HYB 273 towards them. By using ELISA technology, we also have checked the regeneration potentials of the haptens, correlated these results to the affinity constants and found that BAM hapten with an intermediate affinity has better regeneration potential. PMID- 23021815 TI - The effects of body mass index on surface electrocardiograms in young adults. AB - INTRODUCTION: While BMI is known to affect ECG measurements, these effects have not been well characterized in young adults. METHODS: We retrospectively reviewed all ECGs performed in adults 18 to 35 years old at a single institution over a 30 year period. ECG measurements were derived electronically and stratified by WHO BMI category. RESULTS: A total of 55,218 ECGs were included. Increasing BMI led to increased P wave duration and decreasing P, R, and T wave axes. Additionally, while increasing BMI led to less R wave voltage, J point elevation, and T wave amplitude in patients with a BMI >= 18.5 kg/m(2), there was also a decrease in the measured parameters in patients with a BMI <18.5 kg/m(2). DISCUSSION: BMI had significant effects on ECG measurements. For accurate assessment of ECGs, these data should be incorporated into established nomograms. Further investigation into the effects of BMI on the ECG is warranted. PMID- 23021814 TI - The Moli-sani project: computerized ECG database in a population-based cohort study. AB - Computerized electrocardiogram (ECG) acquisition and interpretation may be extremely useful in handling analysis of data from large cohort studies and exploit research on the use of ECG data as prognostic markers for cardiovascular disease. The Moli-sani project (http://www.moli-sani.org) is a population-based cohort study aiming at evaluating the risk factors linked to chronic-degenerative disease with particular regard to cardiovascular disease and cancer and intermediate metabolic phenotypes such as hypertension, diabetes, dyslipidemia, obesity, and metabolic syndrome. Between March 2005 and April 2010, 24 325 people aged 35 years or older, living in the Molise region (Italy), were randomly recruited. A follow-up based on linkage with hospital discharge records and mortality regional registry and reexamination of the cohort is ongoing and will be repeated at prefixed times. Each subject was administered questionnaires on personal and medical history, food consumption, quality of life (FS36), and psychometry. Plasma serum, cellular pellet, and urinary spots were stored in liquid nitrogen. Subjects were measured blood pressure, weight, height, and waist and hip circumferences, and underwent spirometry to evaluate pulmonary diffusion capacity, gas diffusion, and pulmonary volumes. Standard 12-lead resting ECG was performed by a Cardiette ar2100-view electrocardiograph and tracings stored in digital standard communication protocol format for subsequent analysis. The digital ECG database of the Moli-sani project is currently being used to assess the association between physiologic variables and pathophyiosiologic conditions and parameters derived from the ECG signal. This computerized ECG database represents a unique opportunity to identify and assess prognostic factors associated with cardiovascular and metabolic diseases. PMID- 23021816 TI - Prevalence of cardiac arrhythmias in pre-hospital tele-cardiology electrocardiograms of emergency medical service patients referred for syncope. AB - AIM: To evaluate the rate of prevalence of significant arrhythmias in emergency medical service (EMS) subjects referred for syncope and screened with pre hospital tele-cardiology ECG. METHODS: 2648 consecutive EMS patients referred for syncope were evaluated with tele-cardiology support. Pre-hospital ECGs were sent to a single tele-cardiology "hub", active 24/7 and serving a region of 4-million inhabitants, and promptly read by a cardiologist. Prevalence of any arrhythmias or conduction disturbances was recorded. RESULTS: In more than 55% of cases ECG findings were normal; in 13% ECG showed sinus tachycardia, in 9% sinus bradycardia. Prevalence of ventricular tachycardia was 0.20%, while significant AV-disturbances were present in 1.12% of cases (0.11% second-degree type 2 AV block, 0.11% advanced AV-block, 0.19% third-degree AV-block, 0.45% junctional rhythm, 0.26% ventricular rhythm). Limited gender differences were detectable. No significant arrhythmias were found in subjects younger than 30 years. Prevalence of several arrhythmias was age related. CONCLUSIONS: Prevalence of significant arrhythmias among EMS patients referred for syncope and evaluated with pre hospital tele-cardiology ECG is low, and almost absent in subjects below 30 years. Tele-cardiology pre-hospital screening by a single regional "hub" may be helpful for the prompt diagnosis of arrhythmia related syncope. PMID- 23021817 TI - Asystole induced by radiofrequency catheter ablation of slow pathway. AB - Radiofrequency (RF) catheter ablation is a treatment of choice widely used for a variety of supraventricular tachycardia. Transient sinus and atrioventricular (AV) node dysfunctions may occur during RF application to sites remote from the sinus and AV nodes, but they generally resolve quickly after cessation of RF current. We present a case of two episodes of asystole in a 43-year-old man induced by RF catheter ablation of an AV nodal slow pathway. A Bezold-Jarisch like reflex, direct stimulation of parasympathetic fibers traveling to the sinus and AV nodes, RF-induced myocardial injury or pain could be responsible for this situation. PMID- 23021818 TI - Diabetes foot disease: the Cinderella of Australian diabetes management? AB - Diabetes is one of the greatest public health challenges to face Australia. It is already Australia's leading cause of kidney failure, blindness (in those under 60 years) and lower limb amputation, and causes significant cardiovascular disease. Australia's diabetes amputation rate is one of the worst in the developed world, and appears to have significantly increased in the last decade, whereas some other diabetes complication rates appear to have decreased. This paper aims to compare the national burden of disease for the four major diabetes related complications and the availability of government funding to combat these complications, in order to determine where diabetes foot disease ranks in Australia. Our review of relevant national literature indicates foot disease ranks second overall in burden of disease and last in evidenced-based government funding to combat these diabetes complications. This suggests public funding to address foot disease in Australia is disproportionately low when compared to funding dedicated to other diabetes complications. There is ample evidence that appropriate government funding of evidence-based care improves all diabetes complication outcomes and reduces overall costs. Numerous diverse Australian peak bodies have now recommended similar diabetes foot evidence-based strategies that have reduced diabetes amputation rates and associated costs in other developed nations. It would seem intuitive that "it's time" to fund these evidence-based strategies for diabetes foot disease in Australia as well. PMID- 23021819 TI - Interest, rationale, and potential clinical applications of genetic testing for mood disorders: a survey of stakeholders. PMID- 23021822 TI - Glycogen synthase kinase 3beta gene polymorphisms may be associated with bipolar I disorder and the therapeutic response to lithium. AB - BACKGROUND: Glycogen Synthase Kinase 3beta (GSK-3beta) is thought to be a key feature in the therapeutic mechanism of mood stabilizers (e.g., lithium). Overexpression of GSK-3beta might play a role in the pathogenesis of bipolar I disorder. Within the GSK-3beta gene, a promoter single nucleotide polymorphism (SNP) rs334558 was identified associated with transcriptional strength, and an intronic SNP rs6438552 was found to regulate selection of splice acceptor sites. The aim of this study is to test the association between the two polymorphisms and bipolar I disorder. METHODS: We genotyped the two SNPs in 138 Taiwanese bipolar I disorder patients and 131 controls. Lithium treatment efficacy was evaluated for 83 patients who had been treated with lithium carbonate for at least 24 months. RESULTS: We found no association between each of the two SNPs and the risk of bipolar I disorder. Following correction for multiple testing, CT genotype at rs6438552 was associated with an older age of onset than other genotypes (P=0.042) in female patients. Patients with genotype TT at rs334558 (P=0.044) had poorer response to lithium treatment. There was a trend that haplotype C-T increased the risk for bipolar I disorder (adjusted OR=4.22, corrected P=0.084), and patients with haplotype T-T had poorer treatment response to lithium than those with haplotype C-C. LIMITATIONS: Limitations included small sample size, retrospective data collection, and a potential sampling bias. CONCLUSIONS: Despite the several limitations of the study, our results suggested GSK-3beta genetic variants may be associated with the risk of bipolar I disorder, age of disease onset in females, and the therapeutic response to lithium. PMID- 23021820 TI - Posttraumatic stress disorder, depression, and health-related quality of life in patients with bipolar disorder: review and new data from a multi-site community clinic sample. AB - BACKGROUND: Evidence suggests that patients with bipolar disorder have an elevated risk for comorbid posttraumatic stress disorder (PTSD) compared to those without a bipolar diagnosis. Although bipolar disorder is associated with decreased health-related quality of life (HRQOL), it is unclear whether comorbid PTSD interacts to affect HRQOL. METHOD: Baseline data from a multi-site study of patients with bipolar disorder were analyzed. Patient surveys ascertained clinical and demographic information, including physical and mental HRQOL based on the SF-12, mood symptoms (PHQ-9, Internal State Scale), and self-reported co occurring conditions including PTSD. RESULTS: Overall (N=384), 44.9% of patients self-reported co-occurring PTSD. Patients with PTSD had lower physical and mental HRQOL scores compared to those without PTSD (mean (SD) for those with and without PTSD, respectively): Mental Component Scale score 30.51 (8.22) and 32.86 (8.35); Physical Component Scale score 35.56 (7.77) and 37.21 (7.20). After adjusting for demographic and clinical factors including mood symptoms, multiple linear regression analyses revealed that PTSD was no longer significantly associated with physical or mental HRQOL; however, depressive symptoms were independently associated with mental HRQOL (Beta -0.63, p<0.01). CONCLUSION: Depressive symptoms may explain the association between PTSD and mental HRQOL. Clinicians working with these patients will want to emphasize treatment of depression as important towards improving HRQOL for this group. PMID- 23021821 TI - Prevention of recurrence of major depression among emerging adults by a group cognitive-behavioral/interpersonal intervention. AB - BACKGROUND: Among the most serious sequelae to an initial episode of Major Depressive Disorder (MDD) during adolescence is the significant increase in the probability of recurrence. This study reports on an integrated CBT/IPT program, provided in a group format, that was developed to decrease the rate of MDD recurrence in emerging adults. METHODS: Participants were 89 young adults who were not depressed at study entry but had experienced MDD during adolescence. Participants were assigned to a CBT/IPT prevention program or to an assessment only control condition and were followed through the first 2 years of college. RESULTS: Risk for MDD recurrence was reduced more than 50% for the prevention program participants compared to assessment only controls. The intervention also conferred beneficial effects on academic performance for those students who completed the majority of the group sessions. LIMITATIONS: The study included a self-selected sample of emerging adults who were aware of their history of depression. Due to the small sample size, it will be important to evaluate similar interventions in adequately-powered trials to determine if this is a replicable finding. CONCLUSIONS: With 51% of the assessment only participants experiencing a MDD recurrence during the first 2 years of college, these findings support the need for programs designed to prevent MDD recurrence in young adults. The current program, based on IPT and CBT principles, appears to reduce the rate of MDD recurrence among previously depressed emerging adults. PMID- 23021823 TI - The treatment of psychotic depression: is there consensus among guidelines and psychiatrists? AB - BACKGROUND: Psychotic depression (PD) is a prevalent, severe, under-diagnosed and often inadequately treated mental disorder, which has received disproportionally little attention by clinicians, researchers and the pharmaceutical industry. Consequently, the evidence base for optimal clinical practice regarding PD is limited. The aim of this study was to investigate the degree of consensus among international treatment guidelines on PD and to determine whether a potential lack of consensus would be reflected in the clinical practice of Danish psychiatrists. METHODS: 1. Review and comparison of international guidelines on the treatment of PD. 2. Questionnaire based survey regarding Danish psychiatrists' treatment of PD. RESULTS: The nine international treatment guidelines considered in the review have contrasting opinions on the optimal treatment for PD: 6 of 9 suggest antidepressant (AD)+antipsychotic (AP) combination therapy, 3 of 9 recommend AD monotherapy and 5 of 9 find electroconvulsive therapy (ECT) equally appropriate as first line treatment. The 113 surveyed psychiatrists displayed the same lack of consensus. Their preferred treatment was either AD+AP combination therapy (42%), AD monotherapy (31%) or ECT (21%). The first line choices of ADs and APs were tricyclic antidepressants (51%) and quetiapine (62%), respectively. LIMITATIONS: The survey data are subjected to a potential selection bias as the respondents are likely to represent the more informed fraction of psychiatrists. CONCLUSIONS: Our results indicate that both treatment algorithms and clinical practice regarding PD are highly heterogeneous. This finding emphasizes the need for further studies on the treatment of psychotic depression. PMID- 23021824 TI - Peripheral vascular endothelial growth factor level is associated with antidepressant treatment response: results of a preliminary study. AB - BACKGROUND: Recent investigations have revealed multiple actions of vascular endothelial growth factor (VEGF) in the nervous system. The role of VEGF in the molecular background of mood disorders has also been proposed. In this study we were interested in investigating a possible association between VEGF levels and treatment response in patients with a current episode of major depression (MDE). METHODS: 34 patients with MDE were enrolled in our study. Depressive symptoms were monitored by the Montgomery-Asberg Depression Rating Scale at baseline (V(1)) and after a 4-week treatment period (V(2)). Patients with less than a 50% improvement in MADRS total scores during this period were regarded as non responders. RESULTS: Plasma VEGF levels did not change during the treatment period in either the total sample or in the responder and non-responder subsamples. There was a strong trend for higher baseline VEGF levels in the non responder group than in the responder group (p=0.055) and this difference-as a weak trend-was still detectable at the end of the treatment period (p=0.097). Regression analysis revealed that the baseline VEGF level was a significant predictor for the endpoint MADRS score (p=0.02). LIMITATIONS: Sample size was relatively small; sample consists of both patients with MDD and bipolar disorder. CONCLUSIONS: Our preliminary results raise the possibility that baseline levels of peripheral VEGF may predict treatment response in patients with mood disorders. Considering the limitations of our study, further investigations should resolve whether VEGF is a useful biomarker for treatment response in depression in clinical practice. PMID- 23021826 TI - Continuous GSK-3beta overexpression in the hippocampal dentate gyrus induces prodepressant-like effects and increases sensitivity to chronic mild stress in mice. AB - BACKGROUND: Glycogen synthase kinase-3 (GSK-3) has been linked to prodepressant like effects in rodents. However, the roles of GSK-3beta and the hippocampal dentate gyrus in regulating these behavioral effects remain unclear. METHODS: A lentiviral vector was utilized to site-specifically express GSK-3beta constitutively in the hippocampal DG in a mouse model of CMS. We examine the forced swim, tail suspension and the sucrose intake test. Acute and chronic administrations were conducted by dissolving fluoxetine hydrochloride (10ml/kg). We examine behavior tests as before, cellular apoptosis, proliferation and differentiation in the hippocampus. RESULTS: GSK-3beta expression levels persistently and significantly increased in the hippocampus following lenti-GSK 3beta injections. In mice previously exposed to CMS, pre-injection of lentivirus expressing GSK-3beta into the hippocampal dentate gyrus significantly decreased sucrose preferences in the sucrose intake test and increased immobility times in both forced swim and tail suspension tests. In addition, fluoxetine resulted in similar antidepressant-like effects following chronic, but not acute, administrations under the same experimental conditions. Cellular apoptosis was observed in the hippocampal DG using TUNEL, revealing many TUNEL-positive cells in the lenti-GSK-3beta mice. There were no significant changes in proliferation and differentiation. LIMITATIONS: We did not measure more biomarkers which were regulated by GSK-3beta. CONCLUSIONS: Results from this study demonstrated that site-specific injection of a lentivirus induced continuous GSK-3beta expression in the hippocampal dentate gyrus of mice, resulting in prodepressant-like effects and increased sensitivity to chronic mild stress. Furthermore, chronic fluoxetine administration reversed these prodepressant-like effects and decreased neuronal apoptosis in the hippocampal DG in GSK-3beta-overexpressing mice. PMID- 23021825 TI - Major depression and life satisfaction: a population-based twin study. AB - BACKGROUND: The extent to which positive and negative indicators of mental health share etiological influences has been studied to a limited degree only. This study examines the genetic and environmental influences on association between liability to lifetime DSM-IV Major Depressive Disorder (MDD) and dispositional life satisfaction (LS). METHODS: Two-wave questionnaire data on LS (assessed 6 years apart) and lifetime MDD obtained by structured clinical interviews in a population-based sample of adult twins were analysed using structural equation modelling in Mx. RESULTS: The prevalence of lifetime MDD was estimated to be 11.1% and 15.8% in males and females, respectively. Individuals fulfilling the criteria for MDD reported significantly lower levels of LS. The co-variation in MDD and dispositional LS was found to be accounted for by genetic and unique environmental influences only. The phenotypic correlation was estimated to be 0.36, of which genetic influences accounted for 74% and environmental factors the remaining 26%. The correlation between genetic factors for MDD and LS was estimated to be -0.55 and the correlation between unique environmental factors to be -0.22. Heritability was estimated to 0.34 and 0.72 for MDD and LS, respectively. LIMITATIONS: The sample consists of twins only and there are limitations associated with the twin design. CONCLUSIONS: Whereas genetic influences on vulnerability to lifetime MDD are considerably shared with liability to (low) LS, environmental influences are more distinct. Thus, environmental factors associated with risk of MDD do not strongly impact on dispositional LS, and conversely, environmental factors influencing dispositional LS do not strongly buffer against MDD. PMID- 23021827 TI - Factors influencing intentions of female medical students to pursue a surgical career. PMID- 23021829 TI - Techniques in vascular and interventional radiology. Introduction. PMID- 23021830 TI - Balloon-occluded retrograde transvenous obliteration of gastric varices: conception, evolution, and history. AB - The idea of transvenous obliteration of varices that complicate portal hypertension dates back to the 1970s. The clinical use of this minimally invasive procedure was probably lost with the advent of transjugular intrahepatic portosystemic shunt shortly afterward. The concept of retrograde obliteration of a gastrorenal shunt through the left renal vein originated from Olson et al at Indiana University. However, the Japanese (Kanagawa et al and subsequent authors) defined, developed, and technically perfected the clinical implementation of balloon-occluded retrograde transvenous obliteration. The evolution of balloon occluded retrograde transvenous obliteration has come full circle, now gaining popularity in the United States, especially in patients who are not candidates for transjugular intrahepatic portosystemic shunt. PMID- 23021831 TI - Pre- and post-balloon-occluded retrograde transvenous obliteration clinical evaluation, management, and imaging: indications, management protocols, and follow-up. AB - Patients with gastric variceal bleeding require a multidisciplinary team approach, which includes hepatologists, endoscopists, diagnostic radiologists, and interventional radiologists. Upper gastrointestinal endoscopy is the first line diagnosis and management tool for bleeding gastric varices (GVs) as it is with all upper gastrointestinal bleeding scenarios. Traditionally, in the United States, when endoscopy fails to control gastric variceal bleeding, a transjugular intrahepatic portosystemic shunt (TIPS) is performed along the classic teachings of decompressing the portal circulation. However, TIPS has shown inconsistent effectiveness in controlling gastric variceal bleeding. Conversely, the balloon occluded retrograde transvenous obliteration (BRTO) procedure has become common practice in Asia for the management of GVs. The BRTO procedure is gaining popularity in the United States. BRTO has shown to be effective in controlling gastric variceal bleeding with low gastric variceal rebleed rates. Regardless of the endovascular management (TIPS vs BRTO vs both), a multidisciplinary team with adequate preprocedural clinical assessment and management and endoscopic and imaging evaluation is required before and after the endovascular procedure. The article discusses the pre- and post-BRTO clinical evaluation and management, as well as endoscopic and imaging evaluation. Moreover, the article proposes indications, contraindications, and management protocols for the management of GVs. PMID- 23021832 TI - Balloon-occluded antegrade transvenous obliteration with or without balloon occluded retrograde transvenous obliteration for the management of gastric varices: concept and technical applications. AB - Alternative routes for transvenous obliteration are sometimes resorted in the management of gastric varices. These alternative routes can be classified into A, portal venous access routes and B, systemic venous access routes. The portal venous approach to transvenous obliteration is called balloon-occluded antegrade transvenous obliteration (BATO) and is a collective definition, including 1 percutaneous transhepatic obliteration (PTO), 2-through an existing transjugular intrahepatic portosystemic shunt [(Trans-TIPS), and 3-trans-iliocolic vein obliteration (TIO)]. PTO is usually out of necessity; however, trans-TIPS approach is usually used out of serendipity (because the low-risk access route is there). The TIPS for the trans-TIPS BATO is not formed for mere access, but is done to create a TIPS or is done when there is a preexisting TIPS. The trans-TIPS approach can be resorted to in the United States in up to 19% of balloon-occluded retrograde transvenous obliteration (BRTO) cases. PTO is resorted to, out of necessity, in the United States and Japan in 10% of BRTO cases (2%-19% of BRTO cases) and can increase the technical and obliterative success rate of the transvenous obliteration procedure from 84%-98% to 98%-100%. The advantage of BATO as an adjunct to BRTO (combining a BRTO and BATO approach to obliterate the gastric varices) is not only limited to increasing the technical success rate of the obliterative procedure. BATO reduces the risk of overspill of the sclerosant from the gastric variceal system into the portal vein. Moreover, if the BATO is performed from a trans-TIPS approach, any overspill of the sclerosant mixture will partly (if not mostly) go through the patent TIPS to the systemic circulation (lung) rather than the intrahepatic portal vein branches (prevent portal vein embolization). This article discusses the clinical and technical applications, technical considerations, and the outcomes of BATO. PMID- 23021833 TI - Inventory used for balloon-occluded retrograde (BRTO) and antegrade (BATO) transvenous obliteration: sclerosants and balloon occlusion devices. AB - The inventory used for the balloon-occluded retrograde transvenous obliteration (BRTO) and balloon-occluded antegrade transvenous obliteration procedures includes coaxial introducer sheath, catheters, balloon occlusion catheters, possibly microcatheters, possibly coils and preeminent vascular occlusion devices, and sclerosant mixtures. The inventory can be collectively categorized into "hardware" (sheaths, catheters, balloon occlusion devices, and alloy embolic agents) and sclerosant mixtures (contrast and sclerosing agents). The hardware inventory used in Japan is different from that used in the United States. Moreover, the inventory used in Japan is commonly specifically (purpose-built) designed for the BRTO procedure. Conversely, the hardware inventory used in the United States is a "generic" (multipurpose), which operators use for multiple other anatomical and clinical settings. Using different inventories that are not purposefully designed together requires multiple trials and errors to reach size and length compatibility. From a sclerosant standpoint, there is an ongoing paradigm shift toward foam-state sclerosant mixture in Japan and the United States (as of 2006). This article discusses the inventory used for BRTO and balloon-occluded antegrade transvenous obliteration in Japan and the United States and focuses on the inventory (including compatibility of inventory) that has worked and has become popularly used in the United States. The article also discusses the sclerosant mixture components, types and states (foam, froth, or liquid). PMID- 23021834 TI - Balloon-occluded retrograde transvenous obliteration of gastric varices from unconventional systemic veins in the absence of gastrorenal shunts. AB - Balloon-occluded retrograde transvenous obliteration of gastric varices in the absence of a gastrorenal shunts can still be performed through unconventional venous routes, such as the left inferior phrenic (ascending portion or transverse portion), pericardial, and azygous-hemiazygous veins. This requires detailed knowledge of venous anatomy, impeccable preprocedural imaging for planning, and high-skill set techniques with smaller balloon-occlusion catheters. The technical results appear to be high (67%-83% depending on the access venous system available), but are lower than conventional balloon-occluded retrograde transvenous obliteration via the gastrorenal shunt. PMID- 23021836 TI - Carotid intima-media thickness in the Spanish population: reference ranges and association with cardiovascular risk factors. AB - INTRODUCTION AND OBJECTIVES: Carotid intima-media thickness as measured with ultrasonography is an inexpensive and noninvasive predictor of cardiovascular events. The objectives of this study were to determine the population reference ranges of carotid intima-media thickness for individuals aged 35-84 years in Spain and to analyze the association of carotid intima-media thickness with cardiovascular risk factors (age, smoking, diabetes, pulse pressure, lipid profile, and body mass index). METHODS: Population-based cross-sectional study conducted in Gerona (Spain). We described the mean and maximal values of carotid intima-media thickness of the carotid artery and of its 3 segments (common carotid, carotid bulb and internal carotid). We assessed cardiovascular risk factors and analyzed their association with carotid intima-media thickness using adjusted linear regression models. RESULTS: A total of 3161 individuals (54% women) were included, with mean age 58 years. Men showed significantly higher mean common carotid intima-media thickness than did women (0.71 vs 0.67 mm). The strongest predictors of this measure were age (coefficients for 10-year increase: 0.65 and 0.58 for women and men, respectively), smoking in men (coefficient: 0.26), high-density lipoprotein cholesterol in women (coefficient for 10 mg/dL, increase: -0.08) and pulse pressure in both sexes (coefficients for 10 mmHg increase: 0.08 and 0.23 for women and men, respectively). The results were similar for the mean carotid intima-media thickness of all the segments. CONCLUSIONS: This population-based study presents the reference ranges for carotid intima-media thickness in the Spanish population. The main determinants of carotid intima-media thickness were age and pulse pressure in both sexes. PMID- 23021837 TI - [Severe thoracic radionecrosis: muscle-sparing latissimus dorsi flap (MSLD)]. AB - INTRODUCTION: Cutaneous radionecrosis and osteoradionecrosis are severe complications of the radiotherapy which can arise after a variable free interval. The loss of substance is frequently associated with a peripheral radiodermatitis and stays an infectious front door exposing patients to a sepsis. The reference treatment remains surgical and consists in realizing the debridment of necrosis tissues associated with flap in order to cover the soft tissus defect. The purpose of our study is to estimate efficiency and tolerance of management radionecrosis thoracique by muscle-sparing latissimus dorsi flap (MSLD). MATERIAL AND METHODS: We realized a study on a series of cases of thoracic radionecrosis with costal exposure covered by MSLD. Fat transfer into peripheral radiodermitis was performed at the same time surgical. Efficiency and tolerance surgery were estimated. The duration of the postoperative antibiotic treatment was estimated. The complications (hematoma, infection, cutaneous suffering, necrosis, seroma, radionecrosis relapse) were screened. The follow-up was realized by the same surgeon. RESULTS: Seven patients managed by the same surgeon were included, They had radionecrosis after radiotherapy for processing adjuvanting of mastectomy after breast cancer. The average age was 66 years (from 61 to 76 years). The average time of hospitalisation was of four days. The average follow-up was of six months. The average treatment of the antibiotic treatment was four weeks. We didn't notice any complications and any recurrence of the radionecrosis. We noticed one dorsal collection (30 cm(3)) 15 days after surgical procedure for one patient. The follow-up showed a stable and good quality cutaneous cover in six months postoperative. CONCLUSIONS: MSLD flap is reliable and reproducible to cover moderate thoracic defect. The surgical parage-wash has a fundamental importance to avoid any infectious complication. The management of the thoracic radionecrosis is complex and multidisciplinary. In conclusion, MSLD flap seems to be an elegant surgical alternative insuring a custom-made optimal cover with a reduction of the morbidity of the site donor. PMID- 23021838 TI - [Management of weight loss consequences in the male chest: The amputation grafting technique with a L scar]. AB - INTRODUCTION: Following the upsurge in cases of morbid obesity and bariatric surgery, there is after massive weight loss effects of the thorax in man such as pseudogynecomastia extremely poorly tolerated by patients. Treatment aims to correct the excess skin while optimizing the location and quality of scars. Turning our back on techniques derived from mammoplasty, we go into these major forms for mastectomy with grafting the areolo-mammelonar plate and resulting scar in L extended if needed until the axilla. MATERIALS AND METHODS: From 2005 to 2011, we performed 12 mastectomies after massive weight loss (45 kg on average). Patients aged 19 to 64 had an average BMI of 29.2. In five patients, we had started the move by liposuction (190 cc average per side). The mastectomy was performed by placing the scar at the lower edge of the pectoralis major. The areolas previously harvested were placed on the axis of the graft within two to three centimeters above the scar. All patients were reviewed and evaluated in consultation questionnaire with an average follow up of 2 years (6 months-5 years). RESULTS: The average volume of resection was 560 g per side (55 g-2500 g), operative time 155 minutes. Complications consisted of hematoma requiring surgical revision and delayed wound healing in three over 1 month with partial areola necrosis. The overall patient satisfaction was excellent with no secondary correction request. CONCLUSION: In the major pseudogynecomastia, the option is taken immediately for a mastectomy technique which scar is located at the basis of the thorax and may include an axillary extension in L. It effectively corrects the large cutaneous and fat surplus and restores in one time a flat male chest. Satisfaction is high and patients are no more ashamed to expose their chest. PMID- 23021839 TI - In-situ synthesis of fluorescent gold nanoclusters with electrospun fibrous membrane and application on Hg (II) sensing. AB - In the present study, a method for in-situ preparation of fluorescent gold nanoclusters with bovine serum albumin/poly(ethylene oxide) electrospun membrane (BSA/PEO-Au NCs) has been developed to detect Hg(2+). In this work, Au NCs were immobilized both inside and on the surface of fibrous membrane using one-step reduction of HAuCl(4) by BSA. The as-prepared BSA/PEO-Au NCs were able to emit intensive red fluorescence under the excitation of visible light, and the fluorescence could be quenched by Hg(2+). The results indicate that the as prepared BSA/PEO-Au NCs exhibit good sensitivity towards Hg(2+), which might be benefit from the large specific surface area of BSA/PEO fibrous membrane. The biosensor exhibits a linear response to Hg(2+) concentrations ranging from 0.5 nM to 75 nM with a limit of detection (LOD) of 57 pM. Moreover, BSA/PEO-Au NCs shows good selectivity towards other common metal ions. With the advantages of the simple preparation process and good detection performance, the proposed method is anticipated to fabricate other sensitive fluorescence fiber-based sensors of metal nanoclusters. PMID- 23021840 TI - Photonic crystals on copolymer film for bacteria detection. AB - The development of two-dimensional photonic crystals (PCs) on a copolymer film is described in connection with Fresnel reflection spectroscopy and fluorescence microscopy. Label-free detection of Legionella pneumophila was performed using a PC platform with a detection limit of 200 cells/mL. L. pneumophila is well known as the cause of Legionnaires' disease and a lesser form called Pontiac fever. Since death by L. pneumophila infection depends on the early anti-microbial treatment, rapid diagnosis of this disease is critical for efficient treatment and patient survival. Conventional assays have turn-around times measurable in several hours to days, and are limited in their detection of various serogroups. Due to the recent introduction of regulatory guidelines for routine testing of water cooling towers and treatment facilities, biosensors for the on-field detection of Legionella spp. are highly in demand. The versatile and economical immunochips described here can be easily adapted for the monitoring of L. pneumophila serogroups in clinical and environmental samples in a few minutes. PMID- 23021841 TI - Surface-enhanced Raman scattering (SERS) detection of multiple viral antigens using magnetic capture of SERS-active nanoparticles. AB - A highly sensitive immunoassay based on surface-enhanced Raman scattering (SERS) spectroscopy has been developed for multiplex detection of surface envelope and capsid antigens of the viral zoonotic pathogens West Nile virus (WNV) and Rift Valley fever virus (RVFV). Detection was mediated by antibody recognition using Raman reporter-coated Au nanoparticles (GNPs) and paramagnetic nanoparticles (PMPs) conjugated with polyclonal antibodies specific for each antigen target, followed by 785nm laser excitation of magnetically concentrated GNP/antigen/PMP complexes. The discrimination of WNV and RVFV antigen detection in mixed Raman spectra was achieved by SERS enhancement of Raman spectra specific for the Raman reporter dyes Infrared 792 (IR-792) and Nile Blue (NB), respectively. Assay reactions containing dilutions of both target antigens yielded a reduction in the intensification of IR-792 and NB signature spectrum peaks and provided a conservative limit of detection of ~5fg/ml for assays conducted in phosphate buffered saline buffer (PBS) and ~25pg/ml for assays containing PBS spiked with fetal bovine serum. Based on the inherent simplicity of the assay, magnetic capture-based SERS assays afford promise as a biosensor platform that provides high-level multiplex detection sensitivity and can be adapted for portable diagnostic applications in limited resource settings. PMID- 23021842 TI - A novel fluorescent sensor for mutational p53 DNA sequence detection based on click chemistry. AB - A novel fluorescent sensor for DNA sequence has been designed by taking advantages of copper nanoparticles (CuNPs) selectively formed on double stranded (ds) DNA template and Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Copper(II) is derived from CuNPs which previously formed on the dsDNA template, and then copper(II) is reduced to copper(I) by ascorbate, which in turn induced CuAAC reaction between the weak-fluorescent compound (3-azido-7 hydroxycoumarin) and propargyl alcohol to form strong fluorescence compounds (1,2,3-triazole compounds). Since CuNPs are accumulated efficiently in the major groove of dsDNA and ssDNA has no groove, it indicates that the proposed sensor owns the merits of low detection limit, high sensitivity and selectivity for mutational p53 sequence detection. Additionally, the method has been successfully applied to recognize the sequence which contains a single-base mismatch in the short human p53 gene fragment. Furthermore, it has also been applied to detect DNA sequence in complex medium (hela cellular homogenate) with satisfactory results. PMID- 23021843 TI - Several approaches for vitamin D determination by surface plasmon resonance and electrochemical affinity biosensors. AB - This work has been focused on the development of novel optical (Surface Plasmon Resonance) and electrochemical based biosensors for the determination of 25-OH vitamin D (25OHD) which is an important factor involved in avoiding both skeletal damage and a variety of pathological conditions, and to evaluate their potential use in clinical practice. Different approaches to the determination of vitamin D using affinity based biosensors, are described herein; firstly, an immunosensor based on SPR transduction was realized for direct determination of vitamin D, obtaining a LOD of 2 MUg/ml which unfortunately is too far from the needs in clinical analysis. In order to enhance the sensitivity, the vitamin D was modified with gold nanoparticles (AuNPs): the binding of 25OHD with AuNPs determines the amplification of SPR signal, allowing to lower the LOD down to 1 MUg/ml, doubling the sensitivity. An alternative SPR method, based on the indirect determination of vitamin D by means of Vitamin D Binding Protein (VDBP), led to a further sensitivity increase reaching a LOD of 45 ng/ml which is really close to the fixed accomplishment. Finally, an electrochemical transduced biosensor has been realized, based on the reaction of vitamin D with 4 ferrocenylmethyl-1,2,4-triazoline-3,5-dione (FMTAD): once derivatized, the determination of 25OHD was possible in the range 20-200 ng/ml with a LOD of 10 ng/ml. The latter proposed system fits the requirement of determining vitamin D in a concentration range which is of significance for clinical applications; moreover, since a screen printed electrode has been used, this opens the possibility to miniaturize the sensor and developing a portable and easy-to automate point-of-care testing device. The proposed devices provide an improvement with respect to traditional methods that are time and reagents consuming and require radioactive compounds, pretreatment procedures and expensive instrumentation. PMID- 23021844 TI - Re(I) complex doped nanofibers for oxygen optical sensing. AB - In this paper, we design and synthesize a novel diamine ligand of PTO (2-(pyridin 2-yl)-5-p-tolyl-1,3,4-oxadiazole). The crystal structure, photophysical character and electronic nature of its corresponding Re(I) complex of Re(CO)(3)(PTO)Br have been investigated in detail. Experimental data and theoretical calculation suggest that Re(CO)(3)(PTO)Br owns a long-lived yellow phosphorescence which is sensitive towards molecular oxygen. By doping Re(CO)(3)(PTO)Br into a polymer matrix of polystyrene (PS), the emission response of the resulted composite nanofibers towards molecular oxygen is studied. The optimal sample with mean diameter of 600 nm shows a maximum sensitivity of 4.14 with short response time of 14s (here sensitivity is defined as the ratio of emission intensity in pure N(2) atmosphere to that in pure O(2) atmosphere). The composite nanofibers are also found to be photostable enough to experience UV radiation. PMID- 23021845 TI - Thermo-optic characterization of neodymium/nickel doped silica glasses prepared via sol-gel route. AB - Intrinsic as well as rare earth (Neodymium) doped silica glasses with various molar ratio of dopant and a metallic (Nickel) co-dopant is prepared via sol-gel route. The structural characterization of the sample is carried out using X-ray diffraction and Fourier Transform Infrared Spectroscopy. The influence of dopant and doping concentration on the optical properties of silica matrix is investigated via UV-VIS absorption spectroscopy. Effect of dopant on thermal effusivity value of the host matrix is carried out by laser induced open cell photoacoustic technique. Analysis of the results showed that doping affect the thermal effusivity value and results are interpreted in terms of structural modification of the lattice and phonon assisted heat transport mechanism. PMID- 23021846 TI - Hip arthroplasty. AB - Total hip arthroplasty is a cost-effective surgical procedure undertaken to relieve pain and restore function to the arthritic hip joint. More than 1 million arthroplasties are done every year worldwide, and this number is projected to double within the next two decades. Symptomatic osteoarthritis is the indication for surgery in more than 90% of patients, and its incidence is increasing because of an ageing population and the obesity epidemic. Excellent functional outcomes are reported; however, careful patient selection is needed to achieve best possible results. The present economic situation in many developed countries will place increased pressure on containment of costs. Future demand for hip arthroplasty, especially in patients younger than 65 years, emphasises the need for objective outcome measures and joint registries that can track lifetime implant survivorship. New generations of bearing surfaces such as metal-on-metal, ceramic-on-ceramic, and metal-on-ceramic, and techniques such as resurfacing arthroplasty have the potential to improve outcomes and survivorship, but findings from prospective trials are needed to show efficacy. With the recall of some metal-on-metal bearings, new bearing surfaces have to be monitored carefully before they can be assumed to be better than traditional bearings. PMID- 23021847 TI - Massive idiopathic scrotal calcinosis. AB - Idiopathic scrotal calcinosis is a rare, benign condition with the presence of multiple slow-growing yellowish-white calcified asymptomatic nodules that appear within the scrotal skin. The disease affects patients in childhood or early adulthood. The etiology of idiopathic scrotal calcinosis is still controversial. It can extensively affect the scrotal skin, but primary closure is usually achievable with good esthetic outcomes. PMID- 23021848 TI - Innovation as emergence in healthcare: unpacking change from within. AB - The contemporary healthcare literature suffers from a disproportionate focus on 'given' externally created innovations, and belief in ordered, planned and well funded implementation processes. As an alternative, the present paper highlights the potential of emergent change processes, using the continuous invention and re invention of the Rheumatology Quality Registry in Sweden as an example. This 19 year long process, which is still ongoing, does not exhibit the sequential steps that are allegedly determinants of success in the innovation and implementation literature. Yet, it has produced system-wide improvements. We draw on more than 100 informal and formal meetings with practitioners involved in the process studied, observations, documentation analysis and quantitative registry-data. A total of 67 interviews with registry-users and external stakeholders were also performed. The dissipative structures model (complexity theory) was used to analyze the data. The studied process illustrates an ongoing, practice-driven improvement process, which was sparked by abstract and indirect energies that interacted with more concrete innovations such as new drugs. For example, participants tapped new information technologies, changing perspectives and governmental priorities to challenge current ways of working and introduce new ideas. Ideas were realized and spread through various self-organized processes that involved the re-arrangement of existing resources rather than acquisition of new resources. Taken together, these processes brought Swedish rheumatology to new levels of functioning 1992-2011. An important implication of our work is that incremental and practice-driven change processes can significantly transform care systems in the long run. Policy makers need to acknowledge and foster such ongoing innovation processes at micro-level, rather than focusing exclusively on innovations as externally created 'things' that await 'implementation'. PMID- 23021849 TI - Sociocultural influences on mental health service use by Latino older adults for emotional distress: exploring the mediating and moderating role of informal social support. AB - This study investigated the determinants of mental health services for emotional distress by low-income older Latinos living in Los Angeles County (United States). The functional effects of informal support on service use were tested while accounting for dimensions of support and sociocultural factors. Using data from a cross-sectional survey of older Latinos (n = 235), we preformed a secondary data analysis using path analysis with Poisson regression to assess mediation and moderation models by type of perceived support, emotional and instrumental. Data was originally collected between 1998 and 2005. Results indicated that no mediation effects were present however significant moderation effects emerged. Respondents with low levels of linguistic acculturation and informal support used fewer services. Variations by type of informal support emerged, with emotional support presenting the best model fit compared to instrumental support in the moderation model analysis. The direct effects of linguistic acculturation and age remained significant after controlling for need. Findings reveal limited informal support is a risk factor for the underutilization of mental health services by older Latinos with low levels of linguistic acculturation as they age. Integrating support resources that assist in navigating service systems and address language barriers can enhance service use by older Latino adults. Implications for service delivery and program development are discussed. PMID- 23021851 TI - An electrochemical assay for DNA methylation, methyltransferase activity and inhibitor screening based on methyl binding domain protein. AB - DNA methylation is one of important epigenetics events, and responsible to transcription, genomic imprinting and cellular differentiation. Aberrant DNA methylation is always contacted with various diseases. Methyl binding domain (MBD) proteins can specifically bind to the methylated CpG dinucleotides. Conventional assay for DNA methylation normally need bisulfide treatment, methylated nucleotide labeling or PCR amplification. Here, we fabricated a novel electrochemical biosensor for detection of DNA methylation, assay of DNA methyltransferase (MTase) activity and screening of MTase inhibitor based on MBD protein and coomassie brilliant blue G250 (CBB-G250), where the electrochemical signal of CBB-G250 was used to monitor the methylation event. After the hybrids of DNA S1 and DNA S2 were treated with M. SssI MTase in the presence of S adenosylmethionine, the MBD proteins were specifically conjugated to the methylation site of CpG dinucleotides, and then, the MBD proteins were stained with CBB-G250. The electrochemical signal of CBB-G250 increased linearly with increasing M. SssI MTase concentration in the range from 0.1 to 40 unit/mL. Furthermore, the inhibition investigation demonstrates that fisetin and chlorogenic acid can inhibit the M. SssI MTase activity with the IC(50) value of 153.12 and 137.07 MUM, respectively. Therefore, we think that this study may provide a sensitive platform for screening of DNA MTase inhibitors. PMID- 23021852 TI - Polypyrrole based amperometric and potentiometric phosphate biosensors: a comparative study B. AB - The preparation of two electrochemical (potentiometric and amperometric) phosphate biosensors is described and compared. Purine nucleoside phosphorylase (PNP) and xanthine oxidase (XOD) were co-immobilized via entrapment into polypyrrole (PPy) films by galvanostatic polymerization. Polypyrrole entrapment was achieved with 0.5M pyrrole by using a polymerization time of 200 s and a mole ratio of 1:8 (6.2U/mL XOD: 49.6 U/mL PNP) in amperometric phosphate biosensor. Potentiometric bi-layer biosensor PPy-NO(3)/BSA-GLA-PNP-XOD is made of an inner electropolymerized PPy-NO(3) layer and an outer layer of PNP and XOD cross-linked with a mixture of bovine serum albumen (BSA) and gultaraldehyde (GLA).The optimum conditions for potentiometric bi-layer biosensor include a polymerization time of 300 s for the inner layer at an applied current density of 0.25 mA cm(-2), a drying time of 30 min for the outer layer, pH 7, and 0.025MTris-HCl. Sensitive amperometric measurements obtained from PPy-PNP-XOD-Fe(CN)(6)(4-) biosensors were compared with those of potentiometric measurements obtained from PPy NO(3)/BSA/GLA-PNP-XOD bi-layer biosensor. A minimum detectable concentration of 20.0 MUM phosphates and a linear concentration range of 20-200 MUM were achieved with potentiometric PPy-NO(3)/BSA/GLA-PNP-XOD biosensor. In comparison, a minimum detectable concentration of 10 MUM and a linear concentration range of 0.1-1 mM were achieved with amperometric biosensor. The presence of uric and ascorbic acids had the least effect on the performance of the PPy-PNP-XOD-Fe(CN)(6)(4-) amperometric and PPy-NO(3)/BSA/GLA-PNP-XOD potentiometric bi-biosensors, therefore, they will not have any effect on phosphate measurement in both biosensors at levels normally present in water. PPy-NO(3)/BSA-GLA-PNP-XOD potentiometric biosensor was used to analyse phosphate in real samples. PMID- 23021850 TI - Detection of bacterial 16S rRNA using a molecular beacon-based X sensor. AB - We demonstrate how a long structurally constrained RNA can be analyzed in homogeneous solution at ambient temperatures with high specificity using a sophisticated biosensor. The sensor consists of a molecular beacon probe as a signal reporter and two DNA adaptor strands, which have fragments complementary to the reporter and to the analyzed RNA. One adaptor strand uses its long RNA binding arm to unwind the RNA secondary structure. Second adaptor strand with a short RNA-binding arm hybridizes only to a completely complementary site, thus providing high recognition specificity. Overall the three-component sensor and the target RNA form a four-stranded DNA crossover (X) structure. Using this sensor, Escherichia coli16S rRNA was detected in real time with the detection limit of ~0.17 nM. The high specificity of the analysis was proven by differentiating Bacillus subtilis from E. coli 16S rRNA sequences. The sensor responds to the presence of the analyte within seconds. PMID- 23021853 TI - Electrophoretic build-up of multi nanoparticle array for a highly sensitive immunoassay. AB - One of the challenges in shrinking immunoassays to smaller sizes is to immobilize the biological molecules to nanometer-scaled spots. To overcome this complication, we have employed a particle-based immunoassay to create a nanostructured platform with a regular array of sensing elements. The technique makes use of an electrophoretic particle entrapment system (EPES) to immobilize nanoparticles that are coated with biological reagents into wells using a very small trapping potential. To provide useful information for controlling the trapping force and optimal design of the nanoarray, electrophoretic trapping of a nanoparticle was modeled numerically. The trapping efficiency, defined as the fraction of wells occupied by a single particle, was 91%. The performance of the array was demonstrated with a competitive immunoassay for a small molecule analyte, 3-phenoxybenzoic acid (214.2 g mole(-1)). The limit of detection determined with a basic fluorescence microscope was 0.006 MUg l(-1) (30 pM); this represented a sixteen-fold improvement in sensitivity compared to a standard 96 well plate-based ELISA; the improvement was attributed to the small size of the sample volume and the presence of light diffraction among factors unique to this structure. The EPES/nanoarray system promises to offer a new standard in applications that require portable, point-of-care and real-time monitoring with high sensitivity. PMID- 23021854 TI - Anti-EpCAM modified LC-SPDP monolayer on gold microelectrode based electrochemical biosensor for MCF-7 cells detection. AB - A succinimidyl 6-(3-[2-pyridyldithio]-propionamido) hexanoate (LC-SPDP) self assembled monolayer (SAM) prepared onto a 500 MUm (diameter) gold microelectrode (Au) surface has been utilized for covalent immobilization of anti-EpCAM antibody. Amino group on anti-EpCAM antibody was covalently bound with succinimidyl group on SAM via amide bond and unreacted active groups of LC-SPDP were blocked using 1% ethanol amine (EA). These anti-EpCAM/LC-SPDP/Au electrodes were characterized using cyclic voltammetric (CV) and fluorescence techniques, respectively. The anti-EpCAM/LC-SPDP/Au electrodes were exposed to solutions with different MCF-7 cell concentrations and CV technique was used to determine the cell concentration. Further, CV studies on blank 500 and 50 MUm (diameter) gold microelectrodes were used to identify cell via molecular profiling using ferrocene amidopentyl carboxylic acid based redox tagging and magnetic beads based enhancement. CV results confirm that the anti-EpCAM/LC-SPDP/Au based biosensor could detect MCF-7 cells in the range of 1*10(5)-1*10(8) with correlation coefficient of 0.999 and detection limit of 1*10(5) cells ml(-1) i.e. 100 cells in solution used for incubation (1 MUl). Molecular profiling studies suggest that smaller size microelectrode (50 MUm; diameter) with magnetic beads based enhancement can be employed to identify cell type. This work establishes the feasibility of using microelectrode based platform for breast cancer specific MCF-7 cell concentration estimation and their molecular profiling. PMID- 23021855 TI - Effects of paraoxon on serum biochemical parameters and oxidative stress induction in various tissues of Wistar and Norway rats. AB - This study investigates the effects of different doses of paroxon (POX), an active metabolite of the organophosphate pesticide parathion, on some serum biochemical parameters and induction of oxidative stress in various tissues of female Wistar and Norway rats. The rats were intraperitoneally treated with 0.3, 0.7, 1 and 1.5 mg/kg of POX. The parameters were evaluated after 24h. The results showed that the decreased glutathione level and catalase, glutathione-S transferase and lactate dehydrogenase activities in tissues of Wistar rat were higher than Norway rat at higher doses of POX. At these concentrations, POX increased superoxide dismutase activity, malondialdehyde level and some serum biochemical indices. In conclusion, POX induces the production of free radicals and oxidative stress in a dose-dependent manner. Induction of oxidative stress in POX-treated rats is in the order of brain > liver > heart > kidney>spleen. Wistar rat is found to be more sensitive to the toxicity of POX compared to Norway rat. PMID- 23021857 TI - The long and short of it: closing the description-experience "gap" by taking the long-run view. AB - Previous research has shown that many choice biases are attenuated when short-run decisions are reframed to the long run. However, this literature has been limited to description-based choice tasks in which possible outcomes and their probabilities are explicitly specified. A recent literature has emerged showing that many core results found using the description paradigm do not generalize to experience-based choice tasks in which possible outcomes and their probabilities are learned from sequential sampling. In the current study, we investigated whether this description-experience choice gap occurs in the long run. We examined description- and experience-based preferences under two traditional short run framed choice tasks (single-play, repeated-play) and also a long-run frame (multi-play). We found a reduction in the size of the description experience gap in the long-run frame, which was attributable to greater choice maximizing in the description format and reduced underweighting [corrected] of rare events in the experience format. We interpret these results as a "broad bracketing" effect: the long-run mindset attenuates short-run biases such as loss aversion and reliance on small samples. PMID- 23021858 TI - Likelihood ratios, sensitivity, and specificity values can be back-calculated when the odds ratios are known. AB - OBJECTIVE: To provide a solution for calculating the true-positive, false positive, false-negative, and true-negative results from studies where only the odds ratios (ORs), number of patients with the finding, and number of patients with the target condition are given. RESULTS: The quadratic formula shown here allows investigators conducting systematic reviews to back-calculate the sensitivity, specificity, and likelihood ratios (LRs) from the OR. A spreadsheet that requires only the OR, and the row and column total from the 2 * 2 table enables the back-calculation of the individual true positives, false positives, false negatives, and true negatives. Solutions are also available for the special situations when the OR = 1 or the OR is nonestimable because of zero false positives or false negatives. CONCLUSIONS: A simple spreadsheet enables those conducting systematic reviews of diagnostic tests to include studies that report only the OR. This approach should enrich the number of studies retained in meta analyses of diagnostic tests where the desire is to create summary sensitivity, specificity, or LRs. PMID- 23021856 TI - Health information needs and health-related quality of life in a diverse population of long-term cancer survivors. AB - OBJECTIVE: To investigate health information needs and their association with health-related quality of life (HRQOL) in a diverse, population-based sample of long-term cancer survivors. METHODS: We analyzed health information needs from 1197 cancer survivors 4-14 years post-diagnosis drawn from two cancer registries in California. Multivariable regression models were used to identify factors associated with endorsement of total number and different categories of needs. The relationship between number of needs and HRQOL and effect modification by confidence for obtaining information was examined. RESULTS: Survivors reported a high prevalence of unmet information needs in the following categories: side effects & symptoms: 75.8%; tests & treatment: 71.5%; health promotion: 64.5%; interpersonal & emotional: 60.2%; insurance: 39.0%; and sexual functioning & fertility: 34.6%. Survivors who were younger, non-White, and did not receive but wanted a written treatment summary reported a higher number of needs. Number of information needs was inversely related to mental well-being, particularly for those with low confidence for obtaining information (P<0.05). CONCLUSION: These patterns suggest disparities in access to important health information in long term survivors and that affect HRQOL. PRACTICE IMPLICATIONS: Findings suggest a need for tailored interventions to equip survivors with comprehensive health information and to bolster skills for obtaining information. PMID- 23021859 TI - Weighting of the data and analytical approaches may account for differences in overcoming the inadequate representativeness of the respondents to the third wave of a cohort study. AB - OBJECTIVES: Attrition in cohort studies can cause the data to be nonreflective of the original population. Although of little concern if intragroup comparisons are being made or cause and effect assessed, the assessment of bias was undertaken in this study so that intergroup or descriptive analyses could be undertaken. STUDY DESIGN AND SETTING: The North West Adelaide Health Study is a chronic disease and risk factor cohort study undertaken in Adelaide, South Australia. In the original wave (1999), clinical and self-report data were collected from 4,056 adults. In the third wave (2008-2010), 2,710 adults were still actively involved. Comparisons were made against two other data sources: Australian Bureau of Statistics Estimated Residential Population and a regular conducted chronic disease and risk factor surveillance system. RESULTS: Comparisons of demographics (age, sex, area, education, work status, and income) proved to be statistically significantly different. In addition, smoking status, body mass index, and general health status were statistically significant from the comparison group. No statistically significant differences were found for alcohol risk. CONCLUSION: Although the third wave of this cohort study is not representative of the broader population on the variables assessed, weighting of the data and analytical approaches can account for differences. PMID- 23021860 TI - Reduction of peak plantar pressure in people with diabetes-related peripheral neuropathy: an evaluation of the DH Pressure Relief ShoeTM. AB - BACKGROUND: Offloading plantar pressure is a key strategy for the prevention or healing of neuropathic plantar ulcers in diabetes. Non-removable walking casts, such as total contact casts, are currently considered the gold-standard for offloading this type of wound. However, alternative methods for offloading that are more cost effective and easier to use are continually being sought. The aim of this study was to evaluate the capacity of the DH Pressure Relief ShoeTM to offload high pressure areas under the neuropathic foot in diabetes. METHODS: A within-subjects, repeated measures design was used. Sixteen participants with diabetic peripheral neuropathy were recruited and three footwear conditions were evaluated in a randomised order: a canvas shoe (the control), the participants' own standard shoe, and the DH Pressure Relief ShoeTM. The primary outcome was peak plantar pressure, measured using the pedar-X(r) mobile in-shoe system between the three conditions. RESULTS: Data analysis was conducted on 14 out of the 16 participants because two participants could not complete data collection. The mean peak pressure values in kPa (+/-SD) for each condition were: control shoe 315.9 (+/-140.7), participants' standard shoe 273.0 (+/-127.1) and DH Pressure Relief ShoeTM 155.4 (+/-89.9). There was a statistically significant difference in peak plantar pressure between the DH Pressure Relief ShoeTM compared to both the control shoe (p = 0.002) and participants' standard shoe (p = 0.001). The DH Pressure Relief ShoeTM decreased plantar pressures by 51% compared to the control shoe and by 43% compared to participants' standard shoe. Importantly, for a couple of study participants, the DH Pressure Relief ShoeTM appeared unsuitable for day-to-day wearing. CONCLUSIONS: The DH Pressure Relief ShoeTM reduced plantar pressures more than the other two shoe conditions. The DH Pressure Relief ShoeTM may be a useful alternative to current offloading modalities used in clinical management of diabetic foot ulceration. However, clinical trials are needed to test their effectiveness for ulcer healing and to ensure they are useable and safe for patients in everyday activities. PMID- 23021861 TI - Bovine vaccinia, a systemic infection: evidence of fecal shedding, viremia and detection in lymphoid organs. AB - Bovine vaccinia (BV) is a zoonosis caused by Vaccinia virus (VACV) that affects dairy cattle and milkers, causing economic losses and impacting animal and human health. Based on the clinical presentation, BV appears to be a localized disease, with lesions restricted to the skin of affected individuals. However, there are no studies on the pathogenesis of the disease in cows to determine if there is a systemic spread of the virus and if there are different ways of VACV shedding. The objective of this work was to study if there is a systemic spread of VACV in experimentally infected cows and to study the kinetics of VACV circulation in the blood and shedding in the feces of these animals. To this end, eight crossbred lactating cows were used. Three teats of each cow were inoculated with the GP2V strain of VACV. All animals were monitored daily, and blood and fecal samples were collected for 67 days post-infection (dpi). After this period, four of these previously infected cows were immunosuppressed using dexamethasone. Viral DNA was continuously detected and quantified in the blood and feces of these animals in an intermittent way, even after the resolution of the lesions. At slaughter, tissues were collected, and viral DNA was detected and quantified in the mesenteric and retromammary lymph nodes, ileum, spleen and liver. The detection of VACV DNA in the feces for a longer period (67 dpi) and in the lymphatic organs provides new evidence about VACV elimination and suggests that BV could be a systemic infection with a chronic course and viral shedding through the feces. PMID- 23021862 TI - Effect of susceptibility to enterotoxigenic Escherichia coli F4 and of dietary tryptophan on gut microbiota diversity observed in healthy young pigs. AB - Healthy weaned pigs susceptible to enterotoxigenic Escherichia coli F4 (ETEC) require more tryptophan (Trp) to maximize their performance. This may be related to an effect on intestinal microbiota. We studied the intestinal bacterial diversity of healthy pigs with different susceptibility to ETEC and fed different Trp levels. Thirty-six littermate weaned pigs were selected to obtain a set potentially formed of 50% ETEC-susceptible and 50% non-susceptible pigs, based on a Mucin 4 gene polymorphism. Pigs were fed a diet with 0.17 (TrpL) or 0.22 (TrpH) standardized ileal digestible Trp:Lys ratio for 21 days. Slaughtered pigs were classified into non-susceptible, mildly susceptible, and susceptible, by testing ETEC adhesion to intestinal villi. Bacterial diversity in jejunum content was assessed by the 16S rRNA gene-targeted denaturing gradient gel electrophoresis (DGGE) fingerprinting analysis and expressed by the Shannon index. Susceptible pigs had a reduced bacterial diversity, particularly with TrpL diet (p=0.003). The ETEC adhesion class affected the quantification of enterobacteria DNA (p=0.027). One DGGE band, which referred to Clostridium bartlettii, was not evidenced in all the susceptible pigs; less DNA from this microbe was quantified by RT-PCR in the jejunum from TrpH susceptible pigs (p=0.025) compared to TrpL. The gene expression for beta-galactoside alpha-2,3-sialyltransferase 1 was higher in jejunal tissue of ETEC-susceptible pigs (p=0.019). In studies on pig gut microbiota, the presence of intestinal receptors for ETEC should be considered because of their contribution to a reduced bacterial diversity. This effect could be partially reversed by dietary Trp addition. PMID- 23021863 TI - Connecting type VI secretion, quorum sensing, and c-di-GMP production in fish pathogen Vibrio alginolyticus through phosphatase PppA. AB - Vibrio alginolyticus, a Gram-negative marine bacterium, has brought about severe economic damage to the mariculture industry by causing vibriosis in various fish species. We are intrigued in the regulation of the pathogenesis in this bacterium. Here, we reported a complex regulatory connection among the newly defined type VI secretion system (T6SS), quorum sensing (QS), and 3',5'-cyclic diguanylic acid (c-di-GMP) signal through the phosphatase PppA encoded in the T6SS gene cluster of V. alginolyticus. Whole-genome transcriptome analysis revealed various regulatory targets of PppA including the T6SS substrate hemolysin coregulated protein (Hcp), quorum sensing regulator LuxR, exotoxin alkaline serine protease (Asp), flagellar proteins, as well as proteins involved in polysaccharide biosynthesis and transport. Western blot analysis showed PppA served as a negative regulator of the expression and secretion of Hcp1. Mutation of pppA resulted in an increased level of the intracellular second messenger c-di GMP and a decreased expression of the QS regulator LuxR as well as exotoxin Asp. Complementation of intact pppA gene in DeltapppA mutant restored the production of c-di-GMP, LuxR, and Asp to the wild-type level. Phenotypic studies suggested that PppA takes part in the modulation of biofilm formation, motility, and cell aggregation. These results demonstrated new roles of PppA in controlling virulence factors and pleiotropic phenotypes and contributed to our understanding of the regulation of pathogenesis in V. alginolyticus. PMID- 23021864 TI - Recent data on rapid eye movement sleep behavior disorder in patients with Parkinson disease: analysis of behaviors, movements, and periodic limb movements. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) is a fascinating parasomnia in which patients are able to enact their dreams because of a lack of muscle atonia during REM sleep. RBD represents a unique window into the dream world. Frequently associated with Parkinson's disease (PD), RBD raises various issues about dream modifications in this pathology and about aggressiveness during RBD episodes in placid patients during wakefulness. Studies on these behaviors have underlined their non-stereotyped, action-filled and violent characteristics but also their isomorphism with dream content. Complex, learnt behaviors may reflect the cortical involvement in this parasomnia but the more frequent elementary movements and the associated periodic limb movements during sleep also implicate the brainstem. Surprisingly, patients with PD have an improvement of their movements during their RBD as if they were disease-free. Also not yet understood, this improvement of movement during REM sleep raises issues about the pathways involved in RBD and about the possibility of using this pathway to improve movement in PD during the day. PMID- 23021865 TI - Prevalence of sleep abnormalities and their association among hypothyroid patients in an Indian population. AB - OBJECTIVE: To estimate the prevalence of sleep abnormalities and their association with hypothyroidism and metabolic risk factors in a relatively lean urban South Indian population. METHODS: This population-based, cross-sectional study was carried out in the urban population of Chennai, one of the largest metropolitan cities of India. Phase 1 was conducted in the field and involved a door-to-door survey of 26,000 individuals. In phase 2, every tenth subject recruited in phase 1 (n=2600) was invited to our centre for detailed anthropometric and biochemical measurements. For the current study, a subset of 358 subjects with positive family history of hypothyroidism was randomly selected. A validated questionnaire assessing various sleep abnormalities (snoring, daytime sleepiness, lack of refreshing sleep and number of hours of sleep) was administered. Anthropometric and biochemical measurements were obtained to assess metabolic risk factors including thyroid status. RESULTS: Snorers were more often male, older, smokers and had higher BMI, neck circumference, blood pressures, and hypothyroidism. Out of 358 patients, 133 had impaired thyroid function (37.1%) and 64 patients had both snoring and impaired thyroid function (17.8%). Subjects with daytime sleepiness had higher BMI and neck obesity. The overall prevalence of snoring and daytime sleepiness was 52% and 64%, respectively. Both sleep measures were associated with hypothyroid status. Metabolic syndrome was significantly associated with snoring even after adjusting for age, sex, family history of hypothyroidism, physical activity, smoking and alcohol. CONCLUSIONS: The prevalence of snoring and daytime sleepiness is high among urban South Indians who are relatively lean. Both disorders are associated with hypothyroidism, although these associations were stronger in those with obesity. Based on our case prevalence and the other reports cited previously, we can reasonably conclude that thyroid screening of sleep clinic patients is essential. PMID- 23021867 TI - Regulatory T cells and reproduction: how do they do it? AB - Regulatory T cells (Treg cells) identified by expression of Foxp3 play an important role in successful implantation and gestation. Various mechanisms have been proposed to explain their actions, and the more credible and less credible are set out in this review. Induction of Treg cells is believed to occur in response to paternal antigens in seminal plasma at the time of mating, and these Treg cells home to the uterus prior to implantation. Tolerogenic dendritic cells are proposed to play an important role in the generation of Treg cells in the draining lymph nodes and in maintaining Treg activity in the uterus. Recent data indicate that abortion in the CBAxDBA/2 model may be prevented by seminal plasma antigens from DBA/2 and BALB/c males, but H-2(d) restriction suggests that presentation to Treg cells might occur via a novel mechanism. The relevance of findings in mice to human pregnancy problems is also discussed. PMID- 23021866 TI - Toll-like receptor gene variants associated with bacterial vaginosis among HIV-1 infected adolescents. AB - Bacterial vaginosis (BV) is a common vaginal disorder in women of reproductive age, especially among women with HIV-1 infection. Several bacterial products including lipopolysaccharides (LPS), lipoteichoic acids (LTA), and peptidoglycans (PGN) are stimulatory ligands for Toll-like receptors (TLRs), and recent evidence indicates the important role of variation in TLR genes for permitting overgrowth of gram negative and BV-type flora. We assessed whether genetic polymorphisms in five TLR genes (TLR1, TLR2, TLR4, TLR6, and TLR9) could be determinants of differential host immune responses to BV in 159 HIV-1-positive African American adolescents enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) study. BV was assessed biannually and diagnosed either by a Nugent score of at least 7 of 10, or using the Amsel criteria. Cox-proportional hazards regression models, adjusted for concurrent Chlamydia and Gonorrhea infections, douching, and absolute CD4 cell count, were used to identify host genetic factors associated with BV. Two SNPs were associated with BV as diagnosed by the Nugent score and the combined criteria: a minor allele G of rs4986790 (frequency=0.07), which encodes a His to Tyr substitution in TLR4 (HR=1.47, 95% CI 1.15-1.87) and rs187084 (frequency=0.24) on TLR9. The minor allele of rs1898830 (frequency=0.13) was associated with an increased hazard of BV defined by the Amsel criteria (HR=1.86, 95% CI 1.17-2.95). Further studies are warranted to confirm the associations of TLR gene variants and also to understand the underlying pathways and immunogenetic correlates in the context of HIV-1 infection. PMID- 23021868 TI - Evaluation of lumpectomy surgical specimen radiographs in subclinical, in situ and invasive breast cancer, and factors predicting positive margins. AB - PURPOSE: To determine the diagnostic performance of radiological evaluation of the margins of surgical specimens from lumpectomies for subclinical malignant breast lesions. MATERIALS AND METHODS: Retrospective study in two French hospitals including all patients who had a non-palpable in situ (ISDC) or invasive (IDC) ductal carcinoma treated by lumpectomy after radiological localisation. For the analysis, the lesions were divided into two groups depending on the majority component in the definitive histological examination: ISDC or IDC. The radiological margin considered was 10mm. RESULTS: For the 178 lumpectomies studied, the sensitivity of the radiographs of the surgical specimen was 33.3% for ISDC and 50% for IDC. The surgical revision rate was 27.41% for ISDC and 12.64% for IDC. The significant predictive factors for positive margins were the radiological size of the lesions (>10mm) for ISDC (P=0.02) and radiologically positive margins for IDC (P=0.01). Correlation was found between the histological and radiological sizes of the lesion for IDC, but not for ISDC. CONCLUSION: Radiological examination of surgical specimens does not provide a satisfactory evaluation of the histological margins, in particular for ISDC, even with a radiological threshold of 10mm. PMID- 23021869 TI - An assessment of the performance of elastography for the investigation of BI-RADS 4 and BI-RADS 5 breast lesions: correlations with pathological anatomy findings. AB - PURPOSE: To study the diagnostic value of static elastography of the breast (score, histogram, quantitative ratio) in masses classed as BI-RADS 4 and BI-RADS 5 on sonography using the findings from pathological anatomy analyses on the masses as a reference. MATERIALS AND METHODS: A prospective study using a representative sample into 68 masses seen on sonography and their elastography results. For each mass, we determined the elastography colourimetry score (UENO et al. classification, scores 1-3=benign and 4-5=malignant). We studied quantitative elastography parameters based on the Z2/Z1 (fat/lesion) ratio and a histogram showing the pattern of mass stiffness distribution. The results were compared with histology findings (68 lesions assessed, 22 benign lesions and 46 malignant lesions). RESULTS: Elastography was consistent with histology (sensitivity: 73.9%, specificity: 86.4%, PPV: 91.9%, NPV: 61.3%). There were twelve false negatives and three false positives. With the Z2/Z1 ratio, we set a cut-off point of 3.05 for 99.0% specificity. CONCLUSION: Elastography is a reliable technique that is able to assist radiologists in their diagnostic approach to breast pathology. PMID- 23021870 TI - Ovarian venous thrombosis during septicemia due to Fusobacterium necrophorum. PMID- 23021871 TI - A rare gastric polyposis: Cronkhite-Canada syndrome. PMID- 23021873 TI - Applying estimated glomerular filtration rate to an ageing population: are we in danger of becoming ageist? AB - BACKGROUND: Management of CKD is a major public health concern. The introduction of automated eGFR reporting has seen an increase in labelling of elderly patients with CKD. The prognostic significance of the CKD label in this population remains controversial. AIM: To investigate rates of specialist intervention in the over 75's to determine whether these patients may be more appropriately managed in primary care, relieving the burden of excessive outpatient visits in this population. METHODS: Retrospective review of patient notes and laboratory reports over 25 consecutive renal outpatient clinics within a single NHS trust. RESULTS: 546 patients were studied. The mean age of patient was 68.7 years (SD+/-14.9). The over 75's had more advanced renal disease compared to under 75's (mean eGFR 28.2 vs. 41.3 ml/min/1.73 m(2)), but there was no significant difference in eGFR stability between the older and younger cohort or in the overall rate of intervention (32.5% vs. 30.7% p=0.86). The over 75's had a lower mean haemoglobin (11.8 vs. 12.6, p=<0.001) necessitating greater EPO requirements (25.2% vs. 10.5%, p=<0.001). The greatest intervention was seen in the more advanced CKD patients (29% of CKD 3 vs. 55% of CKD 5), and in those with diagnoses requiring immunosuppression. CONCLUSION: Intervention to management may be predictable on the basis of specific diagnoses and advancing CKD stage but not by patient age. We can provide no evidence to suggest that elderly CKD patients are managed any differently to younger patients and in fact have a higher need for attention to and treatment of renal anaemia, validating their attendance in nephrology clinic. PMID- 23021872 TI - Micro-crystallography comes of age. AB - The latest revolution in macromolecular crystallography was incited by the development of dedicated, user friendly, micro-crystallography beam lines. Brilliant X-ray beams of diameter 20 MUm or less, now available at most synchrotron sources, enable structure determination from samples that previously were inaccessible. Relative to traditional crystallography, crystals with one or more small dimensions have diffraction patterns with vastly improved signal-to noise when recorded with an appropriately matched beam size. Structures can be solved from isolated, well diffracting regions within inhomogeneous samples. This review summarizes the technological requirements and approaches to producing micro-beams and how they continue to change the practice of crystallography. PMID- 23021874 TI - Ivabradine in systemic sclerosis related pulmonary arterial hypertension. PMID- 23021875 TI - Adalimumab or infliximab for the prevention or treatment of post-operative recurrence in Crohn's disease. PMID- 23021876 TI - The influence of infliximab and adalimumab on the expression of apoptosis-related proteins in lamina propria mononuclear cells and enterocytes in Crohn's disease - an immunohistochemical study. AB - BACKGROUND AND AIMS: The aim of this study was to assess the influence of anti TNF agents on the expression of apoptosis-related proteins in Crohn's disease (CD) patients. METHODS: The clinical, biochemical and endoscopic activity of CD was assessed with the use of tissue sampling before the initiation of therapy and after induction doses of infliximab and adalimumab. Additionally, the immunohistochemical expression of active caspase 3, TNFR1, Fas, Bcl-2, Bax, CD4 and CD8 proteins was estimated. Patients achieving deep remission were considered as responders. RESULTS: Of the 35 patients qualified for the study, 60% achieved deep remission. In those patients, a significant decrease in the number of CD4 and CD8 positive cells was noted. Also observed was a significant increase in the expression of active caspase 3 in lamina propria mononuclear cells, which correlated with an increase of the pro-apoptotic Bax/Bcl-2 ratio. No change in Fas and TNFR1 expression was observed in those cells. Moreover, there was a significant decrease in active caspase 3 expression in enterocytes, observed independently of the Bax/Bcl-2 ratio. This correlated with a change in TNFR1 expression. No significant changes in the expression of the investigated proteins were noted in non-responders group. CONCLUSIONS: The efficacy of anti-TNF antibodies is, at least partly, dependent on apoptosis modulation. In lamina propria mononuclear cells, the increase of apoptosis is probably the result of the induction of the intrinsic pathway mediated by Bcl-2 family proteins. In enterocytes - the decrease of apoptosis is mediated by the extrinsic pathway, probably via TNFR1. PMID- 23021877 TI - Infrastructures in healthcare: the interplay between generativity and standardization. AB - OBJECTIVE: To investigate how the design, development and implementation process of a new patient-centered portal unfolds by focusing on its evolutionary infrastructural development. DESIGN: We conducted a case study on a patient centred portal in Norway. We used qualitative data collection techniques including observations, interviews and attendance of design workshops with users. We performed an interpretive analysis of the data through the lens of technology enactment. RESULTS: The case analysis reveals that the patient-centred portal has a strong generative character. However, for the enactment of the technology continuous sociotechnical negotiations take place. Grounded in the empirical data and their analysis we complement and expand the existing understanding of generativity. DISCUSSION: We characterize generativity as sociotechnical and resulting from negotiations for technology enactment. We discuss in detail such negotiations and show how they shape the evolution of infrastructures that are generative while standardized. PMID- 23021878 TI - Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. AB - BACKGROUND: Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a T(H)2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma. OBJECTIVE: The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma. METHODS: A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels. RESULTS: There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (-2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy. CONCLUSION: Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways. PMID- 23021879 TI - Obesity is not a risk factor for repeat epinephrine use in the treatment of anaphylaxis. PMID- 23021880 TI - IL10 polymorphisms influence neonatal immune responses, atopic dermatitis, and wheeze at age 3 years. AB - BACKGROUND: IL10 encodes for IL-10, an important anti-inflammatory cytokine with pleiotropic effects. It is crucial for development of immune tolerance, downregulates expression of TH1 cytokines, and is relevant for T-cell regulation. Several IL10 single nucleotide polymorphisms (SNPs) were associated with inflammatory diseases, such as atopic diseases, which might have their onset during early immune maturation. OBJECTIVE: We hypothesized that IL10 SNPs are associated with decreased regulatory T (Treg) cell numbers, TH2-skewed immune responses, and decreased IFN-gamma levels in cord blood parallel with increased proinflammatory markers, subsequently leading to increased atopic diseases until 3 years. METHODS: Eight genetic IL10 variants, represented by 4 linkage disequilibrium blocks (R(2) > 0.80) and 2 distal promoter SNPs, were genotyped in cord blood mononuclear cells of 200 healthy neonates. Cord blood mononuclear cells were cultured unstimulated or after stimulation with lipid A, peptidoglycan, PHA, house dust mite (Der p 1), or Der p 1 plus lipid A. mRNA expression of Treg cell-associated genes (forkhead box protein P3 [FOXP3], glucocorticoid-induced TNF receptor [GITR], lymphocyte activation gene 3 [LAG3]), TH1/TH2 cytokines, TNF-alpha, and GM-CSF were assessed. Atopic and respiratory outcomes (atopic dermatitis [AD] and wheeze) were assessed by means of questionnaire at age 3 years. RESULTS: Carriers of 3 IL10 SNP blocks and both distal promoter SNPs showed reduced expression of Treg cell markers, reduced IL-5 levels, proinflammatory TNF-alpha and GM-CSF, and partially increased IFN-gamma levels. The same SNPs presented as determinant for AD, wheeze, or symptoms of AD, wheeze, or both at age 3 years. CONCLUSIONS: Polymorphisms in IL10 influenced Treg cell marker expression and TH1/TH2 and proinflammatory cytokine secretion early in life. This was relevant for further development of immune-mediated diseases, such as AD and wheeze, in early childhood. PMID- 23021881 TI - Egg-allergic patients can be safely vaccinated against influenza. PMID- 23021882 TI - Birch pollen immunotherapy results in long-term loss of Bet v 1-specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies. AB - BACKGROUND: Early events of specific immunotherapy (SIT) are induction of allergen-specific IL-10-producing T(R)1 cells and production of IgG antibodies, but there is little knowledge about the long-term immune mechanisms responsible for sustained allergen tolerance. OBJECTIVE: Bet v 1-specific immune responses of 16 patients with birch pollen allergy were characterized up to 54 months at defined time points before, during, and after a 3-year period of SIT. METHODS: We sought to analyze allergen-specific T- and B-cell responses. Bet v 1-specific IL 5-, IFN-gamma-, and IL-10-secreting T cells were quantified in peripheral blood, and birch pollen-specific IgE and IgG antibody levels were determined in serum. Furthermore, the inhibitory capacity of SIT-induced IgG was evaluated by blocking allergen binding to IgE and inhibition of facilitated allergen presentation. RESULTS: Seasonal increases in Bet v 1-specific T(H)2 cell numbers ceased to appear after the first year of SIT without deviation to a T(H)1-dominated immune response. Furthermore, the frequency of IL-10-producing T(R)1 cells, which had increased during the first year of SIT, returned to pretreatment levels in the second year. In contrast, allergen-specific IgG antibody concentrations continuously increased during SIT but started to decrease after cessation of treatment. Functional analysis confirmed the ability of the IgG antibodies to inhibit IgE-allergen interactions, which peaked at the end of SIT but then slowly started to decrease. CONCLUSION: Long-term allergen tolerance achieved by SIT is associated with the development of peripheral T-cell tolerance characterized by decreased reactivity of Bet v 1-specific T(H)2 cells and enriched allergen specific IgG competing with IgE antibodies for allergen binding. PMID- 23021883 TI - Adding measures to the asthma outcome measurement toolbox: new findings, new issues. PMID- 23021885 TI - Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison. AB - BACKGROUND: Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy are the 2 most prescribed routes for administering allergen-specific immunotherapy. They were shown to be effective in control of symptoms and in reducing rescue medication use in patients with allergic diseases, but their effectiveness has to be balanced against side effects. In recent years, SLIT has been increasingly prescribed, instead of SCIT, because of improved safety and easy administration. OBJECTIVE: We assessed which route is the most effective in the treatment of patients with seasonal allergic rhinitis to grass pollen. METHODS: An indirect meta-analysis-based comparison between SCIT and SLIT was performed. Treatment efficacy was determined as the standardized mean difference (SMD) in symptom and medication scores obtained with active treatment, SCIT or SLIT, compared with placebo. Studies were included if they were double-blind randomized controlled trials comparing SCIT or SLIT with placebo. Thirty-six randomized controlled trials (3014 patients; 2768 controls) were analyzed. RESULTS: The overall effect size of SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -0.58) was significantly higher than SLIT, both administered via drops (SMD, -0.25; 95% CI, 0.45 to -0.05) and tablets (SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results were reported for medication score (SCIT: SMD, -0.58; 95% CI, -0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00. SLIT tablets SMD, -0.30; 95% CI, 0.44 to -0.16). CONCLUSIONS: Our results provide indirect but solid evidence that SCIT is more effective than SLIT in controlling symptoms and in reducing the use of antiallergic medications in seasonal allergic rhinoconjuntivitis to grass pollen. PMID- 23021887 TI - Guidance is also needed on how to choose from existing asthma-specific quality-of life measures. PMID- 23021884 TI - Modeling asthma exacerbations through lung function in children. AB - BACKGROUND: Formal economic evaluation using a model-based approach is playing an increasingly important role in health care decision making. OBJECTIVE: To develop a model by using an objective measure of lung function-- prebronchodilator FEV(1) as a percent of predicted (FEV(1)% predicted)--as the primary independent factor to predict the frequency of adverse events related to the exacerbation of asthma on a population level. METHODS: We developed a Markov simulation model of childhood asthma by using data from the Childhood Asthma Management Program. The primary outcomes were the result of asthma exacerbations defined as hospitalizations, emergency department (ED) visits, and the need for oral corticosteroid therapy. Predicted monthly frequencies for each acute event were based on negative binomial regression equations estimated from the placebo arm of the Childhood Asthma Management Program with covariates of age, prebronchodilator FEV(1)% predicted, time in study, prior hospitalizations, and prior nocturnal awakenings. RESULTS: Simulated versus observed mean number of acute events were similar within the placebo and treatment groups. While the trial demonstrated treatment effects of 48% reduction in hospitalizations, 46% reduction in ED visits, and 44% reduction in the need for oral corticosteroid therapy at 48 months, the model simulated similar reductions of 49% in hospitalizations, 41% in ED visits, and 46% in the need for oral corticosteroid therapy. CONCLUSIONS: Our findings suggest that longitudinal intervention effects may be modeled through FEV(1)% predicted to estimate hospitalizations, ED visits, and need for oral corticosteroid therapy in childhood asthma for planning and evaluation purposes. PMID- 23021888 TI - Does eczema in infancy cause hay fever, asthma, or both in childhood? Insights from a novel regression model of sibling data. AB - BACKGROUND: The atopic march hypothesis proposes that eczema precedes the development of asthma and allergic rhinitis. OBJECTIVE: We sought to assess the evidence for a causal effect of infantile eczema on childhood hay fever, asthma, or both. METHODS: We used parental reports on infantile eczema and childhood asthma and hay fever for 3778 pairs of 7-year-olds matched to their sibling closest in age within 2 years from the Tasmanian Longitudinal Health Study. We analyzed paired sibling data using a logistic regression model that allowed inference about a causal effect of a familial predictor on a child's outcome by examining the change in association with their cosibling's predictor after adjusting for their own predictor status. RESULTS: Siblings were concordant for infantile eczema (tetrachoric correlation, 0.40). For having both hay fever and asthma by age 7 years, the association with cosibling's eczema was an odds ratio (OR) of 1.98 (95% CI, 1.37-2.86), which reduced after adjusting for own eczema to an OR of 1.65 (95% CI, 1.17-2.34). For having hay fever only, the association with cosibling's eczema was an OR of 1.68 (95% CI, 1.22-2.31) before and an OR of 1.59 (95% CI, 1.19-2.14) after adjusting for own eczema. There was no association between having asthma only and cosibling's eczema (OR, 1.00; 95% CI, 0.77-1.30). CONCLUSIONS: Eczema in infancy might have a causal effect on hay fever in children with and perhaps without asthma. The association of infantile eczema on asthma in children without hay fever, which might be early transient wheeze, is unlikely to be causal or familial. These findings have implications for hay fever prevention. PMID- 23021889 TI - Synthesis, characterization, biological activity and equilibrium studies of metal(II) ion complexes with tridentate hydrazone ligand derived from hydralazine. AB - In the present study, a new hydrazone ligand (2-((2-phthalazin-1 yl)hydrazono)methyl)phenol) prepared by condensation of hydralazine (1 Hydralazinophthalazine) with salicylaldehyde (SAH). The synthesized SAH-hydrazone and its metal complexes have been characterized by elemental analyses, IR, (1)H NMR, solid reflectance, magnetic moment, molar conductance, mass spectra, UV-vis and thermal analysis (TGA). The analytical data of the complexes show the formation of 1:1 [M:L] ratio, where M represents Ni(II), Co(II) and Cu(II) ions, while L represents the deprotonated hydrazone ligand. IR spectra show that SAH is coordinated to the metal ions in a tridentate manner through phthalazine-N, azomethine-N and phenolic-oxygen groups. The ligand and their metal chelates have been screened for their antimicrobial activities using the disc diffusion method against the selected bacteria and fungi. Proton-ligand association constants of (SAH) and the stepwise stability constants of its metal complexes are determined potentiometrically in 0.1 M NaNO(3) at different temperatures and the corresponding thermodynamic parameters were derived and discussed. The order of DeltaG degrees and -DeltaH degrees were found to obey Mn(2+)(7)F(5)), which was responsible for the green emission. The short acyclic chain length of the EO3 ligand, lanthanide contraction, and a bulky picrate anion affected the PL intensity, coordination environment around the Tb(III) ion, and crystal structure of the inner-sphere [Tb(Pic)(2)(H(2)O)(EO3)](+) moiety. The unique crystal structure in the Tb complex contained a half mole of triethylene glycol solvated. The complex had a high thermal stability due to the role of pi-pi stacking interactions of the Pic anions. The appearance of an emission from the ligands suggests that the photoluminescence of ligands cannot be quenched by coordination to the Tb(III) ion in its complex, so the intramolecular energy transfer process from the triplet state of the ligands (T(1)(L)) to the resonant emissive energy level of Tb(III) is not effective. PMID- 23021893 TI - Mandibular resection and reconstruction in the management of extensive ameloblastoma. AB - PURPOSE: To present our experience with the management of 31 extensive mandibular ameloblastomas treated with segmental mandibulectomy, reconstruction with free fibula or iliac crest flap, and rehabilitation with immediate or delayed endosteal dental implants. PATIENTS AND METHODS: The study sample comprised 31 patients with histologically confirmed mandibular ameloblastomas. Primary ameloblastomas were treated in 23 patients, and recurrent ameloblastomas affected 8 patients. Mandibular defect sizes ranged from 3.5 to 12.5 cm (mean, 5.6 cm). A free fibula osseous or osteocutaneous flap was used 17 times for reconstruction; in the remaining 14, a free iliac crest osseous or osteomuscular flap was chosen. Dental implants were positioned in 25 patients; implant procedures were performed simultaneously with reconstruction in 21 cases. RESULTS: All flaps were transplanted successfully, and no major complication occurred postoperatively. Final histologic examinations showed 27 multicystic and 4 unicystic ameloblastomas. Free margins were achieved in all patients. The duration of follow-up was 18 to 120 months (mean, 53.6 months). No patient showed clinical or radiologic signs of recurrence. The dental implant success rate was 100%. CONCLUSIONS: Segmental mandibular resection followed by immediate defect reconstruction with bone-containing free flaps with immediate dental implant placement should be considered as the treatment of choice for extensive mandibular ameloblastomas. PMID- 23021894 TI - Are alexithymia and schizoid personality disorder synonymous diagnoses? AB - Relationships among alexithymia, personality disorders, and higher-order psychopathological and interpersonal dimensions were examined in 199 college students and a close relative of each. Alexithymia, the difficulty to express and identify emotions, was measured by the Observer Alexithymia Scale (OAS; [Haviland, M. G., Warren, W. L., & Riggs, M. L. (2000). An observer scale to measure alexithymia. Psychosomatics, 41, 385-392]), which was completed by each student's relative. Each student completed three self-report measures: the Coolidge Axis II Inventory (CATI; [Coolidge, F. L. (2000). Coolidge Axis II Inventory: Manual. Colorado Springs, CO: Author.), the Five Dimensional Personality Test (5DPT; [van Kampen, D. (2009). Personality and psychopathology: A theory-based revision of Eysenck's PEN model. Clinical Practice and Epidemiology in Mental Health, 5, 9-21]), and the Horney-Coolidge Tridimensional Inventory (HCTI; [Coolidge, F. L. (1998). Horney-Coolidge Tridimensional Inventory: Manual. Colorado Springs, CO: Author]). Results indicated that higher levels of alexithymia are associated with personality disorders and their traits, such as schizoid, avoidant, and paranoid. With regard to the issue of the similarity and difference between alexithymia and schizoid personality disorder, there was sufficient evidence across all of the measures to suggest that they are not synonymous entities. Finally, alexithymic traits were associated with concurrent depressive traits even in a non-clinical sample. PMID- 23021895 TI - Empirical redefinition of delusional disorder and its phenomenology: the DELIREMP study. AB - AIMS: Since Kraepelin, the controversy has persisted surrounding the nature of delusional disorder (DD) as a separate nosological entity or its clinical subtypes. Nevertheless, there has been no systematic study of its psychopathological structure based on patient interviews. Our goal was to empirically explore syndromic subentities in DD. METHODS: A cross-sectional study was conducted in 86 outpatients with DSM-IV-confirmed DD using SCID-I. Psychopathological factors were identified by factor analysis of PANSS scores. The association between these factors and clinical variables (as per standardized instruments) was analyzed using uni- and multivariate techniques. RESULTS: PANSS symptoms were consistent with four factors (Paranoid, Cognitive, Schizoid, and Affective dimensions), accounting for 59.4% of the total variance. The Paranoid Dimension was associated with premorbid paranoid personality disorder, more adverse childhood experiences, chronic course, legal problems, worse global functioning, and poorer treatment adherence and response. The Cognitive Dimension was associated with poorer cognitive functioning, premorbid substance abuse, comorbid somatic diseases, mainly non-prominent visual hallucinations, fewer comorbid depressive disorders, and poorer global functioning. The Schizoid Dimension was associated with being single, a family history of schizophrenia, premorbid personality disorders (largely schizoid and schizotypal), non-prominent auditory hallucinations, and dysthymia. Finally, the Affective Dimension was associated with a family history of depression, premorbid obsessive personality, somatic delusions, absence of reference delusions, tactile and olfactory hallucinations, depressive and anxiety disorders, risk of suicide, and higher perceived stress. CONCLUSION: The identification and clinical validation of four separate psychopathological dimensions in DD provide evidence toward a more accurate conceptualization of DD and its types. PMID- 23021896 TI - Natural variation in learning and memory. AB - Learning is widespread in the animal kingdom. From the small nematode worm Caenorhabditis elegans to humans, learning appears to play a central role in adaptation to local spatial and temporal environmental conditions. Though the neurobiological mechanisms of learning and memory have been intensively studied, the function and adaptive significance of learning has only recently received interest. Using learning, animals may progressively adjust their behavior in response to new environmental conditions, suggesting benefits of learning on animal performance, at least in the short term. How does learning affect the overall fitness of an animal? What are the fitness benefits and costs of learning? How can we explain the natural variation in learning ability observed between individuals, between populations of the same species or between closely related species? What are the ecological circumstances that favor the evolution of learning? There are all emerging questions that are central to a better understanding of the evolution of cognition and animal adaptation. Here I review the recent evidence showing that learning and memory are molded by an animal's lifestyle within its ecological niche. PMID- 23021897 TI - Courtship behavior in Drosophila melanogaster: towards a 'courtship connectome'. AB - The construction of a comprehensive structural, and importantly functional map of the network of elements and connections forming the brain represents the Holy Grail for research groups working in disparate disciplines. Although technical limitations have restricted the mapping of human and mouse 'connectomes' to the level of brain regions, a finer degree of functional resolution is attainable in the fruit fly, Drosophila melanogaster, due to the armamentarium of genetic tools available for this model organism. Currently, one of the most amenable approaches employed by Drosophila neurobiologists involves mapping neuronal circuitry underlying complex innate behaviors - courtship being a classic paradigm. We discuss recent studies aimed at identifying the cellular components of courtship neural circuits, mapping function in these circuits and defining causal relationships between neural activity and behavior. PMID- 23021899 TI - High mortality and low access to care following incident acute myocardial infarction in individuals with schizophrenia. AB - OBJECTIVES: The primary objective of this study was to compare mortality following incident acute myocardial infarction (AMI) among individuals with and without schizophrenia. A secondary objective was to compare the likelihood to receive cardiac procedures and cardiologist visits. METHODS: This retrospective cohort study took place in Ontario, Canada. We studied incident AMI patients who were alive at hospitalization discharge from January 1, 2002 to December 31, 2006. 71,668 subjects were included in the study (402 subjects were excluded because of missing data). The main exposure was a diagnosis of schizophrenia. The main outcome measure was 30-day mortality post-discharge. Secondary outcomes included receipt of cardiac procedures and cardiologist visits within 30 days post-discharge. RESULTS: After risk adjustment, individuals with schizophrenia were 56% more likely to die within 30 days of discharge (OR 1.56, 95% CI 1.08 2.23; p=0.02), but approximately 50% less likely to receive cardiac procedures (OR 0.48, 95% CI 0.40-0.56; p<0.001) or to see a cardiologist within 30 days of discharge (OR 0.53, 95% CI 0.43-0.65; p<0.001). CONCLUSIONS: Individuals with schizophrenia have a significant risk of dying following incident AMI. Despite the elevated mortality risk, individuals with schizophrenia are less likely to receive specialist care and cardiac procedures. Inequities in access to AMI care may be an important point of intervention for individuals with schizophrenia. PMID- 23021900 TI - Prognosis for recovery of posterior interosseous nerve palsy after distal biceps repair. AB - BACKGROUND: There is very little information on the incidence of and usual recovery period for posterior interosseous nerve (PIN) palsies after distal biceps repair. This study examined the incidence and the time to resolution of PIN palsies in a large consecutive series of primary distal biceps repairs. MATERIALS AND METHODS: A retrospective review was performed of a consecutive series of patients treated by 34 fellowship-trained upper extremity surgeons with primary distal biceps repair through a single anterior incision technique. Patients' records were reviewed to determine how many experienced a postoperative PIN palsy, defined as postoperative digital extension weakness on clinical examination. Demographic information, surgical fixation used, and clinical resolution was collect for these patients. All patients had clinical follow-up until complete resolution of PIN palsy symptoms. RESULTS: We found 280 patients who were treated with a single-incision technique and 1 of 2 methods of biceps tendon fixation. Of these, 9 (3.2%) developed a postoperative PIN palsy after primary distal biceps repair. These 9 patients had complete lack of finger and thumb extension at the first postoperative visit and had complete resolution of symptoms at an average of 86 days (range, 41-145 days). CONCLUSIONS: The incidence of PIN palsy after a single-incision distal biceps repair was 3.2% in our series. These injuries typically resolve within 3 months, and at the latest, 5 months after surgery. PMID- 23021898 TI - Insular and anterior cingulate circuits in smokers with schizophrenia. AB - Schizophrenia (SZ) is associated with high rates of smoking. We previously found that resting state functional connectivity (rsFC) between the dorsal anterior cingulate (dACC) and striatum is independently associated with nicotine addiction and psychiatric illness. Since the insula is implicated in nicotine dependence, we hypothesized that SZ smokers will have greater dysfunction in smoking-related insular and dACC circuits than normal control smokers (NC) independent of smoking severity, consistent with an inherent disease-related weakening of smoking related circuits. Nicotine challenge was used to demonstrate that decreased rsFC in identified circuits reflects addiction trait and is not affected by pharmacological state. Twenty-four NC smokers and 20 smokers with SZ matched on nicotine addiction severity participated in a resting state fMRI study and were scanned during two separate sessions while receiving a placebo or nicotine patch, in a randomized, cross-over design. Using individualized, anatomically defined anterior and posterior insula and dACC as regions of interest (ROI), whole brain rsFC was performed using each ROI as a seed. Significant negative correlations between smoking severity and rsFC between insula, dACC and striatum were found for both groups. Furthermore, smokers with SZ demonstrated additive reductions in circuit strength between the dACC and insula compared to NC smokers independent of smoking severity. Nicotine challenge did not significantly alter rsFC in insula-dACC-striatal circuits. Reduced rsFC strength between the insula, dACC and striatum is associated with nicotine addiction severity in both non psychiatrically ill and in SZ smokers. Decreased insula-dACC rsFC may index overlapping circuitry associated with smoking and SZ. PMID- 23021901 TI - Reverse total shoulder arthroplasty for the management of failed shoulder arthroplasty with proximal humeral bone loss: is allograft augmentation necessary? AB - BACKGROUND: Patients undergoing revision shoulder arthroplasty frequently have deficient proximal humeral bone stock. Proximal humeral allograft has been recommended to augment reverse total shoulder arthroplasty (RTSA) to improve stability and function. This study reports the results of RTSA without proximal humeral allograft in patients with proximal humeral bone loss secondary to failed shoulder arthroplasty. MATERIALS AND METHODS: From 2005 to 2008, 251 patients were enrolled in a prospective RTSA cohort study. Significant humeral bone loss was demonstrated in 15 of 56 undergoing revision for failed arthroplasty. Average age was 67 years. Average bone loss measured 38.4 mm (range, 26-72 mm). Patients were followed up for a minimum of 2 years with American Shoulder and Elbow Surgeons (ASES), Subjective Shoulder Value (SSV), Constant Score (CS), and visual analog scale (VAS) pain scores, as well as self-reported satisfaction and radiographs. RESULTS: Patients demonstrated significant improvement in mean CS (23.0 to 44.2), ASES (38.2 to 68.3), ASES activities of daily living (7.0 to 15.9), SSV (19.2 to 75.8), and VAS pain (4.6 to 1.6) scores. Thirteen of 15 patients reported satisfaction (87%). Range of motion improved in forward flexion (38.3 degrees to 103.2 degrees ) and external rotation (-0.5 degrees to 11.9 degrees ). Radiographs demonstrated notching in 3 patients (20%), no humeral subsidence or loosening, and prosthetic fracture of 1 modular humeral stem. CONCLUSIONS: Use of RTSA for failed shoulder arthroplasty and deficient humeral bone stock provides a significant clinical benefit without the need for allograft augmentation. Monoblock humeral component use may diminish risk for prosthetic fracture. PMID- 23021902 TI - The AO Foundation and Orthopaedic Trauma Association (AO/OTA) scapula fracture classification system: focus on glenoid fossa involvement. AB - BACKGROUND: Fractures of the glenoid frequently require surgical treatment. A comprehensive and reliable scapula classification system involving the glenoid fracture patterns is needed to describe the underlying pathology. The AO Scapula Classification Group introduces an appropriate novel system that is presented along with its inter-rater reliability and accuracy. MATERIALS AND METHODS: An iterative consensus process (involving a series of face-to-face meetings and agreement studies) with an international group of 7 experienced shoulder surgeons was used to specify and evaluate a scapular fracture classification system with a focus on fracture patterns of the glenoid fossa. The last evaluation was conducted on a consecutive collection of 120 scapular fractures documented by both plain radiographs and computed tomography scans including 3-dimensional surface rendering. Inter-rater reliability was analyzed with kappa statistics, and accuracy was estimated by latent class modeling. RESULTS: Of 120 scapular fractures, 46 involved the glenoid (38%), with 38 classified as F1 articular rim fractures. The overall median sensitivity and specificity in identifying these fractures were 95% and 93%, respectively. Surgeons' accuracy in classifying F1 fractures ranged from 86% to 100% (median, 94%). Subsequently, classification of simple F1 fractures resulted in a proportion of 36% of anterior rim fractures, 19% of posterior rim fractures, and 45% of short oblique fractures, with accuracies ranging from 85% to 98%. CONCLUSION: This new system for scapular glenoid fractures has proved to be sufficiently reliable and accurate when applied by experienced shoulder surgeons. Further validation of the most detailed system, as well as involvement of surgeons with different levels of training in the framework of clinical routine and research, however, should be considered. PMID- 23021903 TI - Does the dynamic sling effect of the Latarjet procedure improve shoulder stability? A biomechanical evaluation. AB - INTRODUCTION: Glenohumeral instability with glenoid bone loss is commonly treated with the Latarjet procedure. The procedure involves transfer of the coracoid and conjoint tendon, which is thought to provide a stabilizing sling effect; however, its significance is unknown. This study evaluated the effects of the Latarjet procedure, with and without conjoint tendon loading, on shoulder stability and range of motion (ROM). MATERIALS AND METHODS: A custom simulator was used to evaluate anterior shoulder stability and ROM in 8 cadaveric shoulders. Testing conditions included intact, 30% glenoid defect, and Latarjet with and without conjoint loading. Unloaded and 10-N loaded states were tested in adduction and 90 degrees abduction. Outcome variables included dislocation, stiffness (neutral and 60 degrees external rotation), and internal-external rotational ROM. RESULTS: All 30% defects dislocated in abduction external rotation. The loaded Latarjet prevented dislocation in all specimens, whereas the unloaded Latarjet stabilized 6 of 8 specimens. In abduction external rotation, there were no significant differences in stiffness between loaded and unloaded transfers (P = .176). In adduction, there were no significant differences between the intact and the loaded Latarjet (P >= .228); however, in neutral rotation, the unloaded Latarjet (P = .015) and the 30% defects (P = .011) were significantly less stiff. Rotational ROM in abduction was significantly reduced with the loaded Latarjet (P = .014) compared with unloaded Latarjet, and no differences were found in adduction. CONCLUSIONS: These findings indicate that glenohumeral stability is improved, but not fully restored to intact, with conjoint tendon loading. The results support the existence of the sling effect and its importance in augmenting stability provided by the transferred coracoid. PMID- 23021904 TI - Does the "bumper" created during Bankart repair contribute to shoulder stability? AB - BACKGROUND: The aim of this study was to determine the optimal repair configuration for anterior shoulder instability after a labral tear. MATERIALS AND METHODS: Nine fresh, frozen shoulders were used. With a 50-N axial force, the humeral head was translated anteriorly, and the translational force was measured. The measurement was performed with the capsule intact, after creating a Bankart lesion, and after the Bankart repair at 5 different positions: glenoid rim, glenoid surface-2 mm (on the glenoid surface 2 mm from the glenoid rim), glenoid surface-5 mm, scapular neck-2 mm (on the scapular neck 2 mm from the glenoid rim), and scapular neck-5 mm. Glenoid rim fixation was done with and without a "bumper." The "bumper" was created by plicating the capsule to form a thickened mass of tissue. RESULTS: The translational force was restored to the intact level after the glenoid rim fixation. However, there was no significant difference in force after the Bankart repair with and without a "bumper" nor after the glenoid rim fixation and glenoid surface-2 mm. The force significantly decreased after scapular neck-2 mm and scapular neck-5 mm compared with the glenoid rim fixation. CONCLUSION: The anchor fixation on the glenoid face does not increase the translational force compared with the glenoid rim placement, but the placement on the scapular neck decreases the translational force. PMID- 23021905 TI - Prevalence and pattern of glenohumeral injuries among acute high-grade acromioclavicular joint instabilities. AB - BACKGROUND: With increasing numbers of arthroscopically assisted acromioclavicular (AC) joint stabilization procedures has come an increase in reports of concomitant glenohumeral injuries among AC joint separations. The aim of the present study was to evaluate the prevalence, pattern, and cause of glenohumeral pathologies among a large patient population with acute high-grade AC joint instability. MATERIALS AND METHODS: A total of 125 patients (13 women, 112 men) with high-grade AC joint dislocation (6 Rockwood II; 119 Rockwood V) underwent diagnostic glenohumeral arthroscopy before AC joint repair. Pathologic lesions were evaluated for acute or degenerative origin and, if considered relevant, treated all-arthroscopically. RESULTS: Concomitant glenohumeral pathologies were found in 38 of 125 patients (30.4%). Analysis of pathogenesis distinguished different patterns of accompanying injuries: acute intra-articular lesions, related to the recent shoulder trauma, were found in 9 patients (7.2%), degenerative lesions, considered to be unrelated to the recent trauma, were found in 18 (14.4%), and 11 (8.8%) had an unclear traumatic correlation (intermediate group). Within the acute and the degenerative group, affected structures were predominantly partial, articular-sided tears of the anterosuperior rotator cuff, including instabilities of the pulley complex, followed by pathologies of the long head of the biceps and superior labrum anteroposterior lesions. The intermediate group presented mainly with articular-sided partial tears of the subscapularis tendon. CONCLUSIONS: This prospective study showed a high prevalence (30%) of concomitant glenohumeral pathologies, of which some indicate additional surgical therapy and could be missed by an isolated open AC repair. Hence, the arthroscopic approach for AC joint stabilization allows for the diagnosis and treatment of associated intra-articular pathologies. PMID- 23021906 TI - Clinical phenotypes related to smoking cessation. AB - INTRODUCTION: The aim of the current study is the identification of clinical phenotypes of patients visiting a specialized smoking cessation center and the determination of smoking cessation rate for each phenotype, 1 year after the initial evaluation. METHODS: Seven hundred eighty-three smokers who visited the outpatient clinic were included in the study. Demographic data, smoking habits, tobacco dependence and comorbidities were recorded. Smoking cessation rates and carbon monoxide levels were determined 1 year after the initial evaluation. RESULTS: The overall smoking cessation rate 1 year after the initial evaluation was 32.3%. Four distinct phenotypes were identified. The first one included mainly young women with low tobacco dependence and allergic profile. The second and the third ones included mainly men with high tobacco dependence, without comorbidities, treated with varenicline and bupropione SR, respectively. The fourth one included mainly older men with high tobacco dependence and smoking related comorbidities. Smoking cessation rates for each phenotype were 33.8, 39.4, 23.3, and 24.6%, respectively. CONCLUSION: Patients visiting a specialized smoking cessation center can be categorized in different phenotypes. Phenotyping may lead to a more personalized approach concerning smoking cessation. PMID- 23021907 TI - Amoeba stages in the deepest branching heteroloboseans, including Pharyngomonas: evolutionary and systematic implications. AB - The taxon Heterolobosea (Excavata) is a major group of protists well known for its diversity of life stages. Most are amoebae capable of transforming into flagellates (amoeboflagellates), while others are known solely as flagellates or solely as amoebae. The deepest-branching heterolobosean taxon confirmed previously, Pharyngomonas, was generally assumed to be a pure flagellate, suggesting that the amoeba form arose later in the evolution of Heterolobosea sensu lato. Here we report that multiple isolates of Pharyngomonas are actually amoeboflagellates that also have cyst stages, with only amoebae transforming into cysts. The amoeba form of Pharyngomonas showed heterolobosean characteristics (e. g. eruptive movement), but also possessed unusual morphological features like slow-flowing crenulated hyaline crescents with conical subpseudopodia, finger like projections and branching posterior extensions. Furthermore, phylogenetic analyses of 18S ribosomal RNA gene sequences that included two undescribed species of amoebae showed that Pharyngomonas is not the only deep-branching heterolobosean to possess an amoeba stage. These results suggest that possession of an amoeba stage was ancestral for Heterolobosea, unifying this taxon as a group of species with amoeba stages in their lifecycle or derived from organisms with such stages. PMID- 23021908 TI - Latent profile and latent transition analyses of eating disorder phenotypes in a clinical sample: a 6-year follow-up study. AB - The DSM-IV classification of Eating Disorders (EDs) identifies clinical entities showing considerable overlap and diagnostic instability across time. Latent profile analysis (LPA) allows the identification of underlying groups of individuals according to their patterned responses across a set of features. LPA was applied to data regarding EDs symptoms of a clinical sample of 716 EDs patients, with a current DSM-IV diagnosis of threshold and subthreshold EDs. Latent transition analysis (LTA) was used to examine the longitudinal stability of the obtained profiles. The latent profiles were compared for psychopathological variables and long-term outcomes (recovery, relapse), based on a 6-year follow-up after a cognitive behavioural treatment. Five different phenotypes were identified: "severe binging", "moderate binging", "restricted eating", "binge and moderate purging", and "binge and severe purging". The relevance of this characterization was confirmed by the differences in terms of psychopathological features and outcomes. Over the long term, a three-profile solution was adopted, clustering the subjects into "binge eating", "binge eating and purging", and "restricted eating". Latent profiles showed a moderate stability over the 6-year period, with probability estimates of stability within status over time of 0.57 for "binge eating", 0.40 for "binge eating and purging", and 0.41 for "restricted eating". The implications for DSM 5 were discussed, and the relative high rate of transition within phenotypes confirmed the significant instability of EDs phenomenology. PMID- 23021909 TI - Consummatory and anticipatory anhedonia in schizophrenia: stability, and associations with emotional distress and social function over six months. AB - Recent work has suggested that anhedonia in schizophrenia can be understood as involving two separate constructs: deficits in anticipatory and consummatory pleasure. Little is known about the relative stability of these different constructs and their links with clinical features and social function over time. To examine these questions, 51 participants with a diagnosis of schizophrenia or schizoaffective disorder in a non-acute phase of illness were administered the Temporal Experience of Pleasure Scale, the Positive and Negative Syndrome Scale, and Quality of Life Scale at two time points six months apart. Results revealed that baseline scores of both anticipatory and consummatory pleasure were significantly correlated with follow-up scores six months later, suggesting each construct is stable in the short term. The association of anticipatory pleasure at baseline and six months was significantly higher than the relationship between consummatory pleasure at baseline and at six months. Anticipatory pleasure predicted concurrent and prospective levels of positive symptoms, emotional discomfort, and interpersonal function, but not emotion recognition. Consummatory pleasure predicted only concurrent positive symptoms. The link of baseline anticipatory pleasure with emotional discomfort at six months persisted even after controlling for baseline emotional discomfort. Implications for the measurement and conceptualization of anhedonia in schizophrenia are discussed. PMID- 23021910 TI - Replication analysis for composition of the Delirium Motor Subtype Scale (DMSS) in a referral cohort from Northern India. AB - The Delirium Motor Subtype Scale (DMSS) was developed by discerning the best differentiating motor activity symptoms from the Delirium Motor Checklist (DMC), a compilation of psychomotor symptoms from other subjective scales. To broaden its validation we replicated the original work done in a palliative care population in a psychiatric referral population. 100 consecutive C/L Psychiatry referrals with DSM-IV delirium in an Indian general hospital were assessed with the Delirium Rating Scale-Revised-98 (DRS-R98) and DMC and compared to 60 nondelirious hospitalized controls. Disturbances of motor activity were almost invariably present in patients with delirium and at a much higher frequency than in nondelirious control subjects. Principal components analysis identified 5 factors for the DMC where Factor 1 explained 37.3% of the variance and correlated significantly with DRS-R98 motor items. Items loading at >0.65 were selected for the replication scale if they also either correlated significantly with DRS-R98 motor items or were significantly more frequent in delirious patients vs. controls. The resultant scale comprised 12 items (five hyperactive and seven hypoactive) and was similar to the original DMSS. Combining motor items from the original DMSS and replicated version produced a 13-item amended DMSS that may have broader generalizability than the original DMSS. PMID- 23021911 TI - Using multidimensional modeling to combine self-report symptoms with clinical judgment of schizotypy. AB - This study investigated psychometric properties of two widely used instruments to measure subclinical levels of psychosis, the Community Assessment of Psychic Experiences (CAPE) and the Structured Interview for Schizotypy-Revised (SIS-R), and aimed to enhance measurements through the use of multidimensional measurement models. Data were collected in 747 siblings of schizophrenia patients and 341 healthy controls. Multidimensional Item-Response Theory, Mokken Scale and ordinal factor analyses were performed. Both instruments showed good psychometric properties and were measurement invariant across siblings and controls. The latent traits measured by the instruments show a correlation of 0.62 in siblings and 0.47 in controls. Multidimensional modeling resulted in smaller standard errors for SIS-R scores. By exploiting correlations among related traits through multidimensional models, scores from one diagnostic instrument can be estimated more reliably by making use of information from instruments that measure related traits. PMID- 23021912 TI - Fed-batch system for cultivating genetically engineered yeast that produces lactic acid via the fermentative promoter. AB - A simple fed-batch system for cultivating genetically engineered yeast generating lactate under the regulation of the PDC1 promoter was established. Traditional strategies that avoid occurrence of Crabtree effect, such as respiratory quotient (RQ) control or ethanol control, are not applicable to the strain because of reduced generation of ethanol and CO(2) by-products. In this system, the feed rate increased when the pH was >5.0, and decreased when the pH was <5.0. Using this system, cell yields on sucrose increased by approximately 30% compared to that with the conventional RQ control method, due to the early detection of occurrence of Crabtree effect by pH decrease. PMID- 23021913 TI - Retinoic acid-induced protein 3: identification and characterisation of a novel prognostic colon cancer biomarker. AB - AIM OF THE STUDY: Validated molecular biomarkers are urgently required in colon cancer (CC) to accurately define prognosis and, ideally, to predict response to therapeutic modalities such as adjuvant chemotherapy. We aimed to identify and characterise a novel membrane-associated protein in CC tissues which may offer diagnostic and, potentially, therapeutic targeting opportunities. METHODS: Label free mass spectrometric (MS) quantitation was employed to profile matched colon tissues for malignancy-associated proteins. The putative diagnostic utility of a chosen marker was evaluated using immunohistochemistry (IHC) on 367 CC tissue samples contained within the NCI Progression Colon Cancer tissue microarray (TMA) set. RESULTS: Retinoic acid-induced protein 3 (RAI3) was initially identified as a plasma membrane protein overexpressed in CC. Cancer-associated RAI3 over expression was confirmed by RAI3 IHC. Although RAI3 IHC expression patterns were variable within neoplastic epithelium, 76% (n=236) of interpretable CC cases (n=312) displayed diffuse cytoplasmic expression. Of note, a sub-set of CC tissues (n=23, 7.4%) displayed very strong cytoplasmic expression, a feature significantly associated with disease recurrence in Dukes' A-C (stage I-III) patients (hazard ratio (HR)=3.076, [95%confidence interval (CI)=1.738-5.445]; p<0.001) when compared to low or negative expression of RAI3. This association retained univariate significance in Dukes' B/stage II patients only (HR=3.494, [95%CI=1.197-10.20]; p<0.022). Significantly, the prognostic capacity of RAI3 was maintained in the stage I-III cohort following multivariate modelling (HR=2.11, [95%CI 1.109-4.017], p=0.023). CONCLUSION: RAI3 is a putative prognostic marker that identifies a small subset of CC patients with high recurrence risk. This study demonstrates the potential value of modern proteomic technology in clinically relevant applications. PMID- 23021914 TI - Synthetic biotechnology to study and engineer ribosomal bottromycin biosynthesis. AB - Bottromycins represent a promising class of antibiotics binding to the therapeutically unexploited A-site of the bacterial ribosome. By inhibiting translation they are active against clinically important pathogens, such as vancomycin-resistant Enterococci. Structurally, bottromycins are heavily modified peptides exhibiting various unusual biosynthetic features. To set the stage for compound modification and yield optimization, we identified the biosynthetic gene cluster, used synthetic biotechnology approaches to establish and improve heterologous production, and generated analogs by pathway genetic engineering. We unambiguously identified three radical SAM methyltransferase-encoding genes required for various methylations at unactivated carbons yielding tert-butyl valine, methyl-proline, and beta-methyl-phenylalanine residues, plus a gene involved in aspartate methyl-ester formation. Evidence for the formation of the exo-thiazole unit and for a macrocyclodehydration mechanism leading to amidine ring formation is provided. PMID- 23021915 TI - Successful medical treatment for ranula in children. AB - OBJECTIVES: We compare the outcome of medical treatment for ranula versus surgery in children. STUDY DESIGN: Multicentric cohort study. METHODS: The case series includes 37 children with ranulas (diameter 2.7 +/- 1.5 cm). Eighteen patients, including 3 who had relapsed after either simple marsupialization or ranula removal alone, received oral nickel gluconate, mercurius heel, and glandula submandibularis suis D10/D30/D200. Fifteen cases underwent marsupialization with packing, and 2 underwent sublingual gland and ranula en-bloc excision. Two patients who recovered spontaneously shortly after diagnosis were excluded. RESULTS: No recurrences occurred among medical patients. Of the 17 surgical patients, 3 treated with marsupialization with packing relapsed. With the 3 surgical failures from other centers a total of 6 of 20 relapses were considered. Swelling or tension was common in surgical cases but unusual in medical patients. CONCLUSIONS: In this case series oral medical treatment for ranula was very effective and more effective than marsupialization with packing. PMID- 23021917 TI - Solitary myofibroma of the adult mandible: a case report. AB - A 43-year-old woman presented with a swelling in the anterior mandible appearing radiographically as a well-defined radiolucency causing mobility of the anterior teeth. A clinical diagnosis of a radicular cyst led to removal of the lesion and the associated mobile teeth. Postoperative histopathology led to a diagnosis of intraosseous solitary myofibroma of the mandible. Solitary lesions of myofibroma are exceedingly rare in adult jaws, with only 3 previously documented cases. PMID- 23021916 TI - Salivary biomarkers associated with myocardial necrosis: results from an alcohol septal ablation model. AB - OBJECTIVE: To determine if salivary biomarkers demonstrate utility for identifying aspects of myocardial necrosis. METHODS: Twenty-one patients undergoing alcohol septal ablation (ASA) for treatment of hypertrophic cardiomyopathy provided serum and unstimulated whole saliva at baseline and incremental time points post-ASA. Samples were analyzed for seven biomarkers related to myocardial damage, inflammation, and tissue remodeling using immunosorbent assays. Levels were compared with baseline and levels observed in 97 healthy controls. RESULTS: Biomarkers of myocardial damage and inflammation (ie, troponin I, creatine kinase-MB, myoglobin, C-reactive protein) rose in serum 2- to 812-fold after ASA (P < .01). Significant elevations of 2.0- to 3.5-fold were observed with C-reactive protein and troponin I in saliva (P < .02). Significant correlations between levels in serum and saliva were observed for C reactive protein, matrix metalloproteinase-9, and myeloperoxidase (P < .001). CONCLUSIONS: Select salivary biomarkers reflect changes that occur during, and subsequent to, myocardial necrosis caused by ASA. PMID- 23021918 TI - Comparison of external beam radiation therapy and radioactive implants in the management of nonmetastatic oral squamous cell cancer: an analysis of the surveillance epidemiology and end results database. AB - OBJECTIVE: Radiotherapy in oral squamous cell carcinoma (OSCC) could be either through external beam (EBRT) or brachytherapy (BT). In third-world countries, access to novel treatment like BT is limited. This study aimed to compare survival in patients with OSCC treated with EBRT with BT recipients. METHODS: We examined cases of nonmetastatic OSCC between January 1, 1987, and December 31, 2007, in the surveillance epidemiology and end results (SEER) registry. A Cox proportional hazards model was used to determine the adjusted relationship between radiation type and survival. RESULTS: There was no significant difference in survival (adjusted) between patients who were treated with BT and those treated with EBRT (P = .330). However, combining EBRT + BT was associated with significantly better survival compared with EBRT alone (hazard ratios [HR] = 0.61, P < .001) or BT alone (HR = 0.70, P = .024). CONCLUSIONS: The effect of BT on survival was not significantly different from EBRT. PMID- 23021919 TI - Region-specific statistical analysis of landmark configurations applied to rapid maxillary expansion data from cone-beam computerized tomography. AB - OBJECTIVE: The aim of this study was to apply a region-specific method for the statistical analysis of landmark configurations to a rapid maxillary expansion data set obtained from cone-beam computerized tomography. STUDY DESIGN: A method of analyzing landmark configurations using persistent homology and dimensionality reduction is used to analyze region-specific treatment effects involving 2 types of maxillary expansion treatments, compared with a control group. RESULTS: The method identified maxillary width as the primary feature of variability in the data and showed that both treatment groups exhibited significantly greater maxillary expansion than the control group throughout the study period, with no significant differences found between the 2 treatments. CONCLUSIONS: The choice of distance used to compare landmark configurations and the focus on more specific regions of interest produce more detailed results. This approach can be used after a primary analysis with a larger number of landmarks has identified regions deserving further inquiry. PMID- 23021920 TI - Magnetic resonance imaging evaluation of discal attachment of superior head of lateral pterygoid muscle in individuals with symptomatic temporomandibular joint. AB - OBJECTIVE: There has been much speculation on the role of the lateral pterygoid muscle (LPM) in temporomandibular joint (TMJ) internal derangement. As a result, this muscle has been the focus of many reports attempting to understand its possible role in TMJ internal derangement. STUDY DESIGN: Magnetic resonance (MR) imaging exams of 108 TMJ disorder patients were assessed for types of morphologic insertion of the superior head of LPM to the condyle-disc complex and possible correlation with disc position. The investigation was made on the sagittal T1 weighted MR images in closed- and open-mouth positions. RESULTS: There was a lack of correlation between attachment pattern of the superior head of LPM and presence or absence of anterior disc displacement. CONCLUSIONS: The explanation of anterior disc displacement based on the attachment type of the superior head of LPM is unlikely; the type of muscular insertion does not appear to have a predictive or prognostic value for TMJ internal derangement. PMID- 23021921 TI - Reflection of 18F-FDG accumulation in the evaluation of the extent of periapical or periodontal inflammation. AB - OBJECTIVES: To elucidate whether fluorine-18-labeled ((18)F) fluoro-2-deoxy-d glucose (FDG) accumulation can reflect the extent of periodontal inflammation, periapical inflammation, or dental caries. STUDY DESIGN: (18)F-FDG accumulations on positron emission tomography (PET)-computed tomography (CT) were retrospectively compared with the size of the bone resorption areas caused by periodontal inflammation, periapical inflammation, or dental caries on panoramic radiographs, CT, and magnetic resonance imaging (MRI) in 44 subjects. RESULTS: A significant correlation was found between the size of the bone resorption area caused by periodontal (r = 0.595, P < .01) or periapical (r = 0.560, P < .01) inflammation and the highest standardized uptake value (SUVmax) of (18)F-FDG accumulation. A significant correlation was found between the periodontal (r = 0.622, P < .01) or periapical (r = 0.394, P < .01) inflammatory findings on MRI and the SUVmax of (18)F-FDG accumulation. The SUVmax of (18)F-FDG around most teeth with caries was under 1.5. CONCLUSIONS: (18)F-FDG accumulation reflects the extent of dental inflammation, not dental caries. PMID- 23021922 TI - Unilocular radiolucency of the mandible. PMID- 23021923 TI - Mammary analog secretory carcinoma of salivary glands: a report of 2 cases in the lips. AB - OBJECTIVE: This study presents 2 cases of labial mammary analog secretory carcinoma (MASC) including diagnostic criteria and a review of literature. MASC has not been previously described in the dental literature. DESIGN: Two cases of MASC and 1 case of acinic cell carcinoma (ACC) of the lips were reviewed for their microscopic and immunohistochemical features. Fluorescence in situ hybridization (FISH) for the ETV6-NTRK3 translocation was performed. The clinical features of 65 cases previously described in the medical literature are reviewed. RESULTS: MASCs had hematoxylin and eosin features similar to those of ACC but demonstrated larger, globular periodic acid-Schiff positive deposits, whereas ACC had finer granular deposits. MASCs were strongly positive for S100, vimentin, and mammaglobin, whereas ACC was negative for S100 and vimentin and only focally mammaglobin positive. FISH demonstrated that MASCs were positive for ETV6 disruption. CONCLUSION: MASCs are newly described, can occur in a wide age range, favor males, and can be misinterpreted as ACC or adenocarcinoma not otherwise specified by routine microscopy. PMID- 23021924 TI - Tooth abnormalities in congenital infiltrating lipomatosis of the face. AB - OBJECTIVE: The aim of this study was to present a literature review and case series report of tooth abnormalities in congenital infiltrating lipomatosis of the face (CIL-F). METHODS: Four typical cases of CIL-F are presented. Tooth abnormalities in CIL-F documented in the English literature are also reviewed. The clinical and radiological features of tooth abnormalities are summarized. RESULTS: In total, 21 cases with tooth abnormalities in CIL-F were retrieved for analysis. Accelerated tooth formation and eruption (17 cases), macrodontia (9 cases), and root hypoplasia (8 cases) were observed in CIL-F. CONCLUSION: Tooth abnormalities including accelerated tooth formation or eruption, macrodontia, and root hypoplasia are common in CIL-F. PMID- 23021925 TI - Health-related quality of life as a survival predictor for patients with oral cancer: is quality of life associated with long-term overall survival? AB - OBJECTIVE: The aim of the present prospective study was to obtain further insight into health-related quality of life (HR-QoL) as a predictor of survival in a selected cohort of patients with oral cancer. STUDY DESIGN: A total of 124 patients were treated with surgery or combined therapy. All of the recruited patients completed the European Organization for Research and Treatment of Cancer questionnaires QLQC30 and H&N35 on 4 occasions. Overall survival was assessed. Univariate and multivariate Cox proportional hazards regression models were conducted. RESULTS: High baseline HR-QoL score and high pain symptom score were significantly associated with a better survival (HR 0.86 and 0.92 respectively). Swallowing (HR 0.94), and speech (HR 0.92) high baseline scores were also significantly associated with a better survival in the adjusted analyses. CONCLUSIONS: Patients who reported a better HR-QoL at tumor diagnosis had a better survival than patients with a lower HR-QoL baseline score. PMID- 23021926 TI - Temporomandibular joint arthritis in sickle cell disease: a case report. AB - We report a rare case of aseptic arthritis in the temporomandibular joint of a patient with sickle cell anemia. A 22-year-old woman with sickle cell disease, in the 18th week of gestation, was referred by her hematologist to investigate a sudden mouth opening limitation and severe pain on her left cheek. The patient received a standard pain assessment protocol, clinical examination, and complementary exams (complete blood count, hemoglobin electrophoresis, blood solubility test, panoramic radiograph, and magnetic resonance imaging [MRI]). The blood results were consistent with a sickle cell crisis and the MRI showed an inflammatory process around the left temporomandibular joint. Treatment with opioid analgesics and blood transfusion provided good results. Sickle cell anemia is a disease that can cause arthritis of the temporomandibular joint, and although it is rare, clinicians should be attentive to the differential diagnosis in patients with this disease. PMID- 23021927 TI - Criteria and limitations for selecting a sagittal split ramus osteotomy for patients with skeletal mandibular prognathism and open bite. AB - PURPOSE: The purpose of this study is to elucidate the criteria and limitations for selecting a sagittal split ramus osteotomy (SSRO) alone for patients with skeletal mandibular prognathism and open bite. STUDY DESIGN: The relationship between the mandibular relapse after 1 year and the extent of vertical movement following SSRO alone was investigated for patients with skeletal mandibular prognathism and open bite and the criteria were determined. RESULTS: The limitation in SSRO alone was found to be 3-mm vertical movement at the gonion. There was a significant difference in the mandibular relapse between the patients with >3-mm change and <3-mm change. CONCLUSIONS: For patients with skeletal mandibular prognathism and open bite, if the vertical movement at the gonion is <3 mm, SSRO alone could be an effective treatment. However, if the movement is >3 mm, SSRO alone should be avoided and bimaxillary osteotomies may be a preferable treatment. PMID- 23021928 TI - A progressively enlarging swelling of the palate. PMID- 23021929 TI - Menopausal symptoms and the risk of young-onset breast cancer. AB - BACKGROUND: Women with menopausal symptoms have been reported to have reduced risk of breast cancer, possibly reflecting differences in endogenous hormone levels. We examined the associations between menopausal symptoms and breast cancer in women under age 50. METHODS: We carried out a sister-controlled case control study, the Two Sister Study, comparing 1422 women with breast cancer diagnosed before age 50 and their 1669 sisters who were free of breast cancer and had enrolled in the prospective Sister Study cohort. History and age at first occurrence of menopause-associated symptoms (e.g. hot flashes, poor sleep or night sweats) were ascertained using computer-assisted telephone interviews. To equalise opportunity for exposure, we assessed exposures in relation to a sibship based index age (the minimum of the age at diagnosis of the case sister and the age at interview of her control sister(s)), and estimated odds ratios using conditional logistic regression with adjustment for menopausal status and birth order. FINDINGS: Having had menopause-associated symptoms (n=706) prior to the index age was associated with reduced risk of young-onset breast cancer (odds ratio (OR), 0.49; 95% confidence interval (CI), 0.40-0.61). Similar results were seen for hot flashes and for "other" menopausal symptoms. The association between menopausal symptoms and breast cancer risk was somewhat stronger for oestrogen receptor positive tumours than for oestrogen receptor negative tumours (heterogeneity p=0.07). Menopausal status, age at menopause, BMI and hormone replacement therapy did not modify the associations, but the inverse association between menopausal symptoms and breast cancer attenuated with increasing index age (p<0.01). INTERPRETATION: Menopause-associated symptoms were associated with markedly reduced risk of young-onset breast cancer. Further studies are needed to confirm the association and elucidate possible pathways. PMID- 23021930 TI - Recall mammography and psychological distress. AB - BACKGROUND: The aims of this study were (a) to identify psychological distress before and after being diagnosed with or without cancer in women recalled for further investigation because previous screening mammography indicated possible malignancy and (b) to document the willingness to attend and recommend mammography. Study participants included 526 recalled women (82% response) who completed a questionnaire before the recall mammogram and 4 weeks after receiving the result. Psychological distress was measured using the Hospital Anxiety and Depression Scale. RESULTS: Most subjects were diagnosed without cancer (87.6% false-positive rate). Recall after mammography among women with a false-positive mammogram was associated with transiently increased anxiety and a slight increase in depression. However, the level of anxiety was similar to and the level of depression was lower than in the general female Norwegian population. Women who received a cancer diagnosis had higher levels of anxiety and depression than the general female Norwegian population. Nearly all women (99%) were satisfied with their participation in the screening programme; 94% thought it was important, 98% would attend the next round of screening and 99% would recommend other women to attend. CONCLUDING STATEMENT: Recall after mammography was associated with transiently increased anxiety. Four weeks after screening, the level of anxiety was the same and depression was lower compared with the general female Norwegian population. The women were almost unanimously satisfied with their participation in the screening, would participate again and would recommend other women to participate. PMID- 23021932 TI - Where should electronic records for patients be stored? AB - INTRODUCTION: The importance of a nationwide health information infrastructure (NHII) is widely recognized. Patient data may be stored where it happens to be created (the distributed or institution-centric model) or in one place for a given patient (the centralized or patient-centric model). Minimal data is available regarding the performance implications of these alternative architectural choices. OBJECTIVE: To help identify the architecture best suited for efficient and complete nationwide health information exchange based on the large-scale operational characteristics of these architectures. DESIGN: We used simulation to study the impact of health care record (data) fragmentation and probability of encounter on transaction volume and data retrieval failure rate as markers of performance for each of the above architectures. RESULTS: Data fragmentation and the probability of encounter directly correlate with transaction volume and are significantly higher for the distributed model when the number of data nodes >4 (p<0.0001). The number of data retrieval failures increases in proportion to fragmentation and is significantly higher for the distributed model when the number of data nodes >=2 (p<0.0059). CONCLUSION: In simulation studies, the distributed model scaled poorly in terms of data availability and integrity with a higher failure rate when compared to the centralized model of data storage. Choice of architecture may have implications on the efficiency, usability, and effectiveness of the NHII at the point of care. PMID- 23021931 TI - Association analysis between breast cancer genetic variants and mammographic density in a large population-based study (Determinants of Density in Mammographies in Spain) identifies susceptibility loci in TOX3 gene. AB - BACKGROUND: Mammographic density (MD) is regarded as an intermediate phenotype in breast cancer development. This association study investigated the influence of 14 breast cancer susceptibility loci identified through previous genome-wide association studies on MD among the participants in the "Determinants of Density in Mammographies in Spain" (DDM-Spain) study. METHODS: Our study covered a total of 3348 Caucasian women aged 45-68years, recruited from seven Spanish breast cancer screening centres having DNA available. Mammographic density was blindly assessed by a single reader using a semiquantitative scale. Ordinal logistic models, adjusted for age, body mass index and menopausal status, were used to estimate the association between each genotype and MD. RESULTS: Evidence of association with MD was found for variant rs3803662 (TOX3) (Odds Ratio (OR)=1.13, 95% Confidence Interval (CI)=1.03-1.25), and marginal evidence of association for susceptibility loci rs3817198 (LSP1) (OR=1.09, 95% CI=1.00-1.20) and rs2981582 (FGFR2) (OR=0.92, 95% CI=0.84-1.01). Two other loci were associated with MD solely among pre-menopausal women, namely, rs4973768 (SLC4A7) (OR=0.83, 95% CI=0.70-1.00) and rs4415084 (MEPS30) (OR=1.22, 95% CI=1.00-1.49). CONCLUSIONS: Our findings lend some support to the hypothesis which links these susceptibility loci to MD. PMID- 23021933 TI - Guilt and depression: two different factors in individuals with negative symptoms of schizophrenia. AB - OBJECTIVE: Depression is common among schizophrenia patients and constitutes a major risk factor for suicide. Calgary Depression Scale (CDSS) is the most widely used instrument for measuring depression in schizophrenia. CDSS has never been examined in patients with predominant negative symptoms, thus possibly hindering both accurate assessment and understanding of the underlying mechanisms. The current study is the first to examine CDSS' structure in this population. METHODS: We conducted Principal Component Analysis (n=184) for the CDSS items. Thereafter, we correlated emerging factors with psychopathological, demographic and side effect variables. We assessed internal consistency and reliability of the emerging factors, as well as demographic correlations. RESULTS: The analysis yielded two factors: depression-hopelessness and guilt. Factors distinctly correlated with separate variables. Removal of item #7 (early waking) improved internal consistency. The depression-hopelessness factor had an inverse correlation with negative symptoms, and positive correlation with neuroleptic side effects. CONCLUSIONS: CDSS structure indicated of two separate factors, i.e., depression-hopelessness and guilt, suggesting separate underlying processes. The validity of the scale might benefit from a two-fold structure and the removal/replacement of item #7 (early waking). A noteworthy inverse correlation was found between the depression factor and negative symptoms, as well as a positive correlation between depression factor and neuroleptic side effects. PMID- 23021934 TI - [Early rehabilitation for neurologic patients]. AB - Rehabilitation improves the functional prognosis of patients after a neurologic lesion, and tendency is to begin rehabilitation as soon as possible. This review focuses on the interest and the feasibility of very early rehabilitation, initiated from critical care units. It is necessary to precisely assess patients' impairments and disabilities in order to define rehabilitation objectives. Valid and simple tools must support this evaluation. Rehabilitation will be directed to preventing decubitus complications and active rehabilitation. The sooner rehabilitation is started; the better functional prognosis seems to be. PMID- 23021935 TI - [Happy birthday succinylcholine!]. PMID- 23021936 TI - Development of novel oil washing process using bubble potential energy. AB - Oil contaminants attached to soils were separated using the bubble energies from the bursting and coalescence. The separation efficiency increased when the rotary kilns were combined. Wastewater containing separated oil contaminants was treated with the buoyant energy of bubbles and with positively charged bubbles. The water quality of the treated wastewater was good enough for the latter to be used as recycled water for bubble generation. The separation and treatment efficiencies of the novel oil washing process developed in this study was found to be similar to that of the existing oil washing process operated under high-temperature and high-pressure conditions and with dosage of chemicals. PMID- 23021937 TI - Local scale marine modelling of Fukushima releases. Assessment of water and sediment contamination and sensitivity to water circulation description. AB - The dispersion of (137)Cs released from Fukushima nuclear power plant to the sea after the March 11th 2011 tsunami has been studied using numerical models. The 3D dispersion model consists of an advection/diffusion equation with terms describing uptake/release reactions between water and seabed sediments. The dispersion model has been fed with daily currents provided by HYCOM and JCOPE2 ocean models. Seabed sediment (137)Cs patterns obtained using both current data set have been compared. The impact of tides and of atmospheric deposition has been evaluated as well. It has been also found that a 2-step kinetic model (two consecutive reversible reactions) for describing water/sediment interactions produces better results than a 1-step model (one single reversible reaction). PMID- 23021938 TI - Effect of curcumin on in vitro early post-implantation stages of mouse embryo development. AB - OBJECTIVES: This study was designed to examine the embryotoxic potential of the curcumin at the blastocyst stage and during early post-implantation development of mouse embryos in vitro. STUDY DESIGN: Curcumin was administered to ICR mice embryos at a dose of 0, 6, 12, 24 MUM throughout in vitro culture. A total of 1015 embryos were randomly assigned to the different dosage groups. The embryotoxic effects were studied by the exposure of curcumin at the blastocyst, implanted blastocyst and early egg cylinder stages, respectively. For assessment of implantation in vitro and further embryonic differentiation, blastocysts were cultured for 8 days. The cell proliferation of outgrowth blastocysts was analysed by Giemsa staining. RESULTS: Exposure to 24 MUM of curcumin at the implanted blastocyst stage or early egg stage cause adverse effects on development. The percentage of embryos in the later stages of development was changed depending upon the dose of curcumin used. Furthermore, exposure to 24 MUM of curcumin at the blastocyst stage was lethal to all embryos. The number of nuclei per outgrowth of the blastocyst decreased significantly after curcumin pre-treatment. The percentage of trophoblastic giant cells per outgrowth increased significantly after curcumin pre-treatment. CONCLUSIONS: These findings demonstrate that curcumin exerts an adverse effect on mouse embryos during the early post implantation stages of development, equivalent to day 3-day 8 of gestation in vivo. Curcumin treatment or administration should be used carefully at the early post-implantation stage of gestation. PMID- 23021939 TI - What is the role of TPE in management of patients at risk or with pressure ulcer as of 2012? Developing French guidelines for clinical practice. AB - INTRODUCTION: Pressure ulcer (PU) is a common complication in chronic affection, especially neurological disorders and diseases commonly diagnosed in the elderly. For a long period of time, the prevention of skin lesions was taught only in an empirical manner. The development of therapeutic patient education (TPE) sheds a new light on care management for patients with chronic pathologies. OBJECTIVES: Determine the place of TPE in persons at risk of and/or already suffering from pressure ulcer (PU) as of 2012. METHODS: The methodology used is the one promoted by SOFMER, including: a systematic review of the literature with a query of the PASCAL Biomed, PubMed and Cochrane Library databases for data from 2000 through 2010; a compendium of prevailing professional practices and advice from a committee of experts. RESULTS: The review of the literature found six studies including four controlled trials in patients with chronic neurological impairments (most of them with spinal cord injury). No studies were found regarding the elderly. The level of evidence for efficacy in persons with spinal cord injury (SCI) is moderate. The clinical practice study focuses on programs currently underway, dedicated to SCI patients or elderly populations. DISCUSSION: The approach proposed through TPE has its role in a strategy aimed at preventing PU in persons at chronic risk of developing PU. The educational objectives and techniques used must be adapted to the clinical and psychological context and are debated in this review. The co-construction of programs, recommended in the official texts on therapeutic education in France, should help to tailor these programs to the patients' needs. CONCLUSION: TPE is relevant in care management or prevention of PU in persons at chronic risk, patients with spinal cord injury (Grade B) or elderly subjects (Grade C). PMID- 23021940 TI - Care pathways in physical and rehabilitation medicine (PRM): the patient after proximal humeral fracture and shoulder hemi-arthroplasty. AB - This document is part of the "Care Pathways in Physical and Rehabilitation Medicine" series developed by the French Physical and Rehabilitation Medicine Society (Sofmer) and the French Physical and Rehabilitation Medicine Federation (Fedmer). For a given patient profile, each concise document describes the patient's needs, the care objectives in physical and rehabilitation medicine, the required human and material resources, the time course and the expected outcomes. The document is intended to enable physicians, decision-makers, administrators and legal and financial specialists to rapidly understand patient needs and the available care facilities, with a view to organizing and pricing these activities appropriately. Here, patients with acute proximal humeral fracture requiring shoulder hemi-arthroplasty are classified into four care sequences and two clinical categories, both of which are treated according to the same six parameters and by taking account of personal and environmental factors (according to the WHO's International Classification of Functioning, Disability and Health) that may influence patient needs. PMID- 23021941 TI - Care pathways in physical and rehabilitation medicine (PRM): the patient after shoulder stabilization surgery. AB - This document is part of the "Care pathways in physical and rehabilitation medicine" series developed by the French Physical and Rehabilitation Medicine Society (SOFMER) and the French Physical and Rehabilitation Medicine Federation (FEDMER). For a given patient profile, each concise document describes the patient's needs, the care objectives in physical and rehabilitation medicine, the required human and material resources, the time course and the expected outcomes. The document is intended to enable physicians, decision-makers, administrators and legal and financial specialists to rapidly understand patient needs and the available care facilities, with a view to organizing and pricing these activities appropriately. Here, patients with shoulder instability requiring surgical stabilization are classified into five care sequences and two clinical categories, each of which are treated according to the same six parameters and by taking account of personal and environmental factors (according to the WHO's International Classification of Functioning, Disability and Health) that may influence patient needs. PMID- 23021942 TI - Life satisfaction and self-reported impairments in persons with late effects of polio. AB - OBJECTIVE: Decades after an acute poliomyelitis infection many persons experience new symptoms or impairments which may affect their life satisfaction. The objective of this study was to investigate the association between life satisfaction and self-reported impairments in persons with late effects of polio. MATERIAL AND METHODS: One hundred and sixty-nine persons (104 women and 65 men) with prior polio responded on admission to rehabilitation to the Life Satisfaction Questionnaire (LiSat-11) assessing satisfaction with life as a whole and 10 domains of life satisfaction and to a 13-item questionnaire assessing self reported impairments related to late effects of polio. RESULTS: A majority was to some degree satisfied with life as a whole and with all 10 domains of life satisfaction in LiSat-11, but less than 20% was very satisfied or satisfied with their somatic health. Muscle fatigue, muscle weakness, general fatigue, muscle and/or joint pain during physical activity and cold intolerance were the most frequently reported impairments. Overall, those who rated themselves as not satisfied (according to LiSat-11) reported significantly higher degrees of impairment than those who were satisfied. The relationships between the items of life satisfaction in LiSat-11 and the items in the self-report questionnaire varied from -0.01 to -0.64. CONCLUSION: Satisfaction with life as a whole, and different domains of life satisfaction are low to moderately associated with self reported impairments. This implies that rehabilitation interventions must address not only self-reported impairments but also activity limitations and participation restrictions in order to enhance life satisfaction in people with late effects of polio. PMID- 23021943 TI - Clinical condition and transmission of coinfections with human cytomegalovirus in infants of HIV-1 infected mothers in the era of mother-to-child-transmission prophylaxis. AB - BACKGROUND AND AIM: The aim of the study was to evaluate the clinical state and the risk of coinfections in infants of HIV-1-infected women receiving MTCT prophylaxis. METHODS: The study included 35 Polish infants of HIV-1-infected mothers diagnosed for congenital infections. Children were evaluated for HIV-1, HCMV and HCV infection by serological and molecular methods during following visits up to 18th month of life. None of the children received breast milk after birth. RESULTS: HIV-1 infection was found in one child not receiving MTCT prophylaxis, one HCV infection was detected in another infant. HCMV-DNA in the urine was present in 13/35 children (37.14%) in the 10th day and 24/35 children (68.57%) at 4th week of life. The group of children managed with full and incomplete MTCT regimen did not differ in most clinical parameters. Children receiving MTCT prophylaxis were born more frequently as first children (p=0.045) and by cesarean section (p=0.047). HCMV-positive children receiving MTCT prophylaxis were had lower gestational age (p=0.03) and smaller head circumference (p=0.02). They were born more frequently as premature (0.02) and with low birth weight (0.02). Maternal cART and the use of protease inhibitors were not significantly associated with perinatal complications. No differences in CD4+ and CD8+ counts were noted between the group receiving full and incomplete MTCT protocol. CONCLUSIONS: ARV used in MTCT preventive protocols is safe for infants although the risk of the transmission of HCMV coinfection is not reduced. PMID- 23021944 TI - Ligand properties and behaviours in an allosteric age. PMID- 23021945 TI - Pesticide exposure and low birth weight prevalence in Brazil. AB - INTRODUCTION: Brazil is one of the major global consumers of pesticides and exposure to these substances can affect fetal growth. OBJECTIVE: To estimate the correlation between pesticide sales in 1996 and the prevalence of low birth weight during the period 1996-1998 in Brazil. METHOD: This ecological study employed secondary data aggregated at the level of Brazilian micro-regions (cluster of cities). Prevalence of low birth weight in 1996, 1997, and 1998 was obtained from the Brazilian health databases, and per capita pesticides sales in 1996 obtained from the Brazilian Institute of Geography and Statistics were utilized as an indirect measure of population exposure to these chemicals. Spearman correlation coefficient and Prevalence Ratio by quartiles were estimated, considering per capita pesticide sales and the prevalence of low birth weight. RESULTS: A total of 552 micro-regions were analyzed (446 non-urban and 106 urban). In rural areas, the per capita pesticide sales were directly associated with higher prevalence of children born with low birth weight (r=0.403), with birth weights between 1500 and 2500 grams (r=0.366), and very low birth weight birth (r=0.476). All correlations were statistically significant (p<0.001). On the other hand, in urban areas there was no significant correlation. There was a gradual increase in the prevalence of low birth weight according to the quartiles of pesticide consumption. CONCLUSIONS: Pesticide per capita sales may affect the prevalence of newborns with low birth weight in non urban micro-regions of Brazil, indicating the need to strengthen policies and actions to protect the health of populations exposed to pesticides. PMID- 23021946 TI - Hydrothermal processing of duckweed: effect of reaction conditions on product distribution and composition. AB - Influences of operating conditions such as temperature (270-380 degrees C), time (10-120 min), reactor loading (0.5-5.5 g), and K2CO3 loading (0-50 wt.%) on the product (e.g. crude bio-oil, water soluble, gas and solid residue) distribution from the hydrothermal processing of duckweed were determined. Of the four variables, temperature and K2CO3 loading were always the most influential factors to the relative amount of each component. The presence of K2CO3 is unfavorable for the production of bio-oil and gas. Hydrothermal processing duckweed produces a bio-oil that is enriched in carbon and hydrogen and has reduced levels of O compared with the original duckweed feedstock. The higher heating values of the bio-oil were estimated within the range of 32-36 MJ/kg. Major bio-oil constituents include ketones and their alkylated derivatives, alcohols, heterocyclic nitrogen-containing compounds, saturated fatty acids and hydrocarbons. The gaseous products were mainly CO2 and H2, with lesser amounts of CH4 and CO. PMID- 23021947 TI - Techno-economic analysis for a sugarcane biorefinery: Colombian case. AB - In this paper a techno-economic analysis for a sugarcane biorefinery is presented for the Colombian case. It is shown two scenarios for different conversion pathways as function of feedstock distribution and technologies for sugar, fuel ethanol, PHB, anthocyanins and electricity production. These scenarios are compared with the Colombian base case which simultaneously produce sugar, fuel ethanol and electricity. A simulation procedure was used in order to evaluate biorefinery schemes for all the scenarios, using Aspen Plus software, that include productivity analysis, energy calculations and economic evaluation for each process configuration. The results showed that the configuration with the best economic, environmental and social performance is the one that considers fuel ethanol and PHB production from combined cane bagasse and molasses. This result served as the basis to draw recommendations on technological and economic feasibility as well as social aspects for the implementation of such type of biorefinery in Colombia. PMID- 23021948 TI - Towards understanding structural changes of photoperiod-sensitive sorghum biomass during sulfuric acid pretreatment. AB - Wide-angle X-ray diffraction (WAXD) and small-angle X-ray scattering (SAXS) were employed to investigate the structural changes of photoperiod-sensitive sorghum biomass in both crystalline and amorphous domains after sulfuric acid pretreatment. WAXD results suggested that the crystalline cellulose melted at 120 degrees C without significant polymer degradation and cellulose went through a simultaneous hydrolysis and crystallization at 160 degrees C. Both the cellulose crystallinity and the crystal size increased as the temperature increased, which might lower cellulose digestibility. The efficiency of enzymatic hydrolysis (EEH) increased because the cellulose protective structure was compromised and most hemicellulose was removed, resulting in an increase in total surface area as suggested by SAXS results. The radius of gyration of the polymer structure decreased and the lamellar structure was destroyed after pretreatment. Both the EEH and cellulose degradation increased as the temperature increased. The total glucose yield increased to 79.7% as the temperature increased to 160 degrees C. PMID- 23021949 TI - Batch anaerobic co-digestion of Kimchi factory waste silage and swine manure under mesophilic conditions. AB - The objective of this study was to investigate the feasibility of anaerobic co digestion of Kimchi factory waste silage (KFWS) with swine manure (SM). Chinese cabbage (CC) is the major waste generated by a Kimchi factory and KFWS was prepared by mixing CC and rice bran (RB) (70:30 on a dry matter basis). In Experiment I, the biogas potential of CC and RB were measured and, in Experiment II, the test was conducted with different ratios of KFWS and SM (KFWS: SM=0:100; 33:67; 67:33; 100:0 by% volatile solids (VS) basis). KFWS produced a 27% higher biogas yield and a 59% higher methane yield compared to CC. The specific biogas yields increased by 19, 40 and 57% with KFWS-33%, KFWS-67% and KFWS-100%, respectively compared to SM-100% (394 mL/g VS). Similarly, VS removal increased by 37, 51 and 74% with KFWS-33%, KFWS-67% and KFWS-100%, respectively compared to SM-100%. These results suggested that Kimchi factory waste could be effectively treated by making silage, and the silage could be used as a potential co substrate to enhance biogas production from SM digesters. PMID- 23021950 TI - Volatile fatty acids production from marine macroalgae by anaerobic fermentation. AB - Volatile fatty acids (VFAs) were produced from the marine macroalgae, Laminaria japonica, Pachymeniopsis elliptica, and Enteromorpha crinite by anaerobic fermentation using a microbial community derived from a municipal wastewater treatment plant. Methanogen inhibitor (iodoform), pH control, substrate concentration, and alkaline and thermal pretreatments affected VFA productivity. Acetic, propionic, and butyric acids were the main products. A maximum VFA concentration of 15.2g/L was obtained from 50 g/L of L. japonica in three days at 35 degrees C and pH 6.5-7.0. Pretreatment with 0.5 N NaOH improved VFA productivity by 56% compared to control. The result shows the applicability of marine macroalgae as biomass feedstock for the production of VFAs which can be converted to mixed alcohol fuels. PMID- 23021951 TI - Urinary concentrations of pyrethroid metabolites in the convenience sample of an urban population of Northern Poland. AB - Urinary concentrations of pyrethroid metabolites were measured in the first void urine samples collected from 132 healthy people living in the Gdansk region of Northern Poland in 2010 and 2011. Four metabolites of synthetic pyrethroids: cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acids (cis , trans-Cl2CA), cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (Br2CA) and 3-phenoxybenzoic acid (3-PBA) were simultaneously liquid-liquid extracted, derivatized with hexafluoroisopropanol and analyzed by a gas chromatography ion-trap mass spectrometry. All the analytes were detected and quantified in the samples with various frequency, 3-phenoxybenzoic being the most often (80%) and the others less frequently (7-11%). Distribution of 3-PBA concentrations followed log-normal model, the mean concentration of 3 phenoxybenzoic acid: 0.393 MUg/L (0.327 MUg/g creatinine) is similar to those of the other general populations in various regions of the world. Neither sex nor age were predictors of urinary 3-PBA. Our findings suggest wide exposure to pyrethroid insecticides in the Polish general population. There is a continuous need to further study the exposure to synthetic pyrethroids among the general population since there is a strong, increasing trend in their usage. PMID- 23021952 TI - Subsets of nonclonal neighboring CD4+ T cells specifically regulate the frequency of individual antigen-reactive T cells. AB - After an immune response, the expanded population of antigen-specific CD4(+) T cells contract to steady state levels. We have found that the contraction is neither cell-autonomous nor mediated by competition for generic trophic factors, but regulated by relatively rare subsets of neighboring CD4(+) T cells not necessarily of a conventional regulatory T cell lineage. These regulators, referred to as deletors, specifically limit the frequency of particular antigen specific T cells even though they are not reactive to the same agonist as their targets. Instead, an isolated deletor could outcompete the target for recognition of a shared, nonstimulatory endogenous peptide-MHC ligand. This mechanism was sufficient to prevent even agonist-driven autoimmune disease in a lymphopenic environment. Such a targeted regulation of homeostasis within narrow colonies of T cells with related TCR specificities for subthreshold ligands might help to prevent the loss of unrelated TCRs during multiple responses, preserving the valuable diversity of the repertoire. PMID- 23021953 TI - The transcription factors Egr2 and Egr3 are essential for the control of inflammation and antigen-induced proliferation of B and T cells. AB - Lymphocytes provide optimal responses against pathogens with minimal inflammatory pathology. However, the intrinsic mechanisms regulating these responses are unknown. Here, we report that deletion of both transcription factors Egr2 and Egr3 in lymphocytes resulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but also impaired antigen receptor-induced proliferation of B and T cells. Egr2- and Egr3-defective B and T cells had hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigen receptor-induced activation of transcription factor AP-1 was severely impaired. We discovered that Egr2 and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3, inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells. Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis by promoting antigen receptor signaling and controlling inflammation. PMID- 23021954 TI - Evaluation of the cardiac toxicity of N-methyl-glucamine antimoniate in dogs with naturally occurring leishmaniasis. AB - The aim of this study was to evaluate the cardiotoxic effects of pentavalent antimonial compounds in dogs with leishmaniasis. Twenty-eight dogs with clinical disease due to natural infection with Leishmania infantum were treated with 75 mg/kg meglumine antimoniate SC every 12h for 60 days. Serum cardiac troponin I (cTnI) concentrations were determined and routine and 24h ambulatory electrocardiographic monitoring was performed before the onset (T0) and at the end of treatment (T60). No abnormalities were found in routine and 24h electrocardiographic tracings before and after treatment. No statistical difference was found between serum cTnI concentrations or corrected QT intervals at T0 and T60. There was no evidence of laboratory or electrocardiographic features of cardiac toxicity in dogs with leishmaniasis treated with a therapeutic dose of meglumine antimoniate for 60 days. PMID- 23021955 TI - Characterisation of a group of endogenous gammaretroviruses in the canine genome. AB - Bioinformatics were used to identify and characterise 39 pol, 34 gag and five env gammaretroviruses within the canine (Canis lupus familiaris) reference genome. These endogenous retroviruses are monophyletic to the Canidae, predate the divergence of dogs and foxes and are fixed in 20 canine breeds examined. They are transcribed in normal canine tissue but are unlikely to be replication competent in dogs. PMID- 23021956 TI - Pneumococcal infections in oncohematological patients after the introduction of conjugate vaccine. AB - OBJECTIVES: To know the symptoms and predominant serotypes of pneumococcal infection in patients with oncohematological illness after introduction of 7 valent pneumococcal conjugate vaccine. PATIENTS AND METHODS: A prospective study (january 2006-may 2011) was made of all the incident cases of infection in oncohematological patients over 17 years of age in whom Streptococcus pneumoniae was isolated. RESULTS: A total of 131 episodes of incident cases of pneumococcal infection in 122 patients (median age of 67 years) were detected. Of these, 50% were related to health/nosocomial care (P<.001), 39.7% pneumonias and 45.1% lower respiratory tract infections, without radiological condensation. In comparison to the 803 incident cases of pneumococcal infection during the same period as in patients without oncohematological disease, the oncohematological patients were more frequently males (P<.001), had pneumonia episodes with higher FINE scores (P<.001), lower risk of death non-directly associated with pneumococcal infection (P=.006) and showed reduced susceptibility to levofloxacin (P=.043). Non-vaccine serotypes predominated. CONCLUSIONS: Pneumococcal infections in oncohematological patients are more frequent in males, mainly with lung neoplasms. They are heath care related, but not related to chemotherapy or neutropenia. After the introduction of heptavalent conjugate vaccines in pediatrics, the non-vaccine serotypes predominate. PMID- 23021957 TI - [Pediatric nutrition: Severe deficiency complications by using vegetable beverages, four cases report]. AB - INTRODUCTION: The use of vegetable beverages improperly called " vegetable milk " is promoted by food faddism to replace dairy products, even in infant diet whereas it is totally inadequate. CASE REPORTS: Case 1: a 9 month-old infant fed by a rice beverage for 2 months presented hypoalbuminemia (7 g/L) with kwashiorkor syndrome complicated by severe sepsis. Case 2: a 14 month-old infant fed by a rice beverage for 2 months had iron and vitamin B12 deficiency with deep anemia (Hb 35 g/L) and tissue hypoxia (hyperlactacidemia). Case 3: a 13 month-old infant fed by an almond beverage during 3 weeks presented metabolic alkalosis with hypochloremia due to sodium and chloride deficiency and revealed by hypoventilation. Case 4: a 2,5 month-old infant with epileptic encephalopathy was fed by several vegetable beverages (almond, nut, chestnut and soy) for a month and a half and presented deep hyponatremia (96 mmol/L) with coma and respiratory acidosis caused by aspiration pneumonia. He died secondarily. DISCUSSION: Deficiencies promote infections and severe metabolic disorders. Clinical polymorphism lead to diagnosis wandering that can be noxious. The reasons of these diet changes can be nutritional ignorance, perceived milk intolerance or food faddism, sometimes on the advice of an alternative medicine physician. Parental restricted diet or infant immunization recommendations negligence should warn about associated nutritional errors in young infants. CONCLUSION: These avoidable pathologies frequently caused by well-intending but misinformed parents must be reported to Nutrivigilance. This behaviour can be life threatening and must lead, in the most severe cases, to prosecution. PMID- 23021958 TI - A review of catalytic hydrodeoxygenation of lignin-derived phenols from biomass pyrolysis. AB - Catalytic hydrodeoxygenation (HDO) of lignin-derived phenols which are the lowest reactive chemical compounds in biomass pyrolysis oils has been reviewed. The hydrodeoxygenation (HDO) catalysts have been discussed including traditional HDO catalysts such as CoMo/Al(2)O(3) and NiMo/Al(2)O(3) catalysts and transition metal catalysts (noble metals). The mechanism of HDO of lignin-derived phenols was analyzed on the basis of different model compounds. The kinetics of HDO of different lignin-derived model compounds has been investigated. The diversity of bio-oils leads to the complexities of HDO kinetics. The techno-economic analysis indicates that a series of major technical and economical efforts still have to be investigated in details before scaling up the HDO of lignin-derived phenols in existed refinery infrastructure. Examples of future investigation of HDO include significant challenges of improving catalysts and optimum operation conditions, further understanding of kinetics of complex bio-oils, and the availability of sustainable and cost-effective hydrogen source. PMID- 23021959 TI - Sm-like protein enhanced tolerance of recombinant Saccharomyces cerevisiae to inhibitors in hemicellulosic hydrolysate. AB - A current challenge of the cellulosic ethanol industry is to improve the resistance of inhibitors present in biomass hydrolysates. RNA-binding protein gene lsm6 was cloned from industrial Saccharomyces cerevisiae ZU-E8, which is able to conferment glucose and xylose, and transformed into ZU-E8 via expression vector pRS426. The positive transformant ZU-910 with over-expressing lsm6 was identified on the culture plates using high concentration of acetate and re screened by fermentation test. Fermentation by the recombinants was performed in a medium containing 80 g/L xylose and 2 g/L acetic acid or 20 g/L NH(4)Ac/NaAc. After 96 h shaking-flask fermentation, ZU-910 utilized 90.2% xylose with an ethanol yield of 26.9 g/L, which was 8.5- and 10-fold higher than ZU-E8. Further, in the corn stover hemicellulosic hydrolysate fermentation, both the xylose conversion and ethanol production by ZU-910 was larger by 50% and 40% than ZU-E8. ZU-910 has also enhanced tolerance against furfural and SO(4)(2-). PMID- 23021960 TI - Anaerobic conversion of microalgal biomass to sustainable energy carriers--a review. AB - This review discusses anaerobic production of methane, hydrogen, ethanol, butanol and electricity from microalgal biomass. The amenability of microalgal biomass to these bioenergy conversion processes is compared with other aquatic and terrestrial biomass sources. The highest energy yields (kJ g(-1) dry wt. microalgal biomass) reported in the literature have been 14.8 as ethanol, 14.4 as methane, 6.6 as butanol and 1.2 as hydrogen. The highest power density reported from microalgal biomass in microbial fuel cells has been 980 mW m(-2). Sequential production of different energy carriers increases attainable energy yields, but also increases investment and maintenance costs. Microalgal biomass is a promising feedstock for anaerobic energy conversion processes, especially for methanogenic digestion and ethanol fermentation. The reviewed studies have mainly been based on laboratory scale experiments and thus scale-up of anaerobic utilization of microalgal biomass for production of energy carriers is now timely and required for cost-effectiveness comparisons. PMID- 23021961 TI - Silver-nano biohybride material: synthesis, characterization and application in water purification. AB - A green chemical synthesis of silver nanoparticles (AgNPs) through in situ reduction of silver nitrate (AgNO(3)) by a fungal strain of Rhizopus oryzae is described along with the promising eco-friendly role of the synthesized nano silver bioconjugate (NSBC) material in water purification process. The NSBC has been characterized using UV-vis spectroscopy, high resolution transmission electron (HRTEM) microscopy, and Fourier transform infrared (FTIR) spectroscopy. The NSBC exhibits strong antibacterial activity against Escherichia coli and Bacillus subtilis and high adsorption capacity towards different organophosphorous pesticides. Fluorescence and electron microscopic images reveal NSBC binds on the bacterial cell wall, which cause irreversible membrane damage eventually leading to cell death. Proteomic analysis further demonstrates down regulation of protein expression, inhibition of cytosolic and membrane proteins and leakage of cellular content following binding of NSBC with bacterial cell wall. NSBC has been exploited to obtain potable water free from pathogens and pesticides in one step process. PMID- 23021962 TI - The association between testicular ghrelin receptor mRNA and serum testosterone levels in immunocastrated boars. AB - Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHS-R), has various functions. The expression of ghrelin and growth hormone secretagogue receptor type 1a (GHS-R1a) has been demonstrated in rat and human testis, and ghrelin also affects testosterone (T) secretion in vitro, suggesting a role for this molecule in the direct control of testis function. However, whether this signaling system is present in pig testis, and the association with serum T remains largely unexplored. In this study we investigated the relationship between serum T levels and ghrelin and GHS-R1a gene expression in the testes of intact and immunocastrated boars. Testicular tissue and serum samples were collected from seven intact boars and seven recombinant GnRH-I immunocastrated boars. GHS-R1a gene expression in the testis was higher in immunocastrated than intact boars (2.22 +/- 0.71 vs. 0.53 +/- 0.23; P<0.01). Mean serum T levels were markedly lower in immunocastrated than intact boars (0.40 +/- 0.04 vs. 2.10 +/- 0.94 ng/mL, P<0.01). Ghrelin gene expression in testis did not differ between both groups of boars. GHS-R1a gene expression was positively correlated with ghrelin gene expression (r = 0.68, P<0.001), but negatively correlated with serum T concentrations (r = -0.83, P<0.001). Overall, the existence of ghrelin and GHS R1a gene expression in pig testis, and the increase in GHS-R1a gene expression in the testes and the inverse correlation with serum T in immunocastrated boars are highly suggestive of a role for ghrelin in the regulation of mammalian testicular function. PMID- 23021963 TI - Embryo-transfer of the F2 postnatal calorie restricted female rat offspring into a control intra-uterine environment normalizes the metabolic phenotype. AB - OBJECTIVE: Postnatal calorie and growth restriction (PNGR) in the first generation (F1) rat female offspring causes a lean and glucose tolerant phenotype associated with hypoinsulinemia and reduced glucose-stimulated insulin secretion (GSIS). Despite the absence of gestational hyperglycemia in the F1 PNGR female, naturally born second generation (F2) PNGR female adult offspring reportedly exhibit obesity, hyperglycemia with insulin resistance. The objective of this study was to determine the role of the intrauterine environment on the heritability of the trans-generational phenotypic expression in the F2 PNGR female adult offspring. MATERIALS/METHODS: We performed embryo transfer (ET) of the F2 embryos from the procreating F1 pregnant PNGR or control (CON) females to gestate in control recipient rat mothers. Employing stable isotopes glucose metabolic kinetics was determined. RESULTS: Birth weight, postnatal growth pattern and white adipose tissue in female F2 ET-PNGR were similar to ET-CON. Similarly, no differences in basal glucose and insulin concentrations, GSIS, glucose futile cycling and glucose clearance were seen. When compared to F2 ET CON, F2 ET-PNGR showed no overall difference in glucose or hepatic glucose production (HGP) AUCs with minimal hyperglycemia (p<0.04) as a result of unsuppressed endogenous HGP (p<0.02) observed only during the first phase of IVGTT. CONCLUSIONS: We conclude that the lean, glucose tolerant and hypoinsulinemic phenotype with reduced GSIS in the F1 generation is nearly normalized when the embryo-transferred F2 offspring gestates in a normal metabolic environment. This observation supports a role for the intra-uterine environment in modifying the heritability of the trans-generational PNGR phenotype. PMID- 23021964 TI - Wear at the titanium-titanium and the titanium-zirconia implant-abutment interface: a comparative in vitro study. AB - OBJECTIVE: The purpose of this study was to determine and measure the wear of the interface between titanium implants and one-piece zirconia abutments in comparison to titanium abutments. METHODS: 6 implants were secured into epoxy resin blocks. The implant interface of these implants and 6 corresponding abutments (group Zr: three one-piece zirconia abutments; group Ti: three titanium abutments) were examined by a microscope and scanning electron micrograph (SEM). Also the implants and the abutments were scanned by 3D-Micro Computer Tomography (CT). The abutments were connected to the implants and cyclically loaded with 1,200,000 cycles at 100N in a two-axis fatigue testing machine. Afterwards, all specimens were unscrewed and the implants and abutments again were scanned by microscope, SEM and CT. The microscope and SEM images were compared, the CT data were superimposed and the wear was calculated by inspection software. The statistical analysis was carried out with an unpaired t-test. RESULTS: Abutment fracture or screw loosening was not observed during cyclical loading. Comparing the microscope and SEM images more wear was observed on the implants connected to zirconia abutments. The maximum wear on the implant shoulder calculated by the inspection software was 10.2MUm for group Zr, and 0.7MUm for group Ti. The influence of the abutment material on the measured wear was statistically significant (p<=0.001; Levene-test). SIGNIFICANCE: Titanium implants showed higher wear at the implant interface following cyclic loading when connected to one-piece zirconia implant abutments compared to titanium abutments. The clinical relevance is not clear; hence damage of the internal implant connection could result in prosthetic failures up to the need of implant removal. PMID- 23021965 TI - Clinical features of radiologically confirmed pneumonia due to adenovirus in children. AB - BACKGROUND: Clinical features of radiologically confirmed pneumonia due to adenovirus in children have not been comprehensively evaluated. OBJECTIVE: To describe the detailed clinical features of radiologically confirmed adenovirus associated pneumonia in children. STUDY DESIGN: Of 3298 children with a throat virus culture positive for adenovirus treated at a university-affiliated hospital, from January 2000 to June 2008, in northern Taiwan, 80 hospitalized children (2.4%) with radiologically confirmed pneumonia were identified. From four children with incomplete medical records, only demographics were included for analysis. RESULTS: The median age was 2.97 years, ranging from 25 days to 14 years. Seventy-three patients (96%) had fever, with a median duration of 7 days. The three most common respiratory symptoms were cough (99%), rhinorrhea (82%) and dyspnea (42%). Gastrointestinal symptoms were recorded in 80% of the patients, and neurologic symptoms in four children. Leukocytosis (WBC>=15,000/MUL) was noted in 19 (25%) patients. Only six patients (8%) had a normal serum C-reactive protein (CRP) value (<5 mg/L), while 48 patients (63%) had a CRP level >40 mg/L. Seventeen (21%) children required intensive care. Seventy-three patients (96%) recovered uneventfully. Sequelae were seen in two patients and death in 1. Of the 69 isolates with serotyping determination, seven serotypes were identified, with a predominant serotype (type 3 for 73%). CONCLUSION: Less than 5% of the children with adenoviral infection had radiologically confirmed patch pneumonia. The manifestation of pneumonia caused by adenovirus was similar to that of bacterial pneumonia. PMID- 23021966 TI - Ramsay Hunt syndrome with trochlear nerve involvement and EEG abnormalities: multicranial neuritis or encephalitis? PMID- 23021967 TI - Design, synthesis and biological activities of sorafenib derivatives as antitumor agents. AB - A series of novel sorafenib derivatives, 9a-w, was designed and synthesized in high yields using various substituted anilines, and their antiproliferative activities against HCT116, PC-3 and MDA-MB-231 cell lines were also evaluated and described. All compounds exhibited potent antiproliferative activity against HCT116 and PC-3 cells with IC(50)=2.8-52.0 and 2.2-45.6 MUM; compounds 9p and 9q demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines, the cytotoxicity of compound 9r is more potent than that of sorafenib. Compounds (9g, 9p, 9q and 9r) were chosen for further evaluation of the anti-angiogenesis activity, and showed the inhibition of sprout formation from aortic ring ex vivo. The structures of all the newly synthesized compounds were determined by (1)H NMR, (13)C NMR and HRMS. PMID- 23021968 TI - Sequence criteria for the anti-parallel character of protein beta-strands. PMID- 23021969 TI - A biosynthesis/inactivation model for enzymatic WLFs or non-enzymatically mediated cell evolution. AB - We perform the analysis of influence of a 'wall-loosening factor' (hereafter: WLF) activity in cases of isotropic or anisotropic growth of a plant cell/organ. We further explore a generalized form of the Lockhart/Ortega type of equation and make the 'extensibility' Phi (and the yield stress Y) a time and space dependent parameter, able to report on changing (location-dependent) viscoelastic cell wall properties. This procedure results in scalar and tensor equations, which model WLF-mediated isotropic/anisotropic loosening of polymers composing plant cell walls, thereby allowing pressure-driven polymer creep and plant cell expansion growth. An application to six empirical situations, which temporally and spatially vary the amount of WLFs in the cell wall, is anticipated. Combining the resulting explicit formulae with a curve fitting routine provides a new analytical tool that may relate to physiology and biochemistry of the growth process. It is shown, that the regression lines calculated for the derived growth functions perfectly fit (R(2)~/=0.99998) the experimental data. PMID- 23021971 TI - Contemporary role of systematic prostate biopsies: indications, techniques, and implications for patient care. AB - CONTEXT: Prostate cancer (PCa) screening to detect early stage PCa has resulted in increased identification of small-volume, low-grade PCa, many of which meet criteria for clinically indolent disease. Nevertheless, there remains some degree of underdetection of high-risk PCa in substantial numbers of men despite current diagnostic strategies. OBJECTIVE: To discuss the contemporary role of prostate biopsy (PB), focusing on the indications, techniques, and limitations of current PB techniques and evolving techniques affecting patient care. EVIDENCE ACQUISITION: A comprehensive Medline search was performed using the medical subject heading search terms prostate cancer, detection, prostate biopsy, significant cancer, and diagnosis, with restriction to the English language. Emphasis was given to publications within the past 5 yr. EVIDENCE SYNTHESIS: Because abnormal digital rectal examination (DRE) and prostate-specific antigen (PSA) tests alone lack specificity for cancer, there is no universal indication for PB. This lack has inspired exploration for a cancer-specific biomarker and prediction tools such as risk calculators. Indication for biopsy should involve a balance between the underdiagnosis of high-risk cancers and the potential risks for the overdetection of clinically insignificant cancers as well as biopsy related morbidity. Evidence supports the inclusion of laterally directed cores during transrectal ultrasound (TRUS) PB in addition to the traditional sextant pattern, which significantly improves cancer detection without a demonstrable increase in morbidity. These data indicate that such PB templates, typically 12 cores, represent the optimal template in initial PB. Optimised techniques and templates for repeat PB remain controversial. However, debate continues regarding indications, sampling number, and location as well as on the potential of modern image-guided approaches or three-dimensional (3D) mapping biopsy in this unique setting. Additional limitations of repeat PB techniques include associated procedural risks if general anaesthesia is required and inherent sampling errors of template-based techniques that are not targeted to the specific tumour site. CONCLUSIONS: Current data support the utility of extended PB templates for initial TRUS PB intended to detect clinically significant PCa. Repeat PB in the setting of prior negative PB on the grounds of clinical suspicion or for risk stratified approaches to management of low risk PCa requires balancing overdetection of low-risk cancer with the potential to miss significant cancer. Several options, including modern image-guided targeting, biomarker development, transrectal saturation PB, and 3D template mapping PB, are changing the clinical paradigms for evaluation and management. Evidence to support adopting approaches other than the current established standards should be tested through appropriately designed prospective studies. PMID- 23021972 TI - Thromboembolic events following surgery for prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) and surgery are both associated with increased risk of thromboembolic diseases (TED). OBJECTIVE: We assessed risk of TED among men undergoing different types of urologic surgery. DESIGN, SETTING, AND PARTICIPANTS: Using the Prostate Cancer Database Sweden (PCBaSe) Sweden, we identified all men (n=45 065) undergoing pelvic lymph node dissection (PLND), radical prostatectomy (RP) with or without PLND, orchiectomy due to PCa, or a transurethral resection of the prostate (TURP). We identified a comparison cohort from the population. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Main outcomes were deep venous thrombosis (DVT) and pulmonary embolism (PE) as primary diagnoses in the National Patient Register or Cause of Death Register (2002 2010). We calculated hazard ratios (HR) and 95% confidence intervals (CI) using multivariable Cox proportional hazards models. RESULTS AND LIMITATIONS: All surgical procedures were associated with increased risk of TED; laparoscopic and open RP with a PLND were the most strongly associated with TED (HR for PE: 8.1 [95% CI, 2.9-23.0] and 7.8 [95% CI, 4.9-13], respectively). For surgery including a PLND, the risk increased during the second half of the first postoperative month. The HR for PE after TURP in men with PCa was 3.0 (95% CI, 1.8-5.1). Patients with a history of TED had a strongly increased risk of TED (HR for DVT: 4.5; 95% CI, 2.6-8.0). A limitation is lack of information on TED prophylaxis, but its use was standardized during the study period for RP and PLND. Other limitations are lack of information on extent of PLND and lifestyle factors. CONCLUSIONS: Surgeries for PCa, including TURP, are associated with hospitalization for TED. Patients with a history of TED and patients undergoing a PLND were at highest risk. The largest risk was observed from days 14 to 28 postoperatively. Thus, our results suggest that prophylactic measures may be beneficial during the first 4 wk in these patients. PMID- 23021973 TI - Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology. AB - As for other major psychoses, the etiology of schizophrenia still remains poorly understood, involving genetic and epigenetic mechanisms, as well as environmental contributions. In addition, immune alterations have been widely reported in schizophrenic patients, involving both the unspecific and specific pathways of the immune system, and suggesting that infectious/autoimmune processes play an important role in the etiopathogenesis of the disorder. Cytokines, in particular, are supposed to play a critical role in infectious and inflammatory processes, mediating the cross-talk between the brain and the immune system. In this perspective, even though mixed results have been reported, it seems that schizophrenia is associated with an imbalance in inflammatory cytokines. Alterations in the inflammatory and immune systems, moreover, seem to be already present in the early stages of schizophrenia and connected to the neurodevelopmental hypothesis of the disorder, identifying its roots in brain development abnormalities that do not manifest themselves until adolescence or early adulthood. At the same time, neuropathological and longitudinal studies in schizophrenia also support a neurodegenerative hypothesis and, more recently, a novel mixed hypothesis, integrating neurodevelopmental and neurodegenerative models, has been put forward. The present review aims to provide an updated overview of the connections between the immune and inflammatory alterations and the aforementioned hypotheses in schizophrenia. PMID- 23021974 TI - Anxiolytic-like effect of linezolid in experimental mouse models of anxiety. AB - Linezolid, an oxazolidinone class antibiotic is a reversible and nonselective inhibitor of monoamine oxidase (MAO) enzyme, mainly for MAO-A subtype. Its antidepressant-like effect has been previously demonstrated in the rodent models of depression. MAO-A enzyme has been shown to play a role in the pathophysiology of anxiety disorders and inhibition of MAO-A in the brain could be used to treat anxiety disorders. Thus, the objective of this study was to investigate the putative anxiolytic effects of linezolid in rodent models of anxiety. Mice were acutely injected with linezolid (5-40 mg/kg, i.p.), diazepam (2 mg/kg, i.p.) and moclobemide (10 mg/kg., i.p.). Linezolid (20 and 40 mg/kg), diazepam and moclobemide significantly (p<0.05) increased the percentage of time spent and entries into open arms in the elevated plus maze (EPM) test without altering the closed arm entries. Linezolid (10-40 mg/kg) significantly (p<0.05) increased the latency time to leave the light compartment, linezolid (20 and 40 mg/kg) significantly (p<0.05) increased total time spent in light compartment and linezolid (40 mg/kg) significantly (p<0.05) increased the number of transition between compartments in the light/dark (L/D) aversion test. Moreover, diazepam and moclobemide also showed significant (p<0.05) effects on all parameters in the (L/D) test. In addition, linezolid (20 and 40 mg/kg), diazepam and moclobemide significantly (p<0.05) increased the number of and time spent in head dipping, whereas significantly (p<0.05) decreased the head dipping latency in hole board (HB) test. In the present study linezolid at higher doses (20 and 40 mg/kg), diazepam and moclobemide showed more pronounced anxiolytic effects as compared to lower doses of linezolid (5 and 10 mg/kg). Whereas, the effects of linezolid at higher doses, diazepam and moclobemide on mice behavior in anxiety models was found quite similar. In conclusion, these results verified, for the first time, the anxiolytic properties of linezolid and suggest that linezolid may be considered an alternative approach for the management of anxiety disorders. PMID- 23021975 TI - Natalizumab use in pediatric patients with relapsing-remitting multiple sclerosis. AB - BACKGROUND: Not all pediatric patients with relapsing-remitting multiple sclerosis (MS) may respond to traditional disease-modifying therapies. Natalizumab has been shown to be effective but is currently only approved in adults. OBJECTIVE: To analyze the safety and efficacy of natalizumab in patients under 18 years of age diagnosed with MS. METHOD: Data for pediatric patients with MS treated with natalizumab in a compassionate use setting were retrospectively collected and analyzed. RESULTS: Valid data were obtained for nine patients under 18 years from seven different centers (mean age, 15 years 4 months [range 9.8 17.7]; 5 were boys). Patients received a median of 17 infusions of natalizumab (range, 2-31) and eight received at least 12 infusions. For these 8 patients, the median score on the Expanded Disability Status Scale decreased from 3.0 to 1.0 and the median annualized relapse rate decreased from 3.0 to 0. After 12 months, no patients reported gadolinium-enhancing lesions compared to seven at baseline. Four post-baseline adverse events occurred and one patient discontinued due to hypersensitivity reaction. CONCLUSION: Natalizumab is a highly effective treatment as a second-line option in pediatric patients. In as far as the limited numbers allowed comparisons, the safety and efficacy of natalizumab in children was in line with the experience published in adult populations. PMID- 23021976 TI - Can neurobiological pathogenic mechanisms of depression facilitate the development of seizure disorders? AB - People with epilepsy have a high risk of developing depressive disorders, and people with primary depressive disorders have a high risk of developing epilepsy. Furthermore, a lifetime history of depressive disorders has been associated with a poor response of the seizure disorder to pharmacotherapy and epilepsy surgery. The aim of this Review is to identify the principal neurobiological pathogenic mechanisms of depressive disorders with the potential to facilitate the epileptogenic process or cortical hyperexcitability in experimental animal studies or those that can aggravate known pathogenic mechanisms of epilepsy in human beings. These mechanisms include (1) a hyperactive hypothalamic-pituitary adrenal axis; (2) structural and functional abnormalities of cortical structures; (3) increased glutamatergic and decreased GABAergic and serotonergic activity; and (4) immunological abnormalities. The data presented in this Review provide experimental evidence that might begin to explain the bidirectional relation between depressive disorders and epilepsy and that can be regarded as a source for future research. PMID- 23021977 TI - Defibrillation threshold varies during different stages of ventricular fibrillation in canine hearts. AB - BACKGROUND: Recent studies have shown that short duration ventricular fibrillation (SDVF) and long duration ventricular fibrillation (LDVF) are maintained by different mechanisms. The objective of this study is to evaluate how the defibrillation threshold (DFT) varies over the duration of fibrillation since the mechanism of VF maintenance changes as VF progresses. METHODS: Twelve canines were randomly divided into two groups (Group A and B, n=6 each). DFTs were measured three times in each group: SDVF (20s), LDVF (3min in Group A and 7min in Group B) and the first episode of refibrillation after successful defibrillation for LDVF. Two 64-electrode baskets used to globally map the endocardium were deployed into the left ventricle and right ventricle, respectively. RESULTS: LDVF-DFT in Group A was significantly higher than that of Group B (628+/-98V vs 313+/-81V, P<0.001). In Group B, the DFT of refibrillation was significantly increased compared with the LDVF-DFT (570+/-199V vs 313+/-81V, P=0.035) but did not differ from the DFT of refibrillation in Group A (570+/-199V vs 638+/-116V, P=0.39). Highly synchronised activation patterns on the left ventricular endocardium were observed between 3 and 7min of LDVF in Group B but not within 3min-LDVF in Group A or during refibrillation in each group. CONCLUSIONS: DFT varied during different stages of VF. The highly synchronised activation patterns exhibiting after 3min VF might contribute to the decreased LDVF-DFT. PMID- 23021978 TI - Paranasal sinus rhabdomyosarcoma: a rare tumor of poor prognosis. AB - INTRODUCTION: Rhabdomyosarcoma (RMS) is a rare sarcoma, in which paranasal sinus locations are exceptional in adults. CASE REPORT: We report a case of ethmoid metastatic RMS in a 48-year-old patient, discovered in connection with recurrent epistaxis associated with exophthalmia and ophthalmoplegia. The tumor was inoperable and chemotherapy based on adriamycin was initiated. The course was, however, marked by rapid worsening of symptoms and the patient's death. DISCUSSION: Paranasal sinus RMS shows no specific clinical signs, and diagnosis is mainly based on immunohistochemical analysis. The association of surgery and chemo-radiotherapy is the optimal attitude, but surgical resection is often impossible due to local extension. Prognosis in adults is poor. PMID- 23021979 TI - Treatment of cervical paragangliomas. AB - OBJECTIVE: Review of the treatment of cervical paraganglioma. MATERIAL AND METHODS: Review of the literature based on a Medline database. RESULTS: The treatment of choice consists of a multidisciplinary approach based on a detailed clinical, laboratory and radiological work-up. Vascular reconstruction may be necessary when the tumour invades the artery wall. The main complication of surgery is damage to cranial nerves involved in speech and/or swallowing. Treatment of bilateral tumours must be conducted in two stages. The first side to be operated depends on the sites and size of the tumours, as the primary objective is to avoid bilateral vagus nerve palsy. Radiotherapy has been used to treat paragangliomas for several years and achieves tumour stabilization in the majority of cases. Potential indications reported in the literature are: inoperable tumours, recurrence after surgery, some bilateral tumours and malignant tumours. CONCLUSION: Surgery is the standard treatment for cervical paraganglioma. Radiotherapy can be proposed when surgery is contraindicated. PMID- 23021980 TI - Harnessing plasticity to understand learning and treat disease. AB - A large body of evidence suggests that neural plasticity contributes to learning and disease. Recent studies suggest that cortical map plasticity is typically a transient phase that improves learning by increasing the pool of task-relevant responses. Here, I discuss a new perspective on neural plasticity and suggest how plasticity might be targeted to reset dysfunctional circuits. Specifically, a new model is proposed in which map expansion provides a form of replication with variation that supports a Darwinian mechanism to select the most behaviorally useful circuits. Precisely targeted neural plasticity provides a new avenue for the treatment of neurological and psychiatric disorders and is a powerful tool to test the neural mechanisms of learning and memory. PMID- 23021982 TI - Eph/Ephrin signaling in injury and inflammation. AB - The Eph/ephrin receptor-ligand system plays an important role in embryogenesis and adult life, principally by influencing cell behavior through signaling pathways, resulting in modification of the cell cytoskeleton and cell adhesion. There are 10 EphA receptors, and six EphB receptors, distinguished on sequence difference and binding preferences, that interact with the six glycosylphosphatidylinositol-linked ephrin-A ligands and the three transmembrane ephrin-B ligands, respectively. The Eph/ephrin proteins, originally described as developmental regulators that are expressed at low levels postembryonically, are re-expressed after injury to the optic nerve, spinal cord, and brain in fish, amphibians, rodents, and humans. In rodent spinal cord injury, the up-regulation of EphA4 prevents recovery by inhibiting axons from crossing the injury site. Eph/ephrin proteins may be partly responsible for the phenotypic changes to the vascular endothelium in inflammation, which allows fluid and inflammatory cells to pass from the vascular space into the interstitial tissues. Specifically, EphA2/ephrin-A1 signaling in the lung may be responsible for pulmonary inflammation in acute lung injury. A role in T-cell maturation and chronic inflammation (heart failure, inflammatory bowel disease, and rheumatoid arthritis) is also reported. Although there remains much to learn about Eph/ephrin signaling in human disease, and specifically in injury and inflammation, this area of research raises the exciting prospect that novel therapies will be developed that precisely target these pathways. PMID- 23021981 TI - Cerebral malaria: we have come a long way. AB - Despite decades of research, cerebral malaria remains one of the most serious complications of Plasmodium infection and is a significant burden in Sub-Saharan Africa, where, despite effective antiparasitic treatment, survivors develop long term neurological sequelae. Although much remains to be discovered about the pathogenesis of cerebral malaria, The American Journal of Pathology has been seminal in presenting original research from both human and experimental models. These studies have afforded significant insight into the mechanism of cerebral damage in this devastating disease. The present review highlights information gleaned from these studies, especially in terms of their contributions to the understanding of cerebral malaria. PMID- 23021983 TI - Inhibition of metastatic lung cancer in C57BL/6 mice by liposome encapsulated all trans retinoic acid (ATRA). AB - The purpose of this study was to investigate whether all trans retinoic acid (ATRA) incorporated in liposome composed of distearoylphosphatidylcholine (DSPC/cholesterol) could inhibit the metastatic lung cancer in mice more efficiently than free ATRA. Metastatic lung cancer model was developed by intravenous injection of B16F10 cells and it is also referred as melanoma model. In this present study, C57BL/6 mice were divided into several groups as per experimental design and the free ATRA and liposome encapsulated ATRA were given for 21 days at a dose of 0.60 mg/kg body weight/day after cell line implantation. After 21 days, mice were sacrificed at different time interval for ATRA level analysis in serum and lung tissue by HPLC method and the remaining mice were kept for anticancer study. The ATRA level increased significantly in serum and lung tissue in liposome encapsulated ATRA treated mice. In cancer bearing mice, tumor nodule formation decreased and life span increased after receiving liposome encapsulated ATRA treatment than free ATRA treated mice. This result implies that the liposome encapsulated ATRA has maintained more ATRA concentration in lung tissue and showed more inhibition on the lung tumor nodule formation. The results indicate a possible use of liposome encapsulated ATRA in prevention of lung metastasis. PMID- 23021989 TI - Evidence-based oxygen therapy: missed and future opportunities. PMID- 23021990 TI - The effect of lower limb muscle fatigue on obstacle negotiation during walking in older adults. AB - Tripping over obstacles is a common cause of falls in older adults, and muscle fatigue, which can alter walking patterns, may add to this risk. To date, no study has examined the effect of lower limb muscle fatigue on obstacle negotiation in older adults. 30 older adults (13 women, aged 78.3 [6.2] years) negotiated a 12 m obstacle course, while completing a visual secondary task, under two randomized conditions: rested or fatigued. For the fatigue condition, participants performed a repeated sit-to-stand movement, as fast as possible, until they could no longer continue. Participants then immediately began walking trials. Kinematic and kinetic data were collected on approach to, during, and after crossing a height-adjustable target obstacle (10% and 20% of leg length). Repeated measures ANOVA showed a statistically significant increase in lead limb vertical loading rate after stepping over the 10% obstacle when fatigued, relative to rested (P=0.046). No other significant between-condition differences (>0.05) were observed for the other kinematic variables when negotiating the 10% obstacle. Furthermore, no significant between-condition differences (P>0.05) were observed for any kinetic or kinematic variables when negotiating the 20% obstacle. This study describes a feasible method for investigating the consequences of lower limb muscle fatigue on obstacle crossing. The current finding of increased vertical loading rate when fatigued supports the need for further investigation into the effect of muscle fatigue on gait under different environmental conditions, fatiguing a range of muscles, analyzing a more comprehensive array of kinetic and kinematic measures, and in healthy and clinical populations. PMID- 23021991 TI - Scaffold-hopping with zwitterionic CCR3 antagonists: identification and optimisation of a series with good potency and pharmacokinetics leading to the discovery of AZ12436092. AB - The discovery and optimisation of a series of zwitterionic CCR3 antagonists is described. Optimisation of the structure led to AZ12436092, a compound with excellent selectivity over activity at hERG and outstanding pharmacokinetics in preclinical species. PMID- 23021992 TI - Substituted pyrazolones require N2 hydrogen bond donating ability to protect against cytotoxicity from protein aggregation of mutant superoxide dismutase 1. AB - Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease. Although the cause remains unknown, misfolded protein aggregates are seen in neurons of sporadic ALS patients, and familial ALS mutations, including mutations in superoxide dismutase 1 (SOD1), produce proteins with an increased propensity to misfold and aggregate. A structure activity relationship of a lead scaffold exhibiting neuroprotective activity in a G93A-SOD1 mouse model for ALS has been further investigated in a model PC12 cellular assay. Synthesis of biotinylated probes at the N(1) nitrogen of the pyrazolone ring gave compounds (5d-e) that retained activity within 10-fold of the proton-bearing lead compound (5a) and were equipotent with a sterically less cumbersome N(1)-methyl substituted analogue (5b). However, when methyl substitution was introduced at N(1) and N(2) of the pyrazolone ring, the compound was inactive (5c). These data led us to investigate further the pharmacophoric nature of the pyrazolone unit. A range of N(1) substitutions were tolerated, leading to the identification of an N(1)-benzyl substituted pyrazolone (5m), equipotent with 5a. Substitution at N(2) or excision of N(2), however, removed all activity. Therefore, the hydrogen bond donating ability of the N(2)-H of the pyrazolone ring appears to be a critical part of the structure, which will influence further analogue synthesis. PMID- 23021993 TI - Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease. AB - A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency. PMID- 23021994 TI - Identification of pyrimidine derivatives as hSMG-1 inhibitors. AB - hSMG-1 kinase plays a dual role in a highly conserved RNA surveillance pathway termed nonsense-mediated RNA decay (NMD) and in cellular genotoxic stress response. Since deregulation of cellular responses to stress contributes to tumor growth and resistance to chemotherapy, hSMG-1 is a potential target for cancer treatment. From our screening efforts, we have identified pyrimidine derivatives as hSMG-1 kinase inhibitors. We report structure-based optimization of this pan kinase scaffold to improve its biochemical profile and overall kinome selectivity, including mTOR and CDK, to generate the first reported selective hSMG-1 tool compound. PMID- 23021995 TI - RT-qPCR work-flow for single-cell data analysis. AB - Individual cells represent the basic unit in tissues and organisms and are in many aspects unique in their properties. The introduction of new and sensitive techniques to study single-cells opens up new avenues to understand fundamental biological processes. Well established statistical tools and recommendations exist for gene expression data based on traditional cell population measurements. However, these workflows are not suitable, and some steps are even inappropriate, to apply on single-cell data. Here, we present a simple and practical workflow for preprocessing of single-cell data generated by reverse transcription quantitative real-time PCR. The approach is demonstrated on a data set based on profiling of 41 genes in 303 single-cells. For some pre-processing steps we present options and also recommendations. In particular, we demonstrate and discuss different strategies for handling missing data and scaling data for downstream multivariate analysis. The aim of this workflow is provide guide to the rapidly growing community studying single-cells by means of reverse transcription quantitative real-time PCR profiling. PMID- 23021996 TI - The REDUCE Follow-Up Study: low rate of new prostate cancer diagnoses observed during a 2-year, observational, followup study of men who participated in the REDUCE trial. AB - PURPOSE: The primary objective of the REDUCE (REduction by DUtasteride of prostate Cancer Events) Follow-Up Study was to collect data on the occurrence of newly diagnosed prostate cancers for 2 years beyond the 4-year REDUCE study. MATERIALS AND METHODS: The 4-year REDUCE study evaluated prostate cancer risk reduction in men taking dutasteride. This 2-year observational study followed men from REDUCE with a clinic visit shortly after study conclusion and with up to 2 annual telephone calls during which patient reported data were collected regarding prostate cancer events, chronic medication use, prostate specific antigen levels and serious adverse events. No study drug was provided and all biopsies during the 2-year followup were performed for cause. The primary objective was to collect data on the occurrence of new biopsy detectable prostate cancers. Secondary end points included assessment of Gleason score and serious adverse events. RESULTS: A total of 2,751 men enrolled in the followup study with numbers similar to those of the REDUCE former treatment groups (placebo and dutasteride). Few new prostate cancers were detected during the 2-year followup period in either former treatment group. A greater number of cancers were detected in the former dutasteride group than in the former placebo group (14 vs 7 cases). No Gleason score 8-10 prostate cancers were detected in either former treatment group based on central pathology review. No new safety issues were identified during the study. CONCLUSIONS: Two years of followup of the REDUCE study cohort demonstrated a low rate of new prostate cancer diagnoses in the former placebo and dutasteride treated groups. No new Gleason 8-10 cancers were detected. PMID- 23021997 TI - Microcomposition of human urinary calculi using advanced imaging techniques. AB - PURPOSE: Common methods of commercial urolithiasis analysis, such as light microscopy and Fourier transform infrared spectroscopy, provide limited or no information on the molecular composition of stones, which is vital when studying early stone pathogenesis. We used synchrotron radiation based microfocused x-ray fluorescence, x-ray absorption and x-ray diffraction advanced imaging techniques to identify and map the elemental composition, including trace elements, of urinary calculi on a MUm (0.0001 cm) scale. MATERIALS AND METHODS: Human stone samples were obtained during serial percutaneous nephrolithotomy and ureteroscopy procedures. A portion of each sample was sent for commercial stone analysis and a portion was retained for synchrotron radiation based advanced imaging analysis. RESULTS: Synchrotron radiation based methods of stone analysis correctly identified stone composition and provided additional molecular detail on elemental components and spatial distribution in uroliths. Resolution was on the order of a few MUm. CONCLUSIONS: Knowledge of all elements present in lithogenesis at this detail allows for better understanding of early stone formation events, which may provide additional insight to prevent and treat stone formation. PMID- 23021999 TI - Risk and prevention of acute urinary retention after robotic prostatectomy. AB - PURPOSE: Acute urinary retention after catheter removal is a recognized complication following open or robot-assisted radical prostatectomy. We evaluated patient and surgery related risk factors to determine whether acute urinary retention could be prevented. To our knowledge this has not previously been investigated for prostatectomy done by any technique. MATERIALS AND METHODS: We reviewed a single surgeon, robot-assisted radical prostatectomy database of patients treated between February 2008 and June 2011 for acute urinary retention after catheter removal, which was routinely performed 3 to 7 days postoperatively. We compared the characteristics of patients with and without acute urinary retention. RESULTS: Of 1,026 patients 25 (2.4%) experienced acute urinary retention. There was no difference between patients with and without acute urinary retention in mean age, body mass index, blood loss or prostate size, and no difference in the frequency of bladder neck reconstruction or nerve sparing. The catheter was removed an average of 4.1 vs 5.7 days postoperatively in patients with vs without acute urinary retention. Of 25 patients with acute urinary retention 22 (88%) underwent catheter removal on postoperative day 3 or 4. Although only 3 of 381 patients (0.8%) had a leak on cystogram on postoperative day 3 or 4, the acute urinary retention rate when the catheter was removed on day 3 or 4 was 5.8% (22 of 381). This was several times higher than the rate in patients who retained the catheter for greater than 4 days (3 of 645 or 0.5%). CONCLUSIONS: Acute urinary retention develops infrequently after robotic prostatectomy. No patient related risk factors were identified beyond catheterization time. Although the catheter may be removed after 3 or 4 days with rare leaks, the acute urinary retention risk was much less when the catheter was left in place at least 5 days. PMID- 23021998 TI - Inhibition of Rho-kinase improves erectile function, increases nitric oxide signaling and decreases penile apoptosis in a rat model of cavernous nerve injury. AB - PURPOSE: Bilateral cavernous nerve injury results in up-regulation of ROCK signaling in the penis. This is linked to erectile dysfunction in an animal model of post-prostatectomy erectile dysfunction. We evaluated whether daily treatment with the ROCK inhibitor Y-27632 (Tocris Bioscience, Ellisville, Missouri) would prevent erectile dysfunction in a rat model of bilateral cavernous nerve injury. MATERIALS AND METHODS: Sprague-Dawley(r) rats underwent surgery to create sham (14) or bilateral (27) cavernous nerve injury. In the injury group 13 rats received treatment with Y-27632 (5 mg/kg twice daily) and 14 received vehicle. At 14 days after injury, rats underwent cavernous nerve stimulation to determine erectile function. Penes were assessed for neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase. ROCK2 was assessed by Western blot. Cyclic guanosine monophosphate was determined by enzyme-linked immunosorbent assay. Cavernous homogenates were tested for ROCK and protein kinase G enzymatic activity. Penile apoptosis was evaluated using the Apostain technique (Alexis, San Diego, California). Data were analyzed on ROCK using ANOVA and the t test. RESULTS: While erectile function was decreased in rats with bilateral cavernous nerve injury, daily administration of Y-27632 improved erectile responses. Injury decreased neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase but ROCK2 was significantly increased. Y-27632 treatment restored neuronal nitric oxide synthase, nitric oxide synthase membrane-endothelial nitric oxide synthase and cyclic guanosine monophosphate levels, and protein kinase G activity. Treatment significantly decreased ROCK2 protein and ROCK activity. There were significantly fewer apoptotic cells after treatment than in injured controls. CONCLUSIONS: These results provide evidence for up-regulation of the RhoA/ROCK signaling pathway with detrimental effects on erectile function after bilateral cavernous nerve injury. ROCK inhibition improved erectile dysfunction associated with bilateral cavernous nerve injury by preserving penile nitric oxide bioavailability and decreasing penile apoptosis. PMID- 23022000 TI - The forgotten ureteral stent in children: from diagnosis to treatment. AB - PURPOSE: We conducted a multicenter pediatric study of ureteral stents unintentionally left in situ. MATERIALS AND METHODS: A total of 22 patients with encrusted Double-J(r) ureteral stents unintentionally left in situ were treated at 4 centers between January 2007 and March 2012. Stone burdens were estimated using plain radiography and computerized tomography. Treatment decision was made based on clinical and radiological findings or stone burden. RESULTS: Nine girls and 13 boys with a mean age of 9.5 years (range 2 to 16) were analyzed. Mean indwelling time of ureteral stent was 21.7 months (range 6 to 60). Stents were inserted for the indication of urolithiasis (17 patients) and reconstructive urological intervention (5). In 2 patients stents had been placed bilaterally. Mean stent stone burden was 184 mm(2) on plain radiography and 247 mm(2) on computerized tomography, a difference that was statistically significant (p = 0.002). Shock wave lithotripsy was done in 6 cases. Endoscopic procedures were performed in all patients, including ureteroscopy in 8, simple stent removal in 7, endoscopic cystolithotripsy in 6, percutaneous nephrolithotomy in 5, retrograde intrarenal surgery in 3 and percutaneous cystolithotripsy in 2. Surgical removal of each stent required a mean of 1.5 interventions and a mean hospital stay of 4.4 days. CONCLUSIONS: At experienced centers combined endourological techniques can achieve successful and safe management of forgotten stents even in the pediatric age group. Thus, routine preprocedural tomography is a must in children with forgotten ureteral stents. PMID- 23022001 TI - Penile repair in patients with epispadias-exstrophy complex-can we prevent resultant hypospadias? AB - PURPOSE: Male genitalia reconstruction in patients with exstrophy-epispadias complex often leads to secondary hypospadias, thus requiring additional surgery and resulting in possible complications. We describe a technique of male epispadias repair to prevent resultant hypospadias. MATERIALS AND METHODS: The complete penile disassembly technique is modified by multiple Z-plasties, which enable creation of a funnel-like bladder neck and urethral plate lengthening. A total of 29 patients 2 months to 12 years old presenting with pure epispadias and bladder exstrophy were treated with this technique between 2004 and 2011. These patients were compared to 19 patients 1 day to 11 years old with exstrophy epispadias treated with the standard penile disassembly technique between 2000 and 2004. RESULTS: Outcome measures were urethral orifice position, penile length and complications. There was no statistically significant difference between the 2 groups regarding penile length or complications. In the study group the urethra reached the tip of the glans in all patients, whereas the creation of intentional hypospadias was necessary in 6 patients (31.5%) in the control group (p <0.05). CONCLUSIONS: The modified technique was effective in obtaining appropriate meatal location without decreasing the penile length. The complication rate was not changed. Creation of resultant hypospadias at genitalia reconstruction in male epispadias should strongly be prevented. PMID- 23022002 TI - Gout, stone composition and urinary stone risk: a matched case comparative study. AB - PURPOSE: We established the most common stone composition, and serum and urinary biochemical features in patients with gout and urolithiasis. MATERIALS AND METHODS: We retrospectively searched for the records of patients diagnosed with gout among all those in our stone registry. A matched case cohort of stone formers was generated from our registry who had the same age, gender and body mass index. Primary end points were baseline 24-hour urinary metabolic panels and stone composition. Medications were considered. Groups were compared using the Student t and chi-square/Fisher exact tests with significance considered at p <0.05. RESULTS: For stone panel evaluation 181 patients met our inclusion criteria. There was no significant difference in 24-hour uric acid between the nongout and gout cohorts but hyperoxaluria was more common in patients with gout (74% vs 61%, p = 0.009). For stone composition analysis 393 patients were included. The gout cohort had lower calcium oxalate monohydrate (39.4% vs 54.7%), calcium oxalate dihydrate (6.0% vs 11.2%) and calcium phosphate (9.6% vs 14.1%) but higher uric acid (42.7% vs 18.2%, each p <0.001). Pure uric acid stones were more common in patients with gout (52.2% vs 22.3%, p <0.001), while calcium oxalate monohydrate (45.2% vs 68.6%, p <0.001), calcium oxalate dihydrate (0.6% vs 3.5%, p = 0.017) and calcium phosphate (1.6% vs 4.9%, p = 0.033) were more common in nongout cases. Patients with gout who were on allopurinol had fewer pure uric acid stones (30.4% vs 56.4%) and more calcium oxalate monohydrate stones (69.6% vs 40.7%, each p <0.001) than those without medication. CONCLUSIONS: Uric acid stones are the most common pure stone composition in patients with gout but 48% have nonuric acid stones. Allopurinol changes the stone composition distribution in patients with gout to a pattern similar to that in stone formers without gout. PMID- 23022003 TI - Re: lower testosterone levels with luteinizing hormone-releasing hormone agonist therapy than with surgical castration: new insights attained by mass spectrometry. T. M. van der Sluis, H. N. Bui, E. J. Meuleman, A. C. Heijboer, J. F. Hartman,N. van Adrichem, E. Boeve, W. de Ronde, R. J. van Moorselaar and A. N. Vis. J Urol 2012; 187: 1601-1607. PMID- 23022005 TI - Re: semen quality in men who sustained a spinal cord injury during the prepubertal period: F. A. Celigoj, E. Ibrahim, T. C. Aballa, C. M. Lynne and N. L. Brackett J Urol 2012; 188: 521-525. PMID- 23022004 TI - The number of cores taken in patients diagnosed with a single microfocus at initial biopsy is a major predictor of insignificant prostate cancer. AB - PURPOSE: Patients with a single microfocus of prostate cancer at initial biopsy represent the ideal candidates for active surveillance. We investigate whether the number of cores taken affects the concordance rate between microfocus of prostate cancer and the confirmation of a pathologically insignificant prostate cancer at radical prostatectomy. MATERIALS AND METHODS: Data were analyzed from 233 patients with a single microfocus of prostate cancer at initial transrectal prostate biopsy (a single focus of Gleason 6 involving 5% or less of the core) subsequently treated with radical prostatectomy. The chi-square test, cubic spline analyses and logistic regression analyses were used to depict the relationship between the number of cores taken and the probability of confirming the presence of an indolent disease (pathologically confirmed insignificant prostate cancer defined as radical prostatectomy Gleason score 6 or less, tumor volume 0.5 ml or less and organ confined disease). RESULTS: Overall 65 patients (27.9%) showed pathologically confirmed insignificant prostate cancer at radical prostatectomy. The rate of pathologically confirmed insignificant prostate cancer was 3.8%, 29.6% and 39.4% in patients who underwent biopsy of 12 or fewer cores, 13 to 18 cores and 19 or more cores, respectively (p <0.001). After adjusting for the available confounders, age (p = 0.04), number of cores taken (p <0.001) and prostate specific antigen density (p <0.02) were independent predictors of pathologically confirmed insignificant prostate cancer. CONCLUSIONS: Of patients diagnosed with a single microfocus of prostate cancer the number of biopsy cores taken was a major independent predictor of having pathologically confirmed insignificant prostate cancer at radical prostatectomy. Therefore, when active surveillance is considered as a possible alternative in patients with microfocus of prostate cancer, the number of cores taken should be taken into account in decision making. PMID- 23022006 TI - Role of opioid and metabotropic glutamate 5 receptors in pudendal inhibition of bladder overactivity in cats. AB - PURPOSE: We determined the role of opioid and metabotropic glutamate 5 receptors in the pudendal inhibition of bladder overactivity. MATERIALS AND METHODS: Cystometrograms were performed in 11 cats under alpha-chloralose anesthesia by slowly infusing the bladder with saline or 0.25% acetic acid. Pudendal nerve stimulation at intensities of multiple times the threshold to induce observable anal twitching was applied during cystometrogram to inhibit the bladder overactivity induced by acetic acid irritation. Naloxone (0.1, 0.3 and 1 mg/kg intravenously) was administered to block opioid receptors, followed by MTEP (3 and 10 mg/kg intravenously) to block metabotropic glutamate 5 receptors. After each drug dose, pudendal inhibition of bladder overactivity was examined during cystometrogram. RESULTS: Acetic acid irritated the bladder, induced bladder overactivity and significantly decreased mean +/- SE bladder capacity to 23.6% +/ 2.7% of saline control capacity. Pudendal nerve stimulation at 1 to 1.5 and 4 * threshold suppressed bladder overactivity and significantly increased mean capacity to 57.5% +/- 8.1% (p = 0.0005) and 106% +/- 15% (p = 0.0002), respectively, of saline control capacity. Naloxone had no effect on pudendal inhibition but MTEP eliminated the inhibition induced by low intensity stimulation and significantly decreased the inhibition induced by high intensity stimulation (p <0.05). Neither naloxone nor MTEP altered baseline bladder overactivity. CONCLUSIONS: Opioid receptors are not involved in pudendal inhibition of bladder overactivity but metabotropic glutamate 5 receptors are partially involved. Understanding neurotransmitter mechanisms could improve the efficacy of neuromodulation therapy for overactive bladder and identify molecular targets for developing new drugs for overactive bladder. PMID- 23022007 TI - Semen Quality in Men Who Sustained a Spinal Cord Injury During the Prepubertal Period. PMID- 23022008 TI - Urological complications and vesicoureteral reflux following pediatric kidney transplantation. AB - PURPOSE: Ureteral complications of renal transplantation can dramatically impact renal outcomes. We studied whether complications are associated with preexisting genitourinary pathology or transplant using a deceased donor allograft. MATERIALS AND METHODS: We retrospectively reviewed all patients undergoing renal transplantation at our institution between 2000 and 2010. We abstracted patient demographic details, donor type (living vs deceased), end-stage renal disease etiology, reimplant technique, stent use, preoperative and postoperative imaging, history of lower genitourinary pathology and postoperative complication management. RESULTS: A total of 211 kidneys were transplanted into 206 patients (mean age 13.7 years, mean followup 4.6 years). Most patients (89%) underwent extravesical ureteroneocystostomy without stenting (97%), with roughly half (47%) of transplants being from living donors. Preexisting urological pathology was present in 34% of cases. Postoperative obstruction or extravasation occurred in 16 cases (7.6%), of which 15 were acute. Complications were not associated with donor type, preexisting urological pathology other than posterior urethral valves, surgical technique, etiology of end-stage renal disease or patient age. However, posterior urethral valves or other preexisting genitourinary pathology was not associated with an increased likelihood of genitourinary complications. Posterior urethral valves were associated with development of postoperative vesicoureteral reflux (OR 6.7, p = 0.004) but were not associated with stent placement, surgical technique, donor type or etiology of end-stage renal disease. CONCLUSIONS: Patients with posterior urethral valves undergoing renal transplantation are at increased risk for postoperative vesicoureteral reflux but not for other acute surgical complications. There is no association between donor type, etiology of end-stage renal disease, surgical technique or patient age and increased complications. PMID- 23022009 TI - Impact of parturition on chemokine homing factor expression in the vaginal distention model of stress urinary incontinence. AB - PURPOSE: Human childbirth simulated by vaginal distention is known to increase the expression of chemokines and receptors involved in stem cell homing and tissue repair. We hypothesized that pregnancy and parturition in rats contributes to the expression of chemokines and receptors after vaginal distention. MATERIALS AND METHODS: We used 72 age matched female Lewis rats, including virgin rats with and without vaginal distention, and delivered rats with and without vaginal distention. Each rat was sacrificed immediately, or 3 or 7 days after vaginal distention and/or parturition, and the urethra was harvested. Relative expression of chemokines and receptors was determined by real-time polymerase chain reaction. Mixed models were used with the Bonferroni correction for multiple comparisons. RESULTS: Vaginal distention up-regulated urethral expression of CCL7 immediately after injury in virgin and postpartum rats. Hypoxia inducible factor 1alpha and vascular endothelial growth factor were up-regulated only in virgin rats immediately after vaginal distention. CD191 expression was immediately up regulated in postpartum rats without vaginal distention compared to virgin rats without vaginal distention. CD195 was up-regulated in virgin rats 3 days after vaginal distention compared to virgin rats without vaginal distention. CD193 and CXCR4 showed delayed up-regulation in virgin rats 7 days after vaginal distention. CXCL12 was up-regulated in virgin rats 3 days after vaginal distention compared to immediately after vaginal distention. Interleukin-8 and CD192 showed no differential expression. CONCLUSIONS: Vaginal distention results in up-regulation of the chemokines and receptors expressed during tissue injury, which may facilitate the spontaneous functional recovery previously noted. Pregnancy and delivery up-regulated CD191 and attenuated the expression of hypoxia inducible factor-1alpha and vascular endothelial growth factor in the setting of vaginal distention, likely by decreasing hypoxia. PMID- 23022010 TI - A surprisingly low prevalence of demonstrable stress urinary incontinence and pelvic organ prolapse in women with multiple sclerosis followed at a tertiary neurogenic bladder clinic. AB - PURPOSE: We report the prevalence of stress urinary incontinence and pelvic organ prolapse in patients with multiple sclerosis referred to a tertiary care neurogenic bladder clinic. MATERIALS AND METHODS: We queried an institutional review board approved neurogenic bladder database for urodynamic and demographic data on patients with multiple sclerosis followed for lower urinary tract symptoms in a 12-year period. Demographic information included multiple sclerosis classification, age at initial visit, body mass index, parity and pelvic examination findings. Prolapse was defined as stage 2 prolapse or greater. Stress urinary incontinence was defined as urodynamic stress incontinence and/or incontinence on a supine stress test. RESULTS: Included in analysis were 280 women with a mean age of 50 years and a mean 13-year history of multiple sclerosis. Relapse remitting multiple sclerosis was noted in 40% of patients, while 45 (16%) had stress urinary incontinence. Women with stress urinary incontinence had a higher average maximum urine flow (14 vs 9 ml per second, p <0.003), higher voided volume (272 vs 194 cc, p = 0.018) and higher body mass index (30 vs 25 kg/m(2), p <0.005). Overall, 23 women (9%) had pelvic organ prolapse, including 2 (9%) with posterior prolapse only, 8 (35%) with anterior prolapse only and 13 (56%) with posterior and anterior prolapse. There was no difference in age, body mass index or multiple sclerosis subtype between women with vs without pelvic organ prolapse. CONCLUSIONS: The 14% prevalence of demonstrable stress urinary incontinence and 9% rate of pelvic organ prolapse are markedly lower than published historical data on an age matched cohort without multiple sclerosis. The surprisingly low prevalence of stress urinary incontinence and pelvic organ prolapse in women with multiple sclerosis may be attributable to decreased activity, a neurogenically enhanced vesicourethral unit or other functional or anatomical etiologies. PMID- 23022012 TI - A nonhuman primate model of stable urinary sphincter deficiency. AB - PURPOSE: The pathophysiology of urinary sphincter deficiency in women remains incompletely understood and current treatment options have limitations. Female nonhuman primates may represent a relevant animal model for studies of pathophysiology and treatment interventions because of their human-like reproductive and age associated stages of life (premenopause, perimenopause and postmenopause), lower urinary tract structure and bipedal posture. We developed and characterized a nonhuman primate model of defined injury to the urethral sphincter complex. MATERIALS AND METHODS: We used 22 adult female cynomolgus monkeys in which injury to the sphincter complex was created by cauterizing and then transecting its pudendal innervation. Urodynamic studies were performed before and during pudendal and hypogastric nerve stimulation at baseline, and 3, 6 and 12 months after injury. We also analyzed sphincter structure in vivo by cystourethrography, and ex vivo by quantitative histology and immunohistochemistry at these time points. RESULTS: Injury produced a 47% to 50% decrease in maximal urethral pressure (vs baseline p <0.05). It also abolished the increase in maximal urethral pressure in response to pudendal and hypogastric nerve stimulation (vs baseline p >0.05), which persisted more than 12 months after injury. Urodynamic changes were consistent with decreased skeletal and smooth muscle content, decreased nerve responses and an associated decrease in somatic and adrenergic innervation in the sphincter complex. CONCLUSIONS: These structural and urodynamic changes are consistent with those in patients with stress urinary incontinence. They support the usefulness of nonhuman primates as translatable surrogates for pathophysiological studies of urinary sphincter deficiency and testing novel therapies for that condition. PMID- 23022013 TI - Presence and stability of B complex vitamins in bee pollen using different storage conditions. AB - This study has the objective of evaluating the stability of B complex vitamins and its vitamers, for a period of 1year of storage. The pollen samples were stored under room temperature (with and without light) and frozen. The vitamins were quantified by HPLC with fluorescence detection. All proposed vitamins were found in the samples and the dehydration process did not interfere in vitamin content. The variations were (dry basis): 0.59-1.09mg/100g (B(1)); 1.73-2.56 (B(2)); 6.43-15.34 (PP) and 0.33-0.68 (B(6)). After 1year of storage, it can be stated that vitamin B(1) concentration remained constant, while for the others, the concentration loss was dependent on time rather than on storage conditions. All samples were considered vitamin B(2) sources. The influence of the storage time in the concentrations of vitamin B(6) and PP was explained mathematically, through linear regression equations of multivariate analysis. PMID- 23022011 TI - Reactive oxygen species as the molecular modulators of calcium oxalate kidney stone formation: evidence from clinical and experimental investigations. AB - PURPOSE: Idiopathic calcium oxalate kidney stones form while attached to Randall plaques, the subepithelial deposits on renal papillary surfaces. Plaque formation and growth mechanisms are poorly understood. Plaque formation elsewhere in the body is triggered by reactive oxygen species and oxidative stress. This review explores possible reactive oxygen species involvement in plaque formation and calcium oxalate nephrolithiasis. MATERIALS AND METHODS: A search of various databases for the last 8 years identified literature on reactive oxygen species involvement in calcium oxalate nephrolithiasis. The literature was reviewed and results are discussed. RESULTS: Under normal conditions reactive oxygen species production is controlled, increasing as needed and regulating crystallization modulator production. Reactive oxygen species overproduction or decreased antioxidants lead to oxidative stress, inflammation and injury, and are involved in stone comorbidity. All major chronic inflammation markers are detectable in stone patient urine. Patients also have increased urinary excretion of the IalphaI and the thrombin protein families. Results of a recent study of 17,695 participants in NHANES III (National Health and Nutrition Examination Survey) showed significantly lower antioxidants, carotene and beta-cryptoxanthin in those with a kidney stone history. Animal model and tissue culture studies revealed that high oxalate, calcium oxalate and calcium phosphate crystals provoked renal cell reactive oxygen species mediated inflammatory responses. Calcium oxalate crystals induce renin up-regulation and angiotensin II generation. Nonphagocytic NADPH oxidase leads to reactive oxygen species production mediated by protein kinase C. The P-38 MAPK/JNK transduction pathway is turned on. Transcriptional and growth factors, and generated secondary mediators become involved. Chemoattractant and osteopontin production is increased and macrophages infiltrate the renal interstitium around the crystal. Phagocytic NADPH oxidase is probably activated, producing additional reactive oxygen species. Localized inflammation, extracellular matrix and fibrosis develop. Crystallization modulators have a significant role in inflammation and tissue repair. CONCLUSIONS: Based on available data, Randall plaque formation is similar to extracellular matrix mineralization at many body sites. Renal interstitial collagen becomes mineralized, assisting plaque growth through the interstitium until the mineralizing front reaches papillary surface epithelium. Plaque exposure to pelvic urine may also be a result of reactive oxygen species triggered epithelial sloughing. PMID- 23022014 TI - Low molecular weight fucoidan ameliorating the chronic cisplatin-induced delayed gastrointestinal motility in rats. AB - Delayed gastrointestinal (GI) motility is frequent adverse effect associated with chemotherapy due to oxidative stress, activation of 5-HT3 receptors or serotonin releases from enterochromaffin cells. Fucoidan, extracts from brown seaweeds, has been showed antioxidant related favorable pharmacological activities including digestive tract protective effects. Low molecular weight fucoidan (LMF) obtained by acid hydrolysis of high molecular weight fucoidan has been showed more favorable bioactivities. This study was conducted to determine whether or not LMF can prevent delayed GI motility induced by the antineoplastic drug cisplatin chronically administered, once per week for five consecutive weeks. LMF ameliorating the chronic cisplatin treatment related body weight decreases, delayed GI motility, and enhanced the antioxidant defense systems. In addition, LMF also inhibited the cisplatin treatment related GI gastrin and serotonin changes, including enzyme activities involved in serotonin metabolism and enterochromaffin cells. The overall effects of LMF 10mg/kg were similar to that of ondansetron 1mg/kg, a serotonin 5-HT3 receptor antagonist. The present results supported that LMF have favorable ameliorating effect on the delayed GI motility induced by chemotherapy, modulated the GI enterochromaffin cells, serotonin and gastrin-producing cells with antioxidant effects. This effect of LMF may help improve accompanying digestive disorders by chemotherapy. PMID- 23022016 TI - Praziquantel treatment of school children from single and mixed infection foci of intestinal and urogenital schistosomiasis along the Senegal River Basin: monitoring treatment success and re-infection patterns. AB - Following major water development schemes in the 1980s, schistosomiasis has become a serious parasitic disease of children living in the Senegal River Basin. Both urogenital (Schistosoma haematobium) and intestinal (Schistosoma mansoni) schistosomiasis can be highly prevalent in school-aged children, with many individuals infected with both parasites. In order to investigate the transmission and re-infection dynamics of both parasite species, single and mixed infection foci at three villages (Nder and Temeye; S. mansoni and S. haematobium foci and Guia; S. haematobium focus) were studied. In each focus infected children were identified and selected for a 12-month study involving two treatments with praziquantel (40mg/kg) three weeks apart at the beginning of the study and again 6 months into the study. Urine and stool samples were examined for schistosome eggs before and at 6 weeks and 6 months after chemotherapy. Prevalence and intensity of infection were recorded for each child at each time point. Before treatment, in all three villages, the prevalence and intensity of infection was extremely high for both S. mansoni (79-100%) and S. haematobium (81 97%). With the first round of chemotherapy sufficient cure rates (CRs) of both species were achieved in all villages (38-96%) with high egg reduction rates (ERRs) (97-99%). The data show that high and rapid re-infection rates occur, especially for S. mansoni, within a six-month period following treatment. Re infection must be highly linked to ecological and seasonal factors. The persistence of S. mansoni in Nder could raise concern as levels of infection intensity remain high (geometric mean intensity at baseline 653epg changed to 705epg at 12 months) after four rounds of chemotherapy. This phenomenon could be explained by extremely rapid re-infection dynamics or a sub-optimal efficacy of praziquantel against S. mansoni in this village. High intensities in mixed infections may influence disease epidemiology and control warranting further studies. The disease situation in the SRB must be monitored closely and new treatment regimes should be designed and implemented to control schistosomiasis in the school-age population. PMID- 23022015 TI - Developmental effects of prenatal di-n-hexyl phthalate and dicyclohexyl phthalate exposure on reproductive tract of male rats: Postnatal outcomes. AB - The present study is to investigate the effects of in utero di-n-hexyl phthalate (DHP) and dicyclohexyl phthalate exposure (DCHP) on the development of male reproductive tract at prepubertal, pubertal and adult stages. Pregnant rats were exposed to DHP and DCHP at doses of 0, 20, 100 and 500mg/kg/day, by gavage, on gestational days (GD) 6-19. Testosterone (T) levels of prepubertal rats diminished at high dose DHP and middle dose DCHP groups. MIS/AMH levels elevated in DHP and DCHP groups. T levels of pubertal rats decreased in low and high dose DHP and DCHP groups. Inhibin B levels of adult rats diminished in DCHP groups. Atrophic and amorphous tubules, spermatogenic cell debris, apoptotic cells, adherent tubules, Sertoli cell vacuolisation, prostatic atrophic tubules and prostatic intraepithelial neoplasia (PIN) were observed in the reproductive organs of treated animals at all developmental stages. There was an increase in immunoexpression of MIS/AMH in testes of treated rats. There were no changes in sperm head count but percentages of abnormal sperms increased. The diameters of seminiferous and epididymal tubules in treatment groups were significantly lower. This study shows that DHP and DCHP may have antiandrogenic effects on male reproductive development before and after birth. PMID- 23022017 TI - Recombinant Leishmania (Leishmania) infantum Ecto-Nucleoside Triphosphate Diphosphohydrolase NTPDase-2 as a new antigen in canine visceral leishmaniasis diagnosis. AB - Canine visceral leishmaniasis is an important public health concern. In the epidemiological context of human visceral leishmaniasis, dogs are considered the main reservoir of Leishmania parasites; therefore, dogs must be epidemiologically monitored constantly in endemic areas. Furthermore, dog to human transmission has been correlated with emerging urbanization and increasing rates of leishmaniasis infection worldwide. Leishmania (Leishmania) infantum (L. chagasi) is the etiologic agent of visceral leishmaniasis in the New World. In this work, a new L. (L.) infantum (L. chagasi) recombinant antigen, named ATP diphosphohydrolase (rLic-NTPDase-2), intended for use in the immunodiagnosis of CVL was produced and validated. The extracellular domain of ATP diphosphohydrolase was cloned and expressed in the pET21b-Escherichia coli expression system. Indirect ELISA assays were used to detect the purified rLic-NTPDase-2 antigen using a standard canine sera library. This library contained CVL-positive samples, leishmaniasis-negative samples and samples from Trypanosoma cruzi-infected dogs. The results show a high sensitivity of 100% (95% CI=92.60-100.0%) and a high specificity of 100% (95% CI=86.77-100.0%), with a high degree of confidence (k=1). These findings demonstrate the potential use of this recombinant protein in immune diagnosis of canine leishmaniasis and open the possibility of its application to other diagnostic approaches, such as immunochromatography fast lateral flow assays and human leishmaniasis diagnosis. PMID- 23022018 TI - Epstein-Barr virus-associated smooth muscle tumor-report of 3 tumors including 1 intracerebral case with a prominent intratumoral B-lymphocytic component and plasma cells. AB - Three Epstein-Barr virus-associated smooth muscle tumors (intracranial, endobronchial, and paraspinal) in 2 patients are presented. The patient with the intracranial tumor had no concurrent or previous manifestation of this neoplasm and was immunosuppressed because of a renal transplant. The other patient had AIDS and radiologic evidence of involvement of multiple other sites. Although mitotic activity was present, none of the tumors displayed any high-grade malignant histologic features. All tumors were strongly positive for smooth muscle actin and variably expressed h-caldesmon. Desmin was negative in all 3 tumors. The intracranial tumor was associated with prominent intracerebral edema and displayed, in addition to a prominent intratumoral T-cell component, a hitherto unreported component of prominent intratumoral B cells and plasma cells. PMID- 23022019 TI - The efficacy of influenza vaccination is reduced in nursing home older adults with moderate to severe renal impairment. PMID- 23022020 TI - Friedolanostanes and xanthones from the twigs of Garcinia hombroniana. AB - The twigs of Garcinia hombroniana yielded six compounds: two 17,14 friedolanostanes (garcihombronanes K-L, 1-2) and four xanthones (garcihombronones A-D, 3-6) together with 14 known compounds including four friedolanostanes, one lanostane, six xanthones, two benzoic acid derivatives and one biflavonoid. Their structures were elucidated by analysis of spectroscopic data and comparison of the NMR data with those reported previously. Their antibacterial activity against methicillin-resistant Staphylococcus aureus and S. aureus was evaluated. PMID- 23022021 TI - Effects of the bite splint 15-day treatment termination in patients with temporomandibular disorder with a clinical history of sleep bruxism: a longitudinal single-cohort study. AB - OBJECTIVE: The aim of this study was to assess the effects of bite splint (BS) treatment termination in patients treated for temporomandibular disorder (TMD) and sleep bruxism (SB). STUDY DESIGN: This longitudinal single-cohort study assessed 30 patients (29.5 +/- 7.8 years old, 86.7% women) who were successfully treated with BS for SB and TMD for 30 days to 6 months prior to termination of the use of BS. The Research Diagnostic Criteria for TMD Axes I and II, Sleep Assessment Questionnaire, Beck Depression Inventory, and BiteStrip were used to assess TMD signs and symptoms, sleep disorders, depression, and SB at baseline and after 15 days of BS disuse. RESULTS: TMD symptoms, including the disability points, characteristic pain intensity, and present pain at rest, increased significantly (P < 0.05). After 15 days of BS termination, there were no significant differences in SB and depression levels, sleep quality, and TMD signs. CONCLUSIONS: In patients with TMD and SB, BS treatment cessation is not recommended. PMID- 23022022 TI - Oral Candida colonization and candidiasis in patients with psoriasis. AB - OBJECTIVES: The objective of this study was to investigate oral Candida colonization and candidosis in a group of patients with psoriasis and controls. STUDY DESIGN: A total of 100 patients with psoriasis and matched controls underwent the concentrated oral rinse test for Candida isolation. Candida species were identified by the VITEK 2 Identification System. Categorical variables were evaluated using the chi(2) test. The median Candida count was compared using the Mann-Whitney U test. RESULTS: Oral candidiasis was diagnosed in 3% of the patients with psoriasis. The Candida count and prevalence were significantly higher in the patients with psoriasis compared with controls (69% vs 44%, P < .001), but with no relationship to the severity or treatment of psoriasis. Oral Candida was significantly higher in late-onset (at age >=30 years) compared with early-onset psoriasis (at age <30 years). CONCLUSIONS: Patients with psoriasis have increased oral Candida colonization and candidiasis. Further studies are needed to clarify the predisposing factor(s) for oral Candida in patients with psoriasis. PMID- 23022023 TI - Cleft lip, nose, and palate: the nasal septum as the pacemaker for midfacial growth. AB - The need to be aware of the dynamics of cartilage development and growth is encountered by surgeons whenever they attempt to correct craniofacial defects such as unilateral or bilateral cleft lip/cleft palate or midfacial injuries after trauma. Within the craniofacial region, the nasal septal cartilage and the sphenoethmoidal and sphenooccipital cranial synchondroses are distinguished from other craniofacial cartilages in possessing intrinsic growth potential. Indeed, growth of the nasal septal cartilage outstrips the growth of other skeletal and soft tissues in the midface to such an extent that it is the pacemaker for growth of the face and anterior portion of the skull. We revisit and reinforce the importance of the nasal septum as pacemaker with analysis of 3 classes of evidence: in vivo growth of the nasal septum in nonhuman mammalian models; composition and in vitro growth of nasal septal cartilage or chondrocytes; and experience from the surgical repair of unilateral or bilateral facial clefts. PMID- 23022024 TI - Osteonecrosis of the jaw (ONJ) nomenclature--missing the forest for the trees? PMID- 23022026 TI - Histomorphometric and biomechanical analyses of the osseointegration of loaded orthodontic microscrews inserted at different cortical bone thickness sites. AB - OBJECTIVES: The aim of this study was to evaluate the osseointegration of loaded orthodontic microscrews at different cortical bone thickness (CBT) sites. STUDY DESIGN: Forty-eight microscrews were inserted bilaterally in the tibias of 12 beagles, and divided into thick and thin CBT group. After 1, 3, 5, and 7 weeks, the dogs were killed and bone-screw specimens prepared for polyfluorochrome sequential labeling, microscopic computerized tomography (MUCT) analysis, and biomechanical pull-out testing. RESULTS: All MUCT parameters were increased in the thin CBT group, and decreased in the thick CBT group with time passed. Fmax of microscrews in thick CBT sites reached a peak in week 1, but dropped to lowest levels in week 3. Remodeling, apposition, and measured deposition areas of 3 labels were significantly higher in the thin CBT group than in the thick CBT group (P < .05). CONCLUSIONS: Relatively larger CBT is of benefit for primary stability at early time points, whereas thinner CBT is more appropriate for achieving long-term stability with prolonged time. PMID- 23022025 TI - Perception of the esthetic impact of gingival smile on laypersons, dental professionals, and dental students. AB - OBJECTIVE: The aim of this study was to evaluate perceptions regarding esthetic appearance of the smile in cases of orthognathic surgery for correction of maxillary gingival display. STUDY DESIGN: Alterations were made to an extraoral front-view photograph of a gingival smile in normal occlusion by repositioning the maxilla to simulate bone tissue removal and gingival exposure. Images were printed on photographic paper attached to questionnaires distributed among laypersons, professionals, and dental students to evaluate degree of esthetics (n = 150). To evaluate degree of esthetics, an attractiveness-scale was used, with 0 representing hardly attractive, 5 attractive, and 10 very attractive. RESULTS: All of the evaluated groups demonstrated that large gingival extension does not always affect esthetic appearance of the smile. Insufficiently visualized maxillary incisors were considered hardly attractive and received statistically lower scores (P < .05). CONCLUSIONS: According to esthetic parameters, gingiva play important roles in composition of the smile, but only when they are exposed to a small extent. PMID- 23022027 TI - The topological filtration of gamma-structures. AB - In this paper we study gamma-structures filtered by topological genus. gamma structures are a class of RNA pseudoknot structures that plays a key role in the context of polynomial time folding of RNA pseudoknot structures. A gamma structure is composed by specific building blocks, that have topological genus less than or equal to gamma, where composition means concatenation and nesting of such blocks. Our main results are the derivation of a new bivariate generating function for gamma-structures via symbolic methods, the singularity analysis of the solutions and a central limit theorem for the distribution of topological genus in gamma-structures of given length. In our derivation specific bivariate polynomials play a central role. Their coefficients count particular motifs of fixed topological genus and they are of relevance in the context of genus recursion and novel folding algorithms. PMID- 23022028 TI - Scramble competitions can rescue endangered species subject to strong Allee effects. AB - In this article, we study population dynamics of a general two-species discrete time competition model where each species suffers from both strong Allee effects and scramble intra-specific competitions. We focus on how the combinations of the scramble intra-specific and inter-specific competition affect the extinction and coexistence of these two competing species where each species is subject to strong Allee effects. We derive sufficient conditions on the extinction, essential-like extinction and coexistence for such models. One of the most interesting findings is that scramble competitions can promote coexistence of these two species at their high densities. This is supported by the outcome of single species models with strong Allee effects. In addition, we apply theoretical results to a symmetric competition model with strong Allee effects induced by predator saturations where we give a completed study of its possible equilibria and attractors. Numerical simulations are performed to support our results. PMID- 23022029 TI - Symptomatic myositis ossificans following computer navigated total knee replacement: a complication of fixed femoral marker placement. AB - Myositis ossificans is a rare cause of pain following knee arthroplasty. We describe a 72-year-old woman who developed symptomatic early onset myositis ossificans at the femoral marker pin site following navigated knee arthroplasty. PMID- 23022030 TI - Hamstrings and quadriceps muscle contributions to energy generation and dissipation at the knee joint during stance, swing and flight phases of level running. AB - BACKGROUND: Human movements involve the generation and dissipation of mechanical energy at the lower extremity joints. However, it is unclear how the individual knee muscles contribute to the energetics during running. OBJECTIVE: This study aimed to determine how each hamstring and quadricep muscle generates and dissipates energy during stance, swing and flight phases of running. METHODS: A three-dimensional lower extremity musculoskeletal model was used to estimate the energetics of the individual hamstrings (semimembranosus, semitendinosus, biceps femoris long and short-heads) and quadriceps (rectus femoris, vastus medialis, vastus intermedius and vastus lateralis) muscles for a male subject during level running on a treadmill at a speed of 3.96 m/s. RESULTS: Our findings demonstrated that the knee flexors generated energy during stance phase and dissipated energy during swing phase, while the knee extensors dissipated energy during the flexion mode of both stance and swing phases, and generated energy during the extension mode. During flight phase, the knee flexors generated energy during the flight phase transiting from toe-off to swing, while the knee extensors generated energy during the flight phase transiting from swing to heel-strike. CONCLUSION: Individual knee flexors and extensors in the hamstrings and quadriceps play important roles in knee joint energetics, which are necessary for proper execution and stabilization of the stance, swing and flight phases of running. PMID- 23022031 TI - Pre-operative quadriceps strength predicts IKDC2000 scores 6 months after anterior cruciate ligament reconstruction. AB - BACKGROUND: Quadriceps strength deficits are ubiquitous after anterior cruciate ligament (ACL) injury. Deficits prior to surgery can influence knee function post operatively. Inhibition contributes to quadriceps strength deficits after an ACL injury. Body mass index, meniscal injury, and sex influence functional outcomes after ACL reconstruction. The purpose of this study is to examine the relationship of pre-operative quadriceps strength and post-operative knee function and to investigate how other pre-operative factors may influence this relationship. METHODS: After an ACL injury, subjects received pre-operative rehabilitation and performed quadriceps strength testing. Subjects underwent reconstruction and post-operative rehabilitation. Six months after ACL reconstruction, subjects completed the International Knee Documentation Committee 2000 subjective form (IKDC2000). Linear regression models were developed using IKDC2000 scores at 6 months after ACL reconstruction as the dependent variable. RESULTS: Fifty-five subjects had complete pre-operative data and IKDC2000 scores at 6 months after ACL reconstruction. Pre-operative involved quadriceps strength was a significant predictor for IKDC2000 scores 6 months after ACL reconstruction. Sex, meniscal injury, pre-operative BMI, and pre-operative involved quadriceps activation ratio were not significant predictors in the regression model. CONCLUSIONS: Pre-operative quadriceps strength can predict IKDC2000 scores 6 months after ACL reconstruction. Deficits in pre-operative quadriceps strength influence self-reported function 6 months after surgery. Factors that are known to influence quadriceps strength and self-reported outcomes do not influence the relationship between pre-operative quadriceps strength and post-operative IKDC2000 scores. PMID- 23022032 TI - Expression and purification of SfaX(II), a protein involved in regulating adhesion and motility genes in extraintestinal pathogenic Escherichia coli. AB - Pathogenic Escherichia coli strains commonly harbor genes involved in formation of fimbriae, such as the sfa(II) fimbrial gene cluster found in uropathogenic and newborn meningitis isolates. The sfaX(II) gene, located at the distal end of the sfa(II) operon, was recently shown to play a role in controlling virulence related gene expression in extraintestinal pathogenic E. coli (ExPEC). Until now, detailed characterization of the SfaX(II) protein has been hampered by difficulties in obtaining large quantities of soluble protein. By a rational modeling approach, we engineered a Cys70Ser mutation, which successfully improved solubility of the protein. Here, we present the expression, purification, and initial characterization of the recombinant SfaX(IIC70S) mutant. The protein was produced in E. coli BL21 (DE3) cells grown in autoinduction culture media. The plasmid vector harbored DNA encoding the SfaX(IIC70S) protein N-terminally fused with a six histidine (H6) sequence followed by a ZZ tag (a derivative of the Staphylococcus protein A) (H6-ZZ tag). The H6-ZZ tag was cleaved off with Tobacco Etch Virus (TEV) protease and the 166 amino acid full-length homo-dimeric protein was purified using affinity and size-exclusion chromatography. Electrophoretic mobility gel shift assays and atomic force microscopy demonstrated that the protein possesses DNA-binding properties, suggesting that the transcriptional regulatory activity of SfaX(II) can be mediated via direct binding to DNA. PMID- 23022033 TI - Clinical significance of upper-arm cephalic vein patency in autogenous radial cephalic wrist fistulas for hemodialysis. AB - OBJECTIVES: To investigate the significance of upper-arm cephalic veins (UACVs) in radial-cephalic arteriovenous fistulas (RCAVFs), the medical records of 183 patients who had undergone RCAVF creation were reviewed retrospectively. METHODS: The patients were divided into two groups according to the status of the UACV upon preoperative venography: group A of 153 cases (83.6%) with a patent UACV and group B of 30 cases (16.3%) with a stenosed or occluded UACV. The clinical outcomes were compared. RESULT: RCAVFs in group B had a significantly higher maturation failure rate (26.7% vs. 9.8%, p = 0.009) and lower primary/secondary patency rates (log-rank test, p < 0.0001) than those in the group A. The patients in group B required more frequent endovascular intervention to maintain access function (p = 0.002). The most common stenosis site was a draining vein in group B, in comparison to juxta-anastomosis in group A. In the multivariate analyses, the status of the UACV was an independent predictor of the primary and secondary patency rates of RCAVFs (p < 0.005). CONCLUSION: UACV patency has a significant impact on clinical outcome for RCAVFs. When planning an RCAVF placement, venous status including the UACV should be considered. PMID- 23022034 TI - A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. AB - After injury or cytokine stimulation, fibroblasts transdifferentiate into myofibroblasts, contractile cells that secrete extracellular matrix for wound healing and tissue remodeling. Here, a genome-wide screen identified TRPC6, a Ca(2+) channel necessary and sufficient for myofibroblast transformation. TRPC6 overexpression fully activated myofibroblast transformation, while fibroblasts lacking Trpc6 were refractory to transforming growth factor beta (TGF-beta) and angiotensin II-induced transdifferentiation. Trpc6 gene-deleted mice showed impaired dermal and cardiac wound healing after injury. The profibrotic ligands TGF-beta and angiotensin II induced TRPC6 expression through p38 mitogen activated protein kinase (MAPK) serum response factor (SRF) signaling via the TRPC6 promoter. Once induced, TRPC6 activates the Ca(2+)-responsive protein phosphatase calcineurin, which itself induced myofibroblast transdifferentiation. Moreover, inhibition of calcineurin prevented TRPC6-dependent transdifferentiation and dermal wound healing. These results demonstrate an obligate function for TRPC6 and calcineurin in promoting myofibroblast differentiation, suggesting a comprehensive pathway for myofibroblast formation in conjunction with TGF-beta, p38 MAPK, and SRF. PMID- 23022035 TI - p27(Kip1) is a microtubule-associated protein that promotes microtubule polymerization during neuron migration. AB - The migration of cortical interneurons is characterized by extensive morphological changes that result from successive cycles of nucleokinesis and neurite branching. Their molecular bases remain elusive, and the present work describes how p27(Kip1) controls cell-cycle-unrelated signaling pathways to regulate these morphological remodelings. Live imaging reveals that interneurons lacking p27(Kip1) show delayed tangential migration resulting from defects in both nucleokinesis and dynamic branching of the leading process. At the molecular level, p27(Kip1) is a microtubule-associated protein that promotes polymerization of microtubules in extending neurites, thereby contributing to tangential migration. Furthermore, we show that p27(Kip1) controls actomyosin contractions that drive both forward translocation of the nucleus and growth cone splitting. Thus, p27(Kip1) cell-autonomously controls nucleokinesis and neurite branching by regulating both actin and microtubule cytoskeletons. PMID- 23022036 TI - Reproducibility of peroneal motor nerve conduction measurement in older adults. AB - OBJECTIVE: While neuropathy is common in the elderly, nerve conduction (NC) reproducibility in older adults is not well-established. We sought to evaluate intraobserver reproducibility of peroneal motor NC measures in a diverse sample of older adults. METHODS: We measured peroneal motor NC amplitude and velocity in a subset of participants (mean age=82.9+/-2.7, n=62, 50% female, 51.6% black, 35.5% DM) in the Health, Aging, and Body Composition Study. Using coefficients of variation (CVs), intraclass correlation coefficients (ICCs), and Bland Altman Plots, we compared two sets of measurements taken by the same examiner hours apart on the same day. RESULTS: Low CVs (2.15-4.24%) and moderate to high ICCs (0.75-0.99) were observed. No systematic variation was found across measures. Despite small numbers in some subgroups, we found no differences in reproducibility by diabetes, race or study site. CONCLUSION: NC measures have moderate to high intraobsever reproducibility in older adults and are not affected by diabetes, race, or gender. SIGNIFICANCE: These data provide evidence to support use of these measures in aging research. PMID- 23022037 TI - Clinical and electromyographic features of radiation-induced lower cranial neuropathy. AB - OBJECTIVE: Lower cranial neuropathy is a rare complication of radiation therapy for head and neck cancers. Little is known about the clinical and electromyographic features of this complication. METHODS: The records of six patients with radiation-induced lower cranial neuropathy who had undergone electromyographic study were reviewed. All patients were treated with radiation therapy for nasopharyngeal cancer. The total radiation dose was 6996-8280cGy to the nasopharynx and 4680-7020cGy to the neck. The dose per fraction was 180 or 212cGy. RESULTS: Spinal accessory neuropathy occurred in all six patients, glossopharyngeal and vagus neuropathy in five patients, and hypoglossal neuropathy in five patients. The median latency between radiation therapy and lower cranial neuropathy was 61months (range, 20-118months). The lower cranial neuropathies developed insidiously and progressed slowly over a period of years in all patients. Myokymia was seen in three patients and myokymic discharges were demonstrated in five of six patients. CONCLUSIONS: Myokymia and myokymic discharges may be common and typical features of radiation-induced lower cranial neuropathy. SIGNIFICANCE: It is important to make an effort to detect myokymia and myokymic discharges for symptomatic patients suggestive of radiation-induced lower cranial neuropathy. PMID- 23022038 TI - EEG-vigilance regulation during the resting state in obsessive-compulsive disorder. AB - OBJECTIVE: Obsessive compulsive disorder (OCD) has been associated with disturbed sleep-wake cycles and cortical hypermetabolism. However, it still remains unclear whether OCD is associated with a dysregulation of vigilance (i.e. "brain arousal"). VIGALL (Vigilance Algorithm Leipzig) is an EEG-based tool to assess vigilance dynamics. Aim of this study is to test the hypothesis that during resting state less declines to lower vigilance stages are found in unmedicated patients with OCD (n=30) compared to healthy controls (HCs, n=30). METHODS: Fifteen minutes of resting EEG were recorded; preceding sleep duration, nicotine/caffeine consumption and severity of OCD and depressive symptoms were assessed. RESULTS: Significant differences of EEG-vigilance were found for the factor "group" (OCD vs. HC), factor "time" and interaction "group*time" in a repeated measures ANOVA with increased EEG-vigilance in OCD patients. OCD patients showed significantly fewer transitions between EEG-vigilance stages. CONCLUSIONS: In line with findings of disturbed sleep regulation, OCD is associated with altered EEG-vigilance regulation with a failure of declining toward low vigilance stages during rest. SIGNIFICANCE: These results encourage the use of EEG-vigilance regulation for determining subgroups for e.g. studying treatment response and suggest awareness for possible vigilance effects in neuroimaging studies of OCD. PMID- 23022039 TI - Emerging roles of secreted phospholipase A(2) enzymes: an update. AB - Phospholipase A(2) (PLA(2)) enzymes catalyze the hydrolysis of the sn-2 position of glycerophospholipids to produce free fatty acids and lysophospholipids. More than one third of the mammalian PLA(2) enzymes belong to the secreted PLA(2) (sPLA(2)) family, which consists of low molecular mass, Ca(2+)-requiring enzymes with a His-Asp catalytic dyad. Individual sPLA(2) enzymes exhibit unique tissue and cellular localizations and specific enzymatic properties, suggesting their distinct biological roles. The past decade has met a new era of the sPLA(2) research field toward deciphering their in vivo functions by developing several specific tools and methods. These include i) the production of transgenic and knockout mouse lines for several sPLA(2)s, ii) the development of specific analytical tools including the production of large amounts of recombinant sPLA(2) proteins, and iii) applying mass spectrometry lipidomics to unveil their specific enzymatic properties occurring in vivo. It is now obvious that individual sPLA(2)s are involved in diverse biological events through lipid mediator dependent and -independent processes, act redundantly or non-redundantly in the context of physiology and pathophysiology, and may represent potential drug targets or novel bioactive molecules in certain situations. In this review, we will highlight the newest understanding of the biological roles of sPLA(2)s in the past few years. PMID- 23022040 TI - Severe febrile illness in adult hospital admissions in Tanzania: a prospective study in an area of high malaria transmission. AB - Severe febrile illness is a major cause of adult hospital admission in Africa. Studies of non-malarial fever come largely from children or from high HIV prevalence settings. This prospective study of adult admissions with severe febrile illness in a malaria-endemic area with moderate/low HIV prevalence investigated admission diagnosis as well as final diagnosis based on results of investigations. Severe malaria was the admission diagnosis in 148/198 (74.7%) cases. Plasmodium falciparum was identified in 38/188 (20.2%) admissions and 26/198 (13.1%) were bacteraemic, with 13/25 (52%) prescribed empirical antibiotics. HIV was equally common among those with (16/37; 43.2%) and without P. falciparum (50/138; 36.2%) (p=0.44). In 6/22 (27.3%) deaths, blood cultures were positive for a pathogen, with Streptococcus pneumoniae, Escherichia coli and non-Typhi Salmonella predominating. Chest radiography was suspicious for bacterial/mycobacterial disease in 5/22 additional deaths. Systemic inflammatory response syndrome criteria were more sensitive but less specific than WHO severe malaria criteria for predicting mortality. Malaria is overdiagnosed in adults with severe febrile illness and was not associated with mortality in the absence of co-infection in this high-incidence setting. Adults with severe febrile illness should be tested for malaria and HIV using rapid, sensitive tests. Early antibiotic use should be promoted. Improved diagnostics for invasive bacterial disease are needed. PMID- 23022041 TI - Development of a fluorescence polarization binding assay for folate receptor. AB - Folate receptor (FR) has been actively investigated for targeted delivery of therapeutics into cancer cells because this receptor is selectively and highly expressed in carcinomas. Because FR rapidly cycles between the cell surface and cytoplasm, folic acid conjugated to a therapeutic agent can drive targeted therapeutic delivery to cancer cells. We prepared a novel fluorescent ligand Cy5 folate and used it to develop a fluorescence polarization (FP) FR binding assay to determine the binding affinities of FR-targeted molecules. The assay was performed in 96-well microplates using membrane preparations from human KB cells as a source of FR and Cy5 fluorophore-labeled folic acid as a tracer. This high throughput homogeneous assay demonstrates advantages over existing multistep methods in that it minimizes both time and resources spent determining binding affinities. At the optimized conditions, a Z' of 0.64 was achieved in a 96-well format. PMID- 23022042 TI - Amyloid-beta oligomer detection by ELISA in cerebrospinal fluid and brain tissue. AB - Amyloid-beta (Abeta) deposits are important pathological hallmarks of Alzheimer's disease (AD). Abeta aggregates into fibrils; however, the intermediate oligomers are believed to be the most neurotoxic species and, therefore, are of great interest as potential biomarkers. Here, we have developed an enzyme-linked immunosorbent assay (ELISA) specific for Abeta oligomers by using the same capture and (labeled) detection antibody. The ELISA predominantly recognizes relatively small oligomers (10-25 kDa) and not monomers. In brain tissue of APP/PS1 transgenic mice, we found that Abeta oligomer levels increase with age. However, for measurements in human samples, pretreatment to remove human anti mouse antibodies (HAMAs) was required. In HAMA-depleted human hippocampal extracts, the Abeta oligomer concentration was significantly increased in AD compared with nondemented controls. Abeta oligomer levels could also be quantified in pretreated cerebrospinal fluid (CSF) samples; however, no difference was detected between AD and control groups. Our data suggest that levels of small oligomers might not be suitable as biomarkers for AD. In addition, we demonstrate the importance of avoiding HAMA interference in assays to quantify Abeta oligomers in human body fluids. PMID- 23022043 TI - Dispersive solid-phase extraction and immunoassay with internal reference calibration using fatty acid-coated inorganic fluorescent nanoparticles. AB - Dispersive solid-phase extraction (dSPE) using fatty acid-coated Eu2O3 nanoparticles (NPs) was developed, and a direct immunoassay was carried out employing these NPs as support. Secondary antibodies labeled with fluorophore groups were used as reporters, and the intrinsic optical properties of the Eu2O3 NPs were employed as an internal calibration of the detection system. The methodology was optimized for both dSPE-NP amount, sample volume, extraction time, ionic strength, and pH-and immunoassay-immunoreagent concentrations, ionic strength, and incubation time. As proof of concept, the methodology was applied to the bovine serum albumin (BSA)/anti-BSA system, and precision of the method was between 5% and 17% with an IC50 of 100 nM. Then, water samples with high saline content (sea water) were assayed to observe the matrix effect, and average recoveries (n = 3) between 78% and 108% were obtained, demonstrating the reliability of the developed analytical method. Finally, the simultaneous dSPE immunoassay methodology was applied to other compounds with very different chemical characteristics such as an oligonucleotide, the antibiotic sulfamerazine, and the pesticide chlorpyriphos. Although the IC50 values for sulfamerazine were approximately 2400 nM, satisfactory standard curves were obtained. However, poor reproducibility and sensitivity results were obtained for the oligonucleotide and chlorpyriphos preliminary assays. PMID- 23022044 TI - Anti-angiogenic effects of thioridazine involving the FAK-mTOR pathway. AB - Thioridazine is a type of anti-psychotic drug that also includes anti-tumor activity. In this study, we assessed the effects of thioridazine, as a novel anti angiogenic agent, on the suppression of angiogenesis-mediated cell proliferation. Thioridazine was found to inhibit growth in ovarian cancer cells (OVCAR-3 and 2774), but did not possess any inhibitory effects on normal cell types such as HOSE-E6E7, MCF-10A, MRC-5, and BEAS-2B. Thioridazine also suppressed vascular endothelial growth factor (VEGF)-stimulated HUVEC migration in a dose-time dependent manner. We also showed that being treated with thioridazine inhibited VEGF-stimulated proliferation, invasion, and capillary-like structure tube formation in vitro. Thioridazine suppressed phosphorylation of the signaling regulators downstream of the focal adhesion kinase (FAK) through alphavbeta3 integrin, which also include Akt, phosphoinositide-dependent protein kinase 1 (PDK-1), mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), but had no effect on VEGF-stimulated extracellular signal-regulated kinase (ERK) phosphorylation. We found the molecular mechanism of thioridazine to be a novel anti-angiogenic protein. These results provide evidence for the regulation of endothelial cell functions that are relevant to angiogenesis through the suppression of the alphavbeta3/FAK/mTOR signaling pathway. PMID- 23022045 TI - An exploratory study of sunitinib in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive metastatic breast cancer. AB - BACKGROUND: This exploratory study assessed the safety, pharmacokinetics, and antitumor activity of sunitinib combined with docetaxel and trastuzumab. METHODS: Patients with unresectable, locally recurrent or metastatic human epidermal growth factor receptor 2 (HER2)+ breast cancer received sunitinib plus docetaxel and trastuzumab. Sunitinib was administered at 37.5 mg/day for 2 weeks on treatment followed by 1 week off (Schedule 2/1). The primary endpoint was safety; secondary endpoints included pharmacokinetics and antitumor activity. RESULTS: Twenty-six patients enrolled; 24 received at least one dose of sunitinib plus docetaxel and trastuzumab, and one patient received one dose of docetaxel and trastuzumab only. These 25 treated patients were evaluable for safety. Twenty three patients discontinued the study, primarily due to disease progression. The planned dose of sunitinib was maintained in 10 patients and reduced at least once to 25 mg/day in 14 patients. The most common grade 3/4 non-hematologic adverse events were fatigue/asthenia (28%), diarrhea (16%), stomatitis (12%), vomiting (8%) and dyspnea (8%). Neutropenia was reported in all 24 evaluable patients; most events were grade 4. Three grade 1-3 cardiac adverse events occurred. Sunitinib and docetaxel levels were consistent with known single-agent levels, suggesting that there were no clinically relevant drug-drug interactions. Of 22 evaluable patients, 16 (73%) experienced an objective response (all confirmed partial responses). CONCLUSIONS: Sunitinib combined with docetaxel and trastuzumab had an acceptable toxicity profile and showed preliminary antitumor activity as first-line treatment for metastatic HER2+ breast cancer. PMID- 23022046 TI - Predictors of axillary lymph node metastases in early breast cancer and their applicability in clinical practice. AB - PURPOSE: Lymph node involvement is the most important prognostic factor in breast cancer. It is a multifactorial event determined by patient and tumour characteristics. The purpose of this study was to determine clinical and pathological factors predictive for axillary lymph node metastasis (ALNM) in patients with early breast cancer and to build a model to portend lymph node involvement. METHODS: We evaluated 1300 consecutive patients surgically treated in our institution (2007-2009) for cT1-T2 invasive breast cancer. The patient and tumour characteristics evaluated included: age at diagnosis, number of foci, histologic grade, location, tumour size, histologic subtype, lymphovascular invasion (LVI), estrogen-receptor (ER), progesterone-receptor (PR) and Her-2 status. Univariate and multivariate analyses were performed. Factors significantly associated with ALNM by univariate analysis plus histologic subtype were included in the multivariate analysis. RESULTS: By univariate analysis, the incidence of ALNM was significantly associated with the presence of LVI (P < 0.0001), larger tumour size (P < 0.0001), higher histologic grade (P < 0.0001), retroareolar or lateral location in the breast (P < 0.0001), multiple foci (P = 0.0002) and in patients who underwent an axillary lymph node dissection. We found no effect of age, ER/PR nor HER-2 status. By multivariate analysis, ALNM was significantly associated with the presence of LVI (P < 0.0001), larger tumour size (P < 0.0001), axillary lymph node dissection (P = 0.0003), retroareolar and lateral tumour location in the breast (P = 0.0019) and the presence of multiple foci (P = 0.0155). CONCLUSIONS: LVI and tumour size emerged as the most powerful independent predictors of ALNM, followed by the location of the tumour in the breast and the presence of multiple foci. PMID- 23022047 TI - Ciliary neurotrophic factor activates NF-kappaB to enhance mitochondrial bioenergetics and prevent neuropathy in sensory neurons of streptozotocin-induced diabetic rodents. AB - Diabetes causes mitochondrial dysfunction in sensory neurons that may contribute to peripheral neuropathy. Ciliary neurotrophic factor (CNTF) promotes sensory neuron survival and axon regeneration and prevents axonal dwindling, nerve conduction deficits and thermal hypoalgesia in diabetic rats. In this study, we tested the hypothesis that CNTF protects sensory neuron function during diabetes through normalization of impaired mitochondrial bioenergetics. In addition, we investigated whether the NF-kappaB signal transduction pathway was mobilized by CNTF. Neurite outgrowth of sensory neurons derived from streptozotocin (STZ) induced diabetic rats was reduced compared to neurons from control rats and exposure to CNTF for 24 h enhanced neurite outgrowth. CNTF also activated NF kappaB, as assessed by Western blotting for the NF-kappaB p50 subunit and reporter assays for NF-kappaB promoter activity. Conversely, blockade of NF kappaB signaling using SN50 peptide inhibited CNTF-mediated neurite outgrowth. Studies in mice with STZ-induced diabetes demonstrated that systemic therapy with CNTF prevented functional indices of peripheral neuropathy along with deficiencies in dorsal root ganglion (DRG) NF-kappaB p50 expression and DNA binding activity. DRG neurons derived from STZ-diabetic mice also exhibited deficiencies in maximal oxygen consumption rate and associated spare respiratory capacity that were corrected by exposure to CNTF for 24 h in an NF-kappaB dependent manner. We propose that the ability of CNTF to enhance axon regeneration and protect peripheral nerve from structural and functional indices of diabetic peripheral neuropathy is associated with targeting of mitochondrial function, in part via NF-kappaB activation, and improvement of cellular bioenergetics. PMID- 23022049 TI - Use of cardiac septal occluder device on upper GI anastomotic dehiscences: a new endoscopic approach (with video). PMID- 23022048 TI - Inhibition of GABA synthesis in the prefrontal cortex increases locomotor activity but does not affect attention in the 5-choice serial reaction time task. AB - Attention deficits are a core cognitive symptom of schizophrenia; the neuropathology underlying these deficits is not known. Attention is regulated, at least in part, by the prefrontal cortex (PFC), a brain area in which pathology of gamma-aminobutyric acid (GABA) neurons has been consistently observed in post mortem analysis of the brains of people with schizophrenia. Specifically, expression of the 67-kD isoform of the GABA synthesis enzyme glutamic acid decarboxylase (GAD67) is reduced in parvalbumin-containing fast-spiking GABA interneurons. Thus it is hypothesized that reduced cortical GABA synthesis and release may contribute to the attention deficits in schizophrenia. Here the effect of reducing cortical GABA synthesis with l-allylglycine (LAG) on attention was tested using three different versions of the 5-choice serial reaction time task (5CSRTT). Because 5CSRTT performance can be affected by locomotor activity, we also measured this behavior in an open field. Finally, the expression of Fos protein was used as an indirect measure of reduced GABA synthesis. Intra-cortical LAG (10 MUg/0.5 MUl/side) infusions increased Fos expression and resulted in hyperactivity in the open field. Intra-cortical LAG infusions did not affect attention in any version of the 5CSRTT. These results suggest that a general decrease in GABA synthesis is not sufficient to cause attention deficits. It remains to be tested whether a selective decrease in GABA synthesis in parvalbumin-containing GABA neurons could cause attention deficits. Decreased cortical GABA synthesis did increase locomotor activity; this may reflect the positive symptoms of schizophrenia. PMID- 23022050 TI - Clinical features of pharyngeal intraepithelial neoplasias and outcomes of treatment by endoscopic submucosal dissection. AB - BACKGROUND: Endoscopic detection of superficial squamous epithelial lesions of the pharynx has increased. OBJECTIVE: To clarify the association between macroscopic and histologic characteristics of intraepithelial pharyngeal neoplasias, and to evaluate the effectiveness of endoscopic submucosal dissection (ESD) for their treatment. DESIGN: Retrospective analysis of the features of high grade dysplasia or carcinoma in situ (HGD/CIS) versus low-grade dysplasia (LGD) and of ESD-based outcomes. SETTING: Endoscopy department at a university hospital. PATIENTS: Fifty-one patients with 66 lesions treated by ESD from November 2007 to March 2011. RESULTS: Primary hypopharyngeal lesions were significantly more frequent in HGD/CIS than in LGD (54.1% vs 20.7%, P = .011), and oropharyngeal lesions were significantly less frequent in HGD/CIS (45.9% vs 79.3%, P = .011). HGD/CIS lesions were significantly larger than LGD lesions (median 8 mm vs 4 mm, P < .01). Morphologically, type 0-IIa was significantly more frequent in HGD/CIS lesions than in LGD lesions (37.8% vs 3.4%, P < .001), and type 0-IIb was significantly less frequent in HGD/CIS lesions (59.5% vs 96.6%, P < .001). The type IV intraepithelial papillary capillary loop pattern was significantly less frequent in HGD/CIS lesions than in LGD lesions (27.0% vs 55.2%, P = .025), and type V-2 was significantly more frequent in HGD/CIS lesions (18.9% vs 0%, P = .015). The en bloc resection rate was 97%. No serious complications occurred. There were no recurrent or metachronous tumors in the 41 patients followed for more than 1 year (median follow-up 27 months). LIMITATIONS: Retrospective design and single-center study. CONCLUSIONS: HGD/CIS and LGD differ in various clinical features. ESD appears to be an effective treatment for pharyngeal intraepithelial neoplasias. PMID- 23022051 TI - Near-infrared-labeled peptide multimer functions as phage mimic for high affinity, specific targeting of colonic adenomas in vivo (with videos). AB - BACKGROUND: Fluorescent-labeled peptides are being developed to improve the endoscopic detection of colonic dysplasia. OBJECTIVE: To demonstrate a near infrared peptide multimer that functions as a phage mimic for in vivo detection of colonic adenomas. DESIGN: A peptide multimer was synthesized by using trilysine as a dendritic wedge to mimic the presentation of peptides on phage, and all peptides, including the multimer, were fluorescent-labeled with Cy5.5. SETTING: Small-animal imaging facility. ANIMAL SUBJECTS: Genetically engineered CPC;Apc mice that spontaneously develop colonic adenomas. INTERVENTION: Near infrared-labeled AKPGYLS peptide multimer was administered topically into the distal colons of the mice, and endoscopic images of adenomas were captured. Fluorescence intensities were quantified by target-to-background (T/B) ratios, and adenoma dimensions were measured with calipers after imaging. Validation of specific peptide binding was performed on cryosectioned specimens and cells by using confocal microscopy and flow cytometry. MAIN OUTCOME MEASUREMENTS: Fluorescence T/B ratios from colonic adenomas and adjacent normal-appearing mucosa. RESULTS: AKP-multimer, monomer, trilysine core, and Cy5.5 resulted in mean (+/- SD) T/B ratios of 3.85 +/- 0.25, 2.21 +/- 0.13, 1.56 +/- 0.12, and 1.19 +/- 0.11, respectively, P < .01 on in vivo imaging. Peptide multimer showed higher contrast and greater specificity for dysplastic crypts as compared with other probes. Peptide multimer demonstrated significantly greater binding to HT29 cells on flow cytometry and fluorescence microscopy in comparison to monomer and trilysine core. A binding affinity of 6.4 nm/L and time constant of 0.1136 minutes(-1) (8.8 minutes) was measured for multimer. LIMITATIONS: Only distal colonic adenomas were imaged. CONCLUSION: Peptide multimers combine strengths of multiple individual peptides to enhance binding interactions and demonstrate significantly higher specificity and affinity for tumor targets. PMID- 23022052 TI - A novel spirocyclic tropanyl-Delta2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake. AB - A group of spirocyclic tropanyl-Delta(2)-isoxazolines was synthesized exploiting the 1,3-dipolar cycloaddition of nitrile oxides to olefins. Their interaction with the dopamine and serotonin transporters (DAT and SERT, respectively) was evaluated through binding experiments. The majority of the compounds had no inhibitory effects (IC(50) >> 10 MUM), while some had an IC(50) value in the range 5-10 MUM (8a-c, 10b and 11c on DAT, 12b on SERT). Unexpectedly, one of the tertiary amines under investigation, that is 3'-methoxy-8-methyl-spiro{8 azabicyclo[3.2.1]octane-3,5'(4'H)-isoxazole 7a, was able to enhance at a concentration of 10 MUM both [(3)H]citalopram and [(3)H]paroxetine binding to SERT in rat brain homogenate (up to 25%, due to an increase of B(max)) and [(3)H]serotonin uptake (up to 30%) in cortical synaptosomes. This peculiar pharmacological profile of 7a suggests it binds to an allosteric site on SERT, and positions derivative 7a as a very useful tool to investigate SERT machinery. PMID- 23022053 TI - Synthesis and biological evaluation of a series of podophyllotoxins derivatives as a class of potent antitubulin agents. AB - A series of eight novel podophyllotoxin derivatives were designed, synthesized and evaluated for biological activities. The antiproliferative activities were tested against a panel of human cancer cell lines (K562, SGC, Hela and HepG) and the inhibition of tubulin polymerization was also evaluated. Compound 8e displayed significant antiproliferative activities for all four cell lines and strong levels of tubulin polymerization inhibition effect. Combined with cell apoptosis and cell cycle analysis, it demonstrated that compound 3e that effectively interfere with tubulin dynamics prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually dose dependent apoptosis. All experimental measurements were also supported by molecular docking simulations of colchicine binding site, which revealed the governing forces for the binding behavior and a good relationship with anti-tubulin activity and antiproliferative activities. The synthesis and biological studies provided an interesting new class of antitubulin agents for development of lead compounds and also a direction for further structure modification to obtain more potent anti-cancer drugs. PMID- 23022054 TI - Aj-rel and Aj-p105, two evolutionary conserved NF-kappaB homologues in sea cucumber (Apostichopus japonicus) and their involvement in LPS induced immunity. AB - The nuclear factor kappaB (NF-kappaB) has been evolutionary conserved from insects to mammals and plays a major regulatory role in the initiation of physiological responses. In this study, we identified and characterized a primitive and functional NF-kappaB pathway active in the immune defence of the sea cucumber (Apostichopus japonicus). The ancient NF-kappaB homologues, Aj-rel and Aj-p105, share numerous signature motifs with their vertebrate orthologues, notably the Rel Homology Domain, Rel Protein Signature DNA Binding Motif, Nuclear Localization Signal and the Ankyrin Repeats for Aj-p105. Phylogenetic analyses indicate that these homologues belong to class I and II of NF-kappaB respectively. We examined the dimerization of Aj-rel and Aj-p105 and our results demonstrated that Aj-rel forms heterdimers with Aj-p105 and the degradation product of Aj-p105, namely Aj-p50. We further observed that LPS stimulation led to the degradation of Aj-p105 and the nuclear translocation of Aj-rel and Aj-p50. Taken together, our data indicate that the NF-kappaB signaling cascade is active in sea cucumber and plays a crucial role in regulating their immune defence. Our results increase the available information on sea cucumber immunity and provide new information for use in the study of the comparative and evolutionary aspects of immunity. PMID- 23022055 TI - A manganese superoxide dismutase with potent antioxidant activity identified from Oplegnathus fasciatus: genomic structure and transcriptional characterization. AB - In this study, we describe the identification and characterization of manganese superoxide dismutase, an important antioxidant enzyme acting as the chief reactive oxygen species (ROS) scavenger, from rock bream Oplegnathus fasciatus (Of-mMnSOD) at genomic- and transcriptional-levels as well as the biological activity of recombinant protein. The Of-mMnSOD protein portrayed distinct MnSOD family features including signature motifs, metal association sites and the typical active site topology. It was also predicted to be localized in mitochondrial matrix. The Of-mMnSOD had a quinquepartite genome organization encompassing five exons interrupted by four introns. Comparison of its sequence and gene structure with that of other lineages emphasized its strong conservation among different vertebrates. The Of-mMnSOD was ubiquitously transcribed in different rock bream tissues with higher levels in blood cells and metabolically active tissues. Transcription of Of-mMnSOD was kinetically modulated in response to investigational challenges using mitogens (lipopolysaccharide and poly I:C) and live-pathogens (Edwardsiella tarda and rock bream irido virus) in blood cells and liver tissue. The purified recombinant Of-mMnSOD possessed potential antioxidant capacity and actively survived over a range of pH (7.5-11) and temperature (15-40 degrees C) conditions. Collectively, findings of this study suggest that Of-mMnSOD combats against oxidative stress and cellular damages induced by mitogen/pathogen-mediated inflammation, by detoxifying harmful ROS (O(2)(?-)) in rock bream. PMID- 23022056 TI - Factors favoring a degradation or an improvement in activities of daily living (ADL) performance among nursing home (NH) residents: a survival analysis. AB - Different factors influence ADL performance among nursing home (NH) residents in long term care. The aim was to investigate which factors were associated with a significant change of ADL performance in NH residents, and whether or not these factors were gender-specific. The design was a survival analysis. The 10,199 participants resided in ninety Swiss NHs. Their ADL performance had been assessed by the Resident Assessment Instrument Minimum Data Set (RAI-MDS) in the period from 1997 to 2007. Relevant change in ADL performance was defined as 2 levels of change on the ADL scale between two successive assessments. The occurrence of either an improvement or a degradation of the ADL status) was analyzed using the Cox proportional hazard model. The analysis included a total of 10,199 NH residents. Each resident received between 2 and 23 assessments. Poor balance, incontinence, impaired cognition, a low BMI, impaired vision, no daily contact with proxies, impaired hearing and the presence of depression were, by hierarchical order, significant risk factors for NH residents to experience a degradation of ADL performance. Residents, who were incontinent, cognitively impaired or had a high BMI were significantly less likely to improve their ADL abilities. Male residents with cancer were prone to see their ADL improve. The year of NH entry was significantly associated with either degradation or improvement of ADL performance. Measures aiming at improving balance and continence, promoting physical activity, providing appropriate nourishment and cognitive enhancement are important for ADL performance in NH residents. PMID- 23022057 TI - Anxiety disorders and its risk factors among the Sichuan empty-nest older adults: a cross-sectional study. AB - OBJECTIVE: The goal of this study was to determine the prevalence and correlates of anxiety disorders among empty-nest older adults in Sichuan Province, China. METHODS: The study population consisted of 352 subjects over the age of 60 who completed the Self-Rating Anxiety Scale (SAS), the Geriatric Depression Scale Short Form (GDS-SF), the University of California, Los Angeles, Loneliness Scale (UCLA-LS), and the Mini-Mental State Examination (MMSE) questionnaires. The socio demographic information, information on the subjects' general health, and their level of concern about health problems were obtained from self-reports. RESULTS: In the study population, 30.11% of the empty-nest older adults showed anxiety related symptoms or anxiety disorders, with a standardized score of 44.53 +/- 11.01. The levels of anxiety were significantly different in terms of the patients' gender, educational level, occupation, residence, marital status, and income, but not in terms of their age. Patient anxiety had a significantly positive association with depression and loneliness but had a significantly negative association with the MMSE scores. Multiple regression analysis revealed that patients with depression, loneliness, and cognitive impairment, as well as patients who were female, living in rural areas, or living alone were at risk for anxiety disorders. CONCLUSIONS: Anxiety prevails among the empty-nest older adults in Sichuan Province and is mainly associated with health-related characteristics. Physicians should give special attention to older adults with depression, loneliness, and cognitive impairments, especially to women who live alone in rural areas. PMID- 23022059 TI - Influenza B infection complicated by patent foramen ovale and high altitude pulmonary edema. AB - A 34-year-old man presented to a clinic at a ski resort in the Rocky Mountains at 9000 feet (2743 m) with shortness of breath and fatigue, a few days after arriving to altitude from sea level. He was found to be hypoxic with radiographic findings consistent with high altitude pulmonary edema (HAPE). He was treated with high flow oxygen, steroids, and calcium channel blockers and transferred to a lower altitude tertiary care hospital for intensive care unit monitoring and further treatment. During his diagnostic evaluation, he was found to have both a patent foramen ovale and influenza B infection. While patent foramen ovale is a known risk factor for HAPE, there is also some evidence that upper respiratory tract infections in general and influenza in particular may also be risk factors for HAPE. The 2 diseases may share an underlying pulmonary pathophysiology, as both cause noncardiogenic pulmonary edema and alveolar hemorrhage. We report an unusual case of influenza B virus compounded by previously undiagnosed patent foramen ovale, travel to high altitude, and subsequent development of HAPE. PMID- 23022058 TI - Musculoskeletal pain and its treatment among older home-dwelling people: ten-year changes in two Finnish birth cohorts. AB - The purpose of this study is to evaluate the prevalence of musculoskeletal pain and the use of analgesics in two random cohorts of home-dwelling older people 10 years apart (1999 (N = 2044) and 2009 (N = 1610)) in Helsinki, Finland, and to explore which patients characteristics are associated with potential undertreatment or overtreatment of pain. In 1999, the prevalence of daily joint pain interfering with functioning was 16.4% and that of back pain 13.9% among 75 85-year-old people, the respective figures being 21.9% and 17.1% in 2009 (p < 0.001). The proportion of those patients suffering from joint pain and using prescribed analgesics for that was 35.5% in 1999 and 41.5% in 2009 (p < 0.001). The corresponding figures for patients suffering from back pain with analgesics were 38.2% and 48.2% (p < 0.001), respectively. In 2009, 66.1% suffered from any musculoskeletal pain and 28.7% of them were prescribed analgesics, the figures being more frequent among women than men. In addition to higher age, female gender, and painful conditions, also psychiatric symptoms and dizziness tended to be independently associated with analgesic prescriptions. Among persons not reporting pain (N = 545) psychiatric symptoms were overrepresented in the group using prescribed analgesics (22.4% vs. 8.1%, p < 0.05). In conclusion, musculoskeletal pain is still clearly undertreated, but the coverage has increased during 10 years. In addition to pain, several patient characteristics, functioning and psychiatric symptoms, especially, were associated with analgesic prescriptions. PMID- 23022060 TI - Possible association with amphetamine usage and development of high altitude pulmonary edema. PMID- 23022062 TI - Posttraumatic stress disorder. AB - Children are exposed to a variety of traumatic experiences, and each child is unique in his or her response to that trauma. The most common psychiatric disorder that develops after exposure to trauma is posttraumatic stress disorder (PTSD). This article will help pediatric nurse practitioners understand PTSD in terms of diagnosis, epidemiology, risk factors, comorbidity, and treatment. DSM IV diagnostic criteria will be discussed, along with modifications to consider when evaluating very young children for PTSD. Implications for practice will be discussed along with suggested questions to ask parents and children to assess for exposure to trauma. PMID- 23022061 TI - An Arg-rich putative prebiotic protein is as stable as its Lys-rich variant. AB - An Arg-rich peptide called RIA7; sequence ac-ARAAAAAIRAIAAIIRAGGY-am, tetramerizes to form a well folded, four helix X-bundle protein. The Arg side chains are solvent exposed and the hydrophobic core is composed of the side chains from some Alas, all the Iles and the C-terminal Tyr. Since Gly, Ala and Ile, and in lesser amounts Arg and Tyr have been reported to form under putative prebiotic Earth conditions, it is plausible that RIA7-like peptides might have formed on the primitive Earth and interacted with RNAs. The interaction of RIA7 with two RNAs was tested and the formation of insoluble aggregates was observed. These results contrast with previous studies of a Lys-rich variant, called KIA7, which promotes the cleavage of RNAs. Their close structural similarity makes RIA7 and KIA7 an excellent system to compare the relative contributions of Arg and Lys to protein conformational stability. NMR-monitored hydrogen/deuterium exchange measurements and CD-monitored thermal denaturation experiments performed at different peptide and salt concentrations reveal that the conformational stabilities of RIA7 and KIA7 are practically the same. This finding has relevance for protein engineering as Lys is frequently replaced by Arg to improve ligand binding and membrane association and penetration. PMID- 23022063 TI - The information needs of North American parents of children with asthma: a state of-the-science review of the literature. AB - INTRODUCTION: Asthma, the most common chronic disease of childhood, presents diverse challenges to parents who are responsible for its management. Parents must be informed regarding symptom recognition, medications, prevention, and treatment to effectively minimize acute exacerbations and asthma sequela. Current approaches to asthma education do not address the vast range of information needs of parents, and few studies explicitly identify parental information needs in a comprehensive manner. To address this gap and to create a parental information needs taxonomy, a "state-of-the-science" review of the literature was conducted. METHOD: Three electronic databases were searched and articles were screened according to pre-established inclusion criteria. RESULTS: Of 164 articles retrieved, 11 articles met the inclusion criteria and were included in the review. DISCUSSION: Parental information needs can be classified in the following categories: asthma basics, treatment modalities, coping, and medical expectations. This information needs taxonomy may help practitioners better address the information needs of parents of children with asthma. PMID- 23022064 TI - Ghost loci imply Hox and ParaHox existence in the last common ancestor of animals. AB - Hox genes are renowned for patterning animal development, with widespread roles in developmental gene regulation. Despite this importance, their evolutionary origin remains obscure, due to absence of Hox genes (and their evolutionary sisters, the ParaHox genes) from basal lineages and because the phylogenies of these genes are poorly resolved. This has led to debate about whether Hox and ParaHox genes originated coincidently with the origin of animals or instead evolved after the divergence of the earliest animal lineages. Here we use genomic synteny and Monte Carlo-based simulations to resolve Hox/ParaHox origins, our approach being independent of poorly resolved homeodomain phylogenies and better able to accommodate gene loss. We show Trox-2 of placozoans occupies a ParaHox locus. In addition, a separate locus sharing synteny and hence homology with human Hox loci exists in the placozoan genome, but without a Hox-like gene in it. We call this second locus a "ghost" Hox locus, because it is homologous to the human Hox loci, but does not itself contain a Hox gene. Extending our approach to sponges, we discover distinct ghost Hox and ParaHox loci. Thus, distinct Hox and ParaHox loci were present in the last common ancestor of all living animal lineages. PMID- 23022065 TI - Promiscuous honey bee queens increase colony productivity by suppressing worker selfishness. AB - Queen monogamy is ancestral among bees, ants, and wasps (Order Hymenoptera), and the close relatedness that it generates within colonies is considered key for the evolution of eusociality in these lineages. Paradoxically, queens of several eusocial species are extremely promiscuous, a derived behavior that decreases relatedness among workers and fitness gained from rearing siblings but benefits queens by enhancing colony productivity and inducing workers to rear queens' sons instead of less related worker-derived males. Selection for promiscuity would be especially strong if productivity in a singly inseminated queen's colony declined because selfish workers invested in personal reproduction at the expense of performing tasks that contribute to colony productivity. We show in honey bees that workers' ovaries are more developed when queens are singly rather than multiply inseminated and that increasing ovary activation is coupled with reductions in task performance by workers and colony-wide rates of foraging and waggle-dance recruitment. Increased investment in reproductive physiology by selfish workers might result from greater incentive for them to favor worker derived males or because low mating frequency signals a queen's diminished quality or future fecundity. Either possibility fosters selection for queen promiscuity, revealing a novel benefit of it for eusocial insects. PMID- 23022066 TI - RhoGEF and positioning of rappaport-like furrows in the early Drosophila embryo. AB - Early Drosophila embryogenesis is characterized by shifting from astral microtubule-based to central spindle-based positioning of cleavage furrows. Before cellularization, astral microtubules determine metaphase furrow position by producing Rappaport-like furrows, which encompass rather than bisect the spindle. Their positioning is explained by our finding that the conserved central spindle components centralspindlin (mKLP1 and RacGAP50C), Polo, and Fascetto (Prc1) localize to the astral microtubule overlap region. These components and the chromosomal passenger complex localize to the central spindle, though no furrow forms there. We identify the maternally supplied RhoGEF2 as a key factor in metaphase furrow positioning. Unlike the zygotic, central spindle-localized RhoGEF (Pebble), RhoGEF2 localizes to metaphase furrows, a function distinct from RhoGEF/Pebble and likely due to the absence of a RacGAP50C binding domain. Accordingly, we find that ectopic activation of Rho GTPase generates furrows perpendicular to the central spindle during syncytial divisions. Whereas metaphase furrow formation is myosin independent, these ectopic furrows, like conventional furrows, require myosin as well as microtubules. These studies demonstrate that early Drosophila embryogenesis is primed to form furrows at either overlapping astral microtubules or the central spindle. We propose that the shift to the latter is driven by a corresponding shift from RhoGEF2 to Pebble in controlling furrow formation. PMID- 23022067 TI - Two dopaminergic neurons signal to the dorsal fan-shaped body to promote wakefulness in Drosophila. AB - BACKGROUND: The neuronal circuitry underlying sleep is poorly understood. Although dopamine (DA) is thought to play a key role in sleep/wake regulation, the identities of the individual DA neurons and their downstream targets required for this process are unknown. RESULTS: Here, we identify a DA neuron in each PPL1 cluster that promotes wakefulness in Drosophila. Imaging data suggest that the activity of these neurons is increased during wakefulness, consistent with a role in promoting arousal. Strikingly, these neurons project to the dorsal fan-shaped body, which has previously been shown to promote sleep. The reduced sleep caused by activation of DA neurons can be blocked by loss of DopR, and restoration of DopR expression in the fan-shaped body can rescue the wake-promoting effects of DA in a DopR mutant background. CONCLUSIONS: These experiments define a novel arousal circuit at the single-cell level. Because the dorsal fan-shaped body promotes sleep, these data provide a key link between wake and sleep circuits. Furthermore, these findings suggest that inhibition of sleep centers via monoaminergic signaling is an evolutionarily conserved mechanism to promote arousal. PMID- 23022068 TI - Increasing internodal distance in myelinated nerves accelerates nerve conduction to a flat maximum. AB - Predictions that conduction velocities are sensitive to the distance between nodes of Ranvier in myelinated axons have implications for nervous system function during growth and repair. Internodal lengths defined by Schwann cells in hindlimb nerves, for example, can undergo a 4-fold increase during mouse development, and regenerated nerves have internodes that are uniformly short. Nevertheless, the influence of internodal length on conduction speed has limited experimental support. Here, we examined this problem in mice expressing a mutant version of periaxin, a protein required for Schwann cell elongation. Importantly, elongation of mutant Schwann cells was retarded without significant derangements to myelination or axon caliber. In young mice with short mutant Schwann cells, nerve conduction velocity was reduced and motor function was impaired. This demonstrates a functional relationship between internodal distance and conduction speed. Moreover, as internodes lengthened during postnatal growth, conduction velocities recovered to normal values and mutant mice exhibited normal motor and sensory behavior. This restoration of function confirms a further prediction by Huxley and Stampfli that conduction speeds should increase as internodal distances lengthen until a "flat maximum" is reached, beyond which no further gains in conduction velocity accrue. PMID- 23022070 TI - Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials. AB - OBJECTIVE: To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with pyridoxine-dependent epilepsy (PDE) caused by antiquitin (ATQ) deficiency. METHODS: In this observational study, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring. Biochemical outcomes were evaluated using pipecolic acid and alpha-aminoadipic semialdehyde (AASA) levels in body fluids; developmental/cognitive outcomes were evaluated using age appropriate tests and parental observations. RESULTS: Lysine restriction was well tolerated with good compliance; no adverse events were reported. Reduction in biomarker levels (measurement of the last value before and first value after initiation of dietary lysine restriction) ranged from 20 to 67% for plasma pipecolic acid, 13 to 72% for urinary AASA, 45% for plasma AASA and 42% for plasma P6C. For the 1 patient in whom data were available and who showed clinical deterioration upon interruption of diet, cerebrospinal fluid levels decreased by 87.2% for pipecolic acid and 81.7% for AASA. Improvement in age-appropriate skills was observed in 4 out of 5 patients showing pre-diet delays, and seizure control was maintained or improved in 6 out 7 children. CONCLUSIONS: This observational study provides Level 4 evidence that lysine restriction is well tolerated with significant decrease of potentially neurotoxic biomarkers in different body compartments, and with the potential to improve developmental outcomes in children with PDE caused by ATQ deficiency. To generate a strong level of evidence before this potentially burdensome dietary therapy becomes the mainstay treatment, we have established: an international PDE consortium to conduct future studies with an all-inclusive integrated study design; a website containing up-to-date information on PDE; a methodological toolbox; and an online registry to facilitate the participation of interested physicians, scientists, and families in PDE research. PMID- 23022069 TI - Performance of urinary and gene expression biomarkers in detecting the nephrotoxic effects of melamine and cyanuric acid following diverse scenarios of co-exposure. AB - Although standard nephrotoxicity assessments primarily detect impaired renal function, KIM-1, clusterin, NGAL, osteopontin and TIMP-1 were recently identified biomarkers proposed to indicate earlier perturbations in renal integrity. The recent adulteration of infant and pet food with melamine (MEL) and structurally related compounds revealed that co-ingestion of MEL and cyanuric acid (CYA) could form melamine-cyanurate crystals which obstruct renal tubules and induce acute renal failure. This study concurrently evaluated the ability of multiplexed urinary biomarker immunoassays and biomarker gene expression analysis to detect nephrotoxicity in F344 rats co-administered 60ppm each of MEL and CYA in feed or via gavage for 28days. The biomarkers were also evaluated for the ability to differentiate the effects of the compounds when co-administered using diverse dosing schedules (i.e., consecutive vs. staggered gavage) and dosing matrixes (i.e., feed vs. gavage). Our results illustrate the ability of both methods to detect and differentiate the severity of adverse effects in the staggered and consecutive gavage groups at much lower doses than previously observed in animals co-exposed to the compounds in feed. We also demonstrate that these urinary biomarkers outperform traditional diagnostic methods and represent a powerful, non-invasive indicator of chemical-induced nephrotoxicity prior to the onset of renal dysfunction. PMID- 23022071 TI - The methylmalonic aciduria related genes, Mmaa, Mmab, and Mut, are broadly expressed in placental and embryonic tissues during mouse organogenesis. AB - Organ-specific birth defects are seen in patients with some inborn errors of vitamin B(12) metabolism. To determine whether three mouse genes, whose human counterparts are associated with isolated methylmalonic aciduria (Mmaa, Mmab and Mut), show tissue-specific expression during organogenesis, we used in situ hybridization to characterize their pattern of expression in wild type embryos and placentas at embryonic days (E) E10.5, E11.5 and E12.5. These three genes are ubiquitously expressed in the placenta and in embryos at E10.5. At E11.5, we observed tissue specific expression patterns for these three genes in lung, head and Rathke's pouch. At E12.5, although Mut expression was ubiquitous, we found cell-type specific expression patterns for Mmaa and Mmab in the developing craniofacial region, the lung, the liver, and the gut. These results suggest that during organogenesis the proteins encoded by these three genes may interact in only a subset of cells. PMID- 23022072 TI - Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: a nationwide survey in Japan. AB - Hematopoietic stem cell transplantation (HSCT) has not been indicated for patients with mucopolysaccharidosis II (MPS II, Hunter syndrome), while it is indicated for mucopolysaccharidosis I (MPS I) patients <2 years of age and an intelligence quotient (IQ) of >= 70. Even after the approval of enzyme replacement therapy for both of MPS I and II, HSCT is still indicated for patients with MPS I severe form (Hurler syndrome). To evaluate the efficacy and benefit of HSCT in MPS II patients, we carried out a nationwide retrospective study in Japan. Activities of daily living (ADL), IQ, brain magnetic resonance image (MRI) lesions, cardiac valvular regurgitation, and urinary glycosaminoglycan (GAG) were analyzed at baseline and at the most recent visit. We also performed a questionnaire analysis about ADL for an HSCT-treated cohort and an untreated cohort (natural history). Records of 21 patients were collected from eight hospitals. The follow-up period in the retrospective study was 9.6 +/- 3.5 years. ADL was maintained around baseline levels. Cribriform changes and ventricular dilatation on brain MRI were improved in 9/17 and 4/17 patients, respectively. Stabilization of brain atrophy was shown in 11/17 patients. Cardiac valvular regurgitation was diminished in 20/63 valves. Urinary GAG concentration was remarkably lower in HSCT-treated patients than age-matched untreated patients. In the questionnaire analysis, speech deterioration was observed in 12/19 patients in the untreated cohort and 1/7 patient in HSCT-treated cohort. HSCT showed effectiveness towards brain or heart involvement, when performed before signs of brain atrophy or valvular regurgitation appear. We consider HSCT is worthwhile in early stages of the disease for patients with MPS II. PMID- 23022073 TI - Applying and testing the conveniently optimized enzyme mismatch cleavage method to clinical DNA diagnosis. AB - Establishing a simple and effective mutation screening method is one of the most compelling problems with applying genetic diagnosis to clinical use. Because there is no reliable and inexpensive screening system, amplifying by PCR and performing direct sequencing of every coding exon is the gold standard strategy even today. However, this approach is expensive and time consuming, especially when gene size or sample number is large. Previously, we developed CEL nuclease mediated heteroduplex incision with polyacrylamide gel electrophoresis and silver staining (CHIPS) as an ideal simple mutation screening system constructed with only conventional apparatuses and commercially available reagents. In this study, we evaluated the utility of CHIPS technology for genetic diagnosis in clinical practice by applying this system to screening for the COL2A1, WRN and RPS6KA3 mutations in newly diagnosed patients with Stickler syndrome (autosomal dominant inheritance), Werner syndrome (autosomal recessive inheritance) and Coffin-Lowry syndrome (X-linked inheritance), respectively. In all three genes, CHIPS detected all DNA variations including disease causative mutations within a day. Direct sequencing of all coding exons of these genes confirmed 100% sensitivity and specificity. We demonstrate high sensitivity, high cost performance and reliability of this simple system, with compatibility to all inheritance modes. Because of its low technology, CHIPS is ready to use and potentially disseminate to any laboratories in the world. PMID- 23022074 TI - Right-sided retrocaval approach using guidance via the lesser sac for Spieghel lobe resection. AB - BACKGROUND: Few reports describe technical problems encountered in resections of the Spieghel lobe of the liver. METHODS: The relationship of the caudate lobe with the inferior vena cava (IVC) was analyzed using computed tomography in 51 patients without hepatobiliary diseases. Using reconstructed 1 mm axial images, the angles of the most dorsal part of the Spieghel lobe (angle A) and the right hepatic lobe (angle B) around the IVC were measured clockwise from the ventral midpoint of the IVC. RESULTS: In 11 (22%) patients, angle A was 180 degrees or more, thus the retrocaval part of the Spieghel lobe projected rightward beyond the dorsal midline, but in 1 patient (2%) the right dorsal part of the liver extended leftward beyond the dorsal midline. In 20 (39%) patients, angle A was less than 135 degrees. The Spieghel lobe surrounded the IVC most dorsally at 22% of the distance from the top of the retrohepatic IVC. In 9 patients (18%), the retrocaval process of the Spieghel lobe appeared to be connected to the dorsal part of the right lobe. CONCLUSION: The Spieghel lobe sometimes extends to the right, dorsal aspect of the IVC, such that a right-sided approach facilitates securing the retrohepatic IVC through the lesser sac and allows a safe dissection of the protruding portion of this lobe. PMID- 23022076 TI - Application of finite mixture of negative binomial regression models with varying weight parameters for vehicle crash data analysis. AB - Recently, a finite mixture of negative binomial (NB) regression models has been proposed to address the unobserved heterogeneity problem in vehicle crash data. This approach can provide useful information about features of the population under study. For a standard finite mixture of regression models, previous studies have used a fixed weight parameter that is applied to the entire dataset. However, various studies suggest modeling the weight parameter as a function of the explanatory variables in the data. The objective of this study is to investigate the differences on the modeling and fitting results between the two component finite mixture of NB regression models with fixed weight parameters (FMNB-2) and the two-component finite mixture of NB regression models with varying weight parameters (GFMNB-2), and compare the group classification from both models. To accomplish the objective of this study, the FMNB-2 and GFMNB-2 models are applied to two crash datasets. The important findings can be summarized as follows: first, the GFMNB-2 models can provide more reasonable classification results, as well as better statistical fitting performance than the FMNB-2 models; second, the GFMNB-2 models can be used to better reveal the source of dispersion observed in the crash data than the FMNB-2 models. Therefore, it is concluded that in many cases the GFMNB-2 models may be a better alternative to the FMNB-2 models for explaining the heterogeneity and the nature of the dispersion in the crash data. PMID- 23022075 TI - Predicting clinical deterioration in the hospital: the impact of outcome selection. AB - BACKGROUND: Clinical deterioration of ward patients can result in intensive care unit (ICU) transfer, cardiac arrest (CA), and/or death. These different outcomes have been used to develop and test track and trigger systems, but the impact of outcome selection on the performance of prediction algorithms is unknown. METHODS: Patients hospitalized on the wards between November 2008 and August 2011 at an academic hospital were included in the study. Ward vital signs and demographic characteristics were compared across outcomes. The dataset was then split into derivation and validation cohorts. Logistic regression was used to derive four models (one per outcome and a combined outcome) for predicting each event within 24h of a vital sign set. The models were compared in the validation cohort using the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 59,643 patients were included in the study (including 109 ward CAs, 291 deaths, and 2638 ICU transfers). Most mean vital signs within 24h of the events differed statistically, with those before death being the most deranged. Validation model AUCs were highest for predicting mortality (range 0.73 0.82), followed by CA (range 0.74-0.76), and lowest for predicting ICU transfer (range 0.68-0.71). CONCLUSIONS: Despite differences in vital signs before CA, ICU transfer, and death, the different models performed similarly for detecting each outcome. Mortality was the easiest outcome to predict and ICU transfer the most difficult. Studies should be interpreted with these differences in mind. PMID- 23022078 TI - Daily-life contact affects the own-age bias and neural correlates of face memory in elderly participants. AB - Previous studies revealed consistently enhanced recognition memory for same- as compared to other-age faces (own-age bias, OAB) in young adults, but inconsistent results in elderly participants. To resolve these discrepancies, we examined recognition memory and event-related potentials (ERPs) for young and old faces in young participants and two elderly groups, who either reported high or low degrees of daily contact with elderly relative to younger persons. As expected, young adults showed more accurate memory for young versus old faces. While no OAB was found in old/low contact participants, old/high contact participants were more accurate with old versus young faces. ERPs in young adults revealed a parietal old/new effect from 500 to 800 ms (hits>correct rejections) for young but not old faces. Whereas no old/new effect was seen in the old/low contact group, the old/high contact participants exhibited a prominent reversed old/new effect (hitsA) in an uncharacterized gene, RMND1 (required for meiotic nuclear division 1). RMND1 localizes to mitochondria and behaves as an integral membrane protein. Retroviral expression of the wild-type RMND1 cDNA rescued the biochemical phenotype in subject cells, and siRNA-mediated knockdown of the protein recapitulated the defect. BN-PAGE, gel filtration, and mass spectrometry analyses showed that RMND1 forms a high-molecular-weight and most likely homopolymeric complex (~240 kDa) that does not assemble in subject fibroblasts but that is rescued by expression of RMND1 cDNA. The p.Arg417Gln substitution, predicted to be in a coiled-coil domain, which is juxtaposed to a transmembrane domain at the extreme C terminus of the protein, does not alter the steady-state level of RMND1 but might prevent protein-protein interactions in this complex. Our results demonstrate that the RMND1 complex is necessary for mitochondrial translation, possibly by coordinating the assembly or maintenance of the mitochondrial ribosome. PMID- 23022099 TI - Infantile encephaloneuromyopathy and defective mitochondrial translation are due to a homozygous RMND1 mutation. AB - Defects of mitochondrial protein synthesis are clinically and genetically heterogeneous. We previously described a male infant who was born to consanguineous parents and who presented with severe congenital encephalopathy, peripheral neuropathy, myopathy, and lactic acidosis associated with deficiencies of multiple mitochondrial respiratory-chain enzymes and defective mitochondrial translation. In this work, we have characterized four additional affected family members, performed homozygosity mapping, and identified a homozygous splicing mutation in the splice donor site of exon 2 (c.504+1G>A) of RMND1 (required for meiotic nuclear division-1) in the affected individuals. Fibroblasts from affected individuals expressed two aberrant transcripts and had decreased wild type mRNA and deficiencies of mitochondrial respiratory-chain enzymes. The RMND1 mutation caused haploinsufficiency that was rescued by overexpression of the wild type transcript in mutant fibroblasts; this overexpression increased the levels and activities of mitochondrial respiratory-chain proteins. Knockdown of RMND1 via shRNA recapitulated the biochemical defect of the mutant fibroblasts, further supporting a loss-of-function pathomechanism in this disease. RMND1 belongs to the sif2 family, an evolutionary conserved group of proteins that share the DUF155 domain, have unknown function, and have never been associated with human disease. We documented that the protein localizes to mitochondria in mammalian and yeast cells. Further studies are necessary for understanding the function of this protein in mitochondrial protein translation. PMID- 23022100 TI - Discovery and fine mapping of serum protein loci through transethnic meta analysis. AB - Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 * 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease. PMID- 23022102 TI - Estimating genetic effects and quantifying missing heritability explained by identified rare-variant associations. AB - Next-generation sequencing has led to many complex-trait rare-variant (RV) association studies. Although single-variant association analysis can be performed, it is grossly underpowered. Therefore, researchers have developed many RV association tests that aggregate multiple variant sites across a genetic region (e.g., gene), and test for the association between the trait and the aggregated genotype. After these aggregate tests detect an association, it is only possible to estimate the average genetic effect for a group of RVs. As a result of the "winner's curse," such an estimate can be biased. Although for common variants one can obtain unbiased estimates of genetic parameters by analyzing a replication sample, for RVs it is desirable to obtain unbiased genetic estimates for the study where the association is identified. This is because there can be substantial heterogeneity of RV sites and frequencies even among closely related populations. In order to obtain an unbiased estimate for aggregated RV analysis, we developed bootstrap-sample-split algorithms to reduce the bias of the winner's curse. The unbiased estimates are greatly important for understanding the population-specific contribution of RVs to the heritability of complex traits. We also demonstrate both theoretically and via simulations that for aggregate RV analysis the genetic variance for a gene or region will always be underestimated, sometimes substantially, because of the presence of noncausal variants or because of the presence of causal variants with effects of different magnitudes or directions. Therefore, even if RVs play a major role in the complex trait etiologies, a portion of the heritability will remain missing, and the contribution of RVs to the complex-trait etiologies will be underestimated. PMID- 23022101 TI - Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. AB - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder characterized by defective cilia and flagella motility. Chronic destructive-airway disease is caused by abnormal respiratory-tract mucociliary clearance. Abnormal propulsion of sperm flagella contributes to male infertility. Genetic defects in most individuals affected by PCD cause randomization of left right body asymmetry; approximately half show situs inversus or situs ambiguous. Almost 70 years after the hy3 mouse possessing Hydin mutations was described as a recessive hydrocephalus model, we report HYDIN mutations in PCD-affected persons without hydrocephalus. By homozygosity mapping, we identified a PCD-associated locus, chromosomal region 16q21-q23, which contains HYDIN. However, a nearly identical 360 kb paralogous segment (HYDIN2) in chromosomal region 1q21.1 complicated mutational analysis. In three affected German siblings linked to HYDIN, we identified homozygous c.3985G>T mutations that affect an evolutionary conserved splice acceptor site and that subsequently cause aberrantly spliced transcripts predicting premature protein termination in respiratory cells. Parallel whole-exome sequencing identified a homozygous nonsense HYDIN mutation, c.922A>T (p.Lys307(*)), in six individuals from three Faroe Island PCD-affected families that all carried an 8.8 Mb shared haplotype across HYDIN, indicating an ancestral founder mutation in this isolated population. We demonstrate by electron microscopy tomography that, consistent with the effects of loss-of function mutations, HYDIN mutant respiratory cilia lack the C2b projection of the central pair (CP) apparatus; similar findings were reported in Hydin-deficient Chlamydomonas and mice. High-speed videomicroscopy demonstrated markedly reduced beating amplitudes of respiratory cilia and stiff sperm flagella. Like the hy3 mouse model, all nine PCD-affected persons had normal body composition because nodal cilia function is apparently not dependent on the function of the CP apparatus. PMID- 23022103 TI - Effect of intranasal manganese administration on neurotransmission and spatial learning in rats. AB - The effect of intranasal manganese chloride (MnCl(2).4H(2)O) exposure on spatial learning, memory and motor activity was estimated in Morris water maze task in adult rats. Three-month-old male Wistar rats received for 2weeks MnCl(2).4H(2)O at two doses the following: 0.2mg/kg b.w. (Mn0.2) or 0.8mg/kg b.w. (Mn0.8) per day. Control (Con) and manganese-exposed groups were observed for behavioral performance and learning in water maze. ANOVA for repeated measurements did not show any significant differences in acquisition in the water maze between the groups. However, the results of the probe trial on day 5, exhibited spatial memory deficits following manganese treatment. After completion of the behavioral experiment, the regional brain concentrations of neurotransmitters and their metabolites were determined via HPLC in selected brain regions, i.e. prefrontal cortex, hippocampus and striatum. ANOVA demonstrated significant differences in the content of monoamines and metabolites between the treatment groups compared to the controls. Negative correlations between platform crossings on the previous platform position in Southeast (SE) quadrant during the probe trial and neurotransmitter turnover suggest that impairment of spatial memory and cognitive performance after manganese (Mn) treatment is associated with modulation of the serotonergic, noradrenergic and dopaminergic neurotransmission in the brain. These findings show that intranasally applied Mn can impair spatial memory with significant changes in the tissue level and metabolism of monoamines in several brain regions. PMID- 23022104 TI - Properties of dental resins submitted to pH catalysed hydrolysis. AB - OBJECTIVES: This study evaluated the surface microhardness (SM) and roughness (SR) alterations of dental resins submitted to pH catalysed degradation regimens. METHODS: Thirty discs of each TPH Spectrum (Dentsply), Z100 (3M-ESPE), or an unfilled experimental bis-GMA/TEGDMA resin were fabricated, totaling 90 specimens. Each specimen was polymerized for 40 s, finished, polished, and individually stored in deionized water at 37 degrees C for 7 days. Specimens were randomly assigned to the following pH solutions: 1.0, 6.9 or 13, and for SM or SR evaluations (n = 5). Baseline Knoop-hardness of each specimen was obtained by the arithmetic mean of five random micro-indentations. For SR, mean baseline values were obtained by five random surface tracings (R(a)). Specimens were then soaked in one of the following storage media at 37 degrees C: (1) 0.1 M, pH 1.0 HCl, (2) 0.1 N, pH 13.0 NaOCl, and (3) deionized water (pH 6.9). Solutions were replaced daily. Repeated SM and SR measurements were performed at the 3-, 7- and 14-day storage time intervals. For each test and resin, data were analysed by two way ANOVA followed by Tukey's test (alpha = 0.05). RESULTS: There was significant decrease in SM and increase in SR values of composites after storage in alkaline medium. TPH and Z100 presented similar behaviour for SM and SR after immersion in the different media, whereas unfilled resin values showed no significant change. CONCLUSION: Hydrolytic degradation of resin composites seems to begin with the silanized inorganic particles and therefore depend on their composition. SIGNIFICANCE: To accelerate composite hydrolysis and produce quick in vitro microstructural damage, alkaline medium appears to be more suitable than acidic medium. Contemporary resin composite properties seem to withstand neutral and acidic oral environments tolerably well. PMID- 23022106 TI - Influence of sandblasting granulometry and resin cement composition on microtensile bond strength to zirconia ceramic for dental prosthetic frameworks. AB - OBJECTIVES: To evaluate the effect of the particle size of sandblasting and the composition of the resin cement on the microtensile bond strength (MTBS) to zirconia. METHODS: Forty zirconia blocks (Cercon, Dentsply) were polished and randomly treated as follows: Group 1 (NT): no treatment; Group 2 (APA-I): airborne particle abrasion (Cobra, Renfert) using 25-MUm aluminium-oxide (Al(2)O(3))-particles; Group 3 (APA-II): APA with 50-MUm Al(2)O(3)-particles; and Group 4 (APA-III): APA using 110-MUm Al(2)O(3)-particles. Ceramic blocks were duplicated in composite resin. Samples of each pretreatment group were randomly divided into two subgroups depending on the resin cement used for bonding the composite disks to the treated zirconia surfaces. Subgroup 1 (PAN), which was a 10-MDP-containing luting system, used Clearfil Ceramic Primer plus Panavia F 2.0 (Kuraray) and Subgroup 2 (BIF) used Bifix SE (VOCO) self-adhesive cement. After 24h, bonded specimens were cut into 1+/-0.1mm(2) sticks. MTBS values were obtained using a universal testing machine (cross-head speed=0.5mm/min). Failure modes were recorded and the interfacial morphology of the debonded microbars was SEM-assessed. Two-way ANOVA, Student-Newman-Keuls tests, and the step-wise linear regression analysis were performed with the MTBS being the dependent variable (p<0.05). RESULTS: Despite the sandblasting granulometry, PAN bonded to air abraded surfaces attained the highest MTBS and frequently showed mixed fractures. BIF recorded no significant differences in MTBS depending on the conditioning method, and registered the highest rates of premature and adhesive failures. CONCLUSIONS: The 10-MDP-containing luting system seems to be the most suitable to bond zirconium-oxide ceramic, mainly after sandblasting. PMID- 23022105 TI - Misfit and microleakage of implant-supported crown copings obtained by laser sintering and casting techniques, luted with glass-ionomer, resin cements and acrylic/urethane-based agents. AB - OBJECTIVES: This study evaluated the marginal misfit and microleakage of cement retained implant-supported crown copings. METHODS: Single crown structures were constructed with: (1) laser-sintered Co-Cr (LS); (2) vacuum-cast Co-Cr (CC) and (3) vacuum-cast Ni-Cr-Ti (CN). Samples of each alloy group were randomly luted in standard fashion onto machined titanium abutments using: (1) GC Fuji PLUS (FP); (2) Clearfil Esthetic Cement (CEC); (3) RelyX Unicem 2 Automix (RXU) and (4) DentoTemp (DT) (n=15 each). After 60 days of water ageing, vertical discrepancy was SEM-measured and cement microleakage was scored using a digital microscope. Misfit data were subjected to two-way ANOVA and Student-Newman-Keuls multiple comparisons tests. Kruskal-Wallis and Dunn's tests were run for microleakage analysis (alpha=0.05). RESULTS: Regardless of the cement type, LS samples exhibited the best fit, whilst CC and CN performed equally well. Despite the framework alloy and manufacturing technique, FP and DT provide comparably better fit and greater microleakage scores than did CEC and RXU, which showed no differences. CONCLUSIONS: DMLS of Co-Cr may be a reliable alternative to the casting of base metal alloys to obtain well-fitted implant-supported crowns, although all the groups tested were within the clinically acceptable range of vertical discrepancy. No strong correlations were found between misfit and microleakage. Notwithstanding the framework alloy, definitive resin-modified glass-ionomer (FP) and temporary acrylic/urethane-based (DT) cements demonstrated comparably better marginal fit and greater microleakage scores than did 10 methacryloxydecyl-dihydrogen phosphate-based (CEC) and self-adhesive (RXU) dual cure resin agents. PMID- 23022107 TI - The cognitive neuroscience of time perception: how psychological studies might help to dissect the timing system. AB - It is argued that the cognitive neuroscience of time perception does not make sufficient use of a range of experimental techniques and theoretical approaches which might be useful in "dissecting" the human timing system, and thus helping to uncover its neural basis. These techniques are mostly inspired by scalar expectancy theory, but do not depend on acceptance of that model. Most of the methods result in the same physical stimuli giving rise to systematically different time judgements, thus they avoid problems of control which have haunted some areas of the cognitive neuroscience of timing. Among the possibilities are (a) changing the basic duration judgement of stimuli and events, (b) manipulating working memory and reference memories for duration, and (c) changing temporal decision processes. PMID- 23022109 TI - Prevention of postpartum hemorrhage with misoprostol. PMID- 23022110 TI - Possible mechanisms for brain natriuretic peptide resistance in heart failure with a focus on interspecies differences and canine BNP biology. AB - B-type natriuretic peptide or brain natriuretic peptide (BNP) is a cardiac peptide hormone. The principal stimulus for BNP synthesis is myocyte stretch. BNP binds to the natriuretic peptide receptor-A causing increased intracellular cyclic guanosine monophosphate (cGMP) production and shows cardio- and renoprotective effects. However, high endogenous BNP levels are associated with a lack of effect in severe heart failure. Moreover, in experimental heart failure, the response to treatments targeting the natriuretic peptide system is attenuated. This article reviews potential mechanisms that may explain the 'BNP paradox' in heart failure with a focus on interspecies differences, on known and presumed specificities of canine BNP biology, and on experimental studies in dogs. Resistance to BNP is far from fully understood but may be due to post translational modifications and alteration in proBNP processing, receptor downregulation and desensitization, blunted intracellular signalling and increased clearance of BNP(1-32.) Alternatively, resistance to BNP may be due to BNP(1-32) shortening into additional truncated forms that are less biologically effective. Future improvement in understanding of BNP biology may provide the rationale for innovative therapeutic strategies to maximize cardiovascular and renal cGMP bioavailability. PMID- 23022108 TI - Physical experience leads to enhanced object perception in parietal cortex: insights from knot tying. AB - What does it mean to "know" what an object is? Viewing objects from different categories (e.g., tools vs. animals) engages distinct brain regions, but it is unclear whether these differences reflect object categories themselves or the tendency to interact differently with objects from different categories (grasping tools, not animals). Here we test how the brain constructs representations of objects that one learns to name or physically manipulate. Participants learned to name or tie different knots and brain activity was measured whilst performing a perceptual discrimination task with these knots before and after training. Activation in anterior intraparietal sulcus, a region involved in object manipulation, was specifically engaged when participants viewed knots they learned to tie. This suggests that object knowledge is linked to sensorimotor experience and its associated neural systems for object manipulation. Findings are consistent with a theory of embodiment in which there can be clear overlap in brain systems that support conceptual knowledge and control of object manipulation. PMID- 23022111 TI - Congenital cytomegalovirus is the second most frequent cause of bilateral hearing loss in young French children. AB - OBJECTIVE: To estimate the prevalence of congenital cytomegalovirus (cCMV) among causes of bilateral hearing loss in young French children. STUDY DESIGN: Children <3 years old with hearing loss were prospectively included at their first visit to a referral center. Cytomegalovirus polymerase chain reaction was performed on dried blood spots from Guthrie cards. Medical records were reviewed. RESULTS: One hundred children with bilateral hearing loss were included at a median age of 15 months; the prevalence of cCMV was 8% (8/100) (95% CI, 2.7%-13.3%) in this population and 15.4% (8/52) in the subpopulation of children with profound bilateral hearing loss. Delayed neurodevelopment and brain abnormalities on computed tomography scan were found more often in children with cCMV than in children with hearing loss without cCMV (P = .027, P = .005). In 6 of 8 cCMV cases, cCMV infection had not been diagnosed before the study. CONCLUSIONS: In a comprehensive study of the causes of bilateral hearing loss in young French children, cCMV is the second most frequent cause of hearing loss after connexin mutations. It underlines that a majority of French children with hearing loss and cCMV are not diagnosed early and therefore may not benefit from early intervention including the possibility of neonatal antiviral treatment. These results make the case for promoting systematic cytomegalovirus screening in neonates with confirmed hearing loss identified through neonatal hearing screening. PMID- 23022112 TI - First survey on canine leishmaniasis in a non classical area of the disease in Spain (Lleida, Catalonia) based on a veterinary questionnaire and a cross sectional study. AB - The Spanish distribution of canine leishmaniasis (CanL) is heterogeneous and very few data are available for the north of the country, including the province of Lleida (Catalonia, Spain). This work describes the results obtained from a questionnaire sent to veterinarians throughout the province of Lleida. The majority of veterinarians (25/32, 78.1%) believed CanL cases were increasing and that the dogs had been infected locally (30/32, 93.8%). Also, a cross-sectional study was performed on the seroprevalence of CanL in kennel dogs, with and without compatible clinical signs, in the county of Pallars Sobira (Pyrenees of Lleida), where an autochthonous case of CanL had been previously detected. Four serological tests were used (IFAT, ELISA, Western blot, ICF) and dogs that tested positive with at least two immunological methods were considered seropositive and probably infected. 33.1% (48/145) of the dogs were seropositive. The results of a mixed logistic regression model showed that the risk of seropositivity increased with age (OR=1.35, p-value=0.002), among dogs living in the southern part of Pallars Sobira (OR=6.20, p-value=0.025) and among dogs whose owners considered their animals to be at risk of leishmaniasis infection (OR=1.26, p-value=0.024) and who were unaware of anti-sand fly preventive methods (OR=11.6, p value=0.009). The risk decreased when dogs lived in an urban-periurban habitat (OR=0.17, p-value=0.002). The information gathered in the veterinary questionnaires helped us to define the knowledge, perception and awareness of the disease in a naive region, supporting the hypothesis of an existing CanL focus in Pallars Sobira, which was confirmed by the seroepidemiological survey. The seroprevalence study carried out on kennel dogs of local origin proved useful for detecting an autochthonous focus of leishmaniasis through the analysis of a small number of animals. PMID- 23022113 TI - Neoadjuvant chemotherapy in muscle-invasive bladder cancer: ready for prime time? AB - Through a Medline search from January 1, 1998 to February 29, 2012, the literature data supporting the standard use of neoadjuvant or adjuvant chemotherapy in the perioperative setting for muscle-invasive transitional cell carcinoma of the bladder were reviewed. Randomized phase III trials and meta analyses have shown a significant benefit (level I evidence) in overall survival for neoadjuvant chemotherapy, with a 5% absolute benefit at 5 years, provided cisplatin-based combination regimens are used. Major methodological biases preclude any firm conclusion regarding the routine use of adjuvant therapy. The optimal chemotherapy regimen remains to be determined. Predictive biomarkers are urgently needed in order to determine which patients are more likely to benefit from neoadjuvant chemotherapy. PMID- 23022115 TI - Analytical methodology for the study of endosulfan bioremediation under controlled conditions with white rot fungi. AB - A general procedure to study the biodegradation of endosulfan under laboratory conditions by white rot fungi isolated from native sources growing in YNB (yeast nitrogen base) media with 1% of glucose is presented. The evaluation of endosulfan biodegradation as well as endosulfan sulfate, endosulfan ether and endosulfan alcohol production throughout the whole bioremedation process was performed using an original and straightforward validated analytical procedure with recoveries between 78 and 112% at all concentration levels studied except for endosulfan sulfate at 50 mg L(-1) that yielded 128% and RSDs<20%. Under the developed conditions, the basidiomycete Bjerkandera adusta was able to degrade 83% of (alpha+beta) endosulfan after 27 days, 6 mg kg(-1) of endosulfan diol were determined; endosulfan ether and endosulfan sulfate were produced below 1 mg kg( 1) (LOQ, limit of quantitation). PMID- 23022114 TI - Quantitation of cotinine and its metabolites in rat plasma and brain tissue by hydrophilic interaction chromatography tandem mass spectrometry (HILIC-MS/MS). AB - In this work, we developed a sensitive method to quantify cotinine (COT), norcotinine (NCOT), trans-3'-hydroxycotinine (OHCOT) and cotinine-N-oxide (COTNO) in rat plasma and brain tissue, using solid phase extraction (SPE), hydrophilic interaction liquid chromatography (HILIC) and tandem mass spectrometry (MS/MS). The linear range was 1-100 ng/mL for each analyte in rat plasma and brain homogenate (3-300 ng/g brain tissue). The method was validated with precision within 15% relative standard deviation (RSD) and accuracy within 15% relative error (RE). Stable isotope-labeled internal standards (IS) were used for all the analytes to achieve good reproducibility, minimizing the influence of recovery and matrix effects. This method can be used in future studies to simultaneously determine the concentrations of COT and three major metabolites in rat plasma and brain tissue. PMID- 23022116 TI - Cytotoxicity and genotoxicity of sewage treatment plant effluents in rainbow trout cells (RTG-2). AB - The cytotoxicity and genotoxicity of 11 organic fractions from sewage treatment plant (STP) effluents were tested using the RTG-2 rainbow trout permanent cell line. An automated in vitro micronucleus assay developed for RTG-2 cells was used to test the genotoxicity, whereas neutral red uptake, kenacid blue protein assay and ATP content were used to evaluate cytotoxicity. The induction of micronuclei (MN) and alterations in the cell cycle were analysed in these cells by flow cytometry after exposure to the organic fractions for 72 h. More than half of the organic extracts tested demonstrated a significant increase in the MN frequency, thus indicating that most of them can be considered to be genotoxic. The extracts were analysed chemically by GC/MS. Although the most frequently detected compounds in the effluents were bisphenol A (BPA), octylphenol (OP), di-2 ethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP), as well as other possible mutagens, the concentrations cannot explain the genotoxicity of the individual chemicals, thereby suggesting a mixture effect. The results obtained support the need to apply effect-based tests to monitor complex mixtures as the most accurate means of assessing the genotoxicity of environmental samples. PMID- 23022117 TI - Toxicity of untreated and ozone-treated oil sands process-affected water (OSPW) to early life stages of the fathead minnow (Pimephales promelas). AB - Due to a policy of no release, oil sands process-affected water (OSPW), produced by the surface-mining oil sands industry in North Eastern Alberta, Canada, is stored on-site in tailings ponds. Currently, ozonation is considered one possible method for remediation of OSPW by reducing the concentrations of dissolved organic compounds, including naphthenic acids (NAs), which are considered the primary toxic constituents. However, further work was needed to evaluate the effectiveness of ozonation in reducing the toxicity of OSPW and to ensure that ozonation does not increase the toxicity of OSPW. This study examined effects of untreated, ozone-treated, and activated charcoal-treated OSPW (OSPW, O3-OSPW, and AC-OSPW) on the early life stage (ELS) of fathead minnow (Pimephales promelas). Success of hatching of eggs, spontaneous movement, and incidences of hemorrhage, pericardial edema, and malformation of the spine of embryos were examined. To elucidate the mechanism of toxicity, concentrations of reactive oxygen species (ROS) were measured, and the abundances of transcripts of genes involved in biotransformation of xenobiotics, response to oxidative stress, and apoptosis were quantified by real-time PCR. Compared to the control group, which had an embryo survival rate of 97.9 +/- 2.08%, survival was significantly less when exposed to OSPW (43.8 +/- 7.12%). Eggs exposed to untreated OSPW exhibited a significantly greater rate of premature hatching, and embryos exhibited greater spontaneous movement. Incidences of hemorrhage (50.0 +/- 3.40%), pericardial edema (56.3 +/- 7.12%), and malformation of the spine (37.5 +/- 5.38%) were significantly greater in embryos exposed to OSPW compared to controls. These effects are typical of exposure to dioxin-like compounds, however, abundance of transcripts of cyp1a was not significantly greater in embryos exposed to OSPW. Significantly greater concentrations of ROS, and greater abundances of transcripts cyp3a, gst, sod, casp9, and apopen compared to controls, indicated that exposure to OSPW caused oxidative stress, which can result in damage to mitochondria and promote activation of caspase enzymes and apoptotic cell death. Removal of dissolved organic constituents by ozone treatment, or by activated charcoal, significantly attenuated all of the adverse effects associated with untreated OSPW. The results suggest that the organic fraction of OSPW can negatively impact the development of fathead minnow embryos through oxidative stress and apoptosis, and that ozonation attenuates this developmental toxicity. PMID- 23022118 TI - Catalytic oxidative degradation of 17alpha-ethinylestradiol by FeIII-TAML/H2O2: estrogenicities of the products of partial, and extensive oxidation. AB - The oxidative degradation of the oral contraceptive 17alpha-ethinylestradiol (EE(2)) in water by a new advanced catalytic oxidation process was investigated. The oxidant employed was hydrogen peroxide in aqueous solution and the catalyst was the iron tetra-amido macrocyclic ligand (Fe(III)-TAML) complex that has been designated Na[Fe(H(2)O)(B*)] (Fe(III)-B*). EE(2) (10 MUM) was oxidised rapidly by the Fe(III)-B*/H(2)O(2) (5 nM/4 mM) catalytic oxidation system at 25 degrees C, and for reactions at pH 8.40-11.00, no unchanged EE2 was detected in the reaction mixtures after 60 min. No oxidation of EE(2) was detected in blank reactions using either H(2)O(2) or Fe(III)-B* alone. The maximum rate of EE(2) loss occurred at pH 10.21. At this pH the half-life of EE(2) was 2.1 min and the oxidised products showed around 30% estrogenicity removal, as determined by the yeast estrogen screen (YES) bioassay. At pH 11.00, partial oxidation of EE(2) by Fe(III)-B*/H(2)O(2) (5 nM/4 mM) was studied (half-life of EE(2) was 14.5 min) and in this case the initial intermediates formed were a mixture of the epimers 17alpha-ethynyl-1,4-estradiene-10alpha,17beta-diol-3-one (1a) and 17alpha-ethynyl 1,4-estradiene-10beta,17beta-diol-3-one (1b) (identified by LC-ToF-MS and (1)H NMR spectroscopy). Significantly, this product mixture displayed a slightly higher estrogenicity than EE(2) itself, as determined by the YES bioassay. Upon the addition of further aliquots of Fe(III)-B* (to give a Fe(III)-B* concentration of 500 nM) and H(2)O(2) (to bring the concentration up to 4 mM assuming the final concentration had dropped to zero) to this reaction mixture the amounts of 1a and 1b slowly decreased to zero over a 60 min period as they were oxidised to unidentified products that showed no estrogenicity. Thus, partial oxidation of EE(2) gave products that have slightly increased estrogenicity, whereas more extensive oxidation by the advanced catalytic oxidation system completely removed all estrogenicity. These results underscore the importance of controlling the level of oxidation during the removal of EE(2) from water by oxidative processes. PMID- 23022119 TI - Liver dysfunction and its nutritional implications in heart failure. AB - Heart failure is a multifaceted pathophysiologic syndrome, with prevalent dysfunction of other vital organs and systems. The role of the liver in this disease has been little investigated, although up to 80% of patients with heart failure present with some form of liver dysfunction. In addition to its multiple metabolic functions, the liver has a crucial role in the removal of circulating endotoxins and in regulating immune responses and iron homeostasis. Kupffer cells that constitute 80% to 90% of tissue macrophages in the human body play an important role in this regard. A disturbed microcirculation of the liver may decrease endotoxin clearance and increase the hepatic secretion of proinflammatory cytokines. Such an immune activation may in turn alter the expression of hepcidin in the liver, resulting in iron deficiency. The proinflammatory state also is associated with an augmented free radical formation. However, the antioxidant capacity of the liver seems to be inadequate because there is evidence for selenium deficiency in patients with heart failure. The aim of this article was to summarize the various aspects of liver dysfunction in heart failure and to highlight the role of liver-derived factors in the development of specific nutritional deficiencies. Nutritional strategies opposing these deficiencies might present promising additive treatments of heart failure. PMID- 23022120 TI - Azuki bean polyphenols intake during lactation upregulate AMPK in male rat offspring exposed to fetal malnutrition. AB - OBJECTIVE: Fetal malnutrition is an early-life inducer of dyslipidemia and glucose intolerance. The aim of this study was to examine whether maternal azuki bean (Vigna angularis) polyphenol (AP) intake during lactation affects the adenosine monophosphate-activated protein kinase (AMPK) pathway and lipid metabolism in offspring exposed to fetal malnutrition. METHODS: Pregnant Wistar rats were divided into three groups: a control diet offered during gestation and lactation (CC), a low-protein diet during gestation and a control diet during lactation (LPC); and a low-protein diet during gestation and a 1.0% AP-containing control diet during lactation (LPAP). Male pups were randomly selected for the study; half the pups were sacrificed at 3 wk of age and the other half were fed a standard diet and sacrificed at 23 wk. Hepatic triacylglycerol levels, phosphorylation levels of AMPK and acetyl-coenzyme A carboxylase (ACC), and mRNA levels of sterol regulatory element-binding protein-1c (SREBP-1c) were evaluated. RESULTS: Significant decreases in body weights and hepatic triacylglycerol levels were found in the LPAP compared with the LPC group. Plasma adiponectin levels in the LPAP group were higher than those in the LPC group. AMPK phosphorylation was upregulated in the livers and skeletal muscles in young and adult LPAP compared with LPC rats. ACC phosphorylation was upregulated in skeletal muscles of LPAP rats. SREBP-1c mRNA expression was decreased in the livers of LPAP rats. CONCLUSION: Our results suggest that maternal AP intake during lactation upregulates AMPK phosphorylation not only in young but also in adult offspring exposed to fetal malnutrition and may lead to decreased hepatic lipid accumulation by ACC phosphorylation and downregulation of SREBP-1c expression. PMID- 23022121 TI - Homocysteine and cysteine levels in prepubertal children: association with waist circumference and lipid profile. AB - OBJECTIVE: To evaluate homocysteine and total cysteine levels in prepubertal children and to determine the association between these levels and obesity, increased waist circumference, glucose levels, and lipid profile alterations. METHODS: Using a cross-sectional study, 677 prepubertal students 6 to 11 y old were assessed. The weight, height, and waist circumference of the students were measured. Laboratory analyses included triacylglycerols, total cholesterol and its fractions, glucose, vitamin B12, folate, homocysteine, and cysteine. Chi square tests and logistic regression (forward-stepwise) were used for statistical analysis; the significance level was set at 5%. RESULTS: The median age of the students was 8.9 y (6.5-11.5), and the prevalences of overweight and obesity were 90 in 677 (13.3%) and 81 in 677 (12.0%), respectively. An increase in waist circumference was observed in 180 of 677 children (26.6%). Inadequate levels of low-density lipoprotein cholesterol, triacylglycerols, and high-density lipoprotein cholesterol were found in 95 (14.0%), 129 (19.1%), and 179 (26.4%) of the 677 students, respectively. The median homocysteine and total cysteine plasma levels were 5.6 MUmol/L (0.1-11.7) and 365.7 MUmol/L (191.5-589.2), respectively. A multivariate analysis showed that children with a waist circumference above the 90th percentile (7.3 MUmol/L) were 2.4 times (95% confidence interval 1.4-4.0) more likely to have increased homocysteine levels and that children with increased waist circumferences and those with high low-density lipoprotein cholesterol levels were 2.7 (95% confidence interval 1.6-4.6) and 2.1 (95% confidence interval 1.1-4.0) times more likely, respectively, to have total cysteine levels above the 90th percentile (445.0 MUmol/L). CONCLUSION: The association of abdominal obesity in prepuberty with levels of homocysteine and cysteine found in this study of a prepubertal population could be an early and independent predictor of cardiovascular risk. PMID- 23022122 TI - Obesity, systemic inflammation, and increased risk for cardiovascular disease and diabetes among adolescents: a need for screening tools to target interventions. AB - Cardiovascular disease (CVD) and type 2 diabetes mellitus have their roots in childhood, particularly in obese children and adolescents, raising important opportunities for early lifestyle intervention in at-risk individuals. However, not all obese individuals are at the same risk for disease progression. Accurate screening of obese adolescents may identify those in greatest need for intensive intervention to prevent or delay future disease. One potential screening target is obesity-related inflammation, which contributes to insulin resistance, metabolic syndrome, and CVD. In adults, the inflammatory marker high-sensitivity C-reactive protein (hsCRP) has utility for risk stratification and treatment initiation in individuals of intermediate CVD risk. In adolescents, hsCRP shares many of the associations of hsCRP in adults regarding the degree of insulin resistance, metabolic syndrome, and carotid artery media thickness. However, long term data linking increased hsCRP levels-and increased insulin or decreased adiponectin-in childhood to adult disease outcomes are lacking at this time. Future efforts continue to be needed to identify childhood clinical and laboratory characteristics that could be used as screening tests to predict adult disease progression. Such tests may have utility in motivating physicians and patients' families toward lifestyle changes, ultimately improving prevention efforts. PMID- 23022123 TI - Citrulline: from metabolism to therapeutic use. AB - Citrulline possesses a highly specific metabolism that bypasses splanchnic extraction because it is not used by the intestine or taken up by the liver. The administration of citrulline may be used to deliver available nitrogen for protein homeostasis in peripheral tissues and as an arginine precursor synthesized de novo in the kidneys and endothelial and immune cells. Fresh research has shown that citrulline is efficiently transported across the intestinal luminal membrane by a set of transporters belonging to the B0,+, L, and b0,+ systems. Several pharmacokinetic studies have confirmed that citrulline is efficiently absorbed when administered orally. Oral citrulline could be used to deliver arginine to the systemic circulation or as a protein anabolic agent in specific clinical situations, because recent data have suggested that citrulline, although not a component of proteins, stimulates protein synthesis in skeletal muscle through the mammalian target of rapamycin signaling pathway. Hence, citrulline could play a pivotal role in maintaining protein homeostasis and is a promising pharmaconutrient in nutritional support strategies for malnourished patients, especially in aging and sarcopenia. PMID- 23022124 TI - Disordered eating among adolescent female swimmers: dietary, biochemical, and body composition factors. AB - OBJECTIVE: To verify associations among body composition, biochemical parameters, and food intake in adolescent female swimmers with and without disordered eating (DE). METHODS: Seventy-seven athletes 11 to 19 y old from clubs in Rio de Janeiro, Brazil were studied. DE was assessed through three questionnaires (Eating Attitudes Test-26; Bulimic Investigatory Test, Edinburgh; and Body Shape Questionnaire), body composition by dual-energy x-ray absorptiometry, and food intake by a 3-d diet record. Biochemical parameters related to iron, folic acid, and vitamin B12 were analyzed. The Fisher exact test, Mann-Whitney test, and the Spearman coefficient were calculated. RESULTS: DE was found in 44.2% of the sample. DE-positive compared with DE-negative athletes presented greater body fat percentage (11-14 y: 27.5% versus 23.4%, P = 0.023; 15-19 y: 30.2% versus 24.1%, P = 0.006) and fat mass (11-14 y: 13.8 versus 10.3 kg, P = 0.010; 15-19 y: 17.0 versus 13.2 kg, P = 0.027). In relation to food intake, DE-positive athletes presented lower protein consumption in the 11- to 14-y-old group and lower calcium intake adequacy in the 15- to 19-y-old group. Most other dietary parameters showed a low adequacy of consumption, with no difference between athletes with and without DE. Four DE-positive athletes presented anemia or iron deficiency. CONCLUSION: DE-positive compared with DE-negative athletes presented a higher percentage of body fat and fat mass, lower protein consumption in the 11 to 14-y-old group, and lower calcium intake adequacy in the 15- to 19-y-old group. Greater attention should be given to the nutritional state of these athletes, considering the number of adolescents with anemia and an inadequate dietary intake. PMID- 23022125 TI - Ankle-brachial index as a clinical tool. PMID- 23022126 TI - Gait speed vs functional ability in the 'oldest old'. PMID- 23022127 TI - Gpr171, a putative P2Y-like receptor, negatively regulates myeloid differentiation in murine hematopoietic progenitors. AB - Gpr171 is an orphan G-protein-coupled receptor putatively related to the P2Y family of purinergic receptors (P2YRs) for extracellular nucleotides, a group of mediators previously shown to regulate hematopoietic progenitor cells. No information is currently available on the ligand responsible for Gpr171 activation and its biological role remains unknown. We reconstructed Gpr171 phylogenesis in mice and confirmed that Gpr171 is evolutionally related to members of a P2Y gene-cluster localized on mouse chromosome 3. As a first step toward unveiling a role for Gpr171, we investigated its expression profile in murine hematopoietic cells. As opposed to other P2YRs, we found that Gpr171 expression is down-regulated in monocytes and granulocytes, suggesting a negative role in myeloid lineage specification. To test Gpr171 functional role, we next enforced Gpr171 expression in a myeloblastic cell line (32D cells) and in primary Sca-1(+) hematopoietic progenitors, and observed a decreased expression of myeloid markers upon induction of Gpr171, as well as an increased generation of colonies in vitro. Conversely, Gpr171 silencing induced opposite results, diminishing the expression of myeloid markers and the clonogenic potential of 32D cells. In vivo, mice transplanted with hematopoietic progenitor cells overexpressing Gpr171 displayed a significant reduction in the percentage of Mac 1(+)Gr-1(-) cells. As a preliminary step in the investigation of Gpr171 role in murine hematopoiesis, our findings indicate that the orphan receptor Gpr171 negatively regulates myeloid differentiation. Together with phylogenic analyses, our data suggest that Gpr171 may have followed a separate evolutionary pathway as compared to other P2YRs belonging to the same gene cluster. PMID- 23022128 TI - Donor CD3(+) lymphocyte infusion after reduced intensity conditioning allogeneic stem cell transplantation: single-center experience. AB - Donor lymphocyte infusions (DLI) can induce remission in patients with hematologic malignancies who relapse after allogeneic stem cell transplantation. However, graft-vs-host disease (GVHD) remains a major complication of this strategy. We have used escalating doses of DLI for many years, and wanted to assess the risk factors for GVHD and transplant-related mortality as well as disease outcomes according to the reason for DLI. We analyzed 65 patients who received a total of 111 DLI for different reasons and at different intervals after transplantation. Median number of DLI was 2 (range, 1-4), median interval between transplantation and DLI was 9 months (range, 1-41 months) and median number of infused CD3(+) cells/kg recipient body weight was 2.5 * 10(7) (range, 1 * 10(6)-11.8 * 10(7)). Reasons for DLI were relapse or progression in 37 patients (57%), residual disease in 15 patients (23%), and persistence of mixed chimerism in 13 patients (20%). Seven patients (11%) developed acute GVHD grade II to IV and 5 patients (8%) developed extensive chronic GVHD. In univariate analysis, we could identify a transplantation-DLI interval <=6 months, the dose of DLI (>=1 * 10(7)), and DLI number as predictive factors of GVHD. In multivariate analysis, these results were confirmed only for the transplantation-DLI interval (hazard ratio = 19.48; 2.23-170.34; p = 0.007). Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD and transplant-related mortality, supporting further investigation as an upfront modality to enhance the graft-vs-tumor response in high-risk patients. PMID- 23022129 TI - Hematopoietic stem cell fate decisions are regulated by Wnt antagonists: comparisons and current controversies. AB - Wingless and int (Wnt) proteins are secreted proteins that are important for regulating hematopoietic stem cell self-renewal and differentiation in the bone marrow microenvironment in mice. The mechanisms by which Wnt signaling regulates these hematopoietic cell fate decisions are not fully understood. Secreted Wnt antagonists, which are expressed in bone and bone marrow stromal cells, either bind to Wnt ligands directly or block Wnt receptors and co-receptors to halt Wnt mediated signal transduction in both osteolineage and hematopoietic cell types. Secreted frizzled related proteins-1 and -2, Wnt inhibitory factor-1, Dickkopf-1, and Sclerostin are Wnt antagonists that influence hematopoietic cell fate decisions in the bone marrow niche. In this review, we compare and contrast the roles of these Wnt antagonists and their effects on hematopoietic development in mice, and also discuss the clinical significance of targeting Wnt antagonists within the context of hematopoietic disease. PMID- 23022130 TI - Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes. AB - Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed. PMID- 23022131 TI - Interplay of mycolic acids, antimycobacterial compounds and pulmonary surfactant membrane: a biophysical approach to disease. AB - This work focuses on the interaction of mycolic acids (MAs) and two antimycobacterial compounds (Rifabutin and N'-acetyl-Rifabutin) at the pulmonary membrane level to convey a biophysical perspective of their role in disease. For this purpose, accurate biophysical techniques (Langmuir isotherms, Brewster angle microscopy, and polarization-modulation infrared reflection spectroscopy) and lipid model systems were used to mimic biomembranes: MAs mimic bacterial lipids of the Mycobacterium tuberculosis (MTb) membrane, whereas Curosurf(r) was used as the human pulmonary surfactant (PS) membrane model. The results obtained show that high quantities of MAs are responsible for significant changes on PS biophysical properties. At the dynamic inspiratory surface tension, high amounts of MAs decrease the order of the lipid monolayer, which appears to be a concentration dependent effect. These results suggest that the amount of MAs might play a critical role in the initial access of the bacteria to their targets. Both molecules also interact with the PS monolayer at the dynamic inspiratory surface. However, in the presence of higher amounts of MAs, both compounds improve the phospholipid packing and, therefore, the order of the lipid surfactant monolayer. In summary, this work discloses the putative protective effects of antimycobacterial compounds against the MAs induced biophysical impairment of PS lipid monolayers. These protective effects are most of the times overlooked, but can constitute an additional therapeutic value in the treatment of pulmonary tuberculosis (Tb) and may provide significant insights for the design of new and more efficient anti-Tb drugs based on their behavior as membrane ordering agents. PMID- 23022132 TI - Vhc1, a novel transporter belonging to the family of electroneutral cation-Cl(-) cotransporters, participates in the regulation of cation content and morphology of Saccharomyces cerevisiae vacuoles. AB - Cation-Cl(-) cotransporters (CCCs) are integral membrane proteins which catalyze the coordinated symport of Cl(-) with Na(+) and/or K(+) ions in plant and mammalian cells. Here we describe the first Saccharomyces cerevisiae CCC protein, encoded by the YBR235w open reading frame. Subcellular localization studies showed that this yeast CCC is targeted to the vacuolar membrane. Deletion of the YBR235w gene in a salt-sensitive strain (lacking the plasma-membrane cation exporters) resulted in an increased sensitivity to high KCl, altered vacuolar morphology control and decreased survival upon hyperosmotic shock. In addition, deletion of the YBR235w gene in a mutant strain deficient in K(+) uptake produced a significant growth advantage over the parental strain under K(+)-limiting conditions, and a hypersensitivity to the exogenous K(+)/H(+) exchanger nigericin. These results strongly suggest that we have identified a novel yeast vacuolar ion transporter mediating a K(+)-Cl(-) cotransport and playing a role in vacuolar osmoregulation. Considering its identified function, we propose to refer to the yeast YBR235w gene as VHC1 (vacuolar protein homologous to CCC family 1). PMID- 23022133 TI - Uptake, efflux, and mass transfer coefficient of fluorescent PAMAM dendrimers into pancreatic cancer cells. AB - Targeted delivery of imaging agents to cells can be optimized with the understanding of uptake and efflux rates. Cellular uptake of macromolecules is studied frequently with fluorescent probes. We hypothesized that the internalization and efflux of fluorescently labeled macromolecules into and out of mammalian cells could be quantified by confocal microscopy to determine the rate of uptake and efflux, from which the mass transfer coefficient is calculated. The cellular influx and efflux of a third generation poly(amido amine) (PAMAM) dendrimer labeled with an Alexa Fluor 555 dye was measured in Capan-1 pancreatic cancer cells using confocal fluorescence microscopy. The Capan 1 cells were also labeled with 5-chloromethylfluorescein diacetate (CMFDA) green cell tracker dye to delineate cellular boundaries. A dilution curve of the fluorescently labeled PAMAM dendrimer enabled quantification of the concentration of dendrimer in the cell. A simple mass transfer model described the uptake and efflux behavior of the PAMAM dendrimer. The effective mass transfer coefficient was found to be 0.054+/-0.043MUm/min, which corresponds to a rate constant of 0.035+/-0.023min(-1) for uptake of the PAMAM dendrimer into the Capan-1 cells. The effective mass transfer coefficient was shown to predict the efflux behavior of the PAMAM dendrimer from the cell if the fraction of labeled dendrimer undergoing non-specific binding is accounted for. This work introduces a novel method to quantify the mass transfer behavior of fluorescently labeled macromolecules into mammalian cells. PMID- 23022134 TI - Existence of a robust haloacid transport system in a Burkholderia species bacterium. AB - Bacterium Burkholderia sp. MBA4 can utilize haloacids as the sole carbon and energy source for growth. We have previously reported that a haloacid operon, encoding for a dehalogenase (Deh4a) and an associated permease (Deh4p), was responsible for the transformation and uptake of haloacids in MBA4. A disruption of deh4p in MBA4 caused a decrease in monochloroacetate (MCA) uptake, confirming its role as a haloacid transporter. However, this disruptant retained 68% of its MCA-uptake activity indicating the possibility of an alternative system. In this study, we report the identification of a second MCA-inducible haloacid transporter (Dehp2) in MBA4. Its function was confirmed by gene disruption and heterologous expression in Escherichia coli. A dehp2(-) mutant has 30% less, and an E. coli expressing Dehp2 has 40% more, of wildtype MCA-uptake activity. Quantitative RT-PCR illustrated that the minor loss of MCA-uptake activity in single disruptants of deh4p and dehp2 was partly due to a compensatory expression of the alternative gene. Competition assay and kinetics study revealed that Deh4p has a higher affinity for MCA while Dehp2 prefers chloropropionate. A deh4p( )dehp2(-) double mutant retained 36% of MCA-uptake activity, indicating a robustness of the haloacid uptake systems. The MCA uptake activities mediated by Deh4p, Dehp2 and the uncharacterized system were completely abolished by protonophore carbonyl cyanide 3-chlorophenylhydrazone, suggesting that transmembrane electrochemical gradient is the driving force for MCA uptake. PMID- 23022136 TI - Current mutation discovery approaches in Retinitis Pigmentosa. AB - With a worldwide prevalence of about 1 in 3500-5000 individuals, Retinitis Pigmentosa (RP) is the most common form of hereditary retinal degeneration. It is an extremely heterogeneous group of genetically determined retinal diseases leading to progressive loss of vision due to impairment of rod and cone photoreceptors. RP can be inherited as an autosomal-recessive, autosomal dominant, or X-linked trait. Non-Mendelian inheritance patterns such as digenic, maternal (mitochondrial) or compound heterozygosity have also been reported. To date, more than 65 genes have been implicated in syndromic and non-syndromic forms of RP, which account for only about 60% of all RP cases. Due to this high heterogeneity and diversity of inheritance patterns, the molecular diagnosis of syndromic and non-syndromic RP is very challenging, and the heritability of 40% of total RP cases worldwide remains unknown. However new sequencing methodologies, boosted by the human genome project, have contributed to exponential plummeting in sequencing costs, thereby making it feasible to include molecular testing for RP patients in routine clinical practice within the coming years. Here, we summarize the most widely used state-of-the-art technologies currently applied for the molecular diagnosis of RP, and address their strengths and weaknesses for the molecular diagnosis of such a complex genetic disease. PMID- 23022135 TI - Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish. AB - Inositol phosphatases are important regulators of cell signaling and membrane trafficking. Mutations in inositol polyphosphate 5-phosphatase, INPP5E, have been identified in Joubert syndrome, a rare congenital disorder characterized by midbrain malformation, retinitis pigmentosa, renal cysts, and polydactyly. Previous studies have implicated primary cilia abnormalities in Joubert syndrome, yet the role of INPP5E in cilia formation is not well understood. In this study, we examined the function of INPP5E in cilia development in zebrafish. Using specific antisense morpholino oligonucleotides to knockdown Inpp5e expression, we observed phenotypes of microphthalmia, pronephros cysts, pericardial effusion, and left-right body axis asymmetry. The Inpp5e morphant zebrafish exhibited shortened and decreased cilia formation in the Kupffer's vesicle and pronephric ducts as compared to controls. Epinephrine-stimulated melanosome trafficking was delayed in the Inpp5e zebrafish morphants. Expression of human INPP5E expression rescued the phenotypic defects in the Inpp5e morphants. Taken together, we showed that INPP5E is critical for the cilia development in zebrafish. PMID- 23022137 TI - Substitution of isoleucine for threonine at position 190 of S-opsin causes S-cone function abnormalities. AB - Five mutations in the S-cone-opsin gene (OPN1SW) that give rise to different single amino-acid substitutions (L56P, G79R, S214P, P264S, R283Q) are known to be associated with tritan color-vision deficiency. Here we report a sixth OPN1SW mutation (T190I) and the associated color vision phenotype. S-opsin genotyping and clinical evaluation of color vision were performed on affected and unaffected family members and normal controls. Chromatic contrast was tested at different levels of retinal illuminance. Affected family members were heterozygous for a nucleotide change that substituted the amino acid isoleucine (I) in place of threonine (T) that is normally present at position 190 of the S-opsin. The mutation is in extracellular loop II (EII). The association between making tritan errors and having the T190I mutant S opsin was strong (p>0.0001: Fisher's exact test). The performance of subjects with the T190I mutation was significantly different from that of normal trichromats along the tritan vector under all conditions tested (Mann-Whitney U: p<0.05), but not along the protan or deutan vectors. Individuals with the T190I S-opsin mutation behaved as mild tritans at 12.3-92.3Td, but as tritanopes at 1.2-9.2Td, for both light-adapted and dark adapted conditions. The results are consistent with the mutant opsin causing abnormal S-cone function. PMID- 23022139 TI - Recent allopatric divergence and niche evolution in a widespread Palearctic bird, the common rosefinch (Carpodacus erythrinus). AB - A previously published phylogeographic analysis of mtDNA sequences from the widespread Palearctic common rosefinch (Carpodacus erythrinus) suggested the existence of three recently diverged groups, corresponding to the Caucasus, central-western Eurasia, and northeastern Eurasia. We re-evaluated the mtDNA data using coalescence methods and added sequence data from a sex-linked gene. The mtDNA gene tree and SAMOVA supported the distinctiveness of the Caucasian group but not the other two groups. However, UPGMA clustering of mtDNA Phi(ST)-values among populations recovered the three groups. The sex-linked gene tree recovered no phylogeographic signal, which was attributed to recent divergence and insufficient time for sorting of alleles. Overall, coalescence methods indicated a lack of gene flow among the three groups, and population expansion in the central-western and northeastern Eurasia groups. These three groups corresponded to named subspecies, further supporting their validity. A species distribution model revealed potential refugia at the Last Glacial Maximum. These three groups, which we hypothesized are in the early stages of speciation, provided an opportunity for testing tenets of ecological speciation. We showed that the early stages of speciation were not accompanied by ecological niche divergence, consistent with other avian studies. PMID- 23022140 TI - The PNarec method for detection of ancient recombinations through phylogenetic network analysis. AB - Recombinations are known to disrupt bifurcating tree structure of gene genealogies. Although recently occurred recombinations are easily detectable by using conventional methods, recombinations may have occurred at any time. We devised a new method for detecting ancient recombinations through phylogenetic network analysis, and detected five ancient recombinations in gibbon ABO blood group genes [Kitano et al., 2009. Mol. Phylogenet. Evol., 51, 465-471]. We present applications of this method, now named as "PNarec", to various virus sequences as well as HLA genes. PMID- 23022138 TI - Dissociation of pursuit target selection from saccade execution. AB - Pursuit and saccades almost always select the same target. Is this the results of a common selection process or does smooth pursuit obligatorily follow the stimulus targeted by saccades? To address this question, we used microstimulation of the primate superior colliculus (SC) to redirect the eyes from a selected pursuit target to a distracter moving in the opposite direction. During each trial, monkeys pursued a horizontally moving array of colored target stimuli. In half of the trials, this target array was accompanied by a distracter array moving horizontally in the opposite direction, offset by the vertical amplitude of the stimulation-evoked saccade. We stimulated the SC during maintained pursuit on half of the trials, and measured pursuit eye velocity during the 50-ms interval immediately following the stimulation-evoked saccade to the distracter array. Saccades evoked by SC stimulation did not alter pursuit target selection. Pursuit velocity on average changed by less than 10% of that expected if the monkey had completely switched targets. Moreover, the same changes in velocity occurred when there was no distracter, indicating that even these small changes in pursuit velocity were a direct effect of the evoked saccade, not partial selection of the distracter. These results show that motor execution of saccades is not sufficient to select a pursuit target, and support the idea that the coordination of pursuit and saccades is accomplished by a shared target selection process. PMID- 23022141 TI - Coronary perivascular adipose tissue characteristics are related to atherosclerotic plaque size and composition. A post-mortem study. AB - BACKGROUND: Perivascular adipose tissue (pvAT) may influence atherosclerotic plaque formation. We aim to determine the association between the local amount and inflammatory properties of pvAT and the size and composition of atherosclerotic plaque in the left anterior descending artery (LAD). METHODS: Post-mortem, a total of 139 cross sections of the LAD were obtained from 16 patients. PvAT quantity was measured within an area of 3 mm around the LAD (pvAT area (%)). Furthermore, inflammatory properties of pvAT were measured (macrophages/400* field and adipocyte size). From plaque area (mm(2)), plaque/media-ratio was calculated and morphologic characteristics were scored (presence of a lipid core and calcification; collagen and smooth muscle cell content; macrophage (<10, 10-50, >50/400* field) and lymphocyte infiltration (<10, 10-25, >25/400* field)). RESULTS: Plaque/media-ratio increased with increasing pvAT-area (beta0.02; 95%CI 0.01-0.03) and pvAT-macrophages (beta 0.10; 95%CI 0.05-0.16), but not with adipocyte area (beta -0.00; 95%CI -0.07-0.06). PvAT-area was related to the presence of a lipid core (OR 1.05; 95%CI 1.03-1.08) and with macrophage and lymphocyte infiltration of atherosclerotic plaque (per increase in category OR 1.05; 95%CI 1.02-1.07 and OR 1.04; 95%CI 1.01-1.07 respectively). PvAT macrophage infiltration was correlated with adventitia and plaque macrophages. CONCLUSION: PvAT quantity and macrophage infiltration are highly related to atherosclerotic plaque size and composition in patients with coronary atherosclerosis. These results indicate potential involvement of pvAT in coronary atherosclerotic plaque development, although the causality of the relation has yet to be determined. PMID- 23022142 TI - Comparisons of dengue illness classified based on the 1997 and 2009 World Health Organization dengue classification schemes. AB - BACKGROUND/PURPOSE: Dengue cases, traditionally classified as dengue fever (DF) or dengue hemorrhagic fever (DHF) by the World Health Organization (WHO) dengue classification 1997 scheme, are categorized into Group A (without warning signs), Group B [with warning signs (e.g., abdominal pain/vomiting/fluid accumulation/mucosal bleeding/lethargy/liver enlargement/increasing hematocrit with decreasing platelets)], or Group C (severe plasma leakage/severe bleeding/organ failure) by the WHO 2009 version. We compared differences in clinical/laboratory features between patients separately classified as DF/DHF and in Group A/B/C. METHODS: We performed a retrospective analysis of dengue patients diagnosed between 2008 and 2010. RESULTS: A total of 148 adult patients (119 DF/29 DHF; 64 Group A/77 Group B/7 Group C) were included. Compared with DF, significantly younger age, lower hospitalization rate, and higher platelet count were found in Group A. Compared with DHF, higher platelet count was found in Group B. Six of seven patients (86%) classified as Group C fulfilled the criteria of DHF. A cross tabulation showed DF cases were distributed in all of the severity groups stratified by the WHO dengue 2009 scheme (53.8% Group A/45.4% Group B/0.8% Group C); of the DHF cases, 23 (79%) were categorized as Group B, and six (20.7%) as Group C. All patients in Group A fell into the category DF. CONCLUSION: The WHO 2009 scheme is effective in identifying severe dengue cases. Heterogeneity in severity suggests careful severity discrimination in patients classified in Group B is needed. Our data suggest that it is safe to treat patients classified as Group A on an outpatient basis. PMID- 23022143 TI - Tissue-dependence and sensitivity of the systemic RNA interference response in the desert locust, Schistocerca gregaria. AB - We report on a comprehensive study of the systemic RNAi-response in the desert locust, Schistocerca gregaria. Upon intra-abdominal injection of dsRNA for two housekeeping genes (alpha-tubulin 1a and gapdh) in the range of pg amounts of dsRNA per mg tissue, a potent reduction of their corresponding mRNA was obtained. Moreover, the observed transcript knockdown significantly increased in at least a 10 days period and eventually resulted in high mortality upon silencing of the alpha-tubulin 1a gene. A more moderate RNAi-response was however observed in the reproductive systems. Analysis of the tissue-dependent transcript level profile of several putative RNAi-genes indicated reduced levels of two genes, namely sg dicer-2 and sg-argonaute-2, in the reproductive systems. By silencing these components, we confirmed their importance in the RNAi-process and suggest that their expression levels are determinant for tissue-dependent differences in the potency of RNAi in the desert locust. PMID- 23022144 TI - Trifluoroethanol-induced conformational change of tetrameric and monomeric soybean agglutinin: role of structural organization and implication for protein folding and stability. AB - 2,2,2-Trifuoroethanol (TFE)-induced conformational structure change of a beta sheet legume lectin, soybean agglutinin (SBA) has been investigated employing its exclusive structural forms in quaternary (tetramer) and tertiary (monomer) states, by far- and near-UV CD, FTIR, fluorescence, low temperature phosphorescence and chemical modification. Far-UV CD results show that, for SBA tetramer, native atypical beta-conformation transforms to a highly alpha-helical structure, with the helical content reaching 57% in 95% TFE. For SBA monomer, atypical beta-sheet first converts to typical beta-sheet at low TFE concentration (10%), which then leads to a nonnative alpha-helix at higher TFE concentration. From temperature-dependent studies (5-60 degrees C) of TFE perturbation, typical beta-sheet structure appears to be less stable than atypical beta-sheet and the induced helix entails reduced thermal stability. The heat induced transitions are reversible except for atypical to typical beta-sheet conversion. FTIR results reveal a partial alpha-helix conversion at high protein concentration but with quantitative yield. However, aggregation is detected with FTIR at lower TFE concentration, which disappears in more TFE. Near-UV CD, fluorescence and phosphorescence studies imply the existence of an intermediate with native-like secondary and tertiary structure, which could be related to the dissociation of tetramer to monomer. This has been further supported by concentration dependent far-UV CD studies. Chemical modification with N-bromosuccinimide (NBS) shows that all six tryptophans per monomer are solvent-exposed in the induced alpha-helical conformation. These results may provide novel and important insights into the perturbed folding problem of SBA in particular, and beta-sheet oligomeric proteins in general. PMID- 23022145 TI - WITHDRAWN: Protein sumoylation and human diseases. AB - This review has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23022146 TI - Unraveling the antifungal activity of a South American rattlesnake toxin crotamine. AB - Crotamine is a highly basic peptide from the venom of Crotalus durissus terrificus rattlesnake. Its common gene ancestry and structural similarity with the beta-defensins, mainly due to an identical disulfide bond pattern, stimulated us to assess the antimicrobial properties of native, recombinant, and chemically synthesized crotamine. Antimicrobial activities against standard strains and clinical isolates were analyzed by the colorimetric microdilution method showing a weak antibacterial activity against both Gram-positive and Gram-negative bacteria [MIC (Minimum Inhibitory Concentration) of 50->200 MUg/mL], with the exception of Micrococcus luteus [MIC ranging from 1 to 2 MUg/mL]. No detectable activity was observed for the filamentous fungus Aspergillus fumigatus and Trichophyton rubrum at concentrations up to 125 MUg/mL. However, a pronounced antifungal activity against Candida spp., Trichosporon spp., and Cryptococcus neoformans [12.5-50.0 MUg/mL] was observed. Chemically produced synthetic crotamine in general displayed MIC values similar to those observed for native crotamine, whereas recombinant crotamine was overridingly more potent in most assays. On the other hand, derived short linear peptides were not very effective apart from a few exceptions. Pronounced ultrastructure alteration in Candida albicans elicited by crotamine was observed by electron microscopy analyses. The peculiar specificity for highly proliferating cells was confirmed here showing potential low cytotoxic effect of crotamine against nontumoral mammal cell lines (HEK293, PC12, and primary culture astrocyte cells) compared to tumoral B16F10 cells, and no hemolytic activity was observed. Taken together these results suggest that, at low concentration, crotamine is a potentially valuable anti yeast or candicidal agent, with low harmful effects on normal mammal cells, justifying further studies on its mechanisms of action aiming medical and industrial applications. PMID- 23022147 TI - Human papillomavirus vaccination coverage among Greek higher education female students and predictors of vaccine uptake. AB - One of the biggest public health measures to prevent HPV infection, and consequently, cervical cancer, is the HPV vaccine. Greece introduced HPV vaccines to its National Vaccination Program in 2008. The aims of this study were to estimate HPV vaccination coverage among female Greek students in higher education and to identify uptake predictors. We conducted a cross-sectional study. Data was collected through a self-completed questionnaire. The sample size included 3153 women with an 87% participation rate. Overall 25.8% of students reported they had received three doses of the HPV vaccine. Positive predictors of vaccine uptake were: younger age, higher educational level (own and parents), ever previous visit(s) to the gynecologist, always use of condoms, not smokers, not being in a stable relationship and easy access to Health Care Services. Vaccine compliance was unacceptably low despite the fact that the vaccination is free-of-charge. Interventions on college campuses should stress vaccination as a normative behavior. PMID- 23022148 TI - Immunity to tetanus and diphtheria in the UK in 2009. AB - INTRODUCTION: This study aimed to estimate the immunity of the UK population to tetanus and diphtheria, including the potential impact of new glycoconjugatate vaccines, and the addition of diphtheria to the school leaver booster in 1994. METHODS: Residual sera (n=2697) collected in England in 2009/10 were selected from 18 age groups and tested for tetanus and diphtheria antibody. Results were standardised by testing a panel of sera (n=150) to enable comparison with a previously (1996) published serosurvey. Data were then standardised to the UK population. RESULTS: In 2009, 83% of the UK population were protected (>=0.1 IU/mL) against tetanus compared to 76% in 1996 (p=0.079), and 75% had at least basic protection against diphtheria (>=0.01 IU/mL) in 2009 compared to 60% in 1996 (p<0.001). Higher antibody levels were observed in those aged 1-3 years in 2009 compared to 1996 for both tetanus and diphtheria. Higher diphtheria immunity was observed in those aged 16-34 years in 2009 compared to 1996 (geometric mean concentration [GMC] 0.15 IU/mL vs. 0.03 IU/mL, p<0.001). Age groups with the largest proportion of susceptible individuals to both tetanus and diphtheria in 2009 were <1 year old (>29% susceptible), 45-69 years (>20% susceptible) and 70+ years (>32% susceptible). Low immunity was observed in those aged 10-11 years (>19% susceptible), between the scheduled preschool and school leaver booster administration. DISCUSSION: The current schedule appears to induce protective levels; increases in the proportions protected/GMCs were observed for the ages receiving vaccinations according to UK policy. Glycoconjugate vaccines appear to have increased immunity, in particular for diphtheria, in preschool age groups. Diphtheria immunity in teenagers and young adults has increased as a result of the addition of diphtheria to the school leaver booster. However, currently older adults remain susceptible, without any further opportunities for immunisations planned according to the present schedule. PMID- 23022149 TI - Autoimmune disorders after immunisation with Influenza A/H1N1 vaccines with and without adjuvant: EudraVigilance data and literature review. AB - All suspected autoimmune disorders (AID) reported as adverse reactions to EudraVigilance from 1 October 2009 to 31 December 2010 for adjuvanted (CelturaTM, Fluval PTM, FocetriaTM and PandemrixTM) and non-adjuvanted (CantgripTM, CelvapanTM and PanenzaTM) pandemic Influenza A/H1N1 vaccines were analysed to determine whether adjuvanted vaccines were associated with higher reporting of AID than non-adjuvanted ones. AID were identified based on the corresponding MedDRA High Level Group Term. Reports of type 1 diabetes mellitus and multiple sclerosis were also included in the analysis. Causality was assessed based on WHO causality assessment for adverse events following immunisation and Brighton Collaboration criteria for Guillain-Barre syndrome (GBS), idiopathic thrombocytopenic purpura and acute disseminated encephalomyelitis. Of the 50,221 adverse reactions received in EudraVigilance for A/H1N1 vaccines (adjuvanted: 46,173, non-adjuvanted: 4048), 314 were AID (adjuvanted: 276, non-adjuvanted: 38). GBS was the AID with the highest number of reports (125, adjuvanted: 109, non-adjuvanted: 16). Reporting ratios as calculated by the percentages of AID amongst all reported adverse reactions were 0.60% (95% CI: 0.53-0.67) and 0.94% (95% CI: 0.64-1.24) for adjuvanted and non-adjuvanted vaccines, and were 0.26% (95% CI: 0.22-0.31) and 0.37% (95% CI: 0.18-0.56) in a restricted analysis based on diagnostic certainty, causal relationship and plausible temporal association. Reporting rates for all reports of AID using the estimated number of vaccinees as denominator were 6.87 (95% CI: 6.06-7.68) and 9.98 (95% CI: 6.81-13.16) per million for adjuvanted and non-adjuvanted vaccines, and 3.01 (95% CI: 2.47-3.55) and 3.94 (95% CI: 1.95-5.94) per million in the restricted analysis. These results do not suggest a difference in the reporting of AID between adjuvanted and non-adjuvanted A/H1N1 vaccines. In a literature review performed on 31 August 2011, GBS was also the AID the most frequently discussed in association with A/H1N1 vaccination; reporting rates were generally within expected background rates. PMID- 23022150 TI - The risk factors of transmission after the implementation of the routine immunization among children exposed to HBV infected mothers in a developing area in northwest China. AB - We aimed to evaluate the present situation and possible risk factors of HBV transmission after the implementation of the routine immunization among children exposed to HBV infected mothers in a developing area in northwest China. Two hundred and twenty one HBsAg carrier mothers and 247 children born to them were finally recruited in Wuwei city, Gangsu province, China in 2010. Serum samples were taken from those HBsAg carrier mothers and their children. Children who had detectable HBsAg or HBV DNA were considered to be HBV infection. Conditional logistic regression model was used to identify potential risk factors of HBV mother-to-child transmission. Of the 247 children born to HBsAg carrier mothers, 8 (3.24%) were HBsAg positive, 15 (6.07%) were HBV DNA positive. The rate of HBV mother-to-child transmission was 7.29% (18/247). The univariate analysis and multivariate analysis showed that maternal HBV DNA positive (OR=4.83, 95% CI: 1.38-16.98, p=0.0140), the delayed injection of the first dose of HBV vaccine after premature birth (OR=9.73, 95% CI: 1.78-53.21, p=0.0087) and the missing use of HBV vaccine (OR=8.29, 95% CI: 1.42-48.23, p=0.0186) were significantly associated with an increased risk for HBV mother-to-child transmission. The rate of HBV infection of the children received HBV vaccine and HBIG together after birth (2.56%, 4/156) was lower than those children received HBV vaccine alone (11.39%, 9/79) (chi(2)=7.83, p=0.0052). In conclusion, the rate of mother-to child transmission of HBV was still high in the northwest of China. Besides the positivity of maternal HBV DNA and the missing of HBV vaccination after birth, the delayed injection of the first dose of HBV vaccine after premature birth was also a possible independent risk factor for HBV mother-to-child transmission. The HBV prevention and treatment guidelines should make it clear that all of the new born infants need to receive HBV vaccine injection after birth in 24 h, including the premature infants. PMID- 23022151 TI - Impact of wheel running on chronic ethanol intake in aged Syrian hamsters. AB - INTRODUCTION: Alcohol dependence in aging populations is seen as a public health concern, most recently because of the significant proportion of heavy drinking among "Baby Boomers." Basic animal research on the effects of aging on physiological and behavioral regulation of ethanol (EtOH) intake is sparse, since most of this research is limited to younger models of alcoholism. Here, EtOH drinking and preference were measured in groups of aged Syrian hamsters. Further, because voluntary exercise (wheel-running) is a rewarding substitute for EtOH in young adult hamsters, the potential for such reward substitution was also assessed. METHODS: Aged (24 month-old) male hamsters were subjected to a three stage regimen of free-choice EtOH (20% v/v) or water and unlocked or locked running wheels to investigate the modulatory effects of voluntary wheel running on EtOH intake and preference. Levels of fluid intake and activity were recorded daily across 60 days of experimentation. RESULTS: Prior to wheel running, levels of EtOH intake were significantly less than levels of water intake, resulting in a low preference for EtOH (30%). Hamsters with access to an unlocked running wheel had decreased EtOH intake and preference compared with hamsters with access to a locked running wheel. These group differences in EtOH intake and preference were sustained for up to 10 days after running wheels were re-locked. DISCUSSION: These results extend upon those of our previous work in young adult hamsters, indicating that aging dampens EtOH intake and preference. Voluntary wheel running further limited EtOH intake, suggesting that exercise could offer a practical approach for managing late-life alcoholism. PMID- 23022152 TI - Stimulation of cytosolic and mitochondrial calcium mobilization by indomethacin in Caco-2 cells: modulation by the polyphenols quercetin, resveratrol and rutin. AB - BACKGROUND: The effect of indomethacin (INDO) on Ca(2+) mobilization, cytotoxicity, apoptosis and caspase activation and the potential protective effect of quercetin (QUE), resveratrol (RES) and rutin (RUT) were determined in Caco-2 cells. METHODS: Caco-2 cells were incubated with INDO in the presence or absence of QUE, RES or RUT. The concentrations of Ca(2+) in the cytosol (Fluo-3 AM) and mitochondria (Rhod-2 AM) were determined as well as the cytotoxicity (MTT reduction and LDH leakage), apoptosis (TUNEL) and caspase-3 and 9 activities. RESULTS: INDO promoted Ca(2+) efflux from the endoplasmic reticulum (ER), resulting in an early, but transient, increment of cytosolic Ca(2+) at 3.5min, followed by a subsequent increment of intra-mitochondrial Ca(2+) at 24min. INDO also induced cytotoxicity, apoptosis, and increased caspase activities and cytochrome c release. All these alterations were prevented by the inhibitors of the IP3R and RyR receptors, 2-Aminoethoxydiphenyl borate (2-APB) and dantrolene. QUE was the most efficient polyphenol in preventing Ca(2+) mobilization induced by INDO and all of its consequences including cytotoxicity and apoptosis. CONCLUSIONS: In Caco-2 cells, INDO stimulates ER Ca(2+) mobilization, probably through the activation of IP3R and RyR receptors, and the subsequent entry of Ca(2+) into the mitochondria. Polyphenols protected the cells against the Ca(2+) mobilization induced by INDO and its consequences on cytotoxicity and apoptosis. GENERAL SIGNIFICANCE: These results confirm the possibility of using polyphenols and particularly QUE for the protection of the gastroduodenal mucosa in subjects consuming NSAIDs. PMID- 23022153 TI - Propylbenzmethylation at Val-1(alpha) markedly increases the tetramer stability of the PEGylated hemoglobin: a comparison with propylation at Val-1(alpha). AB - BACKGROUND: Hemoglobin (Hb)-based oxygen carriers (HBOCs) are potential pharmaceutical agents that can be used in surgery or emergency medicine. PEGylation can modulate the vasoactivity of Hb and is a widely used approach to develop HBOCs. However, PEGylation can significantly enhance the tetramer-dimer dissociation of Hb, which may perturb the structure of Hb and increase its observed adverse effect. Thus, it is necessary to increase the tetramer stability of the PEGylated Hb. METHODS: Propylbenzmethylation at Val-1(alpha) of HbA was carried out to stabilize the Hb tetramer. The propylbenzmethylated Hb at Val 1(alpha) (PrB-Hb) was used as the starting material for site-specific PEGylation at Cys-93(beta) of Hb using maleimide PEG. Structural and functional properties, autoxidation rate and thermal stability of the resultant product (PEG-PrB-Hb) were measured. RESULTS: Propylbenzmethylation at Val-1(alpha) led to 25-fold and 24-fold decreases in the tetramer-dimer dissociation constant of HbA and PEG-Hb, respectively. The increased tetramer stability is due to the enhanced hydrophobicity of the area around Val-1(alpha) and the increased polar interaction of Hb upon propylbenzmethylation. Thus, the structural and functional properties of PEG-Hb were improved, and its autoxidation rate and thermal denaturation were decreased. CONCLUSION: Propylbenzmethylation at Val-1(alpha) showed higher ability than propylation at Val-1(alpha) to improve the structural and functional properties and decrease the side effect of PEG-Hb. GENERAL SIGNIFICANCE: Our study can facilitate the biotechnological development of stable PEGylated Hb as more advanced HBOC. Our study is also expected to improve the stability of the tetrameric or dimeric proteins (e.g., uric oxidase) by propylbenzmethylation at their N-terminus. PMID- 23022154 TI - Pseudoreflux and detrusor overactivity due to accidental ureteral catheterization during cytometry in a pediatric patient. AB - We present the case of a 9-year-old girl with a neurogenic bladder who had accidental ureteral cannulation with the vesical catheter during cytometry. This is the first reported pediatric case described of this complication, the four prior cases all being in adults. The signs and symptoms of ureteral catheterization differed significantly in this patient from the adult cases. In our patient, malpositioning of the vesical catheter yielded a misleading pressure profile of primarily rhythmic pressure increases suggestive of severe detrusor overactivity and vesicoureteral reflux on fluoroscopy. The reading, however, actually reflected ureteric filling and peristalsis, and these findings resolved when the catheter was properly repositioned. This case highlights the possibility of inadvertent ureteral catheterization, and that, while rare, this complication should be kept in mind when new or unexpected DO or VUR is observed upon filling cystometry. PMID- 23022155 TI - Effects of task constraints on obstacle avoidance strategies in patients with cerebellar disease. AB - The present study examined the effects of cerebellar disease on the organization and execution of obstacle avoidance tasks. To this end, we characterized how variations in the execution demands of the subsequent obstacles in multiple obstacle crossing tasks influenced the stepping performance of the initial obstacle in patients with cerebellar degeneration (CD) by manipulating the height (6 cm and 16 cm) and distance (1 m and 2 m) of the second obstacle. Nine patients with bilateral cerebellar atrophy and nine age-matched normal controls were instructed to walk along an 8 m long pathway and step over two obstacles without contacting them. The primary finding indicated that CD patients exhibited an elevated foot clearance over the initial obstacle when the height demand of the second obstacle was increased. Such abnormal step-height adjustments in CD patients are considered as an adaptive avoidance strategy to diminish the execution demands of complex obstacle tasks and to enhance safe performance. These results suggest that the cerebellum is important for the implementation of optimal stepping strategies to be used during multiple obstacle crossings in which the obstacles have different execution demands. PMID- 23022156 TI - Secondary gait deviations in patients with and without neurological involvement: a systematic review. AB - Pathologies that lead to biomechanical restrictions in human gait interfere with the tightly regulated muscle activation patterns that control the external moments. In order to maintain proper function, secondary mechanisms are required. The aims of this systematic review were (1) to identify secondary mechanisms in pathologic gait that have been described throughout the scientific literature by means of instrumented gait analysis, (2) to distinguish between active compensatory mechanisms and passive physical effects and (3) to identify common compensatory mechanisms that appear to be independent from the underlying disease. A comprehensive literature search revealed 4080 citations for review, whereof 148 studies entered the full-text review. Thirty-six studies were included and the quality of these studies was assessed by two independent reviewers (kappa=0.83). The quality of the included studies showed large variation and several methodological issues were identified. Five studies were further identified describing only passive physical effects, leaving a total of 31 studies reporting on compensations. The qualitative analysis revealed common compensations that appeared to be independent from the underlying pathology. In clinical practice, distinguishing primary from secondary gait deviations can be considered highly important since unnecessary treatment may be avoided. However, given the introduction of general principles of compensatory mechanisms and the fact that certain presumed "compensations" were identified as simple passive physical effects, secondary gait deviations have to be further investigated. Computer simulation studies are valuable, especially in respect of the distinction between compensations and physical effects. Furthermore, the need for a uniform terminology was highlighted. PMID- 23022157 TI - Determining the preferred modality for real-time biofeedback during balance training. AB - Vestibular rehabilitation therapy has been shown to improve balance and gait stability in individuals with vestibular deficits. However, patient compliance with prescribed home exercise programs is variable. Real-time feedback of exercise performance can potentially improve exercise execution, exercise motivation, and rehabilitation outcomes. The goal of this study is to directly compare the effects of visual and vibrotactile feedback on postural performance to inform the selection of a feedback modality for inclusion in a home-based balance rehabilitation device. Eight subjects (46.6+/-10.6years) with peripheral vestibular deficits and eight age-matched control subjects (45.3+/-11.1years) participated in the study. Subjects performed eyes-open tandem Romberg stance trials with (vibrotactile, discrete visual, continuous visual, and multimodal) and without (baseline) feedback. Main outcome measures included medial-lateral (M/L) and anterior-posterior mean and standard deviation of body tilt, percent time spent within a no-feedback zone, and mean score on a comparative ranking survey. Both groups improved performance for each feedback modality compared to baseline, with no significant differences in performance observed among vibrotactile, discrete visual, or multimodal feedback for either group. Subjects with vestibular deficits performed best with continuous visual feedback and ranked it highest. Although the control subjects performed best with continuous visual feedback in terms of mean M/L tilt, they ranked it lowest. Despite the observed improvements, continuous visual feedback involves tracking a moving target, which was noted to induce dizziness in some subjects with vestibular deficits and cannot be used during exercises in which head position is actively changed or during eyes-closed conditions. PMID- 23022158 TI - Photorefractive keratectomy followed by cross-linking versus cross-linking alone for management of progressive keratoconus: two-year follow-up. AB - PURPOSE: To compare visual, refractive, topographic, and corneal higher-order aberration outcome at the 2-year follow-up after customized photorefractive keratectomy (PRK) followed by cross-linking (CXL) as a single procedure versus CXL alone in eyes with progressive keratoconus. DESIGN: Prospective, interventional, nonrandomized clinical trial. METHODS: Seventeen patients (34 eyes) with progressive keratoconus were assigned to 2 groups: the worse eye (17 eyes) was assigned to the PRK plus CXL group and the better eye (17 fellow eyes) was assigned to the CXL group. RESULTS: In the PRK plus CXL group, uncorrected distance acuity improved significantly, from a mean +/- standard deviation of 0.63 +/- 0.36 logarithm of the minimal angle of resolution (logMAR) units to 0.19 +/- 0.17 logMAR units (P < .05) and best distance acuity from 0.06 +/- 0.08 logMAR to 0.03 +/- 0.06 logMAR (P < .05). Manifest refraction spherical equivalent and spherical and cylindrical power improved significantly (P < .05). Simulated keratometry, flattest, steepest, average, cylindrical, apex keratometry, and inferior-superior value decreased significantly (P < .05). Total and coma-like aberrations significantly decreased for all pupil diameters (P < .05). In the CXL group, uncorrected distance acuity improved, but not significantly, from 0.59 +/- 0.29 logMAR units to 0.52 +/- 0.29 logMAR units, and best distance acuity improved from 0.06 +/- 0.11 logMAR units to 0.04 +/- 0.07 logMAR units (P > .05). Manifest refraction spherical equivalent and cylindrical power improvement was not significant (P > .05), unlike spherical power (P < .05). Steepest simulated keratometry, average simulated keratometry, and inferior superior value significantly decreased (P < .05), unlike flattest simulated keratometry, cylindrical simulated keratometry, and apex keratometry (P > .05). Total and coma-like aberrations were not decreased significantly for all pupil diameters (P > .05). No significant endothelial changes were observed in either group. CONCLUSIONS: The PRK plus CXL procedure may be a good option to reduce corneal aberrations and stabilize corneas with progressive keratoconus. PMID- 23022159 TI - Subretinal fluid in uveitic macular edema: effect on vision and response to therapy. AB - PURPOSE: To evaluate the effect of subretinal fluid (SRF), imaged with spectral domain optical coherence tomography (SD-OCT), on visual acuity outcomes in cases of uveitic macular edema (ME), and to analyze the response of SRF and uveitic ME to therapy. DESIGN: Retrospective case series. METHODS: One hundred and one eyes of 75 patients with uveitic ME, as imaged by SD-OCT, were identified at a single tertiary-care referral center. The main outcome measures were best-corrected visual acuity, central subfield thickness (CSFT), and rates of macular edema improvement (>=20% reduction in CSFT), and resolution (defined as reduction of CSFT to <315 MUm) of ME at 3 and 6 months follow-up. RESULTS: Forty eyes of 29 patients had SRF on SD-OCT at presentation, which was associated with greater macular thickness (mean CSFT 488 MUm vs 362 MUm, P = .0001) and worse visual acuity than ME without SRF (20/115 vs 20/51, P = .015). However, eyes with SRF responded more favorably to treatment, and at 3 and 6 months of follow-up they achieved greater rates of improvement and resolution of ME than eyes without SRF (77% improved and 50% resolved at 6 months, vs 20% and 13%, respectively; P = .003 and P = .017, respectively) and recovered to a similar level of visual acuity (20/62 vs 20/42 at 6 months, P = .54). CONCLUSIONS: SRF in uveitic ME is associated with thicker retinas and worse visual acuity on presentation but responds more favorably to treatment and displays greater rates of edema resolution and visual acuity improvement. PMID- 23022160 TI - Topiramate use and the risk of glaucoma development: a population-based follow-up study. AB - PURPOSE: To investigate the risk of glaucoma development after being prescribed topiramate. DESIGN: A retrospective, population-based cohort study using an administrative database. METHODS: The study group comprised 1956 patients who received their first prescription of topiramate between 2001 and 2007. The comparison cohort consisted of 15 648 randomly matched patients who never took topiramate. Each sampled patient was traced for a 1-year period from his or her index date to identify patients who subsequently received a diagnosis of glaucoma. RESULTS: Glaucoma was diagnosed in 0.36%, 0.05%, and 0.66% of the study cohort during the first month, second to third month, and fourth to twelfth month following the index date, respectively. For the comparison cohort, glaucoma was diagnosed in 0.04%, 0.11%, and 0.46% of subjects during the first month, second to third month, and fourth to twelfth month following the index date, respectively. After adjusting for potential confounding factors, patients prescribed topiramate were found to have a 7.41-fold (95% confidence interval [CI] = 2.45-22.46) greater risk of subsequently being diagnosed with glaucoma than the comparison cohort during the first month after the index date. However, this association became statistically nonsignificant during the second-to-third month and fourth-to-twelfth-month periods following the index date between the 2 cohorts (adjusted hazard ratio, 0.56, 95% CI = 0.07-4.29; and 1.35, 95% CI = 0.74 2.47, respectively). CONCLUSIONS: Topiramate use in Taiwan was associated with a significantly increased risk of being diagnosed with glaucoma within the first month after receiving a prescription for the drug. PMID- 23022161 TI - Aggressive posterior retinopathy of prematurity: risk factors for retinal detachment despite confluent laser photocoagulation. AB - PURPOSE: To analyze risk factors for retinal detachment in eyes with aggressive posterior retinopathy of prematurity (ROP) treated with confluent laser photocoagulation. DESIGN: Retrospective, consecutive, interventional case series. METHODS: Infants undergoing laser treatment for aggressive posterior ROP from January 2006 through June 2010 participated. Eyes with retinal detachment (stage 4A, 4B, and 5) at presentation and those lost to follow-up after treatments were excluded. We defined 2 groups based on outcome after confluent laser photocoagulation: retinal detachment or favorable outcome. Two groups were compared for various factors, which included birth weight, gestational age, postconceptional age at laser treatment, zone of disease, preretinal hemorrhage, pre-existing fibrovascular proliferation, tunica vasculosa lentis, laser spots used for primary treatment, need for repeat laser treatment, and new-onset fibrovascular proliferation after laser treatment. Data were analyzed using univariate and multivariate logistic regression analysis. RESULTS: One hundred nineteen eyes of 61 infants underwent laser treatment for aggressive posterior ROP. Ten (8.4%) eyes were excluded and 109 eyes (91.6%) were included. Nineteen (17.4%) of 109 eyes progressed to retinal detachment after laser treatment. On univariate analysis, multiple factors were associated with retinal detachment. Of these, all eyes with posterior zone 1 disease and all eyes demonstrating extensive fibrovascular proliferation (> 3 clock hours) after laser treatment progressed to retinal detachment. On multivariate logistic regression analysis, the most significant predictors of retinal detachment were gestational age of less than 29.5 weeks (P = .006), hemorrhages (P = .003), need for repeat laser treatment (P = .006), and new-onset limited fibrovascular traction (< 3 clock hours) after laser treatment (P = .042). CONCLUSIONS: A gestational age of less than 29.5 weeks, posterior zone 1 disease, and preretinal hemorrhages before laser treatment are the most significant risk factors for retinal detachment in aggressive posterior ROP. Of the events occurring after laser treatment, new onset fibrovascular traction is associated significantly with development of retinal detachment. PMID- 23022162 TI - Relationship between clinical characteristics of polypoidal choroidal vasculopathy and choroidal vascular hyperpermeability. AB - PURPOSE: To investigate the relationship between the clinical characteristics of polypoidal choroidal vasculopathy (PCV) and choroidal vascular hyperpermeability seen on indocyanine green angiography. DESIGN: Retrospective, consecutive, interventional case series. METHODS: We reviewed the medical records and the angiograms of 89 patients with PCV. The relationship between choroidal vascular hyperpermeability and background factors, associated clinical manifestations, and treatment responses to intravitreal injections of ranibizumab were evaluated. RESULTS: Of the 89 patients with PCV, 31 patients (34.8%) demonstrated choroidal vascular hyperpermeability. The patients with choroidal vascular hyperpermeability more frequently showed bilateral neovascular membrane than those without choroidal vascular hyperpermeability (P=.009) and had a significant relationship with a history of central serous chorioretinopathy (CSC) (P=.01). Of the 98 eyes with treatment-naive PCV, 34 eyes with choroidal vascular hyperpermeability demonstrated significantly greater subfoveal thickness than the 64 eyes without choroidal vascular hyperpermeability (P < .001). However, no significant relationship was found between choroidal vascular hyperpermeability and the other biomicroscopic and angiographic phenotypes of PCV. Three monthly intravitreal injections of ranibizumab were performed on 57 patients with treatment-naive PCV, and the presence of choroidal vascular hyperpermeability was significantly related to the persistent retinal fluid 1 month after the third ranibizumab injection (P=.01). CONCLUSIONS: The patients with PCV associated with choroidal vascular hyperpermeability more frequently demonstrated bilateral neovascular membrane, a history of CSC, a thickened choroid, and poor responses to intravitreal injections of ranibizumab than those without choroidal vascular hyperpermeability. PMID- 23022163 TI - Retinal functional changes measured by microperimetry in neovascular age-related macular degeneration treated with ranibizumab. AB - PURPOSE: To evaluate the retinal functional changes measured by scanning laser ophthalmoscope microperimetry in neovascular age-related macular degeneration treated with ranibizumab injections. DESIGN: Prospective, interventional case series. METHODS: A total of 42 eyes of 39 patients with neovascular age-related macular degeneration were included. After an initial 3 loading injections of ranibizumab, 0.5 mg per injection per month, injection was performed as needed. Evaluation of best-corrected visual acuity, microperimetry, and optical coherence tomography were performed before treatment and 3 months, 6 months, and 12 months after treatment. According to the appearance of the subfoveal choroidal neovascular membrane on fluorescein angiography, the study group was divided into patients with a predominantly or purely classic choroidal neovascular membrane, those with a minimally classic choroidal neovascular membrane, and patients with occult choroidal neovascular membrane. RESULTS: In all the subjects, mean retinal sensitivity of the central 12-degree area had increased significantly from 4.89 +/- 3.1 dB to 9.82 +/- 2.1 dB at month 12 (P = .01). The number of absolute scotoma points decreased significantly from 11.3 +/- 3.2 to 5.9 +/- 2.4 at month 12 (P = .01). However, in the subgroup analysis, the mean retinal sensitivity improvement, decreased absolute scotoma size, best-corrected visual acuity improvement, and central macular thickness improvement did not differ significantly among the groups. CONCLUSIONS: Intravitreal 0.5 mg ranibizumab therapy improves retinal function, quantified not only by visual acuity, but also by mean retinal sensitivity and fixation stability, as assessed by scanning laser ophthalmoscope microperimetry. Measurement of retinal sensitivity may facilitate evaluation of the effectiveness of intravitreal ranibizumab treatment in patients with neovascular age-related macular degeneration. PMID- 23022164 TI - Intravitreal ranibizumab for pigment epithelium detachment with subfoveal occult choroidal neovascularization: a prospective 24-month case series. AB - PURPOSE: To assess the effects of intravitreal ranibizumab injection in patients affected by pigment epithelial detachment associated with occult subfoveal choroidal neovascularization. DESIGN: Prospective, interventional case series. METHODS: PARTICIPANTS: Forty eyes of 40 patients were considered for the purpose of the study. Consecutive patients were recruited for a 24-month study. All patients underwent a complete ophthalmic examination, including best-corrected visual acuity on Early Treatment Diabetic Retinopathy Study (ETDRS) charts. After a 3-monthly loading phase, further intravitreal ranibizumab injections were administered on the basis of detection of any type of fluid on optical coherence tomography. PRIMARY OUTCOME MEASURES: Changes in mean best-corrected visual acuity at 12 and 24 months and the proportion of eyes losing fewer than 15 letters (corresponding to 3 ETDRS lines) from baseline visual acuity. SECONDARY OUTCOME MEASURES: Changes in central macular thickness on optical coherence tomography and variation in mean area of the entire lesion. RESULTS: Forty patients were included. Mean best-corrected visual acuity decreased from 20/66 (58 ETDRS letters) to 20/83 (53 letters) at 12 months and 20/112 (489 ETDRS letters) at 24 months (P = .003). Eighty percent and 67.5% of eyes lost fewer than 3 lines at 12 and 24 months, respectively. Mean central macular thickness passed from 545 MUm to 428 MUm at 12 months and 426 MUm at 24 months. Mean lesion area changed from 6826 MUm(2) to 6312 MUm(2) at 12 months and 6010 MUm(2) at 24 months. CONCLUSIONS: The treatment of pigment epithelial detachment associated with occult subfoveal choroidal neovascularization with intravitreal ranibizumab injection after a 3-monthly loading phase and pro re nata strategy can lead to partial results over a 24-month follow-up. Further investigations are warranted to establish the best therapeutic approach to this disease. PMID- 23022165 TI - Ocular torsion among patients with intermittent exotropia: relationships with disease severity factors. AB - OBJECTIVE: To investigate the distribution of ocular torsion in patients with intermittent exotropia and to determine possible correlation between the torsion and the severity of intermittent exotropia. DESIGN: Prospective, comparative study comprising 600 eyes of 300 children. METHODS: One hundred fifty patients with intermittent exotropia between 4 and 15 years of age and another 150 age matched normal controls without strabismus were enrolled prospectively. Digital nonmydriatic fundus photographs were obtained from both eyes of each subject and the disc-foveal angle was calculated using digital image software. All photographs also were graded as normal, extorsion, or intorsion. We compared the size of the disc-foveal angle between the normal and intermittent exotropia group. We analyzed possible correlations between the disc-foveal angle and disease severity factors, including amount of exotropia, Titmus stereoacuity, and duration of strabismus. RESULTS: Mean disc-foveal angle of intermittent exotropia group was significantly larger than that of normal control group (6.13 and 5.13 degrees, respectively; P < .01). Ocular torsion (either extorsion or intorsion) was discovered in 45 (30%) patients among the intermittent exotropia group, whereas it was found in only 16 (11%) individuals among the normal control group (P < .01). The size of disc-foveal angle showed significant positive correlations with the amount of exotropia and the degree of stereoacuity (r = 0.45, P < .01, and r = 0.51, P < .01, respectively). CONCLUSIONS: Ocular torsion could be found not infrequently in patients with intermittent exotropia. Furthermore, the amount of torsion showed a significant relationship to the disease severity of intermittent exotropia. Assessment of ocular torsion could be used as a supplementary tool for evaluating fusion in patients with intermittent exotropia. PMID- 23022166 TI - Preferential hyperacuity perimeter and prognostic factors for metamorphopsia after idiopathic epiretinal membrane surgery. AB - PURPOSE: To document changes in metamorphopsia via preferential hyperacuity perimeter and to identify prognostic factors related to favorable metamorphopsia outcome after idiopathic epiretinal membrane surgery. DESIGN: Prospective, consecutive, interventional case series. METHODS: We prospectively included 29 eyes of 27 patients who underwent successful vitrectomy for idiopathic epiretinal membrane. All eyes underwent examinations before surgery and at 2 weeks and 1, 3, and 6 months after surgery. Metamorphopsia was assessed by using a preferential hyperacuity perimeter. Several clinical factors were analyzed to reveal relationships with final metamorphopsia outcome, including the duration of symptoms, best-corrected visual acuity, and spectral-domain optical coherence tomography findings. Spectral-domain optical coherence tomography findings included assessment of central foveal thickness, and the integrity of the photoreceptor inner segment and outer segment (IS/OS) junction. RESULTS: At baseline, preferential hyperacuity perimeter detected areas of distortion in 15 eyes (51.7%). At 6 months after surgery, there was significant reduction in metamorphopsia (P = .001), which was paralleled with significant improvement of best-corrected visual acuity and reduction of central foveal thickness (P < .001). At 6 months after surgery, the degree of metamorphopsia was related significantly to the severity of preoperative metamorphopsia and central foveal thickness at baseline (rho = 0.856; P < .001; rho = 0.412; P = .027; respectively). Eyes with broadly disrupted IS/OS junction of more than 200 MUm before surgery revealed significantly poorer postoperative metamorphopsia than those with intact or narrowly disrupted IS/OS junction (P = .001). However, duration of symptoms and baseline best-corrected visual acuity were not correlated with final metamorphopsia (P = .625 and P = .052, respectively). CONCLUSIONS: Significant reduction of metamorphopsia paralleled the improvement of best-corrected visual acuity and central foveal thickness until 6 months after idiopathic epiretinal membrane surgery. The significant predictors for postoperative metamorphopsia outcome were the degree of preoperative metamorphopsia, central foveal thickness, and the photoreceptor IS/OS junction integrity at baseline. PMID- 23022167 TI - Four-year treatment results of neovascular age-related macular degeneration with ranibizumab and causes for discontinuation of treatment. AB - PURPOSE: To evaluate 4-year treatment results of neovascular age-related macular degeneration with ranibizumab using a variable dosing regimen. DESIGN: Retrospective, single-center chart review. METHODS: This was a retrospective single-center study that included 855 patients with neovascular age-related macular degeneration receiving treatment with ranibizumab during a 4-year period. Included in the study were patients with a minimum follow-up of 15 months and all patients who terminated treatment regardless of follow-up. RESULTS: A total of 1321 patients were treated over the 4-year period, and 855 patients were eligible for inclusion. Of those, 456 patients were still receiving active treatment, whereas 399 patients had discontinued treatment. Overall treatment results showed a significant decrease in vision from 53.2 Early Treatment Diabetic Retinopathy Study letters (range, 1 to 85 letters) to 50.5 letters (range, 1 to 87 letters; P < .001). Mean follow-up was 23.3 months (range, 4 to 48 months). The reason for discontinuing treatment in 181 patients was no signs of activity, whereas 113 patients were judged to be nontreatable. Thirty-six patients declined further treatment for various reasons. CONCLUSIONS: This report shows that when follow-up extends beyond 2 to 3 years, visual acuity does seem to decrease. Our data show that different responder groups can be identified: bad or nonresponders (approximately 15% of all patients) and good responders (approximately 21% of all patients). These 2 groups in general can be identified within the first 2 years of treatment, whereas the third group of regular responders (approximately 64% of all patients) require continuous monitoring and treatment for years. PMID- 23022168 TI - Evaluation of artificially-weathered standard fuel oil toxicity by marine invertebrate embryogenesis bioassays. AB - wWeathering of petroleum spilled in the marine environment may not only change its physical and chemical properties but also its effects on the marine ecosystem. The objective of this study was to evaluate the toxicity of the water accommodated fraction (WAF) obtained from a standard fuel oil following an environmentally realistic simulated weathering process for a period of 80 d. Experimental flasks with 40 g L(-1) of fuel oil were incubated at 18 degrees C with a 14 h light:10 h dark photoperiod and a photosynthetically active radiation (PAR) intensity of 70 MUE m(-2) s(-1). Samples were taken at four weathering periods: 24 h, 7, 21 and 80 d. WAF toxicity was tested using the sea urchin (Paracentrotus lividus) and mussel (Mytilus galloprovincialis) embryo-larval bioassays and the aromatic hydrocarbons levels (AH) in the WAF were measured by gas chromatography/mass spectrometry. In contrast with the classic assumption of toxicity decrease with oil weathering, the present study shows a progressive increase in WAF toxicity with weathering, being the EC(50) after 80d eightfold lower than the EC(50) at day 1, whereas AH concentration slightly decreased. In the long term, inoculation of WAF with bacteria from a hydrocarbon chronically polluted harbor slightly reduced toxicity. The differences in toxicity between fresh and weathered fuels could not be explained on the basis of the total AH content and the formation of oxidized derivatives is suggested to explain this toxicity increase. PMID- 23022169 TI - Induction of apoptosis in testis of the marine teleost mummichog Fundulus heteroclitus after in vivo exposure to the antifouling biocide 4,5-dichloro-2-n octyl-3(2H)-isothiazolone (Sea-Nine 211). AB - 4,5-dichloro-2-n-octyl-3(2H)-isothiazolone (Sea-Nine 211) has been widely used as an effective antifouling biocide. However, little is known about its reproductive toxicity in fish. Here we investigated testicular toxicity in a marine teleost, the mummichog Fundulus heteroclitus, after exposure to Sea-Nine 211 for 28 d. Although Sea-Nine 211 exposure did not affect germ cell proliferation in testis, terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labeling revealed that the number of apoptotic spermatocytes was increased in the 1.0- and 3.0-MUg L(-1) groups, and significant differences emerged between the 1.0-MUg L( 1) group and control groups. Immunohistochemistry showed that the numbers of cysts expressing caspases 2, 3, 6, and 8 (apoptosis-associated proteins) were significantly increased in the 1.0-MUg L(-1) group, whereas the signal intensity of an anti-apoptotic protein Bcl-xL was reduced in a dose-dependent manner. Moreover, the number of cysts positive for neuronal nitric oxide synthase was twofold higher in the 1.0-MUg L(-1) group than in the control groups. These results suggest that long-term exposure to Sea-Nine 211 induces apoptosis in the testicular germ cells of mummichogs via a caspase-dependent pathway and that oxidative stress via nitric oxide synthesized by neuronal nitric oxide synthase is involved in this induction. PMID- 23022170 TI - Binding interactions of algal-derived dissolved organic matter with metal ions. AB - The nature and composition of dissolved organic matter (DOM) strongly influences its binding properties to heavy metals and thus their fate, mobility and toxicity in aquatic environments. Fluorescence spectroscopy with parallel factor analysis (PARAFAC) was used to characterize DOM exuded by the cosmopolitan freshwater green algae Scenedesmus acutus during early exponential growth phase. One protein like (peak T; C2) and two humic-like components (peaks A+C and A+M, C1 and C3, respectively) were split half validated on 122 emission-excitation matrices (EEMs). Our data show that both humic-like could be associated with biological activities. Unlike Cd, Pb and Zn, Cu strongly binds to algogenic DOM with conditional stability constants (logK) averaging 5.26+/-0.29 (from 4.85 to 5.36). Significant differences in logK values were found between humic-like PARAFAC components, indicating clear differences in the binding properties of humic-like components with copper. PMID- 23022171 TI - Association between single nucleotide polymorphisms of the transforming growth factor beta1 gene and the risk of severe radiation esophagitis in patients with lung cancer. AB - PURPOSE: We investigated the association between single nucleotide polymorphisms (SNPs) in the transforming growth factor beta1 (TGFbeta1) gene and the risk of radiation-induced esophageal toxicity (RE) in patients with non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Ninety-seven NSCLC patients with available genomic DNA samples and mostly treated with intensity modulated radio(chemo)therapy from 2003 to 2006 were used as a test dataset and 101 NSCLC patients treated with 3-dimensional conformal radio(chemo)therapy from 1998 to 2002 were used as a validation set. We genotyped three SNPs of the TGFbeta1 gene (rs1800469:C-509T, rs1800471:G915C, and rs1982073:T869C) by the polymerase chain reaction restriction fragment length polymorphism method. RESULTS: In the test dataset, the CT/TT genotypes of TGFbeta1 rs1800469:C-509T were associated with a statistically significant higher risk of RE grade?3 in univariate (P=0.026) and multivariate analysis (P=0.045) when compared with the CC genotype. These results were again observed in both univariate (P=0.045) and multivariate (P=0.023) analysis in the validation dataset. CONCLUSION: We found and validated that the TGFbeta1 rs1800469:C-509T genotype is associated with severe RE. This response marker may be used for guiding therapy intensity in an individual patient, which would further the goal of individualized therapy. PMID- 23022173 TI - Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. AB - PURPOSE: To explore in a prospective trial the prognostic value of hypoxia imaging before and during radiochemotherapy in patients with locally advanced head and neck cancer. PATIENTS AND METHODS: Twenty-five patients with stage III/IV head and neck cancer were investigated with [(18)F]-fluoromisonidazole (FMISO) PET/CT at four time points during radiochemotherapy (baseline, 8-10 Gy, 18-20 Gy,50-60 Gy). FMISO PET/CT image parameters were extracted including maximum-tumour-to-background (TBR(max)) and thresholded volume at different TBR ratios. CT volume and baseline FDG-PET/CT image parameters were also included. Parameters at all time points were investigated for their prognostic value with the local-progression-free-survival endpoint (LPFS). Significance was evaluated with multivariate Cox (including clinical parameters) and Log-rank tests. RESULTS: FMISO-image parameters were found to have a strong association with the LPFS endpoint, and were strongest at the week 1 and 2 time points (p = 0.023 0.048 and 0.042-0.061 respectively on multivariate Cox). Parameters measured at baseline were only significant on univariate analysis. None of the clinical parameters, and also FDG- or CT-delineated volumes, were significantly associated with LPFS. CONCLUSION: This prospective, exploratory study demonstrated that FMISO-PET/CT imaging during the initial phase of treatment carries strong prognostic value. FMISO-PET/CT imaging at 1 or 2 weeks during treatment could be promising way to select patients that would benefit from hypoxia modification or dose-escalated treatment. A validation study is on-going. PMID- 23022172 TI - Coxsackie-adenovirus receptor as a novel marker of stem cells in treatment resistant non-small cell lung cancer. AB - BACKGROUND: Treatment resistance resulting from the presence of cancer stem cells (CSCs) remains a challenge in cancer treatment. Little is known about possible markers of CSCs in treatment-resistant non-small cell lung cancer (NSCLC). We explored the coxsackie-adenovirus receptor (CAR) as one such marker of CSCs in models of treatment-resistant NSCLC. MATERIALS AND METHODS: Resistant H460 and A549 cell lines were established by repeated exposure to paclitaxel or fractionated radiation. CSC markers were measured by Western blotting and flow cytometry. We also established stable CAR-overexpressing and stable shRNA-CAR knockdown cell lines and assessed their survival, invasiveness, and tumorigenic capabilities with clonogenic, telomerase, Matrigel, and tumor formation assays. RESULTS: CAR expression was associated with CSC phenotype both in vitro and in vivo. CAR-overexpressing cells were more treatment-resistant, self-renewing, and tumorigenic than were parental cells, and shRNA-mediated knockdown of CAR expression was sufficient to inhibit these functions. CAR expression also correlated with the epithelial-mesenchymal transition. CONCLUSIONS: We showed for the first time that CAR is a marker of CSCs and may affect the activities of CSCs in treatment-resistant NSCLC. CAR may prove to be a target for CSC treatment and a predictor of treatment response in patients with NSCLC. PMID- 23022174 TI - The TGF-beta co-receptor endoglin regulates macrophage infiltration and cytokine production in the irradiated mouse kidney. AB - BACKGROUND AND PURPOSE: We previously showed that mice with reduced levels of the transforming growth factor-beta (TGF-beta) co-receptor endoglin (Eng(+/-) mice) develop less fibrosis and vascular damage after kidney irradiation than their wild type (Eng(+/+) mice) littermates; however, the underlying mechanism was unclear. Results from current studies suggest that this occurs via modulation of the radiation-induced inflammatory response. MATERIALS AND METHODS: Kidneys of Eng(+/+) and Eng(+/-) mice were irradiated with 16Gy. Mice were sacrificed at 20weeks after irradiation and gene expression and protein levels were analyzed. RESULTS: Kidney irradiation triggered the infiltration of macrophages in both Eng(+/+) and Eng(+/-) mice, however, levels of macrophage-produced cytokines interleukin 1 beta (Il1b) and interleukin 6 (Il6) were reduced in irradiated Eng(+/-) compared to Eng(+/+) mice. Double immuno-stainings confirmed that IL-6 was produced by macrophages, whereas IL-1beta was mainly detected in other cell types. Accordingly, inflammatory cell precursors derived from the bone marrow of Eng(+/-) mice showed impaired ability to express Il1b and Il6 compared to wild type mice. CONCLUSIONS: Endoglin promotes kidney inflammation after irradiation by regulating macrophage infiltration and interleukin production, thereby promoting pathogenic changes after radiation exposure. PMID- 23022175 TI - Vascular abnormalities associated with acute hypoxia in human melanoma xenografts. AB - BACKGROUND AND PURPOSE: The fraction of hypoxic cells has been shown to differ substantially among human tumors of the same histological type. In this study, a window chamber model was used to identify possible mechanisms leading to the development of highly different hypoxic fractions in A-07 and R-18 human melanoma xenografts. MATERIALS AND METHODS: Chronic and acute hypoxia was assessed in intradermal tumors using an immunohistochemical and a radiobiological assay. Functional and morphological parameters of the vascular networks of tumors growing in dorsal window chambers were assessed with intravital microscopy. RESULTS: R-18 tumors showed significantly higher hypoxic fractions than A-07 tumors, and the difference was mostly due to acute hypoxia. Compared to A-07 tumors, R-18 tumors showed low vascular densities, low vessel diameters, long vessel segments, low blood flow velocities, frequent fluctuations in blood flow, and a high fraction of narrow vessels with absent or very low and varying flux of red blood cells. CONCLUSION: The high fraction of acute hypoxia in R-18 tumors was a consequence of frequent fluctuations in blood flow and red blood cell flux combined with low vascular density. The fluctuations were most likely caused by high geometric resistance to blood flow in the tumor microvasculature. PMID- 23022176 TI - Residual rotational set-up errors after daily cone-beam CT image guided radiotherapy of locally advanced cervical cancer. AB - PURPOSE: Due to the often quite extended treatment fields in cervical cancer radiotherapy, uncorrected rotational set-up errors result in a potential risk of target miss. This study reports on the residual rotational set-up error after using daily cone beam computed tomography (CBCT) to position cervical cancer patients for radiotherapy treatment. METHODS AND MATERIALS: Twenty-five patients with locally advanced cervical cancer had daily CBCT scans (650 CBCTs in total) prior to treatment delivery. We retrospectively analyzed the translational shifts made in the clinic prior to each treatment fraction as well as the residual rotational errors remaining after translational correction. RESULTS: The CBCT guided couch movement resulted in a mean translational 3D vector correction of 7.4 mm. Residual rotational error resulted in a target shift exceeding 5 mm in 57 of the 650 treatment fractions. Three patients alone accounted for 30 of these fractions. Nine patients had no shifts exceeding 5 mm and 13 patients had 5 or less treatment fractions with such shifts. CONCLUSION: Twenty-two of the 25 patients have none or few treatment fractions with target shifts larger than 5mm due to residual rotational error. However, three patients display a significant number of shifts suggesting a more systematic set-up error. PMID- 23022177 TI - High precision bladder cancer irradiation by integrating a library planning procedure of 6 prospectively generated SIB IMRT plans with image guidance using lipiodol markers. AB - PURPOSE: To increase local control and decrease side effects for urinary bladder cancer patients by integrating a library planning procedure with image guidance using lipiodol markers. METHODS AND MATERIALS: Twenty patients with T2-T4N0M0 grade 2-3 invasive bladder carcinoma were treated according to an online adaptive protocol. Initially, the gross tumour volume (GTV) was demarcated during cystoscopy by injecting several drops of lipiodol in the submucosa around the tumour. Subsequently two CT scans were acquired with a full bladder and a voided bladder. On both scans, the boost volume (GTV) and the low-risk bladder volume were delineated. Using an interpolation tool, six concomitant boost IMRT plans with increasing bladder volumes were generated. For each fraction the procedure at the treatment unit was as follows: Firstly, a ConeBeam-CT was acquired and based on the amount of bladder filling the best fitting bladder contours and corresponding GTV and IMRT plans were selected. Secondly, the lipiodol markers were registered using the corresponding GTV contours and it was verified that the corresponding 95%-isodose surface covered the entire bladder. Finally, an online setup correction was applied based on this registration and the corresponding treatment plan was irradiated. RESULTS: The lipiodol markers were very useful in outlining the GTV at the planning CT and for daily setup correction. While the patients strived for a full bladder filling at time of the treatment, this was seldom accomplished. Due to our protocol an appropriate plan with adequate coverage of the PTV and without excessive dose to healthy tissue was delivered every day. The treatment was very well tolerated by all patients. At the end of the treatment no grade 3 urinary or gastro-intestinal toxicity was observed. After a median follow-up of 28 months two local relapses occurred. CONCLUSION: Using the library planning approach combined with online image guidance using lipiodol markers, we were able to deliver a highly conformal dose distribution to all bladder cancer patients achieving promising clinical results. PMID- 23022178 TI - Selective amygdalohippocampectomy versus standard temporal lobectomy in patients with mesial temporal lobe epilepsy and unilateral hippocampal sclerosis. AB - Several studies have demonstrated the positive effect of resective epilepsy surgery in drug-resistant temporal lobe epilepsy (TLE). However, it is still a matter of debate whether selective amygdalohippocampectomy (SAH) or standard temporal lobectomy (STL) are the most effective approaches concerning seizure outcome, quality of life and memory. In each of the two centers participating in this study either SAH or STL was the neurosurgical standard procedure irrespective of contextual aspects. Thus, with this postoperative assessment of resected patients we sought to avoid any selection bias that usually impaired comparative trials of both surgical approaches. We finally identified and studied 95 adult patients who had undergone either SAH (n=46) or STL (n=49) between 1999 and 2009 and fulfilled the inclusion criteria, namely drug-resistant unilateral mesial TLE with hippocampal sclerosis without any further structural lesions. We assessed the postoperative seizure outcome according to the ILAE criteria and postoperative quality of life by means of standardized questionnaires. Finally, we compared postoperative neuropsychological performance in 60 completely seizure free patients (n=27 after SAH, n=33 after STL) prior to, one year after surgery and at a long-term follow-up with a mean of seven years. 78.2% of SAH and 85.7% of STL were seizure-free at the last observation. Quality of life had improved in 95.6% of the SAH patients and 89.8% of the STL patients. These differences were not statistically significant. Left-sided TLE patients had a significantly worse verbal memory outcome irrespective of the surgical method. However, SAH patients had a significantly better outcome concerning visual encoding, verbal and visual short-term memory and visual working memory. In this study, seizure outcome and quality of life did not differ depending on the surgical approach. However, a more selective resection led to better neuropsychological performances. PMID- 23022179 TI - Functional and structural features of adipokine family. AB - In the mid-1990s, the interest in adipose tissue was revived by the discovery of leptin. Since then numerous other hormones have been isolated from white adipose tissue that has no longer considered an inert tissue mainly devoted to energy storage but emerged as an active participant in regulating physiologic and pathologic processes, including immunity and inflammation. Adipose tissue produces and releases a variety of proinflammatory and anti-inflammatory factors, including the adipokines, as well as cytokines and chemokines. Proinflammatory molecules produced by adipose tissue have been implicated as active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. In contrast, reduced leptin levels might predispose to increased susceptibility to infection caused by reduced T-cell responses in malnourished individuals. Altered adipokine levels have been observed in a variety of inflammatory conditions, although their pathogenic role has not been completely clarified. In this paper we want to review: (i) the role of adipose tissue in different biological processes, (ii) the functional and structural description of all the known adipokines subdivided in different subfamilies, (iii) the adipokine involvement in obesity and cancers, and (iv) the adipokine interactome. PMID- 23022180 TI - Discoidin domain receptor 2 (DDR2) regulates proliferation of endochondral cells in mice. AB - Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase that is activated by fibrillar collagens. DDR2 regulates cell proliferation, cell adhesion, migration, and extracellular matrix remodeling. The decrement of endogenous DDR2 represses osteoblastic marker gene expression and osteogenic differentiation in murine preosteoblastic cells, but the functions of DDR2 in chondrogenic cellular proliferation remain unclear. To better understand the role of DDR2 signaling in cellular proliferation in endochondral ossification, we inhibited Ddr2 expression via the inhibitory effect of miRNA on Ddr2 mRNA (miDdr2) and analyzed the cellular proliferation and differentiation in the prechondrocyte ATDC5 cell lines. To investigate DDR2's molecular role in endochondral cellular proliferation in vivo, we also produced transgenic mice in which the expression of truncated, kinase dead (KD) DDR2 protein is induced, and evaluated the DDR2 function in cellular proliferation in chondrocytes. Although the miDdr2-transfected ATDC5 cell lines retained normal differentiation ability, DDR2 reduction finally promoted cellular proliferation in proportion to the decreasing ratio of Ddr2 expression, and it also promoted earlier differentiation to cartilage cells by insulin induction. The layer of hypertrophic chondrocytes in KD Ddr2 transgenic mice was not significantly thicker than that of normal littermates, but the layer of proliferative chondrocytes in KD-Ddr2 transgenic mice was significantly thicker than that of normal littermates. Taken together, our data demonstrated that DDR2 might play a local and essential role in the proliferation of chondrocytes. PMID- 23022181 TI - Therapeutic effects of alpha-iso-cubebenol, a natural compound isolated from the Schisandra chinensis fruit, against sepsis. AB - alpha-Iso-cubebenol, a natural compound isolated from the Schisandra chinensis fruit, strongly enhances survival rate in cecal ligation and puncture (CLP) challenge-induced sepsis. Mechanistically, alpha-iso-cubebenol markedly reduces viable bacteria in the peritoneal fluid and peripheral blood, by increasing production of superoxide anion. alpha-Iso-cubebenol also significantly attenuates widespread immune cell apoptosis in a mouse CLP sepsis model, and inhibits the production of proinflammatory cytokines including interleukin-1beta (IL-1beta) and IL-6 in CLP mice and lipopolysaccharide-stimulated splenocytes. Taken together, the results indicate that alpha-iso-cubebenol can reverse the progression of septic shock by triggering multiple protective downstream signaling pathways to enhance microbial killing and maintain organ function and leukocyte survival. PMID- 23022182 TI - Monoallelic gene targeting in hypoblast stem cells reveals X chromosome inactivation. AB - We recently isolated hypoblast stem cells (HypoSC), which are related to embryonic stem (ES) cells. ES cells efficiently perform homologous recombination (HR) and lack X chromosome inactivation (Xi), but it is unknown whether the same applies to HypoSC. Using the X-linked hypoxanthine phosphoribosyl transferase (HPRT) gene, we find that HypoSC perform HR with similar frequency as ES cells. Monoallelic targeting in female HypoSC eliminated HPRT gene expression, implying epigenetic inactivation of the other allele. Although density-induced differentiation complicated selection, the targeted clones maintained their original properties. These results will facilitate targeted genetic manipulation of HypoSC and the study of Xi. PMID- 23022183 TI - Regression of atherosclerosis in apolipoprotein E-deficient mice by lentivirus mediated gene silencing of lipoprotein-associated phospholipase A2. AB - Overexpression of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is implicated in atherosclerosis. We tested the hypothesis that lentivirus-mediated Lp-PLA(2) silencing could inhibit atherosclerosis in apolipoprotein E-deficient mice. Sixty eight apolipoprotein E-deficient mice were fed a high-fat diet and a constrictive collar was placed around the left carotid artery to induce plaque formation. The mice were randomly divided into control, negative control (NC) and RNA interference (RNAi) groups. Lp-PLA(2) RNAi or scrambled NC lentivirus viral suspensions were constructed and transfected into the carotid plaques 8 weeks after surgery; the control group was administered saline. The carotid plaques were assessed 7 weeks later using hematoxylin and eosin, Masson's trichrome and oil red O staining; plasma and lesion inflammatory gene expression were examined using ELISAs and real-time PCR. Seven weeks after transfection, the serum concentration and plaque mRNA expression of Lp-PLA(2) was significantly lower in the RNAi group, and lead to reduced local and systemic inflammatory gene expression. Lp-PLA(2) RNAi also ameliorated plaque progression, reduced the plaque lipid content and increased the plaque collagen content. The effects of Lp PLA(2) RNAi were independent of serum lipoprotein levels, as the triglyceride and total cholesterol levels of the control, NC and RNAi groups were not significantly different. These findings support the hypothesis that lentivirus mediated Lp-PLA(2) gene silencing has therapeutic potential to inhibit atherosclerosis and increase plaque stability, without altering the plasma lipoprotein profile. PMID- 23022184 TI - Bex2 regulates cell proliferation and apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase pathway. AB - The function of Bex2, a member of the Brain Expressed X-linked gene family, in glioma is controversial and its mechanism is largely unknown. We report here that Bex2 regulates cell proliferation and apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase (JNK) pathway. The expression level of Bex2 is markedly increased in glioma tissues. We observed that Bex2 over-expression promotes cell proliferation, while down-regulation of Bex2 inhibits cell growth. Furthermore, Bex2 down-regulation promotes cell apoptosis and activates the JNK pathway; these effects were abolished by administration of the JNK specific inhibitor, SP600125. Thus, Bex2 may be an important player during the development of glioma. PMID- 23022185 TI - MK5 is degraded in response to doxorubicin and negatively regulates doxorubicin induced apoptosis in hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The mechanisms by which hepatoma cells resist apoptosis induced by doxorubicin are largely unknown. MAPKAPK5 (MK5), also named as p38 regulated/activated protein kinase (PRAK), has been identified as a crucial mediator of skin tumorigenesis in mouse and colon cancerogenesis in human. Here, we describe a novel role of MK5 in doxorubicin-induced apoptosis in human hepatoma cells. Expression of MK5 was highly upregulated in hepatoma cell lines. Doxorubicin rather than other chemotherapeutic drugs reduced MK5 protein level in a time- and concentration-dependent manner in hepatoma cells (HepG2 and Hep3B). We further showed that MK5 degradation induced by doxorubicin was via the 26S proteasome. Remarkably, stable overexpression of MK5 led to decreased cleavage of caspase-3 and PARP and attenuated doxorubicin-induced apoptosis, while stable knockdown of endogenous MK5 sensitized hepatoma cells to doxorubicin, which was coupled with increased cleavage of caspase-3 and PARP. Taken together, our results firstly demonstrate that MK5 is degraded in response to doxorubicin and negatively regulates doxorubicin-induced apoptosis, providing novel insights into the molecular mechanism of doxorubicin resistance in hepatoma cells. PMID- 23022186 TI - Dysregulated balance of retinoid-related orphan receptor gammat-dependent innate lymphoid cells is involved in the pathogenesis of chronic DSS-induced colitis. AB - Retinoid-related orphan receptor (ROR) gammat-expressing and IL-22-producing NKp46(+) innate lymphoid (ILC22) cells reside in the lamina propria of the intestine in mice, suggesting that ILC22 cells contribute to host defense during intestinal damage in models of colitis in mice. Nevertheless, another set of pathological interferon (IFN)-gamma and/or IL-17A-producing innate lymphoid cells (ILC1 and ICL17) may participate in the pathogenesis in different models of colitis. We here showed that RORgammat(+)IL-22(+) ILC22 cells were localized in Thy-1(high)SCA-1(high) and/or Thy-1(high)SCA-1(low) subpopulations of the intestine in normal and dextran sodium sulfate (DSS)-induced colitic RORgammat sufficient Rag-2(-/-) mice. RORgammat-deficient Rag-2(-/-) mice developed more severe DSS-induced colitis accompanied with lower expression of REG3beta and REG3gamma in the colon, but with a lower ratio and absolute number of IFN-gamma producing ILC1 cells as compared to control RORgammat-sufficient Rag-2(-/-) mice. Collectively, not only the presence of ILC22 cells but also the balance of protective and pathogenic ILCs may be involved in the prevention of colitis. PMID- 23022188 TI - Amorphous silica nanoparticles enhance cross-presentation in murine dendritic cells. AB - Nanomaterials (NMs) exhibit unique physicochemical properties and innovative functions, and they are increasingly being used in a wide variety of fields. Ensuring the safety of NMs is now an urgent task. Recently, we reported that amorphous silica nanoparticles (nSPs), one of the most widely used NMs, enhance antigen-specific cellular immune responses and may therefore aggravate immune diseases. Thus, to ensure the design of safer nSPs, investigations into the effect of nSPs on antigen presentation in dendritic cells, which are central orchestrators of the adaptive immune response, are now needed. Here, we show that nSPs with diameters of 70 and 100 nm enhanced exogenous antigen entry into the cytosol from endosomes and induced cross-presentation, whereas submicron-sized silica particles (>100 nm) did not. Furthermore, we show that surface modification of nSPs suppressed cross-presentation. Although further studies are required to investigate whether surface-modified nSPs suppress immune-modulating effects in vivo, the current results indicate that appropriate regulation of the characteristics of nSPs, such as size and surface properties, will be critical for the design of safer nSPs. PMID- 23022187 TI - The anti-inflammatory effects of ethyl acetate on Lipopolysaccharide/D galactosamine challenged mice and Lipopolysaccharide activated RAW264.7 cells. AB - Ethyl acetate (EA) is an ordinary organic compound in fruits, wine and cosmetics, and used as a solvent frequently. With the recent observation in our experiment, we suspected that EA could affect immune function, in particular macrophage activity. In this paper, we tested EA's protect effect against death in Lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced endotoxic shock model in mice. And also found EA decreased the LPS-induced mRNA expression of mediators of inflammation including cyclooxygenase 2 (COX2), inducible NOS (iNOS), and tumor necrosis factor alpha (TNF alpha) in RAW264.7 cells. Consequently, EA decreased the production of, TNF alpha and the inflammatory agent nitric oxide (NO) in RAW264.7 cells treated with LPS. Other pro-inflammatory cytokines such as IL-1h and IL-6 were similarly decreased by EA treatment of RAW264.7 cells. The potential mechanism may associate with NF-kappaB activity as we shown. Taken together, these results suggest that EA has anti-inflammatory properties. PMID- 23022189 TI - Daintain/AIF-1 (Allograft Inflammatory Factor-1) accelerates type 1 diabetes in NOD mice. AB - A large body of experimental evidence suggests that cytokines trigger pancreatic beta-cell death in type 1 diabetes mellitus. Daintain/AIF-1 (Allograft Inflammatory Factor-1), a specific marker for activated macrophages, is accumulated in the pancreatic islets of pre-diabetic BB rats. In the present study, we demonstrate that daintain/AIF-1 is released into blood and the levels of daintain/AIF-1 in the blood of type 1 diabetes-prone non-obese diabetic (NOD) mice suffering from insulitis are significantly higher than that in healthy NOD mice. When injected intravenously into NOD mice, daintain/AIF-1 stimulates white blood cell proliferation, increases the concentrations of blood glucose, impairs insulin expression, up-regulates nitric oxide (NO) production in pancreases and accelerates diabetes in NOD mice, while the antibody against daintain/AIF-1 delays or prevents insulitis in NOD mice. These results imply daintain/AIF-1 triggers type 1 diabetes probably via arousing immune cells activation and induction of NO production in pancreas of NOD mice. PMID- 23022190 TI - Caveolin-1 up-regulates ST6Gal-I to promote the adhesive capability of mouse hepatocarcinoma cells to fibronectin via FAK-mediated adhesion signaling. AB - Caveolin-1 is a major structural protein of caveolae and plays important functions in tumorigenesis and development. Hca-F and Hepa1-6 are mouse hepatocarcinoma cell lines with high and low malignant potential, respectively. Our previous studies revealed that caveolin-1 promoted cell invasion by up regulating the glycosylation of matrix metalloproteinase inducer CD147 of Hepa1-6 and Hca-F cells. However, the roles of caveolin-1 in cell-ECM adhesion and the mechanisms involved remain unknown. This study showed that caveolin-1 overexpression in Hepa1-6 cells up-regulated sialyltransferase ST6Gal-I expression and activated FAK-mediated adhesion signaling, and down-regulation of ST6Gal-I attenuated caveolin-1-induced increase in the adhesive ability of Hepa1 6 cells to fibronectin. Conversely, caveolin-1 knockdown in Hca-F cells inhibited ST6Gal-I expression and FAK signaling-mediated cell adhesion to fibronectin. Re expression of wild-type caveolin-1 or ST6Gal-I rescued the decreased ST6Gal-I expression and adhesion of Hca-F cells caused by caveolin-1 silencing. Further studies indicated that caveolin-1 might regulate ST6Gal-I expression through caveolin-1 scaffolding domain. Taken together, these results demonstrate for the first time that caveolin-1 can up-regulate ST6Gal-I expression and further contribute to promoting mouse hepatocarcinoma cell adhesion to fibronectin by activating FAK-mediated adhesion signaling. PMID- 23022191 TI - Induction of motor neuron differentiation by transduction of Olig2 protein. AB - Olig2 protein, a member of the basic helix-loop-helix transcription factor family, was introduced into the mouse embryonic carcinoma cell line P19 for induction of motor neuron differentiation. We show that Olig2 protein has the ability to permeate the cell membrane without the addition of a protein transduction domain (PTD), similar to other basic helix-loop-helix transcription factors such as MyoD and NeuroD2. Motor neuron differentiation was evaluated for the elongation of neurites and the expression of choline acetyltransferase (ChAT) mRNA, a differentiation marker of motor neurons. By addition of Olig2 protein, motor neuron differentiation was induced in P19 cells. PMID- 23022192 TI - AT motif binding factor 1 (ATBF1) is highly phosphorylated in embryonic brain and protected from cleavage by calpain-1. AB - ATBF1 is a transcription factor that regulates genes responsible for repairing tissues and the protection of cells from oxidative stress. Therefore reduction of ATBF1 promotes susceptibility to varieties of human diseases including neurodegenerative diseases and malignant tumors. The instability of the protein was found to be an important background of diseases. Because ATBF1 is composed of a large 404-kDa protein, it can be easily targeted by proteinases. The protein instability should be a serious problem for the function in the cells and practically for our biochemical study of ATBF1. We have found that calpain-1 is a protease responsible for the degeneration of ATBF1. We observed distinct difference between embryo and adult brain derived ATBF1 regarding the sensitivity to calpain-1. The comparative study showed that eight phosphorylated serine residues (Ser1600, Ser2634, Ser2795, Ser2804, Ser2900, Ser3431, Ser3613, Ser3697) in embryonic brain, but only one site (Ser2634) in adult brain. As long as these amino acids were phosphorylated, ATBF1 derived from embryonic mouse brain showed resistance to cleavage; however, treatment with calf intestine alkaline phosphatase sensitized ATBF1 to be digested by calpain-1. An inhibitor (FK506) against calcineurin, which is a serine/threonine specific phosphatase enhanced the resistance of ATBF1 against the digestion by calpain-1. Taken together, these results demonstrate that these phosphorylation sites on ATBF1 function as a defensive shield to calpain-1. PMID- 23022193 TI - Visualizing the mouse podocyte with multiphoton microscopy. AB - The podocyte is a highly specialized kidney glomerular epithelial cell that plays an essential role in glomerular filtration and is believed to be the target of numerous glomerular diseases leading to proteinuria. Despite the leaps in our understanding of podocyte biology, new methodologies are needed to facilitate research into the cell. Multiphoton microscopy (MPM) was used to image the nephrin knockout/green fluorescent protein (GFP) knock-in heterozygote (Nphs1(tm1Rkl)/J) mouse. The nephrin promoter restricts GFP expression to the podocytes that fluoresce green under excitation. From the exterior of an intact kidney, MPM can peer into the renal parenchyma and visualize the podocytes that outline the globular shape of the glomeruli. Details as fine as the podocyte's secondary processes can be resolved. In contrast, podocytes exhibit no fluorescence in the wildtype mouse and are invisible to MPM. Phenotypically, there are no significant differences between wildtype and Nphs1(tm1Rkl)/J mice in body weight, urinary albumin excretion, creatinine clearance, or glomerular depth. Interestingly, the glomeruli are closer to the kidney capsule in female mice, making the gender the preferred choice for MPM. For the first time, green fluorescent podocytes in a mouse model free of confounding phenotypes can be visualized unequivocally and in the "positive" by MPM, facilitating intravital studies of the podocyte. PMID- 23022194 TI - The functional role of UBA1 cysteine-278 in ubiquitination. AB - Although total UBA1 levels were unchanged, after oxidation for 60 min, we observed dramatic changes in the levels of BIAM-labeled UBA1 in both the membrane and cytosol fractions that suggested oxidative stress induces translocation of UBA1 from the cytosol to the membrane. Notably, in PrdxII(-/-) oxRBCs, ubiquitination levels were reduced about 75% in the membrane fraction after 90 min, even though UBA1 levels were increased. These results suggest ubiquitination levels are determined by UBA1 activity, not the level of UBA1 protein. Levels of ubiquitin conjugate (denoted ~Ub) in HEK293T and CMT93 cells transfected with UBA1(C278S) or UBA1(C632S) were lower than in cells expressing UBA1(WT) or another cysteine mutant. During the reaction, UBA1(WT)~Ub was nearly completely eliminated within 30 min, whereas UBA1(C278S)~Ub and UBA1(C632S)~Ub persisted. Within UBA1(C278S)~Ub, the catalytic cysteine (Cys-632) remained intact; nonetheless, migration of UBA1(C278S)~Ub and UBA1(C632S)~Ub were similar. These data suggest that Cys-278 can affect Ub charging through a change in the structural conformation of UBA1, not through direct interaction at the UBA1-Ub interface. PMID- 23022195 TI - Synexpression group analyses identify new functions of FSTL3, a TGFbeta ligand inhibitor. AB - Follistatin-like 3 (FSTL3) is a secreted glycoprotein that forms inactive complexes with and acts as an endogenous inhibitor of TGFbeta ligands such as activin, myostatin and GDF11. FSTL3 gene deleted mice (FSTL3 KO) are viable, fertile and show a constellation of metabolic abnormalities, including those involving glucose and lipid homoeostasis, suggesting a role for FSTL3 and TGFbeta ligand signaling in these systems. To identify additional roles of FSTL3 and the ligands it inhibits we have used a synexpression analysis strategy. By mining microarray RNA expression data we have identified a group of 9 genes, the expression of which closely follow that of FSTL3 in both mouse and human tissues. After classifying the tissues studied according to physiological systems we found that within each system the expression of a majority, but not all, of the genes are strongly correlated with FSTL3 expression. Further, the best correlation of expression was seen in the cardiovascular system. Importantly, the promoter regions of a number of these synexpression genes have putative SMAD binding elements and in cultured embryonic fibroblasts the expression of a subset of these genes are induced in the absence of FSTL3 or in WT cells upon activin treatment. Taken together, we have identified a group of activin responsive genes the expression of which is closely related to and regulated by FSTL3. These findings link FSTL3 and TGFbeta ligand signaling and a novel subset of the synexpression group of genes to organ/tissue-specific regulatory pathways. PMID- 23022196 TI - Introducing a novel allele for the polymorphism of variable number of tandem repeats in the promoter region of XRCC5. AB - Polymorphism of variable number of tandem repeats (VNTR) in the promoter region of X-ray repair cross-complementing 5 (XRCC5; MIM: 194364, rs6147172) has been reported. The main aim of the present study is to introduce a novel allele for the VNTR polymorphism in the promoter region of XRCC5. The participants of the present study were of 535 (140 males, 395 females), unrelated, adult, healthy Iranian blood donors (Caucasians/Muslims). Genotypes of XRCC5 VNTR were determined by a high resolution melting analysis, and confirmed by DNA sequencing. Based on the sequencing of new bands upper than the 2R allele band, a novel allele was introduced (named 3R allele). The promoter region of XRCC5 contains several copies of Sp1 recognition cis regulatory elements. The novel 3R allele is capable of expanding the number of cis regulatory elements to eight. The prevalence of the 0R, 1R, 2R and 3R alleles in our sample was 0.0645, 0.5439, 0.3794 and 0.0122, respectively. The study group was at the Hardy-Weinberg equilibrium for the genotypic frequencies (chi(2)=3.95, df=6, P=0.73). It is suggested that the prevalence of the novel allele (3R allele) among European populations may be higher than its prevalence among Iranians. PMID- 23022197 TI - BDNF, produced by a TPO-stimulated megakaryocytic cell line, regulates autocrine proliferation. AB - While human platelets release endogenous brain-derived neurotrophic factor (BDNF) upon activation, a previous report on MEG-01, a megakaryocytic cell line, found no trace of BDNF production, and the pathophysiological function of platelet BDNF has remained elusive. In the present study, we demonstrate that MEG-01 produces BDNF in the presence of TPO and that this serves to potentiate cell proliferation. Our in vitro findings suggest that BDNF regulates MEG-01 proliferation in an autocrine manner, and we suggest that BDNF may be a physiological autocrine regulator of megakaryocyte progenitors. PMID- 23022198 TI - The ubiquitin specific protease-4 (USP4) interacts with the S9/Rpn6 subunit of the proteasome. AB - The proteasome is the major non-lysosomal proteolytic machine in cells that, through degradation of ubiquitylated substrates, regulates virtually all cellular functions. Numerous accessory proteins influence the activity of the proteasome by recruiting or deubiquitylating proteasomal substrates, or by maintaining the integrity of the complex. Here we show that the ubiquitin specific protease (USP) 4, a deubiquitylating enzyme with specificity for both Lys48 and Lys63 ubiquitin chains, interacts with the S9/Rpn6 subunit of the proteasome via an internal ubiquitin-like (UBL) domain. S9/Rpn6 acts as a molecular clamp that holds together the proteasomal core and regulatory sub-complexes. Thus, the interaction with USP4 may regulate the structure and function of the proteasome or the turnover of specific proteasomal substrates. PMID- 23022199 TI - A case of an extremely rare unilateral subscapular trunk and axillary artery variation in a male Caucasian: comparison to the prevalence within other populations. AB - A male Caucasian cadaver was found to have a large common trunk that branched off of the first part of the axillary artery of the left arm. This trunk gave rise to all but two arterial branches of the axillary region. The large common trunk first gave off a thoracoacromial artery followed by the main branch, the subscapular artery. The subscapular was the origin of the posterior circumflex humeral and lateral thoracic arteries immediately proximal to bifurcating into its two terminal branches, the circumflex scapular and thoracodorsal arteries. Only the superior thoracic and anterior circumflex humeral arteries arose directly from the axillary artery. Also found was a high origin of the radial artery, noteworthy by its serpentine route. In comparison, in the right arm, no variants appeared in the axillary, subscapular, or brachial arteries. A comparison with branching patterns of axillary arteries from demographically similar and dissimilar populations revealed the extreme rarity of this set of anomalies. PMID- 23022200 TI - Osteomalacia in a patient with Paget's bone disease treated with long-term etidronate. AB - A 93 year-old woman with Paget's disease of bone had been treated with etidronate without interruption during 20 years. The daily dose was usual (5mg/kg/day) but this prescription had never been stopped by her physicians. Two fractures had already occurred in pagetic (right tibia) and non pagetic bones (right fibula) within the last 2 years, and she presented rib fractures, another right tibia fracture and right femur fracture during hospitalization time. X-rays films showed major osteolysis of left ulna and right tibia. Blood samples and technetium bone scan brought no evidence for sarcoma or lytic evolution of the disease. A transiliac bone biopsy on non pagetic bone site confirmed the diagnosis of osteomalacia (increased osteoid parameters), with secondary hyperparathyroidism (hook resorption). In Paget's disease of bone, continuous treatment by etidronate may induce generalized osteomalacia, and increase the risk of fracture in both pagetic and non-pagetic bones. Whereas physicians and pharmaceutical industry try to improve the observance of those drugs, this striking observation also points out that a prescription always needs to be updated. PMID- 23022201 TI - [Recommendations on making decisions and end of life care in neonatology]. AB - Healthcare-professionals who work in neonatal units believe that a very important part of their work is the care of sick newborns, and their families if the neonate has an incurable disease or will die. The effort is focused on preventing disproportionate and unnecessary treatments that result in pain and discomfort, and also separate the child from his family. These situations usually occur when the infant has a terminal illness, extreme immaturity with complications, or severe birth defects. In this paper, the Ethics Working Group of the Spanish Society of Neonatology reflects on decision making at this time of life. The ethical aspects are reviewed, including, limiting treatment, the basis of decision-making process (that should include adequate information), the relationship of trust, and deliberation between parents and professionals to make the right decision. It highlights the importance of caring for the family in a complex situation and of great suffering, when faced with the recommendation of professionals to limit treatment because their child suffers from a disease with a poor prognosis. The care of the sick neonate care at the end of life, and their families requires a considerable effort, dedication and training of all health personnel. The repeated experience of being close to suffering and death can adversely affect the professionals involved. Finally, there is mention of the legal aspects of limiting treatment, how to perform and document decision process, the withdrawal of life support, assessment of symptoms and pain control and sedation. PMID- 23022202 TI - Life as physics and chemistry: A system view of biology. AB - Cellular life can be viewed as one of many physical natural systems that extract free energy from their environments in the most efficient way, according to fundamental physical laws, and grow until limited by inherent physical constraints. Thus, it can be inferred that it is the efficiency of this process that natural selection acts upon. The consequent emphasis on metabolism, rather than replication, points to a metabolism-first origin of life with the adoption of DNA template replication as a second stage development. This order of events implies a cellular regulatory system that pre-dates the involvement of DNA and might, therefore, be based on the information acquired as peptides fold into proteins, rather than on genetic regulatory networks. Such an epigenetic cell regulatory model, the independent attractor model, has already been proposed to explain the phenomenon of radiation induced genomic instability. Here it is extended to provide an epigenetic basis for the morphological and functional diversity that evolution has yielded, based on natural selection of the most efficient free energy transduction. Empirical evidence which challenges the current genetic basis of cell and molecular biology and which supports the above proposal is discussed. PMID- 23022203 TI - Single nucleotide polymorphisms are randomly dispersed and mostly synonymous in partial rpoB and cpn60 genes of Campylobacter showae human isolates. AB - The partial 16S rRNA, rpoB, and cpn60 genes congruently allow this study to identify all the eight isolates as the species Campylobacter showae. To our knowledge, this is the first report to reveal the interspecies and intraspecies sequence variations present in the three genes of the C. showae isolates. PMID- 23022204 TI - Effects of cereal beta-glucans and enzyme inclusion on the porcine gastrointestinal tract microbiota. AB - This study was designed to evaluate the effect barley-based diets vs. oats based diets on levels of Lactobacillus, Bifidobacterium and Enterobacterium in the porcine gastrointestinal tract (GIT). In addition the effect of enzyme supplementation in both diets was explored. Twenty-eight boars were used in a 2 * 2 factorial arrangement and were assigned to 1 of 4 dietary treatments: barley based (B) diet; barley-based diet plus an enzyme supplement (B + ES); oat-based (O) diet or oat-based diet plus an enzyme supplement (O + ES). The enzyme supplement contained endo-1,3-beta-glucanase and endo-1,4-beta-xylanase. Faecal samples were collected from the pigs prior to initiations of the experiment and at slaughter. At slaughter digesta samples were collected from the stomach, ileum, caecum, proximal and distal colon. Alterations in Lactobacillus species composition in the gastrointestinal tract (GIT) were analysed by genus-specific PCR - denaturing gradient gel electrophoresis (DGGE). DGGE profiles indicated that cereal source provoked shifts in Lactobacillus population. The most diverse populations of lactobacilli emerged after feeding the O diets. Enzymes inclusion altered the composition of Lactobacillus species prevalent throughout the GIT in animals fed the B diet, causing a shift in the dominant lactobacilli present in the caecum and proximal colon. No such effect was evident in animals fed the enzyme supplemented O + ES diet. Microbial plate counts revealed that the O diets gave rise to higher counts of Lactobacillus in the caecum and colon and Bifidobacterium counts in the ileum, caecum and colon than the B diets. The O diet caused a 2 log increase in Enterobacterium counts in the proximal colon, no such effects were observed in animals fed the B, the B + ES or the O + ES diets. Overall both O diets had a more positive influence on the counts of the beneficial microorganisms and richness of the Lactobacillus population in the porcine GIT. PMID- 23022205 TI - Transcatheter aortic valve implantation of a CoreValve device using novel real time imaging guidance. AB - Thorough imaging of the aortic valve and related structures is highly important before and during transcatheter aortic-valve implantation. However, conventional aortography is limited for guiding precise valve placement and depends on contrast injections. A real-time imaging system capable of guiding the operator during Edwards-SPAIEN valve procedures has been introduced (C-THV, Paieon, Inc.). We describe the first application of the novel C-THV system during CoreValve implantation in a very challenging clinical scenario that required precise high implantation using minimal contrast. PMID- 23022206 TI - Twisting of peripheral balloon appearing as a non-dilating peroneal artery lesion. AB - Peripheral arterial lesions are usually longer than coronary artery lesions and require longer balloons and stents. Theoretically while advancing a long balloon in a long, high grade lesion with aggressive manipulation, the balloon can twist inside the lesion, but this has not been described before in the literature. Herein we are reporting a case where peripheral balloon (PB) twisted and appeared as a non-dilating lesion. PMID- 23022207 TI - Ankle moment generation and maximum-effort curved sprinting performance. AB - Turning at high speed along acute curves is crucial for athletic performance. One determinant of curved sprinting speed is the ground reaction force that can be created by the supporting limb; the moment generated at the ankle joint may influence such force generation. Body lean associated with curved sprints positions the ankle joints in extreme in-/eversion, and may hinder the ankle moment generation. To examine the influence of ankle moment generation on curved sprinting performance, 17 male subjects performed maximum-effort curved sprints in footwear with and without a wedge. The wedged footwear was constructed with the intention to align the ankle joints closer to their neutral frontal-plane configuration during counter-clockwise curved sprints so greater joint moments might be generated. We found, with the wedged footwear, the average eversion angle of the inside leg ankle was reduced, and the plantarflexion moment generation increased significantly. Meanwhile, the knee extension moment remained unchanged. With the wedged footwear, stance-average centripetal ground reaction force increased significantly while no difference in the vertical ground reaction force was detected. The subjects created a greater centripetal ground reaction impulse in the wedged footwear despite a shortened stance phase when compared to the control. Stance-average curved sprinting speed improved by 4.3% with the wedged footwear. The changes in ankle moment and curved sprinting speed observed in the current study supports the notion that the moment generation at the ankle joint may be a performance constraint for curved sprinting. PMID- 23022208 TI - Methylprednisolone treatment increases the proportion of the highly suppressive HLA-DR(+)-Treg-cells in transplanted patients. AB - Methylprednisolone is widely used to improve immune suppression in transplanted patients threatened by acute rejection. Recently, we showed that the suppressive activity of a Treg cell population depends decisively on their percentage of highly suppressive HLA-DR(high+)-Treg cells, which are strongly reduced in rejecting transplant patients. In order to examine whether the composition of the total CD4(+)CD127(low+/-)FoxP3(+)-Treg cell pool with different Treg-subsets (DR(high+)CD45RA(-)-Tregs, DR(low+)CD45RA(-)-Tregs, DR(-)CD45RA(-)-Tregs, DR( )CD45RA(+)-Tregs) is affected by methylprednisolone bolus therapy we compared the percentages of these four different Treg cell subsets in transplant patients with biopsy proven rejection before and after steroid bolus therapy (n=23). In patients treated with steroid bolus therapy, the percentage of the naive DR( )CD45RA(+)-Tregs was significantly decreased, whereas the percentage of the DR(+)CD45RA(-)-Tregs was significantly increased. By that, the strongest increase was detected for the most suppressive DR(high+)CD45RA(-)-Tregs. However, these effects were only temporarily and closely associated to the duration of the bolus therapy. Our results suggest that besides various anti-inflammatory effects on cells of the adaptive and innate immune system, methylprednisolone also has the capacity to enhance the suppressive activity of the total Treg cell pool by increasing its percentage of highly differentiated and highly suppressive DR(high+)CD45RA(-)-Tregs. PMID- 23022209 TI - From sequence to consequence and back. AB - The genotype-phenotype relation is at the core of theoretical biology. It is argued why a mathematically based explanatory structure of this relation is in principle possible, and why it has to embrace both sequence to consequence and consequence to sequence phenomena. It is suggested that the primary role of DNA in the chain of causality is that its presence allows a living system to induce perturbations of its own dynamics as a function of its own system state or phenome, i.e. it capacitates living systems to self-transcend beyond those morphogenetic limits that exist for non-living open physical systems in general. Dynamic models bridging genotypes with phenotypic variation in a causally cohesive way are shown to provide explanations of genetic phenomena that go well beyond the explanatory domains of statistically oriented genetics theory construction. A theory originally proposed by Rupert Riedl, which implies that the morphospace that is reachable by the standing genetic variation in a population is quite restricted due to systemic constraints, is shown to provide a foundation for a mathematical conceptualization of numerous evolutionary phenomena associated with the phenotypic consequence to sequence relation. The paper may be considered a call to arms to mathematicians and the mathematically inclined to rise to the challenge of developing new formalisms capable of dealing with the deep defining characteristics of living systems. PMID- 23022211 TI - Emotional episodes in the everyday lives of people with schizophrenia: the role of intrinsic motivation and negative symptoms. AB - Research on emotional experience has indicated that subjects with schizophrenia experience less positive, and more negative emotional experience than non psychiatric subjects in natural settings. Differences in the experience of emotion may result from differences in experiences such that everyday activities may evoke emotions. The purpose of this study was to identify if everyday experience of competence and autonomy were related to positive and negative emotion. Adults with schizophrenia spectrum disorders were recruited from day treatment programs (N=45). Data were collected using experience-sampling methods. A number of subjects failed to meet data adequacy (N=13) but did not differ from retained subjects (N=32) in symptoms or cognition. Positive and negative emotion models were analyzed using hierarchical linear modeling Everyday activities were characterized by those reported as easily accomplished and requiring at most moderate talents. Positive emotional experiences were stronger than negative emotional experiences. The majority of variance in positive and negative emotion existed between persons. Negative symptoms were significantly related to positive emotion, but not negative emotion. The perception that motivation for activity was external to subjects (e.g. wished they were doing something else) was related to decreased positive emotion and enhanced negative emotion. Activities that required more exertion for activities was related to enhanced positive emotion, whereas activities that subjects reported they wanted to do was associated with reduced negative emotion. The implications of this study are that everyday experiences of people with schizophrenia do affect emotional experience and that management of experience to enhance positive emotion may have therapeutic benefits. PMID- 23022210 TI - Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. AB - Oncosomes are tumor-derived microvesicles that transmit signaling complexes between cell and tissue compartments. Herein, we show that amoeboid tumor cells export large (1- to 10-MUm diameter) vesicles, derived from bulky cellular protrusions, that contain metalloproteinases, RNA, caveolin-1, and the GTPase ADP ribosylation factor 6, and are biologically active toward tumor cells, endothelial cells, and fibroblasts. We describe methods by which large oncosomes can be selectively sorted by flow cytometry and analyzed independently of vesicles <1 MUm. Structures resembling large oncosomes were identified in the circulation of different mouse models of prostate cancer, and their abundance correlated with tumor progression. Similar large vesicles were also identified in human tumor tissues, but they were not detected in the benign compartment. They were more abundant in metastases. Our results suggest that tumor microvesicles substantially larger than exosome-sized particles can be visualized and quantified in tissues and in the circulation, and isolated and characterized using clinically adaptable methods. These findings also suggest a mechanism by which migrating tumor cells condition the tumor microenvironment and distant sites, thereby potentiating advanced disease. PMID- 23022212 TI - Subacute combined degeneration without nutritional anemia. AB - Subacute combined degeneration (SCD) is a rare neurological complication of cobalamin deficiency, characterized by demyelination of the dorsal and lateral spinal cord. The diagnosis and treatment of SCD can be delayed if a patient does not present with clear clinical and laboratory signs of nutritional anemia, which has a marked effect on neurological recovery. We report a 62-year-old man with SCD with a history of gastric cancer and chronic alcoholism who presented with ataxia, gait disturbance, urinary incontinence, and limb weakness, but without other clinical or laboratory signs of cobalamin deficiency. The SCD diagnosis was confirmed by 3-Tesla MRI, which showed intramedullary signal alteration in the posterior columns of the entire spinal cord. PMID- 23022213 TI - Energy metabolism of rat cerebral cortex, hypothalamus and hypophysis during ageing. AB - Ageing is one of the main risk factors for brain disorders. According to the neuroendocrine theory, ageing modifies the sensitivity of hypothalamus-pituitary adrenal axis to homoeostatic signals coming from the cerebral cortex. The relationships between the energy metabolism of these areas have not been considered yet, in particular with respect to ageing. For these reasons, this study was undertaken to systematically investigate in female Sprague-Dawley rats aged 4, 6, 12, 18, 24, 28 months and in 4-month-old male ones, the catalytic properties of energy-linked enzymes of the Krebs' cycle, electron transport chain, glutamate and related amino acids on different mitochondrial subpopulations, i.e. non-synaptic perikaryal and intra-synaptic (two types) mitochondria. The biochemical enzymatic pattern of these mitochondria shows different expression of the above-mentioned enzymatic activities in the investigated brain areas, including frontal cerebral cortex, hippocampus, striatum, hypothalamus and hypophysis. The study shows that: (i) the energy metabolism of the frontal cerebral cortex is poorly affected by physiological ageing; (ii) the biochemical machinery of non-synaptic perikaryal mitochondria is differently expressed in the considered brain areas; (iii) at 4-6 months, hypothalamus and hypophysis possess lower oxidative metabolism with respect to the frontal cerebral cortex while (iv), during ageing, the opposite situation occurs. We hypothesised that these metabolic modifications likely try to grant HPA functionality in response to the incoming external stress stimuli increased during ageing. It is particularly notable that age-related changes in brain bioenergetics and in mitochondrial functionality may be considered as remarkable factors during physiological ageing and should play important roles in predisposing the brain to physiopathological events, tightly related to molecular mechanisms evoked for pharmacological treatments. PMID- 23022214 TI - Nucleus Accumbens 1, a Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad protein binds to TAR DNA-binding protein 43 and has a potential role in Amyotrophic Lateral Sclerosis. AB - Protein degradation is a critical component of cellular maintenance. The intracellular translocation and targeting of the Ubiquitin Proteasome System (UPS) differentially coordinates a protein's half-life and thereby its function. Nucleus Accumbens 1 (NAC1), a member of the Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad complex (POZ/BTB) family of proteins, participates in the coordinated proteolysis of synaptic proteins by mediating recruitment of the UPS to dendritic spines. Here we report a novel interaction between NAC1 and TAR DNA binding protein 43 (TDP-43), a protein identified as the primary component of ubiquitinated protein aggregates found in patients with Amyotrophic Lateral Sclerosis (ALS). In vitro translated full-length TDP-43 associated with both the POZ/BTB domain and the non-POZ/BTB domain of NAC1 in GST pulldown assays. Other POZ/BTB proteins (including zinc finger POZ/BTB proteins and atypical POZ/BTB proteins) showed weak interactions with TDP-43. In addition, NAC1 and TDP-43 were present in the same immunocomplexes in different regions of mouse brain and spinal cord. In primary spinal cord cultures, TDP-43 expression was mainly nuclear, whereas NAC1 was both nuclear and cytoplasmic. In order to mimic ALS like toxicity in the spinal cord culture system, we elevated extracellular glutamate levels resulting in the selective loss of motor neurons. Using this model, it was found that glutamate toxicity elicited a dose-dependent translocation of TDP-43 out of the nucleus of cholinergic neurons and increased the co-localization of NAC1 and TDP-43. These findings suggest that NAC1 may function to link TDP-43 to the proteasome; thereby, facilitating the post translational modifications of TDP-43 that lead to the development of ALS. PMID- 23022215 TI - Chronic morphine exposure affects contrast response functions of V1 neurons in cats. AB - Opiates disrupt neural functions in many brain areas, including visual cortex. Previous studies have indicated substantial changes of many neuronal response properties induced by chronic morphine exposure in the visual information processing system. However, it remains unclear whether neuronal contrast coding is also affected. To investigate this issue, we measured the contrast response functions (CRFs) of V1 neurons in chronic morphine-treated and saline-treated cats by using extra-cellular single-unit recording techniques. Our results indicated significantly lower contrast sensitivity in morphine-treated cats than in saline-treated cats and V1 neurons in morphine-treated cats exhibited enhanced maximum visual responses, higher baseline responses and lower signal-to-noise ratios compared with saline-treated cats. These findings provide some neurobiological evidence for the morphine-mediated degenerations of the visual cortex, which could underlie the opiate-induced deficits in visual function. PMID- 23022216 TI - Glutamate modulates resting state activity in the perigenual anterior cingulate cortex - a combined fMRI-MRS study. AB - The perigenual anterior cingulate cortex (PACC) shows high resting state activity and is considered part of the default-mode network (DMN). However, the biochemical underpinnings of the PACC's high resting state activity remain unclear. While animal-based evidence points toward a role for the glutamatergic system, the modulation of the resting state activity level by itself as distinguished from stimulus-induced activity remains to be shown in humans. Using combined fMRI-MRS in healthy subjects, we here demonstrate that the PACC resting state concentration of glutamate is directly related to the level of resting state activity in the same region. In contrast, no such relationship could be detected during the anticipation of reward and punishment, nor in an independent control region (the left anterior insula). Taken together, our findings demonstrate for the first time the modulation of the PACC resting state activity level by the concentration of glutamate in the same regions. This contributes to a better understanding of the biochemical basis for the brain's resting state activity as well as providing some clues regarding its apparent pathological upregulation in psychiatric disorders like the major depressive disorder. PMID- 23022217 TI - Hippocampal heat shock protein 25 expression in streptozotocin-induced diabetic mice. AB - Hippocampal abnormalities are believed to increase the risk of cognitive decline in diabetic patients. The underlying mechanism is unknown, but both hyperglycemia and oxidative stress have been implicated. Cellular stresses induce the expression of heat shock protein 25 (HSP25) and this results in cytoprotection. Our aim was to assess hippocampal expression of HSP25 in experimental diabetes. Mice were rendered diabetic by streptozotocin injection. Ten weeks after diabetes onset hippocampal HSP25 expression was studied by immunoblotting and immunohistochemistry (IHC). Expression of glial fibrillary acidic protein, nitrotyrosine, iNOS, HSP72, HSP90, and Cu/Zn superoxide dismutase (SOD) was assessed by either IHC or immunoblotting, Cu/Zn-SOD activity by enzymatic assay, and malondialdehyde (MDA) content by colorimetric assay. Hippocampal HSP25 was significantly increased in diabetic as compared to non-diabetic animals and localized predominantly within the pyramidal neurons layer of the CA1 area. This was paralleled by overexpression of nitrotyrosine, iNOS, SOD expression/activity, and enhanced MDA content. In experimental diabetes, HSP25 is overexpressed in the CA1 pyramidal neurons in parallel with markers of oxidative stress. PMID- 23022218 TI - Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the spared nerve injury model of neuropathic pain. AB - Neuronal hyperexcitability following peripheral nerve lesions may stem from altered activity of voltage-gated sodium channels (VGSCs), which gives rise to allodynia or hyperalgesia. In vitro, the ubiquitin ligase Nedd4-2 is a negative regulator of VGSC alpha-subunits (Na(v)), in particular Na(v)1.7, a key actor in nociceptor excitability. We therefore studied Nedd4-2 in rat nociceptors, its co expression with Na(v)1.7 and Na(v)1.8, and its regulation in pathology. Adult rats were submitted to the spared nerve injury (SNI) model of neuropathic pain or injected with complete Freund's adjuvant (CFA), a model of inflammatory pain. L4 dorsal root ganglia (DRG) were analyzed in sham-operated animals, seven days after SNI and 48 h after CFA with immunofluorescence and Western blot. We observed Nedd4-2 expression in almost 50% of DRG neurons, mostly small and medium sized. A preponderant localization is found in the non-peptidergic sub population. Additionally, 55.7 +/- 2.7% and 55.0 +/- 3.6% of Nedd4-2-positive cells are co-labeled with Na(v)1.7 and Na(v)1.8 respectively. SNI significantly decreases the proportion of Nedd4-2-positive neurons from 45.9 +/- 1.9% to 33.5 +/- 0.7% (p<0.01) and the total Nedd4-2 protein to 44% +/- 0.13% of its basal level (p<0.01, n=4 animals in each group, mean +/- SEM). In contrast, no change in Nedd4-2 was found after peripheral inflammation induced by CFA. These results indicate that Nedd4-2 is present in nociceptive neurons, is downregulated after peripheral nerve injury, and might therefore contribute to the dysregulation of Na(v)s involved in the hyperexcitability associated with peripheral nerve injuries. PMID- 23022219 TI - Exocytosis is impaired in mucopolysaccharidosis IIIA mouse chromaffin cells. AB - Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disorder caused by a deficiency in the activity of the lysosomal hydrolase, sulphamidase, an enzyme involved in the degradation of heparan sulphate. MPS IIIA patients exhibit progressive mental retardation and behavioural disturbance. While neuropathology is the major clinical problem in MPS IIIA patients, there is little understanding of how lysosomal storage generates this phenotype. As reduced neuronal communication can underlie cognitive deficiencies, we investigated whether the secretion of neurotransmitters is altered in MPS IIIA mice; utilising adrenal chromaffin cells, a classical model for studying secretion via exocytosis. MPS IIIA chromaffin cells displayed heparan sulphate storage and electron microscopy revealed large electron-lucent storage compartments. There were also increased numbers of large/elongated chromaffin granules, with a morphology that was similar to immature secretory granules. Carbon fibre amperometry illustrated a significant decrease in the number of exocytotic events for MPS IIIA, when compared to control chromaffin cells. However, there were no changes in the kinetics of release, the amount of catecholamine released per exocytotic event, or the amount of Ca(2+) entry upon stimulation. The increased number of large/elongated granules and reduced number of exocytotic events suggests that either the biogenesis and/or the cell surface docking and fusion potential of these vesicles is impaired in MPS IIIA. If this also occurs in central nervous system neurons, the reduction in neurotransmitter release could help to explain the development of neuropathology in MPS IIIA. PMID- 23022221 TI - Influence of the structure of mood in the assessment of rheumatoid arthritis through the visual analog scale for pain, HAQ and DAS28. AB - OBJECTIVE: To analyze the effect of the structure of mood over the following assessment tools for rheumatoid arthritis: visual analog scale (VAS) for pain, HAQ and DAS28. PATIENTS AND METHODS: We studied 86 patients with recent onset rheumatoid arthritis, of which 75.7% were female, with a mean age at disease onset of 55 years. All patients were administered the Spanish version of the PANAS questionnaire that evaluates the components of positive (PA) and negative mood (AN). Patients belonged to the registry of new-onset arthritis in our center so clinical information was available for 282 patients visits. To determine the effect of PA and AN on each of the dependent variables we performed three multivariate linear regression models using generalized linear models through the Stata glm command 10.1. RESULTS: The mean score for PA and AN in our patients was similar to that described for the healthy Spanish population. The high scores on the subscale of AN were associated with worse scores in both the VAS for pain and the HAQ. By contrast, high scores on PA were associated with better outcomes of disease activity measured by DAS28. CONCLUSION: The structure of mood may influence the tools we use for evaluating patients with rheumatoid arthritis, so it might be advisable to include the PANAS questionnaire as part of that assessment. PMID- 23022222 TI - Agonist stimulation, talin-1, and kindlin-3 are crucial for alpha(IIb)beta(3) activation in a human megakaryoblastic cell line, CMK. AB - Platelet integrin alpha(IIb)beta(3) activation is regulated by inside-out signaling via agonist stimulation. However, when alpha(IIb)beta(3) was exogenously expressed in cell lines such as Chinese hamster ovarian cells, physiological agonists hardly induced alpha(IIb)beta(3) activation. To overcome this disadvantage, we characterized the functional regulation of endogenously expressed alpha(IIb)beta(3) in a megakaryoblastic cell line, CMK, employing an initial velocity assay for PAC-1 binding. We firstly demonstrated that protease activated receptor 1-activating peptide induced robust, but transient alpha(IIb)beta(3) activation in CMK cells with high glycoprotein-Ib expression. Stable talin-1 or kindlin-3 knockdown cells confirmed that the protease-activated receptor 1-activating peptide-induced alpha(IIb)beta(3) activation was dependent on talin-1 and kindlin-3 expression. In sharp contrast to exogenously expressed alpha(IIb)beta(3) in Chinese hamster ovarian cells, transient overexpression of full-length talin (FL-talin) or talin-head domain (THD) alone did not activate alpha(IIb)beta(3) in CMK cells, but required agonist stimulation. Similarly, kindlin-3 overexpression alone did not induce alpha(IIb)beta(3) activation, but it significantly augmented agonist-induced alpha(IIb)beta(3) activation. Several mutants of FL-talin and THD suggested that the head-rod interaction was critical for autoinhibition of talin-1, and the interaction between the THD and the membrane-proximal region of the beta(3) cytoplasmic tail was essential for talin mediated alpha(IIb)beta(3) activation. In addition, THD and kindlin-3 cooperatively augmented protease-activated receptor 1-induced alpha(IIb)beta(3) activation. We proposed that the CMK cell line is an attractive platform for investigating agonist-, talin-1-, and kindlin-3- dependent alpha(IIb)beta(3) activation. PMID- 23022220 TI - The interaction of disrupted type II neuregulin 1 and chronic adolescent stress on adult anxiety- and fear-related behaviors. AB - The incidence of anxiety, mood, substance abuse disorders and schizophrenia increases during adolescence. Epidemiological evidence confirms that exposure to stress during sensitive periods of development can create vulnerabilities that put genetically predisposed individuals at increased risk for psychiatric disorders. Neuregulin 1 (NRG1) is a frequently identified schizophrenia susceptibility gene that has also been associated with the psychotic features of bipolar disorder. Previously, we established that Type II NRG1 is expressed in the hypothalamic-pituitary-adrenal (HPA) axis neurocircuitry. We also found, using a line of Nrg1 hypomorphic rats (Nrg1(Tn)), that genetic disruption of Type II NRG1 results in altered HPA axis function and environmental reactivity. The present studies used the Nrg1(Tn) rats to test whether Type II NRG1 gene disruption and chronic stress exposure during adolescence interact to alter adult anxiety- and fear-related behaviors. Male and female Nrg1(Tn) and wild-type rats were exposed to chronic variable stress (CVS) during mid-adolescence and then tested for anxiety-like behavior, cued fear conditioning and basal corticosterone secretion in adulthood. The disruption of Type II NRG1 alone significantly impacts rat anxiety-related behavior by reversing normal sex-related differences and impairs the ability to acquire cued fear conditioning. Sex-specific interactions between genotype and adolescent stress also were identified such that CVS-treated wild-type females exhibited a slight reduction in anxiety-like behavior and basal corticosterone, while CVS-treated Nrg1(Tn) females exhibited a significant increase in cued fear extinction. These studies confirm the importance of Type II NRG1 in anxiety and fear behaviors and point to adolescence as a time when stressful experiences can shape adult behavior and HPA axis function. PMID- 23022223 TI - Higher-order orchestration of hematopoiesis: is cohesin a new player? AB - Hematopoiesis-the process that generates distinct lineage-committed blood cells from a single multipotent hematopoietic stem cell-is a complex process of cellular differentiation regulated by a set of dynamic transcriptional programs. Cytokines and growth factors, transcription factors, chromatin remodeling, and modifying enzymes have been suggested to enact critical roles during hematopoiesis, leading to the development of myeloid, lymphoid, erythroid and platelet precursors. How is such a complex process orchestrated? Is there a higher order of hematopoiesis regulation? These are some of the unresolved questions in the field of hematopoiesis. Here, we suggest that cohesin, which is known to mediate chromosomal cohesion between sister chromatids, may have a central role in the orchestration of hematopoiesis and serve as a master transcriptional regulator. PMID- 23022224 TI - Pharmacodynamics, tissue distribution, toxicity studies and antitumor efficacy of the vascular targeting fusion toxin VEGF121/rGel. AB - As a part of an ongoing assessment of its mechanism of action, we evaluated the in vivo pharmacokinetics, tissue distribution, toxicity and antitumor efficacy of VEGF(121)/rGel, a novel fusion protein. Pharmacokinetic studies showed that VEGF(121)/rGel cleared from the circulation in a biphasic manner with calculated half-lives of 0.3 and 6h for the alpha and beta phases, respectively. Pharmacokinetic evaluation of (64)Cu-DOTA-VEGF(121)/rGel showed relatively high blood retention 30 min after injection (26.6 +/- 1.73% ID/g), dropping to 11.8 +/ 2.83% and 0.82 +/- 0.11% ID/g at 60 and 240 min post injection, respectively. Tissue uptake studies showed that kidneys, liver and tumor had the highest drug concentrations 48 h after administration. The maximum tolerated dose (MTD), based on a QOD*5 i.v. administration schedule, was found to be 18 mg/kg with an LD(50) of 25mg/kg. Treatment of BALB/c mice with VEGF(121)/rGel at doses up to the MTD caused no alterations in hematologic parameters. However, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) parameters increased in a dose-related manner. The no-observable-adverse-effect-level (NOAEL) was determined to be 20% of the MTD (3.6 mg/kg). VEGF(121)/rGel treatment of mice bearing orthotopically-placed MDA-MB-231 breast tumors caused increased vascular permeability of tumor tissue by 53% compared to saline-treated controls. Immunohistochemical analysis showed significant tumor hypoxia and necrosis as a consequence of vascular damage. In summary, VEGF(121)/rGel appears to be an effective therapeutic agent causing focused damage to tumor vasculature with minimal toxic effects to normal organs. This agent appears to be an excellent candidate for further clinical development. PMID- 23022225 TI - The (pro)renin receptor ((P)RR) can act as a repressor of Wnt signalling. AB - The (pro)renin receptor ((P)RR) and Wnt signalling are both involved in different diseases ranging from cardiac and renal end-organ damage to cancer. (P)RR function involves signalling via the transcription factor promyelocytic leukemia zinc finger protein (PLZF) as well as the furin-mediated generation of vacuolar proton-translocating ATPase (V-ATPase)-associated and soluble (P)RR isoforms. Recently, the (P)RR was described as adaptor protein of Wnt (co)receptors. The aim of this study was to analyse the contribution of these distinct (P)RR functions to Wnt signalling. Using Tcf/Lef reporter gene systems in HEK293T and HepG2 cells and quantification of endogenous axin2 mRNA and protein levels in HEK293T cells we were able to demonstrate that full-length (P)RR acts as a repressor of Wnt signalling in a system preactivated either by Wnt3a stimulation or by constitutively active beta-catenin. These repressive effects are mediated by Dvl but are independent of the mutation status of beta-catenin. Furthermore, the V-ATPase complex, but not PLZF translocation or renin enzymatic activity, is necessary for the induction of Tcf/Lef-responsive genes by Wnt3a. Our data indicate interference of (P)RR and Wnt cascades, a fact that has to be considered concerning pathophysiology of cardio-renal and oncological entities as well as in drug development programs targeting (P)RR or Wnt pathways. PMID- 23022226 TI - High-carbohydrate diets induce hepatic insulin resistance to protect the liver from substrate overload. AB - In population studies hepatic steatosis in subjects with Non-alcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. This association has encouraged debate whether hepatic steatosis is the cause or the consequence of hepatic insulin resistance? Although genome-wide studies have identified several gene variants associated with either hepatic steatosis or type 2 diabetes, no variants have been identified associated with both hepatic steatosis and insulin resistance. Here, the hypothesis is proposed that high carbohydrate diets contribute to the association between hepatic steatosis and insulin resistance through activation of the transcription factor ChREBP (Carbohydrate response element binding protein). Postprandial hyperglycaemia raises the hepatic concentrations of phosphorylated intermediates causing activation of ChREBP and induction of its target genes. These include not only enzymes of glycolysis and lipogenesis that predispose to hepatic steatosis but also glucose 6-phosphatase (G6PC) that catalyses the final reaction in glucose production and GCKR, the inhibitor of hepatic glucokinase that curtails hepatic glucose uptake. Induction of G6PC and GCKR manifests as hepatic glucose intolerance or insulin resistance. Induction of these two genes by high glucose serves to safeguard intrahepatic homeostasis of phosphorylated intermediates. The importance of GCKR in this protective mechanism is supported by "less-active" GCKR variants in association not only with hepatic steatosis and hyperuricaemia but also with lower fasting plasma glucose and decreased insulin resistance. This supports a role for GCKR in restricting hepatic glucose phosphorylation to maintain intrahepatic homeostasis. Pharmacological targeting of the glucokinase GCKR interaction can favour either glucose clearance by the liver or intrahepatic metabolite homeostasis. PMID- 23022227 TI - Identification of a unique nsaid, fluoro-loxoprofen with gastroprotective activity. AB - We previously proposed that direct cytotoxicity of NSAIDs due to their membrane permeabilization activity, together with their ability to decrease gastric prostaglandin E(2), contributes to production of gastric lesions. Compared to loxoprofen (LOX), fluoro-loxoprofen (F-LOX) has much lower membrane permeabilization and gastric ulcerogenic activities but similar anti-inflammatory activity. In this study, we examined the mechanism for this low ulcerogenic activity in rats. Compared to LOX, the level of gastric mucosal cell death was lower following administration of F-LOX. However, the gastric level of prostaglandin E(2) was similar in response to treatment with the two NSAIDs. Oral pre-administration of F-LOX conferred protection against the formation of gastric lesions produced by subsequent administration of LOX and orally administered F LOX resulted in a higher gastric pH value and mucus content. In the presence of a stimulant of gastric acid secretion, the difference in the ulcerogenic activity of F-LOX and LOX was less apparent. Furthermore, an increase in the mucus was observed in gastric cells cultured in the presence of F-LOX in a manner dependent of increase in the cellular level of cAMP. These results suggest that low ulcerogenic activity of F-LOX involves its both low direct cytotoxicity and protective effect against the development of gastric lesions. This protective effect seems to be mediated through an increase in a protective factor (mucus) and a decrease in an aggressive factor (acid). PMID- 23022228 TI - Knockdown of stromal interaction molecule 1 (STIM1) suppresses store-operated calcium entry, cell proliferation and tumorigenicity in human epidermoid carcinoma A431 cells. AB - Store-operated calcium (Ca(2+)) entry (SOCE) is important for cellular activities such as gene transcription, cell cycle progression and proliferation in most non excitable cells. Stromal interaction molecule 1 (STIM1), a newly identified Ca(2+)-sensing protein, monitors the depletion of endoplasmic reticulum (ER) Ca(2+) stores and activates store-operated Ca(2+) channels at the plasma membrane to induce SOCE. To investigate the possible roles of STIM1 in tumor growth in relation to SOCE, we established STIM1 knockdown (KD) clones of human epidermoid carcinoma A431 cells by RNA interference. Thapsigargin, an inhibitor of ER Ca(2+) ATPase, -induced and phospholipase C-coupled receptor agonist-induced SOCEs were reduced in two STIM1 KD clones compared to a negative control clone. Re expression of a KD-resistant full-length STIM1, but not a Ca(2+) release activated Ca(2+) channel activation domain (CAD)-deleted STIM1 mutant, in the KD clone restored the amplitude of SOCE, suggesting the specificity of the STIM1 knockdown. The cell growth of the STIM1 KD clones was slower than that of the negative control clone. DNA synthesis assessed by BrdU incorporation, as well as EGF-stimulated EGF receptor activation, decreased in the STIM1 KD clones. Xenograft growth of the STIM1 KD clones was significantly retarded compared with that of the negative control. Cell migration was attenuated in the STIM1 KD clone and the STIM1 silencing effect was reversed by transient re-expression of the full-length STIM1 but not CAD-deletion mutant. These results indicate that STIM1 plays an important role in SOCE, cell-growth and tumorigenicity in human epidermoid carcinoma A431cells, suggesting the potential use of STIM1-targeting agents for treating epidermoid carcinoma. PMID- 23022229 TI - Tanshinone IIA sodium sulfonate facilitates endocytic HMGB1 uptake. AB - Our seminal discovery of high mobility group box 1 (HMGB1) as a late mediator of lethal systemic inflammation has prompted a new field of investigation for the development of experimental therapeutics. We previously reported that a major Danshen ingredient, tanshinone IIA sodium sulfonate (TSN-SS), selectively inhibited endotoxin-induced HMGB1 release and conferred protection against lethal endotoxemia and sepsis. To investigate the underlying mechanisms by which TSN-SS effectively inhibits HMGB1 release, we examined whether TSN-SS stimulates HMGB1 uptake by macrophages and whether genetic depletion of HMGB1 receptors [e.g., toll-like receptors (TLR)2, TLR4, or the receptor for advanced glycation end product (RAGE)] or pharmacological inhibition of endocytosis impairs TSN-SS facilitated HMGB1 cellular uptake. TSN-SS stimulated internalization of exogenous HMGB1 protein into macrophage cytoplasmic vesicles that subsequently co-localized with microtubule-associated protein light chain 3 (LC3)-positive punctate structures (likely amphisomes). Meanwhile, it time-dependently elevated cellular levels of internalized HMGB1, leading to elevated LC3-II production and aggregation. Although genetic depletion of TLR2, TLR4, and/or RAGE did not impair TSN-SS-mediated HMGB1 uptake, specific inhibitors of the clathrin- and caveolin dependent endocytosis significantly impaired TSN-SS-mediated HMGB1 uptake. Co treatment with a lysosomal inhibitor, bafilomycin A1, led to enhanced accumulation of endogenous LC3-II and internalized exogenous HMGB1 in TSN SS/rHMGB1-treated macrophages. Taken together, these findings suggest that TSN-SS may facilitate HMGB1 endocytic uptake, and subsequently delivered it to LC3 positive vacuoles (possibly amphisomes) for degradation via a lysosome-dependent pathway. PMID- 23022230 TI - Rosuvastatin reduces platelet recruitment by inhibiting NADPH oxidase activation. AB - Rosuvastatin increased vascular endothelial NO and attenuated platelet activation after ischemia-reperfusion in mice; nevertheless, the influence of rosuvastatin on the activation of human platelets and the underlying mechanism has never been investigated. In an in vitro study platelets from 8 healthy donors were incubated with scalar concentrations of rosuvastatin (1-10 MUM) before activation. Platelet recruitment (PR), that mimics the propagation of platelet aggregation and is dependent upon isoprostane formation, was investigated. PR was inhibited by rosuvastatin in concentration-dependent manner concomitantly with down-regulation of platelet release of the pro-thrombotic molecule CD40L. This effect was associated with lower production of platelet reactive oxygen species (ROS), isoprostane and activation of the glycoprotein IIb/IIIa and was counteracted by exogenous addition of isoprostanes. Conversely, rosuvastatin concentration dependently increased platelet NO. Platelet isoprostane formation mainly depends from NADPH oxidase. Rosuvastatin concentration-dependently inhibited platelet sNOX2-dp release, a specific marker of NADPH oxidase activation, PKC phosphorylation and p47(phox) translocation from cytosol to membranes. In an ex vivo study 10 hypercolesterolemic patients were randomly allocated to diet or rosuvastatin (20 mg). We observed that as early as 2h after rosuvastatin PR, platelet isoprostanes formation, platelet CD40L and sNOX2-dp decreased while platelet NO increased; no changes were detected in diet-assigned patients. This study shows that in vitro rosuvastatin impairs platelet activation via inhibition of NOX2-derived oxidative stress. This effect, which is associated ex vivo with acute inhibition of platelet activation, suggests that rosuvastatin behaves as an antiplatelet drug. PMID- 23022231 TI - Signal processing at mammalian carotid body chemoreceptors. AB - Mammalian carotid bodies are richly vascularized chemosensory organs that sense blood levels of O(2), CO(2)/H(+), and glucose and maintain homeostatic regulation of these levels via the reflex control of ventilation. Carotid bodies consist of innervated clusters of type I (or glomus) cells in intimate association with glial-like type II cells. Carotid bodies make afferent connections with fibers from sensory neurons in the petrosal ganglia and receive efferent inhibitory innervation from parasympathetic neurons located in the carotid sinus and glossopharyngeal nerves. There are synapses between type I (chemosensory) cells and petrosal afferent terminals, as well as between neighboring type I cells. There is a broad array of neurotransmitters and neuromodulators and their ionotropic and metabotropic receptors in the carotid body. This allows for complex processing of sensory stimuli (e.g., hypoxia and acid hypercapnia) involving both autocrine and paracrine signaling pathways. This review summarizes and evaluates current knowledge of these pathways and presents an integrated working model on information processing in carotid bodies. Included in this model is a novel hypothesis for a potential role of type II cells as an amplifier for the release of a key excitatory carotid body neurotransmitter, ATP, via P2Y purinoceptors and pannexin-1 channels. PMID- 23022233 TI - Gout: the mechanism of urate crystal nucleation and growth. A hypothesis based in facts. PMID- 23022232 TI - Paracrine and autocrine interactions in the human islet: more than meets the eye. AB - The pancreatic islet secretes the hormones insulin and glucagon to regulate glucose metabolism. To generate an adequate secretory response, islet endocrine cells must receive multiple regulatory signals relaying information about changes in the internal and external environments. Islet cells also need to be made aware about the functional status of neighboring cells through paracrine interactions. All this information is used to orchestrate a hormonal response that contributes to glucose homeostasis. Several neurotransmitters have been proposed to work as paracrine signals in the islet. Most of these, however, have yet to meet the criteria to be considered bona fide paracrine signals, in particular in human islets. Here, we review recent findings describing autocrine and paracrine signaling mechanisms in human islets. These recent results are showing an increasingly complex picture of paracrine interactions in the human islet and emphasize that results from other species cannot be readily extrapolated to the human context. Investigators are unveiling new signaling mechanisms or finding new roles for known paracrine signals in human islets. While it is too early to provide a synthesis, the field of islet research is defining the paracrine and autocrine components that will be used to generate models about how islet function is regulated. Meanwhile, the identified signaling pathways can be proposed as therapeutic targets for treating diabetes, a devastating disease affecting millions worldwide. PMID- 23022234 TI - Cytoreductive surgery plus HIPEC in platinum-sensitive recurrent ovarian cancer patients: a case-control study on survival in patients with two year follow-up. AB - OBJECTIVES: To compare survival data in platinum-sensitive recurrent ovarian cancer patients submitted to secondary cytoreduction (SCR) plus hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) (Cases) and a similar group of women not experiencing HIPEC (Controls). METHODS: Case-control study, matching 30 Cases with 37 Controls, with at least 24 months of follow-up. RESULTS: Groups were comparable for all characteristics, except for a higher proportion of patients with single-nodule relapses is the Controls (19 vs. 6; p=0.011). Median follow-up time was 46 months in the Cases and 36 months in the Controls. Twenty patients (66.6%) experienced secondary recurrence in the Cases and 37 women (100%) in the Controls (p=0.001). Moreover, 7 (23.3%) and 23 (62.2%) patients died of disease in the Cases and Controls respectively (p=0.003). The duration of secondary response was 26 months in the Cases and 15 months in the Controls (p=0.004). CONCLUSIONS: The combination of SCR and HIPEC seems to improve survival rate in patients suffering from platinum-sensitive EOC recurrence with respect to no-HIPEC treatments. This result further supports the need of a randomized trial. PMID- 23022235 TI - Would complex decongestive therapy reveal long term effect and lymphoscintigraphy predict the outcome of lower-limb lymphedema related to gynecologic cancer treatment? AB - OBJECTIVE: The aims of this study were to investigate the long-term effect of complex decongestive therapy (CDT) on lymphedema volume reduction, especially considering the proximal and distal parts of the leg, and to evaluate the utility of pre-therapy lymphoscintigraphy in predicting the response to CDT in patients with lower-limb lymphedema after surgery for gynecologic cancer. METHODS: Medical records of 158 patients with secondary lymphedema of unilateral leg after surgery for gynecological cancer were reviewed retrospectively. They were treated with two weeks of CDT along with self-administered home therapy and were followed up for 24 months. Whole, proximal and distal leg volume was serially measured by using an optoelectric volumeter prior to and immediately after therapy, and follow-up visits at months 3, 6, 12 and 24. Lymphoscintigraphy was performed prior to therapy. RESULTS: The percent volume reduction was 22.1% in the whole leg, 30.9% in the distal leg and 18.4% in the proximal leg immediately after CDT. The volume reduction was maintained for 24 months, but the distal leg was significantly well maintained better than the proximal leg. Extremity radioisotope uptake ratio (EUR) among lymphoscintigraphic findings could predict the improvement of lymphedema volume in the distal, proximal and whole leg. CONCLUSIONS: This study suggests that the long-term edema reducing effects of CDT are better maintained in the distal leg than in the proximal part, and initial lymphoscintigraphic quantitative finding may usefully predict the short and long term response to CDT. PMID- 23022236 TI - Fiber-in-tube solid-phase microextraction with molecularly imprinted coating for sensitive analysis of antibiotic drugs by high performance liquid chromatography. AB - An on line fiber-in-tube solid-phase microextraction (SPME) method was developed by longitudinally packing molecularly imprinted fibers (MIP-fibers) into PEEK tube as the online extraction unit. The obtained device therefore offers a reduced back pressure and rapid kinetics for its longitudinal channels, as well as possesses improved extraction capacity compared with traditional SPME method thanks to the increase of coating volume. In addition, the extraction of analytes was specific by using molecularly imprinted coatings, which greatly reduced the interference of sample matrix. To evaluate the new strategy, the PEEK tube was firstly packed with multiple ofloxacin imprinted fibers (OFL-MIP-fibers) for the analysis of four fluoroquinolones in animal-producing food samples. The extraction yields were significantly increased with the enrichment factors from 69 to 136. Sensitive results were achieved with the limits of detection as low as 0.016-0.11 MUg/L (S/N=3). This method was applied successfully to analysis of fluoroquinolones in pork liver and chicken samples with good repeatability (RSDs less than 7.2%). To expand the method, the PEEK tube was then filling with two different fibers imprinted by ofloxacin and sulfamethazine respectively in order to obtain simultaneous extraction of these two categories of antibiotic drugs. Preliminary results showed the hybrid packing strategy could simultaneously enrich the target analytes from complicated samples. The possibility of applying the method to pork liver sample spiked with fluoroquinolones and sulfonamides was also studied. PMID- 23022237 TI - Sonication-assisted emulsification microextraction combined with vortex-assisted porous membrane-protected micro-solid-phase extraction using mixed zeolitic imidazolate frameworks 8 as sorbent. AB - Mixed zeolitic imidazolate framework 8 (ZIF-8) (nanometer and micron-sized) material were synthesized and applied as sorbent to sonication-assisted emulsification microextraction coupled to vortex-assisted porous membrane protected micro-solid-phase extraction (SAE-VA-MU-SPE) of polycyclic aromatic hydrocarbons (PAHs) from water samples. Better extraction results was obtained by using the mixed sorbent for the extraction of PAHs from aqueous samples, than either nanometer or micron-sized ZIF-8 separately. The developed method proved to be a time-saving, highly efficient (total extraction procedure was less than 10 min), accurate and robust method for water sample pretreatment. Parameters influencing the extraction efficiency such as desorption solvent, extraction solvent volume, emulsification time, desorption time and salt concentration were investigated and optimized. The limits of detection from gas chromatography-mass spectrometric analysis of six PAHs after SAE-VA-MU-SPE ranged between 0.004 and 0.011 ng/ml. The linear ranges were from 0.05 to 50 ng/ml, and the correlation coefficient was higher than 0.9943. The proposed method provides an interesting and innovative approach of combining different microscale sample preparation methods to solve analytical problems that are not easily addressed by the individual procedure alone. PMID- 23022238 TI - Gas chromatographic determination of phosphate-based flame retardants in styrene based polymers from waste electrical and electronic equipment. AB - Two methods for the determination of phosphate-based flame retardants (PFRs) and similar organophosphates (OPs) were developed. Two gas chromatographic systems were applied, one equipped with a quadrupole mass spectrometer (GC/MS), the other with a specific phosphorus-nitrogen detector (GC/PND). A procedure of ultrasonic supported extraction and precipitation (USSE) was applied and verified using in house produced reference materials. Twelve polymer parts of electrical and electronic devices, and eight polymer references were analysed for their PFR contents. The results show that the methods are capable of identifying PFRs in concentration ranges from 3 MUg L(-1) (tricresyl phosphate, TCP) to 12 MUg L(-1) (cresyl diphenyl phosphate, CDP) on GC/PND and from 110 MUg L(-1) (triphenyl phosphine oxide, TPPO) to 3250 MUg L(-1) (tris(ethylhexyl) phosphate, TEHP) on GC/MS in reference solutions. LODs in polymer extracts range from 180 MUg g(-1) (triphenyl phosphate, TPP) to 670 MUg g(-1) (bisphenol-A-bis(diphenyl phosphate), BDP) on GC/PND and from 75 MUg g(-1) (TPPO) to 780 MUg g(-1) (BDP) on GC/MS. The overall procedure time for one sample was less than 45 min (GC/MS) and less than 65 min (GC/PND). PMID- 23022239 TI - On-line comprehensive two-dimensional separations of charged compounds using reversed-phase high performance liquid chromatography and hydrophilic interaction chromatography. Part I: orthogonality and practical peak capacity considerations. AB - Comprehensive on-line two-dimensional liquid chromatography is expected to generate impressive peak capacities, which makes it a method of choice for the analysis of complex samples such as pharmaceutical or biological ones. A comparative study of different sets of chromatographic conditions including stationary phase, mobile phase and column temperature was carried out with mixtures of representative solutes in order to find out the best two-dimensional analytical conditions for charged compounds. Our approach focused on ultra-fast gradient runs in second dimension using HT-UHPLC conditions. The choice of volatile buffers was intended for future coupling with mass spectrometry in order to get another relevant dimension. The potential of various pairs of chromatographic systems was examined by means of two-dimensional gradient data. An attempt is made to rationalize the concept of orthogonality and a method is proposed to assess, for a given pair of chromatographic systems, both the degree of orthogonality and the practical peak capacity. It is shown that the degree of orthogonality between both dimensions is a critical factor but it is not sufficient to definitely appreciate the potential of a given pair of systems. The combination of HILIC and RPLC (HILIC*RPLC or RPLC*HILIC), although providing a very high degree of orthogonality, is disappointing due to the poor peak capacities obtained in HILIC especially with peptide samples. RPLC systems offer a large variety of analytical conditions, some of them leading to appropriate degrees of orthogonality when they are combined. More importantly, due to high column efficiencies along with large separation power, some combinations of RPLC systems leads to very high practical peak capacities. PMID- 23022240 TI - Adsorption models in chiral chromatography. AB - The review delivers the analysis of the literature data on adsorption equilibrium in chiral systems. Chiral adsorbents usually comprise several groups of nonselective and enantioselective active sites. Each group may be heterogeneous in itself. A dynamic equilibrium between different conformations of chiral selectors, nonstoichiometric adsorption, and various secondary equilibria also contribute to the complexity of the phenomenon. In this context, the practice of the use and the limitations of the conventional single-site and two-site models of chiral stationary phase were considered. Special attention was given to problems of the interpretation of experimental results and rational approaches to the selection of physically meaningful adsorption models. The effect of chirality on mass transfer kinetics was also considered, although available information is limited and sometimes ambiguous in order to make solid conclusions. PMID- 23022241 TI - Hybrid monolithic columns coated with cellulose tris(3,5-dimethylphenyl carbamate) for enantioseparations in capillary electrochromatography and capillary liquid chromatography. AB - A hybrid monolithic capillary column synthesized with (3-chloropropyl) trimethoxysilane (CPTMS) and tetramethoxysilane (TMOS) via sol-gel chemistry was in situ coated with cellulose tris(3,5-dimethylphenyl-carbamate) (CDMPC) for enantioseparations in capillary electrochromatography (CEC) and capillary liquid chromatography (CLC). Prior to coating, the prepared CP-silica hybrid monolith was straightforwardly modified with diethylenetriamine (DETA) to introduce NH(2) functionalities via the nucleophilic substitution reaction, which generate the stronger EOF for CEC. The coating condition was optimized to obtain a stable and reproducible chiral stationary phase for enantioseparation. The results indicated that racemic benzoin was baseline separated on the resulting hybrid monolith coated with 30 mg/mL CDMPC in CEC, while several racemates were successfully enantioseparated on the resulting CP-silica hybrid monolithic column coated with 60 mg/mL CDMPC in CLC with RP and NP modes. PMID- 23022242 TI - Long-term high-temperature and pH stability assessment of modern commercially available stationary phases by using retention factor analysis. AB - High-temperature liquid chromatography provides several advantages concerning HPLC method development and is needed to realize special hyphenation techniques. However, hardware limitations and stationary phase degradation can prevent the successful application of this technique. Therefore, column stability is of major importance. The presented study contains results of long-term high-temperature stability tests for eight modern commercially available HPLC stationary phases. Six of them were silica-based reversed-phase C18 columns tested according to an earlier reported procedure (Teutenberg, 2009 [12]). On the basis of the extended data set that covers a wide range of column technologies, a comparative approach using retention factor analysis was evaluated in order to categorize the columns according to their long-term high-temperature stability at 150 degrees C and changing pH value. This approach offers a more objective alternative to conventional listings in which temperature maxima are compared for columns tested under different conditions. Additionally, customized tests are presented for one promising polymer-based C18 stationary phase and an amide column for hydrophilic interaction liquid chromatography. PMID- 23022243 TI - Micellar electrokinetic chromatography: a new simple tool for the analysis of synthetic cannabinoids in herbal blends and for the rapid estimation of their logP values. AB - For the first time a capillary separation based on micellar electrokinetic chromatography (MEKC) with diode array detection (DAD) was developed and validated for the rapid determination of synthetic cannabinoids in herbal blends. Separations were carried out on a 30 MUm(ID) * 40 cm uncoated fused silica capillaries. The optimized buffer electrolyte was composed of 25 mM sodium tetraborate pH 8.0, 30 mM SDS and n-propanol 20% (v/v). Separations were performed at 30 kV. Sample injection conditions were 0.5 psi, 10s. Diazepam and JWH-015 were used as internal standards. The determination of the analytes was based on the UV signal recorded at 220 nm, corresponding to the maximum wavelength of absorbance of the molecules, whereas peak identification and purity check were also performed on the basis of the acquisition of UV spectra between 200 and 400 nm wavelengths. Under the described conditions, the separation of the compounds was achieved in 25 min without any significant interference from the matrix. Linearity was assessed within a concentration range from 5 to 100 MUg/mL. The intra-day and inter-day imprecision values were below 2.45% for relative migration times and below 10.75% for relative peak areas. The present method was successfully applied to the direct determination of synthetic cannabinoids in 15 different herbal blend samples requiring only sample dilution. In addition, the developed MEKC separation was also applied to estimate the octanol/water partition coefficients (logP) of these new and poorly known molecules. PMID- 23022244 TI - Estimation of tibiofemoral static zero position during dynamic drop landing. AB - OBJECTIVE: The objective is to assess the in vivo knee secondary motions intrinsic to flexion in isolation from actual displacements during a landing activity. For this purpose a "static zero position", which denotes the normal tibiofemoral position to the static flexion angle, was introduced to describe the intrinsic secondary motion. METHODS: The three-dimensional motion data of the healthy knee were collected from 13 male and 13 female young adults by using an auto motion analysis system and point cluster technique. First, the relationship between flexion and secondary motion in the static state was determined during a single-leg quasistatic squat. The static zero position during a single-leg drop landing was then calculated by substituting the flexion angle into the flexion secondary relational expression obtained. RESULTS: After the foot-ground contact, the estimated static zero positions shifted monotonically in valgus, internal rotation, and anterior translation in the case of both the male and female groups. For the time-course change, noticeable differences between the actual displacement and estimated static zero position were found from the foot-ground contact up to 25ms after the contact for the valgus/varus and external/internal rotation, and between 20 and 35ms after the contact for the anterior/posterior translation. SUMMARY: The static zero position demonstrated relatively modest but not negligible shift in comparison with the actual displacement. The intrinsic tibiofemoral motion, or baseline shift, would be worth taking into account when examining the fundamental function and injury mechanics of the knee during an impulsive activity. PMID- 23022245 TI - A review of the anatomical, biomechanical and kinematic findings of posterior cruciate ligament injury with respect to non-operative management. AB - An understanding of the kinematics of posterior cruciate ligament (PCL) deficiency is important for the diagnosis and management of patients with isolated PCL injury. The kinematics of PCL injury has been analysed through cadaveric and in vivo imaging studies. Cadaveric studies have detailed the anatomy of the PCL. It consists of two functional bundles, anterolateral and posteromedial, which exhibit different tensioning patterns through the arc of knee flexion. Isolated sectioning of the PCL and its related structures in cadaveric specimens has defined its primary and secondary restraining functions. The PCL is the primary restraint to posterior tibia translation above 30 degrees and is a secondary restraint below 30 degrees of knee flexion. Furthermore, sectioning of the PCL produces increased chondral deformation forces in the medial compartment as the knee flexes. However, the drawback of cadaveric studies is that they can not replicate the contribution of surrounding neuromuscular structures to joint stability that occurs in the clinical setting. To address this, there have been in vivo studies that have examined the kinematics of the PCL deficient knee using imaging modalities whilst subjects perform dynamic manoeuvres. These studies demonstrate significant posterior subluxation of the medial tibia as the knee flexes. The results of these experimental studies are in line with clinical consequences of PCL deficiency. In particular, arthroscopic evaluation of subjects with isolated PCL injuries demonstrate an increased incidence of chondral lesions in the medial compartment. Yet despite the altered kinematics with PCL injury only a minority of patients require surgery for persistent instability and the majority of athletes are able to return to sport following a period of non-operative rehabilitation. Specifically, non-operative management centres on a programme of quadriceps strengthening and hamstring inhibition to minimise posterior tibial load. The mechanism behind the neuromuscular adaptation that allows the majority of athletes to return to sport has been investigated but not clearly elucidated. The purpose of this review paper is to draw together the findings of experimental studies on the anatomical and kinematic effects of PCL injury and summarise their relevance with respect to non-operative management and functional outcome in patients with isolated PCL deficiency. PMID- 23022246 TI - The number of operations negatively influences fascia closure in open abdomen management. AB - BACKGROUND: Open abdomen management applies to a variety of traumatic and inflammatory abdominal conditions. One complication of this technique is inability to achieve primary closure of the abdominal wall. The aim of this study was to determine if the number of abdominal reexplorations influences the success of abdominal closure. METHODS: A review of patients undergoing open abdomen management from January 2007 to 2010 was performed. The indication for surgery, number of operations, and success at primary fascia closure were tabulated. A synthetic or biologic mesh bridge was considered failure to achieve closure. RESULTS: One hundred four patients underwent open abdomen management for trauma, postoperative hemorrhage, infected pancreatic necrosis, and perforated viscus or anastomotic leak. Reoperations ranged from 2 to 25, with a mean of 4.5 reoperations. Primary fascia closure was achieved in 82 patients (79%). Fascia closure was successful in 93% of patients with <=4 reoperations, whereas closure occurred in 32% of patients having >=5 reoperations (P < .05). CONCLUSIONS: Greater than 4 reoperations is significantly associated with failure of the primary fascia closure. Efforts to obtain closure should be undertaken within 4 reoperations. PMID- 23022247 TI - Surgical specialty procedures in rural surgery practices: implications for rural surgery training. AB - BACKGROUND: Specialty procedures constitute one eighth of rural surgery practice. Currently, general surgeons intending to practice in rural hospitals may not get adequate training for specialty procedures, which they will be expected to perform. Better definition of these procedures will help guide rural surgery training. METHODS: Current Procedural Terminology codes for all surgical procedures for 81% of North Dakota and South Dakota rural surgeons were entered into the Dakota Database for Rural Surgery. Specialty procedures were analyzed and compared with the Surgical Council on Resident Education curriculum to determine whether general surgery training is adequate preparation for rural surgery practice. RESULTS: The Dakota Database for Rural Surgery included 46,052 procedures, of which 5,666 (12.3%) were specialty procedures. Highest volume specialty categories included vascular, obstetrics and gynecology, orthopedics, cardiothoracic, urology, and otolaryngology. Common procedures in cardiothoracic and vascular surgery are taught in general surgical residency, while common procedures in obstetrics and gynecology, orthopedics, urology, and otolaryngology are usually not taught in general surgery training. CONCLUSIONS: Optimal training for rural surgery practice should include experience in specialty procedures in obstetrics and gynecology, orthopedics, urology, and otolaryngology. PMID- 23022248 TI - Perioperative supplementation with ascorbic acid does not prevent atrial fibrillation in coronary artery bypass graft patients. AB - BACKGROUND: Atrial fibrillation occurs after approximately 25% to 45% of coronary artery bypass graft (CABG) surgeries. Oxidative stress and related electrophysiological remodeling has been proposed as a potential cause of this atrial fibrillation. Perioperative supplementation of the antioxidant ascorbic acid has been evaluated as a preventive agent. The current investigation was conducted to evaluate the efficacy of ascorbic acid in reducing atrial fibrillation in CABG patients. METHODS: A prospective, randomized, placebo controlled, triple-blind, single-institution study was conducted in nonemergency CABG patients. Subjects were monitored for episodes of arrhythmia and other complications. RESULTS: Eighty-nine treatment and 96 control subjects completed the study protocol. Demographics, comorbidities, and preoperative drugs were similar between groups. Surgical characteristics and postoperative medication use also were similar. The incidence of atrial fibrillation was 30.3% in the treatment group and 30.2% in the control group (P = .985). No difference was found in postoperative complications or mortality. CONCLUSIONS: Our data indicate that supplementation of ascorbic acid in addition to routine postoperative care does not reduce atrial fibrillation after coronary artery bypass grafting. PMID- 23022249 TI - Long-term follow-up of endovascular abdominal aortic aneurysm repair in a rural veteran patient population. AB - BACKGROUND: The endovascular repair of abdominal aortic aneurysms (EVARs) requires follow-up to detect and treat late complications. METHODS: Two hundred eleven patients underwent EVAR for infrarenal, nonruptured abdominal aortic aneurysms from 1999 to 2010 at the Raymond G. Murphy VA Medical Center, Albuquerque, NM. A retrospective review examined patient demographics, comorbidities, the distance the patient lived from the facility, early and late complications, and the device implanted. Statistical analysis included the chi square test for independence, the Fisher exact test, and the 2-sample Mann Whitney U test for means. RESULTS: The mean time from the operation to the first complication was 21 months (standard deviation = 20 months) with a mean follow-up of 48 months (standard deviation = 36 months). The late complication rate was 22.8% (54 patients). Sixteen percent did not require any reinterventions, 57% were treated with percutaneous interventions, and 27% required an open surgical procedure. No single comorbidity, combination of comorbidities, distance the patient lived from the facility, or device implanted was predictive of complications. CONCLUSIONS: EVAR follow-up is essential to detect complications. When complications occur, the majority occur well after the initial treatment, and most can be treated with minimally invasive percutaneous techniques. PMID- 23022250 TI - Do you need a computed tomographic scan to evaluate suspected appendicitis in young men: an administrative database review. AB - BACKGROUND: The purpose of this study was to evaluate the impact of computed tomographic (CT) scans of the abdomen on clinical outcomes and costs in young male patients presenting with suspected appendicitis. METHODS: Discharge data from the University HealthSystem Consortium was accessed for all male patients between 18 and 55 years of age from October 2007 to June 2011. RESULTS: Of a total of 13,228 patients who met the inclusion criteria, 11,340 (85%) were assessed using a CT scan of the abdomen, whereas 1,888 (15%) did not undergo CT evaluation. Patients undergoing CT imaging compared with those without a CT scan had less morbidity (.86% vs 2.2%, P < .0001) and fewer 30-day readmissions (1.8% vs 5.13%, P < .0001). However, CT imaging resulted in a higher overall length of hospital stay and a higher total cost. CONCLUSIONS: This study suggests that in young men with suspected appendicitis, the use of an abdominal CT scan is associated with improved immediate postoperative complications, lower readmission rates with observed higher length of stay, and increased cost of care. PMID- 23022251 TI - Effect of epidural analgesia on postoperative complications following pancreaticoduodenectomy. AB - BACKGROUND: The purpose of this study was to evaluate the effect of epidural analgesia use on postoperative complications in patients undergoing pancreaticoduodenectomy. METHODS: This retrospective cohort study used the 2009 Nationwide Inpatient Sample from the Agency for Healthcare Research and Quality. Patients who underwent pancreaticoduodenectomy were grouped on the basis of whether they received epidural analgesia. The effect of epidural use on the composite end point of major complications including death was investigated using a generalized linear model. RESULTS: Overall, 8,610 cases of pancreaticoduodenectomy occurred within the United States in 2009, and 11.0% of these patients received epidural analgesia. After controlling for various potential confounders, results of the multivariate regression indicated that epidural analgesia use was associated with lower odds of composite complications including death (odds ratio, .61; 95% confidence interval, .37-.99; P = .044). CONCLUSIONS: In patients who underwent pancreaticoduodenectomy, epidural analgesia was associated with significantly lower postoperative composite complications. PMID- 23022252 TI - Safe, timely, convenient, and cost-effective: a single-center experience with bedside placement of enteral feeding tubes by midlevel providers using fluoroscopic guidance. AB - BACKGROUND: Enteral feeding tube placement has been performed by nurses, gastroenterologists using endoscopy, and interventional radiologists. We hypothesized that midlevel providers placed feeding tubes at bedside using fluoroscopy safely, rapidly, and cost-effectively. METHODS: We retrospectively analyzed bedside feeding tube placement under fluoroscopy by trained nurse practitioners. We compared charges for this method with charges for placement by other practitioners. RESULTS: Nurse practitioners placed 632 feeding tubes in 462 patients. Three hundred seventy-nine placements took place in mechanically ventilated placements. Ninety-seven percent of tubes were positioned past the pylorus. The mean fluoroscopy time was 0.7 +/- 1.2 minutes. The mean procedure time was 7.0 +/- 5.1 minutes. All tubes were placed within 24 hours of the request. There were no complications. Institutional charges for tube placement were $149 for nurse practitioners, $226 for gastroenterologists, and $328 for interventional radiologists. CONCLUSIONS: The placement of feeding tubes under fluoroscopy by nurse practitioners is safe, timely, and cost-effective. PMID- 23022253 TI - The impact of an integrated transfusion reduction initiative in patients undergoing resection for colorectal cancer. AB - BACKGROUND: Perioperative blood transfusions in patients with colorectal cancer are associated with increased cost, morbidity, mortality and decreased survival. In 2009, a 3-part transfusion reduction initiative (TRI) was introduced. The hypothesis was that this would decrease transfusions without increasing complications in patients undergoing elective resection for colorectal cancer. METHODS: After institutional review board approval was obtained, the medical records of patients who underwent colon resection before (January 2006 to October 2009) and after (November 2009 to March 2011) the TRI were reviewed. RESULTS: Three hundred sixty-eight patients were included, 272 and 96 in the pre-TRI and post-TRI groups, respectively. Transfusion rates decreased in the post-TRI group compared with the pre-TRI group (15% vs 28%, P = .011). Median postoperative hemoglobin levels among transfused patients were 8.4 and 7.3 g/dL in the pre-TRI and post-TRI groups, respectively (P = .009). There was no difference in complications or 30-day mortality. Transfused patients with stages I to III adenocarcinoma had worse 4-year survival (P < .05). CONCLUSIONS: Perioperative transfusions in colorectal cancer surgery decreased after the implementation of a TRI. Complication rates did not change. Perioperative transfusions were associated with worse survival in patients with stages I to III cancer. PMID- 23022255 TI - Reprint of: Core protein-mediated 5'-3' annealing of the West Nile virus genomic RNA in vitro. AB - Genome cyclization through conserved RNA sequences located in the 5' and 3' terminal regions of flavivirus genomic RNA is essential for virus replication. Although the role of various cis-acting RNA elements in panhandle formation is well characterized, almost nothing is known about the potential contribution of protein cofactors to viral RNA cyclization. Proteins with nucleic acid chaperone activities are encoded by many viruses (e.g., retroviruses, coronaviruses) to facilitate RNA structural rearrangements and RNA-RNA interactions during the viral replicative cycle. Since the core protein of flaviviruses is also endowed with potent RNA chaperone activities, we decided to examine the effect of West Nile virus (WNV) core on 5'-3' genomic RNA annealing in vitro. Core protein binding resulted in a dramatic, dose-dependent increase in 5'-3' complex formation. Mutations introduced in either the UAR (upstream AUG region) or CS (conserved sequence) elements of the viral RNA diminished core protein-dependent annealing, while compensatory mutations restored the 5'-3' RNA interaction. The activity responsible for stimulating RNA annealing was mapped to the C-terminal RNA-binding region of WNV core protein. These results indicate that core protein besides its function in viral particle formation - might be involved in the regulation of flavivirus genomic RNA cyclization, and thus virus replication. PMID- 23022254 TI - Unique prognostic factors in acral lentiginous melanoma. AB - BACKGROUND: This study was performed to identify clinicopathologic factors associated with survival in acral lentiginous melanoma. METHODS: A post hoc analysis of a prospective clinical trial and local database was performed in all patients with acral lentiginous melanomas. Multivariate analyses of factors associated with a tumor-positive sentinel lymph node (SLN) biopsy, disease-free survival (DFS), overall survival (OS), and local and in-transit recurrence-free survival (LITRFS) were performed. Kaplan-Meier survival analyses were performed. RESULTS: Eighty-five patients were identified. Age younger than 59 years and Breslow thickness (BT) of 2.0 mm or greater were independent risk factors for a positive SLN. SLN status was the only independent risk factor for DFS and LITRFS on multivariate analysis. A BT of 2.0 mm or greater was the only independent risk factor for OS. SLN status distinguished differences in DFS, OS, and LITRFS on Kaplan-Meier analysis. CONCLUSIONS: SLN status is the dominant factor for recurrence and survival in acral lentiginous melanoma. BT and ulceration are less important in this histologic subtype. PMID- 23022256 TI - Molecular analysis of SLC25A13 gene in human peripheral blood lymphocytes: Marked transcript diversity, and the feasibility of cDNA cloning as a diagnostic tool for citrin deficiency. AB - Human SLC25A13 gene encodes citrin, the liver-type aspartate-glutamate carrier isoform 2, and SLC25A13 mutations lead to citrin deficiency (CD). The definitive diagnosis of CD relies on SLC25A13 analysis, but conventional DNA analysis could not identify all SLC25A13 mutations. We investigated transcriptional features of SLC25A13 gene in peripheral blood lymphocytes (PBLs) from CD patients and healthy volunteers. SLC25A13 mutations were explored by PCR/LA-PCR, PCR-RFLP and direct sequencing. SLC25A13 cDNA was amplified by RT-PCR, cloned and then sequenced. All diagnoses of the CD patients were confirmed, including a heterozygote of g.2T>C and an unknown mutation yielding an aberrant transcript r.16_212dup. Twenty-eight alternative splice variants (ASVs) were identified from normal SLC25A13 alleles. Among them, r.213_328del took account for 53.7%, the normal transcript r.=, 16.6%, and the remaining 26 novel ASVs, collectively 29.3%, of all cDNA clones. Moreover, similar ASVs, all reflecting corresponsive mutations, were detected from the mutated alleles. These results indicated that the normal SLC25A13 transcript could be cloned, and the abundance of the ASV r.213_328del predicted the existence of a constructively novel protein isoform for this gene in human PBLs. And, the 26 novel ASVs, along with the novel aberrant transcript r.16_212dup and the SNP g.2T>C, enriched the transcript/variation spectrum of SLC25A13 gene in human beings. The findings in this paper, for the first time, uncovered the marked transcript diversity of SLC25A13 gene in human PBLs, and suggested that cDNA cloning analysis of this gene in human PBLs might be a feasible tool for CD molecular diagnosis. PMID- 23022257 TI - Argonaute CLIP--a method to identify in vivo targets of miRNAs. AB - microRNAs are important regulators of gene expression that guide translational repression and degradation of target mRNAs. Only relatively few miRNA targets have been characterized, and computational prediction is hampered by the relatively small number of nucleotides that seem to be involved in target recognition. Argonaute (Ago) crosslinking and immunoprecipitation (CLIP) in combination with next-generation sequencing proved to be a successful method for identifying targets of endogenous cellular miRNAs on a transcriptome-wide scale. Here we review various approaches to Ago CLIP, describe in detail the PAR-CLIP method and provide an outline of the necessary computational analysis for identification of in vivo miRNA binding sites. PMID- 23022258 TI - Occurrence and modeling of pharmaceuticals on a sewage-impacted Mediterranean river and their dynamics under different hydrological conditions. AB - The occurrence of 73 representative pharmacologically active compounds (PhACs) was assessed in a sewage-impacted section of the Llobregat River (NE Catalonia, Spain). This Mediterranean river is characterized by flow rate fluctuations strongly influenced by seasonal rainfall. River flow variations increase the potential environmental risk posed by organic micro-pollutants as their concentrations may increase substantially under low flow conditions. Little is known about the transport behavior of emerging contaminants in surface waters once they are discharged from waste water treatment plants (WWTP) into rivers. This research aimed to study the presence and fate of emerging contaminants under different hydrological conditions by sampling two different sites along the river in different seasons. The highest levels of pharmaceuticals were determined during cold and dry periods. The impact of the flow changes on the concentration of the pharmaceuticals in the river was assessed with the relative sensitive coefficients. Due to expected dilution effects, the response of pharmaceuticals to river flow was negative. Only in a few cases, positive relationships between drug concentrations and flow were detected, suggesting an important role of other hydrological phenomena like sediment re-suspension as well as the source of pollutants. To evaluate the role of other factors influencing PhAC concentrations, a plug-flow model was applied to obtain disappearance constants "k" for a set of selected compounds. Erythromycin presented k values of -0.15 h( 1) in both sites being the compound more efficiently removed from the water column. The k values for ibuprofen, furosemide, enrofloxacin, enalapril, acetaminophen, diclofenac and Ketoprofen were between -0.04 and -0.10 h(-1) showing less disappearance than erythromycin in the water column. However, other compounds presented k values<0.06, which suggested conservative behavior of these compounds in the water column. This study supports the reliability of the calculated k values for the disappearance of compounds in river waters. PMID- 23022259 TI - Mechanical restrictions on biological responses by adherent cells within collagen gels. AB - Cell-seeded collagen and fibrin gels represent excellent assays for studying interactions between adherent interstitial cells and the three-dimensional extracellular matrix in which they reside. Over one hundred papers have employed the free-floating collagen gel assay alone since its introduction in 1979 and much has been learned about mechanobiological responses of diverse types of cells. Yet, given that mechanobiology is the study of biological responses by cells to mechanical stimuli that must respect the basic laws of mechanics, we must quantify better the mechanical conditions that are imposed on or arise in cell-seeded gels. In this paper, we suggest that cell responses and associated changes in matrix organization within the classical free-floating gel assay are highly restricted by the mechanics. In particular, many salient but heretofore unexplained or misinterpreted observations in free-floating gels can be understood in terms of apparent cell-mediated residual stress fields that satisfy quasi-static equilibria and continuity of tractions. There is a continuing need, therefore, to bring together the allied fields of mechanobiology and biomechanics as we continue to elucidate cellular function within both native connective tissues and tissue equivalents that are used in basic scientific investigations or regenerative medicine. PMID- 23022260 TI - Brief embryonic strychnine exposure in zebrafish causes long-term adult behavioral impairment with indications of embryonic synaptic changes. AB - Zebrafish provide a powerful model of the impacts of embryonic toxicant exposure on neural development that may result in long-term behavioral dysfunction. In this study, zebrafish embryos were treated with 1.5mM strychnine for short embryonic time windows to induce transient changes in inhibitory neural signaling, and were subsequently raised in untreated water until adulthood. PCR analysis showed indications that strychnine exposure altered expression of some genes related to glycinergic, GABAergic and glutamatergic neuronal synapses during embryonic development. In adulthood, treated fish showed significant changes in swimming speed and tank diving behavior compared to controls. Taken together, these data show that a short embryonic exposure to a neurotoxicant can alter development of neural synapses and lead to changes in adult behavior. PMID- 23022261 TI - An evidence-based review of cognitive rehabilitation in medical conditions affecting cognitive function. AB - OBJECTIVES: To perform a methodical review of the evidence available for the efficacy of cognitive rehabilitation in individuals with diagnosed medical conditions known to affect cognitive function, and to establish evidence-based recommendations for clinical practice, as appropriate. DATA SOURCES: Ovid Medline and PubMed literature searches were conducted using the terms cognition, cognitive, crossed with the terms rehabilitation, remediation, retraining, training, crossed with 11 medical diagnostic categories. Articles through December 2008 were accessed, with a resulting 2284 abstracts. STUDY SELECTION: A total of 211 articles were selected from initial abstract review. These articles were then assessed by committee members, with agreement of at least 2 members, using 9 exclusion and 3 inclusion criteria. A total of 34 remaining articles were submitted to full review. DATA EXTRACTION: Articles were reviewed under diagnostic categories using specific criteria recorded on structured data sheets. Classification was performed according to guidelines of the American Academy of Neurology, with agreement between 2 committee members necessary for final decisions. DATA SYNTHESIS: Of the 34 studies fully evaluated, 1 was rated as class I, 6 as class II, 2 as class III, and 25 as class IV. Evidence within each diagnostic area was synthesized for the formulation of Practice Standards, Practice Guidelines, and Practice Options, as possible. CONCLUSIONS: Two clinical practice recommendations were advanced, 1 each in the diagnostic areas of brain neoplasms and epilepsy/seizure disorders. Discussion included comments on the research status of the effectiveness of cognitive rehabilitation for cognitive deficits related to these medical conditions, as well as suggestions for future directions in research. PMID- 23022262 TI - Return to primary service among bone marrow transplant rehabilitation inpatients: an index for predicting outcomes. AB - OBJECTIVE: To assess rehabilitation inpatient risk of return to primary (RTP) service in patients with bone marrow transplant (BMT). DESIGN: Retrospective review. SETTING: Inpatient rehabilitation unit within a tertiary referral-based cancer center. PARTICIPANTS: All patients with BMT (131) who were admitted a total of 147 times to inpatient rehabilitation between January 1, 2002, and April 30, 2010. INTERVENTIONS: None. MAIN OUTCOME MEASURES: We analyzed RTP service and demographic information, cancer characteristics, medications, hospital admission characteristics, and laboratory values. RESULTS: A total of 61 (41%) of 147 of BMT admissions were transferred from the inpatient rehabilitation unit back to the primary service. Of those transferred back, 23 (38%) of 61 died after being transferred back to the primary service. Significant or near-significant relationships were found for a platelet count of <43,000 per microliter (P<.01); a creatinine level of >0.9 milligrams/deciliter (P<.01); the presence of an antiviral agent (P=.0501); the presence of an antibacterial agent (P=.0519); the presence of an antifungal agent (P<.05); and leukemia, lymphoma, or multiple myeloma diagnosis (P<.05). Using 5 of these factors, the RTP-BMT index was formulated to determine the likelihood of return to the primary team. CONCLUSIONS: Patients with BMT have a high rate of transfer from the inpatient rehabilitation unit back to the primary service. The RTP-BMT index score can be a useful tool to help clinicians predict the likelihood of return to the primary acute care service. PMID- 23022263 TI - Electronic screening and decision support for poststroke depression: an exploration of doctors' and patients' perceptions of acceptability. AB - OBJECTIVE: To explore clinicians' and patients' perceptions of acceptability of an electronic screening and decision support system for poststroke depression. DESIGN: A mixed-methods study involved participants from 2 convenience samples. SETTING: Outpatient stroke and rehabilitation clinics. PARTICIPANTS: Stroke patients (n=62) completed surveys. Seven clinicians working at clinics targeted by the depression screening process were interviewed using semi-structured interviews. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient data were analyzed from an acceptability survey. Qualitative data analysis involved an inductive thematic approach with constant comparison. RESULTS: Most patients found screening easy to complete and understand, important, and a good way of conveying information to the clinician. Most clinicians did not systematically discuss mood disturbances, with attenuating factors and barriers to identification both influencing identification. Variations in the management of mood centered on the use of pharmacotherapy and role overlap with general practitioners. The screening process assisted with identification and saved time during diagnosis and management. CONCLUSIONS: The positive perceptions of patients and clinicians identified in this study support the concept of routine screening and feedback for poststroke depression. This process has the potential to improve poststroke depression practice to meet national guidelines; however, evaluation of impact on patient outcome is required. PMID- 23022264 TI - NosA, a transcription factor important in Aspergillus fumigatus stress and developmental response, rescues the germination defect of a laeA deletion. AB - Aspergillus fumigatus is an increasingly serious pathogen of immunocompromised patients, causing the often fatal disease invasive aspergillosis (IA). One A. fumigatus virulence determinant of IA is LaeA, a conserved virulence factor in pathogenic fungi. To further understand the role of LaeA in IA, the expression profile of DeltalaeA was compared to wild type, and several transcription factors were found significantly misregulated by LaeA loss. One of the transcription factors up-regulated over 4-fold in the DeltalaeA strain was Afu4g09710, similar in sequence to Aspergillus nidulans NosA, which is involved in sexual development. Here we assessed loss of nosA (DeltanosA) and overexpression of nosA (OE::nosA) on A. fumigatus in both a wild type and DeltalaeA background. Based on the multiple alterations of physiological development of single and double mutants, we suggest that NosA mediates the decreased radial growth and delayed conidial germination observed in DeltalaeA strains, the former in a light dependent manner. The DeltanosA mutant showed increased virulence in the Galleria mellonella larvae model of disseminated aspergillosis, potentially due to its increased growth and germination rate. Furthermore, the A. fumigatus nosA allele was able to partially remediate sexual development in an A. nidulans DeltanosA background. Likewise, the A. nidulans nosA allele was able to restore the menadione sensitivity defect of the A. fumigatus DeltanosA strain, suggesting conservation of function of the NosA protein in these two species. PMID- 23022265 TI - [Intraosseous ganglion cyst of the capitate: a case report]. AB - Intraosseous cyst of the carpal bones is a rare cause of wrist pain. Few cases have been reported. We report a rare case of intraosseous ganglion cyst of the capitate, in a girl aged 16 who plain of chronic pain of the right wrist. The radiological assessment showed an osteolytic lesion with marginal sclerosis. The diagnosis was confirmed by histopathology and treatment consisted of curettage with autologous cancellous bone graft. At 8 months follow-up, the capitate is fully consolidated and the functional result is satisfactory. PMID- 23022267 TI - Tyrosine phosphatase inhibitors combined with retinoic acid can enhance differentiation of neuroblastoma cells and trigger ERK- and AKT-dependent, p53 independent senescence. AB - Retinoic acid (RA)-induced differentiation therapy is partially successful in neuroblastoma treatment. We found that a novel combination of vanadium-based PTP inhibitors with RA induced extensive differentiation in neuroblastoma cells. In contrast to RA alone, this led to either permanent differentiation or senescence after 14days of combined treatment followed by chemical removal. Senescence was dependent in part on synergistic AKT and ERK activation. p21 was also strongly induced, but in contrast to oncogene-induced senescence, p53 was not activated. Vanadium-based inhibitors thus serve strongly to enhance RA's ability to drive differentiation and a novel form of senescence in neuroblastoma cells. PMID- 23022266 TI - Differentiation of cancer cell type and phenotype using quantum dot-gold nanoparticle sensor arrays. AB - We demonstrate rapid and efficient sensing of mammalian cell types and states using nanoparticle-based sensor arrays. These arrays are comprised of cationic quantum dots (QDs) and gold nanoparticles (AuNPs) that interact with cell surfaces to generate distinguishable fluorescence responses based on cell surface signatures. The use of QDs as the recognition elements as well as the signal transducers presents the potential for direct visualization of selective cell surface interactions. Notably, this sensor is unbiased, precluding the requirement of pre-knowledge of cell state biomarkers and thus providing a general approach for phenotypic profiling of cell states, with additional potential for imaging applications. PMID- 23022268 TI - In vitro and in vivo anticancer efficacy of silibinin against human pancreatic cancer BxPC-3 and PANC-1 cells. AB - Silibinin suppresses the growth of many cancers; however, its efficacy against pancreatic cancer has not been evaluated in established preclinical models. Here, we investigated in vitro and in vivo effects of silibinin against lower and advanced stages of human pancreatic carcinoma cells. Silibinin (25-100MUM) treatment for 24-72h caused a dose- and time-dependent cell growth inhibition of 27-77% (P<0.05-0.001) in BxPC-3 cells, and 22-45% (P<0.01-0.001) in PANC-1 cells. Silibinin showed a strong dose-dependent G1 arrest in BxPC-3 cells (upto 72% versus 45% in control; P<0.001), but a moderate response in advanced PANC-1 cells. Cell death observed in cell growth assay, was accompanied by up to 3-fold increase (P<0.001) in apoptosis in BxPC-3 cells, and showed only slight effect on PANC-1 cells. Dietary feeding of silibinin (0.5%, w/w in AIN-93M diet for 7weeks) inhibited BxPC-3 and PANC-1 tumor xenografts growth in nude mice without any apparent change in body weight gain and diet consumption. Tumor volume and weight were decreased by 47% and 34% (P?0.001) in BxPC-3 xenograft, respectively. PANC-1 xenograft showed slower growth kinetics and silibinin decreased tumor volume by 34% (P<0.001) by 7weeks. Another 4weeks of silibinin treatment to PANC-1 xenograft showed 28% and 33% decrease in tumor volume and weight, respectively. Silibinin-fed group of BxPC-3 tumors showed decreased cell proliferation and angiogenesis and an increased apoptosis, however, considerable inhibitory effect was observed only for angiogenesis in PANC-1 tumors. Overall, these findings show both in vitro as well as in vivo anticancer efficacy of silibinin against pancreatic cancer that could involve inhibition of cell proliferation, cell cycle arrest, apoptosis induction and/or decrease in tumor angiogenesis. PMID- 23022269 TI - Investigations to reveal the nature of interactions of human hemoglobin with curcumin using optical techniques. AB - Curcumin (CUR) is an important bioactive compound present in the rhizome of Curcuma longa. Herein, we report the interaction of CUR with human hemoglobin (Hb) using various biophysical methods viz., fluorescence, UV absorption, resonance light scattering spectra (RLS), synchronous fluorescence, fluorescence anisotropy, circular dichroism (CD) and three-dimensional fluorescence. There was a considerable quenching of the intrinsic fluorescence of Hb upon binding to CUR through dynamic quenching mechanism. The distance (r) between the donor and acceptor was obtained from the Forster's theory of fluorescence resonance energy transfer (FRET) and found to be 1.55 nm. Alterations in the conformation of Hb due to its interaction with CUR were confirmed by UV absorption and CD spectroscopic methods. The alpha-helicity of Hb was found to decrease upon binding with CUR. PMID- 23022270 TI - C-terminal modification of monoclonal antibody drugs: amidated species as a general product-related substance. AB - Twelve therapeutic mAbs, comprising 10 IgG1s and 2 IgG4s, were analyzed by a peptide mapping technique to detect and quantify C-terminal modifications. C terminal amidated structures were found in 8 out of the 12 mAbs. An in vitro study using a commercially available peptidylglycine alpha-amidating monooxygenase (PAM) revealed that both IgG1 and IgG4 can be substrates for PAM. This study showed that C-terminal amidation is a general C-terminal modification on the heavy chains of therapeutic mAbs and that C-terminal amidation of mAbs can be catalyzed by a certain PAM(s) in the Chinese hamster ovary (CHO) cells that are widely used for manufacturing therapeutic mAbs. PMID- 23022271 TI - Cytisine confers neuronal protection against excitotoxic injury by down regulating GluN2B-containing NMDA receptors. AB - Cytisine (CYT), one of the principal bioactive components derived from the seeds of Cytisus laborinum L, has been widely used for central nervous system (CNS) diseases treatment. The present study investigated the protective effect of CYT on cultured cortical neural injury induced by N-methyl-d-aspartate (NMDA). Our data showed that CYT conferred protective effect against loss of cellular viability induced by brief exposure to 200 MUM NMDA in a concentration-dependent manner. CYT significantly inhibited the neuronal apoptosis induced by NMDA exposure by reversing intracellular Ca(2+) overload and balancing Bcl-2 and Bax expression levels. Furthermore, CYT significantly reversed the up-regulation of GluN2B-containing NMDA receptors by exposure to NMDA, but it did not affect the level of GluN2A-containing NMDA receptors. These findings suggest that CYT protects cortical neurons, at least partially, by inhibiting the level of GluN2B containing NMDA receptors and regulating Bcl-2 family. PMID- 23022272 TI - In vitro metabolism of diphenyl diselenide in rat liver fractions. Conjugation with GSH and binding to thiol groups. AB - In spite of an extensive literature reporting pharmacological properties of diphenyl diselenide, (PhSe)(2), little is known about its metabolism. The aim of this study was to identify possible metabolic pathways of (PhSe)(2) in vitro to get insights into the mechanism of its toxicity. Rat liver preparations, namely total homogenate, S9 fraction, cytosol and microsomes were used in the incubations. Samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), high-performance liquid chromatography (HPLC) or inductively coupled plasma (ICP). A reduced glutathione (GSH)-selenol adduct (m/z 462) was identified in all liver fraction incubations by LC-MS/MS, suggesting a reaction between (PhSe)(2) and GSH in tissues. Results from incubation of (PhSe)(2) with microsomal fraction showed that (PhSe)(2) disappears from the supernatant without formation of phase I metabolites. The addition of exogenous GSH maintained constant (PhSe)(2) levels in supernatant and significantly reduced the amount of selenium in the precipitate obtained when microsomal incubations were treated with methanol. Addition of N-acetylcysteine (NAC) had a similar effect; moreover, a NAC-selenol adduct similar to the GSH-selenol adduct was identified by LC-MS/MS (m/z 318) in the NAC incubations. The data indicates that (PhSe)(2) probably binds covalently to microsomal components and that GSH and NAC can prevent binding. The depletion of GSH levels in vitro may be related to (PhSe)(2) toxicity. The inhibition of cytochrome P450 (CYP) activity by carbon monoxide or proadifen did not change the amount of (PhSe)(2) in supernatant and selenium levels in the precipitate, neither did the inactivation of the microsomes by heat indicating that binding was not mediated by cytochrome P450 metabolism and was probably due to a direct reaction between (PhSe)(2) and microsomal components. Due to the covalent binding of (PhSe)(2) to microsomal components the potential of (PhSe)(2) to inhibit cytochrome P450 was examined. (PhSe)(2) at a concentration as low as 1 MUM reduced monooxygenase activity with an IC(50) value of 78 MUM. PMID- 23022273 TI - Adsorption of carbon dioxide and nitrogen on zeolite rho prepared by hydrothermal synthesis using 18-crown-6 ether. AB - Zeolite rho was prepared by hydrothermal synthesis using an 18-crown-6 ether (18C6) as a structure-directing agent, and the effects of the calcination temperature for removal of 18C6 on the physicochemical properties and CO(2) adsorption properties were investigated. CO(2) adsorption on zeolite rho calcined at 150 degrees C was lower than that on samples calcined at temperatures above 300 degrees C. For samples calcined above 300 degrees C, CO(2) adsorption increased with increasing calcination temperature up to 400 degrees C. It is thought that the pore volume for adsorption of CO(2) increased as a result of 18C6 removal, resulting in increasing CO(2) adsorption. A decrease in CO(2) adsorption for calcination from 400 degrees C to 500 degrees C was observed. The particle size of zeolite rho increased with increasing 18C6 molar ratio. Particle sizes of 1.0-2.1 MUm and 1.4-2.6 MUm were found by field-emission scanning electron microscopy and dynamic light-scattering, respectively. The particle size is controlled in these regions by adjusting the 18C6 molar ratio. XRD showed that zeolite rho samples with 18C6 molar ratios of 0.25-1.5 had high crystallinity. The adsorbed amount of CO(2) is almost constant, at 3.4 mmol-CO(2)g(-1), regardless of the 18C6 molar ratio. However, CO(2) selectivity, which is the CO(2)/N(2) adsorption ratio, decreased. The amount of CO(2) adsorbed on zeolite rho is lower than that on zeolite NaX, but higher than that on SAPO-34. The CO(2)/N(2) adsorption ratio for zeolite rho was higher than those for SAPO-34 and zeolite NaX. PMID- 23022274 TI - The prefrontal cortex influence over subcortical and limbic regions governs antidepressant response by N=H/(M+R). AB - We review the evidence for relationships between metabolic activity of cortical, subcortical and limbic brain regions in depression and the efficacy of antidepressant agents. The influence of these regions can be described by an algebraic equation, N=H/(M+R), where N represents a homeostatic level of executive function, H represents prefrontal (Brodmann areas 9, 10, 11, 12; 46) and cingulate cortex activity (24, 25; 32), M represents subcortical (hippocampus, parahippocampal gyrus) influences, and R represents limbic (amygdala) influences. This hypothesis is based on depressed prefrontal cortex and enhanced amygdala and hippocampal metabolism in major depressive disorder, and the remission of these changes by most antidepressant interventions. The therapeutic efficacy of antidepressant strategies may depend less on their presumptive molecular mechanisms of action and more on their ability to restore the predominant metabolic and executive functions of the prefrontal cortex, and dampen excessive subcortical and limbic influences. PMID- 23022275 TI - Biomechanical properties of the mandible, as assessed by bending test, in rats fed a low-quality protein. AB - OBJECTIVE: The present study describes the effects of feeding growing rats with diets containing increasing concentrations of wheat gluten (a low quality protein, G) on both the morphometrical and the biomechanical properties of the mandible. DESIGN: Female rats were fed one of six diets containing different concentrations (5-30%) of G between the 30th and 90th days of life. Control rats were fed a diet containing 20% casein (C), which allows a normal growth and development of the bone. Mandibular growth was estimated directly on excised and cleaned bones by taking measurements between anatomical points. Mechanical properties of the right hemimandibles were determined by using a three-point bending mechanical test to obtain a load/deformation curve and estimate the structural properties of the bone. Bone material properties were calculated from structural and geometric properties. The left hemimandibles were ashed and the ash weight obtained. Calcium content was determined by atomic energy absorption. Results were summarised as means+/-SEM. Comparisons between parameters were performed by ANOVA and post-test. RESULTS: None of the G-fed groups could achieve a normal growth performance as compared to the C-fed control group. Like body size, age-related increments in mandibular weight, length, height and area (index of mandibular size) were negatively affected by the G diets, as was the posterior part of the bone (posterior to molar III). The cross-sectional geometry of the mandible (cross-sectional area and rectangular moment of inertia) as well as its structural properties (yielding load, fracture load, and stiffness) were also severely affected by the G diets. However, material properties (Young's modulus and maximum elastic stress) and calcium concentration in ashes and the degree of mineralisation were unaffected. CONCLUSIONS: The differences in strength and stiffness between treated and control rats seemed to be the result of an induced loss of gain in bone growth and mass, in the absence of changes in the quality of the bone mineralised material. PMID- 23022276 TI - Amino acid analysis using core-shell particle column. AB - In this study, the separation efficiency of a core-shell particle column was compared with particle-packed and monolithic silica columns, which showed that the core-shell particle column had a smaller theoretical plate height and that its separation efficiency was not affected significantly by the increase in flow rate. A fast HPLC method using a core-shell particle column was developed for the determination of amino acids. 4-Fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) was used as a fluorescence derivatization reagent for amino acids, followed by separation on a core-shell Kinetex C18 column. The analysis time for 21 NBD-amino acids was within 7min, which was faster than that in our previous studies with conventional particle-packed columns or monolithic silica columns. The linearities of the calibration curves for all the amino acids were found to be good over a range of injection amounts from 40fmol to 40pmol. The accuracies for the amino acid determinations were 90.9-107%. The method was proved to have potential for the fast determination of amino acids in biological samples. PMID- 23022277 TI - Synthesis, biological activity and structure-activity relationship of endomorphin 1/substance P derivatives. AB - Endomorphins have been shown to produce potent analgesia in various rodent models of pain. However, their central administration led to the development of tolerance and physical dependence. Conjugation of C-terminal substance P (SP) fragments to opioids and opioid peptides was previously shown to produce hybrid peptides with strong analgesic activity, with low or no propensity to develop tolerance. In this study, four peptides (2-5) comprised of endomorphin-1 (1) and C-terminal fragments of SP (four or five amino acids, SP(8-11) (2) or SP(7-11) (4), respectively), with an overlapping Phe residue, were synthesized. To overcome low metabolic stability and poor membrane permeability of the peptide, the N-terminus of 2 and 4 was further modified with a C10-carbon lipoamino acid (C10LAA) achieving 3 and 5, respectively. LAA-modification of the hybrid peptides resulted in a significant increase in metabolic stability and membrane permeability compared to peptides 1, 2 and 4. Compound 5 showed potent MU-opioid receptor binding affinity (K(iMU)=3.87 +/- 0.51 nM) with dose-dependent agonist activity in the nanomolar range (IC(50)=45 +/- 13 nM). In silico modeling was used to investigate the binding modes and affinities of compounds 1-5 in the active site of MU-opioid receptors. The docking scores were in agreement with the K(iMU) values obtained in the receptor binding affinity studies. The more active LAA-modified hybrid peptide showed a lower total interaction energy and higher negative value of MolDock score. PMID- 23022278 TI - Design, synthesis and in vitro evaluation of a series of alpha-substituted phenylpropanoic acid PPARgamma agonists to further investigate the stereochemistry-activity relationship. AB - We previously demonstrated that the alpha-benzylphenylpropanoic acid-type PPARgamma-selective agonist 6 exhibited a reversed stereochemistry-activity relationship, that is, the (R)-enantiomer is a more potent PPARgamma agonist than the (S)-enantiomer, compared with structurally similar alpha-ethylphenylpropanoic acid-type PPAR agonists. Here, we designed, synthesized and evaluated the optically active alpha-cyclohexylmethylphenylpropanoic acid derivatives 7 and alpha-phenethylphenylpropanoic acid derivatives 8, respectively. Interestingly, alpha-cyclohexylmethyl derivatives showed reversal of the stereochemistry activity relationship [i.e., (R) more potent than (S)], like alpha-benzyl derivatives, whereas alpha-phenethyl derivatives showed the 'normal' relationship [(S) more potent than (R)]. These results suggested that the presence of a branched carbon atom at the beta-position with respect to the carboxyl group is a critical determinant of the reversed stereochemistry-activity relationship. PMID- 23022279 TI - Analysis of evolution of carbonic anhydrases IV and XV reveals a rich history of gene duplications and a new group of isozymes. AB - Carbonic anhydrase (CA) isozymes CA IV and CA XV are anchored on the extracellular cell surface via glycosylphosphatidylinositol (GPI) linkage. Analysis of evolution of these isozymes in vertebrates reveals an additional group of GPI-linked CAs, CA XVII, which has been lost in mammals. Our work resolves nomenclature issues in GPI-linked fish CAs. Review of expression data brings forth previously unreported tissue and cancer types in which human CA IV is expressed. Analysis of collective glycosylation patterns of GPI-linked CAs suggests functionally important regions on the protein surface. PMID- 23022280 TI - Structure-activity relationship study of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives for potent anti-HIV agents. AB - 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is an antiretroviral agent with submicromolar inhibitory activity against human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. In the current study, the structure-activity relationships of accessory groups at the 3- and 9-positions of pyrimido[1,2-c][1,3]benzothiazin-6-imine were investigated for the development of more potent anti-HIV agents. Several different derivatives containing a 9-aryl group were designed and synthesized using Suzuki-Miyaura cross-coupling and Ullmann coupling reactions. Modification of the m-methoxyphenyl or benzo[d][1,3]dioxol-5-yl group resulted in improved anti-HIV activity. In addition, the 2,4-diazaspiro[5.5]undec-2-ene-fused benzo[e][1,3]thiazine derivatives were designed and tested for their anti-HIV activities. The most potent 9-(benzo[d][1,3]dioxol-5-yl) derivative was two-threefold more effective against several strains of HIV-1 and HIV-2 than the parent compound, PD 404182. PMID- 23022281 TI - New prenylated isoflavonoids as protein tyrosine phosphatase 1B (PTP1B) inhibitors from Erythrina addisoniae. AB - Bioassay-guided fractionation of the EtOAc extract of the root of Erythrina addisoniae (Leguminosae) resulted in the isolation of four new (1-4), along with 2 known prenylated isoflavonoids (5-6). The structures of the isolates were assigned on the basis of spectroscopic data analysis, focusing on interpretation of 1D and 2D NMR, and MS data. All the isolates were evaluated for their inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), as well as their growth inhibition on MCF7, adriamycin-resistant MCF7 (MCF7/ADR), and MDA-MB-231 breast cancer cell lines. Compounds which exhibited PTP1B inhibitory activity (IC(50) values ranging from 4.6 +/- 0.3 to 24.2 +/- 2.1 MUM) showed potential cytotoxic activity (IC(50) values ranging from 3.97 +/- 0.17 to 11.4 +/- 1.9 MUM). Taken together, our data suggest that prenylated isoflavonoids, especially the isoflavone-type skeleton could be considered as new lead compounds against breast cancer via PTP1B inhibition. PMID- 23022283 TI - The airway epithelium in asthma: developmental issues that scar the airways for life? AB - While allergies are very common, affecting ~40% of the population in most Western countries, only a proportion of allergic people develop asthma. This highlights the importance of tissue and cell specific mechanisms that contribute to the disease. As the interface between the inhaled environment and the internal environment of the lung, the epithelium normally possesses numerous mechanisms to maintain an effective protective barrier. However, the inability of the airway epithelium of asthmatics to effectively defend the lung against normally innocuous inhaled agents strongly suggests that asthma must involve defects in the epithelial barrier rather than being primarily an allergic disease. Evidence is accumulating that in asthma, the epithelium does not go through normal stages of development and differentiation and as a consequence, remain somewhat "immature". This in turn leads to a chronic cycle of dysregulated damage and repair which ultimately impacts on the airways function by increasing inflammation, but also by initiating processes that ultimately lead to changes to the structure and function of the airway. PMID- 23022282 TI - Alternative splicing: functional diversity among voltage-gated calcium channels and behavioral consequences. AB - Neuronal voltage-gated calcium channels generate rapid, transient intracellular calcium signals in response to membrane depolarization. Neuronal Ca(V) channels regulate a range of cellular functions and are implicated in a variety of neurological and psychiatric diseases including epilepsy, Parkinson's disease, chronic pain, schizophrenia, and bipolar disorder. Each mammalian Cacna1 gene has the potential to generate tens to thousands of Ca(V) channels by alternative pre mRNA splicing, a process that adds fine granulation to the pool of Ca(V) channel structures and functions. The precise composition of Ca(V) channel splice isoform mRNAs expressed in each cell are controlled by cell-specific splicing factors. The activity of splicing factors are in turn regulated by molecules that encode various cellular features, including cell-type, activity, metabolic states, developmental state, and other factors. The cellular and behavioral consequences of individual sites of Ca(V) splice isoforms are being elucidated, as are the cell-specific splicing factors that control splice isoform selection. Altered patterns of alternative splicing of Ca(V) pre-mRNAs can alter behavior in subtle but measurable ways, with the potential to influence drug efficacy and disease severity. This article is part of a Special Issue entitled: Calcium channels. PMID- 23022284 TI - A four-domain Kunitz-type proteinase inhibitor from Solen grandis is implicated in immune response. AB - Serine proteinase inhibitor (SPI) serves as a negative regulator in immune signal pathway by restraining the activities of serine proteinase (SP) and plays an essential role in the innate immunity. In the present study, a Kunitz-type SPI was identified from the mollusk razor clam Solen grandis (designated as SgKunitz). The full-length cDNA of SgKunitz was of 1284 bp, containing an open reading frame (ORF) of 768 bp. The ORF encoded four Kunitz domains, and their amino acids were well conserved when compared with those in other Kunitz-type SPIs, especially the six cysteines involved in forming of three disulfide bridges in each domain. In addition, the tertiary structure of all the four domains adopted a typical model of Kunitz-type SPI family, indicating SgKunitz was a new member of Kunitz-type SPI superfamily. The mRNA transcripts of SgKunitz were detected in all tested tissues of razor clam, including muscle, mantle, gonad, gill, hepatopancreas and hemocytes, and with the highest expression level in gill. When the razor clams were stimulated by LPS, PGN or beta-1, 3-glucan, the expression level of SgKunitz mRNA in hemocytes was significantly up-regulated (P < 0.01), suggesting SgKunitz might involved in the processes of inhibiting the activity of SPs during the immune responses triggered by various pathogens. Furthermore, the recombinant protein of SgKunitz could effectively inhibit the activities of SP trypsin and chymotrypsin in vitro. The present results suggested SgKunitz could serve as an inhibitor of SP involving in the immune response of S. grandis, and provided helpful evidences to understand the regulation mechanism of immune signal pathway in mollusk. PMID- 23022285 TI - The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes. AB - Thiazolidinedione (TZD) therapy has been associated with an increased risk of bone fractures. Studies in rodents have led to a model in which decreased bone quality in response to TZDs is due to a competition of lineage commitment between osteoblasts (OBs) and adipocytes (ADs) for a common precursor cell, resulting in decreased OB numbers. Our goal was to investigate the effects of TZD exposure on OB-AD lineage determination from primary human bone marrow stromal cells (hBMSCs) both in vitro and in vivo from nondiabetic subjects and patients with type 2 diabetics. Our experimental design included 2 phases. Phase 1 was an in vitro study of TZD effects on the differentiation of hBMSCs into OBs and ADs in nondiabetic subjects. Phase 2 was a randomized, placebo-controlled trial to determine the effects of 6-month pioglitazone treatment in vivo on hBMSC differentiation using AD/OB colony forming unit assays in patients with type 2 diabetes. In vitro, TZDs (pioglitazone and rosiglitazone) enhanced the adipogenesis of hBMSCs, whereas neither altered OB differentiation or function as measured by alkaline phosphatase activity, gene expression, and mineralization. The ability of TZDs to enhance adipogenesis occurred at a specific time/stage of the differentiation process, and pretreating with TZDs did not further enhance adipogenesis. In vivo, 6-month TZD treatment decreased OB precursors, increased AD precursors, and increased total colony number in patients with type 2 diabetes. Our results indicate that TZD exposure in vitro potently stimulates adipogenesis but does not directly alter OB differentiation/mineralization or lineage commitment from hBMSCs. However, TZD treatment in type 2 diabetic patients results in decreased osteoblastogenesis from hBMSCs compared with placebo, indicating an indirect negative effect on OBs and suggesting an alternative model by which TZDs might negatively regulate bone quality. PMID- 23022286 TI - Utilization of health care services by elderly people with National Health Insurance in Taiwan: the heterogeneous health profile approach. AB - OBJECTIVES: Taiwan is now facing an increased prevalence of aging related diseases and escalating healthcare costs. Within the context of the health care system and NHI in Taiwan, the aim of this study was to examine the health profiles of elderly people by using Latent Class Analysis to determine the effects of different health profiles on the health care services utilization and expenditures, and to examine the factors associated with by controlling for the health profiles of elderly people. METHODS: Data came from the 2005 National Health Interview Survey in Taiwan. Among those who were interviewed, 2449 elderly individuals with available health indicators were identified, and 1491 of these had complete socio-economic data and linkage to their utilization of health care services from 2004 to 2007 were analyzed. RESULTS: Four health profiles were identified. The effect of the different health profiles of elderly people on the likelihood of utilization and expenditure on health care services was significant. While comparing with Relative Healthy group, the High Comorbidity group tended to utilize more services in the ambulatory care. The functional impairment group had relatively high probabilities of needing care assistance and the Frail group had higher health care expenditures. Age and gender did not have a significant effect and other associated socio-economic factors were also discussed. CONCLUSIONS: The health status of elderly people includes a variety of health indicators. We suggest that a person-centered approach is needed in order to satisfy needs and forecast expenditures in the future. PMID- 23022287 TI - [Kidney and thyroid dysfunction]. AB - Thyroid hormones influence renal development, kidney structure, renal hemodynamics, glomerular filtration rate, the function of many transport systems along the nephron, and sodium and water homeostasis. Effects of hypothyroidism and hyperthyroidism on kidney function are the result of direct renal effects, as well as systemic hemodynamic, metabolic, and cardiovascular effects. Most of the renal manifestations of thyroid disorders, which are clinically most significant with hypothyroidism, are reversible with treatment. Patients with hypothyroidism can have clinically important reductions in GFR, so screening for hypothyroidism should be considered in patients with unexplained elevations in serum creatinine. Patients with thyroid disorders are also at risk for immune-mediated glomerular diseases. Finally, patients with nephrotic syndrome, as well as acute and chronic kidney injury, have alterations in thyroid gland physiology that can impact thyroid function and the testing of thyroid function status. Dialysis patients have frequently hypothyroidism whose biological diagnosis must be careful. PMID- 23022288 TI - [Predilution online hemodiafiltration: which dose of anticoagulation?]. AB - INTRODUCTION: Patients in end stage renal disease on hemodialysis are in higher risk of bleeding related to the anticoagulation used during a session, so only the lowest effective dose of anticoagulation must be used. The aim of this study was to evaluate the efficacy of predilution in hemodiafiltration with reduced dose of anticoagulation compared to hemodialysis in preventing coagulation of circuits. PATIENTS AND METHODS: This study was conducted in stable hemodialysis patients without high bleeding risk. All patients were treated by two different treatments: (A) conventional hemodialysis, (B) predilution hemodiafiltration with the half dose of anticoagulation used during treatment (A). Other confounding parameters were kept constant during the study. The primary endpoint was the incidence of major thrombotic events judged on a subjective visual score. RESULTS: Twenty-one patients were included (105 sessions for each treatment). Major incidents are occurring more frequently in predilution hemodiafiltration with reduced dose of anticoagulation (P=0.03). The premature discontinuation of sessions was more frequent in predilution hemodiafiltration, this difference was not significant (P=0.07). Duration of sessions was significantly shorter in predilution hemodiafiltration (P=0.03). The higher frequency of thrombotic events in predilution hemodiafiltration has no effect on net ultrafiltration volume achieved in both treatments. CONCLUSION: Predilution hemodiafiltration with a lower dose of anticoagulation did not prevent major clotting of extracorporeal circuit manner at least equivalent to a reference method. PMID- 23022289 TI - [Prospective observational study of angiotensin converting enzyme inhibitors induced hyperkalemia in hospitalized patients with chronic renal failure]. AB - OBJECTIVE: To study the incidence and risk factors of angiotensin converting enzyme inhibitors-induced hyperkalemia in hospitalized patients with hypertension and preexisting chronic renal failure. METHODOLOGY: Two-months prospective observational study was used including all hospitalized patients older than 18 years with a history of hypertension, non-dialyzed chronic renal failure and who had angiotensin converting enzyme prescription at the time of the admission. Hyperkalemia greater than or equal to 5 mmol/L was detected in these patients. The studied variables were demographic, clinical, biological and therapeutic. RESULTS: Eight patients, among 27 included, had a hyperkalemia (2963%). They were 73+/-15 years old. Factors that predispose to hyperkalemia were present in all patients. Hyperkalemia was associated in six cases with decompensation of renal function. The age was associated with hyperkalaemia in patients treated with angiotensin converting enzyme inhibitors (RC=1.21; IC95 1,11-1,46; P=0,021). Diabetes is a possible risk factor (OR=59 021 et, 95 0.93 to 2410, P=0.053). Compared with patients who did not develop hyperkalemia, the occurrence of hyperkalemia in patients included was associated with a longer duration of hospitalization (OR=130, 95 112 to 160, P=0. 022). CONCLUSION: The prescription of angiotensin converting enzyme inhibitors in the elderly with chronic renal failure and diabetes requires careful monitoring of serum potassium. PMID- 23022290 TI - [Magnesium disorders]. AB - Extracellular content in magnesium represents about 1% of total body content, of which plasma magnesium is thus a poor reflect. Hypomagnesaemia is defined by a value lesser than 0.65mmol/L. Its incidence in hospitalized patients ranges between 10 and 15%. Identification of the physiopathology of hypomagnesaemia relies first upon concomitant measurement of plasma and urinary magnesium concentration. Daily magnesium excretion lesser than 1mmol/L or EFMg lesser than 1% sign extra renal origin, due to either low magnesium intake, low intestinal absorption of magnesium or derivation of extracellular magnesium toward bone, such as in bone reparation process after hyperparathyroidism surgery. Daily magnesium excretion higher than 2mmol/L concomitant to hypomagnesaemia indicates native or acquired renal loss of magnesium. Congenital renal and extra-renal losses of magnesium are mainly related to rare monogenic disease, and are inconstantly associated with a renal loss of sodium, potassium and calcium. Recent progress in the genetics of this rare diseases have greatly improved the knowledge about proteins involved in intestinal abortion, renal renal tubular re absorption of magnesium and its regulations. Hypermagnesemia is a rarer metabolic disorder than hypomagnesemia (about 5% of hospitalized patients). Asymptomatic below 2mmol/L, it progressively alters neuromuscular transmission, autonomic sympathic activity and cardiac conduction, with vital risk above 7mol/L. It is due to acute magnesium input into extracellular volume most often associated with a decrease in glomerular filtration rate, limiting the high physiological ability to excrete magnesium input. PMID- 23022291 TI - [Current indications of azathioprine in nephrology]. AB - Azathioprine is an immunosuppressive agent belonging to the antimetabolite family whose action blocks purine synthesis. It inhibits lymphocyte proliferation. In recent years, several trials have clarified the role of this compound used for three main indications: lupus glomerulonephritis, necrotizing vasculitis associated with antineutrophil cytoplasmic antibodies and renal involvement, and kidney transplantation. This review of the literature details practical conditions for the use of azathioprine in these three situations. PMID- 23022292 TI - [Prepare: cross-sectional study on management of chronic kidney disease by nephrologists before dialysis in France]. AB - There are few epidemiologic data on Chronic Kidney Disease management before replacement therapy. The two objectives of the PREPARE study were (1) to describe the characteristics of these patients and accordance to clinical practice guidelines (2) to study nephrologists preference for renal replacement therapy in case of progression to end stage renal disease. PREPARE is a non-interventional cross-sectional study. All the French nephrologists had been solicited to collect information about CKD outpatients not on dialysis, not transplanted, with glomerular filtration rate lower than 60mL/min/1,73m(2), followed on any day between 23 and 27 November 2009. Three hundred and eight investigators included 2089 patients, 59% of them were male, they were on average 69 years old, 15, 37 and 48% had respectively a CKD stage V, stage IV and stage III, the nephropathy was the most often (43%) vascular. The most frequently reported cardiovascular risk factors were hypertension (88%), hypercholesterolemia (53%), diabetes (37%). The average time between diagnosis of nephropathy and the first nephrology consultation was too long 1,5 years. The implementation measures of nephroprotection and treatment of complications of CKD were generally satisfactory. However, preparation for replacement therapy was often too late, haemodialysis was more likely scheduled instead of peritoneal dialysis and without preparation for renal transplantation. PREPARE can therefore highlight the qualities of the current management of CKD by nephrologists in France. Nevertheless, PREPARE also shows weaknesses in preparation for replacement therapy. One can suggest that they could be reduced by systematic access of patients with risk of progression to stage V, as soon as the stage IV, to structured multidisciplinary care. PMID- 23022293 TI - [Higher dialysate calcium is not associated with mortality in hemodialysis patients: results from the French ARNOS study]. AB - Finding the optimal dialysate calcium (DCa) in haemodialysis (HD) patients remains a therapeutic challenge. Besides, the Dialysis Outcomes and Practice Pattern Study (DOPPS) has reported a greater mortality rate using higher DCa doses. The objective was to assess the impact of DCa prescription on survival. Baseline DCa prescriptions were recorded using a cross-sectional analysis of HD patients from the regional ARNOS French cohort. A prospective 42-month survival analysis study was performed. In July 2005, 1294 HD patients were included in this study. DCa at doses of 1.25, 1.5, and 1.75 mmol/L was prescribed in 13.6%, 74.1%, and 12.3% patients, respectively. Using a Cox proportional model adjusted for several parameters, DCa was found to be not significantly associated with survival. Patients receiving 1.75 mmol/L DCa were more frequently treated with online haemodiafiltration, cinacalcet, and shorter dialysis sessions; they had a more frequent history of parathyroidectomy and lower calcium levels. The DCa prescription remained stable after 12 months in 80% of cases. This is an observational study; therefore, only baseline data were recorded for analysis. Higher DCa concentration is not associated with mortality, in contrast to the findings by DOPPS. Prescribing DCa on an individual basis according to various mineral metabolism parameters and treatments appears to be safe irrespective of the DCa dosage. PMID- 23022294 TI - Lipidated analogues of luteinizing hormone-releasing hormone (LHRH) reduce serum levels of follicle-stimulating hormone (FSH) after oral administration. AB - A diverse range of diseases involving the reproductive system are treated with luteinizing hormone-releasing hormone (LHRH) agonists which must be administered daily. Currently, an efficient oral delivery system is not available. Here, we show the facile inclusion of lipoamino acids into the peptide sequence of LHRH, rendering it more stable towards enzymatic degradation, as well as enhancing permeability across Caco-2 cell monolayers. Selected LHRH derivatives were tested in vivo by daily oral administration to rats. The size and weight of the sex organs remained unchanged and the levels of LH were stable over the course of the experiment. However, some of the lipidic peptides (3, 8 and 9) were able to reduce serum levels of follicle-stimulating hormone (FSH), an important finding towards the development of orally available LHRH agonists. PMID- 23022295 TI - Adjuvants to prolong the local anesthetic effects of coated microneedle products. AB - The objective of this study was to identify an adjuvant for anesthetics coated on microneedles to provide rapid onset and prolonged analgesic action with minimal skin tissue reaction. Aqueous lidocaine or prilocaine formulations with or without clonidine or the related analogs, guanfacine and apraclonidine, were dip coated onto polymeric microneedles. The amount of lidocaine or prilocaine coated onto the microneedles was assessed by high performance liquid chromatography (HPLC). Delivery efficiency and dermal pharmacokinetics associated with lidocaine or prilocaine delivered via the microneedles were characterized in vivo using domestic swine. Skin punch biopsies were collected and analyzed to determine the anesthetic concentrations in the skin using HPLC-mass spectrometry (LC-MS). Addition of clonidine to the formulations decreased the systemic absorption rate of the anesthetics from the patch application site without impacting the coating performance or the rapid onset of anesthesia. Formulations with 0.3 wt.% clonidine, identified as the optimal dose for lidocaine-delivery via microneedles, maintained the lidocaine skin concentration above the estimated therapeutic level (100 ng/mg) for 1 h without causing any skin irritation or color change. The other two clonidine analogs, guanfacine and apraclonidine, also led to delayed systemic absorption of lidocaine from the skin, indicating utility in providing prolonged analgesia. PMID- 23022296 TI - Insights into the multi-equilibrium, superstructure system based on beta cyclodextrin and a highly water soluble guest. AB - Pentamidine isethionate (PNT) is an antiprotozoal active in many cases of leishmaniasis, despite the present limitations including high toxicity and parenteral administration. In the present work, a PNT encapsulation strategy into beta-cyclodextrin cavity at 1:1 and 2:1 (betaCD:PNT) molar ratios was used in order to improve the drug's physical and chemical properties. Combining thermodynamic and structural approaches such as isothermal titration calorimetry (ITC), electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance ((1)H NMR, and ROESY) the inclusion process and the thermodynamics parameters were identified. ITC and ESI-MS experimental data suggest the simultaneous formation of different supramolecular complexes in solution. Moreover, NMR data are in accordance with these results, suggesting a deep inclusion of PNT into the betaCD cavity, through correlations observed in 2D ROESY contour maps. The systems were also characterized by FTIR, TG/DTA and SEM. These techniques indicate the formation of inclusion complex in the solid state. In vivo PNT activity was evaluated orally in mice. The inclusion complex showed a significant reduction of parasite load compared to free PNT. PMID- 23022297 TI - Improved plasmid-based system for fully regulated off-to-on gene expression in Escherichia coli: application to production of toxic proteins. AB - In previous work transduction of Escherichia coli with phage lambda particles carrying packaged plasmids was shown to provide complete off-to-on expression of plasmid-borne genes (Cronan, J.E., 2003. J. Bacteriol. 185, 6522-6529). The plasmids used contained the phage lambdacos site (and hence are cosmids) and were very efficiently packaged into lambda phage particles in vivo upon induction of lambda lysogens having an inactivated cos site. However, a shortcoming was that the stocks contained a variable fraction of infectious lambda phage which arose by recombinational repair of the inactive cos site. I report that the construction of E. coli strains that eliminate the background of infectious phage and show that the system can be utilized to express proteins by the phage T7 RNA polymerase/pET vector system. PMID- 23022298 TI - Convergent evolution of a reproductive trait through distinct developmental mechanisms in Drosophila. AB - Convergent morphologies often arise due to similar selective pressures in independent lineages. It is poorly understood whether the same or different developmental genetic mechanisms underlie such convergence. Here we show that independent evolution of a reproductive trait, ovariole number, has resulted from changes in distinct developmental mechanisms, each of which may have a different underlying genetic basis in Drosophila. Ovariole number in Drosophila is species specific, highly variable, and largely under genetic control. Convergent changes in Drosophila ovariole number have evolved independently within and between species. We previously showed that the number of a specific ovarian cell type, terminal filament (TF) cells, determines ovariole number. Here we examine TF cell development in different Drosophila lineages that independently evolved a significantly lower ovariole number than the D. melanogaster Oregon R strain. We show that in these Drosophila lineages, reduction in ovariole number occurs primarily through variations in one of two different developmental mechanisms: (1) reduced number of somatic gonad precursors (SGP cells) specified during embryogenesis; or (2) alterations of somatic gonad cell morphogenesis and differentiation in larval life. Mutations in the D. melanogaster Insulin Receptor (InR) alter SGP cell number but not ovarian morphogenesis, while targeted loss of function of bric-a-brac 2 (bab2) affects morphogenesis without changing SGP cell number. Thus, evolution can produce similar ovariole numbers through distinct developmental mechanisms, likely controlled by different genetic mechanisms. PMID- 23022300 TI - Clinical alarm hazards: a "top ten" health technology safety concern. AB - For the past several years ECRI Institute has published a list of Top Ten Health Technology Hazards. This list is based on ECRI's extensive research in health technology safety and on data provided to its problemreporting systems. For every year that the Top Ten list has been published, Alarm Hazards have been at or near the top of the list. Improving alarm safety requires a systematic review of a hospital's alarm-based technologies and analysis of alarm management policies like alarm escalation strategies and staffing patterns. It also requires careful selection of alarm setting criteria for each clinical care area. This article will overview the clinical alarm problems that have been identified through ECRI Institute's research and analysis of various problem reporting databases, including those operated by ECRI Institute. It will also highlight suggestions for improvement, particularly from a technology design and technology management perspective. PMID- 23022299 TI - REST and its downstream molecule Mek5 regulate survival of primordial germ cells. AB - In mouse embryos, some primordial germ cells (PGCs) are eliminated by apoptosis, but the molecular pathways that lead to PGC survival versus apoptosis have not been fully characterized. Here, we found that REST (repressor element 1-silencing transcription factor), a transcription factor that binds a conserved regulatory element, NRSE/RE1, played a role in PGC survival. REST expression was higher in PGCs than in surrounding somatic cells. Moreover, in mouse embryos with a PGC specific conditional REST mutation, the PGC population experienced more apoptosis and was significantly smaller than that in control embryos; these findings indicated that REST functioned in a cell-autonomous fashion that was critical for PGC survival. Several anti-apoptotic genes were among the previously identified REST-target gene candidates; moreover, some of these genes were downregulated in the REST-deficient PGCs. Mek5, which encodes a component in the a MAP kinase cascade, was one of these downregulated REST-target gene candidates, and a Mek5 mutation, like the REST mutation, caused an increase in PGC apoptosis; these finding suggested that REST promoted PGC survival via regulation of the Mek5 expression. Importantly, there were a normal number of PGCs in the REST mutants at birth, and both the male and female REST-mutant adults were fertile; these final observations revealed that the PGC population was very robust and could recover from a genetically induced reduction in cell number. PMID- 23022301 TI - Estimation performance of a reduced lead system during continuous 12-lead ECG ST segment monitoring. AB - BACKGROUND: Reduced lead systems utilizing patient-specific transformation weights have been reported to achieve superior estimates than those utilizing population-based transformation weights. We report upon the effects of ischemic type electrocardiographic changes on the estimation performance of a reduced lead system when utilizing patient-specific transformation weights and population based transformation weights. METHOD: A reduced lead system that used leads I, II, V2 and V5 to estimate leads V1, V3, V4, and V6 was investigated. Patient specific transformation weights were developed on electrocardiograms containing no ischemic-type changes. Patient-specific and population-based transformations weights were assessed on 45 electrocardiograms with ischemic-type changes and 59 electrocardiograms without ischemic-type changes. RESULTS: For patient-specific transformation weights the estimation performance measured as median root mean squared error values (no ischemic-type changes vs. ischemic-type changes) was found to be (V1, 27.5 MUV vs. 95.8 MUV, P<.001; V3, 33.9 uV vs. 65.2 uV, P<.001; V4, 24.8 MUV vs. 62.0 MUV, P<.001; V6, 11.7 MUV vs. 51.5 MUV, P<.001). The median magnitude of ST-amplitude difference 60 ms after the J-point between patient specific estimated leads and actual recorded leads (no ischemic-type changes vs. ischemic-type changes) was found to be (V1, 18.9 MUV vs. 61.4 MUV, P<.001; V3, 14.3 MUV vs. 61.1 MUV, P<.001; V4, 9.7 MUV vs. 61.3 MUV, P<.001; V6, 5.9 MUV vs. 46.0 MUV, P<.001). CONCLUSION: The estimation performance of patient-specific transformations weights can deteriorate when ischemic-type changes develop. Performance assessment of patient-specific transformation weights should be performed using electrocardiographic data that represent the monitoring situation for which the reduced lead system is targeted. PMID- 23022302 TI - Electrocardiogram in myocardial edema due to Takotsubo syndrome. PMID- 23022303 TI - A review of the role of electrocardiography in the diagnosis of left ventricular hypertrophy in hypertension. AB - ECG remains the first line method for detection of left ventricular hypertrophy (LVH) in patients with hypertension. ECG diagnosis of LVH predicts a several-fold increase in age- and risk factor-adjusted cardiovascular morbidity and mortality in asymptomatic patients with essential hypertension. When compared with traditional ECG methods, Cornell voltage product and multifactorial criteria such as the Perugia criterion allow detection of LVH in a higher proportion of subjects while carrying a high attributable risk for cardiovascular morbidity and mortality. Hence, traditional interpretation of standard ECG maintains an important role for cardiovascular risk stratification in hypertension. PMID- 23022304 TI - Differentiation between left bundle branch block and left ventricular hypertrophy: implications for cardiac resynchronization therapy. AB - Recent clinical trials have demonstrated that cardiac resynchronization therapy (CRT) reduces heart failure hospitalizations and mortality in patients with complete left bundle branch block (LBBB), but potentially not those with right bundle branch block or nonspecific LV conduction delay, such as that due to LV hypertrophy (LVH). Furthermore, endocardial mapping and simulation studies have suggested that one-third of patients diagnosed with LBBB by conventional electrocardiographic criteria are misdiagnosed, and these patients likely have a combination of LVH, LV chamber dilatation and delayed initiation of LV activation (incomplete LBBB). Increase in LV size due to hypertrophy/dilatation and slowed intramyocardial conduction velocity prolong QRS duration in patients with LVH, which can frequently go above the QRS duration threshold of 120 ms conventionally used to diagnose LBBB. New strict criteria for diagnosing complete LBBB have been proposed that utilize longer QRS duration thresholds (130 ms in women and 140 ms in men) and require the presence of mid-QRS notching/slurring in at least 2 of the leads I, aVL, V1, V2, V5 or V6. The emergence of CRT has led to an increased need to differentiate complete LBBB from LVH and other types of intraventricular conduction delay, which should be further studied. PMID- 23022305 TI - The Telemetric and Holter ECG Warehouse (THEW): the first three years of development and research. AB - The Telemetric and Holter ECG Warehouse (THEW) hosts more than 3700 digital 24 Holter ECG recordings from 13 independent studies. In addition to the ECGs, the repository includes patient information in separate clinical database with content varying according to the study focus. In its third year of activities, the THEW database has been accessed by researchers from 37 universities and 16 corporations located in 16 countries worldwide. Twenty publications were released primarily focusing on the development and validation of ECG-based technologies. This communication describes the content of the databases of the repository with brief summary of the research and development projects completed using these data. PMID- 23022306 TI - Changing role of ECG in the evaluation left ventricular hypertrophy. PMID- 23022307 TI - Different types of long-duration ventricular fibrillation: can they be identified by electrocardiography. AB - We tested the hypothesis that after 2 minutes of ventricular fibrillation (VF), periods of highly organized activations occur on the endocardium, arising from an intramural mother rotor or triggered activity originating in the Purkinje fibers. In 6 anesthetized dogs, we recorded electrically induced VF from two-thirds of the endocardium with a 64-electrode basket catheter. In another 12 dogs, the study was repeated with the addition of the early afterdepolarization blocker pinacidil in 6 animals and the delayed afterdepolarization blocker flunarizine in the other 6 animals. We found that, in addition to periods of disorganized chaotic activation (type I pattern), at between 3 and 7 minutes of VF, 2 highly organized patterns were observed (type II pattern, regular activity and type III pattern, triggered activity). When present, these patterns were observed in all 64 electrodes simultaneously. Type II arises from the apex and may be an intramural mother rotor and type III arises focally in Purkinje fibers and may be caused by early afterdepolarizations. The optimal defibrillation strategy may be different for the 3 different VF patterns. Therefore, it is important to determine if these 3 patterns can be differentiated from the body surface electrocardiogram. PMID- 23022308 TI - ECG manifestations of left ventricular electrical remodeling. AB - Research and thinking about the electrocardiographic manifestations of left ventricular hypertrophy has been constrained by a limited conceptual model of the process: heart disease produces chamber enlargement (increased mass), which in turn produces an altered electrocardiogram. The process is much more complex than can be represented in this simple model. A more robust and intricate model is proposed, in which heart (and vascular) disease causes structural changes, electrical changes, biochemical changes, and others, all of which interact to produce electrical remodeling of ventricular myocardium. This electrical remodeling results in a variety of ECG changes. All of these changes interact, leading to an altered clinical course, and to premature death. It is suggested that research, based on this model, can provide new clues to the processes involved, and improve the prediction of clinical outcomes. New directions in research, in recording equipment, and in organizational activities are suggested to test this new model, and to improve the usefulness of the electrocardiogram as a research and diagnostic tool. PMID- 23022309 TI - DYNAMO: concurrent dynamic multi-model source localization method for EEG and/or MEG. AB - This work presents a new dipolar method to estimate the neural sources from separate or combined EEG and MEG data. The novelty lies in the simultaneous estimation and integration of neural sources from different dynamic models with different parameters, leading to a dynamic multi-model solution for the EEG/MEG source localization problem. The first key aspect of this method is defining the source model as a dipolar dynamic system, which allows for the estimation of the probability distribution of the sources within the Bayesian filter estimation framework. A second important aspect is the consideration of several banks of filters that simultaneously estimate and integrate the neural sources of different models. A third relevant aspect is that the final probability estimate is a result of the probabilistic integration of the neural sources of numerous models. Such characteristics lead to a new approach that does not require a prior definition neither of the number of sources or of the underlying temporal dynamics, allowing for the specification of multiple initial prior estimates. The method was validated by three sensor modalities with simulated data designed to impose difficult estimation situations, and with real EEG data recorded in a feedback error-related potential paradigm. On the basis of these evaluations, the method was able to localize the sources with high accuracy. PMID- 23022310 TI - Environmental factors influencing soil testate amoebae in herbaceous and shrubby vegetation along an altitudinal gradient in subarctic tundra (Abisko, Sweden). AB - Shifts in community composition of soil protozoa in response to climate change may substantially influence microbial activity and thereby decomposition processes. However, effects of climate and vegetation on soil protozoa remain poorly understood. We studied the distribution of soil testate amoebae in herbaceous and shrubby vegetation along an altitudinal gradient (from below the treeline at 500 m to the mid-alpine region at 900 m a.s.l.) in subarctic tundra. To explain patterns in abundance, species diversity and assemblage composition of testate amoebae, a data set of microclimate and soil chemical characteristics was collected. Both elevation and vegetation influenced the assemblage composition of testate amoebae. The variation was regulated by interactive effects of summer soil moisture, winter soil temperature, soil pH and nitrate ion concentrations. Besides, soil moisture regulated non-linear patterns in species richness across the gradient. This is the first study showing the effects of winter soil temperatures on species composition of soil protozoa. The effects could be explained by specific adaptations of testate amoebae such as frost-resistant cysts allowing them to survive low winter temperatures. We conclude that the microclimate and soil chemical characteristics are the main drivers of changes in protozoan assemblage composition in response to elevation and vegetation. PMID- 23022311 TI - Periventricular leukomalacia long-term prognosis may be improved by treatment with UDP-glucose, GDNF, and memantine in neonatal rats. AB - The therapeutic effects of UDP-glucose (UDPG), an endogenous agonist of GPR17 that may promote the self-repair of white matter, glial cell line-derived neurotrophic factor (GDNF), a neurotrophic factor correlated with the growth and survival of nerve cells, and memantine, an antagonist of NMDA receptors, were evaluated for functional improvement of neonatal rats with experimental periventricular leukomalacia (PVL). Five day-old neonatal rat pups were subjected to an ischemia-induced model of PVL. The pups were then randomly divided into sham, PVL, PVL plus UDPG, PVL plus GDNF, and PVL plus memantine groups. All pups were weighed and the age at first eye opening recorded. Pathological changes and myelin sheath formation in the white matter were assessed under both light and electron microscopy on day 7 and 21 after induction of PVL. Values of escape latency (EL) and swimming distance (SD) in Morris water maze test, and the modified inclined plane scores in Rivlin inclined plane test were recorded for rats on day 26. Pups in the PVL group were found to be significantly lower in weight (p<0.05), delayed in age at first eye opening (p<0.01), and impaired in their inclined plane (p<0.01) and Morris water maze (p<0.01) performance compared with those in the sham, UDPG, GDNF and memantine groups. Histopathological grading of the white matter classified all pups in the PVL group with significantly more severe injury (p<0.01), and the number and thickness of their myelin sheaths were significantly less (p<0.01), compared to the UDPG, GDNF, memantine, or sham groups. These results indicate that treatment with UDPG, GDNF, and memantine may significantly improve long-term prognosis in neonatal rats with cerebral white matter injury, characteristic of PVL. PMID- 23022313 TI - Body mass, wealth, and inequality in the 19th century: joining the debate surrounding equality and health. AB - We explore relationships among BMI variation, wealth, and inequality in the 19th century US. There was an inverse relationship between BMI and average state-level wealth and a small, inverse relationship with wealth inequality. After controlling for wealth and inequality, farmers had greater BMI values than workers in other occupations, and blacks had greater BMI values because of nutritional deprivation in utero. PMID- 23022312 TI - N-Myc and L-Myc are essential for hair cell formation but not maintenance. AB - Sensorineural hearing loss results from damage to the hair cells of the organ of Corti and is irreversible in mammals. While hair cell regeneration may prove to be the ideal therapy after hearing loss, prevention of initial hair cell loss could provide even more benefit at a lower cost. Previous studies have shown that the deletion of Atoh1 results in embryonic loss of hair cells while the absence of Barhl1, Gfi1, and Pou4f3 leads to the progressive loss of hair cells in newborn mice. We recently reported that in the early embryonic absence of N-Myc (using Pax2-Cre), hair cells in the organ of Corti develop and remain until at least seven days after birth, with subsequent progressive loss. Thus, N-Myc plays a role in hair cell viability; however, it is unclear if this is due to its early expression in hair cell precursors and throughout the growing otocyst as it functions through proliferation or its late expression exclusively in differentiated hair cells. Furthermore, the related family member L-Myc is mostly co-expressed in the ear, including in differentiated hair cells, but its function has not been studied and could be partially redundant to N-Myc. To test for a long-term function of the Mycs in differentiated hair cells, we generated nine unique genotypes knocking out N-Myc and/or L-Myc after initial formation of hair cells using the well-characterized Atoh1-Cre. We tested functionality of the auditory and vestibular systems at both P21 and four months of age and under the administration of the ototoxic drug cisplatin. We conclude that neither N-Myc nor L-Myc is likely to play important roles in long-term hair cell maintenance. Therefore, it is likely that the late-onset loss of hair cells resulting from early deletion of the Mycs leads to an unsustainable developmental defect. PMID- 23022314 TI - In situ distribution and characterization of the organic content of the oyster shell Crassostrea gigas (Mollusca, Bivalvia). AB - Cultivation of commercial oysters is now facing the possible influence of global change in sea water composition, commonly referred to as "ocean acidification". In order to test the potential consequence of the predicted environmental changes, a cultivation experiment was carried out. The left and right valves of the oyster shell Crassostrea gigas differ in their structure; moreover, lenses of non compact layers are irregular. The shell layers of juvenile C. gigas are studied using a variety of highly spatially resolved techniques to establish their composition and structure. Our results confirm the presence of three different calcitic structural types. The role of the lenses of chalky layers is not yet deciplered. Despite a common mineralogy, the elemental composition of the layers differs. The sulphur aminoacids and sulphated polysaccharide contents of the intracrystalline and intercrystalline matrices differ, as well as those of the structural types. The possible different sensitivity of these structures to environmental changes is still unknown. PMID- 23022315 TI - The effects of environmental factors on the virulence of Trichomonas vaginalis. AB - This review focused on potential regulatory mechanisms of Trichomonas vaginalis virulence properties, cytoadherence, cytotoxicity, phagocytosis, hemolysis, induction of apoptosis, and immune evasion in response to environmental factors of the human urogenital tract, iron, zinc, and polyamines. Understanding the multifactorial nature of trichomonal pathogenesis and its regulation may help to unravel the survival strategies of trichomonads and to implement prevention policies, opportune diagnosis, and alternative treatments for control of trichomoniasis. PMID- 23022316 TI - Patterns and predictors of first-line chemotherapy use among adults with advanced non-small cell lung cancer in the cancer research network. AB - BACKGROUND: Relatively low rates of chemotherapy receipt have been observed in older patients diagnosed with advanced non-small cell lung cancer (NSCLC) in SEER Medicare-based studies. However, little is known about variation in first-line NSCLC chemotherapy use in younger patients, health maintenance organization (HMO) based settings, and for high-cost, novel agents, such as bevacizumab and erlotinib. METHODS: A cohort of 6614 stage IIIB/IV NSCLC patients aged >= 21 years diagnosed between 2000 and 2007 was identified at four HMOs that participate in the Cancer Research Network (CRN). Demographic, comorbidity, tumor characteristics, and chemotherapy treatment data were included in logistic regression models to identify factors associated with chemotherapy receipt and tests of association examined secular and age-specific variation in first-line chemotherapy regimens. RESULTS: Within 120 days of diagnosis, 3612 (55%) patients received chemotherapy; increasing from 52% of patients diagnosed in 2000 to 59% in 2007 (p<0.001). Receipt was significantly higher for patients aged <65 years (64% versus 46% in >= 65) and was inversely related to stage and comorbidites (all p<0.001). Carboplatin and paclitaxel were received most frequently. Erlotinib and bevacizumab use in the later years of the study was associated with a significant change in distributions of first-line chemotherapies (p<0.001). CONCLUSIONS: For patients alive 30 days post diagnosis, chemotherapy use was higher in the aged population (>65 years) than previously published estimates, and higher still among younger patients. Chemotherapy use increased over the observation period, and the mix of first-line therapies used changed substantially over time. Of note, novel, high cost treatments were used in first line therapy prior to FDA approval, increasing significantly throughout the study period. These findings demonstrate the utility of HMO CRN data to augment SEER Medicare to conduct comparative effectiveness research related to chemotherapy use and the use of specific agents, especially among younger patients. PMID- 23022317 TI - Successful echocardiography-guided management of refractory postoperative hypotension after Alfieri repair of the mitral valve. PMID- 23022318 TI - Assessing selective sustained attention in 3- to 5-year-old children: evidence from a new paradigm. AB - Selective sustained attention (SSA) is crucial for higher order cognition. Factors promoting SSA are described as exogenous or endogenous. However, there is little research specifying how these factors interact during development, due largely to the paucity of developmentally appropriate paradigms. We report findings from a novel paradigm designed to investigate SSA in preschoolers. The findings indicate that this task (a) has good psychometric and parametric properties and (b) allows investigation of exogenous and endogenous factors within the same task, making it possible to attribute changes in performance to different mechanisms of attentional control rather than to differences in engagement in different tasks. PMID- 23022320 TI - Neovascularity in patellar tendinopathy and the response to eccentric training: a case report using Power Doppler ultrasound. AB - This report describes the case of an amateur soccer player with chronic patellar tendinopathy who underwent ultrasound imaging before and after engaging in an 8 week programme of eccentric exercise. On initial assessment, greyscale ultrasound imaging demonstrated tendon thickening and reduced echogenicity, while Power Doppler imaging demonstrated a large amount of neovascularity. After 8 weeks of an eccentric loading programme, the patient reported significantly improved symptoms and functional scores, while follow-up imaging demonstrated improvement in the echo appearance of the tendon and complete resolution of the neovascularity. The association between neovascularity and symptoms in tendinopathy research is conflicting, with a paucity of research in the area of patellar tendinopathy. While further research is needed to clarify the significance of greyscale and Power Doppler ultrasound changes in relation to symptoms in patellar tendinopathy, ultrasound imaging was shown to be a useful adjunct to diagnosis and outcome assessment in this case. PMID- 23022321 TI - Hypoxia affects cellular responses to plant extracts. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Microenvironmental conditions contribute towards varying cellular responses to plant extract treatments. Hypoxic cancer cells are known to be resistant to radio- and chemo-therapy. New therapeutic strategies specifically targeting these cells are needed. Plant extracts used in Traditional Chinese Medicine (TCM) can offer promising candidates. Despite their widespread usage, information on their effects in hypoxic conditions is still lacking. In this study, we examined the cytotoxicity of a series of known TCM plant extracts under normoxic versus hypoxic conditions. MATERIALS AND METHODS: Pereskia grandifolia, Orthosiphon aristatus, Melastoma malabathricum, Carica papaya, Strobilanthes crispus, Gynura procumbens, Hydrocotyle sibthorpioides, Pereskia bleo and Clinacanthus nutans leaves were dried, blended into powder form, extracted in methanol and evaporated to produce crude extracts. Human Saos-2 osteosarcoma cells were treated with various concentrations of the plant extracts under normoxia or hypoxia (0.5% oxygen). 24h after treatment, an MTT assay was performed and the IC(50) values were calculated. Effect of the extracts on hypoxia inducible factor (HIF) activity was evaluated using a hypoxia-driven firefly luciferase reporter assay. RESULTS: The relative cytotoxicity of each plant extract on Saos-2 cells was different in hypoxic versus normoxic conditions. Hypoxia increased the IC(50) values for Pereskia grandifola and Orthosiphon aristatus extracts, but decreased the IC(50) values for Melastoma malabathricum and Carica papaya extracts. Extracts of Strobilanthes crispus, Gynura procumbens, Hydrocotyle sibthorpioides had equivalent cytotoxic effects under both conditions. Pereskia bleo and Clinacanthus nutans extracts were not toxic to cells within the concentration ranges tested. The most interesting result was noted for the Carica papaya extract, where its IC(50) in hypoxia was reduced by 3-fold when compared to the normoxic condition. This reduction was found to be associated with HIF inhibition. CONCLUSION: Hypoxia variably alters the cytotoxic effects of TCM plant extracts on cancer cells. Carica papaya showed enhanced cytotoxic effect on hypoxic cancer cells by inhibiting HIF activities. These findings provide a plausible approach to killing hypoxic cancer cells in solid tumors. PMID- 23022319 TI - The hexameric helicase DnaB adopts a nonplanar conformation during translocation. AB - DNA polymerases can only synthesize nascent DNA from single-stranded DNA (ssDNA) templates. In bacteria, the unwinding of parental duplex DNA is carried out by the replicative DNA helicase (DnaB) that couples NTP hydrolysis to 5' to 3' translocation. The crystal structure of the DnaB hexamer in complex with GDP AlF(4) and ssDNA reported here reveals that DnaB adopts a closed spiral staircase quaternary structure around an A-form ssDNA with each C-terminal domain coordinating two nucleotides of ssDNA. The structure not only provides structural insights into the translocation mechanism of superfamily IV helicases but also suggests that members of this superfamily employ a translocation mechanism that is distinct from other helicase superfamilies. We propose a hand-over-hand mechanism in which sequential hydrolysis of NTP causes a sequential 5' to 3' movement of the subunits along the helical axis of the staircase, resulting in the unwinding of two nucleotides per subunit. PMID- 23022322 TI - Simo decoction promotes contraction of antral circular smooth muscle mainly via muscarinic M3 receptor. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Simo Decoction (SMD), a traditional Chinese medicine, included four elements, such as Fructus aurantii, Radix aucklandiae, Semen arecae and Radix linderae. It has been used to improve gastrointestinal dysmotility in clinical practice for a long history in China. However, the explicit mechanisms are unclear. The aim of this study was to investigate the effect of SMD on contractions of antral circular smooth muscle strips of Sprague Dawley (SD) rats and its underlying mechanism. MATERIALS AND METHODS: The antral circular strips were prepared in the organ bath under baseline or to be incubated with muscarinic receptor antagonist atropine (10(-6)M), muscarinic M3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (0.4*10( 6)M), muscarinic M2 receptor antagonist gallamine (10(-6)M), adrenergic receptor agonist adrenaline (10(-7)M), exogenous nitric oxide (NO) donor l-arginine (10( 4)M), nicotinic receptor antagonist hexamethonium chloride (10(-4)M) and Ca(2+) channel antagonist nifedipine (30nM), and consecutive concentrations of SMD were added to the bath to observe the strip responses. As a control, the responses of strips after administration with the same volume of Krebs solution as SMD were also noted. The strip responses to acetylcholine (10(-7)-10(-3)M) were also noted in organ bath to compare with SMD-induced contraction. RESULTS: SMD dose dependently evoked hypercontractility of antral circular strips, and the maximal contractile effect of circular smooth muscle induced by SMD was significantly higher than that induced by acetylcholine (10(-3)M). The responses of antral circular strips to SMD were completely antagonized by atropine, 4-DAMP or 4 DAMP+gallamine, but partly inhibited by gallamine and partly suppressed by adrenaline, l-arginine, hexamethonium chloride and nifedipine. CONCLUSIONS: SMD promotes contractions of antral circular strips in rats mainly via activation of muscarinic M3 receptor, but partly via activation of muscarinic M2 receptor, Ca(2+) channel and nicotinic receptor, inhibition of adrenergic receptor and releasing of NO. PMID- 23022323 TI - Modeling the binding mechanism of Alzheimer's Abeta1-42 to nicotinic acetylcholine receptors based on similarity with snake alpha-neurotoxins. AB - For over a decade, it has been known that amyloid beta (Abeta) peptides of Alzheimer's disease bind to the nicotinic alpha7 acetylcholine receptor (AChR) with picomolar affinity, and that snake alpha-neurotoxins competitively inhibit this binding. Here we propose a model of the binding mechanism of Abeta peptides to alpha7-AChR at atomic level. The binding mechanism is based on sequence and structure similarities of Abeta residues with functional residues of snake alpha neurotoxins (ATX) in complex with AChR. The binding mechanism involves residue (Abeta)K28 (similar to (ATX)R32) which forms cation/pi interactions in the acetylcholine binding site, and residues (Abeta)G29-(Abeta)I32 [GAII] (similar to (ATX)G33-(ATX)I36 [GTII]) which form an intermolecular beta-sheet with residues (alpha7)F189-(alpha7)E191 of AChR. Through these interactions, we propose that the AChR serves as a chaperone for Abeta conformational changes from alpha- to beta-hairpin. The interactions which block channel opening provide fundamental insight into Abeta neurotoxicity and cognition impairment, that could contribute to pathogenic processes in Alzheimer's disease, thus paving the way for structure based therapies. PMID- 23022324 TI - Inhibition of neurite outgrowth and alteration of cytoskeletal gene expression by sodium arsenite. AB - Arsenic compounds that are often found in drinking water increase the risk of developmental brain disorders. In this study, we performed live imaging analyses of Neuro-2a cells expressing SCAT3, a caspase-3 cleavage peptide sequence linking two fluorescent proteins; enhanced cyan fluorescence protein (ECFP) and Venus, to determine whether sodium arsenite (NaAsO(2); 0, 1, 5, or 10 MUM) affects both neurite outgrowth and/or induces apoptosis with the same doses and in the same cell cultures. We observed that the area ratio of neurite to cell body in SCAT3 expressing cells was significantly reduced by 5 and 10 MUM NaAsO(2), but not by 1 MUM, although the emission ratio of ECFP to Venus, an endpoint of caspase-3 activity, was not changed. However, cytological assay using apoptotic and necrotic markers resulted in that apoptosis, but not necrosis, was significantly induced in Neuro-2a cells when NaAsO(2) exposure continued after the significant effects of NaAsO(2) on neurite outgrowth were found by live imaging. These results suggested that neurite outgrowth was suppressed by NaAsO(2) prior to NaAsO(2)-induced apoptosis. Next, we examined the effects of NaAsO(2) on cytoskeletal gene expression in Neuro-2a cells. NaAsO(2) increased the mRNA levels of the light and medium subunits of neurofilament and decreased the mRNA levels of tau and tubulin in a dose-dependent manner; no significant effect was found in the mRNA levels of the heavy subunit of neurofilament, microtubule associated protein 2, or actin. The changes in cytoskeletal gene expression are likely responsible for the inhibitory effects of NaAsO(2) on neurite outgrowth. PMID- 23022325 TI - European ring trial to evaluate ELISAs for the diagnosis of infection with Rift Valley fever virus. AB - A ring trial was organized to evaluate Rift Valley fever virus (RVFV) ELISAs by European laboratories. A total of five ELISAs, two of which specific for IgM antibodies, were evaluated by six participants. Sera were derived from cattle or sheep and originated from either a RVFV endemic area, a RVFV-free area or from experimental infection studies. Cohen's kappa analysis showed higher than 90% agreement of two commercially available ELISAs with the virus neutralization test, suggesting that primary screening as well as serological confirmation using these ELISAs is feasible. More extensive validations with sera of known IgM status are, however, required to determine agreement between IgM ELISAs. PMID- 23022326 TI - Mind over chatter: plastic up-regulation of the fMRI salience network directly after EEG neurofeedback. AB - Neurofeedback (NFB) involves a brain-computer interface that allows users to learn to voluntarily control their cortical oscillations, reflected in the electroencephalogram (EEG). Although NFB is being pioneered as a noninvasive tool for treating brain disorders, there is insufficient evidence on the mechanism of its impact on brain function. Furthermore, the dominant rhythm of the human brain is the alpha oscillation (8-12 Hz), yet its behavioral significance remains multifaceted and largely correlative. In this study with 34 healthy participants, we examined whether during the performance of an attentional task, the functional connectivity of distinct fMRI networks would be plastically altered after a 30 min session of voluntary reduction of alpha rhythm (n=17) versus a sham-feedback condition (n=17). We reveal that compared to sham-feedback, NFB induced an increase of connectivity within regions of the salience network involved in intrinsic alertness (dorsal anterior cingulate), which was detectable 30 min after termination of training. The increase in salience network (default-mode network) connectivity was negatively (positively) correlated with changes in 'on task' mind-wandering as well as resting state alpha rhythm. Crucially, we observed a causal dependence between alpha rhythm synchronization during NFB and its subsequent change at resting state, not exhibited by the SHAM group. Our findings provide neurobehavioral evidence for the brain's exquisite functional plasticity, and for a temporally direct impact of NFB on a key cognitive control network, suggesting a promising basis for its use to treat cognitive disorders under physiological conditions. PMID- 23022327 TI - A novel approach for global noise reduction in resting-state fMRI: APPLECOR. AB - Noise in fMRI recordings creates uncertainty when mapping functional networks in the brain. Non-neural physiological processes can introduce correlated noise across much of the brain, altering the apparent strength and extent of intrinsic networks. In this work, a new data-driven noise correction, termed "APPLECOR" (for Affine Parameterization of Physiological Large-scale Error Correction), is introduced. APPLECOR models spatially-common physiological noise as the linear combination of an additive term and a mean-dependent multiplicative term, and then estimates and removes these components. APPLECOR is shown to achieve greater consistency of the default mode network across time and across subjects than was achieved using global mean regression, respiratory volume and heart rate correction (RVHRCOR (Chang et al., 2009)), or no correction. Combining APPLECOR with RVHRCOR regressors attained greater consistency than either correction alone. Use of the proposed noise-reduction approach may help to better identify and delineate the structure of resting state networks. PMID- 23022328 TI - Toxicity of cytotoxic agents to granulocyte-macrophage progenitors is increased in obese Zucker and non-obese but insulin resistant Goto-Kakizaki rats. AB - Increased risk of anticancer chemotherapy in seriously obese patients is known. Obesity may be among factors that predict treatment-related toxicity during chemotherapy. We investigated whether functional changes in granulopoiesis may also contribute to increased myelotoxicity in addition to the known alterations of pharmacokinetic parameters in obesity. Hemopoiesis - as measured by cellularity, frequency of granulocyte-macrophage progenitors (CFU-GM) and total CFU-GM content of the femoral bone marrow - did not differ in obese, insulin resistant Zucker rats compared with Wistar rats. Nevertheless increased sensitivity of their CFU-GM progenitor cells to cytotoxic drugs was found by culturing them in vitro in the presence of carboplatin, doxorubicin and 5 fluorouracil. All drugs were more toxic on CFU-GM progenitor cells of insulin resistant Zucker rats than on CFU-GM cells of the control strain. This might be based on metabolic disorders, at least in part, because we could demonstrate a similar increase in toxicity of the studied anticancer drugs to the CFU-GM progenitors originated from the non-obese but insulin resistant Goto-Kakizaki rats in the same dose ranges. After in vivo administration of rosiglitazone, an insulin sensitizer, the anticancer drug sensitivity of CFU-GM progenitors of Goto Kakizaki rats was decreased concurrently with improvement of insulin resistance. Although the increased treatment-related myelotoxicity and mortality are well known among obese patients with malignant diseases, only the altered half lives, volumes of distribution and clearances of cytotoxic drugs are thought to be the underlying reasons. According to our knowledge the results presented here, are the first observations about an impaired granulopoiesis in obese animals. PMID- 23022329 TI - Selective loss of basal but not receptor-stimulated relaxation by endothelial nitric oxide synthase after isolation of the mouse aorta. AB - Bioavailability of nitric oxide (NO) is mostly studied in isolated blood vessels. We investigated changes in basal and receptor-stimulated endothelial NO synthase (eNOS) activity after isolation of wild-type and Marfan mouse aorta. Starting 1h after dissection, basal NO release was assessed at hourly intervals by its ability to suppress isometric contractions in aortic segments. Relaxation induced by acetylcholine or alpha(2)-adrenoceptor agonist 5-bromo-N-(4,5-dihydro-1H imidazol-2-yl)-6-quinoxalinamine (UK14304) was used to study stimulated NOS activity. One hour after dissection, phenylephrine- or prostaglandin F(2alpha) induced force attained only 17 +/- 4% or 31 +/- 7% of maximum tension in the presence of N(Omega)-nitro-l-arginine-methylesther (l-NAME), and contractions increased to 63 +/- 6% and 82 +/- 11%, respectively at 5h. In contrast, acetylcholine or UK14304 relaxation curves changed minimally. l-NAME and eNOS deficiency abolished basal NO production, unlike inhibitors of neuronal (N(Omega) propyl-l-arginine) or inducible (1400W) NOS. Acetylcholine-induced relaxation was abolished by l-NAME, strongly suppressed by eNOS-deficiency and attenuated by N(Omega)-propyl-l-arginine. In a bioassay based on diethylamine NONOate concentration-response curves the suppression of contractile forces was interpolated into NO equivalents. This showed exponential decay of basal NO, which occurred three times faster in aortas from mice with Marfan syndrome, while acetylcholine-induced relaxation remained unaltered. Immunoblotting showed unchanged eNOS expression, or phosphorylation at Ser1177, Ser617 or Thr495 between 1h and 4h, but Akt phosphorylation declined gradually. The dramatic loss of basal NO release after tissue isolation shows that timing is crucial when studying NO responses. The preservation of receptor-induced relaxation implies differential regulation of basal and stimulated eNOS activity, and phosphoinositide-3-kinase/Akt signalling seems specifically associated with basal eNOS activity. PMID- 23022330 TI - D-serine modulates non-adrenergic non-cholinergic contraction of lower esophageal sphincter in rats. AB - Endogenous D-serine is known to modulate glutamatergic transmission via interaction with the glycine site of N-methyl-D-aspartate (NMDA) receptors. D serine is synthesized by racemization of L-serine using an enzymatic reaction catalyzed by serine racemase. Although much attention has been focused on the role of D-serine within the central nervous system, the physiological role of D serine in enteric nervous system has not been investigated. Lower esophageal sphincter (LES) function is known to be modulated by NMDA-dependent mechanisms. The present study was aimed to study the expression of enzymes involved in D serine metabolism and the function of D-serine in lower esophageal sphincter in rats. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting showed the expression of serine racemase in isolated rat LES. Electrical field stimulation was used to induce non-adrenergic non-cholinergic (NANC) contraction/relaxation of isolated rat LES in an organ bath using an isometric force transducer. The organ bath studies on isolated rat LES showed that incubation with D-serine (100 MUM) is associated with a significant increase in the NANC contraction of isolated LES. This effect of exogenous D-serine was inhibited by NMDA receptor antagonists (MK-801), suggesting that NMDA receptors are involved in the effects of D-serine on NANC contraction of LES. Incubation with D-serine did not show a significant effect on NANC relaxation within our experimental setting. The results of this study suggest that serine racemase is expressed in LES and D-serine modulates contraction of the lower esophageal sphincter in rats. PMID- 23022331 TI - Antinociceptive effect of intrathecal loperamide: role of mu-opioid receptor and calcium channels. AB - Morphine is a gold standard analgesic commonly used to alleviate pain. However, its use is associated with unavoidable side effects including the risk for addiction. Peripherally administered loperamide lacks effect on the central nervous system as it is a substrate for the permeability glycoprotein (P-gp) efflux pump which blocks its entry into brain. However, when administered intrathecally, loperamide has been reported to produce analgesia. The present study investigates the mechanism of the central analgesic effect of loperamide. Adult male Sprague-Dawley rats were subjected to surgery for catheter placement. Following baseline testing, different groups of rats were administered fixed intrathecal doses (1 MUg, 3 MUg, 10 MUg and 30 MUg) of loperamide and morphine. Analgesia was compared employing Hargreaves paw withdrawal apparatus at 15 min, 30 min, 60 min, 90 min and 120 min. Additionally, CTOP, a specific mu-opioid receptor antagonist was co-administered with loperamide to examine the mu-opioid receptor mediated loperamide analgesia. Furthermore, nefiracetam, a calcium channel opener, was co-administered with loperamide or morphine to evaluate the involvement of Ca(2+) channels in Loperamide showed an analgesic effect which was comparable to morphine. However, loperamide produced longer analgesia and the analgesic effect was significantly better at 42 h and 49 h compared to morphine. CTOP completely reversed loperamide analgesia. Though nefiracetam significantly reversed loperamide analgesia, it did not have any effect on morphine induced analgesia. Our findings suggest that loperamide administered intrathecally produces analgesia which is mediated through mu-opioid receptor and subsequent blockade of downstream calcium channels. PMID- 23022332 TI - Interaction of HM30181 with P-glycoprotein at the murine blood-brain barrier assessed with positron emission tomography. AB - HM30181, a potent and selective inhibitor of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp), was shown to enhance oral bioavailability and improve antitumour efficacy of paclitaxel in mouse tumour models. In search for a positron emission tomography (PET) radiotracer to visualise Pgp expression levels at the blood-brain barrier (BBB), we examined the ability of HM30181 to inhibit Pgp at the murine BBB. HM30181 was shown to be approximately equipotent with the reference Pgp inhibitor tariquidar in inhibiting rhodamine 123 efflux from CCRF-CEM T cells (IC(50), tariquidar: 8.2 +/ 2.0 nM, HM30181: 13.1 +/- 2.3 nM). PET scans with the Pgp substrate (R) [(11)C]verapamil in FVB wild-type mice pretreated i.v. with HM30181 (10 or 21 mg/kg) failed to show significant increases in (R)-[(11)C]verapamil brain uptake compared with vehicle treated animals. PET scans with [(11)C]HM30181 showed low and not significantly different brain uptake of [(11)C]HM30181 in wild-type, Mdr1a/b((-/-)) and Bcrp1((-/-)) mice and significantly, i.e. 4.7-fold (P<0.01), higher brain uptake, relative to wild-type animals, in Mdr1a/b((-/-))Bcrp1((-/-)) mice. This was consistent with HM30181 being at microdoses a dual substrate of Pgp and breast cancer resistance protein (Bcrp). In vitro autoradiography on low (EMT6) and high (EMT6Ar1.0) Pgp expressing murine breast tumour sections showed 1.9 times higher binding of [(11)C]HM30181 in EMT6Ar1.0 tumours (P<0.001) which was displaceable with unlabelled tariquidar, elacridar or HM30181 (1 MUM). Our data suggest that HM30181 is not able to inhibit Pgp at the murine BBB at clinically feasible doses and that [(11)C]HM30181 is not suitable as a PET tracer to visualise cerebral Pgp expression levels. PMID- 23022333 TI - L-type Ca(2+) channels, Ca(2+)-induced Ca(2+) release, and BK(Ca) channels in airway stretch-induced contraction. AB - Resistance arteries constrict in response to mechanical stress. This response is myogenic in nature, and reliant on membrane depolarization, activation of L-type Ca(2+) channels, Ca(2+)-induced Ca(2+)-release and large conductance Ca(2+) dependent K(+) channels (BK(Ca)). Airway smooth muscle is also affected by mechanical stress: a deep inspiration produces a bronchodilation in healthy individuals, but bronchoconstriction in moderate to severe asthmatics. In this study, our objective was to investigate the regulation of this airway stretch activated contractile response (R(stretch)), and explore its similarities to the vascular myogenic response. Using a pharmacological approach in intact bovine bronchial segments cannulated horizontally in an organ bath, we showed the ability of carbachol (2-carbamoyloxyethyl-trimethyl-azanium), KCl, neurokinin-A, and U46619 (9,11-dideoxy-9alpha,11alpha-methanoepoxy-prosta-5Z, 13E-dien-1-oic acid) to generate R(stretch) in a concentration-dependent manner. R(stretch) was significantly reduced by nifedipine, ryanodine, and iberiotoxin, suggesting that it possesses characteristics similar to those of the vascular smooth muscle myogenic response, such as a role for membrane depolarization, L-type Ca(2+) channel, ryanodine receptors and BK(Ca) channel activation. This study demonstrates a novel role for the L-type Ca(2+) channel in airway smooth muscle and provides new insights into possible mechanisms regulating the deep inspiration-induced bronchoconstriction seen in asthmatics. PMID- 23022334 TI - Involvement of autophagy in the pharmacological effects of the mTOR inhibitor everolimus in acute kidney injury. AB - Inhibitors of mammalian target of rapamycin (mTOR) have immunosuppressive and anti-cancer effects, but their effects on the progression of kidney disease are not fully understood. Using cells from normal kidney epithelial cell lines, we found that the antiproliferative effects of mTOR inhibitor everolimus accompanied the accumulation of a marker for cellular autophagic activity, the phosphatidylethanolamine-conjugated form of microtubule-associated protein 1 light chain 3 (LC3-II) in cells. We also showed that the primary autophagy factor UNC-51-like kinase 1 was involved in the antiproliferative effects of everolimus. Levels of LC3-II decreased in the kidneys of rats treated with ischemia reperfusion or cisplatin; however, renal LC3-II levels increased after administration of everolimus to rats subjected to ischemia-reperfusion or cisplatin treatment. Simultaneously, increased signals for kidney injury molecule 1 and single-stranded DNA and decreased signals for Ki-67 in the proximal tubules were observed after treatment with everolimus, indicating that everolimus diminished renal function after acute tubular injury. We also found leakage of LC3 protein into rat urine after treatment with everolimus, and urinary LC3 protein was successfully measured between 0.1 and 500ng/mL by using an enzyme linked immunosorbent assay. Urinary LC3 levels were increased after administration of everolimus to rats subjected to ischemia-reperfusion or cisplatin treatment, suggesting that renal LC3-II and urinary LC3 protein are new biomarkers for autophagy in acute kidney injury. Taken together, our results demonstrated that the induction of autophagy by everolimus aggravates tubular dysfunction during recovery from kidney injury. PMID- 23022335 TI - Zinc sulphate attenuates chloride secretion in human colonic mucosae in vitro. AB - Zinc's usefulness in the treatment of diarrhoea is well established as an addition to oral rehydration. Mechanisms of action of zinc have been explored in intestinal epithelia from rodents and in cell lines. The aim was to examine how zinc alters ion transport and signal transduction in human colon in vitro. Voltage clamped colonic sheets obtained at the time of surgical resection were used to quantify ion transport responses to established secretagogues. Nystatin permeabilisation was used to study basolaterally-sited ion channels. Direct actions of zinc were determined using preparations of colonic crypts isolated from human mucosal sheets. Electrophysiological measurements revealed zinc to be an inhibitor of electrogenic ion transport stimulated by forskolin, PGE(2), histamine and carbachol in isolated human colonic epithelium. Basolateral addition of zinc sulphate had no direct effect on the epithelium. To further outline the mechanism of action, levels of secondary intracellular messengers (3', 5'-cyclic adenosine monophosphate; cAMP) were determined in isolated colonic crypts, and were found to be reduced by zinc sulphate. Finally, indirect evidence from nystatin-permeabilised mucosae further suggested that zinc inhibits basolateral K(+) channels, which are critical for transepithelial Cl(-) secretion linked to water flux. Anti-secretory, and therefore anti-diarrhoeal, actions of exogenous zinc are due, at least in part, to direct basolateral epithelial K(+) channel inhibition. PMID- 23022336 TI - Wy14643 improves vascular function in the aorta of the spontaneously hypertensive rat mainly by activating peroxisome proliferator-activated receptors alpha. AB - Experiments were designed to determine if Wy14643 ([[4-chloro-6-[(2,3 dimethylphenyl)amino]-2-pyrimidinyl]thio]-acetic acid), a preferential agonist at peroxisome proliferator-activated receptors (PPAR) alpha, improves vascular function in hypertension, and if so, the mechanism(s) involved. Isometric tension was measured in isolated thoracic aorta of spontaneously hypertensive rats (SHR). Wy14643-induced relaxations in SHR aortic rings were greater than those induced by fenofibrate or rosiglitazone (PPARalpha or PPARgamma agonists, respectively) and were larger in rings with endothelium than those without. Both MK886 [(1-[(4 chlorophenyl)methyl]-3-1,1-dimethylethyl)thio]-(alpha,alpha-dimethyl-5-1 methylethyl)-1H-indole-2-propanoic acid (PPARalpha antagonist) and GW9662 (2 chloro-5-nitrobenzanilide) (PPARgamma antagonists) inhibited Wy14643-induced relaxations. The inhibitory effect of MK886 was more pronounced in rings with endothelium than those without. In SHR aortic rings with endothelium, L-NAME (N(omega)-nitro-L-arginine methyl ester, nitric oxide synthase inhibitor), ODQ (1H-1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one, soluble guanylyl cyclase inhibitor) and compound C [adenosine monophosphate-activated protein kinase (AMPK) inhibitor] reduced Wy14643-induced relaxations. Western blotting studies indicated that Wy14643 and fenofibrate, but not rosiglitazone, increased the phosphorylation of endothelial nitric oxide synthase and AMPK; these effects were abolished by compound C but not L-NAME. Endothelium-dependent contractions evoked by acetylcholine in quiescent SHR aorta in the presence of L-NAME were reduced by Wy14643 and fenofibrate but not by rosiglitazone. MK886, but not GW9662, prevented this effect. Wy14643 and fenofibrate inhibited acetylcholine-induced prostanoid release to the same extent. These findings suggest that PPARalpha agonists induce nitric oxide-mediated relaxation through activation of AMPK and reduce the release of endothelium-dependent contracting factors. Because also of the ability to activate smooth muscle PPARgamma to induce relaxation, Wy14643 offers additional protection against vascular dysfunction of spontaneous hypertension. PMID- 23022337 TI - A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated to improve glycemic control, in particular postprandial hyperglycemic control, in patients with type 2 diabetes. Teneligliptin is a novel chemotype prolylthiazolidine-based DPP-4 inhibitor. The present study aimed to characterize the pharmacological profiles of teneligliptin in vitro and in vivo. Teneligliptin competitively inhibited human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC(50) values of approximately 1 nmol/l. Oral administration of teneligliptin in Wistar rats resulted in the inhibition of plasma DPP-4 with an ED(50) of 0.41 mg/kg. Plasma DPP-4 inhibition was sustained even at 24h after administration of teneligliptin. An oral carbohydrate-loading test in Zucker fatty rats showed that teneligliptin at >= 0.1mg/kg increased the maximum increase in plasma glucagon like peptide-1 and insulin levels, and reduced glucose excursions. This effect was observed over 12h after a dose of 1mg/kg. An oral fat-loading test in Zucker fatty rats also showed that teneligliptin at 1mg/kg reduced triglyceride and free fatty acid excursions. In Zucker fatty rats, repeated administration of teneligliptin for two weeks reduced glucose excursions in the oral carbohydrate loading test and decreased the plasma levels of triglycerides and free fatty acids under non-fasting conditions. The present studies indicate that teneligliptin is a potent, competitive, and long-lasting DPP-4 inhibitor that improves postprandial hyperglycemia and dyslipidemia by both single and repeated administrations. PMID- 23022338 TI - Third generation anti-citrullinated peptide antibody assay is a sensitive marker in rheumatoid factor negative rheumatoid arthritis. AB - INTRODUCTION: We compared 2 anti-citrullinated protein antibody (ACPA) assays using a routine patient cohort. METHODS: Two-hundred ninety-five sera were collected from patients for whom ACPA was ordered and tested for ACPA by QUANTA Lite(r) CCP 3 (INOVA Diagnostics, Inc., San Diego) and EliA(r) CCP (CCP, Phadia, Germany). Rheumatoid factor (RF) was determined using Quantex RF(II) (Biokit, Spain). RESULTS: Acceptable qualitative (96.6%, kappa=0.93) and quantitative agreements (Spearman rho=0.77; p<0.0001) were observed between the two ACPA assays. Nine samples were CCP3+/CCP2- and one sample was CCP2+/CCP3-. Of the 9 CCP3+/CCP2- patients, 6 (66.7%) had RA, one patient had ankylosing spondylitis, one osteoarthritis and one psoriatic arthritis. The CCP3-/CCP2+ patient had juvenile RA. At the manufacturer's cut-offs, the sensitivities and specificities were 77.3%/98.1% (CCP2), 81.6%/96.8% (CCP3) and 65.2%/89.6% (RF), respectively. At 98.7% specificity level, the sensitivities in the total cohort were 59.6% (CCP2) and 69.5% (CCP3) while the sensitivities in the RF-negative group were 49.0% (CCP2) and 57.1% (CCP3). In the RF-negative group, sensitivities for patients with a disease duration of <= 5years were 38.7% (CCP2) and 51.6% (CCP3). CONCLUSION: Discrimination between RA and non-RA patients was better using CCP3, most pronounced in RF-negative RA. PMID- 23022339 TI - Biochemical and molecular characterization of GALT gene from Indian galactosemia patients: identification of 10 novel mutations and their structural and functional implications. AB - Classical Galactosemia is an autosomal recessive disorder of galactose metabolism caused by severe reduction or absence of the galactose-1-phosphate uridyl transferase (GALT) enzyme. Till date, no reports are available on clinical and molecular spectrum of galactosemia from Indian population. The characterization of underlying GALT gene lesions was performed in 55 unrelated galactosemia patients. The GALT mutational spectrum comprised 16 distinct mutations including 10 previously unreported mutations. N314D was the most common mutation with a frequency of 40% followed by Q188R at 2.7%. The novel GALT gene mutations included 6 missense mutations viz. Y89H, Q103R, P166A, S181F, K285R, R333L; one nonsense mutation, S307X and 3 silent mutations--Q103Q, K210K and H319H. The functional significance of the novel GALT missense mutations was investigated using SNPs&GO and SIFT tools. Further, modeling studies using 3D models of mutant and wild type GALT proteins revealed mutations to exert their effects at the molecular level by altering H-bonds, salt bridges, secondary structure or surface features. The study highlighted the heterogeneity of classical galactosemia in the Indian population and also emphasizes the importance of GALT gene analysis in diagnosis of galactosemia. It also revealed that the Indian GALT mutational profile differs significantly from other populations studied. PMID- 23022340 TI - Influence of DNA-repair gene variants on the micronucleus frequency in thyroid cancer patients. AB - The role of different DNA-repair genes (OGG1, XRCC1, XRCC2 and XRCC3) on both the spontaneous and the induced frequency of micronuclei (MN) has been studied in the lymphocytes of a group of 114 patients with differentiated thyroid cancer (DTC). Induction of MN was achieved by treatment of the lymphocytes with 0.5Gy of gamma radiation. The selected genes are involved in base-excision repair (BER) (OGG1, Ser326Cys; XRCC1, Arg280His and Arg399Gln), and in homologous recombination repair (HRR) (XRCC2, Arg188His and XRCC3, IVS5-14G). Genotyping was carried out by use of the iPLEX (Sequenom) technique. Results indicate that only the OGG1 Ser326Cys polymorphism was able to modulate the MN frequency. This effect was only observed in the spontaneous MN frequency (P=0.016), but not in the MN frequency induced after irradiation. In addition, a strong correlation was observed between spontaneous and induced MN frequency, which would suggest an underlying genetic background. PMID- 23022341 TI - [Grade III lipemia retinalis in a 14-year-old girl]. AB - A case of grade III lipemia retinalis is reported in a 14-year-old girl presenting to the emergency department with fatigue and somnolence. Diabetic ketoacidosis diagnostic of type 1 diabetes mellitus and severe hypertriglyceridemia (23,508 mg/dL) were found on routine blood tests. The patient was admitted to the hospital, kept NPO, and intravenous insulin was started. Her symptoms rapidly improved as did the lipid panel and fundus exam. Cases of lipemia retinalis described in the literature typically occur at a blood triglyceride level above 2,000-2,500 mg/dL. A high level of chylomicrons is responsible for the milky appearance of the serum and retinal vessels. Once the blood triglyceride level decreases significantly, the fundus appearance usually returns to normal. PMID- 23022342 TI - [Retinal detachment in preeclampsia: a series of three cases]. AB - Three Afro-Caribbean women presented with a decreased visual acuity associated with preeclampsia during the third trimester of pregnancy. Fundus examination exhibited a serous retinal detachment (SRD). Postpartum fluorescein and indocyanine green angiography indicated subretinal leakage induced by choroidal ischemia. The three patients had an improvement of their visual acuity to 20/20 within 2 to 3 months of the onset of symptoms. Fundus exam and fluorescein angiography showed no further abnormality. SRD in preeclampsia may have an impressive acute presentation but seems to resolve favorably spontaneously without intervention, upon delivery. Nevertheless, SRD must be considered to be a sign of imminent worsening of preeclampsia. PMID- 23022343 TI - [Simplified anesthesia protocol for cataract surgery under topical anesthesia: one year retrospective study]. AB - INTRODUCTION: The reduced supply of anesthesiologists in the hospital setting calls for a reconsideration of anesthesia management for ophthalmology patients. Therefore, a simplified management protocol has been designed through close collaboration between the involved specialists for cataract surgery under topical anesthesia (anesthetic eye drops or sub-Tenon's injection). MATERIALS AND METHODS: At the conclusion of the visit confirming the need for surgery, the surgeon completes a questionnaire designed to elicit a history of the presence of diabetes mellitus (type I or II), prior organ transplantation, chronic renal insufficiency requiring dialysis, communication difficulties, psychiatric disorders, allergy and/or a complex cataract. If one of the items is positive, the patient is scheduled for a preoperative anesthesia consult. If all the items are negative, this anesthesia evaluation is waived. The surgeon explains the fasting requirement and how to take the patient's usual medications on the morning of surgery. The patient continues his/her medications. No lab tests or chest X-ray are performed. If necessary, the surgeon prescribes preoperative antibiotic prophylaxis and any other preparation. During the surgery, the patient receives IV fluids and is monitored via EKG, non-invasive blood pressure and pulse oxymetry by a certified nurse anesthetist. The anesthesiologist on duty (one per every four rooms) is immediately available for the slightest problem. The surgeon signs the postoperative anesthesia note and discharge order. RESULTS: This procedure was assessed by one surgeon over a one year period, including 145 patients (60% of the patients recruited for this surgery), primarily outpatient (77%) under topical anesthesia (Oxybuprocaine((r))+Visthesia((r)), Zeiss) or under sub-Tenon's injection (Xylocaine((r))). No major complications were observed. Seven cases of arterial hypertension, treated with calcium channel blockers (nicardipine), and three episodes of brief anxiety were observed. CONCLUSION: This simplified anesthesia protocol appears to be safe and effective but requires more demanding involvement of the surgeon, whose scope of competence and responsibility must naturally increase. This is the only way by which cataract surgery can remain competitive. PMID- 23022344 TI - Effects of xenon and isoflurane on apoptosis and inflammation in a porcine myocardial infarction model. AB - Volatile anaesthetics can reduce the infarction size in myocardial tissue when administered before and during experimentally induced ischaemia. The aim of this study was to investigate whether xenon is beneficial compared to isoflurane in limiting myocardial tissue apoptosis and inflammation induced by experimental ischaemia-reperfusion injury in a porcine right ventricular infarction model. Twenty-one animals used for this study randomly received isoflurane, xenon or thiopental, (n=6-8 per group). Myocardial infarction was induced for 90min, followed by reperfusion for 120min. Tissues from the left and right ventricles were removed from the sites of infarction, reperfusion and remote areas, and processed for immunohistochemistry. Apoptosis (caspase-3 staining) and neutrophilic infiltration (naphthol AS-D chloroacetate-specific esterase) were assessed and evaluated. Statistical analysis was performed using an ANOVA of repeated measures. Density of apoptotic cells were higher in tissues from animals that were anesthetized with xenon. This effect was significant in comparison to isoflurane (p=0.0177). Neutrophilic infiltration was significantly higher in the right compared to the left ventricle (p<0.001), whereas no significant differences in the number of granulocytes based on the anaesthetic regime or the different tissue areas were found. We conclude that xenon, in the early phase of ischaemia and reperfusion, induces a significant increase in apoptosis compared to isoflurane. Therefore, clinical use of this anaesthetic in cardiocompromised patients should be taken with care until more long-term studies have been carried out. The increased neutrophilic infiltration in the right vs. the left ventricle indicates the right ventricle being more susceptible to ischaemia-reperfusion injury. PMID- 23022345 TI - Promoting engraftment of transplanted neural stem cells/progenitors using biofunctionalised electrospun scaffolds. AB - With the brain's limited capacity for repair, new and innovative approaches are required to promote regeneration. While neural transplantation for a number of neural disease/injuries have been demonstrated, major limitations in the field include poor cell survival and integration. This, in part, is due to the non conducive environment of the adult brain, failing to provide adequate chemical and physical support for new neurons. Here we examine the capacity of fibrous poly epsilon-caprolactone (PCL) scaffolds, biofunctionalised with immobilised glial cell-derived neurotrophic factor (GDNF), to influence primary cortical neural stem cells/progenitors in vitro and enhance integration of these cells following transplantation into the brain parenchyma. Immobilisation of GDNF was confirmed prior to in vitro culturing and at 28 days after implantation into the brain, demonstrating long-term delivery of the protein. In vitro, we demonstrate that PCL with immobilised GDNF (iGDNF) significantly enhances cell viability and neural stem cell/progenitor proliferation compared to conventional 2-dimensional cultureware. Upon implantation, PCL scaffolds including iGDNF enhanced the survival, proliferation, migration, and neurite growth of transplanted cortical cells, whilst suppressing inflammatory reactive astroglia. PMID- 23022346 TI - Electrospun hydroxyapatite-containing chitosan nanofibers crosslinked with genipin for bone tissue engineering. AB - Reconstruction of large bone defects remains problematic in orthopedic and craniofacial clinical practice. Autografts are limited in supply and are associated with donor site morbidity while other materials show poor integration with the host's own bone. This lack of integration is often due to the absence of periosteum, the outer layer of bone that contains osteoprogenitor cells and is critical for the growth and remodeling of bone tissue. In this study we developed a one-step platform to electrospin nanofibrous scaffolds from chitosan, which also contain hydroxyapatite nanoparticles and are crosslinked with genipin. We hypothesized that the resulting composite scaffolds represent a microenvironment that emulates the physical, mineralized structure and mechanical properties of non-weight bearing bone extracellular matrix while promoting osteoblast differentiation and maturation similar to the periosteum. The ultrastructure and physicochemical properties of the scaffolds were studied using scanning electron microscopy and spectroscopic techniques. The average fiber diameters of the electrospun scaffolds were 227 +/- 154 nm as spun, and increased to 335 +/- 119 nm after crosslinking with genipin. Analysis by X-ray diffraction, Fourier transformed infrared spectroscopy and energy dispersive spectroscopy confirmed the presence of characteristic features of hydroxyapatite in the composite chitosan fibers. The Young's modulus of the composite fibrous scaffolds was 142 +/- 13 MPa, which is similar to that of the natural periosteum. Both pure chitosan scaffolds and composite hydroxyapatite-containing chitosan scaffolds supported adhesion, proliferation and osteogenic differentiation of mouse 7F2 osteoblast-like cells. Expression and enzymatic activity of alkaline phosphatase, an early osteogenic marker, were higher in cells cultured on the composite scaffolds as compared to pure chitosan scaffolds, reaching a significant, 2.4 fold, difference by day 14 (p < 0.05). Similarly, cells cultured on hydroxyapatite-containing scaffolds had the highest rate of osteonectin mRNA expression over 2 weeks, indicating enhanced osteoinductivity of the composite scaffolds. Our results suggest that crosslinking electrospun hydroxyapatite containing chitosan with genipin yields bio-composite scaffolds, which combine non-weight-bearing bone mechanical properties with a periosteum-like environment. Such scaffolds will facilitate the proliferation, differentiation and maturation of osteoblast-like cells. We propose that these scaffolds might be useful for the repair and regeneration of maxillofacial defects and injuries. PMID- 23022347 TI - The survival motor neuron protein forms soluble glycine zipper oligomers. AB - The survival motor neuron (SMN) protein forms the oligomeric core of a multiprotein complex that functions in spliceosomal snRNP biogenesis. Loss of function mutations in the SMN gene cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Nearly half of the known SMA patient missense mutations map to the SMN YG-box, a highly conserved oligomerization domain of unknown structure that contains a (YxxG)3 motif. Here, we report that the SMN YG box forms helical oligomers similar to the glycine zippers found in transmembrane channel proteins. A network of tyrosine-glycine packing between helices drives formation of soluble YG-box oligomers, providing a structural basis for understanding SMN oligomerization and for relating defects in oligomerization to the mutations found in SMA patients. These results have important implications for advancing our understanding of SMN function and glycine zipper-mediated helix helix interactions. PMID- 23022348 TI - Structure of the essential MTERF4:NSUN4 protein complex reveals how an MTERF protein collaborates to facilitate rRNA modification. AB - MTERF4 is the first MTERF family member shown to bind RNA and plays an essential role as a regulator of ribosomal biogenesis in mammalian mitochondria. It forms a complex with the rRNA methyltransferase NSUN4 and recruits it to the large ribosomal subunit. In this article, we characterize the interaction between both proteins, demonstrate that MTERF4 strongly stimulates the specificity of NSUN4 during in vitro methylation experiments, and present the 2.0 A resolution crystal structure of the MTERF4:NSUN4 protein complex, lacking 48 residues of the MTERF4 C-terminal acidic tail, bound to S-adenosyl-L-methionine, thus revealing the nature of the interaction between both proteins and the structural conservation of the most divergent of the human MTERF family members. Moreover, the structure suggests a model for RNA binding by the MTERF4:NSUN4 complex, providing insight into the mechanism by which an MTERF family member facilitates rRNA methylation. PMID- 23022349 TI - Movies of ice-embedded particles enhance resolution in electron cryo-microscopy. AB - Low-dose images obtained by electron cryo-microscopy (cryo-EM) are often affected by blurring caused by sample motion during electron beam exposure, degrading signal especially at high resolution. We show here that we can align frames of movies, recorded with a direct electron detector during beam exposure of rotavirus double-layered particles, thereby greatly reducing image blurring caused by beam-induced motion and sample stage instabilities. This procedure increases the efficiency of cryo-EM imaging and enhances the resolution obtained in three-dimensional reconstructions of the particle. Using movies in this way is generally applicable to all cryo-EM samples and should also improve the performance of midrange electron microscopes that may have limited mechanical stability and beam coherence. PMID- 23022350 TI - Visualizing the determinants of viral RNA recognition by innate immune sensor RIG I. AB - Retinoic acid inducible gene-I (RIG-I) is a key intracellular immune receptor for pathogenic RNAs, particularly from RNA viruses. Here, we report the crystal structure of human RIG-I bound to a 5' triphosphorylated RNA hairpin and ADP nucleotide at 2.8 A resolution. The RNA ligand contains all structural features that are essential for optimal recognition by RIG-I, as it mimics the panhandle like signatures within the genome of negative-stranded RNA viruses. RIG-I adopts an intermediate, semiclosed conformation in this product state of ATP hydrolysis. The structure of this complex allows us to visualize the first steps in RIG-I recognition and activation upon viral infection. PMID- 23022351 TI - Targeting the host or the virus: current and novel concepts for antiviral approaches against influenza virus infection. AB - Influenza epidemics and pandemics are constant threats to human health. The application of antiviral drugs provides an immediate and direct control of influenza virus infection. At present, the major strategy for managing patients with influenza is through targeting conserved viral proteins critical for viral replication. Two classes of conventional antiviral drugs, the M2 ion channel blockers and the neuraminidase inhibitors, are frequently used. In recent years, increasing levels of resistance to both drug classes has become a major public health concern, highlighting the urgent need for the development of alternative treatments. Novel classes of antiviral compounds or biomolecules targeting viral replication mechanism are under development, using approaches including high throughput small-molecule screening platforms and structure-based designs. In response to influenza virus infection, host cellular mechanisms are triggered to defend against the invaders. At the same time, viruses as obligate intracellular pathogens have evolved to exploit cellular responses in support of their efficient replication, including antagonizing the host type I interferon response as well as activation of specific cellular pathways at different stages of the replication cycle. Numerous studies have highlighted the possibility of targeting virus-host interactions and host cellular mechanisms to develop new treatment regimens. This review aims to give an overview of current and novel concepts targeting the virus and the host for managing influenza. PMID- 23022352 TI - Influenza virus neuraminidase contributes to the dextran sulfate-dependent suppressive replication of some influenza A virus strains. AB - Dextran sulfate (DS), a negatively charged, sulfated polysaccharide, suppresses the replication of an influenza A virus strain, and this suppression is associated with inhibition of the hemagglutinin (HA)-dependent fusion activity. However, it remains unknown whether the replication of all or just some influenza A virus strains is suppressed by DS, or whether HA is the only target for the replication suppression. In the present study, we found that DS inhibited the replication of some, but not all influenza A virus strains. The suppression in the DS-sensitive strains was dose-dependent and neutralized by diethylaminoethyl dextran (DD), which has a positive charge. The suppression by DS was observed not only at the initial stage of viral infection, which includes viral attachment and entry, but also at the late stage, which includes virus assembly and release from infected cells. Electron microscopy revealed that the DS induced viral aggregation at the cell surface. The neuraminidase (NA) activity of the strains whose viral replication was inhibited at the late stage was also more suppressed by DS than that of the strains whose replication was not inhibited, and this inhibition of NA activity was also neutralized by adding positively charged DD. Furthermore, we found that replacing the NA gene of a strain in which viral replication was inhibited by DS at the late stage with the NA gene from a strain in which viral replication was not inhibited, eliminated the DS-dependent suppression. These results suggest that the influenza virus NA contributes to the DS-suppressible virus release from infected cells at the late stage, and the suppression may involve the inhibition of NA activity by DS's negative charge. PMID- 23022354 TI - Transgenic zebrafish illuminate the dynamics of thyroid morphogenesis and its relationship to cardiovascular development. AB - Among the various organs derived from foregut endoderm, the thyroid gland is unique in that major morphogenic events such as budding from foregut endoderm, descent into subpharyngeal mesenchyme and growth expansion occur in close proximity to cardiovascular tissues. To date, research on thyroid organogenesis was missing one vital tool-a transgenic model that allows to track the dynamic changes in thyroid size, shape and location relative to adjacent cardiovascular tissues in live embryos. In this study, we generated a novel transgenic zebrafish line, tg(tg:mCherry), in which robust and thyroid-specific expression of a membrane version of mCherry enables live imaging of thyroid development in embryos from budding stage throughout formation of functional thyroid follicles. By using various double transgenic models in which EGFP expression additionally labels cardiovascular structures, a high coordination was revealed between thyroid organogenesis and cardiovascular development. Early thyroid development was found to proceed in intimate contact with the distal ventricular myocardium and live imaging confirmed that thyroid budding from the pharyngeal floor is tightly coordinated with the descent of the heart. Four-dimensional imaging of live embryos by selective plane illumination microscopy and 3D-reconstruction of confocal images of stained embryos yielded novel insights into the role of specific pharyngeal vessels, such as the hypobranchial artery (HA), in guiding late thyroid expansion along the pharyngeal midline. An important role of the HA was corroborated by the detailed examination of thyroid development in various zebrafish models showing defective cardiovascular development. In combination, our results from live imaging as well es from 3D-reconstruction of thyroid development in tg(tg:mCherry) embryos provided a first dynamic view of late thyroid organogenesis in zebrafish-a critical resource for the design of future studies addressing the molecular mechanisms of these thyroid-vasculature interactions. PMID- 23022355 TI - Halzoun, an allergic pharyngitis syndrome in Lebanon: the trematode Dicrocoelium dendriticum as an additional cause. AB - Halzoun syndrome typically manifests in the form of an allergic pharyngitis following the consumption of raw or undercooked ovine liver. First described in Lebanon in 1905, it was initially attributed to Fasciola hepatica, while later publications have attributed it to other pathogens. There has been no definitive documentation of the pathogen causing the Lebanese Halzoun syndrome. The aim of our study was to identify the parasite responsible for the pathogenesis of the Lebanese Halzoun syndrome. 32 patients with typical clinical symptoms of Halzoun syndrome were recruited in the emergency room at our hospital from 2005 to 2007. One parasite was isolated from a patient's expectorations, and two others were isolated from pieces of a raw sheep liver retrieved from the patients' dishes. A piece of infected goat liver intended for consumption was also collected from a local butcher. All parasites were examined microscopically for identification. All patients presented with immune allergic-like symptoms of the eyes, ears, nose, or throat. All collected parasites were identified as Dicrocoelium dendriticum. Our study has identified D. dendriticum, rather than Linguatula serrata or F. hepatica, as the prime suspect in the pathogenesis of the Lebanese Halzoun syndrome. PMID- 23022356 TI - Proviral load and the balance of serum cytokines in HTLV-1-asymptomatic infection and in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). AB - This study compared the proviral load and the plasma cytokine profiles (interleukin-IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma) in 87 HTLV-1-infected individuals, including 28 with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), 32 with possible pHAM/TSP and 27 asymptomatic carriers (AC). The control group was composed by 21 HTLV-1-seronegative individuals. Our finding demonstrated that HAM/TSP group presented higher proviral load as compared to all other HTLV-1 groups (p<0.0001). The HAM/TSP group showed higher serum concentration of IL-6 (p=0.0009) as compared to all other groups. Moreover, higher serum concentration of IFN-gamma (p=0.0118) and IL-4 (p=0.0166) were observed in HAM/TSP group as compared to the healthy controls. Additionally, the HAM/TSP group also showed higher serum concentration of TNF-alpha (p=0.0239) and IFN-gamma (p=0.0118) as compared to AC. No differences in the serum concentration of IL-2 and IL-10 were observed among the groups. The analysis of cytokine balance demonstrated that HAM/TSP presented higher pro-inflammatory profile with enhanced IFN-gamma/IL-10 and IFN-gamma/IL-4 ratio as compared to AC and pHAM/TSP. Further analysis pointed out to a positive correlation between the IFN-gamma response and the proviral load in AC. Conversely, a negative association between TNF-alpha and IL-2 with the proviral load was the hallmark of HAM/TSP group. These findings suggested that the proviral load and the pro-inflammatory cytokine profile may be independent events in the peripheral blood of HAM/TSP individuals. The knowledge about the existence of individual virological/immunological behavior upon HTLV-1 infection, may guide to the establishment of more effective therapeutic interventions. PMID- 23022357 TI - Role of serine proteases in inflammation: Bowman-Birk protease inhibitor (BBI) as a potential therapy for autoimmune diseases. AB - Serine proteases, a sub-category of the protease family, participate in various physiologic and pathologic conditions. Serine proteases are involved in different arms of the immune system and play an important role in inflammation. They have been evaluated as therapeutic targets in several inflammatory diseases. The Bowman-Birk protease inhibitor (BBI), a soybean-derived serine protease inhibitor, is resistant to temperature and acidic conditions. These characteristics make it a good candidate for oral administration, with no major side effects. In addition, the therapeutic effect of BBI has been shown in inflammatory diseases and cancer. We have demonstrated the immunoregulatory and anti-inflammatory effects of BBI in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Here we review the role of serine proteases in inflammatory diseases, with emphasis on the potential of BBI as a novel oral therapy for multiple sclerosis. PMID- 23022353 TI - Stable isotope probing in the metagenomics era: a bridge towards improved bioremediation. AB - Microbial biodegradation and biotransformation reactions are essential to most bioremediation processes, yet the specific organisms, genes, and mechanisms involved are often not well understood. Stable isotope probing (SIP) enables researchers to directly link microbial metabolic capability to phylogenetic and metagenomic information within a community context by tracking isotopically labeled substances into phylogenetically and functionally informative biomarkers. SIP is thus applicable as a tool for the identification of active members of the microbial community and associated genes integral to the community functional potential, such as biodegradative processes. The rapid evolution of SIP over the last decade and integration with metagenomics provide researchers with a much deeper insight into potential biodegradative genes, processes, and applications, thereby enabling an improved mechanistic understanding that can facilitate advances in the field of bioremediation. PMID- 23022359 TI - Brassinosteroids tailor stomatal production to different environments. AB - Two recent reports show that brassinosteroids control stomata production by regulating the GSK3-like kinase BIN2-mediated phosphorylation of two different stomatal signalling components resulting in opposite stomatal phenotypes. We discuss how these two mechanisms might differentially control stomatal generation under diverse growth conditions. PMID- 23022360 TI - Serotonin receptors involved in antidepressant effects. AB - The neurotransmitter serotonin (5-hdroxytryptamine; 5-HT) has been implicated in the pathophysiology and treatment of major depression since the serendipitous discovery of antidepressant drugs in the 1950s. However, despite the generalised use of serotonin-enhancing drugs, such as the selective serotonin reuptake inhibitors (SSRIs) and the dual serotonin and norepinephrine reuptake inhibitors (SNRIs), the exact neurobiological mechanisms involved in the therapeutic action of these drugs are poorly understood. Better knowledge of these mechanisms may help to identify new therapeutic targets and to overcome the two main limitations of current treatments: reduced efficacy and slowness of action. Here I review the preclinical and clinical evidence supporting the involvement of different 5-HT receptors in the therapeutic action of antidepressant drugs. Presynaptic 5-HT(1A) and 5-HT(1B) autoreceptors play a major detrimental role in antidepressant treatments, as their activation by the excess of the active (extracellular) 5-HT fraction produced by serotonin transporter (SERT) blockade reduces presynaptic serotonergic function. Conversely, stimulation of postsynaptic 5-HT(1A) receptors in corticolimbic networks appears beneficial for the antidepressant action. The 5 HT(2) receptor family is also involved as 5-HT(2A/2C) receptor blockade improves the antidepressant action of SSRIs, and recent data suggest that 5-HT(2B) receptor activation enhances serotonergic activity. Less is known from the rest of postsynaptic 5-HT receptors. However, 5-HT(3) receptor blockade augments the 5 HT increase evoked by SERT inhibition, and 5-HT(4) receptor activation may have antidepressant effects on its own. Finally, blockade of 5-HT(6) and 5-HT(7) receptors appears also to augment the antidepressant effects of SERT inhibition. PMID- 23022358 TI - Reversion of the ErbB malignant phenotype and the DNA damage response. AB - The ErbB or HER family is a group of membrane bound tyrosine kinase receptors that initiate signal transduction cascades, which are critical to a wide range of biological processes. When over-expressed or mutated, members of this kinase family form homomeric or heteromeric kinase assemblies that are involved in certain human malignancies. Targeted therapy evolved from studies showing that monoclonal antibodies to the ectodomain of ErbB2/neu would reverse the malignant phenotype. Unfortunately, tumors develop resistance to targeted therapies even when coupled with genotoxic insults such as radiation. Radiation treatment predominantly induces double strand DNA breaks, which, if not repaired, are potentially lethal to the cell. Some tumors are resistant to radiation treatment because they effectively repair double strand breaks. We and others have shown that even in the presence of ionizing radiation, active ErbB kinase signaling apparently enhances the repair process, such that transformed cells resist genotoxic signal induced cell death. We review here the current understanding of ErbB signaling and DNA double strand break repair. Some studies have identified a mechanism by which DNA damage is coordinated to assemblies of proteins that associate with SUN domain containing proteins. These assemblies represent a new target for therapy of resistant tumor cells. PMID- 23022361 TI - The effect of the steroid sulfatase inhibitor (p-O-sulfamoyl)-tetradecanoyl tyramine (DU-14) on learning and memory in rats with selective lesion of septal hippocampal cholinergic tract. AB - Dehydroepiandrosterone sulfate (DHEAS), is an excitatory neurosteroid synthesized within the CNS that modulates brain function. Effects associated with augmented DHEAS include learning and memory enhancement. Inhibitors of the steroid sulfatase enzyme increase brain DHEAS levels and can also facilitate learning and memory. This study investigated the effect of steroid sulfatase inhibition on learning and memory in rats with selective cholinergic lesion of the septo hippocampal tract using passive avoidance and delayed matching to position T-maze (DMP) paradigms. The selective cholinergic immunotoxin 192 IgG-saporin (SAP) was infused into the medial septum of animals and then tested using a step-through passive avoidance paradigm or DMP paradigm. Peripheral administration of the steroid sulfatase inhibitor, DU-14, increased step-through latency following footshock in rats with SAP lesion compared to both vehicle treated control and lesioned animals (p<0.05). However, in the DMP task, steroid sulfatase inhibition impaired acquisition in lesioned rats while having no effect on intact animals. These results suggest that steroid sulfatase inhibition facilitates memory associated with contextual fear, but impairs acquisition of spatial memory tasks in rats with selective lesion of the septo-hippocampal tract. PMID- 23022362 TI - Symptomatic meningioma induced by cross-sex hormone treatment in a male-to-female transsexual. AB - Transsexualism is defined as a strong conviction of belonging to the opposite sex in individuals without any physical intersex condition. Cross-sex hormone therapy is an important component of medical treatment of transexuals but it is not exempt from adverse effects. We report a case of a meningioma in a male-to-female transsexual patient treated with estrogens and cyproterone acetate for the past 4 years. He claimed recently severe headache and visual impairment. Blood tests showed normal results. A contrast-enhanced magnetic resonance imaging (MRI) scan revealed a mass in the tuberculum sellae consistent with a meningioma. Treatment was discontinued and tumor resection was performed. Histologic diagnosis confirmed strongly progesterone receptor-positive and estrogen negative meningioma. After surgery, the patient rejected the possibility of continuing with the treatment of estrogens and cyproterone, and so triptorelin (GnRH agonist) was initiated. At 1-year follow-up the patient's symptoms had ameliorated and a MRI scan revealed no recurrence of the tumor. This is the third case reported in the literature of a meningioma after treatment with estrogens and cyproterone acetate. We consider extremely important a long-term follow-up observation of male-to-female transsexual undergoing cross-sex hormone therapy in order to detect as soon as possible the adverse effects that can be derived from this therapy. PMID- 23022363 TI - Acute severe hyponatremia induced by aceclofen in a male patient with central diabetes insipidus. PMID- 23022364 TI - Intestinal microsporidiosis in India: a two year study. AB - Intestinal parasitic pathogens in HIV/AIDS patients include Cryptosporidium sp, Cystoisospora sp, microsporidia and less commonly other parasites. The two most common microsporidia causing intestinal infection are Enterocytozoon bieneusi and Encephalitozoon intestinalis. Most of the Indian studies for intestinal parasitic infections in HIV/AIDS patients have not included microsporidia, due to difficult staining and identification of the parasite. The aim of the present study was to find the prevalence of intestinal microsporidiosis and their species identification along with correlation of CD4 count with parasite positivity and diarrhoea in HIV positive individuals. Stool samples of 363 individuals including 125 HIV seropositive patients with diarrhoea, 158 HIV seropositive patients without diarrhoea, 55 HIV seronegative patients with diarrhoea and 25 healthy controls were obtained from various out-patient departments and in-patients admitted to a tertiary care hospital from August 2008 to October 2009. The stool samples were subjected to examination by wet mount, modified acid fast stain for coccidian parasites and multiplex nested PCR for microsporidia. The overall prevalence of all intestinal parasites among HIV patients in our study was 26.5%. The prevalence of intestinal parasitic pathogens in HIV positive patients with diarrhoea was 43.2%. Microsporidia were the most common parasites detected (14%) in all patients, while in HIV infected patients 15.9% patients had microsporidia infection. The most common species causing intestinal microsporidiosis in our study was E. intestinalis (10.5%). In HIV seropositive individuals with diarrhoea, E. intestinalis was 20.8% and E. bieneusi 8.0% while in HIV seropositive individuals without diarrhoea, E. intestinalis was 3.8% and E. bieneusi 1.9%. E. intestinalis was present in 10.9% of HIV negative individuals with diarrhoea in whom E. bieneusi was not found. There was a significant association between CD4 count <=200/MUl and intestinal parasite positivity. Thus, it can be concluded that intestinal microsporidiosis is under reported but an important disease in India. The predominant species in our study is E. intestinalis , in contrast to other parts of the world where E. bieneusi is more common. PMID- 23022365 TI - Patterns of FOS protein induction in singing female starlings. AB - Females of many songbird species produce song, but information about the neural correlates of singing behavior is limited in this sex. Although well studied in males, activity in premotor song control regions and social behavior regions has not been examined in females during song production. Here, we examined the immediate early gene protein product FOS in both song control and social behavior brain regions after female starlings defending nest boxes responded to an unfamiliar female in a naturalistic setting. We found that females that sang in response to the intruder had much higher numbers of fos-immunoreactive neurons (fos-ir) in the vocal control regions HVC, the robust nucleus of the arcopallium (RA), and the dorsomedial part of the nucleus intercollicularis (DM of the ICo). In HVC, fos-ir correlated positively with song length. In RA, DM and Area X, fos ir correlated positively with number of songs produced. In social behavior regions, singers showed higher fos-ir in the nucleus taeniae of the amygdala, the dorsal part of the bed nucleus of the stria terminalis, and the ventromedial hypothalamus than non-singers. Overall, patterns of fos-ir in song control regions in females were similar to those reported for males, but differences in fos-ir were identified in social behavior regions. These differences may reflect a distinct role for brain regions involved in social behavior in female song, or they may reflect differences in the social function of female and male song. PMID- 23022366 TI - Factors affecting variation in the reproductive investment of female treefrogs, Hyla intermedia. AB - In anurans, fecundity (clutch size) is the most important determinant of female reproductive success. We investigated three possible causes responsible for fecundity variation in female Italian treefrogs, Hyla intermedia, during four breeding seasons: (i) variation in morphological (body size and condition) and life-history (age) traits; (ii) variation in the tradeoff between the number and the size of eggs; (iii) seasonal effects and within-season differences in the timing of deposition. At the population level, we found no evidence for a tradeoff between the number and the size of eggs, because they both correlated positively with females' body size. Conversely, neither age nor post-spawning body condition showed any effect on female reproductive investment. Independent of body size, we found no evidence for variation in reproductive effort among different breeding seasons, but strong evidence for a decrease of clutch size and an increase of egg size with the advancing of a breeding season. To test for the functional significance of the observed temporal variation in allocation strategy, we carried out a rearing experiment in semi-natural conditions on a random sample of ten clutches. The experiment showed a negative effect of clutch size and a positive effect of egg size on both tadpole growth and developmental rates, suggesting that reproductive investment, although constrained by body size, can be adjusted by females to the time of deposition to increase the chances of offspring survival. PMID- 23022367 TI - Which medical devices and/or local drug should be curatively used, as of 2012, for PU patients? How can granulation and epidermidalization be promoted? Developing French guidelines for clinical practice. AB - INTRODUCTION: Management of a patient with pressure ulcer sore(s) must associate local and general treatment. OBJECTIVES: To determine which medical devices other than supports and which treatments may be used for pressure sore healing (granulation tissue and epithelization/epidermidalization) as of 2012. METHODS: Systematic review of the literature querying the databases: PASCAL Biomed, PubMed, and Cochrane library from 2000 through 2010. RESULTS: Data in the literature on granulation tissue and epithelisation/epidermidalization in pressure sore healing are poor. The level of evidence regarding the relative effectiveness of one modern dressing compared to another has remained low. However, the study data on the interest of hydrocolloid dressing compared with impregnated gases are more significant. DISCUSSION: Studies with heterogeneous results and populations have shown low power. Meta-analyses are difficult due to the wide range of therapeutic aims. Further clinical studies with adequate methodology are needed prior to elaboration of more specific recommendations. CONCLUSION: The use of hydrocolloid dressing may be recommended to improve granulation tissue development and epithelization/epidermidalization in pressure sore (Level B). PMID- 23022368 TI - Which medical device and/or which local treatment for prevention in patients with risk factors for pressure sores in 2012? Developing French guidelines for clinical practice. AB - INTRODUCTION: Implementation of a prevention strategy after the identification of risk factors is essential at the entrance in a care unit or in a medical-social unit. OBJECTIVES: Determine which medical devices and which treatments may be used in order to prevent pressure sore in 2012. METHOD: Systematic review of the literature using databases: Pascal, Biomed, PubMed, and Cochrane library between 2000 and 2010. RESULTS: Nursing care including use of soft product, non irritating for the cleaning, hydration of the skin with emollients, protection of fragile skin in case of incontinence by applying a skin protector and application of dressings in front of bony prominences to reduce shear forces, remain valid (level C). DISCUSSION: Nursing cares and use of dressing in patients with high risks of pressure sores are the responsibility of the nurses. The engagement of health care teams involves screening of risk factors and the knowledge of treatments and local devices. CONCLUSION: Local preventive treatment in a patient with risk factors of pressure sore is of great interest at entrance in a care unit or in a medical-social unit. PMID- 23022369 TI - Alveolocapillary model system to study alveolar re-epithelialization. AB - In the present study an in vitro bilayer model system of the pulmonary alveolocapillary barrier was established to investigate the role of the microvascular endothelium on re-epithelialization. The model system, confluent monolayer cultures on opposing sides of a porous membrane, consisted of a human microvascular endothelial cell line (HPMEC-ST1.6R) and an alveolar type II like cell line (A549), stably expressing EGFP and mCherry, respectively. These fluorescent proteins allowed the real time assessment of the integrity of the monolayers and the automated analysis of the wound healing process after a scratch injury. The HPMECs significantly attenuated the speed of re epithelialization, which was associated with the proximity to the A549 layer. Examination of cross-sectional transmission electron micrographs of the model system revealed protrusions through the membrane pores and close contact between the A549 cells and the HPMECs. Immunohistochemical analysis showed that these close contacts consisted of heterocellular gap-, tight- and adherens-junctions. Additional analysis, using a fluorescent probe to assess gap-junctional communication, revealed that the HPMECs and A549 cells were able to exchange the fluorophore, which could be abrogated by disrupting the gap junctions using connexin mimetic peptides. These data suggest that the pulmonary microvascular endothelium may impact the re-epithelialization process. PMID- 23022370 TI - Results from the second Scottish national prevalence survey: the changing epidemiology of healthcare-associated infection in Scotland. AB - BACKGROUND: Healthcare-associated infections (HAIs) are a recognized public health problem worldwide. Point prevalence surveys (PPSs) can be used to measure the burden of all HAI types. AIM: To measure the prevalence of HAI and determine any changes in the epidemiology of HAI since the first Scottish national PPS. METHODS: A national rolling PPS in National Health Service (NHS) acute, NHS non acute, NHS paediatric and independent hospitals was carried out during September and October 2011 using the European Centre for Disease Prevention and Control protocol designed for the European PPS. The prevalence of HAI and distribution of HAI types were measured and the results compared with the first Scottish national HAI point prevalence survey of 2005/2006. RESULTS: The prevalence of HAI was 4.9%, 2.5%, 6.1% and 1.2% in acute, non-acute, paediatric and independent hospitals respectively. The prevalence of HAI was significantly higher in acute hospitals compared with non-acute hospitals. There were no significant differences between the prevalence in the other hospital types. The prevalence of HAI in acute and non-acute hospitals was lower than the first survey by approximately one-third. The proportion of HAIs that were urinary tract infection, surgical site infection and bloodstream infection was higher and the proportion that were gastrointestinal including Clostridium difficile infection was lower in acute hospitals compared with the previous survey. CONCLUSIONS: The epidemiology of HAI has changed in Scotland since the first national survey in 2005/2006, thus infection prevention and control measures require to be refocused in this regard. The lower prevalence and changing epidemiology of HAI in acute and non-acute care suggest that there may be a temporal relationship with the implementation of the national programme of targeted HAI interventions in the intervening period. PMID- 23022371 TI - Epidemiology and molecular investigation of hepatitis C infection following holiday haemodialysis. AB - BACKGROUND: Hepatitis C virus infection (HCV) is not infrequent among haemodialysis patients. Most published reports suggest that patient-to-patient spread, either directly or indirectly, is the most common mode of transmission in renal units. AIM: To investigate the source of an outbreak, and the route of transmission, of acute HCV infection in two Scottish patients occurring within eight weeks of receiving haemodialysis in the same unit while on holiday in Majorca. METHODS: This was an international epidemiological and molecular investigation of HCV infection among a cohort of haemodialysis patients from nine countries. FINDINGS: No further HCV-positive infections were observed among residents and holidaymakers receiving haemodialysis at the unit in Majorca. Molecular investigations confirmed that a Spanish healthcare worker (HCW) was the source of infection for the two Scottish patients. The investigators were unable to determine the route of transmission. CONCLUSIONS: This outbreak is the first reported case of HCW-to-patient transmission of HCV in a renal unit, and the third reported case of transmission involving a HCW who had not performed invasive procedures. The issue of whether renal units are an exceptional case with regards to the risk of transmission associated with non-invasive procedures should be considered, in conjunction with the need to improve surveillance of blood-borne virus transmissions in renal units in the UK and abroad. PMID- 23022372 TI - Microbial monitoring of the hospital environment: why and how? AB - BACKGROUND: The purpose of microbial monitoring of the inanimate environment surrounding a patient can be two-fold; to monitor hygiene standards and also to examine for the presence of specific nosocomial pathogens which may be the source of an outbreak. While both purposes involve routine culture of microorganisms, the methods used for each can differ in order to provide optimal results. The main difference between both purposes is the need for enumeration, site specificity for an aerobic colony count (ACC) for hygiene assessments, and the need to simply detect the presence or absence of multi-resistant nosocomial pathogens for infection control surveillance. AIM: To access current methods used in research studies and during outbreak investigations to detect nosocomial pathogens in the inanimate environment in the clinical setting. METHODS: A Pubmed search of published literature was performed. FINDINGS: Microbial monitoring of the environment can involve the use of swabs, sponges, contact plates and dip slides coupled with a variety of enrichment broths and selective media. The use of molecular methods such as polymerase chain reaction (PCR) can potentially provide a faster turnaround time, resulting in the quicker implementation of infection prevention and control cleaning and disinfection regimens. However, the optimal methods for performing a microbial hygiene evaluation or detecting specific bacterial pathogens are not generally agreed. CONCLUSION: There is a need for agreed standards on the optimal methods, frequency of environmental sampling and acceptable levels of surface contamination within the healthcare system. PMID- 23022373 TI - Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden. AB - BACKGROUND: Currently not much is known regarding the environmental factors involved in primary biliary cirrhosis (PBC). It is even more unclear which factors may determine the subgroup (i.e., AMA status) of patients with PBC. We thus tested AMA+and AMA- PBC patients' sera for antibodies (Abs) against multiple infectious agents. METHODS: Sera from 69 patients with PBC (49 AMA+and 20 AMA-) and 100 matched controls were screened for IgG-Abs against Toxoplasma gondii, Helicobacter pylori, Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B, and hepatitis C utilizing the BioPlex 2200 and ELISA kits (Bio-Rad Laboratories, USA). RESULTS: The prevalence of four anti-infectious agents Abs was significantly elevated among PBC patients when compared with controls, namely anti-T. gondii (ATxA; 71% vs. 40%, p<0.0001), EBV early antigen (EA; 44% vs. 12%, p<0.0001), H. pylori (54% vs. 31%, p<0.01), and CMV (90% vs. 75%, p<0.05) Abs, respectively. The co-occurrence of these four anti-infectious agents Abs was highly common in PBC, whereas this infection burden was rare in healthy subjects (20% vs. 3% respectively, p<0.0001). Furthermore, specific infections interactions possibly increasing PBC risk were noted as well. Seropositivity of ATxA was inversely associated with cirrhosis among PBC patients (p<0.05). Finally, no differences were observed between AMA- sera and their AMA+counterparts with regard to seroprevalence of any of the investigated infectious agents. CONCLUSIONS: We note the association of ATxA and PBC, with the possibility of a milder disease manifestation. We also suggest that multiple exposures to infectious agents may contribute to PBC risk. PMID- 23022374 TI - Two fragrance chemicals may act as toxicants via TRPA1 stimulation rather than via direct mitochondrial action. PMID- 23022375 TI - Relationship between FOXP3 positive populations and cytokine production in systemic lupus erythematosus. AB - In this work we studied CD4+FOXP3+ populations in systemic lupus erythematosus (SLE) and the relationship with Th cytokine production. We found an increment in CD25-FOXP3+ population in SLE associated with CD4+ downregulation and disease progression. CD25low cells were also upregulated and showed increased percentages of FOXP3+ and CD127-/low cells, supporting the activated status of SLE lymphocytes. Despite the normal levels of CD25highFOXP3+ cells, the negative correlations observed in controls with the frequency of IFNgamma, TNFalpha and IL 10 secreting cells were disrupted in patients, supporting a defective Treg function. Also, CD25high cells showed an altered balance in the production of these cytokines. In addition, CD25highFOXP3+ cells correlated directly with IL 17A and IL-8 but not with TGFbeta in SLE. The increased proportion of IL-17+ cells among the CD25high subset and the positive correlation between IL-17 levels and Treg cells suggest a trans-differentiation of Treg into Th17 cells in SLE. PMID- 23022376 TI - Cytokine profile of conditioned medium from human tumor cell lines after acute and fractionated doses of gamma radiation and its effect on survival of bystander tumor cells. AB - Cytokines are known to play pivotal roles in cancer initiation, progression and pathogenesis. Accumulating evidences suggest differences in basal and stress induced cytokine profiles of cancers with diverse origin. However, a comprehensive investigation characterising the cytokine profile of various tumor types after acute and fractionated doses of gamma-irradiation, and its effect on survival of bystander cells is not well known in literature. In the present study, we have evaluated the cytokine secretion profile of human tumor cell lines (HT1080, U373MG, HT29, A549 and MCF-7) either before (basal) or after acute (2, 6 Gy) and fractionated doses (3*2 Gy) of gamma-irradiation in culture medium obtained from these cells by multiplex bead array/ELISA. Moreover, clonogenic assays were performed to evaluate the effect of conditioned medium (CM) on the survival and growth of respective cells. Based on the screening of 28 analytes, our results showed that the basal profiles of these cell lines varied considerably in terms of the number and magnitude of secreted factors, which was minimum in MCF-7. Interestingly, TNF-alpha, IL-1beta, PDGF-AA, TGF-beta1, fractalkine, IL-8, VEGF and GCSF were found in CM of all the cell lines. However, secretion of certain cytokines was cell line-specific. Moreover, CM caused increase in clonogenic survival of respective tumor cells (in the order HT1080>U373MG>HT29>A549>MCF-7), which was correlated with the levels of IL-1beta, IL-6, IL-8, GMCSF and VEGF in their CM. After irradiation, the levels of most of the cytokines increased markedly in a dose dependent manner. The fold change in cytokine levels was lower in irradiated conditioned medium (ICM) of tumor cells collected after fractionated than respective acute dose, except in MCF-7. Interestingly, amongst these cell lines, the radiation-induced fold increase in cytokine levels was maximum in ICM of A549 cells. Moreover, bystander A549 cells treated with respective ICM showed dose dependent decrease in clonogenic survival. In conclusion, present study revealed the similarities and subtle differences in basal and radiation-induced cytokine profile of different tumor cell lines, and its influence on growth and survival of respective bystander cells. These findings may add a new dimension to our current understanding about role of cytokines in cancer biology. PMID- 23022377 TI - An easy-to-perform photometric assay for methyltransferase activity measurements. AB - Methyltransferases (MTs) catalyze the transfer of a methyl group from S adenosylmethionine (SAM) to a suitable substrate. Such methylations are important modifications in secondary metabolisms, especially on natural products produced by polyketide synthases and nonribosomal peptide synthetases, many of which are of special interest due to their prominent pharmacological activities (e.g., lovastatin, cyclosporin). To gain basic biochemical knowledge on the methylation process, it is of immense relevance to simplify methods concerning experimental problems caused by a large variety in substrates. Here, we present a photometric method to analyze MT activity by measuring SAM consumption in a coupled enzyme assay. PMID- 23022378 TI - Evaluation of protein disulfide conversion in vitro using a continuous flow dialysis system. AB - Recombinant therapeutic proteins are heterogeneous due to chemical and physical modifications. Understanding the impact of these modifications on drug safety and efficacy is critical for optimal process development and for setting reasonable specification limits. In this study, we describe the development of an in vitro continuous flow dialysis system to evaluate potential in vivo behavior of thiol adducted species and incorrectly disulfide bonded species of therapeutic proteins. The system is capable of maintaining the low-level cysteine concentrations found in human blood. Liabilities of cysteamine adducted species, incorrectly disulfide bonded species, and the correctly disulfide bonded form of an Fc-fusion protein were studied using this system. Results showed that 90% of the cysteamine adduct converted into the correctly disulfide bonded form and incorrectly disulfide bonded species in approximately 4 h under physiological conditions. Approximately 50% of incorrectly disulfide bonded species converted into the correctly bonded form in 2 days. These results provide valuable information on potential in vivo stability of the cysteamine adduct, incorrectly disulfide bonded species, and the correctly bonded form of the Fc-fusion protein. These are important considerations when evaluating the criticality of product quality attributes. PMID- 23022379 TI - Df31 protein and snoRNAs maintain accessible higher-order structures of chromatin. AB - Packaging of DNA into nucleosomes and the formation of higher-order chromatin structures determine DNA accessibility and activity of genome domains. We identified an RNA-dependent mechanism maintaining the open chromatin structure within euchromatic regions in Drosophila cells. The mechanism of reversible chromatin opening, reconstituted in vitro, depends on the Drosophila decondensation factor 31 (Df31) that specifically binds to RNA and localizes to euchromatic regions. Df31 is capable to tether a heterogeneous pool of short, single-stranded RNAs to chromatin. This class of chromatin-associated RNA (caRNA) is stably linked to chromatin and is largely composed of snoRNAs, which are preferentially bound by Df31. We suggest that the Df31-mediated linkage of snoRNAs and chromatin, forms a RNA-chromatin network resulting in the establishment of open chromatin domains. Analysis of caRNAs in human cells also reveals a strong enrichment of snoRNAs, implying a conserved role for these molecules in higher-order structures of chromatin. PMID- 23022380 TI - NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. AB - Activating mutations in NOTCH1, an essential regulator of T cell development, are frequently found in human T cell acute lymphoblastic leukemia (T-ALL). Despite important advances in our understanding of Notch signal transduction, the regulation of Notch functions in the nucleus remains unclear. Using immunoaffinity purification, we identified NOTCH1 nuclear partners in T-ALL cells and showed that, beyond the well-characterized core activation complex (ICN1-CSL MAML1), NOTCH1 assembles a multifunctional complex containing the transcription coactivator AF4p12, the PBAF nucleosome remodeling complex, and the histone demethylases LSD1 and PHF8 acting through their demethylase activity to promote epigenetic modifications at Notch-target genes. Remarkably, LSD1 functions as a corepressor when associated with CSL-repressor complex and as a NOTCH1 coactivator upon Notch activation. Our work provides new insights into the molecular mechanisms that govern Notch transcriptional activity and represents glimpse into NOTCH1 interaction landscape, which will help in deciphering mechanisms of NOTCH1 functions and regulation. PMID- 23022381 TI - The p23 molecular chaperone and GCN5 acetylase jointly modulate protein-DNA dynamics and open chromatin status. AB - Cellular processes function through multistep pathways that are reliant on the controlled association and disassociation of sequential protein complexes. While dynamic action is critical to propagate and terminate work, the mechanisms used to disassemble biological structures are not fully understood. Here we show that the p23 molecular chaperone initiates disassembly of protein-DNA complexes and that the GCN5 acetyltransferase prolongs the dissociated state through lysine acetylation. By modulating the DNA-bound state, we found that the conserved and essential joint activities of p23 and GCN5 impacted transcription factor activation potential and response time to an environmental cue. Notably, p23 and GCN5 were required to maintain open chromatin regions along the genome, indicating that dynamic protein behavior is a critical feature of various DNA associated events. Our data support a model in which p23 and GCN5 regulate diverse multistep pathways by controlling the longevity of protein-DNA complexes. PMID- 23022383 TI - miR-211 is a prosurvival microRNA that regulates chop expression in a PERK dependent manner. AB - MicroRNAs typically function at the level of posttranscriptional gene silencing within the cytoplasm; however, increasing evidence suggests that they may also function in nuclear, Argonaut-containing complexes, to directly repress target gene transcription. We have investigated the role of microRNAs in mediating endoplasmic reticulum (ER) stress responses. ER stress triggers the activation of three signaling molecules: Ire-1alpha/beta, PERK, and ATF6, whose function is to facilitate adaption to the ensuing stress. We demonstrate that PERK induces miR 211, which in turn attenuates stress-dependent expression of the proapoptotic transcription factor chop/gadd153. MiR-211 directly targets the proximal chop/gadd153 promoter, where it increases histone methylation and represses chop expression. Maximal chop accumulation ultimately correlates with miR-211 downregulation. Our data suggest a model in which PERK-dependent miR-211 induction prevents premature chop accumulation and thereby provides a window of opportunity for the cell to re-establish homeostasis prior to apoptotic commitment. PMID- 23022382 TI - LC3C, bound selectively by a noncanonical LIR motif in NDP52, is required for antibacterial autophagy. AB - Autophagy protects cellular homeostasis by capturing cytosolic components and invading pathogens for lysosomal degradation. Autophagy receptors target cargo to autophagy by binding ATG8 on autophagosomal membranes. The expansion of the ATG8 family in higher eukaryotes suggests that specific interactions with autophagy receptors facilitate differential cargo handling. However, selective interactors of ATG8 orthologs are unknown. Here we show that the selectivity of the autophagy receptor NDP52 for LC3C is crucial for innate immunity since cells lacking either protein cannot protect their cytoplasm against Salmonella. LC3C is required for antibacterial autophagy because in its absence the remaining ATG8 orthologs do not support efficient antibacterial autophagy. Structural analysis revealed that the selectivity of NDP52 for LC3C is conferred by a noncanonical LIR, in which lack of an aromatic residue is balanced by LC3C-specific interactions. Our report illustrates that specificity in the interaction between autophagy receptors and autophagy machinery is of functional importance to execute selective autophagy. PMID- 23022387 TI - MyD88-dependent interleukin-10 production from regulatory CD11b+Gr-1(high) cells suppresses development of acute cerulein pancreatitis in mice. AB - We explored the role of the MyD88 signaling pathway. This pathway mediates the recognition of pathogen-associated molecular patterns and damage-associated molecular patterns via Toll-like receptors (TLRs) and/or IL-1/IL-18 via each cytokine receptor in a murine model of acute pancreatitis induced by cerulein administration. Our analysis revealed that: various TLRs and MyD88 molecules were constitutively expressed in the pancreas of cerulein-treated and untreated wild type (WT) mice. MyD88-/- mice administered cerulein developed severe pancreatitis as compared with MyD88+/+ WT mice. The number of IL-10-expressing CD11b+Gr 1(high) cells in cerulein-administered MyD88-/- mice was significantly decreased. This was in accordance with a reciprocal increase in the infiltration of CD4+ T cells as compared with that in control MyD88+/+ mice. WT mice pretreated with antibiotics and administered cerulein developed milder pancreatitis as compared with control cerulein-administered mice without antibiotic treatment. The MyD88 signaling pathway contributes to the induction of regulatory IL-10-producing macrophages/myeloid-derived suppressor cells, possibly in response to non bacterial components in the damaged pancreas. These results provide a new concept for therapeutic strategies against acute pancreatitis. PMID- 23022384 TI - Membrane protein TM segments are retained at the translocon during integration until the nascent chain cues FRET-detected release into bulk lipid. AB - Most membrane proteins are integrated cotranslationally into the ER membrane at the translocon, where nonpolar nascent protein transmembrane segments (TMSs) are widely believed to partition directly into the nonpolar membrane interior. However, a FRET approach that monitors the separation between a fluorescent labeled TMS and fluorescent phospholipids diffusing in the bulk lipid reveals that TMSs do not immediately enter the lipid phase of the membrane. Instead, TMSs are retained at the translocon by protein-protein interactions until their release into bulk lipid is triggered by translation termination or, in some cases, by the arrival of another nascent chain TMS at a translocon. Nascent chain status and structural elements therefore dictate the timing of TMS release into the lipid phase by altering TMS and flanking sequence interactions with translocons, ribosomes, and associated proteins, thereby controlling when successive TMSs assemble in the bilayer and TMS-delineated loops fold. PMID- 23022388 TI - Profile of toll-like receptors on peripheral blood cells in relation to acute graft-versus-host disease after allogeneic stem cell transplantation. AB - Toll-like receptors (TLRs) play a key role in the cross-talk between the innate and adaptive immune systems. Previous studies investigating associations between certain TLRs and acute graft-versus-host disease (aGVHD) have reported contrasting results, and no studies relating aGVHD to the expression and function of all human TLRs together have been published to date. We prospectively evaluated the expression of 9 TLRs on T lymphocytes and monocytes by flow cytometry in relation to aGVHD in 34 patients. Induction of TNF-alpha, IL-4, IFN gamma, and monocyte chemotactic protein 1 on TLR activation was assessed by ELISA on cell supernatants. Nineteen patients developed aGVHD, at a median time of 28 days (range, 20-50 days) after transplantation. A 2-step multivariate analysis was performed using principal component analysis and multifactor analysis of variance. The levels of TLR-5 expression on monocytes and T lymphocytes were positively correlated to aGVHD (P = .01), whereas levels of TLR-1 and -9 were negative predictors (P = .03 and .01, respectively). This profile of TLR-1, -5, and -9 can promote an overall immunostimulatory/proinflammatory response. If our findings are confirmed by further studies, this TLR profile could be a useful biomarker of aGVHD. PMID- 23022389 TI - Pulmonary hypertensive vasculopathy following tandem autologous transplantation in pediatric patients with central nervous system tumors. AB - Tandem cycles of high-dose chemotherapy are an increasingly being used as alternative to radiation treatment in the management of infants and young children with central nervous system (CNS) tumors. Most of these protocols have a carboplatinum and thiotepa backbone. The toxicities of these regimens have been reported extensively; however, pulmonary arterial vasculopathy (PAV) with pulmonary arterial hypertension (PAH) has not been previously documented in patients treated with this approach. PAH is a disorder of the pulmonary vasculature characterized by a progressive increase in pulmonary vascular resistance, leading to right heart failure and potentially death. We evaluated PAH as a complication after high-dose chemotherapy and autologous stem cell transplantation (SCT). We performed a retrospective evaluation of all pediatric patients diagnosed with a CNS tumor between 2001 and 2010 scheduled to receive 3 cycles of high-dose chemotherapy with carboplatinum (17 mg/kd/day for 2 days) and thiotepa (10 mg/kg/day for 2 days), followed by autologous SCT. Our primary objective was to evaluate the incidence of PAV and PAH in this population, as well as patient outcomes after the development of PAH. Our cohort comprised 20 patients with a median age at diagnosis of 28 months (range, 3-131 months). Three patients developed biopsy-confirmed PAV with PAH, the 2 patients who developed PAV with PAH at the end of the third cycle succumbed to PAH. Death due to PAV and PAH was the sole toxic mortality observed during the study period. PAV with PAH is a major and possibly fatal complication after high-dose chemotherapy and sequential autologous SCT using carboplatinum and thiotepa in a tandem fashion. There is an urgent need to evaluate PAH as a potential complication after each cycle of high-dose chemotherapy when using such regimens in pediatric patients with CNS tumors. PMID- 23022390 TI - Huperzia quadrifariata and Huperzia reflexa alkaloids inhibit acetylcholinesterase activity in vivo in mice brain. AB - Huperzine A, a Lycopodium alkaloid produced by Chinese folk herb Huperzia serrata (Lycopodiaceae), has been shown to be a promising agent for the treatment of Alzheimer's disease due to its potent acetylcholinesterase (AChE) activity, as well its efficacy in the treatment of memory of aged patients. Thus, the effects of two Huperzia species of habitats in Brazil (H. quadrifariata and H. reflexa) with described in vitro AChE inhibition activities were studied and their effects on mice brain AChE inhibition were determined after a single intraperitoneal (i.p.) injection. The alkaloid extracts were administered to mice in various doses (10, 1 and 0.5mg/kg) and acetylcholinesterase activity was measured post mortem in two brain areas using the Ellman's colorimetric method. The AChE activity was found to be significantly reduced in both the cortex and hippocampus, although this activity was less potent than that of reference inhibitor huperzine A (0.5mg/kg). Thus, it appears that H. quadrifariata and H. reflexa alkaloid extracts, shown to inhibit acetylcholinesterase in vitro, also have very potent in vivo effects, suggesting that the Huperzia species may still constitute a promising source of compounds with pharmaceutical interest for Alzheimer's disease. PMID- 23022391 TI - Dose-dependent efficacy of the Vitex agnus castus extract Ze 440 in patients suffering from premenstrual syndrome. AB - BACKGROUND: Preparations of Vitex agnus castus L. (VAC) have been shown to be effective to treat irregular menstrual cycles, cyclical mastalgia and symptoms of the premenstrual syndrome (PMS). However, the dose-effect relationship for the treatment of PMS has not yet been established. This study aimed to investigate the clinical effects of three different doses of the VAC extract Ze 440 in comparison to placebo in patients suffering from PMS. METHODS: In a multicenter, double-blind, placebo-controlled, parallel-group study, 162 female patients with PMS (18-45 years) were randomized to either placebo or different doses of Ze 440 (8, 20 and 30 mg) over three menstrual cycles. PMS symptoms' severity was assessed by patients using visual analog scales (VAS) for the symptoms irritability, mood alteration, anger, headache, bloating and breast fullness. RESULTS: Each of the treatments was well tolerated. Improvement in the total symptom score (TSS) in the 20mg group was significantly higher than in the placebo and 8 mg treatment group. The higher dose of 30 mg, on the other hand, did not significantly decrease symptom severity compared to the 20mg treatment, providing a rational for the usage of 20mg. Corresponding results were observed with the single PMS symptom scores. CONCLUSION: This study demonstrated that the VAC extract Ze 440 was effective in relieving symptoms of PMS, when applied in a dose of 20mg. Therefore, for patients suffering from PMS, 20mg Ze 440 should be the preferred daily dose. PMID- 23022392 TI - Physcomitrella patens: a model for tip cell growth and differentiation. AB - The moss Physcomitrella patens has emerged as an excellent model system owing to its amenability to reverse genetics. The moss gametophyte has three filamentous tissues that grow by tip growth: chloronemata, caulonemata, and rhizoids. Because establishment of the moss plant relies on this form of growth, it is particularly suited for dissecting the molecular basis of tip growth. Recent studies demonstrate that a core set of actin cytoskeletal proteins is essential for tip growth. Additional actin cytoskeletal components are required for modulating growth to produce caulonemata and rhizoids. Differentiation into these cell types has previously been linked to auxin, light and nutrients. Recent studies have identified that core auxin signaling components as well as transcription factors that respond to auxin or nutrient levels are required for tip-growing cell differentiation. Future studies may establish a connection between the actin cytoskeleton and auxin or nutrient-induced cell differentiation. PMID- 23022393 TI - Developmental relaxation of transposable element silencing in plants: functional or byproduct? AB - In plants, the developmental relaxation of transposable element silencing (DRTS) occurs at distinct spatial and temporal points in the normal development of a wild-type individual. Several examples of DRTS have now been described, including in maize shoot apical meristems, and in Arabidopsis meiocytes, endosperm and nurse cells of gametophytes. In this opinion article, we review the known DRTS events and speculate on the function, if any, of DRTS in plants. PMID- 23022394 TI - Using placenta to evaluate the polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) exposure of fetus in a region with high prevalence of neural tube defects. AB - Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants suspected to have various toxic effects, including reproductive toxicity. The aim of this study was to determine the concentrations of PCBs and PBDEs in human placentas and to examine the potential association between in utero exposure to these pollutants and the risk of neural tube defects. Subjects were recruited from a birth defects surveillance program in a rural area of Shanxi Province, China, from 2005 to 2007. 80 placental samples from fetuses/neonates with neural tube defects and 50 samples from healthy newborn infants were analyzed for PCBs and PBDEs using electron-capture negative ionization gas chromatographic mass spectrometry. The median concentrations were 0.89 and 0.54ng/g lipid for the eight PCB congeners and six PBDE congeners detected, respectively. The median concentration of total PCBs was slightly higher in the case samples than in the controls (0.91 vs. 0.89ng/g lipid), but the difference was not significant (P=0.46), as also found for the median concentration of total PBDEs (0.55 vs. 0.54ng/g lipid, P=0.61). For both PCBs and PBDEs, when their placental concentration was above the median of all samples, it was associated with a non-significantly higher or equal risk of neural tube defects. Low levels of PCBs and PBDEs are not likely risk factors for neural tube defects in this population. PMID- 23022396 TI - Differences in growth properties of endometrial cancer in three dimensional (3D) culture and 2D cell monolayer. AB - Three-dimensional (3D) in vitro models have an invaluable role in understanding the behaviour of tumour cells in a well defined microenvironment. This is because some aspects of tumour characteristics cannot be fully recapitulated in a cell monolayer (2D). In the present study, we compared growth patterns, expression of signalling molecules, and metabolism-associated proteins of endometrial cancer cell lines in 3D and 2D cell cultures. Cancer cells formed spherical structures in 3D reconstituted basement membrane (3D rBM), and the morphological appearance was cell line dependent. Cell differentiation was observed after 8 days in the 3D rBM. There was reduced proliferation, detected by less expression of PCNA in 3D rBM than in 2D cell monolayers. The addition of exogenous epidermal growth factor (EGF) to cancer cells induced phosphorylation of EGFR and Akt in both cell culture conditions. The uptake of glucose was selectively altered in the 3D rBM, but there was a lack of association with Glut-1 expression. The secretion of vascular endothelial growth factor (VEGF) and prostaglandin E(2) (PGE(2)) was selectively altered in 3D rBM, and it was cell line dependent. Our data demonstrated that 3D rBM as an in vitro model can influence proliferation and metabolism of endometrial cancer cell behaviour compared to 2D cell monolayer. Changes are specific to individual cell types. The use of 3D rBM is, therefore, important in the in vitro study of targeted anticancer therapies. PMID- 23022395 TI - Calcium mishandling in diastolic dysfunction: mechanisms and potential therapies. AB - Diastolic dysfunction is characterized by slow or incomplete relaxation of the ventricles during diastole, and is an important contributor to heart failure pathophysiology. Clinical symptoms include fatigue, shortness of breath, and pulmonary and peripheral edema, all contributing to decreased quality of life and poor prognosis. There are currently no therapies available that directly target the heart pump defects in diastolic function. Calcium mishandling is a hallmark of heart disease and has been the subject of a large body of research. Efforts are ongoing in a number of gene therapy approaches to normalize the function of calcium handling proteins such as sarcoplasmic reticulum calcium ATPase. An alternative approach to address calcium mishandling in diastolic dysfunction is to introduce calcium buffers to facilitate relaxation of the heart. Parvalbumin is a calcium binding protein found in fast-twitch skeletal muscle and not normally expressed in the heart. Gene transfer of parvalbumin into normal and diseased cardiac myocytes increases relaxation rate but also markedly decreases contraction amplitude. Although parvalbumin binds calcium in a delayed manner, it is not delayed enough to preserve full contractility. Factors contributing to the temporal nature of calcium buffering by parvalbumin are discussed in relation to remediation of diastolic dysfunction. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. PMID- 23022397 TI - Cardiomyocytes derived from pluripotent stem cells: progress and prospects from China. AB - Transplantation of embryonic stem cell- or induced pluripotent stem cell-derived cardiomyocytes (CMs) represents one promising approach for the treatment of myocardial infarction and failing hearts. Cardiac differentiation systems from these pluripotent stem cells (PSCs) can also be employed to better understand early developmental biology, drug discovery, toxicology testing, and disease modeling. A prerequisite to attain these goals is the ability to generate functional CMs in an efficient and reliable way. The lack of CM maturation must also be overcome, and appropriate methods for introducing PSC-CMs into heart while maintaining cell viability must be optimized. The past few years have seen major advances both in the differentiation, characterization and application of these cells to biological systems. Here we review recent progress, especially those performed in China, in basic stem cell biology involving studies of cardiogenesis and CMs through PSC differentiation, approaches for chamber specific CM differentiation, maturation processes involving regulation of intracellular Ca(2+) signals, and applications. PMID- 23022398 TI - NMDA receptor blockade impairs the muscarinic conversion of sub-threshold transient depression into long-lasting LTD in the hippocampus-prefrontal cortex pathway in vivo: correlation with gamma oscillations. AB - Cholinergic fibers from the brainstem and basal forebrain innervate the medial prefrontal cortex (mPFC) modulating neuronal activity and synaptic plasticity responses to hippocampal inputs. Here, we investigated the muscarinic and glutamatergic modulation of long-term depression (LTD) in the intact projections from CA1 to mPFC in vivo. Cortical-evoked responses were recorded in urethane anesthetized rats for 30 min during baseline and 4 h following LTD. In order to test the potentiating effects of pilocarpine (PILO), independent groups of rats received either a microinjection of PILO (40 nmol; i.c.v.) or vehicle, immediately before or 20 min after a sub-threshold LTD protocol (600 pulses, 1 Hz; LFS600). Other groups received either an infusion of the selective NMDA receptor antagonist (AP7; 10 nmol; intra-mPFC) or vehicle, 10 min prior to PILO preceding LFS600, or prior to a supra-threshold LTD protocol (900 pulses, 1 Hz; LFS900). Our results show that PILO converts a transient cortical depression induced by LFS600 into a robust LTD, stable for at least 4 h. When applied after LFS600, PILO does not change either mPFC basal neurotransmission or late LTD. Our data also indicate that NMDA receptor pre-activation is essential to the muscarinic enhancement of mPFC synaptic depression, since AP7 microinjection into the mPFC blocked the conversion of transient depression into long-lasting LTD produced by PILO. In addition, AP7 effectively blocked the long-lasting LTD induced by LFS900. Therefore, our findings suggest that the glutamatergic co activation of prefrontal neurons is important for the effects of PILO on mPFC synaptic depression, which could play an important role in the control of executive and emotional functions. PMID- 23022399 TI - A simple approach for enhanced immune response using engineered dendritic cell targeted nanoparticles. AB - In this study, we demonstrate a simple strategy for enhanced immune response using a two-component dendritic cell (DC) targeted antigen delivery system. One component consists of a recombinant bifunctional fusion protein (bfFp) used for DC targeting, whereas, the other component is made of biotinylated PLGA nanoparticles that encapsulate the antigen. The fusion protein (bfFp) made of a truncated core-streptavidin fused to anti-DEC-205 single chain antibody (scFv) was mixed with ovalbumin-loaded biotinylated NPs that were formulated using biotin-PEG (2000)-PLGA, and the combination, bfFp functionalized NPs was used for DC targeted antigen delivery. In vitro DC uptake studies revealed a 2-fold higher receptor-mediated uptake of bfFp functionalized NPs when compared to non-targeted NPs. Immunization of the mice with the bfFp functionalized NPs in conjunction with DC maturation stimulus (anti-CD40 mAb) enhanced OVA-specific IgG and IgG subclass responses. Splenocytes of these mice secreted significantly higher levels of Th1 (IFN-gamma and IL-2) cytokines upon ex vivo restimulation with OVA. The promising outcomes of the bfFp functionalized DC targeted system support its use as a versatile vaccine delivery system for the design of monovalent or polyvalent vaccines. PMID- 23022400 TI - Cross-reactive neutralizing antibody epitopes against Enterovirus 71 identified by an in silico approach. AB - Currently, infections of hand, foot and mouth disease (HFMD) due to Human Enterovirus 71 (EV71) cannot be prevented or treated, as there are no suitable vaccines or antiviral drugs. This study aimed to identify potential vaccine candidates for EV71 using in silico analysis of its viral capsid proteins. A combined in silico approach utilizing computational hidden Markov model (HMM), propensity scale algorithm, and artificial learning, identified three 15-mer structurally conserved B-cell epitope candidates lying within the EV71 capsid proteins. Peptide vaccine candidates incorporating a target B-cell epitope and a promiscuous T-cell epitope from the related polio virus were synthesized using solid-phase Fmoc chemistry. Inbred BALB/C mice which were inoculated with two 10MUg doses of the synthetic peptide, generated anti-peptide antibodies. Purified IgG isolated from pooled sera of the inoculated mice neutralized EV71 infections in vitro. Furthermore, these neutralizing antibodies were cross-reactive against other members of the Picornaviridae family, demonstrating greater than 50% virus neutralization. This indicates that the current approach is promising for the development of synthetic peptide-based vaccine candidates against Picornaviridae. Development of effective vaccines is of paramount importance in managing the disease in the Asia Pacific regions where this virus is endemic and has significant social, economic and public health ramifications. PMID- 23022401 TI - Non-specific and sex-differential effects of vaccinations on child survival in rural western India. AB - BACKGROUND: Studies from Africa have suggested marked non-specific effects (NSEs) of routine vaccinations with effects on child survival. There have been few studies from Asia. We re-analyzed a study from Maharashtra, India, which had collected information on vaccinations during infancy and survival until 5 years of age. DESIGN: 4138 children born between 1987 and 1989 were visited at home every three months to collect information on nutritional status and vaccinations. Since nutritional status was a determinant of time to vaccinations, we adjusted for nutritional status in the analyzes of the association between vaccinations and mortality. SETTING: 45 contiguous villages in Shirur Administrative Block in Pune District. MAIN OUTCOME MEASURES: Mortality rate ratios (MRR) for different vaccination status groups. RESULTS: The study area has male preferential treatment, but the female-male mortality ratio varied between age groups with different pre-dominant vaccines; it was high in the age group in which diphtheria tetanus-pertussis (DTP) vaccine predominates and low in the age group in which measles vaccine (MV) is given. Children who followed the WHO recommended schedule of first BCG and then DTP vaccination were vaccinated earlier than other children (p<0.01). Two-thirds of the children had received BCG and DTP out-of-sequence, i.e. BCG and DTP simultaneously or BCG after DTP. Children who received BCG and DTP simultaneously or BCG as most recent vaccination had significantly lower mortality than children having DTP as the most recent vaccination, the mortality rate ratio being 0.15 (0.03-0.70). CONCLUSIONS: BCG out-of-sequence may be associated with lower mortality than DTP as the most recent vaccination. Given the public health implications, this possibility should be tested in randomized trials. Excess female mortality may also be related to vaccination policy. PMID- 23022402 TI - Design and implementation of the first randomized controlled trial of coenzyme CoQ10 in children with primary mitochondrial diseases. AB - We report the design and implementation of the first phase 3 trial of CoenzymeQ10 (CoQ10) in children with genetic mitochondrial diseases. A novel, rigorous set of eligibility criteria was established. The trial, which remains open to recruitment, continues to address multiple challenges to the recruitment of patients, including widely condoned empiric use of CoQ10 by individuals with proven or suspected mitochondrial disease and skepticism among professional and lay mitochondrial disease communities about participating in placebo-controlled trials. These attitudes represent significant barriers to the ethical and scientific evaluation--and ultimate approval--of nutritional and pharmacological therapies for patients with life-threatening inborn errors of energy metabolism. PMID- 23022403 TI - Time course modifications in organotypic culture of human neuroretina. AB - The purpose of this study was to characterize organ culture of human neuroretina and to establish survival and early degeneration patterns of neural and glial cells. Sixteen neuroretina explants were prepared from 2 postmortem eyes of 2 individuals. Four explants were used as fresh retina controls, and 12 were evaluated at 3, 6, and 9 days of culture. Neuroretina explants (5 * 5 mm) were cultured in Transwell((r)) dishes with the photoreceptor layer facing the supporting membrane. Culture medium (Neurobasal A-based) was maintained in contact with the membrane beneath the explant. Cryostat and ultrathin sections were prepared for immunohistochemistry and electron microscopy. Neuroretinal modifications were evaluated after toluidine blue staining and after immunostaining for neuronal and glial cell markers. Ultrastructural changes were analyzed by electron microscopy. From 0 to 9 days in culture, there was progressive retinal degeneration, including early pyknosis of photoreceptor nuclei, cellular vacuolization in the ganglion cell layer, decrease of both plexiform layer thicknesses, disruption and truncation of photoreceptor outer segments (OS), and marked reduction in the number of nuclei at both nuclear layers where the cells were less densely packed. At 3 days there was swelling of cone OS with impairment of pedicles, loss of axons and dendrites of horizontal and rod bipolar cells that stained for calbindin (CB) and protein kinase C (PKC alpha), respectively. After 9 days, horizontal cells were pyknotic and without terminal tips. There were similar degenerative processes in the outer plexiform layer for rod bipolar cells and loss of axon terminal lateral varicosities in the inner plexiform layer. Glial fibrillary acidic protein (GFAP) staining did not reveal a dramatic increase of gliosis in Muller cells. However, some Muller cells were CB immunoreactive at 6 days of culture. Over 9 days of culture, human neuroretina explants underwent morphological changes in photoreceptors, particularly the OS and axon terminals, and in postsynaptic horizontal and bipolar cells. These early changes, not previously described in cultured human samples, reproduce some celullar modifications after retinal damage. Thus, this model may be suitable to evaluate therapeutic agents during retinal degeneration processes. PMID- 23022404 TI - Knockout of ccr2 alleviates photoreceptor cell death in a model of retinitis pigmentosa. AB - Neuroinflammation involving CC chemokines such as monocyte chemoattractant protein-1 (MCP-1) has been demonstrated in the pathological process of retinitis pigmentosa (RP), an inherited degenerative retinal disease. However, the mechanism of MCP-1 and its receptor CCR2 involvement in the disease remains unclear. To investigate the role of MCP1/CCR2 in RP pathogenesis, ccr2 mutant RP mice (ccr2(-/-) rd10) were created and analyzed. The expression of MCP-1, RANTES, stromal cell-derived factor (SDF-1), and tumor necrosis factor-alpha (TNF-alpha) in the retinas of wild-type, rd10, and ccr2(-/-) rd10 mice was analyzed using quantitative RT-PCR. Photoreceptor apoptosis (TUNEL staining) and the number of microglia (positive for the F4/80 antibody) in the retina were examined. Retinal function was assessed using electroretinograms, and the structure of the whole retina was analyzed from images obtained using optical coherence tomography (OCT) and by histological examination. The expression levels of MCP-1, RANTES, and SDF 1 increased with time in the rd10 mice but not in the wild-type mice. Rearing the mice in the dark prevented degeneration and resulted in thicker photoreceptor layers at each time point. In those mice, the peaks of chemokine expression shifted to a later time with degeneration, suggesting that the expression of these chemokines was induced during the progression of degeneration. Although the difference was not so obvious, the retina in the ccr2(-/-) rd10 mice was consistently and significantly thicker than that in the rd10 (ccr2(+/+) rd10) mice at all time points. Rhodopsin gene expression was also higher in the ccr2(-/ ) rd10 mice than in rd10 (ccr2(+/+) rd10) mice, suggesting photoreceptor survival in the former. Retinal function was also better preserved in the ccr2(-/-) rd10 mice than in the rd10 mice. The number of microglia in the retinas of the ccr2(-/ ) rd10 mice was significantly lower than that in the retinas of the rd10 mice. Interestingly, the MCP-1 induction that was observed in the retinas of the rd10 mice was diminished in the retinas of the ccr2(-/-) rd10 mice. Our results suggest that the MCP-1/CCR2 system plays a role in retinal degeneration in rd mouse retinas. Retinal MCP-1 expression in the rd mouse retina may be partially controlled by ccr2-positive circulating cells. PMID- 23022405 TI - Biopsy harvesting site and distance from the explant affect conjunctival epithelial phenotype ex vivo. AB - The purpose of the study was to investigate if the number of goblet cells expanded ex vivo from a conjunctival explant is affected by the biopsy harvesting site on the conjunctiva and the distance from the explant. Conjunctival explants from six regions: superior and inferior bulbus, fornix, and tarsus of male Sprague-Dawley rats were grown in RPMI 1640 with 10% fetal bovine serum on coverslips for eight days. Histochemical and immunofluorescent staining of goblet (CK-7/UEA-1/MUC5AC), stratified squamous, non-goblet (CK-4), proliferating (PCNA) and progenitor (ABCG2) cells were analyzed by epifluorescence and laser confocal microscopy. Outgrowth was measured with NIH ImageJ. For statistical analysis the Mann-Whitney test and Spearman's rank-order correlation test were used. Cultures from superior and inferior fornix contained the most goblet cells as indicated by the presence of CK-7+, UEA-1+ and MUC5AC+ cells. Superior and inferior forniceal cultures displayed 60.8% +/- 9.2% and 64.7% +/- 6.7% CK-7+ cells, respectively, compared to the superior tarsal (26.6% +/- 8.4%; P < 0.05), superior bulbar (31.0% +/- 4.0%; P < 0.05), inferior bulbar (38.5% +/- 9.3%; P < 0.05) and inferior tarsal cultures (27.7% +/- 8.3%; P < 0.05). While 28.4% +/- 6.3% of CK 7+ goblet cells co-labeled with PCNA, only 7.4% +/- 1.6% of UEA-1+ goblet cells did (P < 0.01). CK-7+ goblet cells were located at a lower concentration close to the explant (39.8% +/- 3.1%) compared to near the leading edge (58.2% +/- 4.5%; P < 0.05). Both markers for goblet cell secretory product (UEA-1 and MUC5AC), however, displayed the opposite pattern with a higher percentage of positive cells close to the explant than near the leading edge (P < 0.05). The percentage of CK-4+ cells was higher near the explant compared to near the leading edge (P < 0.01). The percentage of CK-7+ goblet cells in the cultures did not correlate with the outgrowth size (r(s) = -0.086; P = 0.435). The percentage of UEA-1+ goblet cells correlated negatively with outgrowth size (r(s) = -0.347; P < 0.01), whereas the percentage of CK-4+ cells correlated positively with the outgrowth size (r(s) = 0.473; P < 0.05). We conclude that forniceal explants yield the highest number of goblet cells ex vivo and thereby seem to be optimal for goblet cell transplantation. We also suggest that CK-7+/UEA-1- cells represent highly proliferative immature goblet cells. These cells could be important during conjunctival migration as they are mostly located close to the leading edge and their density does not decrease with increasing outgrowth size. PMID- 23022406 TI - NADPH oxidase 4 is required for interleukin-1beta-mediated activation of protein kinase Cdelta and downstream activation of c-jun N-terminal kinase signaling in smooth muscle. AB - Reactive oxygen species (ROS) are generated in the vascular wall upon stimulation by proinflammatory cytokines and are important mediators of diverse cellular responses that occur as a result of vascular injury. Members of the NADPH oxidase (NOX) family of proteins have been identified in vascular smooth muscle (VSM) cells as important sources of ROS. In this study, we tested the hypothesis that NOX4 is a proximal mediator of IL-1beta-dependent activation of PKCdelta and increases IL-1beta-stimulated c-Jun kinase (JNK) signaling in primary rat aortic VSM cells. We found that stimulation of VSM cells with IL-1beta increased PKCdelta activity and intracellular ROS generation. SiRNA silencing of NOX4 but not NOX1 ablated the IL-1beta-dependent increase in ROS production. Pharmacological inhibition of PKCdelta activity as well as siRNA depletion of PKCdelta or NOX4 blocked the IL-1beta-dependent activation of JNK. Further studies showed that the IL-1beta-dependent upregulation of inducible NO synthase expression was inhibited through JNK inhibition and NOX4 silencing. Taken together, these results indicate that IL-1beta-dependent activation of PKCdelta is modulated by NOX4-derived ROS. Our study positions PKCdelta as an important redox-sensitive mediator of IL-1beta-dependent signaling and downstream activation of inflammatory mediators in VSM cells. PMID- 23022408 TI - Ankaflavin: a natural novel PPARgamma agonist upregulates Nrf2 to attenuate methylglyoxal-induced diabetes in vivo. AB - Ankaflavin (AK) is an active compound having anti-inflammatory, anti-cancer, antiatherosclerotic, and hypolipidemic effects. We have previously reported that AK acts as an antioxidant and antidiabetic drug; however, the mechanism by which AK prevents diabetes remains unknown. Hyperglycemia is associated with protein glycation, which produces advanced glycation end-products (AGEs). Methylglyoxal (MG)-a metabolite of carbohydrates-is believed to cause insulin resistance by inducing inflammation and pancreas damage. In this work, diabetes was induced in Wistar rats (4 weeks of age) by treating them with MG (600 mg/kg bw) for 4 weeks. We observed that AK (10mg/kg bw) exerted peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist activity, thereby enhancing insulin sensitivity (as indicated by hepatic GLUT2 translocation, PTP1B suppression, and glucose uptake) by downregulating blood glucose and upregulating pancreatic and duodenal homeobox-1 and Maf-A expression and increasing insulin production in MG induced rats. However, these effects were abolished by the administration of GW9662 (PPARgamma antagonist), but the expression of hepatic heme oxygenase-1 (HO 1) and glutamate-cysteine ligase (GCL) was not suppressed in MG-induced rats. Therefore, the nuclear factor erythroid-related factor-2 (Nrf2) activation was investigated. AK did not affect hepatic Nrf2 mRNA or protein expression but significantly increased Nrf2 phosphorylation (serine 40), which was accompanied by increased transcriptional activation of hepatic HO-1 and GCL. These data indicated that AK protected rats from oxidative stress resulting from MG-induced insulin resistance. In contrast, these effects were not detected when the rats were treated with the antidiabetic drug rosiglitazone (10mg/kg bw). Moreover, we found that AK did not inhibit the generation of AGEs in vitro; however, the glutathione (GSH) levels in liver and pancreas of MG-induced rats were elevated in rats administered AK. Therefore, we believe that GSH may lower the MG level, which attenuates the formation of AGEs in the serum, kidney, liver, and pancreas of MG-induced rats. We also found that AK treatment reduced the production of inflammatory factors, such as tumor necrosis factor-alpha and interleukin-1beta. Taken together, the results of our mechanistic study of MG-induced rats suggest that the protective effects of AK against diabetes are mediated by the upregulation of the signaling pathway of Nrf2, which enhances antioxidant activity and serves as a PPARgamma agonist to enhance insulin sensitivity. PMID- 23022407 TI - Redox regulation of the epigenetic landscape in cancer: a role for metabolic reprogramming in remodeling the epigenome. AB - Cancer arises from normal cells that acquire a series of molecular changes; however, the founding events that create the clonogens from which a tumor will arise and progress have been the subject of speculation. Through the efforts of several generations of cancer biologists it has been established that the malignant phenotype is an amalgamation of genetic and metabolic alterations. Numerous theories have suggested that either, or both, of these elements might serve as the impetus for cancer formation. Recently, the epigenetic origins of cancer have been suggested as an additional mechanism giving rise to the malignant phenotype. When the discovery that the enzymes responsible for initiating and perpetuating epigenetic events is linked to metabolism by their cofactors, a new paradigm for the origins of cancer can be created. Here, we summarize the foundation of such a paradigm on the origins of cancer, in which metabolic alterations create an epigenetic progenitor that clonally expands to become cancer. We suggest that metabolic alterations disrupt the production and availability of cofactors such as S-adenosylmethionine, alpha-ketoglutarate, NAD(+), and acetyl-CoA to modify the epigenotype of cells. We further speculate that redox biology can change epigenetic events through oxidation of enzymes and alterations in metabolic cofactors that affect epigenetic events such as DNA methylation. Combined, these metabolic and redox changes serve as the foundation for altering the epigenotype of normal cells and creating the epigenetic progenitor of cancer. PMID- 23022409 TI - Interleukin 6 destabilizes atherosclerotic plaques by downregulating prolyl-4 hydroxylase alpha1 via a mitogen-activated protein kinase and c-Jun pathway. AB - Interleukin 6 (IL-6) is a pivotal cytokine that regulates extracellular matrix metabolism by ameliorating the modification of collagen content, important in fibrous caps of atherosclerotic plaque. Prolyl-4-hydroxylase alpha1 (P4Halpha1) is a key intracellular enzyme required for synthesis of collagen in animals. We investigated the relationship of IL-6 and P4Halpha1 in atherosclerosis-prone mice and human aortic smooth muscle cells (HASMCs). Apolipoprotein E (ApoE)-/- mice were fed a high-fat diet and a perivascular constrictive silica collar was placed on the right common carotid artery to induce atherosclerotic lesions, then mice were divided into two groups for transfection with empty lentivirus or IL-6 lentivirus. HASMCs were transfected with small interfering RNA or treated with recombinant human IL-6. IL-6 significantly downregulated collagen, P4Halpha1 and smooth muscle cell contents in atherosclerotic mouse arteries. Macrophage and lipid contents in the atherosclerotic area were significantly increased with IL-6 treatment. IL-6 significantly downregulated P4Halpha1 expression in HASMCs through an RAF-MEK1/2-ERK1/2 mitogen-activated protein kinase (MAPK) pathway, and c-Jun was involved in the process. Our findings highlight IL-6 destabilize atherosclerotic plaques in mice by downregulating P4Halpha1 via an RAF-MEK1/2 ERK1/2 MAPK and c-Jun pathway. PMID- 23022410 TI - Differential scanning calorimetry as a tool for protein folding and stability. AB - Differential scanning calorimetry measures the heat capacity of states and the excess heat associated with transitions that can be induced by temperature change. The integral of the excess heat capacity is the enthalpy for this process. Despite this potentially intimidating sounding physical chemistry background, DSC has found almost universal application in studying biological macromolecules. In the case of proteins, DSC can be used to determine equilibrium thermodynamic stability and folding mechanism but can also be used in a more qualitative manner screening for thermal stability as an indicator for, ligand binding, pharmaceutical formulation or conditions conducive to crystal growth. DSC usually forms part of a wider biophysical characterisation of the biological system of interest and so the literature is diverse and difficult to categorise for the technique in isolation. This review therefore describes the potential uses of DSC in studying protein folding and stability, giving brief examples of applications from the recent literature. There have also been some interesting developments in the use of DSC to determine barrier heights for fast folding proteins and in studying complex protein mixtures such as human plasma that are considered in more detail. PMID- 23022411 TI - Ignition temperature of magnesium powder clouds: a theoretical model. AB - Minimum ignition temperature of dust clouds (MIT-DC) is an important consideration when adopting explosion prevention measures. This paper presents a model for determining minimum ignition temperature for a magnesium powder cloud under conditions simulating a Godbert-Greenwald (GG) furnace. The model is based on heterogeneous oxidation of metal particles and Newton's law of motion, while correlating particle size, dust concentration, and dust dispersion pressure with MIT-DC. The model predicted values in close agreement with experimental data and is especially useful in predicting temperature and velocity change as particles pass through the furnace tube. PMID- 23022412 TI - Comparison of various organic compounds destruction on rare earths doped Ti/Sb SnO2 electrodes. AB - Ti/Sb-SnO2 and three kinds of rare earths (REs), namely Ce, Gd, and Eu doped Ti/Sb-SnO2 electrodes were prepared and tested for their capacity on electrocatalytic degradation of three kinds of basal aromatic compounds (benzoquinone, hydroquinone and catechol) and six kinds of aliphatic acids (maleic acid, fumaric acid, succinic acid, malonic acid, oxalic acid and acetic acid). The elimination of selected organics as well as their TOC removal with different doped Ti/Sb-SnO2 electrodes was described by first-order kinetics. Compared with Ti/Sb-SnO2, the Gd and Eu doped electrodes show better performance on the degradation of most of the selected organics, while Ce doped electrode shows either closely or lower efficiency on the degradation of these selected organics. Besides electrode material, the molecular structure of organic compound has obvious effect on its degradation in the electrocatalytic process. Catechol is more resistant to the electrophilic attack by hydroxyl radicals than benzoquinone and hydroquinone. The compound with more complicate molecular structure or longer carbon chain is more difficult to be mineralized. The aliphatic acid with higher oxygen content or more double bonds is more readily to be oxidized in the electrocatalytic process. PMID- 23022413 TI - Production of ultra-low-sulfur gasoline: an equilibrium and kinetic analysis on adsorption of sulfur compounds over Ni/MMS sorbents. AB - High performance nickel-based micro-mesoporous silica (Ni/MMS) sorbent was prepared by incipient wetness impregnation with ultrasonic aid (IWI-u) for adsorptive desulfurization (ADS) of commercial gasoline and simulated fuels. The sorbents were characterized with BET, XRD, TPR, SEM, HRTEM and TG/DTG. These results show that 20 wt%Ni/MMS (IWI-u) can still retain the framework of MMS and nickel particles were homogeneously distributed in the MMS channels without any aggregation, which improved significantly the ADS performance of the sorbents. The studies on the ADS kinetics indicate that the adsorption behavior of thiophene (T), benzothiophene (BT) and dibenzothiophene (DBT) over 20 wt%Ni/MMS (IWI-u) can be described appropriately by pseudo second-order kinetic model. The intraparticle diffusion model verified that the steric hindrance and intraparticle diffusion were the rate controlling step of the adsorption process of DBT molecules. Langmuir model can be used to describe the adsorption isotherms for T, BT and DBT due to low coverage. The regeneration sorbent maintains the sulfur removal efficiency of 85.9% for 6 cycles. PMID- 23022414 TI - Detoxification of Cr(VI) in Salvinia minima is related to seasonal-induced changes of thiols, phenolics and antioxidative enzymes. AB - In this study, protein- and non-protein-thiol-containing compounds (THCC), soluble phenolics (SP), proline (Pro), proteins and malondialdehyde (MDA) contents, and antioxidative enzyme activities were analyzed in floating and submerged leaves of Salvinia minima to establish their role against Cr-induced oxidative stress. We analyzed relationships among biochemical responses to different Cr(VI) concentrations to explore underlying mechanisms of Cr detoxification in plants growing under field conditions during summer and winter seasons. Significant increases in THCC were observed in submerged leaves from both seasons, while in floating leaves THCC increased only in summer being decreased in winter. Contrarily SP increased in floating leaves and decreased in submerged ones. MDA increased significantly in winter-leaves, but in summer leaves remained unchanged. Antioxidative enzymes, i.e. guaiacol peroxidase (G POD), superoxide dismutase (SOD) and catalase (CAT) showed different activity patterns. G-POD significantly increased in Cr-treated leaves from both seasons, while SOD increased in submerged leaves only, remaining practically unchanged in floating ones. CAT activity increased in floating leaves from both seasons, whereas in submerged ones was decreased or increased. Proteins increased in both leaf types during summer whereas decreased or remained unchanged in winter. Pro increased in winter-submerged leaves only. Results show that seasonal-induced changes occur in all measured parameters. PMID- 23022415 TI - The effect of treatment stages on the coking wastewater hazardous compounds and their toxicity. AB - This study investigated the change of hazardous materials in coking wastewater at different treatment stages (anaerobic, anaerobic/aerobic, anaerobic/aerobic/photo degradation, anaerobic/aerobic/ozone oxidation treatment) and the effects of them on the development of maize embryos and the activity of amylase and protease in maize seeds. Moreover the interaction of refractory organic matters in the wastewater at different treatment stages with amylase and protease also were determined in vitro. The results show that the biodegradable and the refractory organic compounds in the wastewater both can affect maize embryo development (germination inhibition rate is 19.3% for biodegradable organic compounds). As the treatment stage preceding, the inhibition effect of coking wastewater on the development of the maize embryo (for germination inhibition rates change from 49.3% to 24.6%) and on enzymatic activity (inhibition rates change from 63.9% to 22.4% for amylase) decreases gradually, but the photo-degradation treatment to anaerobic/aerobic effluent can increase its toxicity. The changes in the ability of the refractory organic compounds to bind with enzyme proteins, combined with the analysis of the organic components by GC/MS, show that in the process of coking wastewater treatment no new toxic chemicals were produced. PMID- 23022416 TI - Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype. AB - BACKGROUND: The rs3818361 single nucleotide polymorphism in complement component (3b/4b) receptor-1 (CR1) is associated with increased risk of Alzheimer's disease (AD). Although this novel variant is associated with a small effect size and is unlikely to be useful as a predictor of AD risk, it might provide insights into AD pathogenesis. We examined the association between rs3818361 and brain amyloid deposition in nondemented older individuals. METHODS: We used (11)C-Pittsburgh Compound-B positron emission tomography to quantify brain amyloid burden in 57 nondemented older individuals (mean age 78.5 years) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging. In a replication study, we analyzed (11)C-Pittsburgh Compound-B positron emission tomography data from 22 cognitively normal older individuals (mean age 77.1 years) in the Alzheimer's Disease Neuroimaging Initiative dataset. RESULTS: Risk allele carriers of rs3818361 have lower brain amyloid burden relative to noncarriers. There is a strikingly greater variability in brain amyloid deposition in the noncarrier group relative to risk carriers, an effect explained partly by APOE genotype. In noncarriers of the CR1 risk allele, APOE epsilon4 individuals showed significantly higher brain amyloid burden relative to APOE epsilon4 noncarriers. We also independently replicate our observation of lower brain amyloid burden in risk allele carriers of rs3818361 in the Alzheimer's Disease Neuroimaging Initiative sample. CONCLUSIONS: Our findings suggest complex mechanisms underlying the interaction of CR1, APOE, and brain amyloid pathways in AD. Our results are relevant to treatments targeting brain Abeta in nondemented individuals at risk for AD and suggest that clinical outcomes of such treatments might be influenced by complex gene-gene interactions. PMID- 23022417 TI - The docosanoid neuroprotectin D1 induces homeostatic regulation of neuroinflammation and cell survival. AB - The onset of neurodegenerations and nervous system injury both trigger cell signaling perturbations that lead to damage of neuronal circuits and synapic connections, as well as protective signaling that aims to halt disease onset. Here we review recent findings that support the role of the docosanoid mediator neuroprotectin D1 (NPD1) as an early response or sentinel during the initial phase of nervous system damage. NPD1 is derived from docosahexaenoic acid that is selectively concentrated and retained in the nervous system. The protein misfolding triggers the biosynthesis of NPD1 which in turn downregulates pathways that lead to cell death and changes the outcome to cell survival. Proteotoxic stress as a result of protein misfolding is a widespread event in many neurodegenerative diseases. Therefore, mechanisms and mediators such as NPD1 that curtail consequences of these events are of interest as leads in the search for novel preventive and or therapeutic approaches. PMID- 23022418 TI - Comparison of a new prototype immunochromatographic assay and a commercial enzyme linked immunosorbent assay for the detection of serum antibodies against Toscana virus. AB - Toscana virus (TOSV) is an arthropod-borne virus, transmitted to humans by Phlebotomus spp. Sandflies, which causes neurological diseases such as aseptic meningitis and meningoencephalitis. The commercial enzyme-linked immunosorbent assay (ELISA) is used widely to detect anti-TOSV IgG and IgM antibodies and to allow for rapid diagnosis of infection (Diesse Diagnostica Senese, Siena, Italy). Recently, an immunochromatographic assay (ICA) was developed for human anti-TOSV IgG or IgM detection by InBios International (Seattle, WA, USA). A comparison of the two diagnostic assays was performed on one hundred serum samples collected from patients hospitalized with suspected TOSV meningitis. Both assays were in excellent agreement, for both IgG and IgM detection. For IgM, 64/65 ELISA positive samples were positive by ICA. One serum, positive for specific IgM by ELISA but negative by ICA, was confirmed by direct diagnosis, with TOSV RNA detection in the patient's cerebrospinal fluid by PCR. For IgG, 64 samples were positive by ICA out of 71 ELISA positive samples. The discordant sera were positive by immunofluorescence and neutralization tests. Three out of these seven samples were also positive by IgM ICA. The sensitivity of these new assays compared to ELISA, which is used routinely, was 98.5% for IgM and 90.1% for IgG, while specificity was 100% in both cases. This data shows that ICA could be a reliable alternative test for serological diagnosis of TOSV infection in humans. PMID- 23022419 TI - Contribution of imaging in polymyalgia rheumatica. PMID- 23022420 TI - When first line therapy for AA-amyloidosis secondary to rheumatoid arthritis fails: a correspondence. PMID- 23022421 TI - Bisphosphonates and glucocorticoid-induced osteoporosis: efficacy and tolerability. AB - In this review, the efficacy concern relating to bisphosphonates therapy for glucocorticoid-induced osteoporosis is considered. Sole the randomised clinical trials that including more than 50 patients in each treatment arm were considered. This review also covered the safety of bisphosphonates in the setting of glucocorticoid-induced osteoporosis with specific focus on atrial fibrillation, osteonecrosis of the jaw, upper gastrointestinal adverse events and esophageal cancer risk, atypical fractures and renal safety. These last adverse events have been selected due to the rationale of a possible additive, pathophysiologic or synergetic, deleterious effect of bisphosphonates and glucocorticoid on these organs. The available evidence for glucocorticoid-induced osteoporosis treatment and management is much less important than for post menopausal osteoporosis. However, based on randomised clinical trials with lumbar spine BMD as the primary endpoint after one year, bisphosphonates can be considered as efficacious. Alendronate, etidronate, risedronate and zoledronate prevented declines in spine BMD in adults receiving glucocorticoid. Treatment and prevention studies in glucocorticoid-induced osteoporosis have a short duration and have included smaller population than in post-menopausal osteoporosis. However in this setting, the safety profile of bisphosphonates in glucocorticoid induced osteoporosis was good. Long-term use of bisphosphonates in patients treated with glucocorticoid might be cautiously monitored in order to prevent adverse effects. PMID- 23022422 TI - Efficacy of anakinra in calcium pyrophosphate crystal-induced arthritis: a report of 16 cases and review of the literature. AB - OBJECTIVES: Calcium pyrophosphate (CPP) crystal-induced arthritis occurs particularly in elderly people. This population has frequently associated comorbidities and treatments, which could limit the use of conventional therapies (colchicine, non-steroidal anti-inflammatory drugs and corticosteroids). The aim of the study was to evaluate the efficacy and tolerance of anakinra in patients with CPP crystal-induced arthritis. METHODS: We performed a multicentric retrospective chart review of patients who received anakinra for CPP crystal induced arthritis. Demographic information, comorbidities, co-prescription, short term treatment outcomes, adverse event, complication and subsequent flares were reviewed. RESULTS: A total of 16 patients (12 females, mean age: 80.2+/-11.1 years) received anakinra (100 mg subcutaneously per day). The mean number of anakinra injection was 15.5+/-42.9 per patient (median: 3). All patients had contraindication and/or failure to conventional therapies. The majority (14 [87.5%]) of patients with CPP crystal-induced arthritis demonstrated a beneficial response to anakinra therapy: 10 good responses and four partial responses. A relapse occurred in six (37.5%) patients (mean time to relapse: 3.4+/-4.9 months). One patient had an acute bacterial pneumonitis. CONCLUSION: Our results suggest that anakinra is relatively well tolerated and could be a good option in the treatment of CPP crystal-induced arthritis, illustrating that IL-1beta blockade may be helpful to control flares in patients having CPP crystal-induced arthritis for which conventional therapies are ineffective or contra-indicated. PMID- 23022424 TI - Modified sequential therapy regimens for Helicobacter pylori eradication: a systematic review. AB - BACKGROUND: Different modified sequential therapies have been proposed for Helicobacter pylori eradication. However, the efficacy of these regimens is controversial. METHODS: We performed a systematic review of the literature and pooled-data analysis to assess: (a) the efficacy of different modified sequential therapies for H. pylori eradication, (b) the eradication rates achieved by these regimens as compared to either standard triple therapies or standard sequential regimen when available. RESULTS: Overall 21 trials met inclusion criteria. The most used modified sequential therapy was the seven plus seven tetracycline-based regimen which achieved an overall 73.3% eradication rate (6 trials). Such therapy was more effective than the 14-day triple therapy (77.2% vs. 63.6%; 3 trials). The most used five plus five levofloxacin-based sequential therapy achieved a 95.8% and 90% cure rates when 250 mg and 500 mg levofloxacin twice daily were used, respectively. These success rates were higher as compared to that of either standard sequential or triple therapies. Other modified sequential therapies did not achieved acceptably high cure rates. Contradictory results emerged from 2 studies assessing the efficacy of a levofloxacin-based sequential regimen as a second-line therapy. CONCLUSIONS: Both levofloxacin- and tetracycline-based sequential therapies have been proved to be more effective than standard triple therapies, confirming that the 'sequential' administration of drugs is a successful therapeutic procedure for H. pylori infection. PMID- 23022423 TI - ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population. AB - BACKGROUND: Genetic alterations in the ATP-binding cassette subfamily B member 4 (ABCB4) and ATP-binding cassette subfamily B member 11 (ABCB11) have been associated to the onset of intrahepatic cholestasis of pregnancy (ICP) in predisposed women. AIMS: To identify new and/or frequent ABCB4 and ABCB11 genes variants in a cohort of Italian patients with ICP and to evaluate the possible pathogenetic role for the novel mutations identified. METHODS: DNA of 33 unrelated Italian women with obstetric cholestasis were screened for mutations in the entire coding sequence of ABCB4 and ABCB11 genes. Polymerase chain reaction and automated sequencing was performed on the 27 coding exons of both genes. RESULTS: Genotyping revealed 11 mutations, 5 of whom were novel variants: 2 localized on ABCB4 (p.I587DfsX603, p.I738LfsX744) and 3 on ABCB11 (p.V284D, p.Q558H, p.P731S). The most severe phenotypes were associated with the variants p.I587DfsX603, p.I738LfsX744 and p.V284D. Moreover, the already described mutation p.N510S found in ABCB4 seems to be strictly involved in the onset of ICP in that particular patient. CONCLUSIONS: Our data support the hypothesis of a significant involvement of ABCB4 mutations in the onset of ICP, but also confirm an important role for ABCB11 mutations in increasing the susceptibility to cholestasis of pregnancy. PMID- 23022425 TI - Contrast-enhanced computed tomography and ultrasound-guided liver biopsy to diagnose dysplastic liver nodules in cirrhosis. AB - BACKGROUND: Dysplastic nodules in cirrhosis herald a very high risk of transition to hepatocellular carcinoma. A better understanding of the relationships between dysplastic nodules and hepatocellular carcinoma development may help refining strategies of enhanced follow-up. METHODS: All consecutive cirrhotics with a histologically proven de novo dysplastic nodule, were retrospectively identified and underwent alternating abdominal ultrasound and contrast-computed tomography every 3 months. An ultrasound-guided liver biopsy was the diagnostic gold standard, whereas surveillance and recall policies were according to current guidelines. RESULTS: Among 36 patients with dysplastic nodule (21 low-grade, 15 high-grade, 17.4 +/- 2.6mm), 17 (47%) showed arterial wash-in, 15 (42%) portal/venous hypodensity whereas 4 (11%) had neither pattern. During 6-128 (median 36) months, 21 patients developed a hepatocellular carcinoma at a rate of 13.8% per year, intranodular=8.7% vs extranodular=7.1% per year. Hepatocellular carcinoma occurred more frequently in high-grade than low-grade dysplastic nodules (32.2% vs 9.3% per year, p=0.0039); the maximum time to hepatocellular carcinoma transformation was 27 months for intranodular vs 67 months for extranodular tumours (p=0.025). No contrast-computed tomography pattern predicted neoplastic transformation of dysplastic nodules. CONCLUSION: The histological examination of liver nodules in cirrhosis lacking the imaging hallmark of hepatocellular carcinoma improves both prognostication and outcome of surveillance, since it dictates the intensity of the radiological follow-up. PMID- 23022426 TI - Non-destructive sampling of rock-dwelling microbial communities using sterile adhesive tape. AB - Building stone provides a habitat for an array of microorganisms, many of which have been demonstrated to have a deleterious effect on the appearance and/or structural integrity of stone masonry. It is essential to understand the composition and structure of stone-dwelling (lithobiontic) microbial communities if successful stone conservation strategies are to be applied, particularly in the face of global environmental change. Ideally, the techniques used to sample such assemblages should be non-destructive due to the sensitive conservation status of many stone buildings. This paper quantitatively assesses the performance of sterile adhesive tape as a non-destructive sampling technique and compares the results of tape sampling with an alternative, destructive, sampling method. We used DNA fingerprinting (TRFLP) to characterise the algal, fungal and bacterial communities living on a stone slab. Our results demonstrate that tape sampling may be used to collect viable quantities of microbial DNA from environmental samples. This technique is ideally suited to the sampling of microbial biofilms, particularly when these communities are dominated by green algae. It provides a good approximation of total community diversity (i.e. the aggregate diversity of epilithic and endolithic communities). Tape sampling is straightforward, rapid and cost effective. When combined with molecular analytical techniques, this sampling method has the potential to make a major contribution to efforts to understand the structure of lithobiontic microbial communities and our ability to predict the response of such communities to future environmental change. PMID- 23022427 TI - Development of bacteria identification array to detect lactobacilli in Thai fermented sausage. AB - To improve the quality and safety of food products, there is a need in the food industry for a reliable method for simultaneously monitoring multiple bacterial strains. Microarray technology is a high-throughput screening approach that can provide an alternative for bacteria detection. A total of 164 bacteria-specific probes were designed from 16S rRNA gene sequences to target 12 bacteria species, including lactic acid bacteria and selected food pathogens. After fabrication onto aminosilane-coated slides, hybridization conditions of the array were optimized for high specificity and signal intensities. The array was applied to detect 12 bacteria individually and was specific to all (Lactobacillus plantarum group, L. fermentum, L. brevis, L. delbrueckii, L. casei, L. sakei, Escherichia coli, Staphylococcus aureus, Micrococcus luteus and Listeria monocytogenes) except L. animalis. Multiplex detection using mixed bacteria populations was evaluated and accurate detection was obtained. The feasibility of using the array to detect the target bacteria in food was evaluated with Thai fermented sausages (Nham). Meat samples were collected on days 2, 3 and 7 after natural fermentation, L. plantarum-inoculated fermentation and L. brevis-inoculated fermentation before applying to the array. The naturally-fermented Nham contained L. sakei, L. delbrueckii, L. plantarum and L. fermentum. The L. plantarum inoculated Nham showed a similar lactic acid bacteria population but the positive signal level for L. plantarum was higher than with natural fermentation. The L. brevis-inoculated Nham contained L. brevis, L. plantarum, L. delbrueckii and L. fermentum. The array was used to monitor bacteria population dynamics during the fermentation process. The naturally-fermented and L. brevis-inoculated samples showed lower positive signal levels of L. plantarum on day 2, but signals gradually increased on days 3 and 7 of the fermentation. In contrast, the L. plantarum-started fermentation showed a higher positive signal level on day 2 than the natural and L. brevis-inoculated samples, and the positive signal level remained high on days 3 and 7. The bacteria identification array was proven to be useful as an alternative method to detect and monitor target bacteria populations during food fermentation. PMID- 23022428 TI - Antiplatelet therapy to prevent hemodialysis vascular access failure: systematic review and meta-analysis. AB - BACKGROUND: Hemodialysis vascular access failure occurs often and increases morbidity for people on hemodialysis therapy. Antiplatelet agents may prevent hemodialysis vascular access failure, but potentially may be hazardous in people with end-stage kidney disease who have impaired hemostasis. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials. SETTING & POPULATION: Adults on long-term hemodialysis therapy. SELECTION CRITERIA: Trials evaluating hemodialysis vascular access outcomes identified by searches in Cochrane CENTRAL and Renal Group Trial Registers and Embase, without language restriction. INTERVENTION: Antiplatelet therapy. OUTCOMES: Hemodialysis vascular access failure (thrombosis or loss of patency), failure to attain vascular access suitable for dialysis, need for intervention to attain patency or assist maturation, major bleeding, minor bleeding, and antiplatelet treatment withdrawal. Treatment effects were summarized as RRs with 95% CIs using random effects meta-analysis. RESULTS: 21 eligible trials (4,826 participants) comparing antiplatelet treatment with placebo or no treatment were included. 12 trials (3,118 participants) started antiplatelet therapy around the time of dialysis vascular access surgery and continued treatment for approximately 6 months. Antiplatelet treatment reduced fistula failure (thrombosis or loss of patency) by one-half (6 trials, 1,222 participants; RR, 0.49; 95% CI, 0.30-0.81) but had uncertain effects on graft patency and attaining fistula or graft function suitable for dialysis. Overall, antiplatelet treatment had uncertain effects on major bleeding. LIMITATIONS: Unclear or high risk of bias in most trials and few trial data, particularly for antiplatelet effects on graft function and vascular access suitability for dialysis. CONCLUSIONS: Antiplatelet treatment protects fistula from thrombosis or loss of patency, but has little or no effect on graft patency and uncertain effects on vascular access maturation for dialysis and major bleeding. Interventions that demonstrably improve vascular access suitability for dialysis are needed. PMID- 23022430 TI - Timing deficits in attention-deficit/hyperactivity disorder (ADHD): evidence from neurocognitive and neuroimaging studies. AB - Relatively recently, neurocognitive and neuroimaging studies have indicated that individuals with attention-deficit/hyperactivity disorder (ADHD) may have deficits in a range of timing functions and their underlying neural networks. Despite this evidence, timing deficits in ADHD are still somewhat neglected in the literature and mostly omitted from reviews on ADHD. There is therefore a lack of integrative reviews on the up-to-date evidence on neurocognitive and neurofunctional deficits of timing in ADHD and their significance with respect to other behavioural and cognitive deficits. The present review provides a synthetic overview of the evidence for neurocognitive and neurofunctional deficits in ADHD in timing functions, and integrates this evidence with the cognitive neuroscience literature of the neural substrates of timing. The review demonstrates that ADHD patients are consistently impaired in three major timing domains, in motor timing, perceptual timing and temporal foresight, comprising several timeframes spanning milliseconds, seconds, minutes and longer intervals up to years. The most consistent impairments in ADHD are found in sensorimotor synchronisation, duration discrimination, reproduction and delay discounting. These neurocognitive findings of timing deficits in ADHD are furthermore supported by functional neuroimaging studies that show dysfunctions in the key inferior fronto-striato cerebellar and fronto-parietal networks that mediate the timing functions. Although there is evidence that these timing functions are inter-correlated with other executive functions that are well established to be impaired in the disorder, in particular working memory, attention, and to a lesser degree inhibitory control, the key timing deficits appear to survive when these functions are controlled for, suggesting independent cognitive deficits in the temporal domain. There is furthermore strong evidence for an association between timing deficits and behavioural measures of impulsiveness and inattention, suggesting that timing problems are key to the clinical behavioural profile of ADHD. Emerging evidence shows that the most common treatment of ADHD with the dopamine agonist and psychostimulant Methylphenidate attenuates most timing deficits in ADHD and normalises the abnormally blunted recruitment of the underlying fronto-striato-cerebellar networks. Timing function deficits in ADHD, therefore, next to executive function deficits, form an independent impairment domain, and should receive more attention in neuropsychological, neuroimaging, and pharmacological basic research as well as in translational research aimed to develop pharmacological or non-pharmacological treatment of abnormal timing behaviour and cognition in ADHD. PMID- 23022429 TI - CKiD (CKD in children) prospective cohort study: a review of current findings. AB - Chronic kidney disease (CKD) is a life-long condition associated with substantial morbidity and premature death due to complications from a progressive decrease in kidney function. The incidence and prevalence of all stages of CKD in children continues to increase worldwide. Between 2000 and 2008, the kidney replacement therapy incidence rate in those aged 0-19 years increased 5.9% to 15 per million population, highlighting the importance of CKD research in children. Many comorbid conditions seen in adults with CKD, including cardiovascular disease and cognitive impairment, also are highly prevalent in children, implicitly demonstrating the crucial need for initiating therapy early to improve health outcomes in children with CKD. The CKiD (Chronic Kidney Disease in Children) Study is a prospective cohort study of 586 children aged 1-16 years with an estimated glomerular filtration rate of 30-90 mL/min/1.73 m(2). Since its inception, CKiD has identified risk factors for CKD progression and cardiovascular disease in children with CKD and highlighted the effects of CKD on outcomes unique to children, including neurocognitive development and growth. This review summarizes the findings to date, illustrating the spectrum of CKD associated complications in children and emphasizing areas requiring further investigation. Taken in sum, these elements stress that initiating treatment at an early age is essential for reducing long-term morbidity and mortality in children with CKD. PMID- 23022431 TI - Dissociation of formal and temporal predictability in early auditory evoked potentials. AB - Perceived regularity among events in the environment allows predictions regarding the "when" and the "what" dimensions of future events. In this context, one crucial question concerns the impact and the potentially optimizing effect, of regular temporal structure on the processing of "what", or formal, information. The current study addresses this issue by investigating whether temporal and formal structure interact during early stages of sensory processing, and by relating the respective findings to the concept of a predictive bias in brain function. Analyses were performed on two components of the auditory event-related potential of the electroencephalogram, namely the P50 and the N100. Oddball sequences consisting of frequent standard and infrequent deviant sinusoidal tones were presented with either regular or irregular temporal structure in pre attentive and attentive experimental settings (Schwartze, Rothermich, Schmidt Kassow, & Kotz, 2011). Temporal regularity effects on pre-attentive and attentive processing of deviance. Biological Psychology, 87, 146-151). The results confirm that the P50 and the N100 amplitudes reliably encode formal and temporal predictability. Similar patterns of results obtained with pre-attentive and attentive task instructions, as well as the absence of a significant interaction of formal and temporal structure suggest that the P50 response may be interpreted as an automatic marker of predictability, whereas the N100 may represent a more complex marker, in which formal and temporal structure start interacting as a function of attention. PMID- 23022432 TI - Age differences of multivariate network expressions during task-switching and their associations with behavior. AB - The effect of aging on functional network activation associated with task switching was examined in 24 young (age=25.2+/-2.73 years) and 23 older adults (age=65.2+/-2.65 years) using functional magnetic resonance imaging (fMRI). The study goals were to (1) identify a network shared by both young and older adults, (2) identify additional networks in each age group, and (3) examine the relationship between the networks identified and behavioral performance in task switching. Ordinal trend covariance analysis was used to identify the networks, which takes advantage of increasing activation with greater task demand to isolate the network of regions recruited by task-switching. Two task-related networks were found: a shared network that was strongly expressed by both young and older adults and a second network identified in the young data that was residualized from the shared network. Both networks consisted of regions associated with task-switching in previous studies including the middle frontal gyrus, the precentral gyrus, the anterior cingulate, and the superior parietal lobule. Not only was pattern expression of the shared network associated with reaction time in both age groups, the difference in the pattern expression across task conditions (task-switch minus single-task) was also correlated with the difference in RT across task conditions. On the contrary, expression of the young residual network showed a large age effect such that older adults do not increase expression of the network with greater task demand as young adults do and correlation between expression and accuracy was significant only for young adults. Thus, while a network related to RT is preserved in older adults, a different network related to accuracy is disrupted. PMID- 23022433 TI - Perception of emotions from facial expressions in high-functioning adults with autism. AB - Impairment in social communication is one of the diagnostic hallmarks of autism spectrum disorders, and a large body of research has documented aspects of impaired social cognition in autism, both at the level of the processes and the neural structures involved. Yet one of the most common social communicative abilities in everyday life, the ability to judge somebody's emotion from their facial expression, has yielded conflicting findings. To investigate this issue, we used a sensitive task that has been used to assess facial emotion perception in a number of neurological and psychiatric populations. Fifteen high-functioning adults with autism and 19 control participants rated the emotional intensity of 36 faces displaying basic emotions. Every face was rated 6 times-once for each emotion category. The autism group gave ratings that were significantly less sensitive to a given emotion, and less reliable across repeated testing, resulting in overall decreased specificity in emotion perception. We thus demonstrate a subtle but specific pattern of impairments in facial emotion perception in people with autism. PMID- 23022434 TI - Hunting for diagnosis of cardiac arrest. PMID- 23022435 TI - Seasonal variability and influence of outdoor temperature on body temperature of cardiac arrest victims. AB - AIM OF THE STUDY: Mild therapeutic hypothermia is a major advance in post resuscitation-care. Some questions remain unclear regarding the time to initiate cooling and the time to achieve target temperature below 34 degrees C. We examined whether seasonal variability of outside temperature influences the body temperature of cardiac arrest victims, and if this might have an effect on outcome. METHODS: Patients with witnessed out-of-hospital cardiac arrests were enrolled retrospectively. Temperature variables from 4 climatic stations in Vienna were provided from the Central Institute for Meteorology and Geodynamics. Depending on the outside temperature at the scene the study participants were assigned to a seasonal group. To compare the seasonal groups a Student's t-test or Mann-Whitney U test was performed as appropriate. RESULTS: Of 134 patients, 61 suffered their cardiac arrest during winter, with an outside temperature below 10 degrees C; in 39 patients the event occurred during summer, with an outside temperature above 20 degrees C. Comparing the tympanic temperature recorded at hospital admission, the median of 36 degrees C (IQR 35.3-36.3) during summer differed significantly to winter with a median of 34.9 degrees C (IQR 34-35.6) (p<0.05). This seasonal alterations in core body temperature had no impact on the time-to-target-temperature, survival rate or neurologic recovery. CONCLUSION: The seasonal variability of outside temperature influences body temperature of out-of hospital cardiac arrest victims. PMID- 23022436 TI - Meditation-related increases in GABAB modulated cortical inhibition. AB - BACKGROUND: Recent reports suggest meditation practice improves attentional performance and emotional regulation. The process of meditation apparently increases activation in the prefrontal cortex (PFC) and stimulates the reticular nucleus of the thalamus, implicating the production and delivery of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABAergic inhibitory interneurons have a central role in cortical inhibition (CI), modulating cortical excitability and neural plasticity. OBJECTIVE/HYPOTHESIS: Changes in CI, after completion of a single meditation session, were investigated and compared to a non-meditating control activity. METHODS: Transcranial magnetic stimulation (TMS), a non-invasive method of examining CI, was used to evaluate changes before and after a 60 min meditation session. Seventy right-handed healthy subjects (n = 35 meditators, n = 35 non-meditators) were assessed using TMS related measures of cortical silent period (CSP) and short intra cortical inhibition (SICI), with stimulation of the motor cortex coordinated with EMG recording of peripheral hand muscles. RESULTS: For the meditators, CSP and SICI were measured before and after meditation sessions while age-sex matched healthy control subjects were identically assessed after a non-meditating activity (television watching). The meditators showed a statistically significant increase in CSP after meditation compared to non-meditators after an equivalent period of television watching (P = 0.02) while no significant between-group differences were observed in the SICI. CONCLUSION: These findings indicate meditation processes are linked to GABAergic cortical inhibition, a mechanism previously implicated in improved cognitive performance and enhanced emotional regulation. PMID- 23022437 TI - SAP97 promotes the stability of Nax channels at the plasma membrane. AB - Na(x) is a sodium-level sensor for body fluids expressed in the circumventricular organs in the brain. Na(x) has a putative PSD-95/Disc-large/ZO-1 (PDZ)-binding motif at the carboxyl (C)-terminus. Here we found that several PDZ proteins bind to Na(x) by PDZ-array overlay assay. Among them, synapse-associated protein 97 (SAP97/DLG1) was coexpressed with Na(x) in the subfornical organ. In C6 glioblastoma cells, destruction of the PDZ-binding motif of Na(x) or depletion of SAP97 resulted in a decrease in cell-surface Na(x), which was attenuated with inhibitors of endocytosis. These results indicate that SAP97 contributes to the stabilization of Na(x) channels at the plasma membrane. PMID- 23022438 TI - [NiFe]-hydrogenase maturation: isolation of a HypC-HypD complex carrying diatomic CO and CN- ligands. AB - The HypC and HypD maturases are required for the biosynthesis of the Fe(CN)(2)CO cofactor in the large subunit of [NiFe]-hydrogenases. Using infrared spectroscopy we demonstrate that an anaerobically purified, Strep-tagged HypCD complex from Escherichia coli exhibits absorption bands characteristic of diatomic CO and CN( ) ligands as well as CO(2). Metal and sulphide analyses revealed that along with the [4Fe-4S](2+) cluster in HypD, the complex has two additional oxygen-labile Fe ions. We prove that HypD cysteine 41 is required for the coordination of all three ligands. These findings suggest that the HypCD complex carries minimally the Fe(CN)(2)CO cofactor. PMID- 23022440 TI - Optoelectronic plethysmography compared to spirometry during maximal exercise. AB - The purpose of this study was to compare simultaneous measurements of tidal volume (Vt) by optoelectronic plethysmography (OEP) and spirometry during a maximal cycling exercise test to quantify possible differences between methods. Vt measured simultaneously by OEP and spirometry was collected during a maximal exercise test in thirty healthy participants. The two methods were compared by linear regression and Bland-Altman analysis at submaximal and maximal exercise. The average difference between the two methods and the mean percentage discrepancy were calculated. Submaximal exercise (SM) and maximal exercise (M) Vt measured by OEP and spirometry had very good correlation, SM R=0.963 (p<0.001), M R=0.982 (p<0.001) and high degree of common variance, SM R(2)=0.928, M R(2)=0.983. Bland-Altman analysis demonstrated that during SM, OEP could measure exercise Vt as much as 0.134 L above and -0.025 L below that of spirometry. OEP could measure exercise Vt as much as 0.188 L above and -0.017 L below that of spirometry. The discrepancy between measurements was -2.0 +/- 7.2% at SM and -2.4 +/- 3.9% at M. In conclusion, Vt measurements at during exercise by OEP and spirometry are closely correlated and the difference between measurements was insignificant. PMID- 23022439 TI - Glutathione- and glutaredoxin-dependent reduction of methionine sulfoxide reductase A. AB - A natural fusion occurring between two tandemly repeated glutaredoxin (Grx) modules and a methionine sulfoxide reductase A (MsrA) has been detected in Gracilaria gracilis. Using an in vivo yeast complementation assay and in vitro activity measurements, we demonstrated that this fusion enzyme was able to reduce methionine sulfoxide into methionine using glutathione as a reductant. Consistently, a poplar cytosolic MsrA can be regenerated in vitro by glutaredoxins with an efficiency comparable to that of thioredoxins, but using a different mechanism. We hypothesize that the glutathione/glutaredoxin system could constitute an evolutionary conserved alternative regeneration system for MsrA. PMID- 23022441 TI - Recent advances and contraversies on the role of pulmonary neuroepithelial bodies as airway sensors. AB - Pulmonary neuroepithelial bodies are polymodal sensors widely distributed within the airway mucosa of mammals and other species. Neuroepithelial body cells store and most likely release serotonin and peptides as transmitters. Neuroepithelial bodies have a complex innervation that includes vagal sensory afferent fibers and dorsal root ganglion fibers. Neuroepithelial body cells respond to a number of intraluminal airway stimuli, including hypoxia, hypercarbia, and mechanical stretch. This article reviews recent findings in the cellular and molecular biology of neuroepithelial body cells and their potential role as airway sensors involved in the control of respiration, particularly during the perinatal period. Alternate hypotheses and areas of controversy regarding potential function as mechanosensory receptors involved in pulmonary reflexes are discussed. PMID- 23022442 TI - Evaluation of tyramide solutions for an improved detection and enumeration of single microbial cells in soil by CARD-FISH. AB - Several tyramide solutions were evaluated for the application of fluorescence in situ hybridization with catalyzed reporter deposition (CARD-FISH) in soil. Fluorescently labeled tyramide solutions were synthesized and compared to commercially available tyramides for the detection and quantification of single microbial cells. Among the tyramide solutions tested, a succinimidyl ester of fluorescein diluted with dimethylformamide containing iodophenolboronic acid (SFX DMF-IPBA) gave the best results, yielding highly reproducible cell numbers and detection rates of archaea and bacteria along with negligible non-specific signals. The addition of organic and inorganic compounds to the amplification reagents had a positive impact on the detection of prokaryotic cells. The applicability of SFX-DMF-IPBA for CARD-FISH in soil was further evaluated in soils of different texture. Cell numbers and detection rates of bacteria and archaea remained on a high level independent of the clay or organic matter content. Based on the results obtained in this study, the choice of the tyramide solution used for CARD-FISH has a significant influence on the detection and quantification of single microbial cells in soil. Therefore, we suggest the application of the presented tyramide signal amplification procedure including the tyramide solution SFX-DMF-IPBA for comprehensive CARD-FISH studies investigating the abundance and spatial distribution of soil microorganisms. PMID- 23022443 TI - Development of a custom 16S rRNA gene library for the identification and molecular subtyping of Salmonella enterica. AB - The use of 16S rRNA gene sequencing within the regulatory workflow may help to reduce the time and labor involved in the identification and differentiation of Salmonella enterica isolates. However, a comprehensive, standardized reference library is needed in order to use this method with regulatory samples. The goal of this project was to acquire 16S rRNA partial and full gene sequences for a variety of S. enterica isolates and to use these sequences to build a custom 16S rRNA reference library. A total of 535 S. enterica isolates representing over 100 serotypes and 5 subspecies were selected for 16S rRNA partial gene sequencing (~500 bp) and 66 isolates representing 32 serotypes and 2 subspecies were selected for 16S rRNA full gene sequencing (~1500 bp). PCR, sequencing, and automated sequence assembly and editing were carried out using the MicroSEQ ID Microbial Identification System (Applied Biosystems). High quality sequences were obtained for 94.4% and 95.5% of the isolates sequenced over the partial and full genes, respectively. These sequences did not show sufficient divergence to reliably differentiate serotypes; however, they could be differentiated using 16S rRNA sequence typing based on intragenomic heterogeneity. A total of 83 unique 16S sequence types were obtained for use in the partial gene library and 58 unique 16S sequence types were obtained for entry into the full gene library. Preliminary sequencing results with one isolate analyzed in replicate were promising, with consistent matches to a specific 16S type in the custom library. The result of this study is a custom S. enterica 16S rRNA type library for potential use in the identification of isolates at the species, subspecies, and molecular subtype level. Further work will include validating the method for parameters such as exclusivity, sensitivity, and reproducibility. PMID- 23022444 TI - Simultaneous measurements of oxygen and carbon dioxide fluxes to assess productivity in phytoplankton cultures. AB - We validate a method that simultaneously measures O(2) and CO(2) fluxes by sampling headspace air in phytoplankton cultures. Fluxes were strongly correlated to traditional productivity measures, except for a taxon with unique C metabolism. The method provides accurate, real-time, non-destructive measurements and is recommended for laboratory studies of phytoplankton physiology. PMID- 23022445 TI - Rapid screening of an ordered fosmid library to clone multiple polyketide synthase genes of the phytopathogenic fungus Cladosporium phlei. AB - In previous studies, the biological characteristics of the fungus Cladosporium phlei and its genetic manipulation by transformation were assessed to improve production of the fungal pigment, phleichrome, which is a fungal perylenequinone that plays an important role in the production of a photodynamic therapeutic agent. However, the low production of this metabolite by the wild-type strain has limited its application. Thus, we attempted to clone and characterize the genes that encode polyketide synthases (PKS), which are responsible for the synthesis of fungal pigments such as perylenequinones including phleichrome, elsinochrome and cercosporin. Thus, we performed genomic DNA PCR using 11 different combinations of degenerate primers targeting conserved domains including beta ketoacyl synthase and acyltransferase domains. Sequence comparison of the PCR amplicons revealed a high homology to known PKSs, and four different PKS genes showing a high similarity to three representative types of PKS genes were amplified. To obtain full-length PKS genes, an ordered gene library of a phleichrome-producing C. phlei strain (ATCC 36193) was constructed in a fosmid vector and 4800 clones were analyzed using a simple pyramidal arrangement system. This hierarchical clustering method combines the efficiency of PCR with enhanced specificity. Among the three representative types of PKSs, two reducing, one partially reducing, and one non-reducing PKS were identified. These genes were subsequently cloned, sequenced, and characterized. Biological characterization of these genes to determine their roles in phleichrome production is underway, with the ultimate aim of engineering this pathway to overproduce the desired substance. PMID- 23022446 TI - Genome-wide analytical approaches using semi-quantitative expression proteomics for aromatic hydrocarbon metabolism in Pseudomonas putida F1. AB - Pseudomonas putida F1 can degrade aromatic hydrocarbons to intermediate products of the tricarboxylic acid cycle. To determine key induced proteins and enzymes required for degradation of toluene, ethylbenzene, benzene, p-cymene, and p cumate, we performed comprehensive proteome analysis using a combination of 1-D SDS-PAGE and LC-MS/MS in cells grown in the presence of each aromatic hydrocarbon. Semi-quantitative analysis using protein content calculated from the exponentially modified protein abundance index (emPAI) was performed for each proteome data set, and the resulting data were compared. Of 5250 known proteins in P. putida F1, 1733-2368 expressed proteins were identified. All of the key enzymes in the degradation pathways were identified. Additionally, the proteins induced by the aromatic hydrocarbons, regulators, and transporters were also found. Using K-means clustering analysis of the proteome data sets, substrate specific induced proteins were characterized, ranging from 62 to 164 in number. The functions of most of these proteins were not unknown in relation to the metabolism of aromatic hydrocarbons. These results suggest that the approaches used here are ideal as a primary investigation of the various physiological characteristics of bacterial cells. PMID- 23022447 TI - Evaluation of six commercial DNA extraction kits for recovery of Burkholderia pseudomallei DNA. AB - Six commercially available DNA extraction kits, as well as thermal lysis and proteinase K DNA extraction were evaluated regarding bacterial inactivation, DNA yield and purity, and their use in a Burkholderia pseudomallei real-time PCR. While all methods successfully inactivated the bacteria, by measuring DNA purity and the level of detection by real-time PCR, the proteinase K method was the most sensitive. PMID- 23022448 TI - Effects of maternal cigarette smoking during pregnancy on cognitive parameters of children and young adults: a literature review. AB - The long term effects of maternal smoking during pregnancy on the cognitive development of the child are not well understood due to conflicting findings in past research. The aim of this paper was to provide an up to date, critical review of the literature to determine whether there is evidence of a relationship between tobacco smoke exposure in utero and cognitive functioning. We systematically reviewed observational studies (dated 2000-2011) that examined associations between tobacco smoke exposure in utero due to maternal smoking and performance on cognitive, intelligence, neurodevelopmental and academic tests. Eligible studies were identified through searches of Web of Knowledge, Medline, Science Direct, Google Scholar, CINAHL, EMBASE, Zetoc and Clinicaltrials.gov databases. The review found evidence of a relationship between tobacco smoke exposure in utero and reduced academic achievement and cognitive abilities independent of other variables. Maternal smoking during pregnancy may therefore be a modifiable risk factor for reduced cognitive abilities later in the life of the child. Giving up smoking during pregnancy should be initiated as early as possible to reduce the impact on the child's cognitive development. PMID- 23022449 TI - Primary biliary cirrhosis in Southern Israel: a 20 year follow up study. AB - BACKGROUND: The epidemiology of primary biliary cirrhosis (PBC) in Israel is unknown. We aimed to determine the epidemiology, long-term survival and outcomes of PBC in Southern Israel from 1990 to 2010. METHODS: Case-finding methods and population-based administrative data were used to estimate and evaluate the incidence, prevalence and prognostic factors of outcome in our PBC cohort. RESULTS: 138 cases of PBC were identified. The average annual prevalence of PBC was 255 cases per million. The overall age/sex-adjusted annual incidence of PBC was 10 cases per million from 1990 through 1999 and 20 cases per million from 2000 to 2010. Among 138 incident cases with a total follow-up of 960 persons years from diagnosis, 30 patients (21.7%) died. Survival in PBC patients was significantly lower than that of the age/sex-matched Israeli population. Mortality was significantly increased in patients with an initial MELD score greater than 8 (P<0.001), with portal hypertension (P<0.001), and in non responders to ursodeoxycholic acid (UDCA) therapy according to Barcelona criteria (P=0.005). Out of 138 patients, 95 patients (68.0%) responded to UDCA therapy according to Barcelona and Paris criteria. None of the responders died during the follow-up period as opposed to 30 out of 43 (69.8%) of non-responders. In multivariate analysis the factors associated with response to UDCA were: albumin levels above 3.5 g/dL (P<0.001) and lower degree of fibrosis per liver biopsy (P=0.003). CONCLUSIONS: This study addresses the increasing burden of PBC in Israel and confirms the importance of some clinical and therapeutic factors as predictors of long-term prognosis. PMID- 23022450 TI - Comparing the lower limb tasks questionnaire to the Western Ontario and McMaster Universities Osteoarthritis Index: agreement, responsiveness, and convergence with physical performance for knee osteoarthritis patients. AB - OBJECTIVE: To compare the Lower Limb Tasks Questionnaire (LLTQ) with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in terms of agreement, responsiveness, and convergence. DESIGN: Cross-sectional with an exploratory repeated-measures subsample analysis. SETTING: Community-based seniors' centers and arthritis clinics. PARTICIPANTS: Individuals with symptomatic knee osteoarthritis (N=76) participated, with a subsample of 18 participants contributing to the pre- and postarthroplasty subanalysis. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Bland and Altman plots of agreement with 95% limits of agreement, statistical responsiveness, and standardized response mean (SRM) were calculated for LLTQ and WOMAC subscales. Both t tests and Wilcoxon rank-sum tests were used to examine changes in pre- and postarthroplasty self-reported function, 50-ft walk speed, stair ascent/descent speed, and isometric quadriceps strength. RESULTS: The agreement (bias) of the LLTQ activities of daily living (ADL) subscale when compared with the WOMAC physical function (PF) subscale was 1%+/-10% (mean +/- SD), and the 95% limits of agreement were -19% to +22%. The statistical responsiveness of the WOMAC-PF and LLTQ ADL was 1.17 and -.63, respectively. The SRMs for these scales were .90 and .61, respectively. The WOMAC-PF scores showed a notable improvement over the first 6 weeks postarthroplasty, while LLTQ ADL scores were unchanged. The objective measures of function were all significantly worse at 6 weeks. CONCLUSIONS: The LLTQ demonstrated adequate agreement with the WOMAC and acceptable responsiveness for use in place of the WOMAC in nonspecialized clinics. The LLTQ may more accurately represent functional status after total knee arthroplasty, but further study in larger samples is recommended. PMID- 23022451 TI - Preliminary examination of the relation between participation and confidence in older manual wheelchair users. AB - OBJECTIVE: To examine the relation between frequency of participation and confidence with using a manual wheelchair among community-living, older wheelchair users, and the moderating effect of sex. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: Participants (N=54) who were community-living manual wheelchair users (65% men), were >=50 years of age (mean, 59y), used their wheelchair daily, and had >=6 months experience using a wheelchair. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The 16-item Late Life Disability Instrument and the 65-item Wheelchair Use Confidence Scale measured participation and confidence, respectively. Age, sex, and wheelchair skill measured using the performance-based Wheelchair Skills Test were included as covariates in the multiple regression models. RESULTS: Significant and positive relations exist between participation and (1) confidence (beta=.83, P=.002) and (2) interaction term (beta=.33, P=.05). The R(2) change associated with confidence was 10% (P=.02), and 6% (P=.05) for the interaction term. Subsequent regression analyses revealed that the magnitude of the relation between higher confidence and greater participation is stronger for men (beta=1.05, P=.002) than for women (beta=.44, P=.05). CONCLUSIONS: Confidence with using a manual wheelchair is a positive and significant determinant of frequency of participation of older wheelchair users, after controlling for important covariates. Because the relation is moderated by sex, treatments addressing low confidence may lead to increased frequency of participation, especially for wheelchair users who are men. PMID- 23022452 TI - Phagocytic and oxidative burst activity of neutrophils in patients with spinal cord injury. AB - OBJECTIVE: To evaluate phagocytic activity and neutrophil oxidative burst functions in patients with spinal cord injury (SCI) because alterations in neutrophil metabolic activity can be one of the causes of immune mechanism damage contributing to repeated bacterial infections. DESIGN: A controlled and cross sectional study. SETTING: Departments of physical medicine and rehabilitation and immunology. PARTICIPANTS: Patients with SCI (N=34) and 28 healthy controls. INTERVENTIONS: Phagocytosis and oxidative burst in whole-blood neutrophils were assessed by flow cytometry. The percentage of phagocytizing cells after in vitro incubation with Escherichia coli, phagocytic activity (mean intensity of fluorescence [MIF]) and the percentage of neutrophiloxidative burst, and the MIF value of the production of reactive oxygen intermediates (ROIs) were analyzed. In addition, clinical assessment including the level of injury, American Spinal Injury Association scores, and functional status were carried out. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Although the percentage of E. coli phagocytizing neutrophils was not different between groups, the MIF value of absorbed E. coli was significantly lower in patients with SCI than in controls (P<.05). The MIF value of ROI production by neutrophils with both stimulator of phorbol 12-myristate 13-acetate and E. coli was significantly higher in patients with SCI (P<.05). CONCLUSIONS: In patients with SCI, decreased phagocytic activity of neutrophils may be a result of a regulatory mechanism to minimize the deleterious effects of increased neutrophil burst activity. PMID- 23022453 TI - Metabolic responses to recombinant bioprocesses in Escherichia coli. AB - Escherichia coli has been widely used for the production of recombinant proteins. However, the unbalances between host metabolism and recombinant biosynthesis continue to hamper the efficiency of these recombinant bioprocesses. The additional drainage of biosynthetic precursors toward recombinant processes burdens severely the metabolism of cells that, ultimately, elicits a series of stress responses, reducing biomass growth and recombinant protein production. Several strategies to overcome these metabolic limitations have been implemented; however, in most cases, improvements in recombinant protein expression were achieved at the expense of biomass growth arrest, which significantly hampers the efficiency of recombinant bioprocesses. With the advent of high throughput techniques and modelling approaches that provide a system-level understanding of the cellular systems, it is now expected that new advances in recombinant bioprocesses are achieved. By providing means to deal with these systems, our understanding on the metabolic behaviour of recombinant cells will advance and can be further explored to the design of suitable hosts and more efficient and cost-effective bioprocesses. Here, we review the major metabolic responses associated with recombinant processes and the engineering strategies relevant to overcome these stresses. Moreover, the advantages of applying systems levels engineering strategies to enhance recombinant protein production in E. coli cells are discussed and future perspectives on the advances of mathematical modelling approaches to study these systems are exposed. PMID- 23022455 TI - Regional MeCP2 expression levels in the female MeCP2-deficient mouse brain correlate with specific behavioral impairments. AB - Using female MeCP2-deficient mice as a model, we tested whether MeCP2 expression levels would parallel one another in different regions of the brain and spinal cord, and/or whether the levels of MeCP2 protein in these specific neural regions would correlate with the degree of behavioral impairment seen in individual subjects. Our results show that MeCP2 protein levels are not uniform across different regions of the mosaic brain, and that the relative MeCP2 levels in one region did not necessarily predict its expression levels in other regions of the same mouse. Correlational analysis between region-specific MeCP2 expression levels and the degree of impairment exhibited by mice in specific behavioral tests revealed significant associations. Cortical MeCP2 expression was significantly correlated with general symptomatic severity and daily EEG delta power patterning. Hippocampal MeCP2 expression was significantly correlated with exploratory activity behaviors, anxiety-like behaviors, and epileptiform discharge rates, whereas cerebellar and spinal cord MeCP2 expression levels correlated only with daily EEG delta power patterning. Collectively, our results show that MeCP2 protein expression in female MeCP2-deficient mice is not uniform throughout specific brain regions, and indicate that specific behavioral deficits in these mice may correlate with the region-specific expression levels of the functional MeCP2 allele. PMID- 23022454 TI - Moderate traumatic brain injury promotes neural precursor proliferation without increasing neurogenesis in the adult hippocampus. AB - Traumatic brain injury (TBI) promotes neural stem/progenitor cell (NSC) proliferation in the adult hippocampus; however, it remains inconclusive whether proliferation of these cells results in newly generated mature neurons, leading to increased neurogenesis. When we traced the fates of proliferating cells labeled with bromodeoxyuridine (5-bromo-2-deoxyuridine, BrdU) we found that the number of BrdU-positive cells increased in the hippocampus of TBI mice compared to the sham control. However, double immunostaining to distinguish their cell types showed that most of these cells were glia, and that only a small subpopulation is newborn granular neurons. There was no significant difference with respect to neurogenesis in the adult hippocampus between the injured and the control mice. These results indicate that TBI promotes cell proliferation including astrocyte activation and NSC proliferation. Nevertheless, the majority of the BrdU-positive cells are glia. The neurogenesis is not increased by TBI. These data suggest that TBI activates through promotion of NSC proliferation an innate repair and/or plasticity mechanism in the brain. However, additional intervention is required to increase neurogenesis for successfully repairing the damaged brain following TBI. PMID- 23022456 TI - Neuropeptide Y and its role in CNS disease and repair. AB - Neuropeptide Y (NPY) is widely expressed throughout the CNS and exerts a number of important physiological functions as well as playing a role in pathological conditions such as obesity, anxiety, epilepsy, chronic pain and neurodegenerative disorders. In this review, we highlight some of the recent advances in our understanding of NPY biology and how this may help explain not only its role in health and disease, but also its possible use therapeutically. PMID- 23022457 TI - TAK1 inhibition for treatment of cerebral ischemia. AB - TGFbeta-activated kinase 1 (TAK1), a MAP3 kinase, is involved in at least five signaling cascades that modulate ischemic brain damage. Inhibition of TAK1 may therefore be an efficient way to interfere with multiple mechanisms in ischemic stroke. Indeed, a recent publication in Experimental Neurology confirmed that TAK1 inhibition by 5Z-7-oxozeaenol is neuroprotective. The beneficial effect of 5Z-7-oxozeaenol was associated with a reduced activation of Jun kinase that leads to inflammation and apoptosis. Recently, other TAK1 inhibitors were developed suggesting that TAK1 may prove as an efficient therapeutic target for neurodegenerative diseases if safety issues are not limiting. PMID- 23022458 TI - The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants. AB - The expanding number of disease-causing dysfunctions of synaptic proteins illustrates the importance of investigating newly discovered proteins involved in neuronal transmission. The gene Slc10A4 encodes a recently described carrier protein present in pre-synaptic terminals of cholinergic and monoaminergic neurons. The biological significance of this recently described transporter protein is currently unknown. We here investigated whether absence of the Slc10a4 protein has any impact on function of the cholinergic system. We first investigated the sensitivity of Slc10a4 null mice to cholinergic stimulus in vitro. In contrast to wild type mice, gamma oscillations occurred spontaneously in hippocampal slices from Slc10a4 null mice. Furthermore, moderate treatment of Slc10a4 null slices with the cholinergic agonist carbachol induced epileptiform activity. In vivo, 3-channel EEG measurements in freely behaving mice revealed that Slc10a4 null mice had frequent epileptiform spike-activity before treatment, and developed epileptic seizures, detected by EEG and accompanied by observable behavioral components, more rapidly after injection of the cholinergic agonist pilocarpine. Similar results were obtained on non-operated mice, as evaluated by behavioral seizures and post mortem c-Fos immunohistochemistry. Importantly, Slc10a4 null mice and wild type control mice were equally sensitive to the glutamatergic chemoconvulsant kainic acid, demonstrating that absence of Slc10a4 led to a selective cholinergic hypersensitivity. In summary, we report that absence of the recently discovered synaptic vesicle protein Slc10a4 results in increased sensitivity to cholinergic stimulation. PMID- 23022459 TI - ErbB1 epidermal growth factor receptor is a valid target for reducing the effects of multiple inhibitors of axonal regeneration. AB - Pharmacological inhibitors of epidermal growth factor receptor (ErbB1) attenuate the ability of CNS myelin to inhibit axonal regeneration. However, it has been claimed that such effects are mediated by off-target interactions. We have tested the role of ErbB1 in axonal regeneration by culturing neurons from ErbB1 knockout mice in the presence of various inhibitors of axonal regeneration: CNS myelin, chondroitin sulfate proteoglycans (CSPG), fibrinogen or polyinosinic:polycytidylic acid (poly I:C). We confirmed that ErbB1 was activated in cultures of cerebellar granule cells exposed to inhibitors of axonal regeneration and that ErbB1 kinase inhibitors promoted neurite outgrowth under these conditions. In the presence of myelin, fibrinogen, CSPG and poly I:C ErbB1 /- neurons grew longer neurites than neurons expressing ErbB1. Furthermore, inhibitors of ErbB1 kinase did not improve neurite outgrowth from ErbB1 -/- neurons, ruling out an off-target mechanism of action. ErbB1 kinase activity is therefore a valid target for promoting axonal elongation in the presence of many of the molecules believed to contribute to the failure of axonal regeneration in the injured CNS. PMID- 23022461 TI - Systematic review on factors associated with medication non-adherence in Parkinson's disease. AB - BACKGROUND: Medication non-adherence is prevalent in Parkinson's disease (PD) and results in substantial motor dysfunction. Although various approaches have been suggested to address non-adherence in PD, good quality evidence of associated factors is limited. OBJECTIVE: To systematically review the literature on clinical and demographic factors associated with medication non-adherence in PD. METHODS: We searched five online databases in April 2011 (updated in January 2012): MEDLINE, EMBASE, AMED, PsycINFO and CINAHL for studies reporting data on factors associated with medication non-adherence in people with idiopathic PD. Bibliographies were hand searched to acquire records not identified electronically. Two reviewers independently assessed identified articles for potential inclusion. Data extraction was undertaken using a standardised data extraction form. Methodological quality was assessed against a specially designed quality indicator tool emphasising the detection of threats to internal validity. RESULTS: We identified 1880 records of which six met inclusion criteria. A total of 772 PD patients were included (mean age 62 years, males 61%). We identified eleven factors (six clinical and five demographic) associated with non-adherence. We ranked each factor in order by weight of overall evidence: mood disorders, cognition, poor symptom control/QoL, younger age/longer disease duration, regimen complexity/polypharmacy, risk taking behaviours, poor knowledge of PD/education, lack of spouse/partner, low income, maintaining employment and gender. CONCLUSION: Clinicians should be aware of factors associated with medication non adherence in PD. Targeted interventions should be developed and investigated to establish if addressing factors associated with non-adherence in PD leads to greater medication adherence. PMID- 23022460 TI - Exogenous BDNF enhances the integration of chronically injured axons that regenerate through a peripheral nerve grafted into a chondroitinase-treated spinal cord injury site. AB - Although axons lose some of their intrinsic capacity for growth after their developmental period, some axons retain the potential for regrowth after injury. When provided with a growth-promoting substrate such as a peripheral nerve graft (PNG), severed axons regenerate into and through the graft; however, they stop when they reach the glial scar at the distal graft-host interface that is rich with inhibitory chondroitin sulfate proteoglycans. We previously showed that treatment of a spinal cord injury site with chondroitinase (ChABC) allows axons within the graft to traverse the scar and reinnervate spinal cord, where they form functional synapses. While this improvement in outgrowth was significant, it still represented only a small percentage (<20%) of axons compared to the total number of axons that regenerated into the PNG. Here we tested whether providing exogenous brain-derived neurotrophic factor (BDNF) via lentivirus in tissue distal to the PNG would augment regeneration beyond a ChABC-treated glial interface. We found that ChABC treatment alone promoted axonal regeneration but combining ChABC with BDNF-lentivirus did not increase the number of axons that regenerated back into spinal cord. Combining BDNF with ChABC did increase the number of spinal cord neurons that were trans-synaptically activated during electrical stimulation of the graft, as indicated by c-Fos expression, suggesting that BDNF overexpression improved the functional significance of axons that did reinnervate distal spinal cord tissue. PMID- 23022462 TI - Clinical and epidemiological features of Chryseobacterium indologenes infections: analysis of 215 cases. AB - PURPOSE: This study investigates the clinical and epidemiological features of Chryseobacterium indologenes infections and antimicrobial susceptibilities of C indologenes. METHODS: With 215 C indologenes isolates between January 1, 2004 and September 30, 2011, at a medical center, we analyzed the relationship between the prevalence of C indologenes infections and total prescription of colistin and tigecycline, clinical manifestation, antibiotic susceptibility, and outcomes. RESULTS: Colistin and tigecycline were introduced into clinical use at this medical center since August 2006. The increasing numbers of patients with C indologenes pneumonia and bacteremia correlated to increased consumption of colistin (p = 0.018) or tigecycline (p = 0.049). Among patients with bacteremia and pneumonia, the in-hospital mortality rate was 63.6% and 35.2% (p = 0.015), respectively. Administration of appropriate antibiotics showed significant benefit in 14-day survival in patients with C indologenes bloodstream infection (p = 0.040). In bacteremic patients, old cardiovascular accident (p = 0.036) and cancer (p = 0.014) were the most common comorbidity. The most common co-infection pathogen in patients with C indologenes pneumonia was Acinetobacter baumannii (36/91, 39.6%), followed by Pseudomonas aeruginosa (23/91, 25.3%), carbapenem resistant A baumannii (22/91, 24.2%), and Klebseilla pneumoniae (13/91, 14.3%). Antimicrobial susceptibility testing of the 215 isolates showed that trimethoprim sulfamethoxazole was the most active agent (susceptibility rate: 87.4%), followed by cefoperazone-sulbactam (48.0%). CONCLUSION: The present study showed a trend of increasing prevalence of C indologenes infection after introduction of colistin and tigecycline usage. The bacteremia group had higher mortality rate than the pneumonia group. Increasing resistance to piperacillin-tazobactam, ceftazidime, cefepime, and newer fluoroquinolone were noticed in our analysis. Trimethoprim-sulfamethoxazole was a potential antimicrobial agent in vitro for C indologenes. To avoid collateral damage, we emphasize the importance of antibiotic stewardship program. PMID- 23022463 TI - Clinical features of different genotypes/genogroups of human metapneumovirus in hospitalized children. AB - BACKGROUND/PURPOSE(S): To explore the clinical features of different human metapneumovirus (hMPV) genotypes/genogroups in hospitalized children. METHODS: From January 2005 to April 2010, 3313 children's respiratory specimens sent for the detection of respiratory syncytial virus antigen were also tested for hMPV by real time-polymerase chain reaction. Demographics, clinical presentations, and laboratory findings of patients infected with different genotypes/genogroups of hMPV were compared. RESULTS: A total of 725 samples were positive for hMPV (positive rate, 23%). The F gene was sequenced for 279 isolates; of these, genotype A was identified in 51% (A1, 6.1%; A2, 45%) and genotype B in 49% (B1, 19%; B2, 30%). Medical records of 152 hospitalized children were reviewed. Co infection with other pathogens was 25.7% (39/152). Excluding co-pathogens other than respiratory syncytial virus, a total of 124 children were analyzed. The most common symptoms included cough, fever, rhinorrhea, wheezing and respiratory distress with accessory muscle usage. The main diagnosis was bronchiolitis. The most common chest radiographic findings were increased perihilar infiltrates. No significant difference was found in terms of demographics, clinical manifestations, and laboratory findings among the children infected with different serogroups of hMPV. CONCLUSION: hMPV accounted for a substantial proportion of hospitalized children with lower respiratory tract infection with a high co-infection rate. The A2 subgroup was the most frequently observed, followed by B2. No significant difference was found among patients infected with different genotypes/genogroups of hMPV in terms of clinical manifestations. PMID- 23022464 TI - The Madin-Darby canine kidney cell culture derived influenza A/H5N1 vaccine: a phase I trial in Taiwan. AB - BACKGROUND: Avian H5N1 influenza has caused human infections globally and has a high mortality rate. Rapid production of effective vaccines is needed. METHODS: A phase 1, randomized, observer-blinded clinical trial was conducted to examine the safety and immunogenicity of an inactivated whole virion vaccine against the influenza A/H5N1 virus produced from the Madin-Darby canine kidney (MDCK) cell line. Participants were randomized to four groups and administered two intramuscular doses of vaccine containing 3 MUg hemagglutinin (HA), 3 MUg HA with 300 MUg aluminum phosphate (AlPO4), 6 MUg HA, and 6 MUg HA with 300 MUg AlPO4, respectively, at two visits, 21 days apart. Serum hemagglutination inhibition (HAI) and neutralizing antibody levels were determined at baseline and on Days 21 and 42. RESULTS: Sixty healthy individuals were enrolled. The neutralization assay showed a significant immune response in the 6 MUg with ALPO4 group on Day 42 compared to pre-vaccination levels (11.32+/-9.77 vs. 4.00+/-0, p=0.02). The adjuvant effect in neutralization assay was also significant on Day 42 in the 6 MUg group (4.52+/-1.94 without adjuvant vs. 11.32+/-9.77 with adjuvant, p=0.02). HAI assay also showed an aluminum adjuvant-induced increasing trend in HAI geometric mean titer on Day 42 in the 3 MUg and 6 MUg groups (6.02 versus 8.20, p=0.05 and 5.74 versus 8.21, p=0.14). The most frequent adverse event was local pain (20% to 60%). There were no vaccine-related severe adverse effects. CONCLUSION: MDCK cell line-derived H5N1 vaccine was well tolerated. It is necessary to investigate further the immunogenicity of higher antigen doses and the role of aluminum adjuvant in augmenting the effect of the vaccine. PMID- 23022465 TI - Is graft-versus-leukemia more effective using reduced-intensity conditioning compared with myeloablative conditioning? PMID- 23022466 TI - Haploidentical transplantation: repurposing cyclophosphamide. PMID- 23022469 TI - "Certainty" and expert mental health opinions in legal proceedings. AB - This pilot study addresses the legal and scientific ramifications of the "certainty" expressed by mental health professionals when functioning as expert witnesses in criminal and civil proceedings. The sporadic attention paid to "certainty" in the professional literature has typically taken the form of general policy oriented analyses as opposed to empirical, data-driven investigations. In the current study, 25 doctoral and master's level mental health professionals were provided with 53 different statements. Some statements addressed "certainty" itself in the typical fashion (e.g., "Reasonable Degree of Scientific Certainty," "Reasonable Degree of Medical Certainty," and "Reasonable Degree of Psychological Certainty"). Other statements were confined to specifically legal standards of proof (e.g., "Beyond a Reasonable Doubt," "Preponderance of the Evidence," and "Clear and Convincing"). Additional statements included those that bore at least some direct forensic relevance (e.g., "Based upon All the Data at My Disposal," "In My Medical Opinion," and "In My Clinical Judgment"), as well as those of a non-forensic nature (e.g., "I Would Bet My Life Savings," "On My Word of Honor," and "I Am Personally Convinced"). Ratings were provided on one form as if the participant had uttered the statement, and on another form as if another expert witness had uttered the statement. Overall, participants did not tend to identify traditional legal terms as expressing the highest level of "certainty," and respondents tended to ascribe more "certainty" to the same terms when uttered by themselves as opposed to when uttered by other expert witnesses. Those providing forensic testimony will do well to accommodate the court's traditional requirements while developing and preparing to justify their own notions of just what "certainty" denotes in this context. PMID- 23022467 TI - Association of disparities in known minor histocompatibility antigens with relapse-free survival and graft-versus-host disease after allogeneic stem cell transplantation. AB - Allogeneic stem cell transplantation (allo-SCT) can induce remission in patients with hematologic malignancies due to graft-versus-tumor (GVT) responses. This immune-mediated antitumor effect is often accompanied by detrimental graft-versus host disease (GVHD), however. Both GVT and GVHD are mediated by minor histocompatibility antigen (MiHA)-specific T cells recognizing peptide products from polymorphic genes that differ between recipient and donor. In this study, we evaluated whether mismatches in a panel of 17 MiHAs are associated with clinical outcome after partially T cell-depleted allo-SCT. Comprehensive statistical analysis revealed that DNA mismatches for one or more autosomal-encoded MiHAs was associated with increased relapse-free survival in recipients of sibling transplants (P = .04), particularly in those with multiple myeloma (P = .02). Moreover, mismatches for the ubiquitous Y chromosome-derived MiHAs resulted in a higher incidence of acute GVHD grade III-IV (P = .004), whereas autosomal MiHA mismatches, ubiquitous or restricted to hematopoietic cells, were not associated with severe GVHD. Finally, we found considerable differences among MiHAs in their capability of inducing in vivo T cell responses using dual-color tetramer analysis of peripheral blood samples collected after allo-SCT. Importantly, detection of MiHA-specific T cell responses was associated with improved relapse free survival in recipients of sibling transplants (P = .01). Our findings provide a rationale for further boosting GVT immunity toward autosomal MiHAs with a hematopoietic restriction to improve outcomes after HLA-matched allo-SCT. PMID- 23022468 TI - Immune recovery after allogeneic hematopoietic stem cell transplantation: is it time to revisit how patients are monitored? PMID- 23022470 TI - Alterations in the expression of PSA-NCAM and synaptic proteins in the dorsolateral prefrontal cortex of psychiatric disorder patients. AB - Alterations in the structure and physiology of the prefrontal cortex (PFC) have been found in different psychiatric disorders and some of them involve inhibitory networks, especially in schizophrenia and major depression. Changes in the structure of these networks may be mediated by the polysialylated neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity, expressed in the PFC exclusively by interneurons. Different studies have found that PSA-NCAM expression in the hippocampus and the amygdala is altered in schizophrenia, major depression and animal models of these disorders, in parallel to changes in the expression of molecules related to inhibitory neurotransmission and synaptic plasticity. We have analyzed post-mortem sections of the dorsolateral PFC from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients, to check whether similar alterations occur. PSA-NCAM was found in neuronal somata and neuropil puncta, many of which corresponded to interneurons. PSA-NCAM expression was only reduced significantly in schizophrenic patients, in parallel to a decrease in glutamic acid-decarboxylase-67 (GAD67) and to an increased expression of vesicular glutamate transporter 1 (VGLUT1) in the white matter. Depressed patients showed significant decreases in synaptophysin (SYN) and VGLUT1 expression. Whereas in bipolar patients, decreases in VGLUT1 expression have also been found, together with a reduction of GAD67. These results indicate that the expression of synaptic proteins is altered in the PFC of patients suffering from these disorders and that, particularly in schizophrenia, abnormal PSA-NCAM and GAD67 expression may underlie the alterations observed in inhibitory neurotransmission. PMID- 23022471 TI - Motor cortical excitability and inhibition in acquired mirror pain. AB - 'Mirror pain' describes when the observation of another's pain experience induces a personal experience of pain. It has been suggested that mirror pain could result from changes in neural excitability or inhibition. In this study we used transcranial magnetic stimulation (TMS) to investigate motor cortical excitability in lower-limb amputees who experience mirror pain. Using paired pulse TMS to assess motor cortical inhibition (CI) and cortical facilitation (CF), recordings were taken from the right first dorsal interosseus in lower-limb amputees who experience mirror pain (MP+), lower-limb amputees who do not experience mirror pain (MP-), and non-amputee controls. No differences in CI or CF were observed between the MP+ and both control groups. Thus, when not paired with a pain-related stimulus, changes in motor cortical excitability do not appear to contribute to the experience of mirror pain in lower-limb amputees. PMID- 23022472 TI - Baroreceptor-mediated activation of sympathetic nerve activity to salivary glands. AB - Salivary gland function is regulated by both the sympathetic and parasympathetic nervous systems. Previously we showed that the basal sympathetic outflow to the salivary glands (SNA(SG)) was higher in hypertensive compared to normotensive rats and that diabetes reduced SNA(SG) discharge at both strains. In the present study we sought to investigate how SNA(SG) might be modulated by acute changes in the arterial pressure and whether baroreceptors play a functional role upon this modulation. To this end, we measured blood pressure and SNA(SG) discharge in Wistar-Kyoto rats (WKY-intact) and in WKY submitted to sinoaortic denervation (WKY-SAD). We made the following three major observations: (i) in WKY-intact rats, baroreceptor loading in response to intravenous infusion of the phenylephrine evoked an increase in SNA(SG) spike frequency (81%, p<0.01) accompanying the increase mean arterial pressure (DeltaMAP: +77 +/- 14 mmHg); (ii) baroreceptor unloading with sodium nitroprusside infusion elicited a decrease in SNA(SG) spike frequency (17%, p<0.01) in parallel with the fall in arterial blood pressure (DeltaMAP: -30 +/- 3 mmHg) in WKY-intact rats; iii) in the WKY-SAD rats, phenylephrine-evoked rises in the arterial pressure (DeltaMAP: +56 +/- 6 mmHg) failed to produce significant changes in the SNA(SG) spike frequency. Taken together, these data show that SNA(SG) increases in parallel with pharmacological-induced pressor response in a baroreceptor dependent way in anaesthetised rats. Considering the key role of SNA(SG) in salivary secretion, this mechanism, which differs from the classic cardiac baroreflex feedback loop, strongly suggests that baroreceptor signalling plays a decisive role in the regulation of salivary gland function. PMID- 23022473 TI - Blockade of EGFR signaling promotes glioma stem-like cell invasiveness by abolishing ID3-mediated inhibition of p27(KIP1) and MMP3 expression. AB - Aberrant epidermal growth factor receptor (EGFR) signaling is a typical oncogenic signature in glioblastoma. Here, we show that EGFR inhibition in primary glioma stem cells (GSCs) with oncogenic EGFRvIII and EGFRvIII-transduced glioma stem like cells promotes invasion by decreasing ID3 levels. ID3 suppresses GSC invasiveness by inhibiting p27(KIP1)-RhoA-dependent migration and MMP3 expression. Xenograft and human glioblastoma specimens show that ID3 localizes within glioblastoma cores, whereas p27(KIP1) and MMP3 are predominantly expressed in glioma cells in invasive fronts. Together, our findings show that EGFR inhibition induces GSC invasiveness by abolishing ID3-mediated inhibition of p27(KIP1) and MMP3 expression. PMID- 23022474 TI - Cancer genetics and genomics of human FOX family genes. AB - Forkhead-box (FOX) family proteins, involved in cell growth and differentiation as well as embryogenesis and longevity, are DNA-binding proteins regulating transcription and DNA repair. The focus of this review is on the mechanisms of FOX-related human carcinogenesis. FOXA1 is overexpressed as a result of gene amplification in lung cancer, esophageal cancer, ER-positive breast cancer and anaplastic thyroid cancer and is point-mutated in prostate cancer. FOXA1 overexpression in breast cancer and prostate cancer is associated with good or poor prognosis, respectively. Single nucleotide polymorphism (SNP) within the 5' UTR of the FOXE1 (TTF2) gene is associated with thyroid cancer risk. FOXF1 overexpression in breast cancer is associated with epithelial-to-mesenchymal transition (EMT). FOXM1 is overexpressed owing to gene amplification in basal type breast cancer and diffuse large B-cell lymphoma (DLBCL), and it is transcriptionally upregulated owing to Hedgehog-GLI, hypoxia-HIF1alpha or YAP TEAD signaling activation. FOXM1 overexpression leads to malignant phenotypes by directly upregulating CCNB1, AURKB, MYC and SKP2 and indirectly upregulating ZEB1 and ZEB2 via miR-200b downregulation. Tumor suppressor functions of FOXO transcription factors are lost in cancer cells as a result of chromosomal translocation, deletion, miRNA-mediated repression, AKT-mediated cytoplasmic sequestration or ubiquitination-mediated proteasomal degradation. FOXP1 is upregulated as a result of gene fusion or amplification in DLBCL and MALT lymphoma and also repression of miRNAs, such as miR-1, miR-34a and miR-504. FOXP1 overexpression is associated with poor prognosis in DLBCL, gastric MALT lymphoma and hepatocellular carcinoma but with good prognosis in breast cancer. In neuroblastoma, the entire coding region of the FOXR1 (FOXN5) gene is fused to the MLL or the PAFAH1B gene owing to interstitial deletions. FOXR1 fusion genes function as oncogenes that repress transcription of FOXO target genes. Whole genome sequencing data from tens of thousands of human cancers will uncover the mutational landscape of FOX family genes themselves as well as FOX-binding sites, which will be ultimately applied for cancer diagnostics, prognostics, and therapeutics. PMID- 23022475 TI - Improving the efficacy and safety of engineered T cell therapy for cancer. AB - Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a powerful immunotherapeutics approach against metastatic melanoma. The success of TIL therapy has led to novel strategies for redirecting normal T cells to recognize tumor-associated antigens (TAAs) by genetically engineering tumor antigen-specific T cell receptors (TCRs) or chimeric antigen receptor (CAR) genes. In this manner, large numbers of antigen-specific T cells can be rapidly generated compared with the longer term expansion of TILs. Great efforts have been made to improve these approaches. Initial clinical studies have demonstrated that genetically engineered T cells can mediate tumor regression in vivo. In this review, we discuss the development of TCR and CAR gene-engineered T cells and the safety concerns surrounding the use of these T cells in patients. We highlight the importance of judicious selection of TAAs for modified T cell therapy and propose solutions for potential "on-target, off-organ" toxicity. PMID- 23022477 TI - Inter- and intra-session reliability of muscle activity patterns during cycling. AB - The aim of this study was to determine the inter- and intra-session reliability of the temporal and magnitude components of activity in eight muscles considered important for the leg cycling action. On three separate occasions, 13 male non cyclists and 11 male cyclists completed 6 min of cycling at 135, 150, and 165 W. Cyclists completed two additional 6-min bouts at 215 and 265 W. Surface electromyography was used to record the electrical activity of tibialis anterior, soleus, gastrocnemius medialis, gastrocnemius lateralis, vastus medialis, vastus lateralis, rectus femoris, and gluteus maximus. There were no differences (P > 0.05) in the muscle activity onset and offset or in the iEMG of any muscles between visits. There were also no differences (P > 0.05) between cyclists and non-cyclists in the variability of these parameters. Overall, standard error of measurement (SEM) and intra-class correlation analyses suggested similar reliability of both inter- and intra-session muscle activity onset and offset. The SEM of activity onset in tibialis anterior and activity offset in soleus, gastrocnemius lateralis and rectus femoris was markedly higher than in the other muscles. Intra-session iEMG was reliable (coefficient of variation (CV) = 5.3 13.5%, across all muscles), though a CV range of 15.8-43.1% identified low inter session iEMG reliability. During submaximal cycling, the temporal components of muscle activity exhibit similar intra- and inter-session reliability. The magnitude component of muscle activity is reliable on an intra-session basis, but not on an inter-session basis. PMID- 23022476 TI - Functional inactivation of Rb sensitizes cancer cells to TSC2 inactivation induced cell death. AB - We showed previously that inactivation of TSC2 induces death in cancer cells lacking the Retinoblastoma (Rb) tumor suppressor under stress conditions, suggesting that inactivation of TSC2 can potentially be used as an approach to specifically kill cancers that have lost WT Rb. As Rb is often inactivated in cancers by overexpression of cyclin D1, loss of p16(ink4a) cdk inhibitor, or expression of viral oncoproteins, it will be interesting to determine if such functional inactivation of Rb would similarly sensitize cancer cells to TSC2 inactivation induced cell death. In addition, many cancers lack functional Pten, resulting in increased PI3K/Akt signaling that has been shown to modulate E2F induced cell death. Therefore it will be interesting to test whether loss of Pten will affect TSC2 inactivation induced killing of Rb mutant cancer cells. Here, we show that overexpression of Cyclin D1 or the viral oncogene E1a sensitizes cancer cells to TSC2 knockdown induced cell death and growth inhibition. On the other hand, knockdown of p16(ink4a) sensitizes cancer cells to TSC2 knockdown induced cell death in a manner that is likely dependant on serum induction of Cyclin D1 to inactivate the Rb function. Additionally, we demonstrate that loss of Pten does not interfere with TSC2 knockdown induced cell death in Rb mutant cancer cells. Together, these results suggest that TSC2 is potentially a useful target for a large spectrum of cancer types with an inactivated Rb pathway. PMID- 23022478 TI - Natural killer and natural killer T cells in liver fibrosis. AB - The liver lymphocyte population is enriched with natural killer (NK) cells, which play a key role in host defense against viral infection and tumor transformation. Recent evidence from animal models suggests that NK cells also play an important role in inhibiting liver fibrosis by selectively killing early or senescence activated hepatic stellate cells (HSCs) and by producing the anti-fibrotic cytokine IFN-gamma. Furthermore, clinical studies have revealed that human NK cells can kill primary human HSCs and that the ability of NK cells from HCV patients to kill HSCs is enhanced and correlates inversely with the stages of liver fibrosis. IFN-alpha treatment enhances, while other factors (e.g., alcohol, TGF-beta) attenuate, the cytotoxicity of NK cells against HSCs, thereby differentially regulating liver fibrogenesis. In addition, the mouse liver lymphocyte population is also enriched for natural killer T (NKT) cells, whereas human liver lymphocytes have a much lower percentage of NKT cells. Many studies suggest that NKT cells promote liver fibrogenesis by producing pro-fibrotic cytokines such as IL-4, IL-13, hedgehog ligands, and osteopontin; however, NKT cells may also attenuate liver fibrosis under certain conditions by killing HSCs and by producing IFN-gamma. Finally, the potential for NK and NKT cells to be used as therapeutic targets for anti-fibrotic therapy is discussed. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. PMID- 23022479 TI - Binding of methylene blue to a surface cleft inhibits the oligomerization and fibrillization of prion protein. AB - Neurodegenerative protein misfolding diseases, including prionopathies, share the common feature of accumulating specific misfolded proteins, with a molecular mechanism closely related. Misfolded prion protein (PrP) generates soluble oligomers that, in turn, aggregate into amyloid fibers. Preventing the formation of these entities, crucially associated with the neurotoxic and/or infectious properties of the resulting abnormal PrP, represents an attractive therapeutic strategy to ameliorate prionopathies. We focused our attention into methylene blue (MB), a well-characterized drug, which is under study against Alzheimer's disease and other neurodegenerative disorders. Here, we have undertaken an in vitro study on the effects of MB on oligomerization and fibrillization of human, ovine and murine PrP. We demonstrated that MB affects the kinetics of PrP oligomerization and reduces the amount of oligomer of about 30%, in a pH dependent manner, by using SLS and DSC methodologies. Moreover, TEM images showed that MB completely suppresses fiber formation at a PrP:MB molar ratio of 1:2. Finally, NMR revealed a direct interaction between PrP and MB, which was mapped on a surface cleft including a fibrillogenic region of the protein. Our results allowed to surmise a mechanism of action in which the MB binding to PrP surface markedly interferes with the pathway towards oligomers and fibres. Therefore MB could be considered as a general anti-aggregation compound, acting against proteinopathies. PMID- 23022480 TI - Mpn1, mutated in poikiloderma with neutropenia protein 1, is a conserved 3'-to-5' RNA exonuclease processing U6 small nuclear RNA. AB - Clericuzio-type poikiloderma with neutropenia (PN) is a rare genodermatosis associated with mutations in the C16orf57 gene, which codes for the uncharacterized protein hMpn1. We show here that, in both fission yeasts and humans, Mpn1 processes the spliceosomal U6 small nuclear RNA (snRNA) posttranscriptionally. In Mpn1-deficient cells, U6 molecules carry 3' end polyuridine tails that are longer than those in normal cells and lack a terminal 2',3' cyclic phosphate group. In mpn1Delta yeast cells, U6 snRNA and U4/U6 di small nuclear RNA protein complex levels are diminished, leading to precursor messenger RNA splicing defects, which are reverted by expression of either yeast or human Mpn1 and by overexpression of U6. Recombinant hMpn1 is a 3'-to-5' RNA exonuclease that removes uridines from U6 3' ends, generating terminal 2',3' cyclic phosphates in vitro. Finally, U6 degradation rates increase in mpn1Delta yeasts and in lymphoblasts established from individuals affected by PN. Our data indicate that Mpn1 promotes U6 stability through 3' end posttranscriptional processing and implicate altered U6 metabolism as a potential mechanism for PN pathogenesis. PMID- 23022482 TI - B-Raf and C-Raf are required for melanocyte stem cell self-maintenance. AB - B-Raf and C-Raf kinases have emerged as critical players in melanoma. However, little is known about their role during development and homeostasis of the melanocyte lineage. Here, we report that knockout of B-raf and C-raf genes in this lineage results in normal pigmentation at birth with no defect in migration, proliferation, or differentiation of melanoblasts in mouse hair follicles. In contrast, the double raf knockout mice displayed hair graying resulting from a defect in cell-cycle entry of melanocyte stem cells (MSCs) and their subsequent depletion in the hair follicle bulge. Therefore, Raf signaling is dispensable for early melanocyte lineage development, but necessary for MSC maintenance. PMID- 23022481 TI - FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. AB - Mutations in the RNA binding protein FUS cause amyotrophic lateral sclerosis (ALS), a fatal adult motor neuron disease. Decreased expression of SMN causes the fatal childhood motor neuron disorder spinal muscular atrophy (SMA). The SMN complex localizes in both the cytoplasm and nuclear Gems, and loss of Gems is a cellular hallmark of fibroblasts in patients with SMA. Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN. Functionally, we show that FUS is required for Gem formation in HeLa cells, and expression of FUS containing a severe ALS-causing mutation (R495X) also results in Gem loss. Strikingly, a reduction in Gems is observed in ALS patient fibroblasts expressing either mutant FUS or TDP-43, another ALS causing protein that interacts with FUS. The physical and functional interactions among SMN, FUS, TDP-43, and Gems indicate that ALS and SMA share a biochemical pathway, providing strong support for the view that these motor neuron diseases are related. PMID- 23022483 TI - The rate of increase of short telomeres predicts longevity in mammals. AB - Aberrantly short telomeres result in decreased longevity in both humans and mice with defective telomere maintenance. Normal populations of humans and mice present high interindividual variation in telomere length, but it is unknown whether this is associated with their lifespan potential. To address this issue, we performed a longitudinal telomere length study along the lifespan of wild-type and transgenic telomerase reverse transcriptase mice. We found that mouse telomeres shorten ~100 times faster than human telomeres. Importantly, the rate of increase in the percentage of short telomeres, rather than the rate of telomere shortening per month, was a significant predictor of lifespan in both mouse cohorts, and those individuals who showed a higher rate of increase in the percentage of short telomeres were also the ones with a shorter lifespan. These findings demonstrate that short telomeres have a direct impact on longevity in mammals, and they highlight the importance of performing longitudinal telomere studies to predict longevity. PMID- 23022484 TI - A "forward genomics" approach links genotype to phenotype using independent phenotypic losses among related species. AB - Genotype-phenotype mapping is hampered by countless genomic changes between species. We introduce a computational "forward genomics" strategy that-given only an independently lost phenotype and whole genomes-matches genomic and phenotypic loss patterns to associate specific genomic regions with this phenotype. We conducted genome-wide screens for two metabolic phenotypes. First, our approach correctly matches the inactivated Gulo gene exactly with the species that lost the ability to synthesize vitamin C. Second, we attribute naturally low biliary phospholipid levels in guinea pigs and horses to the inactivated phospholipid transporter Abcb4. Human ABCB4 mutations also result in low phospholipid levels but lead to severe liver disease, suggesting compensatory mechanisms in guinea pig and horse. Our simulation studies, counts of independent changes in existing phenotype surveys, and the forthcoming availability of many new genomes all suggest that forward genomics can be applied to many phenotypes, including those relevant for human evolution and disease. PMID- 23022485 TI - SIRPalpha controls the activity of the phagocyte NADPH oxidase by restricting the expression of gp91(phox). AB - The phagocyte NADPH oxidase mediates oxidative microbial killing in granulocytes and macrophages. However, because the reactive oxygen species produced by the NADPH oxidase can also be toxic to the host, it is essential to control its activity. Little is known about the endogenous mechanism(s) that limits NADPH oxidase activity. Here, we demonstrate that the myeloid-inhibitory receptor SIRPalpha acts as a negative regulator of the phagocyte NADPH oxidase. Phagocytes isolated from SIRPalpha mutant mice were shown to have an enhanced respiratory burst. Furthermore, overexpression of SIRPalpha in human myeloid cells prevented respiratory burst activation. The inhibitory effect required interactions between SIRPalpha and its natural ligand, CD47, as well as signaling through the SIRPalpha cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Suppression of the respiratory burst by SIRPalpha was caused by a selective repression of gp91(phox) expression, the catalytic component of the phagocyte NADPH oxidase complex. Thus, SIRPalpha can limit gp91(phox) expression during myeloid development, thereby controlling the magnitude of the respiratory burst in phagocytes. PMID- 23022486 TI - Confinement to organelle-associated inclusion structures mediates asymmetric inheritance of aggregated protein in budding yeast. AB - The division of the S. cerevisiae budding yeast, which produces one mother cell and one daughter cell, is asymmetric with respect to aging. Remarkably, the asymmetry of yeast aging coincides with asymmetric inheritance of damaged and aggregated proteins by the mother cell. Here, we show that misfolded proteins are retained in the mother cell by being sequestered in juxtanuclear quality control compartment (JUNQ) and insoluble protein deposit (IPOD) inclusions, which are attached to organelles. Upon exposure to stress, misfolded proteins accumulate in stress foci that must be disaggregated by Hsp104 in order to be degraded or processed to JUNQ and IPOD. Cells that fail to deliver aggregates to an inclusion pass on aggregates to subsequent generations. PMID- 23022487 TI - Specific DNA-RNA hybrid recognition by TAL effectors. AB - The transcription activator-like (TAL) effector targets specific host promoter through its central DNA-binding domain, which comprises multiple tandem repeats (TALE repeats). Recent structural analyses revealed that the TALE repeats form a superhelical structure that tracks along the forward strand of the DNA duplex. Here, we demonstrate that TALE repeats specifically recognize a DNA-RNA hybrid where the DNA strand determines the binding specificity. The crystal structure of a designed TALE in complex with the DNA-RNA hybrid was determined at a resolution of 2.5 A. Although TALE repeats are in direct contact with only the DNA strand, the phosphodiester backbone of the RNA strand is inaccessible by macromolecules such as RNases. Consistent with this observation, sequence-specific recognition of an HIV-derived DNA-RNA hybrid by an engineered TALE efficiently blocked RNase H-mediated degradation of the RNA strand. Our study broadens the utility of TALE repeats and suggests potential applications in processes involving DNA replication and retroviral infections. PMID- 23022488 TI - A potential role for an extracellular methanol oxidase secreted by Moniliophthora perniciosa in Witches' broom disease in cacao. AB - The hemibiotrophic basidiomycete fungus Moniliophthora perniciosa, the causal agent of Witches' broom disease (WBD) in cacao, is able to grow on methanol as the sole carbon source. In plants, one of the main sources of methanol is the pectin present in the structure of cell walls. Pectin is composed of highly methylesterified chains of galacturonic acid. The hydrolysis between the methyl radicals and galacturonic acid in esterified pectin, mediated by a pectin methylesterase (PME), releases methanol, which may be decomposed by a methanol oxidase (MOX). The analysis of the M. pernciosa genome revealed putative mox and pme genes. Real-time quantitative RT-PCR performed with RNA from mycelia grown in the presence of methanol or pectin as the sole carbon source and with RNA from infected cacao seedlings in different stages of the progression of WBD indicate that the two genes are coregulated, suggesting that the fungus may be metabolizing the methanol released from pectin. Moreover, immunolocalization of homogalacturonan, the main pectic domain that constitutes the primary cell wall matrix, shows a reduction in the level of pectin methyl esterification in infected cacao seedlings. Although MOX has been classically classified as a peroxisomal enzyme, M. perniciosa presents an extracellular methanol oxidase. Its activity was detected in the fungus culture supernatants, and mass spectrometry analysis indicated the presence of this enzyme in the fungus secretome. Because M. pernciosa possesses all genes classically related to methanol metabolism, we propose a peroxisome-independent model for the utilization of methanol by this fungus, which begins with the extracellular oxidation of methanol derived from the demethylation of pectin and finishes in the cytosol. PMID- 23022489 TI - Bovine paramphistomosis in Galicia (Spain): prevalence, intensity, aetiology and geospatial distribution of the infection. AB - The present study explored various basic aspects of the epidemiology of paramphistomosis in Galicia, the main cattle producing region in Spain. In total, 589 cows from different farms located across the region were selected at random in the slaughterhouse for examination of the rumens and reticula for the presence of Paramphistomidae flukes. Paramphistomes were found in 111 of 589 necropsied cows (18.8%; 95% CI: 15.7-21.9%), with higher prevalences of infection in beef cows than in dairy cows (29.2% vs 13.9%). Although the number of flukes per animal was generally low (median=266 flukes), some cows harboured large parasite burdens (up to 11,895 flukes), which may have harmful effects on their health or productivity. Cows with higher parasite burdens also excreted greater numbers of fluke eggs in their faeces, which suggests that heavily parasitized mature cows play an important role in the transmission of paramphistomosis. This role may be particularly important in Galicia, where the roe deer, which is the only wild ruminant in the study area, was found not to be a reservoir for the infection. The use of morpho-anatomical and molecular techniques applied to a large number of fluke specimens provided reliable confirmation that Calicophoron daubneyi is the only species of the family Paramphistomidae that parasitizes cattle in Galicia. The environmental data from the farms of origin of the necropsied cows were used in Bayesian geostatistical models to predict the probability of infection by C. daubneyi throughout the region. The results revealed the role of environmental risk factors in explaining the geographical heterogeneity in the probability of infection in beef and dairy cattle. These explanatory factors were used to construct predictive maps showing the areas with the highest predicted risk of infection as well as the uncertainty associated with the predictions. PMID- 23022491 TI - Conductance properties of the inwardly rectifying channel, Kir3.2: molecular and Brownian dynamics study. AB - Using the recently unveiled crystal structure, and molecular and Brownian dynamics simulations, we elucidate several conductance properties of the inwardly rectifying potassium channel, Kir3.2, which is implicated in cardiac and neurological disorders. We show that the pore is closed by a hydrophobic gating mechanism similar to that observed in Kv1.2. Once open, potassium ions move into, but not out of, the cell. The asymmetrical current-voltage relationship arises from the lack of negatively charged residues at the narrow intracellular mouth of the channel. When four phenylalanine residues guarding the intracellular gate are mutated to glutamate residues, the channel no longer shows inward rectification. Inward rectification is restored in the mutant Kir3.2 when it becomes blocked by intracellular Mg(2+). Tertiapin, a polypeptide toxin isolated from the honey bee, is known to block several subtypes of the inwardly rectifying channels with differing affinities. We identify critical residues in the toxin and Kir3.2 for the formation of the stable complex. A lysine residue of tertiapin protrudes into the selectivity filter of Kir3.2, while two other basic residues of the toxin form hydrogen bonds with acidic residues located just outside the channel entrance. The depth of the potential of mean force encountered by tertiapin is 16.1kT, thus indicating that the channel will be half-blocked by 0.4MUM of the toxin. PMID- 23022490 TI - Apolar distal pocket mutants of yeast cytochrome c peroxidase: hydrogen peroxide reactivity and cyanide binding of the TriAla, TriVal, and TriLeu variants. AB - Three yeast cytochrome c peroxidase (CcP) variants with apolar distal heme pockets have been constructed. The CcP variants have Arg48, Trp51, and His52 mutated to either all alanines, CcP(triAla), all valines, CcP(triVal), or all leucines, CcP(triLeu). The triple mutants have detectable enzymatic activity at pH 6 but the activity is less than 0.02% that of wild-type CcP. The activity loss is primarily due to the decreased rate of reaction between the triple mutants and H(2)O(2) compared to wild-type CcP. Spectroscopic properties and cyanide binding characteristics of the triple mutants have been investigated over the pH stability region of CcP, pH 4 to 8. The absorption spectra indicate that the CcP triple mutants have hemes that are predominantly five-coordinate, high-spin at pH 5 and six-coordinate, low-spin at pH 8. Cyanide binding to the triple mutants is biphasic indicating that the triple mutants have two slowly-exchanging conformational states with different cyanide affinities. The binding affinity for cyanide is reduced at least two orders of magnitude in the triple mutants compared to wild-type CcP and the rate of cyanide binding is reduced by four to five orders of magnitude. Correlation of the reaction rates of CcP and 12 distal pocket mutants with H(2)O(2) and HCN suggests that both reactions require ionization of the reactants within the distal heme pocket allowing the anion to bind the heme iron. Distal pocket features that promote substrate ionization (basic residues involved in base-catalyzed substrate ionization or polar residues that can stabilize substrate anions) increase the overall rate of reaction with H(2)O(2) and HCN while features that inhibit substrate ionization slow the reactions. PMID- 23022492 TI - Detergent-labile, supramolecular assemblies of KcsA: relative abundance and interactions involved. AB - In this work, we illustrate the ability of the prokaryotic potassium channel KcsA to assemble into a variety of supramolecular clusters of defined sizes containing the tetrameric KcsA as the repeating unit. Such clusters, particularly the larger ones, are markedly detergent-labile and thus, disassemble readily upon exposure to the detergents commonly used in protein purification or conventional electrophoresis analysis. This is a reversible process, as cluster re-assembly occurs upon detergent removal and without the need of added membrane lipids. Interestingly, the dimeric ensemble between two tetrameric KcsA molecules are quite resistant to detergent disassembly to individual KcsA tetramers and along with the latter, are likely the basic building blocks through which the larger clusters are organized. As to the proteins domains involved in clustering, we have observed disassembly of KcsA clusters by SDS-like alkyl sulfates. As these amphiphiles bind to inter-subunit, "non-annular" sites on the protein, these observations suggest that such sites also mediate channel-channel interactions leading to cluster assembly. PMID- 23022493 TI - Resveratrol preconditioning increases methionine sulfoxide reductases A expression and enhances resistance of human neuroblastoma cells to neurotoxins. AB - Methionine sulfoxide reductases A (MsrA) has been postulated to act as a catalytic antioxidant system involved in the protection of oxidative stress induced cell injury. Recently, attention has turned to MsrA in coupling with the pathology of Parkinson's disease, which is closely related to neurotoxins that cause dopaminergic neuron degeneration. Here, we firstly provided evidence that pretreatment with a natural polyphenol resveratrol (RSV) up-regulated the expression of MsrA in human neuroblastoma SH-SY5Y cells. It was also observed that the expression and nuclear translocation of forkhead box group O 3a (FOXO3a), a transcription factor that activates the human MsrA promoter, increased after RSV pretreatment. Nicotinamide , an inhibitor of silent information regulator 1 (SIRT1), prevented RSV-induced elevation of FOXO3a and MsrA expression, indicating that the effect of RSV was mediated by a SIRT1 dependent pathway. RSV preconditioning increased methionine sulfoxide(MetO) reducing activity in SH-SY5Y cells and enhanced their resistance to neurotoxins, including chloramine-T and 1-methyl-4-phenyl-pyridinium. In addition, the enhancement of cell resistance to neurotoxins caused by RSV preconditioning can be largely prevented by MsrA inhibitor dimethyl sulfoxide. Our findings suggest that treatment with polyphenols such as RSV can be used as a potential regulatory strategy for MsrA expression and function. PMID- 23022494 TI - Stress, emotion regulation and cognitive performance: the predictive contributions of trait and state relative frontal EEG alpha asymmetry. AB - The relationship between trait and state measures of frontal lobe EEG alpha-band asymmetry in regard to indexing the approach-withdrawal dimension of emotion is unclear. The comparative predictive power of these constructs to explain emotion regulation and cognitive performance was examined under varying degrees of emotional challenge. The Capability Model posits the neural underpinnings of the relative difference in electrical activity between the left and right frontal lobes as a situational mechanism possibly indexing prefrontal-amygdalar interactions and psychological state. EEG, skin conductance, heart rate and acoustic startle amplitude were collected during a working memory task under three increasing levels of stress (final level was threat of shock). During threat of shock participants with higher state asymmetry exhibited greater emotion regulation compared to those with lower scores as indexed by significant attenuation of eyeblink startle magnitudes. The trait measure of frontal EEG asymmetry failed to account for significant variability in emotion regulation. Results implicate state-specific relative left frontal lobe activity as having an adaptive role in the regulation of emotion during cognitive challenge, but only under conditions of sufficient stress. PMID- 23022495 TI - SPOCK1 is regulated by CHD1L and blocks apoptosis and promotes HCC cell invasiveness and metastasis in mice. AB - BACKGROUND & AIMS: Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L) is an SNF2-like transcription factor involved in the development of human hepatocellular carcinoma (HCC). Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is up-regulated by CHD1L; we investigated its role in hepatocellular carcinogenesis. METHODS: We investigated interactions between SPOCK1 and CHD1L using electrophoretic mobility shift and luciferase reporter assays. Levels of SPOCK1 messenger RNA (mRNA) and protein were measured in samples of HCC and adjacent nontumor liver tissues (135 pairs) and compared using Pearson correlation coefficients. Effects of SPOCK1 overexpression and silencing were determined in HCC cell lines (QGY-7703, PLC 8024, BEL-7402, and QGY-7701). RESULTS: The CHD1L protein bound directly to the promoter region (nt-1662 to +34) of SPOCK1 and activated transcription. Levels of SPOCK1 mRNA and protein were increased in 60% of human HCC samples, compared with nontumor live tissues, and was associated significantly with clinical stage. Levels of SPOCK1 mRNA were increased among tumors that became metastatic, compared with those that did not, and among patients with shorter overall and disease-free survival times. Ectopic expression of SPOCK1 in HCC cells increased proliferation, foci formation, and colony formation in soft agar; these cells also formed larger xenograft tumors, more rapidly, in nude mice than control HCC cells. Silencing SPOCK1 expression with short hairpin RNA had the opposite effects. We found that SPOCK1 prevents apoptosis of HCC cells by activating Akt, to block release of cytochrome c and activation of caspase-9 and caspase-3; these effects were reversed with an Akt inhibitor. HCC cells that overexpressed SPOCK1 expressed higher levels of matrix metallopeptidase 9, were more invasive in Matrigel assays, and formed more metastatic nodules in immunodeficient mice than control HCC cells. CONCLUSIONS: CHD1L activates expression of SPOCK1, which activates Akt signaling to block apoptosis and invasion by HCC cells, in culture and in mice. Levels of SPOCK1 increase with progression of human HCC. SPOCK1 might be used as a prognostic factor or therapeutic target. PMID- 23022496 TI - Incomplete polyp resection during colonoscopy-results of the complete adenoma resection (CARE) study. AB - BACKGROUND & AIMS: Although the adenoma detection rate is used as a measure of colonoscopy quality, there are limited data on the quality of endoscopic resection of detected adenomas. We determined the rate of incompletely resected neoplastic polyps in clinical practice. METHODS: We performed a prospective study on 1427 patients who underwent colonoscopy at 2 medical centers and had at least 1 nonpedunculated polyp (5-20 mm). After polyp removal was considered complete macroscopically, biopsies were obtained from the resection margin. The main outcome was the percentage of incompletely resected neoplastic polyps (incomplete resection rate [IRR]) determined by the presence of neoplastic tissue in post polypectomy biopsies. Associations between IRR and polyp size, morphology, histology, and endoscopist were assessed by regression analysis. RESULTS: Of 346 neoplastic polyps (269 patients; 84.0% men; mean age, 63.4 years) removed by 11 gastroenterologists, 10.1% were incompletely resected. IRR increased with polyp size and was significantly higher for large (10-20 mm) than small (5-9 mm) neoplastic polyps (17.3% vs 6.8%; relative risk = 2.1), and for sessile serrated adenomas/polyps than for conventional adenomas (31.0% vs 7.2%; relative risk = 3.7). The IRR for endoscopists with at least 20 polypectomies ranged from 6.5% to 22.7%; there was a 3.4-fold difference between the highest and lowest IRR after adjusting for size and sessile serrated histology. CONCLUSIONS: Neoplastic polyps are often incompletely resected, and the rate of incomplete resection varies broadly among endoscopists. Incomplete resection might contribute to the development of colon cancers after colonoscopy (interval cancers). Efforts are needed to ensure complete resection, especially of larger lesions. ClinicalTrials.gov Number: NCT01224444. PMID- 23022497 TI - Evaluation of anti-HBV drug resistant mutations among patients with acute symptomatic hepatitis B in the United States. AB - BACKGROUND & AIMS: Reported HBV drug resistance mutations among previously untreated patients with chronic hepatitis B are variable. Whether resistant HBV strains are transmitted in the acute setting is uncertain. We sought to document the presence of antiviral resistance (AVR) mutations in patients with acute HBV (AHB) infection. METHODS: AHB infection was defined by HBsAg/IgM anti-HBc positivity, ALT>10X ULN and compatible clinical history. The TRUGENE HBV kit was used to perform genotyping and direct sequencing of the viral polymerase. INNO LiPA HBV DRv2 and DRv3 were used to detect AVR mutations. Clonal sequencing was conducted on selected specimens. RESULTS: Twenty-three patients were evaluated (mean age, 43 years; 54% male; 39% African American, 39% Caucasian, 13% Hispanic and 4% Asian). The mean peak ALT was 1554.2IU/L and mean peak total serum bilirubin was 12 mg/dl. The HBV DNA median viral load (N = 15) was 5.14 log(10)IU/ml. Nineteen patients were genotype A, and 1 each were genotype C, D, E and G. HBV drug resistance mutations were not detected by direct sequencing or INNO-LiPA. Clonal sequencing was conducted on 192 clones isolated from three patients and showed rtA181T, rtM250V and rtS202G mutations at an overall frequency of 1.54%, 1.39%, and 1.67% respectively. CONCLUSIONS: We detected adefovir/lamivudine and entecavir relevant mutations in a minor population (<2%) of viral clones by clonal sequencing only. The clinical significance of these mutations is uncertain and may represent small populations of quasi-species vs. transmission of drug resistant strains. PMID- 23022498 TI - Semaphorins in bone development, homeostasis, and disease. AB - Semaphorins were originally identified as axon guidance cues in the development of the nervous system. In recent years, numerous studies have determined that they are also involved in organogenesis, vascularization/angiogenesis, oncogenesis, and immune responses. In addition, the mechanisms underlying the diverse functions of semaphorins and their receptors have been identified. Recently, significant advances have been made in our understanding of the roles of semaphorins in bone remodeling, particularly the regulation of osteoclast and osteoblast differentiation and migration. Moreover, dysregulated semaphorin expression causes severe bone diseases, including osteoporosis and osteopetrosis. This review focuses on advanced findings on the role of semaphorins/receptors and their intracellular signaling in the regulation of bone homeostasis. PMID- 23022499 TI - ATP-dependent intercellular Ca2+ signaling in the developing cochlea: facts, fantasies and perspectives. AB - Hearing relies on a sensitive mechanoelectrical transduction process in the cochlea of the inner ear. The cochlea contains sensory, secretory, neural, supporting and epithelial cells which are all essential to the sound transduction process. It is well known that a complex extracellular purinergic signaling system contributes to cochlear homeostasis, altering cochlear sensitivity and neural output via ATP-gated ion channels (P2X receptors) and G protein-coupled P2Y receptors. This review focuses on the emerging roles of ATP that are currently under investigation in the developing sensory epithelium, with particular emphasis on the link between ATP release, Ca(2+) signaling, the expression and function of gap junction proteins connexin26 and connexin30, and the acquisition of hearing. PMID- 23022500 TI - Incidental Epstein-Barr virus associated atypical lymphoid proliferation arising in a left atrial myxoma: a case of long survival without any postsurgical treatment and review of the literature. AB - We report a case of left atrial cardiac myxoma harbouring an incidental atypical B-cell lymphoid proliferation. Histology disclosed classic myxoma cells embedded in a mucopolysaccharide-rich matrix and a micronodular atypical lymphoid proliferation under the surface of the mass. Myxoma cells were immunoreactive for calretinin, while lymphoid cells expressed B lineage markers (CD 20+, CD79a), without evidence of clonality. Moreover, they were LMP1 positive; EBNA2 negative; KSHV/HHV8 negative; and, by in situ hybridization, EBER/Epstein-Barr virus (EBV) positive and Kappa and Lambda negative. According to the 2008 WHO schemes, the present case shares close similarities either with diffuse large B-cell lymphomas growing in the context of long-standing chronic inflammation or with primary effusion lymphomas, solid variant, both associated with EBV infection. This is the sixth case of incidental atypical lymphoid proliferation discovered in a cardiac myxoma reported so far. The optimal treatment of such lesions remains undefined, but their clinical course is indolent. After an accurate staging workup, without any postsurgical treatment, the patient we observed has been well with no recurrence of the disease at 6 years of follow-up. PMID- 23022502 TI - Melanocortin 4 receptor antagonists attenuates morphine antinociceptive tolerance, astroglial activation and cytokines expression in the spinal cord of rat. AB - Chronic use of morphine is accompanied by the development of morphine tolerance, which is one of the major problems associated with opiate treatment. Experimental evidence indicates that melanocortin 4 receptor (MC4R) is involved in development of morphine tolerance. Therefore, we investigated the influence of repeated intrathecal injection of a MC4R antagonist (HS014) on the development of morphine tolerance as measured by hot-plate test. It was also examined whether a single i.t. HS014 administration could counteract the loss of analgesic potency of morphine in morphine tolerant rats. We examined also the influence of i.t. HS014 administration on astrocytes activation and cytokines expression in the spinal cord of rat during morphine tolerance. Morphine treatment (10mg/kg, i.p. twice daily) over 5 days induced tolerance as reflected by a significant reduction of withdrawal latency from 29.67+/-1.81s to 8.67+/-1.70s in the hot-plate test. Repeated coadministration of HS014 and morphine, significantly prevented the development of morphine tolerance. A single administration of an MC4R antagonist restored morphine analgesic potency in morphine tolerant rats. Using immunohistochemical staining, we demonstrated the administration of MC4R during the induction of morphine tolerance inhibited the activation of astrocytes; reduced the expression of proinflammatory cytokines interleukin-1beta, IL-6, and tumor necrosis factor-alpha; upregulated the expression of anti-inflammatory cytokines IL-10 at the L5 lumbar spinal cord. These results suggest that MC4R may be involved in the mechanisms of morphine tolerance and antagonists of this receptor may be a possible new target in the search for strategies preventing the development of morphine tolerance. PMID- 23022501 TI - Behavioral changes and brain energy metabolism dysfunction in rats treated with methamphetamine or dextroamphetamine. AB - Studies have demonstrated that AMPHs produce long-term damage to the brain dopaminergic, serotoninergic and glutamatergic regions. Prefrontal cortex, amygdala, hippocampus and striatum appear to be involved in the toxicity and behavioral changes induced by AMPHs. A single dose of AMPH causes mitochondrial dysfunction and oxidative stress in rat brain. The goal of the present study was thus to investigate the potency of two amphetamines, dextroamphetamine (d-AMPH) and methamphetamine (m-AMPH), on the behavior and energetic dysfunction in the brain of rats. d-AMPH and m-AMPH increased the crossing and rearing behaviors. The numbers of visits to the center were increased by d-AMPH and m-AMPH only at 2mg/kg. Likewise, at a high dose (2 mg/kg), the injection of m-AMPH increased the amount of sniffing. The AMPHs significantly decreased the activities of Krebs cycle enzymes (citrate synthase and succinate dehydrogenase) and mitochondrial respiratory chain complexes (I-IV); nevertheless, this effect varied depending on the brain region evaluated. In summary, this study demonstrated that at high doses, m-AMPH, increased stereotyped (sniffing) behavior in rats, but d-AMPH did not. However, this study shows that d-AMPH and m-AMPH seem to have similar effects on the brains energetic metabolism. PMID- 23022503 TI - Sleep deprivation has a neuroprotective role in a traumatic brain injury of the rat. AB - During the process of a brain injury, responses to produce damage and cell death are activated, but self-protective responses that attempt to maintain the integrity and functionality of the brain are also activated. We have previously reported that the recovery from a traumatic brain injury (TBI) is better in rats if it occurs during the dark phase of the diurnal cycle when rats are in the waking period. This suggests that wakefulness causes a neuroprotective role in this type of injury. Here we report that 24h of total sleep deprivation after a TBI reduces the morphological damage and enhances the recovery of the rats, as seen on a neurobiological scale. PMID- 23022504 TI - Effects of metabotropic glutamate mGlu5 receptor antagonist on tyrosine phosphorylation of NMDA receptor subunits and cell death in the hippocampus after brain ischemia in rats. AB - Tyrosine phosphorylation of the N-methyl-D-aspartate (NMDA) receptor appears to be associated with the regulation of the receptor's ion channel. This study focused on the effect of a metabotropic glutamate mGlu5 receptor antagonist on tyrosine phosphorylation of NMDA receptor subunits and cell death in the hippocampal CA1 region after transient global ischemia and sought to explore their mechanisms. Pretreatment with the mGlu5 receptor antagonist reduced cell death in the hippocampal CA1 region on day 3 after the transient ischemia. Transient ischemia increased the tyrosine phosphorylation of NMDA receptor subunits, which are a major target of Src family tyrosine kinases. Therefore, we investigated the effect of the antagonist on tyrosine phosphorylation of the NMDA receptor subunits after transient ischemia. Tyrosine phosphorylation of the NR2A subunit, but not that of the NR2B one, was inhibited by the mGlu5 receptor antagonist. The administration of the antagonist also attenuated the increase in the amount of active form of Src after the reperfusion. We further demonstrated that the administration of a Src-family kinase inhibitor prevented cell death in the hippocampal CA1 region and attenuated the increase in the tyrosine phosphorylation of the NMDA receptor subunits after the reperfusion. These findings suggest that mGlu5 receptor in the hippocampal CA1 region after transient ischemia is involved in the activation of Src and subsequent tyrosine phosphorylation of NMDA receptor subunits, which actions may contribute to alterations of properties of the NMDA receptor and may be related to pathogenic events leading to neuronal cell death. PMID- 23022505 TI - The viral mimetic polyinosinic:polycytidylic acid (poly I:C) induces cellular responses in primary cultures from rat brain sites with an incomplete blood-brain barrier. AB - Primary microcultures of the organum vasculosum laminae terminalis (OVLT) and the area postrema (AP), brain sites with an incomplete blood-brain barrier, were established from topographically excised rat pup tissue, with cellular identification by marker protein-specific immunocytochemistry. Employing the ratio calcium imaging technique, we showed for the first time that polyinosinic:polycytidylic acid (poly I:C) can induce calcium signalling in single OVLT and AP cells. Poly I:C stimulation caused fast, transient rises in intracellular calcium in about 5% of neurons and astrocytes and some microglial cells. Frequently, the responses of astrocytes and microglial cells showed a shorter onset-latency compared to neurons. In addition, exposure to poly I:C led to a time dependent release of bioactive tumour necrosis factor (TNF) and interleukin-6 (IL-6) into the supernatants of OVLT and AP cultures. The demonstration of direct cellular responses of OVLT- and AP-intrinsic cells to stimulations with poly I:C is in agreement with the discovered existence of Toll like receptor 3 (TLR3), the cognate receptor for poly I:C, in the brain. PMID- 23022506 TI - Fast increase of motor cortical inhibition following postural changes in healthy subjects. AB - BACKGROUND AND AIMS: Postural reactions are associated with changes in the excitability of the motor system. In the present study we investigated the presence of neurophysiological changes of motor cortical areas targeting muscles of the inferior limbs following treatment with a physiotherapy technique aimed to treat postural dysfunctions by stretching postural muscles, global postural reeducation (GPR). METHODS: Twenty healthy subjects were evaluated with paired transcranial magnetic stimulation (TMS) of the motor cortex and recording of motor evoked potentials (MEPs) from peripheral muscles of the inferior limb before and after two GPR manoeuvres applied in different experiments (1 and 2). RESULTS: The effects of GPR were posture- and task-specific: indeed, a GPR manoeuvre applied in standing subjects increased inhibition in cortical areas controlling flexor muscles (Biceps Femoris: p<0.05) while increasing the excitation of cortical areas controlling extensor muscles (Tibialis Anterior: p<0.05). On the other hand, following a GPR manoeuvre applied in subjects in supine position, increased inhibition in cortical areas controlling flexor muscles (Biceps Femoris and Soleus) was not paralleled by excitation of extensor ones (F=12.2; p=0.005). CONCLUSIONS: These findings provide a neurophysiological basis to the clinical benefits associated to physiotherapy and suggest potential applications of treatments based on postural changes on motor cortical disorders. PMID- 23022507 TI - Right lateralized white matter abnormalities in first-episode, drug-naive paranoid schizophrenia. AB - Numerous studies in first-episode schizophrenia suggest the involvement of white matter (WM) abnormalities in multiple regions underlying the pathogenesis of this condition. However, there has never been a neuroimaging study in patients with first-episode, drug-naive paranoid schizophrenia by using tract-based spatial statistics (TBSS) method. Here, we used diffusion tensor imaging (DTI) with TBSS method to investigate the brain WM integrity in patients with first-episode, drug naive paranoid schizophrenia. Twenty patients with first-episode, drug-naive paranoid schizophrenia and 26 healthy subjects matched with age, gender, and education level were scanned with DTI. An automated TBSS approach was employed to analyze the data. Voxel-wise statistics revealed that patients with paranoid schizophrenia had decreased fractional anisotropy (FA) values in the right superior longitudinal fasciculus (SLF) II, the right fornix, the right internal capsule, and the right external capsule compared to healthy subjects. Patients did not have increased FA values in any brain regions compared to healthy subjects. There was no correlation between the FA values in any brain regions and patient demographics and the severity of illness. Our findings suggest right sided alterations of WM integrity in the WM tracts of cortical and subcortical regions may play an important role in the pathogenesis of paranoid schizophrenia. PMID- 23022508 TI - Site-specific protein O-glycosylation modulates proprotein processing - deciphering specific functions of the large polypeptide GalNAc-transferase gene family. AB - BACKGROUND: Posttranslational modifications (PTMs) greatly expand the function and regulation of proteins, and glycosylation is the most abundant and diverse PTM. Of the many different types of protein glycosylation, one is quite unique; GalNAc-type (or mucin-type) O-glycosylation, where biosynthesis is initiated in the Golgi by up to twenty distinct UDP-N-acetyl-alpha-d-galactosamine:polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). These GalNAc-Ts are differentially expressed in cells and have different (although partly overlapping) substrate specificities, which provide for both unique functions and considerable redundancy. Recently we have begun to uncover human diseases associated with deficiencies in GalNAc-T genes (GALNTs). Thus deficiencies in individual GALNTs produce cell and protein specific effects and subtle distinct phenotypes such as hyperphosphatemia with hyperostosis (GALNT3) and dysregulated lipid metabolism (GALNT2). These phenotypes appear to be caused by deficient site specific O-glycosylation that co-regulates proprotein convertase (PC) processing of FGF23 and ANGPTL3, respectively. SCOPE OF REVIEW: Here we summarize recent progress in uncovering the interplay between human O-glycosylation and protease regulated processing and describes other important functions of site-specific O glycosylation in health and disease. MAJOR CONCLUSIONS: Site-specific O glycosylation modifies pro-protein processing and other proteolytic events such as ADAM processing and thus emerges as an important co-regulator of limited proteolytic processing events. GENERAL SIGNIFICANCE: Our appreciation of this function may have been hampered by our sparse knowledge of the O-glycoproteome and in particular sites of O-glycosylation. New strategies for identification of O-glycoproteins have emerged and recently the concept of SimpleCells, i.e. human cell lines made deficient in O-glycan extension by zinc finger nuclease gene targeting, was introduced for broad O-glycoproteome analysis. PMID- 23022509 TI - Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABA(A) receptors. AB - Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic-clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4mg/kg was 100% lethal. The NMDA antagonist, ketamine (35mg/kg) injected ip immediately after the first TMDT induced seizure, did not change number of tonic-clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic-clonic seizures and eliminated lethality through a 60min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA(A) receptor allosteric enhancer diazepam (5mg/kg) greatly reduced seizure manifestations and prevented lethality 60min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning. PMID- 23022510 TI - L-ascorbate attenuates methamphetamine neurotoxicity through enhancing the induction of endogenous heme oxygenase-1. AB - Methamphetamine (METH) is a drug of abuse which causes neurotoxicity and increased risk of developing neurodegenerative diseases. We previously found that METH induces heme oxygenase (HO)-1 expression in neurons and glial cells, and this offers partial protection against METH toxicity. In this study, we investigated the effects of l-ascorbate (vitamin C, Vit. C) on METH toxicity and HO-1 expression in neuronal/glial cocultures. Cell viability and damage were evaluated by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release, respectively. Neuronal and glial localization of HO-1 were identified by double immunofluorescence staining. Reactive oxygen species (ROS) production was measured using the fluorochrome 2',7'-dichlorofluorescin diacetate. HO-1 mRNA and protein expression were examined by RT-qPCR and Western blotting, respectively. Results show that Vit. C induced HO-1 mRNA and protein expressions in time- and concentration-dependent manners. Inhibition of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase (ERK) significantly blocked induction of HO 1 by Vit. C. HO-1 mRNA and protein expressions were significantly elevated by a combination of Vit. C and METH, compared to either Vit. C or METH alone. Pretreatment with Vit. C enhanced METH-induced HO-1 expression and attenuated METH-induced ROS production and neurotoxicity. Pharmacological inhibition of HO activity abolished suppressive effects of Vit. C on METH-induced ROS production and attenuated neurotoxicity. We conclude that induction of HO-1 expression contributes to the attenuation of METH-induced ROS production and neurotoxicity by Vit. C. We suggest that HO-1 induction by Vit. C may serve as a strategy to alleviate METH neurotoxicity. PMID- 23022512 TI - The role of DNA methylation in catechol-enhanced erythroid differentiation of K562 cells. AB - Catechol is one of phenolic metabolites of benzene in vivo. Catechol is also widely used in pharmaceutical and chemical industries. In addition, fruits, vegetables and cigarette smoke also contain catechol. Our precious study showed that several benzene metabolites (phenol, hydroquinone, and 1,2,4-benzenetriol) inhibited erythroid differentiation of K562 cells. In present study, the effect of catechol on erythroid differentiation of K562 cells was investigated. Moreover, to address the role of DNA methylation in catechol-induced effect on erythroid differentiation in K562 cells, methylation levels of erythroid-specific genes were analyzed by Quantitative MassARRAY methylation analysis platform. Benzidine staining showed that exposure to catechol enhanced hemin-induced hemoglobin accumulation in K562 cells in concentration- and time-dependent manners. The mRNA expression of erythroid specific genes, including alpha-globin, beta-globin, gamma-globin, erythroid 5-aminolevulinate synthase, erythroid porphobilinogen deaminase, and transcription factor GATA-1 genes, showed a significant concentration-dependent increase in catechol-treated K562 cells. The exposure to catechol caused a decrease in DNA methylation levels at a few CpG sites in some erythroid specific genes including alpha-globin, beta-globin and erythroid porphobilinogen deaminase genes. These results indicated that catechol improved erythroid differentiation potency of K562 cells at least partly via up regulating transcription of some erythroid related genes, and suggested that inhibition of DNA methylation might be involved in up-regulated expression of some erythroid related genes. PMID- 23022511 TI - Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4. AB - Atrazine, one of the most commonly used herbicides worldwide, acts as an endocrine disruptor, but the mechanism of its action has not been characterized. In this study, we show that atrazine rapidly increases cAMP levels in cultured rat pituitary and testicular Leydig cells in a concentration-dependent manner, but less effectively than 3-isobutyl-1-methylxanthine, a competitive non-specific inhibitor of phosphodiesterases (PDEs). In forskolin (an activator of adenylyl cyclase)- and probenecid (an inhibitor of cyclic nucleotide transporters)-treated cells, but not in 3-isobutyl-1-methylxanthine-treated cells, atrazine further increased cAMP levels, indicating that inhibition of PDEs accounts for accumulation of cAMP. In contrast to cAMP, atrazine did not alter cGMP levels, further indicating that it inhibits cAMP-specific PDEs. Atrazine-induced changes in cAMP levels were sufficient to stimulate prolactin release in pituitary cells and androgen production in Leydig cells, indicating that it acts as an endocrine disrupter both in cells that secrete by exocytosis of prestored hormones and in cells that secrete by de novo hormone synthesis. Rolipram abolished the stimulatory effect of atrazine on cAMP release in both cell types, suggesting that it acts as an inhibitor of PDE4s, isoforms whose mRNA transcripts dominate in pituitary and Leydig cells together with mRNA for PDE8A. In contrast, immortalized lacto-somatotrophs showed low expression of these mRNA transcripts and several fold higher cAMP levels compared to normal pituitary cells, and atrazine was unable to further increase cAMP levels. These results indicate that atrazine acts as a general endocrine disrupter by inhibiting cAMP-specific PDE4s. PMID- 23022513 TI - Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-beta receptor-mediated ERK and p38 pathways. AB - Hepatic fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with accumulation of extracellular matrix (ECM) in the liver. Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrogenesis. Compelling evidence indicates that oxidative stress is concomitant with liver fibrosis irrespective of the underlying etiology. Natural antioxidant ligustrazine exhibits potent antifibrotic activities, but the mechanisms are poorly understood. Our studies were to investigate the ligustrazine effects on HSC activation stimulated by hydrogen peroxide (H(2)O(2)), an in vitro model mimicking the oxidative stress in liver fibrogenesis, and to elucidate the possible mechanisms. Our results demonstrated that H(2)O(2) at 5MUM significantly stimulated HSC proliferation and expression of marker genes of HSC activation; whereas ligustrazine dose-dependently suppressed proliferation and induced apoptosis in H(2)O(2)-activated HSCs, and attenuated expression of fibrotic marker genes. Mechanistic investigations revealed that ligustrazine reduced platelet-derived growth factor-beta receptor (PDGF-betaR) expression and blocked the phosphorylation of extracellular regulated protein kinase (ERK) and p38 kinase, two downstream effectors of PDGF betaR. Further molecular evidence suggested that ligustrazine interruption of ERK and p38 pathways was dependent on the blockade of PDGF-betaR and might be involved in ligustrazine reduction of fibrotic marker gene expression under H(2)O(2) stimulation. Furthermore, ligustrazine modulated some proteins critical for HSC activation and ECM homeostasis in H(2)O(2)-stimulated HSCs. These data collectively indicated that ligustrazine could attenuate HSC activation caused by oxidative stress, providing novel insights into ligustrazine as a therapeutic option for hepatic fibrosis. PMID- 23022514 TI - Mechanisms for ribotoxin-induced ribosomal RNA cleavage. AB - The Type B trichothecene deoxynivalenol (DON), a ribotoxic mycotoxin known to contaminate cereal-based foods, induces ribosomal RNA (rRNA) cleavage in the macrophage via p38-directed activation of caspases. Here we employed the RAW 264.7 murine macrophage model to test the hypothesis that this rRNA cleavage pathway is similarly induced by other ribotoxins. Capillary electrophoresis confirmed that the antibiotic anisomycin (>=25ng/ml), the macrocylic trichothecene satratoxin G (SG) (>=10ng/ml) and ribosome-inactivating protein ricin (>=300ng/ml) induced 18s and 28s rRNA fragmentation patterns identical to that observed for DON. Also, as found for DON, inhibition of p38, double-stranded RNA-activated kinase (PKR) and hematopoietic cell kinase (Hck) suppressed MAPK anisomycin-induced rRNA cleavage, while, in contrast, their inhibition did not affect SG- and ricin-induced rRNA fragmentation. The p53 inhibitor pifithrin-MU and pan caspase inhibitor Z-VAD-FMK suppressed rRNA cleavage induced by anisomycin, SG and ricin, indicating that these ribotoxins shared with DON a conserved downstream pathway. Activation of caspases 8, 9 and 3 concurrently with apoptosis further suggested that rRNA cleavage occurred in parallel with both extrinsic and intrinsic pathways of programmed cell death. When specific inhibitors of cathepsins L and B (lysosomal cysteine cathepsins active at cytosolic neutral pH) were tested, only the former impaired anisomycin-, SG-, ricin- and DON-induced rRNA cleavage. Taken together, the data suggest that (1) all four ribotoxins induced p53-dependent rRNA cleavage via activation of cathepsin L and caspase 3, and (2) activation of p53 by DON and anisomycin involved p38 whereas SG and ricin activated p53 by an alternative mechanism. PMID- 23022516 TI - Characterisation of cationic amphiphilic cyclodextrins for neuronal delivery of siRNA: effect of reversing primary and secondary face modifications. AB - Significant research is focused on the development of non-viral vectors for delivery of siRNA to neurons and the central nervous system. Cyclodextrins (CDs) have shown great promise as efficient and low toxicity gene delivery vectors in various cell types. Here, we investigate two CDs for siRNA delivery in a neuronal cell model. These CDs were substituted on opposite faces (primary and secondary) with amphiphilic and cationic groups. Physical properties of CD.siRNA complexes, including size, charge and stability were measured. In vitro investigations were carried out in immortalised hypothalamic neurons. Neuronal cell uptake was measured by flow cytometry and cytotoxicity was assessed by MTT assay. Knockdown of a luciferase reporter gene was used as a measure of gene silencing efficiency. Both CDs interacted with siRNA, yielding nanosized cationic complexes which exhibited good stability on storage. A favourable toxicity profile was demonstrated for the CD.siRNA complexes. However, only one of the two CDs mediated high levels of neuronal uptake and efficient gene silencing, equivalent to those achieved with a commercial lipid-based vector. Despite the suitability of both CDs as siRNA delivery vectors in terms of their ability to complex siRNA and the properties of the complexes yielded, only one CD achieved good transfection efficiency. This was likely due to the differences in their chemical structures. The effective CD offers great potential as a novel non-toxic vector for neuronal siRNA delivery. PMID- 23022515 TI - Dual effects of fluoxetine on mouse early embryonic development. AB - Fluoxetine, a selective serotonin reuptake inhibitor, regulates a variety of physiological processes, such as cell proliferation and apoptosis, in mammalian cells. Little is known about the role of fluoxetine in early embryonic development. This study was undertaken to investigate the effect of fluoxetine during mouse early embryonic development. Late two-cell stage embryos (2-cells) were cultured in the presence of various concentrations of fluoxetine (1 to 50MUM) for different durations. When late 2-cells were incubated with 5MUM fluoxetine for 6h, the percentage that developed into blastocysts increased compared to the control value. However, late 2-cells exposed to fluoxetine (5MUM) over 24h showed a reduction in blastocyst formation. The addition of fluoxetine (5MUM) together with KN93 or KN62 (calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors) failed to increase blastocyst formation. Fluoxetine treatment inhibited TREK-1 and TREK-2, members of the two-pore domain K(+) channel family expressed in mouse embryos, activities, indicating that fluoxetine induced membrane depolarization in late 2-cells might have resulted from TREK inhibition. In addition, long-term exposure to fluoxetine altered the TREK mRNA expression levels. Furthermore, injection of siRNA targeting TREKs significantly decreased blastocyst formation by ~30% compared to injection of scrambled siRNA. Long-term exposure of fluoxetine had no effect on blastocyst formation of TREK deficient embryos. These results indicate that low-dose and short-term exposures of late 2-cells to fluoxetine probably increase blastocyst formation through activation of CaMKII-dependent signal transduction pathways, whereas long-term exposure decreases mouse early embryonic development through inhibition of TREK channel gating. PMID- 23022517 TI - The relative roles of charge and a recognition peptide in luminal targeting of colorectal cancer by fluorescent polyacrylamide. AB - Real time detection of biomarkers at the mucosal level is imperative for the prevention and efficient treatment of colorectal cancer. Cationized polyacrylamide (CPAA) with increasing charge densities was prepared by radical polymerization of acrylamide and different mol% ratios of N-acryloyl, N'-(tert butyl-carbonyl) diaminoethane. The NIR fluorophore derivative of IR-783, IR-783-S Ph-COOH, was attached to the CPAA to give CPAA-783. After selecting the optimal IR-783-S-Ph-COOH ratio that avoids quenching, the preferential binding of the polymer was tested in SW-620, SW-480, HT-29, and LS-174T cancer cells. The optimal polymeric product was tested in situ in gut sac preparations of the dimethylhydrazine induced rat model. To increase the detection capabilities of CPAA-783, the FITC-labeled peptide EPPT1, that targets the cell transmembrane underglycosylated MUC-1 (uMUC-1), was conjugated to the polymer to obtain CPAA 783-EPPT1. The dually labeled modified polymer was tested in HT-29 and LS-174T cells (over expressing uMUC-1), followed by an examination in an orthotopic mouse model. CPAA-783 preferentially bound to the cancer cells, depending on CRC staging. The best binding occurred when the fraction of the cationic monomer was 100 mol%, labeled with 0.75 mol% of IR-783-S-Ph-COOH. An increase in the recognition of the dually labeled polymeric product, CPAA-783-EPPT1, towards HT 29 and LS-174T cells occurred in the lowest EPPT1molar ratio (0.63 mol%) only, probably due to quenching phenomena and steric hindrance. Similar observation was obtained in the orthotopic mice. It is concluded that fluorescently tagged CPAA can be used for the detection of malignant tissues in colorectal cancer after luminal instillation. Dually targeted CPAA with EPPT1is feasible, but requires further optimization. PMID- 23022518 TI - QSAR, docking and in vitro studies for anti-inflammatory activity of cleomiscosin A methyl ether derivatives. AB - A series of five (6a-8b) novel polyhalogenated derivatives and an interesting ester (9a) derivative have been synthesized from cleomiscosin A methyl ether. All the six derivatives were subjected to in silico QSAR modeling and docking studies and later the predicted results were confirmed through in vitro experiments. QSAR modeling results showed that compounds 6a and 9a possessed anti-inflammatory activity comparable or even higher than diclofenac sodium. Docking results revealed that compounds 9a and 6a showed very good anti-inflammatory activity due to low docking energies of viz., IL6 (-92.45 and -81.993 kcal mol(-1)), TNF-alpha (-94.992 and -69.235 kcal mol(-1)) and IL1beta (-67.462 and -65.985 kcal mol( 1)). Further all the six novel derivatives were subjected for in vitro anti inflammatory activity using primary macrophages cell culture bioassay system. At the initial doses of 1 MUg/ml and 10 MUg/ml, the pro-inflammatory cytokines (IL 1beta, IL-6 and TNF-alpha) were quantified from cell culture supernatant using enzyme linked immunosorbent assay (ELISA). The in vitro effect of 6a-9a on cell viability in mouse peritoneal macrophage cells isolated from mice was evaluated using MTT assay. The in silico and in vitro data suggested that all the derivatives might be considered as potential anti-inflammatory drug-like molecules. PMID- 23022519 TI - Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients? AB - An ideal target-based agent for the treatment of cancer patients should fulfil a number of requirements, including the availability of biomarkers to select the target population, superiority over existing treatments and specific advantages in terms of pharmacokinetics and/or metabolism. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib and afatinib, have been investigated in the treatment of non-small cell lung cancer (NSCLC), and to date a large amount of clinical data are available. The activity of EGFR-TKIs was initially investigated in unselected patients leading to unsatisfactory results. However, the discovery that response to EGFR-TKIs is associated with the presence of activating EGFR mutations in NSCLC, has led to the design of clinical trials in which patients were selected on the basis of the EGFR mutational status or of clinical and pathological features that are highly associated with the presence of EGFR mutations. In this respect, several phase III randomized trials have demonstrated that first-line EGFR-TKIs, compared to chemotherapy, is associated with longer progression-free survival, higher response rate, better toxicity profile and quality of life in patients carrying EGFR mutations. Although no survival advantage was demonstrated, all the trials suffered of a high post-progression treatment cross-over, which predictably undermined the results. This review will summarize the current evidence that strongly support the hypothesis that gefitinib, erlotinib and afatinib are ideal drugs for NSCLC patients carrying EGFR mutations. PMID- 23022520 TI - Differential acid-base regulation in various gills of the green crab Carcinus maenas: Effects of elevated environmental pCO2. AB - Euryhaline decapod crustaceans possess an efficient regulation apparatus located in the gill epithelia, providing a high adaptation potential to varying environmental abiotic conditions. Even though many studies focussed on the osmoregulatory capacity of the gills, acid-base regulatory mechanisms have obtained much less attention. In the present study, underlying principles and effects of elevated pCO(2) on acid-base regulatory patterns were investigated in the green crab Carcinus maenas acclimated to diluted seawater. In gill perfusion experiments, all investigated gills 4-9 were observed to up-regulate the pH of the hemolymph by 0.1-0.2 units. Anterior gills, especially gill 4, were identified to be most efficient in the equivalent proton excretion rate. Ammonia excretion rates mirrored this pattern among gills, indicating a linkage between both processes. In specimen exposed to elevated pCO(2) levels for at least 7 days, mimicking a future ocean scenario as predicted until the year 2300, hemolymph K(+) and ammonia concentrations were significantly elevated, and an increased ammonia excretion rate was observed. A detailed quantitative gene expression analysis revealed that upon elevated pCO(2) exposure, mRNA levels of transcripts hypothesized to be involved in ammonia and acid-base regulation (Rhesus-like protein, membrane-bound carbonic anhydrase, Na(+)/K(+)-ATPase) were affected predominantly in the non-osmoregulating anterior gills. PMID- 23022521 TI - A rapid method to assess the stage differentiation in Leishmania donovani by flow cytometry. AB - In this study we describe a rapid and novel method to assess the morphological stage differentiation in Leishmania donovani by flow cytometry (FCM). FCM is fast, accurate, and inexpensive to study the stage differentiation of promastigote into L. donovani axenic amastigote (LdAxAm). The non-flourimetric FCM method is easy to perform; with requirement of little expertise, and provides unambiguous results. It is an advanced tool, requires minimal time, and no fluorescent dyes. The gradual increase of differentiation and reduction in size from promastigote stage to LdAxAm leads to peak shifting from right to left on histogram. Earlier reports assessed the stage differentiation of Leishmania by studying the expression of stage specific markers like surface or secretory proteins and genes. For validation, conventional methods like microscopic analysis are used. These methods are quite expensive, laborious and time consuming. Non-flourimetric morphological parameters were further validated by conventional methods like optical and scanning electron microscopy. Additionally, differential expression of stage specific genes (e.g. upregulation of amastin and ATP binding cassette A3 (ABCA3) transporter gene transcripts) and differential activity of enzymes (down regulation of secretory acid phosphatase (SAcP) and 3' nucleotidase enzyme activity) in LdAxAm suggest stage differentiation. Therefore, we believe that our method is an alternative tool for high reproducibility and reliability in assessment of stage differentiation. PMID- 23022522 TI - Identification of chemical constituents and larvicidal activity of Kelussia odoratissima Mozaffarian essential oil against two mosquito vectors Anopheles stephensi and Culex pipiens (Diptera: Culicidae). AB - The larvicidal activity of essential oil extracted from an indigenous plant, Kelussia odoratissima Mozaffarian was evaluated against two mosquito species, Anopheles stephensi and Culex pipiens. The chemical composition of the essential oil obtained by hydrodistillation from branch tips and leaf of this plant was determined by GC and GC/MS analysis. Forty-nine constituents were identified in the oil. The main constituents of the oil were Z-ligustilide (77.73%), 2-octen-1 ol acetate (6.27%), E-ligustilide (2.27%) and butylidene phthalide (1.97%). Five different logarithmic concentrations of essential oil were evaluated against the 4th instar larvae of An. Stephensi and Cx. pipiens. The LC(50) and LC(90) values against An. stephensi larvae were 4.88 and 9.60 ppm and for Cx. pipiens were 2.69 and 7.90 ppm, respectively. These properties suggest that K. odoratissima oil has potential source of valuable larvicidal compounds for mosquito larval control. This plant which causes high mortality at lower dose could be considered as a highly active plant. In this paper a guideline suggested for larvicidal activity of plant essential oils. PMID- 23022523 TI - Experimental inhibition of nitric oxide increases Plasmodium relictum (lineage SGS1) parasitaemia. AB - Malaria is a widespread vector-borne disease infecting a wide range of terrestrial vertebrates including reptiles, birds and mammals. In addition to being one of the most deadly infectious diseases for humans, malaria is a threat to wildlife. The host immune system represents the main defence against malaria parasites. Identifying the immune effectors involved in malaria resistance has therefore become a major focus of research. However, this has mostly involved humans and animal models (rodents) and how the immune system regulates malaria progression in non-model organisms has been largely ignored. The aim of the present study was to investigate the role of nitric oxide (NO) as an immune effector contributing to the control of the acute phase of infection with the avian malaria agent Plasmodium relictum. We used experimental infections of domestic canaries in conjunction with the inhibition of the enzyme inducible nitric oxide synthase (iNOS) to assess the protective function of NO during the infection, and the physiological costs paid by the host in the absence of an effective NO response. Our results show that birds treated with the iNOS inhibitor suffered from a higher parasitaemia, but did not pay a higher cost of infection (anaemia). While these findings confirm that NO contributes to the resistance to avian malaria during the acute phase of the infection, they also suggest that parasitaemia and costs of infection can be decoupled. PMID- 23022524 TI - Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic beta cells. AB - Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic beta cells. In the present study, we have identified the expression of TGR5 in pancreatic beta cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated Galpha(s) and caused an increase in intracellular cAMP and Ca(2+). OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective Galpha(s) inhibitor) or U73122 (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, U73122 or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G(s)/cAMP/Ca(2+) pathway. 8-pCPT-2'-O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic beta cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis. PMID- 23022525 TI - Protein Kinase C recognition sites in the cytoplasmic domain of Endothelin Converting Enzyme-1c. AB - Endothelin Converting Enzyme-1 (ECE-1) is essential for the production of the potent vasoconstrictor Endothelin-1 (ET-1). The activation of Protein Kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) can increase ECE-1 phosphorylation, which in turn promotes ECE-1c trafficking to the cell surface where ET-1 production occurs. This study has identified the specific residues in the N-terminal cytoplasmic tail of ECE-1c isoform that are phosphorylated upon the activation of PKC. Levels of phosphorylation are expressed as a % phosphorylation in untreated CHO-K1 cells. We transfected CHO-K1 cells with wild type and mutant forms of ECE-1c (Ala(4)-ECE-1c, Ala(35)ECE-1c and Ala(4/35)ECE 1c) to confirm the involvement of Thr(4) and Ser(35) residues in PMA induced phosphorylation of ECE-1c. Phosphorylation of wild type ECE-1c increased in response to PMA treatment (150+/-13%, unpaired t-test, P<0.05, significantly different compared to untreated control). The two single mutants and one combined mutant significantly reduced the PMA induced phosphorylation (103-117+/-6-13%; unpaired t-test; n=8; P<0.05 significantly different compared to untreated control). The mutations had no effect on the basal ECE-1c phosphorylation. In addition, they had no effect on the catalytic activity as evidenced by the similar rate of substrate cleavage compared to wild type. This study is the first to confirm the residues phosphorylated upon the activation of PKC by PMA. The results complete a gap in our understanding of the mechanism(s) behind PKC induced trafficking of ECE-1. PMID- 23022526 TI - Smad3 linker phosphorylation attenuates Smad3 transcriptional activity and TGF beta1/Smad3-induced epithelial-mesenchymal transition in renal epithelial cells. AB - Transforming growth factor-beta1 (TGF-beta1) has a distinct role in renal fibrosis associated with epithelial-mesenchymal transition (EMT) of the renal tubules and synthesis of extracellular matrix. Smad3 plays an essential role in fibrosis initiated by EMT. Phosphorylation of Smad3 in the C-terminal SSXS motif by type I TGF-beta receptor kinase is essential for mediating TGF-beta response. Smad3 activity is also regulated by phosphorylation in the linker region. However, the functional role of Smad3 linker phosphorylation is not well characterized. We now show that Smad3 EPSM mutant, which mutated the four phosphorylation sites in the linker region, markedly enhanced TGF-beta1-induced EMT of Smad3-deficient primary renal tubular epithelial cells, whereas Smad3 3S-A mutant, which mutated the C-terminal phosphorylation sites, was unable to induce EMT in response to TGF-beta1. Furthermore, immunoblotting and RT-PCR analysis showed a marked induction of fibrogenic gene expression with a significant reduction in E-cadherin in HK2 human renal epithelial cells expressing Smad3 EPSM. TGF-beta1 could not induce the expression of alpha-SMA, vimentin, fibronectin and PAI-1 or reduce the expression of E-cadherin in HK2 cells expressing Smad3 3S-A in response to TGF-beta1. Our results suggest that Smad3 linker phosphorylation has a negative regulatory role on Smad3 transcriptional activity and TGF-beta1/Smad3-induced renal EMT. Elucidation of mechanism regulating the Smad3 linker phosphorylation can provide a new strategy to control renal fibrosis. PMID- 23022527 TI - Polycystic ovary syndrome (PCOS)-like phenotypes in the d-galactose-induced aging mouse model. AB - The D-galactose (D-gal)-induced animal model, which is established by consecutive subcutaneous d-gal injections for approximately 6weeks, has been frequently used for aging research. This animal model has been shown to accelerate aging of the brain, kidneys, liver, and blood cells. However, aging of the female reproductive organs in this animal model has not been reported. The aim of this study was to investigate changes in the ovary in the d-gal-induced aging mouse model. First, we evaluated anti-Mullerian hormone (AMH) as a marker of ovarian aging in blood plasma. We speculated there would be lower AMH levels in d-gal-treated mice because ovarian aging would be induced by d-gal, as reported for other tissues. However, the results showed that AMH levels in d-gal-treated mice were approximately four-fold higher than control mice. Abnormally high AMH levels are detected in ovarian cancer and polycystic ovary syndrome (PCOS) patients. Therefore, we examined PCOS-related markers in this mouse model. Total testosterone levels were high and abnormal estrous cycles were induced in d-gal treated mice. These changes, including AMH levels, in d-gal-treated mice were inhibited by aminoguanidine treatment, an advanced glycation end product reducer. In addition, ovarian cysts were observed in some d-gal-treated mice. These results indicate that with respect to female reproduction, d-gal-treated mice are suitable for PCOS studies, rather than aging studies. PMID- 23022528 TI - The emerging role of T cell cytokines in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is among the most frequent types of cancer and associated with significant mortality. Recent studies suggest that tumor infiltrating T lymphocytes and their immunoregulatory cytokines play a fundamental role in controlling tumor growth and metastasis. Whereas T helper 1 cells and their master transcription factor T-bet have been identified as important regulators of IFN-gamma driven anti-tumoral immune response, IL-17 producing T helper 17 cells expressing RORA/C transcription factors have been found to augment tumor growth and cell proliferation in NSCLC. Furthermore, regulatory T cells were shown to impair immune responses against lung cancer. As modulation of T cell cytokines such as IL-17A has been recently shown to suppress tumor growth in experimental models, anti-cytokine agents emerge as a promising new approach for treatment of lung cancer. PMID- 23022529 TI - Experimental transmission in guinea pigs of H9N2 avian influenza viruses from indoor air of chicken houses. AB - This study aimed to determine the transmission characteristics of H9N2 avian influenza viruses (AIVs) derived from the air. Eight H9N2 AIVs were isolated from chicken houses between 2009 and 2010. We analyzed the phylogenic and pathogenic traits of these isolates. What is more, transmission characteristics in guinea pigs of two airborne isolates were determined in experimental conditions. Phylogenetic analyses indicated that the homologies of HA and NA genes of eight isolates were 95.4-99.7% and 86.6-99.8% respectively. They were able to duplicate in lung tissues of guinea pigs without prior adaptation. Two airborne isolates could both transmit among guinea pigs by direct contact. No infection was detected in aerosol contact animals while H9N2 AIV aerosols were detected in the air of isolators. Aerosol infection dose experiment showed that aerosol median infective dose (ID(50)) of H9N2 AIV to guinea pigs was 3.58*10(6)copies, demonstrating that the aerosols could infect guinea pigs at certain concentrations in experimental condition. In conclusion, H9N2 AIV aerosols were infectious to mammals, suggesting that urgent attention will need to be paid to its transmission. PMID- 23022530 TI - Lysine-71 in the large delta antigen of hepatitis delta virus clade 3 modulates its localization and secretion. AB - Hepatitis delta virus (HDV) is an RNA virus and eight clades of HDV have been identified. HDV clade 3 (HDV-3) is isolated only in the northern area of South America. The outcome of HDV-3 infection is associated with severe fulminant hepatitis. Variations in the large delta antigen (LDAg) between HDV clade 1 (HDV 1) and HDV-3 have been proposed to contribute to differences in viral secretion efficiency, but which changes might be relevant remains unclear. The control of subcellular localization of LDAg has been reported to be associated with post translational modifications, such as phosphorylation and isoprenylation. We have observed evidence for acetylation on the LDAg of HDV-3 (LDAg-3) and LDAg of HDV-1 (LDAg-1). Green fluorescent protein-fused LDAg-3 (GFP-LD3) was used to investigate the cellular distribution and secretion of the protein. Sequence alignment of LDAg amino acids suggested that lysine-71 of LDAg-3 could be an acetylation site. Expression of a mutant form of LDAg-3 with an arginine substitution at lysine-71 (GFP-LD3K71R) showed a distribution of the protein predominantly in the cytoplasm instead of the nucleus. Western blot analyses of secreted empty viral particles (EVPs) revealed a higher amount of secreted GFP LD3K71R compared to GFP-LD3. Furthermore, the ectopic expression of p300, a histone acetyltransferase, led to a reduction of GFP-LD3 in EVPs. By contrast, expression of three histone deacetylases (HDAC-4, -5, and -6) facilitated the secretion of GFP-LD3. Combined, our observations support the hypothesis that the acetylation status of LDAg-3 plays a role in regulating LDAg-3's localization inside the nucleus or cytoplasm, and its secretion. PMID- 23022532 TI - Comparison of neuroprotective effects of five major lipophilic diterpenoids from Danshen extract against experimentally induced transient cerebral ischemic damage. AB - We observed neuroprotective effects of five major lipophilic diterpenes derived from Danshen (Radix Salvia miltiorrhiza) extract, such as cryptotanshinone (CTs), dihydrotanshinone I (DTsI), tanshinone I (TsI), tanshinone IIA (TsIIA) and tanshinone IIB (TsIIB), in the hippocampal CA1 region (CA1) against transient ischemic damage in gerbils. These diterpenes were administered 30min before ischemia-reperfusion and the animals were sacrificed 4days after ischemia reperfusion. In the vehicle-treated-group, cresyl violet positive (CV(+)) cells and neuronal nuclei (NeuN)(+) neurons were significantly decreased in the CA1. However, in the TsI- and CTs-treated-ischemia-groups, CV(+) and NeuN(+) neurons were abundant in the CA1. In the other groups, the number of CV(+) and NeuN(+) neurons was less than the TsI- and CTs-treated-ischemia-groups. In addition, gliosis induced by ischemic damage was apparently blocked in the TsI- and CTs treated-ischemia-groups. These results suggest that TsI and CTs among five major lipophilic diterpenes have strong potentials for neuroprotection against ischemic damage. PMID- 23022533 TI - Microbial transformation of 20(S)-protopanaxadiol by Absidia corymbifera. Cytotoxic activity of the metabolites against human prostate cancer cells. AB - Biotransformation of 20(S)-protopanaxadiol (1) by the fungus Absidia corymbifera AS 3.3387 yielded five metabolites (2-6). On the basis of spectroscopic data analyses, the metabolites were identified as 26-hydroxyl-20(S)-protopanaxadiol (2), 23, 24-en-25-hydroxyl-20(S)-protopanaxadiol (3), 25-hydroxyl-20(S) protopanaxadiol (4), 7beta-hydroxyl-20(S)-protopanaxatriol (5), and 7-oxo-20(S) protopanaxatriol (6), respectively. Among them, 5 and 6 are new compounds. These results indicated that A. corymbifera AS 3.3387 could catalyze the side-chain oxidation-reduction, 7beta hydroxylation, and the specific C-7 dehydrogenation of derivatives of 20(S)-protopanaxadiol. The metabolites 2, 5, and 6 showed the more potent inhibitory effects against DU-145 and PC-3 cell lines than the substrate. PMID- 23022534 TI - Pistagremic acid, a glucosidase inhibitor from Pistacia integerrima. AB - Pistacia integerrima Stewart in traditionally used as folk remedy for various pathological conditions including diabetes. In order to identify the bioactive compound responsible for its folk use in diabetes, a phytochemical and biological study was conducted. Pistagremic acid (PA) was isolated from the dried galls extract of P. integerrima. Strong alpha-glucosidase inhibitory potential of PA was predicted using its molecular docking simulations against yeast alpha glucosidase as a therapeutic target. Significant experimental alpha-glucosidase inhibitory activity of PA confirmed the computational predictions. PA showed potent enzyme inhibitory activity both against yeast (IC(50): 89.12+/-0.12MUM) and rat intestinal (IC(50): 62.47+/-0.09MUM) alpha-glucosidases. Interestingly, acarbose was found to be more than 12 times more potent an inhibitor against mammalian (rat intestinal) enzyme (having IC(50) value 62.47+/-0.09MUM), as compared to the microbial (yeast) enzyme (with IC(50) value 780.21MUM). Molecular binding mode was explored via molecular docking simulations, which revealed hydrogen bonding interactions between PA and important amino acid residues (Asp60, Arg69 and Asp 70 (3.11A)), surrounding the catalytic site of the alpha glucosidase. These interactions could be mainly responsible for their role in potent inhibitory activity of PA. PA has a strong potential to be further investigated as a new lead compound for better management of diabetes. PMID- 23022535 TI - Three new germacrane-type sesquiterpene stereoisomers from the flowers of Chrysanthemum indicum. AB - From the flowers of Chrysanthemum indicum, three new germacrane-type sesquiterpene stereoisomers (1beta,3alpha,5beta-trihydroxyl-7-isopropenyl germacren-4(15), 10(14)-diene (1), 1beta,3beta,5alpha-trihydroxyl-7-isopropenyl germacren-4(15), 10(14)-diene (2), 1beta,3beta,5beta-trihydroxyl-7-isopropenyl germacren-4(15), 10(14)-diene (3)) were isolated, whose structures were elucidated on the basis of extensive spectroscopic analysis. The absolute configuration of compound 1 was determined by a single crystal X-ray diffraction study using a mirror Cu Kalpha radiation. PMID- 23022536 TI - Influence of cyclovirobuxine D on intracellular [Ca(2+)] regulation and the expression of the calcium cycling proteins in rat myocytes. AB - Our previous studies have shown that cyclovirobuxine D (CVB-D) ameliorated the cardiac function in heart failure rats. Considering the relationship between cardiac function and [Ca(2+)]i, and the role of calcium cycling on regulating [Ca(2+)]i, the present study was designed to evaluate the influence of CVB-D on the calcium transient of myocytes from neonatal rats and adult heart failure (HF) rats. The expression of calcium cycling proteins, including L-type calcium channel (LTCC), ryanodine receptor 2 (RYR2), sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) and sodium-calcium exchanger (NCX), were investigated to explore the underlying mechanism. CVB-D increased the intensity of calcium transient, accelerated the process of calcium transient and attenuation in the neonatal and adult myocytes. Furthermore, CVB-D shortened T(peak) and T(attenuation) in the adult myocytes and slowed down the heart rate of neonatal myocytes. Besides, CVB-D increased the expression of RYR2 and SERCA2a, decreased the expression of NCX, but showed no significant effect on LTCC. Thus, it was concluded that CVB-D increased the release and uptake of Ca(2+) in systolic and diastolic period, respectively. CVB-D might not only facilitate the utilization of intracellular Ca(2+), but also prevent the loss of Ca(2+). PMID- 23022537 TI - Divergent strategy for adaptation to drought stress in two sibling species of montium species subgroup: Drosophila kikkawai and Drosophila leontia. AB - Drosophila leontia (warm adapted) has been considered as a sister species of Drosophila kikkawai (sub-cosmopolitan) with a very similar morphology. We found divergent strategies for coping with desiccation stress in these two species of montium subgroup. Interestingly, in contrast to clinal variation for body melanization in D. kikkawai, cuticular lipid mass showed a positive cline in D. leontia across a latitudinal transect. On the basis of isofemale line analysis, within population trait variability in cuticular lipid mass per fly is positively correlated with desiccation resistance and negatively correlated with cuticular water loss in D. leontia. A comparative analysis of water budget of these two species showed that higher abdominal melanization, reduced rate of water loss and greater dehydration tolerance confer higher desiccation resistance in D. kikkawai while the reduced rate of water loss is the only possible mechanism to enhance desiccation tolerance in D. leontia. The use of organic solvents has supported water proofing role of cuticular lipids in D. leontia but not in D. kikkawai. Thus, we may suggest that body melanization and cuticular lipids may represent alternative strategies for coping with dehydration stress in melanic versus non melanic drosophilids. In both these species, carbohydrates were utilized under desiccation stress but a higher level of stored carbohydrates was evident in D. kikkawai. Further, we found increase desiccation resistance in D. kikkawai through acclimation while D. leontia lacks such a response. Thus, species specific divergence in water balance related traits in these species are consistent with their adaptations to wet and dry habitats. PMID- 23022539 TI - GABAergic control of retinal ganglion cell dendritic development. AB - Developing GABAergic neurons mature long before excitatory neurons, and early GABA(A) activity exerts important paracrine effects while neurons extend dendrites and axons and they establish neural connections. One of the unique features of early GABA(A) activity is that it induces membrane depolarization and Ca(2+) influx and it shifts to inhibition when networks mature. Although it has been demonstrated in several systems that early GABA(A) signaling plays a fundamental role in guiding neurite outgrowth, it has never been investigated in the retina. Here we show that chronic GABAergic activity is required for the stabilization and maintenance of newly formed dendritic branches in developing turtle retinal ganglion cells (RGCs) in ovo. Blocking GABA(A) receptors with bicuculline or inhibiting GABA synthesis with l-allylglycine have contrasting effects on dendritic growth and branching in biocytin-labeled RGCs. Dendritic arbor reconstruction shows that bicuculline induces dendritic branch loss without global change in the extent of dendritic fields while l-allylglycine causes the entire tree to shrink. At the same time, multielectrode array recordings and Ca(2+) imaging show that l-allylglycine has similar effects to bicuculline (Leitch et al., 2005) on overall network excitability, preventing the disappearance of immature retinal waves of activity and the GABAergic polarity shift. This study demonstrates for the first time that GABA plays an important role in vivo in stabilizing developing dendrites into mature arbors in the retina. However, the way GABA influences dendritic growth appears to be driven by complex mechanisms that cannot be explained solely on the basis of overall network activity levels. PMID- 23022540 TI - Indwelling catheters and medical implants with FXIIIa inhibitors: A novel approach to the treatment of catheter and medical device-related infections. AB - Central venous catheters (CVCs) are being utilized with increasing frequency in intensive care and general medical wards. In spite of the extensive experience gained in their application, CVCs are related to the long-term risks of catheter sheath formation, infection, and thrombosis (of the catheter or vessel itself) during catheterization. Such CVC-related-complications are associated with increased morbidity, mortality, duration of hospitalization, and medical care cost [1]. The present study incorporates a novel group of Factor XIIIa (FXIIIa, plasma transglutaminase) inhibitors into a lubricious silicone elastomer in order to generate an optimized drug delivery system whereby a secondary sustained drug release profile occurs following an initial burst release for catheters and other medical devices. We propose that the incorporation of FXIIIa inhibitors into catheters, stents, and other medical implant devices would reduce the incidence of catheter sheath formation, thrombotic occlusion, and associated staphylococcal infection. This technique could be used as a local delivery system for extended release with an immediate onset of action for other poorly aqueous soluble compounds. PMID- 23022541 TI - Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation of liver tumours. AB - Recent decades have seen a paradigm shift in the treatment of liver tumours from invasive surgical procedures to minimally invasive image-guided ablation techniques. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a novel, completely non-invasive ablation technique that has the potential to change the field of liver tumour ablation. The image guidance, using MR imaging and MR temperature mapping, provides excellent planning images and real-time temperature information during the ablation procedure. However, before clinical implementation of MR-HIFU for liver tumour ablation is feasible, several organ specific challenges have to be addressed. In this review we discuss the MR-HIFU ablation technique, the liver-specific challenges for MR-HIFU tumour ablation, and the proposed solutions for clinical translation. PMID- 23022542 TI - Polysaccharide gene transfection agents. AB - Gene delivery is a promising technique that involves in vitro or in vivo introduction of exogenous genes into cells for experimental and therapeutic purposes. Successful gene delivery depends on the development of effective and safe delivery vectors. Two main delivery systems, viral and non-viral gene carriers, are currently deployed for gene therapy. While most current gene therapy clinical trials are based on viral approaches, non-viral gene medicines have also emerged as potentially safe and effective for the treatment of a wide variety of genetic and acquired diseases. Non-viral technologies consist of plasmid-based expression systems containing a gene associated with the synthetic gene delivery vector. Polysaccharides compile a large family of heterogenic sequences of monomers with various applications and several advantages as gene delivery agents. This chapter, compiles the recent progress in polysaccharide based gene delivery, it also provides an overview and recent developments of polysaccharide employed for in vitro and in vivo delivery of therapeutically important nucleotides, e.g. plasmid DNA and small interfering RNA. PMID- 23022543 TI - Human insulin adsorption kinetics, conformational changes and amyloidal aggregate formation on hydrophobic surfaces. AB - The formation of insulin amyloidal aggregates on material surfaces is a well known phenomenon with important pharmaceutical and medical implications. Using surface plasmon resonance imaging, we monitor insulin adsorption on model hydrophobic surfaces in real time. Insulin adsorbs in two phases: first, a very fast phase (less than 1 min), where a protein monolayer forms, followed by a slower one that can last for at least 1h, where multilayered protein aggregates are present. The dissociation kinetics reveals the presence of two insulin populations that slowly interconvert: a rapidly dissociating pool and a pool of strongly bound insulin aggregates. After 1h of contact between the protein solution and the surface, the adsorbed insulin has practically stopped dissociating from the surface. The conformation of adsorbed insulin is probed by attenuated total reflection-Fourier transform infrared spectroscopy. Characteristic shifts in the amide A and amide II' bands are associated with insulin adsorption. The amide I band is also distinct from that of soluble or aggregated insulin, and it slowly evolves in time. A 1708 cm-1 peak is observed, which characterizes insulin adsorbed for times longer than 30 min. Finally, Thioflavin T, a marker of extended beta-sheet structures present in amyloid fibers, binds to adsorbed insulin after 30-40 min. Altogether, these results reveal that the conformational change induced in insulin upon binding to hydrophobic surfaces allows further insulin binding from the solution. Adsorbed insulin is thus an intermediate along the alpha-to-beta structural transition that results in the formation of amyloidal fibers on these material surfaces. PMID- 23022538 TI - Are BDNF and glucocorticoid activities calibrated? AB - One hypothesis to account for the onset and severity of neurological disorders is the loss of trophic support. Indeed, changes in the levels and activities of brain-derived neurotrophic factor (BDNF) occur in numerous neurodegenerative and neuropsychiatric diseases. A deficit promotes vulnerability whereas a gain of function facilitates recovery by enhancing survival, synapse formation and synaptic plasticity. Implementation of 'BDNF therapies', however, faces numerous methodological and pharmacokinetic issues. Identifying BDNF mimetics that activate the BDNF receptor or downstream targets of BDNF signaling represent an alternative approach. One mechanism that shows great promise is to study the interplay of BDNF and glucocorticoid hormones, a major class of natural steroid secreted during stress reactions and in synchrony with circadian rhythms. While small amounts of glucocorticoids support normal brain function, excess stimulation by these steroid hormones precipitates stress-related affective disorders. To date, however, because of the paucity of knowledge of underlying cellular mechanisms, deleterious effects of glucocorticoids are not prevented following extreme stress. In the present review, we will discuss the complementary roles shared by BDNF and glucocorticoids in synaptic plasticity, and delineate possible signaling mechanisms mediating these effects. PMID- 23022544 TI - In vivo degradation performance of micro-arc-oxidized magnesium implants: a micro CT study in rats. AB - Biodegradable Mg alloys are of great interest for osteosynthetic applications because they do not require surgical removal after they have served their purpose. In this study, fast-degrading ZX50 Mg-based implants were surface treated by micro-arc oxidation (MAO), to alter the initial degradation, and implanted along with untreated ZX50 controls in the femoral legs of 20 male Sprague-Dawley rats. Their degradation was monitored by microfocus computed tomography (MUCT) over a total observation period of 24weeks, and histological analysis was performed after 4, 12 and 24weeks. While the MAO-treated samples showed almost no corrosion in the first week, they revealed an accelerated degradation rate after the third week, even faster than that of the untreated ZX50 implants. This increase in degradation rate can be explained by an increase in the surface-area-to-volume ratio of MAO-treated implants, which degrade inhomogeneously via localized corrosion attacks. The histological analyses show that the initially improved corrosion resistance of the MAO implants has a positive effect on bone and tissue response: The reduced hydrogen evolution (due to reduced corrosion) makes possible increased osteoblast apposition from the very beginning, thus generating a stable bone-implant interface. As such, MAO treatment appears to be very interesting for osteosynthetic implant applications, as it delays implant degradation immediately after implantation, enhances fracture stabilization, minimizes the burden on the postoperatively irritated surrounding tissue and generates good bone-implant connections, followed by accelerated degradation in the later stage of bone healing. PMID- 23022546 TI - In situ forming collagen-hyaluronic acid membrane structures: mechanism of self assembly and applications in regenerative medicine. AB - Bioactive, in situ forming materials have the potential to complement minimally invasive surgical procedures and enhance tissue healing. For such biomaterials to be adopted in the clinic, they must be cost-effective, easily handled by the surgeon and have a history of biocompatibility. To this end, we report a novel and facile self-assembling strategy to create membranes and encapsulating structures using collagen and hyaluronic acid (HA). Unlike membranes built by layer-by-layer deposition of oppositely charged biomolecules, the collagen-HA membranes described here form a diffusion barrier upon electrostatic interaction of the oppositely charged biomolecules, which is further driven by osmotic pressure imbalances. The resulting membranes have a nanofibrous architecture, a thicknesses of 130 MUm and a tensile modulus (0.59+/-0.06 MPa) that can increase 7-fold using carbodiimide chemistry (4.42+/-1.46 MPa). Collagen-HA membranes support mesenchymal stem cell proliferation and have a slow and steady protein release profile (7% at day 28), offering opportunities for targeted tissue regeneration. We demonstrate the capacity to encapsulate cells by injecting HA into the collagen solution, and enhance allograft and implant biocompatibility through a coating technique. This study describes a novel mechanism of collagen HA membrane formation and provides the groundwork to apply these membranes in a variety of tissue engineering applications. PMID- 23022545 TI - Controlled release of doxorubicin from pH-responsive microgels. AB - Stimuli-responsive hydrogels have enormous potential in drug delivery applications. They can be used for site-specific drug delivery due to environmental variables in the body such as pH and temperature. In this study, we have developed pH-responsive microgels for the delivery of doxorubicin (DOX) in order to optimize its anti-tumor activity while minimizing its systemic toxicity. We used a copolymer of oligo(polyethylene glycol) fumarate (OPF) and sodium methacrylate (SMA) to fabricate the pH-responsive microgels. We demonstrated that the microgels were negatively charged, and the amounts of charge on the microgels were correlated with the SMA concentration in their formulation. The resulting microgels exhibited sensitivity to the pH and ionic strength of the surrounding environment. We demonstrated that DOX was efficiently loaded into the microgels and released in a controlled fashion via an ion-exchange mechanism. Our data revealed that the DOX release was influenced by the pH and ionic strength of the solution. Moreover, we designed a phenomenological mathematical model, based on a stretched exponential function, to quantitatively analyze the cumulative release of DOX. We found a linear correlation between the maximum release of DOX calculated from the model and the SMA concentration in the microgel formulation. The anti-tumor activity of the released DOX was assessed using a human chordoma cell line. Our data revealed that OPF-SMA microgels prolonged the cell killing effect of DOX. PMID- 23022548 TI - Aging behavior of PVA hydrogels for soft tissue applications after in vitro swelling using osmotic pressure solutions. AB - The osmotic pressure of the medium used for in vitro swelling evaluation has been shown to have a significant effect on the swelling behavior of a material. In this study, the effect of osmotic pressure during swelling on poly(vinyl alcohol) hydrogel material properties was evaluated in vitro. Osmotic pressure solutions are necessary in order to mimic the swelling pressure observed in vivo for soft tissues present in load-bearing joints. Hydrogels were characterized after swelling by mechanical testing, X-ray diffraction and optical microscopy in the hydrated state. Results indicated that hydrogel mechanical properties remained tailorable with respect to initial processing parameters; however, significant aging occurred in osmotic solution. This was observed when evaluating the mechanical properties of the hydrogels, which, before swelling, ranged from 0.04 to 0.78 MPa but, after swelling in vitro using osmotic pressure solution, ranged from 0.32 to 0.93 MPa. Significant aging was also noted when evaluating crystallinity, with the relative crystallinity ranging between 0.4 and 5.0% before swelling and between 6.5 nd 8.0% after swelling. When compared to swelling in a non-osmotic pressure solution or in phosphate-buffered saline solution, the mechanical properties were more dependent upon the final swelling content. Furthermore, increases in crystallinity were not as significant after swelling. These results highlight the importance of choosing the appropriate swelling medium for in vitro characterization based on the desired application. PMID- 23022547 TI - Hidden contributions of the enamel rods on the fracture resistance of human teeth. AB - The enamel of human teeth is generally regarded as a brittle material with low fracture toughness. Consequently, the contributions of this tissue in resisting tooth fracture and the importance of its complex microstructure have been largely overlooked. In this study an experimental evaluation of the crack growth resistance of human enamel was conducted to characterize the role of rod (i.e. prism) orientation and degree of decussation on the fracture behavior of this tissue. Incremental crack growth was achieved in-plane, with the rods in directions longitudinal or transverse to their axes. Results showed that the fracture resistance of enamel is both inhomogeneous and spatially anisotropic. Cracks extending transverse to the rods in the outer enamel undergo a lower rise in toughness with extension, and achieve significantly lower fracture resistance than in the longitudinal direction. Though cracks initiating at the surface of teeth may begin extension towards the dentin-enamel junction, they are deflected by the decussated rods and continue growth about the tooth's periphery, transverse to the rods in the outer enamel. This process facilitates dissipation of fracture energy and averts cracks from extending towards the dentin and vital pulp. PMID- 23022549 TI - Cueing effects of target location probability and repetition. AB - The search performance for targets is improved when the targets appear in a specific location more frequently than in other locations. Although this phenomenon, called the "probability cueing effect," has been reported in past studies, it is unclear whether probability cueing is driven by statistical learning and/or intertrial facilitation of the target location. We investigated the underlying mechanisms for probability cueing effects by manipulating probabilities and repetitions of the target appearance at each target location. The first experiment demonstrated that the reaction time benefits of both statistical learning and intertrial facilitation contributed to the probability cueing effect. In contrast, the second and third experiments demonstrated that the probability cueing effect did not occur when target location repetitions on consecutive trials were fully or partially restricted. Also, any intertrial facilitation effects disappeared if there were more than one intervening trials. These results suggest that consecutive target location repetitions throughout the experiment facilitate learning of the target location probability. PMID- 23022550 TI - Pigeons show efficient visual search by category: effects of typicality and practice. AB - Three experiments investigated category search in pigeons, using an artificial category created by morphing of human faces. Four pigeons were trained to search for category members among nonmembers, with each target item consisting of an item-specific component and a common component diagnostic of the category. Experiment 1 found that search was more efficient with homogeneous than heterogeneous distractors. In Experiment 2, the pigeons successfully searched for target exemplars having novel item-specific components. Practice including these items enabled the pigeons to efficiently search for the highly familiar members. The efficient search transferred immediately to more typical novel exemplars in Experiment 3. With further practice, the pigeons eventually developed efficient search for individual less typical exemplars. Results are discussed in the context of visual search theories and automatic processing of individual exemplars. PMID- 23022551 TI - Dynamic modeling of aerobic growth of Shewanella oneidensis. Predicting triauxic growth, flux distributions, and energy requirement for growth. AB - A model-based analysis is conducted to investigate metabolism of Shewanella oneidensis MR-1 strain in aerobic batch culture, which exhibits an intriguing growth pattern by sequentially consuming substrate (i.e., lactate) and by products (i.e., pyruvate and acetate). A general protocol is presented for developing a detailed network-based dynamic model for S. oneidensis based on the Lumped Hybrid Cybernetic Model (L-HCM) framework. The L-HCM, although developed from only limited data, is shown to accurately reproduce exacting dynamic metabolic shifts, and provide reasonable estimates of energy requirement for growth. Flux distributions in S. oneidensis predicted by the L-HCM compare very favorably with (13)C-metabolic flux analysis results reported in the literature. Predictive accuracy is enhanced by incorporating measurements of only a few intracellular fluxes, in addition to extracellular metabolites. The L-HCM developed here for S. oneidensis is consequently a promising tool for the analysis of intracellular flux distribution and metabolic engineering. PMID- 23022552 TI - Effects of denial of reward through maternal contact in the neonatal period on adult hypothalamic-pituitary-adrenal axis function in the rat. AB - Emotional behavioral traits associated with stress response are well documented to be affected by early life events. In the present work, we used a novel paradigm of neonatal experience, in which pups were trained in a T-maze and either received (RER rats) or were denied (DER) the reward of maternal contact, during postnatal days 10-13. We then evaluated stress coping and key factors controlling the function of the hypothalamic-pituitary-adrenal axis in adulthood. Adult male DER rats exposed to a single session of forced swim stress (FSS) showed increased immobility, while RER rats exhibited increased escape attempts. The corticosterone response following this stressor was higher although not prolonged in the DER rats. Their CRH mRNA levels in the PVN were increased up to 2h after the forced swim. However, basal levels of these hormones did not differ among groups. In addition, the DER neonatal experience induced an increase in hippocampal GR but a decrease in CRH-R1 immunopositive cells in the CA1 area of the hippocampus and the central amygdala. Overall, these data show a distinct stress response profile in the DER male rats, characterized by passive coping during the forced swim, increased hormonal response following stress, increased inhibitory control through GR and an indirect contribution of CRH-R1, the latter two factors resulting in a modified regulation of the response termination. It thus appears that DER rats have an enhanced potential for appropriate reactivity upon an incoming challenge, while maintaining in parallel an adequate control of the duration of their stress responses. PMID- 23022553 TI - Development of stevioside Pluronic-F-68 copolymer based PLA-nanoparticles as an antidiabetic nanomedicine. AB - Stevioside (FDA approved nontoxic natural non-caloric sweetener) has been reported to have very good antidiabetic potential but its use as therapeutic drug is restricted in human due to its deprived intestinal absorption and poor bioavailability. We have nano-bioconjugated this molecule on biodegradable Pluronic-F-68 copolymer based PLA nanoparticles by nanoprecipitation method (spherical, size range 110-130 nm) to overcome deprived intestinal absorption and to enhance the bioavailability. The drug loading calculated by the standard calibrated HPLC was 16.32+/-4% (w/w). The in vitro release study showed the initial burst followed by the sustained release. The half release and complete release were observed on 25+/-4 h and 200+/-10 h respectively. This newly formulated nanostevioside showed very high potential to be used as antidiabetic nanomedicine for safe and effective use in vivo. PMID- 23022554 TI - Energy and macronutrient content of familiar beverages interact with pre-meal intervals to determine later food intake, appetite and glycemic response in young adults. AB - The objective was to compare the effects of pre-meal consumption of familiar beverages on appetite, food intake, and glycemic response in healthy young adults. Two short-term experiments compared the effect of consumption at 30 (experiment 1) or 120 min (experiment 2) before a pizza meal of isovolumetric amounts (500 mL) of water (0 kcal), soy beverage (200 kcal), 2% milk (260 kcal), 1% chocolate milk (340 kcal), orange juice (229 kcal) and cow's milk-based infant formula (368 kcal) on food intake and subjective appetite and blood glucose before and after a meal. Pre-meal ingestion of chocolate milk and infant formula reduced food intake compared to water at 30 min, however, beverage type did not affect food intake at 2h. Pre-meal blood glucose was higher after chocolate milk than other caloric beverages from 0 to 30 min (experiment 1), and after chocolate milk and orange juice from 0 to 120 min (experiment 2). Only milk reduced post meal blood glucose in both experiments, suggesting that its effects were independent of meal-time energy intake. Combined pre- and post-meal blood glucose was lower after milk compared to chocolate milk and orange juice, but did not differ from other beverages. Thus, beverage calorie content and inter-meal intervals are primary determinants of food intake in the short-term, but macronutrient composition, especially protein content and composition, may play the greater role in glycemic control. PMID- 23022556 TI - Eat this, not that! Parental demographic correlates of food-related parenting practices. AB - To understand how parents of adolescents attempt to regulate their children's eating behaviors, the prevalence of specific food-related parenting practices (restriction, pressure-to-eat) by sociodemographic characteristics (parent gender, race/ethnicity, education level, employment status, and household income) were examined within a population-based sample of parents (n=3709) of adolescents. Linear regression models were fit to estimate the association between parent sociodemographic characteristics and parental report of food restriction and pressure-to-eat. Overall, findings suggest that use of controlling food-related parenting practices, such as pressuring children to eat and restricting children's intake, is common among parents of adolescents, particularly among parents in racial/ethnic minority subgroups, parents with less than a high school education, and parents with a low household income. Results indicate that that social or cultural traditions, as well as parental access to economic resources, may contribute to a parent's decision to utilize specific food-related parenting practices. Given that previous research has found that restriction and pressure-to-eat food-related parenting practices can negatively impact children's current and future dietary intake, differences in use of these practices by sociodemographic characteristics may contribute, in part, to the disparities that exist in the prevalence of overweight and obesity among adolescents by their race/ethnicity and socioeconomic status. PMID- 23022557 TI - Role of poly(ADP-ribose) polymerases in the regulation of inflammatory processes. AB - PARP enzymes influence the immune system at several key points and thus modulate inflammatory diseases. PARP enzymes affect immune cell maturation and differentiation and regulate the expression of inflammatory mediators such as cytokines, chemokines, inducible nitric oxide synthase and adhesion molecules. Moreover, PARP enzymes are key regulators of cell death during inflammation related oxidative and nitrosative stress. Here we provide an overview of the different inflammatory diseases regulated by PARP enzymes. PMID- 23022555 TI - Rapid onset and reversal of peripheral and central leptin resistance in rats offered chow, sucrose solution, and lard. AB - We previously reported that rats offered choice diet (chow, 30% sucrose solution, lard) increase body fat by 130% within 3 weeks. We tested the effects of choice diet on the development of leptin resistance in rats. Intraperitoneal injection of 2mg/kg leptin inhibited 14 h food intake and weight gain of all rats after 2 days and 4 days of diet. On day 8, choice rats were leptin insensitive and by day 16 they were resistant. Chow rats remained leptin responsive. A second study showed that on day 16 choice, but not chow rats, were centrally leptin resistant (1.5 MUg leptin, 3rd ventricle). In both studies, rats were switched back to chow only after approximately 3 weeks on choice diet and were leptin responsive after 4 days. A third study showed that carcass fat was reduced by 30% 4 days after switching back to chow. A final experiment showed that leptin responsive chow rats, but not leptin resistant choice rats, increased energy expenditure by 12% during the 2.6h after a central leptin injection. Thus, choice diet rapidly induces leptin resistance, but leptin responsiveness is quickly restored when choice is replaced with chow. This rapid onset and reversal of leptin resistance may be associated with changes in either substrate metabolism or adiposity. PMID- 23022558 TI - Equilibrium self-association of tropomyosin. AB - It has recently been reported that tropomyosin exists exclusively as a dimer in physiological salt conditions. It is shown in the present work using analytical ultracentrifugation that, on the contrary, tropomyosin is in equilibrium between monomer, dimer and tetramer with a weak tendency to dimerize and tetramerize. Such a finding has consequences for the assembly of the tropomyosin-actin complex. PMID- 23022560 TI - A new family of bacterial DNA repair proteins annotated by the integration of non homology, distant homology and structural bioinformatic methods. AB - Different bioinformatics methods illuminate different aspects of protein function, from specific catalytic activities to broad functional categories. Here, a triple-pronged approach to predict function for a domain of unknown function, DUF2086, is applied. Distant homology to characterised enzymes and conservation of key residues suggest an oxygenase function. Modelling indicates that the substrate is most likely a nucleic acid. Finally, genomic context analysis linking DUF2086 to DNA repair, leads to a predicted activity of oxidative demethylation of damaged bases in DNA. The newly assigned activity is sporadically present in phyla not containing near relatives of the similarly active repair protein AlkB. PMID- 23022559 TI - Cdk5-mediated phosphorylation of CRMP-2 enhances its interaction with CaV2.2. AB - The axon/dendrite specification collapsin response mediator protein-2 (CRMP-2) bidirectionally regulates N-type voltage-gated Ca(2+) channels (CaV2.2). But how cyclin dependent kinase 5 (Cdk5)-mediated phosphorylation of CRMP-2 affects its interaction/regulation with CaV2.2 is unknown. CRMP-2-mediated enhancement of currents via CaV2.2 was not observed with a Cdk5 phospho-null CRMP-2-S522A mutant or in cells expressing an inactive Cdk5. Concomitant knockdown of endogenous CRMP2 and overexpression of CRMP2-S522A mutant refractory to knockdown phenocopied the reduction in Ca(2+) influx while the Rho kinase CRMP2-T555A mutant was ineffective. Cdk5-phosphorylated CRMP-2 had increased association with CaV2.2. These results identify an important role for Cdk5 in CRMP2-mediated CaV2.2 regulation. PMID- 23022561 TI - Do antioxidants impair signaling by reactive oxygen species and lipid oxidation products? AB - Oxidative modification of biologically essential molecules by reactive oxygen and nitrogen species (ROS/RNS) has been implicated in the pathogenesis of various diseases. At the same time, roles of ROS/RNS as physiological signaling messenger have been established. Lipid oxidation products also have two faces. It is argued that the radical scavenging antioxidants taken from diet or supplement may impair such beneficial effects of ROS/RNS and lipid oxidation products. However, it is unlikely that antioxidants impair physiologically important signaling, since the antioxidants do not scavenge signaling ROS/RNS nor do they inhibit the formation of signaling molecules. Lipid peroxidation products are not produced on purpose and inhibition of lipid peroxidation by antioxidants should be beneficial for maintenance of health and reducing disease risk. PMID- 23022562 TI - Phosphorylation of measles virus phosphoprotein at S86 and/or S151 downregulates viral transcriptional activity. AB - Measles virus phosphoprotein (P protein) is a cofactor of the viral RNA polymerase (L protein) that associates with the nucleoprotein-RNA complex to support viral transcription and replication. Here, we report a significant inverse correlation between the phosphorylation level of MV-P protein and viral transcriptional activity. Upregulation of P protein phosphorylation resulted in reduction of viral transcription. Additionally, we found that strong phosphorylation at S86 and S151 of P protein, which may be generally prevented by association with nucleoprotein, downregulates the viral transcriptional activity. These findings suggest that P protein is involved in regulation of viral transcription through changes in its phosphorylation status. PMID- 23022563 TI - Lateral gene transfer between the Bacteroidetes and Acidobacteria: the case of alpha-L-rhamnosidases. AB - alpha-L-Rhamnosidases catalyze the hydrolysis of the terminal alpha-L-rhamnose residues in various carbohydrates. The catalytic domains in most of these enzymes belong to the families GH78 and GH106 of glycoside hydrolases. In this study, we show that almost all genes encoding the GH78- and GH106-containing proteins from members of the poorly characterized bacterial phylum Acidobacteria originated from precursors belonging to the phylum Bacteroidetes. Members of the Acidobacteria and Bacteroidetes display similar functional capabilities and specialize on degradation of plant-derived organic matter. Several proposed lateral gene transfers between the Acidobacteria and Bacteroidetes occurred presumably during specialization of these bacteria for their environments. PMID- 23022565 TI - Temperature effects on brain tissue in compression. AB - Extensive research has been carried out for at least 50 years to understand the mechanical properties of brain tissue in order to understand the mechanisms of traumatic brain injury (TBI). The observed large variability in experimental results may be due to the inhomogeneous nature of brain tissue and to the broad range of test conditions. However, test temperature is also considered as one of the factors influencing the properties of brain tissue. In this research, the mechanical properties of porcine brain have been investigated at 22 degrees C (room temperature), and at 37 degrees C (body temperature) while maintaining a constant preservation temperature of approximately 4-5 degrees C. Unconfined compression tests were performed at dynamic strain rates of 30 and 50s(-1) using a custom made test apparatus. There was no significant difference (p=0.8559 0.9290) between the average engineering stresses of the brain tissue at the two different temperature conditions. The results of this study should help to understand the behavior of brain tissue at different temperature conditions, particularly in unconfined compression tests. PMID- 23022564 TI - Histaminylation of glutamine residues is a novel posttranslational modification implicated in G-protein signaling. AB - Posttranslational modifications (PTM) have been shown to be essential for protein function and signaling. Here we report the identification of a novel modification, protein transfer of histamine, and provide evidence for its function in G protein signaling. Histamine, known as neurotransmitter and mediator of the inflammatory response, was found incorporated into mastocytoma proteins. Histaminylation was dependent on transglutaminase II. Mass spectrometry confirmed histamine modification of the small and heterotrimeric G proteins Cdc42, Galphao1 and Galphaq. The modification was specific for glutamine residues in the catalytic core, and triggered their constitutive activation. TGM2-mediated histaminylation is thus a novel PTM that functions in G protein signaling. Protein alphamonoaminylations, thus including histaminylation, serotonylation, dopaminylation and norepinephrinylation, hence emerge as a novel class of regulatory PTMs. PMID- 23022566 TI - Fracture properties of growth plate cartilage compared to cortical and trabecular bone in ovine femora. AB - Fracture mechanical parameters (notch tensile strength, specific fracture energy/crack resistance and specific crack initiation energy) of epiphyseal plate cartilage, trabecular bone (metaphysis) and cortical bone (diaphysis) were determined on ovine femur specimens. The fracture behaviour before and after crack initiation was recorded in force-displacement diagrams from wedge splitting tests. Crack propagation was stable both during and after the formation of a principal crack. This is the main advantage of the wedge-splitting method by Tschegg in comparison with tensile tests. Microscopy of the epiphyseal plate during fracture showed fibre elongation and tearing in the crack tip region. The results of this study can help to understand the mechanics of epiphyseal plate injuries and the obtained values can be used for computational simulations and models. PMID- 23022567 TI - Effects of skilled and unskilled training on functional recovery and brain plasticity after focal ischemia in adult rats. AB - Stroke is a leading cause of morbidity and mortality worldwide. Recovery of motor function after stroke can be modified by post-injury experience, but most of surviving patients exhibit persistence of the motor dysfunctions even after rehabilitative therapy. In this study we investigated if skilled and unskilled training induce different motor recovery and brain plasticity after experimental focal ischemia. We tested this hypothesis by evaluating the motor skill relearning and the immunocontent of Synapsin-I, PSD-95 and GFAP (pre and post synaptic elements, as well as surrounding astroglia) in sensorimotor cortex of both hemispheres 6 weeks after endothelin-1-induced focal brain ischemia in rats. Synapsin-I and PSD-95 levels were increased by skilled training in ischemic sensorimotor cortex. The content of GFAP was augmented as a result of focal brain ischemia in ischemic sensorimotor cortex and that was not modified by rehabilitation training. Unexpectedly, animals remained permanently impaired at the end of motor/functional evaluations. Significant modifications in protein expression were not observed in undamaged sensorimotor cortex. We conclude that skilled motor activity can positively affect brain plasticity after focal ischemia despite of no functional improvement in conditions here tested. PMID- 23022568 TI - Bacterial gene loss as a mechanism for gain of antimicrobial resistance. AB - Acquisition of exogenous DNA by pathogenic bacteria represents the basis for much of the acquired antimicrobial resistance in pathogenic bacteria. A more extreme mechanism to avoid the effect of an antibiotic is to delete the drug target, although this would be predicted to be rare since drug targets are often essential genes. Here, we review and discuss the description of a novel mechanism of resistance to the cephalosporin drug ceftazidime caused by loss of a penicillin-binding protein (PBP) in a Gram-negative bacillus (Burkholderia pseudomallei). This organism causes melioidosis across south-east Asia and northern Australia, and is usually treated with two or more weeks of ceftazidime followed by oral antibiotics for three to six months. Comparison of clinical isolates from six patients with melioidosis found initial ceftazidime-susceptible isolates and subsequent ceftazidime-resistant variants. The latter failed to grow on commonly used culture media, rendering these isolates difficult to detect in the diagnostic laboratory. Genomic analysis using pulsed-field gel electrophoresis and array based genomic hybridisation revealed a large-scale genomic deletion comprising 49 genes in the ceftazidime-resistant strains. Mutational analysis of wild-type B. pseudomallei demonstrated that ceftazidime resistance was due to deletion of a gene encoding a PBP 3 present within the region of genomic loss. This provides one explanation for ceftazidime treatment failure, and may be a frequent but undetected event in patients with melioidosis. PMID- 23022569 TI - Innovative use of a bacterial enzyme involved in sialic acid degradation to initiate sialic acid biosynthesis in glycoengineered insect cells. AB - The baculovirus/insect cell system is widely used for recombinant protein production, but it is suboptimal for recombinant glycoprotein production because it does not provide sialylation, which is an essential feature of many glycoprotein biologics. This problem has been addressed by metabolic engineering, which has extended endogenous insect cell N-glycosylation pathways and enabled glycoprotein sialylation by baculovirus/insect cell systems. However, further improvement is needed because even the most extensively engineered baculovirus/insect cell systems require media supplementation with N acetylmannosamine, an expensive sialic acid precursor, for efficient recombinant glycoprotein sialylation. Our solution to this problem focused on E. coli N acetylglucosamine-6-phosphate 2'-epimerase (GNPE), which normally functions in bacterial sialic acid degradation. Considering that insect cells have the product, but not the substrate for this enzyme, we hypothesized that GNPE might drive the reverse reaction in these cells, thereby initiating sialic acid biosynthesis in the absence of media supplementation. We tested this hypothesis by isolating transgenic insect cells expressing E. coli GNPE together with a suite of mammalian genes needed for N-glycoprotein sialylation. Various assays showed that these cells efficiently produced sialic acid, CMP-sialic acid, and sialylated recombinant N-glycoproteins even in growth media without N acetylmannosamine. Thus, this study demonstrated that a eukaryotic recombinant protein production platform can be glycoengineered with a bacterial gene, that a bacterial enzyme which normally functions in sialic acid degradation can be used to initiate sialic acid biosynthesis, and that insect cells expressing this enzyme can produce sialylated N-glycoproteins without N-acetylmannosamine supplementation, which will reduce production costs in glycoengineered baculovirus/insect cell systems. PMID- 23022570 TI - Effect of puuC overexpression and nitrate addition on glycerol metabolism and anaerobic 3-hydroxypropionic acid production in recombinant Klebsiella pneumoniae DeltaglpKDeltadhaT. AB - 3-Hydroxypropionic acid (3-HP), an industrially important platform chemical, is used as a precursor during the production of many commercially important chemicals. Recently, recombinant strains of K. pneumoniae overexpressing an NAD(+)-dependent gamma-glutamyl-gamma-aminobutyraldehyde dehydrogenase (PuuC) enzyme of K. pneumoniae DSM 2026 were shown to produce 3-HP from glycerol without the addition coenzyme B(12), which is expensive. However, 3-HP production in K. pneumoniae is accompanied with NADH generation, and this always results in large accumulation of 1,3-propanediol (1,3-PDO) and lactic acid. In this study, we investigated the potential use of nitrate as an electron acceptor both to regenerate NAD(+) and to prevent the formation of byproducts during anaerobic production of 3-HP from glycerol. Nitrate addition could improve NAD(+) regeneration, but decreased glycerol flux towards 3-HP production. To divert more glycerol towards 3-HP, a novel recombinant strain K. pneumoniae DeltaglpKDeltadhaT (puuC) was developed by disrupting the glpK gene, which encodes glycerol kinase, and the dhaT gene, which encodes 1,3-propanediol oxidoreductase. This strain showed improved cellular NAD(+) concentrations and a high carbon flux towards 3-HP production. Through anaerobic cultivation in the presence of nitrate, this recombinant strain produced more than 40+/-3mM 3-HP with more than 50% yield on glycerol in shake flasks and 250+/-10mM 3-HP with approximately 30% yield on glycerol in a fed-batch bioreactor. PMID- 23022571 TI - Fundamental frequency is key to response of female deer to juvenile distress calls. AB - Considerable attention is currently devoted to understanding acoustic mechanisms underlying animal responses to heterospecific vocalizations. A further complication ensues when the response of two species is asymmetrical. For example, white-tailed deer females approach a speaker only when it plays distress calls of conspecific fawns. Mule deer females approach when hearing distress calls of either white-tailed deer or mule deer. We hypothesized that selective species such as white-tailed deer respond to traits distinctive of their species and less-discriminating species such as mule deer respond to traits shared across species. Through an acoustic analysis of neonatal distress calls of six ungulate species, we found that mean and maximum fundamental frequency (F0) enabled the greatest statistical discrimination, and the pattern of frequency modulation (FM) was shared across species. Contrary to our initial hypothesis, playback experiments revealed that females of the two species respond similarly to manipulation of F0 and FM. F0 was critical to the response of females from both species, which tolerated the same relative F0 variation (approx. 0.6-1.4* the mean F0 for conspecific fawns). This discovery suggests that mule deer females only appear less discriminating because they are tuned to the higher F0 of mule deer distress calls (964 Hz vs. 546 Hz), resulting in a larger absolute response range that encompasses the F0 produced by white-tailed deer fawns. We propose that animals will have larger absolute response ranges, and therefore appear to be less discriminating, when they belong to a species that produces higher F0 calls. PMID- 23022572 TI - Autumn migratory orientation and displacement responses of two willow warbler subspecies (Phylloscopus trochilus trochilus and P. t. acredula) in South Sweden. AB - Topography and historical range expansion has formed a so-called migratory divide between two subspecies of willow warbler (Phylloscopus trochilus) in central Scandinavia. The autumn migratory directions of individuals assigned molecularly to both subspecies and possible hybrids were recorded using orientation cage experiments in southwest and southeast Sweden. We found pronounced differences in willow warblers' orientation in respect to genotype. The mean directions registered in the control experiments were in accordance with the ringing recoveries and analyses of stable isotopes for Scandinavian willow warblers. With the same individuals we performed displacement experiments between both sites. They resulted in non-significant orientation, which could be explained by the intermediate distance of the displacement or reactions to housing, transportation and location. On a separate set of birds we tested whether stress following transportation could explain the disorientation and found that orientation before and after transport was unchanged. Experimental studies of effects of intermediate displacements across longitudes and studies of orientation of hybrid individuals in the zones of migratory divides are crucial for understanding the mechanisms underlying orientation behaviour. Our work further stresses the importance of knowing the migration genotype of a particular bird under study, in order to correctly evaluate expected migration routes. PMID- 23022573 TI - Characterization of a new strain of Taura syndrome virus (TSV) from Colombian shrimp farms and the implication in the selection of TSV resistant lines. AB - Prior to 2004, Colombian shrimp farming benefited from a selection program in which Penaeus vannamei stocks were developed with resistance to Taura syndrome disease (TS). However since 2004, TS reappeared as a significant disease. In 2010, an apparently new strain of TSV (designated as CO 10) was collected in Colombia. Its genome was sequenced and compared with six other fully sequenced isolates. This analysis revealed that the TSV CO 10 is closely related to the isolates from Hawaii and Venezuela. Phylogenetic analysis based on capsid protein 2 (CP2) region from 59 TSV isolates shows that the recent Colombian isolates (2006-2010) form a new cluster and differ from the previous Colombia isolates (1994-1998) by 4% in nucleotide sequence. The virulence of this CO 10 isolate was similar to a Belize TSV determined through experimental infection in P. vannamei showing 100% mortalities and similar survival curves. By RT-qPCR for TSV, the viral loads were also close in the infected shrimp from both CO 10 and Belize at the order of 1*10(10) copies per MUl RNA. To develop TSV-resistant lines, the candidate shrimp should be challenged with virus strains that have been isolated most recently from the regions where they will be cultured. This study suggests that the TSV present in Colombian shrimp farms during the last 5 years is a new TSV strain with high virulence. PMID- 23022574 TI - The delicate balance between vitamin D, calcium and bone homeostasis: lessons learned from intestinal- and osteocyte-specific VDR null mice. AB - The serum calcium levels and the calcium content of the skeleton are highly interdependent. Indeed, bone requires calcium to preserve its strength, but it is at the same time also the predominant calcium storage from which calcium can be mobilized to supply the serum pool. The active form of vitamin D [1,25(OH)2D] plays a crucial role in regulating the transfer of calcium between blood and bone, evidenced by experimental data obtained from systemic, intestinal-specific and osteocyte-specific vitamin D receptor (Vdr) null mice. In fact, 1,25(OH)2D is required to maintain normocalcemia and bone health by enhancing intestinal calcium absorption when dietary calcium intake is normal/low. When, however, insufficient calcium is absorbed via the intestine, 1,25(OH)2D levels will increase and will act on mature osteoblasts and osteocytes to minimize calcium levels in bone tissue in favor of the blood calcium pool. Mechanistically, the high 1,25(OH)2D levels enhance bone remodeling which leads to osteopenia, and suppress bone matrix mineralization by increasing the levels of mineralization inhibitors, which causes hyperosteoidosis and hypomineralization. Thus, depending on the intestinal calcium acquisition, 1,25(OH)2D will target the intestine and/or the skeleton to maintain calcium levels in serum within a normal range. PMID- 23022575 TI - Alterations in tyrosine kinase receptor (Trk) expression induced by insulin-like growth factor-1 in cultured dorsal root ganglion neurons. AB - Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor expressed in small dorsal root ganglion (DRG) neurons. IGF-1 promotes neuronal survival by activating its receptor (IGF-1R). Whether IGF-1 and its signaling pathways influence the expression of tyrosine kinase receptors TrkA, TrkB and TrkC in DRG neurons remains unknown. In the present study, primary cultured DRG neurons were used to determine the effects of IGF-1 on TrkA, TrkB and TrkC expression. The involvement of extracellular signal-regulated protein kinase (ERK1/2) and the effects of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways on IGF-1 were also evaluated. DRG neurons were cultured for 48h and then exposed to IGF-1, PD98059 plus IGF-1, LY294002 plus IGF-1, and PD98059 plus LY294002 plus IGF-1 for an additional 24h. The DRG neurons were continuously exposed to culture medium as a control. All cultures were then processed for detection of mRNA levels of TrkA, TrkB and TrkC using real-time PCR analysis. Protein levels of TrkA, TrkB and TrkC were detected using a Western blot assay. The expression of TrkA, TrkB and TrkC in situ was determined by a fluorescent labeling technique. The levels of phosphorylated ERK1/2 (pERK1/2) and phosphorylated Akt (pAkt) were detected using a Western blot assay. The results indicated that in primary cultured DRG neurons, IGF-1 increased the expression of TrkA and TrkB and their mRNAs but not TrkC or its mRNA. Neither the ERK1/2 inhibitor PD98059 nor the PI3K inhibitor LY294002 alone blocked the effect of IGF-1, but the use of both inhibitors together was effective. IGF-1 may play an important role in regulating the expression of different Trk receptors in DRG neurons through the ERK1/2 and PI3K/Akt signaling pathways. These results suggest that IGF-1 signaling might be a potential target on modifying distinct Trk receptor-mediated biological effects. PMID- 23022577 TI - Tonic eye movements induced by bilateral and unilateral galvanic vestibular stimulation (GVS) in guinea pigs. AB - Galvanic vestibular stimulation (GVS) stimulates primary vestibular afferents innervating the semicircular canals (SCCs) and otoliths found in the inner ear of humans and other mammals, including guinea pigs. To determine which pathways contribute to eye movements generated by this artificial vestibular stimulation in guinea pigs, low current intensities of GVS were passed either bilaterally between the tensor-tympani muscles of the two ears (up to 30 MUA) or unilaterally between one tensor-tympani electrode and an indifferent on the back of the neck (up to 60 MUA). Both forms of GVS were found to selectively generate tonic eye movements without nystagmus, characteristic of the otolith-ocular reflex; the axis of eye rotation did not align with any semicircular canal plane, but was oriented close to the expected axis of eye rotation that would occur in response to the net stimulation of otolith afferents. The induced eye rotation was predominantly vertical with a smaller horizontal deviation and very little torsion. Consistent with the results of previous human studies, the tonic eye movements were found to exhibit bilateral gain enhancement, whereby bilateral GVS generated twice the amplitude of eye rotation as unilateral anodal or cathodal stimulation alone. Eye movement responses to unilateral GVS were symmetrical in amplitude during equivalent intensities of anodal and cathodal stimulation, consistent with the known responses of more regularly and intermediately discharging primary vestibular afferents to GVS. These results together suggest that more regularly discharging otolith-ocular projections may mediate the tonic changes in eye position induced during maintained, low-intensity GVS in guinea pigs. PMID- 23022578 TI - Detection of irradiated beef by nuclear magnetic resonance lipid profiling combined with chemometric techniques. AB - The combination of (1)H NMR lipid profiling with multivariate analysis was applied to differentiate irradiated and non-irradiated beef. Two pattern recognition chemometric procedures, stepwise linear discriminant analysis (sLDA) and artificial neural networks (ANNs), provided a successful discrimination between the groups investigated. sLDA allowed the classification of 100% of the samples into irradiated or non-irradiated beef groups; the same result was obtained by ANNs using the 1 kGy irradiation dose as discriminant value suggested by the network. Furthermore, sLDA allowed the classification of 81.9% of the beef samples according to the irradiation dose (0, 2.5, 4.5 and 8 kGy). (1)H NMR lipid profiling, coupled with multivariate analysis may be considered a suitable and promising screening tool for the rapid detection of irradiated meat in official control of food. PMID- 23022579 TI - The impact of salt and fat level variation on the physiochemical properties and sensory quality of pork breakfast sausages. AB - The sensory and physiochemical properties of sausages with varying fat and salt levels were investigated. Twenty eight sausages were produced with varying concentrations of fat (22.5%, 27.5%, 32.5%, 37.5% w/w) and salt (0.8%, 1%, 1.2%, 1.4%, 1.6%, 2%, 2.4% w/w). Sausages were assessed instrumentally for colour, moisture, fat, cooking loss and texture profile analysis. Consumers (n = 25), evaluated each product in duplicate for colour, texture, tenderness, juiciness, salt taste, meat flavour, off-flavour and overall acceptability using a hedonic scale. Lowering fat produced products which consumers rated as less dark in colour, tougher, less juicy and taste less salty than higher fat products. However, no significant preferred sample was found amongst consumers. Salt reduction in products produced sausages which consumers rated as paler in colour, more tender and with greater meat flavour than higher salt containing products. The sausages containing 1.4% and 1.0% salt were significantly (P<0.01) found to be more acceptable to consumers than other salt levels. PMID- 23022576 TI - Ascorbic acid efficiently enhances neuronal synthesis of norepinephrine from dopamine. AB - Ascorbic acid enhances synthesis of norepinephrine from dopamine in adrenal chromaffin cells by serving as a co-factor for chromaffin granule dopamine beta hydroxylase (DbetaH). However, there is controversy regarding in situ kinetics of the ascorbate effect in chromaffin cells, as well as whether they apply to neuronal cells. In this study we evaluated the stimulation of norepinephrine synthesis from dopamine in cultured SH-SY5Y neuroblastoma cells. These cells contained neither ascorbate nor norepinephrine in culture, but when provided with dopamine, they generated intracellular norepinephrine at rates that were stimulated several-fold by intracellular ascorbate. Ascorbate-induced increases in norepinephrine synthesis in dopamine-treated cells were linear over 60 min, despite saturation of intracellular ascorbate. Norepinephrine accumulation after 60 min of incubation with 100 MUM dopamine was half-maximal at intracellular ascorbate concentrations of 0.2-0.5 mM, which fits well with the literature K(m) for ascorbate of DbetaH using dopamine as a substrate. Moreover, these ascorbate concentrations were generated by initial extracellular ascorbate concentrations of less than 25 MUM due to concentrative accumulation by the ascorbate transporter. Treatment with 100 MUM dopamine acutely increased cellular superoxide generation, which was prevented by ascorbate loading, but associated with a decrease in intracellular ascorbate when the latter was present at concentrations under 1 mM. These results show that ascorbate promptly enhances norepinephrine synthesis from dopamine by neuronal cells that it does so at physiologic intracellular concentrations in accord with the kinetics of DbetaH, and that it both protects cells from superoxide and by providing electrons to DbetaH. PMID- 23022580 TI - Molecular cloning, characterization and expression profiles of multiple leptin genes and a leptin receptor gene in orange-spotted grouper (Epinephelus coioides). AB - Leptin plays key roles in body weight regulation, energy metabolism, food intake, reproduction and immunity in mammals. However, its function in teleosts is still unclear. In the present study, two leptin genes (gLepA and gLepB) and one leptin receptor gene (gLepR) were cloned and characterized in orange-spotted grouper (Epinephelus coioides). The cDNAs of gLepA and gLepB were 671 bp and 684 bp in length, encoding for proteins of 161 amino acid (aa) and 158 aa, respectively. The three-dimensional (3D) structures modeling of gLepA and gLepB showed strong conservation of tertiary structure with that of other vertebrates. The total length of gLepR cDNA was 4242 bp, encoding a protein of 1169 aa which contained all functionally important domains conserved among vertebrate LEPR. Tissue distribution analysis showed that gLepA was highly expressed in cerebellum, liver and ovary, while gLepB mRNA abundantly in the brain regions, as well as in the ovary with some extend. The gLepR was mainly expressed in kidney, head kidney and most of brain regions. Analysis of expression profiles of gLep and gLepR genes during the embryonic stages showed that high expression of gLepR was observed in the brain vesicle stage, while neither gLepA nor gLepB mRNA was detected during different embryonic stages. Finally, fasting and refeeding experiments were carried out to investigate the possible function of leptin genes in food intake and energy metabolism, and the results showed that a significant increase of gLepA expression in the liver was induced by food deprivation in both short-term (7 days) and long-term (3 weeks) fasting and gLepA mRNA upregulation was eliminated after refeeding, while gLepB wasn't detected in the liver of grouper during fasting. No significant differences in hypothalamic leptin and leptin receptor expression were found during short-term fasting and refeeding. Hepatic expression of gLepA mRNA increased significantly 9h after a single meal. These results suggested gLepA, other than gLepB, functioned in the regulation of energy metabolism and food intake in this Perciform fish. PMID- 23022581 TI - Holding water steroid hormones in the African cichlid fish Pseudocrenilabrus multicolor victoriae. AB - Measuring hormone levels multiple times on the same individual across different life stages or treatments can facilitate our understanding of hormonal regulation of physiological and behavioral events. The conventional method of hormone measurement requires blood sampling, which is potentially lethal to small individuals. In fishes, there is an alternative non-invasive method of hormone measurement using the release of hormones across gill membranes from blood into holding water. Validation of this method is required to evaluate its application value to different species. In the present study we used the maternal mouth brooding African cichlid fish, Pseudocrenilabrus multicolor victoriae to (i) investigate whether handling involved in using the holding water technique is a stressor by measuring excreted cortisol in male and female P. multicolor handled one or multiple times, (ii) validate use of this technique by quantifying the relationship between plasma and holding water measures of sex hormones in male P. multicolor, and (iii) demonstrate the biological relevance of this technique using excreted levels of sex hormones in female P. multicolor across different reproductive stages. Excreted cortisol and estradiol levels did not differ between fish handled one or more times, suggesting that the repeated sampling approach over the breeding cycle that we propose to use does not affect the excreted level of the hormone of interest. Measurements from plasma and holding water samples were positively related for both testosterone and estradiol, indicating that the holding water technique is a reliable index of plasma hormone levels. Excreted sex hormone levels varied with reproductive state, suggesting that the technique is a useful, non-invasive measure of sex hormone levels in P. multicolor. PMID- 23022582 TI - Site-specific quantitative analysis of cardiac mitochondrial protein phosphorylation. AB - We report the development of a multiple-reaction monitoring (MRM) strategy specifically tailored to the detection and quantification of mitochondrial protein phosphorylation. We recently derived 68 MRM transitions specific to protein modifications in the respiratory chain, voltage-dependent anion channel, and adenine nucleotide translocase. Here, we have now expanded the total number of MRM transitions to 176 to cover proteins from the tricarboxylic acid cycle, pyruvate dehydrogenase complex, and branched-chain alpha-keto acid dehydrogenase complex. We utilized the transition set to analyze endogenous protein phosphorylation in human heart, mouse heart, and mouse liver. The data demonstrate the potential utility of the MRM workflow for studying the functional details of mitochondrial phosphorylation signaling. This article is part of a Special Issue entitled: From protein structures to clinical applications. PMID- 23022583 TI - Proteins implicated in the increase of adhesivity induced by suberoylanilide hydroxamic acid in leukemic cells. AB - We have previously shown that suberoylanilide hydroxamic acid (SAHA) treatment increases the adhesivity of leukemic cells to fibronectin at clinically relevant concentrations. Now, we present the results of the proteomic analysis of SAHA effects on leukemic cell lines using 2-DE and ProteomLab PF2D system. Histone acetylation at all studied acetylation sites reached the maximal level after 5 to 10 h of SAHA treatment. No difference in histone acetylation between subtoxic and toxic SAHA doses was observed. SAHA treatment induced cofilin phosphorylation at Ser3, an increase in vimentin and paxillin expression and a decrease in stathmin expression as confirmed by western-blotting and immunofluorescence microscopy. The interaction of cofilin with 14-3-3 epsilon was documented using both Duolink system and coimmunoprecipitation. However, this interaction was independent of cofilin Ser3 phosphorylation and the amount of 14-3-3-epsilon-bound cofilin did not rise following SAHA treatment. SAHA-induced increase in the cell adhesivity was associated with an increase in PAK phosphorylation in CML-T1 cells and was abrogated by simultaneous treatment with IPA-3, a PAK inhibitor. The effects of SAHA on JURL-MK1 cells were similar to those of other histone deacetylase inhibitors, tubastatin A and sodium butyrate. The proteome analysis also revealed several potential non-histone targets of histone deacetylases. PMID- 23022585 TI - Renegotiating forensic cultures: between law, science and criminal justice. AB - This article challenges stereotypical conceptions of Law and Science as cultural opposites, arguing that English criminal trial practice is fundamentally congruent with modern science's basic epistemological assumptions, values and methods of inquiry. Although practical tensions undeniably exist, they are explicable-and may be neutralised-by paying closer attention to criminal adjudication's normative ideals and their institutional expression in familiar aspects of common law trial procedure, including evidentiary rules of admissibility, trial by jury, adversarial fact-finding, cross-examination and the ethical duties of expert witnesses. Effective partnerships between lawyers and forensic scientists are indispensable for integrating scientific evidence into criminal proceedings, and must be renegotiated between individual practitioners on an on-going basis. Fruitful interdisciplinary collaboration between scholars with a shared interest in forensic science should dispense with reductive cultural stereotypes of Science and Law. PMID- 23022584 TI - A quantitative proteomic workflow for characterization of frozen clinical biopsies: laser capture microdissection coupled with label-free mass spectrometry. AB - This paper describes a simple, highly efficient and robust proteomic workflow for routine liquid-chromatography tandem mass spectrometry analysis of Laser Microdissection Pressure Catapulting (LMPC) isolates. Highly efficient protein recovery was achieved by optimization of a "one-pot" protein extraction and digestion allowing for reproducible proteomic analysis on as few as 500 LMPC isolated cells. The method was combined with label-free spectral count quantitation to characterize proteomic differences from 3000-10,000 LMPC isolated cells. Significance analysis of spectral count data was accomplished using the edgeR tag-count R package combined with hierarchical cluster analysis. To illustrate the capability of this robust workflow, two examples are presented: 1) analysis of keratinocytes from human punch biopsies of normal skin and a chronic diabetic wound and 2) comparison of glomeruli from needle biopsies of patients with kidney disease. Differentially expressed proteins were validated by use of immunohistochemistry. These examples illustrate that tissue proteomics carried out on limited clinical material can obtain informative proteomic signatures for disease pathogenesis and demonstrate the suitability of this approach for biomarker discovery. PMID- 23022586 TI - Review of research on impacts to biota of discharges of naturally occurring radionuclides in produced water to the marine environment. AB - Produced water has been described as the largest volume waste stream in the exploration and production process of oil and gas. It is accompanied by discharges of naturally occurring radionuclides raising concerns over the potential radiological impacts of produced water on marine biota. In the Northern European marine environment, radioactivity in produced water has received substantial attention owing to the OSPAR Radioactive Substances Strategy which aims at achieving 'concentrations in the environment near background values for naturally occurring radioactive substances'. This review provides an overview of published research on the impacts to biota from naturally occurring radionuclides discharged in produced water by the offshore oil and gas industry. In addition to summarising studies and data that deal directly with the issue of dose and effect, the review also considers studies related to the impact of added chemicals on the fate of discharged radionuclides. The review clearly illustrates that only a limited number of studies have investigated possible impacts on biota from naturally occurring radionuclides present in produced water. Hence, although these studies indicate that the risk to the environment from naturally occurring radionuclides discharged in produced water is negligible, the substantial uncertainties involved in the assessments of impact make it difficult to be conclusive. With regard to the complexity involved in the problem under consideration there is a pressing need to supplement existing data and acquire new knowledge. Finally, the present work identifies some knowledge gaps to indicate future research requirements. PMID- 23022587 TI - Evaluation of in situ capping with clean soils to control phosphate release from sediments. AB - Evaluation of in situ capping with clean soils to control phosphate release from the sediments of a eutrophic bay in Lake Taihu was performed after 18 months of capping. The concentrations of dissolved reactive phosphate (DRP) in pore waters and DRP resupply from native sediments and capped sediments were determined using high-resolution dialysis (HR-Peeper) and a Zr-oxide diffusive gradients in thin films (Zr-oxide DGT) technique. The adsorption isotherm of these sediments was further investigated using a modified Langmuir model. The results showed low concentrations of DRP in pore waters with a low resupply from the sediments for sustaining pore water DRP concentration after capping. The calculated flux to the overlying water following the capping treatment was approximately half of that for the native sediments, implying that the capping reduced the release of phosphate from the sediments. The low resupply of the sediments after capping was further demonstrated by larger partitioning coefficient (K(p)) values and greater adsorption capacity (Q(max)) values, while zero equilibrium concentrations (EPC(0)s) were similar to those in native sediments. The larger K(p) and Q(max) were attributed to higher active Fe and Al introduced by the capping, indicating that the binding of phosphate onto the active Fe and Al played a critical role in reducing the internal loading of phosphorous. PMID- 23022588 TI - Purification and identification of antioxidant peptides from walnut (Juglans regia L.) protein hydrolysates. AB - Walnut proteins were hydrolyzed separately using three different proteases to obtain antioxidant peptides. The antioxidant activities of the hydrolysates were measured using 1,1-diphenyl-2-picryl hydrazyl (DPPH) assay. Among hydrolysates, pepsin hydrolysate obtained by 3h exhibited the highest antioxidant activities, which could also quench the hydroxyl radical, chelate ferrous ion, exhibit reducing power and inhibit the lipid peroxidation. Then, 3-h pepsin hydrolysates were purified sequentially by ultrafiltration, gel filtration and RP-HPLC. The sequence of the peptide with the highest antioxidative activity was identified to be Ala-Asp-Ala-Phe (423.23 Da) using RP-HPLC-ESI-MS, which was identified for the first time from walnut protein hydrolysates. Last, the inhibition of the peptide on lipid peroxidation was similar with that of reduced glutathione (GSH). These results indicate that the protein hydrolysates and/or its isolated peptides may be effectively used as food additives. PMID- 23022589 TI - Expression systems for heterologous production of antimicrobial peptides. AB - Antimicrobial peptides (AMPs) consist of molecules that act on the defense systems of numerous organisms toward multiple pathogens such as bacteria, fungi, parasites and viruses. These compounds have become extremely significant due to the increasing resistance of microorganisms to common antibiotics. However, the low quantity of peptides obtained from direct purification is, to date, still a remarkable bottleneck for scientific and industrial research development. Therefore, this review describes the main heterologous systems currently used for AMP production, including bacteria, fungi and plants, and also the related strategies for reaching greater functional peptide production. The main difficulties of each system are also described in order to provide some directions for AMP production. In summary, data revised here indicate that large scale production of AMPs can be obtained using biotechnological tools, and the products may be applied in the pharmaceutical industry as well as in agribusiness. PMID- 23022590 TI - Fruit fly behavior in response to chemosensory signals. AB - An important question in contemporary sensory neuroscience is how animals perceive their environment and make appropriate behavioral choices based on chemical perceptions. The fruit fly Drosophila melanogaster exhibits robust tastant and odor-evoked behaviors. Understanding how the gustatory and olfactory systems support the perception of these contact and volatile chemicals and translate them into appropriate attraction or avoidance behaviors has made an unprecedented contribution to our knowledge of the organization of chemosensory systems. In this review, I begin by describing the receptors and signaling mechanisms of the Drosophila gustatory and olfactory systems and then highlight their involvement in the control of simple and complex behaviors. The topics addressed include feeding behavior, learning and memory, navigation behavior, neuropeptide modulation of chemosensory behavior, and I conclude with a discussion of recent work that provides insight into pheromone signaling pathways. PMID- 23022591 TI - Insights into buforin II membrane translocation from molecular dynamics simulations. AB - Buforin II is a histone-derived antimicrobial peptide that readily translocates across lipid membranes without causing significant membrane permeabilization. Previous studies showed that mutating the sole proline of buforin II dramatically decreases its translocation. As well, researchers have proposed that the peptide crosses membranes in a cooperative manner by forming transient toroidal pores. This paper reports molecular dynamics simulations designed to investigate the structure of buforin II upon membrane entry and evaluate whether the peptide is able to form toroidal pore structures. These simulations showed a relationship between protein-lipid interactions and increased structural deformations of the buforin N-terminal region promoted by proline. Moreover, simulations with multiple peptides show how buforin II can embed deeply into membranes and potentially form toroidal pores. Together, these simulations provide structural insight into the translocation process for buforin II in addition to providing more general insight into the role proline can play in antimicrobial peptides. PMID- 23022592 TI - Mimotope peptides selected from phage display combinatorial library by serum antibodies of pigs experimentally infected with Taenia solium as leads to developing diagnostic antigens for human neurocysticercosis. AB - Neurocysticercosis is caused by penetration of the tapeworm Taenia solium larvae into the central nervous system resulting in a diverse range of neurologic complications including epilepsy in endemic areas that globalization spreads worldwide. Sensitive and specific immunodiagnosis is needed for the early detection and elimination of the parasite, but the lack of standardized, readily obtainable antigens is a challenge. Here, we used the phage display for resolving the problem. The rationale of the strategy rests on the concept that the screening of combinatorial libraries with polyclonal serum to pathogens reveals families of peptides mimicking the pathogen most immunodominant epitopes indispensable for the successful diagnosis. The screening of a 7mer library with serum IgG of four pigs experimentally infected with parasite followed by computer aided segregation of the selected sequences resulted in the discovery of four clusters of homologous sequences of which one presented a family of ten mimotopes selected by three infected pig serum IgGs; the common motif sequence LSPF carried by the family was considered to be the core of an immunodominant epitope of the parasite critical for the binding with the antibody that selected the mimotopes. The immunoassay testing permitted to select a mimotope whose synthetic peptide free of the phage with the amino acid sequence Leu-Ser-Fen-Pro-Ser-Val-Val that distinguished well a panel of 21 cerebrospinal fluids of neurocysticercosis patients from the fluids of individuals with neurological complications of other etiology. This peptide is proposed as a lead for developing a novel molecularly defined diagnostic antigen(s) for the neurocysticercosis. PMID- 23022593 TI - Early-stage cervical cancer: tumor delineation by magnetic resonance imaging and ultrasound - a European multicenter trial. AB - OBJECTIVE: To compare the diagnostic accuracy of ultrasound (US) and magnetic resonance imaging (MRI) in the preoperative assessment of early-stage cervical cancer using pathologic findings as the reference standard. PATIENTS AND METHODS: Prospective multi-center trial enrolling 209 consecutive women with early-stage cervical cancer (FIGO IA2-IIA) scheduled for surgery. The following parameters were assessed on US and MRI and compared to pathology: remaining tumor, size, tumor stromal invasion<2/3 (superficial) or >=2/3 (deep), and parametrial invasion. RESULTS: Complete data were available for 182 patients. The agreement between US and pathology was excellent for detecting tumors, correctly classifying bulky tumors (>4cm), and detecting deep stromal invasion (kappa values 0.84, 0.82, and 0.81 respectively); and good for classifying small tumors (<2cm) and detecting parametrial invasion (kappa values 0.78 and 0.75, respectively). The agreement between MRI and histology was good for classifying tumors as <2cm, or >4cm, and detecting deep stromal invasion (kappa values 0.71, 0.76, and 0.77, respectively). It was moderately accurate in tumor detection, and in assessing parametrial invasion (kappa values 0.52 and 0.45, respectively). The agreement between histology and US was significantly better in assessing residual tumor (p<0.001) and parametrial invasion (p<0.001) than the results obtained by MRI. Imaging methods were not significantly influenced by previous cone biopsy. CONCLUSION: US and MRI are highly accurate for the preoperative assessment of women with early-stage cervical cancer, although US may be more accurate in detecting residual tumors and assessing parametrial invasion. PMID- 23022594 TI - Evaluation of chemicals requiring metabolic activation in the EpiDermTM 3D human reconstructed skin micronucleus (RSMN) assay. AB - The in vitro human reconstructed skin micronucleus (RSMN) assay in EpiDermTM is a promising new assay for evaluating genotoxicity of dermally applied chemicals. A global pre-validation project sponsored by the European Cosmetics Association (Cosmetics Europe - formerly known as COLIPA), and the European Center for Validation of Alternative Methods (ECVAM), is underway. Results to date demonstrate international inter-laboratory and inter-experimental reproducibility of the assay for chemicals that do not require metabolism [Aardema et al., Mutat. Res. 701 (2010) 123-131]. We have expanded these studies to investigate chemicals that do require metabolic activation: 4-nitroquinoline-N-oxide (4NQO), cyclophosphamide (CP), dimethylbenzanthracene (DMBA), dimethylnitrosamine (DMN), dibenzanthracene (DBA) and benzo(a)pyrene (BaP). In this study, the standard protocol of two applications over 48h was compared with an extended protocol involving three applications over 72h. Extending the treatment period to 72h changed the result significantly only for 4NQO, which was negative in the standard 48h dosing regimen, but positive with the 72h treatment. DMBA and CP were positive in the standard 48h assay (CP induced a more reproducible response with the 72h treatment) and BaP gave mixed results; DBA and DMN were negative in both the 48h and the 72h dosing regimens. While further work with chemicals that require metabolism is needed, it appears that the RMSN assay detects some chemicals that require metabolic activation (4 out of 6 chemicals were positive in one or both protocols). At this point in time, for general testing, the use of a longer treatment period in situations where the standard 48h treatment is negative or questionable is recommended. PMID- 23022595 TI - Therapy response with diffusion MRI: an update. AB - The efficiency of an oncological treatment regimen is often assessed by morphological criteria such as tumour size evaluated by cross-sectional imaging, or by laboratory measurements of plasma biomarkers. Because these types of measures typically allow for assessment of treatment response several weeks or even months after the start of therapy, earlier response assessment that provides insight into tumour function is needed. This is particularly urgent for the evaluation of newer targeted therapies and for fractionated therapies that are delivered over a period of weeks to allow for a change of treatment in non responding patients. Diffusion-weighted MRI (DW-MRI) is a non-invasive imaging tool that does not involve radiation or contrast media, and is sensitive to tissue microstructure and function on a cellular level. DW-MRI parameters have shown sensitivity to treatment response in a growing number of tumour types and organ sites, with additional potential as predictive parameters for treatment outcome. A brief overview of DW-MRI principles is provided here, followed by a review of recent literature in which DW-MRI has been used to monitor and predict tumour response to various therapeutic regimens. PMID- 23022596 TI - Age-related decline of the cytochrome c oxidase subunit expression in the auditory cortex of the mimetic aging rat model associated with the common deletion. AB - The age-related deterioration in the central auditory system is well known to impair the abilities of sound localization and speech perception. However, the mechanisms involved in the age-related central auditory deficiency remain unclear. Previous studies have demonstrated that mitochondrial DNA (mtDNA) deletions accumulated with age in the auditory system. Also, a cytochrome c oxidase (CcO) deficiency has been proposed to be a causal factor in the age related decline in mitochondrial respiratory activity. This study was designed to explore the changes of CcO activity and to investigate the possible relationship between the mtDNA common deletion (CD) and CcO activity as well as the mRNA expression of CcO subunits in the auditory cortex of D-galactose (D-gal)-induced mimetic aging rats at different ages. Moreover, we explored whether peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) were involved in the changes of nuclear- and mitochondrial-encoded CcO subunits in the auditory cortex during aging. Our data demonstrated that d-gal-induced mimetic aging rats exhibited an accelerated accumulation of the CD and a gradual decline in the CcO activity in the auditory cortex during the aging process. The reduction in the CcO activity was correlated with the level of CD load in the auditory cortex. The mRNA expression of CcO subunit III was reduced significantly with age in the d-gal-induced mimetic aging rats. In contrast, the decline in the mRNA expression of subunits I and IV was relatively minor. Additionally, significant increases in the mRNA and protein levels of PGC-1alpha, NRF-1 and TFAM were observed in the auditory cortex of D-gal-induced mimetic aging rats with aging. These findings suggested that the accelerated accumulation of the CD in the auditory cortex may induce a substantial decline in CcO subunit III and lead to a significant decline in the CcO activity progressively with age despite compensatory increases of PGC-1alpha, NRF-1 and TFAM. Therefore, CcO may be a specific intramitochondrial site of age-related deterioration in the auditory cortex, and CcO subunit III might be a target in the development of presbycusis. PMID- 23022597 TI - Noise exposure potentiates the subcellular distribution of nucleotide excision repair proteins within spiral ganglion neurons. AB - Nucleotide excision repair (NER) is a defensive mechanism that limits genomic stress through genetically distinct cascades that employs Cockayne syndrome-A (CSA), the xeroderma pigmentosum-C (XPC) and the xeroderma pigmentosum-A (XPA) proteins. Noise exposure induces stress within the spiral ganglia. Therefore, it was posited that noise exposure would mobilize NER proteins within spiral ganglion neurons. Long-Evans rats were exposed to noise (105 dB SPL/4 h) and cochlear impairment was verified (pre-post DPOAE recordings) then the animals were euthanized via intravascular perfusion for temporal bone harvesting, immunohistochemistry and quantification of intracellular protein distribution. The results revealed that under normal (quiet) conditions the majority (~60%) of spiral ganglion neurons do not express NER proteins, however, a subpopulation (~40%) was NER positive. The overall number of reactive neurons stayed the same following noise exposure but there was significant (p < 0.01) subcellular redistribution of NER proteins. For instance, neurons within the apex exhibited significant (p < 0.01) nuclear accumulation of CSA while neurons within the base revealed significant (p < 0.05) nuclear accumulation of XPC. This spatial heterogeneity suggests a difference in genome defense repertoire between apical and basal coils of the cochlea. Furthermore, noise exposure depleted XPA from the nucleus regardless of location along the cochlear spiral. These findings provide a novel mechanism for interpreting noise-induced neuronal stress. PMID- 23022599 TI - Genetic damage in human cells exposed to non-ionizing radiofrequency fields: a meta-analysis of the data from 88 publications (1990-2011). AB - Based on the 'limited' evidence suggesting an association between exposure to radiofrequency fields (RF) emitted from mobile phones and two types of brain cancer, glioma and acoustic neuroma, the International Agency for Research on Cancer has classified RF as 'possibly carcinogenic to humans' in group 2B. In view of this classification and the positive correlation between increased genetic damage and carcinogenesis, a meta-analysis was conducted to determine whether a significant increase in genetic damage in human cells exposed to RF provides a potential mechanism for its carcinogenic potential. The extent of genetic damage in human cells, assessed from various end-points, viz., single /double-strand breaks in the DNA, incidence of chromosomal aberrations, micronuclei and sister chromatid exchanges, reported in a total of 88 peer reviewed scientific publications during 1990-2011 was considered in the meta analysis. Among the several variables in the experimental protocols used, the influence of five specific variables related to RF exposure characteristics was investigated: (i) frequency, (ii) specific absorption rate, (iii) exposure as continuous wave, pulsed wave and occupationally exposed/mobile phone users, (iv) duration of exposure, and (v) different cell types. The data indicated the following. (1) The magnitude of difference between RF-exposed and sham-/un exposed controls was small with some exceptions. (2) In certain RF exposure conditions there was a statistically significant increase in genotoxicity assessed from some end-points: the effect was observed in studies with small sample size and was largely influenced by publication bias. Studies conducted within the generally recommended RF exposure guidelines showed a smaller effect. (3) The multiple regression analyses and heterogeneity goodness of fit data indicated that factors other than the above five variables as well as the quality of publications have contributed to the overall results. (4) More importantly, the mean indices for chromosomal aberrations, micronuclei and sister chromatid exchange end-points in RF-exposed and sham-/un-exposed controls were within the spontaneous levels reported in a large data-base. Thus, the classification of RF as possibly carcinogenic to humans in group 2B was not supported by genotoxicity based mechanistic evidence. PMID- 23022600 TI - Association analysis between K and -116A variants of butyrylcholinesterase and Alzheimer's disease in a Brazilian population. AB - In Alzheimer's disease (AD) a reduction in acetylcholinesterase (AChE) and an increase in butyrylcholinesterase (BChE) activity are observed. K variant (539T) is the most common variant of the BCHE gene and, although controversial, several studies reported association between K variant and AD. Previous results showed that the K variant alone is not capable of diminishing BChE activity, depending on the presence of the -116A variant. Considering that, we conducted a case control association study using a clinically well defined group of AD patients (n = 82) and age and sex matched control subjects (EC; n = 78) in order to test the association with these variations of BCHE gene in a Brazilian population. The allele, genotype and haplotype frequencies of the K and the -116A variants of BCHE gene were not significantly different between cases and controls. Although not reaching statistical significance, the results suggested that the presence of -116A variant may have a protective effect against AD. The association of the K variant with AD in a controversial manner in different surveys is probably caused by its linkage disequilibrium with -116A that, by reducing BChE activity, potentially increases cholinergic transmission in comparison with usual genotypes. PMID- 23022601 TI - Stabilization and immobilization of aquaporin reconstituted lipid vesicles for water purification. AB - Aquaporins are water channel proteins in biological membranes that have extraordinary water permeability and selectivity. In this work, we have demonstrated that one of their family members, AquaporinZ (AqpZ), can be possibly applied in a pressure-driven water purification process. A nanofiltration membrane was designed and fabricated by immobilization of AqpZ-reconstituted liposomes on a polydopamine (PDA) coated microporous membrane. Amine functionalized proteoliposomes were first deposited via gentle vacuum suction and subsequently conjugated on the PDA layer via an amine-catechol adduct formation. Due to the existence of a polymer network within the lipid bilayers, the membrane could sustain hydraulic pressure of 5 bar as well as the strong surface agitation in nanofiltration tests, indicating a relatively stable membrane structure. In comparison with membrane without AqpZ incorporation, the membrane with AqpZ-to lipid weight ratio of 1:100 increased the water flux by 65% with enhanced NaCl and MgCl(2) rejections of 66.2% and 88.1%, respectively. With AqpZ incorporation, the vesicle immobilized membrane exhibits a promising strategy for high productivity water purification. PMID- 23022602 TI - Low, moderate, or high protein yogurt snacks on appetite control and subsequent eating in healthy women. AB - This study assessed whether afternoon snacks, varying in protein content, influence appetite-control and eating initiation. Fifteen healthy women (age: 26 +/- 2 y) randomly consumed 160 kcal afternoon yogurt snacks containing Low (LP), Moderate (MP), or High (HP) protein (5,14,24 g protein, respectively) or had no snack (NS) for 3 days. On day 4, the volunteers came to our facility to consume a standardized lunch. The respective snack pattern was completed 3h post-lunch. Perceived sensations were measured every 30 min until dinner was voluntarily requested. An ad libitum dinner was then provided. Snacking, regardless of protein content, led to reduced hunger and increased fullness, which were sustained up to 120 min post-snack vs. NS (all, p<0.05). Between snacks, hunger was lower and fullness was higher throughout post-snack following HP vs. LP (p<0.05). Snacking delayed the onset of eating vs. NS (all, p<0.05). Specifically, dinner was requested at 124 +/- 7 min following NS, 152 +/- 7 min with LP, 158 +/- 7 min following MP, and 178 +/- 7 min post-snack for HP. Between snacks, HP led to the latest request time vs. LP (p<0.001) and MP (p<0.05). Although the energy content consumed at dinner was lower following the yogurt snacks vs. NS, the 160 kcal snacks were not fully compensated for at this meal. In conclusion, an afternoon snack of Greek yogurt, containing 24 g protein, led to reduced hunger, increased fullness, and delayed subsequent eating compared to lower protein snacks in healthy women. PMID- 23022603 TI - Human perceptual learning: the effect of pre-exposure schedule depends on task demands. AB - The effects of the pre-exposure schedule (concurrent, intermixed, and blocked) to two similar visual stimuli were assessed in three different tasks. Participants were more accurate identifying one of two pre-exposed stimuli as the target by means of same/different judgments after concurrent than intermixed or blocked pre exposures. Regardless of pre-exposure schedule, participants were accurate in identifying the same target stimulus in a subsequent multiple choice task. However, the other pre-exposed stimulus was incorrectly chosen as the target in a greater proportion after blocked than intermixed or concurrent pre-exposure. Finally, participants who received the blocked schedule showed a greater ability to construct the target in a puzzle test than those who received a concurrent or intermixed schedule. These results suggest that the effect of pre-exposure schedule may depend on task-specific demands. But all these results might be explained by a selective attention mechanism like that proposed by Gibson (1969) to account for perceptual learning. PMID- 23022604 TI - Expansion of the silkworm GMC oxidoreductase genes is associated with immunity. AB - The glucose-methanol-choline (GMC) oxidoreductases constitute a large gene family in insects. Some of these enzymes play roles in developmental or physiological process, such as ecdysteroid metabolism. However, little is known about the functional diversity of the insect GMC family. Here, we identified 43 GMC genes in the silkworm genome, the largest number of GMC genes among all the insect genomes sequenced to date. Similar to the other insects, there is a highly conserved GMC cluster within the second intron of the silkworm flotillin-2 (flo 2) gene. However, the silkworm GMC genes outside of the conserved GMC cluster have experienced a large expansion. Phylogenetic analysis suggested that the silkworm GMCbeta subfamily contained 22 copies and made a major contribution to expansion of the silkworm GMC genes. Eighteen of the 22 members of the silkworm GMCbeta subfamily are located outside of the conserved GMC cluster, and are known as silkworm expansion genes (SEs). Relative-rate tests showed that SEs evolved significantly faster than the GMCbeta genes inside the conserved GMC cluster. Accordingly, the third position GC content (GC3s) and codon bias of SEs are significantly different from those of the GMCbeta genes in the conserved GMC cluster. The elevated evolutionary rate of the silkworm GMCbeta genes outside of the conserved GMC cluster may reflect the evolution of function diversity. At least 24 of the 43 silkworm GMC genes were differently transcribed and expressed in a tissue- or stage-specific manner during the larval stage. Strikingly, microarray data revealed that four different pathogens upregulated most of the silkworm GMCbeta genes. Furthermore, RNA interference of representative upregulated GMCbeta genes reduced the survival rate of the silkworm when infected by pathogens. Taken together, the results suggested that expansion of the silkworm GMC oxidoreductase genes is associated with immunity. PMID- 23022605 TI - Structural insights on the plant salt-overly-sensitive 1 (SOS1) Na(+)/H(+) antiporter. AB - The Arabidopsisthaliana Na(+)/H(+) antiporter salt-overly-sensitive 1 (SOS1) is essential to maintain low intracellular levels of toxic Na(+) under salt stress. Available data show that the plant SOS2 protein kinase and its interacting activator, the SOS3 calcium-binding protein, function together in decoding calcium signals elicited by salt stress and regulating the phosphorylation state and the activity of SOS1. Molecular genetic studies have shown that the activation implies a domain reorganization of the antiporter cytosolic moiety, indicating that there is a clear relationship between function and molecular structure of the antiporter. To provide information on this issue, we have carried out in vivo and in vitro studies on the oligomerization state of SOS1. In addition, we have performed electron microscopy and single-particle reconstruction of negatively stained full-length and active SOS1. Our studies show that the protein is a homodimer that contains a membrane domain similar to that found in other antiporters of the family and an elongated, large, and structured cytosolic domain. Both the transmembrane (TM) and cytosolic moieties contribute to the dimerization of the antiporter. The close contacts between the TM and the cytosolic domains provide a link between regulation and transport activity of the antiporter. PMID- 23022606 TI - Implications for preserving neural stem cells in whole brain radiotherapy and prophylactic cranial irradiation: a review of 2270 metastases in 488 patients. AB - This study delineated the incidence of metastatic involvement of neural stem cell (NSC) regions and further aimed to explore the feasibility of selectively sparing the NSC compartments during whole brain radiotherapy (WBRT) and prophylactic cranial irradiation (PCI). A total of 2270 intracranial metastases in 488 patients were identified. Lesions were classified according to locations, including lesions in the NSC compartments (subventricular zone, SVZ, or hippocampus) and those in the rest of the brain/brainstem. The incidence of involvement of NSC regions was compared between oligometastatic patients (those with 1-4 lesions) and non-oligometastatic patients (those with 5 or more lesions) using a chi-square test. The volume of the NSC regions accounted for 2.23% of the whole brain, and the overall rate of metastatic lesions in NSC regions was 1.1% in 2270 metastases (25/2270), and 4.7% in 488 patients (23/488). Of the NSC region metastases, 7 (0.3%) involved the hippocampus and 18 (0.8%) occurred in the SVZ. Among the 7 hippocampal metastases identified in this study, 1/7 (14.3%) were found in oligometastatic patients, while 6/7 (85.7%) metastases were in non oligometastatic patients. For metastases in the SVZ, all lesions occurred in non oligometastatic patients with none in oligometastatic patients. Metastatic involvement of the NSC compartments was significantly lower in oligometastatic patients (0.15%, 1/670) than in non-oligometastatic patients (1.5%, 24/1600) (P < 0.001). Our retrospective review of 2270 metastases in 488 patients is that the volume of the compartments of NSC regions was 2.23% relative to the whole brain, but the incidence of involvement of the NSC compartments was 1.1%, and the vast majority of NSC lesions were found in non-oligometastatic patients. We believe our data supports selective reduction of doses for these aforementioned structures, when treating oligometastatic patients with WBRT and locally advanced stage small-cell lung cancer patients with PCI. PMID- 23022607 TI - Ammonia induces aquaporin-4 rearrangement in the plasma membrane of cultured astrocytes. AB - Aquaporin-4 (AQP4) is a water channel protein mainly located in the astroglial plasma membrane, the precise function of which in the brain edema that accompanies hepatic encephalopathy (HE) is unclear. Since ammonia is the main pathogenic agent in HE, its effect on AQP4 expression and distribution in confluent primary astroglial cultures was examined via their exposure to ammonium chloride (1, 3 and 5 mM) for 5 and 10 days. Ammonia induced the general inhibition of AQP4 mRNA synthesis except in the 1 mM/5 day treatment. However, the AQP4 protein content measured was dependent on the method of analysis; an apparent increase was recorded in treated cells in in-cell Western assays, while an apparent reduction was seen with the classic Western blot method, perhaps due to differences in AQP4 aggregation. Ammonia might therefore induce the formation of insoluble AQP4 aggregates in the astroglial plasma membrane. The finding of AQP4 in the pellet of classic Western blot samples, plus data obtained via confocal microscopy, atomic force microscopy (using immunolabeled cells with gold nanoparticles) and scanning electron microscopy, all corroborate this hypothesis. The effect of ammonia on AQP4 seems not to be due to any osmotic effect; identical osmotic stress induced by glutamine and salt had no significant effect on the AQP4 content. AQP4 functional analysis (subjecting astrocytes to a hypo osmotic medium and using flow cytometry to measure cell size) demonstrated a smaller water influx in ammonia-treated astrocytes suggesting that AQP4 aggregates are representative of an inactive status; however, more confirmatory studies are required to fully understand the functional status of AQP4 aggregates. The present results suggest that ammonia affects AQP4 expression and distribution, and that astrocytes change their expression of AQP4 mRNA as well as the aggregation status of the ensuing protein depending on the ammonia concentration and duration of exposure. PMID- 23022608 TI - Moderate superoxide production is an early promoter of mitochondrial biogenesis in differentiating N2a neuroblastoma cells. AB - Reactive oxygen species (ROS) have been widely considered as harmful for cell development and as promoters of cell aging by increasing oxidative stress. However, ROS have an important role in cell signaling and they have been demonstrated to be beneficial by triggering hormetic signals, which could protect the organism from later insults. In the present study, N2a murine neuroblastoma cells were used as a paradigm of cell-specific (neural) differentiation partly mediated by ROS. Differentiation was triggered by the established treatments of serum starvation, forskolin or dibutyryl cyclic AMP. A marked differentiation, expressed as the development of neurites, was detected by fixation and staining with coomassie brilliant blue after 48 h treatment. This was accompanied by an increase in mitochondrial mass detected by mitotracker green staining, an increased expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1-alpha (PGC-1alpha) and succinate dehydrogenase activity as detected by MTT. In line with these results, an increase in free radicals, specifically superoxide anion, was detected in differentiating cells by flow cytometry. Superoxide scavenging by MnTBAP and MAPK inhibition by PD98059 partially reversed differentiation and mitochondrial biogenesis. In this way, we demonstrated that mitochondrial biogenesis and differentiation are mediated by superoxide and MAPK cues. Our data suggest that differentiation and mitochondrial biogenesis in N2a cells are part of a hormetic response which is triggered by a modest increase of superoxide anion concentration within the mitochondria. PMID- 23022609 TI - Prenatal stress induces alterations in cerebellar nitric oxide that are correlated with deficits in spatial memory in rat's offspring. AB - Prenatal stress (PS) has been linked to abnormal cognitive, behavioral and psychosocial outcomes in both animals and humans. Since PS has been shown to induce a cerebellar cytoarchitectural disarrangement and cerebellar abnormalities that have been linked to an impairment of behavioral functions, the aim of the present work was to investigate whether the exposure to PS in a period in which the cerebellum is still immature can induce behavioral deficits in the adult and whether this alterations are correlated with changes in nitric oxide (NO) and cellular oxidative mechanisms in offspring's cerebellum. Our results show impairments in spatial memory and territory discrimination in PS adult rats. PS offspring also displayed alterations in cerebellar nitric oxide synthase (NOS) expression and activity. Moreover, a correlation between spatial memory deficits and the increase in NOS activity was found. The results found here may point to a role of cerebellar NO in the behavioral alterations induced by stress during early development stages. PMID- 23022610 TI - A vaccine against methamphetamine attenuates its behavioral effects in mice. AB - BACKGROUND: Vaccines have treatment potential for methamphetamine (MA) addiction. We tested whether a conjugate vaccine against MA (succinyl-methamphetamine keyhole limpet hemocyanin carrier protein; SMA-KLH) would generate MA antibodies and alter MA-induced behaviors. METHODS: Mice were injected with SMA-KLH and received booster administrations 3 and 20 weeks later. Serum antibody titers reached peak levels by 4-6 weeks, remained at a modest level through 18 weeks, peaked again at 22 weeks after the second boost, and were still elevated at 35 weeks. At 7 weeks, groups of vaccinated and non-vaccinated mice were administered one of three MA doses (1, 2 or 3 mg/kg) to assess locomotor activity. RESULTS: Non-vaccinated mice showed dose-dependent effects of MA with hypolocomotion at the lowest dose and elevated activity levels at the highest dose. Both dose effects were reduced in SMA-KLH groups, particularly low dose-induced hypolocomotion at later times post MA administration. Separate groups of vaccinated and non-vaccinated mice were trained in MA place conditioning at 30 weeks with either 0 (vehicle) or 0.5mg/kg MA. Although times spent in the MA paired side did not differ between groups on test vs. baseline sessions, SMA-KLH mice conditioned with MA showed reduced conditioned approach behaviors and decreased conditioned activity levels compared to control groups. CONCLUSION: These data suggest SMA-KLH attenuates the ability of MA to support place conditioning and reduces or delays its locomotor effects. Overall, results support SMA-KLH as a candidate MA vaccine. PMID- 23022611 TI - Structure, DNA binding and cleavage of a new Zn(II)Mn(II) macrocyclic complex. AB - A new heterodinuclear complex of an unsymmetrical macrocycle [ZnMnL(CH(3)O)(2)].H(2)O has been synthesized by the cyclocondensation between N,N'-bis(3-formyl-5-chlorosalicylidene)ethylenediimine and 2-hydroxyl-1,3 propanediamine in the presence of the metal ions, and characterized by elemental analyses, IR spectra and X-ray determination. The interactions of the complex with DNA have been investigated by UV absorption, fluorescence spectroscopy, viscosity measurements and electrochemical studies. Absorption spectroscopic investigation reveals that the complex has good binding propensity to calf thymus DNA by intercalation with a binding constant of 2.52 * 10(5)M(-1). Fluorescence spectroscopy shows that the complex can displace ethidium bromide and bind to DNA, with a quenching constant of 4.37 * 10(3)M(-1). The agarose gel electrophoresis studies show that pBR322 plasmid DNA can be transformed to nicked form and linear form in air by the complex. PMID- 23022612 TI - Optical detection of NADH based on biocatalytic growth of Au-Ag core-shell nanoparticles. AB - We have developed an optical assay for NADH (Dihydronicotinamide adenine dinucleotide) based on the catalytic growth of gold-silver core-shell nanoparticles (Au-Ag-CSNPs). The nanoparticles were immobilized on pretreated glass slide and are shown to catalyze the NADH-mediated reduction of Ag(I) ions in the presence of 1,4-benzoquinone and cetyltrimethyl ammonium ion. This leads to the formation of Au-Ag-CSNPs on the glass. The absorption peak of the Au-Ag CSNPs at 415 nm increases with the concentration of NADH in the solution used, and this can be measured by UV-vis photometry. High-resolution scanning electron microscopy analysis of the morphology of the surface of the Au-Ag-CSNPs before and after the catalytic reaction revealed a growth of their diameter. Under optimal conditions, NADH can be determined in the concentration range from 0.2 to 3.2mM, and the detection limit is 15.6 MUM. The sensor has good precision and good storage stability, simple in operation, and can be fabricated at low costs, which made it suitable for the determination of NADH in complex biological systems and in related degradation processes of contaminants. PMID- 23022613 TI - Vibrational and electronic absorption spectral studies of 5-amino-1-(4 bromophenyl)-3-phenyl-1-H-pyrazole. AB - The FT-IR and FT-Raman spectra of 5-amino-1-(4-bromophenyl)-3-phenyl-1-H-pyrazole have been measured in the regions 4000-400 cm(-1) and 3500-100 cm(-1), respectively. The equilibrium geometry, bonding features and harmonic vibrational frequencies have been carried out with the help of DFT method. The assignments of the vibrational spectra have been carried out with the normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology (SQMFF). The first-order hyperpolarizability (beta(0)) and related properties (MU, alpha(0), and Deltaalpha) of 5A4BP3PP are calculated by using HF/6-31G(d,p) method on the finite field approach. Stability of the molecule arising from hyperconjugative interactions, charge delocalization have been analyzed using natural bonding orbital (NBO) analysis. The results show that electron density (ED) in the sigma(*) and pi(*) antibonding orbitals and second order delocalization energies E(2) confirms the occurrence of the intramolecular charge transfer (ICT) within the molecule. UV-vis spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies, were performed by TDDFT using 6-31G(d,p). The HOMO-LUMO calculations indicating the charge transfer takes place within the molecule. PMID- 23022614 TI - Theoretical investigations of optical spectra and electron paramagnetic resonance spectra of LiCl:Ni2+ crystals. AB - The complete energy matrices (45 * 45) including low symmetry ligand field (C(4v)) and Coulomb interactions for 3d(8) ions have been constructed, and the high-order perturbation formulas of spin-Hamiltonian (SH) parameters g factors g(//), g(?) and zero-field splitting (ZFS) parameter D for ground state (3)A(2g) of the 3d(8) ions in the tetragonal symmetry environment have been derived. In those formulas both the crystal field (CF) mechanism and the charge transfer (CT) mechanism are taken into account. The complete energy matrices and the high-order perturbation formulas are applied to calculate the energy levels and SH parameters of the Ni(2+) ion in LiCl crystal respectively. The results are in reasonable agreement with the experimental data and indicate that CT mechanism plays important role in the understanding of SH parameters, especially the g factors. All the multiplet energy are assigned theoretically and the local structures of LiCl:Ni(2+) are established. PMID- 23022615 TI - Trace mercury ion determination based on the highly selective redox reaction between stannous ion and mercury ion enhanced by gold nanoparticles. AB - A novel resonance light scattering (RLS) spectrometric method for mercury ions (Hg(2+)) determination has been established in this article. Mercury (Hg) nanoparticle formed from the highly selective redox reaction between citrate stabilized stannous ions (Sn(2+)) and Hg(2+). As a result, the RLS intensities of the system can be enhanced and it can be sensitized in the presence of very little amount of gold nanoparticles (AuNPs). According to this phenomenon, trace Hg(2+) in real water sample has been determined directly by RLS spectrometry. It has been found that the enhanced RLS intensities (DeltaI(RLS)) characterized at 395 nm are proportional to the concentration of Hg(2+) in the range of 0.1-30 MUmol L(-1) with a detection limit (3sigma) of 0.051 MUmol L(-1). The method described herein has good sensitivity, selectivity, and without complicated sample pretreatment. Moreover, the feasibility for the analysis of Hg(2+) in a wastewater sample was identified with a good recovery (100.2-106.3%). PMID- 23022616 TI - Zoonotic transmission of Cryptosporidium meleagridis on an organic Swedish farm. AB - We believe that we present the first evidence of zoonotic transmission of the bird parasite, Cryptosporidium meleagridis. Despite being the third most common cause of human cryptosporidiosis, an identified zoonotic source has not been reported to date. We found Cryptosporidium oocysts in pigs, sheep/goats, hens and broiler chickens on a farm with suspected zoonotic transmission. By DNA analysis we identified C. meleagridis in samples from one human, three chickens and one hen. Sequencing of the ssrRNA and 70kDa Heat Shock Protein (HSP) genes showed identical C. meleagridis sequences in the human and chicken samples, which is evidence of zoonotic transmission. The HSP70 sequence was unique. PMID- 23022617 TI - On the pathogenesis of Plasmodium vivax malaria: perspectives from the Brazilian field. AB - Life-threatening Plasmodium vivax malaria cases, while uncommon, have been reported since the early 20th century. Unfortunately, the pathogenesis of these severe vivax malaria cases is still poorly understood. In Brazil, the proportion of vivax malaria cases has been steadily increasing, as have the number of cases presenting serious clinical complications. The most frequent syndromes associated with severe vivax malaria in Brazil are severe anaemia and acute respiratory distress. Additionally, P. vivax infection may also result in complications associated with pregnancy. Here, we review the latest findings on severe vivax malaria in Brazil. We also discuss how the development of targeted field research infrastructure in Brazil is providing clinical and ex vivo experimental data that benefits local and international efforts to understand the pathogenesis of P. vivax. PMID- 23022620 TI - Transcriptomic analysis of four developmental stages of Strongyloides venezuelensis. AB - Strongyloides venezuelensis is one of some 50 species of genus Strongyloides, obligate gastrointestinal parasites of vertebrates, responsible for strongyloidiasis in humans and other domestic/companion animals. Although S. venezuelensis has been widely used as a model species for studying human/animal strongyloidiasis, the sequence information for this species has been quite limited. To create a more comprehensive catalogue of expressed genes for identification of genes potentially involved in animal parasitism, we conducted a de novo sequencing analysis of the transcriptomes from four developmental stages of S. venezuelensis, using a Roche 454 GS FLX Titanium pyrosequencing platform. A total of 14,573 contigs were produced after de novo assemblies of over 2 million sequencing reads and formed a dataset "Vene454". BLAST homology search of Vene454 against proteome and transcriptome data from other animal-parasitic and non animal-parasitic nematode species revealed several interesting genes, which may be potentially related to animal parasitism, including nicotinamide phosphoribosyltransferase and ferrochelatase. The Vene454 dataset analysis also enabled us to identify transcripts that are specifically enriched in each developmental stage. This work represents the first large-scale transcriptome analysis of S. venezuelensis and the first study to examine the transcriptome of the lung L3 developmental stage of any Strongyloides species. The results not only will serve as valuable resources for future functional genomics analyses to understand the molecular aspects of animal parasitism, but also will provide essential information for ongoing whole genome sequencing efforts in this species. PMID- 23022621 TI - The future of cancer prevention. PMID- 23022619 TI - Including osteoprotegerin and collagen IV in a score-based blood test for liver fibrosis increases diagnostic accuracy. AB - BACKGROUND: Noninvasive methods for liver fibrosis evaluation in chronic liver diseases have been recently developed, i.e. transient elastography (FibroscanTM) and blood tests (Fibrometer(r), Fibrotest(r), and Hepascore(r)). In this study, we aimed to design a new score in chronic hepatitis C (CHC) by selecting blood markers in a large panel and we compared its diagnostic performance with those of other noninvasive methods. METHODS: Sixteen blood tests were performed in 306 untreated CHC patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using METAVIR histological fibrosis stage as reference. The new score was constructed by non linear regression using the most accurate biomarkers. RESULTS: Five markers (alpha-2-macroglobulin, apolipoprotein-A1, AST, collagen IV and osteoprotegerin) were included in the new function called Coopscore(c). Using the Obuchowski Index, Coopscore(c) shows higher diagnostic performances than for Fibrometer(r), Fibrotest(r), Hepascore(r) and FibroscanTM in CHC. Association between FibroscanTM and Coopscore(c) might avoid 68% of liver biopsies for the diagnosis of significant fibrosis. CONCLUSION: Coopscore(c) provides higher accuracy than other noninvasive methods for the diagnosis of liver fibrosis in CHC. The association of Coopscore(c) with FibroscanTM increases its predictive value. PMID- 23022618 TI - Basic mechanisms of RNA polymerase II activity and alteration of gene expression in Saccharomyces cerevisiae. AB - Transcription by RNA polymerase II (Pol II), and all RNA polymerases for that matter, may be understood as comprising two cycles. The first cycle relates to the basic mechanism of the transcription process wherein Pol II must select the appropriate nucleoside triphosphate (NTP) substrate complementary to the DNA template, catalyze phosphodiester bond formation, and translocate to the next position on the DNA template. Performing this cycle in an iterative fashion allows the synthesis of RNA chains that can be over one million nucleotides in length in some larger eukaryotes. Overlaid upon this enzymatic cycle, transcription may be divided into another cycle of three phases: initiation, elongation, and termination. Each of these phases has a large number of associated transcription factors that function to promote or regulate the gene expression process. Complicating matters, each phase of the latter transcription cycle are coincident with cotranscriptional RNA processing events. Additionally, transcription takes place within a highly dynamic and regulated chromatin environment. This chromatin environment is radically impacted by active transcription and associated chromatin modifications and remodeling, while also functioning as a major platform for Pol II regulation. This review will focus on our basic knowledge of the Pol II transcription mechanism, and how altered Pol II activity impacts gene expression in vivo in the model eukaryote Saccharomyces cerevisiae. This article is part of a Special Issue entitled: RNA Polymerase II Transcript Elongation. PMID- 23022622 TI - Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing. AB - Populations in many nations today are rapidly ageing. This unprecedented demographic change represents one of the main challenges of our time. A defining property of the ageing process is a marked increase in the risk of mortality and morbidity with age. The incidence of cancer, cardiovascular and neurodegenerative diseases increases non-linearly, sometimes exponentially with age. One of the most important tasks in biogerontology is to develop interventions leading to an increase in healthy lifespan (health span), and a better understanding of basic mechanisms underlying the ageing process itself may lead to interventions able to delay or prevent many or even all age-dependent conditions. One of the putative basic mechanisms of ageing is age-dependent mitochondrial deterioration, closely associated with damage mediated by reactive oxygen species (ROS). Given the central role that mitochondria and mitochondrial dysfunction play not only in ageing but also in apoptosis, cancer, neurodegeneration and other age-related diseases there is great interest in approaches to protect mitochondria from ROS mediated damage. In this review, we explore strategies of targeting mitochondria to reduce mitochondrial oxidative damage with the aim of preventing or delaying age-dependent decline in mitochondrial function and some of the resulting pathologies. We discuss mitochondria-targeted and -localized antioxidants (e.g.: MitoQ, SkQ, ergothioneine), mitochondrial metabolic modulators (e.g. dichloroacetic acid), and uncouplers (e.g.: uncoupling proteins, dinitrophenol) as well as some alternative future approaches for targeting compounds to the mitochondria, including advances from nanotechnology. PMID- 23022623 TI - Whole-body diffusion magnetic resonance imaging in the assessment of lymphoma. AB - The current evidence regarding the usefulness of whole-body diffusion-weighted magnetic resonance imaging (diffusion MRI) in the assessment of lymphoma is reviewed. Diffusion MRI combining both anatomical and bio-physiological information is currently under investigation as a valuable tool in the oncology field including lymphoma, not only for staging but also for the assessment of response. Representative images for each purpose are shown. Diffusion MRI requires no administration of contrast medium and does not use ionizing radiation, which could be particularly advantageous for repeat follow-up surveillance in lymphoma patients. Diffusion MRI may prove to be a useful biomarker in clinical decision making for patients with lymphoma. Large-scale prospective studies are warranted to further establish its complementary value to the current standard of care, [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography. PMID- 23022624 TI - Role of Ox-LDL/LOX-1/NF-kappaB signaling pathway in regulation of atherosclerotic plaque growth by testosterone in male rabbits. AB - OBJECTIVE: The purpose of our study is to investigate the role of oxidized low density lipoprotein (Ox-LDL)/lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1)/nuclear factor-kappaB (NF-kappaB) signaling pathway in the regulation of atherosclerotic plaque growth by testosterone in male atherosclerotic rabbits. METHODS: The male rabbit model was prepared by castration and feeding cholesterol-rich diet. Pathological sections of thoracic aorta were performed hematoxylin-eosin staining to observe aortic morphological changes. Total serum testosterone was measured with chemical luminescent method. Serum Ox-LDL, soluble intercellular adhesion molecule-1 (sICAM-1) and matrix metalloproteinases-2 (MMP2) were assayed using ELISA kit following the manufacturer's instructions. Serum tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL6) were assayed using radioimmunoassay. Expressions of LOX-1 of thoracic aorta were measured by RT-PCR, immunohistochemistry and Western blot methods respectively. RESULTS: There was no significant difference in Ox-LDL level between all groups. The LOX-1 mRNA and protein expression of thoracic aorta were significantly higher in the castrated rabbits as compared with the sham operated ones, and testosterone replacement could reduce the mRNA and protein expression of LOX-1 of thoracic aorta in the castrated rabbits. PIA reduced artery intima thickness and plaque area in castrated rabbits, which was further enhanced by testosterone replacement. PDTC reduced artery intima thickness and plaque area in castrated rabbits, which couldn't be enhanced by testosterone replacement. CONCLUSIONS: Our study demonstrates that testosterone can regulate atherosclerotic plaque progression, affect expression of LOX-1 and NF-kappaB in thoracic aorta and play a role in atherosclerotic plaque growth via NF-kappaB rather than Ox-LDL or LOX-1 in male rabbits. PMID- 23022625 TI - Comparative aspects of polyglutamine binding domain in PQBP-1 among Vertebrata. AB - We investigated the evolutionary conservation of polyglutamine binding protein-1 (PQBP-1) among Vertebrata. PQBP-1s were highly conserved and shared the same domain features including a WW domain, a polar amino acid rich domain (PRD), a nuclear localization signal (NLS), and a C-terminal domain (CTD) among Eutheria, but not always among Vertebrata. PQBP-1s of Vertebrata contained a variable region in the middle portion corresponding to the position of PRD. The full form of PRD including both 7aa and DR/ER repeats was specific to Eutheria. PRD of non eutherian Amniota was minimal. Amphibia had no PRD. The DR/ER repeat was solo in fishes. Agnatha PRD was also rich in polar amino acids, but contained no repetitive sequence. We investigated 3 polyQ-containing proteins known to interact with PQBP-1: BRN-2, Huntingtin, and ATAXIN-1, and showed a diverse nature of protein-protein interaction in Vertebrata. There appears to be no interaction between PQBP-1 and BRN-2, Huntingtin, or ATAXIN-1 in Amphibia, while the interaction between PQBP-1 and BRN-2 is expected to be conserved among Mammalia, and the interaction between PQBP-1 and Huntingtin or ATAXIN-1 depends on the lineage in Eutheria. PMID- 23022626 TI - The aryl hydrocarbon receptor (AhR) 1661G>A polymorphism in human cancer: a meta analysis. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and plays an important role in the development of cancer. Although there have been many epidemiological studies investigating the relationship between genetic polymorphisms in the aryl hydrocarbon receptor (AhR) gene and human cancer risk, the findings remain conflicting. To derive a more precise estimation of association between the AhR 1661G>A polymorphism and risk of cancer, we performed a systematic meta-analysis based on 11 case-control studies, including 8158 cancer cases and 8336 controls. We used odds ratios with 95% confidence intervals (CIs) to estimate the strength of the association. We also performed subgroup analyses, sensitivity analyses and publication bias analyses. Overall, there was not enough evidence to support the hypothesis that the AhR 1661G>A polymorphism was associated with human cancer risk (homozygote comparison: OR=0.974, 95% CI=0.868 to 1.092, P=0.468 for the heterogeneity test; recessive model comparison: OR=0.958, 95% CI=0.859 to 1.068, P=0.767 for the heterogeneity test). Even after stratified analysis of cancer type and source of controls, no significant association was found. This meta-analysis suggested that the AhR 1661G>A polymorphism does not contribute to the development of cancer in humans. We believe that future refinement of experiments and epidemiological studies will confirm this hypothesis. PMID- 23022627 TI - Component analysis of extracellular polymeric substances (EPS) during aerobic sludge granulation using FTIR and 3D-EEM technologies. AB - In recent years, lots of the extracellular polymeric substances (EPS) related researches have focused on its role in the granulation and structural stability of aerobic sludge. Three-dimensional fluorescence spectrum (3D-EEM) and fourier transform infrared spectroscopy (FTIR) technologies were used to analyse the main components of sludge EPS during aerobic sludge granulation in this study. Results showed that the components of sludge EPS tended to be stable during aerobic sludge granulation. The peak F (Ex/Em=230/308.5) from 3D-EEM and the predominant spectral band at approximately 1517 cm(-1) from the FTIR spectra of the matured granular sludge indicated the importance of aromatic protein-like substances together, especially tyrosine in maintaining the stable structure of the granular sludge. Furthermore, the differences in the occurrence position and frequency of C-O bonds (1110-1047 cm(-1)) observed during aerobic sludge granulation showed that the transformations between the isomers and other forms of carbohydrates may be attributed to the formation of aerobic granule. PMID- 23022628 TI - d-beta-Hydroxybutyrate inhibited the apoptosis of PC12 cells induced by H2O2 via inhibiting oxidative stress. AB - Oxidative stress has an important role in neurodegenerative diseases and cerebral ischemic injury. It is reported that d-beta-hydroxybutyrate (DbetaHB), the major component of ketone bodies, is neuroprotective in recent studies. Therefore, in the present work the neuroprotective effects of DbetaHB on H2O2-induced apoptosis mediated by oxidative stress was investigated. PC12 cells were exposed to H2O2 with different concentrations of H2O2 for different times after DbetaHB pretreatment. MTT assay, apoptotic rates, intracellular reactive oxygen species (ROS) level, GSH content, mitochondrial membrane potential (MMP) and caspase-3 activity were determined. The results showed that DbetaHB inhibited the decrease of cell viability induced by H2O2 in PC12 cells. DbetaHB decreased the apoptotic rates induced by H2O2. The changes of intracellular ROS, GSH, MMP and caspase-3 activity due to H2O2 exposure were partially reversed in PC12 cells. So DbetaHB inhibited the apoptosis of PC12 cells induced by H2O2 via inhibiting oxidative stress. PMID- 23022629 TI - Preparation of monoclonal antibodies against poor immunogenic avian influenza virus proteins. AB - This study established a novel method of pre-screening peptides for monoclonal antibody (mAb) production. Whole virus particles were used as antigens to produce mAbs in the first stage. However, most mAbs obtained from this method were aimed toward hemagglutinin. For this reason, synthetic peptides were used as antigens for mAb production that aimed at the AIV proteins with low abundance or poor immunogenicity in the virus particle. The peptides that showed high immunogenicity were designed using bioinformatic tools for immunization. For high throughput, a rabbit was used to screen the immunogenicities of the synthetic peptides. Those showed high immunity were used for mAb preparation in mice. Several new mAbs against PB2, PA, M1, M2, NS1 and NS2 proteins were successfully obtained in this study. Furthermore, the epitopes of M1 and NS1 mAbs were determined using competitive western blot assay and competitive ELISA. This study might simplify the mAb preparation and serves as the basis for developing mAb against poor immunogenic proteins. PMID- 23022630 TI - Assessment of IgG avidity against pertussis toxin and filamentous hemagglutinin via an adapted enzyme-linked immunosorbent assay (ELISA) using ammonium thiocyanate. AB - Antibody avidity, defined as the strength of binding between antibody and antigen, represents a functional measure of affinity maturation of antibodies. Determination of the antibody avidity is usually performed separating high and low avidity antibodies by dissociating agents, but measurement of the antibody avidity in humans is rather complicated, due to the heterogeneity of the antibodies produced in response to complex antigens, e.g. after vaccinations. The purpose of the present study was to evaluate the experimental determinants of the assessment of avidities of IgG antibodies directed against pertussis toxin (IgG anti-PT) and filamentous hemagglutinin (IgG-anti-FHA) produced after pertussis vaccination using an adapted ELISA and ammonium thiocyanate (NH(4)SCN) as dissociating agent. Our experiments revealed that the results of avidity testing depend very much on experimental conditions and may over- or underestimate the relative avidity of IgG-anti-PT and IgG-anti-FHA antibodies. Whereas in our findings avidity seems to be independent from the initial antibody concentration in a wide range of measures, RAI depends on NH(4)SCN concentration, time of incubation and temperature of the reaction. The presented method allows an accurate measurement of the IgG antibody avidity against both Bordetella pertussis antigens PT and FHA, using NH(4)SCN as chaotropic agent in concentrations lower than 3.0M for 20 min time of incubation at 37 degrees C. Different experimental conditions in testing pertussis-specific IgG antibody avidity should be considered in interpretation and comparability of data of different studies. PMID- 23022631 TI - What U.S. data should be used to measure the price elasticity of demand for alcohol? AB - This paper examines how estimates of the price elasticity of demand for beer vary with the choice of alcohol price series examined. Our most important finding is that the commonly used ACCRA price data are unlikely to reliably indicate alcohol demand elasticities-estimates obtained from this source vary drastically and unpredictably. As an alternative, researchers often use beer taxes to proxy for alcohol prices. While the estimated beer taxes elasticities are more stable, there are several problems with using taxes, including difficulties in accounting for cross-price effects. We believe that the most useful estimates reported in this paper are obtained using annual Uniform Product Code (UPC) "barcode" scanner data on grocery store alcohol prices. These estimates suggest relatively low demand elasticity, probably around -0.3, with evidence that the elasticities are considerably overstated in models that control for beer but not wine or spirits prices. PMID- 23022632 TI - Technology-related medication errors in a tertiary hospital: a 5-year analysis of reported medication incidents. AB - PURPOSE: Healthcare technology is meant to reduce medication errors. The objective of this study was to assess unintended errors related to technologies in the medication use process. METHODS: Medication incidents reported from 2006 to 2010 in a main tertiary care hospital were analysed by a pharmacist and technology-related errors were identified. Technology-related errors were further classified as socio-technical errors and device errors. This analysis was conducted using data from medication incident reports which may represent only a small proportion of medication errors that actually takes place in a hospital. Hence, interpretation of results must be tentative. RESULTS: 1538 medication incidents were reported. 17.1% of all incidents were technology-related, of which only 1.9% were device errors, whereas most were socio-technical errors (98.1%). Of these, 61.2% were linked to computerised prescription order entry, 23.2% to bar-coded patient identification labels, 7.2% to infusion pumps, 6.8% to computer aided dispensing label generation and 1.5% to other technologies. The immediate causes for technology-related errors included, poor interface between user and computer (68.1%), improper procedures or rule violations (22.1%), poor interface between user and infusion pump (4.9%), technical defects (1.9%) and others (3.0%). In 11.4% of the technology-related incidents, the error was detected after the drug had been administered. CONCLUSIONS: A considerable proportion of all incidents were technology-related. Most errors were due to socio-technical issues. Unintended and unanticipated errors may happen when using technologies. Therefore, when using technologies, system improvement, awareness, training and monitoring are needed to minimise medication errors. PMID- 23022633 TI - Balloon-pump counterpulsation for management of severe cardiac dysfunction after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To evaluate the use of intraaortic balloon pump (IABP) placement to counter severe cardiac dysfunction after aneurysmal subarachnoid hemorrhage (SAH). METHODS: From August 2006 to October 2011, eight patients (seven women, mean age 47 years +/- 5) with aneurysmal SAH underwent IABP placement. The modified Rankin scale (mRS) was used to assess outcome at discharge and long-term follow-up. RESULTS: Most patients presented in poor Hunt & Hess grade (grade III, 25%; grade IV, 62.5%; grade V, 12.5%). Three patients underwent surgical clipping, and five patients underwent endovascular treatment. All patients had severe cardiogenic shock, with a mean ejection fraction of 21%. One patient (12.5%) experienced transient left leg ischemia attributable to the IABP. No patient deaths occurred. At discharge, one patient was moderately disabled (mRS = 3), two patients were moderately to severely disabled (mRS, 4), and five patients were severely disabled (mRS = 5). The seven patients available for long-term follow-up (mean, 11.25 months) showed substantial functional improvements. Two patients exhibited no significant disability (mRS = 1), two patients exhibited only slight disability (mRS = 2), and 3 patients exhibited moderate to severe disability (mRS = 4). CONCLUSIONS: In select patients, particularly young women with poor-grade SAH, balloon-pump counterpulsation may serve as a useful adjunct in the management of severe cardiac dysfunction after SAH. Further investigation is necessary to define the optimal patient population for this technique. PMID- 23022634 TI - Endoscopic endonasal transsphenoidal "above and below" approach to the retroinfundibular area and interpeduncular cistern--cadaveric study and case illustrations. AB - OBJECTIVE: To evaluate the feasibility of reaching the interpeduncular cistern (IC) through an endoscopic endonasal approach that leaves the pituitary gland in place. METHODS: In a series of 10 injected cadaver heads, the transtuberculum ("above") and transclival ("below") approaches were combined, without pituitary transposition. Using 0-degree, 30-degree, and 45-degree endoscopes, the extent of overlap and if a blind spot occurred were determined. Also, the visualization of the IC was compared with the transposition of the pituitary gland approach. Nonparametric statistics were used to evaluate the results. The approach was implemented in 2 patients. RESULTS: For both the "above" and "below" views, there was a statistically significant increase in field of view when comparing the 0 degree endoscope with either the 30-degree endoscope (P < 0.05) or the 45-degree endoscope (P < 0.05). There was no difference between the 30-degree endoscope and the 45-degree endoscope (P > 0.05) in the "below" approach, but there was a difference (P < 0.05) in the "above" approach. There was no blind spot with any combination of endoscopes. There was no practical statistically significant difference between the transposition approach and the "above and below" approach. The "above and below" approach was used successfully in 2 surgeries. CONCLUSIONS: It is possible to work both "above" and "below" the pituitary gland to reach the IC through an endoscopic endonasal approach. The advantages are the maintenance of normal pituitary and parasellar anatomy and the minimization of the size of the skull base defect. There is no blind spot using this approach that would be revealed with a pituitary transposition. The feasibility of this approach has been confirmed in 2 patients. PMID- 23022635 TI - Outcomes of fusion for lateral atlantoaxial osteoarthritis: meta-analysis and review of literature. AB - OBJECTIVE: Atlantoaxial osteoarthritis (AAOA) is an underrecognized source of neck pain, limitation of range of motion, and cervicogenic headaches. When conservative treatments such as facet injections fail, fusion may be indicated. We reviewed published series describing posterior fusions for atlantoaxial osteoarthritis of the facet joints. METHODS: Online databases were searched for English-language articles describing the diagnosis and treatment of AAOA. Twenty three studies reporting on 246 patients treated with posterior fusion for lateral AAOA fulfilled inclusion criteria. Standard statistical and formal meta-analytic techniques were used to assess outcomes. RESULTS: All studies provided class III evidence. The 30-day perioperative mortality was 1.2% and neurologic injury did not occur. Patients were followed for a mean of nearly 5 years. Fusion was successful in 98% of patients with a single operation and with 99.5% of patients after revision surgery. Intractable preoperative neck pain either resolved completely or improved in 97.7% of patients. Using meta-analytic techniques, the point estimate for improvement or resolution of pain was 92.6% (confidence interval = 86.8%-96.0%) and the rate of arthrodesis for AAOA was 92.2% (confidence interval = 85.6%-95.9%) and there were no differences among the various techniques used for fusion. Operative complications were few. CONCLUSIONS: Posterior C1-2 fusion is a safe and effective treatment option for patients with intractable neck pain secondary to lateral AAOA. Modern fusion options offer a high rate of arthrodesis and low risk of morbidity if conservative therapies fail to provide adequate pain relief. PMID- 23022636 TI - Treatment of spinal synovial cysts. AB - BACKGROUND: Spinal synovial cysts are a known cause of back pain and radiculopathy. With the advent of high-resolution imaging techniques, synovial cysts are increasingly diagnosed. There are a variety of treatment options for these lesions. METHODS: A systematic literature review of published articles reporting outcomes after nonsurgical and surgical management of spinal synovial cysts was performed. RESULTS: There were 51 published studies regarding the treatment of synovial cysts identified. Treatment modalities include observation, steroid injections, percutaneous cyst aspiration, hemilaminectomy or bilateral laminectomy with and without instrumented fusion, and minimally invasive cyst excision. CONCLUSIONS: Based on review of the treatment modalities and outcomes, recommendations for the management of patients with synovial cysts are proposed. Observation can be considered in cases where there is no intractable pain. High risk surgical patients with intractable pain may consider corticosteroid injection or percutaneous cyst aspiration; however, the failure rate of such a procedure approaches 50%. Patients with intractable pain are candidates for surgical resection of the symptomatic cyst. In cases of significant neurologic deficit, motor weakness, back pain, multiple synovial cysts, or spondylolisthesis, bilateral laminectomy and instrumented fusion may offer the best long-term outcome. PMID- 23022637 TI - Prognosis of tinnitus after acoustic neuroma surgery--surgical management of postoperative tinnitus. AB - OBJECTIVE: Tinnitus is a bothersome symptom for patients with acoustic neuroma. We studied the possibility of surgical control of postoperative tinnitus associated with acoustic neuroma. METHODS: Postoperative changes and prognosis of tinnitus were studied in 367 patients treated surgically via a lateral suboccipital retrosigmoid approach. RESULTS: Postoperative prognosis of tinnitus was as follows: resolved in 20%, improved in 22%, unchanged in 35%, changed in 10%, and worsened in 14% of 290 patients who had preoperative tinnitus, and no tinnitus in 78% and appeared in 22% of 77 patients without preoperative tinnitus. Prognosis of postoperative tinnitus was influenced by age, tumor size, preoperative hearing acuity, types of preoperative hearing disturbance, and conditions of the cochlear nerve after tumor resection. Worse prognosis of postoperative tinnitus in the preoperative tinnitus group was found in younger patients, smaller tumor size, better preoperative hearing function, and normal or retrocochlear type of hearing disturbance. Regarding the conditions of the cochlear nerve after tumor resection, prognosis of tinnitus was significantly worse in the group of anatomically preserved cochlear nerve without useful hearing than in the group of cut cochlear nerve. CONCLUSIONS: Deciding whether to cut the cochlear nerve during acoustic neuroma surgery by referring to a flowchart, we proposed in cases where hearing preservation is not intended or judged less possible contributes to controlling postoperative tinnitus. However, regardless of whether the cochlear nerve was cut intraoperatively, tinnitus remained unchanged in 37% of patients, suggesting that their tinnitus originates in the brainstem or post-brainstem pathways before surgery, and it is considered difficult to control postoperative tinnitus in these cases. PMID- 23022638 TI - Effective surgical revascularization improves cerebral hemodynamics and resolves headache in pediatric Moyamoya disease. AB - BACKGROUND: Headache is one of the major clinical presentations in pediatric Moyamoya disease. However, the clinical features and underlying mechanisms are not fully understood. This study aimed to clarify the clinical feature of headache in pediatric Moyamoya disease and the effect of surgical revascularization. METHODS: This study included 29 pediatric patients who underwent superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis and indirect bypass for Moyamoya disease. Their medical records were precisely evaluated to identify the clinical features of their headache. The findings on magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography also were analyzed. RESULTS: Preoperative headache was documented in 11 (38%) of 29 patients. The majority of them complained of severe headache in the frontal or temporal region in the morning. Headache was significantly related to more advanced disease stage and to the decreases in cerebral blood flow and its reactivity to acetazolamide. Surgical revascularization completely resolved headache in all 11 patients. CONCLUSIONS: These findings strongly suggest that disturbed cerebral hemodynamics may play key roles in developing severe headache in pediatric Moyamoya disease. STA-MCA anastomosis and encephalo-duro-myo-arterio-pericranial synangiosis may be effective procedures to rapidly resolve headache by widely supplying collateral blood flow to the operated hemispheres. PMID- 23022639 TI - Detection of compression vessels in trigeminal neuralgia by surface-rendering three-dimensional reconstruction of 1.5- and 3.0-T magnetic resonance imaging. AB - OBJECTIVE: Surface-rendered three-dimensional (3D) 1.5-T magnetic resonance (MR) imaging is useful for presurgical simulation of microvascular decompression. This study compared the sensitivity and specificity of 1.5- and 3.0-T surface-rendered 3D MR imaging for preoperative identification of the compression vessels of trigeminal neuralgia. METHODS: One hundred consecutive patients underwent microvascular decompression for trigeminal neuralgia. Forty and 60 patients were evaluated by 1.5- and 3.0-T MR imaging, respectively. Three-dimensional MR images were constructed on the basis of MR imaging, angiography, and venography data and evaluated to determine the compression vessel before surgery. MR imaging findings were compared with the microsurgical findings to compare the sensitivity and specificity of 1.5- and 3.0-T MR imaging. RESULTS: The agreement between MR imaging and surgical findings depended on the compression vessels. For superior cerebellar artery, 1.5- and 3.0-T MR imaging had 84.4% and 82.7% sensitivity and 100% and 100% specificity, respectively. For anterior inferior cerebellar artery, 1.5- and 3.0-T MR imaging had 33.3% and 50% sensitivity and 92.9% and 95% specificity, respectively. For the petrosal vein, 1.5- and 3.0-T MR imaging had 75% and 64.3% sensitivity and 79.2% and 78.1% specificity, respectively. Complete pain relief was obtained in 36 of 40 and 55 of 60 patients undergoing 1.5- and 3.0-T MR imaging, respectively. CONCLUSIONS: The present study showed that both 1.5- and 3.0-T MR imaging provided high sensitivity and specificity for preoperative assessment of the compression vessels of trigeminal neuralgia. Preoperative 3D imaging provided very high quality presurgical simulation, resulting in excellent clinical outcomes. PMID- 23022640 TI - Cerebral vasospasm and health-related quality of life after subarachnoid hemorrhage. AB - OBJECTIVE: To examine the influence of cerebral vasospasm on health-related quality of life after subarachnoid hemorrhage. An additional objective was to determine how the timing of nimodipine therapy can influence health-related quality of life. METHODS: Patients treated between 1998 and 2008 for nontraumatic subarachnoid hemorrhages were sent a standardized questionnaire for the purposes of documenting their health-related quality of life. Initially the patients were divided into two groups: those with and those without cerebral vasospasm after hemorrhage (radiologically confirmed). They were then differentiated according to four types of treatment options for vasospasm: 1) nimodipine since admission (N = 179); 2) nimodipine since diagnosis of vasospasm (N = 14); 3) no nimodipine/no vasospasm (N = 34); and 4) no nimodipine despite vasospasm (N = 5). Significance was established as P <= 0.05. RESULTS: Evaluable questionnaires were returned by 236 patients (68% women, mean age 56.35 +/- 12.68 years; 32% men, mean age 54.57 +/- 12.20 years). Health-related quality of life generally appeared to be impaired. Yet with the exception of the subscale (1 of 8) of physical role (P = 0.019), there were no differences between patients with and without vasospasm. Variations in the different treatment options revealed significant effects in terms of the component summaries and subscales: physical role and pain, general health, vitality, social functioning, emotional role, mental health, and mental component summary (P <= 0.04). CONCLUSIONS: Cerebral vasospasm had little influence on health-related quality of life in our patient population. Health related quality of life cannot be used as the only argument in favor of treating cerebral vasospasm with nimodipine. PMID- 23022641 TI - Career satisfaction and burnout among U.S. neurosurgeons: a feasibility and pilot study. AB - OBJECTIVE: Neurosurgery is a challenging and stressful field. Excessive stress and professional dissatisfaction can lead to medical errors, negatively impact patient care, and cause physician burnout. Our objective is to develop and critically evaluate a survey measuring professional stress and satisfaction and to obtain preliminary data on sources and degree of stress and the prevalence of burnout among American neurosurgeons. METHODS: A 107-item questionnaire was developed and sent to 169 American neurosurgeons to evaluate career satisfaction and stressors, quality of professional life, and burnout. Participants were also asked about the survey itself. Most variables were evaluated using the Likert type scale. Burnout was measured using the validated Maslach Burnout Inventory. RESULTS: The 85 (50%) respondents were typically male, full-time, board-certified neurosurgeons. Ninety-five percent were satisfied as neurosurgeons (73% very satisfied). Most (88%) would choose neurosurgery again as a career, but only 55% would recommend it to a child. Low salary/income, low collections/billing, and uncertainty regarding future earnings/health care reform were reported as stressful factors by the majority of participants. Compared with published norms, the median scores were lower for emotional exhaustion and depersonalization and higher for personal accomplishment. The burnout rate was 27%. CONCLUSION: Our survey was well received and, according to respondents, encompassed the major issues associated with career stress, satisfaction, and burnout but needs to be shortened. Respondents were generally satisfied with their career but identified several major stressors. A larger study to identify predictors of career satisfaction/dissatisfaction will help generate dialogue on improving the quality of professional life for neurosurgeons. PMID- 23022642 TI - Seizures after aneurysmal subarachnoid hemorrhage: a systematic review of outcomes. AB - OBJECTIVE: The risk for early and late seizures after aneurysmal subarachnoid hemorrhage (aSAH), as well as the effect of antiepileptic drug (AED) prophylaxis and the influence of treatment modality, remain unclear. We conducted a systematic review of case series and randomized trials in the hope of furthering our understanding of the risk of seizures after aSAH and the effect of AED prophylaxis and surgical clipping or endovascular coiling on this important adverse outcome. METHODS: We performed a MEDLINE (1985-2011) search to identify randomized controlled trials and retrospective series of aSAH. Statistical analyses of categorical variables such as presentation and early and late seizures were carried out using chi(2) and Fisher exact tests. RESULTS: We included 25 studies involving 7002 patients. The rate of early postoperative seizure was 2.3%. The rate of late postoperative seizure was 5.5%. The average time to late seizure was 7.45 months. Patients who experienced a late seizure were more likely to have MCA aneurysms, be Hunt/Hess grade III, and be repaired with microsurgical clipping than endovascular coiling. CONCLUSIONS: Despite improved microsurgical techniques and antiepileptic drug prophylaxis, a significant proportion of patients undergoing aneurysm clipping still experience seizures. Seizures may occur years after aneurysm repair, and careful monitoring for late complications remains important. Furthermore, routine perioperative AED use does not seem to prevent seizures after SAH. PMID- 23022643 TI - Which clinical variable influences health-related quality of life the most after spontaneous subarachnoid hemorrhage? Hunt and Hess scale, Fisher score, World Federation of Neurosurgeons score, Brussels coma score, and Glasgow coma score compared. AB - OBJECTIVE: To determine the strength of the correlation between the Hunt and Hess scale, Fisher score, Brussels coma score, World Federation of Neurosurgeons score, and Glasgow coma score and health-related quality of life. METHODS: Evaluable questionnaires from 236 patients (5.6 years [+/- standard deviation, 2.854 years] on average after hemorrhage) were included in the analysis. Quality of life was documented using the MOS-36 item short form health survey. Because of the ordinal nature of the variables, Kendall tau was used for calculation. Significance was established as P <= 0.05. RESULTS: Weak and very weak correlations were found in general (r <= 0.28). The strongest correlations were found between the Glasgow coma score and quality of life (r = 0.236, P = 0.0001). In particular, the "best verbal response" achieved the strongest correlations in the comparison, at r = 0.28/P = 0.0001. The Fisher score showed very weak correlations (r = -0.148/P = 0.012). The Brussels coma score (r = -0.216/P = 0.0001), Hunt and Hess scale (r = -0.197/P = 0.0001), and the World Federation of Neurosurgeons score (r = -0.185/P = 0.0001) revealed stronger correlations, especially in terms of the physical aspects of quality of life. CONCLUSIONS: The Glasgow coma scale revealed the strongest, and the Fisher score showed the weakest correlations. Thus the Fisher score, as an indicator of the severity of a hemorrhage, has little significance in terms of health-related quality of life. PMID- 23022644 TI - Long-term effectiveness of a reconstructive protocol using the nasoseptal flap after endoscopic skull base surgery. AB - OBJECTIVE: To describe the effect on postoperative cerebrospinal fluid (CSF) leak after anterior skull base (ASB) surgery and complications associated with the addition of the vascularized nasoseptal flap (NSF) to an existing reconstruction protocol. METHODS: A prospective database of all patients undergoing endoscopic ASB approaches was reviewed. Patients were divided into three groups based on the date the use of the NSF was adopted. Group A included patients with high-volume CSF leak closed using the NSF in addition to a multilayer closure. Group B included patients operated on during the same time period with no high-volume leak and no NSF. Group C included patients operated on before the adoption of the NSF with all types of CSF leak. Rates of intraoperative and postoperative CSF leak were analyzed for statistical significance. RESULTS: Of 415 consecutive patients undergoing endoscopic ASB surgery, there were 96 in group A, 114 in group B, and 205 in group C. CSF leak rates in group A (3.1%) and group B (2.6%) were significantly lower than in group C (5.9%; P < 0.05). Lumbar drains and the gasket seal closure were performed more frequently in group A (75% and 32%) compared with group B (21% and 12%) and group C (28% and 11%). NSF carried a 2% risk of postoperative mucocele. CONCLUSIONS: The addition of NSF to an algorithm for multilayer closure can decrease the rate of postoperative CSF leak. PMID- 23022645 TI - Early versus delayed endoscopic surgery for carpal tunnel syndrome: prospective randomized study. AB - OBJECTIVE: To compare the effects of early versus delayed endoscopic surgery in patients with moderately severe carpal tunnel syndrome (CTS). METHODS: The study included 100 patients with CTS. Investigations performed before surgery excluded secondary causes. Patients with moderately severe CTS (grade 3-4) were randomly assigned. Bland's neurophysiologic grading scale for CTS was used to assess the patients. Patients underwent an endoscopic carpal tunnel release using an indigenously designed instrument. RESULTS: Following a course of conservative treatment, surgical treatment was offered in two groups: early surgery (n = 51; <1 week after diagnosis) and delayed surgery as per the usual waiting list (n = 49; >6 months after diagnosis). Improvement in both groups was significant (P < 0.001). When both groups were compared, improvement was better for the early surgery group (P < 0.001; confidence interval 6.35-9.12). CONCLUSIONS: On the basis of this study, early endoscopic surgery is proposed in patients with moderately severe CTS. PMID- 23022646 TI - What can be learned from the DECRA study. AB - BACKGROUND: There has been a resurgence of interest in the use of decompressive craniectomy for severe traumatic brain injury (TBI). Numerous studies have shown that the procedure can consistently reduce intracranial pressure (ICP), and a significant number of patients achieve a good long-term functional recovery. However, there has been debate regarding clinical indications and patient selection. METHODS: The DECRA (Decompressive Craniectomy in Patients with Severe Traumatic Brain Injury) study compared patients who underwent early decompressive craniectomy for diffuse TBI with patients who received standard medical therapy. Of patients, 70% in the craniectomy group had an unfavourable outcome versus 51% in the standard care group (odds ratio 2.21 [95% confidence interval 1.14-4.26]; P=0.02). Based on these results, the authors concluded that decompressive craniectomy was associated with more unfavorable outcomes and that by adopting standard medical therapy rather than surgical decompression the health care system would save millions of dollars. These conclusions are not really supported by closer examination of the basic data. There were problems with randomization such that the patients in the surgical arm appeared to have sustained a more severe primary TBI, the ICP threshold of >20 mm Hg for >15 minutes did not reflect clinical practice, and there was a high crossover rate from the standard care arm to the surgical arm. Because of these problems, the DECRA trial has received a great deal of criticism, and some authorities have claimed that the results should have no influence on clinical practice. This claim is perhaps unfair, and an alternative interpretation is offered. RESULTS: Overall, the results of the DECRA study showed that a relatively transient and mild increase in ICP (>20 mm Hg for 15 minutes as recruitment criterion) does not imply that there is significant ongoing secondary brain injury, and any potential improvement obtained by surgical decompression may well be offset by surgical morbidity. CONCLUSIONS: The role of decompressive craniectomy when ICP continues to increase >=20 mm Hg remains to be established. The ongoing RESCUEicp (Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intra-Cranial Pressure) study hopes to address this issue. PMID- 23022647 TI - A solution to meningiomas at the trigone of the lateral ventricle using a contralateral transfalcine approach. AB - BACKGROUND: Access to the trigone of the lateral ventricle is challenging because of the deep location and the intimate relationships to eloquent areas. METHODS: A novel posterior interhemispheric transfalx transprecuneus approach for two meningiomas at the trigone of the lateral ventricle is described. RESULTS: The meningiomas were resected completely with good neurologic outcomes and no operative mortality. CONCLUSIONS: The feasibilities and advantages of this novel approach are discussed. PMID- 23022648 TI - Mesenchymal stem cell transplantation reduces glial cyst and improves functional outcome after spinal cord compression. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent stem cells that have a supportive role in regenerative therapies, especially in the central nervous system, where spontaneous regeneration is limited. MSCs can exert a paracrine activity and modulate the inflammatory response after a central nervous system injury. Spinal cord injury (SCI) leads to permanent neurologic deficits below the injury site, owing to neuronal and axonal damage. Among experimental treatments after SCI, cell transplantation has emerged as a promising approach. METHODS: Using a compression injury model in the mouse spinal cord, MSCs were acutely transplanted into the lesion cavity; injured mice without the graft served as controls. After 26 days, the survival of MSCs was investigated, and their effect on the formation of glial cyst and on injury-related inflammation was evaluated. RESULTS: Grafted MSCs remained permanently undifferentiated. The lesion volume was reduced by 31.6% compared with control mice despite the fact that astroglial and microglial activation was not altered by the graft. Sensory and motor tests showed that MSC cell therapy results in improvement on a battery of behavioral tests compared with control mice: MSC-treated mice versus control mice scored 0.00 versus 0.50 in the posture test, 0.00 versus 1.50 in the hindlimb flexion test, 3.00 versus 2.25 in the sensory test, and 7.50 mistakes versus 15.83 mistakes in the foot-fault test. CONCLUSIONS: These results underscore the therapeutic potential of MSCs, making them promising treatments for central nervous system pathologies. PMID- 23022649 TI - Prehistoric skull trepanation in China. AB - The term trepanation describes the removal of sections of bone from the cranium. Although others may have made earlier reference to trepanation, in 1995, Chinese archeologists discovered a skull at the Neolithic site Fujia from approximately 3000 bc (the Dawenkou Cultural Period), Guangrao, Dongying, Shandong, China, and after careful examination of the specimen, the archeologists suggested that the procedure had been performed on a living patient who subsequently survived. Archeological evidence supports that the practice of trepanation was widespread. PMID- 23022650 TI - Malignant peripheral nerve sheath tumor of the abducens nerve and a review of the literature. AB - BACKGROUND: Malignant peripheral nerve sheath tumors are rare, and intracranial occurrences are even more rare. Treatment strategies have varied widely. This article reports the first case of a malignant peripheral nerve sheath tumor of the abducens nerve and provides a literature review that includes 61 cases of intracranial malignant peripheral nerve sheath tumors. Data were analyzed based on age, sex, treatment, survival, immunohistochemical staining, location, tumor grade, and neurofibromatosis association. These tumors more often affect male persons, and the patients affected have a mean age of 39 years. Most patients underwent subtotal or gross total resection and radiation. Intracranial location varied, but most tumors occurred in the cerebellopontine angle. The literature shows that intracranial malignant peripheral nerve sheath tumors are a heterogeneous group. Their association with neurofibromatosis is less clear than that of their extracranial counterparts. Prognosis is poor, but surgical resection and radiation can enhance chances for longer survival. Our aim was to elucidate information about these tumors. CASE DESCRIPTION: A 30-year-old woman presented with a 6-month history of headaches and diplopia. RESULTS: Neurological examination revealed no focal deficit. Imaging revealed a heterogeneously enhancing retroclival mass without bony destruction. The tumor originated from the ipsilateral abducens nerve and extended into the Dorello canal; it adhered to the brainstem and cranial nerves. Pathology was consistent with low-grade malignant peripheral nerve sheath tumor. CONCLUSIONS: At 3-month follow-up, the patient walked with a cane with no further deficits except mild ataxia, which resolved within 6 months. Magnetic resonance imaging revealed a small residual tumor adherent to the basilar artery. At 1-year follow-up and after ocular surgery to correct lateral rectus palsy, the patient was neurologically intact. PMID- 23022651 TI - Stent-assisted endovascular recanalization of extracranial internal carotid artery occlusion in acute ischemic stroke. AB - OBJECTIVE: Carotid artery occlusions traditionally have extremely poor outcomes with intravenous tissue plasminogen activator treatment or emergent thromboendarterectomy. We retrospectively reviewed our institutional experience with acute carotid occlusions using internal carotid artery endovascular thrombolysis and stent placement. METHODS: We studied the radiographic and clinical characteristics of 17 patients with an acute cervical internal carotid artery occlusion treated with stent-assisted endovascular thrombolysis. Clinical outcomes were assessed by using National Institute of Health Stroke Scale (NIHSS) scores, which were obtained on admission and discharge. Inclusion criteria were an NIHSS score of at least 6 and the presence of significant penumbra on computed tomographic perfusion. Morbidity and mortality data were collected and analyzed. RESULTS: Seventeen candidates met our inclusion criteria, 16 (94%) of whom had successful immediate recanalization of the internal carotid artery. On admission, the mean NIHSS score was 16.5 and the mean modified Rankin Scale score was 4.8. The mean NIHSS score improved to 6.9 on discharge, with a mean modified Rankin Scale score of 2.88. Eight (47%) patients recovered ambulatory function on discharge. The overall mortality rate of our series was 17%. CONCLUSIONS: In the setting of acute ischemic stroke, emergent carotid artery thrombolysis and stenting is a promising treatment for acute carotid occlusions with excellent recanalization rates and favorable clinical outcomes. PMID- 23022652 TI - A comparison of acute hospital charges after tubular versus open microdiskectomy. AB - OBJECTIVE: To determine if tubular microdiskectomy is associated with differences in hospital charges compared with open microdiskectomy. METHODS: A retrospective review of patients who underwent tubular microdiskectomy or open microdiskectomy performed by the senior authors from 2007-2010 was performed. The primary outcome was inflation-adjusted total hospital charges for each procedure using itemized charge data obtained from the hospital finance department. Secondary outcomes included length of stay, complications, and operative times. RESULTS: There were 76 eligible patients (33 open microdiskectomy and 48 tubular microdiskectomy) identified during the study period. The mean total charge was $27,811 (standard deviation $11,198) in the open group compared with $22,358 (standard deviation $8695) in the tubular group. Total charges in the tubular group were on average $5453 less than in the open group (P = 0.02). There were no significant differences in operative times or complications. Length of stay was significantly shorter in the tubular group (mean 1.5 days open vs. 0.9 days tubular, P = 0.01). CONCLUSIONS: This analysis revealed significantly lower acute hospital charges associated with tubular microdiskectomy versus open microdiskectomy at an academic tertiary care hospital. These differences appear to the related to decreased use of postoperative resources in the tubular group. PMID- 23022653 TI - Design of ridge filters for spread-out Bragg peaks with Monte Carlo simulation in carbon ion therapy. AB - Spread-out Bragg peaks made by ridge filters or wheel range modulators are used in charged particle therapy with passive methods to achieve uniform biological responses in irradiated tumors. Following the biological responses needed to design the ridge filters, which were developed at the National Institute of Radiological Sciences in Japan, new ridge filters were designed using recent developments in heavy-ion reactions and dosimetry. The Monte Carlo code of Geant4 was used to calculate the qualities of carbon ion beams in a water phantom. The results obtained from the simulation were corrected so that they agreed with the measurements of depth dose distributions. The calculations of biological responses to fragments other than carbon ions were assumed to be for helium ions. The measured dose distributions with the designed ridge filters were compared to the calculated distributions. A beam modifying system using this adaptable method was successively applied to carbon ion therapy at Gunma University. PMID- 23022654 TI - Monoclonal IgG kappa gammopathy previous to hematopoietic stem cell transplantation in an infant with severe combined immunodeficiency. PMID- 23022655 TI - A TWEAK in lupus nephritis. PMID- 23022656 TI - Occupational physical activity, metabolic syndrome and risk of death from all causes and cardiovascular disease in the HUNT 2 cohort study. AB - OBJECTIVES: To prospectively examine the independent and combined effect of occupational physical activity and metabolic syndrome on all-cause and cardiovascular mortality in a large population-based cohort. METHODS: Data on 37 300 men and women participating in the Norwegian HUNT Study (1995-1997) were linked with the Cause of Death Registry at Statistics Norway. Cox proportional HR with 95% CI were estimated. RESULTS: During a median follow-up of 12.4 years, a total of 1168 persons died. Of these, 278 died from cardiovascular disease. Persons with metabolic syndrome and much walking/lifting at work had a HR of 1.79 (95% CI 1.20 to 2.66) for cardiovascular death referencing persons without metabolic syndrome and much walking/lifting. Using the same reference, persons with metabolic syndrome and sedentary work had a HR of 2.74 (95% CI 1.82 to 4.12) while persons with metabolic syndrome and heavy physical work had a HR of 3.02 (95% CI 1.93 to 4.75). Associations with all-cause mortality were somewhat weaker, and were largely due to deaths from cardiovascular disease. CONCLUSIONS: The association between metabolic syndrome and cardiovascular mortality is stronger for persons with sedentary work and with physically heavy work than for persons with much walking/lifting at work. PMID- 23022659 TI - Three-dimensional anatomy of the Ciona intestinalis tailbud embryo at single-cell resolution. AB - During embryogenesis, chordates pass through a tailbud stage in which the larval tail is formed. Since acquisition of a tadpole-like tail during tailbud stage is one of the key events in the evolution of chordates, understanding the anatomy of the tailbud stage chordate embryo is of special interest. In this study, to understand comprehensively the anatomy of the tailbud embryo at single-cell level, real microscopic image stacks of the tailbud embryo in Ciona intestinalis were reconstructed into a 3D computer model. This comprehensive 3D model of the ascidian tailbud embryo was based on real images of confocal laser scanning microscope (CLSM) and therefore, cell shape, location and cell arrangement reflect real geometries of the tailbud embryo. We found that the tailbud embryo consists of 1579 cells, including 836 epidermal cells, 228 cells in the central nervous system, 218 mesenchymal cells, four trunk ventral cells, two B/B(*)8.11 cells, 36 muscle cells, 40 notochord cells, four primordial germ cells, and 199 endodermal cells. Moreover, we identified for the first time two populations of previously undefined cells (a total of 12 cells) in Ciona: one located in the lateral trunk and the other located under the tail dorsal epidermis. This information provides a first step for understanding how the body plan of the chordate tailbud embryo formed and evolved. PMID- 23022658 TI - A cis-element in the Notch1 locus is involved in the regulation of gene expression in interneuron progenitors. AB - Interneurons comprise approximately one third of the total cortical neurons in the mammalian cerebral cortex. Studies have revealed many details in the generation of this cell type. However, the mechanism that defines interneuron lineage specific gene expression is not well understood. Gene regulatory elements, e.g., promoters, enhancers, and trans-acting factors, are essential for the proper control of gene expression. Here, we report that a novel evolutionarily conserved cis-element in the second intron of the Notch1 locus plays an important role in regulating gene expression in interneuron progenitors. The spatiotemporal activity of the cis-element in the developing central nervous system (CNS) was determined by both transient reporter expression in the developing chick and a transgenic mouse model. Its activity is well correlated with neurogenesis in both the chick and mouse and restricted to neural progenitor cells in the ganglionic eminence that are fated to differentiate into GABAergic interneurons of the neocortex. We further demonstrate that the cis-element activity requires the binding motif for trans-acting factors Gsh1/Barx2/Brn3. Deletion of this binding motif abolishes reporter gene expression. Together, these data provide new insights into the regulatory mechanisms of interneuron development in the vertebrate CNS. PMID- 23022660 TI - An oocyte-specific astacin family protease, alveolin, is released from cortical granules to trigger egg envelope hardening during fertilization in medaka (Oryzias latipes). AB - It has long been hypothesized that in fishes the contents of cortical granules are involved in the hardening of egg envelope following fertilization. We previously purified the egg envelope hardening initiation factor from the exudates released from activated medaka (Oryzias latipes) eggs and tentatively termed this protein alveolin. Alveolin is a member of the astacin metalloprotease family and was proposed to be a protease which hydrolyzes ZPB at one restricted position to allow starting cross-linking with ZPC. Here, we investigated the complete pathway from biosynthesis and accumulation to secretion of alveolin. A single alveolin transcript was detected only in ovarian preparations, confirming the specific expression of alveolin in the ovary. In situ hybridization indicated that the alveolin mRNA is already expressed in the very early previtellogenic oocytes. However, immunocytochemical studies revealed that the appearance of alveolin protein was delayed until the beginning of the vitellogenic stage. The cortical granules isolated from unfertilized eggs contained a high molecular weight form of glycosylated alveolin with a 50kDa relative molecular mass. Hypotonic treatment burst isolated granules in vitro and transformed alveolin to a 21.5kDa form, which is the same size as that of natural alveolin released from eggs upon fertilization. This transformation was inhibited in the presence of leupeptin and 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF), suggesting that a serine protease is involved in alveolin activation upon fertilization. Furthermore, the phylogenetic relationship of alveolin with other vertebrate astacin family members was analyzed. The result shows that alveolin and its teleostean homologs make a new group which is separate from either the hatching enzyme, meprin and BMP1/tolloid groups. PMID- 23022657 TI - Abelson interactor-1 (ABI-1) interacts with MRL adaptor protein MIG-10 and is required in guided cell migrations and process outgrowth in C. elegans. AB - Directed cell migration and process outgrowth are vital to proper development of many metazoan tissues. These processes are dependent on reorganization of the actin cytoskeleton in response to external guidance cues. During development of the nervous system, the MIG-10/RIAM/Lamellipodin (MRL) signaling proteins are thought to transmit positional information from surface guidance cues to the actin polymerization machinery, and thus to promote polarized outgrowth of axons. In C. elegans, mutations in the MRL family member gene mig-10 result in animals that have defects in axon guidance, neuronal migration, and the outgrowth of the processes or 'canals' of the excretory cell, which is required for osmoregulation in the worm. In addition, mig-10 mutant animals have recently been shown to have defects in clustering of vesicles at the synapse. To determine additional molecular partners of MIG-10, we conducted a yeast two-hybrid screen using isoform MIG-10A as bait and isolated Abelson-interactor protein-1 (ABI-1). ABI-1, a downstream target of Abl non-receptor tyrosine kinase, is a member of the WAVE regulatory complex (WRC) involved in the initiation of actin polymerization. Further analysis using a co-immunoprecipitation system confirmed the interaction of MIG-10 and ABI-1 and showed that it requires the SH3 domain of ABI-1. Single mutants for mig-10 and abi-1 displayed similar phenotypes of incomplete migration of the ALM neurons and truncated outgrowth of the excretory cell canals, suggesting that the ABI-1/MIG-10 interaction is relevant in vivo. Cell autonomous expression of MIG-10 isoforms rescued both the neuronal migration and the canal outgrowth defects, showing that MIG-10 functions autonomously in the ALM neurons and the excretory cell. These results suggest that MIG-10 and ABI-1 interact physically to promote cell migration and process outgrowth in vivo. In the excretory canal, ABI-1 is thought to act downstream of UNC-53/NAV2, linking this large scaffolding protein to actin polymerization during excretory canal outgrowth. abi-1(RNAi) enhanced the excretory canal truncation observed in mig-10 mutants, while double mutant analysis between unc-53 and mig-10 showed no increased truncation of the posterior canal beyond that observed in mig-10 mutants. Morphological analysis of mig-10 and unc-53 mutants showed that these genes regulate canal diameter as well as its length, suggesting that defective lumen formation may be linked to the ability of the excretory canal to grow out longitudinally. Taken together, our results suggest that MIG-10, UNC-53, and ABI 1 act sequentially to mediate excretory cell process outgrowth. PMID- 23022661 TI - Organic photovoltaics: potential fate and effects in the environment. AB - In times of dwindling fossil fuels it is particularly crucial to develop novel "green" technologies in order to cover the increasing worldwide demand for energy. Organic photovoltaic solar cells (OPVs) are promising as a renewable energy source due to low energy requirement for production, low resource extraction, and no emission of greenhouse gasses during use. In contrast to silicium-based solar cells, OPVs offer the advantages of light-weight, semi transparency and mechanical flexibility. As to a possible forthcoming large-scale production, the environmental impact of such OPVs should be assessed and compared to currently best available technologies. For the first time, this review compiles the existing knowledge and identifies gaps regarding the environmental impact of such OPVs in a systematic manner. In this regard, we discuss the components of a typical OPV layer by layer. We discuss the probability of enhanced release of OPV-borne components into the environment during use-phase (e.g. UV- and biodegradation) and end-of-life phase (e.g. incineration and waste disposal). For this purpose, we compiled available data on bioavailability, bioaccumulation, biodegradation, and ecotoxicity. Whereas considerable research has already been carried out concerning the ecotoxicity of certain OPV components (e.g. nanoparticles and fullerenes), others have not been investigated at all so far. In conclusion, there is a general lack of information about fate, behavior as well as potential ecotoxicity of most of the main OPV components and their degradation/transformation products. So far, there is no evidence for a worrying threat coming from OPVs, but since at present, no policy and procedures regarding recycling of OPVs are in action, in particular improper disposal upon end-of-life might result in an adverse effect of OPVs in the environment when applied in large-scale. PMID- 23022663 TI - Characterization of a mutation that results in independence of oxidosqualene cyclase (Erg7) activity from the downstream 3-ketoreductase (Erg27) in the yeast ergosterol biosynthetic pathway. AB - In yeast, deletion of ERG27, which encodes the sterol biosynthetic enzyme, 3-keto reductase, results in a concomitant loss of the upstream enzyme, Erg7p, an oxidosqualene cyclase (OSC). However, this phenomenon occurs only in fungi, as mammalian Erg27p orthologues are unable to rescue yeast Erg7p activity. In this study, an erg27 mutant containing the mouse ERG27 orthologue was isolated that was capable of growing without sterol supplementation (FGerg27). GC/MS analysis of this strain showed an accumulation of squalene epoxides, 3-ketosterones, and ergosterol. This strain which was crossed to a wildtype and daughter segregants showed an accumulation of squalene epoxides as well as ergosterol indicating that the mutation entailed a leaky block at ERG7. Upon sequencing the yeast ERG7 gene an A598S alteration was found in a conserved alpha helical region. We theorize that this mutation stabilizes Erg7p in a conformation that mimics Erg27p binding. This mutation, while decreasing OSC activity still retains sufficient residual OSC activity such that the strain in the presence of the mammalian 3-keto reductase enzyme functions and no longer requires the yeast Erg27p. Because sterol biosynthesis occurs in the ER, a fusion protein was synthesized combining Erg7p and Erg28p, a resident ER protein and scaffold of the C-4 demethyation complex. Both FGerg27 and erg27 strains containing this fusion plasmid and the mouse ERG27 orthologue showed restoration of ergosterol biosynthesis with minimal accumulation of squalene epoxides. These results indicate retention of Erg7p in the ER increases its activity and suggest a novel method of regulation of ergosterol biosynthesis. PMID- 23022662 TI - Development of ethyl alcohol-precipitated silk sericin/polyvinyl alcohol scaffolds for accelerated healing of full-thickness wounds. AB - Silk sericin has been recently reported for its advantageous biological properties to promote wound healing. In this study, we established that the ethyl alcohol (EtOH) could be used to precipitate sericin and form the stable sericin/polyvinyl alcohol (PVA) scaffolds without the crosslinking. The sericin/PVA scaffolds were fabricated via freeze-drying and subsequently precipitating in various concentrations of EtOH. The EtOH-precipitated sericin/PVA scaffolds showed denser structure, higher compressive modulus, but lower water swelling ability than the non-precipitated scaffolds. Sericin could be released from the EtOH-precipitated sericin/PVA scaffolds in a sustained manner. After cultured with L929 mouse fibroblasts, the 70 vol% EtOH-precipitated sericin/PVA scaffolds showed the highest potential to promote cell proliferation. After applied to the full-thickness wounds of rats, the 70 vol% EtOH-precipitated sericin/PVA scaffolds showed significantly higher percentage of wound size reduction and higher extent of type III collagen formation and epithelialization, compared with the control scaffolds without sericin. The accelerated wound healing by the 70 vol% EtOH-precipitated sericin/PVA scaffolds was possibly due to (1) the bioactivity of sericin itself to promote wound healing, (2) the sustained release of precipitated sericin from the scaffolds, and (3) the activation and recruitment of wound healing-macrophages by sericin to the wounds. This finding suggested that the EtOH-precipitated sericin/PVA scaffolds were more effective for the wound healing, comparing with the EtOH-precipitated PVA scaffolds without sericin. PMID- 23022664 TI - Autotaxin in embryonic development. AB - Autotaxin (ATX) is a secreted lysophospholipase D that generates the multifunctional lipid mediator lysophosphatidic acid (LPA). LPA signals through six distinct G protein-coupled receptors, acting alone or in concert to activate multiple effector pathways. The ATX-LPA signaling axis is implicated in a remarkably wide variety of physiological and pathological processes and plays a vital role in embryonic development. Disruption of the ATX-encoding gene (Enpp2) in mice results in intrauterine death due to vascular defects in the extra embryonic yolk sac and embryo proper. In addition, Enpp2 (-/-) embryos show impaired neural development. The observed angiogenic defects are attributable, at least in part, to loss of LPA signaling through the Galpha(12/13)-linked RhoA ROCK-actin remodeling pathway. Studies in zebrafish also have uncovered a dual role for ATX in both vascular and neural development; furthermore, they point to a key role for ATX-LPA signaling in the regulation of left-right asymmetry. Here we discuss our present understanding of the role of ATX-LPA signaling in vertebrate development. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. PMID- 23022665 TI - Pharmacological prevention of suicide in patients with major mood disorders. AB - The risk of self-destructive behavior in mood disorders is an inherent phenomenon and suicidal behavior in patients with unipolar or bipolar major mood disorders strongly relates to the presence and severity of depressive episodes. Consequently, early recognition, and successful acute and long-term treatment of depressive disorders is essential for suicide prevention in such patients. Large scale, retrospective and prospective naturalistic long-term clinical studies, including severely ill, frequently suicidal depressives show that appropriate pharmacotherapy markedly reduces suicide morbidity and mortality even in this high-risk population. Supplementary psycho-social interventions further improve the effect. The slightly elevated (but in absolute sense quite low) risk of suicidal behavior among patients taking antidepressants compared to those taking placebo in randomized controlled antidepressant trials on unipolar major depression might be the consequence of the depression-worsening potential of antidepressant monotherapy in subthreshold and mixed bipolar depressed patients included in these trials and falsely diagnosed as suffering from unipolar major depression. Concurrent depression-focused psychotherapies increase the effectiveness of pharmacotherapy and this way contribute to suicide prevention for patients with mood disorders. PMID- 23022666 TI - Solutions for real values in Minkowski four-dimensional space may link macro- and micro-quantum processes in the brain. AB - To test the application of Minkowski space-time (hyperspace) to brain function, the time-dependent inflection values required for a non-negative solution of ?(x2 + y2 + z2-c2t2) was solved for four functional cerebral spaces. The single electron orbit time for the cell membrane, the "neuroquantal unit" of ~10(-20)J for the cell width, the frequency of the universal hydrogen emission (precession) line for cerebral length, and one-half of Planck's constant (the spin of particles constituting matter) for the thickness of the charges associated with the cell membrane potential were the primary solutions. These values may reflect the critical times (or frequencies) when operations shift from imaginary to real within the 4D human brain and could define the thresholds optimal for the transition between energy and matter. PMID- 23022667 TI - Prophage induction in lysogenic Aggregatibacter actinomycetemcomitans cells co cultured with human gingival fibroblasts, and its effect on leukotoxin release. AB - Lysogeny is common among strains of the periodontal pathogen Aggregatibacter actinomycetemcomitans. Since lysogenic induction is known to result in the increased synthesis and release of bacterial toxins from lysogens, it would be important to elucidate the conditions under which induction of these bacteria may occur. Co-cultures of A. actinomycetemcomitans strains (either lysogenic or non lysogenic) and human cells (either gingival fibroblasts or pharyngeal epithelial cells) were prepared. Following incubation, bacteriophage titers of up to 6.2 * 10(7) pfu/ml were detected in the cell-free, spent culture media from the co cultures of the lysogenic A. actinomycetemcomitans strains and the fibroblasts. Little (maximum of 2 * 10(0) pfu/ml) or no titers of phage could be detected in the mono-cultures of the lysogenic A. actinomycetemcomitans strains alone. In contrast, no phage were detectable in the cell-free spent culture media of the lysogens cocultured with the epithelial cells. Futhermore, co-culture of the A. actinomycetemcomitans lysogens with the fibroblasts resulted in enhanced release of the A. actinomycetemcomitans leukotoxin into the culture medium, in comparison with the spent culture media from mono-cultures of the lysogens alone. These results are consistent with the concept that interaction with fibroblasts may mediate prophage induction in lysogenic strains of A. actinomycetemcomitans, and that leukotoxin release is greatly augmented following induction of the lysogens. PMID- 23022668 TI - Histophilus somni causes extracellular trap formation by bovine neutrophils and macrophages. AB - Histophilus somni (formerly Haemophilus somnus) is a Gram-negative pleomorphic coccobacillus that causes respiratory, reproductive, cardiac and neuronal diseases in cattle. H. somni is a member of the bovine respiratory disease complex that causes severe bronchopneumonia in cattle. Previously, it has been reported that bovine neutrophils and macrophages have limited ability to phagocytose and kill H. somni. Recently, it was discovered that bovine neutrophils and macrophages produce extracellular traps in response to Mannheimia haemolytica, another member of the bovine respiratory disease complex. In this study, we demonstrate that H. somni also causes extracellular trap production by bovine neutrophils in a dose- and time-dependent manner, which did not coincide with the release of lactate dehydrogenase, a marker for necrosis. Neutrophil extracellular traps were produced in response to outer membrane vesicles, but not lipooligosacchride alone. Using scanning electron microscopy and confocal microscopy, we observed H. somni cells trapped within a web-like structure. Further analyses demonstrated that bovine neutrophils trapped and killed H. somni in a DNA-dependent manner. Treatment of DNA extracellular traps with DNase I freed H. somni cells and diminished bacterial death. Treatment of bovine monocyte derived macrophages with H. somni cells also caused macrophage extracellular trap formation. These findings suggest that extracellular traps may play a role in the host response to H. somni infection in cattle. PMID- 23022669 TI - A hypothesis on the formation of the primary ossification centers in the membranous neurocranium: a mathematical and computational model. AB - This article develops a model of the appearance and location of the primary centers of ossification in the calvaria. The model uses a system of reaction diffusion equations of two molecules (BMP and Noggin) whose behavior is of type activator-substrate and its solution produces Turing patterns, which represents the primary ossification centers. Additionally, the model includes the level of cell maturation as a function of the location of mesenchymal cells. Thus the mature cells can become osteoblasts due to the action of BMP2. Therefore, with this model, we can have two frontal primary centers, two parietal, and one, two or more occipital centers. The location of these centers in the simplified computational model is highly consistent with those centers found at an embryonic level. PMID- 23022670 TI - Effects of MPEP, a selective metabotropic glutamate mGlu5 ligand, on sleep and wakefulness in the rat. AB - Metabotropic glutamate receptors (mGlu) have been implicated in the regulation of physiological and behavioral processes. Pharmacological evidence involves group I mGlu receptors in the regulation of emotional states and antagonism of these receptors has been proposed as a novel class of anxiolytic drugs having also antidepressant effects. Here, the effects of mGlu5 receptor selective modulation on sleep and wake states are explored. 32 male Wistar rats were implanted with electrodes for recording sleep and wake states. 2-Methyl-6 (phenylethynyl)pyridine hydrochloride (MPEP hydrochloride, 5, 10, and 20 mg/kg, i.p.), a potent, selective and systemically active mGlu5 receptor negative allosteric modulator, or vehicle was administered 1 h after the beginning of the light period. Sleep recordings were conducted for 3 h. MPEP (5, 10, and 20 mg/kg) significantly suppressed rapid eye movement (REM) sleep, decreasing the number of episodes and mean episode duration, and increased its latency. A reduction of light and deep slow wave sleep (SWS) latency was observed in the groups receiving 10 or 20 mg/kg, increasing latency to first wakefulness episode. 10 mg/kg of MPEP also increased non rapid eye movement sleep (NREM). The present results suggest that mGlu5 receptors might be involved in sleep regulation, more specifically in REM sleep, and drugs that block these receptors could potentially benefit the treatment of pathologies were REM sleep is enhanced. PMID- 23022671 TI - Age-associated decrease in serum glial cell line-derived neurotrophic factor levels in patients with major depressive disorder. AB - BACKGROUND: Many studies have supported the role of neurotrophic hypothesis in the pathophysiology of mood disorders. This study examined serum levels of glial cell line-derived neurotrophic factor (GDNF), one of the neurotrophic factors, in patients with major depressive disorder (MDD) at different disease states. METHODS: The serum GDNF levels were measured in 55 patients with MDD (29 severe patients and 26 remitted patients) and 35 healthy controls by ELISA method. Severity of depressive symptoms was assessed using the 17-item Hamilton Rating Scale of Depression (HAM-D) (HAM-D >/= 19 for severe MDD, HAM-D =30 kg/m(2) (stage 0: n = 13, 8.5 +/- 2.2 kPa; stage 1: n = 22, 11.7 +/- 5.2 kPa) (P < .001 and P = .002, respectively, by analysis of variance). High BMI was independently associated with high LSM, in addition to fibrosis stage, among patients with NAFLD. Patients with different waist circumferences had comparable LSMs. CONCLUSIONS: BMI >=30 kg/m(2) is associated with higher LSMs in patients with NAFLD, after adjusting for fibrosis stage. PMID- 23022699 TI - Trends in overall and cause-specific mortality among patients with inflammatory bowel disease from 1982 to 2010. AB - BACKGROUND & AIMS: Treatments for inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) have changed over time, with unclear effects on prognosis. We assessed overall and cause-specific mortality in a Danish cohort of patients with IBD during a 30-year time period. METHODS: We compared data from 36,080 patients with UC and 15,361 with CD, who were diagnosed in Denmark from 1982 to 2010, and compared them with data from 2,858,096 matched individuals from the general population (controls). Overall and cause-specific mortality were estimated by Cox regression analysis, adjusted for age, sex, disease duration, and known comorbidities before IBD diagnosis. Results were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Mortality greatly increased in the first year after individuals were diagnosed with IBD; intermediate-term and long-term mortalities increased by approximately 10% among individuals with UC and 50% among those with CD, compared with the general population. Compared with the time period of 1982-1989, overall mortalities decreased among patients diagnosed with UC from 1990 to 1999 (HR, 0.96; 95% CI, 0.90-1.02) and from 2000 to 2010 (HR, 0.88; 95% CI, 0.82-0.95). These reductions were mainly due to decreased mortality from colorectal cancer, gastrointestinal disorders, and suicide. For individuals with CD, mortality did not change among these time periods because of long-term increases in mortality from infections, cancer, respiratory diseases, and gastrointestinal diseases. CONCLUSIONS: In a Danish cohort, mortality from UC decreased from 1982 to 2010, largely because of reduced mortalities from gastrointestinal disorders and colorectal cancer. People with CD had 50% greater mortality than the general population, and this value did not change during this time period. PMID- 23022700 TI - Through the looking glass: a journey toward optimal endoscopic assessment of disease activity in ulcerative colitis. PMID- 23022701 TI - Successful endoscopic resection of inverted Meckel's diverticulum by double balloon enteroscopy. PMID- 23022702 TI - Comparison of the Danish step test and the watt-max test for estimation of maximal oxygen uptake: the Health2008 study. AB - INTRODUCTION: There is a need for simple and feasible methods for estimation of cardiorespiratory fitness (CRF) in large study populations, as existing methods for valid estimation of maximal oxygen consumption are generally time consuming and relatively expensive to administer. The Danish step test may be a feasible alternative for estimation of VO2max. AIM: To compare a simple fitness test, the Danish step test, to an indirect maximal test, the watt-max test, for estimation of VO2max. METHODS: In the population-based Health2008 study, 2218 men and women aged 30-60 years were invited. Altogether, 795 eligible participants (response rate 35.8%) performed the watt max and the Danish step test. Correlation and agreement between the two VO2max test results was explored by Pearson's rho, Bland-Altman plots, Kappa(w), and gamma coefficients. RESULTS: The correlation between VO2max (ml/kg/min) estimated by the two tests was moderate to high (men: r = 0.69, p < 0.0001; women: r = 0.77, p < 0.0001). The Danish step test slightly overestimated VO2max compared to the watt-max test, more so in women than in men. Agreement between the two tests when VO2max was classified in five levels was gamma = 0.77, Kappa(w )= 0.42 in women, and gamma = 0.64, Kappa(w )= 0.37 in men. CONCLUSION: The Danish step test is a safe and feasible alternative to the more time-consuming watt-max test as a method for estimation of VO2max in large adult population-based studies. PMID- 23022703 TI - Lifestyle modification programmes for patients with coronary heart disease: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Lifestyle modification programmes for coronary heart disease patients have been shown to effectively improve risk factors and related health behaviours, quality of life, reincidence, and mortality. However, improvements in routine cardiac care over the recent years may offset the incremental benefit associated with older programmes. PURPOSE: To determine the efficacy of lifestyle modification programmes for coronary heart disease patients developed over the last decade (1999-2009) by means of a systematic review and meta-analysis. RESULTS: The study included 23 trials (involving 11,085 randomized patients). Lifestyle modification programmes were associated with reduced all-cause mortality (summary OR 1.34, 95% CI 1.10-1.64), cardiac mortality (summary OR 1.48, 95% CI 1.17-1.88), and cardiac readmissions and non-fatal reinfarctions (summary OR 1.35, 95% CI 1.17-1.55). Furthermore, lifestyle modification programmes positively affected risk factors and related lifestyle behaviours at posttreatment (M = 10.2 months), and some of these benefits were maintained at long-term follow up (M = 33.7 months). Improvements in dietary and exercise behaviour were greater for programmes incorporating all four self-regulation techniques (i.e. goal setting, self-monitoring, planning, and feedback techniques) compared to interventions that included none of these techniques. CONCLUSION: The evidence summarized in this meta-analysis confirms the benefits of lifestyle modification programmes - over and above benefits achieved by routine clinical care alone. PMID- 23022704 TI - Effect of dexamethasone on prevention of postoperative nausea, vomiting and pain after caesarean section: a randomised, placebo-controlled, double-blind trial. AB - CONTEXT: Spinal morphine is a common form of postoperative analgesia after caesarean section, but it is associated with postoperative nausea and vomiting. OBJECTIVE: To evaluate the hypothesis that dexamethasone reduces nausea and vomiting in patients undergoing caesarean section under spinal anaesthesia with morphine. DESIGN: Interventional, randomised, double-blinded, placebo-controlled study to evaluate a preoperative single dose of dexamethasone. SETTING: Patients from a tertiary hospital in the city of Sao Paulo, Sao Paulo, Brazil observed from 1 January through 30 June 2008. PATIENTS OR OTHER PARTICIPANTS: Seventy full term pregnant patients (American Society of Anesthesiologists 1 or 2) were studied. Patients were randomly allocated into two groups determined by a computerised table. Exclusion criteria were contraindication to regional anaesthesia, allergy to dexamethasone, opioids or local anaesthetics, hypertension or diabetes originated during pregnancy and use of any antiemetic drug received before surgery. Spinal anaesthesia consisted of hyperbaric bupivacaine and morphine. INTERVENTION: Patients received either dexamethasone 10 mg in 100 ml of isotonic saline, intravenously or 100 ml of isotonic saline (placebo) prior to surgery. MAIN OUTCOME: Incidence of postoperative nausea and vomiting in the first 24 h were rated and recorded. Pain scores at rest and on movement were evaluated using a visual analogue scale. RESULTS: During the first 24 hours, nausea occurred in 12/35 (34.4%) patients receiving dexamethasone and in 32/35 (91.4%) receiving placebo (P<0.001). During the same time period, vomiting occurred in 12/35 (34.4%) patients receiving dexamethasone and in 29/35 (82.9%) receiving placebo (P<0.001). Pain at rest and pain on movement was lower in patients who received dexamethasone at some time points during the study period. CONCLUSION: Dexamethasone reduced the cumulative incidence of nausea and vomiting after caesarean section under spinal anaesthesia with morphine and lowered pain scores on the first postoperative day. PMID- 23022705 TI - Catecholaminergic polymorphic ventricular tachycardia. PMID- 23022706 TI - Arrhythmogenic right ventricular cardiomyopathy. PMID- 23022707 TI - Translational research in atrial fibrillation: a quest for mechanistically based diagnosis and therapy. PMID- 23022709 TI - Sudden cardiac death in hypertrophic cardiomyopathy. PMID- 23022708 TI - Dilated cardiomyopathy. PMID- 23022710 TI - Rotavirus genotypes in Malaysia and universal rotavirus vaccination. AB - Group A rotavirus (RV-A) genotypes isolated in Malaysia was studied to estimate the effectiveness of a universal RV-A vaccination in Malaysia. A simple mathematical model was used, with input from a two-year, two-center, prospective study on hospitalization of RV-A gastroenteritis (RVGE) in young children, published data on RV-A hospitalizations and genotypes, mortality on childhood GE and published genotype-specific efficacy data on two RV-A vaccines. Assuming a 95% vaccine coverage, the overall projected effectiveness was 75.7 to 88.1% for Rotateq and 78.7 to 90.6% for Rotarix(r) against RVGE-related hospitalizations. The projected annual reduction in RVGE-related deaths was 27 to 32 deaths (from 34 deaths) for Rotateq and 28 to 32 deaths annually for Rotarix. A universal RV-A vaccine is efficacious in reducing RVGE-related hospitalizations and mortality in Malaysia. PMID- 23022711 TI - Parental history of premature coronary artery disease does not affect plasma levels of asymmetric dimethylarginine in young healthy adults. AB - INTRODUCTION: Family history of premature coronary artery disease (CAD) is a risk factor of atherogenesis and adverse coronary events. OBJECTIVES: The aim of the study was to establish whether asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide formation, might be elevated in the asymptomatic offspring of patients with early-onset CAD and whether it might contribute to subclinical atherosclerosis. PATIENTS AND METHODS: We studied 20 healthy subjects (10 men and 10 women) aged from 19 to 30 years with a parental history of documented CAD before 60 years of age, and 20 controls with no evidence of parental CAD. ADMA and its isomer, symmetric dimethylarginine (SDMA), were determined by enzyme-linked immunosorbent assays. Mean intima-media thickness (IMT) of the common carotid arteries was assessed by B-mode ultrasound. RESULTS: Characteristics of the 2 groups were similar, except for insignificant tendencies towards higher low-density lipoprotein (LDL) cholesterol (P = 0.07) and estimated glomerular filtration rate (eGFR) (P = 0.06) in the group with a positive family history. Compared with controls, subjects with a parental history of premature CAD had increased IMT (0.54 +/-0.05 vs. 0.48 +/-0.05 mm; P <0.001) and similar levels of ADMA (0.66 +/-0.17 vs. 0.74 +/-0.15 MUmol/l; P = 0.14) and SDMA (0.49 +/-0.07 vs. 0.50 +/-0.07 MUmol/l; P = 0.61). The results did not change substantially on adjustment for LDL cholesterol and eGFR. In a multivariate analysis, parental CAD (P = 0.005) and LDL cholesterol (P = 0.06), but not ADMA, were independent positive IMT predictors. CONCLUSIONS: Our preliminary data suggest that elevated ADMA is not a part of the proatherogenic risk profile in the young adult offspring of patients with premature CAD. PMID- 23022712 TI - Evolutionary dynamics of the E1-E2 viral populations during combination therapy in non-responder patients chronically infected with hepatitis C virus subtype 1b. AB - Half of the patients chronically infected with hepatitis C virus (HCV) genotype 1 fail to respond to pegylated interferon alpha (PEG-IFN) and ribavirin (RBV) therapy. This study assesses the effects of treatment on the evolution of the E1 E2 viral region in non-responder patients infected with HCV-1b. Twenty-three HCV 1b chronically infected patients were studied retrospectively, including 19 non responders to PEG-IFN/RBV therapy (11 null-responders and 8 relapsers) in the study group, and 4 untreated patients in the control group. Genetic and phylogenetic analyses of the E1-E2 viral populations were performed at baseline and at the time of treatment failure to assess changes in genetic variability and evolutionary dynamics during treatment. Baseline virological characteristics were similar in null-responders, relapsers and controls. E1-E2 genetic variability decreased during treatment in non-responders, with a more pronounced decline in relapsers than in null-responders. A specific evolutionary pattern was not observed in null-responders, while a complete substitution of viral variants found at baseline characterised relapser patients. No specific E1-E2 amino acid substitution involved in treatment failure could be identified. In conclusion, although diverse evolutionary patterns with no apparent common adaptive changes were observed during therapy, treatment failure was characterised by a decline in genetic diversity. PMID- 23022713 TI - Proteomic and transcriptional analyses of genes differentially expressed in Giardia duodenalis clones resistant to albendazole. AB - In this study we performed proteomic and transcriptional analyses to identify and characterize genes differentially expressed in Giardia duodenalis clones resistant to albendazole. The expression of proteins and their corresponding mRNAs was analyzed in clones resistant in vitro to different concentrations of albendazole (1.35, 8.0 and 250 MUM) and these were compared with albendazole sensitive clones using two approaches: (1) two-dimensional protein electrophoresis to analyze the proteome by the LC-MS/MS technique, and (2) semi quantitative RT-PCR to assess the mRNA levels of proteins with the highest levels of differential expression .This strategy allowed the identification of eight proteins differentially expressed in albendazole resistant clones with roles in: (a) the cytoskeletal system (alpha 2-giardin and RanBP1), (b) the antioxidant metabolism (NADH oxidase) and (c) energy metabolism (triosephosphate isomerase, phosphoglycerate kinase and ornithine carbamoyltransferase). Gene expression analyses of these genes correlated well with the proteomics results. These observations suggest that resistance to albendazole in Giardia encompasses a complex response involving an altered expression of genes regulated at the transcriptional level that might have an important role in maintaining cell structural stability, coping with oxidative stress and adapting energy supply to a new metabolic status. These molecules are indeed promising targets for drug development. PMID- 23022714 TI - Differential presence of Papillomavirus variants in cervical cancer: an analysis for HPV33, HPV45 and HPV58. AB - BACKGROUND: Certain human papillomaviruses (HPVs) are the causative agents of cervical carcinomas in humans. The identification of the link between infection and cancer has resulted in the successful establishment of clinical strategies such as screening or vaccination programs, aiming to prevent this pathology. More than 150 different HPVs have been described and classified and the large majority of them are not related to cancer. The genus Alphapapillomavirus encompasses many PVs, some of which are identified in humans as oncogenic, according to the epidemiological connection between infection and cervical cancer. Variants of some of these "high-risk" HPVs may have an increased involvement in cervical cancer, although definitive data are still wanting. The aim of the present work was to analyze the presence of HPV33, HPV45 and HPV58 variants in cases of cervical cancer. METHODS: Samples from cervical lesions in the context of different cervical cancer surveys were analyzed for presence of HPV DNA. Samples positive for HPV33, HPV45 or HPV58 DNA were selected and the E6/E7 genes were amplified and sequenced. The phylogenetic relationships of these sequences were inferred using an evolutionary placement algorithm and accordingly classified at the variant level. RESULTS: All viral E6/E7 sequences were successfully placed in the classification schemes of the corresponding viruses. For HPV33 (n=23), 45 (n=61) or 58 (n=29), the distribution of variants found in cases of cervical cancer is not a random sample of the corresponding diversity. In all three HPVs, the respective A variants were more prevalent in the viral DNA-positive cases of cervical cancer analyzed. This is the first study trying to discern the phylogenetic connection between variants of the oncogenic HPV33, 45 and 58, and squamous cell carcinoma of the cervix. PMID- 23022715 TI - Microsatellite-based genotyping of Candida parapsilosis sensu stricto isolates reveals dominance and persistence of a particular epidemiological clone among neonatal intensive care unit patients. AB - In this study, using multilocus microsatellite analysis, we report the genetic characterization of 27 Candida parapsilosis isolates recovered in two different periods of time (2007-2009 and 2011-2012) from infants hospitalized in the neonatal intensive care unit of a hospital in Messina, Italy. The results revealed the persistence and dominance of a particular infectious genotype among NICU patients and highlight the power of the used microsatellite markers in clarifying epidemiologic associations, detect micro-evolutionary variations and facilitating the recognition of outbreaks. PMID- 23022716 TI - Tyrosine depletion lowers in vivo DOPA synthesis in ventral hippocampus. AB - In vivo dopamine synthesis in the medial prefrontal cortex of the rat is sensitive to the availability of tyrosine. Whether other limbic cortical dopamine terminal regions are similarly tyrosine-dependent is not known. In this study we examined the effects of tyrosine depletion on dopamine synthesis and catecholamine levels in the ventral hippocampus. A tyrosine- and phenylalanine free neutral amino acid mixture was used to lower brain tyrosine levels in rats undergoing in vivo microdialysis. In one group, NSD-1015 was included in perfusate to permit measurement of DOPA levels. In a second group, NSD-1015 was not included in perfusate so that catecholamine levels could be assayed. Tyrosine depletion significantly lowered DOPA levels in the NSD-1015 treated group and lowered DOPAC but not dopamine or noradrenaline levels in the group not exposed to NSD-1015. We conclude that while catecholamine synthesis in the ventral hippocampus declines when tyrosine availability is lowered, under basal conditions, compensatory mechanisms are able to maintain stable extracellular catecholamine levels. PMID- 23022718 TI - Spontaneous cries can alter the physiological well-being and cerebral oxygenation of very preterm infants. AB - INTRODUCTION: Infant crying is a major expression of distress and can occur without any exogenous stimulation. Little is known, however, about the effects of crying on physiological homeostasis in very preterm infants (VPIs). METHODS: Environmental, behavioral (video and audio recording) and physiologic (heart rate [HR], respiratory rate [RR], and systemic [SaO(2)] and regional cerebral oxygenation [rSO(2)]) parameters were prospectively evaluated over 10h in 18 VPIs (median gestational age, 28 [27-31] weeks). Only episodes of "spontaneous" and isolated cries were analyzed. Changes in parameters were compared over 5-second periods between baselines and 40s following the onset of crying. Two periods were distinguished: 0-20s (a) and 20-40s (b). Minimal and/or maximal values in these periods were also compared to the baseline. RESULTS: Of the 18 VPIs initially studied, 13 (72%) presented crying episodes (CE). They experienced 210 "spontaneous" and isolated CE, with a median of 9 [range, 1-63] CEs per child. Physiological values varied significantly from the baseline with mainly a mean decrease in HR of -4.8+/-5.3 beats/min (b) after an initial mean increase of +2.6+/-2.0 beats/min (a); a mean decrease in RR of -3.8+/-4.8 cycles/min (a), followed by a mean increase of +5.6+/-7.3 cycles/min (b) and mean unidirectional decreases in SaO(2) and rSO(2) (minimal values) of -1.8+/-2.3% and -2.5+/-3.0%, respectively. CONCLUSION: Spontaneous cries can alter the homeostasis of VPIs. Their possible adverse consequences and high occurrence emphasize the need for better prevention and response to them. PMID- 23022717 TI - Systems biology of complex symptom profiles: capturing interactivity across behavior, brain and immune regulation. AB - As our thinking about the basic principles of biology and medicine continue to evolve, the importance of context and regulatory interaction is becoming increasingly obvious. Biochemical and physiological components do not exist in isolation but instead are part of a tightly integrated network of interacting elements that ensure robustness and support the emergence of complex behavior. This integration permeates all levels of biology from gene regulation, to immune cell signaling, to coordinated patterns of neuronal activity and the resulting psychosocial interaction. Systems biology is an emerging branch of science that sits as a translational catalyst at the interface of the life and computational sciences. While there is no universally accepted definition of systems biology, we attempt to provide an overview of some the basic unifying concepts and current efforts in the field as they apply to illnesses where brain and subsequent behavior are a chief component, for example autism, schizophrenia, depression, and others. Methods in this field currently constitute a broad mosaic that stretches across multiple scales of biology and physiological compartments. While this work by no means constitutes an exhaustive list of all these methods, this work highlights the principal sub-disciplines presently driving the field as well as future directions of progress. PMID- 23022719 TI - Correlation between Environmental Relative Moldiness Index (ERMI) values in French dwellings and other measures of fungal contamination. AB - The Environmental Relative Moldiness Index (ERMI) is a DNA-based metric developed to describe the fungal contamination in US dwellings. Our goal was to determine if the ERMI values in dwellings in north western France were correlated with other measures of fungal contamination. Dust and air samples were obtained from 40 dwellings and analyzed by quantitative PCR and/or by culturing. These dwellings were also inspected and the amount of visible fungal growth estimated in m(2). The ERMI values in these dwellings ranged from -2.7 to 28.8 and the fungal contamination estimates ranged from 0 to 20 m(2). The 40 dwellings were divided into those with a low (<6) or high (>8) ERMI values (n=20 in each). The average ERMI value was 15.70 for the high ERMI compared to 2.68 for the low ERMI dwellings. ERMI values were correlated (significant Kendall's tau values) with concentrations of fungi in air samples analyzed by QPCR or culturing. ERMI values were also correlated (significant Kendall's tau values) with the visible estimates of fungal contamination. Older dwellings were more likely to have higher ERMI values. These results suggest that the ERMI dust sample, which is quick and easy to collect, may be useful in making decisions about reducing fungal exposures in homes. PMID- 23022720 TI - Pedogeochemistry in NE-Brazil - compared to Australia and Europe. AB - A soil geochemical dataset (major and minor elements), based on low-density sampling, is provided for NE-Brazil (ca. 1.7 million km2). It covers an area from about 2 degrees S to 12 degrees S, and from 34 degrees W to 49 degrees W, and refers to top (TOP: 0-20 cm) and bottom (BOT: 30-50 cm) mineral soils. Results are put in perspective using two recent and comparable studies, the National Geochemical Survey of Australia (NGSA) and the European Geochemical Mapping of Agricultural Soils (GEMAS). All median element concentrations in the Brazilian samples are depleted compared to World Soil Averages (WSA), except for Al2O3 and SiO2, which are respectively similar to WSA and enriched in Brazil. While the depletion is moderate for Fe2O3, MnO, P2O5, and TiO2, it reaches an order of magnitude and more for K2O, MgO, CaO, and Na2O. The difference between TOP and BOT concentrations is lower than the variation of either TOP or BOT concentrations between sample sites. Similar spatial distribution and the high correlation between TOP and BOT concentrations suggest that (1) similar processes and parameters are of general relevance for the geochemical composition of TOP and BOT samples, and (2) topsoil and subsoil are not decoupled. Cluster analysis revealed similar results for TOP and BOT samples, yielding three groups of elements/oxides displaying similar behavior: Gr.1 comprising Al2O3, Fe2O3, TiO2, and P2O5; Gr.2 comprising CaO, K2O, MgO, MnO, and Na2O; and Gr.3 being SiO2. Weathering indicators are significantly positively correlated and show similar spatial distributions in TOP and BOT samples. All elements deliver similar mass removal times (time to export all material from a 10 cm soil layer) and clearly discern between the regions: Europe with the fastest "depletion" (12,200 +/- 300 years), followed by Australia (33,200 +/- 3000 years) and Brazil (86,700 +/- 3000 years). Similar results emerge when calculating denudation rates, using independent fluvial denudation data in large basins. PMID- 23022721 TI - Indicator-based water sustainability assessment - a review. AB - In the past few decades, there have been extensive efforts on measuring sustainability. One example is the development of assessment tools based on sustainability indicators. Several individuals and organisations have suggested various indices for assessing sustainability. This paper focuses on the review of water sustainability assessment using the indicator-based approach. It discusses major definitions of sustainable development that have been proposed and more specific concepts of sustainability based on sustainability principles and criteria. It then proceeds with the review of existing definitions, principles and guidelines on sustainable water resource management. The paper then explores elements of indicator-based water sustainability assessment. These elements include the selection of components and indicators, obtaining sub-index values, weighting schemes for components and indicators, aggregation of components and indicators, robustness analysis of the index, and interpretation of the final index value. These six elements are explored considering four existing water sustainability indices and two other sustainability indices that are thought to be useful for the development and use of water sustainability indices. The review presented in this paper on indicator-based water sustainability assessment can provide significant inputs to water stakeholders worldwide for using existing indices, for customising existing indices for their applications, and for developing new water sustainability indices. These indices can provide information on current conditions of water resources, including identifying all factors contributing to the improvement of water resources. This information can be used to communicate the current status of existing water resources to the wider community. Also, the water sustainability indices can be used to assist decision makers to prioritise issues, challenges and programmes related to water resource management. PMID- 23022722 TI - Micro- and nano-environments of C sequestration in soil: a multi-elemental STXM NEXAFS assessment of black C and organomineral associations. AB - Black C is an essential component of the terrestrial C pool and its formation is often credited as a CO(2) sink by transferring the fast-cycling C from the atmosphere-biosphere system into slower cycling C in the geosphere. This study is the first multi-element K- (C, N, Ca, Fe, Al and Si) soft-X-ray STXM-NEXAFS investigation conducted at a submicron-scale spatial resolution specifically targeting black C and its interaction with the mineral and non-black C organic matter in the organomineral assemblage. The STXM-NEXAFS micrographs and spectra demonstrated that pyrogenic C was dominated by quinoide, aromatic, phenol, ketone, alcohol, carboxylic and hydroxylated- and ether-linked C species. There was also evidence for the presence of pyridinic, pyridonic, pyrrolic, amine and nitril N functionalities. The non-black C organic matter contained amino acids, amino sugars, nucleic acids and polysaccharides known to exhibit negatively charged carboxylic, phenolic, enolic, thiolate and phosphate functionalities highly reactive towards metal ions and black C. The metal-rich mineral matrix was composed of phyllosilicate clay minerals, Fe and Al hydroxypolycations, oxides, hydroxides and oxyhydroxide that can attract and bind organic biopolymers. STXM NEXAFS provided evidence for interactive association between pyrogenic C, non black C organic matter and the mineral oxide and oxyhydroxide communities in the organomineral interface. These intimate associations occurred through a "two-way" direct linkage between black C and the mineral or non-black C organic matter or via a "three-way" indirect association where non-black C organic matter could serve as a molecular cross-linking agent binding black C with the mineral matrix or vice versa where inorganic oxides, hydroxides and polycations could act as a bridge to bind black C with non-black C organic matter. The binding and sequestration of black C in the investigated micro- and nano-C repository environments seem to be the combined action of physical entrapment in seemingly terminal biotic exclusion zone through the action of metal oxides and organic matter induced microaggregation and through molecular-level association ranging from ligand exchange, polyvalent cation bridging to weak hydrophobic interactions including van der Waals and H-bonding. PMID- 23022723 TI - Mobile measurements and regression modeling of the spatial particulate matter variability in an urban area. AB - During 5 different periods between summer 2009 and spring 2011, mobile measurements were carried out in the city of Aachen, Germany, in order to capture the spatial variability of particulate matter concentrations in urban and suburban environments. Results show a large spatial variability on a scale of tens of meters, mainly depending on traffic density and building structure. Spatial coefficients of variation exhibit larger spatial variability for PM(10) than for PM(2.5) and larger variability in traffic influenced inner city environments than in suburban areas. Based on the results of an extensive campaign, a regression model is developed for the prediction of PM(10) and PM(2.5) distributions over the city area. The three predictors for the regression model are an exponential PM concentration profile simulated on the basis of PM(10) and PM(2.5) traffic emissions, building density and green area density within radii of 50 m and 100 m. The model shows good agreement between measured and modeled PM levels during the campaign used for the model training with R(2) values of 0.79 and 0.65, RMSE of 1.9 MUg/m(3) and 1 MUg/m(3) for PM(10) and PM(2.5), respectively. The model is further validated using data from the remaining measurement campaigns and modeling of PM levels at monitoring sites that were not used for the training of the regression model. For the total number of 59 monitoring sites, the regression model shows R(2) values of 0.77 (PM(10)) and 0.61 (PM(2.5)) with RMSE of 2.3 MUg/m(3) and 1.2 MUg/m(3). The modeled concentrations are generally in better accordance with measured concentrations for PM(10) than for PM(2.5) concentrations. We attribute this to higher spatial homogeneity of PM(2.5) levels compared to coarse particles. Inner city PM levels at traffic influenced sites are better reproduced by the model than suburban concentrations which exhibit the smallest spatial variability. PMID- 23022724 TI - Comprehensive study of ibuprofen and its metabolites in activated sludge batch experiments and aquatic environment. AB - Even though Ibuprofen is one of the most studied pharmaceutical in the aquatic environment, there is still a lack of information about its fate and the generation of different transformation products along wastewater treatment plants (WWTPs). Ibuprofen biotransformation products can be generated by human metabolism or by microorganisms present in WWTPs and in natural waters, soils, and sediments, which increase the probability to find them in environment. In this work, the presence of ibuprofen and its main metabolites: ibuprofen carboxylic acid (CBX IBU), 2-hydroxylated ibuprofen (2-OH IBU) and 1-hydroxylated ibuprofen (1-OH IBU), was monitored quantitatively along the biodegradation processes occurring in different batch activated sludge (BAS) experiments under different working conditions. Total ibuprofen removal, achieved in almost all the experiments, was related in part to the formation of the metabolites mentioned. Another ibuprofen metabolite, 1,2-dihydroxy ibuprofen, was detected in BAS experiments for the first time. The metabolites 2-OH IBU and 1-OH IBU remained in solution at the end of ibuprofen biodegradation experiments whereas CBX IBU disappeared faster than hydroxylated metabolites. In addition, also the biodegradation of 1-OH IBU, 2-OH IBU and CBX IBU was evaluated in batch experiments: CBX IBU removal occurred at the highest rate followed by IBU, 2-OH IBU, and 1-OH IBU, which exhibited the lowest removal rate. Finally, Ibuprofen and ibuprofen metabolites were monitored in sewage and natural water samples, where they were found at higher levels than expected: the maximum concentration in influent wastewater samples were 13.74, 5.8, 38.4, 94.0MUg/L for IBU, 1-OH IBU, CBX IBU and 2-OH IBU respectively; whereas maximum levels in effluent wastewater samples were 1.9, 1.4, 10.7, 5.9 MUg/L for IBU, 1-OH IBU, CBX IBU and 2-OH IBU respectively. High levels of the compounds were also found in river samples, in particular for CBX IBU, which was detected up to 3.9 MUg/L. PMID- 23022725 TI - Extent and severity of groundwater contamination based on hydrochemistry mechanism of sandy tropical coastal aquifer. AB - Small islands are susceptible to anthropogenic and natural activities, especially in respect of their freshwater supply. The freshwater supply in small islands may be threatened by the encroachment of seawater into freshwater aquifers, usually caused by over pumping. This study focused on the hydrochemistry of the Kapas Island aquifer, which controls the groundwater composition. Groundwater samples were taken from six constructed boreholes for the analysis and measurement of its in-situ and major ions. The experimental results show a positive and significant correlation between Na-Cl (r=0.907; p<0.01), which can be defined as the effect of salinization. The mechanisms involved in groundwater chemistry changes were ion exchange and mineralization. These processes can be demonstrated using Piper's diagram in which the water type has shifted into a Na-HCO(3) water type from a Ca-HCO(3) water type. Saturation indices have been calculated in order to determine the saturation condition related to dissolution or the precipitation state of the aquifer bedrock. About 76% of collected data (n=108) were found to be in the dissolution process of carbonate minerals. Moreover, the correlation between total CEC and Ca shows a positive and strong relationship (r=0.995; p<0.01). This indicates that the major mineral component in Kapas Island is Ca ion, which contributes to the groundwater chemical composition. The output of this research explains the chemical mechanism attributed to the groundwater condition of the Kapas Island aquifer. PMID- 23022726 TI - The incidental cystic pancreas mass: a practical approach. AB - Technical advances in cross-sectional imaging have led to the discovery of incidental cystic pancreatic lesions in the oncology and non-oncology population that in the past remained undetected. These lesions have created a diagnostic and management dilemma for both clinicians and radiologists: should these lesions be ignored, watched, aspirated, or removed? In this review, recommendations concerning the assessment of the more common pancreatic cystic incidental lesions are presented. PMID- 23022727 TI - Structure of a topoisomerase II-DNA-nucleotide complex reveals a new control mechanism for ATPase activity. AB - Type IIA topoisomerases control DNA supercoiling and disentangle chromosomes through a complex ATP-dependent strand-passage mechanism. Although a general framework exists for type IIA topoisomerase function, the architecture of the full-length enzyme has remained undefined. Here we present the structure of a fully catalytic Saccharomyces cerevisiae topoisomerase II homodimer complexed with DNA and a nonhydrolyzable ATP analog. The enzyme adopts a domain-swapped configuration wherein the ATPase domain of one protomer sits atop the nucleolytic region of its partner subunit. This organization produces an unexpected interaction between bound DNA and a conformational transducing element in the ATPase domain, which we show is critical for both DNA-stimulated ATP hydrolysis and global topoisomerase activity. Our data indicate that the ATPase domains pivot about each other to ensure unidirectional strand passage and that this state senses bound DNA to promote ATP turnover and enzyme reset. PMID- 23022728 TI - Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness. AB - Both epigenetic and splicing regulation contribute to tumor progression, but the potential links between these two levels of gene-expression regulation in pathogenesis are not well understood. Here, we report that the mouse and human RNA helicases Ddx17 and Ddx5 contribute to tumor-cell invasiveness by regulating alternative splicing of several DNA- and chromatin-binding factors, including the macroH2A1 histone. We show that macroH2A1 splicing isoforms differentially regulate the transcription of a set of genes involved in redox metabolism. In particular, the SOD3 gene that encodes the extracellular superoxide dismutase and plays a part in cell migration is regulated in an opposite manner by macroH2A1 splicing isoforms. These findings reveal a new regulatory pathway in which splicing factors control the expression of histone variant isoforms that in turn drive a transcription program to switch tumor cells to an invasive phenotype. PMID- 23022729 TI - Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation. AB - A fundamental challenge in mammalian biology has been the elucidation of mechanisms linking DNA methylation and histone post-translational modifications. Human UHRF1 (ubiquitin-like PHD and RING finger domain-containing 1) has multiple domains that bind chromatin, and it is implicated genetically in the maintenance of DNA methylation. However, molecular mechanisms underlying DNA methylation regulation by UHRF1 are poorly defined. Here we show that UHRF1 association with methylated histone H3 Lys9 (H3K9) is required for DNA methylation maintenance. We further show that UHRF1 association with H3K9 methylation is insensitive to adjacent H3 S10 phosphorylation--a known mitotic 'phospho-methyl switch'. Notably, we demonstrate that UHRF1 mitotic chromatin association is necessary for DNA methylation maintenance through regulation of the stability of DNA methyltransferase-1. Collectively, our results define a previously unknown link between H3K9 methylation and the faithful epigenetic inheritance of DNA methylation, establishing a notable mitotic role for UHRF1 in this process. PMID- 23022730 TI - Convergent transcription induces transcriptional gene silencing in fission yeast and mammalian cells. AB - We show that convergent transcription induces transcriptional gene silencing (TGS) in trans for both fission yeast and mammalian cells. This method has advantages over existing strategies to induce gene silencing. Previous studies in fission yeast have characterized TGS as a cis-specific process involving RNA interference that maintains heterochromatic regions such as centromeres. In contrast, in mammalian cells, gene silencing is known to occur through a post transcriptional mechanism that uses exogenous short interfering RNAs or endogenous microRNAs to inactivate mRNA. We now show that the introduction of convergent transcription plasmids into either Schizosaccharomyces pombe or mammalian cells allows the production of double-stranded RNA from inserted gene fragments, resulting in TGS of endogenous genes. We predict that using convergent transcription to induce gene silencing will be a generally useful strategy and allow for a fuller molecular understanding of the biology of TGS. PMID- 23022731 TI - Detection of hepatitis B virus core antigen by phage display mediated TaqMan real time immuno-PCR. AB - The core antigen (HBcAg) of hepatitis B virus (HBV) is one of the markers for the identification of the viral infection. The main purpose of this study was to develop a TaqMan real-time detection assay based on the concept of phage display mediated immuno-PCR (PD-IPCR) for the detection of HBcAg. PD-IPCR combines the advantages of immuno-PCR (IPCR) and phage display technology. IPCR integrates the versatility of enzyme-linked immunosorbent assay (ELISA) with the sensitivity and signal generation power of PCR. Whereas, phage display technology exploits the physical association between the displayed peptide and the encoding DNA within the same phage particle. In this study, a constrained peptide displayed on the surface of an M13 recombinant bacteriophage that interacts tightly with HBcAg was applied as a diagnostic reagent in IPCR. The phage displayed peptide and its encoding DNA can be used to replace monoclonal antibody (mAb) and chemically bound DNA, respectively. This method is able to detect as low as 10ng of HBcAg with 10(8)pfu/ml of the recombinant phage which is about 10,000 times more sensitive than the phage-ELISA. The PD-IPCR provides an alternative means for the detection of HBcAg in human serum samples. PMID- 23022732 TI - Advantages of a dual-tracer model over reference tissue models for binding potential measurement in tumors. AB - The quantification of tumor molecular expression in vivo could have a significant impact for informing and monitoring emerging targeted therapies in oncology. Molecular imaging of targeted tracers can be used to quantify receptor expression in the form of a binding potential (BP) if the arterial input curve or a surrogate of it is also measured. However, the assumptions of the most common approaches (reference tissue models) may not be valid for use in tumors. In this study, the validity of reference tissue models is investigated for use in tumors experimentally and in simulations. Three different tumor lines were grown subcutaneously in athymic mice and the mice were injected with a mixture of an epidermal growth factor receptor-targeted fluorescent tracer and an untargeted fluorescent tracer. A one-compartment plasma input model demonstrated that the transport kinetics of both tracers was significantly different between tumors and all potential reference tissues, and using the reference tissue model resulted in a theoretical underestimation in BP of 50% +/- 37%. On the other hand, the targeted and untargeted tracers demonstrated similar transport kinetics, allowing a dual-tracer approach to be employed to accurately estimate BP (with a theoretical error of 0.23% +/- 9.07%). These findings highlight the potential for using a dual-tracer approach to quantify receptor expression in tumors with abnormal hemodynamics, possibly to inform the choice or progress of molecular cancer therapies. PMID- 23022733 TI - An extended multi-locus molecular typing schema for Streptococcus pneumoniae demonstrates that a limited number of capsular switch events is responsible for serotype heterogeneity of closely related strains from different countries. AB - Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. Pneumococcal strains are classified according to their capsular serotype and through a Multi-Locus Sequence Typing schema (MLST) based on the sequencing of seven housekeeping genes. However, strains with a defined allelic profile (Sequence Type, ST) can have different serotypes, suggesting that the micro evolution of the MLST lineages leads to a considerable degree of phenotypic variability. To better investigate the genetic diversity within these lineages, we set-up and then validated an extended molecular typing schema (96-MLST) based on the sequencing of ninety-six genomic loci. 96-MLST loci were designed within core-genes in a collection of 39 complete genomes of S. pneumoniae. None of the capsular genes was included in the schema. When tested on a collection of 69 isolates, 96-MLST was able to partition strains with the same ST and diverse serotypes into groups that were homogenous for capsular serotype, improving our understanding of the evolution of epidemiologically relevant lineages. Phylogenetic sequence analysis showed that the capsular heterogeneity of three STs that were sampled more extensively could be traced back to a limited number of capsular switch events, indicating that changes of serotype occur occasionally during the short term expansion of clones. Moreover, a geographical structure of ST156 was identified, suggesting that the resolution guaranteed by this method is sufficient for phylogeographic studies. In conclusion, we showed that an extended typing schema was able to characterize the expansion of individual lineages in a complex species such as S. pneumoniae. PMID- 23022734 TI - Bystander effect in glioma suicide gene therapy using bone marrow stromal cells. AB - An established rat intracranial glioma was successfully treated through the tumoricidal bystander effect generated by intratumoral injection of rat bone marrow stromal cells (BMSCs) transduced with the herpes simplex virus-thymidine kinase gene (BMSCtk cells) followed by systemic ganciclovir administration. In the present study, we tested the bystander effect of this treatment strategy when using human BMSCs as the vector cells. Human BMSCtk cells were mixed with various kinds of brain tumor cell lines (human and rat glioma cells) and examined in vitro and in vivo tumoricidal bystander effects, by co-culture study and co implantation study in the nude mouse, respectively. A significant in vitro bystander effect was observed between human BMSCtk cells and any of the tumor cells examined in the ganciclovir-containing medium. A potent in vivo bystander effect against human and rat glioma cells was also demonstrated when ganciclovir was administered. Migratory activity of the human BMSCs toward the tumor cells was enhanced by the conditioned media obtained from both human and rat glioma cells compared to the fresh media. The results of this study have demonstrated that the bystander effect generated by BMSCtk cells and ganciclovir is not cell type-specific, suggesting that the strategy would be quite feasible for clinical use. PMID- 23022735 TI - Synthesis, antitumor, cytotoxic and antioxidant evaluation of some new pyrazolotriazines attached to antipyrine moiety. AB - Iminopropanehydrazonoyl cyanide 4 was achieved upon reaction of antipyrine diazonium salt 2 with 3-iminobutanenitrile (3) in EtOH/AcONa. 3-Aminopyrazole derivative 5 was obtained upon reaction of 4 with hydrazine hydrate. Diazodization of 5 afforded the diazonium salt 6 which coupled with active methylene compounds 7-10, 19, 20, 25, 29 and 32 in pyridine to give aryl hydrazone derivatives 11-14, 21, 22, 26, 30 and 33, respectively. Refluxing of compounds 11-14, 21, 22, 26 and 33 in acetic acid afforded the pyrazolotriazines 15-18, 23, 24, 28 and 35, respectively. The newly synthesized compounds were screened for their cytotoxic and antioxidant activities. The results showed clearly that compounds 4, 5, 13, 22, and 24 displayed promising in vitro anticancer activity against four different cell lines (HepG2, WI 38, VERO and MCF 7). Compounds 4 and 22 are the more potent antioxidant and anticancer agents. On the other hand, most of the compounds exhibited good cytotoxic activity toward (EAC). PMID- 23022736 TI - Recent advances in the cryopreservation of shoot-derived germplasm of economically important fruit trees of Actinidia, Diospyros, Malus, Olea, Prunus, Pyrus and Vitis. AB - This paper presents the advances made over the last decade in cryopreservation of economically important vegetatively propagated fruit trees. Cryopreservation protocols have been established using both dormant buds sampled on field-grown plants and shoot tips sampled on in vitro plantlets. In the case of dormant buds, scions are partially dehydrated by storage at -5 degrees C, and then cooled slowly to -30 degrees C using low cooling rates (c.a. 1 degrees C/h) before immersion in liquid nitrogen. After slow rewarming and rehydration of samples, regrowth takes place either through grafting of buds on rootstocks or excision of apices and inoculation in vitro. In the case of shoot tips of in vitro plantlets, the cryopreservation techniques employed are the following: controlled rate cooling procedures involving slow prefreezing followed by immersion in liquid nitrogen or vitrification-based procedures including encapsulation-dehydration, vitrification, encapsulation-vitrification and droplet-vitrification. The current status of cryopreservation for a series of fruit tree species including Actinidia, Diospyros, Malus, Olea, Prunus, Pyrus and Vitis is presented. Routine application of cryopreservation for long-term germplasm storage in genebanks is currently limited to apple and pear, for which large cryopreserved collections have been established at NCGRP, Fort Collins (USA), using dormant buds and in vitro shoot tips, respectively. However, there are a growing number of examples of pilot scale testing experiments under way for different species in various countries. Progress in the further development and application of cryopreservation techniques will be made through a better understanding of the mechanisms involved in the induction of tolerance to dehydration and cryopreservation in frozen explants. PMID- 23022737 TI - In vitro culture of lavenders (Lavandula spp.) and the production of secondary metabolites. AB - Lavenders (Lavandula spp., Lamiaceae) are aromatic ornamental plants that are used widely in the food, perfume and pharmaceutical industries. The large-scale production of lavenders requires efficient in vitro propagation techniques to avoid the overexploitation of natural populations and to allow the application of biotechnology-based approaches for plant improvement and the production of valuable secondary metabolites. In this review we discuss micropropagation methods that have been developed in several lavender species, mainly based on meristem proliferation and organogenesis. Specific requirements during stages of micropropagation (establishment, shoot multiplication, root induction and acclimatization) and requisites for plant regeneration trough organogenesis, as an important step for the implementation of plant improvement programs, were revised. We also discuss different methods for the in vitro production of valuable secondary metabolites, focusing on the prospects for highly scalable cultures to meet the market demand for lavender-derived products. PMID- 23022739 TI - Systems-level characterization of a host-microbe metabolic symbiosis in the mammalian gut. AB - The human gut microbiota consists of ten times more microorganisms than there are cells in our body, processes otherwise indigestible nutrients, and produces important energy precursors, essential amino acids, and vitamins. In this study, we assembled and validated a genome-scale metabolic reconstruction of Bacteroides thetaiotaomicron (iAH991), a prominent representative of the human gut microbiota, consisting of 1488 reactions, 1152 metabolites, and 991 genes. To create a comprehensive metabolic model of host-microbe interactions, we integrated iAH991 with a previously published mouse metabolic reconstruction, which was extended for intestinal transport and absorption reactions. The two metabolic models were linked through a joint compartment, the lumen, allowing metabolite exchange and providing a route for simulating different dietary regimes. The resulting model consists of 7239 reactions, 5164 metabolites, and 2769 genes. We simultaneously modeled growth of mouse and B. thetaiotaomicron on five different diets varying in fat, carbohydrate, and protein content. The integrated model captured mutually beneficial cross-feeding as well as competitive interactions. Furthermore, we identified metabolites that were exchanged between the two organisms, which were compared with published metabolomics data. This analysis resulted for the first time in a comprehensive description of the co-metabolism between a host and its commensal microbe. We also demonstrate in silico that the presence of B. thetaiotaomicron could rescue the growth phenotype of the host with an otherwise lethal enzymopathy and vice versa. This systems approach represents a powerful tool for modeling metabolic interactions between a gut microbe and its host in health and disease. PMID- 23022738 TI - Movers and shakers: influence of bacteriophages in shaping the mammalian gut microbiota. AB - The human intestinal microbiota is one of the most densely populated ecosystems on Earth, containing up to 10 ( 13) bacteria/g and in some respects can be considered an organ itself given its role in human health. Bacteriophages (phages) are the most abundant replicating entities on the planet and thrive wherever their bacterial hosts exist. They undoubtedly influence the dominant microbial populations in many ecosystems including the human intestine. Within this setting, lysogeny appears to be the preferred life cycle, presumably due to nutrient limitations and lack of suitable hosts protected in biofilms, hence the predator/prey dynamic observed in many ecosystems is absent. On the other hand, free virulent phages in the gut are more common among sufferers of intestinal diseases and have been shown to increase with antibiotic usage. Many of these phages evolve from prophages of intestinal bacteria and emerge under conditions where their bacterial hosts encounter stress suggesting that prophages can significantly alter the microbial community composition. Based on these observations, we propose the "community shuffling" model which hypothesizes that prophage induction contributes to intestinal dysbiosis by altering the ratio of symbionts to pathobionts, enabling pathobiont niche reoccupation. The consequences of the increased phage load on the mammalian immune system are also addressed. While this is an area of intestinal biology which has received little attention, this review assembles evidence from the literature which supports the role of phages as one of the biological drivers behind the composition of the gut microbiota. PMID- 23022740 TI - Genes, physical fitness and ageing. AB - Persons aged 80 years and older are the fastest growing segment of the population. As more individuals live longer, we should try to understand the mechanisms involved in healthy ageing and preserving functional independence in later life. In elderly people, functional independence is directly dependent on physical fitness, and ageing is inevitably associated with the declining functions of systems and organs (heart, lungs, blood vessels, skeletal muscles) that determine physical fitness. Thus, age-related diminished physical fitness contributes to the development of sarcopenia, frailty or disability, all of which severely deteriorate independent living and thus quality of life. Ageing is a complex process involving many variables that interact with one another, including - besides lifestyle factors or chronic diseases - genetics. Thus, several studies have examined the contribution of genetic endowment to a decline in physical fitness and subsequent loss of independence in later life. In this review, we compile information, including data from heritability, candidate-gene association, linkage and genome-wide association studies, on genetic factors that could influence physical fitness in the elderly. PMID- 23022741 TI - The birth of immunopathology: how I went to Paris and met Julius Cruse. AB - This essay honors the lifetime achievements of Julius Cruse. It relates some of my personal experiences of the past and my views of the future in two areas in which Professor Cruse has made lasting contributions-the history of science and scientific communication. We can best chart the future by understanding the past. PMID- 23022743 TI - Cord blood 25-hydroxyvitamin D levels and the risk of acute lower respiratory tract infection in early childhood. AB - OBJECTIVE: To determine the relationship between cord blood 25-hydroxyvitamin D [25 (OH) D] concentrations and the subsequent risk of acute lower respiratory tract infection (ALRI) in the first 2 years of life. PATIENTS AND METHODS: Cord blood from 206 newborns was tested for 25 (OH) D. Medical records covering the first 2 years of life were reviewed, and the diagnosis of ALRI was recorded. RESULTS: Sixty-two (30.1%) infants developed ALRI in their first 2 years of life, of whom 49 (79%) infants had bronchiolitis and 13 (21%) infants had pneumonia. Concentrations of 25 (OH) D were lower in infants who developed ALRI compared with those did not (p < 0.0001). Vitamin D deficiency was associated with increased risk of ALRI (p = 0.000). CONCLUSION: Low cord blood 25 (OH) D levels are associated with increased risk of ALRI in the first 2 years of life. PMID- 23022742 TI - Intratumoral heterogeneity of KRAS mutation is rare in non-small-cell lung cancer. AB - BACKGROUND: Several lines of evidence indicate that mutational activation of KRAS is an early event in the carcinogenesis of non-small cell lung cancer (NSCLC). Nonetheless, previous studies report high frequencies of divergent KRAS mutational status between primary NSCLC and corresponding metastases. This suggests heterogeneity of the primary tumor in respect to its KRAS status. We therefore aimed to examine the frequency and the extent of such intratumoral heterogeneity. METHODS: 40 NSCLC were examined for intratumoral heterogeneity of KRAS mutation (20 adenocarcinomas, 10 squamous cell carcinomas and 10 large cell carcinomas). Three to eight different tumor areas were analyzed for KRAS mutation and up to four corresponding lymph node metastases were included for analysis in nineteen cases. A combination of different methods for screening of heterogeneity and its validation were used including direct sequencing, laser-capture microdissection for tumor cell enrichment and the very sensitive ARMS/S method. RESULTS: Mutations of KRAS were found in 13/30 adenocarcinomas and large cell carcinomas. No mutations were detected in 10 squamous cell carcinomas. Four cases showed heterogeneous KRAS results by direct sequencing. More sensitive methods for KRAS mutation analysis revealed false negative results due to admixture of non-neoplastic cells in all of these samples. Intratumoral heterogeneity of KRAS mutational status was therefore confirmed in none of the analyzed cases. In addition, identical KRAS mutations were present in the primary tumor and the corresponding lymph node metastases in 19 cases examined. CONCLUSIONS: Intratumoral heterogeneity of KRAS mutational status is rare in NSCLC but highly sensitive tools are required to reliably identify these mutations. This finding is in line with the hypothesis that oncogenic activation of KRAS is an early event and a bona fide "driver mutation" in NSCLC. Furthermore, future therapies targeting KRAS will not be limited by intratumoral heterogeneity. PMID- 23022744 TI - Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. AB - OBJECTIVES: The aim of the current Valvular Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)- clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand understanding of patient risk stratification and case selection. BACKGROUND: A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. METHODS AND RESULTS: Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, The Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the United States Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC 2 consensus manuscript was derived. This document also provides an overview of risk assessment and patient stratification that needed to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding, acute kidney injury, vascular complications, conduction disturbances & arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for evaluation of prosthetic valve (dys)function. Definitions for quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. CONCLUSIONS: This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of study results, supplying an increasingly growing body of evidence with respect to transcatheter aortic valve implantation and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavors of applying definitions to other transcatheter valve therapies (for example, mitral valve repair). PMID- 23022745 TI - Factors influencing breast changes after pregnancy. AB - Pregnancy and breastfeeding are major factors reducing breast cancer (BC) risk. A potential mechanism for this effect might be changes in mammographic density, but other factors might be involved. The aim of this study was to investigate factors influencing changes in breast size and breast stiffness after pregnancy. Of a consecutive cohort of 5991 women who gave birth between 1996 and 1999, 559 replied to a questionnaire including questions about breast changes. The women completed their own assessments of changes in breast size and stiffness since their last pregnancy. Factors being investigated regarding their predictive value for these changes were: BMI before pregnancy, weight gain, age at first full-term pregnancy (FFTP), number of pregnancies, breastfeeding, and BMI of the children's fathers. A decrease in breast size was reported in 21.8% of the participants and an increase in 35.1%. With regard to the breast stiffness, 66.4% reported a decrease and only 5% reported an increase. Independent predictors for increased breast size were age at FFTP, increase in BMI since last pregnancy, BMI before pregnancy, and time since FFTP. Factors predictive of greater breast stiffness included age at FFTP, BMI before FFTP, time since FFTP, breastfeeding status, and number of pregnancies. Breast changes after pregnancy depend on several variables, which are described as BC-risk factors. Individual reaction of the female breast to a pregnancy leads to different outcomes with regard to breast size and stiffness. Further studies are needed to clarify whether these individual responses interact with the effect of pregnancy on the BC risk. PMID- 23022746 TI - A computational simulation of reflector and tube effects in ultraviolet phototherapy. AB - While ultraviolet phototherapy is effective at treating a wide range of skin conditions, over exposure to ultraviolet radiation has a number of detrimental effects including but not limited to erythema, ocular damage and even oncogenesis. It is therefore important to quantify and control the dose received in order to maximize the effectiveness of treatment while minimizing the potentially damaging side effects. Recent dose models have been developed for this purpose, incorporating both the irradiance from the phototherapy lamps and the contributions from metallic reflectors. These models have good predictive power, but the situation is complicated by the huge variety of cabin and mirror geometries available. This work simulates a variety of possible treatment configurations to examine the implications these factors have on dose homogeneity and global irradiance, and shows that the relationship between global irradiance and number of tubes is complex and nonlinear. This has implications for both cabin design and treatment planning. PMID- 23022747 TI - Correlated basal expression of immediate early gene egr1 and tyrosine hydroxylase in zebrafish brain and downregulation in olfactory bulb after transitory olfactory deprivation. AB - Imprinting on kin occurs during the sixth day of larval development in zebrafish and depends on olfactory signals. In rodents, the immediate early gene egr1 is involved in maintaining the dopaminergic phenotype of periglomerular olfactory bulb cells in an activity dependent way. Furthermore, egr1 is upregulated in medial amygdalar dopamine cells in some rodents (prairie voles) dependent on social pheromone interactions. Thus, we aimed to investigate whether egr1 is involved in imprinting processes and later kin recognition in zebrafish in olfactory centers, such as the olfactory bulb and suspected medial amygdala. In the present paper, we focus on a basic investigation of basal egr1 expression throughout zebrafish brain development and its co-localization with tyrosine hydroxylase as a marker for dopaminergic neurons. Indeed, there is unambiguous co localization of egr1 and tyrosine hydroxylase in the zebrafish olfactory bulb and hypothetical medial amygdala. Furthermore, as in rodents, ipsilateral transient olfactory deprivation through Triton X-100 treatment of the olfactory epithelium leads to downregulation of egr1 and tyrosine hydroxylase expression in the olfactory bulb, but apparently not in secondary olfactory targets of the zebrafish brain. This indicates that similar processes might be at work in zebrafish and rodent olfactory systems, but their more specific involvement in imprinting in zebrafish has to be further tested. PMID- 23022748 TI - Motor outcome and allodynia are largely unaffected by novel olfactory ensheathing cell grafts to repair low-thoracic lesion gaps in the adult rat spinal cord. AB - Olfactory ensheathing cells (OEC) are a promising graftable cell population for improving functional outcomes after experimental spinal cord injury. However only few studies have focused on experimental models with large cavitations, which require bridging substrates to transfer and maintain the donor cells within the lesion site. Here, a state-of-the-art collagen-based multi-channeled three dimensional scaffold was used to deliver olfactory ensheathing cells to 2 mm long unilateral low-thoracic hemisection cavities. For a period of 10 weeks, allodynia of the hindpaws was monitored using the von Frey hair filament test, while an extensive analysis of motor ability was performed with use of the CatWalk gait analysis system and the BBB locomotor scale. No substantial improvement or deterioration of motor functions was induced and there was no effect on lesion induced allodynia. On the basis of these data, we conclude that relatively large spinal cord lesions with cavitation may present additional hurdles to the therapeutic effect of OEC. Future studies are needed to address the nature that such lesion cavities place on cell grafts. PMID- 23022749 TI - Characterisation of spatial neglect induced by unilateral 6-OHDA lesions on a choice reaction time task in rats. AB - Unilateral dopamine depletion and excitotoxic lesions of the striatum have been shown to induce a contralateral neglect when rats have to respond in a choice reaction time setting. Whereas, in a lateralised setting when response options are to either side of the animal's head all contralateral responding is impaired, testing animals only on one side of the head per day but with a near and far response option, rats are able to correctly respond to contralateral stimuli, but rather bias their responses towards the near hole. Here, we further investigated the nature of the contralateral neglect in egocentric space coding in more detail. Firstly, we tested the effects of near-complete unilateral dopamine depletion on this type of task. Secondly, previous observations suggested that lesioned rats shifted their response strategy which resulted in a response bias towards the most proximal location in contralateral space. In order to "encourage" dopamine depleted rats to respond to the neglected response location we implemented an error correction procedure to the task. Near-complete unilateral dopamine depletion, via 6-hydroxydopamine infusions into the medial forebrain bundle of female Lister Hood rats, resulted in a reduction of usable trials, a near hole bias when animals were tested on the side contralateral to the lesion, as well as increased reaction and movement time latencies. The introduction of an error-correction procedure had no effect on the animals' response bias towards the near contralateral location. Probe trials showed that the bias is most likely the result of responses being misdirected when in a choice situation. The findings further highlight the role of dopamine and an intact striatum to code responses into egocentrically defined space. PMID- 23022750 TI - The effect of long-term high frequency repetitive transcranial magnetic stimulation on working memory in schizophrenia and healthy controls--a randomized placebo-controlled, double-blind fMRI study. AB - In schizophrenia patients negative symptoms and cognitive impairment often persist despite treatment with second generation antipsychotics leading to reduced quality of life and psychosocial functioning. One core cognitive deficit is impaired working memory (WM) suggesting malfunctioning of the dorsolateral prefrontal cortex. High frequency repetitive transcranial magnetic stimulation (rTMS) has been used to transiently facilitate or consolidate neuronal processes. Pilot studies using rTMS have demonstrated improvement of psychopathology in other psychiatric disorders, but a systematic investigation of working memory effects outlasting the stimulation procedure has not been performed so far. The aim of our study was to explore the effect of a 3-week high frequency active or sham 10 Hz rTMS on cognition, specifically on working memory, in schizophrenia patients (n=25) in addition to antipsychotic therapy and in healthy controls (n=22). We used functional magnetic resonance imaging (fMRI) to compare activation patterns during verbal WM (letter 2-back task) before and after 3 weeks treatment with rTMS. Additionally, other cognitive tasks were conducted. 10 Hz rTMS was applied over the left posterior middle frontal gyrus (EEG electrode location F3) with an intensity of 110% of the individual resting motor threshold (RMT) over a total of 15 sessions. Participants recruited the common fronto- parietal and subcortical WM network. Multiple regression analyses revealed no significant activation differences over time in any contrast or sample. According to the ANOVAs for repeated measures performance remained without alterations in all groups. This is the first fMRI study that has systematically investigated this topic within a randomized, placebo-controlled, double-blind design, contrasting the effects in schizophrenia patients and healthy controls. PMID- 23022751 TI - Human handedness: an inherited evolutionary trait. AB - Our objective was to demonstrate that human population-level, right-handedness, is not species specific, precipitated from language areas in the brain, but rather is context specific and inherited from a behavior common to both humans and great apes. In general, previous methods of assessing human handedness have neglected to consider the context of action, or employ methods suitable for direct comparison across species. We employed a bottom-up, context-sensitive method to quantitatively assess manual actions in right-handed, typically developing children during naturalistic behavior. By classifying the target to which participants directed a manual action, as animate (social partner, self) or inanimate (non-living functional objects), we found that children demonstrated a significant right-hand bias for manual actions directed toward inanimate targets, but not for manual actions directed toward animate targets. This pattern was revealed at both the group and individual levels. We used a focal video sampling, corpus data-mining approach to allow for direct comparisons with captive gorillas (Forrester et al. Animal Cognition 2011;14(6):903-7) and chimpanzees (Forrester et al. Animal Cognition, in press). Comparisons of handedness patters support the view that population-level, human handedness, and its origin in cerebral lateralization is not a new or human-unique characteristic. These data are consistent with the theory that human right-handedness is a trait developed through tool use that was inherited from an ancestor common to both humans and great apes. PMID- 23022752 TI - Effects of varying reinforcement probability on pavlovian approach behavior and ultrasonic vocalizations in rats. AB - Long Evans rats (n=32) were trained for 2 weeks to respond to an auditory conditioned stimulus (CS) which signaled the delivery of a 20% sucrose unconditioned stimulus (US) with varying probabilities. Animals were randomly assigned to 1 of 4 groups. In the control groups, the CS signaled sucrose delivery with equal probabilities across two weeks, at 100% (Group 100-100) and 25% (Group 25-25) respectively. In the experimental groups (Group 100-25) and (Group 25-100), sucrose probabilities were switched between weeks 1 and 2. Three behavioral measures were recorded: latency to enter the sucrose port upon CS presentation, head entries throughout the session and ultrasonic vocalizations. The results suggest that all groups formed associations between the CS and US, as evidenced by a decrease in latency to respond to the CS across days. The experimental groups were also able to detect when sucrose probability changed, as evidenced by Group 25-100's increase in head entries, to the level of Group 100 100 in week 2, and Group 100-25's decrease in head entries, to the level of Group 25-25 in week 2. Group 100-25 also produced an increase in "22 kHz" ultrasonic vocalizations following the downshift on the first day of week 2. The increase in this ultrasonic frequency range, which is associated with negative affect in rats, preceded both the decrease in head entries and the increase in missed trials, consistent with a multistage model of behaviors resulting from US probability reduction. PMID- 23022753 TI - Parastomal hernia as a consequence of colorectal cancer resections can prophylactically be controlled by mesh insertion at the time of primary surgery: a literature based systematic review of published trials. AB - AIM: The objective of this article was to systematically analyze the randomized, controlled trials (RCTs) evaluating the role of mesh in the prevention of parastomal hernia (PSH) at the time of primary colorectal resections. METHODS: RCTs evaluating the role of mesh in the prevention of parastomal hernia (PSH) at the time of primary colorectal resections were analysed using RevMan(r), and combined outcomes were expressed as odds ratio (OR) and standardized mean difference (SMD). RESULTS: Three RCTs encompassing 128 patients were retrieved for the electronic databases. There were 64 patients in the mesh group and 64 patients in the no-mesh group. In the fixed effects model, the risk of developing postoperative complications (OR, 1.0; 95% CI, 0.36, 3.20; z=0.0; =1.0) was statistically similar after using mesh for PSH prevention at the time of primary colorectal resection and stoma construction in both groups. However, the risk of developing PSH (OR, 0.11; 95% CI, 0.05, 0.27; z=4.88; P<0.00001) was significantly lower after using mesh and mesh insertion to prevent PSH development statistically did not influence (SMD, -0.42; 95% CI, -0.96, 0.12; z=1.51; P=0.13) the duration of operation. CONCLUSION: The incidence of PSH can be reduced by the insertion of mesh at stoma site at the time of primary stoma construction. A major multicentre RCT recruiting higher number of patients and longer follow up is required before recommending the routine use of mesh for PSH prevention. PMID- 23022754 TI - Management of liver dominant metastatic breast cancer: surgery, chemotherapy, or hepatic arterial therapy - benefits and limitations. AB - AIM: Systemic hormonal and cytotoxic chemotherapy still remains the optimal treatment for metastatic breast cancer with the role of surgery being strictly limited for palliation of metastatic complications or locoregional relapse. However there has been a greater awareness of liver dominant and liver only metastatic disease that remains more refractory to systemic chemotherapy alone. A systematic review was undertaken to define its safety, efficacy and to identify prognostic factors associated with liver only or liver dominant metastatic breast cancer. METHODS: Electronic search of the MEDLINE, PubMed and Scopus databases (January 2000-January 2012) to identify studies reporting outcomes for liver dominant breast cancer metastasis. Two reviewers independently appraised each study using a predetermined protocol. Safety and clinical efficacy was synthesized through a narrative review with full tabulation of results of all included studies. RESULTS: A total of 61 studies were identified that reported liver dominant metastatic breast cancer and comprised a total of 8260 patients. Chemotherapy alone was reported in 27 studies involving 4958 patients with a median overall survival of 17.9 months (range 6 to 29.2). Surgical resection of liver metastasis was reported in 24 studies involving 2552 patients with a median overall survival of 38.1 months (range 10.9 to 57). Hepatic arterial therapy was reported in six studies involving 373 patients with a median overall survival of 27.9 months (range 18.5 to 47). CONCLUSION: Liver dominant or liver only metastatic breast cancer is a common presentation and clinical problem in a subset of patients. Consideration of hepatic resection, ablation or hepatic arterial therapy should be considered, but are still rarely performed. Continued review and identification of liver only-liver dominant is needed to ensure this subset of patients with metastatic breast cancer can achieve optimal improvement in quality of life time. PMID- 23022755 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer. AB - Peritoneal carcinomatosis (PC) arising from colorectal cancer (CRC) is generally considered a terminal condition with few treatment options. However, over the past few decades, new chemotherapeutic and biologic agents have improved the median overall survival of patients with unresectable metastatic disease up to 20 months. There has also been emergence of combining cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with PC. The literature supporting such an approach is significant, though not extensive, mainly consisting of small single-institution series, one international multicenter retrospective review, and one single-institution prospective randomized trial. Yet, there is remarkable homogeneity among the reported clinical outcomes, demonstrating 5-year OS rates of approximately 25-40% for patients undergoing a complete cytoreduction. These studies have fueled increasing interest in the use of CS and HIPEC for metastatic colorectal cancer over the past decade. However, despite the publication of a consensus statement on the role of CS and HIPEC for PC from CRC, there is still controversy regarding its appropriateness, effectiveness, safety, and application in this subset of patients. In this review we analyze the currently available scientific evidence supporting the clinical application of CS and HIPEC in the treatment of PC of colorectal origin. PMID- 23022756 TI - Completely laparoscopic versus open total gastrectomy in stage I-III/C gastric cancer: safety, efficacy and five-year oncologic outcome. AB - AIM: Laparoscopic gastrectomy is becoming a minimally invasive procedure widely accepted by laparoscopic surgeons; yet, many doubts remain about its oncologic efficacy in treating malignant neoplasia. Aim of this study was to analyze our experience comparing completely laparoscopic total gastrectomy to its laparotomic counterpart, about safety, efficacy and five-year oncologic outcome. METHODS: From January 2003 to October 2009, 25 patients with stage I-III/C gastric cancer (TNM Seventh Edition, 2010) were operated on and retrospectively compared to an homogeneous group of patients, stratified for age, stage of disease and comorbidities. Length of surgery, estimated blood loss, postoperative ileus, resumption of oral intake, morbidity, 30 days mortality, number of lymph nodes harvested, five years overall and disease free survival were analyzed, comparing the two groups. RESULTS: There was no conversion. Thirty days mortality was zero for both groups, while morbidity was 16% in the lap group, 32% in the open group (P<0.05). Length of operation was 211+/-23 min for the lap group, and 185+/-19 min for the open group (P>0.05); the estimated blood loss was 250+/-150 mL for the lap group, 495+/-190 mL for the open group (P<0.05). Number of lymph nodes harvested was 35+/-18 for the lap group, 40+/-16 for the open group (P>0.05). No port site metastatic implantation occurred in any patient treated laparoscopically; five years overall and disease free survival were 55.7% and 54.2% for the lap group, 52.9% and 52.1% for the open group, respectively, with no statistical difference (P>0.05). Completely laparoscopic total gastrectomy represents a new challenge for the laparoscopic surgeon. In spite of clear advantage for patients, some debate remains about its oncologic efficacy in the middle and long period, even if many authors report comparable results to open total gastrectomy. In our experience, it is a safe and valid alternative to its open counterpart, with no statistically different number of lymph nodes harvested, five years overall and disease free survival in respect to the open gastrectomy. Yet, it remains a complex procedure requiring high laparoscopic skill. CONCLUSION: In our opinion, completely laparoscopic total gastrectomy is a safe and effective procedure, with long term oncologic results not statistically different from the open procedure; yet, it requires high laparoscopic experience, especially to carry out an extended lymphadenectomy and to fashion the anastomosis. More randomized prospective trials are needed to state this procedure as a new gold-standard in treating stage I-III/C non metastatic gastric cancer. PMID- 23022757 TI - Predictors and outcome of gastrointestinal complications after cardiac surgery. AB - AIM: Gastrointestinal (GI) complications following cardiac surgery are uncommon but may be life-threatening. The aim of this prospective study is to determine the incidence, independent risk factors, and outcomes following GI complications after cardiac surgery. METHODS: Between March 2006 and February 2011, postoperative GI complications were diagnosed in 35 of 7175 consecutive patients who underwent cardiac surgery. Preoperative, intraoperative, and postoperative predictors of complication and death were identified and compared with a control group. We also sought to compare the incidence of GI complications in patients undergoing on-pump and off-pump cardiac surgery. RESULTS: GI complications occurred in 35 (0.48%) patients including upper GI bleeding (29, 82.8%), intestinal ischemia (3, 8.5%) perforated duodenal ulcer (1, 2.8%), volvulus of sigmoid (1, 2.8%), and also one patient (2.8%) had upper GI bleeding because of gastric tumor. Patients in the GI group were an average of 5 years older than patients in the control group (P=0.011). In the on-pump group, 32 (91.4%) patients experienced GI complications, compared with 3(8.6%) in the off-pump group (P=0.011). The incidence per type of procedure was as follows: coronary artery bypass grafting (CABG) (51.4%), single or multiple valve surgery (17.1%), congenital disease (14.2%), combined CABG and valve (8.6%), aortic surgery (5.7%) and the pulmonary artery embolectomy (2.8%). By logistic multivariate analysis, twelve parameters were identified that predicted GI complications: age greater than 65 years, low left ventricular ejection fraction (EF<30%), preoperative creatinine>1.5 mg/dL, on pump operation, prolonged time of cardiopulmonary bypass (CPB), prolonged time of aortic cross clamp, congenital heart disease, aortic dissection, use of intraaortic balloon pump (IABP), blood transfusion, hypotension, and sodium bicarbonate use. Surgical treatment was used in 7 patients (20%) with GI complication. The mortality rate in the surgical group was 85.7% and was the highest in patients who had intestinal ischemia (42.8%). The overall hospital mortality among patients with GI complications was 62.8% (N.=22) compared with a mortality rate of 2.9% (N.=10) in patients without postoperative GI complications (P=0.000). CONCLUSION: GI complications are an infrequent, but serious consequence of cardiac surgery and high index of suspicious is required for their detection. Furthermore, successful outcome can be enhanced by improving cardiac output, prompt diagnosis and early surgical intervention. PMID- 23022758 TI - Intraoperative parathyroid hormone assay during focused parathyroidectomy for primary hyperparathyroidism: is it really mandatory? AB - AIM: Intraoperative parathyroid hormone (PTH) assay has become an essential tool in focused parathyroid surgery. The aim of this study was to evaluate the present role of intraoperative PTH monitoring during focused parathyroidectomy for primary hyperparathyroidism in our experience. METHODS: One hundred sixty-one patients were submitted to focused parathyroidectomy with rapid intraoperative Parathyroid hormone assay monitoring. RESULTS: A >50% decrease of PTH occurred in 147 patients (91.3%); in this group persistent hypercalcemia was found in 1; in the remaining 14 (8.7%) values of PTH decreased less than 50% and bilateral neck exploration was performed. An additional pathologic parathyroid was removed in 8 cases, a third in one; in the other five further neck exploration was negative and in four of these persistent postoperative hypercalcemia was demonstrated. In 136 patients >50% decrease of PTH was obtained after 10 minutes, in the other 11 after 20. The overall operative success of the patients was 96.9% with a 5.6% incidence of multiglandular disease. Intraoperative parathormone monitoring changed the operative management in 8.7% of cases. Intraoperative parathormone monitoring was accurate in predicting operative success or failure in 98.7% of patients, with a sensitivity of 99.3%, a specificity of 92.8%, a positive predictive value of 99.3% and a negative predictive value of 92.8%. DISCUSSION AND CONCLUSION: The measurement of intraoperative PTH represents a useful tool to assist the surgeon during parathyroid surgery and its routine use significantly improves cure rates of focused parathyroidectomy. We believe that the use intraoperative PTH is still mandatory in focused parathyroidectomy avoiding relapses and consequent reintervention. PMID- 23022759 TI - Perioperative PAI-1 values in surgically treated colorectal carcinoma patients under low molecular weight heparin thromboprophylaxis. AB - AIM: We have monitored the perioperative changes of plasmatic values of plasminogen activator inhibitor -1 (PAI-1) in colorectal carcinoma patients depending on the stage of disease and the use of prophylactic low molecular weight heparin (LMWH). METHODS: One hundred 100 colorectal carcinoma patients (64 men and 36 women) with average age of 60, in two randomized groups. All patients were surgically treated using the same technique and in all cases adenocarcinoma was confirmed. Two hours before the surgery, the first group (48 patients) received LMWH-nadroparin calcium in doses of 0.3 or 0.4 mL sc, while the second group (52 patients) received it eight hours after the surgery. Following the surgery, Nadroparin calcium was administered daily using the same dose as before. Blood samples were collected: before the surgery, 10 minutes after the first surgical incision, 8 hours after the surgery, and on the 3rd, 5th and 10 th postoperative days. The staging of the disease (according to the Dukes classification) was compared with the patients' blood plasma concentration of PAI 1. Statistical analysis using the c2 test, the LSD test, Wilcoxon and Mann Whitney test was performed. RESULTS: Adenocarcinoma was patohistologicaly confirmed in all 100 subjects. According to the Dukes classification, 6 patients had stage A, 51 had stage B, and 43 had stage C. PAI-1 measurements showed that baseline measurements were within normal boundaries for both groups. Ten minutes after the first incision a sharp decline of PAI-1 values in the plasma of both patient groups was observed, which could be explained by the use due to the effect on t-PA secreted from the damaged endothelium. PAI-1 values in both groups of subjects have returned to starting (baseline) values, and remained within these values through the third, fourth and fifth measurement in both groups of patients. There was no difference between the two randomized groups which leads to the conclusion that the application of LMWH does not affect PAI-1 values. A statistically significant difference of the tested parameters according to the Dukes classification was obtained only for parameter PAI-1 for pairs Dukes A:B as well as Dukes A:C. A statistically significant correlation was found for plasma values of fibrinolysis inhibitor PAI-1 according to the Dukes classification, but it does not correlate to the tumor invasion through intestinal wall structures. The reason for the statistically significant increase of PAI-1 values in the Dukes A stage remains unclear. CONCLUSION: By activating t-PA and blocking PAI-1, Nadroparin calcium perioperatively makes the haemostasis system stable and balanced. PMID- 23022760 TI - Ruptured aneurysm of the popliteal artery. Is the diagnosis still difficult? AB - The aneurysm of the popliteal artery is the most commonly treated non-aortoiliac aneurysm, accounting for more than 70% of all peripheral aneurysms. The rupture of a popliteal aneurysm is rare and it is often misdiagnosed. In the case of a 46 year old female patient here reported, the patient was referred to our department with the diagnosis of ruptured aneurysm of the right popliteal artery with formation of a large pseudo-aneurysm. We operated the patient on a semi-urgent basis and performed a replacement of the popliteal artery by a saphenous vein graft. Three months after the operation, the patient was free of symptoms. This article's aim was to emphasize on how the pitfalls during clinical examination, as well as the problems of imaging interpretation, can make the diagnosis of ruptured popliteal aneurysm still difficult. PMID- 23022762 TI - Laparoscopic pancreatic necrosectomy: a minimally invasive alternative to laparotomic debridement of pancreatic necrosis. PMID- 23022761 TI - Mechanical ileus due to deflated air-filled intragastric balloon. PMID- 23022763 TI - [Esthesioneuroblastoma]. AB - Esthesioneuroblastoma is an uncommon malignancy originating from olfactive epithelium. Men are more frequently affected than women. Nasal symptoms are the most common revealing signs. Immunohistochemistry helps diagnosis. There is no randomized trial evaluating treatment due to the low incidence of this tumor. Radiotherapy and surgery are the standard of care. Radiotherapy is benefic even in early stage disease. Chemotherapy is indicated in case of locally advanced or metastatic disease. PMID- 23022765 TI - Relative biological effectiveness (RBE) and out-of-field cell survival responses to passive scattering and pencil beam scanning proton beam deliveries. AB - The relative biological effectiveness (RBE) of passive scattered (PS) and pencil beam scanned (PBS) proton beam delivery techniques for uniform beam configurations was determined by clonogenic survival. The radiobiological impact of modulated beam configurations on cell survival occurring in- or out-of-field for both delivery techniques was determined with intercellular communication intact or physically inhibited. Cell survival responses were compared to those observed using a 6 MV photon beam produced with a linear accelerator. DU-145 cells showed no significant difference in survival response to proton beams delivered by PS and PBS or 6 MV photons taking into account a RBE of 1.1 for protons at the centre of the spread out Bragg peak. Significant out-of-field effects similar to those observed for 6 MV photons were observed for both PS and PBS proton deliveries with cell survival decreasing to 50-60% survival for scattered doses of 0.05 and 0.03 Gy for passive scattered and pencil beam scanned beams respectively. The observed out-of-field responses were shown to be dependent on intercellular communication between the in- and out-of-field cell populations. These data demonstrate, for the first time, a similar RBE between passive and actively scanned proton beams and confirm that out-of-field effects may be important determinants of cell survival following exposure to modulated photon and proton fields. PMID- 23022766 TI - Complete trunk severance of a motorcyclist by a traffic sign post at a comparably low collision speed. AB - Traumatic limb amputations and transections of the trunk generally indicate high impact velocities. Complete traumatic severances of the trunk in road accidents however are rarely reported in literature. We describe a case where the trunk of a motorcyclist was completely severed as he hit the post of a traffic sign. Based on the documented end position and damage of the motorcycle, an impact velocity range of 52-80 km/h could be determined for the motorcyclist. To our knowledge, this is the first report on the type and mechanism of injury at this comparatively low collision speed range. PMID- 23022764 TI - Of blood cells and the nervous system: hematopoiesis in the Drosophila larva. AB - Hematopoiesis is well-conserved between Drosophila and vertebrates. Similar as in vertebrates, the sites of hematopoiesis shift during Drosophila development. Blood cells (hemocytes) originate de novo during hematopoietic waves in the embryo and in the Drosophila lymph gland. In contrast, the hematopoietic wave in the larva is based on the colonization of resident hematopoietic sites by differentiated hemocytes that arise in the embryo, much like in vertebrates the colonization of peripheral tissues by primitive macrophages of the yolk sac, or the seeding of fetal liver, spleen and bone marrow by hematopoietic stem and progenitor cells. At the transition to the larval stage, Drosophila embryonic hemocytes retreat to hematopoietic "niches," i.e., segmentally repeated hematopoietic pockets of the larval body wall that are jointly shared with sensory neurons and other cells of the peripheral nervous system (PNS). Hemocytes rely on the PNS for their localization and survival, and are induced to proliferate in these microenvironments, expanding to form the larval hematopoietic system. In this process, differentiated hemocytes from the embryo resume proliferation and self-renew, omitting the need for an undifferentiated prohemocyte progenitor. Larval hematopoiesis is the first Drosophila model for blood cell colonization and niche support by the PNS. It suggests an interface where innocuous or noxious sensory inputs regulate blood cell homeostasis or immune responses. The system adds to the growing concept of nervous system dependence of hematopoietic microenvironments and organ stem cell niches, which is being uncovered across phyla. PMID- 23022768 TI - Hyperpnoeic response independent of limb movements at exercise onset in mice. AB - We have shown that constant-load treadmill exercise in mice produces an abrupt ventilatory increase to a maximal level at exercise onset. We examined what caused this abrupt response. We measured ventilation during 30-min constant-load exercise on a treadmill, below the lactate threshold, in conscious mice. Video analysis showed that hyperpnoea started before locomotion began. Incremental changes in speed did not further increase ventilation during the early phase of exercise. Next, we measured ventilatory responses to a sudden movement of the treadmill belt on which the mice were kept in a stationary position by a mesh cover. Hyperpnoea started concurrently with the sudden belt movement. In the absence of locomotion, ventilation increased to the extent reached during exercise hyperpnoea. Finally, the abrupt response showed plasticity but was attenuated by experience. The present study shows the importance of factors independent of limb movements in the hyperpnoeic response during the early phase of treadmill exercise in mice. PMID- 23022769 TI - Membrane lipids and nuclear DNA are differently susceptive to Fenton reaction substrates in porcine thyroid. AB - Fenton reaction (Fe(2+)+H(2)O(2) -> Fe(3+)+()OH+OH(-)) is of special significance in the thyroid, as both substrates are indispensable for thyroid hormone synthesis, therefore being available presumably at high concentrations under physiological conditions. The study aimed at evaluation if both Fenton reaction substrates are required to induce oxidative damage to membrane lipids and nuclear DNA in porcine thyroid homogenates, and if these macromolecules are vulnerable to the same extent. Thyroid homogenates and nuclear DNA were incubated in the presence of H(2)O(2) and/or Fe(2+). Malondialdehyde+4-hydroxyalkenals (MDA+4-HDA) concentration (lipid peroxidation index) was measured spectrophotometrically, and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) concentration (DNA damage index) by HPLC. Whereas Fenton reaction substrates, used separately, did not affect lipid peroxidation, they increased 8-oxodG level for the highest H(2)O(2) concentration (100mM) and in Fe(2+) concentration-dependent manner (300, 150, 30 and 15 MUM). If Fe(2+) and H(2)O(2) were applied together, lipid peroxidation increased significantly, however without H(2)O(2) concentration- but with clear Fe(2+) concentration-dependent effect. Concerning DNA damage, Fe(2+) enhanced H(2)O(2) effect, whereas Fe(2+) concentration-dependent effect was not changed by H(2)O(2). Excess of exclusively one of Fenton reaction substrates is sufficient to induce oxidative DNA damage, but not lipid peroxidation, in porcine thyroid. Comparing to H(2)O(2), Fe(2+) seems to be a stronger damaging substrate. PMID- 23022767 TI - Face-to-face versus computer-delivered alcohol interventions for college drinkers: a meta-analytic review, 1998 to 2010. AB - Alcohol misuse occurs commonly on college campuses, necessitating prevention programs to help college drinkers reduce consumption and minimize harmful consequences. Computer-delivered interventions (CDIs) have been widely used due to their low cost and ease of dissemination but whether CDIs are efficacious and whether they produce benefits equivalent to face-to-face interventions (FTFIs) remain unclear. Therefore, we identified controlled trials of both CDIs and FTFIs and used meta-analysis (a) to determine the relative efficacy of these two approaches and (b) to test predictors of intervention efficacy. We included studies examining FTFIs (N=5237; 56% female; 87% White) and CDIs (N=32,243; 51% female; 81% White). Independent raters coded participant characteristics, design and methodological features, intervention content, and calculated weighted mean effect sizes using fixed and random-effects models. Analyses indicated that, compared to controls, FTFI participants drank less, drank less frequently, and reported fewer problems at short-term follow-up (d(+)s=0.15-0.19); they continued to consume lower quantities at intermediate (d(+)=0.23) and long-term (d(+)=0.14) follow-ups. Compared to controls, CDI participants reported lower quantities, frequency, and peak intoxication at short-term follow-up (d(+)s=0.13-0.29), but these effects were not maintained. Direct comparisons between FTFI and CDIs were infrequent, but these trials favored the FTFIs on both quantity and problem measures (d(+)s=0.12-0.20). Moderator analyses identified participant and intervention characteristics that influence intervention efficacy. Overall, we conclude that FTFIs provide the most effective and enduring effects. PMID- 23022770 TI - Reply to the letter to the editor. PMID- 23022772 TI - Use of noninvasive positive pressure ventilation in emergency departments of public and private hospitals in Lebanon. AB - Noninvasive positive pressure ventilation is increasingly being used in emergency departments across Europe and North America. To our knowledge, no similar data are available from other countries. The aim of this study is to describe the current use of noninvasive positive pressure ventilation in the emergency departments of Lebanese hospitals. A structured and validated questionnaire was sent to all emergency departments in Lebanon. In Lebanon, 48.4% of emergency departments use noninvasive positive pressure ventilation. It is mostly used for patients with chronic obstructive pulmonary diseases and cardiogenic pulmonary edema. Bilevel and continuous positive airway pressures are the two most widely used modalities for noninvasive positive pressure ventilation. Face mask is the most used patient interface. The use of uniform protocols and training is lacking. Noninvasive positive pressure ventilation in Lebanese emergency departments is underused, with significant potential for improvements in its current practice. PMID- 23022771 TI - Transcriptional analysis of Schistosoma mansoni treated with praziquantel in vitro. AB - Schistosomiasis is one of the foremost health problems in developing countries and has been estimated to account for the loss of up to 56 million annual disability-adjusted life years. Control of the disease relies almost exclusively on praziquantel (PZQ) but this drug does not kill juvenile worms during the early stages of infection or prevent post-treatment reinfection. As the use of PZQ continues to grow, there are fears that drug resistance may become problematic thus there is a need to develop a new generation of more broadly effective anti schistosomal drugs, a task that will be made easier by having an understanding of why PZQ kills sexually mature worms but fails to kill juveniles. Here, we describe the exposure of mixed-sex juvenile and sexually mature male and female Schistosoma mansoni to 1 MUg/mL PZQ in vitro and the use of microarrays to observe changes to the transcriptome associated with drug treatment. Although there was no significant difference in the total number of genes expressed by adult and juvenile schistosomes after treatment, juveniles differentially regulated a greater proportion of their genes. These included genes encoding multiple drug transporter as well as calcium regulatory, stress and apoptosis related proteins. We propose that it is the greater transcriptomic flexibility of juvenile schistosomes that allows them to respond to and survive exposure to PZQ in vivo. PMID- 23022773 TI - Delays in the administration of antimicrobials in the emergency department and the impact of an educational intervention to improve this administration. AB - OBJECTIVES: The aim of the study was to assess the factors associated with delays in emergency department (ED) antimicrobial administration and to determine whether an educational intervention would reduce the incidence of such delays. METHODS: We carried out a retrospective observational cohort study of patients aged 18-89 years who received intravenous antimicrobial(s) in a single ED and were subsequently admitted (March 2011). Using multivariable logistic regression, we analyzed whether demographic and operational factors were significantly associated with delayed ED antimicrobial administration (> 30 min from physician order to nurse initiation time). We then conducted an educational intervention with ED/hospital staff to disseminate knowledge of these identified factors. After the intervention, we carried out a prospective observational cohort study of participants with the same inclusion criteria (March 2012), using the large sample z-test to analyze whether the incidence of such delays was significantly reduced. RESULTS: A total of 575 ED antimicrobial orders (302 patients) before the intervention and 493 antimicrobial orders (275 patients) after the intervention fulfilled the inclusion criteria. The median time to antimicrobial administration (interquartile) was 48 min (17-130 min) before the intervention and 49 min (17-156 min) after the intervention. Variables significantly increasing or decreasing the odds of delayed ED antimicrobial administration were older age [OR: 1.01, 95% confidence interval (CI) 1.003-1.03], one-time dosing (OR: 0.53, 95% CI 0.31-0.92), and second (OR: 2.40, 95% CI 1.39-4.14), and third (OR: 3.66, 95% CI 1.69-7.92) antimicrobial administration (multiple agents ordered). The incidence of antimicrobial administration was 35.8% within 30 min before the intervention and 34.7% after the intervention (z-test: 0.39, P = 0.70). CONCLUSION: Older age, multiple agent orders, and dosing ordering pattern showed a significant association with delays in ED antimicrobial administration. An educational intervention to disseminate knowledge of these factors did not result in a reduction in such delays. PMID- 23022774 TI - Involvement of hepatocellular carcinoma biomarker, cyclase-associated protein 2 in zebrafish body development and cancer progression. AB - Cyclase-associated protein 2 (CAP2) is a conserved protein that is found up regulated in hepatocellular carcinoma (HCC). By using zebrafish, combined with HCC cell lines, we further investigated the role of CAP2. The zebrafish CAP2 sequence was 60% identical to human CAP2 with 77% homology in the C-terminal actin-binding domain, and 58% in the N-terminal cyclase-binding domain. CAP2 expression was observed during zebrafish development and was preferentially expressed in the skeletal muscle and heart. Knockdown using two different morpholinos against CAP2 resulted in a short-body morphant zebrafish phenotype with pericardial edema. CAP2 was observed co-localized with actin in zebrafish skeletal muscle, and in the leading edge of lamellipodium in HCC cell lines. CAP2 silencing resulted in a defect in lamellipodium formation and decreased cell motility in HCC cell lines. Strongly positive expression of CAP2 was observed in 10 of 16 (63%) poorly, 30 of 68 (44%) moderately, and 2 of 21 (10%) well differentiated HCC. CAP2 expression was significantly associated with tumor size, poor differentiation, portal vein invasion, and intrahepatic metastasis. Our results indicate that an important conserved function of CAP2 in higher vertebrates may be associated with the process of skeletal muscle development. CAP2 also played an important role in enhancing cell motility, which may promote a more invasive behavior in the progression of HCC. These findings highlight the link between development and cancer. PMID- 23022776 TI - Occupational exposure to blood and body fluids. AB - Occupational exposure to blood and body fluids is an important hazard for health care workers, which places them at a high risk for blood-borne infections including hepatitis B virus, hepatitis C virus and human immunodeficiency virus and results in psychological and emotional stresses. Several preventive measures have been proposed including pre-exposure (e.g., education, use of standard precautions, use of needle protective devices, and vaccination) and post-exposure (e.g., post-exposure prophylaxis and early detection of disease) prevention. In this article, the importance of occupational exposure to blood and body fluids and the basic concepts of exposure prevention and management are reviewed. PMID- 23022775 TI - A light harvesting Bi-component hydrogel with a riboflavin acceptor. AB - A light harvesting hydrogel, working in a wide range of temperature and pH, of a two component supramolecular complex of melamine and 6,7-dimethoxy-2,4[1H,3H] quinazolinedione (donor) with riboflavin (acceptor) shows a gradual quenching and red shift of the acceptor emission peak with increase in its concentration through a co-assembly process. PMID- 23022777 TI - Inhalational lung disease. AB - Inhalational lung diseases are among the most important occupational diseases. Pneumoconiosis refers to a group of lung diseases result from inhalation of usually inorganic dusts such as silicon dioxide, asbestos, coal, etc., and their deposition in the lungs. The resultant pulmonary disorders depend on the susceptibility of lungs; size, concentration, solubility and fibrogenic properties of the inhaled particles; and duration of exposure. Radiographic manifestations of pneumoconiosis become apparent several years after exposure to the particles. However, for certain types of dusts, e.g., silicone dioxide crystal and beryllium, heavy exposure within a short period can cause an acute disease. Pulmonary involvement in asbestosis is usually in the lower lobes. On the contrary, in silicosis and coal worker pneumoconiosis, the upper lobes are involved predominantly. For imaging evaluation of pneumoconiosis, high-resolution computed tomography (CT) is superior to conventional chest x-ray. Magnetic resonance imaging (MRI) and positron emission tomography (PET) scan are helpful in those with suspected tumoral lesions. In this essay, we reviewed the imaging aspects of inhalational lung disease. PMID- 23022778 TI - Silica exposure and serum angiotensin converting enzyme activity. AB - BACKGROUND: Silicosis is known in industrial workers for centuries. Till recently, the mainstay of its diagnosis and progress was clinical examination of the respiratory system, pulmonary function test and chest radiography. Several biomarkers such as serum angiotensin converting enzyme (ACE) activity have been examined to determine the extent of silicosis. OBJECTIVE: To elucidate the effect of age, gender, duration of exposure to silica dust, smoking habit, and pulmonary function status on the serum ACE activity among quartz stone workers without disease. METHODS: A cross-sectional study was carried out on 134 (111 men and 14 women) workers of quartz stone crushing units were studied. Standard diagnostic criteria were used for diagnosing silicosis and tuberculosis. Pulmonary functions of the participants were also assessed. RESULTS: The mean+/-SD age for participants was 26.1+/-6.3 years (26.6+/-6.3 for men and 21.9+/-4.3 for women). The mean+/-SD duration of exposure was 1.1+/-1.9 years. In the present study, only one case of silicosis and eight cases of tuberculosis were found. The mean+/ SD serum ACE levels for those with and without respiratory disease were 68.44+/ 11.61, and 66.9+/-14.4 IU/L, respectively (p>0.05). CONCLUSION: We could not observe any association between serum ACE activity and age, gender, duration of exposure, smoking habits and pulmonary function status. However, elevated levels of serum ACE was found in a solitary case of silicosis. PMID- 23022779 TI - Occupational lead poisoning in workers of traditional tile factories in Mashhad, Northeast of Iran. AB - BACKGROUND: Occupational lead poisoning is a health problem in Iran. It has not previously been studied in traditional tile makers. OBJECTIVE: To determine the prevalence of lead poisoning and its complications in traditional tile workers in Mashhad, Northwest of Iran. METHODS: We visited workers in two traditional tile factories and collected data by direct history taking and physical examination. Blood and urine lead concentrations were measured by heated graphite atomization technique. RESULTS: Overall, 108 men with mean+/-SD age of 37+/-7.8 years were studied. The mean+/-SD length of daily lead exposure was 9.8+/-6 years. The mean+/-SD blood lead concentration was 520.5+/-323.2 MUg/L. The main objective clinical findings were the presence of lead line (64.8%), peripheral neuropathy of the upper extremities (37%), depressed deep tendon reflexes in the upper extremities (25.7%), tremor (23.3%), peripheral neuropathy of the lower extremities (17%) and abdominal tenderness (15.1%). The subjective findings were mainly attributed to the central nervous system and included loss of memory (57%), moodiness (56.1%), agitation (47.7%), drowsiness (36.4%) and headache (29.9%). There was no statistically significant correlation between the blood lead concentration and glomerular filtration rate. However, there were significant correlations between the blood lead concentration and each of the urine lead concentration (p<0.001), diastolic blood pressure (p = 0.04), serum triglyceride level (p = 0.043), high density lipoprotein level (p = 0.012), and basophilic stippling (p = 0.048). Blood lead level, however, did not have any significant correlation with the presence of lead line. CONCLUSION: In traditional tile workers, lead toxicity is not uncommon and the toxic effects of lead were found more often on the teeth (bone), central and peripheral nervous system, hematological and lipid profiles than on the renal function. PMID- 23022780 TI - Breast cancer: an occupational disease. PMID- 23022781 TI - Phenol burn. PMID- 23022782 TI - Report of audiogram. PMID- 23022783 TI - Does the world need a new journal? PMID- 23022784 TI - The IJOEM: any progress? PMID- 23022785 TI - Conflict of interest in peer-reviewed medical journals: the World Association of Medical Editors (WAME) position on a challenging problem. PMID- 23022786 TI - Privatization of health organization in Iran: how to avoid too much of a good thing? PMID- 23022787 TI - Seroprevalence of brucellosis and risk factors related to high risk occupational groups in Kazeroon, South of Iran. AB - BACKGROUND: Brucellosis is a major zoonosis worldwide. Many people for their professions are at higher risk of contracting the disease. OBJECTIVE: To determine the seroprevalence of brucellosis and its risk factors in a group of high risk professions. METHODS: In a cross-sectional study, all personnel or students of veterinary schools, slaughters and butchers working in the city were invited to participate (n = 141). A comparison group (n = 44) randomly selected from patients who were selected at random from people attended our healthcare center for reasons other than the infectious diseases. RESULTS: 4 veterinarians, 15 veterinary assistants, 42 veterinarian students, 52 butchers, 17 slaughters, 8 slaughterhouse workers and 3 chefs made the first group and 14 storekeepers, 5 students of engineering, 11 clerks, 13 freelance workers, and 1 high school student made the comparison group. While the rate of consumption of most of the studied dairy products was almost similar in both groups, comparison group patients consumed more often milk (p<0.001) and cream (p<0.001) than the high risk group. 11 (7.8%; 95% CI: 3.4%-12.2%) cases from high risk group and none of the comparison group were found seropositive for Brucella. CONCLUSION: Profession is the main factor in seropositivity. Consumption of dairy products and raw milk is not associated with a higher risk of seropositivity. PMID- 23022788 TI - Prevalence of musculoskeletal pain among dentists in Shiraz, Southern Iran. AB - BACKGROUND: Occupational diseases are worldwide. Some dentists believe that they are at a higher risk for development of some musculoskeletal disorders for the postures they should have during work. OBJECTIVE: To determine the prevalence of musculoskeletal pain and their associated occupational factors among dentists from Shiraz, southern Iran. METHODS: In a cross-sectional study, 90 dentists of 375 members of Fars Dental Association were selected at random and asked to complete a self-administered questionnaire. The questions were about personal characteristics, job history, some work characteristics mostly pertaining to dentistry including physical risk factors at work plus any report about the occurrence of low back pain (LBP) and neck pain. RESULTS: Of the 90 questionnaires distributed, 82 (91%) were completed and returned for analyses. Of 82 studied dentists, 42 (51%) were female (mean+/-SD age of 36+/-6.6 yrs) and 40 (49%) were male (mean+/-SD age of 39.4+/-8.7 yrs). 27 (33%; 95% CI: 23%-43%) dentists had LBP; 23 (28%; 95% CI: 18%-38%) had neck pain; and 10 (12%; 95% CI: 5%-19%) had both. Of these 60 dentists who had pain, 27 (45%; 95% CI: 32%-58%) had radicular pain and 28 (47%; 95% CI: 34%-59%) felt numbness and/or paresthesia in their limbs. 33 (55%; 95% CI: 42%-68%) of 60 dentists with musculoskeletal complaint could not identify any factors for their pain. The prevalence of neither LBP nor neck pain were significantly different between men and women. The place of work and the prevalence of complaint of musculoskeletal pain were also not significantly correlated. None of the studied work-related risk factors had a significant association with the complaint of musculoskeletal pain. CONCLUSION: Although the prevalence of LBP and neck pain is high among dentists, we could not find any correlation between the studied work-related risk factors and musculoskeletal disorders. We concluded that dentistry, per se, is probably not an initial factor for development of neither LBP nor neck pain, but it could accentuate the symptoms. PMID- 23022789 TI - Occupational stress and mental health of employees of a petrochemical company before and after privatization. AB - BACKGROUND: Many countries make many of their governmental sectors private. This transition, however, may affect their employees in numerous ways. OBJECTIVE: To determine the level of occupational stress and mental health of employees of a petrochemical company in Isfahan, Central Iran, before and 3 months after privatization. METHODS: Out of the 700 employees of the studied company, using a stratified random sampling technique, 140 persons were selected. We used Steinmetz occupational stress and GHQ-28 questionnaires to determine the level of stress and mental health status of participants. RESULTS: The reliability of the questionnaires used was acceptable (Chronbach alpha coefficients: 0.85 and 0.86, respectively). Job stress level was significantly increased 3 months after privatization; the mean+/-SD job stress score before and after privatization were 22.9+/-10.43 and 28.3+/-12.25, respectively (p<0.001). The mean+/-SD mental health score after privatization (17.57+/-11.63) was also significantly (p<0.001) higher than that before the privatization (13.8+/-6.0). There was a significant (p<0.001) positive correlation between the mental health status score and job score (r = 0.476). CONCLUSION: After privatization, the job stress of employees increased significantly. This increase was associated with a decrease in mental health. To lessen the side effects of privatization, the process should be performed cautiously. PMID- 23022790 TI - Lead poisoning in the world and Iran. AB - Lead is a relatively ubiquitous heavy metal with particular features such as resistance to corrosion, high malleability and wide variety of industrial applications. In medicine, however, it is considered as a slow-acting toxic substance affecting multiple body systems, specifically functioning as a potent neurotoxin in the central nervous system. Lead poisoning may be acute or chronic and can be due to occupational or environmental exposures. The history of lead poisoning dates back to ancient times. The present paper briefly describes the worldwide historical accounts of lead poisoning with a special focus on Iran. PMID- 23022791 TI - Echinococcosis: an occupational disease. AB - Hydatidosis is a common infestation caused by Echinococcus spp. Solitary hydatid cyst of the lung is not uncommon but coexistence of two or more pulmonary cysts are less common. These cysts may drain into the bronchial tree or very rarely into the pleural cavity which causes a poor outcome. Certain people such as slaughters, tanners, stockbreeders, shepherds, butchers, veterinarians and all whose job makes them to work closely with animals are at higher risk of the infection and developing echinococcosis. Herein, we present a 14-year-old shepherd who developed severe chest pain and hydropneumothorax following a minor trauma to his chest. He had two pulmonary hydatid cysts, one of which drained to the left pleural cavity and caused the symptoms. Another cyst was complicated during his hospital course. The patient was treated surgically, received albendazole and discharged home uneventfully. A high index of suspicion is of utmost importance for the correct diagnosis and treatment of hydatid disease in hyperendemic areas and in those whose occupation might put them at a higher risk of contraction of hydatid disease. PMID- 23022792 TI - Global warming: promises in vain. PMID- 23022793 TI - Nursing care of acute sulfur mustard poisoning. PMID- 23022796 TI - Silica nephropathy. AB - Occupational exposure to heavy metals, organic solvents and silica is associated with a variety of renal manifestations. Improved understanding of occupational renal disease provides insight into environmental renal disease, improving knowledge of disease pathogenesis. Silica (SiO2) is an abundant mineral found in sand, rock, and soil. Workers exposed to silica include sandblasters, miners, quarry workers, masons, ceramic workers and glass manufacturers. New cases of silicosis per year have been estimated in the US to be 3600-7300. Exposure to silica has been associated with tubulointerstitial disease, immune-mediated multisystem disease, chronic kidney disease and end-stage renal disease. A rare syndrome of painful, nodular skin lesions has been described in dialysis patients with excessive levels of silicon. Balkan endemic nephropathy is postulated to be due to chronic intoxication with drinking water polluted by silicates released during soil erosion. The mechanism of silica nephrotoxicity is thought to be through direct nephrotoxicity, as well as silica-induced autoimmune diseases such as scleroderma and systemic lupus erythematosus. The renal histopathology varies from focal to crescentic and necrotizing glomerulonephritis with aneurysm formation suggestive of polyarteritis nodosa. The treatment for silica nephrotoxicity is non-specific and depends on the mechanism and stage of the disease. It is quite clear that further research is needed, particularly to elucidate the pathogenesis of silica nephropathy. Considering the importance of diagnosing exposure-related renal disease at early stages, it is imperative to obtain a thorough occupational history in all patients with renal disease, with particular emphasis on exposure to silica, heavy metals, and solvents. PMID- 23022797 TI - Occupational noise-induced hearing loss. AB - Noise-induced hearing loss (NIHL) is a well-known entity in daily practice of otolaryngology. A wide variety of NIHLs are work-related. Occupational noise is the most common cause of NIHL in adults which is up to now considered incurable and the best approach to it is to utilize maximal protection. An effective noise exposure prevention program consists of identification of sources of noise and implementation of controlling measures and regulations at working environments as well as performing periodic audiologic evaluation of those who are working at noisy environments. The present paper, briefly reviews occupational NIHL mainly based on the related data available on PubMed up to early 2010. PMID- 23022798 TI - Upper extremity injured workers stratified by current work status: an examination of health characteristics, work limitations and work instability. AB - BACKGROUND: Upper extremity injured workers are an under-studied population. A descriptive comparison of workers with shoulder, elbow and hand injuries reporting to a Canadian Workplace Safety and Insurance Board (WSIB) clinic was undertaken. OBJECTIVE: To determine if differences existed between injury groups stratified by current work status. METHODS: All WSIB claimants reporting to our upper extremity clinic between 2003 and 2008 were approached to participate in this descriptive study. 314 working and 146 non-working WSIB claimants completed the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH); Short Form health survey (SF36); Worker's Limitations Questionnaire and the Work Instability Scale. Various parametric and non-parametric analyses were used to assess significant differences between groups on demographic, work and health related variables. RESULTS: Hand, followed by the shoulder and elbow were the most common site of injury. Most non-workers listed their current injury as the reason for being off work, and attempted to return to work once since their injury occurrence. Non-workers and a subset of workers at high risk for work loss showed significantly worse mental functioning. Workers identified physical demands as the most frequent injury-related on the job limitation. 60% of current workers were listed as low risk for work loss on the Work Instability Scale. CONCLUSION: Poorer mental functioning, being female and sustaining a shoulder injury were risk factors for work instability. Our cohort of injured non-workers were unable to return to work due to their current injury, reinforcing the need to advocate for modified duties, shorter hours and a work environment where stress and injury recurrence is reduced. Future studies examining pre-injury depression as a risk factor for prolonged work absences are warranted. PMID- 23022799 TI - Clinical and biochemical parameters of children and adolescents applying pesticides. AB - BACKGROUND: The primary agricultural product in Egypt is the cotton crop. Children and adolescents work seasonally in the cotton fields applying pesticides. OBJECTIVE: To examine the effect of pesticide exposure on clinical and biochemical parameters in children and adolescents applying pesticides. METHODS: Male children currently applying pesticides and aged between 9 and 19 years (n = 50) were recruited for this study. They were asked to complete work, health, and exposure questionnaires; examined for any medical and neurological problems with particular attention to sensory and motor functions including cranial nerves, sensory and motor system, and reflexes. From each participant, a blood sample was taken to measure acetylcholinesterase activity, and liver and kidney functions. Children who have never worked in agriculture (n = 50), matched on age, education, and socioeconomic status were also studied and served as controls. RESULTS: More neuromuscular disorders were identified in pesticide applicators than controls. A significant lower level of acetylcholinesterase was found in the applicator group compared to the controls. There was also a significant difference in hematological, renal and hepatic indices in the exposed children compared to the control children. Working more days in the current season and also working more years as a pesticide applicator were both associated with an increase in the prevalence of neuromuscular abnormalities and significant changes in the laboratory tests. CONCLUSION: Children and adolescent pesticide applicators working in farms of Egypt are at risk of developing serious health problems similar to those of adults. PMID- 23022800 TI - Hospital maid: a worker at risk of contracting swine flu. PMID- 23022801 TI - Noise-induced hearing Loss. PMID- 23022803 TI - National Conference on Impact of Climate Change on Biodiversity of Insects and Environment (CBI' 2010). PMID- 23022804 TI - That is not a yesterday's problem. PMID- 23022805 TI - Occupational causes of testicular cancer in adults. AB - Testicular cancer is one of the commonest cancers in men of working age, and is increasing in incidence in Europe and North America. One suggested mechanism of causation is that there is impaired differentiation of germ cells in the pre- or perinatal period, followed by malignant transformation in later life, possibly by a hormonal mechanism. Endocrine disrupting chemicals (EDCs) have been a major focus of interest for etiological research into testicular cancer because they interact with various hormonal pathways. Several EDCs including bisphenol A, phthalates, metals, polychlorinated biphenyls, and organochlorines have been investigated, but there are few studies and those that exist have not been able to assess exposure well. In addition, several studies, particularly those with better exposure assessment, have suggested that workers in electrical occupations have increased risks of testicular cancer. Electromagnetic radiation may have subthermal effects or may disrupt hormone release. Chronodisruption such as due to shift-work could potentially increase the risk of testicular cancer via disruption of hormonal cycles, but only one study has so far investigated this possibility. Lastly, solvent exposure, particularly to dimethylformamide, has been suggested to be associated with testicular cancer, but almost all these studies are based on job title only, with no specific assessment of solvent exposure. In conclusion, there is little evidence available on which to base definitive statements about occupational causes of testicular cancer. Future studies need to improve exposure assessment and develop ways to adjust for possible prenatal factors. PMID- 23022806 TI - Knowledge, awareness and compliance with universal precautions among health care workers at the University Hospital of the West Indies, Jamaica. AB - BACKGROUND: Universal precautions are not well understood or implemented by health care practitioners, though crucial in the prevention and transmission of blood-borne pathogens like HIV. OBJECTIVE: To assess knowledge, awareness and compliance of universal precautions among health care workers at the University Hospital of the West Indies, Jamaica. METHODS: A cross-sectional survey was conducted in September and October 2007. A 28-item self-administered questionnaire was provided to 200 health care workers including medical doctors, medical technologists, nurses and porters to assess their knowledge, awareness and practice towards universal precautions. RESULTS: Almost two-thirds (64.0%) of the respondents were very knowledgeable of universal precautions with significantly more females (75.4%) than males (42.9%) (p<0.0001). More nurses (90.0%), medical doctors (88.0%) and medical technologists (70%) were very knowledgeable of universal precautions (p<0.0001). More respondents (92.9%) who were employed in the health sector for 16 years and over reported high levels of awareness of universal precautions than those who were employed for less than five years (p<0.0001). 28.6% of males and only 6.2% of females reported that they do not use protective gear. More nurses reported frequent use of protective equipment followed by medical technologists and medical doctors (p<0.0001). CONCLUSION: There was adequate knowledge and a fair level of awareness among medical doctors, medical technologists, and nurses towards universal precautions. PMID- 23022807 TI - Association of lead exposure, serum uric acid and parameters of renal function in Nigerian lead-exposed workers. AB - BACKGROUND: The presence of hyperuricemia and renal function impairment, especially in the absence of urate stone formation is strongly suggestive of lead nephropathy. The evaluation of this association is essential in areas where lead exposure is still prevalent and uncontrolled. OBJECTIVE: To determine the relationship between serum uric acid and renal function indices in lead-exposed workers. METHODS: A cross-sectional study of 190 adults with occupational lead exposure and 80 adults (comparison group), matched for age and sex was performed in Port Harcourt, South-south Nigeria. Blood lead was used as the biomarker of lead exposure while serum urea, serum creatinine, urine albumin (using urine albumin:creatinine ratio), estimated glomerular filtration rate (GFR) and serum uric acid were the renal function indices measured. RESULTS: Occupationally lead exposed subjects had a significantly (p = 0.008) higher mean+/-SD blood lead levels (50.37+/-24.58 MUg/dL) than the comparison group (41.40+/-26.85). The mean+/-SD serum urea (8.6+/-2.3 mg/dL), creatinine (1.0+/-0.2 mg/dL) and serum uric acid (4.6+/-1.2 mg/dL) were significantly (p < 0.01) higher in the study subjects than the comparison group (7.6+/-2.4, 0.9+/-0.2, and 3.9+/-1.1 mg/dL, respectively). The mean+/-SD creatinine clearance was significantly (p = 0.002) lower in the study subjects than the comparison group (98.9+/-21.3 vs. 108.2+/ 25.2 mL/min/1.72 m2). Serum uric acid level correlated positively with serum creatinine (r = 0.134) and negatively with GFR (r = -0.151). CONCLUSION: People with occupational lead exposure are at risk of developing hyperuricemia and renal impairment. PMID- 23022808 TI - A comparison between Venables standardized respiratory questionnaire and pre shift spirometry in screening of occupational asthma in a steel industry. AB - BACKGROUND: Occupational asthma (OA) is the most common occupational lung disease in developed countries. One of the causative agents is metal fume that may be encountered in steel industries. Screening for the OA is mainly performed by questionnaire but in our country spirometry is used more commonly. OBJECTIVE: To compare the diagnostic value of the Venables standardized respiratory questionnaire and pre-shift spirometry as screening tools for OA. METHODS: In a cross-sectional study, we investigated 450 workers of a steel industry by the Venables standardized questionnaire. We also performed a pre-shift spirometry as the screening spirometry and a post-shift spirometry. A person with 10% drop in post-shift FEV1 compared with the pre-shift value was considered as asthmatic (our gold-standard). The results of the questionnaire and the pre-shift spirometry were then examined against the gold-standard test results. For each test, sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: The overall prevalence of OA among our studied workers was 3.9% (95% CI: 1.9%-5.9%). The highest rate was seen in those working in catering (25%) and welding (10%) units. Pre-shift spirometry and the questionnaire had low sensitivity (42.9% and 28.6%, respectively) and positive predictive values (16.7% and 3.6%, respectively); moderate specificity (92.4% and 71.6%, respectively) and high negative predictive values (97.9% and 96.5%, respectively). CONCLUSION: Taking into account the ease of use of the questionnaire, it seems that it is more feasible to use questionnaire as the primary screening tool for the diagnosis of OA. PMID- 23022809 TI - Successful replantation of amputated penile shaft following industrial injury. AB - Penile amputation is an uncommon urological emergency. Although rare, traumatic amputation of penis is a challenging injury to treat. However, modern microsurgical reconstruction techniques have improved success rate of penile replantation and become the procedure of choice for managing these patients. Herein, we report on a case of penile amputation following an industrial accident. PMID- 23022810 TI - Swine flu and industrial hygiene. PMID- 23022811 TI - Lead poisoning: the evolving definition. PMID- 23022812 TI - Climate change: adverse health impacts and roles of health professionals. PMID- 23022813 TI - Doctors and climate change. PMID- 23022814 TI - Global climate change and infectious diseases. AB - Climate change is occurring as a result of warming of the earth's atmosphere due to human activity generating excess amounts of greenhouse gases. Because of its potential impact on the hydrologic cycle and severe weather events, climate change is expected to have an enormous effect on human health, including on the burden and distribution of many infectious diseases. The infectious diseases that will be most affected by climate change include those that are spread by insect vectors and by contaminated water. The burden of adverse health effects due to these infectious diseases will fall primarily on developing countries, while it is the developed countries that are primarily responsible for climate change. It is up to governments and individuals to take the lead in halting climate change, and we must increase our understanding of the ecology of infectious diseases in order to protect vulnerable populations. PMID- 23022815 TI - Ear disorders in scuba divers. AB - History of underwater diving dates back to antiquity. Breath-hold technique in diving was known to the ancient nations. However, deep diving progressed only in the early decades of the 19th century as the result of advancements in efficient underwater technologies which subsequently led to invention of sophisticated sets of scuba diving in the 20th century. Currently, diving is performed for various purposes including commercial, recreational, military, underwater construction, oil industry, underwater archeology and scientific assessment of marine life. By increasing popularity of underwater diving, dive-related medical conditions gradually became more evident and created a new challenge for the health care professionals, so that eventually, a specialty the so-called "diving medicine" was established. Most of the diving-associated disorders appear in the head and neck. The most common of all occupational disorders associated with diving are otologic diseases. External otitis has been reported as the most common otolaryngologic problem in underwater divers. Exostosis of the external ear canal may be formed in divers as the result of prolonged diving in cold waters. Other disorders of the ear and paranasal sinuses in underwater divers are caused by barometric pressure change (i.e., barotraumas), and to a lesser extent by decompression sickness. Barotrauma of the middle ear is the most prevalent barotrauma in divers. The inner ear barotraumas, though important, is less common. The present paper is a brief overview of diving-related ear disorders particularly in scuba divers. PMID- 23022816 TI - Sperm chromatin structure, semen quality and lead in blood and seminal fluid of infertile men. AB - BACKGROUND: Exposures to lead above the threshold value of 50-60 MUg/dL have been linked to diminished semen quality parameters. Worldwide, the lead exposure has been diminished during the last years. Therefore, it has become of a great concern to examine the effects of lead exposures on semen quality at low levels of exposure. OBJECTIVE: To evaluate the effect of low level (<20 MUg/dL) blood lead on semen quality and sperm chromatin structure. METHODS: A cross-sectional study was conducted on 29 men with primary infertility attending the outpatient clinic of infertility in Mansoura University Hospital, Egypt, from March to May 2010. Semen quality parameters and sperm flow-cytometry analysis were compared between two groups of infertile men with blood lead level (BLL) above, and below 20 MUg/dL, respectively. RESULTS: The mean BLL in the studied subjects was 20.08 MUg/dL. 45% of the studied men had BLL >= 20 MUg/dL. Non-significant reduction in sperm count, impaired sperm motility and altered sperm morphology were observed in those with BLL >= 20 MUg/dL compared to those with BLL <20 MUg/dL. Concerning semen flow-cytometry analysis, percentage of haploid sperms was significantly lower among men with BLL >= 20 MUg/dL (78%) compared to that among those with BLL <20 MUg/dL (87%). A positive significant correlation was observed between BLL and percentage of diploid sperms. The chromatin condensation was however, negatively correlated with BLL (p<0.05). CONCLUSION: Semen quality of men with primary infertility does not have any correlation with BLL at the cutoff value of 20 MUg/dL. However, even at this low level, a significant decrease in haploid sperm counts and chromatin condensation was observed. PMID- 23022817 TI - Relationships between job stress and worker perceived responsibilities and job characteristics. AB - BACKGROUND: Few studies have examined the relationship between perceived responsibilities by workers and job characteristics and experiences of stress. OBJECTIVE: To examine the relationship between job stress and work responsibilities and job characteristics. METHODS: We analyzed data from 2737 adults who were labor force participants in the province of Alberta, Canada. A logistic regression model was employed to examine factors associated with high job stress. RESULTS: About 18% of the studied workers considered their job as being "highly stressful." Workers who were male, did not consider their job a career or who were highly satisfied with their jobs were significantly less likely to identify their jobs as "highly stressful." The probability of describing a job as "highly stressful" significantly increased as workers perceived their actions have an affect on those around them or when their jobs required additional or variable hours. CONCLUSION: A number of factors are associated with experiencing high work stress including being more engaged with work. This is an important finding for employers, offering insight into where interventions may be targeted. PMID- 23022819 TI - Replantation of amputated penile shaft. PMID- 23022818 TI - Environmental risk factors associated with leptospirosis among butchers and their associates in Jamaica. AB - BACKGROUND: Leptospirosis, a spirochetal zoonosis, is considered an occupational disease of persons engaged in agriculture, sewage works, forestry, and butchery. OBJECTIVE: To determine the environmental sources and the knowledge, attitude and practices for leptospirosis among butchers and slaughterhouse workers, as well as the seroprevalence of leptospirosis among cattle and pigs presented for slaughter. METHODS: Using an interviewer administered questionnaire, all 110 butchers and other slaughterhouse workers in the parishes of Kingston and St. Andrew, Jamaica were surveyed. In addition, 179 blood samples from animals presented for slaughter were tested for anti-Leptospira antibodies using the microscopic agglutination test (MAT). RESULTS: Analyses indicated that people with the studied occupations are at risk for developing leptospirosis due to several environmental risk factors that exist in slaughterhouses. Among the risk factors, limited knowledge of the disease and its transmission, lower educational level attained, younger age and unhealthy behaviors (e.g., hand washing and improper or lack of use of personal protective gears), presence of stray dogs and rodents, and inadequate maintenance of physical plants, were found to be important. Of the total number of animal samples tested, 20 (11%) were positive. Canicola and Hardjo (among cattle) and Bratislava (among pigs) were the major seroreactors. CONCLUSION: Butchers and slaughterhouse workers engaged in animal handling and slaughtering could be frequently exposed to leptospirosis, and hence control strategies targeting at these populations should be implemented. PMID- 23022821 TI - International climate negotiations: health to the rescue? PMID- 23022822 TI - Does bedding affect the airway and allergy? AB - Various cross-sectional and longitudinal studies have suggested that synthetic bedding is associated with asthma, allergic rhinitis and eczema while feather bedding seems to be protective. Synthetic bedding items have higher house dust mite allergen levels than feather bedding items. This is possibly the mechanism involved although fungal and bacterial proinflammatory compounds and volatile organic compounds may play a role. In this review we present and discuss the epidemiological evidence and suggest possible mechanisms. Primary intervention studies are required to show whether feather bedding is protective for the development of childhood asthma and allergic diseases while secondary intervention studies are required to potentially reduce symptoms and medication use in subjects with established disease. PMID- 23022823 TI - Occupational asthma. AB - Occupational asthma is defined as "a disease of variable airflow limitations and/or airway hyper-responsiveness due to causes and conditions attributable to a particular occupational environment and not stimuli that are being encountered outside the workplace." An analysis of general population-based studies published up to 2007 showed that 17.6% of all adult-onset asthma is due to workplace exposures. In this article, Different aspects of occupational asthma are briefly reviewed. PMID- 23022824 TI - Occupational and environmental risk factors of adult primary brain cancers: a systematic review. AB - The incidence of brain neoplasm has been progressively increasing in recent years in the industrialized countries. One of the reasons for this increased incidence could be better access to health care and improved diagnosis in the industrialized countries. It also appears that Caucasians have a higher incidence than blacks or Hispanics or Asians. A number of risk factors have been identified and described including the genetic, ethnic and age-based factors. Certain occupational and environmental factors are also believed to influence the risk of primary adult brain tumors. Potential occupational and environmental factors include exposure to diagnostic and therapeutic radiations, electromagnetic radiation from cellular phones and other wireless devices, infectious agents, air pollution and residence near landfills and high-voltage power lines and jobs as firefighters, farmers, physician, chemists and jobs in industries such as petrochemical, power generation, synthetic rubber manufacturing, agricultural chemicals manufacturing. The purpose of this systematic review is to examine occupational and environmental risk factors of brain neoplasm. A range of occupational and environmental exposures are evaluated for significance of their relationship with adult primary brain tumors. On the basis of this review we suggest a concurrent evaluation of multiple risk factors both within and beyond occupational and environmental domains. The concurrent approach needs to consider better exposure assessment techniques, lifetime occupational exposures, genotypic and phenotypic characteristics and lifestyle and dietary habits. This approach needs to be interdisciplinary with contributions from neurologists, oncologists, epidemiologists and molecular biologists. Conclusive evidence that has eluded multitude of studies with single focus and single exposure needs to multifaceted and multidisciplinary. PMID- 23022825 TI - Toxic levels of some heavy metals in drinking groundwater in Dakahlyia Governorate, Egypt in the year 2010. AB - Fifty-four drinking groundwater samples were collected in April 2010 from some districts of the Dakahlyia governorate, Egypt. The water samples were analyzed by atomic absorption spectrophotometer for iron, manganese, lead, nickel, chromium, zinc, copper, cobalt and cadmium concentrations. All samples but two were found suitable for drinking; from the water sample from Aga district showed slightly higher levels of cadmium and nickel (Ikhtab and Feshbena) than other areas; the concentrations were higher than the permissible limits of Egyptian Ministry of Health and World Health Organization. PMID- 23022826 TI - The illusion of certainty and the certainty of illusion: a caution when reading scientific articles. AB - Critical thinking is necessary to read the scientific literature. However, in addition to questions about the science, often one must also question the meaning of the text. This article provides an example of the analyses needed to understand a single sentence. In so doing, it raises several interesting issues of meaning, measurement, statistical analyses, and the form in which results are presented and interpreted. PMID- 23022827 TI - Swelling of face. Cutaneous anthrax. PMID- 23022829 TI - Problems of editors with authorship in small medical journals. PMID- 23022830 TI - Medical preparedness in radiation accidents: a matter of logistics and communication not treatment! AB - The currently reactor wreckage in Fukushima raised the following important questions: Is our knowledge of the possible dangers of ionizing radiation sufficient to warrant special action? What is the role of the medical community in technical radiation accidents from Windscale to Fukushima? What is the role of the medical community in terrorist radiation attacks? Are we prepared for those challenges? How can medical services communicate information in the media framework? What have we learned recently? And, what should be improved? In this review of the current literature on ionizing radiation, we try to answer these questions. Our conclusion is that medical services have to improve their communication skills and convince the public that the dangers of ionizing radiation can be quantitated within certain limits to support a qualified discussion about its risks and benefits. PMID- 23022831 TI - Impacts of elevated prenatal blood lead on trace element status and pregnancy outcomes in occupationally non-exposed women. AB - BACKGROUND: Lead toxicity has been reported to affect hematopoietic, nervous, reproductive, cardiovascular and urinary tract systems. Many investigators have so far studied the effects of high blood lead levels on pregnancy outcomes. OBJECTIVE: To investigate the effects of elevated maternal blood lead during pregnancy on some trace elements and pregnancy outcomes. METHODS: Blood lead and plasma copper, iron and zinc were measured in 349 pregnant women with a mean +/- SD age of 27.0 +/- 4.8 years, and gestational age of 21.8 +/- 3.1 weeks, at recruitment using atomic absorption spectrophotometer. Maternal and fetal outcomes were recorded during follow-up and at delivery, respectively. A blood lead level of >= 10 MUg/dL was considered high. RESULTS: Women with elevated blood lead had significantly higher plasma copper and iron and lower plasma zinc than women with low blood lead level (<10 MUg/dL). Blood lead level correlated with maternal hemoglobin concentration (r = -0.1054, p = 0.051) and total white blood cell count (r = 0.1045, p = 0.053). Hypertension, malaria and low birth weight were significantly higher (p<0.05) in women with elevated blood lead than in those with low blood lead level. CONCLUSION: Complications of pregnancy may be induced by a high blood lead level possibly through the alterations in trace element metabolism. PMID- 23022832 TI - Prevalence of musculoskeletal disorders among paramedics working in a large hospital in Ahwaz, southwestern Iran in 2010. AB - BACKGROUND: Musculoskeletal disorders (MSDs) are common among employees throughout the world, particularly in high risk groups such as nurses. OBJECTIVE: To determine the prevalence of MSDs among nurses in a large hospital in Ahwaz, southwestern Iran, and to examine its correlation with gender, age, shift working, years at service and smoking. METHODS: Using a self-reported questionnaire-based cross-sectional study, Nordic questionnaire for MSDs was disseminated to all inpatient hospital paramedics (n = 195) in a large hospital in Ahwaz. RESULTS: Questionnaires of 161 participants were completed and returned back for analysis (response rate of 83%). The reported prevalence of MSDs was very high in the studied paramedics so that more than 90% of them reported at least one MSD in last week. The most prevalent site affected was that of neck (64%) followed by head (62.1%), knees (54.7%) and wrists/hands (49.7%); the least frequent disorder was that of elbows (14.3%). MSD was more common in females and increased with age and years of service. Non-shift workers reported more neck and elbows MSDs than shift workers. CONCLUSION: Considering the very high prevalence of MSDs among paramedics, it is suggested that they engage in an exercise program at their work place to lower the risk of MSDs and promote working efficiency. PMID- 23022833 TI - Authorship issues at a New Zealand academic institution. AB - BACKGROUND: Authorship of peer-reviewed publications can create conflict among academics. OBJECTIVE: To document authorship conflicts of academics at a tertiary faculty. METHODS: An anonymous questionnaire eliciting authorship conflicts and knowledge of authorship criteria was administered online to 154 academic staff members at a New Zealand university. RESULTS: 43 academics responded, a response rate of 27.9%. About half of the academics reported authorship conflicts, mainly regarding ownership of data, gift authorship and academic competition. Of the 43 academics, 31 were aware of formal authorship criteria but only 21 could identify the appropriate source. 23 academics correctly identified all the appropriate criteria for authorship according to the International Committee of Medical Journal Editors guidelines. CONCLUSION: Authorship conflicts are prevalent in a New Zealand university that may be related to lack of knowledge of authorship criteria. PMID- 23022834 TI - Sharing research findings with research participants and communities. AB - In occupational and environmental health research, individual, group and community research participants have a unique and vested interest in the research findings. The ethical principles of autonomy, non-maleficence and beneficence are helpful in considering the ethical issues in the disclosure of research findings in occupational and environmental health research. Researchers need to include stakeholders, such as groups and communities, in these discussions and in planning for the dissemination of research findings. These discussions need to occur early in the research process. PMID- 23022835 TI - Lead and infertility. PMID- 23022836 TI - Were you aware of these five typical issues on your heart? PMID- 23022837 TI - Tranexamic Acid: a recipe for saving lives in traumatic bleeding. PMID- 23022838 TI - Precautions for health care workers to avoid hepatitis B and C virus infection. AB - The burden of exposure to blood-borne pathogens (such as hepatitis B and C viruses) is considerable for health care workers. Hepatitis virus transmission requires a non-immune host, an infectious source, and skin or mucous membrane injury. These three aspects are the main fields for preventional interventions. We reviewed major recent studies on this topic to identify precautions health care workers should take to avoid hepatitis B (HBV) and C virus (HCV) infections. Accordingly, this review looks at aspects of epidemiology, risk factors, economy, knowledge, attitudes, practice, and ethics of HBV and HCV that affect health care workers. The risk of transmission depends on the load of pathogen, infectious characteristics and exposure frequency. Health care workers skill levels and the specific hospital department involved appear to be the most important factors in the exposure of health care workers to blood-borne pathogens. However, many health care workers surveyed, believed that educational programs about standard precautions in their setting were not adequate. Obviously, more detailed studies will be needed to clarify risks and opportunities for health care workers precautions aimed at avoiding HBV and HCV infection, especially in emerging health research communities. PMID- 23022839 TI - Increased suicide risk among workers following toxic metal exposure at the Paducah gaseous diffusion plant from 1952 to 2003: a cohort study. AB - BACKGROUND: Suicide is a problem worldwide and occupation is an important risk factor. In the last decade, 55 200 deaths in the US were attributed to occupational risk factors. OBJECTIVE: To determine if toxic metal exposure was associated with suicide risk among Paducah gaseous diffusion plant (PGDP) workers. METHODS: We assembled a cohort of 6820 nuclear industry workers employed from 1952 to 2003. A job-specific exposure matrix (JEM) was used to determine metal exposure likelihood. Uranium exposure was also assessed by urinalysis. All suicide/self-injury International Classification for Disease (ICD) codes were used to identify suicides. Standardized mortality ratios (SMR), odds ratios (OR), and hazard ratios (HR) were used to estimate suicide risk. RESULTS: PGDP suicide victims typically were younger white men. Within exposure likelihood categories, several suicide SMRs were typically elevated for several metals. Only beryllium exposure likelihood was associated with an increased HR. Uranium urine concentration was associated with an elevated suicide risk after stratification by urinalysis frequency. CONCLUSION: Suicide risk is associated with uranium exposure. PMID- 23022841 TI - Asbestos exposure and survival in malignant mesothelioma: a description of 122 consecutive cases at an occupational clinic. AB - BACKGROUND: The natural history and etiology of malignant mesothelioma (MM) is already thoroughly described in the literature, but there is still debate on prognostic factors, and details of asbestos exposure and possible context with clinical and demographic data, have not been investigated comprehensively. OBJECTIVE: Description of patients with MM, focusing on exposure, occupation, survival and prognostic factors. METHODS: Review of medical records of patients with MM from 1984 to 2010 from a Danish Occupational clinic. Survival was estimated using Kaplan-Meier survival analysis and prognostic factors were identified by Cox regression analysis. RESULTS: 110 (90.2%) patients were male, and 12 (9.8%) were female. The median (interquartile rang [IQR]) age was 65 (13) years. Pleural MM was seen in 101 (82.8%) patients, and peritoneal in 11 (9.0%); two (1.6%) had MM to tunica vaginalis testis, and eight (6.6%) to multiple serosal surfaces. We found 68 (55.7%) epithelial tumors, 26 (21.3%) biphasic, and 6 (4.9%) sarcomatoid. 12 (9.8%) patients received tri-modal therapy, 66 (54.1%) received one-/two-modality treatment, and 36 (29.5%) received palliative care. Asbestos exposure was confirmed in 107 (91.0%) patients, probable in four (3.3%), and unidentifiable in 11 (9.0%). The median (IQR) latency was 42 (12.5) years. Exposure predominantly occurred in shipyards. The median overall survival was 1.05 (95% CI: 0.96-1.39) years; 5-year survival was 5.0% (95% CI: 2.0%-13.0%). Female sex, good WHO performance status (PS), epithelial histology and tri-modal treatment were associated with a favorable prognosis. CONCLUSION: MM continuously presents a difficult task diagnostically and therapeutically, and challenges occupational physicians with regard to identification and characterization of asbestos exposure. PMID- 23022840 TI - Sharps injuries among nurses in a Thai regional hospital: prevalence and risk factors. AB - BACKGROUND: Sharps injuries (SIs) are one of the most serious occupational accidents among nurses due to the possible severe consequences, such as the transmission of infectious diseases and inducing of mental impairment. OBJECTIVE: To discover the prevalence of SIs among nurses in a regional hospital in Thailand and to identify factors associated with SIs. METHODS: A cross-sectional study was conducted in 2011. Stratified random sampling was used to select the respondents, with wards as the strata and the number of nurses selected proportional to the size of the ward nurse population. 261 self-administered questionnaires were distributed to nurses who used needles, syringes or other sharp medical equipment in their work. Data were analyzed using chi-square tests, correlation analysis and multiple logistic regression analysis. RESULTS: The prevalence of SIs for the previous 12 months was 55.5% among the 250 nurses who returned a completed questionnaire. Of these, 91.1% were with blood. Needles (52.8%) were the main cause of SIs. The reporting rate of SIs to the hospital was 23.8%. SIs had a significant association with each of marital status, work duration, work department, attitude regarding SI prevention, and preventive management. Using multiple logistic regression analysis, attitude was found to be the strongest predictor of SIs when adjusted for other factors. Nurses who had negative attitudes towards prevention of SIs were nearly two times more likely to have SIs than those with positive attitudes (adjusted odds ratio = 1.86; 95% CI: 1.03 3.38). CONCLUSION: The study showed a high prevalence of SIs, but a low reporting rate. This suggests the reporting system requires simplification and also should include a quick response management component. Promoting positive attitudes to SI prevention, and improving the reporting system would reduce SIs. PMID- 23022842 TI - Work-related health effects among wastewater treatment plants workers. AB - BACKGROUND: Raw sewage contains various pathogenic organisms including bacteria, viruses, fungus, worms and protozoa. Workers at wastewater treatment plants (WWTPs) are exposed to these organisms as well as to H2S gas causing many health hazards. OBJECTIVE: To assess some work-related health effects among WWTPs workers with special emphasis on the most common infections as well as cardiopulmonary disorders. METHODS: 43 workers at Berket Al-Sabih WWTPs were studied. An equal number of non-exposed comparison group were also studied. All participants were asked about their personal demographic data, symptoms suggesting infection, respiratory tract impairment and cardiovascular manifestations. Spirometric measurements were made at the end of the work shift. A resting standard 12-lead ECG was also taken for each participant. For those with a positive ECG finding, echocardiography was also performed. Serum examination for antibodies against hepatitis A virus (HAV) and hepatitis E virus (HEV) was also done. A heparinized blood sample to measure sulf-hemoglobin, as an indicator of H2S exposure, was taken. Stool was analyzed by polymerase chain reaction (PCR) for Leptospira spirochete. RESULTS: WWTPs workers suffered from body ache, abdominal pain, wheeze, asthma and dyspnea more frequently than the comparison group (p<0.05). An obstructive pattern of pulmonary function impairment and a higher mean sulf-hemoglobin% were significantly more common among WWTPs workers than the comparison group. Antibody levels against HAV and HEV as well as frequency of positive stool PCR test results for L. spirochete were significantly higher among WWTPs workers than the comparison group. The prevalence of left ventricular hypertrophy (LVH) according to ECG and mean ejection fraction (EF) as measured by echocardiography were significantly more frequent in WWTPs workers than in the comparison group. CONCLUSION: WWTPs workers are high risk of developing various infections and cardiopulmonary diseases. PMID- 23022843 TI - The prospective toxic effects of some heavy metals overload in surface drinking water of Dakahlia Governorate, Egypt. AB - BACKGROUND: The concentration of heavy metals in drinking water is very important. OBJECTIVE: To to evaluate the chemistry of some heavy metals in surface drinking water of Dakahlia Governorate, Egypt. METHODS: 51 surface drinking water samples were collected from the main surface water stations and compact units in October 2009 and analyzed chemically. 26 water samples were analyzed by atomic absorption spectrophotometer for iron, manganese, lead, nickel, chromium, zinc, copper, cobalt, aluminum, and cadmium concentrations. RESULTS: Aluminum concentration was slightly high in water sample of Bosat network. Cadmium concentration in samples of up-streams of shark and Mit-Khamis stations, networks of Mit-Antar, Demera, Bosat, Bilqas, El-satamony, El-Gamalia, Mit-asim and Bilqas station exceeded the permissible limits of Egyptian Ministry of Health (EMH, 2007) and World Health Organization (WHO, 2008). The nickel concentration in the network samples taken from Shoha, Bosat and El-Gamalia as well as up-stream of Bosat station exceeded the permissible limits. Also, lead concentrations of the network samples of Shoha, Mit-Antar, Demera and Nabaru exceeded the permissible limits. CONCLUSION: Regular chemical analysis of surface drinking water is required. Since these heavy metals are most likely originate from steel, plastics and batteries industries working in the region, we believe that activities of these industries must be stopped or at least limited in urban zones. PMID- 23022845 TI - Post-traumatic Stress Disorder. AB - Unexpected extreme sudden traumatic stressor may cause post-traumatic stress disorder (PTSD). Important traumatic events include war, violent personal assault (e.g., sexual assault, and physical attack), being taken hostage or kidnapped, confinement as a prisoner of war, torture, terrorist attack, severe car accidents, and natural disasters. In childhood age sexual abuse or witnessing serious injuries or unexpected death of a beloved one are among important traumatic events.PTSD can be categorized into two types of acute and chronic PTSD: if symptoms persist for less than three months, it is termed "acute PTSD," otherwise, it is called "chronic PTSD." 60.7% of men and 51.2% of women would experience at least one potentially traumatic event in their lifetime. The lifetime prevalence of PTSD is significantly higher in women than men. Lifetime prevalence of PTSD varies from 0.3% in China to 6.1% in New Zealand. The prevalence of PTSD in crime victims are between 19% and 75%; rates as high as 80% have been reported following rape. The prevalence of PTSD among direct victims of disasters was reported to be 30%-40%; the rate in rescue workers was 10%-20%. The prevalence of PTSD among police, fire, and emergency service workers ranged from 6%-32%. An overall prevalence rate of 4% for the general population, the rate in rescue/recovery occupations ranged from 5% to 32%, with the highest rate reported in search and rescue personnel (25%), firefighters (21%), and workers with no prior training for facing disaster. War is one of the most intense stressors known to man. Armed forces have a higher prevalence of depression, anxiety disorders, alcohol abuse and PTSD. High-risk children who have been abused or experienced natural disasters may have an even higher prevalence of PTSD than adults.Female gender, previous psychiatric problem, intensity and nature of exposure to the traumatic event, and lack of social support are known risk factors for work-related PTSD. Working with severely ill patients, journalists and their families, and audiences who witness serious trauma and war at higher risk of PTSD.The intensity of trauma, pre-trauma demographic variables, neuroticism and temperament traits are the best predictors of the severity of PTSD symptoms. About 84% of those suffering from PTSD may have comorbid conditions including alcohol or drug abuse; feeling shame, despair and hopeless; physical symptoms; employment problems; divorce; and violence which make life harder. PTSD may contribute to the development of many other disorders such as anxiety disorders, major depressive disorder, substance abuse/dependency disorders, alcohol abuse/dependence, conduct disorder, and mania. It causes serious problems, thus its early diagnosis and appropriate treatment are of paramount importance. PMID- 23022846 TI - The prevalence of allergic contact sensitization of practicing and student nurses. AB - BACKGROUND: Contact dermatitis (CD) is a significant problem among nurses. Although there are reports about the prevalence of CD from different parts of the world, data about its frequency in Turkey and about allergic contact sensitization among nurses is insufficient. OBJECTIVE: To define the frequency and patterns of allergic contact sensitization and related symptoms in practicing and student nurses. METHODS: There were 123 nurses in our hospital practicing in the in-patient clinics. All were invited to participate in the study. 69 working in nurses and 79 student nurses participated in the study. The main reason for refusal of nurses was that they were usually having a shower daily after a hard working day and they had to postpone having a bath for 3 days if they had a patch test on their back. A ready-to-use patch test system (TRUE test(R)) with 29 standardized test substances was applied to all of the participants. History about symptoms of CD and allergic diseases was investigated by questionnaire. RESULTS: While 34.8% (24/69) of practicing nurses had symptoms of CD, 19% (15/79) of student nurses reported the symptoms (p = 0.039). The most prevalent positive reaction was to nickel sulfate followed by thimerosal. There was no difference for positive reaction rates between practicing and student nurses. Nurses who had symptoms of CD were older than those without symptoms (p = 0.003). The participants with symptoms of CD were more frequently from practicing nurses (p = 0.047). CONCLUSION: CD is more frequent in practicing nurses than student nurses; allergic contact sensitization is not. This may be attributed to the length of occupation that is also correlated well with the length of exposure to the occupational irritants. PMID- 23022847 TI - Ergonomic and anthropometric consideration for library furniture in an Iranian public university. AB - BACKGROUND: In our competing educational world, students spend a considerable part of their daily life, studying at library furniture. Not surprisingly, due to lack of proper anthropometric databases, these products have typically been ill fitted for the intended user populations. OBJECTIVE: To verify the optimum anthropometric match of library furniture within an academic environment, through a combined qualitative and quantitative approach. METHODS: 267 (120 female and 147 male) students, were subjected to 11 standard anthropometric measurements. In line with the measurements, subjective evaluations were also considered through detailed fitting trials on selected groups of participants. RESULTS: Combinational equations defined the unacceptable furniture dimensions according to elbow and sitting popliteal heights, mainly for smaller and taller divisions of the studied population, which were systematically comparable along with subjective and objective outcomes. In brief, if we classified studied students into "small," "medium," and "tall" groups, the design dimensions should be altered by -5.1, -2.2, and +1.6 cm for chair seat height; and by -8.3, -5.4, and +1.1 cm for table height, for each student group, respectively. CONCLUSION: The furniture size to be used by Iranian students should be changed to fit their anthropometric measures. PMID- 23022848 TI - Existence of insecticides in tap drinking surface and ground water in Dakahlyia Governorate, Egypt in 2011. AB - BACKGROUND: The environmental degradation products of pesticides may enter drinking water and result in serious health problems. OBJECTIVE: To evaluate the occurrence of insecticides in drinking surface and ground water in Dakahlyia Governorate, northern Egypt in 2011. METHODS: We studied blood samples collected from 36 consecutive patients diagnosed with pesticides poisoning and 36 tap drinking water (surface and ground). Blood and water samples were analyzed for pesticides using gas chromatography-electron captured detector (GC-ECD). In addition, blood samples were analyzed for plasma pseudo-cholinesterase level (PChE) and red blood cells acetyl cholinesterase activity (AChE). RESULTS: The results confirmed the presence of high concentrations of insecticides, including organonitrogenous and organochlorine in tap drinking surface and ground water. CONCLUSION: Drinking water contaminated with insecticides constitutes an important health concern in Dakahlyia governorate, Egypt. PMID- 23022849 TI - Reliability and validity of Persian version of World Health Organization health and work performance questionnaire in Iranian health care workers. AB - BACKGROUND: The effect of health status on productivity has widely been studied and discussed in literature. Valid and reliable tools are needed to evaluate the levels of health and productivity and provide detailed information, before any intervention is implemented. World Health Organization Health and Work Performance Questionnaire (HPQ) is a widely used instrument in estimating the workplace costs of health problems in terms of reduced job performance, sickness absence, and work-related accidents and injuries. OBJECTIVE: To assess the reliability and validity of Persian version of HPQ in Iranian health care workers. METHODS: The questionnaire was translated to Persian and back translated. 102 health care workers completed the questionnaire. Absence and sick leave data was extracted from administrative records. RESULTS: Factor analysis revealed acceptable validity for the questionnaire in part A (health). Cronbach's alpha was >0.73 for all scales of Parts B (work) and C (demographic). Questions targeting days of absence and sick-leave had acceptable correlation with administrative records (Pearson's r >0.75), while questions on total hours worked showed lower correlation. CONCLUSION: Persian version of HPQ can be considered a reliable and valid tool in Iranian health workers. PMID- 23022850 TI - Occupational exposure of petroleum depot workers to BTEX compounds. AB - BACKGROUND: Benzene, toluene, ethylbenzene and xylene (BTEX) are the most important toxic volatile compounds in the air and could be easily absorbed through the respiratory tract. In recent years, the risk of exposure to BTEX compounds, especially benzene as a carcinogen, has been considered in petroleum depot stations. OBJECTIVE: To assess the occupational exposure of petroleum depot workers in Iran to BTEX compounds. METHODS: After completing a questionnaire and assessing occupational exposure to BTEX compounds, 78 (46 exposed and 32 non exposed) depot workers were randomly selected to participate in this study. Air sampling and analysis of BTEX was conducted according to the NIOSH method No. 1501. Analysis of urinary hippuric acid, as an indicator of toluene exposure, was carried out according to NIOSH method No. 8300. Personal monitoring of the high exposure group to BTEX compounds was repeated to verify the results obtained in the first phase of the monitoring. RESULTS: Among the 9 operating groups studied, occupational exposure to benzene and toluene was higher in quality control and gasoline loading operators-the median exposure ranged from 0.16 to 1.63 ppm for benzene and 0.2 to 2.72 ppm for toluene. Median exposure of other group members to BTEX compounds was below the detection limit of analytical method (0.07, 0.06, 0.05, and 0.05 ppm, respectively). The level of toluene exposure measured showed correlation with neither post-shift urinary hippuric acid (Spearman's rho = 0.128, p = 0.982) nor with the difference between post- and pre-shift urinary hippuric acid (Spearman's rho = 0.089, p = 0.847) in depot operational workers. CONCLUSION: Gasoline loading operators are exposed to a relatively high level of benzene. PMID- 23022852 TI - Association between workplace and housing conditions and use of pesticide safety practices and personal protective equipment among North Carolina farmworkers in 2010. AB - BACKGROUND: There are inconsistencies about the effects of farmworker housing and workplace conditions and use of self-protective behavior practices and personal protective equipment (PPE). OBJECTIVE: To investigate the association between workplace and housing conditions and farmworker use of pesticide safety practices and PPE. METHODS: This study was conducted in 4 counties in North Carolina, USA, from July to October, 2010, during the agricultural growing season. Farmworkers working in agriculture aged 18 to 62 (n = 187) were administered a structured questionnaire to collect self-reported measures on housing and workplace conditions. Use of pesticide safety and PPE were examined by asking questions about wearing gloves, wearing socks, and wearing a hat. Chi-square and multiple logistic regression analyses were used for statistical analyses. RESULTS: Farmworkers reporting availability of enough hot and cold water for bathing and doing laundry were 13.6 times more likely to use pesticide safety practices (adjusted OR: 13.6, 95% CI: 1.4-135.4), whereas, those who reported that soap for handwashing was always or usually available while doing agricultural work were 7.8 times more likely to use pesticide safety practices (adjusted OR: 7.8, 95% CI: 3.3-18.5). Farmworkers that reported access to water to wash their hands with while performing agricultural work were more likely to use PPE (adjusted OR: 3.4, 95% CI: 1.3-9.2). CONCLUSION: Some migrant farmworker labor camps are not supplying acceptable housing conditions such as 1 handwashing sink per 6 people (n = 10, 5.4%). Use of pesticide safety practices and PPE is greater when farmers provide decontamination supplies. Improvement of housing and workplace conditions are crucial to increase use of pesticide safety practices and PPE. PMID- 23022853 TI - Carbon particles in airway macrophage as a surrogate marker in the early detection of lung diseases. AB - BACKGROUND: It has been shown that inhalation of carbonaceous particulate matter may impair lung function in children. OBJECTIVE: Using the carbon content of airway macrophages as a marker of individual exposure to particulate matter derived from fossil fuel, we sought direct evidence for this association. METHODS: 300 children from puffed rice industrial areas and 300 children from population living in green zone were selected randomly. Airway macrophages were obtained from healthy children through sputum induction, and the grading of ultrafine carbon particles in airway macrophages was measured. Pulmonary function was also measured by spirometry. RESULTS: Pulmonary function tests showed that in industrial area 42.6% and 20.3% of children had moderate obstructive airway disease and restrictive airway disease, respectively. In the green zone area, 7% of children had obstructive airway disease and 6% had restrictive airway disease. Evaluation of airway macrophages for ultrafine carbon particles revealed that in industrial area there were ultrafine carbon particles of grade 2 in 23% of subjects and grade 3 in 8.33% of individuals with obstructive airway disease. In the green zone area, the rates were 1.67% and 0.7%, respectively. CONCLUSION: The study provides a first evidence of the strong association between air pollution and development of airway diseases. Carbon particles in the sputum can be used as a marker for air pollution. PMID- 23022854 TI - Trapezius muscle activity in using ordinary and ergonomically designed dentistry chairs. AB - BACKGROUND: Most dentists complain of musculoskeletal disorders which can be caused by prolonged static posture, lack of suitable rest and other physical and psychological problems. OBJECTIVE: We evaluated a chair with a new ergonomic design which incorporated forward leaning chest and arm supports. METHODS: The chair was evaluated in the laboratory during task simulation and EMG analysis on 12 students and subjectively assessed by 30 professional dentists using an 18 item questionnaire. EMG activity of right and left trapezius muscles for 12 male students with no musculoskeletal disorders was measured while simulating common tasks like working on the teeth of the lower jaw. RESULTS: Normalized EMG data showed significant reduction (p<0.05) in all EMG recordings of the trapezius muscle. Dentists also unanimously preferred the ergonomically designed chair. CONCLUSION: Such ergonomically designed chairs should be introduced as early as possible in student training before bad postural habits are acquired. PMID- 23022855 TI - Cohort study on respiratory and neurological disorders among workers in a bone glue factory in Egypt. AB - BACKGROUND: Glues are strong, liquid adhesive derived from animal tissues. It has been shown that glue sniffing is associated with demyelinating polyneuropathy. The low molecular weight agents which cause occupational lung disease have generally included the isocyanates exposure to which could result in asthma among workers. Toluene is also used widely in glue and adhesive industry and households where toluene exposure and abuse can occur. OBJECTIVE: To study some respiratory and neurological disorders that may arise in workers in a bone glue factory in Queisna industrial zone, Menoufyia governorate, Egypt. METHODS: In a historical cohort study, the exposed participants (n = 50) were recruited from workers in a bone glue factory in Queisna industrial zone, Menoufyia governorate. The unexposed group was selected from workers' relatives who had never worked in glue industry. All participants completed a pre-designed questionnaire on personal and occupational histories. Pulmonary function tests as well as electromyography (EMG) were performed for all participants. Urinary hippuric acid was also measure in all participants. RESULTS: The prevalence of cough, asthmatic attacks and paresthesia were significantly higher among exposed than unexposed participants. Abnormal spirometric measurements (particularly towards obstruction), abnormal EMG and positive urinary hippuric acid were significantly more prevalent among exposed than unexposed group. CONCLUSION: Spirometry and EMG should be included in the periodic medical examination for exposed workers for early detection of respiratory and neurological disorders. Urinary hippuric acid could be a useful indicator of the nerve conduction abnormalities and should be measured periodically for these workers. PMID- 23022856 TI - Excruciating effect of formaldehyde exposure to students in gross anatomy dissection laboratory. AB - BACKGROUND: Formaldehyde is extensively used for preservation of cadavers in departments of anatomy. However, it is a noxious chemical which may cause serious health problems. OBJECTIVE: To assess the effect of exposure of medical students to formaldehyde at the Department of Anatomy, Niger Delta University, Nigeria. METHODS: In a questionnaire-based study, 93 second-year medical students were surveyed at the Department of Human Anatomy, Niger Delta University, Nigeria. The average duration of exposure for each student in the dissection hall was 6 hr/wk. Participants with history of cough, respiratory or skin diseases were excluded from the study. RESULTS: Out of 93 questionnaires distributed, 75 were completed and returned (response rate: 81%). Of 75 students, 58 (77%) were strongly affected by unpleasant smell of formaldehyde. It was followed by "runny or congested nose" and "redness of the eyes." "Skin-related diseases" was identified as the least ranked effect of formaldehyde. CONCLUSION: Due to the numerous health challenges that formaldehyde causes to students in the gross anatomy dissection laboratories, it cannot be considered as a suitable chemical for embalmment of cadaver for dissection. PMID- 23022857 TI - Well waters fluoride in Enugu, Nigeria. AB - Abnormal fluoride levels in drinking water have been associated with adverse health effects. To determine the fluoride content of well waters in Enugu, southeastern Nigeria, water samples from 50 artisan wells chosen by multistage sampling procedure from the 5 zones of Enugu municipality were analyzed in duplicates for their fluoride content. The zonal mean values were 0.60, 0.70, 0.62, 0.62, and 0.63 mg/L for Abakpa Nike, Achara Layout, Obiagu/ Ogui, Trans Ekulu and Uwani, respectively (p<0.05). The mean value for the whole city was 0.63 mg/L. Although, the mean level of fluoride recorded in this study is currently within safe limits (1.5 mg/L, WHO 2011), it is important to monitor continuously the fluoride content of well waters in the municipality in view of the increasing industrial activities going on in the city and heavy reliance on well water for domestic purposes and the widespread use of consumer products containing fluoride. PMID- 23022858 TI - Uniform terminology for a common work scheme? PMID- 23022859 TI - Noise exposure: a continuous dilemma of the industrial environments and modern world. PMID- 23022860 TI - Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Egypt: a multicenter case-control study. AB - BACKGROUND: Despite the advances in medical therapy and technology, the prognosis of idiopathic pulmonary fibrosis (IPF) remains poor and the need for disease prevention based on identifying the risk factors becomes mandatory. Occupational and environmental exposures were studied in several countries and found to play important role in the disease development. However, in Egypt, a little attention has been paid to study the effect of these factors in the disease development. OBJECTIVE: To identify the occupational and environmental risk factors associated with the development of IPF in Egypt. METHODS: A multicenter hospital-based case control study was carried out in chest hospitals affiliated to three Egyptian cities-Cairo, Tanta and Mansoura. Subjects were 201 patients with confirmed IPF (cases) and 205 age-, sex- and residence-matched controls. Data on occupational and environmental factors were obtained from a questionnaire. Multiple logistic regression analysis was used to determine the independent risk factors of IPF in both sexes for single factors with adjustment for age, residence and smoking status. RESULTS: Compared with the controls, the risk of IPF in male workers was observed to increase significantly in chemical and petrochemical industries and carpentry and wood working (OR = 2.56, 95% CI: 1.02-7.01), and with occupational exposures to wood dust and wood preservatives. Among female workers, a significant increase was observed in farming (OR = 3.34, 95% CI: 1.17-10.12), raising birds and occupational exposures to animal feeds, products and dusts and pesticides. Risk of IPF decreased significantly in male workers and insignificantly among female workers in sales and clerical related activities. The environmental exposures to birds and cats were significantly associated with elevated risk of IPF development in both sexes. CONCLUSION: In Egypt, farming, raising birds and wood working are important risk factors for the development of IPF. PMID- 23022861 TI - Occupational exposure of gasoline station workers to BTEX compounds in Bangkok, Thailand. AB - BACKGROUND: Gasoline station workers are exposed to volatile organic compounds such as benzene, toluene, ethylbenzene and xylene (BTEX). OBJECTIVE: To determine the level of exposure to BTEX compounds among gasoline station workers and measure the roadside concentrations of these compounds in the inner and outer areas of Bangkok, Thailand. METHODS: 49 workers at 6 gasoline stations in the inner and outer areas of Bangkok participated in this study. Samples of ambient air were collected from the area near gas pumps at each station and at the roadside in front of the gas stations by charcoal tubes. All samples were analyzed for BTEX compounds by gas chromatography-flame ionized detector (GC FID). RESULTS: The mean BTEX concentration in gas stations was slightly higher than that of the roadside; there was no significant difference in the concentration between inner and outer areas. The mean lifetime cancer risks for workers exposed to benzene and ethylbenzene for 30 years were estimated at 1.75*10-4 and 9.55*10-7. The estimated hazard quotients for BTEX compounds were 0.600, 0.008, 0.007 and 0.002, respectively. The most prevalent symptoms of workers were headache (61%), fatigue (29%) and throat irritation (11%), respectively. Exposure to benzene and toluene was significantly associated with fatigue (p<0.05). CONCLUSION: Exposure to BTEX compounds would increase the risk of cancer in gasoline station workers. Exposure to benzene and toluene may cause fatigue. PMID- 23022862 TI - Novel design of a usable and accurate anthropometric caliper. AB - BACKGROUND: Anthropometric kits are extensively used in workstation and product design projects, and with the advancement of technology, they have turned into highly complex and effective instruments. However, there are still many challenging problems in usability and reliability of application of these kits in real-world settings. OBJECTIVE: To identify the usability and accuracy issues with a conventional anthropometric caliper, and to propose measurable design features to enhance the functionality of the caliper. METHODS: The measurement process using a conventional anthropometric caliper was systematically analyzed through detailed hierarchical task analyses. Also, six qualified anthropometry specialists performed heuristic evaluations to gain valuable insights into major usability issues in relation to the existing body measurement devices. Based on the resulting concepts, a mock-up was developed and evaluated against the desired specifications. RESULTS: Incorrect positioning angle of the caliper, as well as applying various amounts of force by different investigators to push the caliper branches against body parts, appeared to be the main factors introducing inaccuracy to anthropometric data. Installing a spirit level on caliper, and also a pre-programmed microprocessor for real-time saving of the obtained data, facilitated the measurement process for both investigators and subjects. CONCLUSION: Accuracy, followed by usability is the primary concern in designing anthropometric instruments. However, expectations would vary from one specialist to another. Therefore, trade-offs should be made when incorporating innovative features in novel designed body measurement kits. PMID- 23022863 TI - Vestibular symptoms in factory workers subjected to noise for a long period. AB - BACKGROUND: Noise can cause permanent or temporary hearing loss. High levels of noise may stimulate the vestibular system and thereby cause disturbances in the balancing mechanism. OBJECTIVE: To determine the effect of long-term exposure to occupational noise on the vestibular system. METHODS: A dizziness questionnaire was administered to 20 factory workers who were exposed to occupational noise for more than 10 years. The results were compared with 2 control groups. The control group 1 consisted of 20 people who had similar physical activity during work but were not exposed to high level of noise. Control group 2 consisted of 20 students never exposed to hazardous noise. RESULTS: There was significant difference between the experimental group and the 2 control groups in terms of frequency of vestibular symptoms. However, most of the symptoms were subtle in nature. Tinnitus was significantly (p<0.05) more frequent in the experimental group than the 2 control groups. CONCLUSION: Long-term exposure to noise may cause vestibular symptoms before clinically detectable hearing loss. The symptoms are subtle for which they are mostly neglected; the symptoms do not affect the functional ability of workers. PMID- 23022864 TI - Temporary and permanent level shifts in distortion product otoacoustic emissions following noise exposure in an animal model. AB - BACKGROUND: Noise-induced hearing loss (NIHL) is one of the most common occupational illnesses. Most of the studies on NIHL were conducted at high noise levels that people are rarely exposed to but in industries. The function of the outer hair cells (OHCs) is impaired after exposure to industrial noise. Distortion product otoacoustic emissions (DPOAEs) are useful in examination of noise-induced level shifts. OBJECTIVE: To assess the function of OHCs by DPOAE temporary and permanent level shifts (TLSdp and PLSdp) in rabbits exposed to white noise at realistic levels typically found in industrial settings over a broad range of frequencies. METHODS: 12 albino rabbits were divided into two groups: the experimental group rabbits which were exposed to 95 dB SPL white noise at 500-8000 Hz for 8 hrs/day for 5 consecutive days, and the control group rabbits with no exposure to noise. The function of OHCs was examined by DPOAE level (Ldp) in different occasions. The study groups were compared for DPOAE temporary and permanent level shifts (TLSdp and PLSdp) to assess the effect of noise on OHCs function. RESULTS: Noise-induced DPOAE levels (Ldp) were decreased up to 20.65 dB (on day 8) and 18.93 dB (on day 11) at 5888.50 Hz (p = 0.081). TLSdp and PLSdp were significantly decreased up to 17.99 dB and 16.27 dB, respectively in the experimental group. The most and least Ldp were significantly different (p<0.05); they occurred at 5888.50 and 588.00 Hz, respectively. There were significant differences between temporary and permanent threshold shift at various frequencies (p<0.05). These differences were mainly related to 5888.50 Hz compared to other frequencies in each ear (p<0.05). CONCLUSION: DPOAEs are an attractive tool for obtaining information about small temporary or permanent threshold shifts, even when the pure tone audiogram is normal. PMID- 23022866 TI - The palm wine trade: occupational and health hazards. AB - The palm wine trade is an important economic activity for many tropical rural areas worldwide. In West Africa, palm wine holds high sociocultural and traditional values. Wine tappers often climb very tall trees with rudimentary equipment to harvest palm sap and risk severe injuries in the event of a fall. Furthermore, the wine quickly ferments beyond the desired taste and alcohol content, reducing the market power of these tappers. Therefore, to maximize benefits or to enhance shelf life, a variety of components are added to the palm tree sap, introducing the possibility of deadly contaminants. This paper highlights the public health implications of uncontrolled palm wine production and the relative neglect of the wine tapper. We draw from the limited published literature and use Cameroon as a case study. The palm wine trade can be more productive and safe if tappers work in cooperatives to improve their market power. Public health authorities need to monitor the quality of this cheap and common source of alcohol and enact regulations to protect wine tappers from the current level of occupational hazards. There are varying levels of progress to control quality and ensure safety in different parts of the world. Legislation and collaboration with traditional structures may offer a framework for change. PMID- 23022867 TI - Exposure to outdoor air pollution and chronic bronchitis in adults: a case control study. AB - BACKGROUND: Although Lebanon is a highly polluted country, so far no study has specifically been designed to assess the association between outdoor air pollution and chronic bronchitis in this country. OBJECTIVE: To assess the association between exposure to outdoor air pollution and chronic bronchitis in Lebanon. METHODS: A pilot case-control study was conducted in two tertiary care hospitals. Cases consisted of patients diagnosed with chronic bronchitis by a pulmonologist and those epidemiologically confirmed. Controls included individuals free of any respiratory signs or symptoms. After obtaining informed consent, a standardized questionnaire was administered. RESULTS: Bivariate, stratified (over smoking status and gender) and multivariate analyses revealed that passive smoking at home (ORa: 2.56, 95% CI: 1.73-3.80) and at work (ORa: 1.89, 95% CI: 1.13-3.17); older age (ORa: 1.75, 95% CI: 1.55-2.39); lower education (ORa: 1.44, 95% CI: 1.21-1.72); living close to a busy road (ORa: 1.95, 95% CI: 1.31-2.89) and to a local power plant (ORa: 1.62, 95% CI: 1.07-2.45); and heating home by hot air conditioning (ORa: 1.85, 95% CI: 1.00-3.43) were moderately associated with chronic bronchitis; an inverse association was found with heating home electrically (ORa: 0.58, 95% CI: 0.39-0.85). A positive dose effect relationship was observed in those living close to a busy road and to a local diesel exhaust source. CONCLUSION: Chronic bronchitis is associated with outdoor air pollution. PMID- 23022868 TI - Pulmonary problems among quarry workers of stone crushing industrial site at Umuoghara, Ebonyi State, Nigeria. AB - BACKGROUND: Respiratory problem is one of the major health hazards in dust exposed workers; it is a major cause of morbidity and mortality all over the world. OBJECTIVE: To determine the prevalence of respiratory problems and lung function impairment among quarry workers in Ebonyi State, Nigeria. METHODS: Respiratory problems and lung function were studied in 403 quarry workers aged 10 60 years. Respiratory problems were investigated with a questionnaire based on international models adapted for the study population. Lung function was assessed by spirometry and chest roentgenography. RESULTS: The respiratory problems found were chest pain (47.6%), occasional cough (40.7%), occasional shortness of breath (6.5%) and wheezing (5.2%). The mean+/-SD FEV1 and FVC values were significantly decreased with length of exposure-respectively, 3.52+/-0.77 and 3.91+/-0.72 L for <5 years; 2.79+/-0.68 and 3.09+/-0.87 L for 5-10 years; and 2.03+/-0.92 and 2.86+/-0.83 L for >10 years of exposure. Moreover, the mean+/-SD FEV1 and FVC values of smoker (3.37+/-0.81 and 3.56+/-1.02 L, respectively) were significantly (p<0.05) lower than that of non-smokers (3.68+/-1.02 and 3.89+/-0.99 L, respectively) working in the quarry site. CONCLUSION: Chronic exposure to dust due to stone quarrying may increase the risk of respiratory problems and impaired lung function-cigarette smokers are at higher risk. PMID- 23022869 TI - Environmental lead exposure among primary school children in Shebin El-Kom District, Menoufiya Governorate, Egypt. AB - BACKGROUND: Lead still remains an important problem for poor, inner-city, ethnic minority children, with a particular emphasis on lead paint and dust. In Egypt, there is no national survey about the prevalence of elevated blood lead level among children. OBJECTIVE: To assess the environmental lead level as well as to determine blood lead level among primary school children and find out its relationship with their intelligent quotient (IQ), hemoglobin level, hearing impairment and school performance. METHODS: 190 primary school children from rural and urban areas were selected and their blood lead levels (BLL), hemoglobin concentrations, IQ, hearing threshold and school performance were measured. Also, environmental lead level was measured in the school and home. RESULTS: The mean value of environmental lead (MUg/m3) in urban schools air was significantly higher than that in rural areas. BLL had a significant negative correlation with hemoglobin level and IQ; it was positively correlated with the hearing threshold. With increasing BLL, the school performance of children decreased significantly. CONCLUSION: Exposure to lead would deteriorate IQ, school performance and hearing level of school children. Even in the absence of overt clinical manifestations of lead toxicity, lead intoxication should be among differential diagnosis in children presenting anemia, intellectual impairment, poor academic performance and hearing impairment. PMID- 23022870 TI - Immune functions of the garment workers. AB - BACKGROUND: Occupational exposure to cotton dust, fibers, metal fumes and different chemicals used in the aparrel manufacturing industries cause a wide range of physical and psychological health problems in the garment workers that may also affect their immune function. OBJECTIVE: To assess the immune system function in garment workers. METHODS: A total of 45 workers of a garment factory, and 41 control subjects, not exposed to the garment working environment were enrolled in this study. In the study subjects, the complement system function was assessed as bactericidal activity on Escherichia coli DH5alpha cells using the standard plate count method. Serum complement components C3 and C4 were measured by immunoprecipitation, and IgG was measured by immunonephelometry. RESULTS: The bactericidal activity of serum complement in the garment workers (range: 93.5% 99.9%) was significantly (p<0.01) lower than that in the controls (range: 98.6% 100%). The heat-inactivated serum of the workers showed a significantly enhanced bactericidal activity. In the garment workers, the mean levels of complement C3, and C4 were 1.75 and 0.26 g/L, respectively that were close to those of the controls. The mean IgG level in the garment workers was 13.5 g/L that was significantly (p<0.001) higher than that in the controls. CONCLUSION: Working in a garment factory may affect the immune system. PMID- 23022871 TI - Fluoride concentration in potable groundwater in rural areas of Khaf city, Razavi Khorasan Province, northeastern Iran. AB - Long-term exposure to high concentrations of fluoride is associated with several adverse effects on human including dental and skeletal fluorosis. We studied all the groundwater wells located in rural areas of Khaf city, Razavi Province, northeastern Iran between 2009 and 2010. Fluoride concentration of water samples was measured by SPADNS method. We found that in rural areas the fluoride concentration ranged from 0.11 to 3.59 ppm-the level was less than the permissible limit in 31% of studied samples, higher than the permissible limit in 4% of the samples, and within the optimum limit of 1 to 1.5 ppm in 65% of water samples. PMID- 23022872 TI - Bacterial contamination of Indian currency notes (Rupee). PMID- 23022873 TI - In vitro susceptibility of thioredoxins and glutathione to redox modification and aging-related changes in skeletal muscle. AB - Thioredoxins (Trx's) regulate redox signaling and are localized to various cellular compartments. Specific redox-regulated pathways for adaptation of skeletal muscle to contractions are attenuated during aging, but little is known about the roles of Trx's in regulating these pathways. This study investigated the susceptibility of Trx1 and Trx2 in skeletal muscle to oxidation and reduction in vitro and the effects of aging and contractions on Trx1, Trx2, and thioredoxin reductase (TrxR) 1 and 2 contents and nuclear and cytosolic Trx1 and mitochondrial Trx2 redox potentials in vivo. The proportions of cytosolic and nuclear Trx1 and mitochondrial Trx2 in the oxidized or reduced forms were analyzed using redox Western blotting. In myotubes, the mean redox potentials were nuclear Trx1, -251 mV; cytosolic Trx1, -242mV; mitochondrial Trx2, -346mV, data supporting the occurrence of differing redox potentials between cell compartments. Exogenous treatment of myoblasts and myotubes with hydrogen peroxide or dithiothreitol modified glutathione redox status and nuclear and cytosolic Trx1, but mitochondrial Trx2 was unchanged. Tibialis anterior muscles from young and old mice were exposed to isometric muscle contractions in vivo. Aging increased muscle contents of Trx1, Trx2, and TrxR2, but neither aging nor endogenous ROS generated during contractions modified Trx redox potentials, although oxidation of glutathione and other thiols occurred. We conclude that glutathione redox couples in skeletal muscle are more susceptible to oxidation than Trx and that Trx proteins are upregulated during aging, but do not appear to modulate redox-regulated adaptations to contractions that fail during aging. PMID- 23022875 TI - Characterizing the PM2.5-related health benefits of emission reductions for 17 industrial, area and mobile emission sectors across the U.S. AB - BACKGROUND: Air pollution benefits assessments tend to be time and resource intensive. Reduced-form approaches offer computational efficiency, but may introduce uncertainty. Some reduced-form approaches apply simplified air quality models, which may not capture the complex non-linear chemistry governing the formation of certain pollutants such as PM2.5. Other approaches apply the results of sophisticated photochemical modeling, but characterize only a small number of source types in a limited geographic area. METHODS: We apply CAMx source apportionment photochemical modeling, coupled with a PC-based human health benefits software program, to develop a suite of PM2.5 benefit per ton estimates. These per-ton estimates relate emission changes to health impacts and monetized benefits for 17 sectors across the continental U.S., including Electricity Generating Units (EGU), mobile, area and industrial point sources. RESULTS: The benefit per ton of reducing directly emitted PM2.5 is about an order of magnitude larger than reducing emissions of PM2.5 precursor emissions. On a per-ton basis, the value of reducing directly emitted PM2.5 and PM2.5 precursors in 2005 ranges between approximately $1300 (2010$) for reducing a ton of NO(x) from Ocean-Going Vessels to about $450,000 (2010$) for reducing a ton of directly emitted PM2.5 from Iron and Steel facilities. The benefit per ton estimates for 2016 are generally higher than the 2005 estimates. The values estimated here are generally comparable with those generated using photochemical modeling, but larger than those calculated using simplified air quality models. CONCLUSIONS: Our approach characterizes well the per-ton benefits of reducing emissions from a broad array of 17 industrial point, EGU and mobile sectors, while our use of photochemical air quality modeling gives us greater confidence that we have accounted for the non-linear chemistry governing PM2.5 formation. The resulting benefit per-ton estimates thus represent a compromise between approaches that may simplify the treatment of PM2.5 air quality formation and those techniques that are based in photochemical modeling but account for only a small number of emission sources. PMID- 23022874 TI - High Ca2+ load promotes hydrogen peroxide generation via activation of alpha glycerophosphate dehydrogenase in brain mitochondria. AB - H(2)O(2) generation associated with alpha-glycerophosphate (alpha-GP) oxidation was addressed in guinea pig brain mitochondria challenged with high Ca(2+) load (10 MUM). Exposure to 10 MUM Ca(2+) induced an abrupt 2.5-fold increase in H(2)O(2) release compared to that measured in the presence of a physiological cytosolic Ca(2+) concentration (100 nM) from mitochondria respiring on 5 mM alpha GP in the presence of ADP (2 mM). The Ca(2+)-induced stimulation of H(2)O(2) generation was reversible and unaltered by the uniporter blocker Ru 360, indicating that it did not require Ca(2+) uptake into mitochondria. Enhanced H(2)O(2) generation by Ca(2+) was also observed in the absence of ADP when mitochondria exhibited permeability transition pore opening with a decrease in the NAD(P)H level, dissipation of membrane potential, and mitochondrial swelling. Furthermore, mitochondria treated with the pore-forming peptide alamethicin also responded with an elevated H(2)O(2) generation to a challenge with 10 MUM Ca(2+). Ca(2+)-induced promotion of H(2)O(2) formation was further enhanced by the complex III inhibitor myxothiazol. With 20 mM alpha-GP concentration, stimulation of H(2)O(2) formation by Ca(2+) was detected only in the presence, not in the absence, of ADP. It is concluded that alpha-glycerophosphate dehydrogenase, which is accessible to and could be activated by a rise in the level of cytosolic Ca(2+), makes a major contribution to Ca(2+)-stimulated H(2)O(2) generation. This work highlights a unique high-Ca(2+)-stimulated reactive oxygen species-forming mechanism in association with oxidation of alpha-GP, which is largely independent of the bioenergetic state and can proceed even in damaged, functionally incompetent mitochondria. PMID- 23022876 TI - In situ doxorubicin-CaP shell formation on amphiphilic gelatin-iron oxide core as a multifunctional drug delivery system with improved cytocompatibility, pH responsive drug release and MR imaging. AB - An amphiphilic gelatin-iron oxide core/calcium phosphate shell (AGIO@CaP-DOX) nanoparticle was successfully synthesized as an efficient anti-cancer drug delivery system, where doxorubicin (DOX) as a model molecule was encapsulated by electrolytic co-deposition during CaP shell formation. The shell of CaP precipitate played a pivotal role, not only in acting as a drug depot, but also in rendering the drug release rate in a highly pH-dependent controlled manner. Together with MR imaging, highly biocompatible drug-carrying CaP shell and efficient cellular internalization, the AGIO@CaP-DOX nanoparticles developed in this study area promising multifunctional nanodevice for nanotherapeutic approaches. PMID- 23022878 TI - The legacy of chlorinated solvents in the Birmingham aquifer, UK: observations spanning three decades and the challenge of future urban groundwater development. AB - Licensed abstraction well data collected during 1986-2008 from a total of 77 wells mainly located at industrial sites combined with historic land use data from 1975 has allowed insight into the legacy of chlorinated solvent contamination in the Birmingham aquifer that underlies the UK's second largest city. This legacy, expected to be reasonably symptomatic of those occurring in other urban aquifers, was characterised by: dominance of parent solvents, particularly TCE (trichloroethene) that widely exceeded drinking-water quality criteria; greater TCE occurrence in wells in proximity to increased historic land use by the metal/engineering solvent-user industry (the relationship providing a first-pass indicator of future resource development potential); regional groundwater vulnerability controls; well abstraction changes (over months to decades) influential of observed concentration transients and anticipated plume capture or release; persistence of contamination over decades (with less soluble PCE (perchloroethene) showing increased persistence relative to TCE) that was reasonably ascribed to slow contaminant release from DNAPL (dense non-aqueous phase liquid) sources and, or low permeability layers; presence of dechlorination products arising from solvent (bio)degradation, although this key attenuation process appeared to have moderate to weak influence regionally on plumes; and, inadvertent, but significant solvent mass removal from the aquifer by industrial abstractions. Key challenges to realising future urban groundwater development were identified based on the observed legacy and well capture zone simulations. Despite the extensive contamination of the aquifer, it should still be possible to develop wells of high (several megalitres per day) capacity for drinking water supply (or other lower grade uses) without the requirement for solvent treatment. In those areas with higher risk of contamination, our dataset, together with application of emergent risk assessment approaches (that our dataset may serve to validate), could be used to inform potential abstractors as to whether solvent treatment is likely to be required at a particular abstraction site with time. Challenges identified that were relevant to the future development of Birmingham and urban aquifers more generally include the adequacy of groundwater quality monitoring data and uncertainties in contaminant source terms, abstraction well capture zone predictions and plume natural attenuation, in particular degradation rates. The study endorses that despite significant solvent contamination encountered, strategies can, and need, to be increasingly found to reclaim urban aquifer resources and more sustainably meet urban water demands. PMID- 23022877 TI - Suppression of centrosome duplication and amplification by deacetylases. AB - Centrosome duplication is controlled both negatively and positively by a number of proteins. The activities and stabilities of those regulatory proteins are in many cases controlled by posttranslational modifications. Although acetylation and deacetylation are highly common posttranslational modifications, their roles in the regulation of centrosome duplication had not been closely examined. Here, through focusing on the deacetylases, we investigated the role of acetylation/deacetylation in the regulation of centrosome duplication and induction of abnormal amplification of centrosomes. We found that the deacetylation event negatively controls centrosome duplication and amplification. Of the 18 total known deacetylases (HDAC1-11, SIRT1-7), ten deacetylases possess the activity to suppress centrosome amplification, and their centrosome amplification suppressing activities are strongly associated with their abilities to localize to centrosomes. Among them, HDAC1, HDAC5 and SIRT1 show the highest suppressing activities, but each of them suppresses centrosome duplication and/or amplification with its unique mechanism. PMID- 23022879 TI - [The pathomechanism of polycystic ovary syndrome in the light of recent research findings]. AB - The author summarizes the factors which play a role in the development of polycystic ovary syndrome highlighting the impact of intrauterine genetic programming and the importance of the maternal steroid environment. Environmental effects, steroid receptor modulators, endocrine disruptor compounds, and the role of obesity in the development of polycystic ovary syndrome are also discussed. PMID- 23022880 TI - [Three-dimensional speckle-tracking echocardiography -- a further step in non invasive three-dimensional cardiac imaging]. AB - Three-dimensional speckle-tracking echocardiography is a new cardiac imaging methodology, which allows three-dimensional non-invasive evaluation of the myocardial mechanics. The aim of this review is to present this new tool emphasizing its diagnostic potentials and demonstrating its limitations, as well. PMID- 23022881 TI - [Remote ischemic conditioning: short-term effects on rat liver ischemic reperfusion injury]. AB - INTRODUCTION: Several techniques have been developed to reduce ischemic reperfusion injury. A novel method is the remote ischemic perconditioning, applied parallel with target organ ischemia. AIM: The aim of the study was to determine the extent of liver ischemic-reperfusion injury via the application of this novel method. METHODS: Male Wistar rats (n = 30, 10/group) were subjected to 60-minute partial liver ischemia and 60-minute reperfusion. Rats in the perconditioned group received conditioning treatment during the last 40 minutes of liver ischemia by infrarenal aortic clamping. Hepatic and lower limb microcirculation was monitored by laser Doppler flowmeter during reperfusion. After reperfusion, liver samples were taken for routine histological examination and redox-state assessment. Serum transaminase activities and liver tissue heat shock protein-72 expression were measured. RESULTS: Parameters of microcirculation showed significant (p<0.05) improvement in the perconditioned group in comparison with the control. Besides the significant improvement observed in the serum alanine amino-transferase activities, significantly milder tissue injury was detected histologically in the liver sections of the perconditioned group. Moreover, significant improvement was found in the redox state parameters. CONCLUSION: Perconditioning may be a reasonable possibility to reduce liver ischemic-reperfusion injury. PMID- 23022882 TI - [Reflections of a clinician on the switch from human to analogue insulin treatment]. AB - The development of insulin therapy has not been stopped since the manufacturing of human insulin, because better mimic of physiological insulin response made it necessary to modify the human insulin molecule in order to create rapidly absorbing insulin analogues and 24-hour acting basal insulin analogues. Clinical observations indicate that the complete switch from human basal-bolus therapy to insulin analogues means not only "unit-for-unit" switch but it represents a transfer to an insulin therapy with different basal/bolus ratio as a result of different pharmacokinetic and pharmacodynamic properties of insulin and the level of insulin resistance of the patient. With reference to a case-history, the author presents his experience on a switch from human insulin to insulin analogue. Furthermore, the author summarizes data obtained from a few cases reported in international literature which draw the attention to the fact that the basal/bolus ratio should be adjusted individually, which may be the key for the success in the therapy in these cases. PMID- 23022883 TI - [In memory of Dr. Zoltan Bado (1935-1997)]. PMID- 23022884 TI - [Polyhistorism and macrobiotics in the history of medicine during the "reform era" in Hungary. In memory of doctor Michael Kovats]. PMID- 23022885 TI - [Letters to the Editor]. PMID- 23022887 TI - Recent advances in systemic treatments for ovarian cancer. AB - Ovarian cancer remains the leading cause of death from gynaecological cancer. Advances in surgical and chemotherapeutic strategies have led to improvements in outcome. However, the majority of women present with advanced disease with little prospect for cure. In this article, we summarize the systemic management and ovarian cancer and raise a number of important issues: namely the timing of systemic therapy in relation to surgery, the selection of patients who do not require systemic therapy and the development of novel agents. PMID- 23022888 TI - Growth velocity of extremely low birth weight preterms at a tertiary neonatal unit in South Africa. AB - INTRODUCTION: There is wide variation in the feeding practices of extreme low birth weight (ELBW) preterms often guided by tradition and resources. The feeding regimen at Groote Schuur Hospital (GSH) nursery, a tertiary neonatal unit, follows a restricted use of parenteral nutrition and concentrates on early introduction of breast milk. There is a need to determine whether this approach achieves acceptable growth velocity. OBJECTIVES: This study aims to describe the growth velocity of ELBW babies at GSH. DESIGN: This was a retrospective cohort study. METHODOLOGY: Infant hospital records of all ELBW babies born at GSH from 1 March to 31 August 2010 were accessed from a previously collected database and relevant data extracted. Growth data were collected from birth to 8 weeks postnatal age or discharge, whichever came first. RESULTS: Ninety-one ELBW babies were born during the study period. Forty were excluded from the study. Thirty died before discharge, and 10 were excluded for other reasons. The mean (SD) gestation of the cohort was 28.5 (1.6) weeks, and the median (range) birth weight was 875 (640-995) g. The overall mean (SD) growth velocity was 14 (2.9) g/kg/day. There was no statistically significant association between the growth velocity and the type of feed given, days to establishing full enteral feeds, time to regaining birth weight, HIV exposure status, intra-uterine growth restriction or exposure to antenatal steroids. CONCLUSION: In our cohort of ELBW infants, growth velocity was within the range currently deemed acceptable by international consensus. PMID- 23022889 TI - Neu5Acalpha2,6Gal and Neu5Acalpha2,3Gal receptor specificities on influenza viruses determined by a waveguide-mode sensor. AB - To characterize the differences in the receptor-binding specificities of human and avian influenza viruses with glycan chains, the authors performed binding analyses using an evanescent field-coupled waveguide-mode biosensor. The experiments were performed on intact viruses and hemagglutinin proteins, using gold-nanoparticle-conjugated Neu5Acalpha2,6Gal and Neu5Acalpha2,3Gal glycan chains. Several influenza viruses belonging to subtypes H3N2 (A/Udorn/307/1972, A/Shandong/9/1993, A/Kiev/301/1994, A/Panama/2007/1999, A/Wisconsin/67/2005 and A/Brisbane/10/2007), H1N1 (A/Brisbane/59/2007 and A/California/07/2009) and H5N1 (A/chicken/India/NIV33487/2006) were used. High levels of glycan-based discrimination were observed with the H3N2 strain A/Brisbane/10/2007 due to its specificity with Neu5Acalpha2,6Gal, but not with Neu5Acalpha2,3Gal. Possible amino acid residues responsible for the discrimination of human and avian influenza viruses are discussed. These types of sensor-based discriminatory analyses would be very useful for distinguishing between influenza pandemics, especially during the transition and overlapping periods of human and avian influenza viruses with evolutionary changes. PMID- 23022890 TI - Evaluation of an in situ chemically crosslinked hydrogel as a long-term vitreous substitute material. AB - Currently there is no material that can be used as a long-term vitreous substitute, and this remains an unmet clinical need in ophthalmology. In this study, we developed an injectable, in situ chemically crosslinked hydrogel system and evaluated it in a rabbit model. The system consisted of two components, both based on multi-functional poly(ethylene glycol) (PEG) but with complementarily reactive end groups of thiol and active vinyl groups, respectively. The two components are mixed and injected as a solution mixture, react in vivo via the Michael addition route and form a chemically crosslinked hydrogel in situ. The linkages between the end groups and the backbone PEG chains are specially designed to ensure that the final network structure is hydrolysis-resistant. In the rabbit study and with an optimized operation protocol, we demonstrated that the hydrogel indeed formed in situ after injection, and remained transparent and stable during the study period of 9 months without significant adverse reactions. In addition, the hydrogel formed in situ showed rheological properties very similar to the natural vitreous. Therefore, our study demonstrated that this in situ chemically crosslinked PEG gel system is suitable as a potential long-term vitreous substitute. PMID- 23022891 TI - Evaluation of a multi-layer adipose-derived stem cell sheet in a full-thickness wound healing model. AB - Cell sheet technology has been studied for applications such as bone, ligament and skin regeneration. There has been limited examination of adipose-derived stem cells (ASCs) for cell sheet applications. The specific aim of this study was to evaluate ASC sheet technology for wound healing. ASCs were isolated from discarded human abdominal subcutaneous adipose tissue, and ASC cell sheets were created on the surface of fibrin-grafted culture dishes. In vitro examination consisted of the histochemical characterization of the ASC sheets. In vivo experiments consisted of implanting single-layer cell sheets, triple-layer cell sheets or non-treated control onto a full-thickness wound defect (including epidermis, dermis, and subcutaneous fat) in nude mice for 3 weeks. Cell sheets were easily peeled off from the culture dishes using forceps. The single- and triple-layer ASC sheets showed complete extracellular structure via hematoxylin & eosin staining. In vivo, the injury area was measured 7, 10, 14 and 21 days post treatment to assess wound recovery. The ASC sheet-treated groups' injury area was significantly smaller than that of the non-treated control group at all time points except day 21. The triple-layer ASC sheet treatment significantly enhanced wound healing compared to the single-layer ASC sheet at 7, 10 and 14 days. The density of blood vessels showed that ASC cell sheet treatment slightly enhanced total vessel proliferation compared to the empty wound injury treatment. Our studies indicate that ASC sheets present a potentially viable matrix for full thickness defect wound healing in a mouse model. Consequently, our ASC sheet technology represents a substantial advance in developing various types of three dimensional tissues. PMID- 23022893 TI - Remote cerebellar hemorrhage in neurosurgery. AB - Remote cerebellar hemorrhage (RCH) is a rare complication in neurosurgery that remains enigmatic both in underlying mechanism and clinical behavior. The range of procedures associated with RCH is diverse and includes both supratentorial and spinal procedures that entail significant CSF loss or lesion resection. The risk factors identified in the literature are not sufficient in predicting the patients at risk of developing RCH. It thereby remains an unpredictable hazard that requires better understanding of its pathophysiology. This study is a comprehensive review of the available literature to provide an understanding of where it stands so far, and to explain an observation in the literature that may have implications for better understanding the disease. Areas of future research are also identified. PMID- 23022894 TI - An ecological approach to explain suicide by self-immolation among women in rural Iran. AB - Suicide by self-immolation, or lighting oneself on fire, is the most common method of suicide used among women in rural Iran. Understanding the underlying mechanisms that may lead women to commit suicide by self-immolation is necessary for the development of empirically-supported prevention programs. Currently, no integrative approach to the risk factors for self-immolation among women in rural areas, or the interactions between them, is available. Based in ecology theory, we review the risk factors for suicide by self-immolation and present them in terms of ecological theory in an attempt to offer an integrative approach for prevention of self-immolation among women in rural Iran. We conclude by recommending a multifaceted approach to prevention of self-immolation. PMID- 23022892 TI - Peptidylarginine deiminase and protein citrullination in prion diseases: strong evidence of neurodegeneration. AB - The post-translational citrullination (deimination) process is mediated by peptidylarginine deiminases (PADs), which convert peptidylarginine into peptidylcitrulline in the presence of high calcium concentrations. Over the past decade, PADs and protein citrullination have been commonly implicated as abnormal pathological features in neurodegeneration and inflammatory responses associated with diseases such as multiple sclerosis, Alzheimer disease and rheumatoid arthritis. Based on this evidence, we investigated the roles of PADs and citrullination in the pathogenesis of prion diseases. Prion diseases (also known as transmissible spongiform encephalopathies) are fatal neurodegenerative diseases that are pathologically well characterized as the accumulation of disease-associated misfolded prion proteins, spongiform changes, glial cell activation and neuronal loss. We previously demonstrated that the upregulation of PAD2, mainly found in reactive astrocytes of infected brains, leads to excessive citrullination, which is correlated with disease progression. Further, we demonstrated that various cytoskeletal and energy metabolism-associated proteins are particularly vulnerable to citrullination. Our recent in vivo and in vitro studies elicited altered functions of enolase as the result of citrullination; these altered functions included reduced enzyme activity, increased protease sensitivity and enhanced plasminogen-binding affinity. These findings suggest that PAD2 and citrullinated proteins may play a key role in the brain pathology of prion diseases. By extension, we believe that abnormal increases in protein citrullination may be strong evidence of neurodegeneration. PMID- 23022895 TI - Dynamic changes in serum monocyte chemoattractant protein-1, and regulated upon activation, normal T cell expressed and secreted levels in patients with minor intracerebral hemorrhage. AB - OBJECTIVE: To investigate the time expression profile of serum monocyte chemoattractant protein (MCP)-1, and regulated upon activation, normal T cell expressed and secreted (RANTES) after minor intracerebral hemorrhage (ICH). METHODS: This study was carried out in the Department of Neurology in the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. Fifteen consecutive hospitalized patients with minor ICH were enrolled from July 2008 to December 2008. The patients' serum levels of MCP-1 and RANTES were measured by enzyme linked immunosorbent assay (ELISA) on days 1-3, 7, 14, and 30 after the onset of ICH, and compared with that of 10 controls. RESULTS: The serum MCP-1 levels increased immediately on days 1-3 (p=0.000) after onset, and then decreased slightly on day 7 (p=0.001), and day 14 (p=0.000); after day 14, the levels continued to increase and reached their highest levels on day 30 (p=0.000). No statistical differences in MCP-1 levels were found between any time points. The RANTES levels at any time point did not differ significantly from the controls. The levels of MCP-1 and RANTES were not correlated with the serum C-reactive protein (CRP) levels, brain hematoma volumes, acute neurologic impairment, or 3 month outcome. CONCLUSION: The persistent elevation of serum MCP-1 levels after minor ICH may contribute to the acute damage and the repair following an ICH. PMID- 23022896 TI - Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer's disease. A meta-analysis. AB - OBJECTIVE: To obtain a better insight into the effect of the epsilon (e) 4 allele of the apolipoprotein E gene (APOE) on the risk of late onset Alzheimer's disease (LOAD), and assess its heterogeneity in geographic regions. METHODS: We performed a systemic review and meta-analysis of available studies. An electronic and manual search of international and local databases was conducted to identify relevant studies between January 1991 and December 2011 in the Central Library of Tabriz University of Medical Sciences, Tabriz, Iran. All articles related to patients with LOAD that evaluated APOE genotype were included in our study. Two reviewers assessed the inclusion/exclusion criteria, summarized, and analyzed the extracted data. We assessed 21 separate studies overall involving 1480 subjects; the total sample size was 6777. RESULTS: According to the results, there was no heterogeneity among the included studies. The total APOE e4 allele frequency was significantly higher in AD cases compared with control subjects (35% versus 11.43%, p<0.001). The odds ratio (OR) for APOE e4 frequency in AD and control groups was 3.98 (95% confidence interval [CI]: 3.44-4.61). This factor in various geographic regions was different. CONCLUSION: This meta-analysis is strongly supportive of the hypothesis that the APOE e4 allele increases the risk of sporadic LOAD, and determination of the e4 allele in populations may be a useful tool for monitoring demented patients and planning healthcare policies. PMID- 23022897 TI - Evaluation of plasma levels of adrenomedullin and ghrelin, and their correlation with electrophysiological changes in diabetic neuropathy. AB - OBJECTIVE: To evaluate plasma levels of adrenomedullin (AM) and ghrelin and their correlation with the electrophysiological changes in diabetic neuropathy. METHODS: The current study was conducted from March 2008 to November 2010 at the Clinical Physiology Department, King Abdulaziz University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia on 90 females divided into 30 controls (group I), 30 controlled diabetic patients (group II), and 30 with peripheral neuropathy (group III). All electrophysiological and biochemical measurements of AM and ghrelin were investigated. RESULTS: There was a significant decrease of motor and sensory nerve conduction velocity and prolongation of F wave response of median, ulnar, peroneal, and sural nerves in diabetic patients with neuropathy. Ankle/brachial index (A/BI) showed insignificant change in all groups compared with the control group. There was significant decrease of plasma levels of AM and ghrelin in group III compared with group I. The results revealed that AM and ghrelin were positively correlated with peripheral nerves motor and sensory conduction velocities. CONCLUSION: The altered concentration of AM and ghrelin in diabetic neuropathy could indicate a pathophysiological role. The decline of plasma levels of AM and ghrelin in diabetic neuropathy may be a causative factor, they have neuroprotective and vasculoprotective effects, so their lack could induce neuronal injury and advancement of neuropathy, but the precise role of AM and ghrelin in the pathogenesis of diabetic neuropathy is still to be elucidated. PMID- 23022898 TI - Morphology and clinical significance of the distribution of the median nerve within the arm of human cadavers. AB - OBJECTIVE: To describe the patterns of formation, level of beginning, variations of course, and relation of the median nerve within the arm of human cadavers. METHODS: Sixty upper limbs of 20 male and 10 female adult human cadavers were used in this study. The cadavers were obtained from the Anatomy Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia, and the study was conducted between February and December 2011. The axillary regions, arm, and forearm, of each limb were dissected to clarify the different patterns of median nerve formation and distribution within the arm. RESULTS: The formation of the median nerve from 2 roots was found in 88.3% of upper limbs, while in 11.7% of upper limbs, it had 3 roots. Moreover, the median nerve began at the level of the third part of the axillary artery in 93.3% of upper limbs, and at the coracobrachialis muscle insertion in 6.7% of upper limbs. However, in correlation to the brachial artery, the median nerve had 6 patterns of relationship. The median nerve passed deep to the coracobrachialis and brachialis muscles in 8.3% of upper limbs. Meanwhile, the median nerve supplied the front arm muscles in 3.3% of upper limbs where the musculocutaneous nerve was absent. In 13.3% of upper limbs, the musculocutaneous nerve gave a communicating branch to the median nerve. CONCLUSION: Knowledge of such variants of the median nerve helps clinicians and surgeons in the diagnosis of unexplained clinical cases. PMID- 23022899 TI - Prevalence of the foramen arcuale of the atlas in a Saudi population. AB - OBJECTIVE: To describe the prevalence and morphologic characteristics of the foramen arcuale of the atlas vertebra in the Saudi population and propose a simplified classification system. METHODS: A cross-sectional hospital-based study was conducted at King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia from September 2010 to February 2011. During the 6-month period, 453 CT studies of the cervical spine were evaluated for the presence of different degrees of this anatomic variant using a clinically relevant classification system. RESULTS: We found 52.1% (236 patients) to have no degree of osseous bridging, 31.8% (144 patients) had some degree of incomplete posterior osseous bridging, and 16.1% had the complete form of the foramen arcuale. The anomaly showed a male predilection that only reached statistic significance for those on the left side (p=0.016). Patients with a well-developed variant were older than those without the anomaly, but only by 7.46 years (p=0.034). These anomalies showed a propensity for bilaterality, which is a source for concern (kappa=0.592, approximate significance=0.00). CONCLUSION: Compared to data from other countries, this anomaly has a higher prevalence in our population, indicating that further investigations are needed. PMID- 23022900 TI - Prevalence and prediction of abnormal CT scan in pediatric patients presenting with a first seizure. AB - OBJECTIVE: To estimate the prevalence of abnormal neuroimaging in children presenting to the emergency department (ED) with a new-onset seizure, and to identify the significant clinical predictors for an abnormal CT scan. METHODS: In this cross-sectional study, all children age 12 or younger, admitted to the ED at King Abdulaziz Medical City (KAMC) in Riyadh, Kingdom of Saudi Arabia, between January 2005 and December 2010, with a first seizure clinically suspected of neurological condition, and a CT scan before discharge from the ED (N=124), were identified through a chart review. The charts for all patients with abnormal neuroimaging were reviewed for patient characteristics, seizure characteristics, and neuroimaging results. A logistic regression analysis was used to identify the independent predictors of an abnormal CT scan. Statistical significance was calculated at a p-value of <= = 0.05. RESULTS: Abnormal CT results were found in 53/124 patients (42.7%). These were significantly associated with the presence of a lesional CNS disorder (x2 =16.1, p<0.01), developmental delays (Fisher exact test, p<0.01), generalized seizure (x2 =4.17, p=0.04), and the presence of new focal neurological findings (x2 = 21.70, p<0.01). However, after applying a logistic regression analysis to adjust for different confounders, only developmental delay (odds ratio [OR]=4.79, p=0.01) and focal neurological findings (OR=7.85, p=0.006) significantly predicted an abnormal CT scan. CONCLUSION: This study demonstrates a high prevalence of abnormalities identified on the CT scans of children who presented with their first apparent seizure. An emergency CT may be considered in children presenting with their first seizure. PMID- 23022901 TI - Prevalence of risk factors of ischemic stroke in a local Pakistani population. High-density lipoproteins, an emerging risk factor. AB - OBJECTIVE: To ascertain the prevalence of risk factors for ischemic stroke in Pakistani patients at Shifa International Hospital (SIH), Islamabad, Pakistan. METHODS: This retrospective cross-sectional study included patients of either gender, with no age limit admitted to the Department of Neurology at Shifa International Hospital, Islamabad, Pakistan, with the diagnosis of stroke verified by brain CT scan during a period of 2 years from January 2007 to December 2009. The data were analyzed by grouping our patients according to their age based on the frequency of risk factors. Group 1; 25-55 years (23.8%), group 2; 56-71 years (43.4%), and group 3; 72-103 years (32.7%). RESULTS: A total of 418 patients were included in the study; 137 patients were excluded due to incomplete information. The data from the remaining 281 were analyzed. The mean age of the population was 65 +/- 0.8 years, and the male to female ratio was 1.30:1. The most frequent risk factors included hypertension 86.8% followed by diabetes mellitus 59.8%, dyslipidemia 59.1%, and smoking 18.1%. The highest frequency of 4 risk factors was present in the age group 56-71. Gender distribution of risk factors showed that hypertension and dyslipidemia are major risk factors in group 1. Abnormal high-density lipoproteins (HDL) emerged as the major lipid among 3 groups, especially in group 1, which predisposed to stroke. CONCLUSION: A decrease in HDL and control of blood pressure is important to reduce the risk of stroke especially in early age (namely, >= 25 years) and could become an increasingly useful tool to identify patients at a high risk of stroke. PMID- 23022902 TI - The use of transcranial Doppler pulsatility index to guide hyperosmolar therapy. AB - Management of intracranial hypertension is a major cornerstone of neurocritical care. Apart from traumatic brain injury, there are no clear guidelines for intracranial pressure (ICP) monitoring. The insertion of ICP monitors is an invasive procedure with inherent risks and could be contraindicated in case of severe coagulopathy. The transcranial Doppler (TCD) pulsatility index (PI) has emerged as a surrogate marker for ICP. This is a technical report with illustrative cases on the use of PI in the management of high ICP, as a guide for optimal dosing of hyperosmolar agents we use in our institution. The use of TCD PI is a useful adjunct to guide the use of hyperosmolar therapy in various conditions with raised intracranial hypertension. We will discuss the combination of the PI determination with an anatomical evaluation of the optic nerve diameter to eliminate confounding factors in PI determination. PMID- 23022903 TI - An early successful surgical treatment of fibrinolysis-related symptomatic intracerebral hemorrhage without procoagulant therapy. AB - Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is clinically effective at treating acute ischemic stroke. However, the use of thrombolytic therapy is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH). Whether unacceptable surgical hemorrhage occurs after emergent decompressive craniotomy during the first hours for sICH remains unknown. We report a 69-year-old Chinese woman with a fibrinolysis-related sICH, and discuss the efficacy and the safety of craniotomy in this setting. An urgent decompressive craniotomy was performed through a standard pterional approach without any procoagulant therapy before operation. No unacceptable surgical hemorrhage occurred during the first hours after onset of sICH, and the outcome of this patient is fairly good. Early urgent decompressive craniectomy in the treatment of fibrinolysis-related sICH may be a safe therapy, which may improve clinical outcomes. PMID- 23022904 TI - A case of extreme prematurity and delayed diagnosis of pyridoxine-dependent epilepsy. AB - Pyridoxine-dependent epilepsy presents early in life, even in utero. It is usually refractory to conventional antiepileptic medications and responds only to lifelong pyridoxine supplementation. Seizures are usually generalized tonic clonic. We report a 3-year-old child that was born prematurely at 25 weeks of gestation. He presented with abnormal movements in the second month of life. At 10 months of age he presented with status epilepticus, which was refractory to multiple antiepileptic medications and was controlled with intravenous pyridoxine. An elevated level of a-aminoadipic semialdehyde excretion in the urine supported the diagnosis of pyridoxine-dependent epilepsy. Subsequently, a c.1195G>C homozygous mutation in the 5q31 aldehyde dehydrogenase 7A1 gene was confirmed. This case calls for considering pyridoxine-dependent epilepsy and its early management in cases with resistant seizures; even in the presence of extreme prematurity with its neurological consequences. PMID- 23022905 TI - Isolated inferior sagittal sinus thrombosis caused by a rare combination of elevated lipoprotein (a) and iron deficiency anemia. AB - A 21-year-old woman was admitted with right hemiparesis, bilateral papilledema, negative myoclonus of right upper extremity, and bilateral pyramidal findings. An MRI showed no venous flow in the inferior sagittal sinus. Lipoprotein a (Lp [a]) level was high and iron deficiency anemia (IDA) was found. The coexistence of IDA and Lp (a) in patients with cerebral venous thrombosis is a very rare condition in adult patients. These risk factors should be investigated in patients with cerebral venous thrombosis. PMID- 23022906 TI - Contrast-induced encephalopathy following coronary angioplasty with iopromide. PMID- 23022907 TI - A young lady with thalamic stroke mimicking acute Miller Fisher syndrome. PMID- 23022908 TI - Parental age. Risk of autistic disorder. PMID- 23022909 TI - Thioctacid is effective for neuropathy symptoms and hyperglycemia control without pronounced electromyographic changes. PMID- 23022910 TI - The role of anemia in first simple febrile seizure in children aged 6 months to 5 years old. PMID- 23022911 TI - An infant with an unusual cause of lethargy. PMID- 23022912 TI - A comprehensive toolbox for the rapid construction of lacZ fusion reporters. AB - beta-Galactosidase encoded by lacZ remains a popular reporter enzyme. Here, we present three fast and convenient tools that facilitate rapid construction of reporter lacZ fusions. The first enables the simple generation of lacZ (slacZ) based chromosomally encoded reporter fusions within the lac operon in Escherichia coli using Red(r)/ET(r) recombination. The slacZ tool is based on rpsL counter selection in combination with homologous recombination catalyzed by the lambda Red recombinase, and blue/white screening. This permits construction of transcriptional and translational reporter lacZ fusions within a day. The second tool allows the introduction of lacZ reporter fusions into the chromosome by a single-crossover method. The strategy relies on the gamma-origin-based suicide vector pNPTS138-R6KT, which can only replicate in lambdapir E. coli strains. The third tool comprises four pBBR1-based broad-host-range vectors for transcriptional and translational lacZ fusions. The functionality of our toolbox was confirmed by the K(+)-dependent activation of kdp promoter-lacZ fusions in vivo. PMID- 23022913 TI - Upregulation of alpha-synuclein during localized radiation therapy signals the association of cancer-related fatigue with the activation of inflammatory and neuroprotective pathways. AB - PURPOSE: Neuroinflammatory mechanisms are associated with fatigue in neurodegenerative conditions such as Parkinson's. The symptoms in Parkinson's including fatigue are thought to be related to alpha-synuclein overexpression. This study investigated genomic correlates of fatigue experienced by men with prostate cancer receiving external beam radiation therapy (EBRT). PATIENTS AND METHODS: Sixteen men with non-metastatic prostate cancer who were scheduled to receive EBRT were enrolled. Fatigue scores and blood were obtained at baseline (prior to EBRT, D0); one hour following initiation of EBRT (D1), day 7 (D7), day 14 (D14), midpoint (days 19-21, D21), completion (days 38-42, D42), and four weeks post-EBRT (days 68-72, D72). Gene expression profiling using microarray analysis was performed from peripheral blood and confirmatory qPCR and protein (ELISA) analyses verified the microarray results. Correlations between fatigue and gene/protein expressions were determined using a mixed model approach. RESULTS: Microarray data showed significant, differential expression of 463 probesets following EBRT. SNCA had a 2.95-fold change at D21 from baseline. SNCA expression was confirmed by qPCR (p<0.001) and ELISA (p<0.001) over time during EBRT. Fatigue scores were significantly correlated with SNCA gene expression on D14 (r=0.55, p<0.05) and plasma alpha-synuclein concentrations on D42 of EBRT (r=0.54, p=0.04). CONCLUSION: Fatigue experienced during EBRT may be mediated by alpha-synuclein overexpression. Alpha-synuclein may serve as a useful biomarker to understand the mechanisms and pathways related to the development of fatigue in this population. PMID- 23022915 TI - High serum total homocysteine levels accelerate hip bone loss in healthy premenopausal women and men. AB - INTRODUCTION: Despite extensive evidence demonstrating the direct, detrimental role of homocysteine on bone metabolism, the effects of serum total homocysteine (tHcy) on bone loss are still equivocal. In the present study, we performed a longitudinal study on healthy participants of various ages of both sexes in order to investigate the association between serum tHcy concentrations and annualized changes in bone mineral density (BMD). METHODS: A total of 460 Koreans >= 30 years of age received comprehensive, routine health examinations for an average period of 3 years. The BMD at proximal femur sites was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. RESULTS: After adjusting for potential confounders, the rates of bone loss at the proximal femur sites were significantly accelerated in a dose-response fashion across increasing tHcy concentrations in premenopausal women and men, but not in postmenopausal women. Consistently, compared with subjects in the lowest tHcy quartile, premenopausal women in the third and/or highest tHcy quartile and men in the highest tHcy quartile showed significantly higher rates of bone loss at all proximal femur sites (p=0.015-0.048) and at the total femur and femur neck (p=0.008-0.013), respectively. In contrast, there were no differences in terms of bone loss among the tHcy quartiles for postmenopausal women. CONCLUSION: These data provide the first clinical evidence that increased tHcy levels could be an independent risk factor for the future deterioration of bone mass in premenopausal women and men. PMID- 23022914 TI - Maternal transfer of BDE-47 to offspring and neurobehavioral development in C57BL/6J mice. AB - Polybrominated diphenyl ethers (PBDEs) are flame retardants used worldwide in a variety of commercial goods, and are now widely found in both environmental and biological samples. BDE-47 is one of the most pervasive of these PBDE congeners and therefore is of particular concern. In this study C57BL/6J mice were exposed perinatally to 0.03, 0.1 or 1mg/kg/day of BDE-47, a dose range chosen to encompass human exposure levels. Tissue levels of BDE-47 were measured in the blood, brain, fat and milk of dams and in whole fetal homogenate and blood and brain of pups on gestational day (GD) 15, and postnatal days (PNDs) 1, 10 and 21. From GD 15 to PND 1 levels of BDE-47 increased within dam tissues and then decreased from PNDs 1 to 21. Over the period of lactation levels in dam milk were comparatively high when compared to both brain and blood for all dose groups. Measurable levels of BDE-47 were found in the fetus on GD 15 confirming gestational exposure. From PNDs 1 to 21, levels of BDE-47 in pup tissue increased over the period of lactation due to the transfer of BDE-47 through milk. Behavioral tests of fine motor function and learning and memory were carried out between postnatal weeks 5-17 in order to evaluate the neurobehavioral toxicity of BDE-47. Behavioral deficits were only seen in the Barnes spatial maze where mice in the three exposure groups had longer latencies and traveled longer distances to find the escape hole when compared to vehicle control mice. These results support the conclusions that perinatal exposure to BDE-47 can have neurodevelopmental consequences, and that lactational exposure represents a significant exposure risk during development. PMID- 23022916 TI - Adaptive deep brain stimulation (aDBS) controlled by local field potential oscillations. AB - Despite their proven efficacy in treating neurological disorders, especially Parkinson's disease, deep brain stimulation (DBS) systems could be further optimized to maximize treatment benefits. In particular, because current open loop DBS strategies based on fixed stimulation settings leave the typical parkinsonian motor fluctuations and rapid symptom variations partly uncontrolled, research has for several years focused on developing novel "closed-loop" or "adaptive" DBS (aDBS) systems. aDBS consists of a simple closed-loop model designed to measure and analyze a control variable reflecting the patient's clinical condition to elaborate new stimulation settings and send them to an "intelligent" implanted stimulator. The major problem in developing an aDBS system is choosing the ideal control variable for feedback. Here we review current evidence on the advantages of neurosignal-controlled aDBS that uses local field potentials (LFPs) as a control variable, and describe the technology already available to create new aDBS systems, and the potential benefits of aDBS for patients with Parkinson's disease. PMID- 23022918 TI - The ups and downs of beta oscillations in sensorimotor cortex. AB - Since the first descriptions of sensorimotor rhythms by Berger (1929) and by Jasper and Penfield (1949), the potential role of beta oscillations (~13-30 Hz) in the brain has been intensely investigated. We start this review by showing that experimental studies in humans and monkeys have reached a consensus on the facts that sensorimotor beta power is low during movement, transiently increases after movement end (the "beta rebound") and tonically increases during object grasping. Recently, a new surge of studies exploiting more complex sensorimotor tasks including multiple events, such as instructed delay tasks, reveal novel characteristics of beta oscillatory activity. We therefore proceed by critically reviewing also this literature to understand whether modulations of beta oscillations in task epochs other than those during and after movement are consistent across studies, and whether they can be reconciled with a role for beta oscillations in sensorimotor transmission. We indeed find that there are additional processes that also strongly affect sensorimotor beta oscillations, such as visual cue anticipation and processing, fitting with the view that beta oscillations reflect heightened sensorimotor transmission beyond somatosensation. However, there are differences among studies, which may be interpreted more readily if we assume multiple processes, whose effects on the overall measured beta power overlap in time. We conclude that beta oscillations observed in sensorimotor cortex may serve large-scale communication between sensorimotor and other areas and the periphery. PMID- 23022917 TI - Improved efficacy of temporally non-regular deep brain stimulation in Parkinson's disease. AB - High frequency deep brain stimulation is an effective therapy for motor symptoms in Parkinson's disease. However, the relative clinical efficacy of regular versus non-regular temporal patterns of stimulation in Parkinson's disease remains unclear. To determine the temporal characteristics of non-regular temporal patterns of stimulation important for the treatment of Parkinson's disease, we compared the efficacy of temporally regular stimulation with four non-regular patterns of stimulation in subjects with Parkinson's disease using an alternating finger tapping task. The patterns of stimulation were also evaluated in a biophysical model of the parkinsonian basal ganglia that exhibited prominent oscillatory activity in the beta frequency range. The temporal patterns of stimulation differentially improved motor task performance. Three of the non regular patterns of stimulation improved performance of the finger tapping task more than temporally regular stimulation. In the computational model all patterns of deep brain stimulation suppressed beta band oscillatory activity, and the degree of suppression was strongly correlated with the clinical efficacy across stimulation patterns. The three non-regular patterns of stimulation that improved motor performance over regular stimulation also suppressed beta band oscillatory activity in the computational model more effectively than regular stimulation. These data demonstrate that the temporal pattern of stimulation is an important consideration for the clinical efficacy of deep brain stimulation in Parkinson's disease. Furthermore, non-regular patterns of stimulation may ameliorate motor symptoms and suppress pathological rhythmic activity in the basal ganglia more effectively than regular stimulation. Therefore, non-regular patterns of deep brain stimulation may have useful clinical and experimental applications. PMID- 23022919 TI - Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disease that affects neurons and glial cells and leads to dementia. Growing evidence shows that glial changes may precede neuronal alterations and behavioral impairment in the progression of the disease. The modulation of these changes could be addressed as a potential therapeutic strategy. Environmental enrichment has been classically associated to effects on neuronal morphology and function but less attention has been paid to the modulation of glia. We thus characterized astroglial changes in the hippocampus of adult PDAPP-J20 transgenic mice, a model of AD, exposed for 3 months to an enriched environment, from 5 to 8 months of age. Using confocal microscopy, three-dimensional reconstruction and Sholl analysis, we evaluated the morphology of two distinct populations of astrocytes: those associated to amyloid beta plaques and those that were not. We found that plaque-associated astrocytes in PDAPP-J20 mice had an increased volume and process ramification than control astrocytes. Non-plaque-associated astrocytes showed a decrease in volume and an increase in the ramification of GFAP+ processes as compared with control astrocytes. Environmental enrichment prevented these alterations and promoted a cellular morphology similar to that found in control mice. Morphological changes in non-plaque-associated astrocytes were found also at 5 months of age, before amyloid beta deposition in the hippocampus. These results suggest that glial alterations have an early onset in AD pathogenesis and that the exposure to an enriched environment is an appropriate strategy to reverse them. Cellular and molecular pathways involved in this regulation could constitute potential novel therapeutic targets. PMID- 23022920 TI - Inappropriate use of the faecal occult blood test in a university hospital in the Netherlands. AB - OBJECTIVES: Although all international guidelines state that there is no indication to perform a faecal occult blood test (FOBT) in symptomatic patients, we believe the test is frequently used as a diagnostic test. The objective of this study was to investigate whether the current guidelines for FOBT use are being followed in the Netherlands. METHODS: The frequency of reasons for ordering a FOBT in 15 hospitals over a time period of 1 year was determined and the consequences of the test result on the diagnostic workup were determined by a retrospective search of electronic hospital charts. RESULTS: In 14 of the 15 hospitals a FOBT was available and totally 2993 FOBTs were performed in 1 year. A total of 201 electronic charts were retrieved. The FOBTs were ordered because of anaemia (41%), suspicion of rectal bleeding (17%), abdominal pain (14%), changed bowel habits (10%) or others (18%). A positive test result was found in 66 (33%) patients and a negative in 133 (66%). Respectively, 38% (25/66) of the patients with a positive and 41% (55/133) of the patients with a negative test result received a gastrointestinal follow-up investigation. In 25/80 investigations, a possible cause of rectal blood loss was detected, of which 13 had a positive FOBT result. CONCLUSION: This study demonstrates that current guidelines on FOBT use are not followed in the Netherlands and that a FOBT is often used as a diagnostic tool instead of a screening tool, thereby causing confusion and unnecessary delays in the diagnostic workup of patients. PMID- 23022921 TI - Adding variceal status to Child-Turcotte-Pugh score improves its performance in predicting early mortality in cirrhosis: the Child-Turcotte-Pugh-Kumar score. PMID- 23022923 TI - Endoscopic treatment and risk factors of postoperative anastomotic bleeding after gastrectomy for gastric cancer. AB - BACKGROUND: Anastomotic leakage, bleeding, and stricture are major complications after gastrectomy. Of these complications, postoperative anastomotic bleeding is relatively rare, but lethal if not treated immediately. METHODS: Of 2031 patients with gastric cancer who underwent radical gastrectomy (R0 resection) between January 2002 and December 2010, postoperative anastomotic bleeding was observed in 7 patients. The clinicopathological features, postoperative outcomes such as surgical procedures, bleeding sites and, methods used to achieve hemostasis, and the risk factors of anastomotic bleeding of these 7 patients were analyzed. RESULTS: Of the 2031 patients, 1613 and 418 underwent distal and total gastrectomy, respectively. The bleeding sites were as follows: Billroth-I anastomosis using a circular stapler (n = 1), Billroth-II anastomosis by manual suture (n = 5), and esophagojejunostomy using a circular stapler (n = 1). All patients were treated with endoscopic clipping or epinephrine injection. There was no further endoscopic intervention or reoperation for anastomotic bleeding. CONCLUSIONS: Postoperative anastomotic bleeding is an infrequent but potentially life-threatening complication. Scrupulous surgical procedures are essential for the prevention of postoperative bleeding, and endoscopy was useful for both the confirmation of bleeding and therapeutic intervention. PMID- 23022924 TI - Need for standardization of the measurement of preoperative weight in bariatric surgical patients in the UK: A survey of British Obesity and Metabolic Surgery Society (BOMSS) members. AB - BACKGROUND: Weight loss is the most commonly used metric in comparing outcomes after bariatric surgery. This is frequently presented in the form of percentage of excess weight loss (%EWL). Patients' weight is measured at several time points prior to surgery. The time point selected as the preoperative weight can have significant effects upon the measurement of %EWL. This study aimed to investigate whether there was any standardization in the selection of preoperative weight amongst UK bariatric surgery healthcare professionals. METHODS: A questionnaire survey was conducted among the delegates at the British Obesity and Metabolic Surgery Society (BOMSS) meeting in January 2011. RESULTS: A total of 54 delegates (consultant & trainee surgeons, bariatric specialist nurses, dieticians and psychologists) responded to the survey. A wide variation was noted in which preoperative weight was used in the calculation of %EWL, both among various disciplines and also among the same disciplines. The majority (61%) used the preoperative weight recorded at the bariatric surgical assessment clinic prior to surgery. 20% of delegates used the highest recorded preoperative weight. The remainder of delegates used weight recorded on the day of surgery (17%) or the weight recorded during the first visit to a medical physician led weight management clinic (2%). CONCLUSION: Variation in the measurement of the preoperative weight will lead to variations of calculated %EWL between different bariatric units or even between different disciplines in the same unit. This will make comparison of published outcome data difficult. This study highlights the urgent need for standardization. PMID- 23022925 TI - Seeing pink. PMID- 23022926 TI - Interventions to manage compassion fatigue in oncology nursing. PMID- 23022927 TI - Oncology nurse as wounded healer: developing a compassion identity. AB - Oncology nurses caring for patients with complex medical, psychosocial, and spiritual issues-including patients at end of life-rely on current medical interventions to offer comfort to their patients. Equally important, but less acknowledged, is nurses' reliance on the internal processes of reflection and self-care. That internal focus is vital to the longevity of the nurse in a rewarding, but often depleting, arena. Compassion fatigue and burnout among oncology nurses are great risks to professional development and personal growth. Repeated exposure to physical and psychosocial pain and suffering can cause symptoms that resemble those of post-traumatic stress disorder. Awareness of one's own fragility and the need to understand the connections between body, mind, and spirit can assist the clinician in developing a compassion identity that nurses and other clinicians can use to insulate themselves from the stressors of their difficult and rewarding environment. PMID- 23022928 TI - Determining the minimum discard volume for central venous catheter blood draws. AB - This study aimed to determine the minimum discard volume from central venous catheters (CVCs) to avoid dilution or contamination from flush or IV fluids. In 93 adult patients with CVCs, minimum discard volume findings were 9 ml for tunneled and 6 ml for nontunneled catheters. Nurses who obtain samples from CVCs are uniquely positioned to minimize blood loss from sampling. PMID- 23022929 TI - Understanding depression: awareness, assessment, and nursing intervention. AB - Clinical depression often is overlooked by healthcare providers when treating patients with cancer. Oncology nurses are in a pivotal position to assess for depression, communicate any changes in emotional status to the oncology treatment team, and offer support and education to patients and families. This article discusses the symptoms of depression and the available treatment options. PMID- 23022930 TI - Oncology clinical challenges: caring for patients with preexisting psychiatric illness. AB - People with severe mental disorders (SMDs) have a higher mortality rate and reduced life expectancy compared to the general population. Factors that contribute to higher mortality rates include a higher rate of smoking and increased incidence of obesity from lifestyle, diet, or medication side effects. Cancer treatment may exacerbate mood and psychotic symptoms in patients with SMD. Some of the medications used in cancer treatment or the medications used to alleviate the side effects of cancer treatment can have adverse reactions with psychotropic medications. This article examines problems that patients with SMD encounter with their cancer diagnosis and treatment. Oncology nurses in any clinical setting play a pivotal role in identifying the special needs of a patient with SMD and must become familiar with psychosocial issues, psychotropic medications, and SMD to educate and advocate for these patients and their families. Collaborating and coordinating care between oncology and psychiatry providers is needed for optimal patient outcomes. PMID- 23022931 TI - Collaboration, collegiality, and cooperation: consumer health library services and the American Cancer Society navigator role. AB - Patients and family members are overwhelmed by the diagnosis of cancer and often do not know where to look for answers, information on the treatment options, or community resources for support during the cancer journey. A unique relationship was forged with a patient and health education librarian at the Mayo Clinic in Arizona and an American Cancer Society navigator, which encouraged collaboration to better meet the informational and supportive healthcare needs of patients. This article addresses the background of the project, the steps taken to establish the relationship, space allocation, and need for confidentiality. The innovations produced by this partnership also are discussed, including development of cancer pathfinders and cancer communication blogs for patients, as well as comarketing of services. PMID- 23022932 TI - Implementing a distress screening instrument in a university breast cancer clinic: a quality improvement project. AB - Distress remains a pervasive experience of patients with cancer. As a result, a quality improvement project was conducted in the breast cancer clinic of a university cancer center in the midwestern United States. Nurses identified a need to increase identification of distress over a six-month period when they made only eight referrals for distress support during 1,291 patient encounters. The eight referrals were the result of patient exhibitions of severe distress in the clinic. To increase identification of distress, as well as referrals for support before patients exhibited severe distress, the National Comprehensive Cancer Network's Distress Thermometer screening tool was implemented in the clinic from June 1 through July 6, 2010. The instrument was completed by each participant during a patient encounter, followed by a review of the responses with a nurse. Referrals for support were offered by nurses when responses indicated a significant level of distress. Nurses increased identification of distress by using the instrument. In addition, referrals for support increased before patients exhibited severe distress. Nurses are positioned to improve care by identifying distress and making referrals for support. PMID- 23022933 TI - Nutrition education for osteoporosis prevention in men with prostate cancer initiating androgen deprivation therapy. AB - Osteoporosis is a common side effect of treatment with androgen deprivation therapy (ADT) in men with prostate cancer. ADT may prolong survival; however, deterioration of bone mass density occurs soon after initiation. A systematic review of current literature revealed the importance of adequate nutrition during treatment with ADT to reduce the risk of osteoporosis. More specifically, this literature stressed achieving adequate intake of calcium and vitamin D through a combination of supplements and food. The necessity of providing nutrition education to patients with prostate cancer at initiation of ADT was identified. Healthcare professionals, including nurses, oncologists, and dietitians, can be instrumental in identifying patients with prostate cancer initiating ADT who are at risk for osteoporosis. Research on nutrition and lifestyle modification interventions to maintain bone health and reduce fracture risk for patients initiating ADT is limited. Additional research is required to develop and evaluate nutrition education interventions that will reduce the risk and prevent osteoporosis in men on ADT. PMID- 23022934 TI - Veno-occlusive disease in hematopoietic stem cell transplantation recipients. AB - Veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation that affects the liver, as well as other organs. Although mild cases resolve on their own, severe cases of VOD carry a high mortality rate. The diagnosis usually is clinically based, with nonspecific signs such as weight gain, ascites, hepatomegaly, right upper quadrant abdominal pain, and elevated serum bilirubin. Although studies are ongoing, no U.S. Food and Drug Administration-approved treatments for VOD exist to date. Therefore, supportive care is a critical part of the treatment plan. Oncology nurses should be familiar with the risk factors and clinical signs of VOD so that patients can be monitored closely for its occurrence. Accurate and timely recognition of VOD is crucial for appropriate treatment. PMID- 23022936 TI - Toward evidence and theory-based skin care in radiation oncology. AB - Dermatitis is a distressing symptom of radiation therapy, and current care guidelines often lack evidence. Using an evidence-based practice (EBP) model, a multidisciplinary group in an academic medical center reviewed the literature to create departmental patient education materials related to skin care that were grounded in evidence. Recommendations not supported by evidence from randomized, controlled trials were viewed within a stress-reduction framework. Until evidence related to the prevention and treatment of radiation dermatitis is more fully developed, skin care recommendations for patients with cancer who receive radiation may need to be based on evidence and theory. In addition, care for patients with radiation dermatitis should encompass strategies aimed at physical and psychosocial stressors. PMID- 23022935 TI - Irrigation practices in long-term survivors of colorectal cancer with colostomies. AB - For some patients diagnosed with rectal cancer, surgery will involve the creation of a temporary or permanent ostomy. When the colostomy is located in the sigmoid or descending colon, regulation of fecal output can occur through irrigation, a procedure that involves instilling fluid into the bowel to flush out gas and fecal material. When successfully used, irrigation can prevent fecal output between irrigations, providing some control over colostomy output. The purpose of this article is to describe participants of a large, multisite, multi investigator study of health-related quality of life in long-term colorectal cancer survivors who answered questions about colostomy irrigation and reported the potential advantages and disadvantages of the procedure. The article also will explore healthcare professionals' role in ensuring patients and family members are educated and well informed about their options regarding temporary or permanent ostomies. PMID- 23022937 TI - The essentials of chemotherapy-induced infusion reactions. AB - Almost all systemic agents used in cancer therapy can cause infusion-related reactions. Hypersensitivity or infusion reactions to platinum compounds are acquired, whereas reactions to taxanes and monoclonal antibodies usually occur during the first few minutes of the first infusion. By understanding the symptoms and treatment of infusion reactions, healthcare team members can provide timely and appropriate treatment and positively impact patient care. PMID- 23022938 TI - Avoiding failure to rescue situations: a simulation exercise for oncology nurses. AB - This project aimed to improve RNs' recognition of and appropriate responses to failure to rescue situations on a surgical oncology unit. Simulation exercises played a key role in identifying areas of strength, opportunities for improvement, and development of a personalized education plan. In addition, the exercises improved RNs' clinical confidence. PMID- 23022939 TI - Use of mirrors as a nursing intervention to promote patients' acceptance of a new body image. AB - Body image in oncology is a relatively unexplored field. Recent interventions have focused on the use of the mirror in assessing body image. The purpose of this narrative is to increase oncology nurses' awareness of the need to adopt such interventions based on expert judgment and practice when empirical evidence is limited. PMID- 23022940 TI - Finding yourself on the open road. PMID- 23022941 TI - The use of motivational interviewing to promote peer-to-peer support for cancer survivors. AB - Motivational interviewing (MI) as a counseling approach has gained empirical support for its use in a number of settings and for a variety of behaviors. However, the majority of practitioners trained to use MI have been professionals rather than laypeople. This article presents the rationale, design, and evaluation of an MI-based training for cancer survivors and caregivers to deliver peer support. The training and evaluation of the peers ("guides") to encourage practice and increase research knowledge for using MI-based peer support models for cancer care are discussed. Thirteen cancer survivors and two caregivers received two-day DVD-based MI training, as well as supplemental monthly sessions for six months. The guides demonstrated MI proficiency as assessed by the MI Treatment Integrity scale and other process evaluation assessments. MI can be adapted to train laypeople to provide support for groups such as cancer survivors. PMID- 23022942 TI - Adverse effects of denileukin diftitox and their management in patients with cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma with predominant skin manifestations and a relatively indolent course at early stages, but it can be fatal in advanced settings. In the absence of cure, the goal of therapy for CTCL is to induce long-term remissions without further compromising a patient's immune system or quality of life. Denileukin diftitox (DD) is a fusion protein chemotherapeutic agent used for the treatment of persistent or recurrent CTCL. It binds selectively to the high- and intermediate-affinity interleukin-2 receptor (CD25+) on lymphocytes and is internalized by these cells. Inside the cells, the diphtheria toxin portion of fusion protein is cleaved by proteolytic enzymes, causing cell death. DD produces durable responses and may forestall disease progression. This article reviews DD phase III clinical trial data and summarizes one institution's clinical experience in the management of the most frequent and clinically significant adverse effects of DD (e.g., acute infusion reactions, capillary leak syndrome, hypoalbuminemia, visual changes, constitutional symptoms, rash, hepatobiliary disorders). Many DD-associated adverse effects can be managed effectively without dose reduction or interruption of treatment with prudent use of supportive care measures. PMID- 23022943 TI - Pilot study of "miracle fruit" to improve food palatability for patients receiving chemotherapy. AB - Taste changes in patients undergoing chemotherapy are common and can be of long duration, are associated with poor nutrition, and can reduce quality of life. A pilot study of the fruit Synsepalum dulcificum-known as "miracle fruit"-as a novel supportive intervention was conducted with eight patients with cancer who were being treated with chemotherapy and reporting taste changes. Miraculin, a naturally occurring protein in miracle fruit, has the unusual ability to transduce a sweet signal in an acidic environment, profoundly changing food taste profiles for a short duration, masking unpleasant tastes, and increasing the palatability of certain foods. This pilot study was designed to determine whether consumption of the Miracle FruitTM supplement would improve chemotherapy associated taste changes, thereby improving the taste of food and ultimately leading to better nutrition. Four of the participants were given a two-week supply of the supplement and the other four were given a two-week supply of a placebo. After two weeks, the supplement group received a two-week supply of the placebo and the placebo group received a two-week supply of the supplement. Participants recorded food and drink intake in daily food dairies and rated taste changes with each food as better, worse, or no change. All study participants reported positive taste changes with the supplement. PMID- 23022944 TI - Nursing care program for erectile dysfunction after radical prostatectomy. AB - The prevalence of erectile dysfunction (ED) in 114 patients with prostate cancer treated with radical prostatectomy was examined to determine the efficacy of an ED care program in which nurse-provided education plays a fundamental role in the detection and follow-up of ED as well as in treatment compliance. The nursing program consists of four visits during which specific treatment-related information, education and support, active listening, and selection of the treatment best suited to each patient (in consultation with the healthcare team) are provided. One month following bladder catheter removal, 77 of the 114 patients (69%) in the study had ED, with a majority suffering from severe ED. A nursing care program could help minimize ED and enable patients to adapt to their new situation. PMID- 23022945 TI - Two lives intertwined: pregnancy-associated breast cancer. AB - The incidence of concurrent breast cancer and pregnancy (also known as pregnancy associated breast cancer [PABC]) may increase as women delay child bearing. Because of the physiologic changes associated with pregnancy, diagnosis often is delayed, lending to poorer prognostic factors on presentation. Therefore, the clinical challenge in managing PABC involves controlling the cancer while maximizing survival outcomes for the expectant mother without compromising the health and safety of the fetus. Collaboration and communication between multidisciplinary team members are crucial. Education is key in providing a general overview of available diagnostic modalities, endorsing the multidisciplinary approach to care and treatment for the mother and fetus, and identifying the oncology nursing role specific to this patient population. Women with PABC must be kept informed of all aspects of care to ensure active participation in the decision-making process, as they are not only concerned for their own well-being but also that of their unborn child. Anxiety levels often run high and steady communication offers a modicum of control to this already stressed patient population. PMID- 23022946 TI - The final chapter. PMID- 23022947 TI - Fluorescence quenching of fulvic acids by fullerene in water. AB - Fullerene can be suspended in water as nanoscaled-fullerene-aggregates (nC(60)). However, little is known about its biogeochemical cycling in natural waters. In this paper, the interactions between nC(60) and fulvic acids were investigated using fluorescence spectroscopy and fluorescence quenching titration. The results show that the intrinsic fluorescence of fulvic acids was static quenched by adding nC(60). The association constants (log K) of fulvic acids and nC(60) were estimated using a modified Ryan-Weber nonlinear model, and ranged from 6.76 to 7.41 l/mol. The log K was not significantly affected by the concentration levels of fulvic acids from 5.0 to 20.0 mg/l. The log K increased at low pH 3-5, but remained constant at high pH ranging from 5 to 11. The hydrophobic and pi-pi interactions were the likely primary mechanisms. The present observation will be helpful in understanding the environmental behavior of fullerene in natural aquatic ecosystems. PMID- 23022948 TI - Monitoring bioremediation of atrazine in soil microcosms using molecular tools. AB - Molecular tools in microbial community analysis give access to information on catabolic potential and diversity of microbes. Applied in bioremediation, they could provide a new dimension to improve pollution control. This concept has been demonstrated in the study using atrazine as model pollutant. Bioremediation of the herbicide, atrazine, was analyzed in microcosm studies by bioaugmentation, biostimulation and natural attenuation. Genes from the atrazine degrading pathway atzA/B/C/D/E/F, trzN, and trzD were monitored during the course of treatment and results demonstrated variation in atzC, trzD and trzN genes with time. Change in copy number of trzN gene under different treatment processes was demonstrated by real-time PCR. The amplified trzN gene was cloned and sequence data showed homology to genes reported in Arthrobacter and Nocardioides. Results demonstrate that specific target genes can be monitored, quantified and correlated to degradation analysis which would help in predicting the outcome of any bioremediation strategy. PMID- 23022950 TI - Migration of polybrominated diphenyl ethers in biosolids-amended soil. AB - A field investigation was carried out to determine PBDE concentrations over a one year period in agricultural soils onto which 80 tonnes biosolids/hectare had been applied. The PBDE concentrations increased from 80 to 300 pg/g dry weight basis to 300 * 10(3)-600 * 10(3) pg/g dw due to biosolids application, and PBDEs migrated downwards to depths of at least 0.85 m. Concentrations decreased non uniformly with depth. PBDE levels decreased exponentially in the topmost biosolids-amended soils layer, while increasing in the next underlying soil layer over the one-year period. The rate of decrease of total PBDE mass in the top 0.00 0.05 m layer was almost two orders of magnitude greater than the rates of increase in total PBDE mass in the lower layers, indicating that effects such as photodegradation and/or volatilization likely were to have been significant in the surface layer. PMID- 23022949 TI - Incidence of invasive macrophytes on methylmercury budget in temperate lakes: central role of bacterial periphytic communities. AB - Several studies demonstrated high mercury (Hg) methylation and demethylation in the periphyton associated with floating roots in tropical ecosystems. The importance of aquatic plants on methylmercury production in three temperate ecosystems from south-western France was evaluated through Hg species concentrations, and Hg methylation/demethylation activities by using stable isotopic tracers ((199)Hg(II), Me(201)Hg). Hg accumulation and high methylation and demethylation yields were detected in plant roots and periphyton, whereas results for sediment and water were low to insignificant. The presence of sulfate reducing prokaryotes was detected in all compartments (T-RFLP based on dsrAB amplified through nested PCR) and their main role in Hg methylation could be demonstrated. In turn, sulfate reduction inhibition did not affect demethylation activities. The estimation of net MeHg budgets in these ecosystems suggested that aquatic rhizosphere is the principal location for methylmercury production and may represent an important source for the contamination of the aquatic food chain. PMID- 23022951 TI - Finite element modelling of the flexural performance of resorbable phosphate glass fibre reinforced PLA composite bone plates. AB - A finite element method is presented to predict the flexural properties of resorbable phosphate glass fibre reinforced PLA composite bone plates. A novel method for meshing discontinuous fibre architectures is presented, which removes many of the limitations imposed by conventional finite element approaches. The model is used to understand the effects of increasing the span-to-thickness ratio for different fibre architectures used for PBG/PLA composites. A span-to thickness ratio of 16:1 is found to be appropriate for materials with randomly orientated fibres, which agrees well with the test standard. However, for highly aligned materials the model indicates that a span-to-thickness ratio of 80:1 is required, in order to minimise the effects of shear deflection. The model is validated against flexural stiffness data from the literature for a range of polymers, fibres and fibre volume fractions. Generally there is less than 10% error between the FE predictions and experimental values. The model is subsequently used to perform a parametric study to understand what material developments are required to match the properties of PGF/PLA composites to cortical bone. It is concluded that alignment of the fibre is necessary to exceed the 20 GPa target, since the current manufacturing methods limit the fibre length to ~10 mm, which consequently restricts the flexural modulus to ~19 GPa (at 50% volume fraction). PMID- 23022952 TI - Case matched comparison study of the necrosectomy by retroperitoneal approach with transperitoneal approach for necrotizing pancreatitis in patients with CT severity score of 7 and above. AB - BACKGROUND: Minimally invasive necrosectomy through a retroperitoneal approach has shown promising results for the treatment of necrotizing pancreatitis. There is however, little evidence from comparative studies in favor of these techniques over laparotomy. AIM: To perform a case matched comparison of patients with necrotizing pancreatitis who underwent necrosectomy by the retroperitoneal approach with transperitoneal approach, thus minimizing the risk of confounding and selection bias. METHODS: Between August 2008 and March 2011, 85 patients were admitted with pancreatic necrosis. Each of the 15 patients who underwent necrosectomy by retroperitoneal approach using a small flank incision (RP group) were compared with 15 of those treated with necrosectomy by transperitoneal approach (TP group). These patients were matched for the age (+/-10 years), status of infection, CT severity score (+/-2 points), preoperative organ failure and timing for surgery (+/-7 days). RESULTS: Postoperative complications occurred in 4 patients (26.6%) in the RP group and 8 (53.3%) in the TP group (p = 0.248). Reintervention, was required in 4 patients (26.6%) in the RP group and 7 (46.6%) in the TP group (p = 0.366). The median post operative ICU stay was 10 days in the RP group compared to 15 days in the TP group (p = 0.317). Median post operative hospital stay was 26 days in the RP group and 32 days in the TP group (p = 0.431). The total hospital stay among the survivors was 31 days in the RP group and 40 days in the TP group (p = 0.285). CONCLUSIONS: The RP approach for pancreatic necrosectomy through a small flank incision was associated with less post operative morbidity compared to TP approach. The surgical outcomes in terms of post operative new onset organ failure and in hospital mortality were similar in both the groups, but the post op ICU/hospital stay and the total hospital stay was lower in the RP approach group. These results still requires to be confirmed by further randomized studies. PMID- 23022953 TI - New ways of assessing ovarian cancer response: metabolic imaging and beyond. AB - In patients with advanced ovarian cancer, it can be challenging to evaluate response to neoadjuvant chemotherapy on computed tomography (CT) due to disseminated small volume disease and serosal disease. In addition, measuring the change in size of tumour burden takes time in order to allow tumour shrinkage. Despite these challenges, serum CA-125 levels and CT are the standard tools for the assessment of treatment response in ovarian cancer. New functional imaging techniques may allow the identification of response earlier and with higher accuracy. In this review article, we describe the current literature on functional imaging techniques in ovarian cancer response assessment, focusing on fluorodeoxyglucose-positron emission tomography. PMID- 23022954 TI - Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis. AB - BACKGROUND & AIMS: The type of immune response during development of acute pancreatitis (AP) determines disease severity. Pancreatic epithelial cells express the interleukin (IL)-22 receptor A1 (IL-22RA1). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates expression of IL-22. We investigated sources and role of IL-22 in the pancreas, along with the effects of AhR activation on IL-22 expression and AP progression in mice. METHODS: We analyzed the effects of recombinant IL-22, a monoclonal antibody against IL-22, and agonists and antagonists of AhR in mice with AP (induced with caerulein or a choline-deficient diet supplemented with DL ethionine) and control mice. We also analyzed transgenic mice with AhR deficiency (AhR(d) and AhR(-/-) mice). RESULTS: CD4(+) T cells were the main source of IL-22 in pancreatic tissues from healthy mice. During development of AP, numbers of IL 22(+) CD4(+) T cells were reduced, whereas IL-22RA1 was up-regulated. Consistent with high levels of IL-22RA1 expression, pancreatic acinar cells responded to IL 22 signaling via signal transducers and activators of transcription 3; administration of IL-22 reduced AP and associated lung injury in mice. AhR was required for production of IL-22 and protected mice from AP. Mice that did not respond to AhR activation developed AP, but administration of IL-22 reduced AP; blockade of IL-22 reversed the ability of activated AhR to protect against AP. CONCLUSIONS: AhR activation protects mice from AP by inducing expression of IL 22. AhR therefore mediates interactions between pancreatic leukocytes and epithelial cells and might be developed as a therapeutic target. PMID- 23022955 TI - Measurement of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices. AB - BACKGROUND & AIMS: We evaluated whether spleen stiffness (SS), measured by acoustic radiation force impulse imaging, can identify patients who have esophageal varices (EVs); those without EVs would not require endoscopic examination. METHODS: In a prospective study, we measured SS and liver stiffness (LS) in 340 patients with cirrhosis undergoing endoscopic screening for EVs and 16 healthy volunteers (controls) at the Kurashiki Central Hospital in Okayama, Japan. The diagnostic accuracy of SS for the presence of EVs was compared with that of other noninvasive parameters (LS, spleen diameter, and platelet count). Optimal cutoff values of SS were chosen to confidently rule out the presence of varices. RESULTS: Patients with cirrhosis had significantly higher SS and LS values than controls (P < .0001 and P < .0001, respectively). Levels of SS were higher among patients with EVs (n = 132) than controls, and values were highest among patients with high-risk EVs (n = 87). SS had the greatest diagnostic accuracy for the identification of patients with EVs or high-risk EVs compared with other noninvasive parameters, independent of the etiology of cirrhosis. An SS cutoff value of 3.18 m/s identified patients with EVs with a 98.4% negative predictive value, 98.5% sensitivity, 75.0% accuracy, and 0.025 negative likelihood ratio. An SS cutoff value of 3.30 m/s identified patients with high risk EVs with a 99.4% negative predictive value, 98.9% sensitivity, 72.1% accuracy, and 0.018 negative likelihood ratio. SS values less than 3.3 m/s ruled out the presence of high-risk varices in patients with compensated or decompensated cirrhosis. SS could not be measured in 16 patients (4.5%). CONCLUSIONS: Measurements of SS can be used to identify patients with cirrhosis with EVs or high-risk EVs. A cutoff SS was identified that could rule out the presence of varices and could be used as an initial noninvasive screening test; UMIN Clinical Trials Registry number, UMIN000004363. PMID- 23022956 TI - Rat vagus nerve stimulation model of seizure suppression: nNOS and DeltaFos B changes in the brainstem. AB - Vagus nerve stimulation (VNS) is a moderately effective treatment for intractable epilepsy. However, the mechanism of action is poorly understood. The effect of left VNS in amygdala kindled rats was investigated by studying changes in nNOS and DeltaFos B expression in primary and secondary vagus nerve projection nuclei: the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus nerve (DMV), parabrachial nucleus (PBN) and locus coeruleus (LC). Rats were fully kindled by stimulation of the amygdala. Subsequently, when the fully kindled state was reached and then maintained for ten days, rats received a single 3-min train of VNS starting 1min prior to the kindling stimulus and lasting for 2min afterwards. In control animals the vagus nerve was not stimulated. Animals were sacrificed 48h later. The brainstems were stained for neuronal nitric oxide synthase (nNOS) and DeltaFos B. VNS decreased seizure duration with more than 25% in 21% of rats. No VNS associated changes in nNOS immunoreactivity were observed in the NTS and no changes in DeltaFos B were observed in the NTS, PBN, or LC. High nNOS immunopositive cell densities of >300cells/mm(2) were significantly more frequent in the left DMV than in the right (chi(2)(1)=26.2, p<0.01), independent of whether the vagus nerve was stimulated. We conclude that the observed nNOS immunoreactivity in the DMV suggests surgery-induced axonal damage. A 3-min train of VNS in fully kindled rats does not affect DeltaFos B expression in primary and secondary projection nuclei of the vagus nerve. PMID- 23022957 TI - Doppler optical coherence tomography of retinal circulation. AB - Noncontact retinal blood flow measurements are performed with a Fourier domain optical coherence tomography (OCT) system using a circumpapillary double circular scan (CDCS) that scans around the optic nerve head at 3.40 mm and 3.75 mm diameters. The double concentric circles are performed 6 times consecutively over 2 sec. The CDCS scan is saved with Doppler shift information from which flow can be calculated. The standard clinical protocol calls for 3 CDCS scans made with the OCT beam passing through the superonasal edge of the pupil and 3 CDCS scan through the inferonal pupil. This double-angle protocol ensures that acceptable Doppler angle is obtained on each retinal branch vessel in at least 1 scan. The CDCS scan data, a 3-dimensional volumetric OCT scan of the optic disc scan, and a color photograph of the optic disc are used together to obtain retinal blood flow measurement on an eye. We have developed a blood flow measurement software called "Doppler optical coherence tomography of retinal circulation" (DOCTORC). This semi-automated software is used to measure total retinal blood flow, vessel cross section area, and average blood velocity. The flow of each vessel is calculated from the Doppler shift in the vessel cross-sectional area and the Doppler angle between the vessel and the OCT beam. Total retinal blood flow measurement is summed from the veins around the optic disc. The results obtained at our Doppler OCT reading center showed good reproducibility between graders and methods (<10%). Total retinal blood flow could be useful in the management of glaucoma, other retinal diseases, and retinal diseases. In glaucoma patients, OCT retinal blood flow measurement was highly correlated with visual field loss (R(2)>0.57 with visual field pattern deviation). Doppler OCT is a new method to perform rapid, noncontact, and repeatable measurement of total retinal blood flow using widely available Fourier-domain OCT instrumentation. This new technology may improve the practicality of making these measurements in clinical studies and routine clinical practice. PMID- 23022958 TI - Regulation of NF-kappaB-dependent gene expression by ligand-induced endocytosis of the interleukin-1 receptor. AB - Interleukin-1 (IL-1) induces the internalization of its cognate receptor from the plasma membrane. However, it has remained elusive as to how this mechanism affects the IL-1-induced signal transduction. In this study, we used small molecule inhibitors of receptor endocytosis to analyze the effects on IL-1 induced signal transduction pathways. We demonstrate that the inhibition of endocytosis down-modulates IL-1-induced NF-kappaB-dependent gene expression at a level downstream of nuclear translocation and DNA binding of NF-kappaB. Moreover, we report that the reduced NF-kappaB-dependent gene expression disrupts feedback inhibition loops terminating the activation of mitogen-activated protein kinases and down-regulating the expression of IL-1-induced mRNAs. Collectively, we show that the inhibition of endocytosis causes a dysregulation of IL-1-induced signal transduction and gene expression demonstrating an important role for receptor internalization in IL-1 signaling. PMID- 23022959 TI - Functional roles for myosin 1c in cellular signaling pathways. AB - Cellular signaling pathways underlie the transfer of information throughout the cell and to adjoining cells and so govern most critical cellular functions. Increasing evidence points to the molecular motor myosin 1c as a prominent player in many signaling cascades, from the integrin-dependent signaling involved in cell migration to the signaling events underlying insulin resistance. Myosin 1c functions on these pathways both via an important role in regulating lipid raft recycling and also via direct involvement in signaling cascades. This review provides an overview of the functional involvement of myosin 1c in cellular signaling and discusses the possible potential for myosin 1c as a target for drug based treatments for human diseases. PMID- 23022960 TI - Disheveled proteins promote cell growth and tumorigenicity in ALK-positive anaplastic large cell lymphoma. AB - Our previous oligonucleotide array studies revealed that ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL) express high levels of the disheveled proteins (Dvls), a family of proteins that is integral to the Wnt signaling pathways. In this study, we assessed whether the Dvls are important in the pathogenesis of ALK(+)ALCL. By Western blotting, Dvl-2 and Dvl-3 were found to be highly expressed in ALK(+)ALCL cell lines and patient samples. The higher molecular weight forms, consistent with phosphorylated/active Dvl proteins, were observed in these lysates. siRNA knock-down of Dvls did not affect the Wnt canonical pathway, as assessed by the beta-catenin protein levels and nuclear localization. In contrast, the same treatment led to changes in the transcriptional activity of NFAT and the phosphorylation status of Src, both of which are known to be regulated by the Wnt non-canonical signaling pathways in other cell types. Coupled with these biochemical changes, there was a significant decrease in cell growth and soft agar colony formation. NPM-ALK, the oncogenic tyrosine kinase characteristic of ALK(+)ALCL, was found to bind to the Dvls and enhance their tyrosine phosphorylation. In conclusion, our data suggest that the Dvls contribute to the pathogenesis of ALK(+)ALCL via signaling in the Wnt non canonical pathways. To our knowledge, this is the first report demonstrating a physical and functional interaction between the Dvls and an oncogenic tyrosine kinase. PMID- 23022965 TI - [The ATLAS ACS 2-TIMI 51 study]. PMID- 23022961 TI - Beyond cell adhesion: the role of armadillo proteins in the heart. AB - Plakoglobin (PG, gamma-Catenin, JUP), a member of the armadillo protein family and close homolog of beta-catenin, functions to link cell surface cadherin molecules with the cytoskeleton. PG is the only junctional component found in both desmosomes and adherens junctions and thus plays a critical role in the regulation of cell-cell adhesion. Similar to beta-catenin, PG is able to interact with components of the Wnt signaling pathway and directly affect gene expression by binding with LEF/TCF transcription factors. In addition, it has been proposed that PG functions primarily as a competitive inhibitor of beta-catenin transcriptional activity by sequestering LEF/TCF. Compared to beta-catenin, the contribution of PG as a transcriptional regulator in either physiological or pathological conditions is poorly understood. There is increasing clinical interest in PG as both a structural protein as well as a signaling molecule as mutations have been identified in the human PG gene that cause Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and cutaneous syndromes. This review will discuss the connection between altered cell adhesion and gene expression and its contribution to disease pathogenesis. PMID- 23022962 TI - Cripto-1 enhances the canonical Wnt/beta-catenin signaling pathway by binding to LRP5 and LRP6 co-receptors. AB - Cripto-1 is implicated in multiple cellular events, including cell proliferation, motility and angiogenesis, through the activation of an intricate network of signaling pathways. A crosstalk between Cripto-1 and the canonical Wnt/beta catenin signaling pathway has been previously described. In fact, Cripto-1 is a downstream target gene of the canonical Wnt/beta-catenin signaling pathway in the embryo and in colon cancer cells and T-cell factor (Tcf)/lymphoid enhancer factor binding sites have been identified in the promoter and the first intronic region of the mouse and human Cripto-1 genes. We now demonstrate that Cripto-1 modulates signaling through the canonical Wnt/beta-catenin/Tcf pathway by binding to the Wnt co-receptors low-density lipoprotein receptor-related protein (LRP) 5 and LRP6, which facilitates Wnt3a binding to LRP5 and LRP6. Cripto-1 functionally enhances Wnt3a signaling through cytoplasmic stabilization of beta-catenin and elevated beta-catenin/Tcf transcriptional activation. Conversely, Wnt3a further increases Cripto-1 stimulation of migration, invasion and colony formation in soft agar of HC11 mouse mammary epithelial cells, indicating that Cripto-1 and the canonical Wnt/beta-catenin signaling co-operate in regulating motility and in vitro transformation of mammary epithelial cells. PMID- 23022966 TI - [The CE-MARC study]. PMID- 23022967 TI - [Role of cardiovascular magnetic resonance in the differential diagnosis of cardiomyopathies]. AB - Cardiovascular magnetic resonance (CMR) is a unique diagnostic imaging tool for the assessment of cardiomyopathies, allowing a non-invasive detection of the most common diseases of the heart muscle. In the real world, patients with suspected cardiomyopathies who show signs and symptoms of heart failure should undergo a thorough diagnostic evaluation. Besides clinical and echocardiographic assessment, coronary angiography is the most important and common examination performed to detect or rule out coronary artery disease. This approach is relevant for the clinical decision-making, as it may obviate the need for further diagnostic evaluation of the heart structure and muscle function. CMR can reliably detect a variety of heart muscle diseases without requiring bioptic confirmation of the diagnosis. In addition, CMR provides anatomo-functional information that possesses incremental and independent prognostic value. This represents a new paradigm shift as it moves the attention from the coronary arteries to the heart muscle. CMR is useful in establishing the correct diagnosis of several clinical conditions and cardiomyopathies, thus guiding therapeutic strategies and influencing patient prognosis. PMID- 23022968 TI - [Mechanical devices and magnetic resonance imaging: instructions for use]. AB - Magnetic resonance imaging provides excellent spatial resolution and tissue characterization analysis while not exposing patients to ionizing radiation or potentially nephrotoxic iodinate contrast agents. Magnetic resonance imaging has developed into an extensively applied diagnostic tool for all fields of medicine, whilst at the same time an increasing number of patients are being treated with permanent or temporary cardiovascular devices. A thoughtful analysis of cardiovascular devices and their properties related to magnetic field interaction is warranted to improve correct access and safety to magnetic resonance imaging. PMID- 23022969 TI - [Angina with normal coronary arteries: a common but often neglected association]. AB - The angiographic evidence of normal coronary arteries or moderate coronary artery disease is a relatively common finding in patients with a history of angina, with a higher prevalence in females. This condition is not a single pathological entity, but comprises several different presentations, such as cardiac syndrome X, vasospastic angina, myocardial bridges, as well as coronary alterations with more doubtful clinical implications, such as serial moderate coronary artery lesions or focal coronary dilations. These pathological conditions are different in pathophysiology, management, and prognosis, and for this reason their correct diagnostic definition, beyond the angiographic evidence of normal coronary arteries, appears mandatory. This review aims at providing an update in the conundrum of entities comprising angina with normal coronary arteries, and at explaining different diagnostic and therapeutic approaches. PMID- 23022970 TI - [Prevention of the postpericardiotomy syndrome, postoperative effusions, and atrial fibrillation after cardiac surgery, efficacy and safety of colchicine: evidence from the COPPS trial and substudies]. AB - Colchicine has been recently demonstrated to be efficacious and safe for the prevention of several postoperative complications including the postpericardiotomy syndrome (PPS), postoperative pericardial and pleural effusions, and postoperative atrial fibrillation according to the results of the COPPS trial. The aim of the present paper is to critically review the premise, results and implications of this trial for current clinical practice and future research. The COPPS study is a multicenter, double-blind, randomized trial. On the third postoperative day, 360 patients (mean age 65.7 +/- 12.3 years, 66% males) were randomized to receive placebo or colchicine (1.0 mg twice daily for the first day followed by 0.5 mg twice daily for 1 month in patients >=70 kg, and halved doses for patients <70 kg or intolerant to the highest dose). Colchicine significantly reduced the incidence of the PPS at 12 months [relative risk reduction (RRR) 58%; number needed to treat (NNT) 8], postoperative pericardial (RRR 43.9%; NNT 10) and pleural effusions (RRR 52.3%; NNT 8) as well as the incidence of postoperative atrial fibrillation (RRR, 45%; NNT 11) with similar side effects in the study groups. Colchicine is a promising drug for the prevention of several postoperative complications (PPS, postoperative effusions and postoperative atrial fibrillation) based on its anti-inflammatory effects and good tolerability at the study doses. Although further studies are needed before routine recommendation of the drug will be possible for patients undergoing cardiac surgery, colchicine seems to have the potentiality of becoming a new therapeutic standard in the perioperative period. PMID- 23022971 TI - [Snow shoveling and the risk of acute coronary syndromes: literature review and clinical experience during the heavy snowfall in winter 2012]. PMID- 23022972 TI - [Electrocardiographic identification of the culprit artery and occlusion site in ST-elevation myocardial infarction]. AB - BACKGROUND: In clinical practice, the identification of the culprit vessel and the localization of the occlusion site in ST-elevation myocardial infarction (STEMI) are provided by coronary angiography. Over the last few years, however, an increasing body of literature focused upon the reassessment of the ECG as a reliable technique to obtain this useful information. The aim of this study was to evaluate the accuracy of electrocardiographic criteria compared to coronary angiography. METHODS: On the basis of the available literature, we developed an electrocardiographic algorithm based on the analysis of ST-segment elevation and reciprocal depression, whose accuracy was verified through its use in our cohort of 343 consecutive patients during calendar years 2008-2010. All patients underwent emergent percutaneous coronary intervention in the setting of acute STEMI. Patients with left bundle branch block, pacemaker rhythm and/or with a history of previous reperfusion were excluded. The admission electrocardiograms were reviewed by experienced cardiologists blinded to the angiographic findings. RESULTS: The criteria adopted allowed a correct identification of the culprit vessel in 87.5% of cases. The sensitivity for left anterior descending, right coronary artery, left circumflex and diagonal branch/double anterior descending/ramus intermediate was 98.8%, 93.7%, 31.7% and 44.4%, respectively; the specificity was 94.3%, 87.6%, 99.0% and 99.1%, respectively. The proximal/distal location was correctly identified in 62.4% of cases. CONCLUSIONS: Our results confirm that careful interpretation of the ECG, which is a versatile and widely available tool, appears useful for the detection of the culprit vessel and the coronary occlusion site in STEMI patients, with relevant implications for clinical management and selection of appropriate therapeutic strategies. PMID- 23022973 TI - [Intra-aortic balloon counterpulsation in acute coronary syndromes: the thin line between use and over-use. Where is the evidence? Intra-aortic balloon counterpulsation is probably over-used]. PMID- 23022975 TI - [An unusual case of transient ST-segment elevation during hypertensive crisis in a patient with left ventricular hypertrophy]. AB - We report the case of a 73-year-old patient with severe left ventricular hypertrophy presenting with acute ST-segment elevation mimicking acute myocardial infarction on ECG during a hypertensive crisis. Unexpectedly, emergency coronary angiography showed no evidence of coronary thrombosis or spasm. Electrocardiographic alterations gradually resolved after lowering blood pressure. PMID- 23022974 TI - [Intra-aortic balloon counterpulsation in acute coronary syndromes: the thin line between use and over-use: intra-aortic balloon counterpulsation is an essential tool if properly used]. PMID- 23022976 TI - [Iatrogenic dissection of the left coronary artery managed by intravascular ultrasound-guided stenting]. PMID- 23022977 TI - [Comment on the Consensus Document "Coronary stenting and surgery" by Rossini et al]. PMID- 23022978 TI - [Intermittent intravenous infusion of high-dose loop diuretics and risk for iatrogenic ototoxicity: an unresolved issue from the DOSE study]. PMID- 23022979 TI - Chronotherapeutics--a chronopharmaceutical approach to drug delivery in the treatment of asthma. AB - Bronchial asthma is a chronic inflammatory disorder of the airways associated with airflow obstruction that is reversible spontaneously or with treatment. Bronchial asthma is a disease based on established circadian rhythm. The symptoms of asthma worsen during midnight to early morning and therefore it is required to deliver the drug in such fashion that effective treatment can be obtained during the time of asthma attacks. Chronotherapy is an approach that fulfills the criteria of drug delivery at a specific time as per the pathophysiological need of the disease, to improve patient compliance. The current article focuses on the chronotherapy of bronchial asthma, methodologies involved for the existing systems, recent updates and different chronopharmaceutical technologies currently available in the market. Chronotherapy with different categories of bronchial asthma medications also has been reviewed. PMID- 23022980 TI - Smith-Lemli-Opitz syndrome, cardiac defects, and spleen anomalies. PMID- 23022981 TI - Frontotemporal pachygyria-two new patients. AB - We describe two Finnish brothers with frontotemporal pachygyria, intellectual deficiency and mild dysmorphisms. Previously, only a few cases of similar frontotemporal pachygyria have been reported. This report provides further evidence about frontotemporal pachygyria being a distinct genetic entity inherited as an autosomal recessive trait. PMID- 23022982 TI - Neurotrauma outside the high-income setting: a review of audit and data collection strategies. AB - OBJECTIVE: To review the sparse literature that exists on the topic of head injury assessment and management outside high-income settings and attempt to: 1) identify strengths and weaknesses of the currently published clinical data relating to head injuries in lower-income countries; and 2) consider specific objectives for future head injury research in the resource-limited setting. If levels of excellence in neurosurgery are to be sustainably achieved outside high income countries, there must be good systems of research and audit in place both to identify where development is needed and to evaluate the efficacy of development projects already in progress. METHODS: We performed a MEDLINE search of publications between 1980 and 2010 by using the search terms head injuries/craniocerebral trauma/neurotrauma and developing world/developing nations. Information was extracted and compared between publications by using our local head injury evaluation and audit database (OxHEAD) as a quality standard. RESULTS: The issue of traumatic brain injury management in low-income countries is underrepresented in the international literature relative to the scale of the problem. However, epidemiologic data generally are better reported than data relating to in-hospital care and follow-up, which suffers as a result of heterogeneous data collection and categorization techniques. CONCLUSION: The use of standardized scoring systems and outcome measures is likely to improve the comparability of data between studies. A multicenter collaborative approach towards data collection in resource-limited settings may be the most efficient and productive strategy for future research. PMID- 23022983 TI - Chromosomal aberrations in peripheral blood lymphocytes in patients with newly diagnosed celiac and Crohn's disease. AB - OBJECTIVES: The aims of this research were to determine the number of chromosomal aberrations in peripheral blood lymphocytes and to evaluate the number of circulating lymphocytes with CD103, integrin expressed on intraepithelial lymphocytes and preserved in enteropathy-associated T-cell lymphoma, in patients with newly diagnosed Crohn's disease, celiac disease, and healthy controls. METHODS: During the period of 30 months, we included 44 patients. Chromosome aberrations were analyzed in peripheral blood lymphocytes by a single cytogeneticist. Multicolor flow cytometric was used for immunophenotyping of peripheral blood lymphocytes. RESULTS: We found a significantly higher number of chromosomal aberrations/100 metaphases in the celiac and Crohn's disease group compared with the controls (P=0.01) and they also had a significantly higher number of aberrant cells compared with the controls (P<0.001). There was no statistically significant difference between the groups with respect to the percentage of CD103+ and CD8+CD103+ cells between groups (P=0.16 and 0.41, respectively) and no correlation between the total number of chromosomal aberrations and the percentage of CD103+ and CD8+CD103+ cells (P=0.06 and 0.06, respectively). CONCLUSION: Patients with active celiac and newly diagnosed Crohn's disease, before treatment initiation, have a significantly increased number of chromosomal aberrations in peripheral blood lymphocytes. No dissemination of intraepithelial cells in the blood and correlation to the chromosomal aberration was found. PMID- 23022984 TI - Bilateral biliary drainage for malignant hilar obstruction using the 'stent-in stent' method with a Y-stent: efficacy and complications. AB - BACKGROUND: The usefulness of bilateral stent placement for malignant hilar obstruction is still under debate. Nevertheless, many endoscopists advocate the placement of an endoscopic bilateral metal stent using various new devices and techniques. OBJECTIVES: We compared the technical and clinical efficacy, and the short-term and long-term complications of the 'stent-in-stent' method using a Y stent for malignant hilar obstruction between the early and the late period of this study. MATERIALS AND METHODS: Ninety-seven patients treated with Y-stent implantation for malignant hilar obstruction were enrolled retrospectively. In 31 patients treated during the early period, bilateral Y-configured metal stents were placed for malignant hilar obstruction using the older designed Y-stent and a closed-cell second stent. The newly designed Y-stent and a slimmer open-cell second stent were introduced in 66 patients treated during the late period. New techniques learned through experience were gradually applied throughout the entire study period. RESULTS: The rate of successful placement of bilateral stents was significantly higher in patients treated during the late period than those treated during the early period (58.1 vs. 87%; P=0.001). The functional success rate was 97.3%, with no difference between the early and the late periods. Cholangitis occurred as an early complication more frequently during the early period than during the late period (16.1 vs. 1.5%; P=0.012). Cholecystitis as a late complication occurred in 21 of 76 patients (27.6%). The incidence of late complications was similar between the early and the late periods. CONCLUSION: With the development of new devices and increased technical experience, there were better outcomes during the late period compared with the early period. Endoscopic bilateral metal stenting using a Y-stent is an attractive option for the palliative treatment of malignant hilar obstruction. PMID- 23022985 TI - Temporal trends of Barrett's oesophagus and gastro-oesophageal reflux and related oesophageal cancer over a 10-year period in England and Wales and associated proton pump inhibitor and H2RA prescriptions: a GPRD study. AB - INTRODUCTION: There is an increasing burden of gastro-oesophageal reflux disease (GORD) and Barrett's oesophagus (BO), paralleled by an increasing incidence of oesophageal adenocarcinoma. METHODS: Using the General Practice Research Database, we derived the incidence GORD and BO and incidence of oesophageal cancer (OC) populations, between 1996 and 2005. Acid suppression treatment over the study period was also studied. RESULTS: There were 5860 patients with BO and 1 25 519 with GORD. The incidence of BO increased from 0.11 to 0.24/1000 men and from 0.06 to 0.11/1000 women. The incidence of GORD diagnosed in general practice remained stable. There were 69 incident OCs in patients with BOs and 183 incident OCs in patients with GORD occurring more than a year after the GORD diagnosis. The cumulative incidence of OC was 3.00/1000 BO patient years and 0.30/1000 GORD patient years. There was a progressive decrease in H2RA prescriptions from 39 to 14.5% and an increase in proton pump inhibitor prescriptions from 52 to 79% in patients with a new diagnosis of GORD. CONCLUSION: The incidence of BO has doubled from 1996 to 2005, whereas the incidence of GORD has remained stable. OC occurred 10 times more commonly in patients with BO than those with GORD. Proton pump inhibitor prescribing increased gradually over the study period. These trends have significant implications for healthcare planning and financing in the UK and other countries. PMID- 23022986 TI - Towards high-performance DPP-based sensitizers for DSC applications. AB - A novel, asymmetric DPP bridge/core was synthesized and tested in DSC devices. By desymmetrising the DPP core/bridge, a remarkable IPCE of >80% and a maximum power conversion efficiency of 7.7% were achieved. With the use of a wide-bandgap co sensitizer, 8.6% PCE was realized under standard AM1.5G sunlight. PMID- 23022987 TI - Acute myeloid leukemia with translocation (8;16)(p11;p13) and MYST3-CREBBP rearrangement harbors a distinctive microRNA signature targeting RET proto oncogene. AB - Acute myeloid leukemia (AML) with t(8;16)(p11;p13) (t(8;16) AML) has unique clinico-biological characteristics, but its microRNA pattern is unknown. We analyzed 670 microRNAs in seven patients with t(8;16) AML and 113 with other AML subtypes. Hierarchical cluster analysis showed that all t(8;16) AML patients grouped in an independent cluster. Supervised analysis revealed a distinctive signature of 94-microRNAs, most of which were downregulated, including miR-21 and cluster miR-17-92. The mRNA expression analysis of two known transcription factors of these microRNAs (STAT3 and c-Myc, respectively) showed significant downregulation of STAT3 (P=0.04). A bioinformatic analysis showed that 29 of the downregulated microRNAs might be regulated by methylation; we treated a t(8;16) AML sample with 5-aza-2'-deoxycytidine (5-AZA-dC) and trichostatin A and found that 27 microRNAs were re-expressed after treatment. However, there was no difference in methylation status between t(8;16) and other AML subtypes, either overall or in the microRNA promoter. Cross-correlation of mRNA and microRNA expression identified RET as a potential target of several microRNAs. A Renilla luciferase assay and flow cytometry after transfection with pre-microRNAs confirmed that RET is regulated by miR-218, miR-128, miR-27b, miR-15a and miR 195. In conclusion, t(8;16) AML harbors a specific microRNA signature that is partially epigenetically regulated and targets RET proto-oncogene. PMID- 23022988 TI - Visual specific luminescent probing of hybrid G-quadruplex DNA by a ruthenium polypyridyl complex. AB - A novel ruthenium(II) complex with specific luminescent selectivity towards hybrid G-quadruplex DNA was developed that can easily be distinguished by the naked eye without further treatment. PMID- 23022989 TI - Using noninferiority tests to evaluate telemedicine and e-health services: systematic review. AB - BACKGROUND: An increasing number of studies within the field of telemedicine and e-health are designed as noninferiority studies, aiming to show that the telemedicine/e-health solution is not inferior to the traditional way of treating patients. OBJECTIVE: The objective is to review and sum up the status of noninferiority studies within this field, describing advantages and pitfalls of this approach. METHODS: PubMed was searched according to defined criteria, and 16 relevant articles were identified from the period 2008-June 2011. RESULTS: Most of the studies were related to the fields of psychiatry and emergency medicine, and most were published in journals relating to these fields or in general scientific or general medicine journals. All the studies claimed to be noninferiority studies, but 7 out of 16 tested for statistical differences as a proxy of noninferiority. CONCLUSIONS: The methodological quality of the studies varied. We discuss optimal procedures for future noninferiority studies within the field of telemedicine and e-health and situations in which this approach is most appropriate. PMID- 23022990 TI - Should positron emission tomography/computed tomography be the first rather than the last test performed in the assessment of cancer? AB - Cancer is a major cause of illness and death in Western society and is associated with a heavy concomitant economic burden. Although use of imaging comprises only a small proportion of the fiscal impact of cancer, its use has been increasing over recent decades, causing concern amongst funders of health care and efforts to constrain the use of new imaging tests with a relatively high unit cost. In clinical practice, positron emission tomography/computed tomography (PET/CT) is generally performed when less expensive tests have left some uncertainty regarding appropriate management. In this setting, its utility relates to provision of incremental diagnostic information. However, given that superior diagnostic information can positively affect patient management, wherein the majority of costs reside, it may be both more efficient and cost effective to go directly to the most accurate investigation in certain situations. For PET/CT, the ability to provide more accurate assessment of metastatic status than is available from conventional diagnostic paradigms provides a rationale for its independent rather than incremental use in patients presenting with either a high likelihood of malignancy or proven malignancy of a locally advanced nature and an accordingly high risk of metastatic disease. A randomized trial design is described that could be used to test this hypothesis. PMID- 23022991 TI - The Wnt/beta-catenin signaling pathway establishes neuroanatomical asymmetries and their laterality. AB - The vertebrate brain is an immensely complex structure, which exhibits numerous morphological and functional asymmetries. The best described brain asymmetries are found in the diencephalic epithalamus, where the habenulae and the dorso laterally adjacent pineal complex are lateralized in many species. Research in the past decade has shed light on the establishment of the laterality of these structures as well as their asymmetry per se. In particular work in zebrafish (Danio rerio) has substantially contributed to our understanding, which genetic pathways are involved in these processes. The Wnt/beta-catenin pathway has turned out to play a pivotal role in the regulation of brain laterality and asymmetry and acts reiteratively during embryonic development. PMID- 23022992 TI - Measuring the subjective value of risky and ambiguous options using experimental economics and functional MRI methods. AB - Most of the choices we make have uncertain consequences. In some cases the probabilities for different possible outcomes are precisely known, a condition termed "risky". In other cases when probabilities cannot be estimated, this is a condition described as "ambiguous". While most people are averse to both risk and ambiguity(1,2), the degree of those aversions vary substantially across individuals, such that the subjective value of the same risky or ambiguous option can be very different for different individuals. We combine functional MRI (fMRI) with an experimental economics-based method(3 )to assess the neural representation of the subjective values of risky and ambiguous options(4). This technique can be now used to study these neural representations in different populations, such as different age groups and different patient populations. In our experiment, subjects make consequential choices between two alternatives while their neural activation is tracked using fMRI. On each trial subjects choose between lotteries that vary in their monetary amount and in either the probability of winning that amount or the ambiguity level associated with winning. Our parametric design allows us to use each individual's choice behavior to estimate their attitudes towards risk and ambiguity, and thus to estimate the subjective values that each option held for them. Another important feature of the design is that the outcome of the chosen lottery is not revealed during the experiment, so that no learning can take place, and thus the ambiguous options remain ambiguous and risk attitudes are stable. Instead, at the end of the scanning session one or few trials are randomly selected and played for real money. Since subjects do not know beforehand which trials will be selected, they must treat each and every trial as if it and it alone was the one trial on which they will be paid. This design ensures that we can estimate the true subjective value of each option to each subject. We then look for areas in the brain whose activation is correlated with the subjective value of risky options and for areas whose activation is correlated with the subjective value of ambiguous options. PMID- 23022993 TI - Elevated cortisol inhibits adrenocorticotropic hormone- and serotonin-stimulated cortisol secretion from the interrenal cells of the Gulf toadfish (Opsanus beta). AB - Stimulation of the toadfish 5-HT(1A) receptor by serotonin (5-hydroxytryptamine; 5-HT) or 8-OH-DPAT, a 5-HT(1A) receptor agonist, results in a significant elevation in plasma cortisol. Conversely, chronic elevation of plasma cortisol has been shown to decrease brain 5-HT(1A) receptor mRNA and protein levels via the glucocorticoid receptor (GR); however, there appears to be a disconnect between brain levels of the receptor and cortisol release. We hypothesized that elevated plasma cortisol would inhibit both adrenocorticotropic hormone (ACTH)- and 5-HT-stimulated cortisol release from the interrenal cells of Gulf toadfish, that ACTH sensitivity would not be GR-mediated and 5-HT-stimulated cortisol release would not be via the 5-HT(1A) receptor. To test these hypotheses, interrenal cells from uncrowded, crowded, vehicle-, and cortisol-implanted toadfish were incubated with either ACTH, 5-HT or 5-HT receptor agonists, and cortisol secretion was measured. Incubation with ACTH or 5-HT resulted in a stimulation of cortisol secretion in uncrowded toadfish. Cortisol secretion in response to ACTH was not affected in crowded fish; however, interrenal cells from cortisol-implanted toadfish secreted significantly less cortisol than controls, a response that was not reversed upon treatment with the GR antagonist RU486. 5-HT stimulated cortisol release was significantly lower from both crowded and cortisol-implanted toadfish interrenal cells compared to controls. Incubation with either a 5-HT(4) or a 5-HT(2) receptor agonist significantly stimulated cortisol secretion; however, incubation with 8-OH-DPAT did not, suggesting that the 5-HT(1A) receptor is not a mediator of cortisol release at the level of the interrenal cells. Combined, these results explain in part the disconnect between brain 5-HT(1A) levels and cortisol secretion. PMID- 23022994 TI - The effect of isoflurane anaesthesia and vasectomy on circulating corticosterone and ACTH in BALB/c mice. AB - The use of blood corticosterone and faecal corticosterone metabolites as biomarkers of post-surgical stress and pain in laboratory animals has increased during the last decade. However, many aspects of their reliability in laboratory mice remain uninvestigated. This study investigated serum corticosterone and adrenocorticotropic hormone (ACTH) in mice subjected to isoflurane anaesthesia and vasectomy, and mice subjected to isoflurane anaesthesia without surgery. Serum levels of corticosterone and ACTH after pre-treatment with dexamethasone were analysed to provide further information about the stress hormone profiles. Vasectomy resulted in an increase in corticosterone for at least four hours after surgery with a peak 30min after the mice regained righting reflex. Mice subjected to isoflurane anaesthesia without surgery had the highest level of serum corticosterone 5min after regained righting reflex and the level returned to baseline levels four hours after the procedure. In vasectomised mice, treated with dexamethasone, high levels of corticosterone remained 30min after the procedure, whereas the anaesthetised mice, treated with dexamethasone, had significantly lower levels of corticosterone compared to anaesthetised mice not treated with dexamethasone. Thus, dexamethasone effectively inhibited the corticosterone response in the anaesthetised-only mice, but not in the mice subjected to surgery. In conclusion, both isoflurane anaesthesia and vasectomy during isoflurane anaesthesia resulted in an increase in serum glucocorticoids, but the negative feedback mechanism of newly operated mice, was altered. This may have consequences for the interpretation of glucocorticoids measurements as a biomarker of post-surgical stress in mice. PMID- 23022995 TI - c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. AB - BACKGROUND: Activation of the c-Met pathway occurs in a range of malignancies, including papillary renal cell carcinoma (RCC). Its activity in clear cell RCC is less clear. We investigated c-Met expression and inhibition in a large cohort of RCC tumors and cell lines. METHODS: c-Met protein expression was determined by automated quantitative analysis (AQUA) on a tissue microarray (TMA) constructed from 330 RCC tumors paired with adjacent normal renal tissue. c-Met expression and selective inhibition with SU11274 and ARQ 197 were studied in clear cell RCC cell lines. RESULTS: Higher c-Met expression was detected in all RCC subtypes than in the adjacent normal renal tissue (P < 0.0001). Expression was highest in papillary and sarcomatoid subtypes, and high-grade and stage tumors. Higher c-Met expression correlated with worse disease-specific survival [risk ratio = 1.36; 95% confidence interval (CI) 1.08-1.74; P = 0.0091] and was an independent predictor of survival, maintained in clear cell subset analyses. c-Met protein was activated in all cell lines, and proliferation (and colony formation) was blocked by SU11274 and ARQ 197. CONCLUSIONS: c-Met is associated with poor pathologic features and prognosis in RCC. c-Met inhibition demonstrates in vitro activity against clear cell RCC. Further study of ARQ 197 with appropriate biomarker studies in RCC is warranted. PMID- 23022996 TI - Progesterone receptor loss identifies Luminal B breast cancer subgroups at higher risk of relapse. AB - BACKGROUND: The immunohistochemical (IHC) evaluation of estrogen receptor (ER), progesterone receptor (PgR), Ki-67 and HER2 is considered a surrogate means for identifying the molecular subtypes of breast cancer with different prognosis. PATIENTS AND METHODS: We explored patterns of recurrence in 4837 women with breast cancer defined as Luminal B (ER-positive and/or PgR-positive, HER2 positive and/or Ki-67>=14%) by IHC classification. We evaluated four subgroups within the Luminal B subtype according to HER2 expression and PgR status. RESULTS: Patients within the ER+/PgR+/HER2- subgroup presented a 5-year breast cancer-related survival (BCS) of 97% (95% confidence interval (CI), 96-97) and overall survival (OS) of 95% [95% CI, 95-96], the best survivals of the Luminal B subgroups. In the multivariate analysis, the ER+/PgR-/HER2- subgroup was associated with a reduced BCS (HR 1.71; 95%CI, 1.25-2.35) and OS (HR 1.47; 95%CI, 1.10-1.96) when compared with the ER+/PgR+/HER2- subgroup. Also patients within the ER+/PgR-/HER2+ subgroup had a reduced BCS (HR 1.93; 95%CI, 1.32-2.83) and OS (HR 1.62; 95%CI, 1.14-2.30) when compared with ER+/PgR+/HER2- subgroup. On the other hand, no statistically significant differences were found with regard to BCS and OS among patients with ER+/PgR+/HER2+ and patients with ER+/PgR+/HER2- disease. CONCLUSIONS: PgR loss identifies Luminal B breast cancer subgroups at higher risk of relapse and death, both with HER-2-positive and HER-2-negative disease. PMID- 23022997 TI - Human epidermal growth factor receptor-2-positive breast cancer: does estrogen receptor status define two distinct subtypes? AB - BACKGROUND: Human epidermal growth factor receptor-2 (HER2) overexpression occurs in ~20% of breast cancers and has historically been associated with decreased survival. Despite substantial improvements in clinical outcomes, particularly with the emergence of HER2-targeted therapy, a substantial minority of patients still relapses, and progression is inevitable in metastatic disease. Accumulating data indicate that HER2-positive disease is itself a heterogeneous entity. METHODS AND RESULTS: In this article, we qualitatively review the data supporting the classification of HER2-positive disease as at least two separate entities, distinguished by estrogen receptor (ER) status. We summarize differences in clinical outcomes, including response to neoadjuvant therapy, timing and patterns of dissemination, efficacy of therapy in the metastatic setting and survival outcomes. CONCLUSIONS: The collective data are sufficiently strong at this point to propose that ER status defines two distinct subtypes within HER2-positive breast cancer, and we highlight the implications of this knowledge in future research, including understanding of the basic biology of HER2-positive breast cancer and the design of future clinical trials. PMID- 23022998 TI - The prognostic role of TGF-beta signaling pathway in breast cancer patients. AB - BACKGROUND: The transforming growth factor-beta (TGF-beta) pathway has dual effects on tumor growth. Seemingly, discordant results have been published on the relation between TGF-beta signaling markers and prognosis in breast cancer. Improved prognostic information for breast cancer patients might be obtained by assessing interactions among TGF-beta signaling biomarkers. PATIENTS AND METHODS: The expression of nuclear Smad4, nuclear phosphorylated-Smad2 (p-Smad2), and the membranous expression of TGF-beta receptors I and II (TbetaRI and TbetaRII) was determined on a tissue microarray of 574 breast carcinomas. Tumors were stratified according to the Smad4 expression in combination with p-Smad2 expression or Smad4 in combination with the expression of both TGF-beta receptors. RESULTS: Tumors with high expression of TbetaRII, TbetaRI and TbetaRII, and p-Smad2 (P = 0.018, 0.005, and 0.022, respectively), and low expression of Smad4 (P = 0.005) had an unfavorable prognosis concerning progression-free survival. Low Smad4 expression combined with high p-Smad2 expression or low expression of Smad4 combined with high expression of both TGF beta receptors displayed an increased hazard ratio of 3.04 [95% confidence interval (CI) 1.390-6.658] and 2.20 (95% CI 1.464-3.307), respectively, for disease relapse. CONCLUSIONS: Combining TGF-beta biomarkers provides prognostic information for patients with stage I-III breast cancer. This can identify patients at increased risk for disease recurrence that might therefore be candidates for additional treatment. PMID- 23023000 TI - Oral administration of Bifidobacterium longum CECT 7347 modulates jejunal proteome in an in vivo gliadin-induced enteropathy animal model. AB - Celiac disease is an immune-mediated disorder triggered by gluten proteins of wheat (gliadins) and other cereals. Gliadin-mediated effects on weanling animals, sensitized or not with interferon (IFN)-gamma, were investigated. Also, the influence of the co-administration of Bifidobacterium longum CECT 7347 was studied together with changes in the proteome of jejunal sections, using 2DE and MALDITOF-TOF peptide fingerprinting. Findings were compared to results for control animal groups. In the principal component analysis (PCA) of proteome pattern, two components were extracted accounting for 79.8% of variability in the expression of the identified proteins. PCA analysis clearly discriminated between the proteome of animals fed gliadins alone and those fed gliadins and B. longum simultaneously. However, the proteome patterns from animals sensitized with IFN gamma and fed gliadins together with B. longum, or alone, could not be discriminated. Gliadin feeding caused inflammatory effects as well as changes in proteins involved in intracellular ionic homeostasis, lipid turnover, cell motility and redox regulation in intestinal sections. After feeding gliadins to animals sensitized with IFN-gamma, changes were also detected in proteins involved in recruitment and function of inmunocompetent cells, trophic effect on the intestine and organization of myofibers reflecting the more marked gliadin mediated injury in jejunal sections. The administration of the bacterial strain to rats fed gliadins seemed to ameliorate the inflammation caused by gliadin feeding alone, although, in sensitized animals the co-administration of B. longum had less marked effects, which was probably due to the more extensive intestinal mucosal damage. The proteome patterns in animals administered B. longum alone did not reveal any changes reflecting impairment of jejunal functions. PMID- 23022999 TI - Cleavage of hyaluronan is impaired in aged dermal wounds. AB - Changes in extracellular matrix (ECM) are one of many components that contribute to impaired wound healing in aging. This study examined the effect of age on the glycosaminoglycan hyaluronan (HA) in normal and wounded dermis from young (4-6 month-old) and aged (22-24 month-old) mice. HA content and size were similar in the normal dermis of young and aged mice. Dermal explants labeled with [(3)H] glucosamine showed decreased generation of smaller forms of HA in aged explants relative to young explants. Aged mice exhibited delayed wound repair compared with young mice with the greatest differential at 5 days. Expression of hyaluronan synthase (HAS) 2 and 3, and hyaluronidase (HYAL) 1-3 mRNA in wounds of young and aged mice was similar. There was a trend toward a decreased HYAL protein expression in aged wound dermis, which was accompanied by changes in detectable HYAL activity. Total HA content was similar in young and aged wound dermis. There was significantly less HA in the lower MW range (~250 kDa and smaller) in 5-day wound dermis, but not in 9-day wound dermis, from aged mice relative to young mice. We propose that decreased cleavage of HA is an additional component of impaired dermal wound healing in aging. PMID- 23023001 TI - Receptors and other signaling proteins required for serotonin control of locomotion in Caenorhabditis elegans. AB - A better understanding of the molecular mechanisms of signaling by the neurotransmitter serotonin is required to assess the hypothesis that defects in serotonin signaling underlie depression in humans. Caenorhabditis elegans uses serotonin as a neurotransmitter to regulate locomotion, providing a genetic system to analyze serotonin signaling. From large-scale genetic screens we identified 36 mutants of C. elegans in which serotonin fails to have its normal effect of slowing locomotion, and we molecularly identified eight genes affected by 19 of the mutations. Two of the genes encode the serotonin-gated ion channel MOD-1 and the G-protein-coupled serotonin receptor SER-4. mod-1 is expressed in the neurons and muscles that directly control locomotion, while ser-4 is expressed in an almost entirely non-overlapping set of sensory and interneurons. The cells expressing the two receptors are largely not direct postsynaptic targets of serotonergic neurons. We analyzed animals lacking or overexpressing the receptors in various combinations using several assays for serotonin response. We found that the two receptors act in parallel to affect locomotion. Our results show that serotonin functions as an extrasynaptic signal that independently activates multiple receptors at a distance from its release sites and identify at least six additional proteins that appear to act with serotonin receptors to mediate serotonin response. PMID- 23023002 TI - Targeting of >1.5 Mb of human DNA into the mouse X chromosome reveals presence of cis-acting regulators of epigenetic silencing. AB - Regulatory sequences can influence the expression of flanking genes over long distances, and X chromosome inactivation is a classic example of cis-acting epigenetic gene regulation. Knock-ins directed to the Mus musculus Hprt locus offer a unique opportunity to analyze the spread of silencing into different human DNA sequences in the identical genomic environment. X chromosome inactivation of four knock-in constructs, including bacterial artificial chromosome (BAC) integrations of over 195 kb, was demonstrated by both the lack of expression from the inactive X chromosome in females with nonrandom X chromosome inactivation and promoter DNA methylation of the human transgene in females. We further utilized promoter DNA methylation to assess the inactivation status of 74 human reporter constructs comprising >1.5 Mb of DNA. Of the 47 genes examined, only the PHB gene showed female DNA hypomethylation approaching the level seen in males, and escape from X chromosome inactivation was verified by demonstration of expression from the inactive X chromosome. Integration of PHB resulted in lower DNA methylation of the flanking HPRT promoter in females, suggesting the action of a dominant cis-acting escape element. Female-specific DNA hypermethylation of CpG islands not associated with promoters implies a widespread imposition of DNA methylation during X chromosome inactivation; yet transgenes demonstrated differential capacities to accumulate DNA methylation when integrated into the identical location on the inactive X chromosome, suggesting additional cis-acting sequence effects. As only one of the human transgenes analyzed escaped X chromosome inactivation, we conclude that elements permitting ongoing expression from the inactive X are rare in the human genome. PMID- 23023003 TI - Structure-function dissection of the frizzled receptor in Drosophila melanogaster suggests different mechanisms of action in planar polarity and canonical Wnt signaling. AB - Members of the Frizzled family of sevenpass transmembrane receptors signal via the canonical Wnt pathway and also via noncanonical pathways of which the best characterized is the planar polarity pathway. Activation of both canonical and planar polarity signaling requires interaction between Frizzled receptors and cytoplasmic proteins of the Dishevelled family; however, there has been some dispute regarding whether the Frizzled-Dishevelled interactions are the same in both cases. Studies looking at mutated forms of Dishevelled suggested that stable recruitment of Dishevelled to membranes by Frizzled was required only for planar polarity activity, implying that qualitatively different Frizzled-Dishevelled interactions underlie canonical signaling. Conversely, studies looking at the sequence requirements of Frizzled receptors in the fruit fly Drosophila melanogaster for canonical and planar polarity signaling have concluded that there is most likely a common mechanism of action. To understand better Frizzled receptor function, we have carried out a large-scale mutagenesis in Drosophila to isolate novel mutations in frizzled that affect planar polarity activity and have identified a group of missense mutations in cytosolic-facing regions of the Frizzled receptor that block Dishevelled recruitment. Interestingly, although some of these affect both planar polarity and canonical activity, as previously reported for similar lesions, we find a subset that affect only planar polarity activity. These results support the view that qualitatively different Frizzled Dishevelled interactions underlie planar polarity and canonical Wnt signaling. PMID- 23023004 TI - Local ancestry corrects for population structure in Saccharomyces cerevisiae genome-wide association studies. AB - Genome-wide association studies (GWAS) have become an important method for mapping the genetic loci underlying complex phenotypic traits in many species. A crucial issue when performing GWAS is to control for the underlying population structure because not doing so can lead to spurious associations. Population structure is a particularly important issue in nonhuman species since it is often difficult to control for population structure during the study design phase, requiring population structure to be corrected statistically after the data have been collected. It has not yet been established if GWAS is a feasible approach in Saccharomyces cerevisiae, an important model organism and agricultural species. We thus performed an empirical study of statistical methods for controlling for population structure in GWAS using a set of 201 phenotypic traits measured in multiple resequenced strains of S. cerevisiae. We complemented our analysis of real data with an extensive set of simulations. Our main result is that a mixed linear model using the local ancestry of the strain as a covariate is effective at controlling for population structure, consistent with the mosaic structure of many S. cerevisiae strains. We further studied the evolutionary forces acting on the GWAS SNPs and found that SNPs associated with variation in phenotypic traits are enriched for low minor allele frequencies, consistent with the action of negative selection on these SNPs. Despite the effectiveness of local ancestry correction, GWAS remains challenging in highly structured populations, such as S. cerevisiae. Nonetheless, we found that, even after correcting for population structure, there is still sufficient statistical power to recover biologically meaningful associations. PMID- 23023005 TI - Genomic imprinting leads to less selectively maintained polymorphism on X chromosomes. AB - Population-genetic models are developed to investigate the consequences of viability selection at a diallelic X-linked locus subject to genomic imprinting. Under complete paternal-X inactivation, a stable polymorphism is possible under the same conditions as for paternal-autosome inactivation with differential selection on males and females. A necessary but not sufficient condition is that there is sexual conflict, with selection acting in opposite directions in males and females. In contrast, models of complete maternal-X inactivation never admit a stable polymorphism and alleles will either be fixed or lost from the population. Models of complete paternal-X inactivation are more complex than corresponding models of maternal-X inactivation, as inactivation of paternally derived X chromosomes in females screens these chromosomes from selection for a generation. We also demonstrate that polymorphism is possible for incomplete X inactivation, but that the parameter conditions are more restrictive than for complete paternal-X inactivation. Finally, we investigate the effects of recurrent mutation in our models and show that deleterious alleles in mutation selection balance at imprinted X-linked loci are at frequencies rather similar to those with corresponding selection pressures and mutation rates at unimprinted loci. Overall, our results add to the reasons for expecting less selectively maintained allelic variation on X chromosomes. PMID- 23023006 TI - Unusual case of apparent hypermutation in Arabidopsis thaliana. AB - The dms4 (defective in meristem silencing 4) mutant of Arabidopsis thaliana is unique in having defects in both RNA-directed DNA methylation (RdDM) and plant development. DMS4 is an evolutionarily conserved, putative transcription factor of the Iwr1 (interacts with RNA polymerase II) type. DMS4 interacts with Pol II and also with RNA polymerases IV and V, which function in RdDM. Interactions with multiple polymerases may account for the diverse phenotypic effects of dms4 mutations. To dissect further the roles of DMS4 in RdDM and development, we performed a genetic suppressor screen using the dms4-1 allele, which contains in the sixth intron a splice site acceptor mutation that alters splicing and destroys the open reading frame. Following mutagenesis of dms4-1 seeds using ethyl methanesulfonate (EMS), we retrieved four dominant intragenic suppressor mutations that restored DMS4 function and wild-type phenotypes. Three of the four intragenic suppressor mutations created new splice site acceptors, which resulted in reestablishment of the wild-type open reading frame. Remarkably, the intragenic suppressor mutations were recovered at frequencies ranging from 35 to 150 times higher than expected for standard EMS mutagenesis in Arabidopsis. Whole genome sequencing did not reveal an elevated mutation frequency genome-wide, indicating that the apparent hypermutation was confined to four specific sites in the dms4 gene. The localized high mutation frequency correlated with restoration of DMS4 function implies an efficient mechanism for targeted mutagenesis or selection of more fit revertant cells in the shoot apical meristem, thereby rapidly restoring a wild-type phenotype that is transmitted to future generations. PMID- 23023007 TI - Insertional mutagenesis by a hybrid piggyBac and sleeping beauty transposon in the rat. AB - A hybrid piggyBac/Sleeping Beauty transposon-based insertional mutagenesis system that can be mobilized by simple breeding was established in the rat. These transposons were engineered to include gene trap sequences and a tyrosinase (Tyr) pigmentation reporter to rescue the albinism of the genetic background used in the mutagenesis strategy. Single-copy transposon insertions were transposed into the rat genome by co-injection of plasmids carrying the transposon and RNA encoding piggyBac transposase into zygotes. The levels of transgenic Tyr expression were influenced by chromosomal context, leading to transgenic rats with different pigmentation that enabled visual genotyping. Transgenic rats designed to ubiquitously express either piggyBac or Sleeping Beauty transposase were generated by standard zygote injection also on an albino background. Bigenic rats carrying single-copy transposons at known loci and transposase transgenes exhibited coat color mosaicism, indicating somatic transposition. PiggyBac or Sleeping Beauty transposase bigenic rats bred with wild-type albino rats yielded offspring with pigmentation distinct from the initial transposon insertions as a consequence of germline transposition to new loci. The germline transposition frequency for Sleeping Beauty and piggyBac was ~10% or about one new insertion per litter. Approximately 50% of the insertions occurred in introns. Chimeric transcripts containing endogenous and gene trap sequences were identified in Gabrb1 mutant rats. This mutagenesis system based on simple crosses and visual genotyping can be used to generate a collection of single-gene mutations in the rat. PMID- 23023008 TI - Correction of phenotype misclassification based on high-discrimination genetic predictive risk models. AB - Misclassification of phenotype status can seriously affect accuracy in association studies, including studies of genetic risk factors. A common problem is the classification of participants as nondiseased because of insufficient diagnostic workup or because participants have not been followed up long enough to develop disease. Some validated predictive models may have high discrimination in predicting disease. We suggest that information from such models can be used to predict the risk that a nondiseased participant will eventually develop disease and to recode the status of participants predicted to be at highest risk. We evaluate conditions under which recoding results in a maximal net improvement in the accuracy of phenotype classification. Net improvement is expected only when the positive likelihood ratio of the predictive model is larger than the inverse of the odds of disease among apparently nondiseased controls. We conducted simulations to probe the impact of reclassification on the power to detect new risk factors under several scenarios of classification accuracy of the previously developed models. We also apply this framework to a validated model of progression to advanced age-related macular degeneration that uses genetic and nongenetic variables (area under the curve = 0.915). In the training cohort (n = 2,937) and a separate validation cohort (n = 1,227), 195-272 and 78-91 nonprogressor participants, respectively, were reclassified as progressors. Correction of phenotype misclassification based on highly informative predictive models may be helpful in identifying additional genetic and other risk factors, when there are validated risk factors that provide strong discriminating ability. PMID- 23023009 TI - Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular carcinoma: analysis of prognostic factors. AB - BACKGROUND & AIMS: The aim was to assess 10-year outcomes of radiofrequency ablation as a first-line therapy of early-stage hepatocellular carcinoma with an analysis of prognostic factors. METHODS: From April 1999 to April 2011, 1305 patients (male:female=993:312; mean age, 58.4 years) with 1502 early-stage hepatocellular carcinomas (mean size, 2.2 cm) were treated with percutaneous radiofrequency ablation as a first-line option. Follow-up period ranged from 0.4 to 146.6 months (median, 33.4 months). We assessed the 10-year follow-up results of recurrences and survival with the analyses of prognostic factors. RESULTS: Recurrences occurred in 795 patients (1-17 times), which were managed with various therapeutic modalities. The cumulative local tumor progression rates were 27.0% and 36.9% at 5 and 10 years, respectively, for which the only significant risk factor was large tumor size (B=0.584, p=0.001). Cumulative intrahepatic distant and extrahepatic recurrence rates were 73.1% and 88.5%, and 19.1% and 38.2% at 5 and 10 years, respectively. Corresponding overall survival rates were 59.7% and 32.3%, respectively. Poor survival was associated with old age (B=0.043, p=0.010), Child-Pugh class B (B=-1.054, p<0.001), absence of antiviral therapy during follow-up (B=-0.699, p=0.034), and presence of extrahepatic recurrence (B=0.971, p=0.007). CONCLUSIONS: Ten-year survival outcomes after percutaneous radiofrequency ablation as a first-line therapy of hepatocellular carcinoma were excellent despite frequent tumor recurrences. Overall survival was influenced by age, Child-Pugh class, antiviral therapy, or extrahepatic recurrence. PMID- 23023010 TI - Early tacrolimus exposure after liver transplantation: relationship with moderate/severe acute rejection and long-term outcome. AB - BACKGROUND & AIMS: Liver transplant (LT) patients might be overimmunosuppressed as recommendations for tacrolimus trough concentrations (TC) within 4-6 weeks after liver transplantation are set too high (10-15 ng/ml). Early tacrolimus exposure was evaluated in relation to acute rejection and long-term outcomes. METHODS: Four hundred and ninety-three consecutive LT patients receiving tacrolimus as primary immunosuppression (1995-2008) were analyzed. Acute rejection was diagnosed using protocol biopsies at day 6.1 +/- 2.5. Median follow up was 7.3 years (IQR 3.9-10.5). Early tacrolimus exposure (<15 days) was evaluated against moderate/severe acute rejection, chronic rejection, graft loss, chronic renal impairment and mortality using multiple logistic and Cox regression. RESULTS: Maintenance immunosuppression was tacrolimus monotherapy (48.1%), double therapy combination with antimetabolites or steroids (18%), or triple therapy combination with antimetabolites and steroids (33.9%). Histological grade of acute rejection was moderate in 157 cases (31.8%) and severe in 19 cases (3.9%). Tacrolimus TC>7 ng/ml on the day of protocol biopsy was associated with less moderate/severe rejection (23.8%) compared with<7 ng/ml (41.2%) (p = 0.004). Mean tacrolimus TC 7-10 ng/ml within 15 days after LT were associated with reduced risk of graft loss (RR = 0.46; p = 0.014) compared to TC 10-15 ng/ml. A peak TC>20 ng/ml within this period was independently related to higher mortality (RR = 1.67; p = 0.005), particularly due to cardiovascular events, infections and malignancy (RR = 2.15; p = 0.001). Early tacrolimus exposure did not influence chronic rejection (p = 0.58), or chronic renal impairment (p = 0.25). CONCLUSIONS: During the first 2 weeks after LT, tacrolimus TC between 7 and 10 ng/ml are safe in terms of acute rejection and are associated with longer graft survival. PMID- 23023011 TI - Increased viral quasispecies evolution in HBeAg seroconverter patients treated with oral nucleoside therapy. AB - BACKGROUND & AIMS: Increased viral diversity and evolution appear to be a pre HBeAg-seroconversion feature in spontaneous and interferon-treated seroconverters. The aim of this study was to examine the viral evolution pattern in nucleoside analogue related HBeAg-seroconversion. METHODS: This was a case control study consisting of ten lamivudine-treated HBeAg-seroconverters and ten lamivudine-treated non-seroconverters as matching controls. All patients in this study were followed as long as 6 years after starting lamivudine, and cases had three serum time points before HBeAg-seroconversion while controls had three matching serum time points. Nested PCR, cloning and sequencing of HBV precore/core gene were performed. Sequences were aligned with Clustal X 2.0. Phylogenetic trees were constructed and viral diversity, evolutionary rates and patterns of positive selection were evaluated. RESULTS: After starting lamivudine treatment, HBV viral diversity increased in both seroconverters and non seroconverters, but seroconverters showed a significantly higher level of viral diversity that persisted over time by 2.1-fold (p = 0.009). The increased viral diversity correlated with reduced HBV DNA levels (p <0.001). Lamivudine-treated seroconverters had significant reduced HBV DNA concurrent with increased viral diversity after starting treatment (p = 0.001, compared to non-seroconverters, and resembled those of interferon-seroconverters published previously). There was evidence of positive selection in seroconverters with significantly increased amino acid changes compared to non-seroconverters (p <0.001), occurring in recognized T-cell and B-cell epitopes. CONCLUSIONS: Lamivudine-treated HBeAg seroconverters showed a higher viral diversity than non-seroconverters, and the pattern resembled that of interferon-treated seroconverters. The findings strengthen the evidence that increased viral diversity is strongly associated with HBeAg-seroconversion. PMID- 23023012 TI - Alterations in the redox state and liver damage: hints from the EASL Basic School of Hepatology. AB - The importance of a correct balance between oxidative and reductive events has been shown to have a paramount effect on cell function for quite a long time. However, in spite of this body of rapidly growing evidence, the implication of the alteration of the redox state in human disease has been so far much less appreciated. Liver diseases make no exception. Although not fully comprehensive, this article reports what discussed during an EASL Basic School held in 2012 in Trieste, Italy, where the effect of the alteration of the redox state was addressed in different experimental and human models. This translational approach resulted in further stressing the concept that this topic should be expanded in the future not only to better understand how oxidative stress may be linked to a liver damage but also, perhaps more important, how this may be the target for better, more focused treatments. In parallel, understanding how alteration of the redox balance may be associated with liver damage may help define sensitive and ideally early biomarkers of the disorder. PMID- 23023013 TI - Fondaparinux (Arixtra *) hepatotoxicity in a 6 year-old child. PMID- 23023014 TI - Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice. AB - BACKGROUND & AIMS: The important function of toll-like receptor (TLR) 4 in Kupffer cells and hepatic stellate cells (HSCs) has been well documented in alcoholic liver injury. However, little is known about the role of TLR3. Thus, we tested whether TLR3 activation in HSCs and Kupffer cells could attenuate alcoholic liver injury in vivo, and investigated its possible mechanism in vitro. METHODS: Alcoholic liver injury was achieved by feeding wild type (WT), TLR3 knockout (TLR3(-/-)) and interleukin (IL)-10(-/-) mice with high-fat diet plus binge ethanol drinking for 2 weeks. To activate TLR3, polyinosinic-polycytidylic acid (poly I:C) was injected into mice. For in vitro studies, HSCs and Kupffer cells were isolated and treated with poly I:C. RESULTS: In WT mice, poly I:C treatment reduced alcoholic liver injury and fat accumulation by suppressing nuclear factor-kappaB activation and sterol response element-binding protein 1c expression in the liver. In addition, freshly isolated HSCs and Kupffer cells from poly I:C-treated mice showed enhanced expression of IL-10 compared to controls. Infiltrated macrophage numbers and the expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1 and IL-6 on these cells were decreased after poly I:C treatment. In vitro, poly I:C treatment enhanced the expression of IL-10 via a TLR3-dependent mechanism in HSCs and Kupffer cells. Finally, the protective effects of poly I:C on alcoholic liver injury were diminished in TLR3(-/-) and IL-10(-/-) mice. CONCLUSIONS: TLR3 activation ameliorates alcoholic liver injury via the stimulation of IL-10 production in HSCs and Kupffer cells. TLR3 could be a novel therapeutic target for the treatment of alcoholic liver injury. PMID- 23023015 TI - High osteoporotic fracture risk and CVD risk co-exist in postmenopausal women. AB - INTRODUCTION: Osteoporosis related risk factors such as BMD have been associated with cardiovascular endpoints in previous studies but there have been no studies of integrated risk using risk factor algorithms. METHODS: A sample of 358 peri- and postmenopausal women, mean age 59.3 (range 45-74) years were studied. Each individual had bone mineral density (BMD) measurements by dual energy X-ray absorptiometry. Fracture risk was assessed using the WHO FRAX algorithm and cardiovascular disease (CVD) risk using the Framingham Risk Tool. RESULTS: Women with higher 10 year risk of major osteoporotic had significantly higher cardiovascular risk (4.634% vs 8.36%, p=0.001). In multiple regression analysis, 5-year CVD risk was significantly associated with the 10-year risk of having major osteoporotic (beta=0.095, p=0.001) and hip (beta=0.055, p=0.001) fracture. Women with the highest CVD risk were 5.4 times more likely to have higher risk of major osteoporotic fracture. CONCLUSIONS: Fracture risk, determined by using a multiple risk factor algorithm such as FRAX, was positively associated with higher cardiovascular risk determined by using the Framingham Risk Tool. Awareness regarding these concurrent risk factors needs to be raised so that appropriate risk reduction can be implemented. PMID- 23023016 TI - Cutaneous intravascular anaplastic large T-cell lymphoma: a case report and review of the literature. AB - Intravascular lymphoma (IVL) is a rare subtype of extranodal lymphoma. In the 2008 WHO classification of tumors of the hematopoietic and lymphoid tissues intravascular large B-cell lymphoma is included as a distinct entity. IVL of T cell type is not included as a diagnostic category and is only mentioned in passing by Nakamura et al. as "a different entity" in their discussion of intravascular large B-cell lymphoma. T-cell IVL is rare, the majority of cases being of natural killer/T-cell phenotype. Exceptionally rare is primary cutaneous intravascular anaplastic large T-cell lymphoma. We present such a case in an otherwise well 39-year-old female having disease limited to the skin established after detailed staging investigations. This is only the third such case described in the literature. We report the clinicopathological features of this case and also review previously documented cases of cutaneous intravascular anaplastic large cell lymphoma. PMID- 23023017 TI - [Liquid nitrogen biobank: a resource for biomedical research]. AB - Biobanks are a critical resource for "omics" technologies in order to dissect molecular mechanism and gene-environmental interactions of common diseases, such as cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases. Progress in basic biomedicine may contribute to advance personalised medicine in which treatments will no longer be "one size fits all", but instead "tailored" to the molecular and genetic profile of each patient. Currently, there are major efforts worldwide to professionalize biobanks in order to move ahead from a "do it-yourself" tissue collection - as is most frequent at present - for providing high quality preservation and storage of biological samples with potentially greater scientific impact. In this paper, we describe our recent experience in the design and development of a high-security liquid nitrogen storage system ( 196 degrees C) as a key resource for biomedical research. PMID- 23023018 TI - [On the other side of the Sannio Primary Care Centers: the patients' point of view]. AB - The primary care Centers are the first level of care with the task of facilitating the relationship between citizen and general practitioner. This study aims to assess the effects of the new organisation of the Sannio primary care on the patients, through the administration of a questionnaire and the organization of focus groups. Results confirm that association matches well with the changing needs of patients, the goal of cost containment and care decentralization, and that it is important to involve citizens to better understand their needs and to make the appropriate corrections through collaboration between general practitioners and health authorities. PMID- 23023019 TI - [Migraine and ischemic stroke: possible pathogenic relation]. AB - Migraine, especially migraine with aura, is an established risk factor for ischemic lesions of the brain. This disorder affects about 15% of people in developed countries and is three times more common in women than in men. The risk of ischemic stroke appears to be higher in migraine with aura than in migraine without aura. An association between migraine and ischemic stroke has been observed for many years but exact mechanisms by which migraine can lead to stroke are currently still under investigation. A significant association between migraine and ischemic stroke has been demonstrated in population and case-control studies. The observation that stroke may occur during migraine attacks prompts to speculation that migraine may directly cause an ischemic event (migrainous infarct). Alternatively, as stroke occurs more frequently during the interictal phase of migraine, an indirect relation between the two diseases might exist. Both ischemic stroke and migraine with aura might be consequences of many underlying vascular disorders. Meta-analysis also demonstrates that subjects with migraine are at higher risk of showing white matter abnormalities on Magnetic Resonance images. Ultimately, it will be important to determine whether migraine with aura is a modifiable risk factor for ischemic stroke and if preventive medications for migraine or antiplatelet therapy might reduce the risk of ischemic stroke in patients with migraine with aura. In the present paper, I will review epidemiological studies, discuss potential mechanisms of migraine-induced stroke and comorbid ischemic stroke. PMID- 23023020 TI - [Correlation between insulin resistance and endothelial dysfunction assessed by flow-mediated dilation]. AB - Insulin resistance and endothelial dysfunction are major cardiovascular risk factors. The purpose of this study was to determine whether only patients with insulin resistance also have an alteration of endothelial function assessed by ultrasound flow-mediated (FMD). In a population of 165 patients, 30 subjects had only a family history of diabetes and/or sporadic findings of hypoglycemia, and they were assessed for FMD, the glucose and insulin curve. Of these 30 subjects, 20 patients had an alteration of the parameters measured and were related with 20 healthy patients. The study group and the control group showed a markedly significant statistical difference in the performance of the curve insulin, in the calculation of FMD and HOMA. FMD allows to study populations with no apparent cardiovascular risk and to monitor the effectiveness of possible endothelial protective therapy. PMID- 23023021 TI - [Thyrotoxic hypokalemic periodic paralysis: a rare complication of a common disease]. AB - Thyrotoxic periodic paralysis (TPP) is an uncommon but potentially lethal manifestation of hyperthyroidism characterized by muscle paralysis and hypokalemia. We have reported 3 cases of TPP in male patients, which manifested with morning muscle weakness evolved into paralysis. In all patients were found severe hypokalemia, abnormalities on electrocardiogram, and Graves' hyperthyroidism. Intravenous potassium administration led to normalization of potassium levels, and resolution of neurological symptoms. In addition, beta blockers and methimazole were started. Two patients required total thyroidectomy for poor control of hyperthyroidism with antithyroid drug. In patients presenting with periodic paralysis or diffuse muscle weakness thyroid function should be investigated in order to find out the cases secondary to unknown hyperthyroidism and to start an early appropriate combined therapy. The correct management of TPP can prevent serious cardiopulmonary complications. PMID- 23023022 TI - [Color Doppler evaluation and diagnosis of local complications after arterial endovascular procedures]. AB - Diagnostic and therapeutic percutaneous endovascular procedures have become more and more common in recent years, and so also the number of local complications has increased. After such procedures a simple clinical examination may show the presence of an inguinal mass, but does not permit a diagnosis, while Color Doppler and Duplex Scanner can make a differential diagnosis between hematoma, pseudoaneurysm, arteriovenous fistula or other disease. Color Doppler is ubiquitously used to diagnose such complications as it offers a low-cost, easy-to use method, only minimally uncomfortable for the patient. This ultrasound system can provide both anatomic and haemodynamic information. Our study highlights the diagnostic possibilities offered by the Color Doppler and Duplex Scanner and details, using many illustrations and examples, how the most common complications such as hematoma, pseudoaneurysm, arteriovenous fistula and thrombosis are imaged. Hematoma appears as a hypoechogenic zone, with no color inside, as flow is not present. Pseudoaneurysms, unlike hematoma, maintain a connection with an injured blood vessel, and so they show blood flow both inside the lesion and in the communicating channel, with a typical pattern. The arteriovenous fistula is a vascular channel created, after a percutaneous procedure, between an artery and an adjacent vein that have both been damaged. An endovascular thrombus is directly shown as a luminal defect of flow. Other less common complications are discussed and illustrated. PMID- 23023023 TI - Nucleoside diphosphate kinase Nm23-M1 involves in oligodendroglial versus neuronal cell fate decision in vitro. AB - The adult glial progenitor cells were recently shown to be able to produce neurons in central nervous system (CNS) and to become multipotent in vitro. Although the fate decision of glial progenitors was studied extensively, the signals and factors which regulate the timing of neuronal differentiation still remain unknown. To elucidate the mechanisms underlying the neuronal differentiation from glial progenitors, we modified the gene expression profile in NG2(+) glial progenitor cells using enhanced retroviral mutagen (ERM) technique followed by phenotype screening to identify possible gene(s) responsible for glial-neuronal cell fate determination. Among the identified molecules, we found the gene named non-metastatic cell 1 which encodes a nucleoside diphosphate kinase protein A (Nm23-M1 or NME1). So far, the Nm23 members have been shown to be involved in various molecular processes including tumor metastasis, cell proliferation, differentiation and cell fate determination. In the present study, we provide evidence suggesting the role of NME1 in glial-neuronal cell fate determination in vitro. We showed that NME1 is widely expressed in neuronal structures throughout adult mouse CNS. Our immunohistochemical results revealed that NME1 is strongly colocalized with NF200 through white matter of spinal cord and brain. Interestingly, NME1 overexpression in oligodendrocyte progenitor OLN-93 cells potently induced the acquisition of neuronal fate, while its silencing was shown to promote oligodendrocyte differentiation. Furthermore, we demonstrated that dual-functional role of NME1 is achieved through cAMP-dependent protein kinase (PKA). Our data therefore suggested that NME1 acts as a switcher or reprogramming factor which involves in oligodentrocyte versus neuron cell fate specification in vitro. PMID- 23023024 TI - The effects of alpha-tocopherol on oxidative damage and serum levels of Clara cell protein 16 in aspiration pneumonitis induced by bile acids. AB - Our aim in this study is to examine the effects of alpha-tocopherol (AT) on rats with aspiration pneumonitis induced with bile acids (BAs). The animals were divided in to four groups, namely saline group (n = 7), saline + AT group (n = 7), BA group (n = 7), and BA + AT group (n = 7). Saline and BA groups aspirated intratracheally with 1 ml/kg saline and 1 ml/kg bile acids, respectively. AT was given at 20 mg/kg/day dosage for 7 days to the groups. AT group was given 20 mg/kg/day AT for 7 days. Malondialdehyde (MDA), Clara cell protein 16 (CC-16), catalase (CAT), superoxide dismutase (SOD), as well as peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, alveolar exudate, alveolar histiocytes, and necrosis were evaluated. The CAT activity of the BA group was significantly lower than the saline group. In the BA + AT group, there was a significant increase in SOD and CAT activities when compared with that of the BA group. The CC-16 and MDA contents in the BA group were significantly higher than in the saline group. The CC-16 and MDA levels of the BA + AT group were significantly lower than BA group. Histopathologic changes were seen in BA group, and there was a significant decrease in the BA + AT group. In conclusion, AT might be beneficial in the treatment of aspiration pneumonitis induced by BAs because AT decreased oxidative damage and resulted in a decrease in CC-16 levels. PMID- 23023025 TI - Antioxidative and cytoprotective effects of andrographolide against CCl4-induced hepatotoxicity in HepG2 cells. AB - This article describes antioxidative and cytoprotective property of andrographolide, a major active component of the plant Andrographis paniculata (A. paniculata). High yields (2.7%) of andrographolide was isolated from the aerial parts of this plant via silica column chromatography. The purity of the compound was determined by high-performance thin-layer chromatography (HPTLC) and reversed phase high-performance liquid chromatography (HPLC) analysis. The structure was elucidated using techniques such as UV-visible spectrophotometry, elemental analysis, Fourier transform infrared (FT-IR), (1)H nuclear magnetic resonance ((1)H NMR), (13)C nuclear magnetic resonance ((13)C NMR) and mass spectral analysis and the data obtained were comparable with reported results. It was observed that andrographolide exhibited significant antioxidative property (IC50 = 3.2 ug/ml) by its ability to scavenge a stable free radical 1,1-diphenyl 2-picrylhydrazyl (DPPH) as compared to known antioxidants like ascorbic acid, butylated hydroxy toluene (BHT) and the plant extract. The cytoprotective role of andrographolide against carbon tetrachloride (CCl4) toxicity in human hepatoma HepG2 cell line was assessed using trypan blue exclusion test, 3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, by estimation of various leakage enzymes and by measuring the glutathione levels. The recovery obtained for andrographolide treatment in the presence of CCl4 was two-fold compared to A. paniculata extract for all other related biochemical parameters investigated. The results of the study indicate that andrographolide is a potent inhibitor of CCl4-mediated lipid peroxidation. PMID- 23023026 TI - A case of methanol intoxication caused by methomyl pesticide ingestion. AB - When clinicians treat patients with pesticide poisoning, they often pay attention only to the chief toxic agent and ignore the toxicity of the pesticide's additives or solvents. Occasionally, however, a solvent (e.g. methanol) may itself be the cause of poisoning. We report a case of acute methanol intoxication that occurred after ingestion of a methomyl pesticide that contained methanol as an additive. A 49-year-old man was brought to the emergency department in an unconscious state after ingestion of 20 ml of a carbamate pesticide (chief ingredient: methomyl; active ingredient: methanol). Upon arrival, he was semicomatose and did not breathe spontaneously; however, his cholinesterase level was within normal limits and cholinergic symptoms were not observed. High anion gap metabolic acidosis was present. His blood ethanol level was 74.8 mg/dL. The urine methanol level was 55.60 mg/dL, and urine ethanol level was 22.0 mg/dL. He was treated with hemodialysis; subsequently, his metabolic acidosis resolved and he returned to normal mental status. We guessed that methanol, as the solvent of the methomyl, had produced the symptoms. When treating pesticide-poisoned patients, clinicians should identify the solvent used in the pesticide, because solvents such as methanol may exacerbate the symptoms of poisoned patients. PMID- 23023027 TI - Addressing bioterrorism concerns: options for investigating the mechanism of action of Staphylococcus aureus enterotoxin B. AB - Staphylococcal enterotoxin B (SEB) is of concern to military and civilian populations as a bioterrorism threat agent. It is a highly potent toxin produced by Staphylococcus aureus and is stable in storage and under aerosolisation; it is able to produce prolonged highly incapacitating illness at very low-inhaled doses and death at elevated doses. Concerns regarding SEB are compounded by the lack of effective medical countermeasures for mass treatment of affected populations. This article considers the mechanism of action of SEB, the availability of appropriate experimental models for evaluating the efficacy of candidate medical countermeasures with particular reference to the need to realistically model SEB responses in man and the availability of candidate countermeasures (with an emphasis on commercial off-the-shelf options). The proposed in vitro approaches would be in keeping with Dstl's commitment to reduction, refinement and replacement of animal models in biomedical research, particularly in relation to identifying valid alternatives to the use of nonhuman primates in experimental studies. PMID- 23023029 TI - The diuretic effect of urea analog dimethylthiourea in female Wistar rats. AB - Urea plays an important role in the urinary concentrating mechanism in the kidney by contributing greatly in the generation of hyperosmolar medulla due to the presence of urea transporters, which mediate facilitated transport of urea. In this study, we investigated the possible diuretic effect of urea analog and urea transporter inhibitor, dimethylthiourea (DMTU), in rats. Female Wistar rats were divided into two groups, group 1 (control group, n = 7) rats were injected with saline intraperitoneally (i.p.), while group 2 (DMTU group, n = 7) rats were injected with 500 mg/kg DMTU (i.p.) and an additional dose of 125 mg/kg DMTU after 8 h. DMTU administration induced an approximately three times increase in daily urine volume (p < 0.001) and decreased urine osmolality to approximately 35% of controls (p < 0.0001). DMTU also increased free water clearance (p < 0.0001) without a significant change in osmolar clearance. DMTU treatment caused an increase in urea clearance (p < 0.05) and fractional excretion of urea (p < 0.05) with a decrease in serum urea concentration (p < 0.001). DMTU had no effect on creatinine clearance or serum electrolytes, creatinine levels and osmolality. With these findings, we report for the first time that DMTU has a prominent diuretic effect with increased urea excretion, which may be explained by the inhibitory effect of the drug on urea transporters. Our findings suggest that DMTU may be used as a diuretic agent and also could be used as a lead compound for the development of novel diuretics. PMID- 23023028 TI - Impact of DNA polymorphisms in key DNA base excision repair proteins on cancer risk. AB - Genetic variation in DNA repair genes can modulate DNA repair capacity and may be related to cancer risk. However, study findings have been inconsistent. Inheritance of variant DNA repair genes is believed to influence individual susceptibility to the development of environmental cancer. Reliable knowledge on which the base excision repair (BER) sequence variants are associated with cancer risk would help elucidate the mechanism of cancer. Given that most of the previous studies had inadequate statistical power, we have conducted a systematic review on sequence variants in three important BER proteins. Here, we review published studies on the association between polymorphism in candidate BER genes and cancer risk. We focused on three key BER genes: 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease (APE1/APEX1) and x-ray repair cross complementing group 1 (XRCC1). These specific DNA repair genes were selected because of their critical role in maintaining genome integrity and, based on previous studies, suggesting that single-nucleotide polymorphisms (SNPs) in these genes have protective or deleterious effects on cancer risk. A total of 136 articles in the December 13, 2010 MEDLINE database (National Center for Biotechnology Information, http://www.ncbi.nlm.nih.gov/pubmed/) reporting polymorphism in OGG1, XRCC1 or APE1 genes were analyzed. Many of the reported SNPs had diverse association with specific human cancers. For example, there was a positive association between the OGG1 Ser326Cys variant and gastric and lung cancer, while the XRCC1 Arg399Gln variant was associated with reduced cancer risk. Gene-environment interactions have been noted and may be important for colorectal and lung cancer risk and possibly other human cancers. PMID- 23023030 TI - Comparison of VAERS fetal-loss reports during three consecutive influenza seasons: was there a synergistic fetal toxicity associated with the two-vaccine 2009/2010 season? AB - The aim of this study was to compare the number of inactivated-influenza vaccine related spontaneous abortion and stillbirth (SB) reports in the Vaccine Adverse Event Reporting System (VAERS) database during three consecutive flu seasons beginning 2008/2009 and assess the relative fetal death reports associated with the two-vaccine 2009/2010 season. The VAERS database was searched for reports of fetal demise following administration of the influenza vaccine/vaccines to pregnant women. Utilization of an independent surveillance survey and VAERS, two source capture-recapture analysis estimated the reporting completeness in the 2009/2010 flu season. Capture-recapture demonstrated that the VAERS database captured about 13.2% of the total 1321 (95% confidence interval (CI): 815-2795) estimated reports, yielding an ascertainment-corrected rate of 590 fetal-loss reports per million pregnant women vaccinated (or 1 per 1695). The unadjusted fetal-loss report rates for the three consecutive influenza seasons beginning 2008/2009 were 6.8 (95% CI: 0.1-13.1), 77.8 (95% CI: 66.3-89.4), and 12.6 (95% CI: 7.2-18.0) cases per million pregnant women vaccinated, respectively. The observed reporting bias was too low to explain the magnitude increase in fetal demise reporting rates in the VAERS database relative to the reported annual trends. Thus, a synergistic fetal toxicity likely resulted from the administration of both the pandemic (A-H1N1) and seasonal influenza vaccines during the 2009/2010 season. PMID- 23023031 TI - Unraveling the time domains of corticosteroid hormone influences on brain activity: rapid, slow, and chronic modes. AB - Brain cells are continuously exposed to corticosteroid hormones, although the levels vary (e.g., after stress). Corticosteroids alter neural activity via two receptor types, mineralocorticoid (MR) and glucocorticoid receptors (GR). These receptors regulate gene transcription but also, as we now know, act nongenomically. Via nongenomic pathways, MRs enhance and GRs suppress neural activity. In the hypothalamus, inhibitory GR effects contribute to negative feedback regulation of the stress axis. Nongenomic MR actions are also important extrahypothalamically and help organisms to immediately select an appropriate response strategy. Via genomic mechanisms, corticosteroid actions in the basolateral amygdala and ventral-most part of the cornu ammonis 1 hippocampal area are generally excitatory, providing an extended window for encoding of emotional aspects of a stressful event. GRs in hippocampal and prefrontal pyramidal cells increase surface expression of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptors and strengthen glutamatergic signaling through pathways partly overlapping with those involved in long-term potentiation. This raises the threshold for subsequent induction of synaptic potentiation and promotes long-term depression. Synapses activated during stress are thus presumably strengthened but protected against excitatory inputs reaching the cells later. This restores higher cognitive control and promotes, for example, consolidation of stress-related contextual information. When an organism experiences stress early in life or repeatedly in adulthood, the ability to induce synaptic potentiation is strongly reduced and the likelihood to induce depression enhanced, even under rest. Treatment with antiglucocorticoids can ameliorate cellular effects after chronic stress and thus provide an interesting lead for treatment of stress-related disorders. PMID- 23023033 TI - Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies. AB - The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractive targets for therapeutic intervention. There has been a remarkable evolution of PI3K inhibitors in the past 20 years from the early chemical tool compounds to drugs that are showing promise as anticancer agents in clinical trials. The use of animal models and pharmacological tools has expanded our knowledge about the contribution of individual class I PI3K isoforms to immune cell function. In addition, class II and III PI3K isoforms are emerging as nonredundant regulators of immune cell signaling revealing potentially novel targets for disease treatment. Further complexity is added to the PI3K/mTOR/Akt pathway by a number of novel signaling inputs and feedback mechanisms. These can present either caveats or opportunities for novel drug targets. Here, we consider recent advances in 1) our understanding of the contribution of individual PI3K isoforms to immune cell function and their relevance to inflammatory/autoimmune diseases as well as lymphoma and 2) development of small molecules with which to inhibit the PI3K pathway. We also consider whether manipulating other proximal elements of the PI3K signaling cascade (such as class II and III PI3Ks or lipid phosphatases) are likely to be successful in fighting off different immune diseases. PMID- 23023034 TI - Osteochondritis dissecans of the humeral head. AB - The patient was a 16-year-old adolescent male who was referred to an orthopaedic surgeon by his pediatrician for a chief complaint of persistent right shoulder pain and crepitus that limited his ability to participate in sporting activities. The patient's progressively worsening right shoulder pain and crepitus, despite no history of injury, was a concern. Therefore, conventional radiographs were completed, which demonstrated an area of radiolucency involving the humeral head. Due to concern for intra-articular pathology, a magnetic resonance arthrogram was ordered, which demonstrated findings consistent with an osteochondritis dissecans lesion of the humeral head. PMID- 23023035 TI - Multiphoton microscopy of cleared mouse brain expressing YFP. AB - Multiphoton microscopy of intrinsic fluorescence and second harmonic generation (SHG) of whole mouse organs is made possible by optically clearing the organ before imaging.(1,2) However, for organs that contain fluorescent proteins such as GFP and YFP, optical clearing protocols that use methanol dehydration and clear using benzyl alcohol:benzyl benzoate (BABB) while unprotected from light(3) do not preserve the fluorescent signal. The protocol presented here is a novel way in which to perform whole organ optical clearing on mouse brain while preserving the fluorescence signal of YFP expressed in neurons. Altering the optical clearing protocol such that the organ is dehydrated using an ethanol graded series has been found to reduce the damage to the fluorescent proteins and preserve their fluorescent signal for multiphoton imaging.(4) Using an optimized method of optical clearing with ethanol-based dehydration and clearing by BABB while shielded from light, we show high-resolution multiphoton images of yellow fluorescent protein (YFP) expression in the neurons of a mouse brain more than 2 mm beneath the tissue surface. PMID- 23023036 TI - Ferric chloride-catalyzed C-N bond cleavage for the cyclization of arylallenes leading to polysubstituted indenes. AB - A range of arylallenes undergo carbocation-initiated cyclization reaction with N benzylic and N-allylic sulfonamides in the presence of 10 mol% ferric chloride to give structurally diverse polysubstituted indenes in good yields with extremely high regioselectivity. PMID- 23023037 TI - Interdisciplinary interpretations and applications of the concept of scale in landscape research. AB - The spatial dimensions of many social, economic and environmental challenges facing 21st century societies can be addressed through the idea of landscape. The European Landscape Convention--ELC (Council of Europe, 2000--Article 1a) views landscape as representing not simply the environment, but the world "as perceived by people". As a concept, landscape is increasingly understood as uniting the physical, mental, natural and cultural dimensions of human existence; good quality landscapes are thus integral to our well-being. The problems and challenges facing our landscapes require greater understanding of how they function and change, as well as their meanings and values. Scholars working in the area of landscape research have increasingly advocated the need to enhance integrative approaches between the natural, human and applied sciences. However, drawing together the collective insights from across the sciences presents a range of conceptual and methodological issues. The question of scale as it pertains to different scientific realms is a key example of this kind of challenge to integrative approaches. The multi-scale nature of the social, environmental and economic challenges embedded in the landscape demands that scholars address these key issues of scale in their research. The aim of this paper is to review how the concept of scale has been interpreted and applied within the arena of landscape research, focussing specifically on three of the principal disciplinary contributors--ecology/landscape ecology, geography and spatial planning. The objective of this discussion is to synthesise scalar issues that feature within and across these perspectives, to better understand how they impact on the way landscape is conceptualised and thus produced through academic and related policy discourses. It seeks out points of tension as well as convergence when dealing with scale. It reflects on academic, policy and practice related concerns that would form part of longer-term holistic strategies for landscape protection, planning and management in line with those being advocated by the ELC. PMID- 23023032 TI - Unravelling the mystery of capsaicin: a tool to understand and treat pain. AB - A large number of pharmacological studies have used capsaicin as a tool to activate many physiological systems, with an emphasis on pain research but also including functions such as the cardiovascular system, the respiratory system, and the urinary tract. Understanding the actions of capsaicin led to the discovery its receptor, transient receptor potential (TRP) vanilloid subfamily member 1 (TRPV1), part of the superfamily of TRP receptors, sensing external events. This receptor is found on key fine sensory afferents, and so the use of capsaicin to selectively activate pain afferents has been exploited in animal studies, human psychophysics, and imaging studies. Its effects depend on the dose and route of administration and may include sensitization, desensitization, withdrawal of afferent nerve terminals, or even overt death of afferent fibers. The ability of capsaicin to generate central hypersensitivity has been valuable in understanding the consequences and mechanisms behind enhanced central processing of pain. In addition, capsaicin has been used as a therapeutic agent when applied topically, and antagonists of the TRPV1 receptor have been developed. Overall, the numerous uses for capsaicin are clear; hence, the rationale of this review is to bring together and discuss the different types of studies that exploit these actions to shed light upon capsaicin working both as a tool to understand pain but also as a treatment for chronic pain. This review will discuss the various actions of capsaicin and how it lends itself to these different purposes. PMID- 23023038 TI - Selection of an appropriate wastewater treatment technology: a scenario-based multiple-attribute decision-making approach. AB - Many technological alternatives for wastewater treatment are available, ranging from advanced technologies to conventional treatment options. It is difficult to select the most appropriate technology from among a set of available alternatives to treat wastewater at a particular location. Many factors, such as capital costs, operation and maintenance costs and land requirement, are involved in the decision-making process. Sustainability criteria must also be incorporated into the decision-making process such that appropriate technologies are selected for developing economies such as that of India. A scenario-based multiple-attribute decision-making (MADM) methodology has been developed and applied to the selection of wastewater treatment alternative. The four most commonly used wastewater treatment technologies for treatment of municipal wastewater in India are ranked for various scenarios. Six scenarios are developed that capture the regional and local societal priorities of urban, suburban and rural areas and translate them into the mathematical algorithm of the MADM methodology. The articulated scenarios depict the most commonly encountered decision-making situations in addressing technology selection for wastewater treatment in India. A widely used compensatory MADM technique, TOPSIS, has been selected to rank the alternatives. Seven criteria with twelve indicators are formulated to evaluate the alternatives. Different weight matrices are used for each scenario, depending on the priorities of the scenario. This study shows that it is difficult to select the most appropriate wastewater treatment alternative under the "no scenario" condition (equal weights given to each attribute), and the decision making methodology presented in this paper effectively identifies the most appropriate wastewater treatment alternative for each of the scenarios. PMID- 23023039 TI - Low cost adsorbents for the removal of organic pollutants from wastewater. AB - Water pollution due to organic contaminants is a serious issue because of acute toxicities and carcinogenic nature of the pollutants. Among various water treatment methods, adsorption is supposed as the best one due to its inexpensiveness, universal nature and ease of operation. Many waste materials used include fruit wastes, coconut shell, scrap tyres, bark and other tannin-rich materials, sawdust and other wood type materials, rice husk, petroleum wastes, fertilizer wastes, fly ash, sugar industry wastes blast furnace slag, chitosan and seafood processing wastes, seaweed and algae, peat moss, clays, red mud, zeolites, sediment and soil, ore minerals etc. These adsorbents have been found to remove various organic pollutants ranging from 80 to 99.9%. The present article describes the conversion of waste products into effective adsorbents and their application for water treatment. The possible mechanism of adsorption on these adsorbents has also been included in this article. Besides, attempts have been made to discuss the future perspectives of low cost adsorbents in water treatment. PMID- 23023040 TI - Structural analysis of immunostimulating sulfated polysaccharides from Ulva pertusa. AB - Sulfated polysaccharides were extracted from Ulva pertusa and fractionated to obtain the most immunostimulating fraction (F(2)). The glycosidic linkages of the polysaccharides in the fraction F(2) were determined using GC-MS and 2D-NMR spectroscopy after chemical modifications, including reduction and desulfation under various conditions. Methanol was used as a sulfate acceptor for the removal of sulfates from the polysaccharides. When desulfation was carried out at 120 degrees C, the sulfates were removed upto 90.1% from the F(2) fraction without considerable backbone degradation. The GC-MS analysis as well as NMR spectra revealed that the backbone of the polysaccharides was mainly composed of alpha-(1 >4)-L-rhamnopyranosyl, beta-(1->4)-D-glucuronosyl, beta-(1->2)-L-rhamnopyranosyl, and beta-(1->4)-D-xylopyranosyl residues with branches at O-2 position of rhamnose. The sulfate groups were mostly found on glucuronic acid at O-3 position. PMID- 23023041 TI - Synthesis of 3I-O and 2I-O-monosubstituted derivatives of per-6-azido-beta cyclodextrin-potential molecular scaffolds. AB - Alkylation of per-6-azido-beta-cyclodextrin by a suitable electrophilic reagent (cinnamyl bromide or propargyl bromide) gave a mixture of 3(I)-O and 2(I)-O regioisomers. After peracetylation and chromatographic separation on silica gel, pure isomers were isolated. Oxidative cleavage of cinnamyl double bond afforded the corresponding formylmethyl and carboxymethyl derivatives. The prepared scaffold molecules are equipped with two types of reactive groups which have a potential to serve as points of attachment for various compounds. PMID- 23023042 TI - An alternative route for fondaparinux sodium synthesis via selective hydrogenations and sulfation of appropriate pentasaccharides. AB - A new approach for the synthesis of fondaparinux sodium starting from an appropriate protected pentasaccharide is presented. In this procedure, instead of the common last steps: sulfation-hydrogenation-sulfation, reverse ones: hydrogenation-sulfation-hydrogenation, are applied. Fondaparinux is afforded in a satisfactory yield and purity after the selective hydrogenation of the starting pentasaccharide using a continuous flow reactor and one-pot sulfation reaction followed by hydrogenation under catalytic hydrogen transfer conditions. PMID- 23023043 TI - Simple things matter! How reassurance and pain management strategies can improve outcomes in physiotherapy: a case report. AB - Psychological barriers to rehabilitation are generally viewed as pre-existing patient traits that clinicians are asked to evaluate and modify. In the present case report, we provide evidence that these barriers can also be involuntarily created or perpetuated by the clinician himself when too much attention is placed on physical abnormalities. Without discarding the need to treat the presumed biological source of pain, these observations remind rehabilitation professionals about the importance of showing a confident and reassuring attitude toward pain patients to reduce anxiety, promote physical activity, and reinforce self management strategies. PMID- 23023044 TI - Moderate high fat diet increases sucrose self-administration in young rats. AB - We have previously reported that a moderately high fat diet increases motivation for sucrose in adult rats. In this study, we tested the motivational, neurochemical, and metabolic effects of the high fat diet in male rats transitioning through puberty, during 5-8 weeks of age. We observed that the high fat diet increased motivated responding for sucrose, which was independent of either metabolic changes or changes in catecholamine neurotransmitter metabolites in the nucleus accumbens. However, AGRP mRNA levels in the hypothalamus were significantly elevated. We demonstrated that increased activation of AGRP neurons is associated with motivated behavior, and that exogenous (third cerebroventricular) AGRP administration resulted in significantly increased motivation for sucrose. These observations suggest that increased expression and activity of AGRP in the medial hypothalamus may underlie the increased responding for sucrose caused by the high fat diet intervention. Finally, we compared motivation for sucrose in pubertal vs. adult rats and observed increased motivation for sucrose in the pubertal rats, which is consistent with previous reports that young animals and humans have an increased preference for sweet taste, compared with adults. Together, our studies suggest that background diet plays a strong modulatory role in motivation for sweet taste in adolescent animals. PMID- 23023045 TI - Daily energy balance in children and adolescents. Does energy expenditure predict subsequent energy intake? AB - Both physical and sedentary activities primarily impact energy balance through energy expenditure, but they also have important implications in term of ingestive behavior. The literature provides scarce evidence on the relationship between daily activities and subsequent nutritional adaptations in children and adolescents. Sedentary activities and physical exercise are generally considered distinctly despite the fact that they represent the whole continuum of daily activity-induced energy expenditure. This brief review paper examines the impact of daily activities (from vigorous physical activity to imposed sedentary behaviors) on acute energy intake control of lean and obese children and adolescents, and whether energy expenditure is the main predictor of subsequent energy intake in this population. After an overview of the available literature, we conclude that both acute physical activity and sedentary behaviors induce food consumption modifications in children and adolescents but also that the important discrepancy between the methodologies used does not allow any clear conclusion so far. When considering energy intake responses according to the level of energy expenditure generated by those activities, it is clear that energy expenditure is not the main predictor of food consumption in both lean and obese children and adolescents. This suggests that other characteristics of those activities may have a greater impact on calorie intake (such as intensity, duration or induced mental stress) and that energy intake may be mainly determined by non-homeostatic pathways that could override the energetic and hormonal signals. PMID- 23023046 TI - A high-throughput assay for the identification of malarial transmission-blocking drugs and vaccines. AB - Following the cessation of the global malaria eradication initiative in the 1970s, the prime objective of malarial intervention has been to reduce morbidity and mortality. This motivated the development of high throughput assays to determine the impact of interventions on asexual bloodstage parasites. In response to the new eradication agenda, interrupting parasite transmission from the human to the mosquito has been recognised as an important and additional target for intervention. Current assays for Plasmodium mosquito stage development are very low throughput and resource intensive, and are therefore inappropriate for high throughput screening. Using an ookinete-specific GFP reporter strain of the rodent parasite Plasmodium berghei, it has been possible to develop and validate a high biological complexity, high throughput bioassay that can rapidly, reproducibly and accurately evaluate the effect of transmission-blocking drugs or vaccines on the ability of host-derived gametocytes to undergo the essential onward steps of gamete formation, fertilisation and ookinete maturation. This assay may greatly accelerate the development of malaria transmission-blocking interventions. PMID- 23023047 TI - Tricks in Plasmodium's molecular repertoire--escaping 3'UTR excision-based conditional silencing of the chloroquine resistance transporter gene. AB - In the human malaria parasite Plasmodium falciparum, the major determinant of chloroquine resistance, P. falciparum chloroquine resistance transporter (pfcrt), likely plays an essential role in asexual blood stages, thus precluding conventional gene targeting approaches. We attempted to conditionally silence the expression of its ortholog in Plasmodium berghei (pbcrt) through Flp recombinase mediated excision of the 3'untranslated region (UTR) during mosquito passage. However, parasites maintained pbcrt expression despite 3'UTR excision. Characterisation of these pbcrt mRNAs, by 3'rapid amplification of cDNA ends, identified several replacement 3'UTR sequences. Our observations demonstrate the astounding genetic plasticity of this parasite when faced with the loss of an essential gene. PMID- 23023048 TI - Measuring the blockade of malaria transmission--an analysis of the Standard Membrane Feeding Assay. AB - The standard membrane feeding assay (SMFA) is currently considered to be the 'gold standard' for assessing the effectiveness of malaria transmission blocking interventions (TBIs) in vivo. The operation and analysis of SMFAs has varied between laboratories: field scientists often measure TBI efficacy as a reduction in the prevalence of infected mosquitoes whilst laboratory scientists are more likely to quote efficacy as a change in the number of oocysts within the mosquito. These metrics give outputs that differ widely, resulting in a need for greater understanding of how the SMFA informs TBI assessment. Using data from 536 different assays (conducted on Plasmodium falciparum and Plasmodium berghei, in either Anopheles gambiae or Anopheles stephensi) it is shown that the relationship between these metrics is complex, yet predictable. Results demonstrate that the distribution of oocysts between mosquitoes is highly aggregated, making efficacy estimates based on reductions in intensity highly uncertain. Analysis of 30 SMFAs carried out on the same TBI confirms that the observed reduction in prevalence depends upon the parasite exposure (as measured by oocyst intensity in the control group), with assays which have lower exposure appearing more effective. By contrast, if efficacy is estimated as a reduction in oocyst intensity, then this candidate demonstrated constant efficacy, irrespective of the exposure level. To report transmission-blockade efficacy accurately, the results of SMFAs should give both the prevalence and intensity of oocysts in both the control and intervention group. Candidates should be assessed against a range of parasite exposures to allow laboratory results to be extrapolated to different field situations. Currently, many studies assessing TBIs are underpowered and uncertainties in efficacy estimates rarely reported. Statistical techniques that account for oocyst over-dispersion can reduce the number of mosquitoes that need to be dissected and allow TBI candidates from different laboratories to be accurately compared. PMID- 23023049 TI - Multi-institutional neurosurgical training initiative at a tertiary referral center in Mwanza, Tanzania: where we are after 2 years. AB - BACKGROUND: The paucity of neurosurgical care in East Africa remains largely unaddressed. A sustained investment in local health infrastructures and staff training is needed to create an independent surgical capacity. The Madaktari organization has addressed this issue by starting initiatives to train local general surgeons and assistant medical officers in basic neurosurgical procedures. We report illustrative cases since beginning of the program in Mwanza in 2009 and focus on the most recent training period. METHODS: A multi institutional neurosurgical training program and a surgical database was created at a tertiary referral center in Mwanza, Tanzania. We collected clinical data on consecutive patients who underwent a neurosurgical procedure between September 9th and December 1st, 2011. All procedures were performed by a local surgeon under the supervision of a visiting neurosurgeon. Since the inception of the training initiative, comprehensive multidisciplinary training courses in Tanzania and an annual visiting fellowship for East African surgeons to travel to a major U.S. medical center have been established. RESULTS: At initial visits infrastructure and feasibility of complex case scenarios was assessed. Surgeries for brain tumors and complex spinal cases were performed. During the 3-month training period, 62 patients underwent surgery. Pediatric hydrocephalus comprised 52% of patients, 11% suffered from meningomyelocelia, and 6% presented with an encephalocele. A total of 24% of patients were treated for trauma-related conditions, representing 75% of the adult patients. A total of 10% of patients had surgery because of traumatic spine injury, and 15% of operations were on patients with severe head injury. A total of 6% of patients presented with degenerative spine disease. One patient sustained a fatal perioperative complication. At the end of the training period, the local general surgeon was able to perform all basic neurosurgical cases independently. CONCLUSIONS: Neurosurgical care in Tanzania needs to address a diverse, unique disease burden. We found that local surgeons could be enabled to safely perform basic cranial and spinal neurosurgical procedures through immersive, 1-on-1 on-site collaborations, multidisciplinary courses, and educational visiting fellowships. PMID- 23023050 TI - Using unfixed, frozen tissues to study natural mucin distribution. AB - Mucins are complex and heavily glycosylated O-linked glycoproteins, which contain more than 70% carbohydrate by weight(1-3). Secreted mucins, produced by goblet cells and the gastric mucosa, provide the scaffold for a micrometers-thick mucus layer that lines the epithelia of the gut and respiratory tract(3,4). In addition to mucins, mucus layers also contain antimicrobial peptides, cytokines, and immunoglobulins(5-9). The mucus layer is an important part of host innate immunity, and forms the first line of defense against invading microorganisms(8,10-12). As such, the mucus is subject to numerous interactions with microbes, both pathogens and symbionts, and secreted mucins form an important interface for these interactions. The study of such biological interactions usually involves histological methods for tissue collection and staining. The two most commonly used histological methods for tissue collection and preservation in the clinic and in research laboratories are: formalin fixation followed by paraffin embedding, and tissue freezing, followed by embedding in cryo-protectant media. Paraffin-embedded tissue samples produce sections with optimal qualities for histological visualization including clarity and well-defined morphology. However, during the paraffin embedding process a number of epitopes become altered and in order to study these epitopes, tissue sections have to be further processed with one of many epitope retrieval methods(13). Secreted mucins and lipids are extracted from the tissue during the paraffin-embedding clearing step, which requires prolong incubation with organic solvents (xylene or Citrisolv). Therefore this approach is sub-optimal for studies focusing on the nature and distribution of mucins and mucus in vivo. In contrast, freezing tissues in Optimal Cutting Temperature (OCT) embedding medium avoids dehydration and clearing of the sample, and maintains the sample hydration. This allows for better preservation of the hydrated mucus layer, and thus permits the study of the numerous roles of mucins in epithelial biology. As this method requires minimal processing of the tissue, the tissue is preserved in a more natural state. Therefore frozen tissues sections do not require any additional processing prior to staining and can be readily analyzed using immunohistochemistry methods. We demonstrate the preservation of micrometers thick secreted mucus layer in frozen colon samples. This layer is drastically reduced when the same tissues are embedded in paraffin. We also demonstrate immunofluorescence staining of glycan epitopes presented on mucins using plant lectins. The advantage of this approach is that it does not require the use of special fixatives and allows utilizing frozen tissues that may already be preserved in the laboratory. PMID- 23023051 TI - Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. PMID- 23023054 TI - Gene therapy for deaf mice goes viral. PMID- 23023055 TI - Taking a break from huntingtin. PMID- 23023056 TI - Pushing the reset button: chemical-induced conversion of amniotic fluid stem cells into a pluripotent state. PMID- 23023057 TI - Conditional negative selection of gene-modified hematopoietic stem cells. PMID- 23023058 TI - AAV vectors for the nucleolus. PMID- 23023059 TI - Using Drosophila melanogaster to validate metabolism-based insecticide resistance from insect pests. AB - Identifying molecular mechanisms of insecticide resistance is important for preserving insecticide efficacy, developing new insecticides and implementing insect control. The metabolic detoxification of insecticides is a widespread resistance mechanism. Enzymes with the potential to detoxify insecticides are commonly encoded by members of the large cytochrome P450, glutathione S transferase and carboxylesterase gene families, all rapidly evolving in insects. Here, we demonstrate that the model insect Drosophila melanogaster is useful for functionally validating the role of metabolic enzymes in conferring metabolism based insecticide resistance. Alleles of three well-characterized genes from different pest insects were expressed in transgenic D. melanogaster : a carboxylesterase gene (alphaE7) from the Australian sheep blowfly Lucilia cuprina, a glutathione S-transferase gene (GstE2) from the mosquito Anopheles gambiae and a cytochrome P450 gene (Cyp6cm1) from the whitefly Bemisia tabaci. For all genes, expression in D. melanogaster resulted in insecticide resistance phenotypes mirroring those observed in resistant populations of the pest species. Using D. melanogaster to assess the potential for novel metabolic resistance mechanisms to evolve in pest species is discussed. PMID- 23023060 TI - Brain areas involved in acupuncture needling sensation of de qi: a single-photon emission computed tomography (SPECT) study. AB - BACKGROUND: De qi is a sensory response elicited by acupuncture stimulation. According to traditional Chinese medicine (TCM), de qi is essential for clinical efficacy. However, the understanding of the neurobiological basis of de qi is still limited. OBJECTIVE: To investigate the relationship between brain activation and de qi by taking a single-photon emission computed tomography (SPECT) scan while applying acupuncture at TE5. METHODS: A total of 24 volunteers were randomly divided into 4 groups, and received verum or sham acupuncture at true acupuncture point TE5 or a nearby sham point according to grouping. All subjects then received a (99m)Tc-ethylcysteinate dimer (ECD) SPECT scan. RESULTS: All six subjects in the verum acupuncture at true acupuncture point group experienced de qi sensation; in contrast, all six subjects in the sham acupuncture at the sham point group responded with nothing other than non sensation. Compared to the scan results from subjects who experienced non sensation, SPECT scans from subjects with de qi sensation demonstrated significant activated points mainly located in brodmann areas 6, 8, 19, 21, 28, 33, 35, 37, 47, the parahippocampal gyrus, lentiform nucleus, claustrum and red nucleus; deactivated points were seen in brodmann areas 9 and 25. CONCLUSIONS: Verum acupuncture at true acupuncture points is more likely to elicit de qi sensation. De qi sensations mainly resulted in brain area activations, but not deactivations. These brain areas are related to the curative effect of Te5. The acupuncture needle sensations of de qi and sharp pain are associated with different patterns of activations and deactivations in the brain. PMID- 23023064 TI - Distal fibula fracture diagnosed with ultrasound imaging. AB - The patient was a 31-year-old man serving in a military special forces unit at a remote location. He presented to a physical therapist with a chief complaint of worsening right lateral ankle pain that limited his ability to bear weight. Because the patient met the Ottawa ankle rules and there was concern for a fracture, radiographs were indicated. However, the nearest facility with radiographic capabilities was only available through air medical evacuation. Therefore, the physical therapist assessed the patient's ankle with an onsite portable ultrasound imaging unit, which demonstrated cortical irregularity along the distal fibula. PMID- 23023063 TI - FDG-PET/CT based response-adapted treatment. AB - It has been shown that [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) provides robust and reproducible data for early metabolic response assessment in various malignancies. This led to the initiation of several prospective multicenter trials in malignant lymphoma and adenocarcinoma of the esophagogastric junction, in order to investigate whether the use of PET guided treatment individualization results in a survival benefit. In Hodgkin lymphoma and aggressive non-Hodgkin lymphoma, several trials are ongoing. Some studies aim to investigate the use of PET in early identification of metabolic non-responders in order to intensify treatment to improve survival. Other studies aim at reducing toxicity without adversely affecting cure rates by safely de escalating therapy in metabolic responders. In solid tumors the first PET response-adjusted treatment trials have been realized in adenocarcinoma of the esophagogastric junction. These trials showed that patients with an early metabolic response to neoadjuvant chemotherapy benefit from this treatment, whereas metabolic non-responders should switch early to surgery, thus reducing the risk of tumor progression during chemotherapy and the risk of toxic death. The trials provide a model for designing response-guided treatment algorithms in other malignancies. PET-guided treatment algorithms are the promise of the near future; the choice of therapy, its intensity, and its duration will become better adjusted to the biology of the individual patient. Today's major challenge is to investigate the impact on patient outcome of personalized response-adapted treatment concepts. PMID- 23023061 TI - Integrin beta1 regulates leiomyoma cytoskeletal integrity and growth. AB - Uterine leiomyomas are characterized by an excessive extracellular matrix, increased mechanical stress, and increased active RhoA. Previously, we observed that mechanical signaling was attenuated in leiomyoma, but the mechanisms responsible remain unclear. Integrins, especially integrin beta1, are transmembrane adhesion receptors that couple extracellular matrix stresses to the intracellular cytoskeleton to influence cell proliferation and differentiation. Here we characterized integrin and laminin to signaling in leiomyoma cells. We observed a 2.25+/-0.32 fold increased expression of integrin beta1 in leiomyoma cells, compared to myometrial cells. Antibody-mediated inhibition of integrin beta1 led to significant growth inhibition in leiomyoma cells and a loss of cytoskeletal integrity. Specifically, polymerization of actin filaments and formation of focal adhesions were reduced by inhibition of integrin beta1. Inhibition of integrin beta1 in leiomyoma cells led to 0.81+/-0.02 fold decrease in active RhoA, and resembled levels found in serum-starved cells. Likewise, inhibition of integrin beta1 was accompanied by a decrease in phospho-ERK. Compared to myometrial cells, leiomyoma cells demonstrated increased expression of integrin alpha6 subunit to laminin receptor (1.91+/-0.11 fold), and increased expression of laminin 5alpha (1.52+/-0.02), laminin 5beta (3.06+/-0.92), and laminin 5gamma (1.66+/-0.06). Of note, leiomyoma cells grown on laminin matrix appear to realign themselves. Taken together, the findings reveal that the attenuated mechanical signaling in leiomyoma cells is accompanied by an increased expression and a dependence on integrin beta1 signaling in leiomyoma cells, compared to myometrial cells. PMID- 23023065 TI - Lung endothelial cells strengthen, but brain endothelial cells weaken barrier properties of a human alveolar epithelium cell culture model. AB - The blood-air barrier in the lung consists of the alveolar epithelium, the underlying capillary endothelium, their basement membranes and the interstitial space between the cell layers. Little is known about the interactions between the alveolar and the blood compartment. The aim of the present study was to gain first insights into the possible interplay between these two neighbored cell layers. We established an in vitro Transwell model of the alveolar epithelium based on human cell line H441 and investigated the influence of conditioned medium obtained from human lung endothelial cell line HPMEC-ST1.6R on the barrier properties of the H441 layers. As control for tissue specificity H441 layers were exposed to conditioned medium from human brain endothelial cell line hCMEC/D3. Addition of dexamethasone was necessary to obtain stable H441 cell layers. Moreover, dexamethasone increased expression of cell type I markers (caveolin-1, RAGE) and cell type II marker SP-B, whereas decreased the transepithelial electrical resistance (TEER) in a concentration dependent manner. Soluble factors obtained from the lung endothelial cell line increased the barrier significantly proven by TEER values and fluorescein permeability on the functional level and by the differential expression of tight junctional proteins on the molecular level. In contrast to this, soluble factors derived from brain endothelial cells weakened the barrier significantly. In conclusion, soluble factors from lung endothelial cells can strengthen the alveolar epithelium barrier in vitro, which suggests communication between endothelial and epithelial cells regulating the integrity of the blood-air barrier. PMID- 23023066 TI - Interpreted gene expression of human dermal fibroblasts after adipo-, chondro- and osteogenic phenotype shifts. AB - Autologous cell-based therapies promise important developments for reconstructive surgery. In vitro expansion as well as differentiation strategies could provide a substantial benefit to cellular therapies. Human dermal fibroblasts, considered ubiquitous connective tissue cells, can be coaxed towards different cellular fates, are readily available and may altogether be a suitable cell source for tissue engineering strategies. Global gene expression analysis was performed to investigate the changes of the fibroblast phenotype after four-week inductions toward adipocytic, osteoblastic and chondrocytic lineages. Differential gene regulation, interpreted through Gene Set Enrichment Analysis, highlight important similarities and differences of induced fibroblasts compared to control cultures of human fibroblasts, adipocytes, osteoblasts and articular chondrocytes. Fibroblasts show an inherent degree of phenotype plasticity that can be controlled to obtain cells supportive of multiple tissue types. PMID- 23023067 TI - A global downregulation of microRNAs occurs in human quiescent satellite cells during myogenesis. AB - During myogenesis, human satellite cells differentiate and form multinucleated myotubes, while a fraction of the human satellite cells enter quiescence. These quiescent satellite cells are able to activate, proliferate and contribute to muscle regeneration. Post-transcriptional regulation of myogenesis occurs through specific myogenic microRNAs, also known as myomiRs. Although many microRNAs are involved in myotube formation, little is known on the involvement of microRNAs in satellite cells entering quiescence. This current study aims to investigate microRNA involvement during differentiation of human satellite cells, specifically proliferating satellite cells entering quiescence. For this, clonally expanded human satellite cells were differentiated for 5 days, after which myotubes and quiescent satellite cells were separated through FACS sorting. Next, a microRNA microarray comparison of proliferating satellite cells, myotubes and quiescent satellite cells was performed and verified through qRT-PCR. We show that during human satellite cell differentiation, microRNAs are globally downregulated in quiescent satellite cells compared to proliferating satellite cells, in particular microRNA-106b, microRNA-25, microRNA-29c and microRNA-320c. Furthermore, we show that during myogenesis microRNA-1, microRNA-133, microRNA 206 and microRNA-486 are involved in myotube formation rather than satellite cells entering quiescence. Finally, we show an overall decrease in total mRNA in quiescent satellite cells, and an indication that RNaseL regulation plays a role in promoting and maintaining quiescence. Given the importance of quiescent satellite cells in skeletal muscle development and regenerative medicine, it is imperative to distinguish between myotubes and quiescent satellite cells when investigating skeletal muscle development, especially in microRNA studies, since we show that microRNAs are globally downregulated in quiescent human satellite cells. PMID- 23023068 TI - In vitro characterization of proliferation and differentiation of pig satellite cells. AB - Skeletal muscle contains various muscle fiber types exhibiting different contractile properties based on the myosin heavy chain (MyHC) isoform profile. Muscle fiber type composition is highly variable and influences growth performance and meat quality, but underlying mechanisms regulating fiber type composition remain poorly understood. The aim of the present work was to develop a model based on muscle satellite cell culture to further investigate the regulation of adult MyHC isoforms expression in pig skeletal muscle. Satellite cells were harvested from the mostly fast-twitch glycolytic longissimus (LM) and predominantly slow-twitch oxidative rhomboideus (RM) muscles of 6-week-old piglets. Satellite cells were allowed to proliferate up to 80% confluence, reached after 7 day of proliferation (D7), and then induced to differentiate. Kinetics of proliferation and differentiation were similar between muscles and more than 95% of the cells were myogenic (desmin positive) at D7 with a fusion index reaching 65 +/- 9% after 4 day of differentiation. One-dimensional SDS polyacrylamide gel electrophoresis revealed that satellite cells from both muscles only expressed the embryonic and fetal MyHC isoforms in culture, without any of the adult MyHC isoforms that were expressed in vivo. Interestingly, triiodothyronine (T3) induced de novo expression of adult fast and alpha-cardiac MyHC in vitro making our culture system a valuable tool to study de novo expression of adult MyHC isoforms and its regulation by intrinsic and/or extrinsic factors. PMID- 23023069 TI - Multiparametric PET/CT in oncology. AB - The standardized uptake value (SUV) and other measurements of tumour uptake of fluorodeoxyglucose (FDG) on positron emission tomography (PET) can potentially be supplemented by additional imaging parameters derived either from the PET images or from the computed tomography (CT) component of integrated PET/CT examinations including tumour size, CT attenuation, texture (reflecting tumour heterogeneity) and blood flow. This article illustrates the emerging benefits of such a multiparametric approach. Example benefits include greater diagnostic accuracy in characterization of adrenal masses achieved by using both the SUV and measured CT attenuation. Tumour size combined with the SUV can potentially improve the prognostic information available from PET/CT in oesophageal and lung cancer. However, greater improvements may be realized through using CT measurements of texture instead of size. Studies in breast and lung cancer suggest that combined PET/CT measurements of glucose metabolism and blood flow provide correlates for tumour proliferation and angiogenesis, respectively. These combined measurements can be utilized to determine vascular-metabolic phenotypes, which vary with tumour type. Uncoupling of blood flow and metabolism suggests a poor prognosis for larger more advanced tumours, high-grade lesions and tumours responding poorly to treatment. Vascular-metabolic imaging also has the potential to subclassify tumour response to treatment. The additional biomarkers described can be readily incorporated in existing FDG-PET examinations thereby improving the ability of PET/CT to depict tumour biology, characterize potentially malignant lesions, and assess prognosis and therapeutic response. PMID- 23023070 TI - A sensitive liquid chromatography-mass spectrometry method for simultaneous determination of three diterpenoid esters from Euphorbia lathyris L. in rat plasma. AB - A selective and sensitive liquid chromatography-mass spectrometry (LC-MS) method was developed for the simultaneous determination of Euphorbia factor L(1), Euphorbia factor L(2) and Euphorbia factor L(3) from Euphorbiae semen in rat plasma. Larotaxel was added to a 200 MUL plasma sample as the internal standard (IS). The plasma sample was extracted by 2 mL ether and separated on an Elite C(18) column (150 mm * 4.6 mm, 5 MUm) with the mobile phase of methanol-water performing gradient elution within 11.0 min. All the three analytes were detected in the selected ion monitoring (SIM) mode with positive electrospray ionization. The calibration curves were linear in the range of 2.0-200 ng/mL and the lower limits of quantification (LLOQ) were 2.0 ng/mL for all the three analytes. The intra-day and inter-day precisions were all within 8.6% and 14.6% for the three analytes, while the accuracy was less than 9.7% and 7.5%, respectively. The validated method was firstly and successfully applied to the pharmacokinetic study of Euphorbia factor L(1), Euphorbia factor L(2) and Euphorbia factor L(3) from Euphorbiae semen after oral administration in rat plasma. PMID- 23023071 TI - In vivo two-photon imaging of T cell motility in joint-draining lymph nodes in a mouse model of rheumatoid arthritis. AB - Recent imaging studies on intact lymph nodes (LNs) of naive T cell receptor (TCR) transgenic mice have reported that T cells reduce their motility upon contact with relevant antigen-presenting cells (APCs). Using in vivo two-photon imaging of T cells in joint-draining (JD) LNs, we examined whether similar changes in T cell motility are observed in wild type mice. Co-transfer of T cells from naive mice and antigen-experienced T cells from mice with proteoglycan (PG)-induced arthritis into naive or arthritic recipients resulted in prolonged interactions of antigen-experienced T cells with APCs upon intra-articular antigen (PG) injection, indicating that T cells from arthritic wild type mice recapitulate the motile behavior reported in naive TCR-transgenic mice. However, naive T cells also engaged in stable interactions with APCs in the JDLNs of arthritic recipients, suggesting an enhanced ability of APCs in the JDLNs of arthritic hosts to present antigen to either naive or antigen-experienced T cells. PMID- 23023072 TI - Delayed administration of pituitary adenylate cyclase-activating polypeptide 38 ameliorates renal ischemia/reperfusion injury in mice by modulating Toll-like receptors. AB - We investigated whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) ameliorates kidney injury after ischemia/reperfusion (IR) by modulating Toll-like receptor (TLR)-associated signaling pathways. Male C57BL/6 mice were subjected to bilateral renal ischemia for 45 min. PACAP38, 20 MUg in 100 MUl of saline, was administered i.p. at 24 and 48 h after IR, and mice were euthanized at 72h. In IR mice, PACAP38 maintained serum creatinine near control levels (0.81 +/- 0.08 vs. 0.69 +/- 0.17 mg/dl in controls, p=NS, vs. 1.8 +/- 0.03 in saline treated IR mice, p<0.01) and significantly reduced the expression of kidney injury biomarkers. PACAP38 significantly reduced the levels of apoptosis and neutrophil infiltration, and protected against tubular damage. With PCR arrays, 59 of 83 TLR-related genes significantly changed their expression after IR. TLR2 increased 162 fold, followed by Fas-associated death domain (37 fold) and TLR6 (24 fold), while ubiquitin-conjugating enzyme E2 variant 1 (UBE2V1) decreased 55 fold. PACAP38 given 24 and 48 h after IR injury significantly reversed these changes in 56 genes, including TLR2, TLR3, TLR4, TLR6, and genes in the NF-kappaB pathways. The alterations in TLR2, TLR3, TLR6, and UBE2V1 were confirmed by RT PCR. After IR, PACAP38 also suppressed protein levels of TLR-associated cytokines. PACAP38 reversed the changes in IR-activated TLR-associated NF-kappaB signaling pathways even when treatment was delayed 24h. Therefore, PACAP38 could be an effective therapeutic for unexpected IR-mediated renal injury. The prominently IR-induced TLR-related genes identified in this study could be novel drug targets. PMID- 23023073 TI - Markov random field and Gaussian mixture for segmented MRI-based partial volume correction in PET. AB - In this paper we propose a segmented magnetic resonance imaging (MRI) prior-based maximum penalized likelihood deconvolution technique for positron emission tomography (PET) images. The model assumes the existence of activity classes that behave like a hidden Markov random field (MRF) driven by the segmented MRI. We utilize a mean field approximation to compute the likelihood of the MRF. We tested our method on both simulated and clinical data (brain PET) and compared our results with PET images corrected with the re-blurred Van Cittert (VC) algorithm, the simplified Guven (SG) algorithm and the region-based voxel-wise (RBV) technique. We demonstrated our algorithm outperforms the VC algorithm and outperforms SG and RBV corrections when the segmented MRI is inconsistent (e.g. mis-segmentation, lesions, etc) with the PET image. PMID- 23023074 TI - Antidepressant efficacy of agomelatine versus SSRI/SNRI: results from a pooled analysis of head-to-head studies without a placebo control. AB - Pooled analysis of individual patient data was used to compare the antidepressant efficacy of agomelatine with that of selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). We sought head-to-head, double-blind, randomized studies without a placebo arm using antidepressant doses in the licensed range and primary evaluation on the Hamilton scale (HAM-D(17)). Six studies were identified versus venlafaxine, sertraline, fluoxetine, paroxetine or escitalopram. Estimates of differences between treatments were calculated on parameters expressed as the last postbaseline value (6, 8 or 12 weeks). A total of 2034 patients were randomized (age 47.6 +/- 14.9 years; 73% women; HAM-D(17) total score 26.9 +/- 3.0). The full analysis set included 1997 patients (1001 agomelatine; 996 SSRI/SNRI). There was a significant difference between HAM-D(17) total scores, with a greater reduction with agomelatine than with SSRI/SNRI [E(SE), 0.86 (0.35), 95% confidence interval 0.18 1.53, P=0.013], and better rates of response on the HAM-D(17) (P=0.012) and the Clinical Global Impression-Improvement scales (P=0.032). Similar results were found in patients with severe depression. Agomelatine was associated with better tolerability than SSRI/SNRI. Agomelatine has favourable efficacy and tolerability versus a range of SSRIs and SNRIs - including agents considered to have superior efficacy - and may deserve benefit-risk analysis as a first-line treatment of major depressive disorder. PMID- 23023075 TI - Organic electronics-new physical chemistry insight. PMID- 23023076 TI - [Combined treatments in obsessive-compulsive disorder: current knowledge and future prospects]. AB - AIM: Serotonin reuptake inhibitors (SRIs) and/or cognitive-behavioral psychotherapy (CBT) are first-line treatments for obsessive-compulsive disorder (OCD). The study discuss whether: a) combining both treatments ab initio is more effective than either monotherapy alone; and b) a sequential treatment is effective both in responder and non responder patients. METHODS: Have been carried out a search on Medline/PubMed database, selecting clinical randomized controlled studies in English. Have been examined 9 randomized controlled studies where combined treatment ab initio was compared to CBT alone, and 6 where combination treatment was compared to SRI alone. No controlled studies were found for sequential treatments in OCD. Have been then examined naturalistic studies, 2 including responder patients and 7 including non responder patients. RESULTS: Of the 9 studies, 7 didn't find any additional benefit of combining treatments as compared to CBT alone; in 1 study the combination strategy resulted more effective than CBT alone in children and adolescents, and in another in severely depressed adult patients with OCD. As compared to SRIs alone, combining treatments was not more effective in 4 studies, while in 2 studies it was more effective. All studies concerning sequential treatments found evidence of efficacy of this strategy. DISCUSSION: Combining ab initio CBT and SRI has not been found to be clearly superior of either therapy alone, except for patients with severe depression and for children and adolescents. On the contrary, a sequential strategy may be used successfully both to treat residual symptoms in responders and to determine clinical response in resistant patients. PMID- 23023077 TI - [Gamma-hydroxybutyrate (GHB) for mid/long term treatment of alcohol dependence: a systematic review]. AB - AIM: Gamma-hydroxybutyric acid (GHB) is used to treat alcohol withdrawal syndrome (AWS) at short term, and to reduce alcohol relapses among alcohol dependent subjects at mid-term. The objective of this paper is to synthesize results of a Cochrane review on efficacy of GHB for treating alcohol dependence at mid-term. METHODS: The search strategy was conducted on MEDLINE, EMBASE, PsycINFO, CINAHL and on the Cochrane Library. Pharmaceutical companies were contacted and references of papers were checked in order to identify unpublished studies. Randomized controlled trials (RCT), clinical controlled trials (CCT), and controlled prospective studies (CPS) were considered. Three authors blindly evaluated the quality of the studies and extracted the data. RESULTS: Seven RCT studies evaluating efficacy of GHB for treating alcohol dependence at mid-term were included in the review; all were conducted in Italy. GHB appears to be more effective than placebo on alcohol abstinence (RR 2.63; 1.22-5.71), controlled drinking (RR 2.43; 1.07-5.54), relapses to heavy drinking (RR 0.37; 0.21-0.63), and number of daily drinks (MD -4.60; -6.18,-3.02). GHB appears to be more effective than naltrexone on alcohol abstinence (RR 1.78; 1.21-2.62) but not on other outcomes. The effect on Alcohol Craving Scale favours GHB vs placebo (MD 4.50; -5.81,-3.19), vs naltrexone (MD -1.90; -2.45,-1.35) and vs disulfiram (MD 1.40; -1.86,-0.94). Side effects are similar to naltrexone and disulfiram. DISCUSSION: The low number of available studies, the low sample size and the low quality of the included studies limit the validity of the results and suggest the need of conducting new high-quality randomized trials with appropriate sample size. PMID- 23023079 TI - [ASO-TSO, emergency interventions: has anything changed? Old and new psychiatrist's professional responsibilities]. AB - The Law 833 of 1978 on the subject of psychiatric emergency treatments in absence of consensus has contributed to grant mental patients equal guaranties and equal constitutional rights which, until that moment, they had been denied. This standpoint includes TSO in favor of mental patients. Ordered by the constitutional laws which guarantee a person's inviolable rights, TSO finds itself positioned between individual freedom and the freedom of treatment on the one hand, and the right to safeguard health on the other hand. The procedure of TSO is noticeable in its various phases so as to provide for the various levels of safeguarding a person who is temporarily deprived of the capacity to express valid consensus. On the other side it also has a certain amount of flexibility in its application, which guarantees adaptability of the norm in various contexts and various incidental situations. Nevertheless, the complexity of the law on TSO, as well as the interpretation margins of the procedure have contributed to the creation of an application frame which is not free of criticism. In this context, the recommendations of the Conference of Regions and Autonomous Provinces have particular importance. These recommendations deserve careful analysis, both for the presence of elements of novelty (in the very particular cases of TSO for children under 18 and TSO for decisionally impaired subjects) and for the reminder of the full application of "non-hospitalized TSO". The latter was provided for in Law 833/78 but has never been adequately and completely adopted because it has never been explained in its concrete applicability. Therefore, bearing in mind the already known responsibility of a psychiatrist in an emergency case, and with renewed interest in new medical performance a psychiatrist of public service has to guarantee, we are preparing to give our contribution on the subject of professional obligations at a historical moment in which known trials seem to assign the responsibility for the "dangerousness" of a mental patient to the psychiatrist. PMID- 23023078 TI - [Mood stabilizers in the treatment of bipolar disorder mixed states]. AB - INTRODUCTION: Mixed states represent a frequent issue in the context of bipolar disorders (up to 40% of acute phases). They are complex and serious clinical pictures, which pose diagnostic challenges but also require specific treatment interventions. The purpose of this article is to provide an overview of the current literature on the pharmacotherapy of bipolar mixed-states, focusing on mood stabilizers. METHODS: Literature was identified by searches in MEDLINE (Medical Literature Analysis and Retrieval System Online), using PubMed search engine. Studies are chosen if they contained the keywords: "mixed mania or mixed state(s) or mixed episode(s) treatment or therapy". RESULTS: There was a small number of double-blind, placebo-controlled studies focused on the treatment of mixed states. The majority of available data derives from sub-group analysis made on studies that primarily include manic patients. Nevertheless, current evidences underline that, among mood-stabilizers, valproate, olanzapine and aripiprazole could be considered first-line drugs. Lithium has less evidences about its efficacy in the treatment of mixed states, but it could be a valid choice in combined therapies. DISCUSSION: There is a need of further researches on the treatment of mixed states. Less restrictive diagnostic criteria could allow to select big sized samples in order to obtain more specific and meaningful data about the efficacy of drug treatments. PMID- 23023080 TI - Measuring depression with questions about well-being: a study on psychiatric outpatients. AB - BACKGROUND: Most depression rating scales are characterized by negatively-phrased questions, exploring the presence of various symptoms. Questions such as those regarding suicidal ideation or painful experiences may reduce accept-ability or even lead the reader to withdraw participation in the study. Although positively worded items may be useful, it should be acknowledged that without formal testing they cannot be assumed to be equivalent to negatively-worded ones. The aim of the present study was to test the reliability and validity of a depression rating scale including only positively-phrased items. METHODS: Two groups were enrolled in the study: the first comprised 104 adult psychiatric outpatients, the second 88 undergraduate students. All participants completed the depression scale of the Patient Health Questionnaire, the Zung Self-Rating Depression Scale, and the Positively-phrased Depression Scale (PDS), a 10-item self-report instrument in which the items are phrased in a positive way to reflect the absence of symptoms. Psychiatric outpatients also were rated by their clinician on the Hamilton Depression Rating Scale. RESULTS: The internal consistency of the PDS was satisfactory. The correlations between scores on the PDS and on the other depression scales were moderate to high. Mean PDS scores of patients with a diagnosis of depressive disorder were significantly higher than those of patients with other mental disorders. CONCLUSIONS: Despite some limitations, this study suggests that the PDS a valid and reliable instrument which might prove particularly useful for the assessment of depressive symptoms in studies where issues of acceptability are important, such as studies on non-clinical populations, occupational samples, and patients drawn from non-psychiatric settings. PMID- 23023081 TI - Relationship between handedness and persistent emotional distress in adults experiencing an earthquake. AB - AIM: Post-traumatic emotional distress follows exposure to trauma and may be affected by atypical cerebral lateralisation. We aimed to explore the relationship between handedness and emotional dysfunction in people exposed to a nat-ural disaster. METHODS: About 22 months after an earthquake, 326 exposed adults completed the Edinburgh Handedness Inventory, the Impact of Events Scale Revised, and the Insomnia Severity Index. RESULTS: Mixed-handed people, compared to right-handed, had a 3.3 fold increase in odds to have emotional distress. Consistent left-handers scored higher than consistent right- and mixed-handers on the ISI scale. CONCLUSIONS: Findings support that lateral preference is associated with emotion-al distress in people exposed to trauma. PMID- 23023082 TI - Suicide attempts in acute psychiatric referrals with substance use disorders. AB - AIMS: The aim of the present study was to investigate suicidal risk in psychiatric referrals admitted to a University Hospital Emergency Department (ED) who had a substance use disorder. METHODS: The participants were 135 psychiatric referrals (84 men and 51 women) admitted to the ED of the Sant' Andrea Hospital of Rome (Italy) between January 2006 and February 2007. The data were collected for the purpose of this research via electronic medical records of ED patients. RESULTS: Attempters with substance use disorders were more likely to have higher burden of major affective disorders, and psychiatric history than substance use disorder referrals without recent suicide attempt; and they were at higher risk of suicide (higher rates of suicidal ideation reported during the psychiatric interview). CONCLUSIONS: When evaluating suicide attempters with substance use disorders, health professionals working in the ED settings have to assess not only somatic emergencies that can undermine patient's life but also the chance of repetition of suicidal behavior. PMID- 23023083 TI - [Maturity fears and weight phobia in eating disorders: research of a relationship]. AB - AIM: This study investigate presence, the psychopathological and treatment implications of weight phobia and maturity fears in patient with eating disorders. METHODS: The study group comprised 43 patients, with diagnosis DSM-IV TR for anorexia, bulimia and eating disorders not otherwise specified. Subjects completed the following self-administered questionnaires: Eating Disorder Inventory 2 (EDI -2), Body Uneasiness Test (BUT), MMPI-2. RESULTS: Associations emerged between MF and: K-correction, Antisocial behaviour, Cynicism, Negative Treatment Indicators (MMPI-II) and with Ineffectiveness (EDI-II). No association emerged between maturity fears and BUT subscales, neither with the biological variables. DISCUSSION: Maturity fears is a dimension without differences both in the AN that in BN, associated with personality traits, which denotes insecurity, relationship incompetence, ineffectiveness, incapability in to ask and to get help from the others with distrust. It doesn't associate with weight phobia. PMID- 23023084 TI - New evidence in theory of mind deficits in subjects with chronic schizophrenia and first episode: correlation with symptoms, neurocognition and social function. AB - AIM: Currently substantial evidence exists about Theory of Mind (ToM) impairment in subjects affected by chronic and first episode schizophrenia. In particular, in order to enhance the validity of our construct, we used in this study classical false beliefs tasks and advanced theory of mind tasks, together with the application of structural equation model, in order to ex-amine whether we are using ToM tasks with good psychometric properties. The main goal of the present study was to examine ToM deficits in a large sample including subjects suffering from chronic schizophrenia, first episode of schizophrenia and nor-mal controls, by observing in the same task the relationship with symptomatological gravity, neurocognition and social function.Materials and methods. A sample of 178 patients with chronic schizophrenia, a sample of 49 subjects with a first episode of psychosis and 484 healthy controls participated to this study. Measures of social cognition included task of false belief and advanced theory of mind task. RESULTS: No significant differences were found on ToM tasks between subjects affected by chronic and first episode schizophrenia. Social cognition showed in both groups a strong correlation with negative symptoms and social function, but did not evidence any relationship with neurocognition. CONCLUSION; ToM deficits exist in subjects suffering from chronic and first episode schizophrenia. These impairments do not seem to be a consequence of illness condition, they are likely to be state-independent and appear to be the most important cognitive mediator of social functioning in both groups. PMID- 23023085 TI - [Utilizing the Rorschach Test in the diagnosis of gender identity disorder and in the evaluation of eligibility for sex reassignment surgery]. AB - INTRODUCTION: Gender identity disorder (GID) is a mental disorder in which gender identity is incongruent with the anatomical sex, in the absence of any clear and defined genetic or biological alteration. The diagnosis of GID as well as the assessment of patient eligibility for sex reassignment surgery (SRS) are prerequisite to the legal recognition procedure. The aim of this study was to evaluate the usefulness of the Rorschach test in differential diagnosis determination and primarily in providing information on patient eligibility for SRS, in the framework of the clinical, therapeutic and forensic psychometric and psychodiagnostic assessment, and according to the World Professional Association for Transgender Health (WPATH) criteria. MATERIALS AND METHODS: For this purpose we analysed the Rorschach test of 47 patients (33 GID and 14 GID NAS). RESULTS: Results show that GID NAS patients have greater difficulties in stress control and less adaptability, which could lead to disorganisation, impulsiveness, behavioural disorders, as well as higher levels of situational and chronic stress, with altered thought patterns and uncontrolled ideation, a higher frequency of thought disorders and disturbed relations, with lower quality and less adaptive interpersonal relationships, which are characterized by dependency and aggressive behaviours. CONCLUSIONS: This research shows that the Rorschach test cannot be used alone in the determination of the differential diagnosis between GID and GID NAS in the diagnosis and evaluation of patient eligibility for SRS, especially when comparing groups which do not shows significant differences in the prevalence of the main psychopathological disorders. PMID- 23023086 TI - [Diagnostic revision of De Chiricos' case]. AB - An interesting field of psychopathology has been historically oriented towards identifying the links between artistic expression and psychological problems, searching the biographies of various artists for the deep psychological origins of their art. The painter Giorgio De Chirico has been the object of many studies and recently his documented suffering was diagnosed as problems with migraines and temporal epilepsy. However, a precise psychiatric diagnosis is still missing. The authors, using autobiographical and biographical resources, attempt to reconstruct the psychopathological medical history of the painter and subsequently classify the psychiatric diagnoses using the DSM-IV. With this methodology the authors proposed that the artist displayed a personality disorder with narcissistic and paranoid traits and had suffered from somatization disorder and adjustment disorders in three-year periods, from 1909-1911 and 1915-1918. PMID- 23023087 TI - Mesoporous SnO2 agglomerates with hierarchical structures as an efficient dual functional material for dye-sensitized solar cells. AB - Mesoporous SnO(2) agglomerates with hierarchical structures and a high surface area were fabricated through a molten salt method. The SnO(2) demonstrated high photoelectric conversion efficiencies of 3.05% and 6.23% (with TiCl(4) treatment) in dye-sensitized solar cells, which are attributed to its dual functionality of providing high dye-loading and efficient light scattering. PMID- 23023088 TI - Preparation of acute subventricular zone slices for calcium imaging. AB - The subventricular zone (SVZ) is one of the two neurogenic zones in the postnatal brain. The SVZ contains densely packed cells, including neural progenitor cells with astrocytic features (called SVZ astrocytes), neuroblasts, and intermediate progenitor cells. Neuroblasts born in the SVZ tangentially migrate a great distance to the olfactory bulb, where they differentiate into interneurons. Intercellular signaling through adhesion molecules and diffusible signals play important roles in controlling neurogenesis. Many of these signals trigger intercellular calcium activity that transmits information inside and between cells. Calcium activity is thus reflective of the activity of extracellular signals and is an optimal way to understand functional intercellular signaling among SVZ cells. Calcium activity has been studied in many other regions and cell types, including mature astrocytes and neurons. However, the traditional method to load cells with calcium indicator dye (i.e. bath loading) was not efficient at loading all SVZ cell types. Indeed, the cellular density in the SVZ precludes dye diffusion inside the tissue. In addition, preparing sagittal slices will better preserve the three-dimensional arrangement of SVZ cells, particularly the stream of neuroblast migration on the rostral-caudal axis. Here, we describe methods to prepare sagittal sections containing the SVZ, the loading of SVZ cells with calcium indicator dye, and the acquisition of calcium activity with time-lapse movies. We used Fluo-4 AM dye for loading SVZ astrocytes using pressure application inside the tissue. Calcium activity was recorded using a scanning confocal microscope allowing a precise resolution for distinguishing individual cells. Our approach is applicable to other neurogenic zones including the adult hippocampal subgranular zone and embryonic neurogenic zones. In addition, other types of dyes can be applied using the described method. PMID- 23023089 TI - Combining geometric pocket detection and desolvation properties to detect putative ligand binding sites on proteins. AB - The accurate identification of cavities that can bind ligands on the surface of proteins is of major importance for the characterization of the function of proteins based on its structure. In addition it can be helpful for rational structure-based drug design on target proteins of medical relevance and for evaluating the tendency of proteins to aggregate or oligomerize. A new approach termed dPredGB to detect and evaluate putative binding cavities on protein surfaces has been developed. In contrast to existing prediction methods that are based on purely geometric features of binding sites or on possible direct interactions with a putative binding partner the dPredGB approach combines rapid geometric detection with an evaluation of the desolvation properties of the putative binding pocket. It has been tested on a variety of proteins known to bind ligands in bound and unbound conformations. The approach outperforms most available methods and offers also the spatial characterization of the desolvation properties of a binding region. On a test set of proteins the method identifies in 69% of the unbound cases and 85% of the bound cases the known ligand binding cavity as the top ranking prediction. Possibilities to improve the prediction performance even further are also discussed. PMID- 23023090 TI - A novel assay for detecting virus-specific antibodies triggering activation of Fcgamma receptors. AB - IgG responses are crucial in antiviral defence and instrumental for the serodiagnosis of infections. Fcgamma receptors (FcgammaRs), which recognize the Fc-part of IgG, differ regarding their IgG binding affinity, IgG subclass preference, cellular expression profile and pathogen elimination mechanisms elicited upon activation. Assessing their activation in vitro is of fundamental importance, but technically difficult. Therefore, a novel assay for measuring antiviral IgG antibodies triggering activation of individual host Fcgamma receptors was established. The assay comprises the co-cultivation of virus infected target cells with immune IgG antibodies and mouse BW5147 hybridoma cells stably expressing chimeric FcgammaR-CD3zeta chain molecules consisting of the extracellular domain of human FcgammaRIIIA, FcgammaRIIA or FcgammaRI, respectively, fused to the transmembrane and intracellular domains of the mouse CD3zeta chain. Triggering of the chimeric FcgammaR receptors by immune complexes formed on the surface of IgG-opsonized virus-infected target cells resulted in FcgammaR activation leading to IL-2 secretion by BW5147 cells, which was quantified as a surrogate marker in an ELISA. Target cells infected with various human pathogenic viruses including herpes simplex virus type 1 (HSV-1), Epstein Barr virus (EBV), human cytomegalovirus (HCMV), measles virus (MV), and respiratory syncytial virus (RSV) or displaying human immunodeficiency virus-1 (HIV-1) gp120 evoke dose-dependent IgG responses demonstrating the universal applicability of the assay. Taken together, a new reliable and simple tool for measuring antibodies triggering activation of Fcgamma receptors was established. This assay will be instrumental for defining novel correlates of IgG immunity and the design of new therapeutic IgGs. PMID- 23023091 TI - High-throughput, multiplexed IgG subclassing of antigen-specific antibodies from clinical samples. AB - In vivo, the activity of antibodies relies critically on properties of both the variable domain, responsible for antigen recognition, and the constant domain, responsible for innate immune recognition. Here, we describe a flexible, microsphere-based array format for capturing information about both functional ends of disease-specific antibodies from complex, polyclonal clinical serum samples. Using minimal serum, we demonstrate IgG subclass profiling of multiple antibody specificities. We further capture and determine the subclass of epitope specific antibodies. The data generated in this array provides a profile of the humoral immune response with multi-dimensional metrics regarding properties of both variable and constant IgG domains. Significantly, these properties are assessed simultaneously, and therefore information about the relationship between variable and constant domain characteristics is captured, and can be used to predict functions such as antibody effector activity. PMID- 23023092 TI - Characterizing the combinatorial beam angle selection problem. AB - The beam angle selection (BAS) problem in intensity-modulated radiation therapy is often interpreted as a combinatorial optimization problem, i.e. finding the best combination of eta beams in a discrete set of candidate beams. It is well established that the combinatorial BAS problem may be solved efficiently with metaheuristics such as simulated annealing or genetic algorithms. However, the underlying parameters of the optimization process, such as the inclusion of non coplanar candidate beams, the angular resolution in the space of candidate beams, and the number of evaluated beam ensembles as well as the relative performance of different metaheuristics have not yet been systematically investigated. We study these open questions in a meta-analysis of four strategies for combinatorial optimization in order to provide a reference for future research related to the BAS problem in intensity-modulated radiation therapy treatment planning. We introduce a high-performance inverse planning engine for BAS. It performs a full fluence optimization for ~3600 treatment plans per hour while handling up to 50 GB of dose influence data (~1400 candidate beams). For three head and neck patients, we compare the relative performance of a genetic, a cross-entropy, a simulated annealing and a naive iterative algorithm. The selection of ensembles with 5, 7, 9 and 11 beams considering either only coplanar or all feasible candidate beams is studied for an angular resolution of 5 degrees , 10 degrees , 15 degrees and 20 degrees in the space of candidate beams. The impact of different convergence criteria is investigated in comparison to a fixed termination after the evaluation of 10 000 beam ensembles. In total, our simulations comprise a full fluence optimization for about 3000 000 treatment plans. All four combinatorial BAS strategies yield significant improvements of the objective function value and of the corresponding dose distributions compared to standard beam configurations with equi-spaced coplanar beams. The genetic and the cross-entropy algorithms showed faster convergence in the very beginning of the optimization but the simulated annealing algorithm eventually arrived at almost the same objective function values. These three strategies typically yield clinically equivalent treatment plans. The iterative algorithm showed the worst convergence properties. The choice of the termination criterion had a stronger influence on the performance of the simulated annealing algorithm than on the performance of the genetic and the cross-entropy algorithms. We advocate to terminate the optimization process after the evaluation of 1000 beam combinations without objective function decrease. For our simulations, this resulted in an average deviation of the objective function from the reference value after 10 000 evaluated beam ensembles of 0.5% for all metaheuristics. On average, there was only a minor improvement when increasing the angular resolution in the space of candidate beam angles from 20 degrees to 5 degrees . However, we observed significant improvements when considering non-coplanar candidate beams for challenging head and neck cases. PMID- 23023093 TI - Supramolecular metal displacement allows on-fluorescence analysis of manganese(II) in living cells. AB - Due to the importance of Mn(2+) ions in biological processes, it is of growing interest to develop protocols for analysis of Mn(2+) uptake and distribution in cells. A supramolecular metal displacement assay can provide ratiometric fluorescence detection of Mn(2+), allowing for quantitative and longitudinal analysis of Mn(2+) uptake in living cells. PMID- 23023094 TI - Evaluation of plasma proteomic data for Alzheimer disease state classification and for the prediction of progression from mild cognitive impairment to Alzheimer disease. AB - Previous studies that have examined the potential for plasma markers to serve as biomarkers for Alzheimer disease (AD) have studied single analytes and focused on the amyloid-beta and tau isoforms and have failed to yield conclusive results. In this study, we performed a multivariate analysis of 146 plasma analytes (the Human DiscoveryMAP v 1.0 from Rules-Based Medicine) in 527 subjects with AD, mild cognitive impairment (MCI), or cognitively normal elderly subjects from the Alzheimer's Disease Neuroimaging Initiative database. We identified 4 different proteomic signatures, each using 5 to 14 analytes, that differentiate AD from control patients with sensitivity and specificity ranging from 74% to 85%. Five analytes were common to all 4 signatures: apolipoprotein A-II, apolipoprotein E, serum glutamic oxaloacetic transaminase, alpha-1-microglobulin, and brain natriuretic peptide. None of the signatures adequately predicted progression from MCI to AD over a 12- and 24-month period. A new panel of analytes, optimized to predict MCI to AD conversion, was able to provide 55% to 60% predictive accuracy. These data suggest that a simple panel of plasma analytes may provide an adjunctive tool to differentiate AD from controls, may provide mechanistic insights to the etiology of AD, but cannot adequately predict MCI to AD conversion. PMID- 23023096 TI - RECIST rules. AB - Response Evaluation Criteria for Solid Tumours (RECIST) were introduced in 2000 to provide a standardized method for assessing response to treatments. The RECIST Working Group has updated RECIST to Version 1.1. PMID- 23023095 TI - Extrapyramidal signs by dementia severity in Alzheimer disease and dementia with Lewy bodies. AB - Alzheimer disease (AD) and dementia with Lewy bodies (DLB) are common etiologies of dementia with overlapping clinical features. Our objective was to determine which extrapyramidal signs (EPSs) are most helpful in identifying DLB. We analyzed data from the National Alzheimer's Coordinating Center, including demographics, Unified Parkinson's Disease Rating Scale (UPDRS) scores, Mini Mental State Examination (MMSE) scores, and clinical diagnosis. The subjects were divided into 3 groups: AD, DLB, or Lewy body variant (LBV). The UPDRS motor scores were totaled and analyzed within and across the MMSE strata using regression techniques. Further, we divided UPDRS subscores into 9 EPSs, dichotomized as either present or absent. Logistic regression analysis was used to compare each of the EPS in the AD and Lewy body (DLB+LBV) groups. DLB subjects (n=130) were more likely to be male individuals, younger, and have higher MMSE scores (P<0.001) compared with that in AD (n=1826) or LBV (n=105) subjects. Differences were found for total UPDRS score and number of EPSs (P<0.001), after controlling for age, sex, and MMSE. Logistic regression models demonstrated that masked facies best differentiated AD from Lewy body (odds ratio=6.5, P<0.001, 95% confidence interval, 3.8-11.1). If these findings are neuropathologically validated, then the presence of specific EPS may help clinicians better differentiate AD and DLB. PMID- 23023097 TI - Use of proton pump inhibitors and risk of fragility hip fracture in a Mediterranean region. AB - OBJECTIVE: To determine whether there is an increased risk of hip fracture associated with the use of proton pump inhibitors in a Mediterranean area after adjusting for other potential risk factors. METHODS: Retrospective multicenter case-control study carried out in 6 primary health care centers in Catalonia, Spain. Cases were patients aged 50years and over with a fragility hip fracture registered between January 2007 and December 2010, matched with 2 controls by sex and age. DATA COLLECTED: use of proton pump inhibitors (type, dosage) in the 5years previous to the hip fracture, socio-demographic data, body mass index, alcohol and tobacco consumption as well as health conditions and drugs associated with an increase risk of fragility hip fracture. RESULTS: 358 cases were matched with 698 controls. The mean age was 82years old in both groups. Women represented 77.1% in the case group and 76.9% in the control group. Crude association between proton pump inhibitors and hip fracture was 1.44 (95% CI, 1.09-1.89) and adjusted OR was 1.24 (95% CI, 0.93-1.65). No association was found with the continuous or discontinuous use of proton pump inhibitors, OR 1.17 (95% CI, 0.77-1.79), and OR of 1.16 (95% CI, 0.85-1.60) respectively. No association was found when restricting the analysis by sex, OR of 1.19 (95% CI, 0.27-5.14) or by age, younger or older than 80years, OR of 0.72 (95% CI, 0.24-2.15). CONCLUSION: The use of proton pump inhibitors was not associated with an increased risk of hip fracture after adjusting for other risk factors in a Mediterranean area. This result suggests the existence of protective environmental factors linked to this southern area of Europe that eventually could compensate for the potential harm produced by proton pump inhibitors. PMID- 23023098 TI - Brain-derived neurotrophic factor Val66Met polymorphism and alcohol-related phenotypes. AB - Alcoholism is a chronic psychiatric disorder affecting neural pathways that regulate motivation, stress, reward and arousal. Brain-derived neurotrophic factor (BDNF) regulates mood, response to stress and interacts with neurotransmitters and stress systems involved in reward pathways and addiction. Aim of the study was to evaluate the association between a single nucleotide polymorphism (BDNF Val66Met or rs6265) and alcohol related phenotypes in Caucasian patients. In ethnically homogenous Caucasian subjects of the Croatian origin, the BDNF Val66Met genotype distribution was determined in 549 male and 126 female patients with alcohol dependence and in 655 male and 259 female healthy non-alcoholic control subjects. Based on the structured clinical interview, additional detailed clinical interview, the Brown-Goodwin Scale, the Hamilton Rating Scale for Depression and the Clinical Global Impression scores, alcoholic patients were subdivided into those with or without comorbid depression, aggression, delirium tremens, withdrawal syndrome, early/late onset of alcohol abuse, prior suicidal attempt during lifetime, current suicidal behavior, and severity of alcohol dependence. The results showed no significant association between BDNF Val66Met variants and alcohol dependence and/or any of the alcohol related phenotypes in either Caucasian women, or men, with alcohol dependence. There are few limitations of the study. The overall study sample size was large (N=1589) but not well-powered to detect differences in BDNF Val66Met genotype distribution between studied groups. Healthy control women were older than female alcoholic patients. Only one BDNF polymorphism (rs6265) was studied. In conclusion, these data do not support the view that BDNF Val66Met polymorphism correlates with the specific alcohol related phenotypes in ethnically homogenous medication-free Caucasian subjects with alcohol dependence. PMID- 23023099 TI - DECT urate deposits: now you see them, now you don't. PMID- 23023100 TI - 1,25-Dihydroxyvitamin D3-glycoside of herbal origin exhibits delayed release pharmacokinetics when compared to its synthetic counterpart. AB - Vitamin D requires two metabolic steps to become biologically active. In a first step 25-hydroxyvitamin D3 is formed, which acts as storage form. After a tightly controlled step in kidney the active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is formed. Because kidney is the relevant metabolic organ for this conversion, 1,25(OH)2D3 needs to be supplemented in patients with kidney malfunction or kidney failure. Synthetic 1,25(OH)2D3 (calcitriol) has been available as a drug for decades. Due to its high potency and its kinetic profile (fast absorption and rapid elimination) its therapeutic windows has proven to be relatively narrow. A natural form of the active metabolite was identified in a few plants, such as Solanum glaucophyllum (SG) and suggested as alternative for animal and human health. An extract of a SG variety bred for high and uniform level of glycosylated 1,25(OH)2D3 was chemically characterized. Among the typical pharmaceutically inactive plant components (carbohydrates 54.3%, protein 24.9%, minerals 17.1% and water 4.1%) high levels of 1,25(OH)2D3 and a unique flavonoid content was found (1.11mg total quercetin/g extract) consisting exclusively of the quercetin glycosides hyperoside, isoquercetin, rutin and apinosylrutin. The molecular distribution of glycosyl moieties in 1,25(OH)2D3 extracted from SG as determined by gel permeation chromatography was found to be 1-10 hexose units per aglycone. 1,25(OH)2D3-1-beta-glucopyranoside was identified in the SG extract, while a di- and triglycoside have been identified in SG by other groups. The pharmacokinetic properties of synthetic 1,25(OH)2D3 and glycosylated 1,25(OH)2D3 extracted from SG were compared in male rats. When compared to synthetic 1,25(OH)2D3, SG-derived 1,25(OH)2D3 exhibited delayed absorption and elimination characteristics, resulting in delayed Tmax (6-12h vs. 1h) and increased T1/2 (approximately 30h vs. 23h). This putative modified release pattern may be attributed to the glycosylation of herbal 1,25(OH)2D3 because de-glycosylation by ubiquitous intestinal enzymes prior to intestinal uptake of the aglycone appears to be the rate limiting step. In effect, 1,25(OH)2D3 of herbal origin behaves like a precursor of calcitriol, resulting in a wider therapeutic window and thus better pharmacological tolerance. This article is part of a Special Issue entitled 'Vitamin D Workshop.'. PMID- 23023101 TI - Multimorbidity patterns in HIV-infected patients: the role of obesity in chronic disease clustering. AB - BACKGROUND: Increases in multimorbidity and obesity have been noted in HIV infected populations in the current treatment era. Patterns of multimorbid disease clustering and the impact of obesity on multimorbidity are understudied in this population. METHODS: We examined obesity and multimorbidity patterns among 1844 HIV-infected patients in the UAB 1917 Clinic. Exploratory factor analysis was used to identify the underlying factor structure responsible for clustering. Patterns among the resulting morbidity factors by body mass index (BMI) category were explored. Multivariable logistic regression models were fit to identify predictors of multimorbidity cluster patterns. RESULTS: The prevalence of multimorbidity was 65% (1205/1844). Prevalence increased with progressive BMI categories from underweight (64%) to obese (79%). Three multimorbidity clusters were identified: "metabolic," including hypertension, gout, diabetes mellitus, and chronic kidney disease (range, 0.41-0.84; P < 0.001); "Behavioral," including mood disorders, dyslipidemia, chronic obstructive pulmonary disease, chronic ulcer disease, osteoarthritis, obstructive sleep apnea, and cardiac disorders (range, 0.32-0.57; P < 0.001); "Substance Use," including alcohol abuse, substance abuse, tobacco abuse, and hepatitis C (range, 0.53-0.89; P < 0.001). Obesity was associated with increased odds of multimorbidity (obese vs. normal BMI category: OR = 1.52, 95% CI: 1.15 to 2.00). CONCLUSIONS: Three patterns of disease clustering were identified. Obesity was associated with a higher likelihood of multimorbidity. The management of multimorbidity and obesity will need to be addressed in future clinical practice guidelines to enhance long-term outcomes of HIV-infected patients in the current treatment era. PMID- 23023102 TI - Anti-CD4 monoclonal antibody ibalizumab exhibits breadth and potency against HIV 1, with natural resistance mediated by the loss of a V5 glycan in envelope. AB - OBJECTIVES: Passive immunization for the prevention of HIV-1 infection is currently being reenergized. The anti-CD4 monoclonal antibody ibalizumab has demonstrated safety and efficacy in phase 1 and 2 clinical trials for treatment of HIV-1 infection and is undergoing a phase 1 clinical trial in HIV-1 uninfected individuals for prevention. Here, we sought to assess ibalizumab antiviral breadth and potency and to identify determinants of natural preexisting resistance. METHODS: Ibalizumab breadth and potency was assessed against a large clinically relevant panel of HIV-1 pseudoviruses (n = 116) commonly used to assess vaccine candidates. Determinants of resistance were assessed by sequence analysis. RESULTS: Ibalizumab neutralized 92% and 66% of viruses as defined by 50% and 80% inhibition, respectively. Median in vitro neutralization potency by IC50 was 0.03 MUg/mL, substantially lower than the broadly neutralizing mAbs, PG9, or VRC01. The dominant determinant of resistance was the absence of a potential N-linked glycosylation site (PNGS) at the V5 N-terminus (P < 0.001), with the V2 loop length possibly influencing the degree of resistance afforded by the absence of the V5 N-terminal PNGS (P = 0.001). Other significant independent correlates of resistance included PNGS at position 386 and the side chain length of residue 375. Ibalizumab exhibited complementary resistance to VRC01 (P = 0.006) and sCD4 (P < 0.001), in part mediated by the V5 PNGS. CONCLUSIONS: Ibalizumab breadth and potency compared favorably with broadly neutralizing anti HIV-1 monoclonal antibodies, supporting the clinical development of ibalizumab, alone or in combination, for HIV-1 prevention. PMID- 23023103 TI - Urinary markers of kidney injury and kidney function decline in HIV-infected women. AB - OBJECTIVE: HIV-infected persons have substantially higher risk of kidney failure than persons without HIV, but serum creatinine levels are insensitive for detecting declining kidney function. We hypothesized that urine markers of kidney injury would be associated with declining kidney function among HIV-infected women. METHODS: In the Women's Interagency HIV Study, we measured concentrations of albumin-to-creatinine ratio, interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin from stored urine among 908 HIV-infected and 289 HIV-uninfected participants. Primary analyses used cystatin C-based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and 2 follow-up visits over 8 years; secondary analyses used creatinine (CKD-EPI eGFRcr). Each urine biomarker was categorized into tertiles, and kidney decline was modeled with both continuous and dichotomized outcomes. RESULTS: Compared with the lowest tertiles, the highest tertiles of albumin-to-creatinine ratio (-0.15 mL/min per 1.73 m, P < 0.0001), IL 18 (-0.09 mL/min per 1.73 m, P < 0.0001) and KIM-1 (-0.06 mL/min per 1.73 m, P < 0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all 3 biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: >=3% (relative risk = 1.40; 95% confidence interval: 1.04 to 1.89); >=5% (1.88; 1.30 to 2.71); and >=10% (2.16; 1.20 to 3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25 to 2.33) and 10% (1.78; 1.07 to 2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00 to 3.87). CONCLUSIONS: Among HIV-infected women in the Women's Interagency HIV Study cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function. PMID- 23023104 TI - Identification and characterization of novel human glucose-6-phosphate dehydrogenase inhibitors. AB - Glucose-6-phosphate dehydrogenase (G6PD) is the key enzyme of the pentose phosphate pathway, converting glucose-6-phosphate to 6-phosphoglucono-delta lactone with parallel reduction of NADP(+). Several human diseases, including cancer, are associated with increased G6PD activity. To date, only a few G6PD inhibitors have been available. However, adverse side effects and high IC(50) values hamper their use as therapeutics and basic research probes. In this study, we developed a high-throughput screening assay to identify novel human G6PD (hG6PD) inhibitors. Screening the LOPAC (Sigma-Aldrich; 1280 compounds), Spectrum (Microsource Discovery System; 1969 compounds), and DIVERSet (ChemBridge; 49 971 compounds) small-molecule compound collections revealed 139 compounds that presented >=50% hG6PD inhibition. Hit compounds were further included in a secondary and orthogonal assay in order to identify false-positives and to determine IC(50) values. The most potent hG6PD inhibitors presented IC(50) values of <4 uM. Compared with the known hG6PD inhibitors dehydroepiandrosterone and 6 aminonicotinamide, the inhibitors identified in this study were 100- to 1000-fold more potent and showed different mechanisms of enzyme inhibition. One of the newly identified hG6PD inhibitors reduced viability of the mammary carcinoma cell line MCF10-AT1 (IC(50) ~25 uM) more strongly than that of normal MCF10-A cells (IC(50) >50 uM). PMID- 23023105 TI - Development and characterization of a novel membrane assay for full-length BACE-1 at pH 6.0. AB - beta-Site amyloid precursor protein cleaving enzyme-1 (BACE-1) is a transmembrane aspartic protease that mediates the initial cleavage of the amyloid precursor protein (APP), leading to the generation of amyloid-beta (Abeta) peptides that are thought to be causative of Alzheimer's disease (AD). Consequently, inhibition of BACE-1 is an attractive therapeutic approach for the treatment of AD. In general, in vitro biochemical assays to monitor BACE-1 activity have used the extracellular domain of the protein that contains the catalytic active site. This form of BACE-1 is catalytically active at acidic pH and cleaves APP-based peptide substrates at the beta-site. However, this form of BACE-1 does not mimic the natural physiology of BACE-1 and shows minimal activity at pH 6.0, which is more representative of the pH within the intracellular compartments where BACE-1 resides. Moreover, high-throughput screens with recombinant BACE-1 at pH 4.5 have failed to identify tractable leads for drug discovery, and hence, BACE-1 inhibitor development has adopted a rational drug design approach. Here we describe the development and validation of a novel membrane assay comprising full length BACE-1 with measurable activity at pH 6.0, which could be used for the identification of novel inhibitors of BACE-1. PMID- 23023106 TI - Imaging interactions of metal oxide nanoparticles with macrophage cells by ultra high resolution scanning electron microscopy techniques. AB - Use of engineered metal oxide nanoparticles in a plethora of biological applications and custom products has warned about some possible dose-dependent cytotoxic effects. Macrophages are key components of the innate immune system used to study possible toxic effects and internalization of different nanoparticulate materials. In this work, ultra-high resolution field emission scanning electron microscopy (FE-SEM) was used to offer new insights into the dynamical processes of interaction of nanomaterials with macrophage cells dosed with different concentrations of metal oxide nanoparticles (CeO(2), TiO(2) and ZnO). The versatility of FE-SEM has allowed obtaining a detailed characterization of processes of adsorption and endocytosis of nanoparticles, by using advanced analytical and imaging techniques on complete unstained uncoated cells, including secondary electron imaging, high-sensitive backscattered electron imaging, X-ray microanalysis and stereoimaging. Low voltage BF/DF-STEM confirmed nanoparticle adsorption and internalization into endosomes of CeO(2) and TiO(2), whereas ZnO develop apoptosis after 24 h of interaction caused by dissolution and invasion of cell nucleus. Ultra-high resolution scanning electron microscopy techniques provided new insights into interactions of inorganic nanoparticles with macrophage cells with high spatial resolution. PMID- 23023107 TI - Interim susceptibility testing for ceftaroline, a new MRSA-active cephalosporin: selecting potent surrogate beta-lactam markers to predict ceftaroline activity against clinically indicated species. AB - Ceftaroline, the bio-active form of parenterally administered ceftaroline fosamil, is a unique broad-spectrum cephalosporin with in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus and was approved for clinical use by the United States Food and Drug Administration in October 2010. In over a year since ceftaroline fosamil approval, no widely used commercial susceptibility test system has added this new compound to its product, therefore requiring use of alternative agar diffusion methods for clinical microbiology laboratories that want to test clinical isolates for ceftaroline susceptibility. An alternative strategy of applying a surrogate beta-lactam class marker agent was assessed here, using results from 14,902 organisms (2008-2010) sampled in the USA. Very high and acceptable accuracy (>= 99.75%) was observed for predicting ceftaroline susceptibility as follows: 1) use of imipenem or meropenem minimum inhibitory concentrations (MICs) at <= 8 MUg/mL (susceptible and intermediate categories) when testing S. aureus; 2) use of ceftriaxone MIC at <= 2 MUg/mL (susceptible and intermediate categories) when testing Streptococcus pneumoniae as well as other streptococci (S. pyogenes and S. agalactiae); and 3) use of ceftriaxone, or cefepime, or ceftazidime at <= 2 MUg/mL (susceptible category) when testing Haemophilus influenzae. Only when testing indicated Enterobacteriaceae species using ceftriaxone susceptibility results did the ceftaroline-nonsusceptible errors increase (4.11%). These presented analyses offer a validated surrogate marker strategy for ceftaroline susceptibility testing, pending development and validation by the commonly used automated systems and agar diffusion commercial methods. PMID- 23023108 TI - Pollinators' mating rendezvous and the evolution of floral advertisement. AB - Successful cross-fertilization in plant species that rely on animal pollinators depends not just on the number of pollinator visits, but also on these visits' duration. Furthermore, in non-deceptive pollination, a visit's duration depends on the magnitude of the reward provided to the pollinator. Accordingly, plants that rely on biotic pollination have to partition their investment in cross fertilization assurance between attracting pollinator visits - advertisement, and rewarding visitors to assure that the visit is of productive duration. Here we analyze these processes by a combination of optimality methods and game theoretical modeling. Our results indicate that the optimality in such allocation of resources depends on the types of reward offered to the pollinators. More precisely, we show that plants that offer both food reward and mating rendezvous to pollinators will evolve to allocate a higher proportion of their cross fertilization assurance budget to advertisement than plants that offer only food reward. That is, our results indicate that pollinators' mating habits may play a role in floral evolution. PMID- 23023109 TI - Scalable synthesis and device integration of self-registered one-dimensional zinc oxide nanostructures and related materials. AB - On integrating one-dimensional (1D) nanocrystals (nanowires) to useful devices, in this review article, we provide a background on vapor-based growth processes and how they impact device integration strategies. Successful integration of nanowires to devices and their scalability simply rely on where and how nanowires are formed, how they are interfaced to other device components and how they function. In this direction, we will provide a discussion on developed growth strategies for lateral and standing growth of semiconductor nanostructures and assess their success in addressing current challenges of nanotechnology such as mass integration of nanowires, and the necessary accuracy in their positioning and alignment. In this regard, we highlight some of our recent work on formation of two-dimensional (2D)- and three-dimensional (3D)- nanowire and nanowall arrays and provide an overview of their structural and electro-optical properties. This will be followed by discussing potential applications of such hierarchical assemblies in light generation, photocatalysis and conversion of motion to electricity. PMID- 23023110 TI - Flow cytometry-based purification of S. cerevisiae zygotes. AB - Zygotes are essential intermediates between haploid and diploid states in the life cycle of many organisms, including yeast (Figure 1) (1). S. cerevisiae zygotes result from the fusion of haploid cells of distinct mating type (MATa, MATalpha) and give rise to corresponding stable diploids that successively generate as many as 20 diploid progeny as a result of their strikingly asymmetric mitotic divisions (2). Zygote formation is orchestrated by a complex sequence of events: In this process, soluble mating factors bind to cognate receptors, triggering receptor-mediated signaling cascades that facilitate interruption of the cell cycle and culminate in cell-cell fusion. Zygotes may be considered a model for progenitor or stem cell function. Although much has been learned about the formation of zygotes and although zygotes have been used to investigate cell molecular questions of general significance, almost all studies have made use of mating mixtures in which zygotes are intermixed with a majority population of haploid cells (3-8). Many aspects of the biochemistry of zygote formation and the continuing life of the zygote therefore remain uninvestigated. Reports of purification of yeast zygotes describe protocols based on their sedimentation properties (9); however, this sedimentation-based procedure did not yield nearly 90% purity in our hands. Moreover, it has the disadvantage that cells are exposed to hypertonic sorbitol. We therefore have developed a versatile purification procedure. For this purpose, pairs of haploid cells expressing red or green fluorescent proteins were co-incubated to allow zygote formation, harvested at various times, and the resulting zygotes were purified using a flow cytometry based sorting protocol. This technique provides a convenient visual assessment of purity and maturation. The average purity of the fraction is approximately 90%. According to the timing of harvest, zygotes of varying degrees of maturity can be recovered. The purified samples provide a convenient point of departure for " omic" studies, for recovery of initial progeny, and for systematic investigation of this progenitor cell. PMID- 23023111 TI - Virus-binding proteins and their roles in shrimp innate immunity. AB - Disease outbreaks caused by viral pathogens constitute a major limitation to development of the shrimp aquaculture industry. Many research have been conducted to better understand how host shrimp respond to viral infections with the aim of using the gained knowledge to develop better strategies for disease management and control. One approach has been to study the interactions between host and viral proteins, and particularly host virus-binding proteins that might play an important role in the viral infection process. Within the past five years, increasing numbers of virus-binding proteins (VBPs) have been reported in shrimp. Characterization of these molecules has emphasized on their potential therapeutic applications by demonstrating their activities in inhibition of viral replication via in vivo neutralization assay. However, signaling to induce innate antiviral immune responses as a consequence of binding between viral proteins and VBPs remain to be fully elucidated. PMID- 23023112 TI - Imaging beyond RECIST: CT and MRI in molecular therapies. AB - Until recently, almost all systemic antineoplastic therapies in cancer patients aimed at destruction of tumor cells, i.e. they were cytotoxic. The effect of therapy was assessed by measuring the tumor size with a decrease in size suggesting response to therapy and an increase suggesting progression. Modern molecular therapies, however, are mostly not cytotoxic but aim to reduce tumor perfusion or metabolism by blocking specific cell functions without causing cell death. Assessment of tumor size alone may, therefore, not be appropriate in this setting and can even lead to false conclusions. This presentation gives examples of changes at computed tomography (CT) and magnetic resonance imaging (MRI) of tumors undergoing therapy with molecular therapies, highlights potential pitfalls und suggests criteria for response assessment. The presentation focuses on CT and MRI of chest and abdominal tumors and specifically excludes positron emission tomography/CT and brain tumors. PMID- 23023113 TI - Explaining objective responses to zoledronic acid. PMID- 23023114 TI - Stromal cell-derived factor-1alpha and macrophage migration-inhibitory factor induce metastatic behavior in CXCR4-expressing colon cancer cells. AB - Metastasis of cancer cells is a major cause of death in cancer patients. The process of cancer metastasis includes the proliferation of primary cancer cells, local invasion, intravasation and cancer cell survival in blood flow, extravasation and attachment to secondary organs and metastatic growth in a new environment. In these mechanisms of cancer metastasis, CXC chemokine receptor 4 (CXCR4) and its ligand play an important role. Stromal cell-derived factor-1alpha (SDF-1alpha, also known as CXCL12) is well known as a ligand of CXCR4, and macrophage migration-inhibitory factor (MIF) has recently become known as a ligand of CXCR4. In many types of cancers including breast, pancreatic and colorectal cancer (CRC), CXCR4/SDF-1alpha has been investigated in metastasis related cancer behavior, which include cell proliferation, adhesion, migration and invasion. However, CXCR4/MIF has rarely been investigated in the metastatic behavior of colon cancer cells. In this report, the effect of SDF-1alpha or MIF was studied on cell cycle, cell proliferation, adhesion and migration of the CXCR4-expressing colon cancer cell line SW480. SDF-1alpha or MIF caused a decrease in the number of cells in G0/G1 phase and an increase in the numbers of cells in S and G2/M phases. In addition, SDF-1alpha or MIF caused an increase in cell proliferation, cell adhesion to fibronectin and migration. AMD3100, a CXCR4 antagonist, attenuated these effects, which included increased cell proliferation, adhesion and migration due to treatment of CXCR4-expressing colon cancer cells with SDF-1alpha or MIF. In conclusion, SDF-1alpha or MIF affects the metastasis-related behaviors of CXCR4-expressing colon cancer cells. PMID- 23023116 TI - Graphene oxide/polyaniline nanostructures: transformation of 2D sheet to 1D nanotube and in situ reduction. AB - The formation of unique polyaniline nanotubes has been reported in presence of graphene oxide (GO) which plays crucial dual role as dopant and soft template, simultaneously. GO in nanotubes is in situ reduced to reduced GO with restoration of electrical conductivities and enhanced thermal stabilities. PMID- 23023115 TI - A novel microfluidic platform for high-resolution imaging of a three-dimensional cell culture under a controlled hypoxic environment. AB - Low oxygen tensions experienced in various pathological and physiological conditions are a major stimulus for angiogenesis. Hypoxic conditions play a critical role in regulating cellular behaviour including migration, proliferation and differentiation. This study introduces the use of a microfluidic device that allows for the control of oxygen tension for the study of different three dimensional (3D) cell cultures for various applications. The device has a central 3D gel region acting as an external cellular matrix, flanked by media channels. On each side, there is a peripheral gas channel through which suitable gas mixtures are supplied to establish a uniform oxygen tension or gradient within the device. The effects of various parameters, such as gas and media flow rates, device thickness, and diffusion coefficients of oxygen were examined using numerical simulations to determine the characteristics of the microfluidic device. A polycarbonate (PC) film with a low oxygen diffusion coefficient was embedded in the device in proximity above the channels to prevent oxygen diffusion from the incubator environment into the polydimethylsiloxane (PDMS) device. The oxygen tension in the device was then validated experimentally using a ruthenium-coated (Ru-coated) oxygen-sensing glass cover slip which confirmed the establishment of low uniform oxygen tensions (<3%) or an oxygen gradient across the gel region. To demonstrate the utility of the microfluidic device for cellular experiments under hypoxic conditions, migratory studies of MDA-MB-231 human breast cancer cells were performed. The microfluidic device allowed for imaging cellular migration with high-resolution, exhibiting an enhanced migration in hypoxia in comparison to normoxia. This microfluidic device presents itself as a promising platform for the investigation of cellular behaviour in a 3D gel scaffold under varying hypoxic conditions. PMID- 23023117 TI - [Murder. Italy-USA comparative profiles]. AB - This paper, through illustrative cases of homicidal typologies, examines the generally accepted theories on the subject: 1) sociological ones by Lorenz to Sutherland and Cressey, by Berkowitz to Wolfgang and Ferracuti and others; 2) neurobiological ones, which include the involvement of the limbic, hippocampal and parietal lobes of the brain; 3) the psychological (psychodynamic) ones which are not disjoint from the types of individual criminal homicide and related aspects. In the discussion of the types of murders, family and extrafamilial murders are then taken into consideration, with the various meanings of revenge, challenge, other reasons linked to robbery, theft, settling scores leading to youth gangs and drive-by-shootings of marginalized adolescents, crimes related to drugs and to mental disorders. Infanticide and multiple murder, including mass murder and serial killer, conclude the work together with the statistics of murders and family murders in Italy compared to USA, specifically to the crime clock. PMID- 23023118 TI - [Some Italian research on the phenomenon of filicide]. AB - In this work on the phenomenon of filicide, structured on the basis of the examination of hundreds of cases from 1880 to 2010, the five causes were taken into account: the altruistic filicide, the high psychotic component, that of the unwanted child, accidental filicide, and the spouse revenge filicide. Following the observation of Resnick's (1969) 530 psycho-biographiesss, a more structured typing was developed which on the basis of their motive and/or psychopathology divides mother infanticide into 20 categories: the first 10 imply full imputability, stessor events, for piety, immaturity of the mother, hyperactivity of the child, the son of the blame, Medea syndrome, disturbance dependent, narcissistic, or histrionic personality, unwanted child, depression, behavioral disorders involved in the recruitment of drugs. The remaining 10 are those where there may be impairment of traceability for postpartum psychosis (Brief psychotic disorder), Fundus hysterical plus precipitating factors, major depression, schizophrenia, twilight state, psychotic disorder due to a general medical condition, epilepsy, oligophrenia, multiple sclerosis and multiple personality, which however appears to be quite rare. An examination of the causes of death concludes the work. PMID- 23023119 TI - [Liability, moral consciousness and psychopatology. International comparative profiles]. AB - The paper considers the concepts of intentionality, judgment, desire, awareness and the relative scientific, psychological, psychiatric and neurophysiological studies, including the concept of "moral consciousness" and the evolution of moral standards, marked out by Piaget and Kolberg. There are several references to a psychopathology point of view, for which mental infirmity is independent from the verification of an organic substrate and classification in official nosology (it is said, then, that "it is true that mental infirmity can exist even in the absence of a typical disease of the mind, framed in the scientific classification of mental illness, it is still necessary that a defect in part descended from a morbid state, dependent on a pathological changes in clinically ascertained" (as Cass, Sec. I, n. 9739/1997). The concept of illness, then widens to include not only the organic psychoses, but psychic morbid disorders such as psychopathy, neuroses, disorders of affect too: under investigation, therefore, it is no longer the person-body, but the person-psyche. In psychiatry there are existing guidelines which assert an "integrated model" of mental illness, able to explain mental disorder based on different explanatory hypotheses of its nature and origin: essentially consisting of "an integrated vision that takes into account all the variables, biological, psychological, social, relational, that come into play in causing the disease", in such a manner developing from the monocausal etiology of mental illness vision, to a "multifactorial integrated" conception. PMID- 23023120 TI - [Simulation of mental illness]. AB - The DSM-IV-TR defines the simulation an "intentional production of physical or psychological symptoms false or grossly exaggerated, motivated by external incentives". The first point to consider is that it has a near zero prevalence in the general population, occurring almost exclusively in people imprisoned, treated in Forensic Psychiatric Hospital, in individuals subjected to trial, or in personalities seen as deviated from a criminological point of view. Both the criteria to set diagnoses of simulation, previously examined by Foreal and Kaufman since 1943, and the relative suspicion indicators, not separated by 'reasons of simulated behavior, are taken into account. The work also addresses several other meanings of self injurious actions appointed by Bachler, as well as the associationist/mechanistic theories of the classical dynamic model and the differential diagnosis with other conditions of Psychiatric Interest and concludes with the topic of "Premeditation". PMID- 23023121 TI - [The investigative and adversarial process in Italy and the United States]. AB - The structure of the US legal system, which relies on the presence of different courts to provide for the impartial administration of justice, both civil and criminal is discussed. Therefore, all the steps to conviction or acquittal of the American criminal trial, are taken into consideration. However, there is the presumption of innocence of the accused and the prosecution must prove his guilt beyond any reasonable doubt. Another important procedure in the US trial is the jury selection (voir dire), 12 jurors: 6 for the defense and 6 for the prosecution. In Italy it was observed that the autonomy of the police would squeeze the steering function of the prosecutor, and the practice of "under cover" investigation has granted an extension of police activity. PMID- 23023122 TI - [Stalking: clinical and criminological considerations through the results of a research contribution]. AB - Among the extensive results supplied by the psychiatric literature on the subject of stalking, few studies focus on the analysis of persecutory behaviors carried out against mental health professionals, who also identified as one of the most affected sample of victims. Particularly, for studies conducted in this way, further examination requires differentiation according to gender type into the social and personal characteristics of the authors' behavior patterns displayed towards the victims. Aim. To obtaine results by an epidemiological survey conducted in public and private psychiatric care structures in the city of Rome, to assess the incidence of the phenomenon as well as gender differences in behavior patterns practised out by the author for the two sample considered. Methods. Administration of a questionnaire to a sample make up by psychiatrists working in out-patient services for the Departments of Mental Health (ASL) of Rome and to a sample of psychiatrists who practise their professional activity in the private sector. Results. Regarding the incidence of the phenomenon, an increased presence has been found in private mental health care settings in comparison to the public service; regarding to the distribution of the phenomenon according to the sexual identity of the authors among the two samples analyzed, a statistical prevalence of female authors has been found in the sample of private sector. Discussion. The health's professionals, so much liable of victimization, are poorly formed on the phenomenon. So it's urgent to operate with integrated approaches (informative trainings; strengthening of administrative and clinical policies of the profession; multidimensional assessment). PMID- 23023123 TI - Vaccine-induced CD8+ T cells control AIDS virus replication. AB - Developing a vaccine for human immunodeficiency virus (HIV) may be aided by a complete understanding of those rare cases in which some HIV-infected individuals control replication of the virus. Most of these elite controllers express the histocompatibility alleles HLA-B*57 or HLA-B*27 (ref. 3). These alleles remain by far the most robust associations with low concentrations of plasma virus, yet the mechanism of control in these individuals is not entirely clear. Here we vaccinate Indian rhesus macaques that express Mamu-B*08, an animal model for HLA B*27-mediated elite control, with three Mamu-B*08-restricted CD8(+) T-cell epitopes, and demonstrate that these vaccinated animals control replication of the highly pathogenic clonal simian immunodeficiency virus (SIV) mac239 virus. High frequencies of CD8(+) T cells against these Vif and Nef epitopes in the blood, lymph nodes and colon were associated with viral control. Moreover, the frequency of the CD8(+) T-cell response against the Nef RL10 epitope (Nef amino acids 137-146) correlated significantly with reduced acute phase viraemia. Finally, two of the eight vaccinees lost control of viral replication in the chronic phase, concomitant with escape in all three targeted epitopes, further implicating these three CD8(+) T-cell responses in the control of viral replication. Our findings indicate that narrowly targeted vaccine-induced virus specific CD8(+) T-cell responses can control replication of the AIDS virus. PMID- 23023124 TI - Clonal allelic predetermination of immunoglobulin-kappa rearrangement. AB - Although most genes are expressed biallelically, a number of key genomic sites- including immune and olfactory receptor regions--are controlled monoallelically in a stochastic manner, with some cells expressing the maternal allele and others the paternal allele in the target tissue. Very little is known about how this phenomenon is regulated and programmed during development. Here, using mouse immunoglobulin-kappa (Igkappa) as a model system, we demonstrate that although individual haematopoietic stem cells are characterized by allelic plasticity, early lymphoid lineage cells become committed to the choice of a single allele, and this decision is then stably maintained in a clonal manner that predetermines monoallelic rearrangement in B cells. This is accompanied at the molecular level by underlying allelic changes in asynchronous replication timing patterns at the kappa locus. These experiments may serve to define a new concept of stem cell plasticity. PMID- 23023126 TI - The aged niche disrupts muscle stem cell quiescence. AB - The niche is a conserved regulator of stem cell quiescence and function. During ageing, stem cell function declines. To what extent and by what means age-related changes within the niche contribute to this phenomenon are unknown. Here we demonstrate that the aged muscle stem cell niche, the muscle fibre, expresses Fgf2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose their self-renewing capacity. We show in mice that relatively dormant aged satellite cells robustly express sprouty 1 (Spry1), an inhibitor of fibroblast growth factor (FGF) signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing Spry1 results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of Fgfr1 signalling or overexpression of Spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function. PMID- 23023125 TI - A metagenome-wide association study of gut microbiota in type 2 diabetes. AB - Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes. PMID- 23023127 TI - Structure-based prediction of protein-protein interactions on a genome-wide scale. AB - The genome-wide identification of pairs of interacting proteins is an important step in the elucidation of cell regulatory mechanisms. Much of our present knowledge derives from high-throughput techniques such as the yeast two-hybrid assay and affinity purification, as well as from manual curation of experiments on individual systems. A variety of computational approaches based, for example, on sequence homology, gene co-expression and phylogenetic profiles, have also been developed for the genome-wide inference of protein-protein interactions (PPIs). Yet comparative studies suggest that the development of accurate and complete repertoires of PPIs is still in its early stages. Here we show that three-dimensional structural information can be used to predict PPIs with an accuracy and coverage that are superior to predictions based on non-structural evidence. Moreover, an algorithm, termed PrePPI, which combines structural information with other functional clues, is comparable in accuracy to high throughput experiments, yielding over 30,000 high-confidence interactions for yeast and over 300,000 for human. Experimental tests of a number of predictions demonstrate the ability of the PrePPI algorithm to identify unexpected PPIs of considerable biological interest. The surprising effectiveness of three dimensional structural information can be attributed to the use of homology models combined with the exploitation of both close and remote geometric relationships between proteins. PMID- 23023129 TI - En echelon and orthogonal fault ruptures of the 11 April 2012 great intraplate earthquakes. AB - The Indo-Australian plate is undergoing distributed internal deformation caused by the lateral transition along its northern boundary--from an environment of continental collision to an island arc subduction zone. On 11 April 2012, one of the largest strike-slip earthquakes ever recorded (seismic moment magnitude M(w) 8.7) occurred about 100-200 kilometres southwest of the Sumatra subduction zone. Occurrence of great intraplate strike-slip faulting located seaward of a subduction zone is unusual. It results from northwest-southeast compression within the plate caused by the India-Eurasia continental collision to the northwest, together with northeast-southwest extension associated with slab pull stresses as the plate underthrusts Sumatra to the northeast. Here we use seismic wave analyses to reveal that the 11 April 2012 event had an extraordinarily complex four-fault rupture lasting about 160 seconds, and was followed approximately two hours later by a great (M(w) 8.2) aftershock. The mainshock rupture initially expanded bilaterally with large slip (20-30 metres) on a right lateral strike-slip fault trending west-northwest to east-southeast (WNW-ESE), and then bilateral rupture was triggered on an orthogonal left-lateral strike slip fault trending north-northeast to south-southwest (NNE-SSW) that crosses the first fault. This was followed by westward rupture on a second WNW-ESE strike slip fault offset about 150 kilometres towards the southwest from the first fault. Finally, rupture was triggered on another en echelon WNW-ESE fault about 330 kilometres west of the epicentre crossing the Ninetyeast ridge. The great aftershock, with an epicentre located 185 kilometres to the SSW of the mainshock epicentre, ruptured bilaterally on a NNE-SSW fault. The complex faulting limits our resolution of the slip distribution. These great ruptures on a lattice of strike-slip faults that extend through the crust and a further 30-40 kilometres into the upper mantle represent large lithospheric deformation that may eventually lead to a localized boundary between the Indian and Australian plates. PMID- 23023128 TI - Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. AB - Pregnancy is an intricately orchestrated process where immune effector cells with fetal specificity are selectively silenced. This requires the sustained expansion of immune-suppressive maternal FOXP3(+) regulatory T cells (T(reg) cells), because even transient partial ablation triggers fetal-specific effector T-cell activation and pregnancy loss. In turn, many idiopathic pregnancy complications proposed to originate from disrupted fetal tolerance are associated with blunted maternal T(reg) expansion. Importantly, however, the antigen specificity and cellular origin of maternal T(reg) cells that accumulate during gestation remain incompletely defined. Here we show that pregnancy selectively stimulates the accumulation of maternal FOXP3(+) CD4 cells with fetal specificity using tetramer based enrichment that allows the identification of rare endogenous T cells. Interestingly, after delivery, fetal-specific T(reg) cells persist at elevated levels, maintain tolerance to pre-existing fetal antigen, and rapidly re accumulate during subsequent pregnancy. The accelerated expansion of T(reg) cells during secondary pregnancy was driven almost exclusively by proliferation of fetal-specific FOXP3(+) cells retained from prior pregnancy, whereas induced FOXP3 expression and proliferation of pre-existing FOXP3(+) cells each contribute to T(reg) expansion during primary pregnancy. Furthermore, fetal resorption in secondary compared with primary pregnancy becomes more resilient to partial maternal FOXP3(+) cell ablation. Thus, pregnancy imprints FOXP3(+) CD4 cells that sustain protective regulatory memory to fetal antigen. We anticipate that these findings will spark further investigation on maternal regulatory T-cell specificity that unlocks new strategies for improving pregnancy outcomes and novel approaches for therapeutically exploiting T(reg) cell memory. PMID- 23023131 TI - The 11 April 2012 east Indian Ocean earthquake triggered large aftershocks worldwide. AB - Large earthquakes trigger very small earthquakes globally during passage of the seismic waves and during the following several hours to days, but so far remote aftershocks of moment magnitude M >= 5.5 have not been identified, with the lone exception of an M = 6.9 quake remotely triggered by the surface waves from an M = 6.6 quake 4,800 kilometres away. The 2012 east Indian Ocean earthquake that had a moment magnitude of 8.6 is the largest strike-slip event ever recorded. Here we show that the rate of occurrence of remote M >= 5.5 earthquakes (>1,500 kilometres from the epicentre) increased nearly fivefold for six days after the 2012 event, and extended in magnitude to M <= 7. These global aftershocks were located along the four lobes of Love-wave radiation; all struck where the dynamic shear strain is calculated to exceed 10(-7) for at least 100 seconds during dynamic-wave passage. The other M >= 8.5 mainshocks during the past decade are thrusts; after these events, the global rate of occurrence of remote M >= 5.5 events increased by about one-third the rate following the 2012 shock and lasted for only two days, a weaker but possibly real increase. We suggest that the unprecedented delayed triggering power of the 2012 earthquake may have arisen because of its strike-slip source geometry or because the event struck at a time of an unusually low global earthquake rate, perhaps increasing the number of nucleation sites that were very close to failure. PMID- 23023130 TI - Androgenetic haploid embryonic stem cells produce live transgenic mice. AB - Haploids and double haploids are important resources for studying recessive traits and have large impacts on crop breeding, but natural haploids are rare in animals. Mammalian haploids are restricted to germline cells and are occasionally found in tumours with massive chromosome loss. Recent success in establishing haploid embryonic stem (ES) cells in medaka fish and mice raised the possibility of using engineered mammalian haploid cells in genetic studies. However, the availability and functional characterization of mammalian haploid ES cells are still limited. Here we show that mouse androgenetic haploid ES (ahES) cell lines can be established by transferring sperm into an enucleated oocyte. The ahES cells maintain haploidy and stable growth over 30 passages, express pluripotent markers, possess the ability to differentiate into all three germ layers in vitro and in vivo, and contribute to germlines of chimaeras when injected into blastocysts. Although epigenetically distinct from sperm cells, the ahES cells can produce viable and fertile progenies after intracytoplasmic injection into mature oocytes. The oocyte-injection procedure can also produce viable transgenic mice from genetically engineered ahES cells. Our findings show the developmental pluripotency of androgenentic haploids and provide a new tool to quickly produce genetic models for recessive traits. They may also shed new light on assisted reproduction. PMID- 23023132 TI - Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. AB - Mitochondrial respiratory function is frequently impaired in human cancers. However, the mechanisms by which mitochondrial dysfunction contributes to tumour progression remain elusive. Here we show in Drosophila imaginal epithelium that defects in mitochondrial function potently induce tumour progression of surrounding tissue in conjunction with oncogenic Ras. Our data show that Ras activation and mitochondrial dysfunction cooperatively stimulate production of reactive oxygen species, which causes activation of c-Jun amino (N)-terminal kinase (JNK) signalling. JNK cooperates with oncogenic Ras to inactivate the Hippo pathway, leading to upregulation of its targets Unpaired (an interleukin-6 homologue) and Wingless (a Wnt homologue). Mitochondrial dysfunction in Ras activated cells further cooperates with Ras signalling in neighbouring cells with normal mitochondrial function, causing benign tumours to exhibit metastatic behaviour. Our findings provide a mechanistic basis for interclonal tumour progression driven by mitochondrial dysfunction and oncogenic Ras. PMID- 23023134 TI - April 2012 intra-oceanic seismicity off Sumatra boosted by the Banda-Aceh megathrust. AB - Large earthquakes nucleate at tectonic plate boundaries, and their occurrence within a plate's interior remains rare and poorly documented, especially offshore. The two large earthquakes that struck the northeastern Indian Ocean on 11 April 2012 are an exception: they are the largest strike-slip events reported in historical times and triggered large aftershocks worldwide. Yet they occurred within an intra-oceanic setting along the fossil fabric of the extinct Wharton basin, rather than on a discrete plate boundary. Here we show that the 11 April 2012 twin earthquakes are part of a continuing boost of the intraplate deformation between India and Australia that followed the Aceh 2004 and Nias 2005 megathrust earthquakes, subsequent to a stress transfer process recognized at other subduction zones. Using Coulomb stress change calculations, we show that the coseismic slips of the Aceh and Nias earthquakes can promote oceanic left lateral strike-slip earthquakes on pre-existing meridian-aligned fault planes. We further show that persistent viscous relaxation in the asthenospheric mantle several years after the Aceh megathrust explains the time lag between the 2004 megathrust and the 2012 intraplate events. On a short timescale, the 2012 events provide new evidence for the interplay between megathrusts at the subduction interface and intraplate deformation offshore. On a longer geological timescale, the Australian plate, driven by slab-pull forces at the Sunda trench, is detaching from the Indian plate, which is subjected to resisting forces at the Himalayan front. PMID- 23023133 TI - Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. AB - The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed to contribute to the pathology of type 2 diabetes. However, few treatment options exist that directly target ectopic lipid accumulation. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Here we show that decreased VEGF-B signalling in rodent models of type 2 diabetes restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic lipid deposition, increased muscle glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved beta-cell function and ameliorated dyslipidaemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGF-B neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipid-transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal. PMID- 23023136 TI - Resveratrol attenuates hepatotoxicity of rats exposed to arsenic trioxide. AB - Arsenic trioxide (As(2)O(3)) is an environmental pollutant and potent toxicant to humans. However, it also shows substantial anti-cancer activity in individuals with acute promyelocytic leukemia (APL). Unfortunately, As(2)O(3)-treated leukemia patients suffer hepatotoxicity. Resveratrol has been demonstrated to have efficient antioxidant and antineoplastic activities. The study that how As(2)O(3) in combination with resveratrol affects hepatotoxicity and arsenic accumulation in the liver is lacking, and the present study tackles this question. Wistar rats were injected with 3mg/kg As(2)O(3) on alternate days; resveratrol (8mg/kg) was administered 1h before As(2)O(3). Rats were killed on the 8th day to determine histological liver damage, the antioxidant enzymes in serum, the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), and arsenic accumulation in the liver. In the resveratrol+As(2)O(3) group, activities of superoxide dismutase, catalase in serum and GSH/GSSG were significantly increased, histopathological effects were reduced, and arsenic accumulation markedly decreased in the liver, compared with the As(2)O(3)-treated group. Thus, resveratrol attenuated As(2)O(3)-induced hepatotoxicity by decreasing oxidative stress and arsenic accumulation in the liver. These data suggest that use of resveratrol as post-remission therapy of APL and adjunctive therapy in patients with chronic exposure to arsenic may decrease arsenic hepatotoxicity. PMID- 23023137 TI - Novel anti-angiogenic effects of formononetin in human colon cancer cells and tumor xenograft. AB - Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus, a medicinal plant that possesses antitumorigenic properties. Our previous findings demonstrated that formononetin initiates growth-inhibitory and pro-apoptotic activities in human colon cancer cells. In the present study, we aimed to further examine the potential of formononetin in controlling angiogenesis and tumor cell invasiveness in human colon cancer cells and tumor xenografts. The results showed that formononetin downregulated the expression of the key pro-angiogenic factors, including vascular endothelial growth factor (VEGF) and matrix metalloproteinases. We also discovered that the invasiveness of metastatic colon cancer cells was alleviated following drug treatment. The potential anti-angiogenic effect of formononetin was examined in nude mouse xenografts. The tumor size and the number of proliferating cells were reduced in the tumor tissues obtained from the formononetin-treated group. The serum VEGF level was also reduced in the drug-treated animals when compared to the controls. These findings suggest that formononetin inhibits angiogenesis and tumor cell invasion, and thus support its use in the treatment of advanced and metastatic colon cancers. PMID- 23023138 TI - Clinical performance characteristics of the Cervista HPV HR test kit in cervical cancer screening in China. AB - OBJECTIVE: A multicenter clinical trial was performed to evaluate and validate the performance of Cervista HPV HR test and to establish its effectiveness in identifying women at risk of having cervical intraepithelial neoplasia 2 (CIN 2) or higher grade (CIN 2+) in the Chinese population. MATERIALS AND METHODS: Residual ThinPrep Pap Test samples from women who are negative for intraepithelial lesion or malignancy (NILM) and atypical squamous cells of undetermined significance (ASCUS) or higher grade cytology were tested for high risk human papillomavirus (HPV). The HPV test results were compared with histology results to determine the clinical sensitivity, specificity, positive predictive value, and negative predictive value of Cervista HPV HR for CIN 2+. The analytical accuracy of Cervista HPV HR compared with consensus HPV L1 polymerase chain reaction (PCR)/sequencing was also determined. RESULT: A total of 1,064 subjects were enrolled, including 544 with NILM cytology and 520 with ASCUS or higher grade cytology. Complete data sets including cytology, high-risk HPV test, colposcopy, and histology results for all subjects with ASCUS or higher grade were included in the analysis. The positive rate of Cervista HPV HR was 12.5% in patients with NILM and 69.04% in patients with ASCUS or higher grade. The overall percentage agreement between Cervista HPV HR and PCR with bidirectional sequencing was 86.26%, with positive percentage agreement and negative percentage agreement being 93.4% and 83.3%, respectively. In the overall population, the Cervista HPV HR positivity rate was 38.96% compared with 29.08% for PCR/sequencing. The clinical sensitivity and specificity for CIN 2+ of Cervista HPV HR were 98.50% and 68.21%, respectively. The negative and positive predictive values were 99.69% and 30.68%, respectively. CONCLUSIONS: The Cervista HPV HR test, performed on ThinPrep Pap Test samples, has the clinical performance characteristics required by China for use as part of routine cervical cancer screening. PMID- 23023139 TI - VITOM in digital high-definition video exocolposcopy. PMID- 23023141 TI - Cervix cancer screening guideline judgments are not explicit and transparent. PMID- 23023143 TI - Analysis of human mesenchymal stem cells on a cross-linked collagen-based surgical implant material. AB - Biomimetic scaffolds, delivered to the patient with or without cell loading, can offer improved treatments for a range of damaged or diseased tissues. In this work we evaluated the capacity of a cross-linked collagen-based implant material (PermacolTM) to support the survival and growth of multipotent stromal cells or mesenchymal stem cells (MSCs) for potential applications in soft-tissue reconstruction and compared it to uncross-linked collagen. We showed, using confocal imaging, histology, quantitative analysis of seeding efficiencies by the MTT assay and Live/Dead analysis, that PermacolTM supported the adherence, growth and survival of MSCs preserving a healthy cell phenotype. MSCs infiltrated both matrices, although migration rates were significantly higher on uncross-linked matrices for some donors. Our work demonstrates that PermacolTM could maintain human MSCs in long-term culture supporting its use as a cell-seeded biomaterial for durable and strong repair in tissue reconstruction. PMID- 23023144 TI - TiNOx coatings increase human primary osteoblasts proliferation independently of the substrate: a short report. AB - INTRODUCTION: When applied onto SLA titanium, Titanium Nitride Oxide (TiNOx) coatings are known for their stimulating effect on osteoblast proliferation while maintaining a high degree of differentiation. OBJECTIVE: To determine whether the stimulating effect of TiNOx coatings is or is not dependent of the metal substrate. METHODS: A TiNOx coating was deposited on roughened stainless steel (SS-SLA-TiNOx). The proliferation and differentiation of human primary osteoblasts were determined and compared to that observed on standard SLA titanium. To this end, cell proliferation and gene expression were monitored for a time course of 3 weeks, with or without additional stimulation by 100 nM 1.25(OH)2 vitamin D3. RESULTS: A 1.5 fold increase in the proliferation rate of cells grown on SS-SLA-TiNOx as compared to Ti-SLA surfaces was observed. A high level of differentiation was also noted. CONCLUSION: TiNOx coatings yield similar proliferation and differentiation rates when applied onto roughened Ti and SS. This might translate into a more effective osseointegration of endosseous implants made of stronger metals than Ti. PMID- 23023145 TI - Interaction between titanium and phosphoproteins revealed by chromatography column packed with titanium beads. AB - The biochemical mechanism behind the strong binding between titanium and living bone has not been fully elucidated, in spite of worldwide clinical application of this phenomenon. We hypothesized that one of the core mechanisms may reside in the interaction between certain proteins in the host tissues and the implanted titanium. To verify the interaction between titanium and proteins, we chose the technique of chromatography in that titanium spherical beads (45 MUm) were packed into a column to obtain a bed volume of 16*50 mm, which was eluted with phosphate buffered saline (PBS) and a straight gradient system made by using PBS and 25 mM NaOH. Fetal calf serum, albumin, lysozyme, casein, phosvitin and dentin phosphoprotein (phosphophoryn) were applied to the column. Most part of albumin and lysozyme eluted with the breakthrough peak, indicating practically no affinity to titanium. Fetal bovine serum also eluted mostly as the breakthrough peak, but distinct retained peak was observed. On the other hand, alpha-casein, phosvitin and phosphophoryn exhibited a distinct retained peak separated from the breakthrough peak. We proposed that phosphate groups (phosphoserines) in the major phosphoproteins, alpha-casein, phosvitin and phosphophoryn may be involved in the binding of these proteins with titanium. PMID- 23023146 TI - The effect of poly(lactic-co-glycolic acid) (PLGA) coating on the mechanical, biodegradable, bioactive properties and drug release of porous calcium silicate scaffolds. AB - Ideal scaffolds for bone tissue engineering require 3D interconnected porous structures, enough mechanical strength for hand of treatment as well as proper bioactivity and biodegradability. Calcium silicate (CaSiO3, CS) scaffolds have been studied for bone tissue engineering application due to their excellent bioactivity. However, the main disadvantages of CS scaffolds are their low mechanical strength and high alkaline ionic products. In this study, sintered CS scaffolds were prepared and coated with poly(lactic-co-glycolic acid) (PLGA), and the effect of PLGA coating on the mechanical, biodegradable, bioactive properties and drug release of porous CS scaffolds were investigated. The results showed that the PLGA-coated CS scaffolds maintained large pore size and high porosity. The compressive strength of PLGA/CS scaffolds was significantly improved compared to pure CS scaffolds, and increased with the increase of intrinsic viscosity and concentration of PLGA. In addition, the PLGA coating neutralized alkaline level resulted from the ionic products of CS scaffolds and reduced the pH value of biological solution during the degradation of scaffolds. It was found that PLGA/CS scaffolds still maintained excellent apatite-mineralization ability in SBF. Furthermore, the PLGA coating effectively inhibited the burst release and maintained a sustained release of drugs from the CS scaffolds. Our results indicate that the PLGA/CS scaffolds have great potential for bone tissue engineering application by the virtue of improved mechanical strength, and excellent bioactivity, degradation as well as drug-delivery property. PMID- 23023147 TI - Novel hydrocolloid-sheet as wound dressing to stimulate healing-impaired wound healing in diabetic db/db mice. AB - To create a moist environment for wound healing, a hydrocolloid-sheet composed of alginate, chitin/chitosan and fucoidan (ACF-HS) has been developed as a functional wound dressing. ACF-HS gradually adsorbed medium without any maceration and the medium adsorption in vitro reached constant after 18 h. ACF-HS could effectively interact with and protect a healing-impaired wound in diabetic db/db mice, providing a good moist healing environment with exudate. Furthermore, the wound dressing could have other properties like ease of application and removal, and proper adherence. The aim of this study was to evaluate an accelerating effect of ACF-HS on wound healing for healing-impaired wounds in diabetic db/db mice. Round full-thickness skin defects (12 mm in diameter) were made on the back of db/db mice to prepare healing-impaired wounds. After applying ACF-HS to the wounds, the mice were later killed and histological sections of the wound were prepared. Histological examinations showed significantly advanced granulation tissue and capillary formations in the wounds treated with ACF-HS on days 4, 9 and 14 compared with those in commercially available hydrocolloid wound dressing and non-treatment (control). Thus, ACF-HS may serve as a new wound dressing for diabetic healing-impaired wounds. PMID- 23023148 TI - Robust calibration models to predict antipyrine content in various kinds of packaged hospital powder preparations by using near-infrared spectroscopy. AB - The purpose of this study was to evaluate drug content of hospital powder preparations using non-destructive, non-contact, short-term measurements with near-infrared spectroscopy (NIR). Antipyrine (0-50%) was mixed with additive powder, and packed with semi-transparent (SP) or transparent (TP) paper to obtain single packaged samples (SPP and TPP). Double packaged samples were obtained by packing TPP with TP. NIR spectra of the packaged samples were recorded using a NIR spectrometer with a fiber-optic probe. The best calibration model was determined to minimize the standard error of cross-validation (SEP) by the leave out-one method in principal component regression (PCR). The calibration models for SPP and TPP were calculated to be the minimum SEP based on one- and four-PC models by the PCR method, respectively. Plots of predicted and actual drug contents for SPP and TPP showed a straight line with a slope of 0.946 and 0.948, and gamma of 0.965 and 0.980, respectively. On the other hand, the calibration model for the single and double TPP was obtained based on a three-PC model, and the plot of predicted and actual drug content showed a straight line with a slope of 0.942 and gamma of 0.977. PMID- 23023149 TI - Genipin-crosslinked chitosan scaffolds and its efficacy in releasing anti inflammatory medicine. AB - Controlled release carriers are often made into microspheres or tablets. Systematic and quantitative characterization of porous tissue engineered scaffolds as release carriers have not been done. Chitosan and chitosan crosslinked with various concentrations of genipin were made into porous tissue engineered scaffolds. Their thermal and enzymatic stabilities, hydrophobicities, porous structures, swelling and release properties, and compressional moduli were measured. The effects of scaffolds loaded with pentoxifylline (PTX) in suppressing inflammatory reactions in vitro were quantified.Fourier Transform Infrared spectra showed new bond formation after crosslinking chitosan with genipin. As genipin increased from 0.01% to 0.1%, the crosslinked chitosan scaffolds swelled 0.5% to 1.8% less, had 1.9-5% decrease in PTX release efficiencies, became less wettable, were less favorable for initial cell attachment, had 4-20% increase in Young's modulus and were more resistant to enzymatic degradation. In vitro tests showed that when PTX was released more slowly from crosslinked scaffolds, PTX became more effective in suppressing macrophage cells from releasing IL-6 and TNF-alpha. PMID- 23023150 TI - Urothelial carcinoma of the bladder and the upper tract: disparate twins. AB - PURPOSE: Urothelial carcinoma of the bladder is the 4th most common malignancy in men and the 8th most common cause of male cancer death in the United States. Conversely, upper tract urothelial carcinoma accounts for only 5% to 10% of all urothelial carcinoma. Due to the relative preponderance of urothelial carcinoma of the bladder, much of the clinical decision making regarding upper tract urothelial carcinoma is extrapolated from evidence that is based on urothelial carcinoma of the bladder cohorts. In fact, only 1 major urological organization has treatment guidelines specific for upper tract urothelial carcinoma. While significant similarities exist between these 2 diseases, ignoring the important differences may be preventing us from optimizing therapy in patients with upper tract urothelial carcinoma. Therefore, we explored these dissimilarities, including the differential importance of gender, anatomy, staging, intracavitary therapy, surgical lymphadenectomy and perioperative systemic chemotherapy on the behavior of urothelial carcinoma of the bladder and upper tract urothelial carcinoma. MATERIALS AND METHODS: A nonsystematic literature search using the MEDLINE/PubMed(r) database was conducted to identify original articles, review articles and editorials. Searches were limited to the English language and studies in humans and in adults, and used the key words urothelial carcinoma, upper tract urothelial carcinoma or transitional cell carcinoma combined with several different sets of key words to identify appropriate publications for each section of the manuscript. The key words, broken down by section, were 1) epidemiology, sex, gender; 2) location, tumor location; 3) staging, stage; 4) intracavitary, intravesical, topical therapy; 5) lymphadenectomy, lymph node, lymph node dissection and 6) adjuvant, neoadjuvant, chemotherapy. RESULTS: Women who present with urothelial carcinoma of the bladder do so with less favorable tumor characteristics and have worse survival than men. However, gender does not appear to be associated with survival outcomes in upper tract urothelial carcinoma. The prognostic effect that urothelial carcinoma tumor location has on outcomes prediction is a matter of debate, and the influence of tumor location may reflect our technical ability to accurately stage and treat the disease more than the actual tumor biology. Moreover, technical limitations of upper tract urothelial carcinoma sampling compared to transurethral resection for urothelial carcinoma of the bladder are the most important source of staging differences between the 2 diseases. Intravesical chemotherapy and immunotherapy are essential components of standard of care for most nonmuscle invasive bladder cancer, while adjuvant intracavitary therapy for patients with upper tract urothelial carcinoma treated endoscopically or percutaneously has been sparsely used and without any clear guidelines. The widespread adoption of the use of intracavitary therapy in the upper tract will likely not only require additional data to support its efficacy, but will also require a less cumbersome means of administration. Lymphadenectomy at the time of radical cystectomy is widely accepted while lymphadenectomy at the time of radical nephroureterectomy is performed largely at the discretion of the surgeon. Among other reasons, this may be due in part to the variable lymphatic drainage along the course of the ureter compared to the relatively confined lymphatic landing sites for the bladder. Level I evidence has demonstrated a clear survival benefit for systemic chemotherapy before radical surgery or radiation in patients with clinical T2-4N0M0 urothelial carcinoma of the bladder. Such data are not available in the population with upper tract urothelial carcinoma. However, the use of neoadjuvant chemotherapy may be even more important in upper tract urothelial carcinoma than in urothelial carcinoma of the bladder because of the obligatory kidney function loss that occurs at radical nephroureterectomy. CONCLUSIONS: While urothelial carcinoma of the bladder and upper tract urothelial carcinoma share many characteristics, they represent 2 distinct diseases. There are practical, anatomical, biological and molecular differences that warrant consideration when risk stratifying and treating patients with these disparate twin diseases. To overcome the challenges that impede progress toward evidence-based medicine in upper tract urothelial carcinoma, we believe that focused collaborative efforts will best augment our understanding of this rare disease and ultimately improve the care we deliver to our patients. PMID- 23023151 TI - Transperitoneal versus retroperitoneal laparoscopic ureterolithotomy: a prospective randomized comparison study. AB - PURPOSE: We compared laparoscopic transperitoneal and retroperitoneal ureterolithotomy approaches, and determined whether one technique is superior to the other. MATERIALS AND METHODS: In this prospective randomized study from January 2009 to May 2012, 48 patients with proximal or mid ureteral stones underwent transperitoneal laparoscopic ureterolithotomy or retroperitoneal laparoscopic ureterolithotomy. The randomization occurred on a 1:1 basis. Groups 1 and 2 consisted of patients who underwent transperitoneal laparoscopic ureterolithotomy and retroperitoneal laparoscopic ureterolithotomy, respectively. Demographic and clinical characteristics as well as postoperative data were collected and analyzed. Statistical analysis was performed with SPSS(r) version 15.0 using the Fisher exact and Mann-Whitney U tests with p <0.05 considered statistically significant. RESULTS: The difference in visual pain analog score and mean tramadol requirement on days 1 and 2 between the 2 groups was statistically significant, and was higher in group 1 (p <0.05). Postoperative hospital stay and paralytic ileus rates were significantly higher in group 1 (p <0.05). The differences in total operative time and intracorporeal suturing time between the 2 groups were not statistically significant. However, successful stone removal was equal in the 2 groups. CONCLUSIONS: For proximal or mid ureteral large and impacted stones, transperitoneal laparoscopic ureterolithotomy is significantly associated with pain, greater tramadol requirement, ileus and longer hospital stay than retroperitoneal laparoscopic ureterolithotomy. However, successful stone removal remains the same in both groups. PMID- 23023152 TI - Action of bimetallic nanocatalysts under reaction conditions and during catalysis: evolution of chemistry from high vacuum conditions to reaction conditions. AB - Bimetallic catalysts are one of the main categories of metal catalysts due to the tunability of electronic and geometric structures through alloying a second metal. The integration of a second metal creates a vast number of possibilities for varying the surface structure and composition of metal catalysts toward designing new catalysts. It is well acknowledged that the surface composition, atomic arrangement, and electronic state of bimetallic catalysts could be different from those before a chemical reaction or catalysis based on ex situ studies. Thanks to advances in electron-based surface analytical techniques, the surface chemistry and structure of bimetallic nanoparticles can be characterized under reaction conditions and during catalysis using ambient pressure analytical techniques including ambient pressure XPS, ambient pressure STM, X-ray absorption spectroscopy and others. These ambient pressure studies revealed various restructurings in the composition and arrangement of atoms in the surface region of catalysts under reaction conditions or during catalysis compared to that before reaction. These restructurings are driven by thermodynamic and kinetic factors. The surface energy of the constituent metals and adsorption energy of reactant molecules or dissociated species on a metal component are two main factors from the point of view of thermodynamics. Correlations between the authentic surface structure and chemistry of catalysts during catalysis and simultaneous catalytic performance were built for understanding catalytic mechanisms of bimetallic catalysts toward designing new catalysts with high activity, selectivity, and durability. PMID- 23023153 TI - Modeling intracerebral hemorrhage in mice: injection of autologous blood or bacterial collagenase. AB - Spontaneous intracerebral hemorrhage (ICH) defines a potentially life-threatening neurological malady that accounts for 10-15% of all stroke-related hospitalizations and for which no effective treatments are available to date(1,2). Because of the heterogeneity of ICH in humans, various preclinical models are needed to thoroughly explore prospective therapeutic strategies(3). Experimental ICH is commonly induced in rodents by intraparenchymal injection of either autologous blood or bacterial collagenase(4). The appropriate model is selected based on the pathophysiology of hemorrhage induction and injury progression. The blood injection model mimics a rapidly progressing hemorrhage. Alternatively, bacterial collagenase enzymatically disrupts the basal lamina of brain capillaries, causing an active bleed that generally evolves over several hours(5). Resultant perihematomal edema and neurofunctional deficits can be quantified from both models. In this study, we described and evaluated a modified double injection model of autologous whole blood(6) as well as an ICH injection model of bacterial collagenase(7), both of which target the basal ganglia (corpus striatum) of male CD-1 mice. We assessed neurofunctional deficits and brain edema at 24 and 72 hr after ICH induction. Intrastriatal injection of autologous blood (30 MUl) or bacterial collagenase (0.075U) caused reproducible neurofunctional deficits in mice and significantly increased brain edema at 24 and 72 hr after surgery (p<0.05). In conclusion, both models yield consistent hemorrhagic infarcts and represent basic methods for preclinical ICH research. PMID- 23023154 TI - Mechanisms of enhancing visual-speech recognition by prior auditory information. AB - Speech recognition from visual-only faces is difficult, but can be improved by prior information about what is said. Here, we investigated how the human brain uses prior information from auditory speech to improve visual-speech recognition. In a functional magnetic resonance imaging study, participants performed a visual speech recognition task, indicating whether the word spoken in visual-only videos matched the preceding auditory-only speech, and a control task (face-identity recognition) containing exactly the same stimuli. We localized a visual-speech processing network by contrasting activity during visual-speech recognition with the control task. Within this network, the left posterior superior temporal sulcus (STS) showed increased activity and interacted with auditory-speech areas if prior information from auditory speech did not match the visual speech. This mismatch-related activity and the functional connectivity to auditory-speech areas were specific for speech, i.e., they were not present in the control task. The mismatch-related activity correlated positively with performance, indicating that posterior STS was behaviorally relevant for visual-speech recognition. In line with predictive coding frameworks, these findings suggest that prediction error signals are produced if visually presented speech does not match the prediction from preceding auditory speech, and that this mechanism plays a role in optimizing visual-speech recognition by prior information. PMID- 23023155 TI - GPR40: a therapeutic target for mediating insulin secretion (review). AB - G-protein-coupled receptor 40 (GPR40), known as free fatty acid receptor 1, is mainly expressed in pancreatic beta-cells and activated by medium- and long-chain fatty acids. Increasing evidence indicates that the activation of GPR40 in cells causes insulin secretion, and GPR40 has become an attractive therapeutic target for type 2 diabetes. Recently, certain novel GPR40 agonists have been identified that regulate glucose-stimulated insulin secretion, leading to the development of new drugs for the treatment of type 2 diabetes. In this review, we focus on progress in the physiological role of GPR40 and potential drugs targeting GPR40 over the past decade. PMID- 23023157 TI - Aviophobia assessment: validating the Flight Anxiety Situations Questionnaire as a clinical identification measure. AB - An Internet survey was conducted to validate the Flight Anxiety Situations Questionnaire (FAS; Van Gerwen, Spinhoven, Van Dyck, & Diekstra, 1999) as a clinical identification measure for aviophobia. Nine hundred and seventy six people completed the survey. Using further criteria, the total pool was reduced to 98 aviophobics and 474 non-phobics. Receiver operating characteristic analysis and chi-square tests of associations indicated that minimal scores of 56 (as previously reported in research) and 70 on the FAS were useful predictors of being a flying phobic. However, the empirically derived cut-off score of 70 on the FAS had the best overall balance of Type I and Type II error, such that the diagnostic standard for flying phobia was set neither too low nor too high. Given that 60.3% of participants were university students, results may not be generalizable to the general population but may be particularly useful for researchers at these settings. PMID- 23023156 TI - Mineralocorticoid receptor blocker eplerenone reduces pain behaviors in vivo and decreases excitability in small-diameter sensory neurons from local inflamed dorsal root ganglia in vitro. AB - BACKGROUND: Inflammation of the dorsal root ganglia (DRG) may contribute to low back pain, postherpetic neuralgia, and neuropathic pain. The mineralocorticoid receptor (MR) plays a proinflammatory role in many nonrenal tissues, but its role in peripheral pain at the DRG level is not well studied. METHODS: Local inflammation of the L5 DRG with the immune activator zymosan rapidly leads to mechanical hypersensitivity and increased excitability of sensory neurons. Using this pain model, the authors applied the MR antagonist eplerenone locally to the inflamed DRG. Excitability of small-diameter sensory neurons was examined in acute primary culture by using patch clamp techniques. RESULTS: Local eplerenone significantly reduced the mechanical hypersensitivity and shortened its duration. The same dose was ineffective systemically. Immunohistochemical studies showed the MR was present in most neurons and rapidly translocated to the nucleus 1 day after local DRG inflammation. Activation of satellite glia (defined by expression of glial fibrillary acidic protein) in the inflamed DRG was also reduced by local eplerenone. Increased excitability of small-diameter sensory neurons 1 day after inflammation could be observed in vitro. Eplerenone applied in vitro (8-12 h) could reverse this increased excitability. Eplerenone had no effect in neurons isolated from normal, uninflamed DRG. The MR agonist aldosterone (10 nM) applied in vitro increased excitability of neurons isolated from normal DRG. CONCLUSIONS: The MR may have a pronociceptive role in the DRG. Some of its effects may be mediated by neuronal MR. The MR may represent a novel therapeutic target in some pain syndromes. PMID- 23023158 TI - Examination of a cutoff score for the Screen for Child Anxiety Related Emotional Disorders (SCARED) in a non-clinical Spanish population. AB - We aimed to find a valid cutoff score for the Screen for Child Anxiety Related Emotional Disorders, child (SCARED-C) and parent (SCARED-P) Spanish versions for detecting Anxiety Disorders (AD) in a non-clinical population. The predictive accuracy of the SCARED-C and SCARED-P was assessed using the Area Under the Curve (AUC) of ROC curves. In general, the predictive accuracy of the SCARED-C (full version, short version, and four factors) was good and better than that of the SCARED-P. To differentiate between children who meet the diagnostic criteria for any AD and children who do not, we propose cutoff scores of 25 and 17 for the SCARED-C and SCARED-P, respectively. The sensitivities are 75.9% and 62.8%, and the specificities are 68.5% and 69.5%. The SCARED-C factor that had the best predictive accuracy was Somatic panic followed by Separation Anxiety, Generalized Anxiety and Social Phobia. The SCARED-P factor with the best predictive accuracy was Separation Anxiety. The results support the use of SCARED-C as a screening test for Anxiety disorders while SCARED-P should only be used as complementary information. PMID- 23023159 TI - The restrictive concept of good health in patients with hypochondriasis. AB - The restrictive concept of good health and the misinterpretation of bodily symptoms as a sign of illness are considered in the DSM and in well-established cognitive models as central characteristics of hypochondriasis. However, until now it has not been satisfactorily resolved whether this tendency is unique for hypochondriasis. In the current study a modified card sorting technique was used to investigate the extent to which bodily complaints were seen as compatible with a state of good health. We found that patients with hypochondriasis (n = 45) showed a more restrictive concept of good health than anxiety patients (n = 45) and healthy controls (n = 45). Those differences were only observable when a concrete evaluation of own bodily symptoms was carried out in comparison to a more general evaluation of symptoms. The misinterpretation of bodily symptoms demonstrates to be a highly specific characteristic of hypochondriasis. PMID- 23023160 TI - Cannabis use and mental health-related quality of life among individuals with anxiety disorders. AB - Cannabis is the most widely used illicit substance in individuals with anxiety disorders. The aim of this study was to assess mental health-related quality of life (QoL) among individuals with anxiety disorders with and without concurrent cannabis use based on a large representative US sample. Mental health-related QoL of regular cannabis users (N = 144), occasional cannabis users (N = 181) and non users (N = 4427) was assessed using the Short-Form 12-Item Health Survey (SF-12). Among individuals with anxiety disorders, mean SF-12 mental summary scores were significantly lower (indicating a lower QoL) among regular, but not occasional, cannabis users (by 0.8 standard deviations (SDs) and 0.6SD for females and males, respectively) compared to non-users. Adjusting for sociodemographic variables and co-morbid mood disorders, regular, but not occasional, cannabis use was associated with lower mental health summary and subscales scores. Out results highlight the importance of taking into account direct functional and emotional outcomes, as well as frequency of cannabis used, when assessing the impact of cannabis use among individuals with anxiety disorders. PMID- 23023161 TI - Interpretive style and intolerance of uncertainty in individuals with anxiety disorders: a focus on generalized anxiety disorder. AB - Interpretations of negative, positive, and ambiguous situations were examined in individuals with generalized anxiety disorder (GAD), other anxiety disorders (ANX), and no psychiatric condition (CTRL). Additionally, relationships between specific beliefs about uncertainty (Uncertainty Has Negative Behavioral and Self Referent Implications [IUS-NI], and Uncertainty Is Unfair and Spoils Everything [IUS-US]) and interpretations were explored. The first hypothesis (that the clinical groups would report more concern for negative, positive, and ambiguous situations than would the CTRL group) was supported. The second hypothesis (that the GAD group would report more concern for ambiguous situations than would the ANX group) was not supported; both groups reported similar levels of concern for ambiguous situations. Exploratory analyses revealed no differences between the GAD and ANX groups in their interpretations of positive and negative situations. Finally, the IUS-US predicted interpretations of negative and ambiguous situations in the full sample, whereas the IUS-NI did not. Clinical implications are discussed. PMID- 23023163 TI - The online version of the Dutch Penn State Worry Questionnaire: factor structure, predictive validity and reliability. AB - The Penn State Worry Questionnaire (PSWQ) is a widely used self report scale to assess pathological worry. Several studies have shown that the paper-and-pencil version of the PSWQ shows satisfactory psychometric properties. Yet, it is unknown whether the PSWQ is suited to be administered on Internet. As the amount of assessments conducted online is vastly increasing, we examined the factor structure, predictive validity and reliability of the online version of the PSWQ in a large community sample (N = 1025). Confirmatory factor analyses demonstrated that the best fit to the data was provided by a one factor model wherein the reverse-worded items also loaded on a separate method factor. In a second part of the study a self-selected subsample of the total sample (n = 189) kept a log of the frequency and duration of worry episodes for six consecutive days. Worry frequency and worry duration were both predicted by the PSWQ, thereby lending support to its predictive validity. These findings provide preliminary evidence that the online version of the PSWQ possesses psychometric properties that are similar to the paper-and-pencil version. PMID- 23023162 TI - Pharmacological treatment of anxiety disorders: current treatments and future directions. AB - Modern pharmacological treatments for anxiety disorders are safer and more tolerable than they were 30 years ago. Unfortunately, treatment efficacy and duration have not improved in most cases despite a greater understanding of the pathophysiology of anxiety. Moreover, innovative treatments have not reached the market despite billions of research dollars invested in drug development. In reviewing the literature on current treatments, we argue that evidence-based practice would benefit from better research on the causes of incomplete treatment response as well as the comparative efficacy of drug combinations and sequencing. We also survey two broad approaches to the development of innovative anxiety treatments:the continued development of drugs based on specific neuroreceptors and the pharmacological manipulation of fear-related memory. We highlight directions for future research, as neither of these approaches is ready for routine clinical use. PMID- 23023164 TI - Does disgust increase parasympathetic activation in individuals with a history of fainting? A psychophysiological analysis of disgust stimuli with and without blood-injection-injury association. AB - People with blood-injection-injury fear can faint when being confronted with blood, injections or injuries. Page (1994) holds that people with blood-injury phobia faint, because they are disgust sensitive and disgust facilitates fainting by eliciting parasympathetic activity. We tested the following two hypotheses: (1) Disgusting pictures elicit more disgust in blood-injection-injury-anxious people with a history of fainting than they do in controls. (2) Disgust causes parasympathetic activation. Subjects were 24 participants with high blood injection-injury fear and a history of fainting in anxiety relevant situations and 24 subjects with average blood-injection-injury fear and no fainting history. We analyzed self-reported feelings of disgust, anxiety and faintness and reactions in heart rate, skin conductance, blood pressure and respiratory sinus arrhythmia during the confrontation with disgusting pictures with and without blood content. We did not find any evidence that the blood-injection-injury anxious subjects were more disgust sensitive than the control subjects and we also did not find any evidence that disgust elicits parasympathetic activation. PMID- 23023165 TI - Stereotactic ablative body radiotherapy (SABR) for primary and secondary lung tumours. AB - Stereotactic ablative body radiotherapy (SABR) represents a technological breakthrough in radiotherapy technique, with proven benefits to patients in terms of improved tumour control and overall survival. The key components of SABR are described. The current evidence base for SABR for the treatment of primary and secondary lung tumours is appraised, and key ongoing trials are identified. PMID- 23023166 TI - The vagal innervation of the gut and immune homeostasis. AB - The central nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. Recently, in animal models of sepsis, the vagus nerve (VN) has been proposed to play a crucial role in the regulation of the immune response, also referred to as the cholinergic anti-inflammatory pathway. The VN, through release of acetylcholine, dampens immune cell activation by interacting with alpha-7 nicotinic acetylcholine receptors. Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect. In this review, we will discuss the current understanding concerning the mechanisms and effects involved in the cholinergic anti-inflammatory pathway in the gastrointestinal tract. Deeper investigation on this counter-regulatory neuroimmune mechanism will provide new insights in the cross-talk between the nervous and immune system leading to the identification of new therapeutic targets to treat intestinal immune disease. PMID- 23023167 TI - Estrogen-related receptor gamma controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol. AB - BACKGROUND: The hepatic endocannabinoid system and cytochrome P450 2E1 (CYP2E1), a key enzyme causing alcohol-induced reactive oxygen species (ROS) generation, are major contributors to the pathogenesis of alcoholic liver disease. The nuclear hormone receptor oestrogen-related receptor gamma (ERRgamma) is a constitutively active transcriptional activator regulating gene expression. OBJECTIVE: To investigate the role of ERRgamma in the alcohol-mediated regulation of CYP2E1 and to examine the possibility to control alcohol-mediated oxidative stress and liver injury through an ERRgamma inverse agonist. DESIGN: For chronic alcoholic hepatosteatosis study, C57BL/6J wild-type and CB1(-/-) mice were administered alcohol for 4 weeks. GSK5182 and chlormethiazole (CMZ) were given by oral gavage for the last 2 weeks of alcohol feeding. Gene expression profiles and biochemical assays were performed using the liver or blood of mice. RESULTS: Hepatic ERRgamma gene expression induced by alcohol-mediated activation of CB1 receptor results in induction of CYP2E1, while liver-specific ablation of ERRgamma gene expression blocks alcohol-induced expression of CYP2E1 in mouse liver. An ERRgamma inverse agonist significantly ameliorates chronic alcohol induced liver injury in mice through inhibition of CYP2E1-mediated generation of ROS, while inhibition of CYP2E1 by CMZ abrogates the beneficial effects of the inverse agonist. Finally, chronic alcohol-mediated ERRgamma and CYP2E1 gene expression, ROS generation and liver injury in normal mice were nearly abolished in CB1(-/-) mice. CONCLUSIONS: ERRgamma, as a previously unrecognised transcriptional regulator of hepatic CB1 receptor, controls alcohol-induced oxidative stress and liver injury through CYP2E1 induction, and its inverse agonist could ameliorate oxidative liver injury due to chronic alcohol exposure. PMID- 23023168 TI - Two direct targets of cytokinin signaling regulate symbiotic nodulation in Medicago truncatula. AB - Cytokinin regulates many aspects of plant development, and in legume crops, this phytohormone is necessary and sufficient for symbiotic nodule organogenesis, allowing them to fix atmospheric nitrogen. To identify direct links between cytokinins and nodule organogenesis, we determined a consensus sequence bound in vitro by a transcription factor (TF) acting in cytokinin signaling, the nodule enhanced Medicago truncatula Mt RR1 response regulator (RR). Among genes rapidly regulated by cytokinins and containing this so-called RR binding site (RRBS) in their promoters, we found the nodulation-related Type-A RR Mt RR4 and the Nodulation Signaling Pathway 2 (NSP2) TF. Site-directed mutagenesis revealed that RRBS cis-elements in the RR4 and NSP2 promoters are essential for expression during nodule development and for cytokinin induction. Furthermore, a microRNA targeting NSP2 (miR171 h) is also rapidly induced by cytokinins and then shows an expression pattern anticorrelated with NSP2. Other primary targets regulated by cytokinins depending on the Cytokinin Response1 (CRE1) receptor were a cytokinin oxidase/dehydrogenase (CKX1) and a basic Helix-Loop-Helix TF (bHLH476). RNA interference constructs as well as insertion of a Tnt1 retrotransposon in the bHLH gene led to reduced nodulation. Hence, we identified two TFs, NSP2 and bHLH476, as direct cytokinin targets acting at the convergence of phytohormonal and symbiotic cues. PMID- 23023169 TI - Functional analysis of three Arabidopsis ARGONAUTES using slicer-defective mutants. AB - In RNA-directed silencing pathways, ternary complexes result from small RNA guided ARGONAUTE (AGO) associating with target transcripts. Target transcripts are often silenced through direct cleavage (slicing), destabilization through slicer-independent turnover mechanisms, and translational repression. Here, wild type and active-site defective forms of several Arabidopsis thaliana AGO proteins involved in posttranscriptional silencing were used to examine several AGO functions, including small RNA binding, interaction with target RNA, slicing or destabilization of target RNA, secondary small interfering RNA formation, and antiviral activity. Complementation analyses in ago mutant plants revealed that the catalytic residues of AGO1, AGO2, and AGO7 are required to restore the defects of Arabidopsis ago1-25, ago2-1, and zip-1 (AGO7-defective) mutants, respectively. AGO2 had slicer activity in transient assays but could not trigger secondary small interfering RNA biogenesis, and catalytically active AGO2 was necessary for local and systemic antiviral activity against Turnip mosaic virus. Slicer-defective AGOs associated with miRNAs and stabilized AGO-miRNA-target RNA ternary complexes in individual target coimmunoprecipitation assays. In genome wide AGO-miRNA-target RNA coimmunoprecipitation experiments, slicer-defective AGO1-miRNA associated with target RNA more effectively than did wild-type AGO1 miRNA. These data not only reveal functional roles for AGO1, AGO2, and AGO7 slicer activity, but also indicate an approach to capture ternary complexes more efficiently for genome-wide analyses. PMID- 23023170 TI - Plastid localization of the key carotenoid enzyme phytoene synthase is altered by isozyme, allelic variation, and activity. AB - Plant carotenoids have unique physiological roles related to specific plastid suborganellar locations. Carotenoid metabolic engineering could enhance plant adaptation to climate change and improve food security and nutritional value. However, lack of fundamental knowledge on carotenoid pathway localization limits targeted engineering. Phytoene synthase (PSY), a major rate-controlling carotenoid enzyme, is represented by multiple isozymes residing at unknown plastid sites. In maize (Zea mays), the three isozymes were transiently expressed and found either in plastoglobuli or in stroma and thylakoid membranes. PSY1, with one to two residue modifications of naturally occurring functional variants, exhibited altered localization, associated with distorted plastid shape and formation of a fibril phenotype. Mutating the active site of the enzyme reversed this phenotype. Discovery of differential PSY locations, linked with activity and isozyme type, advances the engineering potential for modifying carotenoid biosynthesis. PMID- 23023171 TI - Verticillium infection triggers VASCULAR-RELATED NAC DOMAIN7-dependent de novo xylem formation and enhances drought tolerance in Arabidopsis. AB - The soilborne fungal plant pathogen Verticillium longisporum invades the roots of its Brassicaceae hosts and proliferates in the plant vascular system. Typical aboveground symptoms of Verticillium infection on Brassica napus and Arabidopsis thaliana are stunted growth, vein clearing, and leaf chloroses. Here, we provide evidence that vein clearing is caused by pathogen-induced transdifferentiation of chloroplast-containing bundle sheath cells to functional xylem elements. In addition, our findings suggest that reinitiation of cambial activity and transdifferentiation of xylem parenchyma cells results in xylem hyperplasia within the vasculature of Arabidopsis leaves, hypocotyls, and roots. The observed de novo xylem formation correlates with Verticillium-induced expression of the VASCULAR-RELATED NAC DOMAIN (VND) transcription factor gene VND7. Transgenic Arabidopsis plants expressing the chimeric repressor VND7-SRDX under control of a Verticillium infection-responsive promoter exhibit reduced de novo xylem formation. Interestingly, infected Arabidopsis wild-type plants show higher drought stress tolerance compared with noninfected plants, whereas this effect is attenuated by suppression of VND7 activity. Together, our results suggest that V. longisporum triggers a tissue-specific developmental plant program that compensates for compromised water transport and enhances the water storage capacity of infected Brassicaceae host plants. In conclusion, we provide evidence that this natural plant-fungus pathosystem has conditionally mutualistic features. PMID- 23023173 TI - [Latin American medical journals indexed]. PMID- 23023174 TI - [Colorectal polyps: update on diagnosis]. AB - Histological diagnosis determines the clinical behavior of colorectal polyps. Recently new types of polyps have been described and the classification has become wider and more complex. Our aim is update the current concepts in the knowledge of colorectal polyps. PMID- 23023175 TI - [Celiac disease: descriptive study at the Anglo American clinic]. AB - BACKGROUND: Celiac disease (CD) is a condition in which gluten intake develops an autoimmune response generating intestinal villous atrophy, causing malabsorption. Prevalence worldwide is approximately 1%, in our country it is not known. MATERIAL AND METHODS: Retrospective, descriptive, observational study in Anglo American Clinic between September 2004 and February 2012. We reviewed the medical charts, upper GI endoscopy reports and duodenal biopsy reports of all patients with positive anti TTG results, who were older than 18 years of age. RESULTS: We studied 39 cases, 26 (66.7%) women and 13 (33.3%) men. Mean age was 61.25 years. The symptoms were chronic diarrhea in 32 (82.1%), abdominal pain in 22 (56.4%), abdominal distention in 14 (35.9%), and others in lower frequency. Eight (20.5%) patients had anemia. Just 5 (12.8%) had upper endoscopy findings consistent with CD, and Marsh classification was: 0: 5 (12.7%), I: 1 (2.6%), II: 0 (0%), IIII A: 20 (51.3%), III B: 12 (30.8%) y III C: 1 (2.6%). CONCLUSIONS: CD should be considered as a differential diagnosis of patients with non-specific long-term gastrointestinal symptoms, extraintestinal symptoms should also be taken into account. Diagnosis should be made with anti TTG as the initial test and posteriorly with a duodenal biopsy for staging. PMID- 23023176 TI - [Double balloon enteroscopy in the management of small bowel disease: early experience in the Hospital Nacional Guillermo Almenara Irigoyen. Lima - Peru]. AB - OBJECTIVE: Evaluate the diagnostic and therapeutic utility, safeness, efficacy and complications of double balloon enteroscopy (DBE). METHODS: This prospective, descriptive study of DBE took place between July 2010 and November 2011 at Gastroenterology Service of Hospital Nacional Guillermo Almenara Irigoyen EsSalud. 33 DBE were performed in 30 patients with a double balloon enteroscope: EN-450T5 Fujinon, under conscious sedation and with previous bowel preparation. All of them signed an informed consent. RESULTS: The mean hemoglobin was 9.16 gr. /dl. 16 patients (53%) had capsule endoscopy previous to the exam. The most frequent indication for DBE was gastrointestinal bleeding of obscure origin. The per-oral route was used in 66.7% of the cases reaching a maximum distance of 206 cm. The mean examination time was 137 minutes. The most frequent finding was vascular ectasia. The diagnostic yield was 57.6% (similar to other published series). The therapeutic usefulness is equal to 45.4%. The therapeutic procedure most used was argon beam plasma (ABP). As published by other authors the exam was well tolerated by all patients with no complications after the procedure. CONCLUSIONS: DBE is a secure, useful and efficient technique for the exploration and treatment of small bowel disease, mainly in the cases of gastrointestinal bleeding of unknown origin. PMID- 23023172 TI - Arabidopsis defense against Botrytis cinerea: chronology and regulation deciphered by high-resolution temporal transcriptomic analysis. AB - Transcriptional reprogramming forms a major part of a plant's response to pathogen infection. Many individual components and pathways operating during plant defense have been identified, but our knowledge of how these different components interact is still rudimentary. We generated a high-resolution time series of gene expression profiles from a single Arabidopsis thaliana leaf during infection by the necrotrophic fungal pathogen Botrytis cinerea. Approximately one third of the Arabidopsis genome is differentially expressed during the first 48 h after infection, with the majority of changes in gene expression occurring before significant lesion development. We used computational tools to obtain a detailed chronology of the defense response against B. cinerea, highlighting the times at which signaling and metabolic processes change, and identify transcription factor families operating at different times after infection. Motif enrichment and network inference predicted regulatory interactions, and testing of one such prediction identified a role for TGA3 in defense against necrotrophic pathogens. These data provide an unprecedented level of detail about transcriptional changes during a defense response and are suited to systems biology analyses to generate predictive models of the gene regulatory networks mediating the Arabidopsis response to B. cinerea. PMID- 23023177 TI - [New technique for safe removal of impacted foreign bodies in the upper gastrointestinal tract using reusable variceal "cap" (cup, cap or cylinder)]. AB - OBJECTIVES: The ingestion of a foreign body is one of the most common endoscopic emergencies. Foreign bodies in the upper gastrointestinal tract should be extracted as soon as possible to avoid serious complications such as perforation o bleeding. However, removals of foreign bodies with sharp edges are very difficult and can develop complications during their removal. Various devices have therefore been developed to prevent mucosal injury from the sharp edges during endoscopic extraction. MATERIALS AND METHODS: We report a new technique for the successful foreign body extraction of upper digestive tract using the cap from six shooter variceal banding reused. RESULTS: We present 17 cases (9 males and 8 females). The types of foreign bodies removed were: chicken bones (n:7), fish bones (n:3), denture prosthesis (n:2), food bolus (n:2), long pin (n:1), golden thumb tack (n: 1) and press-through package (n:1). There were no complications. CONCLUSIONS: This new technique is safe and effective. Highlights its advantages: enhanced sight pharyngo esophageal junction, foreign bodies disimpact at that level, food bolus suck, avoid sharp object damage mucosal or scope and decrease time removal. PMID- 23023178 TI - [Cameron lesions: clinical experience]. AB - Cameron lesions are becoming an increasingly important diagnosis in the evaluation of patients with iron deficiency anemia. We describe the demographic data, clinico-pathologic features and therapeutic outcome of a group of patients with Cameron lesions at a single private practice clinic in Lima, Peru. Twelve patients (9 men) were included in the report Median age at diagnosis was 71 years (range 49-91). Five patients had anemia and one of them had severe anemia. 91.7% of our patients presented with large hiatal| hernias. There were 5 patients with anemia and large hernias. Two patients tested positive for H. pylori. Two patients reported chronic NSAIDs use. CONCLUSIONS: Cameron lesions are not an uncommon cause of chronic gastrointestinal bleeding and should be kept in mind in the study of patients with iron deficiency anemia. PMID- 23023179 TI - [Trends in incidence and risk factors associated with the development of pancreatic cancer. Regional Institute of Neoplastic Diseases "Dr. Luis Pinillos Ganoza "- Iren North. 2008 - 2011]. AB - OBJECTIVE: To determine trends in the prevalence and identify the main risk factors associated with the development of pancreatic cancer. MATERIALS AND METHODS: Study of trends in incidence and case-control population consisted of a total of 134 patients. Patients were grouped into: a) CASES: 67 patients diagnosed with pancreatic cancer treated at the Abdomen's Service of the Specialized Surgery Department of the Regional Institute of Neoplastic Diseases "Dr. Luis Pinillos Ganoza "- IREN North during the period 2008 to 2011; and b) CONTROLS: 67 patients diagnosed with gallstones and / or benign biliary disease treated at Belen Hospital in Trujillo during the period 2008 to 2011. RESULTS: The trend curve of incidence of pancreatic cancer showed a curve almost constant throughout the quadrennium 2008 to 2011, with incidence rates of 5.38%, 5.08%, 5.5% and 5.0% respectively. The overall incidence was 5.37%. The trend function was Y = (1756) +/- (0.001) (x), with an R2 = 0.318 (p = 0.436). The main risk factors associated with pancreatic cancer were age bigger and equal to 60 years (p = 0.0001), male sex (p = 0.007), diabetes mellitus (p = 0.002) and family history of malignancy (p = 0.016). CONCLUSIONS: The trend in incidence in pancreatic cancer was low and constant in its appearance was significantly influenced by age, gender, and presence of diabetes mellitus and family history of cancer. PMID- 23023180 TI - [Management of pancreatic cystic tumors in the Alberto Sabogal Sologuren hospital]. AB - INTRODUCTION: Cystic tumors of the pancreas comprise 1% of all neoplasms of the pancreas and 10 to 15% of pancreatic cysts. There are a variety of cystic lesions, of which 90% is made up of serous cystadenomas, mucinous cystic neoplasms, intraductal mucinous neoplasms and solid pseudopapillary neoplasms. MATERIALS AND METHODS: This study describes and analyzes retrospectively the clinical, radiological, surgical, pathological and follow up of 12 patients operated on for cystic tumors of the pancreas in the hospital IV Alberto Sabogal Sologuren, in the period 2005 to 2010. RESULTS: we found 5 (41%) serous cystadenomas with a mean age of 66 years, localized 80% in the head and 20% body; 2 (17%) mucinous cystic neoplasms with a mean age of 54, all located in body, 2 (17%) intraductal mucinous neoplasms with a mean age of 63, all located in the head, and 3 (25%) solid pseudopapillary neoplasms with a mean age of 33 years, located in body 33% and 66% in tail with a predominance of females in a ratio of 3:1. Had abdominal pain (75%), weight loss (17%) and palpable mass (17%). Of the 2 cystic mucinous neoplasms, only one have a low-grade dysplasia, of the two mucinous intraductal neoplasms, one have grade moderate dysplasia and the other with a high degree, the rest of cystic neoplasms were benign. We realize 6 Pancreaticoduodenectomy, 4 corporocaudales pancreatectomies, 2 distal pancreatectomies; of them splenectomy realize in 4 patients (2 in corporocaudal pancreatectomies and 2 distal pancreatectomies). In all cases the preoperative diagnosis was based on abdominal TEM. in 4 patients was expanded with RMN for suspicion of mucinous tumor and in 2 patients was performed CPRE for suspected intraductal tumors. Two patients coursed with atelectasis, and one patient had pancreatic fistula grade A and other mild pancreatitis post-operative. No patient was reoperated. There was no mortality post operative. Postoperative was more for the pancreaticoduodenectomy group. In a 2 year follow up, no observed recurrence and all patients are alive. CONCLUSION: Preoperative diagnosis is crucial given the differences in natural history of the spectrum of lesions. Despite improved radiographic imaging, techniques, definitive diagnosis is only made after studying the resection sample. PMID- 23023181 TI - [Perception of pain during sigmoidoscopy flexible as an additional diagnostic method for irritable bowel syndrome]. AB - INTRODUCTION: Visceral hypersensitivity has been proposed as a biological marker of Irritable bowel syndrome (IBS). OBJECTIVE: To evaluate the pain perception during sigmoidoscopy using a visual analog scale of pain in patients with or without IBS, and to assess the pain perception as diagnostic criteria for IBS. We further assessed the sensitivity, specificity and diagnostic efficiency of pain scores to diagnose IBS. METHODS: A prospective case-control study in patients who underwent sigmoidoscopy for the evaluation of gastrointestinal symptoms. All patients completed Rome III criteria questionnaires and divided into two groups: IBS and non-IBS. All participants reported pain scores on visual analog scales after of study. Differences were evaluated. We calculated a receiver-operator characteristic curve (ROC), sensitivity, specificity and diagnostic efficiency. RESULTS: We analyzed 20 patients with IBS and 20 controls. The pain scores were higher in IBS patients compared with non-IBS patients (median, 52.5 vs. 27.5, p = 0.006). The area under the curve was 0.84, at pain score level of >= 40 mm with a sensitivity, specificity and diagnostic efficiency of 85%, 75% and 80%, respectively. CONCLUSIONS: The degree of pain perception was higher in IBS patients than in non-IBS patients during sigmoidoscopy. A score of pain perception in >= 40 mm may predict the diagnosis of IBS with good sensitivity (85%) and specificity (75%). PMID- 23023182 TI - [A novel endoscopic treatment of pancreas divisum]. AB - Pancreas divisum is the most common congenital malformation of the pancreas that results from the non-fusion or incomplete fusion of the ventral and dorsal portions of the embryonic pancreas. It is found in 7% of autopsy studies (range 1 14%) and is generally asymptomatic. 5% of the patients have symptoms, which are basically cases of abdominal pain and recurrent pancreatitis. We report the case of a woman of 51 y, postcholecystectomy with 2 episodes of pancreatitis with imaging from magnetic resonance of pancreatic divisum with communication between the dorsal and ventral pancreas. We proceeded by endoscopy (ERCP) to dilate the major duct, and then made a minor duct papillotomy and made a hydropneumatic ball dilatation with the catheter balloon up the waist portion. The procedure was successful with 9 months of follow up. PMID- 23023183 TI - [Severe decompensation of hepatitis e in a patient with autoimmune hepatitis: a case report]. AB - We report the case of a patient who initially made the diagnosis of acute hepatitis E virus with a clinical picture of jaundice with elevated liver enzymes and HEV IgM (+), but chronic evolution (More than 6 months) without being an immunosuppressed patient, forced us to exclude different causes that may produce chronic liver disease. And hypergammaglobulinemia was detected in liver biopsy: interface hepatitis, mixed inflammatory infiltrate with predominance of lymphocytes, and presence of portal-portal fibrous tracts, suggestive of severe active chronic hepatitis may be secondary to autoimmune hepatitis associated with hepatitis virus infection E. With these findings, we decided to start treatment for autoimmune hepatitis with prednisone and azathioprine, leading to a decrease in transaminases and coagulation profile to normal, which helped confirm the diagnosis of autoimmune hepatitis and decompensated manifested by acute virus infection of hepatitis E. Full report the case and a review of the literature. PMID- 23023184 TI - [Deep vein thrombosis as an extraintestinal manifestation of ulcerative colitis. Presentation of a case]. AB - Extra-intestinal manifestations of Inflammatory Bowel Disease occur in 25% of cases. Vascular manifestations are rare and occur in 1 to 8% of cases. The most relevant are Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE). They both represent an important cause of morbidity and mortality and increase the risk of DVT recurrence. These are the reasons why prevention and early recognition of these entities are important. There is no agreement yet about the prophylaxis of DVT, neither primary nor secondary, to prevent recurrences in this group of patients. We report the case of a 52 year-old male patient who was admitted due to DVT in the left leg and who was simultaneously diagnosed with Ulcerative Colitis (Truelove activity index:16 points) during this same hospitalization. Doppler ultrasonography of the leg showed a thrombus in the left popliteal vein. Colonoscopy showed nodules, erosions, edema and erythema in the whole colonic mucosa in a continuous fashion. The patient was treated with Sulfazalasine 2gr per day, resulting in total remission of the intestinal complaints, and with Enoxaparin 1.5 IU/Kg per day followed by warfarin 5 mg per day, resulting in disappearance of the popliteal thrombus at 4 weeks. Oral anticoagulant treatment continued for 6 months and no DVT recurrences were seen during follow-up appointments. PMID- 23023185 TI - [Plummer-Vinson syndrome: report of a case and review of literature]. AB - A 39-year-old woman was admitted to our hospital with an eight-month history of dyspnea on exertion, weakness and increasing fatigue. She reported repeated episodes of menometrorrhagia and underwent a myomectomy. She is not a vegetarian. Her menstrual bleeding: 3-5 days per month. Two months ago, she complained of burning sensation of the tongue upon swallowing food and noted brittle nails. She tolerated soft foods. On physical examination, she was pale; her nails were very thin, fragile and somewhat concave. Her oral examination showed angular stomatitis, depapillated tongue and glossitis. The clinical diagnosis was anemia and dysphagia. Laboratory tests were: Hb: 7.0g/dL, MCV: 57.42fL, MCH: 15.82 pg; leukocytes: 4,980; reticulocytes: 2.18%, reticulocyte index: 0.1%, serum iron: 21ug/dl, total iron binding capacity (TIBC): 286, transferrin saturation: 7% and serum ferritin: 27ng/ml. The peripheral blood smear showed anisocytosis and hypochromic microcytic cells. Thevenon test was negative. Abdominal ultrasound: uterine myoma. A barium swallow X-ray showed a 2-mm linear filling defect between the 4th and 5th cervical vertebrae in the anteroposterior and lateral view; it protruded from the anterior wall and reduced esophageal lumen by 60%. In the endoscopy, we found a fibrous web in the cricopharyngeal area. Serial dilatations were performed over a guidewire using Savary-Gilliard dilators with diameter up to 14 mm, improving dysphagia. She was treated with transfusional therapy and parenteral iron. She was discharged with ferrous sulfate and folic acid. The Plummer-Vinson syndrome, Paterson-Brown-Kelly or sideropenic dysphagia is characterized by dysphagia, irondeficiency anemia and upper esophageal web. The syndrome is described as very rare. PMID- 23023186 TI - Visual and high-throughput detection of cancer cells using a graphene oxide-based FRET aptasensing microfluidic chip. AB - Rapid and efficient measurement of cancer cells is a major challenge in early cancer diagnosis. In the present study, a miniature multiplex chip was created for in situ detection of cancer cells by implementing a novel graphene oxide (GO) based Forster resonance energy transfer (FRET) biosensor strategy, i.e. assaying the cell-induced fluorescence recovery from the dye-labeled aptamer/graphene oxide complex. Fluorescence intensity measurement and image analyses demonstrated that this microfluidic biosensing method exhibited rapid, selective and sensitive fluorescence responses to the quantities of the target cancer cells, CCRF-CEM cells. Seven different cancer cell samples can be measured at the same time in such a microfluidic chip. The linear response for target CCRF-CEM cells in a concentration range from 2.5 * 10(1) to 2.5 * 10(4) cells mL(-1) was obtained, with a detection limit about 25 cells mL(-1), which is about ten times lower than those of normal biosensors. The novel fluorescence biosensing microfluidic chip supplies a rapid, visible and high-throughput approach for early cancer diagnosis with high sensitivity and specificity. PMID- 23023187 TI - Rhodium(III)-catalyzed allylic C-H bond amination. Synthesis of cyclic amines from omega-unsaturated N-sulfonylamines. AB - For the first time, intramolecular allylic amination was conducted using rhodium(III) according to an "inner-sphere" type mechanism with amines activated by only one electron-withdrawing group. The activation of C(sp(3))-H bonds was chemoselective and allows the access to a variety of substituted cyclic amines such as pyrrolidines and piperidines. PMID- 23023188 TI - New hospital readmission policy links financial and quality incentives. PMID- 23023189 TI - Hospital staff nurses' shift length associated with safety and quality of care. AB - The objective of this study was to analyze hospital staff nurses' shift length, scheduling characteristics, and nurse reported safety and quality. A secondary analysis of a large nurse survey linked with hospital administrative data was conducted. More than 22 000 registered nurses' reports of shift length and scheduling characteristics were examined. Extended shift lengths were associated with higher odds of reporting poor quality and safety. Policies aimed at reducing the use of extended shifts may be advisable. PMID- 23023190 TI - IL-23 gene expression in PBMCs of patients with coronary artery disease. AB - OBJECTIVE: Both adaptive and innate immune systems are involved in coronary artery disease (CAD). The aim of this study was to evaluate TH17 cytokines expression profiles in un-stimulated peripheral blood lymphocytes (PBMCs) of patients with coronary artery disease. METHODS: Expression profiles of IL-17, IL 23, and TGF-beta1 were determined in individuals with and without CAD using Real time PCR. RESULTS: A significant decrease in IL-23 gene expression in un stimulated PBMCs of patients with CAD compared to those without CAD was found (p=0.003, OR=0.045, 95% CI: 0.006-0.355). CONCLUSION: Our data reinforce the potential role of the IL-23 as a critical regulatory molecule that bridges the innate and adaptive arms of the immune system in the complex mechanisms associated with the development of atherosclerosis. PMID- 23023191 TI - Caveolin-1 expression in thyroid neoplasia spectrum: comparison of two commercial antibodies. AB - We evaluated caveolin-1 expression in the human thyroid neoplasia spectrum with the aim of examining differences in expression as detected by two anti-caveolin-1 antibodies, and secondly, to investigate the association of caveolin-1 expression levels with aggressive papillary thyroid carcinoma (PTC). Immunohistochemical staining using sc894 or AV09019 antibodies revealed that caveolin-1 was generally overexpressed in the PTC group as a whole (classical and follicular variant) when compared to peritumoral tissue (PT), while it was not detected in about half of follicular thyroid carcinoma (FTC) and majority of follicular adenomas (FTA). Caveolin-1 expression decreased in the following order: clPTC, fvPTC, FTC, PT and FTA. The diagnostic accuracy of AV09019 was better than that of sc894 for discriminating: FTA from FTC, FTA or FTC from the follicular variant of PTC, total PTC from nonmalignant tissue, and malignant tumors from nonmalignant tissue. Spearman's analysis revealed positive correlations of caveolin-1 expression and extrathyroidal invasion (p< 0.05) in PTC for both antibodies. Additionally, AV09019 antibody correlated caveolin-1 upregulation with pathological T status. To conclude, as an immunohistochemical marker AV09019 antibody performed better than sc894 in distinguishing certain histotypes of thyroid tumors. In addition, increased expression of caveolin-1 may be considered as an indicator of papillary carcinoma progression. PMID- 23023192 TI - Proximal to distal correlates of the patterns of illicit drug use among night school students in Taiwan. AB - This epidemiological study aimed to investigate illicit drug use by vocational high school night-class students in Taiwan to identify hypothesized proximal and distal factors associated with drug use patterns. Between September 2010 and January 2011, a randomized sample was drawn from 33 vocational high school night classes, enrolling 1079 students already employed outside campus. Subjects completed a validated self-reported questionnaire measuring proximal factors (biological, psychological, and behavioral) and distal factors (living with parents, parents' or siblings' use of legal substances, supervision by primary guardian, and perceived peer influence on drug use). Age, greater sensation seeking behavior and legal substances use (i.e., tobacco and betel nuts) increased odds of being identified as experimental or regular users versus non drug users. Higher rates of rule-breaking behavior were associated with increased odds of being identified as experimental users versus non-drug users. Among distal factors, only perceived peer influence on drug use was significantly associated with experimental and regular drug use. Proximal and distal factors were associated with drug use patterns among vocational high school night-class students. Influence factors identified may help vocational high school officials design effective illicit drug intervention programs for students with different drug use patterns. PMID- 23023193 TI - Molecular and genomic approach for understanding the gene-environment interaction between Nrf2 deficiency and carcinogenic nickel-induced DNA damage. AB - Nickel (II) is a toxic and carcinogenic metal which induces a redox imbalance following oxidative stress. Nuclear factor erythroid-2 related factor 2 (Nrf2) is a redox factor that regulates oxidation/reduction status and consequently mediates cytoprotective responses against exposure to environmental toxicants. In this study, we investigated the protective roles of the Nrf2 gene against oxidative stress and DNA damage induced by nickel at sub-lethal doses. Under nickel exposure conditions, we detected significantly increased intracellular ROS generation, in addition to higher amounts of DNA damage using comet assay and gamma-H2AX immunofluorescence staining in Nrf2 lacking cells, as compared to Nrf2 wild-type cells. In addition, we attempted to identify potential nickel and Nrf2 responsive targets and the relevant pathway. The genomic expression data were analyzed using microarray for the selection of synergistic effect-related genes by Nrf2 knockdown under nickel treatment. In particular, altered expressions of 6 upregulated genes (CAV1, FOSL2, MICA, PIM2, RUNX1 and SLC7A6) and 4 downregulated genes (APLP1, CLSPN, PCAF and PRAME) were confirmed by qRT-PCR. Additionally, using bioinformatics tool, we found that these genes functioned principally in a variety of molecular processes, including oxidative stress response, necrosis, DNA repair and cell survival. Thus, we describe the potential biomarkers regarded as molecular candidates for Nrf2-related cellular protection against nickel exposure. In conclusion, these findings indicate that Nrf2 is an important factor with a protective role in the suppression of mutagenicity and carcinogenicity by environmental nickel exposure in terms of gene-environment interaction. PMID- 23023194 TI - Positioning of CCA-arms of the A- and the P-tRNAs towards the 28S rRNA in the human ribosome. AB - Nucleotides of 28S rRNA involved in binding of the human 80S ribosome with acceptor ends of the A site and the P site tRNAs were determined using two complementary approaches, namely, cross-linking with application of tRNA(Asp) analogues substituted with 4-thiouridine in position 75 or 76 and hydroxyl radical footprinting with the use of the full sized tRNA and the tRNA deprived of the 3'-terminal trinucleotide CCA. In general, these 28S rRNA nucleotides are located in ribosomal regions homologous to the A, P and E sites of the prokaryotic 50S subunit. However, none of the approaches used discovered interactions of the apex of the large rRNA helix 80 with the acceptor end of the P site tRNA typical with prokaryotic ribosomes. Application of the results obtained to available atomic models of 50S and 60S subunits led us to a conclusion that the A site tRNA is actually present in both A/A and A/P states and the P site tRNA in the P/P and P/E states. Thus, the present study gives a biochemical confirmation of the data on the structure and dynamics of the mammalian ribosomal pretranslocation complex obtained with application of cryo electron microscopy and single-molecule FRET [Budkevich et al., 2011]. Moreover, in our study, particular sets of 28S rRNA nucleotides involved in oscillations of tRNAs CCA-termini between their alternative locations in the mammalian 80S ribosome are revealed. PMID- 23023195 TI - Epigenetic aspects of HP1 exchange kinetics in apoptotic chromatin. AB - Apoptotic bodies are the most condensed form of chromatin. In general, chromatin structure and function are mostly dictated by histone post-translational modifications. Thus, we have analyzed the histone signature in apoptotic cells, characterized by pronounced chromatin condensation. Here, H2B mono-acetylation, and H3K9 and H4 acetylation was significantly decreased in apoptotic cells, which maintained a high level of H3K9 methylation. This phenotype was independent of p53 function and distinct levels of anti-apoptotic Bcl2 protein. Interestingly, after etoposide treatment of leukemia and multiple myeloma cells, H3K9 and H4 hypoacetylation was accompanied by increased H3K9me2, but not H3K9me1 or H3K9me3. In adherent mouse fibroblasts, a high level of H3K9me3 and histone deacetylation in apoptotic bodies was likely responsible for the pronounced (~40%) recovery of GFP-HP1alpha and GFP-HP1beta after photobleaching. HP1 mobility in apoptotic cells appeared to be unique because limited exchange after photobleaching was observed for other epigenetically important proteins, including GFP-JMJD2b histone demethylase (~10% fluorescence recovery) or Polycomb group-related GFP BMI1 protein (~20% fluorescence recovery). These findings imply a novel fact that only certain subset of proteins in apoptotic bodies is dynamic. PMID- 23023196 TI - Promoter scanning of the human COX-2 gene with 8-ring polyamides: unexpected weakening of polyamide-DNA binding and selectivity by replacing an internal N-Me pyrrole with beta-alanine. AB - Rules for polyamide-DNA recognition have proved invaluable for the design of sequence-selective DNA binding agents in cell-free systems. However, these rules are not fully transferrable to predicting activity in cells, tissues or animals, and additional refinements to our understanding of DNA recognition would help biomedical studies. Similar complexities are encountered when using internal beta alanines as polyamide building blocks in place of N-methylpyrrole; beta-alanines were introduced in polyamide designs to maintain good hydrogen bonding registry with the target DNA, especially for long polyamides or those with several GC bp (P.B. Dervan, A.R. Urbach, Essays Contemp. Chem. (2001) 327-339). Thus, to clarify important subtleties of molecular recognition, we studied the effects of replacing a single pyrrole with beta-alanine in 8-ring polyamides designed against the Ets-1 transcription factor. Replacement of a single internal N methylpyrrole with beta-alanine to generate a beta/Im pairing in two 8-ring polyamides causes a decrease in DNA binding affinity by two orders of magnitude and decreases DNA binding selectivity, contrary to expectations based on the literature. Measurements were made by fluorescence spectroscopy, quantitative DNA footprinting and surface plasmon resonance, with these vastly different techniques showing excellent agreement. Furthermore, results were validated for a range of DNA substrates from small hairpins to long dsDNA sequences. Docking studies helped show that beta-alanine does not make efficient hydrophobic contacts with the rest of the polyamide or nearby DNA, in contrast to pyrrole. These results help refine design principles and expectations for polyamide-DNA recognition. PMID- 23023197 TI - Chemical polysialylation: design of conjugated human oxyntomodulin with a prolonged anorexic effect in vivo. AB - Recombinant gut hormone oxyntomodulin (OXM) is known to act as a satiety signal in human subjects and has therapeutic potential as an appetite controlling agent. The only form of this hormone that has a prospective use is a modified one, because native OXM has a very short half-life in vivo. Conjugation of OXM and the natural hydrophilic polymer polysialic acid (PSA) may significantly improve its half-life. Chemical polysialylation in vitro was used to create a long-acting form of OXM, the polysialic acid-oxyntomodulin (PSA-OXM) conjugate. The conjugation site was identified using mass shift comparative analysis of Asp-N proteolytic digests. The anorexic effect of the conjugate was tested on the lean, fasted mouse model. A two-stage purification technique was developed to obtain a homogeneous PSA-OXM conjugate, suitable for in vivo testing. The N-terminal backbone primary amino group was found to be the only point of conjugation. The conjugate obtained was resistant to the DPP-IV protease. A single injection of PSA-OXM at 15 MUmol/kg dose was sufficient to maintain a steady decrease in food consumption for 8 h (P < 0.05). The length of the anorexic effect achieved is comparable to other long-acting derivatives of OXM but it requires a much higher dose for administration. It is expected that site-directed attachment of the PSA chain to the inner residues of OXM, away from the site of interaction with receptors, would produce a compound with a higher specific activity but comparable stability in the bloodstream. The conjugation technique used may be used to create OXM derivatives and other related hormones to obtain long-lasting variants, with improved suitability for clinical use. PMID- 23023198 TI - In vitro synthesis of native, fibrous long spacing and segmental long spacing collagen. AB - Collagen fibrils are present in the extracellular matrix of animal tissue to provide structural scaffolding and mechanical strength. These native collagen fibrils have a characteristic banding periodicity of ~67 nm and are formed in vivo through the hierarchical assembly of Type I collagen monomers, which are 300 nm in length and 1.4 nm in diameter. In vitro, by varying the conditions to which the monomer building blocks are exposed, unique structures ranging in length scales up to 50 microns can be constructed, including not only native type fibrils, but also fibrous long spacing and segmental long spacing collagen. Herein, we present procedures for forming the three different collagen structures from a common commercially available collagen monomer. Using the protocols that we and others have published in the past to make these three types typically lead to mixtures of structures. In particular, unbanded fibrils were commonly found when making native collagen, and native fibrils were often present when making fibrous long spacing collagen. These new procedures have the advantage of producing the desired collagen fibril type almost exclusively. The formation of the desired structures is verified by imaging using an atomic force microscope. PMID- 23023199 TI - Commercializing biomedical research through securitization techniques. AB - Biomedical innovation has become riskier, more expensive and more difficult to finance with traditional sources such as private and public equity. Here we propose a financial structure in which a large number of biomedical programs at various stages of development are funded by a single entity to substantially reduce the portfolio's risk. The portfolio entity can finance its activities by issuing debt, a critical advantage because a much larger pool of capital is available for investment in debt versus equity. By employing financial engineering techniques such as securitization, it can raise even greater amounts of more-patient capital. In a simulation using historical data for new molecular entities in oncology from 1990 to 2011, we find that megafunds of $5-15 billion may yield average investment returns of 8.9-11.4% for equity holders and 5-8% for 'research-backed obligation' holders, which are lower than typical venture capital hurdle rates but attractive to pension funds, insurance companies and other large institutional investors. PMID- 23023200 TI - Benefit-risk balance of reoperation for persistent medullary thyroid cancer. AB - OBJECTIVE: This investigation aimed at exploring the prospects of a cure for persistent medullary thyroid cancer (MTC) stratified by basal calcitonin levels before reoperation and the number of lymph node metastases previously removed at outside facilities. BACKGROUND: There is no evidence-based information supporting the balance of surgical benefit and risk in persistent MTC. METHODS: This retrospective study of 334 patients with persistent MTC referred to a tertiary surgical center, who were compared with 367 patients with previously untreated MTC referred to that institution during the same time period, evaluated biochemical cure rates after systematic lymph node dissection. RESULTS: The relationship between the incremental serum calcitonin level before reoperation and the number of lymph node metastases at reoperation and biochemical cure was strong after previous removal of 0 (r = 0.74 and 77%-0%) and 1 to 5 lymph node metastases (r = 0.61 and 60%-0%) elsewhere. It disappeared once more than 5 lymph node metastases had been cleared at other hospitals (nonsignificant and 5%). When serum calcitonin levels were 1000 pg/mL or lower before reoperation, biochemical cure rates were 44% (59 of 133 patients) and 18% (12 of 65 patients) after previous removal of 0 and 1 to 5 lymph node metastases, respectively. These rates plummeted to 5% (2 of 43 patients) after a previous clearance of more than 5 lymph node metastases. When serum calcitonin levels exceeded 1000 pg/mL before reoperation, a biochemical cure was exceptional (1%; 1 of 76 patients). CONCLUSIONS: With serum calcitonin levels of 1000 pg/mL or lower before reoperation and the previous removal of 5 or fewer lymph node metastases, systematic lymph node dissection seems worthwhile for persistent MTC. These findings will need to be validated in independent series before being adopted more widely as a new standard of care. PMID- 23023201 TI - Surgical strategies that may decrease leak after laparoscopic sleeve gastrectomy: a systematic review and meta-analysis of 9991 cases. AB - OBJECTIVE: To conduct a systematic review to identify surgical strategies that may decrease leak after laparoscopic sleeve gastrectomy (LSG). BACKGROUND: LSG is growing in popularity as a primary bariatric procedure. Technical aspects of LSG including bougie size remain controversial. METHODS: Our systematic review yielded 112 studies encompassing 9991 LSG patients. A general estimating equation (GEE) model was used to calculate the odds ratio (OR) for leak based on bougie size, distance from the pylorus, and use of buttressing on the staple line. Baseline characteristics, including age and body mass index (BMI), were included. A linear repeated measures regression model compared excess weight loss (%EWL) between bougie sizes. RESULTS: A total of 198 leaks in 8922 patients (2.2%) were identified. The GEE model revealed that the risk of leak decreased with bougie >=40 Fr (OR = 0.53, 95% CI = [0.37-0.77]; P = 0.0009). Buttressing did not impact leak. There was no difference in %EWL between bougie <40 Fr and bougie >=40 Fr up to 36 months (mean: 70.1% EWL; P = 0.273). Distance from the pylorus did not affect leak or %EWL. CONCLUSIONS: Utilizing bougie >=40 Fr may decrease leak without impacting %EWL up to 3 years. Distance from the pylorus does not impact leak or weight loss. Buttressing does not seem to impact leak; however, if surgeons desire to buttress, bioabsorbable material is the most common type used. Longer-term studies are needed to definitively determine the effect of bougie size on weight loss after LSG. PMID- 23023202 TI - LINE-1 hypomethylation is associated with a poor prognosis among patients with curatively resected esophageal squamous cell carcinoma. AB - OBJECTIVE: To investigate the relationship between the long interspersed nucleotide element-1 (L1/LINE-1) methylation level and the disease-free survival and cancer-specific survival in patients with esophageal squamous cell carcinoma (ESCC). BACKGROUND: Cancer cells exhibit 2 types of deoxyribonucleic acid (DNA) methylation alterations: global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Global DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in the LINE-1 repetitive element is a good indicator of the global DNA methylation level. Although the LINE-1 methylation level is attracting interest as a useful marker for predicting cancer prognosis, the prognostic significance of LINE-1 hypomethylaiton in ESCC remains unclear. METHODS: Using 217 curatively resected ESCC specimens, we quantified the LINE-1 methylation by utilizing the bisulfite pyrosequencing technology. Promoter methylation levels of MGMT and MLH1 were also evaluated by pyrosequencing. RESULTS: ESCC showed significantly lower LINE-1 methylation levels in comparison with matched normal esophageal mucosa (P < 0.0001; N = 50). LINE-1 hypomethylation was significantly associated with disease-free survival [log-rank P = 0.0008; univariate hazard ratio (HR): 2.32, 95% confidence interval (CI): 1.38-3.84, P = 0.0017; multivariate HR: 1.81, 95% CI: 1.06-3.05, P = 0.031] and cancer-specific survival (log-rank P = 0.0020; univariate HR: 2.21, 95% CI: 1.33 3.60, P = 0.0026; multivariate HR: 1.87, 95% CI: 1.12-3.08, P = 0.018]. MGMT and MLH1 hypermethylation were not associated with patient prognosis. CONCLUSIONS: LINE-1 hypomethylation in ESCC is associated with a shorter survival, thus suggesting that it has potential for use as a prognostic biomarker. PMID- 23023203 TI - Projecting surgeon supply using a dynamic model. AB - OBJECTIVE: To develop a projection model to forecast the head count and full-time equivalent supply of surgeons by age, sex, and specialty in the United States from 2009 to 2028. SUMMARY BACKGROUND DATA: The search for the optimal number and specialty mix of surgeons to care for the United States population has taken on increased urgency under health care reform. Expanded insurance coverage and an aging population will increase demand for surgical and other medical services. Accurate forecasts of surgical service capacity are crucial to inform the federal government, training institutions, professional associations, and others charged with improving access to health care. METHODS: The study uses a dynamic stock and flow model that simulates future changes in numbers and specialty type by factoring in changes in surgeon demographics and policy factors. RESULTS: : Forecasts show that overall surgeon supply will decrease 18% during the period form 2009 to 2028 with declines in all specialties except colorectal, pediatric, neurological surgery, and vascular surgery. Model simulations suggest that none of the proposed changes to increase graduate medical education currently under consideration will be sufficient to offset declines. CONCLUSIONS: The length of time it takes to train surgeons, the anticipated decrease in hours worked by surgeons in younger generations, and the potential decreases in graduate medical education funding suggest that there may be an insufficient surgeon workforce to meet population needs. Existing maldistribution patterns are likely to be exacerbated, leading to delayed or lost access to time-sensitive surgical procedures, particularly in rural areas. PMID- 23023204 TI - Outcomes after laparoscopic or open distal gastrectomy for early-stage gastric cancer: a propensity-matched analysis. AB - OBJECTIVE: In a large nationwide administrative database of hospitalized patients, we investigated postoperative outcomes after laparoscopic or open distal gastrectomy in Japan. BACKGROUND: The benefits of laparoscopic gastrectomy, such as decreased length of stay and morbidity, have typically been evaluated only with limited data on the basis of small samples. METHODS: : Using the Japanese Diagnosis Procedure Combination Database, we identified 9388 patients who were preoperatively diagnosed with stage I and II gastric cancer and underwent laparoscopic (n = 3937) or open (n = 5451) distal gastrectomy between July and December 2010. One-to-one propensity score matching was performed to compare in-hospital mortality, postoperative complication rates, length of stay, total costs, and 30-day readmission rates between the 2 groups. RESULTS: Patients with younger age, lower comorbidity index, or stage I cancer were more likely to receive laparoscopic gastrectomy. In the propensity-matched analysis with 2473 pairs, the laparoscopic gastrectomy group in comparison with the open gastrectomy group showed a slight reduction in median postoperative length of stay (13 days vs 15 days, P < 0.001) but a slight increase in median total costs (US $21,510 vs $21,024, P = 0.002). There were no significant differences in in-hospital mortality (0.36% vs 0.28%, P = 0.80), overall postoperative complications (12.9% vs 12.6%, P = 0.73), or 30-day readmission rates (3.2% vs 3.2%, P = 0.94). CONCLUSIONS: In this large nationwide cohort of patients with early-stage gastric cancer, laparoscopic gastrectomy was associated with a statistically significant but slight reduction in postoperative length of stay, but no differences between laparoscopic gastrectomy and open gastrectomy were detected in terms of early mortality and morbidity. PMID- 23023205 TI - Ablation of lung tumours. AB - Radiofrequency, laser, microwave and cryotherapy have all been used for the ablation of lung tumours. However, radiofrequency ablation (RFA) and microwave ablation are the most widely used technologies. RFA has been successfully applied to tumour measuring from <3 to 3.5 cm, either primary or secondary. Lung function usually recovers to pre-ablation values following an initial reduction and the complication profile is well understood. PMID- 23023206 TI - Proteomic analysis of changes in protein expression in serum from animals exposed to paraquat. AB - Paraquat (PQ) poisoning remains a major public health concern in many countries. Extensive research has focused on finding early diagnostic biomarkers of acute PQ poisoning. In order to investigate the characterization of diagnostic biomarkers in PQ poisoning, we utilized proteomic analysis using serum from rats exposed to PQ, and we identified 8 differentially expressed proteins from over 500 protein spots. The expression of apolipoprotein E (ApoE), preprohaptoglobin (Pphg), a precursor of haptoglobin (Hp), and complement component 3 (C3) proteins was greatly induced by PQ exposure while the expression of fibrinogen gamma-chain (FGG) and Ac-158 was dramatically reduced. To further investigate the possibility of ApoE, Pphg and FGG as useful diagnostic biomarkers of PQ poisoning, western blot and qRT-PCR analyses were conducted using cell lines as well as rat and human sera. The expression levels of ApoE, Hp and FGG were significantly altered in the presence of PQ in both rat and human serum suggesting that these proteins may be appropriate candidate molecular biomarkers for the early diagnosis of acute PQ intoxication. PMID- 23023207 TI - Bioinformatics methods for the comparative analysis of metazoan mitochondrial genome sequences. AB - In this review we provide an overview of various bioinformatics methods and tools for the analysis of metazoan mitochondrial genomes. We compare available dedicated databases and present current tools for accurate genome annotation, identification of protein coding genes, and determination of tRNA and rRNA models.We also evaluate various tools and models for phylogenetic tree inference using gene order or sequence based data. As for gene order based methods, we compare rearrangement based and gene cluster based methods for gene order rearrangement analysis. As for sequence based methods, we give special emphasis to substitution models or data treatment that reduces certain systematic biases that are typical for metazoan mitogenomes such as within genome and/or among lineage compositional heterogeneity. PMID- 23023208 TI - Phylogenetic relationships and biogeography of Pseudoxiphophorus (Teleostei: Poeciliidae) based on mitochondrial and nuclear genes. AB - Phylogenetic relationships of species of genus Pseudoxiphophorus have been only tackled in detail based on morphology so far. However, phylogenetic evidence based on molecular data is still lacking. In this study, we have used five molecular markers (mitochondrial cytb, 16S, atp6-8, and nuclear actB and S7) to reconstruct a robust, inclusive phylogeny of Pseudoxiphophorus. Our phylogenetic results strongly disagree with the main morphological hypothesis, and indicate different phylogenetic relationships among the recognized species of Pseudoxiphophorus. Pseudoxiphophorus jonesii is recovered as the sister group of all other Pseudoxiphophorus lineages, and this initial splitting may be associated to the extension of the Mexican Neovolcanic Plateau at the Punta del Morro site (event used to calibrate our dating analysis). The branch leading to all other Pseudoxiphophorus separated subsequently into two major groups, one comprising those lineages occurring in southern Mexico and Guatemala-Belize, and another with those lineages that extended further southwards to Honduras and Nicaragua. This event took place during the Pliocene, and is likely associated with periods of inundation of the Polochic-Motagua fault area. The Isthmus of Tehuantepec also appears to have been a strong biogeographic barrier triggering cladogenesis in Pseudoxiphophorus. Heterandria formosa (traditionally placed as sister to Pseudoxiphophorus) is not sharing the most recent common ancestor with Pseudoxiphophorus, and is recovered as more distantly related to them. Furthermore, Pseudoxiphophorus bimaculatus (the most cosmopolitan species) is also recovered as a polyphyletic assemblage that appears to comprise those Pseudoxiphophorus that have not been assigned to the other eight, more localized species. All this suggests that Pseudoxiphophorus needs a major taxonomic revision as a whole in order to incorporate all existing diversity. PMID- 23023209 TI - Species boundaries in the Himantura uarnak species complex (Myliobatiformes: Dasyatidae). AB - Samples of the 'Himantura uarnak' species complex (H. leoparda, H. uarnak, H. undulata under their current definitions), mostly from the Coral Triangle, were analyzed using nuclear markers and mitochondrial DNA sequences. Genotypes at five intron loci showed four reproductively isolated clusters of individuals. The COI sequences showed four major mitochondrial lineages, each diagnostic of a cluster as defined by nuclear markers. No mitochondrial introgression was detected. The average Kimura-2 parameter nucleotide distance separating clades was 0.061-0.120 (net: 0.055-0.114), while the distance separating individuals within a clade was 0.002-0.008. Additional, partial cytochrome-b gene sequences were used to link these samples with previously published sequences of reference specimens of the three nominal species. One of the clusters was identified as H. undulata and another one, as H. uarnak, while two cryptic species were uncovered within the recently-described H. leoparda, challenging the current morphology-based taxonomy of species within the H. uarnak species complex. PMID- 23023210 TI - Nucleotide, c-di-GMP, c-di-AMP, cGMP, cAMP, (p)ppGpp signaling in bacteria and implications in pathogenesis. AB - For an organism to survive, it must be able to sense its environment and regulate physiological processes accordingly. Understanding how bacteria integrate signals from various environmental factors and quorum sensing autoinducers to regulate the metabolism of various nucleotide second messengers c-di-GMP, c-di-AMP, cGMP, cAMP and ppGpp, which control several key processes required for adaptation is key for efforts to develop agents to curb bacterial infections. In this review, we provide an update of nucleotide signaling in bacteria and show how these signals intersect or integrate to regulate the bacterial phenotype. The intracellular concentrations of nucleotide second messengers in bacteria are regulated by synthases and phosphodiesterases and a significant number of these metabolism enzymes had been biochemically characterized but it is only in the last few years that the effector proteins and RNA riboswitches, which regulate bacterial physiology upon binding to nucleotides, have been identified and characterized by biochemical and structural methods. C-di-GMP, in particular, has attracted immense interest because it is found in many bacteria and regulate both biofilm formation and virulence factors production. In this review, we discuss how the activities of various c-di-GMP effector proteins and riboswitches are modulated upon c-di-GMP binding. Using V. cholerae, E. coli and B. subtilis as models, we discuss how both environmental factors and quorum sensing autoinducers regulate the metabolism and/or processing of nucleotide second messengers. The chemical syntheses of the various nucleotide second messengers and the use of analogs thereof as antibiofilm or immune modulators are also discussed. PMID- 23023211 TI - Acceleration effects of phosphate modification on the decay dynamics of photo generated electrons of TiO2 and its photocatalytic activity. AB - The surface modification with a proper amount of phosphate accelerates the dynamic decay of photogenerated electrons in the nanocrystalline anatase TiO(2) film in the presence of O(2), consequently prolonging greatly the lifetime of photogenerated holes so as to improve the charge separation of TiO(2) and then its photocatalytic activity for degrading gas-phase acetaldehyde and liquid-phase phenol mainly based on the transient absorption spectra and the measurements of electrochemical O(2) reduction and the produced hydroxyl radical amount. The acceleration effects are attributed to the increased amount of adsorbed O(2) by means of the curves of O(2) temperature-programmed desorption. PMID- 23023212 TI - Functional recombinant extra membrane loop of human CD20, an alternative of the full length CD20 antigen. AB - BACKGROUND: Targeting of CD20 antigen with monoclonal antibodies has become the mainstay in the treatment of non-Hodgkin's lymphomas and immunotherapeutic depletion of malignant B cells. Accessibility of antigen is one of the crucial factors in development of monoclonal antibodies against this antigen. One major problem in expression of full length CD20 is aggregation and misfolding. Therefore, production of an alternative polypeptide is easer and favorable comparing to that of a full length transmembrane protein CD20. METHODS: In this study, we expressed the extra membrane loop of hCD20 (exCD20) consisting of a non glycosylated 47-amino acids region. The exCD20 coding sequence was amplified by PCR and cloned in pET32a(+) expression vector. The desired protein was expressed in fusion with thioredoxin and 6* His tag in E. coli Origami strain. ELISA and Western-blotting data were performed to indicate the functionality of this protein. RESULTS: We have obtained the exCD20 recombinant protein which can be detected in ELISA and Western-blot experiments. This recombinant fusion protein was soluble and stable without aggregation and misfolding problems. CONCLUSION: The recombinant extra membrane loop of human CD20 protein in fusion with thioredoxin (exCD20) can be used in function assays and some applications such as ELISA, immuneblotting, affinity purification, immunization, screening, and development of anti-CD20 antibodies. PMID- 23023213 TI - Upregulation of connexins 30 and 32 gap junctions in rat hippocampus at transcription level by chronic central injection of lipopolysaccharide. AB - BACKGROUND: Gap junctions composed of connexins (Cx) are functional in cell defense by propagation of toxic/death molecules to neighboring cells. Hippocampus, one of the brain regions with particular vulnerability to damage, has a wide network of gap junctions. Functional response of astrocytic Cx30 and neuronal Cx32 to hippocampal damage is unknown. METHODS: We infused lipopolysaccharide (LPS) intracerebroventricularly (2.5 mug/rat) once daily for two weeks to create neuroinflammation. The mRNA and protein levels of the Cx were measured in the hippocampus after 1st, 7th and 14th injection by real-time PCR and Western-blot techniques. RESULTS: A significant increase in Cx32 and Cx30 gene expression was observed after 7th and 14th injection of LPS with no significant change in their protein abundance. CONCLUSION: Transcriptional overexpression of hippocampal Cx30 and Cx32 could be an adaptive response to production of intracellular toxic molecules but it is not accompanied with post- transcriptional overexpression and might have no functional impact. PMID- 23023214 TI - A DNA vaccine against Escherichia coli O157:H7. AB - BACKGROUND: Infection with Escherichia coli O157:H7 rarely leads to bloody diarrhea and causes hemolytic uremic syndrome with renal failure that can be deadly dangerous. Intimin, translocated Intimin receptor (Tir), and enterohemorrhagic E. coli (EHEC) secreted protein A (EspA) proteins are the virulence factors expressed by locus of enterocyte effacement locus of EHEC. This bacterium needs EspA as a conduit for Tir delivery into the host cell and the surface arrayed Intimin, which docks the bacterium to the translocated Tir. METHODS: Here we used triplet synthetic gene (eit) which was designed from three genes: espA coding EspA 120 lacking 36 amino acids from the N-terminal of the protein, eae coding Intimin constructed of 282 amino acids from the C-terminal and tir coding Tir 103, residues 258-361 which interacts with Intimin. The multimeric gene was cloned in two eukaryotic vectors pAAV-multiple cloning site green fluorescent protein and pCI-neo. The pAAV was used for gene expression assay in cell line 293T and pCI-neo-EIT (EspA, Intimin, Tir) was used as DNA vaccine in mice. Test groups were injected intramuscularly with pCI-neo-EIT four times and mice control group was injected under the same conditions with PBS or pCI-neo vector. RESULTS: The titration of serums showed that BALB/c mice were successfully immunized with DNA vaccine compared to control groups and also they were protected against challenges of live oral using E. coli O157:H7. CONCLUSION: The results suggest that the DNA vaccine could induce protective immunity either alone or in combination with purified antigens to reduce EHEC infection. PMID- 23023216 TI - Effect of 3alpha-anderostanediol and indomethacin on acquisition, consolidation and retrieval stage of spatial memory in adult male rats. AB - BACKGROUND: Testosterone and its metabolites have important roles in learning and memory. The current study has conducted to assess the effect of pre-training, post-training and pre-probe trial intrahippocampal CA1 administration of 3alpha anderostanediol (one of the metabolites of testosterone) and indomethacin (as 3alpha-hydroxysteroid dehydrogenase enzyme blocker) on acquisition, consolidation and retrieval in Morris water maze (MWM) task. METHODS: Adult male rats were bilaterally cannulated into CA1 region of hippocampus and then received 3alpha diol (0.2, 1, 3 and 6 mug/0.5 mul/side), indomethacin (1.5, 3 and 6 mug/0.5 mul/side), indomethacin (3 mug/0.5 mul/side) + 3alpha-diol (1 mug/0.5 mul/side), 25-35 min before training, immediately after training and 25-35 min before probe trial in MWM task. RESULTS: Our results showed that injection of 3alpha-diol and indomethacin significantly increased the escape latency and traveled distance to find hidden platform in acquisition and consolidation stage, but did not have any effect on retrieval of spatial learning as compared with the control group. CONCLUSION: It is concluded that intra-CA1 administration of 3alpha-diol and indomethacin could impair spatial learning and memory in acquisition and consolidation stage. Also, intrahippocampal injection of indomethacin + 3alpha diol could not change spatial learning and memory impairment effect of indomethacin or 3alpha-diol in MWM task. PMID- 23023215 TI - GSK3beta and CREB3 gene expression profiling in benign and malignant salivary gland tumors. AB - BACKGROUND: Salivary gland tumors (SGT) are rare lesions with uncertain histopathology. One of the major signaling pathways that participate in the development of several tumors is protein kinase A. In this pathway, glycogen synthase kinase beta (GSK3beta) and cAMP responsive element binding protein (CREB3) are two genes which are supposed to be down regulated in most human tumors. The expression level of the genes was evaluated in SGT to scrutinize their possible under expression in these tumors. METHODS: Forty eight fresh tissue samples were obtained from patients with benign and malignant SGT, including pleomorphic adenoma, warthin's tumor, mucoepidermoid carcinoma (MEC), salivary duct carcinoma and carcinoma ex pleomorphic adenoma. Eight normal samples were used as controls. Quantitative real-time PCR was used to analyze the expression level of interest genes. RESULTS: Data was analyzed by statistical methods. GSK3beta was downregulate in all samples and all results were statistically significant (P<0.05). CREB3 did not show a significant decrease or increase in its mRNA expression, but the results were significant in MEC and salivary duct carcinoma. CONCLUSION: GSK3beta down regulation has been reported in many human tumors. This gene stimulates CREB3, inducing cell proliferation and oncogenesis. Our findings showed GSK beta down regulation; however, CREB3 expression level was close to normal group. No association between CREB3 expression and inactivated GSK3beta could be postulated in SGT. PMID- 23023217 TI - Galantamine effect on tularemia pathogenesis in a BALB/c mouse model. AB - BACKGROUND: Galantamine is a drug used for the treatment of Alzheimer's disease and some other cognitive disorders. It is an inhibitor of acetylcholinesterase; however, interaction with nicotinic acetylcholine receptors has also been reported. Owing to the significant role of cholinergic anti-inflammatory pathways in neuro-immunomodulation, we decided to examine the effect of galantamine on tularemia-infected BALB/c mice. METHODS: Animals were infected with Francisella tularensis LVS and treated with galantamine (0.1 mg/kg of body weight). Total mortality over the course of tularemia infection was assessed and interleukin 6 (IL-6) and interferon gamma (IFN-gamma) in plasma samples were measured by enzyme linked immunosorbent assays. Apart from the cytokine assays, biochemical markers such as inorganic phosphate, uric acid, lactate dehydrogenase, gamma glutamyltransferase, creatinine phosphokinase and amylase were assayed. RESULTS: The modulation of immunity by galantamine depended on two opposing processes: up regulation of IFN-gamma and down-regulation of IL-6. Tularemia infection resulted in significant nephropathy, as hyperphosphataemia and hyperuricaemia occurred in infected animals. In addition, galantamine resulted in the mitigation of nephropathy, and markers of kidney dysfunction were modulated. Alterations in mortality were also found in this study. CONCLUSIONS: Galantamine can significantly influence the immune response via the cholinergic anti-inflammatory pathway. Despite the decrease in IL-6 levels, galantamine treatment enhanced protection against the intracellular pathogen F. tularensis, resulting in the remission of some pathology and reduced mortality. PMID- 23023218 TI - Fatty acid composition of human follicular fluid phospholipids and fertilization rate in assisted reproductive techniques. AB - BACKGROUND: Fatty acids are known to be critically important in multiple biological functions. Phospholipid fatty acids of follicular fluid, an important microenvironment for the development of oocytes, may contribute to the women's fertility and the efficacy of assisted reproduction techniques. The aim of this study was to investigate the effect of fatty acid composition of follicular fluid phospholipids on women undergoing assisted reproductive techniques. METHODS: Follicular fluid samples were obtained from 100 patients, referred to Tabriz Alzahra Hospital. Seventy-nine subjects underwent in vitro fertilization (IVF) and the remaining 21 underwent intracytoplasmic sperm injection (ICSI). Total lipid of follicular fluid was extracted and fatty acids were analyzed by gas liquid chromatography. RESULTS: Saturated fatty acids (SFA, P = 0.002) and the ratio of SFA to polyunsaturated fatty acids (P = 0.001) were correlated negatively with a number of mature oocytes after age adjustment. Linoleic acid (P = 0.006) was positively correlated, while the level of arachidonic acid was negatively correlated with fertility percentage after adjustment for body mass index, sperm count, sperm motility. CONCLUSION: Since phospholipids are one of the major components of lipid metabolism, the results of this study highlight the importance of this component in follicular fluid lipid metabolism. Consequently, it is proposed as an index in determination of the rate of success in assisted reproductive techniques such as IVF/ICSI. PMID- 23023219 TI - Identification of a novel arylsulfatase B gene mutation in three unrelated Iranian mucopolysaccharidosis type-VI patients with different phenotype severity. AB - BACKGROUND: Mucopolysaccharidosis type-VI (MPS-VI), which is inherited as an autosomal recessive trait, results from the deficiency of N-acetylgalactosamine 4 sulfatase (arylsulfatase B) activity and the lysosomal accumulation of dermatan sulfate. In this study, ARSB mutation analysis was performed on three unrelated patients who were originally from the West Azerbaijan province of Iran. METHODS: After PCR and direct DNA sequencing, DNA extraction was performed. RESULTS: Sequencing analysis revealed a novel homozygous missense mutation in the ARSB gene at c.1457A 1 year. MEASURES: Paired t-test compared pre and post-implantation weights. Analyses of covariance were run to compare differences in overall weight change as defined by variables of gender, diet, diagnosis, and ethnicity. RESULTS: A significant change in pre-implantation weight (M=26.77, SD=11.29) from post-implantation weight (M=32.11, SD=12.62) was noted. No significant weight change was noted among variables. CONCLUSION: Study participants gained an average of 5.43 kg (SD=4.34) after receiving 1 year of ITB therapy. PMID- 23023253 TI - Rehabilitation planning for children and adolescents with cerebral palsy. AB - OBJECTIVE: To explore the types of procedures and practices in rehabilitation planning for children with cerebral palsy and how multidisciplinary team members experience them. DESIGN, SUBJECTS, AND SETTING: A qualitative research approach was used. Participants were members of multidisciplinary teams in neuropediatric wards at five university hospitals. METHODS: In order to explore the rehabilitation planning procedure within multidisciplinary teams, focus group interviews were conducted. The interviews were tape recorded and transcribed. Three content areas guided the interviews: goal setting, the different transition phases, and the use of the international classification of functioning, disability and health, child and youth version (ICF-CY). Qualitative content analysis was used to analyze the results. RESULTS: Three themes arose from the focus group discussions; challenging goal setting, transition without routines, and ICF-CY not in use. A family-centered service model had been adopted, but there was no clear procedure in the collaboration with parents. Goal setting was found to be challenging and the concern arose of how to integrate goals into the child's everyday life. There was a lack of systematic planning of the different transition phases. There was also a general variation in the rehabilitation planning procedures due to local and regional differences in practice. The ICF-CY was familiar, but not in formal use in clinical practice. CONCLUSION: There is a need to enhance the procedures and to systematize coordination of services in the rehabilitation process. The ICF-CY framework might help to optimize collaborative goal setting and to structure both procedures and documentation of the rehabilitation plans and goals. PMID- 23023255 TI - Treatment of cerebellar cognitive affective syndrome with aripiprazole. AB - This report describes a patient who developed agitation, disorientation, visual hallucinations, inappropriate verbal outbursts, and impaired memory following resection of a choroid plexus papilloma. No medical, neurologic, or metabolic disorders unrelated to the surgery were identified. Five weeks following surgery, treatment with aripiprazole, a partial dopamine agonist, was started to address the delirious state. Improvements in agitation, orientation, memory, and executive functions, as well as a decrease in emotional lability, began within twenty-four hours and continued over the remainder of the inpatient hospitalization. Five months after initial resection, aripiprazole was discontinued without worsening of cognitive or emotional functions. Persistent difficulties with working memory, planning, judgment, and visuospatial skills were noted on neuropsychological examination six months following tumor removal. This case illustrated the therapeutic benefit of aripiprazole for treatment of mental status changes associated with resection of a posterior fossa tumor. PMID- 23023254 TI - Genetics and outcomes after traumatic brain injury (TBI): what do we know about pediatric TBI? AB - Human genetic association studies in individuals with traumatic brain injury (TBI) have increased rapidly over the past few years. Recently, several review articles evaluated the association of genetics with outcomes after TBI. However, almost all of the articles discussed in these reviews focused on adult TBI. The primary objective of this review is to gain a better understanding of which genes and/or genetic polymorphisms have been evaluated in pediatric TBI. Our initial search identified 113 articles. After review of these articles only 5 genetic association studies specific to pediatric TBI were identified. All five of these studies evaluated the apolipoprotein (APOE) gene. The study design and methods of these identified papers will be discussed. An additional search was then performed to evaluate genes beyond APOE that have been evaluated in adult TBI; findings from these studies are highlighted. Larger genetic studies will need to be performed in the future to better elucidate the association of APOE and other genes with outcomes after TBI in children. There is great potential to utilized genetic information to inform prognosis and management after TBI in children; however, we have much work ahead of us to reach the goal of individualized management. PMID- 23023259 TI - Twins, birth weight, cognition, and handedness. PMID- 23023260 TI - Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML. AB - Occurrence of the BCR-ABL(T315I) gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL(T315I). To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL(T315I) CML cells on c-Myc through nonobvious off targets. PMID- 23023261 TI - Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function. AB - Here we report a highly conserved new binding site located at the interface between the protease and helicase domains of the hepatitis C virus (HCV) NS3 protein. Using a chemical lead, identified by fragment screening and structure guided design, we demonstrate that this site has a regulatory function on the protease activity via an allosteric mechanism. We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and thus represent a new class of direct-acting antiviral agents. PMID- 23023262 TI - A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. AB - EZH2 catalyzes trimethylation of histone H3 lysine 27 (H3K27). Point mutations of EZH2 at Tyr641 and Ala677 occur in subpopulations of non-Hodgkin's lymphoma, where they drive H3K27 hypertrimethylation. Here we report the discovery of EPZ005687, a potent inhibitor of EZH2 (K(i) of 24 nM). EPZ005687 has greater than 500-fold selectivity against 15 other protein methyltransferases and has 50-fold selectivity against the closely related enzyme EZH1. The compound reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells. These data suggest that genetic alteration of EZH2 (for example, mutations at Tyr641 or Ala677) results in a critical dependency on enzymatic activity for proliferation (that is, the equivalent of oncogene addiction), thus portending the clinical use of EZH2 inhibitors for cancers in which EZH2 is genetically altered. PMID- 23023263 TI - Morphological, biochemical, physiological and molecular aspects of the response of Fusobacterium nucleatum exposed to subinhibitory concentrations of antimicrobials. AB - Subinhibitory concentrations (SICs) of antimicrobials may result in alterations in bacterial biology with implications for its potential aggression. This has considerable importance for the resident microbiota. Our aim was to analyze the effects of SICs of antimicrobials on the morphological, biochemical, physiological and molecular characteristics of the resident anaerobic Fusobacterium nucleatum. Fourteen strains were obtained from F. nucleatum ATCC 25586, selected by culturing on SICs of ampicillin, ampicillin/sulbactam, clindamycin, chloramphenicol, levofloxacin, metronidazole and piperacillin/tazobactam and subsequent culturing in the absence of drugs. Antimicrobial susceptibility, bacterial morphology, biochemical profiles and biofilm formation were evaluated. Genotyping and analysis of protein profiles were also performed. The antimicrobial susceptibility patterns showed that most of the derived strains were less sensitive to the antimicrobials, even after culturing them without drugs. Morphological and cell complexity alterations were observed, mainly in strains grown in SICs of beta-lactam; these strains also expressed a reduced ability for biofilm formation. The other strains showed an increase in biofilm formation but no apparent morphological changes. Alterations were observed in the carbohydrate metabolism patterns and in the activity of microbial enzymes. Several proteins were positively or negatively regulated and there was polymorphism in the DNA from all derived strains. Therefore, SICs of antimicrobials induce alterations in F. nucleatum, which directly impact its biology. These results emphasize the risk of inadequate antibioticotherapy, which may have serious implications for clinical microbiology and infectious diseases and also may interfere with the host-bacteria relationship. PMID- 23023264 TI - Probing and mapping electrode surfaces in solid oxide fuel cells. AB - Solid oxide fuel cells (SOFCs) are potentially the most efficient and cost effective solution to utilization of a wide variety of fuels beyond hydrogen (1 7). The performance of SOFCs and the rates of many chemical and energy transformation processes in energy storage and conversion devices in general are limited primarily by charge and mass transfer along electrode surfaces and across interfaces. Unfortunately, the mechanistic understanding of these processes is still lacking, due largely to the difficulty of characterizing these processes under in situ conditions. This knowledge gap is a chief obstacle to SOFC commercialization. The development of tools for probing and mapping surface chemistries relevant to electrode reactions is vital to unraveling the mechanisms of surface processes and to achieving rational design of new electrode materials for more efficient energy storage and conversion(2). Among the relatively few in situ surface analysis methods, Raman spectroscopy can be performed even with high temperatures and harsh atmospheres, making it ideal for characterizing chemical processes relevant to SOFC anode performance and degradation(8-12). It can also be used alongside electrochemical measurements, potentially allowing direct correlation of electrochemistry to surface chemistry in an operating cell. Proper in situ Raman mapping measurements would be useful for pin-pointing important anode reaction mechanisms because of its sensitivity to the relevant species, including anode performance degradation through carbon deposition(8, 10, 13, 14) ("coking") and sulfur poisoning(11, 15) and the manner in which surface modifications stave off this degradation(16). The current work demonstrates significant progress towards this capability. In addition, the family of scanning probe microscopy (SPM) techniques provides a special approach to interrogate the electrode surface with nanoscale resolution. Besides the surface topography that is routinely collected by AFM and STM, other properties such as local electronic states, ion diffusion coefficient and surface potential can also be investigated(17-22). In this work, electrochemical measurements, Raman spectroscopy, and SPM were used in conjunction with a novel test electrode platform that consists of a Ni mesh electrode embedded in an yttria-stabilized zirconia (YSZ) electrolyte. Cell performance testing and impedance spectroscopy under fuel containing H2S was characterized, and Raman mapping was used to further elucidate the nature of sulfur poisoning. In situ Raman monitoring was used to investigate coking behavior. Finally, atomic force microscopy (AFM) and electrostatic force microscopy (EFM) were used to further visualize carbon deposition on the nanoscale. From this research, we desire to produce a more complete picture of the SOFC anode. PMID- 23023265 TI - Bibliography--Editors' selection of current world literature. PMID- 23023266 TI - Synergistic effect of surface plasmon resonance and constructed hierarchical TiO2 spheres for dye-sensitized solar cells. AB - We demonstrate a strategy for incorporating plasmon resonant metallic nanoparticles in the construction of hierarchical TiO(2) spheres. Localized electric fields can be produced by the addition of Au nanoparticles, which can excite dye molecules more effectively than incident far-field light. The synergistic effect of surface plasmon resonance with constructed TiO(2) nanostructures has been investigated, and was confirmed by optical spectroscopy, J-V characteristics, EIS analysis and OCVD measurements. When Au nanoparticles are incorporated into the constructed TiO(2) spheres, the device achieves a power conversion efficiency of 6.62%, a 4.6% increase compared to the device based on constructed TiO(2) spheres without plasmon resonant Au nanoparticles, and a 17.4% increase compared to that without any treatment. PMID- 23023267 TI - Non-invasive diagnosis of focal liver lesions: an individualized approach. AB - Modern cross-sectional imaging with multidetector computed tomography (MDCT) or magnetic resonance imaging (MRI) often reveals small focal liver lesions, which puts pressure on the reporting radiologist to characterize these tiny lesions. On the other hand, in patients with underlying diffuse liver disease, such as cirrhosis or severe steatosis, the detection of focal liver lesions can be quite difficult. Strategies for optimal detection and characterization of focal liver lesions should be developed according to the clinical situation, the likelihood of malignant disease and the presence of underlying diffuse liver disease. The presence or absence of a clinical history of cancer determines the algorithm for further characterization: work-up with contrast-enhanced MRI, biopsy or follow up. In patients with chronic liver disease, recent guidelines on the detection of hepatocellular carcinoma (HCC) favour the use of multiphasic MRI or MDCT, which allows confident diagnoses of HCC >1 cm. For lesions <1 cm in chronic liver disease, follow-up is recommended. In patients with moderate to severe steatosis, contrast-enhanced MDCT has low diagnostic yield for the detection of liver lesions; contrast-enhanced MRI is far superior. This review describes successful strategies for the detection and characterization of focal liver lesions in different clinical scenarios. PMID- 23023269 TI - Long-lived charge separated states in nanostructured semiconductor photoelectrodes for the production of solar fuels. AB - The efficient use of sunlight to drive the production of solar fuels requires the photogeneration of suitably long-lived charge separated states capable of driving the multi-electron chemistry of fuel synthesis. Here we discuss a range of promising material design approaches to increasing charge carrier lifetimes, focusing upon semiconductor photoelectrodes for water photolysis and carbon dioxide reduction. Parallels are drawn between the strategies deployed in the development of such artificial systems and those found in natural photosynthesis. We address the use of a range of junctions, including electrolyte/semiconductor, semiconductor/semiconductor and dye sensitized interfaces to provide the spatial separation of charges. A key consideration of the review is the design of such interfaces to achieve a sufficient increase in charge carrier lifetime with a high quantum yield, whilst minimising the energy loss associated with this lifetime gain. PMID- 23023268 TI - National audit of the use of surgery and radiological embolization after failed endoscopic haemostasis for non-variceal upper gastrointestinal bleeding. AB - BACKGROUND: Following non-variceal upper gastrointestinal bleeding (NVUGIB), 10 15 per cent of patients experience further bleeding. Although surgery has been the traditional salvage therapy, there is renewed interest in transcatheter arterial embolization (TAE). This study examined the use, clinical characteristics and outcomes of patients receiving salvage surgery or TAE after failed endoscopic haemostasis for NVUGIB. METHODS: A UK national audit of upper gastrointestinal bleeding was undertaken in May and June 2007. A logistic regression model was used to identify clinical predictors of endoscopic failure. RESULTS: Data were analysed from 4478 patients involving 212 UK centres. Some 533 (11.9 per cent) experienced further bleeding, of whom 163 (30.6 per cent) proceeded to salvage therapy with surgery (97), TAE (60) or both (6). Among surgical patients (mean age 71 years), 66.0 per cent (68 of 103) had a Rockall score of at least 3 and emergency surgery was carried out between midnight and 08.00 hours in 21 per cent, with a consultant surgeon present in 89 per cent of operations. Some 9 per cent of patients had further bleeding after TAE, resulting in later surgery. The mortality rate was 29 per cent after surgery, 10 per cent after TAE and 23.2 per cent among those with further bleeding after the index endoscopy that was managed by endoscopy alone. The strongest predictors of endoscopic failure were coagulopathy (odds ratio 3.27, 95 per cent confidence interval 2.37 to 4.53) and a haemoglobin level of 10 g/dl or less (odds ratio 2.22, 1.71 to 2.87, for haemoglobin 8-10 g/dl). CONCLUSION: Salvage surgery and embolization are required in fewer than 4 per cent of patients with NVUGIB. The high postoperative mortality rate, reflecting age, co-morbidity and severity of bleeding, warrants a prospective study to establish the effectiveness and safety of TAE as an alternative to surgery in the management of bleeding after failure of endoscopic therapy. PMID- 23023271 TI - Advancing the science of delivery: public health services and systems research. PMID- 23023272 TI - Expanding delivery system research in public health settings: lessons from practice-based research networks. AB - BACKGROUND: Delivery system research to identify how best to organize, finance, and implement health improvement strategies has focused heavily on clinical practice settings, with relatively little attention paid to public health settings-where research is made more difficult by wide heterogeneity in settings and limited sources of existing data and measures. This study examines the approaches used by public health practice-based research networks (PBRNs) to expand delivery system research and evidence-based practice in public health settings. METHODS: Practice-based research networks employ quasi-experimental research designs, natural experiments, and mixed-method analytic techniques to evaluate how community partnerships, economic shocks, and policy changes impact delivery processes in public health settings. In addition, network analysis methods are used to assess patterns of interaction between practitioners and researchers within PBRNs to produce and apply research findings. RESULTS: Findings from individual PBRN studies elucidate the roles of information exchange, community resources, and leadership and decision-making structures in shaping implementation outcomes in public health delivery. Network analysis of PBRNs reveals broad engagement of both practitioners and researchers in scientific inquiry, with practitioners in the periphery of these networks reporting particularly large benefits from research participation. CONCLUSIONS: Public health PBRNs provide effective mechanisms for implementing delivery system research and engaging practitioners in the process. These networks also hold promise for accelerating the translation and application of research findings into public health settings. PMID- 23023273 TI - Public health law research: exploring law in public health systems. AB - The importance of law in the organization and operation of public health systems has long been a matter of interest to public health lawyers and practitioners, but empirical research on law as a factor in health system performance has been limited in quantity and sophistication. The emergence of Public Health Law Research and Public Health Systems and Services Research within a coordinated effort to strengthen public health research and practice has dramatically changed matters. This article introduces Public Health Law Research as an integral part of Public Health Systems and Services Research, discusses the challenges of integrating the 2 fields, and highlights 2 examples of current research that demonstrate the benefits of an integrated approach to improve the use of law in public health practice. PMID- 23023274 TI - Developing a taxonomy for the science of improvement in public health. AB - CONTEXT: Quality improvement (QI) methods have been used for almost a decade in public health departments to increase effectiveness and efficiency. Although results are rapidly accumulating, the evidence for the science of improvement is shallow and limited. To advance the use and effectiveness of QI in public health, it is important to develop a science of improvement using practice-based research to build an evidence base for QI projects. OBJECTIVES: This purpose of this study is to advance the science of improvement in public health departments with 3 objectives: (1) establish a taxonomy of QI projects in public health, (2) categorize QI projects undertaken in health departments using the taxonomy, and (3) create an opportunity modes and effects analysis. DESIGN: This study is a qualitative analysis of archival data from 2 separate large databases consisting of 51 QI projects undertaken in public health departments over the last 5 years. SETTING AND PARTICIPANTS: The study involves 2 separate QI collaboratives. One includes Minnesota health departments; the other is a national collaborative. MAIN OUTCOME MEASURES: We propose a standardized case definition, common metrics, and a taxonomy of QI projects to begin building the evidence base for QI in public health and to advance the science of continuous quality improvement. RESULTS: All projects created an aim statement and used metrics while 53% used a specific QI model with an average of 3.25 QI techniques per project. Approximately 40% of the projects incorporated a process control methodology, and 60% of the projects identified the process from beginning to end, while 11 of 12 PHAB (Public Health Accreditation Board) domains were included. CONCLUSIONS: The findings provide a baseline for QI taxonomy to operationalize a science of improvement for public health departments. PMID- 23023275 TI - Public health services and systems research: current state of finance research. AB - There is a growing recognition that the US public health system should strive for efficiency-that it should determine the optimal ways to utilize limited resources to improve and protect public health. The field of public health finance research is a critical part of efforts to understand the most efficient ways to use resources. This article discusses the current state of public health finance research through a review of public health finance literature, chronicles important lessons learned from public health finance research to date, discusses the challenges faced by those seeking to conduct financial research on the public health system, and discusses the role of public health finance research in relation to the broader endeavor of Public Health Services and Systems Research. PMID- 23023276 TI - Governance typology: a consensus classification of state-local health department relationships. AB - CONTEXT: Public health practitioners and researchers often refer to state public health systems as being centralized, decentralized, shared, or mixed. These categories refer to governance of the local public health units within the state and whether they operate under the authority of the state government, local government, shared state and local governance, or a mix of governance structures within the state. OBJECTIVE: This article describes the development of an objective method of classifying states as centralized, decentralized, shared, or mixed. We also discuss some initial analyses that have been conducted to identify how public health resources and activities vary across states with different classifications. DESIGN: Cross-sectional study. SETTING: State health agencies. PARTICIPANTS: Survey respondents were organizational leaders from all 50 state health agencies. MAIN OUTCOME MEASURE(S): Total full-time equivalent employees, total health agency expenditures, expenditures on clinical services, and provision of clinical services. RESULTS: Centralized state health agencies employ more full-time equivalent employees, have higher total expenditures, and provide more clinical services than decentralized state health agencies. Although higher expenditures on clinical services were observed, these differences were not statistically significant. CONCLUSIONS: It is important to take governance classification into account when investigating variation in services, resources, or performance of governmental public health systems. As public health systems and services researchers seek to identify best practices in the organization of public health systems, consistent definition of different types of organization is critical. This system provides an objective and reliable system for classifying governance relationships that allows for comparisons that are meaningful to both practitioners and researchers. PMID- 23023277 TI - Diffusion of practice-based research in local public health: what differentiates adopters from nonadopters? AB - OBJECTIVE: To examine the level of involvement by local health departments (LHDs) in practice-based research (PBR) activities, and determine factors associated with variation in such involvement. DESIGN: A total of 625 LHDs in a nationally representative stratified random sample of LHDs were administered questions about their participation in PBR activities along with the core instrument in the 2010 National Profile of Local Health Departments Study. Using the Profile data set, zero-inflated negative binomial regression is used to examine the relationships among the variables in the model. MAIN OUTCOME MEASURE: The dependent variable was a count variable about the number of PBR activities performed by LHDs. RESULTS: About 62% of LHDs participated in at least one research activity. Participating in research activities was significantly associated with the following characteristics of LHDs: serving a population of 500 000 to 999 999, local governance, having a full-time top executive, having heard of the county health rankings, and having performed a Community Health Assessment in the last 5 years. Of LHDs performing at least one research activity, only LHD jurisdiction size predicted the number of research activities in which LHDs participated. Among these LHDs, the range in participation was from about 12% of research plans developed by LHDs to 37% collected data. CONCLUSIONS AND IMPLICATIONS: Large public health agencies may be overrepresented, raising the risk that research results may not adequately address the needs, uncertainties, and innovations arising in smaller settings. Correcting this imbalance may require mechanisms for greater involvement of low-resource LHDs in PBR and expanded federal support for such activities through PBR networks. PMID- 23023278 TI - Defining organizational capacity for public health services and systems research. AB - More than a decade has passed since a conceptual framework was introduced to guide public health services and systems research (PHSSR) and elucidate the relationships associated with system performance. Since then, research has primarily focused on performance, standards, and key processes, with less emphasis on identification of measures or methods. Capacity lies at one end of the conceptual framework, although little emphasis has been placed on measuring and defining "capacity" of the public health system. This is striking, given organizational capacity is a critical determinant of performance and is necessary for understanding systematic effectiveness, sustainability, or generalizability. As a nascent field, PHSSR needs to develop a definition of organizational capacity and elucidate its relationship within a research framework. Evidence must be developed on the temporal and causal relationships between capacity, process/performance, and outcomes. The purpose of this article was to review research frameworks and capacity measures in various disciplines to expand the existing PHSSR conceptual framework. PMID- 23023279 TI - Measuring the authority of local public health directors in the context of organizational structure: an exploratory, multimodal approach. AB - CONTEXT: Studies have reported a relationship between the organization of public health services and variability in public health practice at the local and state levels. A national research agenda has prioritized practice-based research to understand pathways that lead to this variation and examine the impact of these differences on outcomes. OBJECTIVES: To measure the extent to which Minnesota local health directors report having key authorities and examine the relationship between organizational structure and authority of local health directors. DESIGN: : Multimodal. SETTING: Minnesota local health departments. PARTICIPANTS: Directors of Minnesota local health departments. MAIN OUTCOME MEASURE(S): Director authorities. RESULTS: Most Minnesota local health directors reported having 6 key authorities related to budget preparation and modification and interaction with local elected officials (n = 51, 71%). Twelve directors (16%) reported that they have 4 or fewer of the 6 authorities. The authority most commonly reported as lacking was the authority to initiate communication with locally elected officials (n = 15, 21%). The percentage of directors who reported having all 6 authorities was higher among those in stand-alone departments (82%) than those in combined organizations (50%). CONCLUSIONS: This descriptive study illustrates that emerging practice-based research networks can successfully collaborate on small-scale research projects with immediate application for systems development. Study findings are being used by local public health officials to help articulate their role, aid in succession planning, and inform elected officials, who need to consider the public health implications of potential changes to local public health governance and organization. More studies are needed to refine measurement of authority and structure. PMID- 23023280 TI - The extent of interorganizational resource sharing among local health departments: the association with organizational characteristics and institutional factors. AB - CONTEXT/OBJECTIVE: Resource sharing, arrangements between local health departments (LHDs) for joint programs or to share staff, is a growing occurrence. The post-9/11 influx of federal funding and new public health preparedness responsibilities dramatically increased the occurrence of these inter-LHD relationships, and several states have pursed more intrastate collaboration. This article describes the current state of resource sharing among LHDs and identifies the factors associated with resource sharing. DESIGN AND SETTING: Using the National Association of County & City Health Officials' 2010 Profile Survey, we determined the self-reported number of shared programmatic activities and the number of shared organizational functions for a sample of LHDs. Negative binomial regression models described the relationships between factors suggested by interorganizational theory and the counts of sharing activities. MAIN OUTCOME MEASURES: We examined the extent of resource sharing using 2 different count variables: (1) number of shared programmatic activities and (2) number of shared organizational functions. RESULTS: About one-half of all LHDs are engaged in resource sharing. The extent of sharing was lower for those serving larger populations, with city jurisdictions, or of larger size. Sharing was more extensive for state-governed LHDs, those covering multiple jurisdictions, states with centralized governance, and in instances of financial constraint. CONCLUSIONS: Many LHDs are engaged in a greater extent of resource sharing than others. Leaders of LHDs can work within the context of these factors to leverage resource sharing to meet their organizational needs. PMID- 23023281 TI - Health districts as quality improvement collaboratives and multijurisdictional entities. AB - CONTEXT: Local health departments are increasingly challenged to meet emerging health problems at the same time that they are being challenged with dwindling resources and the demands of accreditation. OBJECTIVE: To assess the capacity of Multicounty health districts to serve as "Quality Improvement Collaboratives" and support local health departments to meet accreditation standards. DESIGN: The study used an online survey tool and follow-up phone calls with key informants in health districts and county health departments in Georgia. Data collection was primarily based on an instrument to measure Quality Improvement Collaboratives that was adapted and tested for use with public health agencies in Georgia. SETTING: The Georgia PBRN conducted this study of health districts and county health departments. The Georgia Department of Public Health supports 18 health districts and 159 county health departments (GA DPH, 2011). The health districts range in county composition from 1 to 16 counties in each district. PARTICIPANTS: Key informants comprised district and county health department staff and county health department board members were identified by 13 participating health district offices. RESULTS: Key opinion leaders from both the rural and nonrural counties agreed that the Districts were important for providing essential services and supporting quality improvement collaboration. Psychometric testing of the Quality Improvement Collaborative assessment public health instrument yielded high scores for validity and reliability. CONCLUSIONS AND IMPLICATIONS: Regionalization of local public health capacity is a critical emerging issue for public health accreditation and quality improvement. This study demonstrated the utility of regionalization across traditional local geopolitical boundaries. PMID- 23023282 TI - Information-seeking behaviors and other factors contributing to successful implementation of evidence-based practices in local health departments. AB - The objective of this article was to describe factors that contribute to successful translation of science into evidence-based practices and their implementation in public health practice agencies, based on a review of the literature and evidence from a series of case studies. The case studies involved structured interviews with key informants in 4 health departments and with 4 corresponding partners from academic institutions. Interviews were recorded and transcribed, coded by 2 independent, trained coders, using a standard codebook. A thematic analysis of codes was conducted. Coding was entered into Atlas TI software for further analysis. Results from the literature review indicated that only approximately half of programs implemented in state and local health departments were evidence based. Lack of time, inadequate funding, and absence of cultural and managerial support-including incentives-are among the most commonly cited barriers to implementing evidence-based practices. Findings from the case studies suggest that these health departments, successful in implementing evidence-based practices, have strong relationships and good communication channels established with their academic partner(s). There is strong leadership engagement from within the health department and in the academic institution. Implementation of evidence-based programs was most often related to high priority community needs and the availability of resources to address these needs. The practice agencies operate with a culture of quality improvement throughout the agency. Information technology, training, how the interventions are bundled, including their complexity and ability to be customized and resource requirements are all fruitful avenues for further research. PMID- 23023283 TI - Assessing the roles of brokerage: an evaluation of a hospital-based Public Health epidemiologist program in North Carolina. AB - CONTEXT: The North Carolina Division of Public Health established an innovative program in 2003 that placed public health epidemiologists (PHEs) in hospitals around the state to improve communication between hospitals and local public health departments (LHDs) and bolster public health surveillance and response. OBJECTIVE: To use social network analysis to assess how the hospital-based PHE program in North Carolina facilitates the exchange of public health surveillance information. DESIGN: Using a Gould-Fernandez brokerage analysis, this study examines communication among organizational actors and their dependence on third parties to broker information and knowledge. PARTICIPANTS: Survey and interview data were collected to identify the interorganizational network among 220 organizational actors and their public health surveillance-related activities, including 11 PHEs, 100 county-level offices of North Carolina's 85 LHDs, and 109 hospitals. MAIN OUTCOME MEASURES: Social network analysis is used to calculate the frequency with which an actor serves as an intermediary in each of the 5 brokerage roles as well as total brokerage equal to the sum of the number of times an actor occupies each role. RESULTS: Results identify a frequent tendency for PHEs to serve as an intermediary between LHDs and hospitals. Interactions between these entities are frequently facilitated by PHEs, with a high measure of degree centrality by LHDs and a low frequency of brokerage among hospitals. CONCLUSIONS: Results validate PHEs' mission to enhance communication between LHDs and hospitals around communicable disease surveillance, reporting, and management. PMID- 23023284 TI - Structural and organizational characteristics associated with performance of essential public health services in small jurisdictions: findings from a statewide study in Massachusetts. AB - BACKGROUND: This study examined jurisdictional, organizational, and structural characteristics associated with capacity to deliver 10 essential public health services (EPHS) in Massachusetts, a state where a majority of local public health departments serve small municipalities. DESIGN: A survey was administered to local health directors or board of health chairs. MEASURES: The main outcome of the study was capacity to perform EPHS, measured by a 25-item screening tool. RESULTS: Seventy percent of the 351 boards of health in Massachusetts participated in the study. Greatest capacity was demonstrated in EPHS 2 (Diagnose and Investigate Health Problems) and EPHS 6 (Enforce Laws and Regulations). The capacity to perform the 8 other essential services was limited. Bivariate analysis indicates that overall capacity to perform EPHS is significantly associated with population size, poverty rate, annual municipal budget, and perceived understanding of the roles and responsibilities of local boards of health among elected municipal officials. The latter was the strongest predictor of overall capacity in multivariate analysis. CONCLUSIONS: Findings are aligned with studies examining factors associated with capacity to perform EPHS in large public health jurisdictions. The results suggest that one strategy for improving capacity to perform EPHS in smaller jurisdictions is to educate elected municipal leaders about the responsibilities of local health officials. Clarification regarding the role small jurisdictions with limited resources can play to ensure the equitable delivery of essential public health services and a strategy for measuring their contributions is important, especially as the national public health accreditation program gains momentum in the United States. PMID- 23023285 TI - Assessment of workforce capacity for Local Health Departments in Nebraska: a perspective from public health programmatic areas. AB - OBJECTIVE: This study assessed the workforce capacity of Nebraska Local Health Departments (LHDs) from the perspective of public health programmatic areas. DESIGN AND OUTCOMES MEASURES: We conducted a mail survey of 21 LHD directors in Nebraska and collected the information on LHD workforce capacity, training, and competency by public health programmatic areas (eg, environmental health, mental health). An FTE shortage index score for each public health programmatic area was calculated to estimate an LHD's current shortage in that area. Spearman correlation analysis was conducted to examine the relationships between LHD capacity, manpower shortage, and staff training and competency. RESULTS: Our results indicated that a significant proportion of the 18 responding LHDs in Nebraska did not have staff to cover the areas of mental health (66.7%), sexually transmitted diseases (44.4%), occupational safety and injury (38.9%), oral health (27.8%), and health disparities (22.2%). The results also suggest that Nebraska's LHDs experienced the greatest workforce shortages in environmental health (mean shortage index = 0.45), followed by chronic diseases (0.44), health disparities (0.41), and sexually transmitted diseases (0.41). CONCLUSIONS: The identified shortage areas should be a high priority for federal and state policy makers to address through developing appropriate strategies and providing adequate funding for LHD workforce development in Nebraska. Using the public health programmatic area approach to collect workforce data may help fill some gaps in the current efforts of LHD workforce enumeration. Future research is needed to examine the validity and reliability of the workforce measures based on public health programmatic areas. PMID- 23023286 TI - Topology of local health officials' advice networks: mind the gaps. AB - OBJECTIVE: To determine how a health officials' advice network might contribute to a high-performing public health systems by facilitating diffusion of innovation and best practices. DESIGN: A secondary analysis of cross-sectional data obtained from the National Association of County and City Health Officials 2010 Profile of local health departments (LHDs) using network analysis. SETTING: The Profile survey is distributed biannually to all 2565 LHDs in the United States. In 2010, it included a network question: "In thinking about your peers who lead other local health departments in the U.S., list the five LHDs whose leaders you communicate with most frequently about administrative, professional, and leadership issues in public health." PARTICIPANTS: The network question was answered only by the top executive. The subjects are 1522 health officials who answered the network question plus 477 named as contacts (n = 1999). MAIN OUTCOME MEASURES: Measurements to assess network topology were density, centralization, transitivity, and reciprocity. At the node level, average centrality, clustering, effective network size, and clique count were measured. The convergence of iterated correlations algorithm was used to detect subgroups. RESULTS: : A sparsely connected core periphery network exhibited minimal evidence of unified communication. Mutually connected small groups tend to clump within state boundaries suggesting gaps in information flow. The pattern persisted at the regional level with an average health official having an effective network of only 2 others. CONCLUSIONS: Communication between peers may not be the primary way professional information diffuses among local health officials. National groups involved in performance improvement may wish to consider strategies to increase the diffusion of best practices and innovations through this network. PMID- 23023287 TI - Composition and duties of local boards of health: findings from a 2011 national survey. AB - OBJECTIVE: To describe the composition and duties of local boards of health (LBOHs). DESIGN: An online and written survey was utilized for data collection. The survey included demographics, roles and responsibilities, orientation and training, and concerns and needs of LBOHs. SETTING: This article seeks to expand what limited information we have on the composition and duties of LBOHs as an important foundational step in analyzing the role of LBOHs in leveraging improved public health outcomes. PARTICIPANTS: In 2011, the mixed methods survey was sent to a random sample of 2420 LBOHs in the 41 states, which meet the definition of having LBOHs. MAIN OUTCOME MEASURE: The data represent responses from 353 LBOHs in 35 states. RESULTS: Elected officials appoint members of 68% of LBOHs. The average board consists of a 7-member, county-based LBOH made up primarily of males (60%) and whites (96%). Hispanics make up 9% of boards. The majority of LBOH chairs have a graduate degree but no formal education or experience in public health. Local boards of health report reviewing public health regulations as their most common power but list recommending the approval of the budget for the local health department as boards' most frequent activity in the past 3 years. CONCLUSIONS: LBOH members and chairs are more similar in demographics to the top executives at local health departments than the general population or the public health workforce. Most LBOH chairs, however, lack experience in public health, and a quarter or more of LBOHs do not use their powers to set or recommend health priorities as a mechanism to leverage better community health outcomes. PMID- 23023288 TI - Local health departments and specific maternal and child health expenditures: relationships between spending and need. AB - OBJECTIVE: As a part of the Public Health Activities and Service Tracking study and in collaboration with partners in 2 Public Health Practice-Based Research Network states, we examined relationships between local health department (LHD) maternal and child health (MCH) expenditures and local needs. DESIGN: We used a multivariate pooled time-series design to estimate ecologic associations between expenditures in 3 MCH-specific service areas and related measures of need from 2005 to 2010 while controlling for other factors. MEASURES: Retrospective expenditure data from LHDs and for 3 MCH services represented annual investments in (1) Special Supplemental Nutrition for Women, Infants, and Children (WIC), (2) family planning, and (3) a composite of Maternal, Infant, Child, and Adolescent (MICA) service. Expenditure data from all LHDs in Florida and Washington were then combined with "need" and control variables. STUDY POPULATION: Our sample consisted of the 102 LHDs in Florida and Washington and the county (or multicounty) jurisdictions they serve. RESULTS: Expenditures for WIC and for our composite of MICA services were strongly associated with need among LHDs in the sample states. For WIC, this association was positive, and for MICA services, this association was negative. Family planning expenditures were weakly associated, in a positive direction. CONCLUSIONS: Findings demonstrate wide variations across programs and LHDs in relation to need and may underscore differences in how programs are funded. Programs with financial disbursements based on guidelines that factor in local needs may be better able to provide service as local needs grow than programs with less needs-based funding allocations. PMID- 23023289 TI - Variability in practices for investigation, prevention, and control of communicable diseases among Washington State's Local health jurisdictions. AB - OBJECTIVE: To assess variability in investigation, prevention, and control of communicable diseases of public health significance among Washington State local health jurisdictions. DESIGN: Online survey conducted from December 2010 to January 2011. SETTING: Washington State local health jurisdictions. PARTICIPANTS: Local health officers in the 35 local health jurisdictions in Washington State. MAIN OUTCOME MEASURES: Variability across local health departments in public health case investigation practices, recommendations, and activities related to animal bites and potential rabies exposures, hepatitis C, meningitis, pertussis, foodborne illness complaints, tuberculosis, reportable animal diseases, provision of health education materials, and use of local disease investigation protocols in addition to statewide case reporting guidelines. RESULTS: We found differences in approaches to investigation of several notifiable diseases. The most pronounced variations were in investigation of hepatitis C cases and recommendations for rabies postexposure prophylaxis. We also found variability in follow-up of low-risk contacts of pertussis cases, testing for latent tuberculosis infection, organization of response to foodborne illness complaints and avian chlamydiosis, and use of zoonotic disease prevention materials. CONCLUSIONS: Washington State residents receive different public health advice and services for communicable disease issues depending on where they reside in the state. Unnecessary variation is undesirable and may undermine public confidence in the public health system. Additional research is needed to better understand reasons for these differences and to determine whether there are policy, funding, or programmatic changes that could address areas in need of standardization. PMID- 23023290 TI - Giving babies the chance they deserve. PMID- 23023291 TI - Hospitals and local health departments: rising to the occasion. PMID- 23023292 TI - More is not always better: adaptive gain control explains dissociation between perception and action. AB - Moving objects generate motion information at different scales, which are processed in the visual system with a bank of spatiotemporal frequency channels. It is not known how the brain pools this information to reconstruct object speed and whether this pooling is generic or adaptive; that is, dependent on the behavioral task. We used rich textured motion stimuli of varying bandwidths to decipher how the human visual motion system computes object speed in different behavioral contexts. We found that, although a simple visuomotor behavior such as short-latency ocular following responses takes advantage of the full distribution of motion signals, perceptual speed discrimination is impaired for stimuli with large bandwidths. Such opposite dependencies can be explained by an adaptive gain control mechanism in which the divisive normalization pool is adjusted to meet the different constraints of perception and action. PMID- 23023294 TI - Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization. AB - Cocaine-induced alterations in synaptic glutamate function in nucleus accumbens are thought to mediate drug-related behaviors such as psychomotor sensitization. However, previous studies have examined global alterations in randomly selected accumbens neurons regardless of their activation state during cocaine-induced behavior. We recently found that a minority of strongly activated Fos-expressing accumbens neurons are necessary for cocaine-induced psychomotor sensitization, whereas the majority of accumbens neurons are less directly involved. We assessed synaptic alterations in these strongly activated accumbens neurons in Fos-GFP mice, which express a fusion protein of Fos and GFP in strongly activated neurons, and compared these alterations with those in surrounding non-activated neurons. Cocaine sensitization produced higher levels of 'silent synapses', which contained functional NMDA receptors and nonfunctional AMPA receptors only in GFP positive neurons, 6-11 d after sensitization. Thus, distinct synaptic alterations are induced in the most strongly activated accumbens neurons that mediate psychomotor sensitization. PMID- 23023293 TI - Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. AB - FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP 43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate-containing motor neurons in sporadic ALS, supporting a common loss-of function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS. PMID- 23023295 TI - Structural and quantitative evidence for dynamic glycome shift on production of induced pluripotent stem cells. AB - We recently reported that induced pluripotent stem cells (iPSCs) prepared from different human origins acquired similar glycan profiles to one another as well as to human embryonic stem cells. Although the results strongly suggested attainment of specific glycan expressions associated with the acquisition of pluripotency, the detailed glycan structures remained to be elucidated. Here, we perform a quantitative glycome analysis targeting both N- and O-linked glycans derived from 201B7 human iPSCs and human dermal fibroblasts as undifferentiated and differentiated cells, respectively. Overall, the fractions of high mannose type N-linked glycans were significantly increased upon induction of pluripotency. Moreover, it became evident that the type of linkage of Sia on N linked glycans was dramatically changed from alpha-2-3 to alpha-2-6, and the expression of alpha-1-2 fucose and type 1 LacNAc structures became clearly apparent, while no such glycan epitopes were detected in fibroblasts. The expression profiles of relevant glycosyltransferase genes were fully consistent with these results. These observations indicate unambiguously the manifestation of a "glycome shift" upon conversion to iPSCs, which may not merely be the result of the initialization of gene expression, but could be involved in a more aggressive manner either in the acquisition or maintenance of the undifferentiated state of iPSCs. PMID- 23023297 TI - Landscape of somatic allelic imbalances and copy number alterations in human lung carcinoma. AB - Lung cancer is the worldwide leading cause of death from cancer and has been shown to be a heterogeneous disease at the genomic level. To delineate the genomic landscape of copy number alterations, amplifications, loss-of heterozygosity (LOH), tumor ploidy and copy-neutral allelic imbalance in lung cancer, microarray-based genomic profiles from 2,141 tumors and cell lines including adenocarcinomas (AC, n = 1,206), squamous cell carcinomas (SqCC, n = 467), large cell carcinomas (n = 37) and small cell lung carcinomas (SCLC, n = 88) were assembled from different repositories. Copy number alteration differences between lung cancer histologies were confirmed in 285 unrelated tumors analyzed by BAC array comparative genomic hybridization. Tumor ploidy patterns were validated by DNA flow cytometry analysis of 129 unrelated cases. Eighty-nine recurrent copy number alterations (55 gains, 34 losses) were identified harboring genes with gene expression putatively driven by gene dosage through integration with gene expression data for 496 cases. Thirteen and 26 of identified regions discriminated AC/SqCC and AC/SqCC/SCLC, respectively, while 48 regions harbored recurrent (n > 15) high-level amplifications comprising established and putative oncogenes, differing in frequency and coamplification patterns between histologies. Lung cancer histologies displayed differences in patterns/frequency of copy number alterations, genomic architecture, LOH, copy neutral allelic imbalance and tumor ploidy, with AC generally displaying less copy number alterations and allelic imbalance. Moreover, a strong association was demonstrated between different types of copy number alterations and allelic imbalances with tumor aneuploidy. In summary, these analyses provide a comprehensive overview of the landscape of genomic alterations in lung cancer, highlighting differences but also similarities between subgroups of the disease. PMID- 23023296 TI - Mass spectrometry-based proteomic analysis of the matrix microenvironment in pluripotent stem cell culture. AB - The cellular microenvironment comprises soluble factors, support cells, and components of the extracellular matrix (ECM) that combine to regulate cellular behavior. Pluripotent stem cells utilize interactions between support cells and soluble factors in the microenvironment to assist in the maintenance of self renewal and the process of differentiation. However, the ECM also plays a significant role in shaping the behavior of human pluripotent stem cells, including embryonic stem cells (hESCs) and induced pluripotent stem cells. Moreover, it has recently been observed that deposited factors in a hESC conditioned matrix have the potential to contribute to the reprogramming of metastatic melanoma cells. Therefore, the ECM component of the pluripotent stem cell microenvironment necessitates further analysis. In this study we first compared the self-renewal and differentiation properties of hESCs grown on MatrigelTM pre-conditioned by hESCs to those on unconditioned MatrigelTM. We determined that culture on conditioned MatrigelTM prevents differentiation when supportive growth factors are removed from the culture medium. To investigate and identify factors potentially responsible for this beneficial effect, we performed a defined SILAC MS-based proteomics screen of hESC-conditioned MatrigelTM. From this proteomics screen, we identified over 80 extracellular proteins in matrix conditioned by hESCs and induced pluripotent stem cells. These included matrix associated factors that participate in key stem cell pluripotency regulatory pathways, such as Nodal/Activin and canonical Wnt signaling. This work represents the first investigation of stem-cell-derived matrices from human pluripotent stem cells using a defined SILAC MS-based proteomics approach. PMID- 23023299 TI - Cognitive phenotype of mathematical learning disabilities: what can we learn from siblings? AB - The sensitivity of number sense as cognitive phenotype for mathematical learning disabilities (MLD) was assessed in siblings of children with MLD (n = 9) and age matched children without family members with MLD (n = 63). A number line estimation paradigm was used as a measure of children's early number sense. In line with the triple code model of Dehaene (1992), three different presentation formats were presented. The results of the study confirmed that number line estimation was related to early arithmetic achievement in kindergarten. In addition siblings were less proficient in number line placements compared to non siblings, with a larger effect size for symbolic and especially number word estimation compared to the non-symbolic results. Siblings also differed from non siblings on procedural and conceptual counting skills and logical thinking in kindergarten. Moreover MLD had a familial aggregation, since about three out of five sibling girls had clinical scores on an Early Numeracy Test in kindergarten, pointing to a risk to develop MLD themselves. Implications of the study to our understanding of MLD are discussed. PMID- 23023298 TI - microRNA-181a is associated with poor prognosis of colorectal cancer. AB - miRNAs regulate gene expression at the post-transcriptional level by degradation of mRNA and translational repression. Recent studies have shown that miR-181a is dysregulated in several types of cancer; however, the clinical significance of miR-181a in colorectal cancer (CRC) remains unclear. We addressed this question by using quantitative real-time PCR (qRT-PCR) to analyze miR-181a expression in 162 CRC patients. There was no significant difference in miR-181a expression in normal colon vs. colorectal cancer tissue. The cancer tissue samples were categorized into a low and high expression group based on miR-181a expression. Comparison of the clinicopathological factors and prognosis in these two groups showed that the high expression group had a significantly poorer prognosis than the low expression group (P=0.011). Multivariate analysis indicated that high miR 181a expression was an independent significant prognostic factor for CRC. However, there no correlation was observed between miR-181a expression and clinicopathological parameters. In vitro analysis revealed that the overexpression of miR-181a repressed the expression of the tumor suppressor, phosphatase and tensin homolog (PTEN) located on chromosome 10, at the mRNA level. These data suggest that miR-181a may be a new independent prognostic factor for CRC patients. PMID- 23023300 TI - Pre-school children with suspected autism spectrum disorders: do girls and boys have the same profiles? AB - The male to female ratio is raised in autism spectrum disorders (ASD). Previous studies have suggested that girls with ASD have more problems with communication than boys, but boys show more repetitive behaviours than girls. In this study, 20 girls, 1.8-3.9 years of age were matched for chronological and developmental age with 20 boys with suspected ASD. All the children were recruited after population screening and referral by Child Health Care Services to a specialised neuropsychiatry clinic, where they underwent comprehensive neuropsychiatric assessments. Comparisons were made with regard to diagnosis, developmental profiles and global disability. No significant gender differences were found. There were strong correlations between results obtained in different developmental areas. The results suggest that either (1) previous studies finding clear gender differences may have overrated discrepancies between girls and boys in ASD, or that (2) there may be girls, who will not be identified in the early years with our current screening instruments. More research with a much larger population representative study samples is required. PMID- 23023301 TI - The role of sustained attention and display medium in reading comprehension among adolescents with ADHD and without it. AB - Difficulties in reading comprehension are common in children and adolescents with Attention Deficit/Hyperactivity Disorder (ADHD). The current study aimed at investigating the relation between sustained attention and reading comprehension among adolescents with and without ADHD. Another goal was to examine the impact of two manipulations of the text on the efficiency of reading comprehension: Spacing (standard- vs. double-spacing) and Type of presentation (computer screen vs. hard copy). Reading comprehension of two groups of adolescents (participants with ADHD and normal controls) was assessed and compared in four different conditions (standard printed, spaced printed, standard on computer screen, spaced on computer screen). In addition, participants completed a visual sustained attention task. Significant differences in reading comprehension and in sustained attention were obtained between the two groups. Also, a significant correlation was obtained between sustained attention and reading comprehension. Moreover, a significant interaction was revealed between presentation-type, spacing and level of sustained attention on reading comprehension. Implications for reading intervention and the importance of early assessment of attention functioning are discussed. PMID- 23023302 TI - Angiotensin receptor blockers worsen renal function and dyspnea on ticagrelor: a potential ticagrelor-angiotensin receptor blocker interaction? AB - Ticagrelor is a new antiplatelet agent that was pitted against clopidogrel in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Because ticagrelor is the first oral, reversible, twice-daily agent, sufficient information on drug interactions is not available. Our objective was to ascertain the safety of ticagrelor with other common medications. The US Food and Drug Administration Complete Response Review indicates that renal adverse events (AEs) and renal function AEs were higher in ticagrelor-treated patients who were concomitantly treated with angiotensin receptor blockers (ARBs) >50% of study days compared to ticagrelor-treated patients who did not receive ARBs >50% of study days. Clopidogrel-treated patients showed a trend for an increase in adverse renal events with ARB use. However, this was not as pronounced as that observed with ticagrelor. Dyspnea was also significantly increased in patients on concomitant ticagrelor-ARB compared to ticagrelor without concomitant ARB and clopidogrel (21.4% vs 14.6% vs 9.9%, respectively) as well as angioedema (0.15% vs 0.09%). Furthermore, in patients with a baseline estimated glomerular filtration rate (eGFR) <30 mL/min, the risk of major bleeding, death, and renal failure was increased in patients on ticagrelor compared to patients on clopidogrel. In patients on ticagrelor, ARBs significantly increased the frequency of renal related AEs, renal function AEs, and dyspnea. Moreover, in patients with a baseline eGFR <30 mL/min, the risk of major bleeding, death, and renal failure was increased in patients on ticagrelor compared to patients on clopidogrel. PMID- 23023304 TI - Metal-free direct amination/aromatization of 2-cyclohexenones to iodo-N arylanilines and N-arylanilines promoted by iodine. AB - An iodine mediated aromatization leading to a one-pot synthesis of iodo-N arylanilines and N-arylanilines is reported. This highly regioselective aliphatic aromatic transformation can be performed with various combinations of 2 cyclohexenones and anilines. The presence of a directing group is crucial for achieving high yields. PMID- 23023303 TI - Cell type and context-specific function of PLAG1 for IGF2 P3 promoter activity. AB - The fetal transcription factor PLAG1 is found to be overexpressed in cancers, and has been suggested to bind the insulin like growth factor 2 (IGF2) P3 promoter, and to activate the IGF2 gene. The expression of IGF2 has partly been linked to loss of CTCF-dependent chromatin insulator function at the H19 imprinting control region (ICR). We investigated the role of PLAG1 for IGF2 regulation in Hep3B and JEG-3 cell lines. Chromatin immunoprecipitation revealed cell type-specific binding of PLAG1 to the IGF2 P3 promoter, which was substantially insensitive to recombinant PLAG1 overexpression in the endogenous context. We hypothesized that the H19 chromatin insulator may be involved in the cell type-specific PLAG1 response. By using a GFP reporter gene/insulator assay plasmid construct with and without the H19 ICR and/or an SV40 enhancer, we confirm that the effect of the insulator is specifically associated with the activity of the IGF2 P3 promoter in the GFP reporter system, and furthermore, that the reporter insulator is functional in JEG-3 but not in Hep3B cells. FACS analysis was used to assess the function of PLAG1 in low endogenously expressing, but Zn-inducible stable PLAG1 expressing JEG-3 cell clones. Considerable increase in IGF2 expression upon PLAG1 induction with a partial insulator overriding activity was found using the reporter constructs. This is in contrast to the effect of the endogenous IGF2 gene which was insensitive to PLAG1 expression in JEG-3, while modestly induced the already highly expressed IGF2 gene in Hep3B cells. We suggest that the PLAG1 binding to the IGF2 P3 promoter and IGF2 expression is cell type-specific, and that the PLAG1 transcription factor acts as a transcriptional facilitator that partially overrides the insulation by the H19 ICR. PMID- 23023305 TI - Perceptions of people living with HIV/AIDS. AB - BACKGROUND: HIV/AIDS being a behavioral disease, appropriate knowledge is important for those who are infected. OBJECTIVES: To elicit and compare knowledge and attitude about HIV/AIDS among newly diagnosed and previously diagnosed HIV/AIDS patients attending or admitted in Calcutta School of Tropical Medicine, (CSTM), Kolkata. MATERIALS AND METHODS: A cross-sectional descriptive study was undertaken among previously diagnosed HIV/AIDS Patients admitted in indoor wards and newly diagnosed HIV/AIDS patients attending Integrated Counseling and Testing Centre (ICTC) of the School of Tropical Medicine, Kolkata. Data were gathered by interviewing patients using a predesigned, pretested, semi-structured questionnaire. RESULTS: More in-patients had heard about AIDS than ICTC patients. Television was the most popular source of information in both groups, followed by health personnel and friends. Correct knowledge about transmission, symptoms, prevention of AIDS, and lifestyles desirable for affected patients was significantly higher among in-patients who had already been counseled, than the newly diagnosed ICTC patients yet to receive. Within each group of patients, the knowledge score was significantly higher among females, Christians, urban residents, patients educated beyond middle school, and non- migrants. In-patients had a significantly higher attitudinal score toward HIV/AIDS. CONCLUSION: Repeated counseling is required to keep up high level of knowledge and positive attitude pertaining to HIV/AIDS to reduce risk behavior, prevent disease transmission, and improve quality of life. PMID- 23023306 TI - The pre-hospital delay in seeking treatment in patients with acute myocardial infarction referring to a central hospital in Kashan, Iran. AB - INTRODUCTION: A cardiovascular disease, especially the acute myocardial infarction (AMI), is the most important health problem worldwide. Pre-hospital delay in seeking medical treatment is an effective factor on patients' outcomes. The aim of this study was to identify the patients' reactions to the signs and symptoms of AMI and identifying the factors contributing to the pre-hospital delay in a central hospital in Kashan, Iran. MATERIALS AND METHODS: In this cross sectional study, a random sample of 248 patients suffering from AMI was recruited. A questionnaire used, which contained demographic data, the time, and place of experiencing the symptoms, and the manner of responding to the initial symptoms. The SPSS software (version, 19 was used for data analysis. RESULT: 248 patients participated in the study, 183 (73.8%) were males and 65 (26.2%) were females. The mean delay time was 127 +/- 174 min. Moreover, 162 patients had arrived at the hospital during the first 60 min after the onset of the symptoms. The variables of being female (P = 0.024), low level of education (P = 0.014), living in urban area (P = 0.01) and referring to the hospital by one's own car instead of using ambulance were accompanied by more pre-hospital delay. 63 patients (25.4%) referred to the hospital by ambulance. CONCLUSION: Despite having only 25% of the patients referring to this center by ambulance, most patients arrived on time to the hospital. PMID- 23023307 TI - Modelling population growth on public water and sanitation facilities using GIS and statistics: a case study of Aboabo, Ghana. AB - BACKGROUND: Effect of population increase on public water and sanitation facilities in densely populated area, Aboabo, Kumasi, Ghana. MATERIALS AND METHODS: Town sheet maps, layout and population census data of Aboabo. GPS for observing spatial locations existing water and sanitation facilities and field verification exercise in the study. GIS for building geodatabase, digitization and Cartographic Visualization. Questionnaires were used to collect non-spatial information on the sanitation facilities and all public facilities. RESULTS: GIS and a Statistical Approach have been respectively used to develop cartographic and mathematical models to analyse, predict and visualize the effect of population increase on public water and sewage facilities in densely populated area. The developed mathematical models correlates with the population at each instance to the required number of water accessible points or standing pipes as well as the number of required public toilet (sewage) facilities. The cartographic and mathematical models provides an efficient and effective means of mitigating diseases associated with water and sanitation; and informs planners and assembly members of the effects of increasing population on public facilities for proper future planning and geospatial decision making; and to ensure proper infrastructural management at the community levels. CONCLUSIONS: Effective decision support systems for analysing, predicting and visualizing public water and sewage facilities in densely populated area. Draws the awareness of the government, concerned groups and non-Governmental Organizations (NGO's) to the extreme detrimental effect that the increase in population has, especially on public water and sewage facilities and how it can be managed at the community level. PMID- 23023308 TI - Efficacy of esmolol administration at different time intervals in attenuating hemodynamic response to tracheal intubation. AB - BACKGROUND: Laryngoscopy and endotracheal intubation are known to cause increase in both arterial blood pressure and heart rate. Several strategies have been evolved to blunt the haemodynamic response to tracheal intubation but each method has its own advantages and disadvantages. Esmolol, a cardio selective Beta-1 blocking drug, can alleviate some of these problems. Esmolol, when administered parenterally, exhibits rapid onset and a short duration of action due to its rapid clearance by red blood cell esterases. Hence we conducted the present study to evaluate the efficacy and optimum time of single bolus esmolol administration in attenuating hypertensive- tachycardiac response to laryngoscopy and tracheal intubation. MATERIALS AND METHODS: The randomized double blind prospective study was conducted in 60 patients, in the age group of 20-40 years, of both sexes, belonging to American Society of Anaesthesiologists (ASA) physical status class I or II and scheduled for elective surgery requiring endotracheal intubation and general anaesthesia. The efficacy and optimum time of single bolus esmolol administration in attenuating hypertensive - tachycardiac response to laryngoscopy and tracheal intubation was evaluated. Patients in group I (n = 20) received bolus administration of injection esmolol 1.5 mg/kg intravenously (iv) 90 seconds before intubation; in group II (n = 20) three minutes before intubation and in group III (n = 20) six minutes before intubation. RESULTS: There was no clinical and statistically significant variation in heart rate in group I and II at different time intervals of the study period but in group III heart rate increased significantly one minute after tracheal intubation. (P < 0.05) One minute after intubation, the increase in systolic, diastolic and mean blood pressure and rate pressure product was statistically significant in group I (P < 0.01) and group III. (P < 0.05) However, in group II increase in systolic blood pressure and rate pressure product was statistically not significant. (P > 0.05) CONCLUSION: To conclude, single intravenous bolus dose of esmolol (1.5 mg/kg) is safe and more effective in attenuating haemodynamic response to laryngoscopy and tracheal intubation when administered three minutes prior to intubation. PMID- 23023309 TI - Can protein carbonyl/glutathione ratio be used as a potential biomarker to assess oxidative stress in alcoholic hepatitis? AB - CONTEXT: Oxidative stress plays a crucial role in the pathogenesis of alcoholic liver disease (ALD). AIM: The present study was undertaken to evaluate the significance of protein carbonyl/glutathione ratio as a biomarker to assess the oxidative stress in alcoholic hepatitis. SETTINGS AND DESIGN: The study included 30 patients with alcoholic hepatitis and 30 age-sex- matched controls. Protein carbonyl (PCO) levels was estimated by modified levine's method, malondialdehyde (MDA) by thiobarbituric acid method, reduced glutathione (GSH) by dithiobis-2 nitrobenzoic acid method, total sialic acid (TSA) by modified aminoff's method, plasma transferases (GGT, AST, and ALT), total protein and albumin using commercial kits adapted to autoanalyzer respectively. STATISTICAL ANALYSIS USED: All data were expressed as mean +/- SEM. Spearman's correlation analysis and receiver operating characteristic curve were performed using SPSS version 16 for Microsoft. A P value < 0.05 was considered as significant. RESULTS: Alcoholic hepatitis patients showed significantly higher levels of PCO, MDA, GGT, AST, AST/ALT, TSA, and significantly lower GSH, total protein and albumin levels. PCO/GSH ratio in these patients showed a significant positive correlation with GGT (r = 0.594, P = 0.000), AST/ALT (r = 0.443 P = 0.000), MDA (r = 0.727, P = 0.000), TSA (r = 0.729, P = 0.000), and a significant negative correlation with total protein (r = -0.683, P = 0.000) and albumin (r = -0.544, P = 0.000). ROC curve showed a cut off value of 2.735, indicating 100% sensitivity and 90% specificity of PCO/GSH at this value. CONCLUSIONS: Alcohol intake regularly for long duration leads to oxidative stress. We suggest that PCO/GSH ratio can be used as a potential biomarker to assess oxidative stress in alcoholic hepatitis. PMID- 23023310 TI - Establishing an optimal "cutoff" threshold for diagnostic lumbar facet blocks: a prospective correlational study. AB - OBJECTIVES: Diagnostic medial branch blocks (MBB) are considered the reference standard for diagnosing facetogenic pain and selecting patients for radiofrequency (RF) denervation. Great controversy exists regarding the ideal cutoff for designating a block as positive. The purpose of this study is to determine the optimal pain relief threshold for selecting patients for RF denervation after diagnostic MBB. METHODS: In this multicenter, prospective correlational study, 61 consecutive patients undergoing lumbar facet RF denervation after experiencing significant pain relief after MBB were enrolled. A positive outcome was defined as a >=50% reduction in back pain at rest or with activity coupled with a positive satisfaction score lasting longer than 3 months. The relationship between pain relief after the blocks and denervation outcomes was evaluated by pairwise correlation matrix, receiver's operating characteristic curve, and stratifying outcomes based on 10- and 17-percentage point intervals for MBB. RESULTS: There were no significant differences in RF outcomes based on any MBB pain relief cutoff over 50%. A trend was noted whereby those patients who obtained <50% pain relief reported poorer outcomes. No optimal threshold for designating a diagnostic block as positive, above 50% pain relief, could be calculated. CONCLUSION: Employing more stringent selection criteria for lumbar facet RF is likely to result in withholding a beneficial procedure from a substantial number of patients, without improving success rates. PMID- 23023311 TI - [Dental care in pregnancy. Ten questions and answers]. AB - Dental care of pregnant patients is a demanding task. On one hand, clinicians are facing patients with an altered physiology that may cause a greater need for treatment. On the other hand, pregnancy in itself as well as the unborn child involves potential contraindications to dental interventions. It is therefore essential that dentists be knowledgeable of the ramifications pregnancy has on medical findings and therapy. Also, clinicians must be able to conduct their treatment based on well-grounded data to avoid any harm to the pregnant woman and her unborn child. This article focuses on facts specifically relevant to clinicians. Based on most current scientific data, we aim to answer the following ten questions: 1. What are the physiological changes during pregnancy? 2. What is the adequate lying position for a pregnant patient? 3. Is there a pregnancy related gingivitis? 4. What is the association between periodontitis, pregnancy and preterm birth? 5. Are there oral manifestations of pregnancy-related therapies? 6. Are caries and erosions inevitable during pregnancy? 7. Should the intake of fluoride be advocated? 8. Is it permissible to x-ray pregnant patients? 9. Is orthodontics contraindicated during pregnancy and 10. Which medication should be administered with caution? PMID- 23023312 TI - Kruppel-like factor 8 is a novel androgen receptor co-activator in human prostate cancer. AB - AIM: Kruppel-like factor 8 (KLF8) plays important roles in cell cycle and oncogenic transformation. On other hand, androgen receptor (AR) is crucial in development of both androgen-dependent and independent prostatic malignancies. The aim of this study is to investigate the role of KLF8 in prostate cancer (PCa) and the relationship between KLF8 and AR. METHODS: Eight human PCa cell lines, including androgen-dependent LNCap cells and androgen-independent 22Rv1 cells, as well as human PCa samples were studied. LNCap cells and 22Rv1 cells were transfected with plasmids encoding full-length wild-type KLF8 or KLF8 shRNA. The expression of KLF8 protein was detected using Western blotting or immunohistochemical staining. Cell proliferation in vitro was measured with MTT assay, and in vivo in a xenograft nude mouse model. Yeast two-hybrid screening, co-immunoprecipitation and pull down assays were used to examine the binding of KLF8 to AR. Luciferase reporter gene assay was used to measure the transcriptional activity of the genes targeted by AR. RESULTS: In 133 human PCa samples, KLF8 protein staining was observed in 92.65% (63/68) of high-grade PCa, 66.15% (43/65) of low-grade PCa, and 6.82% (3/44) of adjacent normal tissues. The expression of KLF8 was significantly associated with poorer overall survival. Overexpression of KLF8 enhanced the proliferation of both LNCap and 22Rv1 cells, while knockdown of endogenous KLF8 suppressed the proliferation. These manipulations exerted similar effects on the tumor volumes in the xenograft nude mouse model. Yeast two-hybrid screening revealed that KLF8 was a novel AR interacting protein. With pull down assay and co-immunoprecipitation assay, we demonstrated that KLF8 bound directly to AR, and KLF8 enhanced AR target gene transcription. CONCLUSION: The results demonstrate that KLF8 is a novel AR transcriptional co-activator that is overexpressed in PCa and may play a role in progression of hormone-refractory PCa. PMID- 23023313 TI - Taxol-induced growth arrest and apoptosis is associated with the upregulation of the Cdk inhibitor, p21WAF1/CIP1, in human breast cancer cells. AB - The anticancer agent, taxol, stabilizes tubulin polymerization, resulting in arrest at the G2/M phase of the cell cycle and apoptotic cell death. However, the molecular mechanism of this growth inhibition and apoptosis is poorly understood. In this study, we used MCF-7 and MDA-MB-231 human breast carcinoma cells which have different estrogen receptor (ER) and tumor suppressor p53 statuses to examine the mechanisms of taxol-induced growth inhibition and apoptosis. Treatment of the cells with taxol resulted in a time-dependent inhibition of cell viability, which was accompanied by an accumulation of cells at G2/M and the sub G1 apoptotic region, determined by flow cytometric analysis. Furthermore, chromatin condensation, DNA ladder formation and proteolytic cleavage of poly(ADP ribose) polymerase (PARP) in both cell lines were observed following treatment with taxol, indicating the occurrence of apoptotic cell death. Western blot analysis using whole cell lysates from MCF-7 and MDA-MB-231 cells treated with taxol demonstrated that taxol treatment inhibited expression of cyclin A and cyclin B1 proteins in a time-dependent manner. The inhibitory effects of taxol on cell growth and apoptosis induced by taxol were also associated with the downregulation of Wee1 kinase expression and a marked induction in the activity of the cyclin-dependent kinase inhibitor, p21WAF/CIP1. Furthermore, taxol elevated p21 promoter activity in both cell lines. These findings suggest that taxol-induced G2/M arrest and apoptosis in human breast carcinoma cells is mediated through the ER- and p53-independent upregulation of p21. PMID- 23023314 TI - Gold nanocluster-catalyzed selective oxidation of sulfide to sulfoxide. AB - Thiolate-protected gold nanoclusters are explored for catalytic application in the selective oxidation of sulfide to sulfoxide by PhIO. The TiO(2)-supported Au(25)(SR)(18) nanocluster catalysts give rise to high catalytic activity (e.g.~97% conv. of Ph-S-CH(3) and ~92% selectivity for Ph-S(=O)-CH(3) sulfoxide) and show excellent recyclability in the sulfoxidation process. PMID- 23023316 TI - Measuring the validity and reliability of ergonomic checklists. AB - OBJECTIVE: Ergonomic practitioners commonly use observational assessment tools, also known as checklists, to identify job hazards with regard to musculoskeletal disorders. However, it is often difficult to determine how effective such checklists are at identifying jobs in which workers are at risk, which complicates resource allocation. A means of dynamically assessing validity is needed. METHOD: This paper focuses on a simple technique with which practitioners can assess the probability that a positive checklist indication accurately identifies an at-risk job. The technique can also be used to study the effect of changes to the checklist and determine whether or not they improve the practical utility of the checklist. Similarly, by manipulating the role of different risk factors assessed on the checklist, it may guide hypotheses as to the relative importance of the risk factors. Finally, the paper briefly suggests the use of control charts to assess and manage inter- and intra-rater reliability rather than more traditional assessment methods such as correlations, Cohen's and Fleiss' kappa. CONCLUSION: The probability that a checklist correctly identifies jobs with regard to risk of musculoskeletal injury is a useful means of assessing the checklist's validity. PMID- 23023317 TI - Knowledge transfer with children and adolescents in promoting comfort, health, and safety in technology use: Strategies and opportunities. AB - OBJECTIVE: This article presents a review of the current literature on knowledge transfer in the use of technology, amongst children and adolescents. PARTICIPANTS: Researchers, teachers, children, adolescents, and related stakeholders are the targeted users of this paper. METHODS: A scoping review and detailed analysis of the review based on ergonomic outcomes of comfort, safety and productivity. RESULTS: The review revealed very few studies addressing the knowledge use and transfer with children or adolescents in this topic area. Current literature on knowledge transfer requires more rigorous evaluation, as well as use of explicit health, occupational and ergonomic outcomes. CONCLUSIONS: This paper concludes the need for a call for future research in the area of knowledge transfer to promote healthy and safe use of technology, in the population of children and adolescents. PMID- 23023319 TI - Exploring the relationships between the use of text message language and the literacy skills of dyslexic and normal students. AB - It is apparent that individuals using text abbreviations as a written convention is a continuingly growing phenomenon. This special writing convention has been referred to as textism usage. However, there is surprisingly little research investigating the impacts of textism use on dyslexic children's cognitive abilities associated with literacy skills. Thus, the relation between textism use, phonological awareness, as well as morphological awareness is not yet clear. This issue is critical and urgent because no conclusive guidance is available for practitioners or educators to refine instructional strategies. Furthermore, given that prior researchers focus mainly on alphabetic language, little research draws attention on non-alphabetic language, in which morphological awareness seems rather significant than phonological awareness. In this study a total of 57 participants across six elementary schools in Taiwan were recruited and were formed into three groups. To effectively collect the textisms used by the participants, this study adopted Facebook as the tool to store the messages because of its high penetration rate of 51 percent in Taiwan. Findings of this study suggested that dyslexic children may get rid of the identification, which might encourage them shift their focuses from others' judgment to selecting a proper textism. To use the textism appropriately requires the dyslexic children realize the meaning of the textism and memorize the spelling/writing convention. Consequently, the dyslexia group in this study performed as well as reading-age group in word recognition and meaning recognition. It seemed that dyslexic children preferred to use contraction, symbol, and combined word. These categories of textism are L-S (logography to semantics) in nature. PMID- 23023318 TI - That liver lesion on MDCT in the oncology patient: is it important? AB - Multidetector-row computed tomography (MDCT) has become the primary imaging test for the staging and follow-up of most malignancies that originate outside of the central nervous system. Technical advances in this imaging technique have led to significant improvement in the detection of metastatic disease to the liver. An unintended by-product of this improving diagnostic acumen is the discovery of incidental hepatic lesions in oncology patients that in the past remained undetected. These ubiquitous, incidentally identified hepatic lesions have created a management dilemma for both clinicians and radiologists: are these lesions benign or do they represent metastases? Naturally, the answer to this question has profound prognostic and therapeutic implications. In this review, guidelines concerning the diagnosis and management of some of the more common hepatic incidental lesions detected in patients with extrahepatic malignancies are presented. PMID- 23023320 TI - A chiral probe for the acute phase proteins alpha-1-acid glycoprotein and alpha-1 antitrypsin based on europium luminescence. AB - Reversible and selective binding of a dynamically racemic europium(III) complex to alpha(1)-acid glycoprotein and alpha(1)-antitrypsin is characterised by a significant change in the europium total emission spectral fingerprint and the switching on of a large circularly polarised luminescence (CPL) signal from the metal centre. Observation of an induced CD into the ligand chromophore in the presence of alpha(1)-AGP allows a structure for the protein-bound complex to be postulated. A direct determination of elevated alpha(1)-AGP levels in human serum was achieved by monitoring changes in the intensity ratio of Eu emission bands. PMID- 23023321 TI - In situ formation of beta-glycosyl imidinium triflate from participating thioglycosyl donors: elaboration to disarmed-armed iterative glycosylation. AB - beta-Glycosyl imidinium triflate is generated from participating thioglycoside donors for disarmed-armed iterative glycosylations and one-pot oligosaccharide synthesis. PMID- 23023323 TI - Resolution recovery in planar bone scans: diagnostic value in metastatic disease. AB - Recovery of spatial resolution lost through increasing lesion-to-detector distance can improve the spatial resolution of planar images. We compare two commercial solutions, HiScan (http://www.scivis.de) and Xact.bone (http://www.ultraspect.com), with unprocessed planar whole-body bone scans. Thirty-five patients with suspected bone metastases were scanned 3 h after injection of 600 MBq (99m)Tc-HMDP at 12 cm/min. Two patients with more than 20 lesions were used for reporter training and were excluded from the analysis. Two blinded reporters categorized each scan as benign, indeterminate or malignant and assigned individual lesions to those same categories. Image quality was first graded on a 1 (worst) to 10 (best) scale for each individual scan, and then all three scans of each patient were ranked according to image quality. Reporter A detected 65, 90 and 83 malignant lesions with the unprocessed scan, HiScan and Xact.bone and 23, 24 and 17 indeterminate lesions, respectively. Reporter B detected 60, 80 and 75 malignant lesions with the unprocessed scan, HiScan and Xact.bone and 17, 16 and 14 indeterminate lesions, respectively. To summarize, reporters A/B detected 38/33% and 28/25% more malignant lesions with HiScan and Xact.bone than with the unprocessed scan, respectively (Friedman's test, P<0.05). The number of indeterminate lesions did not increase, but the percentage of unclear lesions decreased. Mean image quality for the unprocessed scan, HiScan and Xact.bone was 6.5, 9.1 and 7.9 for reporter A and 5.6, 7.5 and 6.7 for reporter B, respectively (P<0.0001). HiScan was ranked best for image quality in 82% of patients and Xact.bone in 18%. Resolution recovery in planar whole-body bone scans significantly increases the absolute number of detectable malignant lesions, decreases the percentage of indeterminate lesions, significantly increases image quality and is an easy-to-implement addition to routine clinical practice. PMID- 23023322 TI - Assessing professional equipoise and views about a future clinical trial of invasive urodynamics prior to surgery for stress urinary incontinence in women: a survey within a mixed methods feasibility study. AB - AIMS: To determine surgeons' views on invasive urodynamic testing (IUT) prior to surgery for stress (SUI) or stress predominant mixed urinary incontinence (MUI). METHODS: Members of British Society of Urogynaecology (BSUG) and British Association of Urological Surgeons Section of Female, Neurological and Urodynamic Urology (BAUS-SFNUU) were sent an email invitation to complete an online "SurveyMonkey(r)" questionnaire regarding their current use of IUT prior to surgical treatment of SUI, their view about the necessity for IUT in various clinical scenarios, and their willingness to randomize patients into a future trial of IUT. A purposive sample of respondents was invited for telephone interview to explore further how they use IUT to inform clinical decisions, and to contextualize questionnaire responses. RESULTS: There were 176/517 (34%) responses, 106/332 (32%) from gynecologists/urogynecologists and 67/185 (36%) from urologists; all respondents had access to IUT, and 89% currently arrange IUT for most women with SUI or stress predominant MUI. For a variety of scenarios with increasingly complex symptoms the level of individual equipoise ("undecided" about IUT) was very low (1-6%) and community equipoise was, at best, 66:34 (IUT "essential" vs. "unnecessary") even for the simplest scenario. Nevertheless, 70% rated the research question underlying the proposed studies "very important" or "extremely important;" 60% recorded a "willingness to randomize" score >=8/10. CONCLUSIONS: Most urogynecologists and urologists consider IUT essential before surgery in SUI with or without other symptoms. Most however recognize the need for further research, and indicated a willingness to recruit into multicenter trials addressing this question. PMID- 23023324 TI - Analysis of SRC oncogenic signaling in colorectal cancer by stable isotope labeling with heavy amino acids in mouse xenografts. AB - The non-receptor tyrosine kinase SRC is frequently deregulated in human colorectal cancer (CRC), and SRC increased activity has been associated with poor clinical outcomes. In nude mice engrafted with human CRC cells, SRC over expression favors tumor growth and is accompanied by a robust increase in tyrosine phosphorylation in tumor cells. How SRC contributes to this tumorigenic process is largely unknown. We analyzed SRC oncogenic signaling in these tumors by means of a novel quantitative proteomic analysis. This method is based on stable isotope labeling with amino acids of xenograft tumors by the addition of [(13)C(6)]-lysine into mouse food. An incorporation level greater than 88% was obtained in xenograft tumors after 30 days of the heavy lysine diet. Quantitative phosphoproteomic analysis of these tumors allowed the identification of 61 proteins that exhibited a significant increase in tyrosine phosphorylation and/or association with tyrosine phosphorylated proteins upon SRC expression. These mainly included molecules implicated in vesicular trafficking and signaling and RNA binding proteins. Most of these proteins were specific targets of SRC signaling in vivo, as they were not identified by analysis via stable isotope labeling by amino acids in cell culture (SILAC) of the same CRC cells in culture. This suggests that oncogenic signaling induced by SRC in tumors significantly differs from that induced by SRC in cell culture. We next confirmed this notion experimentally with the example of the vesicular trafficking protein and SRC substrate TOM1L1. We found that whereas TOM1L1 depletion only slightly affected SRC-induced proliferation of CRC cells in vitro, it drastically decreased tumor growth in xenografted nude mice. We thus concluded that this vesicular trafficking protein plays an important role in SRC-induced tumor growth. Overall, these data show that SILAC analysis in mouse xenografts is a valuable approach for deciphering tyrosine kinase oncogenic signaling in vivo. PMID- 23023325 TI - The effect of G-CSF on F-actin reorganization in HL-60 and K562 cell lines. AB - The aim of this investigation was to show the influence of G-CSF (G-CSF) on the F actin cytoskeleton and the morphology of G-CSFR-proficient HL-60 and G-CSFR deficient K562 cell lines. In the present study, we show changes in F-actin distribution in HL-60 cells after treatment with 5 and 10 ng/ml concentration of G-CSF but also changes in the organization and fluorescence intensity of F-actin in the K562 cell line. After treatment of HL-60 cells with 5 ng/ml concentration of G-CSF we observed an increase in F-actin levels. Additionally, a higher labeling of nuclear F-actin under TEM was observed. Moreover, changes in the cell cycle indicate cell differentiation. On the other hand, in the K562 cell line we observed an increase in the percentage sub-G1 cells following treatment with both concentration of G-CSF. Furthermore, an increase in the percentage of late apoptotic cells after G-CSF treatment was observed. A statistically significant difference in the cytoplasmic F-actin levels was not detected, but nuclear levels were decreased. In conclusion, we suggest that the G-CSF-based reorganization of actin filaments in HL-60 cells is involved in the differentiation process. Moreover, we suggest that the G-CSF-induced changes observed in K562 cells are associated with a G-CSF receptor-independent pathway or its binding to other similar receptors. PMID- 23023326 TI - Involvement of the Src-cortactin pathway in migration induced by IGF-1 and EGF in human breast cancer cells. AB - Cancer cells need to become motile in order to escape the primary tumor and move to distant areas to form metastasis. They move as single cells or as a group, following different stimuli, including growth factors. Among them, insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF) and their receptors have been implicated in the development and progression of human breast carcinoma. In this report, we provide evidence that the tyrosine kinase Src is responsible for migration promoted by both IGF-1 and EGF in MDA-MB-231 and MCF7 cells, although with a different effect. Moreover, both IGF-1 and EGF induce reorganization of actin cytoskeleton in lamellipodia and membrane ruffles in a time- and Src-dependent manner. Furthermore, we analyzed the tyrosine phosphorylation status of the actin-binding protein cortactin upon growth factor stimulation, showing that even the activation of cortactin is time- and Src dependent. In addition, immunofluorescence analysis with anti-paxillin antibody reveals that, after treatment with growth factors, tyrosine phosphorylated cortactin is localized on the plasma membrane in correspondence of focal adhesions. Collectively, our findings suggest a crucial role for Src-mediated activation of cortactin in cell migration, reorganization of actin cytoskeleton and phosphotyrosine cortactin localization to the focal adhesions in human breast cancer cell lines upon both IGF-1 and EGF stimulation. PMID- 23023327 TI - Sleep disturbance at altitude. AB - PURPOSE OF REVIEW: The aim is to describe the impact of altitude upon sleep, the physiology that underpins these changes and the therapeutic solutions that are currently in place. RECENT FINDINGS: On ascending to altitude, lowland residents commonly experience some degree of sleep disturbance. Occasionally, this can prove very uncomfortable and impact upon daytime activities. Historically, the underlying cause of sleep disturbance was thought to be due to the effect of periodic breathing. However, recent research has shown that the link between periodic breathing, lighter stages of sleep and arousals is far from convincing. Instead, it appears that hypoxia has a far wider effect upon sleep at altitude than was previously thought. A number of new approaches to the treatment of sleep disturbance at altitude have recently been identified. Whereas some treat the underlying hypoxia through pharmacological or technological means, others seek to address the symptoms of sleep disturbance more directly. SUMMARY: Many of the current approaches to treating sleep disturbance at altitude have been shown to be well tolerated and successful, although few comparisons have been made. Future research is likely to focus upon matching the safest and most successful approach to the individual and their environment. PMID- 23023329 TI - Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4. AB - Prostate cancer risk-associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk-associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 * 10(-14)) and 19q13.4 (rs103294, P = 5.34 * 10(-16)) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 * 10(-4)). These findings may advance the understanding of genetic susceptibility to prostate cancer. PMID- 23023330 TI - Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa. AB - A highly invasive form of non-typhoidal Salmonella (iNTS) disease has recently been documented in many countries in sub-Saharan Africa. The most common Salmonella enterica serovar causing this disease is Typhimurium (Salmonella Typhimurium). We applied whole-genome sequence-based phylogenetic methods to define the population structure of sub-Saharan African invasive Salmonella Typhimurium isolates and compared these to global Salmonella Typhimurium populations. Notably, the vast majority of sub-Saharan invasive Salmonella Typhimurium isolates fell within two closely related, highly clustered phylogenetic lineages that we estimate emerged independently ~52 and ~35 years ago in close temporal association with the current HIV pandemic. Clonal replacement of isolates from lineage I by those from lineage II was potentially influenced by the use of chloramphenicol for the treatment of iNTS disease. Our analysis suggests that iNTS disease is in part an epidemic in sub-Saharan Africa caused by highly related Salmonella Typhimurium lineages that may have occupied new niches associated with a compromised human population and antibiotic treatment. PMID- 23023331 TI - Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. AB - Sensorineural hearing loss is genetically heterogeneous. Here, we report that mutations in CIB2, which encodes a calcium- and integrin-binding protein, are associated with nonsyndromic deafness (DFNB48) and Usher syndrome type 1J (USH1J). One mutation in CIB2 is a prevalent cause of deafness DFNB48 in Pakistan; other CIB2 mutations contribute to deafness elsewhere in the world. In mice, CIB2 is localized to the mechanosensory stereocilia of inner ear hair cells and to retinal photoreceptor and pigmented epithelium cells. Consistent with molecular modeling predictions of calcium binding, CIB2 significantly decreased the ATP-induced calcium responses in heterologous cells, whereas mutations in deafness DFNB48 altered CIB2 effects on calcium responses. Furthermore, in zebrafish and Drosophila melanogaster, CIB2 is essential for the function and proper development of hair cells and retinal photoreceptor cells. We also show that CIB2 is a new member of the vertebrate Usher interactome. PMID- 23023334 TI - Identifying the intermolecular hydrogen-bonding supramolecular synthons in an indomethacin-nicotinamide cocrystal by solid-state NMR. AB - Two-dimensional (1)H double-quantum and (14)N-(1)H & (1)H-(13)C heteronuclear magic-angle spinning (MAS) NMR spectra recorded at natural isotopic abundance identify specific intermolecular COOH...N(arom) and CH(arom)...O=C hydrogen bonding interactions in the solid-state structure of an indomethacin-nicotinamide cocrystal, thus additionally proving cocrystal formation. PMID- 23023333 TI - CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. AB - Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex but is also suggested to localize to the nuclear matrix and regulate chromatin structure. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) and reduced cerebral cortical size (microcephaly). CHMP1A-mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation. Chromatin immunoprecipitation suggests loss of the normal INK4A repression by BMI in these cells. Morpholino-based knockdown of zebrafish chmp1a resulted in brain defects resembling those seen after bmi1a and bmi1b knockdown, which were partially rescued by INK4A ortholog knockdown, further supporting links between CHMP1A and BMI1-mediated regulation of INK4A. Our results suggest that CHMP1A serves as a critical link between cytoplasmic signals and BMI1-mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells. PMID- 23023332 TI - Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. AB - Elevated transforming growth factor (TGF)-beta signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF beta signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-beta in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-beta activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-beta signaling cascades and higher expression of TGF-beta-responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-beta signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm. PMID- 23023335 TI - On the 'classification' of neurodegenerative disorders: discrete entities, overlap or continuum? AB - The traditional method of classifying neurodegenerative diseases is based on the original clinico-pathological concept supported by 'consensus' criteria and data from molecular pathological studies. This review discusses first, current problems in classification resulting from the coexistence of different classificatory schemes, the presence of disease heterogeneity and multiple pathologies, the use of 'signature' brain lesions in diagnosis, and the existence of pathological processes common to different diseases. Second, three models of neurodegenerative disease are proposed: (1) that distinct diseases exist ('discrete' model), (2) that relatively distinct diseases exist but exhibit overlapping features ('overlap' model), and (3) that distinct diseases do not exist and neurodegenerative disease is a 'continuum' in which there is continuous variation in clinical/pathological features from one case to another ('continuum' model). Third, to distinguish between models, the distribution of the most important molecular 'signature' lesions across the different diseases is reviewed. Such lesions often have poor 'fidelity', i.e., they are not unique to individual disorders but are distributed across many diseases consistent with the overlap or continuum models. Fourth, the question of whether the current classificatory system should be rejected is considered and three alternatives are proposed, viz., objective classification, classification for convenience (a 'dissection'), or analysis as a continuum. PMID- 23023336 TI - Oxidative stress--assassin behind the ischemic stroke. AB - Ischemic stroke is the second leading cause of death and disability worldwide and is associated with significant clinical and socioeconomic implications, emphasizing the need for effective therapies. Several neuroprotective strategies have failed in clinical trials because of poor knowledge of the molecular processes flanked with ischemic stroke. Therefore, uncovering the molecular processes involved in ischemic brain injury is of critical importance. Therapeutic strategies for ischemic stroke remain ineffective, though rapid advances occur in understanding the pathophysiology of the disease. The oxidative stress is one such high-potential phenomenon, the precise role of which needs to be understood during ischemic events. Nevertheless, the studies carried out in preclinical models of ischemic stroke have pointed to the major role of oxidative stress in exacerbating the ischemic injury. Oxidative stress leading to cell death requires generation of free radicals through multiple mechanisms, such as respiratory inhibition, Ca(2+) imbalance, excitotoxicity, reperfusion injury and inflammation. Free radicals are highly reactive to all the molecular targets: lipids, proteins and nucleic acids, modifying their chemical structure and generating oxidation-derived products. This review discusses molecular aspects of oxidative stress in ischemic stroke and catastrophes that set up as an aftermath of the trauma. PMID- 23023337 TI - Sepsis and septic encephalopathy: characteristics and experimental models. AB - The inflammation is a response of the organism to damaging factors and leads to the limitation of the tissue destruction. During the inflammatory process, there is stimulation of the immune system as well as other tissue cells. However, sometimes this reaction is excessive and can bring to the sepsis and development of multiorgan insufficiency. Phenomena observed during sepsis influence also, directly or indirectly on the nervous system and cause septic encephalopathy (SE) with consciousness and cognitive functions loss and other neurological symptoms. Often it can lead to persistent brain injuries, and almost always cause changes, which can be manifested later, even many years after the sepsis. It is supposed that in many cases, septic encephalopathy can be the main reason of death during sepsis. Still increasing concern of SE brought to the development of several animal models of this syndrome, which made possible detailed recognition of phenomena accompanying of septic encephalopathy. They include direct administration of endotoxins, or surgical intervention within the abdominal cavity. Every presented experimental model has advantages and weakness, but they make possible the modeling of the inflammatory reaction and multidirectional examining of accompanying phenomena. PMID- 23023338 TI - Size frequency distributions of beta-amyloid (Abeta) deposits: a comparative study of four neurodegenerative disorders. AB - Deposition of beta-amyloid (Abeta), a 'signature' pathological lesion of Alzheimer's disease (AD), is also characteristic of Down's syndrome (DS), and has been observed in dementia with Lewy bodies (DLB) and corticobasal degeneration (CBD). To determine whether the growth of Abeta deposits was similar in these disorders, the size frequency distributions of the diffuse ('pre-amyloid'), primitive ('neuritic'), and classic ('dense-cored') A beta deposits were compared in AD, DS, DLB, and CBD. All size distributions had essentially the same shape, i.e., they were unimodal and positively skewed. Mean size of Abeta deposits, however, varied between disorders. Mean diameters of the diffuse, primitive, and classic deposits were greatest in DS, DS and CBD, and DS, respectively, while the smallest deposits, on average, were recorded in DLB. Although the shape of the frequency distributions was approximately log-normal, the model underestimated the frequency of smaller deposits and overestimated the frequency of larger deposits in all disorders. A 'power-law' model fitted the size distributions of the primitive deposits in AD, DS, and DLB, and the diffuse deposits in AD. The data suggest: (1) similarities in size distributions of Abeta deposits among disorders, (2) growth of deposits varies with subtype and disorder, (3) different factors are involved in the growth of the diffuse/primitive and classic deposits, and (4) log-normal and power-law models do not completely account for the size frequency distributions. PMID- 23023339 TI - Morphological and quantitative analysis of cerebellar cortical cells in Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative amyloid disease, although a great deal of research has been done, its aetiology is still unknown. In Khachaturian's hypothesis on the involvement of calcium in the aetiology of Alzheimer's disease, particular attention is paid to the disorder of calcium metabolism. Ludo van Bogaert, describing AD, has drawn attention to the presence of a multi-system damage to the brain and described four forms of the disease, including two cerebellar types: cerebellar-pyramidal and cerebellar. The aim of our study was to analyze the expression of calcium-binding proteins (calbindin, calretinin, parvalbumin) in cortical neurons of the cerebellum in patients diagnosed with Alzheimer's disease (experimental group) and in a control group (patients without Alzheimer's disease). We performed the quantitative analysis of the density of Purkinje cells and Bergmann glial cells in the cerebellar cortex. We observed weak immunoreaction with a calretinin antibody in Lugaro cells, and with parvalbumin in Purkinje cells in the experimental group. A weaker expression of calcium-binding proteins in the experimental group may indicate the disturbance of the transport and buffering of intracellular Ca(2+) levels. The quantitative analysis showed that the density of Bergmann glial cells was higher in the experimental group. Our study suggests the disturbance of calcium metabolism in Alzheimer's disease. PMID- 23023340 TI - Dendritic and spinal alterations of the spiny stellate cells of the human visual cortex during normal aging. AB - The visual cortex undergoes age related changes that have been studied mainly in rats Maccaca Mulata, and human beings. Despite the fact that there is no extensive neuronal loss in aged brains, a lot of important pathological changes are found in the morphology of the neurons. The present study describes the morphological alterations of the spiny stel-late cells of the human primary visual cortex during normal aging, using Golgi method, Golgi-Nissl staining and Nissl staining. Two types of spiny stellate cells have been studied. the first one located at layer 4Cbeta and the second one located at layer 4Cbeta. Even if some spiny stel-late cells retain high number of primary dendrites in the aged group there seems to be important spine loss, and extensive dendrite pathology. Age-related changes were more significant in spiny stellate cells of layer 4Cbeta. Dendritic and spinal alterations described in the present study could explain the decline in visual functions during normal aging. PMID- 23023341 TI - Protective effect of paeoniflorin against glutamate-induced neurotoxicity in PC12 cells via Bcl-2/Bax signal pathway. AB - Paeoniflorin (PF), a monoterpene glycoside isolated from the aqueous extract of Radix Paeoniae Alba, is widely used in Traditional Chinese Medicine (TCM) for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we investigated the protective mechanism of PF on glutamate-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. PC12 cells were cultured in vitro, cell viability was assessed by MTT assay, cell apoptosis as well as mitochondrial membrane potential (MMP) were detected by flow cytometric analysis and the expression profiles of apoptosis related proteins including Bcl-2 and Bax were investigated by western blot. The results showed that PF could protect PC12 cells against glutamate-induced injury in a concentration-dependent manner and the mechanism of neuroprotective effect of PF was closely associated with up-regulation of Bcl-2 and down-regulation of Bax. It demonstrated that PF has neuroprotective effect on glutamate-induced apoptosis in PC12 cells via regulating mitochondrial membrane potential and Bcl 2/ Bax signal pathway. PMID- 23023342 TI - Expression of genes FOLR1, BAG1 and LAPTM4B in functioning and non-functioning pituitary adenomas. AB - INTRODUCTION: The mechanism of pathogenesis of adenomas pituitary is still unknown; differences between pituitary cells of different origin are observed. Identification of genes specific to pituitary adenomas should give better understanding of differences in their response to therapy, especially to radiotherapy. The aim of our study was to independently validate differences in the expression of FOLR1, BAG1, LAPTM4B between functioning (FA) and non functioning (NFA) pituitary adenomas reported by microarray-based studies. MATERIAL AND METHODS: Analysis of gene expression was performed by real-time quantitative PCR (QPCR) in 76 pituitary adenomas, 25 functioning and 51 non functioning ones. The expression of the examined genes was normalized to the reference index, obtained by calculation of the geometric mean of reference genes expression: GUS-B, B2M, ACTB, EIF3S10, UBE2D2 and ATP6V1E. RESULTS: Two genes showed significant differences in expression between non-functioning adenomas and functioning ones (FA) (FOLR1 32.4 x greater p = 0.022, BAG1 2.2 x lower p = 0.0002). The expression of LAPTM4B (1.1 x lower) was only insignificantly changed. The expression of FOLR1 in all tumours (functioning and non-functioning) was higher in older patients (over 50 years of age) (p = 0.018). Expression of BAG1 was significantly lower in older patients (p = 0.015). In a subgroup of pure non-functioning adenomas there was a higher expression of FOLR1 in older patients (p = 0.006). Analysis of expression profiles and invasiveness of tumours did not reveal any significant differences both in non-functioning and functioning tumours. CONCLUSIONS: Among pituitary adenomas, the highest level of expression FOLR1 is seen in NFA which are negative by immunohistochemistry to all pituitary hormones while GH-producing adenomas are the only class of pituitary tumours where FOLR1 expression is virtually absent. For BAG1 we confirm a significantly higher expression in functioning (both PRL and GH producing) adenomas than non functioning ones, while LAPTM4B does not exhibit any expression changes between different classes of pituitary tumours. PMID- 23023343 TI - Abscess of cauda equina presenting as lumboischialgic pain: a case report. AB - Spinal intradural abscess is an uncommon form of pathology carrying poor prognosis, unless treated immediately. We report a case of a patient treated for intense lower back pain and neurological symptoms of foot paresis simulating a herniated lumbar disc. It was evident after image diagnostic procedure and surgery that an intradural abscess of cauda equina was the cause. PMID- 23023344 TI - Primary angiitis of the central nervous system: 2 atypical cases. AB - The presence of an angiitis process in the central nervous system (CNS) characterizes different groups of conditions: from idiopathic pachymeningitis to lymphoproliferative disorders. In absence of specific infections, inflammatory and neoplastic diseases, the term "PACNS" (Primary Angiitis of the CNS) was proposed to indicate a peculiar vascular inflammation of unknown origin of meningeal vessels extending to the brain or spinal cord parenchyma. We report two cases of PACNS with peculiar and atypical features: the first one with a possible Epstein Barr Virus (EBV) relationship, the second one with spinal cord involvement only, treated surgically. We also hypothesize a correlation between EBV chronic infection and possible subtypes of PACNS stressing the importance of EBER (EBV-encoded RNA) test in the routine examination of brain biopsies suspicious for PACNS. PMID- 23023345 TI - Sm@C2v(3)-C80: site-hopping motion of endohedral Sm atom and metal-induced effect on redox profile. AB - A new metallofullerene Sm@C(2v)(3)-C(80) was synthesized and characterized. X-Ray analysis showed that the endohedral Sm atom undergoes a hopping motion between several off-center sites, even at low temperature. In addition, a comparative electrochemical study between Sm@C(2v)(3)-C(80) and Yb@C(2v)(3)-C(80) revealed their different redox potentials, suggesting a metal-induced effect on their redox profiles. PMID- 23023347 TI - Effects of acute organophosphate ingestion on cognitive function, assessed with the mini mental state examination. AB - BACKGROUND: Chronic damage to the central nervous system resulting in cognitive impairment has been shown with repeated, low doses of organophosphorus (OP) exposure over month or years. AIM: The study aimed to find out whether there is any cognitive impairment following acute OP exposure that could be detected by a simple screening instrument, the Mini Mental State Examination (MMSE), in clinical settings. SETTINGS AND DESIGN: A cohort study. MATERIALS AND METHODS: The study was conducted with matched controls. Consecutive patients admitted to the hospital with acute ingestion of OP were recruited. Cognitive function was assessed with the MMSE, digit span test, test of long-term memory function and concentration. Patients were assessed twice: at 1 and 6 weeks of exposure. STATISTICAL ANALYSIS: Continuous variables were analyzed with the paired and unpaired T-tests. Non-normally distributed data were analyzed with the Mann Whitney U test and Wilcoxon Signed Rank test. Discrete variables were analyzed with the Chi-square test. RESULTS: There were 60 patients and 61 controls. The mean age (SD) of the patients and controls was 31.5 (11.6) and 31.3 (11.8) years, respectively. Forty-two patients turned up for the second assessment. Significant impairment of cognitive function was seen in the total score of MMSE (95% CI -2.5 to -0.3), orientation (95% CI -1 to -0.2) and language (95% CI -0.9 to -0.1) domains of MMSE, digit span test (95% CI 0.1-1.7) and test of long-term memory function (95% CI 0.3-2.3) in the first assessment compared with the controls. When the results of the second assessment were compared with the controls, no significant differences were seen. CONCLUSION: Although there was a slight transient cognitive impairment detected with the screening tests following acute OP ingestion, no long-term cognitive defects was detected. PMID- 23023348 TI - Reliability of absolute lymphocyte count as a marker to assess the need to initiate antiretroviral therapy in HIV-infected children. AB - BACKGROUND: CD4 counts are a standard laboratory measure of disease progression in HIV-infected children. However, CD4 counting is done by flow cytometry and may not always be possible in every centre treating HIV-infected children in resource limited countries. Absolute Lymphocyte Count (ALC) can be derived easily by performing a routine white blood cell count. The World Health Organization (WHO) in 2006 had recommended ALC to identify HIV-infected children in need of ART in resource-limited settings, when CD4 cell count is not available. AIMS: This study aims to assess the reliability of using ALC as a marker for starting antiretroviral therapy (ART) in HIV-infected children in a tertiary hospital setting. SETTINGS AND DESIGN: Retrospective analysis of 46 HIV-infected children who presented at a pediatric HIV clinic at a tertiary referral centre from 2002 2005. MATERIALS AND METHODS: Using WHO 2006 guidelines for cutoff values of ALC and 2008 guidelines for CD4% as a comparative standard, a retrospective analysis was done on ART-naomicronve HIV-infected children who underwent baseline CD4% and ALC, and sensitivity and specificity of ALC was calculated. STATISTICAL ANALYSIS: Fischer exact two-tailed analysis was used to correlate ALC and CD4 and need for starting ART. RESULTS: Sensitivity of ALC was 27.6% (72.4% were false negatives), specificity was 70.6%, with positive predictive value of 61.5%. On comparison across all clinical stages of disease, only 13/46 children (28.2%) would have been started on ART according to ALC cutoffs versus 29/46 children (63.04%) using CD4 criteria (P value=0.0015). In children with WHO clinical Stage 1 or 2 of disease, only 1/11 (9.1%) children were identified by ALC as requiring ART as opposed to 6/11 (54.5%) children by CD4% (P=0.0635). CONCLUSIONS: ALC is an unreliable marker to determine the need for starting ART in HIV-infected children. PMID- 23023350 TI - Trends of anti-tuberculosis drug resistance pattern in new cases and previously treated cases of extrapulmonary tuberculosis cases in referral hospitals in northern India. AB - BACKGROUND: Drug-resistant tuberculosis is one of major current challenges to global public health. The transmission of resistant strains is increasing as a burden of multidrug-resistant tuberculosis (MDR-TB) patients in extra pulmonary tuberculosis (EPTB) cases in India. AIM AND OBJECTIVES: The aim was to study trends of anti-tuberculosis drug resistance pattern in new cases and previously treated cases of EPTB in referral hospitals in northern India. STUDY DESIGN AND SETTING: A prospectively observational study and referral medical institutions in northern India. MATERIALS AND METHODS: All EPTB specimens were processed for Ziehl Neelsen staining, BACTEC culture and BACTEC NAP test for Mycobacterium tuberculosis complex. All M. tuberculosis complex isolates were performed for radiometric-based drug susceptibility pattern against streptomycin, isoniazid, rifampicin and ethambutol using the 1% proportion method. RESULTS: We found that 165/756 (20.5%) isolates were identified as M. tuberculosis complex by the NAP test. We observed that 39.9% were resistant to first-line antitubercular drugs. The resistance rate was higher in previously treated patients: H (30.3%), R (16.3%), E (15.7%) and S (16.3%). MDR-TB was observed in 13.4%, but, in new cases, this was 11.4% and 19.1% of the previously treated patients (P<0.05). CONCLUSION: MDR-TB is gradually increased in EPTB cases and predominant resistance to previous treated cases of EPTB. The molecular drug sensitivity test (DST) method can be an early decision for chemotherapy in MDR-TB patients. The International Standards of TB Care need to be used by the RNTCP and professional medical associations as a tool to improve TB care in the country. PMID- 23023349 TI - Testing urine samples with rK39 strip as the simplest non-invasive field diagnosis for visceral leishmaniasis: an early report from eastern India. AB - BACKGROUND: Diagnosis of visceral leishmaniasis (VL) is a major obstacle in the control of this disease. The rK39 strip-test using patient's blood is a breakthrough; however, it still requires a blood sample, which is a concern for safety in the field. We tried to simplify the test using the patient's urine instead of blood. AIMS: To observe the sensitivity and specificity of the urine test in comparison with the blood test. MATERIALS AND METHODS: We tested active and post-treatment VL patients, Post Kala azar dermal leishmaniasis (PKDL), VL/HIV and control subjects (healthy, disease suspects and diseased other than VL) with the rK39 strip-test using blood and urine samples. STATISTICAL ANALYSIS: The level of agreement between the urine and blood testing was calculated by inter-rater agreement (kappa) statistics. RESULTS: Forty-two active VL, 40 treated VL, six PKDL, three VL/HIV and 139 controls (54 healthy, 21 disease suspects and 64 diseased other than VL) were tested. All VL-related cases showed positive results with urine as well as blood samples (100%). The urine testing was found to have 100% sensitivity and 86.33% specificity for the diagnosis of VL. Kappa statistic between the two methods was 0.916 (P<0.001). Urine testing had more false-positive results in comparison with blood testing (13.67% vs. 9.45%), but the test subjects were from VL-endemic areas and they might be exposed to Leishmania donovani infection. CONCLUSIONS: The present study has the potentiality of providing a new, yet simplest non-invasive screening tool for VL in remote rural areas. PMID- 23023351 TI - Does follistatin gene have any direct role in the manifestation of polycystic ovary syndrome in Indian women? AB - BACKGROUND: Out of a panel of 37 candidate genes tested for linkage with polycystic ovary syndrome (PCOS), the strongest evidence of linkage was reported in the follistatin (FST) gene region. Subsequently, a couple of studies outside India investigated the FST gene for the presence of any mutations and its association with PCOS and the results were found to be largely inconsistent probably due to differences in the ethnic backgrounds and small sample sizes. AIMS: To screen the FST gene for mutations and to establish their association pattern with PCOS among a large cohort of South Indian women. SETTINGS AND DESIGN: Case-control study. MATERIALS AND METHODS: PCOS cases were recruited according to the 2003 Rotterdam diagnostic criteria. All the exons of the FST gene were amplified and analyzed in all the cases and controls for the presence of mutations using polymerase chain reaction (PCR) and direct DNA sequencing. RESULTS: A total of 549 women consisting of 250 PCOS cases and 299 controls were recruited for the study. No mutations were found in any of the exons of the FST gene in our Indian sample which is consistent with an earlier finding among the Asian women from Singapore. Although three of the four cohorts of Caucasian background studied earlier reported variants, none of them could establish a strong association with PCOS. CONCLUSIONS: The occurrence of the exonic variants of FST gene seems to be dependent on the ethnic background of the subjects under study and its role in the PCOS pathophysiology cannot be established with hitherto available evidence. PMID- 23023352 TI - The utility of repeat enzyme immunoassay testing for the diagnosis of Clostridium difficile infection: a systematic review of the literature. AB - Over the last 20 years, the prevalence of healthcare-associated Clostridium difficile (C. diff) disease has increased. While multiple tests are available for the diagnosis of C. diff infection, enzyme immunoassay (EIA) testing for toxin is the most used. Repeat EIA testing, although of limited utility, is common in medical practice. To assess the utility of repeat EIA testing to diagnose C. diff infections. Systematic literature review. Eligible studies performed >1 EIA test for C. diff toxin and were published in English. Electronic searches of MEDLINE and EMBASE were performed and bibliographies of review articles and conference abstracts were hand searched. Of 805 citations identified, 32 were reviewed in detail and nine were included in the final review. All studies except one were retrospective chart reviews. Seven studies had data on number of participants (32,526), and the overall reporting of test setting and patient characteristics was poor. The prevalence of C. diff infection ranged from 9.1% to 18.5%. The yield of the first EIA test ranged from 8.4% to 16.6%, dropping to 1.5-4.7% with a second test. The utility of repeat testing was evident in outbreak settings, where the yield of repeat testing was 5%. Repeat C. diff testing for hospitalized patients has low clinical utility and may be considered in outbreak settings or when the pre-test probability of disease is high. Future studies should aim to identify patients with a likelihood of disease and determine the utility of repeat testing compared with empiric treatment. PMID- 23023353 TI - Forskolin: upcoming antiglaucoma molecule. AB - Forskolin is the first pharmaceutical drug and product derived from a plant to be approved in India by the DCGI in 2006. Forskolin (7beta-acetoxy-8, 13-epoxy-1a, 6beta, 9a-trihydroxy-labd-14-en-11-one) is a diterpenoid isolated from plant Coleus forskohlii (Lamiaceae). It is a lipid-soluble compound that can penetrate cell membranes and stimulates the enzyme adenylate cyclase which, in turn, stimulates ciliary epithelium to activate cyclic adenosine monophosphate, which decreases intraocular pressure (IOP) by reducing aqueous humor inflow. The topical application of forskolin is capable of reducing IOP in rabbits, monkeys, and humans. In its drug interactions, forskolin may act synergistically with epinephrine, ephedrine and pseudoephedrine. Whereas the effects of anti-clotting medications like warfarin, clopidogre, aspirin, anoxaparin, etc., may be enhanced by forskolin. Forskolin is contraindicated in the medications for people with ulcers as forskolin may increase acid level. Forskolin has a very good shelf-life of five years. Recently, its Ophthalmic inserts and in situ gels for sustained and delayed-release drug delivery systems were tested in New Zealand Albino Rabbits for its antiglaucoma efficacy. This drug review explains Forskolin as a drug, its antiglaucoma potential and recent findings of forskolin as an antiglaucoma agent. The literature search method used for this review was different databases and search engines like PubMed, International Pharmaceutical Abstracts, Google, Medicinal and Aromatic Plants (MAPA). PMID- 23023354 TI - Abiraterone acetate: a novel drug for castration-resistant prostate carcinoma. AB - Androgen-deprivation therapy is the mainstay of treatment for the management of advanced prostate carcinoma till transition to castration-resistant prostate carcinoma (CRPC). Recently, adrenal and intratumoral synthesis of androgens has been found to be the major cause for CRPC. Abiraterone acetate is an orally active, potent and selective inhibitor of 17 a hydroxylase and c 17, 20 lyase, which acts by decreasing the de novo production of androgens with no rise in steroids downstream. Multiple randomized trials have shown significant improvement of >50% decline in prostate-specific antigen (PSA) and time to PSA progression (TTPP) with abiraterone acetate 1000 mg per day in chemotherapy/ketoconazole treated and naive CRPC patients producing reversible and manageable adverse effects due to mineralocorticoid excess. This article reviews the available evidence on efficacy and safety of this drug in CRPC. Searches of Pubmed, Cochrane database, Medscape, Google and clinicaltrial.org were made for terms like CRPC and abiraterone. PMID- 23023355 TI - Hidradenitis suppurativa in a HIV-infected child. AB - Hidradenitis suppurativa (HS), a painful and chronic condition, commonly occurs in women and coincides with post-pubertal increase in sex hormones. A 13-year-old pre-pubertal HIV-infected male child presented to our clinic with a discharging right axillary lymph node swelling. The biopsy of the lesion showed features of HS. The patient was treated with oral antibiotics, oral steroids, and local antibiotic wash. Though the patient responded to this treatment, the clinical response was not adequate and the lesion recurred. Subsequently, the child was started on antiretroviral therapy (zidovudine, lamivudine, and nevirapine). Following these medications, the lesions healed and had not recurred till we last examined the child. Thus, this is a rare presentation of a known condition in an HIV-infected pre-pubertal male child, which did not respond to usual modalities of treatment and had to be treated with antiretroviral therapy. PMID- 23023356 TI - Steatocystoma multiplex--an uncommon lesion with special emphasis on cytological features and cyto-histological correlation. PMID- 23023357 TI - A rare clinical association of high rising epiglottis and short neck. PMID- 23023358 TI - Lung cavities in an infant: could it be tuberculosis? PMID- 23023359 TI - Hydatid disease mimicking urinary tract infection. PMID- 23023360 TI - Female with rash, acute kidney failure and rheumatoid arthritis. AB - This case describes a 42-year-old female with longstanding history of rheumatoid arthritis (RA) and Felty syndrome (FS). She presented with acute renal kidney failure, skin rash and hemoptysis. A clinical suspicion of small vessel vasculitis (SVV) was thought, serology was also positive for various markers of SVV. However, these serology markers could be false-positive in a patient of rheumatoid arthritis. A renal biopsy was performed that led to the final diagnosis of cryoglobulinemic vasculitis. Patient was managed according to the standard guidelines for therapy (plasmafiltration and immunosuppression). It is challenging to manage a patient of RA, in the presence of Felty syndrome-related granulocytopenia and thrombocytopenia. Patient initially showed signs of improvement, but finally succumbed to complications of therapy. The case provides insight into the diagnosis and management of such cases. PMID- 23023361 TI - Mysterious bruises. AB - A 69-year-old man presented with multiple spontaneous bruises in the past 2 weeks. Several large-sized hematomas were found on examination. The initial investigation revealed a prolonged activated partial thromboplastin time (aPTT) with normal platelet count and international normalized ratio. Further investigation revealed a low factor VIII activity secondary to presence of factor VIII inhibitor, making the diagnosis of acquired hemophilia A. Further work-up revealed that pernicious anemia was present and acted as an associated disease. After steroids therapy, his aPTT was normalized and the factor VIII inhibitor titer became undetectable. 2 months later, a relapse occurred and new hematomas appeared at his retropharyngeal space and left arm. His bleeding was controlled by administration of recombinant factor VIIa, and a combined therapy of intravenous steroids and rituximab was given to eradicate the inhibitor. The approach to workup of bleeding disorders as well as treatment of acquired hemophilia A are herein discussed. PMID- 23023362 TI - Body packer syndrome. PMID- 23023363 TI - Excessive consumption of soybean milk and unexplained hepatitis. PMID- 23023364 TI - Ocular dirofilariasis: still in the dark in western India? PMID- 23023365 TI - Pandemic influenza H1N1, legionellosis, splenic rupture, and vascular thrombosis: a dangerous cocktail. PMID- 23023366 TI - Hepatic diffuse intra-sinusoidal metastases of pulmonary small-cell carcinoma. PMID- 23023367 TI - Activation of peroxisome proliferator-activated receptor delta inhibits human macrophage foam cell formation and the inflammatory response induced by very low density lipoprotein. AB - OBJECTIVE: Hypertriglyceridemia is an important risk factor for cardiovascular disease. Elevated plasma very low-density lipoprotein (VLDL) puts insulin resistant patients at risk for atherosclerosis. VLDL readily induces macrophage lipid accumulation and inflammatory responses, for which targeted therapeutic strategies remain elusive. We examined the ability of VLDL to induce macrophage foam cells and the inflammatory response and sought to define the cell signaling cascades involved. We further examined the potential of peroxisome proliferator activated receptor (PPAR) delta activation to attenuate both VLDL-stimulated lipid accumulation and cytokine expression. METHODS AND RESULTS: THP-1 macrophages exposed to VLDL displayed significant triglyceride accumulation, which was attenuated by PPARdelta activation. PPARdelta agonists stimulated a transcriptional program resulting in inhibition of lipoprotein lipase activity, activation of fatty acid uptake, and enhanced beta-oxidation. VLDL-treated macrophages significantly increased the expression of activator protein 1 associated cytokines interleukin-1beta, macrophage inflammatory protein 1alpha, and intercellular adhesion molecule-1. VLDL treatment significantly increased the phosphorylation of both extracellular signal-related kinase 1 and 2 and p38. VLDL reduced AKT phosphorylation as well as its downstream effector forkhead box protein O1, concomitant with increased nuclear forkhead box protein O1. Cells treated with PPARdelta agonists were completely resistant to VLDL-induced expression of inflammatory cytokines, mediated by normalization of mitogen activated protein kinase (MAPK)(erk) and AKT/forkhead box protein O1 signaling. CONCLUSIONS: The combined PPARdelta-mediated reductions of lipid accumulation and inflammatory cytokine expression suggest a novel macrophage-targeted therapeutic option in treating atherosclerosis. PMID- 23023368 TI - Elevation of plasma high-density lipoproteins inhibits development of experimental abdominal aortic aneurysms. AB - OBJECTIVE: Patients with abdominal aortic aneurysms have lower concentrations of high-density lipoproteins (HDLs), leading us to investigate whether increasing plasma HDLs could influence aneurysm formation. METHODS AND RESULTS: Using the angiotensin II-induced hypercholesterolemic and the CaCl(2)-induced normocholesterolemic mouse model of AAA, we investigated the hypothesis that elevation of HDLs inhibits AAA. HDLs elevated before or at the time of AAA induction reduced AAA formation in both models but had no effect on early ruptures. Analysis of protein lysates from specific aortic segments demonstrated site-specific effects of HDLs on early signal transduction and cellular attrition. We found that HDLs reduced extracellular signal related kinases 1/2 activation in the suprarenal segment, while having no effect on p38 mitogen associated protein kinase activation in any aortic segment and inhibiting c-Jun N terminal kinase activation in all aortic segments. In addition, HDL elevation inhibited angiotensin II-induced apoptosis while inducing autophagy in the suprarenal segment of the aorta. Using Illumina gene array profiling we investigated the ability of HDL to modulate basal suprarenal aortic gene expression. CONCLUSIONS: Increasing plasma HDLs inhibit experimental AAA formation, independent of hypercholesterolemia via reduced extracellular signal related kinases 1/2 activation and alteration of the balance of cellular attrition. HDLs modulate genes involved in matrix remodelling, cell migration, and proliferation. PMID- 23023369 TI - Rivaroxaban delivery and reversal at a venous flow rate. AB - OBJECTIVE: Rivaroxaban is an oral anticoagulant that directly targets both free factor Xa and factor Xa in complex with its protein cofactor, factor Va, in the prothrombinase complex. It is approved in the United States for the prophylaxis of deep vein thrombosis and stroke in patients with atrial fibrillation; however, it also carries a black box warning regarding the risk of thrombosis after discontinuation of treatment. The purpose of this study was to determine the degree to which rivaroxaban, over a range of physiologically relevant free plasma concentrations, inhibits preassembled prothrombinase at a typical venous shear rate (100 s(-1)) and to determine the dynamics of rivaroxaban washout. METHODS AND RESULTS: Prothrombinase was assembled on phospholipid-coated glass capillaries. Its activity was characterized with respect to the activation of prothrombin (mean plasma concentration, 1.4 MUmol/L) in the absence and presence of rivaroxaban (2, 5, and 10 nmol/L). The degree of inactivation of preassembled prothrombinase is sensitive to the solution-phase rivaroxaban concentration; however, prothrombinase unmasking upon removal of rivaroxaban is concentration independent. CONCLUSIONS: The model system presented suggests that when rivaroxaban plasma concentrations decrease after cessation of therapy, there will be an unmasking of thrombus-associated prothrombinase that may be related to the reported rebound phenomena. PMID- 23023370 TI - Lipid oxidation in carriers of lecithin:cholesterol acyltransferase gene mutations. AB - OBJECTIVE: Lecithin:cholesterol acyltransferase (LCAT) has been shown to play a role in the depletion of lipid oxidation products, but this has so far not been studied in humans. In this study, we investigated processes and parameters relevant to lipid oxidation in carriers of functional LCAT mutations. METHODS AND RESULTS: In 4 carriers of 2 mutant LCAT alleles, 63 heterozygotes, and 63 family controls, we measured activities of LCAT, paraoxonase 1, and platelet-activating factor-acetylhydrolase; levels of lysophosphatidylcholine molecular species, arachidonic and linoleic acids, and their oxidized derivatives; immunodetectable oxidized phospholipids on apolipoprotein (apo) B-containing and apo(a)-containing lipoproteins; IgM and IgG autoantibodies to malondialdehyde-low-density lipoprotein and IgG and IgM apoB-immune complexes; and the antioxidant capacity of high-density lipoprotein (HDL). In individuals with LCAT mutations, plasma LCAT activity, HDL cholesterol, apoA-I, arachidonic acid, and its oxidized derivatives, oxidized phospholipids on apo(a)-containing lipoproteins, HDL associated platelet-activating factor-acetylhydrolase activity, and the antioxidative capacity of HDL were gene-dose-dependently decreased. Oxidized phospholipids on apoB-containing lipoproteins was increased in heterozygotes (17%; P<0.001) but not in carriers of 2 defective LCAT alleles. CONCLUSIONS: Carriers of LCAT mutations present with significant reductions in LCAT activity, HDL cholesterol, apoA-I, platelet-activating factor-acetylhydrolase activity, and antioxidative potential of HDL, but this is not associated with parameters of increased lipid peroxidation; we did not observe significant changes in the oxidation products of arachidonic acid and linoleic acid, immunoreactive oxidized phospholipids on apo(a)-containing lipoproteins, and IgM and IgG autoantibodies against malondialdehyde-low-density lipoprotein. These data indicate that plasma LCAT activity, HDL-associated platelet-activating factor-acetylhydrolase activity, and HDL cholesterol may not influence the levels of plasma lipid oxidation products. PMID- 23023372 TI - Alanine-glyoxylate aminotransferase-2 metabolizes endogenous methylarginines, regulates NO, and controls blood pressure. AB - OBJECTIVE: Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure. METHODS AND RESULTS: In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesis-driven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (P=0.0052). CONCLUSIONS: Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure. PMID- 23023373 TI - Multimarker risk assessment including osteoprotegerin and CXCL16 in acute coronary syndromes. AB - OBJECTIVE: CXCL16 and osteoprotegerin (OPG) both predict mortality in acute coronary syndromes. We hypothesized that a combination of CXCL16 and OPG concentrations would add prognostic information to the Global Registry of Acute Coronary Events (GRACE) score in patients hospitalized for acute coronary syndromes. METHODS AND RESULTS: We assessed the associations between circulating OPG and soluble CXCL16 levels, obtained within 24 hours of admission (day 1) and after 3 months, and mortality, heart failure and reinfarction in 1322 patients admitted with acute coronary syndromes. After adjustment for the GRACE score, medication, diabetes mellitus and sex, the combination of high values (fourth quartile) for OPG and CXCL16 at baseline was associated with increased short-term (3 months) cardiovascular mortality (hazard ratio, 3.28; 95% CI, 1.84-5.82; P<0.0001). The combined high values were also significantly associated with the long-term (median 91 months) prognosis after adjustment, with hazard ratios 2.18 for cardiovascular mortality (95% CI, 1.62-2.92; P<0.0001), and 2.22 for heart failure (95% CI, 1.67-2.96; P<0.0001). These long-term associations remained significant after further adjustment for left ventricular ejection fraction, C reactive protein, and pro B-type natriuretic peptide. For 635 patients with blood samples within 24 hours and at 3 months, the combination of high CXCL16 and OPG values (fourth quartile) in the early or stable phase was of a similar order associated with mortality and morbidity beyond 3 months. CONCLUSIONS: Circulating CXCL16 and OPG are independent predictors of long-term mortality and heart failure development in acute coronary syndromes patients, even after extensive adjustments. Their combination gives more information than either marker alone. PMID- 23023371 TI - Myeloid-specific IkappaB kinase beta deficiency decreases atherosclerosis in low density lipoprotein receptor-deficient mice. AB - OBJECTIVE: Inflammatory responses are the driving force of atherosclerosis development. IkappaB kinase beta (IKKbeta), a central coordinator in inflammation through regulation of nuclear factor-kappaB, has been implicated in the pathogenesis of atherosclerosis. Macrophages play an essential role in the initiation and progression of atherosclerosis, yet the role of macrophage IKKbeta in atherosclerosis remains elusive and controversial. This study aims to investigate the impact of IKKbeta expression on macrophage functions and to assess the effect of myeloid-specific IKKbeta deletion on atherosclerosis development. METHODS AND RESULTS: To explore the issue of macrophage IKKbeta involvement of atherogenesis, we generated myeloid-specific IKKbeta-deficient low density lipoprotein receptor-deficient mice (IKKbeta(DeltaMye)LDLR(-/-)). Deficiency of IKKbeta in myeloid cells did not affect plasma lipid levels but significantly decreased diet-induced atherosclerotic lesion areas in the aortic root, brachiocephalic artery, and aortic arch of low-density lipoprotein receptor deficient mice. Ablation of myeloid IKKbeta attenuated macrophage inflammatory responses and decreased atherosclerotic lesional inflammation. Furthermore, deficiency of IKKbeta decreased adhesion, migration, and lipid uptake in macrophages. CONCLUSIONS: The present study demonstrates a pivotal role for myeloid IKKbeta expression in atherosclerosis by modulating macrophage functions involved in atherogenesis. These results suggest that inhibiting nuclear factor kappaB activation in macrophages may represent a feasible approach to combat atherosclerosis. PMID- 23023374 TI - Myeloid deletion of nuclear factor erythroid 2-related factor 2 increases atherosclerosis and liver injury. AB - OBJECTIVE: To determine the impact of hematopoietic deletion of nuclear factor- (erythroid-derived 2) like 2 factor (Nrf2) on the development of atherosclerosis and liver injury in an obese, hypercholesterolemic mouse model. METHODS AND RESULTS: Two-month-old male low-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with either wild type or Nrf2-deficient (Nrf2(-/-)) bone marrow cells. At 3 months of age, mice were placed on an obesogenic high-fat diet (HFD), high-cholesterol diet for 7 months. Despite no differences in body weight, body fat percentage, liver fat, plasma glucose, lipids, or insulin, the HFD-fed Nrf2(-/-) bone marrow recipients had increased proinflammatory vascular gene expression, a significant increase in atherosclerosis area (18% versus 28%; P=0.018) and lesion complexity, and a marked increase in liver fibrosis. The acceleration of vascular and liver injury may arise from enhanced macrophage migration, inflammation, and oxidative stress resulting from myeloid Nrf2 deficiency. CONCLUSIONS: Myeloid-derived Nrf2 activity attenuates atherosclerosis development and liver inflammation and fibrosis associated with obesity. Prevention of oxidative stress in macrophage and other myeloid lineage cells may be an important therapeutic target to reduce inflammation-driven complications of obesity. PMID- 23023375 TI - Hydrogen sulfide-releasing aspirin derivative ACS14 exerts strong antithrombotic effects in vitro and in vivo. AB - OBJECTIVE: Hydrogen sulfide (H(2)S)-releasing NSAIDs exert potent anti inflammatory effects beyond classical cyclooxygenase inhibition. Here, we compared the platelet inhibitory effects of the H(2)S-releasing aspirin derivative ACS14 with its mother compound aspirin to analyze additional effects on platelets. METHODS AND RESULTS: In platelets of mice fed with ACS14 for 6 days (50 mg/kg per day), not only arachidonic acid-induced platelet aggregation but also ADP-dependent aggregation was decreased, an effect that was not observed with an equimolar dose of aspirin (23 mg/kg per day). ACS14 led to a significantly longer arterial occlusion time after light-dye-induced endothelial injury as well as decreased thrombus formation after ferric chloride-induced injury in the carotid artery. Bleeding time was not prolonged compared with animals treated with equimolar doses of aspirin. In vitro, in human whole blood, ACS14 (25-500 umol/L) inhibited arachidonic acid-induced platelet aggregation, but compared with aspirin additionally reduced thrombin receptor-activating peptide-, ADP-, and collagen-dependent aggregation. In washed human platelets, ACS14 (500 umol/L) attenuated alphaIIbbeta3 integrin activation and fibrinogen binding and increased intracellular cAMP levels and cAMP-dependent vasodilator stimulated phosphoprotein (VASP) phosphorylation. CONCLUSIONS: The H(2)S releasing aspirin derivative ACS14 exerts strong antiaggregatory effects by impairing the activation of the fibrinogen receptor by mechanisms involving increased intracellular cyclic nucleotides. These additional antithrombotic properties result in a more efficient inhibition of thrombus formation in vivo as achieved with aspirin alone. PMID- 23023376 TI - p62 binding to protein kinase C zeta regulates tumor necrosis factor alpha induced apoptotic pathway in endothelial cells. AB - OBJECTIVE: Protein kinase C (PKC) zeta is a key pathological mediator of endothelial cell apoptosis. p62 is a scaffold protein that regulates several cell signaling pathways by binding to target proteins. Because PKCzeta and p62 contain Phox/Bem1p (PB1) modules that mediate protein-protein interactions, we hypothesized that an interaction between p62 and PKCzeta is required for tumor necrosis factor alpha-induced PKCzeta signaling in endothelial cells. METHODS AND RESULTS: In human umbilical vein endothelial cell, tumor necrosis factor alpha (10 ng/mL) enhanced the interaction between p62 and PKCzeta. Transfection with p62 small interfering RNA reduced the activation of both PKCzeta and its downstream targets JNK and caspase 3, suggesting that p62 is necessary for PKCzeta signaling. Overexpression of only the PB1 domain of p62 inhibited p62 PKCzeta interaction, showing that binding of these 2 proteins is mediated by their PB1 domains. Furthermore, overexpression of the p62 PB1 domain suppressed tumor necrosis factor alpha-induced PKCzeta activation and subsequent activation of JNK and caspase 3. Finally, transfection of either p62 small interfering RNA or the PB1 domain of p62 inhibited human umbilical vein endothelial cell apoptosis. CONCLUSIONS: Our results suggest a novel function of p62 that regulates the activity of PKCzeta by binding to PKCzeta, thereby activating the PKCzeta-JNK-caspase 3 apoptotic pathway in endothelial cells. PMID- 23023378 TI - Incidental solid cystic renal lesion. AB - The growing use of cross-sectional imaging has led to increasing detection of incidental lesions that previously remained undiscovered. These incidental lesions are unexpected, usually asymptomatic and are not related to the patient's presenting complaint or past medical history. Incidental findings in the kidneys are common and most of them are renal masses. On detection of such renal lesions, the question arises as to the diagnosis and subsequent management of these abnormalities. PMID- 23023379 TI - Monocyte expression of Toll-like receptor-4 in patients with stable angina undergoing percutanoeus coronary intervention. AB - BACKGROUND: Toll like receptors (TLRs) are well recognized players in inflammatory conditions. Among them TLR-4 is involved in chronic inflammatory processes such as formation of atherosclerotic plaques. OBJECTIVE: The present study was aimed to examine the effects of percutanoeus coronary intervention (PCI) as a revascularization method on monocyte expression of hTLR-4 and on the serum levels of two proinflammatory cytokines (TNF-alpha and IL-1beta). METHODS: Blood samples were obtained from 41 patients with stable angina who were candidates for PCI. The samples were collected immediately before and 2h and 4h after PCI. The expression of hTLR-4 on CD14+ monocytes and the serum levels of TNF-alpha and IL-1beta were measured using flowcytometry and ELISA techniques, respectively. RESULTS: By comparing the frequency of circulating hTLR-4+/CD14+ monocytes at different time points, it was observed that PCI procedure up regulates the monocyte expression of hTLR-4 (p<0.05). The increase in expression was associated with the elevation of the serum levels of proinflammatory cytokines (p<005). There was a significant correlation between monocyte expression of hTLR-4 and serum levels of TNF-alpha and IL-1beta only before PCI. In spite of parallel increase in the serum levels of proinflammatory cytokines and the monocyte expression of hTLR-4, the correlation did not attain a significant level after PCI intervals. CONCLUSION: PCI is positively associated with an increase in the monocyte expression of hTLR-4. It is also associated with the elevation in the serum levels of proinflmmatory cytokines. These findings suggest that hTLR-4 monocyte expression may be used as a potential prognostic tool in patients with stable angina undergoing PCI. PMID- 23023377 TI - Opposing actions of heat shock protein 90 and 70 regulate nicotinamide adenine dinucleotide phosphate oxidase stability and reactive oxygen species production. AB - OBJECTIVE: Excessive reactive oxygen species contribute to vascular dysfunction. We have previously shown that heat shock protein (Hsp90) inhibitors potently suppress Nox 1 to 3 and 5, and the goals of this study were to identify how molecular chaperones regulate Nox function. METHODS AND RESULTS: In vitro, protein expression of Nox 1 to 2, 5 was decreased by Hsp90 inhibitors in multiple cell types (human pulmonary artery endothelial cells, neutrophils, macrophages, and human saphenous vein). In mice treated with Hsp90 inhibitors, Nox1 expression was reduced in lung along with reduced reactive oxygen species from leukocytes. Elevated reactive oxygen species production in obese (db/db) aorta was suppressed by Hsp90 inhibition. Hsp90 inhibitors did not alter Nox5 micro RNA levels, and proteasome inhibition prevented Nox2 and 5 protein degradation and increased ubiquitin incorporation. Inhibition of Hsp90 upregulated the expression of Hsp70 and Hsp70-bound Nox2, 5 and promoted degradation. Silencing Hsp70 prevented Hsp90 inhibitor-mediated degradation of Nox5. The Hsp70-regulated ubiquitin ligase, carboxyl terminus of Hsp70-interacting protein (CHIP), also bound Nox5 and promoted increased Nox5 ubiquitination and degradation. The chaperone binding and ubiquitination domains of CHIP were required, and the silencing of CHIP blunted Hsp90 inhibitor-mediated degradation of Nox2 and 5. CONCLUSIONS: We conclude that Hsp90 binds to and regulates Nox protein stability. These actions are opposed by Hsp70 and CHIP, which promote the ubiquitination and degradation of Nox proteins and reduce reactive oxygen species production. PMID- 23023380 TI - Toll like receptor-4 896A/G gene variation, a risk factor for migraine headaches. AB - BACKGROUND: The pathogenesis of migraine involves immune-mediated mechanisms in the vascular endothelium. Toll like receptor 4 (TLR-4) is a signaling receptor of innate immunity which plays a role in various neuropathologies related to neuron inflammation. OBJECTIVE: This case/control study is aimed to investigate whether TLR-4 896A/G variation is related to migraine headaches in an Iranian population. METHODS: A total of 170 migraine patients (130 females, mean age 33.24 +/- 11 years) and 170 age, sex, and ethnicity matched healthy controls (118 females, mean age of 31 +/- 10 years) were recruited. Genotyping was carried out using the tetra primer amplification refractory mutation system (ARMS)-PCR. RESULTS: The frequency of G allele was higher in migraine patients than the controls (15% vs. 4.7%; p<0.0001). Interestingly, the distribution of heterozygous 896A/G genotype statistically differed between migraineurs and controls (25.3% vs. 8.2%, p=0.00002, OR 3.87, 95% CI; 2.02-7.4). Multivariate logistic regression analysis indicated that G allele in affected female migraineurs is an independent factor associated with increased risk of migraine (OR 3.2, 95% CI 1.23-8.24, p=0.01). CONCLUSION: Our results showed TLR-4 polymorphism as a genetic risk factor for migraine. However, further studies in different populations are required to elucidate the precise role of TLR-4 896A/G mutation in susceptibility to migraine. PMID- 23023381 TI - Evaluation of the immunomodulatory effect of curdlan on maturation and function of mouse spleen-derived dendritic cells. AB - BACKGROUND: T helper 1 and T helper 17 cells play important roles in immunity against foreign invaders. Differentiation of these Th subsets is affected by state of maturation and cytokines that are produced by dendritic cells (DCs). Curdlan is a linear (1->3)-beta-glucan and has shown activity against tumors and infectious agents. OBJECTIVE: This study aims to investigate whether curdlan plays its role through affecting the maturation and cytokine production by DCs. METHODS: DCs were isolated from the spleen of BALB/c mice by MACS method. After an overnight culture of DCs in the presence of curdlan, the expression levels of CD40, CD86, and MHC-II molecules were determined by flow cytometry. The production of cytokines involved in Th1 and Th17 cell differentiation (IL-12 and IL-6, respectively) was also evaluated by ELISA. Lipopolysaccharide (LPS) treated and untreated cells were considered as positive and negative controls, respectively. RESULTS: The results of this study did not show a significant difference in the levels of surface expression of CD40 (p=0.82), CD86 (p=0.79), and MHC class II (p=0.84) molecules upon exposure to curdlan. However, LPS increased the intensity of CD40 expression on dendritic cells (p=0.04). In addition, it was revealed that curdlan-exposed DCs are not able to produce a significant amount of IL-6 and IL-12 cytokines. Conversely, LPS-treated DCs were able to make a significant amount of IL-12 (p=0.005). CONCLUSION: The results of the present study suggest that curdlan has no effect on Th1 or Th17 differentiation while LPS may induce Th1 deviation by induction of CD40 expression and IL-12 production. PMID- 23023382 TI - Immunoregulatory effects of glutathione during mesenchymal stem cell differentiation to hepatocyte-like cells. AB - BACKGROUND: The role of mesenchymal stem cell in cellular therapy is the subject of interest for many researchers. The differentiation potential of MSCs and abilities in modulations of the recipient's immune system makes them important cells in tissue regenerative studies. MSCs by releasing the proinflammatory cytokines play important role in immunomodulatory systems; however the signaling pathways for releasing of these mediators are not well understood. Glutathione has been shown to play a role in modulation of cytokines in hepatogenic differentiation. OBJECTIVE: In the current study we aimed to investigate the effects of buthionine sulfoximine (BSO, inhibitor for glutathione synthesis) and N-acetylecystin (NAC, an inhibitor for ROS generation) on proinflammatory cytokines production in a hepatogenic differentiation model. RESULTS: BSO and NAC significantly decreased IL-6 and TNF-alpha levels at 14 days of differentiation, whereas, NAC decreased the levels of IL-8 at days 2 and 14 of differentiation. Moreover, intracellular glutathione level during the differentiation was depleted. CONCLUSION: Our current study suggests a novel role of GSH as an immunopharmacological regulatory molecule during hepatogenic differentiation. Finally, this information may shed some light on the understanding of MSCs responses in transplantation and cell therapy in diseases such as chronic hepatic diseases. PMID- 23023383 TI - Strong association of CTLA-4 variation (CT60A/G) and CTLA-4 haplotypes with predisposition of Iranians to head and neck cancer. AB - BACKGROUND: Variations in Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) affect the expression and function of this protein. OBJECTIVE: We aimed to investigate the association of +49 A/G (rs231775), +1822 C/T (rs231779) and +6230 A/G (CT60, rs3087243) genetic variations, as well as the merged haplotypes in CTLA-4 gene with susceptibility to, or progression of head and neck cancer. METHODS: Eighty patients with confirmed head and neck (HN) cancer (age 54.9 +/- 16.1 years) and 85 healthy age/sex-matched controls (age 56.3 +/- 12.4 years) were enrolled in the study. Genotypes were investigated by the PCR-RFLP method. Arlequin software package was used to check for Hardy-Weinberg equilibration, and to estimate the haplotypes. RESULTS: At position +6230 A/G (CT60), AA genotype, as well as A allele was significantly decreased in patients with HN cancers than controls (18.8% vs. 40.7%, p=0.004; odds ratio=0.34, and 46.3% vs. 61.7, p=0.007; odds ratio=0.53%, respectively). Nearly the same results were obtained when we compared the subgroup of patients with squamous cell carcinoma of the HN (SCC-HN) with control subjects. The frequencies of genotypes and alleles at other positions were not significantly different between patients and controls, however ACG, GTA and GCA haplotypes emerged from three investigated loci occurred with significantly more frequencies in patients (p<0.0001), while ACA and GTG haplotypes were more frequent among controls (p<0.0001). Significant differences of haplotypes, genotypes and alleles frequencies resisted the Bonferroni correction. CONCLUSION: Our results suggest that CT60 A allele, as well as ACA and GTG haplotypes in CTLA-4 gene may have protective roles against HN cancer in Iranian population, while ACG, GTA and specially GCA haplotypes may render susceptibility. PMID- 23023384 TI - A clinical randomized trial on endocervical inflammatory cytokines and betamethasone in prime-gravid pregnant women at risk of preterm labor. AB - BACKGROUND: There are strong evidences suggesting the secretion of different cytokines in cervical fluid during preterm labor. Betamethasone is widely administered for several reasons in preterm conditions. OBJECTIVE: To Investigate the possible effect of betamethasone on endocervical cytokine concentration of women at risk of preterm labor. METHODS: In a randomized clinical trial of 80 prime-gravid women in preterm labor between 34 and 37 weeks of gestation, cervical fluids were collected. Endocervical concentration of inflammatory cytokines were analyzed before and 48 hours after betamethasone treatment for the evaluation of IL-8, IL-17, IFN-gamma and TGF-beta. Wilcoxon and Mann-Whitney tests were employed for statistical analysis. chi2 and Student's t tests were used whenever needed. RESULTS: All the measured cytokines showed significant changes in the betamethasone treated group. IL-17 (p=0.001), IL-8 (p=0.001), and IFN-gamma (p<0.05) decreased significantly, while TGF-beta had a significant increase (p<0.05). In the patients who delivered before or on the 7th day of admission, IL-17, IL-8, and IFN-gamma levels were all significantly higher. However, TGF-beta decreased significantly in the same samples in the betamethasone treated group (p<0.05). CONCLUSION: Betamethasone significantly decreases the endocervical pro-inflammatory cytokine concentrations in patients with preterm labor. PMID- 23023385 TI - Antioxidants and proinflamatory cytokines in the sera of patients with cutaneous leishmaniasis. AB - BACKGROUND: Leishmania is a significant health problem in many parts of the world. Tumor necrosis factor (TNF) plays an essential role in Leishmania major infections. OBJECTIVE: To study the pro-inflammatory cytokines and antioxidants in four groups of cutaneous leishmaniasis patients. METHODS: 39 patients were divided into four groups of: 1) active (acute phase of treatment); 2) non-healing (received treatment for almost two years without recovery); 3) healing (recovered upon treatment); and 4) healed (previously received treatment and achieved complete remission) patients. Serum levels of pro-inflammatory cytokines (IL-1B, TNF-alpha, IL-6) and serum antioxidant levels were measured by ELISA and FRAP assays, respectively. RESULTS: While serum antioxidant levels were elevated in the non-healing group, there was no difference among other groups of patients and healthy controls in this regard. Interleukin-1beta showed the highest level in the non-healing group followed by the other groups of patients. The mean serum IL 6 level was highest in the non-healing group, but showed no significant change in the other groups. TNF-alpha and IL-1beta levels were non-significantly elevated in the sera of active and non-healing patients. CONCLUSION: Pro-inflammatory cytokines IL-1beta, TNF-alpha, IL-6 maybe related to the progression of leishmaniasis. Serum antioxidant levels maybe correlated with patient response to drug treatment. PMID- 23023386 TI - New analytical approach to calibrate the co-axial HPGe detectors including correction for source matrix self-attenuation. AB - To calibrate the co-axial HPGe semiconductor detectors, we introduce a new theoretical approach based on the Direct Statistical method proposed by Selim and Abbas (1995, 1996) to calculate the full-energy peak efficiency for cylindrical detectors. The present method depends on the accurate analytical calculation of the average path length covered by the photon inside the detector active volume and the geometrical solid angle Omega, to obtain a simple formula for the efficiency. In addition, the self attenuation coefficient of the source matrix (with a radius greater than the detector's radius), the attenuation factors of the source container and the detector housing materials are also treated by calculating the average path length within these materials. (152)Eu aqueous radioactive sources covering the energy range from 121 to 1408 keV were used. Remarkable agreement between the measured and the calculated efficiencies was achieved with discrepancies less than 2%. PMID- 23023387 TI - Sc2O3, Er2O3, and Y2O3 thin films by MOCVD from volatile guanidinate class of rare-earth precursors. AB - Alternative novel precursor chemistries for the vapor phase deposition of rare earth (RE) oxide thin films were developed by synthesising the homoleptic guanidinate compounds tris(N,N'-diisopropyl-2-dimethylamidoguanidinato) scandium(III) [Sc(DPDMG)(3)] (1), tris(N,N'-diisopropyl-2 dimethylamidoguanidinato)-erbium(III), [Er(DPDMG)(3)] (2) and tris(N,N' diisopropyl-2-dimethylamidoguanidinato)-yttrium(III), [Y(DPDMG)(3)] (3). All three compounds are monomeric as revealed by single crystal X-ray diffraction (XRD) analysis, nuclear magnetic resonance (NMR) and electron impact mass spectrometry (EI-MS). The thermal analysis revealed that the compounds are volatile and very stable under evaporation conditions. Therefore the complexes were evaluated as precursors for the growth of Sc(2)O(3), Er(2)O(3) and Y(2)O(3) thin films, respectively, by metal-organic chemical vapor deposition (MOCVD). Uniform Sc(2)O(3), Er(2)O(3) and Y(2)O(3) films on Si(100) substrates with reproducible quality were grown by MOCVD by the combination of the respective guanidinate precursors and oxygen in the temperature range 350-700 degrees C. The structural, morphological, compositional and electrical properties of the films were investigated in detail. The most relevant film properties are highlighted in relation to the distinct advantages of the novel precursor chemistries in comparison to the commonly used literature known RE precursors. This study shows that compounds 1-3 are very good precursors for MOCVD yielding Sc(2)O(3), Er(2)O(3) and Y(2)O(3) thin films which are stoichiometric and display suitable electrical properties for their potential use as high dielectric constant (high-k) materials. PMID- 23023388 TI - Predictive factors for lymph node metastasis in patients with poorly differentiated early gastric cancer. AB - BACKGROUND: Endoscopic submucosal dissection is gaining popularity in the treatment of early gastric cancer. This study aimed to identify clinicopathological factors predictive of lymph node metastasis in patients with the poorly differentiated early gastric cancer to assess the feasibility of using endoscopic submucosal dissection for these cancers. METHODS: The records of patients with poorly differentiated early gastric cancer who had undergone gastric cancer surgery between January 2002 and December 2009 were reviewed. Associations between clinicopathological factors and the presence of lymph node metastasis were analysed by univariable and multivariable logistic regression analysis. RESULTS: Some 1005 patients were included in the analysis. Univariable analysis indicated that lymph node metastasis was associated with sex, ulceration, tumour size, depth of invasion, macroscopic type, lymphatic invasion and venous invasion. Logistic regression revealed that lymph node metastasis was significantly associated with sex, tumour size, depth of tumour invasion and lymphatic involvement. In the group with none of these risk factors (men with mucosal tumour no larger than 2 cm in size, with no lymphatic involvement), lymph node metastasis was present in four (3.2 per cent) of 124 patients. CONCLUSION: In the present study 3.2 per cent of patients who were negative for all identified risk factors had lymph node metastasis. The use of endoscopic submucosal dissection should be considered carefully in the treatment of poorly differentiated early gastric cancer. PMID- 23023389 TI - Devoured by our own children: the possibility and peril of moral status enhancement. PMID- 23023390 TI - Differential proteomic analysis of HL60 cells treated with secalonic acid F reveals caspase 3-induced cleavage of Rho GDP dissociation inhibitor 2. AB - Secalonic acid F (SAF) has been previously identified, however, little is known about its cytotoxic activity and related cytotoxic mechanism. The aim of this study was to evaluate the cytotoxic activity of SAF isolated from a deep sea originated fungus Penicillium sp. F11 in HL60 cells and to analyze the differences in protein expression of HL60 cells treated with SAF. The CCK-8 assay and Annexin V-FLUOS/PI assay indicated that SAF displayed dose- and time dependent inhibition of HL60 cell proliferation and induced apoptosis. Two dimensional gel electrophoresis (2-DE) analysis of HL60 cells treated with SAF (4 ug/ml) revealed 10 differentially expressed protein spots (P<0.05), 5 upregulated and 5 downregulated. Three spots (1 downregulated and 2 upregulated) were identified as Rho GDP dissociation inhibitor 2 (RhoGDI 2) proteins by MALDI-TOF MS. Western blotting further demonstrated the decreased abundance of full-length RhoGDI 2 together with the increased abundance of caspase 3-cleaved product of RhoGDI 2. The caspase 3 inhibitor Ac-DEVD-CHO could suppress the cytotoxic effect of SAF and significantly block the cleavage of RhoGDI 2. RhoGDI 2 is a cytosolic regulator of Rho GTPase and the caspase 3-cleaved product of RhoGDI 2 can advance progression of the apoptotic process. Our data showed that SAF may modulate RhoGDI 2 levels in HL60 cells, thereby potentially disrupting cell signaling pathways important for HL60 cell function. PMID- 23023391 TI - The p110delta isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. AB - Lipopolysaccharide activates plasma-membrane signaling and endosomal signaling by Toll-like receptor 4 (TLR4) through the TIRAP-MyD88 and TRAM-TRIF adaptor complexes, respectively, but it is unclear how the signaling switch between these cell compartments is coordinated. In dendritic cells, we found that the p110delta isoform of phosphatidylinositol-3-OH kinase (PI(3)K) induced internalization of TLR4 and dissociation of TIRAP from the plasma membrane, followed by calpain mediated degradation of TIRAP. Accordingly, inactivation of p110delta prolonged TIRAP-mediated signaling from the plasma membrane, which augmented proinflammatory cytokine production while decreasing TRAM-dependent endosomal signaling that generated anti-inflammatory cytokines (interleukin 10 and interferon-beta). In line with that altered signaling output, p110delta-deficient mice showed enhanced endotoxin-induced death. Thus, by controlling the 'topology' of TLR4 signaling complexes, p110delta balances overall homeostasis in the TLR4 pathway. PMID- 23023394 TI - Experts' opinions on the benefit of an incidental prenatal diagnosis of sex chromosomal aneuploidy: a qualitative interview survey. AB - OBJECTIVE: Incidental findings in prenatal diagnostic testing may or may not have clear prognostic significance for the phenotype. We studied experts' opinions of the benefit and disadvantage of an incidental prenatal diagnosis of a sex chromosomal aneuploidy (SCA). METHODS: We interviewed 16 experts in the field of counseling and treatment of people with SCA and asked 13 clinical geneticists and genetic associates about the clinical relevance of an incidental prenatal diagnosis of SCA. RESULTS: Most of the experts and clinical geneticists (87.5% and 76.9%, respectively) stated that an incidental prenatal diagnosis of SCA was a benefit for the child and the parents. They acknowledged the possibility of parental decisions to terminate pregnancy. Expert options in screening, training, and treatment of health, behavior, and fertility problems increase with an early diagnosis of SCA. CONCLUSION: Most experts favored an incidental prenatal diagnosis of SCA despite the complex counseling issues and their acknowledgment of possible parental decisions to terminate pregnancy. They believed the benefits greatly outweigh the disadvantages. PMID- 23023392 TI - Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. AB - We assessed gene expression in tissue macrophages from various mouse organs. The diversity in gene expression among different populations of macrophages was considerable. Only a few hundred mRNA transcripts were selectively expressed by macrophages rather than dendritic cells, and many of these were not present in all macrophages. Nonetheless, well-characterized surface markers, including MerTK and FcgammaR1 (CD64), along with a cluster of previously unidentified transcripts, were distinctly and universally associated with mature tissue macrophages. TCEF3, C/EBP-alpha, Bach1 and CREG-1 were among the transcriptional regulators predicted to regulate these core macrophage-associated genes. The mRNA encoding other transcription factors, such as Gata6, was associated with single macrophage populations. We further identified how these transcripts and the proteins they encode facilitated distinguishing macrophages from dendritic cells. PMID- 23023393 TI - The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-kappaB signaling. AB - Immunoglobulin class switching is crucial for the generation of antibody diversity in humoral immunity and, when deregulated, also has severe pathological consequences. How the magnitude of immunoglobulin isotype switching is controlled is still poorly understood. Here we identify the kinase TBK1 as a pivotal negative regulator of class switching to the immunoglobulin A (IgA) isotype. B cell-specific ablation of TBK1 in mice resulted in uncontrolled production of IgA and the development of nephropathy-like disease signs. TBK1 negatively regulated IgA class switching by attenuating noncanonical signaling via the transcription factor NF-kappaB, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-kappaB-inducing kinase NIK. Our findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-kappaB pathway and identify a unique mechanism that controls IgA production. PMID- 23023395 TI - High efficiency multishot interleaved spiral-in/out: acquisition for high resolution BOLD fMRI. AB - Growing demand for high spatial resolution blood oxygenation level dependent (BOLD) functional magnetic resonance imaging faces a challenge of the spatial resolution versus coverage or temporal resolution tradeoff, which can be addressed by methods that afford increased acquisition efficiency. Spiral acquisition trajectories have been shown to be superior to currently prevalent echo-planar imaging in terms of acquisition efficiency, and high spatial resolution can be achieved by employing multiple-shot spiral acquisition. The interleaved spiral in/out trajectory is preferred over spiral-in due to increased BOLD signal contrast-to-noise ratio (CNR) and higher acquisition efficiency than that of spiral-out or noninterleaved spiral in/out trajectories (Law & Glover. Magn Reson Med 2009; 62:829-834.), but to date applicability of the multishot interleaved spiral in/out for high spatial resolution imaging has not been studied. Herein we propose multishot interleaved spiral in/out acquisition and investigate its applicability for high spatial resolution BOLD functional magnetic resonance imaging. Images reconstructed from interleaved spiral-in and out trajectories possess artifacts caused by differences in T2 decay, off resonance, and k-space errors associated with the two trajectories. We analyze the associated errors and demonstrate that application of conjugate phase reconstruction and spectral filtering can substantially mitigate these image artifacts. After applying these processing steps, the multishot interleaved spiral in/out pulse sequence yields high BOLD CNR images at in-plane resolution below 1 * 1 mm while preserving acceptable temporal resolution (4 s) and brain coverage (15 slices of 2 mm thickness). Moreover, this method yields sufficient BOLD CNR at 1.5 mm isotropic resolution for detection of activation in hippocampus associated with cognitive tasks (Stern memory task). The multishot interleaved spiral in/out acquisition is a promising technique for high spatial resolution BOLD functional magnetic resonance imaging applications. PMID- 23023396 TI - Heme plane orientation dependent direct electron transfer of cytochrome c at SAMs/Au electrodes with different wettability. AB - It is proposed that direct electron transfer is dependent on the orientation of the heme plane in cytochrome c (cyt c) assembled on electrode surfaces. Orientation with the heme plane in cyt c parallel to the gold electrode surface favors the direct electron transfer, while vertical orientation of the heme plane makes the direct electron transfer difficult. A preferable electron transport pathway for cyt c is through the axial ligand (His-18) of the heme center rather than the porphyrin ring. PMID- 23023397 TI - CEBP factors regulate telomerase reverse transcriptase promoter activity in whey acidic protein-T mice during mammary carcinogenesis. AB - Telomerase is activated in the majority of invasive breast cancers, but the time point of telomerase activation during mammary carcinogenesis is not clear. We have recently presented a transgenic mouse model to study human telomerase reverse transcriptase (TERT) gene expression in vivo (hTERTp-lacZ). In the present study, hTERTp-lacZxWAP-T bitransgenic mice were generated to analyze the mechanisms responsible for human and mouse TERT upregulation during tumor progression in vivo. We found that telomerase activity and TERT expression were consistently upregulated in SV40-induced invasive mammary tumors compared to normal and hyperplastic tissues and ductal carcinoma in situ (DCIS). Human and mouse TERT genes are regulated similarly in the breast tissue, involving the CEBP transcription factors. Loss of CEBP-alpha and induction of CEBP-beta expression correlated well with the activation of TERT expression in mouse mammary tumors. Transfection of CEBP-alpha into human or murine cells resulted in TERT repression, whereas knockdown of CEBP-alpha in primary human mammary epithelial cells resulted in reactivation of endogenous TERT expression and telomerase activity. Conversely, ectopic expression of CEBP-beta activated endogenous TERT gene expression. Moreover, ChIP and EMSA experiments revealed binding of CEBP alpha and CEBP-beta to human TERT-promoter. This is the first evidence indicating that CEBP-alpha and CEBP-beta are involved in TERT gene regulation during carcinogenesis. PMID- 23023398 TI - Regulation of CXCR4 gene expression in breast cancer cells under diverse stress conditions. AB - Chronic inflammation is a critical component in breast cancer progression. Pro inflammatory mediators along with growth/survival factors within the tumor microenvironment potentiate the expression of pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha), chemotactic cytokines and their receptors (CXCR4, CXCL12, CXCL8) and angiogenic factors (VEGF) that often overcome the effect of anti inflammatory molecules (IL-4, IL-10) thus evading the host's antitumor immunity. Detailed knowledge, therefore, of the regulatory mechanisms determining cytokine levels is essential to understand the pathogenesis of breast cancer. HIF-1alpha and NF-kappaB transcription factors are important players for the establishment of a pro-inflammatory and potentially oncogenic environment. HIF-1alpha is the key mediator of the cellular response to oxygen deprivation and induces the expression of genes involved in survival and angiogenesis within solid hypoxic tumors. The expression of these genes is often modulated by the p53 tumor suppressor protein that induces apoptosis or cell cycle arrest in neoplastic cells. Functional crosstalk between HIF-1alpha and p53 pathways mediated by modulators shared between the two transcription factors such as SRC-1 and SIRT-1 differentially regulate the expression of distinct subsets of their target genes under variable stress conditions. In an attempt to shed light on the complex regulatory mechanisms involved in cancer-related inflammation, we investigated the role of the two common p53 and HIF-1alpha co-regulators SRC-1 and SIRT-1, in the expression of the highly potent metastatic chemokine receptor CXCR4. Both SRC 1 and SIRT-1 overexpression in DSFX-treated MCF-7 cells reduced CXCR4 cellular levels implying that both co-regulators are crucial factors in the determination of the metastatic potential of breast cancer cells. PMID- 23023400 TI - Quo vadis older keratoconus patients? Do they die at younger ages? AB - PURPOSE: To examine the validity of the observations made by specialist corneal surgeons that there seems to be an absence or loss of older patients with keratoconus (KC). METHODS: Using a PubMed search and key words such as KC, epidemiology, mortality, mitral valve prolapse, atopy, and asthma, the literature related to this topic was reviewed. Specialist contact lens fitting practitioners were asked to supply age-related details of KC and nonkeratoconus patients within their practices. RESULTS: Results suggested a marked absence or loss of older KC patients as has been observed by specialist corneal surgeons. Several possible explanations are described including increased mortality associated with mitral valve prolapse, asthma, obesity, and/or obstructive sleep apnea, for example. In addition, gender bias, the influence of progression to keratoplasty or age related diseases, as well as difficulty in traveling to specialist practices and the need for and dependence on specialist contact lens fitting skills of KC patients were considered. The possibility that KC corneas could improve with age related increased natural crosslinking and stiffening is discussed. CONCLUSIONS: An absence or loss of older KC patients has been found in some specialist contact lens fitting practices. Notwithstanding the possible influence of numerous other issues, the absence or loss of KC patients may be because of reduced life expectancy, a topic that seems to warrant further examination. There may be implications for improving the understanding of the pathogenesis of KC if reduced life expectancy can be confirmed and the associated reasons elucidated. PMID- 23023399 TI - Translational repression precedes and is required for ZAP-mediated mRNA decay. AB - Translational repression and mRNA degradation are two major mechanisms for post transcriptional regulation of gene expression. The detailed relationship between these two processes is not yet well established. Zinc-finger antiviral protein (ZAP) inhibits the replication of certain viruses, including human immunodeficiency virus 1, by binding directly to specific viral mRNAs and recruiting cellular mRNA degradation machinery to degrade the target mRNA. Here, we report that ZAP also inhibits the translation of target mRNAs by interfering with the interaction between translational initiation factors eIF4G and eIF4A. Furthermore, we provide evidence that translational repression is required for mRNA degradation and that blocking the degradation of target mRNAs does not affect ZAP-mediated translational repression. We conclude that ZAP can both repress translation and promote degradation of target mRNA, and that translational repression precedes and is required for mRNA degradation. PMID- 23023401 TI - Distribution of cyclosporine A in ocular tissues after topical administration of cyclosporine A cationic emulsions to pigmented rabbits. AB - PURPOSE: The aim of this study was to compare the ocular and systemic distribution of cyclosporine A (CsA) in rabbits after the instillation of preservative-free CsA cationic and anionic emulsions. METHODS: For the single dose pharmacokinetic (PK) study, rabbits were instilled with 50 MUL of the test material. For the multiple-dose PK study, rabbits were instilled twice daily with Restasis or once daily with NOVA22007 for 10 days. At each time point, the cornea, conjunctiva, and whole blood were harvested for CsA quantification. Ocular and systemic distribution were determined after 4 times daily instillations with 50 MUL of 3H-CsA cationic and anionic emulsions for 7 days. Restasis was used as a reference in all studies. RESULTS: Single-dose PK data demonstrated that NOVA22007 0.1% and 0.05% delivered higher CsA concentrations to the cornea than Restasis [concentration maximum (C max): 2692, 1372, and 748 ng/g, respectively] and have a better exposition (area under the curve). Conjunctival Cmax values were 1914, 696, and 849 ng/g and area under the curve values were 3984, 2796, and 2515 ng/g . h, for either dose of the cationic emulsions and Restasis, respectively. The multiple-dose PK and the 3H-CsA distribution data demonstrated that the systemic distribution after repeated instillations was low and comparable for all emulsions. CONCLUSIONS: These data demonstrate that the CsA cationic emulsions were more effective than Restasis at delivering CsA to target tissues, thus confirming the potential advantage of cationic emulsions over anionic emulsions as vehicle for ocular drug delivery for the treatment of ocular surface diseases. PMID- 23023402 TI - Banking of donor tissues for descemet stripping automated endothelial keratoplasty. AB - PURPOSE: The demands for precut lamellar grafts for Descemet stripping automated endothelial keratoplasty rose in our eye bank from 74 in 2007 to 408 in 2010. To meet this expanding requirement, we explored the possibility to preserve these preparations in organ culture. METHODS: Organ cultured corneas, stored in a medium containing 6% dextran, were mounted on a Moria artificial anterior chamber, deprived of the epithelium and then cut with a microkeratome. The posterior lamella was protected by positioning the anterior stromal cap, trephined at a diameter of 8.5 mm and stored at 31 degrees C in the medium containing dextran. The endothelium was examined with trypan blue and alizarin staining and tested for its glycolytic activity (conversion of glucose into lactate). RESULTS: Incubation for a period of 1 week caused a small increase in the cell loss observed after trephination (from 6.2% to 10.6%). After 2 weeks, the decrease in endothelial cell density was 19.9% but the endothelial organization remained intact. The rate of glycolysis remained unchanged during the 2 weeks of preservation, with the majority of glucose uptake accounted for by lactate production. The thickness of the lenticules remained constant, ranging from 170 to 180 MUm during the preservation. CONCLUSIONS: The lamellar grafts for Descemet stripping automated endothelial keratoplasty may be stored in organ culture for 2 weeks without damaging the endothelium or increasing the overall thickness. PMID- 23023403 TI - The effect of pupil dilation on biometric parameters of the Lenstar 900. AB - PURPOSE: To evaluate the effect of pupil dilation on the biometric parameters of the Lenstar LS 900 (Haag Streit AG, Koeniz, Switzerland). METHODS: In this cross sectional study of 33 eyes with cataracts, axial length (AL), anterior chamber depth, intraocular lens (IOL) power, keratometry, and pupil diameter measurements were performed using Lenstar biometry before and after pupil dilatation. Intraobserver repeatability was assessed by taking 2 consecutive recordings of biometric parameters using Lenstar biometry in the undilated pupils of 30 eyes with cataracts. RESULTS: The mean difference in AL measurements from intraobserver readings was -0.001 +/- 0.01 mm. The study group showed a statistically significant change in the first keratometry reading and anterior chamber depth values (P < 0.05); however, the mean difference in AL and IOL power was statistically insignificant between the undilated and dilated pupil Lenstar biometry readings. Three cases in the study group (9.1%) and 1 case in the control group (3.3%) demonstrated changes in IOL power >0.50 diopter. CONCLUSIONS: Dilated and undilated pupil size did not affect the measurement of IOL using the Lenstar biometry. PMID- 23023404 TI - Penetrating keratoplasty versus lamellar keratoplasty for mustard gas-induced keratitis. AB - PURPOSE: To compare the outcomes of penetrating keratoplasty (PK) and lamellar keratoplasty (LK) in patients with mustard gas keratitis. METHODS: A total of 78 eyes of 55 patients with mustard gas keratitis were included. Of these eyes, 27 (34.6%) underwent PK and 51 (63.4%) received LK. Keratolimbal allografts were performed in 11 and 30 eyes of the PK and LK groups, respectively. The study groups were compared in terms of best spectacle-corrected visual acuity, refractive error, and keratometry readings. The Kaplan-Meier survival curve and log-rank test were used to evaluate and compare the cumulative incidence of rejection-free graft survival and graft survival in PK and LK. RESULTS: At the time of keratoplasty, the mean patient ages were 40.3 +/- 4.5 years and 43.4 +/- 8.3 years in the PK and LK groups, respectively (P = 0.08). The patients were followed-up for 53.2 +/- 27.5 and 40.4 +/- 29.6 months, respectively (P = 0.09). At the last follow-up, the 2 study groups were comparable with respect to best spectacle-corrected visual acuity (P = 0.87), refraction (P = 0.08), and keratometric astigmatism (P = 0.27). At the 33-month follow-up examination, the rejection-free graft survival rates were 33.6% in the PK group and 90% in the LK group, with mean durations of 34.6 and 84.8 months, respectively (P < 0.001). Moreover, the graft survival rates were 77.3% and 91.7%, with mean durations of 67.5 and 76.1 months, respectively (P = 0.03). Three eyes that had received LK underwent PK because of significant interface haziness. CONCLUSIONS: LK is preferred to PK in the majority of mustard gas victims. However, PK should always be performed in certain conditions. PMID- 23023405 TI - Atypical continuous keratitis in a case of rheumatoid arthritis accompanying severe scleritis. AB - PURPOSE: Rheumatoid arthritis (RA) often presents with ocular complications: typically dry eye, peripheral corneal ulcer, and scleritis. We report for the first time a case of severe scleritis with RA, accompanying atypical continuous keratitis, which apparently differs from typical peripheral ulcerative keratitis (PUK). METHODS: Observational case report. RESULTS: A 68-year-old woman with RA presented at our hospital complaining of worsening arthritis accompanying ocular injection and discharge. On examination, nodular scleritis and peripheral corneal infiltration were noted. In addition to administering topical steroid and antibiotics, cyclosporine and an oral steroid were added because of the patient's worsening scleritis. Despite gradual improvement of the scleritis, the efficacy of the additional treatments was limited. Four months after initial treatment, the patient presented with uveitis, thought to be caused by a herpetic virus. Antivirus treatment was effective for the uveitis, but atypical continuous keratitis suddenly appeared. The keratitis was located from 4-o'clock to 10 o'clock positions continuously in the midperipheral cornea and apparently differed from herpetic keratitis or PUK as typically seen in RA cases. Immune reaction was suspected, and the keratitis improved within 2 weeks. After that, the introduction of an anti-tumor necrosis factor alpha drug (infliximab) completely resolved the severe scleritis and there was no recurrence of ocular inflammation. CONCLUSION: As is shown in this case, RA can present with atypical continuous keratitis, thought to be a manifestation of an immunologic reaction other than PUK. In addition, although immunosuppressants are often used for the treatment of RA with scleritis, the efficacy is limited. Infliximab may be a useful treatment for treatment-resistant scleritis. PMID- 23023406 TI - Nucleic acid testing and tissue safety: an eye bank's five-year review of HIV and hepatitis testing for donor corneas. AB - PURPOSE: Tissue safety and added testing is a frequent topic of discussion among those who must evaluate donor suitability and assure appropriate testing. Therefore, the purpose of this report was to examine the data of one eye bank (accredited by Eye Bank Association of America) for the presence or absence of reactive serology in 3592 donors over a 5-year period, from 2005 to 2010. METHODS: The number of specific analytes, human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus, that were reactive and the number of multireactive serologies are presented along with reports related to the identification of nucleic acid testing (NAT), NAT-reactive donors in correlation with other antigen or antibody markers. Antigen or antibody markers are enzyme linked immunosorbent assay immunoassay kit determinations. NATs are used to measure the presence of RNA or DNA virus. RESULTS: The 249 donors with reactive serologies serve to confirm the importance of serologic testing in history negative potential donors. Furthermore, the findings of 2 HIV NAT-only reactive individuals is significant because it may indicate an early unrecognized exposure and "window period" infectivity not recognized by antibody testing alone. These results support the appropriate inclusion of this added test to guarantee tissue safety. CONCLUSIONS: The finding of 2 potential donors without identified risk factors but with reactive HIV NAT suggests the need for comprehensive serologic testing in conjunction with medical social history screening. Considered together, screening and testing offer the best allograft tissue safety currently available. PMID- 23023407 TI - Comparative evaluation of topical pranoprofen and fluorometholone in cases with chronic allergic conjunctivitis. AB - PURPOSE: This study was conducted to compare the efficacy of 0.1% fluorometholone and 0.1% pranoprofen in cases with chronic allergic conjunctivitis. METHODS: In an investigator-masked trial, patients with chronic allergic conjunctivitis were randomized to treatment with 4 times daily 0.1% pranoprofen (PN) or 0.1% fluorometholone (FL) eye drops for 4 weeks. A 4-point rating scale assessing the severity of 5 symptoms and 4 signs (0 = none, 1 = mild, 2 = moderate, and 3 = severe) was used. A linear mixed model was used to explore the rate of score changes. Regression analysis was used to evaluate the relation between clinical outcome and age. RESULTS: A total of 75 patients were enrolled at the baseline. There were no significant differences in the demographics and baseline skin prick scores between both groups. Mean baseline scores in PN and FL group were 6.71 +/- 2.28 and 6.41 +/- 2.06, respectively. The scores rapidly decreased to 3.35 +/- 1.58 and 2.91 +/- 1.71 on day 7, respectively. Fluorometholone showed a more rapid effect compared with pranoprofen during the first week of treatment (P < 0.05) but not later. Regression analysis showed that age was negatively associated with response to fluorometholone (younger than 29 years). The intraocular pressure increased by 0.7 mm Hg in the FL group and decreased by 0.5 mm Hg in the PN group on day 28 (P > 0.05). CONCLUSIONS: Both fluorometholone and pranoprofen were effective for management of cases with chronic allergic conjunctivitis. Fluorometholone provided more rapid relief as compared with pranoprofen. The effect of fluorometholone was more pronounced in younger patients. PMID- 23023408 TI - Age-related decrease in human corneal gamma-glutamyltranspeptidase activity. AB - PURPOSE: To investigate age-related effects on human corneal gamma glutamyltranspeptidase (GGT) (ectoenzyme important to maintaining corneal hydration and antioxidant potential via glutathione recapture). METHODS: Age related differences between total, endothelial, and epithelial GGT activity and endothelial cell density were determined for corneas from 29 donors (mean age, 53 +/- 17 years; age range, 13-83 years). GGT activity was determined using a standard colorimetric assay based on the transpeptidation reaction. Corneal GGT localization and expression was determined by immunohistochemistry. RESULTS: Total corneal, endothelial, and epithelial GGT activities in the young (<50 years) donor corneas were 37% (P = 0.02), 44% (P = 0.001), and 36% (P = 0.06) higher, respectively, than in the senior (>=50 years) corneas. The age-related rates of decline for GGT activity were 1.0 unit per year for total cornea, 0.4 to 0.5 unit per year for endothelium, and 0.3 to 0.4 unit per year for epithelium. Notably, endothelial cell density in the young corneas was 14% (P = 0.001) higher than in the senior corneas declining about 100 cells per square millimeter per decade (0.3% per year). GGT activity per 10 endothelial cells decreased at about 0.2 units per year and GGT activity per 10 endothelial cells in the young corneas was 41% higher (P = 0.01) than in the senior corneas. Fewer immunoreactive GGT positive epithelial cells were detected in senior cornea. CONCLUSION: The age related loss of human corneal GGT activity was associated with reductions in endothelial and epithelial GGT activity, being because of reduced number of GGT positive endothelial and epithelial cells and reduced GGT activity per endothelial cell. PMID- 23023409 TI - The effect of low humidity on the human tear film. AB - PURPOSE: To investigate the effect of exposure to a low relative humidity (RH) environment on tear film physiology. METHOD: A controlled environment chamber was used to create 2 different environmental conditions. Ambient temperature was constant in both conditions (21 degrees C) while the RH was set at 40% at the normal condition and at 5% in the desiccating environment. Tear evaporation, noninvasive tear break-up time, lipid layer thickness (LLT), osmolarity, ocular comfort, tear production, and ocular surface temperature were assessed in normal humidity and over a period of 60 minutes in the dry environment. RESULTS: There was significant change in tear evaporation rate (P = 0.00), noninvasive tear break-up time (P = 0.00), LLT (P = 0.00), ocular comfort (P = 0.00), and tear production (P = 0.01) after exposure to the desiccating environment. No significant differences were observed between normal and dry environmental conditions in tear osmolarity (P = 0.09) and ocular surface temperature (P = 0.20). CONCLUSIONS: Evaporation rate, tear LLT, ocular comfort, tear stability, and production were adversely affected by low RH. The tear film parameters observed after exposure to a desiccating environment for 1 hour were similar to those of the dry eye patient. Therefore, to avoid tear film disruption and possible ocular surface damage, the environmental conditions of dry locations need to be improved or the tear film should be protected against adverse environmental conditions. PMID- 23023410 TI - Effects of corneal cross-linking on contrast sensitivity, visual acuity, and corneal topography in patients with keratoconus. AB - PURPOSE: To assess the effects of corneal collagen cross-linking (CXL) on contrast sensitivity (CS), visual acuity, and corneal topography investigating possible predictors of efficacy. METHODS: Sixty-eight eyes of 34 patients with progressive keratoconus were enrolled in this prospective study. CXL was performed in one eye and the other eye was left untreated as a control. CS, best spectacle-corrected visual acuity (BSCVA), simulated keratometry in the steepest meridian (SimK-s), mean power in the central 3-mm zone (C-MP), mean power in the paracentral 3- to 5-mm zone (P-MP), maximum keratometric power in the central zone (C-Kmax), and maximum keratometric power in the paracentral zone (P-Kmax) were evaluated at baseline, 40 days, 3 months, 6 months, 1 year, and after 2 years of follow-up. RESULTS: Treated eyes showed an improvement (P < 0.001) of +0.16 logCS and -0.16 logarithm of the minimum angle of resolution (logMAR) and a reduction in SimK-s of -0.61 diopter (D), C-Kmax -1.11 D, P-Kmax -0.99 D, C-MP 0.39 D, and P-MP -0.30 D. Of the treated eyes, 43.3% had a decrease in C-Kmax greater than 1 D, 50% by 0 to 0.99 D, and 6.7% had an increase of up to +0.89 D. Treated eyes with keratometric apex in the central 3-mm zone (CKA) improved BSCVA -0.19 logMAR and CS +0.19 logCS; whereas in treated eyes with paracentral keratometric apex (PKA), the improvement was -0.13 logMAR and +0.16 logCS. CONCLUSIONS: CXL with riboflavin and UV-A improved CS and inhibited the progression of keratoconus. As a predictor of treatment efficacy, eyes with CKA showed greater improvement in BSCVA after CXL when compared with eyes with PKA. PMID- 23023412 TI - [Structural study on small molecules in biological solid samples by using solid state NMR]. AB - Many small molecule drugs have molecular targets that are non-crystalline and insoluble biological matrices, such as proteins embedded in lipid membrane, cell membranes, and cell walls. To understand the action mechanisms, it is essential to determine the binding structure with atomic-level resolution. Although solution nuclear magnetic resonance (NMR) and X-ray crystallography have been used to determine molecular structures of cell membrane and membrane proteins, these methods are unable to reproduce the complexity of biological systems because either solubilization or crystallization of target molecules is requisite. For structural studies of insoluble non-crystalline biological samples, so-called "biological solids", high resolution distance measurements using solid-state NMR are indispensable techniques, of which rotational-echo double-resonance (REDOR) is one of the most widely used methods. In this paper, a brief introduction to REDOR NMR and its applications to structural studies on the antifungal amphotericin B-membrane phospholipid complex and a structural elucidation of photorespiration metabolites in plant cells without extraction or isolation is provided. PMID- 23023411 TI - The efficacy and safety of episcleral pigmentation removal from pig eyes: using a 532-nm quality-switched Nd: YAG laser. AB - PURPOSE: To evaluate the efficacy and safety of removing episcleral pigmentation from pig eyes using a 532-nm Q-switched Nd:YAG laser. METHODS: Forty-four porcine eyes with episcleral pigmentation were enucleated approximately 3 hours after death. After conjunctival dissection, 0.5*1.0 cm-sized segments of pigmented episcleral surface underwent laser treatment. To determine the minimal energy fluence required for effective episcleral pigmentation removal, the laser output was set to 2, 3.2, 4, 5, and 6 J/cm for 20 eyes. To investigate thermal effects, the surface temperatures of the episclera were measured in the remaining 24 eyes before and after laser treatment in which the minimal energy fluence required to effectively remove episcleral pigmentation was used. RESULTS: Episcleral pigmentation began to fade immediately with a laser setting of 2 J/cm and was satisfactorily removed immediately with a laser setting of 4 J/cm. The increase in surface temperature was 0.90+/-0.37 degrees C from baseline with a laser setting of 4 J/cm (P>0.05). Light-microscopic analysis showed that levels of melanin granules decreased by laser treatment in all tested episcleral tissues. The retinal pigment epithelium and the choroid were not affected by treatment. However, the collagen fiber structure was damaged after laser treatment with settings of more than 5 J/cm, as showed by the loss of straight profiles, although the damage was confined to the outer one third of the scleral stroma. CONCLUSIONS: 532-nm Q-switched Nd:YAG laser treatment is effective and safe for the removal of episcleral pigmentation in pig eyes. Our findings indicate that the laser system may be effective for the removal of episcleral pigmentation in cases of oculodermal melanocytosis, and further investigation is necessary to evaluate long-term safety of laser treatment. PMID- 23023413 TI - [Death domain-associated protein (DAXX)-mediated regulation of transcription and cell death]. AB - Death domain-associated protein (DAXX) is a multifunctional protein that modulates both cell death and transcription. DAXX predominantly localizes in the nucleus and regulates the transcription of genes. Several studies have indicated that DAXX is a mediator of lymphocyte death and/or growth suppression, although it is still unclear whether DAXX pro-cell death function is dependent on its transcriptional functions. We found that DAXX suppresses the gp130/STAT3 dependent cell growth and that DAXX interacts with STAT3 and inhibits its DNA binding activity. Here we will discuss recent developments in our understanding of the nuclear functions of DAXX. PMID- 23023414 TI - [Development of HPLC with high-sensitive and precise electrochemical detection enabling dynamic analysis of compounds of biological importance]. AB - HPLC with electrochemical detection (HPLC-ECD) is an attractive method with sensitivity and selectivity for the determination of redox compounds. However, an improper system makeup or operation is apt not to show such the intrinsic characteristics of the analytical results by HPLC-ECD in regards to biological sample assays. In this review, HPLC-ECD enabling high-sensitive and precise analysis of compounds of biological importance was developed using the following chemometric strategies: spectrum analysis of chromatographic baseline noise, standard deviation (S.D.) of area measurements in baseline noise from stochastic aspects, and optimization of HPLC conditions and method validations in HPLC-ECD using the prediction of precision based on the FUMI (Function of Mutual Information) theory. When HPLC-ECD was established using a capillary column (0.2 mm i.d.), catechins were determined at attomole levels and the present HPLC-ECD was applied to the determination of concentration profiles of catechins in human plasma after green tea ingestion. Moreover, two HPLC-ECD systems for determining acids and bases were developed by the means of the voltammetric reduction of quinone and the oxidation of trolox, respectively. Thus, the application of HPLC ECD methods has been remarkably expanded through the development of novel ECD for the determination of acids and bases which are less active electrochemically. The present methods for determining acids and bases were applied to the pharmacokinetic studies of free fatty acids and theophylline, respectively. In conclusion, it was shown the present HPLC-ECD methods have been successfully applied to biomedical and pharmaceutical analyses. PMID- 23023415 TI - [Development of novel methods for preparing chiral non-steroidal anti inflammatory drugs (NSAIDs) by asymmetric esterification]. AB - A novel and efficient method for preparing chiral 2-arylalkanoic acid derivatives, including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, ketoprofen, fenoprofen, flurbiprofen, and naproxen, and their esters by asymmetric esterification is presented in this paper. A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic 2 arylalkanoic acids with achiral alcohols, using carboxylic anhydrides in the presence of chiral acyl-transfer catalysts. It was found that the combination of the modified benzotetramisole-type catalyst, (S)-beta-Np-BTM, and a newly designed nucleophile, di(alpha-naphthyl)methanol, in the presence of a carboxylic anhydride, p-methoxybenzoic anhydride (PMBA) or pivalic anhydride (Piv2O), is most suitable for producing the corresponding chiral esters from 2-arylpropionic acid derivatives, with high enantiomeric excess under very mild reaction conditions. Using this new chiral acylation system, fairly broad substrate scope could be realized despite the multi-functional groups on the aromatic ring of the substrate. It was also revealed that ortho-substituted aromatic compounds, especially, 2,5-disubstituted aromatic ones were the most suitable compounds for providing a high selectivity. PMID- 23023416 TI - [Study on the discovery of novel chitinase inhibitors based on natural products]. AB - Chitin, the second most abundant polysaccharide in nature, is a constituent of fungal cell walls, the exoskeletons of crustaceans and insects and the microfilarial sheaths of parasitic nematodes. Chitin has, so far, not been found in mammals. Accumulation of chitin by organisms is modulated by chitin synthase mediated biosynthesis and by chitinase-mediated hydrolytic degradation. Thus, chitinases are expected to be specific targets for antifungal, insecticidal and antiparasitic agents. Paradoxically, while chitin does not exist in mammals, human chitinase family members, such as acidic mammalian chitinase, have recently been described, and offer significant potential for the treatment of asthma and other related diseases in humans. This review covers the development of two chitinase inhibitors of natural origin, Argifin and Argadin, isolated from the cultured broth of microorganisms in our laboratory. In particular, the practical total synthesis of these natural products and discovery methods that generate only highly-active compounds using a kinetic target (chitinase)-guided synthesis approach (termed in situ click chemistry) are described. PMID- 23023417 TI - [Factors affecting the pharmacokinetics after living donor liver transplant]. AB - Fifty-five thousand organ transplants are performed each year around the world. It is now estimated that over 300,000 organ transplant recipients are alive worldwide. Most of these transplant recipients will remain on immunosuppressive drugs for the remainder of their lives to prevent rejection episodes. Doses of these medications must be judiciously managed to optimize patient outcomes. Subtherapeutic drug concentrations may lead to graft rejection and subsequent graft loss. Supratherapeutic drug concentrations increase the likelihood of drug toxicities and increase the likelihood of opportunistic infections. In this review, the latest reports concerning the factors affecting the pharmacokinetics of tacrolimus and micafungin after living donor liver transplant (LDLT) are summarized. Our experimental results demonstrate that preoperative assessment of cytochrome P450 3A5 (CYP3A5) genotypes in both recipients and donors and an immune cell function assay would be useful not only for predicting tacrolimus pharmacokinetics but also for defining groups at high-risk of infectious complications after LDLT. Finally, monitoring plasma trough micafungin concentrations allows safe and effective dose titration of micafungin in LDLT recipients with total bilirubin concentrations greater than 5 mg/dL. PMID- 23023418 TI - [Evaluation for antithrombotic agents by a thrombotic model in animals]. AB - To investigate cerebral infarction and intracranial hemorrhage (ICH) in relation to antithrombotic agents, we established an animal stroke model induced by using a combination of a photosensitive dye and local green photoillumination. Microplasmin (MUPli), a derivative of plasmin lacking the five "kringle" domains, was administered in this model, and its effect was studied using magnetic resonance imaging. MUPli treatment reduced cerebral damage 24 h after middle cerebral artery occlusion; it also reduced the expansion of the positive area on perfusion-weighted images between 1 and 24 h and the degree of neurological deficits. Tissue-type plasminogen activator (t-PA), a serine proteinase that converts plasminogen to plasmin, has been approved for treating acute ischemic stroke, but delayed treatment is associated with increased risk of ICH. Plasmin participates in the degradation of fibrin, causing clot lysis, and of various extracellular matrix proteins, either directly or via the activation of matrix metalloproteinases (MMPs). In this study, we observed that MMP-3 is relatively important in the enhanced risk of ICH induced by delayed t-PA treatment for ischemic stroke. In particular, the binding of t-PA with low-density lipoprotein receptor-related protein (LRP) results in the release of MMP-3 by endothelial cells. LRP production is upregulated in endothelial cells exposed to ischemia, and elevated LRP levels have been implicated in the increased ICH risk associated with delayed t-PA treatment. This implies that the t-PA/LRP/MMP-3 pathway may be a suitable target for developing strategies to improve the therapeutic efficacy of t-PA in acute ischemic stroke. PMID- 23023419 TI - [Effect of bisphosphonates on anticancer activity in prostate cancer cells]. AB - Bisphosphonates are widely used to treat for osteoporosis and have recently been suggested to be effective in preventing tumor metastasis to the bone. One of the mechanisms underlying metastasis inhibition by bisphosphonates has been explained on the basis of the direct effects of these drugs on cancer cells in the bone microenvironment. Here we have focused on the effect of bisphosphonates on anticancer activity in prostate cancer cells because these cancer cells frequently metastasize to the bone. We found that nitrogen-containing bisphosphonates induced apoptosis and inhibited invasion in prostate cancer PC-3 cells. Bisphosphonate pretreatment was found to enhance cell death induced by anticancer drugs. The expression of the apoptosis- or invasion- related factors, bcl-2, protein kinase C (PKC), aminopeptidase-N (AP-N), and urokinase-type plasminogen activator (uPA) decreased on treatment with nitrogen-containing bisphosphonates. The molecular mechanisms underlying the decrease in bcl-2, AP-N, and uPA expression involved suppression of protein prenylation through inhibition of the mevalonate pathway. These findings have implications with respect to understanding the mechanisms underlying the suppressive effect of bisphosphonates on bone metastasis of prostate cancer. PMID- 23023420 TI - [In situ photopolymerization of polyacrylamide-based preconcentrator on a microfluidic chip for capillary electrophoresis]. AB - Microchip electrophoresis is widely used for microfluidics and has been studied extensively over the past decade. Translation of capillary electrophoresis methods from traditional capillary systems to a microchip platform provides rapid separation and easy quantitation of sample components. However, most microfluidic systems suffer from critical scaling problems. One promising solution to this problem is online sample preconcentration of all analytes in a sample reservoir before the separation channel. Herein, the following three techniques for online preconcentration during microchip electrophoresis are proposed: (1) in situ fabrication of an ionic polyacrylamide-based preconcentrator on a simple poly(methyl methacrylate) microfluidic chip for perm-selective preconcentration and capillary electrophoretic separation of anionic compounds, (2) simultaneous concentration enrichment and electrophoretic separation of weak acids on a microchip using an in situ photopolymerized carboxylate-type polyacrylamide gels as the perm-selective preconcentrator, and (3) microchip electrophoresis of oligosaccharides using lectin-immobilized preconcentrator gels fabricated by in situ photopolymerization. These techniques are expected to be powerful tools for clinical and pharmaceutical studies with on-line preconcentration during microchip electrophoresis. PMID- 23023422 TI - [Transcriptional regulation of the endothelial cell-specific receptor, Robo4]. AB - Roundabout4 (Robo4) is a transmembrane receptor that belongs to the Robo family of neural cell adhesion molecules. Robo4 has been shown to play a role in endothelial cell (EC) migration, proliferation, angiogenesis, and stabilizing the vasculature. Robo4 is expressed specifically in ECs in the developing embryo, placenta, tumors, and normal tissues. The goal of our study is to understand the mechanism for Robo4 gene expression. In the previous study we demonstrated that EC-specific Robo4 gene expression was regulated by the 3-kb Robo4 promoter in the 5'-flanking region of the human Robo4 gene. In vitro studies demonstrated that the Robo4 promoter is activated by the transcription factors GA-binding protein (GABP) and SP1 through the ETS binding site at -119 and the 2 SP1 binding sites at -42 and -153, respectively. The functional relevance of these sites was confirmed by in vivo reporter gene assays using Hprt locus knock in mice. In addition to the regulation mechanism by transcription factors, our recent study implicated that epigenetic modification of the promoter contributes to the Robo4 gene expression. Here I will discuss the regulation mechanism of Robo4 gene expression by transcription factors and epigenetic control. PMID- 23023421 TI - [TRIC(trimeric intracellular cation)-A channels contribute to blood pressure maintenance in vascular smooth muscle]. AB - TRIC (trimeric intracellular cation) channel subtypes, namely TRIC-A and TRIC-B, are intracellular monovalent cation channels postulated to mediate counter-ion movements facilitating physiological Ca2+ release from intracellular stores. Tric a-knockout mice developed hypertension during the daytime due to enhanced myogenic tone in resistance arteries. There are two Ca2+ release mechanisms in vascular smooth muscle cells (VSMCs); incidental opening of ryanodine receptors (RyRs) generates local Ca2+ sparks to induce hyperpolarization, while agonist induced activation of inositol trisphosphate receptors (IP3Rs) evokes global Ca2+ transients causing contraction. Tric-a gene ablation inhibited RyR-mediated hyperpolarization signaling to stimulate voltage-dependent Ca2+ influx, and adversely enhanced IP3R-mediated Ca2+ transients by overloading Ca2+ stores in VSMCs. Therefore, TRIC-A channels contribute to maintaining blood pressure in vascular smooth muscles. PMID- 23023423 TI - [Development research of new Zn complexes with anti-diabetic effect--structure activity-related studies by displacement of coordination atom]. AB - The number of patients suffering from diabetes mellitus in 2007 was reported to be approximately 200 million people worldwide. Since the finding of insulinomimetic activity of Zn ion, several insulinomimetic Zn complexes have been reported. Zn complexes are expected to be useful in the treatment of diabetes mellitus. We reported that Zn complexes with coordinating sulfur atom exhibit higher insulin-mimetic activity. In this study, we investigated the pharmacological and pharmacokinetic differences between Zn(O4) and Zn(S2O2) coordination environments of tropolonate-Zn complexes with antidiabetic effect. Among the tropolonate-Zn complexes with various coordination environments, di(2 mercaptotropolonato)Zn with the Zn(S2O2) coordination environments was found to exhibit the highest in vitro insulinomimetic activity with respect to glucose uptake in isolated rat adipocytes treated with adrenaline. In vivo experiments, di(2-mercaptotropolonato)Zn was found to exhibit potent hypoglycemic activity and improve insulin resistance in type 2 diabetic KKA(y) mice at a low orally administered daily dose. On the other hand, di(tropolonato)Zn, which has the Zn(O4) coordination mode, had a lesser effect at the same dose. In a pharmacokinetic analysis based on the tracer method, di(2-mercaptotropolonato)Zn was found to be absorbed at a significantly slower rate with a longer half-life than di(tropolonato)Zn. These results suggest that the potent hypoglycemic activity of di(2-mercaptotropolonato)Zn with Zn(S2O2) coordination environments might be attributed to its long half-life. PMID- 23023424 TI - [Development of target-specific gene therapy system by controlling distribution of interferon]. AB - Interferon-gamma (IFN-gamma) is a type II IFN that possesses various biological activities including antivirus effect and antitumor effect. Because of its potent biological activities, IFN-gamma has been used as a therapeutic treatment for cancer patients and is expected to be a therapeutic for other diseases. As the half-life of IFN-gamma in blood circulation is very short, IFN-gamma gene therapy, in which IFN-gamma gene is used to continuously supply IFN-gamma protein, is a promising approach because it can continuously supply IFN-gamma. To improve therapeutic effect of IFN-gamma-based gene therapy, it is important to control the spatiotemporal distribution of IFN-gamma expressed from the plasmid DNA vector encoding IFN-gamma. We developed a method to regulate the time profile of IFN-gamma expressed from plasmid DNA by modifying vector backbone. In addition, we developed a method that can increase retention time of IFN-gamma in blood circulation by designing IFN-gamma encoded in plasmid vector as a fusion protein with mouse serum albumin (MSA). Regulation of time profile of IFN-gamma expression was highly effective in avoiding unwanted effect of IFN-gamma without decreasing therapeutic effect. In addition, gene delivery of MSA-IFN-gamma fusion protein increased retention time of IFN-gamma in blood circulation than native IFN-gamma gene delivery did. Thus, designing both plasmid vector and therapeutic protein encoded by the vector is a promising approach to controlling the spatiotemporal distribution of proteins which can increase the therapeutic potency of IFN-gamma-based gene therapy as well as safety of in vivo IFN-gamma gene therapy. PMID- 23023425 TI - [Search for biofunctional constituents from medicinal foods-elucidation of constituents with anti-proliferation effects and the target molecule from Citrullus colocynthis]. AB - Many foods are known to have not only nutritive and taste values but also medicinal effects. In Egypt, many medicinal foods have been used for the prevention and treatment of various diseases since ancient. However, in most cases, their effective constituents as well as the mechanism of action remained uncharacterized. In the course of our characterization studies on Egyptian medicinal foods and plants, cucurbitane-type triterpene and related compounds such as cucurbitacin E from the fruit of Citrullus colocynthis and the roots of Bryonia cretica were found to show anti-proliferation effects. We therefore synthesized a biotin-linked cucurbitacin E to isolate target proteins based on affinity for the molecule. As a result, cofilin, which regulates the depolymerization of actin, was isolated and suggested to be a target. PMID- 23023426 TI - [The role of microRNA-210 in esophageal squamous cell carcinoma]. AB - In this review, we summarize our findings on microRNA-210 (miR-210) and the target gene, and discuss their significance in human esophageal squamous cell carcinoma (ESCC). MicroRNAs are evolutionarily conserved small noncoding RNAs (20 23 nucleotides) that bind to complementary sequences in the 3' UTR of target mRNAs and regulate gene expression by the cleavage of target mRNAs and/or translational inhibition. MicroRNAs play important roles in the initiation and progression of cancer, and it has been shown that the expression of some microRNAs is altered in malignancies. Carcinomas are derived from epithelial cells, and poor prognosis in patients with carcinoma is associated with the disruption of characteristics of differentiated epithelial cells, such as cell junctions and polarity. Here, we identified miR-210 as one of the microRNAs that is markedly differentially expressed during the process of epithelial differentiation, though the clinical roles of miR-210 in carcinomas remained unknown. We show that the expression of miR-210 is downregulated in ESCC and derived cell lines. Marked decreases in the level of miR-210 were observed especially in poorly differentiated carcinomas. Moreover, we found that miR-210 inhibits cancer cell survival and proliferation. Finally, we identified fibroblast growth factor receptor-like 1 (FGFRL1) as a target gene of miR-210 in ESCC, and demonstrated that FGFRL1 accelerates cancer cell proliferation. Taken together, our findings show an important role for miR-210 as a tumor suppressive microRNA with effects on cancer cell proliferation. PMID- 23023427 TI - [Development of stimulus-responsive amino acids and their application to chemical biology use]. AB - An understanding of the physiological significance of peptides and proteins is indispensable in the fields of life sciences and drug development. Recently, methods for controlling peptide and protein activities using stimuli such as UV irradiation have been attracting much attention because of their potential for clarifying the physiological roles of the peptides/proteins. In this context, we have developed a stimulus-responsive amino acid that induces peptide-bond cleavage after exposure to a stimulus. Although it has previously been reported that stimulus-responsive units can respond to a specific stimulus, our stimulus responsive amino acid is potentially applicable to any stimulus simply by changing the protective group. In this review, the design and synthesis of stimulus-responsive amino acids are described. Their applications in chemical biology, including their use for spatiotemporal control of the activity of peptides in living cells, are also reported. PMID- 23023428 TI - [The role of pharmacy residents as preceptors on clinical training]. AB - Long-term clinical training programs started as part of a 6-year pharmacy course in May 2010. In order to provide training approaches more appropriately and efficiently, it is necessary for teaching facilities to develop effective training systems and curriculums. In Kobe City Medical Center General Hospital, a pharmacy residency system was instituted in 2009, and, based on this, a preceptorship program for clinical training was adopted. In this study, the influence of pharmacy residents as preceptors on clinical training was evaluated based on training reports submitted by 26 students, consisting of a total of 1238 pages; residents' comments were observed in 31.3% of them. Changes in students' awareness were also noted; in the course of training, they became more aware of the responsibility and role of pharmacists, and such awareness appeared to provide a basis for their future goals. Further, although most of the residents' comments were initially made for encouragement, concrete advice gradually increased with time. Residents' commitment to clinical training as preceptors may have facilitated students' understanding of the significance of training, while promoting their own development. PMID- 23023429 TI - Fatigue and its association with sleep disorders, depressive symptoms and anxiety in patients with multiple sclerosis. AB - BACKGROUND AND PURPOSE: The aetiopathogenesis of fatigue in multiple sclerosis (MS) is not clear. It could be associated with structural changes of the central nervous system, but also with mood and sleep disorders. The purpose of the study was to evaluate frequency of fatigue and its association with sleep and mood disorders in MS patients. MATERIAL AND METHODS: The examined group consisted of 122 MS patients (mean age 37.7 +/- 10.8 years). The following questionnaires were used: Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), Athens Insomnia Scale (AIS), Montgomery-Asberg Depression Rating Scale (MADRS), and Hospital Anxiety and Depression Scale (HADS). RESULTS: Fatigue was present in 75 MS patients (61.5%). Excessive daytime sleepiness was observed in 25 (20.5%), insomnia in 73 patients (59.8%). According to MADRS, depressive symptoms were present in 33 (27%), according to HADS in 15 people (12.3%). Anxiety was present in 32 patients (26.2%). We observed an association between fatigue (FSS) and sleep disorders (ESS, AIS) and also between fatigue and either depression (MADRS, HADS-D) or anxiety (HADS-A). The FSS score was not associated with age, sex, disease course and duration, Expanded Disability Status Stage (EDSS), treatment or level of education in MS patients. In inactive professionally people we noted significantly higher FSS scores (44.8 +/- 13.8) in comparison with active individuals (37.2 +/- 14.9; p = 0.0053). CONCLUSIONS: Fatigue is a very common symptom in MS, sometimes associated with sleep disorders, depressive symptoms or anxiety. The treatable causes of fatigue in MS such as sleep and mood disturbances should be identified and treated. PMID- 23023430 TI - Poor insight into memory impairment in patients with Huntington disease. AB - BACKGROUND AND PURPOSE: Patients suffering from Huntington disease (HD) have been shown to present with poor self-awareness of a variety of symptoms. The study aimed to assess the self-awareness of memory impairment in HD in comparison to advanced Parkinson disease (PD), mild PD and cervical dystonia. MATERIAL AND METHODS: Self-awareness was tested in 23 patients with HD by comparing patient and caregiver ratings in reference to clinical control groups (25 patients with advanced PD, 21 with mild PD and 20 with cervical dystonia). Self-awareness was tested using the Self Rating Scale of Memory Functions, which was administered to both the patients and the caregivers. Neuropsychological assessment addressed general cognitive status (Mini-Mental State Examination), verbal learning (Auditory Verbal Learning Test, 15-word list) and mood (Montgomery-Asberg Depression Rating Scale). RESULTS: Patients with HD significantly underestimated their memory dysfunction. Underestimation of memory deficit correlated with disease duration and disease severity in HD. CONCLUSIONS: Huntington disease patients underestimate memory dysfunction. These results add to the previous reports on poor insight in HD in other domains and suggest that anosognosia in HD, albeit usually rather mild, may be a generalized phenomenon. PMID- 23023432 TI - Surgical treatment of intraventricular ependymomas and subependymomas. AB - BACKGROUND AND PURPOSE: The aim of the study was to present our experience in the surgical treatment of intraventricular ependymomas and subependymomas with special consideration to the evaluation of the surgical outcome and risk of tumour recurrence. MATERIAL AND METHODS: We report a series of 36 consecutive patients treated surgically for intraventricular ependymoma or subependymoma in the years 1992-2008. There were 26 lateral ventricle and 10 fourth ventricle tumours. Complete resection was achieved in 19 patients while the remaining 17 patients underwent either subtotal or partial resection. Histopathological evaluation revealed ependymoma, subependymoma and anaplastic ependymoma in 20, 11 and 5 cases, respectively. RESULTS: Eight patients died after surgery due to postoperative brain injury. Five patients were severely disabled postoperatively: one patient developed hemiparesis, three patients presented adynamic syndrome, and one patient developed severe cerebellar ataxia subsequent to vermis injury. All patients with posterior fossa tumours presented with lower cranial nerve deficit. Seventeen patients received radiotherapy postoperatively. There were five recurrent tumours during follow-up; three patients underwent subsequent reoperation. Importantly, five patients with supratentorial tumours and a history of incomplete resection with postoperative radiotherapy had no tumour recurrence in over 10 years' follow-up. CONCLUSIONS: Intraventricular ependymomas and subependymomas still remain a surgical challenge due to a relatively high incidence of incomplete tumour resections and/or permanent neurological complications associated with their removal. Still, even incomplete tumour removal with subsequent radiotherapy facilitates long-term progression-free survival in some cases. PMID- 23023431 TI - Statistical analysis of the intracranial procedures in Poland in 2008-2009. AB - BACKGROUND AND PURPOSE: Quantitative and qualitative analysis of neurosurgical procedures provides important data for assessment of the development and trends in the field of neurosurgery. The authors present statistical data on intracranial procedures (IPs) performed in Poland in 2008-2009. MATERIAL AND METHODS: Data on IPs come from reports of the National Health Fund, grouped according to the system of Diagnosis-Related Groups, group A - nervous system diseases. Data concerning the year 2009 include all IPs performed in Poland. Data from the second half of 2008 to 2009 (18 months) come from 35 neurosurgical centers in Poland, divided by provinces. We analyzed the number of IPs, the cost of procedures, duration of hospitalization and deaths. RESULTS: 20 849 IPs were performed in Poland in 2009. The most common procedure was A12 (6807; 32.65%), and the rarest was A04 (96; 0.46%). The annual cost of all IPs was 228 599 956 PLN. Average cost of the procedure ranged from 1578 PLN (A14) to 47 940 PLN (A03). Duration of the hospitalization ranged between 3 days (A14) and 12 days (A12). The highest percentage of deaths was reported for A01 (n = 1050, 19.06%). Reports from 35 neurosurgical centers in the second half of 2008 and 2009 showed the highest number of IPs per 100 000 population in Kujawsko-Pomorskie (93) and the lowest in Wielkopolskie (27) and Podkarpackie (27). The highest number of IPs (1669) was performed in neurosurgical center M1 (Malopolskie), and the lowest (99) in W1 (Wielkopolskie). CONCLUSIONS: A significant disparity in the number of IPs performed in different centers in Poland was observed. PMID- 23023433 TI - Finite element method for analysis of stresses arising in the skull after external loading in cranio-orbital fractures. AB - BACKGROUND AND PURPOSE: The craniofacial skeleton remains not fully recognised as far as its mechanical resistance properties are concerned. Heretofore, the only available information on the mechanism of cranial bone fractures came from clinical observations, since the clinical evaluation in a living individual is practically impossible. It seems crucial to implement computer methods of virtual research into clinical practice. Such methods, which have long been used in the technical sciences, may either confirm or disprove previous observations. The aim of the study was to identify the areas of stress concentrations caused by external loads, which can lead to cranio-orbital fractures (COF), by the finite element method (FEM). MATERIAL AND METHODS: For numerical analysis, a three dimensional commercially available geometrical model of the skull was used which was imported into software of FEM. Computations were performed with ANSYS 12.1 Static Structural module. The loads were applied laterally to the frontal squama, the zygomatic process and partly to the upper orbital rim to locate dangerous concentration of stresses potentially resulting in COF. RESULTS: Changes in the area of force application revealed differences in values, quality and the extent of the stress distribution. Depending on the area of force application the following parameters would change: the value and area of stresses characteristic of COF. CONCLUSION: The distribution of stresses obtained in this study allowed definition of both the locations most vulnerable to fracture and sites from which fractures may originate or propagate. PMID- 23023434 TI - Cross-cultural adaptation and reliability evaluation of Iranian version of Functional Assessment Measure in spinal cord injury patients. AB - BACKGROUND AND PURPOSE: The aim of this study was to translate and validate the Iranian version of the Functional Assessment Measure (FAM) among patients with spinal cord injury (SCI). MATERIAL AND METHODS: Two hundred patients with SCI participated in this study. A convenience sampling approach was used for selection of the patients. The FAM was translated into Persian language and then independently translated back into English. The reliability of the FAM was assessed by test-retest methods with a 14-day interval for interrater reliability. Intraclass correlation coefficient (ICCs) was calculated and interrater reliability and intrarater reliability were assessed. RESULTS: The mean age of the patients was 35.7 years (SD, 7.2) and 86% of patients were male.The Cronbach alpha coefficient for both raters was above 0.70. Intrarater reliability of the Iranian version of the FAM ranged from good to excellent agreement. The highest level of intrarater reliability was observed for Community mobility (ICC = 0.93). There was good to excellent agreement for interrater reliability of the FAM. The FAM could differentiate between subgroups of patients based on the level of injury but not for the time elapsed from the injury. CONCLUSIONS: Based on the results of this study, the Iranian version of the FAM (FAM-Ir) was highly valid and reliable for evaluation of functional ability in patients with SCI. Therefore, we would suggest that the FAM could also be used as an assessment tool for SCI patients. PMID- 23023435 TI - [Post-polio syndrome. Part I. The "legacy" of forgotten disease, challenges for professionals and polio survivors]. AB - The outcome of paralytic polio was believed to be a stable neurological state. Now, it is established that polio has an additional, slowly progressive phase, called post-polio syndrome (PPS) that develops 30-40 years after the acute poliomyelitis in 25-80% of paralytic and about 40% of nonparalytic polio survivors. The clinical symptoms are nonspecific and usually include muscle weakness, fatigue and muscle or joint pain. Some patients suffer from muscular atrophy, respiratory insufficiency, dysphagia, sleep disturbances or cold intolerance. The etiopathogenesis of PPS is unclear and many factors, such as dysfunction of the surviving motor units, aging, defects of neuromuscular transmission, persistence of viral infection and immunological mechanisms, are considered. PMID- 23023436 TI - [Post-polio syndrome. Part II. Therapeutic management]. AB - The care of patients with post-polio syndrome ought to be carried out by a multidisciplinary team of specialists, including medical professionals, specialists of rehabilitation, psychologists and social workers. Many therapeutic strategies might be employed to reduce the late effects of polio. Today, the management of post-polio syndrome is based on non-pharmacological intervention, including lifestyle modification, decrease of physical activity, rest periods during the day and an individually tailored training program. PMID- 23023437 TI - [Joubert syndrome and related disorders]. AB - The cerebellum plays a role not only in motor control but also in motor learning and cognition. Joubert syndrome is a rare heterogeneous inherited genetic disorder characterized by ataxia, hypotonia, developmental delay, and at least one of the following features: neonatal respiratory disturbances or abnormal eye movement. The estimated frequency of Joubert syndrome in the United States is around 1 : 100 000. The term Joubert syndrome and related disorders (JSRD) has been recently coined to describe all disorders presenting with molar tooth sign on brain neuroimaging. Joubert syndrome is believed to be a representative of a new group of disorders named ciliopathies. The identification of seven causal genes (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67/MKS3, ARL13B, CC2D2A) has led to substantial progress in the understanding of the genetic basis of Joubert syndrome. The authors focus on clinical presentation of JSRD, differential diagnosis and molecular background. PMID- 23023438 TI - [TDP-43 proteinopathies - from frontotemporal lobar degeneration to inclusion body myositis]. AB - TDP-43, a newly described neurodegenerative protein, is of great interest to both neurologists and geneticists. At the beginning, its dysfunction was recognized in sporadic amyotrophic lateral sclerosis, frontotemporal lobar degeneration with ubiquitinated inclusions and in mixed forms. However, it was also proved that TDP 43 inclusions are in addition present in many other diseases, for example in inclusion body myositis. Furthermore, many genes and different loci may be involved in pathological TDP-43 accumulation in cells and tissues. Mutations in the TARDPB gene, progranulin gene (PGRNVCP) as well as a gene on chromosome 9p were found. The present paper is a summary on possible involvement of TDP-43 in various neurodegenerative disorders. PMID- 23023439 TI - [Results of treatment of refractory depression by left vagus nerve stimulation - report of two cases]. AB - Depressive disorders are the fourth most common disease causing the patients' disability worldwide. They are associated with increased morbidity and mortality, not only because of the increased risk of suicide but also because of cardiac complications and stroke. Depression also results in negative economic impacts due to exclusion of treated patients from their daily activities. There is an increased frequency of consultations and hospitalizations in patients with depression. On average, over one third of patients do not respond or poorly respond to conservative treatment. Vagus nerve stimulation (VNS) may be effective in these patients. In March 2001, VNS was recognized in Europe as a treatment for depression in patients who are refractory or intolerant to conservative treatment, both in cases of major depressive episodes and in bipolar disease. In the United States, the method was recognized by the FDA in July 2005 as an adjunct treatment for long-term chronic refractory depression or for recurrent major depressive episodes refractory to conservative treatment in patients over 18 years of age who did not improve after four or more schemes of antidepressant therapy. The following is a report of two cases of patients with depression treated by left VNS. PMID- 23023440 TI - [Schwannoma of the common peroneal nerve. A differential diagnosis versus rare popliteal cyst]. AB - The presented case concerns a patient with neuralgia of the common peroneal nerve and progressive neurological deficit caused by interfascicular growth of schwannoma. The ultrasound diagnostics identified the lesion as a popliteal cyst. Magnetic resonance imaging revealed features of atypical cyst location. Due to the clinical course, it was decided to decompress the nerve trunk. An interfascicular tumor was identified intraoperatively. Particular nerve bundles were separated microsurgically and the tumor of schwannoma morphology was removed. The postoperative course brought resolution of neuralgia and improvement of peroneal nerve function. In the case in question attention was focused on the differential diagnostics of processes located in the popliteal fossa. Imaging examination indicated an atypical cyst location rather than a morphologically solid tumor. The clinical course is essential for determining the nature of the lesion. Decompressing the common peroneal nerve in microsurgical technique allows the prevention of further neurological symptoms in the postoperative course. PMID- 23023441 TI - [Occipito-cervical fixation in plasmocytoma. Method modification. Technical report]. AB - Intraoperative modification of use and stabilization of the Axon system (Synthes) for occipito-cervical fusion in a patient treated oncologically due to plasmocytoma is presented. Pathological fracture, range of the process and damage of anterior cervical fusion necessitated the use of occipito-cervical stabilization. Different anatomical conditions within the occipital bone in the form of its thinning was observed. Fixing with screws was impossible due to the bone structure. In consequence, modification of stabilization with an ad hoc elaborated technique (burr holes in the occipital bone and stabilization with titanium wire) was implemented. Modifications and specific indications related to the clinical course of plasmocytoma are discussed. PMID- 23023442 TI - [Fulminant adhesive arachnoiditis]. AB - Adhesive arachnoiditis is a rare disease with insidious course. It causes damage of the spinal cord and nerve roots. The causes of adhesive arachnoiditis include earlier traumatic injury of the spinal cord, surgery, intrathecal administration of therapeutic substances (e.g. anaesthetics, chemotherapy) or contrast media, bleeding, and inflammation. It can also be idiopathic or iatrogenic. We present the case of a 42-year-old patient with fulminant adhesive arachnoiditis which was provoked by spinal surgery and caused severe neurological disability with profound, progressive, flaccid paraparesis and bladder dysfunction. The electromyography (EMG) showed serious damage of nerves of both lower limbs at the level of motor roots L2-S2 and damage of the motor neuron at the level of Th11 Th12 on the right side. Magnetic resonance imaging of the lumbosacral and thoracic part of the spinal cord demonstrated cystic liquid spaces in the lumen of the dural sac in the bottom part of the cervical spine and at the Th2-Th10 level, modelling the lateral and anterior surface of the cord. Because of the vast lesions, surgery could not be performed. Conservative treatment and rehabilitation brought only a small clinical improvement. PMID- 23023445 TI - Advances in 2D boron nitride nanostructures: nanosheets, nanoribbons, nanomeshes, and hybrids with graphene. AB - The recent surge in graphene research has stimulated interest in the investigation of various 2-dimensional (2D) nanomaterials. Among these materials, the 2D boron nitride (BN) nanostructures are in a unique position. This is because they are the isoelectric analogs to graphene structures and share very similar structural characteristics and many physical properties except for the large band gap. The main forms of the 2D BN nanostructures include nanosheets (BNNSs), nanoribbons (BNNRs), and nanomeshes (BNNMs). BNNRs are essentially BNNSs with narrow widths in which the edge effects become significant; BNNMs are also variations of BNNSs, which are supported on certain metal substrates where strong interactions and the lattice mismatch between the substrate and the nanosheet result in periodic shallow regions on the nanosheet surface. Recently, the hybrids of 2D BN nanostructures with graphene, in the form of either in-plane hybrids or inter-plane heterolayers, have also drawn much attention. In particular, the BNNS-graphene heterolayer architectures are finding important electronic applications as BNNSs may serve as excellent dielectric substrates or separation layers for graphene electronic devices. In this article, we first discuss the structural basics, spectroscopic signatures, and physical properties of the 2D BN nanostructures. Then, various top-down and bottom-up preparation methodologies are reviewed in detail. Several sections are dedicated to the preparation of BNNRs, BNNMs, and BNNS-graphene hybrids, respectively. Following some more discussions on the applications of these unique materials, the article is concluded with a summary and perspectives of this exciting new field. PMID- 23023444 TI - The binding mechanism, multiple binding modes, and allosteric regulation of Staphylococcus aureus Sortase A probed by molecular dynamics simulations. AB - Sortase enzymes are vitally important for the virulence of gram-positive bacteria as they play a key role in the attachment of surface proteins to the cell wall. These enzymes recognize a specific sorting sequence in proteins destined to be displayed on the surface of the bacteria and catalyze the transpeptidation reaction that links it to a cell wall precursor molecule. Because of their role in establishing pathogenicity, and in light of the recent rise of antibiotic resistant bacterial strains, sortase enzymes are novel drug targets. Here, we present a study of the prototypical sortase protein Staphylococcus aureus Sortase A (SrtA). Both conventional and accelerated molecular dynamics simulations of S. aureus SrtA in its apo state and when bound to an LPATG sorting signal (SS) were performed. Results support a binding mechanism that may be characterized as conformational selection followed by induced fit. Additionally, the SS was found to adopt multiple metastable states, thus resolving discrepancies between binding conformations in previously reported experimental structures. Finally, correlation analysis reveals that the SS actively affects allosteric pathways throughout the protein that connect the first and the second substrate binding sites, which are proposed to be located on opposing faces of the protein. Overall, these calculations shed new light on the role of dynamics in the binding mechanism and function of sortase enzymes. PMID- 23023446 TI - The retrobulbar "spot sign" as a discriminator between vasculitic and thrombo embolic affections of the retinal blood supply. AB - PURPOSE: Sudden retinal blindness is a common complication of temporal arteritis (TA). Another common cause is embolic occlusion of the central retinal artery (CRA). The aim of this prospective study was to examine the diagnostic value of hyperechoic material in the CRA for the exclusion of vasculitis as a cause. The authors used orbital color-coded sonography (OCCS) for the detection of hyperechoic material. MATERIALS AND METHODS: 24 patients with sudden vision loss were included in the study after the exclusion of other causes (e. g. vitreous bleeding, retinal detachment). Parallel to routine diagnostic workup, OCCS was performed in all patients. RESULTS: 7 patients with a diagnosis of TA presented with different degrees of hypoperfusion in the CRA without hyperechoic material (referred to as "spot sign") detected by OCCS. Diagnostic workup in the remaining 17 patients revealed other causes of sudden vision loss, such as central retinal artery occlusion (CRAO) (12), anterior ischemic optic neuropathy (AION) (2), upstream vascular stenosis or occlusion (2) and delayed reperfusion of the CRA (1). The hyperechoic "spot sign" was visible in 10 of 12 patients (83 %) with embolic CRAO. The detection of embolic CRAO using the "spot sign" had a sensitivity of 83 % and a specificity of 100 %. The missing "spot sign" in patients with TA was a highly specific finding (p-value 0.01). CONCLUSION: The detection of the "spot sign" specifically minimizes the probability of TA as a reason for sudden blindness. PMID- 23023447 TI - Comparison between CT and CEUS in the diagnosis of pancreatic adenocarcinoma. AB - PURPOSE: The aim of this study is to compare CEUS and MDCT features of pancreatic ductal adenocarcinoma in relation to tumor size. MATERIALS AND METHODS: All patients with pathological diagnosis of pancreatic adenocarcinoma and studied by means of CEUS and MDCT were enrolled in this study. Two radiologists evaluated tumor size, site and imaging appearance. Patients in which at least one method yielded a positive result were divided into 4 groups on the basis of lesion size. For each dimensional category, sensitivity of the two imaging methods was calculated and compared using McNemar test. RESULTS: One hundred thirty-three patients were included in this study. In 9 of 133 patients neither MDCT nor US/CEUS could identify the lesion, while in 9 of 133 patients only MDCT and in 13 of 133 only US/CEUS could identify the lesion. In the remaining 102 patients, both MDCT and US/CEUS yielded a positive result. US/CEUS sensitivity was 86.47% while MDCT sensitivity was 83.58%, with no statistically significant difference (p = 0.523). For lesions smaller than 2 cm US/CEUS had a 100% sensitivity, while MDCT had a 73.33% sensitivity with no statistically significant difference (p = 0.125). For lesions between 2.1 and 3 cm US/CEUS had a sensitivity of 95.35%, while MDCT had a sensitivity of 83.72% with no statistically significant difference (p = 0.180). For lesions between 3.1 and 4 cm, US/CEUS had a sensitivity of 87.88%, while MDCT had a sensitivity of 93.94% with no statistically significant difference (p = 0.688). For lesions larger than 4 cm US/CEUS, had a sensitivity of 90.91%, while MDCT had a sensitivity of 100% with no statistically significant difference (p = 0.250). CONCLUSION: US/CEUS sensitivity in diagnosing pancreatic ductal adenocarcinoma is adequate and does not statistically differ from that of MDCT. US/CEUS sensitivity seems to be higher for small and medium lesions, while MDCT sensitivity is higher for large lesions. By combining both the imaging methods a higher accuracy in diagnosing pancreatic ductal adenocarcinoma can be expected. PMID- 23023448 TI - Impact of preoperative bilateral whole breast sonography in patients with invasive lobular carcinoma: results from two medical centers. AB - PURPOSE: The purpose of this study was to evaluate the sensitivity of bilateral whole breast sonography (BWBS) combined with mammography for the detection of additional lesions, as well as index lesions, in patients with invasive lobular carcinoma (ILC) and to evaluate the impact of BWBS on surgical treatment and cancer staging strategies. MATERIALS AND METHODS: We retrospectively reviewed mammographic and sonographic records of 97 patients with proven ILCs between November 2002 and November 2009. We evaluated the sensitivity of mammography and BWBS for the detection of additional and index lesions. We compared the impact of BWBS on surgical treatment and breast cancer staging between cases with single index lesions and with BWBS-detected additional lesions and index lesions. We compared the differences in sensitivity, surgical treatment procedures and breast cancer staging between BWBS and MRI confined to the patients underwent MRI. RESULTS: The overall sensitivity was 74.4% (93/125 lesions) for mammography and 96.0% (120/125 lesions) for BWBS (p < 0.001). The group with additional lesions detected using US alone exhibited more frequent mastectomy (p = 0.003) and higher N staging (p = 0.051) than did the group with single index lesions. Comparing the BWBS and MRI cases, there were no significant differences in lesion staging, the sensitivity of malignant foci detection (p = 0.074). CONCLUSION: BWBS has a higher sensitivity than does mammography for the detection of index and additional ILC. Detection of additional malignancies using BWBS could affect which strategy is chosen for surgical treatment. PMID- 23023450 TI - [Impact of duplex ultrasound on diagnosis and therapy of Lienalis Steal syndrome following liver transplantation]. PMID- 23023451 TI - Feasibility of 3D ultrasound to evaluate upper extremity nerves. AB - PURPOSE: This study investigates the performance of a 3 D Ultrasound (US) system in imaging elbow and wrist nerves. MATERIALS AND METHODS: Twenty healthy volunteers with asymptomatic median, ulnar and radial nerves were prospectively investigated. Bilateral 3DUS scans of the elbows and wrists were acquired by using a commercially available US scanner (18 MHz, AplioXG, Toshiba) and stored as a 3 D volume by a dedicated software (CURE, Robarts Research Institute). Retrospectively, qualitative (image quality, atypical nerve location, findings potentially associated with compression neuropathy) and quantitative (cross sectional area measurements) evaluations were performed. RESULTS: In all 200 nerves 3DUS was feasible (100%). Image quality was insufficient in 13.5% (25 ulnar nerve elbow, 2 radial nerve) and sonomorphology was not assessable in those nerves. Measurement of cross sectional areas was feasible in all nerves (100%). Median cross-sectional area (range) were: median nerve elbow 7 mm2 (6-9), radial nerve 3 mm2 (1-4), ulnar nerve elbow 8 mm2 (5-11), median nerve wrist 8 mm2 (5 10), and ulnar nerve wrist 4 mm2 (2-6). No significant changes in nerve cross sectional area along each nerve was found. Ulnar nerve subluxation was found in 2 nerves (6.7%). No anconeus epitrochlearis muscle or osteophytes were found. CONCLUSION: 3DUS is a feasible method for assessing nerves of the upper extremity and has been shown to provide a good overview of the median, ulnar and radial nerve at the elbow and wrist, but is limited for evaluation of the ulnar nerve in the cubital tunnel. This technique enables reliable measurements at different locations along the nerve. PMID- 23023452 TI - Spontaneous active bleeding in thoracoacromial artery diagnoses by contrast enhanced ultrasound - a case report. PMID- 23023453 TI - Is US-guided core needle biopsy (CNB) enough in probably benign nodules with interval growth? AB - PURPOSE: To investigate whether ultrasound-guided 14-gauge core needle biopsy (US CNB) is efficient in the diagnosis of probably benign lesions showing interval growth on follow-up US. MATERIALS AND METHODS: From March 2008 to August 2009, 116 breast lesions in 113 women (mean age: 41.2 years, range: 19 - 63 years) which were initially assessed as category 3 showing interval growth on follow-up US underwent US-CNB, and subsequent US-guided vacuum-assisted excision, surgical excision or follow-up US for at least 12 months. Diagnostic performances of US CNB were evaluated with histopathologic results and follow-up US as standard reference. Clinical features of the patient and lesions characteristics including follow-up interval (I), the most increased diameter (D), D per I, increased volume (%V) and %V per I were calculated and compared. RESULTS: Of the 116 lesions, 4 lesions were diagnosed as malignancy and 112 as benign on final pathology. Malignancy rate of probably benign lesions showing interval growth was 3.4 % (4/116). Incorrect biopsy rate was 0.9 % (1/116). Palpability or newly developed suspicious US features were more associated with malignancy, 75.0 to 13.4 % and 50.0 to 25.9 %, respectively, but without significance (p = 0.063 and 0.290). Significant differences were seen in average rank when comparing between benign and malignancy in D, %V, D per follow-up interval (I), and %V/I (p = 0.037, 0.017, 0.043 and 0.009, respectively). CONCLUSION: US-CNB is an efficient diagnostic method for probably benign lesions showing interval growth, with discordant biopsy rate of 0.9 %. PMID- 23023455 TI - Variability of shear wave velocity using different frequencies in acoustic radiation force impulse (ARFI) elastography: a phantom and normal liver study. AB - PURPOSE: To assess the variability of shear wave velocity (SWV) from acoustic radiation force impulse (ARFI) elastography at various depths using different frequencies. MATERIALS AND METHODS: ARFI elastography of the elasticity phantom and normal liver was performed at different depths (2-5 cm) with convex (1-4 MHz) and linear (4-9 MHz) probes. Ten valid SWV measurements at each depth were performed. This was repeated ten times with the phantom and performed in eight healthy volunteers (M:F = 3:5, age 20-34 years). The mean value and standard deviation of the SWV were calculated. RESULTS: In both the phantom and liver, the mean velocities as measured by two probes at the same depth were different. Variabilities of SWV at different depths were also different for the two probes. The depth with lower variability in the phantom was 4 and 5 cm with a convex probe and 2 cm with a linear probe. In the liver, the depth with lower variability was 4 cm with a convex probe and 3 and 4 cm with a linear probe. In comparative analysis of the two probes, the linear probe displayed a lower variability at a depth of 2 and 3 cm in the phantom and at 3 cm in the liver, whereas the convex probe displayed a lower variability at a depth of 4 cm in both the phantom and the liver. CONCLUSION: SWVs and variability are different depending on the depth and the frequency used. SWVs with a low frequency probe had a tendency to be higher at the same depth. To reduce variability of SWV, a high frequency probe is recommended for a depth of 2-3 cm, and a low frequency probe is recommended for a depth of 4-5 cm. PMID- 23023454 TI - Vasa praevia: risk-adapted modification of the conventional management--a retrospective study. AB - PURPOSE: Undiagnosed vasa praevia carries an imminent risk of fetal death and increases with IVF. When diagnosed, the question arises as to whether the conventional prenatal management of routine steroid administration for fetal lung maturation and elective caesarean section in week 35 is generally justified in face of the risks involved. We present a retrospective study of a risk-adapted modification of the conventional management of vasa praevia. MATERIAL AND METHODS: We analysed 11 years of records involving 18 cases of antenatally diagnosed vasa praevia at our perinatal centre. Each case was managed by a risk adapted modification of the conventional treatment where both, the steroid administration and the timing of delivery, were dependent on the patient history and clinical signs for preterm birth. RESULTS: There were no lethal fetal, neonatal, or maternal complications. The earliest caesarean section took place at 34 weeks 1 day, the latest at 37 weeks 1 day, and in more than half of the cases at >= 36 weeks. CONCLUSION: Steroid application is generally recommended for pregnancies before 34 weeks carrying a risk for preterm birth. Thus, retrospectively, none of our cases required steroid administration. This supports our protocol of not obligatorily administering steroids. Delaying the caesarean section up to two weeks beyond the conventionally recommended date of 35 weeks in 78% of our cases resulted in no complications. This justifies the suitability of determining the timing of delivery based on our individual patient assessment. In conclusion, the following recommendations for a risk-adapted management of vasa praevia can be made: 1. weekly evaluation of risk factors for preterm delivery; 2. steroid administration only at risk for preterm birth; 3. admission to hospital with full obstetric and neonatal care facilities between 32 and 34 weeks; 4. elective caesarean section between 35 and 37 weeks, risk-adapted. PMID- 23023456 TI - Impact of two reflex pelvic floor muscle contraction patterns on female stress urinary incontinence. AB - PURPOSE: To explore the impact of two reflex pelvic floor muscle contraction patterns during coughing on incontinence severity and incontinence-related quality of life in women with stress urinary incontinence (SUI). MATERIALS AND METHODS: A total of 208 women with the symptomatic and urodynamic evidence of SUI and 126 women with no experience of urinary incontinence were recruited in a 5 year period. During hard coughs, reflex pelvic floor muscle contraction was detected using introital ultrasound and two reflex contraction patterns were recognized: an inward clitoral motion and a superior-anterior anorectal lift. The assessment of incontinent severity and impact of quality of life included 1-hour pad tests and short forms of the Urogenital Distress Inventory and the Incontinence Impact Questionnaire. RESULTS: There is no significant difference in the demographics and the distribution and concordance of two reflex contractions between women with or without urinary incontinence. Neither type of reflex contraction during coughing was identified in 14 incontinent women (7%) and 5 continent women (4%). The concordant rate for synchronous activities of both reflex contractions during coughing was 80% (167) and 81% (102) for incontinent and continent women, respectively. Incontinent women without clitoral reflex motion had significantly greater incontinent severity on 1-hour pad tests (p = 0.018) and higher sum scores of the short form of Incontinence Impact Questionnaire (p = 0.026). By contrast, incontinent women with and without reflex anorectal lifts had similar incontinence severity and impact. CONCLUSION: In women with SUI, loss of clitoral reflex motion is associated with worse incontinent severity and impact. PMID- 23023457 TI - Dog bites: an opportunity for parent education in the pediatric emergency department. AB - OBJECTIVES: This study focuses on parental report of exposure to dogs and highlights the potential for using a computer kiosk in an urban pediatric emergency department to increase knowledge around dog bite safety. METHODS: Nine hundred one parents of young children completed a kiosk assessment and received a report that contained information aimed at increasing knowledge about either dog bite prevention (PAR-DB, n = 453) or other safety behaviors (PAR-S, n = 448). The participants who received the dog bite prevention report (PAR-DB) were asked questions about exposure to dogs as part of the baseline assessment. All participants were telephoned 2 to 4 weeks later for a follow-up interview to measure knowledge differences. RESULTS: The majority of respondents who answered the exposure questions reported seeing stray dogs (53%) and having dangerous dogs (43%) in their neighborhood. Few respondents reported that their child had been bitten by a dog (1%), but the majority (56%) reported having knowledge of another child having been bitten. Few respondents reported having a dog in their home (11%), and only 1 reported that her dog had bitten a child. A majority (56%) of dogs had not been spayed or neutered. Of families with dogs in the home, 20% reported leaving their child unattended with the dog. A minority (45%) of dogs left alone with children had been spayed or neutered. CONCLUSIONS: PAR-DB parents achieved knowledge gains as a result of the Parent Action Report generated by the kiosk, demonstrating the potential to improve knowledge via a computer kiosk in a busy pediatric emergency department. PMID- 23023458 TI - Use of computed tomography in the emergency department for the diagnosis of pediatric peritonsillar abscess. AB - OBJECTIVE: The objective of this study was to review our pediatric emergency department's (ED's) utilization of computed tomography (CT) in the diagnosis of peritonsillar abscess (PTA) and treatment outcomes. METHODS: This study used case series with chart review. RESULTS: From January 2007 to January 2009, 148 patients were seen in our ED for possible PTA. Mean age at presentation was 11.8 years (range, 10 months to 18 years); 81 (54.7%) of 148 were females. Computed tomography was ordered in 96 (64.9%) of 148 patients, of which 73 (49.3%) 148 were confirmed to have PTA. Mean age of patients who underwent CT was younger when compared with those who did not have CT performed (mean, 11 vs 13 years; P = 0.02). Unilateral PTA was found in 65 (43.9%) of 148, bilateral in 8 (5.4%) of 148, and intratonsillar in 25 patients (16.9%). Concomitant CT findings of parapharyngeal space involvement were found in 19 (12.8%), and retropharyngeal space involvement in 11 (7.4%). Admission was necessary for 104 (71.2%) of 148 patients, whereas 42 were discharged from the ED. Transoral needle aspiration and/or incision and drainage were performed in the ED in 41 patients, with purulence identified in 33 (80.5%) of 41. Rapid strep testing was positive in 40 (32%) of 124 patients tested. Operative treatment was necessary in 44 patients (29.7%), 34 underwent incision and drainage, and 10 underwent quinsy tonsillectomy. CONCLUSIONS: Computed tomography is commonly utilized in the ED for the evaluation of PTA and is ordered more often in younger children. PMID- 23023460 TI - Cost analysis and provider satisfaction with pediatrician in triage. AB - OBJECTIVES: The goals of this study were to (1) conduct a cost-benefit analysis, from a hospital's perspective, of using a pediatrician in triage (PIT) in the emergency department (ED) and (2) assess the impact of a physician in triage on provider satisfaction. METHODS: This was a prospective, controlled trial of PIT (intervention) versus conventional registered nurse-driven triage (control), at an urban, academic, tertiary level pediatric ED, which led to a cost-benefit analysis by looking at the effect that PIT has on length of stay (LOS) and thus on ED revenue. Provider satisfaction was assessed through surveys. RESULTS: During the 8-week study period, a total of 6579 patients were triaged: 3242 in the PIT group and 3337 in the control group. The 2 groups were similar in age, sex, admission rate, left-without-being-seen rate, and level of acuity. The mean LOS in the PIT group was 24.3 minutes shorter than in the control group. The costs of PIT seem to be increased and are not offset by savings; the net margin (total revenue minus costs) was $42,883 per year lower in the PIT than in the control group. Sensitivity analysis showed that if the LOS were reduced by more than 98.4 minutes, the cost savings would favor PIT. Most of the physicians and nurses (67%) reported that PIT facilitated their job. CONCLUSIONS: Placement of a PIT during periods of peak census resulted in shorter stay and notable provider satisfaction but at an incremental cost of $42,883 per year. PMID- 23023459 TI - Herpes simplex testing in neonates in the emergency department. AB - OBJECTIVES: To determine the prevalence of central nervous system (CNS) herpes simplex virus (HSV) infection in neonates evaluated in the emergency department and to identify factors associated with cerebrospinal fluid (CSF) HSV polymerase chain reaction (PCR) testing. An existing testing paradigm was then applied to determine its potential impact on testing frequency. METHODS: This nested case control study included infants aged 0 to 28 days who had lumbar puncture in the emergency department. Multivariate logistic regression was used to identify factors associated with CSF HSV PCR testing. RESULTS: The CSF HSV PCR testing was performed in 266 (47%) of 570 neonates. The prevalence of CNS HSV infection was 0.5% compared with 1.6% for bacterial meningitis. Performance of CSF HSV PCR testing was not associated with known HSV risk factors. Application of a known HSV testing paradigm would have reduced the proportion of infants tested by 21% without missing any of the cases of CNS HSV infection. CONCLUSIONS: The HSV testing remains common despite the low prevalence of HSV infection. The CSF HSV PCR testing is not well aligned with known risk factors. Future testing strategies should incorporate community HSV prevalence, known neonatal risk factors, and clinical judgment. PMID- 23023461 TI - Low rates of follow-up with primary care providers after pediatric emergency department visits for respiratory tract illnesses. AB - OBJECTIVES: We sought to determine diagnosis-specific rates of follow-up with primary care providers (PCPs) after emergency department (ED) visits for respiratory tract illnesses. We hypothesized that follow-up rates would be higher among patients with acute infectious illnesses than among those with asthma. METHODS: This was a retrospective cohort study of a random sample of patients aged 0 to 12 years discharged over a 12-month period from an urban, tertiary care pediatric ED with 4 different respiratory tract illnesses (asthma, bronchiolitis, croup, and pneumonia). Primary care provider follow-up was examined for associations with sociodemographic and clinical factors and with subsequent ED visits. RESULTS: Rates of follow-up in the overall cohort were low: 23.6% (95% confidence interval, 19.7-27.4) by 7 days and 40.5% (95% confidence interval, 36.0-44.9) by 30 days. Compared with patients with asthma, the relative risks (RRs) of follow-up within 7 and 30 days were significantly higher among patients with bronchiolitis and pneumonia, but not with croup. For the cohort as a whole, the RR of follow-up within 7 and 30 days significantly decreased for each 1-year increase in age, and the RR of follow-up within 7 days significantly increased with the provision of explicit ED discharge instructions recommending follow-up. Among patients with asthma, follow-up with PCPs within 30 days was not associated with decreased ED visits for asthma over the following year. CONCLUSIONS: Rates of PCP follow-up were globally low but significantly higher for patients with acute infectious illnesses, for younger patients, and for those receiving explicit ED discharge instructions. PMID- 23023462 TI - Adolescent synthetic cannabinoid exposures reported to Texas poison centers. AB - OBJECTIVE: This study describes the pattern of adolescent synthetic cannabinoid exposures reported to a large statewide poison center system. METHODS: Synthetic cannabinoid exposures among patients younger than 20 years reported to Texas poison centers during January 2010 to June 2011 were identified. The distribution of exposures by various demographic and clinical factors was determined. RESULTS: For 305 adolescent exposures, the mean age was 16.7 years (range, 12-19 y). The exposure was by inhalation in 77.4% of the cases, and 72.1% involved males. The exposure site was the patient's own residence in 70.5% of the cases, and a health care facility was the caller site in 68.9%. The patient was already at or en route to a health care facility in 80.3% of the cases, and the medical outcome was serious in 61.0%. The most frequently reported adverse clinical effects were tachycardia (41.6%), drowsiness/lethargy (24.3%), agitation/irritability (16.4%), vomiting (13.1%), hallucinations/delusions (11.5%), nausea (8.5%), confusion (8.2%), hypertension (7.5%), chest pain (6.9%), and dizziness/vertigo (5.2%). CONCLUSIONS: Adolescent synthetic cannabinoid exposures reported to Texas poison centers were more likely to involve inhalation. The adolescents were more likely to be male. The exposures more often occurred at the patient's own residence and managed at a health care facility with a serious outcome. This pattern of exposures was similar to that observed among adults. PMID- 23023463 TI - A profile of nonurgent emergency department use in an urban pediatric hospital. AB - OBJECTIVES: This study was designed to develop a descriptive profile of parents and caregivers who bring their children to the emergency department (ED) for nonurgent issues and to explore the reasons for presenting to an urban hospital pediatric ED for nonurgent conditions. Such work is necessary to develop effective interventions. METHODS: A total of 106 parents/caregivers whose child was triaged with a nonemergent/urgent condition completed a 15- to 20-minute computerized survey (English and Spanish) in an urban pediatric ED. RESULTS: Most respondents described themselves as Latino (76%) and foreign born (62%). About one half (49%) reported having an annual income of less than $20,000, and 43% of respondents did not have health insurance for themselves. Almost all (95%) of the index children had a primary care physician and health insurance. Despite being triaged as nonurgent, more than one half (63%) described their child's condition as "very" or "extremely" urgent. About one half of the respondents reported not receiving basic information on childhood illnesses from their child's physician. Reasons for nonurgent visits seemed to revolve around issues of convenience and perception of quality of care. CONCLUSIONS: Interventions should focus on health literacy and ensure that parents are provided relevant and accurate education on pediatric illnesses and common safety concerns; by increasing parental education on pediatric health, parents may be better able to assess acuity of their child's health issues. PMID- 23023464 TI - Bispectral analysis during procedural sedation in the pediatric emergency department. AB - OBJECTIVE: Our primary objective was to determine the maximum depth of sedation achieved, as measured by the bispectral (BIS) index monitor, for pediatric patients undergoing procedural sedation in a pediatric emergency department. METHODS: This prospective, blinded, observational study was conducted in a tertiary pediatric emergency department. Procedural sedation and analgesia were performed in the standard manner, with the addition of blinded BIS index monitoring. In addition, both the sedating physician and the procedural physician recorded their clinical impression of the maximum depth of sedation. RESULTS: A convenience sample of 50 patients was enrolled. The median age was 9.2 years (range, 3-15 y). The mean nadir BIS index was 43.1 +/- 17.4 (SD), with a 95% confidence interval from 37.8 to 48.4. This was significantly lower than the BIS index value that is considered to reflect general anesthesia (<60; P > 0.0001). Almost 80% of the analyzed patient sedations were classified as having achieved general anesthesia. When comparing the sedating physician and the procedural physician's clinical assessment of maximal depth of sedation with the nadir BIS index value, there was only slight agreement between the 2 groups (kappa statistics, 0.19 and 0.057, respectively). Ninety-three percent of the sedating physicians and 88% of the procedural physicians underestimated the maximum depth of sedation of their patients. CONCLUSIONS: This study suggests that most pediatric procedural sedation patients spend at least a period in a general anesthetic state. During most procedural sedation, the physicians involved are likely underestimating the maximal depth of sedation for their patients. PMID- 23023465 TI - Transfer of simulated lumbar puncture training to the clinical setting. AB - OBJECTIVE: To show that with a combination of evidence-based didactic and hands on skill demonstration, pediatric interns will be able to correctly perform lumbar punctures (LPs) on neonates in the actual clinical setting. METHODS: Twenty-three pediatric and internal medicine/pediatric first year residents attended a 1-hour course during their orientation. The course consisted of an evidence-based presentation, reviewing anatomy, indications, complications, and techniques for performing LPs, including a video presentation, followed by hands on practice of LPs. All interns were anonymously surveyed preintervention and postintervention. The survey results were compared for each learner. After the intervention, interns were individually assessed by a single investigator using a standardized checklist during an LP of an actual pediatric patient during their first year of residency. RESULTS: Pretest and posttest knowledge improved by approximately 12% (P < 0.05). Preintervention confidence and experience were low among learners. Twenty-one of 23 interns completed a follow-up assessment of an LP on an actual pediatric patient. The average on the assessment was 9.7 +/- 1.1 of 11 (88% +/- 10%). The average number of LP attempts was 1.4 +/- 0.5. The steps most frequently missed were preparing the supplies and performing the LP with the bevel of the needle parallel to the spinal ligament, with only 48% of interns performing each of these steps correctly. CONCLUSIONS: A task trainer-based course improved the confidence and knowledge about an important pediatric procedure. This confidence and knowledge can translate to actual clinical practice. Further investigations are necessary to support this knowledge and skill translation. PMID- 23023467 TI - Acute encephalopathy with pandemic (H1N1) 2009 virus infection. AB - OBJECTIVES: In April 2009, a novel influenza A (H1N1) pdm virus was identified in Mexico and spread quickly around the world. However, the clinical features of acute encephalopathy associated with 2009 pandemic influenza have not yet been elucidated. METHODS: We treated 8 patients (3 boys and 5 girls) aged 4 to 11 years (average age, 8 y 3 months) with influenza virus-associated encephalopathy, who presented at our 2 hospitals between July 2009 and March 2010. We investigated the clinical characteristics, treatments, and outcomes in the patients. RESULTS: In all patients, brain computed tomography showed mild to severe diffuse cerebral edema, and electroencephalography revealed diffuse high voltage slow waves. They were all treated with oseltamivir and methylprednisolone pulse therapy. Six patients recovered without any sequelae; however, the remaining 2 had residual neurological sequelae. These 2 patients presented with severe disturbance of consciousness, and their central nervous system symptoms appeared within 12 hours after the onset of fever. One patient had periventricular leukomalacia and symptomatic epilepsy by perinatal brain hypoxia, and the other patient had 1 complex febrile and 2 febrile seizures. CONCLUSIONS: This study showed that patients with influenza-associated encephalopathy caused by influenza A (H1N1) pdm infection were all older than those with seasonal influenza. Underlying neurological disease or history may be associated with poor prognosis. PMID- 23023466 TI - Respiratory viruses identified in an urban children's hospital emergency department during the 2009 influenza A(H1N1) pandemic. AB - OBJECTIVES: Two surges in influenza-like illness (ILI) visits to Children's Medical Center Emergency Departments, Dallas and Legacy, occurred in late spring (wave 1) and late summer 2009 (wave 2). This study describes respiratory viruses identified during the first weeks of waves 1 and 2 of the 2009 influenza A(H1N1) pandemic (pH1N1) and compares patients infected with pH1N1 with those infected with other respiratory viruses during wave 1. METHODS: From April 27 to May 7 and August 23 to September 7, 2009, nasopharyngeal swab specimens from all patients with temperature 38.2 degrees C or higher plus 2 or more symptoms of ILI were tested by rapid antigen, direct fluorescent antibody, or multiplex polymerase chain reaction assays. Patients with pH1N1 during wave 1 were classified as cases and 3 age- and sex-matched controls were randomly selected from patients with 1 respiratory virus other than pH1N1. Odds ratios (ORs) and associated 95% confidence intervals (95% CIs) of characteristics associated with patients with pH1N1 were estimated using conditional logistic regression models. RESULTS: During wave 1, single viruses identified in 1023 symptomatic children were confirmed pH1N1 (55, 5.4%), rhinovirus (505, 49.4%), parainfluenza 3 (199, 19.5%), and human metapneumovirus (169, 16.5%). By multivariable analysis, duration of fever (OR, 1.49; 95% CI, 1.02-2.20) and myalgia at presentation (OR, 3.09; 95% CI, 1.09-8.76) were independent predictors associated with pH1N1. During wave 2, 114 (59.7%) of single viruses were pH1N1. CONCLUSIONS: During the epidemic of ILI in Spring 2009, other respiratory viruses were identified more frequently than pH1N1 influenza in children with ILIs. Clinical presentation was similar for all respiratory viruses. Molecular diagnostic testing can define the prevalent viruses during community outbreaks and provide guidance to physicians making treatment decisions in emergency departments. PMID- 23023468 TI - A survey of the management of febrile infants in pediatric emergency departments. AB - OBJECTIVE: To determine whether emergency departments (EDs) at pediatric emergency medicine (PEM) fellowship training institutions have a departmental policy regarding the evaluation and management of febrile infants and if reported policies are based on published guidelines (PGs). METHODS: A 32-item telephone survey was administered to PEM fellowship directors (FDs). Departmental demographics and criteria used to evaluate febrile infants were collected. Scenarios were presented regarding the evaluation and management of low-risk febrile infants. Reported consistency among ED attending physicians at the same institution was also assessed. RESULTS: The response rate was 83% (53 of 64). Fifty-one percent (26 of 53) of FDs reported the existence of a departmental policy regarding the evaluation of febrile infants. Of those who have a departmental policy, 19% (5 of 26) stated that it was one of the PGs. The FDs who reported the existence of a departmental policy were significantly more likely to report consistent management by all ED attending physicians in their department compared with those without a departmental policy (81% vs 19%, P < 0.05). The most frequent age and temperature cutoff for a mandatory sepsis evaluation were 28 days (45%, 28 of 53) and 100.4 degrees F (66%, 35 of 53). The FDs reported a lack of consistency among ED attending physicians at the same institution regarding age and temperature (66% and 17% of the time, respectively). Eighty five percent (45 of 53) of FDs reported that a new guideline is needed. CONCLUSIONS: Nearly one half of EDs at PEM fellowship training institutions are reported not to have a departmental policy regarding the management of febrile infants, and departmental policies rarely conform to any of the PGs. There is substantial interdepartmental and intradepartmental practice variability regarding the management of febrile infants and a strong consensus regarding the need for a new guideline. PMID- 23023469 TI - Management of afebrile neonates with skin and soft tissue infections in the pediatric emergency department. AB - OBJECTIVE: To describe the management of afebrile neonatal skin and soft tissue infections (SSTIs) in the pediatric emergency department (PED). METHODS: This is a retrospective cohort study of all patients aged 0 to 28 days seen in the PED for SSTIs from 2004 to 2010. The SSTIs were identified from the International Classification of Diseases, Ninth Revision codes of pustulosis, cellulitis, and abscess. Records were reviewed to determine the absence of fever; anatomical location; cultures of blood, urine, and cerebrospinal fluid; antibiotic usage; and return visits. Data were analyzed to compare admitted versus discharged patients with SSTI subtypes. RESULTS: Of the 136 neonates identified, 104 met inclusion criteria. Afebrile SSTIs included 8 pustulosis, 45 cellulitis, and 51 abscesses. Blood cultures were obtained in 13% of pustulosis, 96% of cellulitis, and 69% of abscesses. No serious bacterial infection was noted. Three blood cultures grew contaminants. Parenteral antibiotics for neonates with pustulosis, cellulitis, and abscesses were given in 13%, 87%, and 59%, respectively. Admission rates for neonates with pustulosis, cellulitis, and abscesses were 13%, 84%, and 55%, respectively. Cases of cellulitis were more likely to have blood cultures drawn (odds ratio [OR], 13.7; 95% confidence interval [CI], 3.03-62.3), receive intravenous antibiotics (OR, 5.87; 95% CI, 2.16-15.0), and be admitted to the hospital (OR, 5.62; 95% CI, 2.16-14.6) as compared with the other SSTI subtypes. CONCLUSIONS: None of the neonates who had cultures drawn had serious bacterial infection. The SSTI subtype correlated with the extent of evaluation and dispositions. The findings of this study will help with management strategies for afebrile neonates with SSTIs in the PED. PMID- 23023470 TI - Procalcitonin as a marker of bacteremia in children with fever and a central venous catheter presenting to the emergency department. AB - OBJECTIVE: To evaluate the clinical use of procalcitonin (PCT) as a rapid marker for the identification of bacteremia in the emergency department (ED) population of children with fever and a central venous catheter (CVC). METHODS: Children were identified on presentation to the ED with a chief complaint of fever and who had a CVC. Fever was defined as 38 degrees C or higher orally. Patients were excluded from the study if they had received antibiotics within the previous 24 hours of presenting to the ED, if they had a peripherally inserted central catheter line or by parental refusal. On presentation to the ED, all patients had a complete blood cell count with differential, blood culture from the central line, and PCT levels drawn. All had empiric antibiotics initiated. Blood culture results were recorded, and in the case of positive cultures, time to positive culture was noted. RESULTS: Sixty-two patients (aged 5 months-18 y) were enrolled, and 14 (23%) had a positive culture. Mean PCT value in bacteremic patients was 18.47 +/- 31.6 ng/mL and 0.65 +/- 1.2 ng/mL in nonbacteremic patients (P < 0.001). Median PCT for negative blood culture was 0.23 ng/mL (interquartile range, 0.11-0.61) and 1.15 ng/mL for a positive blood culture (interquartile range, 0.45-29.16). The receiver operating characteristic analysis identified a level of PCT of 0.3 ng/mL as the best cutoff point that produced a sensitivity of 93% and a specificity of 63% (area under the curve, 0.82). CONCLUSIONS: The PCT levels are useful in identifying children with fever and a CVC who are bacteremic in the ED. PMID- 23023471 TI - The impact of watching cartoons for distraction during painful procedures in the emergency department. AB - OBJECTIVE: The purpose of this study was to determine whether the viewing of cartoons in the acute care setting reduces the perception of pain by pediatric patients. METHODS: A convenience prospective study of pediatric patients in pain was performed at a community teaching level I pediatric and adult emergency department, with 44,000 patient visits per year. The inclusion criteria for entry into the study were any child who presented to the emergency department in acute pain from any cause. The younger children were randomized to watch a Barney cartoon in Spanish or English, and the older children were randomized to view a Tarzan cartoon in Spanish or English. The younger children were assessed 5 minutes before the procedure, during the procedure, and 5 minutes after the procedure using Poker Chip Tool and Faces Scale. The older children were assessed at the same time interval using self-reporting and a visual analog scale. The study was internal review board approved. A difference of 20% or greater was considered a significant difference. The data were analyzed using a general linear model-repeated measures a priori level of significance of P < 0.05. RESULTS: There was a significant difference within subject effects: F(1)= 9.268, significant at 0.03, with observed power at 0.85 or 85%, with the alpha set at 0.05 or less. A comparison of the groups revealed that there were no differences in the causes of pain (F(1) = 0.301, P = 0.585), pain duration (F(1) = 0.062, P = 0.084), or type of anesthesia, if used (F(1) = 0.064, P = 0.804) between groups. This lack of difference was upheld for age (F(1) = 3.0407, P = 0.068), race (F(1) = 0.537, P = 0.466), and sex (F(1) = 0.002, P = 0.964). CONCLUSIONS: The finding that cartoon viewing was effective does illustrate 1 more pain relief tool for use in the ED when pediatric patients present. It is useful because of the fact that it does not interfere with assessment of patients' presenting or underlying problems. The need for more ways in which to address pediatric pain persists. PMID- 23023472 TI - Does a prehospital Glasgow Coma Scale score predict pediatric outcomes? AB - BACKGROUND: Although the Glasgow Coma Scale (GCS) score is widely used by medical professionals to evaluate and predict neurological outcomes, studies using the prehospital (P) GCS score to predict neurological outcomes in children are few. OBJECTIVE: The objective of this study was to determine the agreement between the P GCS score and the emergency department (ED) GCS score, and the association between P GCS score and outcomes at hospital discharge in pediatric patients 5 to 18 years of age. METHODS: Medical record review of children 5 to 18 years old with traumatic brain injury (TBI) was conducted. Children with documented P and ED GCS scores were eligible for enrollment. The hospital records of each enrolled child were reviewed, and the Glasgow outcome score and the disability rating scale scores were calculated. Agreement between the P and ED GCS scores was calculated using chi (kappa statistic). RESULTS: One hundred eighty-five subjects were included. There was strong agreement between P and ED GCS scores (kappa = +0.69; confidence interval, 0.57-0.81). The Glasgow outcome score category improved with improving GCS category. The median disability rating scale score was also similar for P and ED GCS scores and was higher with decreasing GCS. CONCLUSIONS: Our data showed strong agreement between P and ED GCS scores. Also, there was strong association between P GCS scores and short-term outcomes in children with TBI. The results support the use of GCS in prehospital transport destination guidelines for children with TBI. PMID- 23023473 TI - Screening for adolescent anxiety disorders in a pediatric emergency department. AB - OBJECTIVES: Adolescence is a time of increasing risk for some anxiety disorders. Scant data exist on adolescent anxiety in emergency department (ED) settings. We sought to characterize select clinical characteristics and health care use associated with anxiety disorders in a pediatric ED. METHODS: We screened a convenience sample of 100 adolescent-parent dyads presenting to the ED for the presence of child anxiety disorders using the 5-item Screen for Child Anxiety Related Emotional Disorders, parent (SCARED-P) and child (SCARED-C) versions. Additional demographic and clinical data were also collected. RESULTS: The SCARED P and SCARED-C screens identified probable anxiety disorder(s) in 26% to 33% of adolescent participants, respectively. Correlates of positive SCARED-C screens were female sex, asthma, presenting complaint involving headache or migraine, and school absenteeism due to physical problems. Correlates of positive SCARED-P screens were lower parental educational level, presenting complaint involving headache or migraine, and more medical specialty and total medical visits. Few anxious adolescents had received mental health services in the past 6 months. In multivariate models, female sex was independently associated with SCARED-C total score, and presenting complaint involving headache or migraine was independently associated with SCARED-P total score. CONCLUSIONS: The current pilot data suggest that anxiety disorders are more prevalent among adolescent ED patients than among the general population but largely untreated. Several demographic and clinical variables may help to identify occult anxiety disorders. Greater awareness of anxiety disorders in this population may assist in redirecting a pattern of low use of mental health services but higher overall health care use. PMID- 23023474 TI - Children with and without developmental disabilities: sedation medication requirements and adverse events related to sedation. AB - OBJECTIVE: Our objective was to prospectively compare sedation medication requirements and adverse events related to sedation in children with and without developmental disabilities. METHODS: We conducted a prospective, observational, age-matched, 1:2 case-control study of children (3-10 years) sedated for brain magnetic resonance imaging at a tertiary-care children's hospital. Developmental assessment was performed using the Vineland Adaptive Behavioral Scale and by a pediatric neurologist. Patients were sedated according to institutional sedation protocol. Patient demographics, type and dose of sedation medications, depth of sedation, and adverse events were collected. We defined hypoxia as oxygen saturation 90% or less for 30 seconds or longer and requiring airway maneuvers. RESULTS: Seventy children were designated as cases (DD) and 140 as controls (DN). DD had a significantly lower mean Vineland Adaptive Behavioral Scale score than did DN (DD: 62.34 +/- 9.70, DN: 103.0 +/- 13.71; P < 0.001). A combination of pentobarbital and fentanyl (DD: 32/70 [45.7%], DN: 60/140 [42.9%]) and combination of pentobarbital and midazolam (DD: 28/70 [40%], DN: 43/140 [30.7%]) were the most common sedatives used in both groups. There was no difference in the mean dose of pentobarbital (DD:4.68 +/- 1.63 mg/kg, DN:4.67 +/- 1.69 mg/kg; P = 0.9), fentanyl (DD: 0.61 +/- 0.65 MUg/kg, DN: 0.64 +/- 0.65 MUg/kg; P = 0.7), and midazolam (DD: 0.15 +/- 0.17 mg/kg, DN: 0.11 +/- 0.14 mg/kg; P = 0.1). There was no difference in the overall adverse events (DD: 30%, DN: 32.9%; P = 0.7) as well as hypoxia (DD: 10%; DN: 9.3%, P = 0.9). CONCLUSIONS: When compared with DN children, DD children do not require a higher dose of sedatives and do not have a higher incidence of adverse events. PMID- 23023475 TI - The effect of Lactobacillus GG on acute diarrheal illness in the pediatric emergency department. AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of the probiotic Lactobacillus GG (LGG) in reducing the duration of acute infectious diarrhea in the pediatric emergency department. METHODS: We conducted a double blind, randomized controlled trial of children 6 months to 6 years presenting to the pediatric emergency department with a complaint of diarrhea. Patients were randomized to receive either placebo or LGG powder twice daily for 5 days. With each dose, parents recorded the stool history in a home diary and were followed up daily by a blinded researcher. Groups were compared in terms of time to normal stool and number of diarrheal stools. RESULTS: Of 155 patients enrolled, 129 completed the study: 63 in the LGG group and 66 in the placebo group. There was no significant difference in the median (interquartile range) time to normal stool (LGG: 60 hours [37-111] vs placebo: 74 hours [43-120]; P = 0.37) or the number of diarrheal stools (LGG: 5.0 [1-10] vs placebo: 6.5 [2-14]; P = 0.19). Among children who presented with more than 2 days of diarrhea, the LGG group returned to normal stool earlier (LGG: 51 hours [32-78] vs placebo: 74 hours [45 120]; P = 0.02), had fewer episodes of diarrheal stools (LGG: 3.5 [1.0-7.5] vs placebo: 7 [3.0-16.3]; P = 0.02), and were 2.2 times more likely to return to normal stool (95% confidence interval, 1.3-3.9; P = 0.01) compared with children in the placebo group. CONCLUSIONS: Lactobacillus GG may reduce the duration of acute diarrheal illness among children presenting with more than 2 days of symptoms. PMID- 23023476 TI - Who should be reading chest radiographs in the pediatric emergency department? AB - BACKGROUND: Pediatric emergency department chest radiographs are frequently interpreted by the pediatrician, and patient management is based on this interpretation. OBJECTIVE: The purpose of this study was to assess the chest radiograph interpretation discordance rate between pediatricians and pediatric radiologists and determine its clinical significance. METHODS: This study included 1196 patients admitted off-hours to the pediatric emergency department who had chest radiographs as part of the clinical evaluation. The pediatricians' interpretations of the chest radiographs as appeared in the discharge reports were reviewed and compared with the specialist radiologist's ultimate report. RESULTS: Discordant chest radiograph interpretations were found in 332 (28%) of 1196 patients. Of these, 76 (6.3%) were clinically significant. These included 59 initial diagnoses of normal or viral patterns subsequently interpreted as bacterial pattern by the radiologist and 17 radiographs with findings such as chronic lung disease or abnormal heart shadow overlooked or misinterpreted by the pediatrician. CONCLUSIONS: Although the clinically significant discordant rate was relatively low, daily chest radiograph reassessment by pediatric radiologists in a joint meeting with pediatricians has an added value for patient safety, quality assurance, and mutual training. PMID- 23023477 TI - Facilitating surgical research across Europe. PMID- 23023478 TI - Characterization of the weak calcium binding of trimeric globular adiponectin. AB - Adiponectin is secreted from adipose tissue and functions as a protein hormone in regulating glucose metabolism and fatty acid catabolism. Adiponectin plays an important role as a novel risk factor and potential diagnostic and prognostic biomarker in cancer. Crystal structures of globular adiponectin have been resolved with three calcium-binding sites on the top of its central tunnel. However, the calcium-binding property of adiponectin remains elusive. Mouse globular adiponectin was cloned into pET11a and expressed in Escherichia coli. The folding of adiponectin was indicated by the spread of resonances in HSQC spectrum. Luminescence resonance energy transfer was used to obtain the binding constant (K(d)) of Tb(3+) and the inhibitor constant (K(i)) of Ca(2+) for globular adiponectin. The obtained calcium-binding affinity to adiponectin is relatively low (~2 mM), which indicates that the high concentration of adiponectin in circulating system may function as calcium storage bank and buffer the free calcium concentration. PMID- 23023479 TI - Oxovanadium(IV)-catalysed oxidation of dibenzothiophene and 4,6 dimethyldibenzothiophene. AB - The reaction between [V(IV)OSO(4)] and the tetradentate N(2)O(2)-donor Schiff base ligand, N,N-bis(o-hydroxybenzaldehyde)phenylenediamine (sal-HBPD), obtained by the condensation of salicylaldehyde and o-phenylenediamine in a molar ratio of 2 : 1 respectively, resulted in the formation of [V(IV)O(sal-HBPD)]. The molecular structure of [V(IV)O(sal-HBPD)] was determined by single crystal X-ray diffraction, and confirmed the distorted square pyramidal geometry of the complex with the N(2)O(2) binding mode of the tetradentate ligand. The formation of the polymer-supported p[V(IV)O(sal-AHBPD)] proceeded via the nitrosation of sal-HBPD, followed by the reduction with hydrogen to form an amine group that was then linked to Merrifield beads followed by the reaction with [V(IV)OSO(4)]. XPS and EPR were used to confirm the presence of oxovanadium(IV) within the beads. The BET surface area and porosity of the heterogeneous catalyst p[V(IV)O(sal-AHBPD)] were found to be 6.9 m(2) g(-1) and 180.8 A respectively. Microanalysis, TG, UV Vis and FT-IR were used for further characterization of both [V(IV)O(sal-HBPD)] and p[V(IV)O(sal-AHBPD)]. Oxidation of dibenzothiophene (DBT) and 4,6 dimethyldibenzothiophene (4,6-DMDBT) was investigated using [V(IV)O(sal-HBPD)] and p[V(IV)O(sal-AHBPD)] as catalysts. Progress for oxidation of these model compounds was monitored with a gas chromatograph fitted with a flame ionization detector. The oxidation products were characterized using gas chromatography-mass spectrometry, microanalysis and NMR. Dibenzothiophene sulfone (DBTO(2)) and 4,6 dimethyldibenzothiophene sulfone (4,6-DMDBTO(2)) were found to be the main products of oxidation. Oxovanadium(IV) Schiff base microspherical beads, p[V(IV)O(sal-AHBPD)], were able to catalyse the oxidation of sulfur in dibenzothiophene (DBT) and 4,6-dimethyldibenzothiophene (4,6-DMDBT) to a tune of 88.0% and 71.8% respectively after 3 h at 40 degrees C. These oxidation results show promise for potential application of this catalyst in the oxidative desulfurization of crude oils. PMID- 23023480 TI - Hypoxia induces CXCR4 expression and biological activity in gastric cancer cells through activation of hypoxia-inducible factor-1alpha. AB - Given the important role of CXCR4 in cancer metastasis, microenvironmental factors that modulate CXCR4 may have an impact on the process of tumor expansion. Hypoxia is a common feature of solid tumors and a significant microenvironmental factor that drives aggressive behavior. CXCR4 is upregulated in several cancer cells under hypoxic conditions, suggesting a relationship between tumor hypoxia and CXCR4. However, the role of hypoxia in regulating CXCR4 in gastric cancer remains poorly understood. KATO III gastric cancer cells were exposed to hypoxia or normoxia. CXCR4 expression in cells transfected with shRNA specific for HIF 1alpha was investigated by western blotting and flow cytometry. Wound healing, migration and invasion assays were used to assess cell motility and the chemotactic response to CXCL12, a major CXCR4 ligand. CXCR4 expression at the protein level and in the cell membrane was significantly increased in KATO III cells following exposure to hypoxia. This upregulation of CXCR4 was implicated in increased cell motility and enhanced chemotactic responses (migration and invasion) to CXCL12 treatment in vitro. The increases in CXCR4 expression and metastatic potential in gastric cancer cells exposed to hypoxia were blocked by HIF-1alpha-specific shRNA. Our results indicate that hypoxia upregulates CXCR4 in gastric cancer cells in a HIF-1alpha-dependent manner, and that upregulation of CXCR4 plays a role in cancer cell migration and invasion. Thus, disrupting the hypoxia-HIF-1alpha-CXCR4 axis could be an attractive therapeutic strategy for the treatment of gastric cancer. PMID- 23023481 TI - Acute cases of SBV found in cattle in southern England. PMID- 23023482 TI - Views sought on protecting animal welfare at slaughter. PMID- 23023483 TI - Vet restored to the Register. PMID- 23023486 TI - Moredun awards fellowship to 'outstanding' parasitologist. PMID- 23023487 TI - BVA Congress to move to the London Vet Show. PMID- 23023488 TI - Introduction to life as a vet in the UK. PMID- 23023491 TI - Ethics of firing debated at BEVA congress. PMID- 23023492 TI - Working together to tackle the problem of antibiotic resistance. PMID- 23023493 TI - An insight into veterinary education in Iraq. PMID- 23023494 TI - Outbreaks of blackleg in Scottish cattle. PMID- 23023495 TI - Measuring antibiotic use: a way forward. PMID- 23023496 TI - Treatment of equine sarcoids. PMID- 23023497 TI - Noise amplification in parallel whole-head ultra-low-field magnetic resonance imaging using 306 detectors. AB - In ultra-low-field magnetic resonance imaging, arrays of up to hundreds of highly sensitive superconducting quantum interference devices (SQUIDs) can be used to detect the weak magnetic fields emitted by the precessing magnetization. Here, we investigate the noise amplification in sensitivity-encoded ultra-low-field MRI at various acceleration rates using a SQUID array consisting of 102 magnetometers, 102 gradiometers, or 306 magnetometers and gradiometers, to cover the whole head. Our results suggest that SQUID arrays consisting of 102 magnetometers and 102 gradiometers are similar in g-factor distribution. A SQUID array of 306 sensors (102 magnetometers and 204 gradiometers) only marginally improves the g-factor. Corroborating with previous studies, the g-factor in 2D sensitivity-encoded ultra low-field MRI with 9 to 16-fold 2D accelerations using the SQUID array studied here may be acceptable. PMID- 23023498 TI - A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. AB - Hemophilia A is a bleeding disorder resulting from coagulation factor VIII (FVIII) deficiency. Exogenously provided FVIII effectively reduces bleeding complications in patients with severe hemophilia A. In approximately 30% of such patients, however, the 'foreignness' of the FVIII molecule causes them to develop inhibitory antibodies against FVIII (inhibitors), precluding FVIII treatment in this set of patients. Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections. To overcome these drawbacks, we generated a humanized bispecific antibody to factor IXa (FIXa) and factor X (FX), termed hBS23, that places these two factors into spatially appropriate positions and mimics the cofactor function of FVIII. hBS23 exerted coagulation activity in FVIII-deficient plasma, even in the presence of inhibitors, and showed in vivo hemostatic activity in a nonhuman primate model of acquired hemophilia A. Notably, hBS23 had high subcutaneous bioavailability and a 2-week half-life and would not be expected to elicit the development of FVIII-specific inhibitory antibodies, as its molecular structure, and hence antigenicity, differs from that of FVIII. A long-acting, subcutaneously injectable agent that is unaffected by the presence of inhibitors could markedly reduce the burden of care for the treatment of hemophilia A. PMID- 23023499 TI - Naratriptan mitigates CGRP1-associated motor neuron degeneration caused by an expanded polyglutamine repeat tract. AB - Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor (AR) gene. Here, we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene related peptide alpha (CGRP1). In neuronal cells, overexpression of CGRP1 induced cellular damage via the activation of the c-Jun N-terminal kinase (JNK) pathway, whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR. The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA. Naratriptan, a serotonin 1B/1D (5 hydroxytryptamine 1B/1D, or 5-HT1B/1D) receptor agonist, decreased CGRP1 expression via the induction of dual-specificity protein phosphatase 1 (DUSP1), attenuated JNK activity and mitigated pathogenic AR-mediated neuronal damage in cellular and mouse SBMA models. These observations suggest that pharmacological activation of the 5-HT1B/1D receptor may be used therapeutically to treat SBMA and other polyglutamine-related neurodegenerative diseases. PMID- 23023501 TI - Lo, what fools these mortals be. PMID- 23023500 TI - Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. AB - The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal-regulated kinase (ERK) phosphorylation in naive CD4(+) T cells, whereas other signals, such as zeta chain-associated protein kinase 70 (ZAP70) and phospholipase C-gamma1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR 181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4(+) T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3 (cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4(+) T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination. PMID- 23023503 TI - An antiatherosclerotic signaling cascade involving intestinal microbiota, microRNA-10b, and ABCA1/ABCG1-mediated reverse cholesterol transport. PMID- 23023504 TI - Microvascular management of systemic insulin sensitivity. PMID- 23023505 TI - Nitroxyl, redox switches, cardiac myofilaments, and heart failure: a prequel to novel therapeutics? PMID- 23023506 TI - G protein-coupled receptor kinase 5: exploring its hype in cardiac hypertrophy. PMID- 23023507 TI - Impaired G1-arrest, autophagy, and apoptosis in Atg7-knockout mice. PMID- 23023508 TI - (Almost) everything is illuminated: adenosine shines a light on cardioprotection. PMID- 23023509 TI - Oral direct factor Xa inhibitors. AB - Vitamin K antagonists, such as warfarin, have been the mainstay of oral anticoagulation for many decades. Although effective, warfarin has numerous limitations, including a variable dose requirement from patient to patient because of differences in dietary vitamin K intake, common genetic polymorphisms, and multiple drug interactions that affect its pharmacodynamics and metabolism. Consequently, warfarin requires frequent monitoring to ensure that a therapeutic anticoagulant effect has been achieved because excessive anticoagulation can lead to bleeding, and because insufficient anticoagulation can result in thrombosis. Such monitoring is burdensome for patients and physicians and is costly for the health care system. These limitations have prompted the development of new oral anticoagulants that target either factor Xa or thrombin. Although the path to the development of these drugs has been long, the new drugs are at least as effective and safe as warfarin, but they streamline clinical care because they can be administered in fixed doses without routine coagulation monitoring. This article focuses on rivaroxaban, apixaban, and edoxaban, the oral factor Xa inhibitors in the most advanced stages of development. After 20 years of discovery research, these agents are already licensed for several indications. Thus, the long path to finding replacements for warfarin has finally reached fruition. Therefore, development of the oral factor Xa inhibitors represents a translational science success story. PMID- 23023511 TI - Redox signaling in cardiac physiology and pathology. AB - Redox signaling refers to the specific and usually reversible oxidation/reduction modification of molecules involved in cellular signaling pathways. In the heart, redox signaling regulates several physiological processes (eg, excitation contraction coupling) and is involved in a wide variety of pathophysiological and homoeostatic or stress response pathways. Reactive oxygen species involved in cardiac redox signaling may derive from many sources, but NADPH oxidases, as dedicated sources of signaling reactive oxygen species, seem to be especially important. An increasing number of specific posttranslational oxidative modifications involved in cardiac redox signaling are being defined, along with the reactive oxygen species sources that are involved. Here, we review current knowledge on the molecular targets of signaling reactive oxygen species in cardiac cells and their involvement in cardiac physiopathology. Advances in this field may allow the development of targeted therapeutic strategies for conditions such as heart failure as opposed to the general antioxidant approaches that have failed to date. PMID- 23023512 TI - Circulation Research thematic synopsis: cardiovascular development. PMID- 23023510 TI - Novel biological functions of high-density lipoprotein cholesterol. AB - In addition to its role in reverse cholesterol transport, high-density lipoprotein (HDL) cholesterol has direct action on numerous cell types that influence cardiovascular and metabolic health. Cellular responses to HDL entail its capacity to invoke cholesterol efflux that causes signal initiation via scavenger receptor class B, type I, and plasma membrane receptor activation by HDL cargo molecules. In endothelial cells and their progenitors, HDL attenuates apoptosis and stimulates proliferation and migration. HDL also has diverse anti inflammatory actions in both endothelial cells and leukocytes. In vascular smooth muscles, HDL tempers proinflammatory, promigratory, and degradative processes, and through actions on endothelium and platelets HDL is antithrombotic. There are additional actions of HDL of potential cardiovascular consequence that are indirect, including the capacities to promote pancreatic beta-cell insulin secretion, to protect pancreatic beta cells from apoptosis, and to enhance glucose uptake by skeletal muscle myocytes. Furthermore, HDL decreases white adipose tissue mass, increases energy expenditure, and promotes the production of adipose-derived cytokine adiponectin that has its own vascular-protective properties. Many of these numerous actions of HDL have been observed not only in cell culture and animal models but also in human studies, and assessments of these functions are now being applied to patient populations to better-elucidate which actions of HDL may contribute to its cardioprotective potential and how they can be quantified and targeted. Further work on the many mechanisms of HDL action promises to reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health. PMID- 23023513 TI - Letter to the editor on NaV1.8. PMID- 23023515 TI - A facile and general preparation of high-performance noble-metal-based free standing nanomembranes by a reagentless interfacial self-assembly strategy. AB - As a simple and flexible 2D platform, the water-air interface is envisioned as an environmentally-friendly approach to prepare ultrathin free-standing nanomembranes (FNMs) of monolayered nanoparticles of interest via interfacial self-assembly. However, attempts so far have been rather rare due to the lack of efficient methods. In this article, we report on a facile and general strategy for fabrication of a family of noble metal-based FNMs by a simple and reagentless interfacial self-assembly tactics to prepare functional (plasmonic or catalytic) FNMs, such as Au, Ag, Pd, Pt-FNMs and their bimetallic hybrids, Ag/Au-FNMs and Pd/Pt-FNMs. The organic solvent-free process, varying somewhat from metal to metal only in precursors, reducing agents and dosage of reagents used, is found to be a general phenomenon and ligand-independent (irrespective of the monolayer quality of the resulting FNMs), allowing the growth of high-quality noble metal based FNMs with well-defined nanoparticulate and monolayer morphology as large as several square centimeters. Heat treatment (boiling) is performed to accelerate the formation of FNMs within 15 min. More significantly, the as-prepared plasmonic Au-FNMs acting as a SERS substrate show a superior activity; whereas the resulting catalytic Pd-FNMs, except for their excellent ethanol electrooxidation performance, exhibit higher electrocatalytic activity for formic acid oxidation than commercial catalysts. PMID- 23023514 TI - Phosphorylated tubulin adaptor protein CRMP-2 as prognostic marker and candidate therapeutic target for NSCLC. AB - Collapsin response mediator protein-2 (CRMP-2) is the first described and most studied member of a family of proteins that mediate the addition of tubulin dimers to the growing microtubule. CRMPs have mainly been studied in the nervous system, but recently, they have been described in other tissues where they participate in vesicle transport, migration and mitosis. In this work, we aimed at studying the role of CRMP-2 in lung cancer cell division. We first explored the expression of CRMP-2 and phosphorylated (Thr 514) CRMP-2 in 91 samples obtained from patients with localized nonsmall cell lung cancer. We observed a significant correlation between high levels of nuclear phosphorylated CRMP-2 and poor prognosis in those patients. Interestingly, this association was only positive for untreated patients. To provide a mechanistic explanation to these findings, we used in vitro models to analyze the role of CRMP-2 and its phosphorylated forms in cell division. Thus, we observed by confocal microscopy and immunoprecipitation assays that CRMP-2 differentially colocalizes with the mitotic spindle during cell division. The use of phosphodefective or phosphomimetic mutants of CRMP-2 allowed us to prove that anomalies in the phosphorylation status of CRMP-2 result in changes in the mitotic tempo, and increments in the number of multinucleated cells. Finally, here we demonstrate that CRMP-2 phosphorylation impairment, or silencing induces p53 expression and promotes apoptosis through caspase 3 activation. These results pointed to CRMP-2 phosphorylation as a prognostic marker and potential new target to be explored in cancer therapy. PMID- 23023517 TI - Polymer Photovoltaic Cells Based on Polymethacrylate Bearing Semiconducting Side Chains. AB - Polymethacrylate with semiconducting side chains (P1), synthesized by free radical polymerization, was used as a donor material for polymer solar cells. P1 is of high molecular weight (Mn = 82 kg mol(-1)), good thermal stability, narrow band gap (1.87 eV), and low-lying HOMO energy level (-5.24 eV). P1 possesses not only the good film-forming ability of polymers but also the high purity of small organic molecules. Power conversion efficiencies (PCEs) of 0.63% and 1.22% have been obtained for solar cells with M1:PC71BM and P1:PC71BM as the active layers, respectively. With PC61BM as the acceptor, PCEs of M1 and P1 based devices decrease to 0.61% and 0.76%, respectively. To the best of our knowledge, this is the first report that free radical polymerization can be used to prepare polymer donors for photovoltaic applications. PMID- 23023518 TI - Virtual screening and synthesis of new chemical scaffolds as VEGFR-2 kinase inhibitors. AB - VEGFR-2 tyrosine kinase inhibitors are currently receiving high interest in drug discovery process as anticancer agents. We have used virtual screening techniques in order to discover new scaffolds that can be used for developing new VEGFR-2 kinase inhibitors.Similarity ensemble approach was used to reduce the chemical space of ZINC database to select a subset of compounds. A validated structure based pharmacophore was developed and adopted to screen the selected subset. Initial hits mapped to the pharmacophore were filtered using docking and scoring. Selected compounds were synthesized and biologically tested. Compound 9 showed very good cytotoxicity profile against the NCI 60 cancer cell lines, while compound 8 showed reasonable inhibition of VEGFR-2 tyrosine kinase.Stepwise virtual screening of databases such as ZINC may result in new scaffolds for developing VEGFR-2 kinase inhibitors. PMID- 23023519 TI - Dapson in heterocyclic chemistry part VI: synthesis and molecular docking of some novel sulfonebiscompounds of expected anticancer activity. AB - To discover new bioactive lead compounds for medicinal purposes, herein, sulfone biscompounds bearing dihydrothiazoles (3-9, 14, 15), acrylamide (11), thiazolidinones (12, 13, 20), thiophenes (16, 17) and benzothiophene (19) were prepared and tested for their anticancer activity. The structures of the products were confirmed from elemental analysis as well as spectral data. All the synthesized compounds showed remarkable anticancer activity against human breast cancer cell line especially, compound (3) with IC50 value 23.02 uM which was better than that of Doxorubicin by three folds. In order to elucidate the mechanism of action of their cytotoxic activity molecular docking on the active sites of farnesyl transferase and arginine methyl transferase was performed for all synthesized compounds and good results were obtained. PMID- 23023520 TI - Facile synthesis of 2-iodo-spiro[indene-1,1'-isobenzofuran]-3'-ones via iodine promoted cascade cyclization. AB - A novel and efficient synthetic approach to substituted 2-iodo-spiro[indene-1,1' isobenzofuran]-3'-ones has been developed via an iodine-promoted cascade cyclization of 2-(3-hydroxy-3,3-diarylprop-1-yn-1-yl)benzoates. This sequential cascade process is concisely conducted at room temperature. Subsequent palladium catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting iodides proceed smoothly in good yields. PMID- 23023521 TI - Aortic rupture and sac expansion after endovascular repair of abdominal aortic aneurysm. AB - BACKGROUND: Long-term concerns about the durability of endovascular aortic aneurysm repair (EVAR) remain after the publication of controlled trials. Increased expertise in endograft technology, case selection and postoperative reintervention has created a need for reappraisal of the longer-term efficacy of EVAR using contemporary data. METHODS: Patients undergoing infrarenal EVAR between 2004 and 2010 were studied prospectively. Morphological compliance with manufacturers' instructions for use (IFU) was established using three-dimensional computed tomography. The primary outcome measures were all-cause and aneurysm related mortality, postoperative rupture, reintervention and sac expansion. These adverse events were reported using Kaplan-Meier survival analysis, with comparison within, or outside IFU by the log rank test. RESULTS: Some 478 patients of median age 76 years had a median aneurysm diameter of 62.9 mm. Median follow-up was 44 (range 11-94) months; 198 (41.4 per cent) were compliant with IFU. The 30-day mortality rate was 2.1 per cent (10 of 478 patients): nine (2.0 per cent) of 455 patients who had elective and one (4 per cent) of 23 patients who had non-elective surgery. Aneurysm-related mortality was 0.897 deaths per 100 person-years, and all-cause mortality was 8.558 deaths per 100 person-years, with significantly lower survival outside IFU (P = 0.012). Two patients had a late rupture (0.138 per 100 person-years), of whom one died. There were 6.120 reinterventions per 100 person-years, with no difference for aneurysms treated outside IFU (P = 0.136). Primary sac expansion occurred in 6.721 per 100 person years and secondary sac expansion in 4.142 per 100 person-years. CONCLUSION: In this series EVAR had a lower aneurysm-related mortality rate than demonstrated in early controlled trials, and with lower sac expansion rates than reported from image repositories. Data from earlier studies should be applied to current practice with caution. PMID- 23023522 TI - Differential DNA copy number aberrations in the progression of cervical lesions to invasive cervical carcinoma. AB - Host genomic alterations in addition to human papillomavirus (HPV) are needed for cervical precursor lesions to progress to invasive cancer because only a small percentage of women infected by the virus develop disease. However, the genomic alterations during the progression of cervical lesions have not been systematically examined. The aim of this study was to identify differential genomic alterations among cervical intraepithelial neoplasia CIN1, CIN2, CIN3 and cervical squamous cell carcinoma (SCC). Genomic alterations were examined for 15 cases each of CIN1, CIN2, CIN3 and SCC by array-based comparative genomic hybridization (array CGH). The chromosomal regions showing significant differential in DNA copy number aberrations (DCNAs) among CIN1, CIN2, CIN3 and SCC were successfully identified by resampling-based t-test. The chromosomal regions of 5q35.3 and 2q14.3 showed significant DCNAs between CIN1 and CIN2, and between CIN2 and CIN3, respectively, while a significant difference in DCNAs between CIN3 and SCC was observed at 1q24.3, 3p14.1, 3p14.2, 5q13.2, 7p15.3, 7q22.1 and 13q32.3. In addition, the status of DCNAs in 1q43, 2p11.2, 6p11.2, 7p21.1, 7p14.3, 10q24.1, 13q22.3, 13q34 and 16p13.3 was conserved throughout the progression of CIN to SCC. The presence of differential and common DCNAs among CIN1, CIN2, CIN3 and SCC supports that the CIN progression may include continual clonal selection and evolution. This approach also identified 34 probe sets consistently overexpressed when amplified, suggesting an unbiased identification of candidate genes in SCC during cervical cancer progression. PMID- 23023523 TI - UHRF1 expression is upregulated and associated with cellular proliferation in colorectal cancer. AB - Ubiquitin-like with PHD and ring-finger domain 1 (UHRF1) binds to methylated promoters of a number of tumor-suppressor genes, including p16INK4A and p14ARF, by forming complexes with DNA methyltransferases and HDAC1, resulting in the induction of carcinogenesis. Altered UHRF1 expression has been demonstrated in various types of cancers. Previous reports indicate that UHRF1 expression is regulated by E2F-1 expression. We investigated UHRF1 expression using immunohistochemical staining in 231 colorectal cancer and 40 adenoma specimens, analyzed the relationship between UHRF1 expression and clinicopathological findings and the association between UHRF1 and E2F-1 expression. To better understand the biological function of UHRF1 in colorectal cancer, knockdown of UHRF1 expression was performed using siRNA methods. High UHRF1 expression was observed in 152 of 231 (65.8%) colorectal cancer patients, and was detected in 35 of 40 adenoma specimens samples (87.5%). UHRF1 staining was detected in the nucleus of cancer cells, while it was not detected in colonic normal mucosa. High UHRF1 expression was significantly observed in right compared with left hemicolon cancer (p=0.008). Moreover, high UHRF1 expression tended to be associated with depth of invasion (p=0.051). UHRF1 expression was significantly associated with E2F-1 expression (p<0.0001). Knockdown of UHRF1 expression suppressed cellular growth in colon cancer cell lines, HCT116 and SW620. In conclusion, we demonstrated that UHRF1 expression was upregulated in approximately two-thirds of colorectal cancer specimens and was particularly expressed in right compared with left hemicolon cancer. Moreover, knockdown of UHRF1 expression induced growth inhibition in colon cancer cell lines. UHRF1 may be involved in cellular proliferation and molecular pathogenesis of colorectal cancer in the right hemicolon. PMID- 23023525 TI - Closed globe macular injuries after blasts in combat. AB - PURPOSE: To describe the macular findings after closed globe ocular injuries sustained from blasts. METHODS: A retrospective chart review from February 2003 to March 2010 of all soldiers with closed globe ocular injuries sustained during combat with macular findings of trauma on examination was completed. RESULTS: There were 36 eyes that met the inclusion criteria. The mean age of the soldiers was 29.5 years and 97% were men. The average follow-up time was 18.6 months. Improvised explosive device blasts accounted for 86% of injuries. Forty-five percent of soldiers had bilateral ocular injuries. Eight of 36 eyes (22.2%) developed a macular hole. One eye had spontaneous closure and five eyes underwent surgical repair. There was a range of macular findings from retinal pigment epitheliopathy alone to retinal pigment epitheliopathy with full-thickness atrophy. Eight eyes (22.2%) had macular scarring on examination but no optical coherence tomography study. One eye (2.8%) developed phthisis bulbi. Fifteen eyes (42%) had an orbital fracture. Seven eyes (19%) sustained optic neuropathy. CONCLUSION: Closed globe injuries after blasts resulted in a spectrum of macular findings. The integrity of the foveal inner segment/outer segment junction was the most important retinal factor in visual outcomes. Orbital fractures were not found to be a risk factor for developing optic neuropathy and may improve visual outcomes. The rate of long-term complications is unknown, and it is important for ophthalmologists to follow these patients closely. PMID- 23023526 TI - Long-term results of repeated anti-vascular endothelial growth factor therapy in eyes with retinal pigment epithelial tears. AB - PURPOSE: To evaluate the long-term results of retinal pigment epithelium tears in eyes treated with repeated anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Five patients with retinal pigment epithelial tears (without foveal center involvement) after anti-VEGF injection were studied retrospectively. Mean follow-up time was 52 months, with measurements of visual acuity and evaluation of macular findings by angiography and optical coherence tomography during this period. All eyes had a persistent submacular neovascular membrane 30 days after the tear. An anti-VEGF drug was reinjected until the membranes stopped leaking. RESULTS: The mean initial visual acuity immediately after the tear was 20/160, and the mean final visual acuity was 20/60. The number of anti-VEGF reinjections varied from two to eight during the follow-up period. Long-term optical coherence tomography analysis showed reduced fluid and remodeling of the torn retinal pigment epithelium. CONCLUSION: Long-term visual results with repeated anti-VEGF therapy are not as devastating as suggested previously. Visual acuity and metamorphopsia improve with time as long as the neovascular membrane is inactive. Optical coherence tomography changes in the macular area reflect the visual acuity improvement. PMID- 23023527 TI - A novel mutation at the N-terminal domain of the TIMP3 gene in Sorsby fundus dystrophy. AB - PURPOSE: To report a novel mutation occurring in the N-terminal domain of the tissue inhibitor of metalloproteinase 3 (TIMP3) gene in Sorsby fundus dystrophy. METHODS: Retrospective review of medical records of two patients who had clinical features consistent with Sorsby fundus dystrophy. Genetic testing confirmed a mutation in the TIMP3 gene in both patients. RESULTS: Both patients had findings of drusenlike deposits, retinal pigment epithelial and photoreceptor atrophy, and bilateral, recurrent choroidal neovascularization. A strong family history of early onset macular degeneration was present in both. The patients developed choroidal neovascularization at the age of 45 and 48 years, and both had multiple recurrences in both eyes. Genetic testing in both patients confirmed a heterozygous nucleotide change of C113G, causing a Ser38Cys change in Exon 1 of the N-terminal domain of the TIMP3 gene. CONCLUSION: All previously reported mutations in Sorsby fundus dystrophy occur at Exon 5 in the C-terminal domain. We report 2 patients with novel mutations in Exon 1 of the N-terminal domain. Although the mutation occurs at a different location on the TIMP3 gene, the clinical features are similar to other reported patients with Sorsby fundus dystrophy. This finding assists in understanding the pathogenesis of this disorder. PMID- 23023528 TI - Investigation of oral fenretinide for treatment of geographic atrophy in age related macular degeneration. AB - BACKGROUND: Excessive accumulation of retinol-based toxins has been implicated in the pathogenesis of geographic atrophy (GA). Fenretinide, an orally available drug that reduces retinol delivery to the eye through antagonism of serum retinol binding protein (RBP), was used in a 2-year trial to determine whether retinol reduction would be effective in the management of geographic atrophy. METHODS: The efficacy of fenretinide (100 and 300 mg daily, orally) to slow lesion growth in geographic atrophy patients was examined in a 2-year, placebo-controlled double-masked trial that enrolled 246 patients at 30 clinical sites in the United States. RESULTS: Fenretinide treatment produced dose-dependent reversible reductions in serum RBP-retinol that were associated with trends in reduced lesion growth rates. Patients in the 300 mg group who achieved serum retinol levels of <= 1 MUM (<= 2 mg/dL RBP) showed a mean reduction of 0.33 mm in the yearly lesion growth rate compared with subjects in the placebo group (1.70 mm/year vs. 2.03 mm/year, respectively, P = 0.1848). Retinol-binding protein reductions <2 mg/dL correlated with further reductions in lesion growth rates (r = 0.478). Fenretinide treatment also reduced the incidence of choroidal neovascularization (approximately 45% reduction in incidence rate in the combined fenretinide groups vs. placebo, P = 0.0606). This therapeutic effect was not dose dependent and is consistent with anti-angiogenic properties of fenretinide, which have been observed in other disease states. CONCLUSION: The findings of this study and the established safety profile of fenretinide in chronic dosing regimens warrant further study of fenretinide in the treatment of geographic atrophy. PMID- 23023529 TI - Retina rejuvenation therapy for diabetic macular edema: a pilot study. AB - PURPOSE: To prospectively investigate the safety and efficacy of a novel frequency-doubled nanosecond-pulsed laser with discontinuous beam energy distribution (2RT, Ellex) for the treatment of diabetic macular edema. METHODS: Twenty-three consecutive patients (38 eyes) with newly diagnosed diabetic macular edema were recruited and assessed with logarithm of the minimum angle of resolution best-corrected visual acuity, central macular thickness measured with optical coherence tomography (OCT/scanning laser ophthalmoscope, OPKO/OTI), microperimetry, fundus photography, and fundus fluorescein angiography. Macular grid treatments were performed with 2RT laser system by 1 operator. Patients were examined with logarithm of the minimum angle of resolution best-corrected visual acuity, central macular thickness, microperimetry, and fundus photography at 3 weeks and 6 weeks and 3 months and 6 months. Fundus fluorescein angiography was repeated at 3 months and 6 months. RESULTS: Six months postoperatively, 17 patients (28 eyes) completed the study. No complications were identified after 2RT therapy. Intraoperative retinal discoloration was observed in 2 cases, fully resolved at 3 months with no permanent anatomical or functional changes. Mean logarithm of the minimum angle of resolution visual acuity improved from 20/44 at baseline to 20/27 at 6 months. The change in best-corrected visual acuity was significant (P = 0.0190). Central macular thickness in the central 1-mm subfield, retinal exudates and vascular leakage decreased in the majority of patients at 6 months (46, 41, and 55%, respectively), although the change from baseline was not statistically significant. Microperimetry confirmed photoreceptor integrity and showed a trend of improvement that correlated with decreased central macular thickness. CONCLUSION: For the first time, we achieved a beneficial effect on diabetic macular edema without the side effects of conventional laser therapy. The efficacy of this system in comparison with standard argon laser photocoagulation and in the treatment of other conditions affecting the retinal pigment epithelium needs further investigation. PMID- 23023531 TI - Crystal engineering from a 1D chain to a 3D coordination polymer accompanied by a dramatic change in magnetic properties. AB - A unique structural transformation in the crystalline state assisted by coordination substitution is induced during a dehydration process. A 1D chain coordination polymer is irreversibly converted to a 3D interpenetrated network accompanied by a change in magnetic properties from a paramagnetic material to a spin crossover system. PMID- 23023530 TI - Early changes in foveal thickness in eyes with central serous chorioretinopathy. AB - PURPOSE: To investigate when and how fast the foveal thinning occurs in central serous chorioretinopathy. METHODS: Outer nuclear layer (ONL) thickness was measured in 60 eyes of 60 patients with active central serous chorioretinopathy. Patients were divided into 3 groups based on the duration of symptoms; within 1 month (Group A, 25 eyes), 1 to 6 months (Group B, 17 eyes), and >6 months (Group C, 18 eyes). Outer nuclear layer thickness and visual acuity were compared between each group. Some of the patients underwent several examinations and serial changes were analyzed. RESULTS: The ONL thickness was correlated with the duration of symptoms (R = -0.61, P < 0.001). Visual acuity was worse in Group C compared with Group A (P = 0.003). The mean ONL thickness of each group and healthy contralateral eyes was 82.4, 70.2, 53.5, and 89.3 MUm, respectively. Comparisons between each group showed statistical significances. Seventeen eyes in Group A were re-examined between 3 and 6 months after the first visit. The mean ONL thickness significantly decreased from 81.9 MUm to 75.0 MUm (P = 0.020). CONCLUSION: In central serous chorioretinopathy, ONL thinning starts in the early stage and may continue as long as the subretinal fluid persists. PMID- 23023532 TI - Fluorescent and photochromic bifunctional molecular switch based on a stable crystalline metal-viologen complex. AB - An air-stable photoresponsive viologen molecular system is constructed based on a three-fold accordion interpenetrating packing arrangement. The fluorescent modulation process is coupled with a photochromic reaction via energy and electron transfer between the adjacent donor and acceptor groups. PMID- 23023533 TI - Turboprop+: enhanced Turboprop diffusion-weighted imaging with a new phase correction. AB - Faster periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) diffusion-weighted imaging acquisitions, such as Turboprop and X-prop, remain subject to phase errors inherent to a gradient echo readout, which ultimately limits the applied turbo factor (number of gradient echoes between each pair of radiofrequency refocusing pulses) and, thus, scan time reductions. This study introduces a new phase correction to Turboprop, called Turboprop+. This technique employs calibration blades, which generate 2-D phase error maps and are rotated in accordance with the data blades, to correct phase errors arising from off-resonance and system imperfections. The results demonstrate that with a small increase in scan time for collecting calibration blades, Turboprop+ had a superior immunity to the off-resonance-related artifacts when compared to standard Turboprop and recently proposed X-prop with the high turbo factor (turbo factor = 7). Thus, low specific absorption rate and short scan time can be achieved in Turboprop+ using a high turbo factor, whereas off resonance related artifacts are minimized. PMID- 23023534 TI - The up-conversion luminescent properties and silver-modified luminescent enhancement of YVO4:Yb3+, Er3+ NPs. AB - In this paper, the unique up-conversion luminescence (UCL) properties of as prepared and annealing YVO(4):Yb(3+), Er(3+) nanoparticles (NPs, ~100 nm) and the corresponding YVO(4):Yb(3+), Er(3+)@Ag hybrids under 980 nm excitation were systemically studied through power-dependent, temperature-dependent emission spectra and dynamics. It is interesting to determine that the radiative transition rate of (2)H(11/2)/(4)S(3/2)-(4)I(15/2) for Er(3+) ions in YVO(4) is about an order of magnitude faster than that in the other hosts due to the wave function coupling with the 3d orbital of V(5+) and, thus, the up-conversion (UC) green emissions of YVO(4):Yb(3+), Er(3+) NPs is efficient. In addition, efficient novel UC broad band centering around 630 nm (1.97 eV) was observed in YVO(4):Yb(3+), Er(3+) powders, which was attributed to defect emissions related to oxygen vacancies near V(5+) sites in the lattices of YVO(4). In as-prepared YVO(4):Yb(3+), Er(3+)@Ag hybrids colloids, more than one order UCL enhancement than YVO(4):Yb(3+), Er(3+) was observed. Powder and the annealing samples lead the UCL enhancement effect to disappear. The main UCL enhancement mechanism of YVO(4):Yb(3+), Er(3+)@Ag hybrids colloids was attributed to prevent YVO(4):Yb(3+), Er(3+) interaction with the solution, instead of surface plasmon enhancement (SPE) effect. PMID- 23023535 TI - [Indication of video-assisted thoracic surgery for mediastinal mass lesions]. AB - BACKGROUND: Most of mediastinal tumors are benign cysts and neoplasms. Resection is indicated for cystic lesions because of possibility of malignancy, compression symptom and possible rupture in future. However careful observation might be appropriate for asymptomatic tumors without risk of malignancy. Although video assisted thoracoscopic surgery (VATS) is increasingly performed, its indication is still controversial. PATIENTS AND RESULTS: Among 37 mediastinal cystic lesions with confirmed pathological diagnosis, 17 were neoplasms. All of 20 non neoplastic lesions have cyst wall thinner than 5 mm. Five cases( 29%) of neoplastic lesions have cyst wall thinner than 5 mm. Three of them underwent preoperative fluorodeoxyglucose-positron emission tomography( FDG-PET) or PET computed tomography( CT). All 3 neoplastic lesions with thin wall showed accumulation of FDG. None of non-neoplastic cyst had FDG accumulation. Ninety seven patients underwent surgical resection for mediastinal tumors. Out of 51 VATS, 2 were converted to open thoracotomy. One patient with thymoma had ipsilateral pleural recurrence after VATS. Tumor sizes of those 3 patients were larger than 7 cm. CONCLUSIONS: Cystic mediastinal tumor with wall thickness less than 5 mm and no FDG accumulation might be observed without resection because it is very unlikely to be a neoplasm. Mediastinal tumor larger than 7 cm might not be suitable for VATS. PMID- 23023536 TI - [Appropriate surgical approach to cystic thymic lesions]. AB - We retrospectively analyzed surgical approach to cystic thymic lesions based on 25 cases. We classified to 4 groups as follows, 12 thin-wall solitary cysts with low uniform density, 7 solitary cysts with ununiform density, 5 cysts with tumor lesions and 1 multiple cysts. Preoperative image diagnoses were 10 thymic cysts, 7 cystic thymomas, 4 mature teratomas, and 1 each of multilocular thymic cyst and thymic lymphoma. Twenty cases were indicated to video-assisted thoracic surgery( VATS), the other 5 cases were operated by sternotomy. The reasons for thoracotomy were adherence with left brachiocephalic vein(LBCV)3, huge cyst compressing superior vena cava (SVC) 1, diffuse multiple cysts and tumors in hypertrophic thymus 1. Three cases were converted to open thracotomy from VATS because of dense adhesions around LBCV and malignant diagnosis. Final diagnosis are 16 congenital cysts, 3 thymomas, and one each multilocular thymic cyst, mature teratoma, thymic cancer, thymolipoma, venous hemangioma and mucosal associated lymphoid tissue( MALT) lymphoma. Thin-wall solitary cysts with low uniform density are able to diagnosed congenital thymic cysts by computed tomography( CT)/magnetic resonance imaging (MRI) appearances. On the contrary un-uniform density cysts or cysts with tumor lesions are difficult to achieve correct diagnoses by images. These lesions may contain thymoma or thymic cancer, so that rapid pathological examination should be prepared during surgical operation. Cysts adhering to LBCV should be operated by thoracotomy to avoid accidents of massive bleeding. PMID- 23023537 TI - [Surgical treatment for mediastinal cysts]. AB - BACKGROUND: Since most of mediastinal cysts are benign tumors, video-assisted thoracic surgery (VATS) is optimal surgical procedure in recent years. It is important to select an appropriate approach accordance with the various locations of the cysts. METHODS: This is a retrospective review between 2005 and 2011 included 42 cases who had been undergone surgery for mediastinal cysts at the department. RESULTS: There were 19 males and 23 females, mean-age 58.9+/-11.8 year. The cysts in superior portion of the mediastinum, anterior and middle mediastinum were 2, 31, and 9 patients, respectively. Operative procedures included 3 or 4 ports in 11, mini-thoracotomy and 2 or 3 ports in 28, cervical incision and mini-thoracotomy and 2 ports in 1, median sternotomy in 2. Mean operative time was 128.8+/-62.8 minutes. The mean postoperative stay was 5.6+/ 2.1 days. There was hardly a perioperative complication, excepting only 1 case of intraoperative hemorrhage. CONCLUSION: VATS allows various surgical approach to each location of mediastinal cysts, and less invasive procedure. PMID- 23023538 TI - [Three-port complete video-assisted thoracic surgery for mediastinal diseases]. AB - Three port complete video-assisted thoracic surgery( 3-port cVATS) is our standard approach for primary lung cancers. The video image for the assistant is inverted, and the access ports are inserted at the best location decided by preoperative simulation surgery. Using this approach, the forceps of the operator are never interfered by the forceps of the assistant. We present 3-port cVATS applied to the mediastinal diseases difficult to be done via hybrid VATS mainly under direct vision. 1)The superior mediastinal tumor extending above the thoracic inlet. 2)The posterior mediastinal tumor extending to the other side behind the left atrium. 3)Surgical removal of non-traumatic mediastinal hematoma without capsule resection. 4)Simple thymectomy for the small anterior mediastinal tumor. We could carry through every operation via 3-port cVATS from one side of the chest. This is our minute report of 3-port cVATS applied to the mediastinal diseases. PMID- 23023539 TI - [Minimally invasive surgery for thymic disease]. AB - This study describes minimally invasive surgery using video-assisted thoracic surgery (VATS) for thymic diseases. Our procedure has been changed in the last decade from sternum-lifting thoracoscopic surgery with mini-thoracotomy to complete thoracoscopic surgery. Indications for this method include benign thymic disease, non-invasive thymoma or myasthenia gravis (MG). We performed these procedures for 27 cases, including 12 cases of thymic cyst, 10 cases of thymoma without MG, 3 cases of thymoma with MG and 2 cases of MG alone. In all cases of thymoma, tumor size was less than 5 cm. Complete VATS, VATS with mini-thoracotomy and sternum-lifting VATS were performed in 20, 4 and 3 patients, respectively. Complications were phrenic nerve palsy in 2 cases and postoperative bleeding in 1 case. We always use ultrasonic devices in this procedure. No recurrences have been identified in any cases. Even though definitive evidence is lacking for use of a unilateral approach with VATS for thymoma and MG, VATS thymectomy appears acceptable as a less-invasive procedure with less pain and rapid recovery. PMID- 23023540 TI - [Nine myasthenia gravis cases of thoracoscopic extended thymectomy]. AB - The indication of thoracoscopic excision of mediastinal tumor at our department is benign tumor or noninvasive thymoma diagnosed before surgery. For myasthenia gravis, thoracoscopic extended thymectomy is performed with a bilateral thoracic approach using a laparolift, and this procedure is indicated for cases with complication of thymoma with a tumor size up to 5 cm. We performed thoracoscopic extended thymectomy in 9 myasthenia gravis patients between January and October 2011, and achieved favorable postoperative courses with no development of major complications so far. However,surgery required a long time compared to the conventional extended thymectomy employing median sternotomy, showing that further modification of the surgical procedure and improvement of the surgical skill are necessary. We report the details of thoracoscopic extended thymectomy with a bilateral thoracic approach for 9 myasthenia gravis patients performed at our department. PMID- 23023541 TI - [Thoracoscopic thymectomy for thymoma]. AB - Complete resection of Masaoka stage I and II thymoma leads to good prognosis. In recent years, technological development of endoscopy enables thymectomy by thoracoscopic method instead of median sternotomy approach. We perform thoracoscopic thymectomy for thymoma without myasthenia gravis via 2 trocars introduced in unilateral pleural cavity and a small incision on epigastric region with sternal lifting. Thoracoscopic thymectomy for thymoma with myasthenia gravis is performed by bilateral pleural cavity approach with sternal lifting. We had 18 patients with thymoma resected by thoracoscopic thymectomy between 2005 and 2007. Fourteen patients had thymoma with myasthenia gravis. Nine patients had Masaoka I thymoma, 8 had Masaoka II thymoma and 1 had Masaoka III thymoma. The average follow-up period of the patients is 51 months. One patient had a recurrence tumor 56 months after operation. It was developed on the left phrenic nerve from which the resected thymoma had removed. Thoracoscopic thymectomy can be expected as standard surgical treatment for Masaoka I and II thymoma. PMID- 23023542 TI - [Surgery for mediastinal tumor; by video-assisted thoracoscopic thymo thymomectomy with sternal lifting]. AB - The successful key of video-assisted thoracoscopic surgery (VATS) for mediastinal tumor should be appropriate surgical approach according to the site of tumor and relationship between large vessels and tumor. We retrospectively reviewed VATS for mediastinal tumor for 2 years. Thirty-three patients underwent surgery for mediastinal tumor, 19 patients by VATS;12 thymo-thymomectomies (2 myastenia gravis with thymoma), 4 neurinomas, 3 cystic tumors. Thymoma is the most frequent mediastinal tumor and thymo-thymomectomy for thymoma and extended thymectomy for myasthenia gravis is usually recommended. Thymus is located in the narrow anterior mediastinum between sternum and heart. So that we use sternal lifting devices to get working space for video-assisted thoracoscopic thymo-thymomectomy. Our indication is thymic cyst, thymoma (noninvasive to surrounding organs, without dissemination, diameter less than 6 cm, and tolerable for one-lung ventilation), and myasthenia gravis. Video-assisted thoracoscopic thymo thymomectomy using sternal lifting was performed for 12 patients among 19 thymic tumor patients and is considered to be a minimally invasive and safe operative procedure for selected thymoma patients. PMID- 23023543 TI - [Thoracoscopic thymectomy using anterior chest wall lifting method by Kirschner wire]. AB - We performed thoracoscopic thymectomy using a method in which the anterior chest wall was lifted by Kirschner wire passed through the subcutaneous tissue. Between April 2011 and May 2012, 5 cases underwent thoracoscopic thymectomy using this method. Postoperative complications, especially subcutaneous hematoma and pain in the anterior chest wall through which the Kirschner wire was passed, did not occur. This method provided a good operative field in the posterior sternum for safe thymectomy. In addition, the use of an Endocameleon was effective decreasing invisible field blind view during the operation. We concluded that this method is a simple and useful means of elevation of the sternum for thoracoscopic thymectomy. PMID- 23023544 TI - [Single-incision thoracoscopic surgery( SITS) for mediastinal disease]. AB - The use of single-incision laparoscopic surgery is spreading widely, even in Japan, however, in the field of thoracic surgery, there exist no previous reports on the use of the Wound retractor system in single-incision thoracoscopic surgery (SITS) for mediastinal disease. We herein describe the 1st cases of video assisted SITS of the mediastinum. Fifteen patients (5 males, 10 females) with mediastinal disease underwent SITS. The average age of the patients was 66.8( 44 ~ 90) years. The mean operative time was 186.2 minutes. Chest drainage tubes were not placed in 12 cases. Chest tubes were removed after 2.5 days in three cases. The mean postoperative hospital stay was 3.3 (2 ~ 8) days. In this report, the use of an access instrument for SITS is presented. We performed extended thymectomy using Vein harvest during surgery in patients with myasthenia gravis. The device could be handled successfully, thereby avoiding interferences between the operator and assistants. In conclusion, we believe that SITS is a feasible and safe procedure that is beneficial in selected cases. PMID- 23023545 TI - [Malignant disease identified after the emergency cardiac operation]. AB - We experienced 2 patients who died early after emergency cardiac operation because of malignant diseases. In one case, we operated on a 67-year-old woman for infective endocarditis and performed aortic valve replacement, but she died of terminal pancreatic cancer on the 26 postoperative day. In the other case, a 53-year-old woman underwent emergency operation for cardiac tumor of the left atrium. However, the tumor was diagnosed as cardiac sarcoma during the operation, and it could not be completely resected. The sarcoma recurred after 2 months and she passed away. An emergency cardiac operation without enough preoperative examinations sometimes causes a poor prognosis. PMID- 23023546 TI - [Redo ascending aorta replacement using a homograft for graft infection caused by methicillin-resistant Staphylococcus aureus; report of an emergently air transferred case just after Great East Japan Earthquake]. AB - We describe a case of replacement with a cryopreserved homograft for graft infection. A 48-year-old man had been performed ascending aorta replacement using woven dacron graft for type A aortic dissection. Two months ago, methicillin resistant Staphylococcus aureus infection was suspected because of high-grade fever. Computed tomography (CT) scan revealed abscess formation around the prosthetic graft and redo operation using cryopreserved homograft was scheduled to avoid re-infection into mediastinum at Tohoku University Hospital, an institute cooperating with University of Tokyo tissue bank. However, Catastrophic Great East Japan Earthquake occurred the day before the scheduled date, and the patient could not have an operation at the institution. He was transferred to our hospital by helicopter. Then homograft was successfully implanted in ascending aorta after complete excision of infectious graft. PMID- 23023547 TI - [Late mediastinal hematoma presenting cardiac tamponade after re-do off-pump coronary artery bypass grafting in octogenarian; report of a case]. AB - An 86-year-old man was admitted to our hospital with angina due to the instent restenosis. He had a history of coronary artery bypass grafting( CABG). Re-do off pump CABG was performed. Aspirin and warfarin were started on the next day. The drainage tubes were removed on the postoperative day (POD) 2 and clopidogrel was resumed. On POD 9, he complained of nausea and dyspnea even at rest. Chest computed tomography (CT) and transthoracic echocardiography showed anterior mediastinal hematoma. 550 ml bloody effusion was discharged by percutaneous drainage. Because the accumulation of the mediastinal fluid was mainly anterior to the pericardial space, it was thought to be due to oozing from the sternum and soft tissues. The cause was unclear, but both antiplatelet and anticoagulant agents could have caused the oozing. He was discharged without reaccumulation of the effusion. It is important to take account of such delayed complications when multiple antiplatelet and anticoagulant agents are used after cardiovascular surgery especially in the octogenarian. PMID- 23023548 TI - [Residual inferior sinus venosus atrial septal defect after surgical closure of atrial septal defect; report of a case]. AB - Sinus venosus atrial septal defect( SVD) represent 5~10% of atrial septal defect( ASD). In contrast to the more common superior type in which the superior vena cava overrides the pathological interatrial communication, the inferior type with overriding inferior vena cava is extremely rare. We describe a case of residual inferior SVD after surgical closure of ASD. PMID- 23023549 TI - [Total arch replacement for spontaneous rupture of the thoracic aorta;report of a case]. AB - A 75-year-old man without history of trauma and aortic aneurysm presented with chest discomfort. A computed tomography (CT) revealed massive mediastinal hematoma without intimal flap in the aorta. Under hypothermic circulatory arrest, total arch replacement was performed. A transmural tear was found just distal to the left subclavian artery. Aortic dissection was not found macroscopically. When we encounter massive hematoma in the anterior mediastinum or the left thoracic cavity, spontaneous rupture of the thoracic aorta should be suspected, and emergency operation should be performed via optimal surgical approach. PMID- 23023550 TI - [Left atrial myxoma who presented cardiac arrest immediately after the onset of coldness of a leg; report of a case]. AB - A 55-year-old woman visited the emergency department of our hospital with complaint of coldness and pain in her right leg. Two hours after the onset, she suddenly felt dyspnea and temporarily suffered cardiac arrest. Echocardiography revealed a left atrial tumor prolapsing into the left ventricle through the mitral valve. By emergency operation, both the cardiac tumor and the embolus were diagnosed as myxomas. The postoperative course was uneventful. Cardiac failure and arterial embolism are major symptoms of a left atrial myxoma, but there have been no reports of both symptoms occurring at the same time. It is supposed that the changing form of the tumor because of embolus separation could have caused heart failure. We must consider the use of echocardiography to examine cardiac tumors in patients with arterial embolism who do not have cardiac arrhythmias. PMID- 23023551 TI - Topological crystalline insulator states in Pb(1-x)Sn(x)Se. AB - Topological insulators are a class of quantum materials in which time-reversal symmetry, relativistic effects and an inverted band structure result in the occurrence of electronic metallic states on the surfaces of insulating bulk crystals. These helical states exhibit a Dirac-like energy dispersion across the bulk bandgap, and they are topologically protected. Recent theoretical results have suggested the existence of topological crystalline insulators (TCIs), a class of topological insulators in which crystalline symmetry replaces the role of time-reversal symmetry in ensuring topological protection. In this study we show that the narrow-gap semiconductor Pb(1-x)Sn(x)Se is a TCI for x = 0.23. Temperature-dependent angle-resolved photoelectron spectroscopy demonstrates that the material undergoes a temperature-driven topological phase transition from a trivial insulator to a TCI. These experimental findings add a new class to the family of topological insulators, and we anticipate that they will lead to a considerable body of further research as well as detailed studies of topological phase transitions. PMID- 23023552 TI - Switching terahertz waves with gate-controlled active graphene metamaterials. AB - The extraordinary electronic properties of graphene provided the main thrusts for the rapid advance of graphene electronics. In photonics, the gate-controllable electronic properties of graphene provide a route to efficiently manipulate the interaction of photons with graphene, which has recently sparked keen interest in graphene plasmonics. However, the electro-optic tuning capability of unpatterned graphene alone is still not strong enough for practical optoelectronic applications owing to its non-resonant Drude-like behaviour. Here, we demonstrate that substantial gate-induced persistent switching and linear modulation of terahertz waves can be achieved in a two-dimensional metamaterial, into which an atomically thin, gated two-dimensional graphene layer is integrated. The gate controllable light-matter interaction in the graphene layer can be greatly enhanced by the strong resonances of the metamaterial. Although the thickness of the embedded single-layer graphene is more than six orders of magnitude smaller than the wavelength (=30 kg/m(2)). Maternal history and delivery information were obtained through chart abstraction. Differences in gestational age at first visit (GA-1) and adequate PNC were evaluated by BMI category. Data were compared using chi(2) and nonparametric analyses. RESULTS: Overall, 410 women were evaluated. The median GA 1 was 11.1 weeks and 69% had adequate PNC. There was no difference in GA-1 or adequate PNC by BMI category (p = 0.17 and p = 0.66, respectively). When BMI groups were dichotomized into obese and nonobese women, there was no difference in GA-1 or adequate PNC (p = 0.41). CONCLUSION: In our population, obesity is not an independent barrier to receiving early and adequate PNC. Future work is warranted in evaluating the association between obesity and PNC and the perceived barriers to obtaining care. PMID- 23023557 TI - Relationship between the retinal microvasculature and renal volume in low-birth weight babies. AB - OBJECTIVE: We performed a study to assess whether the development of the retinal microvasculature reflects nephron growth and therefore nephron number. STUDY DESIGN: In our study, we determined the association between kidney volume (nephron number) and the retinal microvasculature of term low-birth-weight (LBW) and normal-birth-weight (NBW) infants (11 LBW and 27 NBW). RESULTS: LBW infants had significantly larger retinal arteriolar and venular diameters (104.2 +/- 21.4 versus 87.0 +/- 12.7 MUm; p = 0.004; 146.8 +/- 19.5 versus 128.0 +/- 19.5 MUm; p = 0.01, respectively) compared with NBW infants. LBW infants also had smaller mean renal volumes (9.3 +/- 2.3 versus 12.2 +/- 3.1 ml; p = 0.008). There were negative correlations between retinal arteriolar and venular diameters and renal volumes (r = -0.34, p < 0.05; r = -0.37, p < 0.05, respectively). CONCLUSION: The larger the kidney (and, by implication, the greater the nephron number), the smaller are the diameters of retinal arterioles and venules. Thus, the degree of dilation of the retinal microvasculature provides an indirect index of renal growth. PMID- 23023558 TI - Prevalence of group B Streptococcus colonization in subsequent pregnancies of group B Streptococcus-colonized versus noncolonized women. AB - OBJECTIVE: To determine whether group B Streptococcus (GBS)-colonized pregnant women have an increased prevalence of GBS colonization in subsequent pregnancies. STUDY DESIGN: This retrospective cohort study compared the prevalence of GBS colonization in initial and subsequent pregnancies of 158 women with two or more deliveries at a Midwest institution since the initiation of universal screening for GBS. RESULTS: The GBS colonization rate in index pregnancies was 20%. Colonization rate in subsequent pregnancies for initially GBS-colonized women was 42% compared with 19% for women who were not colonized with GBS in the index pregnancy (p = 0.009). The relative risk for GBS-colonized women to be GBS colonized in subsequent pregnancies was 2.2 (confidence interval = 1.3 to 3.8). CONCLUSION: Previous GBS colonization is a risk factor for GBS colonization in subsequent pregnancies. Consideration of intrapartum chemoprophylaxis in women with a history of GBS colonization, assuming current colonization status is unknown, warrants further investigation. PMID- 23023559 TI - Can intravenous injection of tranexamic acid be used in routine practice with active management of the third stage of labor in vaginal delivery? A randomized controlled study. AB - OBJECTIVE: To estimate the effects of adding intravenous tranexamic acid (TA) to the standard active management of third-stage labor to reduce vaginal blood loss during the third and fourth stages of labor. STUDY DESIGN: A prospective, double blind, equivalence randomized, controlled study was performed. Women were randomly allocated to receive an intravenous infusion of TA (experimental group, n = 228) or 5% glucose (placebo group, n = 226) at delivery of the anterior shoulder. Active management of the third stage of labor, which includes prophylactic injection of 10 IU of oxytocin within 2 minutes of birth, early clamping of the umbilical cord, and controlled cord traction following delivery, was used in both groups. The primary outcome was mean blood loss during the third and fourth stages of labor. RESULTS: Mean estimated blood loss at the third and fourth stages of labor was significantly lower in the experimental group than that in the placebo group (261.5 +/- 146.8 mL versus 349.98 +/- 188.85 mL, respectively; p < 0.001). The frequency of postpartum hemorrhage > 500 mL was also lower in the experimental group (4, 1.8%) compared with that in the placebo controls (15, [6.8%]; relative risk, 3.76; 95% confidence interval, 1.27 to 11.15; p = 0.01). No episode of thrombosis occurred in the women who received TA. CONCLUSIONS: The use of TA with standard active management of the third stage of labor reduced postpartum blood loss, and no increase in the incidence of thromboembolic events was observed. PMID- 23023560 TI - The role of novel biomarkers in early diagnosis and prognosis of acute kidney injury in newborns. AB - Acute kidney injury (AKI) refers to the rapid loss of renal function. In clinical practice, AKI is common among hospitalized patients of all age groups including neonates and remains an important cause of morbidity and mortality due to its late diagnosis and therefore delayed therapeutic intervention. Although the precise incidence of AKI in newborn is unknown, several studies have reported that 8 to 24% of all critically ill newborns in neonatal intensive care units may develop the condition. We aim at reviewing the existing literature on novel serum and urinary biomarkers and discuss their role in the early diagnosis and prognosis of AKI in newborns. Specifically, this review will focus on cystatin C (CysC), neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL 18) in serum and on CysC, NGAL, kidney injury molecule-1, and IL-18 in urine. PMID- 23023562 TI - Research resource: interplay between the genomic and transcriptional networks of androgen receptor and estrogen receptor alpha in luminal breast cancer cells. AB - The cellular response to circulating sex steroids is more than the sum of individual hormone actions, instead representing an interplay between activities of the evolutionarily related steroid hormone receptors. An example of this interaction is in breast cancer, where the risk of dying from estrogen receptor alpha (ERalpha)-positive disease decreases approximately 4-fold when androgen receptor (AR) expression is high. In this study, we used chromatin immunoprecipitation sequencing (ChIP-seq) and microarray expression profiling to investigate the genomic and transcriptional cross talk between AR and ERalpha signaling in a luminal breast cancer cell line model, ZR-75-1. Expression profiling demonstrated reciprocal interference between 5alpha-dihydrotestosterone (DHT)- and 17beta-estradiol (E(2))-induced transcriptional programs. Specifically, regulation of 26% of E(2) and 15% of DHT target genes was significantly affected by cotreatment with the other hormone, in the majority of cases (78-83%) antagonistically. Pathway analysis suggested that DHT cotreatment, for example, depleted E(2)-regulated pathways in cell survival and proliferation. ChIP-seq identified substantial overlap between the steroid receptor cistromes in ZR-75-1 cells, with 10-13% of AR- and ERalpha-binding sites located within 10 kb of the other receptor. Enrichment of androgen response elements in ERalpha binding sites and vice versa was revealed by motif analysis, and AR-binding sites were enriched about E(2)-responsive genes affected by DHT cotreatment. Targeted ChIP and expression analysis revealed locus-specific outcomes when AR and ERalpha bind to the same DNA region. This work provides the first cistrome data for two steroid receptors in the same cell, insight into the antagonistic interplay between estrogens and androgens in luminal breast cancer, and an important resource for future work aimed at evaluating interrelated steroid receptors in different cellular systems. PMID- 23023561 TI - Vav3 enhances androgen receptor splice variant activity and is critical for castration-resistant prostate cancer growth and survival. AB - Advanced or metastatic prostate cancer is treated by androgen deprivation; however, patients inevitably relapse with castration-resistant prostate cancer (CRPC). CRPC remains dependent on androgen receptor (AR) signaling, which may include constitutive, ligand-independent action of naturally occurring AR splice variants. For example, the AR splice variant AR3 (also termed AR-V7) is expressed in CRPC and is linked to poor prognosis. Vav3, a Rho GTPase guanine nucleotide exchange factor, is an AR coactivator that is up-regulated in human prostate cancer compared with benign tissue and in preclinical models of CRPC. Vav3 confers castration-resistant growth to androgen-dependent human prostate cancer cells. Despite the importance of AR coactivators in promoting CRPC, the potential role of these regulatory proteins in modulating AR splice variant activity is unknown. We examined the contributions of Vav3 to AR activity in two CRPC cell lines that naturally express relatively high levels of Vav3 and AR3. Vav3 or AR3 knockdown greatly attenuated cell proliferation, soft agar growth, and ligand independent AR activity. Vav3 potently enhanced the transcriptional activity of AR3 and another clinically relevant AR splice variant, ARv567es. Vav3 knockdown resulted in lowered nuclear AR3 levels, whereas total AR3 levels remained similar. Conversely, overexpression of Vav3 resulted in increased nuclear AR3. Coimmunoprecipitation revealed that AR3 and Vav3 interact. These novel data demonstrating physical and functional interactions between Vav3, a unique AR coactivator, and an AR splice variant provide insights into the mechanisms by which Vav3 exploits and enhances AR signaling in the progression to CRPC. PMID- 23023563 TI - In silico discovery of androgen receptor antagonists with activity in castration resistant prostate cancer. AB - Previously available androgen receptor (AR) antagonists (bicalutamide, flutamide, and nilutamide) have limited activity against AR in prostate cancers that relapse after castration [castration resistant prostate cancer (CRPC)]. However, recent AR competitive antagonists such as MDV3100, generated through chemical modifications to the current AR ligands, appear to have increased activity in CRPC and have novel mechanisms of action. Using pharmacophore models and a refined homology model of the antagonist-liganded AR ligand binding domain, we carried out in silico screens of small molecule libraries and report here on the identification of a series of structurally distinct nonsteroidal small molecule competitive AR antagonists. Despite their unique chemical architectures, compounds representing each of six chemotypes functioned in vitro as pure AR antagonists. Moreover, similarly to MDV3100 and in contrast to previous AR antagonists, these compounds all prevented AR binding to chromatin, consistent with each of the six chemotypes stabilizing a similar AR antagonist conformation. Additional studies with the lead chemotype (chemotype A) showed enhanced AR protein degradation, which was dependent on helix 12 in the AR ligand binding domain. Significantly, chemotype A compounds functioned as AR antagonists in vivo in normal male mice and suppressed AR activity and tumor cell proliferation in human CRPC xenografts. These data indicate that certain ligand-induced structural alterations in the AR ligand binding domain may both impair AR chromatin binding and enhance AR degradation and support continued efforts to develop AR antagonists with unique mechanisms of action and efficacy in CRPC. PMID- 23023564 TI - Sphaeranthus indicus flower derived constituents exhibits synergistic effect against acetylcholinesterase and possess potential antiamnestic activity. AB - OBJECTIVE: The present investigation was aimed at discovery of novel acetylcholinesterase (AChE) inhibitors. METHODS: In vitro AchE inhibitory activity of various extracts of Sphaeranthus indicus flower heads was carried out. The petroleum ether fraction of S. indicus flowers (SIPE) exhibited significant activity. The fraction was found to be rich in sesquiterpene lactone content possibly responsible for in vitro AChE inhibition. In further study, the antiamnesic activities of SIPE in mice on the learning and memory impairments induced by scopolamine (1.0 mg/kg, i.p.) were examined. RESULTS: SIPE (10 mg/kg, p.o.) administration significantly reversed cognitive impairments in mice by passive avoidance test (P < 0.05). It also reduced escape latencies in training trials and prolonged swimming times in the target quadrant during the probe trial in the water maze task (P < 0.05). These results indicated that S. indicus due to its sesquiterpene lactones have anti-cholinesterase activity. A major sesquiterpene lactone, 7-hydroxy frullanolide along with other constituents were isolated from SIPE and evaluated for AchE inhibitory activity. Negative results were obtained in case of isolated compounds. CONCLUSION: Synergistic effect between constituents of SIPE was confirmed to have anti-amnesic activities that may be useful for cognitive impairment treatment. PMID- 23023565 TI - Anti-hyperlipidemic activity of Cucumis melo fruit peel extracts in high cholesterol diet induced hyperlipidemia in rats. AB - Abstract Cucumis melo Linn. (Cucurbitaceae) fruits have been used, traditionally in Indian traditional system of medicine, for the treatment of various disorders such as liver tonic, cardioprotective, antidiabetic, antiobesity, etc. The aim of the present study was to investigate the possible anti-hyperlipidemic activity of Cucumis melo fruit peel (CMFP) methanolic and aqueous extract in high cholesterol diet induced hyperlipidemia in rats. Treatment with CMFP methanolic and aqueous extract showed significant (P<0.01) reduction in gain in body weight, serum lipid profile like total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) level, atherogenic index and increased the serum high density lipoprotein cholesterol (HDL-C) levels in 28 days treatment when compared to the hyperlipidemic control group. The fecal excretion of bile acids and sterols was further increased upon treatment with CMFP methanolic and aqueous extract and standard drug. Administration of methanolic extract of CMFP at a dose of 500 mg/kg showed higher antihyperlipidemic activity as compared to other extract treated groups. The results concluded that CMFP methanolic extract (500 mg/kg) have potent antihyperlipidemic activity in high cholesterol diet induced hyperlipidemia model and which is equipotent activity when compared with atorvastatin treated group. PMID- 23023566 TI - Comparison of effectiveness in antitumor activity between flavonoids and polyphenols of the methanolic extract of roots of Potentilla fulgens in breast cancer cells. AB - Potentilla fulgens has been used for a long time as folk remedy for a variety of ailments without having information on its pharmacological action. The study was intended to determine the effectiveness in antitumor activity among kaempferol (KMP) as flavonoids, ellagic acid (ELA) as polyphenols and methanolic extract of the root of P. fulgens (PRE) in Ehrlich ascites tumour (EA) and MCF-7 cancer cells. The total phenolic and flavonoid content were found to be 138.8 +/- 1.6 mg gallic acid and 401.6 +/- 4.6 mg quercetin per 1 gm of the extract, respectively. The extract resulted in increasing in vivo survivality of mice bearing EA cells and loss of cell viability in a dose-dependent manner in MCF-7 cells. This effect may be attributed to apoptotic cell death as confirmed by flow cytometric analysis and PARP1 proteolysis. Such induction of apoptosis was achieved by suppression of inhibitor of the apoptosis protein survivin. It was observed that endogenous level of glutathione was depleted significantly in MCF-7 cells after the treatment with PRE only but not with KMP or ELA. This induction of apoptotic cell death and lowering the level of glutathione are highly desirable mode for an anticancer agent. PMID- 23023569 TI - Stem cell themes: promises and challenges. PMID- 23023567 TI - Scavenger receptor class B type I is a plasma membrane cholesterol sensor. AB - RATIONALE: Signal initiation by the high-density lipoprotein (HDL) receptor scavenger receptor class B, type I (SR-BI), which is important to actions of HDL on endothelium and other processes, requires cholesterol efflux and the C terminal transmembrane domain. The C-terminal transmembrane domain uniquely interacts with plasma membrane (PM) cholesterol. OBJECTIVE: The molecular basis and functional significance of SR-BI interaction with PM cholesterol are unknown. We tested the hypotheses that the interaction is required for SR-BI signaling, and that it enables SR-BI to serve as a PM cholesterol sensor. METHODS AND RESULTS: In studies performed in COS-M6 cells, mutation of a highly conserved C terminal transmembrane domain glutamine to alanine (SR-BI-Q445A) decreased PM cholesterol interaction with the receptor by 71% without altering HDL binding or cholesterol uptake or efflux, and it yielded a receptor incapable of HDL-induced signaling. Signaling prompted by cholesterol efflux to methyl-beta-cyclodextrin also was prevented, indicating that PM cholesterol interaction with the receptor enables it to serve as a PM cholesterol sensor. Using SR-BI-Q445A, we further demonstrated that PM cholesterol sensing by SR-BI does not influence SR-BI mediated reverse cholesterol transport to the liver in mice. However, the PM cholesterol sensing does underlie apolipoprotein B intracellular trafficking in response to postprandial micelles or methyl-beta-cyclodextrin in cultured enterocytes, and it is required for HDL activation of endothelial NO synthase and migration in cultured endothelial cells and HDL-induced angiogenesis in vivo. CONCLUSIONS: Through interaction with PM cholesterol, SR-BI serves as a PM cholesterol sensor, and the resulting intracellular signaling governs processes in both enterocytes and endothelial cells. PMID- 23023570 TI - Backbone assignment of fully protonated solid proteins by 1H detection and ultrafast magic-angle-spinning NMR spectroscopy. PMID- 23023571 TI - Choice of device for parenchymal transection in laparoscopic hepatectomy. AB - BACKGROUND: Laparoscopic hepatic surgery has only recently become an established field. Technological limitations in devices used to transect the liver parenchyma and control hemostasis have been a rate limiting step. However, as a result of advances in products specifically tailored to liver surgery, there has been steady progress in the complexity of laparoscopic hepatectomies performed, from the minimally invasive fenestration of liver cysts, to peripheral wedge resections, major hepatectomy, and recently donor hepatectomy. Herein, we discuss the role of several laparoscopic devices which include the endoscopic stapler, pre-coagulators, ultrasonic dissector, ultrasonic shears, and vessel sealing devices. CONCLUSION: Laparoscopic liver surgery introduces new challenges to even the experienced surgeon. It is important to have a solid understanding of the advantages and limitations of available instruments in order to safely and effectively expand the use of laparoscopy in hepatic surgery. PMID- 23023572 TI - Review: biomechanical issues in total hip replacement. AB - During total hip arthroplasty, the biomechanics of the joint may be altered by removal of bone and by a change in the center of rotation of the joint. Joint pathologies existing at the time of reconstruction may also affect post-operative joint motion. In order to achieve optimized biomechanics of the replaced joint, it is important to understand the muscle actions that are involved in joint movement and the forces that are imposed on the construct by patient activity. To ensure survivorship of the replacement, intraoperative and long-term stability of the components making up the joint within host bone must be achieved. The patients receiving total hip replacements in the twenty first century tend to be younger, heavier, more active and longer lived than the patients who first received hip implants. Thus, biomechanical decisions are becoming even more important for long-term survivorship of the reconstruction. PMID- 23023573 TI - Prospective randomized study comparing quality of life after shoudice or mesh plug repair for inguinal hernia: short-term results. AB - Postoperative pain is a major obstacle in hernia repair surgery, and the choice of clinically efficacious surgical technique should also result in the least postoperative pain and patients' quality of life (QoL). The aim of this prospective randomized study was to compare two surgical techniques for open inguinal hernia repair by assessing the patients' QoL. Men (18-to-75 years old) with primary unilateral inguinal hernia underwent Mesh Plug (MP; n = 156; Bard (PerFix Plug, CR Bard Inc, Murray Hill, NJ) and Shouldice (S; n = 144) techniques. We evaluated: 1) Intensity of postoperative pain (visual analog scale [VAS]) and 2) quality of life (QoL; Medical Outcomes Study Short-Form 36 [SF 36]). Patients undergoing MP had significantly lower VAS scores on postoperative days (POD) 1 (22.1 vs 27.4, p = .003) and 2 (13.2 vs 21.4, p < .0001) compared to those in the S group. The QoL was also improved in patients undergoing MP on PODs 8 and 45. Total duration of operation, length of hospital stay, and cessation of normal activities were significantly shorter in the MP group. Compared to the S technique, the MP technique results in significantly less postoperative pain and improved QoL. PMID- 23023574 TI - Chronic wound-associated pain, psychological stress, and wound healing. AB - Pain is an unpleasant sensory experience that evokes negative emotions and erodes an individual's quality of life, constituting a significant amount of stress. Chronic-wound patients have described pain as most intense during dressing change and the worst part of living with an ulcer. Wound-related pain is complex, involving a multitude of physiologic and psychologic factors, such as emotional state, culture, personality, meaning, and expectation. Although the exact mechanism(s) remains elusive, a burgeoning body of evidence suggests a close link between stress/anxiety and pain. Wound healing can be compromised by overproduction of cortisol compromising the function of immune system in addition to catecholamines causing vasoconstriction and poor tissue oxygenation. The purpose of this paper is to review the relationships among pain, stress, and wound healing. PMID- 23023575 TI - Can TKA be avoided? Alternate strategies. AB - In the properly selected patient, alternative options to total knee arthroplasty exist for the surgical treatment of knee joint disease. These procedures involve reestablishing healthy cartilage (i.e., bone marrow stimulation, grafting, autologous chondrocyte implantation), mechanical axis correction (i.e., osteotomy), and/or replacing pathologic knee compartments with prosthetic devices (i.e., unicompartmental and bicompartmental knee arthroplasty). Treatment modality selection varies based on a number of factors, including but not limited to age, activity level, treatment history, and lesion size, location, severity, and etiology. Reestablishing healthy cartilage in pathologic knees is dependent on the recipient's capacity and propensity to heal and regenerate new cartilage. Therefore, this technique is typically conducted in young patients, with small- to medium-sized focal chondral or osteochondral lesions. Osteotomy, unicompartmental knee arthroplasty, and bicompartmental knee arthroplasty do not have the same restrictions and are used for patients with larger, isolated knee lesions. This article reviews indications, efficacy, and advancements of existing surgical techniques for the repair or restoration of knee lesion injuries. PMID- 23023576 TI - Procedure simplification: the role of single-use instruments in total knee arthroplasty. AB - In orthopaedic surgery, surgical site contamination leading to periprosthetic infections is a major concern with important morbidity, financial and emotional burden. Single-use instruments developed for total knee arthroplasties are intended to simplify the surgical procedure, decrease the number of surgical trays that require sterilization and reprocessing, decrease the incidence of possible contamination through breaks in surgical wraps, and improve operating room efficiency. As the demand for total knee arthroplasty continues to rise, a greater burden on the healthcare system may be created. The use of single-use instruments, cutting guides, and trials will play an increasing role in total knee arthroplasty through improved operating room efficiency. PMID- 23023577 TI - Litanium expandable pedicle screw for the treatment of degenerative and traumatic spinal diseases in osteoporotic patients: preliminary experience. AB - Osteoporosis is a major global health problem, with over 10 million people currently diagnosed with the disease. Although 80% of osteoporotic patients are women, a considerable number of men are also affected. Also, due to increasing life expectancy, the number of elderly patients with osteoporosis affected by degenerative and traumatic spinal diseases will increase further. Osteoporosis reduces bone quality through negative bone remodelling. Low bone quality can reduce the pull-out strength of pedicle screw, and negative bone remodelling can cause delayed bone fusion. However, pedicle screw instrumentation of the osteoporotic spine carries an increased risk of screw loosening, pull-out, and fixation failure. Our preliminary study aims to investigate the efficiency of expandable pedicle screws (OsseoScrew-Spinal Fixation System, Alphatec Spine Inc., Carlsbad, CA) in osteoporotic spinal patients. All osteoporotic patients with degenerative and traumatic spinal diseases admitted in our department underwent a pre-operative spinal x-Ray and MRI or CT. Pre-operative clinical assesment of patients was based on the visual analog scale (VAS) and Owestry Disability (ODI) questionnaire-a disease-specific outcome measure. Ten osteoporotic patients were treated with expandable pedicle screws (OsseoScrew). Post-operative clinical assessment of patients was based on the VAS and ODI questionnaire at 3 months and 1 year of follow-up. Post-operative radiologic follow-up was performed after 3 days (CT, x-ray); 3 months (x-ray); 6 months (spinal CT); and 1 year (spinal CT). Expandable pedicle screws improved pull-out strength as compared to standard pedicle screws in osteoporotic patients with degenerative and traumatic spinal diseases. PMID- 23023578 TI - A highly selective fluorescent probe for fast detection of hydrogen sulfide in aqueous solution and living cells. AB - A new ratiometric fluorescence probe E1 based on an excited-state intramolecular proton transfer (ESIPT) mechanism for detection of hydrogen sulfide (H(2)S) is reported. E1 responds to H(2)S quickly and showed a 30-fold fluorescence enhancement in 2 minutes. Moreover, E1 can detect H(2)S quantitatively with a detection limit as low as 0.12 MUM in aqueous solution. Its potential for biological applications was confirmed by employing it for fluorescence imaging of H(2)S in living cells. PMID- 23023580 TI - A platform for preparation of monodispersed fluorescent conjugated polymer microspheres with core-shell structures. AB - A strategy to prepare stable monodispersed fluorescent microspheres is developed by modifying the Wessling method to synthesize poly(p-phenylenevinylene) (PPV) on the surface of a highly crosslinked polymer core. The positively charged PPV polymer precursors (pre-PPV) are adsorbed onto the core with negative charges on the surface and then the insoluble fluorescent PPVs form after thermal elimination. Each individual sphere is found to possess a very smooth surface with an even distribution of fluorescence by microscopic techniques. Very small coefficient of variance (CV) values of emission intensity (<4.0%) and size (<2.3%) are realized for microspheres prepared in the same batch. The spheres are demonstrated to have good thermal stability and photostability. PMID- 23023581 TI - RETRACTED: Molecular strategies in manipulation of the starch synthesis pathway for improving storage starch content in plants (review and prospect for increasing storage starch synthesis). AB - Starch is the most widespread and abundant storage carbohydrate in plants. We depend upon starch for our nutrition, exploit its unique properties in industry, and use it as a feedstock for bioethanol production. In recent decades, enormous progress has been made in understanding the genetic and biochemical mechanisms of starch synthesis in plants. Yet, despite this remarkable progress and its obvious economic importance, very little has been achieved in terms of adding value to starch or increasing starch content, particularly in cereal crops. In this paper, we first review recent advances in understanding the biochemistry of starch synthesis, particularly in identifying key enzymes involved in starch assembly. We then assess the progress in molecular strategies for improving storage starch content in plants. Finally, we discuss the problems faced in our profession and present ideas to effectively increase storage starch content in the future. PMID- 23023582 TI - Levels of DNA methylation and histone methylation and acetylation change in root tip cells of soybean seedlings grown at different temperatures. AB - In order to check whether changes in DNA and histone modifications occur in the nuclei of root tip cells of soybean seedlings grown 1) under control conditions (25 degrees C), 2) subjected to chilling stress (10 degrees C) and 3) recovered (25 degrees C) after chilling, measurements of fluorescence intensity with the use of antibodies to heterochromatin as well as to euchromatin markers were carried out. Moreover, the number and sizes of chromocentres were analyzed. The studies showed that during chilling stress the fluorescence intensity for the markers characteristic of heterochromatin increased while for the markers of euchromatin decreased in comparison to the control. After the recovery the converse situation was observed, i.e. increase in fluorescence intensity for euchromatin markers and decrease in heterochromatin markers. The number of chromocentres remained unchanged in the nuclei of all three studied variants. However, differences in the sizes of chromocentres were observed - the highest number of big chromocentres and simultaneously the lowest number of small chromocentres were in the nuclei of stressed plants. Conversely - in the nuclei of recovered plants there were the lowest number of big chromocentres and the highest number of small ones. The treatment of seedlings with the inhibitors of DNA methylation (5-aza-dC) and histone deacetylation (NaBu) also caused changes in fluorescence intensity and chromocentre sizes in soybean nuclei. These results suggest that DNA and histone modification patterns can be altered in soybean nuclei by different growth temperatures and by appropriate inhibitors influencing epigenetic chromatic modifications. PMID- 23023583 TI - MUC1 glycopeptide epitopes predicted by computational glycomics. AB - Bioinformatic tools and databases for glycobiology and glycomics research are playing increasingly important roles in functional studies. However, to verify hypotheses generated by computational glycomics with empirical functional assays is only an emerging field. In this study, we predicted glycan epitopes expressed by a cancer-derived mucin, MUC1, by computational glycomics. MUC1 is expressed by tumor cells with a deficiency in glycosylation. Although numerous diagnostic reagents and cancer vaccines have been designed based on abnormally glycosylated MUC1 sequences, the glycan and peptide sequences responsible for immune responses in vivo are poorly understood. The immunogenicity of synthetic MUC1 glycopeptides bearing Tn or sialyl-Tn antigens have been studied in mouse models, while authentic glyco-epitopes expressed by tumor cells remain unclear. To examine the immunogenicity of authentic cancer derived MUC1 glyco-epitopes, we expressed membrane bound forms of MUC1 tandem repeats in Jurkat, a mutant cancer cell line deficient of mucin-type core-1 beta1-3 galactosyltransferase activity, and immunized mice with cancer cells expressing authentic MUC1 glyco-epitopes. Antibody responses to individual glyco-epitopes were determined by chemically synthesized candidate MUC1 glycopeptides predicted through computational glycomics. Monoclonal antibodies can be generated toward chemically synthesized glycopeptide sequences. With RPAPGS(Tn)TAPPAHG as an example, a monoclonal antibody 16A, showed 25-fold higher binding to glycosylated peptide (EC50=9.278+/ 1.059 ng/ml) compared to its non-glycosylated form (EC(50)=247.3+/-16.29 ng/ml) as measured by ELISA experiments with plate-bound peptides. A library of monoclonal antibodies toward authentic MUC1 glycopeptide epitopes may be a valuable tool for studying glycan and peptide sequences in cancer, as well as reagents for diagnosis and therapy. PMID- 23023584 TI - Role of FBXL20 in human colorectal adenocarcinoma. AB - In the present study, in order to determine whether the FBXL20 gene plays a role in the carcinogenesis of human colorectal adenocarcinoma, the mRNA expression levels of FBXL20 were examined in 30 pairs of human colorectal adenocarcinoma tissues and corresponding adjacent normal colorectal tissues by quantitative real time PCR (qRT-PCR). The pGPU/GFP/Neo-FBXL20 siRNA expression vector was transfected into the human colon carcinoma cell lines, SW480 and SW620. The mRNA levels of beta-catenin, c-Myc, cyclin D1, p53, PP2A, SET and E-cadherin were determined by qRT-PCR, whereas the protein levels of beta-catenin, c-Myc, caspase 3 and SET were examined by western blot analysis. MTT assay and flow cytometry were employed to assess cell proliferation, apoptosis and the cell cycle. As shown by qRT-PCR, FBXL20 mRNA expression was upregulated in 76.7% of the tumor samples. Cell proliferation was inhibited by 33.3% in the SW480-FBXL20 cells and by 22.7% in the SW620-FBXL20 cells, compared to the corresponding control cells. Furthermore, the percentages of apoptotic cells were 21.3 and 17.1% in the SW480 FBXL20 and SW620-FBXL20 cells, whereas the percentages of G1 phase cells in the two cell lines were 90.13 and 78.13%, respectively. In addition, the mRNA expression of SET and E-cadherin was upregulated in the SW480-FBXL20 and SW620 FBXL20 cells, whereas that of beta-catenin, c-Myc, cyclin D1, p53 and PP2A was downregulated. Consistently, the protein expression of beta-catenin and c-Myc was downregulated, whereas that of SET and caspase-3 was upregulated. Based on these results, we can conclude that FBXL20 plays an essential role in the carcinogenesis of human colorectal adenocarcinoma. Moreover, our data suggest that FBXL20 promotes carcinogenesis through the regulation of the Wnt signaling pathway and caspase activation. PMID- 23023586 TI - Aqueous-phase hydroformylation of 1-octene using hydrophilic sulfonate salicylaldimine dendrimers. AB - Water-soluble dendritic ligands based on tris-2-(5-sulfonato salicylaldimine ethyl)amine (5) and DAB-(5-sulfonato salicylaldimine) (6) (DAB = diaminobutane) were synthesized by means of Schiff base condensation and sulfonation reactions. These dendritic ligands were fully characterized by (1)H NMR, (13)C NMR and FT-IR spectroscopy, elemental analysis and mass spectrometry. Dendritic ligands (5 and 6) in combination with [RhCl(COD)](2) (COD = 1,5-cyclooctadiene) were evaluated in aqueous biphasic hydroformylation of 1-octene. New water-soluble mononuclear 5 sulfonato propylsalicylaldimine Rh(i) complexes (7 and 8) were synthesized and characterized using (1)H NMR, (13)C NMR and FT-IR spectroscopy, elemental analysis as well as mass spectrometry. These complexes were applied as catalyst precursors in aqueous biphasic hydroformylation reactions. All the catalyst precursors were active in the hydroformylation of 1-octene under the investigated conditions. Optimal conditions were realized at 75 degrees C (40 bars), where the best selectivity for aldehydes was noticed. Catalyst recycling was achieved up to 5 times with minimal loss in conversion and consistent chemoselectivities and regioselectivities. Less Rh leaching was observed in the dendritic systems (5 and 6)/[RhCl(COD)](2) as compared to mononuclear catalyst precursors (7 and 8) as determined by inductively coupled plasma-mass spectrometry (ICP-MS). PMID- 23023585 TI - Agricultural work and chronic musculoskeletal pain among Latino farm workers: the MICASA study. AB - BACKGROUND: Agriculture poses varied dangers to hired farm workers in the U.S., but little information exists on occupational risks for chronic musculoskeletal pain. We examined common work positions, such as kneeling, carrying heavy loads, and repetitive motion that may increase the risk for chronic musculoskeletal pain. METHODS: MICASA is a population-based study of occupational exposures and health in hired farm workers in California. This analysis includes 759 participants, 18-55 years old, engaged in farm work and residing in Mendota, CA. Chronic pain was defined as pain lasting 6 weeks or longer at specific body sites (back, knee, hip, etc.) over the entire farm work career. RESULTS: Mean age was 37.9 years. Sixty-five percent participants were born in Mexico, 27.7% were born in El Salvador, and 4.2% were U.S-born. Chronic pain was associated with older age and female sex. After adjustment for age, years working in agriculture, and smoking, stooping/bending >30 hr/week among both men (OR = 2.49, 95% CI: 1.03 5.99) and women (OR = 2.15, 95% CI: 1.04-4.46) was associated with chronic hip pain. Driving tractors or other heavy farm equipment >60 hr/week was associated with increased odds of chronic hip pain (OR = 2.16, 95% CI: 1.02-4.54) among men. We also observed significant associations with kneeling or crawling >35 hr/week among women for both chronic back pain (OR = 2.96, 95% CI: 1.27-6.93) and knee pain (OR = 3.02, 95% CI: 1.07-8.50), respectively. CONCLUSIONS: Chronic musculoskeletal pain is prevalent among farm workers and is associated with common work positions. Further research should focus on developing preventive interventions for tasks associated with increased pain risk. These interventions should be targeted to specific types of agricultural tasks. PMID- 23023587 TI - Fluorescence photoswitching based on a photochromic pKa change in an aqueous solution. AB - Reversible fluorescence photoswitching of RSA-AZO dyad 1 was clearly demonstrated in an acidic aqueous solution. The fluorescence photoswitching mechanism is based on the reversible ring opening/closing reactions of the RSA unit induced by a photochromic pK(a) change along with the photoisomerization of the AZO unit. PMID- 23023589 TI - Entropy-driven chemisorption of NO(x) on phosphotungstic acid. AB - Free-energy calculations indicated that the NO(x) adsorption process on heteropolyacids is entropy-driven, as more gas molecules are released than adsorbed by substitution of H(5)O(2)(+) with NO(+) species. P yellow, W light blue, O red, H pink, N small dark blue spheres. PMID- 23023588 TI - MRI biosensor for protein kinase A encoded by a single synthetic gene. AB - PURPOSE: Protein kinases including protein kinase A (PKA) underlie myriad important signaling pathways. The ability to monitor kinase activity in vivo and in real-time with high spatial resolution in genetically specified cellular populations is a yet unmet need, crucial for understanding complex biological systems as well as for preclinical development and screening of novel therapeutics. METHODS: Using the hypothesis that the natural recognition sequences of protein kinases may be detected using chemical exchange saturation transfer magnetic resonance imaging, we designed a genetically encoded biosensor composed of eight tandem repeats of the peptide LRRASLG, a natural target of PKA. RESULTS: This sensor displays a measurable change in chemical exchange saturation transfer signal following phosphorylation by PKA. The natural PKA substrate LRRASLG exhibits a chemical exchange saturation transfer-magnetic resonance imaging contrast at +1.8 and +3.6 ppm, with a >50% change after phosphorylation with minutes-scale temporal resolution. Expression of a synthetic gene encoding eight monomers of LRRASLG yielded two peaks at these chemical exchange saturation transfer frequencies. CONCLUSION: Taken together, these results suggest that this gene may be used to assay PKA levels in a biologically relevant system. Importantly, the design strategy used for this specific sensor may be adapted for a host of clinically interesting protein kinases. PMID- 23023590 TI - Smoking status and survival in the national comprehensive cancer network non small cell lung cancer cohort. AB - BACKGROUND: The objectives of this study were to evaluate survival among current smokers, former smokers, and never smokers who are diagnosed with non-small cell lung cancer (NSCLC). METHODS: The study included patients who participated in the National Comprehensive Cancer Network's NSCLC Database Project. Current, former, and never smokers were compared with respect to overall survival by fitting Cox regression models. RESULTS: Data from 4200 patients were examined, including 618 never smokers, 1483 current smokers, 380 former smokers who quit 1 to 12 months before diagnosis, and 1719 former smokers who quit >12 months before diagnosis. Among patients with stage I, II, and III disease, only never smokers had better survival than current smokers (hazard ratio, 0.47 [95% confidence interval, 0.26 0.85] vs 0.51 [95% confidence interval, 0.38-0.68], respectively). Among patients with stage IV disease, the impact of smoking depended on age: Among younger patients (aged <=55 years), being a never smoker and a former smoker for >=12 months increased survival. After age 85 years, smoking status did not have a significant impact on overall survival. CONCLUSIONS: Patients who were smoking at the time of diagnosis had worse survival compared with never smokers. Among younger patients with stage IV disease, current smokers also had worse survival compared with former smokers who quit >12 months before diagnosis. It is likely that tumor biology plays a major role in the differences observed; however, to improve survival, it is prudent to encourage all smokers to quit smoking if they are diagnosed with NSCLC. PMID- 23023591 TI - Reoperation rate after surgery for lumbar herniated intervertebral disc disease: nationwide cohort study. AB - STUDY DESIGN: Retrospective cohort study using national health insurance data. OBJECTIVE: To provide a longitudinal reoperation rate after surgery for lumbar herniated intervertebral disc (HIVD) disease, and to compare the reoperation rates of surgical methods. SUMMARY OF BACKGROUND DATA: Herniated intervertebral disc disease is the most common cause of lumbar spinal surgery. Despite improved surgical techniques and instrumentation, reoperation cannot be avoided. The reoperation rates were in the range of 6% to 24% in previous studies. A population-based study is less subject to bias; hence, a nationwide longitudinal analysis was warranted. METHODS: A national health insurance database was used to identify a cohort of patients who underwent first surgery for herniated intervertebral disc disease in 2003 and 18,590 patients were selected. Individual patients were followed for at least 5 years through their encrypted unique resident registration number. The primary endpoint was any type of second lumbar surgery. After adjusting for confounding factors, 5 surgical methods (fusion, laminectomy, open discectomy, endoscopic discectomy, and nucleolysis [including mechanical nucleus decompression]) were compared. Open discectomy was used as the reference method. RESULTS: Open discectomy was the most common procedure (68.9%) followed by endoscopic discectomy (16.1%), laminectomy (7.9%), fusion (3.9%), and nucleolysis (3.2%). The cumulative reoperation rate was 5.4% at 3 months, 7.4% at 1 year, 9% at 2 years, 10.5% at 3 years, 12.1% at 4 years, and 13.4% at 5 years. The reoperation rates were 18.6%, 14.7%, 13.8%, 12.4%, and 11.8% after laminectomy, nucleolysis, open discectomy, endoscopic discectomy, and fusion, respectively. Compared with open discectomy, the reoperation rate was higher after laminectomy at 3 months, whereas the other surgical methods had similar rates. CONCLUSION: The cumulative reoperation rate after 5 years was 13.4% and half of the reoperations occurred during the first postoperative year. With the exception of laminectomy, the reoperation rates of the other procedures were not different from that of open discectomy. PMID- 23023592 TI - The effects of dynamic isolated lumbar extensor training on lumbar multifidus functional cross-sectional area and functional status of patients with chronic nonspecific low back pain. AB - STUDY DESIGN: A prospective single-arm trial. OBJECTIVE: To investigate whether dynamic isolated resistance training of global lumbar extensor muscles leads to changes in lumbar multifidus (LM) morphology in terms of cross-sectional muscle, and, if so, whether these changes are associated with observed changes in self experienced functional status of chronic nonspecific low back pain (CNSLBP). SUMMARY OF BACKGROUND DATA: LM morphology is associated with the recurrence of CNSLBP. METHODS: Sixteen male patients underwent a dynamic isolated resistance training program for the lower back muscles of approximately 10 sessions in 12 weeks. In the next 12 weeks, frequency of training was tailored to the patients' need. Participants underwent lumbar magnetic resonance imaging at baseline (T0), after 12 weeks (T12), and after 24 weeks (T24). Functional cross-sectional area was obtained by analyzing the magnetic resonance images. Functional status was assessed using the patient-specific functional scale, Roland-Morris disability questionnaire, and global perceived effect scale. RESULTS: Roland-Morris disability questionnaire and patient-specific functional scale scores showed significant and clinically relevant improvements between baseline and T12, with 44% and 39%, respectively. Between T12 and T24, these scores did not change significantly. Seven participants (44%) reported clinically relevant improvements in global perceived effect at T12. At T24, 1 more participant reported a relevant global perceived effect improvement, whereas 2 participants (13%) reported worsening of their condition. The magnetic resonance imaging analysis showed minor nonsignificant changes in functional cross-sectional area. CONCLUSION: Our study shows that 10 weeks of dynamic isolated training of the lumbar extensors, once a week, leads to clinically relevant improvements in functional status of men with CNSLBP, without accompanying improvements in functional cross-sectional area of LM. These findings suggest that improvement in LM morphology is not a critical success factor in restoring functional status of patients with CNSLBP, at least in the short term (6 mo). PMID- 23023593 TI - Localization of the medial branches of the cervical dorsal rami during cervical laminoplasty. AB - STUDY DESIGN: Observational anatomic study. OBJECTIVE: To give precise information on the surgical anatomy of the medial branches of the cervical dorsal rami. SUMMARY OF BACKGROUND DATA: The anatomy of the medial branches has not been sufficiently described. METHODS: We recorded the location of the medial branches in 94 consecutive patients who underwent laminoplasty for cervical compression myelopathy. A posterior cervical approach was made along the edge of the nuchal ligament, and, after carefully detaching the trapezius muscle from the nuchal ligament; we identified the right-side branches around the semispinalis capitis muscle. We recorded the location of the branches with reference to the spinous processes and the semispinalis capitis and trapezius muscles. In 52 patients, we electrically stimulated the branches and observed the contraction of these muscles. RESULTS: Branches were identified between C3 and C6 spinous process levels in 92 patients. A single branch was identified in 56 patients, 2 branches were identified in 35 patients, and 3 branches were identified in the remaining 1 patient. Branches were located between C3 and C4 (n = 12), between C4 and C5 (n = 80), between C5 and C6 (n = 2), and at C6 (n = 35). There were 4 patterns of final course: 52 branches passed through the medial side of the semispinalis capitis and trapezius muscles and terminated in a subcutaneous area; 50 branches penetrated the semispinalis capitis and trapezius muscles and terminated in a subcutaneous area; 12 branches terminated in the semispinalis capitis muscle; and 15 branches penetrated the semispinalis capitis and terminated at the nuchal ligament. In 19 of 52 patients tested, the semispinalis capitis muscle contracted after electrical stimulation. CONCLUSION: Medial branches of the cervical dorsal rami were discernible in cervical posterior approach laminoplasty and were frequently found adjacent to C4 and C5 spinous processes. The medial branches sometimes supplied motor fibers to the semispinalis capitis muscle. Knowledge of the course of these branches might be helpful for avoiding injury during laminoplasty. PMID- 23023594 TI - Risk of lumbar spine injury from cyclic compressive loading. AB - STUDY DESIGN: Survival analyses of a large cohort of published lumbar spine compression fatigue tests. OBJECTIVE: To produce the first large-scale evaluation of human lumbar spine tolerance to repetitive compressive loading and to evaluate and improve guidelines for human exposure to whole-body vibration and repeated mechanical shock environments. SUMMARY OF BACKGROUND DATA: Several studies have examined the effects of compressive cyclic loading on the lumbar spine. However, no previous effort has coalesced these studies and produced an injury risk analysis with an expanded sample size. Guidelines have been developed for exposure limits to repetitive loading (e.g., ISO 2631-5), but there has been no large-scale verification of the standard against experimental data. METHODS: Survival analyses were performed using the results of 77 male and 28 female cadaveric spinal segment fatigue tests from 6 previously published studies. Segments were fixed at each end and exposed to axial cyclic compression. The effects of the number of cycles, load amplitude, sex, and age were examined through the use of survival analyses. RESULTS: Number of cycles, load amplitude, sex, and age all are significant factors in the likelihood of bony failure in the spinal column. Using a modification of the risk prediction parameter from ISO 2631-5, an injury risk model was developed, which relates risk of vertebral failure to repeated compressive loading. The model predicts lifetime risks less than 7% for industrial machinery exposure from axial compression alone. There was a 38% risk for a high-speed planing craft operator, consistent with epidemiological evidence. CONCLUSION: A spinal fatigue model which predicts the risk of in vitro lumbar spinal failure within a narrow confidence interval has been developed. Age and sex were found to have significant effects on fatigue strength, with sex differences extending beyond those accounted for by endplate area disparities. PMID- 23023595 TI - Re: Zobel BB, Vadala G, Del Vescovo R, et al. T1 rho magnetic resonance imaging quantification of early lumbar intervertebral disc degeneration in healthy young adults. Spine (PhilaPa 1976) . 2012;37:1224-30. PMID- 23023597 TI - A microfluidic device and computational platform for high-throughput live imaging of gene expression. AB - To fully describe gene expression dynamics requires the ability to quantitatively capture expression in individual cells over time. Automated systems for acquiring and analyzing real-time images are needed to obtain unbiased data across many samples and conditions. We developed a microfluidics device, the RootArray, in which 64 Arabidopsis thaliana seedlings can be grown and their roots imaged by confocal microscopy over several days without manual intervention. To achieve high throughput, we decoupled acquisition from analysis. In the acquisition phase, we obtain images at low resolution and segment to identify regions of interest. Coordinates are communicated to the microscope to record the regions of interest at high resolution. In the analysis phase, we reconstruct three dimensional objects from stitched high-resolution images and extract quantitative measurements from a virtual medial section of the root. We tracked hundreds of roots to capture detailed expression patterns of 12 transgenic reporter lines under different conditions. PMID- 23023598 TI - An adaptor from translational to transcriptional control enables predictable assembly of complex regulation. AB - Bacterial regulators of transcriptional elongation are versatile units for building custom genetic switches, as they control the expression of both coding and noncoding RNAs, act on multigene operons and can be predictably tethered into higher-order regulatory functions (a property called composability). Yet the less versatile bacterial regulators of translational initiation are substantially easier to engineer. To bypass this tradeoff, we have developed an adaptor that converts regulators of translational initiation into regulators of transcriptional elongation in Escherichia coli. We applied this adaptor to the construction of several transcriptional attenuators and activators, including a small molecule-triggered attenuator and a group of five mutually orthogonal riboregulators that we assembled into NOR gates of two, three or four RNA inputs. Continued application of our adaptor should produce large collections of transcriptional regulators whose inherent composability can facilitate the predictable engineering of complex synthetic circuits. PMID- 23023596 TI - Global identification of peptidase specificity by multiplex substrate profiling. AB - We developed a simple and rapid multiplex substrate-profiling method to reveal the substrate specificity of any endo- or exopeptidase using liquid chromatography-tandem mass spectrometry sequencing. We generated a physicochemically diverse library of peptides by incorporating all combinations of neighbor and near-neighbor amino acid pairs into decapeptide sequences that are flanked by unique dipeptides at each terminus. Addition of a panel of evolutionarily diverse peptidases to a mixture of these tetradecapeptides generated information on prime and nonprime sites as well as on substrate specificity that matched or expanded upon known substrate motifs. This method biochemically confirmed the activity of the klassevirus 3C protein responsible for polypeptide processing and allowed granzyme B substrates to be ranked by enzymatic turnover efficiency using label-free quantitation of precursor-ion abundance. Additionally, the proteolytic secretions from schistosome parasitic flatworm larvae and a pancreatic cancer cell line were deconvoluted in a subtractive strategy using class-specific peptidase inhibitors. PMID- 23023600 TI - Click reactions in protein chemistry: from the preparation of semisynthetic enzymes to new click enzymes. AB - Click-chemistry is an approach based on cycloaddition reactions which has been successfully used as a chemical approach for complex organic molecules and which has recently starred in a boom in the world of protein chemistry. The advantage of the use of this technique in protein chemistry is based on a very high and efficient chemoselectivity, which usually requires simple or no purification and is extremely rate-accelerated in aqueous media. The perspective discusses some of the most recent advances in the application of this reaction in selective enzyme surface modification for the creation of new semisynthetic enzymes (fluorescence labeled enzymes, peptide-enzyme conjugates, glycosylated enzymes), and interestingly, the recent design and creation of "click" enzymes. PMID- 23023601 TI - Photoisomerization of 1,2-dihydro-1,2-azaborine: a matrix isolation study. PMID- 23023599 TI - Developmental control of replication timing defines a new breed of chromosomal domains with a novel mechanism of chromatin unfolding. AB - We recently identified a set of chromosome domains that are early replicating uniquely in pluripotent cells. Their switch from early to late replication occurs just prior to germ layer commitment, associated with a stable form of gene silencing that is difficult to reverse. Here, we discuss results demonstrating that these domains are among the least sensitive regions in the genome to global digestion by either MNase or restriction enzymes. This inaccessible chromatin state persists whether these regions are in their physically distended early replicating or compact late replicating configuration, despite dramatic changes in 3D chromatin folding and long-range chromatin interactions, and despite large changes in transcriptional activity. This contrasts with the strong correlation between early replication, accessibility, transcriptional activity and open chromatin configuration that is observed genome-wide. We put these results in context with findings from other studies indicating that many structural (DNA sequence) and functional (density and activity of replication origins) properties of developmentally regulated replication timing ("switching") domains resemble properties of constitutively late replicating domains. This suggests that switching domains are a type of late replicating domain within which both replication timing and transcription are subject to unique or additional layers of control not experienced by the bulk of the genome. We predict that understanding the unusual structure of these domains will reveal a novel principle of chromosome folding. PMID- 23023602 TI - Transforming growth factor-beta3 intron 5 polymorphism as a screening marker for non-syndromic cleft lip with or without cleft palate. AB - In this study, we evaluated the effect of transforming growth factor beta3 intron 5 position +104 A?G (TGF-beta3 IVS5+104AG) transition in patients with a non syndromic cleft lip with or without cleft palate (NSCL/P). A total of 68 patients and 114 controls were recruited for the study. A genotyping procedure was carried out using the PCR-RFLP method. For statistical analysis, the Chi-square test was used to compare data between the patient and control groups. The frequencies of the AA, AG and GG genotypes were 24, 29 and 47%, respectively, for the patients and 54, 36 and 10%, respectively, for the control group. The GG genotype and G allele were significantly different in the patient group compared with the control (p=0.0001). We conclude that SfaN1 polymorphism in TGF-beta3 may be a good screening marker for the prediction of NSCL/P in patients. However, more studies with extended sample numbers should be carried out to clarify the effect of the examined gene region on NSCL/P. PMID- 23023603 TI - Job insecurity, work-family imbalance, and hostile work environment: prevalence data from the 2010 National Health Interview Survey. AB - BACKGROUND: Little nationally representative information on job insecurity, work family imbalance, and hostile work environments experienced by workers in the US is available. METHODS: Prevalence rates from the 2010 National Health Interview Survey (NHIS) were calculated for three workplace psychosocial factors (job insecurity, work-family imbalance, bullying/harassment) using SUDAAN to account for the complex NHIS sample design. RESULTS: Data were available for 17,524 adults who worked in the 12 months that preceded the interview. Overall prevalence rates were 31.7% for job insecurity, 16.3% for work-family imbalance, and 7.8% for hostile work environment (being bullied or harassed). The highest prevalence rate of job insecurity was found for construction and extraction occupations. Workers in legal occupations had the highest prevalence rate of work family imbalance. Workers in protective service occupations had the highest prevalence rate of hostile work environment. CONCLUSIONS: We identified demographic characteristics along with industries and occupations with the highest prevalence rates for three adverse workplace psychosocial factors. These data can be used for benchmarking and identification of targets for investigation and intervention activities. PMID- 23023604 TI - Efficient [FeFe] hydrogenase mimic dyads covalently linking to iridium photosensitizer for photocatalytic hydrogen evolution. AB - Two [FeFe] hydrogenase mimics, [Fe(2)(MU-pdt)(CO)(5)L1] (L1 = PPh(2)SPhNH(2)) (Ph = phenyl) (2) and [Fe(2)(MU-pdt)(CO)(5)L2] (L2 = PPh(2)PhNH(2)) (3), and two molecular photocatalysts, [(CO)(5)(MU-pdt)Fe(2)PPh(2)SPhNHCO(bpy)(ppy)(2)Ir]PF(6) (bpy = bipyridine, ppy = 2-phenylpyridine) (2a) and [(CO)(5)(MU pdt)Fe(2)PPh(2)PhNHCO(bpy)(ppy)(2)Ir](PF(6)) (3a), have been designed and synthesized, anchoring Ir(ppy)(2)(mbpy)PF(6) (mbpy = 4-methyl-4'-carbonyl-2,2' bipyridine) (PS) to one of the iron centers of complexes 2 and 3 by forming amide bonds. Molecular dyads 2a, 3a and the intermolecular systems 2, 3 with PS have also been successfully constructed for photoinduced H(2) production using triethylamine (TEA) as a sacrificial electron donor by visible light (>400 nm) in CH(3)CN-H(2)O solution. The time-dependence of H(2) generation and spectroscopic studies suggest that the activity of H(2) evolution can be tuned by addition of a S atom to the phosphane ligand. The highest turnover numbers (TON) of hydrogen evolution obtained are 127, using 2a as a photocatalyst in a supramolecular system, and 138, based on catalyst 2 in a multi-component system. Density functional theory (DFT) computational studies demonstrate that the S atom in the second coordination sphere makes complex 2 accept an electron more easily than 3 and improves the activity in light-induced hydrogen production. PMID- 23023605 TI - Biologically synthesized or bioinspired process-derived iron oxides as catalysts for living cationic polymerization of a vinyl ether. AB - Fe(3)O(4) synthesized by magnetotactic bacteria and alpha-Fe(2)O(3) synthesized via a microbial-mineralization-inspired process functioned as catalysts for the controlled cationic polymerization of a vinyl ether. PMID- 23023606 TI - Swine influenza virus infections in man. AB - Because pigs are susceptible to both avian and human influenza viruses, genetic reassortment between avian, human, and/or swine influenza viruses in the pig host can lead to the generation of novel influenza A viruses (Ma et al. 2009). Since the first serological evidence of a swine influenza virus (SIV) infecting humans in 1958, sporadic cases have continued to occur. In recent years, case reports have been increasing, seemingly in concert with modern pig farming and the emergence of triple reassortant SIVs in swine. SIV infections in man generally are mild or subclinical, and often are not diagnosed; however, SIV infections can be quite serious in patients with underlying medical conditions. As of August 2010, 73 case reports of symptomatic human SIV infections have been documented in the medical literature or reported by health officials (excluding cases of the 2009 pandemic H1N1 influenza virus), of which 7 infections (10 %) resulted in death. While exposure to swine is often considered a risk factor for human SIV infections, 37 of 73 (51 %) reported cases had no known exposure to pigs; consequently, SIV may be crossing the species barrier via transmission routes yet to be acknowledged. In addition, human-to-human transmission was suspected in 10 of 34 (30 %) of the cases with epidemiological investigation. This chapter discusses the observations of illness and infections in humans, risk factors associated with infection, and methods for diagnosing human infections of SIV. PMID- 23023607 TI - [Medicine in a free market]. PMID- 23023608 TI - [Secondary prevention of venous thromboembolism]. PMID- 23023609 TI - [Diabetes and the kidneys]. PMID- 23023610 TI - [Suicidality in the elderly]. PMID- 23023611 TI - [What does ESBL mean?]. PMID- 23023612 TI - [Acute massive pumonary embolism]. PMID- 23023613 TI - [Syncopes: what's new?]. PMID- 23023614 TI - [Chronic kidney disease]. PMID- 23023615 TI - [Pulmonary hypertension]. PMID- 23023616 TI - [Spondyloarthritis including psoriatic arthritis]. PMID- 23023617 TI - [Irritable bowel disease: recent developments]. PMID- 23023619 TI - [Career development of young scientists in internal medicine. Position paper of the German Society of Internal Medicine]. PMID- 23023620 TI - [64-year-old patient with alterations of the fingernails]. PMID- 23023621 TI - [The colocutaneous fistula - a rare complication of percutaneous endoscopic gastrostomy]. AB - HISTORY AND ADMISSION FINDINGS: A 43-year-old woman with spastic tetraparesis, mental retardation and long-term tube feeding was admitted for a replacement of the PEG tube, 15 months after placement and regular use of her first feeding tube. New problems had occurred with local infection and a suspected leakage. The gastrostoma showed a local erythema and increased secretion of putrid fluids, furthermore a tendency to diarrhea had developed. Otherwise the abdomen was inconspicuous. INVESTIGATIONS: All routinely achieved blood tests were normal. Gastroscopy revealed a mucosal scar with a small fistula instead of the expected tip of the PEG tube. A CT scan demonstrated displacement of the tip into the transverse colon. TREATMENT AND COURSE: The displaced PEG tube was removed by colonoscopy. After laparoscopic occlusion of the colocutaneous fistula with a surgical stapler and clearing of further adhesions a new PEG was inserted endoscopically during the same operation with laparoscopic guidance through the pneumoperitoneum. CONCLUSION: The development of a colocutaneous fistula as a result of an unperceived perforation is a rare complication of a PEG placement. Despite of the notable mechanism that the tip of the tube erodes the gastric wall and penetrates into the adjacent colon, the clinic is often oligosymptomatic and can easily been missed. PMID- 23023622 TI - [Lipid therapy in daily routine]. AB - Patients with increased cardiovascular risk profile are frequently seen in general practice. Comprehensive management of modifiable risk factors, in particular dyslipidemia, is mandatory. Many studies in clinical practice have shown a gap between the recommendations in clinical guidelines and the actual situation. Current data on the management situation of patients with high cardiovascular risk is provided by the prospective registry LIMA. Primary care physicians in 2,387 offices throughout Germany documented 13,924 patients with coronary artery disease (CAD), diabetes mellitus or peripheral arterial disease (PAD). Treatment with simvastatin 40 mg was an inclusion criterion. Physicians documented drug utilization, laboratory values (lipids, blood glucose), blood pressure and clinical events over one year and received feedback about the target value attainment of their patients after data entry. Mean age of the patients was 65.7 years, and 61.6 % were men. CAD was reported in 70.6 %, diabetes mellitus in 58.2 % and PAD in 14.9 %. Most patients (68 %) received simvastatin as monotherapy also after the inclusion visit; 20.6 % of patients received in addition the cholesterol absorption inhibitor (ezetimibe) in the first 6 months, and 23.3 % in the second 6 months. Patients achieved the LDL-cholesterol target value in 31.8 % at entry and 50.0 % after one year. The blood pressure target < 140 /90 mmHg was reached by 65.8 % after one year. Of patients with diabetes mellitus 40.0 % reached an HbA1c value below 6.5 %. Clinical events (death, hospitalization, (cardio-) vascular events, and dialysis) were reported by 11.7 % of patients between entry and Month 6, and by 12.0 % between Month 7 and 12. In daily practice comprehensive management of risk factors in patients at high cardiovascular risk remains a challenge. For normalization of increased LDL cholesterol values addition of ezetimibe to existing statin therapy improves the chances of patients for target level attainment. PMID- 23023623 TI - Broadband adiabatic inversion pulses for cross polarization in wideline solid state NMR spectroscopy. AB - Efficient acquisition of ultra-wideline solid-state NMR powder patterns is a continuing challenge. In particular, when the breadth of the powder pattern is much larger than the cross-polarization (CP) excitation bandwidth, transfer efficiencies suffer and experimental times are greatly increased. Presented herein is a CP pulse sequence with an excitation bandwidth that is up to ten times greater than that available from a conventional spin-locked CP pulse sequence. The pulse sequence, broadband adiabatic inversion CP (BRAIN-CP), makes use of the broad, uniformly large frequency profiles of chirped inversion pulses, to provide these same characteristics to the polarization transfer process. A detailed theoretical analysis is given, providing insight into the polarization transfer process involved in BRAIN-CP. Experiments on spin-1/2 nuclei including (119)Sn, (199)Hg and (195)Pt nuclei are presented, and the large bandwidth improvements possible with BRAIN-CP are demonstrated. Furthermore, it is shown that BRAIN-CP can be combined with broadband frequency-swept versions of the Carr Purcell-Meiboom-Gill experiment (for instance with WURST-CPMG, or WCPMG for brevity); the combined BRAIN-CP/WCPMG experiment then provides multiplicative signal enhancements of both CP and multiple-echo acquisition over a broad frequency region. PMID- 23023625 TI - [The roles of intestinal and renal sodium dependent phosphate transporters in phosphate homeostasis]. AB - Inorganic phosphate (Pi) is an essential nutrient for several biological functions, including intracellular signal transduction, the production and function of cell membranes, and energy exchange. To achieve these functions, a transport system is required to transfer Pi across hydrophobic cell membranes. Pi (re) absorption in the small intestine and renal proximal tubules is important for Pi homeostasis. Three types of NaPi transporters (types I - III ) have been identified : solute carrier series SLC17A1 (NPT1/NaPi- I /OATv1) , SLC34 (NaPi- II a, NaPi- II b, NaPi- II c) , and SLC20 (PiT1, PiT2) , respectively. In this review, we discuss the role of NaPi transporters in Pi homeostasis. PMID- 23023624 TI - Rapid 3D-imaging of phosphocreatine recovery kinetics in the human lower leg muscles with compressed sensing. AB - The rate of phosphocreatine (PCr) resynthesis following physical exercise is an accepted index of mitochondrial oxidative metabolism and has been studied extensively with unlocalized (31)P-MRS methods and small surface coils. Imaging experiments using volume coils that measure several muscles simultaneously can provide new insights into the variability of muscle function in healthy and diseased states. However, they are limited by long acquisition times relative to the dynamics of PCr recovery. This work focuses on the implementation of a compressed sensing technique to accelerate imaging of PCr resynthesis following physical exercise, using a modified three-dimensional turbo-spin-echo sequence and principal component analysis as sparsifying transform. The compressed sensing technique was initially validated using 2-fold retrospective undersampling of fully sampled data from four volunteers acquired on a 7T MRI system (voxel size: 1.6 mL, temporal resolution: 24 s), which led to an accurate estimation of the mono-exponential PCr resynthesis rate constant (mean error <6.4%). Acquisitions with prospective 2-fold acceleration (temporal resolution: 12 s) demonstrated that three-dimensional mapping of PCr resynthesis is possible at a temporal resolution that is sufficiently high for characterizing the recovery curve of several muscles in a single measurement. PMID- 23023626 TI - [Hormonal regulation of phosphate balance]. AB - Phosphate homeostasis is maintained by intestine, bone, and kidney, which is regulated by many hormones. In addition to classical hormones such as parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25 (OH) (2)D] , fibroblast growth factor 23 (FGF23) and Klotho have been discovered as novel factors for phosphate metabolism. FGF23 is a circulating hormone that is synthesized by osteocytes and osteoblasts in bone. The physiological actions of FGF23 are to promote phosphaturia and decrease production of 1,25 (OH) (2)D. Klotho was initially identified as an anti-aging protein, but subsequent research revealed multiple functions of Klotho in phosphate metabolism. Klotho directly binds to FGF receptor 1 (FGFR1) and contributes to FGFR1-Klotho complex-mediated signal transduction with higher affinity than FGFR1 or Klotho alone. In addition, the extracellular domain of Klotho is clipped by enzymes and secreted into blood, which exerts phosphaturic effects independently of FGF23. In the regulation of phosphate metabolism, this FGF23-Klotho axis constitutes feedback loops with classical factors such as PTH and 1,25 (OH) (2)D. However, the precise feedback system in the phosphate metabolism remains to be determined and further research is required to provide a greater understanding of the phosphate metabolism system. PMID- 23023627 TI - [Lack of phosphorus intake and nutrition]. AB - Since one gram of protein in food provides approximately 15 mg of phosphorus, phosphorus deficiency frequently observed in patients with protein-energy malnutrition (PEM). Chronic phosphorus deficiency in humans causes proximal myopathy. Acute hypophosphatemia may precipitate rhabdomyolysis. Plasma low phosphorus concentration suppresses erythrocyte synthesis and stores of 2,3 diphosphoglycerate (2,3-DPG) , which plays an important role in the affinity of hemoglobin for oxygen. Symptoms of nervous system dysfunction, such as weakness, apathy, a bedridden state, and intention tremors, are also observed in severe hypophosphatemia. Refeeding syndrome is caused by rapid refeeding in PEM, characterized by hypophosphatemia and has metabolic and clinical complications. This is potentially fatal, yet is preventable. Awareness and identification of at risk patients is crucial to improving management. PMID- 23023628 TI - [A potential link between phosphate and aging]. AB - Mice lacking Klotho or fibroblast growth factor 23 (FGF23) exhibit a premature aging syndrome associated with abnormal mineral metabolism characterized by hyperphosphatemia, hypercalcemia, and hypervitaminosis D. Several genetic and dietary interventions that reduce blood phosphate, calcium, and/or vitamin D levels rescue the premature aging syndrome concomitantly. Notably, the rescue is always associated with decrease in blood phosphate levels, but not necessarily with decrease in calcium or vitamin D, suggesting that hyperphosphatemia is primarily responsible for the premature aging. Hyperphsophatemia, decreased Klotho expression, and aging-like symptoms are often manifested in patients with chronic kidney disease (CKD). Thus, CKD may be viewed as a premature aging syndrome caused by hyperphosphatemia and Klotho deficiency. Further clinical studies are required to verify the link between phosphate and aging and to apply this novel concept to anti-aging medicine. PMID- 23023629 TI - [Dietary reference intakes of phosphorus]. AB - Phosphorus (P) exists at the all organs and plays important physiological roles in the body. A wide range of food contains P, which is absorbed at a higher level (60-70%) and its insufficiency and deficiency are rarely found. P is used as food additives in many processed food, where risk of overconsumption could be an issue. P has less evidence in terms of nutrition. P has the adequate intake and the tolerable upper intake level, for risk reduction of health disorders associated with excess intake, at the Dietary Reference Intakes for Japanese (2010 edition). PMID- 23023630 TI - [Hyperphosphatemia and cardiovascular diseases : impact of vascular calcification and endothelial dysfunction]. AB - Hyperphosphatemia has clinically been associated with total mortality and cardiovascular mortality in patients with chronic renal failure (CRF). Recently, higher serum phosphate levels within the normal range have been shown to be associated with substantially increased risk of cardiovascular events even in patients without CRF. Therefore, it is clear that the phosphate axis may in fact play a role in atherogenesis. Accumulating mechanistic studies regarding local effects of phosphate on the vessel wall have recently provided insight into various pathways that culminate in vascular smooth muscle cell (SMC) calcification. SMC phenotypic change into osteochondrogenic differentiation and SMC apoptosis are essential roles in hyperphosphatemia-induced vascular calcification. In addition, Hyperphosphatemia induces endothelial dysfunction via various mechanisms, including a decline in nitric oxide release due to oxidative stress. The sodium-dependent phosphate cotransporter PiT-1 is required for these effects. This review shows the current knowledge about phosphate-induced changes in the vascular wall, leading to atherosis and sclerosis. PMID- 23023631 TI - [Phosphate and the risk of mortality]. AB - Phosphate is a macronutrient essential for the survival of living organisms, and phosphate depletion impairs cellular functions in various organ systems. However, epidemiological studies have shown that high phosphate level, even within normal range, is a risk factor for cardiovascular disease and all-cause mortality. This association is partly explained by Monckeberg's medial calcification, a characteristic atherosclerosis present in patients with advanced chronic kidney disease. Direct phosphate toxicity to vascular endothelial cells may also contribute to the outcomes. Additionally, recent studies suggest that increased levels of fibroblast growth factor 23 (FGF23) in response to phosphate loading can play a role in cardiovascular disease. However, it should be noted that there is no substantiated evidence to date that decreased phosphate loading lowers the risk of these outcomes. We still need to ascertain who should be treated, what should be monitored, and what kind of strategy we need to implement to alleviate the phosphate burden. PMID- 23023632 TI - [Significance of FGF23 measurement]. AB - Excess and deficient actions of FGF23 cause hypophosphatemic rickets/osteomalacia and hyperphosphatemic tumoral calcinosis, respectively. There are two kinds of assays for FGF23. Full-length assay detects only full-length FGF23 with biological activity. In contrast, C-terminal assay measures both full-length FGF23 and processed C-terminal fragment of FGF23. FGF23 measurement is useful for the diagnosis and follow-up of patients with FGF23-related hypophosphatemic diseases. In addition, full-length assay can be used for the differential diagnosis of hypophosphatemic diseases. Furthermore, many epidemiological studies indicated the association between FGF23 levels and several adverse events including higher mortality, cardiovascular diseases and progression of CKD especially in patients with CKD. Therefore, it is possible that FGF23 can be a new marker in the risk assessment of patients with CKD. PMID- 23023633 TI - [Klotho and phosphate metabolism]. AB - alpha-Klotho was first identified as an aging gene and was later shown to be a regulator of mineral metabolism. Then, alpha-Klotho was reported to function as an obligate coreceptor for fibroblast growth factor 23 (FGF23). Phosphrus regulation of FGF23/Klotho axis is slow. On the other hand, alpha-Klotho is a key player that integrates "a multi-step regulatory system of calcium homeostasis" that rapidly adjusts the extracellular calcium concentration. In addition to its membrane-bound function as a co-receptor for fibroblast growth factor 23, soluble Klotho exerts effects as a circulating substance in plasma and urine. The Klotho protein not only serves as a coreceptor for FGF23, but also functions as a humoral factor. PMID- 23023634 TI - [Phosphate sensing and intestine]. AB - Small intestine plays an important role in the sensing of various nutrients. There is information that would imply the existence of a dietary phosphate sensing mechanism within the intestine. Recent studies suggest that intestinal factors may involve in the alteration of renal phosphate transport. The elucidation of the phosphate sensing mechanism is expected to provide molecular basis for the prevention of the hyperphosphatemia in chronic kidney disease patients. PMID- 23023635 TI - [Phosphate sensing and parathyroid gland]. AB - In the latter 1990s, phosphate, as well as calcium, has been shown to have a direct action on parathyroid function. Since then although many researchers have tried to detect the phosphate sensor in parathyroid gland, none has found it yet. In 2000s, the importance of FGF23 was revealed in patients with autosomal dominant hypophosphatemic rickets and then investigating the role of FGF23 in mineral metabolism has spread. FGF23 target organs comprise those that express coreceptor Klotho, such as kidney and parathyroid glands. While associations of calcium sensing receptor or vitamin D receptor with parathyroid function have been mainly investigated for parathyroid dysfunction, many efforts recently have made to study the effects of FGF23 on parathyroid glands. PMID- 23023636 TI - [Phosphate sensing and osteocyte]. AB - Osteocyte expresses molecules responsible for hereditary hypophosphatemic rickets such as FGF23, DMP1 and PHEX. FGF23 exerts its effects in kidney by decreasing both renal phosphate (Pi) reabsorption and vitamin D activation. It is suggested that DMP1 and PHEX negatively regulate the expression of FGF23, although the underlying mechanisms remain to be elucidated. Circulating level of FGF23 appears to be regulated by systemic factors as well, including vitamin D and PTH. Although it is unknown how mammals sense the Pi availability, it has been recently reported that extracellular Pi itself triggers signal transduction in some cell types such as osteoblasts and chondrocytes, suggesting that osteocytes also respond to the alteration in extracellular Pi level. PMID- 23023637 TI - [Newly development of phosphate binders in hyperphosphatemic patients with kidney dysfunction]. AB - Hyperphosphatemia is the most common complication among patients with chronic kidney disease. Large scale observational studies have identified hyperphosphatemia as an independent risk factor for cardiovascular disease and mortality in hemodialysis patients. The combination therapy of dietary phosphate restriction and phosphate removal with dialysis treatment is still not enough to achieve the serum phosphate within the target. Thererfore, phosphate binders is necessary for many dialyzed patients with hyperphosphatemia. In this article, we will review the detail and development of phosphate binders and recommendation for clinical practice in hyperphosphatemia. PMID- 23023638 TI - [Cinacalcet hydrochloride and phosphate metabolism]. AB - The inhibitory effect of cinacalcet hydrochloride (cinacalcet) on blood phosphorus (P) levels is widely-accepted. However, this effect is only observed in patients on dialysis. Reduction in parathyroid hormone (PTH) induced by cinacalcet increases blood P levels with decreased urinary P excretion in pre dialysis patients with chronic kidney disease (CKD). Similar results observed in normal and CKD rats provide a pharmacological validation of the trade-off hypothesis. The lowering effect of cinacalcet on blood P levels in dialysis patients is attributed to decreased P mobilization from the bone caused by the decreased PTH secretion. It is unlikely that this P-lowering effect of cinacalcet would bring any benefits on the enhanced parathyroid gland function and bone metabolism. On the other hand, the P-lowering effect of this drug is considered to contribute to its inhibitory effects on the development and progression of vascular calcification in dialysis patients. Further studies should examine this beneficial cinacalcet effect would lead to the reduction of the mortality risk. PMID- 23023639 TI - [Phosphate metabolism and nutritional therapy in predialysis patients]. AB - Phosphate metabolism is disordered in patients with chronic kidney disease (CKD). Although there is insufficient evidence in predialysis patients, hyperphosphatemia is closely connected with poor prognosis and cardiovascular disease. The standard approaches to management of elevated serum phosphate are dietary restriction and drug treatment using oral phosphate binders. Treatment of hyperphosphatemia is important in patients with CKD. On the other hand, it is possible that dietary restriction causes protein energy wasting (PEW). It is necessary to pay attention to both hyperphosphatemia and PEW in CKD patients. PMID- 23023640 TI - [Information about phosphorus additives and nutritional counseling]. AB - Hyperphosphatemia is a common disorder in patients with chronic kidney disease (CKD) , and may result in hyperparathyroidism and renal osteodystrophy. Hyperphosphatemia also may contribute to deterioration vascular calcification and increase mortality. Hence, correction and prevention of hyperphosphatemia is a main component of the management of CKD. This goal is usually approached both by administering phosphorus binders and by restricting dietary phosphorus (P) intake. Dietary intake of phosphorus (P) is derived largely from foods with high protein content or food additives and is an important determinant of P balance in patient with CKD. Food additives (PO4) can dramatically increase the amount of P consumed in the daily diet, especially because P is more readily absorbed in its inorganic form. In addition, information about the P content and type in prepared foods is often unavailable or misleading. Therefore, during dietary counseling of patients with CKD, we recommended that they consider both the absolute dietary P content and the P-to-protein ratio of foods and meals including food additives. PMID- 23023641 TI - Inflammasomes in wound healing and fibrosis. AB - Inflammasome signalling and downstream cytokine responses mediated by the inflammasome have been found to play an important role, not only in wound healing but also in fibrosis. The inflammasome regulates the secretion of IL-1beta and IL 18 cytokines, and both are critical for the repair of damaged tissue and play a role in fibrosis. However, what dictates the fine balance between normal wound healing versus fibrosis is yet to be fully elucidated. Further investigations into the role of the inflammasomes in these pathologies will be important for the discovery of novel therapeutics that can abrogate fibrosis or promote wound healing in chronic disease. PMID- 23023642 TI - An initial investigation into the anti-inflammatory activity and antioxidant capacity of alpha-cyclodextrin-complexed Manuka honey. AB - The bioactive properties of Manuka honey are now well recognised, but the nature of honey (a sticky, viscous fluid) can make it hard to use as a health remedy. A new technology using encapsulation of Manuka honey with alpha-cyclodextrin molecules has been developed, creating a free-flowing powder that can easily be added to foods and beverages, or tableted / made into capsules for use in health. In this study, we investigated for antioxidant and anti-inflammatory activity. Antioxidant capacity of raw Manuka honeys and matched complexes was measured using the CUPRAC method. Results showed that the antioxidant activity of honey decreased when complexed, this being directly related to dilution of the final product with alpha-cyclodextrin. Anti-inflammatory activity was assessed by measuring inhibition of neutrophil TNF-alpha secretion. Contradictory results were produced, with both stimulation and inhibition of TNF-alpha being observed. Data from this study indicate that the formation of cyclodextrin-based complexes of Manuka honey may potentiate the anti-inflammatory activity of honey, but this may differ depending on methylglyoxal content and the presence of other factors. PMID- 23023643 TI - An 18.2%-efficient black-silicon solar cell achieved through control of carrier recombination in nanostructures. AB - Silicon nanowire and nanopore arrays promise to reduce manufacturing costs and increase the power conversion efficiency of photovoltaic devices. So far, however, photovoltaic cells based on nanostructured silicon exhibit lower power conversion efficiencies than conventional cells due to the enhanced photocarrier recombination associated with the nanostructures. Here, we identify and separately measure surface recombination and Auger recombination in wafer-based nanostructured silicon solar cells. By identifying the regimes of junction doping concentration in which each mechanism dominates, we were able to design and fabricate an independently confirmed 18.2%-efficient nanostructured 'black silicon' cell that does not need the antireflection coating layer(s) normally required to reach a comparable performance level. Our results suggest design rules for efficient high-surface-area solar cells with nano- and microstructured semiconductor absorbers. PMID- 23023644 TI - Photocurrent of a single photosynthetic protein. AB - Photosynthesis is used by plants, algae and bacteria to convert solar energy into stable chemical energy. The initial stages of this process--where light is absorbed and energy and electrons are transferred--are mediated by reaction centres composed of chlorophyll and carotenoid complexes. It has been previously shown that single small molecules can be used as functional components in electric and optoelectronic circuits, but it has proved difficult to control and probe individual molecules for photovoltaic and photoelectrochemical applications. Here, we show that the photocurrent generated by a single photosynthetic protein-photosystem I-can be measured using a scanning near-field optical microscope set-up. One side of the protein is anchored to a gold surface that acts as an electrode, and the other is contacted by a gold-covered glass tip. The tip functions as both counter electrode and light source. A photocurrent of ~10 pA is recorded from the covalently bound single-protein junctions, which is in agreement with the internal electron transfer times of photosystem I. PMID- 23023645 TI - Low-resistance spin injection into silicon using graphene tunnel barriers. AB - Spin manipulation in a semiconductor offers a new paradigm for device operation beyond Moore's law. Ferromagnetic metals are ideal contacts for spin injection and detection, but the intervening tunnel barrier required to accommodate the large difference in conductivity introduces defects, trapped charge and material interdiffusion, which severely compromise performance. Here, we show that single layer graphene successfully circumvents the classic issue of conductivity mismatch between a metal and a semiconductor for electrical spin injection and detection, providing a highly uniform, chemically inert and thermally robust tunnel barrier. We demonstrate electrical generation and detection of spin accumulation in silicon above room temperature, and show that the contact resistance-area products are two to three orders of magnitude lower than those achieved with oxide tunnel barriers on silicon substrates with identical doping levels. Our results identify a new route to low resistance-area product spin polarized contacts, a key requirement for semiconductor spintronic devices that rely on two-terminal magnetoresistance, including spin-based transistors, logic and memory. PMID- 23023647 TI - A chiral dicationic [8]circulenoid: photochemical origin and facile thermal conversion into a helicene congener. PMID- 23023646 TI - Determination of the elastic moduli of thin samples and adherent cells using conical atomic force microscope tips. AB - The atomic force microscope can detect the mechanical fingerprints of normal and diseased cells at the single-cell level under physiological conditions. However, atomic force microscopy studies of cell mechanics are limited by the 'bottom effect' artefact that arises from the stiff substrates used to culture cells. Because cells adhered to substrates are very thin, this artefact makes cells appear stiffer than they really are. Here, we show an analytical correction that accounts for this artefact when conical tips are used for atomic force microscope measurements of thin samples. Our bottom effect cone correction (BECC) corrects the Sneddon's model, which is widely used to measure Young's modulus, E. Comparing the performance of BECC and Sneddon's model on thin polyacrylamide gels, we find that although Sneddon's model overestimates E, BECC yields E values that are thickness-independent and similar to those obtained on thick regions of the gel. The application of BECC to measurements on live adherent fibroblasts demonstrates a significant improvement on the estimation of their local mechanical properties. PMID- 23023648 TI - Influence of surgical experience in the learning curve of a new approach in hip replacement: anterior mini-invasive vs. standard lateral. AB - There is conflicting evidence regarding the potential benefit of minimally invasive surgery for total hip arthroplasty (THA), especially during the 'learning curve' of individual surgeons. Sixty patients who underwent THA between January and December 2010 were evaluated. The aim was to assess the anterior mini invasive (MI) approach performed in 30 patients during the learning curve of a single experienced hip surgeon compared with the results of 30 patients operated upon through a standard lateral approach by the same surgeon. Operation and hospitalisation times, blood loss, number of transfusions, peri-operative complications and femoral/acetabular component placement were monitored. Harris Hip Score (HHS) and Hip Disability and Osteoarthritis Outcome Score (HOOS) were analysed before and 12 months after surgery. Pain Visual Analogue Scale (VAS) was also recorded 1 week and 1 month after surgery. Hospitalisation, blood loss, number of transfusions and VAS score 1 week postoperatively were significantly lower and operative time was significantly longer in the anterior MI approach. Similar functional outcomes 1 year after surgery, component positioning and complication rates were observed in both groups. The results suggest that anterior MI approach is a safe procedure during the learning curve of an experienced hip surgeon. PMID- 23023650 TI - Ligand effect on the catalytic activity of ruthenium nanoparticles in ionic liquids. AB - Suspensions of small sized (1-2.5 nm) ruthenium nanoparticles (RuNPs) have been obtained by decomposition, under H(2), of (eta(4)-1,5-cyclooctadiene)(eta(6) 1,3,5-cyclooctatriene)ruthenium(0), [Ru(COD)(COT)], in the ionic liquid 1-butyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide, [C(1)C(4)Im][NTf(2)], and in the presence of different compounds acting as ligands: C(8)H(17)NH(2), PPhH(2), PPh(2)H and H(2)O. Previous and new liquid NMR experiments showed that the ligands are coordinated or in the proximity to the surface of the RuNPs. Herein is reported how the ligand affects the catalytic performance (activity and selectivity) compared to a ligand-free system of RuNPs, when RuNPs in [C(1)C(4)Im][NTf(2)] are used as catalysts for the hydrogenation of various unsaturated compounds (1,3-cyclohexadiene, limonene and styrene). It has been observed that sigma-donor ligands increase the activity of the nanoparticles, contrarily to pi-acceptor ones. PMID- 23023649 TI - Heterogeneous epigenetic regulation of TIMP3 in prostate cancer. AB - Tissue inhibitor of metalloproteinase-3 (TIMP3) is a tumor suppressor gene frequently downregulated in prostate cancer. The mechanisms involved in TIMP3 transcriptional repression are not fully understood, but evidence suggests that promoter hypermethylation may not be the predominant epigenetic alteration in prostate cancer. To clarify this issue, we examined the contribution of both CpG site promoter methylation and histone modifications on TIMP3 downregulation. Using publicly available data sets, we confirmed that TIMP3 mRNA expression is decreased in prostate tumors relative to normal glands. Immunohistochemical analysis also showed decreased TIMP3 levels in high-grade primary tumors, but promoter hypermethylation was only detected in 6 of 28 (21%) high-grade specimens. Similarly, in prostate cancer cells, TIMP3 hypermethylation was only observed in DU145 cells. Treatment of DU145 cells with 5-aza-2'-deoxycytidine (5 Aza-CdR) restored TIMP3 expression, and this was significantly amplified by co treating the cells with the HDAC inhibitor trichostatin A (TSA). Alternatively, in cells that did not exhibit aberrant TIMP3 methylation (LNCaP and PC3), TIMP3 expression could be upregulated by the combination of histone methylation inhibitor 3-Deazaneplanocin A (DZNep) and TSA. This reversal of transcriptional repression was associated with decreased H3K27me3 and increased H3K9ac histone marks at the TIMP3 promoter, as demonstrated by chromatin immunoprecipitation. Collectively, these results indicate that histone modifications can contribute to TIMP3 repression in the absence of promoter hypermethylation, and suggest that the combination of histone modifying agents could restore TIMP3 expression in prostate tumors harboring aberrant histone modifications at the TIMP3 promoter. PMID- 23023651 TI - Controllable processes for generating large single crystals of poly(3 hexylthiophene). AB - Sowing the seeds: A simple strategy based on self-seeding allows large single crystals of long regioregular poly(3-hexylthiophene) chains to be grown from solution. When appropriately crystallized, materials differing in their degrees of regioregularity and molecular weights formed monoclinic form II crystals with interdigitated hexyl side groups (see picture). PMID- 23023652 TI - Spectral effects of UV on psoriasis. AB - Ultraviolet B (UVB) is a highly effective, relatively safe, affordable and widely used therapeutic option for moderate psoriasis. Several types of UVB lamp are available to treat psoriasis, both broadband and narrowband, allowing a choice of spectral emission. However despite years of clinical use, the mechanism of action of UVB in clearing psoriasis remained incompletely understood. Moreover, there has been little insight into how the relative effectiveness of different UVB wavelengths linked to the mechanism of action, although it is known that the action spectrum for clearance of psoriasis differs from the action spectrum of erythema. This paper examines the existing literature from which our current treatments have evolved, and offers new insight into the use of keratinocyte apoptosis as a biomarker which may help to optimise UV treatment in the future. When combined with a systems biology approach, this potential biomarker may provide insight into which wavelengths of UV are the most effective in clearing psoriasis, allowing a more rational and potentially an individually tailored approach to optimising phototherapy for psoriasis. PMID- 23023653 TI - Polymorphisms of the IL-18 promoter and bronchial asthma. AB - To study the association of polymorphisms of the IL-18 promoter (-607C/A and 137G/C) with bronchial asthma, 120 subjects with bronchial asthma were selected as the experimental group (49 cases with bronchial asthma and allergic rhinitis as experimental group 1 and 71 cases with bronchial asthma without allergic rhinitis as experimental group 2) and 120 healthy individuals were selected as the control group. A polymerase chain reaction sequence-specific primer (PCR-SSP) was used to identify the genotypic polymorphisms between the experimental and control groups. The results revealed that the frequencies of the CC, CA and AA genotypes at -607C/A in experimental group 1 were 18.37, 40.82 and 40.82%, respectively; these frequencies were 32.39, 54.92 and 12.68%, respectively, in experimental group 2. There was a statistically significant difference in the genotype distribution between experimental groups 1 and 2 (chi2=12.81; P<0.05). The allele frequencies of genotypes C and A were 38.78 and 61.22%, respectively, in experimental group 1 and 59.86 and 40.14%, respectively, in experimental group 2. The allele frequencies at -607C/A were significantly different between experimental groups 1 and 2 (chi2=10.32; P<0.05). Frequencies of genotypes GG, GC and CC at -137C/A in experimental group 1 were 48.98, 46.94 and 4.08%, respectively, and 80.28, 14.08 and 4.08% in experimental group 2 with significant difference (chi2=15.73, P<0.05). Allele frequencies of G and C in experimental group 1 were 72.45 and 27.55%, and 87.32 and 12.68% in experimental group 2 with statistically significant difference (chi2=8.42, P<0.05). In conclusion, polymorphisms of the IL-18 gene promoter at -607C/A and -137G/C were associated with allergic rhinitis in bronchial asthma, indicating that polymorphisms of the IL-18 gene promoter at -607C/A and -137G/C differentially affect the pathogenesis of asthma and allergic rhinitis. PMID- 23023654 TI - Joint modeling of medical cost and survival in complex sample surveys. AB - Medical cost data are typically highly skewed to the right with a large proportion of zero costs. It is also common for these data to be censored because of incomplete follow-up and death. In the case of censoring due to death, it is important to consider the potential dependence between cost and survival. This association can occur because patients who incur a greater amount of medical cost tend to be frailer and hence are more likely to die. To handle this informative censoring issue, joint modeling of cost and survival with shared random effects has been proposed. In this paper, we extend this joint modeling approach to handle a final feature of many medical cost data sets, i.e., Specifically, the fact that data were obtained via a complex survey design. Specifically, we extend the joint model by incorporating the sample weights when estimating the parameters and using the Taylor series linearization approach when calculating the standard errors. We use a simulation study to compare the joint modeling approach with and without these adjustments. The simulation study shows that parameter estimates can be seriously biased when information about the complex survey design is ignored. It also shows that standard errors based on the Taylor series linearization approach provide satisfactory confidence interval coverage. The proposed joint model is applied to monthly hospital costs obtained from the 2004 National Long Term Care Survey. PMID- 23023655 TI - Facile preparation of oriented nanoporous silica films from solvent-free liquid crystalline mixtures. AB - Mixtures of an amphiphilic perylene bisimide derivative and tetramethoxysilane in the absence of solvents have been found to exhibit stable columnar liquid crystalline phases which transform into macroscopically oriented nanoporous silica films as a result of simple mechanical shearing. PMID- 23023656 TI - Ionic self-assembly of electroactive biorecognizable units: electrical contacting of redox glycoenzymes made easy. AB - This work explores the synergistic combination of ionic self-assembly and recognition-directed assembly for the modification of electrode surfaces with redox glycoenzymes on the basis of electroactive glycopolyelectrolyte-surfactant complexes. PMID- 23023657 TI - Continuity of care in a cohort of HIV-infected former jail detainees. AB - This article describes a retrospective cohort study of HIV-infected jail detainees cared for at the Cook County Jail Clinic (CCJC), Illinois, between January and June 2007. Continuity care engagement (CCE) was defined as being seen at least once within 6 months after release at the designated continuity clinics. Being highly active antiretroviral therapy (HAART) naive during or prior to detention, no prior HIV care, and detectable viral load at initial CCJC visit were associated with continuity care nonengagement (CCNE), while being HAART naive during detention was the only independent predictor for CCNE. Identification of at-risk detainees and interventions based on these findings should be considered to improve CCE in this population. PMID- 23023658 TI - Treatment of older and elderly inmates within prisons. AB - An increase in the number of older and elderly inmates in the prison system has sparked controversy regarding current procedures and programs as well as possible solutions. Preservation of human and constitutional rights while maintaining appropriate punishment under the same Constitution and increased fiscal expenditures has called into question whether the correctional system is the correct setting for older and elderly inmates. The changing population in prisons has led to an increase in medical care expenses, causing some states to implement early release programs or to build separate facilities for the geriatric population. Statistics from the U.S. Department of Justice and the Federal Bureau of Prisons in conjunction with empirical studies create a foundation that allows for a comprehensive survey of the problems, current protocols, and prospective practices. PMID- 23023660 TI - Quality really matters: the need to improve specimen quality in biomedical research. AB - Contemporary pathological and molecular analysis depends on high quality human biospecimens. Poor biospecimen quality may compromise such analyses and the resultant inaccurate data published in scientific papers may be contribute to low reproducibility in the biomedical literature and adversely impact clinical translation. Editors of research journals play a key role in improving sample quality in biomedical by implementing established guidelines. The Editors of Histopathology and The Journal of Pathology will now require that researchers follow the BRISQ guidelines (Biospecimen Reporting for Improved Study Quality) in their papers and hope that this will be a model adopted by other journals in this domain. PMID- 23023661 TI - Self-organized origami structures via ion-induced plastic strain. AB - Ion processing of the reactive surface of a free-standing polycrystalline metal film induces a flow of atoms into grain boundaries, resulting in plastic deformation. A thorough experimental and theoretical analysis of this process is presented, along with the demonstration of novel engineering concepts for precisely controlled 3D assembly at micro- and nanoscopic scales. PMID- 23023662 TI - From sequence to function: the impact of the genome sequence on Drosophila biology. PMID- 23023659 TI - Psychotropic drug-drug interactions involving P-glycoprotein. AB - Multidrug resistance P-glycoprotein (P-gp; also known as MDR1 and ABCB1) is expressed in the luminal membrane of the small intestine and blood-brain barrier, and the apical membranes of excretory cells such as hepatocytes and kidney proximal tubule epithelia. P-gp regulates the absorption and elimination of a wide range of compounds, such as digoxin, paclitaxel, HIV protease inhibitors and psychotropic drugs. Its substrate specificity is as broad as that of cytochrome P450 (CYP) 3A4, which encompasses up to 50 % of the currently marketed drugs. There has been considerable interest in variations in the ABCB1 gene as predictors of the pharmacokinetics and/or treatment outcomes of several drug classes, including antidepressants and antipsychotics. Moreover, P-gp-mediated transport activity is saturable, and is subject to modulation by inhibition and induction, which can affect the pharmacokinetics, efficacy or safety of P-gp substrates. In addition, many of the P-gp substrates overlap with CYP3A4 substrates, and several psychotropic drugs that are P-gp substrates are also CYP3A4 substrates. Therefore, psychotropic drugs that are P-gp substrates may cause a drug interaction when P-gp inhibitors and inducers are coadministered, or when psychotropic drugs or other medicines that are P-gp substrates are added to a prescription. Hence, it is clinically important to accumulate data about drug interactions through studies on P-gp, in addition to CYP3A4, to assist in the selection of appropriate psychotropic medications and in avoiding inappropriate combinations of therapeutic agents. There is currently insufficient information available on the psychotropic drug interactions related to P-gp, and therefore we summarize the recent clinical data in this review. PMID- 23023664 TI - Whole-genome expression profile analysis of Drosophila melanogaster immune responses. AB - Drosophila melanogaster is an established model organism for the study of host pathogen interactions. The sequencing of its genome allowed the prediction of all the genes encoded in it and, consequently, enabled a more comprehensive view of its immune responses. Whole-genome transcription analyses of Drosophila response to bacteria, fungi, parasitoids and viruses allow a comparison of the response between different classes of microorganisms and between pathogens of the same class. Overall, there is great diversity in the immune responses but there are a few pathways that are frequently activated. These studies provide a better understanding of how the host resists the infection and responds to the associated damage. Moreover, the data give insights into how microorganisms can manipulate their host and successfully establish an infection. PMID- 23023663 TI - Interpreting the regulatory genome: the genomics of transcription factor function in Drosophila melanogaster. AB - Researchers have now had access to the fully sequenced Drosophila melanogaster genome for over a decade, and the sequenced genomes of 11 additional Drosophila species have been available for almost 5 years, with more species' genomes becoming available every year [Adams MD, Celniker SE, Holt RA, et al. The genome sequence of Drosophila melanogaster. Science 2000;287:2185-95; Clark AG, Eisen MB, Smith DR, et al. Evolution of genes and genomes on the Drosophila phylogeny. Nature 2007;450:203-18]. Although the best studied of the D. melanogaster transcription factors (TFs) were cloned before sequencing of the genome, the availability of sequence data promised to transform our understanding of TFs and gene regulatory networks. Sequenced genomes have allowed researchers to generate tools for high-throughput characterization of gene expression levels, genome-wide TF localization and analyses of evolutionary constraints on DNA elements across multiple species. With an estimated 700 DNA-binding proteins in the Drosophila genome, it will be many years before each potential sequence-specific TF is studied in detail, yet the last decade of functional genomics research has already impacted our view of gene regulatory networks and TF DNA recognition. PMID- 23023666 TI - In search of preclinical robustness. AB - Systematic engagement of statisticians in preclinical research could help address the weaknesses that are undermining the likelihood of subsequent success in drug discovery and development. PMID- 23023665 TI - Genomics of sex determination in Drosophila. AB - Drosophilists have identified many, or perhaps most, of the key regulatory genes determining sex using classical genetics, however, regulatory genes must ultimately result in the deployment of the genome in a quantitative manner, replete with complex interactions with other regulatory pathways. In the last decade, genomics has provided a rich picture of the transcriptional profile of the sexes that underlies sexual dimorphism. The current challenge is linking transcriptional profiles with the regulatory genes. This will be a complex synthesis, but the prospects for progress are outstanding. PMID- 23023667 TI - Economists propose a US$30 billion boost to biomedical R&D. PMID- 23023668 TI - Moving from an asthma pipe dream to a pipeline. PMID- 23023670 TI - Trial watch: dual-acting combination meets heart failure end point. PMID- 23023671 TI - Market watch: upcoming market catalysts in Q4 2012. PMID- 23023672 TI - Patent watch. PMID- 23023673 TI - Michael Snyder. Interview by Asher Mullard. PMID- 23023674 TI - Neurodegenerative disease: EPHA4 inhibition rescues neurodegeneration in ALS. PMID- 23023675 TI - Vaccines: Self-amplifying RNA in lipid nanoparticles: a next-generation vaccine? PMID- 23023678 TI - Fatigue in patients with coronary artery disease: association with thyroid axis hormones and cortisol. AB - OBJECTIVE: In people with coronary artery disease, the association between endocrine measures and fatigue is not well understood. We evaluated possible associations of fatigue and exercise capacity with function of adrenal axis and thyroid axis. METHODS: Sixty-five men and 18 women (mean age 55 years) attending a rehabilitation program were examined using the Multidimensional Fatigue Inventory, Dutch Exertion Fatigue Scale, and the Hospital Anxiety and Depression Scale. Exercise capacity was measured using a bicycle ergometer procedure. Serum concentrations of free triiodothyronine (T3), free thyroxine (T4), morning cortisol, afternoon cortisol, and change in cortisol concentrations (DeltaCortisol) were measured. RESULTS: In univariate regression analysis, lower free T4 concentrations were associated with general and exertion fatigue, lower free T3 concentrations were associated with general and physical fatigue, and lower DeltaCortisol was associated with mental fatigue. After adjusting for age, sex, body mass index, hypertension, previous myocardial infarction, heart failure, diabetes, New York Heart Association functional class, depressive symptoms, and anxiety symptoms, lower free T3 concentrations remained associated with physical fatigue (beta = -.224, p = .03); lower free T4 concentrations, with exertion fatigue (beta = -.219, p = .03); and lower morning cortisol and lower DeltaCortisol concentrations, with mental fatigue (beta = -.193 [p = .03] and beta = -.180 [p =.04], respectively). Exercise capacity was not associated with endocrine factors. CONCLUSIONS: In coronary artery disease patients, increased thyroid hormone concentrations are associated with decreased physical fatigue and decreased exertion fatigue, and increased cortisol concentrations with decreased mental fatigue. Exercise capacity is not associated with endocrine factors. PMID- 23023676 TI - Targeting IL-17 and TH17 cells in chronic inflammation. AB - The key role of interleukin-17 (IL-17) and T helper 17 (T(H)17) cells in tissue inflammation, autoimmunity and host defence led to the experimental targeting of these molecules in mouse models of diseases as well as in clinical settings. Moreover, the demonstration that IL-17 and T(H)17 cells contribute to local and systemic aspects of disease pathogenesis, as well as the finding that the IL-17 T(H)17 cell pathway is regulated by IL-23, prompted the identification of inhibitors. These inhibitors include biotechnology products that target IL-23 as well as the leading member of the IL-17 family, IL-17A, and one of its receptors, IL-17 receptor A. Several clinical trials of these inhibitors are underway, and positive results have been obtained in psoriasis, rheumatoid arthritis and ankylosing spondylitis. This Review focuses on the current knowledge of the IL-17 T(H)17 cell pathway to better understand the positive as well as potential negative consequences of targeting them. PMID- 23023677 TI - Bacterial proteolytic complexes as therapeutic targets. AB - Proteases have been successfully targeted for the treatment of several diseases, including hypertension, type 2 diabetes, multiple myeloma, HIV and hepatitis C virus infections. Given the demonstrated pharmacological tractability of this enzyme family and the pressing need for novel drugs to combat antibiotic resistance, proteases have also attracted interest as antibacterial targets- particularly the widely conserved intracellular bacterial degradative proteases, which are often indispensable for normal bacterial growth or virulence. This Review summarizes the roles of the key prokaryotic degradative proteases, with a focus on the initial efforts and associated challenges in developing specific therapeutic modulators of these enzymes as novel classes of antibacterial drugs. PMID- 23023679 TI - Obstructive sleep apnea, posttraumatic stress disorder, and health in immigrants. AB - OBJECTIVE: To determine whether obstructive sleep apnea mediates the relationship between posttraumatic stress disorder (PTSD) and psychosomatic and somatic disorders and its implications for self-rated health (SRH) among Iraqi immigrants in the United States. METHODS: A random sample of immigrants who had left Iraq before the 1991 Gulf War (n = 145) or after (n = 205) and are residing in metropolitan Detroit responded to a structured interview covering questions on sociodemographics, premigration trauma, SRH, physician-diagnosed and -treated obstructive sleep apnea, somatic disorders, and psychosomatic disorders. Structural equation modeling was used to evaluate the relationship between premigration trauma scores and health, as well as to explore mediating pathways between PTSD, obstructive sleep apnea, and health. RESULTS: The prevalence of obstructive sleep apnea among post-Gulf Warimmigrants (30.2%) was significantly higher than among pre-Gulf War immigrants (0.7%; p < .001). Premigration trauma scores were positively associated with depression and PTSD. Structural equation modeling supported a model in which obstructive sleep apnea mediated the relationship between PTSD and psychosomatic and somatic disorders. Premigration trauma also related directly to SRH. CONCLUSIONS: Part of the PTSD-associated adverse health effects observed in Iraqi immigrants is mediated by obstructive sleep apnea. Because sleep apnea in the current study is based on medical history and current treatment, there is a need for future confirmatory polysomnographic studies. PMID- 23023680 TI - Defective nitric oxide-cyclic guanosine monophosphate signaling in patients with bipolar disorder: a potential role for platelet dysfunction. AB - OBJECTIVE: Bipolar disorder (BD) is associated with elevated cardiovascular mortality rates. We investigated the modulation of l-arginine-nitric oxide (NO) signaling in platelets from patients with BD at different phases. METHODS: Platelets obtained from 28 patients with BD and 10 healthy volunteers were analyzed for l-arginine transport, NO synthase (NOS) activity, cyclic guanosine monophosphate content, and biomarkers of oxidative stress. Expressions of NOS isoforms, soluble guanylyl cyclase, and arginase were also measured in platelets. Amino acid and C-reactive protein levels in plasma were assessed. RESULTS: Plasma concentrations of l-arginine (mean [M] +/- standard error of the mean [SEM] = 97 +/- 10 versus 121 +/- 10 uM) and its transport into platelets (median [interquartile range] = 26.0 [28.6] versus 26.5 [43.9] pmol/10(9) cells per minute) did not differ between patients with BD and controls (p > .05). Patients with BD showed reduced NOS activity (M +/- SEM = 0.037 +/- 0.003 versus 0.135 +/- 0.022 pmol/10(8) cells, p < .001), but not endothelial NOS, inducible NOS, and arginase expression, compared with controls (p > .05). Cyclic guanosine monophosphate content was reduced (M +/- SEM = 0.022 +/- 0.003 versus 0.086 +/- 0.020 pmol/10(8) cells, p < .05) despite the absence of changes in soluble guanylyl cyclase expression (median [interquartile range] = 21.6 [15.5] versus 9.5 [9.4] arbitrary units, p > .05) in patients with BD. Superoxide dismutase activity, but not catalase activity, was increased in patients with BD in the manic phase (M +/- SEM = 2094 +/- 335 versus 172 +/- 17 U/mg protein, p < .001). C-reactive protein was elevated only in manic episodes (M +/- SEM = 0.8 +/- 0.2 versus 0.1 +/- 0.02 mg/L, p < .001). CONCLUSIONS: Impaired NO generation from platelets, inflammation, and oxidative stress may play pivotal roles in the multifaceted process of cardiovascular events in BD. PMID- 23023682 TI - Design and synthesis of an 18F-labeled version of phenylethyl orvinol ([18F]FE PEO) for PET-imaging of opioid receptors. AB - The semisynthetic oripavine derivative phenethyl orvinol (PEO), a full agonist at opioid receptors (OR), is an attractive structural motif for developing 18F labeled PET tracers with a high degree of sensitivity for competition between endogenous and exogenous OR-ligands. The target cold reference compound 6-O-(2 fluoroethyl)-6-O-desmethylphenylethyl orvinol (FE-PEO) was obtained via two separate reaction routes. A three-step synthesis was developed for the preparation of a tosyloxyethyl precursor (TE-TDPEO), the key precursor for a direct, nucleophilic radiofluorination to yield [18F]FE-PEO. The developed radiosynthesis provides the target compound in relevantly high yield and purity, and is adaptable to routine production. PMID- 23023683 TI - An expeditious iodine-catalyzed synthesis of 3-pyrrole-substituted 2 azetidinones. AB - 2-Azetidinones and pyrroles are two highly important classes of molecules in organic and medicinal chemistry. A green and practical method for the synthesis of 3-pyrrole-substituted 2-azetidinones using catalytic amounts of molecular iodine under microwave irradiation has been developed. Following this method, a series of 3-pyrrole- substituted 2-azetidinones have been synthesized with a variety of substituents at N-1 and at C-4. The procedure is equally effective for mono- as well as polyaromatic groups at the N-1 position of the 2-azetidinone ring. The C-4 substituent has no influence either on the yield or the rate of the reaction. Optically pure 3-pyrrole-substituted 2-azetidinones have also been synthesized following this methodology. No deprotection/rearrangement has been identified in this process, even with highly acid sensitive group-containing substrates. A plausible mechanistic pathway has also been suggested based on the evidence obtained from 1H-NMR spectroscopy. The extreme rapidity with excellent reaction yields is believed to be the result of a synergistic effect of the Lewis acid catalyst (molecular iodine) and microwave irradiation. PMID- 23023681 TI - Interactive associations of depression and sleep apnea with adverse clinical outcomes after acute myocardial infarction. AB - OBJECTIVE: Depression and sleep apnea (SA) are common among patients with a recent acute myocardial infarction (AMI), and both are associated with increased risk for adverse outcomes. We tested the hypothesis that there is an interaction between them in relation to post-AMI prognosis. METHODS: Participants were patients with a recent AMI, 337 of them were depressed and 379 were nondepressed, who participated in a substudy of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial. SA was identified from Holter electrocardiogram by an algorithm that detects cyclic variation of heart rate. RESULTS: During a median follow-up of 25 months, 83 (11.6%) patients either died or experienced a recurrent AMI and 43 (6.0%) patients died. Among 94 patients with both depression and SA, these end points occurred in 25 (26.6%) and 20 (21.3%) at 3.9- and 6.9 times higher prevalence than predicted probabilities by ENRICHD clinical risk scores (p <.001 for both). In the patients with depression alone, SA alone, or neither, the prevalence was similar to the predicted probability. Depression and SA showed significant interactions in prediction of these end points (p = .02 and p = .03). SA independently predicted these end points in patients with depression (p = .001 and p <.001) but not in those without depression (p = .84 and p = .73). Similarly, depression independently predicted these end points in patients with SA (p <.001 for both) but not in those without SA (p = .12 and p = .61). CONCLUSIONS: Depression and SA are interactively associated with adverse clinical outcomes after AMI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00313573. PMID- 23023684 TI - Protective effect of total flavonoids of seabuckthorn (Hippophae rhamnoides) in simulated high-altitude polycythemia in rats. AB - Seabuckthorn (Hippophae rhamnoides L.) has been used to treat high altitude diseases. The effects of five-week treatment with total flavonoids of seabuckthorn (35, 70, 140 mg/kg, ig) on cobalt chloride (5.5 mg/kg, ip)- and hypobaric chamber (simulating 5,000 m)-induced high-altitude polycythemia in rats were measured. Total flavonoids decreased red blood cell number, hemoglobin, hematocrit, mean corpuscular hemoglobin levels, span of red blood cell electrophoretic mobility, aggregation index of red blood cell, plasma viscosity, whole blood viscosity, and increased deformation index of red blood cell, erythropoietin level in serum. Total flavonoids increased pH, pO2, Sp(O2), pCO2 levels in arterial blood, and increased Na+, HCO3-, Cl-, but decreased K+ concentrations. Total flavonoids increased mean arterial pressure, left ventricular systolic pressure, end-diastolic pressure, maximal rate of rise and decrease, decreased heart rate and protected right ventricle morphology. Changes in hemodynamic, hematologic parameters, and erythropoietin content suggest that administration of total flavonoids from seabuckthorn may be useful in the prevention of high altitude polycythaemia in rats. PMID- 23023685 TI - E- and Z-isomers of new phytoecdysteroid conjugates from French Polynesian Microsorum membranifolium (Polypodiaceae) fronds. AB - Phytochemical investigation of the fronds of Microsorum membranifolium resulted in the isolation of a new phytoecdysteroid, E-2-deoxy-20-hydroxyecdysone 3-[4-(1 beta-D-glucopyranosyl)]-caffeate (1), together with two known phytoecdysteroids, E-2-deoxy-20-hydroxyecdysone 3-[4-(1-beta-D-glucopyranosyl)]-ferulate (2), E-2 deoxyecdysone 3-[4-(1-beta-D-glucopyranosyl)]-ferulate (3). Their respective Z isomers 4-6 were also observed and identified for the first time. The new structures were elucidated on the basis of extensive spectroscopic data analysis (1D, 2D-NMR and HR-MS techniques). PMID- 23023686 TI - Microwave assisted synthesis of 2,2'-arylene-substituted bis(4H-3,1-benzoxazin-4 one) derivatives using the complex cyanuric chloride/N,N-dimethylformamide. AB - A new and efficient method has been designed to prepare 2,2'-arylene-substituted bis(4H-3,1-benzoxazin-4-one) derivatives by using the mixture of cyanuric chloride and N,N-dimethylformamide in a microwave-assisted reaction. The method used and presented here has good rate enhancement and excellent yields. PMID- 23023687 TI - Synthesis and antitumor evaluation of 6-aryl-substituted benzo[j]phenanthridine- and benzo[g]pyrimido[4,5-c]isoquinolinequinones. AB - A variety of novel 6-arylsubstituted benzo[j]phenanthridine- and benzo[g] pyrimido[4,5-c]isoquinolinequinones were synthesized from 1,4-naphthoquinone, aryl-aldehydes and enaminones via a two-step synthetic approach. The cytotoxic activity of the aminoquinone derivatives was evaluated in vitro against one normal cell line (MRC-5 lung fibroblasts) and three human cancer cell lines (AGS human gastric adenocarcinoma; SK-MES-1 human lung cancer cells, and J82 human bladder carcinoma) in 72-h drug exposure assays using the MTT colorimetric method. Structure-activity relationships within the series of angular quinones reveal that the insertion of pyrrol-2-yl and furan-2-yl groups at the 6-position is more significant for the increase of the potency and selectivity index of the pharmacophores. PMID- 23023688 TI - Recent advances in cyclonucleosides: C-cyclonucleosides and spore photoproducts in damaged DNA. AB - Cyclonucleosides which are fixed in a specific conformation around the glycosyl bond by a carbon and heteroatom chain constitute a unique category of nucleoside derivatives. Because they are structural analogs, cyclonucleosides and oligodeoxynucleotides containing them would be useful tools for investigating the biological functions and conformations of DNA, RNA as well as their steric interactions with proteins. C-Cyclonucleosides bridged by a carbon chain between the base and sugar moieties are the most attractive from the synthetic points of view as well as for use as biological tools. In this review, recent progress of the synthesis of C-cyclonucleosides is surveyed. Among the C-cyclonucleosides, 5',8-C-cyclodeoxyadenosine is one of the well-known derivatives of which the first practical synthesis was reported over 30 years ago. Recently, 5',8-C cyclodeoxyadenosine has attracted considerable interest as a biomarker, since its formation in oxidatively-damaged DNA is considered to be related to various diseases and aging. Another important analogue of cyclonucleosides is a unique thymidine phosphate dimer, a so-called spore photoproduct, which has been found in photo-damaged DNA. Recent advances in the synthesis, mechanism-studies, and stereochemical preference of repairing enzymes related to 5',8-C cyclodeoxyadenosine and spore photoproducts are also reviewed. PMID- 23023689 TI - Degradation kinetics of anthocyanins from European cranberrybush (Viburnum opulus L.) fruit extracts. Effects of temperature, pH and storage solvent. AB - European cranberrybush (Viburnum opulus L.) fruits are well known for their biological properties, of which some are due to the presence of anthocyanins in the berries. Current literature provides little information concerning these fruits. The stability of anthocyanins from Viburnum opulus fruits, in aqueous and ethanolic extracts, stored under darkness for 7 days at different temperatures (2 degrees C, 37 degrees C and 75 degrees C) and pH values (pH = 3 and 7), was studied here. The lowest stability was showed by the anthocyanins from the water extract stored at 75 degrees C and pH = 7, with half-life and constant rate values of 1.98 h and 0.3488 h-1, respectively. The results showed a good correlation between the total anthocyanin content (determined using the pH differential method) and the time of storage, with determination coefficients varying from R2 = 0.9298 to R2 = 0.9971. Results indicate that the storage degradation of anthocyanins followed first-order reaction kinetics under all investigated conditions. PMID- 23023691 TI - Acetaminophen glucuronide and plasma glucose report identical estimates of gluconeogenesis and glycogenolysis for healthy and prediabetic subjects using the deuterated water method. AB - Plasma glucose (2) H-enrichment in positions 5 ((2) H5) and 2 ((2) H2) from deuterated water ((2) H2 O) provides a measure of the gluconeogenic contribution to endogenous glucose production. Urinary glucuronide analysis can circumvent blood sampling but it is not known if glucuronide and glucose enrichments are equal. Thirteen subjects with impaired fasting glucose/impaired glucose tolerance and 11 subjects with normal fasting glucose and normal glucose tolerance ingested (2) H2 O to ~0.5% body water and acetaminophen. Glucose and glucuronide (2) H5 and (2) H2 were measured by (2) H NMR spectroscopy of monoacetone glucose. For normal fasting glucose/normal glucose tolerance, (2) H5 was 0.23 +/- 0.02% and 0.25 +/- 0.02% for glucose and glucuronide, respectively, whereas (2) H2 was 0.47 +/- 0.01% and 0.49 +/- 0.02%, respectively. For impaired fasting glucose/impaired glucose tolerance, (2) H5 was 0.22 +/- 0.01% and 0.26 +/- 0.02% for glucose and glucuronide, respectively, whereas (2) H2 was 0.46 +/- 0.01% and 0.49 +/- 0.02%, respectively. The gluconeogenic contribution to endogenous glucose production measured from glucose and glucuronide were identical for both normal fasting glucose/normal glucose tolerance (48 +/- 4 vs. 51 +/- 3%) and impaired fasting glucose/impaired glucose tolerance (48 +/- 2 vs. 53 +/- 3%). PMID- 23023692 TI - Interaction of methocarbamol and yeast sucrase induces enzyme inhibition. AB - BACKGROUND: Methocarbamol is a skeletal muscle relaxant and is widely used to relieve pain in muscles. Many drugs may have interactions with each other when used at the same time. Yeast sucrase is taken as a drug by patients with congenital sucrase-isomaltase deficiency (CSID). METHODS: In this study, the interaction between methocarbamol and yeast sucrase was investigated. RESULTS: Our results showed that methocarbamol can inhibit sucrase activity and reduce the maximum reaction velocity (Vmax) of the enzyme by a non-competitive pattern. Measurement of IC50 and Ki of the drug revealed that methocarbamol did not bind the enzyme with high affinity. Fluorescence measurement showed that the drug binds to free enzyme and enzyme-substrate complexes that were accompanied by structural changes on the enzyme. Guaifenesin, which has a similar structure to methocarbamol, does not affect the activity of sucrase. CONCLUSIONS: Methocarbamol inhibits sucrase activity and its carbamate group plays a main role in the binding of drug to sucrase. PMID- 23023693 TI - Acetylcholinesterase (AChE) inhibitory activity, antioxidant properties and phenolic composition of two Aframomum species. AB - BACKGROUND: Aframomum species are widely used as a food supplement and remedy in folklore medicine for the management of several diseases. This study was designed to investigate the acetylcholinesterase inhibitory activity and antioxidant properties of phenolic-rich extracts from two Aframomum species: Aframomum danielli (Hook F.) K. Schum (Zingiberaceae) and Aframomum melegueta (Roscoe) K. Schum (Zingiberaceae) seeds. METHODS: Acetylcholinesterase inhibitory activity and antioxidant properties [inhibition of quinolinic acid (QA)-induced lipid peroxidation in rat brain, reducing properties, 2,2-azinobis (3-ethylbenzo thiazoline-6-sulfonate) (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging abilities] using in vitro models were evaluated. Phenolic composition of the seed extracts using reversed phase high performance chromatography (RP HPLC) and gas chromatography coupled with flame ionization detector (GC-FID) were also assessed. RESULTS: Both extracts exhibited acetylcholinesterase inhibitory activity in a dose-dependent manner (125-1000 MUg/mL); however, A. melegueta extract (IC50=373.33 MUg/mL) had a significantly higher (p<0.05) acetylcholinesterase inhibitory activity than A. danielli extract (IC50=417.10 MUg/mL). Furthermore, both extracts significantly decreased QA-elevated brain malondialdehyde (MDA) contents, reduced Fe3+ to Fe2+ and scavenged DPPH and ABTS radicals. Phenolic characterization of the seeds by RP-HPLC at 280 nm showed abundance of quercetin and kaempferol in A. melegueta and chlorogenic acid in A. danielli, whereas GC-FID revealed that p-hydroxybenzoic acid was abundant in both seeds. CONCLUSIONS: Inhibitory effect of these extracts on acetylcholinesterase activity and their antioxidant property could be attributed to the combined effect of phenolic and non-phenolic constituents of the seeds. These effects could be part of the possible biochemical mechanism by which these seeds elicit their protection against oxidative stress in brain; however, A. melegueta showed the more promising potential. PMID- 23023694 TI - The influence of oxonate-induced hyperuricemia and allopurinol on behavioral reactions of random-bred mice. AB - BACKGROUND: Purine metabolism specificity, namely the high level of uric acid in the blood, is considered to be significant in the appearance of intellectually developed primates, as well as in later periods of human development, for personal activity and achievements and even for the formation of genius. Nowadays hyperuricemia is mostly associated with the pathogenesis of hypertension and metabolic syndrome. Its influence on the central nervous system is predominantly set aside. METHODS: The behavioral reactions of random-bred mice with uricase inhibition due to potassium oxonate or xanthine oxidase suppression with allopurinol for three weeks were investigated. RESULTS: Potassium oxonate reduced signs of anxiety in the elevated plus maze. A positive correlation appeared between latency to enter a dark arm and uricemia, so anxiety reduction can be associated with uric acid metabolism changes. Allopurinol reduced anxiety that was not related to the metabolic changes of uric acid, so the involvement of changes in uric acid precursor concentrations cannot be excluded. Potassium oxonate but not allopurinol reduced immobility in a tail suspension test. There was a tendency to increase the duration of swimming to exhaustion against the potassium oxonate background. At the same time, potassium oxonate reduced research activity in the combined open field test and increased the vegetative maintenance of behavioral responses. Allopurinol did not change the results of this test. CONCLUSIONS: A reduction in anxiety and depression level and a tendency to augment physical performance against the potassium oxonate background partly conform to the beneficial evolutionary role of hyperuricemia. PMID- 23023695 TI - Adrenocorticotropic hormone stability in preanalytical phase depends on temperature and proteolytic enzyme inhibitor. PMID- 23023696 TI - Metal release from hip prostheses: cobalt and chromium toxicity and the role of the clinical laboratory. AB - Individuals with advanced hip disease suffer from pain, impaired hip function, and decreased quality of life. Roughly one million metal-on-metal (MoM) hip prostheses have been implanted worldwide in order to ameliorate these issues. While most MoM hip replacements are successful, some patients suffer from serious adverse effects secondary to the release of metal debris due to implant wear and corrosion. MoM hip prostheses are comprised predominantly of cobalt and chromium, and the serum concentration of these metal ions has been shown to correlate with both implant wear and the accumulation of metal debris in the periprosthetic tissue. Consequently, measurement of cobalt and chromium concentrations may be useful in the assessment of implant function and the potential for adverse effects in the follow-up of patients with MoM hip prostheses. The purpose of this Mini Review is to describe the adverse biological consequences of metal release from hip prostheses, provide an overview of the clinical utility of cobalt and chromium measurement and the current recommendations for testing, and alert laboratorians and physicians to the many challenges associated with measuring these metal ions. PMID- 23023697 TI - A new explained-variance based genetic risk score for predictive modeling of disease risk. AB - The goal of association mapping is to identify genetic variants that predict disease, and as the field of human genetics matures, the number of successful association studies is increasing. Many such studies have shown that for many diseases, risk is explained by a reasonably large number of variants that each explains a very small amount of disease risk. This is prompting the use of genetic risk scores in building predictive models, where information across several variants is combined for predictive modeling. In the current study, we compare the performance of four previously proposed genetic risk score methods and present a new method for constructing genetic risk score that incorporates explained variance information. The methods compared include: a simple count Genetic Risk Score, an odds ratio weighted Genetic Risk Score, a direct logistic regression Genetic Risk Score, a polygenic Genetic Risk Score, and the new explained variance weighted Genetic Risk Score. We compare the methods using a wide range of simulations in two steps, with a range of the number of deleterious single nucleotide polymorphisms (SNPs) explaining disease risk, genetic modes, baseline penetrances, sample sizes, relative risks (RR) and minor allele frequencies (MAF). Several measures of model performance were compared including overall power, C-statistic and Akaike's Information Criterion. Our results show the relative performance of methods differs significantly, with the new explained variance weighted GRS (EV-GRS) generally performing favorably to the other methods. PMID- 23023698 TI - Hessian calculation for phylogenetic likelihood based on the pruning algorithm and its applications. AB - We analytically derive the first and second derivatives of the likelihood in maximum likelihood methods for phylogeny. These results enable the Newton-Raphson method to be used for maximising likelihood, which is important because there is a need for faster methods for optimisation of parameters in maximum likelihood methods. Furthermore, the calculation of the Hessian matrix also opens up possibilities for standard likelihood theory to be applied, for inference in phylogeny and for model selection problems. Another application of the Hessian matrix is local influence analysis, which can be used for detecting a number of biologically interesting phenomena. The pruning algorithm has been used to speed up computation of likelihoods for a tree. We explain how it can be used to speed up the computation for the first and second derivatives of the likelihood with respect to branch lengths and other parameters. The results in this paper apply not only to bifurcating trees, but also to general multifurcating trees. We demonstrate the use of our Hessian calculation for the three applications listed above, and compare with existing methods for those applications. PMID- 23023699 TI - Comparison of targeted maximum likelihood and shrinkage estimators of parameters in gene networks. AB - Gene regulatory networks, in which edges between nodes describe interactions between transcription factors (TFs) and their target genes, model regulatory interactions that determine the cell-type and condition-specific expression of genes. Regression methods can be used to identify TF-target gene interactions from gene expression and DNA sequence data. The response variable, i.e. observed gene expression, is modeled as a function of many predictor variables simultaneously. In practice, it is generally not possible to select a single model that clearly achieves the best fit to the observed experimental data and the selected models typically contain overlapping sets of predictor variables. Moreover, parameters that represent the marginal effect of the individual predictors are not always present. In this paper, we use the statistical framework of estimation of variable importance to define variable importance as a parameter of interest and study two different estimators of this parameter in the context of gene regulatory networks. On yeast data we show that the resulting parameter has a biologically appealing interpretation. We apply the proposed methodology on mammalian gene expression data to gain insight into the temporal activity of TFs that underly gene expression changes in F11 cells in response to Forskolin stimulation. PMID- 23023700 TI - DNA pooling and statistical tests for the detection of single nucleotide polymorphisms. AB - The development of next generation genome sequencers gives the opportunity of learning more about the genetic make-up of human and other populations. One important question involves the location of sites at which variation occurs within a population. Our focus will be on the detection of rare variants. Such variants will often not be present in smaller samples and are hard to distinguish from sequencing errors in larger samples. This is particularly true for pooled samples which are often used as part of a cost saving strategy. The focus of this article is on experiments that involve DNA pooling. We derive experimental designs that optimize the power of statistical tests for detecting single nucleotide polymorphisms (SNPs, sites at which there is variation within a population). We also present a new simple test that calls a SNP, if the maximum number of reads of a prospective variant across lanes exceeds a certain threshold. The value of this threshold is defined according to the number of available lanes, the parameters of the genome sequencer and a specified probability of accepting that there is variation at a site when no variation is present. On the basis of this test, we derive pool sizes which are optimal for the detection of rare variants. This test is compared with a likelihood ratio test, which takes into account the number of reads of a prospective variant from all the lanes. It is shown that the threshold based rule achieves a comparable power to this likelihood ratio test and may well be a useful tool in determining near optimal pool sizes for the detection of rare alleles in practical applications. PMID- 23023701 TI - Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. AB - Intrahepatic cholangiocarcinoma (ICC) is the second most common primary malignancy in the liver. ICC has been classified as a malignant tumor arising from cholangiocytes; however, the co-occurrence of ICC and viral hepatitis suggests that ICC originates in hepatocytes. In order to determine the cellular origin of ICC, we used a mouse model of ICC in which hepatocytes and cholangiocytes were labeled with heritable, cell type-specific reporters. Our studies reveal that ICC is generated by biliary lineage cells derived from hepatocytes, rather than cholangiocytes. Additionally, we found that Notch activation is critical for hepatocyte conversion into biliary lineage cells during the onset of ICC and its subsequent malignancy and progression. These findings will help to elucidate the pathogenic mechanism of ICC and to develop therapeutic strategies for this refractory disease. PMID- 23023702 TI - Spleens of myelofibrosis patients contain malignant hematopoietic stem cells. AB - Cancer stem cell behavior is thought to be largely determined by intrinsic properties and by regulatory signals provided by the microenvironment. Myelofibrosis (MF) is characterized by hematopoiesis occurring not only in the marrow but also in extramedullary sites such as the spleen. In order to study the effects of these different microenvironments on primitive malignant hematopoietic cells, we phenotypically and functionally characterized splenic and peripheral blood (PB) MF CD34+ cells from patients with MF. MF spleens contained greater numbers of malignant primitive HPCs than PB. Transplantation of PB MF CD34+ cells into immunodeficient (NOD/SCID/IL2Rgamma(null)) mice resulted in a limited degree of donor cell chimerism and a differentiation program skewed toward myeloid lineages. By contrast, transplanted splenic MF CD34+ cells achieved a higher level of chimerism and generated both myeloid and lymphoid cells that contained molecular or cytogenetic abnormalities indicating their malignant nature. Only splenic MF CD34+ cells were able to sustain hematopoiesis for prolonged periods (9 months) and were able to engraft secondary recipients. These data document the existence of MF stem cells (MF-SCs) that reside in the spleens of MF patients and demonstrate that these MF-SCs retain a differentiation program identical to that of normal hematopoietic stem cells. PMID- 23023703 TI - Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. AB - Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c Myc, SHPTP1, TGF-beta, PPARgamma, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-kappaB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer. PMID- 23023704 TI - Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. AB - Diabetic cardiomyopathy (DbCM), which consists of cardiac hypertrophy and failure in the absence of traditional risk factors, is a major contributor to increased heart failure risk in type 2 diabetes patients. In rodent models of DbCM, cardiac hypertrophy and dysfunction have been shown to depend upon saturated fatty acid (SFA) oversupply and de novo sphingolipid synthesis. However, it is not known whether these effects are mediated by bulk SFAs and sphingolipids or by individual lipid species. In this report, we demonstrate that a diet high in SFA induced cardiac hypertrophy, left ventricular systolic and diastolic dysfunction, and autophagy in mice. Furthermore, treatment with the SFA myristate, but not palmitate, induced hypertrophy and autophagy in adult primary cardiomyocytes. De novo sphingolipid synthesis was required for induction of all pathological features observed both in vitro and in vivo, and autophagy was required for induction of hypertrophy in vitro. Finally, we implicated a specific ceramide N acyl chain length in this process and demonstrated a requirement for (dihydro)ceramide synthase 5 in cardiomyocyte autophagy and myristate-mediated hypertrophy. Thus, this report reveals a requirement for a specific sphingolipid metabolic route and dietary SFAs in the molecular pathogenesis of lipotoxic cardiomyopathy and hypertrophy. PMID- 23023705 TI - Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. AB - A genetic variant in PNPLA3 (PNPLA3(I148M)), a triacylglycerol (TAG) hydrolase, is a major risk factor for nonalcoholic fatty liver disease (NAFLD); however, the mechanism underlying this association is not known. To develop an animal model of PNPLA3-induced fatty liver disease, we generated transgenic mice that overexpress similar amounts of wild-type PNPLA3 (PNPLA3(WT)) or mutant PNPLA3 (PNPLA3(I148M)) either in liver or adipose tissue. Overexpression of the transgenes in adipose tissue did not affect liver fat content. Expression of PNPLA3(I148M), but not PNPLA3(WT), in liver recapitulated the fatty liver phenotype as well as other metabolic features associated with this allele in humans. Metabolic studies provided evidence for 3 distinct alterations in hepatic TAG metabolism in PNPLA3(I148M) transgenic mice: increased formation of fatty acids and TAG, impaired hydrolysis of TAG, and relative depletion of TAG long-chain polyunsaturated fatty acids. These findings suggest that PNPLA3 plays a role in remodeling TAG in lipid droplets, as they accumulate in response to food intake, and that the increase in hepatic TAG levels associated with the I148M substitution results from multiple changes in hepatic TAG metabolism. The development of an animal model that recapitulates the metabolic phenotype of the allele in humans provides a new platform in which to elucidate the role of PNLPA3(I148M) in NAFLD. PMID- 23023706 TI - Mesodermal Pten inactivation leads to alveolar capillary dysplasia- like phenotype. AB - Alveolar capillary dysplasia (ACD) is a congenital, lethal disorder of the pulmonary vasculature. Phosphatase and tensin homologue deleted from chromosome 10 (Pten) encodes a lipid phosphatase controlling key cellular functions, including stem/progenitor cell proliferation and differentiation; however, the role of PTEN in mesodermal lung cell lineage formation remains unexamined. To determine the role of mesodermal PTEN in the ontogeny of various mesenchymal cell lineages during lung development, we specifically deleted Pten in early embryonic lung mesenchyme in mice. Pups lacking Pten died at birth, with evidence of failure in blood oxygenation. Analysis at the cellular level showed defects in angioblast differentiation to endothelial cells and an accompanying accumulation of the angioblast cell population that was associated with disorganized capillary beds. We also found decreased expression of Forkhead box protein F1 (Foxf1), a gene associated with the ACD human phenotype. Analysis of human samples for ACD revealed a significant decrease in PTEN and increased activated protein kinase B (AKT). These studies demonstrate that mesodermal PTEN has a key role in controlling the amplification of angioblasts as well as their differentiation into endothelial cells, thereby directing the establishment of a functional gas exchange interface. Additionally, these mice could serve as a murine model of ACD. PMID- 23023707 TI - HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration. AB - The native capacity of adult skeletal muscles to regenerate is vital to the recovery from physical injuries and dystrophic diseases. Currently, the development of therapeutic interventions has been hindered by the complex regulatory network underlying the process of muscle regeneration. Using a mouse model of skeletal muscle regeneration after injury, we identified hexamethylene bisacetamide inducible 1 (HEXIM1, also referred to as CLP-1), the inhibitory component of the positive transcription elongation factor b (P-TEFb) complex, as a pivotal regulator of skeletal muscle regeneration. Hexim1-haplodeficient muscles exhibited greater mass and preserved function compared with those of WT muscles after injury, as a result of enhanced expansion of satellite cells. Transplanted Hexim1-haplodeficient satellite cells expanded and improved muscle regeneration more effectively than WT satellite cells. Conversely, HEXIM1 overexpression restrained satellite cell proliferation and impeded muscle regeneration. Mechanistically, dissociation of HEXIM1 from P-TEFb and subsequent activation of P-TEFb are required for satellite cell proliferation and the prevention of early myogenic differentiation. These findings suggest a crucial role for the HEXIM1/P-TEFb pathway in the regulation of satellite cell-mediated muscle regeneration and identify HEXIM1 as a potential therapeutic target for degenerative muscular diseases. PMID- 23023709 TI - Lymphoid malignancies: many tumor types, many altered genes, many therapeutic challenges. AB - The lymphoid tissues, including both the B and T cell lineages, are characterized by a unique level of biological complexity due to the anatomical organization of functionally distinct cell subpopulations and complex processes of genetic alteration required to generate immune responses. Not surprisingly, this physiological diversity and complexity is mirrored by the broad spectrum of malignancies derived from lymphocytes. The articles in this Review Series highlight recent progress in selected common lymphoid malignancies, with a focus on the genetic alterations that drive malignant transformation, including those identified by genome-wide analyses. These genetic alterations represent the basis from which cellular pathways of therapeutic relevance can be identified, studied, and eventually targeted. PMID- 23023708 TI - Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics. AB - Addictive diseases, including addiction to heroin, prescription opioids, or cocaine, pose massive personal and public health costs. Addictions are chronic relapsing diseases of the brain caused by drug-induced direct effects and persisting neuroadaptations at the epigenetic, mRNA, neuropeptide, neurotransmitter, or protein levels. These neuroadaptations, which can be specific to drug type, and their resultant behaviors are modified by various internal and external environmental factors, including stress responsivity, addict mindset, and social setting. Specific gene variants, including variants encoding pharmacological target proteins or genes mediating neuroadaptations, also modify vulnerability at particular stages of addiction. Greater understanding of these interacting factors through laboratory-based and translational studies have the potential to optimize early interventions for the therapy of chronic addictive diseases and to reduce the burden of relapse. Here, we review the molecular neurobiology and genetics of opiate addiction, including heroin and prescription opioids, and cocaine addiction. PMID- 23023710 TI - The molecular basis of T cell acute lymphoblastic leukemia. AB - T cell acute lymphoblastic leukemias (T-ALLs) arise from the malignant transformation of hematopoietic progenitors primed toward T cell development, as result of a multistep oncogenic process involving constitutive activation of NOTCH signaling and genetic alterations in transcription factors, signaling oncogenes, and tumor suppressors. Notably, these genetic alterations define distinct molecular groups of T-ALL with specific gene expression signatures and clinicobiological features. This review summarizes recent advances in our understanding of the molecular genetics of T-ALL. PMID- 23023711 TI - Molecular genetics of B-precursor acute lymphoblastic leukemia. AB - B-precursor acute lymphoblastic leukemia (B-ALL) is the most common childhood tumor and the leading cause of cancer-related death in children and young adults. The majority of B-ALL cases are aneuploid or harbor recurring structural chromosomal rearrangements that are important initiating events in leukemogenesis but are insufficient to explain the biology and heterogeneity of disease. Recent studies have used microarrays and sequencing to comprehensively identify all somatic genetic alterations in acute lymphoblastic leukemia (ALL). These studies have identified cryptic or submicroscopic genetic alterations that define new ALL subtypes, cooperate with known chromosomal rearrangements, and influence prognosis. This article reviews these advances, discusses results from ongoing second-generation sequencing studies of ALL, and highlights challenges and opportunities for future genetic profiling approaches. PMID- 23023712 TI - Molecular pathogenesis of mantle cell lymphoma. AB - Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients. PMID- 23023713 TI - Pathogenesis of follicular lymphoma. AB - The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program. Most tumors are characterized by recurrent secondary genetic alterations including genomic gains, losses, and mutations, some providing a growth advantage, including alterations in MLL2, EPHA7, TNFRSF14, and EZH2. The sequence in which these events occur and how they contribute to progression and ultimately to transformation is unclear. Lastly, crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation. PMID- 23023714 TI - Molecular pathogenesis of chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Here, we highlight important genetic alterations that contribute to tumorigenesis, clinical progression, and chemorefractoriness of CLL. All CLLs share a common gene expression profile that suggests derivation from antigen-experienced B cells, a model supported by frequent B cell receptor repertoire skewing and stereotypy. Many CLL patients carry mutated immuno-globulin heavy-chain variable genes, while approximately 35% harbor unmutated IgV genes, which are associated with an inferior outcome. Deletion of chromosome 13q14, which is the most common genetic mutation at diagnosis, is considered an initiating lesion that frequently results in disruption of the tumor suppressor locus DLEU2/MIR15A/MIR16A. Next generation sequencing has revealed additional recurrent genetic lesions that are implicated in CLL pathogenesis. These advancements in the molecular genetics of CLL have important implications for stratifying treatment based on molecular prognosticators and for targeted therapy. PMID- 23023715 TI - Hodgkin lymphoma. AB - Hodgkin lymphoma (HL), a B cell-derived cancer, is one of the most common lymphomas. In HL, the tumor cells--Hodgkin and Reed-Sternberg (HRS) cells--are usually very rare in the tissue. Although HRS cells are derived from mature B cells, they have largely lost their B cell phenotype and show a very unusual co expression of markers of various hematopoietic cell types. HRS cells show deregulated activation of multiple signaling pathways and transcription factors. The activation of these pathways and factors is partly mediated through interactions of HRS cells with various other types of cells in the microenvironment, but also through genetic lesions. The transforming events involved in the pathogenesis of HL are only partly understood, but mutations affecting the NF-kappaB and JAK/STAT pathways are frequent. The dependency of HRS cells on microenvironmental interactions and deregulated signaling pathways may offer novel strategies for targeted therapies. PMID- 23023718 TI - Mechanistic insights into a supramolecular self-assembling catalyst system: evidence for hydrogen bonding during rhodium-catalyzed hydroformylation. AB - The structural integrity and flexibility provided by intermolecular hydrogen bonds leads to the outstanding properties of the 6-diphenylphosphinopyridin-(2H) 1-one ligand (see scheme) in the rhodium-catalyzed hydroformylation of terminal alkenes, as demonstrated by the combination of spectroscopic methods and DFT computations. Hydrogen bonds were also detected in a competent intermediate of the catalytic cycle. PMID- 23023717 TI - Molecular pathogenesis of multiple myeloma and its premalignant precursor. AB - Multiple myeloma is a monoclonal tumor of plasma cells, and its development is preceded by a premalignant tumor with which it shares genetic abnormalities, including universal dysregulation of the cyclin D/retinoblastoma (cyclin D/RB) pathway. A complex interaction with the BM microenvironment, characterized by activation of osteoclasts and suppression of osteoblasts, leads to lytic bone disease. Intratumor genetic heterogeneity, which occurs in addition to intertumor heterogeneity, contributes to the rapid emergence of drug resistance in high-risk disease. Despite recent therapeutic advances, which have doubled the median survival time, myeloma continues to be a mostly incurable disease. Here we review the current understanding of myeloma pathogenesis and insight into new therapeutic strategies provided by animal models and genetic screens. PMID- 23023719 TI - Hemodialysis vascular access: everything you always wanted to know about it (but were afraid to ask). AB - Vascular accesses are essential for effective dialysis treatment. Arteriovenous fistulas, grafts and central venous catheters are the options available to the nephrologist, but they all have their pros and cons. All of the 3 types of vascular access share the same complications but at different rates, and their costs vary enormously, with on balance the arteriovenous fistula being the best choice. Nevertheless, recently the number of incident patients starting dialysis treatment with a venous catheter as vascular access has been steadily increasing. This is true even for more advanced countries such as the United States, where despite the efforts made to promote the use of fistulas, their prevalence is still low compared with Europe. Moreover, nowadays nephrologists are required to master technical skills that once were those of surgeons and to perform interventions to preserve the patency of the access. The aim of this paper is to review the prevalence, benefits and complications of the different vascular accesses in light of the most recent findings. PMID- 23023716 TI - New molecular insights into peripheral T cell lymphomas. AB - Peripheral T cell lymphomas (PTCLs) are heterogeneous neoplasms and represent about 12% of all lymphoid malignancies. They are often regarded as "orphan diseases," a designation that does not reflect their real incidence but rather signifies the difficulties encountered in their classification, diagnosis, and treatment. Here we revise the current understanding of the pathobiological characteristics of the most common nodal PTCLs by focusing on the contribution given by high-throughput technologies and the identification of potential therapeutic targets proposed by translational studies. PMID- 23023720 TI - Kidney transplantation and enzyme replacement therapy in patients with Fabry disease. AB - During Fabry disease, progressive glycosphingolipid deposition in the kidney causes gradual deterioration of renal function with proteinuria, uremia and hypertension. This results in end-stage renal disease (ESRD) which is one of the leading causes of morbidity and premature mortality in affected patients. Given the excellent graft and patient survival generally nowadays, kidney transplantation is the first choice to correct renal dysfunction and improve the overall prognosis of patients with renal failure because of Fabry disease. The benefit of enzyme-replacement therapy (ERT) in kidney transplanted Fabry patients has been controversially discussed and long-term trials focusing on the effectiveness of agalsidase in this patient population are needed. PMID- 23023722 TI - Epidemiology and optimal management in patients with renal artery stenosis. AB - Renovascular hypertension (hypertension induced by renal artery stenosis) is a form of secondary hypertension caused by overactivation of the renin-angiotensin system by the ischemic kidney. Prevalence of renal artery stenosis (RAS) is estimated to be between 2% (unselected hypertensives) and 40% (older patients with other atherosclerotic comorbidities). Most cases of RAS are caused by atherosclerosis; other causes, including fibromuscular dysplasia, vasculitis, thromboembolism and aneurysms, are less frequent. The most frequent clinical presentation of RAS is hypertension. Acute kidney injury, rapid loss of kidney function and episodes of flash pulmonary edema are other symptoms of RAS, especially in bilateral disease. In current practice, RAS therapy includes antiplatelet (aspirin) and lipid-lowering (statin) therapy as well as angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors as a first choice of antihypertensive agents. Angiotensin blockade, however, is contraindicated in bilateral RAS and in RAS of the solitary kidney. This review summarizes the current status and perspectives on the epidemiology and management of renovascular hypertension. PMID- 23023721 TI - Selenium and kidney disease. AB - Selenium (Se) is a trace element that participates as a cofactor in several enzymes (selenoproteins) which act in the regulation of thyroid hormone metabolism, enzymatic antioxidant defenses and the immune system. Se deficiency has been linked to atherosclerosis-related cardiovascular disease, increased risk of viral infections and even with an increased risk of mortality. Low serum Se levels are a frequent finding in patients with acute kidney injury or chronic kidney disease. The relationship between hyposelenemia and the comorbidities associated with renal disease has not been extensively evaluated. It has been reported that both low serum Se levels and renal insufficiency are associated with an increased risk of coronary heart disease mortality and an increased risk for all-cause mortality in adults older than 35 years. A recent report has suggested that hyposelenemia may contribute to immune dysfunction, increasing the risk of death from infectious disease in hemodialysis patients. Some studies have reported that Se status and immune function improve after oral and intravenous Se supplementation in renal patients, reducing the products of oxidative stress. In summary, although there are intriguing relationships between Se physiology and several derangements and comorbidities associated with acute and chronic kidney disease, only a few studies have analyzed the clinical consequences of hyposelenemia in these patients to date. Available data are encouraging and stimulate interest in further studies to clarify the real extent of Se deficiency and the need for Se supplementation in patients with kidney disease. PMID- 23023723 TI - Osteoporosis and adynamic bone in chronic kidney disease. AB - Among the chronic kidney disease-mineral bone disease (CKD-MBD) disorders, osteoporosis and adynamic bone are highly prevalent, and they have been consistently associated with low bone mass, bone fractures, vascular calcifications and greater mortality in general and CKD populations. Despite the fact that osteoporosis and adynamic bone have similar clinical outcomes, they have different pathogeneses and clinical management. In osteoporosis, there is a lack of balance between bone formation and bone resorption, and less new bone is formed to replace bone losses. Osteoporosis is defined by the World Health Organization as "a disease characterized by low bone mineral density and micro architectural deterioration leading to low bone strength and increased risk of fractures." In the general population, there is a good correlation between dual energy X-ray absorptiometry measurements and bone fractures, but this is not the case with CKD patients. Despite the fact that we have a great number of active antiosteoporotic drugs, the experience in CKD patients is limited. Adynamic bone is suspected based on biochemical parameters, mainly parathyroid hormone (PTH) and bone alkaline phosphatase, but it needs to be proven using a bone biopsy, where a low or zero bone formation rate and a reduction or absence of osteoblasts and osteoclasts should be found. The clinical management of adynamic bone has important limitations and currently does not allow taking many active measures. Treatment is mainly based on the prevention of risk factors known to induce PTH oversuppression, such as aluminium and calcium load and very high doses of vitamin D receptor activators. Due to the limitations in the treatment of both conditions, prevention plays a key role in the management of these disorders. PMID- 23023724 TI - Spin canting magnetization in a 3D Cu(II) complex based on molybdate oxide cluster and 5-triazole isophthalic acid. AB - A unique 3D Cu(II) complex based on a molybdate oxide cluster and 5-triazole isophthalic acid was synthesized under hydrothermal condition: {Cu(2)(HL)(2)[Mo(4)O(13)]}.2H(2)O (H(2)L = 5-triazole isophthalic acid) (1). Compound 1 shows a spin canting magnetization behavior, and a definite hysteresis loop with a large coercive field of 6.85 kOe. PMID- 23023725 TI - Domino reactions of donor-acceptor-substituted cyclopropanes for the synthesis of 3,3'-linked oligopyrroles and pyrrolo[3,2-e]indoles. AB - Multiple displacement of oxygen: Electron-rich oligopyrroles and pyrrolo[3,2 e]indoles are generated by a domino process induced by donor-acceptor-substituted cyclopropanes. Up to seven molecules of water are eliminated, thus allowing the introduction of nitrogen and aromaticity. PMID- 23023727 TI - Effects of SASH1 on melanoma cell proliferation and apoptosis in vitro. AB - The SAM and SH3 domain containing 1 (SASH1) gene was originally identified as a potential tumor suppressor gene in breast cancer, mapped on chromosome 6q24.3. The expression of SASH1 plays a prognostic role in human colon cancer. Its expression is frequently downregulated in several human malignancies. However, the biological function of SASH1 in melanoma cells is yet to be determined. In this study, in order to investigate the tumor suppressive effects of the SASH1 gene, an A-375 stable melanoma cell line was established, overexpressing the SASH1 gene. The stable cell line was examined using proliferation assay, apoptosis assay, cell cycle analysis and real-time PCR. The results indicated that the tumor suppressive activity of SASH1 derived from G2/M arrest in A-375 cells, and that the phosphorylation of Cdc2 or the disruption of cyclin B-Cdc2 binding may be responsible for the G2/M arrest. PMID- 23023726 TI - Epigenetic regulation of the glucocorticoid receptor promoter 1(7) in adult rats. AB - Regulation of glucocorticoid receptor (GR) levels is an important stress adaptation mechanism. Transcription factor Nfgi-a and environmentally induced Gr promoter 1 7 methylation have been implicated in fine-tuning the expression of Gr 1 7 transcripts. Here, we investigated Gr promoter 1 7 methylation and Gr 1 7 expression in adult rats exposed to either acute or chronic stress paradigms. A strong negative correlation was observed between the sum of promoter-wide methylation levels and Gr 1 7 transcript levels, independent of the stressor. Methylation of individual sites did not, however, correlate with transcript levels. This suggested that promoter 1 7 was directly regulated by promoter-wide DNA methylation. Although acute stress increased Ngfi-a expression in the hypothalamic paraventricular nucleus (PVN), Gr 1 7 transcript levels remained unaffected despite low methylation levels. Acute stress had little effect on these low methylation levels, except at four hippocampal CpGs. Chronic stress altered the corticosterone response to an acute stressor. In the adrenal and pituitary glands, but not in the brain, this was accompanied by an increase in methylation levels in orchestrated clusters rather than individual CpGs. PVN methylation levels, unaffected by acute or chronic stress, were significantly more variable within- than between-groups, suggesting that they were instated probably during the perinatal period and represent a pre-established trait. Thus, in addition to the known perinatal programming, the Gr 1 7 promoter is epigenetically regulated by chronic stress in adulthood, and retains promoter wide tissue-specific plasticity. Differences in methylation susceptibility between the PVN in the perinatal period and the peripheral HPA axis tissues in adulthood may represent an important "trait" vs. "state" regulation of the Gr gene. PMID- 23023728 TI - Sunscreen use and failures--on site observations on a sun-holiday. AB - With this observation study we aimed to determine how and when sunscreen was used. 20 sun seekers were observed during a one-week sun holiday in Hurghada, Egypt. The sunscreen application thickness was related to part of body, time outdoors, exposure to ultraviolet radiation and to sunburning. Skin sites with sunscreen were exposed to UVR significantly longer and received significantly higher UVR doses than skin sites without sunscreen. They received an average of 0.62 SED [0.0-9.3 SED] (13% of their MED) before the first sunscreen application of the day. The average sunscreen used was SPF15 and the sunscreen application thickness was in average 0.79 mg cm(-)2 giving an approximated effect of SPF3. For different body parts either the total UVR exposure dose or the UVR exposure time and UVR exposure dose before the first sunscreen application were higher for sunburned than non-sunburned skin sites. In the final model gender, skin type and UVR to skin (adjusted for SPF and sunscreen application thickness) were significant predictors of sunburning. The sunscreen application thickness of 0.79 mg cm(-)2 was less than the 2 mg cm(-2) used for testing SPF. The late start of sunscreen use and improper application thickness was ineffective in preventing sunburn, and therefore could not compensate for the risk of prolonged UVR exposure and high UVR doses. Our results lead us to suspect that the protective effect of sunscreen use against DNA-damage, and thereby skin cancer, is minimal the way sunscreen is used under real sun holiday conditions. PMID- 23023729 TI - Identifying and inspiring leadership in interventional cardiology: update on the SCAI Emerging Leader Mentorship (ELM) Program. PMID- 23023730 TI - Preparation and biological evaluation of tumor-specific Ara-C liposomal preparations containing RGDV motif. AB - Arginine-glycine-aspartate (RGD) has been shown to be essential for the recognition of integrins overexpressed in tumor cells, especially during tumor invasion, angiogenesis, and metasis. In this study, a novel tetrapeptide, RGD valine (RGDV), was designed and attached to the N position of 1-beta-D arabinofuranosylcytosine (Ara-C) at the valine end, as a homing device for the delivery of Ara-C to tumor cells. Furthermore, fatty acids of various chain lengths (C(n)H(2n+1)COOH, n = 7, 9, 11, 13, and 15) were attached to the arginine end of RGDV to form a series of C(n)H(2n+1)CO-RGDV-Ara-C compounds. The structures of C(n)H(2n+1)CO-RGDV-Ara-C compounds were confirmed using mass spectrometry and nuclear magnetic resonance. The liposomal preparations of the synthesized C(n)H(2n+1)CO-RGDV-Ara-C compounds were obtained using the film dispersion method in the presence of phospholipids. The particle size, zeta potential, and dispersity index of the liposomes formed were found to be approximately 215 nm (diameter), approximately -30 mV, and <0.3, respectively. The antitumor activity of the liposomal preparations containing the respective C(n)H(2n+1)CO-RGDV-Ara-C compounds was evaluated in mice inoculated with sarcoma S(180). Liposomal Ara-C preparation, liposomal C(11)H(23)CO-V-Ara-C preparation, Ara-C, and C(11)H(23)CO-V-Ara-C sodium carboxymethyl cellulose (CMC-Na) suspensions were used as controls. C(n)H(2n+1)CO-RGDV-Ara-C containing liposomal preparations were shown with an enhanced antitumor activity, likely because of the targeting effect of RGDV. PMID- 23023731 TI - A dual-catalysis approach to the kinetic resolution of 1,2-diaryl-1,2 diaminoethanes. AB - The kinetic resolution of racemic C(2)-symmetric 1,2-diaryl-1,2-diaminoethanes was accomplished for the first time through application of a dual-catalysis approach. PMID- 23023732 TI - Biomarkers of therapeutic response to BCL2 antagonists in cancer. AB - Cancer cells persist by resisting programmed cell death or apoptosis. In particular, an imbalance of proteins that regulate apoptosis leads to lack of response to apoptotic stimuli. Thus, restoring the ability of cancer cells to undergo apoptosis is highly desirable. One apoptosis pathway, the intrinsic pathway, involves perturbation of the mitochondria. The major players of this pathway are the members of the B cell CLL/lymphoma 2 (BCL2) family. Currently, three BCL2 antagonists are in clinical trials for cancer treatment. While these antagonists show various specificity and potency, the development of companion diagnostics is crucial for developing these compounds into viable cancer treatments. In this review we describe predictive and pharmacodynamic biomarkers for these agents. Future directions on biomarker development for this class of antagonist are also discussed. PMID- 23023733 TI - Influence of an interaction between lithium salts and a functional polymorphism in SLC1A2 on the history of illness in bipolar disorder. AB - BACKGROUND: Bipolar disorder (BD) is a recurrent and disabling illness, characterized by periods of depression and mania. The history of the illness differs widely between patients, with episode frequency emerging as a strong predictor of poor illness outcome. Lithium salts are the first-choice long-term mood-stabilizing therapy, but not all patients respond equally to the treatment. Evidence suggests that alterations in glutamatergic systems may contribute to the pathophysiology of depression. Moreover, glutamate signaling is involved in brain development and synaptic plasticity, both of which are modified in individuals affected by BD, and has been implicated in the etiology of the disorder. The inactivation of glutamate is handled by a series of molecular glutamate transporters (excitatory amino acid transporters [EAATs]), among which EAAT2/SLC1A2 is responsible for up to 95% of extracellular glutamate clearance. A functional single-nucleotide polymorphism at -181 bp from the transcription start site of the SLC1A2 gene has been described. This T-to-G (DNA forward strand) polymorphism, commonly known as SLC1A2 -181A>C, affects transporter expression, with the variant G allele inducing a 30% reduction in promoter activity compared with the T allele. OBJECTIVE: The aims of the study were to investigate if factors affecting glutamate function, such as SLC1A2 -181A>C (rs4354668), could affect recurrence of illness in BD, and if they interact with lithium salt treatment. METHODS: We performed an observational study in our university hospital in Milan. We enrolled 110 subjects (76 females, 34 males) affected by BD type I. The exclusion criteria were other diagnoses on Axis I, mental retardation on Axis II, a history of epilepsy, and major medical and neurologic disorders. Fifty-four patients had been treated with lithium salts for more than 6 months. Patients were genotyped for SLC1A2 -181A>C by polymerase chain reaction restriction fragment length polymorphism, and the influence of genotype on BD episode recurrence rates, and the interaction between the single nucleotide polymorphism and lithium treatment, were analyzed. RESULTS: The SLC1A2 -181A>C genotype significantly influenced the total recurrence of episodes, with T/T homozygotes showing a significantly lower frequency of episodes (F = 3.26; p = 0.042), and an interaction between lithium treatment and genotype (F = 3.77; p = 0.026) was found to influence the history of the illness. CONCLUSION: According to our results, the glutamatergic system could be hypothesized to exert some influence on the history of illness in BD. The SLC1A2 functional polymorphism was shown to significantly influence the total episode recurrence rate, with wild type T homozygotes presenting the lowest number of episodes, G homozygotes reporting the highest number, and heterozygotes showing an intermediate phenotype. We confirmed the efficacy of lithium treatment in reducing the recurrence of illness in BD, and we found an interaction between lithium treatment and the SLC1A2 -181A>C genotype, confirming previous studies reporting an interaction between lithium salts and the glutamatergic system. PMID- 23023735 TI - The analysis of social network data: an exciting frontier for statisticians. AB - The catalyst for this paper is the recent interest in the relationship between social networks and an individual's health, which has arisen following a series of papers by Nicholas Christakis and James Fowler on person- to-person spread of health behaviors. In this issue, they provide a detailed explanation of their methods that offers insights, justifications, and responses to criticisms. In this paper, we introduce some of the key statistical methods used in social network analysis and indicate where those used by Christakis and Fowler (CF) fit into the general framework. The intent is to provide the background necessary for readers to be able to make their own evaluation of the work by CF and understand the challenges of research involving social networks. We entertain possible solutions to some of the difficulties encountered in accounting for confounding effects in analyses of peer effects and provide comments on the contributions of CF. PMID- 23023736 TI - Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia. AB - BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency caused by defects of the WAS protein (WASP) gene. Patients with WAS typically demonstrate micro-thrombocytopenia. PROCEDURES: The report describes seven male infants with WAS that initially presented with leukocytosis, monocytosis, and myeloid and erythroid precursors in the peripheral blood (PB) and dysplasia in the bone marrow (BM), which was initially indistinguishable from juvenile myelomonocytic leukaemia (JMML). RESULTS: The median age of affected patients was 1 month (range, 1-4 months). Splenomegaly was absent in four of these patients, which was unusual for JMML. A mutation analysis of genes in the RAS-signalling pathway did not support a diagnosis of JMML. Non-haematological features, such as eczema (n = 7) and bloody stools (n = 6), ultimately led to the diagnosis of WAS at a median age of 4 months (range, 3-8 months), which was confirmed by absent (n = 6) or reduced (n = 1) WASP expression in lymphocytes by flow cytometry (FCM) and a WASP gene mutation. Interestingly, mean platelet volume (MPV) was normal in three of five patients and six of seven patients demonstrated occasional giant platelets, which was not compatible with WAS. CONCLUSIONS: These data suggest that WAS should be considered in male infants presenting with JMML-like features if no molecular markers of JMML can be detected. PMID- 23023737 TI - Bacterial evolution: decoding the bacterial fossil record. PMID- 23023734 TI - Current outlook on molecular pathogenesis and treatment of myeloproliferative neoplasms. AB - Discovery of the JAK2 V617F mutation in the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has stimulated great interest in the underlying molecular mechanisms and treatment of these diseases. Along with acceleration of technologies, novel mutations in genes such as MPL, LNK, and CBL have been discovered that converge on the JAK-STAT pathway. Several additional novel mutations in genes involved in epigenetic regulation of the genome, including TET2, ASXL1, DNMT3A, and IDH1/2, have emerged, in addition to several mutations in cellular splicing machinery. While understanding of the pathogenetic mechanisms of these novel mutations in MPNs has improved, it is still lagging behind the pace of mutation discovery. Concurrent with molecular discoveries, especially with regard to JAK-STAT signaling, therapeutic development has accelerated in recent years. More than ten JAK kinase inhibitors have been advanced into clinical trials. Recently the first JAK2 inhibitor was approved for use in patients with PMF. Most JAK-targeting agents share similar characteristics with regard to clinical benefit, consisting of improvements in splenomegaly, constitutional symptoms, and cytopenias, for example. It remains to be determined if JAK2 inhibitors can considerably impact disease progression and bone marrow histologic features (e.g., fibrosis) or significantly impact the JAK2 allele burden. While JAK2 inhibitors appear to be promising in PV and ET, they need to be compared with standard therapies, such as hydroxyurea or interferon-based therapies. Future clinical development will focus on optimal combination partners and agents that target alternative mechanisms, deepen the response, and achieve molecular remissions. PMID- 23023739 TI - Perovskite B-site compositional control of [110]p polar displacement coupling in an ambient-pressure-stable bismuth-based ferroelectric. PMID- 23023738 TI - Model-based reconstruction of undersampled diffusion tensor k-space data. AB - The practical utility of diffusion tensor imaging, especially for 3D high resolution spin warp experiments of ex vivo specimens, has been hampered by long acquisition times. To accelerate the acquisition, a compressed sensing framework that uses a model-based formulation to reconstruct diffusion tensor fields from undersampled k-space data was presented and evaluated. Accuracies in brain specimen white matter fiber orientation, fractional anisotropy, and mean diffusivity mapping were compared with alternative methods achievable using the same scan time via reduced image resolution, fewer diffusion encoding directions, standard compressed sensing, or asymmetrical sampling reconstruction. The efficiency of the proposed approach was also compared with fully sampled cases across a range of the number of diffusion encoding directions. In general, the proposed approach was found to reduce the image blurring and noise and to provide more accurate fiber orientation, fractional anisotropy, and mean diffusivity measurements compared with the alternative methods. Moreover, depending on the degree of undersampling used and the diffusion tensor imaging parameter examined, the measurement accuracy of the proposed scheme was equivalent to fully sampled diffusion tensor imaging datasets that consist of 33-67% more encoding directions and require proportionally longer scan times. The findings show model-based compressed sensing to be promising for improving the resolution, accuracy, or scan time of diffusion tensor imaging. PMID- 23023740 TI - Iteratively reweighted LASSO for mapping multiple quantitative trait loci. AB - The iteratively reweighted least square (IRLS) method is mostly identical to maximum likelihood (ML) method in terms of parameter estimation and power of quantitative trait locus (QTL) detection. But the IRLS is greatly superior to ML in terms of computing speed and the robustness of parameter estimation. In conjunction with the priors of parameters, ML can analyze multiple QTL model based on Bayesian theory, whereas under a single QTL model, IRLS has very limited statistical power to detect multiple QTLs. In this study, we proposed the iteratively reweighted least absolute shrinkage and selection operator (IRLASSO) for extending IRLS to simultaneously map multiple QTLs. The LASSO with coordinate descent step is employed to efficiently estimate non-zero genetic effect of each locus scanned over entire genome. Simulations demonstrate that IRLASSO has a higher precision of parameter estimation and power to detect QTL than IRLS, and is able to estimate residual variance more accurately than the unweighted LASSO based on LS. Especially, IRLASSO is very fast, usually taking less than five iterations to converge. The barley dataset from the North American Barley Genome Mapping Project is reanalyzed by our proposed method. PMID- 23023741 TI - Characterization of xylan utilization and discovery of a new endoxylanase in Thermoanaerobacterium saccharolyticum through targeted gene deletions. AB - The economical production of fuels and commodity chemicals from lignocellulose requires the utilization of both the cellulose and hemicellulose fractions. Xylanase enzymes allow greater utilization of hemicellulose while also increasing cellulose hydrolysis. Recent metabolic engineering efforts have resulted in a strain of Thermoanaerobacterium saccharolyticum that can convert C(5) and C(6) sugars, as well as insoluble xylan, into ethanol at high yield. To better understand the process of xylan solubilization in this organism, a series of targeted deletions were constructed in the homoethanologenic T. saccharolyticum strain M0355 to characterize xylan hydrolysis and xylose utilization in this organism. While the deletion of beta-xylosidase xylD slowed the growth of T. saccharolyticum on birchwood xylan and led to an accumulation of short-chain xylo oligomers, no other single deletion, including the deletion of the previously characterized endoxylanase XynA, had a phenotype distinct from that of the wild type. This result indicates a multiplicity of xylanase enzymes which facilitate xylan degradation in T. saccharolyticum. Growth on xylan was prevented only when a previously uncharacterized endoxylanase encoded by xynC was also deleted in conjunction with xynA. Sequence analysis of xynC indicates that this enzyme, a low-molecular-weight endoxylanase with homology to glycoside hydrolase family 11 enzymes, is secreted yet untethered to the cell wall. Together, these observations expand our understanding of the enzymatic basis of xylan hydrolysis by T. saccharolyticum. PMID- 23023742 TI - A single, plastic population of Mycosphaerella pinodes causes ascochyta blight on winter and spring peas (Pisum sativum) in France. AB - Plant diseases are caused by pathogen populations continuously subjected to evolutionary forces (genetic flow, selection, and recombination). Ascochyta blight, caused by Mycosphaerella pinodes, is one of the most damaging necrotrophic pathogens of field peas worldwide. In France, both winter and spring peas are cultivated. Although these crops overlap by about 4 months (March to June), primary Ascochyta blight infections are not synchronous on the two crops. This suggests that the disease could be due to two different M. pinodes populations, specialized on either winter or spring pea. To test this hypothesis, 144 pathogen isolates were collected in the field during the winter and spring growing seasons in Rennes (western France), and all the isolates were genotyped using amplified fragment length polymorphism (AFLP) markers. Furthermore, the pathogenicities of 33 isolates randomly chosen within the collection were tested on four pea genotypes (2 winter and 2 spring types) grown under three climatic regimes, simulating winter, late winter, and spring conditions. M. pinodes isolates from winter and spring peas were genetically polymorphic but not differentiated according to the type of cultivars. Isolates from winter pea were more pathogenic than isolates from spring pea on hosts raised under winter conditions, while isolates from spring pea were more pathogenic than those from winter pea on plants raised under spring conditions. These results show that disease developed on winter and spring peas was initiated by a single population of M. pinodes whose pathogenicity is a plastic trait modulated by the physiological status of the host plant. PMID- 23023743 TI - Probing the role of sigma pi interaction and energetics in the catalytic efficiency of endo-1,4-beta-xylanase. AB - Chaetomium globosum endo-1,4-beta-xylanase (XylCg) is distinguished from other xylanases by its high turnover rate (1,860 s(-1)), the highest ever reported for fungal xylanases. One conserved amino acid, W48, in the substrate binding pocket of wild-type XylCg was identified as an important residue affecting XylCg's catalytic efficiency. PMID- 23023744 TI - Chromosomal tet(O)-harboring regions in Campylobacter coli isolates from turkeys and swine. AB - In turkey-derived Campylobacter coli isolates of a unique lineage (cluster II), the tetracycline resistance determinant tet(O) was chromosomal and was part of a gene cassette (transposon) interrupting a Campylobacter jejuni-associated putative citrate transporter gene. In contrast, the swine-derived C. coli strain 6461 harbored a chromosomal tet(O) in a different genomic location. PMID- 23023745 TI - Nanocapsular dispersion of thymol for enhanced dispersibility and increased antimicrobial effectiveness against Escherichia coli O157:H7 and Listeria monocytogenes in model food systems. AB - Essential oils are marginally soluble in water, making it challenging to evenly disperse them in foods and resulting in an increased tendency to bind with food lipids and proteins, resulting in lowered antimicrobial efficacy. In the current study, free and nano-dispersed (ND) thymol were compared in terms of their antimicrobial efficacies against Escherichia coli O157:H7 ATCC 43889 and 43894 and Listeria monocytogenes strains Scott A and 101 in apple cider and 2% reduced fat milk. Apple cider was adjusted to pHs 5.5 and 3.5, and antimicrobial tests were performed at 0.3-, 0.5-, 0.75-, and 1.0-g/liter thymol concentrations at 35, 32, 25, and 4 degrees C. Overall, 0.5 and 1.0 g/liter thymol in nano-dispersion and along with free thymol were inhibitory and bactericidal, respectively, against bacterial strains under all treatment conditions. At pH 5.5, 0.5 g/liter ND thymol was bacteriostatic against L. monocytogenes and E. coli for up to 48 h. At pH 3.5, L. monocytogenes controls did not survive beyond 12 h but E. coli survived and was inhibited by 0.5 g/liter ND thymol after 12 and 48 h in apple cider. E. coli strains were significantly sensitive to 4 degrees C and pH 3.5 (P < 0.05). When bacteria were tested in 2% reduced-fat milk at 35 or 32 degrees C, ND and free thymol demonstrated inhibition at 4.5 g/liter. Thus, the current technology seems to be promising and novel, enabling thymol-containing nano dispersions that are not only transparent but also effective against pathogens in food applications, especially in clear beverages. PMID- 23023746 TI - A new bacterial disease on Mandevilla sanderi, caused by Pseudomonas savastanoi: lessons learned for bacterial diversity studies. AB - Leaf lesions of Mandevilla sanderi were shown to be caused by Pseudomonas savastanoi. While BOX fingerprints were similar for P. savastanoi isolates from different host plants, plasmid restriction patterns and sequencing of plasmid located pathogenicity determinants revealed that Mandevilla isolates contained similar plasmids distinct from those of other isolates. A repA-based detection method was established. PMID- 23023747 TI - Characterization of a broad-specificity beta-glucanase acting on beta-(1,3)-, beta-(1,4)-, and beta-(1,6)-glucans that defines a new glycoside hydrolase family. AB - Here we report the cloning of the Pa_3_10940 gene from the coprophilic fungus Podospora anserina, which encodes a C-terminal family 1 carbohydrate binding module (CBM1) linked to a domain of unknown function. The function of the gene was investigated by expression of the full-length protein and a truncated derivative without the CBM1 domain in the yeast Pichia pastoris. Using a library of polysaccharides of different origins, we demonstrated that the full-length enzyme displays activity toward a broad range of beta-glucan polysaccharides, including laminarin, curdlan, pachyman, lichenan, pustulan, and cellulosic derivatives. Analysis of the products released from polysaccharides revealed that this beta-glucanase is an exo-acting enzyme on beta-(1,3)- and beta-(1,6)-linked glucan substrates and an endo-acting enzyme on beta-(1,4)-linked glucan substrates. Hydrolysis of short beta-(1,3), beta-(1,4), and beta-(1,3)/beta-(1,4) gluco-oligosaccharides confirmed this striking feature and revealed that the enzyme performs in an exo-type mode on the nonreducing end of gluco oligosaccharides. Excision of the CBM1 domain resulted in an inactive enzyme on all substrates tested. To our knowledge, this is the first report of an enzyme that displays bifunctional exo-beta-(1,3)/(1,6) and endo-beta-(1,4) activities toward beta-glucans and therefore cannot readily be assigned to existing Enzyme Commission groups. The amino acid sequence has high sequence identity to hypothetical proteins within the fungal taxa and thus defines a new family of glycoside hydrolases, the GH131 family. PMID- 23023748 TI - Ethylene glycol metabolism by Pseudomonas putida. AB - In this study, we investigated the metabolism of ethylene glycol in the Pseudomonas putida strains KT2440 and JM37 by employing growth and bioconversion experiments, directed mutagenesis, and proteome analysis. We found that strain JM37 grew rapidly with ethylene glycol as a sole source of carbon and energy, while strain KT2440 did not grow within 2 days of incubation under the same conditions. However, bioconversion experiments revealed metabolism of ethylene glycol by both strains, with the temporal accumulation of glycolic acid and glyoxylic acid for strain KT2440. This accumulation was further increased by targeted mutagenesis. The key enzymes and specific differences between the two strains were identified by comparative proteomics. In P. putida JM37, tartronate semialdehyde synthase (Gcl), malate synthase (GlcB), and isocitrate lyase (AceA) were found to be induced in the presence of ethylene glycol or glyoxylic acid. Under the same conditions, strain KT2440 showed induction of AceA only. Despite this difference, the two strains were found to use similar periplasmic dehydrogenases for the initial oxidation step of ethylene glycol, namely, the two redundant pyrroloquinoline quinone (PQQ)-dependent enzymes PedE and PedH. From these results we constructed a new pathway for the metabolism of ethylene glycol in P. putida. Furthermore, we conclude that Pseudomonas putida might serve as a useful platform from which to establish a whole-cell biocatalyst for the production of glyoxylic acid from ethylene glycol. PMID- 23023749 TI - Incidence of Staphylococcus aureus and analysis of associated bacterial communities on food industry surfaces. AB - Biofilms are a common cause of food contamination with undesirable bacteria, such as pathogenic bacteria. Staphylococcus aureus is one of the major bacteria causing food-borne diseases in humans. A study designed to determine the presence of S. aureus on food contact surfaces in dairy, meat, and seafood environments and to identify coexisting microbiota has therefore been carried out. A total of 442 samples were collected, and the presence of S. aureus was confirmed in 6.1% of samples. Sixty-three S. aureus isolates were recovered and typed by random amplification of polymorphic DNA (RAPD). Profiles were clustered into four groups which were related to specific food environments. All isolates harbored some potential virulence factors such as enterotoxin production genes, biofilm formation-associated genes, antibiotic resistance, or lysogeny. PCR-denaturing gradient gel electrophoresis (PCR-DGGE) fingerprints of bacterial communities coexisting with S. aureus revealed the presence of bacteria either involved in food spoilage or of concern for food safety in all food environments. Food industry surfaces could thus be a reservoir for S. aureus forming complex communities with undesirable bacteria in multispecies biofilms. Uneven microbiological conditions were found in each food sector, which indicates the need to improve hygienic conditions in food processing facilities, particularly the removal of bacterial biofilms, to enhance the safety of food products. PMID- 23023750 TI - Expression of Shewanella oneidensis MR-1 [FeFe]-hydrogenase genes in Anabaena sp. strain PCC 7120. AB - H(2) generated from renewable resources holds promise as an environmentally innocuous fuel that releases only energy and water when consumed. In biotechnology, photoautotrophic oxygenic diazotrophs could produce H(2) from water and sunlight using the cells' endogenous nitrogenases. However, nitrogenases have low turnover numbers and require large amounts of ATP. [FeFe] hydrogenases found in other organisms can have 1,000-fold higher turnover numbers and no specific requirement for ATP but are very O(2) sensitive. Certain filamentous cyanobacteria protect nitrogenase from O(2) by sequestering the enzyme within internally micro-oxic, differentiated cells called heterocysts. We heterologously expressed the [FeFe]-hydrogenase operon from Shewanella oneidensis MR-1 in Anabaena sp. strain PCC 7120 using the heterocyst-specific promoter P(hetN). Active [FeFe]-hydrogenase was detected in and could be purified from aerobically grown Anabaena sp. strain PCC 7120, but only when the organism was grown under nitrate-depleted conditions that elicited heterocyst formation. These results suggest that the heterocysts protected the [FeFe]-hydrogenase against inactivation by O(2). PMID- 23023751 TI - A Single-cell genome for Thiovulum sp. AB - We determined a significant fraction of the genome sequence of a representative of Thiovulum, the uncultivated genus of colorless sulfur Epsilonproteobacteria, by analyzing the genome sequences of four individual cells collected from phototrophic mats from Elkhorn Slough, California. These cells were isolated utilizing a microfluidic laser-tweezing system, and their genomes were amplified by multiple-displacement amplification prior to sequencing. Thiovulum is a gradient bacterium found at oxic-anoxic marine interfaces and noted for its distinctive morphology and rapid swimming motility. The genomic sequences of the four individual cells were assembled into a composite genome consisting of 221 contigs covering 2.083 Mb including 2,162 genes. This single-cell genome represents a genomic view of the physiological capabilities of isolated Thiovulum cells. Thiovulum is the second-fastest bacterium ever observed, swimming at 615 MUm/s, and this genome shows that this rapid swimming motility is a result of a standard flagellar machinery that has been extensively characterized in other bacteria. This suggests that standard flagella are capable of propelling bacterial cells at speeds much faster than typically thought. Analysis of the genome suggests that naturally occurring Thiovulum populations are more diverse than previously recognized and that studies performed in the past probably address a wide range of unrecognized genotypic and phenotypic diversities of Thiovulum. The genome presented in this article provides a basis for future isolation-independent studies of Thiovulum, where single-cell and metagenomic tools can be used to differentiate between different Thiovulum genotypes. PMID- 23023752 TI - Effect of frequency and waveform on inactivation of Escherichia coli O157:H7 and Salmonella enterica Serovar Typhimurium in salsa by ohmic heating. AB - The effect of frequency of alternating current during ohmic heating on electrode corrosion, heating rate, inactivation of food-borne pathogens, and quality of salsa was investigated. The impact of waveform on heating rate was also investigated. Salsa was treated with various frequencies (60 Hz to 20 kHz) and waveforms (sine, square, and sawtooth) at a constant electric field strength of 12.5 V/cm. Electrode corrosion did not occur when the frequency exceeded 1 kHz. The heating rate of the sample was dependent on frequency up to 500 Hz, but there was no significant difference (P > 0.05) in the heating rate when the frequency was increased above 1 kHz. The electrical conductivity of the sample increased with a rise in the frequency. At a frequency of 60 Hz, the square wave produced a lower heating rate than that of sine and sawtooth waves. The heating rate between waveforms was not significantly (P > 0.05) different when the frequency was >500 Hz. As the frequency increased, the treatment time required to reduce Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium to below the detection limit (1 log CFU/g) decreased without affecting product quality. These results suggest that ohmic heating can be effectively used to pasteurize salsa and that the effect of inactivation is dependent on frequency and electrical conductivity rather than waveform. PMID- 23023753 TI - Lactate and acrylate metabolism by Megasphaera elsdenii under batch and steady state conditions. AB - The growth of Megasphaera elsdenii on lactate with acrylate and acrylate analogues was studied under batch and steady-state conditions. Under batch conditions, lactate was converted to acetate and propionate, and acrylate was converted into propionate. Acrylate analogues 2-methyl propenoate and 3-butenoate containing a terminal double bond were similarly converted into their respective saturated acids (isobutyrate and butyrate), while crotonate and lactate analogues 3-hydroxybutyrate and (R)-2-hydroxybutyrate were not metabolized. Under carbon limited steady-state conditions, lactate was converted to acetate and butyrate with no propionate formed. As the acrylate concentration in the feed was increased, butyrate and hydrogen formation decreased and propionate was increasingly generated, while the calculated ATP yield was unchanged. M. elsdenii metabolism differs substantially under batch and steady-state conditions. The results support the conclusion that propionate is not formed during lactate limited steady-state growth because of the absence of this substrate to drive the formation of lactyl coenzyme A (CoA) via propionyl-CoA transferase. Acrylate and acrylate analogues are reduced under both batch and steady-state growth conditions after first being converted to thioesters via propionyl-CoA transferase. Our findings demonstrate the central role that CoA transferase activity plays in the utilization of acids by M. elsdenii and allows us to propose a modified acrylate pathway for M. elsdenii. PMID- 23023754 TI - A novel meso-Diaminopimelate dehydrogenase from Symbiobacterium thermophilum: overexpression, characterization, and potential for D-amino acid synthesis. AB - meso-Diaminopimelate dehydrogenase (meso-DAPDH) is an NADP(+)-dependent enzyme which catalyzes the reversible oxidative deamination on the d-configuration of meso-2,6-diaminopimelate to produce l-2-amino-6-oxopimelate. In this study, the gene encoding a meso-diaminopimelate dehydrogenase from Symbiobacterium thermophilum was cloned and expressed in Escherichia coli. In addition to the native substrate meso-2,6-diaminopimelate, the purified enzyme also showed activity toward d-alanine, d-valine, and d-lysine. This enzyme catalyzed the reductive amination of 2-keto acids such as pyruvic acid to generate d-amino acids in up to 99% conversion and 99% enantiomeric excess. Since meso diaminopimelate dehydrogenases are known to be specific to meso-2,6 diaminopimelate, this is a unique wild-type meso-diaminopimelate dehydrogenase with a more relaxed substrate specificity and potential for d-amino acid synthesis. The enzyme is the most stable meso-diaminopimelate dehydrogenase reported to now. Two amino acid residues (F146 and M152) in the substrate binding sites of S. thermophilum meso-DAPDH different from the sequences of other known meso-DAPDHs were replaced with the conserved amino acids in other meso-DAPDHs, and assay of wild-type and mutant enzyme activities revealed that F146 and M152 are not critical in determining the enzyme's substrate specificity. The high thermostability and relaxed substrate profile of S. thermophilum meso-DAPDH warrant it as an excellent starting enzyme for creating effective d-amino acid dehydrogenases by protein engineering. PMID- 23023755 TI - Response of the soil microbial community to changes in precipitation in a semiarid ecosystem. AB - Microbial communities regulate many belowground carbon cycling processes; thus, the impact of climate change on the structure and function of soil microbial communities could, in turn, impact the release or storage of carbon in soils. Here we used a large-scale precipitation manipulation (+18%, -50%, or ambient) in a pinon-juniper woodland (Pinus edulis-Juniperus monosperma) to investigate how changes in precipitation amounts altered soil microbial communities as well as what role seasonal variation in rainfall and plant composition played in the microbial community response. Seasonal variability in precipitation had a larger role in determining the composition of soil microbial communities in 2008 than the direct effect of the experimental precipitation treatments. Bacterial and fungal communities in the dry, relatively moisture-limited premonsoon season were compositionally distinct from communities in the monsoon season, when soil moisture levels and periodicity varied more widely across treatments. Fungal abundance in the drought plots during the dry premonsoon season was particularly low and was 4.7 times greater upon soil wet-up in the monsoon season, suggesting that soil fungi were water limited in the driest plots, which may result in a decrease in fungal degradation of carbon substrates. Additionally, we found that both bacterial and fungal communities beneath pinon pine and juniper were distinct, suggesting that microbial functions beneath these trees are different. We conclude that predicting the response of microbial communities to climate change is highly dependent on seasonal dynamics, background climatic variability, and the composition of the associated aboveground community. PMID- 23023756 TI - Bacteriophage ecology in a commercial cucumber fermentation. AB - To reduce high-salt waste from cucumber fermentations, low-salt fermentations are under development. These fermentations may require the use of starter cultures to ensure normal fermentations. Because potential phage infection can cause starter culture failure, it is important to understand phage ecology in the fermentations. This study investigated the phage ecology in a commercial cucumber fermentation. Brine samples taken from a fermentation tank over a 90-day period were plated onto deMan-Rogosa-Sharpe agar plates. A total of 576 lactic acid bacterial isolates were randomly selected to serve as potential hosts for phage isolation. Filtered brine served as a phage source. Fifty-seven independent phage isolates were obtained, indicating that 10% of the bacterial isolates were sensitive to phage attack. Phage hosts include Lactobacillus brevis (67% of all hosts), Lactobacillus plantarum (21%), Weissella paramesenteroides, Weissella cibaria, and Pediococcus ethanolidurans. Nearly 50% of phages were isolated on day 14, and the majority of them attacked L. brevis. Some phages had a broad host range and were capable of infecting multiple hosts in two genera. Other phages were species specific or strain specific. About 30% of phage isolates produced turbid pinpoint plaques or only caused reduced cell growth on the bacterial lawns. Six phages with distinct host ranges were characterized. The data from this study showed that abundant and diverse phages were present in the commercial cucumber fermentation, which could cause significant mortality to the lactic acid bacteria population. Therefore, a phage control strategy may be needed in low salt cucumber fermentations. PMID- 23023758 TI - s-Block chalcogenoether chemistry--thio- and selenoether coordination with hard Group 2 ions. AB - A highly unusual series of Group 2 complexes with soft thio- and selenoether coordination, [MI(2)([18]aneO(4)E(2))] (M = Ca or Sr; E = S or Se), [CaI(2)([18]aneO(2)S(4))] and [MI(2)([15]aneO(3)S(2))], has been prepared by reaction of anhydrous MI(2) with the macrocycle in dry MeCN solution. The complexes have been characterised via(1)H NMR and IR spectroscopy, microanalysis and crystallographic studies which provide unambiguous confirmation of the M-S/Se coordination. The neutral complexes are seven- or eight-coordinate with the iodo ligands cis. The long M-E bond distances of ~3.0 A indicate weak interactions, but they are significantly less than the sum of the van der Waals radii for M and E, and are important in facilitating isolation of the complexes. Trace hydrolysis of [MI(2)([18]aneO(4)E(2))] and [SrI(2)([15]aneO(3)S(2))] leads, unexpectedly, to displacement of the iodo ligands rather than the S/Se donor functions, and the resulting dicationic [Ca(H(2)O)(2)([18]aneO(4)S(2))]I(2), [Sr(H(2)O)(3)([18]aneO(4)S(2))]I(2).H(2)O, [Sr(H(2)O)(3)([18]aneO(4)Se(2))]I(2) and [Sr(H(2)O)(3)([15]aneO(3)S(2))]I(2) complexes have been structurally characterised, forming eight- and nine-coordinate cations, with all the macrocyclic donor atoms coordinated. Reaction of Ca(CF(3)SO(3))(2) with [18]aneO(4)S(2) in anhydrous MeCN solution similarly affords [Ca(CF(3)SO(3))(2)([18]aneO(4)S(2))], albeit in low yield, also proven crystallographically. Using the MI(2) precursors provides a general entry into this area of coordination chemistry of these Group 2 ions, owing in part at least to their higher solubility in the weak donor (weakly competing) MeCN solvent. While CaCl(2) reacts with 18-crown-6 either directly in MeCN giving [CaCl(2)(18 crown-6)], or in the presence of SbCl(5) (to form trans-[Ca(MeCN)(2)(18-crown 6)][SbCl(6)](2)), neither of these routes works with the oxa-thia or oxa-selena crowns. PMID- 23023757 TI - Novel bacterial community associated with 500-year-old unpreserved archaeological wood from King Henry VIII's Tudor Warship the Mary Rose. AB - A 500-year-old unpreserved Mary Rose sample, historically containing an iron bolt, was analyzed using enrichment cultures and 16S sequencing. The novel community of bacteria present demonstrates a biological pathway of Fe and S oxidation and a range of acid-generating metabolisms, with implications for preservation and biogeochemical cycling. PMID- 23023759 TI - Enantioselective copper(I)-catalyzed borylative aldol cyclizations of enone diones. PMID- 23023760 TI - Optimization of transfection parameters for ultrasound/SonoVue microbubble mediated hAng-1 gene delivery in vitro. AB - This study aimed to explore the effects of microbubble concentration, gene dosage, cell-microbubble mixing mode and fetal bovine serum (FBS) on gene delivery. 293T cells were transfected with Sonovue microbubbles carrying the hAng 1 gene via ultrasound irradiation. Various ultrasound exposure parameters and microbubble and DNA concentrations were investigated. In addition, FBS and the cell suspension or adherent mode was explored. Transfection efficiency and cell viability were used to determine the optimal transfection parameters. hAng-1 gene transfection efficiency gradually increased with elongation of ultrasound exposure and increasing microbubble concentration. However, if ultrasound irradiation exceeded 1.5 W/cm2 and 30 sec or the microbubble concentration was over 20%, hAng-1 gene expression was significantly decreased, coupled with extensive cell death. Gene transfection levels were low under DNA concentrations less than 15 ug/ml. Furthermore, the gene transfer rate was significantly increased under cell suspension mode; FBS had no effect on hAng-1 gene transfection. The integrity of hAng-1 DNA was not affected by ultrasonic irradiation under optimal conditions. The optimal transfection parameters for the hAng-1 gene and Sonovue microbubble were ultrasound exposure of 1.5 W/cm2 and 30 sec, 20% microbubbles, 15 ug/ml of DNA and under cell suspension mode. PMID- 23023761 TI - In situ growth of noble metal nanoparticles on graphene oxide sheets and direct construction of functionalized porous-layered structure on gravimetric microsensors for chemical detection. AB - Noble metal nanoparticles are directly and homogeneously grown onto graphene oxide (GO) sheets in oleylamine. After the oleylamine is removed, the GO sheets are exfoliated by the nanoparticle pillars to further form hierarchical GO nanostructures with molecule accessible nanopores. With specific sensing-groups modified, the porous-layered nanostructure can be constructed onto resonant microcantilevers for chemical sensing. PMID- 23023762 TI - Different characteristics identified by single nucleotide polymorphism array analysis in leukemia suggest the need for different application strategies depending on disease category. AB - The purpose of this study was to evaluate the detection rate of chromosomal rearrangements in leukemia using single nucleotide polymorphism array (SNP-A) in combination with metaphase cytogenetics (MC), with the aim of proposing a practical approach for clinical karyotyping applications of SNP-A. The Genome Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA) was applied in 469 patients with a variety of hematologic malignancies. Combined use of SNP-A with MC improved the detection rate in comparison with MC alone: acute myeloid leukemia (AML) with normal karyotype (NK), 32% versus 0%; core binding factor (CBF)-AML 40% versus 29%; myelodysplastic syndrome (MDS), 54% versus 39%; chronic myeloid leukemia (CML), 24% versus 3%; and acute lymphoblastic leukemia (ALL), 88% versus 63%. Different patterns of abnormalities (especially the type, size, and location) were noted in the leukemia subtypes. Copy neutral loss of heterozygosity lesions was detected in 23% of AML-NK, 3% of CBF-AML, 25% of MDS, 2% of CML, and 20% of ALL. SNP-A also provided information on cryptic deletions and a variety of aneuploidies in ALL, while the benefit was minimal in CML. In conclusion, different patterns of abnormal lesions were presented according to the disease category, thus requiring a different approach of adopting SNP-A-based karyotyping among different leukemia subtypes. PMID- 23023763 TI - Catalytic solid substrate-room temperature phosphorimetry for the determination of residual perphenazine based on the electronic effect of rhodamine 6G. AB - The rhodamine 6G(+) -perphenazine (Rhod 6G(+) -PPH) compound is formed in the ester-exchange reaction between -OH of PPH and -COOC2 H5 of Rhod 6G(+) . PPH was oxidized to a red compound (PPH') in the presence of K2 S2 O8 . Interestingly, the room temperature phosphorescence (RTP) of Rhod 6G(+) was quenched because the -OH of PPH' reacted with -COOC2 H5 of Rhod 6G(+) -PPH to form Rhod 6G(+) -PPH' and PPH, which decreased the pi-electron density (delta) of the carbon atom in the Rhod 6G(+) -PPH' conjugated system and enhanced the nonradiation energy loss of the excited Rhod 6G(+) of the triplet state. The PPH content was directly proportional to the DeltaIp of the system. Thus, a new catalytic solid-substrate room temperature phosphorimetry (SSRTP) method was established for the determination of PPH. The method had high sensitivity (the limit of detection was 0.019 fg/spot, corresponding to a concentration of 4.8 * 10(-14) g/mL; the sampling quantity was 0.40 MUL/spot), good selectivity, convenience and speed. The analytical results were in accordance with those of high-performance liquid chromatography (HPLC). The structures of Rhod 6G(+) , PPH and Rhod 6G(+) -PPH were characterized by infrared spectra. The reaction mechanism by which PPH was determined is discussed. PMID- 23023764 TI - Can exogenous protease inhibitors control dentin matrix degradation? PMID- 23023765 TI - Impact of protease inhibitors on dentin matrix degradation by collagenase. AB - This proof-of-concept study assessed whether the reduction of the degradation of the demineralized organic matrix (DOM) by pre-treatment with protease inhibitors (PI) is effective against dentin matrix loss. Bovine dentin slices were demineralized with 0.87 M citric acid, pH 2.3, for 36 hrs. In sequence, specimens were treated or not (UT, untreated) for 1 min with gels containing epigallocatechin 3-gallate (EGCG, 400 uM), chlorhexidine (CHX, 0.012%), FeSO(4) (1 mM), NaF (1.23%), or no active compound (P, placebo). Specimens were then stored in artificial saliva (5 days, 37 degrees C) with the addition of collagenase (Clostridium histolyticum, 100 U/mL). We analyzed collagen degradation by assaying hydroxyproline (HYP) in the incubation solutions (n = 5) and evaluated the dentin matrix loss by profilometry (n = 12). Data were analyzed by ANOVA and Tukey's test (p < 0.05). Treatment with gels containing EGCG, CHX, or FeSO(4) led to significantly lower HYP concentrations in solution and dentin matrix loss when compared with the other treatments. These results strongly suggest that the preventive effects of the PI tested against dentin erosion are due to their ability to reduce the degradation of the DOM. PMID- 23023766 TI - A review of UVB-mediated photosensitivity disorders. AB - Photosensitivity to UVB is a prominent feature of a small number of congenital skin disorders. In addition UVB may also contribute to the action spectrum of a number of acquired photosensitivity syndromes. The gene mutations underlying the genetically inherited disorders have largely been identified and have provided insights into DNA repair pathways. The pathomechanisms for the acquired disorders are still largely undefined. Few therapeutic options are available so management of all these disorders still relies on rigorous photo-protection. PMID- 23023767 TI - On the choice of doses for phase III clinical trials. AB - Many potential new medicines fail in phase III clinical trials, because of either insufficient efficacy or intolerability. Such failures may be caused by the absence of an effect and also if a suboptimal dose is being tested. It is thus important to consider how to optimise the choice of dose or doses that continue into the confirmatory phase. For many indications, it is common to test one single active dose in phase III. However, phase IIB dose-finding trials are relatively small and often lack the ability of precisely estimating the dose response curves for efficacy and tolerability. Because of this uncertainty in dose response, it is reasonable to consider bringing more than one dose into phase III. Using simple but illustrative models, we find the optimal doses and compare the probability of success, for fixed total sample sizes, when one or two active doses are included in phase III. PMID- 23023768 TI - Electrical detection of spin precession in freely suspended graphene spin valves on cross-linked poly(methyl methacrylate). AB - Spin injection and detection is achieved in freely suspended graphene using cobalt electrodes and a nonlocal spin-valve geometry. The devices are fabricated with a single electron-beam-resist poly(methyl methacrylate) process that minimizes both the fabrication steps and the number of (aggressive) chemicals used, greatly reducing contamination and increasing the yield of high-quality, mechanically stable devices. As-grown devices can present mobilities exceeding 10(4) cm(2) V(-1) s(-1) at room temperature and, because the contacts deposited on graphene are only exposed to acetone and isopropanol, the method is compatible with almost any contacting material. Spin accumulation and spin precession are studied in these nonlocal spin valves. Fitting of Hanle spin precession data in bilayer and multilayer graphene yields a spin relaxation time of ~125-250 ps and a spin diffusion length of 1.7-1.9 MUm at room temperature. PMID- 23023769 TI - New health conditions identified at a regional childhood cancer survivor clinic visit. AB - BACKGROUND: Specialty childhood cancer survivorship clinics have been established to screen for potential treatment-related effects. Given the limited empirical data regarding the merit of survivorship clinics, we assessed the frequencies of newly identified, therapy-related effects in survivors who attended Health, Education, Research, Outcomes for Survivors (HEROS) clinic at Yale during 2003 2009. PROCEDURE: A total of 213 survivors in remission, who were diagnosed with cancer at an age <=21 years and were >=3 years after cancer diagnosis, underwent screening based on cancer treatment exposures according to the children's oncology group long-term follow-up guidelines. The frequencies and associated factors of newly identified health conditions were determined. Odds ratios (OR) and their 95% confidence intervals were estimated using multivariate regression models with stepwise selection. RESULTS: Prior to the HEROS clinic visit, 49% of patients had at least one previously known late complication of therapy. After the visit, a total of 98 new health conditions were identified in 73 patients (34%). Newly identified complications in screened patients included pulmonary dysfunction (23%), endocrinopathy (19%), osteoporosis (17%), dyslipidemia (8%), neurologic impairment (4%), cardiovascular deficit (3%) and subsequent cancer (3%). Age at cancer diagnosis (OR = 1.06 [1.00-1.11]), chest irradiation (OR = 2.92 [1.58-5.40]), and history of >=1 other treatment-related complication(s) (OR = 2.20 [1.18-4.07]) were associated with a higher likelihood of having new conditions identified. CONCLUSION: Risk-based screening at a specialty childhood cancer survivor clinic detected a substantial number of previously unrecognized, treatment-related health complications in a group of survivors already receiving regular medical care elsewhere. PMID- 23023772 TI - Encapsulation of biomacromolecules within polymersomes by electroporation. AB - Biological macromolecules can be encapsulated into preformed polymersomes by controlled temporary destabilization of the vesicle membrane. The morphology and the size of the polymersome are unchanged after electroporation, suggesting that the polymersome membrane is reformed. The surface charge of the biomacromolecules plays a key role for the electroporation process. PMID- 23023773 TI - Liquid-gas dual phase microfluidic system for biocompatible CaCO3 hollow nanoparticles generation and simultaneous molecule doping. AB - Continuous CaCO(3) hollow nanoparticle generation at room temperature with simultaneous molecule doping is realized on a liquid-gas dual phase microfluidic system. PMID- 23023774 TI - Silicone-oil-based subvisible particles: their detection, interactions, and regulation in prefilled container closure systems for biopharmaceuticals. AB - Recent increased regulatory scrutiny concerning subvisible particulates (SbVPs) in parenteral formulations of biologics has led to the publication of numerous articles about the sources, characteristics, implications, and approaches to monitoring and detecting SbVPs. Despite varying opinions on the level of associated risks and method of regulation, nearly all industry scientists and regulators agree on the need for monitoring and reporting visible and subvisible particles. As prefillable drug delivery systems have become a prominent packaging option, silicone oil, a common primary packaging lubricant, may play a role in the appearance of particles. The goal of this article is to complement the current SbVP knowledge base with new insights into the evolution of silicone-oil related particulates and their interactions with components in prefillable systems. We propose a "toolbox" for improved silicone-oil-related particulate detection and enumeration, and discuss the benefits and limitations of approaches for lowering and controlling silicone oil release in parenterals. Finally, we present surface cross-linking of silicone as the recommended solution for achieving significant SbVP reduction without negatively affecting functional performance. PMID- 23023775 TI - Direct patterning of engineered ionic gold nanoparticles via nanoimprint lithography. AB - Gold nanoparticles are engineered for direct imprinting of stable structures. This imprinting strategy provides access to new device architectures, as demonstrated through the fabrication of a prototype photoswitchable device. PMID- 23023780 TI - Coaxial waveguide for travelling wave MRI at ultrahigh fields. AB - At high magnetic fields the performance of a volume-type body coil inside a human sized MR-scanner is influenced by the waveguide action of the scanner's bore. This can result in undesirable strong radio frequency fields B1+) outside the coil's target volume. A radio frequency (RF) transmit system, exploiting this waveguide action of the bore, is proposed in this work. A coaxial waveguide section is introduced between the antenna and the imaging region. It is shown that the coaxial waveguide has several advantages over the initially proposed travelling wave setup based on the cylindrical waveguide. First, a novel radio frequency matching principle (based on the transmission line impedance matching) is feasible with the coaxial waveguide achieving better radio frequency transmission characteristics, such as homogeneity and power efficiency of B1+ field. In case of body torso imaging, the coaxial waveguide prevents unwanted specific absorptive rate (SAR) deposition outside the target region and thus, effectively decreases local peak SAR values by factor of 5. A 3-fold B1+ gain in the prostate can be achieved with the coaxial waveguide in comparison with the initially proposed travelling wave setup. PMID- 23023776 TI - European genetic ancestry is associated with a decreased risk of lupus nephritis. AB - OBJECTIVE: African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than are SLE patients of European descent. This study was undertaken to investigate whether European genetic ancestry protects against the development of lupus nephritis, with the aim of exploring the genetic and socioeconomic factors that might explain this effect. METHODS: This was a cross-sectional study of SLE patients from a multiethnic case collection. Participants were genotyped for 126 single nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. Logistic regression was used to test the association between European ancestry and renal disease. Analyses were adjusted for continental ancestries, socioeconomic status (SES), and candidate genes. RESULTS: Participants (n = 1,906) had, on average, 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among the participants, 656 (34%) had renal disease. A 10% increase in the proportion of European ancestry estimated in each participant was associated with a 15% reduction in the odds of having renal disease, after adjustment for disease duration and sex (odds ratio 0.85, 95% confidence interval 0.82-0.87; P = 1.9 * 10(-30) ). Adjustment for other genetic ancestries, measures of SES, or SNPs in the genes most associated with renal disease (IRF5 [rs4728142], BLK [rs2736340], STAT4 [rs3024912], and HLA-DRB1*0301 and DRB1*1501) did not substantively alter this relationship. CONCLUSION: European ancestry is protective against the development of renal disease in SLE, an effect that is independent of other genetic ancestries, candidate risk alleles, and socioeconomic factors. PMID- 23023777 TI - Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. AB - OBJECTIVE: To compare the usefulness of 3 currently used classification systems in predicting the outcomes of treatment resistance, disease relapse, end-stage renal disease (ESRD), and death in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Three classification systems were applied to 502 patients with biopsy-proven AAV: 1) the Chapel Hill Consensus Conference (CHCC) definition with categories for granulomatosis with polyangiitis (GPA) (Wegener's), microscopic polyangiitis (MPA), and kidney limited disease; 2) the European Medicines Agency (EMA) system with categories for GPA and MPA; and 3) classification based on ANCA with specificity for myeloperoxidase (MPO ANCA) versus ANCA with specificity for proteinase 3 (PR3 ANCA). Outcomes included treatment resistance, relapse, ESRD, and death. Proportional hazards models were compared between systems using an information theoretic approach to rank models by predictive fit. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) and P values are reported. RESULTS: ANCA specificity was predictive of relapse, with PR3 ANCA-positive patients almost twice as likely to relapse as those with MPO ANCA (HR 1.89 [95% CI 1.33-2.69], P = 0.0004), and ANCA specificity had the best predictive model fit (model rank 1) compared to the CHCC and EMA systems. The CHCC and EMA systems did not predict relapse. By ANCA specificity, categories of GPA, MPA, and kidney-limited disease did not distinguish differences in probability of relapse-free survival. None of the systems predicted treatment resistance, ESRD, or death. CONCLUSION: ANCA specificity independently predicts relapse among patients with AAV with renal disease. Classification and diagnostic systems that incorporate ANCA specificity, such as PR3 ANCA-positive MPA and MPO ANCA-positive MPA, provide a more useful tool than the clinical pathologic category alone for predicting relapse. PMID- 23023781 TI - Lewis base stabilized oxophosphonium ions. PMID- 23023782 TI - Correlation between polymorphisms of nicotine acetylcholine acceptor subunit CHRNA3 and lung cancer susceptibility. AB - Both environmental and genetic factors participate in the pathogenesis of lung cancer. The aim of this study was to explore the association between CHRNA3 polymorphisms of the nicotinic acetylcholine receptor gene and lung cancer risk in a hospital-based, case-controlled study. Single nucleotide polymorphisms (SNPs) in CHRNA3 rs3743073 (A>G) were determined using the TaqMan-MGB probe technique in 600 lung cancer cases and 600 normal controls. The differences in genotype and allele frequency were compared between groups and their association with lung cancer. The genotype frequency of rs3743073 (A>G) demonstrated Hardy Weinberg equilibrium (P<0.05). The genotype and allele frequencies were significantly different between the cancer and control groups (P<0.05). Compared with patients with the TT genotype, lung cancer incidence was increased in patients with the TG and GG genotypes (OR=1.68; 95% CI, 1.30-2.19; P<0.05; OR=1.30; 95% CI, 1.05-1.61; P<0.05, respectively). Patients with rs3743073G variant alleles (TG and GG) were at greater risk (OR=0.65; 95% CI, 0.50-0.84; P<0.05) of developing lung cancer. Increased risk associated with rs3743073G variant alleles was observed in male smokers over the age of 60 (P<0.05). In this cohort, the CHRNA3 gene rs3743073G variant genotype significantly increased lung cancer risk, especially in male smokers over the age of 60. PMID- 23023783 TI - Rhodium complexes stabilized by phosphine-functionalized phosphonium ionic liquids used as higher alkene hydroformylation catalysts: influence of the phosphonium headgroup on catalytic activity. AB - Monodentate phosphine-functionalized phosphonium ionic liquids (PFILs) were employed as ligands for Rh complexes and used in the hydroformylation of higher alkenes. Three PFILs were designed by varying the length of the P-alkyl chain attached to the phosphonium moiety, for alkyl = methyl (1), butyl (2), octyl (3), in order to tune their solubility properties. In all PFILs, the phosphonium unit is linked to a diphenylphosphino functionality by an undecyl linker, with bis(trifluoromethylsulfonyl)imide as counter anion. These PFILs were combined with a Rh(I) precursor, [Rh(acac)(CO)(2)], to provide a biphasic hydroformylation catalyst for the transformation of 1-octene, 1-decene and 1-dodecene using tetradecyltributylphosphonium bis(trifluoromethylsulfonyl)imide, [P(4,4,4,14)]NTf(2) as a solvent. Good activities and excellent selectivities were obtained for these PFILs-Rh(I) complexes. Variation of the P-alkyl length in the PFIL ligand influenced the stability, catalytic activity and selectivity of the PFIL-stabilized catalyst. PMID- 23023785 TI - Multi-system repeatability and reproducibility of apparent diffusion coefficient measurement using an ice-water phantom. AB - PURPOSE: To determine quantitative quality control procedures to evaluate technical variability in multi-center measurements of the diffusion coefficient of water as a prerequisite to use of the biomarker apparent diffusion coefficient (ADC) in multi-center clinical trials. MATERIALS AND METHODS: A uniform data acquisition protocol was developed and shared with 18 participating test sites along with a temperature-controlled diffusion phantom delivered to each site. Usable diffusion weighted imaging data of ice water at five b-values were collected on 35 clinical MRI systems from three vendors at two field strengths (1.5 and 3 Tesla [T]) and analyzed at a central processing site. RESULTS: Standard deviation of bore-center ADCs measured across 35 scanners was <2%; error range: -2% to +5% from literature value. Day-to-day repeatability of the measurements was within 4.5%. Intra-exam repeatability at the phantom center was within 1%. Excluding one outlier, inter-site reproducibility of ADC at magnet isocenter was within 3%, although variability increased for off-center measurements. Significant (>10%) vendor-specific and system-specific spatial nonuniformity ADC bias was detected for the off-center measurement that was consistent with gradient nonlinearity. CONCLUSION: Standardization of DWI protocol has improved reproducibility of ADC measurements and allowed identifying spatial ADC nonuniformity as a source of error in multi-site clinical studies. PMID- 23023786 TI - Twelve-year survival of the first living-donor pediatric lung transplantation in Brazil. AB - OBJECTIVE: To report the long-term follow-up of the first living-donor lobar lung transplantation performed in Latin America. DESCRIPTION: The patient was a 12 year-old boy with post-infectious obliterative bronchiolitis with end-stage pulmonary disease. He was on continuous oxygen support, presenting with dyspnea even during minimal activity. He underwent bilateral lobar lung transplantation with living donors. The procedure was performed with the left and right lower lobes of two different related donors. In the second side cardiopulmonary bypass was required. The transplant was uneventful, and the patient was extubated after 14 hours and discharged with 44 days, after resolution of infectious, immunological and drug-related complications. After 12 years of follow-up, he presents with adequate lung function and has resumed his habitual activities. COMMENTS: Living-donor lobar lung transplantation is a complex procedure feasible for the treatment of selected pediatric end-stage pulmonary disease. This particular population might benefit from this approach since the availability of pediatric donors is very scarce and the clinical course of pediatric advanced pulmonary disease may be unpredictable. PMID- 23023787 TI - Four-site cooperative spin crossover in a mononuclear Fe(II) complex. AB - Round and round: A mononuclear Fe(II) complex (see picture) with an N(4)S(2) coordination set has been characterized in four polymorphic forms. Two of the polymorphs display four-site cooperative spin crossover (SCO), shown conclusively by the crystal structure of a fully ordered 1:3 high-spin/low-spin state. The presence of S donor atoms in SCO-active compounds is unusual, and further investigation of Fe(II) complexes for SCO activity is warranted. PMID- 23023788 TI - Dopamine modulates the off pathway in light-adapted mouse retina. AB - DL-2-Amino-4-phosphonobutyric acid (APB) is often used as a tool to block On pathways in studies of interactions between On and Off pathways in retinas. APB is an agonist of mGluR6 receptors and hyperpolarizes the On cone bipolar cells and rod bipolar cells. How APB affects Off responses of retinal ganglion cells (RGCs) in mouse retinas under dark and light adaptation is not clear. The light evoked excitatory postsynaptic currents (light-evoked EPSCs) from Off and On-Off RGCs cells were recorded using whole-cell patch-clamp recording to assess how APB affects Off responses (light-evoked Off EPSCs) of RGCs in dark- and light-adapted mouse retinas. We found that APB differentially affected Off responses of RGCs in dark- and light-adapted mouse retinas. Under dark adaptation, while the APB sensitive Off responses were blocked, APB increased the remaining Off responses (mainly from the secondary rod Off pathways) via removal of inhibition from On pathways to Off pathways. Under light adaptation, APB decreased Off responses. Glycinergic and GABAergic antagonists did not prevent the APB-induced reduction of Off responses of RGCs; however, a dopaminergic type 1 receptor (D(1)) blocker (SCH 23390) and a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker (ZD 7288) prevented the APB-induced reduction of Off responses of RGCs under light adaptation. The results indicated afunctional circuit: On cone bipolar cells to Off cone bipolar cells via D(1) receptors and HCN channels. PMID- 23023789 TI - Race matters: perceptions of race and racism in a sickle cell center. AB - BACKGROUND: Health care disparities based on race have been reported in the management of many diseases. Our goal was to identify perceptions of race and racism among both staff and patients/families with particular attention to provider attitudes as a potential contributor to racial healthcare disparities. PROCEDURE: A confidential survey addressing issues of race and health care was given to all patients with sickle cell disease and their families upon arrival to clinic. The survey was made available online to all staff in the hematology/oncology program. Free text comments were obtained. RESULTS: We received completed surveys from 112 patients/families. Surveys were completed by 135 of 158 staff members (85% return rate). The majority (92.6%) of patients/families identified as black, while 94.1% of staff identified as white (P < 0.001). More patients/families felt that race affects the quality of health care for sickle cell patients (50% vs. 31.6%, P = 0.003). More staff perceived unequal treatment of patients, especially in the inpatient setting (20.9% vs. 10.9%, P = 0.03). CONCLUSIONS: Provider attitudes contribute to continued racial health care disparities. We propose training health care providers on issues of race and racism. Training should provide critical thinking tools for improving medical providers' comfort and skills in caring for patients who are of a different race than their own. PMID- 23023790 TI - Analysis of volatile components in herbal pair Semen Persicae-Flos Carthami by GC MS and chemometric resolution. AB - Analysis of volatile components in herbal pair (HP) Semen Persicae-Flos Carthami (SP-FC) was performed by GC-MS coupled with chemometric resolution method (CRM). Furthermore, temperature-programmed retention indices were used together with mass spectra for identification of the volatile components. With the help of CRM, the two-dimensional data obtained from GC-MS instruments were resolved into a pure chromatogram and a mass spectrum of each chemical compound. By use of these methods upon two-dimensional data, 26, 49, and 59 volatile chemical components in essential oils of single herb Semen Persicae, Flos Carthami, and HP SP-FC were determined qualitatively and quantitatively, accounting for 78.42, 81.08, and 82.48% total contents of essential oil of single herb Semen Persicae, Flos Carthami, and HP SP-FC, respectively. It is shown that the accuracy of qualitative and quantitative analysis can be enhanced greatly by means of CRM. It is further demonstrated that the numbers of volatile chemical components of HP SP FC are almost the addition of those of two single herbs, but the main volatile chemical components of the former are completely different from those of single herb Semen Persicae or Flos Carthami because of chemical reactions and physical changes occurring in the process of decocting two single herbs. This means that chemical components especially pharmacologically active compounds in the recipe might be different from those of single herbs. PMID- 23023791 TI - Relational experiences of family caregivers providing home-based end-of-life care. AB - The multiple relationships involved in home-based end-of-life care have received little systematic analysis. As part of a focused ethnographic study examining client-caregiver-provider relational care experiences within the sociocultural context of home-based end-of-life care, this article describes the provision of end-of-life care to older adults with advanced cancer from the perspective of family caregivers. Data were collected through in-depth interviews (n = 16) with 4 family caregivers and participant observations in each of the 4 households over a 6- to 8-month period. Family caregiving in home-based end-of-life care was portrayed in this study as 3 dialectical relational care experiences: (1) prioritizing care recipient needs-ignoring own needs, (2) feeling connected feeling isolated, and (3) juggling to manage-struggling to survive. Study findings suggest that the sociocultural context of end-of-life care is not conducive to quality care and provide several insights for future directions in nursing practice, policy, and research. PMID- 23023792 TI - Highly enantioselective [4 + 2] cyclization of chloroaldehydes and 1-azadienes catalyzed by N-heterocyclic carbenes. AB - Highly functionalized dihydropyridinones were synthesized via the N-heterocyclic carbene-catalyzed enantioselective [4 + 2] annulation of alpha-chloroaldehydes and azadienes. Hydrogenation of the resulted dihydropyridinones afforded the corresponding piperidinones with high enantiopurity. PMID- 23023793 TI - Measuring electrical properties of thin film fuel cell electrodes by in situ infrared spectroscopy. AB - The electrical conductivities of cathode films on a solid oxide fuel cell electrolyte can be determined quantitatively by in situ infrared spectroscopy over a wide range of temperatures and partial oxygen pressures. This method allows measurement of the electrical conductivity of an electrode film on the electrolyte excluding leakage current effects through the substrate. PMID- 23023794 TI - If life serves up a bowl of cherries, and gout attacks are "the pits": implications for therapy. PMID- 23023795 TI - How to gain evidence in neurorehabilitation: a personal view. AB - Neurorehabilitation is an emerging field driven by developments in neuroscience and biomedical engineering. Most patients that require neurorehabilitation have had a stroke, but other diseases of the brain, spinal cord, or nerves can also be alleviated. Modern therapies in neurorehabilitation focus on reducing impairment and improving function in daily life. As compared with acute care medicine, the clinical evidence for most neurorehabilitative treatments (modern or conventional) is sparse. Clinical trials support constraint-induced movement therapy for the arm and aerobic treadmill training for walking, both high intensity interventions requiring therapist time (i.e., cost) and patient motivation. Promising approaches for the future include robotic training, telerehabilitation at the patient's home, and supportive therapies that promote motivation and compliance. It is argued that a better understanding of the neuroscience of recovery together with results from small-scale and well-focused clinical experiments are necessary to design optimal interventions for specific target groups of patients. PMID- 23023796 TI - Mindray BS-800M1: a new clinical chemistry system with a flexible technology meeting quality performances. PMID- 23023797 TI - Delay in the measurement of eosin-5'-maleimide (EMA) binding does not affect the test result for the diagnosis of hereditary spherocytosis. AB - BACKGROUND: The eosin-5'-maleimide (EMA) binding test is a flow cytometric test widely used to detect hereditary spherocytosis (HS). EMA binds to plasma membrane proteins of red blood cells (RBCs), mainly to band 3 protein. The mean fluorescence of EMA-stained RBCs in HS patients is lower when compared with control RBCs due to the decreased amount of target proteins. EMA dye in aqueous solution is sensitive to light and high temperature. Its fluorescence can decrease when exposed to light or ambient temperatures higher than 4 degrees C. The aim of the study was to evaluate the stability of fluorescence readings of EMA-labeled RBCs over a period of 24 h. METHODS: The EMA test was performed in peripheral blood from 35 patients with microcytic anemia (five with HS, and 30 without HS). Peripheral blood samples were stained immediately after blood collection and analyzed using a flow cytometer at three time points: 0, after 1 and 24 h of storage at 4 degrees C in the darkness. The results are presented as the percentage of normal control RBCs fluorescence. Flow cytometric studies were performed with Cytomics FC500 (Beckman Coulter, USA). RESULTS: In HS patients the mean result of the test reached 66.72%+/-9.26% of normal controls, and in non-HS patients the EMA result was 99.48%+/-5.03% of normal control cells. The results of patients with HS were 66.72%+/-9.26%, 66.90%+/-10.24% and 67.86%+/-11.31% at 0 h, and after 1 and 24 h of storage, respectively. The results obtained from non HS patients at time 0, after 1 and 24 h of storage reached 99.48%+/-5.03%, 99.49%+/-5.34% and 99.78%+/-6.13%, respectively. There was no difference between the results from each time point in samples from patients with or without HS. CONCLUSIONS: Results of the EMA binding test do not depend on storage time of stained samples when stored at 4 degrees C up to 24 h after staining. PMID- 23023798 TI - Contrast and stability of the axon diameter index from microstructure imaging with diffusion MRI. AB - The ActiveAx technique fits the minimal model of white matter diffusion to diffusion MRI data acquired using optimized protocols that provide orientationally invariant indices of axon diameter and density. We investigated how limitations of the available maximal gradient strength (Gmax) on a scanner influence the sensitivity to a range of axon diameters. Multishell high-angular diffusion-imaging (HARDI) protocols for Gmax of 60, 140, 200, and 300 mT/m were optimized for the pulsed-gradient-spin-echo (PGSE) sequence. Data were acquired on a fixed monkey brain and Monte-Carlo simulations supported the results. Increasing Gmax reduces within-voxel variation of the axon diameter index and improves contrast beyond what is achievable with higher signal-to-noise ratio. Simulations reveal an upper bound on the axon diameter (~10 MUm) that pulsed gradient-spin-echo measurements are sensitive to, due to a trade-off between short T2 and the long diffusion time needed to probe larger axon diameters. A lower bound (~2.5 MUm) slightly dependent on Gmax was evident, below which axon diameters are identifiable as small, but impossible to differentiate. These results emphasize the key-role of Gmax for enhancing contrast between axon diameter distributions and are, therefore, relevant in general for microstructure imaging methods and highlight the need for increased Gmax on future commercial systems. PMID- 23023799 TI - Synthesis of aromatic alpha-aminoesters: palladium-catalyzed long-range arylation of primary C sp 3-H bonds. PMID- 23023800 TI - Development and optimization of self-nanoemulsifying drug delivery system with enhanced bioavailability by Box-Behnken design and desirability function. AB - The aim of our study was to characterize and optimize a self-nanoemulsifying drug delivery system (SNEDDS) formulation by a three-factor, three-level Box-Behnken design (BBD) combined with a desirability function. The independent factors were the amounts of Capryol PGMC (X(1)), Tween 20 (X(2)), and Transcutol HP (X(3)). The dependent variables were droplet size (Y(1)), equilibrium solubility (Y(2)), and cumulative percentage of drug released in 15 min (Y(3)) from the SNEDDS formulation. The responses were fitted to a second-order quadratic model and statistical validation of the fitted models was carried out by analysis of variance. Various response surface graphs and contour plots were constructed to understand the effects of different factor level combinations on the responses. The optimized SNEDDS formulation consisting of Capryol PGMC-Tween 20-Transcutol HP at proportions of 5:58.4:40 (w/w) was prepared and a comparison of the predicted values and experimental values was found to be in close agreement. Furthermore, an in vivo pharmacokinetic study of the optimized SNEDDS formulation showed a 2.2-fold increase in relative oral bioavailability compared with that of the suspension. In conclusion, the BBD demonstrated its effectiveness in optimizing the SNEDDS formulation and in understanding the effects of formulation variables on the performance of SNEDDS. PMID- 23023801 TI - Donor-specific human leukocyte antigen antibodies and late graft fibrosis after pediatric liver transplantation: time-associated variables or cause and effect? PMID- 23023804 TI - Nematogenic tetracatenar lanthanidomesogens. AB - We present luminescent liquid-crystalline neodymium(III) complexes that contain three beta-diketonate ligands and a mesogenic 1,10-phenanthroline ligand. Mesomorphism, including a nematic phase--very rare in lanthanide systems--is driven by the highly anisometric phenanthroline. PMID- 23023803 TI - Expression of APP, BACE1, AChE and ChAT in an AD model in rats and the effect of donepezil hydrochloride treatment. AB - The aim of this study was to investigate the pathological changes in a rat model of Alzheimer's disease (AD) and the effect of donepezil hydrochloride (HCl) treatment. The rat model of AD was established by the bilateral injection of amyloid beta1-40 (Abeta1-40) into the hippocampus. Changes in spatial learning and memory functions were examined using the Morris water maze test and changes in catalase (CAT) and glutathione peroxidase (GSH-Px) activities were determined using chemical colorimetry. Moreover, the changes in acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) expression were analyzed using immunohistochemical staining. The mRNA expression levels of the amyloid precursor protein (APP) and beta-secreted enzyme 1 (BACE1) were evaluated using RT-PCR. The effects of donepezil HCl on the aforementioned indices were also observed. The rat memories of the platform quadrants in the blank, sham and donepezil HCl groups were improved compared with those of the rats in the model group. The ratio of swim distance in the fourth platform quadrant (l4) to the total swim distance (l total) for the model group rats (l4/l total) was significantly decreased compared with that for the blank and sham group rats. Following donepezil HCl treatment, the ratio of l4/l total significantly increased. AD modeling caused a significant decrease in the CAT and GSH-Px activities in the brain tissues of the rats. The CAT and GSH-Px activities in the AD model rats significantly increased following donepezil HCl treatment. Moreover, donepezil HCl treatment significantly decreased the AChE, APP and BACE1 mRNA expression levels and increased the ChAT expression levels. Therefore, donepezil HCl was able to significantly decrease learning and memory damage in a rat model of AD. PMID- 23023805 TI - Room-temperature hydrogen sensing with heteronanostructures based on reduced graphene oxide and tin oxide. AB - There's something in the air ... A nanocomposite consisting of well-dispersed SnO(2) and Pt nanoparticles on reduced graphene oxide (see the high-resolution TEM image) exhibited very high responses to hydrogen at concentrations between 0.5 and 3% in air, with response times of 3-7 s and recovery times of 2-6 s. The sensor was prepared by a straightforward microwave-assisted non-aqueous sol-gel approach. PMID- 23023806 TI - Ilizarov distraction and vascularized fibular osteocutaneous graft for postosteomyelitis skeletal deformity of the forearm. AB - The reconstruction of large skeletal defects secondary to osteomyelitis is a challenging problem. This paper reports on the treatment of bone defects caused by osteomyelitis of the radius using an Ilizarov distraction technique and a vascularized fibular graft. A 25-year-old man first presented with a right radial defect caused by osteomyelitis when he was 3 years old. His right forearm was shortened and angulated with a dislocation of the distal radio-ulnar joint. The defect in the radial shaft was noted on a radiograph. The reconstruction of his radial bone defect was performed in three separate operations. A two-stage Ilizarov application was performed. Ten months after this operation, the radial bone defect was reconstructed with a vascularized fibular osteocutaneous graft. The right radius was shortened by 10 mm due to the angulation in the distal fixation of the graft 14 years after surgery. Although limited motions of the right thumb extension and wrist supination were noted, other hand functions were adequately restored. The Ilizarov technique is an effective method for correcting distal radio-ulnar joint dislocations and shortened, angulated ulnar bones. The specific features of the vascularized fibular graft make it suitable for the bone reconstruction of large defects in the radius. PMID- 23023807 TI - Indications of microsurgery in soft tissue sarcomas. AB - Sarcomas are uncommon tumors and free-margin surgical resection remains the single most important treatment in the curative therapy of soft tissue sarcomas. Refinements in surgical techniques have led to increased function preservation and limb salvage. PATIENTS AND METHODS: The records of patients (n = 41) who underwent microsurgical soft tissue reconstruction subsequent to resection of soft tissue sarcoma during the period 1998 to 2010 were reviewed and compared with a general nonmicrosurgery group (n = 188) in relation to clinicopathological characteristics, surgical procedures, postoperative complications, time until start of adjuvant radiation, functional outcome (Toronto Extremity Salvage Score, TESS), local recurrence, free survival, and disease-specific survival. RESULTS: Forty-one patients (age range: 23 to 95 years) received a total of 42 free flaps. When compared with the general nonmicrosurgery group, these patients presented significant differences with regard to location, histological grade, and neoadjuvant treatments. Complications were encountered in 10 cases, including 3 patients with complete flap loss and 1 patient with partial flap loss; other complications were cervical fistulae, knee arthritis, nonconsolidation, and wound infection. Extremity salvage was achieved in 90% (19/21) of limb sarcomas, with these patients showing adequate postoperative ambulation (TESS 77 +/- 16) and adequate use of the upper extremity (TESS 66 +/- 26). Two patients underwent amputation after recurrence. Disease-specific survival rates at 5 and 10 years were 79.49% and 76.93%, respectively. CONCLUSION: The microsurgical repair of sarcoma defects is a reliable option that, though not free of complications, is necessary in selected cases such as patients receiving neoadjuvant treatments and those with head and neck location and high-grade tumors. The procedure enables both adequate oncosurgical resection and function preservation. Our microsurgical sarcoma reconstruction data, based on an observation period of 12 years and presenting the results of 42 free tissue transfers in 41 patients, adds further evidence to the previously published smaller series. PMID- 23023808 TI - Usefulness of Harmonic Focus during anterolateral thigh flap elevation. AB - Meticulous hemostasis and careful ligation of branches are necessary for pedicle dissection during flap elevation. The aim of this study was to evaluate the effectiveness of the Harmonic Focus handpiece (Ethicon Endo-Surgery, Inc., Blue Ash, Cincinnati, OH, USA) in reducing operation time, bleeding volume, and volume of postoperative drainage during anterolateral thigh flap elevation. Ten patients requiring flap elevation were divided into two groups: (1) Harmonic Focus group (three men, two women), and (2) control group (three men, two women). Operating time was found to be lower in the Harmonic Focus group than in the control group. Bleeding volume and postoperative drainage volume were nearly identical in the Harmonic Focus group and the control group, and the number of silk ligatures was significantly lower in the Harmonic Focus group compared with the control group. Although somewhat costly, the Harmonic Scalpel with the Harmonic Focus handpiece is advantageous for flap elevation, and it is likely that Harmonic Scalpel use will increase in plastic surgery. PMID- 23023809 TI - Functional results of limb salvage in below-knee type III C open fractures or traumatic amputations. AB - This study presents the surgical and functional outcomes of below-knee total leg amputation and Gustilo type III C open fracture cases that were considered appropriate for salvage treatment according to a more proactive approach, despite being candidates for amputation according to the current scoring systems. Nineteen patients (21 legs) underwent replantation-revascularization surgery. At least Chen Grade II functional level was the aim. A limb salvage operation was performed in 21 legs in 19 patients (18 male, 1 female). The mean age was 28.5 years (range: 11 to 42 years). Six legs in four patients presented with total amputation, and 15 legs in 15 patients had Gustilo Type III C open fractures. A successful replantation/revascularization was performed in 20 legs, with a Chen Grade I and Grade II functional outcome in 3 and 17 legs, respectively. None of these patients were eligible for salvage operation according to currently used scoring systems. Limb-preserving surgery performed upon the assessment of local and general conditions of the patients with traumatic below-knee amputations or Gustilo Type III C open fractures seems to be a viable therapeutic option that can serve to achieve Chen Grade II functional level in most patients. PMID- 23023810 TI - Effects of recombinant human bone morphogenic protein-2 and human bone marrow derived stromal cells on in vivo bone regeneration of chitosan-poly(ethylene oxide) hydrogel. AB - In vivo bone regeneration of chitosan-poly(ethylene oxide) (PEO) hydrogel in rat carlvarial defects was evaluated by using both human bone marrow-derived stromal cells (hMSCs) and recombinant human bone marrow protein-2 (rhBMP-2) for 4 and 8 weeks. In situ chitosan-PEO hydrogel was fabricated by mixing the precursor solutions of both chitosan-acrylate and PEO-thiol. Fabrication of the injectable hydrogels was modulated from within a minute to hours by controlling the temperature and pHs of the precursor solution. Gel swellings were dependent on the conditions of pHs and temperatures of the precursor solutions, showing higher gel swelling in basic water than in either acidic or neutral water. The compression strengths and in vitro degradation of hydrogels were also evaluated by controlling the concentrations of both precursor solutions and lysozyme, respectively, by referencing to the morphology of the control hydrogel with no enzyme added. Hydrogels showed sustained release of rhodamine-B over time. After implantation of the injectable hydrogels in rat calvarial defects for 4 and 8 weeks, in vivo bone regenerations were compared with by evaluating the degrees of new bone formations with Soft X-ray, microcomputed tomography, and histological stainings of hematoxylin and eosine Y and Masson's trichrome. Degrees of in vivo bone regeneration were controlled by encapsulating in advance either hMSCs, rhBMP 2, or both in the precursor solutions of the hydrogel. The defect implanted with hydrogel only showed higher amount of bone tissue regeneration than that of the control defect site. The defect sites with hydrogel containing both hMSCs and rhBMP-2 demonstrated highest amount of bone tissue regeneration among the samples. PMID- 23023811 TI - Brain-derived neurotrophic factor stimulates proliferation and differentiation of neural stem cells, possibly by triggering the Wnt/beta-catenin signaling pathway. AB - Brain-derived neurotrophic factor (BDNF) has critical functions in promoting survival, expansion, and differentiation of neural stem cells (NSCs), but its downstream regulation mechanism is still not fully understood. The role of BDNF in proliferation and differentiation of NSCs through Wnt/beta-catenin signaling was studied via cell culture of cortical NSCs, Western blotting, immunocytochemistry, and TOPgal (Wnt reporter) analysis in mice. First, BDNF stimulated NSC proliferation dose dependently in cultured neurospheres that exhibited BrdU incorporation and neuronal and glial differentiation abilities. Second, BDNF effectively enhanced cell commitment to neuronal and oligodendrocytic fates, as indicated by increased differentiation marker Tuj-1 (neuronal marker), CNPase (oligodendrocyte marker), and neuronal process extension. Third, BDNF upregulated expression of Wnt/beta-catenin signaling (Wnt1 and free beta-catenin) molecules. Moreover, these promoting effects were significantly inhibited by application of IWR1, a Wnt signaling-specific blocker in culture. The TOPgal mouse experiment further confirmed BDNF-triggered Wnt signaling activation by beta-gal labeling. Finally, an MEK inhibition experiment showed a mediating role of the microtubule-associated protein kinase pathway in BDNF-triggered Wnt/beta-catenin signaling cascades. This study overall has revealed that BDNF might contribute to proliferation and neuronal and oligodendrocytic differentiation of NSCs in vitro, most possibly by triggering the Wnt/beta-catenin signaling pathway. Nevertheless, determining the exact cross talk points at which BDNF might stimulate Wnt/beta-catenin signaling pathway in NSC activity requires further investigation. PMID- 23023812 TI - Comparison of reliability, validity, and responsiveness of the mini-BESTest and Berg Balance Scale in patients with balance disorders. AB - BACKGROUND: Recently, a new tool for assessing dynamic balance impairments has been presented: the 14-item Mini-BESTest. OBJECTIVE: The aim of this study was to compare the psychometric performance of the Mini-BESTest and the Berg Balance Scale (BBS). DESIGN: A prospective, single-group, observational design was used in the study. METHODS: Ninety-three participants (mean age=66.2 years, SD=13.2; 53 women, 40 men) with balance deficits were recruited. Interrater (3 raters) and test-retest (1-3 days) reliability were calculated using intraclass correlation coefficients (ICCs). Responsiveness and minimal important change were assessed (after 10 sessions of physical therapy) using both distribution-based and anchor based methods (external criterion: the 15-point Global Rating of Change [GRC] scale). RESULTS: At baseline, neither floor effects nor ceiling effects were found in either the Mini-BESTest or the BBS. After treatment, the maximum score was found in 12 participants (12.9%) with BBS and in 2 participants (2.1%) with Mini-BESTest. Test-retest reliability for total scores was significantly higher for the Mini-BESTest (ICC=.96) than for the BBS (ICC=.92), whereas interrater reliability was similar (ICC=.98 versus .97, respectively). The standard error of measurement (SEM) was 1.26 and the minimum detectable change at the 95% confidence level (MDC(95)) was 3.5 points for Mini-BESTest, whereas the SEM was 2.18 and the MDC(95) was 6.2 points for the BBS. In receiver operating characteristic curves, the area under the curve was 0.92 for the Mini-BESTest and 0.91 for the BBS. The best minimal important change (MIC) was 4 points for the Mini-BESTest and 7 points for the BBS. After treatment, 38 participants evaluated with the Mini-BESTest and only 23 participants evaluated with the BBS (out of the 40 participants who had a GRC score of >= 3.5) showed a score change equal to or greater than the MIC values. LIMITATIONS: The consecutive sampling method drawn from a single rehabilitation facility and the intrinsic weakness of the GRC for calculating MIC values were limitations of the study. CONCLUSIONS: The 2 scales behave similarly, but the Mini-BESTest appears to have a lower ceiling effect, slightly higher reliability levels, and greater accuracy in classifying individual patients who show significant improvement in balance function. PMID- 23023813 TI - Effect of exercise and weight loss in people who have hip osteoarthritis and are overweight or obese: a prospective cohort study. AB - BACKGROUND: Osteoarthritis (OA) is the most common joint disorder in the world and is recognized as a substantial source of disability. For people with OA of the knee, exercise in combination with weight loss is a proven, effective, conservative treatment option, yet evidence is lacking for people with hip OA. OBJECTIVE: The aim of this study was to obtain preliminary evidence of the effect of a program of exercise in combination with weight loss on physical function in people who have hip OA and are overweight or obese. DESIGN: This investigation was a prospective cohort study. METHODS: Thirty-five people who were 25 years or older, had clinical and radiological evidence of hip OA, and were overweight or obese (body mass index of >25 kg/m(2)) were included. They participated in an 8 month program of exercise in combination with weight loss. A body mass index of 40 kg/m(2) was used as the upper limit. The primary outcome was self-reported physical function, as measured with a subscale of the Western Ontario and McMaster Universities Osteoarthritis Index. Secondary outcome measures included pain and walking tests as quantitative measures of function. RESULTS: Participation in the combination program resulted in a 32.6% improvement in self reported physical function after 8 months, a finding that could be considered clinically relevant. Significant improvements also were seen in pain and on walking tests. LIMITATIONS: The lack of a control group was a limitation of this study. CONCLUSIONS: This appears to be the first study investigating the effect of exercise and weight loss as a combination treatment in people with hip OA. The results provide preliminary evidence that this combination treatment is effective in people with hip OA. PMID- 23023814 TI - Setup of a novel biofeedback prototype for sensorimotor control of the hand and preliminary application in patients with peripheral nerve injuries. AB - BACKGROUND: Biofeedback training is widely used for rehabilitative intervention in patients with central or peripheral nervous impairment to train correct movement patterns; however, no biofeedback apparatus is currently available to correct pinch force ratios for patients with sensory deficiencies. DESIGN: A cross-sectional and longitudinal design was used in an observational measurement study for establishing a prototype and to determine the effects of biofeedback intervention, respectively. OBJECTIVE: This study aimed to develop a computerized evaluation and re-education biofeedback (CERB) prototype for application in clinical settings. METHODS: A CERB prototype was developed integrating pinch apparatus hardware, a biofeedback user-controlled interface, and a data processing/analysis interface to detect momentary pinch performances in 79 people with normal hand sensation. Nine patients with hand sensory impairments were recruited to investigate the effects of training hand function with the CERB prototype. RESULTS: Hand dominance, pinch pattern, and age significantly affected the peak pinch force and force ratio for lifting a 480-g object with a steel surface. In the case of the 79 volunteers with normal hand sensation, hand dominance affected the time lag between peak pinch force and maximum load; however, it was unaffected by pinch pattern or age. Training with the CERB prototype produced significant improvements in force ratio and better performance in the pin insertion subtests, although the results for both 2-point discriminative and Semmes-Weinstein monofilament tests did not change significantly. LIMITATIONS: The intervention findings are preliminary. CONCLUSIONS: This study developed a conjunct system suited for evaluating and restoring sensorimotor function for patients with impaired hand sensibility. The results from the participants with normal hand sensation could serve as a reference database for comparison with patients with nerve injuries. PMID- 23023815 TI - Recovery of chemical estimates by field inhomogeneity neighborhood error detection (REFINED): fat/water separation at 7 tesla. AB - PURPOSE: To reduce swaps in fat-water separation methods, a particular issue on 7 Tesla (T) small animal scanners due to field inhomogeneity, using image postprocessing innovations that detect and correct errors in the B0 field map. MATERIALS AND METHODS: Fat-water decompositions and B0 field maps were computed for images of mice acquired on a 7T Bruker BioSpec scanner, using a computationally efficient method for solving the Markov Random Field formulation of the multi-point Dixon model. The B0 field maps were processed with a novel hole-filling method, based on edge strength between regions, and a novel k-means method, based on field-map intensities, which were iteratively applied to automatically detect and reinitialize error regions in the B0 field maps. Errors were manually assessed in the B0 field maps and chemical parameter maps both before and after error correction. RESULTS: Partial swaps were found in 6% of images when processed with FLAWLESS. After REFINED correction, only 0.7% of images contained partial swaps, resulting in an 88% decrease in error rate. Complete swaps were not problematic. CONCLUSION: Ex post facto error correction is a viable supplement to a priori techniques for producing globally smooth B0 field maps, without partial swaps. With our processing pipeline, it is possible to process image volumes rapidly, robustly, and almost automatically. PMID- 23023816 TI - Super gas barrier and selectivity of graphene oxide-polymer multilayer thin films. AB - Super gas barrier thin films, fabricated with layer-by-layer assembly of polyethylenimine and graphene oxide, exhibit significantly reduced oxygen and carbon dioxide transmission rates. This thin film's nanobrick wall structure also provides high gas selectivity for hydrogen. PMID- 23023817 TI - Analysis of the essential oil of large cardamom (Amomum subulatum Roxb.) growing in different agro-climatic zones of Himachal Pradesh, India. AB - BACKGROUND: The aim of the present study was to investigate variations in the chemical composition of the essential oil from seeds of large cardamom grown at different altitudes in Himachal Pradesh, India. The composition of the essential oil was determined by gas chromatography (GC), gas chromatography-mass spectrometry (GC-MS) and gas chromatography-olfactometry (GC-O). RESULTS: The oil components showed qualitative and quantitative variations in the composition. GC and GC-MS analysis led to the identification of 55 compounds representing 98% of total oil. Major components in the oil were 1,8-cineole, alpha-terpineol, DL limonene, nerolidol, 4-terpineol, delta-terpineol, delta-3-carene, beta-myrcene, germacrene D, alpha-terpinene and longifolenaldehyde. The oil yields obtained were 9.8-19.5 g kg(-1). Cardamom oil from Himachal Pradesh was found to contain new compounds, viz. 4-terpineol, delta-3-carene, trans-sabinene hydrate, 1 phellandrene, alpha-terpinene, bicyclo-germacrene, isopinocarveol and ledenoxid II. alpha-Terpenyl acetate, the major constituent of small cardamom, was also detected in the oil of large cardamom grown in Himachal Pradesh. Application of aroma extract dilution analysis revealed 35 compounds having aroma impact with the flavour dilution factor ranging from 2 to 1024, and 34 of these compounds were identified. The five most intense aromatic components are dl-limonene, 1,8 cineole, beta-myrcene, alpha-pinene, alpha-basabolol. This is the first time that the characterisation of odour-active compounds has been carried out on large cardamom. CONCLUSION: The presence of 4-terpineol, delta-3-carene, trans-sabinene hydrate, 1-phellandrene, alpha-terpinene, 1-terpineol, bicyclogermacrene, isopinocarveol, ledenoxid-II, longifolenaldehyde and alpha-terpenyl acetate make the aroma of the oil different from large cardamom oil of Sikkim and could offer potential as a new food flavour. PMID- 23023819 TI - A path analysis of the variables related to the quality of life of mothers with disabled children in Korea. AB - This study examines how different variables affect the quality of life of mothers of children with disabilities. We attempted to identify the relationship between child variables (age and whether the child has single or multiple disabilities), economic variables (monthly income and average monthly treatment cost), mother related variables (parenting stress) and social variables (social support) as predictors of the quality of life of mothers of children with disabilities, and the path along which these variables affect their quality of life. The dataset comprised 160 mothers of children with disabilities, who resided in Seoul city and Gyeonggi province. The participants answered questions related to their general information, quality of life, social support and parenting stress. The data were analysed using SPSS 17.0 and AMOS 16.0. We found that social support not only influences the quality of life through parenting stress but also is a direct factor. We also found that both whether a child had single or multiple disabilities and the average monthly treatment cost were significant factors that influenced the parent's quality of life indirectly through parenting stress. Moreover, we concluded that whereas the age of children with disabilities is only a direct impact on the mother's quality of life, monthly income has a direct influence on both parenting stress and quality of life separately, but it does not directly influence quality of life through parenting stress. In our opinion, this is the first study that has conducted a holistic analysis of the quality of life of Korean mothers of children with disabilities by considering a range of variables. PMID- 23023818 TI - Cherry consumption and decreased risk of recurrent gout attacks. AB - OBJECTIVE: To study the relationship between cherry intake and the risk of recurrent gout attacks among individuals with gout. METHODS: We conducted a case crossover study to examine the associations of a set of putative risk factors with recurrent gout attacks. Individuals with gout were prospectively recruited and followed up online for 1 year. Participants were asked to provide the following information regarding gout attacks: the onset date of the gout attack, symptoms and signs, medications (including antigout medications), and exposure to potential risk factors (including daily intake of cherries and cherry extract) during the 2-day period prior to the gout attack. We assessed the same exposure information over 2-day control periods. We estimated the risk of recurrent gout attacks related to cherry intake using conditional logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Our study included 633 individuals with gout. Cherry intake over a 2-day period was associated with a 35% lower risk of gout attacks compared with no intake (multivariate OR 0.65 [95% CI 0.50-0.85]). Cherry extract intake showed a similar inverse association (multivariate OR 0.55 [95% CI 0.30-0.98]). The effect of cherry intake persisted across subgroups stratified by sex, obesity status, purine intake, alcohol use, diuretic use, and use of antigout medications. When cherry intake was combined with allopurinol use, the risk of gout attacks was 75% lower than during periods without either exposure (OR 0.25 [95% CI 0.15-0.42]). CONCLUSION: These findings suggest that cherry intake is associated with a lower risk of gout attacks. PMID- 23023820 TI - Facile synthesis of porous ZnO-NiO composite micropolyhedrons and their application for high power supercapacitor electrode materials. AB - Porous ZnO-NiO composite micropolyhedrons have been successfully synthesized by calcination of mixed oxalate (Zn(0.9)Ni(0.1)(C(2)O(4))(2).nH(2)O) precursors in air. The oxalate precursor micropolyhedrons were synthesized by a mild chemical precipitation method without any template or surfactant, and found to have a relatively low decomposition temperature. We have successfully explored the application of the resulting porous ZnO-NiO composite micropolyhedrons as electrochemical capacitors. Electrochemical study shows that the obtained ZnO-NiO composites under different conditions have different electrochemical supercapacitor properties in 3.0 or 1.0 M KOH solutions. The porous ZnO-NiO micropolyhedron material (P1) obtained by calcination of the oxalate precursor at 400 degrees C has a large specific capacitance 649.0 F g(-1) in 3.0 M KOH solution and could maintain 99.1% of this value after 400 cycles at 5.8 A g(-1). Even at a high current density of 58.0 A g(-1), the specific capacitance of P1 is 395.2 F g(-1). PMID- 23023821 TI - Curcumin induces apoptosis of triple-negative breast cancer cells by inhibition of EGFR expression. AB - Curcumin is the major component of the spice turmeric, extracted from the rhizomes of the plant Curcuma longa. It exerts a number of therapeutic effects, including the inhibition of cancer cell proliferation. However, the anti carcinogenic mechanism of curcumin has not been fully elucidated. Triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/EGFR2), is an aggressive breast cancer phenotype with a poor prognosis. In this study, we investigated the effects of curcumin on triple-negative breast cancer cells and the possible molecular mechanisms. The MDA-MB-231 TNBC cells were treated with curcumin, the growth inhibition ratio of the cells was measured by MTT assay, apoptosis was detected by flow cytometry and the expression levels of extracellular regulated protein kinase (ERK1/2), pERK1/2, EGFR and pEGFR were detected by western blotting. After treatment with different concentrations of curcumin, the growth inhibition rates of the MDA-MB-231 breast cancer cells of the 30 umol/ml curcumin-treated group were significantly different from those of the other groups. The level of apoptosis of the curcumin-treated group (26.34%) was significantly different from that of the control group (2.76%). The expression levels of pERK1/2 and pEGFR in the curcumin-treated group were significantly decreased compared with those of the control group. These results indicate that curcumin is able to inhibit the proliferation of TNBC cells. Inhibition of the EGFR signaling pathway is the likely underlying molecular mechanism. PMID- 23023822 TI - Adaptive averaging applied to dynamic imaging of the soft palate. AB - Achieving sufficient temporal and spatial resolution with adequate signal-to noise ratio (SNR) in dynamic soft palate imaging is challenging. Triggered acquisitions require repeated reproducible speech samples, and while real-time imaging is more reliable, it may lack SNR. Adaptive averaging was implemented to improve SNR in nongated imaging during repetition of a speech task. Similar images were identified using localized cross-correlation before averaging. Adaptive averaging was applied to the soft palate region of images from six volunteers and one patient acquired with various sequences. In volunteers, soft palate SNR increased by 53 +/- 17% with four averages. The additional SNR was used to enable reduced slice thickness in two example subjects. Adaptive averaging was also compared to pseudotriggered images in one example and, in another, it was applied to an unrepeated speech task. In a patient with a repaired cleft palate, the technique was used to demonstrate residual velopharyngeal insufficiency. This initial work demonstrates that increased temporal or spatial resolution may be traded for reduced SNR, which can be recovered using adaptive averaging. This will be a valuable tool in assessing velopharyngeal function, particularly in pediatric patients where cooperation may make gated studies difficult or when their head sizes require increased spatial resolution while maintaining temporal resolution. PMID- 23023823 TI - Nursing's role in courage development in patients facing complications of diabetes. AB - The purpose of this study was to explore the experience of nurses in relation to courage development in patients with disabling complications of diabetes. The phenomenon of courage has been explored in philosophy, theology, literature, and other fields of inquiry rooted in the humanities. Nursing inquiry has not often been directed toward an exploration of courage, although coping, compassion, caring, and other experiences integral to the nurse-patient relationship have been examined. The holistic view of the cascading effect of complications on the individual patient is often overlooked. This qualitative study used phenomenological inquiry and included face-to-face interviews of nurses to explore their experience in assisting patients in the development of courage. The experience of courage is investigated as it relates to a specific group of patients who have complications of diabetes. Four categories representing the unique opportunities for courage development by nurses were generated. These categories included education, advocacy, relationship building, and humanization. Each category described nursing intentions and actions and taken together formed an essential structure of courage development. Conclusions indicated that nurses recognize and are able to describe their role in courage development. Implications for improved health through deliberate caring nursing interventions, aimed at courage development, are presented. PMID- 23023824 TI - Comparative analysis of two musical genres within a multisensory environmental intervention. AB - PURPOSE: The purpose of this study was to determine if there were any differences in the behavioral responses of persons with dementia while listening to nonreligious and religious music within a multisensory environment. RESEARCH DESIGN: A within-subjects, repeated measures design was used. METHOD: Participants were exposed to both musical genres during multiple sessions over a 4-week period. Neuropsychiatric symptoms were recorded before and after the musical intervention. Behavioral responses to the music were recorded while listening to the music. FINDINGS: No significant difference was found between the numbers of neuropsychiatric behaviors observed before and after the participants listened to the nonreligious and religious music. A significant difference was found between the musical interventions as a whole and the number of agitated behaviors before and after intervention. No significant difference was found in the observed behavioral responses with the nonreligious and religious music. CONCLUSIONS: Music can be a useful intervention to reduce neuropsychiatric symptoms in persons with dementia. PMID- 23023825 TI - Pectoral girdle and fin anatomy of Gogonasus andrewsae Long, 1985: implications for tetrapodomorph limb evolution. AB - Recently discovered material has yielded new information on the pectoral girdle and fin endoskeleton of Gogonasusandrewsae (Frasnian Gogo Formation, Kimberley Region, Western Australia). These elements permit the first comprehensive description of the anocleithrum, cleithrum, scapulocoracoid, and lepidotrichia. New autapomorphies of Gogonasus include a square exposed region on the supracleithrum, an unusual knob-like process on the scapulocoracoid, a relatively small entepicondyle, and lepidotrichia with I-beam-shaped cross sections. Several poorly ossified regions on the scapulocoracoid and humerus indicate an early ontogenetic state, as with other immature tetrapodomorph fish specimens. A phylogenetic analysis indicates a more stemward position for Gogonasus in a weakly supported clade with other "osteolepidid" taxa, compared to other recent studies placing Gogonasus crownward of osteolepidid fishes and the Tristichopteridae, as the sister taxon to the "Elpistosteglia" + Tetrapoda. A phylogenetic position among megalichthyid fishes is suggested for Sterropterygion, while radiographs of the megalichthyid Cladarosymblema show a scythe-like radius terminating distally with that of the intermedium. New data on the scapulocoracoid of the rhizodontid Barameda reveals a coroacoid crest and small supraglenoid foramen. PMID- 23023826 TI - Characterization and utility of N-unsubstituted imines synthesized from alkyl azides by ruthenium catalysis. PMID- 23023829 TI - Enhanced catalytic activity from proteinoid microspheres. AB - Creating materials that are capable of catalyzing enzymatic reactions could be important to the treatment of both acute and chronic wounds, as well as other topical diseases. As a first step in the design of catalytic biomaterials, a new class of proteinoid microsphere (PM), that includes amino acids found in phosphatase enzyme active sites, has been constructed. This material can significantly enhance catalytic activity for phosphoester hydrolysis, with observed specific activity increases between 35- and 55-fold. Further specific activity increases occur when metal cations, notably iron or zinc, are added to the PMs. Specific activity increases between 140- and 300-fold for these metal modified systems are measured. The phosphatase activity increase is demonstrated for both aromatic phosphate esters as well as the high-energy phosphate bond of adenosine triphosphate. PMs bind substrate heterogeneously on their surfaces in an enthalpically driven reaction that is defined by an overall favorable free energy, but unfavorable entropy. The catalytic PMs have been successfully blended with polyolefin foam and extruded with PLA. These materials remain fully active. PMID- 23023830 TI - Pulsed laser ablation based direct synthesis of single-wall carbon nanotube/PbS quantum dot nanohybrids exhibiting strong, spectrally wide and fast photoresponse. AB - Pulsed laser ablation for the direct synthesis of single-wall carbon nanotube/PbS quantumdot(SWCNT/PbS-QD) nanohybrids is demonstrated. The latitude of the developed pulsed laser deposition process permits not only the control of the size of the PbS-QDs but also the straightforward integration of these novel SWCNT/PbS-QD nanohybrids into photoconductive (PC) devices. Thus, by optimizing the nanohybrid characteristics, PC devices exhibiting not only fast but also strong photoresponse (as high as 1350% at 405 nm) are achieved. PMID- 23023831 TI - Oil accumulation in intact olive fruits measured by near infrared spectroscopy acousto-optically tunable filter. AB - BACKGROUND: A field experiment was conducted to test the reliability of the near infrared spectroscopy (NIR)-acousto-optically tunable filter (AOTF) method to measure mesocarp oil content in vivo against nuclear magnetic resonance (NMR) determinations using three different olive cultivars at different stages of ripening. RESULTS: In the partial least squares model carried out for the cultivar 'Arbequina', the coefficient of determination in calibration (R(2)c) was 0.991, while the coefficient of determination in cross-validation (R(2)cv) was 0.979. For the cultivar 'Frantoio' the indexes were 0.982 and 0.971, respectively; while for the cultivar 'Leccino' R(2)c was 0.977 and R(2)cv was 0.965. Finally, for the combined model (sum of the three varieties) these indexes were 0.921 and 0.903, respectively. The residual predictive deviation (RPD) ratio was insufficient for the predictive model of cultivar 'Leccino' only (1.98), whereas in the other cases the RPD ratios were completely sufficient, within the estimation range over 2.5-3 (2.61 in the global model, and 4.23 in the cultivar 'Frantoio'), or in describing a large capacity with values greater than 5, as in the cultivar 'Arbequina' (9.58). CONCLUSION: NIR-AOTF spectroscopy proved to be a novel, rapid and reliable method to monitor the oil accumulation process in intact olive fruits in the field. The innovative approach of coupling NIR and NMR technologies opens up new scenarios for determining the optimal time for harvesting olive trees to obtain maximum oil production. PMID- 23023833 TI - Efficient and convenient palladium-catalyzed amination of allylic alcohols with N heterocycles. PMID- 23023832 TI - MRI assessment of percutaneous ablation of liver tumors: value of subtraction images. AB - PURPOSE: To evaluate the value of subtraction images when using MRI to assess liver tumors treated with percutaneous ablation. MATERIALS AND METHODS: Following percutaneous ablation of 35 liver tumors, two abdominal radiologists, blinded to outcomes, independently reviewed follow-up MRI examinations for tumoral enhancement suggestive of residual/recurrent tumor and rated their confidence level. After one year, the readers reviewed the same examinations with added subtraction images. Accuracy of the detection of residual/recurrent tumor and contrast-to-noise ratios (CNR; for tumoral enhancement-to-liver, tumoral enhancement-to-ablation zone, and ablation zone-to-liver) were calculated with and without subtraction images and compared using Wilcoxon signed rank test. Interobserver variability was computed using Kappa (kappa) statistics. RESULTS: Residual/recurrent tumor was present in 8 (23.5%) of 34 tumors. Accuracy of detecting residual/recurrent tumor with subtraction images and interobserver agreement (kappa = 0.72, good) were better than accuracy of detecting residual/recurrent tumor and interobserver agreement (kappa = 0.57, moderate) of enhanced MR images without subtraction. Mean CNR of subtraction images was significantly higher than that of enhanced MR images for tumoral enhancement-to liver (0.2 +/- 5 versus 11.6 +/- 14.4, P = 0.03), tumoral enhancement-to-ablation zone (10.1 +/- 12.5 versus 34.4 +/- 29.4, P = 0.02), and ablation zone-to-liver (11.8 +/- 13.3 versus 102.5 +/- 238.4, P = 0.03). CONCLUSION: When using MRI, subtraction images help both detect and exclude residual/recurrent tumor following percutaneous liver ablations. PMID- 23023834 TI - Sweet entanglements--protein:glycan interactions in two HIV-inactivating lectin families. AB - Structures and sugar binding by members of two lectin families, Cyanovirin-N homolog (CVNH) and Oscillatoria Agardhii agglutinin homolog (OAAH), were determined to elucidate the basis for recognition of high-mannose glycans on the HIV envelope glycoprotein gp120. We solved NMR solution and/or crystal structures for several lectins and delineated their carbohydrate specificity by array screening and direct NMR titrations. Both families recognize different epitopes on high-mannose glycans, namely, Manalpha(1-2)Man units at the end of the D1 and D3 arms and alpha3,alpha6-mannopentaose at the central branch point of Man-8 or Man-9 for CVNH and OAAH lectins, respectively. PMID- 23023835 TI - Chemical composition, sources, and deposition fluxes of water-soluble inorganic ions obtained from precipitation chemistry measurements collected at an urban site in northwest China. AB - Precipitation samples were collected at an urban site in Xi'an, northwest China during March to November in 2009 and were then analyzed to determine the pH and concentrations of water-soluble inorganic ions (Na(+), NH(4)(+), K(+), Mg(2+), Ca(2+), SO(4)(2-), NO(3)(-), Cl(-), and F(-)) in precipitation. The pH of precipitation ranged from 4.1 to 7.6 for all of the samples with an annual volume weighted mean of 6.4. While a large portion of the precipitation events were weakly acidic or alkaline, around 30% of the precipitation events in the autumn were strongly acidic. Precipitation events with air masses from the northeast and the southeast were weakly acidic while those with air masses from the northwest and the southwest were alkaline. SO(4)(2-), Ca(2+), NH(4)(+), and NO(3)(-) were dominant ions in the precipitation, accounting for 37%, 25%, 18%, and 9%, respectively, of the total analyzed ions. Ca(2+) and NH(4)(+) were found to be the major neutralizers of precipitation acidity; however, the contribution of Mg(2+), although much lower than those of Ca(2+) and NH(4)(+), was important, in many cases, in changing the precipitation from weakly acidic to weakly alkaline. Enrichment factor analysis confirmed that SO(4)(2-) and NO(3)(-) were produced from anthropogenic sources, Ca(2+), K(+), and 80% Mg(2+) were from crustal sources, and Na(+), Cl(-), and ~20% of Mg(2+) were from marine sources. The annual wet depositions were estimated to be 3.5 t km(-2) per year for sulfur; 2.3 t km(-2) per year for nitrogen, of which 0.8 t km(-2) per year was oxidized nitrogen and 1.5 t km(-2) per year was reduced nitrogen; and 3.0 t km(-2) per year for Ca(2+). PMID- 23023836 TI - Dysfunctional remembered parenting in oncology outpatients affects psychological distress symptoms in a gender-specific manner. AB - Evidence suggests that gender differences appear in a variety of biological and psychological responses to stress and perhaps in coping with acute and chronic illness as well. Dysfunctional parenting is also thought to be involved in the process of coping with stress and illness; hence, the present study aimed to verify whether dysfunctional remembered parenting would influence psychological distress in a gender-specific manner in patients suffering from cancer. Patients attending an outpatient oncology clinic completed the Remembered Relationships with Parents (RRP), Hospital Anxiety and Depression and Spielberger's State-Trait Anxiety Inventory scales and the National Cancer Center Network Distress Thermometer. Although no baseline gender differences were detected, a multivariate analysis confirmed that anxiety and depression symptoms of men and women suffering from cancer are differentially affected by the RRP Control and Alienation scores. Women with remembered parental alienation and overprotection showed significantly more anxiety symptoms than men, whereas men were more vulnerable to remembered alienation than overprotection with regard to the Distress Thermometer scores. These results suggest that remembered dysfunctional parenting is crucially, and in a gender-specific manner, involved in the coping strategy adopted by male and female cancer patients. PMID- 23023837 TI - The prescription drug misuse and abuse epidemic. PMID- 23023838 TI - Rising women. PMID- 23023839 TI - Risk models to improve safety of dispensing high-alert medications in community pharmacies. AB - OBJECTIVES: To determine whether sociotechnical probabilistic risk assessment can create accurate approximations of detailed risk models that describe error pathways, estimate the incidence of preventable adverse drug events (PADEs) with high-alert medications, rank the effectiveness of interventions, and provide a more informative picture of risk in the community pharmacy setting than is available currently. DESIGN: Developmental study. SETTING: 22 community pharmacies representing three U.S. regions. PARTICIPANTS: Model-building group: six pharmacists and three technicians. Model validation group: 11 pharmacists; staff at two pharmacies observed. INTERVENTION: A model-building team built 10 event trees that estimated the incidence of PADEs for four high-alert medications: warfarin, fentanyl transdermal systems, oral methotrexate, and insulin analogs. MAIN OUTCOME MEASURES: Validation of event tree structure and incidence of defined PADEs with targeted medications. RESULTS: PADEs with the highest incidence included dispensing the wrong dose/strength of warfarin as a result of data entry error (1.83/1,000 prescriptions), dispensing warfarin to the wrong patient (1.22/1,000 prescriptions), and dispensing an inappropriate fentanyl system dose due to a prescribing error (7.30/10,000 prescriptions). PADEs with the lowest incidence included dispensing the wrong drug when filling a warfarin prescription (9.43/1 billion prescriptions). The largest quantifiable reductions in risk were provided by increasing patient counseling (27-68% reduction), conducting a second data entry verification process during product verification (50-87% reduction), computer alerts that can't be bypassed easily (up to 100% reduction), opening the bag at the point of sale (56% reduction), and use of barcoding technology (almost a 100,000% increase in risk if technology not used). Combining two or more interventions resulted in further overall reduction in risk. CONCLUSION: The risk models define thousands of ways process failures and behavioral elements combine to lead to PADEs. This level of detail is unavailable from any other source. PMID- 23023841 TI - Pharmacist Assisted Medication Program Enhancing the Regulation of Diabetes (PAMPERED) study. AB - OBJECTIVES: To demonstrate that pharmacists working with physicians and other providers in an ambulatory care setting can improve glucose, blood pressure, and lipid control for patients with type 2 diabetes and to report patient adherence to screening and general preventive measures. DESIGN: Prospective, randomized, clinical practice study. SETTING: Burlington, MA, between January 2001 and August 2003. PATIENTS: 164 patients patients with type 2 diabetes older than 18 years with glycosylated hemoglobin (A1C) greater than 8%. INTERVENTION: Pharmacist patient clinic visits included obtaining a comprehensive medication review; performing targeted physical assessment; ordering laboratory tests; reviewing, modifying, and monitoring patients' medication therapy and providing detailed counseling on all therapies; facilitating self-monitoring of blood glucose; and providing reinforcement of dietary guidelines and exercise. MAIN OUTCOME MEASURE: Effect of clinical pharmacists working with physicians in an ambulatory setting on health measures (e.g., A1C, blood pressure, cholesterol) of patients with diabetes. RESULTS: Baseline characteristics were similar between the two groups. After 1 year, significant improvements occurred for A1C and low-density lipoprotein (LDL) cholesterol in the intervention group compared with the control group (A1C, 7.7% vs. 8.4%; LDL, 93.7 vs. 105.1 mg/dL; P < 0.05). Systolic blood pressure improved for all study patients without a difference between the two groups. Diastolic blood pressure improved significantly in the intervention group compared with the control group (73.4 mm Hg vs. 77.6 mm Hg, P < 0.05). Significantly more intervention patients were screened for retinopathy, neuropathy, and microalbuminuria than control patients ( P < 0.05). CONCLUSION: For all indices measured, this study demonstrated that collaborative diabetes management with a clinical pharmacist can improve overall care. PMID- 23023840 TI - Safety-focused medication therapy management: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of a medication therapy management (MTM) intervention on adverse drug events (ADEs), health care visits, and drug-related problems (DRPs). DESIGN: Randomized, controlled, clinical trial. SETTING: Academic medical center community pharmacies and family medicine clinics at three U.S. sites between December 2007 and January 2010 PATIENTS: Individuals aged 65 years or older with three or more chronic illnesses, six or more prescription medications, and at risk for a DRP. INTERVENTION: At 0 and 3 months, pharmacists conducted comprehensive medication reviews and screened for and resolved DRPs through patient education and recommendations to physicians. MAIN OUTCOME MEASURES: Frequency of ADEs reported by patients and confirmed by clinical algorithm, health care visits at 3 and 6 months, and number of DRPs, pharmacist recommendations, and medication discrepancies. RESULTS: 637 participants enrolled. No differences were observed in potential ADEs or health care visits among the usual care and MTM groups. DRPs declined in both MTM intervention groups over time. Physicians responded to 54.6% of pharmacist recommendations. Enhanced MTM patients had fewer medication list discrepancies than basic MTM patients (33.8% vs. 47.1%, P < 0.001). CONCLUSION: This specific design of MTM was associated with reduced DRPs but did not reduce potential ADEs or health care visits. PMID- 23023842 TI - Effect of social influences on pharmacists' intention to report adverse drug events. AB - OBJECTIVES: To identify the groups or individuals that influence pharmacists' decision making to report adverse drug events (ADEs), determine the differences in social influence or subjective norm between intenders and nonintenders, and determine the relationship between subjective norm toward reporting serious ADEs and practice and demographic characteristics. DESIGN: Nonexperimental cross sectional study. SETTING: Texas during June and July 2009. PARTICIPANTS: 1,500 Texas pharmacists. INTERVENTION: As part of a larger survey, 3 and 18 items were used to assess pharmacists' intentions and subjective norm, respectively, to report serious ADEs to the Food and Drug Administration (FDA). MAIN OUTCOME MEASURE: Pharmacists' subjective norm toward reporting serious ADEs. RESULTS: The survey had a response rate of 26.4% (n = 377). Most pharmacists intended to report serious ADEs that they would encounter (15.87 +/- 4.22 [mean +/- SD], possible range 3-21, neutral = 12). The mean subjective norm scores were moderately high and positive (28.75 +/- 9.38, 1-49, 16), indicating that the referents had a moderate influence on pharmacists regarding reporting serious ADEs to FDA. FDA had the greatest (34.82 +/- 12.16) and drug manufacturers the lowest (21.55 +/- 13.83) social influence. The most important salient referents (important others) in pharmacists' decisions to report serious ADEs were FDA, patients, pharmacy associations, pharmacy managers/bosses, and hospitals and hospital groups. Gender (female equals higher), pharmacists' years of experience (negative correlation), and knowledge of ADE reporting (positive correlation) were associated with subjective norm. CONCLUSION: Pharmacists had a moderately high subjective norm, suggesting that ADE reporting intentions is influenced by others and that the opinions of others are of great importance in pharmacists' intentions regarding ADE reporting. The main drivers of subjective norm were FDA, patients, pharmacy associations, and managers/bosses. PMID- 23023843 TI - Comprehensive medication reviews for elderly patients: findings and recommendations to physicians. AB - OBJECTIVES: To assess drug-related problems (DRPs) documented by specially trained community pharmacists during the Finnish comprehensive medication review (CMR) procedure and to describe the resulting interventions for home-dwelling and assisted-living primary care patients 65 years or older. METHODS: Retrospective analysis of applicable written CMR case reports for primary care patients 65 years or older by 26 community pharmacists attending a 1.5-year CMR accreditation training (174 patients recruited; 121 included in the analysis). The main outcome measures were DRPs and physicians' acceptance of pharmacists' recommendations. RESULTS: The pharmacists reported a total of 785 DRPs (average of 6.5/patient). DRPs were more common among home-dwelling patients (7.2) than those in the assisted-living setting (5.5; P = 0.014) but were similar in nature. Inappropriate drug choices were the most common DRPs (17% of DRPs), involving most often hypnotics and sedatives. Also, indications with no treatment were common (16%), particularly those associated with cardiovascular diseases and osteoporosis. Pharmacists made 649 recommendations, 55% (n = 360) of which were accepted by physicians without revision. In 51% of DRPs (n = 403), CMRs resulted in change of drug therapy; stopping a drug was the most common change. CONCLUSION: Specially trained pharmacists were able to identify DRPs among elderly primary care patients by using a CMR procedure, and more than one-half of the identified DRPs led to medication changes. The pharmacists' special knowledge of geriatric pharmacotherapy and access to clinical patient data were crucial for recognizing DRPs. PMID- 23023844 TI - The other yearly checkup: your Medicare drug plan. AB - OBJECTIVES: To quantify seniors' potential savings for switching to a new prescription drug plan (PDP) for 2011 and to assess predictors of which seniors could save most by reviewing their PDPs annually. METHODS: This cross-sectional analysis included 404 Medicare beneficiaries 65 years or older who selected PDPs at Senior PharmAssist (SPA), a pharmacist-led nonprofit in Durham, NC. RESULTS: Seniors had a mean potential savings of $348 for the year. The 62% of beneficiaries who could save by switching plans had a mean potential savings of $559. None of the factors examined predicted whether seniors would have potential savings. Among those with any potential savings, individuals taking more medications ( P = 0.003), people with no low-income subsidy ( P = 0.0002), and first-time consulters ( P = 0.03) had greater potential savings. CONCLUSION: Some seniors can realize substantial cost savings by changing PDPs annually. Pharmacists can help patients save money, reduce sources of nonadherence, and earn appreciation as professionals by alerting patients to these potential savings and referring them to help in selecting a plan. PMID- 23023845 TI - Dietary approaches to hypertension: a call to pharmacists to promote lifestyle changes. AB - OBJECTIVES: To describe guideline updates regarding a dietary approach to preventing or treating hypertension and to encourage pharmacists to provide education to patients on the Dietary Approaches to Stop Hypertension (DASH) diet and reducing dietary sodium intake. DATA SOURCES: Abstracts and published articles identified by searching Medline (January 2001 to July 2011) and International Pharmaceutical Abstracts (January 2001 to July 2011) using the terms hypertension, cardiovascular risk, risk reduction behavior, health behavior, community pharmacy services, counseling, diet, and sodium-restricted diet, as well as reports from the Institute of Medicine and Dietary Guidelines for Americans 2010. DATA SYNTHESIS: In the Dietary Guidelines for Americans 2010, the recommended daily dietary sodium intakes for individuals with hypertension, chronic kidney disease, and diabetes was reduced to less than 1,500 mg per day. All other healthy individuals are recommended to achieve dietary sodium intakes of less than 2,300 mg per day. Americans are consuming excessive amounts of dietary sodium in the form of processed foods, which poses a barrier to blood pressure control. Pharmacists should recommend the DASH diet as a way to reduce intake of dietary sodium and use available nutrition resources found on the ChooseMyPlate.gov and Food and Drug Administration websites. Pharmacists should integrate approaches using behavioral and motivational strategies to provide education that is culturally sensitive and appeals to individuals with marginal health literacy. CONCLUSION: Community and ambulatory practice pharmacists, as well as collaborative practice models between pharmacists and physicians, should optimize medication management and incorporate lifestyle interventions that reduce dietary sodium intake as part of a comprehensive approach to improve hypertension outcomes. PMID- 23023846 TI - Self-assessment tool for screening patients at risk for drug therapy problems. AB - OBJECTIVE: To describe the development, use, and evaluation of a patient self assessment tool for screening patients at risk for drug therapy problems (DTPs) and potentially interested in receiving a personal consultation with a pharmacist. DESIGN: Quasi-experimental, nonrandomized, controlled study. SETTING: Area Agency on Aging-affiliated senior centers in Florida from April 2005 to December 2005. PARTICIPANTS: 175 clients of an Area Agency on Aging. INTERVENTION: While attending a free seminar on obtaining the best value from their medications, participants completed a 12-item self-assessment tool. The tool was designed to (1) identify participants who were at risk for a DTP and (2) motivate those at risk to participate in a personal pharmacotherapy consultation with a pharmacist on a fee-for-service basis. MAIN OUTCOME MEASURE: Relationship between total score on self-assessment tool and patient acceptance of offer of personal pharmacotherapy consultation. RESULTS: Of 175 participants who attended a free seminar, 69 (39.4%) accepted the offer of a personal pharmacotherapy consultation. The median score on the self-assessment tool in these participants was significantly higher compared with participants who declined a consultation (3 vs. 1, P = 0.0489). The number of DTPs eventually identified during the personal pharmacotherapy consultation was significantly and positively correlated with the total score on the self-assessment tool (rho = 0.3259, P = 0.0110). CONCLUSION: The self-assessment tool appeared to be of use in predicting individuals who were likely to accept the offer of a personal consultation. Higher scores on the self-assessment tool may also predict patients who are likely to have a higher number of DTPs. PMID- 23023847 TI - College of pharmacy-based medication therapy management program for a university system. AB - OBJECTIVE: To document and evaluate the design and operation of a medication therapy management (MTM) benefit and associated MTM clinic developed by the University of Minnesota College of Pharmacy as a covered health plan benefit for University of Minnesota, Duluth (UMD) employees, early retirees, and their dependents. SETTING: Office-based, nondispensing pharmacy at UMD. PRACTICE DESCRIPTION: College of Pharmacy, Duluth faculty developed and provided MTM services as a covered health benefit for UMD beneficiaries. PRACTICE INNOVATION: Partnership between a university campus and a college of pharmacy to design and implement an MTM benefit as part of the university health plan covering current employees, early retirees, and dependents. MAIN OUTCOME MEASURES: MTM benefit design, MTM clinic implementation, patient complexity comparisons, and drug therapy problems identified and addressed. RESULTS: Of 1,000 eligible beneficiaries, 68 (~7%) took advantage of the MTM benefit, consistent with national participation rates but lower than the 25% goal for participation. Beneficiaries receiving MTM services were three times more complex in terms of health resource use than the "typical" UMD beneficiary and were experiencing 7.22 drug therapy problems per patient. CONCLUSION: The UMD MTM clinic was successful in providing UMD beneficiaries access to MTM services. The MTM benefit was subsequently offered throughout the entire University of Minnesota system (Crookston, Duluth, Minneapolis-St. Paul, and Morris). PMID- 23023848 TI - Development and integration of pharmacist clinical services into the patient centered medical home. AB - OBJECTIVES: To describe the development of pharmacist clinical services within a primary care physician practice using a standardized business plan, the extent of clinical pharmacy service integration into the patient-centered medical home (PCMH), and the clinical changes in the pharmacist's patient cohort. SETTING: A two-physician primary care/occupational care practice in Pittsburgh, PA, from May 2007 to December 2011. PRACTICE DESCRIPTION: Pharmacist-led clinic receives physician referrals for medication management, adherence, and disease management services. PRACTICE INNOVATION: Pharmacist practice in a primary care setting with emphasis on integration of clinical services into the medical home model designed by the American Academy of Family Physicians. MAIN OUTCOME MEASURES: Characterization of the patient's pharmacist and services provided by the pharmacist. Glycosylated hemoglobin (A1C), body mass index (BMI), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, and blood pressure. RESULTS: The top five primary referral reasons were diabetes self-management, weight management, medication adherence, hypertension, and dyslipidemia management. Improvements in clinical parameters were demonstrated for lipids and A1C at 1 and 2 years after baseline. Statistically significant improvements in BMI also were observed. CONCLUSION: The pharmacist developed and integrated clinical services into a primary care practice, became an integral member of the clinical team in the two-physician PCMH, and improved patient outcomes. PMID- 23023850 TI - Lawrence Clayton Weaver 1924-2011: shouldn't we try? PMID- 23023851 TI - Landmark article: Air-suspension technique of coating drug particles. 1959. PMID- 23023852 TI - Landmark article: Practice continuity and longevity of women pharmacists. 1969. PMID- 23023853 TI - The vital role of influenza vaccination of health care personnel. PMID- 23023854 TI - Peginesatide acetate, axitinib, and pertuzumab. PMID- 23023855 TI - Science snippets. Drug advertising, response shift in patients with hypertension, and medication error interception. PMID- 23023856 TI - Study of nonparticipation in an employee diabetes program. AB - OBJECTIVES: To determine factors that affect nonparticipation in an employee diabetes program and factors that may increase participation in future employee health programs. METHODS: Participants in this cross-sectional study were adults with type 1 or type 2 diabetes, 18 to 80 years of age, who were covered by employer insurance but chose not to participate in an employer-sponsored diabetes program. Potential factors affecting program participation were assessed through a face-to-face or mailed survey. RESULTS: Of 204 employees or their dependents eligible for the diabetes program, 75 (37%) chose not to participate. Among the nonparticipants, 46 (61%) were eligible for this study. A total of 22 surveys were collected for a 48% response rate. The majority of those individuals surveyed (91%) were aware of the diabetes program and had been notified by mail (42%) or phone (29%). Of those surveyed, 33% did not believe that program incentives had been sufficiently explained to them. Work schedule was not found to be a determinant of participation. More than one-half (52%) of responders identified satisfaction with their current diabetes management as the most notable reason for nonparticipation in the employee diabetes program. CONCLUSION: This study demonstrated that the primary reason for program nonparticipation was patient satisfaction with current physician management of their diabetes. In the future, companies offering health programs should emphasize that the program is being offered to supplement and complement current disease state management, not to replace it. PMID- 23023857 TI - Pharmacist reporting of serious adverse drug events to the Food and Drug Administration. AB - OBJECTIVE: To identify barriers to and facilitators of pharmacist reporting of serious adverse drug events (ADEs) to the Food and Drug Administration (FDA). METHOD: Two focus groups consisting of practicing pharmacists were held in Austin, TX, in 2009. The following open-ended questions were used in the focus groups: (1) What do you think would make it easier to report serious ADEs to the FDA? (2) What do you think would make it more difficult to report serious ADEs to the FDA? A content analysis was performed on the generated transcripts. RESULTS: 13 pharmacists practicing in hospital and community settings in Texas participated. Pharmacists identified 27 barriers to and facilitators of reporting serious ADEs to FDA. Lack of patients' complete medical histories and lack of time were the barriers most frequently cited. Knowledge and awareness of ADEs and ADE reporting emerged as important factors that would facilitate reporting serious ADEs to FDA. CONCLUSION: These findings highlight the factors that facilitate and/or inhibit pharmacist reporting of serious ADEs to FDA. Improved knowledge of ADEs and ADE reporting would facilitate reporting behaviors, while lack of time, lack of complete patient medical histories, and lack of compensation issues serve as important barriers to reporting. Interventions are needed to address these factors. PMID- 23023858 TI - PictureRx: Illustrated medication instructions for patients with limited health literacy. AB - OBJECTIVES: To describe the role of illustrated medication instructions in pharmacy practice, the evidence for their use, and our experience with their implementation. PRACTICE DESCRIPTION: PictureRx is applicable to all pharmacy practice settings. PRACTICE INNOVATION: PictureRx enables pharmacists to rapidly produce evidence-based, illustrated medication instructions that are well understood by patients of all health literacy levels. RESULTS: PictureRx has been studied in a number of settings. The tool was successfully deployed at a busy outpatient pharmacy and in a medical clinic for the underserved and was pilot tested among elderly community-dwelling Medicare recipients. In each of these settings, PictureRx was received favorably by patients, pharmacists, and other health care providers. It improved patients' satisfaction with the pharmacy and knowledge about their medications. Ongoing research is assessing whether PictureRx enhances medication management among Latinos. CONCLUSION: PictureRx helps pharmacists address challenges related to low health literacy and can be implemented in a broad range of practice environments. Ongoing research will delineate the extent to which PictureRx reduces health disparities. PMID- 23023859 TI - Exploratory study of community pharmacists' perceptions about new or transferred prescription incentives. AB - OBJECTIVES: To assess community pharmacists' perceptions of new or transferred prescription incentives on quality of care, pharmacy practice (e.g., workload), and patient base. DESIGN: Cross-sectional study. SETTING: Texas from March through August 2010. PARTICIPANTS: Texas community pharmacists. INTERVENTION: In person and online surveys. MAIN OUTCOME MEASURE: Pharmacists' perceptions of the impact of new or transferred prescription incentives on pharmacy practice and patient care. RESULTS: 74 usable surveys were analyzed. Most pharmacists (74%) worked for employers who participated in prescription incentive promotions (e.g., $10 gift cards). Regarding quality of care, pharmacists perceived patients as being less likely to receive thorough drug interaction screenings (4.0 +/- 1.4 [mean +/- SD]) and reported medication-related problems "sometimes to very often" (3.0 +/- 0.9) as a result of transferring prescriptions. Pharmacists also reported that patients commonly fill prescriptions regardless of medical necessity in order to receive incentives (4.1 +/- 1.0). With respect to pharmacy practice, the majority believed that prescription incentives devalue the profession (4.3 +/- 1.1) and should be eliminated (4.4 +/- 1.0). Pharmacists were not inclined to believe that incentives were effective in attracting new patients and retaining their business (2.0 +/- 1.0). CONCLUSION: Pharmacists believed that prescription incentives are ineffective tools for increasing patient base and may lead to lower quality of care for patients. Pharmacists view prescription incentives as devaluing the profession of pharmacy and exposing patients to medication-related problems. PMID- 23023860 TI - Improved antiretroviral refill adherence in HIV-focused community pharmacies. AB - OBJECTIVE: To determine differences in patient characteristics, antiretroviral therapy (ART) regimen characteristics, and regimen refill adherence for human immunodeficiency virus (HIV)-focused pharmacy (HIV-P) versus traditional pharmacy (TP) users. DESIGN: Retrospective cohort study. SETTING: California Walgreens pharmacies from May 2007 to August 2009. PARTICIPANTS: HIV-positive patients with greater than 30 days of antiretroviral prescription claims. INTERVENTION: Deidentified prescription records for patients filling any ART prescription at any California Walgreens pharmacy during the study period were assessed. MAIN OUTCOME MEASURES: ART regimen refill adherence (calculated by modified medication possession ratio [mMPR]) and dichotomous measure of optimal adherence of 95% or greater. RESULTS: 4,254 HIV-P and 11,679 TP users were included. Compared with TP users, HIV-P users traveled farther to pharmacies (5.03 vs. 1.26 miles, P < 0.01). A greater proportion of HIV-P users filled prescriptions for chronic diseases (35% vs. 30%) and received fixed-dose combination antiretroviral tablets (92% vs. 83%) (all P < 0.01). Median mMPR was higher for HIV-P users (90% vs. 77%, P < 0.0001). After adjusting for age, gender, insurance, medication use, and distance from pharmacy, use of HIV-P (odds ratio 1.90 [95% CI 1.72-2.08]) and fixed-dose combination antiretroviral tablets (3.34 [2.84-3.96]) were most strongly associated with having 95% or greater ART regimen refill adherence. CONCLUSION: For HIV-positive patients struggling with antiretroviral adherence, clinicians may consider minimizing pill burden with combination tablets and referral to an HIV-focused pharmacy. PMID- 23023861 TI - Logistical and fiscal sustainability of a school-based, pharmacist-administered influenza vaccination program. AB - OBJECTIVE: To assess the fiscal and logistical viability of school-based, pharmacist-administered influenza vaccination programs. DESIGN: Econometric observational study. SETTING: Nine schools in the Rincon Unified School District, Santa Rosa, CA. PARTICIPANTS: Safeway Pharmacies; Rincon Unified School District; California Department of Public Health, Immunization Branch; and University of California, San Diego. INTERVENTION: Assessment of direct workflow observations and administrative data. MAIN OUTCOME MEASURES: Unit costs, productivity, and effectiveness of school-based, pharmacist-administered influenza vaccination programs. RESULTS: The results showed a unit cost of $23.63 (compared with $25.60 for mass vaccination and $39.79 for walk-in shot-only vaccination clinics). The productivity index ($0.88) and efficiency index ($1.12) were better compared with data reported for comparable vaccination programs. CONCLUSION: School-based, pharmacist-administered vaccination programs are fiscally and logistically self sustaining, viable alternatives to medical office-based or community-based mass vaccination clinics, and may offer a practical strategy for vaccinating children and adolescents. PMID- 23023862 TI - Student pharmacists' perceptions and awareness of community pharmacy practice residency programs. AB - OBJECTIVES: To assess student exposure to types of pharmacy practice, evaluate awareness and perceptions of community pharmacy residencies, and identify areas of postgraduate training of interest to student pharmacists. DESIGN: Cross sectional, descriptive, online survey study. SETTING: United States, January to April 2008. PARTICIPANTS: Student pharmacists in the final 2 years of the doctor of pharmacy (PharmD) program. INTERVENTION: An online survey was administered to students in the final 2 years of the PharmD program at randomly selected schools of pharmacy by region throughout the United States. MAIN OUTCOME MEASURES: Awareness of student pharmacists regarding community pharmacy residencies and interest in postgraduate training. RESULTS: 254 surveys were completed during the study period. Of the respondents, 95% had previous experience working in a community pharmacy setting. Nearly 90% were aware of community pharmacy residencies. Students who indicated opportunities to publish (odds ratio 2.4 [95% CI 1.34-4.1]), teaching students (2.1 [1.36-3.14]), enjoying the job atmosphere (4.9 [1.54-15.60]), and clinically challenging (4.3 [2.15-8.67]) as desirable career attributes were more likely to be interested in postgraduate training. No significant differences existed in the information sources sought by students interested in community pharmacy residency programs (CPRPs) compared with those interested in other types of postgraduate training. CONCLUSION: The significant predicators of student pharmacists interested in pursuing postgraduate training are in alignment with CPRP training. Further research is needed to market the value of CPRPs through the identified information sources. PMID- 23023863 TI - Racial and ethnic disparities in meeting Part D MTM eligibility criteria among the non-Medicare population. AB - OBJECTIVE To determine whether racial and ethnic minorities were less likely to meet the Medicare Part D eligibility criteria for medication therapy management (MTM) services compared with whites among the adult non-Medicare population, because some non-Medicare health plans have followed the Medicare example. DESIGN Cross-sectional observational study. SETTING United States, 2007-08. PATIENTS 16,691 white, 5,923 black, and 9,242 Hispanic adults (>17 years) among the non Medicare population. INTERVENTION Analysis of the Medical Expenditure Panel Survey. MTM eligibility criteria used by Part D plans in 2008 and 2010-11 were examined. Main and sensitivity analyses were conducted to represent the entire range of the eligibility thresholds used by Part D plans. Analyses also were conducted among individuals with heart disease, diabetes, and hypertension. MAIN OUTCOME MEASURES Proportions and odds of patients meeting Part D MTM eligibility criteria. RESULTS According to the main analysis examining 2008 eligibility criteria, whites had a higher proportion of eligible individuals than did blacks (3.73% vs. 2.57%) and Hispanics (1.53%, P < 0.05 for both comparisons). According to survey-weighted logistic regression adjusting for patient characteristics, blacks and Hispanics had odds ratios for MTM eligibility of 0.60 (95% CI 0.46 0.79) and 0.54 (0.40-0.72), respectively, compared with whites. Sensitivity analyses, analyses examining 2010-11 eligibility criteria, and analyses among individuals with heart disease, diabetes, and hypertension produced similar findings. CONCLUSION Racial and ethnic minorities have lower odds for meeting Part D MTM eligibility criteria than whites among the adult non-Medicare population. MTM eligibility criteria need to be modified to address these disparities. PMID- 23023864 TI - Differences in medication errors between central and remote site telepharmacies. AB - OBJECTIVE: To examine differences in dispensing errors within community telepharmacy practices by comparing error rates across central sites (community telepharmacy sites with pharmacists present) and the corresponding remote sites, which are staffed by registered technicians and overseen by the central site pharmacist. DESIGN: Cross-sectional pilot study with a test group (remote sites) and comparison group (central sites). SETTING: 24 rural community telepharmacies (14 remote sites and 10 central sites). PARTICIPANTS: Pharmacy staff. INTERVENTION: The Pharmacy Quality Commitment (PQC) reporting system was integrated into the North Dakota Telepharmacy Project and used to track dispensing errors over a 45-month period. Both pharmacists and pharmacy technicians were trained on the use of the PQC system. The PQC system focused on two quality-related events (QREs): a "near miss" (i.e., a mistake discovered by the pharmacy staff before a medication reaches the patient) and an "error" (i.e., a mistake discovered after the patient leaves the pharmacy with the medication). MAIN OUTCOME MEASURES: The distribution of QREs across central and remote sites. RESULTS: The remote (central) telepharmacy group reported 47,078 (62,480) prescriptions and a QRE rate of 1.34% (1.43%). QREs at the remote sites were more likely than at the central sites to be caught at the final pharmacist check (58.2% vs. 40.8%, P < 0.01) and less likely to be caught by the patient (0.17% vs. 0.28%, P < 0.01). Remote sites were more likely to include incorrect directions (18.9% vs. 13.4%, P = 0.01) in the medication entry process. CONCLUSION: QRE rates for remote site and central site telepharmacies were consistent with each other and with national estimates in traditional community pharmacies. However, significant differences between central and remote sites existed based on how QREs arose and how they were caught. Pharmacists must recognize this fact and use diligence when working in a telepharmacy setting. PMID- 23023865 TI - Radial multigradient-echo DCE-MRI for 3D K(trans) mapping with individual arterial input function measurement in mouse tumor models. AB - The purpose of this study was to provide proof of concept for a new three dimensional (3D) radial dynamic contrast enhanced MRI acquisition technique, called "Radial Entire Tumor with Individual Arterial input function dynamic contrast-enhanced MRI" (RETIA dynamic contrast-enhanced MRI), which allows for the simultaneous measurement of an arterial input function in the mouse heart at 2 s temporal resolution and coverage of the whole tumor. Alternating 2D and 3D projections contribute to the 2D heart image or 3D tumor data with a 3-cm field of view. Sixty-four 2D images of the heart are obtained during acquisition of each 3D tumor dataset. In a pilot study, global K(trans) and ve values were measured in four mice, in a respiratory motion-animated subcutaneously implanted breast tumor model. This technique is expected to be most useful for the characterization of microvasculature in motion-animated orthotopic tumors. PMID- 23023866 TI - Different patterns of cardiac sympathetic denervation in tremor-type compared to akinetic-rigid-type Parkinson's disease: molecular imaging with 123I-MIBG. AB - The aim of this study was to evaluate the correlation between the clinical motor phenotypes of Parkinson's disease (PD) and 123I-MIBG myocardial uptake. In total, 53 patients with PD [31 males and 22 females, mean age 62+/-10 years; 19 Hoehn & Yahr (H&Y) stage 1, 9 stage 1.5, 15 stage 2 and 10 at stage 3] were examined and subdivided into different clinical forms on the basis of dominance of resting tremor (n=19, TDT) and bradykinesia plus rigidity (n=34, ART). This status was correlated with the semi-quantitative analysis of 123I-MIBG myocardial uptake. An age-matched control group of 18 patients was recruited (8 males and 10 females, mean age 62.4+/-16.3 years). 123I-MIBG myocardial uptake significantly correlated with disease duration in early (r2=0.1894; P=0.0028) and delayed images (r2=0.1795; P=0.0037) in PD patients, while no correlation was found when considering age at examination, UPDRS III motor examination section score and H&Y score. PD patients showed a reduced 123I-MIBG myocardial uptake compared to the control group in early (P=0.0026) and delayed images (P=0.0040), and 123I-MIBG myocardial uptake was significantly lower in delayed images in TDT patients compared with ART patients (P=0.0167). A decrease was detected in the heart-to mediastinum (H/M) ratio in delayed images compared to that of the early images in TDT patients (P=0.0040) and in the whole PD population (P=0.0012), while no differences were found in ART patients (P=0.1043). The results of the present study revealed that the cardiac sympathetic system is more severely impaired in TDT than in ART patients and 123I-MIBG molecular imaging has the potential help in improving therapeutic planning in these patients. PMID- 23023867 TI - Norepinephrine transporter function and human cardiovascular disease. AB - Approximately 80-90% of the norepinephrine released in the brain or in peripheral tissues is taken up again through the neuronal norepinephrine transporter (NET). Pharmacological studies with NET inhibitors showed that NET has opposing effects on cardiovascular sympathetic regulation in the brain and in the periphery. Furthermore, NET is involved in the distribution of sympathetic activity between vasculature, heart, and kidney. Genetic NET dysfunction is a rare cause of the postural tachycardia syndrome. The condition is characterized by excessive adrenergic stimulation of the heart, particularly with standing. Conversely, NET inhibition may be beneficial in hypoadrenergic states, such as central autonomic failure or neurally mediated syncope, which results from acute sympathetic withdrawal. Biochemical studies suggested reduced NET function in some patients with essential hypertension. Furthermore, cardiac NET function appears to be reduced in common heart diseases, such as congestive heart failure, ischemic heart disease, and stress-induced cardiomyopathy. Whether NET dysfunction is a consequence or cause of progressive heart disease in human subjects requires further study. However, studies with the nonselective NET inhibitor sibutramine suggest that reduced NET function could have an adverse effect on the cardiovascular system. Given the widespread use of medications inhibiting NET, the issue deserves more attention. PMID- 23023868 TI - Sildenafil improves microvascular O2 delivery-to-utilization matching and accelerates exercise O2 uptake kinetics in chronic heart failure. AB - Nitric oxide (NO) can temporally and spatially match microvascular oxygen (O(2)) delivery (Qo(2mv)) to O(2) uptake (Vo(2)) in the skeletal muscle, a crucial adjustment-to-exercise tolerance that is impaired in chronic heart failure (CHF). To investigate the effects of NO bioavailability induced by sildenafil intake on muscle Qo(2mv)-to-O(2) utilization matching and Vo(2) kinetics, 10 males with CHF (ejection fraction = 27 +/- 6%) undertook constant work-rate exercise (70-80% peak). Breath-by-breath Vo(2), fractional O(2)extraction in the vastus lateralis {~deoxygenated hemoglobin + myoglobin ([deoxy-Hb + Mb]) by near-infrared spectroscopy}, and cardiac output (CO) were evaluated after sildenafil (50 mg) or placebo. Sildenafil increased exercise tolerance compared with placebo by ~20%, an effect that was related to faster on- and off-exercise Vo(2) kinetics (P < 0.05). Active treatment, however, failed to accelerate CO dynamics (P > 0.05). On exercise [deoxy-Hb + Mb] kinetics were slowed by sildenafil (~25%), and a subsequent response "overshoot" (n = 8) was significantly lessened or even abolished. In contrast, [deoxy-Hb + Mb] recovery was faster with sildenafil (~15%). Improvements in muscle oxygenation with sildenafil were related to faster on-exercise Vo(2) kinetics, blunted oscillations in ventilation (n = 9), and greater exercise capacity (P < 0.05). Sildenafil intake enhanced intramuscular Qo(2mv)-to-Vo(2) matching with beneficial effects on Vo(2) kinetics and exercise tolerance in CHF. The lack of effect on CO suggests that improvement in blood flow to and within skeletal muscles underlies these effects. PMID- 23023869 TI - Strategic localization of heart mitochondrial NOS: a review of the evidence. AB - Heart mitochondria play a central role in cell energy provision and in signaling. Nitric oxide (NO) is a free radical with primary regulatory functions in the heart and involved in a broad array of key processes in cardiac metabolism. Specific NO synthase (NOS) isoforms are confined to distinct locations in cardiomyocytes. The present article reviews the chemical reactions through which NO interacts with biomolecules and exerts some of its crucial roles. Specifically, the article discusses the reactions of NO with mitochondrial targets and the subcellular localization of NOS within the myocardium and analyzes the available data about heart mitochondrial NOS activity and identity. The article also describes the regulation of heart mtNOS by the distinctive mitochondrial environment by showing the effects of Ca(2+), O(2), l-arginine, mitochondrial transmembrane potential, and the metabolic states on heart mitochondrial NO production. The article depicts the effects of NO on heart function and highlights the relevance of NO production within mitochondria. Finally, the evidence on the functional implications of heart mitochondrial NOS is delineated with emphasis on chronic hypoxia and ischemia-reperfusion studies. PMID- 23023870 TI - Sonic hedgehog promotes autophagy of vascular smooth muscle cells. AB - Sonic hedgehog (Shh) is a morphogen critically involved in development that is reexpressed in atherosclerotic lesions. It also stimulates proliferation of vascular smooth muscle cells (SMCs). Autophagy in vascular SMCs is known to promote SMC survival and increase plaque stability. The aim of this study was to investigate whether Shh induces autophagy of vascular SMCs. Our study showed that both Shh protein and microtubule-associated protein 1 light chain 3 (LC3)-II were increased in SMCs within neointimal lesions of mouse common carotid arteries. In cultured mouse aortic SMCs, recombinant mouse Shh stimulated LC3-II levels. Overexpression of wild-type mouse Shh through the tetracycline-regulated expression-inducible system in human aortic SMCs time-dependently increased the levels of LC3-II and also stimulated protein kinase B (AKT) phosphorylation. Pretreatment with AKT inhibitor IV (AKTI IV) inhibited AKT phosphorylation and the increase in LC3-II. Shh-induced autophagy was further confirmed by the formation of autophagosomes as detected by immunostaining and transmission electron microscopy, which was inhibited by AKTI IV. Shh further increased SMC LC3-II in the presence of bafilomycin A1, (2S,3S)-trans-epoxysuccinyl-L leucylamido-3-methylbutane ethyl ester, and pepstatin A or siRNA for the autophagy-related gene 7 (ATG7). In addition, Shh induced SMC proliferation, which was inhibited not only by AKTI IV but also by cyclopamine, an inhibitor of Shh receptor. Inhibition of autophagy with 3-methyladenine (3-MA), bafilomycin A1, or ATG7 siRNA resulted in inhibition of cell proliferation. Treatment with 3 MA, AKTI IV, or cyclopamine inhibited neointima formation in mouse common carotid arteries. Taken together, our results have shown that Shh induces autophagy of vascular SMCs involving AKT activation, suggesting a role of autophagy in Shh induced cellular responses. PMID- 23023871 TI - Altered hemodynamics, endothelial function, and protein expression occur with aortic coarctation and persist after repair. AB - Coarctation of the aorta (CoA) is associated with substantial morbidity despite treatment. Mechanically induced structural and functional vascular changes are implicated; however, their relationship with smooth muscle (SM) phenotypic expression is not fully understood. Using a clinically representative rabbit model of CoA and correction, we quantified mechanical alterations from a 20-mmHg blood pressure (BP) gradient in the thoracic aorta and related the expression of key SM contractile and focal adhesion proteins with remodeling, relaxation, and stiffness. Systolic and mean BP were elevated for CoA rabbits compared with controls leading to remodeling, stiffening, an altered force response, and endothelial dysfunction both proximally and distally. The proximal changes persisted for corrected rabbits despite >12 wk of normal BP (~4 human years). Computational fluid dynamic simulations revealed reduced wall shear stress (WSS) proximally in CoA compared with control and corrected rabbits. Distally, WSS was markedly increased in CoA rabbits due to a stenotic velocity jet, which has persistent effects as WSS was significantly reduced in corrected rabbits. Immunohistochemistry revealed significantly increased nonmuscle myosin and reduced SM myosin heavy chain expression in the proximal arteries of CoA and corrected rabbits but no differences in SM alpha-actin, talin, or fibronectin. These findings indicate that CoA can cause alterations in the SM phenotype contributing to structural and functional changes in the proximal arteries that accompany the mechanical stimuli of elevated BP and altered WSS. Importantly, these changes are not reversed upon BP correction and may serve as markers of disease severity, which explains the persistent morbidity observed in CoA patients. PMID- 23023873 TI - Giant spin-orbit effects on NMR shifts in diamagnetic actinide complexes: guiding the search of uranium(VI) hydride complexes in the correct spectral range. PMID- 23023874 TI - Osteology and postmetamorphic development of Telmatobius oxycephalus (Anura: Telmatobiidae) with an analysis of skeletal variation in the genus. AB - The osteological diversity among species of Telmatobius has been considered conservative. Nonetheless, the degree of ossification of several features varies both intraspecifically and interspecifically. Herein, intraspecific osteological variation and postmetamorphic ontogenetic changes in osteological features are described in Telmatobius oxycephalus. These data are compared with published descriptions of congeners. There is a considerable intraspecific osteological variation in T. oxycephalus, with cranial characters varying polymorphically, and the hyoid and postcranial characters being sexually dimorphic. This intraspecific variation is expressed by subtle differences in the degree of ossification or mineralization. Interspecific variation also can be described in terms of differential development of osteological features; these differences are more obvious than intraspecifically variable characters. The adult skeletons of several species of Telmatobius resemble the morphology observed in early stages of postmetamorphic development of T. oxycephalus. This is especially evident in the neopalatines, parasphenoid, sphenethmoid, exoccipitals, prootics, vomers, nasals, and plectra. These results suggest that within the conservative osteological architecture of Telmatobius, the variation observed is the result of heterochronic changes during the ossification process. PMID- 23023872 TI - Effect of cellular senescence on the albumin permeability of blood-derived endothelial cells. AB - In this study, we tested the hypotheses that endothelial cells (ECs) derived from human umbilical cord blood (hCB-ECs) exhibit low permeability, which increases as hCB-ECs age and undergo senescence, and that the change in the permeability of hCB-ECs is due to changes in tight junction protein localization and the activity of exchange protein activated by cAMP (Epac)1. Albumin permeability across low passage hCB-EC monolayers on Transwell membranes was 10 times lower than for human aortic ECs (HAECs) (P < 0.01) but similar to in vivo values in arteries. Expression of the tight junction protein occludin and tyrosine phosphorylation of occludin were less in hCB-ECs than in HAECs (P < 0.05). More hCB-ECs than HAECs underwent mitosis (P < 0.01). hCB-ECs that underwent >44 population doublings since isolation had a significantly higher permeability than hCB-ECs that underwent <31 population doublings (P < 0.05). This age-related increase in hCB EC permeability was associated with an increase in tyrosine phosphorylation of occludin (P < 0.01); permeability and occludin phosphorylation were reduced by treatment with 2 MUM resveratrol. Tyrosine phosphorylation of occludin and cell age influence the permeability of hCB-ECs, whereas levels of EC proliferation and expression of tight junction proteins did not explain the differences between hCB EC and HAEC permeability. The elevated permeability in late passage hCB-ECs was reduced by 25-40% by elevation of membrane-associated cAMP and activation of the Epac1 pathway. Given the similarity to in vivo permeability to albumin and the high proliferation potential, hCB-ECs may be a suitable in vitro model to study transport-related pathologies and cell aging. PMID- 23023875 TI - Correction of Wassel type IV thumb duplication with zigzag deformity: results of a new method of flexor pollicis longus tendon relocation. AB - The purpose of this study is to present a treatment algorithm and a method of flexor pollicis longus tendon relocation for Wassel type IV thumb duplication with zigzag deformity. Forty-two thumbs in 42 patients were included in this study and the mean follow-up was 4 years. In addition to excision of the extra digit, tendon relocation and metacarpal and/or proximal phalangeal osteotomy were carried out, based on the degree of angulation at the metacarpophalangeal and interphalangeal joints. Tendon relocation was achieved using our pull-out suture technique. The results were assessed using an evaluation form for thumb polydactyly provided by the Japanese Society for Surgery of the Hand. At the time of latest clinical contact, eight cases were rated good, 31 cases fair, and three cases poor. It is useful to decide surgical procedures according to the degree of angulation of the metacarpophalangeal and interphalangeal joints and flexor pollicis longus tendon relocation is important to prevent malalignment at the interphalangeal joint. PMID- 23023876 TI - Active control of ferroelectric switching using defect-dipole engineering. AB - Active control of defect structures and associated polarization switching in a ferroelectric material is achieved without compromising its ferroelectric properties. Based on dipolar interaction between defect dipole and polarization, the unique functionality of the defect dipole to control ferroelectric switching is visualized. This approach can provide a foundation for novel ferroelectric applications, such as high-density multilevel data storage. PMID- 23023877 TI - Neck dissection through a facelift incision. AB - OBJECTIVES/HYPOTHESIS: To determine the feasibility and safety of neck dissection through a facelift incision. STUDY DESIGN: Prospective case series. METHODS: Cadavers and live subjects underwent neck dissection using a facelift incision with and without endoscopic assistance. In the live facelift neck dissection (FLND), the preoperative surgical indications, staging, adjuvant therapy, intraoperative technical procedure, pathology reports on lymph nodes, and short term outcomes were reviewed. RESULTS: FLND was successfully performed in four cadavers and four live subjects, including selective (less than five neck levels removed) and comprehensive (levels I-V removed) neck dissections. All levels were accessible through this approach, with additional retraction required for levels I and IV. Endoscopic assistance was required in one neck dissection for adequate visualization. Short-term complications and number of excised lymph nodes were comparable to those from traditional neck dissection approaches. CONCLUSIONS: Open neck dissection through a facelift incision is feasible and offers an alternate approach to traditional incisions. This can be performed without requiring robotic assistance and with endoscopic assistance only in certain cases. Endoscopic assistance can offer enhanced visualization of the surgical field and complement open direct approaches in neck dissection. Although FLND offers improved cosmetic outcomes when compared to those of traditional neck incisions, further study is required to determine its efficacy and indications. PMID- 23023878 TI - A rare association of fibromuscular dysplasia, renal agenesis, renal arteriovenous fistulae, and vertebral anomalies: expanding the V in VACTERL association. AB - We report on the association of renal agenesis, renal arteriovenous fistulae, fibromuscular dysplasia and vertebral body anomaly in a young female patient with renovascular hypertension. We believe these vertebral and vascular anomalies can be included under the "V" of the VACTERL association; expanding the vascular spectrum of this complex disorder. PMID- 23023880 TI - The clinical value of KANET in studying fetal neurobehavior in normal and at-risk pregnancies. AB - OBJECTIVES: The aim of this study was to evaluate the clinical value of Kurjak's Antenatal Neurodevelopmental Test (KANET), a new test for fetal neurodevelopment. METHODS: One hundred seventeen prenatal neurological tests were performed by the KANET scoring system between 28 and 38 weeks of gestation in 24 low-risk (24 fetuses) and 26 at-risk pregnancies (32 fetuses). The study was completed within 12 months from July 2011 onward. All 56 babies were assessed for early neurological outcome at birth by neonatologists. RESULTS: There were no abnormal KANET scores. Two thirds of all borderline scores were found in the at-risk group. Because KANET was performed more than once in most pregnancies, we introduced the average KANET score. Only one fetus of the "at-risk group" had a borderline average score. This fetus had the only abnormal early neurological outcome of all 56 fetuses. When we compared all 18 borderline KANET scores with fetal diurnal rhythm based on maternal observation, we found that 89% of the borderline scores of the "at-risk" group were at times characterized by the mother as usually "active" periods compared with 33.3% in the low-risk group. CONCLUSION: KANET is suggestive of expressing the risk for neurodevelopmental fetal disorders. Studies designed to investigate the potential connectivity of fetal diurnal rhythm and pregnancy risk status should follow. PMID- 23023881 TI - The national perinatal mortality rate in the State of Qatar during 2011; trends since 1990 and comparative analysis with selected high-income countries: the PEARL study project. AB - OBJECTIVE: To prospectively ascertain Qatar's national perinatal mortality rate (PMR) during 2011, compare it with recent data from selected high-income countries, and analyze trends in Qatar's PMR between 1990 and 2011 using historical data. STUDY DESIGN: A national prospective cohort study. METHODS: National data on live births, stillbirths, and early neonatal mortality (day 0-6) were collected from all public and private maternity units in Qatar (1st January December 31st 2011) and compared with historical perinatal mortality data (1990 2010) ascertained from the database of maternity and neonatal units of Women's Hospital and annual reports of Hamad Medical Corporation (HMC). For inter-country comparison, country data were extracted from the World Health Statistics published by WHO in 2011 and from the European Perinatal Health Report published by the Europeristat project in 2008. RESULTS: A total of 20,725 births (20,583 live births plus 142 stillbirths) were recorded during the study period. Qatar's national PMR during 2011 was 9.55 [early neonatal mortality rate (ENMR) 2.7 and stillbirth rate (SBR) 6.85], which was a significant improvement from a PMR of 13.2 in 1990 [risk ratio (RR) 0.72, 95% confidence interval 0.58-0.89, P=0.002]. This improvement in PMR was more significant in ENMR (P<0.001) than in SBR (P=0.019). The stillbirths constituted 55% of PMR in 1990, which increased to 71.72% of PMR during 2011. The RR of PMR had a significant downwards trend between 1990 and 2011 (P=0.016). Qatar's 2011 PMR, SBR, and ENMR are comparable to those of selected high-income counties. CONCLUSIONS: Qatar's PMR, ENMR, and SBR have significantly improved between 1990 and 2011, and are currently comparable to those of selected high-income countries. An in-depth research to assess the correlates and determinants of stillbirth and perinatal mortality in Qatar is indicated. PMID- 23023882 TI - Effects of parabolic flight and spaceflight on the endocannabinoid system in humans. AB - The endocannabinoid system (ECS) plays an important role in the regulation of physiological functions,from stress and memory regulation to vegetative control and immunity. The ECS is considered a central and peripheral stress response system to emotional or physical challenges and acts through endocannabinoids (ECs), which bind to .their receptors inducing subsequent effecting mechanisms. In our studies, the ECS responses have been assessed through blood concentrations of the ECs anandamide and 2-arachidonoylglycerol. In parallel, saliva cortisol was determined and the degree of perceived stress was quantified by questionnaires. This report summarizes the reactivity of the ECS in humans subjected to brief periods of kinetic stress and weightlessness during parabolic flights and to prolonged stress exposure during life onboard the International Space Station (ISS). Both conditions resulted in a significant increase in circulating ECs. Under the acute stress during parabolic flights, individuals who showed no evidence of motion sickness were in low-stress conditions and had a significant increase of plasma ECs. In contrast,highly stressed individuals with severe motion sickness had an absent EC response and a massive increase in hypothalamic-pituitary-adrenal axis activity. Likewise, chronic but well tolerated exposure to weightlessness and emotional and environmental stressors on the ISS for 6 months resulted in a sustained increase in EC blood concentrations,which returned to baseline values after the cosmonauts'return. These preliminary results suggest that complex environmental stressors result in an increase of circulating ECs and that enhanced EC signaling is probably required for adaptation and tolerance under stressful conditions. PMID- 23023879 TI - Persistent polar depletion of stratospheric ozone and emergent mechanisms of ultraviolet radiation-mediated health dysregulation. AB - Year 2011 noted the first definable ozone "hole" in the Arctic region, serving as an indicator to the continued threat of dangerous ultraviolet radiation (UVR) exposure caused by the deterioration of stratospheric ozone in the northern hemisphere. Despite mandates of the Montreal Protocol to phase out the production of ozone-depleting chemicals (ODCs), the relative stability of ODCs validates popular notions of persistent stratospheric ozone for several decades. Moreover, increased UVR exposure through stratospheric ozone depletion is occurring within a larger context of physiologic stress and climate change across the biosphere. In this review, we provide commentaries on stratospheric ozone depletion with relative comparisons between the well-known Antarctic ozone hole and the newly defined ozone hole in the Arctic. Compared with the Antarctic region, the increased UVR exposure in the Northern Hemisphere poses a threat to denser human populations across North America, Europe, and Asia. In this context, we discuss emerging targets of UVR exposure that can potentially offset normal biologic rhythms in terms of taxonomically conserved photoperiod-dependent seasonal signaling and entrainment of circadian clocks. Consequences of seasonal shifts during critical life history stages can alter fitness and condition, whereas circadian disruption is increasingly becoming associated as a causal link to increased carcinogenesis. We further review the significance of genomic alterations via UVR-induced modulations of phase I and II transcription factors located in skin cells, the aryl hydrocarbon receptor (AhR), and the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2), with emphasis on mechanism that can lead to metabolic shifts and cancer. Although concern for adverse health consequences due to increased UVR exposure are longstanding, recent advances in biochemical research suggest that AhR and Nrf2 transcriptional regulators are likely targets for UVR-mediated dysregulations of rhythmicity and homeostasis among animals, including humans. PMID- 23023883 TI - Intense emotional experiences and enhanced training prevent memory loss induced by post-training amnesic treatments administered to the striatum, amygdala, hippocampus or substantia nigra. AB - Most of the work related to the neurobiological basis of memory has been guided by the memory consolidation theory, which was derived from the seminal work of Miiller and Pilzecker that was published over a century ago. This theory proposes that the transfer from short- to long-term memory is mediated by a process called consolidation,and while consolidation is taking place, the information to be stored is in a labile state. A great deal of experimentation has given strong support to this proposal,as it has been found repeatedly that interference with neural activity shortly after a learning experience impedes durable retention of that experience. A growing body of evidence, however, indicates that intense emotional experiences prevent memory loss induced by amnesic treatments,even when these treatments are administered intracerebrally shortly after the learning experience. This evidence implies that the memory consolidation theory cannot account for long-term memory formation when neural activity is disrupted while consolidation should be taking place, and it calls for new hypotheses to account for these findings. PMID- 23023884 TI - Towards harmonization of quality indicators in laboratory medicine. AB - The identification of reliable quality indicators (QIs) in the total testing process (TTP) represents a crucial step in enabling users to quantify the quality of laboratory services, but the current lack of attention to extra-laboratory factors is in stark contrast with the body of evidence showing the multitude of errors that continue to occur in the pre- and post-analytical phases. Although interesting programs on indicators of the extra-analytical phases have been developed in some countries, there is no consensus on the production of joint recommendations for the adoption of universal QIs and the use of common terminology in the total testing process. In view of the different QIs and terminologies currently used, there an urgent need to harmonize proposed QIs, which should comply with three main principles: they must be patient-centered, consistent with the requirements of the International Standard for medical laboratories accreditation, and address all stages of the TTP. A model of quality indicators (MQI), consensually developed by a group of clinical laboratories according to a project launched by a working group of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), includes 56 QIs related to key processes (34 pre-, 7 intra- and 15 post-analytical phase) and three to support processes. The scope of harmonization in laboratory medicine, more far-reaching than method harmonization, should cover a wider range of topics, namely all steps of the "brain-to-brain loop". The identification of valuable QIs is a key step in paving the way towards quality and patient safety in laboratory medicine. PMID- 23023885 TI - Evaluation of high resolution gel beta(2)-transferrin for detection of cerebrospinal fluid leak. AB - BACKGROUND: Cerebrospinal fluid (CSF) leaks are potentially life-threatening conditions that can be diagnosed by detection of beta(2)-transferrin using protein electrophoresis. Another less commonly available test is beta-trace protein quantitation using immunoassay. The objectives of this study were to evaluate a new immunofixation-based beta(2)-transferrin test for detection of CSF leaks and to compare it to an existing agarose gel electrophoresis test and beta trace protein immunoassay. METHODS: For method comparison, 63 consecutive samples from physician-ordered beta(2)-transferrin tests were analyzed using two different electrophoresis methods, agarose gel fractionation followed by acid violet staining, and high resolution agarose gel electrophoresis followed by beta(2)-transferrin immunofixation. A subset of samples (16/63) were analyzed for beta-trace protein. Results were compared against patient chart data for the presence of a CSF leak. Additional studies were performed to assess the stability, detection limit, and analytical specificity of the beta(2)-transferrin immunofixation test. RESULTS: The beta(2)-transferrin immunofixation test had a sensitivity of 100 % (40/40) and specificity of 71 % (12/17) for detection of CSF leaks. By comparison, the agarose gel test had a sensitivity of 87 % (35/40) and specificity of 94 % (16/17). beta-trace protein had a sensitivity of 100 % (10/10) and specificity of 86 % (5/6). Serum and saliva could be differentiated from CSF by the beta(2)-transferrin immunofixation test based on their migration patterns. However, whole blood samples appeared positive for beta(2)-transferrin at a threshold of ~ 4 g/L hemoglobin. At a cut-off of 3 mg/L, beta-trace protein was increased in 10/10 cases with documented CSF leak and in 1/6 patients without CSF leak. CONCLUSIONS: Both the new immunofixation test for beta(2)-transferrin and the beta-trace protein were effective at detecting CSF leaks. Users of the beta(2)-transferrin immunofixation test should be cautioned against interpreting samples with blood contamination. PMID- 23023887 TI - Photo-fluorodecarboxylation of 2-aryloxy and 2-aryl carboxylic acids. PMID- 23023888 TI - Magnetization transfer-based 3D visualization of foot peripheral nerves. AB - PURPOSE: To investigate magnetization transfer (MT) effects as a new source of contrast for imaging and tracking of peripheral foot nerves. MATERIALS AND METHODS: Two sets of 3D spoiled gradient-echo images acquired with and without a saturation pulse were used to generate MT ratio (MTR) maps of 260 MUm in-plane resolution for eight volunteers at 3T. Scan parameters were adjusted to minimize signal loss due to T2 dephasing, and a dedicated coil was used to improve the inherently low signal-to-noise ratio of small voxels. Resulting MTR values in foot nerves were compared with those in surrounding muscle tissue. RESULTS: Average MTR values for muscle (45.5 +/- 1.4%) and nerve (21.4 +/- 3.1%) were significantly different (P < 0.0001). In general, the difference in MTR values was sufficiently large to allow for intensity-based segmentation and tracking of foot nerves in individual subjects. This procedure was termed MT-based 3D visualization. CONCLUSION: The MTR serves as a new source of contrast for imaging of peripheral foot nerves and provides a means for high spatial resolution tracking of these structures. The proposed methodology is directly applicable on standard clinical MR scanners and could be applied to systemic pathologies, such as diabetes. PMID- 23023889 TI - Curable focal epilepsy. PMID- 23023890 TI - Oxycodone overdose causes naloxone responsive coma and QT prolongation. AB - BACKGROUND: Although there are limited data on oxycodone overdose, it has been suggested that, in addition to central nervous system (CNS) depression, oxycodone may cause QT prolongation. Given the high prescription rate and increasing use of oxycodone, an understanding of its effects and treatment in overdose is necessary. AIM: To investigate the clinical features, electrocardiogram (ECG) parameters and treatment of oxycodone overdose. DESIGN: Retrospective review of a clinical database. METHODS: One hundred and thirty-seven oxycodone overdoses were identified from admissions to a toxicology unit between January 2001 and May 2011. Demographic information, details of ingestion, clinical effects, ECG parameters [heart rate (HR), QT and QRS], naloxone use and length of stay (LOS) were extracted from a clinical database. QT was measured manually and plotted on a QT nomogram. LOS was extracted for all overdoses over the same period. RESULTS: From 137 oxycodone overdoses, 79 (58%) ingested immediate release (IR) and 58 (42%) ingested sustained release (SR) or a combination of IR and SR. The median age was 40 years [interquartile range (IQR): 33-49 years], and 87 were female (64%). The median ingested dose of IR oxycodone was 70 mg (IQR: 40-100, range: 5 200), compared to 240 mg (IQR: 80-530, range: 30-1600) for SR oxycodone. Benzodiazepines were the most frequent co-ingested drug in 52 (38%) cases. No arrhythmias were recorded. Twenty-four patients (18%) had bradycardia of which five had a HR < 50 beats/min. From 116 available ECGs, the median QRS was 95 ms (IQR: 90-102 ms), and there were 20 (17%) abnormal QT-HR pairs. Naloxone boluses were required in 65 admissions (47%), and 34 (25%) required a naloxone infusion. There was higher overall naloxone use with SR and IR + SR (32/58, 55%) compared to IR oxycodone (33/79, 42%). The median LOS was 18 h (IQR: 12-35), which was greater than the median LOS for all toxicology admissions at 15 h (IQR: 8-24) over the same period. Patients requiring a naloxone infusion had an even greater LOS of 36 h (IQR: 20-62 h). CONCLUSION: In addition to the expected CNS depression, the opioid oxycodone can cause bradycardia and QT prolongation in overdose. The SR formulation is associated with the use of naloxone infusions and a longer LOS. PMID- 23023891 TI - Electrocardiogram in Brugada syndrome. PMID- 23023892 TI - Abstracting knowledge from the Protein Data Bank. AB - In the 40 years since its inception, the Protein Data Bank (PDB) has amassed over 80,000 experimentally determined structural models of proteins, plus many models of DNA and RNA fragments. The majority of the protein models have contributed, in some way, to an understanding of their particular protein's function, be it through the conformation of its catalytic residues, the details of its interactions with other proteins, substrate molecules, DNA, and so on. However, the totality of the data in the PDB provides a rich source of more generalized knowledge about proteins, their molecular biology, and evolution. Here, we describe how the focus of protein structural analysis has developed over the past 40 years. (c) 2012 Wiley Periodicals, Inc. Biopolymers 99: 183-188, 2013. PMID- 23023893 TI - College student stressors: a review of the qualitative research. AB - A total of 40 qualitative studies were reviewed and coded according to the college student stressors they represented. These studies utilized a variety of qualitative methods to examine stressors representing the following themes: relationships, lack of resources, academics, the environment, expectations, diversity, transitions and other stressors. Relationship stressors were the most commonly reported theme and covered areas including stress associated with family, romantic, peer and faculty relationships. Three of the themes (relationships, diversity and other) are novel categories of stressors compared with quantitative reviews on the topic, highlighting the importance of gathering both quantitative and qualitative pieces of information. This review contributes to the stress literature by synthesizing and identifying trends in the qualitative student stress research. PMID- 23023894 TI - Alexandre Yersin (1863-1943): Vietnam's 'Fifth Uncle'. PMID- 23023895 TI - Beyond low-density lipoprotein cholesterol: why, who and when. AB - Cardiovascular disease due to atherosclerosis is a leading cause of death around the world, including Singapore. Current treatment strategies primarily target low density lipoprotein (LDL) cholesterol levels. Low levels of high-density lipoprotein (HDL) cholesterol and high triglyceride (TG) levels have been shown to increase the risk of coronary heart disease, but the clinical benefits of raising low HDL cholesterol have only been proven in a limited number of studies. This guide provides an approach on managing low HDL cholesterol levels in terms of lifestyle modifications and pharmacotherapy. PMID- 23023896 TI - Low-lying spinal cord and tethered cord syndrome in children with anorectal malformations. AB - INTRODUCTION: Anorectal malformations (ARMs) and low-lying spinal cord (LLC) are commonly associated owing to their common embryonic origin. LLC may lead to tethered cord syndromes (TCS), requiring surgery. This study aimed to review the incidence of LLC in children with ARMs using ultrasonography (US) and magnetic resonance (MR) imaging, the incidence of TCS and the surgical outcomes of these patients after detethering. METHODS: We conducted a retrospective study of children who underwent surgery for ARMs in 2002-2009 at KK Women's and Children's Hospital, Singapore. RESULTS: Out of 101 (16.8%) ARM patients, 17 had LLC, of which 12 (70.6%) were high ARMs. 12 of the 17 (70.6%) patients had abnormal US and MR imaging findings. Five (29.4%) had normal US but abnormal MR imaging results; in these five patients, MR imaging was performed due to new symptoms and equivocal US findings. These 17 patients subsequently underwent surgical detethering. Three out of seven patients with TCS improved after surgery. None of the 17 patients had any complications. CONCLUSION: LLC appeared to be associated with high ARMs, although this was not statistically significant. LLC should be investigated for whenever ARM is diagnosed, regardless of its type. Lumbar US is useful for first-line screening for LLC. Abnormal US or onset of new symptoms should subsequently be investigated with MR imaging. Equivocal US findings are also likely to benefit from further MR imaging. Surgery to detether LLC can improve outcome in TCS, while prophylactic detethering for asymptomatic patients with lipoma of the filum terminale has very low surgical risk. PMID- 23023897 TI - Percutaneous pedicle screw fixation for thoracolumbar burst fracture: a Singapore experience. AB - INTRODUCTION: This study aimed to evaluate the clinical and radiological outcomes, and safety and efficacy of percutaneous pedicle screw fixation (PPSF) in the treatment of thoracolumbar burst fractures. METHODS: This was a retrospective review of patients with thoracolumbar burst fractures treated with PPSF in a single hospital from 2010 to 2011. Baseline data included patient demographics, mechanism of injuries, fracture level, neurologic status and the number of percutaneous screws inserted. Kyphotic angle correction, vertebral body height restoration and mid-sagittal canal diameter improvement were used to assess radiological outcome. Screw misplacement, operative complications, functional improvement (ASIA score) and pain score on visual analogue scale were used to assess safety and clinical outcomes. RESULTS: 21 patients with 25 thoracolumbar burst fractures were treated with 134 percutaneous screws. There was significant improvement in kyphotic angle correction (mean difference 6.1 degrees, p = 0.006), restoration of anterior and posterior vertebral height (mean difference 19.7%, p < 0.01 and mean difference 6.6%, p = 0.007, respectively) and mid-sagittal canal diameter (mean difference 15.6%, p = 0.007) on discharge. These improvements remained statistically significant at six months post operation for restoration of anterior vertebral body height (mean difference 9.8%, p = 0.05) and mid-sagittal diameter (mean difference 30.0%, p < 0.01). CONCLUSION: In this first local review, we have shown that PPSF is a relatively safe and effective technique for treating selected thoracolumbar burst fractures, and that it yields satisfactory results. However, its long-term outcome and efficacy need to be further evaluated. PMID- 23023898 TI - Spinal cavernous malformations: magnetic resonance imaging and associated findings. AB - INTRODUCTION: We reviewed the clinical features, brain and spinal cord magnetic resonance (MR) imaging findings and associated abnormalities in six patients with spinal cavernous malformations (CMs). METHODS: Lesions were defined on gradient recalled echo (GRE) images but measured on T2-weighted images performed on 1.5- and 3-tesla clinical scanners. RESULTS: Four patients had associated multiple cranial CMs and one patient had multiple spinal CMs. All spinal CMs were predominantly hypointense on GRE images, and most were predominantly hyperintense and surrounded by hypointense edge on T2-weighted images. Other associations included asymptomatic vertebral body and splenic haemangiomas. CONCLUSION: We conclude that intramedullary spinal CMs typically have 'mulberry' or 'popcorn' appearances similar to those of cranial CM. The presence of associated haemangioma or familial cranial CM syndrome on MR imaging may suggest the correct diagnosis without requiring invasive investigations. PMID- 23023899 TI - Standardisation of the neck-shaft angle and measurement of age-, gender- and BMI related changes in the femoral neck using DXA. AB - INTRODUCTION: The morphology of the proximal femur has often been investigated in the literature, but the normal population ranges and standard deviations have still not been determined for this area. This study aimed to determine the age-, gender- and body mass index (BMI)-related changes in the femoral neck, especially on the neck-shaft angle, by using dual-energy X-ray absorptiometry (DXA) measurements. METHODS: Retrospective analyses of DXA images of the proximal femur from 18,943 individuals aged 20-108 years were performed. The age, gender, weight and height of each individual were obtained at the time of bone measurement. Data on theta angle were obtained from DXA measurements. Simple linear regression analysis and Pearson's correlation coefficients were used to investigate the relationships between theta and age, gender and BMI. RESULTS: There was a significant correlation between theta and age (p < 0.001). We also found a significant difference between the various age groups using analysis of variance (p < 0.001), but there was no meaningful correlation between theta and BMI (p = 0.377) and the BMI groups (p = 0.180). There were small but statistically significant differences in the neck-shaft angle between males and females (p < 0.05). CONCLUSION: In this study, DXA-based measurements were used and many parameters of proximal femur geometry were calculated with limited radiation exposure. We have demonstrated that the mean neck-shaft angle is greater in males than in females, and that theta increases with age. We also found a significant difference between different age groups, but no meaningful correlation between theta and BMI. PMID- 23023900 TI - Outcomes of infected grade IIIB open tibial fractures. AB - INTRODUCTION: Infection following grade IIIB open tibial fracture is common. The primary aim of managing this condition is to achieve control of infection before the bone reconstruction procedure is performed. The outcomes for such patients have not been evaluated in the literature. This study was conducted to examine the outcome of a multi-stage procedure for the treatment of infected grade IIIB open tibial fractures. METHODS: Between 2004 and 2008, we treated 11 patients with infected grade IIIB open tibial fractures in our unit. The management of infected grade IIIB open tibial fracture comprised three stages, which included serial debridement, wound closure by local flap surgery and bone reconstruction. The margin of resection and the type of bone reconstruction depended on the anatomical location of the disease, the extent of osteomyelitis and patient preference regarding treatment options. Bone reconstruction procedures included bone grafting, plating, interlocking nail, hybrid and monolateral external fixator, and Ilizarov bone transport. RESULTS: Gram-negative organisms were isolated from all patients. Pseudomonas aeruginosa (P. aeruginosa) (44%) was the most common organism cultured. Infection was resolved in all patients. Nine fractures achieved union, with a mean union time of 15 months. Two patients with P. aeruginosa infection developed non-union of the fracture and refused additional surgery after three years of treatment. CONCLUSION: The multi-stage management approach is well-accepted and effective in controlling infection in infected grade IIIB open tibial fractures. PMID- 23023901 TI - Effectiveness of an algorithm in reducing the number of unnecessary ultrasound scans for deep vein thrombosis: an evaluation report. AB - INTRODUCTION: Patients with suspected deep vein thrombosis (DVT) pose a diagnostic dilemma to the Emergency Department (ED) clinician. This study aimed to implement a known algorithm incorporating the modified Wells criteria and D dimer testing to guide the ED clinician, thus reducing unnecessary ultrasound scans (USS). METHODS: Patients who presented to the ED between August 2008 and April 2009 with suspected DVT underwent Wells scoring. Those with scores < 2 were deemed unlikely to have DVT and underwent D-dimer testing first. Patients with scores >= 2 were regarded as likely to have DVT and underwent urgent USS. USS findings were tabulated as positive or negative/indeterminate for DVT. The latter group was followed up for one year to check whether DVT was missed during the initial USS. RESULTS: 75 patients presented with suspected DVT and underwent USS. Of these, 14 results were positive and 61 were negative. 37 patients had Wells scores < 2, with three (8.1%) having DVT. Another 38 patients had Wells scores >= 2, with 11 (28.9%) having DVT. D-dimer testing was performed on 27 of the 75 patients. Those with DVT had higher average values compared to those without DVT (1.305 vs. 0.595 ug/ml). The majority of patients with raised D-dimer values had cellulitis, although three also had DVT (with values >= 0.99 ug/ml). CONCLUSION: We managed to reduce the number of unnecessary USS and increase the pick-up rate of DVT. A cut-off score >= 2 in our algorithm is suitable for use in the ED setting. PMID- 23023902 TI - The role of clinical pharmacy services in achieving treatment targets in Iranian haemodialysis patients. AB - INTRODUCTION: The number of patients suffering from chronic kidney disease (CKD) is increasing worldwide. Hyperphosphataemia and high serum calcium (Ca) and phosphorus (P) product contribute to the substantial increase in cardiovascular events in CKD patients. Although reports of CKD complications in Iranian haemodialysis (HD) patients are comparable to data from other developed countries, management of these complications has failed to meet generally accepted targets. This study evaluated the impact of clinical pharmacy services in the management of complications in HD patients. METHODS: During a six-month prospective study, clinical pharmacists conducted medical visits in the HD ward and adjusted the patients' medications according to their laboratory findings. RESULTS: Serum Ca concentration was increased in hypocalcaemia patients and decreased in hypercalcaemia patients until it reached the optimal range in both groups. A decline in serum P level was noted in hyperphosphataemia patients, although it did not reach the target range. The Ca * P product decreased in patients with Ca * P > 55 mg2/dL2. Although it did not reach the goal, there was an increase and decrease in serum intact parathyroid hormone (iPTH) concentration in suboptimal and supraoptimal range patients, respectively. Serum Ca, P and iPTH levels did not change in patients with optimal values at the initiation of the study. Haemoglobin concentration increased in anaemic patients and serum ferritin reached target values in all patients. Total cholesterol, low-density lipoprotein cholesterol and triglycerides decreased to near-optimal values in dyslipidaemia patients. CONCLUSION: This study showed that clinical pharmacy services at the HD centre can improve the management of complications in CKD patients. PMID- 23023903 TI - Cervical cancer in Brunei Darussalam. AB - INTRODUCTION: Cervical cancer caused by the human papilloma virus (HPV) is a common cancer in women. There is no published data on the recent incidence of cervical dysplasia, cervical cancer and genital warts caused by the different types of HPVs in Brunei Darussalam. METHODS: A cross-sectional, retrospective study was conducted utilising data from patients diagnosed with cervical cancer during the period 2005-2009 in Brunei Darussalam. The varying incidences of different types of cervical lesions among various ethnic and age groups, and in the overall population, were determined. RESULTS: The mean age-standardised incidence of invasive cervical cancer during the five-year period was 24.9 per 100,000 women per year (95% confidence interval [CI] 21.7, 28.1). Age-specific invasive cervical cancer incidence peaked in the age group 45-59 years. Chinese females tended to have a higher incidence of invasive cervical cancer (28.2 per 100,000 women per year; 95% CI 17.8, 38.7) than Malay females (20.6 per 100,000 women per year; 95% CI 17.1, 24.2), while other ethnic groups in Brunei Darussalam had a significantly lower incidence (6.5 per 100,000 women per year; 95% CI 3.0, 10.0). CONCLUSION: The results suggest that Brunei Darussalam has a relatively higher incidence of cervical cancer compared to its neighbouring countries. The findings support the need for more comprehensive screening, public education programmes and vaccination against HPV in the country. PMID- 23023904 TI - Evidence of oxidative stress in peroxisomal disorders. AB - INTRODUCTION: Peroxisomal disorders are subdivided into peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme deficiency. Many peroxisomal diseases exhibit excessive oxidative stress, leading to neurological alterations and dysfunction. Peroxisomes use oxygen in oxidative reactions that generate hydrogen peroxide. This study aimed to investigate various oxidative stress parameters in patients suffering from peroxisomal disorders. METHODS: A total of 20 patients with peroxisomal disorders, aged six months to 13 years (mean age 5.9 +/- 3.2 years), were compared to 14 healthy controls. All individuals were subjected to full history-taking, including a three-generation pedigree analysis concerning parental consanguinity and similarly affected members in the family, with meticulous clinical examination to detect any malformation or anomaly. Estimation of very-long-chain fatty acids and phytanic acid was done to verify the diagnosis. Brain magnetic resonance imaging, electroencephalogram, visual evoked potential, auditory potential and plain radiography were conducted to assess the pathological condition of the patients. Oxidative stress parameters, including nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD), were estimated in both the patients and controls. RESULTS: Significant increases in both MDA and NO were found in patients with PBDs. It was also demonstrated that SOD was significantly lower in patients with PDB than the controls. CONCLUSION: This study sheds more light on the link between oxidative stress and peroxisomal disorders, as oxidative stress may be a hallmark of peroxisomal disorders. Consequently, one of the useful neuronal rescue strategies could be treatment with antioxidant agents in addition to other lines of treatments. PMID- 23023905 TI - Efficacy of omega-3 fatty acid supplementation on serum levels of tumour necrosis factor-alpha, C-reactive protein and interleukin-2 in type 2 diabetes mellitus patients. AB - INTRODUCTION: Consumption of omega-3 fatty acids can alter the inflammatory response in diabetic patients. This study aimed to determine the effects of omega 3 fatty acid supplementation on the serum levels of C-reactive protein (CRP), interleukin (IL)-2 and tumour necrosis factor-alpha (TNF-alpha) in type 2 diabetes mellitus patients. METHODS: A randomised, double-blind, placebo controlled clinical trial was conducted on 84 subjects aged 45-85 years with at least a two-year history of type 2 diabetes mellitus. Participants were randomly assigned to the treatment or control group. Each subject in the treatment group received three omega-3 capsules per day (eicosapentaenoic acid 1,548 mg; docosahexaenoic acid 828 mg; other omega-3 fatty acids 338 mg), while each subject in the control group received three placebo capsules (sunflower oil 2,100 mg) for a period of eight weeks. At the beginning of the study and post intervention, fasting blood samples were taken and serum concentrations of IL-2, TNF-alpha and CRP were assessed and compared. RESULTS: Serum IL-2 and TNF-alpha levels were significantly reduced in the treatment group compared to the controls (p < 0.01). There was no significant change in serum CRP levels. CONCLUSION: Short-term omega-3 fatty acid supplementation (3 g/day for eight weeks) can decrease the serum levels of TNF-alpha and IL-2 in diabetic patients, with no change in CRP levels. Consumption of omega-3 fatty acid supplements is highly recommended to alleviate inflammation caused by type 2 diabetes mellitus. PMID- 23023907 TI - Cricoid pressure: ritual or effective measure? AB - Cricoid pressure has been long used by clinicians to reduce the risk of aspiration during tracheal intubation. Historically, it is defined by Sellick as temporary occlusion of the upper end of the oesophagus by backward pressure of the cricoid cartilage against the bodies of the cervical vertebrae. The clinical relevance of cricoid pressure has been questioned despite its regular use in clinical practice. In this review, we address some of the controversies related to the use of cricoid pressure. PMID- 23023908 TI - Clinics in diagnostic imaging. 141. Complete anterior cruciate ligament tear. AB - A 38-year-old man presented with right knee pain and swelling following a football injury. Magnetic resonance (MR) imaging showed a complete anterior cruciate ligament (ACL) tear and lateral meniscal tears. The torn ACL was repaired with a graft obtained from the semitendinosus muscle, and the menisci were debrided. The mechanisms of injury to the ACL are varied and may be due to direct or indirect contact with the knee as well as with twisting injuries. Knowledge of the ACL's normal anatomy, together with MR imaging technique and understanding of the appearance of the lesion on MR examination, is crucial to aid in the identification of an ACL tear. Diagnosis of an ACL tear should be based on direct MR imaging signs, although indirect signs may be helpful, particularly in chronic tears. Other associated injuries to be aware of include meniscal and other ligamentous injuries. Normal ACL graft and post-ACL graft reconstruction complications are also briefly discussed. PMID- 23023909 TI - Bowel prolapse following spontaneous rupture of a femoral hernia. AB - This case presents a rare complication of the spontaneous rupture of a femoral hernia in an elderly woman without causing much systemic effect despite the herniated bowel being necrosed and perforated, giving rise to an enterocutaneous fistula. The small bowel had also prolapsed through the fistula opening, making it a very rare and alarming presentation. PMID- 23023910 TI - Subcutaneous dirofilariasis. AB - Subcutaneous dirofilariasis is a parasitic infestation found in endemic areas in Mediterranean countries such as Italy. It is occasionally reported in India, mostly from the state of Kerala. Presentation in an infant is extremely rare. We report a case of subcutaneous dirofilariasis in a child that was diagnosed by ultrasonography and confirmed by surgery. PMID- 23023912 TI - Congenital absence of the vermiform appendix. AB - Agenesis of the vermiform appendix is very rare. The incidence is estimated to be one in 100,000 laparotomies for suspected appendicitis. During a routine dissection of the abdomen in a 60-year-old donated male cadaver, the vermiform appendix was found to be absent. The ileocaecal junction and retrocaecal area were thoroughly searched, but the vermiform appendix was not found or appeared to resemble a tubercle. This is likely the first reported case of agenesis of a vermiform appendix in India. This suggests the possibility that the human vermiform appendix would ultimately become rudimentary or absent in the course of evolution. PMID- 23023911 TI - Complex pattern of a variant hepatic artery. AB - Liver transplantation is the only solution for end-stage liver diseases. The common hepatic artery (CHA) arises from the coeliac trunk (CT), and the right (RHA) and left hepatic (LHA) arteries are its terminal branches. An abnormal arterial pattern would influence the surgical outcome. The anterior layer of the lesser omentum of a female cadaver was cleaned to identify the CHA, which was traced backwards for its origin and toward the porta hepatis for its terminal branches. In this case, the replaced RHA originated from the CT and ran posterior to the portal vein and the common bile duct. The replaced LHA arose from the left gastric artery. The CHA originated from the CT and branched out as the middle hepatic and gastroduodenal arteries. The replaced RHA and LHA with alteration in relation to the neighbouring structures is a complex and rare variant. Knowledge of this uncommon arterial anomaly is beneficial for hepatobiliary surgeons. PMID- 23023913 TI - Oesophageal tuberculosis: rare but not to be forgotten. AB - Tuberculosis remains an important cause of morbidity and mortality, especially in underdeveloped and developing nations. Manifestations could be nonspecific and may mimic many other conditions, including malignancies. Oesophageal involvement is surprisingly rare despite the high prevalence of pulmonary tuberculosis and the close proximity of these two structures. We report two cases of oesophageal tuberculosis; a 73-year-old man with simultaneous oesophageal, stomach and duodenal involvement, and a 45-year-old man with isolated oesophageal involvement. Underlying malignancies were initially suspected in both cases, but they were eventually diagnosed as tuberculosis. PMID- 23023914 TI - Collision adenoma-carcinoid tumour of the colon complicated by carcinoid syndrome. AB - Tumours consisting of a glandular component, either an adenoma or adenocarcinoma, and a carcinoid component are uncommon. These tumours can be differentiated into collision, composite or amphicrine tumours. Most cases reported in the literature were mixed adenocarcinoma-carcinoid tumours. To date, only four cases of mixed adenoma carcinoid tumours have been reported in the literature. This case report describes a unique case of collision adenoma-carcinoid tumour in the colon complicated by carcinoid syndrome in a 45-year-old woman who presented with a one month history of diarrhoea and weight loss. She developed recurrence of the carcinoid component of the tumour four months after endoscopic resection. We conclude that carcinoid syndrome can occur in an adenoma-carcinoid tumour; however, the prognosis of this condition is uncertain. PMID- 23023915 TI - Diffuse large B-cell lymphoma presenting with extensive cutaneous infiltration. AB - We report a case of systemic diffuse large B-cell lymphoma presenting with extensive infiltration of the skin. A 56-year-old woman presented with a two month history of pruritic erythematous plaques and nodules over the neck, trunk and upper limbs. She also had night sweats, weight loss, lethargy and reduced effort tolerance. Systemic examination revealed a pale, ill appearance with hepatosplenomegaly and lymphadenopathy. Blood investigations showed pancytopenia (haemoglobin 6.3 g/dL, total white cell count 3.0 * 10(9)/L, platelet count 138 * 10(9)/L) with a few suspicious mononuclear cells and a mildly elevated lactate dehydrogenase level (478 U/L). Skin biopsy demonstrated diffuse sheets and nodular infiltrates of CD20 and CD79a positive neoplastic cells in the dermis and subcutis. Computed tomography revealed multiple cervical, axillary, mediastinal, para-aortic and mesenteric lymph nodes. Bone marrow aspiration and trephine biopsy confirmed marrow involvement by non-Hodgkin's lymphoma. The patient was treated with chemotherapy, which resulted in resolution of the skin lesions. PMID- 23023916 TI - In vivo (1)H-MRS hepatic lipid profiling in nonalcoholic fatty liver disease: an animal study at 9.4 T. AB - The applicability of the in vivo proton magnetic resonance spectroscopy hepatic lipid profiling (MR-HLP) technique in nonalcoholic fatty liver disease was investigated. Using magnetic resonance spectroscopy, the relative fractions of diunsaturated (fdi), monounsaturated (fmono), and saturated (fsat) fatty acids as well as total hepatic lipid content were estimated in the livers of 8 control and 23 CCl4-treated rats at 9.4 T. The mean steatosis, necrosis, inflammation, and fibrosis scores of the treated group were all significantly higher than those of the control group (P < 0.01). There was a strong correlation between the histopathologic parameters and the MR-HLP parameters (r = 0.775, P < 0.01) where both steatosis and fibrosis are positively correlated with fmono and negatively correlated with fdi. Both necrosis and inflammation, however, were not correlated with any of the MR-HLP parameters. Hepatic lipid composition appears to be changed in association with the severity of steatosis and fibrosis in nonalcoholic fatty liver disease, and these changes can be depicted in vivo by using the MR-HLP method at 9.4 T. Thus, while it may not likely be that MR-HLP helps differentiate between steatohepatitis in its early stages and simple steatosis, these findings altogether are in support of potential applicability of in vivo MR-HLP at high field in nonalcoholic fatty liver disease. PMID- 23023917 TI - Early assessment of acute coronary syndromes in the emergency department: the potential diagnostic value of circulating microRNAs. AB - Previous studies investigating the role of circulating microRNAs in acute coronary syndrome (ACS) were based on small patient numbers, performed no comparison with established markers of cardiac injury and did not have appropriate controls. We determined the potential diagnostic value of circulating microRNAs as novel early biomarkers in 332 suspected ACS patients on presentation to the emergency department (ED) in a prospective single-centre study including cardiac miRNAs (miR-1, -208a and -499), miR-21 and miR-146a. Levels of all miRs studied were significantly increased in 106 patients diagnosed with ACS, even in patients with initially negative high-sensitive (hs) troponin or symptom onset <3 h. MiR-1, miR-499 and miR-21 significantly increased the diagnostic value in all suspected ACS patients when added to hs-troponin T (AUC 0.90). These three miRs were strong predictors of ACS independent of clinical co-variates including patient history and cardiovascular risk factors. Interestingly, the combination of these three miRs resulted in a significantly higher AUC of 0.94 than hs troponin T (0.89). Circulating microRNAs hold great potential as novel early biomarkers for the management of suspected ACS patients. PMID- 23023918 TI - Structural adaptations for ram ventilation: gill fusions in scombrids and billfishes. AB - For ram-gill ventilators such as tunas and mackerels (family Scombridae) and billfishes (families Istiophoridae, Xiphiidae), fusions binding the gill lamellae and filaments prevent gill deformation by a fast and continuous ventilatory stream. This study examines the gills from 28 scombrid and seven billfish species in order to determine how factors such as body size, swimming speed, and the degree of dependence upon ram ventilation influence the site of occurrence and type of fusions. In the family Scombridae there is a progressive increase in the reliance on ram ventilation that correlates with the elaboration of gill fusions. This ranges from mackerels (tribe Scombrini), which only utilize ram ventilation at fast cruising speeds and lack gill fusions, to tunas (tribe Thunnini) of the genus Thunnus, which are obligate ram ventilators and have two distinct fusion types (one binding the gill lamellae and a second connecting the gill filaments). The billfishes appear to have independently evolved gill fusions that rival those of tunas in terms of structural complexity. Examination of a wide range of body sizes for some scombrids and billfishes shows that gill fusions begin to develop at lengths as small as 2.0 cm fork length. In addition to securing the spatial configuration of the gill sieve, gill fusions also appear to increase branchial resistance to slow the high-speed current produced by ram ventilation to distribute flow evenly and optimally to the respiratory exchange surfaces. PMID- 23023919 TI - Lentiviral vector-mediated RNA interference targeted against prohibitin inhibits apoptosis of the retinoic acid-resistant acute promyelocytic leukemia cell line NB4-R1. AB - To investigate the possibility of prohibitin (PHB) inhibition by lentiviral vector-mediated RNA interference (RNAi) and its influence on cell apoptosis in the retinoic acid-resistant acute promyelocytic leukemia cell line NB4-R1, a lentiviral vector encoding a short hairpin RNA (shRNA) targeted against PHB (pGCSIL-GFP-PHB) was constructed and transfected into the packaging cells 293T, and the viral supernatant was collected to transfect NB4-R1 cells. Quantitative real-time fluorescent PCR and western blotting were used to detect the expression levels of PHB. Flow cytometry and detection of enzymatic activity of caspase-3 by western blotting were employed to examine cell apoptosis. Our results provide evidence that the lentiviral vector pGCSIL-GFP-PHB was constructed successfully, and the PHB mRNA and the protein expression inhibitory rates were 90.3 and 95.8%, respectively. When compared to the control group, the activity of caspase-3 decreased significantly, which showed a 57.3% downregulation, and the apoptosis rate was reduced by 44.6% (P<0.05). In conclusion, downregulation of the PHB gene may inhibit apoptosis of NB4-R1 cells, and it is speculated that this was at least partly due to the downregulation of caspase-3, and PHB may be a novel target for gene therapy for retinoic acid-resistant acute promyelocytic leukemia. PMID- 23023920 TI - MGAT2-CDG (CDG-IIa) and dysmorphism. PMID- 23023921 TI - Direct potable reuse of reclaimed wastewater: it is time for a rational discussion. AB - Water shortage arising from rapid population growth and relocation has produced an unprecedented degree of stress on regional water resources. Engineered solutions to relieve water stress are frequently based on the use of water of impaired initial quality. Chief among these impaired waters is reclaimed wastewater. For the most part, however, the breadth of both acceptable uses and use-dependent degree of treatment for reclaimed wastewater remain to be established.The chief advantages of direct potable reuse (DPR) relative to other forms of wastewater reclamation and reuse are that(i) all wastewater reclaimed for DPR can be readily used in water-stressed areas and (ii) delivery to points of use does not require a separate distribution system. The drawbacks are related to the need for highly competent, continuous on-line verification of water quality and the cost of treating all reclaimed wastewater to meet potable use requirements when only a small fraction will be used for potable purposes.We have attempted to explore those differences, providing quantitative comparisons where possible, to support selection among water reuse options in water-stressed areas. PMID- 23023923 TI - Non-invasive prenatal diagnostics of aneuploidy using next-generation DNA sequencing technologies, and clinical considerations. AB - Rapidly developing next-generation sequencing (NGS) technologies produce a large amount of data across the whole human genome and allow a large number of DNA samples to be analyzed simultaneously. Screening cell-free fetal DNA (cffDNA) obtained from maternal blood using NGS technologies has provided new opportunities for non-invasive prenatal diagnosis (NIPD) of fetal aneuploidies. One of the major challenges to the analysis of fetal abnormalities is the development of accurate and reliable algorithms capable of analyzing large numbers of short sequence reads. Several such algorithms have recently been developed. Here, we provide a review of recent NGS-based NIPD methods as well as the available algorithms for short-read sequence analysis. We furthermore introduce the practical application of these algorithms for the detection of different types of fetal aneuploidies, and compare the performance, cost and complexity of each approach for clinical deployment. Our review identifies several main technologies and trends in NGS-based NIPD. The main considerations for clinical development for NIPD and screening tests using DNA sequencing are: accuracy, intellectual property, cost and the ability to screen for a wide range of chromosomal abnormalities and genetic defects. The cost of the diagnostic test depends on the sequencing method, diagnostic algorithm and volume of the tests. If the cost of sequencing equipment and reagents remains at or around current levels, targeted approaches for sequencing-based aneuploidy testing and SNP-based methods are preferred. PMID- 23023922 TI - Effect of particulate matter air pollution on C-reactive protein: a review of epidemiologic studies. AB - Inflammatory response is implicated as a biologic mechanism that links particulate matter (PM) air pollution with health effects. C-reactive protein (CRP), an important acutephase reactant with profound proinflammatory properties, is used clinically as an indicator of the presence and intensity of inflammation. In vitro and in vivo animal studies suggest that CRP levels increase in response to PM exposure, but there was no consistency in epidemiologic studies. Herein, a systematic review was conducted to examine the association between PM exposure and serum CRP levels in humans. Elevated CRP levels were consistently found among children, and CRP elevations were also observed among healthy adults, albeit requiring higher peak levels of PM exposure. PM-induced CRP responses were not consistently found in adults with chronic inflammatory conditions, perhaps because of the use of anti-inflammatory medications in this population. Of the eight examined randomized trials, only one trial with a longer intervention period supported the effect of PM exposure on CRP concentrations. To provide conclusive evidence, further epidemiologic studies are needed to better quantify the magnitude of CRP level changes in response to PM with well-defined study populations and better control of various confounding factors. PMID- 23023924 TI - Readability analysis of healthcare-oriented education resources from the American Academy of Facial Plastic and Reconstructive Surgery. AB - OBJECTIVES/HYPOTHESIS: Deficient health literacy remains a widespread public issue. As such, the National Institutes of Health (NIH) recommends that all patient resources should be written around a sixth-grade level. The authors evaluate healthcare-oriented resources specified for patient use on the American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS) Web site in order to identify potential areas of improvement and highlight those sections that may serve as paradigms for future revisions. STUDY DESIGN: Descriptive and correlational design. METHODS: Seventeen healthcare-oriented resources specifically for patients were downloaded in February 2012 from the American Academy of Facial Plastic and Reconstructive Surgery Web site. Readability assessments of each article were performed using Readability Studio Professional Edition Version 2012.1. These tests included the Flesch Reading Ease, Flesch Kincaid Grade Level, SMOG Grading, Coleman-Liau Index, Gunning-Fog Index, the New Fog Count, the New Dale-Chall Readability Formula, FORCAST formula, Raygor Readability Estimate, and the Fry Graph. RESULTS: Patient health education material found on the AAFPRS Web site has been found to be written at an average grade level of 12th grade using 10 different readability scales. CONCLUSIONS: Modifications of the patient education section of the AAFPRS Web site can increase the readability of the literature, and allow greater comprehension among a wider audience. PMID- 23023925 TI - Subcutaneous tumor volume measurement in the awake, manually restrained mouse using MRI. AB - PURPOSE: To describe a combination of techniques using the excellent volumetric capacities of magnetic resonance imaging (MRI) while avoiding anesthesia and maintaining high-throughput capability for tumor volume measurement in the awake mouse. This approach presents an alternative to calipers which, although cheap, fast, and easy to use, introduce many biases for tumor volume estimation. MATERIALS AND METHODS: The murine CaNT subcutaneous xenograft model was used. A quiet and modestly T2-weighted spin-echo scan was acquired at 4.7T (TE = 15 msec, TR = 1100 msec, 0.5 mm isotropic resolution) while the awake mouse was held by hand in the magnet. This method was compared to standard MR in the anesthetized mouse and caliper measurements. RESULTS: The combination of techniques used allows rapid, accurate, and reproducible measurement of subcutaneous tumor volumes in awake mice. It is less sensitive to both intra- and interoperator derived biases and avoids confounds from the compliance of the fat and skin around the tumor, as well as from the tumor itself. Moreover, the data remain available for retrieval and scrutiny and reanalysis. CONCLUSION: Rapid, accurate, and precise tumor volumetry can be performed in the awake mouse by handheld positioned MR. PMID- 23023926 TI - Piezochromic luminescence based on the molecular aggregation of 9,10-bis((E)-2 (pyrid-2-yl)vinyl)anthracene. PMID- 23023927 TI - Solid-state 73Ge NMR spectroscopy of simple organogermanes. AB - Germanium-73 is an extremely challenging nucleus to examine by NMR spectroscopy due to its unfavorable NMR properties. Through the use of an ultrahigh (21.1 T) magnetic field, a systematic study of a series of simple organogermanes was carried out. In those cases for which X-ray structural data were available, correlations were drawn between the NMR parameters and structural metrics. These data were combined with DFT calculations to obtain insight into the structures of several compounds with unknown crystal structures. PMID- 23023929 TI - Polymersome colloidosomes for enzyme catalysis in a biphasic system. PMID- 23023928 TI - Studying and polishing the PDB's macromolecules. AB - Macromolecular crystal structures are among the best of scientific data, providing detailed insight into these complex and biologically important molecules with a relatively low level of error and subjectivity. However, there are two notable problems with getting the most information from them. The first is that the models are not perfect: there is still opportunity for improving them, and users need to evaluate whether the local reliability in a structure is up to answering their question of interest. The second is that protein and nucleic acid molecules are highly complex and individual, inherently handed and three-dimensional, and the cooperative and subtle interactions that govern their detailed structure and function are not intuitively evident. Thus there is a real need for graphical representations and descriptive classifications that enable molecular 3D literacy. We have spent our career working to understand these elegant molecules ourselves, and building tools to help us and others determine and understand them better. The Protein Data Bank (PDB) has of course been vital and central to this undertaking. Here we combine some history of our involvement as depositors, illustrators, evaluators, and end-users of PDB structures with commentary on how best to study and draw scientific inferences from them. PMID- 23023930 TI - Editorial: molecular endocrinology articles in the spotlight for October 2012. PMID- 23023932 TI - Mapping of oxygen by imaging lipids relaxation enhancement: a potential sensitive endogenous MRI contrast to map variations in tissue oxygenation. AB - PURPOSE: Because of its paramagnetic properties, oxygen may act as an endogenous magnetic resonance imaging contrast agent by changing proton relaxation rates. Changes in tissue oxygen concentrations have been shown to produce changes in relaxation rate R1 of water. The aim of the study was to improve the sensitivity of oxygen enhanced R1 imaging by exploiting the higher solubility of oxygen in lipids (as compared with water) to sensitively monitor changes in tissue oxygen levels by selectively measuring the R1 of lipids. METHODS: The method, with the acronym "MOBILE" (mapping of oxygen by imaging lipids relaxation enhancement), was applied in different mouse models of hypoxic processes on a 11.7 T magnetic resonance imaging system. MOBILE was compared with R*2, R1 of water, and with pO2 measurements (using electron paramagnetic resonance oximetry). MOBILE was also applied in the brain of healthy human volunteers exposed to an oxygen breathing challenge on a 3 T magnetic resonance imaging system. RESULTS: MOBILE was shown to be able to monitor changes in oxygenation in tumor, peripheral, liver, and brain tissues. The clinical translation was demonstrated in human volunteers. CONCLUSION: MOBILE arises as a promising noninvasive and sensitive tool for diagnosis and therapeutic guidance in disorders involving hypoxia. PMID- 23023933 TI - Development and evaluation of a mechanistic bioconcentration model for ionogenic organic chemicals in fish. AB - A mechanistic mass balance bioconcentration model is developed and parameterized for ionogenic organic chemicals (IOCs) in fish and evaluated against a compilation of empirical bioconcentration factors (BCFs). The model is subsequently applied to a set of perfluoroalkyl acids. Key aspects of model development include revised methods to estimate the chemical absorption efficiency of IOCs at the respiratory surface (E(W) ) and the use of distribution ratios to characterize the overall sorption capacity of the organism. Membrane water distribution ratios (D(MW) ) are used to characterize sorption to phospholipids instead of only considering the octanol-water distribution ratio (D(OW) ). Modeled BCFs are well correlated with the observations (e.g., r(2) = 0.68 and 0.75 for organic acids and bases, respectively) and accurate to within a factor of three on average. Model prediction errors appear to be largely the result of uncertainties in the biotransformation rate constant (k(M) ) estimates and the generic approaches for estimating sorption capacity (e.g., D(MW) ). Model performance for the set of perfluoroalkyl acids considered is highly dependent on the input parameters describing hydrophobicity (i.e., log K(OW) of the neutral form). The model applications broadly support the hypothesis that phospholipids contribute substantially to the sorption capacity of fish, particularly for compounds that exhibit a high degree of ionization at biologically relevant pH. Additional empirical data on biotransformation and sorption to phospholipids and subsequent incorporation into property estimation approaches (e.g., k(M) , D(MW) ) are priorities with respect to improving model performance. PMID- 23023934 TI - Platinum-coated porous gold nanorods in methanol electrooxidation: dependence of catalytic activity on ligament size. AB - Here we demonstrate that, in the dealloying process of Au-Ag nanorods, temperature is the key parameter for producing porous Au nanorods with tunable ligament sizes. The vertically aligned Au-Ag alloy nanorods were first synthesized by the electrochemical co-deposition of Au and Ag onto anodic aluminum oxide (AAO) membrane templates. Porous Au nanorods were then obtained by selectively etching Ag away from the precursor Au-Ag alloy nanorods. Control of the ligament size was achieved by controlling the dealloying temperature. Pt deposited on the porous Au nanorods with smaller ligaments exhibited a higher catalytic activity during methanol electrooxidation than those deposited on nanorods with larger ligaments produced by dealloying at higher temperatures. The strong dependence of the catalytic activity on the ligament size of porous Au is principally due to different amounts of carbon monoxide (CO) generated during methanol electrooxidation. Less CO was generated as the ligament size decreased. This finding is of importance for developing highly efficient cathode materials for carrying out methanol electrooxidation in practical applications in which porous Au with a large surface area is used as a supporting substrate. PMID- 23023935 TI - microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. AB - In the present study, we constructed a lentivirus vector encoding the miR-29a precursor and established two stably infected cell lines, PLC-29a and 97L-29a. The overexpression of miR-29a was confirmed by TaqMan RT-PCR and significantly suppressed the growth of the hepatocellular carcinoma cell lines MHCC-97L and PLC. Dual-luciferase reporter assays indicated that the SPARC mRNA 3'UTR was directly targeted by miR-29a since the mutated 3'UTR was not affected. Silencing SPARC expression by RNAi knockdown resulted in a similar effect as miR-29a overexpression on hepatocellular carcinoma (HCC) cell growth regulation. Anti-miR 29a oligonucleotides (AMOs) upregulated the levels of SPARC in the HCC cells. The phosphorylation of AKT/mTOR downstream of SPARC was inhibited in miR-29a overexpressing HCC cells. We further examined and compared the expression levels of miR-29a in HCC tissues and the corresponding nearby non-cancerous liver tissues of 110 patients with HCC by qRT-PCR, and significantly lower expression of miR-29a was observed in the tissues affected by HCC. Our findings demonstrate that the expression of miR-29a is important in the regulation of the SPARC-AKT pathway and HCC growth. PMID- 23023936 TI - P-gp upregulation may be blocked by natural curcuminoids, a novel class of chemoresistance-preventing agent. AB - Once multidrug resistance (MDR) occurs in cancer cells, it is very difficult to reverse since overexpression of P-glycoprotein (P-gp) is accompanied by altered expression of numerous other activated target genes. Previously, we reported that curcumin pretreatment would be an ideal method to prevent acquired drug resistance induced by adriamycin, administered prior to the development of MDR. To further confirm the previous results, we examined the potency of 3 forms of curcuminoids present in turmeric as potent preventers of acquired drug resistance. K562 cells were pretreated with or without curcuminoids for 24 h and co-incubated with adriamycin. P-gp and mdr1 mRNA levels were analyzed separately by flow cytometry and quantitative real-time RT-PCR. In addition, we performed an MTT assay to determine the adriamycin-induced cytotoxicity with or without pretreatment with curcuminoids. Short- and long-term exposure of native K562 cells to adriamycin led to upregulation of P-gp and formation of acquired drug resistance. However, after pretreatment with curcuminoids, the above processes were significantly inhibited. The MTT assay examined the enhanced effect of curcuminoids on adriamycin-induced cytotoxicity. Results from western blotting showed that curcuminoids could inhibit the adriamycin-induced increase of NF kappaB nuclear translocation and activation. Finally, under the long-term exposure model, we proved that curcumin was capable of blocking the occurrence of MDR in the cell line throughout the 56-day culture period. This study reveals that curcuminoids have the potency to block the upregulation of P-gp and its mRNA induced by short- and long-term exposure to adriamycin. Curcuminoids may be a novel class of potent chemoresistance-preventing agent with high safety and the potential for widespread clinical use. PMID- 23023937 TI - 2q24 deletions: further characterization of clinical findings and their relation to the SCN cluster. AB - As the resolution of molecular cytogenetic methods continues to improve, it has become increasingly possible to refine genotype-phenotype correlations based upon gene involvement. We report three new patients with nonrecurrent deletions involving subbands of 2q24. These patients were referred for evaluation of developmental delay, but were found to have unique, nonoverlapping clinical features. Patient 1 presented with infantile seizures, microcephaly, and brain anomalies, along with facial dysmorphism, growth retardation, neuromuscular scoliosis, and later with developmental regression. Array comparative genomic hybridization (aCGH) detected an 8 Mb interstitial deletion encompassing the neuronal sodium channel (SCN) gene cluster. Patient 2 presented with growth retardation, congenital heart defect, and hypotonia. Patient 3 presented with developmental delay and behavioral problems. Patients 2 and 3 had no history of seizures, microcephaly, or brain anomalies and were found to have deletions of 2q24, ~8 Mb and <500 kb respectively, centromeric to and outside the SCN cluster. It has been demonstrated that mutations and copy number variants (CNVs) affecting the SCN gene cluster result in severe, early-onset seizures. It is however, less clear whether haploinsufficiency of regions outside the SCN cluster may result in phenotypically recognizable and clinically significant features. We discuss additional dosage sensitive genes that may exist outside the SCN cluster. Our and published data indicate that 2q24 deletions not involving the SCN cluster are associated with fewer neurobehavioral problems, but may predispose to congenital malformations. PMID- 23023938 TI - Transoral power-assisted marsupialization of vallecular cysts under local anesthesia. PMID- 23023939 TI - Detection of molecular chirality by induced resonance Raman optical activity in europium complexes. AB - Beef up the signal: Induced resonance Raman optical activity (IRROA) in the presence of a europium complex enabled the detection of molecular chirality (see picture) with a 10(4)-fold increase in sensitivity relative to that observed with conventional nonresonant vibrational ROA. The method can thus be used as a sensitive tool for the determination of the absolute configuration and enantiomeric excess of organic and biologically relevant compounds. PMID- 23023940 TI - Tumor volume and subvolume concordance between FDG-PET/CT and diffusion-weighted MRI for squamous cell carcinoma of the cervix. AB - PURPOSE: To compare [(18)F]fluorodeoxyglucose (FDG)/positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI) for evaluating patients with cervical cancer. We compared tumor characteristics on FDG-PET and apparent diffusion coefficient (ADC) maps on diffusion-weighted MRI (DWI) to evaluate concordance of two functional imaging techniques. MATERIALS AND METHODS: Twenty women with cervical cancer underwent pretreatment FDG-PET/CT and pelvic MRI. Images were rigidly fused by pelvic anatomy using coregistration software. Tumor contours on PET images were generated by autosegmentation of the region containing at least 40% of the maximum standardized uptake value (SUV). DWI contours were generated by manual segmentation. Tumor volume similarity was evaluated using the [PET]/[ADC] volume proportion, Dice's coefficient, and the mean SUV isothreshold at the surface of each ADC contour. Tumor subvolume similarity was evaluated with analysis of variance (ANOVA). RESULTS: The [PET]/[ADC] volume proportion was 0.88 +/- 0.14. Dice's coefficient between PET and ADC tumor contours was 0.76 +/- 0.06. The mean SUV isothreshold at the ADC delineated tumor surface was 34 +/- 4%. Subvolumes with increased metabolic activity on FDG-PET also had more restricted diffusion on DWI (P < 0.0001, ANOVA). CONCLUSION: Concordance of functional imaging was observed between FDG PET and DWI for cervical cancer. Tumor subvolumes with increased metabolic activity on FDG-PET also have greater cell density by DWI. PMID- 23023941 TI - Factors affecting feasibility and quality of second-trimester ultrasound scans in obese pregnant women. AB - OBJECTIVES: To evaluate the feasibility of completing in one session a second trimester ultrasound scan in obese pregnant women, to compare the quality of images obtained with those of non-obese women and to analyze factors that can improve the completion rate. METHODS: This prospective study, from 2009 to 2011, included all obese pregnant women (prepregnancy body mass index (BMI) > 30 kg/m2) who had an ultrasound examination at 20-24 weeks in our department, and a control group of pregnant women with normal BMI (20-24.9 kg/m2) who had the same examination. A single operator reviewed the standardized ultrasound images (three biometric and six to assess key anatomical features) required under French guidelines, to assess their presence, evaluate the quality of all images and score the quality of the six anatomical images. Each image was assessed according to between four and six criteria, each worth one point. We sought excellent quality, defined as the frequency of maximum points for a given image type. The factors associated with completing the scan in one session were evaluated with multivariate logistic regression. RESULTS: The obese group included 223 women and the control group 60; a complete scan in one session was achieved in 70.4% and 81.7% of these, respectively (P = 0.08). The completion rate for each image type was at least 95% in the control group and 90% in the obese group, except for diaphragm and right outflow tract images. Significant factors associated with completing the scan in the multivariate model were: having 10 additional minutes for the scan (P = 0.03), moving the fetus so that the back was in posterior or lateral position (P = 0.01), more experienced sonographer (P = 0.03) and thinner maternal abdominal wall thickness (P = 0.01). Overall, the excellence rate varied from 35% to 92% in the normal BMI group and from 18% to 58% in the obese group, and was significantly lower in the latter for all images except abdominal circumference (P = 0.26) and spine (P = 0.06). Anatomical quality scores were also significantly lower in the obese group (22.3 vs. 27.2; P = 0.001). CONCLUSION: Although ultrasound scans of obese pregnant women are feasible, image quality and global anatomical scores are significantly lower among obese than normal-weight women. However, certain simple improvements may increase fetal visualization. PMID- 23023942 TI - The future of the Protein Data Bank. AB - The Worldwide Protein Data Bank (wwPDB) is the international collaboration that manages the deposition, processing and distribution of the PDB archive. The wwPDB's mission is to maintain a single archive of macromolecular structural data that are freely and publicly available to the global community. Its members [RCSB PDB (USA), PDBe (Europe), PDBj (Japan), and BMRB (USA)] host data-deposition sites and mirror the PDB ftp archive. To support future developments in structural biology, the wwPDB partners are addressing organizational, scientific, and technical challenges. PMID- 23023943 TI - Gastroesophageal reflux evaluation in patients affected by chronic cough: Restech versus multichannel intraluminal impedance/pH metry. AB - OBJECTIVES/HYPOTHESIS: Oropharyngeal (OP) pH monitoring has been developed to detect supra-esophageal gastric reflux (SEGR). The results obtained with OP pH metry and multichannel intraluminal impedance/pH monitoring (MII/pH) were compared. STUDY DESIGN: Diagnostic study. METHODS: Ten patients (age 46.33 +/- 9.86 years) presenting with chronic coughing underwent simultaneous OP and MII/pH recording. A 2-minute interval was allowed between events detected with both techniques to be considered simultaneous. RESULTS: A total of 515 reflux episodes were recorded with MII/pH (acid: 181; weakly acid: 310; weakly alkaline: 24); 180 (35%) reached the highest impedance channel (hypo-pharynx); 74/180 (41%) were not related to a change in pH, according to the antimony electrode of the MII/pH catheter located at the upper esophageal sphincter. The OP monitoring measured 39 acid events; 17 (43.6%) were swallows according to MII, and 15 (38.5%) were not associated with MII or pH change. Only seven episodes were detected simultaneously with both techniques (1.3% for MII vs. 18% for OP; P = 0.0002). We found 49 pH-only refluxes at the pH sensor in the hypo-pharynx with MII/pH; only three (6.1%) correlated with OP reflux. Correlation in time between cough and reflux events was positive in 5/10 patients for MII (symptom index 5/10, symptom association probability 4/10), but in 0/10 patients according to OP pH metry. CONCLUSION: OP pH metry detected less reflux episodes than MII/pH; 35% of the OP events were swallows according to impedance. Time correlation between cough and reflux could not be demonstrated with OP pH metry. PMID- 23023944 TI - Monitoring beta-secretase activity in living cells with a membrane-anchored FRET probe. PMID- 23023945 TI - Apolipoprotein E genotype and neurological disease onset in Niemann-Pick disease, type C1. AB - Niemann-Pick disease, type C1 (NPC1) is a lipid storage disorder that results in progressive neurological impairment. The NPC1 phenotype is extremely variable and at the individual level is likely influenced by other genetic traits. In addition to residual function of NPC1 protein, we hypothesize that modifier genes, as frequently observed with other autosomal recessive diseases, influence the NPC phenotype. The NPC1 phenotype includes progressive dementia, and the NPC pathology has some overlap with the pathology of Alzheimer disease (AD). Thus, we examined apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) polymorphisms in a cohort of 15 NPC1 patients with well characterized longitudinal disease progression. Although we did not find any correlations between disease severity and tau polymorphisms, we found significant associations between ApoE polymorphisms and phenotypic severity. Specifically, ApoE4 and ApoE2 alleles were associated, respectively, with increased and decreased disease severity in this cohort of NPC1 patients. These data support the hypothesis that ApoE may play a role in modulating NPC1 neuropathology. PMID- 23023946 TI - Type 2 diabetes and bone. AB - There is a growing body of research showing that diabetes is an independent risk factor for fracture. Type 2 diabetes (T2D), which predominates in older individuals and is increasing globally as a consequence of the obesity epidemic, is associated with normal or even increased dual-energy x-ray absorptiometry (DXA)-derived areal bone mineral density (BMD). Therefore, the paradoxical increase in fracture risk has led to the hypothesis that there are diabetes associated alterations in material and structural properties. An overly glycated collagen matrix, confounded by a low turnover state, in the setting of subtle cortical abnormalities, may lead to compromised biomechanical competence. In current clinical practice, because BMD is central to fracture prediction, a consequence of this paradox is a lack of suitable methods, including FRAX, to predict fracture risk in older adults with T2D. The option of adding diabetes to the FRAX algorithm is appealing but requires additional data from large population-based cohorts. The need for improved methods for identification of fracture in older adults with T2D is an important priority for osteoporosis research. PMID- 23023947 TI - 1-Aryl-4-silylmethyl[60]fullerenes: synthesis, properties, and photovoltaic performance. AB - The efficient nucleophilic addition of aryl Grignard reagents (aryl=4 MeOC(6)H(4), 4-Me(2)NC(6)H(4), Ph, 4-CF(3)C(6)H(4), and thienyl) to C(60) in the presence of DMSO produced 1,2-arylhydro[60]fullerenes after acid treatment. The reactions of the anions of these arylhydro[60]fullerenes with either dimethylphenylsilylmethyl iodide or dimethyl(2-isopropoxyphenyl)silylmethyl iodide yielded the target compounds, 1-aryl-4-silylmethyl[60]fullerenes. The properties and structures of these 1-aryl-4-silylmethyl[60]fullerenes (aryl=4 MeOC(6)H(4), thienyl) were examined by electrochemical studies, X-ray crystallography, flash-photolysis time-resolved microwave-conductivity (FP-TRMC) measurements, and electron-mobility measurements by using a space-charge-limited current (SCLC) model. Organic photovoltaic devices with a polymer-based bulk heterojunction structure and small-molecule-based p-n and p-i-n heterojunction configurations were fabricated by using 1-aryl-4-silylmethyl[60]fullerenes as an electron acceptor. The most efficient device exhibited a power-conversion efficiency of 3.4% (short-circuit current density: 8.1 mA/cm(2), open-circuit voltage: 0.69 V, fill factor: 0.59). PMID- 23023948 TI - Expression of AEG-1 in human T-cell lymphoma enhances the risk of progression. AB - The aim of this study was to examine the expression and role of astrocyte elevated gene-1 (AEG-1) in biological processes of T-cell non-Hodgkin's lymphoma (T-NHL). AEG-1 expression in T-NHL patients was characterized with immunohistochemistry. The expression of AEG-1, survivin, Bcl-2 and Bax in Jurkat and Hut-78 cells was detected by real-time PCR and western blotting. Cell proliferation, cell cycle and apoptosis were measured by MTT and flow cytometry. MMP-2/-9 activity was detected by gelatin zymography. Of the studied tumors, 104 (80.62%) exhibited cytoplasmic AEG-1 immunostaining. AEG-1-siRNA in Jurkat and Hut-78 cells suppressed cell proliferation and induced cell apoptosis, inhibited survivin and Bcl-2/Bax protein expression as well as MMP-2/-9 activity. Downregulation of AEG-1 using siRNA could provide a potential approach for gene therapy against T-NHL, and the antitumor effects may be associated with inhibition of survivin and Bcl-2/Bax protein expression and MMP-2/-9 activity. PMID- 23023949 TI - Protective and antioxidant role of selenium on arsenic trioxide-induced oxidative stress and genotoxicity in the fish hepatoma cell line PLHC-1. AB - In vitro models are useful tools for rapid screening for toxicity, elucidation of mechanisms of toxicity, and understanding complex interactions among environmental toxicants. These evaluations may provide useful information for ecological evaluations if the relationship between in vitro and in vivo effects is established. The present study was undertaken to evaluate the protective effect of selenium on arsenic trioxide (As(2) O(3) )-induced cytotoxicity, DNA damage, and apoptosis. N-acetylcysteine (NAC), a free radical scavenger, was used to determine the involvement of reactive oxygen species (ROS) in As(2) O(3) induced DNA damage and apoptosis. Poeciliopsis lucida hepatocellular carcinoma line 1 (PLHC-1) cells were pretreated with selenium (1, 5, and 10 uM) and NAC (50 and 100 uM) for 2 h. After pretreatment, cells were exposed to 100 uM of As(2) O(3) for 10-, 20-, and 40-h intervals. The As(2) O(3) exposure promoted extensive DNA damage and apoptosis compared to control, while selenium- and NAC-pretreated cells improved cell survival rate against As(2) O(3) -induced cell death. Improved survival likely resulted from increasing glutathione peroxidase activity and reduction of ROS formation, reduction of mitochondrial membrane potential damage, DNA damage, and caspase-3 activity. During As(2) O(3) exposure, selenium played the same role as NAC. The authors conclude that As(2) O(3) -induced DNA damage and apoptosis are mediated by oxidative stress and selenium and that, although toxic at higher concentrations, selenium provides significant protection against As(2) O(3) effects in PLHC-1 cells. PMID- 23023950 TI - A review on antimicrobial activity of mushroom (Basidiomycetes) extracts and isolated compounds. AB - Despite the huge diversity of antibacterial compounds, bacterial resistance to first-choice antibiotics has been drastically increasing. Moreover, the association between multiresistant microorganisms and nosocomial infections highlight the problem, and the urgent need for solutions. Natural resources have been exploited in the last years and among them, mushrooms could be an alternative source of new antimicrobials. In this review, we present an overview of the antimicrobial properties of mushroom extracts and highlight some of the active compounds identified, including low- and high-molecular weight (LMW and HMW, respectively) compounds. LMW compounds are mainly secondary metabolites, such as sesquiterpenes and other terpenes, steroids, anthraquinones, benzoic acid derivatives, and quinolines, but also primary metabolites such as oxalic acid. HMW compounds are mainly peptides and proteins. Data available from the literature indicate a higher antimicrobial activity of mushroom extracts against gram-positive bacteria. Among all the mushrooms, Lentinus edodes is the most studied species and seems to have a broad antimicrobial action against both gram positive and gram-negative bacteria. Plectasin peptide, obtained from Pseudoplectania nigrella, is the isolated compound with the highest antimicrobial activity against gram-positive bacteria, while 2-aminoquinoline, isolated from Leucopaxillus albissimus, presents the highest antimicrobial activity against gram-negative bacteria. PMID- 23023951 TI - Three new sesquiterpenes with cytotoxic activity from Dobinea delavayi. AB - Three new sesquiterpenes dobinins A-C (1-3), together with five known compounds, were isolated from the root of Dobinea delavayi. The structures of the three new compounds were determined on the basis of spectroscopic analysis including 1D-, 2D-NMR and MS techniques as well as by comparison of the spectral data with those of analogous compounds reported in the literatures. Compounds 1-3 were screened for antitumor activity in vitro and exhibited definite cytotoxic activity against the human tumor cell line HL-60 with IC50 levels of 8.0 * 10-5, 4.7 * 10-5, and 5.1 * 10-5 M, respectively. PMID- 23023952 TI - Novel role of red wine-derived polyphenols in the prevention of Alzheimer's disease dementia and brain pathology: experimental approaches and clinical implications. AB - Recent studies suggest that by the middle of this century, as many as 14 million Americans will have Alzheimer's disease, creating an enormous strain on families, the health care system and the federal budget. There are still widespread misconceptions about issues related to the prevention and/or treatment of disease pathogenesis, leaving us unprepared to deal with the disease. To address these challenges, several therapeutic approaches are currently under investigation, mainly in an attempt to delay disease onset and eventually slow down its progression. Recent epidemiological evidence has implicated the protective role of dietary polyphenols from grape products against Alzheimer's disease. Furthermore, experimental evidence supports the hypothesis that certain bioactive grape-derived polyphenols may protect against Alzheimer's disease-type cognitive deterioration, in part by interfering with the generation and assembly of beta amyloid peptides into neurotoxic oligomeric aggregated species. Brain-targeting polyphenols have been shown to significantly reduce the generation of beta amyloid peptides in primary cortico-hippocampal neuron cultures, and preliminary results indicate that they may influence neuronal synaptic plasticity. Recent evidence has also implicated the role of certain grape-derived preparations in beneficially modulating tau neuropathology, including reducing tau aggregation. Studies suggest that dietary polyphenolics may benefit Alzheimer's disease by modulating multiple disease-modifying modalities, both beta-amyloid-dependent and independent mechanisms, and provide impetus for the development of polyphenolic compounds for Alzheimer's disease prevention and/or therapy. PMID- 23023953 TI - Indole alkaloids from Kopsia hainanensis and evaluation of their antimicrobial activity. AB - Three new indole alkaloids, named kopsihainin D (1), kopsihainin E (2), and kopsihainin F (3), along with nine known compounds (4-12) were isolated from the twigs of Kopsia hainanensis. The structures of the new compounds were elucidated by spectroscopic methods including HRESIMS, UV, IR, and NMR. Compounds 1 - 3 and 5 showed inhibitory activity against Staphylococcus aureus with an antibacterial circle diameter of 11.2, 9.1, 10.3 and 9.7 mm, respectively. PMID- 23023954 TI - Diastereoselective metal-catalyzed synthesis of C-aryl and C-vinyl glycosides. AB - Cobalt, the catalyst of choice: The diastereoselective cobalt-catalyzed cross coupling of 1-bromo glycosides and aryl or vinyl Grignard reagents is described. A convenient and inexpensive catalyst, [Co(acac)(3)]/tmeda (acac = acetylacetonate, tmeda = N,N'-tetramethylethylenediamine), gives full alpha selectivity in the mannose and galactose series, and an alpha selectivity in the glucose series with alpha/beta ratios of 1.3:1-3:1. PMID- 23023955 TI - Automatic segmentation of white matter hyperintensities by an extended FitzHugh & Nagumo reaction diffusion model. AB - PURPOSE: To evaluate the efficiency and reproducibility of the extended FitzHugh & Nagumo (FHN) reaction-diffusion model proposed in this study for white matter hyperintensities (WMH) segmentation. MATERIALS AND METHODS: Five types of magnetic resonance T2-weighted fluid-attenuated inversion-recovery (T2FLAIR) images of 127 patients with different scanning parameters from five clinical scanner systems were selected for this study. After skull and scalp removal and denoise, the T2FLAIR images were processed by the proposed extended FHN model to obtain WMH. This new technique replaced the global threshold constant with a local threshold matrix. RESULTS: There was no significant difference between the segmentation results of the training set and the manual contouring against those between the test set and the manual contouring based on similarity index (SI) values (P = 0.5217). The SI values of the five types of T2FLAIR images were 86.0% +/- 15.4%, 85.8% +/- 10.5%, 84.1% +/- 14.8%, 87.2% +/- 14.6%, 86.3% +/- 12.7%, respectively, comparing the segmentation results using the proposed method to the manual delineations. The overall SI value of the images was 86.5% +/- 14.5%. This approach also demonstrated a better WMH segmentation performance over its classic form (P < 0.001). CONCLUSION: The proposed approach is efficient and could provide a more effective and convenient tool for clinical quantitative WMH analysis. PMID- 23023956 TI - Systematic review of outcomes of liver resection for early hepatocellular carcinoma within the Milan criteria. AB - BACKGROUND: Long-term overall survival after liver resection in patients with hepatocellular carcinoma (HCC) within the Milan criteria has been reported to improve in recent years. This study systematically reviewed the outcomes of surgical resection for HCC in patients with good liver function and meeting the Milan criteria for early HCC, published in the past 10 years. METHODS: A literature search was conducted in PubMed for papers on outcomes of surgical resection for HCC published between January 2000 and December 2010. Cochrane systematic review methodology was used for this review. The primary outcome was overall survival. Secondary outcomes included operative mortality and disease free survival. Studies that focused on geriatric populations, paediatric populations, a subset of the Milan criteria (such solitary tumours) or included patients with incidental tumours were excluded, as were case reports, conference abstracts, and studies with a large proportion of Child-Pugh grade C liver cirrhosis or unknown Child-Pugh status. RESULTS: Of 152 studies reviewed, two randomized clinical trials and 27 retrospective case series were eligible for inclusion. The 5-year overall survival rate after resection of HCC ranged from 27 to 81 (median 67) per cent, and the median disease-free survival rate from 21 to 57 (median 37) per cent. There was a trend towards improved overall survival in recent years. The operative mortality rate ranged from 0 to 5 (median 0.7) per cent. CONCLUSION: Surgical resection offers good overall survival for patients with HCC within the Milan criteria and with good liver function, although recurrence rates remain high. Outcomes have tended to improve in more recent years. PMID- 23023957 TI - 'I-shaped' sign in the upper mediastinum: a novel potential marker for antenatal diagnosis of d-transposition of the great arteries. AB - OBJECTIVES: To investigate the 'I-shaped' sign as a novel echocardiographic marker for antenatal diagnosis of d-transposition of the great arteries (dTGA) in routine cardiac examination, and to compare its prevalence in fetuses with dTGA, those with other congenital heart diseases (CHDs) and those with normal structural hearts. METHODS: This retrospective evaluation involved 1134 fetuses undergoing echocardiography to screen for CHD over a 4-year period. I-shaped sign was defined as the characteristic appearance of the aortic arch, resembling the letter 'I', from the most anterior to the most posterior point of the descending aorta visible in the three vessels and trachea view. The frequency of this sign was evaluated in cases with dTGA, those with other cardiac defects and those with normal cardiac structures. RESULTS: CHD was diagnosed in 671 (59.1%) cases, of which 31 (4.6%) had dTGA. I-shaped sign was observed in 30/31 (96.8%) cases of dTGA, compared with 31/640 (4.8%) cases with other cardiac anomalies, which included single ventricle with pulmonary atresia or severe pulmonary stenosis, hypoplastic left heart syndrome with aortic atresia, corrected transposition of the great arteries, and double outlet right ventricle with malposition of the great arteries. I-shaped sign was detected significantly more frequently in the dTGA group compared with the normal group and with the other CHDs group (both P < 0.001) and had 96.8% sensitivity and 97.1% specificity for diagnosis of dTGA. Importantly, I-shaped sign was never observed in fetuses with structurally normal hearts. CONCLUSIONS: Detection on echocardiography of an extremely long vessel with a marked I-shape should raise suspicion of cardiac anomaly, especially dTGA. This marker may therefore aid in the prenatal diagnosis of dTGA during routine ultrasound examination. PMID- 23023958 TI - Evaluating the utility of non-echo-planar diffusion-weighted imaging in the preoperative evaluation of cholesteatoma: a meta-analysis. AB - OBJECTIVES/HYPOTHESIS: To describe the accuracy of non-echo-planar diffusion weighted magnetic resonance imaging (DW MRI) in identifying middle ear cholesteatoma. STUDY DESIGN: A meta-analysis of the published literature. METHODS: A systematic review of the literature was performed to identify studies in which patients suspected of having middle ear cholesteatoma underwent DW MRI scans prior to surgery. A meta-analysis of the included studies was performed. RESULTS: Ten published articles (342 patients) met inclusion criteria. Cholesteatoma was confirmed in 234 patients, of which 204 were detected by DW MRI (true positives) and 30 were not (false negatives). One hundred eight patients did not have cholesteatoma on surgical examination, and of these 100 were correctly identified by MRI (true negatives) whereas eight were not (false positives). The overall sensitivity of DW MRI in detecting cholesteatoma was 0.94 (confidence interval, 0.80-0.98) and specificity 0.94 (confidence interval, 0.85 0.98). DW MRI sequences could not reliably detect cholesteatomas under 3 mm in size. CONCLUSIONS: Non-echo-planar DW MRI is highly sensitive and specific in identifying middle ear cholesteatoma. DW MRI may help to stratify patients into groups of who would benefit from early second-look surgery and those who could be closely observed. LEVEL OF EVIDENCE: 2a. PMID- 23023960 TI - Fine tuning the performance of DSSCs by variation of the pi-spacers in organic dyes that contain a 2,7-diaminofluorene donor. AB - Organic dyes that contain a 2,7-diaminofluorene-based donor, a cyanoacrylic-acid acceptor, and various aromatic conjugation segments, which are composed of benzene, fluorene, carbazole, and thiophene units, as a pi-bridge have been synthesized and characterized by optical, electrochemical, and theoretical investigations. The trends in the absorption and electrochemical properties of these dyes are in accordance with the electron-donating ability of the conjugating segment. Consequently, the dyes that contained a 2,7-carbazole unit in the pi-spacer exhibited red-shifted absorption and lower oxidation potentials than their corresponding fluorene- and phenylene-bridged dyes. However, the enhanced power-conversion efficiency that was exhibited by the fluorene-bridged dyes in the DSSCs was attributed to their broader and intense absorption. Despite the longer-wavelength absorption and reasonable optical density, carbazole bridged dyes exhibited lower power-conversion efficiencies, which were ascribed to the poor alignment of the LUMO level in these dyes, thereby leading to the inhibition of electron injection into the TiO(2) conduction band. PMID- 23023959 TI - Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder. AB - Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth. PMID- 23023961 TI - Is there correlation between electromyography and digital palpation as means of measuring pelvic floor muscle contractility in nulliparous, pregnant, and postpartum women? AB - AIMS: The continence mechanisms depend on the integrity of the pelvic floor muscles. It is therefore important to find simple, reliable, and safe methods to assess its contractility in a clinical setting. This study aims to investigate if digital palpation of the pelvic floor muscles presents correlation with its electromyographic activity. METHODS: The sample consisted of 307 women with mean age of 23.93 years, including 39 nulliparous, 117 primigravid pregnant, 64 primiparous, in post-vaginal delivery, and 87 primiparous women, in post-cesarean section delivery. The assessment consisted of both digital palpation and surface electromyography. One, and the same, highly skilled and experienced physiotherapist, who was able to classify the different grades of contractility accurately, performed digital palpation using the Modified Oxford Grading Scale. Surface electromyography was performed using an intravaginal probe. For electromyography evaluation, three contractions of 5 sec each were recorded, and an average of three Root Mean squares was considered for analysis. Spearman's Coefficient, Jonckheere-Terpstra Test, Kruskal-Wallis as well as Dunn Test were used for statistical analysis. RESULTS: The strong correlation found between the two methods (P < 0.001) indicates that both digital palpation and electromyography can be used in everyday practice, both for clinical use and scientific research, although both have their specific limitations and requirements to avoid the risk of biases. CONCLUSION: There was a correlation between pelvic floor muscle contractility measured by surface electromyography and by digital palpation. Both methods can be used to validate data in research and clinical setting. PMID- 23023962 TI - 2'-Deoxyribonucleoside phosphoramidate triphosphate analogues as alternative substrates for E. coli polymerase III. AB - Thermostable bacterial polymerases like Taq, Therminator and Vent exo(-) are able to perform DNA synthesis by using modified DNA precursors, a property that is exploited in several therapeutic and biotechnological applications. Viral polymerases are also known to accept modified substrates, and this has proven crucial in the development of antiviral therapies. However, non-thermostable polymerases of bacterial origin, or engineered variants, that have similar substrate tolerance and could be used for synthetic biology purposes remain to be identified. We have identified the alpha subunit of Escherichia coli polymerase III (Pol III alpha) as a bacterial polymerase that is able to recognise and process as substrates several pyrophosphate-modified dATP analogues in place of its natural substrate dATP for template-directed DNA synthesis. A number of dATP analogues featuring a modified pyrophosphate group were able to serve as substrates during enzymatic DNA synthesis by Pol III alpha. Features such as the presence of potentially chelating chemical groups and the size and spatial flexibility of the chemical structure seem to be of major importance for the modified leaving group to play its role during the enzymatic reaction. In addition, we could establish that if the pyrophosphate group is altered, deoxynucleotide incorporation proceeds with an efficiency varying with the nature of the nucleobase. Our results represent a great step towards the achievement of a system of artificial DNA synthesis hosted by E. coli and involving the use of altered nucleotide precursors for nucleic acid synthesis. PMID- 23023963 TI - Normal breast parenchyma: contrast enhancement kinetics at dynamic MR mammography -influence of anthropometric measures and menopausal status. AB - PURPOSE: To study T1 baseline signal intensity (SI) and contrast material enhancement kinetics of normal breast parenchyma by using dynamic contrast enhanced (DCE) magnetic resonance (MR) mammography and to determine the influence of anthropometric measures and menopausal status on the variability of these features. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Between June 2008 and September 2011, 345 women (age range, 26-81 years; mean age, 51.3 years +/- 11.6 [standard deviation]) underwent DCE MR mammography, with T1-weighted three-dimensional MR images (repetition time msec/echo time msec, 8.86/4.51; flip angle, 25 degrees ) acquired with a 1.5-T whole-body MR unit before and 1, 2, 3, 4, and 5 minutes after a gadobutrol bolus injection of 0.1 mmol per kilogram of body weight. Regions of interest were traced manually, and T1 SI of parenchyma was recorded. The influence of different predictors of T1 baseline SI and contrast enhancement was studied by using random-effects models. RESULTS: T1 baseline SI varied considerably between women, with a mean of 167.7 +/- 49.2 (71.4-424.7 [range]) and 175.9 +/- 48.9 (51.8-458.3) in the right and the left breast, respectively (P < .01). T1 baseline SI increased linearly with age (P < .0001) and body weight (P < .0001). After contrast material delivery, relative percentage of enhancement was 8.1%, 13.8%, 18.2%, 22.1%, and 24.6% at 1, 2, 3, 4, and 5 minutes, respectively, but varied considerably between women. Contrast enhancement was 9.3% in the lowest quintile and 47.4% in the highest. Contrast enhancement increased with body weight (P < .01) but decreased in postmenopausal women (P < .01). Women with higher baseline T1 SI tended to have a higher contrast enhancement slope. CONCLUSION: Anthropometric measures and menopausal status contribute to a large variability in contrast enhancement of normal breast parenchyma. This might influence the interpretation of contrast enhancement kinetics of breast lesions and current strategies for determining contrast medium dose for breast MR imaging. PMID- 23023964 TI - Iodinated contrast media differentially affect afferent and efferent arteriolar tone and reactivity in mice: a possible explanation for reduced glomerular filtration rate. AB - PURPOSE: To determine the effect of the iodinated contrast medium iodixanol on arteriolar tone in afferent and efferent arterioles of the glomerulus and the functional interactions with the major modulators of arteriolar tone, angiotensin II and nitric oxide, in mice. MATERIALS AND METHODS: Animal handling conformed to the ethics guidelines of the Office for Health and Social Matters of Berlin. Arterioles were isolated from 136 C57BL/6 mice, perfused with either vehicle solution or iodixanol (23 mg of iodine per milliliter) for 20 minutes, followed by angiotensin II administration. Fluorescence of 3-amino-4-(N-methylamino)-2',7' difluorofluorescein (DAF-FM) and dihydroethidium (DHE) were used for quantification of nitric oxide bioavailability and superoxide concentration, respectively. Statistical analysis of time- and dose-dependent data was performed by using the nonparametric test for repeated measurements. RESULTS: With iodixanol, afferent arteriole diameters were significantly reduced from 9.2 um to 8.3 um; in control group, the diameters were increased from 8.7 um to 9.3 um (P = .008). Nitric oxide synthase inhibition augmented iodixanol-induced constriction, with diameters reduced from 9.9 um to 5.8 um (P < .0001). DAF-FM fluorescence increased less during iodixanol treatment and nitric oxide synthase inhibition (3.6% and 3.7% vs 10.7% in control group, P = .009 and P = .049, respectively), indicating impaired nitric oxide bioavailability. With iodixanol, DHE fluorescence ratio was increased by 12% (P < .0001). Angiotensin II responses were enhanced by iodixanol and by nitric oxide synthase inhibition after perfusion with iodixanol (3.3 um and 4.3 um vs 7.5 um [control group] with 1 * 10(-6)/mol/L angiotensin II, P = .03 for both). In contrast, in efferent arterioles, neither their basal diameters nor the responses to angiotensin II were significantly affected by iodixanol. CONCLUSION: A more pronounced effect of iodixanol on afferent than on efferent arterioles may contribute to the reduction of glomerular filtration rate in contrast medium-induced acute kidney injury. Decreased nitric oxide bioavailability and increased concentration of superoxide explain the increased tone and reactivity in afferent arterioles perfused with iodixanol. PMID- 23023965 TI - Alternative diagnoses to suspected appendicitis at CT. AB - PURPOSE: To assess alternative diagnoses in adults undergoing computed tomography (CT) for suspected acute appendicitis in routine clinical practice. MATERIALS AND METHODS: This retrospective study was HIPAA compliant and institutional review board approved; informed consent was waived. A total of 1571 consecutive adults were referred from emergency department or urgent care settings for evaluation of suspected acute appendicitis at a single academic medical center from January 2006 to December 2009. Diagnoses given by board-certified radiologists at nonfocused abdominopelvic CT and ultimate clinical diagnoses by a combination of clinical, surgical, pathologic, and other radiologic findings were analyzed. Comparisons were made by using the Fisher exact test and Mann-Whitney test, where appropriate, with a two-tailed P value of less than .05 used as the criterion for statistical significance. RESULTS: A specific diagnosis at CT examination was made in 867 of 1571 (55.2%) patients. Acute appendicitis was favored in 371 of 1571 (23.6%) patients. An alternative diagnosis other than appendicitis was suggested in 496 of 1571 (31.6%) patients. Among patients with an alternative CT diagnosis, 204 of 496 (41.1%) were hospitalized and 109 of 496 (22.0%) underwent surgical or image-guided intervention for diagnoses other than appendicitis, compared with rates of 14.1% and 4.4%, respectively, among patients in whom a specific diagnosis was not made at CT (P < .0001). The most common broad categories of disease included nonappendiceal gastrointestinal conditions (46.0%), gynecologic conditions (21.6%), genitourinary conditions (16.9%), and hepatopancreaticobiliary conditions (7.7%). CONCLUSION: In adult patients clinically suspected of having acute appendicitis, abdominopelvic CT frequently identifies an alternative cause for symptoms, which often requires hospitalization and surgery for treatment. PMID- 23023966 TI - From Li-O2 to Li-air batteries: carbon nanotubes/ionic liquid gels with a tricontinuous passage of electrons, ions, and oxygen. AB - A salt and battery: The combination of single-walled carbon nanotubes (SWNTs) and an ionic liquid (IL) cross-linked network gel (CNG) allows the conventional three phase reactive interface to be expanded to the whole cross-linked network (see picture). Thus, it integrates high specific energy and specific power with the feasibility of operating in ambient air. PMID- 23023967 TI - Role of Sonic Hedgehog in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease of unknown etiology and uncertain pathogenic mechanisms. Recent studies indicate that the pathogenesis of the disease may involve the abnormal expression of certain developmental pathways. Here we evaluated the expression of Sonic Hedgehog (SHH), Patched-1, Smoothened, and transcription factors glioma associated oncogene homolog (GLI)1 and GLI2 by RT-PCR, as well as their localization in IPF and normal lungs by immunohistochemistry. The effects of SHH on fibroblast proliferation, migration, collagen and fibronectin production, and apoptosis were analyzed by WST-1, Boyden chamber chemotaxis, RT-PCR, Sircol, and annexin V-propidium iodide binding assays, respectively. Our results showed that all the main components of the Sonic signaling pathway were overexpressed in IPF lungs. With the exception of Smoothened, they were also upregulated in IPF fibroblasts. SHH and GLI2 localized to epithelial cells, whereas Patched-1, Smoothened, and GLI1 were observed mainly in fibroblasts and inflammatory cells. No staining was detected in normal lungs. Recombinant SHH increased fibroblast proliferation (P < 0.05), collagen synthesis, (2.5 +/- 0.2 vs. 4.5 +/- 1.0 MUg of collagen/ml; P < 0.05), fibronectin expression (2-3-fold over control), and migration (190.3 +/- 12.4% over control, P < 0.05). No effect was observed on alpha-smooth muscle actin expression. SHH protected lung fibroblasts from TNF alpha/IFN-gamma/Fas-induced apoptosis (14.5 +/- 3.2% vs. 37.3 +/- 7.2%, P < 0.0001). This protection was accompanied by modifications in several apoptosis related proteins, including increased expression of X-linked inhibitor of apoptosis. These findings indicate that the SHH pathway is activated in IPF lungs and that SHH may contribute to IPF pathogenesis by increasing the proliferation, migration, extracellular matrix production, and survival of fibroblasts. PMID- 23023969 TI - Future bronchodilator therapy: a bitter pill to swallow? AB - Maintenance of airway tone, prevention of airway obstruction, and acute relief from bronchospasm are key targets of asthma therapy. This role is currently performed by beta-agonists. However, chronic use of beta-agonists to treat asthma is associated with desensitization of beta-agonist signaling and a resultant loss of bronchodilator effect, worsening of airway hyperreactivity, and increased incidence of asthma-related morbidity and mortality. There have been several attempts to identify novel non-beta-agonist bronchodilators including ATP sensitive potassium channel (K(ATP)) agonists such as cromakalim and its active enantiomer BRL-38227 and the cGMP activators atrial natriuretic peptide (ANP) and BAY 41-22722. However, these either have not made it to clinical trial, required high doses, had little effect in patients, or had a high incidence of side effects. Recent data suggests that a novel bronchodilator target exists, the bitter taste receptor TAS2R. Two recent studies [An SS, Wang WC, Koziol-White CJ, Ahn K, Lee DY, Kurten RC, Panettieri RA Jr, Liggett SB. Am J Physiol Lung Cell Mol Physiol 303: L304-L311, 2012; Pulkkinen V, Manson ML, Safholm J, Adner M, Dahlen SE. Am J Physiol Lung Cell Mol Physiol. doi:10.1152/ajplung.00205.2012.] provide new understanding of the signaling pathways utilized by TAS2Rs to mediate their bronchodilatory effects and how TAS2R-mediated bronchodilation is affected by beta-agonist signaling desensitization. As our understanding of TAS2Rs and their agonists increases, they move closer to a viable therapeutic option; however, further definition is still required and questions remain to be answered. This editorial focus discusses these studies within the context of existing literature and raises questions and challenges for the future development of bitter (better?) therapies for asthma. PMID- 23023970 TI - The physiological legacy of the Fenn, Rahn, and Otis school. AB - Extraordinary advances in respiratory physiology occurred between 1941 and 1956 in the Department of Physiology, University of Rochester. These were principally the result of a collaboration between Wallace Fenn, Hermann Rahn, and Arthur Otis. Remarkably, all three scientists had worked in very dissimilar areas of physiology before and, by their own admission, were largely ignorant of respiratory physiology. However, because of the exigencies of war they were brought together to study the physiology of pressure breathing. The result was that they laid much of the foundations of pulmonary gas exchange and pulmonary mechanics and some of their work is still cited today. In pulmonary gas exchange they exploited the new oxygen-carbon dioxide diagram; clarified the effects of changes of altitude, hyperventilation, and pressure breathing; and pioneered the analysis of ventilation-perfusion relationships. In respiratory mechanics, they carried out groundbreaking work on the pressure-volume behavior of the lung and chest wall and went on to analyze aspects of gas flow and work of breathing. This explosion of ideas from what initially appeared to be a poorly prepared group has lessons for us today. PMID- 23023968 TI - Antioxidant mimetics modulate oxidative stress and cellular signaling in airway epithelial cells infected with respiratory syncytial virus. AB - Respiratory syncytial virus (RSV) is one of the most common causes of bronchiolitis and pneumonia among infants and young children worldwide. In previous investigations, we have shown that RSV infection induces rapid generation of reactive oxygen species (ROS), which modulate viral-induced cellular signaling, and downregulation of antioxidant enzyme (AOE) expression, resulting in oxidative stress in vitro and in vivo, which plays a pathogenetic role in RSV-induced lung disease. In this study, we determined whether pharmacological intervention with synthetic catalytic scavengers could reduce RSV induced proinflammatory gene expression and oxidative cell damage in an in vitro model of infection. Treatment of airway epithelial cells (AECs) with the salen manganese complexes EUK-8 or EUK-189, which possess superoxide dismutase, catalase, and glutathione peroxidase activity, strongly reduced RSV-induced ROS formation by increasing cellular AOE enzymatic activity and levels of the lipid peroxidation products F(2)-8-isoprostane and malondialdehyde, which are markers of oxidative stress. Treatment of AECs with AOE mimetics also significantly inhibited RSV-induced cytokine and chemokine secretion and activation of the transcription factors nuclear factor-kappaB and interferon regulatory factor-3, which orchestrate proinflammatory gene expression. Both EUKs were able to reduce viral replication, when used at high doses. These results suggest that increasing antioxidant cellular capacities can significantly impact RSV-associated oxidative cell damage and cellular signaling and could represent a novel therapeutic approach in modulating virus-induced lung disease. PMID- 23023972 TI - The catabolite repression control protein Crc plays a role in the development of antimicrobial-tolerant subpopulations in Pseudomonas aeruginosa biofilms. AB - Bacteria form complex surface-attached biofilm communities in nature. Biofilm cells differentiate into subpopulations which display tolerance towards antimicrobial agents. However, the signal transduction pathways regulating subpopulation differentiation in biofilms are largely unelucidated. In the present study, we show that the catabolite repression control protein Crc regulates the metabolic state of Pseudomonas aeruginosa cells in biofilms, and plays an important role in the development of antimicrobial-tolerant subpopulations in P. aeruginosa biofilms. PMID- 23023971 TI - Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. AB - Mortality and morbidity of acute lung injury and acute respiratory distress syndrome remain high because of the lack of pharmacological therapies to prevent injury or promote repair. Mesenchymal stem cells (MSCs) prevent lung injury in various experimental models, despite a low proportion of donor-derived cell engraftment, suggesting that MSCs exert their beneficial effects via paracrine mechanisms. We hypothesized that soluble factors secreted by MSCs promote the resolution of lung injury in part by modulating alveolar macrophage (AM) function. We tested the therapeutic effect of MSC-derived conditioned medium (CdM) compared with whole MSCs, lung fibroblasts, and fibroblast-CdM. Intratracheal MSCs and MSC-CdM significantly attenuated lipopolysaccharide (LPS) induced lung neutrophil influx, lung edema, and lung injury as assessed by an established lung injury score. MSC-CdM increased arginase-1 activity and Ym1 expression in LPS-exposed AMs. In vivo, AMs from LPS-MSC and LPS-MSC CdM lungs had enhanced expression of Ym1 and decreased expression of inducible nitric oxide synthase compared with untreated LPS mice. This suggests that MSC-CdM promotes alternative macrophage activation to an M2 "healer" phenotype. Comparative multiplex analysis of MSC- and fibroblast-CdM demonstrated that MSC-CdM contained several factors that may confer therapeutic benefit, including insulin-like growth factor I (IGF-I). Recombinant IGF-I partially reproduced the lung protective effect of MSC-CdM. In summary, MSCs act through a paracrine activity. MSC-CdM promotes the resolution of LPS-induced lung injury by attenuating lung inflammation and promoting a wound healing/anti-inflammatory M2 macrophage phenotype in part via IGF-I. PMID- 23023973 TI - RpoH2 sigma factor controls the photooxidative stress response in a non photosynthetic rhizobacterium, Azospirillum brasilense Sp7. AB - Bacteria belonging to the Alphaproteobacteria normally harbour multiple copies of the heat shock sigma factor (known as sigma(32), sigma(H) or RpoH). Azospirillum brasilense, a non-photosynthetic rhizobacterium, harbours five copies of rpoH genes, one of which is an rpoH2 homologue. The genes around the rpoH2 locus in A. brasilense show synteny with that found in rhizobia. The rpoH2 of A. brasilense was able to complement the temperature-sensitive phenotype of the Escherichia coli rpoH mutant. Inactivation of rpoH2 in A. brasilense results in increased sensitivity to methylene blue and to triphenyl tetrazolium chloride (TTC). Exposure of A. brasilense to TTC and the singlet oxygen-generating agent methylene blue induced several-fold higher expression of rpoH2. Comparison of the proteome of A. brasilense with its rpoH2 deletion mutant and with an A. brasilense strain overexpressing rpoH2 revealed chaperone GroEL, elongation factors (Ef-Tu and EF-G), peptidyl prolyl isomerase, and peptide methionine sulfoxide reductase as the major proteins whose expression was controlled by RpoH2. Here, we show that the RpoH2 sigma factor-controlled photooxidative stress response in A. brasilense is similar to that in the photosynthetic bacterium Rhodobacter sphaeroides, but that RpoH2 is not involved in the detoxification of methylglyoxal in A. brasilense. PMID- 23023974 TI - Molecular characterization and structural instability of the industrially important composite metabolic plasmid pLP712. AB - The widely used plasmid-free Lactococcus lactis strain MG1363 was derived from the industrial dairy starter strain NCDO712. This strain carries a 55.39 kb plasmid encoding genes for lactose catabolism and a serine proteinase involved in casein degradation. We report the DNA sequencing and annotation of pLP712, which revealed additional metabolic genes, including peptidase F, d-lactate dehydrogenase and alpha-keto acid dehydrogenase (E3 complex). Comparison of pLP712 with other large lactococcal lactose and/or proteinase plasmids from L. lactis subsp. cremoris SK11 (pSK11L, pSK11P) and the plant strain L. lactis NCDO1867 (pGdh442) revealed their close relationship. The plasmid appears to have evolved through a series of genetic events as a composite of pGdh442, pSK11L and pSK11P. We describe in detail a scenario by which the metabolic genes relevant to the growth of its host in a milk environment have been unified on one replicon, reflecting the evolution of L. lactis as it changed its biological niche from plants to dairy environments. The extensive structural instability of pLP712 allows easy isolation of derivative plasmids lacking genes for casein degradation and/or lactose catabolism. Plasmid pLP712 is transferable by transduction and conjugation, and both of these processes result in significant molecular rearrangements. We report the detailed molecular analysis of insertion sequence element-mediated genetic rearrangements within pLP712 and several different mechanisms, including homologous recombination and adjacent deletion. Analysis of the integration of the lactose operon into the chromosome highlights the fluidity of the MG1363 integration hotspot and the potential for frequent movement of genes between plasmids and chromosomes in Lactococcus. PMID- 23023975 TI - Correlation of apparent diffusion coefficient values measured by diffusion MRI and MGMT promoter methylation semiquantitatively analyzed with MS-MLPA in patients with glioblastoma multiforme. AB - PURPOSE: To retrospectively determine whether the apparent diffusion coefficient (ADC) values correlate with O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation semiquantitatively analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in patients with glioblastoma. MATERIALS AND METHODS: The study was approved by the Institutional Review Board and was Health Insurance Portability and Accountability Act (HIPAA) compliant. Newly diagnosed patients with glioblastoma (n = 26) were analyzed with an ADC histogram approach based on enhancing solid portion. The methylation status of MGMT promoter was assessed by methylation-specific polymerase chain reaction (MSP) and by MS-MLPA. MS-MLPA is a semiquantitative method that determines the methylation ratio. The Ki-67 labeling index was also analyzed. The mean and 5th percentile ADC values were correlated with MGMT promoter methylation status and Ki-67 labeling index using a linear regression model. Progression-free survival (PFS) was also correlated with the ADC values using Kaplan-Meier survival analysis. RESULTS: The mean methylation ratio was 0.21 +/- 0.20. By MSP, there were 5 methylated and 21 unmethylated tumors. The mean ADC revealed a positive relationship with MGMT promoter methylation ratio (P = 0.015) and was also significantly different according to MSP-determined methylation status (P = 0.011). Median PFS was significantly related with methylation ratio (P = 0.017) and MSP-derived methylation status (P = 0.025). A positive relationship was demonstrated between PFS and the mean ADC value (P = 0.001). The 5th percentile ADC values showed a significant negative relationship with Ki-67 labeling index (P = 0.036). CONCLUSION: We found that ADC values were significantly correlated with PFS as well as with MGMT promoter methylation status. We believe that ADC values may merit further investigation as a noninvasive biomarker for predicting treatment response. PMID- 23023976 TI - Systematic review and meta-analysis of retroperitoneoscopic versus laparoscopic adrenalectomy. AB - BACKGROUND: Laparoscopic adrenalectomy (LA) has replaced open adrenalectomy as the standard operation for non-malignant adrenal tumours. Retroperitoneoscopic adrenalectomy (RA) is an increasingly popular alternative minimally invasive approach. Advocates of each technique claim its superiority, but the issue has yet to be resolved and conclusions are complicated by the existence of a lateral (LRA) and true posterior (PRA) RA. METHODS: A literature search was performed for all comparative studies of RA versus LA. Meta-analysis was performed according to PRISMA guidelines. Odds ratios and standardized mean differences (SMD) were used to compare dichotomous and continuous outcomes respectively. RESULTS: Twenty-two studies were included, reporting on 1257 LAs, 471 LRAs and 238 PRAs. Both PRA and LRA were associated with a reduced length of hospital stay: SMD - 1.45 (95 per cent confidence interval - 2.76 to - 0.14) and - 0.54 (-1.04 to - 0.03) days respectively compared with LA. Interstudy heterogeneity was present throughout the comparisons of hospital stay. When considering only the two randomized clinical trials (RCTs) there was no statistically significant difference in this outcome. One RCT, however, found a reduction in the median time to convalescence of 2.4 weeks in the LRA group. There were no differences in duration of operation, blood loss, time to ambulation and oral intake, or complication rates between techniques. CONCLUSION: RA overall has equivalent outcomes to LA but may be associated with a shorter hospital stay. PMID- 23023977 TI - Therapeutic hypothermia for cardiac arrest: real-world utilization trends and hospital mortality. AB - BACKGROUND: Therapeutic hypothermia (TH) improves outcomes following cardiac arrest in small clinical trials. OBJECTIVE: To study real-world utilization and outcomes in US hospitals. DESIGN: Retrospective cohort study. SETTING: California hospitals. PATIENTS: Patients eligible for therapeutic hypothermia after cardiac arrest. INTERVENTIONS: We analyzed all discharges from California (1999-2008) to identify patients eligible for TH after cardiac arrest. Patients were considered eligible for TH if both cardiac arrest and anoxic brain injury were among the administrative diagnoses (n = 46,833). Patients undergoing TH (n = 204) were identified through billing codes. MEASUREMENTS: TH utilization and in-hospital mortality. RESULTS: Use of TH increased over the study period with 87.3% (178/204) of TH occurring between 2006 and 2008. Few hospitals appeared to perform TH over the study period (47/419, 11.2%). Utilization of TH was concentrated in a few centers, with the top 3 of 419 centers accounting for 31.4% (64/204) of cases. Patients undergoing TH were younger, less likely to be male, more likely to be treated at teaching centers, and had similar comorbidities compared to eligible individuals who did not undergo TH. The adjusted odds ratio for hospital mortality among patients undergoing TH was 0.80 (95% confidence interval [CI] 0.60-1.06, P = 0.11). CONCLUSIONS: TH utilization appears low, but implementation is increasing. Case selection and referral biases limit the analysis of the relationship between center TH volume and in-hospital mortality. PMID- 23023978 TI - Maternal racial origin and adverse pregnancy outcome: a cohort study. AB - OBJECTIVE: To examine the association between maternal racial origin and a wide range of adverse pregnancy outcomes after adjustment for confounding factors in obstetric history and maternal characteristics. METHODS: This was a retrospective study in women with singleton pregnancies attending their first routine hospital visit at 11 + 0 to 13 + 6 weeks of gestation. Data on maternal characteristics, and medical and obstetric history were collected and pregnancy outcomes ascertained. Regression analysis was performed to examine the association between racial origin and adverse pregnancy outcomes including pre-eclampsia (PE), gestational hypertension (GH), gestational diabetes mellitus (GDM), preterm delivery (PTD), small-for-gestational age (SGA), large-for-gestational age (LGA), miscarriage, stillbirth and elective and emergency Cesarean section (CS). RESULTS: The study population included 76 158 singleton pregnancies with a live fetus at 11 + 0 to 13 + 6 weeks. In addition to maternal characteristics and obstetric history, Afro-Caribbean racial origin was associated with increased risk for miscarriage, stillbirth, PE, GH, spontaneous PTD, GDM, SGA and CS. In women of South Asian racial origin there was increased risk for PE, GDM, SGA and CS, and East Asian race contributed to the prediction of GDM and SGA. CONCLUSION: Maternal racial origin should be combined with other maternal characteristics and obstetric history when calculating an individualized adjusted risk for adverse pregnancy outcome. PMID- 23023979 TI - Full genomic analysis of a human rotavirus G1P[8] strain isolated in South Korea. AB - A rotavirus G1P[8] strain C1-81 was isolated from a 5-month-old female infant admitted to hospital with fever and severe diarrhea in Incheon, South Korea. To investigate its full genomic relatedness and its group, the full genome of strain C1-81 was determined. Based on a full genome classification system, C1-81 was shown to possess the typical Wa-like genotype constellation: G1-P[8]-I1-R1-C1-M1 A1-N1-T1-E1-H1. On the basis of sequence similarities, the strain was shown to be the closest related strain to contemporary human rotavirus strains with recent strains isolated in Asia. This C1-81 strain showed the highest degree of nucleic acid similarity (98.8% and 97%) to G1 B4633-03 and P[8] (Thai-1604 and Dhaka8 02), respectively. This is the first report that group A rotavirus was analyzed with G1P[8] in South Korea. The study of the complete genome of the virus will help understanding of the evolution of rotavirus. PMID- 23023980 TI - Advanced complex trait analysis. AB - MOTIVATION: The Genome-wide Complex Trait Analysis (GCTA) software package can quantify the contribution of genetic variation to phenotypic variation for complex traits. However, as those datasets of interest continue to increase in size, GCTA becomes increasingly computationally prohibitive. We present an adapted version, Advanced Complex Trait Analysis (ACTA), demonstrating dramatically improved performance. RESULTS: We restructure the genetic relationship matrix (GRM) estimation phase of the code and introduce the highly optimized parallel Basic Linear Algebra Subprograms (BLAS) library combined with manual parallelization and optimization. We introduce the Linear Algebra PACKage (LAPACK) library into the restricted maximum likelihood (REML) analysis stage. For a test case with 8999 individuals and 279,435 single nucleotide polymorphisms (SNPs), we reduce the total runtime, using a compute node with two multi-core Intel Nehalem CPUs, from ~17 h to ~11 min. AVAILABILITY AND IMPLEMENTATION: The source code is fully available under the GNU Public License, along with Linux binaries. For more information see http://www.epcc.ed.ac.uk/software products/acta. CONTACT: a.gray@ed.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23023981 TI - FeatureStack: Perl module for comparative visualization of gene features. AB - SUMMARY: FeatureStack is a Perl module for the automatic generation of multi-gene images. FeatureStack takes BioPerl-compliant gene or transcript features as input and renders them side by side using a user-defined BioPerl glyph. Output images can be generated in SVG or PNG format. FeatureStack comes with a new BioPerl glyph, decorated_gene, which can highlight protein features on top of gene models. Used in combination, FeatureStack and decorated_gene enable rapid and automated generation of annotation-rich images of stacked gene models that greatly facilitate evolutionary studies of related gene structures and gene families. AVAILABILITY AND IMPLEMENTATION: Bio-Draw-FeatureStack and Bio-Graphics glyph-decorated_gene are freely available at the Comprehensive Perl Archive Network (CPAN) and GitHub. CONTACT: chenn@sfu.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23023982 TI - HiCNorm: removing biases in Hi-C data via Poisson regression. AB - SUMMARY: We propose a parametric model, HiCNorm, to remove systematic biases in the raw Hi-C contact maps, resulting in a simple, fast, yet accurate normalization procedure. Compared with the existing Hi-C normalization method developed by Yaffe and Tanay, HiCNorm has fewer parameters, runs >1000 times faster and achieves higher reproducibility. AVAILABILITY: Freely available on the web at: http://www.people.fas.harvard.edu/~junliu/HiCNorm/. CONTACT: jliu@stat.harvard.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23023983 TI - Adding unaligned sequences into an existing alignment using MAFFT and LAST. AB - Two methods to add unaligned sequences into an existing multiple sequence alignment have been implemented as the '--add' and '--addfragments' options in the MAFFT package. The former option is a basic one and applicable only to full length sequences, whereas the latter option is applicable even when the unaligned sequences are short and fragmentary. These methods internally infer the phylogenetic relationship among the sequences in the existing alignment and the phylogenetic positions of unaligned sequences. Benchmarks based on two independent simulations consistently suggest that the "--addfragments" option outperforms recent methods, PaPaRa and PAGAN, in accuracy for difficult problems and that these three methods appropriately handle easy problems. AVAILABILITY: http://mafft.cbrc.jp/alignment/software/ CONTACT: katoh@ifrec.osaka-u.ac.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23023985 TI - Comments on "A randomized trial of urodynamic testing before stress-incontinence surgery" (N Engl J Med. 2012 May 24;366(21):1987-1997) From the Italian Society of Urodynamics. PMID- 23023984 TI - InterMine: a flexible data warehouse system for the integration and analysis of heterogeneous biological data. AB - SUMMARY: InterMine is an open-source data warehouse system that facilitates the building of databases with complex data integration requirements and a need for a fast customizable query facility. Using InterMine, large biological databases can be created from a range of heterogeneous data sources, and the extensible data model allows for easy integration of new data types. The analysis tools include a flexible query builder, genomic region search and a library of 'widgets' performing various statistical analyses. The results can be exported in many commonly used formats. InterMine is a fully extensible framework where developers can add new tools and functionality. Additionally, there is a comprehensive set of web services, for which client libraries are provided in five commonly used programming languages. AVAILABILITY: Freely available from http://www.intermine.org under the LGPL license. CONTACT: g.micklem@gen.cam.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23023986 TI - Water oxidation by single-site ruthenium complexes: using ligands as redox and proton transfer mediators. PMID- 23023987 TI - Evolutionary imprint of catalytic domains in fungal PKS-NRPS hybrids. AB - Fungal hybrid enzymes consisting of a polyketide synthase (PKS) and a nonribosomal peptide synthetase (NRPS) module are involved in the biosynthesis of a vast array of ecologically and medicinally relevant natural products. Whereas a dozen gene clusters could be assigned to the requisite PKS-NRPS pathways, the programming of the multifunctional enzymes is still enigmatic. Through engineering and heterologously expressing a chimera of PKS (lovastatin synthase, LovB) and NRPS (cytochalasin synthase, CheA) in Aspergillus terreus, we noted the potential incompatibility of a fungal highly reducing PKS (hrPKS) with the NRPS component of fungal PKS-NRPS hybrids. To rationalize the unexpected outcome of the gene fusion experiments, we conducted extensive bioinformatic analyses of fungal PKS-NRPS hybrids and LovB-type PKS. From motif studies and the function of the engineered chimeras, a noncanonical function of C-terminal condensation (C) domains in truncated PKS-NRPS homologues was inferred. More importantly, sequence alignments and phylogenetic trees revealed an evolutionary imprint of the PKS NRPS domains, which reflect the evolutionary history of the entire megasynthase. Furthermore, a detailed investigation of C and adenylation (A) domains provides support for a scenario in which not only the A domain but also the C domain participates in amino acid selection. These findings shed new light on the complex code of this emerging class of multifunctional enzymes and will greatly facilitate future combinatorial biosynthesis and pathway engineering approaches towards natural product analogues. PMID- 23023988 TI - The incident user design in comparative effectiveness research. AB - Comparative effectiveness research includes cohort studies and registries of interventions. When investigators design such studies, how important is it to follow patients from the day they initiated treatment with the study interventions? Our article considers this question and related issues to start a dialogue on the value of the incident user design in comparative effectiveness research. By incident user design, we mean a study that sets the cohort's inception date according to patients' new use of an intervention. In contrast, most epidemiologic studies enroll patients who were currently or recently using an intervention when follow-up began. We take the incident user design as a reasonable default strategy because it reduces biases that can impact non randomized studies, especially when investigators use healthcare databases. We review case studies where investigators have explored the consequences of designing a cohort study by restricting to incident users, but most of the discussion has been informed by expert opinion, not by systematic evidence. PMID- 23023989 TI - A two-photon fluorescent probe for intracellular detection of tyrosinase activity. AB - AAN effective sensor: The two-photon turn-on fluorescent probe NHU was synthesized to optically detect tyrosinase activity in vitro and in melanoma cells. NHU is composed of a 4-aminophenol moiety and a naphthylamine unit, both of which are connected through a urea linkage. Upon exposure to tyrosinase, the 4 aminophenol site is gradually oxidized to the corresponding orthoquinone, ultimately releasing the highly fluorescent product 6-acyl-N-methyl-2 naphthylamine (AAN). PMID- 23023990 TI - Cardiovascular function in adulthood following intrauterine growth restriction with abnormal fetal blood flow. AB - OBJECTIVES: To examine whether intrauterine growth restriction (IUGR) is associated with increased cardiovascular risk later in life. METHODS: We examined 19 young adults (aged 22-25 years) who were born at term after IUGR, along with 18 controls. All had been examined previously with fetal Doppler, and in the present follow-up with echocardiography, carotid echo-tracking ultrasound, applanation tonometry, blood pressure and laser Doppler, in order to characterize their cardiac and vascular geometry and/or function. RESULTS: The diameter of the ascending aorta and the left ventricular diameter were smaller in the IUGR group, but only ascending aortic diameter remained significantly smaller after adjustment for body surface area (P < 0.05). The aortic pressure augmentation index was higher in the IUGR group (P < 0.05). The common carotid artery diameter, intima-media thickness and distensibility as well as left ventricular mass and function were similar in the two groups. IUGR status was found to be an independent predictor of ascending aortic diameter. CONCLUSIONS: IUGR due to placental dysfunction seems to contribute to the higher systolic blood pressure augmentation and the smaller aortic dimensions that are observed in adults more than 20 years later, with possible negative consequences for future left ventricular performance due to increased aortic impedance. PMID- 23023991 TI - Rethinking cardiac risk reduction after noncardiac surgery: the postoperative Carpe diem. AB - Patients undergoing noncardiac surgery frequently experience major adverse cardiac events. As a significant proportion of these patients develop cardiac complications despite optimal use of preoperative clinical risk-prediction algorithms, physicians have long searched for better methods of forecasting and ameliorating cardiac risk in this population. Recently, postoperative troponin levels have been found to be powerful and independent predictors of cardiovascular mortality in patients undergoing noncardiac surgery. Importantly, the predictive properties of these markers outperform preoperative clinical risk prediction algorithms. We thus posit that the assessment of postoperative troponin represents an as yet untapped "golden opportunity" for cardiac risk reduction. As cardiac troponin isolates an unusually high-risk subgroup, we outline a strategy that utilizes this marker to improve cardiac outcomes. Where pertinent, strengths and limitations of this approach are discussed and areas of uncertainty identified. As with all hypotheses, this proposition fuels many questions and calls for a research agenda dedicated to quantifying risk or benefit, and defining best practices. PMID- 23023992 TI - Do different lamivudine-resistant hepatitis B genotypes carry the same risk of entecavir resistance? AB - Entecavir switch is one of the treatment options for lamivudine-resistant hepatitis B (HBV) patients in Asia. This study examined the outcome of patients with different baseline resistance genotypes in a cohort study. In this study, 14 patients with chronic HBV were treated with entecavir 1 mg/day for 5 years. Enrolment criteria include: documented lamivudine resistant mutations, treatment with adefovir 10 mg/day for at least 24 weeks, and Child-Pugh score <7. Most had previous failed adefovir therapy and compensated cirrhosis of the liver. Clinical outcomes, liver biochemistries, and HBV DNA were monitored regularly. Patients with virologic breakthrough were rescued with add-on adefovir. At the end of the treatment period, the mean HBV DNA fell from 5.92 * 10(6) (baseline) to 3.67 * 10(1) IU/ml. The presence of a HBV polymerase rtM204V mutation at the baseline was found to be the major risk factor for adverse outcomes. Compared to the patients with the rtM204I mutant, patients with the rtM204V mutant had increased risk of virologic breakthrough (80% vs. 0%, P = 0.010) requiring add-on adefovir, slower virologic responses (log rank test, P = 0.0011), failure to reach undetectable HBV DNA levels (60% vs. 0%, P = 0.045), and higher risk of entecavir resistance (60% vs. 0%, P = 0.045). All the patients with rtM204I and rtA181 mutants had undetectable HBV DNA from 18th month. In summary, lamivudine resistant HBV patients with the rtM204V mutation have the highest risk of developing entecavir resistance, and entecavir monotherapy should be avoided. Those with the rtM204I and rtA181V mutations may have lower risks, but regular surveillance for viral breakthrough is required. PMID- 23023993 TI - Progress and prospects of pyrrole-imidazole polyamide-fluorophore conjugates as sequence-selective DNA probes. AB - Recently, the versatility of N-methylpyrrole (Py)-N-methylimidazole (Im) polyamide conjugates, which have been developed from the DNA-binding antibiotics distamycin A and netropsin, has been shown. These synthetic small molecules can permeate cells to bind with duplex DNA in a sequence-specific manner, and hence can influence gene expression in vivo. Accordingly, several reports demonstrating the sequence specificity and biological activity of Py-Im polyamides have accumulated. However, the benefits of Py-Im polyamides, in particular those conjugated with fluorophores, has been overlooked. Moreover, clear directions for the employment of these attractive artificial small molecules have not yet been shown. Here, we present a detailed overview of the current and prospective applications of Py-Im polyamide-fluorophore conjugates, including sequence specific recognition with fluorescence emission properties, and their potential roles in biological imaging. PMID- 23023995 TI - The chameleonic nature of diazaperopyrenium recognition processes. PMID- 23023994 TI - Brain vulnerability to chemotherapy toxicities. AB - Chemotherapy-induced cognitive changes have been an increasing concern among cancer survivors. By using adjuvant treatment for breast cancer as the prototype, this manuscript reviews research from neuropsychological, imaging, genetic, and animal model studies that have examined the clinical presentation and potential mechanisms for cognitive changes associated with exposure to chemotherapy. An impressive body of research supports the hypothesis that a subgroup of patients is vulnerable to post-treatment cognitive changes, although not exclusively related to chemotherapy. Further, imaging and animal model studies provide accumulating evidence of putative mechanisms for chemotherapy-induced cognitive change. Models of aging are also reviewed in support of the proposal that cognitive changes associated with cancer and cancer treatments can be viewed in the context of factors that affect the trajectory of normal aging. PMID- 23023996 TI - Evaluation of a new disposable "tampon like" electrostimulation technology (Pelviva(r)) for the treatment of urinary incontinence in women: a 12-week single blind randomized controlled trial. AB - AIMS: To test the null hypothesis that a novel disposable "tampon like" electrostimulation device (Pelviva((r))) is no better than unsupervised pelvic floor muscle exercise for treatment of urinary incontinence in women. METHODS: Pre/post-intervention assessor blinded, single center RCT. A total of 123 community dwelling self referred women with symptoms of stress, urge, or mixed incontinence were randomly assigned to one of two 12-week duration treatments: Pelviva((r)) used for 30 min a day plus unsupervised pelvic floor muscle exercise or unsupervised exercises alone. Outcome measures included ICIQ-UI (primary), ICIQ FLUTSex and global impression of severity and improvement (secondary) completed at recruitment, after 4 weeks of unsupervised exercise and immediately post-treatment. Diary of exercise frequency/type, overall impression, and usage of device was completed mid- and post-treatment. RESULTS: Pelviva((r)) plus exercise produced significantly better outcome than unsupervised exercise alone: 5 points (45%) versus 1 point (10%) for ICIQ-UI (P = 0.014); 67% versus 33% for leak frequency (P = 0.005); 40% versus 20% for leak interference with life (P = 0.018). Incontinence was less bothersome during sex to a greater extent in the Pelviva((r)) group (P = 0.026). Women were enthusiastic about the device, found it comfortable/easy to use and experienced no adverse events. CONCLUSIONS: The Pelviva((r)) device plus unsupervised exercise is more successful than unsupervised pelvic floor muscle exercise alone in treating urinary incontinence. The device is easy/comfortable to use, there are no apparent adverse incidents, and women can manage their incontinence in the privacy of their own home. The product will be launched 2013. PMID- 23024001 TI - HDAC11 is a novel drug target in carcinomas. AB - Inhibition of histone deacetylase (HDAC) activity as stand-alone or combination therapy represents a promising therapeutic approach in oncology. The pan- or class I HDAC inhibitors (HDACi) currently approved or in clinical studies for oncology give rise to dose-limiting toxicities, presumably because of the inhibition of several HDACs. This could potentially be overcome by selective blockade of single HDAC family members. Here we report that HDAC11, the most recently identified zinc-dependent HDAC, is overexpressed in several carcinomas as compared to corresponding healthy tissues. HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in HCT-116 colon, PC-3 prostate, MCF-7 breast and SK-OV-3 ovarian cancer cell lines. The antitumoral effect induced can be mimicked by enforced expression of a catalytically impaired HDAC11 variant, suggesting that inhibition of the enzymatic activity of HDAC11 by small molecules could trigger the desired phenotypic changes. HDAC11 depletion in normal cells causes no changes in metabolic activity and viability, strongly suggesting that tumor-selective effects can be achieved. Altogether, our data show that HDAC11 plays a critical role in cancer cell survival and may represent a novel drug target in oncology. PMID- 23024002 TI - Chance favors the prepared mind. PMID- 23024003 TI - Counseling in fetal medicine: agenesis of the corpus callosum. AB - In this Review, we aim to provide up-to-date and evidence-based answers to common questions regarding the diagnosis and prognosis of prenatally detected agenesis of the corpus callosum (ACC). A systematic literature search was performed to identify all reports of ACC and reference lists of articles were identified. ACC involves partial or complete absence of the main commissural pathway that connects the two cerebral hemispheres, and can be isolated (with no other abnormalities) or complex (coexisting with other abnormalities). It is a rare finding and the prevalence is difficult to estimate because of selection bias in reported series. The corpus callosum (CC) can be assessed on ultrasound by direct visualization, but indirect features, such as ventriculomegaly, absence of the cavum septi pellucidi or widening of interhemispheric fissure, are often the reason for detection in a screening population. Careful imaging in a center with a high level of expertise is required to make a full assessment and to exclude coexisting abnormalities, which occur in about 46% of fetuses. When available, magnetic resonance imaging appears to be an important adjunct as it allows direct visualization. It can reduce false-positive rates on ultrasound and can confirm ACC, it can assess whether this is complete or partial and it can help in detecting coexisting brain abnormalities not seen on ultrasound. The overall rate of chromosomal abnormality in fetuses with ACC is 18%, but this high rate includes both isolated and complex ACC; more recent studies suggest that chromosomal abnormalities are rare in isolated cases. Nevertheless, postnatal follow-up studies suggest that about 15% of cases thought to be isolated prenatally were found to have associated abnormalities after birth. Neurodevelopmental outcome in isolated ACC was recently reported in a systematic review and suggested normal outcome in about 65-75% of cases. Findings need to be considered in light of the several limitations of existing studies, in terms of study design, selection bias, varying definitions and imaging protocols, ascertainment bias and lack of control groups. These uncertainties mean that antenatal counseling is difficult and further large prospective studies are needed. PMID- 23024004 TI - Unusual C=C bond isomerization of an alpha,beta-unsaturated gamma-butyrolactone catalysed by flavoproteins from the old yellow enzyme family. AB - An unexpected, redox-neutral C=C bond isomerization of a gamma-butyrolactone bearing an exo-methylene unit to the thermodynamically more favoured endo isomer (k(cat) =0.076 s(-1) ) catalysed by flavoproteins from the Old Yellow Enzyme family was discovered. Theoretical calculations and kinetic data support a mechanism through which the isomerization proceeds through FMN-mediated hydride addition onto exo-Cbeta, followed by hydride abstraction from endo-Cbeta', which is in line with the well-established C=C bond bioreduction of OYEs. This new isomerase activity enriches the catalytic versatility of ene-reductases. PMID- 23024005 TI - Symptom onset-to-balloon time and mortality in the first seven years after STEMI treated with primary percutaneous coronary intervention. AB - OBJECTIVE: To evaluate the consequence of treatment delay of primary percutaneous coronary intervention (PPCI) on long-term survival. BACKGROUND: Network organisation based on early recognition, shortening prehospital time delays and procedural delays is the cornerstone of optimal clinical results in the acute phase of ST-segment elevation myocardial infarction (STEMI). Nevertheless, the evidence of a relationship between symptom onset-to-balloon time and mortality is weak, and few long-term data are available. SETTING AND MEASURES: In this single centre observational follow-up study, we evaluated the long-term survival of 790 consecutive STEMI patients (mean age 68 +/- 13 years; 73% males) undergoing PPCI <= 12 h from symptom onset, or 12-36 h in the case of persistence of symptoms or hemodynamic instability. RESULTS: The median (IQR) treatment delay, defined as the time from symptom onset to reperfusion, was 180 min (120;310), fairly balanced between patient delay (80 min (40;140)) and system delay (80 min (60 114)). Patients with a treatment delay <180 min displayed lower mortality at 1, 3, 5 and 7 years (12%, 17%, 22% and 26%, respectively) than those with a treatment delay >180 min (15%, 24%, 28% and 37%, respectively). The HR was 0.7 (95% CI 0.5 to 0.9). On univariate and stepwise multiple regression analysis, field triage and transportation (p=0.0001), shorter distance from hospital (p=0.02) and male gender (p=0.02), but not clinical variables, were independent predictors of shorter treatment delay. CONCLUSIONS: Shorter symptom onset-to balloon time predicts long-term lower mortality in STEMI patients treated with PPCI. Our findings emphasise the need to minimise any component of treatment delay. PMID- 23024006 TI - Acute exacerbation of COPD is associated with fourfold elevation of cardiac troponin T. AB - OBJECTIVE: To investigate if acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with myocardial injury, expressed as elevated high sensitive cardiac troponin T (hs-cTnT), and to identify determinants of hs-cTnT in chronic obstructive pulmonary disease (COPD) patients. DESIGN: In a cross sectional study, hs-cTnT in patients hospitalised for AECOPD was compared with hs cTnT in COPD patients in their stable state. SETTING: The study was conducted at a teaching and a pulmonary rehabilitation clinic. PARTICIPANTS: Consecutive admissions to participating units for the years 2010-2011 meeting objective, standardised criteria for AECOPD and stable COPD. MAIN OUTCOMES: Ratio of hs-cTnT in hospitalised AECOPD patients compared with stable COPD patients. Change in the ratio of hs-cTnT per unit increase of relevant covariables. RESULTS: The geometric mean of hs-cTnT in the index group was 25.8 ng/l (95% CI 21.1 to 31.7) compared with 4.55 ng/l (95% CI 3.72 to 5.67) in the reference group. After inclusion of relevant covariables, multiple linear regression analyses showed that the ratio between hs-cTnT in AECOPD patients and the references was 4.26 (95% CI 3.02 to 6.00) and that hs-cTnT increased 1.41-fold (95% CI 1.20 to 1.68), for each quartile increase in leucocyte count in stable COPD but not in AECOPD. Higher hs-cTnT levels were also associated with the presence of pathological q waves (p=0.012) and electrocardiographic left ventricular hypertrophy (p=0.039), long-term oxygen treatment (p=0.002) and decreasing forced expiratory volume in 1 s (p=0.014). A significant univariable association between cTnT and arterial hypoxaemia was also found but this association was attenuated almost to a zero effect after inclusion of relevant covariates. CONCLUSIONS: AECOPD is associated with higher hs-cTnT as compared with stable COPD. In stable COPD, hs-cTnT appears to be positively associated with indices of COPD severity, whereas we were unable to identify significant determinants of hs-cTnT in AECOPD. PMID- 23024007 TI - Rivaroxaban and other novel anticoagulants for stroke prevention in atrial fibrillation: time to embrace the future. PMID- 23024008 TI - Switching to darunavir/ritonavir 800/100 mg once-daily containing regimen maintains virological control in fully suppressed pre-treated patients infected with HIV-1. AB - The objective of this study was to evaluate the switch to once-daily darunavir/ritonavir 800/100 mg in treatment-experienced patients with suppressed HIV-1 replication on a twice-daily ritonavir-boosted protease-inhibitor (bid PI/r) containing regimen, that is in a setting where genotypic resistance test cannot be performed. In this open label, non-comparative, multicenter study, patients on a bid PI/r-containing triple combination, with suppressed viral replication, were switched to once-daily darunavir/r 800/100 mg containing triple combination. The primary endpoint was the proportion of patients with plasma HIV RNA < 50 copies/ml 24 weeks after the switch. Intensive darunavir pharmacokinetic evaluation was performed at Week 4 (W4) in 11 patients. Eighty-five patients were enrolled. All had HIV-RNA < 50 copies/ml at screening with a pre-exposure to a median of 2 PI/r (1-5). By intent-to-treat analysis (missing = failure), 78/85 patients (92%, 95% CI [83;96]) maintained an HIV-RNA < 50 copies/ml at W24. Seven patients experienced protocol-defined treatment failure between baseline and W24: Two had confirmed low-level viral rebound, one discontinued study treatment for adverse event, three withdrew their consent, and one was lost to follow-up. By on treatment analysis, 78/80 patients (97%, 95% CI [91;99]) maintained an HIV-RNA < 50 copies/ml at W24. Results were similar at Week 48. The median area under the darunavir plasma concentration-time curve measured in 11 patients was 61,380 ng hr/ml; darunavir median trough concentration 1,340 ng/ml and darunavir half-life was 12.2 hr. Tolerability of once-daily darunavir/r 800/100 mg was excellent. Optimally suppressed, treatment-experienced patients can switch safely from a twice-daily PI/r regimen to a once-daily darunavir/r 800/100 mg containing regimen. PMID- 23024009 TI - Anion-induced enantioselective cyclization of diynamides to pyrrolidines catalyzed by cationic gold complexes. AB - Only chiral anions do the job! Optically active gold complexes derived from substituted binol hydrogen phosphate catalyze the desymmetrizing cyclization of 1,4-diynamides. This reaction provides access to synthetically useful, chiral methylene pyrrolidines with an all-carbon-substituted quaternary stereocenter. PMID- 23024011 TI - Creating reusable tools from scripts: the Galaxy Tool Factory. AB - MOTIVATION: Galaxy is a software application supporting high-throughput biology analyses and work flows, available as a free on-line service or as source code for local deployment. New tools can be written to extend Galaxy, and these can be shared using public Galaxy Tool Shed (GTS) repositories, but converting even simple scripts into tools requires effort from a skilled developer. RESULTS: The Tool Factory is a novel Galaxy tool that automates the generation of all code needed to execute user-supplied scripts, and wraps them into new Galaxy tools for upload to a GTS, ready for review and installation through the Galaxy administrative interface. AVAILABILITY AND IMPLEMENTATION: The Galaxy administrative interface supports automated installation from the main GTS. Source code and support are available at the project website, https://bitbucket.org/fubar/galaxytoolfactory. The Tool Factory is implemented as an installable Galaxy tool. CONTACT: ross.lazarus@channing.harvard.edu. PMID- 23024010 TI - Site identification in high-throughput RNA-protein interaction data. AB - MOTIVATION: Post-transcriptional and co-transcriptional regulation is a crucial link between genotype and phenotype. The central players are the RNA-binding proteins, and experimental technologies [such as cross-linking with immunoprecipitation- (CLIP-) and RIP-seq] for probing their activities have advanced rapidly over the course of the past decade. Statistically robust, flexible computational methods for binding site identification from high throughput immunoprecipitation assays are largely lacking however. RESULTS: We introduce a method for site identification which provides four key advantages over previous methods: (i) it can be applied on all variations of CLIP and RIP seq technologies, (ii) it accurately models the underlying read-count distributions, (iii) it allows external covariates, such as transcript abundance (which we demonstrate is highly correlated with read count) to inform the site identification process and (iv) it allows for direct comparison of site usage across cell types or conditions. AVAILABILITY AND IMPLEMENTATION: We have implemented our method in a software tool called Piranha. Source code and binaries, licensed under the GNU General Public License (version 3) are freely available for download from http://smithlab.usc.edu. CONTACT: andrewds@usc.edu SUPPLEMENTARY INFORMATION: Supplementary data available at Bioinformatics online. PMID- 23024012 TI - Urinary incontinence after surgery for pelvic organ prolapse. AB - AIMS: This study focused on the changes in urinary incontinence (UI) rates pre- and postoperatively and identified risk factors which predict the presence of symptoms of urgency urinary incontinence (UUI) or stress urinary incontinence (SUI) after surgery for pelvic organ prolapse (POP) without concomitant or previous anti-incontinence surgery. METHODS: All consecutive women who underwent POP surgery without concomitant or previous anti-incontinence surgery in the years 2004-2010 were included. Assessments were performed preoperatively and at 1 year follow-up, including pelvic organ prolapse quantification score and a standardized urogynecological questionnaire (Urogenital Distress Inventory, UDI). Primary outcome of this study was stress and/or urgency UI postoperatively. Furthermore, this study measured the improvement or worsening of UI following surgery using the UDI. Univariable- and multivariable logistic regression with forward selection procedure was used to identify the risk factors. RESULTS: Nine hundred seven patients were included. De novo SUI appeared in 22% and de novo UUI occurred in 21% of the women. At 1-year 42% were cured for UUI and 39% were recovered from SUI by POP surgery alone. The best predictor for the occurrence of postoperative SUI or UUI was the presence of preoperative SUI or UUI. BMI and chronic obstructive pulmonary disease (COPD) were identified as independent risk factors for postoperative SUI. A recurrence in the anterior compartment protected against SUI postoperatively. CONCLUSIONS: Preoperative SUI or UUI is the most important predictor of SUI and UUI postoperatively. BMI and COPD were identified as important risk factors for SUI. PMID- 23024013 TI - Second harmonic generation microscopy as a powerful diagnostic imaging modality for human ovarian cancer. AB - In this study we showed that second-harmonic generation (SHG) microscopy combined with precise methods for images evaluation can be used to detect structural changes in the human ovarian stroma. Using a set of scoring methods (alignment of collagen fibers, anisotropy, and correlation), we found significant differences in the distribution and organization of collagen fibers in the stroma component of serous, mucinous, endometrioid and mixed ovarian tumors as compared with normal ovary tissue. This methodology was capable to differentiate between cancerous and healthy tissue, with clear cut distinction between normal, benign, borderline, and malignant tumors of serous type. Our results indicated that the combination of different image-analysis approaches presented here represent a powerful tool to investigate collagen organization and extracellular matrix remodeling in ovarian tumors. PMID- 23024014 TI - Alcohol consumption and PSA-detected prostate cancer risk--a case-control nested in the ProtecT study. AB - Alcohol is an established carcinogen but not an established risk factor for prostate cancer, despite some recent prospective studies suggesting increased risk among heavy drinkers. The aim of this study was to investigate the role of alcohol on prostate-specific antigen (PSA) levels and prostate cancer risk. Two thousand four hundred PSA detected prostate cancer cases and 12,700 controls matched on age and general practice were identified through a case-control study nested in the PSA-testing phase of a large UK-based randomized controlled trial for prostate cancer treatment (ProtecT). Linear and multinomial logistic regression models were used to estimate ratios of geometric means (RGMs) of PSA and relative risk ratios (RRRs) of prostate cancer by stage and grade, with 95% confidence intervals (CIs), associated with weekly alcohol intake and drinking patterns. We found evidence of lower PSA (RGM 0.98, 95% CI: 0.98-0.99) and decreased risk of low Gleason-grade (RRR 0.96; 95%CI 0.93-0.99) but increased risk of high-grade prostate cancer (RRR 1.04; 95%CI 0.99-1.08; p(difference) =0.004) per 10 units/week increase in alcohol consumption, not explained by current BMI, blood pressure, comorbidities, or reverse causation. This is the first large population-based study to find evidence of lower PSA levels for increasing alcohol consumption, with potential public health implications for the detection of prostate cancer. Our results also support a modestly higher risk of high-grade disease for heavy drinkers, but require independent replication to establish the nature of the association of alcohol with low-grade disease, preferably in cohorts with a heterogeneous case-mix. PMID- 23024015 TI - Comparison of three enthesitis indices in a multicentre, randomized, placebo controlled trial of golimumab in ankylosing spondylitis (GO-RAISE). AB - OBJECTIVE: To compare the abilities of three enthesitis indices to detect improvement in entheseal tenderness with the TNF antagonist golimumab in AS. METHODS: Adult patients with active AS were randomly assigned to receive s.c. injections of placebo or golimumab (50 or 100 mg) every 4 weeks. Patients with inadequate week 16 responses were switched (blinded) from placebo to golimumab 50 mg or from golimumab 50 mg to 100 mg. At week 24, all patients still receiving placebo crossed over to golimumab 50 mg. Enthesitis data through week 52 are reported herein. Enthesitis was measured by a trained, independent assessor who recorded the presence or absence of tenderness in 27 entheses, which allowed simultaneous determination of three different indices [12-point Berlin Index, 17 point University of California, San Francisco (UCSF) Index and 13-point Maastricht AS Enthesitis Score (MASES)]. RESULTS: Three hundred and fifty-six AS patients were randomized to placebo (n = 78), golimumab 50 mg (n = 138) or golimumab 100 mg (n = 140); 355 had enthesitis data available for analysis. Using the UCSF Index, significant improvement from baseline vs placebo was observed for golimumab 100 mg at weeks 14 and 24. Using the MASES, significant improvement for golimumab 100 mg vs placebo at week 14 and a trend toward improvement at week 24 were observed. Using the Berlin Index, significant improvement for golimumab 100 mg vs placebo at week 14 was observed. Effect size determinations for changes to weeks 14, 24 and 52, respectively, in the Berlin (-0.27, -0.34, -0.42), UCSF ( 0.44, -0.61, -0.55) and MASES (-0.30, -0.55, -0.39) indices suggested small to moderate effect sizes. CONCLUSION: In patients with active AS, the UCSF Index appeared most sensitive in detecting the effect of golimumab 100 mg vs placebo on enthesitis. TRIAL REGISTRATION: clinicaltrials.gov, http://www.clinicaltrials.gov, NCT00265083. PMID- 23024016 TI - Effect of fibromyalgia syndrome on the health-related quality of life and economic burden in Korea. AB - OBJECTIVE: To investigate the health-related quality of life (HRQOL) and economic burden of patients with FM syndrome (FMS) and compare the changes in these parameters 3 months before and after FMS diagnosis. METHODS: A total of 2098 patients with FMS (1818 previously diagnosed with FMS and 280 newly diagnosed with FMS) were enrolled in this study. The newly diagnosed patients with FMS participated in a 3-month prospective observational study to assess HRQOL and economic burden in terms of direct health-care costs, direct non-health-care costs and indirect costs. HRQOL was estimated using the Short Form 36 Health Survey. RESULTS: Mean (S.D.) scores obtained on the physical component summary (PCS) and mental component summary (MCS) scales by patients with FMS were 34.01 (7.28) and 37.29 (11.17), respectively. The total expenditure for the 3 months before enrolment was $1481 (S.D. $2206). Indirect costs [$1126 (S.D. $2016)] were about three times higher than direct costs [$355 (S.D. $534)]. The PCS and MCS scores increased to 4.03 (S.D. 6.79) and 4.06 (S.D. 10.57), respectively, 3 months after the initial FMS diagnosis (P < 0.001, both). Total expenditure after FMS diagnosis was reduced by $1025 (S.D. $1347) as compared with costs before FMS diagnosis (P < 0.001). Conclusion. Patients with FMS experience a decline in their HRQOL and constitute a significant economic burden on health-service utilization. The improvement in health-related costs and HRQOL after a diagnosis of FMS demonstrates a need for early diagnosis and treatment of FMS to reduce costs and enhance HRQOL. PMID- 23024017 TI - Osteoclast migration, differentiation and function: novel therapeutic targets for rheumatic diseases. AB - RA is a chronic autoimmune disease characterized by joint synovial inflammation and progressive cartilage/bone destruction. Although various kinds of RA drug have been developed worldwide, there are currently no established methods for preventing RA-associated bone destruction, the most severe outcome of this disease. One of the major pathogenic factors in arthritic bone destruction is the enhanced activity of osteoclasts at inflammatory sites. Osteoclasts are bone resorbing giant polykaryons that differentiate from mononuclear macrophage/monocyte-lineage haematopoietic precursors. Upon stimulation by cytokines, such as M-CSF and RANK ligand, osteoclast precursor monocytes migrate and attach onto the bone surface (migration). They then fuse with each other to form giant cells (differentiation) and mediate bone resorption (function). In this review, we summarize the current understanding regarding the mechanisms underlying these three dynamic steps of osteoclastic activity and discuss novel lines of osteoclast-targeted therapies that will impact future treatment of RA. PMID- 23024018 TI - Adding to complexity: comorbidity in paediatric rheumatic disease. AB - Novel therapies including biologic agents offer paediatric rheumatologists significant opportunity to improve long-term prognosis for children with rheumatic disease. However, comorbidities related to the diseases themselves and their treatments pose specific challenges to be overcome. Prompt recognition and appropriate management will improve quality of life, effectiveness of treatment and overall prognosis. In this review, we discuss key areas of comorbidity frequently encountered in paediatric rheumatology including cardiovascular, renal, genito-urinary and visual comorbidity, bone health, drug-related issues and the influence of rheumatic disease on growth and puberty. PMID- 23024019 TI - Impact of proactive rounding by a rapid response team on patient outcomes at an academic medical center. AB - BACKGROUND: The impact of rapid response teams (RRT) on patient outcomes remains uncertain. OBJECTIVE: To examine the effect of proactive rounding by an RRT on outcomes of hospitalized adults discharged from intensive care. DESIGN: Retrospective, observational study. SETTING: Academic medical center. PATIENTS: All adult patients discharged alive from the intensive care unit (ICU) at the University of California San Francisco Medical Center between January 2006 and June 2009. INTERVENTION: Introduction of proactive rounding by an RRT. MEASUREMENTS: Outcomes included the ICU readmission rate, ICU average length of stay (LOS), and in-hospital mortality of patients discharged from the ICU. Data were obtained from administrative billing databases and analyzed using an interrupted time series (ITS) model. RESULTS: We analyzed 17 months of preintervention data and 25 months of postintervention data. Introduction of proactive rounding by the RRT did not change the ICU readmission rate (6.7% before vs 7.3% after; P = 0.24), the ICU LOS (5.1 days vs 4.9 days; P = 0.24), or the in-hospital mortality of patients discharged from the ICU (6.0% vs 5.5%; P = 0.24). ITS models testing the impact of proactive rounding on secular trends found no improvement in any of the 3 clinical outcomes relative to their preintervention trends. CONCLUSIONS: Proactive rounding by an RRT did not improve patient outcomes, raising further questions about RRT benefits. PMID- 23024020 TI - Simple two-dimensional ultrasound technique to assess intrapartum cervical dilatation: a pilot study. AB - OBJECTIVES: To describe a two-dimensional (2D) ultrasound technique to measure cervical dilatation in labor, and to compare ultrasound with digital measurements. METHODS: 2D transperineal ultrasound was performed in 21 nulliparous women in labor with a singleton fetus in cephalic presentation and cervical dilatation measured before or after a digital vaginal examination. The absolute difference was calculated and Bland-Altman analysis was used to assess the mean difference between digital vaginal examination and ultrasound examination of cervical dilatation. Pearson analysis was used to determine the correlation between digital and ultrasound measurements. Intraclass correlation coefficients (ICCs) with 95% CI were used to evaluate the reliability of the two methods. RESULTS: Satisfactory quality images of the cervix were obtained in 19 of 21 cases. There was positive correlation between 2D ultrasound measurement of cervical dilatation and digital vaginal examination (Pearson coefficient r = 0.821, n = 19, P < 0.001). Bland-Altman analysis showed a mean difference between digital and ultrasound measurements of 0.08 cm (95% limits of agreement: -1.83 to 2.00) and the mean absolute difference was 1.24 cm. The ICC between the two methods was 0.81 (95% CI, 0.58-0.92). CONCLUSIONS: Assessment and measurement of cervical dilatation by 2D transperineal ultrasound is feasible, with close agreement shown between the technique and digital vaginal examination. The technique that we describe could represent an important component of a 'sonopartogram' for ultrasound assessment of labor progress. PMID- 23024021 TI - Mitochondrial dysfunction and lipid accumulation in the human diaphragm during mechanical ventilation. AB - RATIONALE: Mechanical ventilation (MV) is associated with adverse effects on the diaphragm, but the cellular basis for this phenomenon, referred to as ventilator induced diaphragmatic dysfunction (VIDD), is poorly understood. OBJECTIVES: To determine whether mitochondrial function and cellular energy status are disrupted in human diaphragms after MV, and the role of mitochondria-derived oxidative stress in the development of VIDD. METHODS: Diaphragm and biceps specimens obtained from brain-dead organ donors who underwent MV (15-176 h) and age-matched control subjects were compared regarding mitochondrial enzymatic function, mitochondrial DNA integrity, lipid content, and metabolic gene and protein expression. In addition, diaphragmatic force and oxidative stress after exposure to MV for 6 hours were evaluated in mice under different conditions. MEASUREMENTS AND MAIN RESULTS: In human MV diaphragms, mitochondrial biogenesis and content were down-regulated, with a more specific defect of respiratory chain cytochrome c oxidase. Laser capture microdissection of cytochrome-c oxidase-deficient fibers revealed mitochondrial DNA deletions, consistent with damage from oxidative stress. Diaphragmatic lipid accumulation and responses of master cellular metabolic sensors (AMP-activated protein kinase and sirtuins) were consistent with energy substrate excess as a possible stimulus for these changes. In mice, induction of hyperlipidemia worsened diaphragmatic oxidative stress during MV, whereas transgenic overexpression of a mitochondria-localized antioxidant (peroxiredoxin-3) was protective against VIDD. CONCLUSIONS: Our data suggest that mitochondrial dysfunction lies at the nexus between oxidative stress and the impaired diaphragmatic contractility that develops during MV. Energy substrate oversupply relative to demand, resulting from diaphragmatic inactivity during MV, could play an important role in this process. PMID- 23024022 TI - Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. AB - RATIONALE: Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance. OBJECTIVES: To screen drugs that target CSCs to improve the current treatment outcome and overcome drug resistance in patients with lung cancer. METHODS: We used publicly available embryonic stem cell and CSC associated gene signatures to query the Connectivity Map for potential drugs that can, at least in part, reverse the gene expression profile of CSCs. High scores were noted for several phenothiazine-like antipsychotic drugs, including trifluoperazine. We then treated lung CSCs with different EGFR mutation status with trifluoperazine to examine its anti-CSC properties. Lung CSCs resistant to epidermal growth factor receptor-tyrosine kinase inhibitor or cisplatin were treated with trifluoperazine plus gefitinib or trifluoperazine plus cisplatin. Animal models were used for in vivo validation of the anti-CSC effect and synergistic effect of trifluoperazine with gefitinib. MEASUREMENTS AND MAIN RESULTS: We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazine inhibited Wnt/beta-catenin signaling in gefitinib-resistant lung cancer spheroids. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models. CONCLUSIONS: Using in silico drug screening by Connectivity Map followed by empirical validations, we repurposed an existing phenothiazine-like antipsychotic drug, trifluoperazine, as a potential anti-CSC agent that could overcome epidermal growth factor receptor-tyrosine kinase inhibitor and chemotherapy resistance. PMID- 23024023 TI - The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. AB - RATIONALE: Nonadherence to inhaled corticosteroid therapy (ICS) is a major contributor to poor control in difficult asthma, yet it is challenging to ascertain. OBJECTIVES: Identify a test for nonadherence using fractional exhaled nitric oxide (Fe(NO)) suppression after directly observed inhaled corticosteroid (DOICS) treatment. METHODS: Difficult asthma patients with an elevated Fe(NO) (>45 ppb) were recruited as adherent (ICS prescription filling >80%) or nonadherent (filling <50%). They received 7 days of DOICS (budesonide 1,600 MUg) and a test for nonadherence based on changes in Fe(NO) was developed. Using this test, clinic patients were prospectively classified as adherent or nonadherent and this was then validated against prescription filling records, prednisolone assay, and concordance interview. MEASUREMENTS AND MAIN RESULTS: After 7 days of DOICS nonadherent (n = 9) compared with adherent subjects (n = 13) had a greater reduction in Fe(NO) to 47 +/- 21% versus 79 +/- 26% of baseline measurement (P = 0.003), which was also evident after 5 days (P = 0.02) and a Fe(NO) test for nonadherence (area under the curve = 0.86; 95% confidence interval, 0.68-1.00) was defined. Prospective validation in 40 subjects found the test identified 13 as nonadherent; eight confirmed nonadherence during interview (three of whom had excellent prescription filling but did not take medication), five denied nonadherence, two had poor inhaler technique (unintentional nonadherence), and one also denied nonadherence to prednisolone despite nonadherent blood level. Twenty-seven participants were adherent on testing, which was confirmed in 21. Five admitted poor ICS adherence but of these, four were adherent with oral steroids and one with omalizumab. CONCLUSIONS: Fe(NO) suppression after DOICS provides an objective test to distinguish adherent from nonadherent patients with difficult asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 01219036). PMID- 23024025 TI - Characterization of hepatitis B virus mutations in untreated patients co-infected with HIV and HBV based on complete genome sequencing. AB - Co-infection of HBV with HIV results in an accelerated course of HBV-associated chronic liver disease. Several studies have shown that viral mutations are related to disease progression in mono-infection with HBV. However, it is unclear whether HBV mutation patterns might differ between co-infected and mono-infected patients. To compare the frequencies and mutation patterns in the HBV genome between co-infection and mono-infection. Twenty-four treatment-naive co-infected and 31 treatment-naive mono-infected Thai patients were included. HBV mutations were characterized by whole genome sequencing of virus serum samples. The clinical features and frequency of known clinically significant mutations were compared between the two groups. No significant difference between the groups was found with respect to sex, age and HBeAg. However, HBV DNA levels were significantly higher in co-infected patients. The distribution of HBV genotypes was comparable between the two groups and restricted mostly to sub-genotypes C1 and B2. An isolate with recombinants of genotypes G/C1 was also identified in a patient with co-infection. There was no difference in the prevalence of mutations in the enhancer II/basal core promoter/precore region, pre-S/S and polymerase genes between the two groups. In conclusion, dual infections tend to engender increased HBV DNA levels. There was no major difference in the frequencies of common HBV mutations between co-infected and mono-infected patients. Thus, HBV mutations may not contribute to disease pathogenesis in Thai patients with co infection. PMID- 23024024 TI - Rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with virus (mostly rhinovirus) and bacterial infections, but it is not known whether rhinovirus infections precipitate secondary bacterial infections. OBJECTIVES: To investigate relationships between rhinovirus infection and bacterial infection and the role of antimicrobial peptides in COPD exacerbations. METHODS: We infected subjects with moderate COPD and smokers and nonsmokers with normal lung function with rhinovirus. Induced sputum was collected before and repeatedly after rhinovirus infection and virus and bacterial loads measured with quantitative polymerase chain reaction and culture. The antimicrobial peptides secretory leukoprotease inhibitor (SLPI), elafin, pentraxin, LL-37, alpha defensins and beta-defensin-2, and the protease neutrophil elastase were measured in sputum supernatants. MEASUREMENTS AND MAIN RESULTS: After rhinovirus infection, secondary bacterial infection was detected in 60% of subjects with COPD, 9.5% of smokers, and 10% of nonsmokers (P < 0.001). Sputum virus load peaked on Days 5-9 and bacterial load on Day 15. Sputum neutrophil elastase was significantly increased and SLPI and elafin significantly reduced after rhinovirus infection exclusively in subjects with COPD with secondary bacterial infections, and SLPI and elafin levels correlated inversely with bacterial load. CONCLUSIONS: Rhinovirus infections are frequently followed by secondary bacterial infections in COPD and cleavage of the antimicrobial peptides SLPI and elafin by virus-induced neutrophil elastase may precipitate these secondary bacterial infections. Therapy targeting neutrophil elastase or enhancing innate immunity may be useful novel therapies for prevention of secondary bacterial infections in virus-induced COPD exacerbations. PMID- 23024026 TI - B4GALT1 gene knockdown inhibits the hedgehog pathway and reverses multidrug resistance in the human leukemia K562/adriamycin-resistant cell line. AB - B4GALT1 gene encodes type II membrane-bound glycoprotein, named beta-1, 4 galactosyltransferase 1 (beta1, 4-Gal-T1), which can transfer galactose to acceptor sugars. B4GALT1 gene plays important roles in physiological process and disease development. In this study, we investigate the possible role and mechanism of B4GALT1 gene in multidrug resistance of human leukemia cell line. Significantly, higher expression of B4GALT1 was observed in adriamycin-resistant (ADR) K562 cell line (K562/ADR) than that in K562 cell line by real-time polymerase chain reaction and Western blotting. The activity of beta1, 4-Gal-T1 enzyme, and Galbeta-1,4GlcNAc structures on cell membrane glycoproteins was found at higher levels in K562/ADR cells than those in K562 cells. Further analysis of the B4GALT1 deregulation after using RNA interference approach showed that the silencing of B4GALT1 in K562/ADR cells resulted in increased sensitivity to chemotherapeutic drugs both in vitro and in vivo. The activity of the hedgehog signaling pathway affected the chemosensitivity of K562/ADR cells and was downregulated in K562/ADR cells with suppression of B4GALT1 gene. We hypothesize that B4GALT1 is responsible for the overcoming multidrug resistance in human leukemia therapy via regulating the activity of the hedgehog signaling pathway. PMID- 23024027 TI - Heterologous expression and manipulation of three tetracycline biosynthetic pathways. AB - A very accommodating host: Three tetracycline biosynthetic pathways were overexpressed and manipulated in the heterologous host Streptomyces lividans K4 114. Through the inactivation of various genes and characterization of the resulting biosynthetic intermediates, new tetracycline-modifying enzymes were identified (see scheme). PMID- 23024028 TI - 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. PMID- 23024030 TI - Oral glucocorticoids should be included in any recommendation for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in the treatment of rheumatoid arthritis: comment on the article by Singh et al. PMID- 23024029 TI - 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. PMID- 23024032 TI - Predicting bacteremia based on nurse-assessed food consumption at the time of blood culture. AB - BACKGROUND: Bacteremia and its complications are important causes of morbidity and mortality in hospitalized patients. However, the yield of blood cultures is relatively low, with many false-positive results from bacterial contamination. METHODS: We investigated the relationship between patient food consumption and the presence of bacteremia. This was an observational analysis of a cohort of 1179 patients who underwent blood culture analysis between January 2005 and December 2009. Patients with anorexia-inducing conditions, such as gastrointestinal illness and malignant disease treated with chemotherapy, were excluded. Food consumption was rated by nurses as the percentage of food consumed during the meal preceding the blood culture. Groupings were as follows: low consumption (<50%), moderate (>50% to <80%), and high (>80%). RESULTS: Low consumption was observed in 39.8% of patients, moderate in 17.8%, and high in 41.6%. The average body temperature was 38.1 +/- 1.1 degrees C. Bacteremia was present in 18.5%, 3.9%, and 1.4% of patients in the low, moderate, and high food consumption groups, respectively. The negative predictive value was 98.3%, suggesting that bacteremia is very unlikely in the setting of good food intake. CONCLUSION: Bacteremia is an unlikely occurrence in hospitalized patients who maintain adequate food consumption at the time of blood culture. PMID- 23024033 TI - Type 2 diabetes mellitus, insulin-use and risk of bladder cancer in a large cohort study. AB - Type 2 diabetes mellitus (T2DM) is associated with increased bladder cancer incidence in some, but not all, studies. Many studies had limited statistical power and few examined risk by insulin-use, duration of diabetes or cancer stage. We examined the association between T2DM and bladder cancer incidence in the Cancer Prevention Study II Nutrition Cohort, a large prospective study with information on insulin-use and duration of diabetes. Diabetes and insulin-use were ascertained from a questionnaire at study enrollment in 1992 or 1993 and updated in 1997 and every 2 years thereafter. During follow-up through 2007, 1,852 cases of incident bladder cancer were identified among 172,791 participants. Multivariable adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated using extended Cox regression modeling. There were no associations of T2DM with the risk of bladder cancer overall (RR = 1.01, 95% CI: 0.87-1.17), noninvasive disease (RR = 0.93, 95% CI: 0.76-1.14) or invasive disease (RR = 1.13, 95% CI: 0.91-1.40). Compared to participants without T2DM, risk of invasive bladder cancer was higher among participants who had had T2DM for >15 years (RR = 1.63, 95% CI: 1.09-2.43) and among those using insulin (RR = 1.64, 95% CI: 1.18-2.27). These results do not support an association of T2DM with overall bladder cancer incidence, but do suggest positive associations of long-term T2DM and insulin-use or other factors correlated with severe diabetes, with invasive bladder cancer incidence. PMID- 23024034 TI - Depressed mitochondrial biogenesis and dynamic remodeling in mouse tibialis anterior and gastrocnemius induced by 4-week hindlimb unloading. AB - Mitochondrial dynamics is highly involved in muscle atrophy, the slow twitch muscle as soleus, preferentially affected by hindlimb unloading (HU), was well characterized by mitochondrial dysfunction in biogenesis. However, the fast twitch muscles like tibialis anterior (TA) and gastrocnemius (GAS), which are the most massive parts of the hindlimb muscles, are less elucidated on mitochondrial adaptations responding to HU. To investigate the mitochondrial dynamic responses and the involved molecules mediating atrophy in TA and GAS, we studied a 4-week HU mouse model. We found GAS was preferentially affected to atrophy by unloading compared with TA. Furthermore, the depressed mitochondrial biogenesis occurred, accounting for mitochondrial loss in GAS by unloading. PGC-1alpha, as well as its transcriptional/post-translational modification regulators, such as p-CREB, SIRT1, and p-AMPK, were consistently reduced in response to unloading in GAS. Molecules relevant to autophagy, mitochondrial fusion, and fission, were compromised following unloading both in TA and GAS. These results suggested that TA exhibited resistance to unloading induced muscle atrophy while GAS presented significant mitochondrial loss, which might be due to the mitochondrial biogenesis suppressed by the inactivation of PGC-1alpha. However, both in TA and GAS muscles, a similar sedentary mitochondrial dynamics of mitochondrial fusion and fission was induced by unloading though TA exhibited little muscle atrophy. PMID- 23024035 TI - Sample size calculation for recurrent events data in one-arm studies. AB - In some exceptional circumstances, as in very rare diseases, nonrandomized one arm trials are the sole source of evidence to demonstrate efficacy and safety of a new treatment. The design of such studies needs a sound methodological approach in order to provide reliable information, and the determination of the appropriate sample size still represents a critical step of this planning process. As, to our knowledge, no method exists for sample size calculation in one-arm trials with a recurrent event endpoint, we propose here a closed sample size formula. It is derived assuming a mixed Poisson process, and it is based on the asymptotic distribution of the one-sample robust nonparametric test recently developed for the analysis of recurrent events data. The validity of this formula in managing a situation with heterogeneity of event rates, both in time and between patients, and time-varying treatment effect was demonstrated with exhaustive simulation studies. Moreover, although the method requires the specification of a process for events generation, it seems to be robust under erroneous definition of this process, provided that the number of events at the end of the study is similar to the one assumed in the planning phase. The motivating clinical context is represented by a nonrandomized one-arm study on gene therapy in a very rare immunodeficiency in children (ADA-SCID), where a major endpoint is the recurrence of severe infections. PMID- 23024036 TI - Thinness in the pursuit for social safeness: an integrative model of social rank mentality to explain eating psychopathology. AB - The current study tests a model based on social rank mentality investigating whether women who feel inferior and believe others see them negatively, and feel under pressure to compete to avoid social inferiority, present increased body dissatisfaction and drive for thinness and whether these associations are mediated by distinct emotional regulation processes. The predictions from the model proposed were examined through path analyses, in a sample of 125 women from the general population and 102 patients with eating disorders. Results showed that the path model explained 51% of body dissatisfaction variance and 61% of drive for thinness and allowed us to confirm that social ranking variables increased drive for thinness through higher levels of self-criticism and lower levels of self-compassion. The findings suggest that the nuclear eating disorders' features arise as a result of a more self-critical and less compassionate attitude with the self, in the context of a mentality focused on social ranking and competition. KEY PRACTITIONER MESSAGE: The current study explores an innovative comprehensive model based on social rank theory to understand eating disorders' symptoms in women. A mentality focused on ranking, shame and competition predicts body image dissatisfaction. This ranking-focused mentality, along with body image dissatisfaction, leads to drive for thinness through increased self-criticism and decreased self-compassion. These findings support the emergent psychotherapeutic approaches for eating disorders that target self-criticism and self-compassion. PMID- 23024037 TI - DNA detection based on fluorogenic nanospheres. AB - High and dry fluorescence: Fluorogenic nanospheres (green, see scheme) are conjugated to DNA (pink) and used to detect target DNA (aqua). Upon addition of N butylmorpholine (droplet), the nanospheres dissolve, releasing fluorophores, and intense blue fluorescence is emitted at the site of DNA hybridization. The separation of DNA hybridization and signal amplification gives high sensitivity (100 zmol) and selectivity. PMID- 23024038 TI - Nasal and bronchial airway epithelial cell mediator release in children. AB - OBJECTIVE: The present study was designed to test the hypothesis that airway epithelial cell (AEC) mediator release is similar in upper and lower airway AEC in children. METHODS: Nasal and bronchial AEC were collected by brushings from children scheduled for general anesthetic. AEC release of the following mediators was measured: interleukin (IL)-6, IL-8, Granulocyte Colony Stimulating Factor (G CSF), regulated on activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), matrix metallo proteinase (MMP)-9, and tissue inhibitor of metalloproteinases (TIMP)-1. RESULTS: AEC were cultured in 34 children, mean age 7.3 years. Release of IL-6, IL-8, and G-CSF was significantly higher in nasal compared with bronchial AEC but nasal and bronchial AEC release of other mediators was not significantly different. Treatment of AEC with IL-1 beta and tumor necrosis factor-alpha increased secretion of all mediators. Release of IL-6 and GSCF remained higher in nasal AEC compared with bronchial AEC following stimulation. CONCLUSIONS: In epidemiological studies, nasal AEC may be a useful surrogate for bronchial AEC for the study of RANTES, MCP-1, TIMP-1, and MMP-9 release in children but bronchial AEC will remain the gold standard. PMID- 23024039 TI - Role of androgen receptor polyQ chain elongation in Kennedy's disease and use of natural osmolytes as potential therapeutic targets. AB - Instability of CAG triplet repeat encoding polyglutamine (polyQ) stretches in the gene for target protein has been implicated as a putative mechanism in several inherited neurodegenerative diseases. Expansion of polyQ chain length in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease. Although the mechanisms underlying gain-of-neurotoxic function are not completely understood, suggested pathological mechanisms of SBMA involve the formation of AR nuclear and cytoplasmic aggregates, a characteristic feature of patients with SBMA. The fact that certain AR coactivators are sequestered into the nuclear inclusions in SBMA possibly through protein-protein interactions supports the notion that AR transcriptional dysregulation may be a potential pathological mechanism leading to SBMA. AR conformational states associated with aberrant polyQ tract also modulate the interaction of AR with several coactivators. In many cases, such diseases can be treated through protein replacement therapy; however, because recombinant proteins do not cross the blood brain barrier, the effectiveness of such therapies is limited in case of neurodegenerative diseases that warrant alternative therapeutic approaches. Among different approaches, inhibiting protein aggregation with small molecules that can stimulate protein folding and reverse aggregation are the most promising ones. Thus, naturally occurring osmolytes or "chemical chaperones" that can easily cross the blood-brain barrier and stabilize the functional form of a mutated protein by shifting the folding equilibrium away from degradation and/or aggregation is a useful therapeutic approach. In this review, we discuss the role of polyQ chain length extension in the pathophysiology of SBMA and the use of osmolytes as potential therapeutic tool. PMID- 23024040 TI - Risk factors for unplanned transfer to intensive care within 24 hours of admission from the emergency department in an integrated healthcare system. AB - BACKGROUND: Emergency department (ED) ward admissions subsequently transferred to the intensive care unit (ICU) within 24 hours have higher mortality than direct ICU admissions. DESIGN, SETTING, PATIENTS: Describe risk factors for unplanned ICU transfer within 24 hours of ward arrival from the ED. METHODS: Evaluation of 178,315 ED non-ICU admissions to 13 US community hospitals. We tabulated the outcome of unplanned ICU transfer by patient characteristics and hospital volume. We present factors associated with unplanned ICU transfer after adjusting for patient and hospital differences in a hierarchical logistic regression. RESULTS: There were 4,252 (2.4%) non-ICU admissions transferred to the ICU within 24 hours. Admitting diagnoses most associated with unplanned transfer, listed by descending prevalence were: pneumonia (odds ratio [OR] 1.5; 95% confidence interval [CI] 1.2-1.9), myocardial infarction (MI) (OR 1.5; 95% CI 1.2-2.0), chronic obstructive pulmonary disease (COPD) (OR 1.4; 95% CI 1.1-1.9), sepsis (OR 2.5; 95% CI 1.9-3.3), and catastrophic conditions (OR 2.3; 95% CI 1.7-3.0). Other significant predictors included: male sex, Comorbidity Points Score >145, Laboratory Acute Physiology Score >=7, arriving on the ward between 11 PM and 7 AM. Decreased risk was found with admission to monitored transitional care units (OR 0.83; 95% CI 0.77-0.90) and to higher volume hospitals (OR 0.94 per 1,000 additional annual ED inpatient admissions; 95% CI 0.91-0.98). CONCLUSIONS: ED patients admitted with respiratory conditions, MI, or sepsis are at modestly increased risk for unplanned ICU transfer and may benefit from better triage from the ED, earlier intervention, or closer monitoring to prevent acute decompensation. More research is needed to determine how intermediate care units, hospital volume, time of day, and sex affect unplanned ICU transfer. Journal of Hospital Medicine 2013. (c) 2012 Society of Hospital Medicine. PMID- 23024041 TI - A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects. AB - A variety of human birth defects originate in failure of closure of the embryonic neural tube. The genetic cause of the most common nonsyndromic defects, spina bifida (SB) or anencephaly, is considered to be combinations of variants at multiple genes. The genes contributing to the etiology of neural tube closure defects (NTDs) are unknown. Mutations in planar cell polarity (PCP) genes in mice cause a variety of defects including the NTD, craniorachischisis, and sometimes SB or exencephaly (EX); they also demonstrate the role of digenic combinations of PCP mutants in NTDs. Recent studies have sought rare predicted-to-be-deleterious alterations (putative mutations) in coding sequence of PCP genes in human cases with various anomalies of the neural tube. This review summarizes the cumulative results of these studies according to a framework based on the embryopathogenesis of NTDs, and considers some of the insights from the approaches used and the limitations. Rare putative mutations in the PCP genes VANGL2, SCRIB, DACT1, and CELSR1 cumulatively contributed to over 20% of cases with craniorachischisis, a rare defect; no contributing variants were found for PRICKLE1 or PTK7. PCP rare putative mutations had a weaker role in myelomeningocele (SB), being found in approximately 6% of cases and cumulated across CELSR1, FUZ, FZD6, PRICKLE1, VANGL1, and VANGL2. These results demonstrate that PCP gene alterations contribute to the etiology of human NTDs. We recommend that future research should explore other types of PCP gene variant such as regulatory mutations and low frequency (1 to 5%) deleterious polymorphisms. PMID- 23024042 TI - Evaluation of longitudinal clinical outcomes and adherence to care among HIV infected refugees. AB - BACKGROUND: HIV-infected refugees resettled in the United States face many challenges. Longitudinal data regarding HIV-specific outcomes in this population are limited. METHODS: We reviewed charts of 51 HIV-infected sub-Saharan African refugees matched to 102 nonrefugees. Outcomes analyzed included CD4 counts, viral loads (VLs), antiretroviral treatment (ART) use, appointment adherence, opportunistic infections, and resistance mutations. RESULTS: The ART initiation was similar. Appointment adherence was similar in year 1, but refugees were significantly less adherent beyond year 3. Refugees and nonrefugees spent similar amounts of time in care suppressed (83% vs 80%, P = .93). Refugees had higher odds of viremia following undetectable VL (OR 2.3, P < .05). DISCUSSION: Initially, sub-Saharan African HIV-infected refugees have comparable appointment adherence, ART use, and VL suppression to nonrefugees. Overtime refugees were less adherent to appointments and more likely to have postsuppression viremia. The support services provided to refugees early in care may be important for retention in care and treatment success. PMID- 23024043 TI - Cloning and sequence analysis of chitin synthase gene fragments of Demodex mites. AB - To our knowledge, few reports on Demodex studied at the molecular level are available at present. In this study our group, for the first time, cloned, sequenced and analyzed the chitin synthase (CHS) gene fragments of Demodex folliculorum, Demodex brevis, and Demodex canis (three isolates from each species) from Xi'an China, by designing specific primers based on the only partial sequence of the CHS gene of D. canis from Japan, retrieved from GenBank. Results show that amplification was successful only in three D. canis isolates and one D. brevis isolate out of the nine Demodex isolates. The obtained fragments were sequenced to be 339 bp for D. canis and 338 bp for D. brevis. The CHS gene sequence similarities between the three Xi'an D. canis isolates and one Japanese D. canis isolate ranged from 99.7% to 100.0%, and those between four D. canis isolates and one D. brevis isolate were 99.1%-99.4%. Phylogenetic trees based on maximum parsimony (MP) and maximum likelihood (ML) methods shared the same clusters, according with the traditional classification. Two open reading frames (ORFs) were identified in each CHS gene sequenced, and their corresponding amino acid sequences were located at the catalytic domain. The relatively conserved sequences could be deduced to be a CHS class A gene, which is associated with chitin synthesis in the integument of Demodex mites. PMID- 23024045 TI - Acute and subacute oral toxicity of Litsea elliptica Blume essential oil in rats. AB - Litsea elliptica Blume has been traditionally used to treat headache, fever, and stomach ulcer, and has also been used as an insect repellent. The acute and subacute toxicities of L. elliptica essential oil were evaluated orally by gavage in female Sprague-Dawley rats. For the acute toxicity study, L. elliptica essential oil was administered in doses from 500 to 4000 mg/kg (single dose), and in the subacute toxicity test, the following doses were used: 125, 250, and 500 mg/kg, for 28 consecutive days. In the acute toxicity study, L. elliptica essential oil caused dose-dependent adverse behaviours and mortality. The median lethal dose value was 3488.86 mg/kg and the acute non-observed-adversed-effect level value was found to be 500 mg/kg. The subacute toxicity study of L. elliptica essential oil did not reveal alterations in body weight, and food and water consumptions. The haematological and biochemical analyses did not show significant differences between control and treated groups in most of the parameters examined, except for the hemoglobin, mean cell hemoglobin concentration, mean cell volume, mean cell hemoglobin, serum albumin, and serum sodium. However, these differences were still within the normal range. No abnormalities or histopathological changes were observed in the liver, pancreatic islet of Langerhans, and renal glomerulous and tubular cells of all treated groups. In conclusion, L. elliptica essential oil can be classified in the U group, which is defined as a group unlikely to present an acute hazard according to World Health Organization (WHO) classification. PMID- 23024044 TI - Abundance and composition of ammonia-oxidizing bacteria and archaea in different types of soil in the Yangtze River estuary. AB - Tidal flats are soil resources of great significance. Nitrification plays a central role in the nitrogen cycle and is often a critical first step in nitrogen removal from estuarine and coastal environments. We determined the abundance as well as composition of ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA) in different soils during land reclamation process. The abundance of AOA was higher than that of AOB in farm land and wild land while AOA was not detected in tidal flats using real-time polymerase chain reaction (PCR). The different abundances of AOB and AOA were negatively correlated with the salinity. The diversities of AOB and AOA were also investigated using clone libraries by amplification of amoA gene. Among AOB, nearly all sequences belonged to the Nitrosomonas lineage in the initial land reclamation process, i.e., tidal flats, while both Nitrosomonas and Nitrosospira lineages were detected in later and transition phases of land reclamation process, farm land and wild land. The ratio of the numbers of sequences of Nitrosomonas and Nitrosospira lineages was positively correlated with the salinity and the net nitrification rate. As for AOA, there was no obvious correlation with the changes in the physicochemical properties of the soil. This study suggests that AOB may be more import than AOA with respect to influencing the different land reclamation process stages. PMID- 23024046 TI - Effects of total dissolved gas supersaturated water on lethality and catalase activity of Chinese sucker (Myxocyprinus asiaticus Bleeker). AB - Total dissolved gas (TDG) supersaturation caused by dam sluicing can result in gas bubble trauma (GBT) in fish and threaten their survival. In the present study, Chinese suckers (Myxocyprinus asiaticus Bleeker) were exposed to TDG supersaturated water at levels ranging from 120% to 145% for 48 h. The median lethal concentration (LC(50)) and the median lethal time (LT(50)) were determined to evaluate acute lethal effects on Chinese suckers. The results showed that the LC(50) values of 4, 6, 8, and 10 h were 142%, 137%, 135%, and 130%, respectively. The LT(50) values were 3.2, 4.7, 7.8, 9.2, and 43.4 h, respectively, when TDG supersaturated levels were 145%, 140%, 135%, 130%, and 125%. Furthermore, the biological responses in Chinese suckers were studied by assaying the catalase (CAT) activities in gills and muscles at the supersaturation level of 140% within LT(50). The CAT activities in the gills and muscle tissues exhibited a regularity of a decrease after an increase. CAT activities in the muscles were increased significantly at 3/5LT(50) (P<0.05) and then came back to the normal level. However, there were no significant differences between the treatment group (TDG level of 140%) and the control group (TDG level of 100%) on CAT activities in the gills before 3/5LT(50) (P>0.05), but the activities were significantly lower than the normal level at 4/5LT(50) and LT(50) (P<0.05). PMID- 23024047 TI - Absence of postzygotic isolating mechanisms: evidence from experimental hybridization between two species of tropical sea urchins. AB - Two reef margin species of tropical sea urchins, Echinometra sp. C (Ec) and Echinometra oblonga (Eo), occur sympatrically on Okinawa intertidal reefs in southern Japan. Hybridization between these species was examined through a series of cross-fertilization experiments. At limited sperm concentrations, where conspecific crosses reached near 100% fertilization, both heterospecific crosses showed high fertilization rates (81%-85%). The compatibility of the gametes demonstrated that if gamete recognition molecules are involved in fertilization of these species, they are not strongly species-specific. We found that conspecific crosses reached peak fertilization levels much faster than did heterospecific crosses, indicating the presence of a prezygotic barrier to hybridization in the gametes. Larval survival, metamorphosis, and juvenile and adult survival of hybrid groups were nearly identical to those of their parent species. Hybrids from crosses in both directions developed normally through larval stages to sexually mature adults, indicating that neither gametic incompatibility nor hybrid inviability appeared to maintain reproductive isolation between these species. In adults, Ec*Ec crosses gave the highest live weight, followed by Eo (ova)*Ec (sperm), Ec (ova)*Eo (sperm), and Eo*Eo. Other growth performance measures (viz., test size, Aristotle's lantern length, and gonad index) of hybrid groups and their parental siblings showed the same trends. The phenotypic color patterns of the hybrids were closer to the maternal coloration, whereas spine length, tube-foot and gonad spicule characteristics, pedicellaria valve length, and gamete sizes showed intermediate features. Adult F(1) hybrids were completely fertile and displayed high fertilization success in F(1) backcrosses, eliminating the likelihood that hybrid sterility is a postzygotic mechanism of reproductive isolation. Conversely, intensive surveys failed to find hybrid individuals in the field, suggesting the lack or rarity of natural hybridization. This strongly suggests that reproductive isolation is achieved by prezygotic isolating mechanism(s). Of these mechanisms, habitat segregation, gamete competition, differences in spawning times, gametic incompatibility or other genetic and non-genetic factors appear to be important in maintaining the integrity of these species. PMID- 23024048 TI - Hydrogen peroxide functions as a secondary messenger for brassinosteroids-induced CO2 assimilation and carbohydrate metabolism in Cucumis sativus. AB - Brassinosteroids (BRs) are potent regulators of photosynthesis and crop yield in agricultural crops; however, the mechanism by which BRs increase photosynthesis is not fully understood. Here, we show that foliar application of 24 epibrassinolide (EBR) resulted in increases in CO(2) assimilation, hydrogen peroxide (H(2)O(2)) accumulation, and leaf area in cucumber. H(2)O(2) treatment induced increases in CO(2) assimilation whilst inhibition of the H(2)O(2) accumulation by its generation inhibitor or scavenger completely abolished EBR induced CO(2) assimilation. Increases of light harvesting due to larger leaf areas in EBR- and H(2)O(2)-treated plants were accompanied by increases in the photochemical efficiency of photosystem II (Phi(PSII)) and photochemical quenching coefficient (q(P)). EBR and H(2)O(2) both activated carboxylation efficiency of ribulose-1,5-bisphosphate oxygenase/carboxylase (Rubisco) from analysis of CO(2) response curve and in vitro measurement of Rubisco activities. Moreover, EBR and H(2)O(2) increased contents of total soluble sugar, sucrose, hexose, and starch, followed by enhanced activities of sugar metabolism such as sucrose phosphate synthase, sucrose synthase, and invertase. Interestingly, expression of transcripts of enzymes involved in starch and sugar utilization were inhibited by EBR and H(2)O(2). However, the effects of EBR on carbohydrate metabolisms were reversed by the H(2)O(2) generation inhibitor diphenyleneodonium (DPI) or scavenger dimethylthiourea (DMTU) pretreatment. All of these results indicate that H(2)O(2) functions as a secondary messenger for EBR-induced CO(2) assimilation and carbohydrate metabolism in cucumber plants. Our study confirms that H(2)O(2) mediates the regulation of photosynthesis by BRs and suggests that EBR and H(2)O(2) regulate Calvin cycle and sugar metabolism via redox signaling and thus increase the photosynthetic potential and yield of crops. PMID- 23024049 TI - Determination of the geographical origin of Chinese teas based on stable carbon and nitrogen isotope ratios. AB - The objective of this study was to investigate the geographical origin of Chinese teas using carbon and nitrogen stable isotope ratio technology. The results showed that inter-provincial dispersion of teas in Guangdong (GD), Guangxi (GX), Hainan (HA), Fujian (FJ), Shandong (SD), Sichuan (SC), Chongqing (CQ), and Henan (HN) provinces was high, while in Zhejiang (ZJ), Hubei (HB), Yunnan (YN), and Anhui (AH) provinces, it was low. Tea samples from GD, GX, HA, and FJ provinces were clustered in one group and separated from those from AH and HB provinces. Thus, carbon and nitrogen stable isotope ratio technology could discriminate teas from among some provinces of China, but not from among others. Better separation might be obtained with a combination of isotopic ratios and other indexes, such as elemental data and organic components. PMID- 23024050 TI - Kinematics of hip, knee, ankle of the young and elderly Chinese people during kneeling activity. AB - OBJECTIVE: The purpose of this study was to measure the kinematics of the lower limbs of Chinese people during normal kneeling activity, as such data could be valuable in designing joint prosthesis and arthroplasty that meet the needs of Chinese citizens' daily activities. METHODS: Thirty young and twenty elderly Chinese participants with no personal history of joint diseases were recruited, and matched by age (average age: 23.8 years for the young group, 60.8 years for the elderly group). Each participant performed six trials during which three dimensional (3D) kinematics data were collected and the means of the 3D angles of the ankle, knee, and hip joints of two groups were calculated. RESULTS: There were no obvious differences between the two groups in the knee and ankle joints. The mean range of knee flexion was 139.6 degrees for the young group and 140.9 degrees for the elderly group. The mean range of ankle flexion was 35.7 degrees for the young group and 37.6 degrees for the elderly group. The maximal eccentric flexion at the hip joint was 67.5 degrees for the young group compared to 100.5 degrees for the elderly group. CONCLUSIONS: The elderly uses more hip flexion angles than the young when assuming the kneeling posture. The ranges of motion obtained during kneeling activity are greater than the reported mean ranges of motion achieved following joint arthroplasty. The data could be valuable in establishing criteria for lower limb prosthetics and rehabilitation protocol for the Chinese population. PMID- 23024051 TI - Extraction and isolation of the salidroside-type metabolite from zinc (Zn) and cadmium (Cd) hyperaccumulator Sedum alfredii Hance. AB - The active metabolite in the post-harvested biomass of zinc (Zn) and cadmium (Cd) hyperaccumulator Sedum alfredii Hance from phytoextraction is of great interest in China. The current study demonstrates that a salidroside-type metabolite can be yielded from the Zn/Cd hyperaccumulator S. alfredii biomass by means of sonication/ethanol extraction and macroporous resin column (AB-8 type) isolation. The concentrations of Zn and Cd in the salidroside-type metabolite were below the limitation of the national standards. PMID- 23024052 TI - Changes in oviduct structure in the black tiger shrimp, Penaeus monodon, during ovarian maturation. AB - OBJECTIVE: To examine the structure of the oviduct of the shrimp Penaeus monodon. METHODS: The oviducts of P. monodon with three different major groups of ovarian development (Group (Gr.) 1: Stages I & V; Gr. 2: Stages II & III; and Gr. 3: Stage IV) were examined by light, transmission electron, and scanning electron microscopies, respectively. RESULTS: The epithelium of the oviduct in Gr. 1 was composed of tall simple columnar cells with their basal nuclei located on the basement membrane and its thick collagen fibers. In Gr. 2, the oviduct seemed to produce some substances and their epithelial cells became transitional with centrally located nuclei and formed some vacuoles. Obviously, the epithelial cells in Gr. 3 (at Stage IV) were disorganized, disrupted, and shed accumulated spherical secretory substances including some cellular contents into the lumen. CONCLUSIONS: The structural changes of the P. monodon oviduct were related to ovarian maturation stages (Grs. 1-3). Prior to spawning, only the oviduct epithelium at ovary Stage IV produced and secreted a number of spherical secretion substances into the lumen. These substances may act as the oviductal lubricants to facilitate the spawning process. PMID- 23024053 TI - Anaphylaxis and generalized urticaria from eating Chinese bayberry fruit. AB - Chinese bayberry Myrica rubra is a very popular fruit in southeastern China. In spite of its wide consumption, no allergies to this fruit have been reported previously. Here we report on a 40-year-old woman suffering from anaphylaxis to Chinese bayberry fruit. Prick-prick skin tests revealed strong reactions to fresh Chinese bayberry fruits as well as to peach, and weaker reactions to some other fruits including apple, melon, and banana. ImmunoCAP analysis revealed identical titers of specific IgE (4.3 kU(A)/L) to peach extract and its lipid transfer protein (LTP, rPru p 3), which was confirmed by detection of a 9 kD band following immunoblotting. Immunoblot analysis with Chinese bayberry extract gave bands of 22, 45, and 90 kD, but no 9 kD band was recognized. There was also no evidence of LTP recognition for loquat (36 kD) or melon (24 kD). This first report of a severe allergic reaction to Chinese bayberry fruit in a patient with LTP-mediated peach allergy indicates that other as yet unidentified non-pollen related fruit allergens are involved in this new severe fruit allergy. PMID- 23024054 TI - Immediate results of bifurcational stenting assessed with optical coherence tomography. AB - BACKGROUND: A tubular stent may adapt with difficulty to coronary bifurcation lesions (CBLs). METHODS: Time domain or frequency domain (FD) optical coherence tomography (OCT) was performed to assess strut apposition immediately after stent implantation across four segments inside the bifurcation, in a consecutive series of patients. OCT pullbacks were performed in the main vessel (MV). RESULTS: A total of 13,142 struts in 45 CBL in 41 patients were assessed. Strut malapposition was significantly more frequent in the half bifurcation facing the side-branch (SB) ostium (42.9%) than in the proximal segment of the bifurcation 11.8%, half bifurcation opposite the SB 6.7%, or the distal segment 5.7% (all P < 0.0001). Lesions (n = 15) treated with stenting of both MV and SB had a total higher rate of malapposition than those (n = 30) treated with stenting of the MV only (17.6% vs. 9.5%; P = 0.0014). In latter group, lesions treated with FD-OCT guided stent implantation (n = 13) presented a lower rate of malapposition than those treated with conventional angiographic-guided stent implantation (n = 17) (7.1% vs. 17.5%; P = 0.005). CONCLUSIONS: In CBL, strut malapposition is particularly high at the SB ostium. However, a strategy of stenting MV only with adjunctive FD-OCT guidance is associated with lower rates of malapposition. PMID- 23024055 TI - Causes of sudden unexpected death of adult hospital patients. AB - The sudden unexpected death of a hospitalized patient is distressing to the family and the healthcare team. It is also common. Assessment of the causes without autopsy is frequently incorrect. To elucidate the causes of death, 175 cases of adult hospital patients in the University of Pittsburgh Medical Center Health System, who died suddenly and unexpectedly, were investigated with autopsies. The most common cause was judged to be a cardiac arrhythmia, in 58 (33%) of cases, presumptive in 46 cases, because only 12 of these patients were on cardiac monitoring. Of the arrhythmia patients, 36 (62%) had >=75% coronary artery stenosis and 31 (53%) had histological evidence of myocardial infarction, with 15 (26%) of those with subacute or old myocardial infarction lacking a history of myocardial infarction. Hemorrhage was judged the cause of death in 38 (22%) of cases, including 31 (82%) with endogenous coagulopathy, anticoagulation, or antiplatelet therapy. Pulmonary thromboembolism was judged the cause of death in 27 (15%) of cases. Overall, hemorrhage deserves better appreciation as a cause of sudden unexpected death of hospitalized adults. PMID- 23024057 TI - Developing new classification criteria for diffuse idiopathic skeletal hyperostosis: back to square one. AB - OBJECTIVE: To revise the definition of DISH and suggest a classification that may better represent our current knowledge of this entity allowing earlier diagnosis. METHODS: Seven rheumatologists and an orthopaedic surgeon suggested a list of 63 parameters that might be included in a future classification of DISH. Participants rated their level of agreement with each item, expressed in percentages. In a second session, participants discussed each item again and re rated all parameters. Thirty items that were granted >=50% support on average were considered valid for a third round. A questionnaire listing these 30 items was mailed to 39 rheumatologists and orthopaedic surgeons worldwide with a request to answer categorically if they agreed on an item to be included as a criterion for a future classification of DISH. Items were regarded as perfect consensus when at least 95% of the respondents agreed and were regarded as consensus when at least 80% agreed. RESULTS: There was perfect consensus for 2 (6.7%) of the 30 parameters and consensus for another 2 parameters. These items were ossification and bridging osteophytes in each of the three segments of the spine and exuberant bone formation of bone margins. CONCLUSION: At present there is no agreement about the inclusion of extraspinal, constitutional and metabolic manifestations in a new classification of DISH. Investigators with an interest in this condition should be encouraged to restructure the term DISH in an attempt to establish a more sophisticated definition. PMID- 23024056 TI - Transcriptional analyses of two mouse models of spina bifida. AB - BACKGROUND: Spina bifida is one of the most common of all human structural birth defects. Despite considerable effort over several decades, the causes and mechanisms underlying this malformation remain poorly characterized. METHODS: To better understand the pathogenesis of this abnormality, we conducted a microarray study using Mouse Whole Genome Bioarrays which have ~36,000 gene targets, to compare gene expression profiles between two mouse models; CXL-Splotch and FKBP8(Gt(neo)) which express a similar spina bifida phenotype. We anticipated that there would be a collection of overlapping genes or shared genetic pathways at the molecular level indicative of a common mechanism underlying the pathogenesis of spina bifida during embryonic development. RESULTS: A total of 54 genes were determined to be differentially expressed (25 downregulated, 29 upregulated) in the FKBP8Gt((neo)) mouse embryos; whereas 73 genes were differentially expressed (56 downregulated, 17 upregulated) in the CXL-Splotch mouse relative to their wild-type controls. Remarkably, the only two genes that showed decreased expression in both mutants were v-ski sarcoma viral oncogene homolog (Ski), and Zic1, a transcription factor member of the zinc finger family. Confirmation analysis using quantitative real-time (qRT)-PCR indicated that only Zic1 was significantly decreased in both mutants. Gene ontology analysis revealed striking enrichment of genes associated with mesoderm and central nervous system development in the CXL-Splotch mutant embryos, whereas in the FKBP8(Gt(neo)) mutants, the genes involved in dorsal/ventral pattern formation, cell fate specification, and positive regulation of cell differentiation were most likely to be enriched. These results indicate that there are multiple pathways and gene networks perturbed in mouse embryos with shared phenotypes. PMID- 23024058 TI - Augmented ICOS expression in patients with early diffuse cutaneous systemic sclerosis. AB - OBJECTIVE: Inducible costimulator (ICOS), expressed on activated T cells, and its ligand, ICOS ligand (ICOSL), expressed on antigen-presenting cells, have been considered a single receptor-ligand pair. Here we investigated the expression of ICOS and ICOSL in patients with SSc. METHODS: ICOS expression on peripheral blood T cells, and ICOSL expression on B cells and macrophages was determined by flow cytometry. Expression of ICOS and ICOSL was assessed by immunohistological staining and real-time PCR of lesional skin. RESULTS: ICOS expression levels were specifically increased on both peripheral blood memory T cells and Tregs from early dcSSc patients compared with those from healthy controls. Mean ICOSL expression on B cells or macrophages was comparable between SSc patients and healthy controls. ICOS-expressing T cells, ICOSL-expressing macrophages and mRNA levels of ICOS and ICOSL were increased in the lesional skin of patients with early dcSSc. In vitro ICOS costimulation enhanced production of IFN-gamma, IL-4 and IL-17A from T cells in SSc patients vs normal controls. Soluble ICOS levels were significantly increased in SSc patients and were negatively associated with the presence of ACAs and positively associated with CRP values. Serum levels of soluble ICOS were more closely associated with clinical features compared with levels of soluble IL-2 receptor. CONCLUSION: Augmented ICOS signalling may contribute to the pathogenesis of SSc during early progressive disease. Soluble ICOS levels may be used as a serum marker for the activity and severity of SSc. PMID- 23024059 TI - Defining the value of structural inhibition. Is low-dose etanercept inferior to the standard dose? PMID- 23024060 TI - Purification of oogonial stem cells from adult mouse and human ovaries: an assessment of the literature and a view toward the future. AB - Contemporary claims that mitotically active female germ line or oogonial stem cells (OSCs) exist and support oogenesis during postnatal life in mammals have been debated in the field of reproductive biology since March 2004, when a mouse study posed the first serious challenge to the dogma of a fixed pool of oocytes being endowed at birth in more than 50 years. Other studies have since been put forth that further question the validity of this dogma, including the isolation of OSCs from neonatal and adult mouse ovaries by 4 independent groups using multiple strategies. Two of these groups also reported that isolated mouse OSCs, once transplanted back into ovaries of adult female mice, differentiate into fully functional eggs that ovulate, fertilize, and produce healthy embryos and offspring. Arguably, one of the most significant advances in this emerging field was provided by a new research study published this year, which reported the successful isolation and functional characterization of OSCs from ovaries of reproductive age women. Two commentaries on this latest work, one cautiously supportive and one highly skeptical, were published soon afterward. This article evaluates the current literature regarding postnatal oogenesis in mammals and discusses important next steps for future work on OSC biology and function. PMID- 23024061 TI - Increased surfactant protein D fails to improve bacterial clearance and inflammation in serpinB1-/- mice. AB - Previously, we described the protective role of the neutrophil serine protease inhibitor serpinB1 in preventing early mortality of Pseudomonas aeruginosa lung infection by fostering bacterial clearance and limiting inflammatory cytokines and proteolytic damage. Surfactant protein D (SP-D), which maintains the antiinflammatory pulmonary environment and mediates bacterial removal, was degraded in infected serpinB1-deficient mice. Based on the hypothesis that increased SP-D would rescue or mitigate the pathological effects of serpinB1 deletion, we generated two serpinB1(-/-) lines overexpressing lung-specific rat SP-D and inoculated the mice with P. aeruginosa. Contrary to predictions, bacterial counts in the lungs of SP-D(low)serpinB1(-/-) and SP-D(high) serpinB1( /-) mice were 4 logs higher than wild-type and not different from serpinB1(-/-) mice. SP-D overexpression also failed to mitigate inflammation (TNF-alpha), lung injury (free protein, albumin), or excess neutrophil death (free myeloperoxidase, elastase). These pathological markers were higher for infected SP D(high)serpinB1(-/-) mice than for serpinB1(-/-) mice, although the differences were not significant after controlling for multiple comparisons. The failure of transgenic SP-D to rescue antibacterial defense of serpinB1-deficient mice occurred despite 5-fold or 20-fold increased expression levels, largely normal structure, and dose-dependent bacteria-aggregating activity. SP-D of infected wild-type mice was intact in 43-kD monomers by reducing SDS-PAGE. By contrast, proteolytic fragments of 35, 17, and 8 kD were found in infected SP D(low)serpinB1(-/-), SP-D(high) serpinB1(-/-) mice, and serpinB1(-/-) mice. Thus, although therapies to increase lung concentration of SP-D may have beneficial applications, the findings suggest that therapy with SP-D may not be beneficial for lung inflammation or infection if the underlying clinical condition includes excess proteolysis. PMID- 23024062 TI - Regulation of cytotoxic T lymphocyte antigen 4 by cyclic AMP. AB - Recent studies indicate that cyclic AMP (cAMP) induces cytotoxic T lymphocyte antigen (CTLA) 4. CTLA4 is expressed in T cells, and is a negative regulator of T cell activation. CTLA4 expression is regulated by T cell receptor plus CD28 (adaptive immune signaling) at both the transcriptional and post-transcriptional level. Here, we examine the pathways by which cAMP regulates CTLA4 expression, focusing on transcriptional activation. Elevating intracellular cAMP levels by cell-permeable cAMP analogs, the adenylyl cyclase activator, forskolin, or phosphodiesterase inhibitors increases CTLA4 mRNA expression in EL4 murine T cells and primary CD4(+) T cells. Activation of protein kinase A (using the protein kinase A-selective agonist, N6-phenyladenosine-cAMP), but not exchange proteins activated by cAMP (using the exchange proteins activated by cAMP selective 8-pCPT-2Me-cAMP), increases CTLA4 promoter activity. Mutation constructs of the CTLA4 promoter uncover an enhancer binding site located within the -150 to -130 bp region relative to the transcription start site. Promoter analysis and chromatin immunoprecipitation assays suggest that cAMP response element-binding is a putative transcription factor induced by cAMP. We have previously shown that CTLA4 mediates decreased pulmonary inflammation in an LPS induced murine model of acute lung injury (ALI). We observed that LPS can induce CTLA4 transcription via the same cAMP-inducible promoter region. The immunosuppressant, rapamycin, decreases cAMP and LPS-induced CTLA4 transcription in vitro. In vivo, LPS induces cAMP accumulation in bronchoalveolar lavage fluid, bronchoalveolar lavage cells, and lung tissues in ALI. We demonstrate that rapamycin decreases cAMP accumulation and CTLA4 expression in ALI. Together, these data suggest that cAMP may negatively regulate pulmonary inflammatory responses in vivo and in vitro by altering CTLA4 expression. PMID- 23024063 TI - RTP801 is required for ceramide-induced cell-specific death in the murine lung. AB - Key host responses to the stress induced by environmental exposure to cigarette smoke (CS) are responsible for initiating pathogenic effects that may culminate in emphysema development. CS increases lung ceramides, sphingolipids involved in oxidative stress, structural alveolar cell apoptosis, and inhibition of apoptotic cell clearance by alveolar macrophages, leading to the development of emphysema like pathology. RTP801, a hypoxia and oxidative stress sensor, is also increased by CS, and has been recently implicated in both apoptosis and inflammation. We investigated whether inductions of ceramide and RTP801 are mechanistically linked, and evaluated their relative importance in lung cell apoptosis and airspace enlargement in vivo. As reported, direct lung instillation of either RTP801 expression plasmid or ceramides in mice triggered alveolar cell apoptosis and oxidative stress. RTP801 overexpression up-regulated lung ceramide levels 2.6 fold. In turn, instillation of lung ceramides doubled the lung content of RTP801. Cell sorting after lung tissue dissociation into single-cell suspension showed that ceramide triggers both endothelial and epithelial cell apoptosis in vivo. Interestingly, mice lacking rtp801 were protected against ceramide-induced apoptosis of epithelial type II cells, but not type I or endothelial cells. Furthermore, rtp801-null mice were protected from ceramide-induced alveolar enlargement, and exhibited improved static lung compliance compared with wild type mice. In conclusion, ceramide and RTP801 participate in alveolar cell apoptosis through a process of mutual up-regulation, which may result in self amplification loops, leading to alveolar damage. PMID- 23024064 TI - Papers from the 7th International Neural Tube Defects Conference. PMID- 23024065 TI - Transcatheter "thrombin-blood patch" injection: a novel and effective approach to treat catheterization-related arterial perforation. AB - OBJECTIVE: This study aimed to describe the safety and feasibility of transcatheter "thrombin-blood patch" (TBP) injection to treat catheterization related arterial vascular access perforation. BACKGROUND: Vascular access complications are infrequent but potentially life threatening conditions related to percutaneous procedures. Surgical vascular repair are associated with high rates of morbidity and mortality due to advanced cardiovascular disease. METHODS: From October 2007 to July 2010 we studied 23 patients who presented active access arterial bleeding after percutaneous procedures and underwent transcatheter angiographic guided TBP injection across the entry site of the arterial perforation as a primary approach. RESULTS: The mean age of the population was 67 years, predominantly female (78.3%) with high rate of comorbidities including diabetes (30.4%), prior coronary revascularization (50.0%), chronic renal failure (43.5%), and heart failure (56.5%). Thirteen patients (56.5%) developed severe hypotension after the index procedure. The repair procedure had a mean duration of 82 +/- 57 minutes. TBP was injected in all patients. One case additionally required covered-stent to obtain hemostasis. Angiographic success was achieved in the 23 patients; however, one case required a second intervention due to recurrent bleeding, which was effectively treated using covered-stent. All patients were discharged alive and no major cardiovascular events, including myocardial infarction/stroke, were observed. CONCLUSIONS: Transcatheter "thrombin blood patch" injection is a safe, novel technique that allows prompt percutaneous approach to treat catheterization-related arterial perforation. This strategy appears particularly attractive to treat patients who cannot tolerate "open" vascular reconstruction and repair. PMID- 23024066 TI - Effect of fever on hospital presentation, diagnosis, and treatment in patients with H1N1/09 influenza. AB - OBJECTIVE: Fever is typically considered part of the influenza-like illness in hemagglutinin type 1 and neuraminidase type 1 (H1N1/09) influenza. We assessed the proportion of patients that did not have fever as part of their illness prior to hospital presentation. We assessed the role of fever on the delay in hospital presentation, diagnosis, and treatment of these patients. METHODS: We performed a retrospective analysis of all hospitalized adult patients with laboratory confirmed pandemic H1N1/09 at a tertiary care center in the United States from June 1 to December 31, 2009. RESULTS: Fifty-six of 135 study patients (42%) had no fever; 31 (23%) required intensive care unit (ICU) admission, and 9 (7%) died. Those without fever had higher Charlson index (P = 0.01), significantly longer time to hospital presentation (median 4 vs 2 days, P < 0.001), longer time to treatment since the onset of illness (median 5 vs 2 days, P = 0.001), and were more frequently in an ICU (P = 0.01). After adjustment for age (<40 vs >=40) and Charlson index (0, 1-2, >=3), patients without fever had significantly increased likelihood of late hospital presentation (>2 days from the onset of illness) (P = 0.001) and also had increased likelihood of ICU stay (P = 0.05). CONCLUSIONS: Forty-two percent of patients with laboratory-confirmed H1N1/09 did not have fever as part of their illness prior to hospital presentation. Patients without fever had delayed presentation to the hospital and thus experienced delayed treatment. PMID- 23024069 TI - The rapidly emerging role of zerumbone in attenuating tumor growth in systemic malignancies. PMID- 23024067 TI - A multi-center phase Ib study of oxaliplatin (NSC#266046) in combination with fluorouracil and leucovorin in pediatric patients with advanced solid tumors. AB - BACKGROUND: Platinum agents have been used for a variety of cancers, including pivotal use in pediatric tumors for many years. Oxaliplatin, a third generation platinum, has a different side effect profile and may provide improved activity in pediatric cancers. PROCEDURE: Patients 21 years or younger with progressive or refractory malignant solid tumors, including tumors of the central nervous system were enrolled on this multi-center open label, non-randomized Phase 1 dose escalation study. The study used a standard 3 + 3 dose escalation design with 2 dose levels (85 and 100 mg/m(2) ) with an expansion cohort of 15 additional patients at the recommended dose. Patients received oxaliplatin at the assigned dose level and 5-fluorouracil (5-FU) bolus 400 mg/m(2) followed by a 46-hour 5 FU infusion of 2,400 mg/m(2) every 14 days. The leucovorin dose was fixed at 400 mg/m(2) for all cohorts. RESULTS: Thirty-one evaluable patients were enrolled, 8 at 85 mg/m(2) and 23 at 100 mg/m(2) for a total of 121 courses. The median age was 12 years (range 2-19 years). The main toxicities were hematologic, primarily neutrophils and platelets. The most common non-hematologic toxicities were gastrointestinal. Stable disease was noted in 11 patients (54% of evaluable patients) and 1 confirmed partial response in a patient with osteosarcoma. CONCLUSIONS: The maximum planned dose of oxaliplatin at 100 mg/m(2) per dose in combination with 5-FU and leucovorin was safe and well tolerated and in this patient population. This combination demonstrated modest activity in patients with refractory or relapsed solid tumor and warrants further study. Pediatr Blood Cancer 2013;60:230-236. (c) 2012 Wiley Periodicals, Inc. PMID- 23024072 TI - The use of palliative chemotherapy in pediatric oncology patients: a national survey of pediatric oncologists. AB - BACKGROUND: Many children continue receiving chemotherapy after there is no realistic hope for cure. One factor that influences parental decisions to pursue medical therapies is physician preference. To date, no studies have described pediatric oncologists' perspectives and practices regarding palliative chemotherapy (PC). PROCEDURE: We surveyed via email pediatric oncologists practicing in the U.S who are members of the Children's Oncology Group to achieve the following objectives: (1) Describe pediatric oncologists treatment considerations regarding the use of PC. (2) Assess treatment considerations that influenced pediatric oncologists' therapy recommendations for their most recent patient receiving PC. There were 422 participants (40.8%) who completed the survey. RESULTS: The most important factors considered by pediatric oncologists when prescribing PC were the toxicity of the chemotherapy (4.90 mean SD = 0.36 utilizing 5 point scale with 1 = not important to 5 = very important), the preferences of the family (4.57; SD = 0.60), and the potential to decrease symptoms arising from tumor burden (4.42; SD = 0.65). These treatment considerations were not as important when PC was prescribed for their most recent patient. Similarly, the chief aims in prescribing PC were not achieved for recent patients receiving PC. For their most recent patient who received PC, 40.8% believe this treatment was primarily for parental wishes. CONCLUSION: According to 80.2% of pediatric oncologists completing the survey, some patients receive chemotherapy beyond medical benefit and 40.8% of these oncologists have prescribed PC for the purpose of parental wishes to a recent patient. The chief aims in prescribing palliative chemotherapy were not achieved for recent patients. PMID- 23024073 TI - Effect of the nanodiamond host on a nitrogen-vacancy color-centre emission state. AB - Control over the quantum states of individual luminescent nitrogen-vacancy (NV) centres in nanodiamonds (NDs) is demonstrated by careful design of the crystal host: its size, surface functional groups, and interfacing substrate. By progressive etching of the ND host, the NV centres are induced to switch from latent, through continuous, to intermittent or "blinking" emission states. The blinking mechanism of the NV centre in NDs is elucidated and a qualitative model proposed to explain this phenomenon in terms of the centre electron(s) tunnelling to acceptor site(s). These measurements suggest that the substrate material and its proximity to the NV are responsible for the fluorescence intermittency. PMID- 23024074 TI - The games industry plays. PMID- 23024075 TI - Expanding the academic platter. PMID- 23024076 TI - Transient hypothyroxinemia of prematurity does it have clinical relevance? PMID- 23024077 TI - Late preterm births major cause of prematurity and adverse outcomes of neonatal hyperbilirubinemia. PMID- 23024078 TI - Introduction of Haemophilus influenzae type b (Hib) as pentavalent(DPT-HepB-Hib) vaccine in two states of India. PMID- 23024079 TI - A fatal outbreak of Trichosporon asahii sepsis in a neonatal intensive care Unit. AB - We describe an outbreak of Trichosporon asahii in 8 newborn infants with sepsis. Six out of these 8 infants died. The organism was identified on specific culture and morphologic characteristics. The organism was sensitive to amphotericin-B but resistant to fluconazole. Laminar flow unit was suspected to be the source of the outbreak. PMID- 23024080 TI - Shwachman-Diamond Syndrome: are we missing many? AB - Shwachman-Diamond Syndrome (SDS) is a rare inherited disorder characterized by pancreatic insufficiency, bone marrow dysfunction and skeletal abnormalities. It is the most common cause of pancreatic insufficiency in children after cystic fibrosis. We report a child with classical SDS who presented to us predominantly with chronic diarrhea along with delayed growth and neutropenia. PMID- 23024081 TI - Leflunomide in systemic onset Juvenile idiopathic arthritis. AB - Methotrexate, the mainstay of treatment in Juvenile idiopathic arthritis, might not be effective in a few patients of polyarticular and systemic onset juvenile idiopathic arthritis. Use of biologicals like TNF-a blockers, the next line of preferred drugs is constrained by the high cost. We successfully used leflunomide in four patients. PMID- 23024082 TI - Recurrent neonatal organophoshorus poisoning. AB - Organophosphorus poisoning in neonates is extremely rare and needs high index of suspicion to diagnose it. The clinical presentation is often confused with the features of sepsis like apnea, copious oral secretions, diarrhea, letharginess, seizures. There may be recurrence of manifestations due to chronic exposure. We report a classic case admitted in the intensive care unit of our hospital. PMID- 23024083 TI - Prevalence of prehypertension and hypertension among urban and rural school going children. AB - This school based cross sectional study was done to estimate the prevalence of prehypertension and hypertension among apparently healthy school children in urban and rural Mysore. Prevalence of prehypertension and hypertension was 2.9% and 2.8% in urban children and 2.8% and 2% in rural children with no statistically significant difference between them. PMID- 23024084 TI - Antenatal and perinatal care in an ICDS area: progress made in 19 years. AB - ICDS program has made significant improvement in availability and utilization of antenatal and natal care including IFA supplementation, TT administration and delivery by trained personnel. However, postnatal care and promotion and initiation of breastfeeding within 2 hours of birth still remain deficit areas. PMID- 23024085 TI - Non-alcoholic fatty liver disease in children. AB - A cross sectional study was conducted in 100 children, aged 5 to 12 years, to find the prevalence of non-alcoholic fatty liver diseases (NAFLD), at New Delhi. Those with fatty liver on ultrasonography with no apparent etiology, were labeled as NAFLD. Three (3%) children had evidence of fatty liver on ultrasonography. PMID- 23024086 TI - Tracheobronchial stenosis in Keutel syndrome. PMID- 23024087 TI - Panophthalmitis in dengue fever. PMID- 23024088 TI - Bowel gangrene in congenital mesenteric defects not always due to volvulus or strangulation. PMID- 23024089 TI - Barium toxicity a rare presentation of fireworks ingestion. PMID- 23024090 TI - Sharing responsibility a holistic approach to addressing early childhood caries. PMID- 23024091 TI - Native aortic valve endocarditis secondary to Staphylococcus aureus bacteremia. PMID- 23024092 TI - Iatrogenic Cushing syndrome. PMID- 23024093 TI - Congenital cutis laxa. PMID- 23024094 TI - Multifocal cystic osseous tuberculosis with lupus vulgaris. PMID- 23024095 TI - Multiple annular erythematous lesions with trailing scale. PMID- 23024096 TI - Generalized tuberculous gumma. PMID- 23024097 TI - Assessment of potential bias from non-participation in a dynamic clinical cohort of long-term childhood cancer survivors: results from the St. Jude Lifetime Cohort Study. AB - BACKGROUND: To evaluate long-term health outcomes among childhood cancer survivors, St. Jude Children's Research Hospital (SJCRH) has established the St. Jude Lifetime Cohort Study (SJLIFE), comprised of adult survivors who undergo risk-directed clinical assessments. As in any human research study, SJLIFE participants are volunteers who may not represent the source population from which they were recruited. A lack of proportional representation could result in biased estimates of exposure-outcome associations. We compared available demographic, disease, and neighborhood level characteristics between participants and the source population to assess the potential for selection bias. PROCEDURES: Potentially eligible patients for SJLIFE were enumerated as of October 31, 2011. Data from electronic medical records were combined with geocoded census data to develop an analytic data set of 3,108 patients (the evaluable source population) of whom 1,766 (57%) underwent clinical assessment (participants). The ratio of relative frequencies (RRFs) for characteristics was compared between participants and the source population, where RRF = 1.0 indicates equal frequency of the characteristic. RESULTS: Participants and the source population had similar frequencies for most characteristics. Characteristics with modest relative differences (RRFs between 0.86 and 1.11) included sex, distance from SJCRH, primary diagnosis, median household income, median home value, and urbanicity. CONCLUSIONS: Our results indicate a lack of substantive differences in the relative frequencies of demographic, disease, or neighborhood characteristics between participants and the source population in SJLIFE, thus alleviating serious concerns about selective non-participation in this cohort. Bias in specific exposure-outcome relations is still possible and will be considered in individual analyses. PMID- 23024098 TI - Expressed breast milk vs 25% dextrose in procedural pain in neonates, a double blind randomized controlled trial. AB - OBJECTIVE: To compare the effect of expressed breast milk (EBM), 25% dextrose (25 D) and sterile water (SW) on procedural pain in neonates as assessed by the premature infant pain profile (PIPP), changes in heart rate (HR), oxygen saturation (SpO2) and duration of crying. DESIGN: Prospective, double blind, randomized controlled trial. SETTING: Postnatal ward of a tertiary-care hospital. PARTICIPANTS: 210 babies who required venipuncture for blood sampling and who were on oral feeds were recruited into the study after parental informed consent. METHODS: The enrolled babies were randomized into intervention groups (EBM, 25% dextrose) and control group (sterile water). Two ml of test solution was given to baby by paladay (a traditional cup with a spout) 2 min before venipuncture. The face and crying of baby were video graphed by an independent, blinded observer. The facial response to pain (brow bulge, eye squeeze, nasolabial furrow) was analysed from the video. Maximum HR and minimum SpO2 were recorded during, and 1, 3 and 5 min after venipuncture by another blinded observer. OUTCOME VARIABLE: PIPP score, HR, SpO2 and crying time at 0/1/3/5 min after sampling. RESULTS: 160 babies were considered for final analysis with 50 in 25 D, 62 in EBM and 48 in SW group. The mean PIPP score in the 3 groups were 5.22, 6.84 and 11.22 at 0-30 sec after venipuncture; 4.52, 6.34, and 10.88 at 1-11/2 min; 3.96, 6.15 and 9.35 at 3 31/2 min; and 3.12, 4.68 and 7.83 at 5-51/2 min; respectively (P<0.001). The median crying time was 10, 37.5 and 162 seconds in 25 D, EBM and SW groups, respectively (P<0.001). CONCLUSIONS: EBM significantly reduces procedural pain in neonates though to a lesser extent as compared to 25% dextrose. PMID- 23024099 TI - Etiology and outcome of crescentic glomerulonephritis. AB - OBJECTIVE: To determine the etiology, course and predictors of outcome in children with crescentic glomerulonephritis (GN). STUDY DESIGN: Retrospective, descriptive study. SETTING: Pediatric Nephrology Clinic at a referral center in Northern India. METHODS: Clinic records of patients aged <18 year with crescentic GN diagnosed from 2001 - 2010 and followed at least 12 months were reviewed. Crescentic GN, defined as crescents in >=50% glomeruli, was classified based on immunofluorescence findings and serology. Risk factors for renal loss (chronic kidney disease stage 4-5) were determined. RESULTS: Of 36 patients, (median age 10 yr) 17 had immune complex GN and 19 had pauci-immune crescentic GN. The etiologies of the former were lupus nephritis (n=4), postinfectious GN (3), and IgA nephropathy, Henoch Schonlein purpura and membranoproliferative GN type II (2 each). Three patients with pauciimmune GN showed antineutrophil cytoplasmic antibodies (ANCA). Rapidly progressive GN was present in 33 patients, and required dialysis in 12. At median 34 (19-72) months, 2 patients with immune complex GN and 8 with pauciimmune GN showed renal loss. Renal survival was 94.1% at 3 yr, and 75.3% at 8 yr in immune complex GN; in pauciimmune GN survival was 63.2% and 54.1%, respectively (P=0.054). Risk factors for renal loss were oliguria at presentation (hazards ratio, HR 10.50; P=0.037) and need for dialysis (HR 6.33; P=0.024); there was inverse association with proportion of normal glomeruli (HR 0.91; P=0.042). CONCLUSIONS: Pauci-immune GN constitutes one-half of patients with crescentic GN at this center. Patients with pauciimmune GN, chiefly ANCA negative, show higher risk of disease progression. Renal loss is related to severity of initial presentation and extent of glomerular involvement. PMID- 23024100 TI - Neurodevelopmental evaluation of very low birth weight infants with sepsis at 18 to 24 months corrected age. AB - In this cohort study, neurodevelopmental outcome of 20 of 24 surviving very low birth weight infants with sepsis followed up between 2008 and 2009 was compared with 20 control (uninfected infants). We found that plasma interleukin 6 and C reactive protein values were negatively correlated with mental developmental index scores (r = - 0.33, P = 0.03 and r = - 0.40, P = 0.01, respectively) at 18 to 24 months' corrected age. The results of this study indicate that sepsis experienced in the neonatal period seems to be related to low mental developmental index scores at 18 to 24 months' corrected age. PMID- 23024101 TI - Does cord clamp affect the proper positioning of breastfeeding? AB - To determine the appropriateness of breastfeeding position as assessed by 4 point standard objective criteria in the presence of commercial plastic cord clamp. 50 babies each with and without cord clamp were selected randomly in post natal ward. Mean gestational age in both the periods was comparable (39 +/- 1.13 and 39 +/- 1.34 weeks). On evaluation by the standard 4 points of proper positioning, babies with cord clamp failed to keep their head and body straight (66% vs 94%, P=0.001), keep their baby's body touching mothers abdomen (16% vs 94% P 0.000), and body well supported (72% vs 96%, P 0.002). However, both groups were appropriately able to turn baby's body towards mother and nose opposite the nipple (98% vs 88%, P 0.112). On evaluation of mothers satisfaction score, there was no significant difference except in the mother's concern about care of cord clamp (P<0.001). PMID- 23024102 TI - Oral chloral hydrate vs. intranasal midazolam for sedation during computerized tomography. AB - We conducted this single blind randomized clinical trial to compare the efficacy and safety of oral chloral hydrate and intranasal midazolam for induction of sedation for computerized tomography scan of brain in children. Participants aged 1-10 years (n=60) were randomized to receive 100 mg/kg chloral hydrate orally with intra nasal normal saline OR intranasal midazolam 0.2 mg/kg with oral normal saline. Adequate sedation (Ramsay sedation score of four) was obtained and CT scan completed successfully in 76.7% of chloral hydrate group and in 40% of midazolam group (P=0.004). No significant difference was seen for side effects frequency between the two drugs (10% in chloral hydrate, 3.3% in midazolam group; P=0.34). We conclude that oral chloral hydrate can be considered as a safe and effective drug for sedation in children undergoing CT scan of brain. PMID- 23024103 TI - Growth parameters in children with dyspepsia symptoms and Helicobacter pylori infection. AB - Controversy exists about relationship of H. pylori infection and somatic growth retardation of children. The aim of this study was to evaluate the relationship between H. pylori infection and growth parameters in children. 113 children with dyspepsia (4-18 years) were enrolled. C13 urea breath test was performed for determination of H.pylori infection. Height, weight, body mass index (BMI) and standard deviation score (SDS) was calculated and growth parameters were compared between two groups of H.pylori positive and those with negative results. The prevalence of H.pylori infection was 52.2%. There was no meaningful relation between calculated SDS (for height and BMI) and H.pylori infection. PMID- 23024104 TI - Newborn care practices and health seeking behavior in urban slums and villages of Anand, Gujarat. AB - Health status of neonates in urban slums has not been studied in smaller towns. A questionnaire was administered to 154 families of 10 urban slums of Anand (population - 197351) and 160 families from 6 villages of Anand district. The socioeconomic and education status of the slum dwellers versus rural participants were significantly lower (P<0.001). Antenatal care (79.9 vs 94.4%, P<0.001), hospital delivery (82.5 vs 93.8%, P=0.002), neonatal follow-up (27.9 vs 78.8%, P<0.001), health seeking (56.5 vs 91.3%, P<0.001), essential newborn care and exclusive breastfeeding (6.5 vs 85.6%, P<0.001) were also lower in urban slums, as compared to villages, Care seeking was low in urban slums, Hindus and illiterate mothers. Health care and socioeconomic status of neonates in slums of smaller cities is poorer than in surrounding villages. PMID- 23024105 TI - Clinical and immunological profile of systemic lupus erythematosus. AB - Pediatric onset systemic lupus erythematosus (SLE) is not uncommon and female to male ratio varies. Pediatric SLE patients have more severe disease at onset, higher rates of organ involvement and more aggressive clinical course than adults. We compared the clinical and immunological parameters among pediatric SLE and adult SLE from Western India. Twenty five children and 60 adult patients fulfilling American College of Rheumatology SLE criteria were included. Antinuclear antibodies, anti-dsDNA and complement (C3, C4) levels were tested. Of 25 pediatric SLE patients studied, 24% showed CNS involvement vs. 8.3% in adults SLE (P=0.0499). Lupus nephritis was seen in 75% adult patients vs. 52% among children. Hepatosplenomegaly was noted more among adult SLE 26.8% vs 12% among children. Alopecia was an exclusive features among adult SLE. PMID- 23024106 TI - Vitamin D levels differ by cancer diagnosis and decline over time in survivors of childhood cancer. AB - BACKGROUND: The aim of this study was to evaluate serum 25-hydroxyvitamin D (25OHD) concentrations in survivors of childhood cancer and compare levels by underlying diagnosis and as a function of time. PROCEDURE: A retrospective review of 201 pediatric cancer survivors enrolled in a hospital-based cancer survivor registry. Demographic characteristics and 25OHD levels were extracted from the registry. Vitamin D status was determined during routine clinical care and was categorized as normal, insufficient, or deficient. RESULTS: 25OHD levels differed significantly across diagnoses (P = 0.017), with the lowest levels found in patients treated for osteosarcoma, retinoblastoma, hepatoblastoma, and myeloid leukemias. Age was inversely correlated with 25OHD levels (P = 0.03). Average 25OHD level at study entry was 29.8 ng/ml (range: 5-79.7), with 14.4% vitamin D deficient, 39.3% insufficient, and 46.3% normal. 25OHD concentrations decreased 11.4% over time (P < 0.00001). CONCLUSION: Fewer than half of childhood cancer survivors have normal 25OHD concentrations, which further declined over time. Patients with solid tumors were the most affected, despite their lack of routine exposure to glucocorticoids. Future investigations should focus on why vitamin D level varies by diagnosis and how best to replete in this population. PMID- 23024107 TI - Reduction of aflatoxin in rice by different cooking methods. AB - Rice (Oryza sativa Linn) is one of the basic diets in the north of Iran. The aim of present study was to detect total aflatoxin (AFT) in domestic and imported rice in Amol (in the north of Iran) and to evaluate the effect of different cooking methods on the levels of the toxin. For this purpose, 42 rice samples were collected from retail stores. The raw samples were analysed by enzyme-linked immunosorbent assay (ELISA) technique for toxin assessment and then submitted to two different cooking methods including traditional local method and in rice cooker. After treatment, AFT was determined. Results show that the average concentration of AFT in domestic and imported samples was 1.08 +/- 0.02 and 1.89 +/- 0.87 ppb, respectively, which is lower than national and European Union standards. The highest AFT reduction (24.8%) was observed when rice samples were cooked by rice cooker but the difference with local method was not statistically significant (p > 0.05). PMID- 23024108 TI - Testing the efficacy of quercetin in mitigating bisphenol A toxicity in liver and kidney of mice. AB - Quercetin (3,5,7,3',4'-pentahydroxy flavone) is a potent antioxidant found in various fruits and vegetables. The present investigation was an attempt to evaluate the mitigatory effect of quercetin on the damage caused by bisphenol A (BPA; 2,2-bis (4-hydroxyphenyl) propane), a well-known xenoestrogen, on liver and kidney of mice. Swiss strain adult male albino mice were orally administered with 120 and 240 mg/kg body weight (bw)/day BPA with or without quercetin (60 mg/kg bw/day) for 30 days. On the completion of the treatment period, animals were killed; organs were isolated and used for the study. Results revealed that oral administration of BPA for 30 days caused significant and dose-dependent decrease in body weight. Absolute and relative organ weights, total lipid and cholesterol contents were significantly increased in liver and kidney of mice when compared with vehicle control. BPA treatment also caused, when compared with vehicle control, a statistically significant reductions in the activities of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase as well as in glutathione and total ascorbic acid contents; however, significant increase was found in malondialdehyde (MDA) levels. Histopathological studies revealed hepatocellular necrosis, cytoplasmic vacuolization and decrease in hepatocellular compactness in liver as well as distortion of the tubules, increased vacuolization, necrosis and disorganization of glomerulus in the kidney of BPA-treated mice. All these effects were dose dependent. Co-treatment with quercetin (60 mg/kg bw) and BPA (low dose and high dose) alleviates the changes in body weight, as well as absolute and relative organ weights of mice. It also ameliorates the oxidative stress created by BPA by lowering MDA levels and by increasing enzymatic and nonenzymatic antioxidants as well as it brings back the normal histoarchitecture of liver and kidney of mice. The present results revealed that graded doses of BPA caused oxidative damage in liver and kidney of mice, which is mitigated by quercetin. PMID- 23024109 TI - Quercetin protected isolated human erythrocytes against mancozeb-induced oxidative stress. AB - Mancozeb is a fungicide belonging to the ethylene-bisdithiocarbamate group and is widely used in agriculture. The aim of this study was to examine the protective effect of quercetin (QRN) against oxidative stress induced by mancozeb in human erythrocytes. In order to verify this, 5 ml of venous blood was collected and the erythrocytes were separated and divided into equal parts. One part was incubated with different concentrations of mancozeb (0, 10, 30, 100 uM) for 4 h at 37 degrees C. The other part was preincubated with QRN (40 and 80 MUM) for 30 min, followed by mancozeb (0, 10, 30, 100 uM) incubation for 4 h. We found reduction in the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) along with elevated levels of lipid peroxide (LPO) in erythrocytes incubated with 30 and 100 um of mancozeb. Pre incubation with QRN (80 MUM) reversed oxidative stress induced by mancozeb (30 MUM) and inhibited LPO induced at 100 MUM by 64.36%. QRN also reduced the haemolytic effect on erythrocytes but could not prevent the induction of haemolysis by mancozeb. Therefore, these results suggest that QRN may play a role in preventing the oxidative stress induced by mancozeb in human erythrocytes. PMID- 23024110 TI - Synergestic effect of lycopene and melatonin against the genesis of oxidative stress induced by cyclophosphamide in rats. AB - Cyclophosphamide (CP) is an alkylating agent that has been considered effective for cancer treatment. Lycopene, the pigment in tomato fruits, has beneficial effect in the treatment of some diseases. The goal of this study is to evaluate the protective effect of lycopene alone or combined with melatonin (Mel) in inhibiting the oxidative stress and toxic effect of CP in rats. Five groups of rats were included in this study; Group I served as the control. Rats in groups II-V were administrated with single dose of CP (150 mg/kg B.W) interperitoneally for 3 days. On the same day of CP administration, the rats in group III were fed a diet supplemented with lycopene (50 mg/kg of diet), rats in group IV were administered with a dose of 2.5 mg Mel/kg body weight (bw) injected subcutaneously and rats in group V were supplemented with lycopene and a dose of 2.5 mg Mel/kg bw injected subcutaneously. After 15 days the blood samples were collected. Results obtained showed that CP exerted its toxic effect by increasing the free radicals and reactive oxygen species that causes lipid peroxidation and cell damage, and this in turn is detected by elevation in nitric oxide (NO) and malondialdehyde (MDA), while the activities of antioxidants enzymes including (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)) were significantly decreased as compared with the control rats. The combined treatment (Lyco + Mel) group showed potential reduction in these parameters more than those treated with lyco alone. The activities of SOD, CAT and GPx were found significantly high than lyco alone treated rats. A positive significant correlation between NO and MDA (r = .81). In conclusion, these results suggested that supplementation of diet with lycopene and Mel provided antioxidant defense with strong chemopreventive activity against Cp-induced cytotoxicity. PMID- 23024111 TI - Anti-inflammatory potential of curcumin and quercetin in rats: role of oxidative stress, heme oxygenase-1 and TNF-alpha. AB - Flavonoids are group of compounds that have been shown to possess potent anti inflammatory effects in both cellular and animal models of inflammation. In the current study, the single and combined effects of the two flavonoids, curcumin and quercetin, against carrageenan-induced acute inflammation in rats were evaluated with emphasis on the role of oxidative stress, anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha). Curcumin (50 mg/kg), quercetin (50 mg/kg) and a combination of both were orally administered for 14 days before carrageenan injection in rats and compared with the reference nonsteroidal anti-inflammatory drug, indomethacin (10 mg/kg). The percentage increase in paw thickness was calculated. Frozen hind paws were used for the estimation of lipid peroxides (malondialdehyde, MDA), nitric oxide (NO), reduced glutathione (GSH), TNF-alpha level and HO-1 messenger RNA (mRNA) expression. Formalin-fixed hind paws were used for histopathological examination. Results showed that both curcumin and quercetin caused reduction in carrageenin-induced edema and lymphocytes infiltration along with the decrease is being even higher in case of their combination. Additionally, both flavonoids reduced MDA and NO formation, and restored GSH contents in the paw. Furthermore, both flavonoids increased HO-1 mRNA expression and decreased the elevated TNF-alpha level. Results showed that both flavonoids moderately lowered inflammation, while their combination was more effective. Accordingly, this study suggests that the reduction in oxidative stress and modulation of HO-1 mRNA expression and TNF-alpha release by curcumin and quercetin may contribute to the synergistic anti-inflammatory effects of these two flavonoids upon combination. PMID- 23024112 TI - Intensity modulated radiation therapy provides excellent local control in high risk abdominal neuroblastoma. AB - BACKGROUND: Locoregional failure is a significant concern in patients with high risk abdominal neuroblastoma (NB) receiving radiotherapy. Locoregional control outcomes were studied in children with NB receiving intensity modulated radiotherapy (IMRT). PROCEDURE: Twenty children (11 females, 9 males) with NB (median age at diagnosis 3.4 years) receiving IMRT were analyzed for locoregional failure, outcomes, and toxicities. IMRT doses were 23.4 Gy (n = 12), 30 Gy (n = 1), 30.6 Gy (n = 5), and 36.0 Gy (n = 2) based on extent of resection. Five patients had tumors with MYCN amplification, and 19 had metastatic disease. All patients were treated consistently using reproducible immobilization techniques; physiological motion was assessed by 4D-CT, and target localization by cone-beam computed tomography. ICRU 62 volumetric conventions were employed based on institutional data for pediatric target volume and organ motion. RESULTS: No patient developed primary site infield or locoregional failure at a median follow up of 2.2 years. Distant failure (median time to distant failure 1.6 years) occurred in the brain, lungs, or skeletal sites in eight patients, five of whom died. The 2-year event-free survival was 58.5 +/- 13.3% and cumulative incidence of local and distant failures was 0% and 41.5 +/- 11.9%, respectively. Asymptomatic loose stool during RT occurred in nearly all patients, but required no intervention. CONCLUSIONS: IMRT is feasible, safe in the short term, and yields excellent locoregional control. Despite subtotal resection in some cases, locoregional control appeared to be increased by conformal radiotherapy with ICRU 62-compliant volumes. Dose escalation beyond 30.6 Gy may be unnecessary with improved target volume coverage. PMID- 23024113 TI - 131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma. AB - BACKGROUND: (131) I-metaiodobenzylguanidine (MIBG) produces a 37% response rate in relapsed/refractory neuroblastoma, and could be used to improve remission status prior to myeloablative chemotherapy with autologous stem cell transplant (ASCT). The purpose of our report was to evaluate safety and response with MIBG therapy followed by myeloablative busulfan and melphalan (BuMel) with ASCT in patients with refractory neuroblastoma. METHODS: Retrospective chart review was done on patients treated with MIBG (18 mCi/kg) on Day 1 and ASCT on day 14. Six to eight weeks after MIBG, patients without progressive disease received IV busulfan on days -6 to -2 (target Css 700-900), melphalan (140 mg/m2 IV) on day 1, and ASCT on Day 0. Response and toxicity were evaluated after MIBG and again after myeloablative therapy. RESULTS: Eight patients completed MIBG/ASCT followed by BuMel/ASCT. MIBG was well tolerated, with grade 3 or 4 non-hematologic toxicity limited to one patient with sepsis. Grade 3 mucositis occurred in six patients after BuMel/ASCT. One patient developed sinusoidal obstructive syndrome (SOS) and died 50 days post-ASCT following myeloablative conditioning. All patients engrafted neutrophils (median 16.5 days) and platelets (median 32 days) after BuMel, excluding the patient with SOS. After all therapy, there were three complete, two partial, and one minor response in seven evaluable patients. CONCLUSIONS: MIBG at doses up to 18 mCi/kg can be safely administered 6 weeks prior to a BuMel consolidative regimen for refractory neuroblastoma. Preceding MIBG did not impair engraftment following BuMel. This regimen is being further evaluated in a Children's Oncology Group (COG) trial. PMID- 23024114 TI - The impact of genetic and environmental factors on homocysteine levels in preterm neonates. AB - BACKGROUND: Hyperhomocysteinemia may be associated with vascular complications in adults. Whereas pediatric thrombosis risk peaks in neonates, data on homocysteine (Hcy) levels assessed in term and preterm infants during the perinatal period are scarce. In the present study, we aimed to establish Hcy reference values for preterm infants and study their potential associations with the early post-natal health status. Plasma Hcy and hematocrit levels and MTHFR polymorphisms (C677T and A1298C substitution) were studied in a large cohort of preterm infants in a tertiary referral medical center during an 18-month period. Data were collected on maternal history and delivery as well as on post-natal complications. RESULTS: The study cohort included 167 infants whose mean gestational age was 30.98 +/- 2.34 weeks (range: 26-36 weeks), mean birth weight 1327.6 +/- 327 g, and mean Hcy level 7.99 +/- 3.27 (range: 2.2-21.2) umol/L. Maternal intake of folic acid was inversely associated with the babies' Hcy levels (P = 0.0001). Increased Hcy levels positively correlated with birth weight, gestational age (P < 0.005), total number of pregnancies (P = 0.012), and presence of MTHFR polymorphism. Higher Hcy levels were associated with feeding (P = 0.008), especially total parenteral nutrition (P = 0.0001). There was no correlation between Hcy levels and any vascular post-natal complications. CONCLUSIONS: During their post-natal hospitalization, preterm infants may have relatively high, that is, within the adult normal range, Hcy levels which are influenced by genetic and environmental factors. Despite the fact that no correlation was found between Hcy levels and post-natal complications, these associations should be further studied. PMID- 23024115 TI - Tackling missing radiographic progression data: multiple imputation technique compared with inverse probability weights and complete case analysis. AB - OBJECTIVE: To describe the results of different statistical ways of addressing radiographic outcome affected by missing data--multiple imputation technique, inverse probability weights and complete case analysis--using data from an observational study. METHODS: A random sample of 96 RA patients was selected for a follow-up study in which radiographs of hands and feet were scored. Radiographic progression was tested by comparing the change in the total Sharp van der Heijde radiographic score (TSS) and the joint erosion score (JES) from baseline to the end of the second year of follow-up. MI technique, inverse probability weights in weighted estimating equation (WEE) and CC analysis were used to fit a negative binomial regression. RESULTS: Major predictors of radiographic progression were JES and joint space narrowing (JSN) at baseline, together with baseline disease activity measured by DAS28 for TSS and MTX use for JES. Results from CC analysis show larger coefficients and s.e.s compared with MI and weighted techniques. The results from the WEE model were quite in line with those of MI. CONCLUSION: If it seems plausible that CC or MI analysis may be valid, then MI should be preferred because of its greater efficiency. CC analysis resulted in inefficient estimates or, translated into non-statistical terminology, could guide us into inaccurate results and unwise conclusions. The methods discussed here will contribute to the use of alternative approaches for tackling missing data in observational studies. PMID- 23024116 TI - Relapsing polychondritis coexisting with immune thrombocytopenic purpura: an unusual association. PMID- 23024117 TI - The thirteenth international childhood acute lymphoblastic leukemia workshop report: La Jolla, CA, USA, December 7-9, 2011. PMID- 23024120 TI - Cost-effective analysis of oocyte cryopreservation: stunning similarities but differences remain. PMID- 23024119 TI - Identification of genital tract markers in the human seminal plasma using an integrative genomics approach. AB - STUDY QUESTION: Can protein biomarkers of the male genital tract be identified in human seminal plasma? SUMMARY ANSWER: We identified potential biomarkers for each of the organs participating in the secretions of the human seminal plasma. WHAT IS KNOWN ALREADY: The seminal plasma fulfills critical functions for fertility by providing spermatozoa with a protective milieu, promoting their final maturation and modulating the immune responsiveness of the female reproductive tract. It is also considered to be a promising source of biomarkers of male infertility and/or pathologies of the male genital tract. STUDY DESIGN, SIZE, DURATION: This study combines proteomic analyses of normal seminal plasma together with transcriptomic gene expression profiling of human healthy tissues. MATERIALS, SETTING, METHODS: Non-liquefied seminal plasma proteins from a healthy donor were prefractionated using two sequential ProteominerTM libraries. Eight subproteome fractions were collected, trypsin digested and subjected to three successive mass spectrometry analyses for peptide characterization. The list of identified proteins was compared with and merged with other available data sets of the human seminal plasma proteome. The expression of corresponding genes was then investigated using tissue transcriptome profiles to determine where, along the male reproductive tract, these proteins were produced. Finally, tissue specificity of a selected subset of biomarker candidates was validated on human tissues. MAIN RESULTS AND THE ROLE OF CHANCE: We first performed a proteomic analysis of the human seminal plasma and identified 699 proteins. By comparing our protein list with other previous proteomic data sets, we found that 2545 unique proteins have been described so far in the human seminal plasma. We then profiled their expression at the gene level and identified 83 testis, 42 epididymis, 7 seminal vesicle and 17 prostate candidate protein markers. For a subset of testis specific candidates, i.e. TKTL1, LDHC and PGK2, we further validated their germ cell expression and demonstrated that such markers could distinguish between semen from fertile and infertile men. LIMITATIONS, REASONS FOR CAUTION: While some of the markers we identified are well-known tissue-specific products, further dedicated studies to validate the biomarker status of new candidates will be required. Additionally, whether or not the abundance of these proteins is indeed decreased in some specific pathological situations remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: Using an integrative genomics approach, we identified biomarker candidates for each of the organs participating in the seminal plasma production. In this study, we essentially focused on germ cell markers and their potential application for the diagnosis of male infertility. Other types of markers also deserve a focused attention given their potential predictive value for various reproductive disorders, notably for prostate cancers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Proteomics Core Facility at Biogenouest and was funded by Conseil Regional de Bretagne, IBiSA and Agence de la Biomedecine grants. The authors declare that there exists a competing financial interest in this work that is related to a patent application on the use of identified germ cell-specific proteins in an antibody-based assay (FertichipTM) to predict the successful testicular biopsy outcomes in human non-obstructive azoospermia. PMID- 23024121 TI - Development and characterization of nine microsatellite loci for Sisyrinchium micranthum (Iridaceae). AB - PREMISE OF THE STUDY: Sisyrinchium micranthum is an herb with wide distribution and morphological variation, presenting three known cytotypes (2x, 4x, and 6x), which is naturally occurring from Mexico to Argentina. The development of microsatellite markers for this species is important to provide molecular tools to investigate polyploidy origin, as well as its relationship with phenotypic and genetic variability. * METHODS AND RESULTS: Nine microsatellite markers were isolated using an enriched genomic library and characterized in a diploid population. Eight markers generated polymorphic loci in 27 plants of a population from southern Brazil. The number of alleles per locus ranged from two to nine, and the observed and expected heterozygosities varied from 0.192 to 0.741 and from 0.370 to 0.884, respectively. * CONCLUSIONS: These species-specific DNA markers may be useful for further investigations of the involved polyploidization process and the population genetics of S. micranthum. PMID- 23024122 TI - Genetic effects of recent habitat fragmentation in the Thousand-Island Lake region of southeast China on the distylous herb Hedyotis chrysotricha (Rubiaceae). AB - PREMISE OF THE STUDY: Known-age artificial-lake islands provide ideal model systems to elucidate the genetic and evolutionary consequences of anthropogenic habitat fragmentation on very recent time scales. Here, we studied a distylous herb, Hedyotis chrysotricha (Rubiaceae), in the artificially created Thousand Island Lake (TIL) region of southeast China to explore the genetic consequences of islanding for this species. * METHODS: Seven microsatellite loci were used to genotype 384 individuals of H. chrysotricha from 18 populations to estimate genetic diversity, population structure, and demographic parameters. * KEY RESULTS: Island populations had significantly lower mean genetic diversity than those from the western/eastern mainland (e.g., H(E) = 0.381 vs. 0.461) and also displayed higher mean subdivision (F(ST) = 0.12 vs. 0.042/0.051). BayesAss analyses indicated moderate levels of migration rates among most populations, whereas Bottleneck did not provide strong evidence for such effects. In consequence, 2MOD strongly favored a gene flow-drift model over a pure drift model in the study area, but concomitantly revealed a relatively greater influence of drift in the island populations as evidenced by their significantly higher probabilities of allelic coancestry (F = 0.184 vs. 0.085). * CONCLUSIONS: The observed genetic patterns in H. chrysotricha indicate that recent anthropogenic habitat fragmentation in the TIL region can lead to significant loss of genetic diversity in isolated fragments (islands) due to ongoing drift. By contrast, patterns of random mating, gene flow, and population connectivity have not greatly been modified yet, possibly owing to the species' fruit (seed) dispersal capabilities providing resilience in the face of habitat fragmentation. PMID- 23024123 TI - Phylogeography of Buddleja crispa (Buddlejaceae) and its correlation with drainage system evolution in southwestern China. AB - PREMISE OF THE STUDY: Southwestern China is an area of active tectonism and erosion, yielding a dynamic, deeply eroded landscape that is hypothesized to have influenced the genetic structure of the resident populations of plants and animals. However, few studies have been conducted to examine the influence of changing river channels, particularly in the Yarlung Tsangpo area, on genetic distributions in plants. We here examine the population structure of Buddleja crispa, a dominant element of the dry, warm/hot river-valley communities, seeking to delimit the current population genetic structure and its relation to past changes in the courses of the major rivers in this area. * METHODS: Two chloroplast DNA fragments were used to estimate the genetic variation and phylogeographic structure of the populations, and to infer nested clades, of the species. * KEY RESULTS: We detected low intrapopulational haplotype diversity and higher overall population haplotype diversity (h(S) = 0.085, h(T) = 0.781). Molecular variance was mainly observed between groups (81.42%). Robust population genetic structure were detected by AMOVA (F(ST) = 0.967), coinciding with three nested clades (identified by NCPA) and five phylo-groups linked with paleo drainage systems (identified by SAMOVA). No support for extensive spatial or demographical expansion was obtained. * CONCLUSIONS: A general pattern of genetic isolation by vicariance was inferred, and detected disjunct patterns strongly indicate that currently discontinuous drainage systems were historically linked. Most importantly, population subdivisions and genetic variation perfectly reflect the putative Paleo-Red-River drainage pattern, and Yarlung Tsangpo populations are closely related to Central Yunnan Plateau populations, indicating that they were previously connected by ancient river courses. Divergence times between these river systems estimated by molecular dating (in the Pleistocene) agree with previous findings. PMID- 23024124 TI - Eight microsatellite markers for the bulbous buttercup Ranunculus bulbosus (Ranunculaceae). AB - PREMISE OF THE STUDY: Pollen dispersal is a key biological process enabling plant populations to maintain genetic connectivity. Direct estimates of pollen dispersal using paternity assignment or correlated paternity estimates require highly variable genetic markers, of which microsatellites are the markers of choice. * METHODS AND RESULTS: Eight species-specific microsatellites have been developed for Ranunculus bulbosus, combining classical enrichment methods with 454 sequencing. These markers have been used in paternity analysis as well as in pollen-pool analyses and proven to be highly polymorphic (seven to 63 alleles in the largest population studied). An excess of homozygotes in six loci indicate the presence of null alleles. * CONCLUSIONS: These markers are the first microsatellites isolated and tested on R. bulbosus and provide a useful tool for population genetic studies in this common grassland herb. PMID- 23024125 TI - Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma. AB - BACKGROUND: Treatment of eyes with retinoblastoma failing systemic chemoreduction and external beam radiotherapy is seldom efficacious. This study compares the efficacy and toxicity of intra-arterial ophthalmic artery chemotherapy (IAO) to our historical cohort of sequential periocular and systemic chemotherapy in such patients. PATIENTS AND METHODS: Eighteen eyes (15 consecutive patients) were retrospectively evaluated. Eight eyes received IAO for a median of four cycles (range: 2-9) including melphalan alone (n = 3) or after topotecan and carboplatin (n = 4) or topotecan and carboplatin without melphalan (n = 1). Ten eyes received a median of two cycles (range: 1-3) of periocular topotecan (n = 9) or carboplatin (n = 1) followed by intravenous topotecan and cyclophosphamide in three patients if at least stable disease was achieved. Both groups were comparable for disease extension and prior therapy. RESULTS: No extraocular dissemination or second malignancy occurred and all patients are alive. The probability of enucleation-free eye survival at 12 months was 0.87 (95% CI: 0.42 0.97) for the IAO group, compared to 0.1 (95% CI: 0.06-0.35) for the periocular group (P < 0.01). Ocular toxicity was mild and similar in both groups (mostly mild orbital edema). Systemic toxicity was low for IAO and periocular injection, but children who received sequentially intravenous chemotherapy (n = 12 cycles) had five episodes of grade 4 neutropenia, three of which resulted in hospitalizations. No case in the IAO group presented these complications. CONCLUSIONS: IAO is significantly superior to sequential periocular-intravenous topotecan-containing regimens in eyes with relapsed intraocular retinoblastoma with a more favorable toxicity profile. PMID- 23024126 TI - Repeated massive pulmonary air embolism during pacemaker implantation. AB - Pacemaker implantation is associated with the potential for various acute and late complications. Though they rarely occur, massive pulmonary air embolisms are lethal. We report the case of a 72-year old male with sick sinus syndrome who underwent permanent pacemaker implantation. Sedation was administered due to back pain with the resultant appearance of snoring. The procedure was complicated with repeated massive pulmonary air embolisms. The events occurred after the leads had been placed in the sheaths. The patient was successfully resuscitated with fluid challenge, O(2) supplement, vasopressor and catheter aspiration. This case illustrates that in a heavily sedated, snoring patient, the marked negative intrathoracic pressure can overcome the frictional resistance of air to being sucked into the gap between the lead body and sheath's wall. Careful manipulation alone is not enough to prevent pulmonary air embolisms. Aggressive treatment for upper airway obstruction is important. The use of a sheath with a haemostatic valve is strongly recommended if the upper airway obstruction cannot be treated adequately. PMID- 23024127 TI - A 77-year-old man with a prolonged activated partial thromboplastin time. PMID- 23024128 TI - Commentary. PMID- 23024129 TI - Commentary. PMID- 23024130 TI - A urine sample with an orange to red hue, what should we do? PMID- 23024133 TI - The great contrarian: John Ruskin. PMID- 23024134 TI - Estimation of asthma incidence among low-income children in Texas: a novel approach using Medicaid claims data. AB - Few recent estimates of childhood asthma incidence exist in the literature, although the importance of incidence surveillance for understanding asthma risk factors has been recognized. Asthma prevalence, morbidity, and mortality reports have repeatedly shown that low-income children are disproportionately impacted by the disease. The aim of this study was to demonstrate the utility of Medicaid claims data for providing statewide estimates of asthma incidence. Medicaid analytic extract (MAX) data for Texas children aged 0-17 years enrolled in Medicaid between 2004 and 2007 were used to estimate incidence overall and by age group, gender, race, and county of residence. A >=13-month period of continuous enrollment was required in order to distinguish incident from prevalent cases identified in the claims data. The age-adjusted incidence of asthma was 4.26/100 person-years during 2005-2007, higher than reported in other populations. Incidence rates decreased with age, were higher for males than females, differed by race, and tended to be higher in rural than urban areas. This study demonstrates the utility of Medicaid analytic extract data for estimating asthma incidence and describes the methodology required for a population with unstable enrollment. PMID- 23024135 TI - Does shared family background influence the impact of educational differences on early mortality? AB - The mechanisms behind social differences in mortality rates have been debated. The authors examined the extent to which shared family background and health in early life could explain the association between educational status and all-cause mortality rates using a sibling design. The study was register-based and included all individuals born in Denmark between 1950 and 1979 who had at least 1 full sibling born in the same time period (n = 1,381,436). All individuals were followed from 28 years of age until death, emigration, or December 2009. The authors used Cox regression analyses to estimate hazard ratios for mortality according to educational level. Conventional cohort and intersibling analyses were carried out and conducted separately for deaths occurring before and after the age of 45 years, respectively. The cohort analyses showed an inverse association between educational status and all-cause mortality that was strongest for males, increased with younger birth cohorts, and tended to be strongest in the analyses of death before 45 years of age. The associations were attenuated slightly in the intersibling analyses and after adjustment for serious health conditions in early life. Hence, health selection and confounding by factors shared by siblings explained only a minor part of the association between educational level and all-cause mortality. PMID- 23024136 TI - Invited commentary: does the childhood environment influence the association between every x and every y in adulthood? AB - The conditions under which children are raised have a long-term impact on health throughout the life course. Because childhood conditions can have such a strong influence on adult risk factors for disease, failure to account for their influences could distort observed associations between adult risk factors and subsequent health outcomes. In other words, childhood conditions could confound the association between every X and Y when X is measured in adulthood. Comparisons of health outcomes between exposed and unexposed siblings have the potential to eliminate confounding effects due to vulnerability factors shared between siblings (i.e., 50% of their genes and aspects of the childhood environment that affect siblings equally). In a large, population-based study of siblings in Denmark, Sondergaard et al. (Am J Epidemiol. 2012;176(8):675-683) found that individuals with higher educational qualifications lived longer than did their siblings with lower educational qualifications. Their results provide evidence for the returns to health resulting from investment in expanded educational opportunities. However, even sibling designs are not conclusive regarding causality; they remain subject to the unmeasured confounding influences of factors that vary within families. Nonetheless, sibling-based approaches should be used more often in studies of adult risk factors to address the long term influences of the childhood environment on health. PMID- 23024138 TI - Erratum. PMID- 23024137 TI - Incidence of and risk factors for adverse cardiovascular events among patients with systemic lupus erythematosus. AB - Patients with systemic lupus erythematosus (SLE) are at excess risk of cardiovascular events (CVEs). There is uncertainty regarding the relative importance of SLE disease activity, medications, or traditional risk factors in this increased risk. To gain insight into this, the authors analyzed data from a cohort of 1,874 patients with SLE who were seen quarterly at a single clinical center (April 1987-June 2010) using pooled logistic regression analysis. In 9,485 person-years of follow-up, the authors observed 134 CVEs (rate = 14.1/1,000 person-years). This was 2.66 times what would be expected in the general population based on Framingham risk scores (95% confidence interval: 2.16, 3.16). After adjustment for age, CVE rates were not associated with duration of SLE. However, they were associated with average past levels of SLE disease activity and recent levels of circulating anti-double-stranded DNA. Past use of corticosteroids (in the absence of current use) was not associated with CVE rates. However, persons currently using 20 mg/day or more of corticosteroids had a substantial increase in risk even after adjustment for disease activity. Thus, consistent with findings in several recent publications among cohorts with other diseases, current use of corticosteroids was associated with an increased risk of CVEs. These results suggest a short-term impact of corticosteroids on CVE risk. PMID- 23024139 TI - Ulcerative umbrellar lesions in captive moon jelly (Aurelia aurita) medusae. AB - Over a period of 6 months, dozens of moon jelly (Aurelia aurita) medusae from a single-species exhibit at the California Science Center (CSC) developed exumbrellar ulcers. Ulcers were progressive, causing umbrellar creases that expanded radially to the bell rim and occasional adoral erosions that extended into gastrovascular cavities. Husbandry interventions, including addition of ultraviolet light sterilizers, repopulation with fresh cultures, and enclosure disinfection, did not arrest the recurrence of lesions. Biopsies or whole specimens representing 17 medusae (15 affected and 2 grossly unaffected) from CSC and 2 control medusae from Aquarium of the Pacific were submitted to a private diagnostic laboratory and processed for light and electron microscopy. Microscopic lesions were present in all CSC medusae and were not observed or negligible in control medusae. Lesions included ulceration, necrosis, and hyperplasia in all umbrellar layers, with most severe lesions in the exumbrella and amoebocyte infiltration in the underlying mesoglea. Special stains, electron microscopy, and fungal culture did not associate microorganisms with the lesions. Bacterial cultures from the CSC population consistently grew Shewanella and Vibrio spp, both of which were considered commensal. Trauma and environmental stress are proposed as possible causes for the ulcers. PMID- 23024140 TI - Paracoccus tibetensis sp. nov., isolated from Qinghai-Tibet Plateau permafrost. AB - Strain Tibet-S9a3(T) was isolated from Qinghai-Tibet Plateau permafrost, China. The isolate was a Gram-negative, non-motile, non-spore-forming short rod. The 16S rRNA gene sequence indicated that strain Tibet-S9a3(T) was a member of the genus Paracoccus and was closely related to Paracoccus aestuarii B7(T) (98.2 % 16S rRNA gene sequence similarity), 'P. beibuensis' JLT1284 (97.9 %), P. homiensis DD R11(T) (97.4 %), P. zeaxanthinifaciens ATCC 21588(T) (97.4 %) and other type strains of the genus (93.7-96.7 %). The G+C content of the genomic DNA was 69.1 mol% and the major isoprenoid quinone was ubiquinone-10. The major fatty acids were C18 : 1omega7c (87.6 %), C18 : 0 (4.3 %) and C10 : 0 3-OH (2.0 %). DNA-DNA relatedness between strain Tibet-S9a3(T) and P. aestuarii B7(T) was 37.9 %. On the basis of phenotypic and genotypic characteristics, it is suggested that strain Tibet-S9a3(T) represents a novel species of the genus Paracoccus, for which the name Paracoccus tibetensis sp. nov. is proposed. The type strain is Tibet-S9a3(T) ( = CGMCC 1.8925(T) = NBRC 105667(T)). PMID- 23024142 TI - Oscillibacter ruminantium sp. nov., isolated from the rumen of Korean native cattle. AB - A strictly anaerobic, Gram-negative, non-spore-forming bacterium, designated GH1(T), was isolated from the rumen of Korean native cattle (HanWoo). Cells were straight to slightly curved rods (2.0-4.5 um long) and were motile by peritrichous flagella. The isolate grew at 30-45 degrees C (optimum 40 degrees C), at pH 5.5-6.5 (optimum pH 6.0) and with up to 3.5% (w/v) NaCl. Strain GH1(T) produced acid from d-glucose, d-ribose and d-xylose, with butyric acid being the major end product. The genomic DNA G+C content was 54.6 mol%. Based on comparative 16S rRNA gene sequence analysis, strain GH1(T) was most closely related to Oscillibacter valericigenes Sjm18-20(T) (97.3% 16S rRNA gene sequence similarity). DNA-DNA hybridization between strain GH1(T) and O. valericigenes DSM 18026(T) showed 24% reassociation. The major fatty acids were iso-C13:0 (13.0%), iso-C15:0 (17.6%), anteiso-C15:0 (8.4%) and C14:0 (4.1%), and the cellular fatty acid methyl esters as dimethylacetals (DMAs) were C16:0 DMA (17.8%), iso-C15:0 DMA (15.2%) and C14:0 DMA (4.52%). The cell-wall peptidoglycan of strain GH1(T) contained meso-diaminopimelic acid and the major cell-wall sugar was galactose. Based on 16S rRNA gene sequence similarity, phylogenetic analysis, DNA G+C content, DNA-DNA relatedness and distinct phenotypic characteristics, strain GH1(T) is classified in the genus Oscillibacter as a member of a novel species, for which the name Oscillibacter ruminantium sp. nov. is proposed. The type strain is GH1(T) (=KCTC 15176(T)=NBRC 108824(T)=JCM 18333(T)). PMID- 23024141 TI - Sphingobium fontiphilum sp. nov., isolated from a freshwater spring. AB - To investigate the biodiversity of bacteria in the spring water of the Chengcing Lake Park in Taiwan, a Gram-stain-negative, rod-shaped, non-motile, non-spore forming and aerobic bacterial strain, designated strain Chen16-4(T), was isolated and characterized in a taxonomic study using a polyphasic approach. Phylogenetic analyses based on 16S rRNA gene sequences showed that the closest relatives of strain Chen16-4(T) were Sphingobium amiense YT(T), Sphingobium yanoikuyae GIFU 9882(T) and Sphingobium scionense WP01(T), with sequence similarities of 97.6, 97.1 and 97.0 %, respectively. A phylogenetic tree obtained with 16S rRNA gene sequences indicated that strain Chen16-4(T) and these three closest relatives formed an independent phylogenetic clade within the genus Sphingobium. The polar lipid pattern, the presence of spermidine and ubiquinone Q-10, the predominance of C18 : 1omega7c in the cellular fatty acid profile and the DNA G+C content also supported affiliation of the isolate to the genus Sphingobium. The DNA-DNA relatedness of strain Chen16-4(T) with respect to recognized species of the genus Sphingobium was less than 70 %. On the basis of the genotypic, chemotaxonomic and phenotypic data, strain Chen16-4(T) represents a novel species in the genus Sphingobium, for which the name Sphingobium fontiphilum sp. nov. is proposed. The type strain is Chen16-4(T) ( = BCRC 80308(T) = LMG 26342(T) = KCTC 23559(T)). PMID- 23024143 TI - Fonticella tunisiensis gen. nov., sp. nov., isolated from a hot spring. AB - A strictly anaerobic, moderately thermophilic, halotolerant rod, designated BELH25(T), was isolated from a water sample of a Tunisian hot spring. Cells were non-motile, 2-6 um long and 0.4-0.6 um wide, appearing singly or in pairs. The isolate grew at 45-70 degrees C (optimum 55 degrees C), at pH 6.2-8.0 (optimum pH 7.0) and with 0-4% NaCl (optimum 0-2.0%). Sulfate, thiosulfate, elemental sulfur, sulfite, nitrate and nitrite were not used as terminal electron acceptors. Strain BELH25(T) used cellobiose, fructose, galactose, glucose, maltose, mannose, sucrose, starch and yeast extract as electron donors. The main fermentation products from glucose metabolism were formate, acetate, ethanol and CO2. The predominant cellular fatty acids were iso-C15:0, iso-C17:0 and anteiso C15:0. The DNA G+C content was 37.2 mol%. Phylogenetic analysis of the 16S rRNA gene sequence indicated that strain BELH25(T) was most closely related to Caloramator viterbiensis JW/MS-VS5(T) and Fervidicella metallireducens AeB(T) (92.2 and 92.1% sequence similarity, respectively), and the isolate was positioned approximately equidistantly between these genera. Based on phenotypic, phylogenetic and chemotaxonomic characteristics, strain BELH25(T) is proposed to be a member of a novel species of a novel genus within the order Clostridiales, family Clostridiaceae, for which the name Fonticella tunisiensis gen. nov., sp. nov. is proposed. The type strain of the type species is BELH25(T) (=DSM 24455(T)=JCM 17559(T)). PMID- 23024144 TI - Belnapia soli sp. nov., a proteobacterium isolated from grass soil. AB - A Gram-negative, aerobic, non-motile, non-spore-forming, cocci-shaped, red pigmented bacterium, designated strain PB-K8(T), was isolated from grass soil sampled in Daejeon, Republic of Korea. Comparative 16S rRNA gene sequence studies showed that the isolate was clearly affiliated with the class Alphaproteobacteria, and was most closely related to Belnapia moabensis DSM 16746(T) and Belnapia rosea DSM 23312(T), showing a 16S rRNA gene sequence similarity to the type strains of each species of 98.4 and 97.2%, respectively. The cells of strain PB-K8(T) formed red colonies on R2A agar, contained Q-9 as the predominant ubiquinone and included summed feature 3 (C16:1omega7c C16:1omega6c), C16:0, summed feature 8 (C18:1omega7c/C18:1omega6c), C18:1 2-OH and C19:0 cyclo omega8c as the major fatty acids. The G+C content of the genomic DNA of strain PB-K8(T) was 72.1 mol%. Thus, the combined genotypic and phenotypic data supported the conclusion that strain PB-K8(T) represents a novel species of the genus Belnapia, for which the name Belnapia soli sp. nov. is proposed. The type strain is PB-K8(T) (=KCTC 23765(T)=JCM 18033(T)). PMID- 23024145 TI - Dissulfuribacter thermophilus gen. nov., sp. nov., a thermophilic, autotrophic, sulfur-disproportionating, deeply branching deltaproteobacterium from a deep-sea hydrothermal vent. AB - A thermophilic, anaerobic, chemolithoautotrophic bacterium (strain S69(T)) was isolated from a deep-sea hydrothermal vent chimney located on the Eastern Lau Spreading Center and Valu Fa Ridge, Pacific Ocean, at a depth of 1910 m using anoxic medium with elemental sulfur as the only energy source. Cells of strain S69(T) were Gram-negative short rods, 0.4-0.6 um in diameter and 1.0-2.5 um in length, motile with a single polar flagellum. The temperature range for growth was 28-70 degrees C, with an optimum at 61 degrees C. The pH range for growth was 5.6-7.9, with optimum growth at pH 6.8. Growth of strain S69(T) was observed at NaCl concentrations ranging from 0.9 to 5.0%, with an optimum at 1.8-2.7 (w/v). Strain S69(T) grew anaerobically with elemental sulfur as an energy source and bicarbonate/CO2 as a carbon source. Elemental sulfur was disproportionated to sulfide and sulfate. Growth was enhanced in the presence of poorly crystalline Fe(III) oxide (ferrihydrite) as a sulfide-scavenging agent. Strain S69(T) was also able to grow by disproportionation of thiosulfate and sulfite. Sulfate was not used as an electron acceptor either with H2 or with organic electron donors. Analysis of the 16S rRNA gene sequence revealed that the isolate formed a distinct phylogenetic branch within the Deltaproteobacteria. On the basis of its physiological properties and results of phylogenetic analyses, strain S69(T) is considered to represent a novel species of a new genus, for which the name Dissulfuribacter thermophilus gen. nov., sp. nov. is proposed. The type strain of Dissulfuribacter thermophilus is S69(T) (=DSM 25762(T)=VKM B-2760(T)). PMID- 23024146 TI - Zygosaccharomyces sapae sp. nov., isolated from Italian traditional balsamic vinegar. AB - Fourteen yeast isolates were recovered from two traditional balsamic vinegar (TBV) samples collected in the provinces of Modena and Reggio Emilia, Italy. Microsatellite-primed-PCR (MSP-PCR) was used to de-replicate the isolate collection into two representative strains, ABT301(T) and ABT601. Phylogenetic analysis based on the D1/D2 domains of the 26S rRNA gene indicated that these strains represented a distinct species of the genus Zygosaccharomyces, closely related to Zygosaccharomyces rouxii and Zygosaccharomyces mellis. Physiological and morphological tests supported the recognition of a novel taxon of halotolerant, osmotolerant, non-psychrotolerant and maltose-fermentation-negative yeasts showing a chain or star-shaped pattern of budding cells, which remained attached to each other. Morphological observations offered evidence of ascospore formation. A novel species, Zygosaccharomyces sapae sp. nov., is proposed to accommodate these strains, with strain ABT301(T) (= CBS 12607(T) = MUCL 54092(T)) as the type strain. Based on D1/D2 domain phylogenetic analysis, the novel strains shared the highest sequence similarity (100 %) with Zygosaccharomyces sp. strain NCYC 3042, previously isolated from sugar [James, S. A., Bond, C. J., Stratford, M. & Roberts, I. N. (2005). FEMS Yeast Res 5, 747-755]. However, based on phylogenetic (internal transcribed spacers, ITS), PCR fingerprinting and physiological analyses, marked differences were observed between the novel species and strain NCYC 3042, and these results are discussed in more detail. PMID- 23024147 TI - Polycladomyces abyssicola gen. nov., sp. nov., a thermophilic filamentous bacterium isolated from hemipelagic sediment. AB - A novel filamentous bacterium, designated strain JIR-001(T), was isolated from hemipelagic sediment in deep seawater. This strain was non-motile, Gram-positive, aerobic, heterotrophic and thermophilic; colonies were of infinite form and ivory coloured with wrinkles between the centre and the edge of the colony on ISP2 medium. The isolate grew aerobically at 55-73 degrees C with the formation of aerial mycelia; spores were produced singly along the aerial mycelium. These morphological features show some similarities to those of the type strains of some species belonging to the family Thermoactinomycetaceae. Phylogenetic analysis based on 16S rRNA gene sequences confirmed that strain JIR-001(T) belongs to the family Thermoactinomycetaceae within the class Bacilli. Similarity levels between the 16S rRNA gene sequence of strain JIR-001(T) and those of the type strains of Thermoactinomycetaceae species were 85.5-93.5%; highest sequence similarity was with Melghirimyces algeriensis NariEX(T). In the DNA-DNA hybridization assays between strain JIR-001(T) and its phylogenetic neighbours the mean hybridization levels with Melghirimyces algeriensis NariEX(T), Planifilum fimeticola H0165(T), Planifilum fulgidum 500275(T) and Planifilum yunnanense LA5(T) were 5.3-7.5, 2.3-4.7, 2.1-4.8 and 2.5-4.9%, respectively. The DNA G+C content of strain JIR-001(T) was 55.1 mol%. The major fatty acids were iso-C15:0, iso-C17:0, iso-C16:0 and C16:0. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylglycerol, glucolipid, phosphatidylserine, an amino-group containing phospholipid, an unknown phospholipid and two unknown lipids. The predominant menaquinone was MK-7 and the cell-wall peptidoglycan contained meso-diaminopimelic acid, glutamic acid and alanine. On the basis of phenotypic characteristics and 16S rRNA gene sequence comparisons, strain JIR-001(T) is considered to represent a novel species in a new genus of the family Thermoactinomycetaceae, for which the name Polycladomyces abyssicola gen. nov., sp. nov. is proposed. The type strain of Polycladomyces abyssicola is JIR-001(T) (=JCM 18147(T)=CECT 8074(T)). PMID- 23024148 TI - Does the modified Harris hip score reflect patient satisfaction after hip arthroscopy? AB - BACKGROUND: No published studies have explored the relationship between commonly reported clinical outcomes and patient satisfaction after hip arthroscopy. PURPOSE: To compare the modified Harris Hip Score (mHHS) with patient satisfaction in a prospective study over a 2-year period. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We reviewed our institutional database for prospectively collected mHHS and patient satisfaction data from 697 patients. Patients were evaluated preoperatively and at 1 and 2 years after surgery. RESULTS: The mHHS correlated with patient satisfaction at 1 year (P < .001, Pearson R = 0.451) and at 2 years (P < .001, Pearson R = .454). Considering scores from excellent to good as positive results and from fair to poor as negative results, sensitivity was 73% at 1 year and 77% at 2 years. Respectively, the specificity was 64% and 73%, positive predictive value 86% and 91%, negative predictive value 45% and 46%, and accuracy 71% and 76%. At 1- and 2-year follow up, a respective 55% and 54% of patients with fair to poor mHHS were satisfied with the outcome of hip arthroscopy. In contrast, for those patients with an excellent to good mHHS at 1 and 2 years after surgery, 14% and 9%, respectively, were dissatisfied with their outcome. CONCLUSION: Our results show a correlation between patient satisfaction and the mHHS but also demonstrate a limitation of the mHHS as an outcome measure in the prediction of patient satisfaction. Further investigation is required to assess factors beyond current standard orthopaedic clinical outcome measures that may influence patient satisfaction after hip arthroscopy. PMID- 23024149 TI - Do the traditional and modified latarjet techniques produce equivalent reconstruction stability and strength? AB - BACKGROUND: The Latarjet procedure has been described as a reconstructive option for instability associated with substantial glenoid bone defects. A modification, termed the Congruent-Arc, is thought to improve glenoid reconstruction through better articular congruency and greater bone reconstitution. The strengths of these techniques, however, have not been reported. Purpose/ HYPOTHESIS: To compare the fixation stability, strength, glenoid vault load transfer, and joint contact between the Classic and Congruent-Arc techniques. The authors hypothesized that the Classic Latarjet would exhibit inferior joint contact characteristics while having greater stability and strength and more normal glenoid vault strain. STUDY DESIGN: Controlled laboratory study. METHODS: Sixteen shoulder specimens (8 pairs) were tested by loading the glenohumeral joint with the glenoid intact, following creation of a 25% anterior bone defect, and after random assignment to the Classic or Congruent-Arc Latarjet techniques. Specimens were mounted to a testing apparatus that allowed concentric, centralized loading and loading 30 degrees anterior on the glenoid rim. Cyclic loading (100 cycles at 1 Hz) was applied with a staircase protocol (50, 100, 150, and 200 N). Graft interface displacement and glenoid load transfer, quantified in terms of strain, were recorded during loading. Contact was quantified during 50-N loading using a thin pressure sensor. After cyclic loading, specimens were loaded to failure, defined as 5 mm of graft interface displacement. RESULTS: The 30 degrees loading >=100 N resulted in significantly greater graft displacement (P < .004) in the Congruent-Arc group as compared with the Classic (mean displacement range, 0.9 2.6 vs 0.1-0.5 mm, respectively). Failure testing yielded a significantly (P = .010) greater ultimate strength for the Classic (557 N) as compared with the Congruent-Arc (392 N). Load-transfer measurements demonstrated that neither technique's glenoid vault strain values significantly differed from intact (P >= .076). Both techniques resulted in contact areas significantly less than intact (P < .035); however, the Congruent-Arc trended toward better contact characteristics (P = .074). CONCLUSION: The Congruent-Arc results in significantly poorer fixation stability as compared with the Classic technique but did more closely reproduce intact joint contact, which may yield more favorable long-term outcomes. CLINICAL RELEVANCE: Care must be taken in balancing the consideration of initial fixation stability and joint contact for the Congruent-Arc and Classic Latarjet, as these factors have opposing implications for each of the 2 reconstructions' outcomes. PMID- 23024150 TI - Ten-year follow-up of a prospective, randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in the knee joint of athletes. AB - BACKGROUND: Various techniques have proven to be effective for treating articular cartilage defect (ACD) and osteochondral defect (OCD) of the knee joint, but knowledge regarding which method is best still remains uncertain. PURPOSE: To evaluate and compare the outcomes of mosaic-type osteochondral autologous transplantation (OAT) and microfracture (MF) procedures for the treatment of articular cartilage defects of the knee joint in young active athletes. This article represents an update of the clinical results at 10 years. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Between 1998 and 2002, a total of 60 athletes with a mean age of 24.3 years (range, 15-40 years) and with a symptomatic ACD or OCD in the knee were randomized to undergo either OAT or MF. Patients were then evaluated postoperatively using the International Cartilage Repair Society (ICRS) score, Tegner activity score, radiographs, and magnetic resonance imaging. The mean follow-up time was 10.4 years (range, 9-11 years). RESULTS: Three to 10 years after the OAT and MF procedures, patients had lower ICRS and Tegner scores (P < .05), but both groups still had significant clinical improvement over presurgery scores according to ICRS scores at 10-year follow-up. Statistically significantly better results were detected in patients in the OAT group compared with those in the MF group at 10 years (P < .005). At 10-year follow-up, there were 15 failures (26%), including 4 failures (14%) of the OAT and 11 failures (38%) of MF treatment (P < .05). Seven patients (25%) from the OAT group and 14 patients (48%) from the MF group had radiographic evidence of Kellgren-Lawrence grade I osteoarthritis at 10 years, but these differences were not significant (P = .083) or related to the clinical results. The ICRS and Tegner scores of younger athletes (<25 years at the time of primary surgery) remained significantly higher after 10 years compared with older patients (P < .05); 15 of 20 patients (75%) in the OAT group and 8 of 22 patients (37%) in the MF group maintained the same physical activity level. CONCLUSION: The OAT technique for ACD or OCD repair in the athletic population allows for a higher rate of return to and maintenance of sports at the preinjury level compared with MF. PMID- 23024151 TI - Outcomes of arthroscopic repair of panlabral tears of the glenohumeral joint. AB - BACKGROUND: Combined lesions of the glenoid labrum involving tears of the anterior, posterior, and superior labrum have been infrequently reported in the literature. PURPOSE: To evaluate the clinical outcomes of arthroscopic repair of these lesions in a general population using validated scoring instruments, presence of complications, and need for revision surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Fifty-eight patients who had arthroscopic labral repair of tears involving the anterior, posterior, and superior labrum (defined as a panlabral repair) were identified at our institution by retrospective review. All patients underwent arthroscopic labral repair with suture anchor fixation by a uniform approach and with a standardized postoperative protocol. Forty-four patients had a minimum 16-month postoperative follow-up. Outcomes were assessed postoperatively by the American Shoulder and Elbow Surgeons (ASES) score and the Penn Shoulder score. Complications were also documented, including need for revision surgery. RESULTS: The mean age at the time of surgery was 32 years (range, 15-55 years) in the 44 patients. Presenting shoulder complaints included pain alone (40%), instability alone (14%), or pain and instability (45%). Mean number of anchors per repair was 7.9 (range, 5-12). Mean follow-up was 42 months (range, 16-78 months). Mean +/- standard deviation ASES score at final follow-up was 90.1 +/- 17.7 (range, 22-100), and mean Penn Shoulder score was 90.2 +/- 15.3 (range, 38-100). Three of the 4 patients with outcome scores of 70 or less at final follow-up had undergone prior surgery. Thirteen postoperative complications (30%) occurred, with 3 (7%) requiring a second surgery. Five patients (11%) had an instability event following panlabral repair, but only 1 of these patients (2%) required revision surgery for a recurrent labral tear. CONCLUSION: Combined tears of the anterior, posterior, and superior glenoid labrum represent a small but significant portion of labral injuries. Arthroscopic repair of these injuries can be performed with good postoperative outcomes and a low rate of recurrent labral injury. PMID- 23024152 TI - Rotator cuff muscles lose responsiveness to anabolic steroids after tendon tear and musculotendinous retraction: an experimental study in sheep. AB - BACKGROUND: Long-standing rotator cuff tendon tearing is associated with retraction, loss of work capacity, irreversible fatty infiltration, and atrophy of the rotator cuff muscles. Although continuous musculotendinous relengthening can experimentally restore muscular architecture, restoration of atrophy and fatty infiltration is hitherto impossible. HYPOTHESIS: Continuous relengthening with pharmacological stimulation of muscle growth using an anabolic steroid or insulin-like growth factor (IGF) can reverse atrophy and fatty infiltration as well as improve the work capacity of chronically retracted rotator cuff muscles in sheep. STUDY DESIGN: Controlled laboratory study. METHODS: Sixteen weeks after tenotomy of the infraspinatus (ISP) tendon, atrophy and fatty infiltration had developed in the retracted ISP muscle. The musculotendinous unit was continuously relengthened in 14 sheep during 6 weeks: Four sheep were treated without pharmacological stimulation, 4 with intramuscular administration of an anabolic steroid, and 6 with IGF before final repair and rehabilitation (12 weeks). Changes were documented by intraoperative measurements of muscle work capacity, histology, and computed tomography/magnetic resonance imaging. RESULTS: Musculotendinous relengthening by continuous traction resulted in gains of length ranging from 0.7 cm in the IGF group to 1.3 cm in the control group. Fatty infiltration progressed in all groups, and the muscle's cross-sectional area ranged from 71% to 74% of the contralateral side at sacrifice and did not show any differences between groups in weight, volume, histological composition, or work capability of the muscle. The contralateral muscles in the anabolic steroid group, however, showed significantly higher (mean +/- standard deviation) muscle work capacity of 10 +/- 0.9 N.m than the contralateral muscles of the control group (6.8 +/- 2.4 N.m) (P < .05). This was accompanied by an increased mean muscle fiber area as well as by an unusual gain in the animals' weight after injection of the anabolic steroid. CONCLUSION: Subcutaneous continuous relengthening of a chronically retracted musculotendinous unit is feasible and advances the retracted musculotendinous junction toward its original position. This does not change the muscle work capacity. Whereas anabolic steroids have been shown to be effective in preventing classic degenerative muscle changes after tendon tears, neither an anabolic steroid nor IGF contributes to regeneration of the muscle once degenerative changes are established. CLINICAL RELEVANCE: The findings demonstrate that muscle cells lose reactiveness to an anabolic steroid and IGF once retraction has led to fatty infiltration and atrophy of the muscle. Retraction of the muscle after tendon tears must be avoided by early repair, particularly in an athlete, as no regeneration can be achieved by mechanical or pharmacological means at this time. PMID- 23024153 TI - Comparing evolutionary rates for different phenotypic traits on a phylogeny using likelihood. AB - In recent years, likelihood-based approaches have been used with increasing frequency to evaluate macroevolutionary hypotheses of phenotypic evolution under distinct evolutionary processes in a phylogenetic context (e.g., Brownian motion, Ornstein-Uhlenbeck, etc.), and to compare one or more evolutionary rates for the same phenotypic trait along a phylogeny. It is also of interest to determine whether one trait evolves at a faster rate than another trait. However, to date no study has compared phylogenetic evolutionary rates between traits using likelihood, because a formal approach has not yet been proposed. In this article, I describe a new likelihood procedure for comparing evolutionary rates for two or more phenotypic traits on a phylogeny. This approach compares the likelihood of a model where each trait evolves at a distinct evolutionary rate to the likelihood of a model where all traits are constrained to evolve at a common evolutionary rate. The method can also account for within-species measurement error and within species trait covariation if available. Simulations revealed that the method has appropriate Type I error rates and statistical power. Importantly, when compared with existing approaches based on phylogenetically independent contrasts and methods that compare confidence intervals for model parameters, the likelihood method displays preferable statistical properties for a wide range of simulated conditions. Thus, this likelihood-based method extends the phylogenetic comparative biology toolkit and provides evolutionary biologists with a more powerful means of determining when evolutionary rates differ between phenotypic traits. Finally, I provide an empirical example illustrating the approach by comparing rates of evolution for several phenotypic traits in Plethodon salamanders. PMID- 23024154 TI - Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma. AB - OBJECTIVE: To compare the overall survival (OS) of patients treated with 3 mg/kg ipilimumab versus alternative systemic therapies in pretreated unresectable stage III or IV melanoma patients. METHODS: A systematic literature search was performed to identify relevant randomized clinical trials. From these trials, Kaplan-Meier survival curves for each intervention were digitized and combined by means of a Bayesian network meta-analysis (NMA) to compare different drug classes. RESULTS: Of 38 trials identified, 15 formed one interlinked network by drug class to allow for an NMA. Ipilimumab, at a dose of 3 mg/kg, was associated with a greater mean OS time (18.8 months; 95% credible interval [CrI], 15.5-23.0 months) than single-agent chemotherapy (12.3 months; 95% CrI, 6.3-28.0 months), chemotherapy combinations (12.2 months; 95% CrI, 7.1-23.3 months), biochemotherapies (11.9 months; 95% CrI, 7.0-22.0 months), single-agent immunotherapy (11.1 months; 95% CrI, 8.5-16.2 months), and immunotherapy combinations (14.1 months; 95% CrI, 9.0-23.8 months). CONCLUSION: Results of this NMA were in line with previous findings and suggest that OS with ipilimumab is expected to be greater than with alternative systemic therapies, alone or in combination, for the management of pretreated patients with unresectable stage III or IV melanoma. PMID- 23024156 TI - Studies on crenarchaeal tyrosylation accuracy with mutational analyses of tyrosyl tRNA synthetase and tyrosine tRNA from Aeropyrum pernix. AB - Aminoacyl-tRNA synthetases play a key role in the translation of genetic code into correct protein sequences. These enzymes recognize cognate amino acids and tRNAs from noncognate counterparts, and catalyze the formation of aminoacyl tRNAs. While Although several tyrosyl-tRNA synthetases (TyrRSs) from various species have been structurally and functionally well characterized, the crenarchaeal TyrRS remains poorly understood. In this study, we performed mutational analyses on tyrosine tRNA (tRNA(Tyr)) and TyrRS from the crenarchaeon, Aeropyrum pernix, to investigate the molecular recognition mechanism. Kinetics for tyrosylation using in vitro transcript indicated that the discriminator base A73 and adjacent G72 in the acceptor stem are identity elements of tRNA(Tyr), whereas the C1 base and anticodon had modest roles as identity determinants. Intriguingly, in contrast to the identity element of eukaryotic/euryarchaeal TyrRSs, the first base-pair (C1-G72) of the acceptor stem was not essential in crenarchaeal TyrRS as a pair. Furthermore, A. pernix TyrRS mutants were constructed at positions Tyr39 and Asp172, which could form hydrogen bonds with the 4-hydroxyl group of l-tyrosine. The tyrosylation activities with the mutants resulted that Asp172 mutants completely abolished tyrosylation activity, whereas Tyr39 mutants had no effect on activity. Thus, crenarchaeal TyrRS appears to adopt different molecular recognition mechanism from other TyrRSs. PMID- 23024157 TI - Management of crush victims in mass disasters: highlights from recently published recommendations. AB - Crush syndrome is the second most common cause of death after earthquakes (the first most common is direct trauma). Many logistic problems with the treatment of patients with crush syndrome are due to chaotic disaster circumstances; consequently, medical and logistic recommendations on the treatment of crush victims are needed. In a joint initiative of the Renal Disaster Relief Task Force of the International Society of Nephrology and European Renal Best Practice, a work group of nephrologists, intensivists, surgeons, and logisticians with disaster experience or experts in guideline preparation collaborated to provide comprehensive information and recommendations on the management of crush casualties considering their occurrence with "epidemic" dimensions after mass disasters. The result is the monograph "Recommendations for the Management of Crush Victims in Mass Disasters", which may help provide effective health care to disaster victims with renal problems. This article discusses medical and logistic principles of the treatment of crush victims, both at the disaster field and on admission to hospitals, and guidance is described. The importance of early fluid administration even before extrication of the victims and avoidance of potassium containing solutions during the treatment of crush victims is underlined. Also, the logistic problems in treating crush casualties are emphasized. The most important aspects of the recently published recommendations are highlighted. PMID- 23024155 TI - Diagnosis, treatment, and follow-up of borderline ovarian tumors. AB - Borderline ovarian tumors represent a heterogeneous group of noninvasive tumors of uncertain malignant potential with characteristic histology. They occur in younger women, are present at an early stage, and have a favorable prognosis, but symptomatic recurrence and death may be found as long as 20 years after therapy in some patients. The molecular changes in borderline ovarian tumors indicate linkage of this disease to type I ovarian tumors (low-grade ovarian carcinomas). The pathological stage of disease and subclassification of extraovarian disease into invasive and noninvasive implants, together with the presence of postoperative macroscopic residual disease, appear to be the major predictor of recurrence and survival. However, it should be emphasized that the most important negative prognostic factor for recurrence is just the use of conservative surgery, but without any impact on patient survival because most recurrent diseases are of the borderline type-easily curable and with an excellent prognosis. Borderline tumors are difficult masses to correctly preoperatively diagnose using imaging methods because their macroscopic features may overlap with invasive and benign ovarian tumors. Over the past several decades, surgical therapy has shifted from a radical approach to more conservative treatment; however, oncologic safety must always be balanced. Follow-up is essential using routine ultrasound imaging, with special attention paid to the remaining ovary in conservatively treated patients. Current literature on this topic leads to a number of controversies that will be discussed thoroughly in this article, with the aim to provide recommendations for the clinical management of these patients. PMID- 23024158 TI - Differential diagnosis of lupus and primary membranous nephropathies by IgG subclass analysis. AB - BACKGROUND AND OBJECTIVES: Previous studies showed that the accuracy of IgG subclasses (ISs) in differentiating membranous lupus nephritis (MLN) from primary membranous nephropathy (PMN) is <80%. This study hypothesized that diagnostic accuracy of ISs would be increased if renal compartment measurements and decision tree analysis are applied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal biopsy specimens from 41 patients with MLN and 59 patients with PMN between October 2004 and March 2010 were examined, and immunofluorescence staining against IgG1, IgG2, IgG3, and IgG4 as well as C3, C1q, and C4 was evaluated in five different renal compartments (glomerular capillary walls, mesangium, tubules, interstitium, and blood vessels). From IS data, a decision tree to differentiate MLN from PMN was produced (IS decision tree) and its accuracy was compared with that of previous studies. Diagnostic accuracy of the IS decision tree was also compared with that of the complement decision tree as a reference. RESULTS: The demographic information and patterns of IS deposition were similar to those of previous studies. The IS decision tree had, as decision markers, IgG1 in the mesangium and IgG2 and IgG4 along the glomerular capillary wall. The IS decision tree showed higher accuracy (88%) than that of previous studies (<80%) and also that of the complement decision tree (81%). CONCLUSIONS: Accuracy of ISs was increased due to the study methods, but the same methodology was less effective using complement measurements. Appropriate data analysis may enhance diagnostic value, but the analysis alone cannot achieve the ideal diagnostic value. PMID- 23024159 TI - Comparison of symptom management strategies for pain, erectile dysfunction, and depression in patients receiving chronic hemodialysis: a cluster randomized effectiveness trial. AB - BACKGROUND AND OBJECTIVES: Pain, erectile dysfunction (ED), and depression are common yet frequently untreated in chronic hemodialysis patients. This study compared two management strategies for these symptoms in this patient population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Pain, ED, and depression were assessed monthly during an observation usual care phase. Patients were then randomized to 12-month participation in either a feedback arm in which these symptoms were assessed monthly, renal providers were informed of patients' symptoms, and treatment was left treatment at their discretion; or a nurse management arm in which symptoms were assessed monthly and trained nurses were used to evaluate patients and generate and facilitate the implementation of treatment recommendations. RESULTS: Of 288 patients enrolled into observation between January 1, 2009 and March 30, 2010, 220 (76%) were randomized. Compared with the feedback approach, the results (shown as Delta symptom score [95% confidence interval]) indicated that nurse management was not associated with improved pain (0.49 [-0.56, 1.54]), ED (0.20 [-0.55, 0.95]), or depression (0.32 [-0.94, 1.58]). Relative to their symptoms during observation, feedback patients experienced small, statistically significant improvements in pain (-0.98 [-1.67, 0.28]), ED (-0.98 [-1.54, -0.41]), and depression (-1.36 [-2.19, -0.54]), whereas nurse management patients experienced small, statistically significant improvements in ED (-0.78 [-1.41, -0.15]) and depression (-1.04 [-2.04, -0.04]). CONCLUSIONS: Compared with informing renal providers of their patients' pain, ED, and depression and leaving management at their discretion, a nurse-implemented management strategy does not improve these symptoms. Both approaches modestly reduced symptoms relative to usual care. PMID- 23024160 TI - Antiplatelet therapy in the management of cardiovascular disease in patients with CKD: what is the evidence? AB - Antiplatelet agents (APAs) are proven to reduce risk of major cardiovascular events in patients with cardiovascular disease and normal kidney function. With recent post hoc analyses of large trials questioning the safety and efficacy of APAs in CKD, major gaps exist in our understanding of platelet aggregability and the effects of APAs on thrombosis and bleeding in CKD. Clinical practice guidelines are ambiguous about use of such agents in CKD patients, because patients with moderate to advanced CKD were systematically excluded from clinical trials of APAs. CKD patients experience excessive rates of cardiovascular thrombotic events, yet paradoxically are at higher risk for major bleeding while receiving APAs. Furthermore, observational studies suggest that CKD patients may exhibit poor response to APAs. High residual platelet aggregability, as determined by inhibition of platelet aggregation, is associated with increased risk for cardiovascular events. In addition, metabolism of certain APAs may be altered in CKD patients. It is, therefore, imperative to explore the mechanisms responsible for poor response to APAs in CKD patients in order to use these drugs more safely and effectively. This review identifies the knowledge gaps and future trials needed to address those issues with the use of APAs in CKD patients. PMID- 23024161 TI - Relationship between GFR and albuminuria in stage 1 hypertension. AB - BACKGROUND AND OBJECTIVES: Whether glomerular hyperfiltration is implicated in the development of microalbuminuria in hypertension is not well known. This prospective study investigated the relationship between changes in GFR and microalbuminuria in hypertension. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study assessed 534 stage 1 hypertensive participants from the Hypertension and Ambulatory Recording Venetia Study (n=386 men) without microalbuminuria at baseline, who were recruited from 1990 to 1995 and followed for a median of 8.5 years. Mean age was 33.9+/-8.6 years and mean BP was 146.6+/-10.5/94.0+/-5.0 mmHg. Creatinine clearance and 24-hour urinary albumin were measured at study entry and end. Participants were defined as normofilterers (normo) or hyperfilterers (hyper) according to whether GFR was <150 or >=150 ml/min per 1.73 m(2), respectively. Participants were divided into four groups based on GFR changes from baseline to follow-up end: normo->normo (n=395), normo->hyper (n=31), hyper->hyper (n=61), and hyper->normo (n=47). RESULTS: Microalbuminuria progressively increased across the four groups and was 5.3% in normo->normo, 9.7% in normo->hyper, 16.4% in hyper->hyper, and 36.2% in hyper->normo (P<0.001). This association held true in a multivariable logistic regression in which several confounders, ambulatory BP, and other risk factors were taken into account (P<0.001). In particular, hyperfilterers whose GFR decreased to normal at study end had an adjusted odds ratio of 7.8 (95% confidence interval, 3.3-18.2) for development of microalbuminuria compared with participants with normal GFR throughout the study. CONCLUSIONS: These data support the hypothesis for a parabolic association between GFR and urinary albumin in the early stage of hypertension. PMID- 23024162 TI - Urinary albumin excretion patterns of patients with cast nephropathy and other monoclonal gammopathy-related kidney diseases. AB - BACKGROUND AND OBJECTIVES: Multiple myeloma is responsible for a wide variety of renal pathologies. Urinary protein and monoclonal spike cannot be used to diagnose cast nephropathy (CN). Because albuminuria is a hallmark of glomerular disease, this study evaluated the percentage of urinary albumin excretion (%UAE) as a tool to differentiate CN from Ig light chain amyloidosis (AL), light chain deposition disease (LCDD), and acute tubular necrosis (ATN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients were selected from the Renal Biopsy Database and the Dysproteinemia Database. Participants were excluded if laboratory data were missing within 1 week of the renal biopsy. The %UAE was obtained from urine protein electrophoresis. RESULTS: From 1992 to 2011, 260 patients were biopsied (177 with AL, 28 with LCDD, 43 with CN, and 12 with ATN). The %UAE for CN patients was significantly lower (7%) than for ATN (25%), LCDD (55%), and AL (70%) patients (P<0.001). Significant differences were also found in serum creatinine, serum albumin, free light chain ratio, total urine protein, and urine monoclonal spike; only the %UAE remained independently associated with CN in a logistic regression model (P<0.001). The area under the curve for the receiver operator characteristic curve for %UAE was 0.99. At <25%, the %UAE had a sensitivity of 0.98, specificity of 0.94, positive predictive value of 0.75, and negative predictive value of 0.99. CONCLUSIONS: This study showed that %UAE was significantly less in CN than the other three renal lesions and %UAE may thus be helpful in diagnosis of CN. PMID- 23024163 TI - Response to dietary oxalate after bariatric surgery. AB - BACKGROUND AND OBJECTIVES: Bariatric surgery (BS) may be associated with increased oxalate excretion and a higher risk of nephrolithiasis. This study aimed to investigate urinary abnormalities and responses to an acute oxalate load as an indirect assessment of the intestinal absorption of oxalate in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-four-hour urine specimens were collected from 61 patients a median of 48 months after BS (post BS) as well as from 30 morbidly obese (MO) participants; dietary information was obtained through 24-hour food recalls. An oral oxalate load test (OLT), consisting of 2-hour urine samples after overnight fasting and 2, 4, and 6 hours after consuming 375 mg of oxalate (spinach juice), was performed on 21 MO and 22 post-BS patients 12 months after BS. Ten post-BS patients also underwent OLT before surgery (pre-BS). RESULTS: There was a higher percentage of low urinary volume (<1.5 L/d) in post-BS versus MO (P<0.001). Hypocitraturia and hyperoxaluria (P=0.13 and P=0.36, respectively) were more frequent in BS versus MO patients. The OLT showed intragroup (P<0.001 for all periods versus baseline) and intergroup differences (P<0.001 for post-BS versus MO; P=0.03 for post-BS versus pre-BS). The total mean increment in oxaluria after 6 hours of load, expressed as area under the curve, was higher in both post-BS versus MO and in post-BS versus pre-BS participants (P<0.001 for both). CONCLUSIONS: The mean oxaluric response to an oxalate load is markedly elevated in post-bariatric surgery patients, suggesting that increased intestinal absorption of dietary oxalate is a predisposing mechanism for enteric hyperoxaluria. PMID- 23024164 TI - Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. AB - BACKGROUND AND OBJECTIVES: Increased risk of mortality in patients with CKD has been attributed to inflammation. However, the association between kidney function, albuminuria, and biomarkers of inflammation has not been examined in a large cohort of CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study measured the plasma levels of IL-1beta, IL-1 receptor antagonist (IL-1RA), IL-6, TNF-alpha, TGF-beta, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin in 3939 participants enrolled in the Chronic Renal Insufficiency Cohort study between June 2003 and September 2008. An inflammation score was established based on plasma levels of IL-1beta, IL-6, TNF-alpha, hs CRP, and fibrinogen. Estimated GFR (eGFR) and serum cystatin C were used as measures of kidney function. Albuminuria was quantitated by urine albumin to creatinine ratio (UACR). RESULTS: Plasma levels of IL-1beta, IL-1RA, IL-6, TNF alpha, hs-CRP, and fibrinogen were higher among participants with lower levels of eGFR. Inflammation score was higher among those with lower eGFR and higher UACR. In regression analysis adjusted for multiple covariates, eGFR, cystatin C, and UACR were strongly associated with fibrinogen, serum albumin, IL-6, and TNF alpha. Each unit increase in eGFR, cystatin C, and UACR was associated with a 1.2% (95% confidence interval, -1.4, -1), 64.9% (56.8, 73.3) and 0.6% (0.4, 0.8) change in IL-6, respectively (P<0.001). CONCLUSIONS: Biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria. PMID- 23024165 TI - Searching for uremic toxins. AB - Treatment of uremia by hemodialysis has become widespread over the last 40 years and has improved substantially over that time. However, people treated with this modality continue to suffer from multiple disabilities. Retention of organic solutes, especially those poorly removed by hemodialysis, likely contributes to these disabilities. Certain classes of solutes are removed less well than urea by hemodialysis and by the normal kidney. These include protein-bound solutes, relatively large solutes, sequestered compounds, and substances removed at rates higher than urea by the normal kidney. Several strategies could be used to discover the solutes responsible for residual morbidities in standardly dialyzed people. Rather than continue to focus only on urea removal as an index for dialysis adequacy, finding additional approaches for removing toxic solutes with characteristics different from urea (and the similar small solutes it represents) is a desirable and feasible goal. PMID- 23024167 TI - Three common beliefs that are impediments to injury prevention. AB - Three common beliefs that are impediments to injury prevention are: (1) the optimistic belief that nothing bad is going to happen, especially to me ('it will never happen to me'); (2) the fatalistic belief that, if something bad does happen, nothing could have been done to prevent it ('accidents happen'); and (3) the moralistic belief that if the injury happens to someone else (eg, you), you probably deserved it--so do not blame me or expect that I should have done anything to help prevent it ('blaming the victim'). On-line blogs and comments are used to illustrate these beliefs. Counter-arguments are discussed. PMID- 23024166 TI - Attitudes toward strategies to increase organ donation: views of the general public and health professionals. AB - BACKGROUND AND OBJECTIVE: The acceptability of financial incentives for organ donation is contentious. This study sought to determine (1) the acceptability of expense reimbursement or financial incentives by the general public, health professionals involved with organ donation and transplantation, and those with or affected by kidney disease and (2) for the public, whether financial incentives would alter their willingness to consider donation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Web-based survey administered to members of the Canadian public, health professionals, and people with or affected by kidney disease asking questions regarding acceptability of strategies to increase living and deceased kidney donation and willingness to donate a kidney under various financial incentives. RESULTS: Responses were collected from 2004 members of the Canadian public October 11-18, 2011; responses from health professionals (n=339) and people with or affected by kidney disease (n=268) were collected during a 4 week period commencing October 11, 2011. Acceptability of one or more financial incentives to increase deceased and living donation was noted in >70% and 40% of all groups, respectively. Support for monetary payment for living donors was 45%, 14%, and 27% for the public, health professionals, and people with or affected by kidney disease, respectively. Overall, reimbursement of funeral expenses for deceased donors and a tax break for living donors were the most acceptable. CONCLUSION: The general public views regulated financial incentives for living and deceased donation to be acceptable. Future research needs to examine the impact of financial incentives on rates of deceased and living donors. PMID- 23024168 TI - Multidisciplinary efforts toward sustained road safety benefits: integrating place-based and people-based safety analyses. AB - RELEVANT LOCAL INJURY EPIDEMIOLOGY: In Hong Kong, there were, on average, about 19 596 traffic crashes involving 157 deaths and 21 106 injured persons each year between 2006 and 2011. Scientific analyses were conducted by geographers and engineers primarily using the police crash database. Medical professionals have been analysing road traffic injury data from hospital discharge summaries. Moreover, community leaders have been trying to promote local safe communities. BEST PRACTICES: This paper describes the effort of a multidisciplinary team to address road safety problems and to sustain road safety benefits through a public health approach. The multidisciplinary team comprised a geographer, an engineer, medical professionals and community leaders. The project covered four tasks, namely data integration, identification of hazardous road locations, crash analysis and engineering study, and knowledge exchange through various activities involving a WHO-designated local safe community. IMPLEMENTATION: The crash and hospital databases for a district in Hong Kong with 500 000 population were integrated. Based on the integrated database, the public health and people-based approach was adopted to identify hazardous road locations--hot zones--using geographical information systems. Specific hot zones having strong patterns of common factors were considered as treatable locations with a combination of low cost remedial measures. The benefits of the project are sustained through various activities engaging the general public and major stakeholders. RESEARCH AGENDA: More research should be conducted on how institutional support, scientific research and community involvement can be fruitfully combined to achieve the ultimate goal of sustained road safety benefits for people at the community level. PMID- 23024169 TI - Risk factors for burns at home in Kurdish preschool children: a case-control study. AB - BACKGROUND: It is globally reported that young children are at a higher risk of burns but little is known about the individual risk factors. This study was undertaken in 2008 to investigate factors associated with burn injuries in children aged 0-5 years. METHODS: This was a case-control study with cases recruited prospectively from children attending hospital for a new burn injury and controls recruited from children admitted for other conditions. RESULTS: A total of 248 cases and 248 controls were recruited. Cases included scalds (79%), contact burns (17%) and flame injuries (4%). Burns were most commonly caused by tea utensils (42%) and kerosene stoves (36%). Multivariable analyses found that a poor living standard (OR 5.4, 95% CI 2.6 to 11.7), having a child with a higher activity score (OR 5.3, 95% CI 3.4 to 8.5), having a history of burns in other family members (OR 2.8, 95% CI 1.5 to 5.2) and a higher number of home hazards (OR for a one unit increase in hazards score 1.32, 95% CI 1.02 to 1.70) were all associated with a significant increase in the odds of a burn injury. The presence of a second carer (OR 0.42, 95% CI 0.2 to 0.7) and having disability (OR 0.14, 95% CI 0.03 to 0.6) were protective factors. CONCLUSIONS: This information about risk factors for burn injuries can be used to target preventive interventions towards families at the greatest risk of injury. PMID- 23024170 TI - Prescription drugs, drugged driving and per se laws. PMID- 23024171 TI - Comparing apples with apples? Abusive head trauma, drowning and LSVROs. PMID- 23024172 TI - Price and tobacco marketing strategy: lessons from 'dark' markets and implications for the WHO Framework Convention on Tobacco Control. PMID- 23024174 TI - Proceedings of the 13th coordination and planning meeting of the WHO-REMPAN: radiation emergency medical preparedness and assistance network, Nagasaki, Japan, 16-18 February 2011. PMID- 23024175 TI - Successful treatment of localised radiation lesions in rats and humans by mesenchymal stem cell transplantation. AB - Transplantation of mesenchymal stem cells (MSCs), at early and later stages after local exposure of rats to 140 Gy 90Sr/90Y beta radiation, was found to stimulate recovery of damaged skin. The area of local radiation injuries (LRIs) and accelerated healing of radiation ulcers was obtained. Clinical evolution showed the high efficiency of the transplantations of autologous MSCs for the treatment of deep beam ulcers, usually refractive to standard conservative treatment. Analogous to our results in the rats the authors obtained promising results with the application of MSCs for the treatment of severe LRIs in two human patients. Their radiation ulcers showed complete healing after stem cell application. Thus, further developments should determine the best possible conditions for MSC use in LRI treatment. PMID- 23024173 TI - TCF/LEFs and Wnt signaling in the nucleus. AB - T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors are the major end point mediators of Wnt/Wingless signaling throughout metazoans. TCF/LEFs are multifunctional proteins that use their sequence-specific DNA binding and context-dependent interactions to specify which genes will be regulated by Wnts. Much of the work to define their actions has focused on their ability to repress target gene expression when Wnt signals are absent and to recruit beta-catenin to target genes for activation when Wnts are present. Recent advances have highlighted how these on/off actions are regulated by Wnt signals and stabilized beta-catenin. In contrast to invertebrates, which typically contain one TCF/LEF protein that can both activate and repress Wnt targets, gene duplication and isoform complexity of the family in vertebrates have led to specialization, in which individual TCF/LEF isoforms have distinct activities. PMID- 23024176 TI - In vitro perturbations of targets in cancer hallmark processes predict rodent chemical carcinogenesis. AB - Thousands of untested chemicals in the environment require efficient characterization of carcinogenic potential in humans. A proposed solution is rapid testing of chemicals using in vitro high-throughput screening (HTS) assays for targets in pathways linked to disease processes to build models for priority setting and further testing. We describe a model for predicting rodent carcinogenicity based on HTS data from 292 chemicals tested in 672 assays mapping to 455 genes. All data come from the EPA ToxCast project. The model was trained on a subset of 232 chemicals with in vivo rodent carcinogenicity data in the Toxicity Reference Database (ToxRefDB). Individual HTS assays strongly associated with rodent cancers in ToxRefDB were linked to genes, pathways, and hallmark processes documented to be involved in tumor biology and cancer progression. Rodent liver cancer endpoints were linked to well-documented pathways such as peroxisome proliferator-activated receptor signaling and TP53 and novel targets such as PDE5A and PLAUR. Cancer hallmark genes associated with rodent thyroid tumors were found to be linked to human thyroid tumors and autoimmune thyroid disease. A model was developed in which these genes/pathways function as hypothetical enhancers or promoters of rat thyroid tumors, acting secondary to the key initiating event of thyroid hormone disruption. A simple scoring function was generated to identify chemicals with significant in vitro evidence that was predictive of in vivo carcinogenicity in different rat tissues and organs. This scoring function was applied to an external test set of 33 compounds with carcinogenicity classifications from the EPA's Office of Pesticide Programs and successfully (p = 0.024) differentiated between chemicals classified as "possible"/"probable"/"likely" carcinogens and those designated as "not likely" or with "evidence of noncarcinogenicity." This model represents a chemical carcinogenicity prioritization tool supporting targeted testing and functional validation of cancer pathways. PMID- 23024177 TI - Molecular parallels between neural and vascular development. AB - The human central nervous system (CNS) features a network of ~400 miles of blood vessels that receives >20% of the body's cardiac output and uses most of its blood glucose. Many human diseases, including stroke, retinopathy, and cancer, are associated with the biology of CNS blood vessels. These vessels originate from extrinsic cell populations, including endothelial cells and pericytes that colonize the CNS and interact with glia and neurons to establish the blood-brain barrier and control cerebrovascular exchanges. Neurovascular interactions also play important roles in adult neurogenic niches, which harbor a unique population of neural stem cells that are intimately associated with blood vessels. We here review the cellular and molecular mechanisms required to establish the CNS vascular network, with a special focus on neurovascular interactions and the functions of vascular endothelial growth factors. PMID- 23024179 TI - Optimization of the dynamic, Gd-EOB-DTPA-enhanced MRI of the liver: the effect of the injection rate. AB - BACKGROUND: Tissue-specific gadolinium-based contrast agents such as Gd-BOPTA, Gd EOB-DTPA are increasingly used for liver imaging. Despite the added value of the hepatobiliary phase a proper arterial phase is still critical, especially in patients with chronic liver diseases. So far, there are limited data in the literature about the effect of the injection speed of Gd-EOB-DTPA in liver and vessel enhancement. PURPOSE: To evaluate the effect of injection rate on the enhancement of liver parenchyma and vasculature in Gd-EOB-DTPA-enhanced liver MRI. MATERIAL AND METHODS: Eighty patients who underwent Gd-EOB-DTPA-enhanced liver MRI (1.5T multi-channel MR-system) were retrospectively evaluated. We used a Care Bolus technique with an injection rate of 2 mL/s in group 1 (n = 40) and a Care Bolus technique with an injection rate of 1 mL/s in group 2 (n = 40) to determine the start of the arterial-dominant phase. Signal intensities were measured in vascular structures and liver parenchyma. Signal-to-noise-ratio (SNR), SNR increase (SNRi), and percentage enhancement (PE) were calculated and compared by a students t-test. RESULTS: The SNR, SNRi, and PE of the aorta in the arterial phase were significantly higher in group 2 in comparison to group 1 (P = 0.007, P = 0.0043, and P < 0.001, respectively). There were no significant differences concerning the SNR, SNRi, or PE of the portal vein and the normal liver parenchyma between both groups at all time points. CONCLUSION: The study shows that a lower injection rate of 1 mL/s enables a higher enhancement in the aorta in the arterial phase compared with Gd-EOB-DTPA-enhanced MRI with the more commonly used injection rate of 2 mL/s. PMID- 23024180 TI - The necessity of follow-up for radiation skin injuries in patients after percutaneous coronary interventions: radiation skin injuries will often be overlooked clinically. AB - BACKGROUND: Percutaneous coronary intervention (PCI) offers great benefit that could improve a patient's quality of life. However, numerous case reports of patient radiation injury resulting from PCI are being published, these reports likely represent a small fraction of the actual cases. PURPOSE: To demonstrate the appropriate duration of patient follow-up after PCI to identify radiation effects. MATERIAL AND METHODS: We evaluated 400 consecutive PCIs. The radiation dose (dose-area product, cumulative dose, maximum skin dose), number of cine runs, and fluoroscopic time were recorded for all patients. The skin on the patients' backs was reviewed periodically after PCI. RESULTS: Radiation skin effects occurred in six patients from PCI of the right coronary artery in chronic total occlusion (CTO) patients (mild erythema; occurrence rate 1.5%). Skin injury in two patients appeared in cycles. In most cases, erythema was vividly seen at 4 weeks after PCI. CONCLUSION: Careful observation for skin injury is needed. At a few days following PCI, early erythema can be detected through careful observation by well-trained staff. At 7-10 days after PCI, most erythematous pigmentation can be detected. At 4 weeks after PCI, most skin erythema appears clearly, however, some cases of skin erythema occur without back pain. After that, follow-up every 6 months is needed to detect the reappearance of erythema. PMID- 23024178 TI - Drosophila as a model to study mitochondrial dysfunction in Parkinson's disease. AB - Identification of single gene mutations that lead to inherited forms of Parkinson's disease (PD) has provided strong impetus for the use of animal models to study normal functions of these "PD genes" and the cellular defects that occur in the presence of pathogenic PD mutations. Drosophila has emerged as an effective model in PD-related gene studies. Important insights into the cellular basis of PD pathogenesis include the demonstration that two PD genes, PINK1 and parkin, function in a common pathway, with PINK1 positively regulating parkin, to control mitochondrial integrity and maintenance. This is accomplished through regulation of mitochondrial fission/fusion dynamics. Subsequent observations in both fly and mammalian systems showed that these proteins are important for sensing mitochondrial damage and recruiting damaged mitochondria to the quality control machinery for subsequent removal. Here, I begin by reviewing the opportunities and challenges to understanding PD pathogenesis and developing new therapies. I then review the unique tools and technologies available in Drosophila for studying PD genes. Subsequently, I review lessons that we have learned from studies in Drosophila, emphasizing the PINK1/parkin pathway, as well as studies of DJ-1 and Omi/HtrA2, two additional genes associated with PD implicated in regulation of mitochondrial function. I end by discussing how Drosophila can be used to further probe the functions of PINK1 and parkin, and the regulation of mitochondrial quality more generally. In additional to PD, defects in mitochondrial function are associated with normal aging and with many diseases of aging. Thus, insights gained from the studies of mitochondrial dynamics and quality control in Drosophila are likely to be of general significance. PMID- 23024181 TI - Synthetic MRI of the brain in a clinical setting. AB - BACKGROUND: Conventional magnetic resonance imaging (MRI) has relatively long scan times for routine examinations, and the signal intensity of the images is related to the specific MR scanner settings. Due to scanner imperfections and automatic optimizations, it is impossible to compare images in terms of absolute image intensity. Synthetic MRI, a method to generate conventional images based on MR quantification, potentially both decreases examination time and enables quantitative measurements. PURPOSE: To evaluate synthetic MRI of the brain in a clinical setting by assessment of the contrast, the contrast-to-noise ratio (CNR), and the diagnostic quality compared with conventional MR images. MATERIAL AND METHODS: Twenty-two patients had synthetic imaging added to their clinical MR examination. In each patient, 12 regions of interest were placed in the brain images to measure contrast and CNR. Furthermore, general image quality, probable diagnosis, and lesion conspicuity were investigated. RESULTS: Synthetic T1 weighted turbo spin echo and T2-weighted turbo spin echo images had higher contrast but also a higher level of noise, resulting in a similar CNR compared with conventional images. Synthetic T2-weighted FLAIR images had lower contrast and a higher level of noise, which led to a lower CNR. Synthetic images were generally assessed to be of inferior image quality, but agreed with the clinical diagnosis to the same extent as the conventional images. Lesion conspicuity was higher in the synthetic T1-weighted images, which also had a better agreement with the clinical diagnoses than the conventional T1-weighted images. CONCLUSION: Synthetic MR can potentially shorten the MR examination time. Even though the image quality is perceived to be inferior, synthetic images agreed with the clinical diagnosis to the same extent as the conventional images in this study. PMID- 23024182 TI - An MBoC favorite: role of GTP hydrolysis in microtubule dynamics: information from a slowly hydrolyzable analogue, GMPCPP. PMID- 23024183 TI - Reconfiguring the emergency and urgent care workforce: mixed methods study of skills and the everyday work of non-clinical call-handlers in the NHS. AB - OBJECTIVES: To examine the skills and expertise required and used by non-clinical call-handlers doing telephone triage and assessment, supported by a computer decision support system (CDSS) in urgent and emergency care services. METHODS: Comparative case study of three different English emergency and urgent care services. Data consisted of nearly 500 hours of non-participant observation, 61 semi-structured interviews with health service staff, documentary analysis, and a survey of 106 call-handlers. RESULTS: Communication skills and 'allowing the CDSS to drive the assessment' are viewed by the CDSS developers and staff as key competencies for call-handling. Call-handlers demonstrated high levels of experience, skills and expertise in using the CDSS. These workers are often portrayed simply as 'trained users' of technology, but they used a broader set of skills including team work, flexibility and 'translation'. Call-handlers develop a 'pseudo-clinical' expertise and draw upon their experiential knowledge to bring the CDSS into everyday use. CONCLUSIONS: Clinical assessment and triage by non clinical staff supported by a CDSS represents a major change in urgent and emergency care delivery, warranting a detailed examination of call-handlers' skills and expertise. We found that this work appears to have more in common with clinical work and expertise than with other call-centre work that it superficially resembles. Recognizing the range of skills call-handlers demonstrate and developing a better understanding of this should be incorporated into the training for, and management of, emergency and urgent care call handling. PMID- 23024184 TI - The pathogenesis of osteoarthritis involves bone, cartilage and synovial inflammation: may estrogen be a magic bullet? AB - The female predominance of polyarticular osteoarthritis (OA), and in particular the marked increase of OA in women after the menopause points to a likely involvement of female sex hormones in the maintenance of cartilage homeostasis. This perception has inspired many research groups to investigate the role of estrogens in the modulation of cartilage homeostasis with the ultimate aim to clarify whether estrogen replacement therapy (ERT) could provide benefits in preventing the rapid rise in the prevalence of OA in postmenopausal women. The effects of ERT and selective estrogen-receptor modulators on the joint in various experimental models have been investigated. Clinically, the effects of estrogens have been evaluated by post hoc analysis in clinical trials using biochemical markers of cartilage and bone degradation. Lastly, the Women's Health Initiative trial (WHI) investigated the effects of estrogens on the joint and joint replacements. Even though the exact mode of action still needs to be elucidated, the effect involves both direct and indirect mechanisms on the whole joint pathophysiology. Several animal models have demonstrated structural benefits of estrogens, as well as significant effects on joint inflammation. This is in complete alignment with clinical data using biochemical markers of joint degradation which demonstrated approximately 50% inhibition of cartilage destruction. These finding were recently validated in WHI, where women taking estrogens had significantly less joint replacement. In conclusion, the pleiotropic effect of estrogens on several different tissues may match the complicated aetiology of OA in some important aspects. PMID- 23024185 TI - Interaction between selection and biased gene conversion in mammalian protein coding sequence evolution revealed by a phylogenetic covariance analysis. AB - According to the nearly-neutral model, variation in long-term effective population size among species should result in correlated variation in the ratio of nonsynonymous over synonymous substitution rates (dN/dS). Previous empirical investigations in mammals have been consistent with this prediction, suggesting an important role for nearly-neutral effects on protein-coding sequence evolution. GC-biased gene conversion (gBGC), on the other hand, is increasingly recognized as a major evolutionary force shaping genome nucleotide composition. When sufficiently strong compared with random drift, gBGC may significantly interfere with a nearly-neutral regime and impact dN/dS in a complex manner. Here, we investigate the phylogenetic correlations between dN/dS, the equilibrium GC composition (GC*), and several life-history and karyotypic traits in placental mammals. We show that the equilibrium GC composition decreases with body mass and increases with the number of chromosomes, suggesting a modulation of the strength of biased gene conversion due to changes in effective population size and genome wide recombination rate. The variation in dN/dS is complex and only partially fits the prediction of the nearly-neutral theory. However, specifically restricting estimation of the dN/dS ratio on GC-conservative transversions, which are immune from gBGC, results in correlations that are more compatible with a nearly-neutral interpretation. Our investigation indicates the presence of complex interactions between selection and biased gene conversion and suggests that further mechanistic development is warranted, to tease out mutation, selection, drift, and conversion. PMID- 23024186 TI - Human demographic processes and genetic variation as revealed by mtDNA simulations. AB - Humans' ability for rapid dispersal and adaptation has allowed us to colonize diverse geographic and climatic regions of the planet, creating a complex evolutionary history. This complexity can be understood, at least partially, by modeling the underlying demographic parameters in the evolutionary process. In this study, we analyze a model of human evolution in which population size, gene flow (GF), and time are varied. Specifically, we simulate mitochondrial DNA for 42 demographic scenarios, represented by 42 parameter combinations, to describe the initial dispersal of modern humans out of Africa. The analyses include three values for colonization size (CS; 1%, 10%, and 30% of the African population), seven values for rate of GF (10(-6)-0.5), and two values for time of colonization (50,000 and 100,000 years ago). We then estimate summary statistics for the simulated data sets to calculate the percent of explained variation by each parameter and to identify which parameter combinations generate distinct differences in genetic variation, that is, which demographic scenarios can be distinguished from each other. On the basis of these results, we make recommendations about which summary statistics to use according to the parameter of interest. Our results show that CS, GF, and their interaction have the largest effect on genetic variation under our model of human evolution. Comparison with empirical data suggests that 1% of the existing African mitochondrial genetic variation left and colonized the rest of the world (i.e., CS = 1%) and bidirectional GF continued at a level of ~10 individuals per generation (i.e., GF = 10(-3)) after the initial colonization. Our study serves as a model to bridge the gap between the use of simulations for theoretical population genetics and empirical data analysis such as approximate bayesian computation approaches and is, thus, applicable to the study of molecular evolution in any organism. PMID- 23024187 TI - Phylogenetic estimation of timescales using ancient DNA: the effects of temporal sampling scheme and uncertainty in sample ages. AB - In recent years, ancient DNA has increasingly been used for estimating molecular timescales, particularly in studies of substitution rates and demographic histories. Molecular clocks can be calibrated using temporal information from ancient DNA sequences. This information comes from the ages of the ancient samples, which can be estimated by radiocarbon dating the source material or by dating the layers in which the material was deposited. Both methods involve sources of uncertainty. The performance of bayesian phylogenetic inference depends on the information content of the data set, which includes variation in the DNA sequences and the structure of the sample ages. Various sources of estimation error can reduce our ability to estimate rates and timescales accurately and precisely. We investigated the impact of sample-dating uncertainties on the estimation of evolutionary timescale parameters using the software BEAST. Our analyses involved 11 published data sets and focused on estimates of substitution rate and root age. We show that, provided that samples have been accurately dated and have a broad temporal span, it might be unnecessary to account for sample-dating uncertainty in Bayesian phylogenetic analyses of ancient DNA. We also investigated the sample size and temporal span of the ancient DNA sequences needed to estimate phylogenetic timescales reliably. Our results show that the range of sample ages plays a crucial role in determining the quality of the results but that accurate and precise phylogenetic estimates of timescales can be made even with only a few ancient sequences. These findings have important practical consequences for studies of molecular rates, timescales, and population dynamics. PMID- 23024188 TI - Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. AB - Neoplastic cells recruit fibroblasts through various growth factors and cytokines. These "cancer-associated fibroblasts" (CAF) actively interact with neoplastic cells and form a myofibroblastic microenvironment that promotes cancer growth and survival and supports malignancy. Several products of their paracrine signaling repertoire have been recognized as tumor growth and metastasis regulators. However, tumor-promoting cell signaling is not the only reason that makes CAFs key components of the "tumor microenvironment," as CAFs affect both the architecture and growth mechanics of the developing tumor. CAFs participate in the remodeling of peritumoral stroma, which is a prerequisite of neoplastic cell invasion, expansion, and metastasis. CAFs are not present peritumorally as individual cells but they act orchestrated to fully deploy a desmoplastic program, characterized by "syncytial" (or collective) configuration and altered cell adhesion properties. Such myofibroblastic cohorts are reminiscent of those encountered in wound-healing processes. The view of "cancer as a wound that does not heal" led to useful comparisons between wound healing and tumorigenesis and expanded our knowledge of the role of CAF cohorts in cancer. In this integrative model of cancer invasion and metastasis, we propose that the CAF-supported microenvironment has a dual tumor-promoting role. Not only does it provide essential signals for cancer cell dedifferentiation, proliferation, and survival but it also facilitates cancer cell local invasion and metastatic phenomena. PMID- 23024189 TI - Evidence of a functional estrogen receptor in parathyroid adenomas. AB - CONTEXT: Primary hyperparathyroidism (PHPT) is most frequently present in postmenopausal women. Although the involvement of estrogen has been suggested, current literature indicates that parathyroid tumors are estrogen receptor (ER) alpha negative. OBJECTIVE: The aim of the study was to evaluate the expression of ERs and their putative function in parathyroid tumors. DESIGN: A panel of 37 parathyroid tumors was analyzed for expression and promoter methylation of the ESR1 and ESR2 genes as well as expression of the ERalpha and ERbeta1/ERbeta2 proteins. Transcriptome changes in primary cultures of parathyroid adenoma cells after treatment with the selective ERbeta1 agonist diarylpropionitrile (DPN) and 4-hydroxytamoxifen were identified using next-generation RNA sequencing. RESULTS: Immunohistochemistry revealed very low expression of ERalpha, whereas all informative tumors expressed ERbeta1 (n = 35) and ERbeta2 (n = 34). Decreased nuclear staining intensity and mosaic pattern of positive and negative nuclei of ERbeta1 were significantly associated with larger tumor size. Tumor ESR2 levels were significantly higher in female vs. male cases. In cultured cells, significantly increased numbers of genes with modified expression were detected after 48 h, compared to 24-h treatments with DPN or 4-hydroxytamoxifen, including the parathyroid-related genes CASR, VDR, JUN, CALR, and ORAI2. Bioinformatic analysis of transcriptome changes after DPN treatment revealed significant enrichment in gene sets coupled to ER activation, and a highly significant similarity to tumor cells undergoing apoptosis. CONCLUSIONS: Parathyroid tumors express ERbeta1 and ERbeta2. Transcriptional changes after ERbeta1 activation and correlation to clinical features point to a role of estrogen signaling in parathyroid function and disease. PMID- 23024192 TI - UK acid attacks. PMID- 23024190 TI - Zoledronic acid versus alendronate for the prevention of bone loss after heart or liver transplantation. AB - CONTEXT: The first year after transplantation is characterized by rapid bone loss. OBJECTIVE: The aim of this study was to compare zoledronic acid (zoledronate) and alendronate for prevention of transplantation bone loss. DESIGN AND SETTING: A randomized clinical trial was conducted at a transplantation center. PATIENTS: The study included 84 adults undergoing heart or liver transplantation and a concurrently transplanted, nonrandomized reference group of 27 adults with T scores greater than -1.5. INTERVENTIONS: Alendronate (70 mg weekly for 12 months) or one 5-mg infusion of zoledronate were both initiated 26 +/- 8 d after transplantation. MAIN OUTCOME MEASURES: The primary outcome was total hip bone mineral density (BMD) 1 yr after transplantation. Secondary outcomes included femoral neck and lumbar spine BMD and serum C-telopeptide, a bone resorption marker. RESULTS: In the reference group, BMD declined at the spine and hip (P < 0.001). In the randomized groups, hip BMD remained stable. Spine BMD increased in the zoledronate group and did not change in the alendronate group; at 12 months, the 2.2% difference between groups (95% confidence interval, 0.6 to 3.9%; P = 0.009) favored zoledronate. In heart transplant patients, spine BMD declined in the alendronate and increased in the zoledronate group (-3.0 vs. +1.6%, respectively; between-group difference, 4.2%; 95% confidence interval, 2.1 to 6.3%; P < 0.001). In liver transplant patients, spine BMD increased comparably in both groups. Twelve-month C-telopeptide was lower in the zoledronate group than in the alendronate group (79 vs. 49%; P = 0.04). CONCLUSIONS: One 5-mg infusion of zoledronate and weekly alendronate prevent bone loss at the hip and, in liver transplant patients, increase spine BMD. In heart transplant patients, spine bone BMD remained stable with zoledronate but decreased with alendronate. PMID- 23024193 TI - Coroners and medical examiners: mutualism, commensalism or parasitism? AB - The Coroners and Justice Act 2009 includes provisions for reform of the certification of death and the introduction of "Medical Examiners", who will scrutinise the certification of every death that is not referred to the Coroner for investigation. When these changes are implemented, Coroners and Medical Examiners will have to work closely together. But the boundaries between the two roles are not perfectly defined. Will they work together in synergy, or will they interact unwillingly and abrasively? It is clear which approach will be best for the bereaved and for society, but it is less clear what will actually happen. Medical Examiners will be led by a new Chief Medical Examiner, and Coroners will have a Chief Coroner. But these individuals will have limited powers to oblige Coroners and Medical Examiners to collaborate. It seems inevitable that there will be large variations in practice, at least initially. PMID- 23024191 TI - Glitazones exert multiple effects on beta-cell stimulus-secretion coupling. AB - Earlier studies suggest that glitazones exert beneficial effects in patients with type 2 diabetes by directly affecting insulin secretion of beta-cells, besides improving the effectiveness of insulin in peripheral tissues. The effects of glitazones on stimulus-secretion coupling (SSC) are poorly understood. We tested the influence of troglitazone and pioglitazone on different parameters of SSC, including insulin secretion (radioimmunoassay), cell membrane potential, various ion currents (patch-clamp), mitochondrial membrane potential (DeltaPsi), and cytosolic Ca(2+) concentration (fluorescence). Troglitazone exerted stimulatory, inhibitory, or no effects on insulin secretion depending on the drug and glucose concentration. It depolarized the DeltaPsi, thus lowering ATP production, which resulted in opening of ATP-dependent K(+) channels (K(ATP) channels) and reduced insulin secretion. However, it also exerted direct inhibitory effects on K(ATP) channels that can explain enhanced insulin secretion. Troglitazone also inhibited the currents through voltage-dependent Ca(2+) and K(+) channels. Pioglitazone was less effective than troglitazone on all parameters tested. The effects of both glitazones were markedly reduced in the presence of bovine serum albumin. Glitazones exert multiple actions on beta-cell SSC that have to be considered as undesired side effects because the influence of these compounds on beta-cells is not controllable. The final effect on insulin secretion depends on many parameters, including the actual glucose and drug concentration, protein binding of the drug, and the drug by itself. Troglitazone and pioglitazone differ in their influence on SSC. It can be assumed that the effects of pioglitazone on beta-cells are negligible under in vivo conditions. PMID- 23024194 TI - Case study of sudden cardiac death caused by lypomatous hypertrophy of the interatrial septum. AB - Lipomatous hypertrophy of the interatrial septum (LHIS) is a benign cardiac mass characterized by fat accumulation in the interatrial septum. It may represent an incidental autopsy finding or may be associated with atrial arrhythmias, obstructive symptoms or sudden death. The case described here is a peculiar case of sudden death secondary to LHIS. PMID- 23024195 TI - Medico-legal claims following amputations in the UK and Ireland. AB - The causes and outcomes of medico-legal claims following amputation were evaluated. A retrospective analysis of the experience of a consultant surgeon acting as an expert witness within the United Kingdom and Ireland (1990-2010). There were 154 claims referred for an opinion of which 53 related to female patients. The median age was 67 (range, 20-101) years. Forty nine (32%) of the patients were known diabetics. Seventy-eight (51%) of the claims actually arose following a medically expected amputation, i.e. an amputation that was not preventable or due to negligence. The other common causes of claims were a delay in the diagnosis and or treatment of arterial ischaemia (34%), and following iatrogenic injuries (5%). Eleven of the claims are still ongoing, 3 went to trial, 52 (34%) were settled out of court and 83 (54%) were discontinued after the claimants were advised that they were unlikely to win their case. Disclosed settlement amounts are reported. Delays in the diagnosis and or treatment of arterial ischaemia were the commonest reasons that a claimant was successful. Half of claims did not proceed but were not without financial and psychological costs. PMID- 23024196 TI - Weak laws against acid attacks on women: an Indian perspective. AB - Acid attacks, especially on women, have seen an alarming growth in India over the last decade. While these attacks can be attributed to various factors such as the social weakness of women in a male-dominated society, the situation is exacerbated by the general neglect of the lawmakers. As acid is inexpensive and easily available, it serves as an ideal weapon for the perpetrators. Further, as this offence is bailable in certain situations, the punishment does not act as a sufficient deterrent in most cases. This paper describes the horrendous effects that acid attacks have on the victims physically, psychologically and socially. It also examines the contemporary laws governing acid attacks on victims and offenders. Ideas for a better legal approach will also be examined with special reference to acid attacks as a crime, and the validity of specific legal provisions for female victims. PMID- 23024204 TI - Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. AB - Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9 triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1. PMID- 23024205 TI - Thioredoxin reductase type C (NTRC) orchestrates enhanced thermotolerance to Arabidopsis by its redox-dependent holdase chaperone function. AB - Genevestigator analysis has indicated heat shock induction of transcripts for NADPH-thioredoxin reductase, type C (NTRC) in the light. Here we show overexpression of NTRC in Arabidopsis (NTRC degrees (E)) resulting in enhanced tolerance to heat shock, whereas NTRC knockout mutant plants (ntrc1) exhibit a temperature sensitive phenotype. To investigate the underlying mechanism of this phenotype, we analyzed the protein's biochemical properties and protein structure. NTRC assembles into homopolymeric structures of varying complexity with functions as a disulfide reductase, a foldase chaperone, and as a holdase chaperone. The multiple functions of NTRC are closely correlated with protein structure. Complexes of higher molecular weight (HMW) showed stronger activity as a holdase chaperone, while low molecular weight (LMW) species exhibited weaker holdase chaperone activity but stronger disulfide reductase and foldase chaperone activities. Heat shock converted LMW proteins into HMW complexes. Mutations of the two active site Cys residues of NTRC into Ser (C217/454S-NTRC) led to a complete inactivation of its disulfide reductase and foldase chaperone functions, but conferred only a slight decrease in its holdase chaperone function. The overexpression of the mutated C217/454S-NTRC provided Arabidopsis with a similar degree of thermotolerance compared with that of NTRC degrees (E) plants. However, after prolonged incubation under heat shock, NTRC degrees (E) plants tolerated the stress to a higher degree than C217/454S-NTRC degrees (E) plants. The results suggest that the heat shock-mediated holdase chaperone function of NTRC is responsible for the increased thermotolerance of Arabidopsis and the activity is significantly supported by NADPH. PMID- 23024206 TI - Nutrient sensing in plants. PMID- 23024207 TI - Hairpin priming is better suited than in vitro polyadenylation to generate cDNA for plant miRNA qPCR. PMID- 23024208 TI - Genes that respond to H2O2 are also evoked under light in Arabidopsis. PMID- 23024209 TI - The genetic dissection of a short-term response to low CO(2) supports the possibility for peroxide-mediated decarboxylation of photorespiratory intermediates in the peroxisome. PMID- 23024210 TI - A fluorescent alternative to the synthetic strigolactone GR24. AB - Strigolactones have recently been implicated in both above- and below-ground developmental pathways in higher plants. To facilitate the molecular and chemical properties of strigolactones in vitro and in vivo, we have developed a fluorescent strigolactone molecule, CISA-1, synthesized via a novel method which was robust, high-yielding, and used simple starting materials. We demonstrate that CISA-1 has a broad range of known strigolactone activities and further report on an adventitious rooting assay in Arabidopsis which is a highly sensitive and rapid method for testing biological activity of strigolactone analogs. In this rooting assay and the widely used Orobanche germination assay, CISA-1 showed stronger biological activity than the commonly tested GR24. CISA-1 and GR24 were equally effective at inhibiting branching in Arabidopsis inflorescence stems. In both the branching and adventitious rooting assay, we also demonstrated that CISA-1 activity is dependent on the max strigolactone signaling pathway. In water methanol solutions, CISA-1 was about threefold more stable than GR24, which may contribute to the increased activity observed in the various biological tests. PMID- 23024211 TI - European cost-effectiveness analysis of cervical screening strategies for women not vaccinated for HPV: in many scenarios primary HPV screening is preferable to primary cytology screening in women aged over 30 years. PMID- 23024213 TI - RNA-directed DNA methylation is involved in regulating photoperiod-sensitive male sterility in rice. AB - Photoperiod-sensitive male sterility (PSMS) is a valuable germplasm for hybrid rice breeding. Recently, we cloned pms3, a locus controlling PSMS, which encodes a long non-coding RNA called LDMAR required for normal male fertility of the rice plant under long-day conditions. Increased methylation in the promoter of LDMAR in the PSMS rice (Nongken 58S) relative to the wild-type (Nongken 58) reduced expression of LDMAR leading to male sterility under long-day conditions. In this study, we identified a siRNA named Psi-LDMAR in the LDMAR promoter region that was more abundant in Nongken 58S than in Nongken 58. We showed that Psi-LDMAR was likely derived from AK111270, a transcript obtained from the sense strand of the LDMAR promoter with its 3'-end having a 110-base overlap with the 5'-end of LDMAR. Overexpressing AK111270 in Nongken 58S greatly enriched Psi-LDMAR, which induced RNA-directed DNA methylation in the LDMAR promoter and repressed the expression of LDMAR. Reduction of LDMAR in Nongken 58S changed the critical day length for fertility recovery and delayed the fertility recovery under short-day conditions. This result added to our understanding of the molecular mechanism for PSMS. PMID- 23024212 TI - AtPRK2 promotes ROP1 activation via RopGEFs in the control of polarized pollen tube growth. AB - The ROP1 GTPase-based signaling network controls tip growth in Arabidopsis pollen tubes. Our previous studies imply that ROP1 might be directly activated by RopGEF1, which belongs to a plant-specific family of Rho guanine nucleotide exchange factors (RopGEFs) and in turn may be activated by an unknown factor through releasing RopGEF1's auto-inhibition. In this study, we found that RopGEF1 forms a complex with ROP1 and AtPRK2, a receptor-like protein kinase previously shown to interact with RopGEFs. AtPRK2 phosphorylated RopGEF1 in vitro and the atprk1,2,5 triple mutant showed defective pollen tube growth, similar to the phenotype of the ropgef1,9,12,14 quadruple mutant. Overexpression of a dominant negative form of AtPRK2 (DN-PRK2) inhibited pollen germination in Arabidopsis and reduced pollen elongation in tobacco. The DN-PRK2-induced pollen germination defect was rescued by overexpressing a constitutively active form of RopGEF1, RopGEF1(90-457), implying that RopGEF1 acts downstream of AtPRK2. Moreover, AtPRK2 increased ROP1 activity at the apical plasma membrane whereas DN-PRK2 reduced ROP1 activity. Finally, two mutations at the C-terminal putative phosphorylation sites of RopGEF1 (RopGEF1S460A and RopGEF1S480A) eliminated the function of RopGEF1 in vivo. Taken together, our results support the hypothesis that AtPRK2 acts as a positive regulator of the ROP1 signaling pathway most likely by activating RopGEF1 through phosphorylation. PMID- 23024215 TI - Melancholy thoughts. PMID- 23024214 TI - A multipronged strategy of an anti-terminator protein to overcome Rho-dependent transcription termination. AB - One of the important role of Rho-dependent transcription termination in bacteria is to prevent gene expressions from the bacteriophage DNA. The transcription anti termination systems of the lambdoid phages have been designed to overcome this Rho action. The anti-terminator protein N has three interacting regions, which interact with the mRNA, with the NusA and with the RNA polymerase. Here, we show that N uses all these interaction modules to overcome the Rho action. N and Rho co-occupy their overlapping binding sites on the nascent RNA (the nutR/tR1 site), and this configuration slows down the rate of ATP hydrolysis and the rate of RNA release by Rho from the elongation complex. N-RNA polymerase interaction is not too important for this Rho inactivation process near/at the nutR site. This interaction becomes essential when the elongation complex moves away from the nutR site. From the unusual NusA-dependence property of a Rho mutant E134K, a suppressor of N, we deduced that the N-NusA complex in the anti-termination machinery reduces the efficiency of Rho by removing NusA from the termination pathway. We propose that NusA-remodelling is also one of the mechanisms used by N to overcome the termination signals. PMID- 23024216 TI - Publication bias in meta-analysis studies: letter to the editor. PMID- 23024219 TI - Responsiveness of FGF-23 and mineral metabolism to altered dietary phosphate intake in chronic kidney disease (CKD): results of a randomized trial. AB - BACKGROUND: High fibroblast growth factor-23 (FGF-23) levels are associated with adverse outcomes. We studied the responsiveness of FGF-23 and mineral metabolism to altered dietary phosphate intake in chronic kidney disease (CKD) and healthy control patients. METHODS: Thirty patients were enrolled: 18 normophosphatemic CKD subjects and 12 healthy controls. The study duration was 21 days with three 7 day dietary interventions; a high phosphate (HP, 2000 mg/day), low phosphate (750 mg/day) and low phosphate plus phosphate binder (aluminum hydroxide, 500 mg thrice daily with meals), with comparable macronutrient content, administered in random sequence. Baseline and weekly fasting morning measurements of FGF-23, serum phosphate (sPO(4)), 1,25-hydroxyvitamin D (1,25 D) and 24-h urinary calcium (uCa) and phosphate (uPO(4)) were collected. RESULTS: FGF-23 levels were higher in subjects versus controls (72 pg/mL versus 30 pg/mL) at baseline, while sPO(4) remained in the normal range throughout the study. The absolute changes of uPO(4) and uCa for CKD and controls vary according to diet. The absolute changes of FGF 23 and sPO(4) suggest that the effect of the diets might also depend on the CKD status (P-values interaction effect = 0.08 and 0.07, respectively); nonetheless, these changes are evident as a function of dietary interventions, irrespective of CKD status (P-values diet effect = 0.006 and <0.001, respectively). CONCLUSIONS: FGF-23 levels appear to be responsive to changes in diet in both CKD patients and controls. Further studies are required to determine whether lowering dietary phosphate and thus FGF-23 levels are of long-term benefit in CKD patients, irrespective of sPO(4) levels. PMID- 23024220 TI - Specific impairment of proximal tubular cell proliferation by a monoclonal kappa light chain responsible for Fanconi syndrome. AB - BACKGROUND: Fanconi syndrome (FS) is a rare renal disorder featuring proximal tubule dysfunction that may occur following tubular reabsorption of a monoclonal light chain (LC), in patients with multiple myeloma. FS may precede the recognition of multiple myeloma by several years. In most cases, crystalline inclusions of monoclonal kappa LCs are observed within the lysosomes of proximal tubular cells (PTCs) and probably participate in their functional alteration. METHODS: To investigate the mechanism implicated in proximal tubule dysfunction, we compared the effects of kappa LC-CHEB obtained from a patient with myeloma associated FS to those of control kappa LC-BON obtained from a patient without evidence of FS, on the viability and proliferation of two different PTC lines. RESULTS: Our data suggest that the tubular atrophy in myeloma-associated FS does not result from increased apoptosis of PTCs, but from their impaired capacity to proliferate and renew. Indeed, in vitro incubation of cultured PTCs with physiological amounts of the nephrotoxic kappa LC-CHEB was sufficient to cause a depression in DNA synthesis and in cell proliferation. This effect was observed neither with control kappa LC-BON nor in the absence of kappa LC. CONCLUSIONS: The reduced turnover of PTCs may affect tubular repair and regeneration. In addition, the reduced proliferation of myeloma cells producing the same monoclonal kappa LC might explain the frequent association of FS with smoldering multiple myeloma. PMID- 23024221 TI - Diagnostic investigations of patients with chronic progressive external ophthalmoplegia. PMID- 23024222 TI - Risk of selected eye diseases in people admitted to hospital for hypertension or diabetes mellitus: record linkage studies - authors' response. PMID- 23024223 TI - Sensitivity, specificity and likelihood ratios of PCR in the diagnosis of syphilis: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review and estimate pooled sensitivity and specificity of the polymerase chain reaction (PCR) technique compared to recommended reference tests in the diagnosis of suspected syphilis at various stages and in various biological materials. DESIGN: Systematic review and meta analysis. DATA SOURCES: Search of three electronic bibliographic databases from January 1990 to January 2012 and the abstract books of five congresses specialized in the infectious diseases' field (1999-2011). Search key terms included syphilis, Treponema pallidum or neurosyphilis and molecular amplification, polymerase chain reaction or PCR. REVIEW METHODS: We included studies that used both reference tests to diagnose syphilis plus PCR and we presented pooled estimates of PCR sensitivity, specificity, and positive and negative likelihood ratios (LR) per syphilis stages and biological materials. RESULTS: Of 1160 identified abstracts, 69 were selected and 46 studies used adequate reference tests to diagnose syphilis. Sensitivity was highest in the swabs from primary genital or anal chancres (78.4%; 95% CI: 68.2-86.0) and in blood from neonates with congenital syphilis (83.0%; 55.0-95.2). Most pooled specificities were ~95%, except those in blood. A positive PCR is highly informative with a positive LR around 20 in ulcers or skin lesions. In the blood, the positive LR was <10. CONCLUSIONS: The pooled values of LR showed that T. pallidum PCR was more efficient to confirm than to exclude syphilis diagnosis in lesions. PCR is a useful diagnostic tool in ulcers, especially when serology is still negative and in medical settings with a high prevalence of syphilis. PMID- 23024224 TI - Self-collected swabs of the urinary meatus diagnose more Chlamydia trachomatis and Neisseria gonorrhoeae infections than first catch urine from men. AB - OBJECTIVES: To compare first catch urine (FCU) and self-collected urinary meatal swabs for the detection of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) using the APTIMA Combo 2 assay. METHODS: A total of 511 young men from a high risk street youth clinic were studied. Group A (n=293) collected a FCU and a meatal APTIMA swab followed by Group B (n=218) who collected a FCU and two meatal samples using an APTIMA swab and a flocked swab. Order of sample collection was alternated. Individuals in Group B rated collection as easy, difficult or neither, then expressed a preference for sampling and swab type. All subjects performed meatal self-collection in the presence of a study monitor. RESULTS: The combined CT prevalence was 7.8% and 2.7% for NG where 80% of the men were without symptoms. Meatal swabbing identified 35 cases of CT and 14 cases of NG compared to 33 and 11 for FCU. Flocked and APTIMA swabs were equally effective in detecting more cases. The majority of men found self-collection of meatal swabs and urine to be easy. Although 63% preferred urine sampling, 60% of those who preferred swabbing selected the flocked swab. CONCLUSIONS: Collection of meatal swabs could serve as an alternative to urethral swabbing and FCU for the detection of CT and NG. PMID- 23024225 TI - Chlamydia screening, retesting and repeat diagnoses in Cornwall, UK 2003-2009. AB - OBJECTIVES: This study aims to describe the patterns of testing and retesting for chlamydia in Cornwall during the first 5 years of the National Chlamydia Screening Programme. We evaluate the factors associated with retesting and estimate the incidence of chlamydia diagnosis and repeat diagnosis. METHODS: STUDY DESIGN: Secondary database analysis. SELECTION CRITERIA: men and women tested for chlamydia between March 2003 and January 2009 in Cornwall, aged >=12 years and <=25 years at the first test. The factors associated with retesting in those with at least one known test result and at least 14 days follow-up time were analysed using Cox regression and the incidence of diagnosis and repeat diagnosis were calculated. RESULTS: The final dataset consisted of 71 066 records from 49 941 individuals; of whom 59.0% were female and 75.4% were only tested once. There were 48 375 individuals with at least one known test result (negative or positive) and at least 14 days follow-up, included in the Cox regression analysis. Factors associated with testing more than once were (adjusted HR, 95% CI): being female (2.24; 2.14 to 2.34) and initially testing positive (1.43; 1.35 to 1.51). The positivity at first episode declined from 13.2% (1077 cases) in 2003/2004 to 5.8% (843 cases) in 2008/2009. The incidence of diagnosis at the second test was 5.9 per 100 person years in those testing negative at the first test compared with 18.1 per 100 person years in those initially positive. DISCUSSION: Most individuals in this analysis were tested only once, but the testing volume and proportion of repeat tests were highest at the end of the study period. As the testing rate stabilises to 30% coverage, maintaining retesting rates in those previously tested and especially in those previously diagnosed with chlamydia will be necessary for the sustainability of the screening programme. CONCLUSIONS: A key feature of the next 5 years of the screening programme will be to maintain screening and rescreening. PMID- 23024226 TI - The development of a validated checklist for paracentesis: preliminary results. AB - Paracentesis is an invasive procedure known to result in complications. Procedure skills should be taught and evaluated more effectively to improve health care quality. Validated checklists are central to teaching and assessing procedural skills. The results of the first step of the validation of a paracentesis checklist are described. A comprehensive literature review of articles published on paracentesis did not yield a validated checklist. A modified Delphi technique, involving a panel of 8 interdisciplinary, interinstitutional experts, was used to develop a paracentesis checklist. The internal consistency coefficient using Cronbach's alpha was .92. Developing the 24-item paracentesis checklist for teaching and assessing paracentesis is the first step in the validation process. For this checklist to become further validated, it should be implemented and studied in the simulation and clinical environments. PMID- 23024227 TI - Sports and exercise physicians as medical assessors. AB - OBJECTIVE: To clarify the role of sports and exercise physicians as medical assessors. METHODS: Group discussion between senior doctors at a previous annual conference of the Australasian College of Sports Physicians, followed by further discussion between the authors. Clarification of the key requirements of insurers, and formulation of practical advice for those performing this work. RESULTS: Our expertise in performing medical assessments for the purpose of fitness to play sport is a transferable skill. It can also be used to provide medical assessments for injured workers. Our expertise in rehabilitation is also of value to insurers and other interested parties. CONCLUSION: The work is both challenging and rewarding, and can provide additional variety in the working week. PMID- 23024232 TI - Comparison of results and economic analysis of surgical and transcatheter closure of perimembranous ventricular septal defect. AB - OBJECTIVES: The last decade has witnessed considerable improvement in design and implantation techniques for the percutaneous closure of perimembranous ventricular septal defects. This study was undertaken to compare the results and economic analysis of traditional surgery and percutaneous closure with a modified double-disk occluder during hospitalization. METHODS: A total of 345 consecutive patients who underwent isolated perimembranous ventricular septal defect closure were identified between July 2009 and July 2011 in our institution. A total of 157 patients with perimembranous ventricular septal defect (45.5%) underwent percutaneous closure and the remaining 188 patients (54.5%) were treated surgically. RESULTS: In the percutaneous closure group, 156 patients (99.4%) had immediate complete closure and 186 (98.9%) in the surgical group were treated successfully (P = 0.671). The surgical group was significantly younger (P = 0.000) and larger in size (P = 0.000). One case of irreversible complete atrioventricular block and one death occurred in the surgical group. There was no significant difference in terms of hospital stay between the two groups. The total medical cost in the percutaneous closure group was lower compared with that in the surgical group (P = 0.005). Charges for medication, bed occupancy and nursing care of patients undergoing surgical closure were greater than those for patients undergoing transcatheter closure (P = 0.000, P = 0.000, P = 0.000, respectively). None of the patients in the percutaneous closure group required blood transfusion during hospitalization. Charges for radiography, lab and ultrasound in the percutaneous closure group were higher compared with those in the surgical group (P = 0.000, P = 0.000, respectively). CONCLUSIONS: Compared with surgical repair at our institution, the superior clinical outcomes and economic benefits of percutaneous closure are inspiring. Percutaneous closure is a valuable alternative to surgery and allows more patients to be effectively treated in China. PMID- 23024233 TI - Right ventricular outflow tract strategies for repair of tetralogy of Fallot: effect of monocusp valve reconstruction. AB - OBJECTIVES: The absence of a pulmonary valve (PV) after tetralogy of Fallot (TOF) repair has been shown to impact postoperative right ventricular (RV) function. The purposes of this study were to (i) compare early outcomes after PV-sparing vs transannular patching (TAP) with monocusp valve reconstruction or TAP alone and (b) assess the mid-term results after polytetrafluoroethylene (PTFE) membrane monocusp reconstruction. METHODS: From 2003 to 2009, 163 patients underwent TOF repair. Sixty-nine patients (42.3%) underwent a PV-sparing procedure (Group A), 74 (45.4%) underwent PTFE membrane monocusp valve reconstruction (Group B) and 20 (12.3%) underwent TAP only (Group C). Early outcomes were evaluated by the right to-left ventricular pressure ratio, RV outflow tract gradient, tricuspid and PV function, intensive care unit (ICU) parameters and need for reintervention. Group B patients were also evaluated at intermediate term for clinical and echocardiographic parameters, including tricuspid and monocusp valve function and mobility. RESULTS: The median age, weight and PV Z-value of Group B patients were significantly lower; 20.5 months, 9.3 kg and -4, respectively. Postoperatively, the right-to-left ventricular pressure ratio was <0.5 in all groups. Mechanical ventilation time, fluid drainage duration and total ICU stay showed no significant difference between Groups A and B, while Group C was significantly longer (P < 0.01). There were five (3%) early deaths: three from Group A and two from Group B. The incidences of moderate or severe pulmonary insufficiency (PI) on discharge were 8.2% in Group A, 9% in Group B and 50% in Group C (P < 0.001). Among Group B patients, 85% of the evaluated patients had less than moderate PI in the intermediate-term follow-up, QRS duration <140 ms in 83.3% and right-to left ventricular diameter ratio of 0.6 +/- 0.2. Two (2.6%) patients underwent reoperation for monocusp replacement. There were two (2.7%) mid-term deaths. CONCLUSIONS: The use of a PTFE membrane monocusp valve and a valve-sparing strategy prevents immediate PI and improves short-term clinical outcomes. PTFE membrane monocusp appears advantageous in preventing severe intermediate-term PI and facilitates the preservation of RV function. PMID- 23024234 TI - The utility of [18F]-fluorodeoxyglucose positron emission tomography-computed tomography in thymic epithelial tumours. AB - OBJECTIVES: Positron emission tomography using [(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG-PET) plays an important role in many oncological settings. In this study, we assessed the utility of (18)F-FDG PET-CT for predicting the histologic type and stage of thymic epithelial tumours. METHODS: We retrospectively analyzed 58 patients with thymic epithelial tumours who underwent PET-CT before treatment and investigated the relationship between the histologic type based on the World Health Organization classification and the maximum standardized uptake value (SUV(max)) of each tumour. We also analyzed the relationship between the Masaoka tumour stage and the SUV(max). RESULTS: The study included 31 males and 27 females, ranging in age from 25 to 80 years (median: 62 years). The tumour histology of 44 tumours was thymoma and that of the remaining tumours was thymic carcinoma, including 11 squamous cell carcinomas and 3 carcinoids. The Masaoka tumour stage was as follows: Stage I in 8, Stage II in 24, Stage III in 18 and Stage IV in 8 patients. The patients were divided into three groups according to a simplified histologic classification: low-risk thymomas (types A, AB and B1, n = 23), high-risk thymomas (types B2 and B3, n = 21) and thymic carcinomas (n = 14). The SUV(max) of the thymic carcinoma group was significantly higher than those of the low-risk thymoma and high-risk thymoma groups (P < 0.001, respectively). No significant differences between the low-risk thymoma and high risk thymoma groups were observed (P = 0.204). The SUV(max) of Stages III and IV thymomas showed a higher trend toward Stages I and II thymomas (P = 0.060). CONCLUSIONS: PET-CT is a useful modality for predicting the histologic type and tumour stage of thymic epithelial tumours. PMID- 23024235 TI - The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer. AB - OBJECTIVES: Ground-glass opacity (GGO) is a preoperative prognostic factor in resectable lung cancer. However, the impact of GGO on the T factor in the TNM staging system remains unclear and the maximum tumour dimension is also an uncertain measurement for assessing the prognosis of early lung cancer with a mixture of consolidation and GGO. Thus, we sought to determine which the better prognostic factor was, the size of the consolidation on computed tomography scan or the conventional maximum tumour dimension. METHODS: Between January 2004 and January 2011, 398 consecutive clinical stage IA lung cancer patients underwent surgical resection at our hospital. Univariate and multivariate analyses were performed by the logistic regression procedure to determine the relationship between pathological lymph node metastasis-positive status and clinical or radiological findings such as the maximum dimensions of consolidation and the tumour, the presence of air bronchogram, pleural indentation and the preoperative serum carcinoembryonic antigen (CEA) level. RESULTS: Of the 398 patients, 59 (14.8%) had pathological lymph node metastasis. Univariate analysis revealed four significant predictors of pathological nodal involvement: the presence of air bronchogram, the size of consolidation, the maximum tumour dimension and the preoperative CEA level (P < 0.01, respectively). In a multivariate analysis, the size of consolidation and the presence of air a bronchogram were significant predictors of nodal metastasis (P < 0.01, respectively). CONCLUSIONS: The maximum dimension of the consolidation was an independent unfavourable prognostic factor, regardless of the maximum tumour dimension. This could lead to the more accurate prediction of pathological lymph node metastasis with both GGO and consolidation. PMID- 23024236 TI - Regulated tailored suction vs regulated seal: a prospective randomized trial on air leak duration. AB - OBJECTIVE: The objective of this study was to compare the air leak duration of two regulated chest tube modes following pulmonary lobectomy. METHODS: This is a prospective randomized trial on 100 consecutive pulmonary lobectomies (2010-11) performed for lung cancer. A single 24-French chest tube was connected to an electronic system capable of maintaining the pleural pressure within preset values (regulated suction mode) or within a physiological range (regulated seal mode). Patients were randomized to two groups: Group 1, regulated individualized suction (range: -11 to -20 cmH2O, according to lobectomy type); Group 2, regulated seal (-2 cmH2O). The main endpoint was the duration of air leak (h) calculated from the end of the operation to a value consistently below 20 ml/min. Patients with prolonged air leak (>168 h) were connected to a portable device before discharge. Their air leak duration was considered as 192 h. The sample size was calculated to detect 1-day difference in air leak duration with a statistical power of 80%. RESULTS: The two groups were well matched for several baseline and surgical characteristics. No crossovers occurred between groups. The average air leak duration (Group 1: 28 vs Group 2: 22.2, P = 0.6), and the number of patients with prolonged air leak (Group 1: 5 vs Group 2: 4, P = 0.7) and with other complications (Group 1: 6 patients vs Group 2: 7 patients, P = 0.9) were similar between the groups. Sixteen patients of Group 1 and 21 of Group 2 had an air leak present immediately after extubation. Among them, patients of Group 2 (regulated seal) had an air leak lasting 34.5 h less than those of Group 1 (regulated suction) (52.9 vs 87.4, P = 0.07). CONCLUSIONS: Regulated seal is as effective and safe as regulated suction in managing chest tubes following lobectomy. This information demonstrates with objective data the non-superiority of regulated suction vs regulated seal and may assist in future investigations on regulated pleural pressure. PMID- 23024237 TI - Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. AB - Persistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinical relapse in patients with acute lymphoblastic leukemia (ALL). In a phase 2 trial of B-lineage ALL patients with persistent or relapsed MRD, a T cell-engaging bispecific Ab construct induced an 80% MRD response rate. In the present study, we show that after a median follow-up of 33 months, the hematologic relapse-free survival of the entire evaluable study cohort of 20 patients was 61% (Kaplan-Meier estimate). The hema-tologic relapse-free survival rate of a subgroup of 9 patients who received allogeneic hematopoietic stem cell transplantation after blinatumomab treatment was 65% (Kaplan-Meier estimate). Of the subgroup of 6 Philadelphia chromosome-negative MRD responders with no further therapy after blinatumomab, 4 are in ongoing hematologic and molecular remission. We conclude that blinatumomab can induce long-lasting complete remission in B lineage ALL patients with persistent or recurrent MRD. The original study and this follow-up study are registered at www.clinicaltrials.gov as NCT00198991 and NCT00198978, respectively. PMID- 23024240 TI - Response time evaluation for emergency medical service as a part of its performance. AB - The study aimed to evaluate the response time (RT) of a French physician-staffed emergency medical service unit in both first-line and second-line service zones a part of its performance and how best to integrate it into its geographical specificity and showed acceptable RTs (mostly <10 min). Interestingly, because of the particular location next to other districts, RTs are in the same range for some municipalities that are adjacent to the first-line and area. In a new system in which catching areas would not only be based on administrative criteria anymore but also on performance evaluation, RTs for emergency medical service might be optimised. PMID- 23024239 TI - Quality of care as a determinant of health-related quality of life in ill hospitalized adolescents at a tertiary care hospital in North India. AB - OBJECTIVE: To evaluate if quality of care (QoC) provided by hospital is a determinant of ill-hospitalized adolescent's health-related quality of life (HRQoL) from parent's perspective. DESIGN: Prospective cross-sectional study conducted at a tertiary care hospital of Northern India after institutional ethical approval. SETTING: Hospital in pediatric department of a tertiary care, teaching medical University in Lucknow, northern India. PARTICIPANTS: Sick adolescents aged between 10 and 19 years and hospitalized for four categories of illnesses, namely, acute infective; chronic infective, non-hemopoetic; hemopoetic disorders and miscellaneous. INTERVENTION: QOC assessment was done using 'Pyramid instrument' and HRQoL by culturally modified WHOQOL-BREF (World Health Organization Quality of Life-BREF). The Pyramid instrument comprises 43 questions to collect information about awareness of eight indices: namely illness, routines, accessibility, medical treatment, care processes, staff attitude, participation and staff work environment and scored on 1-4 Likert scale. WHOQOL BREF has four domains: physical, psychological, social relations and environment and scored on 1-5 Likert scale. RESULTS: From January 2008 to December 2008, 300 adolescents with a mean age of 12.5 +/- 2.6 years and 61.3% males were included. The pyramid instrument showed a substantial internal consistency (alpha = 0.88, P value < 0.0001). The mean QoC was highest for medical treatment (0.76 +/- 0.13) and lowest for participation (0.54 +/- 0.16). The mean parent's report of child's HRQoL was highest for physical (42.8 +/- 7.4) and lowest for environment domain (37.2 +/- 7.1). Four QoC indices namely, medical treatment, care processes, staff attitude and participation had significant associations with the mean HRQoL. In a hierarchical linear regression, staff attitude was the only significant determinant of HRQoL (beta coefficient: 23.16, 95% confidence interval: 15.8 30.5, P-value < 0.0001). CONCLUSION: The Pyramid instrument is a reliable instrument for assessing parent's perception of QoC provided to hospitalized adolescents in Indian context. QoC was positively associated with HRQoL, thus, an increased focus on QoC especially staff attitude is likely to enhance adolescent's overall HRQoL. PMID- 23024238 TI - Self-antigen recognition by follicular lymphoma B-cell receptors. AB - Follicular lymphoma is a monoclonal B-cell malignancy with each patient's tumor expressing a unique cell surface immunoglobulin (Ig), or B-cell receptor (BCR), that can potentially recognize antigens and/or transduce signals into the tumor cell. Here we evaluated the reactivity of tumor derived Igs for human tissue antigens. Self-reactivity was observed in 26% of tumor Igs (25 of 98). For one follicular lymphoma patient, the recognized self-antigen was identified as myoferlin. This patient's tumor cells bound recombinant myoferlin in proportion to their level of BCR expression, and the binding to myoferlin was preserved despite ongoing somatic hypermutation of Ig variable regions. Furthermore, BCR mediated signaling was induced after culture of tumor cells with myoferlin. These results suggest that antigen stimulation may provide survival signals to tumor cells and that there is a selective pressure to preserve antigen recognition as the tumor evolves. PMID- 23024241 TI - Is external chest compression during cardiopulmonary resuscitation (CPR) most effective when the ascending aorta underlies the 'compression point' of the sternum? PMID- 23024242 TI - At odds with science? PMID- 23024243 TI - Is the lack of effect of smoking cessation aids in population studies explained by recall bias? Comment on the article by Borland et al. (2012). PMID- 23024244 TI - Recall bias does impact on retrospective reports of quit attempts: response to Messer and Pierce. PMID- 23024245 TI - Trends in the use and advertising of discount versus premium snuff. AB - INTRODUCTION: The Conwood Company, a major producer of discount moist snuff, was awarded a $1 billion antitrust settlement in the year 2000 against its leading competitor, the U.S. Smokeless Tobacco Company. The objective of this study was to examine the trends in use and advertising of discount versus premium snuff since the Conwood settlement, a topic seldom addressed in the tobacco control literature. METHODS: 2 sources of data were analyzed in 2011: (a) male snuff users from the 2002-2009 National Surveys on Drug Use and Health (N = 13,172) and (b) total advertisements of moist snuff identified from over 350 consumer magazines dated 2005-2009 (N = 861). For the survey data, demographic and tobacco related measures were assessed as predictors of use of discount versus premium snuff in logistic regression models. For the advertising data, associations were examined between the snuff category and nicotine content, magazine youth readership, and year of magazine publication. RESULTS: The prevalence of discount and premium snuff use among males increased and decreased, respectively, from 2002 to 2009. Significant predictors of using discount versus premium snuff were being an adolescent, being an African-American, being a current or former smoker, living in a less populated region of the country, and using snuff frequently. Discount snuff advertising was associated with publication in magazines with a high youth readership. CONCLUSIONS: Discount snuff has grown in popularity among male adolescents who have been a target of advertising. The tobacco's cheap price and high nicotine content pose a public health problem because of the potential for long-term tobacco use and dependence. PMID- 23024246 TI - Varenicline to stop long-term nicotine replacement use: a double-blind, randomized, placebo-controlled trial. AB - INTRODUCTION: This study evaluated the effect of varenicline in combination with counseling to assist long-term nicotine replacement therapy (NRT) users to quit NRT. METHODS: This was a double-blind, placebo-controlled, randomized trial of varenicline or placebo for 12 weeks, with 52-week follow-up, performed in 1 hospital-based smoking cessation specialist clinic. At the first visit, 139 ex smokers and long-term NRT users were allocated to treatment according to a computer-generated list with random numbers. Visits were scheduled at Weeks 0, 2, 4, 6, 9, 12, and 52. At each visit, nurse-led counseling was delivered, carbon monoxide in expired air, plasma cotinine, and body weight were assessed, and subjects were asked about craving, nausea, and dreams. The primary outcome was 12 week point prevalence quit rate (PPR) of nicotine replacement therapy use. RESULTS: At all time points, the PPR was superior for varenicline versus placebo, although the difference was only statistically significant at 12 and 36 weeks. The PPR was 64.3% (varenicline) versus 40.6% (placebo) at 12 weeks (p = .006), and 42.9% (varenicline) versus 36.2% (placebo) at 52 weeks (NS). The continuous abstinence rate from Week 9 to Week 12 was 48.6 % (varenicline) versus 30.4 % (placebo) (p = .03). Withdrawal symptoms were statistically significantly lower in the varenicline group than the placebo group. CONCLUSION: Varenicline for 12 weeks combined with supportive visits was superior to placebo to get long-term NRT users to quit NRT. A larger study is needed to evaluate long-term efficacy. PMID- 23024247 TI - Research required for the effective implementation of the framework convention on tobacco control, articles 9 and 10. AB - This paper is part of a series of articles intended to set out the research questions that are relevant to the successful implementation of the various provisions of the Framework Convention on Tobacco Control (FCTC). This paper focuses on issues affecting Articles 9 and 10 of the FCTC. This paper focuses on the research that is most important for most countries, rather than on what is desirable in countries with high levels of research capacity. Articles 9 and 10 of the FCTC address the regulation of contents and emissions of tobacco products and regulation of tobacco product disclosure. Such regulation will be essential if the long-term objective of reducing the danger of tobacco products is to be achieved. There are many components of tobacco and tobacco smoke that are excessively toxic and dangerous to the user. Many of these components are carcinogenic and addictive and can be removed or reduced substantially with current known technology. The fact that these components remain in tobacco and tobacco smoke at levels that are unnecessarily dangerous is precisely the reason why the successful implementation of Articles 9 and 10 of the FCTC is important to tobacco control. This paper discusses the scientific challenges involved in successfully implementing Articles 9 and 10 of the FCTC, which focuses on regulating carcinogens and toxins in tobacco and tobacco smoke, the abuse liability of tobacco products, and the additives and engineering features in tobacco products that make tobacco products appealing to future consumers. The research issues we focus on are those required to support the early stages of regulation. As regulation proceeds, new and more sophisticated research questions will undoubtedly emerge. PMID- 23024248 TI - Impact of a comprehensive smoke-free law following a partial smoke-free law on incidence of heart attacks at a rural community hospital. AB - INTRODUCTION: Secondhand smoking (passive smoking) is associated with many negative health effects, primarily respiratory and cardiovascular diseases. Approximately, 46,000 deaths from cardiovascular disease are associated with secondhand smoke exposure annually in the United States, which is roughly 150 deaths in North Dakota. Studies show that passage of smoke-free laws at the community level can reduce the incidence of heart attack. METHODS: We conducted a retrospective review of electronic medical records of patients admitted for heart attacks 4 months prior (April 15, 2010 through August 14, 2010) to implementation of the smoke-free ordinance and 4 months following (August 15, 2010 through December 14, 2010) implementation of the comprehensive smoke-free ordinance in Grand Forks, ND, United States. RESULTS: We found an association between the heart attack rate and implementation of the comprehensive smoke-free law. The heart attack rate prior to the ban was 0.5% (83/16,702) compared with 0.3% (63/18,513) after the ban (p = .023). Thus, the rate of heart attacks decreased 30.6% and number of heart attack admissions decreased 24.1%, from 83 to 63, after implementation of a comprehensive smoke-free law. CONCLUSIONS: We found an implementation of the comprehensive smoke-free law was associated with a decrease in the heart attack rate. The heart attack rate decreased 30.6%. Our finding was similar to previous community level smoke-free law implementation studies and notable for the change going from a partial smoke-free law to a comprehensive smoke-free law. PMID- 23024250 TI - Efficacy of emergency department-initiated tobacco control--systematic review and meta-analysis of randomized controlled trials. AB - AIM: Systematic review and meta-analysis of randomized controlled trials evaluating the efficacy of emergency department-initiated tobacco control (ETC). METHODS: Literature search in 7 databases and gray literature sources. Point prevalence tobacco abstinence at 1-, 3-, 6-, and/or 12-month follow-up was abstracted from each study. The proportionate effect (relative risk) of ETC on tobacco abstinence was calculated separately for each study and follow-up time and pooled, at different follow-up times, by Mantel-Haenszel relative risks. The effects of ETC on combined point prevalence tobacco abstinence across all follow up times were calculated using generalized linear mixed models. RESULTS: Seven studies with overall 1,986 participants were included. The strongest effect of ETC on point prevalence tobacco abstinence was found at 1 month: Relative risk (RR) = 1.47 (3 studies) (95% confidence interval [CI]: 1.06-2.06), while the effect at 3, 6, and 12 months was RR = 1.24 (6 studies) (95% CI: 0.93-1.65); 1.13 (5 studies) (95% CI: 0.86-1.49); and 1.25 (1 study) (95% CI: 0.91-1.72). The benefit on combined point prevalence tobacco abstinence was RR = 1.33 (7 studies) (95% CI: 0.96-1.83), p = .08; with RR = 1.33 (95% CI: 0.92-1.92), p = .10, for the 5 studies combining motivational interviewing and booster phone calls. CONCLUSIONS: ETC combining motivational interviewing and booster phone calls showed a trend toward increased episodically measured tobacco abstinence up to 12 months. More methodologically rigorous trials are needed to effectively evaluate the impact of ETC. PMID- 23024251 TI - The Australian National Standard for rail workers five years on. AB - BACKGROUND: Following the introduction of the National Standard for Health Assessment of Rail Safety Workers, RailCorp train drivers were found to have levels of obesity and hypertension greater than the Australian population prevalence. Cardiovascular risk factors and conditions were the most prevalent health issue and had the greatest impact on fitness for duty. AIMS: To determine whether there has been a change in the prevalence of health conditions in train drivers 5 years after the introduction of the Standard. METHODS: A file review was conducted of all RailCorp drivers and driver recruits assessed between 1 February 2009 and 31 January 2010. RESULTS: The files of 1094 subjects were reviewed. The proportions of drivers with systolic blood pressure >=140 mmHg (35% in 2004/05; 22% in 2009/10, P < 0.001), total cholesterol >=5.5 mmol/L (39%; 32%, P < 0.001) and who smoked (25%; 20%, P < 0.01) all decreased significantly. The proportions of drivers who were obese (40% in 2004/05; 47% in 2009/10, P < 0.001) and who had diabetes (7%; 11%, P < 0.01) and pre-diabetes (2%; 5%, P < 0.001) all increased significantly. CONCLUSIONS: The rate of increase of obesity in drivers is similar to the general population and is also observed in recruits. Increases in the prevalence of diabetes and pre-diabetes are likely to reflect the increased prevalence of obesity and the impact of regular screening. These were offset by improvements in systolic blood pressure, total cholesterol and smoking status, with a neutral overall effect on cardiac risk score. PMID- 23024252 TI - Factors that prolong the 'postmortem interval until finding' (PMI-f) among community-dwelling elderly individuals in Japan: analysis of registration data. AB - OBJECTIVES: To clarify the factors affecting 'postmortem interval until finding' (PMI-f) among elderly unexpected death cases. DESIGN: Cross-sectional study. SETTING: All area of Yamagata prefecture in Japan. PARTICIPANTS: Entering subjects were 5675 elderly cases with age of >=65 years selected from all 9002 cases of unexpected death from 2002 to 2007 in Yamagata prefecture between 2002 and 2007. Our final study subjects consisted of 3387 cases sampled with several criteria to assess the factors to prolong PMI-f. PRIMARY OUTCOME MEASURES: The outcome was the postmortem interval until finding (PMI-f) as the time from death until finding the body which we defined in this study. RESULTS: 'Living alone' showed the highest adjusted HR (3.73, 95% CI 3.37 to 4.13), also 'unnatural death' (1.50, 1.28 to 1.75), 'found at own home' (1.37, 1.22 to 1.55) and 'younger subjects' (0.99, 0.98 to 0.99). In the model including interactions with the household situation, we found 'male subjects living alone' and 'female subjects living with family' tended to be found later. CONCLUSIONS: PMI-f is an effective outcome for quantitative analyses of risk of bodies left. To prevent the elderly dead bodies left for long time, it is necessary to keep regular home based contact with elderly individuals living alone. PMID- 23024249 TI - Development of novel pharmacotherapeutics for tobacco dependence: progress and future directions. AB - INTRODUCTION: The vast majority of tobacco smokers seeking to quit will relapse within the first month of abstinence. Currently available smoking cessation agents have limited utility in increasing rates of smoking cessation and in some cases there are notable safety concerns related to their use. Hence, there is a pressing need to develop safer and more efficacious smoking cessation medications. METHODS: Here, we provide an overview of current efforts to develop new pharmacotherapeutic agents to facilitate smoking cessation, identified from ongoing clinical trials and published reports. RESULTS: Nicotine is considered the major addictive agent in tobacco smoke, and the vast majority of currently available smoking cessation agents act by modulating nicotinic acetylcholine receptor (nAChR) signaling. Accordingly, there is much effort directed toward developing novel small molecule therapeutics and biological agents such as nicotine vaccines for smoking cessation that act by modulating nAChR activity. Our increasing knowledge of the neurobiology of nicotine addiction has revealed new targets for novel smoking cessation therapeutics. Indeed, we highlight many examples of novel small molecule drug development around non-nAChR targets. Finally, there is a growing appreciation that medications already approved for other disease indications could show promise as smoking cessation agents, and we consider examples of such repurposing efforts. CONCLUSION: Ongoing clinical assessment of potential smoking cessation agents offers the promise of new effective medications. Nevertheless, much of our current knowledge of molecular mechanisms of nicotine addiction derived from preclinical studies has not yet been leveraged for medications development. PMID- 23024253 TI - Are socioeconomic disparities in tobacco consumption increasing in India? A repeated cross-sectional multilevel analysis. AB - OBJECTIVES: India bears a significant portion of the global tobacco burden with high prevalence of tobacco use. This study examines the socioeconomic patterning of tobacco use and identifies the changing gender and socioeconomic dynamics in light of the Cigarette Epidemic Model. DESIGN: Secondary analyses of second and third National Family Health Survey (NFHS) data. SETTING AND PARTICIPANTS: Data were analysed from 201 219 men and 255 028 women over two survey rounds. OUTCOMES AND METHODS: Outcomes included smoking (cigarettes, bidis and pipes/cigar), chewed tobacco (paan masala, gutkha and others) and dual use, examined by education, wealth, living environment and caste. Standardised prevalence and percentage change were estimated. Pooled multilevel models estimated the effect of socioeconomic covariates on the log odds of tobacco use by gender, along with fixed and random parameters. FINDINGS: Among men (2005 2006), gradients in smoking by education (illiterates: 44% vs postgraduates: 15%) and chewing (illiterates: 47% vs postgraduates: 19%) were observed. Inverse gradients were also observed by wealth, living environment and caste. Chewed tobacco use by women showed inverse socioeconomic status (SES) gradients comparing the illiterates (7.4%) versus postgraduates (0.33%), and poorest (17%) versus richest (2%) quintiles. However, proportional increases in smoking were higher among more educated (postgraduates (98%) vs high schooling only (17%)) and chewing among richer (richest quintile (49%) vs poorest quintile (35%)). Among women, higher educated showed larger declines for smoking-90% (postgraduates) versus 12% (illiterates). Younger men (15-24 years) showed increasing tobacco use (smoking: 123% and chewing: 112%). Older women (35-49 years) show higher prevalence of smoking (3.2%) compared to younger women (0.3%). CONCLUSIONS: Indian tobacco use patterns show significant diversions from the Cigarette Epidemic Model-from gender and socioeconomic perspectives. Separate analysis by type is needed to further understand social determinants of tobacco use in India. PMID- 23024254 TI - Physicians' response to computerised alerts for psychotropic drugs in older persons: a multilevel analysis of the associated alert, patient and physician characteristics. AB - OBJECTIVE: Computerised drug alerts are expected to reduce patients' risk of adverse drug events. However, physicians over-ride most drug alerts, because they believe that the benefit exceeds the risk. The purpose of this study was to determine the drug alert, patient and physician characteristics associated with the: (1) occurrence of psychotropic drug alerts for elderly patients and the (2) response to these alerts by their primary care physicians. SETTING: Primary care, Quebec, Canada. DESIGN: Prospective cohort study. PARTICIPANTS: Sixty-one physicians using an electronic prescribing and drug alert decision-support system in their practice, and 3413 elderly patients using psychotropic drugs. PRIMARY AND SECONDARY MEASURES: Psychotropic drug class, alert severity, patient risk for fall injuries and physician experience, practice volume and computer use were evaluated in relationship to the likelihood of having: (1) a psychotropic drug alert, (2) the prescription revised in response to an alert. Cluster-adjusted alternating logistic regression was used to assess multilevel predictors of alert occurrence and response. RESULTS: In total 13 080 psychotropic drug alerts were generated in 8931 visits. Alerts were more likely to be generated for male patients at higher risk of fall-related injury and for physicians who established the highest alert threshold. In 9.9% of alerts seen, the prescription was revised. The highest revision rate was for antipsychotic alerts (22.6%). Physicians were more likely to revise prescriptions for severe alerts (OR 2.03; 95%CI 1.39 to 2.98), if patients had cognitive impairment (OR 1.95; 95%CI 1.13 to 3.36), and if they made more visits to their physician (OR 1.05 per 5 visits; 95%CI 1 to 1.09). CONCLUSIONS: Physicians view and respond to a small proportion of alerts, mainly for higher-risk patients. To reduce the risk of psychotropic drug-related fall injuries, a new generation of evidence-based drug alerts should be developed. PMID- 23024255 TI - The Cancer Patient Experiences Questionnaire (CPEQ): reliability and construct validity following a national survey to assess hospital cancer care from the patient perspective. AB - OBJECTIVES: Patient experience questionnaires have been criticised owing to the lack of supporting psychometric evidence. The objective of this study was to describe the development and psychometric evaluation of the Cancer Patient Experiences Questionnaire (CPEQ) in Norway. DESIGN: Questionnaire development was based on a literature review of existing questionnaires, patient interviews, expert-group consultations, pretesting of questionnaire items and a national survey. Psychometric evaluation included exploratory and confirmatory factor analysis, and tests of internal consistency reliability and test-retest reliability. SETTING: Data were collected using a postal survey of cancer patients attending 54 hospitals in all 4 health regions. The subjects were 14 227 adult cancer patients who had attended an outpatient clinic or who had been discharged from an inpatient ward. Patients with all types of cancer were included. Data quality, internal consistency reliability and construct validity were assessed. RESULTS: Of the 13 846 patients who received the CPEQ, 7212 (52%) responded. Exploratory factor analysis identified six scales of outpatient experiences relating to nurse contact, doctor contact, information, organisation, patient safety and contact with next of kin, and seven scales of inpatient experiences, with the addition of hospital standard to the aforementioned scales. All but two of the scales met the criterion of 0.70 for Cronbach's alpha testing, and test-retest correlations ranged from 0.57 to 0.85. Confirmatory factor analysis supported the interpretation of six and seven scales for outpatients and inpatients, respectively. Statistically significant associations based on explicit hypotheses provided evidence for the construct validity of the scales. One additional scale measuring the hospital level was identified (alpha=0.85). CONCLUSIONS: The CPEQ is a self-report instrument that includes the most important aspects of patient experiences with cancer care at hospitals. The instrument was tested following a national survey in Norway; good evidence is provided herein for the internal consistency reliability, test-retest reliability and construct validity. PMID- 23024256 TI - Control of type 1 diabetes mellitus and shift work. AB - BACKGROUND: People with type 1 diabetes may find diabetic control more difficult when working shifts. AIMS: To investigate the proportion of people with type 1 diabetes in employment undertaking shift work and diabetic control as assessed by glycosylated haemoglobin (HbA1c) among individuals undertaking shift work compared to those not doing so. METHODS: A postal questionnaire sent to all those aged 16-65 attending two city hospitals for type 1 diabetes care. HbA1c results were used to assess diabetic control. RESULTS: Twenty-two per cent (296 of 1370 eligible patients) responded. Sixty-seven (23%) respondents were involved in shift work. Shift workers had higher mean HbA1c values than non-shift workers (9.02 versus 8.35; P < 0.01). CONCLUSIONS: Poorer control of diabetes was associated with working shifts in this study. Occupational health practitioners should be aware of this association and be able to advise on management strategies to improve diabetic control while working shifts. PMID- 23024257 TI - Monitoring fitness levels and detecting implications for health in a French population: an observational study. AB - OBJECTIVE: To analyse the physical fitness of a large sample of the French population across different ages. DESIGN: Observational cross-sectional study. SETTING: Data were collected from the Athletic Track and Field Federation, which organised events dedicated to measuring physical fitness. The events took place in 22 regions between 2006 and 2010. PARTICIPANTS: French volunteer citizens (N=31 349) aged between 4 and 80 years old who participated in events dedicated to measuring physical fitness. PRIMARY AND SECONDARY OUTCOME MEASURES: We assessed the results of the following fitness tests: 20 m shuttle run, standing broad jump, repeated squat jump, 4*10 m shuttle run, speed, flexibility and push ups in relation to age and body mass index (BMI) using Spearman's rho, a one-way analysis of variance. A bi-exponential model was used to represent the performance with age. RESULTS: Our major results showed higher performances for men and for subjects with normal BMI at all age groups except for the flexibility test. BMI was strongly correlated across all ages with physical fitness p<0.0001. Furthermore, through bi-exponential model, a mean peak performance was identified at 26.32 years of age for men and 22.18 years of age for women. CONCLUSIONS: Physical fitness assessment using a simple series of tests on the general population offers an important indicator of health status. The possibility of observing the evolution of fitness levels with time provides an important monitoring method from a public health perspective. Further research is needed to reinforce and evaluate the approach. PMID- 23024258 TI - The effect of healthcare delivery privatisation on avoidable mortality: longitudinal cross-regional results from Italy, 1993-2003. AB - BACKGROUND: During the 1990s, Italy privatised a significant portion of its healthcare delivery. The authors compared the effectiveness of private and public sector healthcare delivery in reducing avoidable mortality (deaths that should not occur in the presence of effective medical care). METHODS: The authors calculated the average rate of change in age-standardised avoidable mortality rates in 19 of Italy's regions from 1993 to 2003. Multivariate regression models were used to analyse the relationship between rates of change in avoidable mortality and levels of spending on public versus private healthcare delivery, controlling for potential demographic and economic confounders. RESULTS: Greater spending on public delivery of health services corresponded to faster reductions in avoidable mortality rates. Each ?100 additional public spending per capita on NHS delivery was independently associated with a 1.47% reduction in the rate of avoidable mortality (p=0.003). In contrast, spending on private sector services had no statistically significant effect on avoidable mortality rates (p=0.557). A higher percentage of spending on private sector delivery was associated with higher rates of avoidable mortality (p=0.002). The authors found that neither public nor private sector delivery spending was significantly associated with non avoidable mortality rates, plausibly because non-avoidable mortality is insensitive to healthcare services. CONCLUSION: Public spending was significantly associated with reductions in avoidable mortality rates over time, while greater private sector spending was not at the regional level in Italy. PMID- 23024259 TI - Changing associations between partnership history and risk of accidents, violence and suicides. AB - BACKGROUND: Lower mortality has been systematically found in married when compared with non-married, especially in men, but little is known about marital status differences in mortality from external causes. Furthermore, the role of cohabitation and partnership history in the formation of these differences and how they have been changed over time are poorly understood. METHODS: The incidence of fatal and non-fatal cases of accidents, violence and suicides by partnership history was analysed during 1991-1997 and 2001-2007 in a representative sample of the Finnish population aged 26-59 years. HRs were calculated using Cox proportional hazards models. RESULTS: Incidence rates in accidents, violence and suicides were generally lower in men and women living with a partner than those living alone. Current cohabitation and previous divorce increased the risk of all of these outcomes when compared with married without previous divorce. Higher incidence rates were found in men who had divorced 3 years ago or earlier when compared with those who had divorced later. Generally, these differences were larger in fatal than in non-fatal cases and significantly larger in men. There was little change in these differences between 1991-1997 and 2001-2007. These differences were partly explained by socioeconomic factors but remained statistically significant also after these adjustments. CONCLUSIONS: Currently living without a partner and cohabitation and previous divorce increased the risk of accidents, violence and suicides. This indicates that also other mechanisms than immediate support from a partner are important in the formation of marital status differences in mortality. PMID- 23024260 TI - Activin A stimulates AKR1C3 expression and growth in human prostate cancer. AB - Local androgen synthesis in prostate cancer (PC) may contribute to the development of castration-resistant PC (CRPC), but pathways controlling intratumoral steroidogenic enzyme expression in PC are unknown. We investigated the effects of activin, a factor involved in the regulation of PC growth and steroidogenic enzyme expression in other steroidogenic tissues, on intratumoral steroidogenesis in PC. Activin A effects and regulation of the activin-signaling pathway molecules were studied in the PC cell lines LNCaP, VCaP, and PC-3 and in 13 individual PC xenograft models. Also, expression levels of inhibin betaA- and betaB-subunits (INHBA and INHBB) and of the activin antagonist follistatin were quantitated in patient PC tissues. Activin A induced the expression and enzyme activity of 17beta-hydroxysteroid dehydrogenase enzyme AKR1C3 in LNCaP and VCaP cells. Inhibition of endogenous activin A action in the PC-3 cell line decreased AKR1C3 levels and consequently testosterone synthesis. In return, androgens suppressed INHBA expression in both VCaP cells and the PC xenograft models. The antiproliferative effects of activin A were opposed by physiological concentrations of androstenedione in LNCaP cells. In patient PC tissues, expression levels of INHBA were increased in CRPC samples and correlated with AKR1C3 levels. Moreover, a high ratio of activin subunits to follistatin was associated with a worse metastasis-free survival in patients. In conclusion, activin A is controlled by androgens in PC models and regulates local androgen production. Activin A thus seems to mediate (residual) intratumoral androgen levels and could form a novel therapeutic target in CRPC. PMID- 23024262 TI - Nuclear receptor 5A (NR5A) family regulates 5-aminolevulinic acid synthase 1 (ALAS1) gene expression in steroidogenic cells. AB - 5-Aminolevulinic acid synthase 1 (ALAS1) is a rate-limiting enzyme for heme biosynthesis in mammals. Heme is essential for the catalytic activities of P450 enzymes including steroid metabolic enzymes. Nuclear receptor 5A (NR5A) family proteins, steroidogenic factor-1 (SF-1), and liver receptor homolog-1 (LRH-1) play pivotal roles in regulation of steroidogenic enzymes. Recently, we showed that expression of SF-1/LRH-1 induces differentiation of mesenchymal stem cells into steroidogenic cells. In this study, genome-wide analysis revealed that ALAS1 was a novel SF-1-target gene in differentiated mesenchymal stem cells. Chromatin immunoprecipitation and reporter assays revealed that SF-1/LRH-1 up-regulated ALAS1 gene transcription in steroidogenic cells via binding to a 3.5-kb upstream region of ALAS1. The ALAS1 gene was up-regulated by overexpression of SF-1/LRH-1 in steroidogenic cells and down-regulated by knockdown of SF-1 in these cells. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha, a coactivator of nuclear receptors, also strongly coactivated expression of NR5A target genes. Reporter analysis revealed that peroxisome proliferator-activated receptor-gamma coactivator-1alpha strongly augmented ALAS1 gene transcription caused by SF-1 binding to the 3.5-kb upstream region. Finally knockdown of ALAS1 resulted in reduced progesterone production by steroidogenic cells. These results indicate that ALAS1 is a novel NR5A-target gene and participates in steroid hormone production. PMID- 23024261 TI - Disruption of the melanin-concentrating hormone receptor 1 (MCH1R) affects thyroid function. AB - Melanin-concentrating hormone (MCH) is a peptide produced in the hypothalamus and the zona incerta that acts on one receptor, MCH receptor 1 (MCH1R), in rodents. The MCH system has been implicated in the regulation of several centrally directed physiological responses, including the hypothalamus-pituitary-thyroid axis. Yet a possible direct effect of the MCH system on thyroid function has not been explored in detail. We now show that MCH1R mRNA is expressed in thyroid follicular cells and that mice lacking MCH1R [MCH1R-knockout (KO)] exhibit reduced circulating iodothyronine (T(4), free T(4), T(3), and rT(3)) levels and high TRH and TSH when compared with wild-type (WT) mice. Because the TSH of MCH1R KO mice displays a normal bioactivity, we hypothesize that their hypothyroidism may be caused by defective thyroid function. Yet expression levels of the genes important for thyroid hormones synthesis or secretion are not different between the MCH1R-KO and WT mice. However, the average thyroid follicle size of the MCH1R KO mice is larger than that of WT mice and contained more free and total T(4) and T(3) than the WT glands, suggesting that they are sequestered in the glands. Indeed, when challenged with TSH, the thyroids of MCH1R-KO mice secrete lower amounts of T(4). Similarly, secretion of iodothyronines in the plasma upon (125)I administration is significantly reduced in MCH1R-KO mice. Therefore, the absence of MCH1R affects thyroid function by disrupting thyroid hormone secretion. To our knowledge, this study is the first to link the activity of the MCH system to the thyroid function. PMID- 23024263 TI - Hepatocyte growth factor plays a key role in insulin resistance-associated compensatory mechanisms. AB - Insulin resistance is present in obesity and in type 2 diabetes and is associated with islet cell hyperplasia and hyperinsulinemia, but the driving forces behind this compensatory mechanism are incompletely understood. Previous data have suggested the involvement of an unknown circulating insulin resistance-related beta-cell growth factor. In this context, looking for candidates to be a circulating factor, we realized that hepatocyte growth factor (HGF) is a strong candidate as a link between insulin resistance and increased mass of islets/hyperinsulinemia. Our approach aimed to show a possible cause-effect relationship between increase in circulating HGF levels and compensatory islet hyperplasia/hyperinsulinemia by showing the strength of the association, whether or not is a dose-dependent response, the temporality, consistency, plausibility, and reversibility of the association. In this regard, our data showed: 1) a strong and consistent correlation between HGF and the compensatory mechanism in three animal models of insulin resistance; 2) HGF increases beta-cell mass in a dose-dependent manner; 3) blocking HGF shuts down the compensatory mechanisms; and 4) an increase in HGF levels seems to precede the compensatory response associated with insulin resistance, indicating that these events occur in a sequential mode. Additionally, blockages of HGF receptor (Met) worsen the impaired insulin-induced insulin signaling in liver of diet-induced obesity rats. Overall, our data indicate that HGF is a growth factor playing a key role in islet mass increase and hyperinsulinemia in diet-induced obesity rats and suggest that the HGF-Met axis may have a role on insulin signaling in the liver. PMID- 23024264 TI - Preconditioning of stem cells by oxytocin to improve their therapeutic potential. AB - Principal limitation of cell therapy is cell loss after transplantation because of the interplay between ischemia, inflammation, and apoptosis. We investigated the mechanism of preconditioning of mesenchymal stem cells (MSCs) with oxytocin (OT), which has been proposed as a novel strategy for enhancing therapeutic potential of these cells in ischemic heart. In this study, we demonstrate that rat MSCs express binding sites for OT receptor and OT receptor transcript and protein as detected by RT-PCR and immunofluorescence, respectively. In response to OT (10(-10) to 10(-6) M) treatment, MSCs respond with rapid calcium mobilization and up-regulation of the protective protein kinase B (PKB or Akt) and phospho-ERK1/2 proteins. In OT-stimulated cells, phospho-Akt accumulates intracellularly close to the mitochondrial marker cytochrome c oxidase subunit 4. Functional analyses reveal the involvement of Akt/ERK1/2 pathways in cell proliferation, migration, and protection against the cytotoxic and apoptotic effects of hypoxia and serum deprivation. In addition, OT preconditioning increases MSC glucose uptake. Genes with angiogenic, antiapoptotic, and cardiac antiremodeling properties, such as heat shock proteins (hsps) HSP27, HSP32, HSP70, vascular endothelial growth factor, thrombospondin, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, TIMP-3, and matrix metalloproteinase-2, were also up-regulated upon OT exposure. Moreover, coculture with OT-preconditioned MSC reduces apoptosis, as measured using terminal transferase dUTP nick end labeling assay in newborn rat cardiomyocytes exposed to hypoxia and reoxygenation. In conclusion, these results indicate that OT treatment evokes MSC protection through both intrinsic pathways and secretion of cytoprotective factors. Ex vivo cellular treatment with OT represents an attractive strategy aimed to maximize the biological and functional properties of effector cells. PMID- 23024265 TI - Role of substance P in renal injury during DOCA-salt hypertension. AB - Substance P (SP), a neurokinin-1 receptor (NK-1R) agonist, is mainly produced and stored in primary sensory nerves and, upon its release, participates in cardiovascular and renal functional regulation. This study tests the hypothesis that activation of the NK-1Rs by SP occurs during hypertension induced by deoxycorticosterone (DOCA)-salt treatment, which contributes to renal injury in this model. C57BL/6 mice were subjected to uninephrectomy and DOCA-salt treatment in the presence or absence of administration of selective NK-1 antagonists, L 733,060 (20 mg/kg.d, ip) or RP-67580 (8 mg/kg.d, ip). Five weeks after the treatment, mean arterial pressure determined by the telemetry system increased in DOCA-salt mice but without difference between NK-1R antagonist-treated or NK-1R antagonist-untreated DOCA-salt groups. Plasma SP levels were increased in DOCA salt compared with control mice (P < 0.05). Renal hypertrophy and increased urinary 8-isoprostane and albumin excretion were observed in DOCA-salt compared with control mice (P < 0.05). Periodic acid-Schiff and Masson's trichrome staining showed more severe glomerulosclerosis and tubulointerstitial injury in the renal cortex in DOCA-salt compared with control mice, respectively (P < 0.05). Hydroxyproline assay and F4/80-staining showed that renal collagen levels and interstitial monocyte/macrophage infiltration were greater in DOCA-salt compared with control mice, respectively (P < 0.05). Blockade of the NK-1R with L 733,060 or RP-67580 in DOCA-salt mice suppressed increments in urinary 8 isoprostane and albumin excretion, interstitial monocyte/macrophage infiltration, and glomerulosclerosis and tubulointerstitial injury and fibrosis (P < 0.05). Thus, our data show that blockade of the NK-1Rs alleviates renal functional and tissue injury in the absence of alteration in blood pressure in DOCA-salt hypertensive mice. The results suggest that elevated SP levels during DOCA-salt hypertension play a significant role contributing to renal damage possibly via enhancing oxidative stress and macrophage infiltration of the kidney. PMID- 23024266 TI - Proliferation rates of multiple endocrine neoplasia type 1 (MEN1)-associated tumors. AB - Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid and adrenocortical tumors, and neuroendocrine tumors (NETs) of the pancreas and pituitary. The pancreatic NETs are predominantly gastrinomas and insulinomas, and the pituitary NETs are mostly prolactinomas and somatotrophinomas. We postulated that the different types of pancreatic and pituitary NETs may be partly due to differences in their proliferation rates, and we therefore assessed these in MEN1-associated tumors and gonadal tumors that developed in mice deleted for an Men1 allele (Men1(+/-)). To label proliferating cells in vivo, Men1(+/-) and wild-type (Men1(+/+)) mice were given 5-bromo-2-deoxyuridine (BrdU) in drinking water from 1-12 wk, and tissue sections were immunostained using anti-BrdU and hormone specific antibodies. Proliferation in the tumors of Men1(+/-) mice was significantly (P < 0.001) increased when compared with the corresponding normal Men1(+/+) tissues. Pancreatic, pituitary and adrenocortical proliferation fitted first- and second-order regression lines in Men1(+/+) tissues and Men1(+/-) tumors, respectively, R(2) = 0.999. Apoptosis was similar in Men1(+/-) pancreatic, pituitary, and parathyroid tumors when compared with corresponding normal tissues, decreased in Men1(+/-) adrenocortical tumors, but increased in Men1(+/-) gonadal tumors. Mathematical modeling of NET growth rates (proliferation minus apoptosis rates) predicted that in Men1(+/-) mice, only pancreatic beta-cells, pituitary lactotrophs and somatotrophs could develop into tumors within a murine lifespan. Thus, our studies demonstrate that Men1(+/-) tumors have low proliferation rates (<2%), second-order kinetics, and the higher occurrence of insulinomas, prolactinomas, and somatotrophinomas in MEN1 is consistent with a mathematical model for NET proliferation. PMID- 23024267 TI - Identification of the deleted in split hand/split foot 1 protein as a novel biomarker for human cervical cancer. AB - The morphological detection of early neoplastic transformation leading to cervical cancer remains problematic. In this work, we have identified deleted in split hand/split foot 1 protein (DSS1) as an early biomarker that is specifically upregulated in premalignant and malignant cervical epithelial cells, but is low or undetectable in non-malignant cells. DSS1 mRNA and protein levels are significantly increased in cultured human cervical carcinoma cell lines originating from primary and metastatic tumors. In fact, > 96% of patient tumor tissues were found to have cells with elevated DSS1 when compared with tumor adjacent normal cells. In histological sections of cervical tissue containing either invasive cervical carcinoma or its precursor lesions, DSS1 was readily detected in the tumor cells. Steady-state DSS1 expression by immortalized cervical cancer cell lines was found to be necessary for maintenance of their transformed phenotype, since stable shRNA-mediated depletion of DSS1 in HeLa cells inhibited their proliferation and colony-forming activity in monolayer cultures and prevented division of these cells in soft agar. When DSS1 levels are reduced using shRNA, the cells ultimately undergo apoptosis via activation of p53 and the p53 downstream targets, and cleavage of apoptosis-associated proteins including CPP32/caspase-3, poly(ADP-ribose)polymerase and DNA-PKcs. In addition, silencing of DSS1 makes cervical cancer cells sensitive to cell death after treatment with cisplatin. We conclude that the DSS1 protein is critically involved in the maintenance of the transformed phenotype in cervical cancer cells, and that it might be a specific, robust and reliable marker for early detection, diagnosis and treatment. PMID- 23024268 TI - The novel human p.I587V variant in the ZNF644 gene is unlikely to be the pathogenic cause of dominantly inherited high myopia in a Chinese patient. PMID- 23024270 TI - Integrative genomics in cardiovascular medicine. AB - Integrative genomics studies have greatly advanced our understanding of cardiovascular pathophysiology over the last decade. Here, we highlight the strengths and challenges of this cutting-edge approach and provide examples where novel insights have arisen through the integration of multi-level genomic information and cardiac physiology. Going forward, the integration of comprehensive next-generation sequencing data sets with quantitative phenotypes at the molecular, cellular, and whole-heart level using advanced modelling approaches provides an unprecedented opportunity for cardiovascular science. PMID- 23024269 TI - Insights into dietary flavonoids as molecular templates for the design of anti platelet drugs. AB - Flavonoids are low-molecular weight, aromatic compounds derived from fruits, vegetables, and other plant components. The consumption of these phytochemicals has been reported to be associated with reduced cardiovascular disease (CVD) risk, attributed to their anti-inflammatory, anti-proliferative, and anti thrombotic actions. Flavonoids exert these effects by a number of mechanisms which include attenuation of kinase activity mediated at the cell-receptor level and/or within cells, and are characterized as broad-spectrum kinase inhibitors. Therefore, flavonoid therapy for CVD is potentially complex; the use of these compounds as molecular templates for the design of selective and potent small molecule inhibitors may be a simpler approach to treat this condition. Flavonoids as templates for drug design are, however, poorly exploited despite the development of analogues based on the flavonol, isoflavonone, and isoflavanone subgroups. Further exploitation of this family of compounds is warranted due to a structural diversity that presents great scope for creating novel kinase inhibitors. The use of computational methodologies to define the flavonoid pharmacophore together with biological investigations of their effects on kinase activity, in appropriate cellular systems, is the current approach to characterize key structural features that will inform drug design. This focussed review highlights the potential of flavonoids to guide the design of clinically safer, more selective, and potent small-molecule inhibitors of cell signalling, applicable to anti-platelet therapy. PMID- 23024271 TI - Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation. AB - We have investigated the intracellular sources and physiological function of reactive oxygen species (ROS) produced in primary B cells in response to BCR stimulation. BCR stimulation of primary resting murine B cells induced the rapid production of ROS that occurred within minutes and was maintained for at least 24 h after receptor stimulation. While the early production of ROS (0-2 h) was dependent on the Nox2 isoform of NADPH oxidase, at later stages of B cell activation (6-24 h) ROS were generated by a second pathway, which appeared to be dependent on mitochondrial respiration. B cells from mice deficient in the Nox2 NADPH oxidase complex lacked detectable early production of extracellular and intracellular ROS after BCR stimulation but had normal proximal BCR signaling and BCR-induced activation and proliferation in vitro and mounted normal or somewhat elevated Ab responses in vivo. In contrast, neutralizing both pathways of BCR derived ROS with the scavenger N-acetylcysteine resulted in impaired in vitro BCR induced activation and proliferation and attenuated BCR signaling through the PI3K pathway at later times. These results indicate that the production of ROS downstream of the BCR is derived from at least two distinct cellular sources and plays a critical role at the later stages of B cell activation by promoting sustained BCR signaling via the PI3K pathway, which is needed for effective B cell responses to Ag. PMID- 23024273 TI - Blockade of phosphatidylinositol 3-kinase PI3Kdelta or PI3Kgamma reduces IL-17 and ameliorates imiquimod-induced psoriasis-like dermatitis. AB - Psoriasis is a chronic inflammatory skin disease triggered by interplay between immune mediators from both innate and adaptive immune systems and skin tissue, in which the IL-23/IL-17 axis is critical. PI3Kdelta and PI3Kgamma play important roles in various immune cell functions. We found that mice lacking functional PI3Kdelta or PI3Kgamma are largely protected from imiquimod (IMQ)-induced psoriasis-like dermatitis, correlating with reduced IL-17 levels in the lesions, serum, and the draining lymph nodes. TCRgammadelta T cells were the major IL-17 producing population in the draining lymph nodes and were significantly diminished in IMQ-treated PI3Kdelta knockin and PI3Kgamma knockout mice. We also show that PI3Kdelta and PI3Kgamma inhibitors reduced IFN-gamma production by human TCRgammadelta T cells and IL-17 and IFN-gamma production by PBMCs from psoriatic or healthy donors. In addition, inhibition of PI3Kgamma, but not PI3Kdelta, blocked chemotaxis of CCR6(+)IL-17-producing cells from IMQ-treated mice or healthy human donors. Taken together, these data indicate that PI3Kdelta and/or PI3Kgamma inhibitors should be considered for treating IL-17-driven diseases, such as psoriasis. PMID- 23024272 TI - The inducible tissue-specific expression of the human IL-3/GM-CSF locus is controlled by a complex array of developmentally regulated enhancers. AB - The closely linked human IL-3 and GM-CSF genes are tightly regulated and are expressed in activated T cells and mast cells. In this study, we used transgenic mice to study the developmental regulation of this locus and to identify DNA elements required for its correct activity in vivo. Because these two genes are separated by a CTCF-dependent insulator, and the GM-CSF gene is regulated primarily by its own upstream enhancer, the main objective in this study was to identify regions of the locus required for correct IL-3 gene expression. We initially found that the previously identified proximal upstream IL-3 enhancers were insufficient to account for the in vivo activity of the IL-3 gene. However, an extended analysis of DNase I-hypersensitive sites (DHSs) spanning the entire upstream IL-3 intergenic region revealed the existence of a complex cluster of both constitutive and inducible DHSs spanning the -34- to -40-kb region. The tissue specificity of these DHSs mirrored the activity of the IL-3 gene, and included a highly inducible cyclosporin A-sensitive enhancer at -37 kb that increased IL-3 promoter activity 40-fold. Significantly, inclusion of this region enabled correct in vivo regulation of IL-3 gene expression in T cells, mast cells, and myeloid progenitor cells. PMID- 23024274 TI - Inflammatory signals direct expression of human IL12RB1 into multiple distinct isoforms. AB - IL12RB1 is essential for human resistance to multiple intracellular pathogens, including Mycobacterium tuberculosis. In its absence, the proinflammatory effects of the extracellular cytokines IL-12 and IL-23 fail to occur, and intracellular bacterial growth goes unchecked. Given the recent observation that mouse leukocytes express more than one isoform from il12rb1, we examined whether primary human leukocytes similarly express more than one isoform from IL12RB1. We observed that human leukocytes express as many as 13 distinct isoforms, the relative levels of each being driven by inflammatory stimuli both in vitro and in vivo. Surprisingly, the most abundant isoform present before stimulation is a heretofore uncharacterized intracellular form of the IL-12R (termed "isoform 2") that presumably has limited contact with extracellular cytokine. After stimulation, primary PBMCs, including the CD4(+), CD8(+), and CD56(+) lineages contained therein, alter the splicing of IL12RB1 RNA to increase the relative abundance of isoform 1, which confers IL-12/IL-23 responsiveness. These data demonstrate both a posttranscriptional mechanism by which cells regulate their IL 12/IL-23 responsiveness, and that leukocytes primarily express IL12RB1 in an intracellular form located away from extracellular cytokine. PMID- 23024276 TI - C/EBPbeta is involved in the amplification of early granulocyte precursors during candidemia-induced "emergency" granulopoiesis. AB - Granulopoiesis is tightly regulated to meet host demands during both "steady state" and "emergency" situations, such as infections. The transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) plays critical roles in emergency granulopoiesis, but the precise developmental stages in which C/EBPbeta is required are unknown. In this study, a novel flow cytometric method was developed that successfully dissected mouse bone marrow cells undergoing granulopoiesis into five distinct subpopulations (#1-5) according to their levels of c-Kit and Ly-6G expression. After the induction of candidemia, rapid mobilization of mature granulocytes and an increase in early granulocyte precursors accompanied by cell cycle acceleration was followed by a gradual increase in granulocytes originating from the immature populations. Upon infection, C/EBPbeta was upregulated at the protein level in all the granulopoietic subpopulations. The rapid increase in immature subpopulations #1 and #2 observed in C/EBPbeta knockout mice at 1 d postinfection was attenuated. Candidemia-induced cell cycle acceleration and proliferation of hematopoietic stem/progenitors were also impaired. Taken together, these data suggest that C/EBPbeta is involved in the efficient amplification of early granulocyte precursors during candidemia-induced emergency granulopoiesis. PMID- 23024275 TI - The Yaa locus and IFN-alpha fine-tune germinal center B cell selection in murine systemic lupus erythematosus. AB - Male NZW/BXSB.Yaa (W/B) mice express two copies of TLR7 and develop pathogenic autoantibodies, whereas females with only one copy of TLR7 have attenuated disease. Our goal was to analyze the regulation of the autoantibody response in male and female W/B mice bearing the autoreactive site-directed H chain transgene 3H9. Serum anti-dsDNA Abs appeared in males at 12 wk, and most had high-titer IgG anti-dsDNA and anti-cardiolipin Abs and developed >300 mg/dl proteinuria by 8 mo. Females had only low-titer IgG anti-cardiolipin Abs, and none developed proteinuria by 1 y. Males had a smaller marginal zone than females with a repertoire that was distinct from the follicular repertoire, indicating that the loss of marginal zone B cells was not due to diversion to the follicular compartment. Vk5-43 and Vk5-48, which were rare in the naive repertoire, were markedly overrepresented in the germinal center repertoire of both males and females, but the VJ junctions differed between males and females with higher affinity autoreactive B cells being selected into the germinal centers of males. Administration of IFN-alpha to females induced anti-cardiolipin and anti-DNA autoantibodies and proteinuria and was associated with a male pattern of junctional diversity in Vk5-43 and Vk5-48. Our studies are consistent with the hypothesis that presence of the Yaa locus, which includes an extra copy of Tlr7, or administration of exogenous IFN-alpha relaxes the stringency for selection in the germinal centers resulting in increased autoreactivity of the Ag-driven B cell repertoire. PMID- 23024278 TI - TCR-redirected human T cells inhibit hepatitis C virus replication: hepatotoxic potential is linked to antigen specificity and functional avidity. AB - Virus-specific CTL with high levels of functional avidity have been associated with viral clearance in hepatitis C virus (HCV) infection and with enhanced protective immunity. In chronic HCV infection, lack of antiviral CTL is frequently observed. In this study, we aim to investigate novel HCV TCRs that differ in Ag specificity. This involved isolating new HCV-specific murine TCRs that recognize a conserved HLA-A2-restricted CTL epitope within the nonstructural protein (NS) 5A viral protein and comparing them with TCRs recognizing another conserved CTL target in the NS3 viral protein. This was done by expressing the TCRs in human T cells and analyzing the function of the resulting TCR-transduced T cells. Our result indicates that these TCRs are efficiently assembled in transduced human T cells. They recognize peptide-loaded targets and demonstrate polyfunctional features such as IL-2, IFN-gamma, and TNF-alpha secretion. However, in contrast to NS3-specific TCRs, the NS5A TCR-transduced T cells consist of a smaller proportion of polyfunctional T cells and require more peptide ligands to trigger the effector functions, including degranulation. Despite the differences, NS5A TCRs show effective inhibition of HCV replication in human hepatoma cells with persistent HCV RNA replication. Moreover, cellular injury demonstrated by aspartate aminotransferase release and cell death is less significant in the hepatoma cells following coincubation with NS5A TCR-transduced T cells, which is a property consistent with noncytotoxic antiviral CTLs. Our results suggest that HCV TCR-transduced T cells may be promising for the treatment of patients with chronic HCV infections. PMID- 23024277 TI - Thymic stromal lymphopoietin-dependent basophils promote Th2 cytokine responses following intestinal helminth infection. AB - CD4(+) Th2 cytokine responses promote the development of allergic inflammation and are critical for immunity to parasitic helminth infection. Recent studies highlighted that basophils can promote Th2 cytokine-mediated inflammation and that phenotypic and functional heterogeneity exists between classical IL-3 elicited basophils and thymic stromal lymphopoietin (TSLP)-elicited basophils. However, whether distinct basophil populations develop after helminth infection and their relative contributions to anti-helminth immune responses remain to be defined. After Trichinella spiralis infection of mice, we show that basophil responses are rapidly induced in multiple tissue compartments, including intestinal-draining lymph nodes. Trichinella-induced basophil responses were IL-3 IL-3R independent but critically dependent on TSLP-TSLPR interactions. Selective depletion of basophils after Trichinella infection impaired infection-induced CD4(+) Th2 cytokine responses, suggesting that TSLP-dependent basophils augment Th2 cytokine responses after helminth infection. The identification and functional classification of TSLP-dependent basophils in a helminth infection model, coupled with their recently described role in promoting atopic dermatitis, suggests that these cells may be a critical population in promoting Th2 cytokine associated inflammation in a variety of inflammatory or infectious settings. Collectively, these data suggest that the TSLP-basophil pathway may represent a new target in the design of therapeutic intervention strategies to promote or limit Th2 cytokine-dependent immunity and inflammation. PMID- 23024279 TI - The unique cytoplasmic domain of human FcgammaRIIIA regulates receptor-mediated function. AB - Ligand specificity characterizes receptors for Abs and many other immune receptors, but the common use of the FcR gamma-chain as their signaling subunit challenges the concept that these receptors are functionally distinct. We hypothesized that elements for specificity might be determined by the unique cytoplasmic domain (CY) sequences of the ligand-binding alpha-chains of gamma chain-associated receptors. Among Fcgamma receptors, a protein kinase C (PKC) phosphorylation consensus motif [RSSTR], identified within the FcgammaRIIIa (CD16A) CY by in silico analysis, is specifically phosphorylated by PKCs, unlike other FcRs. Phosphorylated CD16A mediates a more robust calcium flux, tyrosine phosphorylation of Syk, and proinflammatory cytokine production, whereas nonphosphorylatable CD16A is more effective at activation of the Gab2/PI3K pathway, leading to enhanced degranulation. S100A4, a specific protein-binding partner for CD16A-CY newly identified by yeast two-hybrid analysis, inhibits phosphorylation of CD16A-CY by PKC in vitro, and reduction of S100A4 levels in vivo enhances receptor phosphorylation upon cross-linking. Taken together, PKC mediated phosphorylation of CD16A modulates distinct signaling pathways engaged by the receptor. Calcium-activated binding of S100A4 to CD16A, promoted by the initial calcium flux, attenuates the phosphorylation of CY, and, acting as a molecular switch, may both serve as a negative feedback on cytokine production pathways during sustained receptor engagement and favor a shift to degranulation, consistent with the importance of granule release following conjugate formation between CD16A(+) effector cells and target cells. This switch mechanism points to new therapeutic targets and provides a framework for understanding novel receptor polymorphisms. PMID- 23024280 TI - Cutting edge: regulation of intestinal inflammation and barrier function by IL 17C. AB - In the IL-17 family of cytokines, much is known about the sources and functions of IL-17, IL-17F, and IL-25 in the host defense against infection and in inflammatory diseases; however, the physiological function of IL-17C remains poorly understood. Using mice deficient in IL-17C, we demonstrate that this cytokine is crucial for the regulation of an acute experimental colitis elicited by dextran sulfate sodium. In this model, mice lacking IL-17C exhibited exacerbated disease that was associated with increased IL-17 expression by gammadelta T cells and Th17 cells. Moreover, IL-17C directly regulated the expression of the tight junction molecule occludin by colonic epithelial cells. Thus, our data suggest that IL-17C plays a critical role in maintaining mucosal barrier integrity. PMID- 23024282 TI - General rules for clinical and pathological studies on oral cancer: a synopsis. AB - For the doctors and other medical staff treating oral cancers, it is necessary to standardize basic concepts and rules on oral cancers to progress in the treatment, research and diagnosis. Oral cancers are integrated in head and neck cancers and are applied to the general rules on head and neck cancer, but it is considered that more detailed rules based on the characteristics of oral cancers are essential. The objectives of this 'General Rules for Clinical and Pathological Studies on Oral Cancer' are to contribute to the development of the diagnosis, treatment and research of oral cancers based on the correct and useful medical information of clinical, surgical, pathological and image findings accumulated from individual patients at various institutions. PMID- 23024281 TI - Cutting edge: IL-1beta processing during Pseudomonas aeruginosa infection is mediated by neutrophil serine proteases and is independent of NLRC4 and caspase 1. AB - To examine the role of caspase-1 and the NLRC4 inflammasome during bacterial infection, C57BL/6, IL-1beta(-/-), caspase-1(-/-), and NLRC4(-/-) mouse corneas were infected with ExoS/T- or ExoU-expressing Pseudomonas aeruginosa. We found that IL-1beta was essential for neutrophil recruitment and bacterial clearance and was produced by myeloid cells rather than resident cells. In addition, neutrophils were found to be the primary source of mature IL-1beta during infection, and there was no significant difference in IL-1beta processing between C57BL/6 and caspase-1(-/-) or NLRC4(-/-) infected corneas. IL-1beta cleavage by human and mouse neutrophils was blocked by serine protease inhibitors and was impaired in infected neutrophil elastase (NE)(-/-) corneas. NE(-/-) mice also had an impaired ability to clear the infection. Together, these results demonstrate that during P. aeruginosa infection, neutrophils are the primary source of mature IL-1beta and that IL-1beta processing is dependent on serine proteases and not NLRC4 or caspase-1. PMID- 23024283 TI - Recent developments in the management of cancer pain in Japan: education, clinical guidelines and basic research. AB - The Cancer Control Act of Japan came into effect in 2007. Most physicians, however, have not yet had sufficient opportunity to learn about pain management and other clinical palliative care practices. In an attempt to rectify this situation, the Japanese Society for Palliative Medicine has initiated the Palliative care Emphasis program on symptom management and Assessment for Continuous medical Education project. The two major roles of this project are to establish a faculty development program in palliative care, and to provide support for conducting workshops about basic palliative care throughout Japan. Another important movement is the development of a clinical guideline for the management of cancer pain. The Japanese Society for Palliative Medicine developed a clinical guideline for the pharmacological management of cancer pain in 2010. On the other hand, although clinical experience has demonstrated that psychological dependence is not a major concern when morphine is used to control pain in cancer patients, undue anxiety about psychological dependence on morphine in cancer patients has led physicians and patients to use inadequate doses of opioids. In an attempt to remedy this situation, therefore, Japanese basic researchers are cooperatively involved in conducting high-quality basic research to answer clinical questions in palliative care. They have demonstrated to the world, for the first time, that (i) chronic pain dramatically attenuates the reward effects of opioids and that (ii) atypical antipsychotics, such as olanzapine, can suppress morphine-induced emesis and alleviate the sleep dysregulation associated with neuropathic pain in animals. Thus, we are working in close collaboration to establish new strategies for palliative care in Japan. PMID- 23024285 TI - Dendritic cell science: more than 40 years of history. AB - Over 40 years of research into the field of DCs has revolutionized our understanding into the activation and regulation of the immune system. This minireview discusses the major breakthroughs in DC science that have paved the way to the 2011 Nobel Prize in Physiology-Medicine awarded to Bruce A. Beutler and Jules A. Hoffmann (for their discoveries in innate immune recognition) and Ralph M. Steinman (for his discovery of the DC). PMID- 23024284 TI - G-CSF-activated STAT3 enhances production of the chemokine MIP-2 in bone marrow neutrophils. AB - Neutrophil mobilization from the bone marrow is a critical aspect of the innate immune response, enabling a rapid deployment of phagocytes to infected or inflamed tissue. The cytokine G-CSF, which is induced rapidly during infection, elicits a swift and potent mobilizing response, yet its mechanisms of action remain poorly understood. Here, we studied the role of G-CSF and its principal signal transducer STAT3 in regulating expression of the neutrophil chemoattractant MIP-2. Our studies revealed Gr-1(hi) mature neutrophils as major sources of Cxcl2 (MIP-2) mRNA in bone marrow and G-CSF-responsive MIP-2 protein production. Induction of Cxcl2 was regulated directly by G-CSF-activated STAT3 via interaction at a STAT consensus element in the Cxcl2 promoter. G-CSF coordinately stimulated the association of STAT3, induction of the transcriptionally active H3K4me3 modification, and recruitment of RNA Pol II at the Cxcl2 proximal promoter, as well as the promoter region of Il8rb, encoding the MIP-2 receptor. These results suggest that the G-CSF-STAT3 pathway directly regulates transcriptional events that induce neutrophil mobilization. PMID- 23024288 TI - SNVerGUI: a desktop tool for variant analysis of next-generation sequencing data. AB - BACKGROUND: Advances in next generation sequencing (NGS) technology have made it possible to interrogate comprehensively genome-wide genetic variations. However, most existing tools for variation detection are based on command-line interface, which discourages the main end users of NGS data, such as biologists, geneticists and clinicians, from utilising the software. METHOD AND RESULTS: We have developed the SNVerGUI, a graphical user interface (GUI) based tool for variant detection and analysis. Compared with other methods for variant calling, our approach is unique in that it is applicable to both individual and pooled sequencing data. With friendly GUI, end users can easily adjust running parameters to optimise variant calling for their specific needs. SNVerGUI supports commonly used input and output file formats that allows SNVerGUI to be seamlessly integrated into common NGS data analysis pipelines. SNVerGUI is implemented in Java, which is platform-independent and therefore easy to install and run on the commonly used operating systems, such as Linux, Mac, and Windows. Using two real datasets, we have shown that SNVerGUI is capable of analysing very high volume NGS data in a feasible time on personal computers. CONCLUSIONS: SNVerGUI is a fast and easy desktop GUI tool for the identification of genomic variants from pooled sequencing and individual sequencing data. Using this software, users can perform sophisticated variant detection by simply configuring several parameters in a friendly graphical user interface. SNVerGUI makes variant analysis as simple and effortless as possible, and we expect it to become popular among geneticists, clinicians, and biologists. SNVerGUI can be freely downloaded from http://snver.sourceforge.net/snvergui/, and will be continuously updated upon users' feedback. PMID- 23024286 TI - Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients. AB - A hallmark of atopic eczema (AE) is skin barrier dysfunction. Lipids in the stratum corneum (SC), primarily ceramides, fatty acids, and cholesterol, are crucial for the barrier function, but their role in relation to AE is indistinct. Filaggrin is an epithelial barrier protein with a central role in the pathogenesis of AE. Nevertheless, the precise causes of AE-associated barrier dysfunction are largely unknown. In this study, a comprehensive analysis of ceramide composition and lipid organization in nonlesional SC of AE patients and control subjects was performed by means of mass spectrometry, infrared spectroscopy, and X-ray diffraction. In addition, the skin barrier and clinical state of the disease were examined. The level of ceramides with an extreme short chain length is drastically increased in SC of AE patients, which leads to an aberrant lipid organization and a decreased skin barrier function. Changes in SC lipid properties correlate with disease severity but are independent of filaggrin mutations. We demonstrate for the first time that changes in ceramide chain length and lipid organization are directly correlated with the skin barrier defects in nonlesional skin of AE patients. We envisage that these insights will provide a new therapeutic entry in therapy and prevention of AE. PMID- 23024287 TI - A physiologically based in silico kinetic model predicting plasma cholesterol concentrations in humans. AB - Increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. This study describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. This model was directly adapted from a PBK model for mice by incorporation of the reaction catalyzed by cholesterol ester transfer protein and contained 21 biochemical reactions and eight different cholesterol pools. The model was calibrated using published data for humans and validated by comparing model predictions on plasma cholesterol levels of subjects with 10 different genetic mutations (including familial hypercholesterolemia and Smith-Lemli-Opitz syndrome) with experimental data. Average model predictions on total cholesterol were accurate within 36% of the experimental data, which was within the experimental margin. Sensitivity analysis of the model indicated that the HDL cholesterol (HDL-C) concentration was mainly dependent on hepatic transport of cholesterol to HDL, cholesterol ester transfer from HDL to non-HDL, and hepatic uptake of cholesterol from non-HDL-C. Thus, the presented PBK model is a valid tool to predict the effect of genetic mutations on cholesterol concentrations, opening the way for future studies on the effect of different drugs on cholesterol levels in various subpopulations in silico. PMID- 23024289 TI - Antenatal spectrum of CHARGE syndrome in 40 fetuses with CHD7 mutations. AB - BACKGROUND: CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances. METHOD: Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed. RESULTS: Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype-genotype correlation. CONCLUSIONS: Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations. PMID- 23024290 TI - Prokaryote or eukaryote? A unique microorganism from the deep sea. AB - There are only two kinds of organisms on the Earth: prokaryotes and eukaryotes. Although eukaryotes are considered to have evolved from prokaryotes, there were no previously known intermediate forms between them. The differences in their cellular structures are so vast that the problem of how eukaryotes could have evolved from prokaryotes is one of the greatest enigmas in biology. Here, we report a unique organism with cellular structures appearing to have intermediate features between prokaryotes and eukaryotes, which was discovered in the deep sea off the coast of Japan using electron microscopy and structome analysis. The organism was 10 um long and 3 um in diameter, having >100 times the volume of Escherichia coli. It had a large 'nucleoid', consisting of naked DNA fibers, with a single nucleoid membrane and endosymbionts that resemble bacteria, but no mitochondria. Because this organism appears to be a life form distinct from both prokaryotes and eukaryotes but similar to eukaryotes, we named this unique microorganism the 'Myojin parakaryote' with the scientific name of Parakaryon myojinensis ('next to (eu)karyote from Myojin') after the discovery location and its intermediate morphology. The existence of this organism is an indication of a potential evolutionary path between prokaryotes and eukaryotes. PMID- 23024291 TI - Defective pneumococcal-specific Th1 responses in HIV-infected adults precedes a loss of control of pneumococcal colonization. AB - BACKGROUND: African adults infected with human immunodeficiency virus (HIV) have high rates of pneumococcal colonization and invasive disease. Here we have investigated the possibility that HIV disrupts the normal balance of pneumococcal specific helper T cell (Th) 1/Th17 immunity to colonization, resulting in a more permissive nasopharyngeal niche. METHODS: One hundred thirty-six HIV-infected and -uninfected Malawian adults were enrolled in the study. Changes in rates and composition of nasopharyngeal pneumococcal colonization were analyzed using microarray. The underlying pneumococcal-specific Th1/Th17 responses associated with altered pneumococcal colonization were investigated using flow cytometry. RESULTS: We find that pneumococcal carriage is only modestly increased in asymptomatic HIV-infected Malawian adults but that colonization rates rise dramatically during symptomatic disease (HIV(neg) 13%, HIV(asy) 19%, and HIV(sym) 38%). These rates remain high in subjects established on antiretroviral therapy (ART): 33% (at 6-12 months) and 52% (at 18 months), with HIV-infected individuals carrying a broader range of invasive and noninvasive serotypes compared with HIV negative controls. The frequency of multiple serotype carriage (>1 serotype HIV(neg) 26%, HIV(asy) 30%, HIV(sym) 31%, HIV(ART) 31%) is not affected. These changes in colonization are associated with generalized CD4 T-cell depletion, impaired antigen-specific proliferation, and a defect in pneumococcal-specific T cell interferon-gamma but not interleukin 17 production. CONCLUSIONS: These data reveal the persistently poor control of pneumococcal colonization in HIV-infected adults following immune ART-mediated reconstitution, highlighting a potential reservoir for person-to-person spread and vaccine escape. Novel approaches to control colonization either through vaccination or through improvements in the quality of immune reconstitution are required. PMID- 23024292 TI - Revisiting the predictors of a sustained virologic response in the era of direct acting antiviral therapy for hepatitis C virus. AB - Several host (age, sex, race, fibrosis stage, interleukin 28B polymorphism) and viral factors (hepatitis C virus [HCV] genotype, viral load) allow estimating the response to interferon-based therapies (which includes first-generation protease inhibitors) before treatment. However, treatment should not be denied to any patient based on unfavorable factors alone. Metabolic conditions associated with poor response (diabetes, insulin resistance, obesity) and alcohol abuse can be influenced before starting treatment. "On-treatment" predictors of response allow treatment to be tailored to the individual need of the patient. Patients with undetectable HCV RNA after 4 weeks (rapid virologic response [RVR]) have the highest chance for cure (>85%) both by dual and triple therapy. For triple therapy, the decision to shorten treatment requires that the virus remains undetectable for an additional 8 (telaprevir) to 20 (boceprevir) weeks (extended RVR). Based on viral kinetics, an even earlier prediction after 2 weeks of treatment with direct acting antivirals appears feasible. PMID- 23024293 TI - Reply to Chien et al. PMID- 23024294 TI - It's not that simple. PMID- 23024296 TI - Fidaxomicin "chaser" regimen following vancomycin for patients with multiple Clostridium difficile recurrences. PMID- 23024295 TI - Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus. AB - Community-acquired respiratory virus (CARV) infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). Progression to lower respiratory tract infection with clinical and radiological signs of pneumonia and respiratory failure appears to depend on the intrinsic virulence of the specific CARV as well as factors specific to the patient, the underlying disease, and its treatment. To better define the current state of knowledge of CARVs in leukemia and HSCT patients, and to improve CARV diagnosis and management, a working group of the Fourth European Conference on Infections in Leukaemia (ECIL-4) 2011 reviewed the literature on CARVs, graded the available quality of evidence, and made recommendations according to the Infectious Diseases Society of America grading system. Owing to differences in screening, clinical presentation, and therapy for influenza and adenovirus, ECIL-4 recommendations are summarized for CARVs other than influenza and adenovirus. PMID- 23024297 TI - Re: Dietary supplements and cancer prevention: balancing potential benefits against proven harms. PMID- 23024298 TI - Urinary plasmin inhibits TRPV5 in nephrotic-range proteinuria. AB - Urinary proteins that leak through the abnormal glomerulus in nephrotic syndrome may affect tubular transport by interacting with membrane transporters on the luminal side of tubular epithelial cells. Patients with nephrotic syndrome can develop nephrocalcinosis, which animal models suggest may develop from impaired transcellular Ca(2+) reabsorption via TRPV5 in the distal convoluted tubule (DCT). In nephrotic-range proteinuria, filtered plasminogen reaches the luminal side of DCT, where it is cleaved into active plasmin by urokinase. In this study, we found that plasmin purified from the urine of patients with nephrotic-range proteinuria inhibits Ca(2+) uptake in TRPV5-expressing human embryonic kidney 293 cells through the activation of protease-activated receptor-1 (PAR-1). Preincubation with a plasmin inhibitor, a PAR-1 antagonist, or a protein kinase C (PKC) inhibitor abolished the effect of plasmin on TRPV5. In addition, ablation of the PKC phosphorylation site S144 rendered TRPV5 resistant to the action of plasmin. Patch-clamp experiments showed that a decreased TRPV5 pore size and a reduced open probability accompany the plasmin-mediated reduction in Ca(2+) uptake. Furthermore, high-resolution nuclear magnetic resonance spectroscopy demonstrated specific interactions between calmodulin and residues 133-154 of the N-terminus of TRPV5 for both wild-type and phosphorylated (S144pS) peptides. In summary, PAR-1 activation by plasmin induces PKC-mediated phosphorylation of TRPV5, thereby altering calmodulin-TRPV5 binding, resulting in decreased channel activity. These results indicate that urinary plasmin could contribute to the downstream effects of proteinuria on the tubulointerstitium by negatively modulating TRPV5. PMID- 23024300 TI - How practicing dentists can shape dental research: The American Association for Dental Research's vision for the future. PMID- 23024301 TI - Endodontics in general practice. PMID- 23024299 TI - Sialylation determines the nephritogenicity of IgG3 cryoglobulins. AB - Monoclonal 6-19 IgG3 anti-IgG2a rheumatoid factor derived from lupus-prone MRL Fas(lpr) mice can induce GN and cryoglobulinemia, but the features that confer nephritogenic potential are not completely understood. Asparagine-linked oligosaccharide chains of 6-19 IgG3 mAb are poorly galactosylated and hardly sialylated, possibly contributing to the pathogenic potential of 6-19 IgG3 rheumatoid factors. Here, we used the 6-19 model of cryoglobulin-associated GN to define the relative contributions of galactosylation and sialylation, in relation to cryoglobulin activity, to the nephritogenic potential of IgG3 antibodies. We generated one highly sialylated and two distinct more galactosylated 6-19 IgG3 rheumatoid factor variants. Although the mere extent of galactosylation had no effect on either the cryogenic and nephritogenic activities of 6-19 IgG3 rheumatoid factor, terminal sialylation attenuated the nephritogenic potential of 6-19 IgG3 by limiting its cryoglobulin activity. These data suggest a protective role of IgG sialylation against the development of cryoglobulin-mediated GN, highlighting the anti-inflammatory activity of sialylated IgG antibodies. PMID- 23024302 TI - Deciding appropriate care. PMID- 23024303 TI - EMG and TMD. PMID- 23024304 TI - More About TMD. PMID- 23024305 TI - Mandatory reporting of oral injuries indicating possible child abuse. AB - BACKGROUND: The dental professional may see pediatric patients who have signs of intraoral trauma, perioral trauma or both. Evaluation should include the possibility of nonaccidental, deliberately inflicted abuse. Reporting such injuries is mandated. METHODS: The authors reviewed the criminal and civil statutes in all 50 states to determine what role dental professionals are required to play in instances of abuse or neglect. RESULTS: Mandates in all 50 states require that dental professionals be aware of and report instances of child abuse and neglect to the proper state authority. State laws also protect the reporting dental professional from civil retribution. CONCLUSIONS: State laws and dental ethical duties require all dental professionals to be aware of and to report instances of child abuse or neglect. These same laws protect clinicians in this duty. It is the clinician's responsibility to help prevent ongoing injury to people who are incapable of self-protection. CLINICAL IMPLICATIONS: Clinicians should learn to recognize signs of abuse and neglect, which often involve injury to the mouth and dentition. Dental professionals are mandated to report such abuse to state child protection authorities. PMID- 23024306 TI - Multiple endocrine neoplasia in an orthodontic patient: Interprofessional diagnostic and treatment implications. AB - BACKGROUND: Multiple endocrine neoplasia, type 2B (MEN 2B), is an autosomal dominant condition characterized by the development of multiple endocrine tumors. All affected people develop an aggressive form of medullary thyroid cancer (MTC). Without early prophylactic thyroidectomy, the prognosis for patients with MEN 2B is poor; the average age at death is 21 years. CASE DESCRIPTION: The authors present a case of a 16-year-old girl who had a diagnosis of MEN 2B and was treated successfully for metastatic MTC. CLINICAL IMPLICATIONS: Given the striking orofacial manifestations of MEN 2B (marfanoid habitus; dolichocephaly; everted and thickened lips; mucosal neuromas on lips, tongue, buccal mucosa and eyelids), dental professionals are well positioned to recognize the disorder. Early identification of patients with the condition permits screening for preclinical thyroid disease, molecular genetic testing, counseling and lifesaving thyroid surgery. PMID- 23024307 TI - Hemicrania continua in a patient with concomitant dental disease. AB - BACKGROUND: There are nonodontogenic headache disorders that mimic dental pain. One such headache disorder is hemicrania continua (HC). HC is a primary headache syndrome characterized by a continuous, unilateral headache that is completely responsive to indomethacin. Patients may have signs and symptoms that the dentist should differentiate from odontogenic pain and temporomandibular disorders. These symptoms can make the diagnostic process a challenge for dentists if patients' pain has multiple causes. Dentists, thus, must have thorough knowledge of odontogenic and nonodontogenic causes of pain so they can make accurate diagnoses and prepare treatment plans. CASE DESCRIPTION: The authors describe the case of a 41-year-old woman with a six-year history of continuous headaches and a one-year history of temporomandibular dysfunction and odontogenic pain. She sought treatment from a number of dentists and received a diagnosis of right-side facial pain and headache on the basis of the results of clinical and radiologic examinations, which was followed by dental treatment. She did not experience any pain relief. Additional results of our examination led to a diagnosis of HC. CLINICAL IMPLICATIONS: Dentists must consider headache disorders in patients who have continuous headaches after undergoing dental treatment for odontogenic pain. PMID- 23024308 TI - The effects of periodontal curette handle weight and diameter on arm pain: a four month randomized controlled trial. AB - BACKGROUND: The design of periodontal curette handles may cause or aggravate arm pain in dental practitioners. The authors conducted a four-month randomized controlled trial to evaluate the effects of curette handle diameter and weight on arm pain among dental hygienists and dentists. METHODS: One hundred ten dental hygienists and dentists who performed scaling, root planing or dental prophylaxis procedures participated in this study. The authors assessed right wrist/hand, elbow/forearm and shoulder pain levels weekly. They randomized participants to receive either a set of light (14 grams) periodontal curettes with a large diameter (11 millimeters) or a set of heavy (34 g) periodontal curettes with a narrow diameter (8 mm). The authors compared changes in mean pain scores across the study period between intervention groups by using general linear models and controlling for covariates. RESULTS: The improvement in pain scores across the three body regions was greater for participants who used the lighter, wider diameter curettes. In the final adjusted model, the differences were statistically significant only for the shoulder region (P = .02). CONCLUSIONS: The study results show that dental instrument design has an effect on upper extremity pain in dental practitioners. Using a lighter instrument with a wider diameter may be an easy and cost-effective intervention to reduce or prevent upper-extremity pain associated with dental hygiene procedures. CLINICAL IMPLICATIONS: To prevent or reduce arm pain, practitioners should consider using lightweight instruments with large diameters when performing scaling and root planing procedures. PMID- 23024309 TI - A practitioner's guide to developing critical appraisal skills: interventional studies. AB - BACKGROUND AND OVERVIEW: Randomized controlled clinical trials are considered to provide the highest level of evidence for clinical practice, public health policy and evidence-based systematic reviews. Although all randomized controlled clinical trials share basic design characteristics, to assess the outcome of a particular trial one must carefully evaluate specific details of its design and analysis that might bias the study and influence its results. In this article, the authors review key points that practitioners should consider when assessing randomized controlled clinical trials so they can determine the applicability of study results to clinical practice. CONCLUSIONS AND PRACTICE IMPLICATIONS: Dentists encounter a variety of types of evidence when trying to assess the utility of new therapeutic agents and procedures for their clinical practice. This article provides a background to use in evaluating data and selecting studies that provide the most rigorous clinical support for safety and effectiveness. PMID- 23024310 TI - Involvement of Ayurvedic practitioners in oral health care in the United States. AB - BACKGROUND: Ayurveda, an ancient medical science originating in India, also is practiced in the United States. The authors conducted a study primarily to explore the involvement of Ayurvedic practitioners in treating oral diseases. METHODS: Eighty-five practitioners participated in this cross-sectional survey. The authors obtained self-reported data on demographics of the practitioners, the general and oral health conditions they treated, and the treatment modalities used. They performed descriptive statistical and logistic regression analyses by using statistical software. RESULTS: Participants predominantly were female and white or non-Hispanic, as well as part-time practitioners. Their educational backgrounds ranged from a 51/2-year bachelor's degree in Ayurveda to short-term training. Of the 60 respondents who answered the question about treating oral diseases, 25 (42 percent) reported that they did so. Conditions treated were related to oral malodor, gingival or periodontal disease and toothache. Ayurvedic treatments administered for these conditions primarily were preventive in nature. CONCLUSIONS: Ayurvedic practitioners in the United States treat a variety of oral diseases by using predominantly preventive traditional care. Ayurvedic practitioners of Asian origin and those who practiced for a longer duration were more likely to report that they treated oral diseases. Larger, population-based studies are needed to understand more fully the current role of Ayurvedic practitioners in oral health care. Ayurvedic treatment modalities aimed at oral diseases need to be evaluated through rigorous randomized controlled trials for safety and effectiveness. PRACTICE IMPLICATIONS: Patients with limited or no access to oral health care might seek Ayurvedic treatment, and those who have access to conventional oral health care might wish to complement it with Ayurvedic treatment. Practitioners can incorporate preventive Ayurvedic treatments, which are based mainly on natural products, into overall preventive care regimens, if proven safe and effective. PMID- 23024312 TI - Socket preservation of implant sites: A critical summary of Ten Heggeler JMAG, Slot DE, Van der Weijden GA. Effect of socket preservation therapies following tooth extraction in non-molar regions in humans: a systematic review (published online ahead of print Nov. 22, 2010). Clin Oral Implants Res 2011;22(8):779-788. doi:10.1111/j.1600-0501.2010.02064.x. PMID- 23024311 TI - Advancing infection control in dental care settings: factors associated with dentists' implementation of guidelines from the Centers for Disease Control and Prevention. AB - BACKGROUND AND OVERVIEW: The authors set out to identify factors associated with implementation by U.S. dentists of four practices first recommended in the Centers for Disease Control and Prevention's Guidelines for Infection Control in Dental Health-Care Settings-2003. METHODS: In 2008, the authors surveyed a stratified random sample of 6,825 U.S. dentists. The response rate was 49 percent. The authors gathered data regarding dentists' demographic and practice characteristics, attitudes toward infection control, sources of instruction regarding the guidelines and knowledge about the need to use sterile water for surgical procedures. Then they assessed the impact of those factors on the implementation of four recommendations: having an infection control coordinator, maintaining dental unit water quality, documenting percutaneous injuries and using safer medical devices, such as safer syringes and scalpels. The authors conducted bivariate analyses and proportional odds modeling. RESULTS: Responding dentists in 34 percent of practices had implemented none or one of the four recommendations, 40 percent had implemented two of the recommendations and 26 percent had implemented three or four of the recommendations. The likelihood of implementation was higher among dentists who acknowledged the importance of infection control, had practiced dentistry for less than 30 years, had received more continuing dental education credits in infection control, correctly identified more surgical procedures that require the use of sterile water, worked in larger practices and had at least three sources of instruction regarding the guidelines. Dentists with practices in the South Atlantic, Middle Atlantic or East South Central U.S. Census divisions were less likely to have complied. CONCLUSIONS: Implementation of the four recommendations varied among U.S. dentists. Strategies targeted at raising awareness of the importance of infection control, increasing continuing education requirements and developing multiple modes of instruction may increase implementation of current and future Centers for Disease Control and Prevention guidelines. PMID- 23024313 TI - The case for onlays versus tooth-colored crowns. PMID- 23024314 TI - Motivating by means of accountability. PMID- 23024315 TI - What is the appropriate course of action when a member dentist reveals during a local dental society meeting that he may be engaging in unethical behavior? PMID- 23024316 TI - Myofascial pain secondary to medication-induced bruxism. PMID- 23024320 TI - Salivary diagnostics for periodontal diseases. AB - BACKGROUND: and Overview The use of salivary diagnostics continues to develop and advance the field of risk determination for periodontal diseases. Researchers are investigating genetic, microbial and protein biomarkers with the objective of translating findings to such aspects of clinical care as broad patient screening, monitoring and treatment planning. METHODS: /st> In this review, the author briefly explores currently available salivary diagnostics used to identify bacteria prevalent in periodontal disease, and focuses on the future development and use of a variety of rapid disease detection platforms, such as lab-on-a-chip, as a point-of-care device for identification of patients' risk. CONCLUSIONS: and CLINICAL IMPLICATIONS: /st> Several diagnostic tests are commercially available, and point-of-care tests are under development. However, challenges remain regarding the introduction of these technologies to clinical practice and adoption by dental practitioners for promotion of personalized oral health care. PMID- 23024321 TI - Analysis of mitragynine and metabolites in human urine for detecting the use of the psychoactive plant kratom. AB - The leaves of the South Asian plant kratom are described as having stimulating effects at low doses, and opiate-like analgesic and euphoric effects at high doses. A long history of use and abuse has led to the classification of kratom as a controlled substance in its native Thailand and other South Asian countries. However, kratom is not controlled in the United States, and the ready availability of kratom has led to its emergence as an herbal drug of abuse. With the growing popularity of kratom, efficient procedures are needed to detect kratom use. In the current study, both ultra-high-performance liquid chromatography and high-performance liquid chromatography-tandem mass spectrometry methods have been developed and validated for monitoring the major alkaloids and metabolites found in urine following kratom use. The primary unique alkaloid mitragynine is quantified in human urine from 1.00-500.00 ng/mL using mitraphylline as an internal standard. In addition, two metabolites (5 desmethylmitragynine and 17-desmethyldihydromitragynine) and the related active, alkaloid 7-hydroxy-mitragynine, are simultaneously qualitatively monitored. The presence of analytes are confirmed by an information-dependent acquisition enhanced product ion procedure generating full fragmentation data used to positively identify detected analytes. The validated method has been utilized for clinical and forensic analyses of urine for the detection of kratom use. PMID- 23024322 TI - Unfolding the mechanisms of progression of pulmonary emphysema in COPD. PMID- 23024323 TI - Euthanasia: from ethical debate to clinical reality. PMID- 23024324 TI - Presenting the European Forum for TB Innovation: innovative thinking in progressing towards TB elimination in Europe. PMID- 23024325 TI - Towards a total ban on links with the tobacco industry: new rules for the ERS. PMID- 23024326 TI - Reduced plasma fetuin-A levels in patients with obstructive sleep apnoea. PMID- 23024327 TI - Chronic cough and obstructive sleep apnoea: reflux-associated cough hypersensitivity? PMID- 23024328 TI - Moxifloxacin in multidrug-resistant tuberculosis: is there any indication for therapeutic drug monitoring? PMID- 23024329 TI - An uncommon reason for dyspnoea: phrenic paresis secondary to alveolar echinococcosis. PMID- 23024330 TI - Protease-activated receptor-4 deficiency does not protect against bleomycin induced pulmonary fibrosis in mice. PMID- 23024331 TI - Severe pulmonary hypertension leading to heart-lung transplantation and revealing breast cancer. PMID- 23024332 TI - Long-term follow-up of children with congenital chylothorax. PMID- 23024333 TI - Diagnosing COPD and targeted lung cancer screening. PMID- 23024335 TI - Incremental prognostic value of an abnormal baseline spatial QRS-T angle in chronic dialysis patients. AB - AIMS: In order to improve the abysmal outcome of dialysis patients, it is critical to identify patients with a high mortality risk. The spatial QRS-T angle, which can be easily calculated from the 12 lead electrocardiogram (ECG), might be useful in the prognostication in dialysis patients. The objective of this study was to establish the prognostic value of the spatial QRS-T angle. METHODS AND RESULTS: All patients who initiated dialysis therapy between 2002 and 2009 in the hospitals of Leiden (LUMC) and Amsterdam (AMC) at least 3 months on dialysis were included. The spatial QRS-T angle was calculated, from a routinely acquired ECG, and its relationship with mortality was assessed. An abnormal spatial QRS-T angle was defined as >= 130 degrees in men and >= 116 degrees in women. In total, 277 consecutive patients (172 male, mean age 56.3 +/- 17.0) were included. An abnormal spatial QRS-T angle was associated with a higher risk of death from all causes [hazard ratio (HR) 2.33; 95% confidence interval (CI) 1.46 3.70] and especially a higher risk of sudden cardiac death (HR 2.99; 95% CI 1.04 8.60). Furthermore, an abnormal spatial QRS-T angle was of incremental prognostic value, when added to a risk model consisting of known risk factors. CONCLUSION: In chronic dialysis patients the spatial QRS-T angle is a significant and independent predictor of all-cause and especially sudden cardiac death. It implies that this parameter can be used to identify high risk patients. PMID- 23024336 TI - Diagnosis of coronary spastic angina by implantable loop recorder. PMID- 23024337 TI - Accuracy of clinical protocols in SPECT. AB - The accuracy of clinical SPECT is highly dependent on the acquisition and processing parameters, which are selected according to the clinical task. These parameters are usually set within protocols in order to allow for standardization from one study to another and to speed up the clinical routine. METHODS: In the first part of this work, tomographic images of a Jaszczak phantom were obtained on 5 different SPECT systems using 2 common clinical protocols and each system's default acquisition and processing parameters. In the second part, tomographic images of the Jaszczak phantom were obtained using identical acquisition and processing parameters on all systems. Projection data were then transferred to other system software for reconstruction. RESULTS: For the first part of the work, variation in image quality was seen quantitatively among the systems, even when clinical protocols with the same aim were used. The accuracy of the similar reconstruction algorithms and data transfer was determined and summarized. In the second part of this study, the performance of the SPECT systems using similar acquisition protocols and reconstruction software was determined and summarized. CONCLUSION: The default clinical protocols offered by the manufacturer for similar studies may be different from one another. The user should modify these protocols using phantom studies and standardize same-purpose protocols among different software programs. PMID- 23024338 TI - Photomultiplier tube artifacts on 67Ga-citrate imaging caused by loss of correction floods due to an off-peak status of one head of a dual-head gamma camera. AB - gamma-cameras use flood-field corrections to ensure image uniformity during clinical imaging. A loss or corruption of the correction data of one head of a dual-head camera can result in an off-peak artifactual appearance. We present our experience with the occurrence of such an incident on a (67)Ga scan. METHODS: A patient was referred for a whole-body (67)Ga scan to evaluate for causes of neutropenic fever. Whole-body planar and static images of the head, chest, abdomen, pelvis, and lower extremities in multiple projections were obtained. RESULTS: Whole-body images showed decreased image quality on the anterior view obtained with detector 1 and an unremarkable posterior image obtained with detector 2. A problem with detector 2 was suspected, and additional static images were obtained after rotation of the detector heads. The posterior images taken with detector 1 showed photomultiplier tube outlines. The anterior images taken with detector 2 showed improved count and image quality. It was later found that the uniformity map for detector 2 had been lost and that this software malfunction led to the resulting imaging problem. CONCLUSION: When artifacts with an off-peak appearance are seen on scintigraphic images, evaluation of possible causes should include not only isotope window settings but also an incorrect or corrupted uniformity map. PMID- 23024339 TI - Validation of a paper chromatographic methodology as an alternative for determination of the radiochemical purity of Na18F. AB - The aim of the present work was to validate a paper chromatography system as an alternative way to determine the radiochemical purity of Na(18)F. METHODS: The evaluated parameters were specificity, limit of quantification, measurement interval, linearity, precision, accuracy, and robustness. RESULTS: The proposed method proved to be linear (P > 0.05; r(2) = 1.000), precise (relative SD, 8.6%), accurate (mean recovery, 95.9%; relative SD, 1.5%-1.8%), and robust under different conditions since no influence of the operative variables on the chromatographic performance was observed. CONCLUSION: This system can be used as a reliable alternative method to determine the radiochemical purity of Na(18)F samples that can be easily performed in PET radiopharmacies at low cost. PMID- 23024340 TI - Occupational radiation dosimetry assessment using an automated infusion device for positron-emitting radiotracers. AB - Handling and administration of radiopharmaceuticals are a key contributor to staff radiation dose. Shielded automated infusion devices potentially standardize and reduce radiation exposure during procedures. However, loading the devices adds incremental radiation exposure, which may mitigate dose savings. We measured radiation doses from the loading and use of an automated infusion device and compared these with those from manual injection of (18)F radiotracers. METHODS: Adult patients were administered (18)F-FDG or (18)F-FLT before 3-dimensional PET whole-body or brain imaging, respectively. Radioactivity amounts from manual injections performed with protective syringe shields and vial holders were measured by a standard dose calibrator before and after injection. Automated infusions were performed using the shielded infusion device. Staff wore electronic dosimeters at the wrist and trunk. Electronic dosimeters were also worn while multidose (18)F-FDG vials were loaded and unloaded. For each task, background radiation was determined and subtracted from the electronic dosimeter values. RESULTS: Twenty-seven manually injected unit doses yielded a mean administered dose to patients of 480.7 +/- 66.2 MBq (12.99 +/- 1.79 mCi), compared with 431.9 +/- 22.7 MBq (11.67 +/- 0.61 mCi) in 34 automated injections. The mean difference was statistically significant. To control for this difference, results were expressed as a standardized dose per unit of activity. With the automated infusion device, the mean extremity dose per injection was 0.003 +/- 0.002 MUSv/MBq, compared with 0.026 +/- 0.017 MUSv/MBq with manual injections. Mean body dose per procedure with automated infusion was 0.001 MUSv/MBq, versus 0.011 MUSv/MBq with manual injection (P < 0.001). The changing of bulk (18)F-FDG vials in 37 procedures added a mean dose per vial change of 0.89 +/- 1.3 MUSv to the extremities and 0.47 +/- 2.0 MUSv to the body. CONCLUSION: The use of a shielded automatic infusion device in a clinical PET setting resulted in an approximately 10-fold decrease in staff extremity and body doses during the administration of (18)F-labeled radiopharmaceuticals. Loading and unloading bulk vials of radiotracer did not significantly offset these dose savings. PMID- 23024341 TI - Comparing health status in Belarus between 2001-10: a novel method using surveys with different response categories. AB - BACKGROUND: Two population surveys were conducted in Belarus: The Living Conditions, Lifestyle and Health (LLH) in 2001 (n = 2000) and The Health in Times of Transition (HITT) in 2010 (n = 1800). Each survey included a question on health status. The LLH questionnaire provided a 4-point Verbal Response Scale, but the HITT questionnaire used a 5-point scale. When translated into Russian, only two response categories of these scales had identical wording. These differences made a direct comparison of self-reported health status between 2001 and 2010 difficult. METHODS: We conducted a Health Category Response Scale (HCRS) survey in 2010 (n = 570) using a 100ths graduated Visual Analogue Scale (VAS) to understand how the response categories of different scales are perceived by Russian speakers. We implemented the HCRS survey's data to calculate the weighted health status (WHS) for each of the original surveys and to compare health status in Belarus between 2001and 2010. RESULTS: The WHS in Belarus showed a small, but statistically significant, improvement of 2.9 points on a 0-100 scale between 2001 and 2010 (56.2 vs. 59.1). Identical response categories were perceived differently on a 4-point and 5-point VAS. The category 'good' ('Xoroshee') measured ~12 points higher, and the category 'bad/poor' ('Ploxoe') measured ~16 points lower, on the 4-point compared with the 5-point VAS. CONCLUSION: Our HCRS survey and novel method enabled a direct comparison of questions with different response options. When applied to the LLH and HITT projects, we concluded that health status in Belarus has improved between 2001 and 2010. PMID- 23024342 TI - Obesity and early cessation of breastfeeding in Denmark. AB - BACKGROUND: Obesity is associated with early cessation of breastfeeding. Breastfeeding is multi-factorial, and several factors contribute to this association. Our aim was to investigate to what extent socio-demographic and psychosocial characteristics, parity and prenatal conditions could explain the association between high BMI and early cessation of breastfeeding. METHODS: We used data from a randomized trial of 1597 Danish mothers of singleton infants. Self-reported maternal postnatal weight and height were available from 1375 (86%). High BMI was defined as body mass index >= 32 kg/m(2) at ~17 days after delivery. Outcome was cessation of exclusive breastfeeding by 17 weeks post partum used in proportional hazards regression models. RESULTS: In the unadjusted analysis, mothers with high post-partum BMI compared with other mothers had a significantly higher rate of cessation of exclusive breastfeeding, and were more frequently characterized by socio-demographic, psychosocial, perinatal and behavioural factors known to increase the risk of early breastfeeding cessation. In the adjusted analyses (n = 1226), the association between BMI and duration of exclusive breastfeeding depended on parity (P = 0.03). Among primiparae, high BMI was associated with nearly double the risk of early cessation of exclusive breastfeeding (HR = 1.74, 95% CI 1.21-2.50). Among multiparae, the association disappeared when adjusted for socio-demographic factors and previous breastfeeding experience (HR = 0.89, 95% CI 0.62-1.28). CONCLUSION: Parity and previous breastfeeding experience are important factors to include when studying the association between BMI and breastfeeding duration. Intervention to extend the duration of lactation among obese mothers should focus on those with no or little previous breastfeeding experience. PMID- 23024343 TI - Gene cluster encoding cholate catabolism in Rhodococcus spp. AB - Bile acids are highly abundant steroids with important functions in vertebrate digestion. Their catabolism by bacteria is an important component of the carbon cycle, contributes to gut ecology, and has potential commercial applications. We found that Rhodococcus jostii RHA1 grows well on cholate, as well as on its conjugates, taurocholate and glycocholate. The transcriptome of RHA1 growing on cholate revealed 39 genes upregulated on cholate, occurring in a single gene cluster. Reverse transcriptase quantitative PCR confirmed that selected genes in the cluster were upregulated 10-fold on cholate versus on cholesterol. One of these genes, kshA3, encoding a putative 3-ketosteroid-9alpha-hydroxylase, was deleted and found essential for growth on cholate. Two coenzyme A (CoA) synthetases encoded in the cluster, CasG and CasI, were heterologously expressed. CasG was shown to transform cholate to cholyl-CoA, thus initiating side chain degradation. CasI was shown to form CoA derivatives of steroids with isopropanoyl side chains, likely occurring as degradation intermediates. Orthologous gene clusters were identified in all available Rhodococcus genomes, as well as that of Thermomonospora curvata. Moreover, Rhodococcus equi 103S, Rhodococcus ruber Chol 4 and Rhodococcus erythropolis SQ1 each grew on cholate. In contrast, several mycolic acid bacteria lacking the gene cluster were unable to grow on cholate. Our results demonstrate that the above-mentioned gene cluster encodes cholate catabolism and is distinct from a more widely occurring gene cluster encoding cholesterol catabolism. PMID- 23024344 TI - Two transporters essential for reassimilation of novel cholate metabolites by Rhodococcus jostii RHA1. AB - The bacterial uptake of steroids and their metabolites remains poorly understood. We investigated two transporters associated with cholate catabolism in Rhodococcus jostii RHA1. Reverse transcriptase quantitative-PCR indicated that an ATP-binding cassette (ABC) transporter and a major facilitator superfamily (MFS) transporter were upregulated 16.7- and 174-fold, respectively, during the exponential phase of growth on cholate compared to growth on pyruvate. Gene knockout analysis established that these transporters are required for the reassimilation of distinct metabolites that accumulate during growth on cholate. The ABC transporter, encoded by camABCD, was essential for uptake of 1beta(2' propanoate)-3aalpha-H-4alpha(3"(R)-hydroxy-3"-propanoate)-7abeta-methylhexahydro 5-indanone and a desaturated analog. The MFS transporter, encoded by camM, was essential for uptake of 3,7(R),12(S)-trihydroxy-9-oxo-9,10-seco-23,24-bisnorchola 1,3,5(10)-trien-22-oate. These metabolites differ from cholate metabolites reported to be excreted by proteobacteria in that they retain an isopropanoyl side chain at C-17. The uptake of these metabolites was necessary for maximal growth on cholate: a DeltacamB mutant lacking the permease component of the ABC transporter and a DeltacamM mutant lacking the MFS transporter grew to 74% and 77%, respectively, of the yield of the wild type. This study demonstrates for the first time the requirement for specific transporters for uptake of cholate metabolites and highlights the importance and complexity of transport processes associated with bacterial steroid catabolism. PMID- 23024345 TI - Crystal structure of the Klebsiella pneumoniae NFeoB/FeoC complex and roles of FeoC in regulation of Fe2+ transport by the bacterial Feo system. AB - Feo is a transport system commonly used by bacteria to acquire environmental Fe(2+). It consists of three proteins: FeoA, FeoB, and FeoC. FeoB is a large protein with a cytosolic N-terminal domain (NFeoB) that contains a regulatory G protein domain and a helical S domain. The C-terminal region of FeoB is a transmembrane domain that likely acts as the Fe(2+) permease. NFeoB has been shown to form a trimer pore that may function as an Fe(2+) gate. FeoC is a small winged-helix protein that possesses four conserved cysteine residues with a consensus sequence that likely provides binding sites for the [Fe-S] cluster. Therefore, FeoC is presumed to be an [Fe-S] cluster-dependent regulator that directly controls transcription of the feo operon. Despite the apparent significance of the Feo system, however, the function of FeoC has not been experimentally demonstrated. Here, we show that Klebsiella pneumoniae FeoC (KpFeoC) forms a tight complex with the intracellular N-terminal domain of FeoB (KpNFeoB). The crystal structure of the complex reveals that KpFeoC binds to KpNFeoB between the switch II region of the G protein domain and the effector S domain and that the long KpFeoC W1 loop lies above the KpNFeoB nucleotide-binding site. These interactions suggest that KpFeoC modulates the guanine nucleotide mediated signal transduction process. Moreover, we showed that binding of KpFeoC disrupts pore formation by interfering with KpNFeoB trimerization. These results provide strong evidence suggesting that KpFeoC plays a crucial role in regulating Fe(2+) transport in Klebsiella pneumonia in addition to the presumed gene regulator role. PMID- 23024346 TI - Coordinated regulation of gnd, which encodes 6-phosphogluconate dehydrogenase, by the two transcriptional regulators GntR1 and RamA in Corynebacterium glutamicum. AB - The transcriptional regulation of Corynebacterium glutamicum gnd, encoding 6 phosphogluconate dehydrogenase, was investigated. Two transcriptional regulators, GntR1 and RamA, were isolated by affinity purification using gnd promoter DNA. GntR1 was previously identified as a repressor of gluconate utilization genes, including gnd. Involvement of RamA in gnd expression had not been investigated to date. The level of gnd mRNA was barely affected by the single deletion of ramA. However, gnd expression was downregulated in the ramA gntR1 double mutant compared to that of the gntR1 single mutant, suggesting that RamA activates gnd expression. Two RamA binding sites are found in the 5' upstream region of gnd. Mutation proximal to the transcriptional start site diminished the gluconate dependent induction of gnd-lacZ. DNase I footprinting assay revealed two GntR1 binding sites, with one corresponding to a previously proposed site that overlaps with the -10 region. The other site overlaps the RamA binding site. GntR1 binding to this newly identified site inhibits DNA binding of RamA. Therefore, it is likely that GntR1 represses gnd expression by preventing both RNA polymerase and RamA binding to the promoter. In addition, DNA binding activity of RamA was reduced by high concentrations of NAD(P)H but not by NAD(P), implying that RamA senses the redox perturbation of the cell. PMID- 23024347 TI - Intragenic suppressor of a plug deletion nonmotility mutation in PotB, a chimeric stator protein of sodium-driven flagella. AB - The torque of bacterial flagellar motors is generated by interactions between the rotor and the stator and is coupled to the influx of H(+) or Na(+) through the stator. A chimeric protein, PotB, in which the N-terminal region of Vibrio alginolyticus PomB was fused to the C-terminal region of Escherichia coli MotB, can function with PomA as a Na(+)-driven stator in E. coli. Here, we constructed a deletion variant of PotB (with a deletion of residues 41 to 91 [Delta41-91], called PotBDeltaL), which lacks the periplasmic linker region including the segment that works as a "plug" to inhibit premature ion influx. This variant did not confer motile ability, but we isolated a Na(+)-driven, spontaneous suppressor mutant, which has a point mutation (R109P) in the MotB/PomB-specific alpha-helix that connects the transmembrane and peptidoglycan binding domains of PotBDeltaL in the region of MotB. Overproduction of the PomA/PotBDeltaL(R109P) stator inhibited the growth of E. coli cells, suggesting that this stator has high Na(+) conducting activity. Mutational analyses of Arg109 and nearby residues suggest that the structural alteration in this alpha-helix optimizes PotBDeltaL conformation and restores the proper arrangement of transmembrane helices to form a functional channel pore. We speculate that this alpha-helix plays a key role in assembly-coupled stator activation. PMID- 23024348 TI - The two-component sensor KinB acts as a phosphatase to regulate Pseudomonas aeruginosa Virulence. AB - Pseudomonas aeruginosa is an opportunistic pathogen that is capable of causing both acute and chronic infections. P. aeruginosa virulence is subject to sophisticated regulatory control by two-component systems that enable it to sense and respond to environmental stimuli. We recently reported that the two-component sensor KinB regulates virulence in acute P. aeruginosa infection. Furthermore, it regulates acute-virulence-associated phenotypes such as pyocyanin production, elastase production, and motility in a manner independent of its kinase activity. Here we show that KinB regulates virulence through the global sigma factor AlgU, which plays a key role in repressing P. aeruginosa acute-virulence factors, and through its cognate response regulator AlgB. However, we show that rather than phosphorylating AlgB, KinB's primary role in the regulation of virulence is to act as a phosphatase to dephosphorylate AlgB and alleviate phosphorylated AlgB's repression of acute virulence. PMID- 23024350 TI - Yorkshire's influence on the foundation of British Neurology. PMID- 23024349 TI - Phage shock protein C (PspC) of Yersinia enterocolitica is a polytopic membrane protein with implications for regulation of the Psp stress response. AB - Phage shock proteins B (PspB) and C (PspC) are integral cytoplasmic membrane proteins involved in inducing the Yersinia enterocolitica Psp stress response. A fundamental aspect of these proteins that has not been studied in depth is their membrane topologies. Various in silico analyses universally predict that PspB is a bitopic membrane protein with the C terminus inside. However, similar analyses yield conflicting predictions for PspC: a bitopic membrane protein with the C terminus inside, a bitopic membrane protein with the C terminus outside, or a polytopic protein with both termini inside. Previous studies of Escherichia coli PspB-LacZ and PspC-PhoA fusion proteins supported bitopic topologies, with the PspB C terminus inside and the PspC C terminus outside. Here we have used a series of independent approaches to determine the membrane topologies of PspB and PspC in Y. enterocolitica. Our data support the predicted arrangement of PspB, with its C terminus in the cytoplasm. In contrast, data from multiple independent approaches revealed that both termini of PspC are located in the cytoplasm. Additional experiments suggested that the C terminus of PspC might be the recognition site for the FtsH protease and an interaction interface with PspA, both of which would be compatible with its newly proposed cytoplasmic location. This unexpected arrangement of PspC allows a new model for events underlying activation of the Psp response, which is an excellent fit with observations from various previous studies. PMID- 23024351 TI - Epileptic seizure abolition with aromatase inhibition. PMID- 23024352 TI - Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: systematic review and meta-analysis. AB - BACKGROUND: Intracerebral haemorrhage (ICH) remains the most devastating yet unpredictable complication of intravenous thrombolysis for acute ischaemic stroke. We performed a systematic review and meta-analysis, to assess whether the presence of cerebral microbleeds (CMBs) on prethrombolysis MRI scans is associated with an increased risk of ICH. METHODS: We searched PubMed for studies assessing ICH risk in patients with acute ischaemic stroke treated with thrombolysis, in relation to the presence of pre-treatment CMBs. RESULTS: We identified five studies including 790 patients and pooled data in a meta analysis. The CMB (+) versus CMB (-) groups were not significantly different in age, gender or stroke severity. The overall prevalence of CMBs was 135/790 (17.1%). Amongst patients with CMBs, 10/135 (7.4%) experienced a symptomatic ICH after thrombolysis, compared to 29/655 (4.4%) patients without CMBs. The pooled relative risk of ICH was 1.90 (95% CI 0.92 to 3.93; p=0.082). CONCLUSIONS: The available evidence does not demonstrate a statistically significant increased risk of symptomatic ICH after thrombolysis for ischaemic stroke in patients with CMBs. However, in view of the methodological limitations of the studies included, the clinical relevance of any potential hazard associated with CMBs remains uncertain. Further studies are warranted to evaluate whether the risk of ICH might outweigh the benefit of thrombolysis, especially in patients with multiple lobar CMBs suggestive of cerebral amyloid angiopathy. PMID- 23024353 TI - Decision-making in the diagnosis and treatment of stroke-associated pneumonia. AB - BACKGROUND: Stroke-associated pneumonia (SAP) is associated with impaired outcome in acute stroke patients. Current European and American guidelines for acute stroke care are lacking standardised recommendations for the management of SAP. We investigated current diagnostic and treatment practice for SAP in German stroke units (SU). METHODS: We developed a standardised questionnaire including characteristics of SU, questions related to antibiotic treatment approaches of SAP and five case vignettes describing relevant clinical scenarios based on Centers for Disease Control and Prevention (CDC) criteria for 'clinically defined pneumonia'. All certified German SU were invited to take part in the survey. RESULTS: The survey took place from April to August 2010. Of all 162 German SU contacted, 83 (51%) responded. Classification and regression trees analysis suggested that SAP was diagnosed on the basis of clinical criteria such as fever and stroke severity. Chest x-ray showed only limited influence on the diagnosis of SAP. C-reactive protein was frequently requested as additional diagnostic information (38-76%). Group 3 cephalosporines and (acyl-) aminopenicillins/beta lactamase inhibitors are the most frequently used antibiotics (46-60%) in empiric mono (58%) and combination (42%) therapy. A minority of SU (5%) use prophylactic antibiotic treatment. Standardised procedures are available in 61% of SU. CONCLUSION: Clinical criteria were the main determinants for SAP diagnosis. In contrast, chest x-ray--the central diagnostic item in CDC criteria--was of minor importance. Our survey demonstrates heterogeneous diagnostic and therapeutic strategies in German SU. Future studies need to establish and to evaluate standardised criteria for SAP care. PMID- 23024354 TI - Making the incredible credible: afterimages are modulated by contextual edges more than real stimuli. AB - We explored whether color afterimages and faint physical chromatic stimuli are processed equivalently by the visual system. Afterimage visibility in classic illusions appears to be particularly influenced by consistent contexts, while real stimulus versions of these illusions are absent in the literature. Using both a matching and a nulling paradigm, we present converging evidence that luminance edges enhance the perceived saturation of afterimages more than they do physical stimuli of similar appearance. We suggest that afterimages violate the response norms associated with real stimuli. This leads to the afterimage signal being ambiguous for the visual system, and thus more susceptible to modulation by contexts that increase or decrease the probability of the signal representing a real object. This could explain why afterimages are rarely experienced in everyday life, where they will be overruled by inconsistent context. PMID- 23024356 TI - Modeling acuity for optotypes varying in complexity. AB - Watson and Ahumada (2008) described a template model of visual acuity based on an ideal-observer limited by optical filtering, neural filtering, and noise. They computed predictions for selected optotypes and optical aberrations. Here we compare this model's predictions to acuity data for six human observers, each viewing seven different optotype sets, consisting of one set of Sloan letters and six sets of Chinese characters, differing in complexity (Zhang, Zhang, Xue, Liu, & Yu, 2007). Since optical aberrations for the six observers were unknown, we constructed 200 model observers using aberrations collected from 200 normal human eyes (Thibos, Hong, Bradley, & Cheng, 2002). For each condition (observer, optotype set, model observer) we estimated the model noise required to match the data. Expressed as efficiency, performance for Chinese characters was 1.4 to 2.7 times lower than for Sloan letters. Efficiency was weakly and inversely related to perimetric complexity of optotype set. We also compared confusion matrices for human and model observers. Correlations for off-diagonal elements ranged from 0.5 to 0.8 for different sets, and the average correlation for the template model was superior to a geometrical moment model with a comparable number of parameters (Liu, Klein, Xue, Zhang, & Yu, 2009). The template model performed well overall. Estimated psychometric function slopes matched the data, and noise estimates agreed roughly with those obtained independently from contrast sensitivity to Gabor targets. For optotypes of low complexity, the model accurately predicted relative performance. This suggests the model may be used to compare acuities measured with different sets of simple optotypes. PMID- 23024355 TI - An objective method for measuring face detection thresholds using the sweep steady-state visual evoked response. AB - We introduce a sensitive method for measuring face detection thresholds rapidly, objectively, and independently of low-level visual cues. The method is based on the swept parameter steady-state visual evoked potential (ssVEP), in which a stimulus is presented at a specific temporal frequency while parametrically varying ("sweeping") the detectability of the stimulus. Here, the visibility of a face image was increased by progressive derandomization of the phase spectra of the image in a series of equally spaced steps. Alternations between face and fully randomized images at a constant rate (3/s) elicit a robust first harmonic response at 3 Hz specific to the structure of the face. High-density EEG was recorded from 10 human adult participants, who were asked to respond with a button-press as soon as they detected a face. The majority of participants produced an evoked response at the first harmonic (3 Hz) that emerged abruptly between 30% and 35% phase-coherence of the face, which was most prominent on right occipito-temporal sites. Thresholds for face detection were estimated reliably in single participants from 15 trials, or on each of the 15 individual face trials. The ssVEP-derived thresholds correlated with the concurrently measured perceptual face detection thresholds. This first application of the sweep VEP approach to high-level vision provides a sensitive and objective method that could be used to measure and compare visual perception thresholds for various object shapes and levels of categorization in different human populations, including infants and individuals with developmental delay. PMID- 23024357 TI - Zero-dimensional noise: the best mask you never saw. AB - The transmission of weak signals through the visual system is limited by internal noise. Its level can be estimated by adding external noise, which increases the variance within the detecting mechanism, causing masking. But experiments with white noise fail to meet three predictions: (a) noise has too small an influence on the slope of the psychometric function, (b) masking occurs even when the noise sample is identical in each two-alternative forced-choice (2AFC) interval, and (c) double-pass consistency is too low. We show that much of the energy of 2D white noise masks extends well beyond the pass-band of plausible detecting mechanisms and that this suppresses signal activity. These problems are avoided by restricting the external noise energy to the target mechanisms by introducing a pedestal with a mean contrast of 0% and independent contrast jitter in each 2AFC interval (termed zero-dimensional [0D] noise). We compared the jitter condition to masking from 2D white noise in double-pass masking and (novel) contrast matching experiments. Zero-dimensional noise produced the strongest masking, greatest double-pass consistency, and no suppression of perceived contrast, consistent with a noisy ideal observer. Deviations from this behavior for 2D white noise were explained by cross-channel suppression with no need to appeal to induced internal noise or uncertainty. We conclude that (a) results from previous experiments using white pixel noise should be re-evaluated and (b) 0D noise provides a cleaner method for investigating internal variability than pixel noise. Ironically then, the best external noise stimulus does not look noisy. PMID- 23024358 TI - Permeability of priming of pop out to expectations. AB - It is well established that repetition of the same target color across consecutive trials enhances search efficiency for pop-out targets; this phenomenon is known as Priming of Pop out (PoP). In three experiments, we addressed whether PoP interacts with top-down expectations in altering target visibility, which was manipulated via metacontrast masking. The target color either remained the same for n consecutive trials (blocked condition) or changed unpredictably (random condition). The results showed that PoP reduced the efficacy of masking and that its beneficial effect can be either potentiated or attenuated by participants' expectations about the upcoming target color. These findings undermine the view that PoP should be impermeable to top-down factors. In addition, we found evidence that both explicit and implicit expectations interact with PoP. The former can be induced via instructions on the rate of alternation of the target color, and the latter can be induced by random sequences in which repetitions of the same target color exceed those predicted by an internal model of randomness for binary events. In the latter case, more than three repetitions of the same target color led to a decline in target visibility. We speculate that, in the random condition, after few repetitions of the same target, participants developed an expectation for a change; this phenomenon is similar to the "gambler's fallacy." Finally, our analyses revealed no effect of expectation on switch trials (i.e., when the target color changed), which casts doubt on the efficacy of top-down control in feature search. PMID- 23024359 TI - Zinc-binding domain of the bacteriophage T7 DNA primase modulates binding to the DNA template. AB - The zinc-binding domain (ZBD) of prokaryotic DNA primases has been postulated to be crucial for recognition of specific sequences in the single-stranded DNA template. To determine the molecular basis for this role in recognition, we carried out homolog-scanning mutagenesis of the zinc-binding domain of DNA primase of bacteriophage T7 using a bacterial homolog from Geobacillus stearothermophilus. The ability of T7 DNA primase to catalyze template-directed oligoribonucleotide synthesis is eliminated by substitution of any five-amino acid residue-long segment within the ZBD. The most significant defect occurs upon substitution of a region (Pro-16 to Cys-20) spanning two cysteines that coordinate the zinc ion. The role of this region in primase function was further investigated by generating a protein library composed of multiple amino acid substitutions for Pro-16, Asp-18, and Asn-19 followed by genetic screening for functional proteins. Examination of proteins selected from the screening reveals no change in sequence-specific recognition. However, the more positively charged residues in the region facilitate DNA binding, leading to more efficient oligoribonucleotide synthesis on short templates. The results suggest that the zinc-binding mode alone is not responsible for sequence recognition, but rather its interaction with the RNA polymerase domain is critical for DNA binding and for sequence recognition. Consequently, any alteration in the ZBD that disturbs its conformation leads to loss of DNA-dependent oligoribonucleotide synthesis. PMID- 23024360 TI - Distinct roles of the C-terminal 11th transmembrane helix and luminal extension in the partial reactions determining the high Ca2+ affinity of sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2b (SERCA2b). AB - The molecular mechanism underlying the characteristic high apparent Ca(2+) affinity of SERCA2b relative to SERCA1a and SERCA2a isoforms was studied. The C terminal tail of SERCA2b consists of an 11th transmembrane helix (TM11) with an associated 11-amino acid luminal extension (LE). The effects of each of these parts and their interactions with the SERCA environment were examined by transient kinetic analysis of the partial reaction steps in the Ca(2+) transport cycle in mutant and chimeric Ca(2+)-ATPase constructs. Manipulations to the LE of SERCA2b markedly increased the rate of Ca(2+) dissociation from Ca(2)E1. Addition of the SERCA2b tail to SERCA1a slowed Ca(2+) dissociation, but only when the luminal L7/8 loop of SERCA1 was simultaneously replaced with that of SERCA2, thus suggesting that the LE interacts with L7/8 in Ca(2)E1. The interaction of LE with L7/8 is also important for the low rate of the Ca(2)E1P -> E2P conformational transition. These findings can be rationalized in terms of stabilization of the Ca(2)E1 and Ca(2)E1P forms by docking of the LE near L7/8. By contrast, low rates of E2P dephosphorylation and E2 -> E1 transition in SERCA2b depend critically on TM11, particularly in a SERCA2 environment, but do not at all depend on the LE or L7/8. This indicates that interaction of TM11 with SERCA2-specific sequence element(s) elsewhere in the structure is critical in the Ca(2+)-free E2/E2P states. Collectively these properties ensure a higher Ca(2+) affinity of SERCA2b relative to other SERCA isoforms, not only on the cytosolic side, but also on the luminal side. PMID- 23024361 TI - Functional equilibrium of the KcsA structure revealed by NMR. AB - KcsA is a tetrameric K(+) channel that is activated by acidic pH. Under open conditions of the helix bundle crossing, the selectivity filter undergoes an equilibrium between permeable and impermeable conformations. Here we report that the population of the permeable conformation (p(perm)) positively correlates with the tetrameric stability and that the population in reconstituted high density lipoprotein, where KcsA is surrounded by the lipid bilayer, is lower than that in detergent micelles, indicating that dynamic properties of KcsA are different in these two media. Perturbation of the membrane environment by the addition of 1-3% 2,2,2-trifluoroethanol increases p(perm) and the open probability, revealed by NMR and single-channel recording analyses. These results demonstrate that KcsA inactivation is determined not only by the protein itself but also by the surrounding membrane environments. PMID- 23024362 TI - Inhibition of histone deacetylase-induced myocardial repair is mediated by c-kit in infarcted hearts. AB - Histone deacetylases (HDACs) play a critical role in the regulation of gene transcription, cardiac development, and diseases. The aim of this study was to test whether inhibition of HDACs induces myocardial repair and cardiac function restoration through c-kit signaling in mouse myocardial infarction models. Myocardial infarction in wild type Kit(+/+) and Kit(W)/Kit(W-v) mice was created following thoracotomy by applying permanent ligation to the left anterior descending artery. The HDAC inhibitor, trichostatin A (TSA, 0.1 mg/kg), was intraperitoneally injected daily for a consecutive 8 weeks after myocardial infarction. 5-Bromo-2-deoxyuridine (BrdU, 50 mg/kg) was intraperitoneally delivered every other day to pulse-chase label in vivo endogenous cardiac replication. Eight weeks later, inhibition of HDACs in vivo resulted in an improvement in ventricular functional recovery and the prevention of myocardial remodeling in Kit(+/+) mice, which was eliminated in Kit(W)/Kit(W-v) mice. HDAC inhibition promoted cardiac repairs and neovascularization in the infarcted myocardium, which were absent in Kit(W)/Kit(W-v) mice. Re-introduction of TSA treated wild type c-kit(+) CSCs into Kit(W)/Kit(W-v) myocardial infarction heart restored myocardial functional improvement and cardiac repair. To further validate that HDAC inhibition stimulates c-kit(+) cardiac stem cells (CSCs) to facilitate myocardial repair, GFP(+) c-kit(+) CSCs were preconditioned with TSA (50 nmol/liter) for 24 h and re-introduced into infarcted hearts for 2 weeks. Preconditioning of c-kit(+) CSCs via HDAC inhibition with trichostatin A significantly increased c-kit(+) CSC-derived myocytes and microvessels and enhanced functional recovery in myocardial infarction hearts in vivo. Our results provide evidence that HDAC inhibition promotes myocardial repair and prevents cardiac remodeling, which is dependent upon c-kit signaling. PMID- 23024363 TI - Identification of key residues essential for the structural fold and receptor selectivity within the A-chain of human gene-2 (H2) relaxin. AB - Human gene-2 (H2) relaxin is currently in Phase III clinical trials for the treatment of acute heart failure. It is a 53-amino acid insulin-like peptide comprising two chains and three disulfide bonds. It interacts with two of the relaxin family peptide (RXFP) receptors. Although its cognate receptor is RXFP1, it is also able to cross-react with RXFP2, the native receptor for a related peptide, insulin-like peptide 3. In order to understand the basis of this cross reactivity, it is important to elucidate both binding and activation mechanisms of this peptide. The primary binding mechanism of this hormone has been extensively studied and well defined. H2 relaxin binds to the leucine-rich repeats of RXFP1 and RXFP2 using B-chain-specific residues. However, little is known about the secondary interaction that involves the A-chain of H2 relaxin and transmembrane exoloops of the receptors. We demonstrate here through extensive mutation of the A-chain that the secondary interaction between H2 relaxin and RXFP1 is not driven by any single amino acid, although residues Tyr-3, Leu-20, and Phe-23 appear to contribute. Interestingly, these same three residues are important drivers of the affinity and activity of H2 relaxin for RXFP2 with additional minor contributions from Lys-9, His-12, Lys-17, Arg-18, and Arg-22. Our results provide new insights into the mechanism of secondary activation interaction of RXFP1 and RXFP2 by H2 relaxin, leading to a potent and RXFP1 selective analog, H2:A(4-24)(F23A), which was tested in vitro and in vivo and found to significantly inhibit collagen deposition similar to native H2 relaxin. PMID- 23024364 TI - Cathepsin B degrades amyloid-beta in mice expressing wild-type human amyloid precursor protein. AB - Accumulation of amyloid-beta (Abeta), believed to be a key trigger of Alzheimer disease (AD), could result from impaired clearance mechanisms. Previously, we showed that the cysteine protease cathepsin B (CatB) degrades Abeta, most likely by C-terminal truncation, in mice expressing human amyloid precursor protein with familial AD-linked mutations (hAPP(FAD)). In addition, the Abeta-degrading activity of CatB is inhibited by its endogenous inhibitor, cystatin C (CysC). Reducing CysC expression markedly lowers Abeta levels by enhancing CatB-mediated Abeta degradation in hAPP(FAD) mice. However, because a vast majority of AD patients do not carry familial mutations, we investigated how the CysC-CatB axis affects Abeta levels in mice expressing wild-type hAPP (hAPP(WT)). Enhancing CatB activity by CysC deletion significantly lowered total Abeta and Abeta42 levels in hAPP(WT) mice, whereas CatB deletion increased Abeta levels. To determine whether neuron-derived CatB degrades Abeta in vivo, we generated transgenic mice overexpressing CatB under the control of a neuron-specific enolase promoter. Enhancing neuronal CatB activity in hAPP(WT) mice significantly lowered Abeta42 levels. The processing of hAPP(WT) was unaffected by increasing or ablating CatB activity. Thus, the CysC-CatB axis affects degradation of Abeta42 derived from hAPP lacking familial mutations. These findings support the notion that enhancing CatB activity could lower Abeta, especially Abeta42, in AD patients with or without familial mutations. PMID- 23024365 TI - Leptin activates hepatic 5'-AMP-activated protein kinase through sympathetic nervous system and alpha1-adrenergic receptor: a potential mechanism for improvement of fatty liver in lipodystrophy by leptin. AB - BACKGROUND: AMPK activation promotes glucose and lipid metabolism. RESULTS: Hepatic AMPK activities were decreased in fatty liver from lipodystrophic mice, and leptin activated the hepatic AMPK via the alpha-adrenergic effect. CONCLUSION: Leptin improved the fatty liver possibly by activating hepatic AMPK through the central and sympathetic nervous systems. SIGNIFICANCE: Hepatic AMPK plays significant roles in the pathophysiology of lipodystrophy and metabolic action of leptin. Leptin is an adipocyte-derived hormone that regulates energy homeostasis. Leptin treatment strikingly ameliorates metabolic disorders of lipodystrophy, which exhibits ectopic fat accumulation and severe insulin resistant diabetes due to a paucity of adipose tissue. Although leptin is shown to activate 5'-AMP-activated protein kinase (AMPK) in the skeletal muscle, the effect of leptin in the liver is still unclear. We investigated the effect of leptin on hepatic AMPK and its pathophysiological relevance in A-ZIP/F-1 mice, a model of generalized lipodystrophy. Here, we demonstrated that leptin activates hepatic AMPK through the central nervous system and alpha-adrenergic sympathetic nerves. AMPK activities were decreased in the fatty liver of A-ZIP/F-1 mice, and leptin administration increased AMPK activities in the liver as well as in skeletal muscle with significant reduction in triglyceride content. Activation of hepatic AMPK with A769662 also led to a decrease in hepatic triglyceride content and blood glucose levels in A-ZIP/F-1 mice. These results indicate that the down regulation of hepatic AMPK activities plays a pathophysiological role in the metabolic disturbances of lipodystrophy, and the hepatic AMPK activation is involved in the therapeutic effects of leptin. PMID- 23024366 TI - Zebrafish Dkk3a protein regulates the activity of myf5 promoter through interaction with membrane receptor integrin alpha6b. AB - Myogenic regulatory factor Myf5 plays important roles in muscle development. In zebrafish myf5, a microRNA (miR), termed miR-3906 or miR-In300, was reported to silence dickkopf-3-related gene (dkk3r or dkk3a), resulting in repression of myf5 promoter activity. However, the membrane receptor that interacts with ligand Dkk3a to control myf5 expression through signal transduction remains unknown. To address this question, we applied immunoprecipitation and LC-MS/MS to screen putative membrane receptors of Dkk3a, and Integrin alpha6b (Itgalpha6b) was finally identified. To further confirm this, we used cell surface binding assays, which showed that Dkk3a and Itgalpha6b were co-expressed at the cell membrane of HEK-293T cells. Cross-linking immunoprecipitation data also showed high affinity of Itgalpha6b for Dkk3a. We further proved that the beta-propeller repeat domains of Itgalpha6b are key segments bound by Dkk3a. Moreover, when dkk3a and itgalpha6b mRNAs were co-injected into embryos, luciferase activity was up regulated 4-fold greater than that of control embryos. In contrast, the luciferase activities of dkk3a knockdown embryos co-injected with itgalpha6b mRNA and itgalpha6b knockdown embryos co-injected with dkk3a mRNA were decreased in a manner similar to that in control embryos, respectively. Knockdown of itgalpha6b resulted in abnormal somite shape, fewer somitic cells, weaker or absent myf5 expression, and reduced the protein level of phosphorylated p38a in somites. These defective phenotypes of trunk muscular development were similar to those of dkk3a knockdown embryos. We demonstrated that the secreted ligand Dkk3a binds to the membrane receptor Itgalpha6b, which increases the protein level of phosphorylated p38a and activates myf5 promoter activity of zebrafish embryos during myogenesis. PMID- 23024367 TI - The tyrosine kinase c-Met contributes to the pro-tumorigenic function of the p38 kinase in human bile duct cholangiocarcinoma cells. AB - Pro-tumorigenic function of the p38 kinase plays a critical role in human cholangiocarcinogenesis. However, the underlying mechanism remains incompletely understood. Here, we report that c-Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), contributes to the pro-tumorigenic ability of p38 in human cholangiocarcinoma cells. Both p38 and c-Met promote the proliferation and invasion of human cholangiocarcinoma cells. Importantly, inhibition or knockdown of p38 decreased the basal activation of c-Met. Tyrosine phosphatase inhibitor studies revealed that p38 promotes the activity of c-Met, at least in part, by inhibiting dephosphorylation of the receptor. Moreover, density enhanced phosphatase-1 (DEP-1) is involved in p38-mediated inhibiting dephosphorylation of c-Met. Furthermore, p38 inhibits the degradation of c-Met. Taken together, these data provide a potential mechanism to explain how p38 promotes human cholangiocarcinoma cell proliferation and invasion. We propose that the link between p38 and c-Met is implicated in the progression of human cholangiocarcinoma. PMID- 23024368 TI - Serine 111 phosphorylation regulates OCT4A protein subcellular distribution and degradation. AB - Embryonic stem cell self-renewal properties are attributed to critical amounts of OCT4A, but little is known about its post-translational regulation. Sequence analysis revealed that OCT4A contains five putative ERK1/2 phosphorylation sites. Consistent with the hypothesis that OCT4A is a putative ERK1/2 substrate, we demonstrate that OCT4A interacts with ERK1/2 by using both in vitro GST pulldown and in vivo co-immunoprecipitation assays. MS analysis identified phosphorylation of OCT4A at Ser-111. To investigate the possibility that ERK1/2 activation can enhance OCT4A degradation, we analyzed endogenous ubiquitination in cells transfected with FLAG-OCT4A alone or with constitutively active MEK1 (MEK1(CA)), and we observed that the extent of OCT4 ubiquitination was clearly increased when MEK1(CA) was coexpressed and that this increase was more evident after MG132 treatment. These results suggest an increase in OCT4A ubiquitination downstream of MEK1 activation, and this could account for the protein loss observed after FGF2 treatment and MEK1(CA) transfection. Understanding and controlling the mechanism by which stem cells balance self-renewal would substantially advance our knowledge of stem cells. PMID- 23024369 TI - alpha1-Adrenergic receptor control of the cerebral vasculature in humans at rest and during exercise. AB - We tested the hypothesis that pharmacological blockade of alpha(1) adrenoreceptors (by prazosin), at rest and during steady-state dynamic exercise, would impair cerebral autoregulation and result in cerebral vasodilatation in healthy humans. In 10 subjects, beat-to-beat mean arterial pressure and mean middle cerebral artery blood velocity were determined at rest and during low (Ex90) and moderate workload (Ex130) on an upright bicycle ergometer without and with prazosin. Plasma noradrenaline concentrations increased significantly from rest to Ex130 during control conditions (from 1.8 +/- 0.2 to 3.2 +/- 0.3 pmol (ml plasma)(-1)). In the control conditions, the transfer function gain between mean arterial pressure and mean middle cerebral artery blood velocity in the low frequency range was decreased at Ex90 (P = 0.035) and Ex130 (P = 0.027) from rest. A significant increase in critical closing pressure (CCP) was also observed in the control conditions from rest to Ex90 to Ex130 (from 18 +/- 3 to 24 +/- 4 to 31 +/- 4 mmHg). An average of 74 +/- 2% blockade of blood pressure response was achieved with oral prazosin. Following blockade, plasma noradrenaline concentrations further increased at rest and during Ex130 from the control value (from 2.6 +/- 0.3 to 4.4 +/- 0.5 pmol (ml plasma)(-1)). Prazosin also resulted in an increase in low-frequency gain (P < 0.003) compared with the control conditions. Prazosin blockade abolished the increases in CCP during Ex130 and increased the cerebrovascular conductance index (P = 0.018). These data indicate that in the control conditions a strengthening of cerebral autoregulation occurred with moderate dynamic exercise that is associated with an increase in CCP as a result of the exercise-mediated augmentation of sympathetic activity. Given that alpha(1)-adrenergic receptor blockade attenuated the increase in dynamic cerebral autoregulation and CCP, we conclude that increases in sympathetic activity have a role in establishing cerebral vascular tone in humans. PMID- 23024370 TI - Dopamine D1 receptors control exercise hyperpnoea in mice. AB - Previously, we undertook simultaneous recording of ventilation and pulmonary gas exchange in mice and revealed that dopamine D(2) receptors participate in exercise hyperpnoea via behavioural control of ventilation with unchanged pulmonary gas exchange. Here, we examined the hypothesis that D(1) receptors also contribute to exercise hyperpnoea using a D(1) receptor antagonist (SCH 23390; SCH) that crosses the blood-brain barrier, with the same recording technique and protocol as in the previous study. The respiratory responses of mice injected with saline or SCH (50 MUg (kg body weight)(-1), i.p.) were compared during constant-load exercise at 6 m min(-1). Each mouse was set in an airtight treadmill chamber equipped with a differential pressure transducer and open circuit system with a mass spectrometer. At rest, SCH-injected mice had significantly reduced respiratory frequency, minute ventilation and pulmonary gas exchange compared with saline-injected mice. Ventilation during hyperoxic gas inhalation and hypercapnic ventilatory responses between groups were similar. Abrupt increases and sequential declines to the steady-state level were produced by treadmill exercise in both groups of mice. Treatment with SCH lowered the increased levels of respiratory frequency, tidal volume and minute ventilation during the steady state, as well as reducing the O(2) uptake, CO(2) output and body temperature throughout treadmill exercise. These data suggest that D(1) receptors contribute to a resting ventilation level and exercise hyperpnoea during the steady state in parallel with metabolic changes. Notably, the metabolic control of D(1) receptors was important for maintenance of the steady state, and D(1) receptors in hypothalamic nuclei could be involved in this modulation. PMID- 23024372 TI - Discomfort sharing the general practice waiting room with mentally ill patients: a cross-sectional study. AB - BACKGROUND: Most mental illness is managed in general practice rather than specialist psychiatric settings. Management of mental illness in general practice is advocated as being less stigmatizing than psychiatric settings. Thus, other patients' discomfort with sharing the waiting room with the mentally ill may be problematic. OBJECTIVES: To examine prevalence and associations of discomfort of general practice waiting room patients with fellow patients with mental illness and the implications for practices of these attitudes. We sought attitudes reflecting social distance, a core element of stigmatization. METHODS: A cross sectional waiting room questionnaire-based study in 15 Australian general practices. Outcome measures were discomfort sharing a waiting room with patients with mental illness, likelihood of changing GP practice if that practice provided specialized care for patients with mental illness, and the perception that general practice is a setting where patients with mental illness should be treated. RESULTS: Of 1134 participants (response rate 78.5%), 29.7% and 12.2%, respectively, reported they would be uncomfortable sharing a waiting room with a patient with schizophrenia or severe depression/anxiety. Only 29.9% and 48.8%, respectively, felt that general practice was an appropriate location for treatment of schizophrenia or severe depression/anxiety. Ten per cent would change their current practice if it provided specialized care for mentally ill patients. CONCLUSIONS: This desire of general practice patients for social distance from fellow patients with mental illness may have implications for both the GPs with a particular interest in mental disorders and the care-seeking and access to care of patients with mental illness. PMID- 23024371 TI - Tracheal occlusion conditioning causes stress, anxiety and neural state changes in conscious rats. AB - Evidence from human and animal studies indicates that mechanical loads to breathing are stressful stimuli and evoke compensatory behaviours. Conditioning of stressful stimuli is known to cause changes in basal stress levels and behaviour. Individuals with respiratory obstructive diseases repeatedly experience bouts of airway obstruction, which may act as a form of conditioning, and often have affective disorders, such as anxiety and depression. It is unknown whether the development of affective disorders in these individuals results from the unexpected recurring respiratory perturbations. To investigate this possibility, we developed a model to elicit tracheal occlusion (TO) in conscious rats and exposed them to 10 days of TO conditioning. We hypothesized that healthy, conscious animals exposed to TO conditioning would develop stress and anxiety and would have modulated neural activity in respiratory, stress, discriminative and affective neural regions. Following TO conditioning, rats had increased basal corticosterone levels, greater adrenal weights and elevated anxiety levels compared with animals not receiving TO. Significant increases in cytochrome oxidase staining were found in brainstem respiratory nuclei, periaqueductal grey, dorsal raphe, thalamus and insular cortex. These results suggest that healthy animals develop stress and anxiety responses to respiratory load conditioning via inescapable tracheal occlusions, which may be mediated through state changes in specific brain nuclei. PMID- 23024373 TI - Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart. AB - Low birth weight and accelerated postnatal growth lead to increased risk of cardiovascular disease. We reported previously that rats exposed to a low-protein diet in utero and postnatal catch-up growth (recuperated) develop metabolic dysfunction and have reduced life span. Here we explored the hypothesis that cardiac oxidative and nitrosative stress leading to DNA damage and accelerated cellular aging could contribute to these phenotypes. Recuperated animals had a low birth weight (P<0.001) but caught up in weight to controls during lactation. At weaning, recuperated cardiac tissue had increased (P<0.05) protein nitrotyrosination and DNA single-stranded breaks. This condition was preceded by increased expression of DNA damage repair molecules 8-oxoguanine-DNA-glycosylase 1, nei-endonuclease-VIII-like, X-ray-repair-complementing-defective-repair-1, and Nthl endonuclease III-like-1 on d 3. These differences were maintained on d 22 and became more pronounced in the case of 8-oxoguanine-DNA-glycosylase-1 and nei endonuclease-VIII-like. This was accompanied by increases in xanthine oxidase (P<0.001) and NADPH oxidase (P<0.05), major sources of reactive oxygen species (ROS). The detrimental effects of increased ROS in recuperated offspring may be exaggerated at 22 d by reductions (P<0.001) in the antioxidant enzymes peroxiredoxin-3 and CuZn-superoxide-dismutase. We conclude that poor fetal nutrition followed by accelerated postnatal growth results in increased cardiac nitrosative and oxidative-stress and DNA damage, which could contribute to age associated disease risk. PMID- 23024375 TI - Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization. AB - Primary tumors are responsible for 10% of cancer deaths. In most cases, the main cause of mortality is the formation of metastases. Accumulating evidence suggests that a subpopulation of tumor cells with distinct stem-like properties is responsible for tumor initiation, invasive growth, and metastasis formation. This population is defined as cancer stem cells (CSCs). Existing therapies have enhanced the length of survival after diagnosis of cancer but have completely failed in terms of recovery. CSCs appear to be resistant to chemotherapy, may remain quiescent for extended periods, and have affinity for hypoxic environments. The CSCs can be identified and isolated by different methodologies, including isolation by CSC-specific cell surface marker expression, detection of side population phenotype by Hoechst 33342 exclusion, assessment of their ability to grow as floating spheres, and aldehyde dehydrogenase (ALDH) activity assay. None of the methods mentioned are exclusively used to isolate the solid tumor CSCs, highlighting the imperative to delineate more specific markers or to use combinatorial markers and methodologies. This review provides an overview of the main characteristics and approaches used to identify, isolate, and characterize CSCs from solid tumors. PMID- 23024374 TI - Impaired SIRT1 nucleocytoplasmic shuttling in the senescent heart during ischemic stress. AB - A "longevity " gene, sirtuin 1 (SIRT1), can attenuate age-dependent induction of left ventricular dysfunction. This study aimed to characterize the role of SIRT1 in the tolerance of aged heart to ischemic insults. Male C57BL/6 young (4-6 mo) and aged (24-26 mo) mice were used to determine the role of SIRT1 in myocardial ischemia/reperfusion (I/R) tolerance. SIRT1 localization was assessed by confocal microscopy. Immunoblotting was used to evaluate SIRT1 expression and translocation. The results demonstrated that SIRT1 is expressed predominantly as a sumoylated form in cardiomyocyte nuclei. Moreover, cardiac overexpression of desumoylase, sentrin-specific protease 2 (SENP2), significantly reduces nuclear sumoylated SIRT1 levels (P<0.05). Interestingly, I/R stress leads to desumoylation and translocation of nuclear SIRT1 into the cytoplasm in aged but not in young hearts. SIRT1 activity in ischemic young hearts was 3.2-fold higher than that seen in ischemic aged hearts, which suggests that aging causes impaired nucleocytoplasmic shuttling and activation of SIRT1 during ischemic stress. The infarct size in aged and Sirt1(+/-) knockout hearts was higher than that observed in young and Sirt1(+/+) WT littermate hearts, respectively (all P<0.05). SIRT1 agonist, SRT1720, reduced myocardial infarction in both aged and Sirt1(+/-) hearts. Therefore, impaired cardiac SIRT1 activity plays a critical role in the observed increase in susceptibility of the aged heart to I/R injury. SIRT1 agonist can restore this aging-related loss of cardioprotection. PMID- 23024376 TI - Glancing angle Talbot-Lau grating interferometers for phase contrast imaging at high x-ray energy. AB - A Talbot-Lau interferometer is demonstrated using micro-periodic gratings inclined at a glancing angle along the light propagation direction. Due to the increase in the effective thickness of the absorption gratings, the device enables differential phase contrast imaging at high x-ray energy, with improved fringe visibility (contrast). For instance, at 28 degrees glancing angle, we obtain up to ~35% overall interferometer contrast with a spectrum having ~43 keV mean energy, suitable for medical applications. In addition, glancing angle interferometers could provide high contrast at energies above 100 keV, enabling industrial and security applications of phase contrast imaging. PMID- 23024377 TI - Plasma-assisted atomic layer deposition of Al(2)O(3) and parylene C bi-layer encapsulation for chronic implantable electronics. AB - Encapsulation of biomedical implants with complex three dimensional geometries is one of the greatest challenges achieving long-term functionality and stability. This report presents an encapsulation scheme that combines Al(2)O(3) by atomic layer deposition with parylene C for implantable electronic systems. The Al(2)O(3)-parylene C bi-layer was used to encapsulate interdigitated electrodes, which were tested invitro by soak testing in phosphate buffered saline solution at body temperature (37 degrees C) and elevated temperatures (57 degrees C and 67 degrees C) for accelerated lifetime testing up to 5 months. Leakage current and electrochemical impedance spectroscopy were measured for evaluating the integrity and insulation performance of the coating. Leakage current was stably about 15 pA at 5 V dc, and impedance was constantly about 3.5 MOmega at 1 kHz by using electrochemical impedance spectroscopy for samples under 67 degrees C about 5 months (approximately equivalent to 40 months at 37 degrees C). Alumina and parylene coating lasted at least 3 times longer than parylene coated samples tested at 80 degrees C. The excellent insulation performance of the encapsulation shows its potential usefulness for chronic implants. PMID- 23024378 TI - A modified technique for episioplasty. PMID- 23024379 TI - Consideration for the pet's owner during euthanasia. PMID- 23024380 TI - The microbiome - a new frontier of biology. PMID- 23024381 TI - Veterinary medical ethics: an ethicist's commentary on veterinarians and pharmaceutical companies restricting access to a non-prescription product. PMID- 23024382 TI - Ultrasonographic visualization of colonic mesenteric vasculature as an indicator of large colon right dorsal displacement or 180 degrees volvulus (or both) in horses. AB - Visualization of colonic mesenteric vasculature during transabdominal ultrasonographic examination of horses with colic can be a predictor of right dorsal displacement of the large colon or 180 degrees large colon volvulus, or both. Medical records of 82 horses having had surgical treatment of colic and having received a transabdominal ultrasonographic examination on admission were reviewed. Colonic mesenteric vessels were sonographically identified coursing laterally on the right side of the abdomen in 24 of the 82 cases. Horses with colonic vessels identified on ultrasound were 32.5 times more likely to be diagnosed at surgery with either large colon right dorsal displacement or 180 degrees large colon volvulus than those in which vessels were not seen (P < 0.001). Visualization of colonic mesenteric vessels on ultrasound provided a sensitivity of 67.7%, specificity of 97.9%, positive predictive value of 95.8%, and negative predictive value of 81% for large colon right dorsal displacement or 180 degrees large colon volvulus, or both. PMID- 23024383 TI - Zinc-induced hemolytic anemia in a dog caused by ingestion of a game-playing die. AB - A 16-month-old spayed female mixed breed dog was presented with a 1-week history of anorexia, lethargy, diarrhea, vomiting, and difficulty rising. Hematologic evaluation indicated a marked macrocytic hypo-chromic, markedly regenerative anemia. A metallic foreign object in the gastrointestinal tract was identified on abdominal radiographs. Serum zinc concentration was markedly increased. PMID- 23024384 TI - Corynebacterium pseudotuberculosis liver abscess in a mature alpaca (Lama pacos). AB - A mature female alpaca was evaluated for weight loss and a 10-day history of anorexia, diarrhea, abdominal distension, and ventral edema. Ultrasonography revealed a hepatic mass, culture of which identified Corynebacterium pseudotuberculosis. This is the first reported case of an internal caseous lymphadenitis lesion resulting in clinical disease in a camelid. PMID- 23024385 TI - Compounding errors in 2 dogs receiving anticonvulsants. AB - Two cases that involve drug compounding errors are described. One dog exhibited increased seizure activity due to a compounded, flavored phenobarbital solution that deteriorated before the expiration date provided by the compounder. The other dog developed clinical signs of hyperkalemia and bromine toxicity following a 5-fold compounding error in the concentration of potassium bromide (KBr). PMID- 23024387 TI - Surgical retrieval of a metallic foreign body from the spleen of a dog. AB - This is the first report of a metallic foreign body in the spleen of a dog. The animal had abdominal discomfort with a tucked-up abdomen and occasional vomition. Radiography and ultrasonography were used to identify a splenic foreign body which was surgically removed through a ventral midline celiotomy. Migration of the foreign body through the stomach wall was suspected as the most likely cause. PMID- 23024386 TI - Successful surgical treatment of mandibulo-zygomatic arch synostosis secondary to trauma in a dog. AB - This is a report of mandibulo-zygomatic arch synostosis in a dog 7 mo after trauma to the maxilla. Advanced diagnostic imaging was considered essential for characterization of the condition and treatment planning. Surgical excision of the bony proliferation and physiotherapy resulted in improved function within 6 wk. PMID- 23024388 TI - Conference report: antimicrobial stewardship in Canadian agriculture and veterinary medicine. How is Canada doing and what still needs to be done? PMID- 23024389 TI - Intrathoracic pulsion diverticulum in a horse. AB - This is a report of a 12-year-old Swedish Warmblood gelding with a ruptured esophageal pulsion diverticulum associated with atypical clinical signs of colic and septic peritonitis on presentation. The location of this diverticulum at the hiatus was unique and was most likely responsible for the unusual presentation of this horse. PMID- 23024390 TI - Surgical management of 2 different presentations of ear canal atresia in dogs. AB - A 6-year-old French spaniel and a 14-month-old German shepherd dog were diagnosed with ear canal atresia. Based on presentation, computed tomography, and auditory function evaluation, the first dog underwent excision of the horizontal ear canal and bulla curettage, and the second underwent re-anastomosis of the vertical canal to the external meatus. Both dogs had successful outcomes. PMID- 23024391 TI - Clinical and magnetic resonance imaging (MRI) findings of idiopathic aplastic pancytopenia in a dog treated with cyclosporine and azathioprine. AB - A dog was referred for pancytopenia. Bone marrow biopsy showed hypocellular fatty marrow. Magnetic resonance imaging had a high signal on T1-weighted image in the metaphyseal region of the femur. We suggest that MRI could be a valuable supportive diagnostic method and introduce a strategy of treatment with cyclosporine and azathioprine in canine aplastic pancytopenia. PMID- 23024392 TI - Bacterial cholangiohepatitis in a dog. AB - A 9-year-old female Yorkshire terrier was presented for vomiting and diarrhea. Blood chemistry tests revealed hepatic dysfunction, cholestasis, and inflammation. Liver ultrasonography and liver biopsy were consistent with cholangiohepatitis. Fine-needle aspiration of the gallbladder revealed the presence of bacteria later identified as Clostridium spp. The cholangiohepatitis was successfully treated. PMID- 23024393 TI - Early experience with continuous positive airway pressure (CPAP) in 5 horses -- a case series. AB - This case series is the first report of the use of CPAP (continuous positive airway pressure) ventilation in adult horses. Two horses and 3 ponies anesthetized for orthopedic procedures in lateral recumbency received 10 cm H(2)O CPAP. During anesthesia, arterial oxygen partial pressure tended to increase and arterial carbon dioxide pressure tended to increase despite increased minute ventilation index. The measured cardiovascular parameters were within physiologic limits. PMID- 23024394 TI - Feline postvaccinal sarcoma: 20 years later. AB - Comparison of the annual prevalence of feline postvaccinal sarcomas among 11 609 feline skin mass submissions from 1992 to 2010 revealed no decrease in disease prevalence or increase in the age of affected cats in response to changes in vaccine formulation or recommended changes in feline vaccination protocols. PMID- 23024396 TI - Getting the point(s) across. PMID- 23024395 TI - One Health: from theory to practice. AB - One Health approaches to human and veterinary medicine are critical to professionals addressing global issues of food security and disease prevention. However, we have yet to develop a sufficient strategy to translate our theoretical understanding to practical application. This paper will explore the current shortcomings of One Health, within both the medical and veterinary communities, and highlight solutions to overcome these challenges. PMID- 23024397 TI - Congenital radial head luxation in a bulldog puppy. PMID- 23024398 TI - The Pumpkin or the Tiger? Michael Polanyi, Frederick Soddy, and Anticipating Emerging Technologies. AB - Imagine putting together a jigsaw puzzle that works like the board game in the movie "Jumanji": When you finish, whatever the puzzle portrays becomes real. The children playing "Jumanji" learn to prepare for the reality that emerges from the next throw of the dice. But how would this work for the puzzle of scientific research? How do you prepare for unlocking the secrets of the atom, or assembling from the bottom-up nanotechnologies with unforeseen properties - especially when completion of such puzzles lies decades after the first scattered pieces are tentatively assembled? In the inaugural issue of this journal, Michael Polanyi argued that because the progress of science is unpredictable, society must only move forward with solving the puzzle until the picture completes itself. Decades earlier, Frederick Soddy argued that once the potential for danger reveals itself, one must reorient the whole of one's work to avoid it. While both scientists stake out extreme positions, Soddy's approach - together with the action taken by the like-minded Leo Szilard - provides a foundation for the anticipatory governance of emerging technologies. This paper narrates the intertwining stories of Polanyi, Soddy and Szilard, revealing how anticipation influenced governance in the case of atomic weapons and how Polanyi's claim in "The Republic of Science" of an unpredictable and hence ungovernable science is faulty on multiple levels. PMID- 23024399 TI - The Value Question in Metaphysics. AB - Much seems to be at stake in metaphysical questions about, for example, God, free will or morality. One thing that could be at stake is the value of the universe we inhabit-how good or bad it is. We can think of competing philosophical positions as describing possibilities, ways the world might turn out to be, and to which value can be assigned. When, for example, people hope that God exists, or fear that we do not possess free will, they express attitudes towards these possibilities, attitudes that presuppose answers to questions about their comparative value. My aim in this paper is to distinguish these evaluative questions from related questions with which they can be confused, to identify structural constraints on their proper pursuit, and to address objections to their very coherence. Answers to such evaluative questions offer one measure of the importance of philosophical disputes. PMID- 23024400 TI - First impact factor of Indian journal of microbiology. PMID- 23024401 TI - The rise of open access. PMID- 23024402 TI - Hydrogen and Polyhydroxybutyrate Producing Abilities of Bacillus spp. From Glucose in Two Stage System. AB - Metabolic activities of four Bacillus strains to transform glucose into hydrogen (H(2)) and polyhydroxybutyrate (PHB) in two stages were investigated in this study. Under batch culture conditions, Bacillus thuringiensis EGU45 and Bacillus cereus EGU44 evolved 1.67-1.92 mol H(2)/mol glucose, respectively during the initial 3 days of incubation at 37 degrees C. In the next 2 days, the residual glucose solutions along with B. thuringiensis EGU45 shaken at 200 rpm was found to produce PHB yield of 11.3% of dry cell mass. This is the first report among the non-photosynthetic microbes, where the Bacillus spp.-B. thuringiensis and B. cereus strains have been shown to produce H(2) and PHB in same medium under different conditions. PMID- 23024403 TI - Extraction, Purification and Characterization of Thermostable, Alkaline Tolerant alpha-Amylase from Bacillus cereus. AB - Thermostable alkaline alpha-amylase producing bacterium Bacilluscereus strain isolated from Cuddalore harbour waters grew maximally in both shake flask and fermentor, and produced alpha-amylase at 35 degrees C, pH 7.5 and 1.0% of substrate concentrations. alpha-Amylase activity was maximum at 65 degrees C, pH 8.0, 89% of its activity was sustained even at pH 11.0. Added with MnCl(2,) alpha amylase activity showed 4% increase but it was inhibited by EDTA. The molecular weight of the purified alpha-amylase is 42 kDa. PMID- 23024404 TI - A universal method for the identification of bacteria based on general PCR primers. AB - The Universal Method (UM) described here will allow the detection of any bacterial rDNA leading to the identification of that bacterium. The method should allow prompt and accurate identification of bacteria. The principle of the method is simple; when a pure PCR product of the 16S gene is obtained, sequenced, and aligned against bacterial DNA data base, then the bacterium can be identified. Confirmation of identity may follow. In this work, several general 16S primers were designed, mixed and applied successfully against 101 different bacterial isolates. One mixture, the Golden mixture7 (G7) detected all tested isolates (67/67). Other golden mixtures; G11, G10, G12, and G5 were useful as well. The overall sensitivity of the UM was 100% since all 101 isolates were detected yielding intended PCR amplicons. A selected PCR band from each of 40 isolates was sequenced and the bacterium identified to species or genus level using BLAST. The results of the UM were consistent with bacterial identities as validated with other identification methods; cultural, API 20E, API 20NE, or genera and species specific PCR primers. Bacteria identified in the study, covered 34 species distributed among 24 genera. The UM should allow the identification of species, genus, novel species or genera, variations within species, and detection of bacterial DNA in otherwise sterile samples such as blood, cerebrospinal fluid, manufactured products, medical supplies, cosmetics, and other samples. Applicability of the method to identifying members of bacterial communities is discussed. The approach itself can be applied to other taxa such as protists and nematodes. PMID- 23024405 TI - In Vitro Susceptibility of C. albicans and C. neoformens to Potential Metabolites from Streptomycetes. AB - Forty two Streptomycetes isolates from soils of Kodachadri region in Western ghats were recovered by soil dilution technique. Cross streak method was followed for primary screening of antifungal activity. Positive isolates were subjected to secondary screening by cold extraction of fermentation broth in butanol solvent. Six isolates exhibited broad spectrum antifungal activity against all the tested yeast pathogens like Candida albicans, Candida lipolytica, Cryptococcus neoformens and Saccharomyces cerevisiae. One isolate showed excellent antifungal activity against all test organisms with maximum zone of inhibition 60 mm each incase of C. neoformens and C. albicans. Partial characterization of antifungal metabolite by TLC resulted in a purple spot with an R(f) value 0.50. The UV absorption spectra at 218 nm indicated possible chemical nature of the active metabolite as polyene group and purity was assessed by analytical HPLC. PMID- 23024406 TI - Antimicrobial activities of tocklai vegetative tea clones. AB - Thirty-one Tocklai vegetative (TV) tea clones contained caffeine and total catechin 44.39 and 227.55 mg/g dry weight of leaves, respectively. The (-) epigallocatechin gallate (EGCG) was the most abundant (109.60 mg/g) followed by (-)-epigallocatechin (EGC, 44.54 mg/g), (-)-epicatechin gallate (ECG, 41.74 mg/g), (-)-epicatechin (EC, 27.42 mg/g) and +catechin (4.25 mg/g). Total catechins were highest in TV 20 (509.7 mg/g) and lowest in TV 6 (71.7 mg/g). The tea clones that contain high level of total catechin exhibited the strongest antimicrobial activity. Among caffeine and flavanol compounds, theaflavins (TF) present in black tea possess a similar antimicrobial potency as EC present in fresh leaves, and that the conversion of catechins to TF during fermentation in making black tea tends to alter their antimicrobial activities. The bioactive molecules other than catechins present in tea leaves may also contribute towards antimicrobial activity. PMID- 23024407 TI - Isolation and Typing of Canine Parvovirus in CRFK Cell Line in Puducherry, South India. AB - A total of 128 faecal samples/rectal swabs were collected from dogs showing signs of diarrhea/enteritis in and around Puducherry, South India. Eighteen clinical samples, showing high HA titre of 1:512 and above and positivity by polymerase chain reaction (PCR) with CPV-2ab primers, were subjected to virus isolation in CRFK cell line. Of the 18 samples processed, 3 samples (16.6%) were positive for CPV and were confirmed by haemagglutination, dot-ELISA, and IFAT. The three cell culture isolates were characterized as CPV-2b types by multiplex PCR as well as by monoclonal antibody typing. PMID- 23024408 TI - Prevalence of Very Low Numbers of Potential Pathogenic Isolates of Yersiniaenterocolitica and Yersinia intermedia in Traditional Fast Foods of India. AB - In this study, an incidence pattern of 1.7% for Yersiniaenterocolitica and 2.5% for Y. intermedia were observed in an analysis of 120 diversified food samples collected from the local market of Mysore, Southern India. Two native isolates characterized as Y. enterocolitica belonged to biotype 1B and revealed the presence of major virulence related traits such as regulator of virulence, mucoid Yersinia factor regulator, attachment invasion locus, heat stable enterotoxin, Yersinia type II secretory system and phospholipase A in PCR. Force type neighbor joining phylograms generated for Y. enterocolitica based on PCR amplicons of rovA and ypl showed 100% homology with two to three strains of Y. enterocolitica and about 75% homology with several strains of Y. pestis. PMID- 23024409 TI - Endophytic Fungal Flora from Roots and Fruits of an Indian Neem Plant Azadirachta indica A. Juss., and Impact of Culture Media on their Isolation. AB - Azadirachta indica A. Juss. (neem), native to India, is well known worldwide for its insecticidal and ethanopharmacological properties. Although endophytic microbes are known from this plant as only leaves and stems were the subjects of past reports. Now, a variety of procedures and a number of different media were used to isolate the maximum number of endophytic fungi from unripe fruits and roots. A total of 272 isolates of 29 filamentous fungal taxa were isolated at rate of 68.0% from 400 samples of three different individual trees (at locations Az1, Az2, Az3). Mycological agar (MCA) medium yielded the highest number of isolates (95, with a 14.50% isolation rate) with the greatest species richness. Mycelia Sterilia (1, 2, 3) accounted for 11.06%, Coelomycetes 7.25%, while Hyphomycetes showed the maximum number of representative isolates (81.69%). Mycelia-Sterilia (1, 2, 3), based on their 5.8S ITS 1, ITS2 and partial 18S and 28S rDNA sequences were identified as Fusarium solani (99%), Chaetomium globosum (93%) and Chaetomium globosum (93%) respectively. Humicola, Drechslera, Colletotrichum, and Scytalidium sp. were some of the peculiar fungal endophytes recovered from this plant. PMID- 23024410 TI - Extraction of Copper from Malanjkhand Low-Grade Ore by Bacillus stearothermophilus. AB - Thermophilic bacteria are actively prevalent in hot water springs. Their potential to grow and sustain at higher temperatures makes them exceptional compare to other microorganism. The present study was initiated to isolate, identify and determine the feasibility of extraction of copper using thermophilic heterotrophic bacterial strain. Bacillus stearothermophilus is a thermophilic heterotrophic bacterium isolated from hot water spring, Atri, Orissa, India. This bacterium was adapted to low-grade chalcopyrite ore and its efficiency to solubilize copper from Malanjkhand low-grade ore was determined. The low-grade copper ore contains 0.27% Cu, in which the major copper-bearing mineral is chalcopyrite associated with other minerals present as minor phase. Variation in parameters such as pulp-density and temperatures were studied. After 30 days of incubation, it was found that Bacillus stearothermophilus solubilize copper up to 81.25% at pH 6.8 at 60 degrees C. PMID- 23024411 TI - Bioremediation of heavy metals in liquid media through fungi isolated from contaminated sources. AB - Wastewater particularly from electroplating, paint, leather, metal and tanning industries contain enormous amount of heavy metals. Microorganisms including fungi have been reported to exclude heavy metals from wastewater through bioaccumulation and biosorption at low cost and in eco-friendly way. An attempt was, therefore, made to isolate fungi from sites contaminated with heavy metals for higher tolerance and removal of heavy metals from wastewater. Seventy-six fungal isolates tolerant to heavy metals like Pb, Cd, Cr and Ni were isolated from sewage, sludge and industrial effluents containing heavy metals. Four fungi (Phanerochaete chrysosporium, Aspegillus awamori, Aspergillus flavus, Trichoderma viride) also were included in this study. The majority of the fungal isolates were able to tolerate up to 400 ppm concentration of Pb, Cd, Cr and Ni. The most heavy metal tolerant fungi were studied for removal of heavy metals from liquid media at 50 ppm concentration. Results indicated removal of substantial amount of heavy metals by some of the fungi. With respect to Pb, Cd, Cr and Ni, maximum uptake of 59.67, 16.25, 0.55, and 0.55 mg/g was observed by fungi Pb3 (Aspergillus terreus), Trichoderma viride, Cr8 (Trichoderma longibrachiatum), and isolate Ni27 (A. niger) respectively. This indicated the potential of these fungi as biosorbent for removal of heavy metals from wastewater and industrial effluents containing higher concentration of heavy metals. PMID- 23024412 TI - Bioaccumulation of cerium and neodymium by Bacillus cereus isolated from rare earth environments of Chavara and Manavalakurichi, India. AB - Rare earth elements (REEs) are among the common minerals in the Rare earth environment that are very precious and also enhance soil properties. The aim of this present study is to evaluate the accumulation of REEs by bacterial isolates of rare earth environment. Morphological and biochemical characterization were done for 37 bacterial isolates and also molecular studies were carried out using 16S rRNA sequencing method. The assessment of REEs composition in soil samples of Chavara and Manavalakurichi analyzed using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) showed the abundance of Cerium and Neodymium among lanthanides. The bioaccumulation study of rare earth elements by Bacillus cereus were accomplished employing FT-IR spectrum and ICP-OES analysis. The significant accumulation of rare earth elements especially Cerium and Neodymium was noticed in Bacillus cereus isolated from rare earth environment. PMID- 23024413 TI - Partial Purification and Characterization of an Elastase-inhibitory Lipid Derivative from a Cyanobacterium, Microcystis Ku2. AB - A unicyanobacterial isolate of cyanobacterium, identified as Microcystis Ku2, produced a mammalian elastase-inhibitory lipid derivative. Protease inhibitors in cyanobacteria are unequivocally peptides. Since this metabolite appeared in lipid phase, we worked on a hypothesis that whether metabolite other than peptides could be responsible for the characteristic inhibition. It was purified by saponification and reverse phase column chromatography. The resulting compound was tentatively characterized as a glycolipid with structure of sulfated di pentose derivative of ceramide (MW = 956 Da). The apparent IC(50) for elastase was 1.3 MUM. PMID- 23024414 TI - Decolorization of Textile Dyes and Degradation of Mono-Azo Dye Amaranth by Acinetobacter calcoaceticus NCIM 2890. AB - Acinetobacter calcoaceticus NCIM 2890 (A. caloaceticus) was found to decolorize 20 different textile dyes of various classes. Decolorization of an azo dye amaranth was observed effectively (91%) at static anoxic condition, whereas agitated culture grew well but showed less decolorization (68%) within 48 h of incubation. Induction of intracellular and extracellular lignin peroxidase, intracellular laccase, dichlorophenol indophenol (DCIP) reductase and riboflavin reductase represented their involvement in the biodegradation of amaranth. The products obtained after degradation of Amaranth were characterized as naphthalene sulfamide, hydroxyl naphthalene diazonium and naphthalene diazonium. The germination and growth of Sorghum vulgare and Phaseolus mungo seeds, and the growth of E. coli and Bacillus substilis were not inhibited by the metabolic products of the dye. PMID- 23024415 TI - Characterization of the Biocidal Spectrum of Extracellular Filtrates of Microcystis aeruginosa. AB - The effect of dichloromethane (DCM) and ethyl acetate (EA) extract of a cyanobacterium, Microcystis aeruginosa was evaluated against unicellular cyanobacteria and the phytopathogenic fungus Rhizoctonia solani. Fractionation of the filtrate showed the presence of five spots of different Rf values on silica gel coated plates indicating the presence of a number of compounds in the extract. A marked reduction in growth (52%) of the fungus was recorded on the plates supplemented with cyanobacterial extract, indicating the involvement of anti-fungal metabolite(s). The extract did not show any negative influence on seed germination and growth of seedlings of wheat, rice and mung, emphasizing the suitability of the compound for use in agriculture. PMID- 23024416 TI - Toxicity of Crude Extracellular Products of Aeromonas hydrophila on Rohu, Labeo rohita (Ham.). AB - In the present study the haemolytic and proteolytic activity of extracellular products (ECP) secreted from Aeromonas hydrophila (CAHH14 strain) were studied with respect to temperature and different time of incubation as well as its lethal toxicity on rohu, Labeo rohita. The strain was isolated from Catla catla (showing abdominal dropsy symptom) collected from the pond of Central Institute of Freshwater Aquaculture (CIFA), Bhubaneswar, India and was characterized on the basis of biochemical tests. The highest production of haemolysin was achieved when the bacteria was grown at 35 degrees C for 30 h. The proteolytic activity was found to be highest when the bacterium was grown at 30 degrees C for 36 h. The haemolytic and proteolytic toxin produced by Aeromonas hydrophila was found to be lethal to rohu (LD(50) 1.7 * 10(4) cfu/ml). The lethality of ECP was decreased by heating and completely inactivated by boiling at 100 degrees C for 10 min. This indicates that protease activity and haemolytic activity of A. hydrophila ECP was temperature dependant. PMID- 23024417 TI - Rhizobia species: A Boon for "Plant Genetic Engineering". AB - Since past three decades new discoveries in plant genetic engineering have shown remarkable potentials for crop improvement. Agrobacterium Ti plasmid based DNA transfer is no longer the only efficient way of introducing agronomically important genes into plants. Recent studies have explored a novel plant genetic engineering tool, Rhizobia sp., as an alternative to Agrobacterium, thereby expanding the choice of bacterial species in agricultural plant biotechnology. Rhizobia sp. serve as an open license source with no major restrictions in plant biotechnology and help broaden the spectrum for plant biotechnologists with respect to the use of gene transfer vehicles in plants. New efficient transgenic plants can be produced by transferring genes of interest using binary vector carrying Rhizobia sp. Studies focusing on the interactions of Rhizobia sp. with their hosts, for stable and transient transformation and expression of genes, could help in the development of an adequate gene transfer vehicle. Along with being biologically beneficial, it may also bring a new means for fast economic development of transgenic plants, thus giving rise to a new era in plant biotechnology, viz. "Rhizobia mediated transformation technology." PMID- 23024418 TI - Development and comparative evaluation of a competitive ELISA with rose bengal test and a commercial indirect ELISA for serological diagnosis of brucellosis. AB - The development of a competitive ELISA for the detection of brucella-specific antibodies in bovines is described. Anti-brucella guinea pig serum was used as a source of competing antibodies. Lipo-polysaccharide purified from inactivated B. abortus S19 culture was used as antigen for the development of the assay. Sera from cattle were used in the competitive ELISA, rose bengal test and a commercial indirect ELISA. The following cattle sera were tested: (i) known positive sera (n = 80) (ii) known negative sera (n = 100) and (iii) field sera (n = 1184). Based on the receiver operating characteristics curve analysis and frequency distribution of the percentage of inhibition, 30% inhibition was considered the cut-off for positive and negative results. The sensitivity and specificity estimate on comparison with the commercial indirect ELISA was 94.87 and 92.12% respectively. The competitive ELISA described is a simple method for the routine screening of animal sera for detecting Brucella-specific antibodies. PMID- 23024419 TI - Characterization and phylogenetic diversity of carboxymethyl cellulase producing bacillus species from a landfill ecosystem. AB - Total population of cellulose degrading bacteria was studied in a landfill ecosystem as a part of microbial diversity study. Samples were obtained from 3 and 5 feet depth of a local landfill being operated for past 10 years. Among many isolates, 22 bacterial strains were selected based on their capability to decompose carboxymethyl cellulose (CMC). These isolates were cultivated on agar medium with CMC as the carbon source. All isolates were Gram positive, endospore forming and alkalophilic bacteria with optimum growth pH 9-10. They were grouped based on the phenotypic and chemotaxonomic characters and representative strains of different groups along with high carboxymethyl cellulase (CMCase) producing strains were included for further characterization. Analysis of 16S rRNA gene indicated that these strains belong to different species of the genus Bacillus. Maximum CMCase activity of 4.8 U/ml at 50 degrees C was obtained by strain LFC15. Results in the present study indicated the potential of waste land ecosystems such as landfill are potential source for isolation of industrially important microorganisms. PMID- 23024421 TI - A Report on the '51st Annual Conference of Association of Microbiologists of India (AMI) (December 14-17, 2010; Venue: Birla Institute of Technology, Mesra, Ranchi, India). PMID- 23024422 TI - Metagenomics: a quantum jump from bacterial genomics. PMID- 23024423 TI - Tracing the wider impacts of biomedical research: a literature search to develop a novel citation categorisation technique. AB - There is an increasing need both to understand the translation of biomedical research into improved healthcare and to assess the range of wider impacts from health research such as improved health policies, health practices and healthcare. Conducting such assessments is complex and new methods are being sought. Our new approach involves several steps. First, we developed a qualitative citation analysis technique to apply to biomedical research in order to assess the contribution that individual papers made to further research. Second, using this method, we then proposed to trace the citations to the original research through a series of generations of citing papers. Third, we aimed eventually to assess the wider impacts of the various generations. This article describes our comprehensive literature search to inform the new technique. We searched various databases, specific bibliometrics journals and the bibliographies of key papers. After excluding irrelevant papers we reviewed those remaining for either general or specific details that could inform development of our new technique. Various characteristics of citations were identified that had been found to predict their importance to the citing paper including the citation's location; number of citation occasions and whether the author(s) of the cited paper were named within the citing paper. We combined these objective characteristics with subjective approaches also identified from the literature search to develop a citation categorisation technique that would allow us to achieve the first of the steps above, i.e., being able routinely to assess the contribution that individual papers make to further research. PMID- 23024424 TI - Restoration of autonomic dysfunction in children with obstructive sleep apnea after adenotonsillectomy. PMID- 23024425 TI - Sleep and insulin resistance in adolescents. PMID- 23024426 TI - Inability to replicate cerebrospinal fluid histamine deficits in the primary hypersomnias: a back to the drawing board moment. PMID- 23024427 TI - Melatonin: an adjunctive treatment for cardiometabolic disease? PMID- 23024428 TI - An open letter to the sleep and circadian rhythms community: Presidents' viewpoints of the World Sleep Federation (WSF). PMID- 23024429 TI - On the road for a single and reliable objective assessment of sleepiness. PMID- 23024430 TI - GABA-to-ACh ratio in basal forebrain and cerebral cortex varies significantly during sleep. AB - STUDY OBJECTIVES: GABAergic and cholinergic transmission within the basal forebrain and cerebral cortex contribute to the regulation of sleep and wakefulness. In contrast to levels of acetylcholine (ACh), levels of endogenous GABA in basal forebrain and cortex during sleep and wakefulness have not previously been quantified. This study (1) tested the hypothesis that there are differential, state-specific changes in GABA levels within the substantia innominata (SI) region of the basal forebrain and somatosensory cortex; and (2) quantified the ratio of GABAergic to cholinergic transmission in the SI, cortex, and pontine reticular formation during rapid eye movement sleep (REM), non-REM sleep (NREM), and wakefulness. DESIGN: Within/between subjects. SETTING: University of Michigan. PATIENTS OR PARTICIPANTS: Adult, male, purpose bred cats (n = 5). INTERVENTIONS: In vivo microdialysis, high performance liquid chromatography, electrophysiological recordings. MEASUREMENTS AND RESULTS: In the SI, GABA levels were significantly greater during NREM (17%) than during REM. In the cortex, GABA levels were significantly greater during NREM than during wakefulness (39%) and REM (63%). During prolonged wakefulness, there was a linear increase in cortical GABA levels, and the amount of time spent awake accounted for 87% of the variance in GABA. The GABA-to-ACh ratio was largest during NREM for all brain regions. REM was characterized by a 68% decrease in the GABA-to-ACh ratio across brain regions, always due to a decrease in GABA levels. CONCLUSION: Three of the brain regions that comprise the anatomically distributed, sleep generating network have in common a GABA-mediated, sleep-dependent decrease in the GABA-to-ACh ratio. PMID- 23024431 TI - Baroreflex sensitivity after adenotonsillectomy in children with obstructive sleep apnea during wakefulness and sleep. AB - STUDY OBJECTIVES: Children with obstructive sleep apnea have blunted baroreflex sensitivity and increased blood pressure variability. The aim of the study was to test the hypothesis that treatment of sleep apnea by adenotonsillectomy results in significant improvement of baroreflex sensitivity, lowering of blood pressure and blood pressure variability and increase vagal heart rate modulation. STUDY DESIGN: One hundred ninety-four children aged 9.6 +/- 2.3 years were enrolled; 133 had obstructive sleep apnea and 61 were healthy controls. For children with sleep apnea, polysomnography with 3-lead electrocardiography and continuous blood pressure was performed before adenotonsillectomy, then 6 weeks and 6 months postoperatively. Controls underwent the same assessment at study entry and 6 months later. Spontaneous baroreflex sensitivity was measured in the time and frequency domains. Data analyses were performed for available and complete cases. RESULTS: Children with sleep apnea experienced postoperatively an increase in baroreflex sensitivity and decrease in blood pressure variability during wakefulness and sleep. A decrease in blood pressure during sleep and in heart rate during wakefulness was also measured. The improvement in baroreflex sensitivity was predicted by the change in the apnea-hypopnea and arousal indices. A normal pattern of rising baroreflex sensitivity during the night was restored in children with severe apnea after surgery. However, baroreceptor sensitivity did not completely normalize after treatment. CONCLUSION: Treatment of obstructive sleep apnea in children by adenotonsillectomy is associated with gradual improvement in known risk factors for cardiovascular disease. Complete normalization of baroreceptor sensitivity was not achieved 6 months postoperatively. PMID- 23024432 TI - Upper airway collapsibility and genioglossus activity in adolescents during sleep. AB - STUDY OBJECTIVES: Obese patients develop obstructive sleep apnea syndrome (OSAS), at least in part because of a narrowed upper airway. However, many obese adolescents do not develop OSAS, despite having a presumably narrower airway. The reasons for this phenomenon are unclear. The authors hypothesized that obese controls have a compensatory neuromuscular response to subatmospheric pressure loads during sleep, making them less likely to develop upper airway collapse. DESIGN: Patients underwent pressure-flow measurements during sleep while wearing intraoral electrodes to measure genioglossal electromyography (EMGgg). Two techniques were applied to decrease nasal pressure (P(N)) to subatmospheric levels, resulting in an activated and relatively hypotonic upper airway. SETTING: Sleep laboratory. PARTICIPANTS: There were 35 obese patients with OSAS, 28 obese controls, and 43 lean controls. RESULTS: In the activated state, the two control groups had a flatter slope of the pressure-flow relationship and a more negative critical closing pressure (less collapsible) than the OSAS group. In the hypotonic state, the lean controls had a flatter slope of the pressure-flow relationship than the OSAS and obese control groups. In the activated state, the slope of EMGgg versus P(N) was greater in the obese control group than in the OSAS or lean control groups (P = 0.002 and P = 0.028, respectively); there were no differences in the hypotonic state. CONCLUSIONS: Obese controls have vigorous upper airway neuromuscular responses during sleep. Upper airway reflexes normally decline during adolescent development. It is speculated that obese adolescents without OSAS maintain protective upper airway reflexes during adolescent development, whereas those who go on to develop OSAS do not. PMID- 23024433 TI - Sleep duration and insulin resistance in healthy black and white adolescents. AB - STUDY OBJECTIVES: Poor sleep may play a role in insulin resistance and diabetes risk. Yet few studies of sleep and insulin resistance have focused on the important developmental period of adolescence. To address this gap, we examined the association of sleep and insulin resistance in healthy adolescents. DESIGN: Cross-sectional. SETTING: Community setting in one high school. PARTICIPANTS: 245 (137 African Americans, 116 males) high school students. MEASUREMENTS AND RESULTS: Participants provided a fasting blood draw and kept a sleep log and wore a wrist actigraph for one week during the school year. Participants' families were from low to middle class based on family Hollingshead scores. Total sleep time across the week averaged 7.4 h by diary and 6.4 h by actigraph; homeostatic model assessment of insulin resistance ([HOMA-IR] unadjusted) averaged 4.13. Linear regression analyses adjusted for age, race, gender, body mass index, and waist circumference showed that the shorter the sleep, the higher the HOMA-IR, primarily due to sleep duration during the week. No evidence was found for long sleep being associated with elevated HOMA-IR. Fragmented sleep was not associated with HOMA-IR but was associated with glucose levels. CONCLUSIONS: Reduced sleep duration is associated with HOMA-IR in adolescence. Long sleep duration is not associated. Interventions to extend sleep duration may reduce diabetes risk in youth. PMID- 23024434 TI - Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions. AB - STUDY OBJECTIVES: To determine the activity of cerebral histaminergic system evaluated by CSF levels of histamine (HA) and tele-methylhistamine (t-MHA), its major metabolite, and their relationships with hypocretin-1 levels in a large population of patients with hypersomnia and neurological conditions. DESIGN: sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay was developed for the simultaneous quantification of CSF HA and t-MHA. SETTING: ata were collected and CSF hypocretin-1 levels were measured using radioimmunoassay at the Sleep Disorders Center, Montpellier, France. CSF HA and t-MHA were measured in Bioprojet-Biotech, France PARTICIPANTS: One hundred fourteen unrelated patients with a suspicion of central hypersomnia underwent one night of polysomnography followed by the multiple sleep latency test. Sleep disorders were diagnosed clinically and using sleep studies: narcolepsy-cataplexy NC (n = 56), narcolepsy without cataplexy NwC (n = 27), idiopathic hypersomnia IH (n = 11), secondary narcolepsy (n = 3), and unspecified hypersomnia Uns EDS (n = 17). Fifty neurological patients without daytime sleepiness were included as controls. MEASUREMENTS AND RESULTS: No between-hypersomnia group differences were found for CSF HA levels (median 708.62 pM extreme range [55.92-3335.50] in NC; 781.34 [174.08-4391.50] in NwC; 489.42 [177.45-906.70] in IH, and 1155.40 [134.80 2736.59] in Uns EDS) or for t-MHA levels. No association was found between CSF HA, t-MHA, or HA + t-MHA, sleepiness, treatment intake, and frequency of cataplexy. A slight negative correlation was found between age and HA levels. Further adjustment for the age revealed no significant HA levels difference between hypersomnia patients and controls. CONCLUSION: CSF histamine and tele methylhistamine did not significantly differ between patients with narcolepsy cataplexy and other etiologies of non-hypocretin-1 deficient central hypersomnias; these measurements, therefore, are not useful in assessing the etiology or severity of centrally mediated hypersomnia. PMID- 23024435 TI - Prevalence and functional consequences of severe insomnia symptoms in mood and anxiety disorders: results from a nationally representative sample. AB - STUDY OBJECTIVES: To evaluate the prevalence of severe insomnia symptoms and the extent to which they are associated with daytime impairments in comorbid mood and anxiety disorders. DESIGN: Nationally representative cross-sectional survey. SETTING: National Comorbidity Survey-Replication (NCS-R). PARTICIPANTS: There were 5,692 NCS-R respondents with no mood or anxiety disorder (n = 3,711), mood disorders only (n = 327), anxiety disorders only (n = 1,137), and coexisting mood and anxiety disorders (n = 517). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition disorders and severe insomnia symptoms in the past year were assessed using the World Health Organization (WHO) Composite International Diagnostic Interview. The World Health Organization Disability Assessment Schedule (WHO-DAS) indexed eight domains of daytime impairment in the past 30 days, which included self-care, mobility, cognition, social functioning, time out of role, and four components of productive role functioning. Respondents with comorbid mood and anxiety disorders had significantly higher rates of severe insomnia complaints (42.1-62.8%) relative to the three other groups. Severe insomnia complaints were also significantly more prevalent in individuals with mood (25.2-45.6%) or anxiety disorders only (24.9-45.5%) relative to those with no disorder (12.4-24.3%). Moreover, endorsing a severe insomnia complaint in the past year was associated with increased days of impairment across all past-month WHO-DAS domains for respondents with mood-anxiety comorbidity. For the remaining groups, severe insomnia complaints were related to increased days of impairment across all domains except self-care, and additionally mobility for the group with mood disorders only. CONCLUSIONS: Comorbid mood and anxiety disorders are associated with high rates of severe insomnia complaints, which were independently associated with substantial functional impairment. PMID- 23024436 TI - Circadian modulation of consolidated memory retrieval following sleep deprivation in Drosophila. AB - OBJECTIVES: Several lines of evidence indicate that sleep plays a critical role in learning and memory. The aim of this study was to evaluate anesthesia resistant memory following sleep deprivation in Drosophila. DESIGN: Four to 16 h after aversive olfactory training, flies were sleep deprived for 4 h. Memory was assessed 24 h after training. Training, sleep deprivation, and memory tests were performed at different times during the day to evaluate the importance of the time of day for memory formation. The role of circadian rhythms was further evaluated using circadian clock mutants. RESULTS: Memory was disrupted when flies were exposed to 4 h of sleep deprivation during the consolidation phase. Interestingly, normal memory was observed following sleep deprivation when the memory test was performed during the 2 h preceding lights-off, a period characterized by maximum wake in flies. We also show that anesthesia resistant memory was less sensitive to sleep deprivation in flies with disrupted circadian rhythms. CONCLUSIONS: Our results indicate that anesthesia resistant memory, a consolidated memory less costly than long-term memory, is sensitive to sleep deprivation. In addition, we provide evidence that circadian factors influence memory vulnerability to sleep deprivation and memory retrieval. Taken together, the data show that memories weakened by sleep deprivation can be retrieved if the animals are tested at the optimal circadian time. PMID- 23024437 TI - Distinct phase relationships between suprachiasmatic molecular rhythms, cerebral cortex molecular rhythms, and behavioral rhythms in early runner (CAST/EiJ) and nocturnal (C57BL/6J) mice. AB - STUDY OBJECTIVE: We have previously established that CAST/EiJ (CAST) mice differ from normal mice, such as C57BL/6J (B6), in the timing of wheel-running onset relative to light/dark cycles. These mice provide an animal model for studies of the genetic and neurobiological basis for circadian phase misalignment in humans. Neither differences in endogenous circadian period nor the shape of the photic phase response curve explain the difference in the timing of activity onset between CAST and B6 mice, suggesting a mechanism downstream of the circadian clock. Here, we further test the hypothesis that the two strains differ with respect to circadian oscillations at the molecular level. DESIGN: Sleep/wake cycles were examined and rhythms of Period1 (Per1) and Period2 (Per2) expression were measured in the cerebral cortex, suprachiasmatic nucleus (SCN), and other hypothalamic regions. SETTING: Basic sleep and molecular research laboratory. PATIENTS OR PARTICIPANTS: Male mice of the B6 and CAST inbred strains. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Sleep/wake cycles were advanced by approximately 4 h in CAST mice relative to B6 mice. This was paralleled by phase advanced rhythms of Per1 and Per2 expression, as measured byin situ hybridization, in the cerebral cortex of CAST relative to B6. By contrast, the timing of circadian oscillations and the photic induction ofPer1 and Per2 expression in the SCN were unaffected by strain. CONCLUSION: The advanced phase of wheel running and sleep/wake cycles in CAST mice relative to B6 mice is apparently not associated with differences in molecular oscillations in the SCN clock itself, but most likely in mechanisms downstream of the SCN clock. CAST mice may therefore provide a model system to investigate circadian downstream mechanisms underlying unusual patterns of entrainment to the ambient photoperiod. CITATION: Jiang P; Franklin KM; Duncan MJ; O'Hara BF; Wisor JP. Distinct phase relationships between suprachiasmatic molecular rhythms, cerebral cortex molecular rhythms, and behavioral rhythms in early runner (CAST/EiJ) and nocturnal (C57BL/6J) mice. SLEEP 2012;35(10):1385-1394. PMID- 23024438 TI - Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: a randomized controlled trial. AB - STUDY OBJECTIVES: In the United States alone, approximately 22 million people take beta-blockers chronically. These medications suppress endogenous nighttime melatonin secretion, which may explain a reported side effect of insomnia. Therefore, we tested whether nightly melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers. DESIGN: Randomized, double blind, placebo-controlled, parallel-group design. SETTING: Clinical and Translational Research Center at Brigham and Women's Hospital, Boston. PATIENTS: Sixteen hypertensive patients (age 45-64 yr; 9 women) treated with the beta blockers atenolol or metoprolol. INTERVENTIONS: Two 4-day in-laboratory admissions including polysomnographically recorded sleep. After the baseline assessment during the first admission, patients were randomized to 2.5 mg melatonin or placebo (nightly for 3 weeks), after which sleep was assessed again during the second 4-day admission. Baseline-adjusted values are reported. One patient was removed from analysis because of an unstable dose of prescription medication. MEASUREMENTS AND RESULTS: In comparison with placebo, 3 weeks of melatonin supplementation significantly increased total sleep time (+36 min; P = 0.046), increased sleep efficiency (+7.6%; P = 0.046), and decreased sleep onset latency to Stage 2 (-14 min; P = 0.001) as assessed by polysomnography. Compared with placebo, melatonin significantly increased Stage 2 sleep (+41 min; P = 0.037) but did not significantly change the durations of other sleep stages. The sleep onset latency remained significantly shortened on the night after discontinuation of melatonin administration (-25 min; P = 0.001), suggesting a carryover effect. CONCLUSION: n hypertensive patients treated with beta-blockers, 3 weeks of nightly melatonin supplementation significantly improved sleep quality, without apparent tolerance and without rebound sleep disturbance during withdrawal of melatonin supplementation (in fact, a positive carryover effect was demonstrated). These findings may assist in developing countermeasures against sleep disturbances associated with beta-blocker therapy. CLINICAL TRIAL INFORMATION: his study is registered with ClinicalTrials.gov, identifier: NCT00238108; trial name: Melatonin Supplements for Improving Sleep in Individuals with Hypertension; URL: http://www.clinicaltrials.gov/ct2/show/NCT00238108. PMID- 23024439 TI - Sleep disturbances and binge eating disorder symptoms during and after pregnancy. AB - STUDY OBJECTIVE: We compared sleep problems during pregnancy and sleep dissatisfaction 18 months after pregnancy in pregnant women with binge eating disorder (BED) symptoms and pregnant women without an eating disorder. DESIGN: Norwegian Mother and Child Cohort Study (MoBa). PATIENTS OR PARTICIPANTS: Data were gathered from 72,435 women. A total of 1,495 (2.1%) women reported having BED symptoms both before and during pregnancy; 921 (1.3%) reported pre-pregnancy BED symptoms that remitted during pregnancy; 1,235 (1.7%) reported incident BED symptoms during pregnancy; and 68,784 (95.0%) reported no eating disorder symptoms before or during pregnancy (referent). MEASUREMENTS AND RESULTS: Questionnaires were collected at 3 time points, with a median completion time of 17.1 weeks gestation, 30.1 weeks gestation, and 18.7 months after childbirth. We collected information on demographics, eating disorder status before and during pregnancy, sleep problems during the first 18 weeks of pregnancy, hours of sleep during the third trimester, and sleep satisfaction 18 months after childbirth. All BED symptom groups were significantly more likely to report sleep problems during the first 18 weeks of pregnancy than the referent (adjusted odds ratio [OR] = 1.26-1.42, false discovery rate [FDR] P < 0.05). In the third trimester, women with incident BED symptoms during pregnancy were more likely to report more hours of sleep than the referent (adjusted OR = 1.49, FDR P < 0.01). All BED symptom groups had higher odds of reporting more dissatisfaction with sleep 18 months after childbirth (adjusted ORs = 1.28-1.47, FDR P < 0.01). CONCLUSIONS: BED before or during pregnancy is associated with sleeping problems during pregnancy and dissatisfaction with sleep 18 months after childbirth. Health care professionals should inquire about BED during pregnancy as it may be associated with sleep disturbances, in addition to the hallmark eating concerns. PMID- 23024440 TI - Sleep and breathing in high altitude pulmonary edema susceptible subjects at 4,559 meters. AB - STUDY OBJECTIVES: Susceptible subjects ascending rapidly to high altitude develop pulmonary edema (HAPE). We evaluated whether HAPE leads to sleep and breathing disturbances that are alleviated by dexamethasone. DESIGN: Double-blind, randomized, placebo-controlled trial with open-label extension. SETTING: One night in sleep laboratory at 490 m, 2 nights in mountain hut at 4,559 m. PARTICIPANTS: 21 HAPE susceptibles. INTERVENTION: Dexamethasone 2 * 8 mg/d, either 24 h prior to ascent and at 4,559 m (dex-early), or started on day 2 at 4,559 m only (dex-late). MEASUREMENTS: Polysomnography, questionnaires on sleep and acute mountain sickness. RESULTS: Polysomnographies at 490 m were normal. In dex-late (n = 12) at 4,559 m, night 1 and 3, median oxygen saturation was 71% and 80%, apnea/hypopnea index 91.3/h and 9.6/h. In dex-early (n = 9), corresponding values were 78% and 79%, and 85.3/h and 52.3/h (P < 0.05 vs. 490 m, all instances). In dex-late, ascending from 490 m to 4,559 m (night 1), sleep efficiency decreased from 91% to 65%, slow wave sleep from 20% to 8% (P < 0.05, both instances). In dex-early, corresponding sleep efficiencies were 96% and 95%, slow wave sleep 18% and 9% (P < 0.05). From night 1 to 3, sleep efficiency remained unchanged in both groups while slow wave sleep increased to 20% in dex late (P < 0.01). Compared to dex-early, initial AMS scores in dex-late were higher but improved during stay at altitude. CONCLUSIONS: HAPE susceptibles ascending rapidly to high altitude experience pronounced nocturnal hypoxemia, and reduced sleep efficiency and deep sleep. Dexamethasone taken before ascent prevents severe hypoxemia and sleep disturbances, while dexamethasone taken 24 h after arrival at 4,559 m increases oxygenation and deep sleep. PMID- 23024442 TI - ATTACHMENT-BASED INTERVENTION FOR SUBSTANCE-USING MOTHERS: A PRELIMINARY TEST OF THE PROPOSED MECHANISMS OF CHANGE. AB - Although randomized controlled trials examining the efficacy of attachment-based interventions have been increasing in recent years, adequate measurement of treatment integrity, integrity-outcome associations, and mechanisms of change has been rare. The aim of this investigation was to conduct a rigorous test of proposed mechanisms of change in the Mothers and Toddlers Program (MTP) treatment model, a 12-session, attachment-based individual therapy for substance-using mothers of children birth to 3 years of age. The MTP aims to improve maternal reflective functioning (RF) and representation quality (RQ) to bring about second order change in maternal caregiving behavior. Following guidelines from M.K. Nock (2007), it was hypothesized that (a) therapist adherence to unique MTP treatment components would uniquely predict improvement in RF and RQ and that (b) improvement in RF and RQ would function as unique mechanisms of change (when compared with other potential mechanisms-reduction in depression and increase in abstinence from drug use) in the improvement of caregiving behavior. Findings supported each hypothesis, confirming the proposed mechanisms of the treatment model. However, improvement in maternal depression also uniquely predicted improvement in caregiving behavior. Results underscore the potential value of attachment-based parenting interventions for improving mother-child relations and the importance of providing these interventions in clinic settings where mothers have access to comprehensive care (e.g., psychiatric services). PMID- 23024443 TI - Multilevel Societies in Primates and Other Mammals: Introduction to the Special Issue. PMID- 23024441 TI - Learning to live on a Mars day: fatigue countermeasures during the Phoenix Mars Lander mission. AB - STUDY OBJECTIVES: To interact with the robotic Phoenix Mars Lander (PML) spacecraft, mission personnel were required to work on a Mars day (24.65 h) for 78 days. This alien schedule presents a challenge to Earth-bound circadian physiology and a potential risk to workplace performance and safety. We evaluated the acceptability, feasibility, and effectiveness of a fatigue management program to facilitate synchronization with the Mars day and alleviate circadian misalignment, sleep loss, and fatigue. DESIGN: Operational field study. SETTING: PML Science Operations Center. PARTICIPANTS: Scientific and technical personnel supporting PML mission. INTERVENTIONS: Sleep and fatigue education was offered to all support personnel. A subset (n = 19) were offered a short-wavelength (blue) light panel to aid alertness and mitigate/reduce circadian desynchrony. They were assessed using a daily sleep/work diary, continuous wrist actigraphy, and regular performance tests. Subjects also completed 48-h urine collections biweekly for assessment of the circadian 6-sulphatoxymelatonin rhythm. MEASUREMENTS AND RESULTS: Most participants (87%) exhibited a circadian period consistent with adaptation to a Mars day. When synchronized, main sleep duration was 5.98 +/- 0.94 h, but fell to 4.91 +/- 1.22 h when misaligned (P < 0.001). Self-reported levels of fatigue and sleepiness also significantly increased when work was scheduled at an inappropriate circadian phase (P < 0.001). Prolonged wakefulness (>= 21 h) was associated with a decline in performance and alertness (P < 0.03 and P < 0.0001, respectively). CONCLUSIONS: The ability of the participants to adapt successfully to the Mars day suggests that future missions should utilize a similar circadian rhythm and fatigue management program to reduce the risk of sleepiness-related errors that jeopardize personnel safety and health during critical missions. PMID- 23024444 TI - Evolution of Multilevel Social Systems in Nonhuman Primates and Humans. AB - Multilevel (or modular) societies are a distinct type of primate social system whose key features are single-male-multifemale, core units nested within larger social bands. They are not equivalent to fission-fusion societies, with the latter referring to routine variability in associations, either on an individual or subunit level. The purpose of this review is to characterize and operationalize multilevel societies and to outline their putative evolutionary origins. Multilevel societies are prevalent in three primate clades: papionins, Asian colobines, and hominins. For each clade, we portray the most parsimonious phylogenetic pathway leading to a modular system and then review and discuss likely socioecological conditions promoting the establishment and maintenance of these societies. The multilevel system in colobines (most notably Rhinopithecus and Nasalis) has likely evolved as single-male harem systems coalesced, whereas the multilevel system of papionins (Papio hamadryas, Theropithecus gelada) and hominins most likely arose as multimale-multifemale groups split into smaller units. We hypothesize that, although ecological conditions acted as preconditions for the origin of multilevel systems in all three clades, a potentially important catalyst was intraspecific social threat, predominantly bachelor threat in colobines and female coercion/infanticide in papionins and humans. We emphasize that female transfers within bands or genetic relationships among leader males help to maintain modular societies by facilitating interunit tolerance. We still lack a good or even basic understanding of many facets of multilevel sociality. Key remaining questions are how the genetic structure of a multilevel society matches the observed social effort of its members, to what degree cooperation of males of different units is manifest and contributes to band cohesion, and how group coordination, communication, and decision making are achieved. Affiliative and cooperative interunit relations are a hallmark of human societies, and studying the precursors of intergroup pacification in other multilevel primates may provide insights into the evolution of human uniqueness. PMID- 23024445 TI - Multilevel Societies in New World Primates? Flexibility May Characterize the Organization of Peruvian Red Uakaris (Cacajao calvus ucayalii). AB - Researchers have described multilevel societies with one-male, multifemale units (OMUs) forming within a larger group in several catarrhine species, but not in platyrhines. OMUs in multilevel societies are associated with extremely large group sizes, often with >100 individuals, and the only platyrhine genus that forms groups of this size is Cacajao. We review available evidence for multilevel organization and the formation of OMUs in groups of Cacajao, and test predictions for the frequency distribution patterns of male-male and male-female interindividual distances within groups of red-faced uakaris (Cacajao calvus ucayalii), comparing year-round data with those collected at the peak of the breeding season, when group cohesion may be more pronounced. Groups of Cacajao fission and fuse, forming subgroup sizes at frequencies consistent with an OMU organization. In Cacajao calvus ucayalii and Cacajao calvus calvus, bachelor groups are also observed, a characteristic of several catarrhine species that form OMUs. However, researchers have observed both multimale-multifemale groups and groups with a single male and multiple females in Cacajao calvus. The frequency distributions of interindividual distances for male-male and male female dyads are consistent with an OMU-based organization, but alternative interpretations of these data are possible. The distribution of interindividual distances collected during the peak breeding season differed from those collected year-round, indicating seasonal changes in the spatial organization of Cacajao calvus ucayalii. We suggest a high degree of flexibility may characterize the social organization of Cacajao calvus ucayalii, which may form OMUs under certain conditions. Further studies with identifiable individuals, thus far not possible in Cacajao, are required to confirm the social organization. PMID- 23024446 TI - Photochemical degradation study of polyvinyl acetate paints used in artworks by Py-GC/MS. AB - Photochemical degradation of commercial polyvinyl acetate (PVAc) homopolymer and PVAc paints mixed with burnt umber, cobalt blue, cadmium red dark, nickel azo yellow and titanium white commonly used for artworks were studied by pyrolysis gas chromatography/mass spectrometry (Py-GC/MS) and Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR). Py-GC/MS with single-shot technique was used for the characterization of the thermal degradation of PVAc at different temperatures, while the double-shot technique of Py-GC/MS was used to reveal the differences in the specimens before and after UV ageing, including the changes of detectable amounts of deacetylation product - acetic acid and plasticizers such as diethyl phthalate (DEP). Furthermore, the relative concentration of the pyrolysis products of the paint samples could be measured and compared in the second step of the double-shot Py-GC/MS, which are highly dependent on the presence of pigments and the ageing status of PVAc paints. PMID- 23024447 TI - The Intergenerational Effects of Relocation Policies on Indigenous Families. AB - This research utilizes life-course perspective concepts of linked lives and historical time and place to examine the multigenerational effects of relocation experiences on Indigenous families. Data were collected from a longitudinal study currently underway on four American Indian reservations in the Northern Midwest and four Canadian First Nation reserves where residents share a common Indigenous cultural heritage. This paper includes information from 507 10 - 12 year old Indigenous youth and their biological mothers who participated in the study. Results of path analysis revealed significant direct and indirect effects whereby grandparent-generation (G1) participation in government relocation programs negatively impacts not only G1 well being, but also ripples out to affect subsequent generations. PMID- 23024448 TI - Mass Distributions of Linear Chain Polymers. AB - Biochemistry has many examples of linear chain polymers, i.e., molecules formed from a sequence of units from a finite set of possibilities; examples include proteins, RNA, single-stranded DNA, and paired DNA. In the field of mass spectrometry, it is useful to consider the idea of weighted alphabets, with a word inheriting weight from its letters. We describe the distribution of the mass of these words in terms of a simple recurrence relation, the general solution to that relation, and a canonical form that explicitly describes both the exponential form of this distribution and its periodic features, thus explaining a wave pattern that has been observed in protein mass databases. Further, we show that a pure exponential term dominates the distribution and that there is exactly one such purely exponential term. Finally, we illustrate the use of this theorem by describing a formula for the integer mass distribution of peptides and we compare our theoretical results with mass distributions of human and yeast peptides. PMID- 23024449 TI - Four Methods to Estimate the Fractal Dimension from Self-Affine Signals. PMID- 23024450 TI - Synovitis induced by joint lavage with hypertonic saline solutions in healthy dairy calves. AB - The objective of this study was to evaluate the effect of a single joint lavage with 7.2% or 15% hypertonic saline solutions (HSS) on the tarsocrural joints of healthy calves. The tarsi of 10 calves were randomly lavaged with 7.2% HSS, 15% HSS, or isotonic saline. Synovial fluid samples were collected aseptically on days 1 (before joint lavage), 2, 3, 4, and 8 for complete cytological analysis. Lameness, joint swelling, and pain were recorded daily. Calves were euthanized on day 8 for gross and histological analyses of synovial membranes and articular cartilage. Synovitis was evaluated using a scoring system reflecting inflammatory changes in synovial membranes.Joints irrigated with HSS were more distended and painful compared with isotonic control joints. Swelling decreased consistently in the joints lavaged with 7.2% HSS, whereas it remained unchanged in joints lavaged with 15% HSS. Slight to moderate lameness was observed in the joints lavaged with 15% HSS. In comparison to isotonic saline joints, total protein concentration was significantly increased on day 2 and 3 for the joints lavaged with 7.2% HSS (P <= 0.01) and on days 2, 3, and 4 in the joints lavaged with 15% HSS (P <= 0.0006). Gross and histological findings revealed that synovitis was more severe in the joints lavaged with 15% HSS but variable in the joints lavaged with 7.2% HSS. No significant differences were observed for the articular cartilage.Fifteen percent HSS is not recommended for joint lavage. Although irrigation with 7.2% HSS may induce a variable synovitis, it was found appropriate for joint lavage. Its effects on septic joints remain undetermined. PMID- 23024451 TI - Comparison of isolation and expansion techniques for equine osteogenic progenitor cells from periosteal tissue. AB - Stem cell therapy and cell-based therapies using other progenitor cells are becoming the treatment of choice for many equine orthopedic lesions. Important criteria for obtaining autogenous equine progenitor cells in vitro for use in clinical cell-based therapy include the ability to isolate and expand cells repeatedly to high numbers (millions) required for therapy, in a clinically relevant time frame. Cells must also maintain their ability to differentiate into the tissue type of choice. The objective of this study was to compare isolation and expansion techniques for preparation of periosteal-derived osteogenic progenitor cells for use in commercial autogenous cell-based therapy. Cells were allowed to migrate spontaneously from periosteal tissue or were enzymatically released. Isolated cells were expanded using enzymatic detachment of cells and subsequent monolayer or dynamic culture techniques. Viable osteogenic progenitor cells from each group were counted at 2 weeks, and osteogenic potential determined. Cells isolated or expanded using the explant or bioreactor technique yielded cells at a much lower number per gram of tissue compared with that of enzyme digestion and monolayer expansion, but all cells were able to differentiate into the ostoblast phenotype. Osteogenic progenitor cells isolated by enzymatic release and expanded using monolayer culture reached the highest number of viable cells per gram of donor periosteal tissue while maintaining the ability to differentiate into bone forming cells in vitro. This technique would be an easy, consistent method of preparation of equine osteogenic cells for clinical cell based therapy for orthopedic conditions. PMID- 23024452 TI - Effects of high-volume, rapid-fluid therapy on cardiovascular function and hematological values during isoflurane-induced hypotension in healthy dogs. AB - The objective of this study was to determine the effects of the administration of a high volume of isotonic crystalloid at a rapid rate on cardiovascular function in normovolemic, isoflurane-anesthetized dogs during induced hypotension.Using a prospective study, 6 adult dogs were induced to general anesthesia and cardiovascular and hematological values were measured while the dogs were maintained at 3 hemodynamic states: first during light anesthesia with 1.3% end tidal isoflurane (ETI); then during a hypotensive state induced by deep anesthesia with 3% ETI for 45 min while administered 1 mL/kg body weight (BW) per minute of isotonic fluids; and then decreased to 1.6% ETI while receiving 1 mL/kg BW per minute of fluids for 15 min. End-tidal isoflurane (ETI) at 3.0 +/- 0.2% decreased arterial blood pressure (ABP), cardiac index (CI), and stroke volume index (SVI), and increased stroke volume variation (SVV) and central venous pressure (CVP). Fluid administration during 3% ETI decreased only SVV and systemic vascular resistance index (SVRI), while CVP increased progressively. Decreasing ETI to 1.6 +/- 0.1% returned ABP and SVI to baseline (ETI 1.3 +/- 0.1%), while CI and heart rate increased and SVV decreased. There was significant progressive clinical hemodilution of hemoglobin (Hb), packed cell volume (PCV), total protein (TP), colloid osmotic pressure (COP), arterial oxygen content (CaO(2)), and central-venous oxygen content (CcvO(2)).High-volume, rapid-rate administration of an isotonic crystalloid was ineffective in counteracting isoflurane-induced hypotension in normovolemic dogs at a deep plane of anesthesia. Cardiovascular function improved only when anesthetic depth was reduced. Excessive hemodilution and its adverse consequences should be considered when a high volume of crystalloid is administered at a rapid rate. PMID- 23024453 TI - Antimicrobial resistance in fecal generic Escherichia coli and Salmonella spp. obtained from Ontario sheep flocks and associations between antimicrobial use and resistance. AB - The purpose of this study was to examine the prevalence and patterns of antimicrobial resistance (AMR) in enteric bacteria obtained from Ontario sheep flocks, and associations between antimicrobial use (AMU) and AMR. Forty-nine sheep producers participated for a 1-year interval between 2006 and 2008. Two hundred and eighty-three pooled fecal samples were collected from the flocks during initial and final visits. Up to 3 isolates of Salmonella spp. and generic E. coli per pooled fecal sample were tested for susceptibility to 15 antimicrobials. Resistance was infrequent among Salmonella (0%, n = 7 isolates) and low among E. coli (13.1%; n = 849) isolates. A small number of isolates were resistant to antimicrobials classified as being of very high importance to human health. Tetracycline resistance was most frequently observed (12.0%). Logistic regression was used to model potential AMU (qualitative and quantitative) risk factors for tetracycline resistance in generic E. coli from final visits. Qualitative analysis indicated that the use of injectable sulfonamides [including trimethoprim-sulfonamide combinations (TMS)] and tetracycline in the feed and water were significantly associated with tetracycline resistance (OR = 2.6, P = 0.01; and OR = 4.8, P <= 0.01, respectively). Quantitative analysis also indicated that TMS exposure rate was significantly associated with tetracycline resistance, which varied depending on the exposure rate. The exposure rate of tetracycline in the feed and water was only significant after the removal of one influential flock, warranting further research examining flocks with higher tetracycline exposure rates. Although the prevalence of AMR in participating flocks was relatively low, risk factors for resistance were identified. PMID- 23024454 TI - Type 1 and type 2 immune response profiles of commercial dairy cows in 4 regions across Canada. AB - Diseases of dairy cattle have adverse implications for both the dairy industry and animal welfare. Understanding adaptive immune response profiles of cattle on a national scale will provide insight into the potential for improving health and decreasing disease. The objectives of the present study were to evaluate immune response phenotypes of Holstein cows outside the peripartum period and to determine if antibody isotype bias to putative type 1 and type 2 test antigens is maintained. The cows, housed on commercial farms in 4 key dairy regions across Canada, were immunized with test antigens to measure their ability to mount cell mediated immune responses (CMIR) and antibody-mediated immune responses (AMIR). Delayed-type hypersensitivity (DTH) was used as an indicator of CMIR and primary and secondary serum antibodies of the immunoglobulin (Ig) G1 and IgG2 isotypes were used to determine AMIR to the test antigens. Immune response phenotypes varied significantly among regions, herds, and cows. Cows in Alberta had significantly higher DTH responses and secondary responses to the type 2 test antigen than those in other regions. However, cows in Alberta had significantly lower primary antibody responses. It was found that Alberta had the lowest incidence of mastitis caused by Escherichia coli and Staphylococcus aureus compared with other regions. The IgG1/IgG2 antibody isotype ratio confirmed the nature of the test antigens. This was the first study to evaluate adaptive immune response profiles and disease incidence of dairy cows on a national scale and it therefore provides a glimpse of the current situation in Canada. PMID- 23024455 TI - Absence of bactericidal effect of focused shock waves on an in-vitro biofilm model of an implant. AB - The objective of this study was to evaluate the bactericidal effect of shock waves (SWs) on gram-negative or gram-positive monocultured biofilms grown on an orthopedic implant in vitro. Cortical bone screws were individually cultured with Escherichia coli or Staphylococcus epidermidis to produce a biofilm. In each run of 8 screws, 6 screws were treated with shock waves and then sonicated to disrupt the biofilm. One screw was sonicated only and one was not shock waved or sonicated before sampling for plate count dilutions. Post-treatment serial dilutions and plate counts were done on an aliquot from the vial containing each screw to obtain the number of colony-forming units (CFUs). Shock waves were at a constant energy of 0.15 mJ/mm(2). Pulse number and screw orientation were varied. A linear mixed-effects model was used with "treatment" as a fixed effect and "run" as a random effect. Pairwise comparisons of treatments were performed with Tukey-Cramer's adjustment for P-values. Sonicated plate counts were greater than nonsonicated counts for each run. When all sonicated screws were compared to all nonsonicated screws, the counts were significantly increased (P = 0.0091). For each paired comparison between sonicated and shock wave treatment, the only significant difference was in the S. epidermidis biofilm treated at 2000 pulses in a horizontal position, which increased the post-treatment count (P = 0.0445). No bactericidal effects were seen on monocultured biofilms on cortical bone screws treated with shock waves. PMID- 23024456 TI - Dual-label time-resolved fluoroimmunoassay for simultaneous quantification of haptoglobin and C-reactive protein in meat juice from pigs. AB - A new method was developed to simultaneously measure 2 acute-phase proteins (APPs) by time-resolved immunofluorometry. The assay, based on double-label quantification of haptoglobin (Hp) and C-reactive protein (CRP) in meat juice samples from pigs, was constructed by use of a combination of europium and samarium chelate lanthanides as labels. Meat juice samples from 154 pigs were used for analytic and clinical validation of the assay through determination of precision, accuracy, limit of detection, and quantification. The analytic performance of the assay was satisfactory, with good intra-assay and interassay precision and accuracy. The levels of Hp and CRP were increased in the meat juice samples of diseased animals compared with healthy ones. According to the results, higher sensitivity could be achieved if the cut-off values of both proteins were taken into account for clinical relevance rather than used individually. Since the dual assay saved both time and sample, it could be used as a rapid and sensitive screening test in porcine production. PMID- 23024457 TI - Effects of 2 different medetomidine infusion rates on selected neurohormonal and metabolic parameters in dogs. AB - The effects of 2 different 8-hour continuous rate infusions (CRIs) of medetomidine on epinephrine, norepinephrine, cortisol, glucose, and insulin levels were investigated in 6 healthy dogs. Each dog received both treatments and a control as follows: MED1 = 2 MUg/kg bodyweight (BW) loading dose followed by 1 MUg/kg BW per hour CRI; MED2 = 4 MUg/kg BW loading dose followed by 2 MUg/kg BW per hour CRI; and CONTROL = saline bolus followed by a saline CRI. Both infusion rates of medetomidine decreased norepinephrine levels throughout the infusion compared to CONTROL. While norepinephrine levels tended to be lower with the MED2 treatment compared to the MED1, this difference was not significant. No differences in epinephrine, cortisol, glucose, or insulin were documented among any of the treatments at any time point. At the low doses used in this study, both CRIs of medetomidine decreased norepinephrine levels over the 8-hour infusion period, while no effects were observed on epinephrine, cortisol, glucose, and insulin. PMID- 23024458 TI - Analysis of leukocyte populations in Canadian Holsteins classified as high or low immune responders for antibody- or cell-mediated immune response. AB - Selection of dairy cattle for increased milk production with little or no emphasis on health traits leads to an increased prevalence of disease. A possible genetic solution to this problem is to combine production and immune response traits in a weighted selection index. In the current study, leukocyte populations in heifers identified as having a high antibody-mediated immune response (HiAMIR) or high cell-mediated immune response (HiCMIR) phenotype were compared before and after immunization in order to identify leukocyte population profiles associated with these phenotypes. The results demonstrated that the HiCMIR-phenotype animals had a higher baseline proportion of gamma-delta T-cells in peripheral blood. Also, the observed increase in the proportion of B-cells in peripheral blood in response to immunization was greater in the HiAMIR-phenotype animals. It is expected that identifying leukocyte population profiles associated with immune response phenotypes will improve our ability to identify animals with enhanced overall immune responsiveness. PMID- 23024460 TI - The L1-norm best-fit hyperplane problem. AB - We formalize an algorithm for solving the L(1)-norm best-fit hyperplane problem derived using first principles and geometric insights about L(1) projection and L(1) regression. The procedure follows from a new proof of global optimality and relies on the solution of a small number of linear programs. The procedure is implemented for validation and testing. This analysis of the L(1)-norm best-fit hyperplane problem makes the procedure accessible to applications in areas such as location theory, computer vision, and multivariate statistics. PMID- 23024459 TI - Pathogenicity and molecular analysis of an encephalomyocarditis virus isolate from mideastern China. AB - Encephalomyocarditis virus (EMCV) can infect many host species and cause acute myocarditis and sudden death in preweaned piglets. In this study, an EMCV strain (NJ08) was isolated from newborn pigs with clinical signs on a pig farm in mideastern China. It was identified by indirect immunofluorescence assay and reverse-transcription polymerase chain reaction. Experiments showed that the isolate could cause severe clinical symptoms and pathological changes in mice but no obvious clinical and pathological changes in commercial piglets. Complete genomic sequencing showed that the NJ08 strain was 78.3% to 100% identical with other isolates in regions coding for various proteins. Phylogenetic analysis showed that the NJ08 isolate belonged to subgroup Ia. This study confirmed that an EMCV isolate from pigs could be fatal to mice and provided new epidemiologic data on EMCV in China. PMID- 23024461 TI - Silica-dispersed glucose oxidase for glucose sensing: in vitro testing in serum and blood and the effect of condensation pH. AB - The objectives of this study were to examine the feasibility of using glucose oxidase (GOx) dispersed in a silica matrix for glucose monitoring in whole blood, and then to assess whether the flexibility of silica sol-gel chemistry could be exploited to enhance glucose sensor performance and stability. Silica-dispersed GOx was deployed on platinized platinum (Pt) wire to form a Clark-type amperometric glucose sensor. Sensors were calibrated using buffered glucose standard solutions, and then tested against glucose spiked human serum and whole blood. All serum and whole blood measurements met the minimum FDA requirement of falling within the "A+B region" of a Clark Error Grid. To our knowledge this is the first report of using silica-dispersed GOx to measure glucose in whole blood. The effect of condensation pH on sensor performance was assessed by dispersing GOx in silica condensed at pH 3, 7 and 12, and then testing the sensor response against glucose calibration standards. The pH 12 silica sensors had statistically faster response time, and higher sensor sensitivity compared to pH 7, pH 3 silica and glutaraldehyde crosslinked sensors. Membranes of the pH 12 silica had statistically higher glucose diffusion coefficient than did the pH 7 and 3 sensors. GOx dispersed in pH 12 silica also had the longest half life. We hypothesize that the gel-like pH 12 silica gels provided reduced barriers to glucose diffusion, and the more aqueous microenvironment provided greater stability for the enzyme. PMID- 23024462 TI - Atherosclerosis and rheumatoid arthritis: more than a simple association. AB - In the last decades a large amount of evidence linked rheumatoid arthritis (RA) to atherosclerosis. In fact, RA patients have an increased risk of cardiovascular events that is not fully explained by other classic cardiovascular risk factors. RA and atherosclerosis may share several common pathomechanisms and inflammation undoubtedly plays a primary role. The proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-6, involved in the pathogenesis of RA, are also independently predictive of subsequent cardiovascular disease (CVD). In RA, inflammation alters HDL constituents and the concentration of LDL and HDL, thus facilitating atherosclerosis and CVD events. On the other hand, also the increase of oxidative processes, frequently observed in RA, induces atherosclerosis. Interestingly, some genetic polymorphisms associated with RA occurrence enhance atherosclerosis, however, other polymorphisms associated with RA susceptibility do not increase CVD risk. Several other mechanisms may influence atherosclerotic processes in RA. Moreover, atherosclerosis may be directly mediated also by underlying autoimmune processes, and indirectly by the occurrence of metabolic syndrome and impaired physical activity. Finally, the effects of RA therapies on cardiovascular system in general and on atherosclerosis in particular are really wide and different. However, the starting point of every RA treatment is that disease control, or better remission, is the best way we have for the reduction of CVD occurrence. PMID- 23024465 TI - Inflammation and the metabolic syndrome. PMID- 23024464 TI - Hypothermia induced by adenosine 5'-monophosphate attenuates acute lung injury induced by LPS in rats. AB - We have built a rat's model to investigate whether the hypothermia induced by adenosine 5'-monophosphate (5'-AMP) (AIH) could attenuate acute lung injury induced by LPS in rats. We detected the inflammatory cytokine levels in the plasma and bronchoalveolar lavage fluid samples, and we analyzed the pathological changes in the lungs. We have found that AIH can effectively inhibit acute inflammatory reactions and protect the lung from acute injury induced by LPS in rats. PMID- 23024463 TI - Prostaglandin E2 and the suppression of phagocyte innate immune responses in different organs. AB - The local and systemic production of prostaglandin E(2) (PGE(2)) and its actions in phagocytes lead to immunosuppressive conditions. PGE(2) is produced at high levels during inflammation, and its suppressive effects are caused by the ligation of the E prostanoid receptors EP(2) and EP(4), which results in the production of cyclic AMP. However, PGE(2) also exhibits immunostimulatory properties due to binding to EP(3), which results in decreased cAMP levels. The various guanine nucleotide-binding proteins (G proteins) that are coupled to the different EP receptors account for the pleiotropic roles of PGE(2) in different disease states. Here, we discuss the production of PGE(2) and the actions of this prostanoid in phagocytes from different tissues, the relative contribution of PGE(2) to the modulation of innate immune responses, and the novel therapeutic opportunities that can be used to control inflammatory responses. PMID- 23024466 TI - Organic acidurias: an updated review. AB - Organic acidurias are an important class of inherited metabolic disorders arising due to defect in intermediary metabolic pathways of carbohydrate, amino acids and fatty acid oxidation. This review summarizes the current knowledge about the important organic acidurias in the Indian population. Specifically, diagnosis and principles of treatment of organic acidurias are covered. The salient features of common organic acidurias as well as their prevalence in various parts of the world are reviewed in some detail. PMID- 23024467 TI - A review on salivary genomics and proteomics biomarkers in oral cancer. AB - Oral cancer has emerged as an alarming public health problem with increasing incidence and mortality rates all over the world. Therefore, the implementation of newer screening and early detection approaches are of utmost importance which could reduce the morbidity and mortality associated with this disease. Sensitive and specific biomarkers for oral cancer are likely to be most effective for screening, diagnosis, staging and follow-up for this dreaded malignancy. Unlike other deep cancers, oral cancer is located in oral cavity. Hence, the direct contact between saliva and oral cancer lesion makes the measurement of tumor markers in saliva an attractive alternative to serum and tissue testing. The DNA, RNA and protein molecules derived from the living cancer cells can be conveniently obtained from saliva. Thus, salivary biomarkers, a non-invasive alternative to serum and tissue-based biomarkers may be an effective modality for early diagnosis, prognostication and monitoring post therapy status. In the current post-genomic era, various technologies provide opportunities for high throughput approaches to genomics and proteomics; which have been used to evaluate altered expressions of gene and protein targets in saliva of oral cancer patients. The emerging field of salivary biomarkers has great potentials to prove its clinical significance to combat oral cancer. Hence, we have reviewed importance of several salivary genomics and proteomics biomarkers for oral cancer. PMID- 23024468 TI - Mechanism of Antidiabetic Action of Compound GII Purified from Fenugreek (Trigonella foenum graecum) Seeds. AB - To study the mechanism of action of water soluble compound GII purified from fenugreek (Trigonella foenum graecum) seeds which was shown earlier to have antidiabetic effect in the subdiabetic, moderately and severely diabetic rabbits. In rabbits (1-1.5 kg bw) diabetes was induced by intravenous injection of 80 mg/kg bw of alloxan. They were fed with GII at a dose of 50 mg/kg bw daily once in the morning for 15 days in the subdiabetic and moderately diabetic and 30 days in the severely diabetic rabbits. Serum total cholesterol (TC), triglycerides (TG), LDL + VLDL cholesterol [(LDL + VLDL)C], HDL cholesterol [(HDL)C], total tissue lipids, glycogen and enzymes of carbohydrate metabolism (glycolysis, gluconeogenesis, polyol pathway) hexokinase, glucokinase, pyruvate kinase, malic enzyme, glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, aldose reductase and sorbitol dehydrogenase and antioxidant enzymes glutathione peroxidase, glutathione reductase and superoxide dismutase were estimated. Liver and kidney function parameters were also estimated. Treatment with GII for 15 days in the subdiabetic and moderately diabetic rabbits and for 30 days in the severely diabetic rabbits (i) decreased the elevated lipids TC, TG, (LDL + VLDL)C and increased the decreased (HDL)C, (ii) decreased the elevated liver and heart total lipids, TC and TG, (iii) increased the decreased liver and muscle glycogen, (iv) increased the decreased hexokinase, glucokinase, pyruvate kinase, malic enzyme, glucose-6-phosphate dehydrogenase, superoxide dismutase, glutathione peroxidase, (v) decreased the increased glucose-6-phosphatase, sorbitol dehydrogenase, aldose reductase. Results thus show that treatment with GII compound purified from fenugreek seeds for 15 days in the subdiabetic and moderately diabetic and 30 days in the severely diabetic rabbits corrects the altered serum lipids, tissue lipids, glycogen, enzymes of glycolysis, gluconeogenesis, glycogen metabolism, polyol pathway and antioxidant enzymes. Histopathological abnormalities (fatty infiltration and other cellular changes) seen in the pancreas, liver, heart and kidneys were repaired after treatment with GII. In fact partially damaged pancreas was repaired. Liver and kidney function test results were normal in the GII treated animals indicating that GII treatment is safe and free from any side effects. PMID- 23024469 TI - Diagnosis of major organic acidurias in children: two years experience at a tertiary care centre. AB - Organic acid disorders are inherited metabolic disorders in which organic acids accumulate in tissues and biological fluids of affected individuals. Classical organic acidurias include methylmalonic aciduria, propionic aciduria, isovaleric aciduria and maple syrup urine disease (MSUD). They are considered the most frequent metabolic disorders among severely ill children. Patients frequently present with acute symptoms early in life. 420 cases clinically suspected to have organic aciduria, with upper age limit of 12 years for a 2-year period (January 2007-December 2008) were enrolled into this study. Metabolic acidosis and neurological symptoms were the most common signs. Screening tests and thin layer chromatography were done for detection of organic acidurias. Identification and quantitation of organic acids in urine and quantification of amino acids in blood were done by high performance liquid chromatography. Out of 420 patients, 45 patients (10.7%) were found to have organic acidurias. 15 cases of methylmalonic aciduria, 16 cases of propionic aciduria, 13 cases of MSUD, and one case of isovaleric aciduria were diagnosed. Results demonstrate the importance of testing for organic acidurias. Since organic aciduria may cause irreversible brain damage if not treated, we recommend selective screening amongst severely ill children despite implied extra costs. PMID- 23024470 TI - Production and Purification of Rabbit's Polyclonal Antibody Against Factor VIII. AB - The attempt is made to produce recombinant factor VIII but the first step in producing such product is production and purification of rabbit's polyclonal antibody against factor VIII. The second and third steps involve monoclonal antibody and recombinant factor VIII production. Factor VIII is one of the most important coagulating factor where its deficiency leads to diseases like hemophilia type A or classic. It is an inherited disease. Previously, it was obtained through fractionation of blood plasma of blood donors. After processing, factor VIII could be used to manage such patients. Due to transfer of viral disease like hepatitis and HIV through factor VIII obtained by fractionation, high cost of production, insufficiency of the donors and the process of virus removal, thus production of factor VIII through recombinant technology can be useful and helpful. The reaction between antibody and antigen is one the most specific reaction; therefore, such reaction can be employed to identify factor VIII. Thereby, rabbits were injected several times with adjuvant-linked antigen to produce antibody. The antibody was separated from the blood sample, purified and used to identify factor VIII in the research. PMID- 23024471 TI - Efficacy of a fish protein hydrolysate in malnourished children. AB - Protein hydrolysates are good nutritional supplements as their bioactive ingredients can be easily absorbed and utilized for various metabolic activities. A fish protein hydrolysate (Amizate), prepared by a unique process of hydrolysis has the advantage of high di/tri peptide content (<10 kDa) along with essential and non essential amino acids, micronutrients and vitamins. The effect of Amizate on malnourished children (6-8 years, a total of 438) of Grade I and II (Gomez's classification) with respect to immunoglobulins, CD4/CD8 ratios and hemoglobin was examined. Measurement of these parameters during the user trial study (at the beginning and the end after 4 months) indicated that the levels of the immunological parameters were not significantly altered by the Amizate treatment. The values of immunoglobulins and CD4/CD8 ratios of malnourished children (India) are in the normal range and are in accordance with the reported values of various ethnic groups. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12291-011-0145-z) contains supplementary material, which is available to authorized users. PMID- 23024472 TI - Haptoglobin polymorphism and association with complications in ghanaian type 2 diabetic patients. AB - There is scanty information on the role of genetic factors, especially those relating to haptoglobin (Hp) phenotypes in the expression of complications among diabetes mellitus patients in Ghana. In this study, we investigated whether there is any association between Hp phenotypes and diabetic complications and to determine if association of the Hp phenotypes with diabetic complications in Ghanaian diabetics differ from those in Caucasians. A total of 398 participants were randomly recruited into the study. These comprised diabetic patients numbering 290 attending a diabetes Clinic in Ghana and 108 non-diabetic controls from the same community. Analyses of the results indicate that most of the diabetics with complications were of the Hp 2-2 (35%) and Hp 2-1 (23.9%) phenotypes. Fewer diabetics were found to be of the Hp 2-1 M phenotype. The controls were mostly of Hp 1-1 and Hp 2-1 M phenotypes. The odds ratio of having complications in a diabetic with an Hp 2-2 phenotype was 18.27 times greater than that for Hp 0-0. Hp 2-2 phenotype with its poor antioxidant activity may therefore be a useful predictor for the propensity of an individual to develop diabetes complications. PMID- 23024473 TI - Serum cytokine profile in psoriasis-a case-control study in a tertiary care hospital from northern India. AB - Psoriasis is chronic autoimmune hyperproliferative skin disease with a population prevalence of 1.5-3%. The cause of psoriasis is still not fully understood. It has been hypothesized to be an immune-mediated disorder in which the excessive reproduction of keratinocytes is due to cytokines such as interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha, secreted by infiltrating CD4(+) and CD8(+) T cells and natural killer cells. The aim of our study was to determine the serum levels of TNF-alpha, IL-4, IL-6 & IL-10 in psoriasis patients and compare it with healthy controls. 30 clinically diagnosed psoriasis patients and 30 age and sex matched healthy controls were included in the study. The serum cytokine levels were measured by solid phase sandwich ELISA (DIACLONE Research, France). TNF-alpha and IL-6 levels were significantly raised in patients and the results were statistically significant (P < 0.001). IL-4 levels were higher in patients than in controls (1.91 +/- 4.7 pg/ml in cases & 0.9 +/- 0.3 pg/ml in controls) but were not statistically significant. Interestingly, IL-10 levels were found to be higher in controls than in patients but again, it was not statistically significant. Pro-inflammatory cytokines play a pivotal role in the pathogenesis of psoriasis and it is the type 1(TH1) cytokine pattern, i.e., IL-6 & TNF-alpha, which predominate in the psoriatic T cell response. Further studies on IL-10 levels in psoriasis are recommended to establish their exact role in the pathogenesis of the disease. PMID- 23024474 TI - Effect of Lecithin on d-Galactosamine Induced Hepatotoxicity Through Mitochondrial Pathway Involving Bcl-2 and Bax. AB - Twenty four Wistar strain albino rats were used for the investigations. Lecithin 50 and 100 mg/kg b wt was administered for 1 week by oral route. Liver damage was induced by intra peritoneal administration of 400 mg/kg b wt d-galactosamine on the last day. At the end of the study animals were sacrificed and liver enzyme levels, histopathology, mitochondrial integrity, expression of p53, Bax and Bcl-2 mRNA levels were studied. Increases in the liver enzyme levels by d-GalN were significantly inhibited by pretreatment with lecithin. Histopathological observation further confirmed the hepatoprotective effect of lecithin. In addition, the disruption of mitochondrial membrane, up regulation of Bax and down regulation of Bcl-2 mRNA levels in the liver of d-GalN intoxicated rats were effectively prevented by pretreatment with lecithin. The results of the present study validate our conviction that d-GalN causes hepatic damage via mitochondrial pathway involving Bax and Bcl-2. PMID- 23024475 TI - A Simple Economical Method for Assay of Atherogenic Small Dense Low-Density Lipoprotein-Cholesterol (sdLDL-C). AB - In the present study, we report a simple and economical precipitation method for the quantitative determination of small, dense LDL-cholesterol (sdLDL-C) in serum that is considered to be an emerging risk factor for cardiovascular disease. This method consisted of precipitation of lipoproteins of density <1.044 g/ml using heparin-MnCl(2) and quantification of cholesterol existed in the supernatant using reagents for routine cholesterol assay instead of the costly direct low density lipoprotein-cholesterol assay kit. The supernatant contained sdLDL and high-density lipoprotein (HDL) that was confirmed by polyacrylamide gel electrophoresis. sdLDL-C concentration can be calculated by subtracting the HDL-C value from the total cholesterol concentration of the supernatant. sdLDL-C values obtained by this modified method were similar to those obtained by direct assay of sdLDL-C and there was significant correlation between the two methods. In conclusion, this method is highly economical, do not require special equipments and is useful to evaluate atherogenic risk. PMID- 23024476 TI - Combinatorial Determination of Ischemia Modified Albumin and Protein Carbonyl in the Diagnosis of NonST-Elevation Myocardial Infarction. AB - Ischemia modified albumin (IMA) and Protein Carbonyl (PC) have known as proteins that are modified on the similar basis of oxidative stress induced protein modification and may have diagnostic potential in acute myocardial infarction. This study aims to evaluate the ability of using IMA and PC content to diagnose Non-ST elevation myocardial infarction (NSTEMI) and efficiency of combining these two markers. Serum from NSTEMI and healthy control were determined for serum IMA and PC content. The results showed that both of serum IMA level and PC content in NSTEMI was significantly higher than that of healthy controls. However, the PC content showed greater diagnostic performance than IMA. Combinatorial determination of serum IMA level with PC content level was enhanced test efficiency. In conclusion, our finding demonstrated that IMA and PC content can be used as a diagnostic marker for NSTEMI. PMID- 23024477 TI - Acid phosphatase as a marker in malaria. AB - The serum acid phosphatase (ACP) activity and Hemoglobin (Hb) levels were measured in malaria patients and nonmalarial fever patients. The results were compared with normal healthy control subjects. ACP was significantly increased (P < 0.001) in all the malaria patients. ACP was significantly higher in Plasmodium falcifarum malaria and mixed malaria when compared to Plasmodium vivax malaria. Hb levels were significantly decreased in all the malaria patients which indicates that malaria parasite uses host erythrocyte Hb as a major nutrient source. There is negative correlation(r = -0.478) between ACP and Hb in malaria patients, which is highly significant. These results suggest that the measurement of ACP could be used as a marker for malaria. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12291-011-0137-z) contains supplementary material, which is available to authorized users. PMID- 23024478 TI - Biochemical effects of lead exposure on systolic & diastolic blood pressure, heme biosynthesis and hematological parameters in automobile workers of north karnataka (India). AB - The purpose of this study was to find out the effect of lead exposure on systolic and diastolic blood pressure, heme biosynthesis related and hematological parameters of automobile workers. For this study 30 automobile workers were selected and compared with 30 age matched healthy control subjects. Significantly increased blood lead (364%, P < 0.001) and urinary lead (176%, P < 0.001) levels were observed in automobile workers (study group) as compared to controls. Systolic blood pressure (5.32%, P < 0.05) and diastolic blood pressure (5.87%, P < 0.05) were significantly increased in the automobile workers as compared to controls. The significantly decreased non-activated erythrocyte delta aminolevulinic acid dehydratase (delta-ALAD) (-18.51%, P < 0.01) and activated delta-ALAD (-13.29%, P < 0.05) levels were observed in automobile workers as compared to normal healthy control subjects. But the ratio of activated/non activated delta-ALAD was significantly increased (43.83%, P < 0.001) in automobile workers as compared to controls. Excretions of delta-aminolevulinic acid (83.78%, P < 0.001) and porphobilinogen (37%, P < 0.001) in urine were significantly increased in the study group as compared to the controls. In automobile workers heamoglobin (-11.51%, P < 0.001), hematocrit (-4.06%, P < 0.05), mean corpuscle volume (-3.34%, P < 0.05), mean corpuscle hemoglobin ( 5.66%, P < 0.01), mean corpuscle hemoglobin concentration (-7.67%, P < 0.001), red blood cell count (-14.6%, P < 0.001) were significantly decreased and total white blood cell count (11.44%, P < 0.05) increased as compared to the controls. The results of this study clearly indicate that the absorption of lead is more in automobile workers and it affects on blood pressure, heme biosynthesis and hematological parameters observed in this study group. PMID- 23024479 TI - Assessment of endothelial dysfunction in health and disease; using various parameters. AB - Conditions like hypertension, atherosclerosis and diabetes are known to be the result of endothelial dysfunction which could begin early in the life of an individual. The markers of endothelial dysfunction studied in the present work are plasma hemoglobin, serum high sensitivity C-reactive protein (hsCRP) and plasma nitrite and nitrate. We studied the onset of endothelial dysfunction with increase in age as well as in disease condition like newly detected hypertensives and of hypertensive diabetic patients. The mean plasma hemoglobin and hsCRP values were found to increase with age. hsCRP and plasma hemoglobin levels were significantly higher in patient groups as compared to aged-matched controls. On the other hand nitrate and nitrite was significantly higher in patients who suffered from both diabetes and hypertension together and nitrate values were significantly lower in patients who suffered from hypertensive alone. Plasma hemoglobin and hsCRP are associated with endothelial dysfunction and increases both with age as well as in disease condition. PMID- 23024480 TI - Vitamin B(12) Immunoassay on Roche Elecsys 2010: Effects of High Excess Concentration of Serum Vitamin B(12) in CKD Patients on Parenteral Administration. AB - Vitamin B(12) being water soluble is excreted in the urine when administered in excess. The probability of finding an abnormally excess serum concentration would be almost surreal. We report a peculiar clinical situation that may impact the vitamin B(12) immunoassay on the Roche Elecsys 2010 due to excess analyte concentration. In separate episodes (Feb and June 2010), the Biochemistry laboratory of a tertiary-care hospital, Kolkata, India, encountered two critically ill patients with background chronic kidney disease (CKD), low urine output, and on cyanocoabalamin supplementation, who had serum vitamin B(12) concentrations far exceeding expected values; even post dialysis. The B(12) assays (pmol/l) were performed using electrochemiluminiscence immunoassay on Roche Elecsys 2010, the assay validity confirmed by concomitant quality control runs. The immunoassays failed to deliver results, flagged with "signal level below limit". Biotin therapy was ruled out as a possible interferent. In the first episode, re-assay of a repeat draw yielded same outcome; outsourcing on Immulite provided concentration of >738 pmol/l. Serial dilution gave result of >29520 pmol/l on Elecsys 2010. In the second, we gained from past experience. Vitamin B(12) concentration >59040 pmol/l was conveyed to the treating nephrologist the very day. The B(12) immunoassay on the Elecsys 2010 employs sequential incubation steps for competitive binding that is compromised in the event of abnormally excess B(12) concentration in patient sera akin to the prozone effect. This knowledge may be beneficial while assaying sera of CKD patients to avoid financial loss due unnecessary repeats and delay in turnaround time. PMID- 23024481 TI - Profile of plasma amino Acid levels in rats exposed to acute hypoxic hypoxia. AB - The effect of acute hypoxic hypoxia on the profile of plasma amino acids in rats was studied and compared to that resulting from acute liver injury induced by giving carbon tetrachloride. In hypoxic rats exposed to 45% air in N(2) for 5 h, the concentrations of branched chain amino acids, including valine, leucine and isoleucine, and aromatic amino acids such as phenylalanine and tyrosine were significantly increased as compared to those in normoxic rats. The ratio of branched-chain to aromatic amino acids (Fischer's ratio) was significantly decreased. The levels of arginine and citrulline, which are related to the urea cycle, were also depressed. Furthermore, plasma proline level was reduced in hypoxic rats. The activities of plasma marker enzymes for tissue damage remained unchanged during hypoxia, indicating that tissue injury was not induced by exposure to hypoxic conditions. We suggest that the characteristic profile of plasma amino acids and the Fischer ratio are valuable tools for understanding the pathology of acute hypoxia in the absence of systemic tissue damage. PMID- 23024482 TI - A Case of Light Chain Deposition Disease (LCDD) in a Young Patient. AB - Light chain disease is a variant of multiple myeloma in which the malignant population of marrow cells produces free monoclonal light chains but no heavy chain or complete immunoglobulin. The monoclonal light chains are small enough to be freely filtered by the kidneys and become Bence-Jones protein. Light chain disease comprises about 18% of multiple myeloma patients. Here we present a case report of a 38-year-old man who initially presented with complaints of pain in back and low grade fever off and on. He was found to have collapse of D9 and D12 vertebrae along with ascites and right pleural effusion and massive proteinuria. Multiple myeloma was considered as a differential diagnosis based on the investigations but eventually the patient was lost to follow up. This case is reported here as the light chain variant of multiple myeloma leading to deposition disease is less commonly reported and presents considerable difficulties in diagnosis. PMID- 23024483 TI - Primary biliary cirrhosis presenting with gastritis, hyperlipidemia and marked weight loss. AB - We report an unusual presentation of primary biliary cirrhosis. We present the case of a 31-year-old Indian woman who presented to the hospital with non specific complaints of gastritis, reduced appetite and marked weight loss and no complaints of pruritus. Serum liver enzymes were elevated. Cytoplasmic pattern of antinuclear antibodies was found on immunofluorescence microscopy accompanied by positive anti smooth muscle antibody. Endoscopy revealed esophageal varices. Following a liver biopsy, the diagnosis of primary biliary cirrhosis was made. It is important to consider the diagnosis of hepatic cirrhosis when patient presents with gastritis, reduced appetite and marked weight loss in both the presence and absence of ascites. PMID- 23024485 TI - Ionized calcium cannot predict vitamin d deficiency. PMID- 23024484 TI - Obesity and abdominal adiposity in diabetic dyslipidemia. PMID- 23024486 TI - Editorial. PMID- 23024487 TI - Centenary celebrations article: Plasmodium knowlesi: from macaque monkeys to humans in South-east Asia and the risk of its spread in India. AB - The identification of a large focus of Plasmodium knowlesi in Malaysian Borneo and subsequent reports from several countries in South-east Asia has led its recognition as the fifth human malaria parasite. The natural preferred hosts of this species still continue to be macaque monkeys that live in broad-leaf rain forests. This review describes the distribution of macaque monkeys, the Anopheles species belonging to the Leucosphyrus Group that have been incriminated as vectors, morphological and clinical features of this parasite, and the transmission cycles that have been identified for this parasite. As the North eastern states of India share their borders with P. knowlesi malaria endemic countries and because travelers from countries in South-east Asia visit India and vice versa, risks of this parasite entering India and its spread are also discussed. PMID- 23024488 TI - Centenary celebrations article: Cysteine proteases of human malaria parasites. AB - There is an urgent need for new drugs against malaria, which takes millions of lives annually. Cysteine proteases are potential new drug targets, especially when current drugs are showing resistance. Falcipains and vivapains are well characterized cysteine proteases of P. falciparum and P. vivax, respectively. Studies with cysteine protease inhibitors and manipulating cysteine proteases specific genes have suggested their roles in hemoglobin hydrolysis. In P. falciparum, falcipain-2 and falcipain-3 are major hemoglobinases that hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. It is confirmed that disruption of the falcipain-2 gene led to a transient block in hemoglobin hydrolysis, and disruption of falcipain-3 gene was not possible, suggesting that protease is essential for erythrocytic parasites. On the other hand, vivapain-2, vivapain-3 and vivapain-4 are important cysteine proteases of P. vivax, which shared a number of features with falcipain-2 and falcipain-3. A recent study indicates that vivapains and aspartic protease of P. vivax works collaboratively to enhance the parasites' ability to hydrolyze host erythrocyte hemoglobin. Studies also indicate that falcipains and vivapains also hydrolyse the erythrocyte cytoskeleton proteins and involved in rupture of red blood cell. Structural and biochemical analysis of falcipains and vivapains showed that they have unique domains for specific functions. Overall, the complexes of cysteine proteases with small and macromolecular inhibitors provide structural insight to facilitate the drug design. Therefore, giving due importance to the cysteine proteases, this review will briefly focus the recent advancement in the field of cysteine proteases of human malaria parasites. PMID- 23024490 TI - Fecundity and life table of different morphotypes of Phlebotomus argentipes (Diptera: Psychodidae). AB - Phlebotomus argentipes Annandale and Brunetti (Diptera: Psychodidae), the established vector for Visceral Leishmaniasis (VL) have shown some morphological variations in India and its subcontinents. The variable egg laying capacity was found in different morphotypes of P. argentipes with maximum in type III followed by type I and II. The fecundity was enhanced by providing 25% glucose soaked filter paper surface in all types. However, significant increase was found in type-I (P < 0.05). The differences in fecundity indicate the biological variations among P. argentipes population. The findings will be helpful in searching out the sibling species among P. argentipes population. PMID- 23024489 TI - Therapeutic switching in leishmania chemotherapy: a distinct approach towards unsatisfied treatment needs. AB - Current drugs for the treatment of visceral leishmaniasis are inadequate. No novel compound is in the pipeline. Since economic returns on developing a new drug for neglected disease, leishmaniasis is so low that therapeutic switching represents the only realistic strategy. It refers to "alternative drug use" discoveries which differ from the original intent of the drug. Amphotericin B, paromomycin, miltefosine and many other drugs are very successful examples of "new drugs from old". This article reviews the discovery, growth and current status of these drugs and concluded that the potential of this approach (therapeutic switching) may use in the development of new antileishmanials in future also. PMID- 23024491 TI - Characterization of the recent clinical isolates of Indian Kala-azar patients by RAPD-PCR method. AB - Leishmaniasis is one of the most important vector borne diseases caused by kinetoplastid protozoa Leishmania sp. Among all forms of Leishmaniasis, Visceral leishmaniasis (VL) or Kala-azar is the severest form of the illness. VL is characterized by fever, hepatosplenomegaly, anaemia, edema, weight loss and invariably fatal if left untreated. Characterization of Leishmania sp. is extremely necessary to understand the epidemiology, taxonomy and population genetics of the parasites which ultimately helps in designing appropriate drug regimen to combat the disease. In this study, we aimed to type the clinical isolates of Leishmania species collected in the period 2006-2010 from patients (n = 9) diagnosed with Kala-azar and post Kala-azar dermal leishmaniasis (PKDL) by RAPD-PCR method using eight selected primers. Genome of the clinical isolates were amplified and electrophoresed in agarose gel. These were compared with the RAPD PCR profiles of WHO reference strains for L. donovani (DD8) and L. tropica (K27) respectively. We calculated the Jaccard's Similarity Coefficient and found one (study code T5) out of nine isolates as L. tropica while the rest were L. donovani. This pilot study supports the earlier single report claiming that both the species are responsible for Kala-azar in India and it also emphasizes the need for more systematic typing of clinical isolates of Indian Kala-azar. PMID- 23024492 TI - Diversity and seasonal densities of vector anophelines in relation to forest fringe malaria in district Sonitpur, Assam (India). AB - The prevalence and bionomics of known Indian malaria vector anophelines was studied in three forest fringe villages in Sonitpur district of Assam, India. Anopheles philippinensis/nivipes (36.8%) and An. annularis (25.6%) were the most abundant of the seven vector anopheline species recorded. Densities of vector anophelines in general were high during monsoon season and low during winter months. An. dirus s.l. was the most anthropophagic (91.6%) of all the species collected whereas, An. annularis, An. fluviatilis s.l. and An. varuna were predominantly zoophagic. The highest and the lowest slide positivity rates (SPR) was recorded during monsoon (36%) and winter (12.5%) seasons, respectively. SPR was positively correlated with vector anopheline densities (r = 0.902), which itself was found to be correlated with mean minimum temperature and relative humidity (RH). PMID- 23024493 TI - Performance of rapid DiaMed OptiMal-IT((r)) malaria test in an endemic Ghanaian setting. AB - At peripheral health facility levels, the diagnosis of malaria is difficult due to lack of infrastructure. In the study reported here, the diagnostic performance of a batch of 'DiaMed OptiMAL-IT' (Cressier, Switzerland) rapid antigen tests were examined in parallel with routine microscopy for a select population of high risk individuals: 202 pregnant women and 200 children less than 5 years old in an endemic setting in Ghana. Results of both diagnostic methods were compared to that of cross-checking microscopy, taken as gold standard, at the Navrongo Health Research Centre. Of the 402 patients, 218 (54.2%) were confirmed with Plasmodium falciparum infections by cross-checking. All 218 patients (100%) were accurately diagnosed with malaria by routine microscopy. Of these, 151 (69.3%) were positive by DiaMed OptiMAL-IT test (26 false positives, 67 false negatives). DiaMed OptiMAL-IT had the following performance indicators for detection of P. falciparum among pregnant women and children less than 5 years respectively: Sensitivity-50.5% [95% CI (40.6-60.3)], 87.7% [95% CI (78.7-92.1)]; Specificity 82.5% [95% CI (73.1-89.1)], 89.6% [95% CI (80.8-94.8)]; Predictive values for positive tests-75.7% [95% CI (63.7-84.8)], 91.6% [95% CI(85.2-95.8%)]; Predictive values for negative tests-60.6% [95% CI (51.7-68.9)], 83.8% [95% CI (74.5-90.3)]; Likelihood ratio for positive tests-2.88, 10.8; Likelihood ratio for negative tests-0.59, 0.19; Cohens Kappa values-0.33 [95% CI (0.20-0.43), 0.76 [95% CI (0.65-0.83)]. Our results suggest that DiaMed OptiMAL-IT tests should not replace microscopy in our endemic setting. PMID- 23024494 TI - SEM studies on blood cells of Plasmodium berghei infected Balb/c mice treated with artesunate and homeopathic medicine China. AB - The therapeutic efficacy of antimalarial drugs and their effect on various organs in the form of surface morphological deformations can be analyzed using scanning electron microscopy (SEM). Present study has been undertaken on Plasmodium berghei (NK-65), a lethal rodent malaria parasite, to monitor the morphological changes in blood cells induced by the treatment with combination of artesunate and homeopathic medicine . Combination therapy of artesunate (100 mg/kg) and China phi was found to be highly effective in clearing the blood stage infection of Plasmodium berghei and it also enhanced the mean survival time (28 +/- 0 days) of mice. Not much morphological changes were induced on WBCs and RBCs of mice treated with combination therapy but in treated groups the number of live PMN cells was more as observed in AO/EB staining. In normal mice the mononuclear cells were both smooth surfaced and layered surfaced, whereas, polymorphonuclear cells were having finger like projections. The combination of artesunate and China was found to be very effective and did not cause any alteration on the surface of blood cells as observed in SEM. PMID- 23024495 TI - Subcutaneous human dirofilariasis. AB - Subcutaneous human dirofilariasis is caused by the zoonotic filariae Dirofilaria repens. The frequency of reports is increasing in literature during the last few years and is considered by some authors as an emerging zoonosis. Here we report 21 cases of subcutaneous dirofilariasis, which were encountered over a period of 8 years. None of these cases were associated with peripheral eosinophilia. Since these lesions can mimic benign and malignant tumors, it is important to consider this as a differential diagnosis of subcutaneous nodules especially in an endemic area. In this report we would like to emphasize the importance of studying multiple deeper levels in suspected cases of parasitic granuloma to demonstrate the parasite. PMID- 23024496 TI - Haematological profile in Rattus norvegicus during experimental cysticercosis. AB - The present study pertains to the haematological examination of the rats experimentally infected with cysticercosis which revealed significant alterations in several parameters. Haemoglobin concentration was observed to be significantly lower in later stages of cysticercosis with respect to the control rats whereby 36% decline was observed at 60 days post infection (pi). These changes in haemoglobin were more or less parallel to those recorded for RBC counts with 18% reduction at 60 days pi. A significant rise was noticed in the erythrocyte sedimentation rates throughout the course of infection with a maximum increase (42%) at 60 days pi whereas a decline in packed cell volume as the cyst development was also evident. Leucocytosis was observed at 10, 30 and 60 days post infection with 2.6, 2.5 and 1.5 fold increase, respectively. Moreover, haematological indices were prominently altered by cysticercosis indicating macrocytic hypochromia in advance stages of the cyst development. PMID- 23024497 TI - An ophthalmologist survey-based study of the atypical presentations and current treatment practices of ocular toxoplasmosis in India. AB - The last two decades have seen a paradigm shift in the understanding of ocular toxoplasmosis. Post-natally acquired infection with its atypical presentations, has emerged as a common form of the disease. We conducted a questionnaire-based survey to investigate the characteristics of atypical presentations and current treatment practices of ocular toxoplasmosis, in India. A written questionnaire was distributed to ophthalmologists at two major uveitis meetings, held in Hyderabad, India in January, 2009. It evaluated characteristics of atypical presentations of ocular toxoplasmosis and specific treatment-related issues in India. Of 37 respondents who completed the questionnaire, 28 (75.6%) found atypical presentations in less than one-fourth of ocular toxoplasmosis patients. Atypical presentations were mostly seen as primary retinitis lesion, and in healthy immuno-competent individuals. Most ophthalmologists (n = 28, 75.6%) thought viral retinitis to be the most common differential diagnosis for atypical ocular toxoplasmosis and relied on serological tests (n = 19, 51.3%) for the diagnosis. Twenty-three (62.1%) respondents treated all patients with active lesions. A diverse range of treatment regimens were used, trimethoprim sulphamethoxazole combination being most common (n = 12, 32.4%). Corticosteroids were included in all regimens. Atypical presentations of ocular toxoplasmosis were identified by all ophthalmologists, participating in the survey, though not commonly by most. Treatment practices were diverse, reflecting the lack of consensus on this issue. PMID- 23024498 TI - New records of Haemoproteus and Plasmodium (Sporozoa: Haemosporida) of rock pigeon (Columba livia) in India. AB - The prevalence, intensity and morpho-variants of new species of haemosporida (Haemoproteus and Plasmodium) from the rock pigeon, Columba livia are described and illustrated for the first time from Uttar Pradesh state of India. Thin blood smears from 266 C. livia indicated 55.63% (Haemoproteus) and 6.76% (Plasmodium) prevalence and 1-6 pars/100 RBC's (Haemoproteus) and 1-2 pars/100 RBC's (Plasmodium) intensity of infection. The fully grown intracellular gametocytes of Haemoproteus were differentiated into microgametocyte (14.0 * 4.3 MUm) and macrogametocyte (13.9 * 4.7 MUm). Extracorpuscular gametocyte (15.0-17.8 MUm in length, 3.9-7.3 MUm in width) were occasionally visible. Nuclear displacement ratio was 0.2. Plasmodium species was characterized by rounded schizonts and elongated microgametocyte (7.8 * 7.6 MUm) and macrogametocyte (7.8 * 7.7 MUm) with irregular margins. Cells containing schizonts are often rounded and enlarged and those parasitized by gametocytes may be somewhat distorted in shape by lateral hypertrophy. Host cell nuclei are also displaced. Double gametocyte infection of Haemoproteus occasionally present but that of Plasmodium lacking. PMID- 23024499 TI - Two new species of Myxobolus (Myxozoa: Myxosporea: Bivalvulida) infecting an Indian major carp and a cat fish in wetlands of Punjab, India. AB - A survey of parasites of freshwater fishes in Kanjali and Harike wetlands of Punjab (India) revealed the presence of two new myxosporean species belonging to the genus Myxobolus Butschli (Winter (ed): Protozoa, 1882). Spores of the first species, M. saugati sp. nov. parasitizing scales of Labeo rohita (Cypriniformis: Cyprinidae) vern. rohu are characterized in having 'spores measuring 8.3 * 6.6 MUm in size, oval to spherical in valvular view having rounded anterior and posterior ends; polar capsules are two, equal, measuring 4.0 * 2.4 MUm, pyriform with distinct neck at the anterior end; an intercapsular process is absent'. Spores of the second species, Myxobolus szekeli sp. nov. parasitizing internal wall of stomach of Wallago attu (Cypriniformis: Siluridae) vern. mulle are '8.7 * 4.1 MUm in size, elongately ovoidal in valvular view having tapering, bluntly pointed anterior end and rounded posterior end; polar capsules are two, equal, measuring 4.4 * 1.5 MUm, tubular with blunt anterior and rounded posterior ends; polar capsules converge anteriorly but are placed at a distance posteriorly and occupies nearly half of the spore body cavity; an intercapsular process is absent'. PMID- 23024500 TI - A report on various digenetic metacercariae from the freshwater fishes of River Godavari, Rajahmundry. AB - Fishes serve as intermediate hosts to a number of avian digenetic trematodes. A survey on 10 different species of freshwater fishes belonging to 8 families from River Godavari from August 2005 to September 2007 revealed a total of 10 metacercariae of digenetic trematodes from five families i.e., Clinostomidae Luhe, 1901; Diplostomidae Poirier, 1886; Isoparorchiidae (Travassos, 1922); Strigeidae Railliet, 1919 and Heterophyidae (Leiper, 1909) Odhner, 1914. The metacercarial fauna dominated the adult parasitic fauna of the freshwater fishes. PMID- 23024501 TI - Prevalence and pathological lesion of Trichomonas gallinae in pigeons of Iran. AB - This research was conducted to determine the prevalence and pathological lesion of Trichomonas gallinae in pigeons in the northeast part of Iran. Wet mount preparations from the oral cavity/crop of 418 pigeons (Columba livia) captured from various locations in Khorasan province analyzed for T. gallinae by Giemsa's staining between April 2008 and June 2009. A total of 418 pigeons, 37.32% (n = 156) were infected with T. gallinae. Macroscopically, the oropharynx of infected pigeons has white, caseous lesions or stomatitis. Microscopically, there was moderate congestion with infiltration of mononuclear inflammatory cells in the lamina propria of pharynx, hyperplasia of mucous cells in epithelia of trachea with infiltration of mononuclear inflammatory cells, numerous granulomatous foci in the livers with many multinucleated giant cells, tubulointerstitial nephritis with multifocal to diffuse infiltration of mostly mononuclear inflammatory cells in the kidneys. In the present paper we have described for the first time the co existence of both genotypes of T. gallinae based on pathological lesions in this area. PMID- 23024502 TI - Anticestodal activity of Houttuynia cordata leaf extract against Hymenolepis diminuta in experimentally infected rats. AB - The leaves of Houttuynia cordata Thunb. (Saururaceae) are considered to have anthelmintic properties in the traditional medicine of Naga tribes in Northeast India and, therefore, are used by the natives to treat the intestinal worm infections. In the present study, the anticestodal activity of H. cordata leaf extract was investigated against Hymenolepis diminuta, a zoonotic cestode, in experimentally infected albino rats. For the assessment of anticestodal efficacy, the eggs per gram (EPG) of faeces counts and worm loads of animals were monitored following treatment with 200, 400 and 800 mg/kg p.o. doses of leaf extract to different groups of rats harbouring larval, immature and mature H. diminuta infections. The efficacy of the extract was found to be dose-dependent (P < 0.05). Further, the extract showed its maximum efficacy against the mature Hymenolepis worms. In this case, the 800 mg/kg dose of extract significantly reduced (P < 0.001) the EPG counts of animals by 57.09% and worm load by 75.00%, at post-treatment. In comparison, the reference drug praziquantel at 5 mg/kg showed a reduction in the EPG counts and worm load of experimental animals by 80.37 and 87.50%, respectively. These findings indicate that leaves of H. cordata possess significant anticestodal property and provide a rationale for their use in traditional medicine as an anthelmintic. PMID- 23024503 TI - Serodetection of Ehrlichia canis infection in dogs from Ludhiana district of Punjab, India. AB - Dot-ELISA (enzyme-linked immunosorbent assay) Immunocomb((r)) assay was conducted to detect the presence of antibodies against Ehrlichia canis in blood samples of 60 privately owned dogs suspected to be infected with E. canis from the Small Animal Clinics, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana, Punjab (India). Antibodies reactive to E. canis were detected in plasma in 48 samples out of 60 samples by Immunocomb((r)) Dot-ELISA. Out of these 39.58% samples were low positive (Titre 1:20-1:40), 31.25% were medium positive (Titre 1:80-1:640) and 29.16% were high positive (Titre >1,280), for the infection. When examined by microscopy, only two samples revealed typical E. canis morulae. Haemato-cellular examination revealed thrombocytopenia along with anaemia and leucopenia. Results suggest that E. canis infection circulates in dogs in India in low non-detectable numbers by microscopy and is transmitted by the brown dog tick Rhipicephalus sanguineus. PMID- 23024504 TI - Prevalence of pigeon haemosporidians and effect of infection on biochemical factors in Iran. AB - Prevalence of pigeon haemosporidians and effect of infection with Haemoproteus columbae on biochemical factors were investigated in 280 wild pigeons (Columba livia) captured from various locations in Khorasan province, in eastern of Iran, between April 2008 and June 2009. Infection prevalence with H. columbae and Leucocytozoon was detected 50 and 2%, respectively. However, no pigeon showed infection with Plasmodium. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin were the parameters which showed significant differences between parasitized and non parasitized pigeons and high ALT and AST activities and reduced serum albumin level (hypoalbominemia) were observed in pigeons infected with Haemoproteus. High level of AST, ALT, and hypoalbuminemia may be due to impairment of liver cells caused by hepatic migration of parasite for its life cycle. PMID- 23024505 TI - A survey on endoparasites and ectoparasites of stray cats from Mashhad (Iran) and association with risk factors. AB - As there appeared to be no data available on parasite infection of stray cats in the region and considering the potential threat of stray cats for animal and public health, the present study was carried out using biological samples and necropsy finding collected from cats captured in Mashhad city in the northeast of Iran. From a total 52 stray cats examined, 18 (34.6%) were male and 34 (65.4%) were female. Ten species of endoparasites including helminthes and protozoa and two species of ectoparasites were detected in the examined cats. There were two protozoa, five cestodes, three nematodes and two arthropods. Overall 46 cats (88.46%) have been infected with at least one of the parasites. The following parasites, with their respective prevalence, were found; Nematoda: Toxocara cati 28.84%, Toxocara leonina 7.69%, Physaloptera praeputialis 3.84%; Cestoda: Dipylidium caninum 23.08%, Mesocestoides lineatus 13.46%, Taenia taeniaformis 9.6%, Joyeuxiella echinorhyncoides 7.6% and Taenia hydatigena 1.92%; Protozoa: I. felis 23.7%, Haemobartonella felis 1.92%; Arthropoda: Ctenocephalides felis 1.92% and Cheyletiella blakei 1.92%. Based on our data, there was no significant difference in infection rate between male and female animals. However, the age of the cats were found to be an important risk factor associated with parasitic infection. Our results revealed that zoonotic agents, namely T. cati were present in stray cat colonies in the investigated area. In this respect, appropriate control measures should be taken and it is recommended to determine the most appropriate preventive methods. PMID- 23024506 TI - Prevalence of Myrsidea salimalii (Amblycera: Phthiraptera) on striated babblers (Turdoides earlei) (Timaliidae: Passeriformes: Aves). AB - Survey of literature showed that the population characteristics of the phthirapterans parasitizing striated babblers deserved investigation. Hence, 30 birds were examined during 2007-2009 in district Rampur U.P. The prevalence of an amblyceran louse, Myrsidea salimalii on striated babblers was 40%. The mean intensity of infestation and the sample mean abundance were 33.5 and 13.4, respectively. The variance to mean ratio of the population exceeded unity (36.24). The frequency distribution pattern of the louse was aggregated but did not conform to the negative binomial model. Females outnumbered the males in natural condition (M:F-1:1.4) while the nymphal population had an edge over adult population (A:N-1:1.3). PMID- 23024507 TI - Ribosomal DNA and morphological analysis of Dactylogyrus species from freshwater fishes of India. AB - Dactylogyrus species (Dactylogyrideae: Monogenea) are a group of monogenean gill parasites these parasites are highly host specific to freshwater fish of family Cyprinidae. A method is presented for the isolation and morphometric analysis of hamuli marginal hooks and bars form individual dactylogrids monogenoidea using phase contrast microcopy and camera lucida drawing, while simultaneously processing for rDNA analysis using the polymerase chain reaction. The identification and taxonomy of the worms in question was done by the morphometrical methods and rDNA analysis. ITS-1 regions of the rDNA gene of worms were amplified, sequenced and then the discrimination was recorded at the species level. The studied segments were compared with the published data on such segments of other Dactylogyrids species and were found to have significant relationship in the genes and spacer regions of the rDNA. PMID- 23024508 TI - Epidemiological aspects of cystic echinococcosis in slaughtered herbivores in Sari abattoir, North of Iran. AB - A study was conducted to assess the ruminants' hydatidosis in Mazandaran Province, Northern Iran. A total, 1,799 sheep, 985 goats and 362 cattle slaughtered at Sari industrial slaughter house were examined for hydatid cyst infection. The results indicated that 65.2% of sheep, 37.8% of goats and 40.1% of cattle were infected. The liver and lung infection rate in sheep were 18.8 and 4.3%, goats 17.2 and 12.6% and cattle 44.1 and 7.6%, respectively. The study showed that 766 (45.3%) out of 1,691 infected animals had moderate degree of infection. Geographical zone survey indicated that 1,381 (89.2%) out of 1,546 sheep and goats infected with hydatid cyst were non-indigenous and originated from north-eastern provinces of Iran. On the contrary, 50.3% of infected cattle originated from Mazandaran Province (indigenous). PMID- 23024509 TI - Efficacy of fenbendazole, levamisole and ivermectin against gastrointestinal nematodes in Jamunapari goats. AB - Efficacy of fenbendazole, levamisole and ivermectin was checked in comparison to untreated controls in twenty Jamunapari goats, naturally infected with gastrointestinal nematode parasites. Faecal examination at day 0 revealed an egg per gram of 930 +/- 175.1, 1350 +/- 421.1, 1060 +/- 224.9 and 800 +/- 279.7 in group A, B, C and D, respectively having five animals each. The results of larval culture examination revealed the presence of Haemonchus, Trichostrongylus, Oesophagostomum, Bunostomum and Strongyloides spp. in these animals. Faecal egg counts of the animals treated with fenbendazole (group A), levamisole (group B) and ivermectin (group C) were reduced by 23.66, 63.70 and 98.11%, respectively on day 14 post-treatment. PMID- 23024510 TI - Taxometric analysis of helminthes of marine fishes. 1. Pedunculacetabulum spinatum n.sp., from Chorinemus mandetta and Wenyonia rhincodonti n.sp., from Rhincodon typus. AB - The investigations include report of two new worms from marine fishes of Central West Coast of Goa in Arabian Sea. A trematode, Pedunculacetabulum spinatum n.sp. from Chorinemusmandetta and Wenyonia rhincodoni n.sp. from sharks, Rhincodon typus have been described and compared with closer species. The systematics of genus Pedunculacetabulum Yamaguti (Japan J Zool 6:1-112, 1934) has been discussed with detailed evidence of taxometric significance to reinstate this genus. PMID- 23024511 TI - Loa loa macrofilariasis in the eyelid: case report of the first periocular subcutaneous manifestation in India. AB - We report a case of periocular subcutaneous macrofilariasis as an initial sign of a systemic Loa loa infection. Thorough history, eye examination, surgical intervention and parasitological analysis. A periocular adult Loa loa worm was extracted from the left upper eyelid of an Indian lady living in Mumbai after presenting to our department with sensation of worm crawling under the left upper eyelid skin. Patient was admitted and was treated with diethylcarbamazine, oral steroids and albendazole with steroid cover under observation. In an era of increasing global travel, this case highlights the importance of direct questioning of previous travel as signs may be nonspecific and transitory. With clinical suspicion of Loa loa infestation, initiation of systemic investigation should not be prolonged and early treatment should be started under observation. PMID- 23024512 TI - New records of two parasitic cymothoids from Indian fishes. AB - Two parasitic cymothoidae (Crustacea, Isopoda) are reported parasitizing fishes Hemiramphidae in India. Ceratothoa angulata, found in the buccal cavity of its host, is reported for the first time from India. Mothocya plagulophora, a branchial species, already known from the Southwest coast, is now recorded from the Southeast coast of India. Host-parasite relationships are considered. PMID- 23024513 TI - First report of Ctenocephalides felis felis infestation of buffalo calves in Punjab, India. AB - Two female buffalo calves of approximately 3 months of age from Hoshiarpur and Gurdaspur districts of Punjab state, India were found to be moderately infested with the cat flea Ctenocephalides felis felis. The calves were apparently healthy with no clinical signs and skin lesions. The calves were also found to be simultaneously infested with ixodid tick (Rhipicephalus (Boophilus) microplus). Infestations of buffalo calves by C. felis felis is reported for the first time. PMID- 23024514 TI - Toxicity of DMSO, Triton X 100 and Tween 20 against Rhipicephalus (Boophilus) annulatus. AB - The problems associated with synthetic chemical pesticides include resistance, residues, pest resurgence and the adverse effects on non-target organisms. Hence, many ecofriendly newer alternatives are being evaluated among which one of the most important is the use of herbal agents. Many of the plant extracts or its fractions are dissolved in polar or non polar solvents or detergents before tested for acaricidal activity. The solvent or detergent used for dissolving the herbal extract should have little or no acaricidal effects. In the present study, laboratory tests were carried out on engorged female Rhipicephalus (Boophilus) annulatus ticks to detect the toxicity of common diluents such as dimethyl sulfoxide (DMSO), Tween 20 and Triton X 100 at 1% concentration. The result of the study revealed that least acaricidal activity was with Triton X 100 while the other two inhibited the hatching of eggs laid by treated ticks. PMID- 23024515 TI - The over roofing rates of caesarean section. PMID- 23024516 TI - Indian contribution to obstetrics & gynecology. PMID- 23024517 TI - Placental insufficiency and fetal growth restriction. AB - OBJECTIVES: Fetal growth restriction is defined as a pathologic decrease in the rate of fetal growth. The most frequent etiology for late onset fetal growth restriction is uteroplacental dysfunction which is due to inadequate supply of nutrients and oxygen to support normal aerobic growth of the fetus. However, for symmetrical IUGR, fetal chromosomal anomalies, structural anomalies and fetal infections should be carefully excluded. Consequent to the uteroplacental vascular maladaptation of endovascular trophoblastic invasion, there is increased vascular resistance and decreased blood flow to the placenta in the choriodecidual compartment. CONCLUSIONS: This under perfusion of the placenta causes villous damage; that is, total tertiary villous capillary bed is reduced leading to increased placental resistance. These changes can be diagnosed by Doppler and characteristic changes are seen in the uterine, umbilical, middle cerebral arteries and ductus venosus vessels. In severe cases, delivery of the fetus with optimum intrapartum surveillance, or caesarean section, is essential. PMID- 23024518 TI - Comparative study of nifedipine and isoxpurine as tocolytics for preterm labor. AB - OBJECTIVES: This study was done to compare isoxpurine hydrochloride and nifedipine as tocolytic drugs for preterm labor. METHODS: A prospective cohort study of 832 antenatal women with preterm labor was conducted in the Department of Obstetrics & Gynecology. Out of 400 women found eligible for tocolysis, 200 were given isoxpurine hydrochloride while the other 200 were given nifedipine randomly. The data obtained was statistically analyzed on SPSS 10.0 of Windows 2003. RESULTS: Incidence of preterm labor was 22% while the incidence of preterm delivery was 20.9%. Nifedipine was twice more effective than isoxpurine hydrochloride as a tocolytic agent as a tocolytic agent (P value 0.006) while side effects were comparable (P value 0.133). In early-diagnosed preterm labor, nifedipine had higher efficacy than isoxpurine (P value 6.45 * 10(-6)) and also higher efficacy than its own in late diagnosed preterm labor (P value 2.08 * 10( 5)). CONCLUSIONS: There is a high incidence of preterm labor in India. Nifedipine is a better tocolytic drug than isoxpurine hydrochloride, especially when started with the earliest signs of preterm labor. PMID- 23024519 TI - Premature Rupture of Membranes at Term: Immediate Induction With PGE(2) Gel Compared With Delayed Induction With Oxytocin. AB - OBJECTIVES: To compare the effectiveness, safety of immediate induction with PGE(2) gel and expectant management in terms of maternal and fetal outcome in term PROM. METHODS: 100 women were randomized to group A, immediate induction and group B expectant management. RESULTS: Spontaneous vaginal deliveries were more in group B. CS and operative vaginal deliveries were more in group A. CONCLUSION: Expectant management followed by delayed induction with oxytocin is better than immediate induction with PGE(2) gel in term PROM. A good number of women go into spontaneous labor and deliver vaginally with out increase in the Cesarean section rate and infectious morbidity for mother and fetus. PMID- 23024521 TI - Evaluation of sacral rhomboid dimensions to predict contracted pelvis: a pilot study of Indian primigravidae. AB - OBJECTIVE: This prospective study aimed to evaluate dimensions of sacral rhomboid (quadrangular area at lower back) as predictors of Contracted pelvis (CP). METHODS: In 300 uncomplicated primigravidae after 37 weeks gestation, transverse and vertical diagonal (TD and VD) of sacral rhomboid were recorded. Post- delivery, patients fell into two groups: Normal Deliveries (group 1) and CP (group 2, i.e., LSCS for contracted pelvis, instrumental delivery for Non Progress of Labor (NPOL) or birth mishaps). Analysis was done with SPSS version 10.5 and cross tabulation. RESULTS: Rhomboid dimensions were smaller in CP group (P value 0.003 and 0.012. On univariate analysis, 10th percentile cutoff of TD was the most significant risk factor with Odds ratio of 7.5 (95% CI 3.5-16.2). VD and height below 10th percentile had Odds ratio of 2.7 (95% CI 1.2-6.1) and 2.99 (95% CI 1.2-7.3), respectively. Both dimensions of sacral rhomboid below 10th percentile increased risk of CP by 13 times (OR 13, 95% CI 3.5-48.6) and detected 2 out of 3 at risk women. CONCLUSION: Smaller dimensions of sacral rhomboid are promising screening parameter for contracted pelvis which can be used in community to pick up high risk primigravidae. PMID- 23024520 TI - Echocardiographic assessment of cardiovascular hemodynamics in preeclampsia. AB - OBJECTIVE: To assess maternal cardiovascular function using echocardiography in normal and preeclamptic women in the third trimester of pregnancy. METHODS: 40 subjects, 20 with preeclampsia and 20 normotensive controls with >34 weeks gestation and singleton pregnancy were recruited. Baseline characteristics, maternal and fetal outcome were studied with systolic and diastolic parameters on echocardiography. RESULTS: The following parameters were higher in preeclamptic subjects as compared to normotensive controls-mean cardiac output (66.85 +/- 4.56 ml/min vs. 56.1 +/- 1.77 ml/min); mean LV diastolic mass (131.15 +/- 16.85 vs. 104.90 +/- 23.17 g); systolic mass (88.5 +/- 7.34 vs. 83.33 +/- 23.84 g); total vascular resistance (1396.85 +/- 150.2 vs. 1204.5 +/- 71.182 dyne, s cm(5)). Women with preeclampsia delivered smaller babies (2410 +/- 426.16 g) as compared to normotensive controls (2895 +/- 276.20 g). Student 't' test was used as a test of significance. CONCLUSION: Women with preeclampsia have significant systolic and diastolic dysfunction compared to normotensive controls. Blood pressure monitoring alone is insufficient to identify effectively, risk of cardiovascular complications in these subjects. PMID- 23024522 TI - Evaluation of post partum depression in a tertiary hospital. AB - OBJECTIVE: To evaluate the association of different factors with postpartum depression. METHODS: A prospective study conducted in the Department of Obstetrics and Gynecology, Medical College, Kolkata. Six thousand patients, 4-7 days postpartum, were interrogated using Edinburgh Postnatal Depression Scale (EPDS). Sociodemographic factors (age, parity, literacy, socioeconomic status, marital status and family structure), history of psychiatric disorder and abuse, mode of delivery and obstetric outcome were recorded. The results were analyzed statistically using Chi-square test. RESULTS: Incidence of PPD was 25%. Significant association of PPD was seen with poor socioeconomic group (P < 0.05), literacy (P < 0.001), nuclear family structure (P < 0.05), single mother (P < 0.001), past history of psychiatric illness (P < 0.001), history of abuse (P < 0.05), and poor obstetric outcome (P < 0.001). Age, parity and method of delivery showed no association. CONCLUSION: EPDS should be used routinely to screen for PPD among high risk cases. PMID- 23024523 TI - Sublingual misoprostol for cervical priming in surgical first trimester pregnancy termination. AB - OBJECTIVES: To determine the efficacy of 400 mcg sublingual misoprost as an adjunct to suction evacuation in first trimester pregnancy termination. METHOD(S): During the study period of January2006-June 2007, two hundred twenty one pregnant women wanting first trimester pregnancy termination were randomised into two groups. In the study group of one hundred twenty-one women, sublingual misoprostol was used 3 h prior to suction evacuation. In the control group of hundred women, direct suction evacuation was used. In cervical dilatation achieved by misoprostol, time required for suction evacuation, blood loss, pain perceived by patient and complications that occurred in the two groups were compared by STATA 9 stastistical software. RESULT(S): In the study group, mean cervical dilatation was up to 5.61 with Hegar dilator and in control group, it was 5.03. (P = 0.004). Average time required for suction evacuation was 7.28 min in study group and 8.73 min in control group (P < 0.0001). Blood loss was less in study group as compared to those in the controls. In study group, only 10.74% women perceived pain compared to twenty percent women in control group. CONCLUSION(S): Use of sublingual misoprost prior to first trimester pregnancy termination by suction evacuation ripens the cervix so there is less need for cervical dilatation, pain perceived by patient is less, the time required for suction evacuation is less and there is reduction in blood loss. Sublingual misoprostol is effective and safe for cervical ripening and dilatation before suction evacuation. PMID- 23024524 TI - Nifedipine versus ritodrine for suppression of preterm labor and analysis of side effects. AB - OBJECTIVES: To compare the tocolytic efficacy of Nifedipine and Ritodrine, their adverse effects and neonatal outcome. DESIGN: Prospective randomized trial. METHODS: One hundred twenty women with clinical features of preterm labor fulfilling designated inclusion and exclusion criteria were enrolled in the study. They were allocated to either nifedipine group or Ritodrine group by using simple randomization technique. Tocolytic efficacy, maternal side effects and neonatal outcomes were evaluated. Tools of statistical analysis used were Epi Info software and Chi square test. RESULTS: Tocolysis was successful i.e., prolongation of pregnancy for 48 h in 54 (90%) women in Nifedipine group as compared to 41 (68.3%) women in Ritodrine group (P value = 0.003 and chi(2) = 8.54). The prolongation of pregnancy up to 37 weeks was observed in 28 women (46.6%) in Nifedipine group compared to 16 women (26.6%) in Ritodrine group (P value = 0.033). 18 women (30%) in Nifedipine group had side effects compared to 48 women (80%) in Ritodrine group (P value < 0.001). Neonatal outcome was similar in both the groups. CONCLUSION: Oral Nifedipine is cheaper and effective alternative which has fewer and less serious side effects as compared to I.V. Ritodrine for suppression of the preterm labor. PMID- 23024525 TI - A Comparison of Vaginal vs. Oral Misoprostol for Induction of Labor-Double Blind Randomized Trial. AB - OBJECTIVE: To compare efficacy and safety of 50 MUgm misoprostol vaginal with oral for labor induction. METHODS: 110 women at term gestation, Bishop score <=4, with various indications for labor induction were randomized and double blinded. After decoding 51 women had received misoprostol orally and 52 vaginally, four hourly (maximum six doses) or till woman went into active labor. RESULTS: Statistical analysis was done with SPSS 11.0. In vaginal misoprostol group induction delivery interval was significantly less (9.79 vs. 16.47 h) and successful induction was significantly higher (90.38 vs. 74.51%) than oral group, with in 24 h of induction. As for as dose required is concerned in vaginal group 40.38% women needed two doses for delivery, in contrast 35.29% in oral group maximum six doses were required. CONCLUSION: Vaginal route of misoprostol is more effective labor inducing agent than oral. PMID- 23024526 TI - Sex cord stromal tumors-unusual presentations. AB - OBJECTIVES: The sex cord stromal tumors (SCST) account for approximately 7% of all malignant ovarian tumors. They are endocrinologically active tumors of which granulosa cell tumors are the commonest. We describe an analysis of all cases of SCST managed, in our department over the last five years and discuss two cases of unusual presentation of these tumors. METHODS: Ten cases of SCST which were managed in the Department of Gynecology and Obstetrics at University College of Medical Sciences (UCMS) & associated Guru Teg Bahadur hospital, Delhi from Jan. 01 to Dec. 05 were analyzed. RESULTS: Of the total 312 ovarian tumors which were operated in these 5 years, 73 (23.3%) were malignant, 10 cases (13.6%) out of the malignant ovarian tumors were SCST. The age of presentation varied from 4 to 70 years. Four women presented with lump abdomen as their chief complaint, 2 had postmenopausal bleeding, 2 presented with irregular bleeding per-vaginum, 1 woman had secondary amenorrhea and one young girl who was only 41/2 years old developed precocious puberty. The majority of cases (70%) were granulosa cell tumors, 10% were fibromas and 20% thecomas. Maximum patients 9 (90%) were stage I at the time of surgery and only 1 case was stage IV with tumor infiltrating into omentum and gut. CONCLUSION: SCST tumors are rare endocrine active tumors that are essentially unilateral, benign or with a low malignant potential. Though most patients present with one or a combination of symptoms ranging from abnormal vaginal bleeding, abdominal distention and abdominal pain, the signs of Paraneoplastic syndrome (PNS) may be the first indication of the presence of an ovarian malignancy and can even facilitate its diagnosis. PMID- 23024527 TI - Hysteroscopy in evaluation of abnormal uterine bleeding. AB - One-third of all gynaecological consultations are because of abnormal uterine bleeding (AUB). This proportion rises to more than 2/3rd when peri & post menopausal women are considered. In normal to 12 week size uteri, the cause of abnormal bleeding often remains obscure. OBJECTIVES (S): Clinical and hysteroscopic evaluation of the cervical canal & uterine cavity of 100 women with AUB to evaluate various causes of AUB in the study population. METHOD (S): 100 women with AUB and uterine size normal to 12 weeks pregnancy were subjected to clinical & hysteroscopic examination. The cause of bleeding was evaluated. RESULTS: Menorrhagia (30%), menometrorrhagia (16%), oligomenorrhea (16%) and postmenopausal bleeding (2%) were some of the indications for hysteroscopy. Intrauterine pathology was diagnosed in 74% of cases. Hyperplastic endometrium (30%) and mucus polypi (28%) were the most frequent findings. 13% of the cases had multiple finding. A surprising 7% had IUCD in their uteri without their knowledge, while bony spicules was found in 1 patient. Both patients with post menopausal bleeding had atrophic endometrium. CONCLUSION (S): Hysteroscopy can be easily learnt. It gives a clue to diagnosis in AUB and can reduce the burden of hysterectomy in many cases which can be treated by simple procedures. PMID- 23024528 TI - Gonadotropin levels in hypothyroid women of reproductive age group. AB - OBJECTIVE: To study serum gonadotropin (FSH, LH) levels in cases of subclinical and overt hypothyroid women in reproductive age group. MATERIAL AND METHOD: Female patients of reproductive age group attending thyroid clinic of Acharya Vinoba Bhave Hospital were included in the study. Detail menstrual history was taken, and serum FSH and LH levels were estimated by radio immuno assay method. RESULT: Eighty patients were included in the study, out of whom 46 (57.5%) had subclinical hypothyroidism and 34 (42.5%) had overt hypothyroidism. In subclinical hypothyroidism group the menstrual dysfunction which dominated in our study was oligomenorrhea (28.2%) followed by menorrhagia (17.39%). 39.13% had normal menstruation. In overt hypothyroidism group again it was oligomenorrhoea (23.5%) which was the principal menstrual abnormality followed by menorrhagia (17.64%). The percentage of females with normal menstruation was 47.05%. The levels of serum FSH and LH were significantly low in cases of both subclinical and overt hypothyroid women. They were significantly low when done between day 2 and 5 of the cycle. CONCLUSION: Hypothyroidism decreases levels of serum FSH and serum LH. Subclinical hypothyroidism is one of the major etiological factors of infertility. Autoantibodies against thyroid should be searched for in cases of female patients with infertility. PMID- 23024529 TI - Hysterectomy.....Which route? AB - OBJECTIVE: We designed this study to focus on women with mobile uteri benign no larger than 14 weeks, who would ordinarily be considered candidates for vaginal hysterectomy and compare the outcomes when abdominal routes were chosen. We also compared the intra and post operative complications, requirement for blood transfusion, length of hospital stay, between abdominal and vaginal route of hysterectomy. METHOD: In a simple randomized prospective comparative study 200 consecutive patients requiring hysterectomy for benign uterine conditions were analysed over a period of 2 years. (June 2006-May 2008). Group A (n = 100) underwent vaginal hysterectomy (non descent vaginal hysterectomy, NDVH) which was compared with group B (n = 100) who had abdominal hysterectomy. RESULTS: As far as duration of operation, duration of i.v. drip, mobilization in post operative ward, duration of hospital stay, P value was significant. Regarding blood loss P value was insignificant. CONCLUSION: The accessibility of the vaginal passage, disease confined to the uterus and the surgeons experience are the major determining factors for the choice of the route of hysterectomy. PMID- 23024530 TI - Incidence and cytomorphological peculiarities of lower genital tract infections in vault (post hysterectomy) smears versus pap smears from non-hysterectomy subjects: a retrospective study. AB - OBJECTIVE: To evaluate morphology and frequency of lower genital infections in (post hysterectomy) vault smears of women. METHODS: We analyzed vault smears from 500 women who had undergone hysterectomy, either for benign diseases (230) or for carcinoma cervix (270) and findings were compared with Pap smear diagnosis of non hysterectomy subjects. RESULTS: Majority 432/500 (87%) of the vault smears were negative for squamous abnormality in comparison to 381/500 (76%) Pap smears from non-hysterectomy subjects. It was observed that 48 (9.6%) vault smears showed lower genital tract infections, however frequency of infections was reported significantly higher 101 (20.2%) in non-hysterectomy subjects. Gardenerella vaginalis was the leading infection in vault smears 26 (5.2%) due to benign diseases and was prevalent in the fifth and sixth decades of life of women in comparison to 43 (8.2%) in Pap smears with higher prevalence in the fourth decade of life. Trichomonas vaginalis and Human Papillomavirus infection were the second commonest infections in vault smears followed by Candida albicans. CONCLUSION: Cytologically diagnosed gynecological infections were remarkably low 48 (9.6%) in vault smears as compared to 101/500 (20.2%) amongst non-hysterectomy subjects. Infections which mainly thrive at the Squamo-columnar junction i.e. HPV, Chlamydia and HSV were absent or rare in vault smears. Further incidence of infections in the vault smears where hysterectomy was done due to carcinoma cervix was as low as 10 (3.7%) as compared to 38 (16.5%) where hysterectomy was done due to benign uterine diseases. PMID- 23024531 TI - Meconium pseudocyst and ileal atresia secondary to intrauterine intussusception. PMID- 23024532 TI - Successful pregnancy outcome in a patient of chronic myeloid leukemia without therapy. PMID- 23024533 TI - HIV Associated Non-Hodgkin's Lymphoma of the Ovary. PMID- 23024534 TI - The doctor-patient relations & art of practice of medicine. PMID- 23024535 TI - Prevention and management of complications of laparoscopic splenectomy. AB - Laparoscopic splenectomy (LS) has become a commonly performed minimal-access operation. With increasing experience, surgeons are undertaking LS for multiple pathologies and tackling spleens of diverse sizes. LS remains a challenging procedure to be performed by experienced laparoscopic surgeons, well supported by a team. Bleeding remains the commonest intraoperative complication and perhaps the commonest reason for conversion to a laparotomy. Although the incidence of postoperative complications following LS is lower than that after open splenectomy, thrombosis of the splenoportal axis is being increasingly recognised. The present review describes both the common as well as uncommon intraoperative and postoperative complications of LS and outlines measures to be taken for their prevention and management. PMID- 23024536 TI - Factors predicting the axillary lymph node metastasis in breast cancer: is axillary node clearance indicated in every breast cancer patient?: factors predicting the axillary lymphnode metastases in breast cancer. AB - The study was carried out to find out predictors of axillary lymph node metastasis in breast cancer and to evaluate its significance in selecting the group of patients in whom axillary dissection could be avoided. Ninety-five breast cancer patients who underwent mastectomy and axillary dissection were included in the study. Factors like patient's age, tumor size, histopathological type, histological grade and estrogen and progesterone receptor status were correlated with the axillary metastases. Out of 95 cases axillary metastasis was found in 47 (49.47%) cases. There was no correlation between patient's age and tumor size with axillary metastasis (p > 0.05). Based on histopathological typing tumors like ductal carcinoma in situ, tubular carcinoma and mucinous carcinoma showed less tendency for axillary metastasis (p < 0.046). Association was found between histological grade and estrogen receptor and progesterone receptor positivity with presence of axillary metastasis (p < 0.001 and 0.002 respectively). The findings in this study indicate that breast cancer patients having favorable histological type, grade I tumors and estrogen and progesterone receptor negative tumor are good candidates to avoid axillary dissection. PMID- 23024537 TI - Outcome of urethral strictures managed by general surgeons in a rural setting of India. AB - In resource limited settings victims of urethral strictures often seek healthcare,when the strictures are far advanced. For a surgeon, management is indeed a challenging task, given the severity and extent of disease, lack of expertise, enough skills and equipment in the healthcare facility. This study was conducted at a rural teaching hospital in central India. All patients were assessed for the extent and severity of strictures and to rule out other causes of lower urinary obstruction. Outcome of all patients was assessed with American Urological Association Urinary Symptom Score and Urinary Flow Rate (ml/sec) before procedure, post procedure and at 6-12 months. Between 2007 and 2009, 110 patients, between 18-75 years of age were enrolled in this study which showed that a third of patients treated with urethral dilatation and optical internal urethrotomy required another intervention. It is conclude that urethral dilatation and internal optical dilatation result in short term improvement in urine flow rates and symptoms. Urethroplasty, the current gold standard of therapy for urethral strictures, results in outcomes that are clinically meaningful and more cost effective for a patient. The Americal Urological Association (AUA) symptom score and Urinarry Flow Ratemay be used to objectively assess outcome following surgical management of urethral strictures. PMID- 23024538 TI - Comparative study between omentopexy and omental plugging in treatment of giant peptic perforation. AB - Giant peptic perforation is a life threatening surgical emergency with high mortality.. This study aims to compare the success rate between omental plugging and standard omentopexy in the emergency management of giant perforations. A prospective non-randomized study of 23 patients with giant peptic perforation (>=2 cm in diameter) was carried out over a period of 18 months. The highest incidence was seen in the age group of 41-50 years. Intestinal fistula occurred in 23.08% of the omentopexy group compared to none in the omental plugging group. The mean hospital stay was slightly higher in the omentopexy group. Three patients died in the omentopexy group post operatively after 24 h compared to none in the omental plugging group and this was statistically significant (p < 0.05). Omental plugging is associated with lesser morbidity and mortality compared to omentopexy in the management of giant peptic perforations. PMID- 23024539 TI - Perioperative status and complications in opium addicts in Western rajasthan. AB - Opium addiction is rampant in Western Rajasthan and probably has the highest number of opium addicts in the world. The study envisages upon the presentation, diagnosis and various postoperative complications in surgically ill opium addicts vis-a-vis non addicts. The study is purported to benefit clinicians dealing with opium addict patients. The prospective cohort study was conducted at Mahatma Gandhi Hospital, Jodhpur between December 2004 and February 2006 and included cohorts of 71 opium addict and 50 non-addict patients admitted in various surgical wards. The study focused on presentation and the post-surgical complications encountered in these patients vis-a-vis others. The results thus obtained were evaluated statistically (mean+/-SD, SEM, two tailed t test, chi square test), p value of <0.05 was considered as significant. A thorough comparative analysis revealed that opium addict patients had a significantly higher incidence of postoperative respiratory, cardiovascular, systemic and local complications. The requirement of analgesics and duration of hospital stay were also significantly higher as compared to control group. The work concludes that opium addicts suffer a much higher degree of postoperative morbidity as compared to non-addicts. PMID- 23024540 TI - Multidetector computed tomography in large bowel lesions-a study of 100 cases. AB - This study aims to evaluate the role of multidetector computed tomography (MDCT) in detecting and classifying the large bowel lesions. A prospective study of 100 adult patients was conducted from June 2007 to October 2009. Rectal and IV contrast were used for three dimensional reconstruction. Angiography was performed in cases of suspected ischemic pathology. CT colongraphy was done to evaluate adenomas. CT findings were correlated and confirmed by either colonoscopy, biopsy, postoperative findings or follow-up CT. The pathologies were common in 50-70 yrs (44%). M: F ratio was 2:1. Malignant lesions were seen in (55%) followed by inflammatory lesions in 26%, diverticulitis and ischemic colitis in 6% each. Miscellaneous conditions like polyps, volvulus and intussusceptions were seen in 7%. Adenocarcinoma was the common malignancy (81.2%). Present study showed that adenocarcinomas were associated with marked thickening of bowel wall (>1.5 cm) in 85.4% of patients, asymmetrical wall thickening (96.4%), focal involvement (length <10 cm) in 85.5% with heterogeneous post contrast enhancement (96.3%). Inflammatory lesions showed mild thickening (69%),segmental or diffuse involvement (77%), symmetrical wall thickening (89%) and homogenous post contrast enhancement (81%). Ischemic lesions showed marked thickening (83.4%), symmetrical thickening (100%) and homogenous enhancement (100%). Diverticulitis showed marked thickening (100%), asymmetrical wall thickening (66.7%) with heterogeneous post contrast enhancement (100%), with pericolic fluid. Arterial/venous thrombosis was diagnosed in 66.66%. Three per cent had benign adenomatous polyps on CT colonographic studies. MDCT was accurate in 98.2% cases for differentiating between benign and malignant etiology and is the modality of choice. PMID- 23024541 TI - Penile strangulation by metallic rings. AB - A case of penile strangulation in a 35 year old male truck driver by profession reported here. Two metallic rings were self introduced upto the base of penis, in order to prevent spontaneous ejaculation at night. There was marked oedema of penis distal to rings, and these rings were removed with an indigenous technique, non-operatively. PMID- 23024542 TI - A safer technique of closure of peptic ulcer perforation. AB - There are several variations in the technique of closure of peptic ulcer perforation. The technique of closure of perforation by figure of 8 was found to be very effective in dealing with this common problem. PMID- 23024543 TI - Primary osteosarcoma of the breast- a case report and review of literature. AB - Primary Osteosarcoma of the breast is an aggressive and relatively rare tumour whose prognosis is very poor.It is often a diagnostic dilemma to the pathologists and the surgeons are perplexed due to its aggressive behaviour as its pathology and prognostic factors are unclear. Due to its rarity we suggest pooling of tissue samples from various centres in biobanks for future studies (including molecular biological studies) so that its behaviour can be better understood. PMID- 23024544 TI - Distal cholangiocarcinoma with coexistent biliary ascariasis. PMID- 23024545 TI - Metachronous colorectal malignancies. AB - Colorectal cancers (CRC) diagnosed 6 months after primary surgery for colorectal tumors are defined as metachronous CRC. Colonoscopy is the only reliable investigation for diagnosis. Favourable prognosis and survival is seen after conservative resection for metachronous CRCs. Clear guidelines are available for identification of CRCs after primary resection, and many questions remain unanswered regarding the development, management and prevention of CRC. We report here two cases of CRCs. PMID- 23024546 TI - Spontaneous uterine perforation due to pyometra presenting as acute abdomen. AB - Spontaneous perforation of uterus is rare, its incidence being about 0.01%-0.5%. We report a rare case of diffuse peritonitis and pneumoperitoneum caused by spontaneously perforated pyometra. A 50-year postmenopausal lady with abdominal pain was admitted to our hospital. Laparotomy was performed because of the suspicion of gastrointestinal perforation with generalized peritonitis. At laparotomy about 1,500 ml of pus present in peritoneal cavity and whole of alimentary tract and gallbladder were normal.A total abdominal hysterectomy with bilateral salpingooopherectomy was performed. Histopathological study revealed chronic suppurative endometritis with myometritis of the uterus with no evidence of malignancy. Although spontaneously perforated pyometra is rare, a perforated pyometra should therefore be considered when elderly female presents with acute abdomen. PMID- 23024548 TI - Ileal ganglioneuromatosis with adenocarcinoma in a patient with multiple neurofibromatosis. AB - Von Recklinghausen's disease or type 1 neurofibromatosis is an autosomal dominant disease characterized by mucocutaneous neurofibromas, cafe-au-lait spots and involves many organs including gastrointestinal tract. Gastrointestinal involvement in neurofibromatosis is uncommon and is seen 25% patients and nearly 5% of them are only symptomatic (Shekitka and Sobin, Am J Surg Pathol 18:250-257, 1994; Tomita et al., Int J Colorectal Dis 21: 89-91, 2006). PMID- 23024547 TI - Fetus-in-fetu or well-differentiated teratoma- a continued controversy. AB - Fetus in fetu is an uncommon anomaly in pediatric age group. There have been controversies regarding its differentiation from well differentiated teratoma. While presence of axial skeleton has been considered mandatory for diagnosis, there are many reports of fetus in fetu without any vertebral column. It has been suggested that the two entities form a spectrum of lesions depending upon the timing of embryological insult. The present case is another example of a lesion that fits in this spectrum of interesting lesion. PMID- 23024549 TI - Multiple metachronous malignancies, one patient with three primary malignancies. AB - Development of a primary cancer after treatment of the first with radiotherapy or chemotherapy is well documented, but it is common with hematological malignancies. Variety of reasons are suggested by various researchers, but a conclusive evidence is not yet available. Excepting a few correlations like the tamoxifen therapy and endometrial cancer, angiosarcoma of the breast following radiotherapy, occurrence of other metachronous malignancies seem to be dependent on genetic and environmental factors. A patient with three primary malignancies is presented here. PMID- 23024550 TI - Pneumomediastinum and subcutaneous emphysema unusual complications of blunt facial trauma. AB - We described a rare case of pneumomediastinum following an isolated facial trauma. Traumatic pneumomediastinum is usually secondary to a blunt or penetrating neck, chest or abdominal trauma. PMID- 23024551 TI - Asymptomatic Presentation of Bochdalek's Hernia in an Adult. AB - Bochdalek hernia, a type of congenital diaphragmatic hernia usually presents in the immediate neonatal period with respiratory distress. Presentation in an adult is rare and asymptomatic. We report one such case of Bochdalek hernia, in a 35 year old male, who presented only with mild chest discomfort on left side. Radiological investigations were suggestive of a huge left side Bochdalek hernia with stomach and intestines in the left thorax. This case emphasizes the rarity of presentation of Bochdalek hernia in adults and the importance of high clinical suspicion and the role of imaging and surgery in the accurate diagnosis of this abnormality. PMID- 23024552 TI - Cutaneous angiosarcoma in chronic lymphedema: secondary to filariasis. AB - Cutaneous angiosarcoma is a very aggressive tumor with poor prognosis. We report a case of cutaneous angiosarcoma in a patient with elephantiasis. To the best of our knowledge, there are very few cases reported in the literature. As there is no ideal treatment for cutaneous angiosarcoma, early detection can lower the morbidity and mortality from this malignancy. PMID- 23024553 TI - Letter to the editor. PMID- 23024554 TI - Preoperative diagnosis of non-palpable breast lesions. PMID- 23024555 TI - R.g.kar medical college, kolkata-a premiere institute of India: (named after dr. Radha gobinda kar; born on 23.08.1852, died on 19.12.1918). PMID- 23024556 TI - Headache supplement. PMID- 23024557 TI - Prevalence of primary headache disorders in school-going children in Kashmir Valley (North-west India). AB - OBJECTIVE: A prospective prevalence study of primary headache disorders in school going children (8-18 years) in Srinagar district of Kashmir valley was conducted. MATERIALS AND METHODS: The study population comprised of a randomized sample of 5000 school going children in the age group of 8-18 years from various educational institutions of Srinagar city. A self-administered pretested questionnaire was filled by the participants and the diagnosis established by following the International Headache Society criteria (IHS) 2004. RESULTS: The overall prevalence of primary headache disorders was found to be 664/1000. The prevalence of tension-type headache and migraine was found to be 50.99% and 26.98%, respectively. The prevalence revealed an upward trend with increasing age with preponderance for female sex. PMID- 23024558 TI - Primary headaches in restless legs syndrome patients. AB - Earlier studies conducted among migraineurs have shown an association between migraine and restless legs syndrome (RLS). We chose RLS patients and looked for migraine to exclude sample bias. MATERIALS AND METHODS: 99 consecutive subjects of idiopathic RLS were recruited from the sleep clinic during four months period. Physician diagnosis of headache and depressive disorder was made with the help of ICHD-2 and DSM-IV-TR criteria, respectively. Sleep history was gathered. Severity of RLS and insomnia was measured using IRLS (Hindi version) and insomnia severity index Hindi version, respectively. Chi-square test, one way ANOVA and t-test were applied to find out the significance. RESULTS: Primary headache was seen in 51.5% cases of RLS. Migraine was reported by 44.4% subjects and other types of 'primary headaches' were reported by 7.1% subjects. Subjects were divided into- RLS; RLS with migraine and RLS with other headache. Females outnumbered in migraine subgroup (chi(2)=16.46, P<0.001). Prevalence of depression (chi(2)=3.12, P=0.21) and family history of RLS (chi(2)=2.65, P=0.26) were not different among groups. Severity of RLS (P=0.22) or insomnia (P=0.43) were also similar. CONCLUSION: Migraine is frequently found in RLS patients in clinic based samples. Females with RLS are prone to develop migraine. Depression and severity of RLS or insomnia do not affect development of headache. PMID- 23024560 TI - Ophthalmoplegic migraine: A critical analysis and a new proposal. AB - The nosology, classification and pathophysiology of ophthalmoplegic migraine (OM) remains complex and debatable. A recently proposed classification of OM leaves several caveats. A critical analysis of all reported cases of OM (1993-2010) has been made incorporating the authors' own experience to arrive at a simple, unambiguous and easy to use diagnostic criteria and classification of OM. Between 2005 and 2010, 18 adult cases of OM had been seen whose clinical details are summarized. Most had sixth nerve palsies associated with migraine-like headaches lasting more than 4 days. Other possibilities were carefully excluded. All subjects responded to corticosteroids favorably. We prefer using the term ophthalmoplegia with migraine-like headache (OMLH) rather than OM. We classify OMLH as a migraine subtype (1.7) and into two groups-childhood-onset type (where third nerve palsies and nerve enhancement are common) and adult-onset type (where sixth nerve palsies are more common and nerve enhancement unusual). This clinico radiological classification does not in any way hint at any difference in pathophysiology between the two groups. PMID- 23024559 TI - Pathophysiology of migraine. AB - Migraine is a common disabling brain disorder whose pathophysiology is now being better understood. The study of anatomy and physiology of pain producing structures in the cranium and the central nervous system modulation of the input have led to the conclusion that migraine involves alterations in the sub-cortical aminergic sensory modulatory systems that influence the brain widely. PMID- 23024561 TI - Neuroimaging and other investigations in patients presenting with headache. AB - Headache is very common. In the United Kingdom, it accounts for 4.4% of primary care consultations, 30% of referrals to neurology services and 0.5-0.8% of alert patients presenting to emergency departments. Primary headache disorders account for the majority of patients and most patients do not require investigation. Warning features (red flags) in the history and on examination help target those who need investigation and what investigations are required. This article summarizes the typical presentations of the common secondary headaches and what neuroimaging and other investigations are appropriate for each headache type. PMID- 23024562 TI - The acute and preventative treatment of episodic migraine. AB - Episodic migraine is a common debilitating condition with significant worldwide impact. An effective management plan must include acute treatment to relieve the pain and potential disability associated with the attacks and may also include preventative treatments with an aim of decreasing attack frequency and severity in the longer term. Acute treatments must be limited to a maximum of 2-3 days a week to prevent medication overuse headache and focus on simple analgesia, non steroidal anti-inflammatory drugs and triptans. Preventative treatments are numerous and should be considered when migraine attacks are frequent and or disabling, acute medication is failing, in special circumstances such as hemiplegic migraines or if the patient requests them. All preventative medications must be given at therapeutic doses for at least 6-8 weeks before an adequate trial can be judged ineffective. The most important factor in choosing drugs is the patient and the clinical features of their attack and treatment should be tailored to these. Relative co-morbidities will influence drug choice, as will the side effect profile and the efficacy of the drug. First line preventative drugs include beta-blockers, amitriptyline and anti-epileptic drugs such as topiramate and valproate. Drugs with lower efficacy or poorer side effect profiles include selective serotonin reuptake inhibitors (SSRIs), calcium channel antagonists, gabapentin and herbal medicines. PMID- 23024563 TI - Chronic daily headaches. AB - Chronic Daily Headache is a descriptive term that includes disorders with headaches on more days than not and affects 4% of the general population. The condition has a debilitating effect on individuals and society through direct cost to healthcare and indirectly to the economy in general. To successfully manage chronic daily headache syndromes it is important to exclude secondary causes with comprehensive history and relevant investigations; identify risk factors that predict its development and recognise its sub-types to appropriately manage the condition. Chronic migraine, chronic tension-type headache, new daily persistent headache and medication overuse headache accounts for the vast majority of chronic daily headaches. The scope of this article is to review the primary headache disorders. Secondary headaches are not discussed except medication overuse headache that often accompanies primary headache disorders. The article critically reviews the literature on the current understanding of daily headache disorders focusing in particular on recent developments in the treatment of frequent headaches. PMID- 23024564 TI - Trigeminal autonomic cephalalgias: A review of recent diagnostic, therapeutic and pathophysiological developments. AB - The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders that are characterized by strictly unilateral trigeminal distribution pain occurring in association with ipsilateral cranial autonomic symptoms. This group includes cluster headache, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. These disorders are very painful, often considered to be some of the most painful conditions known to mankind, and consequently are highly disabling. They are distinguished by the frequency of attacks of pain, the length of the attacks and very characteristic responses to medical therapy, such that the diagnosis can usually be made clinically, which is important because it dictates therapy. The management of TACs can be very rewarding for physicians and highly beneficial to patients. PMID- 23024565 TI - New daily persistent headache. AB - New daily persistent headache (NDPH) is a chronic headache developing in a person who does not have a past history of headaches. The headache begins acutely and reaches its peak within 3 days. It is important to exclude secondary causes, particularly headaches due to alterations in cerebrospinal fluid (CSF) pressure and volume. A significant proportion of NDPH sufferers may have intractable headaches that are refractory to treatment. The condition is best viewed as a syndrome rather than a diagnosis. The headache can mimic chronic migraine and chronic tension-type headache, and it is also important to exclude secondary causes, particularly headaches due to alterations in CSF pressure and volume. A large proportion of NDPH sufferers have migrainous features to their headache and should be managed with treatments used for treating migraine. A small group of NDPH sufferers may have intractable headaches that are refractory to treatment. PMID- 23024566 TI - Other primary headaches. AB - The 'Other Primary Headaches' include eight recognised benign headache disorders. Primary stabbing headache is a generally benign disorder which often co-exists with other primary headache disorders such as migraine and cluster headache. Primary cough headache is headache precipitated by valsalva; secondary cough has been reported particularly in association with posterior fossa pathology. Primary exertional headache can occur with sudden or gradual onset during, or immediately after, exercise. Similarly headache associated with sexual activity can occur with gradual evolution or sudden onset. Secondary headache is more likely with both exertional and sexual headache of sudden onset. Sudden onset headache, with maximum intensity reached within a minute, is termed thunderclap headache. A benign form of thunderclap headache exists. However, isolated primary and secondary thunderclap headache cannot be clinically differentiated. Therefore all headache of thunderclap onset should be investigated. The primary forms of the aforementioned paroxysmal headaches appear to be Indomethacin sensitive disorders. Hypnic headache is a rare disorder which is termed 'alarm clock headache', exclusively waking patients from sleep. The disorder can be Indomethacin responsive, but can also respond to Lithium and caffeine. New daily persistent headache is a rare and often intractable headache which starts one day and persists daily thereafter for at least 3 months. The clinical syndrome more often has migrainous features or is otherwise has a chronic tension-type headache phenotype. Management is that of the clinical syndrome. Hemicrania continua straddles the disorders of migraine and the trigeminal autonomic cephalalgias and is not dealt with in this review. PMID- 23024567 TI - The art of history-taking in a headache patient. AB - Headache is a common complaint that makes up for approximately 25% of any neurologists outpatient practice. Yet, it is often underdiagnosed and undertreated. Ninety percent of headaches seen in practice are due to a primary headache disorder where there are no confirmatory tests, and neuroimaging studies, if done, are normal. In this situation, a good headache history allows the physician to recognize a pattern that in turn leads to the correct diagnosis. A comprehensive history needs time, interest, focus and establishment of rapport with the patient. When to ask what question to elicit which information, is an art that is acquired by practice and improves with experience. This review discusses the art of history-taking in headache patients across different settings. The nuances of headache history-taking are discussed in detail, particularly the questions related to the time, severity, location and frequency of the headache syndrome in general and the episode in particular. An emphasis is made on the recognition of red flags that help in the identification of secondary headaches. PMID- 23024568 TI - Migraine, cerebrovascular disease and the metabolic syndrome. AB - Evidence is emerging that migraine is not solely a headache disorder. Observations that ischemic stroke could occur in the setting of a migraine attack, and that migraine headaches could be precipitated by cerebral ischemia, initially highlighted a possibly association between migraine and cerebrovascular disease. More recently, large population-based studies that have demonstrated that migraineurs are at increased risk of stroke outside the setting of a migraine attack have prompted the concept that migraine and cerebrovascular disease are comorbid conditions. Explanations for this association are numerous and widely debated, particularly as the comorbid association does not appear to be confined to the cerebral circulation as cardiovascular and peripheral vascular disease also appear to be comorbid with migraine. A growing body of evidence has also suggested that migraineurs are more likely to be obese, hypertensive, hyperlipidemic and have impaired insulin sensitivity, all features of the metabolic syndrome. The comorbid association between migraine and cerebrovascular disease may consequently be explained by migraineurs having the metabolic syndrome and consequently being at increased risk of cerebrovascular disease. This review will summarise the salient evidence suggesting a comorbid association between migraine, cerebrovascular disease and the metabolic syndrome. PMID- 23024569 TI - Behavioural management of migraine. AB - It is important to recognise that migraine is a 'biological' and not a 'psychological' entity. However, psychological factors can be involved in migraine in 4 different ways:- 1) Migraines can be triggered by psychological stressors; 2) Severe migraine can itself be a cause of significant psychological stress which can, in turn, exacerbate the problem; 3) Even if psychological stress is not significantly involved in the genesis of the headache, pain management techniques can help people cope with their pain more effectively; 4) Longitudinal data demonstrate a complex bidirectional association between mood disorders and migraine. Treatment of a co-existing mood disorder, for example with cognitive behavioural techniques, may therefore reduce the impact of migraine. It would thus appear logical to view medical and psychological approaches as potentially synergistic rather than mutually exclusive. Functional imaging indicates that cognition, emotions, and pain experiences change the way the brain processes pain inputs. This may provide a physiological rationale for psychological interventions in pain management. As most studies of psychological management of migraine have been relatively small and the approach often varies between clinicians, the magnitude of benefit, optimum method of delivery, and the length of intervention are uncertain. PMID- 23024570 TI - Tension type headache. AB - Tension type headaches are common in clinical practice. Earlier known by various names, the diagnosis has had psychological connotations. Recent evidence has helped clarify the neurobiological basis and the disorder is increasingly considered more in the preview of neurologists. The classification, clinical features, differential diagnosis and treatment of tension type headache are discussed in this paper. PMID- 23024571 TI - Impact of physician empathy on migraine disability and migraineur compliance. AB - AIMS: We aim to establish the role that perceived physician empathy plays in determining migraineurs' outcomes and compliance with migraine management plans. We checked for associations between perceived physician empathy and clinical outcomes as well as compliance with management plans. MATERIALS AND METHODS: 63 migraineurs were enrolled between July and September 2011. Questionnaire administered at the time of inclusion into the study included self-assessment of disability due to migraine (Migraine Disability Assessment Test) followed by migraineurs' assessment of physician empathy (Consultation and Relational Empathy Measure). Three months later, a telephonic questionnaire ascertained changes in disability due to migraine and compliance with migraine treatment. STATISTICAL ANALYSIS: Data was entered in Microsoft Excel 2010 and analyzed using SPSS 17. Pearson's correlation was employed to analyze the significance of relationship between variables. P-value of less than 0.05 has been considered statistically significant. RESULTS: Statistically significant positive Pearson's correlations are seen between perceived empathy and decrease in migraine disability and symptoms over three months (P < 0.05). Significant positive relationships are also seen between perceived empathy and compliance with diet/meal timings, exercising, de-stressing/sleep pattern modification and medications (P < 0.05). Self-reported compliance is significantly correlated with improved patient outcomes (P < 0.05). CONCLUSIONS: Substantial positive associations are found between perceived physician empathy and migraineurs' outcomes and compliance with management plans. This emphasizes the importance of empathy in migraineur physician communication. PMID- 23024572 TI - Headache symptoms and indoor environmental parameters: Results from the EPA BASE study. AB - OBJECTIVE: The objective of this investigation was to determine the prevalence of migraine and headache symptoms in a national sample of US office employees. Also, we explored the association of headache symptoms with indoor environmental parameters of the work place. BACKGROUND: Sick building syndrome (SBS), which includes headache, is a common global phenomenon, but the underlying environmental cause is uncertain. MATERIALS AND METHODS: We used data from the 1994-1998 US Environmental Protection Agency's (EPA) Building Assessment and Survey Evaluation, a cross-sectional study of workers employed in 100 public and private office buildings across 25 states. The study used a self-administered questionnaire to assess headache frequency and prevalence of self-reported physician-diagnosed (SRPD) migraine. Indoor environmental parameters (IEP) were collected per EPA protocol from each building over a 1-week period and included carbon dioxide, carbon monoxide, temperature, relative humidity, particulate matter, volatile organic compound, illuminance, and sound level. The standards of American Society of Heating, Refrigerating and Air Conditioning Engineers were used to categorize IEP as either within- or out-of-comfort range for human dwelling. These limits delineate whether a parameter value is safe for human dwelling. Out-of-comfort range IEPs are associated with SBS and other human diseases. SRPD migraine and headache frequency were the primary outcome measures of the study. Multivariate logistic regression analyses were employed for the purpose of assessing the association between the outcome variable and IEPs. RESULTS: Of the 4326 participants, 66% were females and 60% were between 30 and 49 years. Headache frequency during the last 4 weeks was as follows: None in 31%, 1-3 days in 38%, 1-3 days per week in 18%, and every or almost every workday in 8%. Females had higher SRPD migraine prevalence compared to males (27% vs. 11%, P<0.001) and were more likely to report any headache in the last month compared to males (75% vs. 53%, P<0.001). Odds of SRPD migraine were higher (P<0.05) for those exposed to IEP out-of-comfort range, and odds of exposure to out-of-comfort range IEPs were higher in groups who reported higher headache frequencies. CONCLUSIONS: Migraine diagnosis and elevated headache frequency are associated with an uncomfortable indoor environment. Periodic assessments and adjustments of IEP may have a beneficial impact on employees who are vulnerable to SBS. PMID- 23024573 TI - A Comparison of Distributional Considerations with Statistical Analysis of Resting State fMRI at 3T and 7T. AB - Ultra-high field 7T magnetic resonance imaging (MRI) offers potentially unprecedented spatial resolution of functional activity within the human brain through increased signal and contrast to noise ratios over traditional 1.5T and 3T MRI scanners. However, the effects physiological and imaging artifacts are also greatly increased. Traditional statistical parametric mapping theories based on distributional properties representative of data acquired at lower fields may be inadequate for new 7T data. Herein, we investigate the model fitting residuals based on two 7T and one 3T protocols. We find that model residuals are substantively more non-Gaussian at 7T relative to 3T. Imaging slices that passed through regions with peak inhomogeneity problems (e.g., mid-brain acquisitions for the 7T hippocampus) exhibited visually higher degrees of distortion along with spatially correlated and extreme values of kurtosis (a measure of non Gaussianity). The impacts of artifacts have been previously addressed for 3T data by estimating the covariance matrix of the regression errors. We further extend the robust estimation approach for autoregressive models and evaluate the qualitative impacts of this technique relative to traditional inference. Clear differences in statistical significance are shown between inferences based on classical versus robust assumptions, which suggest that inferences based on Gaussian assumptions are subject to practical (as well as theoretical) concerns regarding their power and validity. Hence, modern statistical approaches, such as the robust autoregressive model posed herein, are appropriate and suitable for inference with ultra-high field functional magnetic resonance imaging. PMID- 23024574 TI - Antimicrobial and antiprotozoal activities of secondary metabolites from the fungus Eurotium repens. AB - In this study, we examined in vitro antibacterial, antifungal, antimalarial, and antileishmanial activities of secondary metabolites (1-8) isolated from the fungus Eurotium repens. All compounds showed mild to moderate antibacterial or antifungal or both activities except 7. The activity of compound 6 was the best of the group tested. The in vitro antimalarial evaluation of these compounds revealed that compounds 1-3, 5, and 6 showed antimalarial activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum with IC(50) values in the range of 1.1-3.0 MUg/ml without showing any cytotoxicity to the mammalian cells. Compound 5 displayed the highest antimalarial activity. Antileishmanial activity against Leishmania donovani promastigotes was observed for compounds 1-6 with IC(50) values ranging from 6.2 to 23 MUg/ml. Antileishmanial activity of compounds 5 and 6 (IC(50) values of 7.5 and 6.2 MUg/ml, respectively) was more potent than 1-4 (IC(50) values ranging from 19-23 MUg/ml). Compounds 7 and 8 did not show any antiprotozoal effect. Preliminary structure and activity relationship studies indicated that antibacterial, antifungal, antimalarial, and antileishmanial activities associated with phenol derivates (1-6) seem to be dependent on the number of double bonds in the side chain, which would be important for lead optimization in the future. PMID- 23024575 TI - Susceptibility of Gardnerella vaginalis biofilms to natural antimicrobials subtilosin, epsilon-poly-L-lysine, and lauramide arginine ethyl ester. AB - Bacterial vaginosis is a common vaginal infection associated with numerous gynecological and obstetric complications. This condition is characterized by the presence of thick adherent vaginal biofilms, composed mainly of Gardnerella vaginalis. This organism is thought to be the primary aetiological cause of the infection paving the way for various opportunists to colonize the niche. Previously, we reported that the natural antimicrobials subtilosin, epsilon-poly L-lysine, and lauramide arginine ethyl ester selectively inhibit the growth of this pathogen. In this study, we used plate counts to evaluate the efficacy of these antimicrobials against established biofilms of G. vaginalis. Additionally, we validated and compared two rapid methods (ATP viability and resazurin assays) for the assessment of cell viability in the antimicrobial-treated G. vaginalis biofilms. Out of the tested antimicrobials, lauramide arginine ethyl ester had the strongest bactericidal effect, followed by subtilosin, with clindamycin and polylysine showing the weakest effect. In comparison to plate counts, ATP viability and resazurin assays considerably underestimated the bactericidal effect of some antimicrobials. Our results indicate that these assays should be validated for every new application. PMID- 23024576 TI - Agreement in Mother and Father Acceptance-Rejection, Warmth, and Hostility/Rejection/Neglect of Children across Nine Countries. AB - We assessed whether mothers' and fathers' self-reports of acceptance-rejection, warmth, and hostility/rejection/neglect (HRN) of their pre-adolescent children differ cross-nationally and relative to the gender of the parent and child in 10 communities in 9 countries, including China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand, and the United States (N = 998 families). Mothers and fathers in all countries reported a high degree of acceptance and warmth, and a low degree of HRN, but countries also varied. Mothers reported greater acceptance of children than fathers in China, Italy, Sweden, and the United States, and these effects were accounted for by greater self-reported warmth in mothers than fathers in China, Italy, the Philippines, Sweden, and Thailand and less HRN in mothers than fathers in Sweden. Fathers reported greater warmth than mothers in Kenya. Mother and father acceptance-rejection were moderately correlated. Relative levels of mother and father acceptance and rejection appear to be country specific. PMID- 23024577 TI - Current clinical applications of magnifying endoscopy with narrow band imaging in the stomach. AB - Narrow band imaging (NBI), in conjunction with magnifying endoscopy (ME), has arisen more and more attention in the area of advanced endoscopy. By enhancing the mucosal microvascular architecture and surface pattern, it is feasible to use ME-NBI to identify subtle changes associated with gastric inflammation, atrophy, intestinal metaplasia, and early gastric cancer. The new technique thus plays a valuable role in therapeutic decision-making, endoscopic treatment process, postoperative evaluation, and follow-up examination. To date, many criteria or evaluation method of ME-NBI has been proposed. This paper aims to summarize the various diagnosing classifications and the current clinical applications of ME NBI in the stomach. PMID- 23024578 TI - A low-dimensional deformation model for cancer cells in flow. AB - A low-dimensional parametric deformation model of a cancer cell under shear flow is developed. The model is built around an experiment in which MDA-MB-231 adherent cells are subjected to flow with increasing shear. The cell surface deformation is imaged using differential interference contrast microscopy imaging techniques until the cell releases into the flow. We post-process the time sequence of images using an active shape model from which we obtain the principal components of deformation. These principal components are then used to obtain the parameters in an empirical constitutive equation determining the cell deformations as a function of the fluid normal and shear forces imparted. The cell surface is modeled as a 2D Gaussian interface which can be deformed with three active parameters: H (height), sigma(x) (x-width), and sigma(y) (y-width). Fluid forces are calculated on the cell surface by discretizing the surface with regularized Stokeslets, and the flow is driven by a stochastically fluctuating pressure gradient. The Stokeslet strengths are obtained so that viscous boundary conditions are enforced on the surface of the cell and the surrounding plate. We show that the low-dimensional model is able to capture the principal deformations of the cell reasonably well and argue that active shape models can be exploited further as a useful tool to bridge the gap between experiments, models, and numerical simulations in this biological setting. PMID- 23024579 TI - The Effect of Random Edge Removal on Network Degree Sequence. AB - Many networks arise in a random and distributed fashion, and yet result in having a specific type of degree structure: e.g., the WWW, many social networks, biological networks, etc., exhibit power-law, stretched exponential, or similar degree structures. Much work has examined how a graph's degree-structure influences other graph properties such as connectivity, diameter, etc. Probabilistic edge removal models link failures, information spreading, and processes that consider (random) subgraphs. They also model spreading influence of information as in the independent cascade model [20]. We examine what happens to a graph's degree structure under edge failures where the edges are removed independently with identical probabilities. We start by analyzing the effect of edge failure on the degree sequence for power-law and exponential networks, and improve upon results of Martin, Carr & Faulon and Cooper & Lu; then, using intuition from the power-law case, we derive asymptotic results for almost any degree sequence of interest. Our major result shows a classification of degree sequences which leads to simple rules that give much of the new expected degree sequence after random edge-removal; we also provide associated concentration bounds. PMID- 23024580 TI - New joint statement on SIDS and safe sleep. PMID- 23024581 TI - Can children with minor illnesses be safely immunized? PMID- 23024583 TI - Case 1: Chronic cough in a Vietnamese adolescent: Should we be sweating? PMID- 23024582 TI - Case 2: Coma in an apparently well toddler. PMID- 23024584 TI - Complementary and alternative medicine use in children and adolescents with type 1 diabetes. AB - BACKGROUND: The use of complementary and alternative medicine (CAM) in paediatric patients varies between 11% and 68%. There are limited reports of its use in children with type 1 diabetes mellitus (T1DM). OBJECTIVE: To describe the use of CAM in children with T1DM, and the perceptions of both users and nonusers regarding the effect of CAM on diabetes management. DESIGN/METHODS: A cross sectional, anonymous questionnaire survey was mailed to a randomly selected subgroup of patients with T1DM. Each patient's main caregiver was asked to complete the questionnaire. RESULTS: Of 403 questionnaires mailed, 195 (48%) were completed. The mean (+/- SD) age of the children was 12.2+/-4.0 years (56% boys). Use of CAM was reported in 110 children (56%) (vitamins/minerals [n=99], herbal medicine [n=22], dietary supplement [n=13]). When excluding the use of vitamins/minerals, the CAM number dropped to 47 children (24%). Only the current age of the child was significantly different between users and nonusers of CAM. In users, reasons cited for using CAM were to minimize symptoms, improve control, prevent complications and add benefits to insulin. Only 30% of CAM users stated that CAM improved diabetes control. Nonusers cited satisfaction with current diabetes treatment and lack of knowledge as reasons for not using CAM. CONCLUSIONS: CAM use in children with T1DM was frequent, and appeared to be an attempt to improve control or prevent diabetes complications. However, improved control was not reported as a benefit. Diabetes care teams should assess the use of CAM in children with T1DM, and monitor for any potential positive or negative effects. PMID- 23024585 TI - The 'Golden Keys' to health - a healthy lifestyle intervention with randomized individual mentorship for overweight and obesity in adolescents. AB - OBJECTIVE: To conduct a pilot study designed to measure the impact of a healthy lifestyle intervention with or without individualized mentorship on adiposity, metabolic profile, nutrition and physical activity in overweight teens. METHODS: A total of 38 overweight adolescents (body mass index above the 85th percentile) 12 to 16 years of age, who were enrolled in a healthy lifestyle intervention program for six months, were randomly assigned to a nonmentored or individualized mentored intervention. RESULTS: For the entire cohort (final n=32), there was a nonstatistically significant reduction in mean (+/- SD) body mass index z score (2.08+/-0.38 to 2.01+/-0.47, P=0.07) and waist circumference (98+/-10 cm to 96+/ 11 cm, P=0.08), and significant improvements in high-density lipoprotein level (1.08+/-0.24 mmol/L to 1.20+/-0.26 mmol/L, P<0.001), and low-density lipoprotein/high-density lipoprotein ratio (2.55+/-0.84 to 2.26+/-0.87, P<0.001) from baseline to the end of the intervention. Subjects consumed fewer high calorie foods (3.9+/-1.9 to 3.0+/-1.5 servings/day, P=0.01) and snacks (9.7+/-5.5 to 6.8+/-4.0 servings/day, P=0.02), made fewer fast food restaurant visits (1.4+/ 1.3 to 0.8+/-0.9 visits/week, P=0.02), and had less screen time (8.3+/-3.8 to 6.9+/-3.6 h/day, P=0.01). In addition, mentorship was found to be a feasible approach to supporting weight management in obese teens. Our study was underpowered to determine treatment effect, but promising modifications to lifestyle were observed despite the absence of statistically significant improvements in outcomes. CONCLUSIONS: The healthy lifestyle intervention improved subjects' lifestyles and lipid profiles, and the addition of mentorship in this context is feasible. A larger study with a longer intervention time is required to determine whether behavioural changes are associated with clinical improvement and to determine the role of mentorship in promoting lifestyle change. PMID- 23024586 TI - Steroid pulse therapy for Kawasaki disease unresponsive to additional immunoglobulin therapy. AB - BACKGROUND: The optimal management of Kawasaki disease (KD) unresponsive to intravenous immunoglobulin (IVIG) therapy remains unclear. OBJECTIVE: To prospectively evaluate the efficacy and safety of intravenous methylprednisolone pulse (IVMP) therapy in KD cases unresponsive to additional IVIG. METHODS: KD patients who initially received IVIG (2 g/kg/24 h) and acetylsalicylic acid within nine days after disease onset were studied. Patients who did not respond received additional IVIG (2 g/kg/24 h), and those who still did not respond were given IVMP (30 mg/kg/day) for three days, followed by oral prednisolone. The response to treatment, echocardiographic findings and adverse effects were evaluated. RESULTS: Among 412 KD cases, 74 (18.0%) were treated with additional IVIG; 21 (28.4%) of the latter cases subsequently received IVMP followed by prednisolone. All cases became afebrile soon after IVMP infusion and did not have a high-grade fever during treatment with prednisolone for two to six weeks. Four weeks after disease onset, coronary artery lesions (CAL) were diagnosed according to the Japanese Ministry of Health and Welfare or the American Heart Association criteria in two of the 21 cases treated with IVMP plus prednisolone; among all 412 cases, three (0.7%) and eight (1.9%) had CAL according to each criteria, respectively. All CAL regressed completely one year after disease onset. Adverse effects of IVMP, such as hypothermia and sinus bradycardia, resolved spontaneously. CONCLUSIONS: In KD patients unresponsive to additional IVIG, IVMP promptly induced defervescence, and subsequent oral prednisolone suppressed recurrence of fever. IVMP followed by prednisolone therapy may prevent CAL, without severe adverse effects. PMID- 23024587 TI - Meningococcal vaccines in Canada: An update. AB - Meningococcal infection is serious, often resulting in fulminant sepsis or meningitis. There are two main types of meningococcal conjugate vaccine currently available in Canada: serotype C meningococcal conjugate, and quadrivalent conjugate for serotypes A, C, Y, and W-135. The immunological characteristics that inform ongoing immunization policies, as well as some of the limits of current knowledge, are presented. All Canadian children should receive a conjugate meningococcal C vaccine (MCV-C) at 12 months of age, and either a booster dose of MCV-C or of quadrivalent meningococcal vaccine (MCV-4) in adolescence. Children at high risk of invasive meningococcal disease should start MCV-C at two months of age, and be given MCV-4 at two years of age. PMID- 23024588 TI - Preventing respiratory syncytial virus infections. AB - Respiratory syncytial virus infection is the leading cause of lower respiratory tract infections in young children. Palivizumab, a respiratory syncytial virus specific monoclonal antibody, reduces the hospitalization rate of high-risk children but it is very costly. This statement replaces three previous position statements from the Canadian Paediatric Society about this topic, and was updated primarily to discuss recent changes in the American Academy of Pediatrics guidelines in the Canadian context. It reviews the published literature and provides recommendations regarding palivizumab use in high-risk children. PMID- 23024589 TI - Use of influenza vaccines in children with an egg allergy. AB - Children are at increased risk of morbidity from influenza. Influenza vaccines are grown in eggs, leading to a minute amount of egg protein in their composition. Recent research and new practice parameters spurred by the 2009 global influenza pandemic have challenged the need to withhold influenza vaccine from patients with an egg allergy. The available data suggest that anaphylaxis from influenza vaccines is exceptionally rare, even in patients with an egg allergy. Reported allergic reactions to trivalent inactivated influenza vaccine and pH1N1 influenza vaccines have been rare; when reactions occurred, they have not caused anaphylaxis. This position statement reviews the available evidence on influenza vaccine/egg allergy-related anaphylaxis, and recommends protocols to safely administer the trivalent inactivated influenza vaccine in lower- and higher-risk children with an egg allergy. PMID- 23024590 TI - Positional plagiocephaly. AB - Cranial asymmetry occurring as a result of forces that deform skull shape in the supine position is known as deformational plagiocephaly. The risk of plagiocephaly may be modified by positioning the baby on alternate days with the head to the right or the left side, and by increasing time spent in the prone position during awake periods. When deformational plagiocephaly is already present, physiotherapy (including positioning equivalent to the preventive positioning, and exercises as needed for torticollis and positional preference) has been shown to be superior to counselling about preventive positioning only. Helmet therapy (moulding therapy) to reduce skull asymmetry has some drawbacks: it is expensive, significantly inconvenient due to the long hours of use per day and associated with skin complications. There is evidence that helmet therapy may increase the initial rate of improvement of asymmetry, but there is no evidence that it improves the final outcome for patients with moderate or severe plagiocephaly. PMID- 23024591 TI - From genes to vaccine: A breakthrough in the prevention of meningococcal group B disease. AB - Although safe and effective vaccines exist for meningococcal serogroups A, C, W 135 and Y, no vaccine is available for routine use against disease caused by serogroup B (MenB). Consequently, MenB is now the most common cause of invasive meningococcal disease in Canada. MenB causes more than 80% of invasive meningococcal disease in infants and can occur at any age. The mortality and morbidity rates related to this disease are very high. Vaccine development against MenB has been hampered by the fact that MenB polysaccharide is not immunogenic in humans. Although vaccines derived from the outer membrane vesicle have been effective in controlling MenB outbreaks, such vaccines protect against the outbreak strain only. A new vaccine development strategy, reverse vaccinology, has led to the identification of genes coding for surface-exposed proteins, which are able to induce bactericidal antibodies against a broad range of MenB strains. A new vaccine containing a combination of these proteins has been tested in different age groups, in several clinical trials. The data available provide hope that control of MenB through routine vaccination will soon be possible. PMID- 23024592 TI - Mandatory detention of refugee children: A public health issue? PMID- 23024593 TI - Enhanced growth inhibition of osteosarcoma by cytotoxic polymerized liposomal nanoparticles targeting the alcam cell surface receptor. AB - Osteosarcoma is the most common primary malignancy of bone in children, adolescents, and adults. Despite extensive surgery and adjuvant aggressive high dose systemic chemotherapy with potentially severe bystander side effects, cure is attainable in about 70% of patients with localized disease and only 20%-30% of those patients with metastatic disease. Targeted therapies clearly are warranted in improving our treatment of this adolescent killer. However, a lack of osteosarcoma-associated/specific markers has hindered development of targeted therapeutics. We describe a novel osteosarcoma-associated cell surface antigen, ALCAM. We, then, create an engineered anti-ALCAM-hybrid polymerized liposomal nanoparticle immunoconjugate (alpha-AL-HPLN) to specifically target osteosarcoma cells and deliver a cytotoxic chemotherapeutic agent, doxorubicin. We have demonstrated that alpha-AL-HPLNs have significantly enhanced cytotoxicity over untargeted HPLNs and over a conventional liposomal doxorubicin formulation. In this way, alpha-AL-HPLNs are a promising new strategy to specifically deliver cytotoxic agents in osteosarcoma. PMID- 23024594 TI - DNA methylation and gene expression profiling of ewing sarcoma primary tumors reveal genes that are potential targets of epigenetic inactivation. AB - The role of aberrant DNA methylation in Ewing sarcoma is not completely understood. The methylation status of 503 genes in 52 formalin-fixed paraffin embedded EWS tumors and 3 EWS cell lines was compared to human mesenchymal stem cell primary cultures (hMSCs) using bead chip methylation analysis. Relative expression of methylated genes was assessed in 5-Aza-2-deoxycytidine-(5-AZA) treated EWS cell lines and in a cohort of primary EWS samples and hMSCs by gene expression and quantitative RT-PCR. 129 genes demonstrated statistically significant hypermethylation in EWS tumors compared to hMSCs. Thirty-six genes were profoundly methylated in EWS and unmethylated in hMSCs. 5-AZA treatment of EWS cell lines resulted in upregulation of expression of hundreds of genes including 162 that were increased by at least 2-fold. The expression of 19 of 36 candidate hypermethylated genes was increased following 5-AZA. Analysis of gene expression from an independent cohort of tumors confirmed decreased expression of six of nineteen hypermethylated genes (AXL, COL1A1, CYP1B1, LYN, SERPINE1,) and VCAN. Comparing gene expression and DNA methylation analyses proved to be an effective way to identify genes epigenetically regulated in EWS. Further investigation is ongoing to elucidate the role of these epigenetic alterations in EWS pathogenesis. PMID- 23024595 TI - Selection and validation of reference genes for quantitative RT-PCR expression studies of the non-model crop Musa. AB - Gene expression analysis by reverse transcriptase real-time or quantitative polymerase chain reaction (RT-qPCR) is becoming widely used for non-model plant species. Given the high sensitivity of this method, normalization using multiple housekeeping or reference genes is critical, and careful selection of these reference genes is one of the most important steps to obtain reliable results. In this study, reference genes commonly used for other plant species were investigated to identify genes displaying highly uniform expression patterns in different varieties, tissues, developmental stages, fungal infection, and osmotic stress conditions for the non-model crop Musa (banana and plantains). The expression stability of six candidate reference genes was tested on six different sample sets, and the results were analyzed using the publicly available algorithms geNorm and NormFinder. Our results show that variety, plant material, primer set, and gene identity can all influence the robustness and outcome of RT qPCR analysis. In the case of Musa, a combination of three reference genes (EF1, TUB and ACT) can be used for normalization of gene expression data from greenhouse leaf samples. In the case of shoot meristem cultures, numerous combinations can be used because the investigated reference genes exhibited limited variability. In contrast, variability in expression of the reference genes was much larger among leaf samples from plants grown in vitro, for which the best combination of reference genes (L2 and ACT genes) is still suboptimal. Overall, our data confirm that the stability of candidate reference genes should be thoroughly investigated for each experimental condition under investigation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-012-9711-1) contains supplementary material, which is available to authorized users. PMID- 23024596 TI - Proteomic analysis of preharvest sprouting in rye using two-dimensional electrophoresis and mass spectrometry. AB - Qualitative and quantitative differences were found between two-dimensional electrophoretic spectra of 546 proteins from two bulked samples of mature rye grain representing: (1) 20 recombinant inbred lines extremely resistant to preharvest sprouting and (2) 20 recombinant inbred lines extremely susceptible to preharvest sprouting. Mass spectrometry of resolved proteins showed that four spots specific for PHS susceptibility represented high molecular weight glutenin subunit, glutathione transferase, 16.9 kDa heat-shock protein, and monomeric alpha-amylase inhibitor. Two spots specific for PHS resistance contained cytosolic malate dehydrogenase and functionally unrecognized protein with sequence homology to rubber elongation factor protein. Majority of 14 proteins with at least two-fold higher accumulation level in preharvest sprouting susceptible lines relative to that found in sprouting resistant lines, showed sequence homology to proteins involved in defense mechanisms against biotic and abiotic stresses including oxidative stress, and those taking part in energy supply. Two spots were identified as regulatory proteins from the 14-3-3 family with one molecular form prevailing in sprouting susceptible and another form highly accumulated in sprouting resistant lines. Further study establishing map positions of the revealed structural genes in respect to quantitative trait loci for preharvest sprouting in rye should answer the question on their possible status as candidate genes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-012-9721-z) contains supplementary material, which is available to authorized users. PMID- 23024597 TI - Genetic dissection of drought tolerance and recovery potential by quantitative trait locus mapping of a diploid potato population. AB - Potato is the third most important staple food crop in terms of consumption, yet it is relatively susceptible to yield loss because of drought. As a first step towards improving drought tolerance in this crop, we set out to identify the genetic basis for drought tolerance in a diploid potato mapping population. Experiments were carried out under greenhouse conditions in two successive years by recording four physiological, seven growth and three yield parameters under stress and recovery treatments. Genotypes showed significant variation for drought and recovery responses. The traits measured had low to moderately high heritabilities (ranging from 22 to 74 %). A total of 47 quantitative trait loci (QTL) were identified, of which 28 were drought-specific, 17 under recovery treatment and two under well-watered conditions. The majority of these growth and yield QTL co-localized with a QTL for maturity on chromosome 5. Four QTL for delta(13)C, three for chlorophyll content and one for chlorophyll fluorescence (F(v)/F(m)) were found to co-localize with yield and other growth trait QTL identified on other chromosomes. Several multi-year and multi-treatment QTL were detected and QTL * environment interaction was found for delta(13)C. To our knowledge, this is the first comprehensive QTL study on water deficit and recovery potential in potato. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-012-9728-5) contains supplementary material, which is available to authorized users. PMID- 23024598 TI - Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications. AB - Superparamagnetic iron oxide nanoparticles can provide multiple benefits for biomedical applications in aqueous environments such as magnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles' surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality water-dispersible nanoparticles around 10 nm in size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11051-012-1100-5) contains supplementary material, which is available to authorized users. PMID- 23024599 TI - Comparative genomics and genome evolution. PMID- 23024600 TI - Immune related genes underpin the evolution of adaptive immunity in jawless vertebrates. AB - The study of immune related genes in lampreys and hagfish provides a unique perspective on the evolutionary genetic underpinnings of adaptive immunity and the evolution of vertebrate genomes. Separated from their jawed cousins at the stem of the vertebrate lineage, these jawless vertebrates have many of the gene families and gene regulatory networks associated with the defining morphological and physiological features of vertebrates. These include genes vital for innate immunity, inflammation, wound healing, protein degradation, and the development, signaling and trafficking of lymphocytes. Jawless vertebrates recognize antigen by using leucine-rich repeat (LRR) based variable lymphocyte receptors (VLRs), which are very different from the immunoglobulin (Ig) based T cell receptor (TCR) and B cell receptor (BCR) used for antigen recognition by jawed vertebrates. The somatically constructed VLR genes are expressed in monoallelic fashion by T-like and B-like lymphocytes. Jawless and jawed vertebrates thus share many of the genes that provide the molecular infrastructure and physiological context for adaptive immune responses, yet use entirely different genes and mechanisms of combinatorial assembly to generate diverse repertoires of antigen recognition receptors. PMID- 23024601 TI - Evolutionary genomics of immunoglobulin-encoding Loci in vertebrates. AB - Immunoglobulins (or antibodies) are an essential element of the jawed vertebrate adaptive immune response system. These molecules have evolved over the past 500 million years and generated highly specialized proteins that recognize an extraordinarily large number of diverse substances, collectively known as antigens. During vertebrate evolution the diversification of the immunoglobulin encoding loci resulted in differences in the genomic organization, gene content, and ratio of functional genes and pseudogenes. The tinkering process in the immunoglobulin-encoding loci often gave rise to lineage-specific characteristics that were formed by selection to increase species adaptation and fitness. Immunoglobulin loci and their encoded antibodies have been shaped repeatedly by contrasting evolutionary forces, either to conserve the prototypic structure and mechanism of action or to generate alternative and diversified structures and modes of function. Moreover, evolution favored the development of multiple mechanisms of primary and secondary antibody diversification, which are used by different species to effectively generate an almost infinite collection of diverse antibody types. This review summarizes our current knowledge on the genomics and evolution of the immunoglobulin-encoding loci and their protein products in jawed vertebrates. PMID- 23024602 TI - Olfactory receptor multigene family in vertebrates: from the viewpoint of evolutionary genomics. AB - Olfaction is essential for the survival of animals. Diverse odor molecules in the environment are detected by the olfactory receptors (ORs) in the olfactory epithelium of the nasal cavity. There are ~400 and ~1,000 OR genes in the human and mouse genomes, respectively, forming the largest multigene family in mammals. The relationships between ORs and odorants are multiple-to-multiple, which allows for discriminating almost unlimited number of different odorants by a combination of ORs. However, the OR-ligand relationships are still largely unknown, and predicting the quality of odor from its molecular structure is unsuccessful.Extensive bioinformatic analyses using the whole genomes of various organisms revealed a great variation in number of OR genes among species, reflecting the diversity of their living environments. For example, higher primates equipped with a well-developed vision system and dolphins that are secondarily adapted to the aquatic life have considerably smaller numbers of OR genes than most of other mammals do. OR genes are characterized by extremely frequent gene duplications and losses. The OR gene repertories are also diverse among human individuals, explaining the diversity of odor perception such as the specific anosmia.OR genes are present in all vertebrates. The number of OR genes is smaller in teleost fishes than in mammals, while the diversity is higher in the former than the latter. Because the genome of amphioxus, the most basal chordate species, harbors vertebrate-like OR genes, the origin of OR genes can be traced back to the common ancestor of the phylum Chordata. PMID- 23024603 TI - Evolution of genomic structures on Mammalian sex chromosomes. AB - Throughout mammalian evolution, recombination between the two sex chromosomes was suppressed in a stepwise manner. It is thought that the suppression of recombination led to an accumulation of deleterious mutations and frequent genomic rearrangements on the Y chromosome. In this article, we review three evolutionary aspects related to genomic rearrangements and structures, such as inverted repeats (IRs) and palindromes (PDs), on the mammalian sex chromosomes. First, we describe the stepwise manner in which recombination between the X and Y chromosomes was suppressed in placental mammals and discuss a genomic rearrangement that might have led to the formation of present pseudoautosomal boundaries (PAB). Second, we describe ectopic gene conversion between the X and Y chromosomes, and propose possible molecular causes. Third, we focus on the evolutionary mode and timing of PD formation on the X and Y chromosomes. The sequence of the chimpanzee Y chromosome was recently published by two groups. Both groups suggest that rapid evolution of genomic structure occurred on the Y chromosome. Our re-analysis of the sequences confirmed the species-specific mode of human and chimpanzee Y chromosomal evolution. Finally, we present a general outlook regarding the rapid evolution of mammalian sex chromosomes. PMID- 23024604 TI - Evolution of copper transporting ATPases in eukaryotic organisms. AB - Copper is an essential nutrient for most life forms, however in excess it can be harmful. The ATP-driven copper pumps (Copper-ATPases) play critical role in living organisms by maintaining appropriate copper levels in cells and tissues. These evolutionary conserved polytopic membrane proteins are present in all phyla from simplest life forms (bacteria) to highly evolved eukaryotes (Homo sapiens). The presumed early function in metal detoxification remains the main function of Copper-ATPases in prokaryotic kingdom. In eukaryotes, in addition to removing excess copper from the cell, Copper-ATPases have another equally important function - to supply copper to copper dependent enzymes within the secretory pathway. This review focuses on the origin and diversification of Copper ATPases in eukaryotic organisms. From a single Copper ATPase in protozoans, a divergence into two functionally distinct ATPases is observed with the evolutionary appearance of chordates. Among the key functional domains of Copper-ATPases, the metal-binding N-terminal domain could be responsible for functional diversification of the copper ATPases during the course of evolution. PMID- 23024605 TI - Current Status of Echinoderm Genome Analysis - What do we Know? AB - Echinoderms have long served as model organisms for a variety of biological research, especially in the field of developmental biology. Although the genome of the purple sea urchin Strongylocentrotus purpuratus has been sequenced, it is the only echinoderm whose whole genome sequence has been reported. Nevertheless, data is rapidly accumulating on the chromosomes and genomic sequences of all five classes of echinoderms, including the mitochondrial genomes and Hox genes. This blossoming new data will be essential for estimating the phylogenetic relationships among echinoderms, and also to examine the underlying mechanisms by which the diverse morphologies of echinoderms have arisen. PMID- 23024606 TI - Probing Evolutionary Biography of MicroRNAs and Associated Factors. AB - Intergenic DNA, often described as "playground of evolution", harbors a plethora of cis and trans regulatory elements in the form of non-coding RNAs (ncRNAs). The evolution of the silencing mechanism mediated by microRNAs (miRNAs), an important class of ncRNA, involves the proliferation of miRNA biogenesis and effector proteins, continuing innovation of novel families by the diversification of established families and spawning additional paralogous family members. Such evolving miRNA pathways for spatiotemporal regulation of the transcriptome have shaped the evolution of eukaryotic genomes and contributed to the complexity of multicellular organisms. Here, we focus on the emergence of new target specificity of the miRNAs along with the proliferation of core biogenesis and effector modules and show how this has contributed to generate diverse miRNA regulatory pathways. PMID- 23024609 TI - 5-Month-Olds' Categorization of Novel Objects: Task and Measure Dependence. AB - To examine key parameters of the initial conditions in early category learning, two studies compared 5-month-olds' object categorization between tasks involving previously unseen novel objects, and between measures within tasks. Infants in Experiment 1 participated in a visual familiarization / novelty preference (VFNP) task with 2D stimulus images. Infants provided no evidence of categorization by either their looking or their examining even though infants in previous research systematically categorized the same objects by examining when they handled them in 3D. Infants in Experiment 2 participated in a VFNP task with 3D stimulus objects that allowed visual examination of objects' 3D instantiation while denying manual contact with the objects. Under these conditions, infants demonstrated categorization by examining but not by looking. Focused examination appears to be a key component of young infants' ability to form category representations of novel objects, and 3D instantiation appears to better engage such examining. PMID- 23024607 TI - Microbial lifestyle and genome signatures. AB - Microbes are known for their unique ability to adapt to varying lifestyle and environment, even to the extreme or adverse ones. The genomic architecture of a microbe may bear the signatures not only of its phylogenetic position, but also of the kind of lifestyle to which it is adapted. The present review aims to provide an account of the specific genome signatures observed in microbes acclimatized to distinct lifestyles or ecological niches. Niche-specific signatures identified at different levels of microbial genome organization like base composition, GC-skew, purine-pyrimidine ratio, dinucleotide abundance, codon bias, oligonucleotide composition etc. have been discussed. Among the specific cases highlighted in the review are the phenomena of genome shrinkage in obligatory host-restricted microbes, genome expansion in strictly intra-amoebal pathogens, strand-specific codon usage in intracellular species, acquisition of genome islands in pathogenic or symbiotic organisms, discriminatory genomic traits of marine microbes with distinct trophic strategies, and conspicuous sequence features of certain extremophiles like those adapted to high temperature or high salinity. PMID- 23024610 TI - EVALUATION OF INTERFACIAL FLUID DYNAMICAL STRESSES USING THE IMMERSED BOUNDARY METHOD. AB - The goal of this paper is to examine the evaluation of interfacial stresses using a standard, finite difference based, immersed boundary method (IMBM). This calculation is not trivial for two fundamental reasons. First, the immersed boundary is represented by a localized boundary force which is distributed to the underlying fluid grid by a discretized delta function. Second, this discretized delta function is used to impose a spatially averaged no-slip condition at the immersed boundary. These approximations can cause errors in interpolating stresses near the immersed boundary.To identify suitable methods for evaluating stresses, we investigate three model flow problems at very low Reynolds numbers. We compare the results of the immersed boundary calculations to those achieved by the boundary element method (BEM). The stress on an immersed boundary may be calculated either by direct evaluation of the fluid stress (FS) tensor or, for the stress jump, by direct evaluation of the locally distributed boundary force (wall stress or WS). Our first model problem is Poiseuille channel flow. Using an analytical solution of the immersed boundary formulation in this simple case, we demonstrate that FS calculations should be evaluated at a distance of approximately one grid spacing inward from the immersed boundary. For a curved immersed boundary we present a procedure for selecting representative interfacial fluid stresses using the concepts from the Poiseuille flow test problem. For the final two model problems, steady state flow over a bump in a channel and unsteady peristaltic pumping, we present an 'exclusion filtering' technique for accurately measuring stresses. Using this technique, these studies show that the immersed boundary method can provide reliable approximations to interfacial stresses. PMID- 23024608 TI - Current applications of models of genetic effects with interactions across the genome. AB - Models of genetic effects integrate the action of genes, regulatory regions and interactions among alleles across the genome. Such theoretical frameworks are critical for applied studies in at least two ways. First, discovering genetic networks with specific effects underlying traits in populations requires the development of models that implement those effects as parameters-adjusting the implementation of epistasis parameters in genetic models has for instance been a requirement for properly testing for epistasis in gene-mapping studies. Second, studying the properties and implications of models of genetic effects that involve complex genetic networks has proven to be valuable, whether those networks have been revealed for particular organisms or inferred to be of interest from theoretical works and simulations. Here I review the current state of development and recent applications of models of genetic effects. I focus on general models aiming to depict complex genotype-to-phenotype maps and on applications of them to networks of interacting loci. PMID- 23024611 TI - HIV risk behaviors, perceived severity of drug use problems, and prior treatment experience in a sample of young heroin injectors in Dar es Salaam, Tanzania. AB - Interviews were conducted with 203 male and 95 female heroin injectors aged 17 to 25 in Dar es Salaam, Tanzania. Nearly one-quarter of participants reported injecting with needles used by someone else. Few reported cleaning needles with bleach. Multiple sexual partnerships, unprotected sex, and trading sex for money were especially present among women, the majority (55%) of whom was HIV seropositive. Self reports suggest the presence of heroin dependence among users. While most participants expressed a desire to quit their use, only 14 (5%) had been in treatment. There appears to be a large unmet need for heroin use treatment. These findings need to be considered in light of a potential forthcoming wave of heroin injection in sub-Saharan Africa. PMID- 23024612 TI - Angiogenic response to major lung resection for non-small cell lung cancer with video-assisted thoracic surgical and open access. AB - BACKGROUND: Angiogenic factors following oncological surgery is important in tumor recurrence. Vascular endothelial growth factor (VEGF), angiopoietin 1 (Ang 1), Ang-2, soluble VEGF-receptor 1 (sVEGFR1) and sVEGFR2 may influence angiogenesis. This prospective study examined the influence of open and video assisted thoracic surgery (VATS) lung resections for early stage non-small cell lung cancer (NSCLC) on postoperative circulating angiogenic factors. METHODS: Forty-three consecutive patients underwent major lung resection through either VATS (n = 23) or Open thoracotomy (n = 20) over an 8-month period. Blood samples were collected preoperatively and postoperatively on days (POD) 1 and 3 for enzyme linked immunosorbent assay determination of angiogenic factors. RESULTS: Patient demographics were comparable. For all patients undergoing major lung resection, postoperative Ang-1 and sVEGFR2 levels were significantly decreased, while Ang-2 and sVEGFR1 levels markedly increased. No significant peri-operative changes in VEGF levels were observed. Compared with open group, VATS had significantly lower plasma levels of VEGF (VATS 170 +/- 93 pg/mL; Open 486 +/- 641 pg/mL; P = 0.04) and Ang-2 (VATS 2484 +/- 1119 pg/mL; Open 3379 +/- 1287 pg/mL; P = 0.026) on POD3. CONCLUSIONS: Major lung resection for early stage NSCLC leads to a pro-angiogenic status, with increased Ang-2 and decreased Ang-1 productions. VATS is associated with an attenuated angiogenic response with lower circulating VEGF and Ang-2 levels compared with open. Such differences in angiogenic factors may be important in lung cancer biology and recurrence following surgery. PMID- 23024614 TI - Letter from the editor. PMID- 23024613 TI - Salud de Corazon: Cultural Resources for Cardiovascular Health among Older Hispanic Women. AB - The prevalence of cardiovascular disease risk factors in Hispanic women has been substantiated across studies. While many studies have focused on the impact of these risk factors, few qualitative studies have addressed cultural and contextual meanings of cardiovascular health promotion in this population. This research explored cultural resources for cardiovascular health promotion among older Hispanic women. A qualitative descriptive methodological design using focus groups with 7 Hispanic women was used. Culture provided an overarching perspective, guiding identification and choice of resources and supports in order to promote cardiovascular health. Themes included Living Tradition, Caring for Family, Connecting with Friends, Having Faith, and Moving as Life. Data provide an initial step toward generating a more complete understanding of perceived cultural resources for cardiovascular health in older Hispanic women. Researchers and clinicians are increasingly recognizing that individuals, families and communities uniquely define cultural and contextual meaning of cardiovascular health promotion. PMID- 23024615 TI - Technique for margin convergence in rotator cuff repair. AB - The purpose of the present study is to describe the technique of margin convergence for U-shaped rotator cuff tears and report the clinical outcomes and ultrasonography with a minimum of 2 years follow-up. Three hundred eleven patients with a rotator cuff tear were prospectively enrolled in a registry at one institution. Inclusion criteria included any patient undergoing arthroscopic margin convergence for a rotator cuff tear. Exclusion criteria included open or mini-open rotator cuff repairs or suture anchor fixation to the cuff insertion without margin convergence. The outcome measurements included physical examination, manual muscle testing, the American Shoulder and Elbow Surgeons (ASES) score, and ultrasonography. Nineteen patients met the study criteria and 13 were available for 2-year follow-up (68.4%). The mean age of this cohort was 62.2 +/- 7.5 years with a mean pre-operative rotator cuff tear size of 4.0 +/- 1.6 cm. The ASES score increased significantly from 50.0 +/- 17.7 before surgery to 83.3 +/- 19.5 at 2 years (P = 0.01). The active forward elevation also improved from 156.2 +/- 11.9 degrees before surgery to 168.0 +/- 12.1 at 2 years (P = 0.03). The active external rotation 54.4 +/- 14.5 at baseline and improved to 57.1 +/- 19.1 at 2 years (P = 0.04). The strength also increased significantly from 6.7 +/- 6.4 to 10.6 +/- 4.9 lb at 1 year (P = 0.048). The post-operative ultrasound demonstrated that 46.2% of rotator cuff tears were healed at 2 years. In conclusion, margin convergence is a useful technique for U-shaped tears that are difficult to mobilize. PMID- 23024616 TI - Total shoulder arthroplasty utilizing mini-stem humeral components: technique and short-term results. AB - INTRODUCTION: Throughout the field of orthopedic surgery, there has been a trend toward using smaller incisions and implants that preserve as much normal anatomy as possible. The use of bone sparing technology, such as partial and full surface replacements of the humeral head, while attractive in younger patients, does not allow the best exposure for proper glenoid replacement. Additionally, there are other situations when the use of surface replacements is contraindicated. There are also patients with an existing total elbow replacement or a humeral malunion or deformity in which a traditional long-stem component would not fit. For these reasons, a mini-stem humeral component for total shoulder arthroplasty was developed. In this study, we hypothesized that total shoulder replacement using the mini-stem humeral component could provide low complication rates and good to excellent results, as measured by postoperative Constant-Murley and UCLA shoulder scores at minimum 2 years postoperatively. MATERIALS AND METHODS: This was a retrospective review of the first 49 mini-stem shoulder replacements (47 patients) for primary osteoarthritis. There were 26 male and 23 female patients. UCLA Shoulder Score and Constant Murley Scores were obtained on all patients at a minimum of 2 years postoperatively (average 29 months; range 24-43 months). Radiographs were interpreted by a musculoskeletal radiologist. Intraoperative blood loss was documented as was postoperative pain using a visual analog pain scale. RESULTS: Patients experienced over 90% good to excellent results at minimum 2 year follow up. ROM improved significantly in all parameters. Postoperative UCLA scores at final follow up averaged 27.5 while Constant-Murley scores averaged 91. Small lucent lines (<1 mm) were noted in 11 patients. Five of 49 stems were placed in varus but the postoperative result was not affected in any of these patients. One patient suffered an acute subscapularis rupture that required repair. CONCLUSIONS: This is the first report to document the efficacy of mini-stemmed humeral components used during total shoulder arthroplasty. Our study group showed good to excellent results as well as improvement in range of motion at minimum 2-year follow-up. The results presented in this study are comparable to previous outcomes achieved with conventional length humeral components, and suggest that mini-stem humeral components are an effective option for total shoulder arthroplasty. PMID- 23024617 TI - Reliability of determining and measuring acromial enthesophytes. AB - BACKGROUND: Although the reliability of determining acromial morphology has been examined, to date, there has not been an analysis of interobserver and intraobserver reliability on determining the presence and measuring the size of an acromial enthesophyte. QUESTIONS/PURPOSES: The hypothesis of this study was that there will be poor intraobserver and interobserver reliability in the (1) determination of the presence of an acromial enthesophyte, (2) determination of the size of an acromial enthesophyte, and (3) determination of acromial morphology. PATIENTS AND METHODS: Fifteen fellowship-trained orthopedic shoulder surgeons reviewed the radiographs of 15 patients at two different intervals. Measurement of acromial enthesophytes was performed using two techniques: (1) enthesophyte length and (2) enthesophyte-humeral distance. Acromial morphology was also determined. Interobserver and intraobserver agreement was determined using intraclass correlation and kappa statistical methods. RESULTS: The interobserver reliability was fair to moderate and the intraobserver reliability moderate for determining the presence of an acromial enthesophyte. The measurement of the enthesophyte length showed poor interobserver and intraobserver reliability. The measurement of the enthesophyte-humeral distance showed poor interobserver reliability and moderate intraobserver reliability. The interobserver and intraobserver reliability in determining acromial morphology was found to be moderate and good, respectively. CONCLUSIONS: There is fair to moderate reliability among fellowship-trained shoulder surgeons in determining the presence of an acromial enthesophyte. However, there is poor reliability among observers in measuring the size of the enthesophyte. This study suggests that the enthesophyte-humeral distance may be more reliable than the enthesophyte length when measuring the size of the enthesophyte. PMID- 23024618 TI - How Often are Patient and Surgeon Recovery Expectations for Total Joint Arthroplasty Aligned? Results of a Pilot Study. AB - BACKGROUND: Surgeons strive to set patient expectations for recovery following total hip arthroplasty (THA) and total knee arthroplasty (TKA). However, some patients report dissatisfaction after surgery due to unmet expectations. PURPOSE: We compared patients' and surgeon's recovery expectations prior to primary THA and TKA. METHODS: Sixty eight patients scheduled to undergo primary total hip replacement (THR) or total knee replacement (TKR) surgery were enrolled. Before surgery, patients filled out a validated recovery expectations questionnaire that quantified expectations of postoperative pain relief, function, and well-being with a value from 0 to 100 (higher being more optimistic). The surgeon independently completed the same questionnaire for each patient. Overall score and item-specific comparisons were conducted. Correlations were explored between agreement level, demographics, patient-reported health status measures, and patients' assessments of the risk of complications associated with surgery. RESULTS: Most patients undergoing THR or TKR had higher expectations for recovery than their surgeon. Applying the clinically meaningful difference in expectations (>=7 points), 52.5% of the TKA patients' expectations exceeded those of the surgeon, while 22.5% expected less than their surgeon and 60.7% of THA patients' expectations exceeded those of the surgeon, while 21.4% expected less than their surgeon. THA patients with either lower or higher expectations than their surgeon had lower physical and mental health status scores. TKA patients with lower expectations compared to their surgeon had a higher expectation of complications. CONCLUSIONS: More than 50% of the patients had higher expectations than their surgeon and this was driven by expectations of high-level activities and extreme range of motion. Further investigations are needed to understand these differences so as to enhance patient preoperative education. PMID- 23024620 TI - Defining the origins of the iliofemoral, ischiofemoral, and pubofemoral ligaments of the hip capsuloligamentous complex utilizing computer navigation. AB - PURPOSE: To use computer navigation software to investigate the specific origins of the hip capsuloligamentous complex. METHODS: Six fresh frozen cadaver hips were anatomically landmarked utilizing a three-dimensional computer navigation system. The acetabular origins of the iliofemoral, pubofemoral, and ischiofemoral ligaments were statically digitized. Computer software was used to create a 180 degrees (6:00) meridian line positioned over the midpoint of the acetabular notch, and to present the results in a clocklike manner in hours and minutes (00:00) and also degrees relative to the 12 o'clock position. RESULTS: The iliofemoral ligament origin starts at 17 degrees (+/-31 degrees ) from the 12 o'clock position, or 12:35 (+/-1:02) in hours and minutes, and ends at 69 degrees (+/-13 degrees ) or 2:18 (+/-0:25), spanning a mean distance of 52 degrees (+/ 19 degrees ). The ischiofemoral ligament has the broadest origin, starting at 262 degrees (+/-12 degrees ) or 8:44 (+/-0:24), and ending at 353 degrees (+/-17 degrees ) or 11:45 (+/-0:14), spanning a mean distance of 90 degrees (+/-6 degrees ). The pubofemoral ligament origin is the smallest, starting at 121 degrees (+/-5 degrees ) or 4:02 (+/-0:11), and ending at 163 degrees (+/-9 degrees ) or 5:27 (+/-0:18), spanning a mean distance of 42 degrees (+/-5 degrees ). The iliofemoral ligament origin demonstrates the greatest anatomic variability with regards to its location and its size (p = 0.002). CONCLUSION: This study demonstrates that there is significant variability in the size and location of the iliofemoral ligament origin versus the pubofemoral and ischiofemoral ligaments. LEVEL OF EVIDENCE: Level IV anatomic cadaveric study. See the guidelines online for a complete description of level of evidence. PMID- 23024619 TI - Functional and Emotional Results Differ After Aseptic vs Septic Revision Hip Arthroplasty. AB - BACKGROUND: It is widely believed that a deep implant infection leads to poor functional and emotional outcomes following total hip arthroplasty. QUESTIONS/PURPOSE: The purpose of this retrospective comparative review was to determine if patients who undergo two-stage, septic revision hip arthroplasty will have decreased emotional and general health scores, in addition to decreased function, compared to the aseptic revision group. PATIENTS AND METHODS: One hundred forty-five of 195 patients who underwent aseptic total hip revision for aseptic loosening (mean follow-up = 61 months) and 45 of 73 patients who underwent two-stage, septic revision hip arthroplasty (mean follow-up = 48 months) met the inclusion criteria and had a technically successful outcome. All patients were retrospectively evaluated using Harris Hip Scores (HHS), ad hoc questions, and the SF-36 Health Survey. RESULTS: The average HHS were 73.2 +/- 20.5 (aseptic) and 57.4 +/- 20.6 (septic). Significant differences in the SF-36 Health Survey were found between the two groups in: physical functioning (p = 0.026) and role limitations due to physical health (p = 0.004). No significant difference in SF-36 scores was seen in: Energy/Fatigue, General Health Perception, Personal or Emotional Problems, Role Limitations due to Emotional Well Being, Social Functioning, and Bodily Pain. CONCLUSIONS: Two-stage, septic revision produces a poor functional outcome compared to aseptic revision; however, the overall impact of a septic revision emotionally and socially was not significantly different than patients undergoing aseptic revision. PMID- 23024621 TI - Locking and Non-locking Constructs Achieve Similar Radiographic and Clinical Outcomes for Internal Fixation of Intra-articular Distal Humerus Fractures. AB - BACKGROUND: Locking plates have been used increasingly for the management of distal humerus fractures. Studies that compare patient-centered outcomes between locking and non-locking fixation for distal humerus fractures are lacking. QUESTIONS/PURPOSES: The purposes of this study were to (1) determine whether locking plates offered superior fixation compared with non-locking plates for distal humerus fractures, (2) determine whether the use of locking plates was associated with fewer complications, and (3) determine whether locking plate use resulted in superior radiographic outcome compared with non-locking plates. Lastly, another aim was to determine the average cost difference associated with locking plate use versus non-locking plate use for distal humerus fracture fixation. PATIENTS AND METHOD: Demographic, clinical, and radiographic data including loss of fixation, range of motion, rate of infection, nonunion and reoperation, as well as measures of fixation were collected retrospectively and compared on 96 patients with surgically treated AO type 13C distal humerus fractures (65 locking, 31 non-locking) at 6-week and 6-month follow-up. Average costs of locking and non-locking constructs were calculated and compared. RESULTS: Three in 96 (3.1%) of all cases experienced loss of fixation, with no difference between the two groups. There was no difference between locking and non-locking groups with regard to the rate of nonunion, infection, and reoperation at 6 weeks and 6 months. On average, locking plate constructs were 348% more expensive than non-locking constructs. CONCLUSION: While there are some significant differences in radiographic parameters and cost between locking and non-locking constructs for internal fixation of intra-articular distal humerus fractures, there were no statistically significant differences in clinical outcome. PMID- 23024622 TI - Allograft use in anterior cruciate ligament reconstruction. AB - Anterior cruciate ligament (ACL) reconstruction is one of the most common procedures performed by orthopedic surgeons. While autograft reconstruction remains the gold standard, allograft tissues have become a controversial option for ACL reconstruction. No data currently exist regarding recent trends in graft choices, and no consensus exists over which graft type is most appropriate for which patient. In this article, we examine trends in ACL graft choice at our institution, and review the pertinent information a surgeon must consider when making this decision. We reviewed operating room records from 2002 to 2008 to determine trends in graft choice for primary single bundle ACL reconstruction. Total number of procedures performed, graft choices, and patient ages were recorded. Patients were divided into the following age groups: less than 16, 16 to 20, 21 to 30, 31 to 40, 41 to 50, and over 50. Percent of ACL reconstructions using allograft was calculated for each year, as well as for each age group. Data were analyzed for trends in ACL graft choice over this time period as well as for trends in graft choice by age. We hypothesized that the rate of allograft use in primary ACL reconstruction had increased over time and that allograft use was associated with higher patient age. We also review the risks, safety, and standards for tissue procurement. Allograft use increased significantly (p < 0.001) from 2002 (17%) to 2008 (46%). There was also a significant difference (p < 0.001) in average age of patients receiving allografts (40.4 years) and autografts (26.4 years). Allograft use was significantly associated with higher patient age (p < 0.05) and increased with each successive age group from a rate of 9.9% in patients under 16 to 79.9% in patients over 50. Our study found that allograft use in primary ACL reconstruction has significantly increased from 2002 to 2008 and is significantly more common in older patients. PMID- 23024623 TI - Degenerative scoliosis: a review. AB - Degenerative lumbar scoliosis is a coronal deviation of the spine that is prevalent in the elderly population. Although the etiology is unclear, it is associated with progressive and asymmetric degeneration of the disc, facet joints, and other structural spinal elements typically leading to neural element compression. Clinical presentation varies and is frequently associated with axial back pain and neurogenic claudication. Indications for treatment include pain, neurogenic symptoms, and progressive cosmetic deformity. Non-operative treatment includes physical conditioning and exercise, pharmacological agents for pain control, and use of orthotics and invasive modalities like epidural and facet injections. Operative treatment should be contemplated after multi-factorial and multidisciplinary evaluation of the risks and the benefits. Options include decompression, instrumented stabilization with posterior or anterior fusion, correction of deformity, or a combination of these that are tailored to each patient. Incidence of perioperative complications is substantial and must be considered when deciding appropriate operative treatment. The primary goal of surgical treatment is to provide pain relief and to improve the quality of life with minimum risk of complications. PMID- 23024625 TI - Instability following total knee arthroplasty. AB - Background Knee prosthesis instability (KPI) is a frequent cause of failure of total knee arthroplasty. Moreover, the degree of constraint required to achieve immediate and long-term stability in total knee arthroplasty (TKA) is frequently debated. Questions This review aims to define the problem, analyze risk factors, and review strategies for prevention and treatment of KPI. Methods A PubMed (MEDLINE) search of the years 2000 to 2010 was performed using two key words: TKA and instability. One hundred and sixty-five initial articles were identified. The most important (17) articles as judged by the author were selected for this review. The main criteria for selection were that the articles addressed and provided solutions to the diagnosis and treatment of KPI. Results Patient-related risk factors predisposing to post-operative instability include deformity requiring a large surgical correction and aggressive ligament release, general or regional neuromuscular pathology, and hip or foot deformities. KPI can be prevented in most cases with appropriate selection of implants and good surgical technique. When ligament instability is anticipated post-operatively, the need for implants with a greater degree of constraint should be anticipated. In patients without significant varus or valgus malalignment and without significant flexion contracture, the posterior cruciate ligament (PCL) can be retained. However, the PCL should be sacrificed when deformity exists particularly in patients with rheumatoid arthritis, previous patellectomy, previous high tibial osteotomy or distal femoral osteotomy, and posttraumatic osteoarthritis with disruption of the PCL. In most cases, KPI requires revision surgery. Successful outcomes can only be obtained if the cause of KPI is identified and addressed. Conclusions Instability following TKA is a common cause of the need for revision. Typically, knees with deformity, rheumatoid arthritis, previous patellectomy or high tibial osteotomy, and posttraumatic arthritis carry higher risks of post operative instability and are indications for more constrained TKA designs. Instability following TKA usually requires revision surgery which must address the cause of the instability for success. PMID- 23024624 TI - Cervical radiculopathy: a review. AB - BACKGROUND: Cervical radiculopathy is defined as a syndrome of pain and/or sensorimotor deficits due to compression of a cervical nerve root. Understanding of this disease is vital for rapid diagnosis and treatment of patients with this condition, facilitating their recovery and return to regular activity. PURPOSE: This review is designed to clarify (1) the pathophysiology that leads to nerve root compression; (2) the diagnosis of the disease guided by history, physical exam, imaging, and electrophysiology; and (3) operative and non-operative options for treatment and how these should be applied. METHODS: The PubMed database was searched for relevant articles and these articles were reviewed by independent authors. The conclusions are presented in this manuscript. RESULTS: Facet joint spondylosis and herniation of the intervertebral disc are the most common causes of nerve root compression. The clinical consequence of radiculopathy is arm pain or paresthesias in the dermatomal distribution of the affected nerve and may or may not be associated with neck pain and motor weakness. Patient history and clinical examination are important for diagnosis. Further imaging modalities, such as x-ray, computed tomography, magnetic resonance imaging, and electrophysiologic testing, are of importance. Most patients will significantly improve from non-surgical active and passive therapies. Indicated for surgery are patients with clinically significant motor deficits, debilitating pain that is resistant to conservative modalities and/or time, or instability in the setting of disabling radiculopathy. Surgical treatment options include anterior cervical decompression with fusion and posterior cervical laminoforaminotomy. CONCLUSION: Understanding the pathophysiology, diagnosis, treatment indications, and treatment techniques is essential for rapid diagnosis and care of patients with cervical radiculopathy. PMID- 23024626 TI - Imaging findings of ecthyma gangrenosum, an unusual complication of pseudomonas sepsis. AB - A child with acute lymphoblastic leukemia and pseudomonas sepsis rapidly developed left foot pain and swelling. A diagnosis of ecthyma gangrenosum was made. The clinical and imaging features of this unusual entity are discussed. To our knowledge, this is the first description of the MR imaging findings of ecthyma gangrenosum. PMID- 23024627 TI - Venous thrombosis after arthroscopic shoulder surgery: pacemaker leads as a possible cause: pacemaker leads as a possible cause. AB - Deep venous thrombosis is extremely rare after arthroscopic shoulder surgery. In this report, we describe one such case in a patient with a history of cardiac pacemaker placement. He presented with complaints of pain and swelling in the operated extremity several days after rotator cuff surgery and underwent ultrasound evaluation that confirmed thrombosis of the axillary vein with extension into the brachial and basilic veins, down to the level of the elbow. He was treated with Coumadin, as well as enoxaparin (Lovenox) at therapeutic dosages until INR levels were in the therapeutic range. Follow-up ultrasound at 6 months demonstrated successful recanalization of the affected vessels and no further complications were noted. This is the first report we are aware of that documents axillary vein thrombosis in the setting of arthroscopic shoulder surgery. Though the patient had several risk factors for hypercoagulability, including diabetes and hypertension, we suggest that his cardiac pacemaker leads may have contributed to a thrombogenic environment and cite medical literature that reports an association with thrombosis in the axillary and subclavian veins with pacemakers and defibrillators. PMID- 23024628 TI - Guillain-barre syndrome mimicking nerve injury after total hip arthroplasty. AB - BACKGROUND: Guillain-Barre syndrome (GBS) is a rare, acute, inflammatory demyelinating polyneuropathy with a presentation of progressive ascending motor weakness of the extremities, which may extend to the respiratory muscles and require mechanical support. CASE DESCRIPTION: This case describes a healthy male who developed GBS 1 week following otherwise an uncomplicated bilateral total hip arthroplasty surgery. The diagnosis was made based on physical exam significant for bilateral lower extremity weakness and diffuse arreflexia, and confirmed by nerve conduction studies. There were no effects on respiratory function, and the patient underwent a gradual recovery, with near complete return of motor function by 10 weeks following surgery and no functional deficits at 1 year following surgery. Functional activity levels are maintained 4 years postoperatively. LITERATURE REVIEW: A literature review is presented. While GBS has been described in the literature following several different forms of surgery and anesthesia, cases after orthopedic surgery are exceedingly rare. PURPOSES AND CLINICAL RELEVANCE: This case demonstrates that GBS may occur following orthopedic, including total joint arthroplasty, surgery. The presentation of GBS can be variable, but the hallmarks are areflexia and diffuse ascending weakness, with or without sensory symptoms. Rapid diagnosis and treatment are critical for preventing disability and life-threatening sequelae. PMID- 23024629 TI - Inhibition shapes response selectivity in the inferior colliculus by gain modulation. AB - Pharmacological block of inhibition is often used to determine if inhibition contributes to spike selectivity, in which a preferred stimulus evokes more spikes than a null stimulus. When inhibitory block reduces spike selectivity, a common interpretation is that differences between the preferred- and null-evoked inhibitions created the selectivity from less-selective excitatory inputs. In models based on empirical properties of cells from the inferior colliculus (IC) of awake bats, we show that inhibitory differences are not required. Instead, inhibition can enhance spike selectivity by changing the gain, the ratio of output spikes to input current. Within the model, we made preferred stimuli that evoked more spikes than null stimuli using five distinct synaptic mechanisms. In two cases, synaptic selectivity (the differences between the preferred and null inputs) was entirely excitatory, and in two it was entirely inhibitory. In each case, blocking inhibition eliminated spike selectivity. Thus, observing spike rates following inhibitory block did not distinguish among the cases where synaptic selectivity was entirely excitatory or inhibitory. We then did the same modeling experiment using empirical synaptic conductances derived from responses to preferred and null sounds. In most cases, inhibition in the model enhanced spike selectivity mainly by gain modulation and firing rate reduction. Sometimes, inhibition reduced the null gain to zero, eliminating null-evoked spikes. In some cases, inhibition increased the preferred gain more than the null gain, enhancing the difference between the preferred- and null-evoked spikes. Finally, inhibition kept firing rates low. When selectivity is quantified by the selectivity index (SI, the ratio of the difference to the sum of the spikes evoked by the preferred and null stimuli), inhibitory block reduced the SI by increasing overall firing rates. These results are consistent with inhibition shaping spike selectivity by gain control. PMID- 23024630 TI - ADHD classification by a texture analysis of anatomical brain MRI data. AB - The ADHD-200 Global Competition provides an excellent opportunity for building diagnostic classifiers of Attention-Deficit/Hyperactivity Disorder (ADHD) based on resting-state functional MRI (rs-fMRI) and structural MRI data. Here, we introduce a simple method to classify ADHD based on morphological information without using functional data. Our test results show that the accuracy of this approach is competitive with methods based on rs-fMRI data. We used isotropic local binary patterns on three orthogonal planes (LBP-TOP) to extract features from MR brain images. Subsequently, support vector machines (SVM) were used to develop classification models based on the extracted features. In this study, a total of 436 male subjects (210 with ADHD and 226 controls) were analyzed to show the discriminative power of the method. To analyze the properties of this approach, we tested disparate LBP-TOP features from various parcellations and different image resolutions. Additionally, morphological information using a single brain tissue type (i.e., gray matter (GM), white matter (WM), and CSF) was tested. The highest accuracy we achieved was 0.6995. The LBP-TOP was found to provide better discriminative power using whole-brain data as the input. Datasets with higher resolution can train models with increased accuracy. The information from GM plays a more important role than that of other tissue types. These results and the properties of LBP-TOP suggest that most of the disparate feature distribution comes from different patterns of cortical folding. Using LBP-TOP, we provide an ADHD classification model based only on anatomical information, which is easier to obtain in the clinical environment and which is simpler to preprocess compared with rs-fMRI data. PMID- 23024631 TI - The epistemology of Deep Brain Stimulation and neuronal pathophysiology. AB - Deep Brain Stimulation (DBS) is a remarkable therapy succeeding where all manner of pharmacological manipulations and brain transplants fail. The success of DBS has resurrected the relevance of electrophysiology and dynamics on the order of milliseconds. Despite the remarkable effects of DBS, its mechanisms of action are largely unknown. There has been an expanding catalogue of various neuronal and neural responses to DBS or DBS-like stimulation but no clear conceptual encompassing explanatory scheme has emerged despite the technological prowess and intellectual sophistication of the scientists involved. Something is amiss. If the scientific observations are sound, then why has there not been more progress? The alternative is that it may be the hypotheses that frame the questions are at fault as well as the methods of inference (logic) used to validate the hypotheses. An analysis of the past and current notions of the DBS mechanisms of action is the subject in order to identify the presuppositions (premises) and logical fallacies that may be at fault. The hope is that these problems will be avoided in the future so the DBS can realize its full potential quickly. In this regard, the discussion of the methods of inference and presuppositions that underlie many current notions is no different then a critique of experimental methods common in scientific discussions and consequently, examinations of the epistemology and logic are appropriate. This analysis is in keeping with the growing appreciation among scientists and philosophers of science, the scientific observations (data) to not "speak for themselves" nor is the scientific method self-evidently true and that consideration of the underlying inferential methods is necessary. PMID- 23024632 TI - How anatomy shapes dynamics: a semi-analytical study of the brain at rest by a simple spin model. AB - Resting state networks (RSNs) show a surprisingly coherent and robust spatiotemporal organization. Previous theoretical studies demonstrated that these patterns can be understood as emergent on the basis of the underlying neuroanatomical connectivity skeleton. Integrating the biologically realistic DTI/DSI-(Diffusion Tensor Imaging/Diffusion Spectrum Imaging)based neuroanatomical connectivity into a brain model of Ising spin dynamics, we found a system with multiple attractors, which can be studied analytically. The multistable attractor landscape thus defines a functionally meaningful dynamic repertoire of the brain network that is inherently present in the neuroanatomical connectivity. We demonstrate that the more entropy of attractors exists, the richer is the dynamical repertoire and consequently the brain network displays more capabilities of computation. We hypothesize therefore that human brain connectivity developed a scale free type of architecture in order to be able to store a large number of different and flexibly accessible brain functions. PMID- 23024634 TI - Taking a Radical Position: Evidence for Position-Specific Radical Representations in Chinese Character Recognition Using Masked Priming ERP. AB - In the investigation of orthographic representation of Chinese characters, one question that has stimulated much research is whether radicals (character components) are specified for spatial position in a character (e.g., Ding et al., 2004; Tsang and Chen, 2009). Differing from previous work, component or radical position information in this study is conceived in terms of relative frequency across different positions of characters containing it. A lexical decision task in a masked priming paradigm focusing on radicals with preferred position of occurrence was conducted. A radical position that encompasses more characters than other positions was identified to be the preferred position of a particular radical. The prime that was exposed for 96 ms might share a radical with the target in the same or different positions. Moreover, the shared radical appeared either in its preferred or non-preferred position in the target. While response latencies only revealed the effect of graphical similarity, both effects of graphical similarity and radical position preference were found in the event related potential (ERP) results. The former effect was reflected in greater positivity in occipital P1 and greater negativity in N400 for radicals in different positions in prime and target characters. The latter effect manifested as greater negativity in occipital N170 and greater positivity in frontal P200 in the same time window elicited by radicals in their non-preferred position. Equally interesting was the reversal of the effect of radical position preference in N400 with greater negativity associated with radicals in preferred position. These findings identify the early ERP components associated with activation of position-specific radical representations in the orthographic lexicon, and reveal the change in the nature of competition from processing at the radical level to the lexical level. PMID- 23024633 TI - PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis. AB - Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil, or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects, and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF. PMID- 23024635 TI - An emerging role for adenosine and its receptors in bone homeostasis. AB - Bone is continually being remodeled and defects in the processes involved lead to bone diseases. Many regulatory factors are known to influence remodeling but other mechanisms, hitherto unknown, may also be involved. Importantly, our understanding of these currently unknown mechanisms may lead to important new therapies for bone disease. It is accepted that purinergic signaling is involved in bone, and our knowledge of this area has increased significantly over the last 15 years, although most of the published work has studied the role of ATP and other signaling molecules via the P2 family of purinergic receptors. During the last few years, however, there has been increased interest within the bone field in the role of P1 receptors where adenosine is the primary signaling molecule. This review will bring together the current information available in relation to this expanding area of research. PMID- 23024636 TI - Comparison of sepsis-induced transcriptomic changes in a murine model to clinical blood samples identifies common response patterns. AB - Experimental models, mimicking physiology, and molecular dynamics of diseases in human, harbor the possibility to study the effect of interventions and transfer results from bench to bedside. Recent advances in high-throughput technologies, standardized protocols, and integration of knowledge from databases yielded rising consistency and usability of results for inter-species comparisons. Here, we explored similarities and dissimilarities in gene expression from blood samples of a murine sepsis model (peritoneal contamination and infection, PCI) and patients from the pediatric intensive care unit (PICU) measured by microarrays. Applying a consistent pre-processing and analysis workflow, differentially expressed genes (DEG) from PCI and PICU data significantly overlapped. A major fraction of DEG was commonly expressed and mapped to adaptive and innate immune response related pathways, whereas the minor fraction, including the chemokine (C-C motif) ligand 4, exhibited constant inter-species disparities. Reproducibility of transcriptomic observations was validated experimentally in PCI. These data underline, that inter-species comparison can obtain commonly expressed transcriptomic features despite missing homologs and different protocols. Our findings point toward a high suitability of an animal sepsis model and further experimental efforts in order to transfer results from animal experiments to the bedside. PMID- 23024639 TI - Receptor usage and the pathogenesis in acute and chronic virus infections. PMID- 23024637 TI - Prochlorococcus and Synechococcus have Evolved Different Adaptive Mechanisms to Cope with Light and UV Stress. AB - Prochlorococcus and Synechococcus, which numerically dominate vast oceanic areas, are the two most abundant oxygenic phototrophs on Earth. Although they require solar energy for photosynthesis, excess light and associated high UV radiations can induce high levels of oxidative stress that may have deleterious effects on their growth and productivity. Here, we compared the photophysiologies of the model strains Prochlorococcus marinus PCC 9511 and Synechococcus sp. WH7803 grown under a bell-shaped light/dark cycle of high visible light supplemented or not with UV. Prochlorococcus exhibited a higher sensitivity to photoinactivation than Synechococcus under both conditions, as shown by a larger drop of photosystem II (PSII) quantum yield at noon and different diel patterns of the D1 protein pool. In the presence of UV, the PSII repair rate was significantly depressed at noon in Prochlorococcus compared to Synechococcus. Additionally, Prochlorococcus was more sensitive than Synechococcus to oxidative stress, as shown by the different degrees of PSII photoinactivation after addition of hydrogen peroxide. A transcriptional analysis also revealed dramatic discrepancies between the two organisms in the diel expression patterns of several genes involved notably in the biosynthesis and/or repair of photosystems, light-harvesting complexes, CO(2) fixation as well as protection mechanisms against light, UV, and oxidative stress, which likely translate profound differences in their light-controlled regulation. Altogether our results suggest that while Synechococcus has developed efficient ways to cope with light and UV stress, Prochlorococcus cells seemingly survive stressful hours of the day by launching a minimal set of protection mechanisms and by temporarily bringing down several key metabolic processes. This study provides unprecedented insights into understanding the distinct depth distributions and dynamics of these two picocyanobacteria in the field. PMID- 23024638 TI - It only takes one to do many jobs: Amphotericin B as antifungal and immunomodulatory drug. AB - "Amphotericin B acts through pore formation at the cell membrane after binding to ergosterol" is an accepted dogma about the action mechanism of this antifungal, and this sentence is widely found in the literature. But after 60 years of investigation, the action mechanism of Amphotericin B is not fully elucidated. Amphotericin B is a polyene substance that is one of the most effective drugs for the treatment of fungal and parasite infections. As stated above, the first mechanism of action described was pore formation after binding to the ergosterol present in the membrane. But it has also been demonstrated that AmB induces oxidative damage in the cells. Moreover, amphotericin B modulates the immune system, and this activity has been related to the protective effect of the molecule, but also to its toxicity in the host. This review tries to provide a general overview of the main aspects of this molecule, and highlight the multiple effects that this molecule has on both the fungal and host cells. PMID- 23024640 TI - Protective Effector Cells of the Recombinant Asp f3 Anti-Aspergillosis Vaccine. AB - An Aspergillus fumigatus vaccine based on recombinant Asp f3-protein has the potential to prevent aspergillosis in humans, a devastating fungal disease that is the prime obstacle to the success of hematopoietic cell transplantation. This vaccine protects cortisone acetate (CA)-immunosuppressed mice from invasive pulmonary aspergillosis via CD4(+) T cell mediators. Aside from these mediators, the nature of downstream fungicidal effectors is not well understood. Neutrophils and macrophages protect immunocompetent individuals from invasive fungal infections, and selective neutrophil depletion rendered mice susceptible to aspergillosis whereas macrophage depletion failed to increase fungal susceptibility. We investigated the effect of neutrophil depletion on rAsp f3 vaccine protection, and explored differences in pathophysiology and susceptibility between CA-immunosuppression and neutrophil depletion. In addition to being protective under CA-immunosuppression, the vaccine also had a protective effect in neutrophil-depleted mice. However, in non-immunized mice, a 10-fold higher conidial dose was required to induce similar susceptibility to infection with neutrophil depletion than with CA-immunosuppression. The lungs of non immunized neutrophil-depleted mice became invaded by a patchy dense mycelium with highly branched hyphae, and the peribronchial inflammatory infiltrate consisted mainly of CD3(+) T cells and largely lacked macrophages. In contrast, lungs of non-immunized CA-immunosuppressed mice were more evenly scattered with short hyphal elements. With rAsp f3-vaccination, the lungs were largely clear of fungal burden under either immunosuppressive condition. We conclude that neutrophils, although important for innate antifungal protection of immunocompetent hosts, are not the relevant effectors for rAsp f3-vaccine derived protection of immunosuppressed hosts. It is therefore more likely that macrophages represent the crucial effectors of the rAsp f3-based vaccine. PMID- 23024641 TI - Activity based protein profiling to detect serine hydrolase alterations in virus infected cells. AB - Activity-based protein profiling (ABPP) is a newly emerging technique that uses active site-directed probes to monitor the functional status of enzymes. Serine hydrolases are one of the largest families of enzymes in mammals. More than 200 serine hydrolases have been identified, but little is known about their specific roles. Serine hydrolases are involved in a variety of physiological functions, including digestion, immune response, blood coagulation, and reproduction. ABPP has been used recently to investigate host-virus interactions and to understand the molecular pathogenesis of virus infections. Monitoring the altered serine hydrolases during viral infection gives insight into the catalytic activity of these enzymes that will help to identify novel targets for diagnostic and therapeutic application. This review presents the usefulness of ABPP in detecting and analyzing functional annotation of host cell serine hydrolases as a result of host-virus interaction. PMID- 23024642 TI - Non-Biased Enrichment Does Not Improve Quantitative Proteomic Delineation of Reovirus T3D-Infected HeLa Cell Protein Alterations. AB - Mass spectrometry-based methods have allowed elucidation of alterations in complex proteomes, such as eukaryotic cells. Such studies have identified and measured relative abundances of thousands of host proteins after cells are infected with a virus. One of the potential limitations in such studies is that generally only the most abundant proteins are identified, leaving the deep richness of the cellular proteome largely unexplored. We differentially labeled HeLa cells with light and heavy stable isotopic forms of lysine and arginine and infected cells with reovirus strain T3D. Cells were harvested at 24 h post infection. Heavy-labeled infected and light-labeled mock-infected cells were mixed together 1:1. Cells were then divided into cytosol and nuclear fractions and each fraction analyzed, both by standard 2D-HPLC/MS, and also after each fraction had been reacted with a random hexapeptide library (Proteominer((r)) beads) to attempt to enrich for low-abundance cellular proteins. A total of 2,736 proteins were identified by two or more peptides at >99% confidence, of which 66 were significantly up-regulated and 67 were significantly down-regulated. Up regulated proteins included those involved in antimicrobial and antiviral responses, GTPase activity, nucleotide binding, interferon signaling, and enzymes associated with energy generation. Down-regulated proteins included those involved in cell and biological adhesion, regulation of cell proliferation, structural molecule activity, and numerous molecular binding activities. Comparisons of the r(2) correlations, degree of dataset overlap, and numbers of peptides detected suggest that non-biased enrichment approaches may not provide additional data to allow deeper quantitative and comparative mining of complex proteomes. PMID- 23024643 TI - Somatic Populations of PGT135-137 HIV-1-Neutralizing Antibodies Identified by 454 Pyrosequencing and Bioinformatics. AB - Select HIV-1-infected individuals develop sera capable of neutralizing diverse viral strains. The molecular basis of this neutralization is currently being deciphered by the isolation of HIV-1-neutralizing antibodies. In one infected donor, three neutralizing antibodies, PGT135-137, were identified by assessment of neutralization from individually sorted B cells and found to recognize an epitope containing an N-linked glycan at residue 332 on HIV-1 gp120. Here we use next-generation sequencing and bioinformatics methods to interrogate the B cell record of this donor to gain a more complete understanding of the humoral immune response. PGT135-137-gene family specific primers were used to amplify heavy chain and light-chain variable-domain sequences. Pyrosequencing produced 141,298 heavy-chain sequences of IGHV4-39 origin and 87,229 light-chain sequences of IGKV3-15 origin. A number of heavy and light-chain sequences of ~90% identity to PGT137, several to PGT136, and none of high identity to PGT135 were identified. After expansion of these sequences to include close phylogenetic relatives, a total of 202 heavy-chain sequences and 72 light-chain sequences were identified. These sequences were clustered into populations of 95% identity comprising 15 for heavy chain and 10 for light chain, and a select sequence from each population was synthesized and reconstituted with a PGT137-partner chain. Reconstituted antibodies showed varied neutralization phenotypes for HIV-1 clade A and D isolates. Sequence diversity of the antibody population represented by these tested sequences was notably higher than observed with a 454 pyrosequencing control analysis on 10 antibodies of defined sequence, suggesting that this diversity results primarily from somatic maturation. Our results thus provide an example of how pathogens like HIV-1 are opposed by a varied humoral immune response, derived from intrinsic mechanisms of antibody development, and embodied by somatic populations of diverse antibodies. PMID- 23024644 TI - Lactococcal 936-type phages and dairy fermentation problems: from detection to evolution and prevention. AB - The so-called 936-type phages are the most frequently encountered lactococcal phage species in dairy fermentations, where they cause slow or even failed fermentations with concomitant economic losses. Several dairy phage population studies, performed in different geographical locations, have detailed their dominance in dairy phage populations, while various phage-resistance mechanisms have been assessed in a bid to protect against this virulent phage group. The impact of thermal and chemical treatments on 936 phages is an important aspect for dairy technologists and has been assessed in several studies, and has indicated that these phages have adapted to better resist such treatments. The abundance of 936 phage genome sequences has permitted a focused view on genomic content and regions of variation, and the role of such variable regions in the evolution of these phages. Here, we present an overview on detection and global prevalence of the 936 phages, together with their tolerance to industrial treatments and anti-phage strategies. Furthermore, we present a comprehensive review on the comparative genomic analyses of members of this fascinating phage species. PMID- 23024645 TI - Grappling with Proteus: population level approaches to understanding microbial diversity. AB - The emerging fields of microbial population genetics and genomics provide an avenue to study the ecological rules that govern how communities form, function, and evolve. Our struggle to understand the causes and consequences of microbial diversity stems from our inability to define ecologically and evolutionarily meaningful units of diversity. The 16S rRNA-based tools that have been so useful in charting microbial diversity may lack sufficient sensitivity to answer many questions about the ecology and evolution of microbes. Examining genetic diversity with increased resolution is vital to understanding the forces shaping community structure. Population genetic analyses enabled by whole genome sequencing, multilocus sequence analyses, or single-nucleotide polymorphism analyses permit the testing of hypotheses pertaining to the geographic distribution, migration, and habitat preference of specific microbial lineages. Furthermore, these approaches can reveal patterns of gene exchange within and between populations and communities. Tools from microbial population genetics and population genomics can be used to increase the resolution with which we measure microbial diversity, enabling a focus on the scale of genetic diversity at which ecological processes impact evolutionary events. This tighter focus promises to improve our understanding of the causes and consequences of microbial community structure. PMID- 23024646 TI - NLRP3-Inflammasome Activating DAMPs Stimulate an Inflammatory Response in Glia in the Absence of Priming Which Contributes to Brain Inflammation after Injury. AB - Inflammation in the absence of infection (sterile inflammation) contributes to acute injury and chronic disease. Cerebral ischemia is a devastating condition in which the primary injury is caused by reduced blood supply and is therefore sterile. The cytokine interleukin-1beta (IL-1beta) is a key contributor to ischemic brain injury and central inflammatory responses. The release of IL-1beta is regulated by the protease caspase-1, and its activating complex, the inflammasome. Of the known inflammasomes the best characterized, and one that is perceived to sense sterile injury is formed by a pattern recognition receptor called NOD-like receptor pyrin domain containing three (NLRP3). A key feature of NLRP3-inflammasome dependent responses in vitro in macrophages is the requirement of an initial priming stimulus by a pathogen (PAMP), or damage associated molecular pattern (DAMP) respectively. We sought to determine the inflammatory responses of NLRP3-activating DAMPs on brain derived mixed glial cells in the absence of an initial priming stimulus in vitro. In cultured mouse mixed glia the DAMPs ATP, monosodium urate, and calcium pyrophosphate dehydrate crystals had no effect on the expression of IL-1alpha or IL-1beta and induced release only when the cells were primed with a PAMP. In the absence of priming, these DAMPs did however induce inflammation via the production of IL-6 and CXCL1, and the release of the lysosomal protease cathepsin B. Furthermore, the acute phase protein serum amyloid A (SAA) acted as a priming stimulus on glial cells resulting in levels of IL-1 expression comparable to those induced by the PAMP lipopolysaccharide. In vivo, after cerebral ischemia, IL-1 production contributed to increased IL-6 and CXCL1 since these cytokines were profoundly reduced in the ischemic hemispheres from IL-1alpha/beta double KO mice, although injury-induced cytokine responses were not abolished. Thus, DAMPs augment brain inflammation by directly stimulating production of glial derived inflammatory mediators. This is markedly enhanced by DAMP-induced IL-1-release-dependent responses that require a sterile endogenous priming stimulus such as SAA. PMID- 23024647 TI - This I believe: gaining new insights through integrating "old" data. PMID- 23024648 TI - Dynamic alterations in the paternal epigenetic landscape following fertilization. AB - Embryonic development is a complex and dynamic process with frequent changes in gene expression, ultimately leading to cellular differentiation and commitment of various cell lines. These changes are likely preceded by changes to signaling cascades and/or alterations to the epigenetic program in specific cells. The process of epigenetic remodeling begins early in development. In fact, soon after the union of sperm and egg massive epigenetic changes occur across the paternal and maternal epigenetic landscape. The epigenome of these cells includes modifications to the DNA itself, in the form of DNA methylation, as well as nuclear protein content and modification, such as modifications to histones. Sperm chromatin is predominantly packaged by protamines, but following fertilization the sperm pronucleus undergoes remodeling in which maternally derived histones replace protamines, resulting in the relaxation of chromatin and ultimately decondensation of the paternal pronucleus. In addition, active DNA demethylation occurs across the paternal genome prior to the first cell division, effectively erasing many spermatogenesis derived methylation marks. This complex interplay begins the dynamic process by which two haploid cells unite to form a diploid organism. The biology of these events is central to the understanding of sexual reproduction, yet our knowledge regarding the mechanisms involved is extremely limited. This review will explore what is known regarding the post fertilization epigenetic alterations of the paternal chromatin and the implications suggested by the available literature. PMID- 23024651 TI - Evaluation of endoscopic ultrasound image quality is necessary in endosonographic assessment of early gastric cancer invasion depth. AB - We evaluated whether endoscopic ultrasonography (EUS) image quality affects the accuracy of diagnosing the vertical invasion depth of early gastric cancer (EGC). A total of 75 lesions in 75 patients suspected of having EGC were enrolled. All patients underwent EUS examination. Findings of EUS were compared with histopathologic results. We evaluated the effect of the following clinicopathologic factors: location, diameter, surface pattern, concomitant ulceration, histology type, and EUS image quality score. EUS image quality was scored based on detection repeatability, appropriate probe placement, and clarity of the five gastric wall layers including the lesion. Sixty-three lesions (84%) were pathologically mucosal and 12 lesions (16%) were submucosal cancer. Overall accuracy was 82.7%. Significantly more lesions in the upper and middle portions of the stomach were incorrectly diagnosed than in the lower portion (P = 0.0019). Lesion diameter was significantly larger among incorrectly diagnosed lesions (P = 0.0257). Low-quality images were significantly more often associated with incorrectly diagnosed lesions than with correctly diagnosed lesions (P = 0.0001). Multivariate analysis revealed that EUS image quality was associated with EUS staging accuracy (odds ratio, 21.8; 95% confidence interval, 4.5-137.6). Low quality EUS images led to an incorrect diagnosis of invasion depth of EGC, independent of tumor location or size. PMID- 23024649 TI - PPARs in Liver Diseases and Cancer: Epigenetic Regulation by MicroRNAs. AB - Peroxisome-proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that exert in the liver a transcriptional activity regulating a whole spectrum of physiological functions, including cholesterol and bile acid homeostasis, lipid/glucose metabolism, inflammatory responses, regenerative mechanisms, and cell differentiation/proliferation. Dysregulations of the expression, or activity, of specific PPAR isoforms in the liver are therefore believed to represent critical mechanisms contributing to the development of hepatic metabolic diseases, disorders induced by hepatic viral infections, and hepatocellular adenoma and carcinoma. In this regard, specific PPAR agonists have proven to be useful to treat these metabolic diseases, but for cancer therapies, the use of PPAR agonists is still debated. Interestingly, in addition to previously described mechanisms regulating PPARs expression and activity, microRNAs are emerging as new important regulators of PPAR expression and activity in pathophysiological conditions and therefore may represent future therapeutic targets to treat hepatic metabolic disorders and cancers. Here, we reviewed the current knowledge about the general roles of the different PPAR isoforms in common chronic metabolic and infectious liver diseases, as well as in the development of hepatic cancers. Recent works highlighting the regulation of PPARs by microRNAs in both physiological and pathological situations with a focus on the liver are also discussed. PMID- 23024650 TI - The role of peroxisome proliferator-activated receptors in colorectal cancer. AB - Colorectal cancer is one of the most common cancers in the world. Dietary fat intake is a major risk factor for colorectal cancer. Some nuclear hormone receptors play an important role in regulating nutrient metabolism and energy homeostasis. Among these receptors, special attention has been focused on the role of peroxisome proliferator-activated receptors (PPARs) in colorectal cancer, because PPARs are involved in regulation of lipid and carbohydrate metabolism. PPARs are ligand-activated intracellular transcription factors. The PPAR subfamily consists of three subtypes encoded by distinct genes named PPARalpha, PPARbeta/delta, and PPARgamma. PPARgamma is the most extensively studied subtype of PPARs. Even though many investigators have studied the expression and clinical implications of PPARs in colorectal cancer, there are still many controversies about the role of PPARs in colorectal cancer. In this paper, the recent progresses in understanding the role of PPARs in colorectal cancer are summarized. PMID- 23024652 TI - Ophthalmic parasitosis: a review article. AB - Ocular parasitosis in human is more prevalent in geographical areas where environmental factors and poor sanitary conditions favor the parasitism between man and animals. Lesions in the eye can be due to damage directly caused by the infectious pathogen, indirect pathology caused by toxic products, or the immune response incited by infections or ectopic parasitism. The epidemiology of parasitic ocular diseases reflects the habitat of the causative parasites as well as the habits and health status of the patient. An ocular examination may provide clues to the underlying disease/infection, and an awareness of the possibilities of travel-related pathology may shed light on an ocular presentation. This paper is a comprehensive review of the parasitic diseases of the eye. The majority of the clinically important species of parasites involved in eye infection are reviewed in this paper. Parasites are discussed by the disease or infection they cause. PMID- 23024653 TI - Hand Hygiene Practices among Medical Students. AB - Background. Hand hygiene is a cost-effective method in preventing infection transmission. Hand hygiene practices have been found to be faulty in most healthcare settings. We conducted a study to evaluate the awareness, and compliance of hand hygiene among undergraduate medical students during their clinical phase in Qassim College of Medicine, Saudi Arabia. Methods. A questionnaire based on World Health Organization's concept of "Five Moments for Hand Hygiene" was used to evaluate the awareness of the indications for hand hygiene and compliance was observed during Objective Structured Clinical Examination (OSCE) sessions. Sixty students including thirty-six males (60%) and twenty-four females (40%) participated voluntarily in the study. Results. The average awareness regarding the positive indications of hand hygiene was 56%. Rest of the 44% of students were either not sure or unaware of the indications of hygiene. Only 29% of students were able to identify all the five indications for hand hygiene in the questionnaire. Compliance as assessed during OSCE sessions was only 17% with no significant difference between the genders. Conclusion. It was concluded that serious efforts are needed to improve the hand hygiene practices among medical students. PMID- 23024655 TI - Nanoconjugate Platforms Development Based in Poly(beta,L-Malic Acid) Methyl Esters for Tumor Drug Delivery. AB - New copolyesters derived from poly(beta,L-malic acid) have been designed to serve as nanoconjugate platforms in drug delivery. 25% and 50% methylated derivatives (coPMLA-Me(25)H(75) and coPMLA-Me(50)H(50)) with absolute molecular weights of 32 600 Da and 33 100 Da, hydrodynamic diameters of 3.0 nm and 5.2 nm and zeta potential of -15mV and -8.25mV, respectively, were found to destabilize membranes of liposomes at pH 5.0 and pH 7.5 at concentrations above 0.05mg/mL. The copolymers were soluble in PBS (half life of 40 hours) and in human plasma (half life of 15 hours) but they showed tendency to aggregate at high levels of methylation. Fluorescence-labeled copolymers were internalized into MDA-MB-231 breast cancer cells with increased efficiency for the higher methylated copolymer. Viability of cultured brain and breast cancer cell lines indicated moderate toxicity that increased with methylation. The conclusion of the present work is that partially methylated poly(beta,L-malic acid) copolyesters are suitable as nanoconjugate platforms for drug delivery. PMID- 23024654 TI - Merkel cell carcinoma: a retrospective study on 48 cases and review of literature. AB - Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Fourty-eight patients with MCC were observed at the Rare Hormonal Tumors Group of Cremona Hospital, 15 of these with unknown primary site. Due to rarity of Merkel cell carcinoma, clinical experience is generally limited. Data from our series confirm the current recommendations. Wide surgical excision must be associated with radiotherapy also in early stages in order to avoid local relapse and the rapid progression of disease. In advanced stages chemotherapy is the standard despite the short duration of responses and poor quality of life. The data of our series, characterized by a high demand for second opinion, offer some insight about the real rarity of the tumor, the difficulty of managing of disease in our country secondary to a wrong cultural approach to the problem, the indiscriminate use of molecules unnecessary and often expensive, the lack of protocols, and the presence of guidelines often ignored. This results in very poor survival associated with a very low quality of life, requiring to find the right direction towards a correct management of disease. PMID- 23024656 TI - Midventricular Obstructive Hypertrophic Cardiomyopathy during Pregnancy Complicated by Pulmonary Embolism: A Case Report. AB - Hypertrophic cardiomyopathy (HCM) with midventricular obstruction (MVO) is a rare condition occurring in 1% of HCM patients. It is characterized by asymmetric left ventricular hypertrophy with MVO and elevated intraventricular pressure gradients. Pulmonary embolism has been associated with mid-ventricular obstructive HCM. Briefly, this case presents an unusual clinical scenario where a young pregnant woman suffering from hypertrophic obstructive cardiomyopathy presents with dyspnea hemodynamic compromise related to pulmonary embolism illustrating hemodynamic challenges created by pregnancy and surgery. We concluded that simple measures such as communication between the cardiology and obstetric teams, understanding of the hemodynamic changes, anesthetic planning, and monitoring were paramount for the success in our patient. PMID- 23024657 TI - Recurrent meningeal hemangiopericytoma with multiple metastasis and hypoglycemia: a case report. AB - Aims. We report on the unusual case of a 43-year-old man who developed recurrent meningeal hemangiopericytoma and presented with hypoglycemia 6 years after excision of the tumor. Methods and Results. We utilized computed tomography to assure multiple tumor metastasis and cranial recurrence of previous meningeal hemangiopericytoma and clinical laboratory tests and immunohistochemical staining to characterize this case. Magnetic resonance imaging and computed tomography showed the recurrent tumor at original torcular site was increased in size. Abnormal low levels of growth hormone, insulin, and insulin-like growth factor-I except insulin-like growth factor-II were detected in the serum. By immunohistochemistry, the neoplastic cells characteristically express diffusely CD99, bcl2, and variable CD34. After radio- and chemotherapy, serum glucose level of the patient returned to normal. Conclusions. Comparing other brain tumors, meningeal hemangiopericytoma has a higher recurrent and metastatic rate, but this tumor with hypoglycemia is very rare. PMID- 23024658 TI - The Flatworm Macrostomum lignano Is a Powerful Model Organism for Ion Channel and Stem Cell Research. AB - Bioelectrical signals generated by ion channels play crucial roles in many cellular processes in both excitable and nonexcitable cells. Some ion channels are directly implemented in chemical signaling pathways, the others are involved in regulation of cytoplasmic or vesicular ion concentrations, pH, cell volume, and membrane potentials. Together with ion transporters and gap junction complexes, ion channels form steady-state voltage gradients across the cell membranes in nonexcitable cells. These membrane potentials are involved in regulation of such processes as migration guidance, cell proliferation, and body axis patterning during development and regeneration. While the importance of membrane potential in stem cell maintenance, proliferation, and differentiation is evident, the mechanisms of this bioelectric control of stem cell activity are still not well understood, and the role of specific ion channels in these processes remains unclear. Here we introduce the flatworm Macrostomum lignano as a versatile model organism for addressing these topics. We discuss biological and experimental properties of M. lignano, provide an overview of the recently developed experimental tools for this animal model, and demonstrate how manipulation of membrane potential influences regeneration in M. lignano. PMID- 23024659 TI - Clonal populations of amniotic cells by dilution and direct plating: evidence for hidden diversity. AB - Fetal cells are widely considered a superior cell source for regenerative medicine; fetal cells show higher proliferative capacity and have undergone fewer replicative cycles that could generate spontaneous mutations. Fetal cells in amniotic fluid were among the first normal primary cells to be cultured ex vivo, but the undefined composition of amniotic fluid has hindered advance for regenerative applications. We first developed a highly efficient method to generate clonal populations by dilution of amniocentesis samples in media and direct plating without intervening refrigeration, centrifugation, or exposure of cells to the paracrine effects in mixed cell cultures. More than 40 clonal populations were recovered from 4 amniocentesis samples and representative clones were characterized by flow cytometry, conventional assays for differentiation potential, immunofluorescence imaging, and transcript analysis. The results revealed previously unreported diversity among stromal and epithelial cell types and identified unique cell types that could be lost or undetected in mixed cell populations. The differentiation potential of amniotic cells proved to be uncoupled from expression of definitive cell surface or cytoplasmic markers for stromal and epithelial cells. Evidence for diversity among stromal and epithelial cells in amniotic fluid bears on interpretations applied to molecular and functional tests of amniotic cell populations. PMID- 23024660 TI - Bioelectric state and cell cycle control of Mammalian neural stem cells. AB - The concerted action of ion channels and pumps establishing a resting membrane potential has been most thoroughly studied in the context of excitable cells, most notably neurons, but emerging evidences indicate that they are also involved in controlling proliferation and differentiation of nonexcitable somatic stem cells. The importance of understanding stem cell contribution to tissue formation during embryonic development, adult homeostasis, and regeneration in disease has prompted many groups to study and manipulate the membrane potential of stem cells in a variety of systems. In this paper we aimed at summarizing the current knowledge on the role of ion channels and pumps in the context of mammalian corticogenesis with particular emphasis on their contribution to the switch of neural stem cells from proliferation to differentiation and generation of more committed progenitors and neurons, whose lineage during brain development has been recently elucidated. PMID- 23024661 TI - American visceral leishmaniasis: factors associated with lethality in the state of sao paulo, Brazil. AB - Objectives. To identify factors associated with death in visceral leishmaniasis (VL) cases. Patients and Methodology. We evaluated prognostic factors for death from VL in Sao Paulo state, Brazil, from 1999 to 2005. A prognostic study nested in a clinical cohort was carried out by data analysis of 376 medical files. A comparison between VL fatal cases and survivors was performed for clinical, laboratory, and biological features. Association between variables and death was assessed by univariate analysis, and the multiple logistic regression model was used to determine adjusted odds ratio for death, controlling confounding factors. Results. Data analysis identified 53 fatal cases out of 376 patients, between 1999 and 2005 in Sao Paulo state. Lethality was 14.1% (53/376), being higher in patients older than fifty years. The main causes of death were sepsis, bleeding, liver failure, and cardiotoxicity due to treatment. Variables significantly associated with death were severe anemia, bleeding, heart failure, jaundice, diarrhea, fever for more than sixty days, age older than fifty years, and antibiotic use. Conclusion. Educational health measures are needed for the general population and continuing education programs for health professionals working in the affected areas with the purpose of identifying and treating early cases, thus preventing the disease evolution towards death. PMID- 23024663 TI - From "madness" to "mental health problems": reflections on the evolving target of psychiatry. PMID- 23024662 TI - Airway smooth muscle as a target in asthma and the beneficial effects of bronchial thermoplasty. AB - Airflow within the airways is determined directly by the lumenal area of that airway. In this paper, we consider several factors which can reduce airway lumenal area, including thickening and/or active constriction of the airway smooth muscle (ASM). The latter cell type can also contribute in part to inflammation, another feature of asthma, through its ability to take on a synthetic/secretory phenotype. The ASM therefore becomes a strategically important target in the treatment of asthma, given these key contributions to the pathophysiology of that disease. Pharmacological approaches have been developed to elicit relaxation of the ASM, but these are not always effective in all patients, nor do they address the long-term structural changes which impinge on the airway lumen. The recent discovery that thermal energy can be used to ablate smooth muscle has led to the development of a novel physical intervention bronchial thermoplasty-in the treatment of asthma. Here, we review the evolution of this novel approach, consider some of the possible mechanisms that account for its salutary effects, and pose new questions which may lead to even better therapies for asthma. PMID- 23024664 TI - Actions to alleviate the mental health impact of the economic crisis. AB - The current global economic crisis is expected to produce adverse mental health effects that may increase suicide and alcohol-related death rates in affected countries. In nations with greater social safety nets, the health impacts of the economic downturn may be less pronounced. Research indicates that the mental health impact of the economic crisis can be offset by various policy measures. This paper aims to outline how countries can safeguard and support mental health in times of economic downturn. It indicates that good mental health cannot be achieved by the health sector alone. The determinants of mental health often lie outside of the remits of the health system, and all sectors of society have to be involved in the promotion of mental health. Accessible and responsive primary care services support people at risk and can prevent mental health consequences. Any austerity measures imposed on mental health services need to be geared to support the modernization of mental health care provision. Social welfare supports and active labour market programmes aiming at helping people retain or re-gain jobs can counteract the mental health effects of the economic crisis. Family support programmes can also make a difference. Alcohol pricing and restrictions of alcohol availability reduce alcohol harms and save lives. Support to tackle unmanageable debt will also help to reduce the mental health impact of the crisis. While the current economic crisis may have a major impact on mental health and increase mortality due to suicides and alcohol-related disorders, it is also a window of opportunity to reform mental health care and promote a mentally healthy lifestyle. PMID- 23024666 TI - Investigating schizophrenia in a "dish": possibilities, potential and limitations. PMID- 23024665 TI - Differential diagnosis of bipolar disorder in children and adolescents. AB - Issues complicating the differential diagnosis of bipolar disorder in young people are discussed. They include: a) the subtype of bipolar disorder being considered; b) the person's age and stage of development; c) whether one views bipolar disorder more conservatively, requiring clear episodes that mark a distinct change from premorbid levels of function, or more liberally, focusing for instance on severe irritability/explosive outbursts as the mood change; d) who is reporting manic symptoms, and whether symptoms are past and must be recalled or current and more likely to be observed; e) impact of family history. The diagnosis of mania/bipolar I disorder may not become clear for a number of years. This is an impairing disorder, but so are the conditions from which it must be distinguished. Family history may increase the odds that certain symptoms/behaviors are manifestations of bipolar disorder but it does not make the diagnosis. Until there are biomarkers that can confirm the diagnosis, and treatments unique to the condition, it is wise to make a diagnosis of bipolar disorder in children and adolescents provisionally and keep an open mind to the likelihood that revisions may be necessary. PMID- 23024667 TI - Issues and developments on the consumer recovery construct. AB - The consumer recovery model has had increasing influence on mental health practices in the United States, Western Europe, and several other countries. However, adoption of the model has reflected political decisions rather than empirical evidence of the validity of the model or its value for treatment services. The recovery construct is poorly defined, and until recently there has been no reliable and valid measure with which to base a research program. We have developed an empirical measure that is well-suited for both research and clinical applications: the Maryland Assessment of Recovery in Serious Mental Ill-ness (MARS). We briefly describe the MARS and present preliminary data demonstrating that recovery is not a simple by-product of traditional outcome do-mains, but seems to be a distinct construct that may have important implications for understanding consumers with serious mental illness and for evaluating the outcome of treatment programs. PMID- 23024668 TI - Recovery from schizophrenia: form follows functioning. PMID- 23024669 TI - Recovery research: the empirical evidence from England. PMID- 23024670 TI - A stigma perspective on recovery. PMID- 23024671 TI - Agency: its nature and role in recovery from severe mental illness. PMID- 23024672 TI - Consumer models of recovery: can they survive operationalism? PMID- 23024673 TI - Recovery: is consensus possible? PMID- 23024674 TI - The vicissitudes of the recovery construct; or, the challenge of taking "subjective experience" seriously. PMID- 23024675 TI - Consumer perceptions of recovery: an Indian perspective. PMID- 23024676 TI - Consumer recovery: a call for partnership between researchers and consumers. PMID- 23024677 TI - An empirically derived approach to the classification and diagnosis of mood disorders. AB - This article describes a system for diagnosing mood disorders that is empirically derived and designed for its clinical utility in everyday practice. A random national sample of psychiatrists and clinical psychologists described a randomly selected current patient with a measure designed for clinically experienced informants, the Mood Disorder Diagnostic Questionnaire (MDDQ), and completed additional research forms. We applied factor analysis to the MDDQ to identify naturally occurring diagnostic groupings within the patient sample. The analysis yielded three clinically distinct mood disorder dimensions or spectra, consistent with the major mood disturbances included in the DSM and ICD over successive editions (major depression, dysthymia, and mania), along with a suicide risk index. Diagnostic criteria were determined strictly empirically. Initial data using diagnostic efficiency statistics supported the accuracy of the dimensions in discriminating DSM-IV diagnoses; regression analyses supported the discriminant validity of the MDDQ scales; and correlational analysis demonstrated coherent patterns of association with family history of mood disorders and functional outcomes, supporting validity. Perhaps most importantly, the MDDQ diagnostic scales demonstrated incremental validity in predicting adaptive functioning and psychiatric history over and above DSM-IV diagnosis. The empirically derived syndromes can be used to diagnose mood syndromes dimensionally without complex diagnostic algorithms or can be combined into diagnostic prototypes that eliminate the need for ever-expanding categories of mood disorders that are clinically unwieldy. PMID- 23024678 TI - Assessing the diagnostic validity of a structured psychiatric interview in a first-admission hospital sample. AB - The use of structured psychiatric interviews performed by non-clinicians is frequent for research purposes and is becoming increasingly common in clini-cal practice. The validity of such interviews has rarely been evaluated empirically. In this study of a sample of 100 diagnostically heterogeneous, first-admitted inpatients, the results of an assessment with the Structured Clinical Interview for DSM-IV (SCID), yielding a DSM-IV diagnosis and performed by a trained non clinician, were compared with a consensus lifetime best diagnostic estimate (DSM IV) by two experienced research clinicians, based on multiple sources of information, which included videotaped comprehensive semi-structured narrative interviews. The overall kappa agreement was 0.18. The sensitivity and specificity for the diagnosis of schizophrenia by SCID were 19% and 100%, respectively. It is concluded that structured interviews performed by non-clinicians are not recommendable for clinical work and should only be used in research with certain precautions. It is suggested that a revival of systematic theoretical and practical training in psychopathology is an obvious way forward in order to improve the validity and therapeutic utility of psychiatric diagnosis. PMID- 23024679 TI - Lessons learned in developing community mental health care in East and South East Asia. AB - This paper summarizes the findings for the East and South East Asia Region of the WPA Task Force on Steps, Obstacles and Mistakes to Avoid in the Im-plementation of Community Mental Health Care. The paper presents a description of the region, an overview of mental health policies, a critical ap-praisal of community mental health services developed, and a discussion of the key obstacles and challenges. The main recommendations address the needs to campaign to reduce stigma, integrate care within the general health care system, prioritize target groups, strengthen leadership in policy mak-ing, and devise effective funding and economic incentives. PMID- 23024680 TI - Lessons learned in developing community mental health care in Latin American and Caribbean countries. AB - This paper summarizes the findings for the Latin American and Caribbean countries of the WPA Task Force on Steps, Obstacles and Mistakes to Avoid in the Implementation of Community Mental Health Care. It presents an overview of the provision of mental health services in the region; describes key experiences in Argentina, Belize, Brazil, Chile, Cuba, Jamaica and Mexico; and discusses the lessons learned in developing community mental health care. PMID- 23024681 TI - Mobile technologies in psychiatry: providing new perspectives from biology to culture. PMID- 23024682 TI - Promises and limitations of telepsychiatry in rural adult mental health care. PMID- 23024683 TI - The bereavement exclusion may not be applicable in real world settings. PMID- 23024684 TI - Fallacious reasoning in the argument to eliminate the major depression bereavement exclusion in DSM-5. PMID- 23024685 TI - Trainees' views on the future of psychiatry: a plethora of challenges ahead of us. PMID- 23024686 TI - Was the bereavement exclusion originally based on scientific data? PMID- 23024687 TI - The new impact factor and immediacy index of World Psychiatry. PMID- 23024688 TI - The Phenotype of Loneliness. AB - Goossens' (in press) review nicely maps the progression of scientific research from its early focus on loneliness as a dysphoric state that results from the discrepancy between a person's ideal and actual social relationships to its current emphasis on the centrality of loneliness to our very nature as a social species, and he argues that developmental science throughout Europe has a great deal to contribute to our understanding of this construct. He concludes that psychologists should care about research on loneliness for five reasons: (i) it is a well-defined phenotype, (ii) it shows both high stability and individual differences in rates of change across years, (iii) it has adaptive value and evolutionary significance, (iv) it has a genetic substrate that is moderated by social environments, and (v) it has self-maintaining features that can lead to adverse mental health outcomes. Goossen's (2012) review is rife with information and ideas. We focus here on two additional important reasons and on the phenotype of loneliness. PMID- 23024689 TI - Evaluate laser needle effect on blood perfusion signals of contralateral hegu acupoint with wavelet analysis. AB - Our previous studies suggested that the MBF in contralateral Hegu acupoint (IL4) increased after ipsilateral Hegu acupoint was stimulated with manual acupuncture. In this study, twenty-eight (28) healthy volunteers were recruited and were randomly divided into Hegu acupoint stimulation group and Non-Hegu stimulation group. All subjects received the same model stimulation of the laser needle for 30 min in right Hegu acupoint and Non-Hegu acupoint, respectively. MBF of left LI4 was measured by the laser Doppler perfusion imaging system. The original data dealt with morlet wavelet analysis and the average amplitude and power spectral density of different frequency intervals was acquired. The results indicated that right Hegu stimulation with the laser needle might result in the increase of left Hegu acupoint MBF. 40 min later after ceased stimulation, the MBF is still increasing significantly, whereas the MBF has no significantly change in Non-Hegu stimulation group. The wavelet analysis result suggested that compared to Non Hegu stimulation, stimulated to right Hegu acupoint might result in the increase of average amplitude in frequency intervals of 0.0095-0.02 Hz, 0.02-0.06 Hz, and 0.06-0.15 Hz, which might be influenced by the endothelial, neurogenic, and the intrinsic myogenic activity of the vessel wall, respectively. PMID- 23024691 TI - Medicinal plants in the prevention and treatment of chronic diseases. PMID- 23024690 TI - Virgin coconut oil supplementation prevents bone loss in osteoporosis rat model. AB - Oxidative stress and free radicals have been implicated in the pathogenesis of osteoporosis. Therefore, antioxidant compounds have the potential to be used in the prevention and treatment of the disease. In this study, we investigated the effects of virgin coconut oil (VCO) on bone microarchitecture in a postmenopausal osteoporosis rat model. VCO is a different form of coconut oil as it is rich with antioxidants. Three-month-old female rats were randomly grouped into baseline, sham-operated, ovariectomized control (Ovx), and ovariectomized rats fed with 8% VCO in their diet for six weeks (Ovx+VCO). Bone histomorphometry of the right femora was carried out at the end of the study. Rats supplemented with VCO had a significantly greater bone volume and trabecular number while trabecular separation was lower than the Ovx group. In conclusion, VCO was effective in maintaining bone structure and preventing bone loss in estrogen-deficient rat model. PMID- 23024692 TI - The molecular basis of wound healing processes induced by lithospermi radix: a proteomics and biochemical analysis. AB - Lithospermi Radix (LR) is an effective traditional Chinese herb in various types of wound healing; however, its mechanism of action remains unknown. A biochemical and proteomic platform was generated to explore the biological phenomena associated with LR and its active component shikonin. We found that both LR ethanol extracts and shikonin are able to promote cell proliferation by up to 25%. The results of proteomic analysis revealed that twenty-two differentially expressed proteins could be identified when fibroblast cells were treated with LR or shikonin. The functions of those proteins are associated with antioxidant activity, antiapoptosis activity, the regulation of cell mobility, the secretion of collagen, the removal of abnormal proteins, and the promotion of cell proliferation, indicating that the efficacy of LR in wound healing may be derived from a synergistic effect on a number of factors induced by the herbal medicine. Furthermore, an animal model confirmed that LR is able to accelerate wound healing on the flank back of the SD rats. Together these findings help to pinpoint the molecular basis of wound healing process induced by LR. PMID- 23024693 TI - Visual agreement analyses of traditional chinese medicine: a multiple-dimensional scaling approach. AB - The study of TCM agreement in terms of a powerful statistical tool becomes critical in providing objective evaluations. Several previous studies have conducted on the issue of consistency of TCM, and the results have indicated that agreements are low. Traditional agreement measures only provide a single value which is not sufficient to justify if the agreement among several raters is strong or not. In light of this observation, a novel visual agreement analysis for TCM via multiple dimensional scaling (MDS) is proposed in this study. If there are clusters present in the raters in a latent manner, MDS can prove itself as an effective distinguisher. In this study, a group of doctors, consisting of 11 experienced TCM practitioners having clinical experience ranging from 3 to 15 years with a mean of 5.5 years from the Chinese Medicine Department at Changhua Christian Hospital (CCH) in Taiwan were asked to diagnose a total of fifteen tongue images, the Eight Principles derived from the TCM theorem. The results of statistical analysis show that, if there are clusters present in the raters in a latent manner, MDS can prove itself as an effective distinguisher. PMID- 23024694 TI - Ginsenoside Rb1 Prevents MPP(+)-Induced Apoptosis in PC12 Cells by Stimulating Estrogen Receptors with Consequent Activation of ERK1/2, Akt and Inhibition of SAPK/JNK, p38 MAPK. AB - Ginsenoside Rb1 shows neuroprotective effects in various neurons, including dopaminergic cells. However, the precise mechanisms of action are uncertain. In this paper, we examine whether Rb1 has a neuroprotective effect on MPP(+)-induced apoptosis and attempt to clarify the signaling pathway in PC12 cells. Apoptosis of PC12 cells was determined by DNA fragmentation assay, the activation of caspase-3, or by the inactivation of Bcl-xL. Rb1 inhibited MPP(+)-induced caspase 3 activation and DNA fragmentation and activated Bcl-xL in MPP(+)-treated PC12 cells. These antiapoptotic effect was abrogated in PC12 cells transfected with estrogen receptor siRNA. Levels of DNA fragmentation were increased by wortmannin or PD 98059, while they were decreased by SB 203580 or SP 600125 in MPP(+) treated PC12 cells. Rb1 increased phosphorylation levels of ERK1/2 or Akt in MPP(+)-treated PC12 cells, while it reduced phosphorylated p38 or SAPK/JNK. The increased phosphorylation of ERK/1/2 or Akt by Rb1 was abrogated by estrogen receptor siRNA. Rb1-induced inhibition of SAPK/JNK or p38 phosphorylation was also abolished by estrogen receptor siRNA. These results suggest that ginsenoside Rb1 protects PC12 cells from caspase-3-dependent apoptosis through stimulation of estrogen receptor with consequent activation of ERK1/2 and Akt and inhibition of SAPK/JNK and p38. PMID- 23024695 TI - Clinical pathways based on integrative medicine in chinese hospitals improve treatment outcomes for patients with acute myocardial infarction: a multicentre, nonrandomized historically controlled trial. AB - Objective. To determine the impact of an integrative medicine clinical pathways (CPs) on the length of in-hospital stay and on outcomes for patients with acute myocardial infarction (AMI). Methods. A multicenter nonrandomized controlled trial enrolling 197 consecutive patients with AMI at eight urban TCM hospitals was conducted between 1 January 2010 and 31 October 2010. These patients were enrolled in the interventional group after the CPs had been implemented. The control group included 405 patients with AMI from eight hospitals; these patients were treated between 1 January 2008 and 31 December 2009, before the CPs were implemented. Outcome measures were the length of hospital stay costs of medical care, and major cardiovascular events (MACEs) during hospitalization. Results. Compared with the control group, the patients in intervention group had a shorter length of hospital stay (9.2 +/- 4.2 days versus 12.7 +/- 8.6 days, P < 0.05), and reduced healthcare costs in hospital (46365.7 +/- 18266.9 versus 52866.0 +/- 35404.4, P < 0.05). There were statistically significant differences in MACE between the two groups during the hospitalization period (2.5% versus 6.9%, P = 0.03). Conclusion. These data suggest that the development and implementation of the clinical pathways based in Integrative Medicine could further improve quality of care and outcome for patients with AMI. PMID- 23024696 TI - Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - Objective. To investigate the safety (risk) and efficacy (benefit) of Echinacea purpurea extract in the prevention of common cold episodes in a large population over a 4-month period. Methods. 755 healthy subjects were allocated to receive either an alcohol extract from freshly harvested E. purpurea (95% herba and 5% root) or placebo. Participants were required to record adverse events and to rate cold-related issues in a diary throughout the investigation period. Nasal secretions were sampled at acute colds and screened for viruses. Results. A total of 293 adverse events occurred with Echinacea and 306 with placebo treatment. Nine and 10% of participants experienced adverse events, which were at least possibly related to the study drug (adverse drug reactions). Thus, the safety of Echinacea was noninferior to placebo. Echinacea reduced the total number of cold episodes, cumulated episode days within the group, and pain-killer medicated episodes. Echinacea inhibited virally confirmed colds and especially prevented enveloped virus infections (P < 0.05). Echinacea showed maximal effects on recurrent infections, and preventive effects increased with therapy compliance and adherence to the protocol. Conclusions. Compliant prophylactic intake of E. purpurea over a 4-month period appeared to provide a positive risk to benefit ratio. PMID- 23024697 TI - Mechanism by Sambucus nigra Extract Improves Bone Mineral Density in Experimental Diabetes. AB - The effects of polyphenols extracted from Sambucus nigra fruit were studied in streptozotocin- (STZ-) induced hyperglycemic rats to evaluate its possible antioxidant, anti-inflammatory, antiglycosylation activity, and antiosteoporosis effects in diabetes. DEXA bone mineral density tests were performed in order to determine bone mineral density (BMD), bone mineral content (BMC), and fat (%Fat) in control and diabetic animals, before and after polyphenol delivery. As compared to the normoglycemic group, the rats treated with STZ (60 mg/kg body weight) revealed a significant malondialdehyde (MDA) increase, as an index of the lipid peroxidation level, by 69%, while the total antioxidant activity (TAS) dropped by 36%, with a consistently significant decrease (P < 0.05) in the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Also, the treatment of rats with STZ revealed a significant increase of IL-6, glycosylated haemoglobin (HbA(1c)), and osteopenia detected by DEXA bone mineral density tests. The recorded results highlight a significant improvement (P < 0.001) in the antioxidative capacity of the serum in diabetic rats treated with natural polyphenols, bringing back to normal the concentration of reduced glutathione (GSH), as well as an important decrease in the serum concentration of MDA, with improved osteoporosis status. Knowing the effects of polyphenols could lead to the use of the polyphenolic extract of Sambucus nigra as a dietary supplement in diabetic osteoporosis. PMID- 23024698 TI - Mechano-Responsive Hydrogels Crosslinked by Block Copolymer Micelles. AB - Block copolymer micelles (BCMs) were prepared from amphiphilic diblock copolymers of poly(n-butyl acrylate) and poly(acrylic acid) partially modified with 2 hydroxyethyl acrylate. Radical polymerization of acrylamide in the presence of micellar crosslinkers gave rise to elastomeric hydrogels (BCM-PAAm) whose mechanical properties can be tuned by varying the BCM composition. Transmission electron microscopy (TEM) imaging revealed stretch-induced, reversible micelle deformation in BCM-PAAm gels. A model hydrophobic drug, pyrene, loaded into the micelle core prior to the formation of BCM-PAAm gels, was dynamically released in response to externally applied mechanical forces. The BCM-crosslinked hydrogels with combined strength and force-modulated drug release are attractive candidates for the repair and regeneration of mechanically-active tissues. PMID- 23024699 TI - Regulatory T cells and Th17 cells in viral infections: implications for multiple sclerosis and myocarditis. AB - In immune-mediated diseases, Treg and proinflammatory Th17 cells have been suggested to play either suppressor (beneficial) or effector (detrimental) roles, respectively. Tissue damage in viral infections can be caused by direct viral replication or immunopathology. Viral replication can be enhanced by anti inflammatory responses and suppressed by proinflammatory responses. However, Tregs could suppress proinflammatory responses, reducing immunopathology, while Th17 cell-induced inflammation may enhance immunopathology. Here, the roles of Treg and Th17 cells depend on whether tissue damage is caused by direct virus replication or immunopathology, which differ depending on the virus, disease stage and host immune background. Although the precise mechanisms of tissue damage in multiple sclerosis and myocarditis are unclear, both viral replication and immune effector cells have been proposed to cause pathogenesis. Personalized medicine that alters the balance between Treg and Th17 cells may ameliorate viral pathology during infections. PMID- 23024700 TI - The molecular biology of HIV integrase. AB - Integration of viral DNA into cellular DNA is an essential step in the replication cycle of HIV and other retroviruses. The first antiviral drugs that target integrase, the viral enzyme that catalyzes DNA integration, have recently been approved and more are in the pipeline. These drugs bind to an intermediate in DNA integration called the intasome, in which a pair of viral DNA ends are synapsed by a tetramer of integrase, rather than free integrase enzyme. We discuss the biochemical mechanism of integration, which is now quite well understood, and recent progress towards obtaining atomic-resolution structures of HIV intasomes in complex with inhibitors. Such structures are ultimately required to understand the detailed mechanism of inhibition and the mechanisms by which mutations in integrase confer resistance. The path from early biochemical studies to therapeutic inhibitors of integrase highlights the value of basic science in fighting human diseases. PMID- 23024701 TI - Neuron Selection by Relative Importance for Neural Decoding of Dexterous Finger Prosthesis Control Application. AB - Future generations of upper limb prosthesis will have dexterous hand with individual fingers and will be controlled directly by neural signals. Neurons from the primary motor (M1) cortex code for finger movements and provide the source for neural control of dexterous prosthesis. Each neuron's activation can be quantified by the change in firing rate before and after finger movement, and the quantified value is then represented by the neural activity over each trial for the intended movement. Since this neural activity varies with the intended movement, we define the relative importance of each neuron independent of specific intended movements. The relative importance of each neuron is determined by the inter-movement variance of the neural activities for respective intended movements. Neurons are ranked by the relative importance and then a subpopulation of rank-ordered neurons is selected for the neural decoding. The use of the proposed neuron selection method in individual finger movements improved decoding accuracy by 21.5% in the case of decoding with only 5 neurons and by 9.2% in the case of decoding with only 10 neurons. With only 15 highly-ranked neurons, a decoding accuracy of 99.5% was achieved. The performance improvement is still maintained when combined movements of two fingers were included though the decoding accuracy fell to 95.7%. Since the proposed neuron selection method can achieve the targeting accuracy of decoding algorithms with less number of input neurons, it can be significant for developing brain-machine interfaces for direct neural control of hand prostheses. PMID- 23024702 TI - Ultrastable synergistic tetravalent RNA nanoparticles for targeting to cancers. AB - One of the advantages of nanotechnology is the feasibility to construct therapeutic particles carrying multiple therapeutics with defined structure and stoichiometry. The field of RNA nanotechnology is emerging. However, controlled assembly of stable RNA nanoparticles with multiple functionalities which retain their original role is challenging due to refolding after fusion. Herein, we report the construction of thermodynamically stable X-shaped RNA nanoparticles to carry four therapeutic RNA motifs by self-assembly of reengineered small RNA fragments. We proved that each arm of the four helices in the X-motif can harbor one siRNA, ribozyme, or aptamer without affecting the folding of the central pRNA X core, and each daughter RNA molecule within the nanoparticle folds into their respective authentic structures and retains their biological and structural function independently. Gene silencing effects were progressively enhanced as the number of the siRNA in each pRNA-X nanoparticles gradually increased from one to two, three, and four. More importantly, systemic injection of ligand-containing nanoparticles into the tail-vein of mice revealed that the RNA nanoparticles remained intact and strongly bound to cancers without entering the liver, lung or any other organs or tissues, while remaining in cancer tissue for more than 8 h. PMID- 23024703 TI - Narrow-band imaging cystoscopy in non-muscle-invasive bladder cancer: a prospective comparison to the standard approach. AB - OBJECTIVES: A single-centre, prospective trial was performed aiming to assess the impact of narrow-band imaging (NBI) cystoscopy in cases of non-muscle-invasive bladder cancer (NMIBC) in comparison to standard white light cystoscopy (WLC). MATERIALS AND METHODS: A total of 95 NMIBC-suspected consecutive cases were enrolled. The inclusion criteria were hematuria, positive urinary cytology or ultrasound suspicion of bladder tumors. All patients underwent WLC and NBI cystoscopy. Standard resection was performed for all lesions visible in white light and NBI transurethral resection of bladder tumors for only NBI-observed tumors. RESULTS: The overall detection rates of NMIBC and carcinoma in situ (CIS) were significantly improved for NBI (96.2% versus 87.2% and 100% versus 66.7% respectively). Also, NBI cystoscopy showed significantly superior detection for CIS, pTa and overall tumors (95.2% versus 61.9%, 93.9% versus 85.2% and 94.8% versus 83.9% respectively). Additional tumors were diagnosed by NBI in a significant proportion of patients with CIS, pTa, pT1 and NMIBC (55.5% versus 11.1%, 26.5% versus 10.2%, 30% versus 10% and 30.8% versus 10.3%). Postoperative treatment was significantly improved due to NBI results (16.7% versus 5.1%). CONCLUSIONS: NBI cystoscopy represents a valuable diagnostic alternative in patients with NMIBC, with significant improvement in tumor visual accuracy as well as detection. This approach provides a substantial improvement to bladder cancer therapeutic management. PMID- 23024704 TI - Current approaches to bone-targeted therapy in genitourinary malignancies. AB - Bone metastases in patients with genitourinary cancers are associated with increased risk for skeletal-related events including pathologic fractures, spinal cord compression, and the requirement for surgery or palliative radiotherapy to bone. The nitrogen-containing bisphosphonate zoledronic acid and the monoclonal antibody against RANK, denosumab, are approved for the prevention of skeletal related events in genitourinary cancers. These agents have different mechanisms of action and pharmacokinetic profiles, and while both are effective in reducing the risk of skeletal-related events, other clinical effects differ. There is evidence for direct and indirect anticancer activity with zoledronic acid from preclinical studies and emerging data from clinical studies suggesting an effect on patient survival. Potential anticancer mechanisms include inhibition of angiogenesis, enhanced immune surveillance via stimulation of gammadelta T cells, and reduction of circulating tumor cells. A synergistic effect of chemotherapy plus zoledronic acid has also been suggested. Further research is ongoing regarding the roles of these antiresorptive therapies in patients with bone metastases or at high risk for malignant spread to skeletal sites. PMID- 23024705 TI - Dapoxetine: a new option in the medical management of premature ejaculation. AB - Premature ejaculation (PE) is a common male sexual disorder which is associated with substantial personal and interpersonal negative psychological consequences. Pharmacotherapy of PE with off-label antidepressant selective serotonin reuptake inhibitors (SSRIs) is common, effective and safe. Development and regulatory approval of drugs specifically for the treatment of PE will reduce reliance on off-label treatments and serve to fill an unmet treatment need. The objective of this article is to review evidence supporting the efficacy and safety of dapoxetine in the treatment of PE. MEDLINE, Web of Science, PICA, EMBASE and the proceedings of major international and regional scientific meetings were searched for publications or abstracts published during the period 1993-2012 that used the word 'dapoxetine' in the title, abstract or keywords. This search was then manually cross referenced for all papers. This review encompasses studies of dapoxetine pharmacokinetics, animal studies, human phase I, II and III studies, independent postmarketing and pharmacovigilance efficacy and safety studies and drug-interaction studies. Dapoxetine is a potent SSRI which is administered on demand 1-3 h prior to planned sexual contact. It is rapidly absorbed and eliminated, resulting in minimal accumulation, and has dose-proportional pharmacokinetics which are unaffected by multiple dosing. Dapoxetine 30 mg and 60 mg has been evaluated in five industry-sponsored randomized, double-blind, placebo-controlled studies in 6081 men aged at least 18 years. Outcome measures included stopwatch-measured intravaginal ejaculatory latency time (IELT), Premature Ejaculation Profile (PEP) inventory items, Clinical Global Impression of Change (CGIC) in PE, and adverse events. Mean IELT, all PEP items and CGIC improved significantly with both doses of dapoxetine versus placebo (all p <0.001). The most common treatment-related adverse effects included nausea (11.0% for 30 mg, 22.2% for 60 mg), dizziness (5.9% for 30 mg, 10.9% for 60 mg), and headache (5.6% for 30 mg, 8.8% for 60 mg), and evaluation of validated rated scales demonstrated no SSRI class-related effects with dapoxetine use. Dapoxetine, as the first drug developed for PE, is an effective and safe treatment for PE and represents a major advance in sexual medicine. PMID- 23024706 TI - Experience with sunitinib in the treatment of metastatic renal cell carcinoma. AB - Following approval of the oral, multitargeted tyrosine kinase inhibitor sunitinib malate for the treatment of patients with metastatic renal cell carcinoma (mRCC) in Europe and the USA in 2006, the agent has had a substantial impact on the treatment landscape in this setting. Sunitinib is now recommended in international treatment guidelines for the first-line treatment of favourable- or intermediate-risk mRCC and as an alternative option in poor-risk mRCC. In the 6 years since the approval of sunitinib, the range of agents available for the treatment of mRCC has expanded substantially, and this, together with a number of additional therapies in late-stage development, has increased the treatment options available to patients. Results from a phase III trial and a global expanded access study have provided robust data to support the efficacy of sunitinib in mRCC, including in real-world populations. Data also suggest a significant quality of life benefit with sunitinib, with superior patient reported outcomes observed with this agent compared with interferon-alpha therapy. Both clinical and real-world study data also support the safety profile of sunitinib; most treatment-associated adverse events are mild to moderate in severity and can be managed effectively with close monitoring and proactive management. Clinical experience with sunitinib has demonstrated that therapy management, involving optimal dosing, maximum treatment duration and prompt and effective adverse event management, supports optimal patient outcomes with sunitinib. In this review we discuss clinical experience with sunitinib in mRCC, with an emphasis on real-world data, and utilize clinical case studies to examine the successful implementation of therapy management strategies for optimal patient outcomes. An increasing body of evidence suggests that side effects associated with sunitinib therapy, including hypertension, hand-foot syndrome and hypothyroidism, may represent effective markers of treatment response, and these will also be discussed. PMID- 23024707 TI - Experience with the combination of dutasteride and tamsulosin in the long-term management of benign prostatic hyperplasia. AB - Lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) commonly affect older men. These bothersome symptoms can lead to a decreased quality of life. Currently, two classes of drugs - alpha-adrenergic blockers and 5alpha-reductase inhibitors - are prescribed to treat LUTS secondary to BPH. Due to their different mechanisms of action, these medications work in a synergistic manner. Trials of combination therapy have been conducted to assess its effect compared with monotherapy. Current data support combination therapy in men with moderately enlarged prostates and moderate to severe symptoms. PMID- 23024709 TI - Significance of C-reactive protein in osteoarthritis and total knee arthroplasty outcomes. AB - BACKGROUND: The relationship between systemic inflammatory processes to total knee arthroplasty (TKA) outcomes remains unclear. This study investigates the relationship between serum high-sensitivity C-reactive protein (hs-CRP) and functional outcomes post-TKA. METHODS: A total of 31 patients with osteoarthritis (OA) who underwent TKA were enrolled in the study; 15 with hs-CRP <=1.0 mg/l (low hs-CRP group) and 16 subjects with hs-CRP >=4.0 mg/l (high hs-CRP group). During surgery, synovium and bone sections were sequestered, formalin-fixed, and paraffin embedded for slide preparation. Tissue sections were stained with hematoxylin and eosin and analyzed using a light microscope. A total of 12 cytokines were measured in synovial fluid samples from the knee joint at time of surgery and analyzed using the Luminex Multi-Analyte Profiling System. Relationships between cytokines and hs-CRP were assessed using Spearman correlation coefficients. Student's t-tests were used to compare Short Form health outcomes survey (SF-12) health outcomes between high and low hs-CRP, and presurgical and postsurgical visits. RESULTS: Mean +/- standard deviation (SD) baseline and 1-year hs-CRP values for the low hs-CRP group were 0.55 +/- 0.23 mg/l and 1.22 +/- 1.32 mg/l, respectively (n = 15; p = 0.051) and for the high hs CRP group were 7.86 +/- 5.98 mg/l and 14.11 +/- 38.9 mg/l, respectively (n = 13; p = 0.54). Lymphocytes were present in 10 synovium and one bone sample (all but one from high hs-CRP group). Interleukin (IL)-5 and IL-10 were significantly correlated with hs-CRP (p = 0.0137 and p = 0.0029, respectively). The low hs-CRP group exhibited significant improvement in the physical component of SF-12 at 6 and 12 months compared with baseline, whereas the high hs-CRP group exhibited significant improvement only at 6 months. Body mass index (BMI) had a significant positive correlation with presurgical hs-CRP. CONCLUSIONS: The results of this study provide support for inflammatory mechanisms contributing to the OA progression, with hs-CRP being a possible predictive variable, combined with BMI and other comorbidities, of post-TKA function. PMID- 23024708 TI - Sirtuin biology and relevance to diabetes treatment. AB - Sirtuins are a group of NAD(+)-dependent enzymes that post-translationally modify histones and other proteins. Among seven mammalian sirtuins, SIRT1 has been the most extensively studied and has been demonstrated to play a critical role in all major metabolic organs and tissues. SIRT1 regulates glucose and lipid homeostasis in the liver, modulates insulin secretion in pancreatic islets, controls insulin sensitivity and glucose uptake in skeletal muscle, increases adiponectin expression in white adipose tissue and controls food intake and energy expenditure in the brain. Recently, SIRT3 has been demonstrated to modulate insulin sensitivity in skeletal muscle and systemic metabolism, and Sirt3-null mice manifest characteristics of metabolic syndrome on a high-fat diet. Thus, it is reasonable to believe that enhancing the activities of SIRT1 and SIRT3 may be beneficial for Type 2 diabetes. Although it is controversial, the SIRT1 activator SRT1720 has been reported to be effective in improving glucose metabolism and insulin sensitivity in animal models. More research needs to be conducted so that we can better understand the physiological functions and molecular mechanisms of sirtuins in order to therapeutically target these enzymes for diabetes treatment. PMID- 23024710 TI - DUEXIS((r)) (ibuprofen 800 mg, famotidine 26.6 mg): a new approach to gastroprotection for patients with chronic pain and inflammation who require treatment with a nonsteroidal anti-inflammatory drug. AB - Chronic pain conditions affect at least 116 million US adults and more than one third of adults worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively for the treatment of chronic pain due to their efficacy as anti inflammatory and analgesic agents. Gastrointestinal toxicity is the most well known adverse effect of NSAID therapy and it may manifest as dyspepsia, ulcers, or bleeding. Current guidelines for the management of patients who require NSAIDs for chronic pain and inflammation recognize the potential toxicity associated with these drugs and the need for gastroprotection. DUEXIS((r)) (ibuprofen 800 mg, famotidine 26.6 mg) is a proprietary combination, immediate release tablet containing 800 mg of ibuprofen and 26.6 mg of famotidine. The efficacy of DUEXIS((r)) taken three times daily has been demonstrated in two large-scale controlled clinical trials (Registration Endoscopic Studies to Determine Ulcer Formation of HZT-501 Compared with Ibuprofen: Efficacy and Safety Studies (REDUCE) and REDUCE-2) which showed that this new formulation significantly reduced the risk of endoscopic upper gastrointestinal ulcers compared with ibuprofen alone (REDUCE-1, p < 0.0001, REDUCE-2, p <0.05). DUEXIS((r)) was also superior to ibuprofen in decreasing the risk for gastric ulcers (REDUCE-1, p < 0.001, REDUCE-2, p < 0.05) as well as duodenal ulcers (REDUCE-1, p < 0.05, REDUCE 2, p < 0.05). Safety results from these two studies indicated that treatment emergent adverse events occurred in 55% of patients treated with DUEXIS((r))versus 58.7% for ibuprofen, and serious adverse events were recorded for 3.2% of patients treated with DUEXIS((r))versus 3.3% of those on ibuprofen. Adverse events leading to discontinuation occurred in 6.7% of patients treated with DUEXIS((r)) and 7.6% for ibuprofen. The combination of ibuprofen and famotidine in a single tablet has the potential to improve adherence to gastroprotective therapy in patients who require NSAID treatment and the use of a histamine type 2 receptor antagonist rather than a proton-pump inhibitor may decrease the risk for clinically significant drug interactions and adverse events (e.g. interaction with clopidogrel, fracture, pneumonia, Clostridium difficile infection). PMID- 23024711 TI - Role of diagnostic ultrasound in the assessment of musculoskeletal diseases. AB - The wide availability and recent improvement in technology coupled with portability, low cost and safety makes ultrasound the first choice imaging investigation for the evaluation of musculoskeletal diseases. Diagnostic use of ultrasound findings is greatly enhanced by knowledge of the clinical presentation. Conversely, ultrasound skills with its prerequisite anatomical knowledge make the clinical diagnosis more precise and reduce uncertainty in the choice of therapy. Therefore, it is essential for rheumatologists to acquire ultrasonography skills in order to improve patient care. Ultrasound examination provides an excellent opportunity for patient education and to explain the rationale for therapy. This review summarizes the indications for musculoskeletal ultrasound and describes its role in diagnosis, monitoring and prognosis. PMID- 23024712 TI - Bone disease in primary hyperparathyrodism. AB - Nowadays, primary hyperparathyroidism (PHPT) is mostly a mild disease. Overt skeletal manifestations are rare but decreased bone mineral density (BMD) can still be demonstrated. Even in mild cases, excess parathyroid hormone (PTH) increases bone turnover leading to bone loss particularly at cortical sites. Conversely, a relative preservation of cancellous bone has been shown by histomorphometric analyses and advanced imaging techniques. An increased fracture rate has been demonstrated in untreated patients with PHPT at peripheral sites and in the spine. Parathyroidectomy (PTx) is the definitive cure for PHPT. With the restoration of normal PTH, bone resorption is quickly tapered down, while bone formation proceeds at the level of bone multicellular units, which were activated prior to PTx. The rapid refilling of the enlarged remodeling space and the subsequent matrix mineralization will result in an increase in BMD at sites rich in trabecular bone, such as lumbar spine and hip, which mainly occurs during the first 6-12 months after PTx. Cortical bone is less responsive to PTX because of the low rate of bone turnover, but sensible increases in BMD at the distal third of the radius can be observed in the long term. PTx seems to decrease the risk of fractures but more data are needed before a definitive conclusion on this important matter can be reached. Treatment with bisphosphonates can be considered for patients with low BMD who do not undergo PTx. Two-year treatment with alendronate has been shown to decrease bone turnover markers and increase BMD at the lumbar spine and hip, but not at the distal radius. Cinacalcet stably decreased serum calcium levels across a broad range of PHPT severity, but no change in BMD occurred in patients treated for up to 5.5 years. PMID- 23024714 TI - Antiretroviral therapy associated mastopathy. AB - Reports about bilateral breast enlargement in patients on antiretroviral therapy are rare. It forms a constituent of the human immunodeficiency virus lipodystrophy syndrome. Often clinical suspicion followed by appropriate imaging evaluation is confirmative.A case of antiretroviral therapy associated mastopathy is therefore presented here so that increased awareness would obviate the need of mastectomy in such cases. We also emphasise the role of adequate counselling in this scenario in alleviating patients' anxiety. PMID- 23024715 TI - Rituals can kill - A fatal case of brucine poisoning. AB - In some parts of India people follow a religious ritual of drinking an herbal preparation made from the bark of the Alstonia scholaris tree (Blackboard tree) on the day of the new moon in the month of July. This tree could be easily confused with the Strychnos nux vomica tree. Brucine is the predominant alkaloid present in the bark of the Strychnos nux vomica tree. The toxicological property of brucine is similar to strychnine. Brucine is a neurotoxin. A 29-year-old male presented with a history of consumption of an herbal preparation made from the bark of the Strychnos nux vomica tree confusing it for Alstonia scholaris. Soon after, he developed convulsions and later died in hospital on the same day. The aim of this case report is to highlight the fact that people must be cautious when they follow religious rituals. PMID- 23024713 TI - Novel approaches in the treatment of myositis and myopathies. AB - The inflammatory myopathies are a heterogeneous group of disorders characterized by muscle weakness and inflammation. Although no standard therapeutic guidelines exist, traditional treatment has included corticosteroids and a variety of second line immunosuppressants. As treatment of refractory disease has been difficult, newer agents and approaches have been used with varying response. The advent of standardized treatment response criteria by the International Myositis Assessment and Clinical Studies (IMACS) group has helped investigators to evaluate and compare clinical trial outcomes in a more rigorous fashion. The use of intravenous immunoglobulin (IVIG), rituximab, biologic agents including tumor necrosis factor (TNF) inhibitors, stem-cell transplantation, gene therapy, and vascular occlusion resistance training are reviewed here. As our understanding of disease pathogenesis at the immunologic, genetic, and molecular level expands, the discovery of novel therapeutic targets hold promise for the successful treatment of these conditions. PMID- 23024716 TI - Isolated protein S deficiency presenting as catastrophic systemic arterial and subsequently venous thrombosis. AB - Isolated protein S deficiency is an inherited condition having proven association with venous thromboembolism. There is controversy regarding clear association between protein S deficiency and arterial thrombosis. It is therefore necessary to bring focus to this uncommon clinical condition and highlight the probable association with arterial thrombosis facilitating timely diagnosis of this condition. We describe a 48-year-old male with stroke and pulmonary thromboembolism with chronic deep vein thrombosis secondary to isolated protein S deficiency, managed with thrombolysis and long-term anticoagulation. PMID- 23024717 TI - Exercise intervention in New Zealand Polynesian peoples with type 2 diabetes: Cultural considerations and clinical trial recommendations. AB - The Maori and Pacific Islands peoples of New Zealand suffer a greater burden of type 2 diabetes mellitus (T2DM) and associated comorbidities than their European counterparts. Empirical evidence supports the clinical application of aerobic and resistance training for effective diabetes management and potential remission, but few studies have investigated the effectiveness of these interventions in specific ethnic cohorts. We recently conducted the first trial to investigate the effect of prescribed exercise training in Polynesian people with T2DM. This article presents the cultural considerations undertaken to successfully implement the study. The research procedures were accepted and approved by cultural liaisons and potential participants. The approved methodology involved a trial evaluating and comparing the effects of two, 16-week exercise regimens (i.e. aerobic training and resistance training) on glycosylated haemoglobin (HbA1c), related diabetes markers (i.e. insulin resistance, blood lipids, relevant cytokines and anthropometric and hemodynamic indices) and health-related quality of life. Future exercise-related research or implementation strategies in this cohort should focus on cultural awareness and techniques to enhance participation and compliance. Our approach to cultural consultation could be considered by researchers undertaking trials in this and other ethnic populations suffering an extreme burden of T2DM, including indigenous Australians and Americans. PMID- 23024718 TI - Primary tubercular mastopathy. AB - Primary breast tuberculosis is a rare entity in the developed world but is slightly more common in the developing world. All lesions that clinically, pathologically and imaging wise appear benign but do not respond to routine antibiotics, must be worked up for possible tubercular aetiology especially when they present as plain oedema, induration or as non-healing ulcers. Imaging has a role in defining the extent, deciding the type of management and duration of follow-up. This article highlights the clinical and sonographic imaging findings in one such case which was followed up for a period of one year. PMID- 23024720 TI - Cranial melioidosis with extradural extension after a fall in the bathroom. AB - A 32-year-old diabetic male, with a past history of head injury and seizures, presented with a painful swelling over his forehead present for the past three months. Cranial MRI demonstrated the presence of a scalp collection with extradural extension through a bony defect. Biopsy from the area showed caseating necrosis suggestive of tuberculosis. Although the patient failed to return for initiation of anti-tubercular therapy for the next 11 months, the swelling did not progress, and there were no constitutional symptoms. The indolent nature of the swelling prompted re-evaluation and delayed cultures of pus from the collection grew Burkholderia pseudomallei. PMID- 23024719 TI - Coaching Older Adults and Carers to have their preferences Heard (COACH): A randomised controlled trial in an intermediate care setting (study protocol). AB - BACKGROUND: Frail older people who are considering movement into residential aged care or returning home following a hospital admission often face complex and difficult decisions.Despite research interest in this area, a recent Cochrane review was unable to identify any studies of interventions to support decision making in this group that met the experimental or quasi-experimental study design criteria. AIMS: This study tests the impact of a multi-component coaching intervention on the quality of preparation for care transitions, targeted to older adults and informal carers. In addition, the study assesses the impact of investing specialist geriatric resources into consultations with families in an intermediate care setting where decisions about future care needs are being made. METHOD: This study was a randomised controlled trial of 230 older adults admitted to intermediate care in Australia. Masked assessment at 3 and 12 months examined physical functioning, health-related quality of life and utilisation of health and aged care resources. A geriatrician and specialist nurse delivered a coaching intervention to both the older person and their carer/family. Components of the intervention included provision of a Question Prompt List prior to meeting with a geriatrician (to clarify medical conditions and treatments, medications, 'red flags', end of life decisions and options for future health care) and a follow-up meeting with a nurse who remained in telephone contact. Participants received a printed summary and an audio recording of the meeting with the geriatrician. CONCLUSION: The costs and outcomes of the intervention are compared with usual care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12607000638437). PMID- 23024721 TI - Doctors and medical science. PMID- 23024722 TI - Assessment and management of the orthopedic and other complications of Proteus syndrome. AB - PURPOSE: A multidisciplinary workshop was convened at the National Institutes of Health (NIH) to discuss the management of the orthopedic and other complications of Proteus syndrome (PS), a progressive, disproportionate overgrowth disorder. While PS poses many complex challenges, the focus of the workshop was the management of the asymmetric and disorganized skeletal overgrowth that characterizes this multisystem disorder. METHODS: Workshop participants developed recommendations for clinical research and patient management and surveillance to maximize the benefits and reduce the risks of surgical and other interventions. RESULTS: Recommendations for clinical care and management included assessments of skeletal overgrowth and its progression with modalities such as X-ray, magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry, and computerized tomography (CT) imaging. The recommendations also cover the assessment of non orthopedic complications of PS that significantly impact surgical risk, such as pulmonary embolism and lung bullae. Surgical considerations in PS include assessment of the contribution of contractures to deformities and prophylactic soft-tissue release, aggressive and early use of epiphysiodesis and epiphysiostasis, amputation, and spinal bracing. CONCLUSION: Decisions on the timing of orthopedic procedures in children with PS are challenging because they entail balancing the risks of intervention in this high-risk and complex population against the increasing morbidity that patients experience with progressive bony overgrowth. If surgery is delayed too long, the condition may become inoperable. We hope that these recommendations will help clinicians gather appropriate data and assist their patients in making timely treatment decisions. PMID- 23024723 TI - Exposed versus buried wires for fixation of lateral humeral condyle fractures in children: a comparison of safety and efficacy. AB - INTRODUCTION: Displaced fractures of the lateral condyle of the humerus are usually treated with open reduction and fixation with smooth Kirschner wires. These may be passed through the skin and left exposed or buried subcutaneously. Exposed wires may be removed in the outpatient clinic, whereas buried wires require a formal procedure under anaesthesia. This advantage may be offset if there is a higher rate of complications with exposed wires. The aim of this study was to compare the safety and efficacy of exposed and buried wires. STUDY DESIGN: Retrospective cohort. METHODS AND MATERIALS: Children with lateral condyle fractures of the humerus who had undergone surgery were identified from our departmental database. Case records and X-rays of 75 patients were reviewed. RESULTS: Forty-two patients had buried wires and 33 had exposed wires. There were no serious complications in either group. In the exposed wires group, 1 patient had a superficial wound infection that was treated effectively with 1 week of oral antibiotics, while 2 patients had hypergranulation of pin tracts treated with topical silver nitrate. None of the patients showed loss of reduction, deep infection, or any other complications requiring additional procedures. DISCUSSION/CONCLUSIONS: There was no statistically significant difference in the rate of complications between the buried and exposed groups. We conclude that open reduction and exposed wiring is a safe and effective option for lateral condyle fractures, and recommend a period of 4 weeks of K-wire fixation followed by 2 weeks of backslab immobilisation as adequate for union with minimal risk of infection. PMID- 23024724 TI - Synovial sarcoma in patients under 20 years of age: a multicenter study with a minimum follow-up of 10 years. AB - PURPOSE: Synovial sarcoma (SS) is an aggressive soft-tissue tumor noted for late local recurrence and metastasis. This study investigates the long-term outcome of SS in patients of pediatric age and evaluates potential prognostic factors for SS. METHODS: We performed a retrospective review of 13 SS cases in patients younger than 20 years at the time of diagnosis who had a minimum follow-up of 10 years. The mean follow-up for living patients (n = 8) was 20.1 years (12.1-27.6) and for nonsurvivors (n = 5) 4.9 years (range: 2.6-9.3). Nine patients had unplanned excisions (69%), of which 6 (67%) were performed prior to their referral. Re-excisions were necessary in all 13 patients. The factors sex, tumor site, tumor size, tumor grade, histological subtype, fusion type, and type of treatment were evaluated for their prognostic value. RESULTS: Only 2 patients (15%) met the criteria of adequate tumor treatment. Overall, the 5- and 10-year survival rates were 77 and 61%, respectively. The mean time until a local recurrence (n = 5) was 3.2 years (range: 0.7-10.2), while there was a mean time of 2.1 years until the occurrence of late metastases (n = 5; range: 0.8-4.8). A high tumor grade and having a tumor in the trunk were adverse factors in terms of overall, local recurrence-free, and metastasis-free survival. Patients with wide resections or amputations had fewer local recurrences than patients with marginal or intralesional resections. CONCLUSION: Inadequate primary excision of SS results in incomplete excision in the majority of cases. The tumor site, size, and histological grade should be considered when determining a risk-adapted treatment for SS, and wide surgical excision is the surgical intervention of choice. While local recurrence and late metastases appear to occur after a shorter time period in pediatric patients than in adults, in view of the tendency for late recurrence and metastasis with SS, follow-up should be at least 10 years. PMID- 23024725 TI - Clinical value of the Taylor Spatial Frame: a comparison with the Ilizarov and Orthofix fixators. AB - PURPOSE: Evaluation of the advantages and limitations of the Taylor Spatial Frame (TSF) with regard to the healing index (HI), distraction-consolidation time (DCT), accuracy of correction complications, and cost of the device. METHODS: Comparison of results with the traditional Ilizarov apparatus and a unilateral Orthofix fixator in a consecutive patient series with 135 bony deformity corrections. RESULTS: The HI did not differ significantly between all three fixators and was 57 days/cm for all patients. The DCT was significantly shorter for the TSF (148 days) compared to the Ilizarov fixator (204 days) and the Orthofix device (213 days). The accuracy of deformity correction was higher for the TSF than the other devices. The mean values of the measured angles after correction did not differ, but the variance of the results was the lowest. Also, the total rate of complications was considerably lower for the TSF. The Orthofix device showed a high rate of angular deformity during treatment, whereas both ring fixators had a relatively higher number of pin-related problems. CONCLUSIONS: The findings in our patient series suggest the use of the Orthofix apparatus for simple lengthening over short to median distances and the Ilizarov device for the correction of simple bony deformities and pure lengthening over long distances. The TSF allows multiplanar corrections and lengthenings without complex modifications of the device. But, due to the remarkably higher costs, it has not yet been established as our routine device. LEVEL OF EVIDENCE: Level IV case series. Therapeutic Study-Investigating the Results of Treatment. PMID- 23024726 TI - Long-term result after femoral head substitution in postinfectious aplasia of the femoral head. AB - PURPOSE: This case report presents a new and unique surgical greater trochanter split procedure for reconstructing a hip joint after an infantile hip sepsis with consequent aplasia of the femoral head. METHODS: One patient underwent the new trochanter split osteotomy for postinfectious aplasia of the femoral head at the age of 4 years. A follow-up of 17 years is presented. SURGICAL TECHNIQUE: The remaining proximal femur is sagittally split and the medial part is shifted into the acetabulum, preserving the lateral part of the greater trochanter. The osteotomy is fixed by an osseous wedge and K-wires. In contrast to the techniques known so far, it does not harm the vastogluteal muscle sling, thus, significantly reducing abductor lurch. Furthermore, through placing juvenile growth cartilage from the greater trochanter area into the acetabulum, there is, by far, more potential for the regeneration of a femoral head than by the procedures known so far. CONCLUSION: The presented surgical technique is able to improve the biomechanics of a hip joint with postinfectious aplasia of the femoral head. The growth of a new femoral head and the development of a well-shaped acetabulum is enabled. A clinical outcome with a stable joint and very good clinical function can be achieved. PMID- 23024727 TI - Transtibial Ertl amputation for children and adolescents: a case series and literature review. AB - PURPOSE: Despite advances in limb reconstruction, there are still a number of young patients who require trans-tibial amputation. Amputation osteoplasty is a technique first described by Ertl to enhance rehabilitation after trans-tibial amputation. The purpose of the study reported here was to evaluate the results of the original Ertl procedure in skeletally immature patients and to assess whether use of this procedure would result in a diminished incidence of bony overgrowth. METHODS: The cases of four consecutive patients (five amputations) treated between January 2005 and June 2008 were reviewed. Clinical evaluation consisted of the completion of the prosthesis evaluation questionnaire (PEQ) and physical examination. Radiographic analysis was performed to evaluate bone-bridge healing, bone overgrowth, and the development of genu varum as measured by the medial proximal tibial angle (MPTA). RESULTS: The best mean PEQ score in the question section was 91.8 (range 74-100) for 'well being' and the worst mean score was 66.6 (range 50-78) for 'residual limb health'. Examination of the residual limbs revealed no bursae, and all knees were stable with full range of movement. All bony bridges united at an average age of 1.7 (range 1-2) months. One case required stump revision for bony overgrowth, and one case developed asymptomatic mild genu varum. CONCLUSIONS: The original Ertl osteomyoplasty may serve as one of the options for treatment of trans-tibial amputation in older children. CLINICAL RELEVANCE: Our results suggest that the Ertl osteomyoplasty is a feasible option in this challenging patient population. PMID- 23024728 TI - Upper limb motion analysis in children with hemiplegic cerebral palsy: proximal kinematic changes after distal botulinum toxin or surgical treatments. AB - PURPOSE: The purpose of this study is to describe the kinematic changes in children with cerebral palsy (CP) after treatments performed on the forearm, wrist or thumb, with specific attention to the changes around the trunk, shoulder and elbow kinematics. METHODS: With the use of a specific kinematic protocol, we first described the upper limb kinematics in a group of 27 hemiplegic patients during two simple daily tasks. Eight of these children were treated with botulinum toxin (Botox((r)), Allergan) injection or surgery and were, thereafter, evaluated with another kinematic analysis in order to compare the pre- and post therapeutic condition. The target muscles were the pronator teres, flexor carpi radialis, flexor carpi ulnaris, flexor digitorum superficialis, flexor pollicis longus and the adductor pollicis. RESULTS: Significant kinematic changes were found after treatment. Patients increased forearm supination (P < 0.05) and wrist extension (P < 0.05) during both tasks. Patients also decreased trunk flexion/extension range of motion (ROM) (P < 0.05), improved elbow ROM (P < 0.05) and improved internal shoulder rotation (P < 0.05). CONCLUSIONS: Dynamic shoulder or elbow limitations in children with mild hemiplegia involvement could be related to a compensatory movement strategy and/or co-contractions. As these proximal kinematics anomalies are improved after treatments performed at the forearm, wrist and thumb, they should not be treated first but should be reconsidered after the treatment of more distal problems. PMID- 23024730 TI - New Treatment Approaches for Older Adults with Multiple Myeloma. AB - The incidence of multiple myeloma (MM) increases with age, and with the aging of the population, the number of adults with MM is expected to double in the next 20 years. Novel agents, including the immunomodulatory agents thalidomide and lenalidomide, and the proteosome inhibitor bortezomib have dramatically changed the treatment of multiple myeloma in the past decade. The purpose of this review was to examine the recent clinical therapeutic trials in older adults with MM. A number of trials have evaluated the addition of novel agents to the traditional backbone of melphalan and prednisone. The combination of thalidomide with melphalan and prednisone has been evaluated in 7 randomized trials. The combination improves response rates and, in meta-analyses, survival, but at the expense of increased toxicity. Other combination regimens which include lenalidomide or bortezomib likewise are associated with higher response rates, but at the expense of greater toxicity. High dose dexamethasone is excessively toxic in older adults and should be avoided. The roles for high-dose therapy with autologous stem cell transplant or intermediate-dose melphalan with autologous stem cell transplant in older adults with MM in the era of modern therapy remain to be defined. In summary, there are a number of new therapeutic options for older adults with MM, allowing an individualized treatment strategy based on the patient's comorbidities and goals of care. PMID- 23024732 TI - Pleiotropic effects of sitagliptin in the treatment of type 2 diabetes mellitus patients. AB - BACKGROUND: Sitagliptin is a DPP-4 inhibitor that became available for use in Japan three years ago. This study was conducted to identify the pleiotropic effects of sitagliptin other than blood glucose lowering in Japanese type 2 diabetes mellitus patients. METHODS: A retrospective, observational study of 940 type 2 diabetes mellitus patients was conducted. The primary outcome measures were HbA1c, blood pressure, and lipid profiles measured at 0, 4, and 12 weeks of sitagliptin therapy. RESULTS: After 12 weeks of sitagliptin treatment, compared with baseline, HbA1c decreased 0.64% +/- 0.86%; systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased significantly; and serum creatinine (Cr) and uric acid (UA) levels were mildly but significantly elevated. A correlation analysis of the changes in systolic blood pressure, diastolic blood pressure, creatinine, and uric acid (DeltaSBP, DeltaDBP, DeltaCr, DeltaUA) from baseline to 12 weeks showed significant negative correlations between DeltaSBP and DeltaCr, DeltaSBP and DeltaUA, and DeltaDBP and DeltaCr. Total cholesterol and postprandial triglycerides were significantly decreased at both 4 and 12 weeks. Alkaline phosphatase (ALP) decreased significantly, and there was a significant positive correlation between changes in ALP and HbA1c. CONCLUSIONS: Sitagliptin seems to be effective not only in lowering blood glucose but also in lowering blood pressure, lipid, and ALP levels. Sitagliptin appears to contribute to a Na diuretic action due to GLP-1. PMID- 23024733 TI - Clinical Profile of Obstetric Patients Admitted to the Medical-Surgical Intensive Care Unit (MSICU) of an Inner-City Hospital in New York. AB - BACKGROUND: Pregnancy is associated with physiological and anatomical changes that usually occur uneventfully in majority of women. However, these changes can cause major maternal morbidity with potential catastrophic consequences. The purpose of this study is to evaluate the clinical characteristics of obstetric patients admitted to the MSICU of an inner-city hospital in New York. METHODS: A prospective, observational study was conducted among all the obstetric patients admitted to the MSICU between June 1, 2009 and June 30, 2012. RESULTS: A total of 19 obstetric patients were admitted to the MSICU between June 1, 2009 and June 30, 2012. The most common comorbidity on admission was hypertensive disorder. Hemodynamic unstability and shock was the most common admission diagnosis. The mean length of stay was 3.5 days. One patient died. CONCLUSIONS: Obstetric hemorrhage and pregnancy-induced hypertensive disorders remains as the most common entities requiring intensive care unit (ICU) admission among obstetric patients. A multidisciplinary team involvement is essential in the management of these patients. PMID- 23024731 TI - Borderline personality disorder: bipolarity, mood stabilizers and atypical antipsychotics in treatment. AB - In this article, it is aimed to review the efficacies of mood stabilizers and atypical antipsychotics, which are used commonly in psychopharmacological treatments of bipolar and borderline personality disorders. In this context, common phenomenology between borderline personality and bipolar disorders and differential features of clinical diagnosis will be reviewed in line with the literature. Both disorders can demonstrate common features in the diagnostic aspect, and can overlap phenomenologically. Concomitance rate of both disorders is quite high. In order to differentiate these two disorders from each other, quality of mood fluctuations, impulsivity types and linear progression of disorders should be carefully considered. There are various studies in mood stabilizer use, like lithium, carbamazepine, oxcarbazepine, sodium valproate and lamotrigine, in the treatment of borderline personality disorder. Moreover, there are also studies, which have revealed efficacies of risperidone, olanzapine and quetiapine as atypical antipsychotics. It is not easy to differentiate borderline personality disorder from the bipolar disorders. An intensively careful evaluation should be performed. This differentiation may be helpful also for the treatment. There are many studies about efficacy of valproate and lamotrigine in treatment of borderline personality disorder. However, findings related to other mood stabilizers are inadequate. Olanzapine and quetiapine are reported to be more effective among atypical antipsychotics. No drug is approved for the treatment of borderline personality disorder by the entitled authorities, yet. Psychotherapeutic approaches have preserved their significant places in treatment of borderline personality disorder. Moreover, symptom based approach is recommended in use of mood stabilizers and atypical antipsychotics. PMID- 23024734 TI - Restless legs syndrome in multiple myeloma patients. AB - BACKGROUND: Restless legs syndrome (RLS) is a common neurological condition characterized by uncomfortable and unpleasant sensations in the legs that are relieved by movement. It is frequently idiopathic, sometimes associated with specific disorders such as malignancies. Because there is no study relevant to RLS in Multiple Myeloma (MM), we aimed to evaluate the frequency of RLS in MM patients during chemotherapy and examined the relationship between presence of RLS and depression and anxiety in these patients. METHODS: We enrolled a population of 62 adult MM patients for RLS features. RLS was ascertained in MM patients by both the presence of the four essential International RLS Study Group diagnostic criteria and neurological examination. The International RLS Study Group rating scale was used to measure RLS severity. Hospital Anxiety and Depression Scale (HADS) was used to evaluate the levels of depression and anxiety and Short Form-36 (SF-36) to evaluate health related quality of life (HRQOL). RESULTS: A total of 62 MM patients were evaluated. Among them 11 were identified by the screening questionnaire to meet the criteria for RLS (17.74%). MM patients with RLS had higher levels of depression (P < 0.01) and anxiety (P < 0.01) and poorer HRQOL compared with those without RLS. CONCLUSIONS: The frequency of RLS in MM patients is higher than that of expected in the general population. MM patients afflicted by RLS have significantly higher levels of depression, anxiety and poorer HRQOL. Recognition and treatment of RLS in MM patients may be an important target in clinical management and may improve overall health outcomes in these patients. PMID- 23024735 TI - Clinical and magnetic resonance imaging findings of the temporomandibular joint in patients with rheumatoid arthritis. AB - BACKGROUND: The aim of this study is to evaluate temporomandibular joint (TMJ) involvement in patients with rheumatoid arthritis by magnetic resonance imaging (MRI), jaw clenching force, mouth opening, and Fonseca's questionnaire, and to establish the relationship between these findings and clinical, radiologic, and laboratory activity parameters that are unique to rheumatoid arthritis. METHODS: Included in the study were 30 RA patients and 30 healthy volunteers. Jaw clenching force of the entire cases was measured with Istanbul Bite Force Recorder (kg) and the mouth opening was measured with a ruler (cm). Additionally, hand grip forces of patients with rheumatoid arthritis were measured with hand dynamometer (kg). Hand and feet graphs and TMJ MRIs of patients were obtained. MRI findings were classified as normal, mild, medium, and severe. DAS28 and sharp scores of patients were estimated. Sedimentation rate (ESR), C-Reactive protein (CRP) and rheumatoid factor (RF) were checked in the patient group and Fonseca's questionnaires were filled in. RESULTS: A significant difference was not observed between age, gender, and level of education of the groups. Jaw clenching force and mouth opening were established as significantly low in RA group compared to the control group (P < 0.001). A significant correlation was found between jaw clenching force, hand grip force, mouth opening, questionnaire, and MRI findings with the disease duration sharp score, DAS28, and hand grip force of the RA group (P < 0.05). However, a significant correlation was not established with ESR, CRP, and RF (P < 0.001). CONCLUSIONS: Jaw clenching force, mouth opening, and Fonseca's questionnaire can be used as parameters pointing to TMJ involvement in patients with RA. Yet, further studies in which TMJ involvement is followed up since the onset of the disease are of necessity. PMID- 23024736 TI - Assessment of sleep-related breathing disorders in patients with duchenne muscular dystrophy. AB - BACKGROUND: Respiratory failure is a significant cause of morbidity and mortality in neuromuscular diseases. Although clinical findings and respiratory function tests aid in diagnosing sleep-related breathing disorders, polysomnography is the gold standard for the diagnosis of these disorders. We aimed to investigate the role of sleep-wake symptoms and clinical findings of patients with Duchenne muscular dystrophy (DMD) in predicting sleep-related breathing disorders through the comparison of polysomnography findings. In addition, we evaluated the sleep architecture of our patients. METHODS: A total of 35 children (12 patients with DMD and 23 controls) were included in this cross-sectional study. Activity status and clinical severity of the patients were determined by history and clinical findings such as scoliosis, obesity. All subjects were hospitalized for one night in the Sleep Unit and their polysomnography examinations were performed. Sleep, breathing, arousals and limb movements were scored manually according to the American Sleep Disorders Association criteria. RESULTS: Nocturnal and daytime symptoms were present in 50% of patients with DMD, 40.8% were wheelchair-bound and 58% had scoliosis. Obstructive sleep apnea was noted in 16.6% of patients with DMD. The apnea-hypopnea index, leg movement index were significantly higher in the DMD group as compared to the control group (P < 0.05). The number of desaturations, total arousal index and the percentage of total superficial sleep were significantly higher in patients with wheelchair, scoliosis, sleep-wake symptoms. CONCLUSIONS: Being wheelchair-bound or having scoliosis do not predict sleep-related breathing disorders, so patients with DMD should be followed-up via polysomnography. Sleep-wake symptoms should be carefully questioned in these patients and symptomatic patients should be referred to pediatric respiratory units. PMID- 23024737 TI - Emergency Department Pneumonia Patients Who do not Meet the Six-Hour Criteria for Antibiotic Administration: Do They Have a Different Clinical Presentation? AB - BACKGROUND: The Joint Commission (JC) has set a quality of care standard for emergency department (ED) patients diagnosed with community acquired pneumonia (CAP) that states that they are to receive antibiotics within six hours of presentation to the ED. Hospitals have been able to demonstrate that the majority of patients meet these criteria, yet there are still many who do not. Previously published studies have reported that there are several issues that contribute to prolonged times to antibiotic administration including ED crowding and atypical clinical presentations. This study was undertaken to identify factors existing early in the patient encounter that may be associated with failure to meet the Joint Commission's six-hour standard for antibiotic administration. METHODS: This was an IRB-approved, retrospective observational study covering 36 months in an academic emergency department. All adults with an admission diagnosis of CAP were eligible but were excluded if their discharge diagnosis was not CAP, if hospitalized within the previous 14 days, or if HIV positive. Univariate analysis and multiple logistic regression with stepwise variable selection were performed comparing patients who met and did not meet JC standards. The analysis included demographics (age, sex), chief complaint at triage and to doctor (fever, dyspnea, cough, chest pain, weakness/fatigue, abdominal pain), presence of altered mental status, triage vital signs, co-morbidities, day of week and time of day of presentation. RESULTS: A total of 736 cases were eligible; 199 cases met exclusion criteria; 43 charts were unavailable; 494 were included in the study group (363 with complete antibiotic time records; 131 were incomplete). From the univariate analysis, respiratory rate (RR) and oxygen saturation were the only factors that met Bonferroni criteria for statistical significance when comparing those who met and did not meet the JC six-hour criteria (RR 25 +/- 9 vs 22 +/- 6 breaths/minute, respectively, P = 0.002; oxygen saturation 87 +/- 10% vs 92 +/- 5%, respectively, P < 0.001). Multiple logistic regression identified triage pulse rate, oxygen saturation, presence of altered mental status, hour of day, and day of week as variables associated with time to antibiotic administration. Chances for meeting the standard were increased by 10% for each 5-beat increase in pulse rate or 1% decrease in oxygen saturation. If the person exhibited altered mental status, they were > 3.5 times more likely to meet the 6-hour criteria. If they presented to ED between 3 PM and 10 PM chances of meeting criteria were reduced by about 65%. If they presented on a Thursday, chances improved 2.8 times. CONCLUSIONS: Compared to patients who did meet Joint Commission criteria, those who did not receive antibiotics within 6 hours were likely to have triage pulse rates and O(2) saturation levels closer to normal, thus contributing to diagnostic uncertainty. They were also likely to present to the ED at the most crowded time of day. Likelihood to meet JC criteria was improved if O(2) saturation was below normal, pulse rate was elevated, if they exhibited mental confusion, or if they presented to the ED very early or very late in the day, or on a lower census day. PMID- 23024738 TI - Intraoperative adrenal insufficiency in a patient with prader-willi syndrome. AB - Prader-Willi syndrome (PW) is a rare genetic disorder with multi-organ system involvement. These patients present many perioperative challenges including sleep related breathing disorders, morbid obesity, thick salivary secretions, mental retardation, and difficult intravenous access. PW has been suggested to be associated with central adrenal insufficiency. We report a novel case of persistent severe hypotension from previously undiagnosed and asymptomatic adrenal insufficiency in a pediatric patient with Prader-Willi syndrome during spine surgery that resolved upon treatment with hydrocortisone. PMID- 23024739 TI - Severe erosive esophagitis developing after gastric ulcer formation. AB - A 90-year-old woman visited to our institute due to postprandial obstructive sensation of the esophagus. She had suffered from ischemic heart disease and diabetes mellitus, and taken low-dose aspirin for prophylaxis. She also had a history of a large ulcer located on the upper gastric body at 81 years-old. Esophago-gastric junction was normal excepting mild hiatal hernia at that time. The esophagogastroduodenoscopy showed a lump of food at the lower esophagus with severe stricture and mucosal injury. Rabeprazole 20 mg per day was given, and both the inflammatory change and the symptoms improved after the prescription. A probable reason of the development is impaired gastroesophageal motility and acid regurgitation induced by gastric deformity caused after ulcer formation. PMID- 23024740 TI - Ruptured Duodenal Varices Successfully Managed by Endoscopic N-butyl-2 cyanoacrylate Injection. AB - Bleeding from ectopic varices is rare and accounts for only 1% and 5% of all variceal bleeding. However, once the bleeding starts, it becomes difficult to control and is sometimes fatal. We faced a 65-year-old man with ruptured duodenal varices and injected N-butyl-2-cyanoacrylate into the spurting duodenal varices. As a result, oozing was successfully controlled. Subsequently, the patient remained hemodynamically stable, and no repeat -butyl-2-cyanoacrylate injection was needed. He was finally discharged one week later and has been followed-up for the last one year with no signs and symptoms to suggest any recurrence of bleeding. PMID- 23024741 TI - Isolated cavernous hemangioma: a rare benign lesion of the stomach. AB - Gastric cavernous hemangioma is a relatively rare benign gastric disease. Here we report the case of a 25-year-old male patient who had been admitted complaining of epigastric pain and hematemesis. Preoperative imaging indicated that the mass lesion palpated in the epigastric region was a probable mesenchymal tumor of gastric origin. Due to the hypervascular nature and submucosal localization of the mass, we did not obtain definitive preoperative diagnosis by endoscopic biopsy. The histologic diagnosis of cavernous hemangioma was confirmed by post resection histopathologial evaluation of the mass. PMID- 23024742 TI - Limited cutaneous vasculitis associated with levamisole-adulterated cocaine. AB - Levamisole is among the many contaminants that have been detected in seized cocaine throughout North America and Europe. Little is known about the association between levamisole-adulterated cocaine and vasculitis. Herein we describe a case of limited cutaneous vasculitis manifested as retiform purpura and skin necrosis in a user of cocaine contaminated with levamisole. PMID- 23024743 TI - Protective vaccination against infectious bursal disease virus with whole recombinant Kluyveromyces lactis yeast expressing the viral VP2 subunit. AB - Here we report on vaccination approaches against infectious bursal disease (IBD) of poultry that were performed with complete yeast of the species Kluyveromyces lactis (K. lactis). Employing a genetic system that enables the rapid production of stably transfected recombinant K. lactis, we generated yeast strains that expressed defined quantities of the virus capsid forming protein VP2 of infectious bursal disease virus (IBDV). Both, subcutaneous as well as oral vaccination regiments with the heat-inactivated but otherwise untreated yeast induced IBDV-neutralizing antibodies in mice and chickens. A full protection against a subsequent IBDV infection was achieved by subcutaneous inoculation of only milligram amounts of yeast per chicken. Oral vaccination also generated protection: while mortality was observed in control animals after virus challenge, none of the vaccinees died and ca. one-tenth were protected as indicated by the absence of lesions in the bursa of Fabricius. Recombinant K. lactis was thus indicated as a potent tool for the induction of a protective immune response by different applications. Subcutaneously applied K. lactis that expresses the IBDV VP2 was shown to function as an efficacious anti-IBD subunit vaccine. PMID- 23024744 TI - Listeria monocytogenes differential transcriptome analysis reveals temperature dependent Agr regulation and suggests overlaps with other regulons. AB - Listeria monocytogenes is a ubiquitous, opportunistic pathogenic organism. Environmental adaptation requires constant regulation of gene expression. Among transcriptional regulators, AgrA is part of an auto-induction system. Temperature is an environmental cue critical for in vivo adaptation. In order to investigate how temperature may affect AgrA-dependent transcription, we compared the transcriptomes of the parental strain L. monocytogenes EGD-e and its DeltaagrA mutant at the saprophytic temperature of 25 degrees C and in vivo temperature of 37 degrees C. Variations of transcriptome were higher at 37 degrees C than at 25 degrees C. Results suggested that AgrA may be involved in the regulation of nitrogen transport, amino acids, purine and pyrimidine biosynthetic pathways and phage-related functions. Deregulations resulted in a growth advantage at 37 degrees C, but affected salt tolerance. Finally, our results suggest overlaps with PrfA, sigmaB, sigmaH and CodY regulons. These overlaps may suggest that through AgrA, Listeria monocytogenes integrates information on its biotic environment. PMID- 23024746 TI - Evolution of bombesin conjugates for targeted PET imaging of tumors. AB - Bombesin receptors are under intense investigation as molecular targets since they are overexpressed in several prevalent solid tumors. We rationally designed and synthesized a series of modified bombesin (BN) peptide analogs to study the influence of charge and spacers at the N-terminus, as well as amino acid substitutions, on both receptor binding affinity and pharmacokinetics. This enabled development of a novel (64/67)Cu-labeled BN peptide for PET imaging and targeted radiotherapy of BN receptor-positive tumors. Our results show that N terminally positively charged peptide ligands had significantly higher affinity to human gastrin releasing peptide receptor (GRPr) than negatively charged or uncharged ligands (IC(50): 3.2+/-0.5 vs 26.3+/-3.5 vs 41.5+/-2.5 nM). The replacement of Nle(14) by Met, and deletion of D-Tyr(6), further resulted in 8 fold higher affinity. Contrary to significant changes to human GRPr binding, modifications at the N-terminal and at the 6(th), 11(th), and 14(th) position of BN induced only slight influences on affinity to mouse GRPr. [Cu(II)]-CPTA [betaAla(11)] BN(7-14) ([Cu(II)]-BZH7) showed the highest internalization rate into PC-3 cells with relatively slow efflux because of its subnanomolar affinity to GRPr. Interestingly, [(64/67)Cu]-BZH7 also displayed similar affinities to the other 2 human BN receptor subtypes. In vivo studies showed that [(64/67)Cu]-BZH7 had a high accumulation in PC-3 xenografts and allowed for clear-cut visualization of the tumor in PET imaging. In addition, a CPTA-glycine derivative, forming a hippurane-type spacer, enhanced kidney clearance of the radiotracer. These data indicate that the species variation of BN receptor plays an important role in screening radiolabeled BN. As well, the positive charge from the metallated complex at the N-terminal significantly increases affinity to human GRPr. Application of these observations enabled the novel ligand [(64/67)Cu]-BZH7 to clearly visualize PC-3 tumors in vivo. This study provides a strong starting point for optimizing radiopeptides for targeting carcinomas that express any of the BN receptor subtypes. PMID- 23024745 TI - Different patterns of expression and of IL-10 modulation of inflammatory mediators from macrophages of Lyme disease-resistant and -susceptible mice. AB - C57BL/6J (C57) mice develop mild arthritis (Lyme disease-resistant) whereas C3H/HeN (C3H) mice develop severe arthritis (Lyme disease-susceptible) after infection with the spirochete Borrelia burgdorferi. We hypothesized that susceptibility and resistance to Lyme disease, as modeled in mice, is associated with early induction and regulation of inflammatory mediators by innate immune cells after their exposure to live B. burgdorferi spirochetes. Here, we employed multiplex ELISA and qRT-PCR to investigate quantitative differences in the levels of cytokines and chemokines produced by bone marrow-derived macrophages from C57 and C3H mice after these cells were exposed ex vivo to live spirochetes or spirochetal lipoprotein. Upon stimulation, the production of both cytokines and chemokines was up-regulated in macrophages from both mouse strains. Interestingly, however, our results uncovered two distinct patterns of spirochete and lipoprotein-inducible inflammatory mediators displayed by mouse macrophages, such that the magnitude of the chemokine up-regulation was larger in C57 cells than it was in C3H cells, for most chemokines. Conversely, cytokine up-regulation was more intense in C3H cells. Gene transcript analyses showed that the displayed patterns of inflammatory mediators were associated with a TLR2/TLR1 transcript imbalance: C3H macrophages expressed higher TLR2 transcript levels as compared to those expressed by C57 macrophages. Exogenous IL-10 dampened production of inflammatory mediators, especially those elicited by lipoprotein stimulation. Neutralization of endogenously produced IL-10 increased production of inflammatory mediators, notably by macrophages of C57 mice, which also displayed more IL-10 than C3H macrophages. The distinct patterns of pro-inflammatory mediator production, along with TLR2/TLR1 expression, and regulation in macrophages from Lyme disease-resistant and -susceptible mice suggests itself as a blueprint to further investigate differential pathogenesis of Lyme disease. PMID- 23024747 TI - Quantitative modeling assesses the contribution of bond strengthening, rebinding and force sharing to the avidity of biomolecule interactions. AB - Cell adhesion is mediated by numerous membrane receptors. It is desirable to derive the outcome of a cell-surface encounter from the molecular properties of interacting receptors and ligands. However, conventional parameters such as affinity or kinetic constants are often insufficient to account for receptor efficiency. Avidity is a qualitative concept frequently used to describe biomolecule interactions: this includes incompletely defined properties such as the capacity to form multivalent attachments. The aim of this study is to produce a working description of monovalent attachments formed by a model system, then to measure and interpret the behavior of divalent attachments under force. We investigated attachments between antibody-coated microspheres and surfaces coated with sparse monomeric or dimeric ligands. When bonds were subjected to a pulling force, they exhibited both a force-dependent dissociation consistent with Bell's empirical formula and a force- and time-dependent strengthening well described by a single parameter. Divalent attachments were stronger and less dependent on forces than monovalent ones. The proportion of divalent attachments resisting a force of 30 piconewtons for at least 5 s was 3.7 fold higher than that of monovalent attachments. Quantitative modeling showed that this required rebinding, i.e. additional bond formation between surfaces linked by divalent receptors forming only one bond. Further, experimental data were compatible with but did not require stress sharing between bonds within divalent attachments. Thus many ligand-receptor interactions do not behave as single-step reactions in the millisecond to second timescale. Rather, they exhibit progressive stabilization. This explains the high efficiency of multimerized or clustered receptors even when bonds are only subjected to moderate forces. Our approach provides a quantitative way of relating binding avidity to measurable parameters including bond maturation, rebinding and force sharing, provided these parameters have been determined. Also, this provides a quantitative description of the phenomenon of bond strengthening. PMID- 23024748 TI - Catabolic signaling pathways, atrogenes, and ubiquitinated proteins are regulated by the nutritional status in the muscle of the fine flounder. AB - A description of the intracellular mechanisms that modulate skeletal muscle atrophy in early vertebrates is still lacking. In this context, we used the fine flounder, a unique and intriguing fish model, which exhibits remarkably slow growth due to low production of muscle-derived IGF-I, a key growth factor that has been widely acknowledged to prevent and revert muscle atrophy. Key components of the atrophy system were examined in this species using a detailed time-course of sampling points, including two contrasting nutritional periods. Under basal conditions high amounts of the atrogenes MuRF-1 and Atrogin-1 were observed. During fasting, the activation of the P38/MAPK and Akt/FoxO signaling pathways decreased; whereas, the activation of the IkappaBalpha/NFkappaB pathway increased. These changes in signal transduction activation were concomitant with a strong increase in MuRF-1, Atrogin-1, and protein ubiquitination. During short term refeeding, the P38/MAPK and Akt/FoxO signaling pathways were strongly activated, whereas the activation of the IkappaBalpha/NFkappaB pathway decreased significantly. The expression of both atrogenes, as well as the ubiquitination of proteins, dropped significantly during the first hour of refeeding, indicating a strong anti-atrophic condition during the onset of refeeding. During long-term refeeding, Akt remained activated at higher than basal levels until the end of refeeding, and Atrogin-1 expression remained significantly lower during this period. This study shows that the components of the atrophy system in skeletal muscle appeared early in the evolution of vertebrates and some mechanisms have been conserved, whereas others have not. These results represent an important achievement for the area of fish muscle physiology, showing an integrative view of the atrophy system in a non-mammalian species and contributing to novel insights on the molecular basis of muscle growth regulation in earlier vertebrates. PMID- 23024749 TI - Aleuria Aurantia Lectin (AAL)-reactive immunoglobulin G rapidly appears in sera of animals following antigen exposure. AB - We have discovered an Aleuria Aurantia Lectin (AAL)-reactive immunoglobulin G (IgG) that naturally occurs in the circulation of rabbits and mice, following immune responses induced by various foreign antigens. AAL can specifically bind to fucose moieties on glycoproteins. However, most serum IgGs are poorly bound by AAL unless they are denatured or treated with glycosidase. In this study, using an immunogen-independent AAL-antibody microarray assay that we developed, we detected AAL-reactive IgG in the sera of all animals that had been immunized 1-2 weeks previously with various immunogens with and without adjuvants and developed immunogen-specific responses. All of these animals subsequently developed immunogen-specific immune responses. The kinetics of the production of AAL reactive IgG in mice and rabbits were distinct from those of the immunogen specific IgGs elicited in the same animals: they rose and fell within one to two weeks, and peaked between four to seven days after exposure, while immunogen specific IgGs continued to rise during the same period. Mass spectrometric profiling of the Fc glycoforms of purified AAL-reactive IgGs indicates that these are mainly comprised of IgGs with core-fucosylated and either mono-or non galactosylated Fc N-glycan structures. Our results suggest that AAL-reactive IgG could be a previously unrecognized IgG subset that is selectively produced at the onset of a humoral response. PMID- 23024750 TI - Improvement of disease prediction and modeling through the use of meteorological ensembles: human plague in Uganda. AB - Climate and weather influence the occurrence, distribution, and incidence of infectious diseases, particularly those caused by vector-borne or zoonotic pathogens. Thus, models based on meteorological data have helped predict when and where human cases are most likely to occur. Such knowledge aids in targeting limited prevention and control resources and may ultimately reduce the burden of diseases. Paradoxically, localities where such models could yield the greatest benefits, such as tropical regions where morbidity and mortality caused by vector borne diseases is greatest, often lack high-quality in situ local meteorological data. Satellite- and model-based gridded climate datasets can be used to approximate local meteorological conditions in data-sparse regions, however their accuracy varies. Here we investigate how the selection of a particular dataset can influence the outcomes of disease forecasting models. Our model system focuses on plague (Yersinia pestis infection) in the West Nile region of Uganda. The majority of recent human cases have been reported from East Africa and Madagascar, where meteorological observations are sparse and topography yields complex weather patterns. Using an ensemble of meteorological datasets and model averaging techniques we find that the number of suspected cases in the West Nile region was negatively associated with dry season rainfall (December-February) and positively with rainfall prior to the plague season. We demonstrate that ensembles of available meteorological datasets can be used to quantify climatic uncertainty and minimize its impacts on infectious disease models. These methods are particularly valuable in regions with sparse observational networks and high morbidity and mortality from vector-borne diseases. PMID- 23024752 TI - On the fair division of multiple stochastic pies to multiple agents within the Nash bargaining solution. AB - The fair division of a surplus is one of the most widely examined problems. This paper focuses on bargaining problems with fixed disagreement payoffs where risk neutral agents have reached an agreement that is the Nash-bargaining solution (NBS). We consider a stochastic environment, in which the overall return consists of multiple pies with uncertain sizes and we examine how these pies can be allocated with fairness among agents. Specifically, fairness is based on the Aristotle's maxim: "equals should be treated equally and unequals unequally, in proportion to the relevant inequality". In this context, fairness is achieved when all the individual stochastic surplus shares which are allocated to agents are distributed in proportion to the NBS. We introduce a novel algorithm, which can be used to compute the ratio of each pie that should be allocated to each agent, in order to ensure fairness within a symmetric or asymmetric NBS. PMID- 23024751 TI - Determinants of recovery from severe posterior reversible encephalopathy syndrome. AB - OBJECTIVE: Few outcome data are available about posterior reversible encephalopathy syndrome (PRES). We studied 90-day functional outcomes and their determinants in patients with severe PRES. DESIGN: 70 patients with severe PRES admitted to 24 ICUs in 2001-2010 were included in a retrospective cohort study. The main outcome measure was a Glasgow Outcome Scale (GOS) of 5 (good recovery) on day 90. MAIN RESULTS: Consciousness impairment was the most common clinical sign, occurring in 66 (94%) patients. Clinical seizures occurred in 57 (81%) patients. Median mean arterial pressure was 122 (105-143) mmHg on scene. Cerebral imaging abnormalities were bilateral (93%) and predominated in the parietal (93%) and occipital (86%) white matter. Median number of brain areas involved was 4 (3 5). Imaging abnormalities resolved in 43 (88%) patients. Ischaemic and/or haemorrhagic complications occurred in 7 (14%) patients. The most common causes were drug toxicity (44%) and hypertensive encephalopathy (41%). On day 90, 11 (16%) patients had died, 26 (37%) had marked functional impairments (GOS, 2 to 4), and 33 (56%) had a good recovery (GOS, 5). Factors independently associated with GOS<5 were highest glycaemia on day 1 (OR, 1.22; 95%CI, 1.02-1.45, p = 0.03) and time to causative-factor control (OR, 3.3; 95%CI, 1.04-10.46, p = 0.04), whereas GOS = 5 was associated with toxaemia of pregnancy (preeclampsia/eclampsia) (OR, 0.06; 95%CI, 0.01-0.38, p = 0.003). CONCLUSIONS: By day 90 after admission for severe PRES, 44% of survivors had severe functional impairments. Highest glycaemia on day 1 and time to causative-factor control were strong early predictors of outcomes, suggesting areas for improvement. PMID- 23024753 TI - The dose-response decrease in heart rate variability: any association with the metabolites of polycyclic aromatic hydrocarbons in coke oven workers? AB - BACKGROUND: Air pollution has been associated with an increased risk of cardiopulmonary mortality and decreased heart rate variability (HRV). However, it is unclear whether coke oven emissions (COEs) and polycyclic aromatic hydrocarbons (PAHs) are associated with HRV. OBJECTIVES: Our goal in the present study was to investigate the association of exposure to COEs and the urinary metabolite profiles of PAHs with HRV of coke oven workers. METHODS: We measured benzene soluble matter, carbon monoxide, sulfur dioxide, particulate matters, and PAHs at different workplaces of a coke oven plant. We determined 10 urinary PAH metabolites and HRV indices of 1333 workers using gas chromatography-mass spectrometry and a 3-channel digital Holter monitor, respectively. RESULTS: Our results showed that there was a significant COEs-related dose-dependent decrease in HRV, and an inverse relationship between the quartiles of urinary 2 hydroxynaphthalene and five HRV indices (p(trend)<0.01 for all). After adjustment for potential confounders, elevation per interquartile range (IQR) (1.81 ug/mmol creatinine) of urinary 2-hydroxynaphthalene was associated with a 5.46% (95% CI, 2.50-8.32) decrease in standard deviation of NN intervals (SDNN). As workers worked more years, SDNN gradually declined in the same quartiles of 2 hydroxynaphthalene levels (p(trend) = 1.40*10(-4)), especially in workers with the highest levels of 2-hydroxynaphthalene. CONCLUSIONS: Occupational exposure to COEs is associated with a dose-response decrease in HRV. In particular, increased exposure to 2-hydroxynaphthalene is associated with significantly decreased HRV. Increase of working years and exposure levels has resulted in a gradual decline of HRV. PMID- 23024754 TI - ROD1 is a seedless target gene of hypoxia-induced miR-210. AB - Most metazoan microRNA (miRNA) target sites have perfect pairing to the "seed" sequence, a highly conserved region centering on miRNA nucleotides 2-7. Thus, complementarity to this region is a necessary requirement for target prediction algorithms. However, also non-canonical miRNA binding can confer target regulation. Here, we identified a seedless target of miR-210, a master miRNA of the hypoxic response. We analyzed 20 genes that were inversely correlated to miR 210 expression and did not display any complementarity with miR-210 seed sequence. We validated ROD1 (Regulator of Differentiation 1, also named PTBP3, Polypyrimidine Tract Binding protein 3) as a miR-210 seedless transcript enriched in miR-210-containing RNA-induced silencing complexes. ROD1 was not indirectly targeted by a miR-210-induced miRNA. Conversely, we identified a "centered" miR 210 binding site in ROD1 involving 10 consecutive bases in the central portion of miR-210. Reporter assays showed that miR-210 inhibited ROD1 by the direct binding to this sequence, demonstrating that ROD1 is a bona fide seedless target of miR 210. As expected, both ROD1 mRNA and protein were down-modulated upon hypoxia in a miR-210 dependent manner. ROD1 targeting by miR-210 was biologically significant: the rescue of ROD1 inhibition significantly increased hypoxia induced cell death. These data highlight the importance of ROD1 regulation by miR 210 for cell homeostasis. PMID- 23024755 TI - Dietary administration of scallion extract effectively inhibits colorectal tumor growth: cellular and molecular mechanisms in mice. AB - Colorectal cancer is a common malignancy and a leading cause of cancer death worldwide. Diet is known to play an important role in the etiology of colon cancer and dietary chemoprevention is receiving increasing attention for prevention and/or alternative treatment of colon cancers. Allium fistulosum L., commonly known as scallion, is popularly used as a spice or vegetable worldwide, and as a traditional medicine in Asian cultures for treating a variety of diseases. In this study we evaluated the possible beneficial effects of dietary scallion on chemoprevention of colon cancer using a mouse model of colon carcinoma (CT-26 cells subcutaneously inoculated into BALB/c mice). Tumor lysates were subjected to western blotting for analysis of key inflammatory markers, ELISA for analysis of cytokines, and immunohistochemistry for analysis of inflammatory markers. Metabolite profiles of scallion extracts were analyzed by LC-MS/MS. Scallion extracts, particularly hot-water extract, orally fed to mice at 50 mg (dry weight)/kg body weight resulted in significant suppression of tumor growth and enhanced the survival rate of test mice. At the molecular level, scallion extracts inhibited the key inflammatory markers COX-2 and iNOS, and suppressed the expression of various cellular markers known to be involved in tumor apoptosis (apoptosis index), proliferation (cyclin D1 and c-Myc), angiogenesis (VEGF and HIF-1alpha), and tumor invasion (MMP-9 and ICAM-1) when compared with vehicle control-treated mice. Our findings may warrant further investigation of the use of common scallion as a chemopreventive dietary agent to lower the risk of colon cancer. PMID- 23024756 TI - Isolation and characterization of canine amniotic membrane-derived multipotent stem cells. AB - Recent studies have shown that amniotic membrane tissue is a rich source of stem cells in humans. In clinical applications, the amniotic membrane tissue had therapeutic effects on wound healing and corneal surface reconstruction. Here, we successfully isolated and identified multipotent stem cells (MSCs) from canine amniotic membrane tissue. We cultured the canine amniotic membrane-derived multipotent stem cells (cAM-MSCs) in low glucose DMEM medium. cAM-MSCs have a fibroblast-like shape and adhere to tissue culture plastic. We characterized the immunophenotype of cAM-MSCs by flow cytometry and measured cell proliferation by the cumulative population doubling level (CPDL). We performed differentiation studies for the detection of trilineage multipotent ability, under the appropriate culture conditions. Taken together, our results show that cAM-MSCs could be a rich source of stem cells in dogs. Furthermore, cAM-MSCs may be useful as a cell therapy application for veterinary regenerative medicine. PMID- 23024757 TI - Soluble MICA and a MICA variation as possible prognostic biomarkers for HBV induced hepatocellular carcinoma. AB - MHC class I polypeptide-related chain A (MICA) molecule is induced in response to viral infection and various types of stress. We recently reported that a single nucleotide polymorphism (SNP) rs2596542 located in the MICA promoter region was significantly associated with the risk for hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) and also with serum levels of soluble MICA (sMICA). In this study, we focused on the possible involvement of MICA in liver carcinogenesis related to hepatitis B virus (HBV) infection and examined correlation between the MICA polymorphism and the serum sMICA levels in HBV induced HCC patients. The genetic association analysis revealed a nominal association with an SNP rs2596542; a G allele was considered to increase the risk of HBV-induced HCC (P = 0.029 with odds ratio of 1.19). We also found a significant elevation of sMICA in HBV-induced HCC cases. Moreover, a G allele of SNP rs2596542 was significantly associated with increased sMICA levels (P = 0.009). Interestingly, HCC patients with the high serum level of sMICA (>5 pg/ml) exhibited poorer prognosis than those with the low serum level of sMICA (<=5 pg/ml) (P = 0.008). Thus, our results highlight the importance of MICA genetic variations and the significance of sMICA as a predictive biomarker for HBV induced HCC. PMID- 23024758 TI - Global microRNA profiling of the mouse ventricles during development of severe hypertrophic cardiomyopathy and heart failure. AB - MicroRNAs (miRNAs) regulate post-transcriptional gene expression during development and disease. We have determined the miRNA expression levels of early- and end-stage hypertrophic cardiomyopathy (HCM) in a severe, transgenic mouse model of the disease. Five miRNAs were differentially expressed at an early stage of HCM development. Time-course analysis revealed that decreased expression of miR-1 and miR-133a commences at a pre-disease stage, and precedes upregulation of target genes causal of cardiac hypertrophy and extracellular matrix remodelling, suggesting a role for miR-1 and miR-133a in early disease development. At end stage HCM, 16 miRNA are dysregulated to form an expression profile resembling that of other forms of cardiac hypertrophy, suggesting common responses. Analysis of the mRNA transcriptome revealed that miRNAs potentially target 15.7% upregulated and 4.8% downregulated mRNAs at end-stage HCM, and regulate mRNAs associated with cardiac hypertrophy and electrophysiology, calcium signalling, fibrosis, and the TGF-beta signalling pathway. Collectively, these results define the miRNA expression signatures during development and progression of severe HCM and highlight critical miRNA regulated gene networks that are involved in disease pathogenesis. PMID- 23024759 TI - Bisphenol A alters n-6 fatty acid composition and decreases antioxidant enzyme levels in rat testes: a LC-QTOF-based metabolomics study. AB - BACKGROUND: Male reproductive toxicity induced by exposure to bisphenol A (BPA) has been widely reported. The testes have proven to be a major target organ of BPA toxicity, so studying testicular metabolite variation holds promise for the discovery of mechanisms linked to the toxic effects of BPA on reproduction. METHODOLOGY/PRINCIPAL FINDINGS: Male Sprague-Dawley rats were orally administered doses of BPA at the levels of 0, 50 mg/kg/d for 8 weeks. We used an unbiased liquid chromatography-quadrupole time-of-flight (LC-QTOF)-based metabolomics approach to discover, identify, and analyze the variation of testicular metabolites. Two n-6 fatty acids, linoleic acid (LA) and arachidonic acid (AA) were identified as potential testicular biomarkers. Decreased levels of LA and increased levels of AA as well as AA/LA ratio were observed in the testes of the exposed group. According to these suggestions, testicular antioxidant enzyme levels were detected. Testicular superoxide dismutase (SOD) declined significantly in the exposed group compared with that in the non-exposed group, and the glutathione peroxidase (GSH-Px) as well as catalase (CAT) also showed a decreasing trend in BPA treated group. CONCLUSIONS/SIGNIFICANCE: BPA caused testicular n-6 fatty acid composition variation and decreased antioxidant enzyme levels. This study emphasizes that metabolomics brings the promise of biomarkers identification for the discovery of mechanisms underlying reproductive toxicity. PMID- 23024760 TI - Critical role of Klf5 in regulating gene expression during post-eyelid opening maturation of mouse corneas. AB - BACKGROUND: Klf5 plays an important role in maturation and maintenance of the mouse ocular surface. Here, we quantify WT and Klf5-conditional null (Klf5CN) corneal gene expression, identify Klf5-target genes and compare them with the previously identified Klf4-target genes to understand the molecular basis for non redundant functions of Klf4 and Klf5 in the cornea. METHODOLOGY/PRINCIPAL FINDINGS: Postnatal day-11 (PN11) and PN56 WT and Klf5CN corneal transcriptomes were quantified by microarrays to compare gene expression in maturing WT corneas, identify Klf5-target genes, and compare corneal Klf4- and Klf5-target genes. Whole-mount corneal immunofluorescent staining was employed to examine CD45+ cell influx and neovascularization. Effect of Klf5 on expression of desmosomal components was studied by immunofluorescent staining and transient co transfection assays. Expression of 714 and 753 genes was increased, and 299 and 210 genes decreased in PN11 and PN56 Klf5CN corneas, respectively, with 366 concordant increases and 72 concordant decreases. PN56 Klf5CN corneas shared 241 increases and 98 decreases with those previously described in Klf4CN corneas. Xenobiotic metabolism related pathways were enriched among genes decreased in Klf5CN corneas. Expression of angiogenesis and immune response-related genes was elevated, consistent with neovascularization and CD45+ cell influx in Klf5CN corneas. Expression of 1574 genes was increased and 1915 genes decreased in WT PN56 compared with PN11 corneas. Expression of ECM-associated genes decreased, while that of solute carrier family members increased in WT PN56 compared with PN11 corneas. Dsg1a, Dsg1b and Dsp were down-regulated in Klf5CN corneas and their corresponding promoter activities were stimulated by Klf5 in transient co transfection assays. CONCLUSIONS/SIGNIFICANCE: Differences between PN11 and PN56 corneal Klf5-target genes reveal dynamic changes in functions of Klf5 during corneal maturation. Klf5 contributes to corneal epithelial homeostasis by regulating the expression of desmosomal components. Klf4- and Klf5-target genes are largely distinct, consistent with their non-redundant roles in the mouse cornea. PMID- 23024761 TI - Skeletal muscle growth hormone receptor signaling regulates basal, but not fasting-induced, lipid oxidation. AB - BACKGROUND: Growth hormone (GH) stimulates whole-body lipid oxidation, but its regulation of muscle lipid oxidation is not clearly defined. Mice with a skeletal muscle-specific knockout of the GH receptor (mGHRKO model) are protected from high fat diet (HFD)-induced insulin resistance and display increased whole-body carbohydrate utilization. In this study we used the mGRHKO mice to investigate the role of muscle GHR signaling on lipid oxidation under regular chow (RC)- and HFD- fed conditions, and in response to fasting. METHODOLOGY/PRINCIPAL FINDINGS: Expression of lipid oxidation genes was analyzed by real-time PCR in the muscles of RC- and HFD- fed mice, and after 24 h fasting in the HFD-fed mice. Expression of lipid oxidation genes was lower in the muscles of the mGHRKO mice relative to the controls, irrespective of diet. However, in response to 24 h fasting, the HFD fed mGHRKO mice displayed up-regulation of lipid oxidation genes similar to the fasted controls. When subjected to treadmill running challenge, the HFD-fed mGHRKO mice demonstrated increased whole-body lipid utilization. Additionally, under fasted conditions, the adipose tissue of the mGHRKO mice displayed increased lipolysis as compared to both the fed mGHRKO as well as the fasted control mice. CONCLUSIONS/SIGNIFICANCE: Our data show that muscle GHR signaling regulates basal lipid oxidation, but not the induction of lipid oxidation in response to fasting. We further demonstrate that muscle GHR signaling is involved in muscle-adipose tissue cross-talk; however the mechanisms mediating this remain to be elucidated. PMID- 23024762 TI - Kinin B1 receptor in adipocytes regulates glucose tolerance and predisposition to obesity. AB - BACKGROUND: Kinins participate in the pathophysiology of obesity and type 2 diabetes by mechanisms which are not fully understood. Kinin B(1) receptor knockout mice (B(1) (-/-)) are leaner and exhibit improved insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that kinin B(1) receptors in adipocytes play a role in controlling whole body insulin action and glucose homeostasis. Adipocytes isolated from mouse white adipose tissue (WAT) constitutively express kinin B(1) receptors. In these cells, treatment with the B(1) receptor agonist des-Arg(9)-bradykinin improved insulin signaling, GLUT4 translocation, and glucose uptake. Adipocytes from B(1) (-/-) mice showed reduced GLUT4 expression and impaired glucose uptake at both basal and insulin-stimulated states. To investigate the consequences of these phenomena to whole body metabolism, we generated mice where the expression of the kinin B(1) receptor was limited to cells of the adipose tissue (aP2-B(1)/B(1) (-/-)). Similarly to B(1) ( /-) mice, aP2-B(1)/B(1) (-/-) mice were leaner than wild type controls. However, exclusive expression of the kinin B(1) receptor in adipose tissue completely rescued the improved systemic insulin sensitivity phenotype of B(1) (-/-) mice. Adipose tissue gene expression analysis also revealed that genes involved in insulin signaling were significantly affected by the presence of the kinin B(1) receptor in adipose tissue. In agreement, GLUT4 expression and glucose uptake were increased in fat tissue of aP2-B(1)/B(1) (-/-) when compared to B(1) (-/-) mice. When subjected to high fat diet, aP2-B(1)/B(1) (-/-) mice gained more weight than B(1) (-/-) littermates, becoming as obese as the wild types. CONCLUSIONS/SIGNIFICANCE: Thus, kinin B(1) receptor participates in the modulation of insulin action in adipocytes, contributing to systemic insulin sensitivity and predisposition to obesity. PMID- 23024763 TI - Characterization of PbPga1, an antigenic GPI-protein in the pathogenic fungus Paracoccidioides brasiliensis. AB - Paracoccidioides brasiliensis is the etiologic agent of paracoccidioidomycosis (PCM), one of the most prevalent mycosis in Latin America. P. brasiliensis cell wall components interact with host cells and influence the pathogenesis of PCM. Cell wall components, such as glycosylphosphatidylinositol (GPI)-proteins play a critical role in cell adhesion and host tissue invasion. Although the importance of GPI-proteins in the pathogenesis of other medically important fungi is recognized, little is known about their function in P. brasiliensis cells and PCM pathogenesis. We cloned the PbPga1 gene that codifies for a predicted GPI anchored glycoprotein from the dimorphic pathogenic fungus P. brasiliensis. PbPga1 is conserved in Eurotiomycetes fungi and encodes for a protein with potential glycosylation sites in a serine/threonine-rich region, a signal peptide and a putative glycosylphosphatidylinositol attachment signal sequence. Specific chicken anti-rPbPga1 antibody localized PbPga1 on the yeast cell surface at the septum between the mother cell and the bud with stronger staining of the bud. The exposure of murine peritoneal macrophages to rPbPga1 induces TNF-alpha release and nitric oxide (NO) production by macrophages. Furthermore, the presence of O glycosylation sites was demonstrated by beta-elimination under ammonium hydroxide treatment of rPbPga1. Finally, sera from PCM patients recognized rPbPga1 by Western blotting indicating the presence of specific antibodies against rPbPga1. In conclusion, our findings suggest that the PbPga1gene codifies for a cell surface glycoprotein, probably attached to a GPI-anchor, which may play a role in P. brasiliensis cell wall morphogenesis and infection. The induction of inflammatory mediators released by rPbPga1 and the reactivity of PCM patient sera toward rPbPga1 imply that the protein favors the innate mechanisms of defense and induces humoral immunity during P. brasiliensis infection. PMID- 23024764 TI - Towards regional, error-bounded landscape carbon storage estimates for data deficient areas of the world. AB - Monitoring landscape carbon storage is critical for supporting and validating climate change mitigation policies. These may be aimed at reducing deforestation and degradation, or increasing terrestrial carbon storage at local, regional and global levels. However, due to data-deficiencies, default global carbon storage values for given land cover types such as 'lowland tropical forest' are often used, termed 'Tier 1 type' analyses by the Intergovernmental Panel on Climate Change (IPCC). Such estimates may be erroneous when used at regional scales. Furthermore uncertainty assessments are rarely provided leading to estimates of land cover change carbon fluxes of unknown precision which may undermine efforts to properly evaluate land cover policies aimed at altering land cover dynamics. Here, we present a repeatable method to estimate carbon storage values and associated 95% confidence intervals (CI) for all five IPCC carbon pools (aboveground live carbon, litter, coarse woody debris, belowground live carbon and soil carbon) for data-deficient regions, using a combination of existing inventory data and systematic literature searches, weighted to ensure the final values are regionally specific. The method meets the IPCC 'Tier 2' reporting standard. We use this method to estimate carbon storage over an area of33.9 million hectares of eastern Tanzania, reporting values for 30 land cover types. We estimate that this area stored 6.33 (5.92-6.74) Pg C in the year 2000. Carbon storage estimates for the same study area extracted from five published Africa wide or global studies show a mean carbon storage value of ~50% of that reported using our regional values, with four of the five studies reporting lower carbon storage values. This suggests that carbon storage may have been underestimated for this region of Africa. Our study demonstrates the importance of obtaining regionally appropriate carbon storage estimates, and shows how such values can be produced for a relatively low investment. PMID- 23024765 TI - The synergistic effect of chemical carcinogens enhances Epstein-Barr virus reactivation and tumor progression of nasopharyngeal carcinoma cells. AB - Seroepidemiological studies imply a correlation between Epstein-Barr virus (EBV) reactivation and the development of nasopharyngeal carcinoma (NPC). N-nitroso compounds, phorbols, and butyrates are chemicals found in food and herb samples collected from NPC high-risk areas. These chemicals have been reported to be risk factors contributing to the development of NPC, however, the underlying mechanism is not fully understood. We have demonstrated previously that low dose N-methyl N'-nitro-N-nitrosoguanidine (MNNG, 0.1 ug/ml) had a synergistic effect with 12-O tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate (SB) in enhancing EBV reactivation and genome instability in NPC cells harboring EBV. Considering that residents in NPC high-risk areas may contact regularly with these chemical carcinogens, it is vital to elucidate the relation between chemicals and EBV and their contributions to the carcinogenesis of NPC. In this study, we constructed a cell culture model to show that genome instability, alterations of cancer hallmark gene expression, and tumorigenicity were increased after recurrent EBV reactivation in NPC cells following combined treatment of TPA/SB and MNNG. NPC cells latently infected with EBV, NA, and the corresponding EBV-negative cell, NPC-TW01, were periodically treated with MNNG, TPA/SB, or TPA/SB combined with MNNG. With chemically-induced recurrent reactivation of EBV, the degree of genome instability was significantly enhanced in NA cells treated with a combination of TPA/SB and MNNG than those treated individually. The Matrigel invasiveness, as well as the tumorigenicity in mouse, was also enhanced in NA cells after recurrent EBV reactivation. Expression profile analysis by microarray indicates that many carcinogenesis-related genes were altered after recurrent EBV reactivation, and several aberrations observed in cell lines correspond to alterations in NPC lesions. These results indicate that cooperation between chemical carcinogens can enhance the reactivation of EBV and, over recurrent reactivations, lead to alteration of cancer hallmark gene expression with resultant enhancement of tumorigenesis in NPC. PMID- 23024766 TI - Resurgence of HIV infection among men who have sex with men in Switzerland: mathematical modelling study. AB - BACKGROUND: New HIV infections in men who have sex with men (MSM) have increased in Switzerland since 2000 despite combination antiretroviral therapy (cART). The objectives of this mathematical modelling study were: to describe the dynamics of the HIV epidemic in MSM in Switzerland using national data; to explore the effects of hypothetical prevention scenarios; and to conduct a multivariate sensitivity analysis. METHODOLOGY/PRINCIPAL FINDINGS: The model describes HIV transmission, progression and the effects of cART using differential equations. The model was fitted to Swiss HIV and AIDS surveillance data and twelve unknown parameters were estimated. Predicted numbers of diagnosed HIV infections and AIDS cases fitted the observed data well. By the end of 2010, an estimated 13.5% (95% CI 12.5, 14.6%) of all HIV-infected MSM were undiagnosed and accounted for 81.8% (95% CI 81.1, 82.4%) of new HIV infections. The transmission rate was at its lowest from 1995-1999, with a nadir of 46 incident HIV infections in 1999, but increased from 2000. The estimated number of new infections continued to increase to more than 250 in 2010, although the reproduction number was still below the epidemic threshold. Prevention scenarios included temporary reductions in risk behaviour, annual test and treat, and reduction in risk behaviour to levels observed earlier in the epidemic. These led to predicted reductions in new infections from 2 to 26% by 2020. Parameters related to disease progression and relative infectiousness at different HIV stages had the greatest influence on estimates of the net transmission rate. CONCLUSIONS/SIGNIFICANCE: The model outputs suggest that the increase in HIV transmission amongst MSM in Switzerland is the result of continuing risky sexual behaviour, particularly by those unaware of their infection status. Long term reductions in the incidence of HIV infection in MSM in Switzerland will require increased and sustained uptake of effective interventions. PMID- 23024767 TI - Quantitative analysis of monocyte subpopulations in murine atherosclerotic plaques by multiphoton microscopy. AB - The progressive accumulation of monocyte-derived cells in the atherosclerotic plaque is a hallmark of atherosclerosis. However, it is now appreciated that monocytes represent a heterogeneous circulating population of cells that differ in functionality. New approaches are needed to investigate the role of monocyte subpopulations in atherosclerosis since a detailed understanding of their differential mobilization, recruitment, survival and emigration during atherogenesis is of particular importance for development of successful therapeutic strategies. We present a novel methodology for the in vivo examination of monocyte subpopulations in mouse models of atherosclerosis. This approach combines cellular labeling by fluorescent beads with multiphoton microscopy to visualize and monitor monocyte subpopulations in living animals. First, we show that multiphoton microscopy is an accurate and timesaving technique to analyze monocyte subpopulation trafficking and localization in plaques in excised tissues. Next, we demonstrate that multiphoton microscopy can be used to monitor monocyte subpopulation trafficking in atherosclerotic plaques in living animals. This novel methodology should have broad applications and facilitate new insights into the pathogenesis of atherosclerosis and other inflammatory diseases. PMID- 23024768 TI - Prevalent ciliate symbiosis on copepods: high genetic diversity and wide distribution detected using small subunit ribosomal RNA gene. AB - Toward understanding the genetic diversity and distribution of copepod-associated symbiotic ciliates and the evolutionary relationships with their hosts in the marine environment, we developed a small subunit ribosomal RNA gene (18S rDNA) based molecular method and investigated the genetic diversity and genotype distribution of the symbiotic ciliates on copepods. Of the 10 copepod species representing six families collected from six locations of Pacific and Atlantic Oceans, 9 were found to harbor ciliate symbionts. Phylogenetic analysis of the 391 ciliate 18S rDNA sequences obtained revealed seven groups (ribogroups), six (containing 99% of all the sequences) belonging to subclass Apostomatida, the other clustered with peritrich ciliate Vorticella gracilis. Among the Apostomatida groups, Group III were essentially identical to Vampyrophrya pelagica, and the other five groups represented the undocumented ciliates that were close to Vampyrophrya/Gymnodinioides/Hyalophysa. Group VI ciliates were found in all copepod species but one (Calanus sinicus), and were most abundant among all ciliate sequences obtained, indicating that they are the dominant symbiotic ciliates universally associated with copepods. In contrast, some ciliate sequences were found only in some of the copepods examined, suggesting the host selectivity and geographic differentiation of ciliates, which requires further verification by more extensive sampling. Our results reveal the wide occurrence and high genetic diversity of symbiotic ciliates on marine copepods and highlight the need to systematically investigate the host- and geography based genetic differentiation and ecological roles of these ciliates globally. PMID- 23024769 TI - Metabolic expenditures of lunge feeding rorquals across scale: implications for the evolution of filter feeding and the limits to maximum body size. AB - Bulk-filter feeding is an energetically efficient strategy for resource acquisition and assimilation, and facilitates the maintenance of extreme body size as exemplified by baleen whales (Mysticeti) and multiple lineages of bony and cartilaginous fishes. Among mysticetes, rorqual whales (Balaenopteridae) exhibit an intermittent ram filter feeding mode, lunge feeding, which requires the abandonment of body-streamlining in favor of a high-drag, mouth-open configuration aimed at engulfing a very large amount of prey-laden water. Particularly while lunge feeding on krill (the most widespread prey preference among rorquals), the effort required during engulfment involve short bouts of high-intensity muscle activity that demand high metabolic output. We used computational modeling together with morphological and kinematic data on humpback (Megaptera noveaangliae), fin (Balaenoptera physalus), blue (Balaenoptera musculus) and minke (Balaenoptera acutorostrata) whales to estimate engulfment power output in comparison with standard metrics of metabolic rate. The simulations reveal that engulfment metabolism increases across the full body size of the larger rorqual species to nearly 50 times the basal metabolic rate of terrestrial mammals of the same body mass. Moreover, they suggest that the metabolism of the largest body sizes runs with significant oxygen deficits during mouth opening, namely, 20% over maximum VO2 at the size of the largest blue whales, thus requiring significant contributions from anaerobic catabolism during a lunge and significant recovery after a lunge. Our analyses show that engulfment metabolism is also significantly lower for smaller adults, typically one-tenth to one-half VO2|max. These results not only point to a physiological limit on maximum body size in this lineage, but also have major implications for the ontogeny of extant rorquals as well as the evolutionary pathways used by ancestral toothed whales to transition from hunting individual prey items to filter feeding on prey aggregations. PMID- 23024770 TI - Gamma irradiation does not induce detectable changes in DNA methylation directly following exposure of human cells. AB - Environmental chemicals and radiation have often been implicated in producing alterations of the epigenome thus potentially contributing to cancer and other diseases. Ionizing radiation, released during accidents at nuclear power plants or after atomic bomb explosions, is a potentially serious health threat for the exposed human population. This type of high-energy radiation causes DNA damage including single- and double-strand breaks and induces chromosomal rearrangements and mutations, but it is not known if ionizing radiation directly induces changes in the epigenome of irradiated cells. We treated normal human fibroblasts and normal human bronchial epithelial cells with different doses of gamma-radiation emitted from a cesium 137 ((137)Cs) radiation source. After a seven-day recovery period, we analyzed global DNA methylation patterns in the irradiated and control cells using the methylated-CpG island recovery assay (MIRA) in combination with high-resolution microarrays. Bioinformatics analysis revealed only a small number of potential methylation changes with low fold-difference ratios in the irradiated cells. These minor methylation differences seen on the microarrays could not be verified by COBRA (combined bisulfite restriction analysis) or bisulfite sequencing of selected target loci. Our study shows that acute gamma radiation treatment of two types of human cells had no appreciable direct effect on DNA cytosine methylation patterns in exposed cells. PMID- 23024771 TI - Differential risk factors for lacunar stroke depending on the MRI (white and red) subtypes of microangiopathy. AB - BACKGROUND: Leukoaraiosis and cerebral microbleeds (CMB), which represent cerebral microangiopathy, commonly coexist in patients with acute lacunar stroke. Since they may have different impacts on stroke prognosis and treatment, it is important to know the factors associated with leukoaraiosis-predominant vs. CMB predominant microangiopathies. METHODS: We prospectively recruited 226 patients with acute lacunar infarction and divided them into four groups according to the Fazekas' score and the presence of CMB: mild, red (predominant CMB), white (predominant leukoaraiosis) and severe microangiopathy groups. For comparison, we also evaluated 50 patients with intracerebral hemorrhage (ICH). We evaluated the clinical and laboratory findings of microangiopathy subtypes in patients with acute lacunar stroke and then compared them with those of primary ICH. RESULTS: The risk factor profile was different among the groups. Patients with acute lacunar infarct but mild microangiopathy were younger, predominantly male, less hypertensive, and more frequently had smoking and heavy alcohol habits than other groups. The risk factor profile of red microangiopathy was similar to that of ICH but differed from that of white microangiopathy. The subjects in the white microangiopathy group were older and more frequently had diabetes than those in the red microangiopathy or ICH group. After adjustments for other factors, age [odds ratio (OR) 1.13; 95% confidence interval (CI) 1.08-1.18; p<0.001] and diabetes (OR 2.28; 95% CI 1.02-5.13; p = 0.045) were independently associated with white microangiopathy, and age (OR 1.05; 95% CI 1.01-1.08; p = 0.010) was independent predictor for red microangiopathy compared to mild microangiopathy. CONCLUSION: Patients with acute lacunar infarction have a different risk factor profile depending on microangiopathic findings. Our results indicate that diabetes may be an one of determinants of white (leukoaraiosis-predominant) microangiopathy, whereas smoking and alcohol habits in relatively young people may be a determinants of mild microangiopahic changes in patients with lacunar infarction. PMID- 23024772 TI - Harmonia axyridis (Coleoptera: Coccinellidae) exhibits no preference between Bt and non-Bt maize fed Spodoptera frugiperda (Lepidoptera: Noctuidae). AB - A recent shift in managing insect resistance to genetically engineered (GE) maize consists of mixing non-GE seed with GE seed known as "refuge in a bag", which increases the likelihood of predators encountering both prey fed Bt and prey fed non-Bt maize. We therefore conducted laboratory choice-test feeding studies to determine if a predator, Harmonia axyridis, shows any preference between prey fed Bt and non-Bt maize leaves. The prey species was Spodoptera frugiperda, which were fed Bt maize (MON-810), expressing the single Cry1Ab protein, or non-Bt maize. The predators were third instar larvae and female adults of H. axyridis. Individual predators were offered Bt and non-Bt fed prey larvae that had fed for 24, 48 or 72 h. Ten and 15 larvae of each prey type were offered to third instar and adult predators, respectively. Observations of arenas were conducted at 1, 2, 3, 6, 15 and 24 h after the start of the experiment to determine the number and type of prey eaten by each individual predator. Prey larvae that fed on non-Bt leaves were significantly larger than larvae fed Bt leaves. Both predator stages had eaten nearly all the prey by the end of the experiment. However, in all combinations of predator stage and prey age, the number of each prey type consumed did not differ significantly. ELISA measurements confirmed the presence of Cry1Ab in leaf tissue (23-33 ug/g dry weight) and S. frugiperda (2.1-2.2 ug/g), while mean concentrations in H. axyridis were very low (0.01-0.2 ug/g). These results confirm the predatory status of H. axyridis on S. frugiperda and that both H. axyridis adults and larvae show no preference between prey types. The lack of preference between Bt-fed and non-Bt-fed prey should act in favor of insect resistance management strategies using mixtures of GE and non-GE maize seed. PMID- 23024774 TI - HBsAg inhibits IFN-alpha production in plasmacytoid dendritic cells through TNF alpha and IL-10 induction in monocytes. AB - Type I Interferon (IFN) is one of the first lines of defense against viral infection. Plasmacytoid dendritic cells (pDCs) are professional IFN-alpha producing cells that play an important role in the antiviral immune response. Previous studies have reported that IFN-alpha production is impaired in chronic hepatitis B (CHB) patients. However, the mechanisms underlying the impairment in IFN-alpha production are not fully understood. Here, we report that plasma derived hepatitis B surface antigen (HBsAg) and HBsAg expressed in CHO cells can significantly inhibit toll like receptor (TLR) 9-mediated Interferon-alpha (IFN alpha) production in peripheral blood mononuclear cells (PBMCs) from healthy donors. Further analysis indicated that monocytes participate in the inhibitory effect of HBsAg on pDCs through the secretion of TNF-alpha and IL-10. Furthermore, TLR9 expression on pDCs was down-regulated by TNF-alpha, IL-10 and HBsAg treatment. This down-regulation may partially explain the inhibition of IFN alpha production in pDCs. In conclusion, we determined that HBsAg inhibited the production of IFN-alpha by pDCs through the induction of monocytes that secreted TNF-alpha and IL-10 and through the down-regulation of TLR9 expression on pDCs. These data may aid in the development of effective antiviral treatments and lead to the immune control of the viral infections. PMID- 23024773 TI - Increased renal versican expression is associated with progression of chronic kidney disease. AB - Novel prognostic markers for progression of kidney disease are needed to distinguish patients who might benefit from a more aggressive nephroprotective therapy. Expression of the proteoglycan versican was evaluated in renal transcriptomics profiles and in an independent set of 74 renal biopsies. Versican levels were correlated to histologic damage scores and to renal outcome, and versican expression and regulation was evaluated in vitro. In transcriptomics profiles of renal tissue versican was positively correlated with (i) histological parameters in kidney biopsies, (ii) progressive decline of renal function in proteinuric kidney diseases, and (iii) impaired renal function and histology scores in diabetic nephropathy. In an independent cohort of 74 biopsies of glomerular diseases renal RNA levels of versican isoforms V0 and V1, but not V2 and V3 correlated significantly with creatinine after a mean follow up time of 53 months. Versican isoforms V0 and V1 together with serum creatinine at time of biopsy and the degree of glomerulosclerosis predicted 20% and 24% of the variability of creatinine at follow up, which was significantly more than serum creatinine and histological parameters alone (16%). However, when patients with acute kidney failure at time of biopsy (n = 5) were excluded, the additive predictive value of versican V1 was only marginally higher (35%) than creatinine and glomerulosclerosis alone (34%). Versican isoforms V0 and V1 were primarily expressed in vitro in proximal tubule cells and in fibroblasts. The results in humans were confirmed in three rodent models of kidney disease, in which renal versican expression was significantly upregulated as compared to corresponding controls. These data show for the first time an association of renal versican isoform V0 and V1 expression with progressive renal disease. PMID- 23024775 TI - Post-transcriptional and epigenetic regulation of antigen processing machinery (APM) components and HLA-I in cervical cancers from Uighur women. AB - Normal function of human leukocyte antigen class I (HLA-I) and antigen processing machinery (APM) proteins is required for T cell-mediated anti-tumor or antiviral immunity, whereas the tumor survival indicates a failure of the host in immune surveillance associated with the dysfunction in antigen presentation, mainly due to the deregulation in HLA-I and APM expression or function. The posttranscriptional regulation of HLA-I and APM expression may associate with epigenetic modifications in cancer development which was not described so far. Here we showed that the development of cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (CSCC) in Uighur women was accompanied with the partial or total loss of protein expression of HLA-I, beta2-m and APM components, including the transporter associated with antigen processing (TAP1/2), low molecular mass protein (LMP2, LMP7), endoplasmic reticulum aminopeptidase 1(ERAP1), chaperone molecules include calreticulin (CLR), calnexin (CNX) and ERp57, and this was proved again by analysis of transcription of the same genes in addition to three genes HLA-A, B and C coding for HLA-I. By bisulfite sequencing approach, we identified target CpG islands methylated at the gene promoter region of TAP1, TAP2, LMP7, tapasin and ERp57 in cervical carcinoma cells. Further analysis of CpG site specific methylation of these genes in cases of CSCC and CIN demonstrated an inverse correlation of altered CpG island methylation of TAP1, LMP7, and ERp57 with changes in protein expression. Moreover, promoter methylation of these genes was significantly higher in cases positive for human papillomavirus 16 (HPV 16) than negative ones. Our results suggested that epigenetic modifications are responsible for the aberrant expression of certain HLA-I and APM genes, and may help to understand unrevealed mechanisms of tumor escape from immune surveillance in cervical carcinogenesis. PMID- 23024777 TI - Development of transgenic mice containing an introduced stop codon on the human methylmalonyl-CoA mutase locus. AB - The mutation R403stop was found in an individual with mut(0) methylmalonic aciduria (MMA) which resulted from a single base change of C->T in exon 6 of the methylmalonyl-CoA mutase gene (producing a TGA stop codon). In order to accurately model the human MMA disorder we introduced this mutation onto the human methylmalonyl-CoA mutase locus of a bacterial artificial chromosome. A mouse model was developed using this construct.The transgene was found to be intact in the mouse model, with 7 copies integrated at a single site in chromosome 3. The phenotype of the hemizygous mouse was unchanged until crossed against a methylmalonyl-CoA mutase knockout mouse. Pups with no endogenous mouse methylmalonyl-CoA mutase and one copy of the transgene became ill and died within 24 hours. This severe phenotype could be partially rescued by the addition of a transgene carrying two copies of the normal human methylmalonyl-CoA mutase locus. The "humanized" mice were smaller than control litter mates and had high levels of methylmalonic acid in their blood and tissues. This new transgenic MMA stop codon model mimics (at both the phenotypic and genotypic levels) the key features of the human MMA disorder. It will allow the trialing of pharmacological and, cell and gene therapies for the treatment of MMA and other human metabolic disorders caused by stop codon mutations. PMID- 23024776 TI - Asymptomatic endemic Chlamydia pecorum infections reduce growth rates in calves by up to 48 percent. AB - Intracellular Chlamydia (C.) bacteria cause in cattle some acute but rare diseases such as abortion, sporadic bovine encephalomyelitis, kerato conjunctivitis, pneumonia, enteritis and polyarthritis. More frequent, essentially ubiquitous worldwide, are low-level, asymptomatic chlamydial infections in cattle. We investigated the impact of these naturally acquired infections in a cohort of 51 female Holstein and Jersey calves from birth to 15 weeks of age. In biweekly sampling, we measured blood/plasma markers of health and infection and analyzed their association with clinical appearance and growth in dependence of chlamydial infection intensity as determined by mucosal chlamydial burden or contemporaneous anti-chlamydial plasma IgM. Chlamydia 23S rRNA gene PCR and ompA genotyping identified only C. pecorum (strains 1710S, Maeda, and novel strain Smith3v8) in conjunctival and vaginal swabs. All calves acquired the infection but remained clinically asymptomatic. High chlamydial infection associated with reduction of body weight gains by up to 48% and increased conjunctival reddening (P<10(-4)). Simultaneously decreased plasma albumin and increased globulin (P<10(-4)) suggested liver injury by inflammatory mediators as mechanisms for the growth inhibition. This was confirmed by the reduction of plasma insulin like growth factor-1 at high chlamydial infection intensity (P<10(-4)). High anti-C. pecorum IgM associated eight weeks later with 66% increased growth (P = 0.027), indicating a potential for immune protection from C. pecorum-mediated growth depression. The worldwide prevalence of chlamydiae in livestock and their high susceptibility to common feed-additive antibiotics suggests the possibility that suppression of chlamydial infections may be a major contributor to the growth promoting effect of feed-additive antibiotics. PMID- 23024778 TI - Highly doped carbon nanotubes with gold nanoparticles and their influence on electrical conductivity and thermopower of nanocomposites. AB - Carbon nanotubes (CNTs) are often used as conductive fillers in composite materials, but electrical conductivity is limited by the maximum filler concentration that is necessary to maintain composite structures. This paper presents further improvement in electrical conductivity by precipitating gold nanoparticles onto CNTs. In our composites, the concentrations of CNTs and poly (vinyl acetate) were respectively 60 and 10 vol%. Four different gold concentrations, 0, 10, 15, or 20 vol% were used to compare the influence of the gold precipitation on electrical conductivity and thermopower of the composites. The remaining portion was occupied by poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate), which de-bundled and stabilized CNTs in water during synthesis processes. The concentrations of gold nanoparticles are below the percolation threshold of similar composites. However, with 15-vol% gold, the electrical conductivity of our composites was as high as ~6*10(5) S/m, which is at least ~500% higher than those of similar composites as well as orders of magnitude higher than those of other polymer composites containing CNTs and gold particles. According to our analysis with a variable range hopping model, the high conductivity can be attributed to gold doping on CNT networks. Additionally, the electrical properties of composites made of different types of CNTs were also compared. PMID- 23024779 TI - Sepsis-induced acute lung injury (ALI) is milder in diabetic rats and correlates with impaired NFkB activation. AB - Acute lung injury (ALI) develops in response to a direct insult to the lung or secondarily to a systemic inflammatory response, such as sepsis. There is clinical evidence that the incidence and severity of ALI induced by direct insult are lower in diabetics. In the present study we investigated whether the same occurs in ALI secondarily to sepsis and the molecular mechanisms involved. Diabetes was induced in male Wistar rats by alloxan and sepsis by caecal ligation and puncture surgery (CLP). Six hours later, the lungs were examined for oedema and cell infiltration in bronchoalveolar lavage. Alveolar macrophages (AMs) were cultured in vitro for analysis of IkappaB and p65 subunit of NFkappaB phosphorylation and MyD88 and SOCS-1 mRNA. Diabetic rats were more susceptible to sepsis than non-diabetics. In non-diabetic rats, the lung presented oedema, leukocyte infiltration and increased COX2 expression. In diabetic rats these inflammatory events were significantly less intense. To understand why diabetic rats despite being more susceptible to sepsis develop milder ALI, we examined the NFkappaB activation in AMs of animals with sepsis. Whereas in non-diabetic rats the phosphorylation of IkappaB and p65 subunit occurred after 6 h of sepsis induction, this did not occur in diabetics. Moreover, in AMs from diabetic rats the expression of MyD88 mRNA was lower and that of SOCS-1 mRNA was increased compared with AMs from non-diabetic rats. These results show that ALI secondary to sepsis is milder in diabetic rats and this correlates with impaired activation of NFkappaB, increased SOCS-1 and decreased MyD88 mRNA. PMID- 23024781 TI - Respective contribution of chronic conditions to disability in France: results from the national Disability-Health Survey. AB - BACKGROUND: Representative national data on disability are becoming increasingly important in helping policymakers decide on public health strategies. We assessed the respective contribution of chronic health conditions to disability for three age groups (18-40, 40-65, and >65 years old) using data from the 2008-2009 Disability-Health Survey in France. METHODS: Data on 12 chronic conditions and on disability for 24,682 adults living in households were extracted from the Disability-Health Survey results. A weighting factor was applied to obtain representative estimates for the French population. Disability was defined as at least one restriction in activities of daily living (ADL), severe disability as the inability to perform at least one ADL alone, and self-reported disability as a general feeling of being disabled. To account for co-morbidities, we assessed the contribution of each chronic disorder to disability by using the average attributable fraction (AAF). FINDINGS: We estimated that 38.8 million people in France (81.7% [95% CI 80.9;82.6]) had a chronic condition: 14.3% (14.0;14.6) considered themselves disabled, 4.6% (4.4;4.9) were restricted in ADL and 1.7% (1.5;1.8) were severely disabled. Musculoskeletal and sensorial impairments contributed the most to self-reported disability (AAF 15.4% and 12.3%). Neurological and musculoskeletal diseases had the largest impact on disability (AAF 17.4% and 16.4%, respectively). Neurological disorders contributed the most to severe disability (AAF 31.0%). Psychiatric diseases contributed the most to disability categories for patients 18-40 years old (AAFs 23.8%-40.3%). Cardiovascular conditions were also among the top four contributors to disability categories (AAFs 8.5%-11.1%). CONCLUSIONS: Neurological, musculoskeletal, and cardiovascular chronic disorders mainly contribute to disability in France. Psychiatric impairments have a heavy burden for people 18-40 years old. These findings should help policymakers define priorities for health-service delivery in France and perhaps other developed countries. PMID- 23024780 TI - High glucose predisposes gene expression and ERK phosphorylation to apoptosis and impaired glucose-stimulated insulin secretion via the cytoskeleton. AB - Chronic high glucose (HG) inflicts glucotoxicity on vulnerable cell types such as pancreatic beta cells and contributes to insulin resistance and impaired insulin secretion in diabetic patients. To identify HG-induced cellular aberrations that are candidate mediators of glucotoxicity in pancreatic beta cells, we analyzed gene expression in ERoSHK6, a mouse insulin-secreting cell line after chronic HG exposure (six-day exposure to 33.3 mM glucose). Chronic HG exposure which reduced glucose-stimulated insulin secretion (GSIS) increased transcript levels of 185 genes that clustered primarily in 5 processes namely cellular growth and proliferation; cell death; cellular assembly and organization; cell morphology; and cell-to-cell signaling and interaction. The former two were validated by increased apoptosis of ERoSHK6 cells after chronic HG exposure and reaffirmed the vulnerability of beta cells to glucotoxicity. The three remaining processes were partially substantiated by changes in cellular morphology and structure, and instigated an investigation of the cytoskeleton and cell-cell adhesion. These studies revealed a depolymerized actin cytoskeleton that lacked actin stress fibers anchored at vinculin-containing focal adhesion sites as well as loss of E cadherin-mediated cell-cell adherence after exposure to chronic HG, and were concomitant with constitutive ERK1/2 phosphorylation that was refractory to serum and glucose deprivation. Although inhibition of ERK phosphorylation by PD98059 promoted actin polymerization, it increased apoptosis and GSIS impairment. These findings suggest that ERK phosphorylation is a proximate regulator of cellular processes targeted by chronic HG-induced gene expression and that dynamic actin polymerization and depolymerization is important in beta cell survival and function. Therefore, chronic HG alters gene expression and signal transduction to predispose the cytoskeleton towards apoptosis and GSIS impairment. PMID- 23024782 TI - Variation at innate immunity Toll-like receptor genes in a bottlenecked population of a New Zealand robin. AB - Toll-like receptors (TLRs) are an ancient family of genes encoding transmembrane proteins that bind pathogen-specific molecules and initiate both innate and adaptive aspects of the immune response. Our goal was to determine whether these genes show sufficient genetic diversity in a bottlenecked population to be a useful addition or alternative to the more commonly employed major histocompatibility complex (MHC) genotyping in a conservation genetics context. We amplified all known avian TLR genes in a severely bottlenecked population of New Zealand's Stewart Island robin (Petroica australis rakiura), for which reduced microsatellite diversity was previously observed. We genotyped 17-24 birds from a reintroduced island population (including the 12 founders) for nine genes, seven of which were polymorphic. We observed a total of 24 single nucleotide polymorphisms overall, 15 of which were non-synonymous, representing up to five amino-acid variants at a locus. One locus (TLR1LB) showed evidence of past directional selection. Results also confirmed a passerine duplication of TLR7. The levels of TLR diversity that we observe are sufficient to justify their further use in addressing conservation genetic questions, even in bottlenecked populations. PMID- 23024783 TI - Population, behavioural and physiological responses of an urban population of black swans to an intense annual noise event. AB - Wild animals in urban environments are exposed to a broad range of human activities that have the potential to disturb their life history and behaviour. Wildlife responses to disturbance can range from emigration to modified behaviour, or elevated stress, but these responses are rarely evaluated in concert. We simultaneously examined population, behavioural and hormonal responses of an urban population of black swans Cygnus atratus before, during and after an annual disturbance event involving large crowds and intense noise, the Australian Formula One Grand Prix. Black swan population numbers were lowest one week before the event and rose gradually over the course of the study, peaking after the event, suggesting that the disturbance does not trigger mass emigration. We also found no difference in the proportion of time spent on key behaviours such as locomotion, foraging, resting or self-maintenance over the course of the study. However, basal and capture stress-induced corticosterone levels showed significant variation, consistent with a modest physiological response. Basal plasma corticosterone levels were highest before the event and decreased over the course of the study. Capture-induced stress levels peaked during the Grand Prix and then also declined over the remainder of the study. Our results suggest that even intensely noisy and apparently disruptive events may have relatively low measurable short-term impact on population numbers, behaviour or physiology in urban populations with apparently high tolerance to anthropogenic disturbance. Nevertheless, the potential long-term impact of such disturbance on reproductive success, individual fitness and population health will need to be carefully evaluated. PMID- 23024784 TI - Leukaemia inhibitory factor stimulates proliferation of olfactory neuronal progenitors via inducible nitric oxide synthase. AB - Neurogenesis continues in the adult brain and in the adult olfactory epithelium. The cytokine, leukaemia inhibitory factor and nitric oxide are both known to stimulate neuronal progenitor cell proliferation in the olfactory epithelium after injury. Our aim here was to determine whether these observations are independent, specifically, whether leukaemia inhibitory factor triggers neural precursor proliferation via the inducible nitric oxide synthase pathway. We evaluated the effects of leukaemia inhibitory factor on inducible form of nitric oxide synthase (iNOS) expression, and cell proliferation in olfactory epithelial cell cultures and olfactory neurosphere-derived cells. Leukaemia inhibitory factor induced expression of iNOS and increased cell proliferation. An iNOS inhibitor and an anti-leukaemia inhibitory factor receptor blocking antibody inhibited leukaemia inhibitory factor-induced cell proliferation, an effect that was reversed by a NO donor. Altogether, the results strongly suggest that leukaemia inhibitory factor induces iNOS expression, increasing nitric oxide levels, to stimulate proliferation of olfactory neural precursor cells. This finding sheds light on neuronal regeneration occurring after injury of the olfactory epithelium. PMID- 23024785 TI - Acid sphingomyelinase gene knockout ameliorates hyperhomocysteinemic glomerular injury in mice lacking cystathionine-beta-synthase. AB - Acid sphingomyelinase (ASM) has been implicated in the development of hyperhomocysteinemia (hHcys)-induced glomerular oxidative stress and injury. However, it remains unknown whether genetically engineering of ASM gene produces beneficial or detrimental action on hHcys-induced glomerular injury. The present study generated and characterized the mice lacking cystathionine beta-synthase (Cbs) and Asm mouse gene by cross breeding Cbs(+/-) and Asm(+/-) mice. Given that the homozygotes of Cbs(-/-/)Asm(-/-) mice could not survive for 3 weeks. Cbs(+/ /)Asm(+/+), Cbs(+/-/)Asm(+/-) and Cbs(+/-/)Asm(-/-) as well as their Cbs wild type littermates were used to study the role of Asm(-/-) under a background of Cbs(+/-) with hHcys. HPLC analysis revealed that plasma Hcys level was significantly elevated in Cbs heterozygous (Cbs(+/-)) mice with different copies of Asm gene compared to Cbs(+/+) mice with different Asm gene copies. Cbs(+/ /)Asm(+/+) mice had significantly increased renal Asm activity, ceramide production and O(2.)(-) level compared to Cbs(+/+)/Asm(+/+), while Cbs(+/-/)Asm( /-) mice showed significantly reduced renal Asm activity, ceramide production and O(2.)(-) level due to increased plasma Hcys levels. Confocal microscopy demonstrated that colocalization of podocin with ceramide was much lower in Cbs(+/-/)Asm(-/-) mice compared to Cbs(+/-/)Asm(+/+) mice, which was accompanied by a reduced glomerular damage index, albuminuria and proteinuria in Cbs(+/ /)Asm(-/-) mice. Immunofluorescent analyses of the podocin, nephrin and desmin expression also illustrated less podocyte damages in the glomeruli from Cbs(+/ /)Asm(-/-) mice compared to Cbs(+/-/)Asm(+/+) mice. In in vitro studies of podocytes, hHcys-enhanced O(2.)(-) production, desmin expression, and ceramide production as well as decreases in VEGF level and podocin expression in podocytes were substantially attenuated by prior treatment with amitriptyline, an Asm inhibitor. In conclusion, Asm gene knockout or corresponding enzyme inhibition protects the podocytes and glomeruli from hHcys-induced oxidative stress and injury. PMID- 23024786 TI - The role of lipid raft aggregation in the infection of type II pneumocytes by Mycobacterium tuberculosis. AB - Dynamic, cholesterol-dense regions of the plasma membrane, known as lipid rafts (LR), have been observed to develop during and may be directly involved in infection of host cells by various pathogens. This study focuses on LR aggregation induced in alveolar epithelial cells during infection with Mycobacterium tuberculosis (Mtb) bacilli. We report dose- and time-dependent increases in LR aggregation after infection with three different strains at multiplicities of infection of 1, 10 and 100 from 2-24 hr post infection (hpi). Specific strain-dependent variations were noted among H37Rv, HN878 and CDC1551 with H37Rv producing the most significant increase from 15 aggregates per cell (APC) to 27 APC at MOI 100 during the 24 hour infection period. Treatment of epithelial cells with Culture Filtrate Protein, Total Lipids and gamma-irradiated whole cells from each strain failed to induce the level of LR aggregation observed during infection with any of the live strains. However, filtered supernatants from infected epithelial cells did produce comparable LR aggregation, suggesting a secreted mycobacterial product produced during infection of host cells is responsible for LR aggregation. Disruption of lipid raft formation prior to infection indicates that Mtb bacilli utilize LR aggregates for internalization and survival in epithelial cells. Treatment of host cells with the LR-disruption agent Filipin III produced a nearly 22% reduction in viable bacteria for strains H37Rv and HN878, and a 7% reduction for strain CDC1551 after 6 hpi. This study provides evidence for significant mycobacterial-induced changes in the plasma membrane of alveolar epithelial cells and that Mtb strains vary in their ability to facilitate aggregation and utilization of LR. PMID- 23024787 TI - Dynamin 1 regulates amyloid generation through modulation of BACE-1. AB - BACKGROUND: Several lines of investigation support the notion that endocytosis is crucial for Alzheimer's disease (AD) pathogenesis. Substantial evidence have already been reported regarding the mechanisms underlying amyloid precursor protein (APP) traffic, but the regulation of beta-site APP-Cleaving Enzyme 1 (BACE-1) distribution among endosomes, TGN and plasma membrane remains unclear. Dynamin, an important adaptor protein that controls sorting of many molecules, has recently been associated with AD but its functions remain controversial. Here we studied possible roles for dynamin 1 (dyn1) in Abeta biogenesis. PRINCIPAL FINDINGS: We found that genetic perturbation of dyn1 reduces both secreted and intracellular Abeta levels in cell culture. There is a dramatic reduction in BACE 1 cleavage products of APP (sAPPbeta and betaCTF). Moreover, dyn1 knockdown (KD) leads to BACE-1 redistribution from the Golgi-TGN/endosome to the cell surface. There is an increase in the amount of surface holoAPP upon dyn1 KD, with resultant elevation of alpha-secretase cleavage products sAPPalpha and alphaCTF. But no changes are seen in the amount of nicastrin (NCT) or PS1 N-terminal fragment (NTF) at cell surface with dyn1 KD. Furthermore, treatment with a selective dynamin inhibitor Dynasore leads to similar reduction in betaCTF and Abeta levels, comparable to changes with BACE inhibitor treatment. But combined inhibition of BACE-1 and dyn1 does not lead to further reduction in Abeta, suggesting that the Abeta-lowering effects of dynamin inhibition are mainly mediated through regulation of BACE-1 internalization. Abeta levels in dyn1(-/-) primary neurons, as well as in 3-month old dyn1 haploinsufficient animals with AD transgenic background are consistently reduced when compared to their wildtype counterparts. CONCLUSIONS: In summary, these data suggest a previously unknown mechanism by which dyn1 affects amyloid generation through regulation of BACE-1 subcellular localization and therefore its enzymatic activities. PMID- 23024788 TI - Elevated serum ferritin is associated with reduced survival in amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by the loss of motor neurons. Its etiology remains unknown, but several hypothesis have been raised to explain motor neuron death, including oxidative stress. Dysregulation of cellular iron metabolism can lead to increased oxidative stress, and existing data argue for a role of iron metabolism in ALS pathophysiology. METHODS: We performed a retrospective analysis of iron metabolism (IM) variables (serum levels of iron, transferrin, ferritin, and TSC for Transferrin Saturation Coefficient) in a cohort of 694 ALS patients and 297 healthy controls. RESULTS: Serum ferritin levels and TSC were higher, whereas serum transferrin levels were lower in ALS patients than controls. In addition, patients with a high level serum ferritin had a shorter survival time compared to those with low level serum ferritin (618 days versus 921 days for men subgroup; p = .007). Site of onset and ALS-FRS score were not associated with IM variables. CONCLUSION: This study suggests that ALS patients may have increased iron storage, as measured by increased serum ferritin and TSC. Elevated serum ferritin may also have a deleterious impact on survival in ALS. PMID- 23024789 TI - Conserved non-coding regulatory signatures in Arabidopsis co-expressed gene modules. AB - Complex traits and other polygenic processes require coordinated gene expression. Co-expression networks model mRNA co-expression: the product of gene regulatory networks. To identify regulatory mechanisms underlying coordinated gene expression in a tissue-enriched context, ten Arabidopsis thaliana co-expression networks were constructed after manually sorting 4,566 RNA profiling datasets into aerial, flower, leaf, root, rosette, seedling, seed, shoot, whole plant, and global (all samples combined) groups. Collectively, the ten networks contained 30% of the measurable genes of Arabidopsis and were circumscribed into 5,491 modules. Modules were scrutinized for cis regulatory mechanisms putatively encoded in conserved non-coding sequences (CNSs) previously identified as remnants of a whole genome duplication event. We determined the non-random association of 1,361 unique CNSs to 1,904 co-expression network gene modules. Furthermore, the CNS elements were placed in the context of known gene regulatory networks (GRNs) by connecting 250 CNS motifs with known GRN cis elements. Our results provide support for a regulatory role of some CNS elements and suggest the functional consequences of CNS activation of co-expression in specific gene sets dispersed throughout the genome. PMID- 23024790 TI - Histone deacetylase inhibitors induce epithelial-to-mesenchymal transition in prostate cancer cells. AB - Clinical experience of histone deacetylase inhibitors (HDACIs) in patients with solid tumors has been disappointing; however, the molecular mechanism of treatment failure is not known. Therefore, we sought to investigate the molecular mechanism of treatment failure of HDACIs in the present study. We found that HDACIs Trichostatin A (TSA) and Suberoylanilide hydroxamic acid (SAHA) could induce epithelial-to-mesenchymal transition (EMT) phenotype in prostate cancer (PCa) cells, which was associated with changes in cellular morphology consistent with increased expression of transcription factors ZEB1, ZEB2 and Slug, and mesenchymal markers such as vimentin, N-cadherin and Fibronectin. CHIP assay showed acetylation of histone 3 on proximal promoters of selected genes, which was in part responsible for increased expression of EMT markers. Moreover, TSA treatment led to further increase in the expression of Sox2 and Nanog in PCa cells with EMT phenotype, which was associated with cancer stem-like cell (CSLC) characteristics consistent with increased cell motility. Our results suggest that HDACIs alone would lead to tumor aggressiveness, and thus strategies for reverting EMT-phenotype to mesenchymal-to-epithelial transition (MET) phenotype or the reversal of CSLC characteristics prior to the use of HDACIs would be beneficial to realize the value of HDACIs for the treatment of solid tumors especially PCa. PMID- 23024791 TI - Prenatal exposure to TCDD triggers significant modulation of microRNA expression profile in the thymus that affects consequent gene expression. AB - BACKGROUND: MicroRNAs (miRs) are a class of small RNAs that regulate gene expression. There are over 700 miRs encoded in the mouse genome and modulate most of the cellular pathways and functions by controlling gene expression. However, there is not much known about the pathophysiological role of miRs. TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin), an environmental contaminant is well known to induce severe toxicity (acute and chronic) with long-term effects. Also, in utero exposure of fetus to TCDD has been shown to cause thymic atrophy and alterations in T cell differentiation. It is also relevant to understand "the fetal basis of adult disease" hypothesis, which proposes that prenatal exposure to certain forms of nutritional and environmental stress can cause increased susceptibility to clinical disorders later in life. In the current study, therefore, we investigated the effects of prenatal exposure to TCDD on miR profile in fetal thymocytes and searched for their possible role in causing thymic atrophy and alterations in the expression of apoptotic genes. METHODOLOGY/PRINCIPAL FINDINGS: miR arrays of fetal thymocytes post exposure to TCDD and vehicle were performed. Of the 608 mouse miRs screened, 78 miRs were altered more than 1.5 fold and 28 miRs were changed more than 2 fold in fetal thymocytes post-TCDD exposure when compared to vehicle controls. We validated the expression of several of the miRs using RT-PCR. Furthermore, several of the miRs that were downregulated contained highly complementary sequence to the 3'-UTR region of AhR, CYP1A1, Fas and FasL. Also, the Ingenuity Pathway Analysis software and database was used to analyze the 78 miRs that exhibited significant expression changes and revealed that as many as 15 pathways may be affected. CONCLUSIONS/SIGNIFICANCE: These studies revealed that TCDD-mediated alterations in miR expression may be involved in the regulation of its toxicity including cancer, hepatic injury, apoptosis, and cellular development. PMID- 23024792 TI - The inhibition of autophagy sensitises colon cancer cells with wild-type p53 but not mutant p53 to topotecan treatment. AB - BACKGROUND: Topotecan produces DNA damage that induces autophagy in cancer cells. In this study, sensitising topotecan to colon cancer cells with different P53 status via modulation of autophagy was examined. METHODOLOGY/PRINCIPAL FINDINGS: The DNA damage induced by topotecan treatment resulted in cytoprotective autophagy in colon cancer cells with wild-type p53. However, in cells with mutant p53 or p53 knockout, treatment with topotecan induced autophagy-associated cell death. In wild-type p53 colon cancer cells, topotecan treatment activated p53, upregulated the expression of sestrin 2, induced the phosphorylation of the AMPKalpha subunit at Thr172, and inhibited the mTORC1 pathway. Furthermore, the inhibition of autophagy enhanced the anti-tumour effect of topotecan treatment in wild-type p53 colon cancer cells but alleviated the anti-tumour effect of topotecan treatment in p53 knockout cells in vivo. CONCLUSIONS/SIGNIFICANCE: These results imply that the wild-type p53-dependent induction of cytoprotective autophagy is one of the cellular responses that determines the cellular sensitivity to the DNA-damaging drug topotecan. Therefore, our study provides a potential therapeutic strategy that utilises a combination of DNA-damaging agents and autophagy inhibitors for the treatment of colon cancer with wild-type p53. PMID- 23024793 TI - FliC, a flagellin protein, is essential for the growth and virulence of fish pathogen Edwardsiella tarda. AB - Edwardsiella tarda is a flagellated gram-negative bacterium which causes edwardsiellosis in fish. FliC, as a flagellar filament structural protein, is hypothesized to be involved in the pathogenesis of infection. In this study, a fliC in-frame deletion mutant of a virulent isolate of E. tarda was constructed through double crossover allelic exchange by means of the suicide vector pRE112, and its virulence-associated phenotypes and pathogenicity were tested. It was found that the deletion of fliC significantly decreased the diameter of flagella filaments. In addition, the mutant showed reduced pathogenicity to fish by increasing the LD(50) value for 100-fold compared to the wild-type strain, as well as showed impaired bacterial growth, reduced motility, decreased biofilm formation and reduced levels of virulence-associated protein secretion involved in the type III secretion system (TTSS). The phenotypic characteristics of the fliC deletion mutant uncovered in this investigation suggest that fliC plays an essential role in normal flagellum function, bacterial growth, protein secretion by TTSS and bacterial virulence. PMID- 23024794 TI - Evaluation of a novel assay for detection of the fetal marker RASSF1A: facilitating improved diagnostic reliability of noninvasive prenatal diagnosis. AB - BACKGROUND: Analysis of cell free fetal (cff) DNA in maternal plasma is used routinely for non invasive prenatal diagnosis (NIPD) of fetal sex determination, fetal rhesus D status and some single gene disorders. True positive results rely on detection of the fetal target being analysed. No amplification of the target may be interpreted either as a true negative result or a false negative result due to the absence or very low levels of cffDNA. The hypermethylated RASSF1A promoter has been reported as a universal fetal marker to confirm the presence of cffDNA. Using methylation-sensitive restriction enzymes hypomethylated maternal sequences are digested leaving hypermethylated fetal sequences detectable. Complete digestion of maternal sequences is required to eliminate false positive results. METHODS: cfDNA was extracted from maternal plasma (n = 90) and digested with methylation-sensitive and insensitive restriction enzymes. Analysis of RASSF1A, SRY and DYS14 was performed by real-time PCR. RESULTS: Hypermethylated RASSF1A was amplified for 79 samples (88%) indicating the presence of cffDNA. SRY real time PCR results and fetal sex at delivery were 100% accurate. Eleven samples (12%) had no detectable hypermethylated RASSF1A and 10 of these (91%) had gestational ages less than 7 weeks 2 days. Six of these samples were male at delivery, five had inconclusive results for SRY analysis and one sample had no amplifiable SRY. CONCLUSION: Use of this assay for the detection of hypermethylated RASSF1A as a universal fetal marker has the potential to improve the diagnostic reliability of NIPD for fetal sex determination and single gene disorders. PMID- 23024795 TI - A peak-clustering method for MEG group analysis to minimise artefacts due to smoothness. AB - Magnetoencephalography (MEG), a non-invasive technique for characterizing brain electrical activity, is gaining popularity as a tool for assessing group-level differences between experimental conditions. One method for assessing task condition effects involves beamforming, where a weighted sum of field measurements is used to tune activity on a voxel-by-voxel basis. However, this method has been shown to produce inhomogeneous smoothness differences as a function of signal-to-noise across a volumetric image, which can then produce false positives at the group level. Here we describe a novel method for group level analysis with MEG beamformer images that utilizes the peak locations within each participant's volumetric image to assess group-level effects. We compared our peak-clustering algorithm with SnPM using simulated data. We found that our method was immune to artefactual group effects that can arise as a result of inhomogeneous smoothness differences across a volumetric image. We also used our peak-clustering algorithm on experimental data and found that regions were identified that corresponded with task-related regions identified in the literature. These findings suggest that our technique is a robust method for group-level analysis with MEG beamformer images. PMID- 23024796 TI - Dia-interacting protein (DIP) imposes migratory plasticity in mDia2-dependent tumor cells in three-dimensional matrices. AB - Tumor cells rely upon membrane pliancy to escape primary lesions and invade secondary metastatic sites. This process relies upon localized assembly and disassembly cycles of F-actin that support and underlie the plasma membrane. Dynamic actin generates both spear-like and bleb structures respectively characterizing mesenchymal and amoeboid motility programs utilized by metastatic cells in three-dimensional matrices. The molecular mechanism and physiological trigger(s) driving membrane plasticity are poorly understood. mDia formins are F actin assembly factors directing membrane pliancy in motile cells. mDia2 is functionally coupled with its binding partner DIP, regulating cortical actin and inducing membrane blebbing in amoeboid cells. Here we show that mDia2 and DIP co tether to nascent blebs and this linkage is required for bleb formation. DIP controls mesenchymal/amoeboid cell interconvertability, while CXCL12 induces assembly of mDia2:DIP complexes to bleb cortices in 3D matrices. These results demonstrate how DIP-directed mDia2-dependent F-actin dynamics regulate morphological plasticity in motile cancer cells. PMID- 23024797 TI - Overexpressed FATP1, ACSVL4/FATP4 and ACSL1 increase the cellular fatty acid uptake of 3T3-L1 adipocytes but are localized on intracellular membranes. AB - Long chain acyl-CoA synthetases are essential enzymes of lipid metabolism, and have also been implicated in the cellular uptake of fatty acids. It is controversial if some or all of these enzymes have an additional function as fatty acid transporters at the plasma membrane. The most abundant acyl-CoA synthetases in adipocytes are FATP1, ACSVL4/FATP4 and ACSL1. Previous studies have suggested that they increase fatty acid uptake by direct transport across the plasma membrane. Here, we used a gain-of-function approach and established FATP1, ACSVL4/FATP4 and ACSL1 stably expressing 3T3-L1 adipocytes by retroviral transduction. All overexpressing cell lines showed increased acyl-CoA synthetase activity and fatty acid uptake. FATP1 and ACSVL4/FATP4 localized to the endoplasmic reticulum by confocal microscopy and subcellular fractionation whereas ACSL1 was found on mitochondria. Insulin increased fatty acid uptake but without changing the localization of FATP1 or ACSVL4/FATP4. We conclude that overexpressed acyl-CoA synthetases are able to facilitate fatty acid uptake in 3T3-L1 adipocytes. The intracellular localization of FATP1, ACSVL4/FATP4 and ACSL1 indicates that this is an indirect effect. We suggest that metabolic trapping is the mechanism behind the influence of acyl-CoA synthetases on cellular fatty acid uptake. PMID- 23024798 TI - Serine 162, an essential residue for the mitochondrial localization, stability and anti-apoptotic function of Mcl-1. AB - Mcl-1 is an anti-apoptotic member of the Bcl-2 family that plays a key role in normal development, but also in pathologies such as cancer. It has some unusual properties compared to other anti-apoptotic members of the Bcl-2 family, and its expression and function are dynamically regulated by a variety of post transcriptional and post-translational processes. Of note, Mcl-1 protein has a very short half life, and its stability and function may be regulated by reversible phosphorylation. There is also evidence to suggest that it may be localized to different subcellular compartments. The aim of this work was to determine whether residues within the PEST region of Mcl-1 that may undergo reversible phosphorylation, also regulate its subcellular distribution. We show that EGFP:Mcl-1 localizes mainly to the mitochondria of HeLa cells, with some additional cytoplasmic and nuclear localization. The mutations, S64A, S64E, S121A, S159A, T163A and T163E did not significantly affect the localization of Mcl-1. However, mutation of Ser162 to the phospho-null residue, Alanine resulted in an essentially nuclear localization, with some cytoplasmic but no mitochondrial localization. This mutant Mcl-1 protein, S162A, showed significantly decreased stability and it decreased the ability to protect against Bak-induced apoptosis. These data identify a new molecular determinant of Mcl-1 function, localization and stability that may be important for understanding the role of this protein in disease. PMID- 23024799 TI - OsLEA3-2, an abiotic stress induced gene of rice plays a key role in salt and drought tolerance. AB - Late embryogenesis abundant (LEA) proteins are involved in tolerance to drought, cold and high salinity in many different organisms. In this report, a LEA protein producing full-length gene OsLEA3-2 was identified in rice (Oryza sativa) using the Rapid Amplification of cDNA Ends (RACE) method. OsLEA3-2 was found to be only expressed in the embryo and can be induced by abiotic stresses. The coding protein localizes to the nucleus and overexpression of OsLEA3-2 in yeast improved growth performance compared with control under salt- and osmotic-stress conditions. OsLEA3-2 was also inserted into pHB vector and overexpressed in Arabidopsis and rice. The transgenic Arabidopsis seedlings showed better growth on MS media supplemented with 150 mM mannitol or 100 mM NaCl as compared with wild type plants. The transgenic rice also showed significantly stronger growth performance than control under salinity or osmotic stress conditions and were able to recover after 20 days of drought stress. In vitro analysis showed that OsLEA3-2 was able to protect LDH from aggregation on freezing and inactivation on desiccation. These results indicated that OsLEA3-2 plays an important role in tolerance to abiotic stresses. PMID- 23024800 TI - SIRT1 and c-Myc promote liver tumor cell survival and predict poor survival of human hepatocellular carcinomas. AB - The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high a-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma. PMID- 23024801 TI - Zoogeography of intertidal communities in the West Indian Ocean as determined by ocean circulation systems: patterns from the Tetraclita barnacles. AB - The Indian Ocean is the least known ocean in the world with the biogeography of marine species in the West Indian Ocean (WIO) understudied. The hydrography of WIO is characterized by four distinct oceanographic systems and there were few glacial refugia formations in the WIO during the Pleistocene. We used the widely distributed intertidal barnacle Tetraclita to test the hypothesis that the distribution and connectivity of intertidal animals in the WIO are determined by the major oceanographic regime but less influenced by historical events such as Pleistocene glaciations. Tetraclita were studied from 32 locations in the WIO. The diversity and distribution of Tetraclita species in the Indian Ocean were examined based on morphological examination and sequence divergence of two mitochondrial genes (12S rDNA and COI) and one nuclear gene (histone 3, H3). Divergence in DNA sequences revealed the presence of seven evolutionarily significant units (ESUs) of Tetraclita in WIO, with most of them recognized as valid species. The distribution of these ESUs is closely tied to the major oceanographic circulation systems. T. rufotincta is distributed in the Monsoonal Gyre. T. ehsani is present in the Gulf of Oman and NW India. Tetraclita sp. nov. is associated with the Hydrochemical Front at 10 degrees S latitude. T. reni is confined to southern Madagascan and Mauritian waters, influenced by the West Wind Drift. The endemic T. achituvi is restricted to the Red Sea. Tetraclita serrata consists of two ESUs (based on mtDNA analysis) along the east to west coast of South Africa. The two ESUs could not be distinguished from morphological analysis and nuclear H3 sequences. Our results support that intertidal species in the West Indian Ocean are associated with each of the major oceanographic circulation systems which determine gene flow. Geographical distribution is, however, less influenced by the geological history of the region. PMID- 23024802 TI - RpaA regulates the accumulation of monomeric photosystem I and PsbA under high light conditions in Synechocystis sp. PCC 6803. AB - The response regulator RpaA was examined by targeted mutagenesis under high light conditions in Synechocystis sp. PCC 6803. A significant reduction in chlorophyll fluorescence from photosystem I at 77 K was observed in the RpaA mutant cells under high light conditions. Interestingly, the chlorophyll fluorescence emission from the photosystem I trimers at 77 K are similar to that of the wild type, while the chlorophyll fluorescence from the photosystem I monomers was at a much lower level in the mutant than in the wild type under high light conditions. The RpaA inactivation resulted in a dramatic reduction in the monomeric photosystem I and the D1 protein but not the CP47 content. However, there is no significant difference in the transcript levels of psaA or psbA or other genes examined, most of which are involved in photosynthesis, pigment biosynthesis, or stress responses. Under high light conditions, the growth of the mutant was affected, and both the chlorophyll content and the whole-chain oxygen evolution capability of the mutant were found to be significantly lower than those of the wild type, respectively. We propose that RpaA regulates the accumulation of the monomeric photosystem I and the D1 protein under high light conditions. This is the first report demonstrating that inactivation of a stress response regulator has specifically reduced the monomeric photosystem I. It suggests that PS I monomers and PS I trimers can be regulated independently for acclimation of cells to high light stress. PMID- 23024803 TI - Inhibition of the HCV core protein on the immune response to HBV surface antigen and on HBV gene expression and replication in vivo. AB - The hepatitis C virus (HCV) core protein is a multifunctional protein that can interfere with the induction of an immune response. It has been reported that the HCV core protein inhibits HBV replication in vitro. In this study, we test the effect of the HCV core gene on the priming of the immune response to hepatitis B surface antigen (HBsAg) and on the replication of HBV in vivo. Our results showed that the full-length HCV core gene inhibits the induction of an immune response to the heterogeneous antigen, HBsAg, at the site of inoculation when HCV core (pC191) and HBsAg (pHBsAg) expression plasmids are co-administered as DNA vaccines into BALB/c mice. The observed interference effect of the HCV core occurs in the priming stage and is limited to the DNA form of the HBsAg antigen, but not to the protein form. The HCV core reduces the protective effect of the HBsAg when the HBsAg and the HCV core are co-administered as vaccines in an HBV hydrodynamic mouse model because the HCV core induces immune tolerance to the heterogeneous HBsAg DNA antigen. These results suggest that HCV core may play an important role in viral persistence by the attenuation of host immune responses to different antigens. We further tested whether the HCV core interfered with the priming of the immune response in hepatocytes via the hydrodynamic co-injection of an HBV replication-competent plasmid and an HCV core plasmid. The HCV core inhibited HBV replication and antigen expression in both BALB/c (H-2d) and C57BL/6 (H-2b) mice, the mouse models of acute and chronic hepatitis B virus infections. Thus, the HCV core inhibits the induction of a specific immune response to an HBsAg DNA vaccine. However, HCV C also interferes with HBV gene expression and replication in vivo, as observed in patients with coinfection. PMID- 23024804 TI - The pace of cultural evolution. AB - Today, humans inhabit most of the world's terrestrial habitats. This observation has been explained by the fact that we possess a secondary inheritance mechanism, culture, in addition to a genetic system. Because it is assumed that cultural evolution occurs faster than biological evolution, humans can adapt to new ecosystems more rapidly than other animals. This assumption, however, has never been tested empirically. Here, I compare rates of change in human technologies to rates of change in animal morphologies. I find that rates of cultural evolution are inversely correlated with the time interval over which they are measured, which is similar to what is known for biological rates. This correlation explains why the pace of cultural evolution appears faster when measured over recent time periods, where time intervals are often shorter. Controlling for the correlation between rates and time intervals, I show that (1) cultural evolution is faster than biological evolution; (2) this effect holds true even when the generation time of species is controlled for; and (3) culture allows us to evolve over short time scales, which are normally accessible only to short-lived species, while at the same time allowing for us to enjoy the benefits of having a long life history. PMID- 23024805 TI - Emergency room validation of the revised Suicide Trigger Scale (STS-3): a measure of a hypothesized suicide trigger state. AB - BACKGROUND: The Suicide Trigger Scale (STS) was designed to measure the construct of an affective 'suicide trigger state.' This study aims to extend the inpatient setting validation study of the original Suicide Trigger Scale version 2 to the revised Suicide Trigger Scale version 3 (STS-3) in an acute psychiatric emergency room setting. METHODS: The 42-item STS-3 and a brief psychological test battery were administered to 183 adult psychiatric patients with suicidal ideation or attempt in the psychiatric emergency room, and re-administered to subjects at 1 year follow up. Factor analysis, linear and logistic regressions were used to examine construct structure, divergent and convergent validity, and construct validity, respectively. RESULTS: The STS-3 demonstrated strong internal consistency (Cronbach's alpha 0.94). Factor analysis yielded a three-factor solution, which explained 43.4% of the variance. Principal axis factor analysis was used to identify three reliable subscales: Frantic Hopelessness, Ruminative Flooding, and Near-Psychotic Somatization (Cronbach's alphas 0.90, 0.80, and 0.76, respectively). Significant positive associations were observed between Frantic Hopelessness and BSI depression and anxiety subscales, between Ruminative Flooding and BSI anxiety and paranoia subscales, and Near Psychotic Somatization and BSI somatization subscales. Suicidal subjects with suicide attempt history had mean scores 7 points higher than those without history of suicide attempts. Frantic hopelessness was a significant predictor of current suicide attempt when only attempts requiring at least some medical attention were considered. CONCLUSION: The STS-3 measures a distinct clinical entity, provisionally termed the 'suicide trigger state.' Scores on the STS-3 or select subscales appear to relate to degree of suicidality in terms of severity of ideation, history of attempt, and presence of substantive current attempts. Further study is required to confirm the factor structure and better understand the nature of these relations. PMID- 23024806 TI - IP-10 can be measured in dried plasma spots in patients with chronic hepatitis C infection. AB - The chemokine IP-10 (CXCL10) is a candidate marker for hepatitis C virus (HCV) fibrosis monitoring. The aim of this proof-of-concept study is to assess if IP-10 measurements from dried plasma spots (DPS) are accurate in HCV-infected patients with either minimal or significant fibrosis. We measured IP-10 levels in plasma and DPS of 21 HCV-infected patients with cirrhosis and 19 patients with no/little fibrosis (determined with FibroScan). Cirrhotic patients had significantly higher levels of IP-10 compared to patients with minimal fibrosis. DPS and plasma measurements of IP-10 are comparable and the correlation was excellent (r(2) = 0.97, p<0.0001). The DPS based method for IP-10 detection performs well in HCV infected patients with either minimal or significant fibrosis. PMID- 23024808 TI - Functional specialization in proline biosynthesis of melanoma. AB - Proline metabolism is linked to hyperprolinemia, schizophrenia, cutis laxa, and cancer. In the latter case, tumor cells tend to rely on proline biosynthesis rather than salvage. Proline is synthesized from either glutamate or ornithine; both are converted to pyrroline-5-carboxylate (P5C), and then to proline via pyrroline-5-carboxylate reductases (PYCRs). Here, the role of three isozymic versions of PYCR was addressed in human melanoma cells by tracking the fate of (13)C-labeled precursors. Based on these studies we conclude that PYCR1 and PYCR2, which are localized in the mitochondria, are primarily involved in conversion of glutamate to proline. PYCRL, localized in the cytosol, is exclusively linked to the conversion of ornithine to proline. This analysis provides the first clarification of the role of PYCRs to proline biosynthesis. PMID- 23024807 TI - CD80 and CD86 differentially regulate mechanical interactions of T-cells with antigen-presenting dendritic cells and B-cells. AB - Functional T-cell responses are initiated by physical interactions between T cells and antigen-presenting cells (APCs), including dendritic cells (DCs) and B cells. T-cells are activated more effectively by DCs than by B-cells, but little is known about the key molecular mechanisms that underpin the particular potency of DC in triggering T-cell responses. To better understand the influence of physical intercellular interactions on APC efficacy in activating T-cells, we used single cell force spectroscopy to characterize and compare the mechanical forces of interactions between DC:T-cells and B:T-cells. Following antigen stimulation, intercellular interactions of DC:T-cell conjugates were stronger than B:T-cell interactions. DCs induced higher levels of T-cell calcium mobilization and production of IL-2 and IFNgamma than were elicited by B-cells, thus suggesting that tight intercellular contacts are important in providing mechanically stable environment to initiate T-cell activation. Blocking antibodies targeting surface co-stimulatory molecules CD80 or CD86 weakened intercellular interactions and dampen T-cell activation, highlighting the amplificatory roles of CD80/86 in regulating APC:T-cell interactions and T-cell functional activation. The variable strength of mechanical forces between DC:T cells and B:T-cell interactions were not solely dependent on differential APC expression of CD80/86, since DCs were superior to B-cells in promoting strong interactions with T-cells even when CD80 and CD86 were inhibited. These data provide mechanical insights into the effects of co-stimulatory molecules in regulating APC:T-cell interactions. PMID- 23024810 TI - pH-controlled Bacillus thuringiensis Cry1Ac protoxin loading and release from polyelectrolyte microcapsules. AB - Crystal proteins synthesized by Bacillus thuringiensis (Bt) have been used as biopesticides because of their toxicity to the insect larval hosts. To protect the proteins from environmental stress to extend their activity, we have developed a new microcapsule formulation. Poly (acrylic acid) (PAH) and poly (styrene sulfonate) (PSS) were fabricated through layer-by-layer self-assembly based on a CaCO(3) core. Cry1Ac protoxins were loaded into microcapsules through layer-by-layer self-assembly at low pH, and the encapsulated product was stored in water at 4 degrees C. Scanning electron microscopy (SEM) was used to observe the morphology of the capsules. To confirm the successful encapsulation, the loading results were observed with a confocal laser scattering microscope (CLSM), using fluorescein-labeled Cry1Ac protoxin (FITC-Cry1Ac). The protoxins were released from the capsule under the alkaline condition corresponding to the midgut of certain insects, a condition which seldom exists elsewhere in the environment. The following bioassay experiment demonstrated that the microcapsules with Cry1Ac protoxins displayed approximately equivalent insecticidal activity to the Asian corn borer compared with free Cry1Ac protoxins, and empty capsules proved to have no effect on insects. Further result also indicated that the formulation could keep stable under the condition of heat and desiccation. These results suggest that this formulation provides a promising methodology that protects protoxins from the environment and releases them specifically in the target insects' midgut, which has shown potential as biopesticide in the field. PMID- 23024809 TI - A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation. AB - Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8 Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH and uric acid. PMID- 23024811 TI - Preparing to grasp emotionally laden stimuli. AB - BACKGROUND: Contemporary theories of motor control propose that motor planning involves the prediction of the consequences of actions. These predictions include the associated costs as well as the rewarding nature of movements' outcomes. Within the estimation of these costs and rewards would lie the valence, that is, the pleasantness or unpleasantness of a given stimulus with which one is about to interact. The aim of this study was to test if motor preparation encompasses valence. METHODOLOGY/PRINCIPAL FINDINGS: The readiness potential, an electrophysiological marker of motor preparation, was recorded before the grasping of pleasant, neutral and unpleasant stimuli. Items used were balanced in weight and placed inside transparent cylinders to prompt a similar grip among trials. Compared with neutral stimuli, the grasping of pleasant stimuli was preceded by a readiness potential of lower amplitude, whereas that of unpleasant stimuli was associated with a readiness potential of higher amplitude. CONCLUSIONS/SIGNIFICANCE: We show for the first time that the sensorimotor cortex activity preceding the grasping of a stimulus is affected by its valence. Smaller readiness potential amplitudes found for pleasant stimuli could imply in the recruitment of pre-set motor repertoires, whereas higher amplitudes found for unpleasant stimuli would emerge from a discrepancy between the required action and their aversiveness. Our results indicate that the prediction of action outcomes encompasses an estimate of the valence of a stimulus with which one is about to interact. PMID- 23024812 TI - Neuropeptide Y enhances olfactory mucosa responses to odorant in hungry rats. AB - Neuropeptide Y (NPY) plays an important role in regulating appetite and hunger in vertebrates. In the hypothalamus, NPY stimulates food intake under the control of the nutritional status. Previous studies have shown the presence of NPY and receptors in rodent olfactory system, and suggested a neuroproliferative role. Interestingly, NPY was also shown to directly modulate olfactory responses evoked by a food-related odorant in hungry axolotls. We have recently demonstrated that another nutritional cue, insulin, modulates the odorant responses of the rat olfactory mucosa (OM). Therefore, the aim of the present study was to investigate the potential effect of NPY on rat OM responses to odorants, in relation to the animal's nutritional state. We measured the potential NPY modulation of OM responses to odorant, using electro-olfactogram (EOG) recordings, in fed and fasted adult rats. NPY application significantly and transiently increased EOG amplitudes in fasted but not in fed rats. The effects of specific NPY-receptor agonists were similarly quantified, showing that NPY operated mainly through Y1 receptors. These receptors appeared as heterogeneously expressed by olfactory neurons in the OM, and western blot analysis showed that they were overexpressed in fasted rats. These data provide the first evidence that NPY modulates the initial events of odorant detection in the rat OM. Because this modulation depends on the nutritional status of the animal, and is ascribed to NPY, the most potent orexigenic peptide in the central nervous system, it evidences a strong supplementary physiological link between olfaction and nutritional processes. PMID- 23024813 TI - Spine formation pattern of adult-born neurons is differentially modulated by the induction timing and location of hippocampal plasticity. AB - In the adult hippocampus dentate gyrus (DG), newly born neurons are functionally integrated into existing circuits and play important roles in hippocampus dependent memory. However, it remains unclear how neural plasticity regulates the integration pattern of new neurons into preexisting circuits. Because dendritic spines are major postsynaptic sites for excitatory inputs, spines of new neurons were visualized by retrovirus-mediated labeling to evaluate integration. Long term potentiation (LTP) was induced at 12, 16, or 21 days postinfection (dpi), at which time new neurons have no, few, or many spines, respectively. The spine expression patterns were investigated at one or two weeks after LTP induction. Induction at 12 dpi increased later spinogenesis, although the new neurons at 12 dpi didn't respond to the stimulus for LTP induction. Induction at 21 dpi transiently mediated spine enlargement. Surprisingly, LTP induction at 16 dpi reduced the spine density of new neurons. All LTP-mediated changes specifically appeared within the LTP-induced layer. Therefore, neural plasticity differentially regulates the integration of new neurons into the activated circuit, dependent on their developmental stage. Consequently, new neurons at different developmental stages may play distinct roles in processing the acquired information by modulating the connectivity of activated circuits via their integration. PMID- 23024814 TI - Meta-analysis of the relationship between multiple sclerosis and migraine. AB - BACKGROUND: Studies investigating a proposed association between multiple sclerosis (MS) and migraine have produced conflicting results and a great range in the prevalence rate of migraine in MS patients. By meta-analysing all available data we aimed to establish an overall estimate of any association in order to more accurately inform clinicians and care-givers about a potential association between MS and migraine. METHODS: Pubmed and EMBASE were searched to identify suitable studies. Studies were included if they were a case-control study or cohort study in which controls were not reported to have another neurological condition, were available in English, and specified migraine as a headache sub-type. The odds ratio (OR) of migraine in MS patients vs. controls was calculated using the inverse variance with random effects model in Review Manager 5.1. RESULTS: Eight studies were selected for inclusion, yielding a total of 1864 MS patients and 261563 control subjects. We found a significant association between migraine and MS (OR = 2.60, 95% CI 1.12-6.04), although there was significant heterogeneity. Sensitivity analysis showed that migraine without aura was associated with MS OR = 2.29 (95% CI 1.14-4.58), with no significant heterogeneity. CONCLUSIONS: MS patients are more than twice as likely to report migraine as controls. Care providers should be alerted to ask MS patients about migraine in order to treat it and potentially improve quality of life. Future work should further investigate the temporal relationship of this association and relationship to the clinical characteristics of MS. PMID- 23024815 TI - The histone H4 lysine 20 monomethyl mark, set by PR-Set7 and stabilized by L(3)mbt, is necessary for proper interphase chromatin organization. AB - Drosophila PR-Set7 or SET8 is a histone methyltransferase that specifically monomethylates histone H4 lysine 20 (H4K20). L(3)MBT has been identified as a reader of methylated H4K20. It contains several conserved domains including three MBT repeats binding mono- and dimethylated H4K20 peptides. We find that the depletion of PR-Set7 blocks de novo H4K20me1 resulting in the immediate activation of the DNA damage checkpoint, an increase in the size of interphase nuclei, and drastic reduction of cell viability. L(3)mbt on the other hand stabilizes the monomethyl mark, as L(3)mbt-depleted S2 cells show a reduction of more than 60% of bulk monomethylated H4K20 (H4K20me1) while viability is barely affected. Ploidy and basic chromatin structure show only small changes in PR-Set7 depleted cells, but higher order interphase chromatin organization is significantly affected presumably resulting in the activation of the DNA damage checkpoint. In the absence of any other known functions of PR-Set7, the setting of the de novo monomethyl mark appears essential for cell viability in the presence or absence of the DNA damage checkpoint, but once newly assembled chromatin is established the monomethyl mark, protected by L(3)mbt, is dispensable. PMID- 23024816 TI - Neurokinin 1 receptor mediates membrane blebbing and sheer stress-induced microparticle formation in HEK293 cells. AB - Cell-derived microparticles participate in intercellular communication similar to the classical messenger systems of small and macro-molecules that bind to specialized membrane receptors. Microparticles have been implicated in the regulation of a variety of complex physiopathologic processes, such as thrombosis, the control of innate and adaptive immunity, and cancer. The neurokinin 1 receptor (NK1R) is a Gq-coupled receptor present on the membrane of a variety of tissues, including neurons in the central and peripheral nervous system, immune cells, endocrine and exocrine glands, and smooth muscle. The endogenous agonist of NK1R is the undecapeptide substance P (SP). We have previously described intracellular signaling mechanisms that regulate NK1R mediated rapid cell shape changes in HEK293 cells and U373MG cells. In the present study, we show that the activation of NK1R in HEK293 cells, but not in U373MG cells, leads to formation of sheer-stress induced microparticles that stain positive with the membrane-selective fluorescent dye FM 2-10. SP-induced microparticle formation is independent of elevated intracellular calcium concentrations and activation of NK1R present on HEK293-derived microparticles triggers detectable calcium increase in SP-induced microparticles. The ROCK inhibitor Y27632 and the dynamin inhibitor dynasore inhibited membrane blebbing and microparticle formation in HEK293 cells, strongly suggesting that microparticle formation in this cell type is dependent on membrane blebbing. PMID- 23024817 TI - phiC31 integrase-mediated site-specific recombination in barley. AB - The Streptomyces phage phiC31 integrase was tested for its feasibility in excising transgenes from the barley genome through site-specific recombination. We produced transgenic barley plants expressing an active phiC31 integrase and crossed them with transgenic barley plants carrying a target locus for recombination. The target sequence involves a reporter gene encoding green fluorescent protein (GFP), which is flanked by the attB and attP recognition sites for the phiC31 integrase. This sequence disruptively separates a gusA coding sequence from an upstream rice actin promoter. We succeeded in producing site-specific recombination events in the hybrid progeny of 11 independent barley plants carrying the above target sequence after crossing with plants carrying a phiC31 expression cassette. Some of the hybrids displayed fully executed recombination. Excision of the GFP gene fostered activation of the gusA gene, as visualized in tissue of hybrid plants by histochemical staining. The recombinant loci were detected in progeny of selfed F(1), even in individuals lacking the phiC31 transgene, which provides evidence of stability and generative transmission of the recombination events. In several plants that displayed incomplete recombination, extrachromosomal excision circles were identified. Besides the technical advance achieved in this study, the generated phiC31 integrase-expressing barley plants provide foundational stock material for use in future approaches to barley genetic improvement, such as the production of marker free transgenic plants or switching transgene activity. PMID- 23024818 TI - Protein trans-splicing of an atypical split intein showing structural flexibility and cross-reactivity. AB - Inteins catalyze a protein splicing reaction to excise the intein from a precursor protein and join the flanking sequences (exteins) with a peptide bond. In a split intein, the intein fragments (I(N) and I(C)) can reassemble non covalently to catalyze a trans-splicing reaction that joins the exteins from separate polypeptides. An atypical split intein having a very small I(N) and a large I(C) is particularly useful for joining synthetic peptides with recombinant proteins, which can be a generally useful method of introducing site-specific chemical labeling or modifications into proteins. However, a large I(C) derived from an Ssp DnaX intein was found recently to undergo spontaneous C-cleavage, which raised questions regarding its structure-function and ability to trans splice. Here, we show that this I(C) could undergo trans-splicing in the presence of I(N), and the trans-splicing activity completely suppressed the C-cleavage activity. We also found that this I(C) could trans-splice with small I(N) sequences derived from two other inteins, showing a cross-reactivity of this atypical split intein. Furthermore, we found that this I(C) could trans-splice even when the I(N) sequence was embedded in a nearly complete intein sequence, suggesting that the small I(N) could project out of the central pocket of the intein to become accessible to the I(C). Overall, these findings uncovered a new atypical split intein that can be valuable for peptide-protein trans-splicing, and they also revealed an interesting structural flexibility and cross-reactivity at the active site of this intein. PMID- 23024820 TI - Tissue-specific strategies of the very-long chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mouse to compensate a defective fatty acid beta-oxidation. AB - Very long-chain acyl-CoA dehydrogenase (VLCAD)-deficiency is the most common long chain fatty acid oxidation disorder presenting with heterogeneous phenotypes. Similar to many patients with VLCADD, VLCAD-deficient mice (VLCAD(-/-)) remain asymptomatic over a long period of time. In order to identify the involved compensatory mechanisms, wild-type and VLCAD(-/-) mice were fed one year either with a normal diet or with a diet in which medium-chain triglycerides (MCT) replaced long-chain triglycerides, as approved intervention in VLCADD. The expression of the mitochondrial long-chain acyl-CoA dehydrogenase (LCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) was quantified at mRNA and protein level in heart, liver and skeletal muscle. The oxidation capacity of the different tissues was measured by LC-MS/MS using acyl-CoA substrates with a chain length of 8 to 20 carbons. Moreover, in white skeletal muscle the role of glycolysis and concomitant muscle fibre adaptation was investigated. In one year old VLCAD(-/-) mice MCAD and LCAD play an important role in order to compensate deficiency of VLCAD especially in the heart and in the liver. However, the white gastrocnemius muscle develops alternative compensatory mechanism based on a different substrate selection and increased glucose oxidation. Finally, the application of an MCT diet over one year has no effects on LCAD or MCAD expression. MCT results in the VLCAD(-/-) mice only in a very modest improvement of medium-chain acyl-CoA oxidation capacity restricted to cardiac tissue. In conclusion, VLCAD(-/-) mice develop tissue-specific strategies to compensate deficiency of VLCAD either by induction of other mitochondrial acyl-CoA dehydrogenases or by enhancement of glucose oxidation. In the muscle, there is evidence of a muscle fibre type adaptation with a predominance of glycolytic muscle fibres. Dietary modification as represented by an MCT-diet does not improve these strategies long-term. PMID- 23024819 TI - Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives. AB - Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N alkylated analogues of levamisole with the aim of characterizing structure activity relationships with regard to inhibition of angiogenesis. N methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third "cord-like" morphology resembling that of the known drug suramin was observed for an aniline containing derivative. New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted. PMID- 23024821 TI - Interferon-gamma restricts Toxoplasma gondii development in murine skeletal muscle cells via nitric oxide production and immunity-related GTPases. AB - The apicomplexan parasite Toxoplasma gondii is regularly transmitted to humans via the ingestion of contaminated meat products from chronically infected livestock. This route of transmission requires intracellular development and long term survival of the parasite within muscle tissue. In this study, we determined the cell-autonomous immunity of mature primary embryonic or C2C12 skeletal muscle cells (SkMCs) to infection with T. gondii. Non-activated SkMCs and control fibroblasts sustained parasite replication; however, interferon (IFN)-gamma significantly inhibited parasite growth in SkMCs but not in fibroblasts. Intracellular parasite replication was diminished by IFN-gamma whereas host cell invasion was not affected. Tumor necrosis factor (TNF) did not further increase the IFN-gamma-triggered host defense of SkMCs against Toxoplasma. Remarkably, IFN gamma alone or in combination with TNF decreased the high level of T. gondii bradyzoite formation being observed in non-activated SkMCs. Stimulation of SkMCs with IFN-gamma strongly triggered expression of inducible nitric oxide synthase (iNOS) transcripts, and induced significantly higher levels of nitric oxide (NO) in SkMCs than in fibroblasts. Consequently, pharmacological inhibition of iNOS partially abrogated the IFN-gamma-induced toxoplasmacidal activity of SkMCs. In addition, SkMCs strongly up-regulated immunity-regulated GTPases (IRGs) following stimulation with IFN-gamma. IRGs accumulated on Toxoplasma-containing vacuoles in SkMCs in a parasite strain-dependent manner. Subsequent vacuole disruption and signs of degenerating parasites were regularly recognized in IFN-gamma-treated SkMCs infected with type II parasites. Together, murine SkMCs exert potent toxoplasmacidal activity after stimulation with IFN-gamma and have to be considered active participants in the local immune response against Toxoplasma in skeletal muscle. PMID- 23024822 TI - [Necrotized volvulus of the sigmoid in postpartum]. PMID- 23024823 TI - [Costello syndrome: report of a case]. PMID- 23024824 TI - Peritoneal tuberculosis in pregnancy: a case report. AB - Peritoneal tuberculosis in pregnancy is one of the least common forms of extrapulmonory tuberculosis in pregnancy. Early diagnosis is important to prevent obstetrical and neonatal morbidity. We report the case of a 37-year-old pregnant woman who presented with abdominal volume increase, night-sweat, anorexia, loss of weight and abdominal pain at 23 weeks. A peritoneal laparoscopic biopsy was performed and confirmed the diagnosis of tuberculous peritonitis. The patient received antituberculosis chemotherapy. The recovery was good as gave birth to a healthy infant of 3200Kg at 37th week's gestation by vaginal delivery. PMID- 23024825 TI - Associations between national tuberculosis program budgets and tuberculosis outcomes: an ecological study. AB - INTRODUCTION: The objective of this study is to explore the associations between national tuberculosis program (NTP) budget allocation and tuberculosis related outcomes in the World Health Organization's 22 high burden countries from 2007 2009. METHODS: This ecological study used mixed effects and generalized estimating equation models to identify independent associations between NTP budget allocations and various tuberculosis related outcomes. Models were adjusted for a number of independent variables previously noted to be associated with tuberculosis incidence. RESULTS: Increasing the percent of the NTP budget for advocacy, communication and social mobilization was associated with an increase in the case detection rate. Increasing TB-HIV funding was associated with an increase in HIV testing among TB patients. Increasing the percent of the population covered by the Directly Observed Therapy (DOT) program was associated with an increase in drug susceptibility testing. Laboratory funding was positively associated with tuberculosis notification. Increasing the budgets for first line drugs, management and multi-drug resistant tuberculosis (MDR-TB) was associated with a decrease in smear positive deaths. CONCLUSION: Effective TB control is a complex and multifaceted challenge. This study revealed a number of budget allocation related factors associated with improved TB outcome parameters. If confirmed with future longitudinal studies, these findings could help guide NTP managers with allocation decisions. PMID- 23024826 TI - A rare case of nephrotic syndrome revealing mycosis fungoide managed successfully with chemotherapy. AB - The occurrence of the nephrotic syndrome during mycosis fungoide is very unusual. We report a rare case of mycosis fungoide revealed by hydrops related to nephrotic syndrom in a 37-year old male patient. He has been admitted to intensive care unit because of a breathing distress and a hydrophobs. Whole body computed tomography scan revealed bilateral axillary, cervical lymph nodes, tumoral infiltration of the subcutaneous tissue in the cervicothoracic and abdominal regions, multiples bilateral pulmonary metastasis, bilateral pleural effusion, and abdominal effusion; the kidneys were normal. The patient was staged IVb (T3N3M1). He was treated with CHOP (cyclophosphamide, Doxorubicin, Vincristin and prednisone). Evolution after eight cycles of chemotherapy was spectacular. The development of nephrotic syndrom secondary to mycosis fungoide is rare. It requires a multidisciplinary approach with nephrologists and oncologists. PMID- 23024827 TI - [Malignant melanoma of the nasal cavity]. PMID- 23024828 TI - [Syphilitic aortic insufficiency: report of a case]. PMID- 23024829 TI - It is over three decades of graduate education in Epizootiology at the University of Ibadan, Nigeria (1975-2011): is there a need to revise the curriculum? AB - Epizootiology is the study of variable factors, events, forces and circumstances that contribute to the occurrence, distribution, control and prevention of ill health, diseases and other problems in animal groups. It is a key component of veterinary medicine education at the University of Ibadan, Nigeria since 1975. It started as a Graduate Certificate in Epizootiology (GCE) in 1976. Later it was revised into M.Sc. Epizootiology in 1986. At graduate level, epizootiology curriculum has supported the M.Sc. Epizootiology programme. It compliments training in Veterinary Public Health and Preventive Medicine. This epizootiology curriculum has been operational at graduate level for more than three decades. Now in 2011, a consortium of English speaking West African Universities is committed to review the current curriculum at the University of Ibadan to strengthen health systems in an interdependent world with scope for internationalized practicum in disease investigation. Emphases are made towards skills development in molecular studies on disease causal agents and the mapping of associated geographic risk factors, including indigenous knowledge and practices. It is notable that most English-speaking West African countries including Ghana, Liberia, Sierra Leone and Gambia either lack a Veterinary School or just started some, but do not have graduate programme in Epizootiology. Thus, the curriculum at Ibadan is positioned to make impact in three key areas, namely, sub-regional ecosystem health studies, improving human-animal disease surveillance programmes, and in indigenization of bio-technology for monitoring and evaluation of trans-boundary animal disease control interventions for global health in West Africa. PMID- 23024830 TI - [Leiomyosarcoma of the pancreas: a tumor with poor prognosis--clinical case and review of the literature]. PMID- 23024831 TI - [Catheters with implantable chamber: report of a series of 970 cases]. PMID- 23024832 TI - Peak expiratory flow in normal medical students in Maiduguri, Borno state, Nigeria. AB - BACKGROUND: The assessment of lung function is of considerable importance in the diagnosis of respiratory diseases, normal reference values need to be determined. The peak expiratory flow (PEF) is a simple, reproducible and easily affordable test of lung function which has been used in resource poor countries like Nigeria. A study PEF was carried out in medical students of the University of Maiduguri and the result was compared with various prediction equations calculated in other parts of Nigeria. METHODS: It was a cross-sectional study involving 255 medical students. Data was collected between March and June 2010 using MicroPeakTM peak flow meter (Micromedical MEI 2A2 Kent) as the instrument. RESULTS: There was a statistically significant difference between the measured PEF and the predicted values based on different formulae derived from the different parts of Nigeria. However, the values in females in this study was consistent with the one obtained by one investigator in the north western part of the country. PEF positively correlated with the measured anthropometric parameters and age. CONCLUSION: The result of the study showed that the prediction formulae of Njoku et al and Salisu et al may be used in the assessment of PEF of individuals in this environment; however, further studies with larger sample size may be needed. PMID- 23024833 TI - Erratum: Fast Calculations of Electrostatic Solvation Free Energy from Reconstructed Solvent Density using proximal Radial Distribution Functions. PMID- 23024834 TI - Dynamic Nuclear Polarization of Oxygen-17. AB - Oxygen-17 detected DNP NMR of a water/glycerol glass enabled an 80-fold enhancement of signal intensities at 82 K, using the biradical TOTAPOL. The >6,000-fold savings in acquisition time enables (17)O-(1)H distance measurements and heteronuclear correlation experiments. These experiments are the initial demonstration of the feasibility of DNP NMR on quadrupolar (17)O. PMID- 23024835 TI - ACS chemical neuroscience molecule spotlight on Suvorexant. AB - Suvorexant is a dual orexin antagonist currently in Phase III clinical trials for the modulation of sleep and is being developed by Merck. Recent Phase III results showed that patients taking the drug fell asleep faster and slept longer than those on placebo. PMID- 23024836 TI - Nuclear accumulation of beta-catenin and forkhead box O3a in colon cancer: Dangerous liaison. AB - The WNT/beta-catenin and phosphoinositide 3-kinase (PI3K/AKT) signaling cascades both have been implicated in the formation and progression of colorectal cancer. Oncogenic PI3K/AKT signaling suppresses the activity of forkhead box O3a (FOXO3a) transcription factor through phosphorylation leading to its nuclear exclusion. Inhibition of the PI3K/AKT signaling by PI3K or AKT inhibitors results in the translocation of FOXO3a to the nucleus, and is considered to be a promising therapeutic strategy for many cancers including colon cancer. Now, however, a new study in Nature Medicine has revealed a nuclear interaction of beta-catenin with FOXO3a as a promoter of metastatic progression in colon cancer. The work has important implications for the treatment of colon cancers, suggests a companion biomarker strategy to enable a personalized medicine approach, and offers an alternative therapeutic strategy to overcome resistance to PI3K and AKT inhibitors. PMID- 23024837 TI - Turning scar into muscle. AB - After the demonstration that somatic cells could be reprogrammed to a pluripotent state, exciting new prospects were opened for the cardiac regeneration field. It did not take long for the development of strategies to convert somatic cells directly into cardiomyocytes. Despite the intrinsic difficulties of cell reprogramming, such as low efficiency, the therapeutic possibilities created by the ability to turn scar into muscle are enormous. Here, we discuss some of the major advances and strategies used in direct cardiac reprogramming and examine discrepancies and concerns that still need to be resolved in the field. PMID- 23024838 TI - Coronary atherosclerosis: Significance of autophagic armour. AB - Autophagy is a lysosomal degradation pathway of cellular components such as organelles and long-lived proteins. Though a protective role for autophagy has been established in various patho-physiologic conditions such as cancer, neurodegeneration, aging and heart failure, a growing body of evidence now reveals a protective role for autophagy in atherosclerosis, mainly by removing oxidatively damaged organelles and proteins and also by promoting cholesterol egress from the lipid-laden cells. Recent studies by Razani et al and Liao et al unravel novel pathways that might be involved in autophagic protection and in this commentary we highlight the importance of autophagy in atherosclerosis in the light of these two recent papers. PMID- 23024839 TI - Overview of resistant hypertension: A glimpse of the cardiologist's current standpoint. AB - Hypertension is a major risk factor for cardiovascular disease, resulting in increased incidence of cerebrovascular events, ischaemic heart disease, heart failure, and renal impairment. Thus, it is one of the most important preventable causes of premature morbidity and mortality. Despite current knowledge on the management of hypertension and the availability of several effective antihypertensive medications, uncontrolled hypertension remains a common and challenging clinical problem. Resistant hypertension is a complex condition with multiple contributing factors and overlapping comorbidities. Although there is limited hard evidence regarding resistant hypertension, our understanding of this condition has improved recently. This article will present an overview of resistant hypertension and highlight recent publications about this topic. PMID- 23024840 TI - Endovascular treatment of extracranial vertebral artery stenosis. AB - Percutaneous angioplasty and stenting for the treatment of extracranial vertebral artery (VA) stenosis seems a safe, effective and useful technique for resolving symptoms and improving blood flow to the posterior circulation, with a low complication rate and good long-term results. In patients with severe tortuosity of the vessel, stent placement is a real challenge. The new coronary balloon expandable stents may be preferred. A large variability of restenosis rates has been reported. Drug-eluting stents may be the solution. After a comprehensive review of the literature, it can be concluded that percutaneous angioplasty and stenting of extracranial VA stenosis is technically feasible, but there is insufficient evidence from randomized trials to demonstrate that endovascular management is superior to best medical management. PMID- 23024841 TI - Diagnostic neuroradiology: Ready for the neuro-interventional age? AB - Acute cerebral ischemia or stroke is currently considered an emergency for which therapeutic options are available if the therapeutic window of 4.5 h is respected. Imaging modalities have progressed greatly over the last few decades, rendering ischemia detectable in the first hours after the event. However, in order for treatment to be efficacious it is necessary to speed up all the processes before the start of therapy. Thus, one must decrease the time to arrival at the hospital and to the radiological method that is to be employed (be it computed tomography or magnetic resonance imaging); only then will the medical or interventional techniques available fulfill their potential. PMID- 23024843 TI - Cystic malformation of cystic duct: 10 cases and review of literature. AB - AIM: To evaluate cystic malformations of the cystic duct. METHODS: Over a 2-year period, we came across 10 cases of cystic malformation of the cystic duct among patients who were investigated in our radiology department with ultrasonography, multidetector computed tomography, or magnetic resonance imaging for abdominal complaints. Radiological diagnosis of cystic malformation of the cystic duct was made on the basis of a dilated, nonvascular cystic structure near the porta hepatis, and visualization of a clear communication with either the gallbladder, normal caliber cystic duct and/or common bile duct (CBD) on at least one imaging modality. RESULTS: Four of 10 patients had saccular dilatation of the cystic duct. Six patients had fusiform dilatation of the cystic duct, and two of these had only mild fusiform dilatation. Two patients had associated CBD dilatation and one had associated cystic duct calculi and malignancy. CONCLUSION: Cystic malformations of the cystic duct should be recognized as a distinct type of choledochal cyst and should be added as type VI cyst in Todani's classification. PMID- 23024842 TI - Embolization of liver tumors: Past, present and future. AB - Curative therapies for hepatocellular carcinoma (HCC), such as resection and liver transplantation, can only be applied in selected patients with early tumors. More advanced stages require local or systemic therapies. Resection of HCC offers the only hope for cure. Even in patients undergoing resection, recurrences are common. Chemoembolization, a technique combining intra-arterial chemotherapy with selective tumor ischemia, has been shown by randomized controlled trials to be efficacious in the palliative setting. There is now renewed interest in transarterial embolization/transarterial chemoembolization (TACE) with regards to its use as a palliative tool in a combined modality approach, as a neoadjuvant therapy, in bridging therapy before transplantation, for symptomatic indications, and even as an alternative to resection. There have also been rapid advances in the agents being embolized trans-arterially (genes, biological response modifiers, etc.). The current review provides an evidence based overview of the past, present and future trends of TACE in patients with HCC. PMID- 23024845 TI - History of Rabies in Traditional Medicine's Resources and Iranian Research Studies: On the CccasiOn of the World Rabies Day (September 28, 2012). PMID- 23024844 TI - Usefulness of the Guglielmi detachable coil for embolization of a systemic venous collateral after Fontan operation: A case report. AB - Embolization of collateral veins is often treated with rigid coils (Gianturco and interlocking detachable coils type). However, when dealing with tortuous and dilated collateral veins, there is a high risk for technical failure and coil migration due to inflexibility of the coils. To safely and successfully solve this problem, Guglielmi detachable coils (GDC) can be used for embolization. Their flexibility allows for easy navigation in tortuous veins, low risk of unintended coil release or coil migration, and safe deployment. A 12-year-old girl with a single ventricle had severe cyanosis and a low exercise tolerance 5 years after Fontan procedure. The symptoms were caused by a tortuous and dilated collateral from the left phrenic vein into the left pulmonary vein, forming a right-to-left shunt. The collateral, which had a large diameter and high flow, and therefore a high risk of coil migration, was successfully embolized with 8 GDC. There were no complications such as coil migration or cerebral infarction. Transcatheter embolization increased her systemic oxygen saturation from 81%-84% to 94%-95%, and increased her ability to exercise. The embolization procedure using flexible GDC was low risk compared with other rigid coil embolization techniques when performing embolization of tortuous and dilated collateral veins. PMID- 23024846 TI - Evidence-informed Health Policy Making: The Role of Policy Brief. PMID- 23024847 TI - Policy brief on promoting physical activity among adolescents. AB - Regular physical activity (PA) is an underlying factor since childhood and adolescence for having a healthy and active future for life. The aim of this stud y was to review the evidence on increasing the youth PA to develop the national program at country level. At first, the databases were searched using the sensitive keywords, and systematic reviews of the relevant databases were extracted. The studies were evaluated in terms of relevance and methodological quality for effective interventions that were detected. These cases were also identified in the effective interventions: disadvantages, benefits, costs, methods, and limitations of early studies, which were based on systematic review of the studies. Three interventions were identified as physical education curriculum reform, the creation of extra-curricular activities, as well as approaches to environmental and social support. Evidences showed that the relative impact of these interventions were not high. Thus, a combination of all three options of integrated approach is recommended for reducing the sedentary lifestyle of youths. PMID- 23024848 TI - Cytogenetic risks and possible adverse health effects by narcotic substances dependent. AB - OBJECTIVES: Illicit drug abuse has crossed social, economic, and geographical borders, and remains one of the major health problems that modern society is facing worldwide. The role of multiple drug abuse as a basic for chromosome damage has been overlooked and it is important to determine its possible adverse health effects. This study aimed to compare the frequency of chromosomal damages between drug addicts and free drug controls. METHODS: Cytogenetic study was obtained from 146 illicit drug-users and 200 free drug controls. Subjects were grouped into three categories depending on main drug of dependence. RESULTS: Cytogenetic studies on cultured lymphocytes showed an increase the frequency of chromosomal damages among addicts including opiate (5.89%), heroin (7.65%), and crystal (4.9%) when compared with drug free controls (1.45%). The frequency of chromosomal abnormalities was breaks, gaps, marker, and acentric, respectively. CONCLUSIONS: Our findings are also important as they are among the first to suggest here, illicit drug addiction continue to be significant public health problems in Iran. PMID- 23024849 TI - Anti-aquaporin-4 IgG in Patients Presenting with Unilateral Optic Neuritis: A Cohort Study. AB - BACKGROUND: Optic neuritis (ON) can be the first presentation of multiple sclerosis (MS) or neuromyelitis optica (NMO). Anti-aquaporin-4 IgG (AQP4 IgG) is a highly specific and moderately sensitive biomarker for NMO. This study was designed to assess the rate of seropositivity for AQP4 IgG, and the short-term outcome of patients presenting with single isolated ON (SION). METHODS: A cohort of 41 consecutive patients experiencing severe (< 20 / 200) SION (not fulfilling the diagnostic criteria for MS or NMO), was prospectively recruited. Blood sampling was carried out immediately after the diagnosis of ON, and AQP4 IgG was tested qualitatively, using an indirect immunofluorescence kit. After clinical and paraclinical investigations, all the patients were followed up for a short term period of at least 18 months. RESULTS: The seroprevalence among the initial ON patients was 9.7% (4 / 41). The short-term conversion rate to MS and NMO was estimated to be about 7.3 and 4.9%, respectively. The conversion rate to NMO in initially seropositive patients was greater than that for the whole cohort [2 / 4 (50%) vs. 2 / 41 (4.9%); P = 0.035; Odds ratio: 19.5, 95% confidence interval: 1.73 to 219.50]. CONCLUSION: AQP4 IgG seropositive SION patients were more likely to develop NMO in comparison to the total SION population. Further studies, with a longer follow-up period and larger sample sizes are warranted to assess the clinical and prognostic value of assessing AQP4 IgG in SION. PMID- 23024850 TI - The Effect of Adding Magnesium Sulfate to Lidocaine Compared with Paracetamol in Prevention of Acute Pain in Hand Surgery Patients Under Intravenous Regional Anesthesia (IVRA). AB - INTRODUCTION: This study was done to compare the analgesic effects of "magnesium plus lidocaine", "paracetamol plus lidocaine", and "placebo plus lidocaine" on block characteristics for intravenous regional anesthesia (IVRA) in patients undergoing upper extremity orthopedic surgery. METHODS: In a double-blind, placebo-controlled randomized clinical trial, 90 patients were selected and entered randomly into three study groups after applying the inclusion and exclusion criteria. Time to start of the sensory and motor block were measured separately and also the duration of these two block types were measured. Post-op pain assessment was measured using a numeric rating scale. Venous samples were checked and compared regarding blood gas and pH measurements. RESULTS: The time from drug injection to sensory block onset was the shortest in the magnesium plus lidocaine group; the time from drug injection to the time of motor block onset was the shortest in the lidocaine plus magnesium group; the duration of the motor block was the longest in the lidocaine plus magnesium group. DISCUSSION: Addition of magnesium lidocaine in patients undergoing upper extremity orthopedic operations using IVRA decreases significantly the time gap between drug administration and the start of the block; also, this drug combination increases the IVRA block length, while paracetamol does not have such a significant effect. PMID- 23024851 TI - Parents or School Health Trainers, which of them is Appropriate for Menstrual Health Education? AB - OBJECTIVES: The purpose of this community-based participatory research was to compare different training sources for adolescents' menstrual health education. METHODS: From 15 middle schools in Tehran, through quota random sampling, 1823 female students were selected proportionally and allocated randomly to three groups (parent trained, schools' health trainers trained, and control). Following a two-year training program, the adolescents' menstrual health was compared. RESULTS: In the present study, the school health trainers trained group showed a better feeling for menarche, compared to the two other groups (P < 0.001). The need for adolescent health training was emphasized by 82% of the participants; they also believed that the appropriate age for such empowerment courses was about 12 years. In the school health trainers trained group, the offered age was significantly lower than in other groups (P < 0.001). The adolescents trained by the school health trainers had a better practice of habits related to menstrual and hygiene practices, like having a bath during menstruation and the use of sanitary pads or cotton, compared to their counterpart groups (P > 0.05). CONCLUSION: It is suggested that school-based health training leads to better menstrual health promotion and healthy puberty transition, and school health trainers play a key role in this regard. PMID- 23024852 TI - Economic empowerment of women and utilization of maternal delivery care in bangladesh. AB - OBJECTIVE: Maternal mortality is a major public health problem in low-income countries, such as Bangladesh. Women's empowerment in relation to enhanced utilization of delivery care is underexplored. This study investigates the associations between women's economic empowerment and their utilization of maternal health care services in Bangladesh. METHODS: In total, 4925 women (15-49 years of age) with at least one child from whole Bangladesh constituted the study sample. Home delivery without skilled birth attendant and use of institutional delivery services were the main outcome variables used for the analyses. Economic empowerment, neighborhood socioeconomic status, household economic status, and demographic factors were considered as explanatory variables. The chi square test and unadjusted and adjusted logistic regression analyses were applied at the collected data. RESULTS: In the adjusted model, respondent's and husband's education, household economic status, and residency emerged as important predictors for utilization of delivery care services. In the unadjusted model, economically empowered working and microfinanced women displayed more home delivery. CONCLUSION: The current study shows that use of delivery care services is associated with socioeconomic development and can be enhanced by societies that focus on general issues such as schooling, economic wellbeing, and gender based discrimination. PMID- 23024853 TI - The Role of Magnesium Supplementation in Cisplatin-induced Nephrotoxicity in a Rat Model: No Nephroprotectant Effect. AB - OBJECTIVES: Cisplatin (CP) is used as the commonest drug to treat solid tumors. It is accompanied by a nephrotoxicity side effect. The main objective of this study is to investigate the protective role of magnesium (Mg) supplementation in CP-induced nephrotoxicity in a rat model. METHODS: Twenty-nine Wistar rats were randomly assigned to four groups (1-4). Groups 1-3 received 20, 80, and 200 mg/kg magnesium sulfate respectively, for 10 days, but on day 3, a single dose of CP (7 mg/kg, i.p.) was also injected. Group 4 (positive control group) received the same regimen of Groups 1-3 except saline instead magnesium sulfate. One week after CP administration, blood samples were obtained and all animals were killed for kidney histopathological investigations. RESULTS: All CP-treated animals lost weight, and the percentage of weight loss in Group 1 (low dose Mg sulfate treated) was significantly higher compared with the positive control group (Group 4, P < 0.05). The increase in blood urea nitrogen (BUN) and creatinine (Cr) levels in serum in Group 1 were more than those in other groups (P < 0.05). No statistical differences were observed in serum magnesium, nitrite, and total protein levels among the groups. The kidney tissue damage in Groups 1-3 was not significantly different when compared with Group 4. Moreover, the kidney and testis weights in Group 1 were significantly greater than those in the positive control group (P < 0.05). CONCLUSION: Regarding the BUN and Cr levels in the serum, kidneys weight, and the histopathological study, the low dose of Mg supplementation intensifies kidney toxicity and renal dysfunction in CP-induced nephrotoxicity in the rat model. However, the protective role of Mg with moderate and high doses is not certain. PMID- 23024854 TI - Breast Cancer Survival Analysis: Applying the Generalized Gamma Distribution under Different Conditions of the Proportional Hazards and Accelerated Failure Time Assumptions. AB - BACKGROUND: The goal of this study is to extend the applications of parametric survival models so that they include cases in which accelerated failure time (AFT) assumption is not satisfied, and examine parametric and semiparametric models under different proportional hazards (PH) and AFT assumptions. METHODS: The data for 12,531 women diagnosed with breast cancer in British Columbia, Canada, during 1990-1999 were divided into eight groups according to patients' ages and stage of disease, and each group was assumed to have different AFT and PH assumptions. For parametric models, we fitted the saturated generalized gamma (GG) distribution, and compared this with the conventional AFT model. Using a likelihood ratio statistic, both models were compared to the simpler forms including the Weibull and lognormal. For semiparametric models, either Cox's PH model or stratified Cox model was fitted according to the PH assumption and tested using Schoenfeld residuals. The GG family was compared to the log-logistic model using Akaike information criterion (AIC) and Baysian information criterion (BIC). RESULTS: When PH and AFT assumptions were satisfied, semiparametric and parametric models both provided valid descriptions of breast cancer patient survival. When PH assumption was not satisfied but AFT condition held, the parametric models performed better than the stratified Cox model. When neither the PH nor the AFT assumptions were met, the log normal distribution provided a reasonable fit. CONCLUSIONS: When both the PH and AFT assumptions are satisfied, the parametric and semiparametric models provide complementary information. When PH assumption is not satisfied, the parametric models should be considered, whether the AFT assumption is met or not. PMID- 23024855 TI - Influence of aerobic training on cardiovascular and metabolic parameters in ederly hypertensive women. AB - BACKGROUND: Treatment of hypertension includes pharmacological and nonpharmacological interventions. Among the nonpharmacological interventions emphasizes the practice of regular physical exercise. However, the effects of aerobic exercise training on cardiovascular and metabolic parameters in elderly hypertensive women are still controversial. OBJECTIVES: The purpose of this study was to assess the effects of a walking program on metabolic and cardiovascular parameters at rest and during the recovery period following maximal exercise by hypertensive elderly women. METHODS: Twelve elderly women with hypertension started a 2-week walking program. Rest blood cholesterol and anthropometric data, as well as blood pressure and heart rate at rest and after progressive maximal exercise were measured before and after training. RESULTS: There were significant differences between the pre- and posttraining periods in VO(2)max, systolic blood pressure, diastolic blood pressure, and mean blood pressure. There were no changes in serum cholesterol levels after the training. During the recovery period following the progressive test, the fall in heart rate and mean blood pressure after 10 minutes of recovery was significantly higher after training. CONCLUSION: The proposed walking program did not alter serum cholesterol, but it did reduce resting blood pressure, improve aerobic performance and accelerate the fall in heart rate and mean blood pressure during the postprogressive maximal aerobic exercise recovery period in elderly hypertensive women. PMID- 23024856 TI - Recurrent Hydatosis at the Site of Non-union Humerus Fracture. AB - Hydatid disease is still endemic in several regions of the world and is caused by two species of tapeworms, Echinococcus granulosus and Echinococcus alveolaris. It primary involves liver and lung, and bone involvement is relatively rare (0.2 4%), where it is most commonly seen in the spine. The skeletal involvement is usually due to secondary extension such as hematogenous spread. The disease has usually a silent manifestation until a complication exists; so, many cases are diagnosed intraoperatively. Treatment of hydatid disease because of its bone involvement and spillage of fluid with subsequent contamination seeding is difficult, so it has a high mortality rate and many cases will recur. Therefore, we can prevent these occurrences if we treat hydatid disease completely and in the primary stage. Adjuvant medical treatment, if the diagnosis is known, prevents systemic spread and recurrence. Here, we present a primary recurrent hydatosis at the site of non-union humerus fracture. We have pointed out osseous hydatosis as one of the important differential diagnoses in destructive bone lesions and the necessity of its radical resection. PMID- 23024857 TI - Vitamin d in cardiovascular disease. PMID- 23024858 TI - Nettle as a distinct Bronze Age textile plant. AB - It is generally assumed that the production of plant fibre textiles in ancient Europe, especially woven textiles for clothing, was closely linked to the development of agriculture through the use of cultivated textile plants (flax, hemp). Here we present a new investigation of the 2800 year old Lusehoj Bronze Age Textile from Voldtofte, Denmark, which challenges this assumption. We show that the textile is made of imported nettle, most probably from the Karnten Steiermark region, an area which at the time had an otherwise established flax production. Our results thus suggest that the production of woven plant fibre textiles in Bronze Age Europe was based not only on cultivated textile plants but also on the targeted exploitation of wild plants. The Lusehoj find points to a hitherto unrecognized role of nettle as an important textile plant and suggests the need for a re-evaluation of textile production resource management in prehistoric Europe. PMID- 23024859 TI - Folate intake and markers of folate status in women of reproductive age, pregnant and lactating women: a meta-analysis. AB - Background. Pregnant and breastfeeding women are at risk for folate deficiency. Folate supplementation has been shown to be associated with enhanced markers of folate status. However, dose-response analyses for adult women are still lacking. Objective. To assess the dose-response relationship between total folate intake (folic acid plus dietary folate) and markers of folate status (plasma/serum folate, red blood cell folate, and plasma homocysteine); to evaluate potential differences between women in childbearing age, pregnant and lactating women. Methods. Electronic literature searches were carried out on three databases until February 2010. The overall pooled regression coefficient (beta) and SE(beta) were calculated using meta-analysis on a double-log scale. Results. The majority of data was based on nonpregnant, nonlactating women in childbearingage. The pooled estimate of the relationship between folate intake and serum/plasma folate was 0.56 (95% CI = 0.40-0.72, P < 0.00001); that is, the doubling of folate intake increases the folate level in serum/plasma by 47%. For red blood cell folate, the pooled-effect estimate was 0.30 (95% CI = 0.22-0.38, P < 0.00001), that is, +23% for doubling intake. For plasma-homocysteine it was -0.10 (95% = -0.17 to -0.04, P = 0.001), that is, -7% for doubling the intake. Associations tended to be weaker in pregnant and lactating women. Conclusion. Significant relationships between folate intake and serum/plasma folate, red blood cell folate, and plasma homocysteine were quantified. This dose-response methodology may be applied for setting requirements for women in childbearing age, as well as for pregnant and lactating women. PMID- 23024860 TI - Management of venous thromboembolism in patients with advanced gastrointestinal cancers: what is the role of novel oral anticoagulants? AB - Venous thromboembolism (VTE) is a frequent complication of gastrointestinal cancers that increases morbidity and may impact mortality. Low-molecular-weight heparins (LMWHs) and vitamin K antagonists (VKAs) are standard anticoagulation options for the ambulatory gastrointestinal cancer patient with VTE, but both of these agents are challenging to use for various reasons. Novel oral anticoagulants (NOAs) are new, orally available anticoagulants designed to be easier to administer with more reliable pharmacokinetics that eliminate the need for frequent monitoring of various laboratory parameters. This paper reviews the existing efficacy and safety data for the use of NOAs dabigatran etexilate, rivaroxaban, and apixaban and discusses the potential role of these agents in the management of gastrointestinal cancer-related VTE. PMID- 23024861 TI - Low back pain prevalence and associated factors in Iranian population: findings from the national health survey. AB - Background. There are very few studies that had a sample size sufficient to explore the association between factors related to low back pain in a representative sample of the Iranian population. Objective. To examine the relationship between sociodemographic factors, smoking, obesity, and low back pain in Iranian people. Methods. We used Iranian adults respondents (n = 25307) from the National Health Survey. Adjusted odds ratios and 95% confidence intervals were estimated by using logistic regression. Results. The prevalence of low back pain was found in 29.3% of the studied sample. High age, female sex, being married, obesity, low-economic index, being smoker, in a rural residence, and low educational attainment, all increased the odds of low back pain. Conclusions. Our findings add to the evidence on the importance of obesity in relation to low back pain. These results can be used as a basis to reinforce health programs to prevent obesity. PMID- 23024862 TI - Cognitively Stimulating Activities: Effects on Cognition across Four Studies with up to 21 Years of Longitudinal Data. AB - Engagement in cognitively stimulating activities has been considered to maintain or strengthen cognitive skills, thereby minimizing age-related cognitive decline. While the idea that there may be a modifiable behavior that could lower risk for cognitive decline is appealing and potentially empowering for older adults, research findings have not consistently supported the beneficial effects of engaging in cognitively stimulating tasks. Using observational studies of naturalistic cognitive activities, we report a series of mixed effects models that include baseline and change in cognitive activity predicting cognitive outcomes over up to 21 years in four longitudinal studies of aging. Consistent evidence was found for cross-sectional relationships between level of cognitive activity and cognitive test performance. Baseline activity at an earlier age did not, however, predict rate of decline later in life, thus not supporting the concept that engaging in cognitive activity at an earlier point in time increases one's ability to mitigate future age-related cognitive decline. In contrast, change in activity was associated with relative change in cognitive performance. Results therefore suggest that change in cognitive activity from one's previous level has at least a transitory association with cognitive performance measured at the same point in time. PMID- 23024863 TI - Malnutrition-sarcopenia syndrome: is this the future of nutrition screening and assessment for older adults? AB - Malnutrition is common across varying patient populations, particularly older adults, and sarcopenia prevalence increases with advancing age. Both malnutrition and sarcopenia are associated with substantial adverse outcomes affecting both the patient and the healthcare system, including increased morbidity, mortality, rehospitalization rates, and healthcare costs. Healthcare practitioners may assess patients for either malnutrition or sarcopenia; however, many patients clinically present with both conditions, resulting in the syndrome, Malnutrition Sarcopenia Syndrome, which is the clinical presentation of both malnutrition and accelerated age-associated loss of lean body mass, strength, and/or functionality. Clinicians are urged to screen, assess, and treat these conditions currently so as to adequately address the full spectrum of patients' nutritional issues. By examining aspects of both conditions, clinicians can more fully assess their patients' clinical and nutritional status and can tailor targeted therapies to meet their needs and improve outcomes. This proposed syndrome embodies the inherent association of malnutrition and sarcopenia, highlighting their combined impact on clinical outcomes. The objective of this review paper is to characterize Malnutrition-Sarcopenia Syndrome to advance clinical practice, by providing clinicians with the necessary background information to integrate nutritional assessment along with loss of muscle mass and functionality in their everyday clinical practice. PMID- 23024864 TI - Patched knockout mouse models of Basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common human tumor. Mutations in the hedgehog (HH) receptor Patched (PTCH) are the main cause of BCC. Due to their high and increasing incidence, BCC are becoming all the more important for the health care system. Adequate animal models are required for the improvement of current treatment strategies. A good model should reflect the situation in humans (i.e., BCC initiation due to Ptch mutations on an immunocompetent background) and should allow for (i) BCC induction at a defined time point, (ii) analysis of defined BCC stages, and (iii) induction of BCC in 100% of animals. In addition, it should be easy to handle. Here, we compare several currently existing conventional and conditional Ptch knockout mouse models for BCC and their potential use in preclinical research. In addition, we provide new data using conditional Ptch(flox/flox) mice and the K5-Cre-ER(T+/-) driver. PMID- 23024866 TI - How normal is the liver in which the inflammatory type hepatocellular adenoma develops? AB - The inflammatory type hepatocellular adenoma (IHCA) is a subtype of HCA which is a benign liver tumor, predominantly occurring in young women in an otherwise normal liver. IHCA contains either a mutation of gp130 or STAT3. Both mutations lead to a similar morphologic phenotype and to increased expression of C-reactive protein (CRP) and/or serum amyloid-A (SAA). IHCA comprised about 40% of all HCAs and is associated with obesity. We investigated the histomorphological and immunophenotypical changes of the nontumorous liver of 32 resected IHCA specimens. Similar types of changes are present in samples taken adjacent to tumor and distant ones. The lobular architecture is well preserved. Mild/moderate steatosis is found in a high frequency which is in accordance with the median BMI of 32 in our cases. Of note are the regular findings of sinusoidal dilatation, single arteries, and minute CRP foci which are all features of HCA. These distinct CRP foci are mostly found in cases of multiple IHCA which indicates that the remnant liver may also contain IHCA foci. These findings show that the nonlesional liver in IHCA does contain abnormalities, and this may have consequences for the followup, especially since it is known that obesity may stimulate malignant growth. PMID- 23024865 TI - Clinical manifestations of portal hypertension. AB - The portal hypertension is responsible for many of the manifestations of liver cirrhosis. Some of these complications are the direct consequences of portal hypertension, such as gastrointestinal bleeding from ruptured gastroesophageal varices and from portal hypertensive gastropathy and colopathy, ascites and hepatorenal syndrome, and hypersplenism. In other complications, portal hypertension plays a key role, although it is not the only pathophysiological factor in their development. These include spontaneous bacterial peritonitis, hepatic encephalopathy, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and portopulmonary hypertension. PMID- 23024867 TI - Elderly onset of weakness in facioscapulohumeral muscular dystrophy. AB - A 77-year-old male is presented. He had onset of proximal weakness 10 years earlier. His course was slowly progressive. Despite having phenotypic features of facioscapulohumeral muscular dystrophy (FSH), genetic testing for this was delayed because of his age of onset, lack of family history, and benign appearing muscle biopsy. This case is one of the oldest onset of weakness in genetically confirmed FSH and highlights the recognized expansion in phenotype that has occurred since the advent of genetic testing. PMID- 23024868 TI - Laparoscopic salpingectomy for isolated fallopian tube torsion in the third trimester. AB - Isolated tubal torsion is a rare event. The clinical presentation is often nonspecific and the diagnosis is difficult, especially in the gravida abdomen. If left untreated, torsion can result in premature labour and foetal loss, as well as maternal morbidity. Here we present a case of isolated tubal torsion in a primigravida occurring in her third trimester and subsequent successful laparoscopic salpingectomy, rather than laparotomy. We discuss some of the diagnostic difficulties faced and approached to surgery as well as a brief review of the literature. In our case the women went on to successfully complete her pregnancy with no further complications. PMID- 23024869 TI - Spontaneous Rupture of Splenic Artery Aneurysm during the First Trimester of Pregnancy: Report of an Extremely Rare Case and Review of the Literature. AB - Splenic artery aneurysm (SAA) occurs predominantly in women and the majority of them are asymptomatic until rupture. In cases of spontaneous rupture of an SAA, maternal and fetal mortality rates remain extremely high. Furthermore, the spontaneous ruptures of SAAs predominantly appear during the third trimester of pregnancy. We present the third known case of spontaneous SAA rupture during the first trimester of pregnancy, which manifested as sudden hypovolemic collapse and was successfully confronted with combined aggressive resuscitation and emergency surgical operation. PMID- 23024870 TI - A rare case of antepartum spontaneous septostomy in a monochorionic diamniotic twin pregnancy. AB - Spontaneous septostomy in a monochorionic diamniotic twin pregnancy is a rare phenomenon. We present a case of monochorionic diamniotic twin pregnancy with an intact dividing membrane seen in the 1st half of the pregnancy. At 26 weeks, when she was assessed for preterm contractions, the dividing membrane was not documented, which suggested spontaneous septostomy. There had been no invasive procedures during the pregnancy. She subsequently delivered at 29 weeks, secondary to preterm labor. No dividing membrane was noticed at the time of caesarian section. Spontaneous septostomy can complicate the management of monochorionic diamniotic twins by creating a pseudomonoamniotic environment resulting in cord entanglement, and difficulty in the diagnosis and management of twin-twin transfusion syndrome. We believe that such a case should be managed as monochorionic monoamniotic twin gestation. PMID- 23024871 TI - Paget's Disease of the Vulva in Premenopausal Woman Treated with Only Surgery: A Case Report. AB - Paget's disease of the vulva remains a rare condition with only a limited number of cases reported in the literature. It is an uncommon neoplasm usually of postmenopausal white women characterized by controversies in its prevalence, clinical features, treatment strategies, and prognostic. We here report a case of a primary Paget's disease of the vulva in premenopausal woman treated by only surgery with a favorable issue. PMID- 23024872 TI - Chondroid chordoma and nasal adenocarcinoma: an exceptional association. AB - Collision tumors are exceptional, associating two independent tumoral contingents. We report a case of an association of two rare tumors: sinonasal adenocarcinoma and chondroid chordoma. Initially, only adenocarcinoma was diagnosed. The treatment consisted of endoscopic endonasal surgery followed by conventional radiotherapy. After 18 months, a local recurrence was diagnosed after a facial trauma, but the true histology was difficult to assess. The tumor was dual, associating adenocarcinoma and chondroid chordoma, with atypical localization in the ethmoid. Further evolution was particularly aggressive. We discuss the key points of this observation. PMID- 23024873 TI - Coexisting malignant melanoma and blue nevus of the uterine cervix: an unusual combination. AB - Malignant melanoma (MM) and blue nevi of the uterine cervix are an extremely rare neoplasm, probably derived from embryologic migration of melanocytes from the neural crest. MM displays aggressive behavior with a poor prognosis. We report the case of a 76-year-old postmenopausal woman abnormal vaginal bleeding. She underwent a hysterectomy and bilateral salpingo-oophorectomy with paraaortic iliac lymphadenectomy. Histopathological and immunohistochemical studies were consistent with the diagnosis of MM and blue nevi in the uterine cervix. Although it is extremely rare, this case suggests that MM of the uterine cervix should be considered in the differential diagnosis of undifferentiated neoplasm. Early diagnosis is essential in order to warrant a better prognosis, although there are no cases of cure described. PMID- 23024874 TI - Fibrous dysplasia of the palate: report of a case and review of palatal swellings. AB - Fibrous dysplasia is a benign fibroosseous lesion characterised by the replacement of normal bone by excessive proliferation of cellular fibrous connective tissue which is slowly replaced by bone, osteoid, or cementum-like material. It causes bone pain, deformities, and pathological fractures. Fibrous dysplasia (FD) is a sporadic benign skeletal disorder that can affect one bone (monostotic form) or multiple bones (polyostotic form). In this paper, we present case of a monostotic fibrous dysplasia on the hard palate of 14-year-old girl and a tabular review of common palatal swellings. PMID- 23024875 TI - Congenital unilateral hypoplasia of depressor anguli oris. AB - Objectives. Asymmetric facial appearance may originate from abnormalities of facial musculature or facial innervation. We describe clinical features of congenital hypoplasia of depressor anguli oris muscle in a child. Material and Methods. Chart of a 10-month-old female referred to a tertiary care pediatric hospital for assessment of facial paralysis was reviewed. Data included relevant history and physical examination, diagnostic work up, and management. Results. The child presented with asymmetric movement of lower lip since birth. Asymmetry of lower lip was more pronounced when she smiled and cried. Rest of the face movement was symmetric. On examination, the face appeared symmetric at rest. The child had inward deviation of right lower lip when she smiled. Facial nerve function, as determined by frowning/forehead, wrinkling, eye closure, nasolabial fold depth, and tearing, was symmetric. Magnetic resonance imaging of the temporal bones and internal auditory canals were within normal limits. Echocardiogram did not show cardiac abnormality. Auditory brainstem response showed no abnormality. Conclusions. Congenital hypoplasia of depressor anguli oris is a rare anomaly that causes asymmetric crying face. Pediatricians and otolaryngologists need to be cognizant of cardiac, head and neck, and central nervous system anomalies associated with congenital unilateral hypoplasia of depressor anguli oris. PMID- 23024876 TI - Vocal cord dysfunction: a frequently forgotten entity. AB - Vocal cord dysfunction (VCD) is a disorder characterized by unintentional paradoxical adduction of the vocal cords, resulting in episodic shortness of breath, wheezing and stridor. Due to its clinical presentation, this entity is frequently mistaken for asthma. The diagnosis of VCD is made by direct observation of the upper airway by rhinolaryngoscopy, but due to the variable nature of this disorder the diagnosis can sometimes be challenging. We report the case of a 41-year old female referred to our Allergology clinics with the diagnosis of asthma. Thorough investigation revealed VCD as the cause of symptoms. PMID- 23024877 TI - Chorea as the first and only manifestation of systemic lupus erythematosus. AB - We report a case of right-sided hemichorea associated with systemic lupus erythematosus (SLE) in a female patient who presented with involuntary movements of hand and foot, without any other manifestation of SLE. Further workup showed positive tests for antinuclear antibody, anti-Smith antibody, anti-dsDNA, and antiphospholipid antibody (aPL). The patient was started on aspirin and hydroxychloroquine and her chorea resolved after three weeks of followup. This is one of the few reported cases of SLE where chorea is presented as the first and only manifestation of SLE. PMID- 23024878 TI - Pneumoperitoneum, Retropneumoperitoneum, Pneumomediastinum, and Diffuse Subcutaneous Emphysema following Diagnostic Colonoscopy. AB - Colonoscopy is a widely used diagnostic and curative procedure. Extraperitoneal perforation with pneumoretroperitoneum, pneumomediastinum and subcutaneous emphysema combined with intraperitoneal perforation is an extremely rare complication. We report a case of a 78-year-old woman presented to the emergency department with abdominal pain and diffuse abdominal, chest, neck, and facial swelling appeared after a diagnostic colonoscopy. Diagnostic and therapeutic modalities are discussed. PMID- 23024879 TI - Successful Management of Jejunal Perforation in Burkitt's Lymphoma: A Case Report. AB - Burkitt's lymphoma (BL) is rare, rapidly growing, and highly aggressive. Urgent commencement of chemotherapy is vital to prevent complications and promote a favourable prognosis. Any factor causing a delay in the initiation of chemotherapy will affect prognosis significantly. Intestinal perforation is a well-known complication with devastating consequences. It inevitably leads to a delay in the initiation of chemotherapy. There are few reports in the literature that discuss this complication. Furthermore, there are no reports of patients that have survived intestinal perforation occurring prior to the commencement of chemotherapy. We present a case of a 55-year-old male who survived perforation of advanced sporadic BL of the jejunum occurring prior to the commencement of chemotherapy. Critical aspects of the patients care are discussed. PMID- 23024880 TI - Transstomal small bowel evisceration after colonic perforation secondary to ischemic colitis. AB - Intestinal stomas are commonly used in a temporary or permanent fashion in gastrointestinal surgeries. The complication rate of stomas has been reported to vary between 23 and 50%. There is only one case in the literature involving transstomal small bowel evisceration following colonic perforation. In this paper, we aimed to present a patient with a perforated colon secondary to ischemic colitis, which resulted in small bowel evisceration through this perforation site. PMID- 23024881 TI - Penile paraffinoma. AB - Penile paraffinoma is an uncommon entity produced by penile paraffin injections for the purpose of penile enlargement by a nonmedical person. Although it is not a current method of penile enlargement procedures, in our opinion dermatologists and urology specialist should be have knowledge of this entity about diagnosis and management. It will be an aim to share our experiences and views in this paper. PMID- 23024883 TI - Test-retest reliability of a new medial temporal atrophy morphological metric. AB - Clinicians and researchers alike are in need of quantitative and robust measurement tools to assess medial temporal lobe atrophy (MTA) due to Alzheimer's disease (AD). We recently proposed a morphological metric, extracted from T1 weighted magnetic resonance images (MRI), to track and estimate MTA in cohorts of controls, AD, and mild cognitive impairment subjects, at high-risk of progression to dementia. In this paper, we investigated its reliability through analysis of within-session scan/repeat images and scan/rescans from large multicenter studies. In total, we used MRI data from 1051 subjects recruited at over 60 centers. We processed the data identically and calculated our metric for each individual, based on the concept of distance in a high-dimensional space of intensity and shape characteristics. Over 759 subjects, the scan/repeat change in the mean was 1.97% (SD: 21.2%). Over three subjects, the scan/rescan change in the mean was 0.89% (SD: 22.1%). At this level, the minimum trial size required to detect this difference is 68 individuals for both samples. Our scan/repeat and scan/rescan results demonstrate that our MTA assessment metric shows high reliability, a necessary component of validity. PMID- 23024882 TI - Vaccine Development to Treat Alzheimer's Disease Neuropathology in APP/PS1 Transgenic Mice. AB - A novel vaccine addressing the major hallmarks of Alzheimer's disease (AD), senile plaque-like deposits of amyloid beta-protein (Abeta), neurofibrillary tangle-like structures, and glial proinflammatory cytokines, has been developed. The present vaccine takes a new approach to circumvent failures of previous ones tested in mice and humans, including the Elan-Wyeth vaccine (AN1792), which caused massive T-cell activation, resulting in a meningoencephalitis-like reaction. The EB101 vaccine consists of Abeta(1-42) delivered in a novel immunogen-adjuvant composed of liposomes-containing sphingosine-1-phosphate (S1P). EB101 was administered to APPswe/PS1dE9 transgenic mice before and after AD-like pathological symptoms were detectable. Treatment with EB101 results in a marked reduction of Abeta plaque burden, decrease of neurofibrillary tangle-like structure density, and attenuation of astrocytosis. In this transgenic mouse model, EB101 reduces the basal immunological interaction between the T cells and immune activation markers in the affected hippocampal/cortical areas, consistent with decreased amyloidosis-induced inflammation. Therefore, immunization with EB101 prevents and reverses AD-like neuropathology in a significant manner by halting disease progression without developing behavioral spatial deficits in transgenic mice. PMID- 23024884 TI - Cichlid evolution: lessons in diversification 2012. PMID- 23024885 TI - Utilization and utility of clinical laboratory reports with graphical elements. AB - BACKGROUND: Graphical reports that contain charts, images, and tables have potential to convey information more effectively than text-based reports; however, studies have not measured how much clinicians value such features. We sought to identify factors that might influence the utilization of reports with graphical elements postulating that this is a surrogate for relative clinical utility of these graphical elements. MATERIALS AND METHODS: We implemented a pilot project at ARUP laboratories to develop online enhanced laboratory test reports that contained graphical elements. We monitored on-demand clinician access to reports generated for 48 reportable tests over 22 months. We evaluated utilization of reports with graphical elements by clinicians at all institutions that use ARUP as a reference laboratory using descriptive statistics, regression, and meta-analysis tools to evaluate groups of similar test reports. RESULTS: Median download rate by test was 8.6% with high heterogeneity in download rates between tests. Test reports with additional graphical elements were not necessarily downloaded more often than reports without these elements. Recently implemented tests and tests reporting abnormal results were associated with higher download rates (P < 0.01). Higher volume tests were associated with lower download rates (P = 0.03). CONCLUSIONS: In select cases graphical information may be clinically useful, particularly for less frequently ordered tests and in on reports of abnormal results. The utilization data presented could be used as a reference point for other laboratories planning on implementing graphical reporting. However, between-test heterogeneity was high and in many cases graphical elements may add little clinical utility, particularly if these merely reinforce information already contained in text based reports. PMID- 23024886 TI - Diagnosis of dysplasia in upper gastro-intestinal tract biopsies through digital microscopy. AB - BACKGROUND: Whole slide digital imaging (WSDI) offers an alternative to glass slides for diagnostic interpretation. While prior work has concentrated on the use of whole slide digital imaging for routine diagnostic cases, this study focuses on diagnostic interpretation of digital images for a highly challenging area, upper gastro-intestinal (GI) dysplasia. The aim of this study is to study the accuracy and efficiency of WSDI in the diagnosis of upper GI tract dysplasia. MATERIALS AND METHODS: Forty-two hematoxylin and eosin (H and E)-stained slides representing negative, indefinite, low grade and high grade dysplasia were selected and scanned at 20x (Aperio XT). Four attending GI pathologists reviewed the WSDI, then glass slides, with at least 3-4 weeks between each media; glass slides were re-reviewed 16-18 months later. RESULTS: Intraobserver variability for three clinically relevant categories (negative, indefinite/low grade, high grade) was wider for WSDI to glass (kappa range 0.36-0.78) than glass to glass (kappa range 0.58-0.75). In comparison to glass slide review, WSDI review required more time and was associated with an unexpected trend toward downgrading dysplasia. CONCLUSIONS: OUR RESULTS SUGGEST: (1) upper GI dysplasia can be diagnosed using WSDI with similar intraobserver reproducibility as for glass slides; however, this is not true for all pathologists; (2) pathologists may have a tendency to downgrade dysplasia in digital images; and (3) pathologists who use WSDI for interpretation of GI dysplasia cases may benefit from regular, on-going, re-review of paired digital and glass images to ensure the most accurate utilization of digital technology, at least in the early stages of implementation. PMID- 23024887 TI - Dynamic nonrobotic telemicroscopy via skype: A cost effective solution to teleconsultation. AB - CONTEXT: Skype is a peer to peer software application that has been historically used for voice and video calls, instant messaging, and file transfer over the Internet. Few studies are available using Skype specifically for telepathology. AIMS: Our aim is to show that dynamic nonrobotic teleconsultation is possible and even effective via means of a standard microscope camera capable of live acquisition, Skype, an established broad band internet connection, and experienced pathologists. SETTINGS AND DESIGN: Both the consulting "sending" pathologist and consultant "receiving" pathologist are reasonably experienced general surgical pathologists at junior attending level with several years of experience in sign out. Forty-five cases were chosen encompassing a broad range of surgical pathology specimens. The cases were prospectively evaluated with the consultant diagnosis used as a preliminary pathologic impression with the final diagnosis being confirmation. MATERIALS AND METHODS: Versions of Skype 5.0 and above were used along with established broadband internet connections, usually between academic medical institutions. RESULTS: Forty of forty-five cases (89%) were essentially concordant. In four of forty-five cases (9%), the consulting impression gave a differential, but favored an entity which did not match the final diagnosis. Only one case (2%) did the consulting impression not match the final diagnosis; a discordant opinion. CONCLUSIONS: The image quality via Skype screen sharing option is excellent. Essentially no lag time was seen. We have shown in our small pilot study that Skype is an effective cost-efficient means for teleconsultation, particularly in the setting of entity-related differential diagnoses in surgical pathology and when both the consulting and consultant pathologists are reasonably experienced. PMID- 23024888 TI - Experience with CellaVision DM96 for peripheral blood differentials in a large multi-center academic hospital system. AB - CONTEXT AND AIMS: Rapid, accurate peripheral blood differentials are essential to maintain standards of patient care. CellaVision DM96 (CellaVision AB, Lund, Sweden) (CV) is an automated digital morphology and informatics system used to locate, pre-classify, store and transmit images of platelets, red and white blood cells to a trained technologist who confirms or edits CV cell classification. We assessed our experience with CV by evaluating sensitivity, specificity, positive predictive value and negative predictive value for CV in three different patient populations. MATERIALS AND METHODS: We analyzed classification accuracy of CV for white blood cells, erythroblasts, platelets and artefacts over six months for three different university hospitals using CV. RESULTS: CV classified 211,218 events for the adult cancer center; 51,699 events for the adult general hospital; and 8,009 events for the children's hospital with accuracy of CV being 93%, 87.3% and 95.4% respectively. Sensitivity and positive predictive value were <80% for immature granulocytes (band neutrophil, promyelocyte, myelocyte and metamyelocytes) (differences usually within one stage of maturation). Cell types comprising a lower frequency of the total events, including blasts, showed lower accuracy at some sites. CONCLUSIONS: The reduced immature granulocyte classification accuracy may be due in part to the subjectivity in classification of these cells, length of experience with the system and individual expertise of the technologist. Cells with low sensitivity and positive predictive value comprised a minority of the cells and should not significantly affect the technologist re-classification time. CV serves as a clinically useful instrument in performance of peripheral blood differentials. PMID- 23024889 TI - Different tracks for pathology informatics fellowship training: Experiences of and input from trainees in a large multisite fellowship program. AB - BACKGROUND: Pathology Informatics is a new field; a field that is still defining itself even as it begins the formalization, accreditation, and board certification process. At the same time, Pathology itself is changing in a variety of ways that impact informatics, including subspecialization and an increased use of data analysis. In this paper, we examine how these changes impact both the structure of Pathology Informatics fellowship programs and the fellows' goals within those programs. MATERIALS AND METHODS: As part of our regular program review process, the fellows evaluated the value and effectiveness of our existing fellowship tracks (Research Informatics, Clinical Two-year Focused Informatics, Clinical One-year Focused Informatics, and Clinical 1 + 1 Subspecialty Pathology and Informatics). They compared their education, informatics background, and anticipated career paths and analyzed them for correlations between those parameters and the fellowship track chosen. All current and past fellows of the program were actively involved with the project. RESULTS: Fellows' anticipated career paths correlated very well with the specific tracks in the program. A small set of fellows (Clinical - one or two year - Focused Informatics tracks) anticipated clinical careers primarily focused in informatics (Director of Informatics). The majority of the fellows, however, anticipated a career practicing in a Pathology subspecialty, using their informatics training to enhance that practice (Clinical 1 + 1 Subspecialty Pathology and Informatics Track). Significantly, all fellows on this track reported they would not have considered a Clinical Two-year Focused Informatics track if it was the only track offered. The Research and the Clinical One-year Focused Informatics tracks each displayed unique value for different situations. CONCLUSIONS: It seems a "one size fits all" fellowship structure does not fit the needs of the majority of potential Pathology Informatics candidates. Increasingly, these fellowships must be able to accommodate the needs of candidates anticipating a wide range of Pathology Informatics career paths, be able to accommodate Pathology's increasingly subspecialized structure, and do this in a way that respects the multiple fellowships needed to become a subspecialty pathologist and informatician. This is further complicated as Pathology Informatics begins to look outward and takes its place in the growing, and still ill-defined, field of Clinical Informatics, a field that is not confined to just one medical specialty, to one way of practicing medicine, or to one way of providing patient care. PMID- 23024890 TI - A core curriculum for clinical fellowship training in pathology informatics. AB - BACKGROUND: In 2007, our healthcare system established a clinical fellowship program in Pathology Informatics. In 2010 a core didactic course was implemented to supplement the fellowship research and operational rotations. In 2011, the course was enhanced by a formal, structured core curriculum and reading list. We present and discuss our rationale and development process for the Core Curriculum and the role it plays in our Pathology Informatics Fellowship Training Program. MATERIALS AND METHODS: The Core Curriculum for Pathology Informatics was developed, and is maintained, through the combined efforts of our Pathology Informatics Fellows and Faculty. The curriculum was created with a three-tiered structure, consisting of divisions, topics, and subtopics. Primary (required) and suggested readings were selected for each subtopic in the curriculum and incorporated into a curated reading list, which is reviewed and maintained on a regular basis. RESULTS: Our Core Curriculum is composed of four major divisions, 22 topics, and 92 subtopics that cover the wide breadth of Pathology Informatics. The four major divisions include: (1) Information Fundamentals, (2) Information Systems, (3) Workflow and Process, and (4) Governance and Management. A detailed, comprehensive reading list for the curriculum is presented in the Appendix to the manuscript and contains 570 total readings (current as of March 2012). DISCUSSION: The adoption of a formal, core curriculum in a Pathology Informatics fellowship has significant impacts on both fellowship training and the general field of Pathology Informatics itself. For a fellowship, a core curriculum defines a basic, common scope of knowledge that the fellowship expects all of its graduates will know, while at the same time enhancing and broadening the traditional fellowship experience of research and operational rotations. For the field of Pathology Informatics itself, a core curriculum defines to the outside world, including departments, companies, and health systems considering hiring a pathology informatician, the core knowledge set expected of a person trained in the field and, more fundamentally, it helps to define the scope of the field within Pathology and healthcare in general. PMID- 23024891 TI - Use of a wiki as an interactive teaching tool in pathology residency education: Experience with a genomics, research, and informatics in pathology course. AB - BACKGROUND: The need for informatics and genomics training in pathology is critical, yet limited resources for such training are available. In this study we sought to critically test the hypothesis that the incorporation of a wiki (a collaborative writing and publication tool with roots in "Web 2.0") in a combined informatics and genomics course could both (1) serve as an interactive, collaborative educational resource and reference and (2) actively engage trainees by requiring the creation and sharing of educational materials. MATERIALS AND METHODS: A 2-week full-time course at our institution covering genomics, research, and pathology informatics (GRIP) was taught by 36 faculty to 18 second- and third-year pathology residents. The course content included didactic lectures and hands-on demonstrations of technology (e.g., whole-slide scanning, telepathology, and statistics software). Attendees were given pre- and posttests. Residents were trained to use wiki technology (MediaWiki) and requested to construct a wiki about the GRIP course by writing comprehensive online review articles on assigned lectures. To gauge effectiveness, pretest and posttest scores for our course were compared with scores from the previous 7 years from the predecessor course (limited to informatics) given at our institution that did not utilize wikis. RESULTS: Residents constructed 59 peer-reviewed collaborative wiki articles. This group showed a 25% improvement (standard deviation 12%) in test scores, which was greater than the 16% delta recorded in the prior 7 years of our predecessor course (P = 0.006). CONCLUSIONS: Our use of wiki technology provided a wiki containing high-quality content that will form the basis of future pathology informatics and genomics courses and proved to be an effective teaching tool, as evidenced by the significant rise in our resident posttest scores. Data from this project provide support for the notion that active participation in content creation is an effective mechanism for mastery of content. Future residents taking this course will continue to build on this wiki, keeping content current, and thereby benefit from this collaborative teaching tool. PMID- 23024892 TI - Visibility enhancement of common bile duct for laparoscopic cholecystectomy by vivid fiber-optic indication: a porcine experiment trial. AB - Bile duct injury (BDI) is the most serious iatrogenic complication during laparoscopic cholecystectomy (LC) and occurs easily in inexperienced surgeons since the position of common bile duct (CBD) and its related ductal junctions are hard to precisely identify in the hepatic anatomy during surgery. BDI can be devastating, leading to chronic morbidity, high mortality, and prolonged hospitalization. In addition, it is the most frequent injury resulting in litigation and the most likely injury associated with a successful medical malpractice claim against surgeons. This study introduces a novel method for conveniently and rapidly indicating the anatomical location of CBD during LC by the direct fiber-optic illumination of 532-nm diode-pumped solid state laser through a microstructured plastic optical fiber to avoid the wrong identification of CBD and the injury from mistakenly cutting the CBD that can lead to permanent and even life threatening consequences. Six porcine were used for preliminary intra-CBD illumination experiments via laparotomy and direct duodenal incision to insert the invented CBD illumination laser catheter with nonharmful but satisfactory visual optical density. PMID- 23024893 TI - Three-color femtosecond source for simultaneous excitation of three fluorescent proteins in two-photon fluorescence microscopy. AB - We demonstrate a fiber-based, three-color femtosecond source for simultaneous imaging of three fluorescent proteins (FPs) using two-photon fluorescence microscopy (2PM). The three excitation wavelengths at 775 nm, 864 nm and 950 nm, are obtained through second harmonic generation (SHG) of the 1550-nm pump laser and the 1728-nm and 1900-nm solitons generated through soliton self-frequency shift (SSFS) in a large-mode-area (LMA) fiber. These energetic pulses are well matched to the two-photon excitation peaks of red, cyan and yellow fluorescent proteins (TagRFPs, TagCFPs, and TagYFPs) for efficient excitation. We demonstrate simultaneous 2PM of human melanoma cells expressing a "rainbow" combination of these three fluorescent proteins. PMID- 23024894 TI - Monitoring airway mucus flow and ciliary activity with optical coherence tomography. AB - Muco-ciliary transport in the human airway is a crucial defense mechanism for removing inhaled pathogens. Optical coherence tomography (OCT) is well-suited to monitor functional dynamics of cilia and mucus on the airway epithelium. Here we demonstrate several OCT-based methods upon an actively transporting in vitro bronchial epithelial model and ex vivo mouse trachea. We show quantitative flow imaging of optically turbid mucus, semi-quantitative analysis of the ciliary beat frequency, and functional imaging of the periciliary layer. These may translate to clinical methods for endoscopic monitoring of muco-ciliary transport in diseases such as cystic fibrosis and chronic obstructive pulmonary disease (COPD). PMID- 23024895 TI - Biomolecule kinetics measurements in flow cell integrated porous silicon waveguides. AB - A grating-coupled porous silicon (PSi) waveguide with an integrated polydimethylsiloxane (PDMS) flow cell is demonstrated as a platform for near real time detection of chemical and biological molecules. This sensor platform not only allows for quantification of molecular binding events, but also provides a means to improve understanding of diffusion and binding mechanisms in constricted nanoscale geometries. Molecular binding events in the waveguide are monitored by angle-resolved reflectance measurements. Diffusion coefficients and adsorption and desorption rate constants of different sized chemical linkers and nucleic acid molecules are determined based on the rate of change of the measured resonance angle. Experimental results show that the diffusion coefficient in PSi is smaller than that in free solutions, and the PSi morphology slows the molecular adsorption rate constant by a factor of 10(2)-10(4) compared to that of flat surface interactions. Calculations based on simplified mass balance equations and COMSOL simulations give good agreement with experimental data. PMID- 23024896 TI - Measurement of orientation and susceptibility ratios using a polarization resolved second-harmonic generation holographic microscope. AB - Three-dimensional second-harmonic fields, sample orientation, and susceptibility ratios of biological samples are measured using polarization-resolved second harmonic generation (SHG) microscopy. The three-dimensional (3D) polarization is gathered by measurement of a series of holograms for which excitation and analyzer polarizations are systematically varied, and the 3D SHG field is recovered through numerical back propagation. Harmonophore orientation is resolved in 3D from a sub-set of polarization-resolved SHG holograms. We further expand on previous approaches for the determination of susceptibility ratios, adding the calculation of multiple ratio values to allow intrinsic verification. PMID- 23024897 TI - Localized surface plasmon microscopy of submicron domain structures of mixed lipid bilayers. AB - We propose scanning localized surface plasmon microscopy of mixed lipid bilayers with submicron domain structures. Our observation technique, which employs localized surface plasmons excited on a flat metal surface as a sensing probe, provides non-label and non-contact imaging with the spatial resolution of ~ 170 nm. We experimentally show that submicron domain structures of mixed lipid bilayers can be observed. A detailed analysis finds that the domains are classified into two groups. PMID- 23024898 TI - Quantifying collagen structure in breast biopsies using second-harmonic generation imaging. AB - Quantitative second-harmonic generation imaging is employed to assess stromal collagen in normal, hyperplastic, dysplastic, and malignant breast tissues. The cellular scale organization is quantified using Fourier transform-second harmonic generation imaging (FT-SHG), while the molecular scale organization is quantified using polarization-resolved second-harmonic generation measurements (P-SHG). In the case of FT-SHG, we apply a parameter that quantifies the regularity in collagen fiber orientation and find that malignant tissue contains locally aligned fibers compared to other tissue conditions. Alternatively, using P-SHG we calculate the ratio of tensor elements (d(15)/d(31), d(22)/d(31), and d(33)/d(31)) of the second-order susceptibility chi(2) for collagen fibers in breast biopsies. In particular, d(15)/d(31) shows potential differences across the tissue pathology. We also find that trigonal symmetry (3m) is a more appropriate model to describe collagen fibers in malignant tissues as opposed to the conventionally used hexagonal symmetry (C6). This novel method of targeting collagen fibers using a combination of two quantitative SHG techniques, FT-SHG and P-SHG, holds promise for breast tissue analysis and applications to characterizing cancer in a manner that is compatible with clinical practice. PMID- 23024899 TI - Singular value decomposition based regularization prior to spectral mixing improves crosstalk in dynamic imaging using spectral diffuse optical tomography. AB - The spectrally constrained diffuse optical tomography (DOT) method relies on incorporating spectral prior information directly into the image reconstruction algorithm, thereby correlating the underlying optical properties across multiple wavelengths. Although this method has been shown to provide a solution that is stable, the use of conventional Tikhonov-type regularization techniques can lead to additional crosstalk between parameters, particularly in linear, single-step dynamic imaging applications. This is due mainly to the suboptimal regularization of the spectral Jacobian matrix, which smoothes not only the image-data space, but also the spectral mapping space. In this work a novel regularization technique based on the singular value decomposition (SVD) is presented that preserves the spectral prior information while regularizing the Jacobian matrix, leading to dramatically reduced crosstalk between the recovered parameters. Using simulated data, images of changes in oxygenated and deoxygenated hemoglobin concentrations are reconstructed via the SVD-based approach and compared with images reconstructed by using non-spectral and conventional spectral methods. In a 2D, two wavelength example, it is shown that the proposed approach provides a 98% reduction in crosstalk between recovered parameters as compared with conventional spectral reconstruction algorithms, and 60% as compared with non spectrally constrained algorithms. Using a subject specific multilayered model of the human head, a noiseless dynamic simulation of cortical activation is performed to further demonstrate such improvement in crosstalk. However, with the addition of realistic noise in the data, both non-spectral and proposed algorithms perform similarly, indicating that the use of spectrally constrained reconstruction algorithms in dynamic DOT may be limited by the contrast of the signal as well as the noise characteristics of the system. PMID- 23024900 TI - Distributed scanning volumetric SDOCT for motion corrected corneal biometry. AB - We present a method, termed distributed scanning OCT (DSOCT), which reduces the effects of patient motion on corneal biometry utilizing current-generation clinically available spectral domain optical coherence tomography (SDOCT) systems. We first performed a pilot study of the power spectrum of normal patient axial eye motion based on repeated (M-mode) SDOCT. Using DSOCT to reduce the effects of patient motion, we conducted a preliminary patient study comparing the measured anterior and posterior corneal curvatures and the calculated corneal power to both corneal topography and Scheimpflug photography in normal subjects. The repeatability for the measured radius of curvature of both anterior and posterior surfaces as well as calculated corneal refractive power using DSOCT was comparable to those of both topography and Scheimpflug photography. PMID- 23024901 TI - Measurement and correction of transverse chromatic offsets for multi-wavelength retinal microscopy in the living eye. AB - A special challenge arises when pursuing multi-wavelength imaging of retinal tissue in vivo, because the eye's optics must be used as the main focusing elements, and they introduce significant chromatic dispersion. Here we present an image-based method to measure and correct for the eye's transverse chromatic aberrations rapidly, non-invasively, and with high precision. We validate the technique against hyperacute psychophysical performance and the standard chromatic human eye model. In vivo correction of chromatic dispersion will enable confocal multi-wavelength images of the living retina to be aligned, and allow targeted chromatic stimulation of the photoreceptor mosaic to be performed accurately with sub-cellular resolution. PMID- 23024902 TI - Characterization of materials for optimal near-infrared and x-ray imaging of the breast. AB - Development of a detector case for complete co-registration of images in a non fiber-based combined near-infrared spectral tomography and digital breast tomosynthesis, required analysis to find materials that could support a breast under full mammographic compression without affecting the x-ray images or the quality of the near infrared measurements. Several possible solutions were considered, and many types of plastics were tested in the development of the detector case. Light channeling within the detector case changed the data obtained in resin and agarose phantoms, lowering recovered absorption values. Additional developments focusing on blocking stray light were successful and permitted a normal subject imaging exam. PMID- 23024903 TI - Polarized multispectral imaging in a rigid endoscope based on elastic light scattering spectroscopy. AB - Elastic light scattering spectroscopy (LSS) is widely utilized to investigate cellular structures in cultured cells and various tissues. However, few imaging systems, especially endoscopic imaging systems, can implement LSS. It is the aim of this work to create a polarized multispectral imaging system based around a rigid endoscope to detect micrometer sized particles using LSS. The instrument first validated with different sized mono-disperse polystyrene microspheres, then an image is reconstructed based on LSS which shows the differentiation of different sized microspheres. Finally a preliminary experiment is conducted to demonstrate its capability to discriminate different types of cells. PMID- 23024904 TI - Ultrasound modulation of coherent light in a multiple-scattering medium: experimental verification of nonzero average phase carried by light. AB - We demonstrate the phase fluctuation introduced by oscillation of scattering centers in the focal volume of an ultrasound transducer in an optical tomography experiment has a nonzero mean. The conditions to be met for the above are: (i) the frequency of the ultrasound should be in the vicinity of the most dominant natural frequency of vibration of the ultrasound focal volume, (ii) the corresponding acoustic wavelength should be much larger than [Formula: see text], a modified transport mean-free-path applicable for phase decorrelation and (iii) the focal volume of the ultrasound transducer should not be larger than 4 - 5 times [Formula: see text]. We demonstrate through simulations that as the ratio of the ultrasound focal volume to [Formula: see text] increases, the average of the phase fluctuation decreases and becomes zero when the focal volume becomes greater than around [Formula: see text]; and through simulations and experiments that as the acoustic frequency increases from 100 Hz to 1 MHz, the average phase decreases to zero. Through experiments done in chicken breast we show that the average phase increases from around 110 degrees to 130 degrees when the background medium is changed from water to glycerol, indicating that the average of the phase fluctuation can be used to sense changes in refractive index deep within tissue. PMID- 23024905 TI - Cell death detection by quantitative three-dimensional single-cell tomography. AB - Ultrahigh-resolution optical coherence tomography (UR-OCT) has been used for the first time to our knowledge to study single-cell basal cell carcinoma (BCC) in vitro. This noninvasive, in situ, label-free technique with deep imaging depth enables three-dimensional analysis of scattering properties of single cells with cellular spatial resolution. From three-dimensional UR-OCT imaging, live and dead BCC cells can be easily identified based on morphological observation. We developed a novel method to automatically extract characteristic parameters of a single cell from data volume, and quantitative comparison and parametric analysis were performed. The results demonstrate the capability of UR-OCT to detect cell death at the cellular level. PMID- 23024906 TI - The influence of frontal sinus in brain activation measurements by near-infrared spectroscopy analyzed by realistic head models. AB - Adequate modeling of light propagation in the head is important to predict the sensitivity of NIRS signal and the spatial sensitivity profile of source-detector pairs. The 3D realistic head models of which the geometry is based upon the anatomical images acquired by magnetic resonance imaging and x-ray computed tomography are constructed to investigate the influence of the frontal sinus on the NIRS signal and spatial sensitivity. Light propagation in the head is strongly affected by the presence of the frontal sinus. The light tends to propagate around the frontal sinus. The influence of the frontal sinus on the sensitivity of the NIRS signal to the brain activation is not consistent and depends on the depth of the frontal sinus, the optical properties of the superficial tissues and the relative position between the source-detector pair and the frontal sinus. The frontal sinus located in the shallow region of the skull tends to reduce the sensitivity of the NIRS signal while the deep frontal sinus can increase the sensitivity of the NIRS signal. PMID- 23024907 TI - Compressive sensing based reconstruction in bioluminescence tomography improves image resolution and robustness to noise. AB - Bioluminescence Tomography attempts to quantify 3-dimensional luminophore distributions from surface measurements of the light distribution. The reconstruction problem is typically severely under-determined due to the number and location of measurements, but in certain cases the molecules or cells of interest form localised clusters, resulting in a distribution of luminophores that is spatially sparse. A Conjugate Gradient-based reconstruction algorithm using Compressive Sensing was designed to take advantage of this sparsity, using a multistage sparsity reduction approach to remove the need to choose sparsity weighting a priori. Numerical simulations were used to examine the effect of noise on reconstruction accuracy. Tomographic bioluminescence measurements of a Caliper XPM-2 Phantom Mouse were acquired and reconstructions from simulation and this experimental data show that Compressive Sensing-based reconstruction is superior to standard reconstruction techniques, particularly in the presence of noise. PMID- 23024908 TI - Interlesion differences in the local photodynamic therapy response of oral cavity lesions assessed by diffuse optical spectroscopies. AB - Photodynamic therapy (PDT) efficacy depends on the local dose deposited in the lesion as well as oxygen availability in the lesion. We report significant interlesion differences between two patients with oral lesions treated with the same drug dose and similar light dose of 2-1[hexyloxyethyl]-2 devinylpyropheophorbide-a (HPPH)-mediated photodynamic therapy (PDT). Pre-PDT and PDT-induced changes in hemodynamic parameters and HPPH photosensitizer content, quantified by diffuse optical methods, demonstrated substantial differences between the two lesions. The differences in PDT action determined by the oxidative cross-linking of signal transducer and activator of transcription 3 (STAT3), a molecular measure of accumulated local PDT photoreaction, also showed >100-fold difference between the lesions, greatly exceeding what would be expected from the slight difference in light dose. Our results suggest diffuse optical spectroscopies can provide in vivo metrics that are indicative of local PDT dose in oral lesions. PMID- 23024909 TI - Human tissue color as viewed in high dynamic range optical spectral transmission measurements. AB - High dynamic range optical-to-near-infrared transmission measurements for different parts of human body in the spectral range from 650 to 950 nm have been performed. Experimentally measured spectra are correlated with Monte Carlo simulations using chromaticity coordinates in CIE 1976 L*a*b* color space. Both a qualitative and a quantitative agreement have been found, paving a new way of characterizing human tissues in vivo. The newly developed experimental and computational platform for assessing tissue transmission spectra is anticipated to have a considerable impact on identifying favorable conditions for laser surgery and optical diagnostics, while providing supplementary information about tissue properties. PMID- 23024911 TI - Label-free characterization of living human induced pluripotent stem cells by subcellular topographic imaging technique using full-field quantitative phase microscopy coupled with interference reflection microscopy. AB - There is a need for a noninvasive technique to monitor living pluripotent stem cell condition without any labeling. We present an optical imaging technique that is able to capture information about optical path difference through the cell and cell adhesion properties simultaneously using a combination of quantitative phase microscopy (QPM) and interference reflection microscopy (IRM) techniques. As a novel application of QPM and IRM, this multimodal imaging technique demonstrated its ability to distinguish the undifferentiated status of human induced pluripotent stem (hiPS) cells quantitatively based on the variation of optical path difference between the nucleus and cytoplasm as well as hiPS cell-specific cell adhesion properties. PMID- 23024910 TI - Real-time 3D and 4D Fourier domain Doppler optical coherence tomography based on dual graphics processing units. AB - We present real-time 3D (2D cross-sectional image plus time) and 4D (3D volume plus time) phase-resolved Doppler OCT (PRDOCT) imaging based on configuration of dual graphics processing units (GPU). A GPU-accelerated phase-resolving processing algorithm was developed and implemented. We combined a structural image intensity-based thresholding mask and average window method to improve the signal-to-noise ratio of the Doppler phase image. A 2D simultaneous display of the structure and Doppler flow images was presented at a frame rate of 70 fps with an image size of 1000 * 1024 (X * Z) pixels. A 3D volume rendering of tissue structure and flow images-each with a size of 512 * 512 pixels-was presented 64.9 milliseconds after every volume scanning cycle with a volume size of 500 * 256 * 512 (X * Y * Z) voxels, with an acquisition time window of only 3.7 seconds. To the best of our knowledge, this is the first time that an online, simultaneous structure and Doppler flow volume visualization has been achieved. Maximum system processing speed was measured to be 249,000 A-scans per second with each A-scan size of 2048 pixels. PMID- 23024912 TI - Short-coherence off-axis holographic phase microscopy of live cell dynamics. AB - We demonstrate a single-shot holographic phase microscope that combines short coherence laser pulses with an off-axis geometry. By introducing a controlled pulse front tilt, ultrashort pulses are made to interfere over a large field-of view without loss of fringe contrast. With this microscope, quantitative phase images of live cells can be recorded in a full-field geometry without moving parts. We perform phase imaging of HEK293 cells, to study the dynamics of cell volume regulation in response to an osmotic shock. PMID- 23024913 TI - Direct laser trapping for measuring the behavior of transfused erythrocytes in a sickle cell anemia patient. AB - Using a laser trap, we have studied the properties of erythrocytes from a sickle cell anemia patient (SCA) after receiving an intravenous blood transfusion, and a normal adult individual carrying normal adult hemoglobin. The hemoglobin type and quantitation assessment was carried out by high performance liquid chromatography (HPLC). We conducted an analysis of the size distributions of the cells. By targeting those erythrocytes in the overlapping regions of size distributions, we have investigated their properties when the cells are trapped and released. The efficacy of the transfusion treatment is also studied by comparing the relative changes in deformation and the relaxation-time of the cells in the two samples. PMID- 23024914 TI - Characterization of a 3D optrode array for infrared neural stimulation. AB - This paper characterizes the Utah Slant Optrode Array (USOA) as a means to deliver infrared light deep into tissue. An undoped crystalline silicon (100) substrate was used to fabricate 10 * 10 arrays of optrodes with rows of varying lengths from 0.5 mm to 1.5 mm on a 400-MUm pitch. Light delivery from optical fibers and loss mechanisms through these Si optrodes were characterized, with the primary loss mechanisms being Fresnel reflection, coupling, radiation losses from the tapered shank and total internal reflection in the tips. Transmission at the optrode tips with different optical fiber core diameters and light in-coupling interfaces was investigated. At lambda = 1.55MUm, the highest optrode transmittance of 34.7%, relative to the optical fiber output power, was obtained with a 50-MUm multi-mode fiber butt-coupled to the optrode through an intervening medium of index n = 1.66. Maximum power is directed into the optrodes when using fibers with core diameters of 200 MUm or less. In addition, the output power varied with the optrode length/taper such that longer and less tapered optrodes exhibited higher light transmission efficiency. Output beam profiles and potential impacts on physiological tests were also examined. Future work is expected to improve USOA efficiency to greater than 64%. PMID- 23024915 TI - Impact of intraocular pressure on changes of blood flow in the retina, choroid, and optic nerve head in rats investigated by optical microangiography. AB - In this paper, we demonstrate the use of optical coherence tomography/optical microangiography (OCT/OMAG) to image and measure the effects of acute intraocular pressure (IOP) elevation on retinal, choroidal and optic nerve head (ONH) perfusion in the rat eye. In the experiments, IOP was elevated from 10 to 100 mmHg in 10 mmHg increments. At each IOP level, three-dimensional data volumes were captured using an ultrahigh sensitive (UHS) OMAG scanning protocol for 3D volumetric perfusion imaging, followed by repeated B-scans for Doppler OMAG analysis to determine blood flow velocity. Velocity and vessel diameter measurements were used to calculate blood flow in selected retinal blood vessels. Choroidal perfusion was calculated by determining the peripapillary choroidal filling at each pressure level and calculating this as a percentage of area filling at baseline (10 mmHg). ONH blood perfusion was calculated as the percentage of blood flow area over a segmented ONH area to a depth 150 microns posterior to the choroidal opening. We show that volumetric blood flow reconstructions revealed detailed 3D maps, to the capillary level, of the retinal, choroidal and ONH microvasculature, revealing retinal arterioles, capillaries and veins, the choroidal opening and a consistent presence of the central retinal artery inferior to the ONH. While OCT structural images revealed a reversible compression of the ONH and vasculature with elevated IOP, OMAG successfully documented changes in retinal, choroidal and ONH blood perfusion and allowed quantitative measurements of these changes. Starting from 30 mm Hg, retinal blood flow (RBF) diminished linearly with increasing IOP and was nearly extinguished at 100 mm Hg, with full recovery after return of IOP to baseline. Choroidal filling was unaffected until IOP reached 60 mmHg, then decreased to 20% of baseline at IOP 100 mmHg, and normalized when IOP returned to baseline. A reduction in ONH blood perfusion at higher IOP's was also observed, but shadow from overlying retinal vessels at lower IOP's limited precise measurements of changes in ONH capillary perfusion compared to baseline. Therefore, OCT/OMAG can be a useful tool to image and measure blood flow in the retina, choroidal and ONH of the rat eye as well as document the effects of elevated IOP on blood flow in these vascular beds. PMID- 23024916 TI - Imaging granularity of leukocytes with third harmonic generation microscopy. AB - Using third harmonic generation (THG) microscopy, we demonstrate that granularity differences of leukocytes can be revealed without a label. Excited by a 1230 nm femtosecond laser, THG signals were generated at a significantly higher level in neutrophils than other mononuclear cells, whereas signals in agranular lymphocytes were one order of magnitude smaller. Interestingly, the characteristic THG features can also be observed in vivo to track the newly recruited leukocytes following lipopolysaccharide (LPS) challenge. These results suggest that label-free THG imaging may provide timely tracking of leukocyte movement without disturbing the normal cellular or physiological status. PMID- 23024917 TI - Application of non-negative matrix factorization to multispectral FLIM data analysis. AB - Existing methods of interpreting fluorescence lifetime imaging microscopy (FLIM) images are based on comparing the intensity and lifetime values at each pixel with those of known fluorophores. This method becomes unwieldy and subjective in many practical applications where there are several fluorescing species contributing to the bulk fluorescence signal, and even more so in the case of multispectral FLIM. Non-negative matrix factorization (NMF) is a multivariate data analysis technique aimed at extracting non-negative signatures of pure components and their non-negative abundances from an additive mixture of those components. In this paper, we present the application of NMF to multispectral time-domain FLIM data to obtain a new set of FLIM features (relative abundance of constituent fluorophores). These features are more intuitive and easier to interpret than the standard fluorescence intensity and lifetime values. The proposed approach, unlike several FLIM data analysis methods, is not limited by the number of constituent fluorescing species or their possibly complex decay dynamics. Moreover, the new set of FLIM features can be obtained by processing raw multispectral FLIM intensity data, thereby rendering time deconvolution unnecessary and resulting in lesser computational time and relaxed SNR requirements. The performance of the NMF method was validated on simulated and experimental multispectral time-domain FLIM data. The NMF features were also compared against the standard intensity and lifetime features, in terms of their ability to discriminate between different types of atherosclerotic plaques. PMID- 23024918 TI - Spectral domain detection in low-coherence spectroscopy. AB - Low-coherence spectroscopy (LCS) offers the valuable possibility to measure quantitative and wavelength resolved optical property spectra within a tissue volume of choice that is controllable both in size and in depth. Until now, only time domain detection was investigated for LCS (tdLCS), but spectral domain detection offers a theoretical speed/sensitivity advantage over tdLCS. In this article, we introduce a method for spectral domain detection in LCS (sdLCS), with optimal sensitivity as a function of measurement depth. We validate our method computationally in a simulation and experimentally on a phantom with known optical properties. The attenuation, absorption and scattering coefficient spectra from the phantom that were measured by sdLCS agree well with the expected optical properties and the measured optical properties by tdLCS. PMID- 23024919 TI - Design considerations for polarization-sensitive optical coherence tomography with a single input polarization state. AB - Using a generalized design for a polarization-sensitive optical coherence tomography (PS-OCT) system with a single input polarization state (SIPS), we prove the existence of an infinitely large design space over which it is possible to develop simple PS-OCT systems that yield closed form expressions for birefringence. Through simulation and experiment, we validate this analysis by demonstrating new configurations for PS-OCT systems, and present guidelines for the general design of such systems in light of their inherent inaccuracies. After accounting for systemic errors, alternative designs exhibit similar performance on average to the traditional SIPS PS-OCT system. This analysis could be extended to systems with multiple input polarization states and could usher in a new generation of PS-OCT systems optimally designed to probe specific birefringent samples with high accuracy. PMID- 23024920 TI - Dynamic diffuse optical tomography imaging of peripheral arterial disease. AB - Peripheral arterial disease (PAD) is the narrowing of arteries due to plaque accumulation in the vascular walls. This leads to insufficient blood supply to the extremities and can ultimately cause cell death. Currently available methods are ineffective in diagnosing PAD in patients with calcified arteries, such as those with diabetes. In this paper we investigate the potential of dynamic diffuse optical tomography (DDOT) as an alternative way to assess PAD in the lower extremities. DDOT is a non-invasive, non-ionizing imaging modality that uses near-infrared light to create spatio-temporal maps of oxy- and deoxy hemoglobin in tissue. We present three case studies in which we used DDOT to visualize vascular perfusion of a healthy volunteer, a PAD patient and a diabetic PAD patient with calcified arteries. These preliminary results show significant differences in DDOT time-traces and images between all three cases, underscoring the potential of DDOT as a new diagnostic tool. PMID- 23024921 TI - Multichannel diffuse optical Raman tomography for bone characterization in vivo: a phantom study. AB - Raman spectroscopy is used to gather information on the mineral and organic components of bone tissue to analyze their composition. By measuring the Raman signal of bone through spatially offset Raman spectroscopy the health of the bone can be determined. We've customized a system with 8 collection channels that consist of individual fibers, which are coupled to separate spectrometers and cooled CCDs. This parallel detection system was used to scan gelatin phantoms with Teflon inclusions of two sizes. Raman signals were decoupled from the autofluorescence background using channel specific polynomial fitting. Images with high contrast to background ratios of Raman yield and accurate spatial resolution were recovered using a model-based diffuse tomography approach. PMID- 23024923 TI - Variable-sized bar targets for characterizing three-dimensional resolution in OCT. AB - Resolution is an important figure of merit for imaging systems. We designed, fabricated and tested an optical phantom that mimics the simplicity of an Air Force Test Chart but can characterize both the axial and lateral resolution of optical coherence tomography systems. The phantom is simple to fabricate, simple to use and functions in versatile environments. PMID- 23024922 TI - Sentinel lymph nodes fluorescence detection and imaging using Patent Blue V bound to human serum albumin. AB - Patent Blue V (PBV), a dye used clinically for sentinel lymph node detection, was mixed with human serum albumin (HSA). After binding to HSA, the fluorescence quantum yield increased from 5 * 10(-4) to 1.7 * 10(-2), which was enough to allow fluorescence detection and imaging of its distribution. A detection threshold, evaluated in scattering test objects, lower than 2.5 nmol * L(-1) was obtained, using a single-probe setup with a 5-mW incident light power. The detection sensitivity using a fluorescence imaging device was in the umol * L(-1) range, with a noncooled CCD camera. Preclinical evaluation was performed on a rat model and permitted to observe inflamed nodes on all animals. PMID- 23024924 TI - On the use of photoacoustics to detect red blood cell aggregation. AB - The feasibility of detecting red blood cell (RBC) aggregation with photoacoustics (PAs) was investigated theoretically and experimentally using human and porcine RBCs. The theoretical PA signals and spectra generated from such samples were examined for several hematocrit levels and aggregates sizes. The effect of a finite transducer bandwidth on the received PA signal was also examined. The simulation results suggest that the dominant frequency of the PA signals from non aggregated RBCs decreases towards clinical frequency ranges as the aggregate size increases. The experimentally measured mean spectral power increased by ~6 dB for the largest aggregate compared to the non-aggregated samples. Such results confirm the theoretical predictions and illustrate the potential of using PA imaging for detecting RBC aggregation. PMID- 23024925 TI - Role of Personalized Medicine in the Identification and Characterization of Parkinson's Disease in Asymptomatic Subjects. PMID- 23024926 TI - Methods for studying rodent intestinal lipoprotein production and metabolism. AB - Lipid absorption begins with the digestion of dietary triacylglycerol and ultimately results in the secretion of triacylglycerol in chylomicrons into the lymphatics. Additionally, the intestine also secretes numerous proteins and peptides involved in lipid and lipoprotein metabolism in response to food. Ultimately, chylomicrons and these proteins, peptides, and hormones are found in lymph. The lymph fistula rat model has traditionally been used to study this intestinal absorption of nutrients, especially lipids, but recently, this model has also been used for studying the secretion of hormones by the small intestine. The protocols described in this article include the lymph fistula rat and mouse model, as well as in vivo chylomicron metabolism studies. These experimental models are helpful for the study of metabolic phenotypes, the characterization of intestinal lipid absorption and transport, and determining peripheral metabolism of intestinally derived lipoproteins. PMID- 23024927 TI - Genetically Engineered Mice by Pronuclear DNA microinjection. AB - The generation of transgenic mice by DNA microinjection is a powerful tool to investigate the molecular regulation of gene expression, development, and disease. The power of this technology is that foreign DNA can be introduced into every cell of a developing organism and the phenotypic impact of this genetic modification can be investigated in a system under the constraints of normal development and physiology. The generation of transgenic mice requires the preparation of the transgene DNA construction, collection of one-cell fertilized mouse embryos, injection of the transgene into mouse embryos, and transfer of the surviving embryos. Mice born from such manipulations are then screened for the presence of the transgene. The execution of these procedures requires a highly efficient system otherwise the cost of the generation of these mice can be cost prohibitive. However, the production of these animals can serve as an invaluable research resource. PMID- 23024928 TI - Spatial regulation of interleukin-6 signaling in response to neurodegenerative stressors in the retina. AB - Neuroinflammation, defined as the induction of immune-related processes within the central nervous system, is recognized as a component of many neurodegenerative disorders, including glaucomatous degeneration of retinal ganglion cells (RGCs). Previous work in vitro identified IL-6 as a potential neuroprotective factor for RGCs, particularly those challenged by glaucoma related stressors. Here we examined the temporal and spatial characteristics of IL-6 signaling in response to two stressors related to RGC neurodegeneration: age and elevated intraocular pressure (IOP). Using ELISA, immunoblotting, immunolabeling and quantitative microscopy, we measured and compared whole retina and RGC-related expression of IL-6 and IL-6Ralpha in normal retina (young C57), retina susceptible to glaucomatous neurodegeneration (young DBA/2), aging retina (aged C57) and aging retina challenged by elevated IOP (aged DBA/2). We found that: 1) neurodegenerative stressors induce alterations in whole retina expression of IL-6 and IL-6Ralpha, 2) these whole retina changes do not reflect the immediate milieu of RGCs, where IL-6 and IL-6Ralpha expression is spatially variable and 3) the extent and magnitude of this spatial variability is stressor dependent. Our data provide the first evidence that neurodegenerative stressors produce microenvironments of IL-6 signaling in retina and that the nature and magnitude of spatial regulation is dependent on the identity of the stressor. PMID- 23024930 TI - Cyclodextrin-PEI-Tat Polymer as a Vector for Plasmid DNA Delivery to Placenta Mesenchymal Stem Cells. AB - This study aims to modify a cyclodextrin-PEI-based polymer, PEI-beta-CyD, with the TAT peptide for plasmid DNA delivery to placenta mesenchymal stem cells (PMSCs). By using the disulfide exchange between the SPDP-activated PEI-beta-CyD and TAT peptide, the TAT-PEI-beta-CyD polymer was fabricated and the success of this was confirmed by the presence of characteristic peaks for PEI (at delta 2.8 3.2 ppm), CyD (at delta 5.2, 3.8-4.0 and 3.4-3.6 ppm) and TAT (at delta 1.6-1.9 and 6.8-7.2 ppm) in the (1)H NMR spectrum of TAT-PEI-beta-CyD. The polymer plasmid-DNA polyplex could condense DNA at an N/P ratio of 7.0-8.0, and form nanoparticles with the size of 150.6+/-5.6 nm at its optimal N/P ratio (20/1). By examining the transfection efficiency and cytotoxicity of TAT-PEI-beta-CyD, conjugation of the TAT peptide onto PEI-beta-CyD was demonstrated to improve the transfection efficiency of PEI-beta-CyD in PMSCs after 48 and 96 hours of post transfection incubation. The viability of PEI-beta-CyD-treated PMSCs was shown to be over 80% after 5 h of treatment and 24 h of post-treatment incubation. In summary, this study showed that the TAT-PEI-beta-CyD polymer as a vector for plasmid DNA delivery to PMSCs and other cells warrants further investigations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12668-011-0010-9) contains supplementary material, which is available to authorized users. PMID- 23024929 TI - The miRNA Regulation of Stem Cells. AB - The miRNA pathway, as a fundamental mechanism of gene regulation, plays a key role in controlling the establishment, self-renewal, and differentiation of stem cells. Such regulation is manifested as fine-tuning the temporal- and tissue specificity of gene expression. This fine-tuning function is achieved by (1) miRNAs form positive and negative feedback loops with transcription factors and epigenetic factors to exert concerted control of given biological processes; and/or (2) different miRNAs converge to control one or more mRNA targets in a signaling pathway. These regulatory mechanisms are found in embryonic stem cells, iPS cells, and adult tissue stem cells. The distinct expression profiles of miRNAs and their regulatory roles in various types of stem cells render these RNAs potentially effective tools for clinical diagnosis and therapy. PMID- 23024931 TI - Extra vestibular schwannoma: a two year experience. AB - We present series of head, neck extracranial non-vestibular schwannomas treated during 2-year period. All patients with head and neck schwannomas treated at our department from April 2007 to July 2009 were reviewed. There was female predominance (72%). The mean age at diagnosis was 38 years. All (100%) presented with a neck mass. Most common nerves of origin were the vagus and the cervical sympathetic chain. Treatment for all cases was complete excision with nerve preservation. Among all schwannoma patients, postoperative neural deficit occurred in four with partial to complete resolution in three. The follow-up period was 24 months. Non-vestibular extracranial head and neck schwannomas most frequently present as an innocuous longstanding unilateral parapharyngeal neck mass. Preoperative diagnosis may be aided by fine-needle cytology and magnetic resonance imaging or computed tomographic imaging. The mainstay of treatment is complete intracapsular excision preserving the nerve of origin. PMID- 23024932 TI - Three cases of vagal nerve schwannoma and review of literature. AB - Schwannoma arising from the vagus is an uncommon (2-5%) benign nerve tumour. This tumour most often presents as a slow growing asymptomatic solitary neck mass which rarely undergoes malignant transformation. Definitive pre-operative diagnosis may be difficult and investigations such as FNAC have low specificity. The carotid artery and internal jugular vein may be displaced antero-laterally. Diagnosis is based on clinical suspicion and confirmation is obtained by means of surgical pathology. Surgical excision is the treatment of choice for this tumour, with recurrence being rare. We describe three cases of schwannoma involving the vagus who presented differently to our unit during past 5 years. PMID- 23024933 TI - Foreign body aspiration: demographic trends and foreign bodies posing a risk. AB - This study was done to find out modern demographic trends of aspiration and different foreign bodies posing a risk. For this study, 94 patients with suspected foreign body aspiration (FBA) were selected. Detailed history, especially age, suspected Foreign body (FB) and mode of onset were noted and a thorough clinical examination was done. X-ray chest and neck, antero-posterior and lateral view was the only investigation done in all. Rigid bronchoscopy under general anaesthesia was done in all the cases of suspected FBA for diagnostic cum therapeutic purpose. Among 94 patients 70.2% i.e. 66 were within 5 years of age and most were within 2-3 years of age. Rigid bronchoscopy was done in all the cases and foreign body was successfully retrieved in 78.7% of cases. Bronchoscopy was negative in the rest of the cases. The Most common site of lodgment was the right bronchus followed by the left bronchus, the trachea and other sites. Vegetables were the most common FBs as they were found in 26 cases. Whistles from small plastic toys were the single most common FB(15). Other foreign bodies were small plastic and metallic parts, safety pins, jewellery etc. Children under 5 years of age are at greatest risk of FBA. Different vegetables and whistles of low grade toys are the most commonly aspirated FB. Detailed history is most important for diagnosis. X-ray is not a reliable tool for diagnosis. Bronchoscopy should be done whenever a foreign body is suspected in the airway. PMID- 23024934 TI - Benefit of using muscle relaxants in the routine treatment protocol of oral submucosal fibrosis: a pilot study. AB - The aim of this present work is to describe the nature and extent of fibrosis within muscle and to correlate this with the mouth opening (MO) in OSE patients and to prove our results in improvement of mouth opening in patients with OSMF with use of "muscle relaxants" along with other modalities of treatment . The study was conducted on 40 patients who visited our outpatient department with grade 3 (<19 mm) mouth opening. 20 of these patients underwent the routine treatment protocol of weekly injection of hyaluronidase with hydrocortisone and antioxidant capsules with added lycopene for 1 month. The remaining test subjects in addition to the routine injections and antioxidants were given skeletal muscle relaxants like thiocolchicoside or chlorzoxazone. The mouth opening (interincisal distance of maxillary and mandibular incisors at maximum possible mouth opening) was measured and graded as follows: grade 1 (>40 mm), grade 2 (20-39 mm) and grade 3 (<19 mm) with the help of vernier callipers after the study period of 1 month. 17 out of the 20 test patients who received muscle relaxants in addition to the routine protocol showed marked improvement with shift from grade 3 (<19 mm) to grade 1 (>40 mm) i.e. a greater than 20 mm improvement in mouth opening. Using muscle relaxants as a adjuvant therapy in the routine protocol of treatment of oral submucosal fibrosis will not only cater and halt the problem of fibrosis but also will take care of the muscle spasm and inflammation which also inadvertently contribute to the restricted mouth opening. We found excellent improvement on adding muscle relaxants to the routine protocol which was not just an objective but also a subjective success. PMID- 23024935 TI - Retrospective analysis of the effectiveness of functional endoscopic sinus surgery in the treatment of adult chronic rhinisinusitis refractory to medical treatment. AB - Chronic rhinosinusitis (CRS) is a common disease that restricts the quality of life of millions of involved patients. The aim of the study was to evaluate how functional endoscopic sinus surgery (FESS) modifies patients symptom profile and to also confirm that FESS is the modality of treatment in patients with refractory CRS. The study was retrospective analysis. 105 patients with symptoms of CRS were included in the study (between August 2006 to July 2009). Patients were assessed for CRS symptoms preoperatively and postoperatively using grading symptoms. Statistical analysis using Chi square test. Leading symptom of CRS was nasal obstruction followed by headache. Furthermore patients reported of anosmia, facial pressure, postnasal drip, purulent nasal discharge, halitosis, dental pain, cough, earache. None of the patients had fever as their complaint. After a postoperative followup of 6 months there was improvement in the symptoms. All minor symptoms had 100% improvement. Nasal obstruction responded best, next followed by (all symptoms P value <0.001). An overall improvement of 86.66% was recorded. The restriction of quality of life in patients with CRS is mainly caused by these symptoms, which can be improved in excellent fashion by FESS in majority of the patients. PMID- 23024936 TI - Invasive rhino-orbital aspergillosis. AB - Invasive aspergillosis usually affects immune-compromised patients and is common in diabetics. Proptosis, visual loss and ophthalmoplegia due to intra-orbital extension are common presentations. Three out of five patients in our series were immune-compromised. All the patients had visual loss and three patients presented with unilateral blindness. Three patients were treated by surgical debridement followed by Amphotericin B therapy. Two patients who had intra-cranial extension of the disease died during the treatment. Only one patient had improvement in vision following the treatment. High index of suspicion in immune-compromised patients, early diagnosis and prompt aggressive treatment is required to achieve clinical cure. PMID- 23024937 TI - Routine Electrocardiography Request in Adenoidectomy: Is it necessary? AB - To evaluate the relevance of routine electrocardiographic request in pre operative work-up of children undergoing adenoidectomy. This is a two year prospective study of children with obstructive adenoid that had adenoidectomy. This is a tertiary hospital based study at the Otorhinolaryngology Department of University College Hospital, Ibadan. Children (<=12 years) with clinical and radiological evidence of an obstructive adenoid were investigated. Information obtained with an interviewer assisted questionnaire included the biodata, clinical presentation of the patients, ECG findings, echocardiographic findings, cardiothoracic ratio, palatal airway and ratio of adenoid diameter to the nasopharyngeal diameter. The adenoid volume was measured after adenoidectomy. The results were analyzed using SPSS version 14 and level of statistical significance was P < 0.05. There were seventy four patients; 45 (60.8%) males and 29 (39.2%) females with a mean age of 38.35 months, S.D +/- 30.32 (range 5-144 months). All the patients presented with mouth breathing and recurrent mucopurulent rhinorrhea. Mild snoring was detected in 18 (25%) patients, moderate snoring in 39 (54.17%) patients and severe snoring in 15 (20.83%) patients. Mild apnea was observed in 55 (74.32%) patients and moderate in 19 (25.68%) patients. Only seven (9.46%) patients had abnormal electrocardiographic findings but their ejection fraction on echocardiography ranged from 63 to 72% with a mean value of 68.17%, S.D +/- 3.22. Cardiac complications of enlarged obstructive adenoid appear not to be common. Routine preoperative electrocardiography should therefore be restricted to only the high risk patients. PMID- 23024938 TI - Role of measurement of antioxidant enzymes in evaluation of antioxidant therapy in tobacco abusers with oral leukoplakia. AB - Antioxidants are widely used in chemoprevention of malignancy. Numerous studies in medical literature have reported the evaluation of this treatment protocol by indirect methodology-epidemiology, invitro studies, pharmacology and animal models etc. However, there is a paucity of literature on the measurement of antioxidant enzymes as a parameter for assessing the outcome of antioxidant therapy. This study explores the efficacy and outcome of antioxidant enzyme assay in relation to antioxidant therapy in tobacco abusers, hitherto unreported in medical literature. A prospective cohort study with control in 50 patients carried out at a tertiary care teaching Institution (Institute of Medical Sciences, Banaras Hindu University, Varanasi, India). Out of these patients, 10 patients acted as control, rest 40 patients-all tobacco users in some form, were divided into three groups on the basis of histopathological grading of dysplasia no dysplasia, mild or moderate dysplasia. The levels of Lipid peroxidase (LPO), Superoxide dismutase (SOD) and Catalase (CAT) in mucosa and serum were assayed in each group, and re-evaluated at the end of 3 months after intervention with antioxidant treatment. To detect any alteration in degree of dysplasia a repeat biopsy was also done at the end of 3 months. The results were statistically analysed using paired t test. A statistically significant decrease in level of LPO and SOD, and an increase in CAT levels were recorded both in mucosa and serum. However, no change in dysplasia and no new case of dysplasia were observed. Further, antioxidant treatment was continued for a year and the final out come of the lesion was assessed by "Carter's criteria". A final success rate of 74.19% was recorded in terms of partial or complete regression of the lesion. This study confirms the therapeutic efficacy of antioxidants in oral leukoplakia, and cites the importance of LPO, SOD and CAT in evaluating the efficacy of antioxidant treatment. However, the study failed to elucidate any relationship between enzyme measurement and the final outcome of the lesion. PMID- 23024939 TI - Assessment of Operative Blood Loss and the Factors Affecting it in Tonsillectomy and Adenotonsillectomy. AB - To estimate the average operative blood loss in tonsillectomy and adenotonsillectomy and the various factors affecting it. A prospective study of estimation of blood loss in 100 patients who underwent tonsillectomy and adenotonsillectomy. Data collected included the age, sex, operative indication, clotting time, Hb levels and usage of pre-operative antibiotics. Cold knife dissection method for tonsillectomy and curettage method for adenoidectomy were used. Measurement by calorimetric method of estimation being simple and accurate was used for estimation. Study undertaken at a tertiary referral hospital catering to an urban, semi-urban and rural populace. Blood loss was more in males and increases as age advances both in adenotonsillectomy and tonsillectomy. Blood loss was more in fibrosed tonsils, at lower hemoglobin levels and at higher clotting times. It was less in cases who received pre-operative antibiotics. The average blood losses in males and females during tonsillectomy were 106.91 and 96.26 ml respectively. In adenotonsillectomy, the average blood losses in males and females were 81.44 and 76.82 ml respectively. In our series we found that blood loss in tonsillectomy and adenotonsillectomy depended on various factors like age, sex, the type of tonsillitis, method of dissection, hemoglobin concentration, clotting time and the use of antibiotics. All these factors must be taken into consideration while taking up patients especially those who cannot tolerate blood loss, for surgery. PMID- 23024940 TI - Distant metastases to nasal cavities and paranasal sinuses case series. AB - Metastatic tumors to the nasal cavity and paranasal sinuses are far less common than primary cancer in this location. Review of the 2004-2010 pathology records of patients with sinonasal malignancy, revealed three cases with distant metastases to this region from primary sites in kidney, prostate and breast. The clinical presentation, histopathological findings and clinical outcome is presented for each patient. Metastases to the nose and paranasal sinuses usually respond poorly to treatment and have a poor prognosis. This report highlights the importance of suspecting metastases in patients with a previous history of malignancy. Therefore, thorough history and clinical evaluation is mandatory in any known/treated case of cancer. PMID- 23024941 TI - Statico-Dynamic Island Laryngoplasty with Crossed Musculoplasty and Transmitted Dynamism (for Vocal Cord Palsy): a New Technique. AB - Only static medialisation of the paralysed vocal cord is most commonly performed today for vocal cord palsy which does not offer very good voice post-operatively. Colledge and Balance's (1927) operation of anastomosis of the phrenic nerve to the recurrent laryngeal nerve for laryngeal palsy or Tuckers (1976) nerve muscle pedicle technique has not offered significant reanimation of the paralysed muscles of the vocal cord. Moreover, it is virtually impossible to offer dynamism to the paralysed muscles; but dynamism can conveniently be transmitted to the paralysed vocal cord by appropriate muscle transplantation as has been done in palatopharyngoplasty for rhinolalia aperta (Ghosh 1983, 1986). Isshiki's laryngoplasty operations (1977) also offer only static correction. In view of the above short comings, the present statico-dynamic operation was conceptualised. A new technique of medialisation of the paralysed vocal cord statico-dynamically for improvement of voice is described here. In one operation, such as this, both arytenoid adduction and vocal cord adduction are expected to be achieved. A rectangular island of lamina of the thyroid cartilage, attached to the inner perichondrium, on the paralysed side, is created by drilling an endless canal on the lateral aspect of the thyroid lamina to the level of the inner perichondrium. The mobile cartilage island along with the vocal cord and the arytenoid is fixed in a medialised position. Dynamism is quintessential for normal vocal cord function. For this, superiorly and inferiorly based superior and inferior bellies of the omohyoideus are passed over the island of cartilage crossing each other, forming the 'crossed musculoplasty'. By their contractions further adduction of the island along with its attached vocal cord is brought about, thus further improving the quality of voice. PMID- 23024942 TI - Outcome of endoscopic sinus surgery in patients with symptomatic chronic rhinosinusitis with minimal changes on computerised tomography. AB - This study was designed to assess the efficacy of functional endoscopic sinus surgery (FESS) in chronic rhinosinusitis (CRS) patients with minimal radiological findings, and based on one centre, prospective randomized controlled study, conducted in the Department of Otorhinolaryngology, Lady Hardinge Medical College, New Delhi. All the CRS out-patients (>18 years) refractory to 3 weeks of medical therapy were radiologically evaluated with computerised tomographic scan (CT) of nose and paranasal sinuses. These patients were grouped based on CT scoring (Lund Mackay staging system): group A (CT score 0-6) and group B (CT score 7-24); with 35 patients in each group. All the patients underwent FESS using Messerklinger technique. Symptom scoring of all the patients was done using visual analog scale preoperatively and postoperatively at 1-, 3-, 6- and 12-month follow-up. CRS patients with minimal evidence of disease on CT showed statistically significant improvement in symptom scores after FESS. There was no significant difference noted in the overall symptom score improvement as well as for improvement in specific symptoms in both the groups. Further, there was no correlation between the pre-operative symptoms and CT scores. A good subjective outcome in terms of symptom improvement can be obtained with FESS in patients with CRS with minimal evidence of disease on CT. PMID- 23024943 TI - Comparative Efficacy and Safety of Various Anti-Microbials in Patients of Acute Rhinosinusitis at Tertiary-Care Hospital in Uttarakhand (UK). AB - To compare the efficacy of gatifloxacin, azithromycin with amoxicillin as positive control for the treatment of Acute rhinosinusitis (ARS). To monitor adverse drug reaction profile of amoxicillin, azithromycin and gatifloxacin in patient of ARS. An open randomized trial of comparative efficacy and safety of amoxicillin, azithromycin and gatifloxacin in patients with ARS. Patients were randomized into three groups as under: group 1: patients on oral amoxicillin 500 mg TDS for 10 days; group 2: patients on oral azithromycin 500 mg OD for 5 days; group 3: patients on oral gatifloxacin 400 mg OD for 10 days. Patients were evaluated for signs and symptoms at day 1, day 7 (for group 2), on day 12 (for group 1, 3) as primary end points and 28 days after post therapy as secondary end point. All the three antimicrobial drugs i.e., amoxicillin, azithromycin and gatifloxacin were effective in reducing symptoms of acute sinusitis on visual analogue scale scoring. Azithromycin showed significant improvement radiographically on day 7 (P < 0.01) and on day 35 (P < 0.01). Gatifloxacin elicited very highly significant improvement radiographically on day 40 (P < 0.001) and significant improvement on day 12 (P < 0.01) when compared with amoxicillin. Azithromycin, the ketolide was associated with lesser adverse effects as compared to amoxicillin. All the three antimicrobial drugs i.e., amoxicillin, azithromycin and gatifloxacin were effective in reducing symptoms of acute sinusitis on visual analogue scale scoring. Gatifloxacin was found to be most effective drug both in terms of improvement in signs and symptoms on visual analogue scale and radiographic scoring and was associated with least adverse events in comparison to rest of two drugs under study. PMID- 23024944 TI - A Comparative Study of FNAC and Histopathology of Thyroid Swellings. AB - Neck swelling is a common clinical presentation in ENT practice and it carries significant morbidity and even mortality if not managed properly. Thyroid swelling being the most common type we conducted a prospective study to assess the role of FNAC in diagnosing the nature of thyroid swelling and comparing its result with histopathology finding. It was observed that FNAC is a very reliable test having high sensitivity and specificity in thyroid swelling. PMID- 23024945 TI - Rare nasal tumours in kumaon region of uttarakhand: a clinical observation. AB - To review the cases of nasal mass in the Kumaon region of Uttarakhand and observe the incidence of rare nasal tumours and their atypical presentation. A prospective study conducted at ENT dept of STMF Hospital & U.F.H.T medical college at Haldwani in the Nainital district of Uttarakhand. This state has approx.ninty lacs of population out of which 50 %resides in Kumaon region. hence this should be taken as a sample study and considering the topographical condition of this region this is the only one medical college where facilities like CT Scan and MRI are available so most of the patients of this region are referred to this medical college. Cases were selected from the patients attending ENT OPD with nasal mass during the period of August 2005-Sep 2008. History and physical examination were done according to a proforma. All patients were routinely investigated. CT Scan of nose and PNS were done in each case. Biopsy along with immunohistochemistry (if required) were done in each case. Out of 160,136 patients attending the ENT OPD of the hospital during the period of August 2005-September 2008, of which total 200 (0.1241)% patients presenting with nasal mass were included in the study. Age of the patient ranged from 5 to 70 years. Maximum patients were seen in the age group of 31-40 (37%) The most common symptom was nasal blockage (97.5%). The most common tumour was squamous papilloma (90%). Here we are describing the presentation and abnormal features of some of the rare nasal tumours, which comprised only 4.5% (9 cases) of the 200 patients of nasal mass seen during the period. In the Kumaon region of Uttarakhand patients with tumours of nose and paranasal sinuses usually present late to the clinician due to poverty and ignorance. Their presentation was variable and many times disease was highly advanced. If proper diagnostic facilities are available in the region, timely intervention can be done and maximum benefit can be extended to the patient. PMID- 23024946 TI - A case report of f.B (cellular battery) in 18 days old child. PMID- 23024947 TI - Superficial siderosis of the CNS and otoneurological manifestations. AB - Superficial siderosis is an uncommon condition occurring in central nervous system (CNS) due to deposition of hemosiderin in the subpial meningeal layer causing progressive neurological dysfunction. The classical clinical manifestation is a triad of chronic ataxia, bipyramidal signs and progressive bilateral symmetrical sensorineural hearing loss (SNHL). It has rarely been reported in Indian literature. We report an unusual case of superficial siderosis in a 60-year-old farmer who presented with the above triad along with involvement of olfactory nerve. We present this case to highlight the fact that progressive SNHL can be an important sign for the early awareness of this rare disorder. The literature on superficial siderosis is reviewed and the pathogenesis is discussed. PMID- 23024948 TI - Angiolipoma larynx: a case report. AB - We report an extremely rare case of angiolipoma larynx Case report and a review of the world literature concerning angiolipoma are presented. A case of tumour of the larynx in a 72-year-old male who underwent excision by a lateral pharyngotomy approach. Histopathological diagnosis was angiolipoma. 19 cases of angiolipoma have been reported from head and neck region, none from the larynx. To our knowledge this is the first report in the world literature of angiolipoma larynx. PMID- 23024949 TI - Acute airway obstruction by spontaneous hemorrhage into thyroid nodule. AB - A 73-year-old man was transferred after cardiopulmonary resuscitation with endotracheal intubation. The neck computed tomography revealed about a 6.5 * 5 cm homogeneous, mildly enhancing cystic mass in the thyroid isthmus, occupying nearly the entire lower central neck region and compressing the trachea. An emergency subtotal thyroidectomy was performed. PMID- 23024950 TI - Necrotizing fasciitis: an unusual presentation. AB - Necrotizing fasciitis (NF) is rare but life threatening multimicrobial soft tissue infection characterized by progressive, usually rapid, necrotizing process of the subcutaneous tissues and fascial planes, with resulting skin gangrene and systemic toxicity. The groin, abdomen and extremities are the most frequent sites involved by this disease and it is rarely seen in the head and neck region. NF of the head and neck region has a potentially high morbidity and mortality. Delay in diagnosis leads to poor outcome. Hence early recognition and aggressive management is imperative for successful outcome. Here we present a case of acute onset of cervical necrotizing fasciitis in a young male. PMID- 23024951 TI - Giant pleomorphic adenoma of the nasal septum. AB - Pleomorphic adenoma is the most common benign tumor of the salivary glands, mainly arising from major salivary glands such as parotis and submandibular gland. In rare cases, however, pleomorphic adenoma presents in various unusual sites such as the nasal cavity, paranasal sinuses, hypopharynx, pharynx, larynx, trachea and lacrimal glands. We present a rare case of 80-year-old woman with pleomorphic adenoma of the nasal cavity. PMID- 23024952 TI - Eagle's Syndrome: Report of Three Cases. AB - Eagle's syndrome is defined as the symptomatic elongation of the styloid process or mineralization of the stylohyoid ligament complex. It can present as a variety of different symptoms which can mislead the otolaryngologist and the dentist in diagnosing the condition. We are presenting three cases of Eagle's syndrome describing the importance of digital palpation through tonsillar fossa and use of panoramic radiographs in confirming the elongation of styloid process. PMID- 23024953 TI - Paraganglioma of the oropharynx. AB - Paraganglioma is a rare tumor in head and neck region. A 35 years male presented with huge swelling of tonsillar region occupying a large portion of oropharynx. Tumor had been dissected out transorally. HPE showed extra-adrenal paraganglioma. It is being reported because of its rare clinical presentation and unusual surgical approach. PMID- 23024954 TI - Wegener's granulomatosis of nose: a case report. AB - Wegener's granulomatosis is an uncommon Condition characterized by necrotising granulomatosis of upper and lowers respiratory tract and glomerulonephritis. We present here a unique case of 50 year old female with localised involvement of nose and adjoining area. PMID- 23024955 TI - Lingual gastric duplication cyst in a new born. AB - A rare case of gastric duplication cyst of tongue is reported. PMID- 23024956 TI - Glial Heterotopia in ENT-Two Case Reports and Review of Literature. AB - The purpose of presenting these case reports is to highlight the occurrence of heterotopic glial tissue of the tongue and nose in children. So far, literature review has revealed few case reports of such lesions in neonates, but our patients presented with this unique lesion at the age of two and a half years and 3 years. This is a rare congenital anomaly in the tongue, which can mimic a lingual thyroid, teratoma, dermoid cyst etc. Surgical excision is mandatory when the lesion causes obstructive symptoms. The authors discuss the problems in diagnosis, pathology and management and review the literature. PMID- 23024957 TI - Reader's Views Lacrimal Sac Diverticulum due to Rhinosporidiosis. PMID- 23024958 TI - In reference to the article a comparative study between endoscopic middle meatal antrostomy and caldwell-luc surgery in the treatment of chronic maxillary sinusitis: by k. Joe jacob . shibu george . s. Preethi . v. S. Arunraj. PMID- 23024961 TI - Investigating dynamical deformations of tumor cells in circulation: predictions from a theoretical model. AB - It is inevitable for tumor cells to deal with various mechanical forces in order to move from primary to metastatic sites. In particular, the circulating tumor cells that have detached from the primary tumor and entered into the bloodstream need to survive in a completely new microenvironment. They must withstand hemodynamic forces and overcome the effects of fluid shear before they can leave the vascular system (extravasate) to establish new metastatic foci. One of the hypotheses of the tumor cell extravasation process is based on the so called "adhesion cascade" that was formulated and observed in the context of leukocytes circulating in the vascular system. During this process, the cell needs to switch between various locomotion strategies, from floating with the blood stream, to rolling on the endothelial wall, to tumor cell arrest and crawling, and finally tumor cell transmigration through the endothelial layer. The goal of this project is to use computational mechanical modeling to investigate the fundamental biophysical parameters of tumor cells in circulation. As a first step to build a robust in silico model, we consider a single cell exposed to the blood flow. We examine parameters related to structure of the actin network, cell nucleus and adhesion links between the tumor and endothelial cells that allow for successful transition between different transport modes of the adhesion cascade. PMID- 23024962 TI - Fibromyalgia syndrome: still a medical dilemma. PMID- 23024963 TI - If fibromyalgia did not exist, we should have invented it. A short history of a controversial syndrome. AB - Fibromyalgia is a recent disease, and some physicians remain doubtful about its reality. The history of fibromyalgia is a story of controversies: the fight between subjectivity and cartesianism, and between old mind and body concepts. Fibromyalgia represents the emblematic condition of unexplained medical symptoms, far from well-defined diseases with objective biomarkers. In this review we will follow the fibromyalgia story along the ages and sciences to better understand this complex pain disorder, between soma and psyche, and between medicine and psycho-sociology and to demonstrate that fibromyalgia exist, we have not invented it. PMID- 23024964 TI - Diagnosis and diagnostic tests for fibromyalgia (syndrome). AB - OBJECTIVES: To present diagnostic criteria for the clinical diagnosis of fibromyalgia syndrome (FMS) and to offer a scheme for diagnostic work-up in clinical practice. METHODS: Narrative review of the literature, consensus documents by the American College of Rheumatology (ACR), evidence-based interdisciplinary German guidelines on the diagnosis and management of FMS. RESULTS: The ACR 1990 classification criteria emphasized tender points and widespread pain as the key features of FMS. In 2010, the ACR proposed preliminary diagnostic criteria for fibromyalgia that abandoned the tender point count and placed increased emphasis of patient symptoms. A later modification of the ACR 2010 criteria for use in surveys employed a self-report questionnaire (Fibromyalgia Survey Questionnaire FSQ) to assess patient symptoms. The FSQ can be used to assist physician's diagnosis of FMS. We recommend a stepwise diagnostic work-up of patients with chronic widespread pain (CWP) in primary care: Complete medical history including medication, complete medical examination, basic laboratory tests to screen for inflammatory or endocrinology diseases, referral to specialists only in case of suspected somatic diseases, assessment of limitations of daily functioning, screening for other functional somatic symptoms and mental disorders, and referring to mental health specialists in case of mental disorder. CONCLUSIONS: The diagnosis of FMS is easy in most patients with CWP and does not ordinarily require a rheumatologist. A rheumatologist's expertise might be needed to exclude difficult to diagnose or concomitant inflammatory rheumatic diseases. In the presence of mental illness referral to a mental health specialist for evaluation is recommended. PMID- 23024966 TI - Pain assessment strategies in patients with musculoskeletal conditions. AB - Valid and reliable assessment of pain is fundamental for both clinical trials and effective pain management. The nature of pain makes objective measurement impossible. Chronic musculoskeletal pain assessment and its impact on physical, emotional and social functions require multidimensional qualitative tools and healthrelated quality of life instruments. The recommendations concerning outcome measurements for pain trials are useful for making routine assessments that should include an evaluation of pain, fatigue, disturbed sleep, physical functioning, emotional functioning, patient global ratings of satisfaction, and quality of life. Despite the growing availability of instruments and theoretical publications related to measuring the various aspects of chronic pain, there is still little agreement and no unified approach has been devised. There is, therefore, still a considerable need for the development of a core set of measurement tools and response criteria, as well as for the development and refinement of the related instruments, standardized assessor training, the cross cultural adaptation of health status questionnaires, electronic data capture, and the introduction of valid, reliable and responsive standardized quantitative measurement procedures into routine clinical care. This article reviews a selection of the instruments used to assess chronic musculoskeletal pain, including validated newly developed and well-established screening instruments, and discusses their advantages and limitations. PMID- 23024965 TI - Fibromyalgia dyscognition: concepts and issues. AB - Fibromyalgia is characterized by widespread pain and tenderness; however, comorbid cognitive difficulties are a common complaint among patients. Known as fibro fog or dyscognition, this symptom comprises difficulties with complex cognitive processes including memory, executive function, concentration and attention. While the mechanisms that initiate and maintain these cognitive deficits are still largely unknown, recent research has increased the understanding of subjective symptoms and objectively-determined deficits in cognitive performance. Treatments have also improved to include complementary cognitive and physical strategies. This review focuses on issues of dyscognition in fibromyalgia. Details of objective testing methods are not within the scope of this paper. PMID- 23024967 TI - Pediatric fibromyalgia. AB - Fibromyalgia (FM) is currently defined as chronic widespread pain (CWP) with allodynia or hyperalgesia to pressure pain. It is classified as one of the large group of soft-tissue pain syndromes. Pain is the cardinal symptom of FM; however, most patients also experience additional symptoms such as debilitating fatigue, disrupted or non-restorative sleep, functional bowel disturbances, and a variety of neuropsychiatric problems, including cognitive dysfunction, anxiety and depressive symptoms. Its pathogenesis is not entirely understood, although it is currently believed to be the result of a central nervous system (CNS) malfunction that increases pain transmission and perception. FMS usually involves females, and in these patients it often makes its first appearance during menopause. But it is often diagnosed both in young as well as elderly individuals. Pediatric FMS is a frustrating condition affecting children and adolescents at a crucial stage of their physical and emotional development. Pediatric FMS is an important differential diagnosis to be considered in the evaluation of children suffering from widespread musculoskeletal pain, and must be differentiated from a spectrum of inflammatory joint disorders such as juvenile idiopathic arthritis (JIA), juvenile ankylosing spondylitis, etc. The management of pediatric FMS is centered on the issues of education, behavioral and cognitive change (with a strong emphasis on physical exercise), and a relatively minor role for pharmacological treatment with medications such as muscle relaxants, analgesics and tricyclic agents. PMID- 23024968 TI - Neurophysiological background for physical therapies in fibromyalgia. AB - This paper describes the techniques for controlling pain by the physical means that are most widely used clinically, particularly in the case of fibromyalgia. They are grouped on the basis of the physical energy used: mechanical, thermal (including magnetic and electromagnetic), and light (LASER). The main underlying neurophysiological mechanisms are gate activation, the stimulation of descending systems of pain control, and the endogenous opiate system. PMID- 23024970 TI - Fibromyalgia and sexual problems. AB - The aim of this review was to describe the recent literature concerning sexual dysfunction in fibromyalgic patients. To this end, we used the common online databases PubMed, MEDLINE and EMBASE (up to June 2012) and searched for the key words fibromyalgia (FM) and sexual dysfunction. All the studies examined underlined that FM is strictly associated with sexual dysfunction in women. The major findings observed were related to a decreased sexual desire and arousal, decreased experience of orgasm, and in some studies an increase in genital pain. The psychological aspects, together with the stress related to the constant presence of chronic widespread pain, fatigue and sleep disturbances, are certainly a major factor that adversely affects the sexuality of the patient with FM. Moreover, the drugs most commonly used in these cases may interfere negatively on the sexuality and sexual function of these patients. Therefore, the therapeutic intervention should be targeted and the side effects should be weighed up against the positive effects. It is of the utmost importance to recognise the problem of sexuality and sexual dysfunction in a more complex form of its expression and undertake a multidisciplinary therapeutic intervention to improve the quality of FM patients' life. PMID- 23024969 TI - Identification of subgroups among fibromyalgia patients. AB - This paper presents some hypotheses concerning the identification of homogeneous subgroups among fibromyalgia (FM) patients in order to improve the management of the disease. It also reviews the available literature about this subject. Three methods for subgrouping are discussed according to clinical features, biomarkers, and gait analysis. Clinical subgrouping based on cluster analysis has been used for the identification of homogeneous subgroups of patients and, more recently, homogeneous clinical features. So far, longitudinal studies using clinical subgroups to direct treatment and predict outcome are still required. Biomarkers in FM, which is a neurobiological disease, are of promising interest, nevertheless currently, none of them can be used to subgroup FM patients. Due to the fact that cortical and subcortical mechanisms of gait control share some cognitive functions which are involved in FM, gait markers have been proposed to evaluate and to subgroup FM patients, in clinical settings. Three out of 4 core FM symptoms are linked to gait markers. Kinesia measured by means of cranio caudal power is correlated to pain, and could be proposed to assess pain behavior (kinesiophobia). Stride frequency, which is linked to physical component, allows the identification of a hyperkinetic subgroup. Moreover, SF has been correlated to fatigue during the 6 minute walking test. Stride regularity, which expresses the unsteadiness of gait, is correlated to cognitive dysfunction in FM. Decreased stride regularity allows the recognition of a homogeneous subgroup characterized by an increased anxiety and depression, and decreased cognitive functions. These results need further studies to be validated and so used in the daily clinical practice. PMID- 23024971 TI - Psychiatric problems in fibromyalgia: clinical and neurobiological links between mood disorders and fibromyalgia. AB - OBJECTIVES: To review the literature addressing the relationship between mood disorders and fibromyalgia/chronic pain and our current understanding of overlapping pathophysiological processes and pain and depression circuitry. METHODS: We selectively reviewed articles on the co-occurrence of mood disorders and fibromyalgia/chronic pain published between 1990 and July 2012 in PubMed. Bibliographies and cross references were considered and included when appropriate. RESULTS: Forty-nine out of 138 publications were retained for review. The vast majority of the studies found an association between depression and fibromyalgia. There is evidence that depression is often accompanied by symptoms of opposite polarity characterised by heights of mood, thinking and behaviour that have a considerable impact on pharmacological treatment. Recent developments support the view that the high rates of fibromyalgia and mood disorder comorbidity is generated by largely overlapping pathophysiological processes in the brain, that provide a neurobiological basis for the bidirectional, mutually exacerbating and disabling relationship between pain and depression. CONCLUSIONS: The finding of comparable pathophysiological characteristics of pain and depression provides a framework for understanding the relationship between the two conditions and sheds some light on neurobiological and therapeutic aspects. PMID- 23024972 TI - Cognitive-behavioral and operant-behavioral therapy for people with fibromyalgia. AB - The current article reviews the cognitive-behavioral (CB) and operant-behavioral perspectives on chronic pain and suggests an answer to the question why changes in behaviors, attitudes, and emotions are associated with decreases in pain severity and impact discussing potential psychobiological mechanisms that may underlie cognitive and behavioral techniques. The impact of learning such as classical and operant conditioning in behaviors and physical responses including baroreflex sensitivity (BRS), as well as the influence of cognitions on pain perception and impact will be presented to explain general efficacy of cognitive behavior therapy (CBT) and operant-behavioral therapy (OBT) in the treatment of people with fibromyalgia (FM) describing some of the limitations of published outcome studies. We discuss advances in moderation and mediation of treatment outcomes. Lastly, we will discuss the need for research that takes into account evidence-based medicine, methods that address treatment responders and non responders, individual trajectories, how we might advance and refine CBT and OBT, and strategies related to relapse prevention, maintenance, and adherence enhancement taking advantage of evolving, technological methods of service delivery. We provide recommendations of how to move forward in approaching studies of CBT and OBT efficacy as a function of better understanding of patient characteristics and contextual factors. We advocate for the potential of the CB perspective and principle of learning for all health care providers regardless of discipline or training and will give examples for making more effective the patient-rheumatologist-relationship by using the principles discussed. PMID- 23024973 TI - Fibromyalgia and arthritides. AB - Fibromyalgia (FM) is a chronic pain syndrome that affects at least 2% of the adult population. It is characterised by widespread pain, fatigue, sleep alterations and distress, and emerging evidence suggests a central nervous system (CNS) malfunction that increases pain transmission and perception. FM is often associated with other diseases that act as confounding and aggravating factors, such as rheumatoid arthritis (RA), spondyloarthritides (SpA), osteoarthritis (OA) and thyroid disease. Mechanism-based FM management should consider both peripheral and central pain, including effects due to cerebral input and that come from the descending inhibitory pathways. Rheumatologists should be able to distinguish primary and secondary FM, and need new guidelines and instruments to avoid making mistakes, bearing in mind that the diffuse pain of arthritides compromises the patients' quality of life. PMID- 23024974 TI - Nanopatterned submicron pores as a shield for nonspecific binding in surface plasmon resonance-based sensing. AB - We present a novel approach to tackle the most common drawback of using surface plasmon resonance for analyte screening in complex biological matrices--the nonspecific binding to the sensor chip surface. By using a perforated membrane supported by a polymeric gel structure at the evanescent wave penetration depth, we have fabricated a non-fouling sieve above the sensing region. The sieve shields the evanescent wave from nonspecific interactions which interfere with SPR sensing by minimizing the fouled area of the polymeric gel and preventing the translocation of large particles, e.g. micelles or aggregates. The nanopatterned macropores were fabricated by means of colloidal lithography and plasma enhanced chemical vapor deposition of a polyethylene oxide-like film on top of a polymeric gel matrix commonly used in surface plasmon resonance analysis. The sieve was characterized using surface plasmon resonance imaging, contact angle, atomic force microscopy and scanning electron microscopy. The performance of the sieve was studied using an immunoassay for detection of antibiotic residues in full fat milk and porcine serum. The non-fouling membrane presented pores in the 92-138 nm range organized in a hexagonal crystal lattice with a clearance of about 5% of the total surface. Functionally, the membrane with the nanopatterned macropores showed significant improvements in immunoassay robustness and sensitivity in untreated complex samples. The utilization of the sensor built-in sieve for measurements in complex matrices offers reduction in pre-analytical sample preparation steps and thus shortens the total analysis time. PMID- 23024976 TI - A study of pH-dependent photodegradation of amiloride by a multivariate curve resolution approach to combined kinetic and acid-base titration UV data. AB - Amiloride photostability at different pH values was studied in depth by applying Multivariate Curve Resolution Alternating Least Squares (MCR-ALS) to the UV spectrophotometric data from drug solutions exposed to stressing irradiation. Resolution of all degradation photoproducts was possible by simultaneous spectrophotometric analysis of kinetic photodegradation and acid-base titration experiments. Amiloride photodegradation showed to be strongly dependent on pH. Two hard modelling constraints were sequentially used in MCR-ALS for the unambiguous resolution of all the species involved in the photodegradation process. An amiloride acid-base system was defined by using the equilibrium constraint, and the photodegradation pathway was modelled taking into account the kinetic constraint. The simultaneous analysis of photodegradation and titration experiments revealed the presence of eight different species, which were differently distributed according to pH and time. Concentration profiles of all the species as well as their pure spectra were resolved and kinetic rate constants were estimated. The values of rate constants changed with pH and under alkaline conditions the degradation pathway and photoproducts also changed. These results were compared to those obtained by LC-MS analysis from drug photodegradation experiments. MS analysis allowed the identification of up to five species and showed the simultaneous presence of more than one acid-base equilibrium. PMID- 23024975 TI - A new strategy for imaging biomolecular events through interactions between liquid crystals and oil-in-water emulsions. AB - In this study, we demonstrate a new strategy to image biomolecular events through interactions between liquid crystals (LCs) and oil-in-water emulsions. The optical response had a dark appearance when a nematic LC, 4-cyano-4' pentylbiphenyl (5CB), is in contact with emulsion droplets of glyceryl trioleate (GT). In contrast, the optical response had a bright appearance when 5CB is in contact with GT emulsions decorated with surfactants such as sodium oleate. Since lipase can hydrolyze GT and produce oleic acid, the optical response also displays a bright appearance after 5CB has been in contact with a mixture of lipase and GT emulsions. These results indicate the feasibility of monitoring biomolecular events through interactions between LCs and oil-in-water emulsions. PMID- 23024978 TI - Abstracts of the Chicago Multidisciplinary Symposium in Thoracic Oncology. September 6-8, 2012. Chicago, Illinois, USA. PMID- 23024977 TI - Synthesis of ethers from esters via Fe-catalyzed hydrosilylation. AB - Triiron dodecacarbonyl allows for the selective reduction of esters into the corresponding ethers. This protocol has a wide substrate scope. In addition, cholesteryl pelarogonate has been reduced under the reaction conditions with an excellent yield. PMID- 23024979 TI - A conversation with Donald Seldin. Interview by Ushma Neill. PMID- 23024982 TI - European medical laboratory accreditation. Present situation and steps to harmonisation. AB - Accreditation of medical laboratories in Europe is primarily according to ISO15189. The percentage of accredited laboratories is still small. The time spent on an assessment is quite different between countries. More important is the way the assessment process is carried out. Harmonisation in accrediting medical laboratories is the main task of the Health Care Committee within EA (European cooperation of Accreditation). The EFCC Working Group on Accreditation strongly contributes as the representative of laboratory professionals. An important item is the use of flexible scope. The intention is that all tests within a medical discipline are offered for accreditation. This is not yet normal practice. Other items concern accreditation of point-of-care testing (POCT) - reliability of the pre-analytical phase, when the phlebotomy is not done by the laboratory, and practical use of uncertainty and verification. Also the diversity in time spent for an assessment is discussed. The added value of accreditation is strongly dependent upon the assessors who have an important task. Their training and calibration needs continuous input. The medical laboratory professionals should participate in all aspects concerning the quality system, starting with the standard, working on the guidelines, the assessment itself, and input in the accreditation bodies. PMID- 23024981 TI - Liver function from Y to Z. AB - In the 1960s, my lab was interested in understanding how bilirubin and other organic anions are transferred from the plasma through the liver cell and into the bile. We performed gel filtration of liver supernatants and identified two protein fractions, designated Y and Z, which bound organic anions including bilirubin, and thus we proposed that they were involved in hepatic uptake of organic anions from plasma. Subsequently, the Y and Z proteins responsible for this binding activity were purified, cloned, and sequenced. Y was identified as a member of the glutathione S-transferase (GST) protein family and Z found to be a member of the fatty acid-binding protein (FABP) family. These proteins have since been shown to have additional surprising roles, but understanding of their full role in physiology and disease has not yet been achieved. PMID- 23024983 TI - Experience of Medecins Sans Frontieres in laboratory medicine in resource-limited settings. AB - In medical humanitarian assistance, the diagnosis of diseases plays a crucial role. Laboratory investigations are one of the main diagnostic tools utilized in Medecins Sans Frontieres' (MSF) programs. Currently MSF supports and/or operates more than 130 laboratories in approximately 45 countries. The variety of analysis offered depends largely on the context of the program and the availability of context adapted tools and ranges from sophisticated laboratories specializing in tuberculosis culture to small laboratories within a primary health care program or operating as mobile clinics. The largest laboratories in MSF are found in programs with the main objective to diagnose, treat and monitor patients with tuberculosis and/or human immunodeficiency virus. Other MSF programs are either disease-specific (e.g., malaria, Chagas, kala azar or visceral leishmaniasis, sleeping sickness, malnutrition, sexually transmitted infections) or are integrated in primary or secondary health care structures. PMID- 23024984 TI - Highlights in inflammatory bowel disease--from bench to bedside. AB - Approximately 3.6 million people in Europe and the USA suffer from recurrent auto immune-mediated inflammation of the gastrointestinal tract. Inflammatory bowel disease (IBD) comprises two entities: Crohn's disease (CD) and ulcerative colitis (UC). In the past, experimental studies (mostly in mice) have improved our understanding of the aberrant interaction between the intestinal microbiota and the immune system. The perturbed immune reaction in IBD exhibits specific and individual cytokine responses that distinguish the two variants. A deep understanding of the immunological response at every stage of the chronic disease enables the provision of modern, efficient medical treatment that takes into account individual immunological and genetic characteristics. In this review, the current knowledge on the epidemiology and genetics of IBD is summarized, and new pathogenetic insights as well as promising future therapeutic options are described. PMID- 23024985 TI - US Supreme Court paves way for health reform. PMID- 23024986 TI - The state of chemotherapy in France. PMID- 23024987 TI - NICE guidance on abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen. PMID- 23024988 TI - NICE guidance on erlotinib for first-line treatment of EGFR-TK mutation-positive advanced or metastatic non-small-cell lung cancer. PMID- 23024989 TI - Lapatinib or trastuzumab in combination with an aromatase inhibitor for first line treatment of metastatic hormone-receptor-positive breast cancer that overexpresses HER2. PMID- 23024990 TI - 14th World Congress on Gastrointestinal Cancer. PMID- 23024993 TI - European Medicines Agency assesses safety reporting at Roche. PMID- 23024991 TI - Data used to justify Indian HPV vaccination trial questioned. PMID- 23024992 TI - Potential therapeutic target for triple-negative breast cancer. PMID- 23024994 TI - Preimplantation genetic diagnosis for mutated BRCA genes. PMID- 23024995 TI - Parent-controlled analgesia for paediatric pain management. PMID- 23024997 TI - Australia to be first country to vaccinate boys against HPV. PMID- 23024996 TI - Natural gamma radiation and childhood leukaemia. PMID- 23024998 TI - Chemokine receptor blockade in graft-versus-host disease. PMID- 23024999 TI - One in five need reoperation after breast-conserving surgery. PMID- 23025001 TI - Authorship: Who's on first? PMID- 23025000 TI - US Medicare to cut radiotherapy times and payments. PMID- 23025002 TI - AAAS S&T policy fellows. Four decades on, fellows make global impact on science policy. PMID- 23025003 TI - In memoriam tribute to James A. Shaver, MD. PMID- 23025004 TI - XVIII Latin American Congress of the Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition (LASPGHAN). PMID- 23025005 TI - Abstracts of the keynote addresses from the Royal Australian and New Zealand College of Psychiatrists (RANZCP) 2012 Congress. May 20-24, 2012. Hobart, Tasmania. PMID- 23025006 TI - Abstracts of the 32nd European Peptide Symposium. September 2-7, 2012. Athens, Greece. PMID- 23025007 TI - A second wind for the president. PMID- 23025008 TI - Therapy deficit. PMID- 23025009 TI - Abstracts of the XXIII European Congress of Perinatal Medicine. June 13-16, 2012. Paris, France. PMID- 23025010 TI - Poison postures. PMID- 23025011 TI - Southern U.S.: plenty of AIDS, few HIV experts. PMID- 23025012 TI - Women in Argentina infected by stable partners. PMID- 23025013 TI - Over-the-counter rapid HIV test approved. PMID- 23025014 TI - Chronic HBV cases largely untreated. PMID- 23025015 TI - [Tuberculosis Annual Report 2010--(3) Childhood tuberculosis]. AB - The number of newly notified childhood tuberculosis (TB) cases (TB in patients aged 0-14 years) in Japan in 2010 was 89, which corresponds to a notification rate of 0.53 per 100,000 population. The annual notified numbers and rates of childhood TB decreased steadily until 2006, after which the number dropped to below 100 and have since remained stable. Among the 89 childhood TB patients notified in 2010, 30 (33.7%) were aged 0-4 years, 26 (29.2%) were 5-9 years, and 33 (37.1%) were 10-14 years. In 2010, the number and proportion of TB patients aged 10-14 years were remarkably increased as compared to those in previous years. In the same year, 25 (28.1%) extrapulmonary TB cases were reported in children, while no TB meningitis or miliary TB cases were reported. The number of foreigners with childhood TB increased from 5 in 2008 and 3 in 2009 to 9 (10.1%) in 2010. In 2010, 30 patients (33.7%) with TB symptoms were identified at medical institutions, and 40 (44.9%) were identified by contact investigation of household members. These accounted for nearly 80% of the childhood TB cases detected, similar to the trend in previous years. Of the 47 prefectures in Japan, 15 reported no cases of childhood TB in 2010. Childhood TB cases were concentrated in the metropolitan areas such as the Tokyo Metropolitan Area (23 cases) and Kanagawa Prefecture (9 cases). In recent years, the number and rate of childhood TB cases in Japan have remained low; however, further efforts to eliminate childhood TB will require early detection and treatment of infectious cases, efficient contact investigations, and sustaining good TB prevention practices. PMID- 23025017 TI - Cancer treatments may harm the heart. Doctors strive to prevent the cure for one disease from causing another. PMID- 23025018 TI - Ask the doctors. I am 90 years old and have had severe heart failure for seven years after having a heart attack. I have an implantable defibrillator. It has never gone off. It is near the end of its lifetime, and the cardiologist asked me if I want it replaced. What would you advise? PMID- 23025019 TI - Ask the doctors. I am a 62-year-old female with no chronic health problems, but I am about 10 pounds overweight. My new doctor wants to put me on a statin immediately. My total cholesterol is 187: my LDL is 129, my HDL is 47, and my triglycerides are 55. He is concerned because my father died of a heart attack from coronary artery disease. The doctor wants my HDL to be above 60 and my LDL to be below 100. Could this result be achieved by weight loss, dietary changes, and exercise alone? If not, which statin would you recommend? PMID- 23025020 TI - When an implantable defibrillator fails. Here are the options when the leads on your device stop working. PMID- 23025021 TI - Resuming sex after a heart attack. A new report answers the questions on everyone's mind. PMID- 23025022 TI - Dual antiplatelet therapy after stenting. More than 12 months of treatment might not be necessary. PMID- 23025023 TI - Know your heart-related stroke risk. For unknown reasons, women are at higher risk than men. PMID- 23025024 TI - Measure blood pressure in both arms. A significant difference may point to increased cardiac risk. PMID- 23025025 TI - Bleeding risk with aspirin must be balanced against benefit. PMID- 23025026 TI - Heart problems from Z-Pak. PMID- 23025027 TI - An Aingeal to watch over you. PMID- 23025028 TI - New research shows radiofrequency ablation as safe as medication therapy. A recent study finds that ablation with pulmonary vein isolation also outperformed standard medical therapy in reducing the odds of recurring episodes of atrial fibrillation. PMID- 23025029 TI - Dietary calcium may be healthier for the heart than supplements. Recent study suggests supplements may raise the risk of heart attack. PMID- 23025030 TI - How Nordic walking and Mozart may improve heart health. Studies show alternative therapies can aid in managing conditions such as heart failure and high blood pressure. PMID- 23025031 TI - Fitness may help overcome effects of family history of hypertension. New study further underscores the heart-healthy benefits of regular exercise. PMID- 23025032 TI - CPAP adherence may reduce risk of new onset hypertension. Two new studies reaffirm continuous positive airway pressure therapy as a proven means of protecting against heart problems in sleep apnea patients. PMID- 23025033 TI - I have had atrial fibrillation for six years and was recently diagnosed with pulmonary arterial hypertension (PAH). I was taken off warfarin (Coumadin) and was put on tadalafil (Adcirca). What can you tell me about PAH and will I be on Adcirca for a long time? PMID- 23025035 TI - Animal crowding and farm animal welfare. PMID- 23025034 TI - I am a heart attack survivor who takes medication for hypertension and high cholesterol, both of which seem to be managed well. I often hear about the dangers of overdoing it in cold weather, such as too much snow shoveling, but I wonder about what precautions heart patients should take in very hot weather. What sort of strain is the heat putting on my heart? PMID- 23025036 TI - Adoption of adjunct faculty by veterinary schools. PMID- 23025037 TI - Distributed teaching model at the University of Calgary Faculty of Veterinary Medicine. PMID- 23025039 TI - [Health service research (21). On attending the National Health Policy Conference]. PMID- 23025038 TI - Carotid ultrasound as predictor of atherosclerosis in rheumatoid arthritis. PMID- 23025040 TI - [Passion for neuroanatomical research and education]. PMID- 23025042 TI - [Habenula and the asymmetric development of the vertebrate brain]. PMID- 23025041 TI - [My profile and hope for the anatomy]. PMID- 23025043 TI - [Expression of ATP receptors in the pain pathway]. PMID- 23025044 TI - [Effects of nootropic drugs on behavior of BALB/c and C57BL/6 mice in the exploratory cross-maze test]. AB - Exploratory behavior, locomotor activity, and anxiety in inbred mice of C57BL/6 and BALB/c strains subchronically treated with placebo or various types of nootropic (cognition enhancing) drugs (piracetam, phenotropil, noopept, semax, pantogam, nooglutil) have been evaluated using the exploratory cross-maze test. It was found that BALB/c mice in comparison to C57BL/6 mice are characterized by greater anxiety and lower efficiency of exploratory behavior in the previously unfamiliar environment. All tested drugs clearly improved the exploratory behavior in BALB/c mice only. In BALB/c mice, piracetam, phenotropil, noopept, and semax also reduced anxiety, while phenotropil additionally increased locomotor activity. Thus, the nootropic drugs displayed clear positive modulation of spontaneous orientation in the mice strain with initially low exploratory efficiency (BALB/c) in the cross-maze test. Some drugs (pantogam, nooglutil) exhibited only nootropic properties, while the other drugs exhibited both nootropic effects on the exploratory activity and produced modulation of the anxiety level (piracetam, fenotropil, noopept, semax) and locomotor activity (fenotropil). PMID- 23025045 TI - [Comparative study of the influence of succinate-containing preparations on mitochondrial respiration in rat brain cells]. AB - It has been established by polarographic measurements that preparations containing succinate, such as cytoflavin (0.85 mM succinate), mexidol, and amtizol succinate (at a concentration of 0.85 mM) but not reamberin (0.045 mM succinate), nearly equally (by 35-45%) increase oxygen consumption in rat brain mitochondria. On the other hand, malonate - inhibitor of the respiratory complex II (succinate dehydrogenase) of mitochondrial chain suppressed the stimulating effect of these drugs. PMID- 23025046 TI - [Analysis of 8-OH-DPAT and NAN-190 effects in young prenatally stressed rats under experimental estrogen deficiency conditions]. AB - The present work was aimed at a comparative investigation of the effects of chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT1A receptors antagonist NAN-190 (0.1 mg/kg, i.p.) for 14 days on anxiety-like behavior in prenatally stressed female with the experimental estrogen deficiency induced by ovariectomy. Chronic administration of 8-OH-DPAT to ovariectomized prenatally stressed females resulted in an anxiolytic effect and led to correction of the impaired levels of follitropine and estradiol. Administration of NAN-190 to ovariectomized prenatally stressed females increased the level of anxiety and more profoundly destroyed a relation between the levels of gonadotropic hormones and peripheral gonadal hormones. PMID- 23025047 TI - [Peculiarities of cerebrovascular effects of GABA conjugate with docosahexaenoyl dopamine under conditions of separate and combined vascular pathology of brain and heart]. AB - A GABA conjugate with docosahexaenoyl dophamine (DHED) enhanced local cerebral blood flow in rats under conditions of global transient cerebral ischemia, experimental myocardial infarction, and combined vascular pathology of brain and heart. At the same time, the GABA-DHED conjugate did not influence brain hemoperfusion in intact animals. The cerebrovascular effect of this conjugate is determined by its direct action on the vascular tone, since no changes in blood pressure have been observed. Under conditions of the combined vascular pathology of brain and heart, the cerebrovascular effect of GABA-DHED conjugate is inhibited by bicuculline, which is evidence for the involvement of GABAergic mechanisms in the drug action upon cerebrovascular tone. PMID- 23025048 TI - [Effectiveness of 3-hydroxypyridine and succinic acid derivatives in complex treatment of primary open-angle glaucoma]. AB - Prospective, placebo-controlled, single-blind, randomized clinical investigation of the influence of domestic 3-hydroxypyridine and succinic acid derivatives (emoxipin, reamberin, mexidol) on the effectiveness of a complex treatment of primary open-angle glaucoma (POAG) has been performed in a group of patients. It is established that intravenous infusion of 3-hydroxypyridine derivatives (emoxipin and mexidol) for two weeks, beginning 14 days after the start of POAG treatment, produced a retinoprotective action, with three months postponed changes in the central retinal artery (CRA) blood velocity. The retinoprotective effect of emoxipin (single dose, 150 mg) was manifested by reduction in the horizontal size of blind spot in two weeks, with the subsequent reduction of the CRA end-diastolic blood velocity observed three months after finish of the infusion therapy. The administration of mexidol (single dose, 300 mg) after 14 days of treatment led to widening of the summarized field of vision (test-object square, 16 mm), accompanied by a decrease in the electrosensitivity threshold of the optic nerve and the intensity of POAG-associated hypothymia. All indices of CRA blood velocity increased three months after termination of mexidol infusions. Reamberin (single dose, 400 ml 1,5% solution of reamberine, containing polyelectrolyte and meglumine succinate mixture) did not show retinoprotective action, but caused proatherogenic changes of blood lipids and 3 months postponed CRA end-diastolic blood velocity increase. The effect of mexidol (which is a derivative of both 3- hydroxypyridine and succinic acid) exceeds that of separate 3-hydroxypyridine (emoxipin) and succinic acid (reamberin) derivatives in the degree of retinoprotection and positive effect on the optic nerve condition and mood of POAG patients. PMID- 23025049 TI - [Influence of reamberin on the photohemotherapy of endogenous intoxication caused by acute experimental pancreatitis]. AB - Combined application of photohemotherapy and antihypoxant reamberin for the treatment of endogenous intoxication favors fast (within one day) restoration of the functional condition of lungs and prevents the development of respiratory distress syndrome. High efficiency of the combined therapy is related to a fast stabilization of membranes, which is determined by the ability to correct lipid metabolism in lung tissues. PMID- 23025050 TI - [Effect of combined therapy with melaxen on lipid peroxidation rate and citrate content in blood serum of patients with drug-induced hepatitis diagnosis]. AB - A combined therapy with melaxen led to a decrease in the activity of gamma glutamyl transpeptidase and the level of diene conjugates in blood serum of patients with the drug-induced hepatitis developing on the background of administration of antituberculous preparations. These changes are indicative of pronounced antioxidant and hepatoprotective properties of the drug. In addition, there was a decrease in the content of citrate and a change in the activity of aconitate hydratase toward a normal level, which reflects a decrease in the degree of pathologic oxidative stress development and is evidence of the antiradical effect of melaxen. PMID- 23025051 TI - [Hepatoprotective and immunomodulatory effects of infliximab on experimental alcoholic steatohepatitis]. AB - The effect of infliximab (1 and 10 mg/kg, i.p., during 10 days) on alcoholic steatohepatitis has been studied in rats fed with ethanol-containing liquid diet over 10 weeks. Both doses of infliximab showed immunomodulatory and anti inflammatory effects, whereas only the maximum drug dose significantly decreased lipid accumulation in the liver. It can be concluded that infliximab (10 mg/kg) acts as an effective hepatoprotector, anti-inflammatory agent, and immunomodulator in rats with experimental alcoholic steatohepatitis. PMID- 23025052 TI - [Cycloferon: mechanism of action, functions and application]. AB - In recent years, both interferons and inductors of endogenous interferon production find increasing use in clinical practice. The latter agents are characterized by high antiviral and immunomodulatory activity in the absence of serious side effects, which makes it possible to prescribe long courses if necessary. One of the most frequently used interferon inductors is cycloferon. Diverse effects of cycloferon on biochemical and cellular cascades (including induction of alpha- and beta-interferon, inhibition ofproapoptotic factors such as tumor necrosis factor and interleukin 1-beta) suggest that it also takes active part in the regulation of apoptosis, one of the most important processes of cell activity that opens up new prospects for the therapeutic use of cycloferon. PMID- 23025053 TI - Lower chronic hepatitis B in South Asia despite all odds: bucking the trend of other infectious diseases. PMID- 23025054 TI - Chronic hepatitis B in Nepal: an Asian country with low prevalence of HBV infection. AB - Sandwiched between China, a country with high prevalence of hepatitis B surface antigen (HBsAg) and 30% of the world's HBsAg carriers, and India which has intermediate HBsAg prevalence and 10% of the world's carriers, Nepal has the lowest prevalence of hepatitis B virus (HBV) infection in Asia, with an HBsAg carrier rate of 0.9%. This treatise discusses the probable causes of this low prevalence based on published literature on the subject. The HBsAg prevalence among pregnant women in Nepal is low (0.5%) and none of those examined were HBeAg positive. The highest prevalence of HBsAg was found in the 6-15 years age group. The low prevalence of this infection in the country was due to an absence of significant vertical transmission and its predominant spread by horizontal transmission among the adolescent age group. PMID- 23025055 TI - Tuberculosis and liver disease: management issues. AB - Tuberculosis is one of the most common diseases in India and has attained epidemic proportions. Tuberculosis and liver are related in many ways. Liver disease can occur due to hepatic tuberculosis or the treatment with various anti tubercular drugs may precipitate hepatic injury or patients with chronic liver disease may develop tuberculosis and pose special management problems. Tuberculosis per se can affect liver in three forms. The most common form is the diffuse hepatic involvement, seen along with pulmonary or miliary tuberculosis. The second is granulomatous hepatitis and the third, much rarer form presents as focal/local tuberculoma or abscess. Tubercular disease of liver occurring along with pulmonary involvement as in disseminated tuberculosis is treated with standard regimen for pulmonary tuberculosis. Granulomatous hepatitis and tubercular liver abscess are treated like any other extra-pulmonary tubercular lesions without any extra risk of hepatotoxicity by anti-tubercular drugs. Treatment of tuberculosis in patients who already have a chronic liver disease poses various clinical challenges. There is an increased risk of drug induced hepatitis in these patients and its implications are potentially more serious in these patients as their hepatic reserve is already depleted. However, hepatotoxic anti-tubercular drugs can be safely used in these patients if the number of drugs used is adjusted appropriately. Thus, the main principle is to closely monitor the patient for signs of worsening liver disease and to reduce the number of hepatotoxic drugs in the anti-tubercular regimen according to the severity of underlying liver disease. PMID- 23025056 TI - Role of the lower esophageal sphincter on esophageal acid exposure - a review of over 2000 patients. AB - BACKGROUND AND AIM: Three lower esophageal sphincter (LES) characteristics associated with gastro-esophageal reflux disease (GERD) are, LES pressure = 6 mmHg, abdominal length (AL) <1 cm and overall length (OL) <2 cm. The objective of this study was to validate this relationship and evaluate the extent of impact various LES characteristics have on the degree of distal esophageal acid exposure. METHODS: A retrospective review of a prospectively maintained database identified patients who underwent esophageal manometry and pH studies at Creighton University Medical Center between 1984 and 2008. Patients with esophageal body dysmotility, prior foregut surgery, missing data, no documented symptoms or no pH study, were excluded. Study subjects were categorized as follows: (1) normal LES (N-LES): patients with LES pressure of 6-26 mmHg, AL = 1.0 cm and OL = 2 cm; (2) incompetent LES (Inc-LES): patients with LES pressure <6.0 mmHg orAL <1 cm or OL <2 cm; and (3) hypertensive LES (HTN-LES): patients with LES pressure >26.0 mmHg with AL = 1 cm and OL = 2 cm. The DeMeester score was used to compare differences in acid exposure between different groups. RESULTS: Two thousand and twenty patients satisfied study criteria. Distal esophageal acid exposure as reflected by the DeMeester score in patients with Inc LES (median=20.05) was significantly higher than in patients with an N-LES (median=9.5), which in turn was significantly higher than in patients with an HTN LES. Increasing LES pressure and AL provided protection against acid exposure in a graded fashion. Increasing number of inadequate LES characteristics were associated with an increase both in the percentage of patients with abnormal DeMeester score and the degree of acid exposure. CONCLUSION: LES pressure (=6 mmHg) and AL (<1 cm) are associated with increased lower esophageal acid exposure, and need to be addressed for definitive management of GERD. PMID- 23025057 TI - A randomized trial of 24 versus 48 weeks of peginterferon alpha-2a plus ribavirin in Egyptian patients with hepatitis C virus genotype 4 and rapid viral response. AB - BACKGROUND AND AIM: Little data is available regarding the 24-week therapy with pegylated interferon and ribavirin in Egyptian patients with hepatitis C virus (HCV) genotype 4 infection. We aimed to investigate the efficacy of 24-week versus 48-week peginterferon alpha-2a plus ribavirin therapy in patients with HCV genotype 4 infection with with rapid virological response. METHODS: This trial included 102 patients with HCV genotype 4 infection and low viral load. They were treated with peginterferon alpha-2a (180 microg/week) plus ribavirin. Patients (87/102) with a rapid virological response were randomized for a total treatment duration of 24 weeks (group A: 43) or 48 weeks (group B:44). Virological responses (EVR: early virological response, EOTR: end of treatment response, and SVR: sustained virological response) were assessed for each group. RESULTS: In group A, EVR was achieved in 37/43 (84%) patients, while EOTR was achieved in 34/43 (79%) patients and SVR in 30/43 (70%) patients. In group B, on the other hand EVR was achieved in 38/44 (84%) patients, while EOTR was achieved in 35/44 (80%) patients and SVR in 32/44 (73%) patients. No significant difference in SVR rates was observed between the two groups. The rate of adverse events was higher in group B, with lower adherence rates than group A. CONCLUSIONS: In patients with chronic HCV genotype 4 infection with rapid virological response and low viral loads, a 24-week peginterferon alpha-2a plus ribavirin therapy is as effective as a 48-week therapy with lower rate of adverse events. PMID- 23025058 TI - Celiac disease in the Red Sea state of Sudan. AB - BACKGROUND AND AIM: Celiac disease is characterized by sensitivity to gluten that results in inflammation and atrophy of the small intestine mucosa. The aim of this research was to document the presence of celiac disease and to describe its clinical presentations in the tribes living in the Red Sea state of Sudan. METHODS: 172 patients suspected to have celiac disease, were examined at the Red Sea Medical Center laboratory, Port Sudan, Sudan, from August 2008 to September 2011. All clinical data was collected using questionnaires. Serum samples were obtained from all patients for serological detection of anti-gliadin (AG) and anti-tissue transglutamase (ATTG) antibodies (IgG and IgA) using the enzyme linked immuno-sorbent assay (ELISA). RESULTS: 128 patients were found to have celiac disease. The commonest presenting symptom was chronic diarrhea (20.3%) followed by weight loss (14%). Males and females were nearly equally affected. All age groups were affected with a peak incidence between 5 to 10 years. CONCLUSIONS: Celiac disease occurs in the Red Sea state and may well be under diagnosed. The combination of IgA AGA and IgA ATTG tests represent a good diagnostic method to confirm celiac disease in suspected cases. Special attention needs to be given to methods that encourage adherence to gluten-free diet in affected people in this region. PMID- 23025059 TI - Superiority of non-capsulated 14C-urea breath test over capsule based method for detection of Helicobacter pylori infection - a preliminary report. AB - BACKGROUND: 14C-urea breath test (14C-UBT) is employed as a 'gold standard' technique for the detection of active gastric Helicobacter pylori infection and is recommended as the best option for "test-and-treat" strategy in primary health care centers. AIM: To compare the performance of capsulated and non-capsulated 14C-UBT protocols for the detection of H. pylori infection in patients. METHODS: Fifty eight H. pylori infected patients underwent routine upper GI endoscopy and biopsies were processed for rapid urease test (RUT) and histopathology examination. Capsulated 14C-UBT was done in a novel way by using 74 kBq of 14C urea along with 6.0 MBq of 99mTc-diethylene triamine penta-acetic acid (99mTc DTPA) to simultaneously monitor the movement and the fate of ingested capsule after delineating the stomach contour by using 20.0 MBq of 99mTechnetium pertechnetate (99mTcO4-) under dual head gamma camera. Non-capsulated 14C-UBT was performed within 2 days of the previous test and the results of these protocols were compared. RESULTS: In 3 out of 58 H. pylori positive cases (5.17%), 14C-UBT results were found to be negative by using the capsulated method. Interestingly, on monitoring the real time images of the capsule in these cases it was found that misdiagnosis of H. pylori infection occurred mainly due to either rapid transit of the 14C-urea containing capsule from the upper gastric tract or its incomplete resolution in the stomach during the phase of breath collection. CONCLUSION: Use of non-capsulated '4C-UBT protocol appears to be a superior option than the conventional capsule based technique for the detection of H. pylori infection. PMID- 23025060 TI - Indocyanine green clearance test (using spectrophotometry) and its correlation with model for end stage liver disease (MELD) score in Indian patients with cirrhosis of liver. AB - BACKGROUND: Child Turcotte Pugh (CTP) score and Model for End Stage Liver Disease (MELD) are used commonly to assess the prognosis of liver disease but the disadvantage of these static tests is their inability to identify the functional reserve of the liver. Among all quantitative liver function tests indocyanine green (ICG) clearance test is most widely used and has been used to determine operative risk before hepatectomy and to assess prognosis of patients with cirrhosis. AIM: To correlate indocyanine green (ICG) clearance test with MELD score in patients with cirrhosis of liver. METHODS: Forty patients with cirrhosis of liver were included and divided into two groups according to their CTP scores. Group A had 20 patients with CTP class A and group B had 20 patients with CTP class B. After ICG injection, ICG retention at 15 minutes (ICGR 15) and ICG clearance rate were calculated. RESULTS: In group A, the mean ICGR15 was 32.86% +/- 6.4% while in group B it was 51.08% +/-12.8% (p <0.001). ICG clearance rates were 4.3% +/- 2.8% and 3.5% +/- 3.8% per minute in group A and B respectively. MELD score had a strong positive correlation with ICGR15 but a negative correlation with ICG clearance rate. On ROC curve analysis, AUC for MELD was 0.805 vs. 0.88 for ICGR15 in assessing prognosis of patients with cirrhosis. The sensitivity and specificity of MELD score was 60% and 80% respectively while that of ICGR15 was 85% and 90% respectively. CONCLUSION: ICGR15 has a higher sensitivity and specificity than MELD score in assessing the prognosis of patients with cirrhosis of liver. PMID- 23025061 TI - A series on intestinal strongyloidiasis in immunocompetent and immunocompromised hosts. AB - BACKGROUND: Strongyloidiasis, endemic in tropical areas, may be asymptomatic in immunocompetent subjects or may cause potentially fatal hyper-infection in immunocompromised patients. METHODS: Of the 13,885 patients referred to the parasitology laboratory at our tertiary care referral center for stool microscopy, 15 were diagnosed as strongyloidiasis over a 6 year period. We assessed these patients retrospectively. RESULTS: Most patients were young (median age 32 years, range 3-66) males (12, 80%). Seven patients (46.6%) were immunocompromised. All patients were symptomatic, and symptoms included chronic diarrhea (4, 26.7%), acute diarrhea (1,6.7%), abdominal pain (6, 40%), weight loss (3, 20%), cough (2, 13.33%), vomiting (1, 6.7%), anemia (10, 66.7%) and eosinophilia (3, 20%). Thirteen patients (86.6%) were diagnosed on first stool microscopy. Duodenal biopsy showed normal histology in twelve (80%) and partial villous atrophy in one (6.7%) patient. Stool microscopy also revealed giardiasis and cryptosporidiosis in one patient each. Nine patients responded well to ivermectin and albendazole, one died and five were lost to follow-up. CONCLUSIONS: In endemic areas, even immunocompetent subjects may suffer from symptomatic strongyloidiasis and associated eosinophilia is uncommon. PMID- 23025062 TI - Percutaneous transhepatic hepaticogastrostomy for portal biliopathy: a novel approach. PMID- 23025063 TI - Segmental ileal dilatation: an unsuspected cause of neonatal intestinal obstruction. PMID- 23025064 TI - Cryptococcal meningitis in a patient with hepatitis C virus related decompensated cirrhosis: coincidental or immunologically related? PMID- 23025065 TI - Laparoscopic non-resectional management of grade III isolated pancreatic injury. PMID- 23025066 TI - Endoscopically diagnosed fistula between hepatic artery and first part of duodenum as a cause of massive upper gastrointestinal hemorrhage. PMID- 23025067 TI - Spontaneous perforation of bile duct. PMID- 23025068 TI - Splenic rupture mimicking dengue shock syndrome. PMID- 23025069 TI - A rare case of gallbladder carcinoma metastases to the breast treated with curative intent. PMID- 23025070 TI - Adenoendocrinecarcinoma of gallbladder in a patient with primary sclerosing cholangitis and ulcerative colitis. PMID- 23025071 TI - Revision shunt for Budd-Chiari syndrome. PMID- 23025072 TI - Demography of zooplankton (Anuraeopsis fissa, Brachionus rubens and Moina macrocopa) fed Chlorella vulgaris and Scenedesmus acutus cultured on different media. AB - Generally zooplankton growth is often limited by the quality of their algal diet. A cheaper common practice in aquaculture, is to culture algae with fertilizers; however, the demography of zooplankton when fed these algae has not yet been evaluated. We studied the population growth and life table demography of the rotifers Anuraeopsis fissa and Brachionus rubens, and the cladoceran Moina macrocopa. For this, the algae Scenedesmus acutus or Chlorella vulgaris were cultured on defined (Bold's basal) medium or the commercial liquid fertilizer (Bayfolan). Experiments were conducted at one algal concentration 1.0 x 10(6) cells/mL of C. vulgaris or its equivalent dry weight of 0.5 x 10(6) cells/mL of S. acutus. The population dynamics were tested at 23 +/- 1 degrees C in 100 mL transparent jars, each with 50mL of the test medium, with an initial density of 0.5indiv/mL, for a total of 48 test jars (3 zooplankton 2 algal species x 2 culture media x 4 replicates). For the life table experiments with M. macrocopa, we introduced 10 neonates (<24h old) into each test jar containing the specific algal type and concentration. For the rotifer experiments, we set 5mL tubes with one neonate each and 10 replicates for each algal species and culture medium. We found that the average rotifer life span was not influenced by the diet, but for M. macrocopa fed S. acutus cultured in Bold's medium, the average lifespan was significantly lower than with the other diets. The gross and net reproductive rates of A. fissa (ranging from 18-36 offspring per female) were significantly higher for C vulgaris cultured in Bold medium. Regardless of the culture medium, Chlorella resulted in significantly higher gross and net reproductive rates for B. rubens than S. acutus diets. The reproductive rates of M. macrocopa were significantly higher in all the tested diets except when fed with S. acutus in Bold medium. The population increase rate, derived from growth experiments of A. fissa and B. rubens, ranged from 0.1-0.25/d and were significantly higher on C vulgaris cultured in liquid fertilizer as compared to the other diets. The growth rates of M. macrocopa ranged from 0.1 to 0.38/d, and were highest with diets of C. vulgaris cultured in Bold medium and S. acutus cultured in fertilizer. Thus, regardless of the culture medium used, the growth rates of the evaluated zooplankton species were higher with Chlorella than with Scenedesmus. The peak population density was highest (2 800ind/mL) for A. fissa fed Chlorella that was cultured on liquid fertilizers, while B. rubens and M. macrocopa had peak abundances of 480 and 12ind/mL, respectively under similar conditions. PMID- 23025073 TI - Limnology in El Dorado: some surprising aspects of the regulation of phytoplankton productive capacity in a high-altitude Andean lake (Laguna de Guatavita, Colombia). AB - High-altitude mountain lakes remain understudied, mostly because of their relative inaccessibility. Laguna de Guatavita, a small, equatorial, high-altitude crater lake in the Eastern Range of the Colombian Andes, was once of high cultural importance to pre-Columban inhabitants, the original location of the legendary El Dorado. We investigated the factors regulating the primary production in Laguna de Guatavita (4degrees58'50" N - 73degrees46'43" W, alt. 2 935m.a.s.l., area: 0.11km2, maximum depth: 30m), during a series of three intensive field campaigns, which were conducted over a year-long period in 2003 2004. In each, standard profiles of temperature, oxygen concentration and light intensity were determined on each of 16-18 consecutive days. Samples were collected and analysed for chlorophyll and for biologically-significant solutes in GF/F-filtered water (NH4+, NO3(-), NO2(-); soluble reactive phosphorus). Primary production was also determined, by oxygen generation, on each day of the campaign. Our results showed that the productive potential of the lake was typically modest (campaign averages of 45-90mg C/m2.h) but that many of the regulating factors were not those anticipated intuitively. The lake is demonstrably meromictic, reminiscent ofkarstic dolines in higher latitudes, its stratification being maintained by solute- concentration gradients. Light penetration is poor, attributable to the turbidity owing to fine calcite and other particulates in suspension. Net primary production in the mixolimnion of Laguna de Guavita is sensitive to day-to-day variations in solar irradiance at the surface. However, deficiencies in nutrient availability, especially nitrogen, also constrain the capacity of the lake to support a phytoplankton. We deduced that Laguna de Guatavita is something of a limnological enigma, atypical of the common anticipation of a "mountain lake". While doubtlessly not unique, comparable descriptions of similar sites elsewhere are sufficiently rare to justify the presentation of the data from Laguna de Guatavita that our studies have revealed so far. PMID- 23025074 TI - [Stony coral recruitment in coral reefs at different distances from pollution sources in Habana, Cuba]. AB - The effect of pollution on coral recruitment has been insufficiently studied. This research deals with coral recruitment in coastal areas and aimed to determine the variations of density and dominant species of corals recruits in sites at different distances from pollution sources. The composition and structure of stony coral (scleractinian and milleporids) recruit associations were characterized in the fringing reef of Western Havana, Cuba. This reef is influenced by urban pollution from the Almendares River and a sewage outlet located at its mouth. Four sites were sampled on the upper fore reef escarpment at 10m deep every three months between July 2007 and May 2008. A 25cm side quadrat was used to determine the density and taxonomic composition of recruits smaller than 3cm in diameter. Sampling units were placed following a random systematic pattern. The mean density of recruits was determined both at assemble and species level. Bifactoral ANOVA tests were applied to compare mean densities at both sampling sites and dates. Student-Newman-Keuls test was applied to compare pairs of means. Cluster and nMDS analyses were applied to evaluate between site similarities. The predominant species was Siderastrea siderea followed by S. radians and Porites astreoides. Recruit densities were similar among La Puntilla, Calle 16 and Acuario sites. Lower densities were always found in Malec6n. Significant differences in mean stony recruit densities were found both between sites and sampling dates. The statistic analysis did not show significant spatial-temporal interactions. Malec6n, the most polluted site, showed the lowest recruit density and the greater presence of species considered as indicators of organic pollution, sedimentation and abrasion. The density of recruit species was higher in October 2007 and lower in May 2008, and it was apparently influenced by reproduction and cold front seasons, respectively. The higher dominance and abundance of S. siderea, S. radians and P. astreoides recruits were apparently due to their high reproductive potential and resistance to disturbances. The identity of dominant species was apparently related to distance from major pollution sources. We highly recommended the replication of this research in other areas of the greater Caribbean region to test the generality of present results and to compare among areas. Future research should take into account the influence of other environmental factors, along with an appraisal of recruit species tolerance to these factors, to better ponder the effect of urban pollution on recruitment. Areas with well assessed pollution regimes are recommended for research. PMID- 23025075 TI - The relationship between physical and biological habitat conditions and hermatypic coral recruits abundance within insular reefs (Colombian Caribbean). AB - Little evidence exists on the dependence between the presence and abundance of juvenile hermatypic corals and the conditions of their habitats, despite that juveniles contribute with the understanding of the community structure and its reproductive success. To assess this, the abundance of nine species of juvenile corals was correlated with eight macro-habitat (location of the reef on shelf, depth) and micro-habitat (type and inclination of the substrate, exposure to light, texture and amount of sediment accumulated on bottom, potential growth area for juveniles) conditions. Sampling was conducted in four insular coral reefs in the Colombian Caribbean: two oceanic and two continental reefs (influenced by large rivers), covering a total of 600m2 and the distribution of corals on a vertical gradient. Contingency tables and coefficients (magnitude) and multiple correspondence analyses were used to evaluate the dependency ratios for each species. The results showed that Agaricia tenuifolia displayed the most robust pattern of dependence (two high and two moderate), significant for juveniles present at a high frequency in continental reefs, devoid of potential area for juvenile growth (surrounded by macroalgae), and covering horizontal substrates exposed to light. The juveniles were associated with a habitat of moderate to high bottom accumulation of extremely fine sediment. Porites astreoides presented four moderate dependencies; ocean reefs between 2-16m depths, a high frequency of juveniles on horizontal substrates, exposed to light, non-sedimented and occupied by competitors. Siderastrea siderea displayed three moderate dependences for juveniles in cryptic zones, inclined substrate and devoid of competitors. A. lamarcki, Leptoseris cucullata and A. agaricites presented two moderate dependences; these species share high abundance of juveniles in habitats with no sediment, exposed to light and occupied by competitors (except A. agaricites). The P. porites, Favia fragum and Montastraea cavernosa species had a moderate dependence with high incidence of juveniles in ocean reefs and microhabitats exposed to light. For the nine species, results indicate that the presence (colonization), abundance and survival of juveniles, depend on certain species-specific particularities of the habitat. However, the juveniles show high tolerance and plasticity to a range of habitat variables, given their independence and low dependence observed in over 50% of the variables assessed. PMID- 23025076 TI - Testing aggregation hypotheses among Neotropical trees and shrubs: results from a 50-ha plot over 20 years of sampling. AB - Spatial patterns of tropical trees and shrubs are important to understanding their interaction and the resultant structure of tropical rainforests. To assess this issue, we took advantage of previously collected data, on Neotropical tree and shrub stem identified to species and mapped for spatial coordinates in a 50ha plot, with a frequency of every five years and over a 20 year period. These stems data were first placed into four groups, regardless of species, depending on their location in the vertical strata of the rainforest (shrubs, understory trees, mid-sized trees, tall trees) and then used to generate aggregation patterns for each sampling year. We found shrubs and understory trees clumped at small spatial scales of a few meters for several of the years sampled. Alternatively, mid-sized trees and tall trees did not clump, nor did they show uniform (regular) patterns, during any sampling period. In general (1) groups found higher in the canopy did not show aggregation on the ground and (2) the spatial patterns of all four groups showed similarity among different sampling years, thereby supporting a "shifting mosaic" view of plant communities over large areas. Spatial analysis, such as this one, are critical to understanding and predicting tree spaces, tree-tree replacements and the Neotropical forest patterns, such as biodiversity and those needed for sustainability efforts, they produce. PMID- 23025077 TI - Who is who in the understory: the contribution of resident and transitory groups of species to plant richness in forest assemblages. AB - The forest understory is made up of resident and transitory species and can be much richer than the canopy. With the purpose to describe the contribution of these groups to the woody understory, five Atlantic Forest fragments were selected and studied in Northeastern Brazil. In order to analyze the understory's structure, the sample included woody individuals with circumference at breast height (CBH) smaller than 15cm and circumference at ground level (CGL) greater than 3cm, regardless of height. The recorded species were quantified and classified into functional stratification categories (resident and transitory), and the floristic similarity between the understory and the tree stratum was calculated. Species' importance in the understory was analyzed by height and total natural regeneration classes based on a regeneration index. The understory was richer in species (median=63.8, SD=21.72, n=5 fragments) than the tree stratum (43.8, 18.14, 5), and the similarity between these components was relatively high (median=0.54, SD=0.09). The results also showed that the studied understory in the forest fragments was mainly composed by transitory species (median=67.01%, SD=3.76), that were well distributed among height classes and had the highest densities, which may favor their future presence in the canopy's structure and composition. The typical understory species were grouped into two strata: the lower understory, made up of species that generally do not reach more than 4m in height (mostly species from families Piperaceae, Rubiaceae and Melastomataceae); and the upper understory, with intermediate heights between the lower understory and the canopy, but with average heights that were not higher than 10m (mainly of species from families Anonnaceae, Clusiaceae and Myrtaceae). These families' richness was commonly used as an indicator of the vegetation's successional stage; however, such results must be seen with caution as they show that these families co-occurred and were highly important in different strata. Studying the understory is fundamental because it represents a floristically rich stratum with a unique structure, which promotes the natural regeneration of the tree stratum. PMID- 23025078 TI - Dynamics of leaf litter humidity, depth and quantity: two restoration strategies failed to mimic ground microhabitat conditions of a low montane and premontane forest in Costa Rica. AB - Little is known about how restoration strategies affect aspects like leaf litter's quantity, depth and humidity. I analyzed leaf litter's quantity, depth and humidity yearly patterns in a primary tropical lower montane wet forest and two restored areas: a 15 year old secondary forest (unassisted restoration) and a 40 year old Cupressus lusitanica plantation (natural understory). The three habitats are located in the Rio Macho Forest Reserve, Costa Rica. Twenty litter samples were taken every three months (April 2009-April 2010) in each habitat; humidity was measured in 439g samples (average), depth and quantity were measured in five points inside 50x50cm plots. None of the restoration strategies reproduced the primary forest leaf litter humidity, depth and quantity yearly patterns. Primary forest leaf litter humidity was higher and more stable (mean=73.2), followed by secondary forest (mean=63.3) and cypress plantation (mean=52.9) (Kruskall-Wallis=77.93, n=232, p=0.00). In the primary (Kruskal Wallis=31.63, n=78, p<0.001) and secondary (Kruskal-Wallis=11.79, n=75, p=0.008) forest litter accumulation was higher during April due to strong winds. In the primary forest (Kruskal-wallis=21.83, n=78, p<0.001) and the cypress plantation (Kruskal-wallis=39.99, n=80, p<0.001) leaf litter depth was shallow in October because heavy rains compacted it. Depth patterns were different from quantity patterns and described the leaf litter's structure in different ecosystems though the year. September 01. PMID- 23025079 TI - [The effect of chromium removal by algae-bacteria Bostrychia calliptera (Rhodomelaceae) consortia under laboratory conditions]. AB - Water pollution is one of the most important environmental problems worldwide. Recently, biotechnology studies have oriented efforts to study algae-bacterium consortia with the aim to understand the mechanisms to find a possible solution in environmental sciences. This study determined the percentage of chromium removal by the alga-bacterium association exposed to a set of different chromium concentrations under controlled in vitro conditions. Wild plants of Bostrychia calliptera associated with bacterial populations were collected from Dagua River, Pacific coast of Colombia, and were monitored in the laboratory. The trial was conducted with synthetic seawater in bioreactors at two chromium levels: 5 and 10mg/L, and four different experimental treatments: i) algae-bacteria (AB), ii) algae with antibiotic (AA), iii) algal surface sediment, Natural Bacterial Consortium (CBN), and iv) the control without algae or bacteria. The experimental design followed a model of two factors (chromium concentration x combination types) with repeated measures using one factor. The microbial population behavior and the chromium concentration percentage were monitored by using atomic absorption spectroscopy (AAS). According to the data, Algae-bacteria (AB) treatment was the most efficient combination at 10mg/L (87%), whereas the bacterial consortia (CBN) was the most efficient at 5mg/L (62.85%). The results showed significant differences of chromium uptake between algae-bacteria (AB) and natural bacterial consortia (CBN), meaning the importance of those treatments in the chromium removal from coastal waters. PMID- 23025080 TI - Differential effects of land use on ant and herbivore insect communities associated with Caryocar brasiliense (Caryocaraceae). AB - Simplification of natural habitats leads to a modification of the community associated with a host plant. Pequi trees (Caryocar brasiliense) are common to find in central Brazil, especially in the middle of monocultures, such as soy, corn, pasturelands or Eucalyptus plantations. On this scenario we hypothesized that habitat modification differentially affects the diversity of ants and herbivore insects associated with this species. The aim of the work was to test if C. brasiliense trees located in human modified habitats, support a lower species richness and abundance of ants, and a greater species richness and abundance of insect herbivores, compared to preserved cerrado habitats. The study was conducted in a Cerrado area located in Northern Minas Gerais State, Brazil. Ants and herbivore insects were collected monthly during 2005 using beating technique. The results showed that ant species richness was higher in pequi trees located in preserved Cerrado, followed by trees in pastureland and Eucalyptus plantation, respectively. The ant abundance was lower in the Eucalyptus plantation but no difference in ant abundance was observed between trees in pastureland and the preserved Cerrado. Moreover, herbivore insects exhibited lower number of species and individuals in trees located in the preserved Cerrado than in the pastureland and Eucalyptus plantation. We concluded that habitats simplified by human activities may result in diversity loss and may change species interactions. PMID- 23025081 TI - [Filamentous and phosphate solubilizing fungi relationships with some edaphic parameters and coffee plantations management]. AB - Soil properties and the environment have multiple outcomes on fungal communities. Although, the interaction effects between management intensity, pH, available phosphorus, organic carbon, soil texture and different fractions of water stable macro-aggregates on the communities of microscopic filamentous fungi (MFF), iron phosphate solubilizing fungi (PSF-Fe), and iron and calcium phosphate solubilizing fungi (PSF-(Fe+Ca)), have been previously evaluated in field conditions, this has never been performed in terms of their combined effects, neither with phosphate solubilizing fungi. To assess this, we collected 40 composite soil samples from eight Mexican and Colombian coffee plantations, with different management intensities and physico-chemical edaphic parameters, during 2008-2009. We isolated different communities of MFF, PSF-Fe and PSF-(Fe+Ca), by wet sieving and soil particles culture in Potato-Dextrose-Agar from soil samples, and we classified isolates in terms of their phosphate solubilizing ability. Following the principal component analysis results, we decided to analyze fungal communities and abiotic factors interactions for each country separately. Structural Equation Models revealed that organic carbon was positively associated to MFF richness and number of isolates (lambda>0.58), but its relationship with PSF-Fe and PSF-(Fe+Ca) were variable; while the available phosphorus, pH and water stable macro-aggregate fractions did not show a clear pattern. Management intensity was negatively related to PSF-Fe (lambda < or = -0.21) morphotype richness and the number of isolates in Colombian coffee plantations. We found that the relationships of clay and organic carbon content, and available phosphorus and soil pH, with the species richness and number of isolates of MFF, PSF-Fe and PSF-(Fe+Ca) were highly variable; this made impossible to generalize the responses between saprotrophic fungal groups and geographic zones. The management intensity was not related to species richness and number of isolates of MFF in any coffee areas, while for PSF the relationship could not be defined. The different water stable macro-aggregates fractions did not show a defined pattern in relation to the species richness and the number of isolates of saprophytic and phosphate solubilizing fungi (PSF). This study highlights the need to take into account edaphic and geographic context in order to reach a better understanding of the intensity management effects on MFF and PSF function in agroecosystems. PMID- 23025082 TI - Chemical and genetic diversity among some wild stands of Calligonum polygonoides (Polygonaceae) from the Thar Desert of Rajasthan. AB - The arid Western Rajasthan, where the Thar Desert of India is immersed, is mostly covered by sand dunes, a common landscape. The region has confronted with fragilities of natural resources, low, erratic and ill-distributed rainfall, and is covered up with many perennial hardy shrubs. Calligonumpolygonoides, the most common perennial shrub, is widely present in some localities of this Thar Desert. In this study, we evaluated the diversity present among 54 wild Calligonum polygonoides plants, sampled from eight different locations within the Thar Desert. Our methods included chemical/nutritional characteristics and random amplified polymorphic DNA (RAPD). Both chemical and molecular methods produced wider range of diversity, however, RAPD detected comparatively more diversity. A total of 163 band positions were produced by ten RAPD primers, of which 147 were found polymorphic with 90.18% polymorphism. RAPD-based Jaccard's similarity coefficients ranged from 0.43-0.89. The analysis of various chemical and mineral constituents revealed that phog is an excellent source of calcium, potassium and phosphorous while relatively poor in zinc. Among minerals, average potassium content was found maximum (2 430mg/100g) with 0.14 CV. Zinc was observed comparably less in quantity while highest variable with CV 0.73. The chemical based Manhattan dissimilarity coefficient values ranged from 0.01-0.22 with an average of 0.12. The comparison of the clusters obtained based on the chemical and mineral parameters with those of the RAPD data showed that the groups formed in both cases showed different patterns of relationships among the samples. Broader range of diversity might be due to the out breeding behavior of C. polygonoides and indicates the good adaptability of the plants in the region studied. However, low diversity observed in the Bikaner province is alarming and suggests that anthropogenic activities leading to heavy population disturbances can affect the genetic composition of the species in a considerable way. PMID- 23025083 TI - [Seasonal micronutrients concentration in leaves of four forest species from Parque Chaqueno, Argentina]. AB - Nutrients cycling is a fundamental component in the functioning of forest ecosystems. Leaves of different forest species observe specific chemical composition, and some seasonal differences in biomass production, may be related to climate fluctuations and/or changes in plant phenology and the variation on nutrient contents. The objective of this study was to analyze the seasonal variability ofFe, Mn, Cu and Zn concentrations in leaves of Gleditsia amorphoides (Ga); Patagonula americana (Pa); Maclura tinctoria (Mt) and Astronium balansae (Ab) from Colonia Benitez Strict Nature Reserve (Chaco, Argentina). The leaves of each forest species were collected monthly, dried at 70 degrees C and their weight by tree species were recorded. Samples for analytical determinations were prepared by humid oxidation of organic substances from vegetal nets, using oxidant acids such as ternary mixture of HNO3-H2SO4-HClO4. After digestion, total micronutrients leaves concentrations were determined by atomic absortion spectrophotometry. Leaves Fe highest values were detected during fall in Mt (76.1mg/kg), Pa (75.2mg/kg), Ab (59.5mg/kg) and Ga (45.3mg/kg). Highest foliar concentrations of Mn were detected in Pa (54.0mg/kg), Ga (50.0mg/kg), Mt (48.0mg/kg), and Ab with the lower Mn concentration (39.7mg/ kg). No significant differences were found for Cu between the different forest species, standing for Pa (11.3mg/ kg), Ga and Mt (11.0mg/kg) and Ab (10.4mg/kg). With regard to leaves Zn, highest concentrations were found in Mt (347.4mg/kg), Ga (319.9mg/kg), Pa (280.2mg/kg) and Ab (255.7mg/kg). Generally, a marked seasonal variation was observed for Mn and Cu concentrations (except in Ga) and Zn (except in Pa), with no statistical differences for Fe. In the species studied, the concentration of micronutrients analyzed showed a marked and erratic seasonal variation, attributed to the relationship established between the native species, and the strong influence of the environment over a long period of time, especially temperature and rainfall. PMID- 23025084 TI - [Growth modeling of Albizia niopoides (Mimosaceae) using dendrochronological methods]. AB - The annual growth rings in tropical trees are fairly common, but their study is relatively recent. Growth rings were found in trees of Albizia niopoides from the Porce River Canyon, Central Cordillera of the Colombian Andes. A total of 33 cross-sections were collected from trees distributed throughout the study area from 664-870masl. Cross-dating, spaguetti plot and 14C analyses were used to demonstrate ring annuality, assuming as hypothesis that these are real annual growth rings. A combination of descriptive analysis of time series (smoothing and pre-whitening) to filter climate noise and nonlinear regression with weighted residuals was used to fit the diameter to Korfs growth model, in which the coefficient of determination reaches values close to 100%. The positive residual autocorrelation of order 1, although not significant, is explained by the existence of energy reserves in the stem and by the accumulation of diameter increments required for the construction of the diameter growth model. The current and mean annual maximum increment rates are 1.03 and 0.94cm/year at ages 18 and 46 years old, respectively. These trees are classified within the group of fast growing species which can reach a cut diameter of over 50cm in approximately 52 years. PMID- 23025085 TI - Aerial organ anatomy of Smilax syphilitica (Smilacaceae). AB - Smilax L. in Brazil is represented by 32 taxa and it is a taxonomically difficult genus because the plants are dioecious and show wide phenotypic variation. The analysis and use of leaf anatomy characters is recognized as a frequently successful taxonomic method to distinguish between individual taxon, when floral material is absent or minute differences in flowers and foliage exist such as in Smilax. The aim of this study was to characterize the anatomical features of the aerial organs in Smilax syphilitica collected from the Atlantic Rainforest, in Santa Teresa-ES and the Smilax aff. syphilitica from the Amazon Rainforest, in Manaus, Brazil. For this, a total of three samples of Smilax were collected per site. Sample leaves and stems were fixed with FAA 50, embedded in historesin, sectioned on a rotary microtome, stained and mounted in synthetic resin. Additionally, histochemical tests were performed and cuticle ornamentation was analyzed with standard scanning electron microscopy. S. syphilitica and S. aff. syphilitica differed in cuticle ornamentation, epidermal cell arrangement and wall thickness, stomata type and orientation, calcium oxalate crystal type, and position of stem thorns. Leaf blades of S. syphilitica from the Amazon Rainforest have a network of rounded ridges on both sides, while in S. aff. syphilitica, these ridges are parallel and the spaces between them are filled with numerous membranous platelets. Viewed from the front, the epidermal cells of S. syphilitica have sinuous walls (even more pronounced in samples from the Amazon); while in S. aff. syphilitica, these cells are also sinuous but elongated in the cross-section of the blade and arranged in parallel. Stomata of S. syphilitica are paracytic, whereas in S. aff. syphilitica, are both paracytic and anisocytic, and their polar axes are directed towards the mid-vein. Calcium oxalate crystals in S. syphilitica are prisms, whereas in S. aff. syphilitica, crystal sand. Thorns occur in nodes and internodes in S. syphilitica but only in internodes in S. af. syphilitica. These features have proven to be of diagnostic value and may support a separation into two species, but future studies are needed to confirm that S. aff. syphilitica is indeed a new taxon. PMID- 23025086 TI - [Distribution, density and size structure of Oreaster reticulatus and Luidia senegalensis (Echinodermata: Asteroidea) in Cubagua Island, Venezuela]. AB - There is limited biological information about the starfish Oreaster reticulatus and the nine-armed starfish Luidia senegalensis in Venezuelan waters. These species are currently considered threatened in many localities of the Caribbean, Brazil and Colombia. Therefore, the aim of this study was to describe their population density, size distribution and population structure in Cubagua Island. During 2008, 52 stations located around the island were evaluated using band transects of 50m2. Each organism was counted and measured (maximum radius), and its size was compared to the maturity length reported in the literature. The results for O. reticulatus include: 167.3ind./ha; 33% juveniles and 67% adults; average size of 10.7 +/- 5cm (range: 2.2-21cm); a wide distribution around the island, with higher densities in the Eastern and Southwest areas. The 50% of the specimens were found in seagrass beds, 25% in sand, 16% in areas covered by decomposed seaweeds, 9% in oyster beds and 1% coralline patches. The densities of O. reticulatus were higher than those reported in the Caribbean, Panama and Puerto Rico, but lower than Venezuelan National Parks: Mochima and Morrocoy; as well as in the Virgin Islands and Belize. For L. senegalensis we found an average density of 40ind./ha; 95% exceeded the reported size at maturity, with mean length of 12cm +/- 3.5cm (range: 3.5-22.3cm); they were found only in 15% of the stations of which 92.5% were sandy bottoms and the other 7.5% oyster beds. The degree of aggregation of L. senegalensis was greater than O. reticulatus, with an estimated k of 0.06. However, it was not possible to compare the densities of L. senegalensis with any other study. For both species is recommended to carry out reproductive studies and to monitor their population densities to infer temporal variations. PMID- 23025087 TI - Faunistic analysis of the caridean shrimps inhabiting seagrasses along the NW coast of the Gulf of Mexico and Caribbean Sea. AB - Seagrass meadows are highly productive and ecologically important habitats in estuaries and coastal lagoons, and contain a variety of faunal communities, from which the caridean shrimps are a dominant component. The purpose of this work was to analyze the environmental parameters of water and sediments, with the biological components in seagrass epifaunal communities, from the Western Gulf of Mexico and the Caribbean Sea. For this, density and diversity of caridean shrimps were analyzed and correlated with environmental parameters and seagrass biomass, and zoogeographic affinities were determined. The spatial distribution of caridean shrimps was recorded for 12 localities with Halodule wrightii and Thalassia testudinum monospecific seagrass meadows. A total of 72158 individuals of 16 taxa were collected. Among results, the Hippolytidae resulted the most abundant group (92.3%) with eight species, and was followed by Palaemonidae with 7.6% of the abundance and seven species, and the Alpheidae with only one genus. From the total of collected carideans, a 37.3% was found in H. wrightii and 62.7% in T. testudinum. The dominant species were Hippolyte zostericola (12.39ind./m2), Tozeuma carolinense (9.5ind./m2), Thor dobkini (4.84ind./m2) and Palaemonetes vulgaris (4.87ind./m2). The zoogeographic distribution of the carideans presented two groups: species of the Virginian-Carolinean province representing its Southern limit (43.75%) and species of the Brazilian-Caribbean province representing its Northern limit (56.25%). The species H. zostericola, T. carolinense, P. vulgaris, P. pugio and P. intermedius are widely distributed along the Western Atlantic coast. This study has base line information for seagrass habitats, the community of epifaunal carideans and their ecological affinities, previous to the oil spill in the Gulf of Mexico. PMID- 23025088 TI - [Spatial distribution of Ocypode quadrata (Decapoda: Ocypodidae) in eight beaches of North-Eastern Cuba]. AB - Studies on the ecology of Ocypode quadrata have been mostly carried out in the Northern and Southern part of its distribution range. In despite that this species is common in Cuban beaches, there are no quantitative studies regarding its abundance and spatial distribution. The aim of this study was to report some aspects about the spatial variation of O. quadrata density in sandy beaches, with different levels of human influence, in the North coast of Eastern Cuba. For this, on May 2010, eight beaches with different levels of human influence were surveyed. On each beach, the number of crabs burrows were counted in 45 quadrats of 4m2 located in three different strata (P1, P2 and P3). According to burrow opening diameter, crabs were separated into young and adults forms. To determine the existence of statistical differences in the density of crab burrows among beaches and strata, a two-way ANOVA was developed with a Scheffe-procedure post hoc test. A total of 355 burrows were counted in 360 sample units. The composition by size classes was 237 burrows for young and 118 for adults. From the total of burrows, 74% were located in P1, 20% in P2 and 6% in P3. The higher concentration of burrows was found at Jiguani beach (0.52 +/- 0.08 burrows/m2) while the lesser concentration was found at Estero Ciego beach (0.06 +/- 0.01 burrows/m2). Most of the beaches did not present significant differences in the burrows density (Scheffe, p>0.05), according to ANOVA results, in despite their different human influence level. Density of individuals was significantly higher in the upper intertidal (P1) areas (Scheffe, p<0.05) with predominance of young crabs. Total density diminished in P2 and P3 strata where a predominance of adult individuals was observed. The interaction term of beach and strata evidenced that the pattern of variation among strata was not the same for all beaches. The general pattern of adults and young specimen spatial distribution in the beaches was very similar to those reported in the literature. In the present study, the first conducted in Cuban beaches, we did not find evidence of direct relationship between the level of human impact and the density of ghost crab burrows. PMID- 23025089 TI - A new species of Urocopitid land snail from Haiti and a discussion of the genus Autocoptis (Gastropoda: Urocoptidae). AB - Autocoptis paulsoni n. sp. is described from Haiti. It is characterized by its large size, its cylindrical-tapered shape, its fine costate sculpture on the teleoconch, a distinct but weak circum basal keel and its abbreviate conical juvenile shell. It is most similar to Autocoptis gruneri (Dunker 1844), which is redescribed, and its distribution is reviewed. The taxonomic status of the genus Autocoptis Pilsbry 1902 and its subgenus Urocoptola Clench, 1 935 are reviewed. The genus is endemic to Hispaniola and satellite islands. PMID- 23025090 TI - Defense response of susceptible and resistant Biomphalaria alexandrina snails against Schistosoma mansoni infection. AB - In Egypt, Biomphalaria alexandrina is the intermediate host for Schistosoma mansoni. The fates of Schistosoma miracidia in the snails varies between different species of Biomphalaria. The internal defense system is one of the factors that influence the susceptibility pattern of the snails. The interaction between Biomphalaria snails and S. mansoni needs to be identified for each species, and even between the members of the same species with different degrees of susceptibility. In the present study, the first generation of susceptible and resistant parents of B. alexandrina was examined histologically at the 30th day post exposure. The study includes the characterization of the immune response, as expressed by tissue reactions, of susceptible and resistant B. alexandrina snails against S. mansoni. It was also designed to determine the impact of the resistance increase in parent snails, on the mechanisms of interaction of their offspring against infection. The results showed that the infection rate of the offspring from the susceptible parents was 92%. No susceptible offspring was produced from the resistant parents. When the parents were of equal number of susceptible and resistant snails, they gave an offspring with an infection rate of 20%. Susceptible snails that had susceptible parents showed a higher degree of susceptibility than those that had both susceptible and resistant parents. A common feature of the resistant snails was the absence of any viable parasites. The tissue reactions of the resistant snails having only resistant parents occurred at the site of miracidial penetration. In resistant snails for which susceptible ones were included in their parents, the reactions occurred in the deep tissues. These results characterized the immune response of B. alexandrina snails against Schistosoma infection which was found to occur by two different mechanisms. One type of defense occurs in highly resistant snails, and employs direct miracidial destruction soon after parasite penetration. The other type occurs in less resistant snails where a delayed resistance development occurs after the dissemination of the sporocysts in the snail tissues. It seems that B. alexandrina snails respond more or less similar to B. glabrata. The results also proved that the immune response of the internal defense system increased with increasing the number of the inherited resistant genes. PMID- 23025091 TI - [Population structure of Polythore gigantea (Odonata: Polythoridae) in lotic systems with different conservation states in Antioquia-Colombia]. AB - The knowledge about population structure and dynamics of some neotropical species, especially those living in lotic systems is still barely studied. This study had the aim to assess if the conservation status of some lotic systems, is related to some demographic variables of P. gigantea, so this may be used as a model for ecological monitoring. For this, we evaluated the population structure of P. gigantea three times per month (almost one sampling event every eight days) in four streams of the state of Antioquia, Colombia, from March-June 2009. The specimens were collected using entomological nets along a transect of 200m in the littoral zone of each stream. The insects were marked on the wings and the population size was estimated with the mark-recapture method. Our results showed that the largest population size was recorded for the stream "La Catedral" with aprox 299 individuals, followed by the stream "La Doctora" with 218 individuals. Nevertheless, no significant differences in population size among the evaluated streams were found; and no statistical relationships were found between vegetation variables and the population size of P. gigantea. However, taking into account the limited dispersal capacity of P. gigantea, its survival in the studied streams was considered to be at risk, due to the continuous modification of large riparian forest areas, which cause the increase of forest patches, with different levels of interconnection, and hinder long-term permanence of populations. PMID- 23025092 TI - [Bioecological characteristics of earthworm populations (Oligochaeta: Glossoscolecidae) in a natural and a protected savanna in the central Llanos of Venezuela]. AB - In tropical savannas, the earthworm communities have a predominant role since they regulate the soil structure and dynamics of the organic matter. To study the effect on earthworm populations in two differently managed savannas, we compared the general aspects of the biology and ecology of earthworm populations from a 40 years protected savanna (SP) with no fire or cattle raising at the Estaci6n Biol6gica de los Llanos, Venezuela (EBLL), and a natural savanna (SNI), under normal burning and cattle raising management conditions. Sampling was carried out at the end of the dry season (April), and at the peak of the wet season (July August). The main physical properties of soils per system were estimated. In each system, in plots of 90x90m, five fixed sampling units were selected at random; and at each sampling point one soil monolith of 25x25x30cm was collected per unit. Earthworms were extracted using the hand sorting extraction method; and the flotation method was used to estimate the density of cocoons. The earthworms were classified in different ecological categories considering their pigmentation, size and depth profile distribution. As a result of the savanna protection, physical parameters were modified in relation to SNI. The SP soils had higher soil moisture when compared to SNI. Soil moisture varied with depth during the dry season since, after the start of the rainy season, the soil was saturated. Field capacity in the SP was greater than that in the SNI. The surface apparent bulk density of soil was lower in the SP respect SNI, reflecting a lower soil compaction. Total average for the density and biomass of earthworms differed greatly, showing higher values in the SP. The earthworm density average in SP ranged between 25.6-85 individuals/m2 and the average biomass between 6.92 23.23g/m2. While in SNI, earthworms were only found in August, with a mean density of 22.40individuals/m2 and a mean biomass of 5.17g/m2. The vertical distribution pattern was only analyzed for the SP, and as in the SNI, no earthworms were found during the dry season; in the SP, a migration of earthworms to deeper layers during the dry season was observed; while in the rainy season they moved to upper soil layers to feed. The systems were characterized by abundance in juvenile Glossoscolecidae family earthworms which might be included in the endo-anecic ecological category. Results suggest that savanna agricultural management can modify an important fraction of pedofauna, particularly their earthworm communities, by modification of soil properties. PMID- 23025093 TI - Selection of perching site background color by Hamadryas feronia (Lepidoptera: Nymphalidae) in Costa Rica: implications for industrial melanism. AB - Observations of the increased frequency of melanic forms in moths of the genus Biston in Great Britain after the industrial revolution lead to the development of the theory of Industrial Melanism. Nonetheless, arguments against that interpretation of the experimental evidence have polarized acceptance of the concept. New evidence based on diurnal butterflies is more credible because it involves behavior that can be seen in action, during daylight, and because the natural history of the selected species is well known. An experiment was carried out in which three substrate colors (white, black, and gray) were employed to test the landing preferences of Hamadryas feronia. A marked preference was observed for landing on white and gray, and a chi-square (N=644 tests) showed evidence of a preference by males to land on white, and for females to land on gray. Black was rejected perhaps because it provides very little background matching with the butterfly's colors. The butterfly habit of perching selectively on particular color substrates is a genetically fixed behavior, where the males possibly choose white as a tactic to be noticed by females and attract them, whereas females prefer gray to enhance crypsis and avoid attracting predators. PMID- 23025094 TI - [Approach to Spodoptera (Lepidoptera: Noctuidae) phylogeny based on the sequence of the cytocrhome oxydase I (COI) mitochondrial gene]. AB - The genus Spodoptera includes 30 species of moths considered important pests worldwide, with a great representation in the Western Hemisphere. In general, Noctuidae species have morphological similarities that have caused some difficulties for assertive species identification by conventional methods. The purpose of this work was to generate an approach to the genus phylogeny from several species of the genus Spodoptera and the species Bombyx mori as an out group, with the use of molecular tools. For this, a total of 102 S. frugiperda larvae were obtained at random in corn, cotton, rice, grass and sorghum, during late 2006 and early 2009, from Colombia. We took ADN samples from the larval posterior part and we analyzed a fragment of 451 base pairs of the mitochondrial gene cytochrome oxydase I (COI), to produce a maximum likelihood (ML) tree by using 62 sequences (29 Colombian haplotypes were used). Our results showed a great genetic differentiation (K2 distances) amongst S. frugiperda haplotypes from Colombia and the United States, condition supported by the estimators obtained for haplotype diversity and polymorphism. The obtained ML tree clustered most of the species with bootstrapping values from 73-99% in the interior branches; with low values also observed in some of the branches. In addition, this tree clustered two species of the Eastern hemisphere (S littoralis and S. litura) and eight species of the Western hemisphere (S. androgea, S. dolichos, S. eridania, S. exigua, S. frugiperda, S. latifascia, S. ornithogalli and S. pulchella). In Colombia, S. frugiperda, S. ornithogalli and S. albula represent a group of species referred as "the Spodoptera complex" of cotton crops, and our work demonstrated that sequencing a fragment of the COI gene, allows researchers to differentiate the first two species, and thus it can be used as an alternative method to taxonomic keys based on morphology. Finally, the ML tree did not cluster S. frugiperda with S. ornithogalli, suggesting that both species do not share the same recent ancestral even though they coexist in cotton. We suggest sequencing other genes (mitochondrial and nuclear) to increase our understanding of this genus evolution. PMID- 23025095 TI - [Geometric wing morphometrics for Chrysomya albiceps and C. megacephala identification (Diptera: Calliphoridae) from Venezuela]. AB - Calliphoridae is one of the families with the greatest number of species with forensic importance, which immature stages feed and develop on decaying material. In Venezuela, there are few studies on this taxon reporting the dominance of Chrysomya over other carrion flies. The goal of this study was to analyze the variations on wing morphometrics, to support the identification of two forensic flies. For this we photographed a total of 168 wings from C. albiceps (n=111) and C. megacephala (n=57). Landmark coordinate (x, y) configurations were registered and aligned by Generalized Procrustes Analysis. Principal Component Analysis and shape significance test based on Procrustes distance were implemented. Statistical analysis of variance found significant differences in wing isometric size (Kruskal-Wallis). The PCA showed the separation between species, and shape test showed significant differences (F Goodall's). The main differences between both species were localized on subcosta rupture, join of R(2+3) with wing border, join of dm-cu, and join of Cu with bm-cu, suggesting that wing morphometrics is a suitable tool in the discrimination of blowfly species. PMID- 23025096 TI - [Sexual behavior of Alpaida veniliae (Araneae: Araueidae)]. AB - Studies in transgenic soybean crops in Buenos Aires province, Argentina, revealed that Alpaida veniliae is one of the most abundant species in the guild of orb web spiders. This species is an effective natural enemy of insect pests affecting this crop. In the present study we carried out a descriptive and quantitative analysis of sexual behavior (courtship, mating and post-mating) of A. veniliae. The spiders were collected in transgenic soybean crops located in Chivilcoy (35 degrees 01' S - 60 degrees 06' W), Buenos Aires, Argentina, and reared under laboratory conditions. Based on observations of 20 couples (with virgin females), behavioral units of male and female in terms of postures and movements, including details on duration and frequency, were described at all stages of sexual activity (courtship, mating and post-mating). Courtship exhibited the greatest number and duration of behavioral units in both sexes. Male and female had a sequence of 16 and nine units, respectively, being the frequency of repetitions of the units significantly higher in the male. Mating was brief and males used a single palp to fill only one of the female spermathecae, after which the female became unreceptive. Mating had two behavioral units in the male and only one in the female. During post-mating males had three and females two behavioral units. The average duration of the whole sexual behavior was 541.90 +/- 123.1 seconds for the male and 338.20 +/- 74.1 seconds for the female. Alpaida veniliae females rarely accept a second mating with the same or another male (remating), indicating a strict monogamy. In 46% of observed mating, the female cannibalized the male after it. Females became unattractive after mating, since stop producing sex pheromones, causing a reduction of the male vibratory courtship. The high cost of courtship, including the risk of cannibalism, would reinforce the selectivity of males towards receptive virgin females. PMID- 23025097 TI - Fishery of the Green Jack Caranx caballus (Osteichytes: Carangidae) in Las Perlas Archipelago, Pacific Panama. AB - Green Jacks, Caranx caballus, are distributed along the Eastern Pacific coast. In Panama, C. caballus was heavily fished around Las Perlas Archipelago to sustain local markets until 2007, when the archipelago was declared a marine protected area. This first study in Panama, analyzed a sample of 4 990 individuals from Las Perlas, obtained monthly from June 2005 to June 2006, from landings at the central fish market. Average total length was 36.1 +/- 6.4cm and optimum length 38.9cm. Approximately 68% of fish lengths were within +/-10% of the optimal length but only six (15%) were considered mega-spawners. The von Bertalanffy parameters describe a long-lived and fast growing species, while mortality rates revealed that C. caballus is under high fishing pressure. Standard length at which half of the population is mature was 38.8cm, and the size at which individuals matured massively, 33cm. Only 10-13% of the fish were immature. C. caballus reproduces two to three times per year, with peaks in December, April, and probably September, and recruits to the population at least twice per year. Catch per unit effort (CPUE) was best predicted by minimum annual values of the Multivariate ENSO/LNSO Index (MEI) (R2=0.54). Results show that C. caballus in Pacific Panama is overfished. We recommend the raising of the minimum capture/landing size of this species in order to increase the proportion of mega spawners in the population and guarantee the sustainability of this resource. PMID- 23025098 TI - Heavy metal profile of water, sediment and freshwater cat fish, Chrysichthys nigrodigitatus (Siluriformes: Bagridae), of Cross River, Nigeria. AB - Cross River serves as a major source of drinking water, transportation, agricultural activities and fishing in Cross River State, Nigeria. Since there is no formal control of effluents discharged into the river, it is important to monitor the levels of metals contaminants in it, thus assessing its suitability for domestic and agricultural use. In order to determine this, three sampling stations designated as Ikom (Station I), Obubra Ogada (Station II) and Calabar (Station III) were randomly selected to study. For this, ten samples of the freshwater Silver Catfish (Chryshchythys nigrogitatus) (29.4-39.5cm SL, 310 510g), sediment and water were collected from each sampling Station from June 2009-June 2010. The heavy metals profiles ofZn, Cu, Fe, Co, Pb, Cd and Cr, in water, sediments and fish muscle were analyzed by atomic absorption spectrophotometry (AAS). In fish, the heavy metals concentration was found to be Cu>Fe>Zn>Cu>Pb>Cd>Co; the highest mean concentration of Copper (0.297 +/- 0.022 microg/g), Cadmium (0.011 +/- 0.007 microg/g), Iron (0.371 +/- 0.489 microg/g), Lead (0.008 +/- 0.008 microg/g), were determined for the fish. In water, the order was found to be Fe>Pb>Zn>Cu>Cr>Cd>Co; the highest mean concentration of Iron (0.009 +/- 0.00) microg/g), Copper (0.015 +/- 0.01 microg/g), Lead (0.0002 +/- 0.00 microg/g) Cadmium (0.0006 +/- 0.001 microg/g), Zinc (0.0036 +/- 0.003 microg/g), were observed in the surface water, respectively. The highest mean concentration of Copper (0.037 +/- 0.03 microg/g), Iron (0.053 +/- 0.04 microg/g), Lead (0.0002 +/- 0.00 microg/g), Cobalt (0.0002 +/- 0.00 microg/g), Cadmium (0.0006 +/- 0.001 microg/g) and Zinc (.009 +/- 0.0015 microg/g) was observed in the bottom water. In sediments, the concentration order found was Zn>Fe>Cu>Pb>Co>Cd; the highest mean concentration of 0.057 +/- 0.04 microg/g, 0.043 +/- 0.03 microg/g, 0.0006 +/- 0.00 microg/g, 0.0002 +/- 0.00 microg/g, 0.0009 +/- 0.00 microg/g, 0.099 +/- 0.00404 microg/g in Iron, Copper, Lead, Cobalt, Cadmium and Zinc were observed in the sediment, respectively; Chromium was not detected in the sediment for the whole sampling area. Most of the heavy metals were below the maximum allowable levels set by the WHO, FEPA and USEPA, except Zinc which mean concentration of 0.099 +/- 0.00404 microg/g was above the recommended limit of 0.0766 microg/g of USEPA in the sediment at Ikom. This implies that the waste assimilation capacity of the river is high, a phenomenon that could be ascribed to dilution, sedimentation and continuous water exchange. This is an indication that an urban and industrial waste discharged into the Cross River has a significant effect on the ecological balance of the river. Thus fish species from the Cross River harvested are safe for human consumption. PMID- 23025099 TI - [Reproductive behavior of Opistognathus rosenblatti (Perciformes: Opistognathidae) in captivity]. AB - The Blue Spotted Jawfish O. rosenblatti, is an endemic species from the Gulf of California, included in the local list of protected species. With few biological reports, this species is appreciated in the aquarium industry due to its coloration and digging behaviour, and has a considerable value. With the aim to generate valuable biological information, eight fishes were caught at Loreto Natural Marine Protected Area. Captured fishes were juveniles, and just three of them were kept in an aquarium conditioned with gravel, pieces of shells and coral as substrata. Temperature and photoperiod conditions were stable, and they were supplied with a variety of live and inert feeds. Fishes reached maturity in eight months, according to literature reports, displaying mature male courtship coloration and upward movements in the water column. Fishes spawned several times over more than two years in captivity. Presences of egg masses, or some evidence of egg shell or larvae, were registered in 50 occasions. Male took care of eggs in his shelter, but never in his mouth. Egg masses had an average of 3 592 eggs, with a hatching rate close to 99%. Eggs were apparently rounded having three diameter measurements with significant differences (1.17mm mean higher diameter, SD=0.054; 1.13mm mean lower diameter, 0.058; 0.99mm mean height, 0.045; n=125). Most of corion eggs had four, rarely six filaments; with a single oil drop (0.30mm mean diameter, 0.021, n=59). Incubation lasted 10.4 days (9-14), depending on water temperature (21.0-25.3 degrees C). Egg hatching occurred after darkness, emerging newly hatched larvae of 4.51mm mean notochord length (0.082, n=30), with reserves exhausted, eyes pigmented and mouth opened, ready to eat. This study represents the first report on this species courtship displaying, spawning and some basic characteristics of eggs masses and larvae in captivity. Also, their flexibility and adaptability of individual behaviour to particular environment conditions, lead to consider worth their commercial culture, as already occur with other species of this family. PMID- 23025100 TI - [Temporal and spatial variation of shorebirds in Barra de Navidad lagoon, Jalisco, during three non-breeding seasons]. AB - Resident and migratory shorebirds inhabit different kinds of wetlands such as lagoons, rivers and seashores among others. In recent years, these areas have been importantly affected by urban, agriculture and touristic activities, such as the Barra de Navidad lagoon, for which little information is available to support conservation programs. The aim of this work was to describe shorebirds temporal and spatial distribution in Barra de Navidad lagoon during three non-breeding seasons (1999-2000, 2006-2007 and 2008-2009). For this, monthly censuses were performed from November-April with the purpose of registering all the shorebirds species. We were able to identify 19 shorebirds species (three residents and 16 winter visitors), of which Charadrius wilsonia, Limosa fedoa and Tringa semipalmata were the most abundant. The greater number of species was registered for November, December and March of the first and third seasons. The greater number of individuals was registered when birds were feeding during low tides, mainly in December, January and February of the first and third seasons. At low tide, there was a great number of species and individuals in zone C. This area had muddy substrates that were exposed during low tides and were used to feed. Barra de Navidad lagoon provided suitable habitats for feeding and resting for resident and migratory birds. Twelve of the 19 species were considered as priority within the Mexican bird conservation strategy. However, these habitats are threatened by human activities performed in the nearby areas of the lagoon that may have negative consequences for the distribution, abundance and conservation of these species. PMID- 23025101 TI - Reproduction of the non-native fish Lepomis gibbosus (Perciformes: Centrarchidae) in Brazil. AB - Minas Gerais is the fourth largest Brazilian state, and has an estimate of 354 native fish species. However, these fish species may be threatened, as this state has the highest rank of fish introductions reported for Brazil and South America. As one from the total of 85 non-native species detected, Lepomis gibbosus was introduced in the 60s to serve both as foragefish and to improve sport fishing. In this study, we evaluated the establishment of L. gibbosus in a shallow lake in the city ofOuro Preto, Doce River basin, state of Minas Gerais, Southeastern Brazil. We collected fish with fishing rods every two months from March 2002 February 2003. Fragments of gonads from a total of 226 females and 226 males were obtained and processed following standard histological techniques; then 5-7 microm thickness sections were taken and stained in hematoxylin-eosin. Besides, for each specimen, the biometric measurements included the standard length (SL) and body weight (BW); and the sex ratio was obtained. The reproductive cycle stages were confirmed by the distribution of oocytes and spermatogenic cells. The type of spawning was determined by the frequency distribution of the reproductive cycle stages and ovarian histology. Based on the microscopic characteristics of the gonads, the following stages of the reproductive cycle were determined: one=Rest, two=Mature, three=Spawned for females or Spent for males; males and females in reproduction were found throughout the study period. Post-spawned ovaries containing oocytes in stages one (initial perinucleolar), two (advanced perinucleolar), three (pre-vitellogenic), four (vitellogenic) and post-ovulatory follicles indicated fractionated-type spawning in this species. The smallest breeding male and female measured were 4.6 and 4.9cm standard length, respectively, suggesting stunting. The sex ratio did not vary between males and females along the year and bimonthly, being 1:1. Moreover, L. gibbosus appears to be at stage three of biological invasion: establishment through reproduction. We suggest to deliver information about "non-native species" through lectures in schools, colleges/universities, NGOs, government and environmental agencies in the cities and villages, in order to try to prevent environmental degradation by the introduction of non-native fish such as L. gibbosus in the region. We also recommend high fines for red-handed, and the import ban of non-native fish species to the region. PMID- 23025102 TI - Composition and abundance of small mammal communities in forest fragments and vegetation corridors in Southern Minas Gerais, Brazil. AB - Habitat fragmentation leads to isolation and reduce habitat areas, in addition to a series of negative effects on natural populations, affecting richness, abundance and distribution of animal species. In such a context, habitat corridors serve as an alternative for connectivity in fragmented landscapes, minimizing the effects of structural isolation of different habitat areas. This study evaluated the richness, composition and abundance of small mammal communities in forest fragments and in the relevant vegetation corridors that connect these fragments, located in Southern Minas Gerais, Southeastern Brazil. Ten sites were sampled (five forest fragments and five vegetation corridors) using the capture-mark-recapture method, from April 2007-March 2008. A total sampling effort of 6 300 trapnights resulted in 656 captures of 249 individuals. Across the 10 sites sampled, 11 small mammal species were recorded. Multidimensional scaling (MDS) ordinations and ANOSIM based on the composition of small mammal communities within the corridor and fragment revealed a qualitative difference between the two environments. Regarding abundance, there was no significant difference between corridors and fragments. In comparing mean values of abundance per species in each environment, only Cerradomys subflavus showed a significant difference, being more abundant in the corridor environment. Results suggest that the presence of several small mammal species in the corridor environment, in relatively high abundances, could indicate corridors use as habitat, though they might also facilitate and/or allow the movement of individuals using different habitat patches (fragments). PMID- 23025103 TI - Use of the paca, Cuniculus paca (Rodentia: Agoutidae) in the Sierra de Tabasco State Park, Mexico. AB - Cuniculus paca is widely distributed throughout the Neotropics. Known as the paca, it is the largest rodent in the Mexican tropical forests, and one of the most used as a subsistence species for its meat. Since colonial times, this species has been subject of an unreported hunting pressure. For this reason, the aim of this work was to describe the use of the paca by the inhabitants of the Sierra de Tabasco State Park (STSP) using sampling areas in a matrix of vegetation with different degrees of disturbance, and different types of land use. We included both preserved areas: owing to the presence of large continuous areas of fragmented rainforest and areas that are not preserved, with smaller rainforest fragments and more isolated. To obtain information about paca use, we interviewed 176 people (>18 years old) who live in the STSP. All those interviewed had eaten paca meat, and indicated that this species is most frequently observed in the rainforest during the dry season. Hunting and trapping were the most common ways to obtain pacas, rather than gifting or purchasing, and firearms and dogs are used to hunt them. We estimated that these interviewed group had hunted a total of 488 paca in the year prior to the study. PMID- 23025104 TI - [Potential distribution of jaguar, Panthera onca (Carnivora: Felidae) in Guerrero, Mexico: persistence of areas for its conservation]. AB - Studies about the permanence of natural protected areas are important, because they contribute to the promotion of the conservation target and to optimize economical and human resources of specific areas. Although there are no natural protected areas in Guerrero, it has suitable habitat for the jaguar, a common species used for planning and management of conservation areas. Since, there is actual evidence that environmental and anthropogenic variables may modify vertebrate species distribution with time, in this study we predicted the potential distribution of Panthera onca using MaxEnt for this Southeastern region. In addition, we made a projection considering the effect of a moderate climate change scenario, to evaluate the stability of the conservation area for a period of 24 years. Furthermore, we applied three threat scenarios for the actual prediction to define conservation priorities areas. In our results, we have found that 18 361Km2 (29%) of this state has a permanent suitable habitat for jaguar conservation in the Sierra Madre del Sur and Pacific coast, with a possible loss of 2 000km2 in 24 years. This habitat is characterized by a 56% of temperate forest (mainly conifers and hardwoods 34%), and 35% of tropical deciduous forest. With the projections, the Southeastern region resulted with the higher anthropogenic impacts, while at the same time, an area of 7 900km2 in the Central Western state was determined as a priority for conservation. To assure jaguar conservation, we propose the inclusion of this new conservation area, which is located in the Sierra Madre del Sur, with which we may potentially preserve other 250 species of threatened vertebrates. This way, the suggested habitat conservation may represent a local effort in Guerrero and will strengthen the biological corridor network for P. onca protection in Latin America. PMID- 23025105 TI - [Population dynamics, roost selection and reproductive patterns of some cave bats from western of Mexico]. AB - Population dynamics, roost selection and reproductive patterns of some cave bats from Western of Mexico. Almost half of bat species that occur in Mexico use caves as permanent or temporal roosts. However, the ecological studies about cave bat communities are scarce. In this work we studied the population dynamics, roost selection and reproductive patterns of some bats present in El Salitre Cave, Colima, Mexico. We carried out monthly samplings between August 2003-March 2005 using a harp trap for bats capture, we took their biological data and marked some of them with plastic rings. We also explored the cave to locate bat colonies and register microclimatic conditions in each cave section. We captured a total of 16 409 bats of which 31% were Mormoops megalophylla, 24.5% Pteronotus personatus, 23% P. davyi, 8.2% P. parnellii, 5.8% Natalus mexicanus and 5.3% Glossophaga soricina. Macrotus waterhousii, G. morenoi, Desmodus rotundus, Balantiopteryx plicata, and Glyphonycteris sylvestris represented only 2.2% of the captures. Some bat species used the cave as a permanent day roost while others as a seasonal one, and their population size varied markedly along the year and between rainy and dry seasons. Most bat population peaks were linked with their reproductive periods. The Pteronotus species and N. mexicanus exhibited sexual segregation during the breeding season. The mormoopids and N. mexicanus occupied deeper parts of the cave with temperatures >25.8 degrees C and relative humidity >99%. The phyllostomids occupied intermediate sections where the ambient was less hot and humid, with temperatures of 23.2-28.3 degrees C and humidity of 74-89.9%. Some individuals of B. plicata and G. sylvestris were seen occasionally occupying one chamber near the entrance two, where temperature and humidity were of 23.2 degrees C and 84.2%, respectively. The mormoopids and N. mexicanus showed a pattern of seasonal monoestry, synchronized with rainy season. Glossophaga soricina had a pattern of bimodal seasonal poliestry, with one reproductive peak to early of dry season and another to last of this season. Macrotus waterhousii did not exhibit a seasonal pattern, with parturitions occurring throughout the year. Our results indicate a seasonal replacement between several species as well as seasonal movements to other caves. The data indicate that the carrying capacity of the cave is mainly determined by the availability of roosting sites. The selection of roosting sites is linked to the close relationship between microclimatic conditions and the species physiological characteristics. The reproduction of mormoopids and N. mexicanus was mostly influenced by rainfall which determinates food availability. PMID- 23025106 TI - Annulata orstediana: publication dates, composition and annotated taxonomic list, with some comments on Hemipodus (Polychaeta: Glyceridae). AB - The collecting trips by Orsted and Kroyer in Central and South America resulted in a series of papers by Grube, the Annulata orstediana which contained the proposal for seven genera and descriptions for 84 species. There are some problems dealing with the correct number of contributions, their publication dates, the correct citation for the authors for each species name and sometimes even for the type locality. In order to improve the current situation, we have consulted the original publications together with the corresponding collections. Our results indicate that there were only three parts in the series which were published in the journal, and repagination in reprints sometimes caused some further confusion. Additionally, we provided some review comments on the species current status and we added a short nomenclatural note on Hemipodus (Polychaeta: Glyceridae) trying to clarify the correct generic name and type species. PMID- 23025107 TI - Post-transplant lymphoproliferative disorders after solid organ transplantation in children. AB - Post-transplant lymphoproliferative disease (PTLD) is a well recognized complication of solid organ transplantation (SOT) or bone marrow transplantation (BMT) associated with therapeutic immunosuppression (IS), first reported in 1968. Risk factors, therapy, and outcomes differ between PTLD observed following BMT and SOT. PTLD is a potentially fatal complication in the clinical course of transplant recipients, representing the most common malignancy after SOT in children and the second in the adult setting. This review presents the predisposing risk factors to the development of PTLD, along with clinical aspects, diagnostic work-up and therapeutic options in order to obtain a durable and complete remission with minimal toxicity. The extreme diversity of clinical presentations, sometimes with rapidly aggressive evolution, together with the heterogeneity of imagistic and histological findings, have proven the importance of the high degree of clinical suspicion. The early recognition and the prompt adequate treatment may improve the outcome. PMID- 23025108 TI - Peripheral nerve allograft, a reconstructive solution: outcomes and benefits. AB - Every year millions of individuals worldwide require complex reconstructive procedures as a result of various traumatic events. Recent success in composite tissue allotransplant, has shown that allografts generally present an enormous potential in reconstructive surgery. Peripheral nerve allograft represents a relatively new research field, therefore many aspects are still to be clarified. The main interests of this study concerning nerve allograft are directed to harvesting from cadaver or living donor, allografts denaturation and conservation, recipient tolerance to allograft, immunosuppressive medication, and quantifying the outcomes of nerve regeneration. PMID- 23025109 TI - Median to ulnar nerve anastomosis: a review of the literature. AB - Median to Ulnar nerve anastomosis in the forearm has been shown to be of clinical significance leading to "anomalous" innervation and is correlated with misdiagnosis during the assessment of nerve lesions, injuries and Carpal Tunnel Syndrome (CTS). In 1763, Martin first described the anastomosis and Gruber next mentioning it, in 1870 thus referred to as Martin--Gruber anastomosis. Despite its long history, its nature remains unclear. Many anatomical, electrophysiological, histological and genetic studies have been published, reporting the anastomosis' frequency, citing its clinical importance and classifying it into various classes and types. Diagnosis is made mostly with electrophysiological studies whereby researchers have cited certain clues taking into consideration the asymptomatic nature of the anastomosis. The current literature on median to ulnar nerve anastomosis is reviewed, highlighting its frequency and clinical significance making an excellent tool for correct diagnosis in many clinicians. PMID- 23025110 TI - POSSUM, a potentially useful tool for prediction of morbidity in patients undergoing central pancreatectomy. AB - AIM: Central pancreatectomy is a pancreas-sparing alternative to standard pancreatic resections, and it is associated with substantial morbidity. The aim of the present study is to assess the utility of the POSSUM scoring system in the prediction of the postoperative complications after central pancreatectomy, which would help identify the patients who are at the highest risk of developing complications. METHODS: A retrospective analysis of 24 patients who underwent central pancreatectomies (2002-2010) was performed. The POSSUM score was calculated for each patient and was correlated with observed morbidity. RESULTS: The mean POSSUM score was 32, thus predicting morbidity in 9 out of 24 patients. This risk assessment proved to be quite accurate, as 13 patients (54%) actually developed postoperative complications (chi-squared = 3.2101, p = 0.073). The predictive value of the POSSUM was strongest for the < or = 20%, 60-80% and > or = 80% morbidity risk cohorts (O/E ratio 1). CONCLUSIONS: The identification of a scoring system to predict the development of severe complications after central pancreatectomy may stratify the patients' risk and lead to a tailored approach of this surgical procedure. Although POSSUM seems to predict morbidity after central pancreatectomy, further studies involving larger numbers of patients should be conducted to confirm this effect. PMID- 23025111 TI - Management of bile duct injuries secondary to laparoscopic and open cholecystectomy. The experience of a single surgical department. AB - Cholecystectomy is one of the most performed surgical interventions in general surgery. Laparoscopic cholecystectomy was associated with an increasing occurrence of biliary ducts lesions. The aim of this study is to draw the attention towards the permanent risk of these kind of complications, the curative difficulties and identifying the best therapeutic solution in order to obtain favorable results on long term. METHOD: There were retrospectively and prospectively analysed all the cases with diagnosis of iatrogenic biliary ducts lesion hospitalized and operated during 1987-2008 in the Surgical Clinic No 3 Cluj Napoca. RESULTS: The yearly distribution showed an increasing number of biliary lesions operated in the Surgical Clinic No 3 Cluj-Napoca. 81% of the iatrogenic lesions in our study occurred postlaparoscopic cholecystectomy, and 19% secondary to an open cholecystectomy. One hundred thirty-six patients had major biliary lesions (D, E classes according to Strasberg Soper) and 47 patients had minor lesions (A-C classes). The medium hospitalization range was 17 days. Eighty - three patients (45.3%) needed one, two or three surgical interventions before the complete cure of the lesions. The most frequent complication was plague suppuration (12.5%). The cardio-renal-pulmonary complications were present in 8.7% of the patients and the intra-abdominal abscess in 3.8% of the patients. The anastomotic fistula was present in 11% of the operated patients and 6% global mortality. CONCLUSIONS: The iatrogenic lesions of the biliary ducts are characterized by a complicated evolution, with series of interventions and progressive evolution to biliary stenosis. Delaying the final biliary treatment and the high number of interventions performed before patients were referred to hepato-biliary specialised centres lead to an increasing morbidity and hospitalization costs. PMID- 23025112 TI - Laparoscopic approach to ovarian dermoid cysts. AB - INTRODUCTION: Ovarian dermoid cysts (mature cystic teratomas) are a benign type of germ cell tumours and the most common ovarian neoplasms in women of fertile age. The aim of this study was to analyze the safety of the laparoscopic approach in ovarian dermoid cysts. METHODS: We performed a prospective study between 2006 and ' 2010 including 38 mature cystic teratomas treated either laparoscopically or by open access. All preoperative and postoperative data were included in an MS Access database and statistically analysed with SPSS v. 17 for Windows. RESULTS: The study group was divided into 2 subgroups according to the approach: laparoscopic (25 cases - 2 conversions) and classic (13 cases). The mean age of the patients was 40.34 years (range 19-74): 36.92 years for laparoscopic group and significantly higher 46.21 years for open approach group. Twelve cases were admitted as emergencies either because of complications (torsion or rupture of the teratoma) (11 cases) or associated with acute appendicitis (one case). The latter did not influence the decision for open or laparoscopic approach. Only 29 out of 38 cases had preoperative measurement of CA 125. CA 19-9 was performed in 27 cases and elevated levels were found in 21 cases (78%). Cysts over 10 cm presented higher values of CA 19-9. The mean cysts diameter was 11.29 cm (range 2 27 cm): 13.93 cm mean cyst diameter for open approach vs 9.75 cm for laparoscopic approach. The specimen removal required aspiration of the content for cysts bigger the 10 cm in laparoscopic approach. Mean hospital stay was 4.05 days (range 2-6 days) for the laparoscopic group, significantly lower when compared with the open approach group: 6.96 days (range 5-16 days). CONCLUSIONS: Laparoscopic management of ovarian dermoid tumours is a safe and efficient procedure. It does not increase complications rate in comparison with the open approach, offering a shorter hospital stay, a quick recovery and very important, it allows a conservative treatment, especially in premenopausal women who want to be pregnant. PMID- 23025113 TI - Six months results of laparoscopic sleeve gastrectomy in treatment of obesity and its metabolic complications. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become a popular bariatric surgical procedure, with proven results in achieving weight loss, however data regarding its effectiveness on metabolic syndrome (MetS) components are scarce. The aims of the present study were to assess the outcomes of LSG on weight loss and obesity associated metabolic complications at six months following intervention. PATIENTS AND METHODS: This was a retrospective study on 124 consecutive obese patients (29.8% men), who had undergone LSG between 01/01/2008 and 12/31/2010, in a highly specialized clinic. The dynamic of anthropometric and biochemical data between baseline and six months following LSG were evaluated. We also determined the change in MetS prevalence and used logistic regression to estimate predictors of MetS remission RESULTS: 6 months after LSG, the body mass index (BMI) decreased from 46.84 +/- 8.62 to 33.81 +/- 7.04 kg/m2 (p < 0.001). Mean excess BMI loss (EBL) was 65.24 +/- 25.16%. The best results on weight loss were observed in young patients, not affected by MetS, with lower initial BMI. Lipids profile suffered a significant improvement (HDL cholesterol increased, while LDL, total cholesterol, triglycerides decreased, p < 0.05 for each). HOMA IR values decreased by 75.2%, from 5.24 +/- 4.49 to 1.30 +/- 1.22 (p < 0.001). MetS prevalence was reduced from 74.3% to 18.4% (p < 0.001). In multivariate analysis, % EBL remained the only significant predictor of MetS remission, the risk for lack of a MetS remission being practically 3 times higher in patients with EBL < 50%, compared to those with EBL > 50% (OR: 2.97, CI: 1.1-10.23, p < 0.05). CONCLUSIONS: As early as 6 months after LSG we recorded a significant weight loss and improvement in insulin resistance and lipids metabolism, as well as an impressive reduction in metabolic syndrome prevalence. PMID- 23025114 TI - Multi-organ resections for colorectal cancer: analysis of potential factors with role in the occurrence of postoperative complications and deaths. AB - AIM: Multi-organ resection for colorectal malignancy is a topic of interest nowadays as it raises the issue of benefits versus increased morbidity. This study aims to identify factors that may influence the development of postoperative complications and death following multivisceral resection. METHODS: The study included 107 patients hospitalized in the Surgical Clinic III of Cluj Napoca, who underwent multivisceral resections for colorectal cancer pathology. This is a retrospective study covering the period between 2006 and 2010. This study compares the morbidity and mortality following multi-organ resections for locally advanced colorectal cancer, with results in patients with uncomplicated colorectal resections. The study also highlights the impact that certain factors have on the development of postoperative complications. RESULTS: This study shows a higher incidence of death and postoperative complications in the case of multiorgan resections. The differences were found to be statistically significant as follows: postoperative complications: 26% after multiorgan resection and 14% after uncomplicated resection respectively (p = 0.001); postoperative death: 11% after multi-organ resection and 3% after uncomplicated resection respectively (p < 0.001). The factors that have influenced in a negative way the postoperative evolution of the patients were: diabetes, personal history of malignant disease, associated heart disease, major abdominal surgery prior enrolling, the number of resected organs and increased intraoperative blood loss (over 500 ml). CONCLUSION: In cases of locally advanced colorectal neoplasm, multiorgan resection should become the standard indication, as it offers patients their only chance of survival, comparable to that obtained in less advanced stages of the disease. This indication is underlined by the high resecability rate (R0) accomplished in our service. Preoperative compensation of the associated pathologies, the surgery performed by experienced teams, as well as providing an adequate intensive care are required to reduce the postoperative risks. PMID- 23025115 TI - Relationship between the incidence of idiopathic lower extremity deep vein thrombosis and the location of the thrombus depending on the changes in atmospheric pressure. AB - AIM: The study analysed the relationship between the incidence of idiopathic lower extremity deep vein thrombosis (DVT) and the location of the thrombus with changes in atmospheric pressure. MATERIAL AND METHOD: During the two year period between May 2009 and April 2011, inclusively, 124 consecutive patients were diagnosed as having idiopathic lower extremity DVT at the Vascular Surgical clinic "Clinical Center of Nis", Serbia. RESULTS: The increased average daily values of atmospheric pressure for 1 millibar on the day when the event took place and 7 days before, were associated (p < 0,05) with the increase of the total risk of the occurrence of lower extremity idiopathic DVT for 5,1% (0,7 9,8%), as well as with the occurrence of idiopathic DVT above the knees (p < 0,05) for 5,9% (0,9-11,0%). The increase in the average atmospheric pressure by 1 millibar on the day when the event took place and 7 days before this in the subgroup of patients under the age of 45 years, and on the day when the event took place and 3 days before it in the subgroup of patients of the age of 45 and above, was related with the increased risk of the occurrence of lower extremity idiopathic DVT. CONCLUSION: The increase of daily values of atmospheric pressure shows a significant relationship with the incidences of idiopathic lower extremity DVT and the location of the thrombus above the knee. PMID- 23025116 TI - Sparing anti-pseudomonas antibiotics in intraabdominal infections. AB - The progress of surgery allowed the timely source control of the intraabdominal infections (IAIs); the availability and use of the broad-spectrum antibiotics resulted in an important reduction of the morbidity and mortality over the last century. Nevertheless, this pathology remains a major challenge for surgeons, internists, infectious diseases and microbiology specialists. The increased bacterial resistance and its spread within institutions limits the antibiotic treatment options and patients'outcome. This phenomenon is more obvious in Gram negative bacilli which are the main cause of the IAIs. This paper brings into discussion the criteria which would help reducing the use of anti-pseudomonas antibiotics in the initial empirical treatment when they are not necessary, and also outlines the available therapies for these infections. PMID- 23025117 TI - Does VEGF have an effect on the survival of a long random skin flap by its application at the recipient area? AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a hormone-like molecule which has been shown to act on a specific receptor system and in this way to be the basic regulator of angiogenesis. The effect on the survival of a long random skin flap was examined by exogenous administration of this cytokine, at flap's recipient site. MATERIALS & METHODS: A standard dorsal skin flap measuring 1.5 x 7.5cm was elevated in eighteen wistar rats with the pedicle centered and attached between the lower angles of the scapulae. The length to width ratio was relatively high (5:1). The rats were divided in two groups of nine. In group A, flap was elevated and a skin defect was created next to it. Normal saline was injected into the fascia of the defect and the flap was transposed and secured over the previously created recipient site. In group B, flap was elevated and transposed to a previous created defect, as before, where, this time, injections of VEGF were applied into the fascia of the recipient bed. Seven days later the rats were euthanized and the flaps were excised. The underlying fascias of the recipient beds were also excised in the same dimensions. The specimens were measured, photographed and put into formalin 10%. Immunohistochemical staining and histological analysis followed. RESULTS: The differentiation between the surviving and the necrotic skin was macroscopically clear within seven days time. In group A, the mean flap survival percentage was 36.8%. In group B the percentage was 56.3%, respectively. Neovascularization of the fascia of the recipient bed was also demonstrated when VEGF had been injected. CONCLUSIONS: Exogenous administration of VEGF into the recipient bed of a skin flap improved the survival rate even though the flap's length was relatively high compared to its width. PMID- 23025118 TI - Retrospective study regarding objectives and results of upper limb transplant. AB - INTRODUCTION: Upper limb amputation causes a severe permanent disability. Upper limb transplantation is subject to treatment to prevent rejection and influenced by organizational, socioeconomic, psychological, ethical factors. Analysis of the results creates the potential for continuing this work in specific conditions in our country. MATERIAL AND METHODS: We retrospectively analyzed data from the literature. Upon completion of documentation (May 2011) there were 74 transplants in 53 patients worldwide. We have studied the available information on the surgical interventions and their results. RESULTS: Upper limb allograft has a complex structure comprising tissue with variable antigenicity. Surgery is performed by a large multidisciplinary team, whose increased experience leads to a shorter length of the operation. The postoperative follow-up and rehabilitation program are standardized, and patients' compliance is essential. The greatest advances have occurred in immunosuppression protocols. CONCLUSION: The upper limb transplantation was performed in 20 centers of 12 countries so far. The specification of the indications and contraindications, the proper selection of patients, the increasing experience and new immunosuppression protocols provide a higher success rate and quality of functional outcome. By applying these conceptual acquisitions we will be able to create conditions for the integration of our country in this globally convergent scientific effort. PMID- 23025119 TI - Robotic surgery of locally advanced gastric cancer: a single-surgeon experience of 41 cases. AB - The mainstay of curative gastric cancer treatment is open gastric resection with regional lymph node dissection. Minimally invasive surgery is yet to become an established technique with a well defined role. Robotic surgery has by-passed some of the limitations of conventional laparoscopy and has proven both safe and feasible. We present our initial experience with robotic surgery based on 41 gastric cancer patients. We especially wish to underline the advantages of the robotic system when performing the digestive tract anastomoses. We present the techniques of end-to-side eso-jejunoanastomoses (using a circular stapler or manual suture) and side-to-side eso-jejunoanastomoses. In our hands, the results with circular stapled anastomoses were good and we advocate against manual suturing when performing anastomoses in robotic surgery. Moreover, we recommend performing totally intracorporeal anastomoses which have a better post-operative outcome, especially in obese patients. We present three methods of realising the total intracorporeal eso-jejuno-anastomosis with a circular stapler: manual purse string suture, using the OrVil and the double stapling technique. The eso jejunoanastomosis is one of the most difficult steps in performing the total gastrectomy, but these techniques allow the surgeon to choose the best option for each case. We consider that surgeons who undertake total gastrectomies must have a special training in performing these anastomoses. PMID- 23025120 TI - Giant fibrovascular esophageal polyp misdiagnosed as achalasia. AB - A 59 years old woman was admitted in our unit accusing longtime dysphagia and regurgitation. On admission, the patient was wearing a 3 month old definitive feeding gastrostomy tube. The contrast swallow, endoscopy and esophageal manometry established the diagnostic--achalasia. We removed the gastrostomy tube and we performed an open Heller myotomy. The postoperative period was uneventful and the patient was discharged one week later with affirmatively unimpaired deglutition. One month later, the patient was admitted via emergency with a giant fibrous tumor arising from her mouth after an episode of strong coughing and vomiting. The repeated endoscopy showed a giant esophageal polyp that was missed by the previous investigations, originating from pharingoesophageal junction. The esophageal polyp was resected by cervical approach with good postoperative outcome. The polyp's particular extreme dimensions (27 cm) prevented the acute asphyxia by blockage at the laryngeal level, possibly provoked by smaller tumors. As postoperative one month barium swallow showed a normal esophageal aspect, a final question remains--was achalasia real or an erroneous diagnosis was established the second time too? PMID- 23025121 TI - Perforated appendix with periappendicular abscess in a inguinal hernia sac- Amyand's hernia. AB - Amyand's hernia is a rare form of inguinal hernia, where the appendix is included in the hernia sac. We present the emergency case of an 81-year-old patient with right inguinal pseudo-tumor, accompanied by marked local pain, nausea, low grade fever and bowel disorders. Emergency surgery is indicated due to a suspected incarcerated inguinal hernia with imminent strangulation. The intraoperatory findings reveal the presence of a periappendicular abscess as the cause of gangrenous appendicitis, perforated in the right indirect inguinal hernia sac. The practice includes the evacuation of the abscess, appendectomy and surgical cure of the inguinal hernia--Bassini's procedure, Douglas drainage and subcutaneous drainage. The postoperative outcome was favorable, the patient being discharged on the fifth postoperative day. Postoperative checks performed at 3 and 9 months have not revealed the presence of a hernia recurrence. PMID- 23025122 TI - A clinical case of Fournier gangrene. AB - OBJECTIVE: To present a case of Fournier gangrene and the specific surgical therapy CASE PRESENTATION: A 71-year old patient with a two days history of pain in the perineal region, swelling, developing necrosis and foul-smelling lesions was examined in emergency settings. The swelling of subcutaneous plane involved the flank regions, mainly on the left side. The investigations were performed (full blood count, blood urea, electrolytes, coagulation profile). A Fournier gangrene was diagnosed and surgery performed under general anesthesia. Broad spectrum antibiotics were given concomitantly. The first surgical procedure consisted in surgical debridement and excision of all the necrotic tissue. Cultures were taken. We performed counter incisions bilaterally on both flanks. The communication through the fascial planes was clearly demonstrated, especially on the left side. A loop colostomy was also performed. Multiple re-excisions were further employed. Due to a precarious evolution, the patient were on mechanical ventilation for 13 days. Inotrope medication was given for a total of 19 days and, the antibiotherapy adapted to the antibiogram (Bacterioides eggerthii was identified). The reconstruction of the perineum was later performed and, after 3 months, the colostomy was closed in good conditions without further complications. CONCLUSION: Early recognition and aggressive surgical excision are mandatory for success in patients with Fournier gangrene. Colonic diversion can be very useful if employed from the beginning. PMID- 23025123 TI - Intestinal perforated malignant melanoma: diagnostic and therapeutic difficulties. AB - The intestinal malignant melanoma is a rare occurrence in the daily surgical practice, with difficult diagnosis (even on usual pathologic examination) and therapeutic attitude. Most of the lesions are secondary to a cutaneous primary melanoma, but there are cases in which the original site may not be discovered, and are considered as primitive intestinal melanomas. This paper presents the case of a 50 year old male patient, diagnosed and operated as emergency with acute abdomen caused by a tumoral perforation of the small bowel; several tumors, in different stages of local evolution, were discovered during laparotomy. A triple enterectomy with end-to-end entero-enteral anastomosis was performed, with uneventful postoperative recovery. The later postoperative evolution was marked by the occurrence of multiple subcutaneous recurrences and a bulky metastasis in the mediastinum; 18 month after the initial surgery, the patient died due to the melanoma recurrence. Diagnostic and therapeutic difficulties are discussed in this paper, related especially to the differential diagnosis of the origin of the intestinal lesion (a metastatic melanoma with unknown primary site or a primary malignant melanoma of the small bowel), since no other sites of origin were discovered after a thorough examination. PMID- 23025124 TI - Mucinous adenocarcinoma of the urinary bladder after long-term duodeno-renal and colovesical fistula--case report. AB - Primary adenocarcinoma of the urinary bladder is a rare neoplasm. It accounts for 1-2% of all bladder carcinomas and sometimes may be found in the bladder diverticula. Fistula between duodenum and renal pelvis is another rarity while colovesical fistula is not so uncommon. We present a case of a 40 years old man who had surgery for colovesical and duodenorenal fistula and subsequently developed adenocarcinoma of the urinary bladder. PMID- 23025125 TI - [The 20th Congress of the European Endoscopic Surgery, Bruxelles, June 21-23, 2012]. PMID- 23025126 TI - The hidden curriculum. AB - The Uniformed Services University of the Health Sciences Internal Medicine Third Year Clerkship Program recently instituted an academic exercise to be completed by medical students during the first 6 weeks of their 12 weeks of Internal Medicine. The academic exercise involves reflecting on professional values through art and being exposed to the hidden curriculum of professionalism. Students are instructed at the beginning of their clerkship to observe the professional activities of their teachers, peers, ancillary staff, and of themselves. Students are provided a selection of art pieces to choose from. They select one which best exemplifies the professional activity they observed and are then to write a structured, reflective article. PMID- 23025127 TI - Projected rates of psychological disorders and suicidality among soldiers based on simulations of matched general population data. AB - Limited data are available on lifetime prevalence and age-of-onset distributions of psychological disorders and suicidal behaviors among Army personnel. We used simulation methods to approximate such estimates based on analysis of data from a U.S. national general population survey with the sociodemographic profile of U.S. Army personnel. Estimated lifetime prevalence of any Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) anxiety, mood, behavior, or substance disorder in this sample was 53.1% (17.7% for mood disorders, 27.2% for anxiety disorders, 22.7% for behavior disorders, and 14.4% for substance disorders). The vast majority of cases had onsets before the expected age of enlistment if they were in the Army (91.6%). Lifetime prevalence was 14.2% for suicidal ideation, 5.4% for suicide plans, and 4.5% for suicide attempts. The proportion of estimated preenlistment onsets was between 68.4% (suicide plans) and 82.4% (suicidal ideation). Externalizing disorders with onsets before expected age of enlistment and internalizing disorders with onsets after expected age of enlistment significantly predicted postenlistment suicide attempts, with population attributable risk proportions of 41.8% and 38.8%, respectively. Implications of these findings are discussed for interventions designed to screen, detect, and treat psychological disorders and suicidality in the Army. PMID- 23025128 TI - No effect of mild nonconcussive injury on neurocognitive functioning in U.S. Army soldiers deployed to Iraq. AB - With neurocognitive testing being heavily relied on for concussion assessments in the U.S. Warfighter, there is a need to investigate the impact of nonconcussive injury on neurocognitive functioning. OBJECTIVES: To determine if a nonconcussive injury may have a negative effect on neurocognitive functioning in a deployment setting. METHODS: The current study compared scores on computerized and traditional neurocognitive tests of 166 Soldiers deployed to Iraq. Performance on a battery of tests was compared between a group of healthy deployed Soldiers (n = 102) versus a group of deployed Soldiers seeking outpatient care for mild injuries not involving the head or blast exposure (n = 62). RESULTS: The injured group's performance was not significantly lower on any of the measures administered compared to healthy Soldiers. CONCLUSIONS: The results suggest that there was no significant effect of nonconcussive injury on neurocognitive functioning. Findings lend support to feasibility of using neurocognitive tests to evaluate the effects of concussion in theater. PMID- 23025129 TI - Healing Touch with Guided Imagery for PTSD in returning active duty military: a randomized controlled trial. AB - Post-traumatic stress disorder (PTSD) remains a significant problem in returning military and warrants swift and effective treatment. We conducted a randomized controlled trial to determine whether a complementary medicine intervention (Healing Touch with Guided Imagery [HT+GI]) reduced PTSD symptoms as compared to treatment as usual (TAU) returning combat-exposed active duty military with significant PTSD symptoms. Active duty military (n = 123) were randomized to 6 sessions (within 3 weeks) of HT+GI vs. TAU. The primary outcome was PTSD symptoms; secondary outcomes were depression, quality of life, and hostility. Repeated measures analysis of covariance with intent-to-treat analyses revealed statistically and clinically significant reduction in PTSD symptoms (p < 0.0005, Cohen's d = 0.85) as well as depression (p < 0.0005, Cohen's d = 0.70) for HT+GI vs. TAU. HT+GI also showed significant improvements in mental quality of life (p = 0.002, Cohen's d = 0.58) and cynicism (p = 0.001, Cohen's d = 0.49) vs. TAU. Participation in a complementary medicine intervention resulted in a clinically significant reduction in PTSD and related symptoms in a returning, combat-exposed active duty military population. Further investigation of GT and biofield therapy approaches for mitigating PTSD in military populations is warranted. PMID- 23025130 TI - Review: management of adjustment disorder in the deployed setting. AB - Adjustment disorder is a maladaptive response to a stressor that causes functional impairment. The contribution of deployment stress on the diagnosis and treatment of adjustment disorder has not been previously explored. Despite the high cost and commonality of adjustment disorder as a behavioral health condition diagnosed during deployment, there are few clinical trials and no standardized recommendations found in this review related to treatment of military service members in the deployed setting. This manuscript reviews the best practices for adjustment disorder management and applies these principles to create clinical guidelines and an algorithm for treatment in the deployed setting. PMID- 23025131 TI - The role of military chaplains in mental health care of the deployed service member. AB - This research utilized a cross-sectional design secondarily analyzing data from active duty military health care personnel who anonymously completed the "2005 Department of Defense Survey of Health Related Behaviors Among Active Duty Military Personnel." Sample for this analysis of Operation Iraqi Freedom/Operation Enduring Freedom deployed mental health seeking service members was N = 447. Religiosity/spirituality and psychological distress experienced by active duty military personnel who sought help from military mental health providers (MH), military chaplains (CHC) or both (CHC & MH) were explored and compared. Greater psychosocial distress seen in the CHC & MH group could be a reflection of a successful collaborative model for mental health care that is currently promoted by the military where chaplains are first line providers in an effort to provide services to those in greatest need and ultimately provide them with care from a trained mental health professional. Research and evaluation of chaplain training programs and collaborative models is recommended. PMID- 23025132 TI - Prevalence of childhood trauma among U.S. Army soldiers with suicidal behavior. AB - In 2009, suicide was reported to be the third leading cause of death among U.S. Army personnel. The increase of suicides in the Army indicates the need for additional research to better understand the problem. Research in civilian populations found that experiencing childhood trauma increases the risk for various negative health outcomes, including suicide and suicide attempts, during adulthood. To date, there has been very little focus on pre-existing mental health before joining the service because of a lack of existing data. Participants were active duty Army Soldiers who attempted or completed suicide as identified by the Department of Defense Suicide Event Report. Among Soldiers exhibiting suicidal behavior, analyses were completed to identify significant associations with specific types of childhood trauma experienced before joining the Army. The prevalence of childhood trauma in this population was 43.3% among the suicide cases and 64.7% among the attempt cases. The most common types of childhood trauma among Soldiers were family problems and abuse. The need for further research among military populations is clear given the high prevalence of childhood trauma found among these Soldiers with suicidal behavior and the lack of complete data for this population. PMID- 23025133 TI - Spice, bath salts, and the U.S. military: the emergence of synthetic cannabinoid receptor agonists and cathinones in the U.S. Armed Forces. AB - Designer drugs are synthetic compounds that contain modified molecular structures of illegal or controlled substances. They are produced clandestinely with the intent to elicit effects similar to controlled substances while circumventing existing drug laws. Two classes of designer drugs that have risen to recent prominence are "spice," synthetic cannabinoid receptor agonists that mimic the effect of tetrahydrocannabinol, the active ingredient in cannabis, and "bath salts," synthetic cathinones, stimulants structurally related to amphetamines that have effects similar to cocaine and methamphetamine. Although these substances have only gained prominence recently, service members of the U.S. armed forces have not been immune to spice and bath salt abuse. These substances are often perceived as safe and are available via the Internet, in head shops and from dealers. Spice and bath salt abuse is increasingly associated with serious medical and psychiatric problems. Military health care providers must be familiar with these important new classes of drugs. This article discusses the background, current civilian and military legal status, clinical effects, pharmacology, and clinical management of synthetic cannabinoid receptor agonists and synthetic cathinones. PMID- 23025134 TI - Substance abuse counselor and client reports of mental health screening and enhanced practices. AB - OBJECTIVE: The objective of this study was to examine mental health screening practices and attitudes from both counselor and client perspectives in the U.S. Marine Corps substance abuse program. METHOD: This study examined mental health screening practices and attitudes of 23 substance abuse counselors and 442 clients from six Marine Corps substance abuse counseling centers. RESULTS: After receiving training on screening and enhanced counseling practices, 76% of counselors reported that they almost always screened their clients for post traumatic stress symptoms. Seventy-three percent of clients agreed that substance abuse counselors should ask about their clients' stress concerns. CONCLUSION: Overall, implementing screening for common mental disorders was feasible in this setting. Counselors may need further support to increase collaboration with mental health professionals and adapt treatment plans to address co-occurring mental health conditions. PMID- 23025135 TI - Preparedness of orthopaedic surgeons for modern battlefield surgery. AB - Over 220 U.S. Army orthopaedic surgeons have deployed during the Global War on Terrorism (GWOT). This study documents the orthopaedic procedures performed during the GWOT and identifies training that prepared surgeons for deployment. It reveals deficiencies in surgeons' preparedness and intends to improve predeployment training. All surgeons deployed during the GWOT from 2001 to 2007 were surveyed. Questions fit 4 general categories: deployment demographics, medical and surgical experiences, predeployment preparation, and self-perceived preparedness during deployment. Response rate was 70%. Surgeons averaged 138 adult operative cases and 26 pediatric cases per deployment. All surgeons performed irrigation and debridement, 94% external fixation, 93% amputations, 89% arthrotomies, 86% open reduction and internal fixation, and 76% soft-tissue coverage procedures. Residency and fellowship contributed most to surgeon preparedness for deployment. Surgeons generally reported high levels of preparedness, but nearly 1 in 6 reported low levels of medical, surgical and physical preparedness. More reported low levels of mental preparedness. Soft tissue coverage was the most frequently reported surgical deficiency. This study documents the number and types of orthopaedic procedures performed during the GWOT and identifies the self-perceived preparedness deficiencies of surgeons in a combat environment. Improvements in predeployment training are needed to better prepare surgeons for managing battlefield causalities. PMID- 23025136 TI - Analysis of the causes of death of casualties in field military setting. AB - OBJECTIVE: We assessed the causes of death of military casualties in order to determine the characteristics of injury and to determine how survivability can be improved. METHODS: A retrospective review of the trauma registry of the Israel Defense Forces was conducted. The causes of death were determined. Casualties that were found alive but died later at any level of care were included. RESULTS: Information about casualties that was recorded during the years 2002-2009 was reviewed. Eighty-one fatalities were included in the analysis. Fifty-one (63%) fatalities were caused by gunshot wounds. Analysis of the data regarding the cause of death revealed that 66 (81.5%) of the casualties died because of hemorrhage and 25 (30.9%) because of head trauma. Of the casualties that died of hemorrhage, 12 (18.2%) had neck or limbs potentially compressible hemorrhage. All fatalities from hemorrhage died before arriving at a medical facility. CONCLUSION: Torso noncompressible hemorrhage was found to be the main cause of death among the casualties investigated. Potentially compressible hemorrhage and head injury are significant too. Research and development of means to treat hemorrhage and emphasis on distribution of means to stop hemorrhage and on training may improve outcome of potentially compressible hemorrhage. PMID- 23025137 TI - Trends in musculoskeletal disorders and related health care utilization among conscripts in Finland, 1967-2006. AB - OBJECTIVES: The aim was to investigate time trends in musculoskeletal disorders (MSDs) among Finnish conscripts over a period of 40 years. METHODS: A nationally representative health examination survey (the Health 2000 study) was carried out in 2000-2001 among 10,000 adult Finns. All 18- to 50-year-old men were further sampled (n = 2674) and those with completion of the 6 to 12 month compulsory service were included. (n = 2296). Time trends in consultations because of MSDs during service and findings at call-up examinations were analysed. RESULTS: From 1967 to 2006 altogether 4872 MSD-related consultations were done, most commonly because of problems in the ankle or foot, knee, or back. The proportion of conscripts visiting military health care because of MSDs increased 1.6-fold (from 44 to 72%). The average number of MSD-related consultations per conscript tripled. The proportion of conscripts with > or = 6 consultations increased 5 fold and those seeking care for multisite symptoms increased 10-fold. No increase in symptoms or findings before service could be seen at preservice examinations. CONCLUSIONS: Conscripts seek care because of musculoskeletal symptoms considerably more often nowadays than before. More attention should be focused to the prevention of traumatic and overexertion injuries of the lower limbs, although the reasons for increasing careseeking should be further investigated. PMID- 23025138 TI - Implementation of a multidisciplinary program for active duty personnel seeking care for low back pain in a U.S. Navy Medical Center: a feasibility study. AB - The aim of the pilot study was to evaluate a multidisciplinary program for nonspecific low back pain (NSLBP) at a major U.S. Navy base. In this single blinded randomized clinical trial, subjects were drawn from a larger, prospective cohort of active duty service members seeking care for NSLBP pain at a U.S. Navy Branch Medical Clinic. Outcome measures included return to work, self-reported pain, function, and psychological distress. Subjects were randomly allocated to one of two study arms: a multidisciplinary reconditioning program or the current standard of care for low back pain. The intervention lasted 4 weeks with a 12 week follow-up. Thirty-three subjects were enrolled. Subjects allocated to multidisciplinary care reported significantly lower perceived disability (p = 0.014) and less pain than those allocated to usual care at the end of the intervention period. All subjects returned to their usual duty following the conclusion of the intervention. The implementation of the intervention program was successful. Subjects in the multidisciplinary program showed a clinically significant improvement in the perception of disability compared to the usual care group. This is an important finding since perception of disability is associated with long-term functional outcome. PMID- 23025139 TI - A multiple intervention strategy for reducing femoral neck stress injuries and other serious overuse injuries in U.S. Army Basic Combat Training. AB - We hypothesized that the use of evidence based injury prevention strategies would lead to a reduction in the incidence of femoral neck stress injuries (FNSIs) and other serious overuse injuries in U.S. Army Basic Combat Training (BCT). An injury prevention strategy began in late 2008 that included: (1) leadership education, (2) leadership enforcement of proven methods, and (3) injury surveillance and reporting. Data on FNSI and removal from training for injury were analyzed based on the fiscal year 2006 through 2010 (n = 210,002). For men, FNSI were reduced from 13 to 20 cases/10,000 recruits per year (2006-2008) to 8 cases/10,000 recruits in 2010 (p < 0.01); for women, FNSI were reduced from 35 to 41 cases/10,000 recruits per year (2006-2008) to 18 cases/10,000 recruits per year in 2010 (p < 0.01). For men, removals from training for injury were reduced from 0.8 to 1.1 cases/100 recruits per year (2006-2008) to 0.5 cases/100 recruits in 2010 (p < 0.01); for women removal from training for injury was reduced from 2.3 to 2.4 cases/100 recruits (2006-2008) to 1.0 case/100 recruits per years in 2010 (p < 0.01). The time course of the changes suggests that following specific injury prevention methods was effective in reducing injuries. PMID- 23025140 TI - Modifying the U.S. Air Force Fitness Test to reflect physical combat fitness: one study's perspective. AB - Within the past few years, the U.S. Army and U.S. Marine Corps have either incorporated or in the process of incorporating physical fitness tests that assess a soldier's fitness capability in a combat environment. In this article, we investigate how the U.S. Air Force Physical Fitness Test (AFPFT) events compare to sister-services' physical fitness test events with respect to their predictability of a proxy for combat fitness. Using linear regression via ordinary least squares, we demonstrate that the AFPFT correlates poorly with an airman's combat fitness. AFPFT scores had minimal predictability (adjusted R2 0.20-0.23). Investigating all of the individual events from the three services tests, we develop a new Air Force fitness to consider and to adopt. The test incorporates a timed 1/2-mile run, 30-lb dumbbell lifts in 2 minutes, and maximum number of push-ups in 1 minute. The adjusted R2 for this model was 0.90, an almost 300% improvement over the current test, in terms of predicting combat fitness. PMID- 23025141 TI - The acute medical management of detained Somali pirates and their captives. AB - Over the last several years, piracy off the coast of East Africa has resulted in significant risks to merchant vessels and their crews. There have been multiple instances of both pirates being detained and captives being liberated by military vessels. The unique health concerns of this population have been minimally studied and military health providers must be prepared to identify and manage potential medical conditions. In an attempt to provide further guidance for providers, this article reviews the limited available literature and identifies potential health concerns of pirates and recently released captives. In addition to traumatic injuries, specific medical concerns that must be considered include infectious disease, wound management, dehydration, hypothermia, malnutrition, electrolyte disturbance, and potential psychiatric conditions. Infectious disease is also a major threat. Malaria, tuberculosis, and intestinal parasites likely pose the greatest risk. A careful medical screening along with an extensive intake history and physical examination are essential for rapid identification and initial management of this unique population. PMID- 23025142 TI - Use of the dental disease nonbattle injury encounter module to assess the emergency rate on an Army military installation within the United States. AB - The objectives of this study are (1) to establish a baseline rate for dental emergencies (DE) occurring within a Brigade Combat Team (BCT) garrisoned on a military installation located in the continental United States (CONUS), and (2) to determine if differences in risk of DE are observed in soldiers of different Dental Fitness Classifications (DFC). Data concerning DE were documented by Army Dental Corps providers using CONUS Dental Disease Nonbattle Injury Emergency Encounter module of the Corporate Dental Application (CDA). The data were collected from September 1, 2011 to December 15, 2011. The number of soldiers at risk, the BCT dental readiness, the DFC of each soldier who experienced a DE, and the date of the dental visit that preceded the DE were documented from CDA. The estimated rate of 221 DE per 1,000 soldiers per year was observed. The risk of DE for DFC 3 soldiers was five times that of soldiers who were DFC 1 or 2. Assessing the DE rate of a BCT in garrison is useful for stakeholders and policymakers who must accommodate the impact of DE on mission readiness. PMID- 23025143 TI - Prognostic value of coronary computed tomographic angiography among 1,125 consecutive military health care beneficiaries without known coronary artery disease. AB - We sought to assess the prognostic value of coronary computed tomography angiography (CCTA) among military health care system beneficiaries. We identified 1,125 consecutive symptomatic patients without known coronary artery disease (CAD) referred for 64-slice CCTA (2006-2010) at a single center. CAD was assessed as none, < 50%, or > or = 50% (obstructive) coronary stenosis. A combined endpoint of major adverse events (death, myocardial infarction [MI], coronary revascularization > 90 days after CCTA) was assessed by Kaplan-Meier and Cox proportional hazards. The mean age was 50 +/- 12 years, 59% were male, and 617 (55%) had no CAD, 411 (37%) nonobstructive CAD, and 97 (9%) obstructive CAD on CCTA. During 2.0 +/- 1.1-year follow-up, there were 6 deaths, 3 MIs, and 6 revascularizations. There was 1 event in the no-CAD group (0.08%/year), 4 events in the nonobstructive group (0.5%/year), and 9 events in patients with obstructive CAD (4.5%/year) (p < 0.001). Patients with obstructive CAD had significantly increased combined adverse events. Increasing angina typicality and risk factors (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05-1.46; p = 0.01) and obstructive CAD (HR 12.1, 95% CI 3.99-36.9; p < 0.001) were independently predictive of events. Absence of CAD was associated with very low event rates, providing military health care system patients and providers confidence in regards to cardiovascular risk, future deployments, and occupational assignments. PMID- 23025144 TI - Evaluation of two commercial immunoassays used to screen patients for systemic lupus erythematosus. AB - Diagnosing systemic lupus erythematosus (SLE) can be challenging as laboratory screening methods, although sensitive, lack specificity. The poor specificity of autoimmune testing produces more false positive results than true positive results. False positive results can cause stress to patients without autoimmune disease and require unnecessary rheumatology consultation to rule out disease. Our objective was to evaluate two screening assays to reduce the number of false positives while maintaining high sensitivity. In this study, we evaluated two immunoassays, the AtheNA Multi-Lyte II ANA System and QUANTA Lite ANA ELISA, to screen patients for SLE. All positive screening results were compared to immunoflourescent ANA testing using theHEp-2000 ANA System. A chart review was performed on all patients tested to determine clinical diagnosis of SLE. The QuantaLite ANA ELISA produced significantly more false positive results than the AtheNA Multi-Lyte II Test System when screening for SLE in our patient population. PMID- 23025145 TI - In-flight speech intelligibility evaluation of a service member with sensorineural hearing loss: case report. AB - This case report describes the in-flight speech intelligibility evaluation of an aircraft crewmember with pure tone audiometric thresholds that exceed the U.S. Army's flight standards. Results of in-flight speech intelligibility testing highlight the inability to predict functional auditory abilities from pure tone audiometry and underscore the importance of conducting validated functional hearing evaluations to determine aviation fitness-for-duty. PMID- 23025146 TI - High serum albumin ascites gradient ascites--an atypical presentation of metastatic pancreatic cancer. AB - Pancreatic adenocarcinoma has less than a 5% 5-year survival rate, and metastatic disease is associated with a median survival of 4.5 months. A typical presentation often includes evidence of biliary obstruction, abdominal pain, jaundice, and weight loss. Significant ascites is not commonly seen at initial presentation and, when present, is typically associated with a low serum albumin ascites gradient (SAAG). We discuss a patient who presented with high-SAAG ascites as her initial presentation, only to be later diagnosed with metastatic pancreatic adenocarcinoma. PMID- 23025147 TI - In response to: "Are effort measures sensitive to cognitive impairment?" Published in the December issue (Mil Med 2011; 176 (12): 1426-31). PMID- 23025148 TI - [New European clinical guidelines on dyslipidemias]. AB - In the new European clinical guidelines on dyslipidemias, screening of the risk for cardiovascular diseace is recommended by using lipid assays for all patients who are at high risk due to their clinical characteristics, and for men over 40 years of age and women of over 50 years of age. The starting point in the guidelines is an assessment of individual total risk based on traditional risk factors, i.e. LDL cholesterol level, blood pressure, smoking and age. With respect of dyslipidemia, the effect of HDL cholesterol and triglyceride levels on the total risk is recommended to complement the information provided by the LDL cholesterol level. PMID- 23025149 TI - [The puzzle of glomerulonephritides is closer to be saved]. AB - Glomerulonephritides are a mixed group of kidney diseases, the diagnosis and classification of which being based on renal biopsy. Over the last few years revolutionary findings on the pathogenesis of these diseases have been made. Above all the previously obscure immunopathogenesis of focal segmental glomerulosclerosis and membranous nephropathy have begun to unravel. New ideas are bringing new diagnostic methods to the diagnostics and monitoring of these diseases. At the same time their treatments are increasingly focusing on the underlying immunological phenomena. PMID- 23025150 TI - [Cognitive functions in substance use disorder of young adults]. AB - Neuropsychological investigations have revealed that substance use disorders of young adults are associated with abnormalities in several areas of cognitive functions as well as in general cognitive functioning. Longitudinal studies have, however, indicated that the observed differences in cognition are most likely explained by differences preceding the substance abuse as well as by short-term effects of the drugs. Cognitive abnormalities associated with substance use disorders of young adults are, however, mild and most probably do not have major effects on the treatment of substance use disorders. PMID- 23025151 TI - [Botulinum toxin as a biological weapon]. AB - Botulism is caused by botulinum neurotoxin produced by the bacterium Clostridium botulinum. It is a flaccid paralysis in which consciousness and nociception are preserved. Natural botulism typically results from ingestion of inadequately heated or unheated vacuum-packed foods. In addition, botulinum toxin is one of the most feared biological weapons. In the diagnosis and treatment of botulism early suspicion is essential. Several coinciding or local clusters without a typical connecting source, or an uncommon type of toxin may indicate an intentionally caused epidemic. PMID- 23025152 TI - [Attitudes towards biobanks among Finnish people]. AB - Compared to other Europeans, Finns by and large have rather positive attitudes towards biobanks. However, there are many concerns and hopes about biobank activities. Knowledge on biobank operations are scarce, and more information is needed. The future challenges of biobanks include maintenance of transparency in the long-term and returning data to all parties. Because public opinion may easily have an effect to one's will to participate and support the biobanks, maintenance of long range biobank activities and of trust will be essential. PMID- 23025153 TI - [Complications of hydrocephalus shunting]. AB - The most common problems related to cerebrospinal fluid shunt are obstruction, infection and overdrainage. The incidence of shunt complications is higher when less time has elapsed since the previous shunt surgery. Nearly all shunt patients end up with one or multiple reoperations. Thorough history, head scan (ultrasound, CT or MRI) and plain x-ray (shunt series) are the corner stones when reviewing shunt problems. Patients with obstructed shunt and increased intracranial pressure need urgent shunt revision. Shunt infection usually gives rise to fever with no other origin. Blood culture and shunt tap (CSF sample) often confirm the etiology. Often a neurosurgical evaluation is required to solve a shunt problem. PMID- 23025154 TI - [Whipple's disease--a rare and severe systemic infection]. AB - Whipple's disease is a very rare systemic infection caused by the bacterium Tropheryma whipplei. If untreated it can be fatal. Approximately one thousand infections caused by this microorganism have been reported globally. Our two patients with Whipple's disease suffered from weight loss, diarrhea and abdominal pain and distention, and were diagnosed with microcytic anemia and significant hypoalbuminemia. In the third patient the manifestation was blood culture negative endocarditis causing aortic insufficiency, atrial fibrillation and coronary embolisation. Antimicrobial drug therapy was effective for all three patients. PMID- 23025155 TI - [Duodenal levodopa infusion for advanced Parkinson's disease in Finland 2006 2010]. AB - BACKGROUND: Deep brain stimulation (DBS) has been used for treatment of advanced Parkinson's disease (PD) since 1990's. Duodenal levodopa infusion (DLI) has been available since 2006. MATERIALS AND METHODS: Patient records of DLI patients and clinical data of DBS patients from 2006-2010 were requested from all university and central hospitals in Finland. RESULTS: DLI was tested on 105 patients. 84 had a favourable response and were on long-term treatment. 85 patients underwent DBS operation. Technical problems and complications were common in DLI treated patients. CONCLUSIONS: DLI has become as popular as DBS in the treatment of advanced PD, but has a quite high complication rate. PMID- 23025156 TI - Contrasting predictions of low- and high-threshold models for the detection of changing visual features. AB - Change blindness is the failure of observers to notice otherwise obvious changes to a visual scene when those changes are masked in some way (eg by blotches or a blanking ofthe screen). Typically, change blindness is taken as evidence that our representation of the visual world is capacity limited. The locus of this capacity limit is thought to be visual short-term memory (vSTM). The capacity of vSTM is usually estimated with a high-threshold model which assumes that each element in the stimulus array is either fully encoded or not encoded at all, and, furthermore, that false alarms can arise only by guessing, not by noise. Low threshold models, by contrast, suggest that false alarms can arise by noise at the level of detection/discrimination and/or decision. In this study, we use a well-controlled stimulus display in which a single element changes over a blanking of the screen and contrast predictions from a popular high-threshold model of vSTM with the predictions of a low-threshold model (specifically, the sample-size model) of visual search and vSTM. The data were better predicted by the low-threshold model. PMID- 23025157 TI - Attentional capture without awareness in complex visual tasks. AB - Abrupt onsets of visual cues capture an observer's attention, even when the cues do not reach the observer's visual awareness. In the present study, we investigated the effects of subthreshold cues on the performance of a useful field of view task. Participants localized a target stimulus presented in the peripheral visual field while identifying a character presented at the fovea. Before the presentation of central and peripheral targets, a suprathreshold or subthreshold cue indicating a likely location of the peripheral target was presented. We found that the suprathreshold cue led to both a benefit in the valid trials and cost in the invalid trials, while the subthreshold cue produced only a benefit in the valid trials without a cost in the invalid trials. Similar patterns of results were also observed when the cue preceded the targets by 10 200 ms, although a small cost was observed for the 12 deg eccentricity at the stimulus onset asynchronies of 50 ms and 100 ms in the subthreshold condition. These results indicate that attentional capture occurs without awareness of the cue and suggest that the effect of the cue on the spatial shift of attention would be different between the suprathreshold and subthreshold conditions. PMID- 23025158 TI - The identification of unfolding facial expressions. AB - We asked whether the identification of emotional facial expressions (FEs) involves the simultaneous perception of the facial configuration or the detection of emotion-specific diagnostic cues. We recorded at high speed (500 frames s-1) the unfolding of the FE in five actors, each expressing six emotions (anger, surprise, happiness, disgust, fear, sadness). Recordings were coded every 10 frames (20 ms of real time) with the Facial Action Coding System (FACS, Ekman et al 2002, Salt Lake City, UT: Research Nexus eBook) to identify the facial actions contributing to each expression, and their intensity changes over time. Recordings were shown in slow motion (1/20 of recording speed) to one hundred observers in a forced-choice identification task. Participants were asked to identify the emotion during the presentation as soon as they felt confident to do so. Responses were recorded along with the associated response times (RTs). The RT probability density functions for both correct and incorrect responses were correlated with the facial activity during the presentation. There were systematic correlations between facial activities, response probabilities, and RT peaks, and significant differences in RT distributions for correct and incorrect answers. The results show that a reliable response is possible long before the full FE configuration is reached. This suggests that identification is reached by integrating in time individual diagnostic facial actions, and does not require perceiving the full apex configuration. PMID- 23025159 TI - Experience produces the atypicality bias in object perception. AB - When a morph face is produced with equal physical contributions from a typical parent face and an atypical parent face, the morph is judged to be more similar to the atypical parent. This discontinuity between physical and perceptual distance relationships, called the "atypicality bias" (Tanaka et al 1998, Cognition 68 199-220), has also been demonstrated with non-face objects (birds and cars; Tanaka and Corneille 2007 Perception & Psychophysics 69 619-627). We tested whether the atypicality bias can be induced for a novel set of artificial objects. Two categories of "blob" stimuli were generated, each composed of typical and atypical members. Morphs averaged from typical and atypical parent exemplars were used to test the presence of an atypicality bias before and after participants were familiarized with blob items. In experiment 1, participants were trained to discriminate between the two blob categories. An atypicality bias was evident after, but not prior to, category training. In experiment 2, participants rated the pleasantness of the blobs instead of learning to categorize them; an atypicality bias was present only after the ratings task. This finding suggests that relatively passive exposure to exemplars is sufficient to influence perceptions of similarity, and that the atypicality bias is a manifestation of this influence. PMID- 23025161 TI - Perceptually plausible sounds facilitate visually induced self-motion perception (vection). AB - We examined whether and how sounds influence visually induced illusory self motion (vection). Visual stimuli were presented for 40 s. They were made radially, expanding or contracting visual motion field and luminance-defined gratings drifting in a vertical or horizontal direction. Auditory stimuli were presented with the visual stimuli in most conditions; we employed sounds that increased or decreased in intensity, or ascended or descended in frequency. As a result, the sound which increased in intensity facilitated forward vection, and the sound which ascended/descended in frequency facilitated upward/downward vection. The perceptual plausibility of the sound for the corresponding self motion seemed an important factor of enhancing vection. PMID- 23025160 TI - Matching reality in the arts: self-referential neural processing of naturalistic compared to surrealistic images. AB - How are works of art that present scenes that match potential expectations processed in the brain, in contrast to such scenes that can never occur in real life because they would violate physical laws? Using functional magnetic resonance imaging, we investigated the processing of surrealistic and naturalistic images in visual artworks. Looking at naturalistic paintings leads to a significantly higher activation in the visual cortex and in the precuneus. Humans apparently own a sensitive mechanism even for artistic representations of the visual world to separate the impossible from what potentially matches physical reality. The observation reported here also suggests that sensory input corresponding to a realistic representation of the visual world elicits higher self-referential processing. PMID- 23025162 TI - Forward masking of dynamic acoustic intensity: effects of intensity region and end-level. AB - Overestimation of loudness change typically occurs in response to up-ramp auditory stimuli (increasing intensity) relative to down-ramps (decreasing intensity) matched on frequency, duration, and end-level. In the experiment reported, forward masking is used to investigate a sensory component of up-ramp overestimation: persistence of excitation after stimulus presentation. White noise and synthetic vowel 3.6 s up-ramp and down-ramp maskers were presented over two regions of intensity change (40-60 dB SPL, 60-80 dB SPL). Three participants detected 10 ms 1.5 kHz pure tone signals presented at masker-offset to signal offset delays of 10, 20, 30, 50, 90, 170 ms. Masking magnitude was significantly greater in response to up-ramps compared with down-ramps for masker-signal delays up to and including 50 ms. When controlling for an end-level recency bias (40-60 dB SPL up-ramp vs 80-60 dB SPL down-ramp), the difference in masking magnitude between up-ramps and down-ramps was not significant at each masker-signal delay. Greater sensory persistence in response to up-ramps is argued to have minimal effect on perceptual overestimation of loudness change when response biases are controlled. An explanation based on sensory adaptation is discussed. PMID- 23025163 TI - The nature and origin of cross-modal associations to odours. AB - Several studies have demonstrated reliable cross-modal associations between odours and various visual, auditory, taste, and somatosensory attributes. How these associations arise is not well understood. We examined whether cross-modal associations to odours themselves form distinct groups, and whether these groupings relate to semantic (nameability, familiarity) and perceptual (intensity, irritancy, and hedonics) olfactory attributes. Participants evaluated 20 odours, varying in all of the latter attributes, and reported their visual, auditory, gustatory, and somatosensory associations for each. Significant inter rater agreement was observed for all modalities except audition, and responses in all modalities were consistent with those obtained on a repeat test session 2 weeks later. Two groups of cross-modal odour associates emerged: one of which was related to the semantic attributes of odours and another which related to their perceptual attributes. The exception was taste, which was significantly associated with both. While these results suggest that both semantic and perceptual mechanisms underpin odour cross-modal matches, the data also point to the importance of hedonics as a further contributing mechanism. PMID- 23025164 TI - Cross-sensory correspondences and naive conceptions of natural phenomena. AB - Cross-sensory correspondences automatically intrude on performance in elaborate laboratory tasks (see Spence 2011 Attention, Perception, & Psychophysics 73 971 995, for a review). Outside such tasks, might they be responsible for some popular misconceptions about natural phenomena? Four simple demonstrations reveal how the correspondences between surface-lightness and weight, and between surface lightness and auditory pitch, generate misconceptions about the weight and movement of objects and the vocalisations of animals. Specifically, people expect darker objects to be heavier than lighter-coloured objects, to free-fall more quickly, to roll across a table more slowly, and to make lower-pitched vocalisations when they come to life. PMID- 23025165 TI - Payoff changes sensitivity by modulating the processing style. AB - In a perceptual decision-making task, we compared a neutral payoff and two asymmetric payoffs: a liberal one, favouring positive responses, and a conservative one, favouring negative responses. Participants were presented with ambiguous images composed of superimposed target and non-target photographs, and asked to decide whether the target dominated in the picture. Signal-detection analysis demonstrated that the liberal payoff yielded significantly higher sensitivity than other payoffs. We argue that the liberal payoff encourages confirming the target's domination, hence making it easier to ignore non-target elements of the picture. We conclude that payoff can influence perceptual decisions by changing the approach to the perceptual task, and how attention is allocated between different elements of the sensory input. PMID- 23025166 TI - The sensitivity of a lower limb model to axial rotation offsets and muscle bounds at the knee. AB - Soft tissue artifacts during motion capture can lead to errors in kinematics and incorrect estimation of joint angles and segment motion. The aim of this study was to evaluate the effect of shank segment axial rotation and knee rotator muscle bounds on predicted muscle and joint forces in a musculoskeletal model of the lower limb. A maximal height jump for ten subjects was analysed using the original motion data and then modified for different levels of internal and external rotation, and with the upper force bound doubled for five muscles. Both externally rotating the shank and doubling the muscle bounds increased the ability of the model to find a solution in regions of high loading. Muscle force levels in popliteus and tensor fascia latae showed statistically significant differences, but less so in plantaris, sartorius or gracilis. The shear and patellofemoral joint forces were found to be significantly affected by axial rotation during specific phases of the motion and were dependent on the amount of rotation. Fewer differences were observed when doubling the muscle bounds, except for the patellofemoral force and plantaris and sartorius muscle force, which were significantly increased in many of the jump phases. These results give an insight into the behaviour of the model and give an indication of the importance of accurate kinematics and subject-specific geometry. PMID- 23025167 TI - Cruciate ligament loading during common knee rehabilitation exercises. AB - Cruciate ligament injuries are common and may lead to dysfunction if not rehabilitated. Understanding how to progress anterior cruciate ligament and posterior cruciate ligament loading, early after injury or reconstruction, helps clinicians prescribe rehabilitation exercises in a safe manner to enhance recovery. Commonly prescribed therapeutic exercises include both weight-bearing exercise and non-weight-bearing exercise. This review was written to summarize and provide an update on the available literature on cruciate ligament loading during commonly used therapeutic exercises. In general, weight-bearing exercise produces smaller loads on the anterior cruciate ligament and posterior cruciate ligament compared with non-weight-bearing exercise. The anterior cruciate ligament is loaded less at higher knee angles (i.e. 50-100 degrees). Squatting and lunging with a more forward trunk tilt and moving the resistance pad proximally on the leg during the seated knee extension unloads the anterior cruciate ligament. The posterior cruciate ligament is less loaded at lower knee angles (i.e. 0-50 degrees), and may be progressed from level ground walking to a one-leg squat, lunges, wall squat, leg press, and the two-leg squat (from smallest to greatest). Exercise type and technique variation affect cruciate ligament loading, such that the clinician may prescribe therapeutic exercises to progress ligament loading safely, while ensuring optimal recovery of the musculoskeletal system. PMID- 23025168 TI - Effects of muscle-equivalent forces on the biomechanical behavior of proximal femur fracture models: a pilot study on artificial bones. AB - INTRODUCTION: There has been extensive analysis of the influence of muscle forces and their effects on the biomechanical behavior of the proximal femur. Nevertheless, these forces have only been taken into account in a handful of biomechanical studies in the field of traumatology. The aim of this study was to analyze the biomechanical behavior of two typical fracture models of the proximal femur based on muscle-equivalent forces. METHOD: Plate osteosynthesis was performed on two groups of artificial femora to stabilize either a trochanteric osteotomy (n= 5) or a femur shaft osteotomy (n = 5). After fixation axial loading was applied to the constructs first without muscle-equivalent forces and then with the addition of these forces (abductor groups and vastus lateralis). Displacement at the osteotomy site and the stiffness of the whole construct were measured during loading. RESULTS: Comparison of the two loading modes revealed no significant differences for displacement or stiffness for the trochanteric fractures. For the femur shaft fractures, a significant difference was found for displacement (p = 0.023) and stiffness (p = 0.003) with or without muscle equivalent forces. CONCLUSION: The loading protocol for implant testing on femur shaft fractures should include muscle-equivalent forces. For trochanteric fractures, consideration of muscle forces is not entirely necessary since they will have little effect on the results, for example, when comparing implants. PMID- 23025169 TI - Iterative design and testing of a modular anterior plate for lumbar spine fixation applications. AB - In this study, a modular anterior lumbar plate is designed and tested in an iterative fashion. The study starts with a basic design that is built by combining same-sized modules; an approach that allow inventory costs to be decreased. The basic design is iteratively improved guided by the results of biomechanical tests performed on each new design. At the end of three iterations of improvements, the design is complete and the plate is of sufficient quality for it to be used in anterior surgical operations. Using these plates creates the advantage of being able to increase the size and slot count during surgical operations, even when some of the modules are already fixed to vertebrae. The designed modular plate is shown to be as safe for use as a rigid plate in terms of its static and fatigue biomechanical performances. PMID- 23025170 TI - Polycaprolactone-starch blends with corn-based coupling agent: physical properties and in vitro analysis. AB - In an attempt to improve properties of polycaprolcatone-starch blend, this study uses zein as coupling agent in preparing the blend through a single-step process. Zein, which has affinity to both polar and non-polar groups, is expected to improve miscibility between the blends' constituents and its overall biocompatibility. Mechanical properties of the blend were tested and further characterizations (Fourier transform infrared spectroscopy, thermal properties) were performed to analyze the effect of zein as an addition to the blend's physical properties. The blend's biocompatibility was examined by indirect methods (contact angle and weight gain after immersion in simulated body fluid) and in vitro analysis. No significant effect on the blend's strength and stiffness was caused by adding zein. Hydrophilicity and cell affinity were improved when zein was added. Zein did not perform as a coupling agent that improved miscibility between polycaprolactone and starch, but its addition improved the blend's biocompatibility. PMID- 23025171 TI - Standardising the clinical assessment of coronal knee laxity. AB - Clinical laxity tests are used for assessing knee ligament injuries and for soft tissue balancing in total knee arthroplasty. This study reports the development and validation of a quantitative technique of assessing collateral knee laxity through accurate measurement of potential variables during routine clinical examination. The hypothesis was that standardisation of a clinical stress test would result in a repeatable range of laxity measurements. Non-invasive infrared tracking technology with kinematic registration of joint centres gave real-time measurement of both coronal and sagittal mechanical tibiofemoral alignment Knee flexion, moment arm and magnitude of the applied force were all measured and standardised. Three clinicians then performed six knee laxity examinations on a single volunteer using a target moment of 18 Nm. Standardised laxity measurements had small standard deviations (within 1. 1 degree) for each clinician and similar mean values between clinicians, with the valgus laxity assessment (mean of 3 degrees) being slightly more consistent than varus (means of 4 degrees or 5 degrees). The manual technique of coronal knee laxity assessment was successfully quantified and standardised, leading to a narrow range of measurements (within the accuracy of the measurement system). Minimising the subjective variables of clinical examination could improve current knowledge of soft tissue knee behaviour. PMID- 23025172 TI - On-line analysis of cracking in cortical bone under wedge penetration. AB - Understanding the mechanism of crack propagation during bone cutting is necessary for the development of realistic bone cutting models. This article studies the on line fractural behaviour of cortical bone caused by penetration with a sharp metallic wedge mounted on an on-line loading stage within an X-ray microfocus computed tomography system. The experimental results demonstrated anisotropy in crack propagation depending on the penetration direction with regard to the longitudinal bone axis and relate the crack growth to the extent of penetration. Scanning electron microscopy is performed to analyse the mechanism of cracking in the two phase microstructure of compact bone. PMID- 23025173 TI - Evaluation of direct and indirect additive manufacture of maxillofacial prostheses. AB - The efficacy of computer-aided technologies in the design and manufacture of maxillofacial prostheses has not been fully proven. This paper presents research into the evaluation of direct and indirect additive manufacture of a maxillofacial prosthesis against conventional laboratory-based techniques. An implant/magnet-retained nasal prosthesis case from a UK maxillofacial unit was selected as a case study. A benchmark prosthesis was fabricated using conventional laboratory-based techniques for comparison against additive manufactured prostheses. For the computer-aided workflow, photogrammetry, computer-aided design and additive manufacture (AM) methods were evaluated in direct prosthesis body fabrication and indirect production using an additively manufactured mould. Qualitative analysis of position, shape, colour and edge quality was undertaken. Mechanical testing to ISO standards was also used to compare the silicone rubber used in the conventional prosthesis with the AM material. Critical evaluation has shown that utilising a computer-aided work-flow can produce a prosthesis body that is comparable to that produced using existing best practice. Technical limitations currently prevent the direct fabrication method demonstrated in this paper from being clinically viable. This research helps prosthesis providers understand the application of a computer-aided approach and guides technology developers and researchers to address the limitations identified. PMID- 23025174 TI - A linear-actuated torsional device to replicate clinically relevant spiral fractures in long bones. AB - To better understand the mechanisms underlying spiral fracture we would like to carry out biomechanical tests of long bones loaded in torsion to failure. A device was fabricated to perform torsional tests of long bones using a single axis linear actuator. The principal operation of the device was to transform the vertical displacement of a material testing machine's linear actuator into rotational movement using a spur gear and rack system. Accuracy and precision of the device were quantified using cast-acrylic rods with known torque-rotation behavior. Cadaveric experimentation was used to replicate a clinically relevant spiral fracture in eleven human proximal tibiae; strain-gage data were recorded for a single specimen. The device had an experimental error of less than 0.2 Nm and was repeatable to within 0.3%. Strain gage data were in line with those expected from pure torsion and the cadaveric tibiae illustrated spiral fractures at ultimate torque and rotation values of 130.6 +/- 53.2 Nm and 8.3 +/- 1.5 degrees, respectively. Ultimate torque was highly correlated with DXA assessed bone mineral density (r = 0.87; p < 0.00 1). The device presented is applicable to any torsional testing of long bone when only a single-axis linear actuator is available. PMID- 23025175 TI - Development of Leishmania parasites in Culicoides nubeculosus (Diptera: Ceratopogonidae) and implications for screening vector competence. AB - Biting midges of the genus Forcipomyia (Diptera: Ceratopogonidae) have recently been implicated as vectors of kinetoplastid parasites in the Leishmania enrietti complex. This study assesses susceptibility of one of the few successfully colonized Ceratopogonidae, Culicoides nubeculosus Meigen, to infection with Leishmania parasites infecting humans. While Leishmania infantum initially developed in the midgut of C. nubeculosus until 2 d postfeeding, parasite populations on day 3 were considerably reduced. Despite this, a polymerase chain reaction-based assay continued to indicate presence of L. infantum for up to 7 d after the bloodmeal. These findings are discussed within the wider context of implicating arthropods as vectors of Leishmania and it is suggested that conventional polymerase chain reaction use in vector-competence studies should be accompanied by direct microscopical observations. PMID- 23025176 TI - Estimation of population size and dispersal of Aedes polynesiensis on Toamaro motu, French Polynesia. AB - Mark-release-recapture methods were used to compare Aedes polynesiensis Marks adult numbers and dispersal between dry and wet seasons in a closed population on a small island (motu) in French Polynesia. Females were more than three times more common during wet (December 2008) than dry (May 2007) season samplings although high numbers of vectors were collected during both seasons. Lincoln Petersen estimates for Ae. polynesiensis females on the motu were 6,055 per hectare for the dry season and 18,860 per hectare for the wet season. Marked females dispersed rapidly to all parts of the motu and survived until recaptures on days 1-5 after release. Males were not adequately sampled using human sentinels or Biogent Sentinel traps. PMID- 23025177 TI - Overwintering survival of nymphal Ixodes scapularis (Acari: Ixodidae) under natural conditions. AB - Blacklegged ticks (Ixodes scapularis Say) are exquisitely sensitive to very cold and dry conditions. For this reason it has long been assumed that climatic differences among locations and within microhabitats have a strong influence on variation in their survival over winter. This assumption, however, rests largely on laboratory exposures and on broad-scale associations between climatic variables and the observed distributions of ticks. We present the results of a study of the overwintering survival of I. scapularis nymphs in their natural environment from October through May in two locations in New York State using a repeated sampling strategy to determine when mortality occurred, and whether those events coincide with extreme conditions. We then fit these data to a simple, flexible statistical model in which the hazard of mortality varies with measurable conditions, here minimum daily temperature and mean daily relative humidity. Regardless of winter conditions, > 80% of ticks survived at both sites. A model with constant hazard (i.e., independent of temperature and humidity) was best supported by the data. Although models with hazard increasing at temperatures below 0 deg C and at > 90% relative humidity provided slightly better fits to the data, these models were less parsimonious. These results weaken the expectation that cold-related overwintering mortality necessarily plays a major role in restricting populations of these ticks and thus, risk of tick-borne zoonoses. PMID- 23025178 TI - Strain specific differences in intraspecific competition in Aedes albopictus (Diptera: Culicidae). AB - Malathion is an organophosphate insecticide that is used for the control of adult mosquitoes and agricultural pests. Recent studies have shown that malathion affects competition among mosquitoes in the larval stage. Individuals from laboratory colonies are often used in experiments but it is not known whether there is a difference between laboratory and field strains in their response to competition and malathion. Intraspecific larval competition in the presence of malathion (0.11 mg/liter) was compared between laboratory and field strains of Aedes albopictus (Skuse), a native of Asia that has established in the United States. There was no difference in the responses of the two strains to the presence of malathion. The fitness (finite growth rate) of the field strain decreased at the highest larval density tested but there was no difference in fitness across densities for the laboratory strain. This finding suggests that laboratory rearing could reduce sensitivity to crowding. PMID- 23025179 TI - Inhibition against mosquito cytochrome P450 enzymes by rhinacanthin-A, -B, and -C elicits synergism on cypermethrin cytotoxicity in Spodoptera frugiperda cells. AB - Rhinacanthus nasutus (Acanthaceae) is a shrub reported to contain insecticidal activities. The current study was conducted to determine whether R. nasutus constituents could inhibit benzyloxyresorufin O-debenzylation (BROD) mediated by CYP6AA3 and CYP6P7. Both enzymes have shown pyrethroid degradation activity and been implicated to play role in pyrethroid resistance in Anopheles minumus (Theobald) mosquito, a malaria vector. Three compounds, rhinacanthin-A, -B, and C that exhibited potent inhibitory activity were isolated and purified from aerial part of R. nasutus. Their kinetic parameters and modes of inhibition were determined. Rhinacanthin-B was the most potent inhibitor in in vitro inhibition assay and exhibited mechanism-based inhibition against both CYP6AA3 and CYP6P7. Rhinacanthin-C which is a major compound of R. nasutus reversibly inhibited both enzymes in vitro with 2-4 folds less inhibitory potency than rhinacanthin-B. In contrast, rhinacanthin-A reversibly inhibited CYP6AA3, but inhibition against CYP6P7 was a mechanism-based inhibition type. Where mechanism-based inhibition was found, the inhibition showed characteristic of time-, concentration dependence, and requirement of NADPH. Using 3-(4, 5-dimethylthiazol-2-y-l)-2, 5 diphenyltetrazolium bromide (MTT) cytotoxicity assay in intact Spodoptera frugiperda (Sf9) cells, the three compounds increased susceptibility of CYP6AA3- and CYP6P7-expressing cells to cypermethrin cytotoxicity because of inhibition effect on mosquito enzymes. The combined inhibition effect on mosquito cytochrome P450 enzyme and synergistic effect on cypermethrin cytotoxicity of the three R. nasutus compounds could be beneficial for resistance management strategies in mosquito vector control. PMID- 23025180 TI - An inexpensive and effective larval diet for Anopheles arabiensis (Diptera: Culicidae): eat like a horse, a bird, or a fish? AB - A successful sterile insect technique program depends upon mass production of good-quality sterile insects for release into a target area. Specifically, to control Anopheles arabiensis Patton (Diptera: Culicidae) in a pilot area in northern Sudan, 1 million An. arabiensis sterile males per day are needed. To reach this production objective, mosquito mass rearing is indispensable and larval diet, a key parameter for the production of healthy male mosquitoes, needs to be cost-effective. The Koi Floating Blend fish food, previously used at the Food and Agriculture Organization/International Atomic Energy Agency Insect Pest Control Laboratory for the routine rearing of the An. arabiensis colony, is no longer available. The aim of this study was to find a cheap and effective substitute for the discontinued diet. Several candidate powdered diets that are commercially available were tested to determine the best diet. By using mixture experiment principles and response surface methodology, the combination of two components, bovine liver powder and tuna meal, showed the best results in terms of larval survival, developmental, rate and adult size. The addition of a vitamin mixture further improved the diet. These positive production results coupled with the relatively low cost of our blend demonstrated the possibility of its use for mass rearing purpose. PMID- 23025181 TI - First detection of multiple knockdown resistance (kdr)-like mutations in voltage gated sodium channel using three new genotyping methods in Anopheles sinensis from Guangxi Province, China. AB - To investigate knockdown resistance (kdr)-like mutations associated with pyrethroid resistance in Anopheles sinensis (Wiedemann, 1828), from Guangxi province, southwest China, a segment of a sodium channel gene was sequenced and genotyped using three new genotyping assays. Direct sequencing revealed the presence of TTG-to-TCG and TG-to-TTT mutations at allele position L1014, which led to L1014S and L1014F substitutions in a few individual and two novel substitutions of N1013S and L1014W in two DNA templates. A low frequency of the kdr allele mostly in the heterozygous state of L1014S and L1014F was observed in this mosquito population. In this study, the genotyping of An. sinensis using three polymerase chain reaction-based methods generated consistent results, which agreed with the results of DNA sequencing. In total, 52 mosquitoes were genotyped using a direct sequencing assay. The number of mosquitoes and their genotypes were as follows: L/L = 24, L/S = 19, L/F = 8, and F/W = 1. The allelic frequency of L1014, 1014S, and 1014F were 72, 18, and 9%, respectively. PMID- 23025182 TI - Efficacy of residual insecticide Biflex AquaMax applied as barrier treatments for managing mosquito populations in suburban residential properties in southeast Queensland. AB - The pyrethroid insecticide Biflex AquaMax (bifenthrin) was evaluated for its ability to suppress coastal mosquito populations in a controlled suburban backyard study in Mango Hill, Queensland, Australia. The insecticide was applied to perimeter vegetation, fencing in selected backyards, or both, and mosquito populations were monitored weekly from 3 wk before to 8 wk after treatment (11 wk total) by using CDC miniature light traps and human bait landing rates. In addition, bioassays were conducted on vegetation and wood surfaces to monitor residual activity. The two most common species in light trap collections were the Ross River Virus vectors Aedes vigilax (Skuse) and Culex annulirostris Skuse. After treatment, Ae. vigilax populations in treated properties were significantly lower (75-90%) compared with untreated properties. In contrast, Cx. annulirotris, Coquillettidia xanthogaster (Edwards) and Mansonia uniformis (Theobald) populations were not impacted by the treatment. Bioassays revealed that the product gave better residual mortality when applied to vegetation (94.6 +/- 11.8%) than wooden surfaces (75.9 +/- 29.1%) during the 8-wk posttreatment period. PMID- 23025183 TI - Efficacy of indoor residual spraying using lambda-cyhalothrin for controlling nontarget vector fleas (Siphonaptera) on commensal rats in a plague endemic region of northwestern Uganda. AB - Over the past two decades, the majority of human plague cases have been reported from areas in Africa, including Uganda. In an effort to develop affordable plague control methods within an integrated vector control framework, we evaluated the efficacy of indoor residual spraying (IRS) techniques commonly used for mosquito control for controlling fleas on hut-dwelling commensal rodents in a plague endemic region of Uganda. We evaluated both the standard IRS spraying (walls and ceiling) and a modified IRS technique that included insecticide application on not only on walls and ceiling but also a portion of the floor of each treated hut. Our study demonstrated that both the standard and modified IRS applications were effective at significantly reducing the flea burden and flea infestation of commensal rodents for up to 100 d after application, suggesting that IRS could potentially provide simultaneous control of mosquito and fleaborne diseases. PMID- 23025184 TI - Efficacy and environmental persistence of nootkatone for the control of the blacklegged tick (Acari: Ixodidae) in residential landscapes. AB - The ability of the plant-derived compound nootkatone to control nymphs of the blacklegged tick, Ixodes scapularis Say, was evaluated at lawn perimeter plots at homes in Lyme disease endemic areas of Connecticut. Three formulations of nootkatone ranging from 0.05 to 0.84% (0.06 - 1.03 g AI/m2) were applied by a hydraulic sprayer from 2008 to 2010. In 2008, the 0.84% emulsifiable nootkatone formulation provided 100% control of I. scapularis through week 1, but declined to 49 and 0% by 2 and 3 wk posttreatment, respectively. A combination of 0.05% nootkatone and entomopathogenic fungus, Metarhizium brunneum Petch F52, resulted in 50% control for the first week posttreatment and no control in subsequent weeks. The 0.84% emulsifiable nootkatone formulation was phytotoxic, although no damage was observed with the 0.05% formulation with Metarhizium. Residual analysis of nootkatone collected on filter paper disks showed that > or = 95% of the emulsified nootkatone for both formulations was lost within 7 d after application. A lignin-encapsulated nootkatone formulation (0.56 and 0.46% in 2009 and 2010, respectively) provided 100% control of I. scapularis for 8 wk in 2009 and, in 2010, 67% control at approximately 1 wk posttreatment with respect to the pretreatment counts, although there was no difference in tick abundance posttreatment. A 0.60% Maillard-reaction encapsulated nootkatone formulation in 2010 provided a similar level of control (62%). Nootkatone in the lignin and Maillard formulations were more persistent than the emulsifiable formulation. Little or no phytotoxicity was observed with the encapsulated formulations. Encapsulating nootkatone reduced phytotoxicity and appeared to reduce environmental loss. While nootkatone can provide effective tick control, further work is needed to refine formulations to address phytotoxicity, yet provide sufficient material to control ticks. PMID- 23025185 TI - Comparisons of life-history characteristics of a genetic sexing strain with laboratory strains of Anopheles arabiensis (Diptera: Culicidae) from northern Sudan. AB - A genetic sex separation strain (GSS) has been created for Anopheles arabiensis (Patton) (Diptera: Culicidae), one of the major African malaria vectors, for use in controlling wild populations of this species via the sterile insect technique (SIT). This GSS strain, "ANO IPCL1," allows sex separation by a translocation linking a dieldrin resistance allele and the Y chromosome. Differences between ANO IPCL1 relative to wild strains might reflect its field performance and therefore are of concern. Of more immediate interest is how differences might affect production during mass rearing. Life-history parameters were measured for the ANO IPCL1 strain and the two wild strains from which it originated. Although developmental rate differences were found among them, none were large. However, a major observed variation was the very low intrinsic fertility of ANO IPCL1 because of the translocation itself. This resulted in a much lower rate of increase: ANO IPCL1 was able to double its population size, in 7.8 +/- 0.4 d, whereas Dongola and Sennar strains could do so in 4.9 +/- 0.5 and 5.6 +/- 0.4 d. The presence of the Y-autosome translocation mainly affected the natural fertility of the males, and this will require amplification steps during mass rearing. PMID- 23025186 TI - Efficacy of pyriproxyfen-treated nets in sterilizing and shortening the longevity of Anopheles gambiae (Diptera: Culicidae). AB - Pyrethroid-resistant malaria vectors have become a serious threat for malaria control, and bed nets that reduce the development of resistance are urgently needed. Here, we tested the effects of bed nets treated with the insect growth regulator pyriproxyfen against adult female Anopheles gambiae Giles (Diptera: Culicidae) under laboratory conditions. Noninsecticidal nets made of 195 denier monofilament polyethylene with a mesh size of 75 holes per square inch (equivalent to the Olyset Net) were dipped in a 0.1, 0.01, or 0.001% (wt:vol) alcohol solution of pyriproxyfen and dried overnight. Adult females of an insecticide-susceptible An. gambiae strain were exposed to treated and untreated nets before and after a bloodmeal. Bioassays showed that females were completely sterilized after exposure to 0.1% (35 mg [AI]/m2) and 0.01% pyriproxyfen-treated nets both before and after a bloodmeal. In addition, adult longevity decreased after exposure to the pyriproxyfen-treated nets in a concentration-dependent manner. The sterilizing and life-shortening effects of pyriproxyfen on the vector mosquito indicate that the combined use of pyriproxyfen and pyrethroids on bed nets has the potential to provide better malaria control and prevent the further development of pyrethroid resistance in malaria vectors. PMID- 23025187 TI - Individual and combined releases of Muscidifurax raptor and M. raptorellus (Hymenoptera: Pteromalidae) as a biological control tactic targeting house flies in dairy calf facilities. AB - The impact of commercially reared house fly parasitoids released into nine dairy calf coverall facilities were evaluated over 3 yr. Individual and equally mixed ratios of the pteromalid parasitoids Muscidifurax raptor Girault and Saunders and M. raptorellus Kogan and Legner were released at a rate of 500 parasitoids per calf per week for 8 wk. Prerelease, release, and postrelease parasitism was monitored using nearly 100,000 sentinel house fly, Musca domestica L., pupae during the 3 yr study. In general, very few adult parasitoids were recovered during the prerelease period and on the no-release farms during any period. However, considerable numbers of M. raptor and M. raptorellus were recovered from sentinel pupae on respective release farms. As expected, the greatest successful parasitism occurred during release periods, with a drop during postrelease periods. High successful parasitism and uneclosed pupae on M. raptorellus release farms suggests that this parasitoid was aggressive in attacking hosts with progeny production at approximately four wasps per pupa. Solitary releases of M. raptor provided sentinel mortality between 31 and 38%, whereas sentinel mortality on M. raptorellus-release farms was double, at 59-80%. Using mixed releases of the two species, overall fly mortality was slightly lower than that observed on M. raptorellus-only farms. This study documents the advantage of releasing M. raptorellus rather than M. raptor on New York dairy calf facilities, as supported by higher parasitism rates and lower costs (35-75%) for purchase of these gregarious wasps, as 75-80% fewer parasitized pupae are needed to achieve similar adult parasitoid levels. PMID- 23025188 TI - Chemical composition and repellency of essential oils from four medicinal plants against Ixodes ricinus nymphs (Acari: Ixodidae). AB - In our search for effective tick repellents from plant origin, we investigated the effect of essential oils of four medicinal and culinary plants belonging to the family Lamiaceae on nymphs of the tick Ixodes ricinus (L.). The essential oils of the dry leaves of Rosmarinus officinalis (Rosemary) (L.), Mentha spicata (Spearmint) (L.), Origanum majorana (Majoram) (L.), and Ocimum basilicum (Basil) (L.) were isolated by steam distillation and 15 microg/cm2 concentration of oils was tested against ticks in a laboratory bioassay. The oils of R. officinalis, M. spicata, and O. majorana showed strong repellency against the ticks 100, 93.2, and 84.3%, respectively, whereas O. basilicum only showed 64.5% repellency. When tested in the field, the oils of R. officinalis and M. spicata showed 68.3 and 59.4% repellency at a concentration of 6.5 microg/cm2 on the test cloths. The oils were analyzed by gas chromatography mass spectrometry and the major compounds from the most repellent oils were 1,8-cineole, camphor, linalool, 4 terpineol, borneol, and carvone. PMID- 23025189 TI - Carbon dioxide fumigation for controlling bed bugs. AB - We investigated the potential of carbon dioxide (CO2) fumigation as a method for controlling bed bugs, Cimex lectularius L. The effect of bed bug developmental stage, temperature, and CO2 concentration on the minimum time to kill 100% of bed bugs was determined. The minimum CO2 concentration lethal to all bed bug stages was approximately 30% with 24 h exposure time at 25 degrees C. The minimum fumigation time required to kill 100% of eggs using 100% CO2 at 20, 25, and 30 degrees C were 3, 7, and 8 h, respectively; the minimum fumigation time to kill 100% of adult males/nymphs were 8, 13, and 14 h, respectively. The minimum time to kill 100% of adult males/nymphs using 50 and 70% CO2 at 25 degrees C were 18 and 16 h, respectively. We found that eggs were not completely killed after 24 h fumigation when the CO2 concentration was lower than 80%. Thus, bed bug eggs were more susceptible to 100% CO2 fumigation than nymphs and adult males but more tolerant than nymphs and adult males with lower CO2 concentration (50-80%). There were no significant differences among nymphs, adult males, and adult females in their susceptibility to 100% CO2 fumigation. A 24 h fumigation in sealed 158 liter (42 gallon) heavy duty garbage bags filled 90% full with fabric materials and/or boxes and 1,350 g dry ice per bag was sufficient to kill all stages of bed bugs hidden in the materials at room temperature (23-24 degrees C). Sealed heavy duty garbage bags maintained > or = 94% CO2 for at least 24 h. Custom-made double zipper plastic bags (122 x 183 cm) were also used to evaluate the effectiveness of CO2 fumigation for controlling bed bugs. Each bag was filled with fabric and boxes to 50-90% full. Bed bugs were hidden in various locations of each bag. CO2 was introduced into the bags through a CO2 cylinder. CO2 fumigation lasting 24-48 h was sufficient to kill all stages of bed bugs at room temperature, depending on the quantity of materials placed in each bag and whether CO2 was introduced one or two times at the onset. CO2 is an effective alternative to conventional fumigants for eliminating bed bugs hiding in infested household items such as clothing, shoes, books, electronics, sofas, and so forth. PMID- 23025190 TI - Toxicity of Zanthoxylum piperitum and Zanthoxylum armatum oil constituents and related compounds to Stomoxys calcitrans (Diptera: Muscidae). AB - Zanthoxylum plants (Rutaceae) have drawn attention because they contain insecticidal principles against insects. An assessment was made of the insecticidal and acetylcholinesterase (AChE) inhibitory activities of Zanthoxylum piperitum steam distillate and Zanthoxylum armatum seed oil, their 28 constituents, and eight structurally related compounds against female stable fly, Stomoxys calcitrans (L.). Results were compared with those of two organophosphorus insecticides chlorpyrifos and dichlorvos. Potent fumigant toxicity was observed with cuminaldehyde, thymol, (1S)-(-)-verbenone, (-) myrtenal, carvacrol, (S)-(Z)-verbenol, Zanthoxylum piperitum steam distillate, cuminyl alcohol, Zanthoxylum armatum seed oil, piperitone, (-)-(Z)-myrtanol, and citronellal (LC50, 0.075-0.456 microg/cm3). However, they were five orders of magnitude less toxic than either chlorpyrifos or dichlorvos. An in vitro bioassay using female fly heads indicates that strong AChE inhibition was produced by citronellyl acetate, alpha-pinene, thymol, carvacrol, and alpha-terpineol (1.20 2.73 mM), but no direct correlation between fly toxicity and AChE inhibition by the test compounds was observed. Structure-activity relationships indicate that structural characteristics, such as carbon skeleton, degrees of saturation and types of functional groups, and vapor pressure parameter, appear to play a role in determining toxicities of the test monoterpenoids to stable flies. Global efforts to reduce the level of highly toxic synthetic insecticides in the agricultural environment justify further studies on Z. piperitum and Z. armatum oil-derived materials as potential insecticides for the control of stable fly populations. PMID- 23025191 TI - Host preference of the arbovirus vector Culex erraticus (Diptera: Culicidae) at Sonso Lake, Cauca Valley Department, Colombia. AB - Culex erraticus (Dyar & Knab) is a competent vector of Eastern equine encephalitis virus and subtype IC Venezuelan equine encephalitis virus, and both St. Louis encephalitis virus and West Nile virus have been isolated from field collected specimens. Previous bloodmeal analysis studies have shown this species to be a generalist, feeding on a variety of mammals, birds, reptiles, and amphibians. This behavior can bridge arboviral transmission across different vertebrate groups. Our study examined the host preference of Cx. erraticus at Sonso Lake in Colombia. From July to August 2008, blood-engorged mosquitoes were collected from resting boxes, while vertebrate abundance was determined to calculate host preference. Based on mitochondrial DNA analysis of bloodmeals, birds were the predominant hosts (57.6%), followed by mammals (30.8%), and reptiles (6.7%); 9.5% of the bloodmeals were mixed. The most commonly fed upon species were: limpkin, black-crowned night-heron, striated heron, human, and capybara. Forage ratios showed the least bittern, limpkin, Cocoi heron, striated heron, capybara, and black-crowned night heron were preferred hosts across all vertebrates. Of the available avifauna, the least bittern, limpkin, striated heron, Cocoi heron, and black-crowned night heron were preferred, whereas the bare faced ibis, great egret, snowy egret, and cattle egret were under-used. This study shows that while Cx. erraticus is an opportunistic feeder, using diverse vertebrate hosts in the environment, certain avian species are targeted preferentially for bloodmeals. PMID- 23025192 TI - Decapitation improves detection of Wolbachia pipientis (Rickettsiales: Anaplasmataceae) in Culex pipiens (Diptera: Culicidae) mosquitoes by the polymerase chain reaction. AB - Polymerase chain reaction (PCR) is often used to detect microorganisms, pathogens, or both, including the reproductive parasite Wolbachia pipientis (Rickettsiales: Anaplasmataceae), in mosquitoes. Natural populations of Culex pipiens L. (Diptera: Culicidae) mosquitoes are infected with one or more strains of W. pipientis, and crosses between mosquitoes harboring different Wolbachia strains provide one of the best-known examples of cytoplasmic incompatibililty (CI). When we used PCR to monitor Wolbachia in the Buckeye strain of Culex pipiens, and in a Wolbachia-cured sister colony obtained by tetracycline treatment, we noted false negative PCR reactions with DNA samples from infected mosquitoes; these results were inconsistent with direct microscopic observation of Wolbachia-like particles in gonads dissected from mosquitoes in the same population. Assays with diluted template often improved detection of positive samples, suggesting that DNA prepared from whole mosquitoes contained an inhibitor of the PCR reaction. We reconciled discrepancies between PCR and microscopy by systematic measurement of the PCR reaction in the presence of an internal standard. Mosquito decapitation before DNA extraction restored the reliability of the PCR reaction, allowing accurate determination of Wolbachia infection status in infected and tetracycline-cured mosquito populations, consistent with microscopic examination. Using PCR primers based on the Tr1 gene, we confirmed that the Wolbachia infection in the Buckeye strain of Culex pipiens belongs to the genotype designated wPip1. Finally, to explore more widely the distribution of PCR inhibitors, we demonstrated that DNA isolated from the cricket, Acheta domesticus (L.); the beetle, Tenebrio molitor L.; the honey bee, Apis mellifera L.; and the mosquito, Anopheles punctipennis Say also contained PCR inhibitors. These results underscore the importance of measuring the presence of inhibitors in PCR templates by using a known positive standard, and provide an approach that will facilitate use of PCR to monitor environmental samples of mosquitoes that harbor endosymbionts or pathogenic organisms. PMID- 23025193 TI - Life cycle completion of parasite Ascogregarina taiwanensis (Apicomplexa: Lecudinidae) in non-native host Ochlerotatus japonicus (Diptera: Culicidae). AB - Ascogregarina taiwanensis (Lien and Levine), a protist gut parasite of Aedes albopictus (Skuse), is not known to complete its life cycle within the potential competitor species, Ochlerotatus japonicus (Theobald). In a laboratory cross infection study we demonstrated that A. taiwanensis completed its life cycle within Oc. japonicus and remained infectious. We also sampled cohabitating mosquito larvae in Mercer County, NJ, and based on ribosomal DNA sequence data, we determined that Oc. japonicus cohabitating with Ae. albopictus can become infected with A. taiwanensis. PMID- 23025194 TI - Effect of the volume of organic infusion used in gravid traps for collecting Culex quinquefasciatus (Diptera: Culicidae). AB - Traps that selectively collect gravid mosquitoes have advantages over other collection methods for the purpose of disease surveillance: they trap mosquitoes with a higher probability of carrying disease as they have blood fed on at least one occasion. Gravid traps typically use infusions of organic material to attract gravid mosquitoes, particularly Culex quinquefasciatus (Say). These infusions are heavy and have an unpleasant odor, presenting logistical difficulties for disease monitoring programs. Typically, gravid traps use 4 liters of infusion. The present trial compared the responses of gravid female mosquitoes to 2 and 4 liters of infusion to see if equivalent numbers of mosquitoes could be collected using the smaller volume. In an attempt to better understand the effects of volume of infusion on mosquito oviposition behavior, egg laying on the two volumes was also monitored. There was a significant difference between the mean numbers of egg rafts laid on 2 and 4 liters of infusion. However, the mean numbers of gravid Cu. quinquefasciatus collected in gravid traps with 2 and 4 liters were not significantly different. The results indicate that 2 liters can be used instead of 4 liters for gravid trapping, significantly reducing the cost and logistical difficulties associated with such efforts. The behavioral responses of gravid females to different volumes are also discussed. PMID- 23025195 TI - Oviposition restraint and developmental alterations in the ectoparasitic wasp, Nasonia vitripennis, when utilizing puparia resulting from different size maggot masses of Lucilia illustris, Protophormia terraenovae, and Sarcophaga bullata. AB - Adult females of the ectoparasitoid Nasonia vitripennis (Walker) are capable of distinguishing between hosts of different quality, and then correspondingly adjust clutch sizes and sex ratios of the offspring. In this study, we examined whether the size of the maggot mass, and presumably the developmental temperature, influenced the suitability of the resulting fly pupal and pharate adult stages as hosts for N. vitripennis. Three sizes of maggot masses (100; 500; and 1,000 individuals per mass) were selected for use to generate hosts based on previous studies characterizing developmental and heat shock response differences for the flies. For all host species tested (Lucilia illustris, Protophormia terraenovae, and Sarcophaga bullata), the rate of parasitism by N. vitripennis decreased with increasing maggot mass size. When successful parasitism did occur, parasitoid development increased in duration, clutch sizes decreased, mortality from egg hatch to adult emergence elevated, male biased sex ratios were produced, and adult wasp body sizes were truncated with increasing fly larval density. These wasp life history features are consistent with reductions in host quality. Host quality reductions corresponded to production of heat shock proteins 23, 60, and 70. Heat shock protein synthesis appeared to occur at the expense of normal protein production because total hemolymph protein concentrations decreased with increased larval density in maggot masses. These observations argue that use of N. vitripennis in criminal investigations to estimate periods of insect activity or a minimum post mortem interval must take into account the maggot mass history of the hosts used by the wasp. PMID- 23025196 TI - Biocompatibility of antimicrobials to maggot debridement therapy: medical maggots Lucilia sericata (Diptera: Calliphoridae) exhibit tolerance to clinical maximum doses of antimicrobials. AB - The larvae of calliphorid flies are used to debride wounds of patients with severe tissue destruction, often concurrently with antimicrobials. The current study evaluates the effects of ceftazidime, tobramycin, amikacin, gentamicin, polymyxin B, doxycycline, paromomycin, amphotericin B, sodium stibogluconate, and miltefosine at 1, 10, and 100 x the Maximum Clinical Concentration (mg/kg/d) in raw liver assays. Effects on larvae were small and depended on dose and antimicrobial formulation, with hours in assay (24 or 48 h) having a significant effect on larval survival. Sodium stibgluconate had the strongest effect on maggot survival (80.0% at 48 h). These results suggest that the antimicrobials tested here may be used simultaneously with maggot debridement therapy, and may actually increase the effectiveness of maggot debridement therapy in certain applications where >1 x Maximum Clinical Concentration is indicated, such as topical creams for cutaneous leishmaniasis. PMID- 23025197 TI - Predicting weekly variation of Culex tarsalis (Diptera: Culicidae) West Nile virus infection in a newly endemic region, the Canadian prairies. AB - West Nile virus (WNV) spread across most of North America within a short time period after its incursion into the Western Hemisphere. The Canadian prairies had the highest human incidence of WNV disease in Canada, particularly in 2007. Statistical modeling and geographic information systems can be used to develop a predictive model and facilitate the mobilization of targeted disease management strategies. Using data collected between 2005 and 2008, we constructed models integrating abiotic and biotic factors to predict the WNV infection rate in female Culex tarsalis Coquillett, the primary vector of WNV in the Canadian prairies. During the study period, the highest mean Cx. tarsalis infection rate was during week 34 (late August). The Cx. tarsalis infection rate increased with increasing Cx. tarsalis abundance and mean temperature lagged from 1 to 8 wk, but decreased with increasing mean precipitation lagged from 2 to 6 wk. Furthermore, precipitation was a 'distorter variable' that altered the association between Cx. tarsalis abundance and the WNV infection rate. Our model clarified how weather influenced the Cx. tarsalis infection rate in the Canadian prairies, a newly and highly WNV endemic region of North America. An understanding of the role of lagged weather variables was essential for providing sufficient lead time to predict WNV occurrence, and for implementing disease control and prevention strategies. Furthermore, it is a useful tool for assessing the potential effects of future climate change on WNV in areas near its northern distributional limit. PMID- 23025198 TI - Some like it cool: the effect of ambient temperature on the size of Anopheles funestus from southern Mozambique. AB - The wing lengths of 3,553 unfed, recently emerged, and 13,256 gravid female Anopheles funestus Giles from exit collections, undertaken between March 2004 and May 2005, were measured. Only in the warmest months were mean wing lengths of unfed females significantly smaller than gravid females. Mean wing lengths of unfed, females varied from 2.26 mm (Bootstrap 95% CI [2.25-2.27]) in January when mean air temperatures were 24.8 degrees C to 2.70 mm (Bootstrap 95% CI [2.68 2.72]) in July when mean temperatures were 8.4 degrees C cooler. Mean wing lengths increased by 0.05 mm for each degree decrease in air temperature. Temperature explained 60% of the variation in wing length. PMID- 23025199 TI - Sand fly fauna in Chapare, Bolivia: an endemic focus of Leishmania (Viannia) braziliensis. AB - Data on the distribution and abundance of Lutzomyia spp. (Diptera: Psychodidae) in Bolivia is scarce. Sand flies from an area of Leishmania (Viannia) braziliensis endemicity in the Isiboro-Secure National Park in the Department of Cochabamba were captured and identified to species. In total, 945 sand flies (789 females and 156 males) belonging to 15 species were collected from the four collection points in two study villages in 2007. With 549 (58.1%) specimens, Lutzomyia shawi was the most abundant species, followed by Lutzomyia (Trichophoromyia) sp. (22.2%), Lutzomyia llanosmartinsi (8.3%), Lutzomyia antunesi (4.3%), and Lutzomyia olmeca (2.1%). Abundance and species composition varied between rainy and dry seasons, with 99.3% of all sand flies being collected outdoors. Because of species abundance and confirmed Leishmania infection in previous entomological collections, we believe Lu. shawi is the vector of L. (Viannia) braziliensis in Isiboro-Secure National Park. PMID- 23025200 TI - [Herman Wijffels: "Veterinarian has a role in conservation of natural animal husbandry"]. PMID- 23025201 TI - [Poultices and keeping wet]. PMID- 23025202 TI - [Vera Veltkamp: 'Development project helps increase use of talents']. PMID- 23025203 TI - [Surveillance]. PMID- 23025204 TI - [Avian chlamydiosis (parrot disease, psittacosis, ornithosis)]. PMID- 23025205 TI - [Is being licked by dogs not dirty?]. AB - Being licked by pet dogs is frequently a common advice in articles for the uninitiated. An overview is given about the special antibacterial and wound healing properties of human and canine saliva. New developments in the human area are presumably assigned to dog saliva. Because of the presence of a quite different mouth flora including various potential zoonotic pathogens, it is strictly not advised to let dogs lick the wounds or face of the human. PMID- 23025206 TI - [Cartilage 'copying' with a bioprinter]. PMID- 23025207 TI - [Horses are masters at compensating]. PMID- 23025208 TI - [More attention needed for pets minima]. PMID- 23025209 TI - [New 'community' makes reporting horse diseases possible]. PMID- 23025210 TI - [Animal welfare as a factor in final transportation of farm animals]. PMID- 23025211 TI - [Protocol to measure animal welfare in chicks and chickens]. PMID- 23025212 TI - [An agreement is an agreement]. PMID- 23025213 TI - [Veterinary medicine should not let themselves get run over]. PMID- 23025214 TI - [New rules antibiotics should be workable]. PMID- 23025215 TI - Case study: Flagler Hospital improves revenue by helping self-pay patients. PMID- 23025216 TI - Segmenting patient accounts: a balance between compassion and collections. PMID- 23025217 TI - Medicaid eligibility tool helps uninsured learn coverage options. PMID- 23025218 TI - Good health adds life to years. PMID- 23025219 TI - Antepartum cardiorespiratory fitness (CRF) quantification by estimation of maximal oxygen consumption (Vo2 max) in pregnant South Indian women. AB - The aim of the study was to calculate the maximal oxygen consumption (Vo2max) for pregnant women of varying trimesters and to quantify the cardiorespiratory fitness (CRF)with the objective of being able to determine the exercise dose for antenatal women which can be prescribed to achieve optimal exercise benefits during various trimesters. A study group comprising 64 pregnant women with uncomplicated singleton pregnancy and control group with 77 non-pregnant women were subjected to Cooper's 12 minutes walk test. From the distance covered in 12 minutes, Vo2max was calculated. The Vo2max values were statistically analysed between the non-pregnant and pregnant and also its variability among the trimesters. Percentile tables of Vo2max were drawn and multiple comparisons were applied. Results show that the Vo2max values among non-pregnant and first trimester ranges between 18 and 22 ml/kg/minute. Trimesters II and III had a range of Vo2max values between 16-20 and 14-18 ml/kg/minute respectively. The CRF of pregnant women significantly reduced to 6%, 9% and 18% in each trimester respectively when compared with the reference table framed out of non-pregnant Vo2max values. Among the study group the reduction in Vo2max values had no statistical significance between first 2 trimesters but trimester III significantly differs from other trimesters. The exercise prescription cannot be the same for pregnant and non-pregnant women. Even among the pregnant women, III trimester needs separate exercise prescription from the other two trimesters as CRF is markedly compromised towards term. PMID- 23025220 TI - Predictive value of bedside clinical signs and symptoms in early diagnosis of deep vein thrombosis in acutely ill medical patients with special reference to deep vein thrombosis prophylaxis. AB - Deep vein thrombosis (DVT) is highly elusive in the sense, that being so common among acutely ill hospitalised patients with multiple risk factors yet remain mostly unrecognised particularly at the early stage. Pulmonary thrombo-embolism (PTE), the most sinister acute complication of DVT carries a high mortality on one hand and involves expensive medicare and investigations on the other hand. Many studies that have been undertaken in recent past on this important clinical issue have produced a wealth of published data to show that in the absence of prophylaxis for DVT in such a setting the mortality rates were significantly high. The need to exphasise importance of DVT prophylaxis has now become a unified word in the management of acutely ill medical patient. This article emphasises the advantages of astute bedside clinical examination in identifying DVT early and the need for prophylaxis to prevent this morose condition. PMID- 23025221 TI - Adverse drug reactions to antimicrobial agents in a tertiary care hospital in Nagpur. AB - Adverse drug reactions are a major cause of hospital admission and in-hospital morbidity. Antimicrobial agents are one of the most commonly prescribed groups of drugs leading to adverse drug reactions. But, limited data is available from hospital settings in our country. Hence, it is important to understand the characteristics of adverse reactions associated with their use. This study was planned to detect the adverse drug reactions through spontaneous reporting system and analyse them using standard assessment scales. It is an observational, prospective study performed in patients attending outpatient department, in patient department and casualty of tertiary care hospital from 1st June 2005 to 31st May 2009. Patients were examined for adverse drug reactions by spontaneous adverse drug reactions reporting system. Among 2639 total adverse drug reactions reported, 1315 (49.82%) were due to antimicrobial agents. The agents most frequently associated with adverse drug reactions were cotrimoxazole (19.54%), ampicillin (18.25%), rifampicin (6.6%) and azithromycin (5.3%). It is observed that commonly used drugs like antimicrobial agents were causing maximum adverse drug reactions. This study provides a database of adverse drug reactions due to common drugs, which will help clinicians for optimum and safe use of these drugs. PMID- 23025222 TI - A study of heart rate variablity tests and lipid profile in postmenopausal women. AB - This study was designed to test the hypothesis of alteration of cardiovascular autonomic functions in healthy postmenopausal women and relation of lipid metabolism. Sixty postmenopausal women without any gross systemic disease were selected. The parameters recorded were, Valsalva ratio, heart rate variation with deep breath test, heart rate response to postural change (30:15 R-R interval ratio) and lipid profile. Significant differences in all test results were noticed among the premenopausal and postmenopausal groups. Thirty-seven subjects in postmenopusal group were found to have abnormal autonomic functions while 23 had normal autonomic functions. Results of heart rate variability tests showed significant decrease in values of Valsalva ratio, deep breath test, and 30:15 R-R interval ratio in subjects having abnormal autonomic functions. Results of lipid profile showed significant increase in values of total cholesterol (TC), low density lipoprotein (LDL), triglyceride (TG), cholesterol/ high density lipoprotein (HDL) ratio and insignificant decrease in HDL values in subjects having abnormal autonomic functions. The findings showed that the changes in sex hormone levels, after menopause may alter the autonomic nervous system response and lipid metabolism. It was found that postmenopausal women who had significantly decreased values of heart rate variability tests also had significant increase in values of TC, LDL, TG, cholesterol/HDL ratio and insignificant decrease in values of HDL, suggesting that dyslipidaemia may be an important factor for development of autonomic dysfunction. PMID- 23025223 TI - A tertiary level hospital-based study on frequency of changing presbyopic glasses in primary open angle glaucoma patients. AB - A tertiary level hospital-based case control study on frequency of changing presbyopic glasses among primary open angle glaucoma cases was carried out jointly by the departments of community medicine and ophthalmology from 1st July to 31st December, 2008. Each of the case and control groups included 31 persons. Odd's ratio of 4.55 (95% CI = 1.37-15.68) using epi-info version 3.2 showed that among primary open angle glaucoma cases the time of changing spectacles at < or = 2 years was 4.55 times more than that among control group; Pearson's Chi-square test (chi2 = 7.94, df = 1, p = 0.00) was statistically significant; Z-test for proportion = 2.56, p=0.01. So changing spectacles at < or = 2 years among patients would help the paramedical workers/paramedical ophthalmic assistants in the community to refer the patients earlier to ophthalmologists for further investigation and management. PMID- 23025224 TI - Usefulness of serum CA-15.3 in the management of benign breast lesion. AB - Benign breast lesion is an important risk factor for breast cancer and elevated CA-15.3 in serum is a well established marker of breast cancer. Core-needle biopsy is now the method of choice to sample non-palpable mammographic abnormality and as well as clinically palpable lesion. To asses relationship of serum CA-15.3 with different histologic entities of benign breast lesion and usefulness of this marker in predicting breast cancer in this high risk group, a study was conducted among 140 patients who had a diagnosis of benign breast lesion and malignancy following fine needle aspiration cytology (FNAC) at department of surgery, Medical College, Kolkata between 2007 and 2009. We prospectively estimated serum CA-15.3 level in all patients. Different histologic entities of benign breast lesion, who showed serum CA-15.3 level >30U/ml underwent tru-cut biopsy to detect malignancy. Of 140 patients studied, 50 were stamped as malignancy and 90 as benign after FNAC of which 20 patients had fibroadenoma, 25 had fibro-adenoma with fibrocystic disease, 20 had fibrocystic disease with epitheliosis and 25 had fibrocystic disease with atypia. All breast cancer patients and 10 each from fibro-adenoma with fibrocystic disease, fibrocystic disease with epitheliosis and fibrocystic disease with atypia had serum CA -15.3 level>30U/ml. Thirty patients with benign breast lesion who had raised CA-15.3 underwent core-needle biopsy. Fifteen patients were detected to have intraductal carcinoma, mostly with fibrocystic disease with atypia. Clinical applicability of serum CA-15.3 to detect breast cancer should be strongly considered in management of patients with benign breast lesion and tru-cut biopsy than FNAC be done before benign breast lesion being stamped as benign. Biopsy results that are not concordant with the targeted lesion require surgical biopsy. PMID- 23025225 TI - Rhinoplasty in atrophic rhinitis. AB - Rhinoplasty in atrophic rhinitis is a difficult surgery because the dorsal skin is adherent to the underlying structures. There is also more chance of postoperative infection. The experience of various types of rhinoplasty in 15 atrophic rhinitis patients is presented here. The patients were from the age group 17 to 35 years. Most of the operations were done under local anaesthesia. Commonest graft used was conchal-cartilage. Bone graft was avoided for augmentation because of its high rate of absorption in atrophic rhinitis. Young's operation was done in 5 patients in one side along with rhinoplasty. Young's operation was done only with skin layer. PMID- 23025226 TI - Managing post acute congestive phase by combined manual small incision cataract surgery and trabeculectomy: a prospective study. AB - The purpose of the study was to evaluate the therapeutic efficacy of manual small incision cataract surgery (SICS) and trabeculectomy as management option for acute angle closure glaucoma. The first 6 cases of 14 cases of acute angle closure glaucoma seen over a period of 18 months underwent surgical peripheral buttonhole iridectomy (PBHI) after their intra-ocular pressure (IOP) was controlled medically. Subsequently 8 cases underwent manual SICS+trabeculectomy as an alternative procedure after their IOP control who needed further surgery and overall patients' comfort. The results showed sustained visual acuity remained 6/9 or better in all the patients of SICS + trabeculectomy group, compared 6/12 or worse in the PBHI group. Mean non-contact tonometry reading at the end of 6 weeks was 10.2 mm Hg in the second group compared to 14.6 in the first group. None of the patients in the second group ever needed surgery in a 4 month follow-up, whereas 3 patients in the first group had to be operated again for cataract or uncomplicated IOP. Manual SICS+ trabeculectomy offers a good, economical and rational therapeutic alternative to traditional PBHI in the postcongestive phase. PMID- 23025227 TI - The role of general physician in managing diabetes with self monitoring of blood glucose. AB - There is an alarming rise in the prevalence of diabetes in India. The long term microvascular and macrovascular complications of diabetes, especially in a genetically susceptible population, can be devastating. There is strong evidence that better glycaemic control, especially early in the course of diabetes, can lead to significant reductions in both microvascular and macrovascular complications. There are various tools available to intensify glycaemic control in a safe manner. One such important tool is self monitoring of blood glucose (SMBG) using a hand held glucose meter. Unfortunately, SMBG is underutilised in India due to various factors. The aim of this article is to increase the awareness of SMBG, so that general physicians can use this tool in a logical manner to improve glycaemic control and thereby reduce long term complications in patients with diabetes. PMID- 23025228 TI - Corneal ulcer with Scopulariopsis brevicaulis and Staphylococcus aureus--a rare case report. AB - Scopulariopsis brevicaulis is a saprophytic fungus, found in soil. It causes human nail infection. Corneal ulcer with this organism is unusual. Here a case of a 36-year-old farmer is reported who developed a paracentral corneal ulcer in the right eye. The ulcer was caused by mixed infection with Staphylococcus aureus and Scopulariopsis brevicaulis. It was treated with topical natamycin 5% and moxifloxacin 0.5% drops. This is a unique case of corneal ulcer with mixed infection of Staphylococcus aureus and Scopulariopsis brevicaulis without any history of trauma, which was treated successfully, resulting in a minimal corneal opacity. PMID- 23025229 TI - A case of scrub typhus with haematuria. AB - Scrub typhus, once endemic in India, has virtually disappeared from our country. Recently, there have been many case reports of scrub typhus. Haematuria in scrub typhus is a rare presentation, but it has been reported earlier. Here one such case of a 55-year-old man is reported who presented with fever and arthralgia. There was an erythematous maculopapular rash on his body. One enlarged lymph node in the right axilla and hepatomegaly were elicited. Weil-Felix reaction Ox-K was positive with 1:360 dilution. Doxycycline was advised for 7 days. Two months after follow-up, he had no symptoms. PMID- 23025230 TI - Idiopathic scrotal calcinosis--a case report. AB - Idiopathic scrotal calcinosis is a rare disorder characterised by multiple calcified nodules on the scrotal skin appearing in childhood or early adulthood. The exact aetiology is not known and calcium level in the blood remains normal in all individuals. Since only a few cases have been reported in the literature, a case is reported here with a review of literature. The present case is of a 40 year-old male presenting with dysuria and multiple painless nodules on the scrotum. PMID- 23025231 TI - Cavernous haemangioma of cervix--a case report. AB - Benign vascular tumours and haemangiomas in particular are rarely found in uterine cervix. Most of the lesions are asymptomatic incidental findings but sometimes they may cause abnormal vaginal bleeding. A case of cavernous haemangioma of cervix in a 28-year-old woman is described with review of literature. PMID- 23025232 TI - Pregnancy following gastric by-pass for morbid obesity. AB - Bariatric surgery is a promising treatment and called for morbid obesity refractory to medical treatment. Obese women of reproductive age group are at risk for obstetric complications. A 29 years old premigravida of 37 weeks gestation having developed gestational diabetes mellitus at 20 weeks and pregnancy induced hypertension at 36 weeks who had undergone gastric by-pass earlier was admitted to labour ward for induction of labour. She had undergone emergency caesarean section following failed induction. Baby was born healthy, weight being 2.7 kg. The mother received intermittent pneumatic compression intra operatively and injection delteparin sodium 5000 units subcutaneously once daily for 3 days. She was discharged on 7th postoperative day. PMID- 23025233 TI - Auto-immune pancreatitis--an uncommon type of chronic pancreatitis. AB - Auto-immune pancreatitis is an increasingly recognised disorder of presumed auto immune aetiology. It has to be differentiated from other forms of chronic pancreatitis and pancreatic cancer as it has dramatic response with steroid therapy. So, early and prompt diagnosis of this disorder in early stage of disease is essential. Here a case of auto-immune pancreatitis in a 16 years old young male is reported. PMID- 23025234 TI - Structural, chemical, optical, and electrical evolution of SnO(x) films deposited by reactive rf magnetron sputtering. AB - In this paper, SnO(x) films were produced by reactive radio frequency magnetron sputtering under various oxygen partial pressure (P(O)) in conjunction with a thermal annealing at 200 degrees C afterwards. The obtained SnO(x) films were systematically studied by means of various techniques, including X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy, spectroscopic ellipsometry, and Hall-effect measurement. The structural, chemical, and electrical evolution of the SnO(x) films was found to experience three stages: polycrystalline SnO phase dominated section with p-type conduction at P(O) <= 9.9%; amorphous SnO(2) phase dominated area at P(O) >= 12.3%, exhibiting n-type characteristics; and conductivity dilemma area in between the above mentioned sections, featuring the coexistence of SnO and SnO(2) phases with compatible and opposite contribution to the conductivity. The polycrystalline to amorphous film structure transition was ascribed to the enhanced crystallization temperature due to the perturbed structural disorder by incorporating Sn(4+) into the SnO matrix. The inversion from p-type to n-type conduction with P(O) variation is believed to result from the competition between the donor and acceptor generation process, i.e., the n-type behavior would be present if the donor effect is overwhelming, and vice versa. In addition, with increasing P(O), the refractive index decreased from 3.0 to 1.8 and the band gaps increased from 1.5 to 3.5 eV, respectively. PMID- 23025235 TI - Iron-catalyzed N-alkylation of azoles via cleavage of an sp3 C-H bond adjacent to a nitrogen atom. AB - Iron-catalyzed direct C-N bond formation between azoles and amides is described. The oxidative coupling reactions of sp(3) C-H bonds adjacent to a nitrogen atom in amides and sulfonamides with the N-H bond in azoles proceeded smoothly in the presence of FeCl(2) and di-tert-butyl peroxide (DTBP). PMID- 23025236 TI - The tetramer of p53 in the absence of DNA forms a relaxed quaternary state. AB - p53 is a tetrameric multidomain protein that triggers the anticancer cellular response to stress. We have calculated a three-dimensional reconstruction of full length human p53 in the absence of DNA using single-particle electron microscopy. The reconstruction of DNA-free full-length p53 shows a square-shaped structure with four distinct domains and a hollow center. In comparison with the known compacted DNA-bound full-length p53 structures, the DNA-free p53 tetramer adopts a relaxed conformation with separated monomers and oligomerization interfaces different from those of the DNA-bound conformation. PMID- 23025237 TI - Synthesis and electrochemistry of organometallic cobaltadithiaazulenes. AB - Reaction of tropolone or hinokitiol with phosphorus pentasulfide (P(2)S(5)) directly gives the sulfurized precursor [PS(2)(SST)](2) or [PS(2)(SSH)](2) (SST = dithiotropolonato or SSH = dithiohinokitiolato). The resulting [PS(2)(SST)](2) or [PS(2)(SSH)](2) is further reacted with [CpCoI(2)(CO)] (Cp = eta(5) cyclopentadienyl) to form the organometallic [CpCo(I)(SST)] (1) or [CpCo(I)(SSH)] (2), respectively. 1 and 2 have a cobaltadithiaazulene ring containing one cobalt and two sulfur atoms in the five-membered ring of azulene. Although X-ray structure analysis of 1 reveals the iodide-coordinated structure, 1 becomes the iodide-free complex [CpCo(SST)](+) (4(+)) in solution. Electrochemical studies of 4(+) by CV and spectroelectrochemical measurements (ESR, UV-vis-NIR) in solution are carried out. 4(+) is stepwise reduced by 2e(-) to form the stable neutral radical (4(*)) and unstable anion (4(-)). It is proposed that the anion 4(-) undergoes dimerization to afford the dimer (6(2-)) by anion radical coupling at the 5 or 7 position in the seven-membered ring of the cobaltadithiaazulene, since the similar anion radical coupling of a reduced azulene has been reported. Electrochemical reoxidation of 6(2-) slowly undergoes monomerization, giving the original monomer 4(*). DFT calculation of 4(+) explains that there is a delocalized lowest unoccupied molecular orbital (LUMO) in the whole molecule, and that of radical 4(*) has a delocalized singly occupied molecular orbital (SOMO). In these CpCo-SST (or SSH) complexes, there could be metal/ligand electron transfer since the SST (or SSH) ligand is potentially redox active. The spin density distribution of 4(-) obtained by the DFT method supports the mechanism of the anion radical coupling at the 5 or 7 position in the seven-membered ring. PMID- 23025238 TI - Alternating current scanning electrochemical microscopy with simultaneous fast scan cyclic voltammetry. AB - Fast-scan cyclic voltammetry (FSCV) is combined with alternating current scanning electrochemical microscopy (AC-SECM) for simultaneous measurements of impedance and faradaic current. Scan rates of 10-1000 V s(-1) were used for voltammetry, while a high-frequency (100 kHz), low-amplitude (10 mV rms) sine wave was added to the voltammetric waveform for the ac measurement. Both a lock-in amplifier and an analog circuit were used to measure the amplitude of the resultant ac signal. The effect of the added sine wave on the voltammetry at a carbon fiber electrode was investigated and found to have negligible effect. The combined FSCV and ac measurements were used to provide simultaneous chemical and topographical information about a substrate using a single carbon fiber probe. The technique is demonstrated in living cell culture, where cellular respiration and topography were simultaneously imaged without the addition of a redox mediator. This approach promises to be useful for the topographical and multidimensional chemical imaging of substrates. PMID- 23025239 TI - Adsorption of polymer-surfactant mixtures at the oil-water interface. AB - Small-angle neutron scattering, zeta potential measurements, and dynamic light scattering have been used to investigate the adsorption of polymer-surfactant mixtures at the oil-water interface. The water-hexadecane interface investigated was in the form of small oil-in-water emulsion droplets stabilized by the anionic surfactant sodium dodecyl sulfate, SDS. The impact of the addition of two different cationic polymers, poly(ethyleneimine), PEI, and poly(dimethyldiallylammonium chloride), polydmdaac, on the SDS adsorption at the oil-water interface was studied. For both polymers, the addition of the polymer enhances the SDS adsorption at low SDS concentrations at the oil-water interface due to a strong surface polyelectrolyte-surfactant interaction and complexation, but the effects are not as pronounced as at the air-water interface. For PEI/SDS, the adsorption was largely independent of solution pH and increasing PEI concentration. In marked contrast to the adsorption at the air-water interface, only monolayer adsorption and no multilayer adsorption was observed. For the SDS polydmdaac mixture, the enhanced SDS adsorption was in the form of a monolayer, and the adsorption increased with increasing polymer concentration. The strong SDS/polydmdaac surface interaction resulted in regions of emulsion instability. The zeta potential measurements showed that the combination of SDS and polydmdaac at the interface resulted in charge reversal at the interface. This correlates with the regions of emulsion stability at both high and low polymer concentrations, such that the instabilities arise in the regions of low or zero surface charge. The results presented and their interpretation represent a development in the understanding of polymer-surfactant adsorption at the oil water interface. PMID- 23025240 TI - New method for the simultaneous identification of cow, sheep, goat, and water buffalo in dairy products by analysis of short species-specific mitochondrial DNA targets. AB - A novel method is presented here as an analytical tool for food control and authentication of dairy products manufactured from the milk of cow, sheep, goat, and buffalo. The method is based on multiplex polymerase chain reaction (PCR) of species-specific mitochondrial DNA (mtDNA) targets followed by fragment size analysis by capillary electrophoresis. The method includes (a) simultaneous detection of four species, (b) internal control for DNA extraction and PCR, (c) mtDNA as a target for PCR, (d) amplicons of <200 bp, and (e) flexibility in the electrophoresis and fragment size detection method. Species identification proved to be straightforward, efficient, sensitive, and robust. The method is sensitive to an at least 1% (v/v) relative proportion of milk in binary mixtures. A survey of commercial products showed that 12.5% failed to conform to the description of the contents, by either the introduction or absence of listed species, thus demonstrating the relevance of this type of testing. PMID- 23025241 TI - Determination of required hydrophilic-lipophilic balance of citronella oil and development of stable cream formulation. AB - CONTEXT: Citronella oil is reported to have excellent mosquito-repellent activity. To develop a stable cream formulation (emulsion), its hydrophilic lipophilic balance (HLB) value is important. OBJECTIVE: To determine required hydrophilic-lipophilic balance (rHLB) value of citronella oil and to develop stable cream formulation. MATERIALS AND METHODS: Emulsions of citronella oil were prepared by phase inversion temperature technique using water, Tween 80 and Span 80. A first series of 11 emulsions with HLB values ranging from 5.0 to 15.0 and a second series of eight emulsions with smaller interval in HLB values from 11.0 to 13.8 were prepared. Emulsions were evaluated for creaming index, droplet size and turbidity to determine rHLB. Utilizing determined rHLB, citronella oil cream was formulated and evaluated for different texture parameters. rHLB of light liquid paraffin was also determined for validation of methodology. RESULTS: rHLB of light liquid paraffin and citronella oil was determined to be 11.80 and 12.60, respectively. Stable citronella oil cream was developed with 10% emulsifier blend. Texture parameters were found to be consistent over the entire storage period. DISCUSSION: Creaming index, droplet diameter, percent increase in droplet diameter and turbidity are the established parameters to determine rHLB and to develop stable emulsion. Emulsions with optimum emulsifier concentration resulted in less percentage creaming index, smallest droplet, less percentage increase in droplet diameter and highest turbidity. Texture properties evaluation ensures the stability of the developed cream. CONCLUSION: rHLB value of citronella oil was found 12.6 and a stable cream was formulated utilizing determined rHLB. PMID- 23025242 TI - [5C + 1N] annulations: two novel routes to substituted dihydrofuro[3,2 c]pyridines. AB - Two novel routes based on [5C + 1N] annulations for the synthesis of 2,3 dihydrofuro[3,2-c]pyridines are described. Ammonium acetate (NH(4)OAc) is used as an ammonia source in both routes. The first route utilizes 1-acyl-1 [(dimethylamino)alkenoyl]cyclopropanes as a five-carbon 1,5-bielectrophilic species and combines the [5C + 1N] annulation and regioselective ring-enlargement of cyclopropyl ketone into one pot, whereas the second route utilizes 3-acyl-2 [(dimethylamino)alkenyl]-4,5-dihydrofurans as the five-carbon synthons, which involves a sequential intermolecular aza-addition, intramolecular aza nucleophilic addition/elimination, and dehydration reaction. PMID- 23025243 TI - Estimation of traffic accident costs: a prompted model. AB - Traffic accidents are the reason for 25% of unnatural deaths in Iran. The main objective of this study is to find a simple model for the estimation of economic costs especially in Islamic countries (like Iran) in a straightforward manner. The model can show the magnitude of traffic accident costs with monetary equivalent. Data were collected from different sources that included traffic police records, insurance companies and hospitals. The conceptual framework, in our study, was based on the method of Ayati. He used this method for the estimation of economic costs in Iran. We promoted his method via minimum variables. Our final model has only three available variables which can be taken from insurance companies and police records. The running model showed that the traffic accident costs were US$2.2 million in 2007 for our case study route. PMID- 23025244 TI - Synthesis and biological evaluation of 5-benzylidenepyrimidine-2,4,6(1H,3H,5H) trione derivatives for the treatment of obesity-related nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD), one of chronic liver diseases, seems to be rising as the obesity epidemic continues. In this study, 54 novel (thio)barbituric acid derivatives have been synthesized and evaluated for pharmacological activity. 7h exhibited potent glucose-lowering effects on insulin resistant HepG2 cells and regulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 7h at 25 mg kg(-1) day(-1) for 4 weeks improved the progression of high fat diet-induced NAFLD by reducing the weight of body, liver, and fat, as well as modulating serum levels of fasting glucose, insulin, triglycerides, LDL-c, ALT, adiponectin and hepatic contents of triglycerides, total cholesterol. H&E stainings revealed that 7h blocked fat deposition in liver and the increase of adipocyte number and size in adipose tissues from NAFLD. Furthermore, treatment with 7h alleviated the obese clinical symptoms, recovered serum biomarkers to appropriate ranges, and improved glucose tolerance by OGTT and IGTT in DIO mice. PMID- 23025245 TI - Type of vegetable oils used in cooking and risk of metabolic syndrome among Asian Indians. AB - There is little data on the type of vegetable oil used and the prevalence of metabolic syndrome (MS) in Asian Indians. Food frequency questionnaire was used to document the type of cooking oil in 1875 adults in Chennai city. MS was assessed by new harmonizing criteria. The prevalence of MS was higher among sunflower oil users (30.7%) than palmolein (23.2%) and traditional oil (17.1%, p < 0.001) users. The higher prevalence of MS in sunflower oil group persisted even when stratified according to body mass index, except in obese groups. The risk of MS was further compounded by quantity of refined cereals consumed. Higher LA%E and linoleic acid/alpha-linolenic acid ratio in sunflower oil probably contributes to increased risk of MS. PMID- 23025246 TI - Late-onset sensorineural hearing loss due to congenital cytomegalovirus infection: could head injury be a trigger? PMID- 23025247 TI - Criminal justice involvement, trauma, and negative affect in Iraq and Afghanistan war era veterans. AB - OBJECTIVE: Although criminal behavior in veterans has been cited as a growing problem, little is known about why some veterans are at increased risk for arrest. Theories of criminal behavior postulate that people who have been exposed to stressful environments or traumatic events and who report negative affect such as anger and irritability are at increased risk of antisocial conduct. METHOD: We hypothesized veterans with posttraumatic stress disorder (PTSD) or traumatic brain injury (TBI) who report anger/irritability would show higher rates of criminal arrests. To test this, we examined data in a national survey of N = 1,388 Iraq and Afghanistan war era veterans. RESULTS: We found that 9% of respondents reported arrests since returning home from military service. Most arrests were associated with nonviolent criminal behavior resulting in incarceration for less than 2 weeks. Unadjusted bivariate analyses revealed that veterans with probable PTSD or TBI who reported anger/irritability were more likely to be arrested than were other veterans. In multivariate analyses, arrests were found to be significantly related to younger age, male gender, having witnessed family violence, prior history of arrest, alcohol/drug misuse, and PTSD with high anger/irritability but were not significantly related to combat exposure or TBI. CONCLUSIONS: Findings show that a subset of veterans with PTSD and negative affect may be at increased risk of criminal arrest. Because arrests were more strongly linked to substance abuse and criminal history, clinicians should also consider non-PTSD factors when evaluating and treating veterans with criminal justice involvement. PMID- 23025248 TI - Reductions in traumatic stress following a coping intervention were mediated by decreases in avoidant coping for people living with HIV/AIDS and childhood sexual abuse. AB - OBJECTIVE: To examine whether (a) Living in the Face of Trauma (LIFT), a group intervention to address coping with HIV and childhood sexual abuse (CSA), significantly reduced traumatic stress over a 1-year follow-up period more than an attention-matched support group comparison intervention; and (b) reductions in avoidant coping over time mediated reductions in traumatic stress. METHOD: In a randomized controlled trial, 247 participants completed measures of traumatic stress and avoidant coping at pre- and post intervention, and at 4-, 8-, and 12 month follow-ups. Latent growth curve modeling examined changes over the 5 time points; standardized path coefficients provide estimates of effects. RESULTS: As compared with the support intervention, the coping intervention led to a reduction in traumatic stress over time (b = -.20, p < .02). Participants in the coping intervention also reduced their use of avoidant coping strategies more than did participants in the support intervention (b = -.22, p < .05). Mediation analyses showed reductions in avoidant coping related to reductions in traumatic stress (b = 1.45, p < .001), and the direct effect of the intervention on traumatic stress was no longer significant (b = .04, ns), suggesting that changes in avoidant coping completely mediated intervention effects on traumatic stress. CONCLUSIONS: The LIFT intervention significantly reduced traumatic stress over time, and changes in avoidant coping strategies mediated this effect, suggesting a focus on current stressors and coping skills improvement are important components in addressing traumatic stress for adults living with HIV and CSA. PMID- 23025249 TI - A multisite randomized trial of a cognitive skills program for male mentally disordered offenders: violence and antisocial behavior outcomes. AB - OBJECTIVE: Despite a large evidence base indicating that cognitive skills programs can reduce reoffending in individuals without mental illness, there have been no randomized controlled trials (RCTs) to determine their effectiveness in mentally disordered offenders (MDOs). In the first RCT of a cognitive skills program for MDOs, we aimed to investigate whether participation in the Reasoning and Rehabilitation (R&R) program reduced violence and antisocial behavior in this population. METHOD: Eighty-four male inpatients with a psychotic disorder and a history of violence were recruited from medium secure forensic hospitals. Participants were randomized to receive the R&R program, consisting of 36 two hour sessions, or treatment as usual (TAU). Incidents of violence and antisocial behavior (verbal aggression, substance use, and leave violations) were assessed during treatment and at 12-months posttreatment. RESULTS: Relative to the TAU group, incident rates of verbal aggression and leave violations during the treatment period were significantly lower in the R&R group; the effect on verbal aggression was maintained at 12-months posttreatment. Half of those randomized to receive R&R did not complete treatment; post hoc analyses were therefore conducted to compare treatment responses in program completers and noncompleters. After controlling for psychopathic traits, incidents of violence, verbal aggression, and leave violations during treatment were significantly lower in program completers, and there were significant effects of program completion on verbal aggression and substance use at 12-months posttreatment. CONCLUSIONS: R&R leads to a reduction in incidents of antisocial behavior in MDO populations, with potentially greater impact on those who complete treatment. PMID- 23025251 TI - Molecular dynamics simulations of the thermal stability of tteRBP and ecRBP. AB - Molecular dynamics simulations were performed for investigating the thermal stability of the extremely thermophilic Thermoanaerobacter tengcongensis ribose binding protein (tteRBP) and the mesophilic homologous Escherichia coli ribose binding protein (ecRBP). The simulations for the two proteins were carried out under the room temperature (300 K) and the optimal activity temperature (tteRBP 375 K and ecRBP 329 K), respectively. The comparative analyses of the trajectories show that the two proteins have stable overall structures at the two temperatures; further analyses indicate that they both have strong side-chain interactions and different backbone flexibilities at the different temperatures. The tteRBP 375 K and ecRBP 329 K have stronger internal motion and higher flexibility than tteRBP 300 K and ecRBP 300 K, respectively, it is noted that the flexibility of tteRBP is much higher than that of ecRBP at the two temperatures. Therefore, tteRBP 375 K can adapt to high temperature due to its higher flexibility of backbone. Combining with the researches by Cuneo et al., it is concluded that the side-chain interactions and flexibility of backbone are both the key factors to maintain thermal stability of the two proteins. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:22. PMID- 23025252 TI - Journals' impact and pecking order: tyranny and tyrannosaurs. PMID- 23025253 TI - Community implementation of PMTO(TM): impacts on referrals to specialist services and schools. AB - In 2000, the city of Hafnarfjordur, Iceland, implemented Parent Management Training--Oregon Model (PMTO(TM)) to prevent and treat behavioral problems among children. This paper describes the implementation and findings regarding impacts in the community. As hypothesized, findings showed that the number of referrals to specialist services decreased in Hafnarfjordur following PMTO implementation and increased in two comparison communities not implementing the method. Within the Hafnarfjordur community, recorded instances of behavior problems reduced in elementary schools working in line with PMTO. The results presented are the first such findings in Iceland and suggest the kinds of systematic changes communities may experience following the implementation of an evidence-based program. PMID- 23025250 TI - Psychosocial factors and behavioral medicine interventions in asthma. AB - OBJECTIVE: This review examines the evidence for psychosocial influences in asthma and behavioral medicine approaches to its treatment. METHOD: We conducted a systematic review of the literature on psychosocial influences and the evidence for behavioral interventions in asthma with a focus on research in the past 10 years and clinical trials. Additional attention was directed at promising new developments in the field. RESULTS: Psychosocial factors can influence the pathogenesis and pathophysiology of asthma, either directly through autonomic, endocrine, immunological, and central nervous system mechanisms or indirectly through lifestyle factors, health behaviors, illness cognitions, and disease management, including medication adherence and trigger avoidance. The recent decade has witnessed surging interest in behavioral interventions that target the various pathways of influence. Among these, self-management training, breathing training, and exercise or physical activation programs have proved particularly useful, whereas other essential or promising interventions, such as smoking cessation, dietary programs, perception and biofeedback training, and suggestive or expressive psychotherapy, require further, more rigorous evaluation. Given the high comorbidity with anxiety and mood disorders, further evaluation of illness specific cognitive behavior therapy is of particular importance. Progress has also been made in devising community-based and culturally tailored intervention programs. CONCLUSION: In concert with an essential medication treatment, behavioral medicine treatment of asthma is moving closer toward an integrated biopsychosocial approach to disease management. PMID- 23025255 TI - Justifying community benefit requirements in international research. AB - It is widely agreed that foreign sponsors of research in low- and middle-income countries (LMICs) are morally required to ensure that their research benefits the broader host community. There is no agreement, however, about how much benefit or what type of benefit research sponsors must provide, nor is there agreement about what group of people is entitled to benefit. To settle these questions, it is necessary to examine why research sponsors have an obligation to benefit the broader host community, not only their subjects. Justifying this claim is not straightforward. There are three justifications for an obligation to benefit host communities that each apply to some research, but not to all. Each requires a different amount of benefit, and each requires benefit to be directed toward a different group. If research involves significant net risk to LMIC subjects, research must provide adequate benefit to people in LMICs to avoid an unjustified appeal to subjects' altruism. If research places significant burdens on public resources, research must provide fair compensation to the community whose public resources are burdened. If research is for profit, research sponsors must contribute adequately to the upkeep of public goods from which they benefit in order to avoid the wrong of free-riding, even if their use of these public goods is not burdensome. PMID- 23025254 TI - Unbiased discovery of interactions at a control locus driving expression of the cancer-specific therapeutic and diagnostic target, mesothelin. AB - Although significant effort is expended on identifying transcripts/proteins that are up-regulated in cancer, there are few reports on systematic elucidation of transcriptional mechanisms underlying such druggable cancer-specific targets. The mesothelin (MSLN) gene offers a promising subject, being expressed in a restricted pattern normally, yet highly overexpressed in almost one-third of human malignancies and a target of cancer immunotherapeutic trials. CanScript, a cis promoter element, appears to control MSLN cancer-specific expression; its related genomic sequences may up-regulate other cancer markers. CanScript is a 20 nt bipartite element consisting of an SP1-like motif and a consensus MCAT sequence. The latter recruits TEAD (TEA domain) family members, which are universally expressed. Exploration of the active CanScript element, especially the proteins binding to the SP1-like motif, thus could reveal cancer-specific features having diagnostic or therapeutic interest. The efficient identification of sequence-specific DNA-binding proteins at a given locus, however, has lagged in biomarker explorations. We used two orthogonal proteomics approaches--unbiased SILAC (stable isotope labeling by amino acids in cell culture)/DNA affinity capture/mass spectrometry survey (SD-MS) and a large transcription factor protein microarray (TFM)--and functional validation to explore systematically the CanScript interactome. SD-MS produced nine candidates, and TFM, 18. The screens agreed in confirming binding by TEAD proteins and by newly identified NAB1 and NFATc. Among other identified candidates, we found functional roles for ZNF24, NAB1 and RFX1 in MSLN expression by cancer cells. Combined interactome screens yield an efficient, reproducible, sensitive, and unbiased approach to identify sequence-specific DNA-binding proteins and other participants in disease-specific DNA elements. PMID- 23025256 TI - Functional and structural change in diabetic eyes. Interim results from an ongoing longitudinal prospective study. AB - PURPOSE: To presents results after 18 months of follow-up of a longitudinal study aiming at exploring the correlation between diabetic retinal vascular lesions and functional change. METHODS: Patients were consecutively recruited from attendees to the screening program for diabetic retinopathy. Subjects are followed every sixth month for the first 3 years and thereafter annually up to 5 years. Progression of diabetic retinopathy is evaluated using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale and improvement/deterioration in visual fields by predefined significance limits for change. RESULTS: Of 81 subjects, with no/mild/moderate diabetic retinopathy included, 76 have passed the 18-month visit. At that time, retinal progression by two steps according to the ETDRS scale had occurred in two subjects. Visual acuity was -0.14 logMAR and had decreased with two letters (0.04 logMAR) (p < 0.001) from baseline. The global visual field index mean deviation was almost unchanged with a negligible improvement of 0.03 dB (p = 0.79). In 21 subjects, repeated significant deterioration was seen in >=10% of all points tested in the field, while almost no improved points were noted. The two subjects with retinal progression were not among those 21 with indication of perimetric progression. CONCLUSIONS: This is, to our knowledge, the first longitudinal study evaluating change of visual fields in a representative diabetic cohort with no or mild/moderate retinopathy. In this interim report, we demonstrate deteriorated perimetric sensitivity in subjects already at 18 months of follow-up. The results will have implications for evaluating change in visual function in future clinical trials. PMID- 23025257 TI - Cervical dilation at the time of cesarean section for dystocia -- effect on subsequent trial of labor. AB - OBJECTIVE: To investigate the effect of cervical dilation at the time of cesarean section due to dystocia and success in a subsequent pregnancy of attempted vaginal delivery. DESIGN: Retrospective study. SETTING: University hospital in Copenhagen capital area. POPULATION: All women with a prior cesarean section due to dystocia who had undergone a subsequent pregnancy with a singleton delivery during 2006-2010. METHODS: Medical records were reviewed for prior vaginal birth, cervical dilation reached before cesarean section and induction of labor, gestational age, use of oxytocin, epidural anesthesia and mode of birth was collected. RESULTS: A total of 889 women were included; 373 had had a trial of labor. The success rate for vaginal birth among women with prior cesarean section for dystocia at 4-8 cm dilation was 39%, but 59% for women in whom prior cesarean section had been done at a fully or almost fully dilated cervix (9-10 cm) (p < 0.001). Among the women with a previous vaginal delivery prior to their cesarean section, the success rate for vaginal birth was 76.2%, in contrast to 48.9% in the group without a previous vaginal delivery (p < 0.01). CONCLUSION: Women who had a trial of labor after a prior cesarean section for dystocia done late in labor and women with a vaginal delivery prior to their cesarean section had a greater chance of a successful vaginal birth during a subsequent delivery. PMID- 23025258 TI - Estrogen receptor alpha antagonists mediate changes in CCL20 and CXCL1 secretions in the murine female reproductive tract. AB - PROBLEM: Estradiol regulates chemokine secretion from uterine epithelial cells, but little is known about estradiol regulation in vivo or the role of estrogen receptors (ERs). METHOD: CCL20 and CXCL1 present in reproductive washes following treatment with selective estrogen receptor modulators (SERMs) were compared with that during estrous and following estradiol-treated ovariectomized BALB/c mice. Cellular regulation was determined using isolated vaginal and uterine epithelial/stromal cells in vitro. RESULTS: Uterine and vaginal chemokine secretion is cyclically regulated with CCL20 at low levels but CXCL1 at high levels during high estradiol, generally mimicking estradiol effect in vivo. ERalpha but not ERbeta regulated CCL20/CXCL1 secretion by uterine epithelial cells in vitro and vaginal CCL20 in vivo. Estradiol/SERMs failed to alter uterine CCL20 secretion in ovariectomized mice. Diminished uterine epithelial ERalpha staining following ovariectomy corresponded with estradiol unresponsiveness of uterine tissue. CONCLUSION: Estrogen receptors alpha regulates CCL20/CXCL1 secretion in the female reproductive tract, and ERalpha antagonists directly oppose the regulation by estradiol. Understanding ER-mediated antimicrobial chemokine expression is important to elucidate cyclic susceptibility to sexually transmitted pathogens. PMID- 23025260 TI - GAMETES: a fast, direct algorithm for generating pure, strict, epistatic models with random architectures. AB - BACKGROUND: Geneticists who look beyond single locus disease associations require additional strategies for the detection of complex multi-locus effects. Epistasis, a multi-locus masking effect, presents a particular challenge, and has been the target of bioinformatic development. Thorough evaluation of new algorithms calls for simulation studies in which known disease models are sought. To date, the best methods for generating simulated multi-locus epistatic models rely on genetic algorithms. However, such methods are computationally expensive, difficult to adapt to multiple objectives, and unlikely to yield models with a precise form of epistasis which we refer to as pure and strict. Purely and strictly epistatic models constitute the worst-case in terms of detecting disease associations, since such associations may only be observed if all n-loci are included in the disease model. This makes them an attractive gold standard for simulation studies considering complex multi-locus effects. RESULTS: We introduce GAMETES, a user-friendly software package and algorithm which generates complex biallelic single nucleotide polymorphism (SNP) disease models for simulation studies. GAMETES rapidly and precisely generates random, pure, strict n-locus models with specified genetic constraints. These constraints include heritability, minor allele frequencies of the SNPs, and population prevalence. GAMETES also includes a simple dataset simulation strategy which may be utilized to rapidly generate an archive of simulated datasets for given genetic models. We highlight the utility and limitations of GAMETES with an example simulation study using MDR, an algorithm designed to detect epistasis. CONCLUSIONS: GAMETES is a fast, flexible, and precise tool for generating complex n-locus models with random architectures. While GAMETES has a limited ability to generate models with higher heritabilities, it is proficient at generating the lower heritability models typically used in simulation studies evaluating new algorithms. In addition, the GAMETES modeling strategy may be flexibly combined with any dataset simulation strategy. Beyond dataset simulation, GAMETES could be employed to pursue theoretical characterization of genetic models and epistasis. PMID- 23025259 TI - The pediatric sepsis biomarker risk model. AB - INTRODUCTION: The intrinsic heterogeneity of clinical septic shock is a major challenge. For clinical trials, individual patient management, and quality improvement efforts, it is unclear which patients are least likely to survive and thus benefit from alternative treatment approaches. A robust risk stratification tool would greatly aid decision-making. The objective of our study was to derive and test a multi-biomarker-based risk model to predict outcome in pediatric septic shock. METHODS: Twelve candidate serum protein stratification biomarkers were identified from previous genome-wide expression profiling. To derive the risk stratification tool, biomarkers were measured in serum samples from 220 unselected children with septic shock, obtained during the first 24 hours of admission to the intensive care unit. Classification and Regression Tree (CART) analysis was used to generate a decision tree to predict 28-day all-cause mortality based on both biomarkers and clinical variables. The derived tree was subsequently tested in an independent cohort of 135 children with septic shock. RESULTS: The derived decision tree included five biomarkers. In the derivation cohort, sensitivity for mortality was 91% (95% CI 70 - 98), specificity was 86% (80 - 90), positive predictive value was 43% (29 - 58), and negative predictive value was 99% (95 - 100). When applied to the test cohort, sensitivity was 89% (64 - 98) and specificity was 64% (55 - 73). In an updated model including all 355 subjects in the combined derivation and test cohorts, sensitivity for mortality was 93% (79 - 98), specificity was 74% (69 - 79), positive predictive value was 32% (24 - 41), and negative predictive value was 99% (96 - 100). False positive subjects in the updated model had greater illness severity compared to the true negative subjects, as measured by persistence of organ failure, length of stay, and intensive care unit free days. CONCLUSIONS: The pediatric sepsis biomarker risk model (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl) reliably identifies children at risk of death and greater illness severity from pediatric septic shock. PERSEVERE has the potential to substantially enhance clinical decision making, to adjust for risk in clinical trials, and to serve as a septic shock-specific quality metric. PMID- 23025261 TI - A cluster-randomized controlled trial of strategies to increase adolescents' physical activity and motivation during physical education lessons: the Motivating Active Learning in Physical Education (MALP) trial. AB - BACKGROUND: The physical activity (PA) levels of many children and adolescents in Australia are currently insufficient to promote health benefits. Physical education (PE) programs aim to promote PA and reach nearly all school-aged children, but PA levels within PE lessons are often low. PE teachers may influence children's motivation to be physically active in PE lessons, but little is known about teacher strategies that effectively motivate children to participate in PA, and few intervention studies have examined motivational strategies in PE. The purpose of this study was to compare the effect of three motivational strategies, each based on Self-Determination Theory (SDT), on PA levels, and their hypothesized antecedents, during year 8 PE lessons. METHODS/DESIGN: This study employed a cluster-randomized controlled trial design. Following a familiarization session, PA levels and hypothesized PA antecedents were measured during a baseline lesson and a post-intervention or control lesson. Teachers (n = 16) and their classes from five secondary schools in Sydney, Australia were randomly assigned into four blocks and instructed to provide one of four 20-min lesson teaching strategy conditions: (1) explaining the relevance of activities; (2) providing choice from PA options selected by the teacher; (3) providing equipment and free choice of activities; or (4) usual practice. The primary outcomes were lesson time spent in moderate-to-vigorous PA, and motivation towards the lesson. Secondary outcomes were perceptions of teacher behavior, psychological needs satisfaction, and lesson time spent in sedentary behavior. PA and sedentary behavior were measured during baseline and post intervention lessons with waist-mounted Actigraph GT3X accelerometers. Teacher behavior, psychological needs satisfaction, and motivation were assessed via questionnaires at the end of each lesson. Linear mixed-model analyses will be run on all outcomes, with students nested within teachers as a random effect. DISCUSSION: Study findings will inform the development of effective SDT-based teaching strategy interventions to enhance students' psychological needs satisfaction, motivation, and PA levels. More effective teaching strategies may be identified that are capable of improving adolescents' PA levels, and thereby provide beneficial population health outcomes. TRIAL REGISTRATION: This trial is registered with Current Controlled Trials and is traceable as ISRCTN07038258. PMID- 23025262 TI - In the company of cowbirds, Molothrus ater ater: robust patterns of sociability predict reproductive performance. AB - Many species exhibit behavioral tendencies that are stable over time and across contexts. Robust variation in sociability, or the propensity to approach others, is widespread across the vertebrates. Nonetheless, the influence of sociability on reproductive performance is largely unknown. In this study, we explore the relationship between sociability and reproductive behavior in flocks of Brown headed Cowbirds (Molothrus ater ater). In spring 2011, we separated birds into three large aviaries based on the number of approaches they initiated and received during fall 2010. Females were separated into high, intermediate, and low sociable flocks, while male sociability was spread evenly across the three flocks. Here we report for the first time that different patterns of social approach tendencies in the fall predicted reproductive behavior in the spring. The high sociable flocks contained more laying females who produced more eggs in contrast to the other flocks. Male courtship behavior was comparable across the three flocks. These findings suggest that robust variation in sociability is an important factor in reproductive performance. PMID- 23025263 TI - The future is bright and predictable: the development of prospective life stories across childhood and adolescence. AB - When do children develop the ability to imagine their future lives in terms of a coherent prospective life story? We investigated whether this ability develops in parallel with the ability to construct a life story for the past and narratives about single autobiographical events in the past and future. Four groups of school children aged 9 to 15 years imagined their future lives and produced past life stories, as well as a cultural life script (i.e., culturally shared assumptions as to the order and timing of important life events). They also produced narratives about single autobiographical events to take place in the near future or recent past. Past and prospective life story coherences developed in parallel across ages, that is, older children told more coherent life stories than younger children, irrespective of temporal direction. However, children produced more coherent stories about single events in the past than in the future. Across age groups, prospective life stories were shorter, contained more life script events and were more positive than past life stories. Life script normativity increased with age and predicted the coherence of prospective, but not of past, life stories. The findings indicate that the ability to tell coherent life stories for the past and future develops in parallel and relies on similar processes. Life script abilities might be a major factor in the development of past and prospective life story coherences but not for the development of single event story coherences. PMID- 23025264 TI - The developmental significance of late adolescent substance use for early adult functioning. AB - This study examines the predictive significance of late adolescent substance use groups (i.e., abstainers, experimental users, at-risk users, and abusers) for early adult adaptation. Participants (N = 159) were drawn from a prospective longitudinal study of first-born children of low-income mothers. At 17.5 years of age, participants were assigned to substance use groups on the basis of their level of substance use involvement. At 26 years, early adult competence was assessed in the areas of education, work, romantic relationships, and global adaptation. Results indicate that 17.5-year substance use group membership significantly predicted high school completion, regular involvement in a long term romantic relationship, good or better work ethic, and good or better global adjustment at 26 years when controlling for gender; IQ; 16-year internalizing and externalizing behavior problems, parental monitoring, and peer competence; and current substance use at 26 years. Group comparisons indicate that late adolescent substance use experimenters were significantly more likely in early adulthood to have (a) a high school diploma or higher level of education compared with abstainers (OR = 8.83); (b) regular involvement in long-term romantic relationships (OR = 3.23), and good or better global adaptation (OR = 4.08) compared with at-risk users; and (c) good or better work ethic (OR = 4.04) compared with abusers. This research indicates that patterns of late adolescent substance use has implications for early adult functioning in salient developmental domains. PMID- 23025265 TI - Family income and early achievement across the urban-rural continuum. AB - Rural and suburban children account for the majority of poor children in the United States. Yet, most research examining poverty's associations with child development is focused on urban samples. Using nationally representative data from the Early Childhood Longitudinal Study, Birth Cohort (N ~ 6,600), this study examines whether the form and magnitude of income's relationship with early achievement differ across the urban-rural continuum. Results suggest that there are urbanicity-related differences in the functional form of the association between income and early achievement, with nonlinear associations in urban and suburban areas and a linear relationship in rural areas. The magnitude of the association between income and early reading and math skills also differs across the urban-rural continuum, such that income increases are related to the greatest improvements in early academic skills in large urban areas and only slight improvements in rural areas. PMID- 23025266 TI - Children's sleep and adjustment: a residualized change analysis. AB - We investigated longitudinal relations between children's sleep and symptoms of depression, anxiety, and anger/aggression. We expected that initial sleep problems and increases in these problems over time would be associated with worse adjustment outcomes. The study had 3 waves with 1-year lags. At Time 1 [T1], 128 girls and 123 boys (M age = 8.23 years, SD = 0.73) participated; M ages at Time 2 (T2) and Time 3 (T3) = 9.31 years (SD = 0.79) and 10.28 (SD = 0.99). The sample was diverse in relation to economic adversity and ethnicity (66% European and 34% African American). Higher initial levels and increases in sleep/wake problems or sleepiness over 3 years predicted higher levels of depression and anxiety symptoms at T3, controlling for T1 levels. These associations were more pronounced for girls, African American children, and children from lower socioeconomic status homes. Findings build on a small body of literature addressing links between sleep and adjustment longitudinally and highlight the importance of adequate sleep for children's optimal development, especially within the broader sociocultural milieu.. PMID- 23025267 TI - Plasma alemtuzumab levels in patients with chronic lymphocytic leukemia treated with alemtuzumab combined with chemotherapy reflect the efficacy of the treatment: a hypothesis. AB - In the HOVON68 trial comparing subcutaneous low-dose alemtuzumab (LD-A) used together with fludarabine (F) and cyclophosphamide (C) with FC alone in high-risk chronic lymphocytic leukemia (CLL), LD-AFC resulted in significantly more clinical and molecular responses than FC, but also in more opportunistic infections. In a subgroup analysis of alemtuzumab trough levels during treatment by a sensitive enzyme-linked immunosorbent assay (ELISA) method, detectable levels were found in 4/6 complete and 0/3 partial responders. A relationship between alemtuzumab plasma levels, response and duration of lymphocytopenia was evident. We hypothesize that following combination therapy, the response may not be a function of the alemtuzumab levels, but the opposite, that plasma alemtuzumab levels are a function of the efficacy of the entire treatment, and the fewer leukemic target cells that are remaining, the higher are the levels of plasma alemtuzumab. This concept may well provide a guide for alemtuzumab dosage in future trials. PMID- 23025268 TI - Measurement in occupational therapy. PMID- 23025270 TI - Longitudinal and reciprocal associations between coparenting conflict and father engagement. AB - The major goal of the present study was to examine the reciprocal and longitudinal associations between coparenting conflict and father engagement with children during the early childhood years. Using data from the Early Childhood Longitudinal Survey--Birth Cohort (N = 3600), the findings supported the hypothesis that father engagement at 9 months has a significant effect on coparenting conflict at 24 and 48 months, but there was limited support for the hypothesis that early coparenting conflict has an effect on later engagement. The direct and indirect findings also suggest that fathers' engagement with young children has different longitudinal effects on coparenting conflict depending on the type of activity in which fathers are engaged. Whereas fathers' physical care at 9 months was associated with increased levels of later coparenting conflict, fathers' cognitive stimulation at 9 months was associated with lower levels of later coparenting conflict. Implications for programs for fathers and families are discussed. PMID- 23025269 TI - New biomarker for neovascular age-related macular degeneration: eotaxin-2. AB - Recently, eotaxin-CCR3 was reported to play an important role in choroidal neovascularization (CNV) development and was documented to be superior than vascular endothelial growth factor-A treatment when tested in CNV animals. As eotaxin studies are lacking in the human age-related macular degeneration (AMD) patients, we sought to determine whether eotaxin-2 (CCL24) has any association with inflammatory processes that occur in CNV. CCL24 levels were determined by enzyme linked immunosorbant assay (ELISA) after normalization to total serum protein and levels of ELISA were correlated to various risk factors in about 133 AMD patients and 80 healthy controls. The CCL24 levels were significantly higher in wet AMD patients as compared with dry AMD and normal controls. There was a significant difference when compared among wet AMD patients (i.e., minimally classic, predominantly classic, and occult). We also report significant difference in the CCL24 levels of Avastin-treated and untreated AMD patients. This study shows that CCL24 levels were found to be significantly increased in AMD patients despite Avastin treatment as compared with normal controls and those without Avastin, indicating that CCL24 may have an association with CNV and may be an important target to validate future therapeutic approaches in AMD in tandem with Avastin treatment. PMID- 23025271 TI - Identification of structural motifs in the E2 glycoprotein of Chikungunya involved in virus-host interaction. AB - Chikungunya fever is one of the reemerging vector-borne diseases. It has become a major global health problem especially in the developing countries. There are no vaccines or specific antiviral drugs available to date. This study reports small molecule inhibitors of envelope glycoprotein 2 (E2 glycoprotein) which are predicted based on Chikungunya virus-host interactions. E2 glycoprotein of Chikungunya virus interacts at 216 residue of the host receptor protein which plays a vital role in initiating infection. Understanding the structural aspects of E2 glycoprotein is crucial to develop specific inhibitors to prevent the virus binding from host receptors. In silico method was adopted to predict the sequence motifs of envelope protein, as the method like yeast two hybrid system is laborious, time consuming, and costly. The E2 glycoprotein structure of the Indian isolate was modeled using two templates (2XFC and 3JOC) and then validated. The class III PDZ domain binding motif was found to be identified at 213-216 amino acids. The corresponding peptide structures which recognize the PDZ domain binding motif were identified by the literature search and were used for generating five point pharmacophore model (ADDDR) containing acceptor, donor and aromatic ring features. Databases such as Asinex, TosLab and Maybridge were searched for the matches for the predicted pharmacophore model. Two compounds were identified as lead molecules as their glide score is > 5 kcal/mol. Since the pharmacophore model is developed based on Chikungunya virus-host interaction, it can be used for designing promising antiviral lead compounds for the treatment of Chikungunya fever.An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:21. PMID- 23025273 TI - Horse meat consumption affects iron status, lipid profile and fatty acid composition of red blood cells in healthy volunteers. AB - This study investigated the effect of moderate consumption of horse meat on iron status, lipid profile and fatty acid composition of red blood cells in healthy male volunteers. Fifty-two subjects were randomly assigned to two groups of 26 subjects each: a test group consuming two portions of 175 g/week of horse meat, and a control group that abstained from eating horse meat during the 90 days trial. Before and after 90 days, blood samples were collected for analysis. Horse meat consumption significantly (p <= 0.05) reduced serum levels of total and low density lipoprotein cholesterol ( - 6.2% and - 9.1%, respectively) and transferrin ( - 4.6%). Total n - 3, long chain polyunsaturated fatty acids n - 3 and docosahexeanoic acid content in erythrocytes increased (p <= 0.05) by about 7.8%, 8% and 11%, respectively. In conclusion, the regular consumption of horse meat may contribute to the dietary intake of n - 3 polyunsaturated fatty acids and may improve lipid profile and iron status in healthy subjects. PMID- 23025275 TI - A lost link between a flightless parrot and a parasitic plant and the potential role of coprolites in conservation paleobiology. AB - Late Quaternary extinctions and population fragmentations have severely disrupted animal-plant interactions globally. Detection of disrupted interactions often relies on anachronistic plant characteristics, such as spines in the absence of large herbivores or large fruit without dispersers. However, obvious anachronisms are relatively uncommon, and it can be difficult to prove a direct link between the anachronism and a particular faunal taxon. Analysis of coprolites (fossil feces) provides a novel way of exposing lost interactions between animals (depositors) and consumed organisms. We analyzed ancient DNA to show that a coprolite from the South Island of New Zealand was deposited by the rare and threatened kakapo (Strigops habroptilus), a large, nocturnal, flightless parrot. When we analyzed the pollen and spore content of the coprolite, we found pollen from the cryptic root-parasite Dactylanthus taylorii. The relatively high abundance (8.9% of total pollen and spores) of this zoophilous pollen type in the coprolite supports the hypothesis of a former direct feeding interaction between kakapo and D. taylorii. The ranges of both species have contracted substantially since human settlement, and their present distributions no longer overlap. Currently, the lesser short-tailed bat (Mystacina tuberculata) is the only known native pollinator of D. taylorii, but our finding raises the possibility that birds, and other small fauna, could have once fed on and pollinated the plant. If confirmed, through experimental work and observations, this finding may inform conservation of the plant. For example, it may be possible to translocate D. taylorii to predator-free offshore islands that lack bats but have thriving populations of endemic nectar-feeding birds. The study of coprolites of rare or extinct taxonomic groups provides a unique way forward to expand existing knowledge of lost plant and animal interactions and to identify pollination and dispersal syndromes. This approach of linking paleobiology with neoecology offers significant untapped potential to help inform conservation and restoration plans. PMID- 23025272 TI - Hemoglobin redox reactions and red blood cell aging. AB - SIGNIFICANCE: The physiological mechanism(s) for recognition and removal of red blood cells (RBCs) from circulation after 120 days of its lifespan is not fully understood. Many of the processes thought to be associated with the removal of RBCs involve oxidative stress. We have focused on hemoglobin (Hb) redox reactions, which is the major source of RBC oxidative stress. RECENT ADVANCES: The importance of Hb redox reactions have been shown to originate in large parts from the continuous slow autoxidation of Hb producing superoxide and its dramatic increase under hypoxic conditions. In addition, oxidative stress has been shown to be associated with redox reactions that originate from Hb reactions with nitrite and nitric oxide (NO) and the resultant formation of highly toxic peroxynitrite when NO reacts with superoxide released during Hb autoxidation. CRITICAL ISSUES: The interaction of Hb, particularly under hypoxic conditions with band 3 of the RBC membrane is critical for the generating the RBC membrane changes that trigger the removal of cells from circulation. These changes include exposure of antigenic sites, increased calcium leakage into the RBC, and the resultant leakage of potassium out of the RBC causing cell shrinkage and impaired deformability. FUTURE DIRECTIONS: The need to understand the oxidative damage to specific membrane proteins that result from redox reactions occurring when Hb is bound to the membrane. Proteomic studies that can pinpoint the specific proteins damaged under different conditions will help elucidate the cellular aging processes that result in cells being removed from circulation. PMID- 23025276 TI - Reaction pathway and free energy profile for conversion of pi-conjugation modes in porphyrin isomer. AB - Porphycene is a structural isomer of porphyrin with 18pi-conjugated aromatic character. Porphycene modified with trifluoromethyl (CF(3)) groups in the periphery of the framework readily affords the isolable 20pi-conjugated antiaromatic form through a reaction with a proton-donating reductant. The 20pi conjugated form can be characterized by not only a variety of spectroscopies in solutions but also X-ray crystallography. This paper focuses on the free energy profile in the conversion of the 18pi-conjugated porphycene into the 20pi conjugated form. From the results of kinetics, electrochemical measurements, and acid/base titrations, the 20pi-conjugated CF(3) porphycene is formed by a concerted proton-electron transfer (CPET) from a hydroquinone reagent to the 18pi conjugated form. The hydrogen-atom affinity of the 18pi-conjugated CF(3) porphycene (for two hydrogen atoms) was calculated to be -490 kJ mol(-1), indicating that the N-H bonds in the 20pi-conjugated form are rather easily cleaved. This reflects the antiaromatic characteristics of the 20pi-conjugated porphycene. We propose that the kinetic and thermochemical analysis using redox potentials and pK(a) data is applicable for determining the reaction pathway in conversion of aromatic/antiaromatic mode of pi-conjugated macrocycles as well as popular investigations for oxidations of organic molecules. PMID- 23025277 TI - Drop-on-demand sample introduction system coupled with the flowing atmospheric pressure afterglow for direct molecular analysis of complex liquid microvolume samples. AB - One of the fastest developing fields in analytical spectrochemistry in recent years is ambient desorption/ionization mass spectrometry (ADI-MS). This burgeoning interest has been due to the demonstrated advantages of the method: simple mass spectra, little or no sample preparation, and applicability to samples in the solid, liquid, or gaseous state. One such ADI-MS source, the flowing atmospheric-pressure afterglow (FAPA), is capable of direct analysis of solids just by aiming the source at the solid surface and sampling the produced ions into a mass spectrometer. However, direct introduction of significant volumes of liquid samples into this source has not been possible, as solvent loads can quench the afterglow and, thus, the formation of reagent ions. As a result, the analysis of liquid samples is preferably carried out by analyzing dried residues or by desorbing small amounts of liquid samples directly from the liquid surface. In the former case, reproducibility of sample introduction is crucial if quantitative results are desired. In the present study, introduction of liquid samples as very small droplets helps overcome the issues of sample positioning and reduced levels of solvent intake. A recently developed "drop-on demand" (DOD) aerosol generator is capable of reproducibly producing very small volumes of liquid (~17 pL). In this paper, the coupling of FAPA-MS and DOD is reported and applications are suggested. Analytes representing different classes of substances were tested and limits of detections were determined. Matrix tolerance was investigated for drugs of abuse and their metabolites by analyzing raw urine samples and quantification without the use of internal standards. Limits of detection below 2 MUg/mL, without sample pretreatment, were obtained. PMID- 23025278 TI - Racing carbon atoms. Atomic motion reaction coordinates and structural effects on Newtonian kinetic isotope effects. AB - Intramolecular (13)C kinetic isotope effects were determined for the dimerization of methacrolein. Trajectory studies accurately predict the isotope effects and support an origin in Newton's second law of motion, with no involvement of zero point energy or transition state recrossing. Atomic motion reaction coordinate diagrams are introduced as a way to qualitatively understand the selectivity. PMID- 23025279 TI - Effects of linker torsional constraints on the rate of ground-state hole transfer in porphyrin dyads. AB - Understanding hole/electron-transfer processes among interacting constituents of multicomponent molecular architectures is central to the fields of artificial photosynthesis and molecular electronics. Herein, we utilize a recently demonstrated (203)Tl/(205)Tl hyperfine "clocking" strategy to probe the rate of hole/electron transfer in the monocations of a series of three thallium-chelated porphyrin dyads, designated Tl(2)-U, Tl(2)-M, and Tl(2)-B, that are linked via diarylethynes wherein the number of ortho-dimethyl substituents on the aryl group of the linker systematically increases (none, one, and two, respectively). Variable-temperature (160-340 K) EPR studies on the monocations of the three dyads were used to examine the thermal activation behavior of the hole/electron transfer process and reveal the following: (1) Hole/electron transfer at room temperature (295 K) slows as torsional constraints are added to the diarylethyne linker [k(Tl(2)-U) > k(Tl(2)-M) > k(Tl(2)-B)], with rate constants that correspond to time constants in the 2-5 ns regime. (2) As the temperature decreases, the hole/electron-transfer rates for the monocations of the three types of dyads converge and then cross over. At the lowest temperatures examined (160-170 K), the trend in the hole/electron-transfer rates is essentially reversed [k(Tl(2)-B) > k(Tl(2)-M) ~ k(Tl(2)-U)]. The trends in the temperature dependence of hole/electron-transfer among the three dyads are consistent with torsional motions of the aryl rings of the linker providing for thermal activation of the process at higher temperatures in the case of the less torsionally constrained dyads, Tl(2)-U and Tl(2)-M. In the case of the most torsionally constrained dyad, Tl(2)-B, the hole/electron-transfer process is activationless at all temperatures studied. The reversal in rates of hole/electron transfer among the three dyads at low temperature is qualitatively explained by the results of density functional theory calculations, which predict that static electronic factors could dominate the hole/electron-transfer process when torsional dynamics are thermally diminished. PMID- 23025280 TI - Early events in plastid protein degradation in stay-green Arabidopsis reveal differential regulation beyond the retention of LHCII and chlorophyll. AB - An individually darkened leaf model was used to study protein changes in the Arabidopsis mutant stay-green1 (sgr1) to partially mimic the process of leaf covering senescence that occurs naturally in the shaded rosettes of Arabidopsis plants. Utilizing this controlled and predictable induced senescence model has allowed the direct comparison of sgr1 with Col-0 during the developmental period preceding the retention of chlorophyll and light harvesting complex II (LHCII) in sgr1 and the induction of senescence in Col-0. Quantitative proteomic analysis of soluble leaf proteins from sgr1 and Col-0 before the initiation of senescence has revealed a range of differences in plastid soluble protein abundance in sgr1 when compared to Col-0. Changes were also observed in membrane located machinery for photosystem II (PSII), in Calvin cycle components, proteins involved in redox control of the stromal compartment and ammonia assimilation that differentiated sgr1 during the early stages of the senescence process. The changes in PSII abundance were accompanied with a lower capacity of photosynthetic CO(2) assimilation in sgr1 than Col-0 after return of plants to lighted conditions following 3 and 5 days of darkness. A light-harvesting chlorophyll-a/b binding protein (LHCB2) was retained during the later stages of senescence in sgr1 but this was accompanied by an enhanced loss of oxygen evolving complex (OEC) subunits from PSII, which was confirmed by Western blotting, and an enhanced stability of PSII repair proteins in sgr1, compared to Col-0. Together these data provide insights into the significant differences in the steady-state proteome in sgr1 and its response to senescence, showing this cosmetic stay-green mutant is in fact significantly different to wild-type plants both before and during leaf senescence. PMID- 23025281 TI - Epigenetics and the environment in bioethics. AB - A rich literature in public health has demonstrated that health is strongly influenced by a host of environmental factors that can vary according to social, economic, geographic, cultural or physical contexts. Bioethicists should, we argue, recognize this and--where appropriate--work to integrate environmental concerns into their field of study and their ethical deliberations. In this article, we present an argument grounded in scientific research at the molecular level that will be familiar to--and so hopefully more persuasive for--the biomedically-inclined in the bioethics community. Specifically, we argue that the relatively new field of molecular epigenetics provides novel information that should serve as additional justification for expanding the scope of bioethics to include environmental and public health concerns. We begin by presenting two distinct visions of bioethics: the individualistic and rights-oriented and the communitarian and responsibility-oriented. We follow with a description of biochemical characteristics distinguishing epigenetics from genetics, in order to emphasize the very close relationship that exists between the environment and gene expression. This then leads to a discussion of the importance of the environment in determining individual and population health, which, we argue, should shift bioethics towards a Potterian view that promotes a communitarian based sense of responsibility for the environment, in order to fully account for justice considerations and improve public health. PMID- 23025282 TI - Antibiotic and antimalarial quinones from fungus-growing ant-associated Pseudonocardia sp. AB - Three new members of the angucycline class of antibiotics, pseudonocardones A-C (1-3), along with the known antibiotics 6-deoxy-8-O-methylrabelomycin (4) and X 14881 E (5) have been isolated from the culture of a Pseudonocardia strain associated with the fungus-growing ant Apterostigma dentigerum. Compounds 4 and 5 showed antibiotic activity against Bacillus subtilis 3610 and liver-stage Plasmodium berghei, while 1-3 were inactive or only weakly active in a variety of biological assays. Compound 5 also showed moderate cytotoxicity against HepG2 cells. PMID- 23025283 TI - Complete thermodynamic and kinetic characterization of the isomer-specific interaction between Pin1-WW domain and the amyloid precursor protein cytoplasmic tail phosphorylated at Thr668. AB - Peptidyl prolyl cis-trans isomerization acts as an effective molecular timer that plays significant roles in biological and pathological processes. Enzymes such as Pin1 catalyze cis-trans isomerization, accelerating the otherwise slow isomerization rate into time scales relevant for cellular signaling. Here we have combined NMR line shape analysis, fluorescence spectroscopy, and isothermal titration calorimetry to determine the kinetic and thermodynamic parameters describing the trans-specific interaction between the binding domain of Pin1 (WW domain) and a key cis-trans molecular switch in the amyloid precursor protein cytoplasmic tail. A three-state model, in which the cis-trans isomerization equilibrium is coupled to the binding equilibrium through the trans isomer, was found to fit the data well. The trans isomer binds the WW domain with ~22 MUM affinity via very fast association (approaching the diffusion limit) and dissociation rates. The common structural and electrostatic characteristics of Pin1 substrates, which contain a phosphorylated serine/threonine-proline motif, suggest that very rapid binding kinetics are a general feature of Pin1 interactions with other substrates. The fast binding kinetics of the WW domain allows rapid response of Pin1 to the dynamic events of phosphorylation and dephosphorylation in the cell that alter the relative populations of diverse Pin1 substrates. Furthermore, our results also highlight the vastly different rates at which slow uncatalyzed cis-trans isomerization and fast isomer-specific binding events occur. These results, along with the experimental methods presented herein, should guide future experiments aimed at the thermodynamic and kinetic characterization of cis-trans molecular switches and isomer-specific interactions involved in various biological processes. PMID- 23025285 TI - GFP-like phototransformation mechanisms in the cytotoxic fluorescent protein KillerRed unraveled by structural and spectroscopic investigations. AB - KillerRed (KR) is a red fluorescent protein recognized as an efficient genetically encoded photosensitizer. KR generates reactive oxygen species via a complex process of photoreactions, ending up in photobleaching, the mechanism of which remains obscure. In order to clarify these mechanisms, we focus on a single mutant V44A (A44-KR) exhibiting the solely green component of KR. We report on the laser-induced structural transformations of A44-KR at cryogenic temperature, which we have investigated by combining UV-vis fluorescence/absorption spectroscopy with X-ray crystallography. Like the well-known GFP, A44-KR possesses a mixture of protonated (A) absorbing at 397 and deprotonated (B) absorbing at 515 nm chromophores, which are stressed by intense prolonged violet and blue laser sources. Both illuminations directly drive the B-chromophores toward a bleached trans isomerized form. A-type chromophores are sensitive only to violet illumination and are phototransformed either into a deprotonated green fluorescent form by decarboxylation of E218 or into a bleached form with a disordered p-hydroxybenzylidene. In crystallo spectroscopy at cryo-temperature allowed the identification and dissection of an exhaustive scheme of intermediates and end-products resulting from the phototransformation of A44-KR. This constitutes a framework for understanding the photochemistry of the photosensitizer KillerRed. PMID- 23025286 TI - A new estimator of the discovery probability. AB - Species sampling problems have a long history in ecological and biological studies and a number of issues, including the evaluation of species richness, the design of sampling experiments, and the estimation of rare species variety, are to be addressed. Such inferential problems have recently emerged also in genomic applications, however, exhibiting some peculiar features that make them more challenging: specifically, one has to deal with very large populations (genomic libraries) containing a huge number of distinct species (genes) and only a small portion of the library has been sampled (sequenced). These aspects motivate the Bayesian nonparametric approach we undertake, since it allows to achieve the degree of flexibility typically needed in this framework. Based on an observed sample of size n, focus will be on prediction of a key aspect of the outcome from an additional sample of size m, namely, the so-called discovery probability. In particular, conditionally on an observed basic sample of size n, we derive a novel estimator of the probability of detecting, at the (n+m+1)th observation, species that have been observed with any given frequency in the enlarged sample of size n+m. Such an estimator admits a closed-form expression that can be exactly evaluated. The result we obtain allows us to quantify both the rate at which rare species are detected and the achieved sample coverage of abundant species, as m increases. Natural applications are represented by the estimation of the probability of discovering rare genes within genomic libraries and the results are illustrated by means of two expressed sequence tags datasets. PMID- 23025287 TI - Nanostructured surfactant-based systems for the removal of polymers from wall paintings: a small-angle neutron scattering study. AB - Nanostructured soft matter systems represent effective and long-lasting solutions with respect to traditional and often obsolete methodologies for the conservation of works of art. In particular, complex fluids such as micelles and microemulsions are the most performing media for the removal of organic materials from porous supports, like wall paintings or stones. In this Article, we report on the characterization of two systems, EAPC and XYL, which have shown good to optimal performances in the removal of organic polymers from wall paintings. EAPC is a five-components fluid composed of water, sodium dodecylsulfate (SDS), 1 pentanol (PeOH), propylene carbonate (PC), and ethyl acetate (EA), while XYL is a "classical" o/w microemulsion, where p-xylene droplets are stabilized in water by SDS and PeOH. Small-angle neutron scattering (SANS) with contrast variation is used to infer a detailed picture of the structure of these complex fluids, with a particular focus on the partition of the components between the bulk phase and the nanocompartments. We found that, differently from XYL, the EAPC system is neither a microemulsion nor a simple micellar solution, with the cosolvents partitioned between the dispersing phase and the disperse droplets. These different structural features play a key role in defining the cleaning effectiveness and specifically the kinetics of interaction between the nanofluid and the polymeric coating to be removed, which is of paramount importance for the application in the field. Both of these nanofluids are effective in polymer removal, but EAPC is considerably more efficient and versatile. The composition and the structure at the nanoscale determine the capability of removing a broad range of different polymer coatings from porous materials. A representative case study is here described, addressing a particularly challenging conservative issue, which is the removal of a multilayered aged coating that was irreversibly damaging the pictorial layer of the Annunciation Basilica in Nazareth. PMID- 23025284 TI - Oxygen transport in the microcirculation and its regulation. AB - OBJECTIVE: Cells require energy to carry out their functions and they typically use oxidative phosphorylation to generate the needed ATP. Thus, cells have a continuous need for oxygen, which they receive by diffusion from the blood through the interstitial fluid. The circulatory system pumps oxygen-rich blood through a network of increasingly minute vessels, the microcirculation. The structure of the microcirculation is such that all cells have at least one nearby capillary for diffusive exchange of oxygen and red blood cells release the oxygen bound to hemoglobin as they traverse capillaries. METHODS: This review focuses first on the historical development of techniques to measure oxygen at various sites in the microcirculation, including the blood, interstitium, and cells. RESULTS: Next, approaches are described as to how these techniques have been employed to make discoveries about different aspects of oxygen transport. Finally, ways in which oxygen might participate in the regulation of blood flow toward matching oxygen supply to oxygen demand is discussed. CONCLUSIONS: Overall, the transport of oxygen to the cells of the body is one of the most critical functions of the cardiovascular system and it is in the microcirculation where the final local determinants of oxygen supply, oxygen demand, and their regulation are decided. PMID- 23025288 TI - Influence of the variation of the alkyl chain length of N-alkyl-beta-D glycosylamine derivatives on antifungal properties. AB - Twelve new glucosidic and galactosidic derivatives of N-alkylaminosugars with different alkylamines from 6 to 18 carbons were synthesized and characterized by (1)H and (13)C NMR. Their antifungal activity against the food fungal pathogen Aspergillus niger was evaluated using the radial growth assay. The influence of the variation of the alkyl chain length of N-alkylaminosugars on the mycelium growth was then discussed. Inhibition by the different alkylamines is shown as a biostatic effect rather than a biocidal effect. It was observed that alkylamines keep their antifungal properties after a thermal treatment compatible with food packaging and processing. PMID- 23025289 TI - Analyses of body composition charts among younger and older Chinese children and adolescents aged 5 to 18 years. AB - BACKGROUND: Childhood obesity has become a major public health problem in China. The objective of this study was to examine the effect of age and sex on the relationship between fat-free mass (FFM) and fat mass (FM), fat-free mass index (FFMI) and fat mass index (FMI) in Chinese children using body composition chart analysis, and to compare the changing pattern with Caucasian and Japanese counterparts. METHODS: A total of 1458 children (790 boys and 668 girls) between 5 and 18 years of age were studied to determine a body composition by bioelectrical impedance analysis. The relationship of FFM and FM, FFMI and FMI were delineated by body composition charts. RESULTS: Different changing patterns in body composition were observed during 5-11y (younger age group), and 12-18y (older age group), with non-significant sex difference with FM and FMI for the younger age group and significant sex and age differences for the older age group. For the younger age group, simultaneous increase of FFM and FM was found in both genders. However, for the older age group, the increase in weight and BMI with age is largely due to the increment of FFM and FFMI in boys, and of FM and FMI in girls. In addition, different changing patterns in body composition exist between Chinese children and their Caucasian and Japanese counterparts, largely due to the higher fat mass component in Chinese subjects. CONCLUSIONS: Our results indicate that age- and gender-related changing patterns of body composition in Chinese children may differ at different growth stage, and differ with those in Caucasian and Japanese children at the same age period. Such changing patterns should be considered when designing the intervention proposal for childhood obesity in China. PMID- 23025290 TI - Occurrence and co-existence of localized musculoskeletal symptoms and findings in work-attending orchestra musicians - an exploratory cross-sectional study. AB - BACKGROUND: Due to ergonomic exposure musicians are at risk of work-related musculoskeletal disorders in the neck, back, and upper extremities. The literature confirms musculoskeletal problems in these anatomic regions among orchestra musicians. METHODS: An explorative cross-sectional study among 441 musicians from six Danish symphony orchestras; 216 underwent a clinical examination constructed for the purpose. Prior to the examination the musicians rated their maximally perceived trouble within the last week on a scheme blinded to the examiner. Accessibility to the clinical examination differed between orchestras.The aims were to assess the prevalence of 1) perceived symptoms within the previous week in the neck, back and limbs and of 2) clinical findings in the neck, back, and upper extremities, and 3) to investigate the co-existence of the perceived symptoms and clinical findings. RESULTS: Symptoms and findings were most common in the neck, back, and shoulders. Due to a poor co-existence between self-reported symptoms and clinical findings musicians experiencing bodily trouble could not be identified through this clinical examination. Free accessibility to the examination was of major importance to participation. CONCLUSIONS: In compliance with the purpose, perceived symptoms within the previous week and present clinical findings were assessed. Although both symptoms and findings were most frequent in the neck, back, and shoulders the co-existence of anatomically localized symptoms and findings was generally quite poor in this study.Discrepancy between symptoms and findings might be caused by the participants currently attending work and therefore being relatively healthy, and the fluctuating nature of musculoskeletal problems. Furthermore from a comparison of different measuring units - self-reported symptoms being period prevalence rates and clinical findings point prevalence rates; a bias which may also be inherent in similar studies combining self-reported questionnaire data and clinical findings. PMID- 23025291 TI - Word fluency performance and strategies in children with cochlear implants: age dependent effects? AB - Word fluency was examined in 73 Swedish children aged 6-9 years divided into two age groups, 6-7 and 8-9 years; 34 deaf children with cochlear implants (CI) (15 girls/19 boys) and 39 age-matched children with normal hearing (NH) (20 girls/19 boys). One purpose was to compare the ability to retrieve words in two different word fluency tasks; one phonemically based (FAS letter fluency) and one semantically based (animal fluency). A second purpose was to examine retrieval strategies in the two tasks by conducting an analysis of clustering and switching of word sequences. In general we found that age was an important factor for word fluency ability, in both the CI and the NH groups. It was also demonstrated that children with CI aged 8-9 years retrieved significantly fewer words and used less efficient strategies in the retrieval process, especially on the phonemically based task compared to children with NH of the same ages, whereas children 6-7 years performed similarly in both groups regarding number of retrieved words and use of strategies. The results are discussed with respect to factors such as age differences in performance for children with CI, especially for the phonemically based task. PMID- 23025292 TI - Metabolic profile of porcine corneas after photodynamic cross-linking treatment. PMID- 23025293 TI - The feasibility and short-term benefits of Blue Prescription: a novel intervention to enable physical activity for people with multiple sclerosis. AB - PURPOSE: Participation in physical activity for people with Multiple sclerosis (MS) is important but can be difficult to sustain long-term. Facilitators for long-term adherence include choice over activity and control over level of engagement, coupled with support, advice and encouragement from a physiotherapist. This is the basis of Blue Prescription, a novel physiotherapy approach aimed at optimising long-term adherence with physical activity. We evaluated the feasibility and short-term benefits of Blue Prescription in people with MS. METHODS: Twenty-seven people with MS (mean age: 51 +/- 11 years, with a range of MS type and disability) were assessed at baseline and immediately post intervention with the MS Impact Scale, MS Self-efficacy Scale, and European Quality of Life Questionnaire. Change in outcomes were analysed with Wilcoxon signed ranks tests. RESULTS: All participants, irrespective of level of disability, were able to choose a physical activity and to engage in it. The physical component MS Impact Scale score significantly improved by a median change of 6.5 (95% CI = -10.5 to -2.0; p = 0.007; effect size = 0.38). There were no other significant changes in outcomes. CONCLUSION: Blue Prescription appears feasible and potentially beneficial, particularly in reducing the negative impacts of MS upon individuals, and thus warrants further evaluation. PMID- 23025294 TI - Diagnosing large granular lymphocyte leukemia is bloody difficult. PMID- 23025295 TI - Opioids in pain management of mesothelioma and lung cancer patients. AB - BACKGROUND: Lung cancer and mesothelioma are malignant tumors with generally dismal prognosis and therefore palliative pain treatment constitutes a challenge for the clinician. OBJECTIVES: The aim of this study was to compare the outcomes of pain treatment with opioids among mesothelioma and lung cancer patients treated for palliation and assess factors which confound to optimal treatment. PATIENTS AND METHODS: A sub-cohort of 373 lung cancer and 22 mesothelioma patients was identified in multi-center European Pharmacogenetic Opioid Study (EPOS) cohort. A nested case-control (1:4) setting was designed to estimate the pain and other covariates distinguishing 22 mesothelioma- (= cases) and 88 lung cancer patients (controls), analyzed using univariate- and multivariate conditional (fixed-effects) logistic regression models. RESULTS: The mean total daily dose of opioids varied from 30.0 to 960.0 mg (mean 275, median 160 mg, SD 293) in mesothelioma, and from 10 to 5072 mg (mean 414, median 175, SD 788) in lung cancer patients (p = 0.420). In both groups, pain was mostly experienced as moderate and severe and it was frequently accompanied by depression, poor sleep, anxiety and fatigue. Four mesothelioma patients (18%) and seven lung cancer patients (10%) experienced complete pain relief with opioids by self-assessment. Assessments of pain severity by the patients and their physicians deviated significantly in mesothelioma (p = 0.039 McNemar test), as well as in lung cancer (p = 0.0001). In conditional logistic regression, no significant differences were found in distribution of pain covariates between lung cancer and mesothelioma patients. CONCLUSION: Pain perception by the patients was associated frequently with other symptoms and complete pain control with opioids was achieved only with minority of patients both with mesothelioma and advanced lung cancer. Adequate pain control requires continuous monitoring and tailoring the dose to patient's individual needs and tolerance, recognition of accompanying symptoms such as depression and poor sleep, and their management. PMID- 23025296 TI - Physiological demands of downhill mountain biking. AB - Mountain biking is a popular recreational pursuit and the physiological demands of cross-country style riding have been well documented. However, little is known regarding the growing discipline of gravity-assisted downhill cycling. We characterised the physiological demands of downhill mountain biking under typical riding conditions. Riding oxygen consumption (VO(2)) and heart rate (HR) were measured on 11 male and eight female experienced downhill cyclists and compared with data during a standardised incremental to maximum (VO(2max)) exercise test. The mean VO(2) while riding was 23.1 +/- 6.9 ml . kg(-1) . min(-1) or 52 +/- 14% of VO(2max) with corresponding heart rates of 146 +/- 11 bpm (80 +/- 6% HRmax). Over 65% of the ride was in a zone at or above an intensity level associated with improvements in health-related fitness. However, the participants' heart rates and ratings of perceived exertion were artificially inflated in comparison with the actual metabolic demands of the downhill ride. Substantial muscular fatigue was evident in grip strength, which decreased 5.4 +/- 9.4 kg (5.5 +/- 11.2%, P = 0.03) post-ride. Participation in downhill mountain biking is associated with significant physiological demands, which are in a range associated with beneficial effects on health-related fitness. PMID- 23025297 TI - Protein and mineral nutrient contents in kernels from 72 sweet almond cultivars and accessions grown in France, Greece and Italy. AB - Almond protein and potassium (K), phosphorus (P), calcium (Ca) and magnesium (Mg) contents were determined in 72 cultivars and accessions grown in France, Greece and Italy, as part of the networking of European SAFENUT AGRI GEN RES project, which aimed to explore and valorize the almond genetic resources in Europe. Great variation was found in the nutrient content and the amount of nutrient supplied when consuming the recommended daily amount of one serving of almond, among the different genotypes assayed. The variation among the different genotypes was greatest for Ca, followed by the protein content; the latter also exhibited the lowest variation considering the harvest year. Results from a principal component analysis showed that P and Mg were the most discriminant elements for categorizing samples. Cluster analysis showed groups of samples with interesting characteristics for breeding. There was no clear distinction among the different origins of samples. Correlation analyses between weather conditions and the nutrients assayed showed that the mean temperature recorded in the period between March and September was positively correlated with Ca and P only in France, a place where the greatest climatic difference between years was observed. PMID- 23025298 TI - Potential therapeutic effects of natural heme oxygenase-1 inducers in cardiovascular diseases. AB - SIGNIFICANCE: Many physiological effects of natural antioxidants, their extracts or their major active components, have been reported in recent decades. Most of these compounds are characterized by a phenolic structure, similar to that of alpha-tocopherol, and present antioxidant properties that have been demonstrated both in vitro and in vivo. Polyphenols may increase the capacity of endogenous antioxidant defenses and modulate the cellular redox state. Such effects may have wide-ranging consequences for cellular growth and differentiation. CRITICAL ISSUES: The majority of in vitro and in vivo studies conducted so far have attributed the protective effect of bioactive polyphenols to their chemical reactivity toward free radicals and their capacity to prevent the oxidation of important intracellular components. One possible protective molecular mechanism of polyphenols is nuclear factor erythroid 2-related factor (Nrf2) activation, which in turn regulates a number of detoxification enzymes. RECENT ADVANCES: Among the latter, the heme oxygenase-1 (HO-1) pathway is likely to contribute to the established and powerful antioxidant/anti-inflammatory properties of polyphenols. In this context, it is interesting to note that induction of HO-1 expression by means of natural compounds contributes to prevention of cardiovascular diseases in various experimental models. FUTURE DIRECTIONS: The focus of this review is on the role of natural HO-1 inducers as a potential therapeutic strategy to protect the cardiovascular system against various stressors in several pathological conditions. PMID- 23025299 TI - Correlates of daily leisure-time physical activity in a community sample: Narrow personality traits and practical barriers. AB - OBJECTIVE: Previous studies examining correlates of leisure time physical activity (LTPA) have identified personality factors that are correlated with LTPA and practical factors that impede LTPA. The purpose of the present study was to test how several narrow traits predict daily reports of LTPA and to test whether traits that predict LTPA moderate the effects of practical barriers. METHODS: 1192 participants completed baseline measures of personality, then reported their LTPA and several situational and environmental factors daily for 25 days. We used generalized estimating equations to measure how personality traits, practical barriers, and interactions between these factors affected (1) the odds of engaging in LTPA and (2) the duration of daily LTPA. RESULTS: Higher standing on Activity and Discipline and lower standing on Assertiveness predicted greater odds of engaging in LTPA and longer duration of LTPA, and higher standing on Aesthetics predicted shorter duration of LTPA. Poor weather conditions and less leisure time were associated with less LTPA, and effects of these barriers were generally greater among participants 30 and older. In participants older than 30, poor weather was associated with less LTPA among those with lower standing on Activity but was not associated with LTPA among those high in Activity. Despite Discipline's overall positive association with LTPA, less leisure time and less routineness were greater barriers for those high in Discipline. CONCLUSIONS: Assessing narrow personality traits could help target LTPA interventions to individual patients' needs and could help identify important new personality dynamics that affect LTPA. PMID- 23025300 TI - The relationship between help-seeking attitudes and masculine norms among monozygotic male twins discordant for sexual orientation. AB - OBJECTIVE: In general, heterosexual men are less favorable to asking for help compared to women and gay men. This can be problematic if a man avoids professional help when he is experiencing significant psychological distress. Yet, it is unclear to what degree such attitudes among men are due to innate differences or social environments. Studying twins provides one avenue for teasing apart these relationships. METHOD: We recruited 38 pairs of monozygotic male twins (Mage = 35.87 years, SD = 9.52) raised together and who were discordant for sexual orientation. They completed measures of psychological distress (Symptom Checklist-90-Revised), positive attitudes toward psychological help-seeking behavior, and emphasis with fulfilling traditional masculine norms. RESULTS: Contrary to predictions, the heterosexual twins expressed more symptoms of specific distress-hostility (r = .30), paranoid ideation (r = .26), and psychoticism (r = .24)-than their gay cotwins. As predicted, heterosexual men were less favorable to seeking help (r = .25) and expressed greater emphasis on masculine norms (r = .26) than their cotwins. Within each group of men, unique aspects of masculine norms were significantly related to attitudes toward psychological help-seeking behavior. CONCLUSION: The findings lend credence to the hypothesis that social environments influence attitudes and behaviors that are stereotypically masculine and potentially detrimental to men's health. PMID- 23025301 TI - Whose intentions predict? Power over condom use within heterosexual dyads. AB - According to major theories of behavioral prediction, the most proximal psychological predictor of an individual's behavior is that individual's intention. With respect to interdependent behaviors such as condom use, however, relationship dynamics influence individuals' power to make decisions and to act. OBJECTIVE: The current study examines how relationship dynamics impact 3 condom use relevant outcomes: (a) the individual forming his or her own intention to use condoms, (b) the couple forming their joint intention to use condoms, and (c) actual condom use behavior. METHOD: We conducted a 2-wave longitudinal study of young heterosexual adult couples at high risk for HIV infection involving the collection of both individual- and couple-derived data. RESULTS: Results demonstrate the importance of both person (e.g., biological sex and dispositional dominance) and relational (e.g., relational power and amount of interest in the relationship, operationalized as commitment and perceived alternatives to the relationship) factors in predicting condom use intentions and behavior. Individuals who are lower in dispositional dominance are likely to incorporate their partner's intentions into their own individual intentions; the intentions of individuals who have less interest in the relationship are more highly predictive of the couple's joint intention; and the intentions of men and individuals higher in relationship power are more likely to exert a direct influence on condom use. CONCLUSIONS: These findings have implications for improving the health of high-risk individuals, including suggesting situations in which individuals are highly influenced by their partners' intentions. PMID- 23025302 TI - Spouses' attempts to regulate day-to-day dietary adherence among patients with type 2 diabetes. AB - OBJECTIVE: To investigate daily dietary adherence and diabetes-specific distress among older adults with type 2 diabetes mellitus (T2DM) as a function of spouses' diet-related support and diet-related control (persuasion and pressure) and whether these daily processes differ among couples who do and do not appraise responsibility for managing T2DM as shared. METHODS: End-of-day diaries were completed by 126 couples in which one partner had T2DM (patient) and the other did not (spouse). Using electronic diary methods, each partner independently recorded data for 24 consecutive days (patients recorded their day's dietary adherence and diabetes-specific distress; spouses recorded their day's involvement in patients' dietary management). To assess dietary adherence, patients reported the extent to which they followed dietary recommendations that day with items from the Summary of Diabetes Self-Care Activities Measure. To assess diabetes-specific distress, patients reported the extent to which they worried about diabetes that day using items from the Problem Areas in Diabetes (PAID) scale. RESULTS: Multilevel modeling revealed that, relative to the prior day, spouses' diet-related support was associated with increases in patients' adherence whereas diet-related persuasion and pressure were associated with decreases in adherence; spouses' pressure was associated with increases in patients' diabetes-specific distress. When partners appraised responsibility for managing T2DM as shared, support was associated with decreases in diabetes specific distress; pressure was associated with decreases in adherence. CONCLUSIONS: Our findings offer insight into partners' day-to-day disease-related interactions and identify those that are likely to be beneficial versus detrimental for patients' physical and psychological health. PMID- 23025303 TI - Examining causal components and a mediating process underlying self-generated health arguments for exercise and smoking cessation. AB - OBJECTIVE: Self-persuasion-generating one's own arguments for engaging in a specific behavior-can be an effective strategy to promote health behavior change, yet the causal processes that explain why it is effective are not well-specified. We sought to elucidate specific causal components and a mediating process of self persuasion in two health behavior domains: physical activity and smoking. METHODS: In two experiments, participants were randomized to write or read arguments about regular exercise (Study 1: N = 76; college students) or smoking cessation (Study 2: N = 107; daily smokers). In Study 2, we also manipulated the argument content (matched vs. mismatched participants' own concerns about smoking) to isolate its effect from the effect of argument source (self vs. other). Study outcomes included participants' reports of argument ratings, attitudes, behavioral intentions (Studies 1 & 2), and cessation attempts at 1 month (Study 2). RESULTS: In Study 1, self-generated arguments about exercise were evaluated more positively than other arguments (p = .01, d = .63), and this biased processing mediated the self-generated argument effect on attitudes toward exercise (beta = .08, 95% CI = .01, .18). In Study 2, the findings suggested that biased processing occurs because self-generated argument content matches people's own health concerns and not because of the argument source (self vs. other). In addition, self-generated arguments indirectly led to greater behavior change intentions (Studies 1 & 2) and a greater likelihood of a smoking cessation attempt (Study 2). CONCLUSIONS: The findings elucidate a causal component and a mediating process that explain why self-persuasion and related behavior change interventions, such as motivational interviewing, are effective. Findings also suggest that self-generated arguments may be an efficient way to deliver message interventions aimed at changing health behaviors. PMID- 23025304 TI - Oxygen-initiated chain mechanism for hydride transfer between NADH and NAD+ models. Reaction of 1-benzyl-3-cyanoquinolinium ion with N-methyl-9,10 dihydroacridine in acetonitrile. AB - A reinvestigation of the formal hydride transfer reaction of 1-benzyl-3 cyanoquinolinium ion (BQCN(+)) with N-methyl-9,10-dihydroacridine (MAH) in acetonitrile (AN) confirmed that the reaction takes place in more than one step and revealed a new mechanism that had not previously been considered. These facts are unequivocally established on the basis of conventional pseudo-first-order kinetics. It was observed that even residual oxygen under glovebox conditions initiates a chain process leading to the same products and under some conditions is accompanied by a large increase in the apparent rate constant for product formation with time. The efficiency of the latter process, when reactions are carried out in AN with rigorous attempts to remove air, is low but appears to be much more pronounced when MAH is the reactant in large excess. On the other hand, the intentional presence of air in AN ([air] = half-saturated) leads to a much greater proportion of the chain pathway, which is still favored by high concentrations of MAH. The latter observation suggests that a reaction intermediate reacts with oxygen to initiate the chain process in which MAH participates. Kinetic studies at short times show that there is no kinetic isotope effect on the initial step in the reaction, which is the same for the two competing processes. Our observation of the chain pathway of an NADH model compound under aerobic conditions is likely to be of importance in similar biological processes where air is always present. PMID- 23025305 TI - 2-Pyrenyl-DNA: synthesis, pairing, and fluorescence properties. AB - Multiple 2-pyrenyl-C-nucleosides were incorporated into the center of a DNA duplex resulting in stable pyrene self-recognition and excimer formation. This helical pyrene array may find use in DNA-mediated charge transfer and in the creation of DNA-based sensors. PMID- 23025306 TI - Sensitized photodecomposition of organic bisphosphonates by singlet oxygen. AB - During efforts to stabilize metal oxide bound chromophores for photoelectrochemical applications, a novel photochemical reaction has been discovered. In the reaction, the bisphosphonate functional groups C(PO(3)H(2))(2)(OH) in the metal complex [Ru(bpy)(2)(4,4' (C(OH)(PO(3)H(2))(2)bpy)](2+) are converted into -COOH and H(3)PO(4). The reaction occurs by sensitized formation of (1)O(2) by the lowest metal-to-ligand charge transfer excited state(s) of [Ru(bpy)(2)(4,4' (C(PO(3)H(2))(2)(OH))(2)(bpy))](2+)* followed by (1)O(2) oxidation of the bisphosphonate substituent. A related reaction occurs for the bisphosphonate based drug, risedronic acid, in the presence of O(2), light, and a singlet oxygen sensitizer ([Ru(bpy)(3)](2+) or Rose Bengal). PMID- 23025307 TI - Combined metabonomic and quantitative real-time PCR analyses reveal systems metabolic changes in Jurkat T-cells treated with HIV-1 Tat protein. AB - HIV-1 Tat protein is released by infected cells and can affect bystander uninfected T cells and induce numerous biological responses which contribute to its pathogenesis. To elucidate the complex pathogenic mechanism, we conducted a comprehensive investigation on Tat protein-related extracellular and intracellular metabolic changes in Jurkat T-cells using combined gas chromatography-mass spectrometry (GC-MS), reversed-phase liquid chromatography mass spectrometry (RPLC-MS) and a hydrophilic interaction liquid chromatography mass spectrometry (HILIC-MS)-based metabonomics approach. Quantitative real-time PCR (qRT-PCR) analyses were further employed to measure expressions of several relevant enzymes together with perturbed metabolic pathways. Combined metabonomic and qRT-PCR analyses revealed that HIV-1 Tat caused significant and comprehensive metabolic changes, as represented by significant changes of 37 metabolites and 10 relevant enzymes in HIV-1 Tat-treated cells. Using MetaboAnalyst 2.0, it was found that 11 pathways (Impact-value >0.10) among the regulated pathways were acutely perturbed, including sphingolipid metabolism, glycine, serine and threonine metabolism, pyruvate metabolism, inositol phosphate metabolism, arginine and proline metabolism, citrate cycle, phenylalanine metabolism, tryptophan metabolism, pentose phosphate pathway, glycerophospholipid metabolism, glycolysis or gluconeogenesis. These results provide metabolic evidence of the complex pathogenic mechanism of HIV-1 Tat protein as a "viral toxin", and would help obligate Tat protein as "an important target" for therapeutic intervention and vaccine development. PMID- 23025308 TI - Insight into TPMT(*)23 mutation mis-folding using molecular dynamics simulation and protein structure analysis. AB - Thiopurine S-methyltransferase (TPMT) is an important enzyme that metabolizes thiopurine drugs. This enzyme exhibits a large number of interindividual polymorphism. TPMT(*)23 polymorphism has been reported in a few cases in the world in co-dominance with TPMT(*)3A. The phenotype has been reported to affect enzyme activity in vivo and in vitro. Its underlying structural basis is not clarified yet. In our study, the wild type (WT) protein structure was analyzed and the amino acids bordering water channels in thiopurine sites were identified. Molecular dynamics of both the WT and TPMT(*)23 mutation was carried out. In addition, the effects of this mutation, especially on the thiopurine site which is closed with a pincer like mechanism, were investigated. We focused on explaining how a locally occurred A167G substitution propagated through hydrogen bonds alteration to induce structural modification which affects both thiopurine and S-adenosylmethionine receptors. Finally, a genetic prediction of mutation functional consequences has been conducted confirming altered activity. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:20. PMID- 23025309 TI - Unique challenges for this generation of dental graduates. PMID- 23025310 TI - Management of high caries-risk patients: part 2--treatment. PMID- 23025311 TI - Utilization of digital technologies for fabrication of definitive implant supported restorations. AB - The introduction 7 years ago of specially coded healing abutments dramatically simplified the task of obtaining implant impressions. Such coded abutments eliminated the need for impression copings, instead enabling supragingival impressions to be made and sent to the laboratory for fabrication of patient specific abutments and restorations. Combining this technology with digital oral scanning has the potential to further simplify the time between impression-making and delivery of a definitive restoration, and it offers additional benefits to both patients and clinicians. This article explains how oral scanners can be used to obtain digital impressions of encoded healing abutments. A case report illustrating this approach is also presented. PMID- 23025312 TI - COMMENTARY. Utilization of digital technologies for fabrication of definitive implant-supported restorations. PMID- 23025313 TI - Treatment concept with CAD/CAM-fabricated high-density polymer temporary restorations. AB - Tooth wear in younger patients is perceived worldwide as an increasing problem. Its etiology is multifactorial (erosion, abrasion, attrition), and its treatment is challenging for the dental practitioner specifically when a great loss of the vertical dimension of occlusion has occurred. The aim of this article is to present a treatment approach for complex cases with high loss of tooth structure using computer-aided design/computer-aided manufacturing (CAD/CAM)-fabricated temporary high-density polymer restorations without any preparations. New manufacturing technologies and innovative materials such as high-density polymers offer good possibilities for restorations during the pretreatment period. This is especially important in circumstances requiring massive corrections of color, form, or position. Pretreatment periods are indispensable in refining important factors such as lip-position dynamics as well as the correct position of the smile line, which cannot be adequately assessed in the dental laboratory. In the presented case report, CAD/CAM-fabricated non-preparation restorations were adhesively placed on the worn dentition without any further loss of tooth structure. Such an approach provides the opportunity to "test-drive" the new restoration design in terms of function, phonetics, and esthetics, thus improving the predictability of the definitive restorations design. If any change in the design is required, it can be cost-effectively achieved through simple modification or replacement of the restorations. PMID- 23025314 TI - COMMENTARY. Treatment concept with CAD/CAM-fabricated high-density polymer temporary restorations. PMID- 23025315 TI - Presurgical planning in implant restorations: correct interpretation of cone-beam computed tomography for improved imaging. AB - Contemporary implant dentistry is a primarily prosthetically driven treatment. The implant position is defined during the diagnostic phase, and the radiographic guide (template) indicates accurately the area of concern on the cone-beam computed tomography (CBCT). CBCT is an essential diagnostic key to a successful treatment plan in many cases. The aim of this paper was to underline the importance of proper alignment of the scanning levels in CBCT in order to avoid distorted cross-sectional images. As demonstrated with two clinical cases in this preliminary study, the initial scanning images of the CBCT must be drawn parallel to the occlusal plane, as defined by the diagnostic wax-up of the final restoration. The radiographic template offers valuable information about the planned location and inclination of the implant and the restoration. Proper image reconstruction following the dental scan can contribute significantly to accurate cross-sectional images and detailed presurgical planning. PMID- 23025316 TI - COMMENTARY. Presurgical planning in implant restorations: correct interpretation of cone-beam computed tomography for improved imaging. PMID- 23025317 TI - Incisal translucency of vital natural unrestored teeth: a clinical study. AB - INTRODUCTION: Understanding the distribution of incisal translucency will provide clinicians a guide to use this knowledge to improve the esthetic replication of anterior restorations. The aim of this study is to investigate the distribution of incisal translucency of unrestored vital natural maxillary central, lateral, and canine vital teeth from a stratified population in different age, gender, and race. MATERIALS AND METHODS: A total of 120 subjects were recruited for this study. Six subjects with equal gender balance from four racial/ethnic groups (White, Black, Asian, and others) were recruited from each of the following age groups: 18 to 29 years, 30 to 39 years, 40 to 49 years, 50 to 59 years, and 60 to 85 years. Potential subjects were clinically screened to determine if three specific anterior teeth (maxillary central incisor, lateral incisor, and canine) were non-restored, natural permanent teeth free from external staining or bleaching. A digital imaging and shade analysis device was used to measure tooth translucency. RESULTS: Statistically significant interaction (p < 0.001) was found for the groups. The interaction between race and gender was not statistically significant (p = 0.485). However, the interaction between race and age (p = 0.03), age and gender (p = 0.015), and among age, race, and gender (p < 0.001) was found statistically significant according to the analysis of variance test results. The interaction between race and gender was not statistically significant (p = 0.485). PMID- 23025318 TI - COMMENTARY. Incisal translucency of vital natural unrestored teeth: a clinical study. PMID- 23025319 TI - Dentin bond strengths of four adhesion strategies after thermal fatigue and 6 month water storage. AB - STATEMENT OF PROBLEM: The stability of current dental adhesives after artificial aging may depend on the adhesion strategy. PURPOSE: To evaluate the effect of thermal fatigue and water storage on the dentin microtensile bond strengths (uTBS) of four adhesion strategies. MATERIALS AND METHODS: Forty-eight human molars were assigned to four dentin adhesives: FL--OptiBond FL (Kerr Corporation, Orange, CA, USA); SOLO--OptiBond SOLO Plus (Kerr Corporation); XTR--OptiBond XTR (Kerr Corporation); and AIO--OptiBond All-in-One (Kerr Corporation). Teeth were restored with a hybrid composite, and sectioned to obtained bonded beams. For each adhesive, one-third of the central and peripheral beams were assigned to one of three aging conditions: (1) kept in distilled water for 24 hours (24 h); (2) thermocycled (TC) for 20,000 cycles; and (3) stored in distilled water for 6 months (6M). Beams were tested in tension mode. Statistical analysis (p < 0.05) was computed using Analysis of Variance and Fisher's Least Significant Difference post hoc test. RESULTS: The highest mean uTBS for 24 h, TC, and 6M were obtained with XTR, but only the 6M mean uTBS were significantly higher than those of the other three adhesives. For FL, mean uTBS decreased significantly from 24 h to TC. For SOLO, mean uTBS remained stable over the three aging conditions. Mean uTBS for AIO decreased significantly from 24 h to 6M. CONCLUSION: The self-etch adhesives XTR and AIO performed similarly or better than the etch-and-rinse adhesives FL and SOLO for all three testing conditions. Their aging stability seems to be material-dependent. PMID- 23025320 TI - COMMENTARY. Dentin bond strengths of four adhesion strategies after thermal fatigue and 6-month water storage. PMID- 23025321 TI - Critical appraisal. Reversal of compromised bonding after bleaching. AB - Bleaching with peroxide agents compromises the adhesion of resin-based materials to enamel and dentin. The problem is likely caused by delayed release of oxygen from the teeth that inhibits resin polymerization at the interface. The typical method for avoiding problems with bonding to bleached teeth is simply to delay the bonding procedure for a week or two after bleaching. However, there is evidence that bonding can be done immediately if bleaching is followed by the application of an antioxidant. This Critical Appraisal reviews some of the published reports on the reversal of compromised bonding after bleaching via the use of antioxidants such as sodium ascorbate. PMID- 23025322 TI - Insights into the glycosaminoglycan-mediated cytotoxic mechanism of eosinophil cationic protein revealed by NMR. AB - Protein-glycosaminoglycan interactions are essential in many biological processes and human diseases, yet how their recognition occurs is poorly understood. Eosinophil cationic protein (ECP) is a cytotoxic ribonuclease that interacts with glycosaminoglycans at the cell surface; this promotes the destabilization of the cellular membrane and triggers ECP's toxic activity. To understand this membrane destabilization event and the differences in the toxicity of ECP and its homologues, the high resolution solution structure of the complex between full length folded ECP and a heparin-derived trisaccharide (O-iPr-alpha-D-GlcNS6S alpha(1-4)-L-IdoA2S-alpha(1-4)-D-GlcNS6S) has been solved by NMR methods and molecular dynamics simulations. The bound protein retains the tertiary structure of the free protein. The (2)S(0) conformation of the IdoA ring is preferably recognized by the protein. We have identified the precise location of the heparin binding site, dissected the specific interactions responsible for molecular recognition, and defined the structural requirements for this interaction. The structure reveals the contribution of Arg7, Gln14, and His15 in helix alpha1, Gln40 in strand beta1, His64 in loop 4, and His128 in strand beta6 in the recognition event and corroborates the previously reported participation of residues Arg34-Asn39. The participation of the catalytic triad (His15, Lys38, His128) in recognizing the heparin mimetic reveals, at atomic resolution, the mechanism of heparin's inhibition of ECP's ribonucleolytic activity. We have integrated all the available data to propose a molecular model for the membrane interaction process. The solved NMR complex provides the structural model necessary to design inhibitors to block ECP's toxicity implicated in eosinophil pathologies. PMID- 23025323 TI - Electrosteric stabilization and its role in cooperative magnetophoresis of colloidal magnetic nanoparticles. AB - A detailed study on the conflicting role that colloid stability plays in magnetophoresis is presented. Magnetic iron oxide particles (MIOPs) that were sterically stabilized via surface modification with poly(sodium 4-styrene sulfonate) of different molecular weights (i.e., 70 and 1000 kDa) were employed as our model system. Both sedimentation kinetics and quartz crystal microbalance with dissipation (QCM-D) measurements suggested that PSS 70 kDa is a better stabilizer as compared to PSS 1000 kDa. This observation is mostly attributed to the bridging flocculation of PSS 1000 kDa decorated MIOPs originated from the extended polymeric conformation layer. Later, a lab-scale high gradient magnetic separation (HGMS) device was designed to study the magnetophoretic collection of MIOPs. Our experimental results revealed that the more colloidally stable the MIOP suspension is, the harder it is to be magnetically isolated by HGMS. At 50 mg/L, naked MIOPs without coating can be easily captured by HGMS at separation efficiency up to 96.9 +/- 2.6%. However, the degree of separation dropped quite drastically to 83.1 +/- 1.2% and 67.7 +/- 4.6%, for MIOPs with PSS 1000k and PSS 70k coating, respectively. This observation clearly implies that polyelectrolyte coating that was usually employed to electrosterically stabilize a colloidal system in turn compromises the magnetic isolation efficiency. By artificially destroying the colloidal stability of the MIOPs with ionic strength increment, the ability for HGMS to recover the most stable suspension (i.e., PSS 70k-coated MIOPs) increased to >86% at 100 mM monovalent ion (Na(+)) or at 10 mM divalent ion (Ca(2+)). This observation has verified the conflicting role of colloidal stability in magnetophoretic separation. PMID- 23025324 TI - Myeloid neoplasms with eosinophilia and FIP1L1-PDGFRA fusion gene: another point of view. PMID- 23025325 TI - Seventy-two total knee arthroplasties performed in patients with haemophilia using continuous infusion. AB - BACKGROUND AND OBJECTIVES: Total knee replacement (TKR) is the treatment of choice in case of end-stage knee arthropathy, the main complication of haemophilia. We report here a retrospective evaluation of 72 total knee replacement in 51 haemophilia A and B patients using continuous infusion of factor concentrates (CIFC). MATERIALS AND METHODS: Patients were evaluated on the basis of the following efficacy and safety criteria: range of motion, surgery related blood loss by three different methods, factor consumption and occurrence of short and long term complications. RESULTS: Kaplan-Meier analysis showed a removal-free survival of TKRs of 88.4% 10years after surgery. Most patients were satisfied with their prosthesis and described pain relief and improved mobility and better quality of life after surgery. The long term follow-up showed a mean range of motion at 86 degrees with a flexion deformity of 4 degrees . The blood loss differed significantly according to the method used for measurement. No life threatening bleeding occurred. Twenty six haematomas (36.1%) and 2 haemarthroses (2.7%) occurred in 38.8% of cases during the first three postoperative weeks, with no significant impact on the orthopaedic outcome. The average factor consumption during hospitalization was 79IU/kg/day for patients with haemophilia A and 99IU/kg/day for patients with haemophilia B. Infections occurred in 4.1% of patients. One patient with severe haemophilia A developed an inhibitor. CONCLUSIONS: The multidisciplinary approach and the homogeneous management of our large cohort allowed the achievement of excellent functional results. Our results confirmed previously reported data on the safety and efficacy of CIFC in situations requiring intensive factor replacement, such as TKR surgery. PMID- 23025326 TI - The modified Medical Research Council scale for the assessment of dyspnea in daily living in obesity: a pilot study. AB - BACKGROUND: Dyspnea is very frequent in obese subjects. However, its assessment is complex in clinical practice. The modified Medical Research Council scale (mMRC scale) is largely used in the assessment of dyspnea in chronic respiratory diseases, but has not been validated in obesity. The objectives of this study were to evaluate the use of the mMRC scale in the assessment of dyspnea in obese subjects and to analyze its relationships with the 6-minute walk test (6MWT), lung function and biological parameters. METHODS: Forty-five obese subjects (17 M/28 F, BMI: 43 +/- 9 kg/m2) were included in this pilot study. Dyspnea in daily living was evaluated by the mMRC scale and exertional dyspnea was evaluated by the Borg scale after 6MWT. Pulmonary function tests included spirometry, plethysmography, diffusing capacity of carbon monoxide and arterial blood gases. Fasting blood glucose, total cholesterol, triglyceride, N-terminal pro brain natriuretic peptide, C-reactive protein and hemoglobin levels were analyzed. RESULTS: Eighty-four percent of patients had a mMRC >= 1 and 40% a mMRC >= 2. Compared to subjects with no dyspnea (mMRC = 0), a mMRC >= 1 was associated with a higher BMI (44 +/- 9 vs 36 +/- 5 kg/m2, p = 0.01), and a lower expiratory reserve volume (ERV) (50 +/- 31 vs 91 +/- 32%, p = 0.004), forced expiratory volume in one second (FEV1) (86 +/- 17 vs 101 +/- 16%, p = 0.04) and distance covered in 6MWT (401 +/- 107 vs 524 +/- 72 m, p = 0.007). A mMRC >= 2 was associated with a higher Borg score after the 6MWT (4.7 +/- 2.5 vs 6.5 +/- 1.5, p < 0.05). CONCLUSION: This study confirms that dyspnea is very frequent in obese subjects. The differences between the "dyspneic" and the "non dyspneic" groups assessed by the mMRC scale for BMI, ERV, FEV1 and distance covered in 6MWT suggests that the mMRC scale might be an useful and easy-to-use tool to assess dyspnea in daily living in obese subjects. PMID- 23025327 TI - Cholesterol determines and limits rHDL formation from human plasma apolipoprotein A-II and phospholipid membranes. AB - Apolipoprotein (apo) A-II, the second most abundant protein after apo A-I of human plasma high-density lipoproteins (HDL), is the most lipophilic of the exchangeable apolipoproteins. The rate of microsolubilization of dimyristoylphosphatidylcholine (DMPC) membranes by apo A-I to give rHDL increases as the level of membrane free cholesterol (FC) increases up to 20 mol % when the level of reaction decreases to nil. Given its greater lipophilicity, we tested the hypothesis that apo A-II and its reduced and carboxymethylated monomer (rcm apo A-II) would form rHDL at a membrane FC content of >20 mol %. According to turbidimetric titrations, the DMPC/apo A-II stoichiometry is 65/1 (moles to moles). At this stoichiometry, apo A-II forms rHDL from DMPC and FC. Contrary to our hypothesis, apo A-II, like apo A-I, reacts poorly with DMPC containing >=20 mol % FC. The rate of formation of rHDL from rcm apo A-II and DMPC at all FC mole percentages is faster than that of apo A-II but nil at 20 mol % FC. In parallel reactions, monomeric and dimeric apo A-II form large FC-rich rHDL coexisting with smaller FC-poor rHDL; increasing the FC mole percentage increases the number and size of FC-rich rHDL. On the basis of the compositions of coexisting large and small rHDL, the free energy of transfer of FC from the smallest to the largest particle is approximately -1.2 kJ. On the basis of our data, we propose a model in which apo A-I and apo A-II bind to DMPC via surface defects that disappear at 20 mol % FC. These data suggest apo A-II-containing HDL formed intrahepatically are likely cholesterol-rich compared to the smaller intracellular lipid-poor apo A-I HDL. PMID- 23025328 TI - Subzero temperature chromatography for reduced back-exchange and improved dynamic range in amide hydrogen/deuterium exchange mass spectrometry. AB - Amide hydrogen/deuterium exchange is a commonly used technique for studying the dynamics of proteins and their interactions with other proteins or ligands. When coupled with liquid chromatography and mass spectrometry, hydrogen/deuterium exchange provides several unique advantages over other structural characterization techniques including very high sensitivity, the ability to analyze proteins in complex environments, and a large mass range. A fundamental limitation of the technique arises from the loss of the deuterium label (back exchange) during the course of the analysis. A method to limit loss of the label during the separation stage of the analysis using subzero temperature reversed phase chromatography is presented. The approach is facilitated by the use of buffer modifiers that prevent freezing. We evaluated ethylene glycol, dimethyl formamide, formamide, and methanol for their freezing point suppression capabilities, effects on peptide retention, and their compatibilities with electrospray ionization. Ethylene glycol was used extensively because of its good electrospray ionization compatibility; however, formamide has potential to be a superior modifier if detrimental effects on ionization can be overcome. It is demonstrated using suitable buffer modifiers that separations can be performed at temperatures as low as -30 degrees C with negligible loss of the deuterium label, even during long chromatographic separations. The reduction in back exchange is shown to increase the dynamic range of hydrogen/deuterium exchange mass spectrometry in terms of mixture complexity and the magnitude with which changes in deuteration level can be quantified. PMID- 23025329 TI - Randomized controlled trials of maternal-fetal surgery: a challenge to clinical equipoise. AB - This article focuses on maternal-fetal surgery (MFS) and on the concept of clinical equipoise that is a widely accepted requirement for conducting randomized controlled trials (RCT). There are at least three reasons why equipoise is unsuitable for MFS. First, the concept is based on a misconception about the nature of clinical research and the status of research subjects. Second, given that it is not clear who the research subject/s in MFS is/are, if clinical equipoise is to be used as a criterion to test the ethical appropriateness of RCT, its meaning should be unambiguous. Third, because of the multidisciplinary character of MFS, it is not clear who should be in equipoise. As a result, we lack an adequate criterion for the ethical review of MFS protocols. In our account, which is based on Chervenak and McCullough's seminal work in the field of obstetric ethics, equipoise is abandoned. and RCT involving MFS can be ethically initiated when a multidisciplinary ethics review board (ERB), having an evidence-based assessment of the risks involved, is convinced that the value of answering the research hypothesis, for the sake of the health interests of future pregnant women carrying fetuses with certain congenital birth defects, justifies the actual risks research participants might suffer within a set limit of low/manageable. PMID- 23025330 TI - Molecular epidemiological studies on animal trypanosomiases in Ghana. AB - BACKGROUND: African trypanosomes are extracellular protozoan parasites that are transmitted between mammalian hosts by the bite of an infected tsetse fly. Human African Trypanosomiasis (HAT) or sleeping sickness is caused by Trypanosoma brucei rhodesiense or T. brucei gambiense, while African Animal Trypanosomiasis (AAT) is caused mainly by T. vivax, T. congolense, T. simiae,T. evansi and T. brucei brucei. Trypanosomiasis is of public health importance in humans and is also the major constraint for livestock productivity in sub-Saharan African countries. Scanty information exists about the trypanosomiasis status in Ghana especially regarding molecular epidemiology. Therefore, this study intended to apply molecular tools to identify and characterize trypanosomes in Ghana. METHODS: A total of 219 tsetse flies, 248 pigs and 146 cattle blood samples were collected from Adidome and Koforidua regions in Ghana in 2010. Initial PCR assays were conducted using the internal transcribed spacer one (ITS1) of ribosomal DNA (rDNA) primers, which can detect most of the pathogenic trypanosome species and T. vivax-specific cathepsin L-like gene primers. In addition, species- or subgroup-specific PCRs were performed for T. b. rhodesiense, T. b. gambiense, T. evansi and three subgroups of T. congolense. RESULTS: The overall prevalence of trypanosomes were 17.4% (38/219), 57.5% (84/146) and 28.6% (71/248) in tsetse flies, cattle and pigs, respectively. T. congolense subgroup-specific PCR revealed that T. congolense Savannah (52.6%) and T. congolense Forest (66.0%) were the endemic subgroups in Ghana with 18.6% being mixed infections. T. evansi was detected in a single tsetse fly. Human infective trypanosomes were not detected in the tested samples. CONCLUSION: Our results showed that there is a high prevalence of parasites in both tsetse flies and livestock in the study areas in Ghana. This enhances the need to strengthen control policies and institute measures that help prevent the spread of the parasites. PMID- 23025331 TI - Hispidin analogue davallialactone attenuates carbon tetrachloride-induced hepatotoxicity in mice. AB - In this study the protective effects of davallialactone (1), isolated from Inonotus xeranticus, have been examined against carbon tetrachloride (CCl4 induced acute liver injury. Mice received subcutaneous injection of 1 (2.5, 5, and 10 mg/kg) for three days before CCl4 injection (1 mg/kg). Protection from liver injury by 1 was confirmed by the observation of decreased serum transaminases and diminished necrosis of liver tissue. Reduced hepatic injury was very similar to that observed with silymarin, a known hepatoprotective drug used in this work for comparison. The groups treated with 1 had reduced reactive oxygen species (ROS), reduced serum malonyldialdehyde levels, and increased levels of liver Cu/Zn superoxide dismutase, as compared to the CCl4 control group. The expression of heme oxygenase-1 in the liver tissue was increased and the activity of liver cytochrome P4502E1 was restored in the mice treated with 1. In addition, levels of serum tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), numbers of macrophage, and cleaved caspase-3-positive hepatocytes were reduced in the groups treated with 1. These findings suggest that davallialactone has protective effects against CCl4 induced acute liver injury, and this protection is likely due to the suppression of ROS-induced lipid peroxidation and inflammatory response. PMID- 23025332 TI - Are gait and mobility measures responsive to change following botulinum toxin injections in adults with lower limb spasticity? AB - PURPOSE: To determine whether gait and mobility measures are responsive to change following botulinum toxin (BoNT) injections in adults with lower limb spasticity. METHOD: Independently ambulant adults who attended a spasticity clinic for lower limb BoNT injections were eligible to participate. The 10 m walk test (shoes on and off), timed up and go test and 6-min walk test were performed before injection and 1 month later. Participants completed a global rating of change scale (GRCS) at follow up. Comparisons were made between participants' ratings of change and change in walking performance. Effect sizes (ES) and standard error of measurement (SEM) were calculated for each outcome. RESULTS: Thirty-nine patients (22 female, 17 male; mean age 51 +/- 12 years; range 26-74 years) with a median spasticity duration of 53 months participated. Statistically significant changes were found in all gait and mobility measures at 1 month following injection. All ES were small (<0.2) and SEM for each measure was large. The global rating of change scale (GRCS) indicated that 66% of participants perceived that their walking had improved. However, there was a significant relationship between GRCS and performance on walking tests for the 10 m walk test with shoes off (p = 0.01) and timed up and go test (p = 0.02) only. CONCLUSION: Commonly used walking tests may not be responsive to change following BoNT injection. The small ES suggest that BoNT has a modest effect on walking ability. Tests of walking performance may not be sufficient to capture all clinically relevant changes in walking ability following BoNT injection of the lower limb. PMID- 23025333 TI - Efficacy and safety of autologous cultured melanocytes delivered on poly (DL lactic acid) film: a prospective, open-label, randomized, multicenter study. AB - BACKGROUND: Small vitiliginous patches have been treated with epidermal grafts or their cell suspensions. In an attempt to overcome some of the shortcomings of cell suspension delivery, we have delivered melanocytes on a polymeric film. OBJECTIVES: To evaluate the clinical effectiveness of a cultured graft consisting of autologous cultured melanocytes on a poly (DL-lactic acid) (PLA) film in subjects with stable vitiligo. METHODS: A prospective open-label, randomized, multicenter clinical trial was conducted with 22 patients. Each subject was treated with cultured graft and polyurethane dressing (control arm) after epidermal ablation and followed for up to 9 months. The extent of repigmentation in the treated sites was compared with that control sites at days 90, 180, and 270. RESULTS: In the treatment arm, a minimum of 70% repigmentation was observed in five subjects at day 90; nine at day 180, and 10 at day 270. In the control arm, only one subject showed repigmentation until day 270. None of the test sites reported any recurrence of vitiliginous patches by the end of the study. CONCLUSIONS: Cultured melanocytes delivered on PLA film were efficacious and safe when applied on patients with stable vitiligo. PMID- 23025334 TI - Global effects of local human population density and distance to markets on the condition of coral reef fisheries. AB - Coral reef fisheries support the livelihoods of millions of people but have been severely and negatively affected by anthropogenic activities. We conducted a systematic review of published data on the biomass of coral reef fishes to explore how the condition of reef fisheries is related to the density of local human populations, proximity of the reef to markets, and key environmental variables (including broad geomorphologic reef type, reef area, and net productivity). When only population density and environmental covariates were considered, high variability in fisheries conditions at low human population densities resulted in relatively weak explanatory models. The presence or absence of human settlements, habitat type, and distance to fish markets provided a much stronger explanatory model for the condition of reef fisheries. Fish biomass remained relatively low within 14 km of markets, then biomass increased exponentially as distance from reefs to markets increased. Our results suggest the need for an increased science and policy focus on markets as both a key driver of the condition of reef fisheries and a potential source of solutions. PMID- 23025335 TI - Determination of estrogens in pork and chicken samples by stir bar sorptive extraction combined with high-performance liquid chromatography-ultraviolet detection. AB - A poly(dimethylsiloxane) (PDMS)/beta-cyclodextrin (beta-CD)/divinylbenzene (DVB) coated stir bar was prepared by the sol-gel technique for the stir bar sorptive extraction (SBSE) of four estrogens from animal-derived foods, followed by liquid desorption (LD) and high-performance liquid chromatography-ultraviolet (HPLC-UV) detection. The influence of the coating composition on SBSE of target estrogens was investigated by an orthogonal experiment design, and the prepared PDMS/beta CD/DVB-coated stir bars show good reproducibility. Under the optimal experimental conditions, the limits of detection (S/N = 3) of the developed PDMS/beta-CD/DVB SBSE-LD-HPLC-UV method were 0.21-1.6 MUg/L for the target estrogens with enrichment factors of 19-51-fold, the dynamic linear range was 2-2000 MUg/L, and the relative standard deviations of the method ranged from 6.0% to 9.7% (n = 8, c = 100 MUg/L) and from 8.4% to 11.7% (n = 8, c = 10 MUg/L). The developed method was simple, sensitive, and selective and was successfully applied to the analysis of estrogens in pork and chicken samples. PMID- 23025337 TI - The influence of two common dementia types on visual symptoms. PMID- 23025336 TI - The Mozart effect in patients suffering from tinnitus. AB - CONCLUSION: The study suggests that Mozart therapy could be a valid alternative to the common sound therapy methods in tinnitus patients. OBJECTIVES: The aim of the study was to evaluate the presence of the Mozart effect as indexed by a variation in tinnitus intensity and tolerability. METHOD: Sixty-two individuals aged between 22 and 78 years, reporting tinnitus for at least 1 year, were enrolled for the study. All patients attended a 1 h cognitive behavioral counseling session and listened to Mozart's sonata k448 for 1 h per day for a month. Afterwards patients listened to Beethoven's Fur Elise sonata for 1 h per day for a month. To evaluate the general stress level, the impact of tinnitus on patients' quality of life, and the intensity of tinnitus, patients were invited to participate in three tests: the Measure du Stress Psychologique (MSP) questionnaire, the Tinnitus Handicap Inventory (THI), and a 0 to 10 visual analog scale (VAS). RESULTS: For all the parameters investigated, MSP, THI, and intensity, there was a general significant improvement between the pre- and post listening evaluation. A significant improvement, as regards THI and intensity, could already be appreciated after a single exposure to Mozart's sonata. PMID- 23025338 TI - Time-varying latent effect model for longitudinal data with informative observation times. AB - In analysis of longitudinal data, it is not uncommon that observation times of repeated measurements are subject-specific and correlated with underlying longitudinal outcomes. Taking account of the dependence between observation times and longitudinal outcomes is critical under these situations to assure the validity of statistical inference. In this article, we propose a flexible joint model for longitudinal data analysis in the presence of informative observation times. In particular, the new procedure considers the shared random-effect model and assumes a time-varying coefficient for the latent variable, allowing a flexible way of modeling longitudinal outcomes while adjusting their association with observation times. Estimating equations are developed for parameter estimation. We show that the resulting estimators are consistent and asymptotically normal, with variance-covariance matrix that has a closed form and can be consistently estimated by the usual plug-in method. One additional advantage of the procedure is that it provides a unified framework to test whether the effect of the latent variable is zero, constant, or time-varying. Simulation studies show that the proposed approach is appropriate for practical use. An application to a bladder cancer data is also given to illustrate the methodology. PMID- 23025339 TI - Three dimensional musculoskeletal modelling of the abdominal crunch resistance training exercise. AB - The aim of this study was to evaluate the benefits and limitations of using three dimensional (3D) musculoskeletal modelling (LifeModeler) in assessing the safety and efficacy of exercising on an abdominal crunch resistance training machine. Three anthropometric cases were studied, representing a 5th percentile female, and 50th percentile and 95th percentile male. Results indicated that the LifeModeler default model was capable of solving the forward dynamics simulations without adjustments. The modelling was able to indicate high risk for back injury when performing the abdominal crunch exercise as a result of the unacceptable intervertebral joint loading that occurs during the exercise. Individuals with small anthropometric dimensions such as some females and children cannot be accommodated suitably on the abdominal crunch machine which negatively impacts exercise posture and technique. Hip flexor muscle contribution in the execution of the exercise for the 5th percentile female was substantial thus reducing the efficacy of the exercise in isolating the abdominal muscles. PMID- 23025340 TI - Comparison between single-cell cultures and tissue cultures as model systems for evaluating the modulation of gene expression by food bioactives. AB - In this study, we sought the use of cultured human abdominal aortic aneurysm (AAA) tissue to investigate the transcriptional effects of some bioactives, whose role in the prevention of atherosclerotic plaque development through the regulation of gene expression has been hypothesized. After supplementation with n - 3 polyunsaturated fatty acids or epigallocatechin-3-gallate, the expression of five genes involved in cholesterol metabolism was assessed in cultures of AAA tissue obtained during elective open surgery, and compared to the results obtained in a single-cell culture model (HepG2 cells). All bioactives modulated gene expression in HepG2 cells, while no effects were observed in the tissue culture due to the shortcomings of the tissue model, which showed high within patient variations and high between-patient variations in gene expression. Results herein reported underline that the choice of the model system is a critical point in the evaluation of the transcriptional effects of bioactives. PMID- 23025341 TI - The naked mole-rat response to oxidative stress: just deal with it. AB - SIGNIFICANCE: The oxidative stress theory of aging has been the most widely accepted theory of aging providing insights into why we age and die for over 50 years, despite mounting evidence from a multitude of species indicating that there is no direct relationship between reactive oxygen species (ROS) and longevity. Here we explore how different species, including the longest lived rodent, the naked mole-rat, have defied the most predominant aging theory. RECENT ADVANCES: In the case of extremely long-lived naked mole-rat, levels of ROS production are found to be similar to mice, antioxidant defenses unexceptional, and even under constitutive conditions, naked mole-rats combine a pro-oxidant intracellular milieu with high, steady state levels of oxidative damage. Clearly, naked mole-rats can tolerate this level of oxidative stress and must have mechanisms in place to prevent its translation into potentially lethal diseases. CRITICAL ISSUES: In addition to the naked mole-rat, other species from across the phylogenetic spectrum and even certain mouse strains do not support this theory. Moreover, overexpressing or knocking down antioxidant levels alters levels of oxidative damage and even cancer incidence, but does not modulate lifespan. FUTURE DIRECTIONS: Perhaps, it is not oxidative stress that modulates healthspan and longevity, but other cytoprotective mechanisms that allow animals to deal with high levels of oxidative damage and stress, and nevertheless live long, relatively healthy lifespans. Studying these mechanisms in uniquely long-lived species, like the naked mole-rat, may help us tease out the key contributors to aging and longevity. PMID- 23025342 TI - Treatment strategy based on gemcitabine-containing salvage chemotherapy used with intent to proceed to second stem cell transplant for patients with Hodgkin lymphoma relapsing after a prior autologous transplant. AB - This report is an analysis of patients with Hodgkin lymphoma who relapsed after autologous stem cell transplant (autoHCT) and who were treated with gemcitabine based therapy as a bridge to either allogeneic or second autologous transplant. Sixteen patients were treated with gemcitabine, cisplatin and steroid and 21 with gemcitabine plus vinorelbine. The overall response rate was 68%. The grade 3-4 toxicity was myelosupression and infections. Fifteen patients proceeded to allogeneic and five to autologous transplant. Two-year overall survival (OS) and progression-free survival (PFS) for all patients were 36% and 25%, respectively. In multivariate analysis, relapse > 6 months after autoHCT and response to gemcitabine-based chemotherapy were associated with superior OS and response to gemcitabine-based chemotherapy with improved PFS. A treatment strategy based on gemcitabine-containing chemotherapy and second transplant appears to be an effective treatment option for patients relapsing > 6 months after autoHCT, providing a median survival time of 34 months. PMID- 23025343 TI - Pd(II)-catalyzed dehydrogenative olefination of terminal arylalkynes with allylic ethers: general and selective access to linear (Z)-1,3-enynes. AB - This work demonstrates a green and efficient method to prepare 1,3-enynes via Pd(II)-catalyzed direct dehydrogenative olefination of terminal arylalkynes with unactived allylic ethers. Various terminal arylalkynes can participate in the reaction, stereoselectively affording the desired conjugated (Z)-1,3-enynes in moderate to good yields. PMID- 23025345 TI - Synergism and inhibition in the combination of visible light and HMPA in SmI2 reductions. AB - The reaction of six substrates (diphenylacetylene, benzonitrile, methyl benzoate, phenylacetylene, naphthalene, and 1-chloro-4-ethylbenzene) with SmI(2) in the presence of MeOH or TFE was studied. The reactions were monitored under three different conditions: (a) irradiation, (b) irradiation in the presence of HMPA, and (c) reactions in the presence of HMPA in the dark. The combination of visible light and HMPA was found in some cases to be synergistic, in others to be additive, and in four cases to be inhibitive. The Marcus theory provides a good understanding of the synergistic and the additivity phenomena. The inhibitive effect is traced to the post electron transfer step in which Sm(3+) plays an important role. Once coordinated to HMPA, Sm(3+) is less capable of assisting in the protonation of the radical anion or the expulsion of the leaving group. Ranking according to the substrate's electron affinity shows that inhibition is manifested for the three least electrophilic substrates: phenylacetylene, naphthalene, and 1-chloro-4-ethylbenzene. Typical of these substrates is the short lifetime of their radical anions. Thus, if a step consecutive to electron transfer is slow and cannot compete successfully with the rapid back electron transfer, the benefit of having the electron transfer step enhanced is much reduced. PMID- 23025344 TI - Improving N-glycan coverage using HPLC-MS with electrospray ionization at subambient pressure. AB - Human serum glycan profiling with mass spectrometry (MS) has been employed to study several disease conditions and is demonstrating promise in, for example, clinical biomarker discovery. However, the low glycan ionization efficiency and the large dynamic range of glycan concentrations in human sera can hinder comprehensive profiling. In particular, large glycans are problematic because they are present at low concentrations and are prone to fragmentation. Here we show that, following liquid chromatographic separation on graphite columns, subambient pressure ionization with nanoelectrospray (SPIN)-MS can expand the serum glycome profile in comparison with the conventional atmospheric pressure electrospray ionization (ESI)-MS with a heated capillary inlet. Notably, the ions generated by the SPIN interface were observed at higher charge states for approximately half of the annotated glycans. Out of a total of 130 detected glycans, 34 were only detected with the SPIN-MS, resulting in improved coverage of glycan families as well as of glycans with larger numbers of labile monosaccharides. PMID- 23025346 TI - Intoxicated witnesses and suspects: an archival analysis of their involvement in criminal case processing. AB - Research about intoxicated witnesses and criminal suspects is surprisingly limited, considering the police believe that they are quite ubiquitous. In the present study, we assessed the involvement of intoxicated witnesses and suspects in the investigation of rape, robbery, and assault crimes by analyzing cases that were referred by the police to a prosecutor's office. Results indicated that intoxicated witnesses and suspects played an appreciable role in criminal investigations: Intoxicated witnesses were just as likely as sober ones to provide a description of the culprit and to take an identification test, suggesting criminal investigators treat intoxicated and sober witnesses similarly. Moreover, intoxicated suspects typically admitted to the police that they had consumed alcohol and/or drugs, and they were usually arrested on the same day as the crime. This archival analysis highlights the many ways in which alcohol impacts testimony during criminal investigations and underscores the need for additional research to investigate best practices for obtaining testimony from intoxicated witnesses and suspects. PMID- 23025347 TI - Quantitative analysis and characterization of self-assembled DNA on a silver surface. AB - Self-assembled monolayers of DNA on a silver surface were prepared and characterized by polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS), fluorescence imaging, and (32)P radioactive labeling. The buffer concentration of the DNA solution and the surface roughness of the silver substrate were found to affect the surface coverage of DNA and its hybridization. At low buffer concentrations, surface coverage and hybridization were greatly reduced. Ethidium bromide intercalated into the adsorbed dsDNA clearly indicates the presence of dsDNA. PMID- 23025348 TI - In defense of prenatal genetic interventions. AB - Jurgen Habermas has argued against prenatal genetic interventions used to influence traits on the grounds that only biogenetic contingency in the conception of children preserves the conditions that make the presumption of moral equality possible. This argument fails for a number of reasons. The contingency that Habermas points to as the condition of moral equality is an artifact of evolutionary contingency and not inviolable in itself. Moreover, as a precedent for genetic interventions, parents and society already affect children's traits, which is to say there is moral precedent for influencing the traits of descendants. A veil-of-ignorance methodology can also be used to justify prenatal interventions through its method of advance consent and its preservation of the contingency of human identities in a moral sense. In any case, the selection of children's traits does not undermine the prospects of authoring a life since their future remains just as contingent morally as if no trait had been selected. Ironically, the prospect of preserving human beings as they are--to counteract genetic drift--might even require interventions to preserve the ability to author a life in a moral sense. In light of these analyses, Habermas' concerns about prenatal genetic interventions cannot succeed as objections to their practice as a matter of principle; the merits of these interventions must be evaluated individually. PMID- 23025349 TI - Validated in vitro/in vivo correlation of prolonged-release oxycodone/naloxone with differing dissolution rates in relation to gastrointestinal transit times. AB - OBJECTIVES: To formally establish the relationship between oxycodone dissolution, in vitro, from a prolonged-release, oral, combination of oxycodone and naloxone (OXN PR) tablets with in vivo absorption, by developing a validated Level A in vitro/in vivo correlation (IVIVC) and subsequently ascertaining the temporal absorption of oxycodone during gastrointestinal transit. METHODS: In vitro dissolution data from formulations of OXN PR (20/10 mg) tablets with slow, medium and fast dissolution rates were generated using United States Pharmacopeia I apparatus 2 (paddle at 50 rpm) in simulated gastric fluid, pH 1.2. These batches were administered to healthy volunteers and plasma concentration data were collected during a randomised, open-label, cross-over study. A Level A correlation was established for oxycodone through the determination of in vivo absorption profiles obtained by deconvolution of plasma concentrations with in vitro dissolution data. The IVIVC model was validated using the internal predictability assessment. RESULTS: A Level A correlation between the in vitro and in vivo release data was established. The polynomial function describing the IVIVC produced a goodness of fit (R(2)) of 0.99. CONCLUSIONS: The rate of absorption of oxycodone from OXN PR tablets correlated well with the in vitro release rates, demonstrating that a Level A IVIVC with internal predictability has been successfully developed for OXN PR tablets. In conjunction with a previous gastrointestinal transit study, this report demonstrates that the majority of oxycodone enters the circulation before reaching the colon, thus it is important that naloxone counteracts opioid-induced bowel dysfunction throughout the entire gut. PMID- 23025350 TI - Identification of pim kinases as novel targets for PJ34 with confounding effects in PARP biology. AB - Small molecules are widely used in chemical biology without complete knowledge of their target profile, at risk of deriving conclusions that ignore potential confounding effects from unknown off-target interactions. The prediction and further experimental confirmation of novel affinities for PJ34 on Pim1 (IC(50) = 3.7 MUM) and Pim2 (IC(50) = 16 MUM) serine/threonine kinases, together with their involvement in many of the processes relevant to PARP biology, questions the appropriateness of using PJ34 as a chemical tool to probe the biological role of PARP1 and PARP2 at the high micromolar concentrations applied in most studies. PMID- 23025351 TI - Proteomic evaluation of inflammatory proteins in rat spleen interstitial fluid and lymph during LPS-induced systemic inflammation reveals increased levels of ADAMST1. AB - The spleen is a part of the immune system and is involved in the response to a systemic inflammation induced by blood borne pathogens that may induce sepsis. Knowledge about the protein composition of the spleen microenvironment in a control situation and during systemic inflammation may contribute to our understanding of the pathophysiology of sepsis. To our knowledge, the proteome of the fluid phase of the spleen microenvironment has not previously been investigated. In order to access the proximal fluid surrounding the splenic cells, we collected postnodal efferent spleen lymph from rats by cannulation, and spleen interstitial fluid (IF) by centrifugation. The origin of the isolated spleen IF was assessed by the extracellular tracer (51)Cr-EDTA and the plasma tracer (125)I-HSA. Spleen lymph, IF, and plasma samples were collected during lipopolysaccharide (LPS) induced systemic inflammation and analyzed using a cytokine multiplex assay and, for the first time, using label-free mass spectrometry based proteomics. The concentrations of TNF-alpha, IL-1beta, IL-6, and IL-10 increased severalfold in all fluids after LPS exposure. In total, 281, 201, and 236 proteins were identified in lymph, IF, and plasma, respectively, and several of these were detected after LPS only. A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) was detected by proteomics (the pro- region) in lymph only after LPS. ADAMTS1 was assessed by ELISA (the metalloproteinase domain), and the concentration was significantly higher in IF and lymph than in plasma in a control situation, showing local production in the spleen. A dramatic increase in ADAMTS1 was detected in lymph, IF, and plasma after LPS exposure. In conclusion, the procedures we used to isolate IF and lymph from the spleen during LPS enabled detection of locally produced proteins. Furthermore, we have demonstrated that the inflammatory proteome is different in the spleen microenvironment when compared to that in plasma. PMID- 23025353 TI - A new method of computing the vertebral heart scale by means of direct standardisation. AB - OBJECTIVES: The aim of this study was to describe and compare a simplified vertebral heart scale computation method (Objective VHS) with the original Buchanan method (Buchanan VHS). METHODS: The Objective VHS was compared to the Buchanan VHS method in 42 dogs including 14 healthy dogs and 28 dogs with mitral insufficiency. For the Objective VHS, the sum of the length of the long and short axes of the cardiac silhouette obtained in centimetres using a metric ruler was subsequently converted into units of vertebral length by means of a direct standardization method. The Buchanan VHS was obtained as previously described. RESULTS: No significant differences in vertebral heart scale values were found between the two methods in all dogs. There was a strong positive correlation (0.99) between Objective VHS and Buchanan VHS. CLINICAL SIGNIFICANCE: The use of a direct standardization method based on a unit conversion allows -computation of vertebral heart scale values without transposing long and short axes to the cranial edge of T4. PMID- 23025354 TI - Assessment of management to mitigate anthropogenic effects on large whales. AB - United States and Canadian governments have responded to legal requirements to reduce human-induced whale mortality via vessel strikes and entanglement in fishing gear by implementing a suite of regulatory actions. We analyzed the spatial and temporal patterns of mortality of large whales in the Northwest Atlantic (23.5 degrees N to 48.0 degrees N), 1970 through 2009, in the context of management changes. We used a multinomial logistic model fitted by maximum likelihood to detect trends in cause-specific mortalities with time. We compared the number of human-caused mortalities with U.S. federally established levels of potential biological removal (i.e., species-specific sustainable human-caused mortality). From 1970 through 2009, 1762 mortalities (all known) and serious injuries (likely fatal) involved 8 species of large whales. We determined cause of death for 43% of all mortalities; of those, 67% (502) resulted from human interactions. Entanglement in fishing gear was the primary cause of death across all species (n = 323), followed by natural causes (n = 248) and vessel strikes (n = 171). Established sustainable levels of mortality were consistently exceeded in 2 species by up to 650%. Probabilities of entanglement and vessel-strike mortality increased significantly from 1990 through 2009. There was no significant change in the local intensity of all or vessel-strike mortalities before and after 2003, the year after which numerous mitigation efforts were enacted. So far, regulatory efforts have not reduced the lethal effects of human activities to large whales on a population-range basis, although we do not exclude the possibility of success of targeted measures for specific local habitats that were not within the resolution of our analyses. It is unclear how shortfalls in management design or compliance relate to our findings. Analyses such as the one we conducted are crucial in critically evaluating wildlife management decisions. The results of these analyses can provide managers with direction for modifying regulated measures and can be applied globally to mortality-driven conservation issues. PMID- 23025355 TI - Determination of thermally induced trans-fatty acids in soybean oil by attenuated total reflectance fourier transform infrared spectroscopy and gas chromatography analysis. AB - The intake of edible oil containing trans-fatty acids has deleterious effects mainly on the cardiovascular system. Thermal processes such as refining and frying cause the formation of trans-fatty acids in edible oil. This study was conducted to investigate the possible formation of trans-fatty acids because of the heat treatment of soybean oil. The types of trans-fatty acids in heated soybean oil are determined by attenuated total reflectance Fourier transform infrared spectroscopy and gas chromatography-mass spectrometry methods. The effects of the heating temperature on the trans-fatty acids in soybean oil were evaluated using gas chromatography flame ionization detection analysis. Results show that heat treatment at 240 degrees C causes the formation of trans-fatty acids in soybean oil and the amount of trans-fatty acids increases with heating time. The only peak observed at 966 cm(-1) of the samples indicates the formation of nonconjugated trans isomers in the heated soybean oil. The major types of trans-fatty acids formed were trans-polyunsaturated fatty acids. Significant increases (P < 0.05) in the amounts of two trans-linoleic acids (C18:2-9c,12t and C18:2-9t,12c) and four trans-linolenic acids (C18:3-9c,12c,15t, C18:3-9t,12c,15c, and C18:3-9t,12t,15c/C18:3-9t,12c,15t) in soybean oil heated to temperatures exceeding 200 degrees C were compared with those of the control sample. The heating temperature and duration should be considered to reduce the formation of trans-fatty acids during thermal treatment. PMID- 23025352 TI - Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion. AB - This paper reviews and synthesizes functional imaging research that over the past decade has begun to offer new insights into the brain mechanisms underlying emotion regulation. Toward that end, the first section of the paper outlines a model of the processes and neural systems involved in emotion generation and regulation. The second section surveys recent research supporting and elaborating the model, focusing primarily on studies of the most commonly investigated strategy, which is known as reappraisal. At its core, the model specifies how prefrontal and cingulate control systems modulate activity in perceptual, semantic, and affect systems as a function of one's regulatory goals, tactics, and the nature of the stimuli and emotions being regulated. This section also shows how the model can be generalized to understand the brain mechanisms underlying other emotion regulation strategies as well as a range of other allied phenomena. The third and last section considers directions for future research, including how basic models of emotion regulation can be translated to understand changes in emotion across the life span and in clinical disorders. PMID- 23025356 TI - The plain facts about tobacco's future. PMID- 23025358 TI - Strong public support for plain packaging of tobacco products. PMID- 23025359 TI - Analysis of national data shows mixed evidence of hardening among Australian smokers. AB - OBJECTIVE: According to the 'hardening hypothesis', the proportion of smokers that are 'low-probability quitters' will increase as societal disapproval of smoking increases. This paper examines whether there has been increased hardening in Australian smokers over the past decade as reflected in an increased prevalence of psychological distress and social disadvantage among current smokers. METHODS: The relationship between psychological distress, living in a disadvantaged area and level of education was determined using logistic regression at two time points 7 to 10 years apart in three cross-sectional household survey series: National Drug Strategy Household Survey (NDSHS), National Health Survey (NHS) and National Survey of Mental Health and Well-being (NSMHW). RESULTS: The relationships between smoking and living in the most disadvantaged areas and having completed less than 12 years of schooling strengthened between 2001 and 2010 in the NDSHS, but there were no significant changes between survey years in the NHS and NSMHW. There was no significant change in the relationship between smoking and psychological distress between survey years in any of the survey series. CONCLUSION: Social disadvantage may be increasing among current smokers, but the results were inconsistent between survey series, presenting weak evidence that the population of Australian smokers hardened as smoking prevalence declined by approximately 4% over the last decade. IMPLICATIONS: A greater focus on intensive individual-level tobacco cessation interventions does not appear warranted at this time. PMID- 23025360 TI - Access to cigarettes by young New Zealand smokers: little change from 2000 to 2008. AB - OBJECTIVE: To examine trends in young New Zealanders' access to cigarettes from 2002 to 2008. METHODS: Self-reports of young smokers' commercial sources of cigarettes, requests for proof of age and being refused a sale, and the amount spent on cigarettes, were analysed from the 2002 and 2004 Youth Lifestyles Surveys and 2006 and 2008 Year 10 In-depth Surveys of 14 to 15 year olds in New Zealand (NZ). RESULTS: Most young smokers obtain cigarettes through non commercial sources; however, one-third bought their cigarettes from shops in 2008, with no evidence of a change in proportions purchasing from major retail outlets since 2000. Few young smokers were asked to show proof of age when purchasing cigarettes, with no evidence over time of more young smokers being asked for proof of age, but reports of being refused the sale of cigarettes decreased from 2000. Participants reporting being asked for proof of age had nearly six times the odds of being refused sale. The amount spent on cigarettes did not change over the study period. CONCLUSION: Many young smokers continue to purchase cigarettes from commercial outlets, with no evidence of change in purchasing from major outlets such as dairies, service stations, supermarkets or liquor stores since 2000. The fact that few young smokers reported being asked to show proof of age suggests the need for stronger measures to ensure that retailers comply with New Zealand legislation regarding under-age sales of tobacco. IMPLICATIONS: With an infringement notice scheme being implemented and tobacco price rises, there may be an increase in accessing cigarettes through social sources. It remains important to monitor commercial tobacco sales to young people to determine the efficacy of policy change. PMID- 23025361 TI - Folate status and socio-demographic predictors of folate status, among a national cohort of women aged 26-36 in Australia, 2004-2006. AB - OBJECTIVE: To describe serum folate status and the socio-demographic correlates of serum folate status in a national sample of women aged 26-36 years in Australia, 2004-2006. METHODS: Stored serum samples from 1,046 women, collected as part of the Childhood Determinants of Adult Health study, were analysed for serum folate. RESULTS: Median (IQR) serum folate was 27.1 nmol/L (18.8-35.0 nmol/L) with only 7.0% of samples below 11 nmol/L. Serum folate was positively associated with supplement use, educational level, occupational status and urban dwelling. CONCLUSIONS: In this population-based sample, most women had folate levels in the normal range with few having low serum folate. Those of lower socioeconomic position or with poorer health behaviours had lower folate levels, though most were still within the normal range. IMPLICATIONS: In the absence of comprehensive national survey data on the folate status of women of child-bearing age, these data provide a valuable baseline for evaluating the impact of mandatory folic acid fortification in Australia, which commenced in 2009. It is likely that mandatory fortification of the food supply with folic acid will reduce the disparities in folate status between socioeconomic groups and in people with poorer health behaviours. PMID- 23025362 TI - The case for improving road safety in Pacific Islands: a population-based study from Fiji (TRIP 6). AB - OBJECTIVE: To estimate the incidence and demographic characteristics associated with road traffic injuries (RTIs) resulting in deaths or hospital admission for 12 hours or more in Viti Levu, Fiji. METHODS: Analysis of the prospective population-based Fiji Injury Surveillance in Hospitals database (October 2005 - September 2006). RESULTS: Of the 374 RTI cases identified (17% of all injuries), 72% were males and one third were aged 15-29 years. RTI fatalities (10.3 per 100,000 per year) were higher among Indians compared to Fijians. Two-thirds of deaths (largely ascribed to head, chest and abdominal trauma) occurred before hospital admission. CONCLUSION AND IMPLICATIONS: While the RTI fatality rate was comparable to the global average for high-income countries, the level of motorisation in Fiji is considerably lower. To avert rising RTI rates with increasing motorisation, Fiji requires a robust road safety strategy alongside effective trauma-care services and a reliable population-based RTI surveillance system. PMID- 23025363 TI - Decreasing length of maternal hospital stay is not associated with increased readmission rates. AB - OBJECTIVE: To investigate changes in maternal length of postnatal stay by mode of birth and hospital type, and examine concurrent maternal readmission rates and reasons for readmission. METHODS: Linked birth and hospital separation data were used to investigated mothers' birth admissions (n=597,475) and readmissions (n=19,094) in the six weeks post-birth in New South Wales, 2001-2007. Outcomes were postnatal length of stay (mean days) and rate of readmission per 100 deliveries. Poisson regression was used to investigate annual readmission rates and Wilcoxon-Mann-Whitney test was used to compare length of readmission stays. RESULTS: The overall mean postnatal length of stay declined from 3.7 days in 2001 to 3.4 days in 2007. Private hospitals had longer stays after Caesarean and vaginal deliveries, but mean length of stay fell for both private and public hospitals, and both modes of birth. The maternal readmission rate fell from 3.4% in 2001 to 3.0% in 2007. Leading primary diagnoses at readmission following vaginal birth were postpartum haemorrhage and breast/ lactation complications and following Caesarean section were wound complications and breast/ lactation complications. CONCLUSIONS: Despite the decrease in mean length of stay for birth admissions, there was no increase, and in fact a decrease, in the rate of postnatal readmissions. IMPLICATIONS: Current practices in hospital length of stay and care for women giving birth do not appear to be having serious adverse health effects as measured by readmissions. PMID- 23025364 TI - Earlier translation of evidence into public subsidy may prevent morbidity and mortality: an example using statins in diabetics with normal cholesterol levels. AB - OBJECTIVE: To determine the effects on cardiovascular outcomes and costs of a delay in subsidising statins for Australian normolipidaemic diabetics aged 60-79 years that occurred between 2002 and 2006. METHODS: The Australian normolipidaemic diabetic population aged 60-79 with no history of coronary heart disease (CHD) or stroke was estimated from the Australian Bureau of Statistics (National Health Survey 2001 and 2002 population estimates). The number of CHD and stroke events expected to have occurred between 2002 and 2006 were estimated from the United Kingdom Prospective Diabetes Study Risk Engine. The proportion of these events that may have been prevented by the use of statins in this population was estimated using risk reduction values from the Heart Protection Study. RESULTS: The target population was estimated as 186,501. In this population, 3,205 (95% confidence interval (CI) 2567, 4003) CHD events, of which 1,456 (95% CI 908, 2334) would have been fatal, could have been prevented if all patients had been treated with statins. In addition, 2,150 (95% CI 1515, 3052) ischaemic strokes could have been prevented. The net cost to the government would have been about $136 million per year over the four-year period. CONCLUSIONS: Delays in the adoption of statins on the Pharmaceutical Benefits Scheme based on evidence available at the time for specific populations may have led to preventable morbidity and mortality. Implications The effects of delays in translating new evidence into public subsidies for drugs are measurable and are likely to be significant. PMID- 23025365 TI - Competing risk analysis of mortality from invasive cutaneous melanoma in New South Wales: a population-based study, 1988-2007. AB - OBJECTIVE: Accurate estimates of risk of death from melanoma, based on the most recent information, are desirable, especially if secular improvements in survival have occurred. This study aims to investigate prognostic factors and temporal changes in mortality from primary invasive cutaneous melanoma (CM) and to predict cumulative probabilities of death from CM. METHODS: Cases of CM from the NSW Central Cancer Registry (NSWCCR) diagnosed in 1988-2007 were analysed. We used Fine and Gray competing risks models to investigate prognostic factors associated with CM mortality, along with period effects of year of diagnosis. Adjusted cumulative probabilities of CM death were then estimated. RESULTS: Of 52,330 CM cases, 5291 (10%) died from CM and 8290 (16%) from other causes. Patients with tumours thicker than 4 mm had 9.5 times the risk of death from CM compared to those with tumours 1 mm or less (subhazard ratio [SHR] 9.52; 95%CI:8.42-10.77). Risk of melanoma death was 31% lower in 2003-2007 compared to 1988-1992 (SHR 0.69; 95%CI: 0.63-0.76). Other risk factors for CM mortality included older age and male gender. Assuming the estimated period effect for a diagnosis in 2003 2007 applies now, the predicted probability of CM death within 10 years of diagnosis of a tumour 4+ mm thick is 26% in males and 19% in females. CONCLUSION: This study highlights the importance of awareness and early detection and shows a significant improvement in survival from CM since 1988. PMID- 23025366 TI - Submissions to the Australian and New Zealand Review of Food Labelling Law and Policy support traffic light nutrition labelling. AB - OBJECTIVE: Food labels to support healthier choices are an important potential intervention for improving population health by reducing obesity and diet-related disease. This study examines the use of research evidence about traffic light nutrition labelling in submissions to the Review of Food Labelling Law and Policy conducted in Australia and New Zealand. METHODS: Content analysis of final submissions to the Review and a literature review of documents reporting research evidence about traffic light labelling. RESULTS: Sixty-two submitters to the Review were categorised as 'supporters' of traffic light labelling and 29 as 'opponents'. Supporters focused on studies showing traffic light labels were better than other systems at helping consumers identify healthier food options. Opponents cited evidence that traffic light labels were no better than other systems in this respect and noted a lack of evidence that they led to changes in food consumption. A literature review demonstrated that, as a group, submitters had drawn attention to most of the relevant research evidence on traffic light labelling. Both supporters and opponents were, however, selective in their use of evidence. CONCLUSIONS: The weight of evidence suggested that traffic light labelling has strengths in helping consumers to identify healthier food options. Further research would be valuable in informing the development of an interpretive front-of-pack labelling system. IMPLICATIONS: The findings have significant implications for the development of front-of-pack nutrition labelling currently being considered in Australia and New Zealand. PMID- 23025367 TI - Empirical evidence suggests adverse climate events have not affected Australian women's health and well-being. AB - OBJECTIVE: To compare the health and well-being of women by exposure to adverse climate events. An Exceptional Circumstance declaration (EC) was used as a proxy for adverse climate events. The Australian government may provide financial support to people living in EC areas, i.e. areas experiencing a one in 20-25 year event (drought, flood or fire) that results in a severe, extended downturn in farm or farm-related income. METHODS: Data from 6,584 53-58 year old non metropolitan women participating in the 2004 survey of the Australian Longitudinal Study on Women's Health (ALSWH) were linked to EC data. Generalised linear models were used to analyse differences in SF-36 General Health (GH) and Mental Health (MH) and perceived stress by EC for all women. Models were adjusted for demographic, health-related and psychosocial factors potentially on the pathway between EC and health. Given that the effects on health were expected to be greater in vulnerable people, analyses were repeated for women with worse socioeconomic circumstances. RESULTS: GH, MH and stress did not differ for the 3,366 women in EC areas and 3,218 women in non-EC areas. GH, MH and stress were worse among vulnerable women (who had difficulty managing on available income) regardless of EC. CONCLUSION AND IMPLICATIONS: This research adds to the existing literature on climate change, associated adverse climate events and health, by suggesting that multiple resources available in high income countries, including government support and individual psychosocial resources may mitigate some of the health impacts of adverse climate events, even among vulnerable people. PMID- 23025368 TI - New directions in health care and disability: the need for a shared understanding of human functioning. AB - OBJECTIVE: Human 'functioning' is about how people live on a day-to-day basis. This paper sets out the case for adopting a common language about functioning that would improve population health information and information sharing across health and community service systems. APPROACH: Modern health systems recognise the importance of human functioning in addition to diagnosis and disease prevention. 'Functioning' is important in the context of chronic disease, mental health, healthy ageing, and the right of people with disabilities and their carers to participate in society. We outline major directions in the health system and their relationship to the concept of functioning. CONCLUSIONS AND IMPLICATIONS: The concept of functioning has not been used explicitly and consistently in Australian health and human service systems, which nevertheless deal with the 20% of the population who experience difficulties in functioning. The International Classification of Functioning, Disability and Health (ICF) is the international standard for definition, classification, information and measurement of functioning. While it has been partially implemented in Australia, it should be used more broadly, across health and community services, as the basis for information on functioning. This is an intended parallel to the use of the ICD as the standard classification and code list for disease monitoring and related health information systems. Monitoring health status and planning interventions and resources require information about people's functioning in their daily lives as well as their diseases. Such information should be based on the international standards developed for this purpose. PMID- 23025369 TI - The burden of insomnia on individual function and healthcare consumption in Australia. AB - OBJECTIVE: To determine the extent to which insomnia poses an independent burden on individual function and healthcare use in Australia. METHODS: Cross-sectional data from 8,841 respondents and representative of the Australian population aged 16 to 85 in the 2007 National Mental Health and Wellbeing Survey were analysed. Insomnia was defined as 'sleeping only in short bursts and being awake most of the night' during the past week. This measure was validated against common epidemiological indicators of insomnia. Associations between insomnia, disability and healthcare consumption were explored using multivariate logistic regression. RESULTS: Insomnia was reported by 5.6% of adults and was associated with older age, female gender, pain and psychological distress. Controlling for these and other a priori confounders, insomnia was associated with greater odds of (Adjusted Odds Ratio; 95% CI): disability days (1.62; 1.20-2.18), difficulties in daily activities (1.60; 1.10-2.31), life dissatisfaction (2.34; 1.11-4.93), use of sleep medication (1.78; 1.12-2.82) and a higher number of visits to general practitioners (1.57; 1.06-2.33). Insomnia was not significantly associated with the use of medications for mental health (1.17; 0.82-1.67), hospital admissions (1.31; 0.82-1.67), the use of complementary and alternative medicine (1.10; 0.73 1.67) or unmet need for healthcare (1.22; 0.84-1.77). CONCLUSIONS: One in twenty adult Australians experience a level of insomnia that is independently associated with impairments in functioning and increased use of healthcare. IMPLICATIONS: Increasing public and clinician awareness of the impact of insomnia, and promotion of available insomnia treatments may be warranted. PMID- 23025370 TI - School and individual-level characteristics are associated with children's moderate to vigorous-intensity physical activity during school recess. AB - OBJECTIVE: The objective of this study was to identify school environmental characteristics associated with moderate to vigorous physical activity during school recess, including morning and lunch breaks. METHODS: Accelerometry data, child-level characteristics and school physical activity, policy and socio cultural data were collected from 408 sixth grade children (mean age 11 years) attending 27 metropolitan primary schools in Perth, Western Australia. Hierarchical modelling identified key characteristics associated with children's recess moderate to vigorous physical activity (RMVPA). RESULTS: Nearly 40% of variability in children's RMVPA was explained by school environment and individual characteristics identified in this study. Children's higher daily RMVPA was associated with newer schools, schools with a higher number of grassed surfaces per child and fewer shaded grassed surfaces, and the physical education coordinator meeting Australian physical activity guidelines. CONCLUSIONS: Characteristics of the school physical and social environments are strongly correlated with children's MPVA during recess. IMPLICATIONS: The school environment is an ideal target for maximising children's physical activity during recess. Future research could examine the impact of modifying these environmental characteristics on children's school physical activity. PMID- 23025371 TI - Videoconferencing could reduce the number of mental health patients transferred from outlying facilities to a regional mental health unit. AB - OBJECTIVE: To determine if the addition of a video link to the existing phone connection, enabling patients admitted for mental and behavioural disorders to be seen by a centrally located psychiatrist or mental health clinician, would change the probability of these patients being transferred to the central mental health unit. METHODS: Data analysed were patients admitted (n=1,943) to a health services regional hospital with a primary diagnosis of mental and behavioural disorders (ICD10-AM code F00-F99) between January 2002 and December 2010. The probability of being transferred was modelled using multilevel random intercept logistic regression. The introduction of videoconferencing in January 2008 was examined by testing if the inclusion of a binary intervention variable was significant when added to the best fitting risk adjustment model. RESULTS: After the introduction of videoconferencing the percentage of patients transferred fell from 66.8% (95%CI 64.0 to 69.5) to 59.6% (95%CI 56.1 to 63.1) (chi(2) =10.42, p=0.001). After adjusting for age, sex, clustering in hospitals and repeat visits the odds of transfer were 0.69 (95%CI 0.49 to 0.97) of previous. Aboriginality, being non-Australian, long-term linear trend, admitted on the weekends or after hours were not significant predictors of the probability of transfer. CONCLUSIONS AND IMPLICATIONS: The ability for the psychiatrist or senior mental health clinician to see mental health patients via videoconferencing was associated with a reduced probability of the patient being transferred. This satisfies the preference of patients to remain in their community and access mental health services. PMID- 23025372 TI - Increased prevalence of chronic physical health disorders in Australians with diagnosed mental illness. AB - OBJECTIVE: To compare chronic physical health disorder prevalence amongst Australian adults with and without mental illness. METHOD: Total n=1,716 participants (58% female) with a mean age of 52 +/- 13 years (range: 18 to 89 years) completed an online survey of Australian adults in 2010. Outcome measures including prevalence of chronic physical conditions and self-reported body mass index (BMI) in n=387 (23%) with a self-reported mental illness diagnosis were compared to respondents without mental illness. RESULTS: A significantly higher proportion of participants with mental illness were obese (BMI >= 30; 31 vs 24%, p=0.005). Adjusted odds ratios (OR) for coronary heart disease, diabetes, chronic bronchitis or emphysema, asthma, irritable bowel syndrome, and food allergies or intolerances (OR range: 1.54-3.19) demonstrated that chronic physical disorders were significantly more common in participants with a mental illness. CONCLUSION: Australian adults with a diagnosis for mental illness have a significantly increased likelihood of demonstrating chronic physical health disorders compared to persons without mental illness. IMPLICATIONS: Health professionals must be alert to the increased likelihood of comorbid chronic physical disorders in persons with a mental illness and should consider the adoption of holistic approaches when treating those with either a mental or physical illness. PMID- 23025373 TI - Anti-depressant use during pregnancy in Australia: findings from the Longitudinal Study of Australian Children. PMID- 23025374 TI - Majority rule for assigning Aboriginality in linked hospital data. PMID- 23025375 TI - Letter to the editor from Australian Red Cross. PMID- 23025376 TI - Assessment of infant mattress firmness: a do-it-yourself safety test to reduce the risk of asphyxiation. PMID- 23025377 TI - Conventionally accepted risk factors do not explain higher rates of middle ear disease in remote Indigenous children: an ecological study. PMID- 23025378 TI - Response to folic acid article. PMID- 23025379 TI - Serving-size information on nutrition labels in Australia. PMID- 23025380 TI - Paediatric influenza vaccination program suspension: effect on childhood vaccine uptake. PMID- 23025381 TI - A refreshing poison: one-quarter of young New Zealand smokers choose menthol. PMID- 23025382 TI - Redox switching of adenosine-5'-phosphosulfate kinase with photoactivatable atomic oxygen precursors. AB - Adenosine-5'-phosphosulfate kinase (APSK) catalyzes the phosphorylation of adenosine-5'-phospho-sulfate (APS) to 3'-phospho-APS (PAPS). In plants, this enzymatic activity is biochemically regulated through an intersubunit disulfide bond between Cys86 and Cys119 in the N-terminal loop of APSK. To examine if O((3)P) generated by the photodeoxygenation of 2,8 dihydroxymethyldibenzothiophene S-oxide could specifically oxidize APSK at its regulatory site, APSK was irradiated in the presence of 2,8 dihydroxymethyldibenzothiophene S-oxide. Near-quantitative alteration of APSK from the enzymatically active monomeric form to the inhibited dimeric form was achieved. The photoinduced increase of dimeric APSK was strongly implicated to arise from the formation of the Cys86-Cys119 disulfide bond. PMID- 23025384 TI - Effect of microplasmin on the clearance of vitreous haemorrhage from an experimental model in rabbits. AB - PURPOSE: Microplasmin is known to alter the structure of the vitreous gel. The current experiments were designed to assess its ability to enhance clearance of an experimentally induced vitreous haemorrhage, and to compare it to ovine hyaluronidase. METHODS: Twenty-five rabbits were used for this experiment, divided into five groups; groups 1-3 are microplasmin-treated eyes with 25, 75 and 125 MUg, respectively. Group 4 treated with 55 IU of hyaluronidase, while group 5 was treated with normal saline (control). Eyes were injected in the mid vitreous with 0.05 ml of autologous blood obtained from the marginal ear vein. One week later, all the groups were injected with the test solution injected in mid-vitreous as stated above. Clearance of the vitreous haemorrhage was assessed weekly indirect ophthalmoscopy for 8 weeks. RESULTS: Microplasmin-treated eyes showed a significant clearance of the vitreous haemorrhage in a dose-dependent fashion, where group 3 (125 MUg) had the highest clearance rate in comparison with control eyes. Hyaluronidase-treated eyes showed a similar clearance rate as group 3. In addition, group 3 showed a complete posterior vitreous detachment, which did not develop in hyaluronidase-treated eyes. CONCLUSION: Microplasmin may be a useful agent to accelerate the clearance of vitreous haemorrhage. PMID- 23025385 TI - Long-term follow-up and salvage surgery in patients with T2N0M0 squamous cell carcinoma of the glottic larynx who received concurrent chemoradiation therapy with carboplatin (CBDCA) - AUC 1.5 vs AUC 2.0. AB - CONCLUSION: Patients who received concurrent chemoradiation therapy with carboplatin were followed up on a long-term basis. In 25 patients treated with carboplatin at an AUC of 2.0 mg/ml, the complete response (CR), 10-year survival, and 10-year larynx preservation rates were 96.0%, 91.1%, and 75.2%, respectively, and the safety margin for partial laryngectomy was 4 mm from the gross tumor. OBJECTIVES: To perform long-term follow-up of the therapeutic outcomes of concurrent chemoradiation therapy and salvage surgery to determine the additive and synergistic effects of anticancer drugs combined with chemoradiotherapy. METHODS: Fifty male patients (aged 33-76 years) with untreated T2N0M0 squamous cell carcinoma of the glottic larynx were included. Carboplatin was intravenously administered once a week for 4 weeks. Radiotherapy was delivered by an external beam of 4 MV linac X-ray (total = 66 Gy). RESULTS: The AUC 1.5 combination group showed overall response, CR, 5-year survival, 10-year survival, 5-year larynx preservation, and 10-year larynx preservation rates of 100.0%, 68.0%, 83.4%, 77.0%, 75.2%, and 75.2%, respectively. The AUC 2.0 combination group showed corresponding rates of 100%, 96.0%, 95.7%, 91.1%, 82.9%, and 72.7%, respectively. The most common side effects of grade 3 or more were leukopenia, neutropenia, and mucositis (stomatitis), and all were reversible. Thirteen patients (52.0%) in the AUC 1.5 combination group and nine patients (36.0%) in the AUC 2.0 combination group required salvage surgery. Histologically, concurrent chemoradiation therapy with carboplatin caused more severe cancer tissue degeneration. Pathological examinations indicated that the safety margin for partial laryngectomy was 4 mm from the gross tumor. PMID- 23025383 TI - Development of recombinant hemoglobin-based oxygen carriers. AB - SIGNIFICANCE: The worldwide blood shortage has generated a significant demand for alternatives to whole blood and packed red blood cells for use in transfusion therapy. One such alternative involves the use of acellular recombinant hemoglobin (Hb) as an oxygen carrier. RECENT ADVANCES: Large amounts of recombinant human Hb can be expressed and purified from transgenic Escherichia coli. The physiological suitability of this material can be enhanced using protein-engineering strategies to address specific efficacy and toxicity issues. Mutagenesis of Hb can (i) adjust dioxygen affinity over a 100-fold range, (ii) reduce nitric oxide (NO) scavenging over 30-fold without compromising dioxygen binding, (iii) slow the rate of autooxidation, (iv) slow the rate of hemin loss, (v) impede subunit dissociation, and (vi) diminish irreversible subunit denaturation. Recombinant Hb production is potentially unlimited and readily subjected to current good manufacturing practices, but may be restricted by cost. Acellular Hb-based O(2) carriers have superior shelf-life compared to red blood cells, are universally compatible, and provide an alternative for patients for whom no other alternative blood products are available or acceptable. CRITICAL ISSUES: Remaining objectives include increasing Hb stability, mitigating iron catalyzed and iron-centered oxidative reactivity, lowering the rate of hemin loss, and lowering the costs of expression and purification. Although many mutations and chemical modifications have been proposed to address these issues, the precise ensemble of mutations has not yet been identified. FUTURE DIRECTIONS: Future studies are aimed at selecting various combinations of mutations that can reduce NO scavenging, autooxidation, oxidative degradation, and denaturation without compromising O(2) delivery, and then investigating their suitability and safety in vivo. PMID- 23025386 TI - Xentrivalpeptides A-Q: depsipeptide diversification in Xenorhabdus. AB - Seventeen depsipeptides, xentrivalpeptides A-Q (1-17), have been identified from an entomopathogenic Xenorhabdus sp. Whereas the structure of xentrivalpeptide A (1) was determined after its isolation by NMR spectroscopy and the advanced Marfey's method, the structures of all other derivatives were determined using a combination of stable isotope labeling and detailed MS analysis. PMID- 23025388 TI - Global DNA methylation not increased in chronic hemodialysis patients: a case control study. AB - Patients with chronic kidney disease have an increased risk of cardiovascular disease and mortality. Since DNA methylation is an important mechanism modulating the gene expression associated with aging, inflammation, and atherosclerosis, the objective of this study was to determine the possible effect of the uremic milieu on global DNA methylation and DNA methyltransferase (DNMT) expression in uremic status by comparing chronic hemodialysis (HD) patients with the normal population. Twenty normal subjects and twenty chronic dialysis patients with similar ages, sex, and body mass indexes (BMIs) were included. We evaluated the clinical characteristics; the levels of homocysteine, total indoxyl sulfate (IS), and total p-cresol sulfate (PCS); and the DNMT messenger RNA expression and global DNA methylation in the peripheral blood leukocytes. The chronic HD patients had significantly higher blood urea nitrogen (BUN), creatinine (Cr), uric acid, Ca, P, intact parathyroid harmone (iPTH), cholesterol, high sensitivity C-reactive protein (hs-CRP), total indoxyl sulphate (IS) and p-cresol sulphate (PCS), and homocysteine than the normal subjects. The expression of DNMT 1 and 3a did not differ significantly between these two study groups. The chronic HD patients had significantly decreased DNMT 3b expression in the leukocytes. There were no significant correlations between the global DNA methylation and the levels of IS, PCS, and homocysteine. We concluded that chronic HD patients may have lower DNMT 3b expression than normal subjects. However, the status of global DNA methylation may not change significantly in uremic patients when compared with the normal population. PMID- 23025387 TI - Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of patients with ankylosing spondylitis. AB - BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease of spine and sacroiliac joints; it is characterized by new bone formation, and the disease processes can be accompanied by osteoporosis. In the present study, we investigated changes in bone mineral density (BMD) and in the levels of various bone turnover-related biomarkers and cytokines in a cohort of AS patients, with regard to clinical parameters, disease activity, and treatment regimen. METHODS: 55 AS patients and 33 healthy controls included in the study. Spinal mobility was assessed by the Bath Ankylosing Spondylitis Metrology Index (BASMI), and radiologic changes were scored by the Bath Ankylosing Spondylitis Radiologic Index (BASRI). Patients were also evaluated with the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Bone mineral density (BMD) assessed by dual energy X-ray absorptiometry. Various biomarkers and cytokines of bone turnover including osteoprotegerin (OPG), serum band 5 tartrate-resistant acid phosphatase (TRAP-5), soluble receptor activator of nuclear factor kappa-B ligand (sRANKL), secreted frizzled-related protein 1 (sFRP-1), Dickkopf-related protein 1 (DKK-1), and sclerostin were studied. RESULTS: The levels of TRAP-5, NTX, sRANKL, sclerostin, sFRP-1, DKK-1, and IFNgamma, were similar between the patients and controls (p > 0.05), while BMD of femoral neck, and OPG levels were significantly lower in AS patients (p < 0.05). In a subgroup analysis, patients with active disease had significantly higher concentrations of OPG compared with the inactive group. Rest of the biomarkers and cytokines of bone turnover were similar between the active and inactive disease groups. Subgroup analysis of patients receiving anti TNFalpha agents and conventional therapy revealed that OPG concentrations were significantly lower in the patients receiving biological drugs, while BAP and DKK 1 were significantly higher in the patients treated with conventional agents. CONCLUSIONS: In this cross-sectional study we showed that OPG levels were significantly lower in AS patients compared to healthy subjects. On the other hand, the levels of wingless (Wnt) signal pathway inhibitors seem not altered. Ectopic bone formation in AS may be related to dysfunction of these molecules at the cellular level. PMID- 23025389 TI - Parasitylenchus bifurcatus n. sp. (Tylenchida: Allantonematidae) parasitizing Harmonia axyridis (Coleoptera: Coccinellidae). AB - BACKGROUND: The harlequin ladybird, Harmonia axyridis Pallas (Coleoptera: Coccinellidae) is native to central and eastern Asia and was purposely introduced into Europe to control aphids. While it proved to be a good biological control agent, its rapid spread and buildup of large populations made it a nuisance, since it overwinters in homes, emits unpleasant odors, stains fabrics, occasionally bites humans and feeds on apples, pears and grapes. Aside from the above, the ravenous appetite of H. axyridis results in their consumption of harmless native insects, including even other ladybird beetles. A study of the natural enemies of H. axyridis in Denmark revealed the presence of nematodes. The present study describes this nematode parasite and discusses aspects of its development and ecology. METHODS: Adult harlequin ladybird beetles were collected from March to November from four localities in Copenhagen on different plant species. In addition, groups of last-instar larvae and pupae (n = 50) were examined for the presence of nematodes. Living and recently dead nematodes were removed from adult H. axyridis in 0.5% saline solution, the nematodes were then heat killed (at 75C), fixed in 5% formalin and transferred to glycerin on slides for further examination and measurements. RESULTS: A new species of Allantonematidae (Tylenchida), Parasitylenchus bifurcatus n. sp., is described from adults of the harlequin ladybird, Harmonia axyridis in Denmark. The new species is characterized by a straight stylet lacking basal thickenings, a bursa and a forked tail tip in the vermiform (infective) females and juvenile males. The new species is compared with P. coccinellinae previously described from ladybird beetles in France. Parasitism resulted in depletion of the fat body and partial or complete atrophy of the reproductive organs of the beetles. Infections occurred throughout the year with rates of parasitism reaching up to 35%. The rate increased to 60% when field-collected ladybirds were incubated for 30 days in the laboratory. CONCLUSIONS: The production of subsequent generations within the host with only the fertilized females (not the males) leaving the hosts and the absence of parasitism of the larvae and pupae is an impressive developmental modification of P. bifurcatus. It is proposed that the vermiform (infective) females pass from one adult host to another when the beetles are hibernating or in assemblage groups. Rates of parasitism show that P. bifurcatus could be a significant biological control agent of H. axyridis. PMID- 23025390 TI - Yellow mustard bran attenuates glycaemic response of a semi-solid food in young healthy men. AB - In a randomized, repeated-measures design, the glycaemic response and satiety ratings of a potato and leek soup were compared with and without the addition of 5 g of yellow mustard bran. Ten healthy, non-smoking, moderately active male subjects (mean age of 21.1 years and mean body mass index 23.2 kg/m(2)) were recruited to the study. Capillary blood glucose and satiety were measured at 0, 15, 30, 45, 60, 90 and 120 min, postprandial of each food. The incremental area under the blood glucose curve, blood glucose at each time point and satiety rating were calculated and compared via paired t-test. Mean blood glucose values at 15, 30 and 90 min (p < 0.0001, p < 0.0001 and p = 0.0059, respectively) were all significantly lower with the addition of 5 g of yellow mustard bran. In conclusion, this study demonstrated the attenuation of postprandial glycaemic response following the addition of 5 g of yellow mustard bran to a soup. PMID- 23025391 TI - Self-control as predictor of school grades, life balance, and flow in adolescents. AB - BACKGROUND: Recently, several studies have shown that strength of self-control is a crucial factor in determining positive outcomes in individuals' lives. Most attention has been directed to the relationships that self-control has with learning and academic achievement. AIMS: This article analyses the effects of self-control not only on school grades but also on the experience of life balance and flow. It is theorized that students with a higher level of self-control are better able to distribute their time in a satisfying way over academic and leisure matters, and are better able to shield their studying against distractions. SAMPLES: A total of 697 eighth graders with a mean age of 13.4 years participated in the longitudinal study. METHOD: Students completed a questionnaire containing measures of self-control, school grades, subjective life balance, and flow while studying at the beginning and at the end of the school year. Structural equation modelling was used to analyse the relationships between the constructs. RESULTS AND CONCLUSIONS: Results of cross-lagged analyses show that self-control predicted school grades, life balance, and flow. The findings suggest that self-control may assist adolescents to be better prepared, not only for school, but also for coordinating their investments in different areas of their lives. PMID- 23025392 TI - The adaptation and validation of the CEQ and the R-SPQ-2F to the Japanese tertiary environment. AB - BACKGROUND: Student learning theory (SLT) has established associations between students' approaches to learning and their perceptions of the learning environment. SLT may provide a useful framework for researching student learning within the Japanese tertiary sector. AIMS: The study aims to explore and validate the Course Experience Questionnaire (CEQ) and the Revised Study Process Questionnaire (R-SPQ-2F) in the Japanese four-year tertiary context. SAMPLE: Mixed-major students from one Japanese four-year tertiary institution voluntarily completed the CEQ (n= 370). A separate group of students completed the CEQ and R SPQ-2F (n= 269). Methods. CEQ data from the first sample were analysed using exploratory factor analysis (EFA). CEQ and R-SPQ-2F data from the second sample were analysed using confirmatory factor analysis (CFA). RESULTS: EFA of the CEQ resulted in four factors: Good Teaching (GT), Generic Skills (GS), Appropriate Workload (AW), and Appropriate Assessment (AA). CFA confirmed these factors with the second sample. CFA of the R-SPQ-2F resulted in an item parcel-based, two factor model. Correlations between some CEQ and R-SPQ-2F constructs were consistent with previous results. However, other findings from this research suggest that SLT constructs may be constituted differently in the Japanese context. CONCLUSIONS: This study represents an initial investigation of key SLT constructs in the Japanese context. Results suggest some SLT constructs are meaningful in this context, but further scale development may be desirable before more advanced modeling is employed. PMID- 23025393 TI - Teacher efficacy and pupil behaviour: the structure of teachers' individual and collective beliefs and their relationship with numbers of pupils excluded from school. AB - BACKGROUND: Previous work has yielded knowledge of teachers' attributions for children's behaviour. Other studies have helped to develop understanding of teachers' efficacy beliefs. Little work has been undertaken to examine teachers' efficacy beliefs with regard to classroom behaviour. AIMS: This study aimed to investigate the relationship between teachers' individual and collective beliefs about their efficacy with children's behaviour and whether these beliefs were associated with the use of exclusion as a sanction. SAMPLE: A total of 197 teachers from 31 primary and nursery schools in the North East of England participated. METHODS: Participants responded to questionnaires to assess their individual and collective efficacy beliefs. Demographic and school level data were also collected. RESULTS: Factor analysis indicated that teachers' individual efficacy beliefs were best represented by three factors: 'Classroom Management', 'Children's Engagement', 'Instructional Strategies' that corresponded well to previous findings. Analysis of collective efficacy beliefs showed a similar structure that differed from previous findings. Individual efficacy was not associated with numbers of children excluded. One factor 'Addressing External Influences' in the collective beliefs was negatively correlated with numbers of children excluded and appeared to mitigate the deleterious effects associated with socio-economic deprivation. CONCLUSIONS: This study adds weight to the importance of understanding and supporting teachers' beliefs in their collective efficacy. In particular, this study underlines the need for strategies that will endorse and develop teachers' beliefs in their ability to manage children's behaviour successfully. PMID- 23025394 TI - Social-emotional characteristics of gifted accelerated and non-accelerated students in the Netherlands. AB - BACKGROUND: In the studies of acceleration conducted so far a multidimensional perspective has largely been neglected. No attempt has been made to relate social emotional characteristics of accelerated versus non-accelerated students in perspective of environmental factors. AIMS: In this study, social-emotional characteristics of accelerated gifted students in the Netherlands were examined in relation to personal and environmental factors. SAMPLES: Self-concept and social contacts of accelerated (n = 148) and non-accelerated (n = 55) gifted students, aged 4 to 27 (M = 11.22, SD = 4.27) were measured. METHOD: Self-concept and social contacts of accelerated and non-accelerated gifted students were measured using a questionnaire and a diary, and parents of these students evaluated their behavioural characteristics. Gender and birth order were studied as personal factors and grade, classroom, teachers' gender, teaching experience, and the quality of parent-school contact as environmental factors. RESULTS: The results showed minimal differences in the social-emotional characteristics of accelerated and non-accelerated gifted students. The few differences we found favoured the accelerated students. We also found that multiple grade skipping does not have negative effects on social-emotional characteristics, and that long term effects of acceleration tend to be positive. As regards the possible modulation of personal and environmental factors, we merely found an impact of such factors in the non-accelerated group. CONCLUSIONS: The results of this study strongly suggest that social-emotional characteristics of accelerated gifted students and non-accelerated gifted students are largely similar. These results thus do not support worries expressed by teachers about the acceleration of gifted students. Our findings parallel the outcomes of earlier studies in the United States and Germany in that we observed that acceleration does not harm gifted students, not even in the case of multiple grade skipping. On the contrary, there is a suggestion in the data that accelerated students are more socially competent than non-accelerated students. The findings in this study can reassure those parents and teachers who worry about the social-emotional consequences of acceleration in school: If a student is gifted, acceleration seems to be a sound and, in many cases, appropriate measure in gifted education. PMID- 23025395 TI - Justice judgements, school failure, and adolescent deviant behaviour. AB - BACKGROUND: The current paper is based on two different approaches. One is the relational model of authority (Tyler & Lind, 1992), which addresses the effects of justice perceptions on the legitimacy of authorities and behavioural compliance. The other is Emler and Reicher's theory (1995, 2005), which explains the involvement of adolescents in delinquency through their relationship with the institutional authorities of society. AIMS: To provide empirical evidence for the linkage of these perspectives, analysing the relationship between justice perceptions about teachers and the involvement of adolescents in deviant behaviour. Our hypotheses are that teachers' justice is negatively related with deviant behaviour and that this relationship is mediated through the evaluation of institutional authorities, after controlling for school failure. SAMPLE: Three hundred and ninety adolescents aged between 14 and 17 years. METHODS: Participants completed the following scales: perceptions of justice about teachers, evaluation of institutional authorities, and deviant behaviour. Data were examined through correlation and bootstrap analyses. RESULTS: Justice judgments about teachers were negatively related with deviant behaviour, and this relationship was partially mediated by the evaluation of institutional authorities, even after controlling for school failure. However, procedural justice revealed a much stronger relationship with deviance, compared to distributive justice. CONCLUSIONS: As predicted, these results suggest that when adolescents perceive school authorities as fair, other institutional authorities are likely to be perceived in a similar way and the more those authorities are positively evaluated, the less often adolescents engage in deviant conduct. Results are discussed according to the theories underlying our hypothesis. Directions for future research are suggested. PMID- 23025396 TI - Need satisfaction, work-school interference and school dropout: an application of self-determination theory. AB - BACKGROUND: In many parts of the world, it is common for secondary school students to be involved in part-time employment. Research shows that working can have a negative impact on school engagement. However, the majority of studies have focused on the amount of time that students spend working rather than on the quality of work experience and its influence on school engagement. AIMS: This study explored the relation of part-time work and school experiences to dropout intentions among secondary school and junior college students. The study was conceptualized from a self-determination theory perspective (Deci & Ryan, 2000). SAMPLE: Participants were 3,248 students from rural and suburban schools in the greater region of Montreal, Canada. METHOD: Questionnaires were used to assess the number of hours worked, the extent to which work interfered with or facilitated school functioning, autonomy, competence, and relatedness experienced in the work and school domains. School performance and school dropout intentions were also assessed. RESULTS: A curvilinear relation between work hours and dropout intentions was found, reflecting that part-time work began to be associated with higher dropout intentions only when students worked more than 7 hr per week. Analyses also showed that work-school interference was related to dropout intentions, and that this variable served to mediate the relation of employer autonomy support to dropout intentions. CONCLUSIONS: These results suggest that both the quantity and the quality of students' part-time work experiences need to be considered when examining the relation of work to school engagement. PMID- 23025397 TI - Reading development in a tracked school system: a longitudinal study over 3 years using propensity score matching. AB - BACKGROUND: Assigning students to different school tracks on the basis of their achievement levels is a widely used strategy that aims at giving students the best possible learning opportunity. There is, however, a growing body of literature that questions such positive effects of tracking. AIMS: This study compared the developmental trajectories of reading comprehension and decoding speed between students at academic track schools that typically prepare students for university entrance and students at non-academic track schools that usually prepare students for vocational education. SAMPLE: In a longitudinal design with three occasions of data collection, the authors drew on a sample of N= 1,508 5th graders (age at T1 about 11 years, age at T3 about 14 years) from 60 schools in Germany. The academic track sample comprised n= 568 students; the non-academic track sample comprised n= 940 students. METHOD: Achievement measures were obtained by standardized tests of reading comprehension and decoding speed. Students at the different tracks were closely matched using propensity scores. To compare students' growth trajectories between the different school tracks, we applied multi-group latent growth curve models. RESULTS: Comparable results were recorded for the complete (unmatched) sample and for the matched pairs. In all cases, students at the different tracks displayed a similar growth in reading comprehension, whereas larger growth rates for students at academic track schools were recorded for decoding speed. CONCLUSIONS: Our findings contribute to an increasing body of literature suggesting that tracking might have undesired side effects. PMID- 23025398 TI - The nature of rhyme processing in preliterate children. AB - BACKGROUND: Rhyme awareness is one of the earliest forms of phonological awareness to develop and is assessed in many developmental studies by means of a simple rhyme task. The influence of more demanding experimental paradigms on rhyme judgment performance is often neglected. Addressing this issue may also shed light on whether rhyme processing is more global or analytical in nature. AIMS: The aim of the present study was to examine whether lexical status and global similarity relations influenced rhyme judgments in kindergarten children and if so, if there is an interaction between these two factors. SAMPLE: Participants were 41 monolingual Dutch-speaking preliterate kindergartners (average age 6.0 years) who had not yet received any formal reading education. METHOD: To examine the effects of lexical status and phonological similarity processing, the kindergartners were asked to make rhyme judgements on (pseudo) word targets that rhymed, phonologically overlapped or were unrelated to (pseudo) word primes. RESULTS: Both a lexicality effect (pseudo-words were more difficult than words) and a global similarity effect (globally similar non-rhyming items were more difficult to reject than unrelated items) were observed. In addition, whereas in words the global similarity effect was only present in accuracy outcomes, in pseudo-words it was also observed in the response latencies. Furthermore, a large global similarity effect in pseudo-words correlated with a low score on short-term memory skills and grapheme knowledge. CONCLUSIONS: Increasing task demands led to a more detailed assessment of rhyme processing skills. Current assessment paradigms should therefore be extended with more demanding conditions. In light of the views on rhyme processing, we propose that a combination of global and analytical strategies is used to make a correct rhyme judgment. PMID- 23025399 TI - Changes in teacher-student relationships. AB - BACKGROUND: Although teacher-student relationships lie at the heart of students' schooling experience, fundamental questions regarding these relationships remain unanswered. AIMS: This study investigates three related questions about these relationships: To what extent do they change from the beginning to the end of a school year? Are any emergent changes associated with shifts in students' academic or motivational outcomes? Are certain 'upstream' factors associated with improvements or declines in teacher-student relationships? SAMPLE: We investigate these questions with a sample of middle school students (N = 119) and their teachers (N = 30). METHODS. Through a novel approach which accounts for both perspectives within teacher-student relationships, we assess these relationships at the beginning and end of the school year. Using multi-level models, we examine how changes in these relationships are associated with changes in students' grades, homework completion rates, self-efficacy, and effort. In addition, we examine associations with two potential precursors to teacher-student relationships: students' accuracy in taking their teachers' perspective and their perceptions of similarity to their teachers. RESULTS: We find that substantial changes occur in these relationships from the beginning to the end of the year; these changes are associated with shifts in important student outcomes; and changes in students' social perspective taking accuracy and perceived similarity to their teachers correspond with changes in teacher-student relationships. CONCLUSIONS: Given the malleability of teacher-student relationships and their importance for key achievement and motivational outcomes, we advocate for researchers to conduct field experiments to inform how to improve these critical relationships. PMID- 23025400 TI - Probing hyperconjugation experimentally with the conformational deuterium isotope effect. AB - Hyperconjugation underlies many chemical phenomena of fundamental and practical importance. Owing to a great deal of interest in the anomeric effect, anomeric like hyperconjugative effects have been thoroughly investigated in oxygen containing systems. However, such interactions in the second- and third-row chalcogens are less well-understood and have generated some controversy. Here, we show that the conformational deuterium isotope effect, in combination with Saunders' isotopic perturbation method, permits sensitive and direct experimental probing of the conformational equilibria in dioxane, dithiane, and diselenane analogues by variable-temperature, dynamic NMR spectroscopy. We find that the magnitude of the conformational deuterium isotope effect is 252.1, 28.3, and 7.1 J/mol (+/-10%) for the oxygen, sulfur, and selenium analogues, respectively. These results reveal the periodic trend for hyperconjugation in the chalcogens, which reflect a decreasing n(x)->sigma(C-H(D)) interaction throughout the period, as supported by IR spectroscopy and in agreement with DFT calculations and a natural bond order analysis. PMID- 23025401 TI - Changes in protein profiles of multiple myeloma cells in response to bortezomib. AB - The objective of this study was to determine the changes in protein profiles of U 266 multiple myeloma cells in response to bortezomib. Bortezomib inhibited cell proliferation and increased the loss of mitochondrial membrane potential and caspase-3 activity in a dose-dependent manner. DECODON Delta2D Version 4.3 software demonstrated 37 differentially expressed protein spots: five proteins were newly formed, 10 proteins were lost, 12 proteins were up-regulated and 10 proteins were down-regulated in bortezomib-treated cells as compared to untreated cells. Some of the identified proteins after mass spectrometric analysis were as follows: apoptosis regulatory protein Siva (newly formed), caspase recruitment domain-containing protein 14 (lost), Ras-related protein Rab-25 (up-regulated), nuclear factor kappaB (NF-kappaB) p105 subunit (down-regulated). In summary, differentially expressed proteins of MM U-266 cells in response to bortezomib were analyzed and identified. The data obtained from this study may indicate the use of bortezomib for the treatment of various diseases. PMID- 23025402 TI - One-phase synthesis of surface modified gold nanoparticles and generation of SERS substrate by seed growth method. AB - In this study, we report a novel and facile single-phase synthesis of stable AuNP CTAB(NA) conjugates with good dispersibility, bearing a bilayer of cationic surfactant, cetyltrimethylammonium bromide (CTAB) supported by N-nonylamine (NA) as a cosurfactant. We investigated AuNP-CTAB(NA) conjugates by (1)H NMR spectroscopy, UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and transmission electron microscopy (TEM). These studies suggest the presence of a CTAB bilayer on the nanoparticles surface forming an admicelle and NA embedded in the hydrophobic core of that bilayer. AuNP-CTAB(NA) conjugates remain dispersed in water even in the presence of high concentrations of salt and over a wide range of solution pHs. These conjugates further grow bigger when treated with additional AuCl(4)(-), CTAB, and NA in the presence of the mild reducing agent, hydroquinone (HQ). The larger AuNP CTAB(NA)-1 conjugates serve as SERS (surface-enhanced Raman Scattering) substrate of Raman active dye even at nanomolar concentrations. PMID- 23025404 TI - Separation of leukocytes from blood using spiral channel with trapezoid cross section. AB - Inertial microfluidics has recently drawn wide attention as an efficient, high throughput microfluidic cell separation method. However, the achieved separation resolution and throughput, as well as the issues with cell dispersion due to cell cell interaction, have appeared to be limiting factors in the application of the technique to real-world samples such as blood and other biological fluids. In this paper, we present a novel design of a spiral inertial microfluidic (trapezoidal cross-section) sorter with enhanced separation resolution and demonstrate its ability in separating/recovering polymorphonuclear leukocytes (PMNs) and mononuclear leukocytes (MNLs) from diluted human blood (1-2% hematocrit) with high efficiency (>80%). PMNs enriched by our method also showed negligible activation as compared to original input sample, while the conventional red blood cell (RBC) lysis method clearly induced artificial activation of the sensitive PMNs. Therefore, our proposed technique would be a promising alternative to enrich/separate sensitive blood cells for therapeutic or diagnostic applications. PMID- 23025403 TI - Addressing statistical biases in nucleotide-derived protein databases for proteogenomic search strategies. AB - Proteogenomics has the potential to advance genome annotation through high quality peptide identifications derived from mass spectrometry experiments, which demonstrate a given gene or isoform is expressed and translated at the protein level. This can advance our understanding of genome function, discovering novel genes and gene structure that have not yet been identified or validated. Because of the high-throughput shotgun nature of most proteomics experiments, it is essential to carefully control for false positives and prevent any potential misannotation. A number of statistical procedures to deal with this are in wide use in proteomics, calculating false discovery rate (FDR) and posterior error probability (PEP) values for groups and individual peptide spectrum matches (PSMs). These methods control for multiple testing and exploit decoy databases to estimate statistical significance. Here, we show that database choice has a major effect on these confidence estimates leading to significant differences in the number of PSMs reported. We note that standard target:decoy approaches using six frame translations of nucleotide sequences, such as assembled transcriptome data, apparently underestimate the confidence assigned to the PSMs. The source of this error stems from the inflated and unusual nature of the six-frame database, where for every target sequence there exists five "incorrect" targets that are unlikely to code for protein. The attendant FDR and PEP estimates lead to fewer accepted PSMs at fixed thresholds, and we show that this effect is a product of the database and statistical modeling and not the search engine. A variety of approaches to limit database size and remove noncoding target sequences are examined and discussed in terms of the altered statistical estimates generated and PSMs reported. These results are of importance to groups carrying out proteogenomics, aiming to maximize the validation and discovery of gene structure in sequenced genomes, while still controlling for false positives. PMID- 23025405 TI - Impact of SO(2) on Arabidopsis thaliana transcriptome in wildtype and sulfite oxidase knockout plants analyzed by RNA deep sequencing. AB - High concentrations of sulfur dioxide (SO(2) ) as an air pollutant, and its derivative sulfite, cause abiotic stress that can lead to cell death. It is currently unknown to what extent plant fumigation triggers specific transcriptional responses. To address this question, and to test the hypothesis that sulfite oxidase (SO) is acting in SO(2) detoxification, we compared Arabidopsis wildtype (WT) and SO knockout lines (SO-KO) facing the impact of 600 nl l(-1) SO(2) , using RNAseq to quantify absolute transcript abundances. These transcriptome data were correlated to sulfur metabolism-related enzyme activities and metabolites obtained from identical samples in a previous study. SO-KO plants exhibited remarkable and broad regulative responses at the mRNA level, especially in transcripts related to sulfur metabolism enzymes, but also in those related to stress response and senescence. Focusing on SO regulation, no alterations were detectable in the WT, whereas in SO-KO plants we found up-regulation of two splice variants of the SO gene, although this gene is not functional in this line. Our data provide evidence for the highly specific coregulation between SO and sulfur-related enzymes like APS reductase, and suggest two novel candidates for involvement in SO(2) detoxification: an apoplastic peroxidase, and defensins as putative cysteine mass storages. PMID- 23025406 TI - Molecular modeling study bioactive natural product of khellin analogues as a novel potential pharmacophore of EGFR inhibitors. AB - Khelline is naturally occurring furochromone exhibited significant Epidermal Growth Factor Receptor (EGFR) inhibitory activity. The newly synthesized compounds 2-5 displayed the most potent EGFR inhibitory activity on MCF-7 and HeLa. In vitro study against 59 different human tumour cell lines derived from nine cancer type in NCI (USA), which was presented and documented. Molecular docking simulation was performed to position compounds 1-5 into the EGFR active site to determine the probable binding mode. PMID- 23025407 TI - Isolation of bilberry anthocyanidin 3-glycosides bearing ortho-dihydroxyl groups on the B ring by forming an aluminum complex and their antioxidant activity. AB - Bilberry anthocyanin bearing an ortho-dihydroxyl group on the B ring was selectively isolated by complex formation with flavocommelin and aluminum ions (Al(3+)). The interaction between the anthocyanins, flavocommelin, and Al(3+) might have happened in a manner similar to rigid supramolecules, such as commelinin, protocyanin, and other complex pigments. Complex blue pigment (CP, 8.85 +/- 0.26 mg) with Al(3+) was formed from 18.6 mg (15 MUmol) of bilberry pigment, 18.2 mg (30 MUmol, 2.0 equiv) of flavocommelin, and 0.03 mL of 0.5 M aluminum chloride aqueous solution (15 MUmol, 1.0 equiv), yielding 36.5 +/- 0.7% recovery of anthocyanins in the complex after precipitation by ethanol. Consequently, anthocyanins bearing ortho-dihydroxyl groups on the B rings (delphinidin 3-glycosides, cyanidin 3-glycosides, and petunidin 3-glycosides) predominating (98.0 +/- 0.2%) in the complex were selectively isolated in a dose dependent manner by the addition of Al(3+), increasing the antioxidative activity of the mixture of anthocyanins. PMID- 23025409 TI - From the editors. Deep uncertainty. PMID- 23025410 TI - Acid-mediated prevention of aspartimide formation in solid phase peptide synthesis. AB - Aspartimide formation is one of the major obstacles that impedes the solid phase synthesis of large peptides and proteins. Until now, no cost-effective strategy to suppress this side reaction has been developed. Here it is demonstrated that addition of small amounts of organic acids to the standard Fmoc cleavage agent piperidine efficiently prevents formation of aspartimide side products. This effect is shown to be virtually independent of the acid strength. PMID- 23025408 TI - The genetics of sex chromosomes: evolution and implications for hybrid incompatibility. AB - Heteromorphic sex chromosomes, where one sex has two different types of sex chromosomes, face very different evolutionary consequences than do autosomes. Two important features of sex chromosomes arise from being present in only one copy in one of the sexes: dosage compensation and the meiotic silencing of sex chromosomes. Other differences arise because sex chromosomes spend unequal amounts of time in each sex. Thus, the impact of evolutionary processes (mutation, selection, genetic drift, and meiotic drive) differs substantially between each sex chromosome, and between the sex chromosomes and the autosomes. Sex chromosomes also play a disproportionate role in Haldane's rule and other important patterns related to hybrid incompatibility, and thus speciation. We review the consequences of sex chromosomes on hybrid incompatibility. A theme running through this review is that epigenetic processes, notably those related to chromatin, may be more important to the evolution of sex chromosomes and the evolution of hybrid incompatibility than previously recognized. PMID- 23025411 TI - Etiology of venous thrombosis: the need for small original studies. PMID- 23025412 TI - Reading disc-based bioassays with standard computer drives. AB - Traditional methods of disease diagnosis are both time-consuming and labor intensive, and many tests require expensive instrumentation and trained professionals, which restricts their use to biomedical laboratories. Because patients can wait several days (even weeks) for the results, the consequences of delayed treatment could be disastrous. Therefore, affordable and simple point-of care (POC) biosensor devices could fill a diagnostic niche in the clinic or even at home, as personal glucose meters do for diabetics. These devices would allow patients to check their own health conditions and enable physicians to make prompt treatment decisions, which could improve the chances for rapid recovery and cure. Compact discs (CDs) provide inexpensive substrate materials for the preparation of microarray biochips, and conventional computer drives/disc players can be adapted as precise optical reading devices for signal processing. Researchers can employ the polycarbonate (PC) base of a CD as an alternative substrate to glass slides or silicon wafers for the preparation of microanalytical devices. Using the characteristic optical phenomena occurring on the metal layer of a CD, researchers can develop biosensors based on advanced spectroscopic readout (interferometry or surface plasmon resonance). If researchers integrate microfluidic functions with CD mechanics, they can control fluid transfer through the spinning motion of the disc, leading to "lab-on-a-CD" devices. Over the last decade, our laboratory has focused on the construction of POC biosensor devices from off-the-shelf CDs or DVDs and standard computer drives. Besides the initial studies of the suitability of CDs for surface and materials chemistry research (fabrication of self-assembled monolayers and oxide nanostructures), we have demonstrated that an ordinary optical drive, without modification of either the hardware or the software driver, can function as the signal transducing element for reading disc-based bioassays quantitatively. In this Account, we first provide a brief introduction to CD-related materials chemistry and microfluidics research. Then we describe the mild chemistry developed in our laboratory for the preparation of computer-readable biomolecular screening assays: photochemical activation of the polycarbonate (PC) disc surface and immobilization and delivery of probe and target biomolecules. We thoroughly discuss the analysis of the molecular recognition events: researchers can "read" these devices quantitatively with an unmodified optical drive of any personal computer. Finally, and critically, we illustrate our digitized molecular diagnosis approach with three trial systems: DNA hybridization, antibody-antigen binding, and ultrasensitive lead detection with a DNAzyme assay. These examples demonstrate the broad potential of this new analytical/diagnostic tool for medical screening, on-site food/water safety testing, and remote environmental monitoring. PMID- 23025413 TI - Incorporation of an A1/A2-difunctionalized pillar[5]arene into a metal-organic framework. AB - An efficient synthetic route to an A1/A2-difunctionalized pillar[5]arene containing resolvable planar chirality has been developed and the arene employed as a strut in the synthesis of P5A-MOF-1, which has been demonstrated by X-ray powder diffraction analysis--supported by modeling--to be isoreticular with MOF 5. This metal-organic framework has an active domain that expresses good and selective uptake of neutral and positively charged electron-poor aromatic guests, which effect color changes of the cubic crystals from faint yellow to deep orange, arising from charge transfer between the guests and active domain of P5A MOF-1. PMID- 23025414 TI - Multiple functions of FADD in apoptosis, NF-kappaB-related signaling, and heart development in Xenopus embryos. AB - FADD is an adaptor protein that transmits apoptotic signals from death receptors. Additionally, FADD has been shown to play a role in various functions including cell proliferation. However, the physiological role of FADD during embryonic development remains to be delineated. Here, we show the novel roles FADD plays in development and the molecular mechanisms of these roles in Xenopus embryos. By whole-mount in situ hybridization and RT-PCR analysis, we observed that fadd is constantly expressed in early embryos. The upregulation or downregulation of FADD proteins by embryonic manipulation resulted in induction of apoptosis or size changes in the heart during development. Expression of a truncated form of FADD, FADDdd, which lacks pro-apoptotic activity, caused growth retardation of embryos associated with dramatic expressional fluctuations of genes that are regulated by NF-kappaB. Moreover, we isolated a homolog of mammalian cullin-4 (Cul4), a component of the ubiquitin E3 ligase family, as a FADDdd-interacting molecule in Xenopus embryos. Thus, our study shows that FADD has multiple functions in embryos; it plays a part in the regulation of NF-kappaB activation and heart formation, in addition to apoptosis. Furthermore, our findings provide new insights into how Cul4-based ligase is related to FADD signaling in embryogenesis. PMID- 23025415 TI - Anatomic distribution of hematolymphoid malignancies in the head and neck: 7 years of experience with 122 patients in a single institution. AB - CONCLUSION: Most hematolymphoid malignancies in the head and neck were malignant lymphomas that most often occurred in sexagenarian men. Approximately 80% of them were B-cell lymphomas with a predominance of diffuse large B-cell lymphoma (DLBCL) in both nodal and extranodal sites. Our results were compatible with those in a previous study that was conducted in the central part of Japan. OBJECTIVES: This analysis was performed to describe the anatomic distribution of hematolymphoid malignancies that were diagnosed by biopsy in our department. METHODS: Clinical medical records of 122 patients with hematolymphoid malignancies in the head and neck from January 2004 to December 2010 were retrospectively reviewed. The anatomic site of origin according to the histopathology of each malignancy was analyzed. RESULTS: The incidence ratio of hematolymphoid malignancies was 15.1%. The male:female ratio was 2.3:1. Ages ranged from 17 to 89 years (median, 66). Of the 122 cases, 121 were lymphoid neoplasms (4 cases of Hodgkin lymphoma and 117 cases of non-Hodgkin lymphoma) and the remaining 1 was myeloid. The most common histopathology was DLBCL (54.9%), followed by follicular lymphoma (8.2%), and peripheral T-cell lymphoma (8.2%). Most commonly, the oropharynx (36.1%) and the cervical lymph node (34.4%) were affected. PMID- 23025417 TI - Dibenzocycloheptanoids from the leaves of Cinnamomum subavenium. AB - Five dibenzocycloheptatrienes (1-3, 5, and 6) and one dibenzocycloheptadiene (8) together with 16 known compounds were isolated from the leaves of Cinnamomum subavenium. Application of HPLC-SPE-NMR to a selected fraction afforded two additional dibenzocycloheptatrienes (4, 7). The glycosides 2-7 comprise two diastereomers because of the chiral glycosyl moiety and the axial chirality of the biphenyl system. Their structures were elucidated via ECD and 2D NMR analyses and chemical degradation. Subavenosides D (5) and E (6) showed moderate inhibitory activity against alpha-glucosidase type IV from Bacillus stearothermophilus with IC50 values of 50.7 and 19.0 MUM, respectively. PMID- 23025416 TI - New insights into the link between DNA damage and apoptosis. AB - SIGNIFICANCE: When lesions are unrepaired or there are defects in the DNA repair system, DNA damage is often correlated to apoptosis. However, different kinds of lesions and different degrees of lesion severity can trigger numerous signaling responses. RECENT ADVANCES: DNA repair proteins involved in specific DNA repair pathways can modulate the function or activity of some apoptotic factors, further emphasizing the crosstalk between DNA damage and cell death. CRITICAL ISSUES: Here, we discuss the signaling networks that link DNA damage to apoptosis, and we focus on post-translational modifications, leading to crucial changes in protein behavior, following various kinds of DNA damage. Moreover, we analyze the existence of apoptosis-related functions of typical repair proteins, leading to diverse, often-overlapping, DNA damage responses. FUTURE DIRECTIONS: The better understanding of the regulation and the functionality of key DNA repair proteins, also involved in apoptosis regulation, has the potential of modulating the cell outcomes on DNA damage, particularly in the context of cancer treatment. PMID- 23025419 TI - Total phenolic contents and free-radical scavenging activities of grape (Vitis vinifera L.) and grape products. AB - Grape is one of the world's largest fruit crops, with an approximate annual production of 58 million metric tons, and it is well known that the grape skins, seeds and stems, waste products generated during wine and grape juice processing, are rich sources of polyphenols. It contains flavonoids, phenolic acids and stilbenes. In this study, we tried to determine antioxidant properties and phenolic contents of grape and grape products (fresh fruit, seed, dried fruit, molasses, pestil, vinegar) of ethanol and water extracts. Antioxidant properties of extracts were investigated by DPPH(?), ABTS(?+), superoxide, H(2)O(2) scavenging, reducing power, metal chelating activity and determination of total phenolic contents. The seed extracts revealed highest ABTS(?+), DPPH(?), H(2)O(2) scavenging and reducing power activities. Furthermore, these extracts showed higher total phenolic contents than other grape product extracts. PMID- 23025418 TI - Evaluation of gut modulatory and bronchodilator activities of Amaranthus spinosus Linn. AB - BACKGROUND: The aqueous-methanolic extract of Amaranthus spinosus (A. spinosus Linn.,) whole plant, was studied for its laxative, spasmolytic and bronchodilator activities to validate some of its medicinal uses. METHODS: The crude extract of A. spinosus was studied in-vivo for bronchodilator and laxative activities and in vitro using isolated tissue preparations which were mounted in tissue baths assembly containing physiological salt solutions, maintained at 37 degrees C and aerated with carbogen, to assess the spasmolytic effect and to find out the possible underlying mechanisms. RESULTS: In the in-vivo experiments in mice, the administration of A. spinosus increased fecal output at doses of 100 and 300 mg/kg showing laxative activity. It also inhibited carbachol-induced bronchospasm in anesthetized rats at 1, 3, 10 and 30 mg/kg indicative of bronchodilator activity. When tested on isolated gut preparations, the plant extract showed a concentration-dependent (0.01-10.0 mg/ml) spasmogenic effect in spontaneously contracting rabbit jejunum and guinea-pig ileum. The spasmogenic effect was partially blocked in tissues pretreated with atropine (0.1 MUM). When tested on K+ (80 mM)-induced sustained contractions in isolated rabbit jejunum, the plant extract caused complete relaxation and also produced a shift in the Ca++ concentration-response curves (CRCs) towards right, similar to diltiazem. In rabbit trachea, the plant extract completely inhibited K+ (80 mM) and carbachol (CCh, 1 MUM)-induced contractions at 1 mg/ml but pretreatment of tissue with propranolol (1 MUM), caused around 10 fold shift in the inhibitory CRCs of the plant extract constructed against CCh-induced contraction. The plant extract (up to 0.3 mg/ml) also increased both force and rate of spontaneous contractions of isolated guinea-pig atria, followed by relaxation at higher concentration (1.0 5.0 mg/ml). The cardio-stimulant effect was abolished in the presence of propranolol, similar to that of isoprenaline. Activity-directed fractionation revealed that the spasmolytic component(s) was separated in the organic fraction, whereas the spasmogenic component was concentrated in the aqueous fraction. CONCLUSION: These results indicate that A. spinosus possesses laxative activity partially mediated through cholinergic action. The spasmolytic effect was mediated through calcium channel blocking (CCB), while bronchodilator activity through a combination of beta-adrenergic and CCB pathways, which may explain the traditional uses of A. spinosus in gut and airways disorders. PMID- 23025420 TI - Copper(I) hydroxyapatite catalyzed Sonogashira reaction of alkynes with styrenyl bromides. Reaction of cis-styrenyl bromides forming unsymmetric diynes. AB - An efficient Sonogashira coupling of terminal alkynes and styrenyl bromides has been achieved under the catalysis of hydroxyapatite-supported copper(I). The trans-styrenyl bromides produce the usual trans-enyne products, whereas the cis styrenyl bromides lead to unsymmetric 1,3-diynes by the cross coupling of terminal alkyne and the alkyne generated from the cis-styrenyl bromide. A series of trans-enynes and unsymmetric 1,3-diynes have been synthesized by this protocol. PMID- 23025421 TI - A public health and budget impact analysis of vaccinating at-risk adults and the elderly against pneumococcal diseases in Germany. AB - To assess the comparative public health and budget impact over 5 years of several pneumococcal vaccination strategies (23-valent pneumococcal polysaccharide vaccine [PPV23] and/or 13-valent pneumococcal conjugate vaccine [PCV13]) in Germany, within the context of changing invasive pneumococcal disease (IPD) incidence over time. A multi-cohort, population-based Markov model was developed. Uncertainty around vaccine effectiveness, costs and IPD incidence change was handled through scenario analyses. Between 2012 and 2016, the introduction of PCV13 in adults, compared with the use of PPV23, would be associated with a net estimated budget increase of ?59.7 million (+6.7%) to ?151.6 million (+13.7%). Impact on IPD incidence ranged from -113 cases (-0.8%) to +298 cases (+2.8%). Introducing PCV13 in adults is expected to significantly affect healthcare budgets. Adult vaccination with PPV23 remains the optimal vaccination strategy from public health and budget perspectives. PMID- 23025422 TI - Cost-effectiveness of vaccinating adults with the 23-valent pneumococcal polysaccharide vaccine (PPV23) in Germany. AB - The introduction of routine infant vaccination against pneumococcal disease has resulted in a decreased overall invasive pneumococcal disease incidence in adults but also a change in invasive pneumococcal disease serotypes. This study aimed to assess the cost-effectiveness of 23-valent pneumococcal polysaccharide vaccine (PPV23) in Germany in this context. A population-based Markov model was developed. A cohort of adults currently eligible for vaccination was followed until death. Adult vaccination with PPV23 was associated with an incremental cost effectiveness ratio of ?17,065/quality-adjusted life years gained from the third party payer's perspective. Univariate sensitivity analyses showed that the incremental cost-effectiveness ratio was below ?50,000/quality-adjusted life years gained in most test scenarios. The model suggests that adult PPV23 vaccination is cost effective in Germany, due to its broad serotype coverage. This is despite epidemiological changes in Streptococcus pneumoniae serotypes caused by wider use of pneumococcal conjugate vaccines during childhood. PMID- 23025423 TI - Inner filter effect on surface enhanced Raman spectroscopic measurement. AB - Presented herein is a combined experimental and computational study of the gold nanoparticle (AuNP) inner filter effect on surface enhanced Raman spectroscopic (SERS) measurements. Using a bianalyte strategy in which dithiopurine (DTP) and ethanol were employed as the model analytes, we demonstrated that AuNPs enhance DTP's Raman signal but attenuate ethanol's Raman intensity. Combined time resolved UV-vis and Raman measurements showed that AuNP aggregation has significant and an exactly opposite impact on the AuNP inner filter effect and SERS enhancement. This research provides critical new insights regarding SERS signal variation and offers a simple methodology for reliable determination of the SERS enhancement factors. PMID- 23025424 TI - Adherence improvement in Dutch glaucoma patients: a randomized controlled trial. AB - PURPOSE: To study the effect of patient education and the TravAlert((r)) Eyot((r)) drop guider on intraocular pressure (IOP) and adherence in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT) monitored with the TravAlert((r)) dosing aid. METHODS: Multicentre, randomized, controlled clinical trial among 18 Dutch hospitals. Patients were randomized to one of the four study arms: (1) use of the dosing aid, (2) use of the dosing aid with the drop guider, (3) use of the dosing aid together with patient education or (4) use of the dosing aid and drop guider together with patient education. IOP was recorded at baseline and after 3 and 6 months. Data on adherence generated by the dosing aid were collected and studied at the end of the study. RESULTS: Mean IOP dropped from 20.3 +/- 5.7 mmHg at baseline to 16.3 +/- 4.0 mmHg (right eye) after 6 months and from 20.2 +/- 5.9 mmHg to 16.4 +/- 4.1 mmHg (left eye). The mean adherence rate was 0.91 +/- 0.1. IOP and adherence rate were not statistically different between the study arms. Patients with 'drug holidays' had a significantly higher mean IOP after 6 months. Patients who used the drop guider were less adherent. A lower adherence level was also associated with new patients with glaucoma and patients with a lower level of knowledge on glaucoma. CONCLUSION: Patient education is especially useful for new patients with glaucoma. The use of a drop guider does not improve adherence. Especially patients with 'drug holidays' are at risk for developing uncontrolled IOP levels. PMID- 23025425 TI - Sirtuin1 single nucleotide polymorphism (A2191G) is a diagnostic marker for vibration-induced white finger disease. AB - BACKGROUND: Vibration-induced white finger disease (VWF), also known as hand-arm vibration syndrome, is a secondary form of Raynaud's disease, affecting the blood vessels and nerves. So far, little is known about the pathogenesisof the disease. VWF is associated with an episodic reduction in peripheral blood flow. Sirtuin 1, a class III histone deacetylase, has been described to regulate the endothelium dependent vasodilation by targeting endothelial nitric oxide synthase. We assessed Sirt1single nucleotide polymorphisms in patients with VWF to further elucidate the role of sirtuin 1 in the pathogenesis of VWF. METHODS: Peripheral blood samples were obtained from 74 patients with VWF (male 93.2%, female 6.8%, median age 53 years) and from 317 healthy volunteers (gender equally distributed, below 30 years of age). Genomic DNA was extracted from peripheral blood mononuclear cells and screened for potential Sirt1single nucleotide polymorphisms. Four putative genetic polymorphisms out of 113 within the Sirt1 genomic region (NCBI Gene Reference: NM_012238.3) were assessed. Allelic discrimination was performed by TaqMan-polymerasechainreaction-based allele specific genotyping single nucleotide polymorphism assays. RESULTS: Sirt1single nucleotide polymorphism A2191G (Assay C_25611590_10, rs35224060) was identified within Sirt1 exon 9 (amino acid position 731, Ile -> Val), with differing allelic frequencies in the VWF population (A/A: 70.5%, A/G: 29.5%, G/G: 0%) and the control population (A/A: 99.7%, A/G: 0.3%, G/G: 0.5%), with significance levels of P < 0.001 (Mann-Whitney U test (two-tailed) P <0.001; F-exact t-test and Chi square test with Yates correction (all two-tailed): P <0.0001). The heterogeneous A/G genotype in base pair position 2191 is significantly overrepresented in the VWF patient population when compared with healthy controls. CONCLUSION: We identified theSirt1A2191Gsingle nucleotide polymorphism as a diagnostic marker for VWF. PMID- 23025426 TI - Chemical passivation processes for biofunctionalization schemes on semiconductor surfaces. AB - In developing novel designs for semiconductor-based biosensors and for biofunctionalization of semiconductors in general, it is extremely important to be able to block the reaction sites present on a surface following the biomodification from further chemical transformations. This procedure is required both to protect the surface from oxidation and to allow for molecular-level control of the biomolecular interactions at the topmost layer. In this work, the biosensor model system is designed based on a single-strand biotin-modified thiol DNA attached to the silicon substrate. The binding of this thiol-DNA to the surface is performed through the cross-linker sulfosuccinimidyl-4-(N maleimidomethyl)-cyclohexane-1-carboxylate (SSMCC) attached to the 11-amino-1 undecene monolayer on Si(111) surface. Streptavidin-coated gold nanoparticles are used to test the reactivity of the surface and to examine the role of passivation in the entire scheme. The passivation of the remaining surface reactive sites is achieved via a reaction with 1-octadecanethiol (ODT). This approach tests both the stability of the silicon/organic layer interface and the passivation of the biofunctionalized surface on top of the organic layer. Microscopy and spectroscopy studies are combined to interrogate this model system before and after surface passivation. PMID- 23025427 TI - Parvovirus transmission by blood products - a cause for concern? AB - The introduction of dual viral inactivation of clotting factor concentrates has practically eliminated infections by viruses associated with significant pathogenicity over the last 20 years. Despite this, theoretical concerns about transmission of infection have remained, as it is known that currently available viral inactivation methods are unable to eliminate parvovirus B19 or prions from these products. Recently, concern has been raised following the identification of the new parvoviruses, human parvovirus 4 (PARV4) and new genotypes of parvovirus B19, in blood products. Parvoviruses do not cause chronic pathogenicity similar to human immunodeficiency virus or hepatitis C virus, but nevertheless may cause clinical manifestations, especially in immunosuppressed patients. Manufacturers should institute measures, such as minipool polymerase chain reaction testing, to ensure that their products contain no known viruses. So far, human bocavirus, another new genus of parvovirus, has not been detected in fractionated blood products, and unless their presence can be demonstrated, routine testing during manufacture is not essential. Continued surveillance of the patients and of the safety of blood products remains an important ongoing issue. PMID- 23025428 TI - A study of incidence of AKI in critically ill patients. AB - BACKGROUND: There have been many studies to estimate the incidence of acute kidney injury (AKI) in critically ill patients. However, results were variable due to the non-usage of uniform criteria and retrospective design of most studies. There are no new studies from the developing countries looking at AKI in these patients since adoption of uniform Acute Kidney Injury Network (AKIN) criteria. METHODS: In this prospective observational study from a tertiary care hospital in India, we enrolled 100 consecutively admitted critically ill patients and followed them during hospital stay. AKI was defined by AKIN criteria. Both the groups of patients, those who developed AKI and those who did not develop AKI, were then followed during the course of their hospital stay. RESULTS: AKI occurred in 33 patients with an incidence rate of 17.3 per person year. Thirty one out of 33 (93.9%) patients died in the AKI group, whereas 31 out of 67 (53.7%) patients died in the non-AKI group. Independent risk factors for AKI were older age (adjusted relative risk (RR) = 4.42, 95% CI = 2.57-5.23), septic shock (adjusted RR = 2.82, 95% CI = 1.43-3.80), prolonged duration of mechanical ventilation (adjusted RR = 2.35, 95% CI = 1.09-3.6), higher acute physiology and chronic health evaluation II (APACHE II) score (adjusted RR = 2.74, 95% CI = 1.28 4.13), and higher sequential organ failure assessment (SOFA) score (adjusted RR = 2.53, 95% CI = 1.04-4.08). Development of AKI was an independent risk factor for mortality (adjusted RR = 1.76, 95% CI = 1.25-1.84). CONCLUSION: Older patients, those with septic shock, and those requiring prolonged mechanical ventilation had increased risk for AKI. AKI was an independent predictor of mortality. PMID- 23025429 TI - Using corrected serum chloride and predicted bicarbonate concentrations to interpret acid-base status in dogs. AB - BACKGROUND: Changes in water balance and the presence of unmeasured anions perturb the inverse relationship between serum chloride (Cl) and bicarbonate (HCO(3) ) concentrations in people, affecting accurate interpretation of acid base status. OBJECTIVES: The aim of this study was to demonstrate that corrected serum Cl and predicted HCO(3) concentrations, based on serum sodium (Na) concentration and anion gap (AG), would be inversely correlated and could be used to better characterize causes of acid-base disorders in dogs. METHODS: In this retrospective study, electrolyte data from dogs with at least one abnormality in serum Na, Cl, or HCO(3) concentrations were analyzed. Profiles were classified before and after calculations using 2 methods, a modified Feldman and an institutional method, to correct Cl concentration and predict HCO(3) concentrations based on Na concentration and AG. Dogs were classified as low (L), normal (N), or high (H) based on Cl (first letter) and HCO(3) (second letter) concentrations, as follows: LL, LN, LH, NL, NN, NH, HL, HN, or HH. RESULTS: For profiles from 261 dogs, reclassifying corrected Cl and predicted HCO(3) concentrations resulted in a shift from the initial classification into a different one in 73% of dogs; in most cases, the shift was to LH, NN, or HL categories. Albumin concentration was a significant factor in acid-base balance. CONCLUSIONS: When interpreting acid-base status based on results of a standard biochemical panel, erroneous conclusions can be drawn if concentrations of Na, unmeasured anions, and albumin are not taken into account. The inverse relationship between serum Cl and HCO(3) concentrations may be used to identify frequent acid-base disorders as well as to unmask abnormalities obscured by irregularities in water balance or AG. PMID- 23025430 TI - Soil biotic impact on plant species shoot chemistry and hyperspectral reflectance patterns. AB - Recent studies revealed that plant-soil biotic interactions may cause changes in above-ground plant chemistry. It would be a new step in below-ground-above-ground interaction research if such above-ground chemistry changes could be efficiently detected. Here we test how hyperspectral reflectance may be used to study such plant-soil biotic interactions in a nondestructive and rapid way. The native plant species Jacobaea vulgaris and Jacobaea erucifolius, and the exotic invader Senecio inaequidens were grown in different soil biotic conditions. Biomass, chemical content and shoot reflectance between 400 and 2500 nm wavelengths were determined. The data were analysed with multivariate statistics. Exposing the plants to soil biota enhanced the content of defence compounds. The highest increase (400%) was observed for the exotic invader S. inaequidens. Chemical and spectral data enabled plant species to be classified with an accuracy > 85%. Plants grown in different soil conditions were classified with 50-60% correctness. Our data suggest that soil microorganisms can affect plant chemistry and spectral reflectance. Further studies should test the potential to study plant-soil biotic interactions in the field. Such techniques could help to monitor, among other things, where invasive exotic plant species develop biotic resistance or the development of hotspots of crop soil diseases. PMID- 23025431 TI - Three-component domino reactions for selective formation of indeno[1,2-b]indole derivatives. AB - Efficient three-component domino strategies for the synthesis of multifunctionalized tetracyclic indeno[1,2-b]indole derivatives with different substituted patterns have been established successfully. The first pathway involves a novel sequential methyl migration, aromatization, and esterification, while a second reaction in HOAc leads to compounds 6 with high syn diastereoselectivity. Both reactions showed attractive features including mild conditions, convenient one-pot operation, short reaction times of 15-32 min, and excellent regio- and/or stereoselectivity. PMID- 23025432 TI - Interaction of over-the-counter drugs with curcumin: influence on stability and bioactivities in intestinal cells. AB - Curcumin, a major constituent in rhizomes of Curcuma longa L., has shown various biological activities. It has widely been used as a food additive to provide potential health benefits. In the present study, we investigated changes in chemical stability and cytotoxic properties of curcumin and commonly consumed over-the-counter (OTC) drugs including ibuprofen, acetylsalicylic acid (Asp), and acetaminophen (AAP), through their interactions. Stability of curcumin was significantly improved in phosphate-buffered saline or 0.01 N HCl containing each OTC drug; Asp showed the most prominent effect. Stability of Asp or AAP during 24 h incubation with curcumin was not changed significantly. Cytotoxic effects of curcumin were enhanced in the presence of the OTC drugs on INT 407 normal intestinal and HCT 116 colon cancer cells. Relative cytotoxicity of curcumin (>10 MUM) under the drug-treated conditions was significantly higher. Cellular uptake of curcumin in HCT 116 cells increased significantly when incubated with Asp or AAP. Intracellular thiol levels of the cells treated with curcumin were further reduced in the presence of the OTC drugs. The present study provides information that commonly consumed OTC drugs affect chemical stability of curcumin in physiological conditions, and certain bioactivities of curcumin can be altered through their interactions. PMID- 23025433 TI - Experimental design and primary data analysis methods for comparing adaptive interventions. AB - In recent years, research in the area of intervention development has been shifting from the traditional fixed-intervention approach to adaptive interventions, which allow greater individualization and adaptation of intervention options (i.e., intervention type and/or dosage) over time. Adaptive interventions are operationalized via a sequence of decision rules that specify how intervention options should be adapted to an individual's characteristics and changing needs, with the general aim to optimize the long-term effectiveness of the intervention. Here, we review adaptive interventions, discussing the potential contribution of this concept to research in the behavioral and social sciences. We then propose the sequential multiple assignment randomized trial (SMART), an experimental design useful for addressing research questions that inform the construction of high-quality adaptive interventions. To clarify the SMART approach and its advantages, we compare SMART with other experimental approaches. We also provide methods for analyzing data from SMART to address primary research questions that inform the construction of a high-quality adaptive intervention. PMID- 23025434 TI - Q-learning: a data analysis method for constructing adaptive interventions. AB - Increasing interest in individualizing and adapting intervention services over time has led to the development of adaptive interventions. Adaptive interventions operationalize the individualization of a sequence of intervention options over time via the use of decision rules that input participant information and output intervention recommendations. We introduce Q-learning, which is a generalization of regression analysis to settings in which a sequence of decisions regarding intervention options or services is made. The use of Q is to indicate that this method is used to assess the relative quality of the intervention options. In particular, we use Q-learning with linear regression to estimate the optimal (i.e., most effective) sequence of decision rules. We illustrate how Q-learning can be used with data from sequential multiple assignment randomized trials (SMARTs; Murphy, 2005) to inform the construction of a more deeply tailored sequence of decision rules than those embedded in the SMART design. We also discuss the advantages of Q-learning compared to other data analysis approaches. Finally, we use the Adaptive Interventions for Children With ADHD SMART study (Center for Children and Families, University at Buffalo, State University of New York, William E. Pelham as principal investigator) for illustration. PMID- 23025435 TI - Short-term prophylaxis in hereditary angioedema due to deficiency of the C1 inhibitor--a long-term survey. AB - BACKGROUND: Hereditary angioedema is a potentially life-threatening disorder, because edema occurring in the mucosa of the upper airways can lead to suffocation. The management of HAE consists of avoiding the triggering factors, prophylaxis, and the acute treatment of edematous episodes. Medical procedures can also provoke edematous attacks, and therefore, short-term prophylaxis (STP) is recommended before such interventions. Our aim was to evaluate the efficacy and safety of STP administered before medical procedures. METHODS: We conducted a retrospective analysis before and a prospective survey after establishing the diagnosis in a group of 137 (60 males, 77 females; 20 pediatric and 117 adult) patients with HAE. Both were implemented using questionnaires, patient diaries and hospital charts focusing on medical interventions provoking edematous attack, and the medicinal products (C1-INH concentrate, tranexamic acid, and danazol) administered for STP. RESULTS: Comparing surgical interventions performed without pre-event STP (in 39/89 patients before HAE was diagnosed), or after STP (in 3/55 cases after diagnosis), we found a significant (P < 0.0001, Fisher's exact test) reduction in the number of edematous episodes. Evaluating the efficacy of the drugs administered for STP revealed that C1-INH concentrate (Berinert((r)) , CSL Behring, Marburg, Germany) was significantly (P = 0.0096, Fisher's exact test) superior to orally administered drugs in reducing the instances of postprocedural edema. None of the medicinal products caused adverse events potentially related to STP. CONCLUSIONS: STP reduces the number of postprocedural edematous episodes. C1-INH concentrate is safe and effective for prophylaxis. When this agent is not available, danazol is a potential alternative for prophylaxis before elective medical interventions. PMID- 23025437 TI - The SLAM family member CD84 is regulated by ADAM10 and calpain in platelets. AB - BACKGROUND AND OBJECTIVE: Ectodomain shedding is a major mechanism to modulate platelet receptor signaling and to downregulate platelet reactivity. Proteins of the a disintegrin and metalloproteinase (ADAM) family are implicated in the shedding of various platelet receptors. The signaling lymphocyte activation molecule (SLAM) family receptor CD84 is highly expressed in platelets and immune cells, but its role in platelet physiology is not well explored. Because of its ability to form homodimers, CD84 has been suggested to mediate contact-dependent signaling and contribute to thrombus stability. However, nothing is known about the cellular regulation of CD84. METHODS: We studied the regulation of CD84 in murine platelets by biochemical approaches and use of three different genetically modified mouse lines. Regulation of CD84 in human platelets was studied using inhibitors and biochemical approaches. RESULTS: We show that CD84 is cleaved from the surface of human and murine platelets in response to different shedding inducing agents and platelet receptor agonists. CD84 downregulation occurs through ectodomain-shedding and intracellular cleavage. Studies in transgenic mice identified ADAM10 as the principal sheddase responsible for CD84 cleavage, whereas ADAM17 was dispensable. Western blot analyses revealed calpain-mediated intracellular cleavage of the CD84 C-terminus, occurring simultaneously with, but independently of, ectodomain shedding. Furthermore, analysis of plasma and serum samples from transgenic mice demonstrated that CD84 is constitutively shed from the platelet surface by ADAM10 in vivo. CONCLUSIONS: These results reveal a dual regulation mechanism for platelet CD84 by simultaneous extra- and intracellular cleavage that may modulate platelet-platelet and platelet-immune cell interactions. PMID- 23025439 TI - Dispositional optimism in adolescents with cancer: differential associations of optimism and pessimism with positive and negative aspects of well-being. AB - OBJECTIVES: Dispositional optimism is often considered to be a unidimensional construct. Recent studies suggest, however, that optimism and pessimism are separate dimensions. In this study we investigated two issues. First, the levels of optimism and pessimism in adolescents with cancer compared with healthy controls and second, the individual effects of optimism and pessimism on concurrent and longitudinal well-being. DESIGN: A matched case-control design was used to examine whether adolescents with cancer and healthy adolescents differed with regard to optimism and pessimism. The second part of the study was employed in a prospective design with assessments in the patient group at 3 and 6 months post-diagnosis. METHODS: Thirty-three adolescents with cancer (3 months post diagnosis) and 66 matched controls completed a measure on dispositional optimism (i.e., optimism and pessimism). In addition, patients completed measures on positive and negative aspects of well-being at 3 and 6 months post-diagnosis. RESULTS: Although adolescents with cancer were not more optimistic than their healthy peers, they were significantly less pessimistic. Zero order and semi partial correlations showed that optimism and pessimism are related to different aspects of well-being. Specifically, we found a cohesive pattern in which optimism predicts positive aspects and pessimism negative aspects of well-being. CONCLUSIONS: The high levels of overall optimism often found in patients with cancer might in fact result from low pessimism instead of high optimism. Furthermore, as our study shows that optimism and pessimism are differentially associated with aspects of well-being, it provides strong support for the bidimensionality of dispositional optimism. PMID- 23025440 TI - Study of the thermoelectric properties of lead selenide doped with boron, gallium, indium, or thallium. AB - Group IIIA elements (B, Ga, In, and Tl) have been doped into PbSe for enhancement of thermoelectric properties. The electrical conductivity, Seebeck coefficient, and thermal conductivity were systematically studied. Room-temperature Hall measurements showed an effective increase in the electron concentration upon both Ga and In doping and the hole concentration upon Tl doping to ~7 * 10(19) cm(-3). No resonant doping phenomenon was observed when PbSe was doped with B, Ga, or In. The highest room-temperature power factor ~2.5 * 10(-3) W m(-1) K(-2) was obtained for PbSe doped with 2 atom % B. However, the power factor in B-doped samples decreased with increasing temperature, opposite to the trend for the other dopants. A figure of merit (ZT) of ~1.2 at ~873 K was achieved in PbSe doped with 0.5 atom % Ga or In. With Tl doping, modification of the band structure around the Fermi level helped to increase the Seebeck coefficient, and the lattice thermal conductivity decreased, probably as a result of effective phonon scattering by both the heavy Tl(3+) ions and the increased grain boundary density after ball milling. The highest p-type ZT value was ~1.0 at ~723 K. PMID- 23025438 TI - Redox metabolism in mitochondria of trypanosomatids. AB - SIGNIFICANCE: In the single mitochondrion of protozoan trypanosomatid parasites there are several sites for the generation and elimination of reactive oxygen species (ROS), a class of molecules that exhibit a dual role in cells, either as regulatory mediators or as cytotoxic effectors. RECENT ADVANCES: Formation of ROS in trypanosomatid mitochondria can be induced by various drug compounds. Importantly, it can also be triggered by specific physiologic stimuli, indicating that this phenomenon may occur in living parasites as well. Elimination of ROS in these organelles is attributed to the activity of two iron-dependent superoxide dismutases (FeSODs) and up to three different peroxidases (a cytochrome c peroxidase and two thiol peroxidases). CRITICAL ISSUES: Data regarding the formation of ROS in trypanosomatid mitochondria are limited and nonsystematic. Another critical issue refers to the exact contribution of mitochondrial FeSODs and peroxidases for ROS removal, given that their antioxidant activity is not essential when abrogated individually. This suggests some level of functional overlapping or that ROS produced in mitochondria under normal conditions can be removed noncatalytically. Also still unsolved is the mechanism by which mitochondrial thiol peroxidases are regenerated to their reduced (active) form. FUTURE DIRECTIONS: The production of intramitochondrial ROS under physiologic conditions and their implication in parasite biology should be further clarified. The relative importance of enzymatic versus nonenzymatic mechanisms for ROS elimination in trypanosomatid mitochondria also requires investigation. Simultaneous depletion of several redundant antioxidant enzymes and determination of noncatalytic antioxidants are possible ways to achieve this. PMID- 23025441 TI - Mortality associated with exposure to carbon monoxide in WHO European Member States. AB - In closed environments, the concentration of carbon monoxide (CO) can easily rise to health-threatening levels. CO-related incidents are often caused by poor condition or inappropriate use of indoor combustion devices as well as structure fires but are also due to suicides. To evaluate the incidence of CO poisoning in Europe, national data on CO-related mortality and morbidity were compiled from Member States of the WHO European Region using a standardized data collection form. National data on CO poisoning were provided by 28 Member States. Within the maximum reporting period (1980-2008), a total of 140 490 CO-related deaths were reported (annual death rate of 2.2/100 000). The number of hospital admissions available from six countries was 31 473. Unintentional CO deaths accounted for 54.7% of the CO-related deaths (35.9%: unintentional inhalation; 18.8%: related to structure fires). The intentional deaths related to CO exposure account for 38.6% of all CO-related deaths (38.1%: suicides; 0.5%: homicides). CO exposure is preventable but causes a substantial amount of deaths in many European countries. More efficient measures and policies to prevent CO poisoning and better reporting of CO mortality are necessary. PMID- 23025442 TI - Spinal intradural teratomas: developmental programs gone awry? AB - Intradural spinal teratomas are rare tumors of the spinal cord that are infrequently encountered in children. Although the mechanistic basis for the formation of these tumors is unclear, several lines of evidence suggest that a dysembryogenic process in the embryo results in their formation. The authors present a case of spinal intradural teratoma in an 18-year-old, previously healthy man and review the literature linking the development of these tumors to defects in neurulation and embryogenesis. PMID- 23025443 TI - The role of primary cilia in the pathophysiology of neural tube defects. AB - Neural tube defects (NTDs) are a set of disorders that occur from perturbation of normal neural development. They occur in open or closed forms anywhere along the craniospinal axis and often result from a complex interaction between environmental and genetic factors. One burgeoning area of genetics research is the effect of cilia signaling on the developing neural tube and how the disruption of primary cilia leads to the development of NTDs. Recent progress has implicated the hedgehog (Hh), wingless-type integration site family (Wnt), and planar cell polarity (PCP) pathways in primary cilia as involved in normal neural tube patterning. A set of disorders involving cilia function, known as ciliopathies, offers insight into abnormal neural development. In this article, the authors discuss the common ciliopathies, such as Meckel-Gruber and Joubert syndromes, that are associated with NTDs, and review cilia-related signaling cascades responsible for mammalian neural tube development. Understanding the contribution of cilia in the formation of NTDs may provide greater insight into this common set of pediatric neurological disorders. PMID- 23025444 TI - Lipomyelomeningocele: pathology, treatment, and outcomes. AB - Lipomyelomeningocele represents a rare but complex neurological disorder that may present with neurological deterioration secondary to an inherent tethered spinal cord. Radiological testing is beneficial in determining the morphology of the malformation. Specialized testing such as urodynamic studies and neurophysiological testing may be beneficial in assessing for neurological dysfunction secondary to the lipomyelomeningocele. Early surgical intervention may be beneficial in preventing further neurological decline. PMID- 23025445 TI - Management of urological dysfunction in pediatric patients with spinal dysraphism: review of the literature. AB - An intact, fully functional spine is the result of a complex sequence of embryological events involving both nervous and musculoskeletal system precursors. Deviations from this highly ordered system can result in congenital abnormalities ranging from clinically insignificant cosmetic changes to CNS malformations that are incompatible with life. Closure of the neural tube, which is believed to be the embryological event gone awry in these cases, is complete by just 28 days' gestation, often before pregnancy is detected. Although progress has been made to help prevent neural tube defects in the children of those attempting to conceive, these congenital deformities unfortunately continue to affect a startling number of infants worldwide each year. Furthermore, the precise mechanisms governing closure of the neural tube and how they might be interrupted remain elusive. What is known is that there are a large number of individuals who must deal with congenital spine dysraphism and the clinical sequelae on a daily basis. Bladder and urinary dysfunction are frequently encountered, and urological care is a critical, often neglected, component in the lifelong multidisciplinary approach to treatment. Although many treatment strategies have been devised, a need remains for evidence-based interventions, analysis of quality of life, and preemptive education of both caregivers and patients as they grow older. Pediatric neurosurgeons in particular have the unique opportunity to address these issues, often in the first few days of life and throughout pre- and postoperative evaluation. With proper management instituted at birth, many patients could potentially delay or avoid the potential urological complications resulting from congenital neurogenic bladder. PMID- 23025446 TI - Unusual presentation of congenital dermal sinus: tethered spinal cord with intradural epidermoid and dual paramedian cutaneous ostia. AB - The authors present the first report of spinal congenital dermal sinus with paramedian dual ostia leading to 2 intradural epidermoid cysts. This 7-year-old girl had a history of recurrent left paramedian lumbosacral subcutaneous abscesses, with no chemical or pyogenic meningitis. Admission MRI studies demonstrated bilateral lumbar dermal sinus tracts and a tethered spinal cord. At surgery to release the tethered spinal cord the authors encountered paramedian dermal sinus tracts with dual ostia, as well as 2 intradural epidermoid cysts that were not readily apparent on MRI studies. Congenital dermal sinus should be considered in the differential diagnosis of lumbar subcutaneous abscesses, even if the neurocutaneous signatures are located off the midline. PMID- 23025447 TI - Introduction: neural tube defects. PMID- 23025448 TI - Chemiluminescence switching on peroxidase-like Fe3O4 nanoparticles for selective detection and simultaneous determination of various pesticides. AB - To achieve selectivity in direct chemiluminescence (CL) detection is very significant and a great challenge as well. Here, we report a novel concept of developing intrinsically selective CL switching at the surface of Fe(3)O(4) nanoparticles for the sensitive detection and simultaneous determination of various pesticides. Fe(3)O(4) nanoparticles have peroxidase-like catalytic activity and catalyze the decomposition of dissolved oxygen to generate superoxide anions, so that the CL intensity of luminol was amplified by at least 20 times. The CL signals can be quenched by the addition of ethanol because ethanol readily reacts with superoxide anions as a radical scavenger. However, the quenching effect can be inhibited through the specific binding of target molecules on Fe(3)O(4) nanoparticles, leading to CL "turn-on" in the presence of ethanol. The novel CL "switching-on" concept demonstrated unique advantages in the detection of pesticide residues. Using the surface coordinative reactions, nonredox pesticide ethoprophos were sensitively detected with a detection limit of 0.1 nM and had a very wide detection range of 0.1 nM to 100 MUM. More importantly, the selectivity of CL switching is tunable through the special surface modification of Fe(3)O(4) nanoparticles, and these Fe(3)O(4) nanoparticles with different surface groups can generate unique CL response pattern for the simultaneous determination of various pesticides. Meanwhile, the superparamagnetic properties of Fe(3)O(4) nanoparticles provide a simple magnetic separation approach to attain interference-free measurement for real detection. The very facile and versatile strategy reported here should open a new window to exploration of selective CL molecular switching and application of magnetic nanoparticles for chemo/biodetection. PMID- 23025449 TI - Children with severe or moderate obstructive sleep apnoea syndrome show a high incidence of persistence after adenotonsillectomy. AB - CONCLUSION: Persistent obstructive sleep apnoea syndrome (OSAS) occurs in approximately 20% of normal-weight children after adenotonsillectomy (T&A) and, in nearly 70% of them, it is caused by adenoid regrowth. Patients with severe or moderate OSAS showed a high incidence of persistent disease even after T&A. Allergic disease, severity and large adenoid size are associated with adenoid regrowth and persistent disease. OBJECTIVES: To investigate factors contributing to persistent OSAS and adenoid regrowth after T&A in normal-weight children. METHODS: This was a prospective, observational study at a single institute and involved 49 normal-weight children with severe or moderate OSAS (apnoea-hypopnoea index, AHI, >= 5) who underwent T&A. Background information, nasal endoscopic data and pre- and postoperative polysomnographic data were collected. A third polysomnography (PSG) was performed 1.5 year postoperatively in children who subsequently developed symptoms of sleep disturbance. RESULTS: Thirteen children (27%, 13/49) were symptomatic 1.5 years after T&A. Allergic rhinitis (38.5% vs 11.1%, p = 0.03) and allergic disease (69.2% vs 30.6%, p = 0.02) were seen more frequently in these children. A third PSG confirmed persistent disease (AHI >= 5) in nine children (18.4%, 9/49). Six children (12.2%, 6/49) were diagnosed as having adenoid regrowth and three (6.1%, 3/49) underwent revision adenoidectomy. PMID- 23025450 TI - Homeopathy for mental fatigue: lessons from a randomized, triple blind, placebo controlled cross-over clinical trial. AB - BACKGROUND: Difficulty in controlling attention can lead to mental fatigue in the healthy population. We identified one trial reporting a benefit in patients' attention using a homeopathic formula preparation. One component of the preparation was potassium phosphate, widely available off the shelf as Kali phos 6x for cognitive problems. The aim of this exploratory trial was to assess the effectiveness of Kali phos 6x for attention problems associated with mental fatigue. METHODS: We recruited student and staff volunteers (University of York) with self-reported mental fatigue, excluding any using homeopathy or prescribed stimulants, or with a diagnosis of chronic fatigue syndrome. In a triple blind, cross-over, placebo-controlled clinical trial, 86 volunteers were randomized to receive Kali phos 6x or identical placebo 10 minutes before taking a psychological test of attention (Stroop Colour-Word Test). One week later they were crossed over and took the other preparation before repeating the test. RESULTS: We found no evidence of a treatment effect in a comparison of Kali phos 6x with placebo (Kali phos minus placebo = -1.1 (95% CI -3.0 to 0.9, P = 0.3) Stroop score units, Cohen effect size = -0.17) even when allowing for a weak period effect with accuracy scores in the second period being higher than those in the first (P = 0.05). We observed a ceiling effect in the Stroop test which undermined our ability to interpret this result. CONCLUSIONS: Kali phos 6x was not found to be effective in reducing mental fatigue. A ceiling effect in our primary outcome measure meant that we could not rule out a type II error. Thorough piloting of an adequate outcome measure could have led to an unequivocal result. CURRENT CONTROLLED TRIALS: ISRCTN16521161. PMID- 23025451 TI - Prevalence and COPD phenotype for a suboptimal peak inspiratory flow rate against the simulated resistance of the Diskus(r) dry powder inhaler. AB - BACKGROUND: Patients who exhibit a suboptimal peak inspiratory flow rate (PIFR) against the resistance (resist) of a dry powder inhaler (DPI) may not be able to effectively inhale the medication into their lower respiratory tract. PIFRresist was measured using the In-Check DIAL((r)) to simulate the resistance of the Diskus((r)) DPI in patients with chronic obstructive pulmonary disease (COPD) who were >= 60 years of age and had forced expiratory volume in 1 sec (FEV1) of <= 50% predicted. Our objectives were to: establish the prevalence of a suboptimal PIFRresist (< 60 L/min) in this population; identify a phenotype of patients with COPD who exhibit a suboptimal PIFRresist; and assess test-retest reliability of PIFRresist. METHODS: PIFRresist and inspiratory capacity (IC) were measured after spirometry was performed in patients with advanced COPD. Repeat measurement of PIFRresist was performed in a subset of patients who returned for scheduled follow-up appointments. RESULTS: The prevalence of a PIFRresist of <60 L/min was 19% among 213 patients. The clinical phenotype of these 41 patients included predominantly female gender (80%), shorter height, and lower values for forced vital capacity (FVC) and IC as percentage predicted compared with the 172 patients with PIFRresist of > 60 L/min. Multivariate regression analysis performed on all patients demonstrated that age, gender, height, FVC % predicted, and IC % predicted were independent predictors of PIFRresist (R(2)=36%). Repeat testing showed no difference between the PIFRresist values. CONCLUSIONS: Approximately one out of five patients with advanced COPD and >= 60 years of age exhibited a suboptimal PIFRresist against the Diskus. For the first time, a clinical phenotype of such patients with a suboptimal PIFRresist was identified. It is reasonable to measure a patient's PIFR against the simulated resistance of a specific DPI if there is concern about clinical benefit using the dry powder medication. PMID- 23025452 TI - In vitro tests for aerosol deposition. III: effect of inhaler insertion angle on aerosol deposition. AB - BACKGROUND: Inhaler orientation with respect to a patient's mouth may be an important variable determining the efficiency of aerosol lung delivery. The effect of insertion angle on regional deposition was evaluated for a series of inhalers using concurrent in vitro and computational fluid dynamics (CFD) analysis. METHODS: Geometrically realistic physical mouth-throat (MT) and upper tracheobronchial (TB) models were constructed to connect different inhalers at a series of insertion angles relative to the horizontal plane of the model. These models were used to assess albuterol sulfate deposition from the Novolizer((r)) dry powder inhaler (DPI), Proventil((r)) HFA pressurized metered dose inhaler (MDI), and Respimat((r)) Soft MistTM Inhaler (SMI) following the actuation of a single dose. Drug deposition from Novolizer DPI was studied for Salbulin((r)) and an experimental "drug only" formulation. Albuterol sulfate was recovered and quantified from the device and the MT and TB regions. RESULTS: Significant differences in MT and total lung dose (TLD) of albuterol sulfate deposition were not observed for Salbulin Novolizer DPI and Respimat SMI inserted at different angles. In contrast, drug-only Novolizer DPI and Proventil HFA MDI showed a significant difference in MT and TLD deposition using different insertion angles. For drug-only Novolizer DPI and Proventil HFA MDI, the lowest and the highest MT depositions were observed at +10 degrees and -20 degrees , respectively; for Respimat SMI and Salbulin Novolizer DPI, these angles were -10 degrees and +10 degrees , and +20 degrees and -20 degrees , respectively. CFD simulations were in agreement with the experimental results and illustrated shifts in local particle deposition associated with changes in insertion angle. CONCLUSION: The effect of inhaler orientation at the inhaler-mouth interface on MT aerosol deposition appeared to be dependent on velocity, aerosol size, and formulation. These findings not only demonstrate the need for patient education on correct inhaler orientation, but provide important new methods for those designing new inhalers. PMID- 23025453 TI - Tiotropium inhaler devices: seeking convenience when mortality is at stake? PMID- 23025454 TI - Vitamin and antioxidant rich diet increases MLH1 promoter DNA methylation in DMT2 subjects. AB - BACKGROUND: Oxidative stress may lead to an increased level of unrepaired cellular DNA damage, which is discussed as one risk for tumor initiation. Mismatch repair (MMR) enzymes act as proofreading complexes that maintain the genomic integrity and MMR-deficient cells show an increased mutation rate. One important gene in the MMR complex is the MutL homolog 1 (MLH1) gene. Since a diet rich in antioxidants has the potential to counteract harmful effects by reactive oxygen species (ROS), we investigated the impact of an antioxidant, folate, and vitamin rich diet on the epigenetic pattern of MLH1. These effects were analyzed in individuals with non-insulin depended diabetes mellitus type 2 (NIDDM2) and impaired fasting glucose (IFG). METHODS: In this post-hoc analysis of a randomized trial we analyzed DNA methylation of MLH1, MSH2, and MGMT at baseline and after 8 weeks of intervention, consisting of 300 g vegetables and 25 ml plant oil rich in polyunsaturated fatty acids per day. DNA methylation was quantified using combined bisulfite restriction enzyme analysis (COBRA) and pyrosequencing. MLH1 and DNMT1 mRNA expression were investigated by qRT-PCR. DNA damage was assessed by COMET assay. Student's two-tailed paired t test and one-way ANOVA with Scheffe corrected Post hoc test was used to determine significant methylation and expression differences. Two-tailed Pearson test was used to determine correlations between methylation level, gene expression, and DNA strand break amount. RESULTS: The intervention resulted in significantly higher CpG methylation in two particular MLH1 promoter regions and the MGMT promoter. DNA strand breaks and methylation levels correlated significantly. The expression of MLH1, DNMT1, and the promoter methylation of MSH2 remained stable. CpG methylation levels and gene expression did not correlate. CONCLUSION: This vitamin and antioxidant rich diet affected the CpG methylation of MLH1. The higher methylation might be a result of the ROS scavenging antioxidant rich diet, leading to lower activity of DNA demethylating enzymes. Our results suggest the hypothesis of CpG demethylation via DNA repair enzymes under these circumstances. NIDDM2 and IFG patients benefit from this simple dietary intervention involving epigenetic and DNA repair mechanisms. PMID- 23025456 TI - Estimates of biological variation in routinely measured biochemical analytes in clinically healthy dogs. AB - BACKGROUND: The degree of biological variation in routinely measured concentrations and activities of biochemical analytes has not been well defined in client-owned pet dogs. OBJECTIVES: The aim of this study was to define indices of biological variation and, where appropriate, indices of individuality and critical change values for routinely measured serum biochemical analytes in a group of clinically healthy dogs owned and housed privately. METHODS: A prospective cohort study was conducted. Serum samples obtained from clinically healthy adult dogs at varying intervals over a 12-week period were analyzed. For each sample, a panel of 14 analytes was measured. Three levels of outlier analyses were applied (analytical, intra-individual, and inter-individual), followed by nested ANOVA to calculate intra-individual, inter-individual, and analytical coefficients of variation (CV(I), CV(G), and CV(A), respectively). RESULTS: Specimens from 11 dogs were analyzed. Individuality indices ranged from 0.9 for glucose and total triglyceride concentrations to 3.4 for ALT activity. Analytical variation (CV(A) ) was > 1/2 CV(I) for 9/14 analytes, failing to meet criteria for acceptable analytical variation when defining critical change values. Where analyzer performance was acceptable, critical change values ranged from 26.4% for glucose concentration to 84.0% for total triglyceride concentration. CONCLUSIONS: Many frequently measured analytes included in routine serum biochemical panels have high individuality. Thus, use of standard reference intervals to monitor changes over time in an individual is likely to miss meaningful biological change. PMID- 23025455 TI - Brain antioxidant status in a high pressure-induced rat model of glaucoma. AB - PURPOSE: The goal of the present study is to establish the antioxidant status in the brain of a high pressure-induced rat model. METHODS: Ocular hypertension was induced in rats (n = 12) cauterizing two episcleral veins under a surgical microscope. A sham procedure (n = 12) was performed in the control group. The markers evaluated in the brain 7 days after surgery were as follows: spontaneous chemiluminescence, protein carbonylation, nitrite concentration, total reactive antioxidant potential (TRAP), ascorbic acid, glutathione, vitamin E and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase. RESULTS: Chemiluminescence in glaucoma was 55% higher than in controls (393 +/- 20 cpm/mg protein, p < 0.001). Protein carbonylation in glaucoma was 93% higher than in controls (1.15 +/- 0.18 nmol/mg protein, p < 0.001). Nitrite concentration was 5.30 +/- 0.25 MUM for glaucoma (controls 4.41 +/- 0.24 MUM, p < 0.05). Total reactive antioxidant potential decreased by 42% in glaucoma (controls 153 +/- 14 MUM Trolox, p < 0.001). Ascorbic acid was 67 +/- 26 MUM for glaucoma (controls 275 +/- 22 MUM, p < 0.001). Vitamin E was 0.58 +/- 0.05 MUmol/g organ for glaucoma (controls 1.10 +/- 0.06 MUmol/g organ, p < 0.01). Glutathione was 1.98 +/- 0.13 MUmol/g organ for glaucoma (controls 8.19 +/- 0.71 MUmol/g organ, p < 0.001). Superoxide dismutase and GPx were increased in glaucoma by 42 and 59%, respectively (p < 0.05). CONCLUSIONS: Reactive oxygen and nitrogen species were increased in glaucoma, the increase in chemiluminescence, protein carbonylation and nitrite levels could be evidenced by this situation. The decrease in nonenzymatic antioxidants and a compensatory increase in SOD and GPx activity may have been a consequence of an increase in oxidative processes. PMID- 23025457 TI - Migration route estimation of the Jeju striped field mouse Apodemus agrarius chejuensis (Rodentia, Muridae). AB - The taxonomic relationship between two Korean field mice species, Apodemus agrarius coreae and A. a. chejuensis, as well as their possible historic migration routes, was examined by molecular genetic analysis of the complete mitochondrial cytochrome b gene of 73 mice collected from the Korean Peninsula and Jeju Island. Our findings suggest that A. a. coreae and A. a. chejuensis populations expanded and dispersed rapidly. Bayesian and network analysis showed that A. a. chejuensis is a clearly distinct population, and that A. a. chejuensis originated from the ancestral lineage of A. a. coreae. Based on our data, we hypothesize that the A. a. coreae population originated from eastern China or elsewhere. After the last glacial epoch, the lineage isolated from A. a. coreae had adapted to the new environment of Jeju Island, and with the reproductive isolation caused by the geographic barrier, this lineage eventually became a distinct population. PMID- 23025458 TI - Modulation of inflammation by mesenchymal stem cell transplantation in peritoneal dialysis in rats. AB - AIM: The purpose of this study was to determine the effect of mesenchymal stem cell (MSC) transplantation on the peritoneal morphology and inflammation markers in rat models of peritoneal dialysis (PD). MATERIALS AND METHODS: Wistar albino rats were divided into two groups: control (C) (n = 8) and experimental groups (n = 50). PD solution was given to the experimental group during 6 weeks. Then, experimental group was divided into three groups as PD, MSC, and placebo (P) groups. MSC group was treated with MSC (1.5 * 10(6) cells/kg) and P group was treated with phosphate buffer solution via intraperitoneal injection. Evaluation was performed to C and PD groups at the end of 6 weeks and to MSC and P groups at second and third week of the treatment (MSC-2, P-2, MSC-3, and P-3 groups). RESULTS: The submesothelial area was significantly thickened in PD and P groups compared to C and MSC groups. Peritoneal fibrosis was seen in P-3 group but not in MSC group. There were no significant differences between the MSC-3 and C groups according to morphological findings. Levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were significantly increased in MSC-2 group compared to the other groups (p-values ranged from 0.0001 to 0.04). TNF-alpha and IL-6 levels in MSC-3 and P-3 groups were lower than PD and C groups (p < 0.0001 for TNF-alpha and p = 0.0001-0.002 for IL-6). CONCLUSION: Giving MSC may protect the peritoneal membrane from the deleterious effect of PD and extend the life of the peritoneal membrane. Our study is the first on this issue and more detailed studies are needed. PMID- 23025459 TI - Molecular determinants of platelet delta storage pool deficiencies: an update. AB - Delta storage pool deficiency (delta-SPD) is a rare heterogeneous group of platelet disorders characterized by a reduction in the number or content of dense granules. delta-SPD causes a mild to moderate bleeding diathesis characterized mainly by mucocutaneous bleeding. Currently, no specific treatment is available and the therapeutic approach is based on prevention of excessive bleeding. However, during the last few years, important insights into the pathophysiology of delta-SPD have been achieved using mouse models and dense granule deficiency associated congenital diseases, such as Hermansky-Pudlak syndrome and Chediak Higashi syndrome. It thus appears that delta-SPD represents a genetically heterogeneous group of intracellular vesicle biogenesis and/or trafficking disorders. This review summarizes recent data regarding the molecular mechanisms together with clinical features of the different types of delta-SPD. Although the molecular basis of isolated inherited delta-SPD remains currently unknown, next generation sequencing strategies should enable researchers to identify the causative genes. Identification of those genes should contribute to our understanding of the pathophysiology, represent useful tools for genetic diagnosis, and eventually lead to new specific therapeutic approaches. PMID- 23025460 TI - Organic-inorganic hybrid mesoporous polymers fabricated by using (CTA)2S2O8 as self-decomposed soft templates. AB - Organic-inorganic hybrid mesoporous polymers were successfully synthesized by using a template-directed free radical polymerization technique in aqueous solution at 0-5 degrees C with oxidative complexes as self-decomposed soft templates. The oxidative complexes ((CTA)(2)S(2)O(8)), which were formed between anionic oxidant (S(2)O(8)(2-)) and cationic surfactant (cetyltrimethylammonium bromide, CTAB) at 0-5 degrees C, can be automatically decomposed due to the reduction of S(2)O(8)(2-). No additional treatment was needed to remove the templates. The reactive functional monomer, 3-(trimethoxysilyl)propyl methacrylate (TMSPMA), was used as main monomer. Styrene was used as the comonomer. With simultaneous free radical copolymerization of TMSPMA and styrene, condensation of methoxysilyl groups, and the self-decomposition of (CTA)(2)S(2)O(8), organic-inorganic hybrid mesoporous polymers were successfully obtained. The mesoporous structures and morphologies of the resultant hybrid mesoporous polymers were found to be strongly dependent on the feed amounts of TMSPMA and styrene. In the absence of styrene, the hybrid polymer PTMSPMA exhibited mesh-like bicontinuous structures with mesopores and high surface area (335 m(2)/g). With the incorporation of styrene, mesoporous nanoparticles were obtained. The surface areas of the mesoporous nanoparticles decreased with the increase of styrene contents. The adsorption capabilities of such mesoporous polymers for organic dye (Congo red) and protein (bovine serum albumin) were also studied. PMID- 23025461 TI - Considerations underlying the use of mixed group validation. AB - Mixed Group Validation (MGV) is an approach for estimating the diagnostic accuracy of tests. MGV is a promising alternative to the more commonly used Known Groups Validation (KGV) approach for estimating diagnostic accuracy. The advantage of MGV lies in the fact that the approach does not require a perfect external validity criterion or gold standard. However, the research designs where MGV is most appropriate have not been thoroughly explored. We give a brief description of the ideal research design to minimize error for MGV studies, test whether the MGV assumptions hold with clinical data, evaluate whether there is evidence of assumption violation among published MGV studies, give a practical description of the MGV assumptions, and describe an example of an optimal use of MGV. Ultimately, we conclude that MGV is not generally superior to KGV but may be used in some cases where the assumptions and standard error have been considered appropriately. PMID- 23025462 TI - Facile and general preparation of multifunctional main-chain cationic polymers through application of robust, efficient, and orthogonal click chemistries. AB - Poly(beta-hydroxyl amine)s are prepared from readily available small molecular building blocks at ambient conditions. These macromolecules can be transformed into main-chain cationic polymers upon quaternization of the backbone amine units. The modular and mild nature of the synthesis allows for incorporation of multiple (2-4) chemically distinct reactive sites in the polymer chain. Modifications of the reactive sites afford multifunctional polymers with tunable properties. The orthogonal nature of the involved chemistries sets the synthetic pathway free from any functional group protection/deprotection requirements. This feature also allows for alteration of the modification sequence. PMID- 23025463 TI - Multiresidue automated turbulent flow online LC-MS/MS method for the determination of antibiotics in milk. AB - A fast and reliable multiresidue method is reported for the identification and quantification of 36 different compounds from seven different classes of antibiotics (aminoglycosides, sulfonamides, macrolides, quinolones, tetracyclines, lincosamides and trimethoprim) in milk. Automated online sample cleanup was applied using turbulent flow chromatography (Transcend TLX system), directly coupled to a mass spectrometer (MS/MS) for sensitive and specific detection. The method involved a simple extraction/protein precipitation using acetonitrile, followed by centrifugation and filtration. After this preliminary step, the extract was injected into the TLX-ESI-MS/MS using optimised turbulent flow and liquid chromatography (LC) conditions. Single-laboratory validation of the method was carried out according to the Directive 2002/657/EC, clearly demonstrating the suitability of this method for quantitative determination of this wide range of antibiotics in milk. A small survey, which covered milk samples of different origin and varied fat content, demonstrated the robustness of this method and its suitability for enforcement purposes. PMID- 23025464 TI - Synthesis of rubrolide analogues as new inhibitors of the photosynthetic electron transport chain. AB - Many natural products have been used as a model for the development of new drugs and agrochemicals. Following this strategy 11 rubrolide analogues, bearing electron-withdrawing and -donating groups at both benzene rings, were prepared starting from commercially available mucobromic acid. The ability of all compounds to inhibit the photosynthetic electron transport chain in the chloroplast was investigated. The rubrolide analogues were effective in interfering with the light-driven ferricyanide reduction by isolated chloroplasts. The IC(50) values of the most active derivatives are in fact only 1 order of magnitude higher than those of commercial herbicides sharing the same mode of action, such as Diuron (0.27 MUM). QSAR studies indicate that the most efficient compounds are those having higher ability to accept electrons, either by a reduction process or by an electrophilic reaction mechanism. The results obtained suggest that the rubrolide analogues represent promising candidates for the development of new active principles targeting photosynthesis to be used as herbicides. PMID- 23025465 TI - The influence of narrative risk communication on feelings of cancer risk. AB - OBJECTIVE: Evidence is accumulating for the importance of feelings of risk in explaining cancer preventive behaviours, but best practices for influencing these feelings are limited. The aim of this experimental study was to compare the effects of narrative and non-narrative risk communication about sunbed use on ease of imagination and feelings of cancer risk. DESIGN AND METHODS: A total of 233 female sunbed users in the general Dutch population were randomly assigned to one of three conditions: a narrative message (i.e., personal testimonial), a non narrative cognitive message (i.e., factual risk information using cognitive-laden words), or a non-narrative affective message (i.e., factual risk information using affective-laden words). Ease of imagination and feelings of risk were assessed directly after the risk information was given (T1). Three weeks after the baseline session, feelings of risk were measured again (T2). RESULTS: The results revealed that sunbed users who were exposed to narrative risk information could better imagine themselves developing skin cancer and reported higher feelings of skin cancer risk at T1. Moreover, ease of imagination mediated the effects of message type on feelings of risk at T1 and T2. CONCLUSION: The findings provide support for the effects of narrative risk communication in influencing feelings of cancer risk through ease of imagination. Cancer prevention programmes may therefore benefit from including narrative risk information. Future research is important to investigate other mechanisms of narrative information and their most effective content and format. STATEMENT OF CONTRIBUTION: What is already known on this subject? Evidence is growing for the importance of feelings of risk in explaining cancer preventive behaviours. Narratives have increasingly been considered as an effective format for persuasive risk messages and studies have shown narrative risk communication to be effective in influencing cognitive risk beliefs. What does this study add? Increasing understanding of how feelings of cancer risk can be influenced since best practices for influencing these feelings are limited. Extending knowledge about the underlying mechanisms of narrative effects on feelings of cancer risk (i.e., the mediating role of ease of imagination) using a non-student sample. The findings provide support for the effects of narrative risk communication in influencing feelings of cancer risk through ease of imagination. PMID- 23025466 TI - Clinical accuracy for diagnosis of antiphospholipid syndrome in systemic lupus erythematosus: evaluation of 23 possible combinations of antiphospholipid antibody specificities. AB - OBJECTIVES: To evaluate the clinical accuracy of antiphospholipid antibody (aPL) specificities both individually and/or in combination, in a wide cohort of systemic lupus erythematosus (SLE) patients in an attempt to identify a panel of tests that may provide the best accuracy for diagnosing antiphospholipid syndrome (APS). PATIENTS AND METHODS: This study included 230 patients (218 women, mean age 42.7 +/- 11.9 years, mean disease duration 12.2 +/- 8.7 years), all fulfilling the 1982 criteria for SLE. All patients were tested for lupus anticoagulant (LA), anti-cardiolipin (aCL), anti-beta(2) glycoprotein I (anti beta2GPI), solid phase anti-prothrombin (aPT), anti phosphatidylserine/prothrombin (aPS/PT), and anti-phosphatidylethanolamine (aPE) antibodies. Sensitivity, specificity and predictive values were calculated. The diagnostic accuracy for each combination of tests was assessed by ROC and their area under the curve analysis as well as by the Youden's index (YI). RESULTS: Testing for six aPL derived 23 possible combinations of results. Among them, LA + anti-beta(2)GPI + aPS/PT had the best diagnostic accuracy for APS as a whole and individually for both thrombosis and pregnancy loss (AUC 0.712, OR 3.73 [95% CI 1.82-5.38], P = 0.0001, YI = 0.32 and AUC 0.709, OR 3.75 [95% CI 2.13-6.62], P = 0.0001, YI = 0.37 and AUC 0.677, OR 4.82 [95% CI 2.17-10.72], P = 0.0007, YI = 0.38, respectively) and the best specificity when compared with all the other obtainable combination of tests. Triple positivity for LA + anti-beta(2)GPI + aPS/PT was more strongly associated with clinical events (thrombosis and/or PL) when compared with double or single positivity (OR 23.2 [95% CI 2.57-46.2] vs. OR 7.3 [95% CI 2.21-25.97], OR 5.7 [95% CI 2.12-17.01] or OR 3.11 [95% CI 1.56-7.8] for single positivity for LA, aPS/PT and anti-beta(2)GPI, respectively). CONCLUSIONS: Combining LA, anti-beta(2)GPI and aPS/PT improves the diagnostic power and helps in stratifying the risk for each patient, according to their aPL profile. PMID- 23025467 TI - Longevity of implant crowns and 2-unit cantilevered resin-bonded bridges. AB - OBJECTIVE: To compare "survival" and "success" of implant-supported crowns (ISC) and tooth-supported 2-unit cantilevered resin-bonded bridges (cRBB) in the rehabilitation of a bounded single tooth space (BSTS), after an observation period of >=5 years. METHODS: A case-control study among subjects who received ISC or cRBB rehabilitation at a teaching hospital. The (i) survival (retention in mouth) and (ii) success (absence of complications requiring intervention) for the ISCs and cRBBs were compared (overall, supporting structures and that of the prostheses). Rates of survival and success were compared using log-rank statistics. Prevalence of survival and success (categories) were compared by chi square/Fisher's exact test. RESULTS: Seventy eight subjects participated in this study (39 ISC and 39 cRBB cases). Both had a mean observation time exceeding 100 months, P > 0.05. ISCs and cRBBs had similar survival rates: overall (P = 0.96), supporting structures (P = 0.14) and prostheses (P = 0.44) There was a significant difference in the rate of overall success between ISCs and cRBBs (P = 0.03), specifically with respect to the success rate of the supporting structures (P = 0.03). There was also a significant difference in the prevalence of supporting structures categorized as a "success": ISCs (69.2%) and cRBBs (89.7%), P = 0.03. Biological complications of supporting structures were more common among ISCs (25.6%) compared with cRBBs (7.7%), P = 0.03. CONCLUSION: Implant supported crowns and cRBBs in the rehabilitation of a BSTS survive similarly after at least 5 years. However, cRBBs had a higher success rate and were more frequently categorized as successful than ISCs. Notably, there were fewer biological complications of cRBBs supporting structures than ISCs. PMID- 23025468 TI - Diastereoselective multicomponent reaction in water: synthesis of 2 azapyrrolizidine alkaloid analogues. AB - Synthesis of the 2-aza analogues of the pyrrolizidine alkaloid motif with two contiguous stereocenters has been achieved with high regio-, chemo-, and diastereoselectivity by an innovative multicomponent reaction in water. This elegant tactic has integrated the principles of privileged substructure-based Diversity Oriented Synthesis (pDOS) and Biology Oriented Synthesis (BIOS) to access a biologically relevant scaffold. PMID- 23025470 TI - The genetic basis of mood and anxiety disorders - changing paradigms. AB - Family, twin and epidemiologic studies all point to an important genetic contribution to the risk to develop mood and anxiety disorders. While some progress has been made in identifying relevant pathomechanisms for these disorders, candidate based strategies have often yielded controversial findings. Hopes were thus high when genome-wide genetic association studies became available and affordable and allowed a hypothesis-free approach to study genetic risk factors for these disorders. In an unprecendented scientific collaborative effort, large international consortia formed to allow the analysis of these genome-wide association datasets across thousands of cases and controls ([1] and see also http://www.broadinstitute.org/mpg/ricopili/). Now that large meta analyses of genome-wide association studies (GWAS) have been published for bipolar disorder and major depression it has become clear that main effects of common variants are difficult to identify in these disorders, suggesting that additional approaches maybe needed to understand the genetic basis of these disorders [2,3]. PMID- 23025469 TI - Role of physiological levels of 4-hydroxynonenal on adipocyte biology: implications for obesity and metabolic syndrome. AB - Lipid peroxidation products such as 4-hydroxynonenal (HNE) are known to be increased in response to oxidative stress, and are known to cause dysfunction and pathology in a variety of tissues during periods of oxidative stress. The aim of the current study was to determine the chronic (repeated HNE exposure) and acute effects of physiological concentrations of HNE toward multiple aspects of adipocyte biology using differentiated 3T3-L1 adipocytes. Our studies demonstrate that acute and repeated exposure of adipocytes to physiological concentrations of HNE is sufficient to promote subsequent oxidative stress, impaired adipogenesis, alter the expression of adipokines, and increase lipolytic gene expression and subsequent increase in free fatty acid (FFA) release. These results provide an insight in to the role of HNE-induced oxidative stress in regulation of adipocyte differentiation and adipose dysfunction. Taken together, these data indicate a potential role for HNE promoting diverse effects toward adipocyte homeostasis and adipocyte differentiation, which may be important to the pathogenesis observed in obesity and metabolic syndrome. PMID- 23025471 TI - Incidence of cancer among residents of high temperature geothermal areas in Iceland: a census based study 1981 to 2010. AB - BACKGROUND: Residents of geothermal areas are exposed to geothermal emissions and water containing hydrogen sulphide and radon. We aim to study the association of the residence in high temperature geothermal area with the risk of cancer. METHODS: This is an observational cohort study where the population of a high temperature geothermal area (35,707 person years) was compared with the population of a cold, non-geothermal area (571,509 person years). The cohort originates from the 1981 National Census. The follow up from 1981 to 2010 was based on record linkage by personal identifier with nation-wide death and cancer registries. Through the registries it was possible to ascertain emigration and vital status and to identify the cancer cases, 95% of which had histological verification. The hazard ratio (HR) and 95% confidence intervals (CI) were estimated in Cox-model, adjusted for age, gender, education and housing. RESULTS: Adjusted HR in the high-temperature geothermal area for all cancers was 1.22 (95% CI 1.05 to 1.42) as compared with the cold area. The HR for pancreatic cancer was 2.85 (95% CI 1.39 to 5.86), breast cancer 1.59 (95% CI 1.10 to 2.31), lymphoid and hematopoietic cancer 1.64 (95% CI 1.00 to 2.66), and non-Hodgkins lymphoma 3.25 (95% CI 1.73 to 6.07). The HR for basal cell carcinoma of the skin was 1.61 (95% CI 1.10 to 2.35). The HRs were increased for cancers of the nasal cavities, larynx, lung, prostate, thyroid gland and for soft tissue sarcoma; however the 95% CIs included unity. CONCLUSIONS: More precise information on chemical and physical exposures are needed to draw firm conclusions from the findings. The significant excess risk of breast cancer, and basal cell carcinoma of the skin, and the suggested excess risk of other radiation-sensitive cancers, calls for measurement of the content of the gas emissions and the hot water, which have been of concern in previous studies in volcanic areas. There are indications of an exposure-response relationship, as the risk was higher in comparison with the cold than with the warm reference area. Social status has been taken into account and data on reproductive factors and smoking habits show that these do not seem to explain the increased risk of cancers, however unknown confounding can not be excluded. PMID- 23025472 TI - Mitochondrial dysfunction in aging and longevity: a causal or protective role? AB - SIGNIFICANCE: Among the most highly investigated theories of aging is the mitochondrial theory of aging. The basis of this theory includes a central role for altered or compromised mitochondrial function in the pathophysiologic declines associated with aging. In general, studies in various organisms, including nematodes, rodents, and humans, have largely upheld that aging is associated with mitochondrial dysfunction. However, results from a number of studies directly testing the mitochondrial theory of aging by modulating oxidant production or scavenging in vivo in rodents have generally been inconsistent with predictions of the theory. RECENT ADVANCES: Interestingly, electron transport chain mutations or deletions in invertebrates and mice that causes mitochondrial dysfunction paradoxically leads to enhanced longevity, further challenging the mitochondrial theory of aging. CRITICAL ISSUES: How can mitochondrial dysfunction contribute to lifespan extension in the mitochondrial mutants, and what does it mean for the mitochondrial theory of aging? FUTURE DIRECTIONS: It will be important to determine the potential mechanisms that lead to enhanced longevity in the mammalian mitochondrial mutants. PMID- 23025473 TI - Fluorogenic azidofluoresceins for biological imaging. AB - Fluorogenic probes activated by bioorthogonal chemical reactions can enable biomolecule imaging in situations where it is not possible to wash away unbound probe. One challenge for the development of such probes is the a priori identification of structures that will undergo a dramatic fluorescence enhancement by virtue of the chemical transformation. With the aid of density functional theory calculations reported previously by Nagano and co-workers, we identified azidofluorescein derivatives that were predicted to undergo an increase in fluorescence quantum yield upon Cu-catalyzed or Cu-free cycloaddition with linear or cyclic alkynes, respectively. Four derivatives were experimentally verified in model reactions, and one, a 4-azidonaphthylfluorescein analogue, was further shown to label alkyne-functionalized proteins in vitro and glycoproteins on cells with excellent selectivity. The azidofluorescein derivative also enabled cell imaging under no-wash conditions with good signal above background. This work establishes a platform for the rational design of fluorogenic azide probes with spectral properties tailored for biological imaging. PMID- 23025474 TI - Effects of temporal fine structure stimulation on Mandarin speech recognition in cochlear implant users. AB - CONCLUSION: The investigated experimental coding strategies significantly improved tone identification as compared with the participants' everyday audio processor settings. However, this benefit could not be attributed entirely to temporal fine structure stimulation but seems to be caused by decreasing the lower corner frequency of the filter bank. The 6 week habituation period used in this study might have been too short to allow the listeners to derive additional lexical information from the unfamiliar stimulation patterns. OBJECTIVES: To evaluate a cochlear implant coding strategy that explicitly conveys temporal fine structure information in the context of the tonal language Mandarin. METHODS: The study was designed as a longitudinal, monocentric, prospective, controlled, and randomized cross-over study and included 12 postlingually deafened adults, who were experienced cochlear implant users. Two experimental coding strategies, one of which explicitly presents temporal fine structure information, were compared to the participants' personal TEMPO+ speech processors, which do not convey fine structure information. RESULTS: Both experimental coding strategies improved tone identification by approximately 11 percentage points. This improvement was significant in the female speaker test. Sentence perception, as assessed with the M-HINT test, and quality of life scores were identical with all three coding strategies. PMID- 23025475 TI - The D3 F-box protein is a key component in host strigolactone responses essential for arbuscular mycorrhizal symbiosis. AB - Arbuscular mycorrhiza (AM) represents an ancient endosymbiosis between plant roots and Glomeromycota fungi. Strigolactones (SLs), plant-derived terpenoid lactones, activate hyphal branching of AM fungi before physical contact. Lack of SL biosynthesis results in lower colonization of AM fungi. The F-box protein, DWARF3 (D3), and the hydrolase family protein DWARF14 (D14) are crucial for SL responses in rice. Here we conducted AM fungal colonization assays with the SL insensitive d3 and d14 mutants. The d3 mutant exhibited strong defects in AM fungal colonization, whereas the d14 mutant showed higher AM fungal colonization. As D14 has a homologous protein, D14-LIKE, we generated D14-LIKE knockdown lines by RNA interference in the wildtype and d14 background. D14 and D14-LIKE double knockdown lines exhibited similar colonization rates as those of the d14-1 mutant. D3 is crucial for establishing AM symbiosis in rice, whereas D14 and D14 LIKE are not. Our results suggest distinct roles for these SL-related components in AM symbiosis. PMID- 23025476 TI - Aspartic acid-promoted highly selective and sensitive colorimetric sensing of cysteine in rat brain. AB - Direct selective determination of cysteine in the cerebral system is of great importance because of the crucial roles of cysteine in physiological and pathological processes. In this study, we report a sensitive and selective colorimetric assay for cysteine in the rat brain with gold nanoparticles (Au-NPs) as the signal readout. Initially, Au-NPs synthesized with citrate as the stabilizer are red in color and exhibit absorption at 520 nm. The addition of an aqueous solution (20 MUL) of cysteine or aspartic acid alone to a 200 MUL Au-NP dispersion causes no aggregation, while the addition of an aqueous solution of cysteine into a Au-NP dispersion containing aspartic acid (1.8 mM) causes the aggregation of Au-NPs and thus results in the color change of the colloid from wine red to blue. These changes are ascribed to the ion pair interaction between aspartic acid and cysteine on the interface between Au-NPs and solution. The concentration of cysteine can be visualized with the naked eye and determined by UV-vis spectroscopy. The signal output shows a linear relationship for cysteine within the concentration range from 0.166 to 1.67 MUM with a detection limit of 100 nM. The assay demonstrated here is highly selective and is free from the interference of other natural amino acids and other thiol-containing species as well as the species commonly existing in the brain such as lactate, ascorbic acid, and glucose. The basal dialysate level of cysteine in the microdialysate from the striatum of adult male Sprague-Dawley rats is determined to be around 9.6 +/- 2.1 MUM. The method demonstrated here is facile but reliable and durable and is envisaged to be applicable to understanding the chemical essence involved in physiological and pathological events associated with cysteine. PMID- 23025477 TI - Assessing quality of care in pediatric asthma: applicability of a revised version of the QUOTE-CNSLD questionnaire. AB - AIM: To establish the validity and applicability of a revised version of the QUality Of care Through the patient's Eyes-Chronic Non Specific Lung Disease (QUOTE-CNSLD) instrument in a population of children with controlled and partly controlled asthma. METHODS: Randomized controlled trial evaluating quality of care in three follow-up settings: follow-up by the general practitioner, the pediatrician, and the specialized asthma nurse, for a period of 2 years. RESULTS: One hundred and seven children were recruited, 45 from general practice and 62 from hospital practice. The revised QUOTE-CNSLD instrument completed by parents at baseline (T0), after 1 year (T1) and after 2 years (T2) showed that a process , a structure-, and an asthma-specific domain could be deduced (Cronbach's alpha of 0.81, 0.82, and 0.62). A separate five-item "child-specific" questionnaire about their caregiver, completed by children, has a Cronbach's alpha of 0.88. The revised instrument could discriminate between quality of care in different follow up settings for children with stable asthma, and the asthma-specific domain showed particularly discriminative properties. Quality aspects with potential for improvement could be derived from the scores in all three study groups. CONCLUSION: The revised QUOTE-CNSLD instrument is applicable in a pediatric population with stable asthma and it has discriminative value between different follow-up settings. PMID- 23025478 TI - Mitogenomics reveals two subspecies in Coelomactra antiquata (Mollusca: Bivalvia). AB - The mitochondrial genome sequence of Coelomactra antiquata (Mollusca: Bivalvia) in Zhangzhou (zz-mtDNA) was fully sequenced and compared with that in Rizhao (rz mtDNA) in this study. A tRNA (tRNA (Met) ) located between tRNA (Ala) and cox1 genes was identified in zz-mtDNA but not in rz-mtDNA. The largest non-coding region (NCR; MNR) contained 11 copies 99nt tandem repeat sequences exclusively in rz-mtDNA, while the second largest NCR with 400 bp between tRNA (Ala) and tRNA (Met) in zz-mtDNA was absent in rz-mtDNA. Secondary structures of ZZ and RZ C. antiquata rRNAs are significantly different. The mitochondrial genomic characteristics clearly indicate that there are at least two subspecies in C. antiquata. PMID- 23025479 TI - Activation of caspases-9, -3 and -8 in human platelets triggered by BH3-only mimetic ABT-737 and calcium ionophore A23187: caspase-8 is activated via bypass of the death receptors. AB - Platelet apoptosis and activation have been studied in human platelets treated with BH3-only mimetic ABT-737 and calcium ionophore A23187, agents triggering apoptosis through the intrinsic mitochondrial pathway. Platelet apoptosis was determined as activation of crucial apoptosis-associated caspases, initiator caspase-9 of intrinsic apoptosis pathway, executioner caspase-3 and initiator caspase-8 of extrinsic death receptor pathway, and platelet activation was detected by P-selectin (CD62) exposure on the platelet surface. We found that ABT 737 predominantly induced activation of caspases-9, -3 and -8 rather than CD62 exposure, whereas A23187 induces both caspases activation and CD62 exposure. Caspase-8 activation was stimulated independently of the extrinsic apoptosis pathway via mitochondrial membrane permeabilization and depolarization. These data suggest that (i) caspase-8 activation is triggered in ABT-737- and A23187 treated anucleate platelets through the mitochondria-initiated caspase activation cascade bypassing the death receptors, and (ii) ABT-737-treated platelets are a useful experimental tool for discerning the role of platelet apoptosis in platelet function and survival. PMID- 23025480 TI - Synthesis route to supported gold nanoparticle layered double hydroxides as efficient catalysts in the electrooxidation of methanol. AB - This work describes a new one-step method for the preparation of AuNP/LDH nanocomposites via the polyol route. The novelty of this facile, simple synthesis is the absence of additional reactants such as reductive agents or stabilizer, which gives the possibility to obtain phase-pure systems free of undesiderable effect. The AuNP formation is confirmed by SEM, TEM, PXRD, and XAS; moreover, the electrochemical characterization is also reported. The electrocatalytic behavior of AuNP/LDH nanocomposites has been investigated with respect to the oxidation of methanol in basic media and compared with that of pristine NiAl-Ac. The 4-fold highest catalytic efficiency observed with AuNP/LDH nanocomposites suggests the presence of a synergic effect between Ni and AuNP sites. The combination of these experimental findings with the low-cost synthesis procedure paves the way for the exploitation of the presented nanocomposites materials as catalysts for methanol fuel cells. PMID- 23025481 TI - Visual motion perception predicts driving hazard perception ability. AB - PURPOSE: To examine the basis of previous findings of an association between indices of driving safety and visual motion sensitivity and to examine whether this association could be explained by low-level changes in visual function. METHODS: A total of 36 visually normal participants (aged 19-80 years) completed a battery of standard vision tests including visual acuity, contrast sensitivity and automated visual fields and two tests of motion perception including sensitivity for movement of a drifting Gabor stimulus and sensitivity for displacement in a random dot kinematogram (Dmin ). Participants also completed a hazard perception test (HPT), which measured participants' response times to hazards embedded in video recordings of real-world driving, which has been shown to be linked to crash risk. RESULTS: Dmin for the random dot stimulus ranged from -0.88 to -0.12 log minutes of arc, and the minimum drift rate for the Gabor stimulus ranged from 0.01 to 0.35 cycles per second. Both measures of motion sensitivity significantly predicted response times on the HPT. In addition, while the relationship involving the HPT and motion sensitivity for the random dot kinematogram was partially explained by the other visual function measures, the relationship with sensitivity for detection of the drifting Gabor stimulus remained significant even after controlling for these variables. CONCLUSION: These findings suggest that motion perception plays an important role in the visual perception of driving-relevant hazards independent of other areas of visual function and should be further explored as a predictive test of driving safety. Future research should explore the causes of reduced motion perception to develop better interventions to improve road safety. PMID- 23025482 TI - Stereospecific cross-coupling of secondary organotrifluoroborates: potassium 1 (benzyloxy)alkyltrifluoroborates. AB - Potassium 1-(alkoxy/acyloxy)alkyltrifluoroborates have been synthesized through a copper-catalyzed diboration of aldehydes and subsequent conversion of the resulting potassium 1-(hydroxy)alkyltrifluoroborates. The palladium-catalyzed Suzuki-Miyaura reaction employing the potassium 1 (benzyloxy)alkyltrifluoroborates with aryl and heteroaryl chlorides provides access to protected secondary alcohols in high yields. The beta-hydride elimination pathway is avoided through use of the benzyl protecting group, which is proposed to stabilize the diorganopalladium intermediate by coordination of the arene to the metal center. This cross-coupling is stereospecific with complete retention of stereochemistry. PMID- 23025483 TI - Fumagillin-induced aseptic meningoencephalitis in a kidney transplant recipient with microsporidiosis. AB - Microsporidiosis is an opportunistic infection in organ transplant recipients and patients with other cellular immunodeficiency. Fumagillin is an effective treatment against Enterocytozoon bieneusi, one of the two main species causing the microsporidiosis involved in human diseases. We report the first case, to our knowledge, of a probable drug-induced aseptic meningoencephalitis, after administration of fumagillin in a kidney transplant recipient with microsporidiosis. PMID- 23025484 TI - Uncontrolled allergic rhinitis and chronic rhinosinusitis: where do we stand today? AB - State-of-the-art documents like ARIA and EPOS provide clinicians with evidence based treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS), respectively. The currently available medications can alleviate symptoms associated with AR and RS. In real life, a significant percentage of patients with AR and CRS continue to experience bothersome symptoms despite adequate treatment. This group with so-called severe chronic upper airway disease (SCUAD) represents a therapeutic challenge. The concept of control of disease has only recently been introduced in the field of AR and CRS. In case of poor control of symptoms despite guideline-directed pharmacotherapy, one needs to consider the presence of SCUAD but also treatment-related, diagnosis-related and/or patient related factors. Treatment-related issues of uncontrolled upper airway disease are linked with the correct choice of treatment and route of administration, symptom-oriented treatment and the evaluation of the need for immunotherapy in allergic patients. The diagnosis of AR and CRS should be reconsidered in case of uncontrolled disease, excluding concomitant anatomic nasal deformities, global airway dysfunction and systemic diseases. Patient-related issues responsible for the lack of control in chronic upper airway inflammation are often but not always linked with adherence to the prescribed medication and education. This review is an initiative taken by the ENT section of the EAACI in conjunction with ARIA and EPOS experts who felt the need to provide a comprehensive overview of the current state of the art of control in upper airway inflammation and stressing the unmet needs in this domain. PMID- 23025486 TI - Survey of deoxynivalenol and its conjugates deoxynivalenol-3-glucoside and 3 acetyl-deoxynivalenol in 374 beer samples. AB - Beer is one of the most popular beverages worldwide. Malted cereal grains are among the basic ingredients and hence mycotoxin contamination might occur. Previous studies reported the presence of the Fusarium mycotoxins deoxynivalenol (DON) and 3-acetyl-deoxynivalenol (3ADON), as well as of the masked mycotoxin deoxynivalenol-3-glucoside (D3G) in beer. In the present survey, 374 beer samples from 38 countries with a focus on Austrian (156) and German (64) beers were analysed for the presence of D3G, DON and 3ADON. Beers were assigned to the following six categories: pale (217), wheat (46), dark (47), bock (20), nonalcoholic beers (19) and shandies (25). In total, 348 and 289 beers (93 and 77%, respectively) contained D3G and DON at the levels above the limit of detection, whereas 3ADON was not detected in any of the samples. Average concentrations of all beers were 6.9 ug L(-1) for D3G and 8.4 ug L(-1) in the case of DON. Nonalcoholic beers and shandies showed the lowest contaminations, 1.5 and 3.2 ug L(-1) for D3G and 2.7 and 4.4 ug L(-1) for DON, respectively. In bock beers characterised by a higher gravity, a significant trichothecene load of 14.8 ug L(-1) D3G and 12.4 ug L(-1) DON was found. The highest contamination (81 ug L(-1) D3G, 89 ug L(-1) DON) was detected in a pale beer from Austria, underlining the importance of this study for food safety. The molar D3G to DON ratio ranged between 0.11 and 1.25 and was 0.56 on average. Concluding, the average contamination of beer is not of toxicological concern for moderate beer drinkers. However, in the case of heavy beer drinkers, beer consumption may considerably contribute to the overall intake of DON, which might even lead to exceeding the maximum tolerable limits established for this Fusarium toxin. PMID- 23025485 TI - Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis. AB - Human IgG Fc glycosylation modulates immunological effector functions such as antibody-dependent cellular cytotoxicity and phagocytosis. Engineering of Fc glycans therefore enables fine-tuning of the therapeutic properties of monoclonal antibodies. The N-linked glycans of Fc are typically complex-type, forming a network of noncovalent interactions along the protein surface of the Cgamma2 domain. Here, we manipulate the mammalian glycan-processing pathway to trap IgG1 Fc at sequential stages of maturation, from oligomannose- to hybrid- to complex type glycans, and show that the Fc is structurally stabilized following the transition of glycans from their hybrid- to complex-type state. X-ray crystallographic analysis of this hybrid-type intermediate reveals that N-linked glycans undergo conformational changes upon maturation, including a flip within the trimannosyl core. Our crystal structure of this intermediate reveals a molecular basis for antibody biogenesis and provides a template for the structure guided engineering of the protein-glycan interface of therapeutic antibodies. PMID- 23025487 TI - How do erythrocytes contribute to the ABTS* scavenging capacity of blood? AB - It has been suggested lately that erythrocytes contribute significantly to the oxidant scavenging capacity (OSC) of blood and that surface adsorption of polyphenols enhances the antioxidant capacity of erythrocytes. The aim of this study was to examine the contribution of erythrocytes to the OSC of whole blood measured with a substrate not penetrating into the cells. Comparison of reduction of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical (ABTS*) by whole blood and blood plasma indicates that erythrocytes do contribute to ABTS* reduction but their contribution is lower with respect to plasma. ABTS* reduction by erythrocytes and its enhancement by polyphenols were inhibited by thiol reagents (N-ethylmaleimide and iodacetate). These reagents inhibited also the reduction of extracellular ferricyanide by erythrocytes and its enhancement by polyphenols. On this basis we postulate that the contribution of erythrocytes to the blood OSC estimated by ABTS* decolorization is at least partly due to the transmembrane-reducing system, which activity is routinely assayed by ferricyanide reduction. PMID- 23025489 TI - Precision of fit of implant-supported screw-retained 10-unit computer-aided designed and computer-aided-manufactured frameworks made from zirconium dioxide and titanium: an in vitro study. AB - OBJECTIVE: To analyze the precision of fit of implant-supported screw-retained computer-aided-designed and computer-aided-manufactured (CAD/CAM) zirconium dioxide (ZrO) frameworks. MATERIALS AND METHODS: Computer-aided-designed and computer-aided-manufactured ZrO frameworks (NobelProcera) for a screw-retained 10 unit implant-supported reconstruction on six implants (FDI positions 15, 13, 11, 21, 23, 25) were fabricated using a laser (ZrO-L, N = 6) and a mechanical scanner (ZrO-M, N = 5) for digitizing the implant platform and the cuspid-supporting framework resin pattern. Laser-scanned CAD/CAM titanium (TIT-L, N = 6) and cast CoCrW-alloy frameworks (Cast, N = 5) fabricated on the same model and designed similar to the ZrO frameworks were the control. The one-screw test (implant 25 screw-retained) was applied to assess the vertical microgap between implant and framework platform with a scanning electron microscope. The mean microgap was calculated from approximal and buccal values. Statistical comparison was performed with non-parametric tests. RESULTS: No statistically significant pairwise difference was observed between the relative effects of vertical microgap between ZrO-L (median 14 MUm; 95% CI 10-26 MUm), ZrO-M (18 MUm; 12-27 MUm) and TIT-L (15 MUm; 6-18 MUm), whereas the values of Cast (236 MUm; 181-301 MUm) were significantly higher (P < 0.001) than the three CAD/CAM groups. A monotonous trend of increasing values from implant 23 to 15 was observed in all groups (ZrO-L, ZrO-M and Cast P < 0.001, TIT-L P = 0.044). CONCLUSIONS: Optical and tactile scanners with CAD/CAM technology allow for the fabrication of highly accurate long-span screw-retained ZrO implant-reconstructions. Titanium frameworks showed the most consistent precision. Fit of the cast alloy frameworks was clinically inacceptable. PMID- 23025488 TI - Many roles of the bacterial envelope reducing pathways. AB - SIGNIFICANCE: The cell envelope of aerobic bacteria is an oxidizing environment in which most cysteine residues are involved in disulfide bonds. However, reducing redox pathways are also present in this cellular compartment where they provide electrons to a variety of cellular processes. The membrane protein DsbD plays a central role in these pathways by functioning as an electron hub that dispatches electrons received from the cytoplasmic thioredoxin system to periplasmic oxidoreductases. RECENT ADVANCES: Recent data have revealed that DsbD provides reducing equivalents to a large array of periplasmic redox proteins. Those proteins use the reducing power received from DsbD to correct non-native disulfides, mature c-type cytochromes, protect cysteines on secreted proteins from irreversible oxidation, reduce methionine sulfoxides, and scavenge reactive oxygen species such as hydrogen peroxide. CRITICAL ISSUES: Despite the prominent role played by DsbD, we have a poor understanding of how this protein transfers electrons across the inner membrane. Another critical issue will be to grasp the full physiological significance of the new reducing pathways that have been identified in the cell envelope such as the peroxide reduction pathway. FUTURE DIRECTIONS: A detailed understanding of DsbD's mechanism will require solving the structure of this intriguing protein. Moreover, bioinformatic, biochemical, and genetic approaches need to be combined for a better comprehension of the broad spectrum of periplasmic reducing systems present in bacteria, which will likely lead to the discovery of novel pathways. PMID- 23025491 TI - The relationship between oxidative stress, inflammation, and atherosclerosis in renal transplant and end-stage renal disease patients. AB - OBJECTIVES: Cardiovascular risk is increased in the early stages of chronic kidney disease (CKD) and is also found to be ongoing in renal transplant (Rtx) patients. As a sign of atherosclerosis, increased carotid intima-media thickness (CIMT) has been widely accepted as a strong predictor of cardiovascular disease (CVD) and mortality in the end-stage renal disease (ESRD) patients. Ischemia modified albumin (IMA), pentraxin-3 (PTX-3), and neutrophil-to-lymphocyte ratio (NLR) were introduced as oxidative stress and inflammatory biomarkers in ESRD. The role of Rtx in terms of atherogenesis, oxidative stress, and inflammation is still unclear. We aimed to investigate the relationship between IMA, PTX-3, NLR, and CIMT in Rtx patients without overt CVD and to compare these results with those obtained from healthy subjects and ESRD patients receiving hemodialysis (HD) and peritoneal dialysis (PD). DESIGN AND METHODS: Cross-sectional analysis in which CIMT measurements, NLR, and serum PTX-3 and IMA levels were assessed in 18 Rtx patients (10 females; mean age: 40.0 +/- 13.3 years), 16 PD patients (7 females; 40.2 +/- 12.9 years), 14 HD patients (8 females; 46.6 +/- 10.7 years), and 19 healthy subjects (9 females; 36.9 +/- 8.9 years). RESULTS: IMA, PTX-3, and high-sensitive C-reactive protein (hs-CRP) levels, NLR, and CIMT of Rtx patients were found to be significantly higher compared with healthy subjects ( p = 0.04, p < 0.0001, p < 0.005, p = 0.005, and p = 0.005, respectively). IMA level was positively correlated with hs-CRP and PTX-3 levels, NLR, and CIMT when all participants were included (r = 0.338, p = 0.005; r = 0.485, p < 0.0001; r = 0.304, p = 0.013; and r = 0.499, p < 0.0001, respectively). CONCLUSION: There has been ongoing inflammation, oxidative stress, and atherosclerosis in Rtx patients. PMID- 23025490 TI - Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiology. AB - Bipolar disorder (BD) is a multi-factorial disorder caused by genetic and environmental influences. It has a large genetic component, with heritability estimated between 59-93%. Recent genome-wide association studies (GWAS) using large BD patient populations have identified a number of genes with strong statistical evidence for association with susceptibility for BD. Among the most significant and replicated genes is ankyrin 3 (ANK3), a large gene that encodes multiple isoforms of the ankyrin G protein. This article reviews the current evidence for genetic association of ANK3 with BD, followed by a comprehensive overview of the known biology of the ankyrin G protein, focusing on its neural functions and their potential relevance to BD. Ankyrin G is a scaffold protein that is known to have many essential functions in the brain, although the mechanism by which it contributes to BD is unknown. These functions include organizational roles for subcellular domains in neurons including the axon initial segment and nodes of Ranvier, through which ankyrin G orchestrates the localization of key ion channels and GABAergic presynaptic terminals, as well as creating a diffusion barrier that limits transport into the axon and helps define axo-dendritic polarity. Ankyrin G is postulated to have similar structural and organizational roles at synaptic terminals. Finally, ankyrin G is implicated in both neurogenesis and neuroprotection. ANK3 and other BD risk genes participate in some of the same biological pathways and neural processes that highlight several mechanisms by which they may contribute to BD pathophysiology. Biological investigation in cellular and animal model systems will be critical for elucidating the mechanism through which ANK3 confers risk of BD. This knowledge is expected to lead to a better understanding of the brain abnormalities contributing to BD symptoms, and to potentially identify new targets for treatment and intervention approaches. PMID- 23025492 TI - Biomimetic sheath membrane via electrospinning for antiadhesion of repaired tendon. AB - The hierarchical architecture and complex biologic functions of native sheath make its biomimetic substitute a daunting challenge. In this study, a biomimetic bilayer sheath membrane consisting of hyaluronic acid-loaded poly(epsilon caprolactone) (HA/PCL) fibrous membrane as the inner layer and PCL fibrous membrane as the outer layer was fabricated by a combination of sequential and microgel electrospinning technologies. This material was characterized by mechanical testing and analysis of morphology, surface wettability, and drug release. Results of an in vitro drug release study showed sustained release. The outer layer had fewer cells proliferating on its surface compared to tissue culture plates or the inner layer. In a chicken model, peritendinous adhesions were reduced and tendon gliding were improved by the application of this sheath membrane. Taken together, our results demonstrate that such a biomimetic bilayer sheath can release HA sustainably as well as promoting tendon gliding and preventing adhesion. PMID- 23025493 TI - Broad-spectrum resistance of Arabidopsis C24 to downy mildew is mediated by different combinations of isolate-specific loci. AB - Most natural Arabidopsis thaliana accessions are susceptible to one or more isolates of the downy mildew pathogen Hyaloperonospora arabidopsidis (Hpa). However, Arabidopsis C24 has proved resistant to all Hpa isolates tested so far. Here we describe the complex genetic basis of broad-spectrum resistance in C24. The genetics of C24 resistance to three Hpa isolates was analyzed by segregation analysis and quantitative trait locus (QTL) mapping on recombinant inbred and introgression lines. Resistance of C24 to downy mildew was found to be a multigenic trait with complex inheritance. Many identified resistance loci were isolate-specific and located on different chromosomes. Among the C24 resistance QTLs, we found dominant, codominant and recessive loci. Interestingly, none of the identified loci significantly contributed to resistance against all three tested Hpa isolates. Our study demonstrates that broad-spectrum resistance of Arabidopsis C24 to Hpa is based on different combinations of multiple isolate specific loci. The identified quantitative resistance loci are particularly promising as they provide an important basis for the cloning of susceptibility- and immunity-related genes. PMID- 23025494 TI - Influenza epidemics, seasonality, and the effects of cold weather on cardiac mortality. AB - BACKGROUND: More people die in the winter from cardiac disease, and there are competing hypotheses to explain this. The authors conducted a study in 48 US cities to determine how much of the seasonal pattern in cardiac deaths could be explained by influenza epidemics, whether that allowed a more parsimonious control for season than traditional spline models, and whether such control changed the short term association with temperature. METHODS: The authors obtained counts of daily cardiac deaths and of emergency hospital admissions of the elderly for influenza during 1992-2000. Quasi-Poisson regression models were conducted estimating the association between daily cardiac mortality, and temperature. RESULTS: Controlling for influenza admissions provided a more parsimonious model with better Generalized Cross-Validation, lower residual serial correlation, and better captured Winter peaks. The temperature-response function was not greatly affected by adjusting for influenza. The pooled estimated increase in risk for a temperature decrease from 0 to -5 degrees C was 1.6% (95% confidence interval (CI) 1.1-2.1%). Influenza accounted for 2.3% of cardiac deaths over this period. CONCLUSIONS: The results suggest that including epidemic data explained most of the irregular seasonal pattern (about 18% of the total seasonal variation), allowing more parsimonious models than when adjusting for seasonality only with smooth functions of time. The effect of cold temperature is not confounded by epidemics. PMID- 23025495 TI - Outcome of patients with suspected lower limb symptomatic deep vein thrombosis and a normal ultrasound-based initial diagnostic workup: a prospective study. PMID- 23025496 TI - Micropatterned thermoresponsive surfaces by polymerization of monomer crystals: modulating cellular morphology and cell-substrate interactions. AB - A novel and facile approach has been developed to create thermoresponsive surfaces with macroscale patterns together with microscale features. The surface patterns were formed by applying macroscale nucleation agent patterns onto saturated N-isopropylacrylamide monomer solution membranes to induce the divergent growth of needlelike monomer crystals; the patterned monomer crystals were then photopolymerized to form patterned thermoresponsive films. A series of analytical tools (i.e., scanning electron microscopy, profilometry, and contact angle measurement) were used to characterize the properties of the patterned films. Cell coculture on this patterned thermoresponsive films enables cell separation and sorting by modulating temperature- and topography-dependent cell substrate interactions and cell morphology, respectively. This versatile technique allows the formation of various macroscale patterns with microscale features over large areas, and on most solid substrates, within minutes, all of this without the need for expensive equipment and facilities. Such patterned surfaces can act as both in vitro tumor models and separation platforms for cancer studies. This method can also be applied to other cell-based biological studies and clinical applications. PMID- 23025497 TI - What is your diagnosis? Ascites fluid from a dog with abdominal distension. PMID- 23025498 TI - Synthesis of 4'-thiosemicarbazonegriseofulvin and its effects on the control of enzymatic browning and postharvest disease of fruits. AB - 4'-Thiosemicarbazonegriseofulvin, a new thiosemicarbazide derivative of griseofulvin, was synthesized and evaluated for its potential in the control of enzymatic browning and postharvest disease of fruits. Browning on fruits is mainly due to the enzymatic oxidation of phenolic compounds catalyzed by tyrosinase. 4'-Thiosemicarbazonegriseofulvin could effectively inhibit the activity of tyrosinase, and its 50% inhibitory concentration (IC(50)) against tyrosinase was determined to be 37.8 MUM. It was a reversible and noncompetitive inhibitor of tyrosinase, and its inhibition constant (K(I)) was determined to be 38.42 MUM. The antifungal activity of 4'-thiosemicarbazonegriseofulvin was studied against four fungi (Fusarium oxysporum, Fusarium moniliforme, Fusarium solani, and Colletotrichum truncatum) that often cause postharvest diseases of fruits. The results showed that 4'-thiosemicarbazonegriseofulvin could also strongly inhibit the mycelial growth of the four target fungi; the 50% lethal concentration (LC(50)) values were 5.4, 7.0, 15.3, and 1.5 mM, respectively. PMID- 23025499 TI - Interprofessional education between nurse prescribing and medical students: a qualitative study. AB - Prescriptive authority has been extended in the UK to include non-medical healthcare professionals. However, uptake and use of prescribing by these professionals are inconsistent. Collaborative practice is key for its successful implementation, and such practice is a benefit of interprofessional education (IPE). This study explored the feasibility of IPE between nurse prescribers at Anglia Ruskin University and 3rd year medical students at the University of Cambridge. Three focus groups and three individual interviews were undertaken with nurse and medical prescribing students, following shared learning sessions on drug interactions, prescription writing and legal issues and accountability. Benefits included the opportunity for mutual understanding of prescribing training and role. Medical students valued the opportunity to be able to gain an insight into nurses' views about prescribing. The level and breadth of pharmacology knowledge of medical and nursing students differed. Location of sessions, scheduling of classes and balancing of students acted as barriers to learning. PMID- 23025500 TI - When compliments fail to flatter: American individualism and responses to positive stereotypes. AB - Five studies show that being the target of a positive stereotype is a negative interpersonal experience for those from individualistic cultures because positive stereotypes interfere with their desire to be seen as individuals separate from their groups. U.S.-born Asian Americans and women who heard a positive stereotype about their group in an intergroup interaction (e.g., "Asians are good at math," "women are nurturing") derogated their partner and experienced greater negative emotions than those who heard no stereotype. Negative reactions were mediated by a sense of being depersonalized, or "lumped together" with others in one's group, by the positive stereotype (Studies 1-3). Cross-cultural differences (Study 4) and an experimental manipulation of cultural self-construal (Study 5) demonstrated that those with an independent self-construal reacted more negatively to positive stereotypes than those with an interdependent self construal. By bringing together research on stereotypes from the target's perspective with research on culture, this work demonstrates how cultural self construals inform the way people interpret and respond to being the target of positive stereotypes. PMID- 23025501 TI - Detection of Schmallenberg virus in different Culicoides spp. by real-time RT PCR. AB - To identify possible vectors of Schmallenberg virus (SBV), we tested pools containing heads of biting midges (Culicoides) that were caught during the summer and early autumn of 2011 at several places in Belgium by real-time RT-PCR. Pools of heads originating from following species: C. obsoletus complex, C. dewulfi and C. chiopterus were found positive, strongly indicating that these species are relevant vectors for SBV. PMID- 23025502 TI - Synthesis of ynone trifluoroborates toward functionalized pyrazoles. AB - The synthesis of a range of novel ynone trifluoroborates has been achieved, in a two-pot process from propargylic alcohols. These alkynes have been subsequently used in the formation of a range of pyrazole trifluoroborate salts via cyclization with hydrazines. The products are generated with high levels of regiocontrol and in excellent yields and represent versatile synthetic intermediates. PMID- 23025503 TI - PRDX4, an endoplasmic reticulum-localized peroxiredoxin at the crossroads between enzymatic oxidative protein folding and nonenzymatic protein oxidation. AB - SIGNIFICANCE: Peroxiredoxin 4 (PRDX4) is an endoplasmic reticulum (ER)-resident peroxiredoxin that has the characteristic of coupling hydrogen peroxide (H(2)O(2)) catabolism with oxidative protein folding. This enzymatic arrangement involves the ingenious use of H(2)O(2) as a substrate to streamline protein metabolism. RECENT ADVANCES: Mice with compound mutations in Prdx4 and Ero1 have revealed the physiological implication that PRDX4 is a fine-tuned enzymatic mediator of oxidative folding. Remarkably, by simultaneously triggering slow disulfide bond formation and the buildup of H(2)O(2), the lack of PRDX4 and endoplasmic oxidoreductin 1 (ERO1) exposes the thiols of new client proteins to competing H(2)O(2)-mediated oxidation, which leads to an increase in sulfenylated proteins. Such oxygenated thiol derivatives exploit ascorbate as their reductant, thus accelerating its clearance. This relay of events culminates in an altered extracellular matrix (ECM) and a senescent phenotype. CRITICAL ISSUES AND FUTURE DIRECTIONS: By combining H(2)O(2) metabolism with oxidative folding, PRDX4 protects nascent proteins from an alternative oxidative fate, and cells from the consequences of having misfolded proteins. This highlights the importance of kinetic-regulated disulfide formation at physiological level, and the presence of an exquisite backup system to protect ER redox homeostasis. By altering ECM architecture, ascorbate depletion in the cells triggers an integrated signaling cascade. This sequence of events is part of a multifaceted response linking the ER and the nucleus, which helps cells to overcome ER redox impairment. Furthermore, the relationship between the protein sulfenylation and ascorbate depletion suggests that it would be interesting to explore the metabolism of ascorbate in pathological conditions accompanied by oxidative stress and a defective ECM. PMID- 23025504 TI - Malakoplakia after renal transplantation in the current era of immunosuppressive therapy: case report and literature review. AB - Malakoplakia is a rare chronic granulomatous disease of unknown cause. It is thought to be caused by an acquired bactericidal defect of macrophages. Malakoplakia is associated with chronic infections and immunosuppression. Although it occurs mainly in the urinary tract, it has already been reported in almost every organ system. The isolation of bacteria, especially Escherichia coli, is common in malakoplakia patients. Here, we present a case of primary cutaneous malakoplakia in a kidney transplant recipient who had been taking prednisone, tacrolimus, and mycophenolate. Culture of a lesion grew Burkholderia cepacia complex. Treatment with high doses of trimethoprim-sulfamethoxazole was successful. We also present a systematic review of the literature, identifying 4 previously reported cases of malakoplakia after renal transplantation under similar immunosuppressive therapy, most occurring in the urinary tract or perineum and following benign courses to cure. Data in the literature suggest that malakoplakia has become even rarer since changes were made in the immunosuppressive therapy employed after kidney transplantation. PMID- 23025505 TI - CBL mutations do not frequently occur in paediatric acute myeloid leukaemia. AB - RAS-pathway mutations, causing a proliferative advantage, occur in acute myeloid leukaemia (AML) and MLL-rearranged leukaemia. Recently, mutations in the Casitas B lineage lymphoma (CBL) gene were reported to be involved in RAS-pathway activation in various myeloid malignancies, but their role in paediatric AML is still unknown. We performed mutation analysis of 283 newly diagnosed and 33 relapsed paediatric AML cases. Only two mutant cases (0.7%) were identified in the newly diagnosed paediatric AML samples, of which one was MLL-rearranged. Both mutant cases showed CBL mRNA expression in the range of the non-mutated cases. Phosphorylated extracellular signal-regulated kinase (pERK) was not correlated with CBL protein expression (n = 11). In conclusion, we report a very low CBL mutation frequency in paediatric AML, which, together with the lack of difference in protein and mRNA expression, illustrates the limited role of CBL in paediatric AML. PMID- 23025507 TI - Risk stratification of follicular variant of papillary thyroid carcinoma. AB - BACKGROUND: Recent studies have described an encapsulated and an infiltrative form of follicular variant of papillary thyroid carcinoma (FVPTC). While encapsulated tumors have been reported to have virtually no metastatic potential or recurrence risk if angioinvasion and capsular penetration are absent, infiltrative tumors have been found to have a significant metastatic potential and a risk of recurrence. In our experience, a substantial number of FVPTCs are neither fully encapsulated nor infiltrative, but instead are partially encapsulated (PE) or well-circumscribed (WC). Thus, the aim of this study was to investigate the metastatic potential and recurrence risk of PE/WC FVPTCs in comparison with that of encapsulated and infiltrative tumors. METHODS: We studied 77 FVPTCs resected between 2000 and 2002 and characterized the tumors as encapsulated, PE/WC, or infiltrative. Histologic assessment was then correlated with lymph node status and clinical outcome. RESULTS: In our cohort, 27 (35%) tumors were encapsulated, 35 (45%) were PE/WC, and 15 (19%) were infiltrative. Lymph node status was similar between PE/WC and encapsulated tumors, but was significantly different between encapsulated and infiltrative groups (p<0.001), and PE/WC and infiltrative groups (p<0.001). Lymph node metastases were absent in all 15 cases of encapsulated tumors and all 9 cases of PE/WC tumors with sampled lymph nodes, but were present in 7 of 9 (78%) cases of infiltrative tumors with sampled lymph nodes. For patients with available clinical follow-up (66 cases, 86%), the median follow-up time was 111 months. No patients with encapsulated tumors recurred, one (3%) patient with a PE/WC tumor had recurrent/residual disease, and two (15%) patients with infiltrative tumors had recurrent/residual disease. The one patient with a PE/WC tumor who had recurrent/residual disease had a tumor bed recurrence 7 years after initial resection. Significantly, this was the only patient in the PE/WC group that had a positive resection margin. CONCLUSIONS: Our results demonstrate that PE/WC FVPTCs have a very low metastatic potential/recurrence risk, indicating that they should be distinguished from more aggressive infiltrative FVPTCs. PMID- 23025508 TI - A positive serum basophil histamine release assay is a marker for ciclosporin responsiveness in patients with chronic spontaneous urticaria. AB - The electronic records of 398 patients with chronic spontaneous urticaria (CSU) who had had a serum basophil histamine release assay (BHRA) performed as a marker of functional autoantibodies were audited. The BHRA was positive in 105 patients (26.4%). Fifty eight were treated with ciclosporin because they were H1 anti histamine unresponsive. CSU patients with a positive BHRA were more likely to respond clinically (P<0.001) and to have raised thyroid autoantibodies (P<0.02) than those with a negative BHRA. The BHRA offers a useful predictive biomarker for a good response of H1 antihistamine-unresponsive CSU patients to ciclosporin. PMID- 23025509 TI - The complete mitochondrial genome of the yellow peach moth Dichocrocis punctiferalis (Lepidoptera: Pyralidae). AB - The complete mitochondrial genome of Dichocrocis punctiferalis (Lepidoptera: Pyralidae) was determined (GenBank accession number JX448619). The genome is 15,355 bp long with 37 typical animal mitochondrial genes and an A+T-rich region. As in other sequenced mitochondrial genomes of Lepidoptera, trnM was rearranged to the upstream of trnI-trnQ-trnM cluster compared with the pupative ancestral arrangement of insects. All protein-coding genes start with ATN start codon except for the gene cox1, which uses CGA as in other lepidopteran species. Seven protein-coding genes stop with termination codon TAA. Four protein-coding genes use incomplete stop codons TA and two use T. The A+T-region is located between rrnS and trnM with a length of 338 bp. This is the first completely sequenced mitochondrial genome from the family Pyralidae. PMID- 23025510 TI - Structure and dynamics of proton transfer in liquid imidazole. A molecular dynamics simulation. AB - Proton transfer (PT) via the Grotthuss mechanism in liquid imidazole (im) at 393 K is studied with molecular dynamics simulation using a reactive multistate empirical valence bond (MS-EVB) model. It is found that the proton is tightly binded to an imidazole to form an imidazolium (imH(+)), which is solvated in a distorted Eigen-like complex (im-imH(+)-im), whereas the Zundel-like complex (im H(+)-im) is rare. PT occurs via an Eigen-Zundel-Eigen scenario for switching the identity of imH(+) from an Eigen-like complex to another, intermediated by a Zundel-like complex. Structural and dynamical analyses demonstrate that PT in imidazole can be considered as a local event with very short spatial/temporal correlation, characterized by a few "rattling" or recurrent PT events. At long time scale, the trend of the PT correlation function may be recast with the diffusion model of reversible geminate recombination toward the power-law decay. The formation of the hydrogen bonds (HBs) for the imidazole molecules between the first and second solvation shell of imH(+) is crucial to pave the PT pathway. The above features may be understood by the flexibility of the HBs in liquid imidazole, as a stable HB network is essential for the Grotthuss mechanism. PMID- 23025511 TI - The CRTH2 antagonist OC000459 reduces nasal and ocular symptoms in allergic subjects exposed to grass pollen, a randomised, placebo-controlled, double-blind trial. AB - BACKGROUND: CRTH2 mediates activation of Th2 cells, eosinophils and basophils in response to prostaglandin D(2). The CRTH2 antagonist OC000459 has previously been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma. The objective of the present study was to determine the involvement of CRTH2 in promoting nasal and ocular symptoms in allergic subjects exposed to grass pollen. METHODS: A single centre, randomised, double-blind, placebo-controlled, two-way crossover study was conducted in 35 male subjects allergic to grass pollen comparing OC000459 200 mg bid with placebo for 8 days. Subjects were exposed to grass pollen (>= 1400 grains/m(3)) for 6 h on the 2nd and 8th days of treatment and assessed for nasal symptoms, ocular symptoms, other symptoms, nasal secretion weight and rhinomanometry over the 6-h period. After a washout period of 3 weeks, subjects were switched to the alternative treatment for a further 8 days. The trial was registered on the clinical trials.gov database (Identifier NCT01448902). RESULTS: During the first treatment period, treatment with OC000459 significantly reduced both nasal and ocular symptoms in allergic subjects compared with placebo after challenge with grass pollen. A significant effect was observed on the 2nd day of dosing which was increased on the 8th day of dosing. The therapeutic effects of OC000459 persisted into the second treatment period despite a 3-week washout phase. The safety profile of OC000459 was similar to that of placebo. CONCLUSION: Treatment with OC000459 was well tolerated and led to a significant and persistent reduction in the symptoms of rhinoconjunctivitis. PMID- 23025512 TI - The susceptibility of soil enzymes to inhibition by leaf litter tannins is dependent on the tannin chemistry, enzyme class and vegetation history. AB - By inhibiting soil enzymes, tannins play an important role in soil carbon (C) and nitrogen (N) mineralization. The role of tannin chemistry in this inhibitory process, in conjunction with enzyme classes and isoforms, is less well understood. Here, we compared the inhibition efficiencies of mixed tannins (MTs, mostly limited to angiosperms) and condensed tannins (CTs, produced mostly by gymnosperms) against the potential activity of beta-glucosidase (BG), N-acetyl glucosaminidase (NAG), and peroxidase in two soils that differed in their vegetation histories. Compared with CTs, MTs exhibited 50% more inhibition of almond (Prunus dulcis) BG activity and greater inhibition of the potential NAG activity in the gymnosperm-acclimatized soils. CTs exhibited lower BG inhibition in the angiosperm-acclimated soils, whereas both types of tannins exhibited higher peroxidase inhibition in the angiosperm soils than in gymnosperm soils. At all of the tested tannin concentrations, irrespective of the tannin type and site history, the potential peroxidase activity was inhibited two-fold more than the hydrolase activity and was positively associated with the redox-buffering efficiency of tannins. Our finding that the inhibitory activities and mechanisms of MTs and CTs are dependent on the vegetative history and enzyme class is novel and furthers our understanding of the role of tannins and soil isoenzymes in decomposition. PMID- 23025514 TI - Five-year results of a randomized controlled clinical trial comparing zirconia and titanium abutments supporting single-implant crowns in canine and posterior regions. AB - OBJECTIVES: To test the survival rates, and the technical and biological complication rates of customized zirconia and titanium abutments 5 years after crown insertion. MATERIAL AND METHODS: Twenty-two patients with 40 single implants in maxillary and mandibular canine and posterior regions were included. The implant sites were randomly assigned to zirconia abutments supporting all ceramic crowns or titanium abutments supporting metal-ceramic crowns. Clinical examinations were performed at baseline, and at 6, 12, 36 and 60 months of follow up. The abutments and reconstructions were examined for technical and/or biological complications. Probing pocket depth (PPD), plaque control record (PCR) and Bleeding on Probing (BOP) were assessed at abutments (test) and analogous contralateral teeth (control). Radiographs of the implants revealed the bone level (BL) on mesial (mBL) and distal sides (dBL). Data were statistically analyzed with nonparametric mixed models provided by Brunner and Langer and STATA (P < 0.05). RESULTS: Eighteen patients with 18 zirconia and 10 titanium abutments were available at a mean follow-up of 5.6 years (range 4.5-6.3 years). No abutment fracture or loss of a reconstruction occurred. Hence, the survival rate was 100% for both. Survival of implants supporting zirconia abutments was 88.9% and 90% for implants supporting titanium abutments. Chipping of the veneering ceramic occurred at three metal-ceramic crowns supported by titanium abutments. No significant differences were found at the zirconia and titanium abutments for PPD (meanPPDZrO2 3.3 +/- 0.6 mm, mPPDTi 3.6 +/- 1.1 mm), PCR (mPCRZrO2 0.1 +/- 0.3, mPCRTi 0.3 +/- 0.2) and BOP (mBOPZrO2 0.5 +/- 0.3, mBOPTi 0.6 +/- 0.3). Moreover, the BL was similar at implants supporting zirconia and titanium abutments (mBLZrO2 1.8 +/- 0.5, dBLZrO2 2.0 +/- 0.8; mBLTi 2.0 +/- 0.8, dBLTi 1.9 +/- 0.8). CONCLUSIONS: There were no statistically or clinically relevant differences between the 5-year survival rates, and the technical and biological complication rates of zirconia and titanium abutments in posterior regions. PMID- 23025516 TI - An efficient asymmetric biomimetic transamination of alpha-keto esters to chiral alpha-amino esters. AB - An efficient asymmetric biomimetic transamination of alpha-keto esters with quinine derivatives as chiral bases was described. A wide variety of alpha-amino esters containing various functional groups can be synthesized in high yield and enantioselectivity. PMID- 23025515 TI - Correlation between mesenteric fat thickness and serum apolipoproteins in patients with peripheral arterial occlusive disease. AB - BACKGROUND: Visceral fat possesses the most detrimental potential for cardiovascular morbidity through the release of adipokines, as well as metabolic and proinflammatory mediators, which adversely affect metabolic and vascular homeostasis. Among the different types of visceral adipose tissue, mesenteric fat is considered particularly detrimental, due to its close proximity to the portal circulation, affecting directly the liver, which is the main regulator of body metabolic homeostasis. Mesenteric fat can be reliably estimated using abdominal ultrasonography, the only available imaging method able to depict individual mesenteric leaves. Aim of the present study was to investigate the correlation of mesenteric fat thickness (MFT) with serum apolipoprotein levels in patients undergoing digital subtraction angiography in a single center. METHODS: 35 male patients with peripheral arterial disease were examined. After careful examination of the periumbilical area, the mesenteric leaves were identified. The maximal distance between each pair of sequential leaves was measured, and the mean value of the three thickest leaves was determined as the mesenteric fat thickness. Six apolipoprotein fasting serum concentrations were measured using a Luminex proteomics platform (xMAP Multiplex immunoassay): apolipoprotein A-I (apoAI), apolipoprotein A-II (apoAII), apolipoprotein B (apoB), apolipoprotein C II (apoCII), apolipoprotein C-III (apoCIII) and apolipoprotein E (apoE). RESULTS: MFT correlated with apoAII and apoB serum concentrations. The correlations with apoAII and apoB remained significant following correction for BMI. No correlations were noted between MFT and serum apoAI, apoCII, apoCIII or apoE levels before or after adjustment for BMI. CONCLUSIONS: Our study indicates that MFT is significantly correlated with the concentration of atherogenic low density lipoproteins particles, as well as with apoAII, a determinant of free fatty acids levels. No correlation was observed between mesenteric fat thickness and very low density lipoprotein or chylomicron particles concentration. PMID- 23025517 TI - Familial risks for childhood acute lymphocytic leukaemia in Sweden and Finland: far exceeding the effects of known germline variants. AB - Despite recent successes in the identification of genetic susceptibility loci, no familial risk has been demonstrated for childhood acute lymphoblastic leukaemia (ALL). We identified 3994 childhood ALL cases from two cancer registries; family members were obtained from population registers. The standardized incidence ratio for familial risk in singleton siblings and twins was 3.2 (95% confidence interval 1.5-5.9) and 162.6 (70.2-320.4), respectively. The present data constitute the first demonstration of familial risk for singleton siblings; the high risk for twins is believed to result from shared prenatal blood circulation. The data suggest that currently unidentified genetic loci underlie these observed familial effects. PMID- 23025518 TI - When emotion does and does not impair performance: a Garner theory of the emotional Stroop effect. AB - It takes people longer to name the ink colour of emotion or threat words than that of neutral words, the emotional Stroop effect (ESE). In three experiments with normal and patient populations, we show that the ESE is a special case of a generic attention model and effect entailed in Garner's speeded classification paradigm. Guided by the Garner model we demonstrate that task-irrelevant dimensions that differ in salience can produce the ESE and mimic it with neutral stimuli. When each word appears in a constant colour, as mandated in the correlation condition of the Garner design, the ESE is eliminated. This important result is consistent with the attention account of the ESE. We conclude that when emotion stimuli appear in a random fashion they interfere with task performance. However, when emotion stimuli are correlated with features of the ongoing task they help task performance not least due to their extreme salience. PMID- 23025520 TI - Theileriosis in a reindeer (Rangifer tarandus tarandus) associated with a potentially novel Theileria sp. AB - A 5-year-old male neutered reindeer (Rangifer tarandus tarandus) from Missouri was presented with a 3-week history of anorexia, respiratory distress, lethargy, and weight loss. Blood smear review revealed that a small percentage of RBCs contained small (1-2 MUm in length) pleomorphic piroplasms (signet ring, rod- or pear-shaped, and elongate forms) with an eccentric magenta nucleus and basophilic cytoplasm. Nested PCR to specifically amplify a portion of the piroplasm small subunit ribosomal RNA (SSU rRNA) gene was performed on DNA extracted from an EDTA specimen of whole blood. Subsequent sequence analyses showed similarity between the reindeer hemoparasite and Theileria spp SSU rRNA gene sequences in the GenBank database, with highest similarity to those of a Theileria sp in a White tailed deer from North Texas (AY735132, AY735133). The reindeer and North Texas Theileria sp are genetically distinct from, albeit closely related to, the White tailed deer Theileria sp (subsequently referred to as T cervi). To the authors' knowledge, this is the first identification of Theileria of this genotype in a reindeer. Historically, T tarandirangiferis infection was found with associated mortality in reindeer in Russia, but reports predate molecular characterization. Hence, the relationship of T tarandirangiferis with either T cervi or this agent remains unknown. T cervi is not typically pathogenic in White-tailed deer in the US unless the animal is immune-compromised by stress or disease; however, mortality from T cervi infection in reindeer has been reported. PMID- 23025521 TI - Analytical chemistry is alive and well all over Africa! PMID- 23025519 TI - Pharmacokinetics of low-dose cidofovir in kidney transplant recipients with BK virus infection. AB - BACKGROUND: BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low-dose cidofovir regimen are not known in kidney transplant recipients. METHODS: We investigated the pharmacokinetics (PK) of low-dose cidofovir (0.24 - 0.62 mg/kg) both without and with oral probenecid in 9 transplant patients with persistent BK viremia without nephropathy in a crossover design. RESULTS: The mean estimated glomerular filtration rate (eGFR) of the study participants was 46.2 mL/min/1.73 m(2) (range: 17-75 mL/min/1.73 m(2) ). The contribution of active renal secretion to cidofovir total body clearance was assessed by evaluating the effect of probenecid on cidofovir PK. Maximum cidofovir plasma concentrations, which averaged approximately 1 MUg/mL, were significantly below the 36 MUg/mL 50% effective concentration in vitro for cidofovir against BKV. The plasma concentration of cidofovir declined with an overall disposition half-life of 5.1 +/- 3.5 and 5.3 +/- 2.9 h in the absence and in the presence of probenecid, respectively (P > 0.05). CONCLUSIONS: Cidofovir clearance and eGFR were linearly related irrespective of probenecid administration (r(2) = 0.8 without probenecid; r(2) = 0.7 with probenecid). This relationship allows for the prediction of systemic cidofovir exposure in individual patients and may be utilized to evaluate exposure-response relationships to optimize the cidofovir dosing regimen for BKV infection. PMID- 23025522 TI - Emergence of foot-and-mouth disease virus SAT 2 in Egypt during 2012. AB - The epidemiology of foot-and-mouth disease (FMD) in North Africa is complicated by the co-circulation of endemic FMD viruses (FMDV), as well as sporadic incursions of exotic viral strains from the Middle East and Sub-Saharan Africa. This report describes the molecular characterization of SAT 2 FMD viruses that have caused widespread field outbreaks of FMD in Egypt during February and March 2012. Phylogenetic analysis showed that viruses from these outbreaks fell into two distinct lineages within the SAT 2 topotype VII, which were distinct from a contemporary SAT 2 lineage of the same toptype from Libya. These were the first FMD outbreaks due to this serotype in Egypt since 1950 and required the development of a tailored real-time reverse-transcription PCR assay that can be used in the laboratory to distinguish FMD viruses of these lineages from other endemic FMD viruses that might be present in North Africa. These data highlight the ease by which FMDV can cross international boundaries and emphasize the importance of deploying systems to continuously monitor the global epidemiology of this disease. PMID- 23025523 TI - Inhaled hydrogen sulfide protects against lipopolysaccharide-induced acute lung injury in mice. AB - BACKGROUND: Local pulmonary and systemic infections can lead to acute lung injury (ALI). The resulting lung damage can evoke lung failure and multiple organ dysfunction associated with increased mortality. Hydrogen sulfide (H2S) appears to represent a new therapeutic approach to ALI. The gas has been shown to mediate potent anti-inflammatory and organ protective effects in vivo. This study was designed to define its potentially protective role in sepsis-induced lung injury. METHODS: C57BL/6 N mice received lipopolysaccharide (LPS) intranasally in the absence or presence of 80 parts per million H2S. After 6 h, acute lung injury was determined by comparative histology. Bronchoalveolar lavage (BAL) fluid was analyzed for total protein content and differential cell counting. BAL and serum were further analyzed for interleukin-1beta, macrophage inflammatory protein-2, and/or myeloperoxidase glycoprotein levels by enzyme-linked immunosorbent assays. Differences between groups were analyzed by one way analysis of variance. RESULTS: Histological analysis revealed that LPS instillation led to increased alveolar wall thickening, cellular infiltration, and to an elevated ALI score. In the presence of H2S these changes were not observed despite LPS treatment. Moreover, neutrophil influx, and pro-inflammatory cytokine release were enhanced in BAL fluid of LPS-treated mice, but comparable to control levels in H2S treated mice. In addition, myeloperoxidase levels were increased in serum after LPS challenge and this was prevented by H2S inhalation. CONCLUSION: Inhalation of hydrogen sulfide protects against LPS-induced acute lung injury by attenuating pro-inflammatory responses. PMID- 23025524 TI - Redox considerations in the phagosome: current concepts, controversies, and future challenges. PMID- 23025525 TI - Complete mitochondrial genome of Scaphiodonichthys acanthopterus (Cypriniformes, Cyprinidae). AB - In this study, we sequenced the complete mitochondrial genome of Scaphiodonichthys acanthopterus (Cypriniformes, Cyprinidae). This mitochondrial genome, consisting of 16,612 base pairs (bp), encoded genes for 13 protein-coding genes, two ribosomal RNAs, 22 transfer RNAs, and one non-coding control region as those found in other vertebrates, with the gene order identical to that of typical vertebrates. The control region, of 941 bp in length, is located between tRNA (Pro) and tRNA (Phe) . The overall base composition of the heavy strand shows T 25.23%, C 26.85%, A 31.96%, and G 15.95%, with a slight AT bias of 57.19%. PMID- 23025527 TI - Myoglobin unfolding in crowding and confinement. AB - Crowding and confinement have often been used synonymously with regard to their effect on the structure and dynamics of proteins. In this work, we have investigated the unfolding of the protein myoglobin (Mb) entrapped in the confinement of the water pool of AOT reverse micelles and in the presence of some commonly used macromolecular crowding agents (Ficoll 70, Dextran 70, and Dextran 40). Our results reveal that confinement effects can be quite destabilizing in nature for Mb with the extent of distortion depending on a host of factors apart from the size of the confining cage. Effects of the crowding agents on myoglobin also show a deviation from the general notion that synthetic macromolecular crowding agents are always stabilizing in nature. Ficoll 70 was observed to be particularly destabilizing in its influence on Mb unfolding. Moreover, tryptophan lifetime studies point to the fact that the Trp-heme distance in Mb might not always be a reliable probe of the secondary structural dissolution of the protein. PMID- 23025526 TI - Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. AB - BACKGROUND: Thyrotropin receptor (TSHR) antibodies that stimulate the thyroid (TSAb) cause Graves' hyperthyroidism and TSHR antibodies which block thyrotropin action (TBAb) are occasionally responsible for hypothyroidism. Unusual patients switch from TSAb to TBAb (or vice versa) with concomitant thyroid function changes. We have examined case reports to obtain insight into the basis for "switching." SUMMARY: TBAb to TSAb switching occurs in patients treated with levothyroxine (LT4); the reverse switch (TBAb to TSAb) occurs after anti-thyroid drug therapy; TSAb/TBAb alterations may occur during pregnancy and are well recognized in transient neonatal thyroid dysfunction. Factors that may impact the shift include: (i) LT4 treatment, usually associated with decreased thyroid autoantibodies, in unusual patients induces or enhances thyroid autoantibody levels; (ii) antithyroid drug treatment decreases thyroid autoantibody levels; (iii) hyperthyroidism can polarize antigen-presenting cells, leading to impaired development of regulatory T cells, thereby compromising control of autoimmunity; (iv) immune-suppression/hemodilution reduces thyroid autoantibodies during pregnancy and rebounds postpartum; (v) maternally transferred IgG transiently impacts thyroid function in neonates until metabolized; (vi) a Graves' disease model involving immunizing TSHR-knockout mice with mouse TSHR-adenovirus and transfer of TSHR antibody-secreting splenocytes to athymic mice demonstrates the TSAb to TBAb shift, paralleling the outcome of maternally transferred "term limited" TSHR antibodies in neonates. Finally, perhaps most important, as illustrated by dilution analyses of patients' sera in vitro, TSHR antibody concentrations and affinities play a critical role in switching TSAb and TBAb functional activities in vivo. CONCLUSIONS: Switching between TBAb and TSAb (or vice versa) occurs in unusual patients after LT4 therapy for hypothyroidism or anti-thyroid drug treatment for Graves' disease. These changes involve differences in TSAb versus TBAb concentrations, affinities and/or potencies in individual patients. Thus, anti-thyroid drugs or suppression/hemodilution in pregnancy reduce initially low TSAb levels even further, leading to TBAb dominance. In contrast, TSAb emergence after LT4 administration may be sufficient to counteract TBAb inhibition. The occurrence of "switching" emphasizes the need for careful patient monitoring and management. Finally, whole genome screening of relatively rare "switch" patients and appropriate Graves' and Hashimoto's controls could provide unexpected and valuable information regarding the basis for thyroid autoimmunity. PMID- 23025528 TI - Two persons with multiple disabilities use camera-based microswitch technology to control stimulation with small mouth and eyelid responses. AB - BACKGROUND: A camera-based microswitch technology was recently developed to monitor small facial responses of persons with multiple disabilities and allow those responses to control environmental stimulation. This study assessed such a technology with 2 new participants using slight variations of previous responses. METHOD: The technology involved a computer with a CPU using a 2GHz clock, a USB video camera with 16-mm lens, and special software. Small colour spots were used under the lower lip of one participant and on the eyelid of the other participant to aid the camera and computer to detect their mouth and eyelid responses. The study involved an ABAB design and included a 3-week post-intervention check. RESULTS: The participants' mouth and eyelid responses increased during the intervention (B) phases and post-intervention check (i.e., when the technology allowed them to control stimulation). CONCLUSIONS: Camera-based microswitch technology can help persons with multiple disabilities control stimulation with small responses. PMID- 23025529 TI - Functional independence in pediatric-onset spinal cord injury: two levels of mediation. AB - PURPOSE/OBJECTIVE: To test 3 models that examine the relationship of posttraumatic stress (PTS), family functioning (FF), and level of spinal cord injury (SCI) to functional independence (FI) among patients with pediatric-onset SCI. RESEARCH METHOD/DESIGN: Participants were 109 pediatric spinal cord injury patients, ages 11-24 years, from 2 surgical and rehabilitation hospitals. Data from 2 previous cross-sectional studies included the Posttraumatic Diagnostic Scale, the Family Assessment Device, and the Pediatric Orthopedic Surgeons of North America Pediatric Musculoskeletal Functional Health Questionnaire. Path analyses were used to test 3 hypothesized models: that PTS would mediate the relationship between FF and FI, that PTS Avoidance symptoms would mediate the relationship between other PTS symptom clusters and FI, and that these 2 models would show adequate fit to the data when integrated into an overarching model to depict the interrelationship of level of SCI (tetraplegia v. paraplegia), FF, PTS symptom clusters, and FI. RESULTS: Results from the first model indicated that PTS mediated the relationship between FF and FI. In addition, the Avoidance symptom cluster of PTS mediated the relationships between PTS Reexperiencing symptoms and FI and between the PTS Arousal symptom cluster and FI. A third model integrated the previous 2 models and supported these 2 levels of mediation. CONCLUSIONS/IMPLICATIONS: Level of SCI related directly to FI, and PTS mediated the relationship between FF and FI; PTS Avoidance mediated the relationships between Intrusive Reexperiencing and FI and between PTS Arousal and FI. PMID- 23025530 TI - Insights on the mechanism of formation of protein microspheres in a biphasic system. AB - Microspheres of bovine serum albumin (BSA) and silk fibroin are produced by applying ultrasound in a biphasic system consisting of an aqueous protein solution and an organic solvent. The protein microspheres are dispersed in an aqueous media where the protein remains at the interface covering the organic solvent. This only occurs when high shear forces are applied that induce changes to force the protein to the interface. Fourier transform infrared results indicate a large increase in the content of the beta-sheet during the formation of silk fibroin microspheres. Molecular dynamics simulations show a clear adaption on the 3D structure of BSA when stabilized at the interface, without major changes in secondary structure. Further studies demonstrate that high water content, oil solvents, and larger peptides with separated and clear hydrophobic and hydrophilic areas lead to more stable and smaller spheres. This is the first time that these results are presented. We also present herein the rationale to produce tailored protein microspheres with a controlled size, controlled charge, and increased stability. PMID- 23025531 TI - The genetic basis for natural variation in heteroblasty in Antirrhinum. AB - Heteroblasty refers to the changes in leaf shape and size (allometry) along stems. Although evolutionary changes involving heteroblasty might contribute to leaf diversity, little is known of the extent to which heteroblasty differs between species or how it might relate to other aspects of allometry or other developmental transitions. Here, we develop a computational model that can quantify differences in leaf allometry between Antirrhinum (snapdragon) species, including variation in heteroblasty. It allows the underlying genes to be mapped in inter-species hybrids, and their effects to be studied in similar genetic backgrounds. Heteroblasty correlates with overall variation in leaf allometry, so species with smaller, rounder leaves produce their largest leaves earlier in development. This involves genes that affect both characters together and is exaggerated by additional genes with multiplicative effects on leaf size. A further heteroblasty gene also alters leaf spacing, but none affect other developmental transitions, including flowering. We suggest that differences in heteroblasty have co-evolved with overall leaf shape and size in Antirrhinum because these characters are constrained by common underlying genes. By contrast, heteroblasty is not correlated with other developmental transitions, with the exception of internode length, suggesting independent genetic control and evolution. PMID- 23025532 TI - Clinical significance of quantitative cytomegalovirus detection in bronchoalveolar lavage fluid in lung transplant recipients. AB - OBJECTIVES: Cytomegalovirus (CMV) is an important pathogen after lung transplant (LTx) and may be associated with bronchiolitis obliterans syndrome (BOS). We assessed the outcome of LTx patients with CMV DNA-positive bronchoalveolar lavage (BAL) during surveillance. METHODS: A single-center retrospective study was performed. Outpatients transplanted between September 2007 and February 2010, who had undergone at least 3 BALs, were included. CMV DNA load in BAL was measured by polymerase chain reaction (PCR). Monitoring of peripheral blood antigenemia was performed simultaneously. RESULTS: In total, 103 LTx patients underwent 1118 BALs. During median follow-up of 639 days (interquartile range, 495-780), 53 (51%) patients exhibited at least 1 positive CMV PCR in BAL. The incidence of positive CMV PCR varied post transplantation, with 6%, 30%, and 25% of BALs testing positive at <6 months, 6-24 months, and >24 months, respectively. Neither CMV BAL positivity, positive CMV antigenemia, nor dual positivity were significantly associated with BOS-free survival during follow-up. Patients with CMV-positive BAL more frequently developed CMV antigenemia in the first year (44% vs. 5%, respectively, log-rank P < 0.001). CONCLUSIONS: Detection of CMV-positive BAL after the sixth month appears common, but did not correlate with BOS-free survival after LTx in this study. An increased risk of developing blood antigenemia was observed in patients with positive CMV PCR in BAL, warranting close follow-up. PMID- 23025533 TI - Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and, potentially, other non-Hodgkin lymphoma subtypes. AB - A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P = 0.01; rs210142: P = 6.8 * 10(-3)). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes. PMID- 23025534 TI - On protein crowding and bilayer bulging in spontaneous vesicle formation. AB - Spontaneous aggregation of lipids into bilayers and vesicles is a key property for the formation of biological membranes. Understanding the compartmentalization achieved by vesicle formation is an important step toward understanding the origin of life, and is crucial in current efforts to develop artificial life. Spontaneously formed vesicles may be applied as artificial cells if they can efficiently encapsulate biomacromolecules. Recent studies report an enhanced concentration of encapsulated proteins during vesicle formation. In order to obtain more insight into this encapsulation process, here we simulate the spontaneous transition of flat bilayers to vesicles in the presence of solvated model proteins using molecular dynamics simulations. In the bilayer-vesicle transition, which is found to be unaffected by the presence of the solvated proteins, the bilayer edge remains at almost the same height, while the center of the membrane bulges out, a molecular pathway we denominate "bilayer bulging". This bulging results in an interior protein concentration that is significantly lower than that of the solution. By means of an increased protein-membrane interaction, enhanced encapsulation of proteins inside the vesicles could be achieved in our simulations. PMID- 23025535 TI - Extraosseous plasmacytoma with an aggressive course occurring solely in the CNS. AB - Extraosseous (extramedullary) plasmacytoma is a relatively indolent neoplasm that constitutes 3-5% of all plasma cell neoplasms. Rare cases have been reported to truly occur in the CNS and not as an extension from a nasal lesion. EBV expression in plasma cell neoplasms has been reported in very few cases that are mainly post-transplant or occurring in severely immunosuppressed patients. We report a case of extraosseous plasmacytoma with an aggressive course in an HIV positive individual that occurred solely in the CNS, showing EBV expression by in situ hybridization, and presenting as an intraparenchymal mass as well as in the CSF. PMID- 23025537 TI - Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes. AB - BACKGROUND: Obesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity. Inhibition of the inflammatory enzymes, matrix metalloproteinases (MMPs), for 6 months in rodent models restores insulin receptor function and insulin sensitivity. METHODS: This 12-week double-blind, randomized, placebo (PL)-controlled proof-of concept study was performed to determine if the MMP inhibitor (MMPI), doxycycline, decreased global markers of inflammation and enhanced muscle insulin sensitivity in obese people with type 2 diabetes (DM2). The study included non DM2 controls (n = 15), and DM2 subjects randomized to PL (n = 13) or doxycycline 100 mg twice daily (MMPI; n = 11). All participants were evaluated on Day 1; MMPI and PL groups were also evaluated after 84 days of treatment. RESULTS: There was a significant decrease in inflammatory markers C-reactive protein (P < 0.05) and myeloperoxidase (P = 0.01) in the MMPI but not PL group. The MMPI also significantly increased skeletal muscle activated/total insulin signaling mediators: 3'phosphoinositide kinase-1 (PDK1) (p < 0.03), protein kinase B (PKB/Akt) (p < 0.004), and glycogen synthase kinase 3beta (GSK3beta) (p < 0.03). CONCLUSIONS: This study demonstrated short term treatment of people with diabetes with an MMPI resulted in decreased inflammation and improved insulin sensitivity. Larger, longer studies are warranted to determine if doxycycline can improve glucose control in people with diabetes. TRIAL REGISTRATION: Clinicaltrials.gov NCT01375491. PMID- 23025538 TI - The search for biomarkers of disease: surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, tears, and thyroid associated ophthalmopathy. PMID- 23025539 TI - Pros and cons of robotic transaxillary thyroidectomy. PMID- 23025540 TI - Pros of robotic transaxillary thyroid surgery: its impact on cancer control and surgical quality. PMID- 23025541 TI - Robotic thyroidectomy: must we drive a luxury sedan to arrive at our destination safely? PMID- 23025542 TI - Detection of PAX8/PPARG and RET/PTC rearrangements is feasible in routine air dried fine needle aspiration smears. AB - BACKGROUND: The diagnostic limitations of fine needle aspiration (FNA), like the indeterminate category, can be partially overcome by molecular analysis. As PAX8/PPARG and RET/PTC rearrangements have been detected in follicular thyroid carcinomas (FTCs) and papillary thyroid carcinomas (PTCs), their detection in FNA smears could improve the FNA diagnosis. To date, these rearrangements have never been analyzed in routine air-dried FNA smears, but only in frozen tissue, formalin-fixed paraffin-embedded (FFPE) tissue, and in fresh FNA material. Fixed routine air-dried FNA samples have hitherto been judged as generally not suitable for testing these rearrangements in a clinical setting. Therefore, the objective of the present study was to investigate the feasibility of extracting RNA from routine air-dried FNA smears for the detection of these rearrangements with real time polymerase chain reaction (RT-PCR). METHODS: A new method for RNA extraction from routine air-dried FNA smears was established, which allowed analysis for the presence of four variants of PAX8/PPARG and RET/PTC 1 and RET/PTC 3, which were analyzed in 106 routine FNA smears and the corresponding surgically obtained FFPE tissues using real-time quantitative PCR (RT-qPCR). To assess RNA quality, an intron-spanning PAX8 cDNA was amplified. RESULTS: Acceptable RNA quality was obtained from 95% of the FNA samples and 92% of the FFPE samples. PAX8/PPARG was detected in 4 of 96 FFPEs and in 6 of 96 FNAs. PAX8/PPARG was present in 4 of 10 FTCs and in 3 of 42 follicular adenomas (FAs). Similarly, RET/PTC was found in 3 of 96 FFPEs and in 4 of 96 FNAs. Two of 21 PTC samples and 3 of 42 FA samples carried this rearrangement. CONCLUSION: These data are the first to show the feasibility of extracting RNA from routine air-dried FNA smears for the detection of PAX8/PPARG and RET/PTC rearrangements with RT-qPCR. These promising methodological advances, if confirmed in larger series of FNA and FFPE samples, may lead to the introduction of molecular analysis of routine air-dried FNA smears in everyday practice. PMID- 23025544 TI - The genotype of RAET1L (ULBP6), a ligand for human NKG2D (KLRK1), markedly influences the clinical outcome of allogeneic stem cell transplantation. AB - NKG2D (KLRK1) is an activating receptor on natural killer (NK) and T-cells and binds a diverse panel of polymorphic ligands encoded by the MIC and RAET1 gene families. We studied the clinical importance of retinoic acid early transcript-1 (RAET1) polymorphism in allogeneic stem cell transplantation (SCT) by determining the frequency of 18 single nucleotide polymorphisms (SNPs) and individual RAET1 alleles in 371 patient-donor pairs and relating this to clinical outcome. A strong association was observed between the presence of five SNPs within the patient RAET1L (ULBP6) gene and relapse-free survival and overall survival. Two common alleles of RAET1L were determined and the presence of the protective RAET1L*02 allele in the patient was associated with a relapse-free survival of 44% at 8 years compared with just 25% in patients who lacked a RAET1L*02 allele (P < 0.001). Overall survival at this time was 55% in those with RAET1L*02 allele compared to 39% in patients who lacked a RAET1L*02 allele (P = 0.003). These novel findings indicate a critical role for NKG2D-RAET1L interactions in determining SCT clinical outcome and show RAET1L may have an important influence on regulating the strength of the alloreactive immune response. The data will be of value in guiding the development of future transplant therapy protocols. PMID- 23025545 TI - Redox and nitrosative regulation of cardiac remodeling. AB - Heart disease is a major cause of death and morbidity worldwide, particularly so in industrialized nations. A major contributor to its varied pathophysiology is abnormal oxidative/reductive and nitrosative stress. While oxidant-scavenging therapies for cardiovascular disease have been disappointing to date, new insights into the precise sources of oxidative/nitrosative stress, its compartmentalized targets, and the modulators designed to control it are paving the way for a very different approach. This issue of the journal presents a Forum highlighting recent work from an international network of investigators that focuses on the role of oxidative/nitrosative stress in the remodeling heart. PMID- 23025546 TI - Application of ruthenium complexes of triazole-containing tridentate ligands to asymmetric transfer hydrogenation of ketones. AB - The synthesis of a series of tridentate ligands based on a homochiral 1,2-diamine structure attached to a triazole group and their subsequent applications to the asymmetric transfer hydrogenation of ketones are described. In the best cases, alcohols of up to 93% ee were obtained. Although base is not required, the use of Ru(3)(CO)(12) as metal source is essential, indicating a unique mechanism for the formation of the active catalyst. PMID- 23025547 TI - Poorer sleep quality is associated with lower emotion-regulation ability in a laboratory paradigm. AB - Theoretical models suggest a positive relationship between sleep quality and individuals' ability to regulate emotion. However, few studies have empirically tested this hypothesised link using standardised laboratory measures of emotion regulation ability. The present research examined the relationship between sleep quality and the ability to implement a type of emotion regulation that has particularly important implications for psychological health: cognitive reappraisal (cognitively reframing an emotional event so as to dampen its impact). To do so, 156 participants (86 male) reported on their past week's sleep quality. Their ability to implement cognitive reappraisal (CRA) was then measured with a standardised laboratory challenge. Participants with poorer self-reported sleep quality exhibited lower CRA, even after controlling for fourteen potential key confounds (e.g., age, negative affect, mood disorder symptoms, stress). This finding is consistent with the idea that poorer sleep quality impairs individuals' ability to engage in the crucial task of regulating negative emotions. PMID- 23025548 TI - Facial contact dermatitis and the irritant potential of mobile phone screens. AB - A teenager with atopic dermatitis presented with a 12-month history of recurrent, pruritic, round and polygonal patches on her face. Patch tests using the European standard series (including nickel, chromium, and cobalt chloride), a plastic and glue series of allergens, polyester components, and personal and environmental products in contact with the patient were conducted. For the patient and 3 of 14 healthy volunteers, positive reactions were observed to the patient's mobile phone touchscreen (TS), an extract solution from the TS, and a non-TS phone of another brand. Accordingly, the patient's dermatitis disappeared when contact with mobile phone screens was avoided. PMID- 23025549 TI - Arabidopsis mutants of sphingolipid fatty acid alpha-hydroxylases accumulate ceramides and salicylates. AB - In Arabidopsis, the fatty acid moiety of sphingolipids is mainly alpha hydroxylated. The consequences of a reduction in this modification were analysed. Mutants of both Fatty Acid Hydroxylase genes (AtFAH1 and AtFAH2) were analysed for sphingolipid profiles. To elucidate further consequences of the mutations, metabolic analyses were performed and the influence on pathogen defence was determined. Ceramide and glucosylceramide profiles of double-mutant plants showed a reduction in sphingolipids with alpha-hydroxylated fatty acid moieties, and an accumulation of sphingolipids without these moieties. In addition, the free trihydroxylated long-chain bases and ceramides were increased by five- and ten fold, respectively, whereas the amount of glucosylceramides was decreased by 25%. Metabolite analysis of the double mutant revealed salicylates as enriched metabolites. Infection experiments supported the metabolic changes, as the double mutant showed an enhanced disease-resistant phenotype for infection with the obligate biotrophic pathogen Golovinomyces cichoracearum. In summary, these results suggest that fatty acid hydroxylation of ceramides is important for the biosynthesis of complex sphingolipids. Its absence leads to the accumulation of long-chain bases and ceramides as their precursors. This increases salicylate levels and resistance towards obligate biotrophic fungal pathogens, confirming a role of sphingolipids in salicylic acid-dependent defence reactions. PMID- 23025550 TI - Cultivation in human serum reduces adipose tissue-derived mesenchymal stromal cell adhesion to laminin and endothelium and reduces capillary entrapment. AB - The increasing use of mesenchymal stromal cells (MSC) in clinical cellular therapy requires a safe and controlled production process compliant with Good Manufacturing Practice guidelines. Pooled blood group AB human serum (HS) has been used to replace fetal bovine serum (FBS), critically rated by the regulatory agencies, since it can support the expansion of adipose tissue-derived mesenchymal stromal cells (ASC). However, it remains unknown whether the choice of serum affects application-relevant characteristics of ASC. A microarray-based screen has revealed differentially expressed adhesion and extracellular matrix associated molecules in HS- and FBS-ASC. Since cell therapy relies on the cells' efficacy to home and engraft, HS- and FBS-ASC were compared by analyzing adhesion, migration, and transmigration as well as short-term homing in vivo. HS cultivated ASC demonstrated a higher adhesion to plastic, but reduced adhesion to extracellular matrix molecules, that is, laminin, and to endothelial cells both under static and flow conditions. Migration and transmigration assays confirmed the attraction of ASC by the tumor conditioned medium irrespective of the supplement. Coinjecting differently labeled HS- and FBS-ASC into nonobese diabetic, severe combined immunodeficiency mice revealed reduced numbers of HS ASC in lungs and liver. This has been interpreted as reduced capillary entrapment. Our data indicate that varying the serum supplement may alter application-relevant characteristics of ASC, such as adhesion, as well as lung entrapment after infusion. Appropriate injury models and further molecular analyses are required to provide mechanistic insight into the differential effects of HS versus FBS on ASC cultures. PMID- 23025551 TI - A single nuclease-resistant linkage in DNA as a versatile tool for the characterization of DNA lesions: application to the guanine oxidative lesion "G+34" generated by metalloporphyrin/KHSO(5) reagent. AB - The oxidation of an oligonucleotide containing a single nuclease-resistant phosphodiester link, a stereoisomerically pure methylphosphonate, by manganese (Mn-TMPyP) or iron (Fe-TMPyP) porphyrin associated to KHSO(5) allowed the isolation and characterization of a guanine lesion corresponding to an increase of mass of 34 amu as compared to guanine ("G+34"), namely, 5-carboxamido-5 formamido-2-iminohydantoin. Enzymatic digestion of the damaged oligonucleotide afforded, apart from the undamaged nucleotide monomer pool, a unique dinucleotide doubly modified with a methylphosphonate and an oxidized guanine base that is suitable for NMR analysis. The method can be applied to the study of any DNA lesion. More importantly, the method can be extended to the analysis of DNA damage in a sequence context. Any preselected residue in a DNA sequence may be individually analyzed by the easy introduction of a single nuclease-resistant link at the 3'- or 5'-position. PMID- 23025552 TI - Contrasted patterns of selective pressure in three recent paralogous gene pairs in the Medicago genus (L.). AB - BACKGROUND: Gene duplications are a molecular mechanism potentially mediating generation of functional novelty. However, the probabilities of maintenance and functional divergence of duplicated genes are shaped by selective pressures acting on gene copies immediately after the duplication event. The ratio of non synonymous to synonymous substitution rates in protein-coding sequences provides a means to investigate selective pressures based on genic sequences. Three molecular signatures can reveal early stages of functional divergence between gene copies: change in the level of purifying selection between paralogous genes, occurrence of positive selection, and transient relaxed purifying selection following gene duplication. We studied three pairs of genes that are known to be involved in an interaction with symbiotic bacteria and were recently duplicated in the history of the Medicago genus (Fabaceae). We sequenced two pairs of polygalacturonase genes (Pg11-Pg3 and Pg11a-Pg11c) and one pair of auxine transporter-like genes (Lax2-Lax4) in 17 species belonging to the Medicago genus, and sought for molecular signatures of differentiation between copies. RESULTS: Selective histories revealed by these three signatures of molecular differentiation were found to be markedly different between each pair of paralogs. We found sites under positive selection in the Pg11 paralogs while Pg3 has mainly evolved under purifying selection. The most recent paralogs examined Pg11a and Pg11c, are both undergoing positive selection and might be acquiring new functions. Lax2 and Lax4 paralogs are both under strong purifying selection, but still underwent a temporary relaxation of purifying selection immediately after duplication. CONCLUSIONS: This study illustrates the variety of selective pressures undergone by duplicated genes and the effect of age of the duplication. We found that relaxation of selective constraints immediately after duplication might promote adaptive divergence. PMID- 23025554 TI - Enhancing the efficacy of fouling-release coatings against fouling by Mytilus galloprovincialis using nanofillers. AB - Fouling-release (FR) coatings minimise the adhesion strength of fouling organisms. This study describes improved technologies to control the settlement and adhesion of the important fouling organism Mytilus galloprovincialis by incorporating the nanofillers titanium dioxide (TiO(2)) and carbon nanotubes (CNTs) in polydimethylsiloxane (PDMS) matrices. The incorporation of TiO(2) prevented larval settlement when photoactivated with UV light, even at the lowest concentration of the nanofiller (3.75 wt%). Notably, there was 100% mortality of pediveligers exposed to photoactivated TiO(2). However, plantigrades initially settled to photoactivated TiO(2), but their adhesion strength was significantly reduced on these surfaces in comparison to blank PDMS. In addition, plantigrades had high mortality after 6 h. In contrast to the enhanced antifouling and FR properties of PDMS incorporating TiO(2), the incorporation of CNTs had no effect on the settlement and adhesion of M. galloprovincialis. PMID- 23025553 TI - Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety. AB - BACKGROUND: The disappointing clinical failures of five topical vaginal microbicides have provided new insights into factors that impact microbicide safety and efficacy. Specifically, the greater risk for human immunodeficiency virus type 1 (HIV-1) acquisition associated with multiple uses of a nonoxynol-9 (N-9)-containing product has highlighted the importance of application frequency as a variable during pre-clinical microbicide development, particularly in animal model studies. METHODS: To evaluate an association between application frequency and N-9 toxicity, experiments were performed using a mouse model of cervicovaginal microbicide safety. In this model system, changes in cervical and vaginal epithelial integrity, cytokine release, and immune cell infiltration were assessed after single and multiple exposures to N-9. RESULTS: After the initial application of N-9 (aqueous, 1%), considerable damage to the cervical epithelium (but not the vaginal epithelium) was observed as early as 10 min post-exposure and up to 8 h post-exposure. Subsequent daily exposures (up to 4 days) were characterized by diminished cervical toxicity relative to single exposures of like duration. Levels of pro-inflammatory cytokines released into the cervicovaginal lumen and the degree of CD14-positive immune cell infiltration proximal to the cervical epithelium were also dependent on the number of N-9 exposures. CONCLUSIONS: Rather than causing cumulative cervical epithelial damage, repeated applications of N-9 were characterized by decreased sensitivity to N-9-associated toxicity and lower levels of immune cell recruitment. These results provide new insights into the failure of N-9-based microbicides and illustrate the importance of considering multiple exposure protocols in pre clinical microbicide development strategies. PMID- 23025555 TI - Bilateral intraventricular mass in a child. PMID- 23025556 TI - Probing the effect of drug loading and humidity on the mechanical properties of solid dispersions with nanoindentation: antiplasticization of a polymer by a drug molecule. AB - Amorphous solid dispersions of clotrimazole in the polymer Kollidon VA64 were prepared as films in concentrations from 0% to 100% in 10% by weight increments. Nanoindentation was performed on each film at 18% and 49% relative humidity to assess the effect of drug loading and humidity on the mechanical properties of the solid dispersions. Although the addition of clotrimazole to the polymer reduces the glass transition temperature of the system as measured by differential scanning calorimetry, the hardness, reduced elastic modulus, and storage modulus were found to increase to values greater than those of either pure component up to drug loadings of approximately 60% by weight. Further addition of clotrimazole to the system resulted in decreased hardness and moduli with increased drug load. Dynamic vapor sorption of the dispersions shows that the hygroscopicity of the system is reduced as clotrimazole is added to the polymer. PMID- 23025557 TI - Enzyme-responsive polymeric supra-amphiphiles formed by the complexation of chitosan and ATP. AB - Chitosan and adenosine-5'-triphosphate (ATP) are employed as building blocks to fabricate polymeric supra-amphiphiles based on electrostatic interactions, which can self-assemble to form spherical aggregates. The spherical aggregates inherit the phosphotase responsiveness of ATP. Compared to our previous work, this enzyme responsive system can be more biocompatible and block polymers are not needed in preparation, which makes it possible to fabricate the chitosan-based enzyme responsive assemblies in a large-scale, cheap way. Therefore, the application of the assemblies for nanocontainers and drug delivery is greatly anticipated. PMID- 23025558 TI - Dynamic evocation of hand action representations during sentence comprehension. AB - When listening to a sentence describing an interaction with a manipulable object, understanding the actor's intentions is shown to have a striking influence on action representations evoked during comprehension. Subjects performed a cued reach and grasp response while listening to a context sentence. Responses were primed when they were consistent with the proximal intention of an actor ("John lifted the cell phone..."), but this effect was evanescent and appeared only when sentences mentioned the proximal intention first. When the sentence structure was changed to mention the distal intention first ("To clear the shelf..."), priming effects were no longer context specific and actions pertaining to the function of an object were clearly favored. These results are not compatible with a straightforward mental-simulation account of sentence comprehension but instead reflect a hierarchy of intentions distinguishing how and why actions are performed. PMID- 23025559 TI - A knowledge-based theory of rising scores on "culture-free" tests. AB - Secular gains in intelligence test scores have perplexed researchers since they were documented by Flynn (1984, 1987). Gains are most pronounced on abstract, so called culture-free tests, prompting Flynn (2007) to attribute them to problem solving skills availed by scientifically advanced cultures. We propose that recent-born individuals have adopted an approach to analogy that enables them to infer higher level relations requiring roles that are not intrinsic to the objects that constitute initial representations of items. This proposal is translated into item-specific predictions about differences between cohorts in pass rates and item-response patterns on the Raven's Matrices (Flynn, 1987), a seemingly culture-free test that registers the largest Flynn effect. Consistent with predictions, archival data reveal that individuals born around 1940 are less able to map objects at higher levels of relational abstraction than individuals born around 1990. Polytomous Rasch models verify predicted violations of measurement invariance, as raw scores are found to underestimate the number of analogical rules inferred by members of the earlier cohort relative to members of the later cohort who achieve the same overall score. The work provides a plausible cognitive account of the Flynn effect, furthers understanding of the cognition of matrix reasoning, and underscores the need to consider how test takers select item responses. PMID- 23025560 TI - Distance from a distance: psychological distance reduces sensitivity to any further psychological distance. AB - What is the difference between far and further? Investigations into such psychological distancing--removal from an egocentric reference point--have suggested similarities between geographical space, time, probability, and social distance. We draw on these similarities to propose that experiencing any kind of distance will reduce sensitivity to any other distance. Nine studies varied the initial distance of an event and assessed sensitivity to a second distance. Consistently, people were less responsive to a given span of distance when it was distal versus proximal. This effect held using each of the four distances as the initial instantiation of distance; it also held using each dimension to assess sensitivity to distance (i.e., as the second distance dimension). These findings suggest that the dimensions of psychological distance share a common, interchangeable meaning and that the cross-dimension difference between far and further is less than that between near and far. PMID- 23025561 TI - A dose of ruthlessness: interpersonal moral judgment is hardened by the anti anxiety drug lorazepam. AB - Neuroimaging data suggest that emotional brain systems are more strongly engaged by moral dilemmas in which innocent people are directly harmed than by dilemmas in which harm is remotely inflicted. In order to test the possibility that this emotional engagement involves anxiety, we investigated the effects of 1 mg and 2 mg of the anti-anxiety drug lorazepam on the response choices of 40 healthy volunteers (20 male) in moral-personal, moral-impersonal, and nonmoral dilemmas. We found that lorazepam caused a dose-dependent increase in participants' willingness to endorse responses that directly harm other humans in moral personal dilemmas but did not significantly affect response choices in moral impersonal dilemmas or nonmoral dilemmas. Within the set of moral-personal dilemmas that we administered, lorazepam increased the willingness to harm others in dilemmas where harm was inflicted for selfish reasons (dubbed low-conflict dilemmas) as well as responses to dilemmas where others were harmed for utilitarian reasons (i.e., for the greater good, dubbed high-conflict dilemmas). This suggests that anxiety exerts a general inhibitory effect on harmful acts toward other humans regardless of whether the motivation for those harmful acts is selfish or utilitarian. Lorazepam is also a sedative drug, but we found that lorazepam slowed decision times equally in all 3 dilemma types. This finding implies that its specific capacity to increase ruthlessness in moral-personal dilemmas was not a confound caused by sedation. PMID- 23025562 TI - Constraints in task-set control: modality dominance patterns among effector systems. AB - Flexibility in configuring task sets allows people to adequately respond to environmental stimuli in different contexts, such as in dual-task situations. In the present study, we examined to what extent response control is influenced by the modality of a concurrently executed response. In Experiment 1, participants responded to auditory stimuli with either vocal responses and/or saccades. In Experiment 2, vocal responses were combined with manual responses. In both experiments, we found asymmetric dual-response costs, that is, the response time difference between single- and dual-response conditions varied between response modalities. It is important to note that the same (vocal) response showed substantial dual-response costs when combined with saccades (Experiment 1) but no such costs when combined with manual responses (Experiment 2). Experiment 3, combining saccades with manual responses, revealed stronger dual-response costs for manual responses than for saccades. Together, these findings suggest an ordinal dominance pattern among response modalities, representing flexible, response-based resource scheduling during task-set configuration. PMID- 23025563 TI - Complete mitochondrial genome of the endangered Asian giant softshell turtle Pelochelys cantorii (Testudinata: Trionychidae). AB - The complete mitogenomes of the endangered Asian giant softshell turtle Pelochelys cantorii (Testudinata: Trionychidae) were first determined from two living specimens, with the lengths of 17,612 and 17,499 bp, which showed the typical mitogenomic characteristics of vertebrates. An A+1 frameshift mutation at position 174 of the ND3 gene was identified. Seven point mutations were found between the two mitogenomes. The length variation of the two mitogenomes was due to the different repeat numbers of the tandem motifs in the control regions. PMID- 23025564 TI - Influence of chorionicity in intra-partum management of twin deliveries. AB - OBJECTIVE: To analyze morbidity and mortality in twin pregnancies as a function of the type of delivery and chorionicity. DESIGN: Retrospective cohort study. METHODS: Analysis of the type of delivery, intertwin time interval, and perinatal variables of >1000 twin deliveries during a 10-year period. MAIN OUTCOME MEASURE: Influence of delivery type and chorionicity on perinatal outcome. RESULTS: The rate of cesarean sections was 42.4%. No differences were found as a function of chorionicity or as a function of presentation of the second twin. Cesarean sections were performed after vaginal delivery of the first twin in 1.8% of cases, being more common if the second baby was in a non-cephalic presentation (6.9% vs. 0.4%, p < 0.05). The average twin-to-twin delivery time interval was longer in the cases where the second had a cephalic presentation (8.26 +/- 7.75 min vs. 6.81 +/- 5.97 min, p < 0.05). The umbilical artery pH was lower the longer the interval between the birth of the twins, both in monochorionic and dichorionic. CONCLUSIONS: According to the results, vaginal delivery is as safe as elective caesarean section in twin pregnancies where the first twin is in cephalic presentation and the intrapartum management should not vary due to chorionicity. PMID- 23025565 TI - Extensive emphysematous pyelonephritis in a renal allograft treated conservatively: case report and review of the literature. AB - Emphysematous pyelonephritis (EPN) is a rare occurrence in renal allografts. An aggressive approach resulting in transplant nephrectomy is viewed as the standard of care. Over the recent years, treatment with percutaneous drainage (PCD) of the renal and perinephric collections and appropriate antibiotics has been reported with good success in lesser grades of this infection. Only 4 cases of extensive EPN disease with Escherichia coli, treated with conservative management, are reported in the English-language literature. We present a case of severe EPN caused by Klebsiella pneumoniae, successfully managed with early PCD, and propose a step-up strategy aimed toward graft preservation. PMID- 23025566 TI - Inhibitors of mTOR and risks of allograft failure and mortality in kidney transplantation. AB - Data on long-term outcomes of users of inhibitors of the mammalian target of rapamycin (mTORI) are lacking in kidney transplantation. In an analysis of 139 370 US kidney transplant recipients between 1999 through 2010, we compared clinical outcomes among users of mTORIs versus calcineurin inhibitors (CNI) in their primary immunosuppresive regimen. During the first 2 years posttransplantation, primary use of mTORIs without CNIs (N = 3237) was associated with greater risks of allograft failure and death compared with a CNI-based regimen (N = 125 623); the hazard ratio (HR) of the composite outcome ranged from 3.67 (95% confidence interval [CI], 3.12-4.32) after discharge to 1.40 (95% CI 1.26-1.57) by year 2. During years 2-8, primary use of mTORIs without CNIs was independently associated with greater risks of death (HR 1.25; 95% CI, 1.11-1.41) and the composite (HR 1.17; 95%CI, 1.08-1.27) in fully adjusted analyses. The results were qualitatively unchanged in subgroups defined by medical history, immunological risk and clinical course during the index transplant hospitalization. In a propensity-score matched cohort, use of mTORIs was associated with significantly worse outcomes during the first 2 years and greater risks of death (HR 1.21; 95% CI, 1.05-1.39) and the composite (HR 1.18; 95% CI, 1.08-1.30) in years 2-8. Compared with CNI-based regimens, use of an mTORI-based regimen for primary immunosuppression in kidney transplantation was associated with inferior recipient survival. PMID- 23025567 TI - Interactions between lead-zirconate titanate, polyacrylic acid, and polyvinyl butyral in ethanol and their influence on electrophoretic deposition behavior. AB - Electrophoretic deposition (EPD) is an attractive method for the fabrication of a few tens of micrometer-thick piezoelectric layers on complex-shape substrates that are used for manufacturing high-frequency transducers. Niobium-doped lead zirconate titanate (PZT Nb) particles were stabilized in ethanol using poly(acrylic acid) (PAA). With Fourier-transform infrared spectroscopy (FT-IR), we found that the deprotonated carboxylic group from the PAA is coordinated with the metal in the perovskite PZT Nb structure, resulting in a stable ethanol-based suspension. The hydroxyl group from the polyvinyl butyral added into the suspension to prevent the formation of cracks in the as-deposited layer did not interact with the PAA-covered PZT Nb particles. PVB acts as a free polymer in ethanol-based suspensions. The electrophoretic deposition of micro- and nanometer sized PZT Nb particles from ethanol-based suspensions onto electroded alumina substrates was attempted in order to obtain uniform, crack-free deposits. The interactions between the PZT Nb particles, the PAA, and the PVB in ethanol will be discussed and related to the properties of the suspensions, the deposition yield and the morphology of the as-deposited PZT Nb thick film. PMID- 23025569 TI - CuI-mediated sequential iodination/cycloetherification of o-arylphenols: synthesis of 2- or 4-iododibenzofurans and mechanistic studies. AB - An efficient synthesis of 2- or 4-iododibenzofurans through CuI-mediated sequential iodination/cycloetherification of two aromatic C-H bonds in o arylphenols has been developed. Both the preexisting electron-withdrawing groups (NO(2), CN, and CHO) and the newly introduced iodide are readily modified for a focused dibenzofuran library synthesis. Mechanistic studies and DFT calculations suggest that a Cu(III)-mediated rate-limiting C-H activation step is involved in cycloetherification. PMID- 23025568 TI - Effect of a family focused active play intervention on sedentary time and physical activity in preschool children. AB - BACKGROUND: Early childhood provides a window of opportunity for the promotion of physical activity. Given the limited effectiveness of interventions to date, new approaches are needed. Socio-ecological models suggest that involving parents as intervention targets may be effective in fostering healthier lifestyles in children. This study describes the effectiveness of a family-focused 'Active Play' intervention in decreasing sedentary time and increasing total physical activity in preschool children. METHOD: Seventy-seven families were recruited from 8 randomly selected SureStart children's centres in the North West of England. Centres were randomly assigned to either an intervention (n = 4) or a comparison group (n = 4). Parents and children in the intervention group received a 10-week active play programme delivered by trained active play professionals; this included an activity and educational component. Families in the comparison group were asked to maintain their usual routine. Each participating parent and child wore a uni-axial accelerometer for 7 days at baseline and post-test. Week and weekend day sedentary time and total physical activity adjusted for child- and home- level covariates were analysed using multilevel analyses. RESULTS: Significant intervention effects were observed for sedentary time and physical activity for both week and weekend days. Children in the intervention group engaged in 1.5% and 4.3% less sedentary time during week and weekend days, respectively and 4.5% and 13.1% more physical activity during week and weekend days, respectively than children in the comparison group. Parent's participation in sport and their physical activity levels, child's sex, availability of media in the home and attendance at organised activities were significant predictors of sedentary time and physical activity in this age group. CONCLUSION: A 10-week family focused active play intervention produced positive changes in sedentary time and total physical activity levels in preschool children. Specific covariates were identified as having a significant effect on the outcome measures. Moreover, children whose parents were active engaged in less sedentary time and more physical activity suggesting that parent's activity habits are mediators of physical activity engagement in this age group. PMID- 23025570 TI - Density functional study on the cytochrome-mediated S-oxidation: identification of crucial reactive intermediate on the metabolic path of thiazolidinediones. AB - S-Oxidation is an important cytochrome P450 (CYP450)-catalyzed reaction, and the structural and energetic details of this process can only be studied by using quantum chemical methods. Thiazolidinedione (TZD) ring metabolism involving initial S-oxidation leads to the generation of reactive metabolites (RMs) and subsequent toxicity forcing the withdrawal of the glitazone class of drugs, thus, the study of the biochemical pathway of TZD ring metabolism is a subject of interest. The S-oxidation of the TZD ring and the formation of the isocyanate intermediate (ISC) was implicated as a possible pathway; however, there are several questions still unanswered in this biochemical pathway. The current study focuses on the CYP450-mediated S-oxidation, fate of the sulfoxide product (TZDSO), ring cleavage to ISC, and formation of nucleophilic adducts. The process of S-oxidation was explored by using Cpd I (iron(IV)-oxo porphyrin, to mimic CYP450) at TZVP/6-311+G(d) basis set. The barriers were calculated after incorporating dispersion and solvent corrections. The metabolic conversion from TZDSO to ISC (studied at B3LYP/6-311++G(2df,3pd)//B3LYP/6-31+G(d)) required a novel protonated intermediate, TZDSOH(+). The effect of higher basis sets (6 311+G(d,p), aug-cc-pvqz) on this conversion was studied. TZDSOH(+) was observed to be more reactive and thermodynamically accessible than ISC, indicating that TZDSOH(+) is the actual reactive intermediate leading to toxicity of the TZD class of compounds. PMID- 23025571 TI - Subcongenic analysis of tabw2 obesity QTL on mouse chromosome 6. AB - BACKGROUND: We previously established a congenic mouse strain with TALLYHO/Jng (TH) donor segment on chromosome 6 in a C57BL/6 (B6) background that harbors an obesity quantitative trait locus, tabw2. The B6.TH-tabw2 congenic mice developed increased adiposity that became exacerbated upon feeding a high fat-high sucrose (HFS) diet. To fine map the tabw2, in this study we generated and characterized subcongenic lines with smaller TH donor segments. RESULTS: We fixed four subcongenic lines, with maximum size of donor segment retained in the lines ranging from 10.8 - 92.5 Mb. For mapping, all the subcongenic mice, along with B6.TH-tabw2 congenic and B6-homozygous control mice were fed either chow or HFS diets, and their post-mortem fat pads were weighed. Mice were also characterized for energy expenditure, respiratory exchange ratio, locomotor activity, and food intake. As previously reported, B6.TH-tabw2 congenic mice showed a significantly larger fat mass than controls on both diets. On chow, a subcongenic line retaining the distal region of the TH donor congenic interval exhibited significantly larger fat mass than B6-homozygous controls, and comparable that to B6.TH-tabw2 congenic mice. Two nested subcongenic lines within that region suggested that the effect of tabw2 on obesity could be attributed to at least two subloci. On HFS diets, on the other hand, all the subcongenic mice had significantly larger fat mass than controls without genotype differences, but none of them had fat mass as large as the original congenic mice. This possibly implicates that further genetic complexity involves in the effect of tabw2 on diet-induced obesity. Significantly reduced locomotor activity was exhibited in B6.TH-tabw2 congenic and subcongenic mice compared to controls when animals were fed HFS diets. B6.TH-tabw2 congenic mice, but not subcongenic mice, also had significantly increased food intake on HFS diets. CONCLUSIONS: It appears that at least two subloci explaining the tabw2 effect under chow feeding map to the distal region of the congenic interval, whereas the diet-induced obesity mediated by tabw2 is attributed to more complex genetic mechanism. PMID- 23025572 TI - Extensive hypertrophic scarring after toxic epidermal necrolysis in a child. AB - Stevens-Johnson syndrome and toxic epidermal necrolysis are some of the most serious, usually drug-induced, skin reactions. We report a case of severe toxic epidermal necrolysis in a child, which in addition to ophthalmic sequelae, caused extensive hypertrophic scarring of the skin. Such a course is uncommon and has rarely been described in the literature. PMID- 23025573 TI - Kinematic changes in jaw and lip control of children with cerebral palsy following participation in a motor-speech (PROMPT) intervention. AB - This study evaluates kinematic movements of the jaw and lips in six children (3 11 years) with moderate-to-severe speech impairment associated with cerebral palsy before, during, and after participation in a motor-speech (PROMPT) intervention program. An ABCA single subject research design was implemented. Subsequent to the baseline phase (A), phase B targeted each participant's first intervention priority on the PROMPT motor-speech hierarchy. Phase C then targeted one level higher. A reference group of 12 typically-developing peers, age- and sex-matched to each participant with CP, was recruited for comparison in the interpretation of the kinematic data. Jaw and lip measurements of distance, velocity, and duration, during the production of 11 untrained stimulus words, were obtained at the end of each study phase using 3D motion analysis (Vicon Motus 9.1). All participants showed significant changes in specific movement characteristics of the jaw and lips. Kinematic changes were associated with significant positive changes to speech intelligibility in five of the six participants. This study makes a contribution to providing evidence that supports the use of a treatment approach aligned with dynamic systems theory to improve the motor-speech movement patterns and speech intelligibility in children with cerebral palsy. PMID- 23025575 TI - Quantitative fracture strength and plasticity measurements of lithiated silicon nanowires by in situ TEM tensile experiments. AB - We report in situ tensile strength measurement of fully lithiated Si (Li-Si alloy) nanowires inside a transmission electron microscope. A specially designed dual probe with an atomic force microscopy cantilever and a scanning tunneling microscopy electrode was used to conduct lithiation of Si nanowires and then perform in situ tension of the lithiated nanowires. The axial tensile strength decreased from the initial value of 3.6 GPa for the pristine unlithiated Si nanowires to 0.72 GPa for the lithiated Li-Si alloy. We observed large fracture strain ranging from 8% to 16% for Li-Si alloy, 70% of which remained permanent after fracture. This indicates a certain degree of tensile plasticity in the lithiated silicon before fracture, important for constitutive modeling of the lithium-ion battery cyclability. We also compare the ab initio computed ideal strengths with our measured strengths and attribute the differences to the morphology and flaws in the lithiated nanowires. PMID- 23025576 TI - X-ray imaging of leaf venation networks. AB - Leaf venation networks mediate many plant resource fluxes and are therefore of broad interest to research questions in plant physiology, systematics, paleoecology, and physics. However, the study of these networks is limited by slow and destructive imaging methods. X-ray imaging of leaf veins is potentially rapid, of high resolution, and nondestructive. Here, we have developed theory for absorption- and phase-contrast X-ray imaging. We then experimentally test these approaches using a synchrotron light source and two commercially available X-ray instruments. Using synchrotron light, we found that major veins could be consistently visualized using absorption-contrast imaging with X-ray energies < 10 keV, while both major and minor veins could be consistently visualized with the use of an iodine contrast agent at an X-ray energy of 33.269 keV. Phase contrast imaging at a range of energies provided high resolution but highlighted individual cell walls more than veins. Both approaches allowed several hundred samples to be processed per d. Commercial X-ray instruments were able to resolve major veins and some minor veins using absorption contrast. These results show that both commercial and synchrotron X-ray imaging can be successfully applied to leaf venation networks, facilitating research in multiple fields. PMID- 23025577 TI - Differentiation of human adipose-derived stem cells into fat involves reactive oxygen species and Forkhead box O1 mediated upregulation of antioxidant enzymes. AB - Both reactive oxygen species (ROS) and Forkhead box O (FOXO) family transcription factors are involved in the regulation of adipogenic differentiation of preadipocytes and stem cells. While FOXO has a pivotal role in maintaining cellular redox homeostasis, the interactions between ROS and FOXO during adipogenesis are not clear. Here we examined how ROS and FOXO regulate adipogenesis in human adipose-derived stem cells (hASC). The identity of isolated cells was confirmed by their surface marker expression pattern typical for human mesenchymal stem cells (positive for CD29, CD44, CD73, CD90, and CD105, negative for CD45 and CD31). Using a standard adipogenic cocktail consisting of insulin, dexamethasone, indomethacin, and 3-Isobutyl-1-methylanxthine (IDII), adipogenesis was induced in hASC, which was accompanied by ROS generation. Scavenging ROS production with N-acetyl-L-cysteine or EUK-8, a catalytic mimetic of superoxide dismutase (SOD) and catalase, inhibited IDII-induced adipogenesis. We then mimicked IDII-induced oxidative stress through a lentiviral overexpression of Nox4 and an exogenous application of hydrogen peroxide in hASC and both manipulations significantly enhanced adipogenesis without changing the adipogenic differentiation rate. These data suggest that ROS promoted lipid accumulation in hASC undergoing adipogenesis. Antioxidant enzymes, including SOD2, catalase, and glutathione peroxidase were upregulated by IDII during adipogenesis, and these effects were blunted by FOXO1 silencing, which also suppressed significantly IDII induced adipogenesis. Our findings demonstrated a balance of ROS generation and endogenous antioxidants in cells undergoing adipogenesis. Approaches targeting ROS and/or FOXO1 in adipocytes may bring new strategies to prevent and treat obesity and metabolic syndrome. PMID- 23025578 TI - Stability of N-glycosidic bond of (5'S)-8,5'-cyclo-2'-deoxyguanosine. AB - 8,5'-Cyclopurine deoxynucleosides are unique tandem lesions containing an additional covalent bond between the base and the sugar. These mutagenic and genotoxic lesions are repaired only by nucleotide excision repair. The N glycosidic (or C1'-N9) bond of 2'-deoxyguanosine (dG) derivatives is usually susceptible to acid hydrolysis, but even after cleavage of this bond of the cyclopurine lesions, the base would remain attached to the sugar. Here, the stability of the N-glycosidic bond and the products formed by formic acid hydrolysis of (5'S)-8,5'-cyclo-2'-deoxyguanosine (S-cdG) were investigated. For comparison, the stability of the N-glycosidic bond of 8,5'-cyclo-2',5' dideoxyguanosine (ddcdG), 8-methyl-2'-deoxyguanosine (8-Me-dG), 7,8-dihydro-8-oxo 2'-deoxyguanosine (8-Oxo-dG), and dG was also studied. In various acid conditions, S-cdG and ddcdG exhibited similar stability to hydrolysis. Likewise, 8-Me-dG and dG showed comparable stability, but the half-lives of the cyclic dG lesions were at least 5-fold higher than those of dG or 8-Me-dG. NMR studies were carried out to investigate the products formed after the cleavage of the C1'-N9 bond. 2-Deoxyribose generated alpha and beta anomers of deoxyribopyranose and deoxyribopyranose oligomers following acid treatment. S-cdG gave alpha- and beta deoxyribopyranose linked guanine as the major products, but alpha and beta anomers of deoxyribofuranose linked guanine and other products were also detected. The N-glycosidic bond of 8-Oxo-dG was found exceptionally stable in acid. Computational studies determined that both the protonation of the N7 atom and the rate constant in the bond breaking step control the overall kinetics of hydrolysis, but both varied for the molecules studied indicating a delicate balance between the two steps. Nevertheless, the computational approach successfully predicted the trend observed experimentally. For 8-Oxo-dG, the low pK(a) of O(8) and N3 prevented appreciable protonation, making the free energy for N-glycosidic bond cleavage in the subsequent step very high. PMID- 23025579 TI - Importance of subaerial biofilms and airborne microflora in the deterioration of stonework: a molecular study. AB - The study characterized the sessile microbial communities on mortar and stone in Milan University's Richini's Courtyard and investigated the relationship between airborne and surface-associated microbial communities. Active colonization was found in three locations: green and black patinas were present on mortar and black spots on stone. Confocal laser scanning microscopy, scanning electron microscopy and culture-independent molecular methods revealed that the biofilm causing deterioration was dominated by green algae and black fungi. The mortar used for restoration contained acrylic and siloxane resins that could be used by microorganisms as carbon and energy sources thereby causing proliferation of the biofilm. Epifluorescence microscopy and culture-based methods highlighted a variety of airborne microflora. Bacterial and fungal counts were quantitatively similar to those reported in other investigations of urban areas, the exception being fungi during summer (1-2 orders of magnitude higher). For the first time in the cultural heritage field, culture-independent molecular methods were used to resolve the structure of airborne communities near discoloured surfaces, and to investigate the relationship between such communities and surface-associated biofilms. PMID- 23025580 TI - Olig2-positive cells in glioneuronal tumors show both glial and neuronal characters: the implication of a common progenitor cell? AB - Glioneuronal tumors (GNTs) are rare neoplasms consisting of both glial and neuronal components. Among the GNTs, dysembryoplastic neuroepithelial tumors (DNTs), papillary glioneuronal tumors (PGNTs), and rosette-forming glioneuronal tumors of the fourth ventricle (RGNTs) share the character of being mainly composed of small round Olig2-positive tumor cells. Using immunohistochemistry and fluorescence in situ hybridization, we examined a series of 35 GNT cases (11 DNTs, 15 PGNTs and 9 RGNTs) on the characteristics of Olig2-positive tumor cells. Histologically, Olig2-positive cells showed small round forms in most GNTs; however, there were a small number of Olig2-positive cells with neuronal morphology only in a PGNT case. These cells expressed both glial and neuronal markers by double immunostaining. With regard to labeling indices and intensity, only PGNT cells expressed neuronal markers, including alpha-internexin and neurofilament. These findings also suggest that some Olig2-positive PGNT cells may show neuronal differentiation. In GNTs, a considerable number of Olig2 positive cells showed immunopositivity for cyclin D1 and/or platelet-derived growth factor receptor alpha (PDGFRalpha), which are markers for oligodendrocyte progenitor cells. These immunostainings were particularly strong in DNTs. In RGNTs, Olig2-positive cells formed "neurocytic rosettes". Furthermore, they were also immunopositive for glial markers, including GFAP, PDGFRalpha and cyclin D1. These findings indicate the heterogeneous characteristics of Olig2-positive cells in GNTs, and some of them also exhibited neuronal features. So it is possible that a part of Olig2-positive GNT cells have characteristics similar to those of progenitor cells. PMID- 23025582 TI - Smoking rates among hospital nurses in Longkou city, China. AB - This study was undertaken as one of the first investigations of nurses' smoking habits in Longkou city, Shandong Province, China. An anonymous cross-sectional survey was administered as part of a larger investigation of healthcare professionals at a university teaching hospital during 2008. A total of 88 nurses responded to the survey, from whom tobacco-related data were provided by 83 of them (94%). Their overall smoking rate was very low (1%), with no male nurses reporting themselves to be current tobacco users. Overall, the current study suggests that smoking rates are very low among Chinese nurses in Longkou city, Shandong Province. These results are also consistent with studies of nurses' tobacco use conducted in other regions of China. PMID- 23025581 TI - Context-dependent control over attentional capture. AB - A number of studies have demonstrated that the likelihood of a salient item capturing attention is dependent on the "attentional set" an individual employs in a given situation. The instantiation of an attentional set is often viewed as a strategic, voluntary process, relying on working memory systems that represent immediate task priorities. However, influential theories of attention and automaticity propose that goal-directed control can operate more or less automatically on the basis of longer term task representations, a notion supported by a number of recent studies. Here, we provide evidence that longer term contextual learning can rapidly and automatically influence the instantiation of a given attentional set. Observers learned associations between specific attentional sets and specific task-irrelevant background scenes during a training session, and in the ensuing test session, simply reinstating particular scenes on a trial-by-trial basis biased observers to employ the associated attentional set. This directly influenced the magnitude of attentional capture, suggesting that memory for the context in which a task is performed can play an important role in the ability to instantiate a particular attentional set and overcome distraction by salient, task-irrelevant information. PMID- 23025583 TI - Room-temperature super hydrogel as dye adsorption agent. AB - Supramolecular hydrogels were prepared in the mixtures of a chiral amphiphilic lithocholic acid (LCA) and a nonionic surfactant, dodecyldimethylamine oxide (C(12)DMAO), in water. With the addition of LCA to C(12)DMAO micellar solutions, a transition from micelles to gels occurs at room temperature. Hydrogels can form at very low concentrations (below 0.1 wt %), exhibiting a super gelation capability. The rheological measurements show a strong mechanical strength with an elastic modulus exceeding 5000 Pa and a yield stress exceeding 100 Pa. Microstructures determined by TEM, SEM, and AFM observations demonstrate that the gels are formed by intertwined helical fibrils. The formation of fibrils is induced by enormous cycles of units composed of two LCA molecules and four C(12)DMAO molecules driven by comprehensive noncovalent interaction, especially the hydrogen bonds produced in two reversed LCA molecules and the C(12)DMAOH(+) C(12)DMAO pairs. The xerogels show excellent adsorption capability of the toxic dye with a maximum adsorption value of 202 mg.g(-1). PMID- 23025584 TI - Does stress increase imitation of drinking behavior? An experimental study in a (semi-)naturalistic context. AB - BACKGROUND: That alcohol consumption is strongly influenced by the drinking behavior of social company has been demonstrated in observational research. However, not everyone is equally vulnerable to other people's drinking, and it is important to unravel which factors underlie these individual differences. This study focuses on the role of psychosocial stress in attempting to explain individual differences in the propensity to imitate alcohol consumption. METHODS: With a 2 (confederate's drinking condition: alcohol vs. soda) * 2 (participant's stress condition: stress vs. no stress) experimental design, we tested whether the tendency to imitate other people's drinking was related to participants' induced stress levels. The young male adults (N = 106) were randomly assigned to each of the conditions. In each session, directly after the stress or no-stress period, confederates and participants entered a bar laboratory where we observed their drinking behavior. Prior to entering the session, confederates were instructed to drink alcohol or soda. RESULTS: Participants in both stress and no stress conditions consumed substantially more alcohol when confederates drank alcohol than when they drank soda. There was no difference in alcohol consumed between stress and no-stress conditions. No moderating effect of stress on the tendency to drink along with peers was found. CONCLUSIONS: Generally, it appears that among young male adults, imitation of alcohol consumption is a robust phenomenon not dependent on individual stress levels. PMID- 23025585 TI - Noble polymeric surface conjugated with zwitterionic moieties and antibodies for the isolation of exosomes from human serum. AB - New zwitterionic polymer-coated immunoaffinity beads were developed to resist nonspecific protein adsorption from undiluted human serum for diagnostic applications of exosomes. A zwitterionic sulfobetaine monomer with an amine functional group was employed for simple surface chemistry and antifouling properties. An exosomal biomarker protein, epithelial cell adhesion molecule (EpCAM), was selected as a target molecule in this work. The beads were coated with polyacrylic acids (PAA) for increasing biorecognition sites, and protein G was then conjugated with carboxylic acid groups on the surfaces for controlling EpCAM antibody orientation. The remaining free carboxylic acid groups were modified with sulfobetaine moieties, and anti-EpCAM antibody was finally introduced. The amount of anti-EpCAM on the beads was increased by 40% when compared with PAA-uncoated beads. The surfaces of the beads exhibited near-net zero charge, and nonspecific protein adsorption was effectively suppressed by sulfobetaine moieties. EpCAM was captured from undiluted human serum with almost the same degree of efficiency as from PBS buffer solution using the newly developed immunoaffinity beads. PMID- 23025586 TI - Management of severe idiopathic oligohydramnios: is antepartum transabdominal amnioinfusion really a treatment option? AB - OBJECTIVE: The aim of this study was an evaluation of the role of antepartum transabdominal amnioinfusion (APTA) in the management of severe idiopathic oligohydramnios with a view to improving the pregnancy outcome. METHODS: The study comprised an analysis of 20 pregnant women with severe oligohydramnios who were treated with APTA in 2009 and 2012. The pregnancy outcomes and the complications of the procedure were analysed. RESULTS: The mean gestational age at first treatment was 22 weeks 3 days. The preprocedure amniotic fluid index of <5 cm was restored by the treatment to 8 cm. More than a half of the pregnancies (66.7%, 8/12) treated with APTA finished with spontaneous abortion in the second trimester, mostly due to rupture of the membranes (as a consequence of retroamniotic filling with saline in four cases). The later the oligohydramnios developed, the higher the probability of a significant prolongation of the gestation. CONCLUSIONS: Although APTA is a useful procedure in the management of severe oligohydramnios, it may be followed by a relatively high rate of rupture of the membranes, particularly in the second trimester. Paradoxically, a higher volume of infused saline into the amniotic cavity is associated with a significantly lower risk of rupture. PMID- 23025587 TI - The complete mitochondrial genome sequence of Rastrelliger kanagurta (Perciformes: Scombridae). AB - In this study, the complete mitochondrial DNA genome sequence of Rastrelliger kanagurta has been determined. The mitogenome was 16,537 bp in length. It consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 2 non coding regions. The A+T content of the mitochondrial genome of R. kanagurta was 52.29%, and the content was 26.92% for A, 30.67% for C, 17.03% for G, and 25.37% for T. The complete mitogenome of R. kanagurta can provide an important data for the studies on molecular systematics, species identification, stock evaluation, conservation genetics, and evolutionary adaptation mechanisms. PMID- 23025588 TI - Aluminum-doped ceria-zirconia solid solutions with enhanced thermal stability and high oxygen storage capacity. AB - A facile solvothermal method to synthesize aluminum-doped ceria-zirconia (Ce0.5Zr0.5-xAlxO2-x/2, x = 0.1 to 0.4) solid solutions was carried out using Ce(NH4)2(NO3)6, Zr(NO3)3.2H2O Al(NO3)3.9H2O, and NH4OH as the starting materials at 200 degrees C for 24 h. The obtained solid solutions from the solvothermal reaction were calcined at 1,000 degrees C for 20 h in air atmosphere to evaluate the thermal stability. The synthesized Ce0.5Zr0.3Al0.2O1.9 particle was characterized for the oxygen storage capacity (OSC) in automotive catalysis. For the characterization, X-ray diffraction, transmission electron microscopy, and the Brunauer-Emmet-Teller (BET) technique were employed. The OSC values of all samples were measured at 600 degrees C using thermogravimetric-differential thermal analysis. Ce0.5Zr0.3Al0.2O1.9 solid solutions calcined at 1,000 degrees C for 20 h with a BET surface area of 18 m2 g-1 exhibited a considerably high OSC of 427 MUmol-O g-1 and good OSC performance stability. The same synthesis route was employed for the preparation of the CeO2 and Ce0.5Zr0.5O2. The incorporation of aluminum ion in the lattice of ceria-based catalyst greatly enhanced the thermal stability and OSC. PMID- 23025589 TI - Ways forward to identify new ACPA targets in RA. AB - Anti-citrullinated protein antibodies (ACPAs) of the IgG subtype have become a critical hallmark of HLA-associated rheumatoid arthritis (RA) and point to important contributions from the adaptive immune system. To dissect the contributing autoimmune reactions, investigators must not only identify the protein targets of ACPA but also define the precise peptides recognized by the immune system. Several possible approaches could be used to achieve this goal, and sensitive mass spectrometry of relevant tissue is a promising way forward in advancing our detailed understanding of autoimmune immune reactions involved in RA pathogenesis. PMID- 23025590 TI - Spatial and temporal variation of whirling disease risk in Montana spring creeks and rivers. AB - Spring creeks are important spawning and rearing areas for wild trout, but the stable flows, cool temperatures, and high nutrient levels that characterize these unique habitats may also make them highly susceptible to establishment and proliferation of the whirling disease pathogen Myxobolus cerebralis. We evaluated the spatial and temporal dynamics in whirling disease risk by using sentinel rainbow trout Oncorhynchus mykiss fry in nine different spring creeks and their conjoining rivers or reservoirs in Montana over a 20-month period. Whirling disease risk was high in five of the seven pathogen-positive spring creek study sites; at these sites, prevalence levels exceeded 90% and over 50% of sentinel fry had moderate to high infection severity scores. Spring creeks generally had higher disease prevalence and severity than paired river or reservoir sites. Fine sediment levels varied widely among springs creeks with high and low whirling disease risk, and we found no significant association between fine sediment level and infection severity. The low risk measured for some spring creeks was likely attributable to the pathogen invasion being in its early stages rather than to environmental characteristics limiting the severity of infection. High whirling disease risk occurred over a wide range of temperatures at spring creek sites (4.5-13 degrees C) and river sites (1.7-12.5 degrees C). There was an unusual seasonal cycle of infection in spring creeks, with peak infection levels occurring from late fall to early spring and declining to near zero in late spring to early fall. The low infection risk during spring suggests that spring spawning trout would be at a low risk of infection, even in spring creeks with otherwise high disease severity. In contrast, fry of fall-spawning trout may be much more susceptible to infection in spring creek environments. PMID- 23025591 TI - Effect of dietary supplementation with Achyranthes aspera seed on larval rohu Labeo rohita challenged with Aeromonas hydrophila. AB - Larval rohu Labeo rohita were fed four different diets: three of the diets contained Achyranthes aspera (prickly chaff-flower) seeds at 0.10% (D1), 0.25% (D2), or 0.50% (D3); the fourth diet was a control diet (D4; no A. aspera supplementation). After 70 d, the rohu were injected intraperitoneally with live Aeromonas hydrophila. Mortality of fish was recorded for 7 d. In the D4 group, the first mortality was observed within 12 h of exposure, whereas in the D1-D3 treatment groups, mortality was first observed at 24 h postexposure. In the D4 group, 50% of fish died within 72 h of exposure, whereas in the D3 group, 10-15% mortality occurred between 72 and 84 h. The cumulative mortality rate was 50% for D4, 40% for D1, 35% for D2, and 15% for D3. Total tissue protein level in the larvae was higher for the D2 and D3 groups than for the other groups. Glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, and thiobarbituric acid reactive substance levels were significantly lower in D3 larvae than in the other groups, whereas lysozyme and nitric oxide synthase levels were significantly higher in D3 larvae compared with the other groups. Dietary supplementation with A. aspera seeds at the 0.50% level provided protection against oxidative stress, prevented tissue damage, and enhanced disease resistance in rohu larvae. PMID- 23025593 TI - Endosymbiotic calcifying bacteria: a new cue to the origin of calcification in metazoa? AB - Sponges show the highest diversity of associated bacteria among marine invertebrates. Immunological evidence traces the origin of the sponge bacterial symbioses to the Precambrian era. Hence, sponges appear to be ideally suited for studying the evolutionary origins of prokaryote-metazoan associations. Sponges produce either calcareous or siliceous skeletons, which only coexist in a relict group of demosponges, the sclerosponges. We report here, for the first time, intensive calcification in nonsclerosponge siliceous demosponges. Calcification is mediated by endosymbiotic bacteria (calcibacteria) located in archeocyte-like sponge cells. These calcibacteria are devoid of bacterial walls and divide within sponge cells until they became surrounded by a calcitic sheet, being subsequently extruded to the sponge subectosomal (subepithelial) zone. Thousands of bacteria produced calcitic spherules cover the surface of the host sponges, forming a cortex-like structure that mimics a rudimentary peripheral skeleton. Calcibacteria are vertically transferred to the sponge larvae during embryogenesis. Calcium detoxification may have generated this symbiotic association, with some additional benefits for the sponges, such as skeletal formation and deterrence from predation. This unique symbiosis holds implications for sponge biology and may advance discussions on the role of bacteria in early biocalcification processes in metazoans. PMID- 23025594 TI - Ancient tepui summits harbor young rather than old lineages of endemic frogs. AB - The flattop mountains (tepuis) of South America are ancient remnants of the Precambrian Guiana Shield plateau. The tepui summits, isolated by their surrounding cliffs that can be up to 1000 m tall, are thought of as "islands in the sky," harboring relict flora and fauna that underwent vicariant speciation due to plateau fragmentation. High endemicity atop tepui summits support the idea of an ancient "Lost World" biota. However, recent work suggests that dispersal between lowlands and summits has occurred long after tepui formation indicating that tepui summits may not be as isolated from the lowlands as researchers have long suggested. Neither view of the origin of the tepui biota (i.e., ancient vicariance vs. recent dispersal) has strong empirical support owing to a lack of studies. We test diversification hypotheses of the Guiana Shield highlands by estimating divergence times of an endemic group of treefrogs, Tepuihyla. We find that diversification of this group does not support an ancient origin for this taxon; instead, divergence times among the highland species are 2-5 Ma. Our data indicate that most highland speciation occurred during the Pliocene. Thus, this unparalleled landscape known as "The Lost World" is inhabited, in part, not by Early Tertiary relicts but neoendemics. PMID- 23025592 TI - Aerosolized antimicrobial agents based on degradable dextran nanoparticles loaded with silver carbene complexes. AB - Degradable acetalated dextran (Ac-DEX) nanoparticles were prepared and loaded with a hydrophobic silver carbene complex (SCC) by a single-emulsion process. The resulting particles were characterized for morphology and size distribution using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The average particle size and particle size distribution were found to be a function of the ratio of the organic phase to the surfactant containing aqueous phase with a 1:5 volume ratio of Ac-DEX CH(2)Cl(2) (organic):PBS (aqueous) being optimal for the formulation of nanoparticles with an average size of 100 +/- 40 nm and a low polydispersity. The SCC loading was found to increase with an increase in the SCC quantity in the initial feed used during particle formulation up to 30% (w/w); however, the encapsulation efficiency was observed to be the best at a feed ratio of 20% (w/w). In vitro efficacy testing of the SCC loaded Ac-DEX nanoparticles demonstrated their activity against both Gram-negative and Gram-positive bacteria; the nanoparticles inhibited the growth of every bacterial species tested. As expected, a higher concentration of drug was required to inhibit bacterial growth when the drug was encapsulated within the nanoparticle formulations compared with the free drug illustrating the desired depot release. Compared with free drug, the Ac-DEX nanoparticles were much more readily suspended in an aqueous phase and subsequently aerosolized, thus providing an effective method of pulmonary drug delivery. PMID- 23025595 TI - Deep diversification and long-term persistence in the South American 'dry diagonal': integrating continent-wide phylogeography and distribution modeling of geckos. AB - The relative influence of Neogene geomorphological events and Quaternary climatic changes as causal mechanisms on Neotropical diversification remains largely speculative, as most divergence timing inferences are based on a single locus and have limited taxonomic or geographic sampling. To investigate these influences, we use a multilocus (two mitochondrial and 11 nuclear genes) range-wide sampling of Phyllopezus pollicaris, a gecko complex widely distributed across the poorly studied South American 'dry diagonal' biomes. Our approach couples traditional and model-based phylogeography with geospatial methods, and demonstrates Miocene diversification and limited influence of Pleistocene climatic fluctuations on P. pollicaris. Phylogeographic structure and distribution models highlight that persistence across multiple isolated regions shaped the diversification of this species complex. Approximate Bayesian computation supports hypotheses of allopatric and ecological/sympatric speciation between lineages that largely coincide with genetic clusters associated with Chaco, Cerrado, and Caatinga, standing for complex diversification between the 'dry diagonal' biomes. We recover extremely high genetic diversity and suggest that eight well-supported clades may be valid species, with direct implications for taxonomy and conservation assessments. These patterns exemplify how low-vagility species complexes, characterized by strong genetic structure and pre-Pleistocene divergence histories, represent ideal radiations to investigate broad biogeographic histories of associated biomes. PMID- 23025596 TI - Testing the link between population genetic differentiation and clade diversification in Costa Rican orchids. AB - Species population genetics could be an important factor explaining variation in clade species richness. Here, we use newly generated amplified fragment length polymorphism (AFLP) data to test whether five pairs of sister clades of Costa Rican orchids that differ greatly in species richness also differ in average neutral genetic differentiation within species, expecting that if the strength of processes promoting differentiation within species is phylogenetically heritable, then clades with greater genetic differentiation should diversify more. Contrary to expectation, neutral genetic differentiation does not correlate directly with total diversification in the clades studied. Neutral genetic differentiation varies greatly among species and shows no heritability within clades. Half of the variation in neutral genetic differentiation among populations can be explained by ecological variables, and species-level traits explain the most variation. Unexpectedly, we find no isolation by distance in any species, but genetic differentiation is greater between populations occupying different niches. This pattern corresponds with those observed for microscopic eukaryotes and could reflect effective widespread dispersal of tiny and numerous orchid seeds. Although not providing a definitive answer to whether population genetics processes affect clade diversification, this work highlights the potential for addressing new macroevolutionary questions using a comparative population genetic approach. PMID- 23025597 TI - Dynamic transmission, host quality, and population structure in a multihost parasite of bumblebees. AB - The evolutionary ecology of multihost parasites is predicted to depend upon patterns of host quality and the dynamics of transmission networks. Depending upon the differences in host quality and transmission asymmetries, as well as the balance between intra- and interspecific transmission, the evolution of specialist or generalist strategies is predicted. Using a trypanosome parasite of bumblebees, we ask how host quality and transmission networks relate to parasite population structure across host species, and thus the potential for the evolution of specialist strains adapted to different host species. Host species differed in quality, with parasite growth varying across host species. Highly asymmetric transmission networks, together with differences in host quality, likely explain local population structure of the parasite across host species. However, parasite population structure across years was highly dynamic, with parasite populations varying significantly from one year to the next within individual species at a given site. This suggests that, while host quality and transmission may provide the opportunity for short-term host specialization by the parasite, repeated bottlenecking of the parasite, in combination with its own reproductive biology, overrides these smaller scale effects, resulting in the evolution of a generalist parasite. PMID- 23025598 TI - Coevolution between maternal transfer of immunity and other resistance strategies against pathogens. AB - Among the wide variety of resistance mechanisms to parasitism, the transgenerational transfer of immunity from mother to offspring has largely been overlooked and never included in evolutionary or coevolutionary studies of resistance mechanisms. Here we study the evolution and coevolution of various resistance mechanisms with a special focus on maternal transfer of immunity. In particular we show that maternal transfer of immunity is only expected to evolve when cross immunity is high and when the pathogens have an intermediate virulence. We also show that the outcome of the coevolution between various resistance mechanisms depends critically on the life span of the host. We predict that short-lived species should invest in avoidance strategies, whereas long lived species should invest in acquired resistance mechanisms. These results may help understanding the diversity of resistance strategies that have evolved in vertebrate species. Our framework also provides a general basis for the study of the evolution of other transgenerational resistance mechanisms. PMID- 23025599 TI - Antibody selection and amino acid reversions. AB - Pathogens adapt to antibody surveillance through amino acid replacements in targeted protein regions, or epitopes, that interfere with antibody binding. However, such escape mutations may exact a fitness cost due to impaired protein function. Here, it is hypothesized that the recurring generation of specific neutralizing antibodies to an epitope region as it evolves in response to antibody selection will cause amino acid reversions by releasing early escape mutations from immune selection. The plausibility of this hypothesis was tested with stochastic simulation of adaptation at the molecular sequence level in finite populations. Under the conditions of strong selection and weak mutation, the rates of allele fixation and amino acid reversion increased with population size and selection coefficients. These rates decreased with population size, however, if mutation became strong, because clonal interference reduced the rate of adaptation. The model successfully predicts the rate of reversion per allele fixation for an important human immunodeficiency virus type 1 (HIV-1) antibody epitope region. Therefore, antibody selection may generate complex adaptive dynamics. PMID- 23025600 TI - Sexual selection affects the evolution of lifespan and ageing in the decorated cricket Gryllodes sigillatus. AB - Recent work suggests that sexual selection can influence the evolution of ageing and lifespan by shaping the optimal timing and relative costliness of reproductive effort in the sexes. We used inbred lines of the decorated cricket, Gryllodes sigillatus, to estimate the genetic (co)variance between age-dependent reproductive effort, lifespan, and ageing within and between the sexes. Sexual selection theory predicts that males should die sooner and age more rapidly than females. However, a reversal of this pattern may be favored if reproductive effort increases with age in males but not in females. We found that male calling effort increased with age, whereas female fecundity decreased, and that males lived longer and aged more slowly than females. These divergent life-history strategies were underpinned by a positive genetic correlation between early-life reproductive effort and ageing rate in both sexes, although this relationship was stronger in females. Despite these sex differences in life-history schedules, age dependent reproductive effort, lifespan, and ageing exhibited strong positive intersexual genetic correlations. This should, in theory, constrain the independent evolution of these traits in the sexes and may promote intralocus sexual conflict. Our study highlights the importance of sexual selection to the evolution of sex differences in ageing and lifespan in G. sigillatus. PMID- 23025601 TI - Reduced genetic variance among high fitness individuals: inferring stabilizing selection on male sexual displays in Drosophila serrata. AB - Directional selection is prevalent in nature, yet phenotypes tend to remain relatively constant, suggesting a limit to trait evolution. However, the genetic basis of this limit is unresolved. Given widespread pleiotropy, opposing selection on a trait may arise from the effects of the underlying alleles on other traits under selection, generating net stabilizing selection on trait genetic variance. These pleiotropic costs of trait exaggeration may arise through any number of other traits, making them hard to detect in phenotypic analyses. Stabilizing selection can be inferred, however, if genetic variance is greater among low- compared to high-fitness individuals. We extend a recently suggested approach to provide a direct test of a difference in genetic variance for a suite of cuticular hydrocarbons (CHCs) in Drosophila serrata. Despite strong directional sexual selection on these traits, genetic variance differed between high- and low-fitness individuals and was greater among the low-fitness males for seven of eight CHCs, significantly more than expected by chance. Univariate tests of a difference in genetic variance were nonsignificant but likely have low power. Our results suggest that further CHC exaggeration in D. serrata in response to sexual selection is limited by pleiotropic costs mediated through other traits. PMID- 23025602 TI - Extra-pair paternity and the variance in male fitness in song sparrows (Melospiza melodia). AB - The variance in fitness across population members can influence major evolutionary processes. In socially monogamous but genetically polygynandrous species, extra-pair paternity (EPP) is widely hypothesized to increase the variance in male fitness compared to that arising given the socially monogamous mating system. This hypothesis has not been definitively tested because comprehensive data describing males' apparent (social) and realized (genetic) fitness have been lacking. We used 16 years of comprehensive social and genetic paternity data for an entire free-living song sparrow (Melospiza melodia) population to quantify and compare variances in male apparent and realized fitness, and to quantify the contribution of the variances in within-pair reproductive success (WPRS) and extra-pair reproductive success (EPRS) and their covariance to the variance in realized fitness. Overall, EPP increased the variance in male fitness by only 0-27% across different fitness and variance measures. This relatively small effect reflected the presence of socially unpaired males with zero apparent and low realized fitness, small covariance between WPRS and EPRS, and large variance in WPRS that was relatively unaffected by EPP. Therefore, although EPP altered individual males' contributions to future generations, its impact on population-level parameters such as the opportunity for selection and effective population size was limited. PMID- 23025603 TI - The eco-evolutionary responses of a generalist consumer to resource competition. AB - This article explores the combined evolutionary and ecological responses of resource uptake abilities in a generalist consumer to exploitative competition for one resource using a simple 2-resource model. It compares the sizes of ecologically and evolutionarily caused changes in population densities in cases where the original consumer has a strong or a weak trade-off in its abilities to consume the two resources. The analysis also compares the responses of the original species to competition when the competitor's population size is or is not limited by the shared resource. Although divergence in resource use traits in the resident generalist consumer is expected under all scenarios when resources are substitutable, the changes in population densities of the resources and resident consumer frequently differ between scenarios. The population of the original consumer often decreases as a result of its own adaptive divergence, and this decrease is often much greater than the initial ecological decrease. If the evolving consumer has a strong trade-off, the overlapped resource increases in equilibrium population density in response to being consumed by a generalist competitor. Some of these predictions differ qualitatively in alternative scenarios involving sustained variation in population densities or nutritionally essential resources. PMID- 23025604 TI - Slowly switching between environments facilitates reverse evolution in small populations. AB - Natural populations must constantly adapt to ever-changing environmental conditions. A particularly interesting question is whether such adaptations can be reversed by returning the population to an ancestral environment. Such evolutionary reversals have been observed in both natural and laboratory populations. However, the factors that determine the reversibility of evolution are still under debate. The time scales of environmental change vary over a wide range, but little is known about how the rate of environmental change influences the reversibility of evolution. Here, we demonstrate computationally that slowly switching between environments increases the reversibility of evolution for small populations that are subject to only modest clonal interference. For small populations, slow switching reduces the mean number of mutations acquired in a new environment and also increases the probability of reverse evolution at each of these "genetic distances." As the population size increases, slow switching no longer reduces the genetic distance, thus decreasing the evolutionary reversibility. We confirm this effect using both a phenomenological model of clonal interference and also a Wright-Fisher stochastic simulation that incorporates genetic diversity. Our results suggest that the rate of environmental change is a key determinant of the reversibility of evolution, and provides testable hypotheses for experimental evolution. PMID- 23025605 TI - The evolution of XY recombination: sexually antagonistic selection versus deleterious mutation load. AB - Recombination arrest between X and Y chromosomes, driven by sexually antagonistic genes, is expected to induce their progressive differentiation. However, in contrast to birds and mammals (which display the predicted pattern), most cold blooded vertebrates have homomorphic sex chromosomes. Two main hypotheses have been proposed to account for this, namely high turnover rates of sex-determining systems and occasional XY recombination. Using individual-based simulations, we formalize the evolution of XY recombination (here mediated by sex reversal; the "fountain-of-youth" model) under the contrasting forces of sexually antagonistic selection and deleterious mutations. The shift between the domains of elimination and accumulation occurs at much lower selection coefficients for the Y than for the X. In the absence of dosage compensation, mildly deleterious mutations accumulating on the Y depress male fitness, thereby providing incentives for XY recombination. Under our settings, this occurs via "demasculinization" of the Y, allowing recombination in XY (sex-reversed) females. As we also show, this generates a conflict with the X, which coevolves to oppose sex reversal. The resulting rare events of XY sex reversal are enough to purge the Y from its load of deleterious mutations. Our results support the "fountain of youth" as a plausible mechanism to account for the maintenance of sex-chromosome homomorphy. PMID- 23025606 TI - Paternal effects on the expression of a male polyphenism. AB - Polyphenic traits are widespread, but compared to other traits, relatively few studies have explored the mechanisms that influence their inheritance. Here we investigated the relative importance of additive, nonadditive genetic, and parental sources of variation in the expression of polyphenic male dimorphism in the mite Rhizoglyphus echinopus, a species in which males are either fighters or scramblers. We established eight inbred lines through eight generations of full sibling matings, and then crossed the inbred lines in a partial diallel design. Nymphs were isolated and raised to adulthood with ad libitum food. At adulthood, male morph was recorded for all male offspring. Using a Cockerham-Weir model, we found strong paternal effects for this polyphenic trait that could be either linked to the Y chromosome of males or an indirect genetic effect that is environmentally transmitted. In additional analyses, we were able to corroborate the paternal effects but also detected significant additive effects questioning the Cockerham-Weir analysis. This study reveals the potential importance of paternal effects on the expression of polyphenic traits and sheds light on the complex genetic architecture of these traits. PMID- 23025607 TI - The dynamics of mitochondrial mutations causing male infertility in spatially structured populations. AB - Mitochondrial genomes are usually inherited maternally and therefore there is no direct selection against mutations that have deleterious effects in males only (mother's curse). This is true in particular for mitochondrial mutations that reduce the fertility of their male carriers, as has been reported in a number of species. Using both analytical methods and computer simulations, we demonstrate that spatial population structure can induce strong selection against such male infertility mutations. This is because (1) infertile males may reduce the fecundity of the females they mate with and (2) population structure induces increased levels of inbreeding, so that the fitness of females carrying the mutation is more strongly reduced than the fitness of wild-type females. Selection against mitochondrial male infertility mutations increases with decreasing deme size and migration rates, and in particular with female migration rates. On the other hand, the migration model (e.g., island or stepping stone model) has generally only minor effects on the fate of the mitochondrial mutations. PMID- 23025608 TI - Naturally occurring mitochondrial DNA haplotypes exhibit metabolic differences: insight into functional properties of mitochondria. AB - Linking the mitochondrial genotype and the organismal phenotype is of paramount importance in evolution of mitochondria. In this study, we determined the differences in catalytic properties of mitochondria dictated by divergences in the siII and siIII haplogroups of Drosophila simulans using introgressions of siII mtDNA type into the siIII nuclear background. We used a novel in situ method (permeabilized fibers) that allowed us to accurately measure the consumption of oxygen by mitochondria in constructed siII-introgressed flies and in siIII control flies. Our results showed that the catalytic capacity of the electron transport system is not impaired by introgressions, suggesting that the functional properties of mitochondria are tightly related to the mtDNA haplogroup and not to the nuclear DNA or to the mito-nuclear interactions. This is the first study, to our knowledge, that demonstrates a naturally occurring haplogroup can confer specific functional differences in aspects of mitochondrial metabolism. This study illustrates the importance of mtDNA changes on organelle evolution and highlights the potential bioenergetic and metabolic impacts that divergent mitochondrial haplogroups may have upon a wide variety of species including humans. PMID- 23025609 TI - The contribution of female meiotic drive to the evolution of neo-sex chromosomes. AB - Sex chromosomes undergo rapid turnover in certain taxonomic groups. One of the mechanisms of sex chromosome turnover involves fusions between sex chromosomes and autosomes. Sexual antagonism, heterozygote advantage, and genetic drift have been proposed as the drivers for the fixation of this evolutionary event. However, all empirical patterns of the prevalence of multiple sex chromosome systems across different taxa cannot be simply explained by these three mechanisms. In this study, we propose that female meiotic drive may contribute to the evolution of neo-sex chromosomes. The results of this study showed that in mammals, the XY(1) Y(2) sex chromosome system is more prevalent in species with karyotypes of more biarmed chromosomes, whereas the X(1) X(2) Y sex chromosome system is more prevalent in species with predominantly acrocentric chromosomes. In species where biarmed chromosomes are favored by female meiotic drive, X autosome fusions (XY(1) Y(2) sex chromosome system) will be also favored by female meiotic drive. In contrast, in species with more acrocentric chromosomes, Y-autosome fusions (X(1) X(2) Y sex chromosome system) will be favored just because of the biased mutation rate toward chromosomal fusions. Further consideration should be given to female meiotic drive as a mechanism in the fixation of neo-sex chromosomes. PMID- 23025610 TI - Evidence of adaptation from ancestral variation in young populations of beach mice. AB - To understand how organisms adapt to novel habitats, which involves both demographic and selective events, we require knowledge of the evolutionary history of populations and also selected alleles. There are still few cases in which the precise mutations (and hence, defined alleles) that contribute to adaptive change have been identified in nature; one exception is the genetic basis of camouflaging pigmentation of oldfield mice (Peromyscus polionotus) that have colonized the sandy dunes of Florida's Gulf Coast. To quantify the genomic impact of colonization as well as the signature of selection, we resequenced 5000 1.5-kb noncoding loci as well as a 160-kb genomic region surrounding the melanocortin-1 receptor (Mc1r), a gene that contributes to pigmentation differences, in beach and mainland populations. Using a genome-wide phylogenetic approach, we recovered a single monophyletic group comprised of beach mice, consistent with a single colonization event of the Gulf Coast. We also found evidence of a severe founder event, estimated to have occurred less than 3000 years ago. In this demographic context, we show that all beach subspecies share a single derived light Mc1r allele, which was likely selected from standing genetic variation that originated in the mainland. Surprisingly, we were unable to identify a clear signature of selection in the Mc1r region, despite independent evidence that this locus contributes to adaptive coloration. Nonetheless, these data allow us to reconstruct and compare the evolutionary history of populations and alleles to better understand how adaptive evolution, following the colonization of a novel habitat, proceeds in nature. PMID- 23025611 TI - A test for environmental effects on behavioral isolation in two species of killifish. AB - Behavioral isolation is a common and potent mechanism of reproductive isolation. Determining the extent to which behavioral isolation varies with environmental conditions is critical to understanding speciation and the maintenance of species boundaries. Here, we tested the effect of salinity on behavioral isolation (female species recognition, male-male competition, and male species recognition) between two closely related killifish (Lucania goodei and L. parva) that differ in salinity tolerance. We performed no-choice assays and behavioral trials where males could compete and court females in fresh water (0 ppt) and brackish water (15 ppt). We found high levels of behavioral isolation that did not vary as a function of salinity. In behavioral trials, male species recognition of females was strong and asymmetric between the two species. Lucania goodei males preferred conspecifics and rarely courted or mated with L. parva females. Lucania parva males preferred conspecifics but readily courted and mated with L. goodei females. This asymmetry matches previously documented asymmetries in hybrid offspring fitness. Crosses between L. parva males and L. goodei females produce fully viable/fertile hybrids, but crosses between L. goodei males and L. parva females produce males with reduced fertility. Hence, behavioral isolation may have evolved in part due to reinforcement. PMID- 23025613 TI - Seasonal mortality patterns in non-human primates: implications for variation in selection pressures across environments. AB - Examining seasonal mortality patterns can yield insights into the drivers of mortality and thus potential selection pressures acting on individuals in different environments. We compiled adult and juvenile mortality data from nine wild non-human primate taxa to investigate the role of seasonality in patterns of mortality and address the following questions: Is mortality highly seasonal across species? Does greater environmental seasonality lead to more seasonal mortality patterns? If mortality is seasonal, is it higher during wet seasons or during periods of food scarcity? and Do folivores show less seasonal mortality than frugivores? We found seasonal mortality patterns in five of nine taxa, and mortality was more often tied to wet seasons than food-scarce periods, a relationship that may be driven by disease. Controlling for phylogeny, we found a positive relationship between the degree of environmental seasonality and mortality, with folivores exhibiting more seasonal mortality than frugivores. These results suggest that mortality patterns are influenced both by diet and degree of environmental seasonality. Applied to a wider array of taxa, analyses of seasonal mortality patterns may aid understanding of life-history evolution and selection pressures acting across a broad spectrum of environments and spatial and temporal scales. PMID- 23025614 TI - Violation of Dollo's law: evidence of muscle reversions in primate phylogeny and their implications for the understanding of the ontogeny, evolution, and anatomical variations of modern humans. AB - According to Dollo's law, once a complex structure is lost it is unlikely to be reacquired. In this article, we report new data obtained from our myology-based cladistic analyses of primate phylogeny, which provide evidence of anatomical reversions violating Dollo's law: of the 220 character state changes unambiguously optimized in the most parsimonious primate tree, 28 (13%) are evolutionary reversions, and of these 28 reversions six (21%) occurred in the nodes that lead to the origin of modern humans; nine (32%) violate Dollo's law. In some of these nine cases, the structures that were lost in adults of the last common ancestor and are absent in adults of most subgroups of a clade are actually present in early ontogenetic stages of karyotypically normal individuals as well as in later ontogenetic stages of karyotypically abnormal members of those subgroups. Violations of Dollo's law may thus result from the maintenance of ancestral developmental pathways during long periods of trait absence preceding the reacquisition of the trait through paedomorphic events. For instance, the presence of contrahentes and intermetacarpales in adult chimpanzees is likely due to a prolonged/delayed development of the hand musculature, that is, in this case chimpanzees are more neotenic than modern humans. PMID- 23025612 TI - Maintenance of genetic variation in human personality: testing evolutionary models by estimating heritability due to common causal variants and investigating the effect of distant inbreeding. AB - Personality traits are basic dimensions of behavioral variation, and twin, family, and adoption studies show that around 30% of the between-individual variation is due to genetic variation. There is rapidly growing interest in understanding the evolutionary basis of this genetic variation. Several evolutionary mechanisms could explain how genetic variation is maintained in traits, and each of these makes predictions in terms of the relative contribution of rare and common genetic variants to personality variation, the magnitude of nonadditive genetic influences, and whether personality is affected by inbreeding. Using genome-wide single nucleotide polymorphism (SNP) data from > 8000 individuals, we estimated that little variation in the Cloninger personality dimensions (7.2% on average) is due to the combined effect of common, additive genetic variants across the genome, suggesting that most heritable variation in personality is due to rare variant effects and/or a combination of dominance and epistasis. Furthermore, higher levels of inbreeding were associated with less socially desirable personality trait levels in three of the four personality dimensions. These findings are consistent with genetic variation in personality traits having been maintained by mutation-selection balance. PMID- 23025615 TI - Partial reproductive isolation of a recently derived resident-freshwater population of threespine stickleback (Gasterosteus aculeatus) from its putative anadromous ancestor. AB - We used no-choice mating trials to test for assortative mating between a newly derived resident-freshwater population (8-22 generations since founding) of threespine stickleback (Gasterosteus aculeatus) in Loberg Lake, Alaska and its putative anadromous ancestor as well as a morphologically convergent but distantly related resident-freshwater population. Partial reproductive isolation has evolved between the Loberg Lake population and its ancestor within a remarkably short time period. However, Loberg stickleback readily mate with morphologically similar, but distantly related resident-freshwater stickleback. Partial premating isolation is asymmetrical; anadromous females and smaller resident-freshwater males from Loberg Lake readily mate, but the anadromous males and smaller Loberg females do not. Our results indicate that premating isolation can begin to evolve in allopatry within a few generations after isolation as a correlated effect of evolution of reduced body size. PMID- 23025616 TI - The cellular immune response of Daphnia magna under host-parasite genetic variation and variation in initial dose. AB - In invertebrate-parasite systems, the likelihood of infection following parasite exposure is often dependent on the specific combination of host and parasite genotypes (termed genetic specificity). Genetic specificity can maintain diversity in host and parasite populations and is a major component of the Red Queen hypothesis. However, invertebrate immune systems are thought to only distinguish between broad classes of parasite. Using a natural host-parasite system with a well-established pattern of genetic specificity, the crustacean Daphnia magna and its bacterial parasite Pasteuria ramosa, we found that only hosts from susceptible host-parasite genetic combinations mounted a cellular response following exposure to the parasite. These data are compatible with the hypothesis that genetic specificity is attributable to barrier defenses at the site of infection (the gut), and that the systemic immune response is general, reporting the number of parasite spores entering the hemocoel. Further supporting this, we found that larger cellular responses occurred at higher initial parasite doses. By studying the natural infection route, where parasites must pass barrier defenses before interacting with systemic immune responses, these data shed light on which components of invertebrate defense underlie genetic specificity. PMID- 23025617 TI - Support for the immunocompetence handicap hypothesis in the wild: hormonal manipulation decreases survival in sick damselflies. AB - The immunocompetence handicap hypothesis (ICHH) states that hormones enhance sexual trait expression but impair immunity. Previous tests of the ICHH have been hampered by experimental design problems. Here, we report on an experimental test of the ICHH that includes manipulations of both hormones and infections in males of the territorial damselfly, Hetaerina americana, with accurate survival measurements. We conducted a fully factorial experiment subjecting each individual to one of three topical treatments: methoprene (a juvenile hormone analog), acetone, or control, and one of three injection treatments: bacteria, PBS, or control. We measured survival of manipulated males in both the wild and in captivity. As predicted, survival was most heavily impaired in methoprene bacteria males than in the other groups in the wild, and no survival differences emerged in captive animals. This result confirms that survival is one cost an animal pays for increased hormonal levels. This corroborates theoretical predictions of the ICHH. PMID- 23025618 TI - Genome size is not correlated with effective population size in the Oryza species. AB - Genome sizes vary widely across the tree of life and the evolutionary mechanism underlined remains largely unknown. Lynch and Conery (2003) proposed that evolution of genome complexity was driven mainly by nonadaptive stochastic forces and presented the observation that genome size was negatively correlated with effective population size (N(e)) as a strong support for their hypothesis. Here, we analyzed the relation between N(e) and genome size for 10 diploid Oryza species that showed about fourfold genome size variation. Using sequences of more than 20 nuclear genes, we estimated N(e) for each species after correction for the effects of demography and heterogeneity of mutation rates among loci and species. Pairwise comparisons and correlation analyses did not detect a negative relationship between N(e) and genome size despite about 6.5-fold interspecies N(e) variation. By calculating phylogenetically independent contrasts (PICs) for N(e), we repeated correlation analysis and did not find any correlation between N(e) and genome size. These observations suggest that the genome size variation in the Oryza species cannot be explained simply by the effect of effective population size. PMID- 23025620 TI - Congenital cutaneous hemangioma causing cardiac failure: a case report and review of the literature. AB - We present a case of a large congenital hemangioma (CH) on the neck causing cardiac failure and thrombocytopenia in a female neonate. A trial of medical therapy with corticosteroids and propranolol was attempted, but the patient ultimately underwent definitive treatment with embolization and surgical resection with a positive outcome. A review of the English language literature revealed 16 previously reported cases of CHs complicated by congestive heart failure. This series supports known demographic features of CHs, including a lack of gender discrepancy and a predilection to affect the head and neck. These CHs are rarely diagnosed in utero; most patients present with a mass at birth. Cardiac failure is identified prenatally or in the first days of life. A mild to moderate thrombocytopenia and coagulopathy, which is likely transient and distinct from classic Kasabach-Merritt phenomenon, accompanies many of these cases. There is a 30% associated mortality rate. Both medical and interventional treatment modalities have been reported. Steroids are the most commonly used medication, but without any clear benefit. We hypothesize that, based on its possible mechanisms of action,propranolol may be a more effective treatment for CHs requiring treatment. As surgical intervention may be necessary, we recommend a multidisciplinary approach to treating patients with problematic CHs. PMID- 23025619 TI - Metabolic brain covariant networks as revealed by FDG-PET with reference to resting-state fMRI networks. AB - The human brain is inherently organized as separate networks, as has been widely revealed by resting-state functional magnetic resonance imaging (fMRI). Although the large-scale functional connectivity can be partially explained by the underlying white-matter structural connectivity, the question of whether the underlying functional connectivity is related to brain metabolic factors is still largely unanswered. The present study investigated the presence of metabolic covariant networks across subjects using a set of fluorodeoxyglucose ((18)F, FDG) positron-emission tomography (PET) images. Spatial-independent component analysis was performed on the subject series of FDG-PET images. A number of networks that were mainly homotopic regions could be identified, including visual, auditory, motor, cerebellar, and subcortical networks. However, the anterior-posterior networks such as the default-mode and left frontoparietal networks could not be observed. Region-of-interest-based correlation analysis confirmed that the intersubject metabolic covariances within the default-mode and left frontoparietal networks were reduced as compared with corresponding time-series correlations using resting-state fMRI from an independent sample. In contrast, homotopic intersubject metabolic covariances observed using PET were comparable to the corresponding fMRI resting-state time-series correlations. The current study provides preliminary illustration, suggesting that the human brain metabolism pertains to organized covariance patterns that might partially reflect functional connectivity as revealed by resting-state blood oxygen level dependent (BOLD). The discrepancy between the PET covariance and BOLD functional connectivity might reflect the differences of energy consumption coupling and ongoing neural synchronization within these brain networks. PMID- 23025621 TI - The resistive bolometer for radiated power measurement on EAST. AB - The resistive bolometer system has been successfully employed on experimental advanced superconducting tokamak for the first time to measure the radiated power of plasma. The bolometer detectors are based on 4 MUm thick Pt absorbers deposited on 1.5 MUm thick SiN membranes. The system consists of 3 cameras with a total of 48 channels. The detector and the system setup are described in detail. The detector calibration and typical measurement results are presented as well. PMID- 23025622 TI - Note: statistical errors estimation for Thomson scattering diagnostics. AB - A practical way of estimating statistical errors of a Thomson scattering diagnostic measuring plasma electron temperature and density is described. Analytically derived expressions are successfully tested with Monte Carlo simulations and implemented in an automatic data processing code of the JET LIDAR diagnostic. PMID- 23025623 TI - Genetic variation in DNMT3B and increased global DNA methylation is associated with suicide attempts in psychiatric patients. AB - Recently, a significant epigenetic component in the pathology of suicide has been realized. Here we investigate candidate functional SNPs in epigenetic-regulatory genes, DNMT1 and DNMT3B, for association with suicide attempt (SA) among patients with co-existing psychiatric illness. In addition, global DNA methylation levels [5-methyl cytosine (5-mC%)] between SA and psychiatric controls were quantified using the Methylflash Methylated DNA Quantification Kit. DNA was obtained from blood of 79 suicide attempters and 80 non-attempters, assessed for DSM-IV Axis I disorders. Functional SNPs were selected for each gene (DNMT1; n = 7, DNMT3B; n = 10), and genotyped. A SNP (rs2424932) residing in the 3' UTR of the DNMT3B gene was associated with SA compared with a non-attempter control group (P = 0.001; Chi-squared test, Bonferroni adjusted P value = 0.02). Moreover, haplotype analysis identified a DNMT3B haplotype which differed between cases and controls, however this association did not hold after Bonferroni correction (P = 0.01, Bonferroni adjusted P value = 0.56). Global methylation analysis showed that psychiatric patients with a history of SA had significantly higher levels of global DNA methylation compared with controls (P = 0.018, Student's t-test). In conclusion, this is the first report investigating polymorphisms in DNMT genes and global DNA methylation quantification in SA risk. Preliminary findings suggest that allelic variability in DNMT3B may be relevant to the underlying diathesis for suicidal acts and our findings support the hypothesis that aberrant DNA methylation profiles may contribute to the biology of suicidal acts. Thus, analysis of global DNA hypermethylation in blood may represent a biomarker for increased SA risk in psychiatric patients. PMID- 23025624 TI - Determination of nicotianamine in soy sauce and other plant-based foods by LC MS/MS. AB - Nicotianamine is a nonproteinogenic amino acid, known to be an important metal chelator in plants. Recently, the antihypertensive effect of nicotianamine was discovered. In this study, a simple method to determine nicotianamine was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with a multimode ODS column. This method does not need derivatizing or ion-pairing reagents to retain nicotianamine, which is known for its poor retention on reversed-phase columns because of its high polarity. Moreover, this method showed a sufficient limit of detection (0.5 ng/mL), so it was found to be suitable for the analysis of nicotianamine in soy sauce and other foods, without cleanup. To subtract the matrix effect during LC-MS/MS analysis, a standard addition method was used. The levels of nicotianamine in soy sauce ranged from <0.25 to 71 MUg/g. Nicotianamine was also determined in other foods, including soy milk, vegetable juice, fruit juice, and bottled tea. PMID- 23025626 TI - Adrenal cortical carcinoma in a child, a rare cause of paediatric endocrinopathy: case report and literature review. AB - Adrenal cortical carcinomas (ACC) are rare tumours, most commonly reported in adult patients. However, an important peak in incidence occurs in paediatric patients. ACC is a rare cause of paediatric endocrinopathy which may masquerade as a non-neoplastic disease process. Herein we present ACC in a five-year-old female patient. Histopathological features associated with poor outcome included tumour weight >500 g, tumour size >10.5 cm, invasive properties, confluent tumour necrosis, high nuclear grade and high proliferation index assessed by Ki67 immunohistochemistry. This article focuses on clinical features, treatment, pathological characteristics, evolving classification and genetic significance of ACC in paediatric patients. PMID- 23025625 TI - The venom-gland transcriptome of the eastern diamondback rattlesnake (Crotalus adamanteus). AB - BACKGROUND: Snake venoms have significant impacts on human populations through the morbidity and mortality associated with snakebites and as sources of drugs, drug leads, and physiological research tools. Genes expressed by venom-gland tissue, including those encoding toxic proteins, have therefore been sequenced but only with relatively sparse coverage resulting from the low-throughput sequencing approaches available. High-throughput approaches based on 454 pyrosequencing have recently been applied to the study of snake venoms to give the most complete characterizations to date of the genes expressed in active venom glands, but such approaches are costly and still provide a far-from complete characterization of the genes expressed during venom production. RESULTS: We describe the de novo assembly and analysis of the venom-gland transcriptome of an eastern diamondback rattlesnake (Crotalus adamanteus) based on 95,643,958 pairs of quality-filtered, 100-base-pair Illumina reads. We identified 123 unique, full-length toxin-coding sequences, which cluster into 78 groups with less than 1% nucleotide divergence, and 2,879 unique, full-length nontoxin coding sequences. The toxin sequences accounted for 35.4% of the total reads, and the nontoxin sequences for an additional 27.5%. The most highly expressed toxin was a small myotoxin related to crotamine, which accounted for 5.9% of the total reads. Snake-venom metalloproteinases accounted for the highest percentage of reads mapping to a toxin class (24.4%), followed by C-type lectins (22.2%) and serine proteinases (20.0%). The most diverse toxin classes were the C type lectins (21 clusters), the snake-venom metalloproteinases (16 clusters), and the serine proteinases (14 clusters). The high-abundance nontoxin transcripts were predominantly those involved in protein folding and translation, consistent with the protein-secretory function of the tissue. CONCLUSIONS: We have provided the most complete characterization of the genes expressed in an active snake venom gland to date, producing insights into snakebite pathology and guidance for snakebite treatment for the largest rattlesnake species and arguably the most dangerous snake native to the United States of America, C. adamanteus. We have more than doubled the number of sequenced toxins for this species and created extensive genomic resources for snakes based entirely on de novo assembly of Illumina sequence data. PMID- 23025627 TI - Photoelectron imaging and theoretical calculations of bimetallic clusters: AgCu-, AgCu2(-), and Ag2Cu-. AB - Bimetallic clusters of AgCu(-), AgCu(2)(-), and Ag(2)Cu(-) are investigated by using photoelectron imaging and theoretical calculations. Their photoelectron spectra have been obtained at the wavelength of 355 nm and that of AgCu(-) is also acquired at 1064 nm. The ground state vertical detachment energies of these three clusters are measured to be 0.96 (1), 2.39 (5), and 2.41 (5) eV. The ground state adiabatic detachment energy of AgCu(-) is measured to be 0.93 (1) eV. Other spectroscopic constants of AgCu(-) including its frequency, bond length, and dissociation energy (relative to the products Ag(-) and Cu) are determined to be 191(15) cm(-1), 2.487(10) A, and 1.39 eV according to its spectrum at 1064 nm. Only upper limits of the ground state adiabatic detachment energies of AgCu(2)(-) and Ag(2)Cu(-) are estimated by using their spectra at 355 nm. The structures and properties of AgCu(-), AgCu(2)(-), Ag(2)Cu(-), and their neutral counterparts are also computed by using a strategy where the structural optimizations are performed with the PW91PW91 method and the energy calculations are performed with the CCSD (T) method. The calculations are in better agreement with the experiments than most of the previous theoretical work. PMID- 23025628 TI - Kinetic control of catalytic CVD for high-quality graphene at low temperatures. AB - Low-temperature (~600 degrees C), scalable chemical vapor deposition of high quality, uniform monolayer graphene is demonstrated with a mapped Raman 2D/G ratio of >3.2, D/G ratio <=0.08, and carrier mobilities of >=3000 cm(2) V(-1) s( 1) on SiO(2) support. A kinetic growth model for graphene CVD based on flux balances is established, which is well supported by a systematic study of Ni based polycrystalline catalysts. A finite carbon solubility of the catalyst is thereby a key advantage, as it allows the catalyst bulk to act as a mediating carbon sink while optimized graphene growth occurs by only locally saturating the catalyst surface with carbon. This also enables a route to the controlled formation of Bernal stacked bi- and few-layered graphene. The model is relevant to all catalyst materials and can readily serve as a general process rationale for optimized graphene CVD. PMID- 23025629 TI - Mesenchymal stem cells and the treatment of conditions and diseases: the less glittering side of a conspicuous stem cell for basic research. AB - Not too long ago, several motivated and forward-looking articles were published describing the cellular and molecular properties of mesenchymal stem cells (MSCs), specially highlighting their potential for self-renewal, commitment, differentiation, and maturation into specific mesoderm-derived lineages. A very influential publication of that period entitled "Mesenchymal stem cells: No longer second class marrow citizens" [1] raised the point of view that "...challenges to harness MSC cell therapy to treat diseases ... need to wait for the full comprehension that marrow is a rich source of mesenchyme-derived cells whose potential is still far from fully appreciated." Whether or not the prophecy of Gerson was fulfilled, in the last 8 years it has become evident that infusing MSCs into patients suffering a variety of disorders represents a viable option for medical treatment. Accordingly, a vast number of articles have explored the privileged cellular and molecular features of MSCs prepared from sources other than the canonical, represented by the bone marrow. This review will provide more information neither related to the biological attractiveness of MSCs nor to the success after their clinical use. Rather, we would like to underscore several "critical and tangential" issues, not always discussed in biomedical publications, but relevant to the clinical utilization of bone-marrow-derived MSCs. PMID- 23025630 TI - Tibial nerve tumor in a 72-year-old man. PMID- 23025631 TI - Validation of composite finite elements efficiently simulating elasticity of trabecular bone. AB - Patient-specific analyses of the mechanical properties of bones become increasingly important for the management of patients with osteoporosis. The potential of composite finite elements (CFEs), a novel FE technique, to assess the apparent stiffness of vertebral trabecular bone is investigated in this study. Segmented volumes of cylindrical specimens of trabecular bone are compared to measured volumes. Elasticity under uniaxial loading conditions is simulated; apparent stiffnesses are compared to experimentally determined values. Computational efficiency is assessed and recommendations for simulation parameters are given. Validating apparent uniaxial stiffnesses results in concordance correlation coefficients 0.69 <= r(c) <= 0.92 for resolutions finer than 168 MUm, and an average error of 5.8% between experimental and numerical results at 24 MUm resolution. As an application, the code was used to compute local, macroscopic stiffness tensors for the trabecular structure of a lumbar vertebra. The presented technique allows for computing stiffness using smooth FE meshes at resolutions that are well achievable in peripheral high resolution quantitative CT. Therefore, CFEs could be a valuable tool for the patient specific assessment of bone stiffness. PMID- 23025632 TI - Ethnographic study of a good death among elderly Japanese Americans. AB - Most humans desire a good death, but the nursing literature on culture-specific responses to older life, especially on issues of death and dying among Japanese Americans, is still limited. The pattern of beliefs about a good death held by elderly Japanese Americans living in Hawaii was explored. A qualitative study using ethnography and in-depth interviewing was employed. Eighteen healthy and active elderly participants were interviewed, and data analyzed using ethnography to extract categories and themes, and four supplementary interviews with experts were held for triangulation of the data. Four themes emerged, however, in this paper, the predominate one, not being a burden to family, was discussed. The participants believed burdening someone in their culture has an extremely negative implication. Sufficient preparation for older life and death, family support, friends support, and finance were their strategies to avoid being a burden. Nurses need to understand that the concept of good death is unique to every culture. Such knowledge will help them to plan and provide appropriate end of-life care, and will reduce the risk of living wills being ignored. PMID- 23025634 TI - Picosecond kinetics of strongly coupled excitons and surface plasmon polaritons. AB - Coupling between excitons of CdSe nanocrystal quantum dots (NQDs) and surface plasmon polaritons (SPPs) of an Ag film attached to a prism have been studied by steady-state and transient reflectivity measurements in the Kretschmann geometry. In these experiments, the angle of incidence of the probe beam selects hybrid exciton/SPP states with different wavevectors and exciton/SPP compositions. The dynamics measured in the transient reflectivity experiments are sensitive to the composition of the hybrid states. Specifically, fast dynamics are observed at probe wavevectors where the lower hybrid state has predominant SPP character. In contrast, at probe wavevectors where the lower hybrid state is predominantly excitonic, the dynamics are similar to that measured for CdSe NQDs on glass. PMID- 23025633 TI - Immunologic risk factors for early mortality after starting antiretroviral therapy in HIV-infected Zambian children. AB - To explore immunologic risk factors for death within 90 days of highly active antiretroviral therapy (HAART) initiation, CD4(+) and CD8(+) T cell subsets were measured by flow cytometry and characterized by logistic regression in 149 Zambian children between 9 months and 10 years of age enrolled in a prospective, observational study of the impact of HAART on measles immunity. Of 21 children who died during follow-up, 17 (81%) had known dates of death and 16 (76%) died within 90 days of initiating HAART. Young age and low weight-for-age z-scores were associated with increased risks of mortality within 90 days of starting HAART, whereas CD4(+) T cell percentage was not associated with mortality. After adjusting for these factors, each 10% increase in CD8(+) effector T cells increased the odds of overall mortality [OR=1.43 (95% CI: 1.08, 1.90)] and was marginally associated with early mortality [OR=1.29 (95% CI: 0.97, 1.72)]. Conversely, each 10% increase in CD4(+) central memory T cells decreased the odds of overall [OR=0.06 (95% CI: 0.01, 0.59)] and early mortality [OR=0.09 (95% CI: 0.01, 0.97)]. Logistic regression prediction models demonstrated areas under the receiver-operator characteristic curves of >=85% for early and overall mortality, with bootstrapped sensitivities of 82-85% upon validation, supporting the predictive accuracy of the models. CD4(+) and CD8(+) T cell subsets may be more accurate predictors of early mortality than CD4(+) T cell percentages and could be used to identify children who would benefit from more frequent clinical monitoring after initiating HAART. PMID- 23025636 TI - Age of onset and neuropsychological functioning in alcohol dependent inpatients. AB - BACKGROUND: Differences in clinical characteristics between early and late onset alcohol dependent patients have been examined intensively, but little is known about the differences in neuropsychological functioning between these patient groups. Clinical characteristics and neuropsychological functions of inpatients with early onset and late onset alcohol dependence are therefore investigated in this study. METHODS: Ninety-three abstinent alcohol dependent inpatients meeting a current diagnosis of DSM-IV alcohol dependence were divided into early onset alcohol dependent patients (EOA; <=25 years; n = 36) and late onset alcohol dependent patients (LOA; >25 years; n = 57). Patients using psychoactive medication and patients dependent on other substances than alcohol (and nicotine) were excluded. A comprehensive neuropsychological test battery was administered. RESULTS: EOA reported higher trait impulsivity, antisocial traits, and attention deficit hyperactivity disorder-related traits and exhibited an impulsive reflection style, especially in a high-risk context, compared with LOA. Against expectations, EOA performed significantly better on measures of planning, cognitive control, visual memory, and delayed recognition memory than LOA, whereas no significant group differences occurred on measures of delay discounting, digit span, and attention. Better Stroop interference, better visual memory, and a more impulsive reflection style was predictive of an early age of onset, and explained a significant and additional amount of variance (18.8%) on top of the clinical characteristics, together explaining 53.4% of the variance. CONCLUSIONS: Both clinical characteristics and neuropsychological variables contributed independently to the age of onset of problematic alcohol use. Results indicate that especially an impulsive reflection style, besides higher trait impulsivity, may be the core feature of early onset alcohol dependence. However, the contribution of the neuropsychological variables is complex and more research is needed to clarify the role of psychiatric comorbidity and poly-substance abuse in an unselected sample of alcohol dependent patients. PMID- 23025637 TI - Radioactive smart probe for potential corrected matrix metalloproteinase imaging. AB - Although various activatable optical probes have been developed to visualize metalloproteinase (MMP) activities in vivo, precise quantification of the enzyme activity is limited due to the inherent scattering and attenuation (limited depth penetration) properties of optical imaging. In this investigation, a novel activatable peptide probe (64)Cu-BBQ650-PLGVR-K(Cy5.5)-E-K(DOTA)-OH was constructed to detect tumor MMP activity in vivo. This agent is optically quenched in its native form, but releases strong fluorescence upon cleavage by selected enzymes. MMP specificity was confirmed both in vitro and in vivo by fluorescent imaging studies. The use of a single modality to image biomarkers/processes may lead to erroneous interpretation of imaging data. The introduction of a quantitative imaging modality, such as PET, would make it feasible to correct the enzyme activity determined from optical imaging. In this proof of principle report, we demonstrated the feasibility of correcting the activatable optical imaging data through the PET signal. This approach provides an attractive new strategy for accurate imaging of MMP activity, which may also be applied for other protease imaging. PMID- 23025638 TI - 4th International Forum on Rheumatoid Arthritis: Great times near the Great Wall. PMID- 23025639 TI - Support needs of siblings of people with developmental disabilities. AB - This qualitative study examines the support needs of adult siblings of people with developmental disabilities. A survey completed by 139 siblings of people with developmental disabilities captured the needs of adult siblings through 2 open-ended questions. A grounded theory approach was used, and the sibling responses anchored the analysis, interpretation of findings, and discussion using the constant comparison method. Eleven core variables and 3 overarching themes emerged. Three overarching themes for sibling support needs include: (a) getting disability-related information, (b) getting support for their caregiving role, and (c) enhancing the formal support system to address sibling needs. PMID- 23025640 TI - Colonoscopy and colorectal cancer screening in adults with intellectual and developmental disabilities: review of a series of cases and recommendations for examination. AB - Adults with intellectual and developmental disabilities (IDD) frequently have comorbidities that might interfere with colonoscopy preparation and examination. In this article, the authors review their experience with colonoscopies performed from 2002 through 2010 on adults with IDD at a state institution to evaluate quality and safety of examinations and to formulate a plan to improve quality. In addition to IDD, these individuals had associated comorbidities, including digestive motility disorders and epilepsy. Results were compared with examinations performed in a random group of 40 adults without IDD examined between 2004 and 2008. The authors discovered a high rate of colonoscopy preparation failure and failed examinations in the IDD group. Preparation complications were also noted. The authors recommend careful preoperative evaluation of individuals with IDD and limiting colonoscopy to individuals who are able to tolerate preparation and comply with hydration. PMID- 23025641 TI - Understanding differences in neurotypical and autism spectrum special interests through Internet forums. AB - Special interests are frequently developed by individuals with autism spectrum disorder, expressed as an intense focus on specific topics. Neurotypical individuals also develop special interests, often in the form of hobbies. Although past research has focused on special interests held by children with autism spectrum disorder, little is known about their role in adulthood. The current study investigated differences in the content, number, and specificity of the special interests held by adult individuals with autism spectrum disorder and neurotypical individuals, using Internet discussion forums as a data source. Quantitative analysis of forum posts revealed significant differences between the diagnostic groups. Individuals with autism spectrum disorder reported having more interests in systemizing domains, more specific interests, and a greater number of interests overall than neurotypical individuals. Understanding special interests can lead to the development of educational and therapeutic programs that facilitate the acquirement of other important social and communication skills. PMID- 23025642 TI - Strategies for organizational change from group homes to individualized supports. AB - Organizations are increasingly looking to convert from facility-based services for adults with developmental disabilities to individualized supports. Such conversion involves not only a change in services but a transformation of organizational culture. This qualitative study involved four organizations that have made sustained efforts to transform. Although the approach taken by each organization was unique, there were also some common strategies, which included generating commitment to common values and mission, a turn or return to authentic person-centered planning, shifting power and control, using community supports and relationships, moving away from facility-based settings, and nurturing staff engagement. Ultimately, organizational change is an ongoing process that requires organizational perseverance and commitment. PMID- 23025643 TI - Moderating effects of autism on parent views of genetic screening for aggression. AB - Advances in gene-environment interaction research have revealed genes that are associated with aggression. However, little is known about parent perceptions of genetic screening for behavioral symptoms like aggression as opposed to diagnosing disabilities. These perceptions may influence future research endeavors involving genetic linkage studies to behavior, including proactive approaches for parents to avoid events leading to aggression. The purpose of this study was to solicit the perspectives of parents who have children with autism about screening for genes associated with aggression, compared to responses from those who have children without disabilities and those planning to have children. Parents of children with autism were more likely to support screening and the use of the results to seek treatment if necessary. Results are discussed in the context of surveillance screening and systematic early intervention for behavioral symptoms related to autism. The results may provide insight for clincians, researchers, policymakers, and advocacy groups related to diagnosing and treating aggression in people with autism. PMID- 23025644 TI - Resistance and resilience in a life full of professionals and labels: narrative snapshots of Chris. AB - In this article, the authors relate the life of Chris through narrative snapshots. Chris asked the authors to tell her story. They decided that it could be used to provide an insight into the different ways people with labels are confronted with professional practices and rituals. Although Chris lived a "tough life," her story is full of resilience and resistance. Chris will be kept in the authors' memory as a strong woman, a teacher, and a friend. PMID- 23025647 TI - Ultrastructural findings in adrenal cortical adenomas clinically mimicking pheochromocytoma: a comparison with other adrenal tumors and tissue preparation techniques. AB - Adrenal cortical tumors clinically mimicking pheochromocytomas are extremely rare, with 14 cases in the literature. The authors describe 2 patients with adrenal cortical adenoma (ACA) and catecholamine elevations. The impact of tissue preparation methods on electron microscopy (EM) images was assessed in ACA mimicking pheochromocytoma, pheochromocytoma, and ACA lacking pheochromocytoma like symptoms. Ten adrenal cortical tumors were examined using EM after a variety of tissue preparation techniques, including fixation with glutaraldehyde, formalin for varying lengths of time followed by glutaraldehyde, and/or formalin followed by paraffin embedding. Electron micrographs were assessed for image quality and the presence of dense secretory granules and eccentric, norepinephrine (NE)-type granules. Images created from tissue fixed in glutaraldehyde and/or formalin and embedded in resin were of good quality, while those derived from paraffin-embedded specimens were poor with disrupted cellular architecture. When pheochromocytoma was fixed in glutaraldehyde for 24 h or in formalin for 8 days, eccentric granules were identified. These granules were absent when tissue was fixed in formalin for 20 days or was obtained from a paraffin block. ACA without pheochromocytoma-like symptoms and ACA mimicking pheochromocytoma both had noneccentric dense-core granules on EM regardless of tissue preparation, and eccentric NE-type granules were absent. ACA is a rare cause of pheochromocytoma-like symptoms. These tumors lack eccentric, NE-type dense-core granules present in pheochromocytoma. Glutaraldehyde alone or formalin fixation followed by glutaraldehyde produces electron micrographs that may aid in the diagnosis of adrenal cortical tumors, whereas formalin-fixed, paraffin embedded tissue results in images that are inadequate. PMID- 23025648 TI - Xenotransplanted human prostate carcinoma (DU145) cells develop into carcinomas and cribriform carcinomas: ultrastructural aspects. AB - Androgen-independent, human prostate carcinoma cells (DU145) develop into solid, carcinomatous xenotransplants on the diaphragm of nu/nu mice. Tumors encompass at least two poorly differentiated cell types: a rapidly dividing, eosinophilic cell comprises the main cell population and a few, but large basophilic cells able to invade the peritoneal stroma, the muscular tissue, lymph vessels. Poor cell contacts, intracytoplasmic lumina, and signet cells are noted. Lysosomal activities are reflected by entoses and programmed cell deaths forming cribriform carcinomas. In large tumors, degraded cells may align with others to facilitate formation of blood supply routes. Malignant cells would spread via ascites and through lymphatics. PMID- 23025649 TI - Detection of mercury in the 411-year-old beard hairs of the astronomer Tycho Brahe by elemental analysis in electron microscopy. AB - Hairs more than 400 years old of the famous astronomer Tycho Brahe were studied by electron microscopy to evaluate the hypothesis that Johannes Kepler murdered his teacher Brahe by mercury intoxication. The beard hairs showed a well preserved ultrastructure with typical hair scales and melanosomes. The authors detected an accumulation of electron-dense granules of about 10 nm inside the outer hair scales, but not in the hair shaft and roots. At the places of these heavy-metal-containing granules they detected mercury besides other elements by energy dispersive X-ray analysis (EDX, Oxford, UK) in a field cathode scanning electron microscope (SEM, Gemini, Zeiss). The mercury-containing granules were found over the whole length of hairs, but only in the outer hair scales. Nevertheless, surface coatings of hairs were free of mercury. This distribution of mercury does not support the murder hypothesis, but could be related to precipitation of mercury dust from the air during long-term alchemistic activities. PMID- 23025650 TI - Tumor multiplicity is an independent prognostic factor of non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guerin immunotherapy. AB - BACKGROUND: Bacillus Calmette-Guerin (BCG) immunotherapy is regarded as the current treatment of choice for non muscle invasive bladder cancer (NMIBC), though its efficacy is limited by high recurrence and progression rate. Identification of factor prognosticators that might be helpful in discriminating between responders and nonresponders to BCG treatment is therefore of major clinical importance. The aim of this study is to evaluate the prognostic factors of recurrence after intravesical adjuvant BCG immunotherapy in patients with NMIBC. METHODS: we retrospectively reviewed the clinical and pathologic data of primary NMIBC from 112 patients who were treated with transurethral resection followed by BCG-immunotherapy. Time follow-up was 30 months. The prognostic significance of tumor stage, grade, multiplicity, age, sex and smoking in determining the risk for recurrence after BCG therapy was studied with both univariate and multivariate methods of analysis. RESULTS: According to univariate analysis of the prognostic significance for tumor stage, grade, loci number, sex, age and smoking, the pT1 stage and multiplicity seem to be associated in a statistically significant manner with higher risk for recurrence (P = 0.009, P = 0.011, respectively). In the other hand, multivariate analysis showed that only multiplicity was an independent significant prognosticator. CONCLUSION: Significant independent predictor for recurrence was multiplicity which offers important clinical information and may be a useful tool in the selection of suitable candidates for BCG-immunotherapy. PMID- 23025651 TI - Skin and sural nerve biopsies: ultrastructural findings in the first genetically confirmed cases of CADASIL in Serbia. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular disorder caused by Notch3 gene mutations. The main histopathological hallmark is granular osmiophilic material (GOM) deposited in the close vicinity of vascular smooth muscle cells (VSMCs). The authors report the first 7 ultrastructurally and genetically confirmed cases of CADASIL in Serbia. Samples of skin and sural nerve were investigated by transmission electron microscopy. GOM deposits were observed around degenerated VSMCs in all the skin biopsies examined. Sural nerve biopsies revealed severe alterations of nerve fibers, endoneurial blood vessels with GOM deposits, endoneurial fibroblasts, and perineurial myofibroblasts. Total genomic DNA was extracted from peripheral blood leukocytes, and exons 2-6 of the Notch3 gene were amplified by PCR and subsequently sequenced. Four different mutations in exons 2 (Cys65Tyr), 3 (Gly89Cys and Arg90Cys), and 6 (Ala319Cys), which determine the CADASIL disease, were detected among all described patients. A novel missense mutation Gly89Cys involving exon 3 was detected. Due to the difficulties in the determination of the Notch3 mutations, these data suggest that electron microscopic analysis for GOMs in dermal vessel wall provides a rapid and reliable screening method for this disease. PMID- 23025652 TI - Time-dependent morphological and biochemical changes following cutaneous thermal burn injury and their modulation by copper nicotinate complex: an animal model. AB - BACKGROUND: Thermal tissue injury is partly mediated by reactive oxygen metabolites. Oxygen free radicals are contributory to local tissue damage following thermal injury and accordingly an interventional therapy using antioxidants may be beneficial. Copper nicotinate complex can scavenge reactive oxygen species (i.e., has antioxidant activity). OBJECTIVES: To examine time related morphological and biochemical changes following skin thermal injury and their modulation by copper nicotinate complex. MATERIALS AND METHODS: An animal model composed of 80 albino rats was established. Ten rats (nonburn group) served as a control group. Seventy rats (burn group) were anesthetized, given a 10% total body surface area, full-thickness burn. Ten rats (from the postburn group) were sacrificed after 24 h (without treatment, i.e., untreated-burn group). The remaining rats were divided into three subgroups (20 rats, each) and were treated topically either with soft paraffin, moist exposed burn ointment (MEBO, a standard therapeutic treatment for burns), or copper nicotinate complex. Five animals from each subgroup were sacrificed every week over a period of 4 weeks. The morphological and biochemical changes were evaluated and compared among the different groups. RESULTS: High levels of the plasma and skin nitiric oxide (marker of oxidative stress) were observed in the untreated-burn group. These levels were significantly low following the application of copper nicotinate complex. Low levels of plasma and skin superoxide dismutase (marker of oxidative stress) and plasma ceruloplasmin were observed in the untreated-burn group. These levels were significantly high following copper nicotinate complex treatment. The total and differential leukocyte counts were low following the onset of the thermal injury. They gradually returned to normal levels over a 4-week period following the application of MEBO or copper nicotinate complex. Compared to untreated-burn group, postburn-healing changes (resolution of the inflammatory reaction, reepithelization of the epidermis, angiogenesis, deposition of collagen fibers, and recovery of the subcellualr organelles) were significantly accelerated following the application of either MEBO or copper nicotinate complex. CONCLUSIONS: Application of copper nicotinate complex was associated with improved healing of the thermal burns of the skin. The underlying molecular changes underlying these effects await further investigations. PMID- 23025653 TI - Effects of cyclic increase in gonadotropins on the in vitro development of primordial follicles to antral stage. AB - The aim of this study was to evaluate the effects of FSH and LH on follicle development during a long-term culture of cryopreserved human ovarian tissue, using morphological and ultrastructural examinations. Thawed ovarian tissue slices from a 4-year-old child with Wilms tumor were cultured for 32 weeks in two different culture conditions, without (medium A) and with (medium B) a monthly peaked increase in FSH and LH. At week 32, in the medium B cultured tissue, a cluster of preantral follicles associated with two oocytes prematurely ovulated was observed, suggesting that the cyclic increase of gonadotropins promoted thawed follicles to grow up to the antral stage. However, the integrity and coordinated follicle development were not maintained. Indeed, ultrastructural analysis showed a well-preserved "naked" oocyte with concomitant features of immaturity and maturity, as if this culture condition had led to an asynchronous maturation of oocyte cytoplasmic components. PMID- 23025654 TI - A diagnostic mystery solved by electron microscopy: a case of an "atypical" lymphoproliferative disorder. AB - An elderly woman with a previous diagnosis of atypical chronic lymphocytic leukemia (CLL) was noted to have a strikingly abnormal blood film, with the lymphocytes displaying numerous large cytoplasmic granules. This appearance had not been described before in the literature to the best of the authors' knowledge. After a series of investigations, electron microscopy was eventually performed, which demonstrated that the abnormal granules were composed of immunoglobulin crystals. The immunofixation study confirmed that they were monoclonal IgM paraprotein. These results led to a change of diagnosis to lymphoplasmacytic lymphoma. This report illustrates how electron microscopy can be used as a valuable additional diagnostic tool in difficult cases. PMID- 23025655 TI - On modeling weak sinks in MODPATH. AB - Regional groundwater flow systems often contain both strong sinks and weak sinks. A strong sink extracts water from the entire aquifer depth, while a weak sink lets some water pass underneath or over the actual sink. The numerical groundwater flow model MODFLOW may allow a sink cell to act as a strong or weak sink, hence extracting all water that enters the cell or allowing some of that water to pass. A physical strong sink can be modeled by either a strong sink cell or a weak sink cell, with the latter generally occurring in low-resolution models. Likewise, a physical weak sink may also be represented by either type of sink cell. The representation of weak sinks in the particle tracing code MODPATH is more equivocal than in MODFLOW. With the appropriate parameterization of MODPATH, particle traces and their associated travel times to weak sink streams can be modeled with adequate accuracy, even in single layer models. Weak sink well cells, on the other hand, require special measures as proposed in the literature to generate correct particle traces and individual travel times and hence capture zones. We found that the transit time distributions for well water generally do not require special measures provided aquifer properties are locally homogeneous and the well draws water from the entire aquifer depth, an important observation for determining the response of a well to non-point contaminant inputs. PMID- 23025656 TI - Hypertrichosis lanuginosa congenita treated with diode laser epilation during infancy. AB - We report the case of a girl with hypertrichosis lanuginosa congenita treated with diode laser depilation since the age of 9 months. The treatment was well tolerated, and neither general nor local anesthesia was needed. A reduction of approximately 80% of facial and body hair was noted, which improved her condition significantly. PMID- 23025657 TI - Zn-doped p-type gallium phosphide nanowire photocathodes from a surfactant-free solution synthesis. AB - Gallium phosphide (GaP) nanowire photocathodes synthesized using a surfactant free solution-liquid-solid (SLS) method were investigated for their photoelectrochemical evolution of hydrogen. Zinc as a p-type dopant was introduced into the nanowires during synthesis to optimize the photocathode's response. Investigation of the electrical properties of Zn-doped GaP nanowires confirmed their p-type conductivity. After optimization of the nanowire diameter and Zn doping concentration, higher absorbed photon-to-current efficiency (APCE) over the spectrum was achieved. The versatility of the SLS synthesis and the capability to control the electrical properties suggest that our approach could be generalized to other III-V and II-VI semiconductors. PMID- 23025658 TI - Risk of intrapartum cervical lacerations in women with cerclage. AB - OBJECTIVE: The aim of our study was to estimate whether the placement of cerclage in pregnancy to prevent preterm birth (PTB) is associated with higher incidence of intrapartum cervical lacerations. METHODS: A retrospective cohort study was conducted on singleton pregnancies with risk factors for PTB. The study group consisted of women with either a history- or ultrasound-indicated cerclage placed between 12 and 24 weeks of gestation, while the control group consisted of women with similar risk factors for PTB but who did not receive a cerclage. Primary outcome was the incidence of intrapartum cervical lacerations. A sample size calculation was performed on the basis of the results of previous studies on cervical lacerations. RESULTS: We identified 134 women who had a cerclage placed in pregnancy. They were compared with 236 controls with no cerclage. Cases and controls had similar risk factors for cervical lacerations. Cervical lacerations occurred with similar frequencies in the cerclage and no-cerclage group (2.2 vs 1.3%, p = 0.78). There was no significant difference between the two groups for the risk of cervical lacerations (RR 1.76, 95% CI: 0.36-8.60). CONCLUSIONS: Cerclage placement during pregnancy is not associated with an increased risk of intrapartum cervical lacerations. PMID- 23025659 TI - Influence of temperature on the heterogeneous reaction of formic acid on alpha Al2O3. AB - Despite increased awareness of the role played by heterogeneous reactions of formic acid on mineral aerosol, the experimental determination of how these atmospheric reaction rates vary with temperature remain a crucially important part of atmosphere science. Here we report the first measurement of heterogeneous uptake of formic acid on alpha-Al(2)O(3) as a function of temperature (T = 240 298 K) at ambient pressure using diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). From the analysis of the spectral features, crystalline HCOOH was identified at low temperature besides common product (formate ions) on the surface. It was also interesting to find that crystalline HCOOH can continue to react with alpha-Al(2)O(3). The reaction mechanisms at both room and low temperature were discussed. Furthermore, the reactive uptake coefficients were acquired and found to increase with decreasing temperature. Finally, the atmospheric lifetime of formic acid because of heterogeneous loss on mineral aerosol was estimated at temperatures related to the upper troposphere. PMID- 23025661 TI - Critical analysis of CCSD data quality. AB - Systematization and classification of carbohydrates contribute greatly to development of modern biomedical sciences. CCSD (CarbBank) data constitute the significant part of nearly all existing carbohydrate databases. However, these data have not been verified from their original deposit. During the expansion of Bacterial Carbohydrate Structure Database (BCSDB) project, we checked CCSD data quality and found that about 35% of records contained errors. The CCSD data cannot be used without manual verification, while CCSD errors migrate from database to database. PMID- 23025662 TI - Molecular control of male reproductive development and pollen fertility in rice. AB - Anther development and male fertility are essential biological processes for flowering plants and are important for crop seed production. Genetic manipulation of male fertility/sterility is critical for crop hybrid breeding. Rice (Oryza sativa L.) male sterility phenotypes, including genic male sterility, hybrid male sterility, and cytoplasmic male sterility, are generally caused by mutations of fertility-related genes, by incompatible interactions between divergent allelic or non-allelic genes, or by genetic incompatibilities between cytoplasmic and nuclear genomes. Here, we review the recent advances in the molecular basis of anther development and male fertility-sterility conversion in specific genetic backgrounds, and the interactions with certain environmental factors. The highlighted findings in this review have significant implications in both basic studies and rice genetic improvement. PMID- 23025663 TI - Enrichment of semiconducting single-walled carbon nanotubes by carbothermic reaction for use in all-nanotube field effect transistors. AB - Selective removal of metallic single-walled carbon nanotubes (SWCNTs) and consequent enrichment of semiconducting SWCNTs were achieved through an efficient carbothermic reaction with a NiO thin film at a relatively low temperature of 350 degrees C. All-SWCNT field effect transistors (FETs) were fabricated with the aid of a patterned NiO mask, in which the as-grown SWCNTs behaving as source/drain electrodes and the remaining semiconducting SWCNTs that survive in the carbothermic reaction as a channel material. The all-SWCNT FETs demonstrate improved current ON/OFF ratios of ~10(3). PMID- 23025660 TI - Good CoP, bad CoP? Interrogating the immune responses to primate lentiviral vaccines. AB - Correlates of protection (CoPs) against infection by primate lentiviruses remain undefined. Modest protection against HIV-1 was observed in one human vaccine trial, whereas previous trials and vaccine-challenge experiments in non-human primates have yielded inconsistent but intriguing results. Although high levels of neutralizing antibodies are known to protect macaques from mucosal and intravenous viral challenges, antibody or other adaptive immune responses associated with protection might also be mere markers of innate immunity or susceptibility. Specific strategies for augmenting the design of both human trials and animal experiments could help to identify mechanistic correlates of protection and clarify the influences of confounding factors. Robust protection may, however, require the combined actions of immune responses and other host factors, thereby limiting what inferences can be drawn from statistical associations. Here, we discuss how to analyze immune protection against primate lentiviruses, and how host factors could influence both the elicitation and effectiveness of vaccine-induced responses. PMID- 23025665 TI - A meta-analysis of genome-wide association studies of follicular lymphoma. AB - BACKGROUND: B-cell non-Hodgkin lymphoma represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is one of the most common subtypes. Family and epidemiological studies suggest an important genetic role in the etiology of FL. In recent genome-wide association studies (GWAS) of FL, several genetic susceptibility loci have been identified on chromosome 6p21.33 (rs6457327) and 6p21.32 (rs10484561, rs2647012) in the human leukocyte antigen class I and class II regions. To identify new genetic variants and further elucidate the genetic basis of FL, a meta-analysis was performed of the top 1000 SNPs associated with FL risk from two GWAS in the US, Denmark and Sweden (592 cases, 1541 controls), with independent validation in 107 cases and 681 controls. RESULTS: rs9275517 and rs3117222 in the HLA class II region were validated and inversely associated with FL risk (rs9275517: OR = 0.63, 95% CI = 0.55-0.73, p = 4.03 * 10(-11); rs3117222: OR = 0.66, 95% CI = 0.57-0.77, p = 1.45 * 10(-7)). rs9275517, which is in high linkage disequilibrium with rs2647012 (r2 = 0.9), was no longer associated with FL after conditioning on rs2647012. The rs3117222 association was independent of established FL SNPs, but not of the HLA DPB1*0301 allele. Using publicly available gene expression profiles with matching genotype information, we found that rs3117222 also was significantly correlated with increased HLA-DPB1 expression. CONCLUSIONS: By performing a meta-analysis of two GWAS of FL, we further validated the relevance of HLA-DPB1*0301 as a protective allele in the pathogenesis of FL. Moreover, the protective rs3117222 A allele correlated with increased levels of HLA-DPB1, suggesting a possible disease mechanism involving HLA-DPB1 expression regulation. Our results add further support to the major role of HLA genetic variation in the pathogenesis of FL. PMID- 23025666 TI - Influence of college peers on disordered eating in women and men at 10-year follow-up. AB - Research supports both concurrent and prospective associations between peer behaviors and disordered eating levels in late adolescent and young adult men and women. However, no study has examined peer influence after a follow-up duration over which peer groups change dramatically. This study examined how college roommates' dieting predicted disordered eating levels in women (n = 566) and men (n = 233) at 10-year follow-up. For women, college roommates' dieting significantly predicted Eating Disorder Inventory Drive for Thinness and Bulimia scores and purging at 10-year follow-up. Findings highlight the potential for school-based, peer-led interventions to have long-term benefits in women. PMID- 23025667 TI - The presence of local mesenchymal progenitor cells in human degenerated intervertebral discs and possibilities to influence these in vitro: a descriptive study in humans. AB - Low back pain is common and degenerated discs (DDs) are believed to be a major cause. In non-degenerated intervertebral discs (IVDs) presence of stem/progenitor cells was recently reported in different mammals (rabbit, rat, pig). Understanding processes of disc degeneration and regenerative mechanisms within DDs is important. The aim of the study was to examine the presence of local stem/progenitor cells in human DDs and if these cell populations could respond to paracrine stimulation in vitro. Tissue biopsies from the IVD region (L3-S1) were collected from 15 patients, age 34-69 years, undergoing surgery (spinal fusion) and mesenchymal stem cells (MSCs) (iliac crest) from 2 donors. Non-DD cells were collected from 1 donor (scoliosis) and chordoma tissue was obtained from (positive control, stem cell markers) 2 donors. The IVD biopsies were investigated for gene and protein expression of: OCT3/4, CD105, CD90, STRO-1, and NOTCH1. DD cell cultures (pellet mass) were performed with conditioned media from MSCs and non-degenerated IVD cells. Pellets were investigated after 7, 14, 28 days for the same stem cell markers as above. Gene expression of OCT3/4 and STRO 1 was detected in 13/15 patient samples, CD105 in 14/15 samples, and CD90 and NOTCH1 were detected 15/15 samples. Immunohistochemistry analysis supported findings on the protein level, in cells sparsely distributed in DDs tissues. DDs cell cultures displayed more undifferentiated appearance with increased expression of CD105, CD90, STRO-1, OCT3/4, NOTCH1, and JAGGED1, which was observed when cultured in conditioned cell culture media from MSCs compared to cell cultures cultured with conditioned media from non-DD cells. Expression of OCT3/4 (multipotency marker) and NOTCH1 (regulator of cell fate), MSC-markers, CD105, CD90, and STRO-1, indicate that primitive cell populations are present within DDs. Furthermore, the possibility to influence cells from DDs by paracrine signaling /soluble factors from MSCs and from nondegenerated IVD cells was observed in vitro indicating that repair processes within human DDs may be stimulated. PMID- 23025668 TI - Avian pathology. Editorial. PMID- 23025669 TI - The long view: Salmonella--the last forty years. AB - As a part of the 40th anniversary celebrations of Avian Pathology we review the last four decades of Salmonella research which has led to major progress in our understanding of the bacteriology and infection biology of the organism through the huge advances in molecular biology and immunology that have accompanied technical advances in biology generally. In many countries combinations of improvements in management, sometimes under legislative pressure and supported by a number of basic biological interventions, have resulted in reductions in incidence in the Salmonella serovars that are commonly associated with food poisoning to unprecedented low levels in parent flocks, broilers and layers. Utilisation of the information generated during the past few decades should improve the efficacy of surveillance and biological interventions both for the intestinal carriage that is associated most frequently with human infection and also for systemic diseases, including fowl typhoid and pullorum disease. These two diseases continue to be major economic problems in many countries where the possibilities for improvements in hygiene may be limited but which, nevertheless, are increasingly a significant part of the global economy in poultry meat. PMID- 23025670 TI - Effect of infection route and concurrent infectious bronchitis virus vaccination on Mycoplasma gallisepticum disease pathology in an experimental model. AB - The study of Mycoplasma gallisepticum (MG) infection is needed, not only to understand the disease process but also to understand the mechanisms by which MG vaccines protect the host. Many model systems have been used to study the MG disease process. This work compared two different routes of infection (intratracheal versus eye drop) in commercial pullets, looking for differences in the pathology (air sac and tracheal lesion scores, and tracheal mucosal thickness) and the humoral immune response (measured by serum plate agglutination) of the host. The impact of concurrent infectious bronchitis virus vaccination on disease outcomes was also determined. Results showed that the intratracheal route of MG infection caused increased air sac and tracheal lesion scores and tracheal mucosal thickness at one week post infection, whereas the eye drop route produced no noticeable pathology. However, tracheal mucosal thicknesses of intratracheally challenged pullets were not statistically different from those of the eye drop challenged or control pullets at two and three weeks post infection. Concurrent infectious bronchitis virus vaccination had a negligible outcome on disease pathology. Vaccination of specific-pathogen free chickens with the F-strain MG vaccine completely protected them against the effects of MG intratracheal infectious challenge, as evidenced by a lack of significant difference in air sac and tracheal lesion scores and tracheal mucosal thickness with those of unchallenged media control chickens. PMID- 23025673 TI - Should we view patient complaints as a resource? PMID- 23025674 TI - Novel technique for isolating and dressing enteroatmospheric fistulae. PMID- 23025675 TI - Blind pouch syndrome following enteroanastomosis. PMID- 23025676 TI - Angioblastic T-cell lymphoma of the gall bladder. PMID- 23025677 TI - Unusual nasopharyngeal mass in a young woman. PMID- 23025678 TI - Unusual retroperitoneal splenosis confirmed by laparoscopic retroperitoneal excisional biopsy. PMID- 23025679 TI - Idiopathic calcinosis cutis infection as an unusual mimic of pilonidal abscess. PMID- 23025680 TI - Re: Surgical services: shaping future directions. PMID- 23025681 TI - How surgeons may lessen the risk of being sued. PMID- 23025682 TI - Metastatic clear-cell renal carcinoma to the parotid. PMID- 23025683 TI - Diaphragmatic eventration and gastric volvulus treated by laparoscopic gastropexy. PMID- 23025684 TI - Incarcerated hernia around a suprapubic catheter. PMID- 23025685 TI - Eyelid reconstruction: expanding the applications of the keystone perforator island flap concept. PMID- 23025686 TI - A nonlinear dynamic finite element approach for simulating muscular hydrostats. AB - An implicit nonlinear finite element model for simulating biological muscle mechanics is developed. The numerical method is suitable for dynamic simulations of three-dimensional, nonlinear, nearly incompressible, hyperelastic materials that undergo large deformations. These features characterise biological muscles, which consist of fibres and connective tissues. It can be assumed that the stress distribution inside the muscles is the superposition of stresses along the fibres and the connective tissues. The mechanical behaviour of the surrounding tissues is determined by adopting a Mooney-Rivlin constitutive model, while the mechanical description of fibres is considered to be the sum of active and passive stresses. Due to the nonlinear nature of the problem, evaluation of the Jacobian matrix is carried out in order to subsequently utilise the standard Newton-Raphson iterative procedure and to carry out time integration with an implicit scheme. The proposed methodology is implemented into our in-house, open source, finite element software, which is validated by comparing numerical results with experimental measurements and other numerical results. Finally, the numerical procedure is utilised to simulate primitive octopus arm manoeuvres, such as bending and reaching. PMID- 23025687 TI - Quality evaluation of the available Internet information regarding pain during orthodontic treatment. AB - OBJECTIVE: To investigate the quality of the data disseminated via the Internet regarding pain experienced by orthodontic patients. MATERIALS AND METHODS: A systematic online search was performed for 'orthodontic pain' and 'braces pain' separately using five search engines. The first 25 results from each search term engine combination were pooled for analysis. After excluding advertising sites, discussion groups, video feeds, and links to scientific articles, 25 Web pages were evaluated in terms of accuracy, readability, accessibility, usability, and reliability using recommended research methodology; reference textbook material, the Flesch Reading Ease Score; and the LIDA instrument. Author and information details were also recorded. RESULTS: Overall, the results indicated a variable quality of the available informational material. Although the readability of the Web sites was generally acceptable, the individual LIDA categories were rated of medium or low quality, with average scores ranging from 16.9% to 86.2%. The orthodontic relevance of the Web sites was not accompanied by the highest assessment results, and vice versa. CONCLUSIONS: The quality of the orthodontic pain information cited by Web sources appears to be highly variable. Further structural development of health information technology along with public referral to reliable sources by specialists are recommended. PMID- 23025688 TI - Validation of a multiplex chip-based assay for the detection of autoantibodies against citrullinated peptides. AB - INTRODUCTION: Autoantibodies directed against citrullinated proteins/peptides (ACPAs) are highly specific and predictive for the development of rheumatoid arthritis (RA). Different subgroups of RA patients, which have different prognoses and may require different treatments, are characterized by different autoantibody profiles. The objective of this study was to develop a microarray for the detection of multiple RA-associated autoantibodies, initially focusing on responses against citrullinated epitopes on candidate autoantigens in RA. METHODS: The microarray is based on Phadia's ImmunoCAP ISAC system, with which reactivity to more than 100 antigens can be analyzed simultaneously, by using minute serum volumes (< 10 MUl). Twelve citrullinated peptides, and the corresponding native arginine-containing control peptides, were immobilized in an arrayed fashion onto a chemically modified glass slide, allowing a three dimensional layer with high binding capacity. The assay was optimized concerning serum dilution and glass surface, whereas each individual antigen was optimized concerning coupling chemistry, antigen concentration, and selection of spotting buffer. The performance of each peptide in the ImmunoCAP ISAC system was compared with the performance in enzyme-linked immunosorbent assays (ELISAs). Serum from 927 RA patients and 461 healthy controls from a matched case-control study were applied onto reaction sites on glass slides, followed by fluorescent-labeled anti human immunoglobulin G (IgG) antibody. Fluorescence intensities were detected with a laser scanner, and the results analyzed by using image-analysis software. RESULTS: Strong correlations between the ImmunoCAP ISAC system and ELISA results were found for individual citrullinated peptides (Spearman rho typically between 0.75 and 0.90). Reactivity of RA sera with the peptides was seen mainly in the anticyclic citrullinated peptide 2 (CCP2)-positive subset, but some additional reactivity with single citrullinated peptides was seen in the anti-CCP2-negative subset. Adjusting for reactivity against arginine-containing control peptides did not uniformly change the diagnostic performance for antibodies against the individual citrullinated peptides. CONCLUSIONS: The multiplexed array, for detection of autoantibodies against multiple citrullinated epitopes on candidate RA autoantigens, will be of benefit in studies of RA pathogenesis, diagnosis, and potentially as a guide to individualized treatment. PMID- 23025689 TI - Closed-form approximations for two-dimensional groundwater age patterns in a fresh water lens. AB - Simple closed-form approximations are presented for calculating the steady-state groundwater age distribution in two-dimensional vertical cross sections of idealized fresh water lenses overlying salt water, for aquifers that are vertically semi-infinite and of finite thickness. The approximations are developed on the basis of existing one-dimensional analytical solutions for travel-time calculation in fresh water lenses and approximate streamline formulations. The two-dimensional age distributions based on the closed-form solutions match convincingly with numerical simulations. As expected, notable deviations from the numerical solution are encountered at the groundwater flow divide and when submarine groundwater discharge occurs. Ratios of recharge over hydraulic conductivities are varied to explore how the magnitude of the deviations changes, and it is found that the approximate closed-form solutions perform well over a range of conditions found in natural systems. PMID- 23025691 TI - HbA1c and metabolic syndrome. PMID- 23025692 TI - Abdominal obesity and the risk of venous thromboembolism among women: a potential role of interleukin-6. AB - BACKGROUND: Abdominal obesity increases the risk of venous thromboembolism (VTE). It remains unclear to what extent inflammation contributes to the risk of VTE from abdominal obesity. Our objectives were to investigate the association between abdominal obesity and VTE and the effect of inflammation on this association in a case-control study comprised of women. METHODS: We included 84 patients with VTE (18-60 years of age) and 100 controls. Waist circumference (WC), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) levels were determined at least 7 months after the thrombotic event. RESULTS: A total of 51 patients (61%) and 43 (43%) controls had abdominal obesity (WC >=88 cm). The odds ratios (OR) adjusted for age were 2.40 [95% confidence interval (CI) 1.06-5.41; P=0.035] for a WC >=88 cm compared to a WC <80 cm; the association was attenuated after adjusting for IL-6 (OR 1.86, 95% CI 0.80-4.33; P=0.149). For every 10-cm increment in WC, the risk of VTE adjusted for age increased by 1.38 (95% CI 1.08-1.77; P=0.010). The effect of an increased WC on the risk of VTE was again attenuated when IL-6 was entered in the regression model (OR 1.24, 95% CI 0.95-1.61; P=0.109). Risk estimates did not substantially change with adjustment for hsCRP. CONCLUSION: Our data indicate that the association between VTE and an increased WC was attenuated after adjustment for IL-6, suggesting a potential role of this interleukin in mediating the link between abdominal obesity and VTE. PMID- 23025690 TI - Intranasal oxytocin blocks alcohol withdrawal in human subjects. AB - BACKGROUND: The neuropeptide, oxytocin (OT), has been reported to block tolerance formation to alcohol and decrease withdrawal symptoms in alcohol-dependent rodents. Numerous recent studies in human subjects indicate that OT administered by the intranasal route penetrates into and exerts effects within the brain. METHODS: In a randomized, double-blind clinical trial, intranasal OT (24 IU/dose, N = 7) or placebo (N = 4) was given twice daily for 3 days in alcohol-dependent subjects admitted to a research unit for medical detoxification using Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score-driven PRN administration of lorazepam. Subjects rated themselves on the Alcohol Withdrawal Symptom Checklist (AWSC) each time CIWA scores were obtained. Subjects also completed the Penn Alcohol Craving Scale, an Alcohol Craving Visual Analog Scale (ACVAS) and the Profile of Mood States (POMS) on inpatient days 2 and 3. RESULTS: All subjects had drunk heavily each day for at least 2 weeks prior to study and had previously experienced withdrawal upon stopping/decreasing alcohol consumption. OT was superior to placebo in reducing alcohol withdrawal as evidenced by: less total lorazepam required to complete detoxification (3.4 mg [4.7, SD] vs. 16.5 [4.4], p = 0.0015), lower mean CIWA scores on admission day 1 (4.3 [2.3] vs. 11.8 [0.4], p < 0.0001) and day 2 (3.4 [2.2] vs. 11.1 [3.6], p < 0.002), lower AWSC scores on days 1 and 2 (p < 0.02; p = 0.07), and lower ACVAS ratings (p = 0.01) and lower POMS Tension/Anxiety subscale scores on day 2 (p < 0.01). CONCLUSIONS: This is the first demonstration that OT treatment may block alcohol withdrawal in human subjects. Our results are consistent with previous findings in rodents that OT inhibits neuroadaptation to and withdrawal from alcohol. OT could have advantages over benzodiazepines in managing alcohol withdrawal because it may reverse rather than maintain sedative-hypnotic tolerance. It will be important to test whether OT treatment is effective in reducing drinking in alcohol-dependent outpatients. PMID- 23025693 TI - Epidemiology of tick-borne encephalitis in the Czech Republic 1970-2008. AB - This article presents major epidemiologic features of tick-borne encephalitis (TBE) in the Czech Republic, using data of laboratory-confirmed cases since 1970. A total of 17,053 cases of TBE were reported in the Czech Republic (population 10 million) in 1970-2008. The data show several important features. First, the pattern of TBE incidence changed over time. Until the end of the 1970s, TBE was characterized by periods of alternately higher and lower incidence (between 180 and 595 cases per year); the 1980s were a period of low incidence with minimum variability; since the beginning of the 1990 s, there has been a steep rise in incidence, with marked year-to-year variation (e.g., 745 cases were registered in 1995, and a maximum of 1029 cases were registered in 2006). Second, the age distribution of TBE incidence has changed. Until the end of 1990 s, incidence peaked among those 15-19 years of age, with a gradual decline with age. In the 2000s, however, TBE incidence has been rising in those aged 60-64 years, with a sharp decline in those older than 65 years. Third, the seasonal pattern of TBE has changed markedly over time. In the earlier period, incidence had a clear peak in July/August; since the 1990 s, more cases have occurred in earlier and later months of the year. The proportion of cases occurring in April, May, October, and November increased from 9% in the 1970s to 23% in 2000-2008. Fourth, the geographical distribution of TBE also changed over time, with TBE increasingly occurring in the mountainous districts at higher altitudes. These changes in incidence patterns appear to be linked with changes in climatic and meteorological conditions. The link between climate change and TBE incidence is plausible, since TBE is a recreation-related infection associated with outdoor activities, and since climatic changes affect the life cycle of the vector. PMID- 23025694 TI - Isolation of yellow fever virus from mosquitoes in Misiones province, Argentina. AB - Yellow fever (YF) is a viral hemorrhagic fever endemic to tropical regions of South America and Africa. From 2007 to 2009 an important epidemic/epizootic of YF was detected in different populations of howler monkeys (Alouatta species) in Misiones, a northeastern Argentinian province. Yellow fever virus (YFV) infection was researched and documented by laboratory tests in humans and in dead Alouatta caraya. The objective of that research was to investigate the circulation of YFV in mosquitoes, which could be implicated in the sylvatic transmission of YF in Argentina. The above-mentioned mosquitoes were captured in the same geographical region where the epizootic took place. A YFV strain was isolated in cell culture from pools of Sabethes albiprivus. This study is not only the first isolation of YFV from mosquitoes in Argentina, but it is also the first YFV isolation reported in the species Sabethes albiprivus, suggesting that this species might be playing a key role in sylvatic YF in Argentina. PMID- 23025695 TI - Ehrlichiosis and zoonotic anaplasmosis in suburban areas of Beijing, China. AB - In 2006, an unusual nosocomial outbreak of anaplasmosis occurred in Anhui Province, China. To follow these emerging tickborne-rickettsioses, a larger survey of Ehrlichia chaffeensis and Anaplasma phagocytophilum seroprevalence among farm worker populations, and the divergence of the partial 16S rRNA gene sequences of A. phagocytophilum among domestic animals, were conducted in Yanqing, Miyun, and Tongzhou Counties in Beijing from March to April, 2009. Blood samples from 562 farmers, 90 goats, 73 cattle, and 2 dogs were collected. IgG antibodies against E. chaffeensis and A. phagocytophilum were assayed by micro indirect immunofluorescence assay (IFA). Partial fragments of 16S rRNA genes of A. phagocytophilum were amplified from blood DNA from domestic animals and their sequences analyzed. The total E. chaffeensis and A. phagocytophilum seroprevalence among the farm worker population was 16.4% and 14.1%, respectively. For domestic animals, the seropositive rates of A. phagocytophilum for goats, cattle, and dogs, were 2.3%, 0%, and 0%, respectively. The PCR positive rates for A. phagocytophilum in goats and cattle were 48.9% and 23.9%, respectively. Three dominant genetic groups of Chinese A. phagocytophilum isolates were determined for goats and cattle, and these isolate varieties were broadly identified in China, Japan, and Korea. The prevalence of E. chaffeensis and A. phagocytophilum among farmers and domestic animals in Beijing rural areas was also demonstrated. The diagnoses and differential diagnoses of these emerging infectious diseases should be emphasized in clinics, and further ecological investigation of E. chaffeensis and A. phagocytophilum vectors and hosts is needed. PMID- 23025696 TI - Semiconducting cross-linked polymer nanowires prepared by high-energy single particle track reactions. AB - High-energy charged particle irradiation of cross-linking polymers gives nanowires formed by cross-linking reactions along the ion track trajectories. Here, the direct formation of nanowires consisting of a conjugated polymer by single-particle nanofabrication technique (SPNT) is investigated. Poly(9,9'-di-n octylfluorene) (PFO), regioregular poly(3-hexylthiophene) (rrP3HT), and poly[2 methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) underwent an efficient cross-linking reaction upon irradiation, resulting in the formation of 1-dimensional nanostructures with high and desired aspect ratio reaching up to ~200. The size of nanowires was perfectly interpreted by well-sophisticated theoretical aspects based on the statistical theory of polymer backbone configurations, suggesting that simple cross-linking reactions of the polymers determine the size and structure of nanowires. PFO based nanostructures exhibited sharp and intense emission with high fluorescence quantum yield indicating the absence of any significant inter/intra polymer chromophore interactions in the nanowires assemblies. PMID- 23025697 TI - Successful combination treatment of a patient with progressive juvenile localized scleroderma (morphea) using imatinib, corticosteroids, and methotrexate. AB - We report a case of progressive juvenile localized scleroderma (JLS or morphea) treated with a combination of imatinib, corticosteroids, and methotrexate. This therapy halted the progressive skin thickening and the hand and finger joint deformity in the early stages of the disease. We conclude that imatinib used in addition to standard treatment with systemic corticosteroids and methotrexate may be of therapeutic benefit for individuals with JLS. PMID- 23025699 TI - Predicting the localized/delocalized character of mixed-valence diquinone radical anions. Toward the right answer for the right reason. AB - The Robin-Day class II/III mixed-valence character is established quantum chemically for a series of mixed-valence diquinone radical anions. Particular emphasis is placed on the radical anion of tetrathiafulvalenedibenzoquinone, Q TTF-Q, which has recently been used to evaluate constrained density functional approaches (CDFT) and new range hybrid functionals. Using a computational protocol based on hybrid functionals with 35-42% exact-exchange admixture and inclusion of solvent models during the structure optimization, it is demonstrated that a) Q-TTF-Q(*-), 1, and the related diquinone radical anions 2-4 are all delocalized class III species in the gas phase and in nonpolar solvents, in contrast to previous assumptions; b) 1,4,5,8-anthracenetetraone radical anion, 2, remains class III in polar aprotic solvents, c) systems 1, 3 and 4 become class II, providing excellent agreement between computed and experimental intervalence charge-transfer excitations, thermal electron-transfer (ET) barriers and ESR hyperfine couplings. The direct conductor-like screening model for real solvents (D-COSMO-RS) allows the inclusion of specific hydrogen-bonding effects without the computational effort of molecular dynamics simulations and provides increased ET barriers, as well as a predicted incipient symmetry breaking for 2, due to hydrogen bonding in alcohol solvents. For the first time D-COSMO-RS optimizations in solvent mixtures have been evaluated. As previous computational studies of Q TTF-Q(*-) neglected solvent effects during structure optimizations and obtained charge localization in gas-phase optimizations by CDFT or by exaggerated exact exchange admixtures, they provided at best the right answer for the wrong reason. PMID- 23025698 TI - A retrospective analysis of amniocenteses performed for advanced maternal age and various other indications in Turkish women. AB - OBJECTIVE: Prenatal cytogenetic diagnostic methods for the diagnosis of fetal chromosomal anomalies have been used reliably over the last 40 years. Advanced maternal age has become a basic indication for amniocentesis. METHODS: We examined the results of the chromosome analyses of 3485 women that had amniocentesis for any reason during their antenatal care in our perinatology clinic in 2007-2009. Amniocentesis was performed for advanced maternal age in 1456 women (41.8%) and for other reasons in the remaining 2029 women (58.2%). Chromosomal anomalies were examined numerically and structurally. RESULTS: When the amniocentesis results of the patients were reviewed as numerically normal or abnormal; 40 (2.7%) of 1456 amniocentesis procedures performed for advanced maternal age, 5 (0.9%) of 531 procedures performed for an increased double-test risk and 14 (1.3%) of 1095 procedures performed for an increased triple test risk were found to have chromosomal aneuploidy. CONCLUSIONS: Maternal age is still the most prevalent indication for genetic amniocentesis other than positive prenatal screening tests. Among women with advanced maternal age, prenatal ultrasonography for soft markers of chromosomal aneuploidy accompanied with maternal serum biochemical screening tests should be evaluated during the decision making process of genetic amniocentesis. PMID- 23025700 TI - Identification of a conserved linear B-cell epitope in the M protein of porcine epidemic diarrhea virus. AB - BACKGROUND: The major structural protein of coronaviruses, the membrane (M) protein, can elicit the formation of protective antibodies, but little information is available about the M protein of porcine epidemic diarrhea virus (PEDV). Identification of epitopes on the PEDV M protein will be helpful in the elucidation of the antigenic properties of this protein. RESULTS: One hybridoma cell line secreting anti-M protein monoclonal antibody (McAb) was generated and designated 4D4. To map the epitopes on the PEDV M protein, a total of 17 partially overlapping fragments covering the C-terminus of M protein were expressed as fusion proteins with a 6*His tag or a GST tag. A linear motif, 193TGWAFYVR200, was identified by enzyme-linked immunosorbent assay (ELISA) and western blot (WB) analysis using McAb 4D4. The motif 195WAFYVR200 was the minimal requirement for reactivity, as demonstrated by removing amino acids individually from both ends of the motif 193TGWAFYVR200. The result of WB analysis showed that the 4D4-defined epitope could be recognized by PEDV-positive serum, but not transmissible gastroenteritis virus (TGEV)-positive serum. Furthermore, this epitope was highly conserved among different PEDV strains, as shown by alignment and comparison of sequences. CONCLUSION: A McAb, 4D4, directed against the M protein of PEDV, was obtained, and the 4D4-defined minimal epitope sequence was 195WAFYVR200. The McAb could serve as a candidate for development of a McAb-based antigen capture ELISA for detection of PEDV. The epitope identified provides a basis for the development of epitope-based differential diagnostic techniques and may be useful in the design of epitope-based vaccines. PMID- 23025701 TI - Effects of the pulse frequency of low-level laser therapy on the tooth movement speed of rat molars. AB - OBJECTIVE: The purpose of this study was to compare the speed of the orthodontic tooth movement of rat molars under continuous wave (CW) and pulsed wave (PW) low level laser therapy (LLLT). BACKGROUND DATA: It remains unclear whether LLLT can increase the speed of tooth movement, and no consensus has been established regarding the appropriate parameters and experimental design of LLLT. MATERIALS AND METHODS: Orthodontic movement was induced in 40 rats with 10g coil springs. Rats were randomly assigned to five groups. In Group I, the maxillary left first molars were irradiated with CW by a gallium aluminum arsenide (GaAlAs) diode laser source (830 nm, 180 mW, 3.6 J/cm(2), and 0.9 W/cm(2) for 4 sec at three locations for 3 consecutive days). In Groups II, III, and IV, animals were irradiated with PW at 2, 4, and 8 Hz, respectively (50% duty cycle, average power of 90 mW, 3.6 J/cm(2), and 0.45 W/cm(2) for 8 sec at three locations for 3 consecutive days). Group V served as the control (no irradiation). The movement distance was measured on days 3, 7, and 14. RESULTS: Although there were no significant differences among the irradiation groups, significant differences were found between the control and irradiation groups starting from day 3. CONCLUSIONS: The CW and PW treatments both led to faster orthodontic tooth movement compared with the control group. PMID- 23025702 TI - Skin penetration time-profiles for continuous 810 nm and Superpulsed 904 nm lasers in a rat model. AB - OBJECTIVE: The purpose of this study was to investigate the rat skin penetration abilities of two commercially available low-level laser therapy (LLLT) devices during 150 sec of irradiation. BACKGROUND DATA: Effective LLLT irradiation typically lasts from 20 sec up to a few minutes, but the LLLT time-profiles for skin penetration of light energy have not yet been investigated. MATERIALS AND METHODS: Sixty-two skin flaps overlaying rat's gastrocnemius muscles were harvested and immediately irradiated with LLLT devices. Irradiation was performed either with a 810 nm, 200 mW continuous wave laser, or with a 904 nm, 60 mW superpulsed laser, and the amount of penetrating light energy was measured by an optical power meter and registered at seven time points (range, 1-150 sec). RESULTS: With the continuous wave 810 nm laser probe in skin contact, the amount of penetrating light energy was stable at ~20% (SEM+/-0.6) of the initial optical output during 150 sec irradiation. However, irradiation with the superpulsed 904 nm, 60 mW laser showed a linear increase in penetrating energy from 38% (SEM+/ 1.4) to 58% (SEM+/-3.5) during 150 sec of exposure. The skin penetration abilities were significantly different (p<0.01) between the two lasers at all measured time points. CONCLUSIONS: LLLT irradiation through rat skin leaves sufficient subdermal light energy to influence pathological processes and tissue repair. The finding that superpulsed 904 nm LLLT light energy penetrates 2-3 easier through the rat skin barrier than 810 nm continuous wave LLLT, corresponds well with results of LLLT dose analyses in systematic reviews of LLLT in musculoskeletal disorders. This may explain why the differentiation between these laser types has been needed in the clinical dosage recommendations of World Association for Laser Therapy. PMID- 23025703 TI - In vitro evaluation of the effects of different treatment procedures on dentine tubules. AB - OBJECTIVE: The objective of this preliminary study was to evaluate the occluding effect of topical gaseous ozone application and Er:YAG laser on human dentine tubules by scanning electron microscopic (SEM) analysis. METHODS: Twenty-four dentine specimens were divided into three groups. Group I, including specimens treated only with citric acid, served as the control. Group II was treated with Er:YAG (30 Hz 60 mJ, 10 sec), and Group III received only topical gaseous ozone application (10 sec at level 2). Diameters and the number of open dentinal tubules per 100 MUm(2) were counted from SEM photomigrophraphs at *2000 magnification. RESULTS: In terms of diameters and numbers of open dentinal tubules per 100 MUm(2), both treatment modalities presented significant occlusion. The mean values of the diameters and the number of open dentinal tubules per 100 MUm(2) were observed in Group I, Group II, and Group III, in decreasing order. Significant differences were found among the groups in favor of the topical gaseous ozone applied group. CONCLUSIONS: The dentine tubules in both treatment groups were occluded, however more marked occlusion were seen in ozone treated group. PMID- 23025704 TI - Generation and characterization of human cryptorchid-specific induced pluripotent stem cells from urine. AB - Cryptorchidism is a common congenital birth defect in human beings with the possible complication of infertility. An in vitro model of cryptorchidism might be valuable due to the inaccessibility of human embryos for research purposes. In this study, we reprogrammed urine cells containing genetic variations in insulin like factor 3, zinc finger (ZNF) 214, and ZNF215 from a cryptorchid patient by introducing human OCT4, SOX2, C-MYC, and KLF4 with lentivirus. The cells were then replated on irradiated mouse embryonic fibroblasts and cultured with the human embryonic stem (ES) cell medium. The compact colonies with well-defined borders were manually picked, and 2 induced pluripotent cell lines were fully characterized. Our results demonstrated that these 2 cell lines were similar to human ES cells in morphological appearance, marker expression, and epigenetic status of the pluripotent cell-specific gene, OCT4. These cells could be differentiated into cells of all 3 germ layers in teratomas and in vitro, including into the VASA-positive germ cell lineage. Both parental urine cells and the reprogrammed cells possessed the normal karyotype and the same short tandem repeat loci, indicating that these 2 cell population share the same genetic identity. This establishment and characterization of human urine-derived cryptorchid-specific induced pluripotent stem cells could present a good human genetic system for future studies investigating the molecular mechanism of cryptorchidism. PMID- 23025705 TI - "We weren't using condoms because we were trying to conceive": the need for reproductive counseling for HIV-positive women in clinical care. AB - Although a significant number of HIV-positive women intend to have children in the future, few work with providers to safely plan pregnancy. We conducted 20 semistructured in depth interviews with HIV-positive adolescent and adult women receiving HIV clinical care in an urban setting. Participants were purposively sampled to include diversity in age and childbearing plans. Interview transcripts were analyzed and coded independently by two study team members before reaching consensus on emergent themes. Among this sample of HIV-positive women (mean age=27.9, 95% African American, 50% on antiretroviral therapy [ART], 65% want a biological child), only 25% reported discussing their childbearing goals with their HIV provider. Women actively trying to conceive recognized the risk to themselves and their partner, but had not talked with their provider about safer conception strategies. Data regarding provider communication about childbearing were organized by the following emergent themes: (1) confusion and concern on how to conceive safely, (2) provider characteristics or dynamics that influenced communication, and (3) provider guidance offered regarding childbearing. Even in this unique study setting in which referrals for preconception counseling are possible, women were unaware of this specialized service. Provider initiated reproductive counseling is needed to strategically avoid or plan pregnancy and reduce risk of transmission to partners and infants rather than leaving it to chance, which can have major health implications. PMID- 23025706 TI - Noradrenergic receptor activation alters the migration and distribution of interneurons in the developing neocortex (commentary on Riccio et al.). PMID- 23025707 TI - Drinking initiation and problematic drinking among Latino adolescents: explanations of the immigrant paradox. AB - Studies indicate that U.S.-born Latino teens exhibit higher rates of alcohol use compared with their foreign-born counterparts. Different hypotheses have been advanced to explain the mechanisms underlying this immigrant paradox, including the erosion of protective cultural factors across generations and increased exposure to risky peer environments in the United States. The present study examined whether the immigrant paradox applies to drinking initiation and problematic drinking among Latino adolescents, and tested whether generational differences in family protective factors and peer risk factors might explain the immigrant paradox. A nationally representative sample of Latino teens (N = 2,482) of Cuban, Mexican, and Puerto Rican origin from 3 immigrant generations (21% first generation, 33% second generation, and 46% third and later generations) was obtained from the National Longitudinal Study of Adolescent Health. Logistic and negative binomial regression models indicated that early drinking initiation and problematic alcohol use were more prevalent among later-generation youth, supporting the immigrant paradox. Erosion of family closeness and increased association with substance-using peers mediated the relationship between generation and alcohol use patterns in this sample. Results provide support for culturally sensitive interventions that target peer perceptions of substance use and bolster protective family values among Latino adolescents. PMID- 23025708 TI - The suitability of the South Oaks Gambling Screen-Revised for Adolescents (SOGS RA) as a screening tool: IRT-based evidence. AB - The South Oaks Gambling Screen-Revised for Adolescents (SOGS-RA) is one of the most widely used measures of adolescent gambling. We aimed to provide evidence of its suitability as a screening tool applying item response theory (IRT). The scale was administered to 981 adolescents (64% males; mean age = 16.57 years, SD = 1.63 years) attending high school. Analyses were carried out with a sample of 871 respondents, that is, adolescents who have gambled at least once during the previous year. Once the prerequisite of unidimensionality was confirmed through confirmatory factor analysis, unidimensional IRT analyses were performed. The 2 parameter logistic model was used in order to estimate item parameters (severity and discrimination) and the test information function. Results showed that item severity ranged from medium to high, and most of the items showed large discrimination parameters, indicating that the scale accurately measures medium to high levels of problem gambling. These regions of the trait were associated with the greatest amount of information, indicating that the SOGS-RA provides a reliable measure for identifying both problem gamblers and adolescents at risk of developing maladaptive behaviors deriving from gambling. The IRT-based evidence supports the suitability of the SOGS-RA as a screening tool in adolescent populations. PMID- 23025709 TI - Is low therapist empathy toxic? AB - One of the largest determinants of client outcomes is the counselor who provides treatment. Therapists often vary widely in effectiveness, even when delivering standardized manual-guided treatment. In particular, the therapeutic skill of accurate empathy originally described by Carl Rogers has been found to account for a meaningful proportion of variance in therapeutic alliance and in addiction treatment outcomes. High-empathy counselors appear to have higher success rates regardless of theoretical orientation. Low-empathy and confrontational counseling, in contrast, has been associated with higher drop-out and relapse rates, weaker therapeutic alliance, and less client change. The authors propose emphasis on empathic listening skills as an evidence-based practice in the hiring and training of counselors to improve outcomes and prevent harm in addiction treatment. PMID- 23025711 TI - Clinical involvement and transparency in medical apps: reply to O'Neill and Brady. PMID- 23025710 TI - Genome-wide metabolic (re-) annotation of Kluyveromyces lactis. AB - BACKGROUND: Even before having its genome sequence published in 2004, Kluyveromyces lactis had long been considered a model organism for studies in genetics and physiology. Research on Kluyveromyces lactis is quite advanced and this yeast species is one of the few with which it is possible to perform formal genetic analysis. Nevertheless, until now, no complete metabolic functional annotation has been performed to the proteins encoded in the Kluyveromyces lactis genome. RESULTS: In this work, a new metabolic genome-wide functional re annotation of the proteins encoded in the Kluyveromyces lactis genome was performed, resulting in the annotation of 1759 genes with metabolic functions, and the development of a methodology supported by merlin (software developed in house). The new annotation includes novelties, such as the assignment of transporter superfamily numbers to genes identified as transporter proteins. Thus, the genes annotated with metabolic functions could be exclusively enzymatic (1410 genes), transporter proteins encoding genes (301 genes) or have both metabolic activities (48 genes). The new annotation produced by this work largely surpassed the Kluyveromyces lactis currently available annotations. A comparison with KEGG's annotation revealed a match with 844 (~90%) of the genes annotated by KEGG, while adding 850 new gene annotations. Moreover, there are 32 genes with annotations different from KEGG. CONCLUSIONS: The methodology developed throughout this work can be used to re-annotate any yeast or, with a little tweak of the reference organism, the proteins encoded in any sequenced genome. The new annotation provided by this study offers basic knowledge which might be useful for the scientific community working on this model yeast, because new functions have been identified for the so-called metabolic genes. Furthermore, it served as the basis for the reconstruction of a compartmentalized, genome-scale metabolic model of Kluyveromyces lactis, which is currently being finished. PMID- 23025712 TI - Coliform bacteria in New Jersey domestic wells: influence of geology, laboratory, and method. AB - Following passage of the New Jersey Private Well Testing Act, 50,800 domestic wells were tested between 2002 and 2007 for the presence of total coliform (TC) bacteria. Wells containing TC bacteria were further tested for either fecal coliform or Escherichia coli (FC/E. coli) bacteria. Analysis of the data, generated by 39 laboratories, revealed that the rate of coliform detections in groundwater (GW) was influenced by the laboratory and the method used, and also by geology. Based on one sample per well, TC and FC/E. coli were detected in wells located in bedrock 3 and 3.7 times more frequently, respectively, than in wells located in the unconsolidated strata of the Coastal Plain. In bedrock, detection rates were higher in sedimentary rock than in igneous or metamorphic rock. Ice-age glaciers also influenced detection rates, most likely by removing material in some areas and depositing thick layers of unconsolidated material in other areas. In bedrock, coliform bacteria were detected more often in wells with a pH of 3 to 6 than in wells with a pH of 7 to 10 whereas the reverse was true in the Coastal Plain. TC and FC/E. coli bacteria were detected in 33 and 9.5%, respectively, of sedimentary rock wells with pH 3 to 6. Conversely, for Coastal Plain wells with pH 3 to 6, detection rates were 4.4% for TC and 0.6% for FC/E. coli. PMID- 23025713 TI - Effects of umbilical cord serum eye drops in a mouse model of ocular chemical burn. AB - PURPOSE: To evaluate the effect of umbilical cord serum (UCS) eye drops on corneal wound healing and haze in a mouse model of ocular chemical burn and compare with that of peripheral blood serum (PBS) eye drops or artificial tears (AT). METHODS: Chemical burn of the ocular surface was induced by 1N NaOH in C57BL/6 mice. Injured mice were topically treated with 20% UCS, 20% PBS, or AT four times daily. The changes of corneal epithelial defects and degree of haze were analyzed at 6 h, 1, 2, 3, 5, and 7 days, and histological examination was performed at 3 and 7 days. The concentration of IL-1beta in the cornea was measured by enzyme-linked immunosorbent assay at 7 days after treatment. RESULTS: The UCS group showed lower epithelial defect parameters compared with the PBS group at 1 and 2 days (p < 0.05), and with the AT group from 1-5 days (p < 0.05). The haze scores were significantly lower in the UCS group than in the PBS group at 2 and 3 days (p < 0.05), and in the AT group from 2-7 days (p < 0.05). Histological examination showed better epithelial integrity and lower stromal inflammation and edema in the UCS group than the other groups. IL-1beta levels were 99.71 +/- 85.22 and 230.76 +/- 102.67 pg/ml in the UCS and PBS groups, respectively (p = 0.03). CONCLUSIONS: UCS eye drops are more effective in improving corneal wound healing and reducing corneal haze compared with PBS eye drops and AT in experimental chemical burns. PMID- 23025714 TI - Impact of hormone receptor status on patterns of recurrence and clinical outcomes among patients with human epidermal growth factor-2-positive breast cancer in the National Comprehensive Cancer Network: a prospective cohort study. AB - INTRODUCTION: In gene expression experiments, hormone receptor (HR) positive/human epidermal growth factor-2 (HER2)-positive tumors generally cluster within the luminal B subset; whereas HR-negative/HER2-positive tumors reside in the HER2-enriched subset. We investigated whether the clinical behavior of HER2 positive tumors differs by HR status. METHODS: We evaluated 3,394 patients who presented to National Comprehensive Cancer Network (NCCN) centers with stage I to III HER2-positive breast cancer between 2000 and 2007. Tumors were grouped as HR positive/HER2-positive (HR+/HER2+) or HR-negative/HER2-positive (HR-/HER2+). Chi square, logistic regression and Cox hazard proportional regression were used to compare groups. RESULTS: Median follow-up was four years. Patients with HR-/HER2+ tumors (n = 1,379, 41% of total) were more likely than those with HR+/HER-2+ disease (n = 2,015, 59% of total) to present with high histologic grade and higher stages (P <0.001). Recurrences were recorded for 458 patients. HR-/HER2+ patients were less likely to experience first recurrence in bone (univariate Odds Ratio (OR) = 0.53, 95% Confidence Interval (CI): 0.34 to 0.82, P = 0.005) and more likely to recur in brain (univariate OR = 1.75, 95% CI: 1.05 to 2.93, P = 0.033). A lower risk of recurrence in bone persisted after adjusting for age, stage and adjuvant trastuzumab therapy (OR = 0.53, 95% CI: 0.34 to 0.83, P = 0.005) and when first and subsequent sites of recurrence were both considered (multivariable OR = 0.55, 95% CI: 0.37 to 0.80, P = 0.002). CONCLUSIONS: Presenting features, patterns of recurrence and survival of HER2-positive breast cancer differed by HR status. These differences should be further explored and integrated in the design of clinical trials. PMID- 23025715 TI - Occurrence and human exposure of p-hydroxybenzoic acid esters (parabens), bisphenol A diglycidyl ether (BADGE), and their hydrolysis products in indoor dust from the United States and three East Asian countries. AB - p-Hydroxybenzoic acid esters (parabens) and bisphenol A diglycidyl ether (BADGE) are widely present in personal care products, food packages, and material coatings. Nevertheless, little is known about the occurrence of these compounds in indoor dust. In this study, we collected 158 indoor dust samples from the U.S., China, Korea, and Japan and determined the concentrations of 11 target chemicals, viz., six parabens and their common hydrolysis product, 4 hydroxybenzoic acid (4-HB), as well as BADGE and its three hydrolysis products (BADGE.H(2)O, BADGE.2H(2)O, and BADGE.HCl.H(2)O). All of the target compounds were found in dust samples from four countries. Concentrations of sum of six parabens in dust were on the order of several hundred to several thousands of nanogram per gram. Geometric mean concentrations of BADGEs in dust ranged from 1300 to 2890 ng/g among four countries. Methyl paraben (MeP), propyl paraben (PrP), BADGE.2H(2)O, and BADGE.HCl.H(2)O were the predominant compounds found in dust samples. This is the first report of BADGE and its hydrolysis products (BADGEs) in indoor dust samples and of parabens in indoor dust from Asian countries. On the basis of the measured concentrations of target chemicals, we estimated the daily intake (EDI) via dust ingestion. The EDIs of parabens via dust ingestion were 5-10 times higher in children than in adults. Among the four countries studied, the EDIs of parabens (5.4 ng/kg-bw/day) and BADGEs (6.5 ng/kg bw/day) through dust ingestion were the highest for children in Korea and Japan. PMID- 23025716 TI - Significance of uteroplacental Doppler at midtrimester in patients with favourable obstetric history. AB - OBJECTIVE: To reassess the usefulness of midtrimester uterine Doppler in low-risk multiparous women. METHODS: We prospectively recruited low-risk pregnant women at 20-22 weeks attending our clinic. Among those, women with a favourable obstetric history (group A) were distinguished from nulliparous (group B) and of each group we measured uterine artery Doppler (pulsatility index (PI)). We evaluated the accuracy of uterine artery Doppler in the prediction of preeclampsia and small for gestational age (SGA) neonates. RESULTS: Between January 2009 and October 2010, 382 women were included in the study of which 147 in group A and 235 in group B. Overall, 26/382 (6.8%) women presented preeclampsia and SGA occurred in 59/382 (15.4%) cases. In our population, at a 10% false positive rate (FPR) uterine artery Doppler showed a detection rate (DR) of 19.2% for preeclampsia and of 37.3% for SGA, with a higher sensitivity for SGA neonates delivered <= vs. >34 weeks (87% vs. 29.4%). The univariable receiver operating characteristics (ROC) curve by uterine artery PI yielded a significant prediction only for SGA in nulliparous women (areas under the curve (AUC) of 0.70; 95% CI 0.60-0.79). CONCLUSIONS: Our data confirmed that midtrimester uterine artery Doppler is not an efficient strategy in anticipating the risk of pregnancy complications among low-risk multiparous women. PMID- 23025717 TI - Auto-amplification of cortisol actions in human carotid atheroma is linked to arterial remodeling and stroke. AB - High cortisol and aldosterone levels increase cardiovascular risk, but the respective roles of each hormone within the arterial wall remain controversial. We tested the hypothesis that cortisol production within the arterial wall may contribute to atherosclerotic remodeling and act through illicit activation of the mineralocorticoid receptor (MR). Gene expression studies of the corticoid system components and marker genes of the atherosclerotic process in human carotid atheroma plaque and nearby macroscopically intact tissue (MIT) were considered together with clinical data and compared with pharmacological stimulations of human vascular smooth muscle cells (VSMCs) in contractile or lipid-storing phenotypes. The components of corticoid production and action were present and active within the human carotid wall and VSMCs. Atheroma plaque and lipid-storing VSMCs expressed 11beta-hydroxysteroid deshydrogenase-1 (11beta HSD1) at two- to tenfold higher levels than MIT or contractile VSMCs. The 11beta HSD1 expression was stimulated by cortisol and cortisone, especially in lipid storing VSMCs. MR mRNA level was lower in atheroma and lipid-storing VSMCs and downregulated via MR by fludrocortisone and cortisol. Cortisol upregulated collagen1 and MCP-1 mRNAs via the glucocorticoid receptor (GRalpha), in both VSMC phenotypes, whereas fludrocortisone stimulated the collagen1 expression only in lipid-storing VSMCs. The GRalpha mRNA level in MIT was higher in patients with previous stroke and correlated positively with the collagen1 mRNA but negatively with diastolic blood pressure. Local cortisol production by 11beta-HSD1, and its action via high parietal GRalpha could be relevant from the first step of atherosclerotic remodeling and auto-amplify with transdifferentiation of VSMCs during atheroma progression. PMID- 23025718 TI - Molecular recognition in different environments: beta-cyclodextrin dimer formation in organic solvents. AB - Electrostatic and van der Waals interactions as well as entropy contribute to the energetics governing macromolecular complexation in biomolecules. Hydrogen bonds play a particularly important role in such interactions. Here we use molecular dynamics (MD) simulations to investigate the hydrogen bond (HB) orientations of free beta-cyclodextrin (beta-CD) and head-to-head dimerization of beta-CD monomers with and without guest molecules in different environments, namely, in 10 different solvents covering a wide range of polarity. Potentials of mean force for the dimer dissociation are derived from umbrella sampling simulations, allowing determination of the binding affinity between monomers. The HB orientations are in good agreement with available experimental data in water and dimethyl sulfoxide, yielding confidence in the force field used. HB exchanges at the secondary rim of beta-CD are observed with a fast rate in water and with a low rate or even no exchange in other solvents. Orientational preferences of interglucopyranose HBs and their effects on the beta-CD structure in these solvents are discussed in detail. Polar solvents with stronger HB accepting abilities can interrupt intermolecular HBs more easily, resulting in a less stable dimer. Guest molecules included in the channel-type cavity strengthen the binding affinity between two monomers to some extent, particularly in polar solvents. Formation of the head-to-head dimer is therefore solvent-dependent and guest-modulated. There is only limited correlation between the dimer binding energies and solvent properties like the dielectric constant. This implies that implicit solvent models will not be capable of predicting important properties like binding energy for other solvents than water without a complete reparameterization. This work provides a deeper comprehension on the properties of beta-CD, and implications for the application of cyclodextrins in aqueous and nonaqueous media are discussed. PMID- 23025719 TI - Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors. AB - Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma >= 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF. PMID- 23025720 TI - Flaws in the fabric? PMID- 23025721 TI - General practice trials: the importance of creating evidence. PMID- 23025722 TI - Arthroscopy to treat osteoarthritis of the knee? PMID- 23025723 TI - Australian general practice: primed for the "patient-centred medical home"? PMID- 23025724 TI - From the Cochrane Library: What we know, and what we know we don't know. PMID- 23025726 TI - It's not about choice: the supermarket and obesity. PMID- 23025727 TI - Automated office blood pressure measurement for routine clinical practice. PMID- 23025728 TI - Improving effectiveness of clinical medicine: the need for better translation of science into practice. AB - Published research evidence does not automatically diffuse into clinical practice but requires active processes of translation that start with clinicians' awareness of the science and end with patient adherence to the recommended care. Many barriers thwart the uptake of valid and clinically important research into practice, with cognitive, motivational and sociological factors on the part of health professionals being among the most important. Encouraging clinicians to question the level of scientific certainty underpinning clinical practice and to actively seek evidence that may better inform clinical decisions is a priority for improving health care effectiveness. Although there are effective strategies for improving translation of research into practice, implementing them requires agreement between and buy-in from professional and managerial stakeholders. PMID- 23025729 TI - Overactive bladder in men as a marker of cardiometabolic risk. PMID- 23025730 TI - Harm minimisation in Australian prisons--health protection still depends on where you serve your time. PMID- 23025731 TI - Genetic research in Indigenous health: significant progress, substantial challenges. PMID- 23025732 TI - Genetic research in Indigenous health: significant progress, substantial challenges. PMID- 23025733 TI - Genetic research in Indigenous health: significant progress, substantial challenges. Comment. PMID- 23025735 TI - A cluster randomised controlled trial of vascular risk factor management in general practice. AB - OBJECTIVE: To evaluate the impact of a lifestyle intervention in Australian general practice to reduce the risk of vascular disease. DESIGN, SETTING AND PARTICIPANTS: Stratified cluster randomised controlled trial among 30 general practices in New South Wales from July 2008 to January 2010. Patients aged 40-64 years were invited to participate. The subgroup who were 40-55 years of age were included only if they had either hypertension or dyslipidaemia. INTERVENTION: A general practice-based health-check with brief lifestyle counselling and referral of high-risk patients to a program consisting of one to two individual visits with an exercise physiologist or dietitian, and six group sessions. MAIN OUTCOME MEASURES: Outcomes at baseline, 6 and 12 months included the behavioural and physiological risk factors for vascular disease - self-reported diet and physical activity, and measured weight, body mass index, waist circumference, blood lipid and blood sugar levels, and blood pressure. RESULTS: Of the 3128 patients who were invited, 958 patients (30.6%) responded and 814 were eligible to participate. Of these, 699 commenced the study, and 655 remained in the study at 12 months. Physical activity levels increased to a greater extent in the intervention group than the control group at 6 and 12 months (P = 0.005). There were no other changes in behavioural or physiological outcomes or in estimated absolute risk of cardiovascular disease at 12 months. Of the 384 enrolled in the intervention group, 117 patients (30.5%) attended the minimum number of group program sessions and lost more weight (mean weight loss, 1.06 kg) than those who did not attend the minimum number of sessions (mean weight gain, 0.73 kg). CONCLUSION: While patients who received counselling by their general practitioner increased self-reported physical activity, only those who attended the group sessions sustained an improvement in weight. However, more research is needed to determine whether group programs offer significant benefits over individual counselling in general practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12607000423415. PMID- 23025736 TI - Care of patients with a diagnosis of chronic obstructive pulmonary disease: a cluster randomised controlled trial. AB - OBJECTIVE: To evaluate a partnership model of care for patients with a diagnosis of chronic obstructive pulmonary disease (COPD). DESIGN, SETTING AND PARTICIPANTS: Cluster randomised controlled trial with blinded outcome assessment of 44 general practices in south-western Sydney comprising 451 people with a diagnosis of COPD, conducted between 2006 and 2009. INTERVENTION: Participants from intervention group practices were visited at their home by a registered nurse with specific training in COPD care who worked with the general practitioner, the patient and other health professionals to develop and implement an individualised care plan based on best-practice guidelines. Participants from control group practices received usual care. MAIN OUTCOME MEASURES: The primary outcome was disease-related quality of life measured using the St George's Respiratory Questionnaire (SGRQ) at 12-month follow-up. Other outcomes were overall quality of life, lung function, smoking status, immunisation status, patient knowledge of COPD, and health service use. RESULTS: Of the 451 participants, 257 (57.8%) were confirmed as having COPD on post-bronchodilator spirometry. Follow-up was completed for 330 patients (73.2%). At 12 months, there was no statistically significant difference in the mean SGRQ scores between intervention and control groups (38.7 v 37.6; difference, 1.1; 95% CI, - 1.53 3.74; P = 0.41) or in measures of quality of life, lung function and smoking status. Compared with the control group, in the intervention group, attendance at pulmonary rehabilitation was more frequent (31.1% v 9.6%; OR, 5.16; 95% CI, 2.40 11.10; P = 0.002) and the mean COPD knowledge score was higher (10.5 v 9.8; difference, 0.70; CI, 0.10-1.21; P = 0.02). CONCLUSION: The nurse-GP partnership intervention did not have an impact on disease-related quality of life at 12 month follow-up. However, there was evidence of improved quality of care, in particular, in attendance at pulmonary rehabilitation and patient knowledge of COPD. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN012606000304538. PMID- 23025737 TI - Trends in elective knee arthroscopies in a population-based cohort, 2000-2009. AB - OBJECTIVE: To assess the use of elective knee arthroscopy procedures for all adults 20 years and older, and for adults with a concomitant diagnosis of osteoarthritis (OA) in Victoria. DESIGN, SETTING AND PATIENTS: Retrospective, longitudinal cohort study of 807 030 elective orthopaedic admissions using routinely collected public and private hospital data from 1 July 2000 to 30 June 2009. MAIN OUTCOME MEASURE: Trends in rates of elective knee arthroscopy in the time period (defined as a statistically significant change in the incident rate ratio for each financial year with respect to the reference year). Subgroup analyses were undertaken for patients with an associated diagnosis of OA. RESULTS: There were 190 881 admissions for 159 528 patients having an elective knee arthroscopic procedure. There was a significant decrease in arthroscopic procedures from the 2000-01 financial year, after adjusting for growth in elective orthopaedic volume and relevant patient and hospital characteristics. The trend did not apply to patients with osteoarthritis of the knee. A significant shift in the use of multiday procedures undertaken in high volume, public hospital settings to same-day admissions in the private sector was also identified. CONCLUSIONS: The overall rate of elective knee arthroscopy in Victorian hospitals has decreased. There has been no sustained reduction in arthroscopy use for people with a concomitant diagnosis of OA, despite published evidence questioning the effectiveness of the procedures. PMID- 23025738 TI - Quality indicators of diabetes care: an example of remote-area Aboriginal primary health care over 10 years. AB - OBJECTIVES: To describe service characteristics of Derby Aboriginal Health Service (DAHS) and document diabetes management activities and intermediate clinical outcomes for Aboriginal patients with type 2 diabetes. DESIGN, SETTING AND PATIENTS: Retrospective audit of records for patients >= 15 years old who had a confirmed diagnosis of type 2 diabetes, received primary health care from DAHS for at least 6 continuous months between 1 July 1999 and 30 June 2009, resided in the Derby area and were not on renal replacement therapy. MAIN OUTCOME MEASURES: Electronic records of blood pressure (BP), glycated haemoglobin (HbA(1c)) level, weight, albumin-creatinine ratio, creatinine level or estimated glomerular filtration rate, lipid levels and smoking status during each audit year; and proportions of patients who met clinical targets for HbA(1c), BP and cholesterol. RESULTS: Over the 10 years, the proportion of clinical care activities undertaken according to regional protocols increased significantly, with very high levels recorded in the last 3 years (at least 70% of patients had each activity recorded). There were significant improvements in systolic BP, diastolic BP and cholesterol levels over the 10 years (P < 0.001 for all). In the final year, 69% of patients had at least half their BP measurements <= 130/80 mmHg and 83% had median annual cholesterol levels of < 5.5 mmol/L. There were small improvements in HbA(1c) levels that approached statistical significance (P = 0.05). In the final year, 34% of patients had median annual HbA(1c) levels of <= 7.0%. CONCLUSIONS: This study shows that diabetes monitoring and outcomes can be improved and maintained over a 10-year period in a well supported remote Aboriginal community-controlled health service setting. PMID- 23025739 TI - Severe drug-induced hypersensitivity syndrome with a shared HLA-B allele. PMID- 23025740 TI - Who will know my story now? PMID- 23025741 TI - The bright sides of assimilation. PMID- 23025742 TI - The gap. PMID- 23025743 TI - Insight into the structure-function relationship of the nonheme iron halogenases involved in the biosynthesis of 4-chlorothreonine --Thr3 from Streptomyces sp. OH 5093 and SyrB2 from Pseudomonas syringae pv. syringae B301DR. AB - Molecular cloning of the biosynthetic gene cluster involved in the production of free 4-chlorothreonine in Streptomyces sp. OH-5093 showed the presence of six ORFs: thr1, thr2, thr3, orf1, orf2 and thr4. According to bioinformatic analysis, thr1, thr2, thr3 and thr4 encode a free-standing adenylation domain, a carrier protein, an Fe(II) nonheme alpha-ketoglutarate-dependent halogenase and a thioesterase, respectively, indicating the role of these genes in the activation and halogenation of threonine and the release of 4-chlorothreonine in a pathway closely reflecting the formation of this amino acid in the biosynthesis of the lipodepsipeptide syringomycin from Pseudomonas syringae pv. syringae B301DR. Orf1 and orf2 show sequence similarity with alanyl/threonyl-tRNA synthetases editing domains and drug metabolite transporters, respectively. We show that thr3 can replace the halogenase gene syrB2 in the biosynthesis of syringomycin, by functional complementation of the mutant P. s. pv. syringae strain BR135A1 inactivated in syrB2. We also provide an insight into the structure-function relationship of halogenases Thr3 and SyrB2 using homology modelling and site directed mutagenesis. PMID- 23025744 TI - Building an ontology for assistive technology using the Delphi method. AB - The aim of this study was to use the Delphi method to develop and validate an ontology for one class of assistive technology (AT), namely physically controllable pointing devices. A three-round, structured process consisting of responses to a series of questionnaires was used to identify items and categories of importance to pointing device prescription from six occupational therapists with AT expertise. The intraclass correlation coefficient (ICC) was used to assess the interrater reliability of items included in categories related to the pointing devices and to the user profile by the six experts during each Delphi round. During the first round, the ICC ranged from 0.19 to 0.97; this improved to ICCs ranging from 0.72 to 1.0 during the second round. A full consensus was reached by the experts during the final round which included 218 items, divided into five categories, for the pointing device list, and 168 items, divided into six categories, for the user profile list. This ontology is expected to help achieve a more systematic regulation of the AT field, leading to greater standardization and increased knowledge sharing, which may help novice clinicians to achieve a level of competence in matching AT to a person with special needs. PMID- 23025745 TI - Biofilm infections, their resilience to therapy and innovative treatment strategies. AB - Biofilm formation of microorganisms causes persistent tissue and foreign body infections resistant to treatment with antimicrobial agents. Up to 80% of human bacterial infections are biofilm associated; such infections are most frequently caused by Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus and Enterobacteria such as Escherichia coli. The accurate diagnosis of biofilm infections is often difficult, which prevents the appropriate choice of treatment. As biofilm infections significantly contribute to patient morbidity and substantial healthcare costs, novel strategies to treat these infections are urgently required. Nucleotide second messengers, c-di-GMP, (p)ppGpp and potentially c-di-AMP, are major regulators of biofilm formation and associated antibiotic tolerance. Consequently, different components of these signalling networks might be appropriate targets for antibiofilm therapy in combination with antibiotic treatment strategies. In addition, cyclic di-nucleotides are microbial associated molecular patterns with an almost universal presence. Their conserved structures sensed by the eukaryotic host have a widespread effect on the immune system. Thus, cyclic di-nucleotides are also potential immunotherapeutic agents to treat antibiotic-resistant bacterial infections. PMID- 23025746 TI - Guidelines for psychological evaluations in child protection matters. AB - The problems of abused and neglected children are epidemic in our society (U.S. Department of Health and Human Services, Administration on Children, Youth, and Families, 2008) and create issues that psychologists may be called upon to address. Psychologists are positioned to contribute significantly to decision making in child protection matters. Psychological data and expertise may provide sources of information and a perspective not otherwise available to courts regarding the functioning of parties, and thus may increase the fairness of decisions by the court, state agency, or other party. such matters. These guidelines are a revision of the 1999 "Guidelines for Psychological Evaluations in Child Protection Matters" (American Psychological Association [APA], 1999). These guidelines are informed by APA's "Ethical Principles of Psychologists and Code of Conduct" ("APA Ethics Code"; APA, 2002a, 2010). PMID- 23025747 TI - Specialty guidelines for forensic psychology. AB - In the past 50 years forensic psychological practice has expanded dramatically. Because the practice of forensic psychology differs in important ways from more traditional practice areas (Monahan, 1980) the "Specialty Guidelines for Forensic Psychologists" were developed and published in 1991 (Committee on Ethical Guidelines for Forensic Psychologists, 1991). These Specialty Guidelines for Forensic Psychology were developed by the American Psychology-Law Society (Division 41 of the American Psychological Association [APA]) and the American Academy of Forensic Psychology. They were adopted by the APA Council of Representatives on August 3, 2011. PMID- 23025748 TI - Guidelines for psychological practice in health care delivery systems. AB - Psychologists practice in an increasingly diverse range of health care delivery systems. The following guidelines are intended to assist psychologists, other health care providers, administrators in health care delivery systems, and the public to conceptualize the roles and responsibilities of psychologists in these diverse contexts. These guidelines revise and build upon earlier guidelines regarding hospital privileges, credentialing, and bylaws specific to hospital settings. Renamed "Guidelines for Psychological Practice in Health Care Delivery Systems," they were developed by the Committee on Professional Practice and Standards (COPPS). PMID- 23025750 TI - Benign intraocular teratoid medulloepithelioma causing glaucoma in an 11-year-old Arabian mare. AB - CASE DESCRIPTION: An 11-year-old Arabian mare was presented for investigation of a visible, pale-colored intraocular mass in the right eye. CLINICAL FINDINGS: An intraocular mass was detected clinically and ultrasonographically as originating from the superior temporal quadrant of the ciliary body and iris and causing secondary glaucoma. The echodense mass was occupying the majority of the vitreous chamber and extended into the anterior chamber. The left eye appeared normal. TREATMENT AND OUTCOME: Enucleation was recommended for therapeutic and diagnostic purposes. No adjuvant treatment was given. Histopathological examination demonstrated a benign intraocular teratoid medulloepithelioma located at the ciliary body. Immunohistochemical studies showed that neoplastic cells were positive for vimentin, S-100 protein, neuron-specific enolase (NSE), and nestin and negative for glial fibrillary acidic protein (GFAP). Electron microscopy revealed abundant cellular matrix and blood vessels surrounding tumor cells, which had indented, round to oval nuclei. There were also apoptotic bodies and cells containing melanosomes of variable shape and size. Eight years later, the horse has had no recurrence and maintains normal vision in the left eye. CLINICAL RELEVANCE: This is the first report of a benign teratoid intraocular medulloepithelioma in an adult horse and the ultrastructural and immunohistochemical characterization of a teratoid medulloepithelioma in this species. PMID- 23025751 TI - Myelofibrosis associated with vitamin D deficiency rickets in an older aged child. PMID- 23025749 TI - Transcriptomic and metabolomic analysis of Yukon Thellungiella plants grown in cabinets and their natural habitat show phenotypic plasticity. AB - BACKGROUND: Thellungiella salsuginea is an important model plant due to its natural tolerance to abiotic stresses including salt, cold, and water deficits. Microarray and metabolite profiling have shown that Thellungiella undergoes stress-responsive changes in transcript and organic solute abundance when grown under controlled environmental conditions. However, few reports assess the capacity of plants to display stress-responsive traits in natural habitats where concurrent stresses are the norm. RESULTS: To determine whether stress-responsive changes observed in cabinet-grown plants are recapitulated in the field, we analyzed leaf transcript and metabolic profiles of Thellungiella growing in its native Yukon habitat during two years of contrasting meteorological conditions. We found 673 genes showing differential expression between field and unstressed, chamber-grown plants. There were comparatively few overlaps between genes expressed under field and cabinet treatment-specific conditions. Only 20 of 99 drought-responsive genes were expressed both in the field during a year of low precipitation and in plants subjected to drought treatments in cabinets. There was also a general pattern of lower abundance among metabolites found in field plants relative to control or stress-treated plants in growth cabinets. Nutrient availability may explain some of the observed differences. For example, proline accumulated to high levels in cold and salt-stressed cabinet-grown plants but proline content was, by comparison, negligible in plants at a saline Yukon field site. We show that proline accumulated in a stress-responsive manner in Thellungiella plants salinized in growth cabinets and in salt-stressed seedlings when nitrogen was provided at 1.0 mM. In seedlings grown on 0.1 mM nitrogen medium, the proline content was low while carbohydrates increased. The relatively higher content of sugar-like compounds in field plants and seedlings on low nitrogen media suggests that Thellungiella shows metabolic plasticity in response to environmental stress and that resource availability can influence the expression of stress tolerance traits under field conditions. CONCLUSION: Comparisons between Thellungiella plants responding to stress in cabinets and in their natural habitats showed differences but also overlap between transcript and metabolite profiles. The traits in common offer potential targets for improving crops that must respond appropriately to multiple, concurrent stresses. PMID- 23025752 TI - Photocycle of the LOV-STAS protein from the pathogen Listeria monocytogenes. AB - Listeria monocytogenes, a food-borne bacterial pathogen causing significant human mortality, propagates by expressing genes in response to environmental signals, such as temperature and pH. Listeria gene (lmo0799) encodes a protein homologous to the Bacillus subtilis YtvA, which has a flavin-light, oxygen or voltage (LOV) domain and a Sulfate Transporters Anti-Sigma factor antagonist (STAS) output domain that regulates transcription-initiation factor Sigma B in the bacterial stress response upon exposure to light. This could be significant for the pathogenesis of listeriosis because Sigma B has been linked to virulence of Listeria, and the Listeria Lmo0799 protein has recently been identified as a virulence factor activated by blue light. We have cloned, expressed heterologously in Escherichia coli and purified the full-length LM-LOV-STAS protein. Although it exhibits photochemical activity similar to that of YtvA, LM LOV-STAS lacks an almost universally conserved arginine in the flavin-binding site, as well as another positively charged residue, a lysine in YtvA. The absence of these positive charges was found to destabilize retention of the flavin mononucleotide (FMN) chromophore in the LM-LOV-STAS protein, particularly at higher temperatures. The unusual sequence of the LM-LOV-STAS protein alters both spectral features and activation/deactivation kinetics, potentially expanding the sensory capacity of this LOV domain, e.g. to detect light plus cold. PMID- 23025753 TI - Total and methylated mercury in the Beaufort Sea: the role of local and recent organic remineralization. AB - Mercury is a major contaminant in the Arctic marine ecosystem. While extensive studies have been conducted on mercury in the Arctic's atmosphere and biota, far less is known about the distribution and dynamics of mercury species in the Arctic Ocean. Here, we present vertical profiles for total mercury (Hg(T)) and total methylated mercury (MeHg(T), sum of monomethylmercury and dimethylmercury) from the Beaufort Sea of the Arctic Ocean at locations with differing sea ice conditions. The concentration of Hg(T) ranged from 0.40 to 2.9 pM, with a surface enrichment that can be attributed to a combination of sea ice-modified atmospheric deposition and riverine input. The concentration of MeHg(T) ranged from <0.04 to 0.59 pM, with a subsurface peak occurring at the same depth as a nutrient maximum with lower dissolved oxygen, which is consistent with the recent findings in the Pacific Ocean, Southern Ocean, and Mediterranean Sea. However, unlike the interior ocean regions, the nutrient maximum in the Beaufort Sea is predominantly an advective feature produced over the Chukchi Shelf. On the basis of the short lifetime of monomethylmercury in seawater, we propose that the MeHg(T) profile in the Beaufort Sea reflects the local, short-term remineralization of labile organic matter, and not the larger signal of organic remineralization advected from the Chukchi Sea in the halocline. The finding that MeHg(T) is produced locally, reflecting recent strength of organic matter cycling, not only explains wide variance in MeHg(T) in seawater and biota over time and space, but also implies that MeHg(T) could be used as an indicator of the recent export flux of labile organic matter. PMID- 23025754 TI - Conservation of avian germplasm by xenogeneic transplantation of spermatogonia from sexually mature donors. AB - Approximately 12.5% of all 9,920 extant bird species in the world are threatened with extinction, and yet conservation efforts through natural breeding of captive species continue to encounter difficulties. However, sperm cryopreservation and artificial insemination offer potential benefits over natural breeding, but their applicability is still limited in nondomestic species. In this study, we aimed to exploit the potential of germ cell xenotransplantation as an alternative tool for preserving germplasm of endangered birds. The study was designed to investigate whether transfer of either spermatogonia-enriched cell fraction (SEF) or crude testicular cell fraction (CTF) from adult Japanese quails (as a model for wild species) would result in recolonization of gamma-irradiated gonads of adult recipient chickens. One month after transplantation, 75% of recipients injected with SEF and 25% of recipients injected with CTF resumed spermatogenesis. However, it took more than 3 months for 33% of the negative controls to resume marginal production of sperm. Some SEF recipients produced more spermatozoa bearing head morphology compared with donor controls. DNA analysis using quail specific primers did not detect donor's DNA in these recipients' semen. However, 6 months after xenotransplantation, presence of quail germ cells was demonstrated by polymerase chain reaction and by immunohistochemistry in 1 rooster injected with SEF. These findings indicate that spermatogonia from adult quails were capable of colonizing immunocompetent testis of adult chickens but failed to produce sufficient sperm. Despite this limitation, the present approach represents a potential conservation tool that may be used to rescue germ cells of endangered adult male birds. PMID- 23025755 TI - Isolation of human MHC class II-restricted T cell receptors from the autologous T cell repertoire with potent anti-leukaemic reactivity. AB - Adoptive transfer of T cells genetically modified with tumour-specific T-cell receptors (TCR) is a promising novel approach in the treatment of cancer. We have previously isolated an allorestricted MHC class I-restricted TCR with specificity for Formin-like protein 1 (FMNL1) with potent activity against chronic lymphocytic leukaemia cells. CD4(+) T cells have been described to be highly important for tumour elimination although TCR derived from CD4(+) T cells with anti-tumour reactivity have been only rarely described. In this study we aimed to isolate MHC class-II-restricted CD4(+) T cells and TCR with specificity for leukaemia antigens. We used professional antigen-presenting cells pulsed with the leukaemia-associated and tumour-associated antigen FMNL1 for stimulation of autologous T cells in vitro. We isolated two CD4(+) HLA-DR-restricted T-cell clones and T-cell-derived TCR with so far unknown specificity but high reactivity against lymphoma cells and native malignant cells derived from HLA-matched patients with diverse leukaemias. Moreover, characterization of the TCR after TCR gene transfer revealed that specific characteristics of isolated TCR as reactivity in response to Toll-like receptors were transferable on effector cells. Our results have a major impact on the development of novel immunotherapies. They demonstrate that TCR with potent HLA-DR-restricted anti leukaemic reactivity against so far undefined self-restricted antigens can be isolated from the healthy autorestricted CD4(+) T-cell repertoire and these TCR are highly interesting candidate tools for novel immunotherapies. PMID- 23025756 TI - Effect of activated human polymorphonuclear leucocytes on T lymphocyte proliferation and viability. AB - Human polymorphonuclear leucocytes (PMN) are thought to be immunosuppressive. The suppressive mechanism(s) used by PMN are, however, not well defined and in this study they were analysed using T-cell responses to CD3(+) CD28 monoclonal antibodies (mAb) as a readout. We demonstrate that in vitro activated PMN (PMN(act)) can, without any T-cell interaction, induce apparent T-cell suppression by inhibiting the stimulatory capacity of the CD3 mAb. However, a cell-directed suppression of T-cell proliferation was observed when PMN(act) were added to pre-activated T cells that are already committed to polyclonal proliferation. This suppression was partially reversed by catalase addition (P < 0.01) and largely reversed by addition of exogenous interleukin-2 (P < 0.001) but was not significantly reduced by nitric oxide synthase inhibition, myeloperoxidase inhibition or addition of excess arginine. Following removal of PMN(act) , suppressed T cells could respond normally to further stimulation. In addition to suppressing proliferation, co-culture with PMN(act) also induced a significant decrease in T-cell viability that was reversed by catalase addition (P < 0.05). The addition of the arginase inhibitor N-hydroxy-nor-l-arginine induced both a further significant, catalase-sensitive, loss in T-cell viability and increased nitrite release (P < 0.001). These data demonstrate that PMN, when activated, can both induce T-cell death and reversibly inhibit proliferation of activated T cells. The mechanisms underlying these distinct processes and the effects of arginase inhibitors on PMN induced cytotoxicity merit further investigation. PMID- 23025757 TI - Antitussive effects of the peripherally restricted GABAB receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABAB receptor selective agonists. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABAB receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux therapy that reduces the frequency of transient lower esophageal sphincter relaxations (TLESR; the major cause of reflux) in animals and in patients with GERD. GABAB receptor agonists have also been shown to possess antitussive effects in patients and in animals independent of their effects on TLESR, suggesting that lesogaberan may be a promising treatment for chronic cough. METHODS: We have assessed the direct antitussive effects of lesogaberan (AZD3355). The effects of other GABAB receptor agonists were also determined. Coughing was evoked in awake guinea pigs using aerosol challenges with citric acid. RESULTS: Lesogaberan dose-dependently inhibited citric acid evoked coughing in guinea pigs. Comparable effects of the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA) on cough were also observed. Baclofen produced obvious signs of sedation and respiratory depression. By contrast, both lesogaberan and 3-APPiA (both inactivated centrally by GABA transporters) were devoid of sedative effects and did not alter respiratory rate. CONCLUSIONS: Together, the data suggest that lesogaberan and related GABAB receptor agonists may hold promise as safe and effective antitussive agents largely devoid of CNS side effects. PMID- 23025759 TI - Reducing neonatal mortality and expenditure in the era of health care crisis: is it possible? PMID- 23025760 TI - Universal screening for inherited metabolic diseases in the neonate (and the fetus). AB - The traditional focus of newborn screening for inherited metabolic diseases is to test infants for medical conditions that may cause significant morbidity and mortality unless treatment is initiated early. A major change began with the application of tandem mass spectrometry to the quantitative analysis of amino acids and acylcarnitines in dried blood spots. Beyond the lack of a consensus on disease selection, the pace of introduction for expanded screening programs has been slow and patchy among and within countries. Universal metabolic screening poses important ethical issues, related to possible ambiguous findings, late onset diseases, conditions, such as lysosomal storage disorders, with no clear cut evidence on when and how to start a therapy. The possible application of next generation sequencing to newborn screening has been recently proposed. In the near future it will be also possible to perform a genetic and mutational scan across the whole genome of the fetus in a non-invasive manner by analyzing cell free fetal DNA in maternal blood as early as the 5th week of gestational age. These high-throughput methods applied to neonatal and non-invasive prenatal screening of genetic diseases, including inborn errors of metabolism, are raising further technical, political and ethical issues. PMID- 23025758 TI - Blast wave exposure impairs memory and decreases axon initial segment length. AB - Exposure to a blast wave has been proposed to cause mild traumatic brain injury (mTBI), with symptoms including altered cognition, memory, and behavior. This idea, however, remains controversial, and the mechanisms of blast-induced brain injury remain unknown. To begin to resolve these questions, we constructed a simple compressed air shock tube, placed rats inside the tube, and exposed them to a highly reproducible and controlled blast wave. Consistent with the generation of a mild injury, 2 weeks after exposure to the blast, we found that motor performance was unaffected, and a panel of common injury markers showed little or no significant changes in expression in the cortex, corpus callosum, or hippocampus. Similarly, we were unable to detect elevated spectrin breakdown products in brains collected from blast-exposed rats. Using an object recognition task, however, we found that rats exposed to a blast wave spent significantly less time exploring a novel object when compared with control rats. Intriguingly, we also observed a significant shortening of the axon initial segment (AIS) in both the cortex and hippocampus of blast-exposed rats, suggesting altered neuronal excitability after exposure to a blast. A computational model showed that shortening the AIS increased both threshold and the interspike interval of repetitively firing neurons. These results support the conclusion that exposure to a single blast wave can lead to mTBI with accompanying cognitive impairment and subcellular changes in the molecular organization of neurons. PMID- 23025762 TI - Metabolomics explained to perinatologists and pediatricians. AB - Metabolomics is a new approach based on the systematic study of the full complement of low-molecular weight compounds (e.g. sugars, lipids, hormones, vitamins, secondary metabolites), both endogenous and exogenous, found within a cell, tissue, biofluid or organism. In order to avoid false expectation by using a metabolomics approach, it is important to have: (i) a properly planned design of the study based on a clear question to be answered, (ii) an appropriate knowledge of the equipments available; (iii) a proper statistical analysis and support and (iv) a validation of the results obtained. In the present short review, these topics will be briefly described. PMID- 23025763 TI - Physiopathology of intrauterine growth retardation: from classic data to metabolomics. AB - It is well known that adverse conditions during intrauterine life, such as intrauterine growth restriction (IUGR), can result in permanent changes in the physiology and metabolism of the newborn, which in turn leads to an increased risk of disease in adulthood (fetal origin of adult disease hypothesis). In the first part of this review the epidemiological studies in which a correlation between low birth weight and chronic pathologies in adulthood was observed are reported. The second part of the review is focused on metabolomics studies that have revealed an altered metabolism in IUGR patients compared to controls. Together with more classic biomarkers of IUGR, such as endothelin-1, leptin, protein S100B and visfatin, the new holistic metabolomics approach has assumed a crescent role in the identification of disorders in the neonatal metabolic profile, determined by the interconnection of the different processes. PMID- 23025761 TI - Epidemiology of congenital hypothyroidism: what can be deduced from the Italian registry of infants with congenital hypothyroidism. AB - In Italy, the nationwide newborn screening programme for congenital hypothyroidism (CH) represents an integrated approach to the disease including screening tests, diagnosis, treatment, follow up and nation-wide surveillance of the disease. The latter is performed by the Italian National Registry of Infants with Congenital Hypothyroidism (INRICH). The INRICH is a population-based Registry, this implies that results obtained in the analyses conducted on the data collected in the INRICH are highly representative, can be easily used to improve the health of CH children, and provide information critical to understanding the etiology of the disease. Over the years, the INRICH has contributed: i) to improve procedures for diagnosis, treatment and follow-up of affected babies, by identifying critical points in screening program procedures; ii) to estimate the incidence of CH and the prevalence of the different forms of the disease (thyroid dysgenesis, normally located and shaped thyroid) in our country; iii) to provide a unique opportunity for research into this condition given the large amount and the high quality of information collected in this registry. PMID- 23025764 TI - Metabolomic approach to foetal and neonatal heart. AB - Metabolomics is an emerging and powerful technology that provides an accurate and dynamic picture of the phenotype of mammalian systems through the study of endogenous and exogenous metabolites in their tissues or body fluids. In the last 10 years, an increase in the number of papers about metabolomics applied to cardiovascular risk factors and diseases has been observed. Anyway, the majority of these studies involved adult patients. In this article, all the up to now examples of metabolomics applied to the study of cardiovascular physiology, disease onset and progression during foetal and neonatal life have been reviewed. An outlook of the requirements for future researches has been also discussed. PMID- 23025765 TI - Pharmaceutical research and metabolomics in the newborn. AB - Newborns are a particularly vulnerable population. The response to a drug in terms of efficacy and toxicity varies widely from one newborn to another. Inter individual variation in drug response is strongly affected by the patient's biochemical state at the time of therapy, as reflected by his metabolic phenotype, which in turn results from the interaction of both genetic and non genetic factors. These factors contribute to the difficulties in accurate drug prescribing and dosing and to the increased risk of adverse drug reactions in the neonatal population. Metabolomics has been found to be particularly suitable for pharmaceutical Research & Development, with a range of successful applications that include preclinical safety evaluation of drug candidates, predicting the metabolism and toxicity of a drug based on the analysis of a pre-dose metabolic profile (pharmacometabolomics), and identification of drug-related alterations in metabolic pathways. Pharmacometabolomics is a rapidly developing field which refers to the direct measurement of metabolites in an individual's body fluids to predict or evaluate the metabolism of pharmaceuticals. The implementation of metabolomic techniques in pharmaceutical research has the potential to greatly enhance our understanding of mechanisms of drug effects, of undesirable drug reactions and of the biological processes underlying individual variations in drug response phenotypes. A more extensive clinical use of metabolomics could be a decisive step towards personalized drug therapy, with the ultimate aim to match the right drug to the right patient. Some applications of metabolomics in pharmaceutical research are discussed, with special focus on clinical use in Neonatology. PMID- 23025766 TI - Top-down platform for deciphering the human salivary proteome. AB - Proteomic platforms can be classified in bottom-up strategies, which analyze the sample after proteolytic digestion, and top-down strategies, which analyze the intact naturally occurring proteome. Bottom-up platforms are high-throughput because they can investigate a large number of proteins, regardless of their dimension. Nonetheless, information on post-translational modifications (PTMs) can be lost, especially those regarding naturally occurring cleavages and alternative splicing. Top-down platforms cannot cover vast proteomes, however, they can disclose subtle structural variations occurring during protein maturation and allow label-free relative quantifications in an unlimited number of samples. A repertoire of 256 masses belonging to naturally occurring proteins and peptides consistently detected by RP-HPLC-ESI-MS analysis of the acidic soluble fraction of human whole saliva is presented in this study. Of them, 233 have been identified, while 23 are still pending for the definitive characterization. The present review reports average and mono-isotopic masses of the peptides and proteins detected, RP-HPLC elution times, PTMs, origin and quali quantitative variations observed in several physiological and pathological conditions. The information reported can be a reference for users of top-down RP HPLC-ESI-MS proteomic platforms applied to the study of the human salivary proteome as well as of other human bodily fluids. PMID- 23025767 TI - Research in human resuscitation: what we learn from animals. AB - AIM: It was not until the 18th century that scientists throughout Europe established humane societies to develop resuscitation techniques and to keep registries of successful and unsuccessful cases. Since then, the science and art of cardiopulmonary resuscitation have flourished, multiple international organizations were found, and guidelines are proposed every 5 years in an everlasting attempt to improve the outcome of cardiac arrest victims. The aim of this article is to present the role of animal models in resuscitation research. METHODS: A comprehensive search in PubMed, CINAHL, Cochrane Library, and Scopus databases was performed. RESULTS: Mice, rats, and swine have been established as experimental models for conducting resuscitation research. The choice of the animal model is not a simple task, as there are multiple parameters that have to be considered when designing an experiment. CONCLUSION: Animal models are used extensively in resuscitation research and possess a central role in the effort towards a better understanding of the underlying mechanisms. However, experimental results should always be cautiously extrapolated in humans. PMID- 23025768 TI - C-reactive protein levels in the first days of life: a systematic statistical approach. AB - OBJECTIVE: Microbial neonatal infections are responsible for considerable morbidity and mortality and for this reason there is a growing interest for new approaches in the clinical government of this human affection. Using an integrated statistical model, this work investigated the role of the C-reactive protein (CRP) in the diagnosis of sepsis and therapy assessment in newborns admitted in neonatal intensive care unit. METHODS: 386 newborns admitted in neonatal intensive care unit were enrolled in this work. Different clinical laboratory parameters, such as: CRP level, blood culture, complete blood cell count, urine and other blood tests were assessed for the first 7 days after birth. Several statistical methods have been used to estimate the correlation CRP septicaemia, using Chi-squared, Pearson, analysis of the variance and Poisson distribution. RESULTS: a statistical positive correlation (CRP value vs. septicaemia status) was observed to integrate the analysis of the variance and Poisson distribution methods, especially in the first days after birth. CONCLUSION: A correct statistical evaluation of CRP values could be significant for risk prediction and subsequent prompt therapy in neonatal sepsis. PMID- 23025769 TI - Soluble CD14 subtype (sCD14-ST) presepsin in critically ill preterm newborns: preliminary reference ranges. AB - Soluble CD14 subtype (sCD14-ST), also named presepsin, is a 13 kDa truncated form of soluble CD14 (sCD14), consisting of 64 amino acid residues. Systemic inflammation and sepsis are characterized by an early, significant increase in sCD14-ST presepsin blood concentration and thus, this small polypeptide has been proposed as a novel, reliable biomarker for the management of sepsis. We enrolled twenty-six consecutive non-septic preterm newborns with gestational age (GA) between 26 and 36 weeks) admitted to NICU after the first day of life for various severe diseases. sCD14-ST presepsin was measure on whole blood samples by a rapid commercial available chemiluminescent enzyme immunoassay (CLEIA) based on a non competitive CLEIA. The mean sCD14-ST presepsin blood level in 26 preterm newborns was 643.1 ng/L, with a standard deviation (SD) of 303.8 ng/L; the median value was 578 ng/L. Our results clearly suggest no correlation between GA and sCD14-ST presepsin blood level between 26 and 36 weeks and thus it is reasonable to adopt a unique reference range for preterm newborns. PMID- 23025770 TI - Assessment of fetal inflammatory syndrome by "classical" markers in the management of preterm labor: a possible lesson from metabolomics and system biology. AB - There exists a huge gap between protocols issued by scientific bodies and evidence derived by system biology studies on the multifactorial origin of threatened preterm delivery and their different associations with neonatal outcome. The objective of this prospective study was the analysis obstetrical and neonatal outcome in a cohort of pregnant patients treated for the risk of preterm delivery according to maternal and fetal assessment determined by amniotic fluid samples. Methods. Threatened preterm delivery and premature rupture of membranes between 24 + 1 and 32 + 6 weeks of gestation were treated by prolonged tocolytic regimens and if necessary by antibiotics for maternal infections when intra amniotic inflammation (IAI) was excluded on the basis of negative white blood cell count in the amniotic fluid, or opposite, by delivery after a course of betamethasone and 48 hours maintenance tocolysis. Twenty-three cases were compared with 22 historical controls treated by the same teams according to the 48 hours treat and wait criteria. In addition to this, cases with normal and abnormal amniotic fluid white blood cell were compared. Results. Maternal and fetal conditions at admission were not significantly different between the study and control cohort for all maternal and fetal variables. Clinical indices were significantly improved as regard to latency from admission to delivery, number of newborns admitted to neonatal intensive care unit and length of stay in neonatal intensive care unit. Not any perinatal death or sepsis occurred in the study cohort. Overall, improved neonatal outcomes were observed in the study cohort. Composite major neonatal eventful outcomes occurred in 26% of cases vs. 50% in controls. The limited number of cases was not powered enough to reach a statistical significance for these variables. Continued tocolysis on demand and full regimen of mono or combined antibiotic regimen for maternal infection achieved significantly longer delay between admission to delivery with improved in neonatal outcome in cases negative for IAI: only 2 of 14 newborns suffered of major neonatal complications vs. 4 of 9 newborns delivered for IAI. Conclusions. Fetuses without IAI can be treated conservatively and their stay in utero prolonged without harm. However, we confirmed that when IAI is already active in utero a worse neonatal outcome is already partly predetermined. These positive findings must be interpreted with cautions given the limited number of cases considered by this study. PMID- 23025771 TI - A metabolomic study of preterm human and formula milk by high resolution NMR and GC/MS analysis: preliminary results. AB - OBJECTIVE: The aim of the present study was to investigate the metabolic profile of preterm human breast milk (HBM) by using a metabolomic approach. METHODS: NMR spectroscopy and GC/MS were used to analyze the water-soluble and lipid fractions extracted from milk samples obtained from mothers giving birth at 26-36 weeks of gestation. For the sake of comparison, preterm formula milk was also studied. RESULTS: The multivariate statistical analysis of the data evidenced biochemical variability both between preterm HBM and commercial milk and within the group of HBM samples. CONCLUSIONS: The preliminary results of this study suggest that metabolomics may provide a promising tool to study aspects related to the nutrition and health of preterm infant. PMID- 23025772 TI - Multiple organ failure syndrome in the newborn: morphological and immunohistochemical data. AB - Multiple organ failure (MOF) syndrome, also known as multiple organ dysfunction syndrome (MODS) represents a common but complex problem in critically ill patients in neonatal intensive care unit (NICU) centers, and a major cause of morbidity and mortality in newborns. MOF is considered the result of an inappropriate generalized inflammatory response of the newborn to a variety of acute insults. This study was aimed at analyzing, at histology, multiple organ pathological changes in two newborns admitted to the NICU center of our University Hospital, who showed a progressive clinical picture of MOF, in order to verify the pathological changes of vascular structures and of endothelial cells in the different organs affected by MOF. All the samples obtained at autopsy for histological examination showed specific organ pathological changes, especially related to modifications in vascular structures and, in particular, in endothelial cells. The most interesting findings were found in the intestinal barrier, in the lower respiratory tract and in the endothelial barrier. The loss of the gut barrier could allow the passage into the blood of microbial factors that could trigger the production of tumor necrosis factor alpha (TNFalpha) leading to endothelial damage. Our preliminary study underlines the principal role probably played by intestinal and vascular changes in the origin of MOF in newborns. PMID- 23025773 TI - The pine-cone body: an intermediate structure between the cap mesenchyme and the renal vesicle in the developing nod mouse kidney revealed by an ultrastructural study. AB - Nephrogenesis is mainly characterized by the interaction of two distinct renal constituents, the ureteric bud and the metanephric mesenchyme. In this paper we describe by means of light and electron microscopic techniques the morphological events that take place during the early stages of cap mesenchymal formation. Samples of normal renal tissue were excised from newborn NOD mice and processed by standard light and electron microscopy techniques. In all samples examined we detected the presence of several cap mesenchymal aggregates in different stages of differentiation. They varied from small solid nodules with few ovoid cells to bigger pine-cone-like aggregates, characterized by a peculiar distribution and morphology of their cellular constituents. Our data highlight, for the first time, the presence of a specific cap mesenchymal structure, the pine-cone body and show, at ultrastructural level, how each cap aggregate epithelializes proceeding in stages from a condensed mesenchymal aggregate to the renal vesicle, through the intermediate "pine-cone body" stage. PMID- 23025774 TI - Seminars in neonatal hematology. PMID- 23025775 TI - Expected erythrocyte, platelet and neutrophil values for term and preterm neonates. AB - Reference ranges are an important guide for properly interpreting the clinical laboratory studies obtained from newborn infants. To judge whether the data contained in a CBC (complete blood count) is "normal," a neonatologist cannot utilize the normal ranges of CBCs constructed by sampling healthy adult volunteers. This is because important developmental differences are present between CBC values from adults vs. neonates. Also, differences in gestational age and post-natal age of neonates result in a need to have separate sets of reference range values for each. Otherwise, much confusion can exist in determining whether the CBC values are lower or higher than they should be. We reasoned that reference ranges constructed from very large databases would be a valuable new tool for neonatologists. To create these, we used the electronic data of Intermountain Healthcare, a multihospital healthcare system in the western USA, focusing on each of the various CBC elements. This presentation will review this process and display some of the novel clinically useful findings resulting from these studies. PMID- 23025776 TI - Erythropoietin in anemia of prematurity. PMID- 23025777 TI - Association between red cell transfusions and necrotizing enterocolitis. AB - OBJECTIVE: Several case reports and retrospective studies have reported a temporal association between red blood cell (RBC) transfusions and necrotizing enterocolitis (NEC). In this article, we review the clinical evidence and biological plausibility of the association between RBC transfusions and NEC. METHODS: A literature search was performed using the databases PubMed, EMBASE, and Scopus, and the electronic archive of abstracts presented at the annual meetings of the Pediatric Academic Societies. RESULTS: Among all cases of NEC, 25 -40% patients were noted to have received an RBC transfusion within a 48 hour period prior to onset of NEC. Compared to infants who developed NEC unrelated to transfusion, neonates with transfusion-associated NEC were born at an earlier gestation, had lower birth weights, and had a delayed onset at 3-5 weeks of postnatal age. CONCLUSIONS: Based on current clinical evidence, transfusion associated NEC appears to be a plausible clinical entity. However, there is a need for cautious interpretation of data because all the studies that have been conducted until date are retrospective, and therefore, susceptible to bias. A large, prospective, multi-center trial is needed to evaluate the association between RBC transfusion and NEC. PMID- 23025778 TI - More clearly defining the risks of erythrocyte transfusion in the NICU. AB - OBJECTIVE: Red blood cell (RBC) transfusions convey benefits but they also carry risks. Among NICU patients, some transfusion risks are well defined and their occurrence odds can be estimated and weighed against benefits. However other risks are poorly defined and it is not currently possible to estimate their occurrence adds or weigh these against benefits. METHODS: We reviewed publications in the past 15 years, listed in PubMed, dealing with risks and benefits of RBC transfusions to newborn infants. RESULTS: Risks of RBC transfusion to adult patients decreased significantly with the advent of nucleic acid testing for viral pathogens. However, new or previously unknown risks of transfusions have been suggested for neonatal recipients. These include developmental delay, intraventricular hemorrhage, and necrotizing enterocolitis. These potential transfusion risks are all currently in the form of statistical associations, and cause-and-effect relationships have not been proven. Mean of reducing transfusions, tested during the past 15 years, include adopting transfusions guidelines, erythropoietic stimulating agents, delayed cord clamping, cord stripping, drawing all NICU admission blood tests from the placenta, and limiting phlebotomy losses for blood testing. DISCUSSION: We advocate always attempt to weigh benefits and risks when ordering a transfusion for a neonatal patient. Certainly some such are life-saving or otherwise clearly beneficial. Perhaps others carry risks unbalanced by meager benefit. Efforts to improve NICU transfusion practice have been proposed and appear to be working to diminish costs and improve outcomes. PMID- 23025779 TI - A consistent approach to platelet transfusion in the NICU. AB - Platelet transfusions are the principal means of treating thrombocytopenia in neonatal intensive care units (NICUs), and are generally used as treatment of thrombocytopenic neonates who have active bleeding and as prophylactic administration in thrombocytopenic neonates who do not have hemorrhage but appear to be at high risk for bleeding. In this article, we summarize the rationale, benefits and risks of platelet transfusions in neonates. We review the importance of choosing the best product available for platelet transfusion, and we emphasize the importance of adopting and adhering to transfusion guidelines. PMID- 23025780 TI - Erythropoiesis and the approach to anemia in premature infants. AB - OBJECTIVE: To review causes of anemia in preterm infants and to suggest potential preventive measures. METHODS: Data for this review is obtained from review of the literature. RESULTS: An approach to investigating and treating causes of neonatal anemia is outlined. CONCLUSIONS: Clinical practices can significantly impact anemia in premature infants. Delayed cord clamping, decreasing phlebotomy loss and optimizing nutritional support are practices that may decrease the severity of anemia, thereby decreasing the need for transfusions or erythropoietin treatment. PMID- 23025781 TI - Evaluation of neutropenia and neutrophilia in preterm infants. AB - OBJECTIVE: Neutrophil counts are used routinely as part of the sepsis evaluation in newborn infants. In this article, we review the normal blood neutrophil concentrations and the clinical approach to neutropenia and neutrophilia in the neonatal period. METHODS: A literature search was performed using the databases PubMed, EMBASE, and Scopus, and the electronic archive of abstracts presented at the annual meetings of the Pediatric Academic Societies. RESULTS: Neutropenia and neutrophilia are documented frequently in premature infants. Neutropenia can be seen in up to 8% of all infants admitted to neonatal intensive care. Neutrophilia is even more common, reported in up to 40% of all preterm infants. CONCLUSIONS: Neutrophil counts should be carefully evaluated in premature neonates. Maternal and perinatal history, physical examination, and a limited laboratory assessment is usually adequate for making a diagnosis in most infants. PMID- 23025782 TI - Oxidative injury in neonatal erythrocytes. AB - Erythrocytes are continuously exposed to free radicals (FR) injury due to their high cellular oxygen concentration and heme iron. The autoxidation of oxyhaemoglobin to methaemoglobin, generating superoxide anion radical, represents the main source of FR in erythrocytes. The erythrocyte membrane is particularly sensitive to oxidative damage due to its high polyunsaturated fatty acid content, and hence, it represents an important system to evaluate the effect of oxidative stress (OS). Information on how red cells OS is triggered and mechanisms of erythrocytes oxidative pressure from plasma may provide a partial answer to questions about the causes of the anaemia of prematurity and about red cell involvement in hypoxia. The recent insights about the mechanism of oxidative injury of red cells and the evidence of relationships between erythrocyte, OS and hypoxia suggest that increased haemolysis is induced by severe hypoxia and acidosis in the perinatal period. PMID- 23025784 TI - Cardiopulmonary resuscitation after traumatic cardiac arrest--there are survivors: registries must speak about it. PMID- 23025785 TI - Differential impacts of brassicaceous and nonbrassicaceous oilseed meals on soil bacterial and fungal communities. AB - Demand for alternative fuels has sparked renewed interest in the production of biodiesel from oil-rich seeds. Oilseed meals are a byproduct of this process, and given their relatively high nutrient content, land application represents a potential value-added use. In this microcosm-based study, soil microbial community responses to amendments of a glucosinolate-containing brassicaceous oilseed meal (Brassica juncea, mustard), a non-glucosinolate-containing, nonbrassicaceous oilseed meal (Linum usitatissimum, flax), and a nonoilseed biomass (Sorghum bicolor) were characterized using a 28-day time series of replicated 16S rRNA gene and fungal ITS gene sequence libraries. We hypothesized that biomass type and glucosinolate content would alter community composition but that effects would diminish over time. Distinct separation occurred by amendment type, with mustard inducing large increases in the abundance of bacterial taxa associated with fungal disease suppression (e.g. Bacillus, Pseudomonas, and Streptomyces spp.). Dramatic shifts were seen among the fungi, too, with phylotype richness decreasing by > 60% following mustard addition. Changes in bacterial and fungal community composition were rapid, and distinct community types persisted throughout the study. Oilseed amendment, and mustard in particular, has the potential to alter soil microbial community structure substantially, and such changes are likely to be important in the context of ecosystem health. PMID- 23025786 TI - Radiofluorinated derivatives of 2-(phosphonomethyl)pentanedioic acid as inhibitors of prostate specific membrane antigen (PSMA) for the imaging of prostate cancer. AB - For prostate cancer, prostate specific membrane antigen (PSMA) has been identified as a diagnostic and therapeutic target. Fluorinated derivatives of 2 (phosphonomethyl)pentanedioic acid were designed and synthesized to explore whether this fluorine-substituent is tolerated in the pentanedioic acid moiety that is common to almost all PSMA targeting small molecule inhibitors. The binding affinities of the racemic and individual stereoisomers of 2-fluoro-4 (phosphonomethyl)pentanedioic acid were determined and showed that the introduction of fluorine was well tolerated. The radiosynthesis of the analogous 2-[(18)F]fluoro-4-(phosphonomethyl)pentanedioic acid was developed and evaluated in vivo with the PSMA positive LNCaP human prostate cancer cell. The biological results demonstrated specific binding of the tracer to PSMA positive tumors in mice. These results warrant the further evaluation of this class of compounds as radiolabeled tracers for the detection and staging of prostate cancer. PMID- 23025788 TI - Encouraging treatment outcomes of pediatric rhabdomyosarcoma: a developing world experience. PMID- 23025787 TI - Astrogliosis during acute and chronic cuprizone demyelination and implications for remyelination. AB - In multiple sclerosis, microglia/macrophage activation and astrocyte reactivity are important components of the lesion environment that can impact remyelination. The current study characterizes these glial populations relative to expression of candidate regulatory molecules in cuprizone demyelinated corpus callosum. Importantly, periods of recovery after acute or chronic cuprizone demyelination are examined to compare conditions of efficient versus limited remyelination, respectively. Microglial activation attenuates after early demyelination. In contrast, astrocyte reactivity persists throughout demyelination and a 6-week recovery period following either acute or chronic demyelination. This astrocyte reaction is characterized by (a) early proliferation, (b) increased expression of GFAP (glial fibrillary acidic protein), Vim (vimentin), Fn1 (fibronectin) and CSPGs (chondroitin sulphate proteoglycans) and (c) elaboration of a dense network of processes. Glial processes elongated in the axonal plane persist throughout lesion areas during both the robust remyelination that follows acute demyelination and the partial remyelination that follows chronic demyelination. However, prolonged astrocyte reactivity with chronic cuprizone treatment does not progress to barrier formation, i.e. dense compaction of astrocyte processes to wall off the lesion area. Multiple candidate growth factors and inflammatory signals in the lesion environment show strong correlations with GFAP across the acute cuprizone demyelination and recovery time course, yet there is more divergence across the progression of chronic cuprizone demyelination and recovery. However, differential glial scar formation does not appear to be responsible for differential remyelination during recovery in the cuprizone model. The astrocyte phenotype and lesion characteristics in this demyelination model inform studies to identify triggers of non-remyelinating sclerosis in chronic multiple sclerosis lesions. PMID- 23025789 TI - Validation of cord blood split products prepared by an automated method. AB - OBJECTIVES: In this study, we studied whether the contents of the two compartments of automatically processed cord blood (CB) units are comparable with respect to cell counts and viability and therefore suitable for clinical therapy. BACKGROUND: CB-derived stem cells are increasingly used for allogeneic transplantation. Many centres prepare the transplants by automated methods allowing to split the product into two portions. METHODS: CB was collected at different sites in Germany and transported to a single centre for processing. Before and after cryopreservation laboratory analyses were performed to compare the quality of the two CB segments. RESULTS: In total, 33 products were processed [mean collection volume: 18.6 +/- 1.2 mL (range 15.2-20.2 mL) segment A; mean: 4.7 +/- 0.3 mL (range 4.2-5.2 mL) segment B]. CD34+ cell counts, viability of CD34+ cells and many other haematological parameters showed a good comparibility between the two segments. However, lymphocyte counts and results of clonogenic assays were significantly different between the two segments of the split product. CONCLUSION: We conclude that the preparation of the cord blood unit by the automated process results in a homogenous distribution of stem and progenitor cells. However, our findings show that the clonogenic capacity differs between the two segments. PMID- 23025790 TI - Few-atom fluorescent silver clusters assemble at programmed sites on DNA nanotubes. AB - We show that DNA hairpins template the site-specific assembly of fluorescent few atom Ag clusters on DNA nanotubes. Fluorescent clusters form only at hairpin sites and not on the double-stranded DNA scaffold, allowing for spatially programmed self-assembly. Ag clusters synthesized on hairpins protruding from DNA nanotubes can have nearly identical fluorescence spectra to those synthesized on free hairpins of identical sequence. Analysis of the stepwise photobleaching of individual clusters suggests a chemical yield of ~45%. Given the well-established sequence-specific optical properties of DNA stabilized Ag clusters, these results point the way toward high yield assembly of metal cluster fluorophores with control over spectra as well as spatial arrangement. PMID- 23025791 TI - Developing ethical awareness in global health: four cases for medical educators. AB - In recent years, the growth of interest in global health among medical students and residents has led to an abundance of short-term training opportunities in low resource environments. Given the disparities in resources, needs and expectations between visitors and their hosts, these experiences can raise complex ethical concerns. Recent calls for best practices and ethical guidelines indicate a need for the development of ethical awareness among medical trainees, their sponsoring and host institutions, and supervising faculty. As a teaching tool to promote this awareness, we developed a scenario that captures many common ethical issues from four different perspectives. Each perspective is presented in case format followed by questions. Taken together, the four cases may be used to identify many of the elements of a well-designed global health training experience. PMID- 23025792 TI - FILAMENTOUS FLOWER controls lateral organ development by acting as both an activator and a repressor. AB - BACKGROUND: The YABBY (YAB) family of transcription factors participate in a diverse range of processes that include leaf and floral patterning, organ growth, and the control of shoot apical meristem organisation and activity. How these disparate functions are regulated is not clear, but based on interactions with the LEUNIG-class of co-repressors, it has been proposed that YABs act as transcriptional repressors. In the light of recent work showing that DNA-binding proteins associated with the yeast co-repressor TUP1 can also function as activators, we have examined the transcriptional activity of the YABs. RESULTS: Of the four Arabidopsis YABs tested in yeast, only FILAMENTOUS FLOWER (FIL) activated reporter gene expression. Similar analysis with Antirrhinum YABs identified the FIL ortholog GRAMINIFOLIA as an activator. Plant-based transactivation assays not only confirmed the potential of FIL to activate transcription, but also extended this property to the FIL paralog YABBY3 (YAB3). Subsequent transcriptomic analysis of lines expressing a steroid-inducible FIL protein revealed groups of genes that responded either positively or negatively to YAB induction. Included in the positively regulated group of genes were the polarity regulators KANADI1 (KAN1), AUXIN RESPONSE FACTOR 4 (ARF4) and ASYMMETRIC LEAVES1 (AS1). We also show that modifying FIL to function as an obligate repressor causes strong yab loss-of-function phenotypes. CONCLUSIONS: Collectively these data show that FIL functions as a transcriptional activator in plants and that this activity is involved in leaf patterning. Interestingly, our study also supports the idea that FIL can act as a repressor, as transcriptomic analysis identified negatively regulated FIL-response genes. To reconcile these observations, we propose that YABs are bifunctional transcription factors that participate in both positive and negative regulation. These findings fit a model of leaf development in which adaxial/abaxial patterning is maintained by a regulatory network consisting of positive feedback loops. PMID- 23025793 TI - MAIGO2 is involved in abscisic acid-mediated response to abiotic stresses and Golgi-to-ER retrograde transport. AB - The central role of multisubunit tethering complexes in intracellular trafficking has been established in yeast and mammalian systems. However, little is known about their roles in the stress responses and the early secretory pathway in Arabidopsis. In this study, Maigo2 (MAG2), which is equivalent to the yeast Tip20p and mammalian Rad50-interacting protein, is found to be required for the responses to salt stress, osmotic stress and abscisic acid in seed germination and vegetative growth, and MAG2-like (MAG2L) is partially redundant with MAG2 in response to environmental stresses. MAG2 strongly interacts with the central region of ZW10, and both proteins are important as plant endoplasmic reticulum (ER)-stress regulators. ER morphology and vacuolar protein trafficking are unaffected in the mag2, mag2l and zw10 mutants, and the secretory marker to the apoplast is correctly transported in mag2 plants, which indicate that MAG2 functions as a complex with ZW10, and is potentially involved in Golgi-to-ER retrograde trafficking. Therefore, a new role for ER-Golgi membrane trafficking in abiotic-stress and ER-stress responses is discovered. PMID- 23025794 TI - Preferred delay and phase-frequency response of open-canal hearing aids with music at low insertion gain. AB - OBJECTIVE: Preferences between low delays and phase-frequency responses of behind the-ear, open-canal hearing aids were investigated with acoustic conditions deemed sensitive to delay effects by normal-hearing listeners. DESIGN: Hearing aids with the following selectable delay and phase response options were fitted at low insertion gain: (1) 1.4 ms delay, minimum phase; (2) 3.4 ms delay, minimum phase; and (3) 3.4 ms delay, linear phase. Blind paired comparisons were made between processing options and between each option and a muted hearing-aid output with two music stimuli. The three alternative forced choice responses were "Slightly prefer", "Prefer", or "Strongly prefer". STUDY SAMPLE: Twelve hearing impaired musicians. RESULTS: At the 3.4-ms delay, the minimum-phase response was significantly preferred to the linear-phase response for one music sample and vice-versa for the other sample with a sign test (p < 0.04) but not a Wilcoxon signed rank test that accounted for the low preference strength. Preferences between all other processing conditions were not significant. CONCLUSIONS: In acoustic conditions sensitive to delay effects, delays of 1.4 or 3.4 ms were either not detected or no less preferable than no delayed aided signal. It is unclear whether different phase-frequency responses may be preferred with different music stimuli. PMID- 23025795 TI - Embedded single-walled carbon nanotubes locally perturb DOPC phospholipid bilayers. AB - Understanding and controlling how carbon nanotubes interact with phospholipid membranes is necessary for preventing adverse effects of these relatively new, but still exciting, materials. Futuristic applications envision incorporating carbon nanotubes in liposomes for personalized medicine, controlled delivery, and imaging. Because of their ability to penetrate phospholipid bilayers, nanotubes could serve as nanoscale syringes to deliver molecular cargo and develop gene therapy. Several experimental reports available on the subject demonstrate the need for a better understanding, at the molecular level, of whether carbon nanotubes penetrate, reside, and perturb phospholipid bilayers. Using all-atom molecular dynamics simulations, we quantify how short carbon nanotubes (~6 nm in length) embedded within a DOPC phospholipid membrane perturb the structure, organization, and dynamics of the lipid molecules within the membrane. It is found that the structural perturbation is very short-ranged, although it becomes pronounced when bundles of carbon nanotubes are formed within the membrane. The presence of the nanotubes is found to reduce the mobility of lipid molecules within the membrane and to perturb the structure of interfacial water. Our observations suggest that the local perturbations in the lipid structure caused by the nanotubes could lead to enhanced penetration of molecular compounds across the membrane. PMID- 23025796 TI - Weight misperception and its barriers to keep health weight in Chinese children. AB - AIMS: To examine the prevalence rate of misperception, assess the relationship between weight perception and weight-related behaviors in Chinese children. METHODS: A total of 2708 children aged 7-12 years from five public primary schools and their parents completed questionnaires assessing social demographic background, dietary and activity related factors. Weight and height were measured by trained investigators. The prevalence of misperception was defined by comparing calculated BMI and their perceived weight status. Log-binomial model yielded adjusted prevalence ratios (PRs) for each behavior by weight misperception in boys and girls separately. RESULTS: Misperception was more prevalent in normal weight children 33.3% for girls and 40.5% for boys and boys were more likely to underestimate their weight status than girls. Associations were observed between misperceived thinness and eating before bed, want to eat seeing others eating, eating sugar and snacks frequently, monophagia and choosy in food both in girls and boys. And associations between misperceived fatness and depression and want to eat seeing others eating were found only in girls. CONCLUSIONS: Our findings underscore the importance of weight perception in shaping realistic body image among normal weight children. Education must be introduced to help children accurately look on their body shape. PMID- 23025797 TI - Statins in pneumonia--magic versus science? AB - Several studies have investigated the use of statins as an adjunct in the treatment of pneumonia, some with conflicting conclusions. The most recent of these large observational studies again suggests statin use is associated with an improved outcome for patients with pneumonia. How best to incorporate these findings into current practice is of great interest. Hidden confounders plague database interrogation and so cast doubt on the real or causal nature of observed associations. Data from large, observational studies must be complemented by smaller biological studies and randomised controlled trials in an effort to complete missing pieces in the biological puzzle of the use of statins in patients with pneumonia. PMID- 23025798 TI - Biocidal polymers: synthesis and antimicrobial properties of benzaldehyde derivatives immobilized onto amine-terminated polyacrylonitrile. AB - BACKGROUND: The design and applications of antimicrobial polymers is a growing field. Antimicrobial polymers can help to solve the problems associated with the use of conventional antimicrobial agents. Polymers with active functional groups can act as a carrier system for antimicrobial agents. In our study, we aim to prepare and develop some antimicrobial polymers for biomedical applications and water treatment. RESULTS: The antimicrobial polymers based on polyacrylonitrile (PAN) were prepared. Functional groups were created onto polyacrylonitrile via amination using different types of diamines such as ethylenediamine (EDA) and hexamethylenediamine (HMDA) to yield amine-terminated polymers. Antimicrobial polymers were obtained by immobilization of benzaldehyde and its derivatives which include, 4-hydroxybenzaldehyde and 2,4-dihydroxybenzaldehyde onto amine terminated polymers. The antimicrobial activity of the prepared polymers against different types of microorganisms including Gram-positive bacteria (Staphylococcus aureus), Gram-negative bacteria (Pseudomonas aeruginosa; Escherichia coli; and Salmonella typhi) as well as fungi (Aspergillus flavus, Aspergillus niger, Candida albicans, Cryptpcoccus neoformans) were explored by the cut plug method and viable cell counting methods. CONCLUSIONS: Amine terminated polyacrylonitrile were used as a novel polymeric carrier for benzaldehyde derivatives as antimicrobial agents. The prepared polymers can inhibit the growth of the microorganisms. The activity was varied according to the tested microorganism as well as the polymer microstructure. It was found that the activity increased with increasing the number phenolic hydroxyl group of the bioactive group. Finally, it is anticipated that the prepared antimicrobial polymers would be of great help in the field of biomedical applications and biological water treatment. PMID- 23025799 TI - Atmospheric short-chain chlorinated paraffins in China, Japan, and South Korea. AB - This study presents the first investigation of concentrations and congener group patterns of atmospheric short-chain chlorinated paraffins (SCCPs) throughout East Asia. Based on an absorption rate calibration experiment, a spatial survey of SCCPs was performed using passive air samplers in China, Japan, and South Korea during two separate periods in 2008. The atmospheric concentrations of SCCPs in China were clearly greater than those in Japan and South Korea, both of which exceed the levels determined for other regions of the world. C(10) components were the most abundant type of SCCPs in China, whereas C(11) components were dominant in Japan and South Korea. With respect to the total chlorine content, Cl(6) and Cl(5) were the predominant compounds in China and Japan; however, Cl(6) and Cl(7) were predominant in South Korea. A similar pattern was also found for remote sites within China, Japan, and South Korea, respectively. Together with the back-trajectories calculated for the remote sites, the results indicate that the SCCPs in the air of East Asia were mainly influenced by local sources due to their relatively low long-range atmospheric transport potential compared to other POPs. PMID- 23025800 TI - Diversity of Salmonella in biofilms and water in a headwater ecosystem. AB - The diversity of Salmonella was analysed in biofilm and water samples from the spring and slough arms of Spring Lake, the headwaters of the San Marcos River, Texas, during the drought of 2011, with only one potential run-off event at the beginning of the study. Salmonellae were detected in semiselective enrichment cultures by end-point PCR during the entire sampling period of (11 sampling events during 2 months). From the spring arm site, 73% of the biofilms and 41% of the water samples were positive for salmonellae, while only 9% of the biofilms and 23% of the water samples were positive from the slough arm site. Salmonellae could be isolated from all positive samples, with higher diversity in biofilms compared with water samples and more strains obtained from the spring arm than from the slough arm. Differences between sites were generally caused by less frequently detected isolates, while the majority of isolates that were present in both biofilms and water from both sites was represented by three strains only. Quantification attempts by quantitative PCR directly in samples without prior enrichment did not result in a reliable detection of salmonellae, suggesting that numbers in all samples were below the detection limit. PMID- 23025801 TI - The word frequency effect in first- and second-language word recognition: a lexical entrenchment account. AB - We investigate the origin of differences in the word frequency effect between native speakers and second-language speakers. In a large-scale analysis of English word identification times we find that group-level differences are fully accounted for by the individual language proficiency scores. Furthermore, exactly the same quantitative relation between word frequency and proficiency is found for monolinguals and three different bilingual populations (Dutch-English, French English, and German-English). We conclude that the larger frequency effects for second-language processing than for native-language processing can be explained by within-language characteristics and thus need not be the consequence of "being bilingual" (i.e., a qualitative difference). More specifically, we argue that language proficiency increases lexical entrenchment, which leads to a reduced frequency effect, irrespective of bilingualism, language dominance, and language similarity. PMID- 23025802 TI - Short-interval intracortical inhibition in knee extensors during locomotor cycling. AB - AIM: Short-interval intracortical inhibition (SICI) can provide information on changes in cortical responsiveness during voluntary contractions. It is, however, unknown whether the magnitude of SICI changes throughout the cycle of rhythmic movements such as leg cycling. METHODS: The effects of four conditioning stimulus (CS) intensities, 70, 80, 90 and 95% of active motor threshold (AMT), on the magnitude of SICI were tested during three conditions: (1) activation phase of the electromyography (EMG) burst, (2) deactivation phase of the EMG burst and (3) static contractions. The three conditions were matched for EMG amplitude and test motor-evoked potential (MEP) size with reference to the vastus lateralis muscle. Responses were also recorded from rectus femoris and vastus medialis. RESULTS: short-interval cortical inhibition was weak during static knee contractions (15% reduction in control MEP) relative to previous reports during contractions in other muscle groups. SICI was abolished during the activation phase of the knee extensor EMG burst (P > 0.05), but present (approx. 90% of control MEP size) during the deactivation phase of EMG (P < 0.05). Furthermore, inhibition was elicited at a lower CS intensity during the deactivation phase of EMG during cycling than during static contractions (70 AMT vs. 90% AMT). CONCLUSION: The results suggest that the efficacy of intracortical inhibitory projections to knee extensor corticomotoneurons is particularly weak during muscle activation. A lower threshold of activation for inhibitory cells during deactivation phase of cycling EMG was evident, and there was a phasic modulation of intracortical inhibition affecting corticospinal projections to the working muscles. PMID- 23025803 TI - Cognitive recovery and development after traumatic brain injury in childhood: a person-oriented, longitudinal study. AB - Influence of childhood traumatic brain injury (TBI) on cognitive recovery and subsequent development is poorly understood. In this longitudinal study we used cluster analysis to explore acute stage individual profiles of injury age and cognition in 118 children with traumatic brain injury. Repeated measures of cognitive function were conducted at 30 months, indicating recovery, and 10 years post-injury, indicating development. Nine clusters were identified. Recovery was evident in three clusters, two of them with low functioning profiles. Developmental gains occurred for three clusters and an acute profile of higher freedom from distractibility (FFD) and lower processing speed (PS) was related to positive differences. One cluster, average low functioning and especially low verbal comprehension, demonstrated a slower development than peers. This suggests that developmental change after TBI in childhood takes place on a continuum, with both chance of long-term catching up, and risk of poor development. An acute profile of higher FFD and lower PS seemed to reflect injury consequences and were followed by developmental gains. These results challenge previous findings, and warrant further investigation. PMID- 23025804 TI - Dark plasmonic breathing modes in silver nanodisks. AB - We map the complete plasmonic spectrum of silver nanodisks by electron energy loss spectroscopy and show that the mode which couples strongest to the electron beam has radial symmetry with no net dipole moment. Therefore, this mode does not couple to light and has escaped from observation in optical experiments. This radial breathing mode has the character of an extended two-dimensional surface plasmon with a wavenumber determined by the circular disk confinement. Its strong near fields can impact the hybridization in coupled plasmonic nanoparticles as well as couplings with nearby quantum emitters. PMID- 23025805 TI - Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors. AB - Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure-activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation-initiation machinery (i.e., complex 5'-untranslated region UTR) relative to simple 5'UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds 74 and 76 were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol. PMID- 23025806 TI - Comparison of the symptoms of menopause and symptoms of thyroid disease in Japanese women aged 35-59 years. AB - OBJECTIVE: In this study, we surveyed thyroid function abnormalities and menopausal symptoms in young as well as in menopausal women. METHODS: We conducted a random survey among outpatients at our facility from September 2008 to June 2011. The study included 853 women aged 35-59 years. We assessed the subjects according to the Simplified Menopause Index, menstrual status, thyroid hormone measurements (thyroid stimulating hormone, free thyroxine, free triiodothyronine), the presence of Hashimoto's disease antibodies (anti-thyroid peroxidase antibody or anti-thyroglobulin antibody), the presence of Grave's disease (anti-TSH receptor antibody), markers of thyroid tumor (high thyroglobulin), and thyroid ultrasonography studies. The data were analyzed by means of the statistical program JMP version 8.0. RESULTS: 'Facial flushing', 'sweating', and 'thyroid tumor' were all positively related with age and menstrual status. 'Breathlessness and palpitations' were positively related to Grave's disease. Moreover, 'sweating', 'irritability', and 'stiff shoulders, low back pain, and joint pain' were related to thyroid tumors. 'Insomnia' decreased with age. Patients with Hashimoto's disease were very rare because they were usually treated at other hospitals that specialize in thyroid disease. CONCLUSION: The symptoms of thyroid function abnormalities were shown to be very similar to menopausal symptoms and were found to occur in younger women before the onset of menopause. This study shows the need to differentiate menopausal symptoms from those of thyroid diseases. PMID- 23025807 TI - Conflict cultures in organizations: how leaders shape conflict cultures and their organizational-level consequences. AB - Anecdotal evidence abounds that organizations have distinct conflict cultures, or socially shared norms for how conflict should be managed. However, research to date has largely focused on conflict management styles at the individual and small group level, and has yet to examine whether organizations create socially shared and normative ways to manage conflict. In a sample of leaders and members from 92 branches of a large bank, factor analysis and aggregation analyses show that 3 conflict cultures-collaborative, dominating, and avoidant-operate at the unit level of analysis. Building on Lewin, Lippitt, and White's (1939) classic work, we find that leaders' own conflict management behaviors are associated with distinct unit conflict cultures. The results also demonstrate that conflict cultures have implications for macro branch-level outcomes, including branch viability (i.e., cohesion, potency, and burnout) and branch performance (i.e., creativity and customer service). A conflict culture perspective moves beyond the individual level and provides new insight into the dynamics of conflict management in organizational contexts. PMID- 23025808 TI - Looking down: the influence of contempt and compassion on emergent leadership categorizations. AB - By integrating the literatures on implicit leadership and the social functions of discrete emotions, we develop and test a theoretical model of emotion expression and leadership categorizations. Specifically, we examine the influence of 2 socio comparative emotions-compassion and contempt-on assessments of leadership made both in 1st impression contexts and over time. To demonstrate both internal and external validity, Studies 1a and 1b provide laboratory and field evidence to show that expressing the discrete emotions of contempt and compassion positively relates to perceptions that an individual is a leader. Study 2 tests the mechanism explaining these associations. Specifically, we show that in a leadership emergence context, contempt and compassion both positively relate to perceptions that the expresser is a leader because each provides cues matching the implicit theory that leaders have higher intelligence. Our findings add to a growing body of literature focused on identifying the processes through which leaders emerge in groups, showing that emotions are an important input to this process. We discuss the implications of our findings and how they might guide future research efforts. PMID- 23025809 TI - Essential role of transient receptor potential vanilloid type 1 in evodiamine mediated protection against atherosclerosis. AB - AIM: We investigated whether transient receptor potential vanilloid type 1 (TRPV1) was involved in the therapeutic effect of evodiamine, a main bioactive component in the fruit of Evodiae rutaecarpa, on the development of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/ )TRPV1(-/-) mice. METHODS: Histopathology was examined by haematoxylin and eosin staining, levels of cytokines and mediators were evaluated by ELISA kits, and protein expression was determined by Western blotting. RESULTS: Chronic administration with evodiamine (10 mg kg(-1) body weight) reduced the size of atherosclerotic lesions and alleviated the hyperlipidaemia and systemic inflammation, as well as hepatic macrovesicular steatosis, in ApoE(-/-) mice. Treating ApoE(-/-) mice with evodiamine enhanced hepatic cholesterol clearance, as revealed by upregulation of hepatic low-density lipoprotein receptor and ATP binding cassette (ABC) transporters ABCG5, ABCG8 and cholesterol 7alpha hydrolase. Genetic deletion of TRPV1 in ApoE(-/-) mice promoted the progression of atherosclerosis; elevated the serum levels of cholesterol, cytokines and chemokines; and exacerbated hepatic macrovesicular steatosis. Moreover, genetic deletion of TRPV1 abrogated the evodiamine-evoked atheroprotection but not anti obesity effect in ApoE(-/-) mice. CONCLUSION: Evodiamine may confer novel TRPV1 dependent atheroprotection and TRPV1-independent anti-obesity action. PMID- 23025812 TI - Modulation of a ligand's energy landscape and kinetics by the chemical environment. AB - Understanding how the chemical environment modulates the predominant conformations and kinetics of flexible molecules is a core interest of biochemistry and a prerequisite for the rational design of synthetic catalysts. This study combines molecular dynamics simulation and Markov state models (MSMs) to a systematic computational strategy for investigating the effect of the chemical environment of a molecule on its conformations and kinetics. MSMs allow quantities to be computed that are otherwise difficult to access, such as the metastable sets, their free energies, and the relaxation time scales related to the rare transitions between metastable states. Additionally, MSMs are useful to identify observables that may act as sensors for the conformational or binding state of the molecule, thus guiding the design of experiments. In the present study, the conformation dynamics of UDP-GlcNAc are studied in vacuum, water, water + Mg(2+), and in the protein UDP-GlcNAc 2-epimerase. It is found that addition of Mg(2+) significantly affects the conformational stability, thermodynamics, and kinetics of UDP-GlcNAc. In particular, the slowest structural process, puckering of the GlcNAc sugar, depends on the overall conformation of UDP-GlcNAc and may thus act as a sensor of whether Mg(2+) is bound or not. Interestingly, transferring the molecule from vacuum to water makes the protein binding conformations UDP-GlcNAc first accessible, while adding Mg(2+) further stabilizes them by specifically associating to binding-competent conformations. While Mg(2+) is not cocrystallized in the UDP-GlcNAc 2-epimerase complex, the selectively stabilized Mg(2+)/UDP-GlcNAc complex may be a template for the bound state, and Mg(2+) may accompany the binding-competent ligand conformation to the binding pocket. This serves as a possible explanation of the enhanced epimerization rate in the presence of Mg(2+). This role of Mg(2+) has previously not been described and opens the question whether "binding co-factors" may be a concept of general relevance for protein-ligand binding. PMID- 23025810 TI - Anomalous aortic origin of coronary arteries from the opposite sinus: a critical appraisal of risk. AB - BACKGROUND: Anomalous aortic origin of the coronary artery (AAOCA) from the opposite sinus of Valsalva with an interarterial course has received much attention due to its association with sudden death in otherwise healthy individuals. AAOCA is relatively common and may have significant public health implications. While our knowledge of its pathophysiology and natural history remains incomplete, an emphasis has been placed on surgical correction. DISCUSSION: In 2005 we published a review examining the rates of sudden death with AAOCA, as well as complications of surgical management. Evidence now points even more strongly to lower rates of sudden death, while surgical outcomes data now better documents associated risks. SUMMARY: Armed with this updated information, we agree with the need for a national registry to better track patients with AAOCA. We submit that the risks of surgical management outweigh any benefits in the asymptomatic patient with anomalous right coronary artery, and expectant management should also be strongly considered even in asymptomatic patients with anomalous left coronary artery. PMID- 23025813 TI - Guest authors in an Iranian journal. AB - BACKGROUND: Although most biomedical journals have adopted the authorship criteria established by the International Committee of Medical Journal Editors (ICMJE) in 1985, little is known about the extent Iranian researchers are familiar with these criteria. OBJECTIVES: The study seeks to evaluate the number of authors fulfilling ICMJE authorship criteria (considering the names mentioned in the byline of 12 issues of the Archives of Iranian Medicine (AIM) journal), and to determine the type of contribution made by each author. MATERIALS AND METHODS: The fulfilment of authorship criteria and contribution percentage of each researcher were evaluated according to their position in the bylines of 12 issues of the Archives of Iranian Medicine (AIM) journal published from January 2005 to October 2007. We asked corresponding authors to answer our questionnaire which was designed to assess authorship criteria and contribution. RESULTS: A total of 576 researchers' names were in the studied article bylines. The ratio of authors to articles was 3.48 in 2005, 4.06 in 2006, and 5.59 in 2007. Sixty three out of 128 corresponding authors (49.21%) responded to our questionnaire, so we evaluated 296 researchers' names, from which 186 authors (62.83%) met the authorship criteria; 110 authors (37.17%) were identified as guest authors, 97 of which deserved to be mentioned in the acknowledgement section. The major criteria used for authors order was their participation in research projects in addition to article writing, mostly determined by the corresponding author. Two authors (0.67%) whose names were not mentioned in the articles were considered to be ghost writers as the articles were based on the results of their thesis. CONCLUSION: It is essential to make Iranian researchers familiar with ICMJE authorship criteria and to encourage applying the criteria in scientific writing. PMID- 23025814 TI - Introduction to the focus issue on marine boundary layer: ocean atmosphere interactions processes. PMID- 23025815 TI - Identification of Tyr241 as a key catalytic base in the family 4 glycoside hydrolase BglT from Thermotoga maritima. AB - While the vast majority of glycosidases catalyze glycoside hydrolysis via oxocarbenium ion-like transition states and typically employ carboxylic acid residues as acid/base or nucleophile catalysts, two subfamilies of these enzymes (GH4 and GH109 in the CAZY classification) conduct hydrolysis via a redox assisted mechanism involving anionic transition states. While good evidence of this mechanism has been obtained, the identities of the catalytic residues involved have not yet been confirmed. Mechanistic analyses of mutants of the 6 phospho-beta-glucosidase from Thermotoga maritima (BglT), in which the active site tyrosine residue (Tyr 241) has been replaced with Phe and Ala, provide support for its role as a catalytic base. The pH dependence of k(cat) and k(cat)/K(m), particularly of the acidic limb corresponding to the base, is shifted relative to that of the wild-type enzyme. Kinetic isotope effects for hydrolysis of substrates deuterated at C1, C2, and C3 by the Tyr 241 mutants are strongly pH-dependent, with essentially full primary kinetic isotope effects being observed for the 2-deutero substrate at low pH with the Tyr241Ala mutant. This is consistent with a slowing of the deprotonation step upon removal of the base. PMID- 23025811 TI - Regular aerobic exercise protects against impaired fasting plasma glucose associated vascular endothelial dysfunction with aging. AB - In the present study, we tested the hypothesis that age-associated vascular endothelial dysfunction is exacerbated by IFG (impaired fasting plasma glucose) and that regular aerobic exercise prevents this effect. Data were analysed from a cohort of 131 non-smoking men and women without overt clinical disease. Compared with young adult controls (age=24+/-1 years, n=29; values are means+/-S.E.M.), brachial artery FMD (flow-mediated dilation), a measure of conduit artery EDD (endothelium-dependent dilation), was 33% lower [7.93+/-0.33 against 5.27+/ 0.37%Delta (% change), P<0.05] in MA/O (middle-aged/older) adults with NFG (normal fasting plasma glucose) (<=99 mg/dl, 62+/-1 years, n=35). In MA/O adults with IFG (100-125 mg/dl, 64+/-1 years, n=28), FMD was 30% lower (3.37+/ 0.35%Delta) than in their peers with NFG and 58% lower than young controls (P<0.05). Brachial artery FMD was greater (6.38+/-0.35%Delta) in MA/O adults with NFG who regularly performed aerobic exercise (>45 min/day for >=5 days/week, 62+/ 1 years, n=23) compared with their non-exercising peers and only slightly less than young controls (P<0.05). Most importantly, FMD was completely preserved in MA/O adults with IFG who regularly performed aerobic exercise (6.99+/-0.69%Delta, 65+/-1 years, n=16). In the pooled sample, fasting plasma glucose was inversely related to FMD (r=-0.42, P<0.01) and was the strongest independent predictor of FMD (R(2)=0.32). Group differences in FMD were not affected by other subject characteristics or brachial artery properties, including brachial artery dilation to sublingual NTG (nitroglycerine, i.e. endothelium-independent dilation). IFG exacerbates age-associated vascular endothelial dysfunction and this adverse effect is completely prevented in MA/O adults who regularly perform aerobic exercise. PMID- 23025816 TI - Electrical control of optical plasmon resonance with graphene. AB - Surface plasmon has the unique capability to concentrate light into subwavelength volume. Active plasmon devices using electrostatic gating can enable flexible control of the plasmon excitations, which has been demonstrated recently in terahertz plasmonic structures. Controlling plasmon resonance at optical frequencies, however, remains a significant challenge because gate-induced free electrons have very weak responses at optical frequencies. Here we achieve efficient control of near-infrared plasmon resonance in a hybrid graphene-gold nanorod system. Exploiting the uniquely strong and gate-tunable optical transitions of graphene, we are able to significantly modulate both the resonance frequency and quality factor of gold nanorod plasmon. Our analysis shows that the plasmon-graphene coupling is remarkably strong: even a single electron in graphene at the plasmonic hotspot could have an observable effect on plasmon scattering intensity. Such hybrid graphene-nanometallic structure provides a powerful way for electrical control of plasmon resonances at optical frequencies and could enable novel plasmonic sensing down to single charge transfer events. PMID- 23025817 TI - Method for simultaneous analysis of eight analogues of vitamin D using liquid chromatography tandem mass spectrometry. AB - BACKGROUND: Despite considerable global investigation over several decades, the roles of vitamin D in health and disease development remains convoluted. One recognised issue is the difficulty of accurately measuring the active forms of vitamin D. Advances made include some new methods addressing the potential interference by excluding epimers and isobars. However, there is no evidence that epimers are without function. Therefore, the aim of this study was to develop and validate, for the first time, a new assay to simultaneously measure levels of six forms of vitamin D along with two epimers. The assay was applied to multilevel certified reference material (CRM) and 25 pooled human sera samples, obtained from the Vitamin D External Quality Assessment Scheme (DEQAS), to demonstrate its efficiency. RESULTS: The assay is capable of simultaneously measuring eight vitamin D analogues over the calibration ranges and LODs (in nmol/L) of: 1alpha25(OH)2D2 [0.015-1; 0.01], 1alpha25(OH)2D3 [0.1-100; 0.01], 25OHD3 [0.5 100, 0.025], 3-epi-25OHD3 [0.1-100, 0.05], 25OHD2 [0.5-100, 0.025], 3-epi-25OHD2 [0.1-100, 0.05], vitamin D3 [0.5-100, 0.05] and vitamin D2 [0.5-100, 0.05], using stanozolol-d3 as internal standard. Certified reference material and external quality control samples (DEQAS) were analysed to meet the standards outlined by National Institute of Standards and Technology (NIST). Validation steps included recovery and both precision and accuracy under inter- and intra-day variation limit of detection, and analysis of each analyte over a linear range. All validation parameters were in line with acceptable Food and Drug Administration (FDA) guidelines. All eight analogues were quantified with the 25OHD levels being commensurate with DEQAS data. CONCLUSIONS: This report details the application of a new LC-MS/MS based assay for the efficient analysis of eight analogues of vitamin D over a range of samples, which is a significant advance over the existing methods. Simultaneous measure of eight vitamin D analogues does not compromise the analytical capability of the assay to quantify the commonly used biomarker (25OHD) for vitamin D status. The results demonstrate the feasibility of applying the assay in research and clinical practice that i) excludes misleading measures owing to epimers and isobars and ii) is able to quantify the excluded component to facilitate further in vivo investigation into the roles of ubiquitous epimers. PMID- 23025818 TI - Supportive breeding boosts natural population abundance with minimal negative impacts on fitness of a wild population of Chinook salmon. AB - While supportive breeding programmes strive to minimize negative genetic impacts to populations, case studies have found evidence for reduced fitness of artificially produced individuals when they reproduce in the wild. Pedigrees of two complete generations were tracked with molecular markers to investigate differences in reproductive success (RS) of wild and hatchery-reared Chinook salmon spawning in the natural environment to address questions regarding the demographic and genetic impacts of supplementation to a natural population. Results show a demographic boost to the population from supplementation. On average, fish taken into the hatchery produced 4.7 times more adult offspring, and 1.3 times more adult grand-offspring than naturally reproducing fish. Of the wild and hatchery fish that successfully reproduced, we found no significant differences in RS between any comparisons, but hatchery-reared males typically had lower RS values than wild males. Mean relative reproductive success (RRS) for hatchery F(1) females and males was 1.11 (P = 0.84) and 0.89 (P = 0.56), respectively. RRS of hatchery-reared fish (H) that mated in the wild with either hatchery or wild-origin (W) fish was generally equivalent to W * W matings. Mean RRS of H * W and H * H matings was 1.07 (P = 0.92) and 0.94 (P = 0.95), respectively. We conclude that fish chosen for hatchery rearing did not have a detectable negative impact on the fitness of wild fish by mating with them for a single generation. Results suggest that supplementation following similar management practices (e.g. 100% local, wild-origin brood stock) can successfully boost population size with minimal impacts on the fitness of salmon in the wild. PMID- 23025819 TI - Effects of elevated CO2 and temperature on photosynthesis and leaf traits of an understory dwarf bamboo in subalpine forest zone, China. AB - The dwarf bamboo (Fargesia rufa Yi), growing understory in subalpine dark coniferous forest, is one of the main foods for giant panda, and it influences the regeneration of subalpine coniferous forests in southwestern China. To investigate the effects of elevated CO2, temperature and their combination, the dwarf bamboo plantlets were exposed to two CO2 regimes (ambient and double ambient CO2 concentration) and two temperatures (ambient and +2.2 degrees C) in growth chambers. Gas exchange, leaf traits and carbohydrates concentration were measured after the 150-day experiment. Elevated CO2 significantly increased the net photosynthetic rate (Anet ), intrinsic water-use efficiency (WUEi ) and carbon isotope composition (delta13C) and decreased stomatal conductance (g(s)) and total chlorophyll concentration based on mass (Chl(m)) and area (Chl(a)). On the other hand, elevated CO2 decreased specific leaf area (SLA), which was increased by elevated temperature. Elevated CO2 also increased foliar carbon concentration based on mass (C(m)) and area (C(a)), nitrogen concentration based on area (N(a)), carbohydrates concentration (i.e. sucrose, sugar, starch and non structural carbohydrates) and the slope of the A(net)-N(a) relationship. However, elevated temperature decreased C(m), C(a) and N(a). The combination of elevated CO2 and temperature hardly affected SLA, C(m), C(a), N(m), N(a), Chl(m) and Chl(a). Variables Anet and Na had positive linear relationships in all treatments. Our results showed that photosynthetic acclimation did not occur in dwarf bamboo at elevated CO2 and it could adjust physiology and morphology to enable the capture of more light, to increase WUE and improve nutritional conditions. PMID- 23025821 TI - The influence of action on episodic memory: a virtual reality study. AB - A range of empirical findings suggest that active learning is important for memory. However, few studies have focused on the mechanisms underlying this enactment effect in episodic memory using complex environments. Research using virtual reality has yielded inconsistent results. We postulated that the effect of action depends on the degree of interaction with the environment and freedom in the planning of an itinerary. To test these hypotheses, we disentangled the interaction and planning components of action to investigate whether each enhances factual and spatial memory. Seventy-two participants (36 male and 36 female) explored a virtual town in one of three experimental conditions: (a) a passive condition where participants were immersed as passenger of the car (no interaction, no planning); (b) a planning-only condition (the subject chose the itinerary but did not drive the car); (c) an interaction-only condition (the subject drove the car but the itinerary was fixed). We found that itinerary choice and motor control both enhanced spatial memory, while factual memory was impaired by online motor control. The role of action in memory is discussed. PMID- 23025820 TI - Repeated mild traumatic brain injury: mechanisms of cerebral vulnerability. AB - Among the 3.5 million annual new head injury cases is a subpopulation of children and young adults who experience repeated traumatic brain injury (TBI). The duration of vulnerability after a single TBI remains unknown, and biomarkers have yet to be determined. Decreases in glucose metabolism (cerebral metabolic rate of glucose [CMRglc]) are consistently observed after experimental and human TBI. In the current study, it is hypothesized that the duration of vulnerability is related to the duration of decreased CMRglc and that a single mild TBI (mTBI) increases the brain's vulnerability to a second insult for a period, during which a subsequent mTBI will worsen the outcome. Postnatal day 35 rats were given sham, single mTBI, or two mTBI at 24-h or 120-h intervals. (14)C-2-deoxy-D-glucose autoradiography was conducted at 1 or 3 days post-injury to calculate CMRglc. At 24 h after a single mTBI, CMRglc is decreased by 19% in both the parietal cortex and hippocampus, but approached sham levels by 3 days post-injury. When a second mTBI is introduced during the CMRglc depression of the first injury, the consequent CMRglc is depressed (36.5%) at 24 h and remains depressed (25%) at 3 days. In contrast, when the second mTBI is introduced after the metabolic recovery of the first injury, the consequent CMRglc depression is similar to that seen with a single injury. Results suggest that the duration of metabolic depression reflects the time-course of vulnerability to second injury in the juvenile brain and could serve as a valuable biomarker in establishing window of vulnerability guidelines. PMID- 23025822 TI - Palladium-catalyzed ortho-alkoxylation of anilides via C-H activation. AB - A palladium-catalyzed ortho-alkoxylation of anilides with both primary and secondary alcohols via ligand-directed C-H activation has been explored. This alkoxylation promoted by catalytic methanesulfonic acid proceeds well at room temperature in most cases and affords aryl alkyl ethers in moderate to good yields. PMID- 23025823 TI - Biochemical alterations induced by acute oral doses of iron oxide nanoparticles in Wistar rats. AB - Magnetic iron oxide nanoparticles with appropriate surface chemistry have been widely used with potential new applications in biomedical industry. Therefore, the aim of this study was to assess the size-, dose-, and time-dependent effects, after acute oral exposure to iron oxide-30 NP (Fe(2)O(3)-30), on various biochemical enzyme activities of clinical significances in a female Wistar rat model. Rats were exposed to three different doses (500, 1,000, and 2,000 mg/kg) of Fe(2)O(3)-30 and Fe(2)O(3)-Bulk along with control. Fe(2)O(3)-30 had no effect on growth, behavior, and nutritional performance of animals. Fe(2)O(3)-30 caused significant inhibition of acetylcholinestrase in red blood cells as well as in brains of treated rats. Further, more than 50% inhibition of total, Na(+)-K(+), Mg(2+), and Ca(2+)-ATPases activities, as observed in brains of exposed female rats, may be the result of disturbances in cellular physiology and the iono regulatory process. Activation of the hepatotoxicity marker enzymes, aspartate aminotransferase and alanine aminotransferase, was recorded in serum and liver, whereas inhibition was observed in kidney. Similarly, enhancement of lactate dehydrogenase activity was observed in serum and liver; however, a decrease in enzyme levels was observed in kidneys of Fe(2)O(3)-30-treated rats. On the other hand, Fe(2)O(3)-Bulk did not depict any significant changes in these biochemical parameters, and alterations were near to control. Therefore, this study suggests that exposure to nanosize particles at acute doses may cause adverse changes in animal biochemical profiles. The use of the rat model signifies the correlation with the human system. PMID- 23025824 TI - Inhibition of Acyl-CoA: cholesterol acyltransferase (ACAT), overexpression of cholesterol transporter gene, and protection of amyloid beta (Abeta) oligomers induced neuronal cell death by tricyclic pyrone molecules. AB - A major effort in Alzheimer's disease therapeutic development has targeted Abeta and downstream events. We have synthesized a small library of tricyclic pyrone compounds. Their protective action in MC65 cells and inhibition of ACAT along with the upregulation of cholesterol transporter gene were investigated. Five active compounds exhibited potencies in the nanomolar ranges. The multiple effects of the compounds on Abeta and cellular cholesterol pathways could be potential mechanisms underlying the protective effects in vivo. PMID- 23025825 TI - The risks and rewards of expanding ICU capacity. AB - ICU capacity strain is associated with increased morbidity and lost hospital revenue, leading many hospitals to increase the number of ICU beds. However, this approach can lead to inefficiency and waste. A recent report in Critical Care highlights a different approach: creating new service lines for low-risk patients. In this case, the authors started a post-anesthesia care unit with an intensivist-led care team, resulting in lower hospital costs with no changes in ICU mortality. Although this type of change carries some risks, and will not work for every hospital, it is an example of the creative solutions hospitals must sometimes undertake to maintain the supply of critical care in response to a rising demand. PMID- 23025826 TI - Bronchiectasis and severe respiratory insufficiency associated with a new surfactant protein C mutation. PMID- 23025827 TI - The Plasmodium falciparum schizont phosphoproteome reveals extensive phosphatidylinositol and cAMP-protein kinase A signaling. AB - The asexual blood stages of Plasmodium falciparum cause the most lethal form of human malaria. During growth within an infected red blood cell, parasite multiplication and formation of invasive merozoites is called schizogony. Here, we present a detailed analysis of the phosphoproteome of P. falciparum schizonts revealing 2541 unique phosphorylation sites, including 871 novel sites. Prominent roles for cAMP-dependent protein kinase A- and phosphatidylinositol-signaling were identified following analysis by functional enrichment, phosphoprotein interaction network clustering and phospho-motif identification tools. We observed that most key enzymes in the inositol pathway are phosphorylated, which strongly suggests additional levels of regulation and crosstalk with other protein kinases that coregulate different biological processes. A distinct pattern of phosphorylation of proteins involved in merozoite egress and red blood cell invasion was noted. The analyses also revealed that cAMP-PKA signaling is implicated in a wide variety of processes including motility. We verified this finding experimentally using an in vitro kinase assay and identified three novel PKA substrates associated with the glideosome motor complex: myosin A, GAP45 and CDPK1. Therefore, in addition to an established role for CDPK1 in the motor complex, this study reveals the coinvolvement of PKA, further implicating cAMP as an important regulator of host cell invasion. PMID- 23025828 TI - Magnetic field polarity fails to influence the directional signal carried by the head direction cell network and the behavior of rats in a task requiring magnetic field orientation. AB - Many different species of animals including mole rats, pigeons, and sea turtles are thought to use the magnetic field of the earth for navigational guidance. While laboratory rats are commonly used for navigational research, and brain networks have been described in these animals that presumably mediate accurate spatial navigation, little has been done to determine the role of the geomagnetic field in these brain networks and in the navigational behavior of these animals. In Experiment 1, anterior thalamic head direction (HD) cells were recorded in female Long-Evans rats while they foraged in an environment subjected to an experimentally generated magnetic field of earth-strength intensity, the polarity of which could be shifted from one session to another. Despite previous work that has shown that the preferred direction of HD cells can be controlled by the position of familiar landmarks in a recording environment, the directional signal of HD cells was not influenced by the polarity of the magnetic field in the enclosure. Because this finding could be attributed to the animal being insensitive or inattentive to the magnetic field, in Experiment 2, rats were trained in a choice maze task dependent on the ability of the animals to sense the polarity of the experimentally controlled magnetic field. Over the course of 28 days of training, performance failed to improve to a level above chance, providing evidence that the spatial behavior of laboratory rats (and the associated HD network) is insensitive to the polarity of the geomagnetic field. PMID- 23025829 TI - Individual-level consistency of different laterality measures in the goldbelly topminnow. AB - In humans, hemispheric language dominance is, to some degree, associated with handedness. Significant associations have been reported between several other lateralized functions. Much less is known about the organization of cerebral asymmetries in nonhuman species and, in particular, whether the presence of reversed asymmetry of one function is associated with a reversal of other lateralized functions or, instead, if cognitive functions lateralize independently. In this study, we compare four measures of sensory and motor laterality in the same individuals in a sample of goldbelly topminnows. A significant association was found between two measures of eye preference and two measures of motor laterality, but sensory and motor asymmetries were uncorrelated. We found interesting that individuals preferring to examine a predator with the right eye tended to use the left eye to look at a shoal mate and the reverse was true for fish that monitored predators with the left eye. This complementarity of functions could be adaptively advantageous for a small social fish, because it allows an individual to monitor the movements of its shoal mates with one eye as the other eye remains free to scan the surroundings for the presence of predators. PMID- 23025830 TI - Repeated fluoxetine administration during adolescence stimulates aggressive behavior and alters serotonin and vasopressin neural development in hamsters. AB - Fluoxetine is the only selective serotonin reuptake inhibitor registered for the treatment of major depressive disorder in pediatric populations, despite reports that it is disproportionately associated with an array of adverse side effects that include agitation, hostility, and overt acts of pathological aggression and violence in youth. This study examined the effects of repeated adolescent fluoxetine administration on offensive aggression and the development of the serotonin (5HT) and vasopressin (AVP) neural systems modulating this behavior using pubertal Syrian hamsters (Mesocricetus auratus) as an adolescent-animal model. Adolescent hamsters administered fluoxetine were tested for offensive aggression using the resident/intruder test, sacrificed the following day, and, using immunohistochemistry, examined for 5HT and AVP afferent innervation/development to areas of the brain implicated in aggression control. Repeated exposure to a low dose (0.3 mg/kg/day) of fluoxetine during adolescence increased nearly all measures of offensive aggression (i.e., upright offensive attacks, lateral attacks, flank/rump bites, pursuits, flank marks), whereas measures of social interest (i.e., olfactory investigation, contact time), comfort (i.e., grooming), and locomotion (i.e., contact time, cage climbing) remained constant. Fluoxetine exposure also increased 5HT and AVP afferent development to brain areas implicated in aggressive behavior, most notably the latero-anterior hypothalamus (LAH)-an area of convergence for developmental and neuroplastic changes correlated with offensive aggression in hamsters. These data indicate that repeated administration of clinically relevant doses of fluoxetine during adolescent development directly stimulates aggressive behavior and alters LAH 5HT and AVP development, yet only alterations in AVP afferent development within the LAH correlate with the fluoxetine-induced aggressive behavioral phenotype. PMID- 23025831 TI - Evidence that the rat hippocampus has contrasting roles in object recognition memory and object recency memory. AB - Adult rats with extensive, bilateral neurotoxic lesions of the hippocampus showed normal forgetting curves for object recognition memory, yet were impaired on closely related tests of object recency memory. The present findings point to specific mechanisms for temporal order information (recency) that are dependent on the hippocampus and do not involve object recognition memory. The object recognition tests measured rats exploring simultaneously presented objects, one novel and the other familiar. Task difficulty was varied by altering the retention delays after presentation of the familiar object, so creating a forgetting curve. Hippocampal lesions had no apparent effect, despite using an apparatus (bow-tie maze) where it was possible to give lists of objects that might be expected to increase stimulus interference. In contrast, the same hippocampal lesions impaired the normal preference for an older (less recent) familiar object over a more recent, familiar object. A correlation was found between the loss of septal hippocampal tissue and this impairment in recency memory. The dissociation in the present study between recognition memory (spared) and recency memory (impaired) was unusually compelling, because it was possible to test the same objects for both forms of memory within the same session and within the same apparatus. The object recency deficit is of additional interest as it provides an example of a nonspatial memory deficit following hippocampal damage. PMID- 23025832 TI - Cocaine- and amphetamine-regulated transcript in the nucleus accumbens shell attenuates context-induced reinstatement of alcohol seeking. AB - We investigated the impact of cocaine- and amphetamine-regulated transcript (CART) in the nucleus accumbens shell (AcbSh) on context-induced reinstatement of alcoholic beer-seeking. Rats were trained to respond for 4% (vol/vol) alcoholic beer in one context (A) followed by extinction in a second context (B). Rats were subsequently tested for renewal of extinguished responding in the training context (A). Return to the training context elicited responding (reinstatement), whereas intra-AcbSh injections of CART (55-102) attenuated reinstatement without affecting general behavioral activity (Experiment 1). CART (55-102) attenuated reinstatement dose-dependently across the 0.025 - 2.5 MUg range (Experiment 2), and no effect was observed with the inactive CART (1-27) fragment (Experiment 3). Together, these findings suggest that intra-AcbSh CART (55-102) modulates the impact of drug-associated environments on reward seeking behavior. PMID- 23025834 TI - Noradrenergic but not cholinergic modulation of olfactory bulb during processing of near threshold concentration stimuli. AB - Neuromodulatory systems such as noradrenaline (NE), acetylcholine (ACh), and serotonin (5HT) serve important functions in sensory perception. We use the olfactory bulb (OB) as a model system to study the roles of individual neuromodulators in sensory perception. Using a spontaneous, nonreward motivated detection task, as well as a reward-motivated task, we show that rats can easily respond to odorants at very low concentrations when motivated to do so in a food rewarded task, despite not showing spontaneous responses to these low concentration odorants. Using the same tasks paired with local bulbar infusions of noradrenergic and cholinergic drugs, we then show that rats engage their noradrenergic, but not their cholinergic system, to better respond to near threshold odorants. These results suggest that while cholinergic modulation of OB function is mostly important for odor decorrelation and discrimination, noradrenergic modulation is important for signal-to-noise modulation. PMID- 23025833 TI - The anterior thalamus is critical for overcoming interference in a context dependent odor discrimination task. AB - The anterior thalamus (AT) is anatomically interconnected with the hippocampus and other structures known to be involved in memory, and the AT is involved in many of the same learning and memory functions as the hippocampus. For example, like the hippocampus, the AT is involved in spatial cognition and episodic memory. The hippocampus also has a well-documented role in contextual memory processes, but it is not known whether the AT is similarly involved in contextual memory. In the present study, we assessed the role of the AT in contextual memory processes by temporarily inactivating the AT and training rats on a recently developed context-based olfactory list learning task, which was designed to assess the use of contextual information to resolve interference. Rats were trained on one list of odor discrimination problems, followed by training on a second list in either the same context or a different context. In order to induce interference, some of the odors appeared on both lists with their predictive value reversed. Control rats that learned the two lists in different contexts performed significantly better than rats that learned the two lists in the same context. However, AT lesions completely abolished this contextual learning advantage, a result that is very similar to the effects of hippocampal inactivation. These findings demonstrate that the AT, like the hippocampus, is involved in contextual memory and suggest that the hippocampus and AT are part of a functional circuit involved in contextual memory. PMID- 23025835 TI - Moderate stress enhances memory persistence: are adrenergic mechanisms involved? AB - Memory persistence in the inhibitory avoidance (IA) task has been recently shown to require a new event of consolidation 12 hr after acquisition. The immobilization stress (IS) model is largely used to study the effects of stress on memory. In this study we investigated the interactions between stress by immobilization and its effect on the persistence of memory, and also a possible effect mediated by beta-adrenergic modulation of stress on memory persistence. An enhancement of long-term memory (LTM) persistence caused by stress through immobilization applied 12 hr after IA training was observed when the animals were submitted to 15 min or 1 hr of IS, but not to 3 hr. The reversal of this memory enhancement caused by IS was observed when the beta-adrenergic antagonist propranolol was infused intraperitoneally prior to stress, which implies that beta-adrenergic receptors are involved in stress enhancement of LTM persistence. PMID- 23025836 TI - SSRIs, adolescents, and aggression: tempering human implications regarding SSRI induced aggression in hamsters: comment on Ricci and Melloni (2012). AB - The safety and efficacy of selective serotonin reuptake inhibitors (SSRIs) in adolescents is a topic of great import, complexity, and controversy. Conflicting evidence derived from clinical trials, translational research, and basic science demands that investigators in the field use critical thinking in the synthesis of evidence from varying sources. The new study by Ricci and Melloni presented in the current issue of this journal shows that exposure to low-dose fluoxetine during adolescence predisposes Syrian hamsters to offensive aggression, with demonstrable neurophysiologic changes. This work adds to the understanding of the mammalian neuropathways of aggression, but is limited in its direct generalizability to human adolescent clinical populations. PMID- 23025837 TI - A randomized, double-blind, double-dummy, multicenter, controlled trial on brotizolam intervention in outpatients with insomnia. AB - AIM: To investigate the efficacy and safety of brotizolam in outpatients with insomnia. METHODS: This randomized, double-blind, double-dummy, multicenter, controlled trial recruited 253 outpatients randomized to receive either brotizolam (n = 126) or estazolam (n = 127) for 14 days followed by 1 week of follow-up for rebound detection. Sleep Dysfunction Rating Scale (SDRS) and Clinical General Impression Scale were applied for efficacy evaluation. Safety evaluation was based on data regarding vital signs, physical examination, lab tests, ECG and collection of adverse events. RESULTS: Full Analyses Set (FAS) and Safety Set (SS) included data of 251 subjects, with 126 from brotizolam group and 125 from estazolam group. Per Protocol Set (PPS) analysis included data of 235 subjects, with 121 and 114 from each group. After 14 days of treatment, there was no difference with statistical significance between the two groups regarding SDRS total score change from baseline. FAS and PPS analysis showed that the brotizolam is non-inferior to estazolam in efficacy evaluation. There was also no difference with statistical significance regarding rebound rate between brotizolam and estazolam group in FAS. The rate of adverse event in two groups was with no statistically significant difference in SS. CONCLUSION: Brotizolam is effective and safe in relieving the symptoms of insomnia. PMID- 23025838 TI - Early traumatic life events, parental attitudes, family history, and birth risk factors in patients with depressive disorder and healthy controls. AB - OBJECTIVE: Only few studies have compared the frequency of traumatic life events during childhood in inpatients with depression with a healthy control group. METHODS: Consecutively admitted inpatients with depression (n = 79), most of whom belonged to the melancholic subtype (n = 73; 92.4%), and healthy controls (n = 110) were investigated using a comprehensive retrospective interview with 203 questions regarding childhood traumatic life events, parental attitudes, family history of psychiatric disorders and birth risk factors. RESULTS: Depressed patients had significantly more severe traumatic events (mean score 1.33; SD 1.4) than control subjects (0.85; SD 1.2) on a 0-10 point "severe trauma scale". 70.9% (n = 56) of the depressed patients, but only 48.2% (n = 53) of the controls reported at least one severe traumatic event. When looking at single events, only few differences were found between patients and controls. Compared to controls, patients described significantly higher rates of psychiatric disorders in their families, in particular depression. Parental rearing styles were rated as more unfavorable in the patient group. In a logistic regression model, of all possible etiological factors examined, only a family history of psychiatric disorders showed a significant influence (OR = 3.6). CONCLUSIONS: Melancholic depression seems to be less associated with traumatic events than other psychiatric disorders. PMID- 23025839 TI - Factors predicting suicidal ideation in the preceding 12 months among patients attending a community psychiatric outpatient clinic. AB - BACKGROUND: Predictive factors are used to alert the clinician to the necessity of carrying out a suicide risk assessment in those patients whose demographic and clinical characteristics suggest the possibility of suicide. AIM: To identify demographic and clinical variables that could predict suicidal ideation in psychiatric outpatients. METHODS: 150 consecutive return patients attending a psychiatric outpatient clinic were approached and requested to complete a clinician-administered semi-structured questionnaire designed to assess the aims of the study. The questionnaire comprised 18 questions most of which had either a checklist of possible answers or a yes/no answer. Data was analysed with descriptive statistics, univariate analysis and logistic regression using SPSS version 17. RESULTS: Of the 150 patients approached with written information, 133 consented to take part in the study giving a response rate of 88.7%. The mean age was 40.6 years (s.d = 12.7). On univariate analysis, there was a statistically significant relationship (P < 0.05) between three of the predictor variables (age, marital status and history of self-harm) and the likelihood of experiencing suicidal ideation in the preceding 12 months. However, with all other factors controlled for, only two of the independent variables (history of self-harm and no history of psychiatric inpatient treatment) significantly predicted suicidal ideation in the previous 12 months with odds ratios of 5.409 and 2.836 respectively. CONCLUSION: Amongst variables studied, having a history of self harm or no previous history of psychiatric inpatient treatment was the best predictor of suicidal ideation in the preceding year in a population of patients attending a psychiatric outpatient review clinic. PMID- 23025842 TI - Transvaginal ultrasonography -- a helpful tool for the gynecologist in the diagnosis of a rare cause of obstructive ileus. PMID- 23025843 TI - Challenges facing ophthalmic start-up companies in developing new devices or medicines. PMID- 23025844 TI - All-cause and cause-specific mortality associated with diabetes in prevalent hemodialysis patients. AB - BACKGROUND: Diabetes is the most common risk factor for end-stage renal disease (ESRD) and has been associated with increased risk of death. In order to better understand the influence of diabetes on outcomes in hemodialysis, we examine the risk of death of diabetic participants in the HEMODIALYSIS (HEMO) study. METHODS: In the HEMO study, 823 (44.6%) participants were classified as diabetic. Using the Schoenfeld residual test, we found that diabetes violated the proportional hazards assumption. Based on this result, we fit two non-proportional hazard models: Cox's time varying covariate model (Cox-TVC) that allows the hazard for diabetes to change linearly with time and Gray's time-varying coefficient model. RESULTS: Using the Cox-TVC, the hazard ratio (HR) for diabetes increased with each year of follow up (p = 0.02) for all cause mortality. Using Gray's model, the HR for diabetes ranged from 1.41 to 2.21 (p <0.01). The HR for diabetes using Gray's model exhibited a different pattern, being relatively stable at 1.5 for the first 3 years in the study and increasing afterwards. CONCLUSION: Risk of death associated with diabetes in ESRD increases over time and suggests that an increasing risk of death among diabetes may be underappreciated when using conventional survival models. PMID- 23025845 TI - Comparison of gene expression profiling between lung fibrotic and emphysematous tissues sampled from patients with combined pulmonary fibrosis and emphysema. AB - BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is characterized by both emphysema of the upper zone and diffuse parenchymal lung disease with fibrosis of the lower zone of the lung on chest computed tomography. The aim of this study was to investigate the mechanism of CPFE regarding gene expressions by comparing the results of microarray sequences between fibrotic and emphysematous lesions in the lungs of CPFE patients. RESULTS: The expression profiles of the fibrotic and emphysematous lesions were remarkably different in terms of function. Genes related to the immune system, structural constituents of the cytoskeleton, and cellular adhesion were overexpressed in fibrotic lesions, while genes associated with the cellular fraction, cell membrane structures, vascular growth and biology, second-messenger-mediated signaling, and lung development (all processes that contribute to the destruction and repair of cells, vessels, and the lung) were overexpressed in emphysematous lesions. CONCLUSIONS: The differences in gene expression were detected in fibrotic and emphysematous lesions in CPFE patients. We propose that the development of coexisting fibrotic and emphysematous lesions in CPFE is implemented by these different patterns of gene expressions. PMID- 23025846 TI - Optimal loading of molecular bonds. AB - A corollary of the Bell equation of bond rupture is that the bond transfers a maximal impulse during its lifetime when the applied force equals k(B)T/x*. It is proposed that the designs of biological systems converge toward loading bonds with this optimal force to minimize the need for self-healing and to optimize energy transfer. PMID- 23025847 TI - The N-methylated peptide SEN304 powerfully inhibits Abeta(1-42) toxicity by perturbing oligomer formation. AB - Oligomeric forms of beta-amyloid (Abeta) have potent neurotoxic activity and are the primary cause of neuronal injury and cell death in Alzheimer's disease (AD). Compounds that perturb oligomer formation or structure may therefore be therapeutic for AD. We previously reported that d-[(chGly)-(Tyr)-(chGly)-(chGly) (mLeu)]-NH(2) (SEN304) is able to inhibit Abeta aggregation and toxicity, shown primarily by thioflavin T fluorescence and MTT (Kokkoni, N. et al. (2006) N Methylated peptide inhibitors of beta-amyloid aggregation and toxicity. Optimisation of inhibitor structure. Biochemistry 45, 9906-9918). Here we extensively characterize how SEN304 affects Abeta(1-42) aggregation and toxicity, using biophysical assays (thioflavin T, circular dichroism, SDS-PAGE, size exclusion chromatography, surface plasmon resonance, traveling wave ion mobility mass spectrometry, electron microscopy, ELISA), toxicity assays in cell culture (MTT and lactate dehydrogenase in human SH-SHY5Y cells, mouse neuronal cell death and synaptophysin) and long-term potentiation in a rat hippocampal brain slice. These data, with dose response curves, show that SEN304 is a powerful inhibitor of Abeta(1-42) toxicity, particularly effective at preventing Abeta inhibition of long-term potentiation. It can bind directly to Abeta(1-42), delay beta-sheet formation and promote aggregation of toxic oligomers into a nontoxic form, with a different morphology that cannot bind thioflavin T. SEN304 appears to work by inducing aggregation, and hence removal, of Abeta oligomers. It is therefore a promising lead compound for Alzheimer's disease. PMID- 23025848 TI - Activation of electrophilicity of stable Y-delocalized carbamate cations in intramolecular aromatic substitution reaction: evidence for formation of diprotonated carbamates leading to generation of isocyanates. AB - Although cations with three heteroatoms, such as monoprotonated guanidine and urea, are stabilized by Y-shaped conjugation and such Y-conjugated cations are sufficiently basic to be further protonated (or protosolvated) to dications in strongly acid media, only O-monoprotonated species have been detected in the case of carbamates even in magic acid. We found that the trifluoromethanesulfonic acid catalyzed cyclization of arylethylcarbamates proceeds to afford dihydroisoquinolones in high yield. In strong acids, methyl carbamates are fully O-monoprotonated, and these monocations do not undergo cyclization even under heating. But, as the acidity of the reaction medium is further increased, the cyclization reaction of methyl phenethylcarbamates starts to proceed as a first order reaction, with a linear relationship between rate and acidity. The sign and magnitude of the entropy of activation DeltaS(?) were found to be similar to those of other A(Ac)1 reactions. These results strongly support the idea that further protonation of the O-protonated carbamates is involved in the cyclization, but the concentration of the dications is very low and suggests that the rate-determining step is dissociation of methanol from the diprotonated carbamate to generate protonated isocyanate, which reacts with the aromatic ring. Therefore, O-protonated carbamates are weak bases in sharp contrast to other Y shaped monocations. PMID- 23025850 TI - Interplay of metallophilic interactions, pi-pi stacking, and ligand substituent effects in the structures and luminescence properties of neutral Pt(II) and Pd(II) aryl isocyanide complexes. AB - Packing interactions in the crystal structures of a series of cis-M(CNAr)(2)Cl(2) complexes (M = Pt, Pd; Ar = substituted phenyl) were examined and correlated with the luminescence properties of the Pt complexes. The structures of the PhNC and p tolyl isocyanide complexes exhibit extended chains of metallophilic interactions with M...M distances of 3.24-3.25 and 3.34 A, respectively, with nearly isostructural Pt and Pd compounds. Both structure types contain void channels running parallel to the M...M chains. The channels are 3-4 A wide and vacant for the phenyl structures, while those in the p-tolyl structures are up to 7.6 A wide and contain water. These channeled structures are stabilized by a combination of metallophilic bonding and aryl pi-pi stacking interactions. The Pt structure with 4-F substituents also features extended Pt...Pt chains, but with longer 3.79 A distances alternating with shorter 3.37 A contacts. Structures with 4-CF(3) and 4 OMe substituents exhibit mostly isolated dimers of M...M contacts. In complexes with 2,6-dimethylphenyl isocyanide, steric hindrance precludes any short M...M contacts. The primary effect of aryl substitution is to provide alternative packing motifs, such as CF(3)...pi and CH(3)...pi interactions, that either augment or disrupt the combination of metallophilic contacts and pi-pi stacking needed to stabilize extended M...M chains. Differences in the Pt and Pd structures containing 4-F and 4-OMe substituents are consistent with a higher driving force for metallophilic interactions for Pt versus Pd. The M-C and M-Cl bond distances indicate a slightly higher trans influence for aryl isocyanides bound to Pt versus Pd. The three extended Pt...Pt chain structures display luminescence assignable to (dsigma*->psigma) excited states, demonstrating the existence of substantial orbital communication along the metal-metal chains. Face indexing shows that the preferred crystal growth axis is along the metal-metal chains for the luminescent structures. Variable temperature structural studies showed that both M...M and pi-pi interactions contract upon cooling. Overall, this study suggests that synergy with pi-pi and other interactions is necessary to stabilize extended M...M chain structures. Thus, efforts to design functional materials based on metallophilic bonding must consider the full array of available packing motifs. PMID- 23025849 TI - Primary health-care patients' reasons for complaint-related worry and relief. AB - AIM: Primary care patients are commonly worried about their complaints when consulting their doctor. Knowing the reasons behind patients' worries would enhance consultation practices. The aim of this study was to find out the reasons patients themselves give for their worries before a consultation and for possible relief or persistent worry after the consultation. BACKGROUND: Our previous study using quantitative methods suggested that worried patients were uncertain about what was wrong with them and they perceived their complaints as serious. These results left some aspects unanswered; for instance, why did the patients consider their complaints severe. METHODS: We conducted semi-structured interviews of patients, aged 18-39 years, with somatic complaints other than a common cold (n = 40), both before and after a consultation, and the patients described their reasons for worry in their own words. These qualitative data were analysed using thematic content analysis. FINDINGS: The patients gave as reasons for their worries uncertainty, consequences of their complaints (eg, inability to work), insufficient control (eg, inadequate treatment) and prognosis. The patients were relieved when their uncertainty was diminished by getting an explanation for their complaint or when they achieved more control by getting treatment for their complaint. After a consultation, their reasons for worry, except for concern about the ability to function, tended to be replaced by other reasons. Psychological consequences and mistrust in health care also played a role in persistent worry. Our findings offer support to the patient-centred clinical method in primary care. To address the patients' worries properly, the GP should bring them up for discussion. Special attention should be given to worries about the ability to function, as they tend to persist even after a consultation. PMID- 23025851 TI - ICRP Publication 119: Compendium of dose coefficients based on ICRP Publication 60. AB - This report is a compilation of dose coefficients for intakes of radionuclides by workers and members of the public, and conversion coefficients for use in occupational radiological protection against external radiation from Publications 68, 72, and 74 (ICRP, 1994b, 1996a,b). It serves as a comprehensive reference for dose coefficients based on the primary radiation protection guidance given in the Publication 60 recommendations (ICRP, 1991). The coefficients tabulated in this publication will be superseded in due course by values based on the Publication 103 recommendations (ICRP, 2007). PMID- 23025852 TI - Desire for control and optimistic time predictions. AB - Few studies have investigated individual differences in time predictions. We report two experiments that show an interaction between the personality trait Desirability of Control and reward conditions on predictions of performance time. When motivated to perform a task quickly, participants with a strong desire for control produced more optimistic predictions than those with a weaker desire for control. This effect could also be observed for a completely uncontrollable task. The results are discussed in relation to the finding that power produces more optimistic predictions, and extend this work by ruling out some previously suggested explanations. PMID- 23025854 TI - It takes a village. PMID- 23025855 TI - Radiology lessons from Greek history. PMID- 23025856 TI - Health care reform: third gear's all right. PMID- 23025857 TI - Leadership in conflict: part 2. AB - Don't start stupid fights, and don't make enemies (except on purpose!). Fight for a reason or a goal. Have a plan for ending the conflict that includes the details when, where,why, how, and who. Within the fight, see it as a complex negotiation. Although you may get emotional, try to stay cerebral and understand what you and your opponent are doing and when it is time to stop. When the fighting stops, repair the damage and start preparing for the next conflict. PMID- 23025858 TI - A short walk. PMID- 23025859 TI - Introduction to the special issue-Health Care Reform: darkness before dawn? PMID- 23025860 TI - Roots of health care reform. AB - The health care reform legislation of 2010 was a response to chronic issues in the US health care system that had been unresolved for decades. Whether health care reform is implemented in its current form or in a variant, the issues to address remain the same. In addition, those issues that have not been specifically addressed in national legislation remain areas of potential future policy. PMID- 23025861 TI - Drivers of health reform in the United States: 2012 and beyond. AB - American medicine has seen radical changes in the past decade. In particular, radiology has been affected, notably first with the passage of the Deficit Reduction Act in 2005 and then with the Patient Protection and Affordable Care Act in 2010. Health care reforms are not only driven by political agendas. This process is also a response to underlying social, economic, and technological realities. It is unlikely that reform efforts will just evaporate because of a single change in government or with a decision by the US Supreme Court. Regardless of who sits in the Oval Office and which party controls Congress, there are forces that will need to be addressed through policy changes in the coming years. The underlying drivers of health care reform are legion, but health care inflation, fiscal mismanagement by government, poor planning for demographic changes that affect entitlement programs, questions about the quality of health outcomes, and a desire for universal health care were all central factors in the reforms put forth since 2009. Radiologists should be preparing now for continued change in both the public and private sectors in health care for the foreseeable future. These changes are likely to have profound impacts on our profession. Radiologists and their groups should plan to pay greater attention to these events and should seek to have a much greater level of involvement in the political and social processes that lead to policy changes in health care. PMID- 23025862 TI - Utilization management in radiology, part 1: rationale, history, and current status. AB - Previous growth in the utilization of medical imaging has led to numerous efforts to reduce associated spending. Although these have historically been directed toward unit cost reductions, recent interest has emerged by various stakeholders in curbing inappropriate utilization. Radiology benefits managers have widespread market penetration and have been promoted largely by the payer community as effective mechanisms to curb increases in imaging volume. The provider community has tended to favor real-time order entry decision support systems. These have demonstrated comparable effectiveness to radiology benefits managers in early projects but currently have only limited market penetration. In this first of a two-part series, the rationale for the development of utilization management programs will be discussed and their history and current status reviewed. PMID- 23025863 TI - Utilization management in radiology, part 2: perspectives and future directions. AB - Increased utilization of medical imaging in the early part of the last decade has resulted in numerous efforts to reduce associated spending. Recent initiatives have focused on managing utilization with radiology benefits managers and real time order entry decision support systems. Although these approaches might seem mutually exclusive and their application to radiology appears unique, the historical convergence and broad acceptance of both programs within the pharmacy sector may offer parallels for their potential future in medical imaging. In this second installment of a two-part series, anticipated trends in radiology utilization management are reviewed. Perspectives on current and future potential roles of radiologists in such initiatives are discussed, particularly in light of emerging physician payment models. PMID- 23025864 TI - Clinical decision support and acute low back pain: evidence-based order sets. AB - Low back pain is one of the most common reasons for visits to physicians in the ambulatory care setting. Estimated medical expenditures related to low back pain have increased disproportionately relative to the more modest increase in the prevalence of self-reported low back pain in the past decade. The increase in spine care expenditures has not been associated with improved patient outcomes. Evidence-based order templates presented in this article are designed to assist practitioners through the process of managing patients with acute low back pain. A logical method of choosing, developing, and implementing clinical decision support interventions is presented that is based on the best available scientific evidence. These templates may be reasonably expected to improve patient care, decrease inappropriate imaging utilization, reduce the inappropriate use of steroids and narcotics, and potentially decrease the number of inappropriate invasive procedures. PMID- 23025865 TI - Measuring radiology's value in time saved. AB - Because radiology has historically not measured its added value to patient care and thus not communicated it in easily understood terms to all stakeholders, the specialty must correct this to prepare for the eventual transition from the current fee-for-service payment schedule to new value-based reimbursement systems. Given the increasing risk for marginalization, radiologists need to engage clinicians and managers to map the processes and associated costs of episodes of patient care to identify areas for providing and improving integrated diagnostic information and to measure the value thereof. In such time-driven, activity-based costing practices, radiologists should highlight how proper investments in the information generated by imaging and how radiologists' associated consultative and coordination of services can save greater resources downstream, especially in the nonrenewable resource of physician time, an increasingly scarce health care resource. Using physician time in the most efficient way will be a key element for decreasing health care costs at the aggregate level. Therefore, expressing radiology's contribution in terms of downstream physician time saved is a metric that can be easily understood by all stakeholders. In a conceptual framework centered on value, the specialty of radiology must focus more on its most important product, actionable information, rather than on imaging technologies themselves. Information, unlike imaging technologies, does not depreciate with time but rather increases in value the more it is used. PMID- 23025866 TI - Introduction to value-based payment modifiers. AB - Value-based payment modifiers were legislated by Congress in the 2010 Patient Protection and Affordable Care Act. It is clear in the legislation, and the corresponding proposals published by the secretary of the US Department of Health and Human Services in late 2011, that the intent is to move from paying physicians for reporting to paying physicians for performance. The proposals, developed jointly with CMS, specify that the calculation of payments for performance will be a composite of quality and cost measures. The base year for determining performance benchmarks for the performance measures will be 2013, and the measures will be applied to physician payments on a limited basis beginning in 2015 and to all physician payments by 2017. The role of medical specialty boards, such as the ABR, in the development and deployment of measures is highlighted in this context. CMS's recent conversations with board representatives have indicated their view that the boards' measure development activities are key to increasing physician (especially specialist) participation in the Physician Quality Reporting System to 50% by 2015, from 20% to 30% today. The ABR will continue its past activities in this arena, working with the American Board of Medical Specialties, CMS, and specialty societies, so that ABR diplomates will be able to simultaneously complete their Maintenance of Certification requirements, satisfy the requirements for CMS incentives, and avoid penalties. PMID- 23025867 TI - Patient-centered outcomes in imaging: quantifying value. AB - The Patient-Centered Outcomes Research Institute was created in response to a mandate to conduct comparative effectiveness research in clinical care to inform decision making. The institute will be funded by the Patient-Centered Outcomes Research Trust Fund, through congressional set-asides, and by Medicare and private health insurers, through a per beneficiary fee. The institute is governed by a board with a broad stakeholder constitution. Key committees set the national agenda for patient-centered outcomes research, the agenda for funding priorities, and communication and dissemination of the evidence with the goal of increasing the rate of implementation of the evidence into policy. In imaging, patient centered outcomes go beyond the traditional metrics of patient satisfaction. Instead, these outcomes need to encompass the benefits and harms, focus on outcomes relevant to patients, and provide information to inform decision making. Therefore, radiologists need to be involved as stakeholders in the design, conduct, and dissemination of this research. PMID- 23025868 TI - Radiology liability update: review of claims, trends, high-risk conditions and practices, and tort reform alternatives. AB - Radiology liability claims data are reviewed to explore the risk for suit and adverse judgments or settlements among radiologists, assess high-risk imaging conditions, and identify high-risk practice issues. Possible medical malpractice tort reform options are reviewed. PMID- 23025869 TI - The accountable health care act of Massachusetts: mixed results for an experiment in universal health care coverage. AB - The affordable health care act of Massachusetts, signed into law in 2006, resulted in 98% of Massachusetts residents' having some form of insurance coverage by 2011, the highest coverage rate for residents of any state in the nation. With a strong economy, a low unemployment rate, a robust health care delivery system, an extremely low number of undocumented immigrants, and a low baseline uninsured rate, Massachusetts was well positioned for such an effort. Ingredients included mandates, the creation of separate insurance vehicles directed to both poverty-level and non-poverty-level residents, and the reallocation of the former free care pool. The mandates included consumer mandates and employer mandates; the consumer mandate applies to all Massachusetts residents at the risk of losing personal state tax exemptions, and the employer mandate applies to all Massachusetts businesses with 10 or more employees at the risk of per employee financial penalties. The insurance vehicles were created with premiums allocated on the basis of ability to pay by income classes. Unexpected effects included escalating taxpayer health care costs, with taxpayers shouldering the burden for the newly insured, continuing escalating health care costs at a rate greater than the national average, overburdening primary caregivers as newly insured sought new primary care gatekeepers in a system with primary caregiver shortages, and deprivation of support to the safety-net hospitals as a result of siphoned commonwealth free care pool funds. This exercise demonstrates specific benefits and shortfalls of the Massachusetts health care reform experiment, given the conditions and circumstances found in Massachusetts at the time of implementation. PMID- 23025870 TI - A radiologist's guide to the federal election of 2012: what you should know before you go into the booth. AB - The results of the federal election of 2012 will likely have very substantial impacts on the practice of radiology. Health care reform is likely to continue under the administration of either of the two major candidates, albeit in very different ways. In particular, radiologists should be aware of the candidates' positions on how their plans will affect key issues facing radiology. There are many issues at stake. These include reimbursement, multiple-procedure discounting, utilization rates, bundled care, accountable care organizations and capitation, justification of procedures, tort reform, and taxation policies. The election coincides with a period of fiscal crisis in the US government coupled with a relatively weak economic recovery in the United States and an ongoing fiscal and economic crisis in Europe. The pressures in the United States are further magnified by a profound demographic shift as the baby boom generation retires in record numbers, increasing the payment requirement on the major entitlement programs, Medicare and Social Security. These forces are heightening the pressures at the federal level for substantial change in how health care is regulated and reimbursed. The author reviews the positions of the major candidates and their parties on health care and evaluates election outcome scenarios that radiologists and their groups should plan for over the period from 2013 to 2017. PMID- 23025871 TI - ACR Appropriateness Criteria((r)) acute nonspecific chest pain-low probability of coronary artery disease. AB - This document outlines the usefulness of available diagnostic imaging for patients without known coronary artery disease and at low probability for having coronary artery disease who do not present with classic signs, symptoms, or electrocardiographic abnormalities indicating acute coronary syndrome but rather with nonspecific chest pain leading to a differential diagnosis, including pulmonary, gastrointestinal, or musculoskeletal pathologies. A number of imaging modalities are available to evaluate the broad spectrum of possible pathologies in these patients, such as chest radiography, multidetector CT, MRI, ventilation perfusion scans, cardiac perfusion scintigraphy, transesophageal and transthoracic echocardiography, PET, spine and rib radiography, barium esophageal and upper gastrointestinal studies, and abdominal ultrasound. It is considered appropriate to start the assessment of these patients with a low-cost, low-risk diagnostic test such as a chest x-ray. Contrast-enhanced gated cardiac and ungated thoracic multidetector CT as well as transthoracic echocardiography are also usually considered as appropriate in the evaluation of these patients as a second step if necessary. A number of rest and stress single-photon emission CT myocardial perfusion imaging, ventilation-perfusion scanning, aortic and chest MR angiographic, and more specific x-ray and abdominal examinations may be appropriate as a third layer of testing, whereas MRI of the heart or coronary arteries and invasive testing such as transesophageal echocardiography or selective coronary angiography are not considered appropriate in these patients. Given the low risk of these patients, it is mandated to minimize radiation exposure as much as possible using advanced and appropriate testing protocols. The ACR Appropriateness Criteria(r) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 23025872 TI - Should you use open-source software applications in your practice? PMID- 23025873 TI - Why a dose of compliance is good medicine. PMID- 23025874 TI - PACS and the potential for medical errors. PMID- 23025875 TI - The iPad in radiology resident education. PMID- 23025876 TI - Red shell: defining tissue toxicity in stereotactic body radiation therapy. PMID- 23025878 TI - Re: "to text or not to text?". PMID- 23025879 TI - Pituitary origin of persistently elevated human chorionic gonadotropin in a patient with gonadal failure. AB - OBJECTIVE: To report a case of persistently elevated low levels of hCG to increase awareness of pituitary origin of persistently elevated hCG in patients with gonadal failure. DESIGN: Case report and literature review. SETTING: Large university-affiliated infertility practice. PATIENT(S): A 16-year-old patient with primary amenorrhea, normal secondary sex characteristics, ovarian failure, and a 46,XY karyotype. Her past medical history was significant for focal segmental glomerulosclerosis, leading to a diagnosis of Frasier syndrome. INTERVENTION(S): At age 31 years, she desired pregnancy by oocyte donation and was found to have persistently elevated low levels of hCG (>35 mIU/mL). MAIN OUTCOME MEASURE(S): Pituitary hCG. RESULT(S): Both serum free beta-hCG and hyperglycosylated hCG were undetectable. Total serum hCG diluted appropriately was not blocked by blocking agent and was detected in the urine. Subsequent treatment with exogenous E(2), in preparation of a donor oocyte cycle, suppressed her hCG levels (down to 8 mIU/mL). These results indicated a pituitary source of the serum hCG. CONCLUSION(S): This report reinforces the need to consider pituitary hCG as the origin of persistently elevated hCG levels in patients with gonadal failure. Although levels of hCG <14 mIU/mL have been considered normal in postmenopausal women, our case suggests that patients with gonadal failure at younger ages might have a higher pituitary output of hCG. PMID- 23025880 TI - Cardiac autonomic modulation in polycystic ovary syndrome: does the phenotype matter? AB - OBJECTIVE: To assess whether heart rate variability (HRV) at rest and during sympathetic stimulation is disturbed in patients with different polycystic ovary syndrome (PCOS) phenotypes in comparison to healthy controls. DESIGN: Cross sectional study. SETTING: University hospital. PATIENT(S): Thirty women with classic, anovulatory PCOS, 16 women with ovulatory PCOS, and 23 age-paired women with regular and proven ovulatory cycles. INTERVENTION(S): Anthropometric and hormonal evaluation and analysis of HRV (time and frequency domain HRV indices) at rest and after a mental stress test. MAIN OUTCOME MEASURE(S): Difference between HRV components during rest and stress. RESULT(S): Mean age was 22.80 +/- 5.80 years in patients with classic PCOS, 19.81 +/- 6.43 years in ovulatory PCOS, and 22.65 +/- 5.89 years in controls. During mental stress, patients with classic PCOS showed lower HRV response when compared with the control group, even after adjustment for body mass index (BMI) and age. When patients with classic and ovulatory PCOS were considered together, total T levels were inversely associated with the low frequency component, low frequency/high frequency ratio, and the difference between high frequency response at rest and after the stress test. CONCLUSION(S): Young patients with the classic PCOS phenotype have an impaired autonomic modulation in response to sympathetic stimulation that is typical of considerably older women, or of advanced age. PMID- 23025881 TI - Elective cryopreservation of all embryos with subsequent cryothaw embryo transfer in patients at risk for ovarian hyperstimulation syndrome reduces the risk of adverse obstetric outcomes: a preliminary study. AB - OBJECTIVE: To test the hypothesis that patients who undergo elective cryopreservation of all embryos, due to risk of ovarian hyperstimulation syndrome and elevated peak serum estradiol (E(2)), previously defined as level >3,450 pg/mL (90th percentile) during in vitro fertilization (IVF), will be less likely to have small for gestational age (SGA) infants and preeclampsia as compared with patients with elevated peak serum E(2) who undergo fresh embryo transfer (ET). DESIGN: Cohort study. SETTING: Tertiary care academic medical center. PATIENT(S): Twenty women who underwent elective cryopreservation of all embryos with subsequent cryothaw ET and 32 similar women with elevated peak E(2) during controlled ovarian hyperstimulation for IVF who underwent a fresh ET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prevalence of SGA infants and development of preeclampsia in patients with cryothaw ET or fresh ET in the setting of elevated peak E(2). RESULT(S): After adjusting for confounders (body mass index, antral follicle count, peak serum E(2) level) using forward stepwise logistic regression, the patients who elected cryopreservation of all embryos and subsequent cryothaw ET were statistically significantly less likely to deliver SGA infants as compared with the patients who had fresh ET in the setting of elevated peak E(2). In the entire cohort, a total of seven women had preeclampsia, all of whom had had fresh ET in the setting of elevated peak serum E(2): 7 (21.9%) in the fresh ET group versus 0 women in the elective cryopreservation group. CONCLUSION(S): This preliminary study suggests that elective cryopreservation of all embryos in patients with elevated peak serum E(2) for subsequent cryothaw ET in cycles with a better physiologic hormonal milieu may reduce the odds of SGA and preeclampsia in IVF singleton deliveries. PMID- 23025882 TI - Modifiable aspects of in vitro fertilization to reduce perinatal morbidity. PMID- 23025883 TI - Interleukin-19 and interleukin-22 serum levels are decreased in patients with ovarian endometrioma. AB - OBJECTIVE: To determine the serum levels of interleukin (IL)-10 family ILs in women with ovarian endometriosis and investigate the correlation of these levels with disease activity. DESIGN: A case-control laboratory study. SETTING: Tertiary care university hospital. PATIENT(S): Two hundred nineteen women, with (n = 112) and without (n = 107) endometriosis. INTERVENTION(S): Complete surgical excision with pathological analysis. MAIN OUTCOME MEASURE(S): Blood samples were obtained during surgical procedures. IL-10, -19, -20, and -22 were assayed by ELISA in sera, and the concentrations correlated with the extent and the severity of the disease. RESULT(S): IL-19 was detectable in 18.3% and IL-22 in 47.9% of sera samples from all 219 women studied. Serum IL-19 was lower in women with endometriosis (median, 292.7 pg/mL; range, 32.2-1,339.3) than in endometriosis free women (median, 1,035.8 pg/mL; range, 32.2-2,000.0). In addition, serum IL-22 levels were decreased in women affected by endometriosis (median, 352.0 pg/mL; range, 31.2-1,392.2) as compared with endometriosis-free women (median, 709.2 pg/mL; range, 73.3-2,012.0). We found significant correlations between serum IL 22 concentrations and intensity of deep dyspareunia (r = -0.303) and noncyclic chronic pelvic pain (r = -0.212). IL-19 was correlated with the intensity of deep dyspareunia (r = -0.749). CONCLUSION(S): Serum IL-19 and IL-22 are decreased in women with ovarian endometrioma. IL-10 family ILs may be involved in the pathogenesis of endometriosis. PMID- 23025884 TI - Enhanced adhesion of elastic materials to small-scale wrinkles. AB - The adhesive properties of a material can be greatly affected simply by wrinkling its surface. We show the importance of selecting the wrinkle feature sizes (amplitude, b; and wavelength, lambda) that complement the material-defined length scale related to the adhesion energy and modulus. A rigid circular cylindrical punch patterned with aligned wrinkles ranging in amplitude from 0.5 to 5.0 MUm with a fixed aspect ratio of 0.1 is used to characterize the adhesion of elastic films of smooth poly(dimethyl siloxane) (PDMS). The cross-linker concentration used to form the PDMS layers is varied to determine the impact of material properties on wrinkled surface adhesion. The elastic films have an average thickness of 240 MUm and the average probe radius is 1 mm, leading to a confined contact scenario. The separation stress and work of debonding are presented for each cross-linker concentration with testing rates ranging over 3 orders of magnitude. For stiffer films (10 wt % cross-linker, E' ~ 3.00 MPa), small wrinkles (b ~ 0.5 MUm) increase the separation stress by nearly 200% relative to a smooth interface whereas large wrinkles (b ~ 5.0 MUm) are shown to reduce adhesion significantly. A substantial increase in the debonding energy is also observed for these small-amplitude wrinkles contacting stiff materials. No discernible impact of wrinkled surface topography on the adhesion of softer (2 and 4 wt % cross-linker, 0.05 MPa < E' < 0.30 MPa) films is measured. PMID- 23025890 TI - An observational study to determine the effect of delayed admission to the intensive care unit on patient outcome. AB - INTRODUCTION: Delayed patient admission to the intensive care unit (ICU) due to lack of bed availability is a common problem, but the effect on patient outcome is not fully known. METHODS: A retrospective study was performed using departmental computerised records to determine the effect of delayed ICU admission and temporary management within the operating theatre suite on patient outcome. Emergency surgical and medical patients admitted to the ICU (2003 to 2007) were divided into delay (more than three hours from referral to admission) and no-delay (three or fewer hours from referral to admission) groups. Our primary outcome measure was length of ICU stay. Secondary outcome measures were mortality rates and duration of organ support. RESULTS: A total of 1,609 eligible patients were included and 149 (9.3%) had a delayed admission. The delay and no delay groups had similar baseline characteristics. Median ICU stay was 5.1 days (delay) and 4.5 days (no-delay) (P = 0.55) and ICU mortality was 26.8% (delay) and 24.2% (no-delay) (P = 0.47). Following adjustment for demographic and baseline characteristics there was no difference in either length of ICU stay or mortality rates between groups. ICU admission delay was associated with both an increased requirement for advanced respiratory support (92.3% delay vs. 76.4% no delay, P <0.01) and a longer time spent ventilated (median four days delay vs. three days no-delay, P = 0.04). CONCLUSIONS: No significant difference in length of ICU stay or mortality rate was demonstrated between the delay and no-delay cohorts. Patients within the delay group had a significantly greater requirement for advanced respiratory support and spent a longer time ventilated. PMID- 23025892 TI - Organ sales: exploitative at any price? AB - In many cases, claims that a transaction is exploitative will focus on the details of the transaction, such as the price paid or conditions. For example, in a claim that a worker is exploited, the grounds for the claim are usually that the pay is not sufficient or the working conditions too dangerous. In some cases, however, the claim that a transaction is exploitative is not seen to rely on these finer details. Many, for example, claim that organ sales would be exploitative, in a way that doesn't seem to depend on the details. This article considers, but ultimately rejects, a number of arguments which could be used to defend this sort of claim. PMID- 23025891 TI - Structure-activity studies of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes: a novel class of highly potent nicotinic receptor ligands. AB - The potential for nicotinic ligands with affinity for the alpha4beta2 or alpha7 subtypes to treat such diverse diseases as nicotine addiction, neuropathic pain, and neurodegenerative and cognitive disorders has been exhibited clinically for several compounds while preclinical activity in relevant in vivo models has been demonstrated for many more. For several therapeutic programs, we sought nicotinic ligands with various combinations of affinity and function across both subtypes, with an emphasis on dual alpha4beta2-alpha7 ligands, to explore the possibility of synergistic effects. We report here the structure-activity relationships (SAR) for a novel series of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes and characterize many of the analogues for activity at multiple nicotinic subtypes. PMID- 23025893 TI - Responses of seedling growth and antioxidant activity to excess iron and copper in Triticum aestivum L. AB - The purpose of this study was to analyze phytotoxicity mechanism involved in root growth and to compare physiological changes in the leaves of wheat seedlings exposed to short term iron (Fe) and copper (Cu) stresses (0, 100, 300 and 500MUM). All applied Fe or Cu concentrations reduced root and shoot lengths, but seed germination was inhibited by Cu only at 500MUM. Analyses using fluorescent dye 2',7'-dichlorodihydrofluorescein diacetate indicated enhanced H(2)O(2) levels in seedling roots under Fe and Cu treatments. Cu stress at the same concentration induced a great reduction in cell viability and a strong damage on membrane lipid in the roots with respect to Fe treatment. Significant increases in the total chlorophyll (chl) content including chl a and chl b were observed in response to higher Fe concentrations, whereas the highest Cu concentration (500MUM) led to significant decreases in the total chl content including chl a. Additionally, leaf peroxidase (POD) and ascorbate peroxidase (APX) were stimulated by Fe stress, but the highest Fe concentration exhibited inhibitory effect on leaf APX activity. In contrast, copper treatment resulted in an elevation in leaf catalase and POD activities. Therefore, H(2)O(2) content in the leaves associated with copper was significantly lower than that with iron at the same concentration. PMID- 23025894 TI - Biochemical and bioaccumulation approaches for investigating marine pollution using Mediterranean rainbow wrasse, Coris julis (Linneaus 1798). AB - A multibiomarkers approach was used in order to estimate and monitor marine pollution. Coris julis (Linneaus, 1758) was chosen as a sentinel organism, and the specimens were collected from three well-known sites along the Ionic coast of Sicily: the protected marine area (P.M.A) "Cyclop's Islands" of Acitrezza (CT), used as a control site, Riposto (CT), and the industrial site of Augusta (SR). Abiotic levels of contaminants were also detected. High levels of biotic and abiotic accumulation were found at the industrial site in which the presence of genotoxic and oxidative damage were also evidenced, measured by Micronuclei, Alkaline and Fpg-modified Comet assays. The protein expression analysis showed metallothioneins (MTs) as good tissue-specific markers of metal accumulation. Their levels were significantly higher in muscle than in liver tissue for all the sampling sites, with a positive correlation among tissue levels and the degree of pollution at the sites. Conversely, heat shock proteins 70 (HSP70) expression was higher in Augusta and Riposto than in the control site, but no significant difference was found between the examined tissues among all sites. PMID- 23025895 TI - Ecotoxicological impact of sunlight assisted photoreduction of hexavalent chromium present in wastewater with zinc oxide nanoparticles on common Anabaena flos-aquae. AB - Hexavalent chromium is more toxic and carcinogenic compared to its trivalent counterpart. Hexavalent chromium can be photocatalytically reduced to trivalent one using zinc oxide semiconductor and solar or UV radiation as light source. But an important ecological aspect is whether the net toxicity decreases after the photocatalytic process. In the present work, we have selected Anabaena flos-aquae as the model organism and examined whether the net toxicity to which it has been exposed in water decreases after photocatalytic reduction of hexavalent chromium using ZnO semiconductor as photocatalyst. We have studied the cumulative toxicities of both chromium (before and after treatment) and ZnO (both nano and micro) separately and as a suspension of ZnO in chromium. Quantitative cell surface roughness analysis was conducted using AFM to confirm the changes in cell surface properties. PMID- 23025896 TI - Chromosome anomalies in bone marrow as primary cause of aplastic or hypoplastic conditions and peripheral cytopenia: disorders due to secondary impairment of RUNX1 and MPL genes. AB - BACKGROUND: Chromosome changes in the bone marrow (BM) of patients with persistent cytopenia are often considered diagnostic for a myelodysplastic syndrome (MDS). Comprehensive cytogenetic evaluations may give evidence of the real pathogenetic role of these changes in cases with cytopenia without morphological signs of MDS. RESULTS: Chromosome anomalies were found in the BM of three patients, without any morphological evidence of MDS: 1) an acquired complex rearrangement of chromosome 21 in a boy with severe aplastic anaemia (SAA); the rearrangement caused the loss of exons 2-8 of the RUNX1 gene with subsequent hypoexpression. 2) a constitutional complex rearrangement of chromosome 21 in a girl with congenital thrombocytopenia; the rearrangement led to RUNX1 disruption and hypoexpression. 3) an acquired paracentric inversion of chromosome 1, in which two regions at the breakpoints were shown to be lost, in a boy with aplastic anaemia; the MPL gene, localized in chromosome 1 short arms was not mutated neither disrupted, but its expression was severely reduced: we postulate that the aplastic anaemia was due to position effects acting both in cis and in trans, and causing Congenital Amegakaryocytic Thrombocytopenia (CAMT). CONCLUSIONS: A clonal anomaly in BM does not imply per se a diagnosis of MDS: a subgroup of BM hypoplastic disorders is directly due to chromosome structural anomalies with effects on specific genes, as was the case of RUNX1 and MPL in the patients here reported with diagnosis of SAA, thrombocytopenia, and CAMT. The anomaly may be either acquired or constitutional, and it may act by deletion/disruption of the gene, or by position effects. Full cytogenetic investigations, including a-CGH, should always be part of the diagnostic evaluation of patients with BM aplasia/hypoplasia and peripheral cytopenias. PMID- 23025897 TI - Utilizing the GAAA tetraloop/receptor to facilitate crystal packing and determination of the structure of a CUG RNA helix. AB - Myotonic dystrophy type 1 (DM1) is a microsatellite expansion disorder caused by the aberrant expansion of CTG repeats in the 3'-untranslated region of the DMPK gene. When transcribed, the toxic RNA CUG repeats sequester RNA binding proteins, which leads to disease symptoms. The expanded CUG repeats can adopt a double stranded structure, and targeting this helix is a therapeutic strategy for DM1. To improve our understanding of the 5'CUG/3'GUC motif and how it may interact with proteins and small molecules, we designed a short CUG helix attached to a GAAA tetraloop/receptor to facilitate crystal packing. Here we report the highest resolution structure (1.95 A) to date of a GAAA tetraloop/receptor and the CUG helix it was used to crystallize. Within the CUG helix, we identify two different forms of noncanonical U-U pairs and reconfirm that CUG repeats are essentially A form. An analysis of all noncanonical U-U pairs in the context of CUG repeats revealed six different classes of conformations that the noncanonical U-U pairs are able to adopt. PMID- 23025898 TI - Peri-operative care in adults with congenital heart disease: room for improvement in after care. AB - BACKGROUND: Patient satisfaction with care has received little attention within the field of congenital heart disease. Our objective was to examine patient satisfaction with the care received when undergoing open-heart surgery in order to identify the best and worst aspects of peri-operative care. Moreover, we examined whether having contact with a specialised nurse in addition to usual care is associated with higher patient satisfaction levels. METHODS: Patient satisfaction was measured by the Satisfaction with Hospital Care Questionnaire, evaluating nine aspects of care by answering individual items and giving overall grades. A top 10 of the best and worst items was selected. Linear regression analyses were used to examine the relationship between having contact with a specialised nurse and patient satisfaction (9 grades), independent of patient characteristics--sex, age, educational level, and health status. RESULTS: Data were available for 75 patients. Grades ranged from 6.74 for "discharge and after care" to 8.18 for "medical care". In all, 21% of patients were dissatisfied with the clarity of the information about lifestyle adjustments given by the surgeon. However, patients who had contact with a specialised nurse were more satisfied with the provided information (B-coefficient is 0.497, p-value is 0.038), independent of patient characteristics. CONCLUSIONS: Patients were satisfied with the received care, although there is room for improvement, especially in discharge and after care and the clarity of the information provided by the surgeon. This gap in care can be compensated for by specialised nurses, as patients who were counselled by a specialised nurse were more satisfied with the provided information. PMID- 23025899 TI - Density functional investigation of the water oxidation by iron complexes based on tetradentate nitrogen ligands. AB - Recently it was discovered that the iron coordination complex L(N4)Fe(II)(OTf)(2) (1) (L(N4) = neutral tetraazadendate ligand and OTf = OSO(2)CF(3)) and its analogues are efficient water oxidizing catalysts (WOCs) in aqueous acidic solution with excess amount of ceric(IV) ammonium nitrate (CAN), [Ce(IV)(NO(3))(6)](NH(4))(2), as sacrificial oxidants. The probable mechanism of water oxidation by these catalysts was explored on the basis of density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations for 1 as a representative WOC. We examined the conversion of 1 to the resting intermediate [L(N4)Fe(IV)(O)(OH(2))](2+) [2(IV)] as well as two catalytic cycles involving 2(IV): one proposed by Fillol et al. [Nat. Chem. 2011, 3, 1] in which the Fe oxidation states of the intermediate species vary from +2 to +5, and the alternative cycle in which they remain constant at +4. In addition, we investigated the role of the sacrificial oxidant CAN in driving the catalytic cycle. Our DFT and TD-DFT calculations confirm the experimental observation that 2(IV) is the resting species, and indicate that the catalytic cycle in which the Fe oxidation states of the intermediate species remain at +4 is energetically more favorable. PMID- 23025900 TI - Apis mellifera venom induces different cell death pathways in Trypanosoma cruzi. AB - Chagas disease chemotherapy is based on drugs that exhibit toxic effects and have limited efficacy, such as Benznidazole. Therefore, research into new chemotherapeutic agents from natural sources needs to be exploited. Apis mellifera venom consists of many biologically active molecules and has been reported to exhibit remarkable anti-cancer effects, often promoting an apoptosis like death phenotype. This study demonstrates that A. mellifera venom can affect the growth, viability and ultrastructure of all Trypanosoma cruzi developmental forms, including intracellular amastigotes, at concentrations 15- to 100-fold lower than those required to cause toxic effects in mammalian cells. The ultrastructural changes induced by the venom in the different developmental forms led us to hypothesize the occurrence of different programmed cell death pathways. Autophagic cell death, characterized by the presence of autophagosomes-like organelles and a strong monodansyl cadaverine labelling, appears to be the main death mechanism in epimastigotes. In contrast, increased TUNEL staining, abnormal nuclear chromatin condensation and kDNA disorganization was observed in venom treated trypomastigotes, suggesting cell death by an apoptotic mechanism. On the other hand, intracellular amastigotes presented a heterogeneous cell death phenotype profile, where apoptosis-like death seemed to be predominant. Our findings confirm the great potential of A. mellifera venom as a source for the development of new drugs for the treatment of neglected diseases such as Chagas disease. PMID- 23025901 TI - Effects of high-fat chow on heart tissue in acute and chronic experimental murine schistosomiasis mansoni. AB - This study aimed to investigate myocardial injuries in mice infected with Schistosoma mansoni and fed a high-fat chow. Sections of myocardial tissue from S. mansoni-infected mice, and controls that had been killed 9 and 17 weeks post infection, were stained with H&E and Picrosirius red. Histopathological examination, stereological design-based method (optical disector) and morphometry (vessels, cardiomyocytes and an amount of collagen) were used. Data were analysed using two-way ANOVA. Regardless of time of infection, myocardial tissue from the infected mice fed high-fat chow showed myocarditis characterized by a higher number of inflammatory foci, several areas displaying coagulation of cardiac fibres, a greater loss of cardiomyocytes and fibroblast proliferation than in the standard chow control. Comparing infected mice from acute and chronic infections, a higher cardiomyocyte hyperplasia (P < 0.0001) and higher amounts of collagen (P < 0.05) were observed than in standard chow control. In addition, all animals fed high-fat chow showed lower numerical density and total number of cardiomyocytes (P < 0.05), thicker vessel walls and narrowed luminal intramyocardial vessels (P > 0.05) than in the standard chow control. Altogether the data supported the view that a double burden has a synergistic deleterious effect on the myocardial tissue. PMID- 23025902 TI - Consistent differences in macroparasite community composition among populations of three-spined sticklebacks, Gasterosteus aculeatus L. AB - Parasite ecologists are often interested in the repeatability of patterns in parasite communities in space and/or time, because of implications for the dynamics of host-parasite interactions. Field studies usually examine temporal and spatial variation in isolation or limit themselves to a small number of host populations. Here, we studied the macroparasite communities of 12 populations of three-spined stickleback, Gasterosteus aculeatus L., on North Uist, Scotland, separated by small geographical distances, during the breeding season in 2 consecutive years (2007 and 2008) to determine: (1) the extent of spatial variation in macroparasite communities, (2) whether this variation is consistent across years, and (3) whether habitat characteristics can explain differences in macroparasite community composition among populations. We found substantial variation in parasite communities among populations. Generally, measures of parasite community composition were higher in 2008 than in 2007, but this effect of year was consistent across populations, such that the relative differences in these measures among populations changed little between years. These data suggest that there is short-term stability in the spatial variation in macroparasite communities of North Uist sticklebacks. However, none of the 5 habitat characteristics measured explained spatial variation in any measure of parasite community composition. PMID- 23025903 TI - The role of the invasive polychaete Ficopomatus enigmaticus (Fauvel, 1923) (Serpulidae) as facilitator of parasite transmission in Mar Chiquita coastal lagoon (Buenos Aires, Argentina). AB - In Mar Chiquita coastal lagoon (Argentina), the reefs of the invasive polychaete Ficopomatus enigmaticus (Serpulidae) serve as concentration areas for invertebrates and vertebrates and as potential foci of parasite transmission (mainly digeneans). To analyse the role of F. enigmaticus as facilitator of parasite transmission, and to evaluate the influence of the habitats selected by 2 species of cochliopid snails (Heleobia conexa and Heleobia australis), on the richness and on the prevalence of the digenean assemblages that parasitize them, 1945 snails were collected from 2 sampling sites. The comparisons between larval digenean communities parasitizing both snail hosts revealed significant differences related to the overall prevalence and the prevalence contributed by birds in the snails collected from reefs. These results support the idea that the reefs may increase the number of links between intermediate and definitive hosts of digeneans, facilitating parasite transmission only when the aggregates of F. enigmaticus become the unique habitat of the snail host. This first report of an exotic species acting as facilitator of parasite transmission in an estuarine area highlights the importance of analysing the effects of the assimilation process of exotic species by recently colonized environments (including the possible effects on parasite transmission). PMID- 23025905 TI - Kaczmarzyc et al.: A systematic review of the recurrence rate for keratocystic odontogenic tumour in relation to treatment modalities. PMID- 23025906 TI - Instructor comfort level in high-fidelity simulation. AB - BACKGROUND: The literature in the use of simulation in nursing education has expanded significantly over the past 5-10 years. What it is like as an instructor who facilitates this experience is largely unexplored. This paper is part of a larger ethnographic study, and represents findings related to the comfort level of instructors facilitating in high-fidelity simulation (HFS). OBJECTIVES: The question of what is it like to engage in simulated clinical experiences as an instructor is presented in this paper. DESIGN AND PARTICIPANTS: Twenty instructors participated in two separate focus groups and two instructors participated in individual interviews. The average years of nursing experience for this group was over 20 years, whereas the number of years of experience as a clinical instructor was less than five years. METHODS: Ethical approval was obtained from two academic institutions. A focused ethnography was conducted and included two terms of participant observations, recorded field notes, individual interviews and focus groups. Data was coded and then sorted for themes related to the instructor experience. RESULTS: The primary results focus on the comfort level of instructors in HFS, and what instructors believe this meant to student learning in HFS. CONCLUSIONS: What the instructor does during HFS and how they feel about their ability to facilitate HFS has a perceived effect on student learning. PMID- 23025904 TI - Up-regulation of platelet-derived growth factor-A is responsible for the failure of re-initiated interferon alpha treatment in hepatocellular carcinoma. AB - BACKGROUND: Postoperative interferon-alpha(IFN-alpha) treatment delays hepatocellular carcinoma(HCC) recurrence and prolongs patient survival, and may thus be an effective form of adjuvant therapy. However, clinical observations found that HCC recurs in some patients within 8 months of IFN-alpha treatment being discontinued. We investigated whether HCC regrowth appears after IFN-alpha is discontinued, whether re-initiated IFN-alpha is effective, and the underlying mechanisms of IFN-alpha treatment. METHODS: The human HCC nude mouse model LCI D20 was used to study the effects of IFN-alpha treatment, discontinued IFN-alpha treatment, and re-initiated IFN-alpha treatment on tumor growth. Tumor weight, microvessel density(MVD), serum vascular endothelial growth factor (VEGF), and tumor cell apoptosis were analyzed. Angiogenesis-related factors were studied using cDNA microarray in different tumor samples and confirmed using reverse transcription-polymerase chain reaction(RT-PCR) and Western blotting assays. Finally, imatinib was added with re-initiated IFN-alpha treatment to improve efficacy. RESULTS: IFN-alpha (1.5 * 107 U/kg/day for 20 days) suppressed HCC growth by 60.3% and decreased MVD by 52.2% compared with the control. However, tumor regrowth occurred after IFN-alpha was discontinued, and re-initiated IFN alpha treatment was not effective for inhibiting tumor growth or reducing MVD compared with a saline-treated group. cDNA microarray showed VEGF was down regulated while platelet-derived growth factor-A (PDGF-A) was up-regulated when IFN-alpha treatment was re-initiated. These findings were further confirmed with RT-PCR and Western blotting assay. The combination of imatinib with re-initiated IFN-alpha reduced HCC weight by 30.7% and decreased MVD by 31.1% compared with IFN-alpha treatment only (P=0.003 and 0.015, respectively). CONCLUSION: Tumor regrowth occurred after IFN-alpha treatment was discontinued. Re-initiated IFN alpha treatment was not effective and was associated with up-regulation of PDGF A, while the VEGF remained suppressed. The combination of a PDGF-receptor inhibitor with IFN-alpha improved the effect of the re-initiated treatment. PMID- 23025907 TI - Transitional flow analysis in the carotid artery bifurcation by proper orthogonal decomposition and particle image velocimetry. AB - Blood flow instabilities in the carotid artery bifurcation have been highly correlated to clot formation and mobilization resulting in ischemic stroke. In this work, PIV-measured flow velocities in normal and stenosed carotid artery bifurcation models were analyzed by means of proper orthogonal decomposition (POD). Through POD analysis, transition to more complex flow was visualized and quantified for increasing stenosis severity. While no evidence of transitional flow was seen in the normal model, the 50%-stenosed model started to show characteristics of transitional flow, which became highly evident in the 70% model, with greatest manifestation during the systolic phase of the cardiac cycle. By means of a model comparison, we demonstrate two quantitative measures of the flow complexity through the power-law decay slope of the energy spectrum and the global entropy. The more complex flow in the 70%-stenosed model showed a flatter slope of energy decay (-0.91 compared to -1.34 for 50% stenosis) and higher entropy values (0.26 compared to 0.17). Finally, the minimum temporal resolution required for POD analysis of carotid artery flow was found to be 100 Hz when determined through a more typical energy-mode convergence test, as compared to 400 Hz based on global entropy values. PMID- 23025909 TI - Mechanistic assessment of S(N)Ar displacement of halides from 1-halo-2,4 dinitrobenzenes by selected primary and secondary amines: Bronsted and Mayr analyses. AB - Pseudo-first-order rate constants (k(obsd)) have been measured spectrophotometrically for nucleophilic substitution reactions of 1-X-2,4 dinitrobenzenes (1a-d, X = F, Cl, Br, I) with various primary and secondary amines in MeCN and H(2)O at 25.0 +/- 0.1 degrees C. The plots of k(obsd) vs [amine] curve upward for reactions of 1a (X = F) with secondary amines in MeCN. In contrast, the corresponding plots for the other reactions of 1b-d with primary and secondary amines in MeCN and H(2)O are linear. The Bronsted-type plots for reactions of 1a-d with a series of secondary amines are linear with beta(nuc) = 1.00 for the reaction of 1a and 0.52 +/- 0.01 for those of 1b-d. Factors governing reaction mechanisms (e.g., solvent, halogen atoms, H-bonding interactions, amine types) have been discussed. Kinetic data were also analyzed in terms of the Mayr nucleophilicity parameter for the amines with each aromatic substrate. Provisional Mayr electrophilicity parameter (E) values for 1-X-2,4 dinitrobenzenes have been determined: E = -14.1 for X = F, E = -17.6 for X = Cl and Br, and E = -18.3 for X = I. These values are consistent with the range and order of E values for heteroaromatic superelectrophiles and normal 6-pi aromatic electrophiles. PMID- 23025910 TI - Gallbladder cancer: past, present and an uncertain future. AB - Although gallbladder cancer (GBC) is the most common malignancy of the biliary tract, its relatively low incidence and confounding symptomatology result in advanced disease at the time presentation, contributing to the poor prognosis and decreased survival associated with this disease. It is therefore increasingly important to understand its pathogenesis and risk factors to allow for the earliest possible diagnosis. To date, gallbladder cancer is poorly understood compared to other malignancies, and is still most commonly discovered incidentally after cholecystectomy. Moreover, while much is known about biliary neoplasms as a whole, understanding the clinical and molecular nuances of GBC as a separate disease process will prove a cornerstone in the development of early intervention, potential screening and overall more effective treatment strategies. The present work reviews the most current understanding of the pathogenesis, diagnosis, staging and natural history of GBC, with additional focus on surgical treatment. Further, review of current adjuvant therapies for unresectable and advanced disease as well as prognostic factors provide fertile ground for the development of future studies which will hopefully improve treatment outcomes and affect overall survival for this highly morbid, poorly understood malignancy. PMID- 23025911 TI - Clinical and pathological analysis of malignancies arising from alimentary tract duplications. AB - BACKGROUND: Malignant change is a rare complication of alimentary tract duplications. METHODS: Articles concerning malignancies arising from alimentary tract duplications published from 1955 to 2012 on PubMed were extensively reviewed. These cases were reclassified and analyzed according to sites of clinical manifestations, diagnostic examinations, methods of management, pathological findings, clinical staging and prognosis. RESULTS: There were 64 citations in the literature that provided adequate descriptions of 67 cases of malignancies arising from alimentary tract duplications near the oesophagus (n = 6), stomach (n = 10), small intestine (n = 19), appendix (n = 1) and large intestine (n = 31). Among the cases described above, 57 underwent surgical treatment. In 43 patients with known prognosis, 7 died of tumour progression. In another 5 cases, the tumours recurred and metastasized recurred and metastasised after surgery at an average of 11.4 months. CONCLUSIONS: For relieving symptoms and preventing malignant change, all duplications should be considered for surgery. Unfortunately, prognosis is generally poor once malignancy has occurred in the duplications. PMID- 23025912 TI - New horizons for antiviral drug discovery from virus-host protein interaction networks. AB - Viruses are recurrent socio economical and health problems each year worldwide. Current drugs are mainly directed against viral components and select resistant strains that urge the need to develop new antiviral therapeutics. High-throughput screening technologies now allow to draw comprehensive genome-wide maps of physical and genetic virus-host interactions. This has been done recently for several viruses such as HIV, HCV, DENV and FLUAV and revealed a wealth of potential antiviral cellular targets. Systems-level analysis of virus-host protein networks and subnetworks begins to uncover several specific points of intervention for a human centered drug development. We present here this new paradigm in antiviral drug discovery together with the first promising antiviral molecules. PMID- 23025913 TI - Staying ahead of viruses: a never ending task. PMID- 23025914 TI - Closing the gap: the challenges in converging theoretical, computational, experimental and real-life studies in virus evolution. PMID- 23025915 TI - The role of the surgeon in the application of the scientific method to new orthopaedic devices. PMID- 23025916 TI - Drug-drug interactions between antiretroviral and immunosuppressive agents in HIV infected patients after solid organ transplantation: a review. AB - Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive therapy proved to be extremely challenging, as witnessed by high rates of allograft rejection and drug toxicity, but the profound drug-drug interactions between immunosuppressants and cART, especially protease inhibitors (PIs) also play an important role. Caution and frequent drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients. Furthermore, the pharmacokinetics of glucocorticoids and mTOR inhibitors are seriously affected by PIs. With the introduction of integrase inhibitors, CCR5-antagonists and fusion inhibitors which cause significantly less pharmacokinetic interactions, have minor overlapping toxicity, and offer the advantage of pharmacodynamic synergy, it is time to revaluate what may be considered the optimal antiretroviral regimen in SOT recipients. In this review we provide a brief overview of the recent success of SOT in the HIV population, and an update on the pharmacokinetic and pharmacodynamic interactions between currently available cART and immunosuppressants in HIV-infected patients, who underwent SOT. PMID- 23025918 TI - The fifth electron in the fully reduced caa(3) from Thermus thermophilus is competent in proton pumping. AB - The time-resolved kinetics of membrane potential generation coupled to oxidation of the fully reduced (five-electron) caa(3) cytochrome oxidase from Thermus thermophilus by oxygen was studied in a single-turnover regime. In order to calibrate the number of charges that move across the vesicle membrane in the different reaction steps, the reverse electron transfer from heme a(3) to heme a and further to the cytochrome c/Cu(A) has been resolved upon photodissociation of CO from the mixed valence enzyme in the absence of oxygen. The reverse electron transfer from heme a(3) to heme a and further to the cytochrome c/Cu(A) pair is resolved as a single transition with tau~40 MUs. In the reaction of the fully reduced cytochrome caa(3) with oxygen, the first electrogenic phase (tau~30 MUs) is linked to OO bond cleavage and generation of the P(R) state. The next electrogenic component (tau~50 MUs) is associated with the P(R)->F transition and together with the previous reaction step it is coupled to translocation of about two charges across the membrane. The three subsequent electrogenic phases, with time constants of ~0.25 ms, ~1.4 ms and ~4 ms, are linked to the conversion of the binuclear center through the F->O(H)->E(H) transitions, and result in additional transfer of four charges through the membrane dielectric. This indicates that the delivery of the fifth electron from heme c to the binuclear center is coupled to pumping of an additional proton across the membrane. PMID- 23025919 TI - Zinc, cadmium, and mercury complexes of a pyridyloxy-substituted cyclotriphosphazene: syntheses, structures, and fluxional behavior. AB - The synthesis and characterization of the fluxional, d(10) cyclotriphosphazene complexes, [MLCl(2)] (M = Zn, Cd, and Hg; L = spiro-[(1,1'-biphenyl)-2,2' dioxy]tetrakis(4-methyl-2-pyridyloxy)cyclotriphosphazene), are described. Single crystal X-ray structures show that the zinc complex has crystallized into two crystal forms: one as a tetrahedral species, with a N(2)Cl(2) donor set in which a geminal pair of the pendant pyridyloxy nitrogen atoms binds to the zinc, and the other as a trigonal-bipyramidal (tbp) one, with an N(3)Cl(2) donor set. The third nitrogen atom comes from the phosphazene ring and the two pyridyl ligands are non-geminal. The asymmetric unit of the cadmium complex contains three structurally distinct molecules. One molecule has a tbp structure similar to that of the zinc complex. The second molecule has a six-coordinate, distorted octahedral geometry around the cadmium center with a N(4)Cl(2) donor set, with three of the nitrogen donor atoms coming from the pendant pyridyloxy arms. The third site contains a tbp complex and a distorted octahedral species with a relative occupancy of 3:1. The identification of these three different forms in the one crystal suggests that the energy difference between the tbp and distorted octahedral isomers is not large. Quantitative analysis of the (1)H NMR and variable-temperature (31)P NMR spectra of the zinc, cadmium, and mercury complexes in a CD(2)Cl(2) solution, coupled with the X-ray structural results, shows that an associative fluxional mechanism (DeltaS(++) < -65 J mol(-1) K(-1)) is operating. PMID- 23025920 TI - Use of diagnostic information submitted to the United Kingdom Central Cardiac Audit Database: development of categorisation and allocation algorithms. AB - OBJECTIVE: To categorise records according to primary cardiac diagnosis in the United Kingdom Central Cardiac Audit Database in order to add this information to a risk adjustment model for paediatric cardiac surgery. DESIGN: Codes from the International Paediatric Congenital Cardiac Code were mapped to recognisable primary cardiac diagnosis groupings, allocated using a hierarchy and less refined diagnosis groups, based on the number of functional ventricles and presence of aortic obstruction. SETTING: A National Clinical Audit Database. Patients Children undergoing cardiac interventions: the proportions for each diagnosis scheme are presented for 13,551 first patient surgical episodes since 2004. RESULTS: In Scheme 1, the most prevalent diagnoses nationally were ventricular septal defect (13%), patent ductus arteriosus (10.4%), and tetralogy of Fallot (9.5%). In Scheme 2, the prevalence of a biventricular heart without aortic obstruction was 64.2% and with aortic obstruction was 14.1%; the prevalence of a functionally univentricular heart without aortic obstruction was 4.3% and with aortic obstruction was 4.7%; the prevalence of unknown (ambiguous) number of ventricles was 8.4%; and the prevalence of acquired heart disease only was 2.2%. Diagnostic groups added to procedural information: of the 17% of all operations classed as "not a specific procedure", 97.1% had a diagnosis identified in Scheme 1 and 97.2% in Scheme 2. CONCLUSIONS: Diagnostic information adds to surgical procedural data when the complexity of case mix is analysed in a national database. These diagnostic categorisation schemes may be used for future investigation of the frequency of conditions and evaluation of long-term outcome over a series of procedures. PMID- 23025921 TI - End-of-life decisions and the reinvented Rule of Double Effect: a critical analysis. AB - The Rule of Double Effect (RDE) holds that it may be permissible to harm an individual while acting for the sake of a proportionate good, given that the harm is not an intended means to the good but merely a foreseen side-effect. Although frequently used in medical ethical reasoning, the rule has been repeatedly questioned in the past few decades. However, Daniel Sulmasy, a proponent who has done a lot of work lately defending the RDE, has recently presented a reformulated and more detailed version of the rule. Thanks to its greater precision, this reinvented RDE avoids several problems thought to plague the traditional RDE. Although an improvement compared with the traditional version, we argue that Sulmasy's reinvented RDE will not stand closer scrutiny. Not only has the range of proper applicability narrowed significantly, but, more importantly, Sulmasy fails to establish that there is a morally relevant distinction between intended and foreseen effects. In particular, he fails to establish that there is any distinction that can account for the alleged moral difference between sedation therapy and euthanasia. PMID- 23025922 TI - Phospholipases A2: unveiling the secrets of a functionally versatile group of snake venom toxins. AB - Phospholipases A(2) (PLA(2)s) are abundant components of snake venoms, where they play toxic and digestive roles. Despite having a similar three-dimensional structure, venom PLA(2)s exert an amazing variety of toxic and pharmacological effects, which include neurotoxic, myotoxic, hemolytic, edematogenic, hyperalgesic, pro-inflammatory, hypotensive, platelet-aggregation inhibitory, anticoagulant, cytotoxic, and bactericidal activities. Toxinologists have made significant contributions to deciphering the structure, molecular evolution, mechanisms of action, receptors, role of enzymatic activity for toxicity, structural determinants of toxicity and selectivity, and the impact of these enzymes in the overall pathophysiology of snakebite envenoming. The present work highlights some of the most relevant contributions in the study of venom PLA(2)s, including the personal accounts of the authors of these studies. PMID- 23025923 TI - Autobiographical memory and sense of self. AB - Despite a strong intuitive and theoretical tradition linking autobiographical memory and sense of self, there are few coherent, testable models that exemplify how these constructs relate. Without any clear theoretical starting point, research efforts have been fragmented, with many different fields of psychology operating in relative isolation, using different methodological approaches and a confusing array of self-related terminology. We attempt to bridge the widening gap between theory and research by proposing a novel framework for sense of self and memory. This simple model delineates sense of self along 2 dimensions: the subjective versus objective and the present versus temporally extended aspects of sense of self. The 4 resulting components of sense of self are argued to relate to autobiographical memory in important, but very different, ways. Subjective sense of self provides a crucial precondition for episodic memory, which in turn is a prerequisite for phenomenological continuity. Autobiographical memory, and particularly its semanticized forms, are important for the formation and maintenance of a mental representation of the objective self in the present moment and across time. This model does not represent a new theoretical direction for the study of sense of self and memory; to the contrary, it is deeply grounded in the theoretical work of the past few decades. Its novelty is that it translates this theoretical groundwork into a form that is readily accessible for researchers. We review evidence for our model and suggest ways that it may provide a roadmap for future research efforts. PMID- 23025924 TI - Vantage sensitivity: individual differences in response to positive experiences. AB - The notion that some people are more vulnerable to adversity as a function of inherent risk characteristics is widely embraced in most fields of psychology. This is reflected in the popularity of the diathesis-stress framework, which has received a vast amount of empirical support over the years. Much less effort has been directed toward the investigation of endogenous factors associated with variability in response to positive influences. One reason for the failure to investigate individual differences in response to positive experiences as a function of endogenous factors may be the absence of adequate theoretical frameworks. According to the differential-susceptibility hypothesis, individuals generally vary in their developmental plasticity regardless of whether they are exposed to negative or positive influences--a notion derived from evolutionary reasoning. On the basis of this now well-supported proposition, we advance herein the new concept of vantage sensitivity, reflecting variation in response to exclusively positive experiences as a function of individual endogenous characteristics. After distinguishing vantage sensitivity from theoretically related concepts of differential-susceptibility and resilience, we review some recent empirical evidence for vantage sensitivity featuring behavioral, physiological, and genetic factors as moderators of a wide range of positive experiences ranging from family environment and psychotherapy to educational intervention. Thereafter, we discuss genetic and environmental factors contributing to individual differences in vantage sensitivity, potential mechanisms underlying vantage sensitivity, and practical implications. PMID- 23025927 TI - Dual inversion recovery ultrashort echo time (DIR-UTE) imaging and quantification of the zone of calcified cartilage (ZCC). AB - OBJECTIVE: To develop ultrashort echo time (UTE) magnetic resonance imaging (MRI) techniques to image the zone of calcified cartilage (ZCC), and quantify its T2*, T1 and T1rho. DESIGN: In this feasibility study a dual inversion recovery UTE (DIR-UTE) sequence was developed for high contrast imaging of the ZCC. T2* of the ZCC was measured with DIR-UTE acquisitions at progressively increasing TEs. T1 of the ZCC was measured with saturation recovery UTE acquisitions at progressively increasing saturation recovery times. T1rho of the ZCC was measured with spin locking prepared DIR-UTE acquisitions at progressively increasing spin-locking times. RESULTS: The feasibility of the qualitative and quantitative DIR-UTE techniques was demonstrated on phantoms and in six cadaveric patellae using a clinical 3 T scanner. On average the ZCC has a short T2* ranging from 1.0 to 3.3 ms (mean +/- standard deviation = 2.0 +/- 1.2 ms), a short T1 ranging from 256 to 389 ms (mean +/- standard deviation = 305 +/- 45 ms), and a short T1rho ranging from 2.2 to 4.6 ms (mean +/- standard deviation = 3.6 +/- 1.2 ms). CONCLUSION: UTE MR based techniques have been developed for high resolution imaging of the ZCC and quantitative evaluation of its T2*, T1 and T1rho relaxation times, providing non-invasive assessment of collagen orientation and proteoglycan content at the ZCC and the bone cartilage interface. These measurements may be useful for non-invasive assessment of the ZCC, including understanding the involvement of this tissue component in osteoarthritis. PMID- 23025928 TI - Characterization of nitrotyrosine as a biomarker for arthritis and joint injury. AB - OBJECTIVES: To characterize the utility of nitrotyrosine (NT) as a biomarker for arthritis and joint injury. DESIGN: Synovial fluid, plasma, and urine from patients diagnosed with osteoarthritis (OA), rheumatoid arthritis (RA), anterior cruciate ligament (ACL) injury, meniscus injury and pseudogout, and knee-healthy volunteers were analyzed for concentrations of NT, nitrate and nitrite (NO(x)), matrix metalloproteinase (MMP)-3, MMP-1, MMP-9, more than 40 chemokines and cytokines. RESULTS: In OA, plasma and synovial fluid NT were increased versus healthy volunteers. Synovial fluid to plasma NT ratios were elevated in OA patients. Synovial fluid from patients with ACL and meniscus injury and pseudogout had increased levels of NT (P < 0.001). In these samples, NT levels significantly correlated with ARGS-aggrecan neoepitope generated by aggrecanase cleavage of aggrecan (P <= 0.001), cross-linked C-telopeptides of type II collagen (P < 0.001), MMP-1 (P = 0.008), and MMP-3 (P <= 0.001). In RA, plasma NT decreased following 6 months of anti-tumor necrosis factor (TNF) treatment. For every 1.1% change in log(10) NT, there was a 1.0% change in the log(10) disease activity scores (DAS28-3 CRP). Both predicted and observed DAS28-3 CRP showed a robust linear relationship with NT. RA plasma NT positively correlated with CRP, MMP-3 and interferon gamma-induced protein 10. CONCLUSIONS: NT may serve as a useful biomarker for arthritis and joint injury. In RA, NT is highly correlated with several biomarkers and clinical correlates of disease activity and responds to anti-TNF therapy. PMID- 23025926 TI - Bone and cartilage demonstrate changes localized to bone marrow edema-like lesions within osteoarthritic knees. AB - OBJECTIVE: Our objective is to understand the biological and mechanical pathways linking cartilage, bone, and marrow changes in the progression of osteoarthritis (OA). The aim of the present study was to evaluate bone structure and composition within bone marrow edema-like lesion (BMEL) regions associated with knee OA. METHODS: Tibial plateau specimens (n = 18) were collected from 10 subjects with knee OA during total knee arthroplasty (TKA). Magnetic resonance (MR) imaging was used to identify BMEL and quantify metrics of cartilage composition. Micro computed tomography (MUCT) and high-resolution peripheral quantitative computed tomography (HR-pQCT) were used to quantify density and microstructure of the subchondral trabecular bone. Fourier transform infrared (FTIR) spectroscopy was used to quantify tissue composition. RESULTS: Trabecular bone within BMEL was higher in volume fraction, with more and thicker trabeculae that were more plate like in structure compared to unaffected regions. BMEL trabecular tissue composition had decreased phosphate and carbonate content. Marrow infiltration by a fibrous collagen network and evidence of increased bone remodeling were present. Structural and compositional changes were specifically localized to regions underlying cartilage degradation. CONCLUSION: These results support the paradigm of focal interactions among bone, marrow, and cartilage in the progression of knee OA. Quantitative evaluation of tissue changes and interactions may aid in the understanding of disease pathophysiology and provide imaging markers for disease progression. PMID- 23025929 TI - Usefulness of specific OA biomarkers, thrombin-cleaved osteopontin, in the posterior cruciate ligament OA rabbit model. AB - OBJECTIVE: We undertook this study to determine whether thrombin-cleaved osteopontin (OPN) in synovial fluid (SF) represents a useful marker of osteoarthritis (OA) progression in the posterior cruciate ligament transection (PCLT) OA rabbit model. METHOD: PCLT was performed on the right knee joints of 48 rabbits. The rabbits were then sacrificed separately at 4, 8, 16, and 24 weeks post-surgery, when the joint was harvested and macroscopic and histological assessments of articular cartilage were performed. Thrombin-cleaved OPN product in SF was determined using Western blotting and the levels were measured using an enzyme-linked immunoassay. RESULTS: The macroscopic and histological scores for PCLT knees were already elevated 4 weeks after surgery and increased with time. Western blotting showed the presence of thrombin-cleaved OPN in SF from PCLT knees. Thrombin-cleaved OPN levels in SF were elevated at 4 weeks (P < 0.001) and were elevated peaking at 24 weeks (P < 0.00001) after PCLT compared to baseline. A positive significant correlation was found between thrombin-cleaved OPN levels and the macroscopic scores (8 weeks: rho = 0.695, P = 0.012; 16 weeks: rho = 0.751, P = 0.005; 24 weeks: rho = 0.660, P = 0.020). Furthermore, the same correlation was noted between thrombin-cleaved OPN levels and the histological scores (4 weeks: rho = 0.609, P = 0.036; 8 weeks: rho = 0.662, P = 0.019; 16 weeks: rho = 0.827, P = 0.001; 24 weeks: rho = 0.813, P = 0.001). CONCLUSION: In this rabbit model of PCLT, thrombin-cleaved OPN levels in SF appear to provide a useful marker of OA disease severity and progression. PMID- 23025925 TI - Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. AB - Phase II metabolic enzymes are a battery of critical proteins that detoxify xenobiotics by increasing their hydrophilicity and enhancing their disposal. These enzymes have long been studied for their preventative and protective effects against mutagens and carcinogens and for their regulation via the Keap1 (Kelch-like ECH associated protein 1)/Nrf2 (Nuclear factor erythroid 2 related factor 2)/ARE (antioxidant response elements) pathway. Recently, a series of studies have reported the altered expression of phase II genes in postmortem tissue of patients with various neurological diseases. These observations hint at a role for phase II enzymes in the evolution of such conditions. Furthermore, promising findings reveal that overexpression of phase II genes, either by genetic or chemical approaches, confers neuroprotection in vitro and in vivo. Therefore, there is a need to summarize the current literature on phase II genes in the central nervous system (CNS). This should help guide future studies on phase II genes as therapeutic targets in neurological diseases. In this review, we first briefly introduce the concept of phase I, II and III enzymes, with a special focus on phase II enzymes. We then discuss their expression regulation, their inducers and executors. Following this background, we expand our discussion to the neuroprotective effects of phase II enzymes and the potential application of Nrf2 inducers to the treatment of neurological diseases. PMID- 23025930 TI - Examining the measurement of novel drug perceptions: Salvia divinorum, gender, and peer substance use. AB - Researchers commonly use a person's perception of the drug use of friends to determine the impact that peers exert on one's own behavior. Recently, there has been concern over this measure's validity. Novel drugs, which are either newly discovered drugs or existing substances only recently used for recreational purposes, may be used so infrequently that people have too few observable opportunities to accurately develop perceptions of their peer's use. Employing survey data collected in 2009 from 2,154 individuals within friendship pairs in the Southeast United States, we explore how gender affects perceptions of the infrequently used, novel drug Salvia divinorum. The study's limitations are noted. PMID- 23025931 TI - Predictive factors of acute renal failure in colon and rectal surgery. AB - Postoperative acute renal failure (ARF) is a major factor of morbidity and mortality in colon and rectal surgery. The objectives of this study were: 1) to determine the frequency of ARF in colorectal surgery; and 2) to evaluate the impact of patient characteristics, comorbidities, resection type, pathology, surgical technique, and admission type on ARF. Using the National Inpatient Sample database, we examined the clinical data of patients who underwent colon and rectal resection from 2006 to 2008. A total of 975,825 patients underwent colorectal resection during this period. Overall, the rate of ARF was 7.41 per cent (elective surgery: 3.38% vs emergent surgery: 12.99% ; P<0.01). Using multivariate regression analysis, chronic renal failure (adjusted odds ratio [AOR], 5.37), emergent operation (AOR, 2.64), total colectomy (AOR, 2.61), age 65 years or older (AOR, 2.02), liver disease (AOR, 1.82), congestive heart failure (AOR, 1.81), alcohol abuse (AOR, 1.67), peripheral vascular disease (AOR, 1.50), obesity (AOR, 1.45), malignant tumor (AOR, 1.44), open operation (AOR, 1.37), male sex (AOR, 1.37), left colectomy (AOR, 1.32), black race (AOR, 1.22), and teaching hospital (AOR, 1.05) were associated with higher risk of ARF. There was no association between hypertension, diabetes, chronic lung disease, smoking, transverse colectomy, proctectomy, diverticulitis, ulcerative colitis, or Crohn's disease and ARF. Chronic renal failure, emergent operation, total colectomy and age 65 years or older are potent independent predictors of ARF. In high-risk circumstances, specific care should be taken to prevent renal insults. PMID- 23025932 TI - Predictive factors of acute respiratory failure in esophagectomy for esophageal malignancy. AB - Acute respiratory failure (ARespF) is a common complication after esophagectomy that contributes to higher morbidity and mortality. Using the Nationwide Inpatient Sample database, we sought to identify predictors of ARespF in 6352 patients who underwent esophagectomy for malignancy between 2006 and 2008. Multivariate regression analyses were performed to identify preoperative factors (patient characteristics, comorbidities, procedural type, tumor's location, hospital teaching status, and payer type) predictive of ARespF in esophagectomy. The overall rate of ARespF was 27.08 per cent. For comorbidities, independent risk factors for higher rate of ARF included weight loss (adjusted odds ratio [AOR], 3.63; 95% confidence interval [CI], 3.02 to 4.37), pulmonary hypertension (AOR, 2.38; 95% CI, 1.85 to 3.45), congestive heart failure (AOR, 2.35; 95% CI, 1.77 to 3.13), liver disease (AOR, 1.95; 95% CI, 1.22 to 3.12), chronic lung disease (AOR, 1.40; 95% CI, 1.17 to 1.66), and anemia (AOR, 1.26; 95% CI, 1.04 to 1.51). Cervical location of malignancy (AOR, 2.32; 95% CI, 1.51 to 3.56), total esophagectomy (AOR, 1.64; 95% CI, 1.41 to 1.90), and nonteaching hospital (AOR, 1.45; 95% CI, 1.20 to 1.75) were independent risk factors for ARespF. There was no effect of age, gender, race, hypertension, diabetes, renal failure, obesity, smoking, peripheral vascular disorder, or payer type on ARespF. We identified multiple preoperative risk factors that have an impact on development of ARespF after esophagectomy. Surgeons can use these factors to inform patients of potential risks and should consider these factors during surgical-decision making. PMID- 23025933 TI - Analysis of radiation exposure during endovascular aneurysm repair. AB - Endovascular aneurysm repair (EVAR) is now the preferred procedure for abdominal aortic aneurysm repair. As a result of the need for fluoroscopy during EVAR, radiation exposure is a potential hazard. We studied the quantity of radiation delivered during EVAR to identify risks for excessive exposure. Fluoroscopy time, contrast volume used, and procedural details were recorded prospectively during EVARs. Using data collected from similar EVARs, an equation was derived to calculate approximate dose-area product (DAP) from fluoroscopy time. DAP values were then compared between procedures in which a relevant postdeployment procedure (PDP) was necessary intraoperatively with those without. Clinical data on 17 patients were collected. The mean age of patients was 68 (+/-9) years. Fluoroscopy times and approximate DAP values were found to be significantly higher in the seven patients with a PDP compared with the 10 patients without an intraoperative PDP (31.2 [+/-9.6] vs 22.7 [+/-6.0] minutes, P=0.033 and 537 [+/ 165] vs 390 [+/-103] Gy.cm2, P=0.033, respectively). The average amount of contrast volume used was not significantly different between groups. Radiation emitted during EVARs with PDPs was significantly greater relative to those without PDPs. Device design and operators should thus aim to decrease PDPs and to minimize fluoroscopy time. PMID- 23025934 TI - Robotic-assisted extralevator abdominoperineal resection in the lithotomy position: technique and early outcomes. AB - Extralevator abdominoperineal resection (E-APR) has been advocated as a superior procedure to achieve negative circumferential resection margins (CRMs) for sphincter-invading rectal cancers. An open total mesorectal excision is performed followed by perineal dissection with resection of the levators in the prone position. We describe a novel minimally invasive robotic approach carried out in the lithotomy position. Using the robotic arms to dissect the rectum and divide the levator fibers at their origin, the dissection is carried out in the ischiorectal space as distally as possible. From May to July 2011, six cases of robotic E-APR for rectal cancer were performed. The mean age was 54.5 years old. Mean operating time was 335 minutes. Mean estimated blood loss was 250 mL. There were no conversions to the open approach. A cylindrical specimen was obtained in all patients without perforation. All CRMs were negative. Mean hospital stay was 5 days. Two patients developed perineal wound infections and one developed a small bowel obstruction postoperatively. Robotic-assisted E-APR performed in the lithotomy position is safe and feasible. Future studies are needed to define the benefits of this technique. PMID- 23025935 TI - FAST enough? A validation study for focused assessment with sonography for trauma ultrasounds in a Level II trauma center. AB - The Focused Assessment with Sonography for Trauma (FAST) is widely used as the initial screening tool for abdominal trauma. Several recent studies have questioned its use. Using the Trauma Registry, 1 year of data at a Level II trauma center were reviewed. All trauma patients with dictated FAST examinations were identified. Disconcordant findings were reviewed. Predictive values for determining intraperitoneal injuries were calculated. Nine hundred seventy-four designated trauma patients were entered into the Trauma Registry. Of these, 633 had dictated FAST examinations. There were 533 true-negatives, 11 true positives, 77 false-negatives, and six false-positives. Of the 77 false negatives, 33 had retroperitoneal injuries and 25 had intraperitoneal injuries. No adverse outcomes were identified from diagnostic delay. For predicting intraperitoneal injury, FAST had a negative predictive value of 96 per cent, positive predictive value of 63 per cent, sensitivity of 29 per cent, specificity of 99 per cent, and accuracy of 95 per cent. Our data demonstrate that FAST was useful for the initial assessment of intraperitoneal injuries. FAST was 95 per cent accurate and allowed for rapid triage to operative management when indicated. The data also confirm that a negative FAST does not exclude abdominal injury. PMID- 23025936 TI - Enhanced recovery protocol: implementation at a county institution with limited resources. AB - The benefits of an enhanced recovery protocol (ERP) in colorectal surgery have been well described; however, data on the implementation process is minimal, especially in a resource-limited institution. The purpose of this study was to evaluate outcomes during implementation of a physician-driven ERP at a public funded institution. We retrospectively reviewed all elective colorectal surgery during a transition from standard care to an ERP (implemented via a standard order sheet). Data regarding use of care plan, length of stay (LOS), and rates of postoperative complications and readmission were recorded. One hundred eleven patients were included in the study; however, complete use of the ERP after its introduction occurred in a total of 50 patients for a compliance rate of 60 per cent (95% confidence interval [CI], 49 to 70). Late implementation of ERP diet, analgesics, and activity were the most common process errors. Full application of the ERP reduced mean LOS by 3 days (P=0.002), and there was a trend toward decreased postoperative morbidity without an increase in readmission rate (P=0.61). Full implementation of an ERP for colorectal surgery faces many challenges in a resource-limited county institution; however, when fully applied, the ERP safely reduced overall LOS, which is important in cost containment. PMID- 23025937 TI - Time to failure of arterial shunts in a pig hemorrhagic shock model. AB - Temporary vascular shunts (TVSs) are relied on frequently in the current military theater. Details of their physiology and outcome are of increasing interest and needed to further define their place in the management of trauma. This study was conducted using a porcine hemorrhagic shock model and aimed to 1) establish the time to failure of short, proximally placed vascular shunts; and 2) examine histological changes in the shunted artery. The external iliac artery of male pigs was transected and a straight shunt secured in place. Hemorrhagic shock was then induced by rapidly removing 40 per cent of blood volume and maintaining severe hypotension for 40 minutes before resuscitation. Animals were observed for up to 6 days for limb function as well as overall physiological status. At the conclusion of the experiment, status of the shunt and adjacent artery was evaluated by an independent pathologist. The presence of thrombi and inflammation within the proximal and distal artery was graded. Among the 10 animals tested, nine subjects survived the initial surgery. All shunts remained patent with mean time of 4.2+/-1.2 days of observation. Three-position histological analysis of the connected arterial tissues revealed minimal acute inflammation and minimal or thrombus. The results suggest that TVSs in proximal arteries remain functional for at least 48 to 72 hours in proximal arteries even without anticoagulation in the setting of brief hemorrhagic shock. This knowledge may aid combat evacuation patterns. PMID- 23025938 TI - Lymph node harvest in emergent versus elective colon resections. AB - Quality measures for prognostication of colon cancer include the removal of 12 or more lymph nodes during colon resection. The purpose of this study was to determine whether emergent surgery is associated with inadequate lymph node harvest. The National Cancer Database (NCDB) was queried for colon cancer patients operated on at Huntington Memorial Hospital, Pasadena, California, from 2005 to 2010. Demographic data, indication for surgery, surgeon, stage, lymph node harvest, tumor location, method of surgery, chemotherapy use, and survival were recorded. Univariate analyses were performed to compare lymph node harvest with the variables listed. Three hundred fifty-three patients underwent colon resection between 2005 and 2010. Two hundred ninety-six patients with Stage I to III disease underwent 253 elective (85%) and 43 emergent (15%) colectomies. There was no statistical difference between rates of adequate lymph node harvest in emergent and elective patient groups (86.0 vs 88.1%, P=0.7). Inferior long-term survival was associated with emergent indication and inferior lymph node harvest. Lymph node harvest adequacy showed a gradual increase over time from 79.5 per cent in 2005 to 95.5 per cent in 2010. Despite a perception that emergent surgery is associated with inadequate lymphadenectomy, 5-year data from Huntington Memorial Hospital participation in NCDB does not suggest inferior lymph node harvests in patients operated on for obstruction or perforation. PMID- 23025939 TI - The evolution of surgical technique for total gastrectomy over a 12-year period: a single institution's experience. AB - Despite the wide acceptance of laparoscopic surgical techniques, its use for gastric cancer has been limited. Laparoscopic total gastrectomy poses many technical challenges when compared with open gastrectomy. Our objective was to evaluate our institutional experience and surgical technique for total gastrectomy. Through a review of patients undergoing total gastrectomy (1999 to 2011), 50 patients were identified. During the first decade, 25 per cent of total gastrectomies were performed laparoscopically compared with 77 per cent since 2009. Compared with open cases, laparoscopic cases yielded a significantly higher number of examined lymph nodes (29 vs 19), lower estimated blood loss (200 vs 450 mL), and shorter length of stay (8 vs 14 days). Median operative time, average tumor size, and number of positive lymph nodes were not different. Morbidity rates were much lower in the laparoscopic series; and 30-day mortality rates were similar in both groups. Laparoscopic total gastrectomy and D2 lymphadenectomy are comparable in safety and have improved efficacy than our open total gastrectomy experience. After initiation of a laparoscopic total gastrectomy program in 2009, the majority of cases in our institution are now performed by laparoscopic techniques. PMID- 23025940 TI - A 3-year experience with necrotizing fasciitis: favorable outcomes despite operative delays in a busy acute care hospital. AB - Necrotizing fasciitis is a rare severe soft tissue infection that has historically been associated with high mortality. We sought to evaluate our experience with necrotizing fasciitis focusing on outcomes based on timing of operative intervention. Our study hypothesis was that delays in surgical management would negatively impact outcomes. Fifty-four patients were identified for a retrospective chart review from January 2008 to January 2011. Data analysis included demographics, admission laboratory values, imaging results, examination findings, timing and nature of operations, length of stay (LOS), and outcomes. Surgical intervention in 12 hours or more was considered a delay in care. Our study cohort was high risk based on a high prevalence of intravenous drug abuse, diabetes mellitus, hypertension, and end-stage liver disease. The average time to surgical intervention was 18+/-25 hours and the overall mortality rate was 16 per cent. A delay to surgery did not impact mortality or the number of debridements and LOS. Mortality was high, 45 per cent, in patients requiring amputation. We observed a high-risk population managed with aggressive surgical care for necrotizing fasciitis. Our mortality was low compared with historical data and surgical delays did not impact outcomes. Those patients requiring amputation had worse outcomes. PMID- 23025941 TI - Laparoscopic versus open colon resections in California: a cross-sectional analysis. AB - Laparoscopic surgery is associated with decreased hospital length of stay, improved perioperative morbidity, and faster return to work compared with open procedures. Despite these benefits, laparoscopy has not been universally adopted with recent implementation estimates ranging from 10 to 30 per cent. The purpose of this study was to analyze the adoption of laparoscopic techniques for colon resections in California in 2009 based on institutional colectomy volume status. A total of 14,736 patients from 320 hospitals was analyzed. The laparoscopic to open case ratios for the low (zero to 17 cases/year), medium (18 to 50 cases/year), and high (greater than 50 cases/year) volume centers were: 0.32, 0.50, and 0.92, respectively. Although the data confirmed that a laparoscopic approach reduced length of stay (LOS) regardless of volume, lower adopters of laparoscopic colectomy had a longer overall total LOS, likely related to preponderance of open cases. Therefore, the data show that higher-volume institutions appear to have implemented laparoscopic colectomy for more of their case volume, and this adoption may account for the better institutional outcomes observed in these centers. PMID- 23025942 TI - Two-wheel vehicular trauma: an age-based analysis. AB - We retrospectively reviewed a series of 516 patients with motorcycle (n=353) and bicycle (n=162) injuries; 384 patients (74%) were younger than age 50 years and 132 (26%) were older. No significant differences by age group were seen in gender, helmet use, substance use, complications, or mortality. Older patients had more severe (Injury Severity Score [ISS] greater than 15) injuries (35 vs 18%; P<0.001), longer intensive care unit stay (1.8 vs 0.9 days; P=0.03), and more frequent discharge to subacute facilities (27 vs 10%; P<0.001). When analyzed by vehicle type, fewer older bicyclists used helmets (63 vs 99%; P<0.001) and more sustained severe head injuries (42 vs 16%; P=0.002) and critical (ISS greater than 25) overall injuries (19 vs 6%; P=0.033). Among older patients, independent predictors of mortality included emergent intubation (P<0.001), critical injury (P=0.006), severe head/neck injury (P=0.027), tachycardia at presentation (P=0.014), and female gender (P=0.026). We conclude that motorcycle and bicycle accidents cause major injuries in older patients with substantial use of hospital and posthospital resources. Older bicyclists are vulnerable to head injury and to greater functional decline. Helmet use among older bicyclists should be a direct target for a public health campaign. PMID- 23025943 TI - Intraoperative electron radiotherapy boost as a component of adjuvant radiation for breast cancer in the community setting. AB - To reduce toxicity/treatment time and improve accuracy, intraoperative electron radiotherapy (IOERT) was used as an alternative to electron beam radiation therapy boost. Primary objective was to determine feasibility and acute toxicity. From August 2009 to June 2011, 50 patients (age 32 to 76 years) with in situ or invasive breast cancer (Stage 0 to IIIA) were treated. Toxicity assessed according to standard National Cancer Institute scales. Median tumor size was 20 mm (range, 6 to 80 mm) with 43 infiltrating ductal, two infiltrating lobular, and five ductal in situ carcinoma. A single 10-Gy fraction boost was given to the tumor bed after resection followed by whole-breast radiotherapy. After IOERT, three patients required completion axillary lymph node dissection, eight had reexcision resulting from positive margins, and four opted for completion mastectomy. The median follow-up was 10 months (range, 2 to 24 months). Ten patients had Grade 1 and one reported Grade 2 breast pain 2 weeks after IOERT; all resolved at 6 weeks. Two patients had delay in wound healing, but none developed a wound infection. Three patients reported symptomatic fat necrosis. No other toxicities were reported. IOERT resulted in a reduction in treatment time, was not associated with additional toxicity or change in the acute toxicity profile, and is a feasible treatment option in a community hospital setting. PMID- 23025944 TI - Admission variables predictive of gangrenous cholecystitis. AB - The objective of the present study was to identify admission clinical factors associated with gangrenous cholecystitis (GC) and factors associated with conversion to open cholecystectomy. We retrospectively evaluated 391 patients over a 17-month period who underwent urgent laparoscopic cholecystectomy for a diagnosis of acute cholecystitis. Eighty-nine patients with pathologically proven GC were compared with 302 patients without GC. On multivariable logistic regression, predictors of GC included male gender, white blood cell count greater than 14,000/mm3, heart rate greater than 90 beats per minute, and sodium 135 mg/dL or less. Conversion rate to open cholecystectomy was 7.9 per cent overall, 4 per cent for non-GC, and 19 per cent for GC (odds ratio, 0.2; 95% confidence interval, 0.1 to 0.4; P<0.00001). Conversion was predicted by increasing number of days to surgery, total bilirubin, and white blood cell count. Complication rate was higher in the GC group (10.1 vs 3.6% in the acute cholecystitis group, P=0.01). The increased rate of conversion observed with surgery delay suggests that early laparoscopic cholecystectomy may be preferable in most patients. PMID- 23025945 TI - Hospital type predicts surgical complications for infants with hypertrophic pyloric stenosis. AB - Pyloromyotomy is a common surgery performed for hypertrophic pyloric stenosis at community and children's hospitals. To determine hospital-level factors that may affect clinical outcomes, infants requiring pyloromyotomy from 1999 to 2007 (n=8379) were retrospectively reviewed from the California linked birth cohort data set. Hospital case volume and type (community, children's, adult hospital with children's unit) were examined. Surgical complications, prolonged length of stay (LOS), and 30-day readmission were analyzed with multivariate logistic regression. Overall, surgical complications occurred in 166 (2%) infants, 35 (21%) after discharge. Readmission occurred in 285 (3.4%) infants with 69 (24%) admitted to hospitals that did not perform the initial surgery. Infants treated at community hospitals (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.1 to 4.0) experienced an increased likelihood of surgical complications. Odds of surgical complications did not vary by hospital case volume. Prolonged LOS was increased at community hospitals (OR, 1.7; 95% CI, 1.2 to 2.3), low- (OR, 2.1; 95% CI, 1.3 to 3.4), and medium-volume (OR, 1.6; 95% CI, 1.0 to 2.7) hospitals. Hospital type and volume did not impact 30-day readmission. In conclusion, specialized surgical care for infants administered at pediatric centers appears to influence pyloromyotomy complications more than hospital case volume. Institutional components contributing to improved outcomes in specialty centers warrant further investigation. PMID- 23025946 TI - Laparoscopic versus open appendectomy: outcomes analysis. AB - The advantages of laparoscopic appendectomy (LA) over open appendectomy (OA) are unclear. This study compares the outcomes of LA versus OA. A retrospective study from 1998 to 2008 of patients (18 years or older) with appendicitis was performed from 12 medical centers. Study outcomes included 30-day postoperative morbidity and length of hospitalization (LOH). Overall, 16,512 patients were included in this study (LA=10,075, OA=6437). Male patients (LA=52.9% vs OA=57.3%, P<0.0001) and patients with perforated appendicitis (LA=19.3% vs OA=32.8%, P<0.0001) were more likely to undergo OA. LA for nonperforated appendicitis was associated with a lower wound infection rate (LA=1.9% vs OA=3.1%, P<0.0001) and shorter LOH (LA=1.4+/-1.2 vs OA=1.7+/-1.2 days, P<0.0001). Similar results were seen with LA for perforated appendicitis (wound infection: LA=5.0% vs OA=9.1%, P<0.0001; LOH: LA=3.8+/-2.7 vs OA=5.2+/-3.0, P<0.0001). Postoperative abscess drainage and readmission rates were similar between LA and OA for both nonperforated and perforated appendicitis. Multivariable analysis demonstrated that LA was associated with lower wound infection (odds ratio [OR], 0.6; 95% confidence interval [CI], 0.5 to 0.7), higher abscess drainage (OR, 1.3; 95% CI, 1.1 to 1.6), and shorter LOH. In conclusion, LA continues to be the preferred operation for appendicitis in adults. PMID- 23025947 TI - Magnetic resonance imaging-guided breast biopsy in lesions not visualized by mammogram or ultrasound. AB - The use of magnetic resonance imaging (MRI) for the diagnosis and evaluation of breast lesions is still in evolution. The aim of this study was to evaluate the outcome of MR-guided biopsy for suspicious lesions seen on MRI but not visualized by mammography or ultrasound. A retrospective review was conducted on all patients undergoing MRI-guided core needle biopsy at a National Cancer Institute designated comprehensive cancer center. Biopsies were performed using a 1.5-Tesla MR with a seven-channel breast coil taking six cores in a clock face configuration with a 10-gauge vacuum-assisted VACORA biopsy device. One hundred twenty-seven patients underwent 187 biopsies without major complication. The lesion size ranged from 4 to 12 mm. Pathology on MRI-guided core biopsy material revealed 126 (68%) benign lesions. Of these, 12 were intraductal papillomas and two were fibroadenomas. Sixty-one (32%) were deemed clinically significant and included the following pathology: invasive cancer 19 patients (10%), ductal carcinoma in situ (DCIS) in 25 patients (13%), atypical ductal hyperplasia (ADH) 15 patients (8%), and lobular carcinoma in situ in one patient (1%). There were two specimens upgraded from ADH to DCIS and one specimen that was biopsied was called ADH but there was no residual atypia on final pathology. With a median follow-up of 24 months, there were no patients with benign pathology returning with a clinically significant lesion later. MRI-guided biopsy provides an accurate and safe method for sampling suspicious lesions when no other reasonable means of biopsy is available. MRI-guided biopsy yielded clinically significant findings in approximately one-third of the sampled specimens. This technique can provide a good representative sample of clinically significant pathology. MRI guided biopsy is a relatively new modality, which can provide a nonsurgical diagnostic specimen in the absence of mammographic or ultrasound findings. PMID- 23025948 TI - An appraisal of radiofrequency ablation and surgical resection for hepatocellular carcinoma: results from the surveillance, epidemiology, and end results registry. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, but only a small percentage of patients are eligible for curative surgical intervention. Over the past decade, radiofrequency ablation (RFA) has been increasingly shown to offer long-term survival benefits. Our study objective was to compare outcomes of patients with HCC who underwent surgical resection with those who received RFA. Using the Surveillance, Epidemiology, and End Results registry, we identified 1209 (21%) and 4595 (79%) patients with HCC who received RFA and surgical resection, respectively, between the years 1988 and 2008. When comparing the groups, patients undergoing RFA were older (years, 62.6 vs 58.7; P<0.001) and had smaller tumors (less than 5 cm; 84.4 vs 61.2%; P<0.001), yet patients who underwent surgical resection had improved survival over patients undergoing RFA (median survival, 5 vs 3 years, respectively; P<0.001). Univariate and multivariate analysis verified the superiority of surgical resection over ablation (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.60 to 0.80; P<0.001 and HR, 0.57; 95% CI, 0.52 to 0.63; P<0.001, respectively). In summary, our investigation demonstrates that surgical resection provides durable long-term survival for surgical candidates with HCC; however, RFA remains an appropriate alternative therapy that also provides long-term survival in select patients. PMID- 23025949 TI - Prevalence of methicillin-resistant Staphylococcus aureus in elective surgical patients at a public teaching hospital: an analysis of 1039 patients. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an increasingly common cause of postoperative surgical site infections (SSIs). It is unclear, however, whether asymptomatic colonization or nosocomial acquisition of MRSA results in postoperative SSI. We conducted a retrospective review of patients screened for MRSA between May 2008 and October 2010 at our institution. End points included rates of MRSA infection, SSI, and the cost of routine MRSA screening of patients undergoing elective surgery. Of the 1039 patients screened preoperatively, 48 (4.6%) tested positive for MRSA by nasal or oral swab, whereas 991 (95.4%) tested negative. Forty-five (93.8%) MRSA-positive patients received vancomycin or linezolid and three (6.25%) received cefazolin perioperatively. Three (6.25%) MRSA-positive patients developed postoperative SSIs. Two required rehospitalization for intravenous antimicrobials, whereas a third patient required removal of infected abdominal mesh. Twenty (2.02%) MRSA-negative patients and four (5.26%) unscreened patients developed non-MRSA SSIs. Regardless of MRSA status, none of 609 patients who had a laparoscopic procedure or inguinal hernia repair developed SSI. Twenty-two patients needed to be screened to obtain one positive test. The role of MRSA screening and longer perioperative coverage for MRSA-positive patients undergoing complex elective procedures remains to be determined. PMID- 23025950 TI - Risk factors for postoperative urinary tract infection and urinary retention in patients undergoing surgery for colorectal cancer. AB - The aim of this study was to analyze risk factors for postoperative urinary tract infection (UTI) and urinary retention (UR) in patients with colorectal cancer. Using Nationwide Inpatient Sample 2006-2009, a retrospective analysis of surgical patients with colorectal cancer was conducted. Patients were stratified into groups, with or without UTI/UR. The LASSO algorithm for logistic regression identified independent risk factors. A total of 93,931 surgical patients with colorectal cancer were identified. The incidences of UTI and UR were 5.91 and 2.52 per cent, respectively. Overall in-hospital mortality was 2.68 per cent. The UTI group demonstrated significantly higher in-hospital mortality rates compared with those without. Both UTI and UR groups were associated with prolonged hospital stay and increased hospital charge. Multivariate logistic regression analysis revealed age older than 60 years, females, anemia, congestive heart failure, coagulopathy, diabetes with chronic complications, fluid and electrolyte, paralysis, pulmonary circulation disorders, renal failure, and weight loss were independent risk factors of UTI. Age older than 60 years, male gender, rectal and rectosigmoid cancers, and postoperative anastomotic leakage and ileus were independent risk factors for UR. Postoperative UTI increases in-house mortality. Postoperative UTI/UR in patients with colorectal cancer increases length of stay and hospital charges. Knowledge of these specific risk factors for UTI and UR is needed to counsel patients and prevent these complications in this high-risk population. PMID- 23025951 TI - Pneumatosis in post-Whipple patients. AB - Pneumatosis intestinalis (PI) is the finding of air in the wall of the intestine. Clinical significance ranges from an incidental radiologic finding to an indicator of life-threatening disease requiring surgical intervention. We report the incidence and consequence of PI in a 7-year, single-surgeon, retrospective review. Data from demographics, imaging, and outcomes were analyzed. Two-tailed Fisher's exact test was performed to analyze the difference between groups. A total of 214 patients underwent a Whipple procedure with a routinely placed feeding tube during this period. Most had a gastrojejunal feeding tube, 80.4 per cent. Thirteen patients developed PI. Overall reoperation rate was nine of 201 versus four of 13 in the PI group (P<0.02). Three patients taken back to the operating room with peritonitis and PI had a necrotic bowel. A fourth patient was taken to surgery for unrelenting upper gastrointestinal bleeding. The remaining nine were managed nonoperatively with resolution of PI. The 90-day death rate in those without PI was 2.9 per cent versus 23.3 per cent with PI (P<0.02). Isolated PI can be managed nonoperatively; however, in the presence of peritonitis, it is a strong predictor of lethal complications. PMID- 23025952 TI - Fluorodeoxyglucose positron emission tomography-computed tomography: a novel approach for the diagnosis of cholecystitis for equivocal diagnoses after ultrasound imaging. AB - Although hepatobiliary iminodiacetic acid (HIDA) scan is often used when the diagnosis of cholecystitis remains questionable after ultrasound, it carries a high false-positive rate and has other limitations. Fluorodeoxyglucose positron emission tomography-computed tomography (18FDG PET-CT) has recently gained enthusiasm for its ability to detect infection and inflammation. In this study, we evaluate the accuracy of 18FDG PET-CT in diagnosing cholecystitis. Nineteen patients with suspected cholecystitis (Group S) underwent PET-CT and 10 had positive PET-CT findings. Of these 10, nine underwent cholecystectomies, and pathology confirmed cholecystitis in all nine. One patient was managed nonoperatively as a result of multiple comorbidities. Of the nine patients with negative PET-CT, six were managed nonoperatively, safely discharged, and had no readmissions at 3-month follow-up. The other three patients with negative PET-CT underwent cholecystectomies, and two showed no cholecystitis on pathology. The third had mild to moderate cholecystitis with focal mucosal erosion/ulceration without gallbladder wall thickening on pathology. 18FDG PET-CT detected gallbladder inflammation in all but one patient with pathology-proven cholecystitis with a sensitivity and specificity of 0.90 and 1.00, respectively. 18FDG-PET-CT appears to be a promising, rapid, direct, and accurate test in diagnosing cholecystitis and could replace HIDA scan in cases that remain equivocal after ultrasound. PMID- 23025953 TI - Risk for contrast-induced nephropathy in elderly trauma patients. AB - The objective of this study was to determine if elderly trauma patients are at risk for contrast-induced nephropathy (CIN). A retrospective study was conducted identifying 362 patients 65 years and older in our Level I trauma center who received computerized tomography (CT) scans with intravenous contrast. CIN was defined as a 25 per cent increase in serum creatinine levels or a 0.5 mg/dL increase above baseline after CT. History of diabetes mellitus, hospital length of stay, intensive care unit length of stay, Injury Severity Score (ISS), and age were recorded. Eighteen per cent (21 of 118) of the patients had a peak in creatinine, 12 per cent (14 of 118) peaked and returned to baseline, and 6 per cent (7 of 118) peaked and stayed high. Pre-CT elevated creatinine, diabetes mellitus, increased hospital length of stay, ISS, and age show little association to CIN. The data suggest that CIN in elderly trauma patients is rare, regardless of history of diabetes mellitus, age, creatinine, high ISS, or result in higher length of stay. Therefore, there is little justification for the delay in diagnosis to assess a patient's renal susceptibility. PMID- 23025954 TI - Obesity increases the odds of acquiring and incarcerating noninguinal abdominal wall hernias. AB - The current data available describing the relationship of obesity and abdominal wall hernias is sparse. The objective of this study was to investigate the current prevalence of noninguinal abdominal wall hernias and their correlation with body mass index (BMI) and other demographic risk factors. Patients with umbilical, incisional, ventral, epigastric, or Spigelian hernias with or without incarceration were identified using the regional database for 14 hospitals over a 3-year period. Patients were stratified based on their BMI. Univariate and multivariate analyses were performed to distinguish other significant risk factors associated with the hernias. Of 2,807,414 patients, 26,268 (0.9%) had one of the specified diagnoses. Average age of the patients was 52 years and 61 per cent were male. The majority of patients had nonincarcerated umbilical hernias (74%). Average BMI was 32 kg/m2. Compared with patients with a normal BMI, the odds of having a hernia increased with BMI: BMI of 25 to 29.9 kg/m2 odds ratio (OR) 1.63, BMI of 30 to 39.9 kg/m2 OR 2.62, BMI 40 to 49.9 kg/m2 OR 3.91, BMI 50 to 59.9 kg/m2 OR 4.85, and BMI greater than 60 kg/m2 OR 5.17 (P<0.0001). Age older than 50 years was associated with a higher risk for having a hernia (OR, 2.12; 95% [CI], 2.07 to 2.17), whereas female gender was associated with a lower risk (OR, 0.53; 95% CI, 0.52 to 0.55). Those with incarcerated hernias had a higher average BMI (32 kg/m2 vs 35 kg/m2; P<0.0001). Overall, BMI greater than 40 kg/m2 showed an increased chance of incarceration, and a BMI greater than 60 kg/m2 had the highest chance of incarceration, OR 12.7 (P<0.0001). Age older than 50 years and female gender were also associated with a higher risk of incarceration (OR, 1.28; 95% CI, 1.02 to 1.59 and OR, 1.80; CI, 1.45 to 2.24). Increasing BMI and increasing age are associated with a higher prevalence and an increased risk of incarceration of noninguinal abdominal wall hernias. PMID- 23025956 TI - Effect of socioeconomic status on surgery for pancreatic adenocarcinoma. AB - Survival for pancreatic cancer remains poor. Surgical resection remains the only chance for cure. The intent of this study was to investigate the role of socioeconomic status (SES) on resection rates for pancreatic adenocarcinoma. The National Cancer Institute's Surveillance, Epidemiology, and End results database was used to identify patients with pancreatic adenocarcinoma. Disease was deemed resectable or unresectable based on the extent of disease code. Median family income was used as a SES variable to compare patients who underwent resection with those who did not. Median family income was organized into three categories based on definitions from the national census: less than $34,680 (low income), $34,680 to $48,650 (middle), and greater than $48,650 (high income). A total of 5,908 patients with potentially resectable disease were included. A total of 3,331 patients did not have a surgical resection despite having resectable disease. Subgroup analysis of income status revealed that patients with a low or middle income were less likely to have a resection when compared with those with high income (33.0 vs 39.9 vs 45.8%, P=0.0001). Multivariate analysis revealed that low and middle SES and race were significant predictors of resection. Ongoing study of access to health care may help define the means to eliminate the disparities in the care of patients with pancreatic adenocarcinoma. PMID- 23025955 TI - Postmastectomy radiation of latissimus dorsi myocutaneous flap reconstruction is well tolerated in women with breast cancer. AB - Chest wall irradiation decreases locoregional recurrence and breast cancer related mortality in women at high risk for recurrence after mastectomy. Many women undergoing mastectomy desire immediate breast reconstruction. Postmastectomy radiation therapy (PMRT), however, increases the risk of surgical complications and may adversely affect the reconstructed breast. We compared outcomes of immediate latissimus dorsi myocutaneous flap (Lat Flap) versus tissue expander/implant (EI) reconstruction after mastectomy followed by PMRT in 29 women with invasive breast cancer treated at a single institution between 2009 and 2011. Although patients undergoing EI reconstruction were slightly younger and more frequently underwent bilateral mastectomy, there were no major differences between the groups with respect to patient or tumor characteristics. With a median follow-up of 11 months (Lat Flap) and 13 months (EI) after completion of PMRT, there was a trend toward more wound complications requiring reoperation, including expander/implant loss (n=3), in the EI group. Capsular contracture was the most common sequela of PMRT in the Lat Flap group (67%) but this was easily treated with capsulotomy at the time of nipple-areola reconstruction. Immediate breast reconstruction with a latissimus dorsi myocutaneous flap is a viable option for women undergoing mastectomy who are likely to require chest wall irradiation. PMID- 23025957 TI - Development and use of a novel cardiovascular simulator: time for a paradigm shift? AB - Understanding cardiovascular physiology, pharmacology, and treatment of shock is heavily emphasized in current medical school and surgical training. Performance of individuals in treatment of critical illness remains poor despite regular didactic sessions. We have developed a PC computer-based simulator capable of integrating basic hemodynamic parameters to dynamically generate a realistic patient monitor. The methodology includes physiological feedback as found in humans. The trainees are able to learn through a series of scenarios or ad lib manipulation of parameters. Participants including medical students, nurses, and residents were given a pretest before attending either a 30-minute didactic or a 10- or 30-minute simulator session. A posttest was administered to evaluate performance after the intervention. Twenty-four participants were equally randomized with 12 receiving simulator training. Although the two groups had similar pretest scores (P>0.5), the simulator group showed a 24 per cent improvement, whereas the lecture group showed a 10 per cent improvement in the posttest score (P=0.008). Simulations in surgery and critical care are in early stages of development. Access to such simulators on a personal computer can greatly enhance understanding of the cardiovascular system. These simulators appear to be very effective and may become an integral adjunct to traditional classroom teaching methods. PMID- 23025958 TI - Association between postoperative complications and reoperation for patients undergoing geriatric surgery and the effect of reoperation on mortality. AB - Elderly patients have greater risk for postoperative adverse events (PAEs). The study examines the rates of reoperation, the association between PAEs and reoperation, and the effect of reoperation on mortality for patients 65 years of age or older undergoing colorectal resections (CRRs), pancreatic resections (PRs), and lower extremity bypass (LEB) in 2010 American College of Surgeons National Surgical Quality Improvement Program. The models evaluating associations between reoperation and preoperative factors, PAEs, and mortality were developed using multiple logistic regression. The reoperation rates were 6.41 per cent for CRR (n=11,084), 6.79 per cent for PR (n=1,606), and 15.04 per cent for LEB (n=4,170). Preoperative factors predicting reoperation included indications for surgery, procedure category, emergency status, and systemic sepsis. The PAEs most strongly associated with reoperation were wound dehiscence for CRR (odds ratio [OR], 15.286; 95% confidence interval [CI], 11.035 to 21.175) and for PR (OR, 19.656; 8.677 to 44.531) and for LEB, graft failure (OR, 28.151; 18.030 to 43.954) and organ space surgical site infection (OR, 15.753; 6.938 to 35.711). Higher rates of mortality occurred with reoperation for patients undergoing CRR (16.88 vs 5.45%, P<0.0001), PR (28.44 vs 2.14%, P<0.0001), and LEB (6.22 vs 3.05%, P<0.0001). For elderly patients undergoing general and vascular surgery, reoperation occurs frequently, is strongly associated with other PAEs, and may elevate risk of mortality for this vulnerable population. PMID- 23025959 TI - A simple algorithm for drain management after pancreaticoduodenectomy. AB - Pancreatic fistula (PF) continues to be the Achilles' heel of pancreaticoduodenectomy (PD) with both morbidity and mortality linked to its occurrence. The optimal drain management strategy after PD remains unclear. We evaluated drain amylase (DA) levels on postoperative Day (POD) 0 to 5 in 76 consecutive patients undergoing PD to determine the patterns associated with PF. Of these 76 patients, eight patients (11%) developed Grade A, B, or C PF by International Study Group of Pancreatic Fistula criteria. POD 1 DA levels correlated closely with PF rates when high (greater than 5000 U/L, 100% PF rate) and low (less than 100 U/L, 2% PF rate). In patients with intermediate POD 1 DA (100 to 5000 U/L), 42 and 74 per cent had low DA levels on POD 3 and 5, respectively, and the PF rate was four of 31 (13%). Overall, the temporal pattern of decreasing DA levels after PD correlates closely with the risk of PF, and only two patients (5%) developed PF after early DA levels had normalized. Based on these data, we propose an algorithm of monitoring DA daily with drain removal when the level is less than 100 U/L. In our patient group drain removal would have occurred on a mean of 1.8 days and median 1 day after surgery. PMID- 23025960 TI - A prospective single-institution evaluation of current practices of early postoperative feeding after elective intestinal surgery. AB - Postoperative diet advancement in patients undergoing elective small bowel or colorectal surgery by general surgeons (GSs) and colorectal surgeons (CRSs) was prospectively evaluated. Demographic (age and gender), disease location (small bowel or colorectum), surgical approach (laparoscopic or open), and surgeon characteristics (GS or GRS) were tabulated. Postoperative feeding after surgery on postoperative Day (POD) 1 was assessed. Operations involved the colorectum (n=43 [72%]) or small bowel (n=17 [28%]) and were performed using laparoscopy (n=38 [63%]) or open (n=22 [37%]) techniques. Operations were performed by GSs (n=30) or CRSs (n=30). Early feeding was ordered on POD 1 on 34 patients (57%). The remaining 26 patients (43%) were kept nothing by mouth. Factors associated with early feeding included age younger than 50 years (P=.004), surgery done by CRSs (P<0.0001), operations on the colorectum (P=0.04), and laparoscopic surgery (P=0.07). Multivariable analysis revealed that age younger than 50 years (odds ratio [OR], 9.5; 95% confidence interval [CI], 1.8 to 52; P=0.01), surgery done by CRSs (OR, 16.3; 95% CI, 3.4 to 79.6; P=0.001), and use of laparoscopic surgery (OR, 12; 95% CI, 2.1 to 67; P=0.007) were associated with early postoperative feeding. Early postoperative feeding does not appear to be applied commonly in clinical practice. Younger patient age, surgery done by CRSs, and laparoscopy are associated with the use of early postoperative feeding after elective intestinal surgery. PMID- 23025961 TI - The evolving management of infected pancreatic necrosis. AB - Management of infected pancreatic necrosis (IPN) has for decades been based on early operative debridement. This approach is associated with mortality rates as high as 58 per cent. Recently, the care of these patients has evolved and emphasizes delayed operation and early intervention with percutaneous drainage. In 2002, we began to incorporate these new principles for the treatment of IPN and herein characterize the recent UCLA experience with management of IPN. A retrospective review of patients with IPN treated at UCLA between 2002 and 2011 was conducted. Mean patient age was 53.4 years. Mean Ranson's score was 3.3+/-2.3 and average number of concurrent comorbidities 3.2+/-2.5. All patients were treated with intravenous antibiotics. Thirteen of 18 patients (72.2%) had percutaneous drainage catheters placed (mean 1.1 drains per patient). Two patients were treated with percutaneous drainage alone. Sixteen of 18 (88.9%) eventually underwent surgical debridement. Of the operative patients, mean time from diagnosis to surgery was 28.4 days. The mortality in this group was 16.7 per cent. In conclusion, antibiotics and percutaneous drainage is an acceptable and possibly preferable initial therapeutic strategy for patients with IPN. Delayed operation and early intervention with percutaneous drainage appears to improve mortality for these patients. PMID- 23025962 TI - The current role of magnetic resonance imaging for diagnosing cervical spine injury in blunt trauma patients with negative computed tomography scan. AB - Clearance of cervical spine (CS) precautions in the neurologically altered blunt trauma patient can be difficult. Physical examination is not reliable, and although computed tomography (CT) may reveal no evidence of fracture, it is generally believed to be an inferior modality for assessing ligamentous and cord injuries. However, magnetic resonance imaging (MRI) is expensive and may be risky in critically ill patients. Conversely, prolonged rigid collar use is associated with pressure ulceration and other complications. Multidetector CT raises the possibility of clearing CS on the basis of CT alone. We performed a retrospective review at our Level I trauma center of all blunt trauma patients with Glasgow Coma Scale Score 14 or less who underwent both CT and MRI CS with negative CT. One hundred fourteen patients met inclusion criteria, of which 23 had MRI findings. Seven (6%) of these had neurologic deficits and/or a change in management on the basis of MRI findings. Although use of the single-slice scanner was significantly associated with MRI findings (odds ratio, 2.62; P=0.023), no significant clinical risk factors were identified. Patients with MRI findings were heterogeneous in terms of age, mechanism, and Injury Severity Score. We conclude that CS MRI continues play a vital role in the workup of neurologically altered patients. PMID- 23025963 TI - Intraductal papillary lesions of the breast: clinical and pathological correlation. AB - Papillary lesions of the breast range from a spectrum of benign intraductal papillomas with and without atypia to papillary carcinoma. Distinction between benign and malignant lesions on core needle biopsy (CNB) is difficult without surgical excision. We examined if clinical findings in patients with benign intraductal papillomas (IP) on CNB correlate with pathology at surgical excision. Between 1998 and 2011, 103 patients were identified with a papillary lesion on CNB. Clinical variables were studied to determine if there was clinical correlation with pathological outcomes at final surgical excision. Of the 103 patients, 59 (57%) patients had IP on initial CNB and were included in our analysis. On final pathology, 17 (29%) of these were upstaged to intraductal papilloma with atypia and six (10%) were found to have carcinoma. A clinically palpable mass was the only significant predictor of upstaging to malignancy (P<0.05). No radiographic findings were found to be significant predictors of pathological upstaging. In conclusion, surgical excision is still recommended for benign papillary lesions diagnosed on CNB because the correlation with clinical and radiological findings does not assure benign pathology. PMID- 23025964 TI - Decreased intracranial pressure monitor use at level II trauma centers is associated with increased mortality. AB - Previous investigations suggest outcome differences at Level I and Level II trauma centers. We examined use of intracranial pressure (ICP) monitors at Level I and Level II trauma centers after traumatic brain injury (TBI) and its effect on mortality. The 2007 to 2008 National Trauma Databank was reviewed for patients with an indication for ICP monitoring based on Brain Trauma Foundation (BTF) guidelines. Demographic and clinical outcomes at Level I and Level II centers were compared by regression modeling. Overall, 15,921 patients met inclusion criteria; 11,017 were admitted to a Level I and 4,904 to a Level II trauma center. Patients with TBI admitted to a Level II trauma center had a lower rate of Injury Severity Score greater than 16 (80 vs 82%, P<0.01) and lower frequency of head Abbreviated Injury Score greater than 3 (80 vs 82%, P<0.01). After regression modeling, patients with TBI admitted to a Level II trauma center were 31 per cent less likely to receive an ICP monitor (adjusted odds ratio [AOR], 0.69; P<0.01) and had a significantly higher mortality (AOR, 1.12; P<0.01). Admission to a Level II trauma center after severe TBI is associated with a decreased use of ICP monitoring in patients who meet BTF criteria as well as an increased mortality. These differences should be validated prospectively to narrow these discrepancies in care and outcomes between Level I and Level II centers. PMID- 23025965 TI - Open appendectomy: no longer an intern case. AB - Laparoscopy and work-hour restrictions are altering surgical training. We hypothesized interns were no longer gaining experience in open appendectomy, historically an intern index case. We retrospectively reviewed Accreditation Council for Graduate Medical Education (ACGME) case logs of postgraduate Year (PGY) 1 general surgery trainees from our academic teaching program for the last 9 years. Number of appendectomies performed (Current Procedural Terminology codes 44950, 44960, and 44970) were recorded and analyzed. The national ACGME database was similarly evaluated for resident experience during junior (PGY-1 to 4) years. Data were available for 47 residents completing internship at our institution between 2003 and 2011. Mean number of appendectomies performed per intern steadily decreased throughout the study period from 22 in 2003 to 5 in 2011 (P=0.0367). Mean percentage of cases done open decreased from 79.5 to 2.4 per cent (P=0.0001). National data found residents graduating in the year 2000 performed an average of 26.6 open appendectomies during junior years, whereas those graduating in 2011 had done only 13.7. Surgical trainees are performing fewer open appendectomies than just several years ago. Open appendectomy traditionally served as an introduction to open surgery. Because outcome differences are small between open and laparoscopic appendectomy, we propose teaching institutions consider performing open appendectomies in select patients to preserve an important educational experience. PMID- 23025966 TI - Laparoscopic transgastric endoscopy after Roux-en-Y gastric bypass: case series and review of the literature. AB - Endoscopic access to the gastric remnant and pancreatobiliary tree is technically difficult after Roux-en-Y gastric bypass even when facilitated by the use of specialized techniques such as balloon enteroscopy and the use of overtubes. Furthermore, such techniques are not universally available at all medical centers. We describe a case series of 13 patients with a history of Roux-en-Y gastric bypass for the treatment of morbid obesity who underwent laparoscopic transgastric endoscopy through the gastric remnant to access the duodenum or biliary tree. Charts of these patients were reviewed for demographics, indications for procedure, length of stay, morbidity, and mortality. Four of the patients had failed prior attempts to access the excluded anatomy through traditional transoral endoscopy. Two patients underwent transgastric endoscopy for evaluation of gastrointestinal bleeding. Of the 11 patients for whom endoscopic retrograde cholangiopancreatography was planned, all underwent successful biliary cannulation and sphincterotomy. There were no conversions to an open procedure or complications during the follow-up period. Laparoscopic transgastric endoscopy is a safe and reliable method to access the excluded stomach and biliary tree in patients with a history of Roux-en-Y gastric bypass. PMID- 23025967 TI - Closed-suction drain placement at laparotomy in isolated solid organ injury is not associated with decreased risk of deep surgical site infection. AB - The purpose of this study was to investigate the role of intra-abdominal closed suction drainage after emergent trauma laparotomy for isolated solid organ injuries (iSOI) and to determine its association with deep surgical site infections (DSSI). All patients subjected to trauma laparotomy between January 2006 and December 2008 for an iSOI at two Level I urban trauma centers were identified. Patients with isolated hepatic, splenic, or renal injuries were included. Study variables extracted included demographics, clinical characteristics, intra-abdominal injuries, drain placement, DSSI, septic events, intensive care unit and hospital length of stay, and in-hospital mortality. Diagnosis of DSSI was based on abdominal computed tomography scan demonstrating an intra-abdominal collection combined with fever and elevated white blood cell count. For the analysis, patients were stratified based on injury severity. To identify an independent association between closed-suction drain placement and DSSI, stepwise logistic regression analysis was performed. Overall, 142 patients met the inclusion criteria with 80 per cent (n=114) having severe iSOI. In 47 per cent (n=53) of the patients with a severe injury, an intra-abdominal drain was placed. A drain was placed more often in patients with a blunt trauma with more severe injury defined by Injury Severity Score and abdominal Abbreviated Injury Scale Score and those who underwent splenectomy (P<0.05). There was a three-fold increased risk of DSSI in patients subjected to drain placement (odds ratio, 2.8; 95% confidence interval, 1.0 to 8.2; P=0.046). Subgroup analysis demonstrated those who sustained severe hepatic injury receiving a drain had a significantly increase risk of DSSI (P=0.02). There was no statistical difference in the rate of DSSI based on the presence or absence of an intra-abdominal drain after severe splenic injury (17 vs 18%, P=0.88). The use of intra-abdominal closed-suction drains after iSOI is not associated with decreased risk of DSSI. PMID- 23025968 TI - Necrotising enterocolitis in infants with congenital heart disease: the role of enteral feeds. AB - OBJECTIVE: Necrotising enterocolitis is a rare, though catastrophic complication that may occur in term newborns with congenital heart disease. There is considerable controversy regarding the factors that lead to necrotising enterocolitis in this population. We sought to determine the incidence of necrotising enterocolitis among term and near-term newborns with congenital heart disease, focusing on the relationship of enteral feeding to this complication. METHODS: In this retrospective study, we identified the incidence of necrotising enterocolitis among 1551 newborns admitted to our cardiac intensive care unit between July 1, 2002 and July 1, 2010. In order to understand the impact of enteral feeding upon the development of necrotising enterocolitis, we undertook a nested 2:1 matched case-control analysis to compare feeding patterns in an age- and lesion-matched control population. RESULTS: Necrotising enterocolitis developed in 45 term or near-term infants (3%). The majority of these cases, 27 (60%), occurred in the post-operative period after the introduction of enteral feeds. This subgroup was used for matched analysis. There were no differences in enteral feeding patterns among the patients who developed necrotising enterocolitis and their matched controls. The overall mortality rate for patients who developed necrotising enterocolitis was 24.4% (11 out of 45). CONCLUSIONS: Despite numerous advances in the care of infants with congenital heart disease, necrotising enterocolitis remains a significant source of morbidity and mortality. In these infants, there is no clear relationship between enteral feeding patterns and the development of necrotising enterocolitis in the post operative period. The benefits of graduated feeding advancements to avoid the development of necrotising enterocolitis remain unproven. PMID- 23025969 TI - Damus-Kaye-Stansel procedure 5 years after Fontan operation with ligated main pulmonary artery. AB - We report a case of tricuspid atresia with transposed great arteries and rudimentary right ventricle owing to which the patient developed severe subaortic stenosis and restrictive bulboventricular foramen 5 years after her extracardiac Fontan operation. She underwent a successful modified Damus-Kaye-Stansel operation using her native pulmonary valve. Spiral cardiac computed tomography with three-dimensional reconstructions was instrumental in pre-operative surgical planning. PMID- 23025970 TI - Factors associated with prophylactic plasma transfusion before vascular catheterization in non-bleeding critically ill adults with prolonged prothrombin time: a case-control study. AB - BACKGROUND: Fresh-frozen plasma (FFP) is widely used in critically ill patients, despite a weak evidence base. Factors that influence the decision to transfuse FFP before intravascular catheter insertion are poorly described. METHODS: We undertook a case-controlled study based on a prospective cohort study of 1923 admissions to 29 intensive care units in the UK. Non-bleeding patients with an international normalized ratio (INR) >=1.5 who underwent intravascular catheterization, but no other invasive procedure, were identified. We compared patient characteristics, illness-related factors, and biochemical and haematological variables between patients who did or did not receive pre procedural FFP. RESULTS: One hundred and eighty-six patients fulfilled the criteria; 26 received FFP during the 24 h before line insertion (cases) and 160 did not (controls). Factors associated with greater use of prophylactic FFP by clinicians were pre-existing chronic liver disease (P=0.01), higher serum bilirubin before procedure (P=0.01), lower platelet count (P=0.01), higher activated partial thromboplastin time (P=0.001), lower fibrinogen (P=0.01), and concurrent red cell transfusion despite the absence of bleeding (P=0.001). There was no difference in pre-procedural INR [median (1st, 3rd quartile) cases: 1.95 (1.85, 2.6); controls 1.8 (1.6, 2.3); P=0.19]. The mean FFP dose was 11.1 ml kg( 1) (sd 5.7 ml kg(-1)); 53.8% of cases were transfused <10 ml kg(-1). CONCLUSIONS: Chronic liver disease and more abnormal coagulation tests were associated with greater probability of pre-procedural FFP administration before vascular catheterization, whereas the severity of prothrombin time prolongation alone was not. FFP was more likely to be administered when red cells were also transfused, even in the absence of bleeding. PMID- 23025971 TI - Coarctation of the aorta in the setting of tetralogy of Fallot: an uncommon cause of myocardial dysfunction. AB - The combination of both right and left heart obstruction has only rarely been described in the medical literature. We present three cases of coarctation of the aorta in patients with variants of tetralogy of Fallot and hypothesise that this condition may be more common than previously suspected and could represent a hidden cause of morbidity in patients with pulmonary atresia/ventricular septal defect. PMID- 23025972 TI - Pulsatile tinnitus caused by an aneurysm of the transverse-sigmoid sinus: a new case report and review of literature. AB - A 28-year-old woman consulted for disabling pulsatile tinnitus. Clinical examination suggested a venous etiology. An aneurysm of the transverse-sigmoid sinus was identified on computed tomography angiography (CTA) and confirmed by digital subtraction angiography. Endovascular occlusion of the aneurysm with detachable coils permanently eliminated the bruit. Thus, this report is of a new case of pulsatile tinnitus caused by an aneurysm of the transverse-sigmoid sinus, with a focus on a literature review and etiopathophysiology. Embryological studies suggest that these aneurysms represent a partial remnant of the petrosquamous sinus. PMID- 23025974 TI - Eosinophilic esophagitis: a clinical, endoscopic, and histopathologic review. PMID- 23025973 TI - Transgastrically placed endoscopic vacuum-assisted closure system as an addition to transgastric necrosectomy in necrotizing pancreatitis (with video). AB - BACKGROUND: Endoscopic transluminal debridement of infected pancreatic necrosis has been proved to be an important alternative to surgical debridement. Recently, endoscopic vacuum-assisted closure (EVAC) has been described as a new effective treatment option in upper intestinal anastomotic leaks. OBJECTIVE: To test whether the EVAC can be applied to transgastrically accessible infected cavities. DESIGN: Single-center case study. SETTING: Academic medical center. PATIENTS: Two patients with necrotizing pancreatitis. MAIN OUTCOME MEASUREMENT: Successful closure of leak. RESULTS: We successfully applied EVAC to treat transgastrically accessible necrotic cavities. LIMITATIONS: Small case number. CONCLUSIONS: EVAC might be an important additional endoscopic treatment option for infected pancreatic necrosis, especially if established endoscopic treatment options fail. PMID- 23025975 TI - Accuracy of automatic detection of small-bowel mucosa by second-generation colon capsule endoscopy. AB - BACKGROUND: Colon capsule endoscopy (CCE) is a noninvasive technique for the detection of colorectal lesions. However, for CCE to be offered as an out-of clinic procedure, the system needs to automatically alert the patient when to ingest the laxative (booster). OBJECTIVE: We tested the reliability of the automatic detection of the small-bowel (SB) mucosa and the subsequent alert for booster ingestion by the Data Recorder 3 (DR3) of the second-generation CCE (CCE 2). DESIGN AND SETTING: Retrospective analysis. PATIENTS AND INTERVENTION: Data from 120 consecutive cases of CCE-2 were analyzed for proper DR3 automatic detection of the capsule entering the SB to prompt the patient to ingest the laxative booster. MAIN OUTCOME MEASUREMENTS: Accuracy of the DR3 for detecting the SB mucosa. RESULTS: The DR3 correctly identified the proper time for ingestion of the laxative (booster) in 118 of 120 cases, corresponding to a sensitivity of 98.3% (95% CI, 97%-100%). The median time difference between DR3 automatic SB detection to the observed entrance of the capsule into the SB was 3 minutes 30 seconds (interquartile range 2 minutes 35 seconds to 5 minutes 57 seconds). LIMITATION: Retrospective analysis. CONCLUSIONS: The 98.3% sensitivity of the DR3 for automatic identification of the SB mucosa and subsequent alert for the first laxative (booster) ingestion paves the way for CCE-2 to be offered as an out-of-clinic procedure. PMID- 23025976 TI - Absence of a gallbladder does not always mean a cholecystectomy. PMID- 23025977 TI - Application of magnifying endoscopy with narrow-band imaging in diagnosing gastric lesions: a prospective study. AB - BACKGROUND: Magnifying endoscopy with narrow-band imaging (ME-NBI) can more clearly assess the surface pattern and microvascular architecture of gastric lesions. OBJECTIVE: To evaluate the diagnostic efficacy of ME-NBI in patients with early gastric cancer. DESIGN: Prospective study. SETTING: Single academic center. PATIENTS: This study involved 164 suspected gastric lesions in 146 consecutive patients who underwent ME-NBI for additional differential diagnosis before treatment. INTERVENTION: ME-NBI findings were classified into 3 groups based on irregularities, absence of surface pattern, and microvascular architecture. All lesions were treated endoscopically or surgically, and ME-NBI diagnosis was compared with histopathological findings. MAIN OUTCOME MEASUREMENTS: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of real-time ME-NBI diagnosis were determined. RESULTS: The sensitivity, specificity, and accuracy of ME-NBI were 97.3%, 84.4%, and 90.2%, respectively, in distinguishing between cancerous and noncancerous lesions and were 92.3%, 89.7%, and 90.4%, respectively, in distinguishing undifferentiated from differentiated adenocarcinoma. ME-NBI accurately predicted depth of invasion in 37 of 39 differentiated adenocarcinomas (95%). LIMITATIONS: The sample size was relatively small. CONCLUSIONS: ME-NBI can successfully distinguish between cancerous and noncancerous lesions and between undifferentiated and differentiated adenocarcinomas. Of the 3 patterns on ME-NBI, type A is mainly characteristic of noncancerous lesions, type B is a good indicator of differentiated adenocarcinoma and intramucosal/superficially invasive cancers, and type C is indicative of undifferentiated adenocarcinoma or differentiated cancer with deep submucosal invasion. PMID- 23025979 TI - The alien limb phenomenon and Creutzfeldt-Jakob disease. PMID- 23025980 TI - Role of Bibersteinia trehalosi, respiratory syncytial virus, and parainfluenza-3 virus in bighorn sheep pneumonia. AB - Pneumonic bighorn sheep (BHS) have been found to be culture- and/or sero-positive for Bibersteinia trehalosi, respiratory syncytial virus (RSV), and parainfluenza 3 virus (PI-3). The objective of this study was to determine whether these pathogens can cause fatal pneumonia in BHS. In the first study, two groups of four BHS each were intra-tracheally administered with leukotoxin-positive (Group I) or leukotoxin-negative (Group II) B. trehalosi. All four animals in Group I developed severe pneumonia, and two of them died within 3 days. The other two animals showed severe pneumonic lesions on euthanasia and necropsy. Animals in Group II neither died nor showed gross pneumonic lesions on necropsy, suggesting that leukotoxin-positive, but not leukotoxin-negative, B. trehalosi can cause fatal pneumonia in BHS. In the second study, two other groups of four BHS (Groups III and IV) were intra-nasally administered with a mixture of RSV and PI-3. Four days later, RSV/PI-3-inoculated Group IV and another group of four BHS (Group V, positive control) were intra-nasally administered with Mannheimia haemolytica, the pathogen that consistently causes fatal pneumonia in BHS. All four animals in group III developed pneumonia, but did not die during the study period. However all four animals in Group IV, and three animals in Group V developed severe pneumonia and died within two days of M. haemolytica inoculation. The fourth animal in Group V showed severe pneumonic lesions on euthanasia and necropsy. These findings suggest that RSV/PI-3 can cause non-fatal pneumonia, but are not necessary predisposing agents for M. haemolytica-caused pneumonia of BHS. PMID- 23025981 TI - Catechol-O-methyltransferase Val158Met polymorphism influences anxiety, depression, and disability, but not pressure pain sensitivity, in women with fibromyalgia syndrome. AB - Our aim was to assess the relationship of the Val158Met polymorphism to pain, anxiety, depression, functional ability, and pressure pain sensitivity in women with fibromyalgia (FMS). One hundred (n = 100) women with FMS diagnosed according to the American College of Rheumatology criteria participated. A numerical pain rate scale (0-10) was used to assess the intensity of pain; the Hospital Anxiety and Depression Scale was calculated to determine anxiety and depression; and functional ability was determined with the Fibromyalgia Impact Questionnaire. Further, pressure pain thresholds (PPTs) were bilaterally assessed over C5-C6 zygapophyseal joints, second metacarpal, and tibialis anterior muscles. Finally, after amplifying Val158Met polymorphisms by polymerase chain reaction, catechol-O methyltransferase (COMT) genotype was divided into Val/Val, Val/Met, or Met/Met genotypes. Women with FMS with the Met/Met genotype exhibited higher disability (F = 11.836; P < .001), anxiety (F = 13.385; P < .001), and depression (F = 6.931; P = .002) than those with Val/Val and Val/Met genotypes. No differences for the intensity of widespread pain (F = .154; P = .857) and PPT levels over C5 C6 joints (F = 1.014; P = .336), second metacarpal (F = .216; P = .806), and tibialis anterior muscle (F = 1.179; P = .311) were found. Our results suggest that the Val158Met COMT polymorphism modulated some psychological variables but not pressure pain sensitivity in FMS, because women carrying the Met/Met genotype show higher disability, depression, and anxiety but similar PPTs than those with Val/Met or Val/Val genotypes. This study is important because it strives to understand potential genetic factors that predispose some women with FMS to exhibit a more severe phenotypic expression of the disease. Future studies are needed to elucidate potential relevance of the differences. PERSPECTIVE: This study suggests that the Val158Met COMT polymorphism modulated some psychological variables but not pressure pain sensitivity in FMS because women with FMS carrying the Met/Met genotype exhibit higher disability, depression, and anxiety than but similar PPTs to those with Val/Met and Val/Val genotypes. This study provides further evidence of potential genetic factors that predispose women with FMS to exhibit the disease more severely. PMID- 23025982 TI - Effects of regular and abusive intake of alcohol at weekends on physiological parameters in Spanish young. AB - OBJECTIVES: The aim of this study was to evaluate the effects of excessive intake at weekends, on different parameters in young university students. STUDY DESIGN: Cross sectional, descriptive study. METHODS: A group of 180 subjects were selected (young males between 18 and 22 years old) and were classified into three groups by their alcohol consumption habits: The control group of non-drinkers (ND; n = 60), the group of one day/weekend drinkers (1D/W, n = 60) and the group of two day/weekend drinkers (2D/W, n = 60). An evaluation of the body composition, a spirometry test (FVC, PEF and MVV), a maximal cycle ergometer test (Heart rate, blood pressure, VO2 max, total watts and time test until exhaustion), a blood sample (GOT, Triglycerides, Total Cholesterol, HDL cholesterol, LDL cholesterol and Glucose) were performed. RESULTS: It was observed that 2D/W group presented significantly higher levels than ND in the following parameters: total cholesterol [185.66 (16.06) compared to 154.28 (25.53) mg/dl]; triglycerides [113.66 (22.47) compared to 45.75 (12.76) mg/dl]; systolic blood pressure [130 (9.50) compared to 115 (5.77) mmHg] and waist to hip ratio [0.92 (0.08) compared to 0.84 (0.05)], and 1D/W group also showed significantly higher levels of triglycerides [71.04 (24.31) compared to 45.75 (12.76) mg/dl] than ND. Moreover, it was confirmed that the accumulation of triglycerides in weekend drinkers is influenced by smoking and the lack of physical activity, and that the relationship between alcohol drinking and systolic blood pressure could be modified by smoking. CONCLUSIONS: Young people's abusive intake of alcohol at weekends can cause negative changes in various health parameters, similar to those observed in alcoholics that drink regularly during the week. PMID- 23025983 TI - The efficacy of fuel treatment in mitigating property loss during wildfires: Insights from analysis of the severity of the catastrophic fires in 2009 in Victoria, Australia. AB - Treatment of fuel (e.g. prescribed fire, logging) in fire-prone ecosystems is done to reduce risks to people and their property but effects require quantification, particularly under severe weather conditions when the destructive potential of fires on human infrastructure is maximised. We analysed the relative effects of fuel age (i.e. indicative of the effectiveness of prescribed fire) and logging on remotely sensed (SPOT imagery) severity of fires which occurred in eucalypt forests in Victoria, Australia in 2009. These fires burned under the most severe weather conditions recorded in Australia and caused large losses of life and property. Statistical models of the probability of contrasting extremes of severity (crown fire versus fire confined to the understorey) were developed based on effects of fuel age, logging, weather, topography and forest type. Weather was the primary influence on severity, though it was reduced at low fuel ages in Moderate but not Catastrophic, Very High or Low fire-weather conditions. Probability of crown fires was higher in recently logged areas than in areas logged decades before, indicating likely ineffectiveness as a fuel treatment. The results suggest that recently burnt areas (up to 5-10 years) may reduce the intensity of the fire but not sufficiently to increase the chance of effective suppression under severe weather conditions. Since house loss was most likely under these conditions (67%), effects of prescribed burning across landscapes on house loss are likely to be small when weather conditions are severe. Fuel treatments need to be located close to houses in order to effectively mitigate risk of loss. PMID- 23025984 TI - Respondent uncertainty in contingent valuation of preventing beach erosion: an analysis with a polychotomous choice question. AB - Respondent uncertainty is often considered as one of the main limitations of stated preference methods, which are nowadays being widely used for valuing environmental goods and services. This article examines the effect of respondent uncertainty on welfare estimates by applying the contingent valuation method. This is done in the context of beach protection against erosion. Respondent certainty levels are elicited using a five-category polychotomous choice question. Two different uncertainty calibration techniques are tested, namely one that treats uncertain responses as missing and another in which uncertain 'yes' responses are recoded as 'no' responses. We found no evidence that the former technique offers any gains over the conventional model assuming certainty. The latter calibration technique systematically reduces welfare estimates. The reduction is statistically significant only when the most certain 'yes' responses are recoded as 'no' responses. The article further identifies determinants of respondent uncertainty. Finally, it explores how real market experience affects respondent uncertainty. PMID- 23025985 TI - Estimating the economic value of cultural ecosystem services in an urbanizing area using hedonic pricing. AB - A need exists to increase both knowledge and recognition of the values associated with ecosystem services and amenities. This article explores the use of hedonic pricing as a tool for eliciting these values. We take a case study approach, valuing several services provided by ecosystems, namely aesthetic quality (views), access to outdoor recreation, and the benefits provided by tree cover in Dakota County, Minnesota, USA. Our results indicate that these services are valued by local residents and that hedonic pricing can be used to elicit at least a portion of this value. We find that many aspects of the aesthetic environment significantly impact home sale prices. Total view area as well as the areas of some land-cover types (water and lawn) in views positively influenced home sale prices while views of impervious surfaces generally negatively influenced home sale price. Access to outdoor recreation areas significantly and positively influenced home sale prices as did tree cover in the neighborhood surrounding a home. These results illustrate the ability of hedonic pricing to identify partial values for ecosystem services and amenities in a manner that is highly relevant to local and regional planning. These values could be used to increase policy maker and public awareness of ecosystem services and could improve their consideration in planning and policy decisions. PMID- 23025986 TI - Probability of finding an HLA-matched donor in immediate and extended families: the Jordanian experience. AB - Information regarding the probability of finding HLA-matched related donor for a patient awaiting hematopoietic stem cell transplantation (HSCT) in developing countries is scanty. We performed a retrospective review of HLA genotypes and related data for 1254 consecutive patients and their families at King Hussein Cancer Center in Amman, Jordan, between 2003 and 2011 to evaluate the chance of finding HLA-matched donor. The median family size was 5 for all patients in the study (range, 1-14), and the average number of donors was 1.4 +/- 0.9 for pediatric patients and 1.6 +/- 0.9 for adults. Overall, the probability of finding an HLA-matched related donor at our center was 65.5% (60.6% in pediatric patients and 74% in adults). Of the total identified donors, 18% were nonsibling donors after an immediate and/or extended family search in the pediatric group, and 6% were nonsibling donors in the adult group. Overall, 13% of donors were nonsibling donors. We conclude that the probability of finding a matched related donor for HSCT in Jordan is much higher than that reported in Western countries and Asia (65% versus 25%). We expect a similar trend in other developing and Arab countries. We recommend integrating an extended family search before or concomitantly with an unrelated donor search. PMID- 23025987 TI - Recipient PTPN22 -1123 C/C genotype predicts acute graft-versus-host disease after HLA fully matched unrelated bone marrow transplantation for hematologic malignancies. AB - PTPN22 is a critical negative regulator of T cell responses. Its promoter gene variant (rs2488457, -1123G>C) has been reported to be associated with autoimmune diseases. This study analyzed the impact of the PTPN22 variant on transplantation outcomes in a cohort of 663 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The recipient C/C genotype versus the recipient G/G genotype resulted in a lower incidence of grade II-IV acute graft-versus-host disease (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.29-0.85; P = .01), as well as a higher incidence of relapse (HR, 1.78; 95% CI, 1.10-2.90; P = .02), as demonstrated on multivariate analysis. In patients with high-risk disease, the recipient C/C genotype was associated with significantly worse overall survival rates than the recipient G/G genotype (HR, 1.60; 95% CI, 1.02 2.51; P = .04), whereas this effect was absent in patients with standard-risk disease. In addition, the donor G/C genotype was associated with a lower incidence of relapse (HR, 0.58; 95% CI, 0.40-0.85), which did not influence survival. Our findings suggest that PTPN22 genotyping could be useful in predicting prognoses and creating therapeutic strategies for improving the final outcomes of allogeneic BMT. PMID- 23025988 TI - Prevention of acute graft-versus-host disease in a xenogeneic SCID mouse model by the humanized anti-CD74 antagonistic antibody milatuzumab. AB - Prevention and treatment of graft-versus-host disease (GVHD) remains a major challenge, given that current T-cell depletion and mainstay immunosuppressive therapies compromise preexisting T-cell immunity, often leading to severe infections and disease relapse. Thus, there is a critical need for novel anti GVHD agents that can spare protective T-cell memory. Here we show that milatuzumab (hLL1), a humanized anti-CD74 antagonist monoclonal antibody, can moderately reduce the numbers of CD74-expressing B cells and myeloid dendritic cells, but has no effect on the survival of T cells that are CD74(-). Consequently, milatuzumab inhibits allogeneic T-cell proliferation in mixed leukocyte reactions. In a human/mouse xenogeneic SCID mouse model in which GVHD is induced and mediated by engrafted human CD4(+) T cells and dendritic cells, milatuzumab effectively prevents the onset and manifestations of acute GVHD, suppresses serum levels of human IFN-gamma and IL-5, eliminates the infiltration of human lymphocytes into GVHD target organs (ie, lung, liver, and spleen), and significantly promotes survival (90% versus 20% for controls; P = .0012). Importantly, exposure to milatuzumab does not affect the number of cytomegalovirus-specific, IFN-gamma-producing human CD8(+) T cells in allogeneic mixed leukocyte reactions. These encouraging results warrant further exploration of milatuzumab as a possible new therapeutic agent for GVHD. PMID- 23025989 TI - Use of mechanical ventilation and renal replacement therapy in critically ill hematopoietic stem cell transplant recipients. AB - Hematopoietic stem cell transplantation (HSCT) is a treatment option for both malignant and nonmalignant disorders. HSCT patients remain at high risk for multiorgan failure, with previous studies noting mortality rates exceeding 90% when mechanical ventilation (MV) is required. We propose that advancements in critical care management and HSCT practices have improved these dismal outcomes. We performed a retrospective review of admissions to our bone marrow transplant unit between 2006 and 2010. All HSCT recipients requiring admission to the bone marrow transplant unit who received MV or renal replacement therapy (RRT) were evaluated. A total of 68 patients required MV. Twenty patients required RRT, all of whom required MV. Fifty-nine of the 68 ventilated patients died, for an overall mortality rate of 86.8%. The presence of renal failure and concomitant respiratory or liver dysfunction at the time of intubation was associated with a mortality rate of 100%. High mortality persists in our HSCT population requiring artificial support despite overall advances in critical care and HSCT practices. Critical care triage and management decisions in this high-risk population remain challenging. PMID- 23025990 TI - Complete spontaneous remission of diffuse large B-cell lymphoma of the maxillary sinus after concurrent infections. PMID- 23025991 TI - Predictive factors of survival after thalidomide therapy in advanced multiple myeloma: long-term follow-up of a prospective multicenter nonrandomized phase II study in 120 patients. AB - Thalidomide monotherapy has demonstrated consistent results in the treatment of advanced multiple myeloma. We report a 9-year follow-up of a French multicenter nonrandomized phase II study that evaluated the effect of oral thalidomide in 120 patients with advanced multiple myeloma. Independent predictors of survival were response to last therapy, performance status, serum beta(2)-microglobulin level, platelet count, and response at day 60 of treatment. BACKGROUND: Thalidomide monotherapy has demonstrated consistent results in the treatment of advanced multiple myeloma. PATIENTS AND METHODS: We report the 9-year follow-up of a French multicenter, nonrandomized, phase II study that evaluated the effect of oral thalidomide in advanced multiple myeloma. Thalidomide was started at 200 mg/d and increased to 400 mg/d at day 15. RESULTS: One hundred twenty patients were enrolled in 2 months at 33 centers. The overall response rate was 31.7% (38/120) on day 60. Overall survival rates were 47.5% (95% confidence interval [CI], 38.6-56.4), 25.0% (95% CI, 17.3-32.7), 11.7% (95% CI, 5.9-17.4), and 7.5% (95% CI, 2.8-12.2) at 1, 3, 6, and 9 years, respectively. Independent predictors of short survival at 1, 3, 6, and 9 years were multiple myeloma refractory to last therapy, performance status >= 2, serum beta(2)-microglobulin level >= 3.5 mg/L, platelet count < 152 * 10(9)/L, and nonresponse at day 60 (Cox proportional hazards regression model). CONCLUSION: Our study identified 5 independent unfavorable prognostic factors associated with short survival. These prognostic factors were very robust, allowing the prediction of patient survival not only during the first year but also during 3, 6, and even 9 years after the beginning of treatment. PMID- 23025993 TI - Analysis of presentations to on-site medical units during World Youth Day 2008. AB - World Youth Day 2008 was held in Sydney, Australia in July 2008. New South Wales (NSW) Health, the government health provider in Australia's most populous state, worked with partner agencies to provide medical services via on-site medical units at key event venues. A post-event review of medical records from the on site medical units indicated 465 patient presentations, comprised largely of infectious respiratory symptoms and general health concerns of a primary care nature. Providing on-site health services is considered an important risk mitigation action for many mass gatherings, especially those that generate a substantial temporary population of participants and take place over a number of days. PMID- 23025992 TI - Simulating the maintenance of a rare fish morph experiencing negative frequency dependent selection. AB - Empirical work assessing the maintenance of rare genotypes in natural populations is difficult over very long time scales. Skirting this problematic issue is possible with theory and simulations. Major theoretical constructs, including mutation-selection balance and balancing selection, explain the theoretical maintenance of rare genotypes, and the occurrence of multiple, rare genotypes over time. Additionally, numerical simulations are valuable tools for assessing evolving biological systems because they allow for monitoring systems over long time scales, as well as for controlling model parameters, thus contributing to the exploration of system dynamics that cannot be assessed in nature. Here we employed numerical simulations to explore the importance of several biological factors that contribute to the maintenance of a fish color-pattern polymorphism. We present a numerical model of a two-morph fish polymorphism that allowed us to test the sensitivity of the rare morph's persistence and the population's stability to multiple parameters. Our simulations ran over 10,000 years (where one year is approximately one generation) and demonstrated the maintenance of a stable polymorphism with a rare morph which persisted at a frequency of ~10(-2), which is in-fact the frequency of the rare, mottled black mosquitofish morph in natural populations. This pigmentation polymorphism is stable, independent of changes in population size, but can be destabilized with very high predation when coupled with very low birth rates. Employing models with empirical fitness estimates is a valuable tool for monitoring rare vertebrate morphs in nature, however few studies exist that have accomplished this task. Our approach can be adapted for modeling rare morphs (particularly in additional live-bearing fishes like sailfin mollies) that also harbor rare, pigmentation morphs within large populations. PMID- 23025994 TI - Duration of untreated psychosis and negative symptoms--a systematic review and meta-analysis of individual patient data. AB - BACKGROUND: Longer duration of untreated psychosis (DUP) is associated with poorer outcome in terms of positive symptoms, relapse rate, and time to remission. In contrast, the association with negative symptoms is less consistent. AIMS: The study had three aims. First, to arrive at a more precise estimate of the correlation between DUP and negative symptoms than previous reviews, by substantially increasing the amount of available data. Second, to see whether the strength of this correlation attenuated over longer follow-up intervals. Third, to determine whether there is a relationship between DUP and changes in negative symptoms. METHOD: Relevant databases were searched for studies published between December 1992 and March 2009 that reported data on DUP and negative symptoms. We obtained individual patient data where possible and calculated summary correlations between DUP and negative symptoms for each study at baseline, short and long-term follow-up. We used multilevel regression analysis to examine whether the effect of DUP on negative symptoms was the greatest in the early stages of illness. RESULTS: We included 28 non-overlapping studies from the 402 papers detected by the search strategy. After contacting the authors we obtained individual patient data from 16 of these studies involving 3339 participants. The mean DUP was 61.4 weeks (SD=132.7, median DUP=12.0). Shorter DUP was significantly associated with less severe negative symptoms at baseline and also at short (1-2 years) and longer term follow-up (5-8 years) (r=0.117, 0.180 and 0.202 respectively, p<0.001). The relationship between improvement in negative symptoms and DUP was found to be non-linear: people with a DUP shorter than 9 months showed substantially greater negative symptom reduction than those with a DUP of greater than 9 months. CONCLUSIONS: Shorter DUP is associated with less severe negative symptoms at short and long-term follow up, especially when the DUP is less than 9 months. Since there is no effective treatment for negative symptoms, reducing DUP to less than 9 months may be the best way to ameliorate them. PMID- 23025995 TI - Cognitive functioning in at-risk mental states for psychosis and 2-year clinical outcome. AB - BACKGROUND: Cognitive impairment is prevalent in at-risk mental states (ARMS) for psychosis. METHOD: We studied cognitive functioning at baseline in ARMS individuals and investigated its power to predict ARMS persistence and remission at 2-year follow-up. RESULTS: 196 patients were recruited. At baseline the ARMS population included 26 subjects meeting basic symptom (BS) criteria and 73 subjects fulfilling ultra-high risk (UHR) criteria. Two control groups were defined: 48 patients in a first episode of psychosis (FE), and 49 help-seeking patient controls (PCO). In 144 patients follow-up data were obtained. The 2-year risk of conversion to psychosis was 20%. Remission from an initial UHR state occurred in two thirds of the follow-up sample. UHR patients that converted to psychosis or did not remit during the follow-up (UHR(n-rem)) showed similar impairment in global cognitive functioning at baseline as the FE group, whereas global cognitive functioning in UHR patients with subsequent remission (UHR(rem)) approximated performances of the BS and PCO groups. UHR(n-rem) and UHR(rem) patients differed significantly on immediate verbal memory, but showed similarly impaired executive functions. Normal immediate verbal memory uniquely predicted remission from an at-risk state with a positive predictive value of 82%. CONCLUSIONS: Cognitive deficits are a characteristic feature of true ARMS patients. Verbal memory function appears critical in determining outcome. PMID- 23025996 TI - Identification of novel 3,5-diarylpyrazoline derivatives containing salicylamide moiety as potential anti-melanoma agents. AB - There is an accumulating body of experimental evidences validating oncogenic BRAF(V600E) as a therapeutic target and offering opportunities for anti-melanoma drug development. Encouraged by the positive results of pyrazole derivatives as BRAF(V600E) inhibitors, we sought to design diverse novel potential BRAF(V600E) inhibitors as antitumor agents based on pyrazole skeleton. In silico and in vitro screening of our designed pyrazole derivatives has identified Hit 1 as BRAF(V600E) inhibitor. Based on its structure and through further structure modification, compound 25, which exhibited the most potent inhibitory activity with an IC(50) value of 0.16 MUM for BRAF(V600E) and GI(50) value of 0.24 MUM for mutant BRAF-dependent melanoma cells, was obtained. The 3D-QSAR models and the molecular docking simulation were introduced to analyze the structure-activity relationship. PMID- 23025997 TI - Modifications around the hydroxamic acid chelating group of fosmidomycin, an inhibitor of the metalloenzyme 1-deoxyxylulose 5-phosphate reductoisomerase (DXR). AB - Fosmidomycin derivatives in which the hydroxamic acid group has been replaced by several bidentate chelators as potential hydroxamic alternatives were prepared and tested against the DXR from Escherichia coli. These results illustrate the predominant role of the hydroxamate functional group as the most effective metal binding group in DXR inhibitors. PMID- 23025999 TI - Structure-based design of pyridopyrimidinediones as dipeptidyl peptidase IV inhibitors. AB - Dipeptidyl peptidase IV (DPP-4) inhibitors have been shown to enhance GLP-1 levels and thereby improve hyperglycemia in type II diabetes. From a small fragment hit, using structure-based design, we have discovered a new class of non covalent, potent and selective DPP-4 inhibitors. PMID- 23025998 TI - Identification of a novel and orally available benzimidazole derivative as an NPY Y5 receptor antagonist with in vivo efficacy. AB - Optimization of lead compound 2 is described, mainly focusing on modification at the C-2 position of the benzimidazole core. Replacement of the phenyl linker of 2 with saturated rings resulted in identification of compound 8b which combines high Y5 receptor binding affinity with a good ADME profile leading to in vivo efficacy. PMID- 23026000 TI - Synthesis, anti-inflammatory and antimicrobial evaluation of novel 1-acetyl-3,5 diaryl-4,5-dihydro (1H) pyrazole derivatives bearing urea, thiourea and sulfonamide moieties. AB - A series of novel 1-acetyl-3-(3,4-dimethoxypheny)-5-(4-(3 (arylureido/arylthioureido/arylsulfonamido) phenyl)-4,5-dihydropyrazole derivatives of biological interest have been prepared by sequential cyclization of 1-(4-nitrophenyl)-3-(3,4-dimethoxyphenyl)-pro-2-ene-1 with hydrazine hydrate, reduction followed by reaction of resulting amine with different arylisocyanates or arylisothiocyanates or arylsulfonyl chlorides. All the synthesized compounds (1-32) have been screened for their pro-inflammatory cytokines (TNF-alpha and IL 6) and antimicrobial activity (antibacterial and antifungal). Biological evaluation study showed, the compounds 4, 5, 9, 11, 14 and 16 found to have promising anti-inflammatory activity (up to 61-85% TNF-alpha and 76-93% IL-6 inhibitory activity) at concentration of 10 MUM with reference to standard dexamethasone (76% TNF-alpha and 86% IL-6 inhibitory activity at 1 MUM). Compounds 24, 26, 27, 28 and 29 exhibited promising antimicrobial activity at MIC values ranging from 70 to 10 MUg/mL against all the selected pathogenic bacteria and fungi. PMID- 23026001 TI - A call to action: epidemiologists assert themselves with scientific data. PMID- 23026002 TI - China and the US: asbestos in common. PMID- 23026003 TI - Hazards faced by informal recyclers in the squatter communities of Asuncion, Paraguay. AB - BACKGROUND: Informal recycling is widespread in developing countries and involves the collection, sorting, and selling of recyclable materials. Workers are exposed to hazards including the risk of cuts and musculoskeletal injury, infection, exposure to medical waste, and respiratory conditions like bronchitis, pneumonia, and sinusitis and often use insufficient personal protective equipment. OBJECTIVE: Assess the occupational and environmental health hazards faced by informal recyclers working at a landfill in Asuncion, Paraguay. METHODS: We surveyed 102 informal recyclers and 12 formal recyclers about occupational health, workplace safety, general health, and household economics. Personal air samples were used to assess respirable dust and nobel metal exposure on 18 workers. RESULTS: Exposures to hazards such as syringes, medical waste, and broken glass as well as risk factors such as eating food found in the trash, lack of personal protective equipment (PPE), and inadequate sanitation were frequent among informal recyclers. Minors under 18 years of age constituted 13% of the workforce and experienced equal or greater exposure to these hazards. Formal recyclers had better access to water, sanitation, PPE, and experienced fewer cuts, injuries, and illnesses than formal recyclers. Informal recyclers were exposed to respirable dust that were considerably higher than they would have been exposed to at home or doing other work in their neighborhood. CONCLUSIONS: Better regulation of sharps and medical waste and the provision of adequate sanitation and personal protective equipment would address the most pressing occupational health issues in this high risk group. PMID- 23026004 TI - The effects of ambient temperature variation on respiratory hospitalizations in summer, New York State. AB - OBJECTIVE: A time-series study was used to assess the effect of temperature variation during summer on respiratory disease in New York State. METHODS: Daily respiratory admissions were linked with various meteorological indicators including daily and weekly temperature variation from June-August, 1991-2004. Two stage Bayesian hierarchical models were used to first compute percent excess risks at the region level while controlling for air pollutants and time-varying variables using Poisson generalized additive models, and then to pool statewide estimates together after controlling for regional confounders. RESULTS: This study found that the daily temperature range between maximum and minimum temperature was associated with a 0.27-0.38% increased risk of admission. Minimum temperature (TMIN) above the previous 6-day average was associated with a 0.93% higher risk of respiratory morbidity. Multiday temperature ranges within 5 and 7 days were associated with 0.49 and 0.73% increases in admissions, respectively. CONCLUSIONS: We concluded that daily and multiday temperature variation may increase respiratory hospitalizations with a larger risk associated with TMIN. PMID- 23026005 TI - Contributions of inhalation and dermal exposure to chlorpyrifos dose in Egyptian cotton field workers. AB - OBJECTIVE: Chlorpyrifos exposures were assessed in 12 Egyptian cotton field workers. METHODS: 3,5,6-trichloro-2-pyridinol (TCPy) was measured in 24-hour urine samples to estimate absorbed dose. Workshift air samples were used to calculate chlorpyrifos inhalation dose. RESULTS: Patches on legs had the highest chlorpyrifos loading rates among body regions sampled. Geometric mean chlorpyrifos air concentrations were 5.1, 8.2, and 45.0 MUg/m(3) for engineers, technicians, and applicators, respectively; peak TCPy urinary concentrations were 75-129, 78-261, and 487-1659 MUg/l, respectively; geometric mean doses were 5.2 5.4, 8.6-9.7, and 50-57 MUg/kg, respectively, considering TCPy excretion half life values of 27 and 41 hours. All worker doses exceeded the acceptable operator exposure level of 1.5 MUg/kg/day. An estimated 94-96% of the dose was attributed to dermal exposure, calculated as the difference between total dose and inhalation dose. DISCUSSION: Interventions to reduce dermal exposure are warranted in this population, particularly for the hands, feet, and legs. PMID- 23026006 TI - Musculoskeletal symptoms among female garment factory workers in Sri Lanka. AB - OBJECTIVES: To assess the prevalence of musculoskeletal symptoms and their association with sociodemographic risk factors among female garment factory workers in Sri Lanka. METHODS: 1058 randomly selected female garment factory workers employed in the free trade zone of Kogalla, Sri Lanka were recruited to complete two interviewer-administered questionnaires assessing musculoskeletal symptoms and health behaviors. DISCUSSION: Musculoskeletal complaints among female garment workers in the FTZ of Kogalla are less common than expected. Sociocultural factors may have resulted in underreporting and similarly contribute to the low rates of healthcare utilization by these women. RESULTS: 164 (15.5%) of workers reported musculoskeletal symptoms occurring more than 3 times or lasting a week or more during the previous 12-month period. Back (57.3%) and knee (31.7%) were the most common sites of pain. Although most symptomatic women reported that their problems interfered with work and leisure activities, very few missed work as a result of their pain. Prevalence correlated positively with increased age and industry tenure of less than 12 months. Job type, body mass index, and education were not significant predictors of musculoskeletal symptoms. PMID- 23026007 TI - Toxicology of food dyes. AB - BACKGROUND: Food dyes, synthesized originally from coal tar and now petroleum, have long been controversial because of safety concerns. Many dyes have been banned because of their adverse effects on laboratory animals or inadequate testing. CONCLUSIONS: This review finds that all of the nine currently US approved dyes raise health concerns of varying degrees. Red 3 causes cancer in animals, and there is evidence that several other dyes also are carcinogenic. Three dyes (Red 40, Yellow 5, and Yellow 6) have been found to be contaminated with benzidine or other carcinogens. At least four dyes (Blue 1, Red 40, Yellow 5, and Yellow 6) cause hypersensitivity reactions. Numerous microbiological and rodent studies of Yellow 5 were positive for genotoxicity. Toxicity tests on two dyes (Citrus Red 2 and Orange B) also suggest safety concerns, but Citrus Red 2 is used at low levels and only on some Florida oranges and Orange B has not been used for several years. The inadequacy of much of the testing and the evidence for carcinogenicity, genotoxicity, and hypersensitivity, coupled with the fact that dyes do not improve the safety or nutritional quality of foods, indicates that all of the currently used dyes should be removed from the food supply and replaced, if at all, by safer colorings. It is recommended that regulatory authorities require better and independent toxicity testing, exercise greater caution regarding continued approval of these dyes, and in the future approve only well-tested, safe dyes. PMID- 23026008 TI - An updated review on asbestos and related diseases in China. AB - BACKGROUND: Asbestos is an industrial mineral that can cause diseases such as asbestosis, lung cancer, and mesothelioma. Asbestos consumption in China has increased steadily since the 1960s and is currently at half a million tonnes per year. Work conditions in the asbestos-related industries are poor and exposure levels frequently exceed the occupational exposure limit. OBJECTIVE: To provide an updated overview on asbestos production and consumption in China and discuss what is known about the resulting burden of asbestos-related diseases. FINDINGS: China is the world's top chrysotile consumer and second largest producer. Over a million people may be occupationally exposed, yet reliable disease statistics are unavailable and the national burden of asbestos-related disease (ARD) is not well known. Nevertheless, ARD prevalence, incidence, and mortality are expected to be high and will increase for many decades due to the volume of asbestos consumed historically, and a long latency period. CONCLUSIONS: Government policies to prevent ARD have been implemented but more actions are necessary to ensure compliance and ultimately, the complete elimination of asbestos to prevent a heavy future disease burden. PMID- 23026009 TI - Carcinogenicity and regulation of caramel colorings. AB - 2- and 4-methylimidazoles are present as contaminants in caramel colorings manufactured with ammonia catalysts. Both contaminants have been shown to induce cancer in animals and may be present in caramel colorings in amounts that exceed federal guidelines. California requires warning notices on products that could lead to consumption of more than 30 micrograms per day. The US Food and Drug Administration should bar the use of excessively contaminated caramel coloring in food. PMID- 23026011 TI - Electrochemical behaviors of single microcrystals of iron Hexacyanides/NaCl solid solution. AB - Solid-state solution with excellent ionic conductivity and redox activity has potential applications in electrochemical microdevices, such as transistors, switches, sensors, and actuators, due to its controllable assembly, integration, and package in microchips. In this paper, we present an electrochemical method to synthesize single microcrystals of an iron hexacyanides/NaCl solid solution and to assemble them into microdevices based on scanning electrochemical cell microscopy. The redox behaviors of the single microcrystals were investigated systematically, especially in the "all-in-solid-state", that is, without exposure to any external liquid environment. The unique metal/solid solution interface has similar electrochemical properties as the conventional metal/liquid solution interface. The apparent concentration of ion hexacyanides (1.05 * 10(-3) mol/L), the diffusion coefficient of the counterion Na(+) (8.05 * 10(-8) cm(2)/s), and the electron transfer rate in the lattice (1.22 * 10(-4) cm/s) were evaluated from the data obtained through all-in-solid-state cyclic voltammetry and electrochemical impedance. All the results are comparable to the conventional metal/solution theory of electrochemistry. PMID- 23026013 TI - The site of interference in the saccadic Stroop effect. AB - In two experiments, the source of competition in the saccadic Stroop effect was investigated. Colored strings of letters were presented at fixation with colored patches in the surround. The task of the participants was to make an eye movement to the patch in the same color as the central string of letters. Three types of cues were compared: Either the string of letters composed a word indicating a direction (the saccadic Stroop condition), or it was a set of arrow signs, or a peripheral stimulus appeared. Whereas response times and saccade errors were similarly influenced by the different types of cues, saccade trajectory deviations away from the cue were found only for peripheral onsets. A second experiment demonstrated that the absence of the curvature effects for direction words was not due to insufficient time to process the words. The results raise doubts on whether the saccadic Stroop effect is effectively an oculomotor effect and could pose a challenge to models of saccade target selection. PMID- 23026014 TI - A novel antimicrobial peptide derived from modified N-terminal domain of bovine lactoferrin: design, synthesis, activity against multidrug-resistant bacteria and Candida. AB - Lactoferrin (LF) is believed to contribute to the host's defense against microbial infections. This work focuses on the antibacterial and antifungal activities of a designed peptide, L10 (WFRKQLKW) by modifying the first eight N terminal residues of bovine LF by selective homologous substitution of amino acids on the basis of hydrophobicity, L10 has shown potent antibacterial and antifungal properties against clinically isolated extended spectrum beta lactamases (ESBL), producing gram-negative bacteria as well as Candida strains with minimal inhibitory concentrations (MIC) ranging from 1 to 8 MUg/mL and 6.5 MUg/mL, respectively. The peptide was found to be least hemolytic at a concentration of 800 MUg/mL. Interaction with lipopolysaccharide (LPS) and lipid A (LA) suggests that the peptide targets the membrane of gram-negative bacteria. The membrane interactive nature of the peptide, both antibacterial and antifungal, was further confirmed by visual observations employing electron microscopy. Further analyses, by means of propidium iodide based flow cytometry, also supported the membrane permeabilization of Candida cells. The peptide was also found to possess anti-inflammatory properties, by virtue of its ability to inhibit cyclooxygenase-2 (COX-2). L10 therefore emerges as a potential therapeutic remedial solution for infections caused by ESBL positive, gram negative bacteria and multidrug-resistant (MDR) fungal strains, on account of its multifunctional activities. This study may open up new approach to develop and design novel antimicrobials. PMID- 23026012 TI - Recovery of peripheral refractive errors and ocular shape in rhesus monkeys (Macaca mulatta) with experimentally induced myopia. AB - This study aimed to investigate the changes in ocular shape and relative peripheral refraction during the recovery from myopia produced by form deprivation (FD) and hyperopic defocus. FD was imposed in six monkeys by securing a diffuser lens over one eye; hyperopic defocus was produced in another six monkeys by fitting one eye with -3D spectacle. When unrestricted vision was re established, the treated eyes recovered from the vision-induced central and peripheral refractive errors. The recovery of peripheral refractive errors was associated with corresponding changes in the shape of the posterior globe. The results suggest that vision can actively regulate ocular shape and the development of central and peripheral refractions in infant primates. PMID- 23026016 TI - Formal training in forensic mental health: psychiatry and psychology. AB - The field of forensic mental health has grown exponentially in the past decades to include forensic psychiatrists and psychologists serving as the primary experts to the court systems. However, many colleagues have chosen to pursue the avenue of serving as forensic experts without obtaining formal training and experience. This article discusses the importance of formal education, training and experience for psychiatrists and psychologists working in forensic settings and the ethical implications that befall those who fail to obtain such credentials. Specific aspects of training and supervised experience are discussed in detail. PMID- 23026017 TI - Hans C. Freeman preface. PMID- 23026018 TI - Factors associated with the age of natural menopause and menopausal symptoms in Chinese women. AB - OBJECTIVE: To investigate the factors associated with the age of natural menopause and menopausal symptoms in a large population of Chinese middle-aged women. STUDY DESIGN: In this cross-sectional study, a total of 20,275 women (40 65 years) attending health screening in Jiangsu Province of China were enrolled. A structured questionnaire was used to collect data of demographics, menopausal status, chronic diseases, reproductive history, etc. Also we evaluated the severity of menopausal symptoms by Kupperman menopause index (KMI). MAIN OUTCOME MEASURE: Menopausal age and scorings of Kupperman menopause index. RESULTS: The overall median age at natural menopause was 50 years. Lower educational level, poor economic status, lower body mass index (BMI), age at menarche less than 14 years, nulliparity and smoking were associated with earlier onset of natural menopause (P<0.05). The most frequently symptoms in postmenopausal women were sexual problems (57.05%), muscle/joint pain (53.29%) and insomnia (51.02%), while fatigue, insomnia and muscle/joint pain were predominant symptoms in pre- and peri-menopausal women. After adjusting for confounding factors, logistic regression analysis revealed that women with poor educational background, low income, divorce, higher BMI, higher parity, smoking and chronic diseases presented higher KMI scores (P<0.05). CONCLUSION: The study provided an estimate of median age at natural menopause in Chinese women. The main factors contributing to earlier onset of menopause and severity of menopausal symptoms were lower educational level, poor economic status, and smoking. Thus, this study provides important insights for physicians to prevent and treat menopause related symptoms. PMID- 23026019 TI - Detection of prostate cancer by sialic acid level in patients with non-diagnostic levels of prostate-specific antigen. AB - INTRODUCTION: Ideally, there will be reproducible markers easily and non invasively available to test for malignancy, or alternative procedures when there is no accurate marker available. For prostate cancer, one of the most common cancers in men, levels of prostate-specific antigen (PSA) lack specificity and sensitivity for the determination of malignancy when they fall within a range of values termed the 'grey zone'. OBJECTIVE: To examine the predictive value of sialic acid in prostate neoplasms. STUDY DESIGN: In our study of diagnostic accuracy we recruited 70 men complaining of urinary symptoms who presented in the urology department as outpatients or inpatients. All patients were checked with biopsy and pathology in order to relate benign and malignant lesions of the prostate to levels of sialic acid, a member of a family of acetylated products of neuraminic acid, which has so far proved to be a very sensitive and accurate marker of malignancy. RESULTS: The sialic acid level was found to be elevated in patients with prostate cancer (mean 75.06+/-10.4 mg/dl) and reduced in patients with benign prostate hyperplasia (mean 57.086+/-8.7 mg/dl) (p<0.01); it had a sensitivity of 86% and specificity of 84% in diagnosing malignancy. CONCLUSION: Sialic acid can be used as an adjunct in predicting prostate malignancy when PSA values fall in the grey zone. PMID- 23026020 TI - Gender and sex differences in prevalence of major depression in coronary artery disease patients: a meta-analysis. AB - BACKGROUND: Depression is related to increased morbidity and mortality in the general population and among patients with coronary artery disease (CAD). The prevalence of major depression is two-times higher in women than men in the general population, but whether this pattern holds true in the CAD population has not been established. OBJECTIVE: To test, through quantitative synthesis, whether women with CAD have a greater prevalence of major depression than men. METHOD: MEDLINE, EMBASE, and PsycINFO electronic databases were searched. Authors of key articles were contacted to identify other relevant publications. The titles and abstracts were screened by the first author and the selected full-text articles were independently screened by the first and second authors based on pre-defined inclusion criteria. Major depression had to be diagnosed through structured clinical interviews during cardiac-related hospitalization or post-CAD hospitalization. Meta-analysis was undertaken using the Review Manager 5 software program. All pooled analyses were based on random-effects models. RESULTS: Eight eligible cohort and cross-sectional studies reporting data for 2072 participants (509 [24.6%] women) were included. Overall, major depression was observed in 95 (18.7%) women and 187 (12.0%) men. In the pooled analysis, prevalence of major depression was significantly greater in women compared to men (odds ratio=1.77, 95% confidence interval=1.21-2.58, p<.01). Heterogeneity was considered low to moderate (I(2)=36.0%). CONCLUSION: Consistent with the general population, the prevalence of major depression is two-times greater in women than men with CAD. Women with CAD may warrant greater emphasis in efforts to identify and treat depression. PMID- 23026021 TI - Social categories are shaped by social experience. AB - A new study by Rhodes and colleagues offers insight into the development of social essentialism - the belief that members of social categories share essential properties (e.g., attitudes, psychological capacities). The challenge now is to consider these issues in children raised in the more diverse social environments that constitute the range of human experience. PMID- 23026022 TI - Top-down attention and consciousness: comment on Cohen et al. PMID- 23026024 TI - Does the hydric environment affect the incubation of small rigid-shelled turtle eggs? AB - Hydric environments are hypothesized to have minor effects on the embryonic development of rigid-shelled turtle eggs due to the low water permeability of the eggshell. However, the water reserve in the eggs may still influence their resistance to environmentally induced dehydration. We incubated rigid-shelled turtle eggs (Pelodiscus sinensis) on different moist substrates (from -12 to 750kPa) to test the hypothesis that small rigid-shelled eggs would be sensitive to hydric environments. The hydric treatment significantly affected the incubation period, with eggs incubated in the moistest and driest substrates taking longer to hatch than those on the medium-moisture substrates. Hatching success was slightly lower for eggs incubated in dry conditions than those in wet conditions, but the difference was not statistically significant. The heart rates of early embryos were lower on moist substrates than those on dry substrates, but this difference disappeared in late embryos. Hatchlings from the moistest substrate were larger (in carapace length and width) and heavier than those from drier substrates. However, the dry body mass of the hatchlings did not differ among the hydric treatments. The functional performance (righting response) of the hatchlings was affected by the hydric environment. The time to right was shorter for the hatchlings from the substrate of -12kPa than those from -220kPa. These results are consistent with the hypothesis that the hydric environment may significantly affect developing embryos and the resulting hatchlings in turtle species, such as P. sinensis, with small rigid-shelled eggs. PMID- 23026023 TI - Lymph node ratio and pN staging show different superiority as prognostic predictors depending on the number of lymph nodes dissected in Chinese patients with luminal A breast cancer. AB - BACKGROUND: The lymph node ratio (LNR) classification has shown superiority to pN staging (the number of positive lymph nodes) in breast cancers, but it has not been examined according to whether sufficient lymph nodes have been dissected. METHODS: All Chinese patients with luminal A breast cancer with positive lymph nodes seen at Sun Yat-sen University Cancer Center between 1995 and 2009 were enrolled. Disease-free survival (DFS) and overall survival (OS) were the endpoints, and the patients were further classified into 2 groups according to whether <= 10 or > 10 lymph nodes were dissected. RESULTS: For the whole group, the OS curves of the pN stages overlapped, whereas they were separated in the LNR survival curves. LNR was an independent prognostic factor for OS and DFS, whereas the pN stage was not. In the <= 10 lymph nodes dissected group, both OS and DFS curves were clearly separated in the pN staging but overlapped in the LNR classification. In the > 10 lymph nodes dissected group, LNR showed no overlap in the OS curves and was an independent prognostic factor of OS and DFS when compared with pN staging. CONCLUSION: In Chinese patients with luminal A breast cancer, LNR classification and the pN stage show different superiority as prognostic predictors according to whether > 10 or < 10 lymph nodes are dissected. PMID- 23026025 TI - What parents say about disclosing the end of their pregnancy due to fetal abnormality. AB - OBJECTIVE: to describe men's and women's experiences of deciding whether to tell people in their social network, including their children, about their pregnancy loss following a termination for fetal abnormality. DESIGN: secondary analysis of qualitative narrative interview data informed by a critical realist approach. SETTING: respondents were recruited throughout the United Kingdom and interviewed at home between 2004 and 2005. PARTICIPANTS: twenty-eight women and nine men who had ended a pregnancy diagnosed with a fetal abnormality and who talked about disclosing or not disclosing the termination to others. FINDINGS: few respondents reported having any advice or information about whether or how to disclose their termination. None said they completely concealed their decision from adults in their social network; most said they disclosed selectively, telling close friends and family they had terminated and acquaintances they had miscarried. Most respondents reported telling their young children that the baby had died but did not reveal that they had chosen to end the pregnancy. A minority had not told their existing offspring about the pregnancy loss. Common reasons given for (partially) concealing a termination were: guilt over the decision; to avoid being judged; and to protect other people's feelings. Common reasons for disclosure were: others knew of the pregnancy; needing time off work; needing practical help and/or emotional support during diagnosis and termination; and wanting recognition of their loss. Positive consequences of disclosure were said to be getting more support and less criticism than expected; negative consequences included not getting the anticipated support and empathy; and encountering disapproval. Some respondents felt that concealing their pregnancy loss from their children had resulted in their confusion over the cause of their parents' distress. Some men said they found it hard to access emotional support from their social networks because of expectations about how men 'should' deal with emotions. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: midwives have to make difficult judgements about what, how and when to provide information when trying to support and advise parents who have ended a pregnancy due to fetal abnormality. Further education and training in this area could be of benefit. Midwives could signpost parents to existing sources of advice around disclosure, taking into account parents' individual preferences, help parents to consider the potential implications of disclosure and concealment and different ways of disclosing. They could also recommend alternative sources of emotional support, bearing in mind that men in particular may find it harder to access support from their social networks. PMID- 23026026 TI - Hepatic expression of toll-like receptors 3, 4, and 9 in primary biliary cirrhosis and chronic hepatitis C. AB - Toll-like receptors (TLRs) may play a role in the inflammatory patterns observed in primary biliary cirrhosis (PBC) and chronic hepatitis C (CHC). We investigated TLR 3, 4 and 9 expression in PBC and CHC using immunohistochemical staining. METHODS: Patient biopsies of PBC (N=11) and CHC (N=15) were compared to disease free livers (n=7). The extent of TLR staining was assessed separately according to a semi-quantitative scale for hepatocytes, cholangiocytes and portal mononuclear cells (PMC). RESULTS: In hepatocytes, TLR4 expression was increased (PBC; P=0.019), as was TLR9 (PBC; P=0.006, CHC; P=0.001). Cholangiocyte expression of TLRs 4 and 3 was reduced in both PBC (TLR4; P<0.0001, TLR3; P=0.006) and CHC (TLR4; P<0.0001, TLR3; P=0.014). Cholangiocyte expression of TLR9 was elevated for both groups and was significant in CHC (P=0.0115). PMCs showed up-regulation of TLR9 in PBC (P=0.022) and CHC (P=0.0001), with almost no expression of TLR 3 or 4. CONCLUSIONS: In PBC and CHC, hepatocytes showed increased TLR 4 and 9 expression without change in TLR3. Cholangiocytes showed increased TLR9 expression as opposed to down-regulation of TLRs 3 and 4. PMCs in both diseases had significantly increased TLR 9 expression perhaps implicating TLR9 expression in chronic liver inflammation. PMID- 23026027 TI - Protective role of vitamins E and C against oxidative stress caused by intermittent cold exposure in aging rat's frontoparietal cortex. AB - This study examined the role of vitamins E and C in combating oxidative stress (OS) caused by intermittent cold exposure (ICE) in the frontoparietal cortex (FPC) of adult (3 months), late-adult (12 months), middle-aged (18 months) and old (24 months) male Wistar rats. Each age group was divided into sub-groups, control (CON), cold-exposed at 5 degrees C (C5), control supplementees (CON+S) and cold-exposed supplementees (C5+S). The supplement was a daily dose of 400mg vitamin C and 50I.U.of vitamin E/kg body weight. Cold exposure lasted 2h/day for 4 weeks. All age groups except the old showed an increase in the final body mass in the cold-exposed. The feeding efficiency was higher in the cold-exposed irrespective of age. OS as reflected in age-related increased levels of hydrogen peroxide, protein carbonyl, advanced oxidation protein products and malondialdehyde showed further increase with ICE in the FPC. However, vitamins E and C supplementation attenuated the ICE-induced OS. ICE depleted the levels of tissue vitamins E and C while supplementation resulted in increased levels. Further age emerged as a significant factor in ICE-induced stress and also the response to vitamins E and C supplementation. Behavioral studies are underway to examine the findings on ICE-induced oxidative injury in the FPC, and the prospects for using vitamins E and C in cold exposures in the aged. PMID- 23026028 TI - Triage during mass gatherings. AB - Triage is a complex process and is one means for determining which patients most need access to limited resources. Triage has been studied extensively, particularly in relation to triage in overcrowded emergency departments, where individuals presenting for treatment often are competing for the available stretchers. Research also has been done in relation to the use of prehospital and field triage during mass-casualty incidents and disasters. In contrast, scant research has been done to develop and test an effective triage approach for use in mass-gathering and mass-participation events, although there is a growing body of knowledge regarding the health needs of persons attending large events. Existing triage and acuity scoring systems are suboptimal for this unique population, as these events can involve high patient presentation rates (PPR) and, occasionally, critically ill patients. Mass-gathering events are dangerous; a higher incidence of injury occurs than would be expected from general population statistics. The need for an effective triage and acuity scoring system for use during mass gatherings is clear, as these events not only create multiple patient encounters, but also have the potential to become mass-casualty incidents. Furthermore, triage during a large-scale disaster or mass-casualty incident requires that multiple, local agencies work together, necessitating a common language for triage and acuity scoring. In reviewing existing literature with regard to triage systems that might be employed for this population, it is noted that existing systems are biased toward traumatic injuries, usually ignoring mitigating factors such as alcohol and drug use and environmental exposures. Moreover, there is a substantial amount of over-triage that occurs with existing prehospital triage systems, which may lead to misallocation of limited resources. This manuscript presents a review of the available literature and proposes a triage system for use during mass gatherings that also may be used in the setting of mass-casualty incidents or disaster responses. PMID- 23026029 TI - Delving deeper: MCL-1's contributions to normal and cancer biology. AB - BCL-2 molecules are regulators of programmed cell death and defects in this pathway contribute to human diseases. One family member, MCL-1, is unique because its expression is tightly regulated and it is essential for promoting the survival of myriad cellular lineages. Additionally, MCL-1 promotes the maintenance of normal mitochondrial morphology and energy production. Dissection of these functions revealed recently that they depend on separate mitochondrial sublocalizations. MCL-1's antiapoptotic activity is restricted to the outer mitochondrial membrane (OMM), whereas its function in mitochondrial physiology requires localization to the matrix. These findings provide an attractive model for how MCL-1's diverse functions may contribute to normal cell homeostasis and function. MCL-1 is highly amplified in human cancer, suggesting that these functions may contribute to malignant cell growth and evasion of apoptosis. PMID- 23026031 TI - Directed cytoskeleton self-organization. AB - The cytoskeleton architecture supports many cellular functions. Cytoskeleton networks form complex intracellular structures that vary during the cell cycle and between different cell types according to their physiological role. These structures do not emerge spontaneously. They result from the interplay between intrinsic self-organization properties and the conditions imposed by spatial boundaries. Along these boundaries, cytoskeleton filaments are anchored, repulsed, aligned, or reoriented. Such local effects can propagate alterations throughout the network and guide cytoskeleton assembly over relatively large distances. The experimental manipulation of spatial boundaries using microfabrication methods has revealed the underlying physical processes directing cytoskeleton self-organization. Here we review, step-by-step, from molecules to tissues, how the rules that govern assembly have been identified. We describe how complementary approaches, all based on controlling geometric conditions, from in vitro reconstruction to in vivo observation, shed new light on these fundamental organizing principles. PMID- 23026032 TI - Seeking health advice from social networks in low-income urban neighborhoods. AB - OBJECTIVES: To examine how individuals residing in low-income neighborhoods use their social networks for health advice. METHODS: Secondary data analysis of 363 individuals living in low-income neighborhoods was conducted using social network analysis and logistic regression techniques. RESULTS: Findings suggest that residents typically seek health advice from one or 2 friends and family members rather than a health professional. Age and family history of illness increased the likelihood that one would seek support whereas the combination of anxiety and depression decreased advice seeking. CONCLUSIONS: Findings support the need for multidisciplinary strategies for disseminating health information through informal social networks. PMID- 23026030 TI - MicroRNAs and neurodegeneration: role and impact. AB - Neurodegenerative diseases are typically late-onset, progressive disorders that affect neural function and integrity. Although most attention has been focused on the genetic underpinnings of familial disease, mechanisms are likely to be shared with more predominant sporadic forms, which can be influenced by age, environment, and genetic inputs. Previous work has largely addressed the roles of select protein-coding genes; however, disease pathogenesis is complicated and can be modulated through not just protein-coding genes, but also regulatory mechanisms mediated by the exploding world of small non-coding RNAs. Here, we focus on emerging roles of miRNAs in age-associated events impacting long-term brain integrity and neurodegenerative disease. PMID- 23026033 TI - Osteoporosis prevention behaviors practiced among youth in Taichung City, Taiwan. AB - OBJECTIVE: To examine demographic characteristics, knowledge, and attitudes of adolescents on osteoprotective practices in Taichung City, Taiwan. METHODS: Using convenience sampling, 329 students from randomly selected high schools and colleges were recruited to respond to a 58-item questionnaire. RESULTS: Adolescents had significantly higher overall osteoprotective behavior practice scores than those of young adults (P<0.001). Those self-described as healthy had significantly higher osteoprotective behavior scores. Younger participants had significantly higher scores regarding osteoprotective behaviors. CONCLUSIONS: Young people in Taiwan have moderate knowledge about osteoporosis and do practice osteoprotective behaviors, but infrequently. Osteoporosis knowledge and attitudes are not associated with osteoprotective behaviors. PMID- 23026034 TI - Alcohol and sexual consent scale: development and validation. AB - OBJECTIVE: To establish a short measure of attitudes toward sexual consent in the context of alcohol consumption. METHODS: Using a multistage and systematic measurement development process, the investigators developed the Alcohol and Sexual Consent Scale using a sample of college students. RESULTS: The resulting 12-item scale, the Alcohol and Sexual Consent Scale, was examined across a variety of validation measures. The measure is related to alcohol consumption, sexual habits, and sexual victimization and/or perpetration. CONCLUSIONS: The Alcohol and Sexual Consent Scale can be used to serve as an outcome measure in sexual assault prevention programming. PMID- 23026035 TI - Neighborhood environment profiles for physical activity among older adults. AB - OBJECTIVES: To explore among older adults whether multivariate neighborhood profiles were associated with physical activity (PA) and BMI. METHODS: Adults (66 97 years) were recruited from Baltimore-Washington, DC (n=360), and Seattle-King County, Washington (n=368), regions. Latent profile analyses were conducted using the Neighborhood Environment Walkability Scale. ANCOVA models tested for criterion validity of profiles by examining relationships to PA and BMI. RESULTS: Neighborhood profiles differed significantly by as much as 10 minutes/day for moderate-to-vigorous PA, 1.1 hours/week for walking for errands, and almost 50 minutes/week for leisure PA. CONCLUSIONS: Environmental variables resulted in meaningful neighborhood patterns that explained large differences in seniors' health outcomes. PMID- 23026036 TI - Cognitive and emotional responses to human papillomavirus test results in men. AB - OBJECTIVE: To report psychosocial differences between self-reported HPV-positive and HPV-negative Florida men. METHOD: Men (n=536) in an HPV natural-history study completed a cross-sectional survey (2007-2010). RESULTS: Most participants were white, non-Hispanic, and unmarried with some college education. HPV knowledge was high overall. HPV-positive men reported more negative emotions and perceived threat (P<0.05). HPV-negative men were more likely to disclose test results. Most men (91%) reported strong intentions for the HPV vaccine if it became available for men. CONCLUSIONS: Men reported an array of responses to HPV tests with intentions to receive the HPV vaccine. Findings are important for HPV-related health messages for men. PMID- 23026038 TI - Social-ecological factors of leisure-time physical activity in Black adults. AB - OBJECTIVES: To develop and test an explicative model of leisure-time physical activity (LTPA), including 6 selected contributory factors: self-efficacy, self regulation, social support, perceived physical environment, outcome-expectancy value, and policy beliefs. METHODS: A social-ecological model of LTPA using the structural equation modeling technique was estimated in a regional, church-going sample of 649 African Americans. RESULTS: The results indicated this model is good fit to the data. LTPA was associated with self-regulation and gender directly (P<.05) and social support, self-efficacy, perceived access to LTPA facilities, and positive outcome-expectancy value indirectly (P<.05). CONCLUSIONS: Multitiered interventions considering cultural relevance are recommended to improve LTPA engagement. PMID- 23026037 TI - Work hours and perceived time barriers to healthful eating among young adults. AB - OBJECTIVE: To describe time-related beliefs and behaviors regarding healthful eating, indicators of dietary intake, and their associations with the number of weekly hours of paid work among young adults. METHODS: Population-based study in a diverse cohort (N=2287). RESULTS: Working > 40 hours per week was associated with time-related barriers to healthful eating most persistently among young adult men. Associations were found among females working both part-time and > 40 hours per week with both time-related barriers and dietary intake. CONCLUSIONS: Findings indicate that intervention strategies, ideally those addressing time burden, are needed to promote healthful eating among young, working adults. PMID- 23026039 TI - Stages of change in hearing-protection behavior, cognition, and hearing status. AB - OBJECTIVE: To determine stages of hearing-protection behavioral change and their relationships with cognitions and hearing status. METHOD: A cross-sectional study of 769 construction workers who completed a survey and audiometric tests. RESULTS: The majority of participants (over 64%) were in the preparation stage. Participants in the action/maintenance stage demonstrated significantly greater benefits, self-efficacy, and interpersonal influence; fewer barriers; and better hearing. This is the first study that shows significantly better health outcome, hearing ability, as the stage progresses. CONCLUSION: Study demonstrates preliminary validity of the stages of change with hearing-protection behavior. Future hearing-protection intervention should integrate the stages of change to increase effectiveness. PMID- 23026040 TI - Legislator voting and behavioral science theory: a systematic review. AB - OBJECTIVES: To examine the application of behavioral science theories to explain the voting behavior of legislators for public health policies. METHODS: We conducted a systematic review to identify studies that examined factors associated with legislator support, intention to vote, or actual votes on public health policies, emphasizing those grounded in behavior science theory. RESULTS: Twenty-one papers met our inclusion criteria, and 6 were explicitly grounded in a behavioral science theory. CONCLUSIONS: Behavioral science theories, and the theory of planned behavior in particular, provide a framework for understanding legislator voting behavior and can be used by advocates to advance pro-health policies. PMID- 23026041 TI - Early socioeconomic disadvantage and young adult sexual health. AB - OBJECTIVE: To test a longitudinal and multilevel model predicting young adult risky sexual behaviors and sexually transmitted infections. METHODS: Data from 14,058 participants in 3 waves were used to link community and family disadvantage, adolescent adjustment problems, and risky sexual behaviors with STIs. RESULTS: Community-level disadvantage, being African American, and being female remained predictors of sexual behaviors and STIs whereas adolescent adjustment mediated the effect of several family characteristics. CONCLUSIONS: This study demonstrates how individual-, family-, and community-level characteristics and vulnerabilities contribute to young adult sexual risk and STI prevalence. Findings indicate specific individual characteristics and childhood experiences that should be specific targets of STI prevention efforts. PMID- 23026042 TI - Perceived risk of cervical cancer in Appalachian women. AB - OBJECTIVE: To examine perceptions of cervical cancer risk in elevated-risk Appalachians. METHODS: Appalachian women (n=571) completed interviews examining self-regulation model factors relevant to perceived risk of cervical cancer. RESULTS: Women with good/very good knowledge of cervical cancer, greater worry, and history of sexually transmitted infection had higher odds of rating their perceived risk as somewhat/much higher than did other women. Former smokers, compared to never smokers, had lower risk perceptions. CONCLUSIONS: Self regulation model factors are important to understanding perceptions of cervical cancer risk in underserved women. The relationship of smoking and worry to perceived risk may be a target for intervention. PMID- 23026043 TI - Relations between anhedonia and physical activity. AB - OBJECTIVE: To examine the relation of 2 measures of anhedonia-a specific facet of depression indicative of inability to experience pleasure-to physical activity (PA). METHOD: Cross-sectional correlational survey study of 157 college students (73% female, M age 19.9 years). RESULTS: One or both measures of anhedonia were inversely associated with walking frequency, moderate-intensity PA frequency and duration, and vigorous-intensity PA frequency and duration (betas -16 to -.27, Ps < .05). Some of these associations were statistically mediated by lower PA enjoyment. CONCLUSIONS: Deficient pleasure may be an important affective mechanism underlying PA behavior. PMID- 23026044 TI - Chlorophyll triplet quenching by fucoxanthin in the fucoxanthin-chlorophyll protein from the diatom Cyclotella meneghiniana. AB - In this work we present an optically detected magnetic resonance (ODMR) study on the triplet states populated under illumination in the isolated fucoxanthin chlorophyll light-harvesting complex from the diatom Cyclotella meneghiniana. Evidence for the quenching of chlorophyll triplet states by fucoxanthin is provided, showing that this carotenoid is able to perform the photoprotective role. For the first time, the magnetic parameters characterizing the fucoxanthin triplet state have been determined. The results reveal analogies but also differences with respect to the triplet-triplet energy transfer process, which involves chlorophylls a and carotenoids in the LHC complex from dinoflagellates and LHCII from higher plants. The degree of efficiency of the photoprotection mechanism, in these light harvesting complexes, is discussed in terms of pigment protein structure. PMID- 23026045 TI - Hearing restoration in a deaf animal model with intravenous transplantation of mesenchymal stem cells derived from human umbilical cord blood. AB - OBJECTIVE: This study was performed to confirm the effect of transplantation of human umbilical cord blood mesenchymal stem cells (UCB-MSCs) on hearing restoration in a sensorineural hearing loss (SNHL) animal model. MATERIAL AND METHODS: UCB was collected from pregnant women after obtaining consent, and mesenchymal stem cells (MSCs) were extracted. We established an SNHL model and transplanted UCB-MSCs through the brachial vein of the guinea pigs. The animals were divided into 4 groups: animals with normal hearing, animals with SNHL, animals with SNHL and injected with saline, and animals with SNHL and transplanted with UCB-MSCs. Hearing tests were conducted at 1, 3, and 5 weeks, and the results were compared by grading auditory brainstem response (ABR) recordings and distortion product otoacoustic emissions (DPOAEs) for each treatment. Lastly, cochlear pathological features were examined, and surface preparations and morphological changes in each animal model were compared using hematoxylin and eosin staining and light microscopy studies. RESULTS: In SNHL group, decreased DPOAEs and increased ABR threshold were noted. Furthermore, in the SNHL group, ABR hearing thresholds were unconverted and were similar to those observed in deafness. The transplanted UCB-MSC group showed a significant improvement in hearing threshold (40 dB) compared to that in all the SNHL group (80-90 dB). Examination of the SNHL animals' cochlear morphological features demonstrated a noticeable lack of spiral ganglion cells and also showed degenerated outer hair cells. However, the transplanted UCB-MSCs showed an increase in spiral ganglion and hair cells. CONCLUSION: Intravenous transplantation of UCB-MSCs can enhance hearing thresholds, outer-hair cells and increase the number of spiral ganglion neurons (SGNs). PMID- 23026046 TI - Sperm-specific glyceraldehyde-3-phosphate dehydrogenase is expressed in melanoma cells. AB - Sperm-specific glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDS) is normally expressed only in sperms, but not in somatic tissues. Analysis of the expression of GAPDS mRNA in different cancer cell lines shows that the content of GAPDS mRNA is enhanced in some lines of melanoma cells. The purpose of the study was to assay melanoma cells for the expression of protein GAPDS. Three different lines of melanoma cells were investigated. By data of Western blotting, all investigated cells contain a 37-kDa fragment of GAPDS polypeptide chain, which corresponds to the enzyme GAPDS lacking N-terminal amino acid sequence that attaches the enzyme to the cytoskeleton of the sperm flagellum. The results suggest that GAPDS is expressed in melanoma cells without N-terminal domain. The immunoprecipitation of proteins from melanoma cell extracts using rabbit polyclonal antibodies against native GAPDS allowed isolation of complexes containing 37-kDa subunit of GAPDS and full-length subunit of somatic glyceraldehyde-3-phosphate dehydrogenase (GAPD). The results indicate that melanoma cells express both isoenzymes, which results in the formation of heterotetrameric complexes. Immunocytochemical staining of melanoma cells revealed native GAPDS in the cytoplasm. It is assumed that the expression of GAPDS in melanoma cells may facilitate glycolysis and prevent the induction of apoptosis. PMID- 23026047 TI - Targeting ILK and beta4 integrin abrogates the invasive potential of ovarian cancer. AB - Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of beta1 and beta4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of beta1 and beta4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of beta4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of beta4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting beta4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer. PMID- 23026048 TI - High glucose induces inflammatory cytokine through protein kinase C-induced toll like receptor 2 pathway in gingival fibroblasts. AB - Toll-like receptors (TLRs) play a key role in innate immune response and inflammation, especially in periodontitis. Meanwhile, hyperglycemia can induce inflammation in diabetes complications. However, the activity of TLRs in periodontitis complicated with hyperglycemia is still unclear. In the present study, high glucose (25 mmol/l) significantly induced TLR2 expression in gingival fibroblasts (p<0.05). Also, high glucose increased nuclear factor kappa B (NF kappaB) p65 nuclear activity, tumor necrosis factor-alpha (TNF-alpha) and interleukin-lbeta (IL-1beta) levels. Protein kinase C (PKC)-alpha and delta knockdown with siRNA significantly decreased TLR2 and NF-kappaB p65 expression (p<0.05), whereas inhibition of PKC-beta had no effect on TLR2 and NF-kappaB p65 under high glucose (p<0.05). Additional studies revealed that TLR2 knockdown significantly abrogated high-glucose-induced NF-kappaB expression and inflammatory cytokine secretion. Collectively, these data suggest that high glucose stimulates TNF-alpha and IL-1beta secretion via inducing TLR2 through PKC alpha and PKC-delta in human gingival fibroblasts. PMID- 23026050 TI - Cereblon inhibits proteasome activity by binding to the 20S core proteasome subunit beta type 4. AB - In humans, mutations in the gene encoding cereblon (CRBN) are associated with mental retardation. Although CRBN has been investigated in several cellular contexts, its function remains unclear. Here, we demonstrate that CRBN plays a role in regulating the ubiquitin-proteasome system (UPS). Heterologous expression of CRBN inhibited proteasome activity in a human neuroblastoma cell line. Furthermore, proteasome subunit beta type 4 (PSMB4), the beta7 subunit of the 20S core complex, was identified as a direct binding partner of CRBN. These findings suggest that CRBN may modulate proteasome activity by directly interacting with the beta7 subunit. PMID- 23026049 TI - c-Met inhibitor SU11274 enhances the response of the prostate cancer cell line DU145 to ionizing radiation. AB - Hormone-refractory prostate cancer shows substantial resistance to most conventional therapies including radiotherapy, constitutes a key impediment to curing patients with the disease. c-Met overexpression plays a key role in prostate cancer tumorigenesis and disease progression. Here, we demonstrate that c-Met inhibition by SU11274 could significantly suppress cell survival and proliferation as well as enhance the radiosensitivity of DU145 cells. The underlying mechanisms of the effects of SU11274 on DU145 cells may include the inhibition of c-Met signaling, depolarization of the mitochondrial membrane potential, impairment of DNA repair function, abrogation of cell cycle arrest, and enhancement of cell death. Our study is the first to show the effectiveness of combining c-Met inhibition with ionizing radiation to cure hormone-refractory prostate cancer. PMID- 23026051 TI - A folding-after-binding mechanism describes the recognition between the transactivation domain of c-Myb and the KIX domain of the CREB-binding protein. AB - A large body of evidence suggests that a considerable fraction of the human proteome may be at least in part intrinsically unstructured. While disordered, intrinsically unstructured proteins are nevertheless functional and mediate many interactions. Despite their significant role in regulation, however, little is known about the molecular mechanism whereby intrinsically unstructured proteins exert their function. This basic problem is critical to establish the role, if any, of disorder in cellular systems. Here we present kinetic experiments supporting a mechanism of binding-induced-folding when the KIX domain of the CREB binding protein binds the transactivation domain of c-Myb, an intrinsically unstructured domain. The high-resolution structure of this physiologically important complex was previously determined by NMR spectroscopy. Our data reveal that c-Myb recognizes KIX by first forming a weak encounter complex in a disordered conformation, which is subsequently locked-in by a folding step, i.e. binding precedes folding. On the basis of the pH dependence of the observed combination and dissociation rate constants we propose a plausible mechanism for complex formation. The implications of our results in the light of previous work on intrinsically unstructured systems are discussed. PMID- 23026052 TI - Saccharomyces cerevisiae Hrq1 requires a long 3'-tailed DNA substrate for helicase activity. AB - RecQ helicases are well conserved proteins from bacteria to human and function in various DNA metabolism for maintenance of genome stability. Five RecQ helicases are found in humans, whereas only one RecQ helicase has been described in lower eukaryotes. However, recent studies predicted the presence of a second RecQ helicase, Hrq1, in fungal genomes and verified it as a functional gene in fission yeast. Here we show that 3'-5' helicase activity is intrinsically associated with Hrq1 of Saccharomyces cerevisiae. We also determined several biochemical properties of Hrq1 helicase distinguishable from those of other RecQ helicase members. Hrq1 is able to unwind relatively long duplex DNA up to 120-bp and is significantly stimulated by a preexisting fork structure. Further, the most striking feature of Hrq1 is its absolute requirement for a long 3'-tail (?70-nt) for efficient unwinding of duplex DNA. We also found that Hrq1 has potent DNA strand annealing activity. Our results indicate that Hrq1 has vigorous helicase activity that deserves further characterization to expand our understanding of RecQ helicases. PMID- 23026053 TI - Kinetic analysis of reverse transcriptase activity of bacterial family A DNA polymerases. AB - Some bacterial thermostable, wild-type or genetically engineered family A DNA polymerases have reverse transcriptase activity. However, difference in reverse transcriptase activities of family A DNA polymerases and retroviral reverse transcriptases (RTs) is unclear. In this study, comparative kinetic analysis was performed for the reverse transcriptase activities of the wild-type enzyme of family A DNA polymerase (M1pol(WT)) from Thermus thermophilus M1 and the variant enzyme of family A DNA polymerase (K4pol(L329A)), in which the mutation of Leu329 >Ala is undertaken, from Thermotoga petrophila K4. In the incorporation of dTTP into poly(rA)-p(dT)(45), the reaction rates of K4pol(L329A) and M1pol(WT) exhibited a saturated profile of the Michaelis-Menten kinetics for dTTP concentrations but a substrate inhibition profile for poly(rA)-p(dT)(45) concentrations. In contrast, the reaction rates of Moloney murine leukemia virus (MMLV) RT exhibited saturated profiles for both dTTP and poly(rA)-p(dT)(45) concentrations. This suggests that high concentrations of DNA-primed RNA template decrease the efficiency of cDNA synthesis with bacterial family A DNA polymerases. PMID- 23026054 TI - Evaluation of drug and sunscreen permeation via skin irradiated with UVA and UVB: comparisons of normal skin and chronologically aged skin. AB - BACKGROUND: Ultraviolet (UV) exposure is the predominant cause of skin aging. A systematic evaluation of drug skin permeation via photoaged skin is lacking. OBJECTIVES: The aim of this work was to investigate whether UVA and UVB affect absorption by the skin of drugs and sunscreens, including tetracycline, quercetin, and oxybenzone. METHODS: The dorsal skin of nude mice was subjected to UVA (24 and 39 J/cm(2)) or UVB (150, 200, and 250 mJ/cm(2)) irradiation. Levels of skin water loss, erythema, and sebum were evaluated, and histological examinations of COX-2 and claudin-1 expressions were carried out. Permeation of the permeants into and through the skin was determined in vitro using a Franz cell. In vivo skin uptake was also evaluated. Senescent skin (24 weeks old) was used for comparison. RESULTS: Wrinkling and scaling were significant signs of skin treated with UVA and UVB, respectively. The level of claudin-1, an indicator of tight junctions (TJs), was reduced by UVA and UVB irradiation. UVA enhanced tetracycline and quercetin skin deposition by 11- and 2-fold, respectively. A similar enhancement was shown for flux profiles. Surprisingly, a lower UVA dose revealed greater enhancement compared to the higher dose. The skin deposition and flux of tetracycline both decreased with UVB exposure. UVB also significantly reduced quercetin flux. The skin absorption behavior of chronologically aged skin approximated that of the UVA group, with photoaged skin showing higher enhancement. UV generally exhibited a negligible effect on modulating oxybenzone permeation. CONCLUSIONS: Skin disruption produced by UV does not necessarily result in enhanced skin absorption. It depends on the UV wavelength, irradiated energy, and physicochemical properties of the permeant. To the best of our knowledge, this is the first report establishing drug permeation profiles for UV irradiated skin. PMID- 23026055 TI - Microarray analysis of microRNA expression in cutaneous squamous cell carcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) are a novel class of short RNAs that are capable epigenetically regulating gene expression in eukaryotes. MicroRNAs have been shown to be dysregulated in a variety of cancers. The data on miRNA expression in cutaneous squamous cell carcinoma (cSCC) are very limited, and microarray-based miRNA expression profiles of cSCC have not yet been determined. OBJECTIVE: To describe differentially expressed miRNAs in cSCC. METHODS: Seven patients with cSCC were enrolled in the present study. Tumor biopsies (n=7) were taken from the center of each tumor. Adjacent healthy skin (n=7) was biopsied as a control (intraindividual control). miRNA expression profiles of all specimens were detected by microarray miRNA expression profiling based on miRBAse 16 scanning for 1205 potential human miRNA target sequences. The microarray results were confirmed by TaqMan quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Non-stringent filtering with a non-adjusted p <= 0.05 revealed thirteen up-regulated and eighteen down-regulated miRNAs. Non-stringent filtering with a non-adjusted p <= 0.01 revealed three up-regulated (hsa-miR-135b, hsa-miR-424 and hsa-miR-766) and six down-regulated (hsa-miR-30a*, hsa-miR-378, hsa-miR-145, hsa miR-140-3p, hsa-miR-30a and hsa-miR-26a) miRNAs in cSCC. CONCLUSION: This study reveals differentially expressed miRNAs that may play a role in the molecular pathogenesis of cSCC and that are excellent candidates for further validation and functional analysis. PMID- 23026057 TI - Effects of nicotine on electroencephalographic (EEG) and behavioural measures of visual working memory in non-smokers during a dual-task paradigm. AB - Research in smokers has shown that nicotine may have the ability to improve certain aspects of cognitive performance, including working memory and attention, processes which implicate frontal and frontal-parietal brain networks. There is limited research on the cognitive effects of nicotine and their associated neural underpinnings in non-smokers. This study examined the effects of acute nicotine on a working memory task alone or combined with a visual detection task (single- and dual-task conditions) using electroencephalographic (EEG) recordings and behavioural performance measures. Twenty non-smokers (13 females; 7 males) received nicotine gum (6 mg) in a double-blind, randomized, placebo-controlled, repeated measures design. Spectral EEG, together with response speed and accuracy measures, were obtained while participants completed a series of N-Back tasks under single- and dual-task conditions. Nicotine failed to exert any significant effects on performance measures, however, EEG changes were observed, primarily in frontal recordings, which varied with memory load, task condition and hemisphere. These findings, discussed in relation to previous studies in smokers, support the notion that nicotine may modulate central executive systems and contribute to smoking behaviour. PMID- 23026058 TI - Amphetamine-induced locomotion in a hyperdopaminergic ADHD mouse model depends on genetic background. AB - We previously generated a knock-in mouse line with a cocaine-insensitive dopamine transporter (DAT-CI mice). These mice lost several behavioral responses to cocaine, but retained their response to amphetamine. DAT-CI mice are hyperdopaminergic due to reduced DAT function, and may thus be a good model for studying attention deficit hyperactivity disorder (ADHD). These mice had been behaviorally characterized while they were on a mixed genetic background. However as the colony was propagated over time, the mixed genetics were shifted toward a pure C57Bl/6J background--via a common breeding scheme known as "backcrossing." Several phenotypes appeared to have changed during this time frame. In this study, we investigated whether backcrossing altered the hyperlocomotive phenotype and behavioral responses to amphetamine, a drug used to treat ADHD. C57-congenic DAT-CI mice had high spontaneous locomotor activity that could be suppressed by low doses of amphetamine. Furthermore, their locomotion was not stimulated by very high doses of amphetamine (20mg/kg). After the reversion to a mixed genetic background by breeding with the 129 strain, the C57:129 hybrid DAT-CI mice displayed reduced basal locomotor activity compared to the C57-congenic mutant mice, and regained locomotor stimulation by high-dose amphetamine. The calming effect of amphetamine at low doses was retained in both strains. In summary, reduced DAT function in DAT-CI mice leads to a hyperdopaminergic state, and an ADHD-like phenotype in both strains. The data show that the genetic background of DAT-CI mice affects their locomotor phenotypes and their responses to amphetamine. Since the differences in genetic background between the strains of mice have a significant impact on the ADHD-like phenotype and the response to amphetamine, further study with these strains could identify the genetic underpinnings affecting the severity of ADHD-related symptoms and the treatment response. PMID- 23026056 TI - Dopamine and glutamate release in the dorsolateral caudate putamen following withdrawal from cocaine self-administration in rats. AB - Evidence suggests that cocaine addiction may involve progressive neuroadaptive changes in the dorsolateral caudate putamen (dlCPu). While cocaine seeking following abstinence from chronic self-administration requires intact dlCPu function, in vivo neurotransmitter release in the dlCPu has not been investigated. The current study measured dlCPu dopamine (DA) and glutamate (GLU) release during drug seeking following limited or extended abstinence, as well as in response to a cocaine priming injection alone. Male, Sprague-Dawley rats self administered cocaine (0.2mg/50MUl infusion, i.v.) for 10days (2h/day). In vivo microdialysis occurred in the self-administration chamber after 1 and 14days of abstinence (Experiment 1). A separate set of animals that completed self administration as well as drug naive controls received a cocaine priming injection (20mg/kg) during concurrent microdialysis (Experiment 2). DA release increased during drug seeking in the self-administration context at both 1 and 14days post abstinence. In contrast, GLU release only increased after 1day of abstinence. Furthermore, animals with a cocaine self-administration history showed enhanced DA and GLU release following cocaine challenge as compared to drug naive controls. These results indicate that chronic cocaine self administration enhances dlCPu DA and GLU under both drug-paired context and drug primed conditions. PMID- 23026059 TI - Interactions of CB1 and mGlu5 receptor antagonists in food intake, anxiety and memory models in rats. AB - CB(1) receptor antagonists proved to be effective anti-obesity drugs, however, their depressive and anxiogenic effects became also evident. Finding solution to overcome these psychiatric side effects is still in focus of research. Based on the available clinical and preclinical results we hypothesized that the combination of CB(1) and mGlu(5) receptor antagonisms may result in a pharmacological intervention, where the anxiolytic mGlu(5) receptor inhibition may counteract the anxiogenic psychiatric side effects of CB(1) antagonism, while CB(1) antagonism may ameliorate the memory impairing effect of mGlu(5) receptor antagonism. Further, the two components will synergistically interact in blocking food-intake and reducing obesity. For testing the interaction of mGlu(5) and CB(1) receptor antagonism MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pridine; SIB-1757, 6-methyl-2-(phenylazo)-3-pyridinol)] (mGlu(5) antagonist) and rimonabant [(5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1 yl)-1H-pyrazole-3-carboxamide)hydrochloride] (CB(1) antagonist) were used. All experiments were carried out in rats. Effects of the compounds on anxiety were tested in two foot shock induced ultrasonic vocalization paradigms, appetite suppression was assessed in the food intake test, while memory effects were tested in a context conditioned ultrasonic vocalization setup. MTEP abolished the anxiogenic effect of rimonabant, while there was an additive cooperation in suppressing appetite. However, rimonabant did not ameliorate the memory impairing effect of MTEP. By combination of CB(1) and mGluR5 antagonism, anxiety related side effects might be attenuated, appetite suppression maintained, nevertheless, the possible emergence of unwanted memory impairments can overshadow its therapeutic success. PMID- 23026060 TI - Metabotropic glutamate receptor 5 modulates behavioral and hypothermic responses to toluene in rats. AB - Toluene, a widely used and commonly abused organic solvent, produces various behavioral disturbances in both humans and animals. Blockade of N-methyl-d aspartate (NMDA) receptors has been suggested to play a critical role in acute toluene-induced behavioral manifestations. Activation of type 5 metabotropic glutamate receptors (mGluR5) attenuates behavioral responses induced by NMDA receptor blockade. The present study elucidated the role of mGluR5 on toluene induced behavioral and hypothermic responses. Male Sprague-Dawley rats received the mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) or antagonist 6 methyl-2-[phenylethynyl]-pyridine (MPEP) prior to toluene administration. Rotarod test, step-down inhibitory avoidance learning task, and rectal temperature were monitored. Pretreatment of CHPG and MPEP attenuated and potentiated these toluene induced responses, respectively. In addition, the inhibitory effects of CHPG on toluene-induced motor incoordination, learning impairment, and hypothermia were reversed by the protein kinase C (PKC) inhibitor chelerythrine chloride. These findings suggest that mGluR5 may modulate the neural circuits responsible for motor incoordination, learning impairment, and hypothermic action of toluene through a PKC-dependent signal transduction pathway. PMID- 23026061 TI - Protective effects of nizofenone administration on the cognitive impairments induced by chronic restraint stress in mice. AB - The present study was aimed to investigate the effects of nizofenone administration on the chronic restraint stress-induced cognitive impairments in mice. Adult male mice were randomized into five groups: control group, nizofenone control group, chronic restraint stress group, and nizofenone treatment groups (3.0mg/kg and 9.0mg/kg). The changes of cognitive performances were examined by Morris water maze (MWM), open field and step-through tests. Our results showed that the cognitive performances in CRS group were markedly deteriorated, accompanied by noticeable alterations in oxidative parameters, acetylcholinesterase activity and catecholamines levels in the hippocampus and the prefrontal cortex. These changes could be reversed by nizofenone treatment. Moreover, CRS group showed higher corticosterone levels and lower catecholamines levels in the serum, which were reversed in the nizofenone treatment groups. Collectively, the present results suggested the potential of nizofenone in attenuating the CRS-induced cognitive impairments. PMID- 23026066 TI - Detection and characterization of endogenous retroviruses in the horse genome by in silico analysis. AB - Endogenous retroviruses (ERVs) are proviral phases of exogenous retroviruses that have become incorporated into the host genome. Little is known about ERVs in the horse genome. By combining 3 bioinformatic approaches, we detected 1947 putative ERVs in the horse genome. These equine ERVs are not scattered randomly across the genome and are especially abundant in the X chromosome. Based on phylogenetic relationships, some of these equine ERVs were classified into 15 previously uncharacterized families of Classes I, II and III. Compared with the cow and other species, the horse genome appears to container fewer ERVs. Although this could be due to limitations of the detection process, it could also stem from characteristics of the horse genome or the effect of the domestication process. PMID- 23026062 TI - Avoidance disruptive effect of clozapine and olanzapine is potentiated by increasing the test trials: further test of the motivational salience hypothesis. AB - Antipsychotic drugs suppress animals' ability to avoid an aversive stimulus in the conditioned avoidance response model (CAR). This behavioral effect is thought to reflect antipsychotic activity and is suggested to be mediated by a drug's action in attenuating the motivational salience of a conditioned stimulus (CS). In the present study, we tested whether atypical antipsychotic drugs clozapine and olanzapine act through this behavioral mechanism by manipulating the number of avoidance test trials. We reasoned that more CS trials in the presence of clozapine or olanzapine would afford the drug more opportunities to decrease the motivational salience of the CS, thus avoidance decline would be greater with the increase of CS trials in each test session. In two separate experiments, adult male Sprague-Dawley rats were tested under clozapine (5.0mg/kg, sc), olanzapine (0.5mg/kg, sc) or vehicle (sterile water) for 6 consecutive days in three CS trial conditions (i.e. 3, 10, and 40 CS trials per session). Two days later, all rats were tested under the same 40-trial session after receiving clozapine (5.0mg/kg, sc) or olanzapine (0.5mg/kg, sc). Results show that repeated clozapine and olanzapine treatment persistently decreased avoidance response, and this effect was potentiated by the increase of number of CS trials in the test sessions, as the clozapine-treated or olanzapine-treated rats tested under the 40 trial or 10-trial condition had significantly lower avoidance and faster decline across-sessions than those tested under the 3-trial condition. This potentiated effect was not only seen in the total avoidance percentage, but also observed in the within-session decline pattern in the last three drug test sessions and in the final 40-trial test session. These findings suggest that the clinical efficacy of a drug can be enhanced by increasing the exposure of symptoms in the presence of the drug. PMID- 23026067 TI - Sequestered disc fragment mimicking a psoas abscess. AB - BACKGROUND CONTEXT: If a herniated lumbar disc fragment extrudes and migrates away from the spinal column, the radiographic appearances can be confusing. STUDY DESIGN: In this article, we report a rare case of a sequestrated disc fragment in the psoas muscle, discrete from the adjacent disc space, which presented with features similar to a psoas abscess on imaging studies. CONCLUSIONS: It is vital that in such cases the correct diagnosis is made to avoid unnecessary treatments and inappropriate management. PMID- 23026069 TI - Efficacy and safety of weekly paclitaxel combined with cetuximab in the treatment of pretreated recurrent/metastatic head and neck cancer patients. AB - INTRODUCTION: The addition of cetuximab to weekly paclitaxel has demonstrated high efficacy in the first-line treatment of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). However, this combination has been widely extended to patients who present resistance to first line chemotherapy (CT) or those who are not candidates for platinum-based CT. MATERIAL AND METHODS: We have retrospectively analyzed the efficacy and safety of cetuximab in combination with weekly paclitaxel in patients with R/M-SCCHN who present disease progression after platinum schedules or those who were not candidates for platinum-based CT. Patients received weekly paclitaxel 80mg/m(2) and cetuximab 250mg/m(2) (initial dose of 400mg/m(2)) until progression or unacceptable toxicity. RESULTS: Twenty-two patients were included. Median age was 58 (43-68), ECOG PS (0/1/2): 6/10/4, 19 patients had received prior platinum based treatment (nine patients were platinum-sensitive and nine were platinum refractory). With a median follow-up of 6.18months (range 1.3-29.7), overall response rate (ORR) was 55% (95% CI 31-76%):1 (5%) complete response and 9 (50%) partial responses. Median duration of response was 10.23months. Median progression free survival (PFS) and overall survival (OS) were 5.4 and 9.1months, respectively. There were no differences in response rate according to platinum sensitivity (66% sensitive vs 44% refractory; P=0.61). The main toxicity consisted of rash in 70% of patients (5% grade 3), with an association between rash severity and ORR (grade 0-1: 33% vs grade 2-3: 64%; P=0.03) and a trend for better PFS and OS. CONCLUSION: Weekly paclitaxel in combination with cetuximab is a well tolerated and highly active second-line treatment in patients with R/MSCCHN who experience disease progression after platinum-based CT, including those who present resistant disease. Our results suggest that the efficacy of this combination is apparently superior than the published data on single agent cetuximab in this setting. PMID- 23026068 TI - Comparative analysis of clinical outcomes in patients with osteoporotic vertebral compression fractures (OVCFs): conservative treatment versus balloon kyphoplasty. AB - BACKGROUND CONTEXT: Most osteoporotic vertebral compression fractures (OVCFs) can be treated conservatively. Recently, kyphoplasty has become a common treatment for painful osteoporotic compression fractures and has shown numerous benefits, such as early pain control and height restoration of the collapsed vertebral body. In spite of being a simple procedure, numerous complications related to kyphoplasty have been reported. Moreover, there is limited evidence to support its superiority. PURPOSE: To compare the clinical outcomes of patients with OVCF according to different treatment modalities and identify clinical risk factors related to failure of conservative treatment of OVCF. STUDY DESIGN: A prospective study consisting of a review of case report forms. PATIENTS SAMPLE: We prospectively enrolled 259 patients who had one or two acute painful OVCFs confirmed by magnetic resonance imaging. All patients were treated conservatively in the initial 3 weeks. Kyphoplasty was performed in 91 patients who complained of sustained back pain and disability in spite of conservative treatment for the initial 3 weeks. OUTCOME MEASURES: Pain score using visual analog scale (VAS) and the Oswestry Disability Index (ODI). METHODS: Participants were stratified according to age, sex, level and number of fractures, bone mineral density, body mass index (BMI), collapse rates, and history of spine fractures. Pain scores using VASs were assessed at 1 week and at 1, 3, 6, and 12 months. RESULTS: A total of 259 patients were enrolled, and 231 patients (82 of 91 patients in the kyphoplasty group [KP] and 149 of 168 patients in the conservative treatment group) completed the 1-year follow-up. About 65% of patients were treated successfully with conservative treatment. Risk factors for failure of 3 weeks of conservative treatment were older age (older than 78.5 years), severe osteoporosis (t score less than -2.95), overweight (BMI more than 25.5), and larger collapse rates (more than 28.5%). There were significant reductions in VAS and ODI scores in both groups at each follow-up assessment. At the first month, better clinical results were observed in KP. However, there were no significant differences in outcome measures between the two groups at 3, 6, or 12 months. Thirteen subsequent compression fractures (five in KP and eight in the conservative treatment group) occurred during the 1-year follow-up period. CONCLUSION: Both treatments of OVCF showed successful clinical results at the end of the 1-year follow-up period. Kyphoplasty showed better outcomes in the first month only. Given these results, prompt kyphoplasty should not be indicated in the case of a patient with OVCF that has no risk factors for failure with conservative treatment. Rather, a trial of conservative, 3-week treatment would be beneficial. PMID- 23026070 TI - Structural and functional characterization of pituitary adenylyl cyclase activating polypeptide (PACAP)/PACAP-related peptide (PRP) and its receptor in olive flounder (Paralichthys olivaceus). AB - We identified full-length cDNAs encoding pituitary adenylyl cyclase-activating polypeptide (PACAP), PACAP-related peptide (PRP), and PACAP-specific receptor (PAC1R) from olive flounder, Paralichthys olivaceus. Two variant mRNA forms were created by alternative splicing. Comparison of genomic and cDNA sequences of the PRP-PACAP precursor revealed that skipping of exon 4 within PRP resulted in two variant transcripts: a long form encoding both PRP and PACAP and a short form encoding PACAP only. Both transcripts were constitutively observed only in the brain, whereas the short form appeared in gut tissues, such as the intestine and pyloric cecum in fish challenged with a pathogen, but not in healthy fish. Furthermore, expression of the long PRP/PACAP transcript gradually increased in the intestine of flounder challenged with bacteria, suggesting that PRP and/or PACAP may serve as a regulator(s) of the immune system, especially in the gastrointestinal tract of olive flounder. The biological functions of PACAP and PRP were investigated by exogenous treatment of flounder embryogenic cells (hirame natural embryonic cells, HINAE cells) with synthetic peptides of fPACAP 38 and/or fPRP-45. Intracellular cyclic adenosine monophosphate (cAMP) production in PAC1R-overexpressing HINAE cells was regulated by fPACAP-38 in a concentration dependent manner, but was not regulated by fPRP-45. Results from real-time quantitative polymerase chain reaction revealed that PAC1R mRNA was specifically induced by fPACAP-38 but not by fPRP-45; PACAP significantly increased TNF-alpha mRNA but not growth hormone (GH) mRNA in HINAE cells; however, PRP affected GH but not TNF-alpha mRNA expression. These results suggest that the expression ratio of PRP and PACAP is regulated at the transcriptional level depending on the tissues and conditions, and that the unique biological roles of PRP and PACAP differ from that of mammalian PRP. PMID- 23026071 TI - Beta-adrenoceptors in the medial amygdaloid nucleus modulate the tachycardiac response to restraint stress in rats. AB - In the present study, we investigated the involvement of beta-adrenoceptors in the medial amygdaloid nucleus (MeA) in cardiovascular responses evoked in rats submitted to an acute restraint stress. We first pretreated Wistar rats with the nonselective beta-adrenoceptor antagonist propranolol microinjected bilaterally into the MeA (10, 15, and 20 nmol/100 nL) 10 min before exposure to acute restraint. The pretreatment with propranolol did not affect the blood pressure (BP) increase evoked by restraint. However, it increased the tachycardiac response caused by acute restraint when animals were pretreated with a dose of 15 nmol, without a significant effect on the BP response. This result indicates that beta-adrenoceptors in the MeA have an inhibitory influence on restraint-evoked heart rate (HR) changes. Pretreatment with the selective beta(2)-adrenoceptor antagonist ICI 118,551 (10, 15, and 20 nmol/100 nL) significantly increased the restraint-evoked tachycardiac response after doses of 15 and 20 nmol, an effect that was similar to that observed after the pretreatment with propranolol at a dose of 15 nmol, without a significant effect on the BP response. Pretreatment of the MeA with the selective beta(1)-adrenoceptor antagonist CGP 20712 (10, 15, and 20 nmol/100 nL) caused an opposite effect on the HR response, and a significant decrease in the restraint-evoked tachycardia was observed only after the dose of 20 nmol, without a significant effect on the BP response. Because propranolol is an equipotent antagonist of both beta(1) and beta(2)-adrenoceptors, and opposite effects were observed after the treatment with the higher doses of the selective antagonists ICI 118,551 and CGP 20712, the narrow window in the dose-response to propranolol could be explained by a functional antagonism resulting from the simultaneous inhibition of beta(1) and beta(2)-adrenoceptors by the treatment with propranolol. The present results suggest that beta(2)-adrenoceptors have an inhibitory influence on the restraint-evoked tachycardiac response, whereas beta(1)-adrenoceptors have a facilitatory influence on the restraint-evoked tachycardiac response. PMID- 23026072 TI - Enhanced SCN7A/Nax expression contributes to bone cancer pain by increasing excitability of neurons in dorsal root ganglion. AB - Bone pain is one of the most common complications in cancer patients with bone metastases, and has the most significant impact on quality of life for patients. Patients with bone cancer pain may be difficult to treat due to the poor understanding of the mechanisms; therefore, the mechanisms of bone cancer pain required elucidation for developing new therapeutics. Recent studies show that SCN7A/Nax channel serves as a sodium-level sensor of the body fluid that controls the Na-intake behavior by changing the excitability of neurons. In the current study, the expression of SCN7A/Nax and the excitability of primary sensory neurons in bone cancer pain rats were examined. The analgesic effects of knockdown SCN7A/Nax channel using RNAi lentivirus intrathecal treatment were evaluated with a behavioral test. The results showed that implantation of sarcoma induced ongoing and movement-evoked pain behaviors, whereas SCN7A/Nax knockdown prevented the onset of these hyperalgesia. Immunohistochemistry showed that SCN7A/Nax was located in the medium- to large-sized neurons in dorsal root ganglions (DRGs). The proportion of SCN7A/Nax-positive cells was significantly increased in DRGs ipsilateral to sarcoma implantation. Immunostaining results were further confirmed by Western blot and real time-polymerase chain reaction (RT-PCR) analyses. Recording from primary sensory neurons in excised rat dorsal root ganglias, we found that most of SCN7A/Nax-positive neurons exhibited subthreshold oscillations, depolarized resting membrane potential and more negative threshold of action potential. These electrophysiological changes of neurons increased ectopic spike discharge which was thought to be an important generator of chronic pain, however, the hyperexcitability was completely reversed by SCN7A/Nax knockdown. These results demonstrate that enhanced expression of SCN7A/Nax channel within distinct subpopulation of DRG neurons contributes to bone cancer pain by increasing the excitability of these neurons. These findings may lead to novel strategies for the treatment of bone cancer pain. PMID- 23026073 TI - Socioeconomic inequality in birth weight and gestational age in Denmark 1996 2007: using a family-based approach to explore alternative explanations. AB - A large body of literature has reported associations between socioeconomic position and adverse pregnancy outcomes even in affluent egalitarian welfare states. This study explored the nature of this relationship by examining women who changed socioeconomic position between pregnancies and women who were siblings but were different in terms of socioeconomic position. Data consisted of 471,215 live born singletons born in Denmark 1997-2007 with at least one sibling or one first cousin. We examined parental educational attainment and household income in relation to preterm birth and small for gestational age using Cox regression. Household income was only weakly related to these outcomes. Paternal education was strongly associated with the outcomes only in the cohort analyses. Maternal education was inversely associated with preterm birth only in the cohort analyses, where the least educated women had the highest risk. Maternal education was inversely associated with the risk of small for gestational age in cohort analyses, attenuated between mothers who were siblings, and not present between children who were siblings. For example, the hazard ratio of preterm birth of women with a college/university degree when compared to women with only mandatory education was 0.64 (95% confidence interval: 0.60-0.67) in the cohort analysis, 0.90 (0.78-1.04) between mothers who were siblings, and 1.01 (0.82-1.24) between children who were siblings. The corresponding hazard ratios of small for gestational age were 0.54 (0.52-0.56), 0.72 (0.63-0.83), and 1.02 (0.84-1.24). This suggests that the associations were partly explained by factors shared between mothers who are siblings. In conclusion, the early life circumstances of mothers appear to be important in understanding the association between education, preterm birth and small for gestational age. PMID- 23026074 TI - A network approach for researching political feasibility of healthcare reform: the case of universal healthcare system in Taiwan. AB - This study evaluates the political feasibility of healthcare reform taking place in Taiwan in the past decade. Since Taiwan adopted National Health Insurance (NHI) in 1995, it has provided coverage for virtually all of the island's citizens. However, the imbalance between expenditure and revenue has resulted in a cycle of unsustainable spending which has necessitated financial reforms and political confrontations. By applying social network analysis, this paper examines multiple types of ties between policy elites and power distribution that have evolved in crucial policy events of the NHI's financial reforms between 1998 and 2010. Data sources include official documents and 62 social network interviews that were held with government officials and related unofficial policy participants. Blockmodeling and multidimensional scaling (MDS) are used to determine the major participants and network structures in the NHI domain, as well as the influential policy actors, based on information transmission, resource exchange, reputation attribution and action-set coalition networks in Taiwan's current political situation. The results show that although both public actors and all medical associations are the leading actors in the NHI reform, without good communication with societal actors, the promotion of reform proposals ends in failure. As a tool of political feasibility evaluation, social network analysis can map the political conflict between policy stakeholders systematically when policy makers pursue the result of policy adoption. PMID- 23026075 TI - Inter-professional electronic documents and child health: a study of persisting non-electronic communication in the use of electronic documents. AB - Information and communication technologies are widely used in health and social care settings to replace previous means of record keeping, assessment and communication. Commentary on the strengths and weaknesses of such systems abound, thus it is useful to examine how they are used in practice. This article draws on findings from two separate studies, conducted between 2005 and 2007, which examined how child health and welfare professionals use electronic documents in Finland and England. Known respectively as Miranda and CAF, these systems are different in terms of structure and function but in their everyday use common features are identified, notably the continued use of and reliance on non electronic means of communication. Based on interviews with professionals, three forms of non-electronic communication are described: alternative records, phone calls and letters, which facilitate the sharing of the electronic record. Finally, the electronic documents are further analysed as potential boundary objects which aim to create common understanding between sites and professionals. PMID- 23026076 TI - An optimized technology platform for the rapid multiplex molecular analysis of genetic alterations associated with leukemia. AB - Molecular methods play a critical role in the accurate diagnosis of leukemia by complementing morphologic, cytochemical, immunophenotypic, and cytogenetic analyses. We developed a multiplex reverse transcription-polymerase chain reaction (RT-PCR) method combined with liquid bead array cytometry for the rapid detection of genetic alterations associated with leukemia. Fusion transcripts corresponding to the most common recurrent chromosomal translocations were reproducibly detected in as low as 0.1-10 ng of total RNA with an analytical sensitivity of 0.01-1%. Multiday, multilot, multioperator, and multi-instrument precision studies, for a total of 678 independent measures in 46 runs, showed a very high reproducibility with 100% agreement among replicates. Using multiplex panels for four to 20 independent targets, we demonstrate the flexibility of the method to codetect rare splicing isoforms, discriminate among multiple variants generated by unique cytogenetic abnormalities, identify distinct chromosomal partners involved with 11q23 or 17q21 rearrangements, and assess cryptic abnormalities not detectable by standard cytogenetics such as the t(12;21), del(1p32), or NPM1 mutations. Overall, three different internal control transcripts and 34 variants resulting from 18 abnormal chromosomal sites were evaluated. These results underscore the value of the multiplex assay system as a sensitive and reliable technology platform for the characterization of relevant genetic alterations in leukemia. PMID- 23026077 TI - Is dairy product consumption associated with the incidence of CHD? AB - OBJECTIVE: Studies examining the association of dairy consumption with incident CHD have yielded inconsistent results. The current prospective study examined the association between dairy consumption and CHD in a population-based sample of older community-dwelling adults. DESIGN: Baseline CHD risk factors were assessed and an FFQ was self-administered. Participants were followed for morbidity and mortality with periodic clinic visits and annual mailed questionnaires for an average of 16?2 years, with a 96% follow-up rate for fatal and non-fatal CHD. SETTING: Community. SUBJECTS: Participants were 751 men and 1008 women aged 50-93 years who attended a clinic visit in 1984-1987. RESULTS: At baseline the mean age was 70.6 (SD 9.8) years for men and 70.1 (SD 9.3) years for women. Participants who developed CHD during follow-up were significantly older (P < 0.001), had higher BMI (P = 0.035) and higher total cholesterol (P = 0.050), and were more likely to be male (P < 0.001), diabetic (P = 0.011) and hypertensive (P < 0.001), than those who did not develop CHD. Multivariate regression analyses adjusting for age, BMI, diabetes, hypertension, LDL-cholesterol and oestrogen use (in women) indicated that women who consumed low-fat cheese 'sometimes/often' and women who consumed non-fat milk 'sometimes/often' had an increased risk of incident CHD (hazard ratio 52.32; 95% CI 1.57, 3.41) and CHD (hazard ratio 51.48; 95% CI 1.02, 2.16) compared with women who 'never/rarely' ate these dairy products. CONCLUSIONS: Woman with higher intake of low-fat cheese and non-fat milk seem to have a higher risk of incident CHD. This needs further investigation considering recent evidence of cardiovascular benefits from certain dairy fat. PMID- 23026078 TI - Simvastatin attenuates axonal injury after experimental traumatic brain injury and promotes neurite outgrowth of primary cortical neurons. AB - The beneficial effects of simvastatin on experimental traumatic brain injury (TBI) have been demonstrated in previous studies. In this study, we investigated the effects of simvastatin on axonal injury and neurite outgrowth after experimental TBI and explored the underlying mechanisms. Wistar rats were subjected to controlled cortical impact or sham surgery. Saline or simvastatin was administered for 14 days. A modified neurological severity score (mNSS) test was performed to evaluate functional recovery. Immunohistochemistry studies using synaptophysin, neurofilament H (NF-H) and amyloid-beta precursor protein (APP) were performed to examine synaptogenesis and axonal injury. Primary cortical neurons (PCNs) were subjected to oxygen glucose deprivation (OGD) followed by various treatments. Western blot analysis was utilized to assess the activation of phosphatidylinositol-3 kinase (PI-3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3beta (GSK-3beta)/adenomatous polyposis coli (APC) pathways. Simvastatin decreased the density of APP-positive profiles and increased the density of NF-H -positive profiles. Simvastatin reduced mNSS, which was correlated with the increase of axonal density. Simvastatin treatment stimulated the neurite outgrowth of PCNs after OGD, which was attenuated by LY294002 and enhanced by lithium chloride (LiCl). Simvastatin activated Akt and mTOR, inactivated GSK-3beta and dephosphorylated APC in the injured PCNs. Our data suggest that simvastatin reduces axonal injury, enhances neurite outgrowth and promotes neurological functional recovery after experimental TBI. The beneficial effects of simvastatin on neurite outgrowth may be mediated through manipulation of the PI-3K/Akt/mTOR and PI-3K/GSK-3beta/APC pathways. PMID- 23026079 TI - Evaluating the potential for rostral diffusion in the cerebral ventricles using angiotensin II-induced drinking in rats. AB - In spite of evidence to the contrary, concern that substances injected into the fourth ventricle (4V) reach forebrain structures challenges the validity of using these injections to evaluate the role of hindbrain structures. Injection of AngII into the lateral ventricle (LV) increases water intake, but a similar response is not observed after injection into the 4V. This alone suggests the requirement of forebrain structures, but the potential for a counteracting, anti-dipsogenic pressor response to hindbrain AngII allows for lingering concern that this competing effect of AngII, rather than lack of forebrain access, underlies the negative result. Here, we used a double cannulation approach (LV and 4V) to evaluate the effect of the AngII receptor antagonist, losartan, on the drinking response to AngII injected into the LV. Injections of losartan into the LV blocked the dipsogenic response to AngII given 5min later into the LV. There was no effect, however, when losartan was injected into 4V, even when we used a dose of losartan that was 25 times greater than needed when injected into the LV. Collectively, these experiments suggest that concerns about diffusion from hindbrain ventricles to forebrain structures are overstated and can be circumvented using proper dose and timing of injections. Moreover, these data provide additional support to the existing literature showing that forebrain structures are key sites in the stimulation of drinking behavior by AngII. PMID- 23026080 TI - Active site mapping of trypsin, thrombin and matriptase-2 by sulfamoyl benzamidines. AB - The benzamidine moiety, a well-known arginine mimetic, has been introduced in a variety of ligands, including peptidomimetic inhibitors of trypsin-like serine proteases. According to their primary substrate specificity, the benzamidine residue interacts with the negatively charged aspartate at the bottom of the S1 pocket of such enzymes. Six series of benzamidine derivatives (1-73) were synthesized and evaluated as inhibitors of two prototype serine proteases, that is, bovine trypsin and human thrombin. As a further target, human matriptase-2, a recently discovered type II transmembrane serine protease, was investigated. Matriptase-2 represents an important regulatory protease in iron homeostasis by down-regulation of the hepcidin expression. Compounds 1-73 were designed to contain a fixed sulfamoyl benzamidine moiety as arginine mimetic and a linker connected additional substructure, such as a tert-butyl ester, carboxylate or second benzamidine functionality. A systematic mapping approach was performed with these inhibitors to scan the active site of the three target proteases. In particular, bisbenzamidines, able to interact with both the S1 and S3/S4 binding sites, showed notable affinity. In branched bisbenzamidines 66-73 containing a third hydrophobic residue, opposite effects of the stereochemistry on trypsin and thrombin inhibition were observed. PMID- 23026081 TI - Synthesis of imidacloprid derivatives with a chiral alkylated imidazolidine ring and evaluation of their insecticidal activity and affinity to the nicotinic acetylcholine receptor. AB - A series of imidacloprid (IMI) derivatives with an alkylated imidazolidine ring were asymmetrically synthesized to evaluate their insecticidal activity against adult female housefly, Musca domestica, and affinity to the nicotinic acetylcholine receptor of the flies. The bulkier the alkyl group, the lower was the receptor affinity, but the derivatives methylated and ethylated at the R-5 position of the imidazolidine ring were equipotent to the unsubstituted compound. Quantitative structure-activity relationship (QSAR) analysis of the receptor affinity demonstrated that the introduction of a substituent into the imidazolidine ring was fundamentally disadvantageous, but the introduction of a substituent at the R-5-position was permissible in the case of its small size. The binding model of the synthesized derivatives with the receptor supported the QSAR analysis, indicating the existence of space for a short alkyl group around the R-5-position in the ligand-binding site. In addition, positive correlation was observed between the insecticidal activity and receptor affinity, suggesting that the receptor affinity was the primary factor in influencing the insecticidal activity even if the imidazolidine ring was modified. PMID- 23026082 TI - The antitumor agent doxorubicin binds to Fanconi anemia group F protein. AB - Doxorubicin, a commonly used cancer chemotherapy agent, elicits several potent biological effects, including synergistic-antitumor activity in combination with cisplatin. However, the mechanism of this synergism remains obscure. Here, we employed an improved T7 phage display screening method to identify Fanconi anemia group F protein (FANCF) as a doxorubicin-binding protein. The FANCF-doxorubicin interaction was confirmed by pull-down assay and SPR analysis. FANCF is a component of the Fanconi anemia complex, which monoubiquitinates D2 protein of Fanconi anemia group as a cellular response against DNA cross-linkers such as cisplatin. We observed that the monoubiquitination was inhibited by doxorubicin treatment. PMID- 23026083 TI - Small-molecular inhibitors of Ca2+-induced mitochondrial permeability transition (MPT) derived from muscle relaxant dantrolene. AB - A structure consisting of substituted hydantoin linked to a 5-(halophenyl)furan-2 yl group via an amide bond was identified as a promising scaffold for development of low-molecular-weight therapeutic agents to treat vascular dysfunction, including ischemia/reperfusion injury. Among the compounds synthesized, 5-(3,5 dichlorophenyl)-N-{2,4-dioxo-3-[(pyridin-3-yl)methyl]imidazolidin-1-yl}-2 furamide (17) possessed the most potent inhibitory activity against Ca(2+) induced mitochondrial swelling. The structural development, synthesis and structure-activity relationship of these compounds are described. PMID- 23026084 TI - Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer's disease. AB - The optimization of our previous lead compound 1 (AChE IC(50)=3.31 MUM) through synthesis and pharmacology of a series of novel carbamates is reported. The synthesized compounds were evaluated against mouse brain AChE enzyme using the colorimetric method described by Ellman et al. The three compounds 6a (IC(50)=2.57MUM), 6b (IC(50)=0.70 MUM) and 6i (IC(50)=2.56 MUM) exhibited potent in vitro AChE inhibitory activities comparable to the drug rivastigmine (IC(50)=1.11 MUM). Among them, the compound 6b has been selected as possible optimized lead for further neuropharmacological studies. In addition, the AChE carbamate Michaelis complexes of these potent compounds including rivastigmine and ganstigmine have been modeled using covalent docking protocol of GOLD and important direct/indirect interactions contributing to stabilization of the AChE carbamate Michaelis complexes have been investigated. PMID- 23026086 TI - Tandem photoaffinity labeling-bioorthogonal conjugation in medicinal chemistry. AB - Photoaffinity labeling has a longstanding history as a powerful biochemical technique. However, photoaffinity labeling has significantly evolved over the past decade principally due to its coupling with bioorthogonal/click chemistry reactions. This review aims to highlight tandem photoaffinity labeling bioorthogonal conjugation as a chemical approach in medicinal chemistry and chemical biology. In particular, recent examples of using this strategy for affinity-based protein profiling (AfBPP), drug target identification, binding ensemble profiling, studying endogenous biological molecules, and imaging applications will be presented. Additionally, recent advances in the development of 'all-in-one' compact moieties possessing a photoreactive group and clickable handle will be discussed. PMID- 23026085 TI - Chemometric QSAR modeling and in silico design of carbonic anhydrase inhibition of a coral secretory isoform by sulfonamide. AB - Scleractinian coral stylophora pistillata carbonic anhydrase (STPCA) enzyme is a secreted isoform, plays a direct role in bio-mineralization. Sulfonamides, including some clinically used derivatives are the most important class of STPCA inhibitors. In order to search for efficient STPCA inhibitors molecules, the present work deals with quantitative structure-activity relationship (QSAR) studies of a series of 36 bioactive molecules. A heuristic algorithm selects the best multiple linear regression (MLR) equation showed the correlation between the observed values and the calculated values of activity is very good (N=36, Se=0.1683, r(2)=0.9158, F=54.3809, rcv(2)=0.8569). The novelty of this work is not only to explore the structural attributes of bioactive molecules but also to design and predict in silico the STPCA inhibitory activity of new not yet synthesized compounds. The analyzed prediction set includes many molecules having greater computed activity than observed value of inhibitory activity. PMID- 23026087 TI - New hypothesis elucidates self-incompatibility in the olive tree regarding S alleles dominance relationships as in the sporophytic model. AB - Most olive varieties are not strictly self-incompatible, nevertheless, they request foreign pollen to enhance fruit yield, and consequently orchards should contain pollinisers to ensure fruit set of the main variety. The best way to choose pollinisers is to experiment numerous crosses in a diallel design. Here, the genetic mode of inheritance of SI in the olive is deciphered and it does not correspond to the GSI type, but to the SSI type. It leaves S-allele dominance relationship expression in the male (pollen and pollen tube), but not in the female (stigma and style). Thus, a pair-wise combination of varieties may be inter-compatible in one direction (male to female, or female to male) and inter incompatible in the other direction. Dominance relationships also explain different levels of self-pollination observed in varieties. Little efficient pollinisers were found and predicted in varieties; nevertheless, some new efficient pair-wise allele combinations are predicted and could be created. This model enables one to forecast compatibility without waiting for several years of yield records and to choose pollinisers in silico. PMID- 23026088 TI - Ultrastructure of vitellogenesis and vitellocytes in the trypanorhynch cestode Aporhynchus menezesi, a parasite of the velvet belly lanternshark Etmopterus spinax. AB - This is the first TEM examination of vitellogenesis in the cestode Aporhynchus menezesi, a parasite of the velvet belly lanternshark Etmopterus spinax and a member of a little-studied trypanorhynch family, the Aporhynchidae. The synthetic activity of vitellocytes plays two important functions in the developmental biology of cestodes: (1) their shell-globules serve in eggshell formation; and (2) their accumulated reserves of glycogen and lipids represent a food source for the developing embryo. In A. menezesi, vitelline follicles consist of cells at various stages of development, from peripheral, immature cells of the gonial type to mature cells towards the centre of the follicle. These stages are: (I) immature; (II) early differentiation; (III) advanced maturation; and (IV) mature. Gradual changes involved in this process occur within each stage. Vitellogenesis involves: (1) an increase in cell volume; (2) the development of a smooth endoplasmic reticulum and an accelerated formation and accumulation of both unsaturated and saturated lipid droplets, along with their continuous enlargement and fusion; (3) the formation of individual beta-glycogen particles and their accumulation in the form of glycogen islands scattered among lipid droplets in the cytoplasm of maturing and mature vitellocytes; (4) the rapid accumulation of large, moderately saturated lipid droplets accompanied by dense accumulations of beta-glycogen along with proteinaceous shell-globules or shell-globule clusters in the peripheral layer during the advanced stage of maturation; (5) the development of cisternae of granular endoplasmic reticulum that produce dense, proteinaceous shell-globules; (6) the development of Golgi complexes engaged in the packaging of this material; and (7) the progressive and continuous enlargement of shell-globules into very large clusters in the peripheral layer during the advanced stage of maturation. Vitellogenesis in A. menezesi, only to some extent, resembles that previously described for four other trypanorhynchs. It differs in: (i) the reversed order of secretory activities in the differentiating vitellocytes, namely the accumulation of large lipid droplets accompanied by glycogenesis or beta-glycogen formation during early differentiation (stage II), i.e. before the secretory activity, which is predominantly protein synthesis for shell-globule formation (stage III); (ii) the very heavy accumulation of large lipid droplets during the final stage of cytodifferentiation (stage IV); and (iii) the small number of beta-glycogen particles present in mature vitellocytes. Ultracytochemical staining with PA-TCH SP for glycogen proved positive for a small number of beta-glycogen particles in differentiating and mature vitellocytes. Hypotheses, concerning the interrelationships of patterns of vitellogenesis, possible modes of egg formation, embryonic development and life-cycles, are commented upon. PMID- 23026090 TI - An enigmatic new stick insect from the Philippine Islands (Insecta: Phasmatodea). AB - A new genus and species of stick insect is described and figured from Mount Halcon, on the Philippine island of Mindoro. Conlephasma enigma gen. et sp. n. is a stout, flightless, and apparently ground-dwelling species with vivid integumental colors. When disturbed, specimens spray a defensive secretion from the prothoracic exocrine glands. The systematic position of Conlephasma within Euphasmatodea is unclear. The elongated galealobulus and the trichome area located laterally in the galea, represent unusual apomorphic characters of the maxilla that could indicate affinities with Necrosciinae or Pseudophasmatinae. All tibiae exhibit the anareolate condition. Euplantulae are of two types: those of tarsomeres I-IV feature a nubby microstructure, whilst the one on the ventral side of the pretarsus is smooth. Males are characterized by the presence of a well-developed vomer on the tenth abdominal segment. A distinctive and apomorphic trait of female terminalia is represented by the elongated tenth abdominal tergum. Conlephasma can represent an interesting taxon for studies on the evolution of the stick and leaf insects. PMID- 23026089 TI - [Bioaccumulation of cadmium and zinc in tomato (Lycopersicon esculentum L.)]. AB - This work aims at evaluating the accumulation of cadmium (Cd) and zinc (Zn) (trace elements) in the organs of young tomato plants (Lycopersicon esculentum L. var. Rio Grande) and their effects on the rate of chlorophyll and enzyme activities involved in the antioxidant system: catalase (CAT), glutathion-S transferase (GST) and peroxysase ascorbate (APX). Plants previously grown on a basic nutrient solution were undergoing treatment for 7 days, either by increasing concentrations of CdCl(2) or ZnSO(4) (0, 50, 100, 250, 500 MUM) or by the combined concentrations of Cd and Zn (100/50, 100/100, 100/250, 100/500 MUM). The results concerning the determination of metals in the various compartments of tomato plants as a function of increasing concentrations of Cd or Zn, suggest a greater accumulation of Cd and Zn in the roots compared to leaves. The combined treatment (Cd/Zn) interferes with the absorption of the two elements according to their concentrations in the culture medium. The presence of Zn at low concentrations (50 MUM of Zn/100 MUM Cd) has little influence on the accumulation of Cd in the roots and leaves, while the absorption of these two elements in the leaves increases and decreases in roots when their concentrations are equivalent (100/100 MUM) compared to treatment alone. When the concentration of Zn is higher than that of Cd (500 MUM of Zn/100 MUM Cd) absorption of the latter is inhibited in the roots while increasing their translocation to the leaves. Meanwhile, the dosage of chlorophylls shows that they tend to decrease in a dose-dependent for both treatments (Cd or Cd/Zn), however, treatment with low concentrations of Zn (50 and 100 MUM) stimulates chlorophyll synthesis. However, treatment with different concentrations of Cd seems to induce the activity of the enzymes studied (CAT, APX, GST). It is the same for treatment with different concentrations of Zn and this particularly for the highest concentrations. Finally, the combined treatment (Zn/Cd) also appears to cause enzyme inductions: CAT, APX and GST. PMID- 23026091 TI - Computer vision as a method complementary to molecular analysis: grapevine cultivar seeds case study. AB - Despite different breeding events, as well as the domestication phenomena which contributed to enrich the grape varietal heritage in Sardinia, many local varieties simply are the product of linguistic distorting due to the wide heterogeneity historic-cultural of the island. This phenomenon generated a great assortment of grape names, that, together with the huge real number of cultivars, is the cause of the incredible current grapevine Sardinian panorama. The goal of this article is to compare the published molecular data of 40 Sardinian autochthonous cultivars with the results achieved by the germplasm phenotypical characterization, on the basis of morpho-colorimetric features and Elliptic Fourier Descriptors (EFDs), measured by image analysis. Statistical classifiers were implemented to discriminate dissimilar seeds and carry out hypothetical synonymy groups to compare with those proposed on the basis of Simple Sequence Repeat (SSR) markers. This work represents the first trial to validate a morpho colorimetric characterization method by direct comparison with molecular data, proving that the 113 measured features of the germplasm resulted adequate to achieve a clear discrimination among the synonymy groups. PMID- 23026092 TI - Extraction conditions of Antheraea mylitta sericin with high yields and minimum molecular weight degradation. AB - Although the technique for extracting the Bombyx mori sericin has been extensively known, the extraction of sericin from wild-silkworm cocoons is not yet standardized. The aim of this study was to find the optimal conditions for the extraction of sericin from Antheraea mylitta cocoons, with high yields and minimum degradation. We attempted to apply various protocols for the extraction of the A. mylitta sericin (AmS). Among these, we found that the extraction of AmS with a sodium carbonate solution exhibited the highest yield except the conventional soap-alkali extraction. To find the optimal conditions for the AmS extraction with the sodium carbonate, we changed the concentration of sodium carbonate and the treatment time. With an increase in the sodium carbonate concentration and the extraction time, the yield of AmS increased, but the molecular weight (MW) of AmS decreased. Considering the yield, molecular weight distribution (MWD) and amino acid composition of AmS, we suggest that the optimal conditions for the AmS extraction require treatment with 0.02 M sodium carbonate and boiling for 60 min. PMID- 23026095 TI - Asian and Hispanic Americans' cancer fatalism and colon cancer screening. AB - OBJECTIVES: To explore fatalistic attributions of colon cancer development among Asian and Hispanic Americans in comparison with non-Hispanic whites; also to examine the impacts of fatalism on adherence to the colon cancer screening guideline. METHODS: For the analysis, the 2005 Health Information National Trends Survey data were employed. RESULTS: Both Asian and Hispanic Americans were more likely to make fatalistic attribution and were less likely to follow the guideline than whites. Particularly for Asians, fatalism was a significant predictor for not adhering to the guideline. CONCLUSIONS: These findings emphasize the need for cultural interventions to disrupt fatalistic attitudes towards colon cancer preventions. PMID- 23026096 TI - Understanding the health beliefs and practices of East African refugees. AB - OBJECTIVES: To explore East African refugees' perceptions, ideas, and beliefs about health and health care, as well as the ways in which health information is shared within their communities. METHODS: This study consisted of 2 focus groups with a total of 15 participants, including East African community leaders and health professionals. RESULTS: East African refugees in the United States have strong cultural, religious, and traditional health practices that shape their health behavior and influence their interactions with Western health care systems. CONCLUSIONS: Health care providers who understand refugees' beliefs about health may achieve more compliance with refugee patients. PMID- 23026097 TI - Correlates of strength exercise in colorectal cancer survivors. AB - OBJECTIVE: To estimate the prevalence and correlates of meeting the public health strength exercise guidelines (>=2 days/week) in colorectal cancer (CRC) survivors. METHODS: A random sample of 600 CRC survivors in Alberta, Canada, completed a mailed questionnaire assessing medical, demographic, and behavioral variables and participation in strength exercise. RESULTS: About a quarter (25.5%) of CRC survivors were meeting strength exercise guidelines. In multivariate analysis, meeting guidelines was associated with being male (p = .052), married (p = .079), a drinker (p = .006), in better health (p < .001), nonsmoking (p = .023), and nonobese (p = .010). CONCLUSIONS: Interventions to increase strength exercise participation in CRC survivors are needed. PMID- 23026094 TI - Core OCD symptoms: exploration of specificity and relations with psychopathology. AB - Obsessive-compulsive disorder (OCD) is a heterogeneous condition, comprised of multiple symptom domains. This study used aggregate composite scales representing three core OCD dimensions (Checking, Cleaning, and Rituals), as well as Hoarding, to examine the discriminant validity, diagnostic specificity, and predictive ability of OCD symptom scales. The core OCD scales demonstrated strong patterns of convergent and discriminant validity - suggesting that these dimensions are distinct from other self-reported symptoms - whereas hoarding symptoms correlated just as strongly with OCD and non-OCD symptoms in most analyses. Across analyses, our results indicated that Checking is a particularly strong, specific marker of OCD diagnosis, whereas the specificity of Cleaning and Hoarding to OCD was less strong. Finally, the OCD Checking scale was the only significant predictor of OCD diagnosis in logistic regression analyses. Results are discussed with regard to the importance of assessing OCD symptom dimensions separately and implications for classification. PMID- 23026098 TI - Time perspective and smoking, obesity, and exercise in a community sample. AB - OBJECTIVE: To examine associations between time perspective and smoking, body mass index, and exercise. METHODS: In this community-based survey, adults reported smoking and exercise habits and weight and height and completed the Zimbardo Time Perspective Inventory. RESULTS: Subjects (N=265) who were more future oriented reported more frequent exercise, but were more likely to smoke. Fatalistic and hedonistic present orientations were not associated with smoking, obesity, or exercise. CONCLUSIONS: Time perspective is not consistently associated with common health behaviors in adults. PMID- 23026099 TI - Understanding controlled drinking behavior among Korean male workers. AB - OBJECTIVES: To understand the predictors of controlled drinking in Korean male workers with a structural equation modeling based on Ajzen's theory of planned behavior. METHODS: A cross-sectional survey design was used with a total of 315 male workers from 20 workplaces. RESULTS: The modified model accounted for 58% of intentions and 20% of controlled drinking behavior. The component most increasing intentions was perceived behavior control (PBC), and the components increasing controlled drinking behavior were intentions and PBC in the modified model. CONCLUSIONS: Intervention programs should be designed to increase intentions and PBC to improve controlled drinking behavior in male workers. PMID- 23026100 TI - Activity patterns and perceptions about active transport to school. AB - OBJECTIVES: To document physical activity patterns and perceptions about active transport to school. METHODS: Children's activity was measured. Children and parents were surveyed about active transport to school. RESULTS: Children were most active after (465 +/- 20 cpm) and least active before (379 +/- 18 cpm) and during school (351 +/- 13 cpm). Weight was not related to activity. Boys were more confident than girls, whereas parents felt more confident than children did about active transport. CONCLUSIONS: Active transport programs will likely have a greater impact on before-school activity than after school. Perceptions concerning active transport should be assessed, and parent/child discrepancies rectified prior to program implementation. PMID- 23026101 TI - Smoking among East Asian college students: prevalence and correlates. AB - OBJECTIVES: To compare the prevalence and correlates of cigarette smoking among East Asian college students. METHODS: Data were collected from college students (N=16,558) in China, Hong Kong, Malaysia, Singapore, South Korea, and Taiwan (response rate: 78%). RESULTS: Religion was independently associated with college students' smoking in China (adjusted odds ratio [AOR] = 1.82) and South Korea (AOR = 0.80). Being a heavy drinker and having a higher exposure to secondhand smoke were associated with higher smoking rates (Ps < .001). CONCLUSIONS: The East Asian economies show a varied prevalence of college smoking but a similar pattern of relationship with its correlates. PMID- 23026102 TI - Evaluating community capacity to address obesity in the Dan River region: a case study. AB - OBJECTIVE: To qualitatively evaluate community capacity among an emerging coalition initiated to address complex regional obesity problems. METHODS: Guided by dimensions of community capacity, this case study applies semistructured qualitative interviews among 12 key stakeholders engaged in the Dan River Partnership for a Healthy Community (DRPHC). RESULTS: In-depth qualitative data reveals important contextualized information related to community capacity dimensions such as participation, community power, resources, leadership, organizational structure, and partnership. CONCLUSION: Findings have provided critical direction for the continued development and sustainability of DRPHC efforts. Others could apply a similar evaluation to better understand factors that promote the development and maintenance of their coalitions. PMID- 23026104 TI - Multidimensional control beliefs, socioeconomic status, and health. AB - OBJECTIVES: To investigate the role of control beliefs in the relationship between SES and health. METHODS: Two different aspects of perceived control - contingency beliefs (locus of control) and competence beliefs (self-efficacy) - were examined in relation to subjective SES and physical health outcomes (subjective health, functional impairment, chronic health problems, and acute health symptoms) in a diverse sample of undergraduates (N=231). RESULTS: Low self efficacy was directly associated with poorer health outcomes and mediated the relationship between low SES and health, whereas locus of control did not. CONCLUSIONS: Health behavior interventions targeting generalized competence beliefs may benefit individuals from low SES backgrounds. PMID- 23026103 TI - Diet, acculturation, and BMI in Hispanics living in southern Nevada. AB - OBJECTIVE: To examine the association of fruit and vegetable intake, acculturation, and BMI in Hispanics living in southern Nevada. METHODS: Logistic regression was employed to assess the relationship of acculturation to daily intake of fruit and vegetables. RESULTS: Regression showed that greater acculturation (p = .002) and being male (p = .011) are predictive of lower fruit and vegetable consumption. CONCLUSIONS: Our results for the HA population are consistent with national data. To understand the incentives and barriers to healthier eating within southern Nevada Hispanic populations and to effectively address the resource and programming needs, longitudinal research will be required. PMID- 23026105 TI - Feasibility of interactive voice response methods in health behavior research with immigrant Latinos. AB - OBJECTIVES: Determine the feasibility of using interactive voice response (IVR) for conducting daily diary research with immigrant Latinos. METHODS: Baseline data containing demographic, health, and job-related characteristics were obtained from immigrant Latino construction workers (N=119). Participants also completed an IVR-based daily diary for 21 consecutive days. RESULTS: Over one third (37%) of the sample adhered to the 21-day protocol; a comparable percent age (38.7%) initiated but did not adhere to the protocol; and 24% never began the diary protocol. Adherence was generally not predicted by demographic, health, or job-related characteristics. CONCLUSIONS: IVR technology makes diary studies with Latino samples feasible. PMID- 23026106 TI - Tobacco use, cessation, and home smoking rules in a Hispanic community. AB - OBJECTIVE: To determine prevalence of smoking, quit ratios, and home smoking rules among Hispanics residing in colonias in El Paso, Texas. METHODS: Face-to face interviews with 1485 Hispanic adults. GeoFrameTM field enumeration methods were used to develop a sampling frame from households in randomly selected colonias. RESULTS: The overall percent of current cigarette smoking was 14.6% (95% CI 12.4 to 16.8); Over 55% of smokers reported a serious quit attempt. Participants overwhelmingly reported that smoking was not allowed in their homes. CONCLUSIONS: Prevalence estimates for current smoking and restriction in the home were similar to those reported for recent national surveys. PMID- 23026107 TI - Factors associated with first-time use of preventive services in the United States. AB - OBJECTIVE: To examine factors associated with first-time use of preventive services based on the Behavioral Model of Health Services Use. METHODS: Nine panels of the Medical Expenditure Panel Survey were merged to identify first-time users of 8 preventive services: blood pressure check, cholesterol screening, colonoscopy, flu vaccination, routine physical, Pap smear, mammogram, and clinical breast examination. Multivariate logistic regressions and sample weights were used. RESULTS: Insurance coverage, access to care, and racial/ethnic minorities are associated with higher odds of first-time use. Findings based on cross-sectional data may not be valid for first-time use. CONCLUSIONS: Increased insurance coverage, better access to care, and a focus on minority population can help nonusers of preventive care to make the transition. PMID- 23026108 TI - Age-related concomitants of obtaining mental health care in adulthood. AB - OBJECTIVE: To examine the associations between predisposing and need factors and receipt of mental health care and to examine age as a moderator of these associations. METHODS: Participants (N=521) were surveyed as part of a larger study on health and adaptation. RESULTS: Obtaining mental health care was predicted by more reliance on approach coping, and more depressive and medical symptoms. Interactions of age x depressive symptoms and age x gender revealed that middle-aged adults with more depressive symptoms and middle-aged men were less likely to obtain care. CONCLUSIONS: Middle-aged men and middle-aged adults with depression may not be obtaining needed mental health care. PMID- 23026109 TI - Neighborhood preference, walkability and walking in overweight/obese men. AB - OBJECTIVES: To investigate whether self-selection moderated the effects of walkability on walking in overweight and obese men. METHODS: 240 overweight and obese men completed measures on importance of walkability when choosing a neighborhood (selection) and preference for walkable features in general (preference). IPAQ measured walking. A walkbility index was derived from geographic information systems (GIS). RESULTS: Walkability was associated with walking for transportation (p = .027) and neighborhood selection was associated with walking for transportation (p = .002) and total walking (p = .001). Preference was associated with leisure walking (p = .045) and preference moderated the relationship between walkability and total walking (p = .059). CONCLUSION: Walkability and self-selection are both important to walking behavior. PMID- 23026110 TI - Patients with colorectal and renal cell carcinoma diagnoses appear to be at risk for additional malignancies. AB - Patients with colorectal cancer (CRC) and renal cell carcinoma (RCC) may be at risk for additional primary malignancies. A review of 101 patients with these concurrent diagnoses was performed. Forty-two percent of patients had 1 or more additional malignancies; none appeared to be associated with Lynch syndrome (LS). This suggests the need for careful follow-up in these patients and further study. BACKGROUND: Small studies have demonstrated that patients who have both colorectal and renal cell carcinoma may be at increased risk for the development of additional malignancies. A possible genetic basis has been suggested. Our study describes the clinicopathologic features of these patients and clarifies the relationship of this cohort with Lynch syndrome (LS). METHODS: Patients with primary CRC and RCC treated at our institution were identified. Medical records were reviewed for demographic and clinical information. Immunohistochemical staining for mismatch repair (MMR) proteins was performed on tumor tissue when possible. RESULTS: During the study period, 24,642 patients were treated for CRC and 7,366 were treated for RCC at our institution. One hundred seventy-nine patients had both diagnoses, with 101 patients eligible for inclusion in our cohort. Tumors were typically early stage. The 2 cancers presented as synchronous lesions in 42% of patients. Thirty-two patients had 1 additional primary malignancy, 7 patients had 2 additional primary malignancies, and 3 patients had 3 additional primary malignancies. No patient had a family history that met the Amsterdam II criteria (AC) for LS, but 50% had family members with 1 malignancy. One of 10 colorectal tumors analyzed for the absence of MMR protein expression demonstrated the absence of MSH6, but the corresponding RCC demonstrated intact expression of all 4 MMR proteins. CONCLUSION: It is rare for patients to be diagnosed with both CRC and RCC. The clinicopathologic features of this cohort and the results of immunohistochemical analysis performed on a sample of these patients do not suggest LS. However, the high rate of additional carcinomas suggests a need for careful follow-up. Multicenter longitudinal studies are warranted to further understand the natural history and possible genetic basis for this entity. PMID- 23026111 TI - Treatment of pulmonary colorectal metastases by radiofrequency ablation. AB - We evaluated the local tumor control and the survival benefit achieved with radiofrequency ablation (RFA) for nonoperable lung metastases in 45 patients with colorectal cancer. Median survival from the time of RFA was 46 months. One-, 2- and 3-year local tumor progression (LTP)-free survival rates were 92%, 77%, and 77%, respectively. RFA offers very good local control in patients with pulmonary metastases from colorectal cancer. BACKGROUND: Radiofrequency ablation has emerged as a potential, lung function-preserving treatment of colorectal lung metastases. PATIENTS AND METHODS: Forty-five patients with colorectal pulmonary metastases underwent computed tomography-guided RFA from December 2004 to June 2010. A baseline posttreatment scan was obtained 4-6 weeks after RFA and follow up imaging studies every 3 months thereafter were obtained and compared to evaluate the tumor progression at site of ablation or elsewhere. The primary end points were LTP-free survival and overall survival from RFA procedure. The Kaplan Meier method was used to analyze the end points. A Cox proportional hazard model with robust inference was used to estimate the associations between baseline factors and survival end points. RESULTS: Sixty-nine metastases were ablated in 45 patients. Tumor size ranged from 0.4 to 3.5 cm. The median number of metastases ablated per patient was 1 (range, 1-3). Median follow-up after RFA was 18 months. Median survival from the time of RFA was 46 months (95% confidence interval [CI], 27.8-47.3). One-, 2- and 3-year overall survival rates from the time of RFA were 95% (95% CI, 82%-99%), 72% (95% CI, 52%-85%), and 50% (95% CI, 26%-71%), respectively. Nine of 69 lesions (13%) progressed and 4 were retreated with no progression after second RFA. Median time to progression was not reached. LTP-free survival from RFA was 92% (95% CI, 82%-97%) at 1 year, 77% (95% CI, 58% 88%) at 2 years, and 77% (95% CI, 58%-88%) at 3 years. CONCLUSION: Radiofrequency ablation of lung metastases is an effective minimally invasive, parenchymal sparing technique that has very good local control rates in patients with pulmonary metastases from colorectal cancer, with LTP-free survival of 77% at 3 years. PMID- 23026112 TI - Femoral nerve palsy following traumatic posterior dislocation of the native hip. PMID- 23026113 TI - Fracture of the distal radius with radial artery injury: injury description and outcome of vascular repair. AB - INTRODUCTION: The ideal treatment of an isolated radial artery injury that is associated with a fracture of the distal radius is unknown. Our purposes were to assess the incidence of this injury pattern and to describe the outcomes of our treatment protocol. We hypothesised that combined routine repair of the artery during operative treatment results in a satisfactory outcome. METHODS: Our study group consisted of 14 patients who were treated by one surgeon with a consistent treatment algorithm. The average follow-up duration was 52 weeks. Our control group consisted of 380 patients with fracture of the distal radius without radial artery injury, who were treated by the same surgeon during a 3-year period. RESULTS: We observed a 2% incidence of isolated radial artery injury in patients treated with open reduction and internal fixation (ORIF) of the distal radius. Outcomes were comparable to those reported for operative treatment of fractures of the distal radius without radial artery injury. CONCLUSIONS: Our protocol resulted in adequate outcomes, a 71% patency rate (five of seven fractures with adequate vascular follow-up) and no evidence of symptoms related to a poorly perfused hand. PMID- 23026114 TI - Four-part fracture dislocations of the proximal humerus in young adults: results of fixation. AB - INTRODUCTION: Four-part fracture dislocations of the proximal humerus occurring in young age are extremely difficult fractures with a high incidence of complications. The risk of avascular necrosis is high; hence, prosthetic replacement is the treatment of choice in older patients with these complex fractures; on the other hand, the longevity of the prosthesis is the main concern in young age. Thus, every effort should be made to fix these fractures in the young. The purpose of this study is to evaluate the results of fixation in a series of young patients with four-part fracture dislocations; to support the trend to fix these fractures; and reserve prosthetic replacement to older patients. METHODS: In a prospective study, 39 patients younger than 40 years of age with four-part fracture dislocations were treated with open reduction and fixation either with K-wires or with a proximal humerus plate. Ethibond sutures were used in all patients to supplement fixation of tuberosities. In 18 patients, the dislocation was anterior and in 21 patients it was posterior. Twelve patients had an anatomic neck fracture and 27 had a surgical neck fracture. Surgery was performed within 1 week after the injury. Physiotherapy was initiated according to the general condition of the patient and the stability of fixation; the average time was 5 days after surgery. RESULTS: Patients were followed up for an average of 26 months. Union was achieved in 36 patients and three patients had nonunion, all in anatomic neck fractures. Avascular necrosis developed in eight patients, seven of which were fractures of the anatomic neck and one was in the surgical neck. The average Constant score was 77; 26 patients were pain free, nine had mild pain and four had moderate pain. The mean active anterior elevation was 145 degrees . Patients were divided into two groups based on the anatomic configuration of the fracture; in 12 patients (group 1), the head was fractured at the anatomical neck and in 27 patients (group 2), the head was fractured at the surgical neck. In group 2, the active anterior elevation was significantly better and the Constant score was higher. CONCLUSIONS: Anatomical reduction and rigid fixation with meticulous surgical technique can lead to satisfactory results. The results in surgical neck fractures are superior to anatomic neck fractures with significantly less complications. PMID- 23026115 TI - Trochanteric fossa or piriform fossa of the femur: time for standardised terminology? AB - Piriform fossa, trochanteric fossa and greater trochanteric tip have each been described as entry points for antegrade femoral nailing. However, the terminology used for these entry points is confusing. The accuracy of the entry point nomenclature in published text and illustrations was recorded in this review study. The trochanteric fossa, a deep depression at the base of the femoral neck is indicated as 'piriform fossa' in the vast majority of the publications. Other publications indicate the insertion site of the tendon of the piriformis muscle on the greater trochanteric tip as 'piriform fossa'. As a result of recurrent terminology error and consistent reproductions of it, the recommended entry point in literature is confusing and seems to need standardisation. The piriform fossa does not appear to exist in the femoral region. The trochanteric fossa is the standard entry point which most surgeons recommend for facilitating a standard straight intramedullary nail, as is in line with the medullary canal. The greater trochanteric tip is the lateral entry point for intramedullary nails with a proximal lateral bend. PMID- 23026116 TI - Centriole asymmetry determines algal cell geometry. AB - The mechanisms that determine the shape and organization of cells remain largely unknown. Green algae such as Chlamydomonas provide excellent model systems for studying cell geometry owing to their highly reproducible cell organization. Structural and genetic studies suggest that asymmetry of the centriole (basal body) plays a critical determining role in organizing the internal organization of algal cells, through the attachment of microtubule rootlets and other large fiber systems to specific sets of microtubule triplets on the centriole. Thus to understand cell organization, it will be critical to understand how the different triplets of the centriole come to have distinct molecular identities. PMID- 23026117 TI - Membrane and walls: who is master, who is servant? AB - Specialised plant cell types often locally modify their cell walls as part of a developmental program, as do cells that are challenged by particular environmental conditions. Modifications can include deposition of secondary cellulose, callose, cutin, suberin or lignin. Although the biosyntheses of cell wall components are more and more understood, little is known about the mechanisms that control localised deposition of wall materials. During metaxylem vessel differentiation, site-specific cell wall deposition is locally prevented by the microtubule depolymerising protein MIDD1, which disassembles the cytoskeleton and precludes the cellulose synthase complex from depositing cellulose. As a result, metaxylem vessel secondary cell wall appears pitted. How MIDD1 is tethered at the plasma membrane and how other cell wall polymers are locally deposited remain elusive. Casparian strips in the root endodermis represent a further example of local cell wall deposition. The recent discovery of the Casparian Strip membrane domain Proteins (CASPs), which are located at the plasma membrane and are important for the site-specific deposition of lignin during Casparian strip development, establishes the root endodermis as an attractive model system to study the mechanisms of localised cell wall modifications. How secondary modifications are modulated and monitored during development or in response to environmental changes is another question that still misses a complete picture. PMID- 23026118 TI - Comparative effects of pentobarbital on spontaneous and evoked transmitter release from inhibitory and excitatory nerve terminals in rat CA3 neurons. AB - Pentobarbital (PB) modulates GABA(A) receptor-mediated postsynaptic responses through various mechanisms, and can directly activate the channel at higher doses. These channels exist both pre- and postsynaptically, and on the soma outside the synapse. PB also inhibits voltage-dependent Na+ and Ca2+ channels to decrease excitatory synaptic transmission. Just how these different sites of action combine to contribute to the overall effects of PB on inhibitory and excitatory synaptic transmission is less clear. To compare these pre- and postsynaptic actions of PB, we used a 'synaptic bouton' preparation of isolated rat hippocampal CA3 pyramidal neurons where we could measure in single neurons the effects of PB on spontaneous and single bouton evoked GABAergic inhibitory and glutamatergic excitatory postsynaptic currents (sIPSCs, sEPSCs, eIPSCs and eEPSCs), respectively. Low (sedative) concentrations (3-10 MUM) of PB increased the frequency and amplitude of sIPSCs and sEPSCs, and also presynaptically increased the amplitude of both eIPSCs and eEPSCs. There was no change in current kinetics at this low concentration. At higher concentrations (30-300 MUM), PB decreased the frequency, and increased the amplitude of sIPSCs, and presynaptically decreased the amplitude of eIPSCs. The current decay phase of sIPSCs and eIPSCs was increased. An increase in both frequency and amplitude was seen for sEPSCs, while the eIPSCs was also decreased by a bicuculline-sensitive presynaptic effect. The results confirm the multiple sites of action of PB on inhibitory and excitatory transmission and demonstrate that the most sensitive site of action is on transmitter release, via effects on presynaptic GABA(A) receptors. At low concentrations, however, both glutamate and GABA release is similarly enhanced, making the final effects on neuronal excitability difficult to predict and dependent on the particular systems involved and/or on subtle differences in susceptibility amongst individuals. At higher concentrations, release of both transmitters is decreased, while the postsynaptic effects to increase IPSPs and decrease EPSCs would be expected to both results in reduced neuronal excitability. PMID- 23026119 TI - Engineering the push and pull of lipid biosynthesis in oleaginous yeast Yarrowia lipolytica for biofuel production. AB - Microbial oil production by heterotrophic organisms is a promising path for the cost-effective production of biofuels from renewable resources provided high conversion yields can be achieved. To this end, we have engineered the oleaginous yeast Yarrowia lipolytica. We first established an expression platform for high expression using an intron-containing translation elongation factor-1alpha (TEF) promoter and showed that this expression system is capable of increasing gene expression 17-fold over the intronless TEF promoter. We then used this platform for the overexpression of diacylglycerol acyltransferase (DGA1), the final step of the triglyceride (TAG) synthesis pathway, which yielded a 4-fold increase in lipid production over control, to a lipid content of 33.8% of dry cell weight (DCW). We also show that the overexpression of acetyl-CoA carboxylase (ACC1), the first committed step of fatty acid synthesis, increased lipid content 2-fold over control, or 17.9% lipid content. Next we combined the two genes in a tandem gene construct for the simultaneous coexpression of ACC1 and DGA1, which further increased lipid content to 41.4%, demonstrating synergistic effects of ACC1+DGA1 coexpression. The lipid production characteristics of the ACC1+DGA1 transformant were explored in a 2-L bioreactor fermentation, achieving 61.7% lipid content after 120h. The overall yield and productivity were 0.195g/g and 0.143g/L/h, respectively, while the maximum yield and productivity were 0.270g/g and 0.253g/L/h during the lipid accumulation phase of the fermentation. This work demonstrates the excellent capacity for lipid production by the oleaginous yeast Y. lipolytica and the effects of metabolic engineering of two important steps of the lipid synthesis pathway, which acts to divert flux towards the lipid synthesis and creates driving force for TAG synthesis. PMID- 23026120 TI - A dynamic metabolite valve for the control of central carbon metabolism. AB - Successful redirection of endogenous resources into heterologous pathways is a central tenet in the creation of efficient microbial cell factories. This redirection, however, may come at a price of poor biomass accumulation, reduced cofactor regeneration and low recombinant enzyme expression. In this study, we propose a metabolite valve to mitigate these issues by dynamically tuning endogenous processes to balance the demands of cell health and pathway efficiency. A control node of glucose utilization, glucokinase (Glk), was exogenously manipulated through either engineered antisense RNA or an inverting gene circuit. Using these techniques, we were able to directly control glycolytic flux, reducing the specific growth rate of engineered Escherichia coli by up to 50% without altering final biomass accumulation. This modulation was accompanied by successful redirection of glucose into a model pathway leading to an increase in the pathway yield and reduced carbon waste to acetate. This work represents one of the first examples of the dynamic redirection of glucose away from central carbon metabolism and enables the creation of novel, efficient intracellular pathways with glucose used directly as a substrate. PMID- 23026121 TI - Mathematical optimization applications in metabolic networks. AB - Genome-scale metabolic models are increasingly becoming available for a variety of microorganisms. This has spurred the development of a wide array of computational tools, and in particular, mathematical optimization approaches, to assist in fundamental metabolic network analyses and redesign efforts. This review highlights a number of optimization-based frameworks developed towards addressing challenges in the analysis and engineering of metabolic networks. In particular, three major types of studies are covered here including exploring model predictions, correction and improvement of models of metabolism, and redesign of metabolic networks for the targeted overproduction of a desired compound. Overall, the methods reviewed in this paper highlight the diversity of queries, breadth of questions and complexity of redesigns that are amenable to mathematical optimization strategies. PMID- 23026122 TI - Enhancing fatty acid production by the expression of the regulatory transcription factor FadR. AB - Fatty acids are important precursors to biofuels. The Escherichia coli FadR is a transcription factor that regulates several processes in fatty acid biosynthesis, degradation, and membrane transport. By tuning the expression of FadR in an engineered E. coli host, we were able to increase fatty acid titer by 7.5-fold over our previously engineered fatty acid-producing strain, reaching 5.2+/-0.5g/L and 73% of the theoretical yield. The mechanism by which FadR enhanced fatty acid yield was studied by whole-genome transcriptional analysis (microarray) and targeted proteomics. Overexpression of FadR led to transcriptional changes for many genes, including genes involved in fatty acid pathways. The biggest transcriptional changes in fatty acid pathway genes included fabB, fabF, and accA. Overexpression of any of these genes alone did not result in a high yield comparable to fadR expression, indicating that FadR enhanced fatty acid production globally by tuning the expression levels of many genes to optimal levels. PMID- 23026123 TI - Spanish registry on heart transplantation. 23rd official report of the Spanish Society of Cardiology Working Group on Heart Failure and Heart Transplantation (1984-2011). AB - INTRODUCTION AND OBJECTIVES: The purpose of this article is to present the results obtained from heart transplantation since this therapeutic modality first began to be used in Spain in May 1984. METHODS: A descriptive analysis was performed of all heart transplantations performed until 31 December 2011. RESULTS: The total number of transplantations is 6528. The average clinical profile of the Spanish heart transplantation patient in 2011 was that of a 53 year-old male who had been diagnosed with nonrevascularizable ischemic heart disease accompanied by severely depressed ventricular function and poor functional status. The implanted heart was typically from a 38-year-old donor who had died from brain hemorrhage. The average waiting list time was 122 days. Mean survival time has progressively increased over the years. For the overall series, the probability of survival at 1, 5, 10, and 15 years was 77%, 66%, 53%, and 39%, respectively, whereas over the past 5 years the probability of survival at 1 and 5 years was 80% and 73%, respectively. The most frequent cause of death was acute graft failure (16%), followed by infection (15.6%), the combination of graft vascular disease and sudden death (14%), tumors (12.3%) and acute rejection (7.7%). CONCLUSIONS: The survival rates obtained in Spain from heart transplantation, especially in recent years, place heart transplantation as the treatment of choice in irreversible heart failure patients without other established medical or surgical options. PMID- 23026124 TI - The role of ventricular assist devices in advanced heart failure. PMID- 23026125 TI - Combined organic-inorganic fouling of forward osmosis hollow fiber membranes. AB - This research focused on combined organic-inorganic fouling and cleaning studies of forward osmosis (FO) membranes. Various organic/inorganic model foulants such as sodium alginate, bovine serum albumin (BSA) and silica nanoparticles were applied to polyamide-polyethersulfone FO hollow fiber membranes fabricated in our laboratory. In order to understand all possible interactions, experiments were performed with a single foulant as well as combinations of foulants. Experimental results suggested that the degree of FO membrane fouling could be promoted by synergistic effect of organic foulants, the presence of divalent cations, low cross-flow velocity and high permeation drag force. The water flux of fouled FO hollow fibers could be fully restored by simple physical cleaning. It was also found that hydrodynamic regime played an important role in combined organic inorganic fouling of FO membranes. PMID- 23026126 TI - Effect of pH on the formation of disinfection byproducts in swimming pool water- is less THM better? AB - This study investigated the formation and predicted toxicity of different groups of disinfection byproducts (DBPs) from human exudates in relation to chlorination of pool water at different pH values. Specifically, the formation of the DBP groups trihalomethanes (THMs), haloacetic acids (HAAs), haloacetonitriles (HANs) and trichloramine (NCl(3)), resulting from the chlorination of body fluid analog, were investigated at 6.0 <= pH <= 8.0. Either the initial concentration of active chorine or free chlorine was kept constant in the tested pH range. THM formation was reduced by decreasing pH but HAN, and NCl(3) formation increased at decreasing pH whereas the formation of HAAs remained constant. Under our experimental conditions, the formation of NCl(3) (suspected asthma inducing compound) at pH = 6.0 was an order of magnitude higher than at pH = 7.5. Furthermore, the effect of the presence of bromide on DBP formation was investigated and found to follow the same pH dependency as without bromide present, with the overall DBP formation increasing, except for HAAs. Estimation of genotoxicity and cytotoxicity of the chlorinated human exudates showed that among the quantified DBP groups, HAN formation were responsible for the majority of the toxicity from the measured DBPs in both absence and presence of bromide. PMID- 23026128 TI - Unaltered histaminergic system in depression: a postmortem study. AB - BACKGROUND: Rodent experiments suggested that the neuronal histaminergic system may be involved in symptoms of depression. METHODS: We determined, therefore, in postmortem tissue of 12 mood disorder patients (8 major depression disorder (MDD) and 4 bipolar disorder (BD)) and 12 well matched controls the expression of the rate-limiting enzyme for histamine production and histidine decarboxylase in the tuberomamillary nucleus (TMN) by quantitative in situ hybridization. In addition we used qPCR to determine the expression of the 4 histamine receptors and of the enzyme breaking down histamine, histamine N-methyltransferase (HMT), in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulated cortex (ACC). RESULTS: No changes were observed in the expression of these molecules, except for a significant lower HMT mRNA expression in the ACC of MDD subjects. LIMITATIONS: Several inherent and potentially confounding factors of a postmortem study, such as medication and cause of death, did not seem to affect the conclusions. The group size was relatively small but well documented, both clinically and neuropathologically. CONCLUSION: Except for a lower HMT mRNA expression in the ACC of MDD subjects, the neuronal histaminergic system did not show significant changes, either in the rate limiting enzyme involved in its production or in its receptors in 2 main projection sites, the ACC/DLPFC. PMID- 23026127 TI - Polysomnographic sleep patterns of non-depressed, non-medicated children with generalized anxiety disorder. AB - BACKGROUND: Polysomnographic (PSG) studies of children with psychiatric illness have primarily focused on depressed samples. Children with generalized anxiety disorder (GAD) report high rates of sleep problems yet investigation of objective sleep patterns in non-depressed children with GAD are unavailable. Identification of unique clinical features linking early GAD with sleep disturbance, including possible HPA activation during the pre-sleep period, is needed to inform effective treatments. METHOD: Thirty non-medicated, pre-pubescent children (ages 7-11 years) were assessed including 15 children with GAD and 15 matched healthy controls. Anxious children had GAD as their primary diagnosis and did not meet criteria for secondary mood disorders. All participants underwent structured diagnostic assessment and laboratory-based polysomnography (PSG). State anxiety and salivary cortisol were assessed prior to light out on the PSG night. RESULTS: Children with GAD showed significantly increased sleep onset latency and reduced latency to rapid eye movement (REM) sleep compared to controls. Marginal differences in the form of reduced sleep efficiency and increased total REM sleep also were found in the GAD group. Pre-sleep anxiety and cortisol levels did not differ between the two groups. LIMITATIONS: A small sample size, time-limited assessment of cortisol, and possible first night effects should be considered. CONCLUSIONS: Results of this study provide initial evidence of PSG-based differences in children with GAD compared to controls. Follow-up studies are needed to explore the course of sleep alterations and whether targeting sleep problems early in the course of GAD might improve clinical outcomes. PMID- 23026129 TI - Prevalence and risk factors for symptoms of common mental disorders in early and late pregnancy in Vietnamese women: a prospective population-based study. AB - BACKGROUND: Little is known about the prevalence of and risk factors for common mental disorders (CMD) in pregnant women in low-income countries. The aim of this study was to establish the prevalence of and psychosocial risk factors for clinically significant symptoms of CMD in early and late pregnancy in women in rural Viet Nam. METHODS: A population-based sample of women was surveyed in early and late pregnancy. CMD were assessed by the Edinburgh Postnatal Depression Scale Viet Nam Validation and psychosocial risks by study-specific structured interviews. RESULTS: In total 497/523 (97%) eligible women were recruited and 419 (84%) provided complete data. Prevalence of CMD only in early pregnancy was 22.4% (95% CI 18.4-26.4); only in late pregnancy was 10.7% (95% CI 7.8-13.7) and at both assessment waves was 17.4% (95% CI 13.8-21.1). Non-economic and economic coincidental life adversity, intimate partner violence, past pregnancy loss, and childhood abuse were positively associated with persistent antenatal CMD. Older age, having a preference for the baby's sex, and nulli- or primiparity were risk factors for CMD in early pregnancy. CONCLUSIONS: Persistent antenatal CMD are prevalent in rural areas of Viet Nam. Psychosocial risk factors play a major role in this significant public health problem. PMID- 23026130 TI - Percutaneous cementoplasty for the treatment of extraspinal painful bone lesion, a prospective study. AB - PURPOSE: The current gold standard treatment of localized painful bone lesion is radiotherapy but this technique has limitations. Our study aims to demonstrate that cementoplasty is an efficient alternative for these palliatives indications when lesions involve extraspinal bones. We prospectively followed 20 patients who received a percutaneous cementoplasty on painful lytic bone lesions between May 2008 and May 2010. MATERIALS: Seventeen patients also had difficulty walking in relation to the pain experienced. The clinical indication for treatment was severe pain (>=4 on the numeric scale) due to bone lesion on CT or MRI. All procedures (except one) were performed under local anesthesia. RESULTS: Feasibility was 100% without immediate complications. The patients experienced a significant and rapid decrease of their pain (4.1 points, P<000.1) and this effect was sustained over the long term (7.75 months of follow-up on average). Sixty-four percent of patients treated on the lower limbs and pelvis improved mobility. CONCLUSION: In our experience, percutaneous cementoplasty may be a safe and effective palliative treatment for localized painful lytic lesion. Combining CT and fluoroscopic guidance seems to be the safer option because of extravertebral localization. Smart fill of the bone and careful selection of patient determine the effectiveness of the procedure. Diffuse painful lesions and long bone diaphysis should not be good indications. PMID- 23026131 TI - Changes in the acquisition and consumption of food plants and their relationship with indigenous perceptions of health in a Guarani village, Sao Paulo, Brazil. AB - OBJECTIVE: The present study investigated Guarani village interviewees' diet changes over time, their perceptions about the changes and the effects of these changes on their health. DESIGN: The study employed qualitative methods with a sample of Guarani Indians selected by snowball sampling. Ethnographic methods and techniques included field diaries, informal and unstructured interviews and participant observation. SETTING: The Tenonde Pora Guarani village is located in the district of Parelheiros, Sao Paulo, Brazil. Interviews were conducted from July 2008 to December 2009. SUBJECTS: Fifteen Guarani Indians, males and females in age categories ranging from youths to elders, took part in the study. RESULTS: The interviewees reported changes in how food was obtained, the occurrence of food substitutions and food species abandonment, recipe changes and the introduction of new foods. Some ritual use of plants was maintained. Disease frequency was found to increase because of this change and a lack of obedience to Nhanderu (the Guarani God). A lack of space for daily traditional activities (e.g. farming, hunting) was found to result in sedentary lifestyles. CONCLUSIONS: The village location was a key factor in the Guarani diet change, although some rituals related to available plants were preserved. PMID- 23026132 TI - Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene, decreased leptin mRNA expression, and decreased leptin serum levels. AB - Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9*10(-5)) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients. PMID- 23026133 TI - The metabolomic signature of malignant glioma reflects accelerated anabolic metabolism. AB - Although considerable progress has been made toward understanding glioblastoma biology through large-scale genetic and protein expression analyses, little is known about the underlying metabolic alterations promoting their aggressive phenotype. We conducted global metabolomic profiling on patient-derived glioma specimens and identified specific metabolic programs differentiating low- and high-grade tumors, with the metabolic signature of glioblastoma reflecting accelerated anabolic metabolism. When coupled with transcriptional profiles, we identified the metabolic phenotype of the mesenchymal subtype to consist of accumulation of the glycolytic intermediate phosphoenolpyruvate and decreased pyruvate kinase activity. Unbiased hierarchical clustering of metabolomic profiles identified three subclasses, which we term energetic, anabolic, and phospholipid catabolism with prognostic relevance. These studies represent the first global metabolomic profiling of glioma, offering a previously undescribed window into their metabolic heterogeneity, and provide the requisite framework for strategies designed to target metabolism in this rapidly fatal malignancy. PMID- 23026134 TI - ICOS-ligand expression on plasmacytoid dendritic cells supports breast cancer progression by promoting the accumulation of immunosuppressive CD4+ T cells. AB - Human breast tumors are infiltrated by memory CD4(+) T cells along with increased numbers of regulatory T cells (Treg) and plasmacytoid dendritic cells (pDC) that facilitate immune escape and correlate with poor prognosis. Here, we report that inducible costimulatory molecule (ICOS), a T cell costimulatory molecule of the CTLA4/PD1/CD28 family, is expressed mostly by tumor-associated Treg in primary breast tumors. A large proportion of these ICOS(+) Treg were Ki67(+) and this evident proliferative expansion was found to rely on interactions with tumor associated pDC. Indeed, tumor-associated Treg highly expanded in presence of pDC but failed to proliferate under CD3/CD28 signal. In vitro experiments revealed that the addition of a neutralizing anti-ICOS antibody blocked pDC-induced Treg expansion and interleukin-10 secretion by memory CD4(+) T cells, establishing a pivotal role for ICOS in this process. Supporting these findings, the presence of ICOS(+) cells in clinical specimens of breast cancer correlated with a poor prognosis. Together, our results highlight an important relationship between Treg and pDC in breast tumors, and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells. These findings strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer. PMID- 23026136 TI - E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation. AB - To identify novel oncogenic E3 ubiquitin ligases as anticancer targets, we screened an E3 ubiquitin ligase siRNA library containing siRNA pools against 555 individual E3s using the sulphorhodamine B assay in the MDA-MB-231 breast cancer cell line and the PC3 prostate cancer cell line. RNF126 was identified and validated as a candidate from this screening. Knockdown of RNF126 dramatically decreased cell viability in these cancer cell lines. Consistently, RNF126 knockdown delayed cell-cycle G(1)-S progression and decreased cell proliferation. Using protein array analysis we found that RNF126 silencing increased cell-cycle dependent kinase inhibitor p21(cip) protein levels in both MDA-MB-231 and PC3. Knockdown of RNF126 stabilized the p21 protein rather than increased p21 mRNA levels. We showed that RNF126 interacts with p21 and RNF126 overexpression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner. RNF126 knockdown induced loss of cell viability in MDA-MB-231 and PC-3 can be partially rescued by depletion of p21. RNF126 stable knockdown in PC3 inhibited tumor growth in SCID mice. Finally, we found that RNF126 is highly expressed in a subset of breast cancer cell lines and negatively correlated with p21 expression levels. These findings suggest that RNF126 promotes cancer cell proliferation by targeting p21 for ubiquitin-mediated degradation. RNF126 could be a novel therapeutic target in breast and prostate cancers. PMID- 23026135 TI - Geminin functions downstream of p53 in K-ras-induced gene amplification of dihydrofolate reductase. AB - DNA strand breakage and perturbation of cell-cycle progression contribute to gene amplification events that can drive cancer. In cells lacking p53, DNA damage does not trigger an effective cell-cycle arrest and in this setting promotes gene amplification. This is also increased in cells harboring oncogenic Ras, in which cell-cycle arrest is perturbed and ROS levels that cause DNA single strand breaks are elevated. This study focused on the effects of v-K-ras and p53 on Methotrexate (MTX)-mediated DHFR amplification. Rat lung epithelial cells expressing v-K-ras or murine lung cancer LKR cells harboring active K-ras continued cell-cycle progression when treated with MTX. However, upon loss of p53, amplification of DHFR and formation of MTX-resistant colonies occurred. Expression levels of cyclin A, Geminin, and Cdt1 were increased in v-K-ras transfectants. Geminin was sufficient to prevent the occurrence of multiple replications via interaction with Cdt1 after MTX treatment, and DHFR amplification proceeded in v-K-ras transfectants that possess a functional p53 in the absence of geminin. Taken together, our findings indicate that p53 not only regulates cell-cycle progression, but also functions through geminin to prevent DHFR amplification and protect genomic integrity. PMID- 23026137 TI - An insertion/deletion polymorphism within RERT-lncRNA modulates hepatocellular carcinoma risk. AB - The Prolyl hydroxylase 1 (EGLN2) is known to affect tumorigenesis by regulating the degradation of hypoxia-inducible factor. Polymorphisms in EGLN2 may facilitate cancer cell survival under hypoxic conditions and directly associate with cancer susceptibility. Here, we examined the contribution of a 4-bp insertion/deletion polymorphism (rs10680577) within the distal promoter of EGLN2 to the risk of hepatocelluar carcinoma (HCC) in Chinese populations. The contribution of rs10680577 to HCC risk was investigated in 623 HCC cases and 1,242 controls and replicated in an independent case-control study consisting of 444 HCC cases and 450 controls. Logistic regression analysis showed that the deletion allele of rs10680577 was significantly associated with increased risk for HCC occurrence in both case-control studies [OR = 1.40; 95% confidence interval (CI) = 1.18-1.66, P < 0.0001; OR = 1.49; 95% CI = 1.18-1.88, P = 0.0007]. Such positive association was more pronounced in current smokers (OR = 3.49, 95% CI = 2.24-5.45) than nonsmokers (OR = 1.24, 95% CI = 1.03-1.50; heterogeneity P = 0.0002). Genotype-phenotype correlation studies showed that the deletion allele was significantly correlated with higher expression of both EGLN2 and RERT-lncRNA [a long noncoding RNA whose sequence overlaps with Ras-related GTP-binding protein 4b (RAB4B) and EGLN2)] in vivo and in vitro. Furthermore, RERT-lncRNA expression was also significantly correlated with EGLN2 expression in vivo, consistent with in vitro gain-of-function study that showed overexpressing RERT-lncRNA upregulated EGLN2. Finally, in silico prediction suggested that the insertion allele could disrupt the structure of RERT-lncRNA. Taken together, our findings provided strong evidence for the hypothesis that rs10680577 contributes to hepatocarcinogenesis, possibly by affecting RERT-lncRNA structure and subsequently EGLN2 expression, making it a promising biomarker for early diagnosis of HCC. PMID- 23026139 TI - Reflex modulation of ovarian estradiol secretion by noxious mechanical stimulation of a hindpaw in anesthetized rats. AB - Previously, we demonstrated that electrical stimulation of the superior ovarian nerve in rats reduces the ovarian estradiol secretion rate. In the present study, we examined the effect of noxious mechanical afferent stimulation (pinching) of a hindpaw on the ovarian estradiol secretion rate in rats. The rats were anesthetized on the day of estrus, and the ovarian venous blood was collected intermittently. The secretion rate of estradiol from the ovary was calculated from differences in the estradiol concentration between ovarian venous plasma and systemic arterial blood plasma, and from the flow rate of ovarian venous plasma. Pinching stimulation of a hindpaw for 5 min decreased the estradiol secretion rate from the ovary. A significant reduction of the estradiol secretion rate began at 5 min after the end of the stimulation and lasted for 20 min. The minimum decrease in estradiol secretion rate was 71.1 +/- 14.0% of the prestimulus basal values at 15 min after the stimulation ended. The decrease responses of the ovarian estradiol secretion rate were abolished by bilateral severance of the superior ovarian nerves. The efferent activity of the superior ovarian nerves was increased following hindpaw pinching. After spinal transection at the second cervical level, the increased response of the superior ovarian nerve activity by hindpaw pinching was abolished. These results indicate that noxious mechanical stimulation of a hindpaw decreases the estradiol secretion rate from the ovary, and that the response is due to reflex activation of ovarian sympathetic nerves, mediated by supraspinal structures. PMID- 23026138 TI - Methamphetamine regulation of sulfotransferase 1A1 and 2A1 expression in rat brain sections. AB - Sulfotransferase catalyzed sulfation regulates the biological activities of various neurotransmitters/hormones and detoxifies xenobiotics. Rat sulfotransferase rSULT1A1 catalyzes the sulfation of neurotransmitters and xenobiotic phenolic compounds. rSULT2A1 catalyzes the sulfation of hydroxysteroids and xenobiotic alcoholic compounds. In this work, Western blot and real-time RT-PCR were used to investigate the effect of methamphetamine on rSULT1A1 and rSULT2A1 protein and mRNA expression in rat cerebellum, frontal cortex, hippocampus, and striatum. After 1-day treatment, significant induction of rSULT1A1 was observed only in the cerebellum; rSULT2A1 was induced significantly in the cerebellum, frontal cortex, and hippocampus. After 7 days of exposure, rSULT1A1 was induced in the cerebellum, frontal cortex, and hippocampus, while rSULT2A1 was induced significantly in all four regions. Western blot results agreed with the real-time RT-PCR results, suggesting that the induction occurred at the gene transcriptional level. Results indicate that rSULT1A1 and rSULT2A1 are expressed in rat frontal cortex, cerebellum, striatum, and hippocampus. rSULT1A1 and rSULT2A1are inducible by methamphetamine in rat brain sections in a time dependable manner. rSULT2A1 is more inducible than rSULT1A1 by methamphetamine in rat brain sections. Induction activity of methamphetamine is in the order of cerebellum>frontal cortex, hippocampus>striatum. These results suggest that the physiological functions of rSULT1A1 and rSULT2A1 in different brain regions can be affected by methamphetamine. PMID- 23026140 TI - Single cell genomics: an individual look at microbes. AB - Single cell genomics (SCG) uncovers hereditary information at the most basic level of biological organization. It is emerging as a powerful complement to cultivation-based and microbial community-focused research approaches. SCG has been instrumental in identifying metabolic features, evolutionary histories and inter-organismal interactions of the uncultured microbial groups that dominate many environments and biogeochemical cycles. The SCG approach also holds great promise in microbial microevolution studies and industrial bioprospecting. Methods for SCG consist of a series of integrated processes, beginning with the collection and preservation of environmental samples, followed by physical separation, lysis and whole genome amplification of individual cells, and culminating in genomic sequencing and the inference of encoded biological features. PMID- 23026141 TI - New psychoactive substances. PMID- 23026144 TI - Responses of mink to auditory stimuli: prerequisites for applying the 'cognitive bias' approach. AB - The aim of the study was to determine and validate prerequisites for applying a cognitive (judgement) bias approach to assessing welfare in farmed mink (Neovison vison). We investigated discrimination ability and associative learning ability using auditory cues. The mink (n=15 females) were divided into two groups (High, n=8; Low, n=7, representing the frequency of the tone they were habituated to, 18 and 2 kHz respectively) and were tested using a habituation-dishabituation procedure in experiment 1. In experiment 2 one auditory stimulus was followed by an inter-trial-interval (safe/neutral situation), whereas another auditory stimulus was followed by an aversive stimulus (air blow) before the inter-trial interval (danger situation). We observed behaviour including latencies to show a response during both experiments. The High mink showed significant habituation in experiment 1 but the Low mink only showed habituation in experiment 2. Regardless of the frequency used (2 and 18 kHz), cues predicting the danger situation initially elicited slower responses compared to those predicting the safe situation but quickly became faster. Using auditory cues as discrimination stimuli for female farmed mink in a judgement bias approach would thus appear to be feasible. However several specific issues are to be considered in order to successfully adapt a cognitive bias approach to mink, and these are discussed. PMID- 23026145 TI - Queens defense by workers in the highly polygynous ant Crematogaster pygmaea (Hymenoptera: Myrmicinae). AB - Some aspects of the biology of Crematogaster pygmaea, a highly polydomous and polygynous ant, are more commonly found in monogynous species. One such characteristic is the high attractiveness of its queens. In this study, this attractiveness was assessed under varying experimental conditions to investigate the factors responsible for its expression and variation, and to identify the nature of queen attractiveness. It was shown (1) that C. pygmaea queens are highly attractive to the workers that cluster on and around them (retinue), (2) that the attractiveness of C. pygmaea queens is context-dependent, i.e., it increases with increasing degree of potential danger to the queen, (3) that the attractiveness signal of C. pygmaea queens is chemically based, and (4) that this signal is persistent and apparently not colony-specific. The proposed hypothesis is that the C. pygmaea queens constantly release an attractiveness signal that is "read" by the workers, in a dependent way linked to the context, and that the main function of this attractiveness is to protect queens. This protection would have a high adaptive value in the context of the social structure and the reproductive strategies in C. pygmaea. PMID- 23026146 TI - Social facilitation of male song by male and female conspecifics in the zebra finch, Taeniopygia guttata. AB - Zebra finches are a ubiquitous model system for the study of vocal learning in animal communication. Their song has been well described, but its possible function(s) in social communication are only partly understood. The so-called 'directed song' is a high-intensity, high-performance song given during courtship in close proximity to the female, which is known to mediate mate choice and mating. However, this singing mode constitutes only a fraction of zebra finch males' prolific song output. Potential communicative functions of their second, 'undirected' singing mode remain unresolved in the face of contradicting reports of both facilitating and inhibiting effects of social company on singing. We addressed this issue by experimentally manipulating social contexts in a within subject design, comparing a solo versus male or female only company condition, each lasting for 24h. Males' total song output was significantly higher when a conspecific was in audible and visible distance than when they were alone. Male and female company had an equally facilitating effect on song output. Our findings thus indicate that singing motivation is facilitated rather than inhibited by social company, suggesting that singing in zebra finches might function both in inter- and intrasexual communication. PMID- 23026147 TI - The differential response of workers and queens of the ant Lasius niger to an environment marked by workers: ants dislike the unknown. AB - It is well known that ants can use cuticular hydrocarbons (CHCs) as a specific recognition cue. Most previous studies addressed the perception of CHCs occurring on the cuticle. However, the presence of CHCs in the environment (e.g., on the substrate) and the role of these compounds as a signal cue are less clear. In this study of the ant L. niger, CHCs were extracted from corpses of workers, from the legs of workers and from filter paper marked by workers. Behavioural choice tests were then performed to study the reactions of workers and queens to CHC passively deposited on the substrate by walking workers. A GC-MS analysis of the CHCs revealed a complex mixture of 28 peaks composed of linear alkanes, alkenes and mono-, di- or trimethylalkane. This mixture was consistently present in the three sources tested (corpses of workers, the tarsus of workers and paper marked by walking workers). Nevertheless, discriminant analyses distinguished clearly among the three types of profiles. The results of our behavioural experiments showed that the workers were able to distinguish between marked and unmarked papers but that they exhibited no preferences for different types of marked papers (papers marked by workers from their own colony or papers marked by workers from a different colony). In queens, the perception of marked papers depended on age or physiological state. Just-mated queens did not discriminate between unmarked papers and papers marked by an alien colony. In contrast, the egg-laying queens 3 days after mating significantly favoured the marked papers. We discuss the ecological relevance of the differences in decision-making between castes. PMID- 23026148 TI - Biogenic calcite granules--are brachiopods different? AB - Brachiopods are still one of the least studied groups of organisms in terms of biomineralization despite recent studies indicating the presence of highly complex biomineral structures, particularly in taxa with calcitic shells. Here, we analyze the nanostructure of calcite biominerals, fibers and semi-nacre tablets, in brachiopod shells by high-resolution scanning electron microscopy (SEM) and atomic force microscopy (AFM). We demonstrate that basic mechanisms of carbonate biomineralization are not uniform within the phylum, with semi-nacre tablets composed of spherical aggregates with sub-rounded granules and fibers composed of large, triangular or rod-like particles composed of small sub-rounded granules (40-60 nm). Additionally, proteinaceous envelopes surrounding calcite fibers have been shown for the first time to have a dual function: providing a micro-environment in which granules are produced and acting as the organic template for particle orientation as fiber components. In summary, these new findings in brachiopod shells reveal a complex and distinctive style of biomineralization among carbonate-producing organisms. PMID- 23026149 TI - The impact of sheep grazing on the carbon balance of a peatland. AB - Estimates of the greenhouse gas (GHG) fluxes resulting from sheep grazing upon upland peat soils have never been fully quantified. Previous studies have been limited to individual flux pathways or to comparing the presence to the absence of sheep grazing. Therefore, this study combines a model of the physical impact of grazing with models of: biomass production; energy usage in sheep; and peat accumulation. These combined modelling approaches enabled this study to consider the indirect and direct impacts of sheep upon the carbon and greenhouse gas balance of a peatland at different grazing intensities as well as the changes between grazing intensities. The study considered four vegetation scenarios (Calluna sp., Molinia sp.; reseeded grasses, and Agrostis-Festuca grassland) and a mixed vegetation scenario based upon the vegetation typical of upland peat ecosystems in northern England. Each scenario was considered for altitudes between 350 and 900 m above sea level and for grazing intensities between 0.1 and 2 ewes/ha. The study can show that the total GHG flux at the vegetative carrying capacity tended to decline with increasing altitude for all vegetation scenarios considered except for Molinia sp. The average total GHG flux for all scenarios was 1505 kg CO(2)eq/ha/yr/(ewe/ha), and on average 89% of the fluxes were directly from the sheep and not from the soil, and are therefore not unique to a peat soil environment. The study suggests that emission factors for upland sheep have been greatly underestimated. By comparing the total flux due to grazers to the flux to or from the soil that allows the study to define a GHG carry capacity, i.e. the grazing intensity at which the flux due to grazing is equal to the sink represented by the peat soils, this GHG carrying capacity varies between 0.2 and 1.7 ewes/ha with this capacity declining with increasing altitude for all model scenarios. PMID- 23026150 TI - Agriculture has changed the amount and composition of dissolved organic matter in Central European headwater streams. AB - Dissolved organic matter (DOM) is an important part of the global carbon cycle and significantly influences aquatic ecosystem functions. Recent studies suggest that its amount and composition in freshwaters may be altered by agricultural land use, whereby the influence of preceding in-stream production and processing is not clear. To assess the land use effect on DOM amount and composition for the export from terrestrial to freshwater systems at the land-water interface, we sampled headwater streams draining agricultural and near-pristine catchments (forested and wetland) in the North German plains. To account for spatial and seasonal variation, we conducted a screening of DOM amount (53 sites) and composition (42 sites), and conducted bi-weekly samplings to investigate seasonal variation at eight sites over one year. Concentrations of dissolved organic carbon (DOC) were significantly higher for agricultural and wetland catchments than for forested catchments. Moreover, DOC loads exhibited higher seasonal variation for agricultural and wetland catchments than for forested catchments, which was due to higher variation in discharge. Parallel Factor Analysis revealed that the composition of DOM in agricultural catchments was significantly different from the other studied catchment types, and was characterized by low redox state and high structural complexity. Moreover, a gradient from protein- to humic-like fluorescence significantly separated forested from agricultural and wetland catchments. The contribution of humic-like DOM was strongly and positively related to DOC concentration, suggesting a mechanistic coupling of both. The effects of land use on patterns of DOC concentration and DOM composition were consistent across seasons, implying that land use strongly regulates DOM export. Overall, this study clearly shows the seasonally independent importance of agricultural land use for the amount and composition of DOM fluxes from the terrestrial zone to surface waters. These altered fluxes may affect ecosystem metabolism and health of agricultural headwaters and downstream situated aquatic ecosystems. PMID- 23026151 TI - Bacterial and fungal markers in tobacco smoke. AB - Previous research has demonstrated that cigarette smoke contains bacterial and fungal components including lipopolysaccharide (LPS) and ergosterol. In the present study we used gas chromatography-mass spectrometry to analyze tobacco as well as mainstream and second hand smoke for 3-hydroxy fatty acids (3-OH FAs) of 10 to 18 carbon chain lengths, used as LPS markers, and ergosterol, used as a marker of fungal biomass. The air concentrations of LPS were 0.0017 n mol/m(3) (N=5) and 0.0007/m(3) (N=6) in the smoking vs. non-smoking rooms (p=0.0559) of the studied private houses, and 0.0231 n mol/m(3) (N=5) vs. 0.0006 n mol/m(3) (N=5) (p=0.0173), respectively, at the worksite. The air concentrations of ergosterol were also significantly higher in rooms with ongoing smoking than in rooms without smoking. A positive correlation was found between LPS and ergosterol in rooms with smoking but not in rooms without smoking. 3-OH C14:0 was the main 3-OH FA, followed by 3-OH C12:0, both in mainstream and second hand smoke and in phenol:water smoke extracts prepared in order to purify the LPS. The Limulus activity of the phenolic phase of tobacco was 3900 endotoxin units (EU)/cigarette; the corresponding amount of the smoke, collected on filters from 8 puffs, was 4 EU/cigarette. Tobacco smoking has been associated with a range of inflammatory airway conditions including COPD, asthma, bronchitis, alveolar hypersensitivity etc. Significant levels of LPS and ergosterol were identified in tobacco smoke and these observations support the hypothesis that microbial components of tobacco smoke contribute to inflammation and airway disease. PMID- 23026152 TI - Effect of soil type on distribution and bioaccessibility of metal contaminants in shooting range soils. AB - Shooting ranges from Department of Defence sites around Australia were investigated for extent of metal contamination. Shooting range soils contained concentrations ranging from 399 to 10,403 mg/kg Pb, 6.57 to 252 mg/kg Sb, 28.7 to 1250 mg/kg Cu, 5.63 to 153 mg/kg Zn, 1.35 to 8.8 mg/kg Ni and 3.08 to 15.8 mg/kg As. Metal(loid)s were primarily concentrated in the stop butt and the surface soil (0-10 cm). The distribution of contamination reflected firing activity, soil properties, climate and management practices. Climatic variations among sites in Australia are significant, with a temperate climate in the south and tropical climate with high rainfall in the north. Up to 8% of total Pb resided in soil fines (<0.075 mm), due to the fragmentation of bullets on impact. Distribution and bioaccessibility varied between each site. Acidic Townsville soil had the highest proportion of water extractable Pb at 10%, compared to the alkaline Murray Bridge with only 2% Pb water extractable. Soil properties such as CEC, pH and dissolved organic carbon influence mobility. This is reflected in the subsoil concentrations of Pb in Townsville and Darwin which are up to 30 and 46% of surface concentration in the subsoil respectively. Similarly bioaccessibility is influenced by soil properties and ranges from 46% in Townsville to 70% in Perth. Acidic pH promotes dissolution of secondary minerals and the downward movement of Pb in the profile. The secondary Pb minerals formed as a result of weathering in these soils were cerussite, hydrocerussite, pyromorphite, galena and anglesite. Copper oxide was also reported on fragments from bullet jackets. These results have implications for range management. PMID- 23026154 TI - Effects of low-intensity pulsed ultrasound on autogenous bone graft healing. AB - OBJECTIVE: Pulsed ultrasonic waves have been shown to accelerate bone healing. The aim of this study was to evaluate the effects of low-intensity pulsed ultrasound on bone healing. STUDY DESIGN: Thirty-two femurs from 16 skeletally mature male Wistar albino rats were used. Two defects were produced in each femur with a 3-mm-diameter trephine bur and then autogenous cortical grafts were placed in 1 defect. The animals in the experiment group received a daily 20-minute ultrasound treatment for 15 days. All animals were killed on the 18th postoperative day. RESULTS: Dual-energy x-ray absorptiometry values and biochemical markers in the experimental side were significantly higher than those in the control side at the early period of bone healing. CONCLUSIONS: Low intensity pulsed ultrasound treatment accelerates bone healing both in bone defects and in bone defects filled with cortical autogenous block graft. PMID- 23026153 TI - Rate constants of oxidation of unsaturated fatty esters studied by chemiluminescence. AB - This study deals with oxidation kinetics of three unsaturated fatty esters: methyl oleate, methyl linoleate and methyl linolenate at temperatures ranging from 90 to 150 degrees C. The reaction was monitored by chemiluminescence. A kinetic model was derived from a simple mechanistic scheme, in which initiation is due to hydroperoxides decomposition, whereas propagation results from the abstraction of the most labile hydrogen and termination results only from the bimolecular combination of peroxyl radicals. Analysis of induction period duration indicated that hydroperoxides mainly decompose by a bimolecular process. The model well predicts the main features of the experimental chemiluminescence curves. Kinetic parameters of the three unsaturated fatty esters were assessed from inverse method and discussed. PMID- 23026155 TI - Carbon monoxide: mechanisms of action and potential clinical implications. AB - Small amounts of carbon monoxide (CO) are continuously produced in mammals. The intracellular levels of CO can increase under stressful conditions following the induction of HO-1 (heme oxygnase-1), a ubiquitous enzyme responsible for the catabolism of heme. Unlike nitric oxide, which is a free radical, CO does not contain free electrons but may be involved in oxidative stress. The carbonate radical has been proposed to be a key mediator of oxidative damage resulting from peroxynitrite production, likewise, the precursor of the carbonate radical anion being bicarbonate and carbon dioxide. We report herein some of the transcription factors and protein kinases involved in the regulation of vascular HO-1 expression. Beyond its widely feared toxicity, CO has revealed a very important biological activity as a signaling molecule with marked protective actions namely against apoptosis and endothelial oxidative damage. Abnormal metabolism and function of CO contribute to the pathogenesis and development of cardiovascular diseases. Important results have been reported in which CO and CO-releasing molecules (CO-RMs) prevent intimal hyperplasia by arresting hyperproliferative vascular smooth muscle cells and increased mobilization and recruitment of bone marrow-derived progenitor cells. Clinical studies have demonstrated beneficial properties of CO-RMs in transplantation. The anti-inflammatory properties of CO and CO-RMs have been demonstrated in a multitude of animal models of inflammation, suggesting a possible therapeutic application for inflammatory diseases. The development of a technology concerning CO-RMs that controls the delivery and action of CO under different pathological conditions represents a major step forward in the development of CO-based pharmaceuticals with therapeutic applications. PMID- 23026156 TI - Communicating inherited genetic risk between parent and child: a meta-thematic synthesis. AB - OBJECTIVES: Communicating genetic risk is a distressing process for families affected by inherited genetic conditions. This systematic review identifies and explores the challenges faced by parents and their (non)affected or at risk children caused by the (non)disclosure of genetic risk information. DESIGN: Qualitative meta-synthesis and thematic analysis. DATA SOURCES: Ovid databases; Ovid 'in progress', British Nursing Index, Embase, Medline and Psychinfo were combined with searches of EBSCOhost databases; CINAHL and ERIC and Web of science and ZETOC databases using truncations of communication, chronic illness and disease and words relating to family with specific genetic conditions; Cystic Fibrosis, Duchenne Muscular Dystrophy, Familial Adenomatous Polyposis, Hereditary Non-polyposis Colorectal Cancer, Huntington's Disease, Neurofibromatosis and Sickle Cell Anaemia. This was augmented with free Internet and hand searches and an exploration of the bibliographies of all included papers. REVIEW METHOD: All papers were quality assessed to ascertain their research quality and methodological rigour. RESULTS: A total of 2033 citations were retrieved. Following the removal of duplicates, irrelevant articles and the application of an inclusion criterion, 12 articles remained. A further three papers were omitted due to poor quality leaving nine papers which focussed on the disclosure of genetic information between parent and child (<18 years). Eight papers were qualitative in design and one used a mixed method approach. Thematic synthesis produced four themes that inform the structure of the paper; disclosure, emotions involved in disclosure, desired disclosure and recommendations. CONCLUSION: Disclosure of genetic risk information within families is a highly complex and affective process often resulting in delayed disclosure. This can lead to increased family tensions generated by misunderstanding, blame and secrecy. Early, age appropriate disclosure can better prepare children for future considerations such as care planning and reproductive decision-making. It also contributes to effective coping strategies that promote enhanced adaptation and emotional well being. Early disclosure also reduces parental anxieties concerning disclosure from an unwitting source. Research shows that children and young people want their parents to engage in open and honest discussions about the genetic condition. Therefore to help facilitate effective family communication health professionals should provide family centred care and better emotional and informational support. PMID- 23026157 TI - Effects of a "two-hit" model of organ damage on the systemic inflammatory response and development of laminitis in horses. AB - The role of endotoxemia in the development of laminitis remains unclear. Although systemic inflammation is a risk factor for laminitis in hospitalized horses, experimental endotoxin administration fails to induce the disease. While not sufficient to cause laminitis by itself, endotoxemia might predispose laminar tissue to damage from other mediators during systemic inflammation. In "two-hit" models of organ damage, sequential exposure to inflammatory stimuli primes the immune system and causes exaggerated inflammatory responses during sepsis. Acute laminitis shares many characteristics with sepsis-associated organ failure, therefore an equine "two-hit" sepsis model was employed to test the hypothesis that laminitis develops with increased frequency and severity when repeated inflammatory events exacerbate systemic inflammation and organ damage. Twenty four light breed mares (10) and geldings (14) with chronic disease conditions or behavioral abnormalities unrelated to laminitis that warranted euthanasia were obtained for the study. Horses were randomly assigned to receive an 8-h intravenous infusion of either lipopolysaccharide (5 ng/kg/h) or saline beginning at -24h, followed by oligofructose (OF; 5 g/kg) via nasogastric tube at 0 h. Euthanasia and tissue collection occurred at Obel grade 2 laminitis, or at 48 h if laminitis had not developed. Liver biopsies were performed at 24h in laminitis non-responders. Blood cytokine gene expression was measured throughout the study period. Lipopolysaccharide and OF administration independently increased mean rectal temperature (P<0.001), heart rate (P=0.003), respiratory rate (P<0.001), and blood interleukin (IL)-1beta gene expression (P<0.0016), but responses to OF were not exaggerated in endotoxin-pretreated horses. The laminitis induction rate did not differ between treatment groups and was 63% overall. When horses were classified as laminitis responders and non-responders, area under the blood IL 1beta expression curve (P=0.010) and liver and lung gene expression of IL-1beta, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha (P<0.05) were higher in responders following OF administration. The results indicate that endotoxin pretreatment did not enhance responses to OF. However, systemic inflammation was more pronounced in laminitis responders compared to non-responders, and tissue generated inflammatory mediators could pose a greater risk than those produced by circulating leukocytes. PMID- 23026159 TI - Phospholipid metabolism and nuclear function: roles of the lipin family of phosphatidic acid phosphatases. AB - Phospholipids play important roles in nuclear function as dynamic building blocks for the biogenesis of the nuclear membrane, as well as signals by which the nucleus communicates with other organelles, and regulate a variety of nuclear events. The mechanisms underlying the nuclear roles of phospholipids remain poorly understood. Lipins represent a family of phosphatidic acid (PA) phosphatases that are conserved from yeasts to humans and perform essential functions in lipid metabolism. Several studies have identified key roles for lipins and their regulators in nuclear envelope organization, gene expression and the maintenance of lipid homeostasis in yeast and metazoans. This review discusses recent advances in understanding the roles of lipins in nuclear structure and function. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. PMID- 23026160 TI - Implication of organic acids in the long-distance transport and the accumulation of lead in Sesuvium portulacastrum and Brassica juncea. AB - The implication of organic acids in Pb translocation was studied in two species varying in shoot lead accumulation, Sesuvium portulacastrum and Brassica juncea. Citric, fumaric, malic and alpha-cetoglutaric acids were separated and determined by HPLC technique in shoots, roots and xylem saps of the both species grown in nutrient solutions added with 200 and 400 MUM of Pb(II). The lead content of the xylem saps was determined by ICP-MS. Results showed that S. portulacastrum is more tolerant to Pb than B. juncea. Lead concentration in xylem sap of the S. portulacastrum was significantly greater than in that of B. juncea. For both species, a positive correlation was established between lead and citrate concentrations in xylem sap. However minor relationship was observed for fumaric, malic and alpha-cetoglutaric acids. In the shoots lead treatment also induced a significant increase in citric acid concentration. Both observations suggest the implication of citric acid in lead translocation and shoot accumulation in S. portulacastrum and B. juncea. The relatively high accumulation of citric acid in xylem sap and shoot of S. portulacastrum could explain its high potential to translocate and accumulate this metal in shoot suggesting their possible use to remediate Pb polluted soils. PMID- 23026161 TI - Tree vegetation and waste amendments to improve the physical condition of copper mine soils. AB - Mine soils are often physically degraded, which hinders plants development. The untreated soils at the depleted copper mine in Touro (Galicia, north-west Spain) have no vegetation and are probably physically degraded. These mine soils were reclaimed both by planting trees and amending with waste (sewage sludge and paper mill residues). The purpose was to determine the effect of these treatments on the physical quality of the soils of the Touro mine under field conditions. We evaluated the physical situation of both the settling pond and the mine tailings in Touro, then comparing them with their respective treated areas: vegetated, amended or with both treatments at the same time. We corroborated that the physical degradation of untreated soils was considerable: low porosity, high density and less than 50% of water stable aggregates. The trees that were planted increased porosity, probably due to root activity. The added amendments increased the mean weight diameter (MWD), the percentage of water stable aggregates (WSA) and the stability index (SI) due to the high organic carbon content in the added wastes. We verified that using both treatments at the same time is better than using only one to improve the physical situation of mine soils. PMID- 23026162 TI - Formation of disinfection by-products: effect of temperature and kinetic modeling. AB - The temperature of drinking water fluctuates naturally in water distribution systems as well as often deliberately heated for household or public uses. In this study, the temperature effect on the formation of disinfection by-products (DBPs) was investigated by monitoring the temporal variations of twenty-one DBPs during the chlorination of a humic precursors-containing water at different temperatures. It was found that chloroform, DCAA, TCAA, DCAN and CH were detected at the considerable level of tens of MUg L(-1). The three regulated DBPs (chloroform, DCAA and TCAA) were found increasing with both contact time and water temperature, while the five typical emerging DBPs (DCAN, CH, TCNM 1,1-DCPN and 1,1,1-TCPN) revealed the significant auto-decomposition in addition to the initial growth in the first few hours. Increasing water temperature could enhance the formation rates of all the eight detected DBPs and the decomposition rates of the five emerging DBPs. Further, a kinetic model was developed for the simulation of DBP formation. The validity and universality of the model were verified by its excellent correlation with the detected values of each DBP species at various temperatures. The formation rates of 1,1-DCPN and 1,1,1-TCPN, and the decomposition rate of 1,1,1-TCPN were faster as compared to the other DBPs. And the formation reaction activation energies of CH, DCAN and 1,1-DCPN were relatively large, indicating that their occurrence levels in the finished water were more susceptible to temperature variations. PMID- 23026164 TI - Nanometer scale tomographic investigation of fine scale precipitates in a CuFeNi granular system by three-dimensional field ion microscopy. AB - The microstructure of Cu80Fe10Ni10 (at. %) granular ribbons was investigated by means of three-dimensional field ion microscopy (3D FIM). This ribbon is composed of magnetic precipitates embedded in a nonmagnetic matrix. The magnetic precipitates have a diameter smaller than 5 nm in the as-spun state and are coherent with the matrix. No accurate characterization of such a microstructure has been performed so far. A tomographic characterization of the microstructure of melt spun and annealed Cu80Fe10Ni10 ribbon was achieved with 3D FIM at the atomic scale. A precise determination of the size distribution, number density, and distance between the precipitates was carried out. The mean diameter for the precipitates is 4 nm in the as-spun state. After 2 h at 350 degrees C, there is an increase of the size of the precipitates, while after 2 h at 400 degrees C the mean diameter of the precipitates decreases. Those data were used as inputs in models that describe the magnetic and magnetoresistive properties of this alloy. PMID- 23026158 TI - Surfactant phospholipid metabolism. AB - Pulmonary surfactant is essential for life and is composed of a complex lipoprotein-like mixture that lines the inner surface of the lung to prevent alveolar collapse at the end of expiration. The molecular composition of surfactant depends on highly integrated and regulated processes involving its biosynthesis, remodeling, degradation, and intracellular trafficking. Despite its multicomponent composition, the study of surfactant phospholipid metabolism has focused on two predominant components, disaturated phosphatidylcholine that confers surface-tension lowering activities, and phosphatidylglycerol, recently implicated in innate immune defense. Future studies providing a better understanding of the molecular control and physiological relevance of minor surfactant lipid components are needed. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. PMID- 23026163 TI - Role of electrode materials for the anodic oxidation of a real landfill leachate- comparison between Ti-Ru-Sn ternary oxide, PbO(2) and boron-doped diamond anode. AB - In this paper the electrocatalytic properties of Ti-Ru-Sn ternary oxide (TiRuSnO(2)), PbO(2) and boron-doped diamond (BDD) anodes have been compared for the electrochemical oxidation of a real landfill leachate from an old municipal solid waste landfill (average values of COD 780 mg dm(-3) and NH(4)(+)-N266 mg dm(-3)). The experiments have been performed using an undivided flow cell equipped with a stainless steel cathode, under constant current of 2 A and flow rate of 420 dm(3) h(-1). The performance of the electrodes has been compared measuring the time evolution of aromatic compounds, COD, ammonium, colour removal, current efficiency and energy consumption. The experimental results indicated that after 8 h of electrolyses TiRuSnO(2) anode yields only 35% COD, 52% colour and 65% ammonium removal. Using PbO(2) ammonium and colour were completely removed but a residual COD (i.e. 115 mg dm(-3)) was present. On the contrary BDD enables complete COD, colour and ammonium removal due to the electrogeneration of hydroxyl radicals from water discharge and active chlorine from chloride ions oxidation. BDD also exhibits greater current efficiency along with a significantly lower energy cost than other electrodes. These results indicated that the electrochemical oxidation with BDD anode is an effective process for the treatment of landfill leachate. PMID- 23026165 TI - Anesthesia for special needs--small infants. PMID- 23026166 TI - Patient-controlled analgesia (PCA) following video-assisted thoracoscopic lobectomy: comparison of epidural PCA and intravenous PCA. AB - OBJECTIVES: To compare the efficacy and side effects of epidural patient controlled analgesia (EPCA) with those of intravenous patient-controlled analgesia (IVPCA) in fast-track video-assisted thoracoscopic (VATS) lobectomy. PATIENTS AND METHODS: EPCA or IVPCA was chosen by patients and was started immediately following tracheal extubation in the wake of completion of VATS lobectomy. EPCA analgesia was carried out with the PCA device programmed to deliver a bolus dose of 3 mL of 0.1% bupivacaine combined with 1.2 MUg/mL fentanyl, and continuous epidural infusion at a rate of 4 mL/hour through an epidural catheter placed at the T(6-7) or T(7-8) level. IVPCA was made possible by a patient controlled infusion pump programmed to deliver 0.1% morphine with a loading dose of 3 mg, and the controlled bolus of 1 mg, at a lockout interval of 5 minutes. A rescue dose of 5 mg intravenous morphine was available for all patients in postoperative care unit. Pain management was assessed with visual analog scale at rest (VAS-R) and during motion (VAS-M); side effects including nausea, vomiting, pruritus, dizziness and sleepiness were recorded and analyzed from postoperative Day 1 (POD1) to Day 3 (POD3). RESULTS: This study included 105 patients. Satisfactory pain control was achieved, although 9/70 patients in the EPCA group and 5/35 patients in the IVPCA group needed rescue morphine in the recovery room. The VAS-R was significantly higher on POD1 than on POD2 or POD3 in both groups (p < 0.001). The VAS-R and VAS-M were comparable in both groups on POD1 and POD3 but significant lower VAS-M was seen in the EPCA group on POD2 (p = 0.008). Higher incidence of dizziness was found in the IVPCA group on POD1 (p = 0.044) but the EPCA group had a higher incidence of pruritus on POD2 (p = 0.024) and POD3 (p = 0.03). CONCLUSION: Our results indicated that the necessity of pain control was higher on POD1 for VATS lobectomy. Both EPCA and IVPCA can provide an adequate, continuous and effective means for postoperative pain management and a lower VAS-M was found in EPCA on POD2. PMID- 23026167 TI - Perioperative transfusion-related acute lung injury: a retrospective analysis. AB - OBJECTIVE: Transfusion-related acute lung injury (TRALI) is the leading morbidity and mortality in hemotherapy in the United States. Although it is a serious complication of blood transfusion, it is still underestimated and under-reported because of under-recognition and misdiagnosis. In this report, we present 15 surgical patients who developed pulmonary complications secondary to blood transfusion during the perioperative period. METHODS: A 3-year retrospective analysis of 14,441 patients who received blood transfusion intraoperatively in our Taoyuan center was carried out. 15 patients suspected to be subject to TRALI perioperatively were sorted out for analysis of their clinical characteristics. RESULTS: All of the 15 patients received inhalational general anesthesia, of whom 10 were anesthetized with sevoflurane, four with desflurane, and one with isoflurane. One patient died on the first postoperative day due to multiorgan failure whereas 14 others who were managed with oxygen therapy or mechanical ventilation recovered uneventfully within 72 hours. CONCLUSIONS: TRALI must be recognized as one of the leading causes of mortality related to blood transfusion. Oxygen support is often sufficient in mild TRALI while ventilatory support is required in severe TRALI. The strategy to minimize such a risk using blood products from male donors or from female donors without history of pregnancy or having a negative leukocyte antibody screening can help reduce severe immune mediated TRALI. PMID- 23026168 TI - An open label trial of the effects and safety profile of extended-release tramadol in the management of chronic pain. AB - OBJECTIVES: Tramadol is a synthetic centrally-acting opioid analgesic. The newly developed extended-release formulation of tramadol offers a more stable plasma concentration and could improve patients' compliance. The purpose of this study was to evaluate the efficacy, safety, and adverse events of extended release tramadol in Taiwanese patients with moderate to severe chronic noncancer pain. METHODS: Sixty-six patients with moderate to severe chronic noncancer pain previously treated with conventional tramadol but unsatisfied with its efficacy were enrolled from four medical centers. The patients received the extended release tramadol once daily for a week. RESULTS: The usage of extended-release tramadol was more efficacious as the patients' visual analog scale score dropped significantly (-16 +/- 14.1). In this study, the reported adverse events were similar to those of previous studies. Thirty patients reported adverse events and one patient reported a serious adverse event but was justified unrelated to the study drug. The most common adverse event was dizziness, followed by vomiting, nausea, somnolence, and constipation in sequence. In this study, patients with dizziness were observed to have a lower initial pain score (p = 0.032). Furthermore, the rate of premature termination and dizziness was closely correlated (p = 0.027). CONCLUSION: Patients with chronic pain could obtain significantly better pain relief after the switch to larger doses of extended release tramadol with safety and without severe adverse effects in a short period of time. Less severe adverse effects (no life-threatening event) was the leading cause of premature termination. PMID- 23026169 TI - Ultra-low-dose naloxone enhances the antinociceptive effect of morphine in PTX treated rats: regulation on global histone methylation. AB - OBJECTIVE: Epigenetic reprogramming may have a possible role in neuropathic pain development; the present study examined the global patterns of lysine histone modification. In this serial study we analyzed the levels of histone 3 lysine 4 monomethylation, histone 3 lysine 4 dimethylation, and histone 3 lysine 9 trimethylation in pertussis toxin (PTX)-induced thermal hyperalgesic rat spinal cords. METHODS: Male Wistar rats implanted with an intrathecal catheter received a single intrathecal PTX (1 MUg in 5 MUl saline) injection. Four days later, they were randomly assigned to receive either a single injection of saline, or ultra low-dose naloxone (15 ng in 5 MUl saline), followed by morphine (10 MUg in 5 MUl saline) injection 30 minutes later. RESULTS: The results showed that PTX injection induced thermal hyperalgesia and significant increase of global histone methylation in the spinal cords. Intrathecal morphine alone did not affect the thermal hyperalgesia and global histone methylation. In contrast, intrathecal administration of ultra-low-dose naloxone plus morphine significantly attenuated the PTX-induced thermal hyperalgesia and down-regulated the global histone methylation. CONCLUSION: The results suggest that ultra-low-dose naloxone might be clinical valuable for neuropathic pain management via regulating global histone modification. PMID- 23026170 TI - Levobupivacaine differentially suppresses platelet aggregation by modulating calcium release in a dose-dependent manner. AB - OBJECTIVE: Levobupivacaine, an amide local anesthetic widely used in regional anesthesia, is reported in recent studies that it is a potent inhibitor of platelet functions. However, the concentrations of levobupivacaine were limitedly estimated in these reports. Additionally, the mechanisms by which it affects platelet function and blood coagulation is still not entirely known. The purpose of this study was to further investigate its effects on platelet function and the possible signaling mechanisms under various concentrations of levobupivacaine. METHODS: Blood samples collected from healthy volunteers were separated into whole blood, platelet-rich-plasma and washed platelets. The effect of levobupivacaine on platelet aggregation was studied using platelet function analyzer (PFA-100) and platelet aggregometer. Agonist-induced platelet adenosine triphosphate (ATP) release, cytosolic calcium mobilization, thromboxane B2 (TxB2) secretion and platelet P-selectin translocation under various concentrations of levobupivacaine were investigated. RESULTS: Our results indicated that levobupivacaine possessed negative effect on platelet aggregation. The closure times of (PFA-100) were lengthened and the agonist-induced platelet aggregation was significantly attenuated by levobupivacaine even at a low dose (50 MUgml( 1)). Pretreatment with levobupivacaine produced significant changes in agonist induced platelet P-selectin translocation, ATP release, thromboxane A2 (TxA2) production, and calcium mobilization in a dose-dependent manner. The p38 mitogen activated protein kinases (MAPK), protein kinase C (PKC) delta subtype, cytosolic phospholipase A2 (cPLA2), and protein kinase B (PKB or Akt) were involved in collagen-induced platelet signaling, which would be responsible for antiplatelet effects of levobupivacaine. CONCLUSION: We explored possible targets of levobupivacaine on platelets aggregation signaling mechanisms. Our data revealed that p38 MAPK, PKC delta subtype, cPLA2, and Akt were pathways involved in collagen-induced platelet signaling, which might be responsible for antiplatelet effects of levobupivacaine. Our study did provide direct evidence bolstering the critical mechanisms of levobupivacaine within different contexts. Additionally, levobupivacaine imposed a negative effect on platelet aggregation through multiple signaling pathways. PMID- 23026171 TI - Dental anesthesia for patients with special needs. AB - To offer individualized dental treatment to certain patients who cannot tolerate dental treatment, sedation or general anesthesia is required. The needs could be either medical, mental, or psychological. The most common indications for sedation or general anesthesia are lack of cooperation, multiple morbidities, and pediatric autism. In adults, cognitive impairment and multiple morbidities are most commonly encountered indications. Because of suboptimal home care, incomplete medical history, poor preoperative management, lack of cooperation, and developmental abnormalities, it is a challenge to prepare anesthesia for patients with special needs. The American Society of Anesthesiology (ASA) has proposed guidelines for office-based anesthesia for ambulatory surgery. In patients with ASA physical status IV and V, sedation or general anesthesia for treatment in the dental office is not recommended. The distinction between sedation levels and general anesthesia is not clear. If intravenous general anesthesia without tracheal intubation is chosen for dental procedures, full cooperation between the dentist, dental assistant, and anesthesiologist is needed. Teamwork between the dentist and healthcare provider is key to achieve safe and successful dental treatment under sedation or general anesthesia in the patient with special needs. PMID- 23026172 TI - Anesthesia for awake video-assisted thoracic surgery. AB - Awake video-assisted thoracic surgery (VATS) has been increasingly employed in a variety of procedures involving pleura, lungs, and mediastinum. Adequate anesthesia and analgesia obtained from thoracic epidural anesthetic (TEA) allow VATS to be performed in awake patients. The potential general anesthesia-related adverse effects, such as intubation-related trauma, pneumonia, ventilator associated lung injury, effects of neuromuscular blocking agents, and postoperative nausea and vomiting, can thus be avoided. Moreover, TEA holds the benefits of reducing pulmonary and cardiac morbidities and mortalities after noncardiac surgery. Patients who undergo awake VATS may also benefit from the efficient contraction of the dependent hemidiaphragm and preserved hypoxic pulmonary vasoconstriction during surgically-induced pneumothorax. Preliminary results from early case series have indicated certain benefits, including greater patient satisfaction, less nursing care, less sore throat, earlier resumption of oral intake, lower rate of morbidity, reduced perioperative pain, reduced cost, and shorter hospital stay. However, anesthesia for awake VATS presents a particular challenge to anesthesiologists and requires extra vigilance. Potential hazards include paradoxical respiration and mediastinum shift after surgery induced pneumothorax, which may cause progressive hypoxia, hypercapnia and hypotension. Anesthesiologists should be acquainted with the procedure to be performed, be knowledgeable on the physiological changes, be aware of the potential problems, and have good judgment on suitable timing for conversion of regional anesthesia to intubation general anesthesia in enforced circumstance. PMID- 23026173 TI - Combinations of fentanyl and levobupivacaine for post-thoracotomy pain. AB - The aim of the present study is to evaluate the analgesic activity, patient satisfaction, and side effect profile of different concentrations of levobupivacaine plus fentanyl administered through thoracic epidural patient controlled analgesia in patients undergoing thoracotomy. The study included 60 patients who were randomly divided into three groups. At the end of the surgery, group I (n = 20) received 0.125% levobupivacaine plus 3 mg fentanyl, group II received 0.1% levobupivacaine plus 3 mg fentanyl, and group III received 0.05% levobupivacaine plus 3 mg fentanyl via an epidural catheter placed at the level of T(10-11) or T(11-12). For all groups, the patient-controlled analgesia device was programmed to deliver a loading dose of 14 mL at an infusion rate of 4 mL/h, and a bolus dose of 2 mL/h, with a locked out interval of 15 minutes and 60 mL of a 4-hour limit. The following parameters were evaluated at 5, 10, 15, 20, 30, and 40 minutes and at 1, 2, 4, 8, 16, and 24 hours after admission to the intensive care unit, at which nausea and vomiting scales, Visual Analog Scale I-II, Ramsay sedation scale, Bromage scale, pupil diameter, arterial blood pressure, heart rate, respiratory rate, and SpO(2) were measured and recorded. Any side effect was also documented. As the result of the evaluation, visual Analog Scale I-II scores, patient satisfaction scores, mean arterial blood pressure, and heart rate significantly differed in group I as compared with groups II and III. No side effects were encountered except mild nausea, which was seen in group III and did not require treatment. Motor blockage, pupil size, respiratory rate, and SpO(2) were not monitored in any of the patients in all groups. In conclusion, our study suggested that the use of 0.125% levobupivacaine, together with 3 mg/mL fentanyl, constitutes a good combination, and can be used safely without causing hemodynamic change and motor block. PMID- 23026174 TI - Anesthesia for oncogenic osteomalacia--a rare paraneoplastic syndrome. AB - Two patients with a diagnosis of oncogenic osteomalacia are described. This rare disease, characterized by secretion of fibroblast growth factor-23 by the tumor cells, causes myopathy, extreme debilitation and severe osteopathy because of severe hypophosphatemia. Both patients presented with severe bone pain, pathological fractures and proximal muscle weakness. Multiple diagnostic tools had to be utilized to settle the diagnosis of this rare disease. Although supplemental therapy for hypophosphatemia is usually started preoperatively, surgical excision of the causative tumor is the only definite treatment. Surgery is almost always curative; however, there is a lack of discourse in the literature regarding the anesthetic implications for the disease. The complete pathophysiology of the disease, clinical picture, its diagnostic intricacies as well as the salient points in its anesthetic management are discussed in this report. PMID- 23026175 TI - Aphonia induced by conversion disorder during a Cesarean section. AB - Aphonia induced by conversion disorder during surgery is a rare event. We report a woman 28 years of age who was undergoing a Cesarean section under epidural anesthesia. The patient sustained aphonia without detected neurologic deficits. Emergency consultations of a psychiatrist and neurologist were carried out in the operating room postoperatively. After a thorough medical and neurologic work-up, the consultative psychiatrist and the neurologist unanimously made the diagnosis of conversion disorder. Thirty-six hours after the operation, the patient's voice started to return. We venture on sharing the findings of this case with our fellow anesthesiologists in order to highlight discussion and illuminate the differential diagnosis. We have reviewed the literature and excluded an organic lesion as the culprit of the event. PMID- 23026176 TI - Successful tracheal intubation with Airtaq optical laryngoscope for severe ankylosing spondylitis. PMID- 23026177 TI - Understanding the germicidal effects of silver nanoparticles. PMID- 23026178 TI - False positive results for amphetamine in urine of a patient with diabetes mellitus. PMID- 23026179 TI - Omalizumab: an update on efficacy and safety in moderate-to-severe allergic asthma. AB - Omalizumab is an anti-immunoglobulin E (anti-IgE) monoclonal antibody approved in the United States since 2003 for treatment of moderate-to-severe allergic asthma in adults and adolescents (aged >=12 years) inadequately controlled with inhaled corticosteroids (ICSs). Current treatment guidelines recommend considering the addition of omalizumab if allergic asthma symptoms are not adequately controlled with high-dose ICS + long-acting beta-agonist (LABA) therapy. This study was designed to review the clinical efficacy and safety of omalizumab as established in previously published pivotal clinical trials used to support registration in the United States, i.e., primarily including patients receiving only concomitant ICS therapy, as well as results from the recently completed additional study, which specifically enrolled patients who were poorly controlled despite high dose ICS + LABA therapy +/- additional controllers (including oral corticosteroids [OCSs]). Summary of published omalizumab pivotal trials and associated extension trials, plus key results from the additional study, were used. Pediatric data (i.e., <12 years) were outside the scope of this article. Treatment with omalizumab significantly reduced asthma exacerbations versus placebo when added to ICS therapy during both steroid-stable and steroid reduction phases of two pivotal trials. In the additional study, omalizumab significantly reduced asthma exacerbation rates versus placebo when added to high-dose ICS + LABA therapy with or without other controller medications. Results from the additional clinical study further support current asthma guideline recommendations to consider omalizumab in steps 5 or 6 for persistent allergic asthma patients whose symptoms are not adequately controlled despite high-dose ICS + LABA therapy +/- additional controllers (including OCS). PMID- 23026180 TI - Efficacy and safety of once-daily treatment with beclomethasone dipropionate nasal aerosol in subjects with seasonal allergic rhinitis. AB - An aerosol formulation may be preferred by some allergic rhinitis (AR) patients, to avoid the "wet feeling" and nasal runoff associated with aqueous nasal corticosteroid sprays. Beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol is a recently developed, nonaqueous, nonchlorofluorocarbon formulation of BDP for the treatment of AR. This study was designed to evaluate the efficacy, safety, and quality-of-life benefits of BDP nasal aerosol in subjects with seasonal AR (SAR). Eligible subjects (>=12 years of age) enrolled in this 2-week study were randomized to either BDP nasal aerosol at 320 MUg/day (n = 169) or placebo (n = 171). Efficacy assessments included reflective and instantaneous total nasal symptom scores (rTNSS and iTNSS, respectively), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, reflective and instantaneous total ocular symptom scores (rTOSS and iTOSS, respectively), and physician-assessed total nasal symptom score (PNSS). Safety and tolerability were also assessed. Subjects receiving BDP nasal aerosol showed a significantly greater improvement from baseline in average A.M. and P.M. rTNSS versus placebo (treatment difference, -0.91; 95% confidence interval, -1.3, -0.5; p < 0.001) over 2 weeks of treatment. Greater improvements in rTNSS with BDP nasal aerosol compared with placebo were evident by day 2 and were maintained throughout the treatment period. Similarly, significant improvements were seen with BDP nasal aerosol in iTNSS (p < 0.001) and RQLQ score (p = 0.005) compared with placebo. Treatment with BDP nasal aerosol also resulted in greater improvements in rTOSS (p = 0.002), iTOSS (p = 0.003), and PNSS (p < 0.001) relative to placebo. BDP nasal aerosol was well tolerated and the overall safety profile was similar to placebo. Results from this clinical study indicated that BDP nasal aerosol provided significant AR symptom relief and was well tolerated in patients with SAR with an overall safety profile similar to placebo. Clinicaltrials.gov identifier: NCT01024608. PMID- 23026181 TI - Comparison of nasal steroid with antihistamine in prophylactic treatment against pollinosis using an environmental challenge chamber. AB - Environmental challenge chambers (ECC) have been used to expose people to pollen allergens within a stable atmosphere and to examine the efficacy of treatment. Although pollinosis is one of the typical IgE-mediated type I allergic diseases, allergic inflammation is thought to contribute to the fundamental pathogenesis and prophylactic treatment may reduce exacerbations of pollinosis. The purpose of this study was to compare the efficacy of prophylactic treatment with nasal steroid (mometasone furoate nasal spray) or an antihistamine (fexofenadine) in the control of cedar pollinosis using the ECC. In a randomized, double-blind two way crossover study, 48 patients received nasal steroid or antihistamine for 7 consecutive days (days 1-7). On day 8, patients were exposed to cedar pollen (8000 grains/m(3)) in the ECC for 3 hours. Nasal symptoms induced by pollen exposure were assessed. Total nasal symptom scores (TNSSs) during the exposure in the ECC were not significantly different between the antihistamine and the nasal steroid groups. Nasal symptoms induced by pollen exposure using the ECC persisted for up to 3 days. TNSSs after pollen exposure on days 8-11 were significantly lower in the nasal steroid group compared with the antihistamine group. Prophylactic treatment with nasal steroid is more effective than antihistamine against pollinosis, particularly in the late phase. Clinical trial registration JAPIC CTI 101182 (www.clinicaltrials.jp/user/ctiMain_e.jsp). PMID- 23026182 TI - Safety of ragweed sublingual allergy immunotherapy tablets in adults with allergic rhinoconjunctivitis. AB - A sublingually administered allergy immunotherapy tablet (AIT) is under development to treat ragweed (Ambrosia artemisiifolia)-induced allergic rhinoconjunctivitis (ARC). This study investigates the optimal tolerable dose of once daily ragweed pollen AIT.Subjects 18-50 years old with ragweed-induced ARC were enrolled at two U.S. centers in a double-blind, placebo-controlled,dose escalation study outside ragweed season. Groups (12 subjects each) were to be randomized 3:1 to 28 days of active treatment (groups assigned in sequence to 3, 6, 12, 24, 50, or 100 units of Ambrosia artemislifolia major allergen 1 [Amb a 1 U],without dose buildup at any level) or matching placebo. Recruitment to 50 Amb a 1-U was discontinued because of adverse events (AEs) after four AIT subjects were enrolled; 100 Amb a 1-U was not initiated. Fifty-three subjects were randomized (AIT,n = 40; placebo, n = 13); four discontinued, all because of AEs (AIT, n = 3; placebo, n = 1). Treatment-related AEs (TRAEs) were more frequent with AIT (73%) than placebo (31%), increasing with dose level. AIT TRAEs were mostly mild (94%) or moderate(5%). No serious TRAEs or anaphylactic shock occurred. The most common TRAEs with AIT were localized pruritus, nasal irritation, and throat irritation. Median onset for common AIT application site reactions was 24 <= hours after first treatment (median duration, 15-50 minutes). AIT increased immunoglobulin (Ig) significantly more than placebo (ragweed specific IgE [6, 12, and 24 Amb a 1-U]; IgG4 [all doses]; p < 0.05). Three subjects in dose groups >= 24 Amb a 1-U experienced symptoms suggestive of systemic reaction. Of tested doses, ragweed AIT 24 =10% drop of forced expiratory volume in 1 second after exercise. Patients were defined as having exercise-induced bronchoconstriction (EIB) if at least one of the two tests was positive. We analyzed the impact of season and of patient reported asthma season on ECT sensitivity. We performed 21 ECTs in the summer and 77 in other seasons. Summer tests were positive in 14.3% of patients versus 33.8% in other seasons (p = 0.11). In patients with confirmed EIB, the sensitivity (95% CI) of a summer test was 0.25 (0.007-0.57), compared with 0.76 (0.58-0.89) in other seasons. Tests performed out of personal asthma season were positive in 10.0% of tests compared with 37.1% of tests during personal asthma season (p = 0.007). In patients with confirmed EIB, the sensitivity (95% CI) of a test performed out of asthma season was 0.27 (0.07-0.61), compared with 0.74 (0.55 0.87) during season. The sensitivity of ECT performed in the summer or outside of the personal asthma season is about one-third of ECT performed not in the summer or during personal asthma season. We suggest performing ECTs during personal asthma season and not in the summer if there is no asthma season known. PMID- 23026184 TI - Provocation tests with the offending nonsteroidal anti-inflammatory drugs in patients with urticaria/angioedema reactions. AB - The provocation test (PT) with the suspected drug represents the gold standard in the diagnosis of non-IgE hypersensitivity reactions to nonsteroidal anti inflammatory drugs (NSAIDs). Nevertheless, there is no consensus regarding the clinical management of suspected NSAID-sensitive patients. This study assessed if a PT with the suspected drug is a reliable and safe proceeding to confirm NSAID hypersensitivity in patients with a clinical history of urticaria/angioedema (Urt/AE). It also analyzed different patient characteristics (such as gender, age, atopy, dermographism, time interval between the last drug reaction, and number of previous NSAID reactions) in relation to PT positivity. One hundred fifty-nine patients with Urt/AE apparently related to assumption of one or more NSAIDs underwent PT with the suspected drugs. Moreover, to distinguish single/multiple NSAID reactivity in patients who did not tolerate the offending NSAID, another strong cyclooxygenase-1 inhibitor PT was performed. PT was negative in 142/159 patients (89.31%), ruling out a diagnosis of NSAIDs hypersensitivity; 17/159 patients (10.69%) experienced a reaction of Urt/AE during the PT: 8 patients were diagnosed as single reactors to NSAIDs and 4 as multiple reactors to NSAIDs. Those with a history of multiple NSAID reactions and male patients were both more likely to have a positive PT. Our results suggest that in all patients with history of NSAID cutaneous reactions, the NSAID hypersensitivity should be confirmed by an oral PT and that the diagnostic proceeding can safely start with the offending NSAID. PMID- 23026185 TI - C1-inhibitor therapy for hereditary angioedema attacks: prospective patient assessments of health-related quality of life. AB - C1-inhibitor (INH) concentrate, which is recommended as first-line treatment for acute hereditary angioedema (HAE) attacks in many countries, was recently approved in the United States. We sought to solicit patients' feedback about their health-related quality of life (HRQoL) while being treated with C1-INH concentrate for acute HAE attacks under real-world conditions, as well as the personal impact of the availability of C1-INH on lifestyle and mental health domains. Subjects enrolled in an open-label study of C1-INH at 20 U/kg for acute HAE attacks were invited to participate in a prospectively designed survey to solicit "real-time" patient responses that were collected via an interactive voice response service or online with a personal computer. Eighteen subjects submitted 60 quarterly HRQoL and treatment impact survey responses over 29 months. Seventeen of 18 patients responding reported mean short form 12 HRQoL scores that were within a normal range. More than one-half indicated that C1-INH availability made them feel somewhat or much better, and >80% reported having a better outlook on the future and feeling more secure about the danger of life threatening attacks. These data confirm a high level of HRQoL and a positive impact in lifestyle and emotional domains among patients who were treated for acute attacks of HAE with C1-INH concentrate. PMID- 23026187 TI - Recurrent septic shock in a 34-year-old woman. AB - A 34-year-old woman presented to the Emergency Room (ER) with an acute presentation of septic shock that required fluid and pressor support in the Intensive Care Unit. History revealed this was her third episode of such a presentation with asymptomatic periods in between. She responded well to medical interventions but reported persistent joint pain. Immunologic workup revealed her diagnosis. PMID- 23026186 TI - Is it just lactose intolerance? AB - Acquired delayed-onset hypolactasia is a common autosomal recessive condition. Cow's milk allergies, conversely, are less common conditions that may manifest with equivalent symptoms and are able to simulate and/or aggravate lactose intolerance. This study was designed to evaluate the contribution of IgE mediated cow's milk sensitization to the symptomatology of adult patients with lactose-free diet refractory lactose intolerance. Forty-six adult patients with lactose intolerance and persistent symptoms despite a lactose-free diet underwent skin-prick test to investigate cow's milk, goat's milk, and soy protein-specific IgE. SDS-PAGE immunoblotting was used to investigate the presence of cow's milk protein-specific IgE. The percentage of patients who had skin reactions to whole cow's milk, alpha-lactalbumin, beta-lactoglobulin, caseins, goat's milk, and soy was 69.5, 36.9, 56.5, 56.5%, 54.3, and 50%, respectively. The percentage of patients with immunoblot-detected IgE specific for alpha-lactalbumin, beta lactoglobulin, caseins, and bovine serum albumin was 21.7, 63, 67.3, and 2.1%, respectively. IgE-mediated sensitization to cow's milk is a frequent comorbidity in subjects with lactose-free diet refractory lactose intolerance and is worth consideration in patients with this condition. PMID- 23026188 TI - A 71-year-old man with anaphylaxis after eating grits. PMID- 23026189 TI - Labs and slabs: television crime drama and the quest for forensic realism. AB - This essay examines how crime dramas produced during, and since, the 1990s became marked by the quest for 'forensic realism'. In particular, the essay traces a landmark shift in the development of forensic realism in the form of the ground breaking British police drama Prime Suspect in 1991. It is argued that this television series not only represents a turning point in television history, but that it also constitutes a key text in the broader cultural turn towards forensic fascination. Prime Suspect vividly revealed and displayed corpses, crime scenes and post-mortem photos in an unprecedented fashion for television. This essay shows how in the process it established new standards and expectations regarding the aesthetics and thematic content of the perceived 'realism' of the crime genre. Through an analysis of the reception and impact of Prime Suspect the essay also demonstrates how crime drama's increasing fascination with forensic realism has driven debate over just what kinds of stories and images constitute acceptable or appropriate subject matter for popular entertainment, and for the medium of television itself. PMID- 23026190 TI - Modulation of respiratory sinus arrhythmia in rats with central pattern generator hardware. AB - We report on the modulation of respiratory sinus arrhythmia in rats with central pattern generator (CPG) hardware made of silicon neurons. The neurons are made to compete through mutually inhibitory synapses to provide timed electrical oscillations that stimulate the peripheral end of vagus nerve at specific points of the respiratory cycle: the inspiratory phase (phi(1)), the early expiratory phase (phi(2)) and the late expiratory phase (phi(3)). In this way the CPG hardware mimics the neuron populations in the brainstem which through connections with cardiac vagal motoneurones control respiratory sinus arrhythmia (RSA). Here, we time the output of the CPG hardware from the phrenic nerve activity recorded from rats while monitoring heart rate changes evoked by vagal nerve stimulation (derived from ECG) controlled by the CPG. This neuroelectric stimulation has the effect of reducing the heart rate and increasing the arterial pressure. The artificially induced RSA strongly depends on the timing of pulses within the breathing cycle. It is strongest when the vagus nerve is stimulated during the inspiratory phase (phi(1)) or the early expiratory phase (phi(2)) in which case the heart rate slows by 50% of the normal rate. Heart rate modulation is less when the same exact stimulus is applied during the late expiratory phase (phi(3)). These trials show that neurostimulation by CPG hardware can augment respiratory sinus arrhythmia. The CPG hardware technology opens a new line of therapeutic possibilities for prosthetic devices that restore RSA in patients where respiratory-cardiac coupling has been lost. PMID- 23026191 TI - An MEG compatible system for measuring skin conductance responses. AB - We present the design of a low-cost system for recording galvanic skin conductance responses (SCRs) from humans in a magnetically shielded room (MSR) simultaneously to magnetoencephalography (MEG). Such a system was so far not available to the MEG community. Its availability is of utmost importance for neuroscience, since it will allow the concurrent assessment of the autonomic and central nervous system activity. The overall system design optimizes high signal to noise ratio (SNR) of SCRs and achieves minimal distortion of the MEG signal. Its development was based on a fiber-optic transformer, with voltage to optical transduction inside the MSR and demodulation outside the MSR. The system was calibrated and tested inside the MEG environment by using a 151-channel CTF whole head system (VSM MedTech Ltd.). MEG measurements were recorded simultaneously to SCRs from five healthy participants to test whether the developed system does not generate artifacts in the MEG data. Two measurements were performed for each participant; one without the system in the MSR, and one with the system in the MSR, connected to the participant and in operation. The data were analyzed using the time and frequency domains in separate statistical analysis. No significant differences were observed between the two sessions for any statistic index. Our results show that the system allows high quality simultaneous recordings of SCRs and MEG signals in the MSR, and can therefore be used as routine addendum to neuroscience experiments. PMID- 23026192 TI - Phenotype, differentiation, and function differ in rat and mouse neocortical astrocytes cultured under the same conditions. AB - The study of slowly progressing brain diseases in which glial cells play a pathogenic role requires astrocytes that have been cultured for several weeks. We characterized neocortical astrocytes, grown for up to 42 days in vitro (DIV), from newborn rats and mice by indirect immunofluorescence technique, Western blot, and real-time RT-PCR analyses. We obtained highly enriched rat and mouse astrocyte cultures, where most cells were positively stained for the astrocyte markers GFAP, vimentin, and S100beta, whereas neuronal and oligodendrocyte markers were undetectable. The protein and mRNA levels of GFAP, vimentin, and nestin were higher in rat than in mouse astrocytes. From 28 to 42 DIV, the levels of vimentin and nestin, but not of GFAP, decreased in both species, with an increase in the vimentin-GFAP ratio of 1.7 for rat, and of 0.9 for mouse astrocytes suggesting that the rat cultures were more differentiated than the mouse cultures, although both remained partially immature. The protoplasmic appearance of the cells, the negative A2B5 immunoreactivity, and the expression of the glutamate transporters GLAST and GLT-1 indicate that the rat and mouse cultures contained mainly type I astrocytes. The protein levels of GLAST and GLT 1 decreased from 28 to 42 DIV in the mouse, but not in the rat astrocytes, suggesting that the rat cultures are suitable for functional studies. Thus, under the same culture conditions, astrocyte cultures from rats and mice differ in phenotype, differentiation, and functionality. This finding should be taken into account when long-lasting glial reaction patterns are being studied. PMID- 23026194 TI - Usefulness of epithelial cell adhesion molecule expression in the algorithmic approach to Lynch syndrome identification. AB - Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer syndrome, is caused by germ-line mutations in the mismatch repair system genes. Recently, a new mechanism involving the epithelial cell adhesion molecule (EPCAM)/TACSTD1 gene has been shown to be responsible in cases with abnormal MSH2 expression. Of interest, 3' exons deletions of the EPCAM gene, which is located upstream of MSH2 in chromosome 2, are associated with MSH2 promoter hypermethylation. EPCAM protein, expressed in epithelial tissues, is encoded by the EPCAM/TACSTD1 gene. Our study's aim was to explore EPCAM expression in colorectal carcinomas of MSH2-associated LS cases to evaluate the usefulness of EPCAM protein expression in the algorithm approach to LS population screening. We included a total of 19 MSH2-negative colorectal carcinomas from 14 different patients in whom we were able to perform a complete germ-line analysis. Nine patients showed a deleterious germ-line mutation that involved the MSH2 gene in 3 instances and the EPCAM gene exon 9 in 6 instances. All patients harboring the EPCAM mutation belonged to the same family. Of the 19 colorectal carcinomas, EPCAM expression loss was seen in only 5 tumors, all of them from patients showing a germ-line EPCAM deletion. Of interest, 6 tumors from 3 different patients carrying the same germ-line EPCAM deletion showed normal EPCAM expression. In conclusion, owing to the high specificity of EPCAM protein expression to identify LS patients carrying an EPCAM deletion, we recommend adding EPCAM immunohistochemistry to the LS diagnostic algorithm in MSH2-negative colorectal carcinoma. PMID- 23026195 TI - Nuclear Stat5a/b predicts early recurrence and prostate cancer-specific death in patients treated by radical prostatectomy. AB - There is an urgent need for reliable markers to identify patients whose prostate cancer (PCa) will recur after initial therapy and progress to lethal disease. Gleason score (GS) is considered the most accurate predictive marker for disease specific mortality after primary treatment of localized PCa. Most PCas cluster into groups of GS 6 and 7 with considerable variation in the disease recurrence and disease-specific death. In preclinical PCa models, Stat5a/b promotes PCa growth and progression. Stat5a/b is critical for PCa cell viability in vitro and for tumor growth in vivo and promotes metastatic dissemination of cancer in nude mice. Here, we analyzed the predictive value of high nuclear Stat5a/b protein levels in 2 cohorts of PCas: Material I (n = 562) PCas treated by radical prostatectomy (RP), and Material II (n = 106) PCas treated by deferred palliative therapy. In intermediate GS PCas treated by radical prostatectomy, high levels of nuclear Stat5a/b predicted both early recurrence (univariable analysis; P < .0001, multivariable analysis; HR = 1.82, P = .017) and early PCa-specific death (univariable analysis; P = .028). In addition, high nuclear Stat5a/b predicted early disease recurrence in both univariable (P < .0001) and multivariable (HR = 1.61; P = .012) analysis in the entire cohort of patients treated by RP regardless of the GS. Patients treated by deferred palliative therapy, elevated nuclear Stat5a/b expression was associated with early PCa-specific death by univariable Cox regression analysis (HR = 1.59; 95% CI = [1.04, 2.44]; P = .034). If confirmed in future prospective studies, nuclear Stat5a/b may become a useful independent predictive marker of recurrence of lethal PCa after RP for intermediate GS PCas. PMID- 23026196 TI - Pulmonary-type adenocarcinoma and signet ring mucinous adenocarcinoma arising in an ovarian dermoid cyst: report of a unique case. AB - Dermoid cysts are common benign ovarian germ cell neoplasms. Occasionally, one of the mature elements undergoes malignant transformation resulting in the formation of a somatic malignancy; most commonly this is squamous carcinoma. We report a unique case where 2 separate malignancies arose within a dermoid cyst, one a signet ring mucinous adenocarcinoma and the other a pulmonary-type adenocarcinoma. There have been only occasional earlier case reports of a possible pulmonary-type adenocarcinoma arising in a dermoid cyst. In the case we report, the pulmonary-type adenocarcinoma was closely associated with a bronchial structure and exhibited diffuse positive immunohistochemical staining with TTF1, PE10, and napsin A. Molecular studies revealed no evidence of epidermal growth factor receptor mutation, a molecular alteration which may be found in primary pulmonary adenocarcinoma. PMID- 23026198 TI - Four-protein signature accurately predicts lymph node metastasis and survival in oral squamous cell carcinoma. AB - The presence of lymph node (LN) metastasis significantly affects the survival of patients with oral squamous cell carcinoma (OSCC). Successful detection and removal of positive LNs are crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the LNs, where up to a third of clinically diagnosed metastasis negative (N0) patients actually have metastasis-positive LNs in the neck. We developed a molecular signature in the primary tumor that could predict LN metastasis in OSCC. A total of 211 cores from 55 individuals were included in the study. Eleven proteins were evaluated using immunohistochemical analysis in a tissue microarray. Of the 11 biomarkers evaluated using receiver operating curve analysis, epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2/neu), laminin, gamma 2 (LAMC2), and ras homolog family member C (RHOC) were found to be significantly associated with the presence of LN metastasis. Unsupervised hierarchical clustering-demonstrated expression patterns of these 4 proteins could be used to differentiate specimens that have positive LN metastasis from those that are negative for LN metastasis. Collectively, EGFR, HER-2/neu, LAMC2, and RHOC have a specificity of 87.5% and a sensitivity of 70%, with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated that the LN signature could independently predict disease specific survival (P = .036). The 4-protein LN signature validated in an independent set of samples strongly suggests that it could reliably distinguish patients with LN metastasis from those who were metastasis-free and therefore could be a prognostic tool for the management of patients with OSCC. PMID- 23026197 TI - Small cell-like change in prostatic intraepithelial neoplasia, intraductal carcinoma, and invasive prostatic carcinoma: a study of 7 cases. AB - Small cell carcinoma of the prostate is associated with poor prognosis and different treatment from conventional acinar adenocarcinoma. Given the important clinicopathologic implications of a diagnosis of small cell carcinoma, we report 7 cases showing unusual, extensive small cell-like change in intraductal carcinoma and invasive carcinoma. Prostatic biopsies from 3 patients and radical prostatectomy specimens from 4 patients showed variably extensive small cell-like high-grade prostatic intraepithelial neoplasia and intraductal carcinoma. Five cases were associated with conventional acinar adenocarcinoma (2 cases with Gleason score 4 + 3 = 7; 3 cases with Gleason 3 + 4 = 7). No small cell carcinoma was seen. Small and large ducts with small cell-like change showed solid and cribriform proliferations of atypical cells with abrupt transition between centrally located populations of small cells and more typical large dysplastic cells at the duct periphery. Rosette-like formations were noted within some involved ducts. Small cell-like change was characterized by crowded cells with uniformly bland vesicular nuclei and minimal cytoplasm and no significant mitotic or apoptotic activity. In 3 cases, similar small cell-like morphology was noted focally in invasive carcinoma. The small cell-like areas were negative for synaptophysin and chromogranin, focally positive for TTF-1, and weakly positive for racemase. Ki-67 labeled less than 5% with predominant labeling of the larger atypical cells and minimal reactivity in the small cell-like population. In summary, small cell-like change in prostatic intraepithelial neoplasia, intraductal carcinoma, and invasive carcinoma is not associated with small cell carcinoma; shows no immunohistochemical evidence of neuroendocrine differentiation; and likely is not an adverse prognostic feature. PMID- 23026199 TI - Ultraviolet Leaks from CFLs. PMID- 23026200 TI - Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice. AB - Lack of tau expression has been reported to protect against excitotoxicity and to prevent memory deficits in mice expressing mutant amyloid precursor protein (APP) identified in familial Alzheimer disease. In APP mice, mutant presenilin 1 (PS1) enhances generation of Abeta42 and inhibits cell survival pathways. It is unknown whether the deficient phenotype induced by concomitant expression of mutant PS1 is rescued by absence of tau. In this study, we have analyzed the effect of tau deletion in mice expressing mutant APP and PS1. Although APP/PS1/tau(+/+) mice had a reduced survival, developed spatial memory deficits at 6 months and motor impairments at 12 months, these deficits were rescued in APP/PS1/tau(-/-) mice. Neuronal loss and synaptic loss in APP/PS1/tau(+/+) mice were rescued in the APP/PS1/tau(-/-) mice. The amyloid plaque burden was decreased by roughly 50% in the cortex and the spinal cord of the APP/PS1/tau(-/-) mice. The levels of soluble and insoluble Abeta40 and Abeta42, and the Abeta42/Abeta40 ratio were reduced in APP/PS1/tau(-/-) mice. Levels of phosphorylated APP, of beta-C terminal fragments (CTFs), and of beta-secretase 1 (BACE1) were also reduced, suggesting that beta-secretase cleavage of APP was reduced in APP/PS1/tau(-/-) mice. Our results indicate that tau deletion had a protective effect against amyloid induced toxicity even in the presence of mutant PS1 and reduced the production of Abeta. PMID- 23026202 TI - At the cross-roads: an on-road examination of driving errors at intersections. AB - A significant proportion of road trauma occurs at intersections. Understanding the nature of driving errors at intersections therefore has the potential to lead to significant injury reductions. To further understand how the complexity of modern intersections shapes behaviour of these errors are compared to errors made mid-block, and the role of wider systems failures in intersection error causation is investigated in an on-road study. Twenty-five participants drove a pre determined urban route incorporating 25 intersections. Two in-vehicle observers recorded the errors made while a range of other data was collected, including driver verbal protocols, video, driver eye glance behaviour and vehicle data (e.g., speed, braking and lane position). Participants also completed a post trial cognitive task analysis interview. Participants were found to make 39 specific error types, with speeding violations the most common. Participants made significantly more errors at intersections compared to mid-block, with misjudgement, action and perceptual/observation errors more commonly observed at intersections. Traffic signal configuration was found to play a key role in intersection error causation, with drivers making more errors at partially signalised compared to fully signalised intersections. PMID- 23026203 TI - Long term bicycle related head injury trends for New South Wales, Australia following mandatory helmet legislation. AB - Since the 1991 enactment of mandatory helmet legislation (MHL) for cyclists in New South Wales (NSW), Australia, there has been extensive debate as to its effect on head injury rates at a population level. Many previous studies have focused on the impact of MHL around the time of enactment, while little has been done to examine the ongoing effects. We aimed to extend prior work by investigating long-term trends in cyclist head and arm injuries over the period 1991-2010. The counts of cyclists hospitalised with head or arm injuries were jointly modelled with log-linear regression. The simultaneous modelling of related injury mechanisms avoids the need for actual exposure data and accounts for the effects of changes in the cycling environment, cycling behaviour and general safety improvements. Models were run separately with population counts, bicycle imports, the average weekday counts of cyclists in Sydney CBD and cycling estimates from survey data as proxy exposures. Overall, arm injuries were higher than head injuries throughout the study period, consistent with previous post-MHL observations. The trends in the two injury groups also significantly diverged, such that the gap between rates increased with time. The results suggest that the initial observed benefit of MHL has been maintained over the ensuing decades. There is a notable additional safety benefit after 2006 that is associated with an increase in cycling infrastructure spending. This implies that the effect of MHL is ongoing and progress in cycling safety in NSW has and will continue to benefit from focusing on broader issues such as increasing cycling infrastructure. PMID- 23026201 TI - Role of WNT/beta-catenin signaling in rejuvenating myogenic differentiation of aged mesenchymal stem cells from cardiac patients. AB - Autologous stem cell therapy has not been as effective as forecasted from preclinical studies. Patient age was reported as an important contributing factor. The goal of this study was to uncover age-dependent mechanisms of stem cell dysfunction and to investigate possible means to restore the cellular function. Bone marrow mesenchymal stem cells (MSCs) were isolated from cardiovascular patients. Cell proliferation and number of colonies were inversely correlated with patient age. Myogenic differentiation of MSCs in culture was induced with 5-azacytidine. Differentiation correlated with age, with less differentiation in MSCs from aged patients. We performed real-time PCR to identify genes in the WNT/beta-catenin signaling network and found that transcript levels of CTNNB1, LEF1, FZD8, WNT3A, and SFRP4 were negatively correlated with age, whereas FOSL1, LRP6, and FZD6 were positively correlated with age. Protein evaluation showed that beta-catenin nuclear translocation correlated with age and was lower in aged MSCs. Aged MSCs treated with lithium chloride-to increase the bioavailability of beta-catenin-recovered their capacity for myogenic differentiation through myocyte enhancer factor 2C but not with the knockdown of beta-catenin using small-interfering RNA. This study may be the first to relate reduced nuclear beta-catenin bioavailability in MSCs from aged patients. Most important, this abnormality was potentially recoverable, providing a target for improving the function of bone marrow stem cells and their clinical utility in aged patients. PMID- 23026204 TI - Detection of biofilm-grown Aspergillus fumigatus by means of atomic force spectroscopy: ultrastructural effects of alginate lyase. AB - Aspergillus fumigatus has become a leading cause of fungal morbidity and mortality, especially in immunocompromised patients. This fungus is able to grow as a multicellular community and produce a hydrophobic extracellular matrix (ECM), mainly composed of galactomannan and alpha-1,3 glucans, to protect itself from host defenses and antimicrobial drugs. This matrix envelops the fungus hyphae, binding them into a contiguous sheath on the colony surface, forming a biofilm and increasing the fungal resistance to adverse environmental factors. Adherence to host cells and resistance to physical removal play a key role in fungal colonization and invasion of the host and in a wide range of infections. Here we show that, by using atomic force spectroscopy, it is possible to exploit the peculiar hydrophobicity of the biofilm components (i.e., cell walls, ECM) to detect the biofilm spread, its growth, and lysis on rough surfaces. By means of this approach, we demonstrate that alginate lyase, an enzyme known to reduce negatively charged alginate levels in microbial biofilms, reduces the biofilm adhesion forces suggesting a loss of ECM from the biofilm, which could be used to enhance pharmacological treatments. PMID- 23026205 TI - DNA damage after continuous irradiation: findings in mice compared with human epidemiologic data. PMID- 23026206 TI - The leptin receptor Gln223Arg polymorphism (rs1137101) mediates the postprandial lipaemic response, but only in males. AB - OBJECTIVE: An exaggerated postprandial triacylglycerol (TAG) response is an important determinant of cardiovascular disease risk. With increased recognition of the role of leptin in systemic macronutrient metabolism, we used a candidate gene approach to examine the impact of the common leptin receptor (LEPR) Gln223Arg polymorphism (rs1137101) on postprandial lipaemia. METHODS AND RESULTS: Healthy adults (n = 251) underwent a sequential meal postprandial investigation, in which blood samples were taken at regular intervals after a test breakfast (t = 0) and lunch (t = 330 min). Fasting total- and low-density lipoprotein cholesterol were 9% lower in the ArgArg than GlnArg group (P < 0.04), whereas fasting TAG was 27% lower in the ArgArg than GlnGln group (P < 0.02). The magnitude of the postprandial TAG response was also significantly lower in the ArgArg compared with the GlnArg and GlnGln genotypes, with a 26% lower area under the curve (AUC) and incremental AUC in the ArgArg individuals (P <= 0.023). Genotype*gender interactions were evident for fasting and postprandial TAG responses (P < 0.05), with the genotype effect only evident in males. Regression analysis indicated that the LEPR genotype and genotype*gender interactions were independent predictors of the TAG AUC, accounting for 6.3% of the variance. Our main findings were replicated in the independent LIPGENE-Cordoba postprandial cohort of metabolic syndrome subjects (n = 75), with a 52% lower TAG AUC in the ArgArg than GlnGln male subjects (P = 0.018). CONCLUSION: We report for the first time that the common LEPR Gln223Arg genotype is an important predictor of postprandial TAG in males. The mechanistic basis of these associations remains to be determined. PMID- 23026207 TI - First draft genome sequence of the Japanese eel, Anguilla japonica. AB - The Japanese eel is a much appreciated research object and very important for Asian aquaculture; however, its genomic resources are still limited. We have used a streamlined bioinformatics pipeline for the de novo assembly of the genome sequence of the Japanese eel from raw Illumina sequence reads. The total assembled genome has a size of 1.15 Gbp, which is divided over 323,776 scaffolds with an N50 of 52,849 bp, a minimum scaffold size of 200 bp and a maximum scaffold size of 1.14 Mbp. Direct comparison of a representative set of scaffolds revealed that all the Hox genes and their intergenic distances are almost perfectly conserved between the European and the Japanese eel. The first draft genome sequence of an organism strongly catalyzes research progress in multiple fields. Therefore, the Japanese eel genome sequence will provide a rich resource of data for all scientists working on this important fish species. PMID- 23026208 TI - Identification of one novel mutation in the EVC2 gene in a Chinese family with Ellis-van Creveld syndrome. AB - Ellis-van Creveld syndrome (EvC) is a rare autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. It is caused by biallelic mutations in the EVC or EVC2 gene. Here, we identified a novel nonsense mutation p.W828X (c.2484G>A) in exon 14 and a recurrent nonsense mutation p. R399X (c.1195C>T) in exon 10 of EVC2 gene in a Chinese boy with EvC. Identification of a novel genotype in EvC will provide clues to the phenotype-genotype relations and may assist not only in the clinical diagnosis of EvC but also in the interpretation of genetic information used for prenatal diagnosis and genetic counseling. PMID- 23026209 TI - The glutathione-S-transferase gene polymorphisms (GSTM1 and GSTT1) and idiopathic male infertility risk: a meta-analysis. AB - Published data on the association between male infertility and the glutathione-S transferase (GST) gene polymorphism are inclusive. To drive a more precise estimation, we performed a meta-analysis based on 1897 cases and 1785 controls from 15 published case-control studies. PubMed and CBMdisc literature research were conducted to identify all eligible studies investigating such a relationship. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. In the overall analysis, the frequency of glutathione-S-transferase Mu-1 (GSTM1) null genotype was significantly associated with susceptibility to idiopathic male infertility. In further stratified analysis by sperm concentration of the case group, no significantly increased risk of azoospermia was found in either GSTM1 null or glutathione-S-transferase Theta-1 (GSTT1) null genotype. Compared with a significant relationship between GSTM1 null genotype and oligoasthenoteratozoospermia (OAT), GSTT1 null genotype was not associated with the OAT risk. Additionally, a subgroup analysis on ethnicity showed no notable association between the polymorphism and the risk of idiopathic male infertility in any of GSTM1 null and GSTT1 null genotype, neither in Asian nor in European populations. In conclusion, these results support that the GSTM1 null genotype mainly contributes to idiopathic male infertility susceptibility, particularly to OAT. PMID- 23026210 TI - Characterization of gene rearrangements resulted from genomic structural aberrations in human esophageal squamous cell carcinoma KYSE150 cells. AB - Chromosomal rearrangements and involved genes have been reported to play important roles in the development and progression of human malignancies. But the gene rearrangements in esophageal squamous cell carcinoma (ESCC) remain to be identified. In the present study, array-based comparative genomic hybridization (array-CGH) was performed on the ESCC cell line KYSE150. Eight disrupted genes were detected according to the obviously distinct unbalanced breakpoints. The splitting of these genes was validated by dual-color fluorescence in-situ hybridization (FISH). By using rapid amplification of cDNA ends (RACE), genome walking and sequencing analysis, we further identified gene disruptions and rearrangements. A fusion transcript DTL-1q42.2 was derived from an intrachromosomal rearrangement of chromosome 1. Highly amplified segments of DTL and PTPRD were self-rearranged. The sequences on either side of the junctions possess micro-homology with each other. FISH results indicated that the split DTL and PTPRD were also involved in comprising parts of the derivative chromosomes resulted from t(1q;9p;12p) and t(9;1;9). Further, we found that regions harboring DTL (1q32.3) and PTPRD (9p23) were also splitting in ESCC tumors. The data supplement significant information on the existing genetic background of KYSE150, which may be used as a model for studying these gene rearrangements. PMID- 23026211 TI - New yeast/E. coli/Drosophila triple shuttle vectors for efficient generation of Drosophila P element transformation constructs. AB - We have generated a set of novel triple shuttle vectors that facilitate the construction of Drosophila-P-element transformations vectors. These YED-vectors allow the insertion of any kind of sequence at any chosen position due to the presence of a yeast casette which ensures replication and allows for homologous recombination in Saccharomyces cerevisiae. As a proof of principle we generated several reporter constructs and tested them in transgenic flies for expression and correct subcellular localization. YED-vectors can be used for many purposes including promoter analysis or the expression of tagged or truncated proteins. Thus, time-consuming conventional restriction site based multi-step cloning procedures can be circumvented by using the new YED-vectors. The new set of triple shuttle vectors will be highly beneficial for the rapid construction of complex Drosophila transformation plasmids. PMID- 23026212 TI - Two single nucleotide polymorphisms in the human nescient helix-loop-helix 2 (NHLH2) gene reduce mRNA stability and DNA binding. AB - Nescient helix-loop-helix-2 (NHLH2) is a basic helix-loop-helix transcription factor, which has been implicated, using mouse knockouts, in adult body weight regulation and fertility. A scan of the known single nucleotide polymorphisms (SNPs) in the NHLH2 gene revealed one in the 3' untranslated region (3'UTR), which lies within an AUUUA RNA stability motif. A second SNP is nonsynonymous within the coding region of NHLH2, and was found in a genome-wide association study for obesity. Both of these SNPs were examined for their effect on NLHL2 by creating mouse mimics and examining mRNA stability, and protein function in mouse hypothalamic cell lines. The 3'UTR SNP causes increased instability and, when the SNP-containing Nhlh2 3'UTR is attached to luciferase mRNA, reduced protein levels in cells. The nonsynonymous SNP at position 83 in the protein changes an alanine residue, conserved in NHLH2 orthologs through the Drosophila sp. to a proline residue. This change affects migration of the protein on an SDS-PAGE gel, and appears to alter secondary structure of the protein, as predicted using in silico methods. These results provide functional information on two rare human SNPs in the NHLH2 gene. One of these has been linked to human obese phenotypes, while the other is present in a relatively high proportion of individuals. Given their effects on NHLH2 protein levels, both SNPs deserve further analysis in whether they are causative and/or additive for human body weight and fertility phenotypes. PMID- 23026213 TI - The co-existence of two growth hormone receptors and their differential expression profiles between female and male tongue sole (Cynoglossus semilaevis). AB - Growth hormone receptor (Ghr) is a single-transmembrane pass protein which is important in initiating the ability of growth hormone (Gh) to regulate development and somatic growth in vertebrates. In this study, molecular cloning, expression analysis of two different ghr genes (ghr1 and ghr2) in the tongue sole (Cynoglossus semilaevis) was conducted. As a result, the ghr1 and ghr2 cDNA sequences are 2364 bp and 3125 bp, each of which encodes a transmembrane protein of 633 and 561 amino acids (aa), respectively. Besides, the ghr1 gene includes nine exons and eight introns. The sex-specific tissue expression was analyzed by using 14 tissues from females, normal males and extra-large male adults. Both the ghr1 and ghr2 were predominantly expressed in the liver, and the ghr1 expression level in normal males was 1.6 and 1.4 times as much as those in females and extra large males, while the ghr2 mRNA expression level in normal males was 1.1 and 1.2 times as much as those in females and extra-large males, respectively. Ontogenetic expression analysis at early life stages indicated that the ghr1 and ghr2 mRNAs were detected at all of the 35 sampling points (from oosphere to 410days-old). Furthermore, the sex differences in ghr mRNA expressions were also examined by using a full-sib family of C. semilaevis. Significantly higher levels of ghr1 mRNA were observed in males than in females at most stages of the sampling period (P<0.01). The ghr2 mRNA expression at most stages exhibited a significant sexual difference at each sampling point (P<0.01) without any variation trend related with the sexes during the whole sampling period. PMID- 23026214 TI - Molecular pathogenesis of fibrochondrogenesis: is it really simple COL11A1 deficiency? PMID- 23026215 TI - An RNA electrophoretic mobility shift and mutational analysis of rnp-4f 5'-UTR intron splicing regulatory proteins in Drosophila reveals a novel new role for a dADAR protein isoform. AB - Alternative splicing greatly enhances the diversity of proteins encoded by eukaryotic genomes, and is also important in gene expression control. In contrast to the great depth of knowledge as to molecular mechanisms in the splicing pathway itself, relatively little is known about the regulatory events behind this process. The 5'-UTR and 3'-UTR in pre-mRNAs play a variety of roles in controlling eukaryotic gene expression, including translational modulation, and nearly 4000 of the roughly 14,000 protein coding genes in Drosophila contain introns of unknown functional significance in their 5'-UTR. Here we report the results of an RNA electrophoretic mobility shift analysis of Drosophila rnp-4f 5' UTR intron 0 splicing regulatory proteins. The pre-mRNA potential regulatory element consists of an evolutionarily-conserved 177-nt stem-loop arising from pairing of intron 0 with part of adjacent exon 2. Incubation of in vitro transcribed probe with embryo protein extract is shown to result in two shifted RNA-protein bands, and protein extract from a dADAR null mutant fly line results in only one shifted band. A mutated stem-loop in which the conserved exon 2 primary sequence is changed but secondary structure maintained by introducing compensatory base changes results in diminished band shifts. To test the hypothesis that dADAR plays a role in intron splicing regulation in vivo, levels of unspliced rnp-4f mRNA in dADAR mutant were compared to wild-type via real-time qRT-PCR. The results show that during embryogenesis unspliced rnp-4f mRNA levels fall by up to 85% in the mutant, in support of the hypothesis. Taken together, these results demonstrate a novel role for dADAR protein in rnp-4f 5'-UTR alternative intron splicing regulation which is consistent with a previously proposed model. PMID- 23026216 TI - A new deletion in 5'-end of dystrophin gene removing M and P promoters and dystrophin muscle enhancers. AB - We describe a 3-year-old boy who, at age of 8 months, during investigations for upper respiratory tract infection was found to have an incidental grossly elevated CK of 20,000 UI/l. Investigations showed only mild calf hypertrophy and absent Gower's sign, normal cognitive function. Electromyography (EMG) showed myopathic features. Electrocardiography and echocardiography were normal. His muscle biopsy revealed myopathic features indicating Duchenne-type dystrophy. Immunohistochemistry for dystrophin N-terminal, C-terminal and mid-rod antibodies analysis showed the complete absence of dystrophin in the muscle fibers. Genetic studies showed a 141.1 Kb deletion removing muscle promoter, muscle exon 1, Purkinje promoter, Purkinje exon 1, dystrophin muscle enhancers similar to one previously reported in a DMD patient who exhibited some residual expression of dystrophin. The difference in dystrophin expression between these two patients might be due to the extension of deletions. The precise delimitation of the macrodeletion here described provides a better understanding of functional organization of the 5' end of the DMD gene. PMID- 23026217 TI - Identification and expression analysis of early cold-induced genes from cold hardy Citrus relative Poncirus trifoliata (L.) Raf. AB - Citrus is one of the most economically important fruit crops growing in subtropical and tropical regions. Most commercially important Citrus varieties are susceptible to cold; therefore, low and freezing temperatures are the main limiting factors for citrus production in subtropical areas. Since Poncirus trifoliata (L.) Raf. is a cold-hardy, interfertile Citrus relative, it serves as a genetic resource for improving cold tolerance in cold sensitive commercial Citrus species. While gene induced in response to long-term cold acclimation was previously identified in Poncirus, early response of Poncirus to cold has not been explored in detail. To identify early cold-responsive genes, a subtractive cDNA library was constructed using 4-h cold-treated and untreated control Poncirus seedlings in this study. A total of 210 randomly picked clones from the subtracted library with cold-induced genes were sequenced. The sequences obtained from the majority of these clones shared homology with previously identified cold induced and/or environmental stress-regulated genes in other plants. Reverse northern blot analysis of the expression of these cDNAs with cold-treated and untreated control probes revealed that expression of 64 cDNAs was increased two to 11 fold in response to 4-h cold treatment. While the majority of these genes were related with cell rescue, defense, cell death and aging, transcription, metabolism, protein fate, energy, cellular communication and signal transduction, transport facilitation and development, some of them did not show homology with genes with known functions. Individual expression analysis of nine selected genes by semi-quantitative RT-PCR using mRNA from cold-treated and untreated control plants confirmed that the expression of selected cDNAs was all induced in response to cold. The results demonstrated that although a few genes were commonly induced in response to both short and long-term cold acclimation in Poncirus, majority of early cold-responsive genes were different from previously identified late cold-responsive genes in Poncirus. PMID- 23026218 TI - Enteral calcium infusion used successfully as treatment for a patient with hereditary vitamin D resistant rickets (HVDRR) without alopecia: a novel mutation. AB - BACKGROUND: We report a novel mutation in a case of hereditary vitamin D resistant rickets (HVDRR) without alopecia and successful management of this condition with the intravenous formulation of calcium chloride delivered via gastric tube. CLINICAL CASE: A 22 month old male (length -3.4 SDS; weight -2.1 SDS) presented with failure to thrive, short stature, severe hypocalcemia and gross motor delay. He did not have alopecia. Initial blood tests and history were thought possibly to suggest vitamin D deficiency rickets: calcium 5.1mg/dL, (8.8 10.8); phosphorus 4.1mg/dL, (4.5-5.5); alkaline phosphatase 1481 U/L (80-220); intact PTH 537.1 pg/mL (10-71). Subsequently, vitamin D studies returned that were consistent with HVDRR: 25-hydroxyvitamin D 34 ng/mL (20-100); 1,25 dihydroxyvitamin D 507 pg/mL. This diagnosis was confirmed by DNA sequencing. His subsequent clinical course was complicated by the fact that IV calcium was not a viable option for this patient, and his calcium levels could not be well controlled on oral calcium citrate or calcium glubionate therapy. Eventually, we were able to maintain calcium levels above 8 mg/dL using the intravenous preparation of calcium chloride administered via gastric tube. GENETIC STUDIES: A unique homozygous T to C base substitution was found in exon 6 in the vitamin D receptor (VDR) gene. This mutation causes leucine to be converted to proline at position 227 in helix 3 in the VDR ligand binding domain (LBD). The mutation rendered the VDR non-functional, leading to HVDRR, with absence of alopecia. CONCLUSION: HVDRR should be considered in a patient with profound hypocalcemia which is refractory to conventional therapy of vitamin D deficiency rickets even without evidence of alopecia. We report the first case of HVDRR with a novel mutation in the LBD that was successfully treated with enteral treatment using a calcium chloride infusion. PMID- 23026219 TI - Intergenic region between TATA-box binding protein and proteasome subunit C3 genes of Medaka function as the bidirectional promoter in vitro and in vivo. AB - In the genome of eukaryotic organisms, each protein-coding gene has the unique promoter in the 5'-flanking region, and the direction of the promoter is usually controlled unidirectional. In this study, we revealed that the intergenic region between TATA-box binding protein (tbp) and proteasome subunit C3 (psmc3) genes in Medaka functions as bidirectional promoter in vitro and in vivo. The tbp and psmc3 genes were allocated as a head-to-head configuration with a 719bp intergenic region. A comparative analysis of gene arrangement surrounding loci of tbp in vertebrates also illustrated that it was unique in Acanthopterygii lineage. The transcription activities were about 1.2 times for tbp direction and 0.7 times for psmc3 direction against that of SV40 promoter in Medaka fibroblasts, respectively. A dual fluorescent reporter assay directly showed that the bidirectional promoter could express two divergent genes concurrently without disruption of RNA polymerase II elongation. In addition, an analysis of sequential deletion of this promoter suggested that the ETS binding site was necessary for maximum expression of downstream gene, and only the ETS binding site was shared from fish to mammals. In mammals, high correlation with CpG islands was observed in such bidirectional promoters, no association was found in the tbp/psmc3 bidirectional promoter in Medaka. These results suggest that molecular machineries of fish bidirectional promoter may be somehow different from those of mammals but the cis-acting element for binding ETS transcription factors is essential for divergent gene expression. PMID- 23026220 TI - Establishment and characterization of an epithelial cell line from thymus of Catla catla (Hamilton, 1822). AB - A cell line, CTE, derived from catla (Catla catla) thymus has been established by explant method and subcultured for more than 70 passages over a period of 400 days. The cell line has been maintained in L-15 (Leibovitz) medium supplemented with 10% fetal bovine serum. CTE cell line consists of homogeneous population of epithelial-like cells and grows optimally at 28 degrees C. Karyotype analysis revealed that the modal chromosome number of CTE cells was 50. Partial amplification, sequencing and alignment of fragments of two mitochondrial genes 16S rRNA and COI confirmed that CTE cell line originated from catla. Significant green fluorescent signals were observed when the cell line was transfected with phrGFP II-N mammalian expression vector, indicating its potential utility for transgenic and genetic manipulation studies. The CTE cells showed strong positivity for cytokeratin, indicating that cell line was epithelial in nature. The flow cytometric analysis of cell line revealed a higher number of cells in S phase at 48 h, suggesting a high growth rate. The extracellular products of Vibrio cholerae MTCC 3904 were toxic to the CTE cells. This cell line was not susceptible to fish betanodavirus, the causative agent of viral nervous necrosis in a large variety of marine fish. PMID- 23026221 TI - The antibody response to Epstein-Barr virions is altered in multiple sclerosis. AB - Infection with Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), and patients with MS have an increased antibody response to some EBV antigens. The major antigens of EBV are only partly defined. Our hypothesis is that the antibody response to EBV is altered in MS. With ELISA, we found that antibodies to EB virions were increased in both serum and CSF of MS patients. Western blots demonstrated that there are multiple different antigens recognized. The antibody response was generally higher in MS to all EBV antigens, with particularly significant increases for certain antigens. We conclude that the antibody response to EBV in MS is generally increased with altered specificity. PMID- 23026222 TI - Glatiramer Acetate administration does not reduce damage after cerebral ischemia in mice. AB - Inflammation plays a key role in ischemic stroke pathophysiology: microglial/macrophage cells and type-1 helper cells (Th1) seem deleterious, while type-2 helper cells (Th2) and regulatory T cells (Treg) seem protective. CD4 Th0 differentiation is modulated by microglial cytokine secretion. Glatiramer Acetate (GA) is an immunomodulatory drug that has been approved for the treatment of human multiple sclerosis by means of a number of mechanisms: reduced microglial activation and pro-inflammatory cytokine production, Th0 differentiation shifting from Th2 to Th2 and Treg with anti-inflammatory cytokine production and increased neurogenesis. We induced permanent (pMCAo) or transient middle cerebral artery occlusion (tMCAo) and GA (2 mg) or vehicle was injected subcutaneously immediately after cerebral ischemia. Mice were sacrificed at D3 to measure neurological deficit, infarct volume, microglial cell density and qPCR of TNFalpha and IL-1beta (pro-inflammatory microglial cytokines), IFNgamma (Th2 cytokine), IL-4 (Th2 cytokine), TGFbeta and IL-10 (Treg cytokines), and at D7 to evaluate neurological deficit, infarct volume and neurogenesis assessment. We showed that in GA-treated pMCAo mice, infarct volume, microglial cell density and cytokine secretion were not significantly modified at D3, while neurogenesis was enhanced at D7 without significant infarct volume reduction. In GA-treated tMCAo mice, microglial pro-inflammatory cytokines IL-1beta and TNFalpha were significantly decreased without modification of microglial/macrophage cell density, cytokine secretion, neurological deficit or infarct volume at D3, or modification of neurological deficit, neurogenesis or infarct volume at D7. In conclusion, Glatiramer Acetate administered after cerebral ischemia does not reduce infarct volume or improve neurological deficit in mice despite a significant increase in neurogenesis in pMCAo and a microglial pro-inflammatory cytokine reduction in tMCAo. PMID- 23026223 TI - A new automated NaCl based robust method for routine production of gallium-68 labeled peptides. AB - A new NaCl based method for preparation of gallium-68 labeled radiopharmaceuticals has been adapted for use with an automated gallium-68 generator system. The method was evaluated based on 56 preparations of [(68)Ga]DOTATOC and compared to a similar acetone-based approach. Advantages of the new NaCl approach include reduced preparation time (<15 min) and removal of organic solvents. The method produces high peptide-bound % (>97%), and specific activity (>40 MBq nmole(-1) [(68)Ga]DOTATOC) and is well-suited for clinical production of radiopharmaceuticals. PMID- 23026224 TI - A method for determining the free (unbound) concentration of ten beta-lactam antibiotics in human plasma using high performance liquid chromatography with ultraviolet detection. AB - With the clinical imperative to further research in the area of optimising antibiotic dosing in the intensive care setting, a simple high performance liquid chromatography method was developed and validated for routinely determining the free (unbound) concentration of ten beta-lactam antibiotics in 200 MUL of human plasma. Antibiotics determined include three cephalosporins (ceftriaxone, cephazolin and cephalotin); two carbapenems (meropenem and ertapenem); and five penicillins (ampicillin, piperacillin, benzylpenicillin, flucloxacillin and dicloxacillin). There was a single common sample preparation method involving ultracentrifugation and stabilisation. Chromatography was performed on a Waters XBridge C18 column with, depending on analytes, one of four acetonitrile phosphate buffered mobile phases. Peaks of interest were detected via ultraviolet absorbance at 210, 260 and 304 nm. The method has been validated and used in a pathology laboratory for therapeutic drug monitoring in critically ill patients. The significant variability in the level of protein binding that is common with antibiotics traditionally considered to have high protein binding (e.g. ceftriaxone, cephazolin, ertapenem, flucloxacillin and dicloxacillin) suggests that this assay should be preferred for measuring the pharmacologically active concentration of beta-lactam antibiotics in a therapeutic drug monitoring programme. PMID- 23026225 TI - Metabolite discovery of helicidum in rat urine with XCMS based on the data of ultra performance liquid chromatography coupled to time-of-flight mass spectrometry. AB - The present study demonstrates the use of XCMS (various forms (X) of chromatography coupled to mass spectrometry), an open-source software tool primarily used in bioinformatics, on the data of ultra-performance liquid chromatography connected online with a mass spectrometer (UPLC/MS) for the discovery of the metabolites of helicidum in urine after oral single dosage to rats. Helicidum (formaldehydephenyl-O-beta-D-pyranosyl alloside) is the major active component of the fruits of Helicid hilagirica Beed. In China, it is often used in the clinic to treat neurasthenic syndromes, vascular headache, and trigeminal neuralgia with high efficacy and low side effect and toxicity. The urine samples of five rats were collected during 0-4, 4-8, 8-12, 12-16, 16-20, 20 24, 24-32, 32-40, and 40-48 h, respectively, after oral administration of helicidum at a dosage of 25.0 mg/kg. A UPLC coupled to time-of-flight MS (UPLC/TOF MS) was used to analyze the samples. Concerning XCMS, the ".raw" format files were preliminarily converted to the open mzXML format using massWolf-4.3.1 (http://sourceforge.net/projects/sashimi/files/massWolf%20(MassLynx%20converter)/ . For converting lots of files a time, we wrote a tool rawTomzXML which also uses massWolf-4.3.1. The data were processed using XCMS version l.26.0 (http://www.bioconductor.org/packages/2.8/bioc/html/xcms.html) running under R version 2.13 (http://http://www.r-project.org/) which provided the running platform for XCMS. The "centWave" method from XCMS was used for chromatographic peak detection. Based on the m/z data of the metabolites obtained by XCMS, MS was used to identify the molecular formula. Nine metabolites were finally found and identified. For six of them, the bio-transformation mechanisms of the parent compound was elucidated: glucuronide conjugation (C(19)H(24)O(14)), reduction (C(13)H(18)O(7)), oxidation (C(13)H(16)O(8)), methylation (C(14)H(18)O(7)), and the mixed transformation of reduction, methylation, and acetylation (C(16)H(22)O(8)). For the other three metabolites, C(11)H(19)N(3)O(9), C(11)H(21)N(3)O(9), and C(14)H(15)NO(7), the bio-transformation mechanisms remain unknown and need further investigation. Calculated as mass of helicidum, the cumulative urine excretion rate of the metabolites was 8.39%. The amount of oxidized helicidum was more than 50% among the metabolites while the parent compound helicidum was 13.28% and the reduced helicidum 11.72%, indicating that oxidation was the major bio-transformation that occurred in vivo. PMID- 23026226 TI - A rapid validated UHPLC-PDA method for anthocyanins quantification from Euterpe oleracea fruits. AB - The aim of this work is to develop the first validated UHPLC-PDA method for major anthocyanins quantification in Euterpe oleracea fruits after fast extraction procedures and samples preparation. The separation was performed on HSS C18 column (1.8 MUm) using a gradient elution with acetonitrile and 5% formic acid in a total run time of only 17 min. Total error and accuracy profiles were used as criteria for the validation process. Calibration in the matrix was found to be more accurate than calibration without matrix. Trueness (<6.76% relative bias), repeatability (<4.6% RSD), intermediate precision (<5.3% RSD), selectivity, response function and linearity for major anthocyanins, cyanidin-3-glucoside and cyanidin-3-rutinoside, were evaluated. The concentration range validated was 1-48 MUg/mL for both compounds. In addition two cyanidin-di-O-glycosides were detected for the fist time in this fruit. We also showed that a first extraction of the fruits with ethyl acetate removes the lipophilic compounds and allows an easier extraction by methanol and quantification of anthocyanins in this extract. PMID- 23026227 TI - Determination of naftopidil enantiomers in rat plasma using chiral solid phases and pre-column derivatization high-performance liquid chromatography. AB - Two bioanalytical HPLC methods (chiral solid phases (CSPs) HPLC and pre-column derivatization HPLC) were developed and validated for the determination of naftopidil enantiomers in rat plasma. Analytes were extracted from biomaterials by liquid-liquid extraction. The pre-column derivatization HPLC method employed (+)-diacetyl-L-tartaric anhydride (DATAN) as the pre-column derivatization reagent, and subsequent separation of diastereomers was conducted on an Agilent Hypersil ODS column with a mixture of methanol-acetonitrile-phosphate buffer (pH 4.1; 20 mM) (40:30:30, v/v/v) flowing at 1 mL/min as the mobile phase. The CSPs HPLC method utilized a Chiralpak IA column with a mobile phase of methanol acetonitrile-acetate buffer (pH 5.3; 5 mM) (50:25:25, v/v/v) flowing at 0.5 mL/min. In both methods, the analytes were monitored using a fluorescence detector with an excitation wavelength of 290 nm and an emission wavelength of 340 nm. Both methods were consistent (RSD<15% by the derivatization method and<10% by the CSPs method) and linear (r>9950). Compared to the pre-column derivatization method, the CSPs method had lower quantification limits (10.6/9.6 ng/mL of (+)-/(-)-naftopidil by derivatization method and 1.1/1.8 ng/mL of (+)-/( )-naftopidil by CSPs method), and was simpler to carry out. The validated CSPs method was successfully applied in a pharmacokinetic study of naftopidil enantiomers in rats, which showed that pharmacokinetic parameters of (+)- and (-) NAF after intravenous administration of (+/-)-NAF were similar. PMID- 23026228 TI - Liquid chromatography-tandem mass spectrometry method for determination of five antidepressants and four atypical antipsychotics and their main metabolites in human serum. AB - The rapid and simple ultra performance liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination parent drugs: sertraline, fluoxetine, citalopram, paroxetine, venlafaxine, clozapine, olanzapine, quetiapine, risperidone, and their active and nonactive metabolites N-desmethylsertraline, norfluoxetine, desmethylcitalopram, didemethylcitalopram, N-desmethylvenlafaxine, O-desmethylvenlafaxine, N desmethylclozapine, N-desmethylolanzapine, 2-hydroxyolanzapine and 9 hydroxyrisperidone in human serum. Precipitation of serum proteins was performed with a precipitation reagent consisting of 0.05% solution of ZnSO(4).7H(2)O in acetonitrile/methanol (40:60, v/v). Alprenolol was used as an internal standard. Chromatographic separation was carried out on a BEH C18 column using gradient elution mobile phase A (2 mmol/L ammonium acetate, 0.1% formic acid in 5% acetonitrile, v/v/v) and B (2 mmol/L ammonium acetate, 0.1% formic acid in 95% acetonitrile, v/v/v). Electrospray in positive mode was used for ionization. Detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring. Analysis time was 5 min. Drugs were separated into three groups with low, medium and high levels. Correlation coefficients of calibration curves were in the range 0.995-1.000. Coefficients of variation were 4.2-9.5% for intra-assay and 3.0-11.9% for inter-assay. Recoveries were 87.1-110% for intra-assay and 88.1-108.2% for inter-assay. The method was fully validated and can be successfully applied for routine analyses. PMID- 23026229 TI - Multiple small hyperintense lesions in the subcortical white matter on cranial MR images in two Turkish brothers with cold-induced sweating syndrome caused by a novel missense mutation in the CRLF1 gene. AB - Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder characterized by excess sweating induced by cold exposure, camptodactyly and kyphoscoliosis. CISS is genetically heterogeneous. Deficiency of the CRLF1 or the CLCF1 gene function results in one of two clinically indistuinguishable disorders called CISS1 and CISS2, respectively. We present two Turkish brothers (22 and 13 years old) who had excess sweating induced by cold exposure, severe dorsal scoliosis, camptodactyly, reduced pain sensitivity and marfanoid habitus. The patients were homozygous and their parents heterozygous for a novel missense mutation c.413C>T (p.Pro138Leu) in CRLF1 gene. The cranial magnetic resonance imaging (MRI) of two patients also showed multiple small hyperintense lesions in the subcortical white matter. Similar MRI finding has also been reported in a Japanese woman with CISS1 and marfanoid habitus. The lesions found in the present cases showed no characteristic features. However, multiple small hyperintense lesions in subcortical white matter on T2 weighted and fluid attenuation inversion recovery (FLAIR) images may support the clinical diagnosis of CISS. PMID- 23026231 TI - Is standard multivariate analysis sufficient in clinical and epidemiological studies? AB - Clinical tests and epidemiological studies often produce large amounts of data, being multivariate in nature. The respective analysis is, in most cases, of importance comparable to the clinical and sampling tasks. Simple, easily interpretable techniques from chemometrics provide most of the ingredients to carry out this analysis. We have selected available data from different sources pertaining to cancer diagnosis and incidence: (1) cytological diagnosis of breast cancer, (2) classification of breast tissues through parameters obtained from impedance spectra and (3) distribution of new cancer cases in the United States. Hierarchical cluster analysis (HCA) is needed especially in cases where there is no a priori identification of classes, suggesting a structure of the data based on clusters. These clusters or the classes, are then further detailed and rationalized by principal component analysis (PCA). Partial least squares (PLS) and linear discriminant analysis (LDA) provide further insight into the systems. An additional step for understanding the data set is the removal of less characteristic data (NR) using a density-based approach, so as to make it more clearly defined. Results clearly reveal that breast cytology diagnosis relies on variables conveying mostly the same type of information, being thus interchangeable in nature. In the study on tissue characterization by electrical measurements, the distribution of the different types of tissues can be easily constructed. Finally, the distribution of new cancer cases possesses clear, easily unravelled, geographical patterns. PMID- 23026230 TI - Linear enhancement after radio-frequency ablation for hepatocellular carcinoma: is it a sign of recurrence? AB - This prospective study was performed in 179 hepatocellular carcinoma (HCC) lesions treated by radio-frequency ablation (RFA) to explore the clinical outcome of "linear enhancement" on contrast-enhanced sonogram. Thirty-three lesions (18.4%) showed linear enhancement, a linear-shaped positive enhancement in the RFA-treated area. Seventeen of them were followed up with no treatment (remaining 16; dropout in eight, additional RFA in six and ineffective treatment in two) and three lesions (3/17, 17.6%) showed local tumor progression corresponding to linear enhancement at 7, 14, 19 months after RFA. Although there was no significant difference in local recurrence rate between the lesions with (3/17) and without linear enhancement (10/35), local tumor progression inside the ablation zone occurred only in the lesions with linear enhancement. In conclusion, linear enhancement inside the RFA-treated area should be followed up within 7 months because it has a risk of local tumor progression. Histology of linear enhancement and its influence on distant recurrence remain to be solved. PMID- 23026232 TI - Terminology representation guidelines for biomedical ontologies in the semantic web notations. AB - Terminologies and ontologies are increasingly prevalent in healthcare and biomedicine. However they suffer from inconsistent renderings, distribution formats, and syntax that make applications through common terminologies services challenging. To address the problem, one could posit a shared representation syntax, associated schema, and tags. We identified a set of commonly-used elements in biomedical ontologies and terminologies based on our experience with the Common Terminology Services 2 (CTS2) Specification as well as the Lexical Grid (LexGrid) project. We propose guidelines for precisely such a shared terminology model, and recommend tags assembled from SKOS, OWL, Dublin Core, RDF Schema, and DCMI meta-terms. We divide these guidelines into lexical information (e.g. synonyms, and definitions) and semantic information (e.g. hierarchies). The latter we distinguish for use by informal terminologies vs. formal ontologies. We then evaluate the guidelines with a spectrum of widely used terminologies and ontologies to examine how the lexical guidelines are implemented, and whether our proposed guidelines would enhance interoperability. PMID- 23026234 TI - Detection of antinuclear antibodies by automated indirect immunofluorescence analysis. AB - BACKGROUND: Testing for antinuclear antibodies is useful for the diagnosis of systemic rheumatic diseases. Automated systems for image acquisition and interpretation of indirect immunofluorescence-based tests are increasingly used. The diagnostic performance of such automated approach in untreated patients has not been reported. METHODS: Antinuclear antibodies were measured by automated indirect immunofluorescence using Zenit G. Sight on HEp2 and HEp2000 substrate in 268 consecutive samples submitted to the laboratory for antinuclear antibody testing, and in 231 patients with a systemic rheumatic disease at the time of diagnosis, 143 blood donors, 134 patients with chronic fatigue syndrome, and 133 diseased controls. RESULTS: Image acquisition by G-Sight was of high quality. The accuracy of pattern assignment was limited. There was a significant correlation between automated estimation of fluorescence intensity (probability index of positivity) and end-point titer. Probability index interval specific likelihood ratios for systemic rheumatic disease increased with increasing level of positivity probability. With the HEp-2 substrate, the likelihood ratio for systemic lupus erythematosus was 0.06, 0.4, 6.8, 12.1, and 43.9 for a probability measure of positivity of <=10, 11-<=30, 31-<=50, 51-<=85, and >85, respectively. CONCLUSION: Quantitative data generated by automated image acquisition facilitates standardized interpretation. PMID- 23026233 TI - A graph-based recovery and decomposition of Swanson's hypothesis using semantic predications. AB - OBJECTIVES: This paper presents a methodology for recovering and decomposing Swanson's Raynaud Syndrome-Fish Oil hypothesis semi-automatically. The methodology leverages the semantics of assertions extracted from biomedical literature (called semantic predications) along with structured background knowledge and graph-based algorithms to semi-automatically capture the informative associations originally discovered manually by Swanson. Demonstrating that Swanson's manually intensive techniques can be undertaken semi automatically, paves the way for fully automatic semantics-based hypothesis generation from scientific literature. METHODS: Semantic predications obtained from biomedical literature allow the construction of labeled directed graphs which contain various associations among concepts from the literature. By aggregating such associations into informative subgraphs, some of the relevant details originally articulated by Swanson have been uncovered. However, by leveraging background knowledge to bridge important knowledge gaps in the literature, a methodology for semi-automatically capturing the detailed associations originally explicated in natural language by Swanson, has been developed. RESULTS: Our methodology not only recovered the three associations commonly recognized as Swanson's hypothesis, but also decomposed them into an additional 16 detailed associations, formulated as chains of semantic predications. Altogether, 14 out of the 19 associations that can be attributed to Swanson were retrieved using our approach. To the best of our knowledge, such an in-depth recovery and decomposition of Swanson's hypothesis has never been attempted. CONCLUSION: In this work therefore, we presented a methodology to semi automatically recover and decompose Swanson's RS-DFO hypothesis using semantic representations and graph algorithms. Our methodology provides new insights into potential prerequisites for semantics-driven Literature-Based Discovery (LBD). Based on our observations, three critical aspects of LBD include: (1) the need for more expressive representations beyond Swanson's ABC model; (2) an ability to accurately extract semantic information from text; and (3) the semantic integration of scientific literature and structured background knowledge. PMID- 23026235 TI - The effect of aryl hydrocarbon receptor ligands on the expression of polymerase (DNA directed) kappa (Polkappa), polymerase RNA II (DNA directed) polypeptide A (PolR2a), CYP1B1 and CYP1A1 genes in rat liver. AB - The aryl hydrocarbon receptor (AhR) mediates a variety of biological responses to ubiquitous environmental pollutants. AhR is ligand activated transcription factor with high affinities for aromatic planar compounds such as beta-naphthoflavone (BNF), 3-methylcholanthrene (3-MC), benzo[a]pyrene (BaP) or dioxin (TCDD). After binding appropriate ligand, AhR trigger induction of expression of some phase I and phase II drug metabolizing genes together with numerous other genes. One of such gene appear to be polymerase (DNA directed) kappa (Polkappa). Polkappa gene encodes newly identified low fidelity DNA polymerase. The enzyme bypasses benzo[a]pyrene-N2-dG lesions in a mostly error free manner by incorporating predominantly dC opposite the bulky lesions. It was demonstrated that AhR activation increases expression of the mouse Polkappa gene and probably human POLK gene. In this study we examined the effect of i.p. administration of different AhR ligands on the expression of Polkappa, RNA polymerase II polypeptide A (PolR2a) and cytochrome P450 1B1 (CYP1B1), the genes controlled by AhR in Sprague-Dawley rat liver. Quantitative real-time RT-PCR analysis revealed significant induction in the mRNA expression levels of Polkappa and PolR2a following BNF treatment. Time courses of mRNA expression after treatment with BNF were similar in both genes, with maximal increases at 8h after treatment. The maximal induction of CYP1B1 and CYP1A1 expression was observed after 24 and 8h after BNF injection, respectively. TCDD treatment caused the significant increase in the mRNA level of CYP1B1 at 72h after administration of the ligand but no effect on Polkappa and PolR2a mRNA expression was observed. These results confirm connection between AhR and Polkappa, and strongly suggest that AhR up-regulates the mRNA transcription of PolR2a as well. However physiological importance of AhR dependent regulation of PolR2a expression must be further elucidated. PMID- 23026236 TI - Synaptic degradation of cardiac autonomic nerves in streptozotocin-induced diabetic rats. AB - BACKGROUND: Cardiac autonomic neuropathy (CAN) is a common complication in type I diabetes mellitus (DM). Nevertheless, the relationship between functional and structural disturbances of cardiac autonomic nerves remains unclear. METHODS AND RESULTS: To clarify this relationship, we studied heart rate variability (HRV) and ultrastructural changes of cardiac autonomic nerves in streptozotocin (STZ) induced DM in rats. STZ was injected (65mg/kg intravenous) into the tail vein of male Wistar rats to destroy beta cells in the pancreatic islets. After STZ injection, fasting blood sugar (FBS) increased from baseline values of 75+/ 3mg/dl up to 328+/-12mg/dl within 1week and it reached up to 353+/-24mg/dl within 17weeks. HR in these rats was decreased within 20days and low HR was maintained for the observation period. TP and HF power started decreasing 20days after STZ injection, and this decrease progressed throughout the observation period. The L/H power ratio was decreased 80days after STZ. Electron microscopic findings indicated a depletion of neurotransmitter vesicles and degradation of parasympathetic nerve endings but not of sympathetic ones in the SA node region of the heart in the early stages of DM. In the late stages of DM, the same region showed degradation of both sympathetic and parasympathetic nerve endings. CONCLUSION: Synaptic degradation in parasympathetic nerves immediately after the onset of DM, and in sympathetic nerves much later in the development of DM is consistent with functional derangements in cardiac autonomic nerve activities assessed by HRV analysis. PMID- 23026238 TI - Anti-ovarian antibodies in sera of patients with ovarian tumors. AB - AIM OF PAPER: The purpose of this study was to assess the presence of anti ovarian autoantibodies in sera of patients with ovarian tumors. MATERIALS AND METHODS: The study group consisted of 82 patients treated at the Division of Gynecological Surgery, Poznan University of Medical Sciences, Poland in 2007 2011. 46 patients with malignant ovarian tumors and 36 patients diagnosed with benign ovarian tumor were included into the study. Age-matched healthy control groups consisted of 15 women and 19 men. Anti-ovarian autoantibodies in serum were assessed with the use of indirect immunofluorescence. The presence of anti ovarian autoantibodies in serum was correlated with clinical and histopathological features of the disease. RESULTS: Serum anti-ovarian autoantibodies were found in 59% (27/46) of patients with malignant ovarian tumors, compared to 55% (20/36) and 26% (4/15) of patients with benign ovarian tumors and healthy female controls respectively. The difference was statistically significant (P=0.04). All serum samples from the male controls were negative. Anti-ovarian antibodies occurred more often among advanced stage (III and IV stage according to FIGO, P=0.037) and grade 3 (P=0.049) ovarian cancers, however, there were no differences in median progression-free survival (P=0.388). The presence of anti-ovarian antibodies was neither influenced by histopathological type of the tumor, menopausal status, presence of ascites nor CA125 levels. Seropositivity for anti-ovarian antibodies was correlated positively with patients' age and negatively with tumor size. CONCLUSIONS: Anti-ovarian autoantibodies develop with higher frequency in ovarian cancer comparing to healthy controls, however with similar proportion to benign ovarian tumors patients. The presence of antibodies against normal ovarian tissue correlates with ovarian cancer aggressiveness. PMID- 23026237 TI - Construction, expression, and characterization of an anti-tumor immunotoxin containing the human anti-c-Met single-chain antibody and PE38KDEL. AB - Recombinant immunotoxins consisting of small antibody fragments fused to cytotoxic moieties are being evaluated for use in prospective antibody-targeted cancer therapies. A receptor tyrosine kinase known as c-Met is overexpressed in a vast range of human malignancies, making it an ideal target for antibody-mediated delivery of numerous cytotoxic agents. A single Fab molecule capable of binding to human c-Met with high affinity and specificity was previously identified using antibody phage-display technology. In order to develop a molecule to increase both the cytotoxicity and anti-tumor activity of the anti-c-Met molecule, a recombinant immunotoxin anti-c-Met/PE38KDEL was constructed and expressed by fusing the human anti-c-Met single-chain variable fragment (ScFv) with a modified Pseudomonas exotoxin A (PE38KDEL). Purified anti-c-Met/PE38KDEL was demonstrated to specifically bind to cells of c-Met-positive human hepatoma cell lines, causing a proliferation defect by inducing caspase-3/8-mediated apoptosis, as observed by in vitro assays. Furthermore, anti-c-Met/PE38KDEL administration was shown to inhibit the growth of hepatocellular carcinoma xenografts in vivo through suppression of Ki-67 expression and enhancement of tumor cell apoptosis rates. Cumulatively, the current findings demonstrate the successful construction of a recombinant immunotoxin capable of accurately targeting c-Met-positive human hepatoma cell lines both in vitro and in vivo, providing a novel compound with potential for applications as an alternative therapy for c-Met-positive cancer management. PMID- 23026239 TI - The burden of allergic rhinitis on patients' quality of life. PMID- 23026241 TI - Energy development linked with earthquakes. PMID- 23026243 TI - Changes in health service delivery for cardiac patients: implications for workforce planning and patient outcomes. AB - BACKGROUND: Traditional dedicated coronary care units (CCU) are being decommissioned and cardiology precincts are evolving. These precincts often have cardiac and non-cardiac patients with a diverse array of acuity levels. Critical care trained cardiac nurses are frequently caring for lower acuity patients resulting in a deskilling of this experienced workforce. AIM: The aim of this paper was to discuss the implications of restructuring CCUs on nursing workforce and patient outcomes. METHOD: An integrated literature review was conducted. The following databases were searched for articles published between January 2000 and December 2011: Ovid Medline, CINHAL, EMBASE and Cochrane. Additional studies obtained from the articles searched and policy documents from key professional organisations and government departments were reviewed. RESULTS: This review has highlighted the association between workforce, qualifications and quality of care. Studies have shown the relationship between an increase in critical care qualified nursing staff and an improvement in patient outcomes. Inadequate staffing levels were also shown to be associated with an increase in adverse events. Cardiology precincts have the potential to adversely impact on critical care trained cardiac nursing workforce and patient outcomes. CONCLUSION: The implications that these new models have on the critical care cardiac nurse workforce are crucial to health care reform, quality of in-hospital care, sentinel events and patient outcomes. PMID- 23026244 TI - Surgical navigation as a measuring tool. PMID- 23026245 TI - Accuracy of cup height and medialization in THA for dysplastic hip osteoarthritis using an imageless navigation system. AB - In total hip arthroplasty (THA) for dysplastic hip osteoarthritis, bony deformity makes it difficult to identify the correct cup height and medialization. The authors developed a new technique for registration and navigation of cup position for dysplastic hips using an imageless navigation system. Eighty dysplastic hips (Crowe type I, n=58; type II, n=18; type III, n=4) underwent THA. Thirty-four hips were operated on while in the supine position and 46 hips were operated on while in the lateral position. Before capsulectomy, the anterior pelvic plane and the position of the femur were registered. After exposure of the acetabulum, the teardrop, posterior rim, and medial wall of the acetabulum were registered. Then the cup height, cup medialization, cup inclination, anteversion, and leg lengthening were navigated. The difference between the navigated and radiographic cup heights was 4.5 +/- 4.0 mm, the difference in cup medialization was 3.0 +/- 2.5 mm, the difference in cup inclination was 4.3 degrees +/- 3.1 degrees , the difference in cup anteversion was 5.5 degrees +/- 3.8 degrees , and the difference in leg lengthening was 3.7 +/- 3.0 mm. Comparison of the first 20 cases with the last 20 cases showed that the accuracy of cup medialization was significantly improved. These differences were not affected by Crowe type or surgical position. Because the correct cup height and medialization are key issues in THA for dysplastic hip osteoarthritis, the accuracy of cup height and medialization in this imageless navigation system were acceptable for clinical application. PMID- 23026246 TI - Computed tomography assessment of image-free navigation-assisted cup placement in THA in an Asian population. AB - The authors hypothesized that an image-free navigation system would be more accurate than postoperative 3-dimensional (3-D) reconstructed computed tomography (CT) for acetabular cup inclination and anteversion during total hip arthroplasty (THA) in an Asian population. Eighty-one THAs were performed in 72 patients using the OrthoPilot image-free navigation system (B. Braun Aesculap, Tuttlingen, Germany). Cup placement position was measured by postoperative 3-D CT and compared with intraoperative navigation data. The discrepancies between the navigation data and the 3-D CT data were analyzed, as well as the correlation factors that affected the discrepancies. The discrepancies between the navigation data and the 3-D CT data were -1.5 degrees +/- 7.1 degrees (P=.04) for anteversion and -1.1 degrees +/- 7.6 degrees (P=.02) for inclination. The accuracy and precision of the anteversion discrepancies were 5.6 degrees +/- 4.4 degrees and 3.2 degrees , respectively. The accuracy and precision of the inclination discrepancies were 4.5 degrees +/- 4.4 degrees and 2.8 degrees , respectively. Five (6%) outliers existed in terms of the safe zones of anteversion and inclination. The main correlated factor among the pelvic geometry was tilt rather than rotation and obliquity of the bony anterior pelvic plane.In an Asian population, the calculated accuracy and precision of acetabular cup inclination and anteversion during THA were more reliable and the outliers were reduced using the OrthoPilot navigation system. However, discrepancies existed between intraoperative navigation data and postoperative 3-D CT data. The pelvic geometry of biometrical factors influenced the discrepancies in the navigation data. PMID- 23026247 TI - Navigated anterior cruciate ligament reconstruction: radiographic validation of a nonimage-based system. AB - The authors compared the intraoperative navigated measurements of the location of the tibial and femoral tunnels during arthroscopic-assisted anterior cruciate ligament reconstruction to the postoperative measurements performed on standard plain radiographs in 56 patients. The position of the center of the tibial and femoral tunnels was measured intraoperatively with the OrthoPilot (B. Braun Aesculap, Tuttlingen, Germany) and postoperatively on plain anteroposterior and lateral radiographs. The center of the tibial tunnel was located at 43% of the mediolateral tibial dimension intraoperatively and at 41% of the mediolateral tibial dimension postoperatively (P=.14). The center of the tibial tunnel tibial was located at 40% of the anteroposterior tibial dimension intraoperatively and at 35% of the anteroposterior tibial dimension postoperatively (P=.01). The center of the femoral tunnel was located at 85% of the anteroposterior femoral dimension intraoperatively and at 76% of the anteroposterior femoral dimension postoperatively (P<.001). A significant correlation was found between intraoperative navigated and postoperative radiographic measurements only at the femur. Good agreement existed between all navigated and radiographic measurements. The OrthoPilot navigation system allows an accurate measurement of the location of the tibial and femoral tunnels during anterior cruciate ligament reconstruction. PMID- 23026248 TI - Use of simple algorithms to predict screw length facilitates navigation controlled medial opening-wedge osteotomy using the TomoFix HTO system. AB - This study was performed to establish simple algorithms to predict proper screw lengths for the 4 proximal holes of TomoFix plates (Synthes GmbH; Solothurn, Switzerland) based on radiographic mediolateral (ML) and anteroposterior (AP) dimensions of the proximal tibia and to determine how well these algorithms function for navigation-controlled medial opening-wedge high tibial osteotomy (HTO) using TomoFix. Experimental HTO surgery was performed in proximal tibial models manufactured for 30 patients undergoing HTO to determine the longest screw lengths for the 4 proximal holes of TomoFix plates. Eight algorithms were created for the 4 proximal screws by investigating the relationships between measured screw lengths and radiographic dimensions and were used for 30 navigation controlled medial opening-wedge HTOs. The algorithms used to predict screw length were: screw A=ML width-20 mm and AP length+5 mm; screw B=ML width-25 mm and AP length; screw C=ML width-35 mm and AP length-10 mm; and screw D=ML width-40 mm and AP length-15 mm. All 30 surgeries were performed with no perioperative adverse events. Mean operative time was 47.1 minutes, and no far cortex perforation of more than 3 mm was observed for any of the 4 proximal screws. Mean mechanical tibiofemoral angle and weight load line coordinate at the knee joint were valgus 3.7 degrees and 62.9%, respectively. Targeted alignment was achieved in 28 (93%) knees for a mechanical tibiofemoral angle between valgus 2 degrees and 6 degrees , and in 25 (83%) knees for a weight load line coordinate between 55% and 70%. The authors propose the use of the developed algorithms to select proper screw lengths for medial opening wedge HTO using the TomoFix HTO system. PMID- 23026249 TI - Assessing whether preoperative templates and planning can replace intraoperative computer-assisted surgery measurements in total knee arthroplasty. AB - It is incumbent on the orthopedic community to assess current technologies available to predict the size of implants used for total knee arthroplasty (TKA) and whether they can accurately represent what will be visualized by surgeons intraoperatively. This study highlights the traditional practice of TKA by applying digitization software to streamline existing knowledge preoperatively in an effort to more accurately dimension the implants. The primary goal of the study was to assess the predictive value of a digitized templating system for TKA. The secondary goal was to ascertain whether varus, valgus, and flexion deformities were accurately predicted to intraoperative measures using computer assisted surgery. Forty-three patients were prospectively assessed using standard of-care 36-inch anteroposterior evaluations for determining mechanical angle and flexion contractures. Simultaneously, traditional radiographs were used as a sizing tool for the digitized software program. Statistical evaluation was completed by 2-tailed t test with incorporation of a varied window of acceptance (+/- 3 degrees and +/- 2 degrees in mechanical angle and flexion contracture measurements, respectively). This study showed a poor correlation between the predictive value of the digitization software; just one-third of the cases were accurately predicted. PMID- 23026250 TI - Computer-assisted total knee arthroplasty after prior femoral fracture without hardware removal. AB - This study presents a consecutive series of patients who underwent total knee arthroplasty (TKA) after prior distal femoral fracture without hardware removal. The purpose of this study was to determine the effectiveness of computer-assisted TKA in patients with posttraumatic arthritis, specifically those with retained hardware after prior distal femoral fracture. The study group included a consecutive series of 16 patients who had developed posttraumatic knee arthritis after a distal femoral fracture with retention of hardware (group A). Patients in the study group were matched with patients who had undergone a computer-assisted TKA using the same implant and software (group B). The indication for TKA in all group B patients was atraumatic arthritis, and surgery was performed during the same period as that in the study group. Patients were matched for age, sex, preoperative range of motion, preoperative severity of arthritis, type and grade of deformity, and implant features. No statistically significant differences existed between the 2 study groups in terms of operative time, duration of hospital stay, or intra- and postoperative complications. At last follow-up, no statistically significant differences existed in Knee Society Scores and Western Ontario and McMaster Universities Arthritis Index scores. Implant alignment and radiological parameters were similar in both groups. This study demonstrated that posttraumatic knee arthritis after prior distal femoral fracture can be safely managed using a computer-assisted TKA without hardware removal. Comparison between the study group and a matched group with atraumatic arthritis showed similar postoperative results and complication rates. PMID- 23026251 TI - Total knee arthroplasty kinematics may be assessed using computer modeling: a feasibility study. AB - The next generational leap in computer navigation will hopefully aid surgeons in personalizing surgical techniques to patients' individual anatomical variables to optimize outcomes. To effectively use the information obtained in the operating room, a multitude of kinematic variables must be conveyed to the orthopedic surgeon in a usable and coherent manner. This study used an intraoperative navigation system to record passive knee kinematics after a total knee arthroplastyperformed. The clinical measures were taken via research software with the ability to record kinematic data in 10-second intervals. The data from 10 consecutive clinical cases were averaged, and the translation (anterior/posterior) and rotation (internal/external) were recorded and compared from 0 degrees to 100 degrees of flexion to allow for comparison with the previously recorded computer model. Model and clinical curves compared favorably, with less than 1 degrees rotational and 1.5-mm differences, on average. The comparison of information and analyses were reviewed to indicate how they might be interpreted in the operating room for future use during surgery to allow a more personalized approach to improving functional outcomes after total knee arthroplasty. PMID- 23026252 TI - Femur positioning in navigated total knee arthroplasty. AB - Navigated total knee arthroplasty (TKA) results in better restoration of neutral mechanical axis than does the conventional technique. Nevertheless, coronal malalignment has not been eliminated. It is yet unknown whether errors in implant positioning occur more on the femoral side, more on the tibial side, or equally on both sides. The hypothesis of this study was that a predominance of coronal component malalignment exists on the tibial side in navigated tibia-first TKA.Fifty-seven consecutive navigated (OrthoPilot; B. Braun Aesculap, Tuttlingen, Germany) TKAs were included in this retrospective study. Pre- and postoperative digital whole-leg standing radiographs were analyzed. Coronal alignment was measured for the whole leg pre- and postoperatively. Lateral distal femur angle and medial proximal tibia angle were analyzed on the preoperative radiographs. On the postoperative radiographs, coronal alignment of the femoral and tibial components were measured separately in reference to the tibial and femoral mechanical axis. The coronal alignment improved from 8.2 degrees +/- 3.7 degrees preoperatively to 1.1 degrees +/- 1.2 degrees postoperatively, with 5 (8%) outliers outside the 3 degrees window. The femoral component was malaligned (0.6 degrees +/- 0.6 degrees ), whereas the tibial component showed a significantly higher deviation from the mechanical axis of 1.0 degrees +/- 1.1 degrees (P=.009). The femoral component was positioned more precisely than the tibial component. The latter influences gap management in the tibia-first technique and may thereby have a relevant effect on joint stability. Accuracy of the surgical technique and differences in the mathematical algorithm for the determination of landmarks are possible reasons for the difference in precision between the femoral and tibial component positioning. PMID- 23026253 TI - Differences in measurement of lower limb alignment among different registration methods of navigation and radiographs in TKA using the OrthoPilot system. AB - The purposes of this study were (1) to compare lower limb alignment measurements between radiographs and computer-assisted surgery and (2) to evaluate the discrepancy in lower limb alignment between computer-assisted surgery with a high tibial osteotomy protocol and computer-assisted surgery with a total knee arthroplasty (TKA) protocol in the same knee. Seventy-one TKAs were performed on patients with primary osteoarthritis using computer-assisted surgery. Preoperative lower limb alignment was measured using the mechanical axis during bipedal, weight-bearing, whole-leg anteroposterior radiography (measure 1). The intraoperative mechanical axis was measured with computer-assisted surgery according to the high tibial osteotomy protocol before joint exposure (measure 2). After changing the software and joint exposure, the intraoperative mechanical axis was measured with computer-assisted surgery according to TKA protocol (measure 3). After final TKA implantation, the lower limb mechanical axis was measured with computer-assisted surgery following the TKA protocol (measure 4). Postoperative lower limb alignment was measured using the mechanical axis on whole-leg standing anteroposterior radiographs (measure 5). The mechanical axis and median value from each group were compared. Factors affecting the mechanical axis measurement were also analyzed. The difference in the mechanical axis between measures 1 and 2, measures 1 and 3, and measures 2 and 3 was significant (P<.0001, <.0001, and =.0007, respectively). The difference between measures 4 and 5 was also significant (P<.0001). Factors affecting the mechanical axis measurement, such as age, height, weight, and range of motion, showed no correlation (R(2)=.07244 and adjusted R(2)=.01622). The pre- and postoperative radiological measurements of limb alignment using the mechanical axis were different from the intraoperative measurements with navigation. PMID- 23026254 TI - Influence of a secondary downsizing of the femoral component on the extension gap: a cadaveric study. AB - The purpose of this study was to evaluate the effect of a secondary reduction of the femoral component size on flexion and extension gaps intraoperatively in posterior-stabilized total knee arthroplasty (PS-TKA) monitored by computer assisted surgery. The authors hypothesized that cutting additional bone on the posterior femoral condyle may increase the extension gap due to the posterior capsule and soft tissue loosening. Reduction of the femoral component size was performed by additional 4-in-1 cuts after the PS-TKA on 15 cadaveric knees using a ligamentous tension device with the aid of computer-assisted surgery. Measurements of the medial and lateral flexion gaps, as well as the medial and lateral extension gaps, were recorded before and after reducing the femoral component size. Trial components were used from a mobile-bearing total knee system.After reducing the femoral component size, the medial and lateral flexion and extension gaps measured larger than their initial size. The mean increases of the medial extension and flexion gaps and the lateral extension and flexion gaps were 1.3 +/- 0.9, 1.0 +/- 1.2, 1.1 +/- 1.2, and 1.3 +/- 1.3 mm, respectively; all 4 differences were significant (P <= .05). Surgeons should be aware of the effect of downsizing components intraoperatively because it might lead to an extension laxity. Thus, a downsizing of the femoral component may compromise the postoperative stability of TKA. PMID- 23026255 TI - Posterior tibial slope in medial opening-wedge high tibial osteotomy: 2-D versus 3-D navigation. AB - Although opening-wedge high tibial osteotomy (HTO) is used to correct deformities, it can simultaneously alter tibial slope in the sagittal plane because of the triangular configuration of the proximal tibia, and this undesired change in tibial slope can influence knee kinematics, stability, and joint contact pressure. Therefore, medial opening-wedge HTO is a technically demanding procedure despite the use of 2-dimensional (2-D) navigation. The authors evaluated the posterior tibial slope pre- and postoperatively in patients who underwent navigation-assisted opening-wedge HTO and compared posterior slope changes for 2-D and 3-dimensional (3-D) navigation versions. Patients were randomly divided into 2 groups based on the navigation system used: group A (2-D guidance for coronal alignment; 17 patients) and group B (3-D guidance for coronal and sagittal alignments; 17 patients). Postoperatively, the mechanical axis was corrected to a mean valgus of 2.81 degrees (range, 1 degrees -5.4 degrees ) in group A and 3.15 degrees (range, 1.5 degrees -5.6 degrees ) in group B. A significant intergroup difference existed for the amount of posterior tibial slope change (Delta slope) pre- and postoperatively (P=.04).Opening-wedge HTO using navigation offers accurate alignment of the lower limb. In particular, the use of 3-D navigation results in significantly less change in the posterior tibial slope postoperatively than does the use of 2-D navigation. Accordingly, the authors recommend the use of 3-D navigation systems because they provide real time intraoperative information about coronal, sagittal, and transverse axes and guide the maintenance of the native posterior tibial slope. PMID- 23026256 TI - Three-dimensional synchrotron virtual paleohistology: a new insight into the world of fossil bone microstructures. AB - The recent developments of phase-contrast synchrotron imaging techniques have been of great interest for paleontologists, providing three-dimensional (3D) tomographic images of anatomical structures, thereby leading to new paleobiological insights and the discovery of new species. However, until now, it has not been used on features smaller than 5-7 MUm voxel size in fossil bones. Because much information is contained within the 3D histological architecture of bone, including an ontogenetic record, crucial for understanding the paleobiology of fossil species, the application of phase-contrast synchrotron tomography to bone at higher resolutions is potentially of great interest. Here we use this technique to provide new 3D insights into the submicron-scale histology of fossil and recent bones, based on the development of new pink-beam configurations, data acquisition strategies, and improved processing tools. Not only do the scans reveal by nondestructive means all of the major features of the histology at a resolution comparable to that of optical microscopy, they provide 3D information that cannot be obtained by any other method. PMID- 23026257 TI - Simultaneous determination of veterinary antibiotics and hormone in broiler manure, soil and manure compost by liquid chromatography-tandem mass spectrometry. AB - A multi-residue analytical method was developed to quantify nine antibiotics and one hormone in soil, broiler manure and manure compost. The developed method was based on ultrasonic extraction with MeOH:ACN:EDTA:McIlvaine buffer, solid phase extraction (SPE) using HLB (3 cc/60 mg) cartridge, followed by instrumental analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with 25 min total run time. It was validated and tested on soil, broiler manure and manure compost samples and showed that the method is able to simultaneously detect and quantify the target analytes with good selectivity and sensitivity. The developed method was linear in a concentration range from its instrumental quantification limit (IQL) to 500 ng/mL, with correlation coefficients higher than 0.999. The overall method performance was good for the majority of the analytes, with recoveries range from 63% to 121% in all the sample matrices. The method quantification limit (MQL) for the 10 target analytes in the soil, broiler manure and manure compost samples were 2-10, 3-16 and 5-15 MUg/kg dry weight (DW), respectively. The method has also included tilmicosin, an antibiotic known to be reported in the environment for the first time. The developed method was then applied on broiler manure samples and its relative manure amended agricultural soil samples to identify and quantify veterinary antibiotic and hormone residues in the environment. These analytes were detected in broiler manure and soil samples, with maximum concentrations reaching up to 78516.1 MUg/kg DW (doxycycline) and 1331.4 MUg/kg DW (flumequine), respectively. The results showed that the method can potentially be adopted for the analysis of veterinary antibiotic and hormone wastes in solid environmental matrices. PMID- 23026258 TI - Adsorption and separation behavior of yttrium and strontium in nitric acid solution by extraction chromatography using a macroporous silica-based adsorbent. AB - To separate (90)Y from the fission product (90)Sr-(90)Y group, a silica-based TODGA/SiO(2)-P adsorbent was prepared by impregnating N,N,N',N'-tetraoctyl-3 oxapentane-1,5-diamide (TODGA) extractant into the macroporous SiO(2)-P support with a mean diameter of 60 MUm. The adsorption behavior of Sr(II) and Y(III) onto TODGA/SiO(2)-P adsorbent from HNO(3) solution and their mutual separation were investigated. Under the experimental conditions, this adsorbent showed high adsorption affinity to Y(III) and weak adsorption to Sr(II). It was found that the adsorption process of Y(III) could be expressed by both of Langmuir monomolecular layer adsorption mode and the pseudo-second order model. From the results of stability experiments, it became clear that TODGA/SiO(2)-P adsorbent is stable in 3M HNO(3) solution for 1 month contact time at 298 K. Using a column packed with TODGA/SiO(2)-P adsorbent, Sr(II) and Y(III) were eluted by distilled water and diethylenetriamine pentaacetic acid (DTPA) solution, respectively. The separation of Y(III) from Sr(II)-Y(III) group was achieved successfully. PMID- 23026259 TI - Post-run target screening strategy for ultra high performance liquid chromatography coupled to Orbitrap based veterinary drug residue analysis in animal urine. AB - The performance of liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) post-run target screening for veterinary drug residue analysis (sulfonamides, tetracyclines and quinolones) in animal urine has been critically evaluated. It was found that retention time information still remains an essential information and that accurate masses together with relative isotopic abundance data alone are not sufficient for many residue applications. Post-run target screening requires the careful setting of parameters to achieve near zero false negative (above a defined threshold level) and a manageable numbers of false positive findings. HRMS offers many possibilities for the reduction of false positives (e.g. isotopic ratio, isotopic fine structure, exact mass of fragment ions). However, the successful use of such tools requires a sufficient ion intensity. This is often not available when trace level compounds are to be detected. Nevertheless, the proposed method is sufficiently sensitive to detect the veterinary drugs at the relevant concentration levels in urine. This means that the approach is well suited to significantly reduce the number of corresponding meat samples which have to be analyzed in a final step for the regulatory relevant quantification of residue levels in meat. The semi quantitative screening of many samples for a large number of analytes within a short period of time requires the availability of software tools which provide fast and reliable answers. PMID- 23026260 TI - Sensitive and simple determination of bromate in foods disinfected with hypochlorite reagents using high performance liquid chromatography with post column derivatization. AB - A novel analytical method for the quantification of bromate in fresh foods using high performance liquid chromatography (HPLC) with a post-column reaction has been developed. The fresh food sample solutions were pretreated with homogenization, centrifugal ultrafiltration and subsequent solid phase extraction using a strong anion-exchange resin. After separation on a strong anion-exchange chromatography column using a highly concentrated NaCl solution (0.3M) as the eluent, the bromate was quantified by detection using a post-column reaction with a non-carcinogenic reagent (tetramethylbenzidine). The developed HPLC technique made it possible to quantify bromate in salt-rich fresh foods. The recoveries from fresh foods spiked with bromate at low levels (2 or 10 ng/g) satisfactorily ranged from 75.3 to 90.7%. The lowest quantification limit in fresh foods was estimated to be 0.6 ng/g as bromic acid. The method should be helpful for the quantification of bromate in fresh foods disinfected with hypochlorite solutions. PMID- 23026262 TI - A generalization of a chromatographic response function for application in non target one- and two-dimensional chromatography of complex samples. AB - New flexible chromatographic response functions for one-dimensional (DCRF(f)) and two-dimensional chromatography (DCRF(f,2D)) are put forward and tested for estimating the quality index of separation in non-targeted chromatographic analysis of complex samples. These functions, based on already tested functions, have three clear-cut criteria: number of chromatographic peaks, degree of chromatographic separation, and time spent in the analysis. However, unlike the existing functions, they allow an accurate weighing and adjustment of these criteria according to the needs of the analyst. Special attention was given to the time spent in the analysis by introducing a time-saving criterion, which allowed its application in time dependent chromatographic systems. The performance and flexibility of the strategies based on the developed response functions are tested in different chromatographic scenarios and for several application possibilities using simulated chromatograms. PMID- 23026261 TI - Purification of human immunoglobulins A, G and M from Cohn fraction II/III by small peptide affinity chromatography. AB - This work describes attempts to purify human IgG, IgA and IgM from Cohn fraction II/III using HWRGWV affinity peptide resin. The effects of peptide density and different elution additives on recovery of the three antibodies were investigated. At low peptide density, salting-in salts such as magnesium chloride and calcium chloride facilitated antibody elution. Ethylene glycol, urea and arginine also facilitated elution because of their ability to decrease hydrophobic interactions, hydrogen bonding and electrostatic interactions. However, at high peptide density, no recovery improvements were observed because of increased non-specific hydrophobic interactions. The final elution conditions for each antibody were chosen based on the resulting yields and purities when a 10:2:1mg/mL mixture of human IgG, IgA and IgM was used as starting material. Different pretreatment methods were employed in order to improve the purity of antibodies from Cohn fraction II/III. After pretreatment with caprylic acid precipitation or combination of caprylic acid and polyethylene glycol precipitation, purities over 95% and yields of about 60% were obtained for hIgG, which are comparable to current chromatographic purification methods involving two chromatography steps when hIgG is isolated from plasma fractions. A hIgA enriched fraction with 42% hIgA and 56% hIgG, as well as a hIgM enriched fraction with 46% hIgM, 28% hIgA and 24% hIgG, were obtained as the by-products. PMID- 23026264 TI - Potential of the octanol-water partition coefficient (logP) to predict the dermal penetration behaviour of amphiphilic compounds in aqueous solutions. AB - Aqueous amphiphilic compounds may exhibit enhanced skin penetration compared with neat compounds. Conventional models do not predict this percutaneous penetration behaviour. We investigated the potential of the octanol-water partition coefficient (logP) to predict dermal fluxes for eight compounds applied neat and as 50% aqueous solutions in diffusion cell experiments using human skin. Data for seven other compounds were accessed from literature. In total, seven glycol ethers, three alcohols, two glycols, and three other chemicals were considered. Of these 15 compounds, 10 penetrated faster through the skin as aqueous solutions than as neat compounds. The other five compounds exhibited larger fluxes as neat applications. For 13 of the 15 compounds, a consistent relationship was identified between the percutaneous penetration behaviour and the logP. Compared with the neat applications, positive logP were associated with larger fluxes for eight of the diluted compounds, and negative logP were associated with smaller fluxes for five of the diluted compounds. Our study demonstrates that decreases or enhancements in dermal penetration upon aqueous dilution can be predicted for many compounds from the sign of logP (i.e., positive or negative). This approach may be suitable as a first approximation in risk assessments of dermal exposure. PMID- 23026263 TI - Modifications of the bacterial reverse mutation test reveals mutagenicity of TiO(2) nanoparticles and byproducts from a sunscreen TiO(2)-based nanocomposite. AB - The bacterial reverse mutation test, recommended by the Organization for Economic Co-operation and Development (OECD) to determine genotoxicity of chemical compounds, has been recently used by several authors to investigate nanoparticles. Surprisingly, test results have been negative, whereas in vitro mammalian cell tests often give positive genotoxic responses. In the present study, we used the fluctuation test procedure with the Salmonella typhimurium strains TA97a, TA98, TA100 and TA102 to determine the mutagenic potential of TiO(2) nanoparticles (NP-TiO(2)) and showed that, when it is used conventionally, this test is not suitable for nanoparticle genotoxicity assessment. Indeed, the medium used during exposure prevents electrostatic interactions between bacterial cells and nanoparticles, leading to false-negative responses. We showed that a simple pre-exposure of bacteria to NP-TiO(2) in a low ionic strength solution (NaCl 10mM) at a pH below the nanoparticle isoelectric points (pH 5.5) can strongly improve the accuracy of the test. Thus, based on these improvements, we have demonstrated the genotoxicity of the engineered NP-TiO(2) tested and a NP TiO(2) byproduct from a sunscreen nanocomposite. It was also shown that strain TA102 is more sensitive than the other strains, suggesting an oxidative stress mediated mechanism of genotoxicity. PMID- 23026265 TI - Estrogenic effects and their action mechanism of the major active components of party pill drugs. AB - Benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) are commonly used constituents of party pill drugs. They are reported to induce psychoactive effects such as euphoria and provide effects similar with other illicit drugs such as methylenedioxymethamphetamine (MDMA). A great deal of evidence has proven that party pills, as alternatives for MDMA, exert harmful effects on users. However, their toxicological effects have not been fully understood and endocrine disruptive effects are still unknown. In this study, we identified estrogenic effects of BZP and TFMPP by using in vitro and in vivo assays. BZP and TFMPP stimulated cell proliferation in a dose-dependent manner, while co-treatment with tamoxifen and BZP or TFMPP showed a decrease of E(2)-induced cell proliferation. In an estrogen sensitive reporter gene assay, BZP and TFMPP significantly increased transcriptional activities of party pill drugs. In addition, ER-related genes, PR and pS2, were significantly stimulated by BZP and TFMPP. These results indicated that BZP and TFMPP could have estrogenic activities related to the ER mediated pathway. Unlike the in vitro assay results, BZP and TFMPP did not show significant effects on weight increase in a rodent uterotrophic assay. However, further studies would be necessary to verify the estrogenic activities of BZP and TFMPP by a chronic exposure animal study. PMID- 23026266 TI - Applicable thermostatted models to crowd dynamics: comment on "Thermostatted kinetic equations as models for complex systems in physics and life sciences" by Carlo Bianca. PMID- 23026267 TI - Thermostatted kinetic theory for complex systems: comment on "Thermostatted kinetic equations as models for complex systems in physics and life sciences" by Carlo Bianca. PMID- 23026268 TI - Biomass torrefaction: modeling of volatile and solid product evolution kinetics. AB - The aim of this work is the development of a kinetics model for the evolution of the volatile and solid product composition during torrefaction conditions between 200 and 300 degrees C. Coupled to an existing two step solid mass loss kinetics mechanism, this model describes the volatile release kinetics in terms of a set of identifiable chemical components, permitting the solid product composition to be estimated by mass conservation. Results show that most of the volatiles released during the first stage include highly oxygenated species such as water, acetic acid, and carbon dioxide, while volatiles released during the second step are composed primarily of lactic acid, methanol, and acetic acid. This kinetics model will be used in the development of a model to describe reaction energy balance and heat release dynamics. PMID- 23026269 TI - Feasibility and acceptability of rapid HIV test screening (DEPIVIH) by French family physicians. AB - BACKGROUND: In France, around 50,000 people were unaware of their HIV positivity at the end of 2008. The latest guidelines recommend routine screening of all adults. Family physicians have been identified as key persons for this new policy. Rapid HIV tests (RHT) have been proposed as an alternative to conventional blood tests. OBJECTIVES: The authors assessed the feasibility and acceptability of RHT test based screening in French community practice. METHOD: We made a prospective interventional study of the BioMerieux VIKIA((r)) HIV 1/2 RHT among French family physicians. Data on the RHT was posted in the physician's waiting room. RESULTS: Sixty-two French physicians, mostly family practitioners, included 383 patients with a mean age of 36.2 years, from June to October 2010. Twenty-two percent (83) of these patients had never been tested for HIV. The RHT was proposed and 382 tests were accepted and performed (acceptability rate of 99.7%). Sixty-five percent of the tests were made on the patient's request. The tested population represented 1.5% of consulting patients during the study period (feasibility rate). Patients were quite satisfied but physicians less so. Test steps and capillary blood sampling were the main source of difficulty mentioned. At the end of the study, 59% of physicians were ready to continue using RHT in their daily practice. CONCLUSION: Routine RHT screening in community practice is feasible and well accepted by patients. It was the first screening test for 22% of our patients. Its feasibility was limited by capillary blood sampling technique and time constraints during consultation. PMID- 23026270 TI - Epidemiology of esophageal cancer. AB - This article discusses the incidence, geographic differences, and risk factors for the 2 most common cancers of the esophagus: squamous cell and adenocarcinoma. PMID- 23026271 TI - Molecular basis of esophageal cancer development and progression. AB - This article discusses the molecular basis of esophageal cancer development and subsequent progression of disease. Differing epidemiologic factors are associated with esophageal adenocarcinoma and squamous cell carcinoma. These 2 different histologic types have differing putative underlying mechanisms of transdifferentiation from normal esophageal mucosa to malignant histologies via gene dysregulation, biochemical modifications, and altered cell signaling pathways. Our developing understanding of the molecular events underlying esophageal cancer is leading to the establishment of identifiable biomarkers and the clinical use of molecularly targeted treatment agents. The identification of driving genetic mutations and altered signaling pathways has also had favorable outcomes. PMID- 23026272 TI - Diagnosis and staging of cancer of the esophagus and esophagogastric junction. AB - Esophageal/esophagogastric junction cancer staging in the 7th edition of the AJCC staging manual is data driven and harmonized with gastric staging. New definitions are Tis, T4, regional lymph node, N, and M. Nonanatomic characteristics (histopathologic cell type, histologic grade, cancer location) and TNM classifications determine stage groupings. Classifications before treatment define clinical stage (cTNM or ycTNM). Current best clinical staging modalities include endoscopic ultrasonography for T and N and CT/PET for M. Classifications at resection define pathologic stage (pTNM or ypTNM). Accurate pathologic stage requires communication/cooperation between surgeon and pathologist. Classifications are defined at retreatment (rTNM) and autopsy (aTNM). PMID- 23026273 TI - Medical evaluation of patients preparing for an esophagectomy. AB - Despite important improvements in the multimodal treatment of upper gastrointestinal tumors in recent years, surgery is still the standard of care and the best way to cure and palliate patients with esophageal cancer. There has been significant improvement in both clinical oncologic staging and functional preoperative evaluation of patients in the last few decades. Despite improvements, esophagectomy is still associated with high operative risk. Diligent perioperative evaluation and risk stratification lead to better outcomes. PMID- 23026275 TI - Management of stage 1 esophageal cancer. AB - Barrett esophagus surveillance programs and more liberal use of upper endoscopy are leading to the identification of more patients with high-grade dysplasia or early stage esophageal adenocarcinoma. These patients have several options for therapy, including endoscopic mucosal resection, vagal-sparing esophagectomy, and a combination of endoscopic resection and ablation. Factors that should be considered include the length of the Barrett segment, the presence of a nodule or ulcer within the Barrett segment, and the age and overall physical condition of the patient. Of particular importance will be the incidence of recurrent Barrett esophagus or cancer in the long-term in patients that were initially successfully treated endoscopically. PMID- 23026276 TI - Management of T2 esophageal cancer. AB - Patients with clinically staged T2N0 esophageal cancer are a small subset of patients for whom therapy is not standardized. Current clinical staging modalities are lacking in providing accurate staging for the presumed T2N0 subset. Problems with overstaging and understaging can each have adverse consequences for the patient. Furthermore, the benefit of induction therapy versus esophagectomy followed by adjuvant therapy for upstaged patients is unproven. The management of this challenging group of patients is reviewed. PMID- 23026274 TI - Diagnosis and management of Barrett's esophagus. AB - Barrett esophagus is characterized by the replacement of squamous mucosa in the esophagus by specialized intestinal metaplasia. Its clinical significance lies in it being the strongest risk factor for and known precursor for esophageal adenocarcinoma. Diagnosis requires endoscopic confirmation of columnar metaplasia in the distal esophagus and histologic confirmation of specialized intestinal metaplasia. Recommendations for the management of subjects diagnosed with Barrett esophagus include periodic endoscopic surveillance to detect the development of high-grade dysplasia or adenocarcinoma. Careful endoscopic evaluation with high resolution endoscopy and endoscopic resection is recommended in the evaluation of subjects with high-grade dysplasia and early adenocarcinoma. PMID- 23026277 TI - Management of advanced-stage operable esophageal cancer. AB - The incidence of esophageal cancer is increasing in the developed world, with a relative increase in adenocarcinoma compared with squamous cell carcinoma. The distensible nature of the esophagus results in delayed development of symptoms associated with esophageal cancer; hence many patients have locally advanced or metastatic cancer at the time of initial presentation. Although resection remains the treatment of choice for early-stage esophageal cancer, the best treatment strategy for locally advanced esophageal cancer is debatable and, consequently, varies at different centers. This article discusses the published literature on various available therapeutic options for the treatment of locally advanced esophageal cancer. PMID- 23026278 TI - Management of gastroesophageal junction tumors. AB - Tumors of the gastroesophageal junction have historically been treated as either gastric or esophageal cancer depending on institutional preferences. The Siewert classification system was designed to provide a more precise means of characterizing these tumors. In general, surgical treatment of Siewert 1 tumors is via esophagectomy. Siewert 2 and 3 tumors may be treated with either esophagectomy with proximal gastrectomy or extended total gastrectomy provided negative margins are obtained. All but the earliest stage tumors should be considered for neoadjuvant chemoradiotherapy. PMID- 23026279 TI - Definitive chemoradiotherapy for esophageal carcinoma. AB - Radiation therapy plays an important role in the treatment of esophageal cancer. Radiation therapy may be combined with chemotherapy, used as a component of induction therapy, used in the adjuvant setting, or used for palliation of advanced disease. Chemotherapy is also occasionally used as a solitary treatment modality for patients with esophageal cancer. Current treatment protocols include multiple agents, and agents directed against specific molecular targets have been investigated in clinical trials. This article discusses future directions related to the selection of radiation treatment protocols, novel targeted chemotherapeutic agents, and the selection of patients for surgery. PMID- 23026280 TI - Traditional techniques of esophagectomy. AB - Several well described and accepted traditional techniques exist for the performance of an open esophagectomy. The rationale for selecting one of these techniques is determined by the location and histology of the disease being treated and surgeon and institutional preferences. Large retrospective studies and a limited number of prospective studies have comparatively evaluated the operative and long-term oncologic outcomes of transthoracic versus transhiatal surgical approaches, which indicate trends toward higher perioperative complications but improved long-term outcomes among patients treated with a transthoracic approach. Other retrospective studies investigated the extent of a thoracic lympadenectomy that is necessary at the time of an esophagectomy to optimize survival. PMID- 23026281 TI - Minimally invasive esophagectomy. AB - Minimally invasive esophagectomy (MIE) has become an established approach for the treatment of esophageal carcinoma. In comparison with open esophagectomy MIE reduces blood loss, respiratory complications, and length of hospital stay. At the University of Pittsburgh, the authors now predominantly perform a laparoscopic-thoracoscopic Ivor Lewis esophagectomy. This article details this technique, discusses the recently published series of more than 1000 esophagectomies performed by the authors during the last 15 years, and reviews the current literature on MIE. PMID- 23026282 TI - Esophageal reconstruction with alternative conduits. AB - Alternative conduits for esophageal replacement become necessary when the stomach is unavailable for use. Common options for conduit creation include the jejunum and the colon. Prior abdominal operations, inflammatory bowel disease, or other mesenteric or abdominal disorders may limit use of either organ and a thorough history is essential when planning for alternative reconstruction. Most often the jejunum is free of intrinsic disease and provides a long segment for esophageal replacement. Limitations on the length of conduit that can be constructed with the jejunum have largely been overcome. A colonic conduit can also provide adequate length to reach the neck. PMID- 23026283 TI - Complications of esophagectomy. AB - Esophagectomy remains the gold standard curative therapy for the treatment of esophageal cancer. Despite 125 years of evolution, esophagectomy remains a demanding procedure associated with a 5% to 10% mortality and a 50% morbidity rate. Knowledge of the multitude of techniques possible for performing this complex procedure, as well as the host of associated complications, is vital for the practitioner aspiring to treat this challenging disease. PMID- 23026284 TI - Quality of life after an esophagectomy. AB - Specialized centers have reduced the adverse outcomes associated with esophagectomy in the last 2 decades and now report operative mortalities of less than 5%. With the expanding use of screening endoscopy, early invasive esophageal adenocarcinoma is diagnosed more commonly. As a result, more patients enjoy long term survival after curative resection. Simultaneously, emerging evidence supports the equivalence of competing endoscopic therapies for treatment of very early cancers and benign diseases. Accordingly, surgical resection requires re evaluation using enhanced parameters to enable more meaningful comparative outcome analyses. This article summarizes the current evidence and examines future directions regarding esophagectomy quality of life. PMID- 23026285 TI - Palliative therapy for patients with unresectable esophageal carcinoma. AB - Most patients diagnosed with carcinoma of the esophagus do not undergo therapy with curative intent. The focus of treatment for these patients is to maximize their progression-free survival and palliate the most common sequelae of their disease: dysphagia, malnutrition, pain, and intraluminal tumor bleeding. This article discusses the available treatment options for palliation of patients with unresectable esophageal cancer. PMID- 23026286 TI - Contemporary management of esophageal malignancy. PMID- 23026287 TI - Contemporary management of esophageal malignancy. PMID- 23026289 TI - Direct determination of tin in whole blood and urine by GF AAS. AB - OBJECTIVE: The aim of this work was to develop a procedure for the determination of tin in whole blood and urine by GF AAS with a minimum sample pre-treatment, using Pd/Mg as chemical modifier. DESIGN AND METHODS: The analyses of tin were conducted using an atomic absorption spectrometer with Zeeman background correction. The laboratory staff volunteered blood and urine samples for the experimental studies and application of the methodology. RESULTS: Samples were just diluted with 0.2% v/v Triton X-100, and pyrolysis and atomization temperatures of 1300 and 2200 degrees C were used. External calibration was performed with matrix matched calibration solutions. Limits of detection of 2.7 and 0.8 MUgL(-1) were reached for blood and urine, respectively. The method was applied to the determination of Sn in blood and urine of eleven subjects not occupationally exposed, working in a laboratory of toxicology in a large Brazilian city, and the results ranged from 7.4 to 11.2 MUgL(-1) and <=0.8 to 2.2 MUgL(-1), for blood and urine, respectively. Accuracy was assessed by analysis of standard reference materials for tin in blood (Contox I, lot TM144-1097, Kaulson Laboratories, USA) and urine (Seronorm, lot 0511545, Sero AS, Norway). CONCLUSIONS: Results showed good agreement between experimental and reference values according to the Student's t test at 95% of confidence. PMID- 23026288 TI - Impact of age, sex, obesity, and steroid use on quinolone-associated tendon disorders. AB - BACKGROUND: Quinolone antibiotics are associated with increased risk of tendinopathy. Identifying at-risk individuals has important clinical implications. We examined whether age, sex, glucocorticoid use, obesity, diabetes, and renal failure/dialysis predispose individuals to the adverse effects of quinolones. METHODS: Among 6.4 million patients in The Health Improvement Network (THIN) database, 28,907 cases of Achilles tendonitis and 7685 cases of tendon rupture were identified in a case-crossover study. For each participant, we ascertained whether there was a prescription of a quinolone and comparison antibiotic within 30 days before the diagnosis of tendon disorder (case period) and a prescription of the same medications within 30 days 1 year before disease diagnosis (control period). RESULTS: Use of quinolones was strongly associated with an increased risk of Achilles tendonitis (odds ratio [OR], 4.3; 95% confidence interval [CI], 3.2-5.7) and tendon rupture (OR, 2.0; 95% CI, 1.2-3.3). No association was found between the use of other antibiotics and either outcome. The association with Achilles tendonitis was stronger among participants who were aged more than 60 years (OR, 8.3 vs 1.6), who were nonobese (OR, 7.7 vs 2.4), and who used oral glucocorticoids (OR, 9.1 vs 3.2). The association was nonsignificantly stronger in women (OR, 5.0 vs 3.6), diabetic persons (OR, 7.0 vs 4.1), and those in renal failure or receiving dialysis (OR, 20.0 vs 3.9). The effect for tendon rupture was stronger in women, with borderline significance in glucocorticoid users and nonobese persons. CONCLUSION: Quinolone-associated tendinopathy is more pronounced among elderly persons, nonobese persons, and individuals with concurrent use of glucocorticoids. PMID- 23026290 TI - Gleditsioside B, a triterpene saponin isolated from the anomalous fruits of Gleditsia sinensis Lam., abrogates bFGF-induced endothelial cell migration through preventing the activation of MMP-2 and FAK via inhibiting ERK and PI3K/AKT signaling pathways. AB - Angiogenesis has become an attractive target for the treatment of certain diseases such as cancer and rheumatoid arthritis. Our previous studies demonstrated that the saponin fraction from Gleditsia sinensis fruits had anti angiogenic potential, and Gleditsiosides B (GB) was probably the main active constituent. In the present study, we assessed the effect of GB on endothelial cell migration, a crucial event in angiogenesis, and explored the underlying mechanisms. The migration of endothelial cells was assessed by transwell. The expressions of MMP-2/-9 and TIMP-1/-2 were analyzed by Western blotting, and the activities of MMP-2/-9 were detected by gelatin zymography assay. Moreover, migration-related proteins and signaling pathways, including FAK, MAPKs and PI3K/AKT, were analyzed by Western blotting. It was shown that GB, at a concentration of 10 MUM without significant cytotoxicity, could effectively abrogate the migration of human umbilical vein endothelial cells (HUVECs) induced by bFGF. GB also inhibited the expression and activity of MMP-2, elevated the expression of TIMP-1, and restrained the phosphorylations of FAK, ERK, PI3K and AKT in a concentration-dependent manner. The findings suggest that GB was able to abrogate the migration of endothelial cells through down-regulating the activation of MMP-2 and FAK via preventing ERK and PI3K/AKT signaling pathways. PMID- 23026291 TI - Coexistence of allergic bronchopulmonary aspergillosis and atopic dermatitis: is total IgE level useful to identify relapses of allergic bronchopulmonary aspergillosis? PMID- 23026292 TI - Phenotype properties and status of corticosteroid resistance among patients with uncontrolled asthma. AB - BACKGROUND: Control cannot be achieved in some asthmatics although optimal monitoring and treatment is administered. Glucocorticoid (GC) resistance is one of the reasons of poor asthma control. We aimed to investigate GC resistance by lymphocyte proliferation suppression test (LPST) in uncontrolled asthmatics. METHODS: After assessing asthma control level of 77 asthmatics their treatment was adjusted upon GINA guidelines. They were followed-up for three to six months and the patients who remained uncontrolled were accepted as uncontrolled patients. Steroid resistance test (SRT) was applied to them (7-14 days oral prednisolone) and the patients who were still uncontrolled and/or had a FEV1 increase <15% after SRT were assessed as the "case group" while the remaining composed the "control group". Optimal treatment was adjusted and at the end of a follow-up period LPST was performed to both groups. RESULTS: Fourteen of the case (n=22) and four (n=8) of the control groups could be evaluated by LPST. Proliferated lymphocytes were observed to be significantly suppressed in all dexamethasone concentrations in the control group (p=0.001). However, in the case group LPST was positive only at 10(-6) and 10(-4) concentrations although statistically not significant (p=0.147). There was no significant relationship between clinically GC resistance and LPST positivity (p=0.405). CONCLUSION: We determined that in vitro responses to the GCs were significantly declined in the uncontrolled asthma cases. An SRT alone does not seem to be very sensitive for evaluating GC sensitivity, LPST may be performed for demonstrating GC responsiveness in asthmatic patients in addition to SRT. PMID- 23026293 TI - Genotype-specific mutations in the polymerase gene of hepatitis B virus potentially associated with resistance to oral antiviral therapy. AB - The evolution of hepatitis B virus (HBV) and the role of different variants during antiviral therapy may be influenced by HBV genotype. We have therefore analysed substitutions potentially related to nucleos(t)ide analogues (NAs) resistance at 42 positions within RT-region in a cohort of patients with chronic hepatitis B in relation to HBV-genotype. RT mutations analysis was performed by direct sequencing in 200 NAs-naive patients and in 64 LAM or LAM+ADV experienced patients with NAs resistance, infected mainly by HBV-genotypes D and A. 27 polymorphic-sites were identified among the 42 positions analysed and 64 novel mutations were detected in 23 positions. Genotype-D displayed the highest mutation frequency (6.4%) among all HBV-genotypes analysed. Single or multiple mutations were detected in 80% of naive patients. Overall, the most frequent single mutations were at residues rt54, rt53 and rt91 which may associate with significantly lower HBV-DNA levels (p=0.001). Comparison with sequencing data of patients failing LMV or LAM+ADV therapy revealed an higher frequency of novel genotype-specific mutations if compared with naive patients: 3 mutations under LAM monotherapy in HBV-D (rtS85F; rtL91I; rtC256G) and 3 mutations under ADV therapy in HBV-A (rtI53V; rtW153R; rtF221Y). In HBV-D treated patients the dominant resistance mutation was rtL80V (31.4%) and rtM204I (60%) in LAM+ADV group while LAM-treated patients showed a preference of rtM204V (51.9%). Interestingly, none of HBV-A patients had mutation rtM204I under ADV add-on treatment but all of them had the "V" AA substitution. These results suggested that in patients with CHB, HBV-genotype might be relevant in the evolution and development of drug resistance showing also different mutation patterns in the YMDD motif between HBV genotype D and A. PMID- 23026294 TI - NF-kappaB-mediated inverse regulation of fractalkine and CX3CR1 during CLP induced sepsis. AB - Fractalkine is a unique member of the CX3C chemokine family by unfolding its potential through the chemokine (C-X3-C motif) receptor 1 (CX3CR1) with dual function acting both as an adhesion molecule and a soluble chemokine. The regulation of this chemokine is still not clear. Therefore, we were interested in the regulation of fractalkine and of CX3CR1 in experimental sepsis. In addition, we investigated the role of NF-kappaB for the regulation of fractalkine and of CX3CR1. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found elevated fractalkine mRNA levels in the heart, lung, kidney, and liver, as well as increased plasma levels 24 and 48h after CLP, respectively. In parallel, CLP resulted in a significant downregulation of CX3CR1 mRNA receptor expression in all investigated murine tissues. Septic mice that were pretreated with the selective NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) were found to have a decreased liberation of proinflammtory cytokines such as TNF alpha, IL-1beta, IL-6, or IFN-gamma. Further PDTC pretreatment attenuated CLP induced downregulation of CX3CR1 mRNA as well as CLP-induced upregulation of fractalkine mRNA expression in the heart, lung, kidney, liver, and the increase in fractalkine plasma levels of septic mice. In addition, CLP-induced downregulation of renal CX3CR1 protein expression was inhibited by PDTC pretreatment. Taken together, our data indicate a CLP-induced inverse regulation of the expression between the relating ligand and the receptor with an upregulation of fractalkine and downregulation of CX3CR1, which seems to be mediated by the transcripting factor NF-kappaB likely via reduced liberation of proinflammtory cytokines in the whole murine organism. PMID- 23026295 TI - Circulating IL-6 concentrations and associated anthropometric and metabolic parameters in South Asian men and women in comparison to European whites. AB - OBJECTIVE: To determine any ethnic differences in circulating interleukin (IL)-6 concentrations among SAs and Europeans, and to assess their relationship with body composition and insulin resistance measures. METHODS: Body composition was assessed among 80 SA and European men and women using anthropometry, dual-energy X-ray absorptiometry and abdominal CT scan. Oral glucose tolerance tests with insulin response were performed to assess insulin resistance measures. IL-6 levels were measured by high sensitivity ELISA. RESULTS: Median IL-6 values were higher in SA compared with European women: 1.94 mg/l versus 1.51 mg/l, p=0.041, but not so in men (1.56 mg/l versus 1.57 mg/l). Only measures of obesity, in particular percentage fat area (r=0.6, p=0.003), were positively correlated with IL-6 in SAs. Differences in body fat percentage (visceral and total) could explain up to 30% of the IL-6 difference between Asian and European women. CONCLUSION: SA women have elevated circulating IL-6 levels, in part due to greater visceral and percent fat levels compared with European women. This observation may in part explain why Asians are at elevated cardiovascular disease risk. Future studies should address the effects of lifestyle factors (physical activity, diet) on plasma IL-6 concentrations in SA women. PMID- 23026296 TI - Describing the environmental fate of diuron in a tropical river catchment. AB - The use of the herbicide diuron on sugarcane fields along the river catchments of the Great Barrier Reef (GBR) in Australia is an issue of concern due to high levels of diuron reported in the GBR lagoon, and has recently led to a restriction on the use of diuron during the 2011/12 wet season. An important question in this context is how much diuron is mobilised from the agricultural area by strong rainfall and floods in the wet season and transferred to the GBR lagoon. We have set up a multimedia chemical fate model for a tropical catchment to describe the fate of diuron within the Tully River catchment, Queensland, Australia. The model includes highly variable rainfall based on meteorological data from the Tully River catchment and a flood water compartment on top of the agricultural soil that is present during times for which floods were reported. The model is driven by diuron application data estimated for the Tully River catchment and is solved for time-dependent diuron concentrations in agricultural soil and seawater. Model results show that on average 25% of the diuron applied every year is transferred to the GBR lagoon with rainwater and flood water runoff. Diuron concentrations estimated for the seawater range from 0.1 ng/L to 12 ng/L and are in good agreement with concentrations measured in the GBR lagoon. The uncertainty of the diuron concentrations estimated for seawater is approximately a factor of two and mainly derives from uncertainty in the diuron degradation half-life in soil, properties of the soil compartment such as organic matter content, and the speed of the seawater current removing diuron dissolved in seawater from the seawater compartment of the model. PMID- 23026297 TI - Cox model setup may lead to erroneous conclusions. PMID- 23026299 TI - Photoreactive, core-shell cross-linked/hollow microspheres prepared by delayed addition of cross-linker in dispersion polymerization for antifouling and immobilization of protein. AB - When dispersion polymerization of styrene (St) had run for 3h, after particle rapidly growing stage, 4,4'-dimethacryloyloxybenzophenone (DMABP) cross-linker was added to reaction system and photoreactive, core(PSt)-shell(Poly(St-co DMABP)) particles with rich benzophenone (BP) groups on surface were prepared. Polymerization of DMABP could occurred mainly on the preformed core of PSt because its diffusion could be impeded by (1) compactness of particles formed at the moment of cross-linker addition (more than 80% of monomer had been consumed, particles were no longer fully swollen by monomer), (2) reduced polarity of continuous phase, and (3) immediate occurrence of cross-linking. Subsequently, photoreactive, cross-linked hollow particles were yielded by removal of uncross linked core in THF. SEM and TEM observation demonstrated the formation of core shell structure and improvement of shell thickness when DMABP content increased. UV-vis spectra analysis on polymer dissolved in THF indicated that there is no polymer of DMABP in core. FTIR spectra analysis and XPS measurement further revealed that BP component on particle surface was enriched when amount of DMABP increased. Finally, an anti-fouling polymer (poly (ethylene glycol), PEG) and protein of mouse IgG was immobilized on particle surface under UV irradiation, as confirmed by FTIR spectra analysis, SEM observation and TMB color reaction. PMID- 23026300 TI - Synthesis of noble metal/graphene nanocomposites without surfactants by one-step reduction of metal salt and graphene oxide. AB - We carried out hydrazine-free, surfactant-free synthesis of noble metal/graphene nanocomposites. The reduction of the noble metals and GO was carried out simultaneously in hot water using ascorbic acid as a reductant. In the noble metal/graphene nanocomposites of Pd, Pt, Au, and Ag nanoparticles, the GO and metal salts were reduced completely by this synthetic method. In addition, the Pd/graphene nanocomposites showed good catalytic activity in the Suzuki coupling reaction and could be reused many times without loss of catalytic activity. PMID- 23026301 TI - Immobilization of chondroitin sulfate to lipid membranes and its interactions with ECM proteins. AB - Glycosaminoglycans (GAGs) in the extracellular matrix (ECM) have multiple functions in tissues including providing support, mediating cell division and differentiation, and taking part in important interactions with proteins, e.g. growth factors. Studying GAG related interactions is inherently difficult and requires suitable interaction platforms. We show two strategies to covalently couple the GAG chondroitin sulfate (CS) to supported lipid bilayers (SLBs), either by (a) activating carboxy-functionalized phospholipids in the lipid bilayer, followed by the addition of hydrazide-functionalized CS, or by (b) activating naturally occurring carboxyl groups on CS prior to addition to an amino-functionalized SLB. Bilayer formation and subsequent immobilization was followed in real-time using the Quartz Crystal Microbalance with Dissipation monitoring, a technique that provides unique information when studying highly hydrated molecular films. The two strategies yielded thin CS films (in the nanometer range) with similar viscoelastic properties. Fluidity of the lipid bilayer was retained when CS was coupled. The application of the CS interaction platform was exemplified for type I collagen and the bone inducing growth factor bone morphogenetic protein-2 (BMP-2). The addition of collagen to immoblized CS resulted in soft layers whereas layers formed by addition of BMP-2 were denser, independent on the immobilization strategy used. PMID- 23026303 TI - The effect of Bunsimgi-eum on Hwa-byung: randomized, double blind, placebo controlled trial. AB - ETHNOPHAMACOLOGICAL RELEVANCE: Bunsimgi-eum (BSGE), a prescription for stagnation of the seven emotions, is being used on neuropsychiatric symptoms in clinical traditional Korean medicine. AIM OF THE STUDY: The purpose of this research is to examine the effect of BSGE on Hwa-byung's symptoms. MATERIALS AND METHODS: Randomized, double blinded, placebo-controlled study was set and patients diagnosed as Hwa-byung, were treated with Bunsimgi-eum or controlled medication. Score change of 100mm Visual Analog Scale (VAS) for chest discomfort, Likert scale for major symptom of Hwa-byung, STAXI-K, STAI-K, and BDI-K, were analyzed. RESULTS: 100mm Visual Analog Scale (VAS) for chest discomfort was measured as the 1st evaluative instrument. Experimental group showed greater inclination for score change, but there were no significance. In all other valuation scales, scores improved significantly within each group, but there were no significant difference between the groups. CONCLUSION: These data show that BSGE's effect on Hwa-byung did not exceed that of placebo. PMID- 23026304 TI - Medicinal plants used by the Bapedi traditional healers to treat diarrhoea in the Limpopo Province, South Africa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This paper provides ethnobotanical information on medicinal plants used to treat diarrhoea in the Limpopo Province, South Africa. Documentation of this nature usually provides the basis for selecting medicinal plants for future phytochemical and pharmaceutical studies aimed at developing new, effective and affordable plant-derived diarrhoea remedies. AIM OF THE STUDY: To record and document medicinal plants used by the Bapedi traditional healers to treat diarrhoea in the Limpopo Province, South Africa. MATERIALS AND METHODS: In order to record and document medicinal plants used by the Bapedi traditional healers to treat diarrhoea, 51 healers from 17 municipalities covering Capricorn, Sekhukhune and Waterberg districts in the Limpopo Province, South Africa were interviewed between January and July 2011. Data collected included the names of plants, plant part(s) used, methods of herbal preparation, administration, dosage and duration of treatments. Voucher specimens of the plants used by the Bapedi traditional healers to treat diarrhoea were collected, identified and deposited as future reference material at the Larry-Leach Herbarium (UNIN), University of Limpopo. RESULTS: A total of 20 plant species representing 16 families and 20 genera were found to be commonly used by the Bapedi traditional healers to treat and manage diarrhoea in the Limpopo Province, South Africa. The largest proportion of the medicinal plants belonged to the families Anacardiaceae, Asteraceae, Fabaceae and Malvaceae (10% each). The most frequently used species were Punica granatum (39.2%), Grewia bicolor (33.3%), Dombeya rotundifolia (21.6%), Commiphora marlothii (19.6%) and Acacia senegal (13.7%). The roots were the most commonly used plant part (50%), followed by leaves (20%), bark (15%), fruits (10%), pericarp, seed, tuber and whole plants (5% each). Mono therapies based on preparations made from a single plant species were the most dominant (90%). All medicinal preparations were taken orally for 1 week or until diarrhoea subsided. The therapeutic claims of the medicinal plants documented in this study are well supported by literature, with 70% of the species having anti-diarrhoeal properties or are used as diarrhoea remedies both in South Africa and also in other countries. CONCLUSION: This study reveals that local communities in the Limpopo Province, South Africa still depend on traditional medicines for basic healthcare; and the use of traditional medicines is still an integral part of their socio-cultural life. PMID- 23026305 TI - Induction of quinone oxidoreductase 1 enzyme by Rhazya stricta through Nrf2 dependent mechanism. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhazya stricta Decne. (Apocynaceae) is a common medicinal plant in the Arabian Peninsula, Pakistan and India. Rhazya stricta has been used traditionally to treat several diseases including tumors; however, the underlying mechanism is still not fully elucidated. AIM OF THE STUDY: The aim of this study is to examine the ability of Rhazya stricta to induce a key enzyme involved in cancer chemoprevention, NAD(P)H:quinone oxidoreductase 1 (Nqo1) in murine and human hepatoma cells. Nqo1 is regulated by the nuclear factor erythroid 2-related factor 2 (Nrf2) and the aryl hydrocarbon receptor (AhR) transcription factors. MATERIALS AND METHODS: Rhazya stricta leaves were extracted using ethanol, the strong basic alkaloid fraction (AF) was isolated according to a bioassay-guided fractionation and its mass spectrum was used as a fingerprint for its identity. The effect of increasing concentrations of AF on Nqo1 was tested in murine hepatoma Hepa 1c1c7 and human HepG2 cells. The role of Nrf2-dependent mechanism was tested by using Nrf2-dependent luciferase assay and by determining the Nrf2 nuclear accumulation in Hepa 1c1c7 cells. The role of AhR dependent mechanism was assessed by using an AhR-deficient version of murine hepatoma c12 cells. RESULTS: AF significantly induced the Nqo1 at mRNA, protein and catalytic activity levels in murine hepatoma Hepa 1c1c7 cells. Moreover, the induction of Nqo1 by AF was completely abolished by using the transcriptional inhibitor, actinomycin D, implying a role of transcriptional regulation. In addition, the role of Nrf2 signaling pathway was confirmed by the induction of Nrf2-dependent luciferase activity and the induced Nrf2 nuclear accumulation in Hepa 1c1c7 cells. Interestingly, AF induced Nqo1 at mRNA and catalytic activity in c12 and HepG2 cells. Finally, the AF induced the Nrf2-dependent luciferase activity in HepG2 cells, confirming the role of Nrf2 in its regulation. CONCLUSIONS: The present study presents the first evidence that Rhazya stricta and its active strongly basic alkaloid fraction induce the chemopreventative enzyme, Nqo1 through Nrf2-dependent mechanism. PMID- 23026307 TI - Antimicrobial assays of three native British plants used in Anglo-Saxon medicine for wound healing formulations in 10th century England. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Three important Anglo-Saxon medical texts from the 10th century contain herbal formulations for over 250 plant species, many of which have yet to be evaluated for their phytochemical and/or pharmacological properties. In this study, three native British plants were selected to determine antimicrobial activity relevant to treating bacterial infections and wounds. MATERIALS AND METHODS: Several preparations of Agrimonia eupatoria L., Arctium minus (Hill) Bernh. and Potentilla reptans L. were screened for antimicrobial activity against selected Gram-positive and Gram-negative bacteria of relevance in wounds using a 96 well plate microdilution method (200, 40 and 8MUg/mL). Minimum inhibitory concentration (MIC) values were determined for the most potent extracts from 2 to 0.004mg/mL and HPLC chromatograms examined by multivariate analysis. Principle components analysis (PCA) was used to identify chemical differences between antimicrobial activity of the crude extracts. RESULTS: The HPLC-PCA score plots attributed HPLC peaks to the antimicrobial activity with all three plants inhibiting growth of Gram-positive Staphylococcus aureus by >50% in four or more extracts. The first two principal components (PC) represented 87% of the dataset variance. The P. reptans 75% ethanol root extract exhibited the greatest range of activity with MIC(50) at 31.25MUg/mL to a total MIC that was also the minimum bactericidal concentration (MBC) at 1mg/mL. Additionally, the root of P. reptans, inhibited growth of Gram-negative bacteria with the 75% ethanol extract having a MIC(50) at 1mg/mL against Pseudomonas aeruginosa and the decoction a MIC(50) at 3.9MUg/mL against Escherichia coli. CONCLUSIONS: The results indicate a moderate antimicrobial activity against common wound pathogens for P. reptans suggesting it may well have been effective for treating wound and bacterial infections. Anglo-Saxon literary heritage may provide a credible basis for researching new antimicrobial formulations. Our approach encompassing advanced analytical technologies and chemometric models paves the way for systematic investigation of Anglo-Saxon medical literature for further therapeutic indications to uncover knowledge of native British plants, some of which are currently lost to modern Western herbal medicine. PMID- 23026306 TI - Identification and evaluation of anti hepatitis C virus phytochemicals from Eclipta alba. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Eclipta alba, traditionally known as bhringraj, has been used in Ayurvedic medicine for more than 1000 years in India. It is used for the treatment of infective hepatitis, liver cirrhosis, liver enlargement and other ailments of liver and gall bladder in India. The aim of this study was to evaluate anti-hepatitis C virus activity present in the Eclipta alba extract, perform bioassay based fractionation and identify anti-HCV phytochemicals from the active fractions. MATERIALS AND METHODS: Identification of active compounds was performed by bio-activity guided fractionation approach. Active isolates were separated by the combination of silica gel chromatography and preparative scale reverse phase HPLC. Eclipta alba extract and its isolates were examined for their ability to inhibit HCV replicase (HCV NS5B) activity in vitro and HCV replication in a cell culture system carrying replicating HCV subgenomic RNA replicon. The purified isolates were also examined for their binding affinity to HCV replicase by fluorescence quenching and their cytotoxicity by MTT assay. RESULTS: Eclipta alba extract strongly inhibited RNA dependent RNA polymerase (RdRp) activity of HCV replicase in vitro. In cell culture system, it effectively inhibited HCV replication which resulted in reduced HCV RNA titer and translation level of viral proteins. Bioassay-based fractionations of the extracts and purification of anti-HCV phytochemicals present in the active fractions have identified three compounds, wedelolactone, luteolin, and apigenin. These compounds exhibited dose dependent inhibition of HCV replicase in vitro, and anti-HCV replication activity in the cell culture system CONCLUSION: Eclipta alba extract and phytochemicals isolated from active fractions display anti-HCV activity in vitro and in cell culture system. The standardized Eclipta alba extract or its isolates can be used as an effective alternative and complementary treatment against HCV. PMID- 23026308 TI - Herb-drug pharmacokinetic interaction between radix astragali and pioglitazone in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Radix astragali (RA) was the most frequently used traditional Chinese medicine (TCM) according to the statistics on 52 anti diabetic formulas recorded in New National Traditional Chinese Medicine; it was employed in 34 out of the 52 formulas. The aim of this study was to elucidate potential pharmacokinetic interaction between RA and pioglitazone, and to provide guidance for clinical medicine safety. MATERIALS AND METHODS: A specific and rapid UPLC-MS/MS method was established to quantify pioglitazone in rat plasma. Then healthy and type 2 diabetes mellitus (T2DM) rats were each divided into control and RA decoction (RAD) administration groups-healthy, healthy-RAD, T2DM, T2DM-RAD; pharmacokinetics of pioglitazone was carried out after RAD was administrated to rats for 7 days. RESULTS: The established UPLC-MS/MS method was rapid, specific, and precise. Between healthy and healthy-RAD groups, half-life (T(1/2)), area under the curve (AUC (0-t)), Vz/F, and Cl/F showed mild yet statistically significant differences; no significant difference for any above parameter was detected between T2DM and T2DM-RAD groups. CONCLUSION: RAD co administration did not affect the pharmacokinetics of pioglitazone especially in diabetic groups; RA and pioglitazone might be feasible herb-drug co effectiveness. PMID- 23026309 TI - Partial acceptor photobleaching-based quantitative FRET method completely overcoming emission spectral crosstalks. AB - Based on the quantitative fluorescence resonance energy transfer (FRET) method named PbFRET we reported recently, we herein developed a partial acceptor photobleaching-based quantitative FRET algorithm named B-PbFRET method. B-PbFRET overcomes not only the acceptor excitation crosstalk and donor emission spectral crosstalk but also the acceptor emission spectral crosstalk that harasses previous methods including fluorescence lifetime (FLIM), fluorescence recovery of donor after acceptor photobleaching, and acceptor sensitized emission (SE)-based methods. B-PbFRET method is implemented by simultaneously measuring the fluorescence intensity of both donor and acceptor channels at donor excitation before and after partial acceptor photobleaching, and it can directly measure the FRET efficiency (E) without any verified references. Based on the theoretical analysis of B-PbFRET, we also developed a more straightforward correction method named C-PbFRET to obtain the absolute E from the value measured by PbFRET for a given donor-acceptor pair. We validated both B-PbFRET and C-PbFRET methods by measuring the E of two linked constructs, 18AA and SCAT3 proteins, in single living cells, and our data demonstrated that both B-PbFRET and C-PbFRET methods can directly measure the absolute E of the linked constructs inside living cells under different degrees of acceptor emission spectral crosstalk. PMID- 23026310 TI - Danshensu is the major marker for the antioxidant and vasorelaxation effects of Danshen (Salvia miltiorrhiza) water-extracts produced by different heat water extractions. AB - Some of the major components of Danshen (Salvia miltiorrhiza), a widely used Chinese herbal medicine rich in phenolic acids, are thermosensitive and may degrade to other phenolic acids during extractions with heating. The chemical profiles of Danshen water-extract may vary with different heat water extraction at different temperatures, affecting the composition and bioactivity of the extracts. In this study, six water-extracts of Danshen obtained from heat reflux water extraction and microwave-assisted extraction with water (MAE-W) at different temperatures were tested for their composition and pharmacological effects. Among these extracts, the third-round MAE-W (100 degrees C) extract had the highest phenolic acids and tanshinones contents, with the strongest antioxidant activity in 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay and ferric reducing/antioxidant potential (FRAP) assay. This extract also showed the strongest inhibitory effects on 2,2'-azobis-2-amidinopropane (AAPH) induced hemolysis in human red blood cells, hydrogen peroxide-induced apoptosis in rat heart H9c2 cells and the highest relaxation effects on rat basilar artery. The antioxidant effects of Danshen water-extracts linearly correlated to their relaxation effects (r=0.895-0.977). Through multiple linear regression analysis, danshensu was found to be the most significant marker in the antioxidant and vasodilation effects of Danshen water-extract, while tanshinone IIA as the marker on hydrogen peroxide-induced apoptosis in rat heart H9c2 cells. Danshensu is, therefore, a useful marker for the quality control of Danshen water-extracts in antioxidant and vasodilation, while tanshinone IIA for anti-apoptotic potential of different extracts. PMID- 23026311 TI - High endogenous adenosine plasma concentration is associated with atrial fibrillation during cardiac surgery with cardiopulmonary bypass. PMID- 23026312 TI - HISH-SIMS analysis of bacterial uptake of algal-derived carbon in the Rio de la Plata estuary. AB - One of the main goals of microbial ecologists is to assess the contribution of distinct bacterial groups to biogeochemical processes, e.g. carbon cycling. Until very recently, it was not possible to quantify the uptake of a given compound at single cell level. The advent of nano-scale secondary-ion mass spectrometry (nanoSIMS), and its combination with halogen in situ hybridization (HISH) opened up this possibility. Despite its power, difficulties in cell identification during analysis of environmental samples might render this approach challenging for certain applications. A pilot study, designed to quantify the incorporation of phytoplankton-derived carbon by the main clades of heterotrophic aquatic bacteria (i.e. Alphaproteobacteria, Gammaproteobacteria, Bacteroidetes), is used to exemplify and suggest potential solutions to these technical difficulties. The results obtained indicate that the main aquatic bacterial clades quantitatively differ in the incorporation of algae-derived organic matter. From the methodological point of view, they highlight the importance of the concentration of the target cells, which needs to be sufficient to allow for a rapid mapping under the nanoSIMS. Moreover, when working with highly productive waters, organic and inorganic particles pose a serious problem for cell recognition based on HISH SIMS. In this work several technical suggestions are presented to minimize the above mentioned difficulties, including alternatives to improve the halogen labeling of the cells and proposing the use of a combination of FISH and HISH along with a mapping system. This approach considerably enhances the reliability of cell identification and the speed of the subsequent nanoSIMS analysis in such complex samples. PMID- 23026313 TI - Fast amplitude modulation detector for scanning force microscopy with high Q factor. AB - Amplitude modulation (AM) scanning force microscopy (SFM) is superior to frequency modulation SFM in simplicity, sensitivity, and stability, but is still replaced by the latter because it is too slow when the Q factor is high (bandwidth < 0.5 Hz for Q > 50,000 and resonant frequency omega0 < 50 kHz). We report a close-loop AM detector that has an 18 Hz bandwidth, better than 1 mHz frequency resolution and excellent response to step frequency changes even for Q ~ 60,000 and omega0 ~ 32 kHz. Its superiority is well shown by the comparison of magnetic force microscope images taken under the new and old AM detection modes with the tip and scan area (videotape sample) being unchanged. Also important is that shifting the driving frequency from near the resonance peak to further away from the peak does not decrease the frequency resolution as much as we expect (but can increase the response speed). PMID- 23026314 TI - Anticipatory action planning increases from 3 to 10 years of age in typically developing children. AB - The primary aim of this study was to assess the development of action planning in a group of typically developing children aged 3 to 10 years (N=351). The second aim was to assess reliability of the action planning task and to relate the results of the action planning task to results of validated upper limb motor performance tests. Participants performed an action planning task in which they needed to grasp an object (a wooden play sword) and place it into a tight-fitting hole. Our main dependent variable was the grip type that participants used; that is, we measured whether initial grip was adapted in such a way that children reached a comfortable posture at the end of the action (the end-state comfort effect). Older children planned their actions more often in line with the end state comfort effect compared with younger children. Test-retest and interrater reliability of the action planning task were good, with intraclass correlation coefficients (ICCs) of .90 and .95, respectively. We compared the action planning task with manual dexterity tests in a subset of participants (n=197). We found a marginal relation with the manual dexterity tests, indicating that the action planning task measures different processes. In sum, our study showed that action planning increases from 3 to 10 years of age and that the experimental task we used is reliable in assessing anticipatory planning. Therefore, it may be used as a reliable additional test to investigate the degree to which motor behavior is affected at the cognitive level of anticipatory planning. PMID- 23026316 TI - Kinetics of switch grass pellet thermal decomposition under inert and oxidizing atmospheres. AB - Grass pellets are a renewable resource that have energy content similar to that of wood. However, the higher ash and chlorine content affects combustion. Thermal degradation analysis of a fuel is useful in developing effective combustion. Thermogravimetric analysis (TGA) of the thermal degradation of grass pellets under inert (nitrogen) and oxidizing (air) atmospheres was conducted. Non isothermal conditions were employed with 4 different heating rates. Kinetic parameters (activation energy and pre-exponential factors) were estimated using the iso-conversional method. Both pyrolysis and oxidative atmospheric thermal degradation exhibited two major loss process: volatilization of cellulose, hemicelluloses and lignin and burning or slow oxidation of the residual char. The activation energy and pre-exponential factors were high for the oxidizing environment. During pyrolysis, major decomposition occurred with 40% to 75% conversion of the mass to gas with an activation energy of 314 kJ/mol. In air the decomposition occurred with 30% to 55% conversion with an activation energy of 556 kJ/mol. There was a substantial effect of heating rate on mass loss and mass loss rate. The TG shifted to higher temperature ranges on increasing the heating rate. In both pyrolyzing and oxidizing conditions, average combustion and devolatilization rates increased. Enhanced combustion takes place with higher activation energy in oxidizing atmosphere compared to the inert atmosphere due to presence of air. PMID- 23026317 TI - Experimental and modeling study on nitric oxide removal in a biotrickling filter using Chelatococcus daeguensis under thermophilic condition. AB - In this study, the development of a thermophilic biotrickling filter (BTF) system to inoculate a newly isolated strain of Chelatococcus daeguensis TAD1 for the effective treatment of nitric oxide (NO) is described. It was successfully started up in 35days and effectively removed NO from the oxygen contained simulated gas at 50 degrees C. A mathematical model based on the mass transfer in gas-biofilm interface and chemical oxidation in gas phase was developed. Steady state experimental data under different inlet NO concentration and empty bed retention time (EBRT) condition were used to verify the proposed model. The model can well reproduce the experimental results and the sensitivity analysis demonstrates that the model is not dependent on the accuracy of the parameters excessively. PMID- 23026318 TI - Effect of ammonia oxidizing bacteria (AOB) kinetics on bioaugmentation. AB - Bioaugmentation with ammonium oxidizing bacteria (AOB) was tested for 620d. A seeding reactor (R1), two seeded reactors (R2 at 21 degrees C; R3 at 15 degrees C) and an unseeded-control reactor (R4 at 21 degrees C) were operated in parallel (2.4= 2 SPECT examinations in 2005-2007. PE was defined as minor (<20% perfusion defect on SPECT, n=86), medium (20-50% perfusion defect on SPECT, n=99), or major (>50% perfusion defect on SPECT, n=42). RESULTS: At second V/P SPECT examination, complete resolution of perfusion defects had occurred in 45 (52%) patients with minor PE after 8.2 +/- 7.4 months, in 29 (29%) of patients with medium PE after 6.2 +/- 5.9 months, and in 2(5%) of patients with major PE after 6.5 +/- 0.7 months. During 47 +/- 24 months of follow up, 37(16 %) patients suffered recurrent PE. Of these 37, 34 (92%) showed residual perfusion defects at the second V/P SPECT examination. Recurrence of PE was also predicted by advanced age and female gender. However, in multivariate regression analysis, recurrence was only predicted by age (p=0.0013) and residual perfusion defect on V/P SPECT (p=0.0039). CONCLUSION: In conclusion, complete resolution of PE was common in patients with minor PE, whereas residual perfusion defects were widespread in patients with medium and major PE. PE patients identified with persistent perfusion defects at follow-up SPECT have a high risk of PE recurrence. PMID- 23026381 TI - Occurrence and clinical significance of in-hospital acquired thrombocytopenia in patients undergoing transcatheter device closure for congenital heart defect. AB - BACKGROUND: Acquired thrombocytopenia in patients treated by percutaneous coronary intervention is associated with hemorrhagic complications and prolonged in-hospital stay. This study sought to study the prevalence of thrombocytopenia in patients who underwent transcatheter device closure for congenital heart defect (CHD) and its relationship with clinical consequences. METHODS AND RESULTS: 299 patients with CHD who underwent successful transcatheter closure were prospectively studied. Thrombocytopenia developed in 135 (45.2%) patients; n=100 (33.4%) mild (100-150 * 10(9)/L), n=25 (8.4%) moderate (50-100 * 10(9)/L), and n=10 (3.3%) severe (P<50 * 10(9)/L), respectively. From baseline, platelet counts tended to decrease on the 1st day after the procedure and reached a nadir level on the 3rd day, then gradually recovered to baseline values on the 9th day. By multivariate analysis, severe thrombocytopenia developed more frequently in patients who had larger device size (OR 2.755, P=0.000), and residue shunt (OR 2.069, P=0.009). Patients who developed thrombocytopenia, compared with those who did not, had higher in-hospital rates of hemorrhagic complications (11.9% vs. 3.0%, P<0.003), greater requirement for elevating platelet medical treatment or platelet transfusion (4.4% vs. 0, P=0.021), longer hospital stay (median 14 vs. 9 days, P<0.001). Severe thrombocytopenia was an independent predictor of hemorrhagic complications (hazard ratio 8.083, 95% CI 4.021-16.237, P=0.001). Compare with patients without thrombocytopenia, bleeding events were markedly increased (11.9% vs. 3.0%, P=0.003) in those with thrombocytopenia during hospitalization. CONCLUSION: The size of occluder and other risk factors are independently associated with thrombocytopenia. Thrombocytopenia provides prognostic information, related to increased bleeding events. PMID- 23026382 TI - Radiation treatment of patients with primary pediatric malignancies: risk of developing thyroid cancer as a secondary malignancy. AB - BACKGROUND: The aim of this study was to estimate the risk of thyroid cancer as a secondary malignancy after radiation treatment of primary pediatric malignancies. METHODS: Using the Surveillance, Epidemiology, and End Results database, we identified 7,670 patients from 1973 to 1988 with primary pediatric malignancies. The relative risk of thyroid cancer in irradiated patients was calculated using the Poisson regression model, and the Cox proportional hazards regression model was used for survival rates. RESULTS: The relative risk (RR) of thyroid cancer for children who received radiation was 2.22 (95% confidence interval [CI], 1.15 4.29). It was highest for central nervous system cancer (RR = 4.47) and lowest for those with leukemia (RR = 1.75). Mortality was significantly reduced for patients who received radiation as children; the hazard ratio was .80 (95% CI, .75-.86). CONCLUSIONS: Radiation for pediatric malignancies increases the risk of developing thyroid cancer as a secondary malignancy; however, these patients had localized disease and lower 20-year mortality. PMID- 23026383 TI - Evaluation of changes in breast architecture after preoperative chemotherapy for breast cancer. AB - BACKGROUND: Although use of preoperative chemotherapy for breast cancer is increasing, resultant changes in breast architecture have not been described. The purpose of this study was to examine breast architecture changes in response to chemotherapy by the placement of 4 peripheral clips. METHODS: In a prospective case-series of breast cancer patients selected to undergo preoperative chemotherapy, 4 clips were placed peripherally to each mass using sonographic guidance. Mammograms documented tumor size and clip locations both before chemotherapy and after chemotherapy. Percentage reduction in area was calculated based on the tumor dimensions and distances between clips. RESULTS: In 16 participants, 87.5% of lesions had a significant response to chemotherapy. Changes in clip measurements varied widely from significant reduction to significant increase and did not correlate with changes in tumor size. The Pearson correlation coefficient comparing changes in tumor size and clip measurements was .036 (P = .895). CONCLUSIONS: There was no correlation between reduction in tumor size and change in clip measurements. Further research should be conducted using noncompression breast imaging modalities to eliminate possible distortion caused by mammographic compression. PMID- 23026384 TI - Support for blood alcohol screening in pediatric trauma. AB - BACKGROUND: Alcohol intoxication in pediatric trauma is underappreciated. The aim of this study was to characterize alcohol screening rates in pediatric trauma. METHODS: The Los Angeles County Trauma System Database was queried for all patients aged <= 18 years who required admission between 2003 and 2008. Patients were compared by age and gender. RESULTS: A total of 18,598 patients met the inclusion criteria; 4,899 (26.3%) underwent blood alcohol screening, and 2,797 (57.1%) of those screened positive. Screening increased with age (3.3% for 0-9 years, 15.1% for 10-14 years, and 45.4% for 15-18 years; P < .01), as did alcohol intoxication (1.9% for 0-9 years, 5.8% 10-14 years, and 27.3% for 15-18 years; P < .01). Male gender predicted higher mortality in those aged 15 to 18 years (adjusted odds ratio, 1.7; P < .01), while alcohol intoxication did not (adjusted odds ratio, .97; P = .84). CONCLUSIONS: Alcohol intoxication is common in adolescent trauma patients. Screening is encouraged for pediatric trauma patients aged >=10 years who require admission. PMID- 23026385 TI - Docking investigation and binding interaction of benzimidazole derivative with bovine serum albumin. AB - (1)H NMR, (13)C NMR and Mass spectral analysis have been made for 1-(4 fluorobenzyl)-2-(4-fluorophenyl)-1H-benzo[d]imidazole (FBFPB). The mutual interaction of FBFPB with bovine serum albumin (BSA) was investigated using absorption, fluorescence and synchronous fluorescence spectral studies. The binding distance has been determined based on the theory of Forester's non radiation energy transfer (FRET). The calculated quenching constants (K(sv)) were 2.84 * 10(4), 2.55 * 10(4) and 2.37 * 10(4) at 301, 310 and 318 K respectively. The Stern-Volmer quenching constant (K(sv)), binding site number (n), apparent binding constant (K(A)) and corresponding thermodynamic parameters (DeltaG, DeltaH and DeltaS) were calculated. The interaction between FBFPB and BSA have discussed by molecular docking technique. PMID- 23026386 TI - Advances in the knowledge of light emission by firefly luciferin and oxyluciferin. AB - Firefly luciferase is the most important and studied bioluminescence system. Due to very interesting characteristics, this system has gained numerous biomedical, pharmaceutical and bioanalytical applications, among others. In order to improve the use of this system, various researchers have tried to understand experimentally the colour of bioluminescence, and to create ways of tuning the colour emitted. The objective of this manuscript is to review the experimental studies of firefly luciferin and oxyluciferin, and related analogues, fluorescence and bioluminescence. PMID- 23026387 TI - Contribution of reactive oxygen species to UV-B-induced damage in bacteria. AB - The present work aimed to identify the reactive oxygen species (ROS) produced during UV-B exposure and their biochemical targets, in a set of bacterial isolates displaying different UV susceptibilities. For that, specific exogenous ROS scavengers (catalase/CAT, superoxide dismutase/SOD, sodium azide and mannitol) were used. Biological effects were assessed from total bacterial number, colony counts and heterotrophic activity (glucose uptake and respiration). DNA strand breakage, ROS generation, oxidative damage to proteins and lipids were used as markers of oxidative stress. Sodium azide conferred a statistically significant protection in terms of lipid oxidation and cell survival, suggesting that singlet oxygen might play an important role in UV-B induced cell inactivation. Mannitol exerted a significant protection against DNA strand breakage and protein carbonylation, assigning hydroxyl radicals to DNA and protein damage. The addition of exogenous CAT and SOD significantly protected the capacity for glucose uptake and respiration, suggesting that superoxide and H(2)O(2) are involved in the impairment of activity during UV-B exposure. The observation that amendment with ROS scavengers can sometimes also exert a pro oxidant effect suggests that the intracellular oxidant status of the cell ultimately determines the efficiency of antioxidant defenses. PMID- 23026388 TI - Etiology of pulmonary complications of human immunodeficiency virus-1-infected patients in Taiwan in the era of combination antiretroviral therapy: a prospective observational study. AB - OBJECTIVES: We aimed to investigate the etiology of pulmonary complications of human immunodeficiency virus-(HIV)-1-infected patients in Taiwan in the era of combination antiretroviral therapy (cART). METHODS: From July 2009 to March 2012, a prospective observational study was conducted to identify the etiology of pulmonary complications in HIV-1-infected patients who sought HIV care at a university hospital in Taiwan. A stepwise diagnostic approach was adopted, which included radiography, serology, microbiology, bronchoscopy or video-assisted thoracoscopic surgery, and polymerase chain reaction assays for cytomegalovirus and Pneumocystis jirovecii. RESULTS: During the study period, a total of 203 episodes of pulmonary complications that occurred in 190 patients with a mean CD4 count of 123 * 10(6) cells/L were analyzed. Thirty-eight episodes (18.7%) occurred in patients with a CD4 count >200 * 10(6) cells/L, 71 (35.0%) between 50 and 200 * 10(6) cells/L, and 94 (46.3%) <50 * 10(6) cells/L. Pneumocystis pneumonia accounted for more than half of the complications in patients with a CD4 count <200 * 10(6) cells/L. In patients with a CD4 count >200 * 10(6) cells/L, the etiology of pulmonary complications was diverse, with bacterial infections (47.4%) being the most common, followed by tuberculosis (15.8%) and lung edema (13.2%). Pneumocystosis and cytomegalovirus pneumonitis were seen mostly or exclusively in patients with a CD4 count <200 * 10(6) cells/L and were the leading causes of interstitial pneumonitis. On the other hand, empyema, legionellosis, and lung edema were more commonly seen in patients with a CD4 count >200 * 10(6) cells/L. CONCLUSIONS: The etiology of pulmonary complications in HIV-1-infected patients was diverse and varied with the categories of CD4 counts. Pneumocystosis remained the leading cause of pulmonary complications in patients with lower CD4 counts in Taiwan in the cART era. PMID- 23026389 TI - A steep learning curve: decoding epigenetic influence on behavior and mental health. PMID- 23026390 TI - Derivatives of the cationic plant alkaloids berberine and palmatine amplify protonophorous activity of fatty acids in model membranes and mitochondria. AB - Previously it has been shown by our group that berberine and palmatine, penetrating cations of plant origin, when conjugated with plastoquinone (SkQBerb and SkQPalm), can accumulate in isolated mitochondria or in mitochondria of living cells and effectively protect them from oxidative damage. In the present work, we demonstrate that SkQBerb, SkQPalm, and their analogs lacking the plastoquinone moiety (C10Berb and C10Palm) operate as mitochondria-targeted compounds facilitating protonophorous effect of free fatty acids. These compounds induce proton transport mediated by small concentrations of added fatty acids both in planar and liposomal model lipid membranes. In mitochondria, such an effect can be carried out by endogenous fatty acids and the adenine nucleotide translocase. PMID- 23026393 TI - Medication errors in residential aged care facilities: a distributed cognition analysis of the information exchange process. AB - BACKGROUND: Medication safety is a pressing concern for residential aged care facilities (RACFs). Retrospective studies in RACF settings identify inadequate communication between RACFs, doctors, hospitals and community pharmacies as the major cause of medication errors. Existing literature offers limited insight about the gaps in the existing information exchange process that may lead to medication errors. The aim of this research was to explicate the cognitive distribution that underlies RACF medication ordering and delivery to identify gaps in medication-related information exchange which lead to medication errors in RACFs. METHODS: The study was undertaken in three RACFs in Sydney, Australia. Data were generated through ethnographic field work over a period of five months (May-September 2011). Triangulated analysis of data primarily focused on examining the transformation and exchange of information between different media across the process. RESULTS: The findings of this study highlight the extensive scope and intense nature of information exchange in RACF medication ordering and delivery. Rather than attributing error to individual care providers, the explication of distributed cognition processes enabled the identification of gaps in three information exchange dimensions which potentially contribute to the occurrence of medication errors namely: (1) design of medication charts which complicates order processing and record keeping (2) lack of coordination mechanisms between participants which results in misalignment of local practices (3) reliance on restricted communication bandwidth channels mainly telephone and fax which complicates the information processing requirements. The study demonstrates how the identification of these gaps enhances understanding of medication errors in RACFs. CONCLUSIONS: Application of the theoretical lens of distributed cognition can assist in enhancing our understanding of medication errors in RACFs through identification of gaps in information exchange. Understanding the dynamics of the cognitive process can inform the design of interventions to manage errors and improve residents' safety. PMID- 23026394 TI - The impact of recurrent non-muscle-invasive bladder cancer on progression. PMID- 23026395 TI - The changing face of renal cell carcinoma: the impact of systematic genetic sequencing on our understanding of this tumor's biology. PMID- 23026396 TI - Activation of calcineurin is mainly responsible for the calcium sensitivity of gene deletion mutations in the genome of budding yeast. AB - Here we have identified 120 gene deletion mutants that are sensitive to 0.4M calcium in Saccharomyces cerevisiae. Twenty-seven of these mutants are of genes involved in the vacuolar protein sorting pathway, including those encoding the seven components of the ESCRT complexes, and ten of them encode the components and assembly factors of the vacuolar H(+)-ATPase. Both Mediator and Paf1 complexes modulating the activity of the general transcription machinery are involved in the calcium sensitivity of yeast cells. Most of these mutants show elevated intracellular calcium contents in response to calcium stress. The calcium sensitivity of 106 mutants can be completely suppressed by 10mM Mg(2+), 56 of which can also be suppressed by the inhibitor of calcineurin, cyclosporine A. Therefore, the calcium sensitivity of nearly a half of these 120 mutations is at least partially due to the activation of calcineurin and can be modulated by magnesium ion. PMID- 23026398 TI - 3D surface imaging for monitoring intrafraction motion in frameless stereotactic body radiotherapy of lung cancer. AB - PURPOSE: To investigate the accuracy of surface imaging for monitoring intrafraction motion purposes in frameless stereotactic body radiotherapy (SBRT) of lung cancer by comparison with cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Thirty-six patients (18 males, 18 females) were included. During each fraction, three CBCT scans were acquired; CBCT1: before treatment, CBCT2: after correction for tumor misalignment, and CBCT3: after treatment. Intrafraction motion was derived by registering CBCT2 and CBCT3 to the mid ventilation planning CT scan. Surfaces were captured concurrently with CBCT acquisitions. Retrospectively, for each set of surfaces, an average surface was created: Surface1, Surface2, and Surface3. Subsequently, Surface3 was registered to Surface2 to assess intrafraction motion. For the differences between CBCT- and surface-imaging-derived 3D intrafraction motions, group mean, systematic error, random error and limits of agreement (LOA) were calculated. RESULTS: Group mean, systematic and random errors were smaller for females than for males: 0.4 vs. 1.3, 1.3 vs. 3.1, and 1.7 vs. 3.3 mm respectively. For female patients deviations between CBCT-tumor- and 3D-surface-imaging-derived intrafraction motions were between -3.3 and 4.3 mm (95% LOA). For male patients these were substantially larger: -5.9-9.5mm. CONCLUSION: Surface imaging is a promising technology for monitoring intrafraction motion purposes in SBRT for female patients. PMID- 23026397 TI - GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders. AB - Genome wide association studies in human autoimmune disorders have provided a long list of alleles with rather modest degrees of risk. A large fraction of these associations are probably owing to either quantitative differences in gene expression or amino acid changes that regulate quantitative aspects of the immune response. While functional studies are still lacking for most of these associations, we present examples of autoimmune disease risk alleles that influence quantitative changes in lymphocyte activation, cytokine signaling and dendritic cell function. The analysis of immune quantitative traits associated with autoimmune loci is clearly going to be an important component of understanding the pathogenesis of autoimmunity. This will require both new and more efficient ways of characterizing the normal immune system, as well as large population resources in which genotype-phenotype correlations can be convincingly demonstrated. Future development of new therapies will depend on understanding the mechanistic underpinnings of immune regulation by these new risk loci. PMID- 23026399 TI - Detection of Merkel cell polyomavirus in chronic lymphocytic leukemia T-cells. AB - Chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) is the most common B cell leukemia/lymphoma, effecting >15,000 patients/year. There has been a proposed limited antigenic etiology, at least in some cases, of CLL/SLL based upon immunoglobulin heavy chain stereotypy found across unrelated cases, suggesting viral source may provide such antigenic stimulation. With an established epidemiological link between CLL/SLL and Merkel cell carcinoma (MCC), there has been some interest in investigating a possible leukemogenic role of Merkel cell polyomavirus (MCPyV), which is found in 80% of MCC cases. Recent studies have shown that MCPyV is present in lymphocytes in a small percentage of CLL/SLL cases, but the specific tropism for lymphocytes has not been well established. In this study, we used quantitative PCR to investigate the presence of MCPyV in fluorescence activated cell sorted purified B- and T-cells from 23 CLL/SLL cases. Three of 23 cases (13%) had detectable MCPyV in T-cells, and none of the cases had detectable MCPyV in B-cells. These findings suggest that MCPyV may have tropism for T-cells in addition to previously reported neoplastic B cells. PMID- 23026400 TI - Early gene expression differences in inbred mouse strains with susceptibility to pulmonary adenomas. AB - Lung cancer is the most common cause of cancer-related deaths in both men and women, and effective preventatives are rare due to the difficulty of early detection. Specific gene expression signatures have been identified in individuals that already developed lung cancer. To identify if gene expression differences could be detected in individuals before the onset of the disease, we obtained lung tissues for microarray analysis from young, healthy mice of 9 inbred strains with known differences in their susceptibility to spontaneous pulmonary adenomas when aged. We found that the most common differentially expressed genes among all possible 36 strain comparisons showed significant associations with cancer- and inflammation-related processes. Significant expression differences between susceptible and resistant strains were detected for Aldh3a1, Cxcr1 and 7, Dpt, and Nptx1-genes with known cancer-related functions, and Cd209, Cxcr1 and 7, and Plag2g1b-genes with known inflammatory related functions. Whereas Aldh3a1, Cd209, Dpt, and Pla2g1b had increased expression, Cxcr1 and 7, and Nptx1 had decreased expression in strains susceptible to pulmonary adenomas. Thus, our study shows that expression differences between susceptible and resistant strains can be detected in young and healthy mice without manifestation of pulmonary adenomas and, thus, may provide an opportunity of early detection. Finally, the identified genes have previously been reported for human non-small cell lung cancer suggesting that molecular pathways may be shared between these two cancer types. PMID- 23026401 TI - The public health and policy implications of epigenetics and pediatric health research. PMID- 23026402 TI - [The States General to a cardiac plan]. PMID- 23026404 TI - Three-dimensional chemistry of multiphase nanomaterials by energy-filtered transmission electron microscopy tomography. AB - A three-dimensional (3D) study of multiphase nanostructures by chemically selective electron tomography combining tomographic approach and energy-filtered imaging is reported. The implementation of this technique at the nanometer scale requires careful procedures for data acquisition, computing, and analysis. Based on the performances of modern transmission electron microscopy equipment and on developments in data processing, electron tomography in the energy-filtered imaging mode is shown to be a very appropriate analysis tool to provide 3D chemical maps at the nanoscale. Two examples highlight the usefulness of analytical electron tomography to investigate inhomogeneous 3D nanostructures, such as multiphase specimens or core-shell nanoparticles. The capability of discerning in a silica-alumina porous particle the two different components is illustrated. A quantitative analysis in the whole specimen and toward the pore surface is reported. This tool is shown to open new perspectives in catalysis by providing a way to characterize precisely 3D nanostructures from a chemical point of view. PMID- 23026403 TI - Cardiac syndrome X and microvascular coronary dysfunction. AB - Women with cardiac chest pain indicated by signs and symptoms of myocardial ischemia in the absence of obstructive CAD are often labelled as cardiac syndrome X (CSX). A subset of patients with CSX may have symptoms of ischemia due to microvascular dysfunction. Angina due to microvascular coronary dysfunction (MCD) is an etiologic mechanism in women with vascular dysfunction. New data provide improve understanding of coronary vascular dysfunction and resultant myocardial ischemia that characterize MCD among patients with cardiac syndrome X. MCD has an adverse prognosis and health care cost expenditure comparable to obstructive CAD. The high prevalence of this condition, particularly in women, adverse prognosis and substantial health care costs, coupled with a lack of evidence regarding treatment strategies, places MCD as a research priority area. PMID- 23026405 TI - Autophagy regulates trans fatty acid-mediated apoptosis in primary cardiac myofibroblasts. AB - Trans fats are not a homogeneous group of molecules and less is known about the cellular effects of individual members of the group. Vaccenic acid (VA) and elaidic acid (EA) are the predominant trans monoenes in ruminant fats and vegetable oil, respectively. Here, we investigated the mechanism of cell death induced by VA and EA on primary rat ventricular myofibroblasts (rVF). The MTT assay demonstrated that both VA and EA (200MUM, 0-72 h) reduced cell viability in rVF (P<0.001). The FACS assay confirmed that both VA and EA induced apoptosis in rVF, and this was concomitant with elevation in cleaved caspase-9, -3 and -7, but not caspase-8. VA and EA decreased the expression ratio of Bcl2:Bax, induced Bax translocation to mitochondria and decrease in mitochondrial membrane potential (Deltapsi). BAX and BAX/BAK silencing in mouse embryonic fibroblasts (MEF) inhibited VA and EA-induced cell death compared to the corresponding wild type cells. Transmission electron microscopy revealed that VA and EA also induced macroautophagosome formation in rVF, and immunoblot analysis confirmed the induction of several autophagy markers: LC3-beta lipidation, Atg5-12 accumulation, and increased beclin-1. Finally, deletion of autophagy genes, ATG3 and ATG5 significantly inhibited VA and EA-induced cell death (P<0.001). Our findings show for the first time that trans fat acid (TFA) induces simultaneous apoptosis and autophagy in rVF. Furthermore, TFA-induced autophagy is required for this pro-apoptotic effect. Further studies to address the effect of TFA on the heart may reveal significant translational value for prevention of TFA-linked heart disease. PMID- 23026406 TI - The effects of adenosine A2A receptor knockout on renal interstitial fibrosis in a mouse model of unilateral ureteral obstruction. AB - Adenosine A2A receptor (A2AR) plays an important regulatory role in the processes of inflammation and fibrosis. However, it is unknown whether A2AR can mediate renal interstitial fibrosis (RIF). To evaluate the effect of genetic A2AR knockout (KO) on the pathological progress of RIF, we applied a unilateral ureteral obstruction (UUO) model of RIF on A2AR KO mice and their wild-type (WT) littermates. Renal pathological assessment was performed at different post-UUO stages using hematoxylin and eosin (H&E) and Masson's trichrome staining as well as quantitative morphological analysis. Our data demonstrated that: (i) the extent of RIF was determined by the development of UUO in a time-dependent manner; (ii) A2AR KO exacerbated the pathological progress of RIF in mice at the early post-UUO stage, i.e. day 3 and day 7; (iii) the profibrotic effect of A2AR KO was prominent until the late post-UUO stage, i.e. day 14, at which RIF reached a similar severity level in A2AR KO and WT mice. Our findings revealed that A2AR KO significantly exacerbated the progression of UUO-induced RIF in mice, prominently at the initial stage. PMID- 23026407 TI - Reoperative coronary artery bypass surgery: avoiding repeat median sternotomy. AB - BACKGROUND: Mortality and morbidity in reoperative coronary artery surgery are considered to be higher than those for initial surgery. Contributing factors include cardiac injury and damage to patent grafts in repeat median sternotomy. To avoid these complications, reoperative cases were performed off pump to avoid repeat median sternotomy. METHODS: The study subjects were 79 patients who underwent reoperations while utilizing off-pump coronary artery bypass grafting to avoid the need for repeat median sternotomies. All operations were performed by the same surgeon in the period from January 1996 to December 2010. RESULTS: The mean duration from initial surgery to reoperation was 6 years and 5 months. Reported reasons for reoperation were de novo coronary lesion in 16 patients, graft failure in 33 patients, and de novo coronary lesion plus graft failure in 47 patients. All cases underwent surgery off pump. The approach was left anterior small thoracotomy (35 patients), transdiaphragmatic approach (21 patients), left posterolateral thoracotomy (9 patients), left anterior small thoracotomy plus transdiaphragmatic approach (9 patients), left posterolateral thoracotomy plus transdiaphragmatic approach (4 patients), and small median sternotomy plus left anterior small thoracotomy (1 patient). There were no deaths among the 79 patients in whom repeat median sternotomy was avoided, and all grafts were patent. CONCLUSIONS: Reoperative coronary artery surgery that avoids repeat median sternotomy can prevent cardiac injury and damage to patent grafts. Furthermore, it does not require blood transfusion. Thus, it is an effective method of reducing mortality and morbidity even in reoperative cases. PMID- 23026408 TI - Pattern of clues: evidence of distinct DNA methylation in newborns of smoking women. PMID- 23026409 TI - Osteoarthritis of the knee: why does exercise work? A qualitative study of the literature. AB - The effectiveness of exercise to reduce pain and improve functioning in osteoarthritis of the knee (OAk) is well substantiated. Underlying mechanisms are still under debate and better understanding of the pathways involved may contribute to more targeted treatment strategies. The present qualitative analysis of the literature aims to provide an overview of theoretical models that are put forward to explain the beneficial treatment effects of exercise in OAk. An inductive qualitative approach, based on the 'grounded theory' of Glaser and Straus, was used. Twenty-two studies emphasizing on exercise therapy for OAk, collected from three Cochrane reviews and nine guidelines of the Physiotherapy Evidence Database (PEDRO) published between 2000 and 2012, were included. The introduction and discussion parts of these papers were screened for explanations of exercise-induced benefits in OAk patients. Seventy-three key points were identified which were subdivided into 16 core theoretical concepts. Finally, 5 categories were formed: neuromuscular, peri-articular, intra-articular, psychosocial components, and general fitness and health. We referred to scientific evidence that was used in the included studies to describe and categorize the concepts. Future research on exercise in OAk should allow distinguishing the contribution of different potential pathways to the treatment effects. PMID- 23026410 TI - Improved outcome after spinal cord compression injury in mice treated with docosahexaenoic acid. AB - In this study we have characterised the locomotor recovery, and temporal profile of cell loss, in a novel thoracic compression spinal cord injury (SCI) in the mouse. We have also shown that treatment with docosahexaenoic acid (DHA) is neuroprotective in this model of SCI, strengthening the growing literature demonstrating that omega-3 polyunsaturated fatty acids are neuroprotective after SCI. Compression SCI in C57BL/6 mice was produced by placing a 10 g weight for 5 min onto a 2 mm * 1.5 mm platform applied to the dura at vertebral level T12. Mice partly recovered from complete hindlimb paralysis and by 28 days post surgery had plateaued at an average BMS locomotor score of 4.2, equivalent to weight support with plantar stepping. During the same period, neuronal loss at the epicentre increased from 26% of ventral horn neurons by day 1, to 68% by day 28. Delayed loss of oligodendrocytes was also seen (e.g. 84% by day 28 in the dorsal columns) and microglia/macrophage activation was maximal at 7 days. In contrast, axonal damage, judged by a decrease in the non-phosphorylated form of 200 kD neurofilament, was an early event, as the loss was seen by day 1 and did not change markedly over time. Mice that received an intravenous (i.v.) injection of 500 nmol/kg DHA 30 min after SCI, showed improved locomotor recovery and, at 28 day survival, reduced neuronal, oligodendrocyte and neurofilament loss, and reduced microglia/macrophage activation. For some of these indices of SCI, enrichment of the diet with 400 mg/kg/day DHA led to further improvement. However, dietary DHA supplementation, without the initial i.v. injection, was ineffective. PMID- 23026411 TI - Bone alterations in hepatitis C virus infected patients. AB - BACKGROUND AND AIMS: Most studies have shown that patients with chronic hepatitis C virus (HCV) infection are affected by osteoporosis. However, liver function impairment and deranged nutrition may both play a role in the bone alterations observed. In some works no osteoporosis was found, and some cases of osteosclerosis have been reported. The aim of the study is to assess bone alterations in treatment-naive, well-nourished HCV patients, in order to discern whether or not HCV infection causes osteoporosis. METHODS: Whole-body bone densitometry and assessment of T-score at lumbar spine and hip were performed to 40 patients and 40 age- and sex-matched controls, with a Lunar Prodigy Advance (General Electric, Piscataway, NJ, USA). All the patients underwent liver biopsy. Nutritional evaluation was performed by subjective nutritional assessment, body mass index (BMI), and densitometric assessment of total lean mass and total fat mass. Serum osteocalcin, osteoprotegerin, RANKL, PTH, crosslaps, vitamin D3, testosterone, IGF-1, and estradiol were determined. RESULTS: Patients did not show differences in total bone mineral density (BMD) or T-score with controls. On the contrary, about a third of them showed positive T scores. Patients showed lower IGF-1, vitamin D3 and testosterone, but higher telopeptide levels, and a trend to higher osteoprotegerin levels. Multivariate analyses disclosed that age, sex, and total lean mass were the only parameters independently related with BMD. CONCLUSIONS: Therefore, chronic HCV infection in well nourished patients with preserved liver function does not cause osteoporosis. PMID- 23026412 TI - Rapid and convenient detection of ascorbic acid using a fluorescent nitroxide switch. AB - Ascorbic acid is a small-molecule reductant with multiple functions in vivo. Reducing ascorbic acid intake leads to a lack of hydroxylation of prolines and lysines, causing a looser triple helix and resulting in scurvy. Ascorbic acid also acts as an antioxidant to prevent oxidative stress. Because ascorbic acid is related to disease states, rapid and convenient detection of ascorbic acid should be useful in diagnosis. Nitroxide is reduced to the corresponding hydroxylamine by ascorbic acid and a sensitive and novel approach to its detection employs covalent coupling of nitroxide with a fluorophore, leading to intramolecular quenching of fluorescence emission by electron-exchange interactions. Here, we developed a new fluorophore-nitroxide probe, Naph-DiPy nitroxide, for ascorbic acid. Naph-DiPy nitroxide rapidly reacted with ascorbic acid and showed fluorescence enhancement, but not in response to other reductants or reactive oxygen species. To confirm the practical usefulness of the fluorophore-nitroxide probe, we demonstrated the use of Naph-DiPy nitroxide for the measurement of ascorbic acid in the plasma of osteogenic disorder Shionogi rats when fed an ascorbic acid-deficient diet. The results suggest that this novel fluorophore nitroxide probe could sensitively and easily detect ascorbic acid and be useful as a tool for the diagnosis of disease states. PMID- 23026413 TI - A multilevel analytical approach for detection and visualization of intracellular NO production and nitrosation events using diaminofluoresceins. AB - Diaminofluoresceins are widely used probes for detection and intracellular localization of NO formation in cultured/isolated cells and intact tissues. The fluorinated derivative 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM) has gained increasing popularity in recent years because of its improved NO sensitivity, pH stability, and resistance to photobleaching compared to the first generation compound, DAF-2. Detection of NO production by either reagent relies on conversion of the parent compound into a fluorescent triazole, DAF-FM-T and DAF-2-T, respectively. Although this reaction is specific for NO and/or reactive nitrosating species, it is also affected by the presence of oxidants/antioxidants. Moreover, the reaction with other molecules can lead to the formation of fluorescent products other than the expected triazole. Thus additional controls and structural confirmation of the reaction products are essential. Using human red blood cells as an exemplary cellular system we here describe robust protocols for the analysis of intracellular DAF-FM-T formation using an array of fluorescence-based methods (laser-scanning fluorescence microscopy, flow cytometry, and fluorimetry) and analytical separation techniques (reversed-phase HPLC and LC-MS/MS). When used in combination, these assays afford unequivocal identification of the fluorescent signal as being derived from NO and are applicable to most other cellular systems without or with only minor modifications. PMID- 23026414 TI - Rapid susceptibility testing for herpes simplex virus type 1 using real-time PCR. AB - BACKGROUND: Susceptibility testing of herpes simplex virus type 1 (HSV-1) is traditionally performed by a plaque reduction assay (PRA), but this is labor intensive, time consuming and has a manual read out. OBJECTIVES: The goal of this study was to develop an internally controlled real time PCR-based phenotypical susceptibility test for HSV-1 that is suitable for use in a clinical diagnostic setting. STUDY DESIGN: A DNA reduction assay (DRA) was developed and validated on a test panel of 26 well-characterized isolates of varying susceptibility to aciclovir or foscarnet, including low-level resistant isolates. The DRA consisted of pre-culture of a clinical sample for 48 h and subsequent culture in the presence of antivirals for 24 h. Viral DNA concentration in the culture lysates was measured by an internally controlled quantitative real-time HSV-1 PCR and corrected for cell count and lysis by beta-globin PCR. DRA results were compared to results from PRA and sequence analysis. RESULTS: DRA results were in accordance with PRA results for both aciclovir and foscarnet susceptibility and appeared to have good discriminative value for low-level resistance due to UL30 gene mutations. Although the direct application of DRA in clinical samples appeared not possible, short pre-culture of 48 h was sufficient and ensured results within a clinically relevant time frame of 5 days. CONCLUSIONS: DRA is an accurate, rapid and easy to perform phenotypical susceptibility test for HSV-1. PMID- 23026416 TI - Endoscopic third ventriculostomy associated 3D-construcive inference steady state MRI for obstructed hydrocephalus: a retrospective study. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) is a developing therapeutic stratagem for obstructive hydrocephalus (OH). The aim of this study was to determine the relevance of third ventricle diagnostic imaging by three dimensional constructive inference in steady state (3D CISS) MRI in patients with OH and to access the preoperative and postoperative values of this technique in patients undergoing endoscopic third ventriculostomy (ETV). METHODS: Forty-six patients with an existing obstruction below the posterior part of the third ventricle underwent 3D CISS sequence MRI on a 1.5 T superconductive MR scanner and were included into this retrospective study. 19 patients were treated with ETV. Regression analysis of the correlation between third ventricle enlargement (TVE) and hydrocephalus degree (HD) and between TVE and third ventricle floor thickness (TVFT) was calculated. In the 19 ETV cases the incisions were marked according to MR images, and the 3D-CISS sequence imaging and the surgical outcome were compared before and after ETV. RESULTS: By virtue of 3D-CISS 97.83% third ventricle floors and 91.30% basilar arteries (BA) could be visualized, and there was a positive correlation between TVE and HD and a negative correlation between TVE and TVFT in this group. All incision sites on the scalp could be marked correctly. The degree of enlargement of the third ventricle allowed a prediction of the technical challenge to puncture the third ventricle floor. The position and route of BA could be demonstrated avoiding intraoperative iatrogenic lesions. At follow-up, 100% of the fistulas of the third ventricle floor could be measured on 3D-CISS images. The mean diameter of the fistulas was 6.12+/-0.96 mm; in 91.67%, new CSF fluid directions could be demonstrated; in 83.33%, enlarged ventricle system got withdrawn, and 91.67% patients showed relief of initial symptoms. 1 patient needed the implantation of a ventriculoperitoneal shunt 7 months after EVT. The preoperative HD compared with postoperative HD (P<.01); the preoperative TVE compared with postoperative TVE (P<.05). CONCLUSION: Images of the 3D-CISS sequence on MRI can visualize the third ventricle accurately and provide a reliable method for the evaluation of ETV pre- and postoperatively. The degree of enlargement of the third ventricle in patients with obstructive hydrocephalus is associated with the thickness of third ventricle floor and allows a prediction of the difficulty to puncture in ETV. PMID- 23026417 TI - Better look (and think) twice--TNF-alpha-inhibition and multiple sclerosis. PMID- 23026418 TI - Idiopathic spontaneous intraspinal intramedullary hemorrhage: a report of two cases and literature review. PMID- 23026419 TI - [Tuberculous involvement of the esophagus]. AB - Tuberculous involvement of the oesophagus is a rare disease in our country. We report the case of a 76-year-old patient with tuberculous involvement of the oesophagus, who developped an oesophago-lymph nodes fistula. These fistulas are used to be treated by antituberculous chemotherapy. The surgical treatment is rarely needed. PMID- 23026420 TI - Invited commentary. PMID- 23026421 TI - Patients with chronic obstructive pulmonary disease have shorter survival but superior endovascular outcomes after endovascular aneurysm repair. AB - OBJECTIVE: This study determined the effect of pulmonary disease on outcomes after endovascular abdominal (EVAR) and endovascular thoracoabdominal aortic aneurysm (eTAAA) repair. METHODS: A prospective study of high-risk patients undergoing EVAR and eTAAA repair between 1998 and 2009 was used to contrast clinical and endovascular outcomes between patients with (group 1) and without (group 2) chronic obstructive pulmonary disease (COPD). COPD patients were classified in accordance with the severity of their pulmonary disease using the Global Initiative for Chronic Obstructive Lung Disease criteria. Survival, morphologic changes, and complications were assessed using Cox models and life table analyses. The cause and timing of deaths between the groups was compared. RESULTS: Of 905 patients analyzed, 289 (32%) had COPD (group 1) and the remaining patients (group 2) did not have COPD. EVAR was performed in 334 patients (37%), and fenestrated or branched devices were used in the remaining 571 (63%). Group 1 patients were younger (73.5 +/- 6.7 vs 75.6 +/- 8.2 years), had a better glomerular filtration rate (67.8 +/- 25.8 vs 61.0 +/- 23.3 mL/min/1.73 m(2)), had higher hematocrits (41.6 +/- 5.0 vs 40.5 +/- 4.6), and had more extensive aneurysms. Mean follow-up was 39.5 +/- 30.9 months. Early (3% vs 3%) and late (2% vs 1%) aneurysm-related deaths were similar between the two groups. Survival in group 1 depended on the severity of disease. Survival in patients with Global Initiative for Chronic Obstructive Lung Disease classification I and II was similar to group 2. Those with classifications III and IV demonstrated lower survival rates. Relevant pulmonary function test variables included a lower forced expiratory volume in 1 second and forced expiratory flow in the middle 50%, which were associated with decreased survival. Surrogate endovascular outcome analyses demonstrated that group 1 patients had fewer endoleaks (20% vs 25%; P = .05) and more rapid sac shrinkage rate (1.66 mm/y difference; P < .001). CONCLUSIONS: The perioperative risk of death between COPD patients and non-COPD patients is eliminated when endovascular techniques are used. Long-term survival in COPD patients is most strongly related to the severity of their disease, and forced expiratory volume in 1 second and forced expiratory flow in the middle 50% are reasonable indicators of poor long-term outcomes. Morphologic changes after EVAR and eTAAA repair are more favorable in COPD patients, with a lower endoleak rate and faster sac shrinkage. PMID- 23026422 TI - Commentary regarding "lower-extremity endovascular interventions for Medicare beneficiaries: comparative effectiveness as a function of provider specialty" by Zafar et al. J Vasc Interv Radiol 2012;23:3-9. PMID- 23026423 TI - "Sigmoidization" of the hypogastric artery. PMID- 23026424 TI - Stent-assisted detachable coil embolization of a late-onset wide-necked anastomotic renal allograft artery pseudoaneurysm. PMID- 23026425 TI - Supervised walking therapy in patients with intermittent claudication. AB - OBJECTIVE: Exercise therapy is a common intervention for the management of intermittent claudication (IC). However, considerable uncertainty remains about the effect of different exercise components such as intensity, duration, or content of the exercise programs. The aim of this study was to assess the effectiveness of supervised walking therapy (SWT) as treatment in patients with IC and to update and identify the most important exercise components resulting in an optimal training protocol for patients with IC. METHODS: A systematic literature search using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases was performed. Randomized controlled trials (RCTs) published between January 1966 and February 2012 were included if they evaluated the effectiveness of SWT. Predefined exercise components were extracted, including treadmill use during training, claudication pain end point used during walking, length of the SWT program, and total training volume. A meta-analysis and meta-regression was performed to evaluate the weighted mean difference in maximum walking distance (MWD) and pain-free walking distance (PFWD) between SWT and noninterventional observation. RESULTS: Twenty-five RCTs (1054 patients) comparing SWT vs noninterventional observation showed a weighted mean difference of 180 meters (95% confidence interval, 130-230 meters) in MWD and 128 meters (95% confidence interval, 92-165 meters) in PFWD, both in favor of the SWT group. In multivariable meta-regression analysis, none of the predefined exercise components were independently associated with significant improvements in MWD or PFWD. CONCLUSIONS: SWT is effective in improving MWD and PFWD in patients with IC. However, pooled results from the RCTs did not identify any of the exercise components including intensity, duration, or content of the program as being independently associated with improvements in MWD or PFWD. PMID- 23026426 TI - Ethics of medical finance: when is enough too much? PMID- 23026427 TI - TheCardiovascular Fellows Bootcamp. AB - General surgery residents graduate with an inconsistent knowledge of cardiovascular disease and an inadequate skill set for the practice of vascular surgery. Vascular educators have proposed to overcome these challenges by incorporating standardized milestones and simulation curricula into vascular education, but at present, nonclinical vascular education remains nonstandardized. The first step in this direction is to lay a foundation of knowledge and skill for trainees nationwide, and regionalized courses have begun to be offered to address this need. Through the Methodist DeBakey Institute for Cardiovascular Education, we have developed our own course, The Cardiovascular Fellows Bootcamp. The principles behind The Cardiovascular Fellows Bootcamp are teach early, teach the basics, teach broadly, and teach multiple cardiovascular disciplines, and over a 3-day weekend of didactic lectures and skill training, we aim to lay a foundation for cardiovascular training that prepares the trainees for their fellowship. In this article, we describe the way in which our course is run and the thought process behind our approach. We also address some of the practical concerns that make hosting a course of this magnitude feasible and our plans for improving and expanding in the future. PMID- 23026428 TI - Role of the podiatrist in diabetic limb salvage. AB - Podiatrists play an important role in the multidisciplinary team in diabetic limb salvage. Podiatry is a specialty that is licensed in the diagnoses and treatment of pathologies of the foot and ankle. The treatment includes both conservative and surgical modalities. Understanding the biomechanics of the lower extremity is principally emphasized in the education and training of a podiatrist. This is particularly important in the context of the diabetic foot where biomechanical abnormalities often precede ulcer development. Preventive ulcer development strategies employed by a podiatrist include regular monitoring, routine care of calluses, and insert/shoe recommendations. Further, clinic-based ulcer care as well as surgery that include prophylactic and acute intervention can translate to the preservation of a functional limb. Finally, continuous podiatric management can prevent ulcer recurrence through offloading strategies and diabetic foot education. PMID- 23026429 TI - Superficial venous thrombosis and compression ultrasound imaging. PMID- 23026430 TI - Regarding "inferior vena cava resection and reconstruction for retroperitoneal tumor excision". PMID- 23026431 TI - Regarding "outcomes of percutaneous endovascular intervention for type II endoleak with aneurysm expansion". PMID- 23026433 TI - Regarding "outcomes and practice patterns in patients undergoing lower extremity bypass". PMID- 23026435 TI - Element of Surprise? Rice as a source of arsenic in children's diets. PMID- 23026436 TI - Tidal volume inflection and its sensory consequences during exercise in patients with stable asthma. AB - Sixteen patients with stable asthma performed a symptom-limited constant work rate CWR cycle exercise during which breathing pattern, operating lung volumes, dyspnea intensity and its qualitative descriptors were measured. An inflection in the relation between tidal volume (V(T)) and ventilation (V(E)) was observed in each subject. The sense of "work/effort" was the dominant dyspnea descriptor selected up to the V(T)/V(E) inflection, whereas after it dyspnea intensity and the selection frequency of "unsatisfied inspiration" rose steeply in 37.5% of subjects in whom inspiratory reserve volume (IRV) had decreased to a critical level of 0.6L at the V(T) inflection point. In contrast, dyspnea increased linearly with exercise time and V(E), and "work/effort" was the dominant descriptor selected throughout exercise in 62.5% of subjects in whom the V(T)/V(E) inflection occurred at a preserved IRV. The V(T) inflection during exercise in patients with stable asthma marked a mechanical event with important sensory consequences only when it occurred at a critical reduced IRV. PMID- 23026437 TI - High frequency mechanical ventilation affects respiratory system mechanics differently in C57BL/6J and BALB/c adult mice. AB - We tested the hypothesis that high frequency ventilation affects respiratory system mechanical functions in C57BL/6J and BALB/c mice. We measured respiratory mechanics by the forced oscillation technique over 1h in anesthetized, intubated, ventilated BALB/c and C57BL/6J male mice. We did not detect any change in airway resistance, Rn, tissue damping, G, tissue elastance, H and hysteresivity, eta in BALB/c mice during 1h of ventilation at 150 or at 450 breaths/min; nor did we find a difference between BALB/c mice ventilated at 150 breaths/min compared with 450 breaths/min. Among C57BL/6J mice, except for H, all parameters remained unchanged over 1h of ventilation in mice ventilated at 150 breaths/min. However, after 10 and 30 min of ventilation at 450 breaths/min, Rn, and respiratory system compliance were lower, and eta was higher, than their starting value. We conclude that high frequency mechanical ventilation affects respiratory system mechanics differently in C57BL/6J and BALB/c adult mice. PMID- 23026438 TI - Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients. AB - BACKGROUND: This study evaluated the dose-response of the new long-acting muscarinic antagonist umeclidinium (GSK573719) in patients with COPD. METHODS: This randomized, double-blind, placebo-controlled, parallel-group study evaluated three once-daily doses of umeclidinium (125, 250 and 500 MUg) for 28 days in 285 patients with COPD having FEV(1) of 35-70% predicted (mean (SD) age=61.4 (8.41); mean (SD) post-bronchodilator FEV(1)=1.577 (0.450)). The primary endpoint was morning trough FEV(1) at Day 29. Secondary endpoints included 0-6h weighted mean FEV(1) and serial FEV(1) measured over 6h post-dose and at trough. Safety and pharmacokinetics were also assessed. RESULTS: All doses of umeclidinium significantly increased trough FEV(1) over placebo from 150 to 168 mL (p<0.001), 0-6h weighted mean FEV(1) from 113 to 211 mL (p<0.001), and serial FEV(1) at each point in time over 24h. Reductions in salbutamol use and improvements in FVC were noted for all doses. Umeclidinium was well tolerated with no apparent treatment related changes in vital signs. CONCLUSION: Once-daily umeclidinium provides clinically significant, sustained improvement in lung function and is well tolerated. PMID- 23026439 TI - Stop or stop-change--does it make any difference for the inhibition process? AB - In the course of daily living altering environmental conditions or changing internal states often cause us to abandon obsolete planned or initiated actions and force us to update our behavior. The stop-change paradigm, an extension of the very popular stop-signal paradigm, allows the investigation of response inhibition and response re-engagement in a laboratory setting. This is very important as everyday life rarely calls for the complete suppression of actions without subsequent behavioral adjustment. The present review first gives a short overview on stop-signal inhibition and its behavioral and neural models before summarizing the findings in the stop-change domain. In doing so, this review shall contribute to a better understanding of the functional and neural architecture of response inhibition and re-engagement. Moreover, the question is raised whether the same or different inhibition process(es) are involved in stop signal- and stop-change inhibition. PMID- 23026440 TI - Human myxovirus resistance protein 1 (MxA) as a useful marker in the differential diagnosis of subcutaneous lymphoma vs. lupus erythematosus profundus. AB - BACKGROUND: Substantial clinicohistologic overlap exists between lupus erythematosus profundus (LEP) and lymphomas involving the subcutis, including subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and primary cutaneous gamma/delta T-cell lymphoma (GDTCL). Unequivocal markers separating the entities are not established. OBJECTIVES: To explore the usefulness of interferon alpha (INF-alpha)-induced protein, myxovirus resistance protein 1 (MxA), in the differential diagnosis of these entities, as studies show that the expression pattern of MxA follows the distribution of the inflammatory infiltrate in cutaneous lupus, while INF- alpha is not known to operate in lymphoma. MATERIALS AND METHODS: MxA immunohistochemistry was performed on skin biopsies from 5 patients with a clinical and histological diagnosis of SPTCL, 9 patients with GDTCL and 9 patients with LEP. RESULTS: In SPTCL and GDTCL, MxA was primarily seen in macrophages and generally did not exceed 20% of the infiltrate. In contrast, a significant portion of the subcutaneous infiltrate was positive for MxA in LEP, with 50% of the infiltrate staining on average. A greater number of macrophages and lymphocytes stained with a greater intensity as well (P<0.001). Moreover, endothelial cell staining was uniquely identified in LEP but not in lymphoma. CONCLUSION: Although specificity is not 100%, minimal staining of MxA is a predictor for SPTCL or GDTCL. Conversely, extensive staining for MxA both qualitatively and quantitatively is a feature of LEP. Endothelial staining also appears to be specific for LEP. PMID- 23026441 TI - Strain measurement in semiconductor heterostructures by scanning transmission electron microscopy. AB - This article deals with the measurement of strain in semiconductor heterostructures from convergent beam electron diffraction patterns. In particular, three different algorithms in the field of (circular) pattern recognition are presented that are able to detect diffracted disc positions accurately, from which the strain in growth direction is calculated. Although the three approaches are very different as one is based on edge detection, one on rotational averages, and one on cross correlation with masks, it is found that identical strain profiles result for an In x Ga1-x N y As1-y /GaAs heterostructure consisting of five compressively and tensile strained layers. We achieve a precision of strain measurements of 7-9.10-4 and a spatial resolution of 0.5-0.7 nm over the whole width of the layer stack which was 350 nm. Being already very applicable to strain measurements in contemporary nanostructures, we additionally suggest future hardware and software designs optimized for fast and direct acquisition of strain distributions, motivated by the present studies. PMID- 23026442 TI - Long-term amphetamine treatment exacerbates inflammatory lung reaction while decreases airway hyper-responsiveness after allergic stimulus in rats. AB - Asthma is an allergic lung disease can be modulated by drugs that modify the activity of central nervous system (CNS) such as amphetamine (AMPH). AMPH is a highly abused drug that exerts potent effects on behavior and immunity. In this study we investigated the mechanism involved in the effects of long-term AMPH treatment on the increased magnitude of allergic lung response. We evaluated mast cells degranulation, cytokines release, airways responsiveness and, expression of adhesion molecules. Male Wistar rats were treated with AMPH or vehicle (PBS) for 21 days and sensitized with ovalbumin (OVA) one week after the first injection of vehicle or AMPH. Fourteen days after the sensitization, the rats were challenged with an OVA aerosol, and 24h later their parameters were analyzed. In allergic rats, the treatment with AMPH exacerbated the lung cell recruitment due increased expression of ICAM-1, PECAM-1 and Mac-1 in granulocytes and macrophages recovered from bronchoalveolar lavage. Elevated levels of IL-4, but decreased levels of IL 10 were also found in samples of lung explants after AMPH treatment. Conversely, the ex-vivo tracheal hyper-responsiveness to methacholine (MCh) was reduced by AMPH treatment, whereas the force contraction of tracheal segments due to in vitro antigen challenge remained unaltered. Our findings suggest that lung inflammation and airway hyper-responsiveness due to OVA challenge are under the distinct control of AMPH during long-term treatment. Our data strongly indicate that AMPH positively modulates allergic lung inflammation via the increase of ICAM-1, PECAM-1, Mac-1 and IL-4. AMPH also abrogates the release of the anti inflammatory cytokine IL-10. PMID- 23026443 TI - Naturally mutated envelope protein domain I of Chinese B dengue virus attenuated human dendritic cell maturation. AB - Dengue virus (DENV) can infect human dendritic cells (DCs), and cause a spectrum of clinical symptoms. Envelope protein of DENV contains three distinct domains, including domain I (DI), domain II (DII) and domain III (DIII), and plays important roles in receptor binding and induction of protective antibodies. Previously, a new DENV-2 type virus (named B strain) with eight gene mutations in DI of the envelope protein was isolated from a dengue hemorrhagic fever patient. BALB/c mice infected with DENV B strain showed more prolonged viremia than mice infected with the New Guinea C (NGC) strain. However, the mechanism of prolonged viremia was not determined. In this study, DI proteins derived from B and NGC strains of DENV were expressed in Rosetta (DE3) host bacteria and purified by affinity chromatography after refolding. A flow cytometry-based binding assay and confocal microscopy indicated that both proteins could bind to human DCs induced from peripheral blood mononuclear cells (PBMCs), but DI of the B strain had a lower affinity than DI of the NGC strain, and viable B virus also show less binding efficiency with DCs. In addition, DI of the NGC strain, but not the B strain, induced IL-12 secretion and phenotypic maturation of DCs, such as up regulated expression of CD80, CD83, CD86 and HLA-DR. NGC strain could induce more virus specific IgM/IgG. These results suggest that the naturally mutated envelope protein DI of the Chinese B strain of DENV cannot induce DC maturation as high efficiency as that of NGC strain, which may be the partial reason that DENV B strain escapes immune recognition and induce prolonged viremia. The mutated B strain envelope protein is not a good candidate for subunit vaccine target. PMID- 23026444 TI - Effects of intravenous immunoglobulin on alpha synuclein aggregation and neurotoxicity. AB - alpha-Synuclein is thought to contribute to the pathogenesis of Parkinson's disease (PD). It is the main protein in Lewy bodies, the pathognomonic inclusion bodies in the PD substantia nigra, and mutations which increase its aggregation and/or expression are associated with familial early-onset parkinsonism. Soluble oligomers are considered to be alpha-synuclein's most neurotoxic conformation. We previously reported that intravenous immunoglobulin (IVIG) products contain specific antibodies to alpha-synuclein which do not prevent development of four day alpha-synuclein oligomers. The objective of this study was to further examine IVIG's effects on alpha-synuclein's aggregation and neurotoxicity. The IVIG product Gammagard (Baxter Healthcare) did not prevent the development of nine-day alpha-synuclein oligomers, nor did it degrade preformed oligomers, as shown by western blots performed on gels run under reducing/denaturing conditions and native gels. In western blots of native gels, an additional low molecular weight band (~22 kDa) was detected in alpha-synuclein incubated for four days in Gammagard, but not in Gammagard alone. No significant differences were found for Thioflavin-T reactivity between alpha-synuclein amorphous aggregates grown in Gammagard vs. those grown in phosphate-buffered saline. Gammagard partially protected SK-N-BE(2)M17 human neuroblastoma cells against alpha-synuclein oligomer toxicity (p = 0.007 vs. protective effects of normal human IgG). These findings suggest that although IVIG does not prevent alpha-synuclein aggregation, it still may reduce alpha-synuclein neurotoxicity through an unknown mechanism. PMID- 23026445 TI - Respiratory physiotherapy can increase lower esophageal sphincter pressure in GERD patients. AB - BACKGROUND: Inspiratory muscle training (IMT) has been shown to increase diaphragm thickness. We evaluated the effect of IMT on mid-respiratory pressure (MRP) in patients with gastroesophageal reflux disease (GERD) and hypotensive lower esophageal sphincter (LES), and compared the results with a sham group. METHODS: Twenty consecutive patients (progressive loading group) and 9 controls (sham group) were included. All patients had end expiratory pressure (EEP) between 5 and 10 mmHg, underwent esophageal manometry and pulmonary function tests before and after 8 weeks of training, and used a threshold IMT twice daily. The threshold IMT was set at 30% of the maximal inspiratory pressure for the progressive loading group; while, the threshold for sham-treated patients was set at 7 cmH(2)O for the whole period. RESULTS: There was an increase in MRP in 15 (75%) patients in the progressive loading group, with an average gain of 46.6% (p < 0.01), and in six (66%) patients in the sham group with a mean increase of 26.2% (p < 0.01). However, there was no significant difference between the groups (p = 0.507). The EEP also increased compared with measurements before training (p < 0.01), but it did not differ between groups (p = 0.727). CONCLUSION: IMT increased LES pressure in patients with GERD, in both the treatment and sham groups, after an eight-week program. Although there was no statistically significant difference between groups, suggesting the pressure increase in LES occurs regardless of the resistance load of the threshold IMT. These findings need to be confirmed in further studies with a larger sample. REGISTRATION NUMBER: 0922/09. PMID- 23026446 TI - Thyroxine lipophilicity is dominated by its zwitterionic microspecies. AB - Species-specific partition coefficients were determined for a triprotic molecule for the first time. Thyroxine, the vitally important thyroid hormone which exists in solution in the forms of eight microspecies due to its phenolate, amino and carboxylate basic sites, was studied by combined methods of microspeciation and lipophilicity. Partition of the individual microspecies was mimicked by model compounds of the closest possible similarity, then correction factors were determined and introduced. The non-charged microspecies is only 2.40 times as lipophilic as its zwitterionic protonation isomer, showing that for thyroxine the iodinated aromatic rings are the structural elements that determine the lipophilicity of this molecule, and the protonation state of the other substituents plays only a minor role. The overwhelming dominance of the zwitterionic form, however, ensures that its contribution to the overall lipophilicity exceeds 14,500 times that of the non-charged one. This fact is so far the sharpest counter-example of the widespread belief that passive diffusion into lipophilic media is predominated by the non-charged species. The lipophilicity profile of thyroxine is expressed, calculated and depicted in terms of species-specific lipophilicities over the entire pH range. PMID- 23026447 TI - Phase behavior of rifampicin in cholesterol-based liquid crystals and polyethylene glycol. AB - The phase behavior of rifampicin in cholesteryl-based carbonate esters (CCEs), cholesterol and polyethylene glycol4000 (PEG4000) was determined to evaluate their potential in the formulation of dry powder inhalation dosage forms. To guide the identification of the most suitable liquid crystalline system for the solubilization of rifampicin, the dielectric constants were evaluated. Thereafter, the phase behavior of various mixtures were characterized by polarized light microscope (PLM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Among the mixed carrier systems, the cholesteryl cetyl carbonate (CCC) and PEG4000 system at 1:1 mole ratios yielded a homogeneous mixture with relatively high rifampicin content. This result was consistent with the prediction based on the dielectric constants. The phase diagram contained a eutectic point at CCC:PEG4000 (1:1) and 50 degrees C. Finally, the rifampicin drug was successfully incorporated into CCC and PEG system at a 1:6:6 mole ratio. Such a system would be amenable for oral inhalation. PMID- 23026448 TI - High-time resolution and size-segregated elemental composition in high-intensity pyrotechnic exposures. AB - Typical of festivals in Eastern Spain, mascletas are high-intensity pyrotechnic events where thousands of firecrackers are burnt in an intense, rapid episode that generates short-lived heavy aerosol clouds. High temporal resolution and size distribution characterisation of aerosol components were performed to evaluate the effects of the brief (<30 min) and acute exposure on the spectators present. Very high concentrations of firework specific elements, especially in the fine fraction, were reached during mascletas, with values of about 500 MUg/m(3) for K and 300 MUg/m(3) for Cl. Sr, Al, Mg, Ba, Cu, Co, Zn, and Pb concentration increase factors of more than 100 (1000 for Sr and Ba) were observed in the fine fraction with respect to background levels. Crustal origin elements, like Ca, Fe, Si, Ti, also showed an important concentration rise (~10 times above background levels) but this is due to dust resuspension by pyrotechnic explosions. The crustal components are mainly in the coarse mode (>90% elemental mass), between 2 and 3 MUm. Most firework related metals are concentrated in the submicrometric region (>80%) with a trimodal size distribution. This may be interesting to epidemiologists given the toxic effects that such fine, metal-rich particles can have on human health. PMID- 23026449 TI - Characterization of ammonium retention processes onto cactus leaves fibers using FTIR, EDX and SEM analysis. AB - In order to reduce the impact of nitrogen pollution and to increase the agronomic value of plant wastes to be reused as organic fertilizer, we have investigated the removal of ammonium from aqueous solutions onto cactus leave fibers (CLF), and the mechanisms involved in the retention of ammonium at CLF surface. The results showed that ammonium retention onto these fibers occurred for a wide pH (6-10) and temperature ranges (20-60 degrees C) and the biosorption potential of CLF increased with temperature from 1.4 to 2.3 mg g(-1) for initial concentration of 50 mg L(-1). The modeling studies showed that the ammonium biosorption was well described by the pseudo-second-order model, predicting therefore, chemisorption interactions-type at earlier stages and by intraparticle diffusion at later stages. Biosorption is governed by film diffusion process at higher concentrations and by particle diffusion process at higher temperatures. The surface of CLF determined by SEM revealed the presence of cracks and cavities which may allow the intraparticle diffusion and the ion exchange processes. Moreover, FTIR and EDX analysis before and after ammonium retention showed that the main mechanisms involved in the removal of ammonium were the ionic exchange by calcium ions as well as H(+) and the complexation with carboxylic, alcoholic and phenolic groups. PMID- 23026450 TI - Expanding the active pH range of Escherichia coli glutamate decarboxylase by breaking the cooperativeness. AB - Bacterial glutamate decarboxylase (GAD) transforms glutamate into gamma aminobutyric acid (GABA) with the consumption of a proton. The enzyme is active under acidic environments only and sharply loses its activity as pH approaches neutrality with concomitant structural deformation. In an attempt to understand better the role of this cooperative loss of activity upon pH shifts, we prepared and studied a series of GAD site-specific mutants. In this report, we show that the cooperativeness was kept intact by at least two residues, Glu89 and His465, of which Glu89 is newly identified to be involved in the cooperativity system of GAD. Double mutation on these residues not only broke the cooperativity in the activity change but also yielded a mutant GAD that retained the activity at neutral pH. The resulting mutant GAD that was active at neutral pH inhibited the cell growth in a glycerol medium by converting intracellular Glu into GABA in an uncontrolled manner, which explains in part why the cooperativeness of GAD has to be kept by several layers of safety keepers. This unexpected result might be utilized to convert a low-valued by-product of biodiesel production, glycerol, into value-added product, GABA. PMID- 23026451 TI - Evaluation systems of generated forces of skeletal muscle cell-based bio actuators. AB - Skeletal muscle is the most abundant tissue in the body, and its capability of generating an active force is one of the most significant features. In order to study the physiology and disorders related to the skeletal muscle using cells in vitro, the active force should be evaluated, in addition to molecular and cell biological experiments performed. This article reviews an evaluation system for the active tension generated by cultured skeletal muscle cells or tissue engineered skeletal muscles. First, we focused on experimental models involving a single or several myotubes. Then, we focused on the systems for tissue-engineered skeletal muscles consisting of much larger numbers of myotubes. Such systems can be used to study the physiology of the skeletal muscle, screen drug candidates for skeletal muscle-related disorders, and improve the function of tissue engineered skeletal muscle. PMID- 23026452 TI - Biodegradation of 4-bromophenol by Arthrobacter chlorophenolicus A6T in a newly designed packed bed reactor. AB - Bromophenol is listed as a priority pollutant by the U.S. EPA. However, there has been no report on the removal of bromophenol in any biological system that is operated in a continuous mode. The efficiency of Arthrobacter chlorophenolicus A6(T) on the biodegradation of 4-bromophenol (4-BP) in a newly designed packed bed reactor (PBR) was evaluated with different influent 4-BP concentrations between 400 mg l(-1) and 1200 mg l(-1) and hydraulic retention times (HRTs) between 24 h and 7.5 h. The response of the PBR to 4-BP shock loadings was also tested, and the bioreactor was found to adequately handle these shock loadings. The percentage of effluent toxicity in the PBR was tested using mixed microbial consortia as the test species; this experiment was performed using a 4-BP influent concentration of 1200 mg l(-1) and HRTs between 24 h and 7.5 h. A maximal 98% effluent toxicity removal was achieved when the PBR was operated at an HRT of 24 h. In the present study, 4-BP was used as the sole source of carbon and energy, and the complete removal of 4-BP was achieved with 4-BP loading rates of up to 2277 mg l(-1) day(-1). PMID- 23026453 TI - Optimization of Entamoeba histolytica culturing in vitro. AB - Entamoeba histolytica is among the most deadly parasites accounting for the second highest mortality rate among parasitic diseases. Nevertheless, contrary to trypanosomatids, this protozoan in hardly studied by parasitology groups. This astonishing discrepancy is largely due to the remarkable intricate conditions required for parasite proliferation in vitro, particularly whenever large cell numbers are required. The present study was undertaken in order to optimize E. histolytica culturing harvest, using mineral oil layers preventing culture medium air contact to maintain anaerobic conditions in culture plate wells. 2*10(4) trophozoites were plated on each well in 2.0 mL YI-S-33 medium, supplemented with bovine serum and 700 MUL mineral oil. Parasites were daily quantified by light microscopy counting for up to 96 h and trophozoite motility was also assessed. We notice that E. histolytica cultures in 24-well plates reached several-fold higher cell densities, particularly whenever the mineral oil layer was placed on top of the medium surface, blocking the air interface. At least 99% of the parasites were vigorously motile for 72 h in oil-containing wells, whereas only less than 5% displayed significant motility in oil-devoid wells. In order to determine whether such different growth responses were due at least in part to the oxidative stress, we used the reactive oxidant species fluorescent probe dihydroethidium (DHE). The remarkably higher DHE parasite labeling in oil-devoid cultures indicate that oxidative stress reduction can play a significant role in elevated growth rates observed in oil supplemented cultures. Propidium iodide and Trypan blue dye-exclusion assays indicate that parasite necrosis resulted from the stressing conditions. The present study indicates that E. histolytica culturing in oil-sealed wells may comprise a valuable tool for bioactivity of antiparasitic compounds. PMID- 23026454 TI - Toxoplasma gondii: bioinformatics analysis, cloning and expression of a novel protein TgIMP1. AB - Toxoplasma gondii is an obligate intracellular protozoan parasite, infecting a large variety of animals and human beings. In recent years, the study of DNA vaccine against T. gondii has made a great progress; however, few vaccines have completely controlled toxoplasmosis. Thus people started to look for more effective antigenic proteins. Here we report a novel T. gondii protein termed immune mapped protein 1 (TgIMP1). We used multiple bioinformatics approaches to predict the physical and chemical characters, signal peptide, transmembrane domain, epitope, topological structure and function of the protein, and we theoretically determined that the TgIMP1 has multiple epitopes, and with immunogenicity, suggesting that the TgIMP1 may be a vaccine candidate against toxoplasmosis. Then the gene coding TgIMP1 was obtained by PCR and connected with cloning vector. Recombinant plasmid was identified by PCR, double digestion and sequencing analysis. Then the TgIMP1 gene was directly inserted into the eukaryotic expression vector pBudCE4.1, so that the recombinant eukaryotic expression plasmid pBudCE4.1-TgIMP1 was constructed. After identification by PCR and restriction enzyme digestion, the recombinant plasmid pBudCE4.1-TgIMP1 was transfected into cells of HFF, and then identified by RT-PCR. The results showed that the eukaryotic expression plasmid pBudCE4.1-TgIMP1 was constructed and was transfected to the HFF cells successfully. PMID- 23026455 TI - Trichinella spiralis: monoclonal antibody against the muscular larvae for the detection of circulating and fecal antigens in experimentally infected rats. AB - In this work we search for antigens of Trichinella spiralis in sera and stool of rats experimentally infected. The kinetic of antibodies to excretory and secretory (ES) antigens of muscle larvae (ML) was also determined. Wistar rats were infected with 15 ML per gram of body weight and blood samples were collected weekly for 10 weeks. Antibodies were studied using an indirect ELISA. For detection of circulating antigens and coproantigens, a sandwich ELISA was developed with the use of polyclonal rabbit antibodies obtained against the total extract of ML and an IgM monoclonal antibody (Mab) against ES antigens of ML. No reactivity was observed between Mab and the total worm antigens of Angiostrongylus cantonensis, Ascaris suum, Echinococcus granulosus, Fasciola hepatica, Strongyloides stercoralis, Taenia solium, Toxocara canis and Trichuris trichiura. The IgM Mab recognized antigens of 45, 49, and 55 kDa in ES antigens and was unable to bind ES antigens deglycosylated with trifluoromethanesulphonic acid (TFMS) indicating that a glycan structure is present in the epitope recognized by this Mab. The sensitivity of sandwich ELISA was 1 ng/mL. Circulating antigens were detected in all infected rats between 3 and 8 weeks post infection and coproantigens were found during the first two days post infection. Antibodies were detected since the third week post infection through the end of experiment. These results suggested that antigen detection by our sandwich ELISA could be a useful complementary laboratory test for antibody detection. PMID- 23026456 TI - Electrodiagnostic evaluation of compressive nerve injuries of the upper extremities. AB - Electrodiagnostic testing includes electromyography and nerve conduction studies that are physiologic tests used in the diagnosis of peripheral nerve injuries. It is a supplement rather than a replacement for a physical examination. This article reviews the terminology as well as the findings seen and used in electrodiagnostic studies. Common compression nerve injuries including the median, ulnar, radial, axillary, and suprascapular nerves and their electrical findings are reviewed. PMID- 23026457 TI - Physical examination of upper extremity compressive neuropathies. AB - A thorough history and physical examination are vital to the assessment of upper extremity compressive neuropathies. This article summarizes relevant anatomy and physical examination findings associated with upper extremity compressive neuropathies. PMID- 23026458 TI - Open versus endoscopic carpal tunnel release. AB - Carpal tunnel syndrome is a very common hand condition, which after a failure of conservative treatment can be treated successfully with surgical decompression in either an open or endoscopic manner. On comparing the two techniques there may be some subtle differences; however, both can provide an excellent outcome. This article provides a detailed review of each technique as well as their comparative differences in terms of technique, outcomes, and complications. PMID- 23026459 TI - Evaluation and treatment of failed carpal tunnel release. AB - Treatment failure and complications are encountered in 1% to 25% of all carpal tunnel releases. Besides hematoma, infection, skin necrosis, and intraoperative iatrogenic injuries, persistence and recurrence should be included in this discussion. Persistence is often related to incomplete release. Similar symptoms recurring after a symptom-free interval of 6 months are considered recurrent and may be caused by intraneural or perineural scarring. Adequate diagnosis and treatment of these failures can be challenging. Operative release is the main treatment consisting of complete decompression of the median nerve. In some circumstances, coverage of the median nerve may be necessary. PMID- 23026460 TI - Late reconstruction of median nerve palsy. AB - The median nerve provides sensory innervation to the radial aspect of the hand, including the palm, thumb, index, long, and half of the ring fingers. It provides motor innervation to most of the volar forearm musculature and, importantly, to m ost of thenar musculature. The main goal of median nerve reconstructive procedures is to restore thumb opposition. There are a variety of transfers that can achieve this goal but tendon transfers must recreate thumb opposition, which involves 3 basics movements: thumb abduction, flexion, and pronation. Many tendon transfers exist and the choice of tendon transfer should be tailored to the patient's needs. PMID- 23026461 TI - Acute carpal tunnel syndrome. AB - Acute carpal tunnel syndrome is characterized by rapid onset of median neuropathy caused by sudden increases in carpal tunnel pressures, which leads to ischemia of the median nerve. The most common cause is traumatic injury, although atraumatic sources should also be recognized. Patients generally complain of pain, lose two point discrimination, and may demonstrate elevated compartment pressure on measurement. Prompt recognition and surgical decompression are imperative to spare median nerve viability. PMID- 23026462 TI - Ulnar tunnel syndrome. AB - Ulnar tunnel syndrome could be broadly defined as a compressive neuropathy of the ulnar nerve at the level of the wrist. The ulnar tunnel, or Guyon's canal, has a complex and variable anatomy. Various factors may precipitate the onset of ulnar tunnel syndrome. Patient presentation depends on the anatomic zone of ulnar nerve compression: zone I compression, motor and sensory signs and symptoms; zone II compression, isolated motor deficits; and zone III compression; purely sensory deficits. Conservative treatment such as activity modification may be helpful, but often, surgical exploration of the ulnar tunnel with subsequent ulnar nerve decompression is indicated. PMID- 23026463 TI - Cubital tunnel syndrome. AB - Compression of the ulnar nerve at the elbow, or cubital tunnel syndrome, is the second most common peripheral nerve compression syndrome in the upper extremity. Diagnosis is made through a good history and physical examination. Electrodiagnostic testing can confirm the diagnosis and severity of injury to the nerve. Surgical intervention is indicated when nonoperative treatment does not relieve the symptoms. There is currently no consensus on the best surgical treatment of cubital tunnel syndrome. However, the only randomized prospective studies to compare treatment options to date indicate that simple decompression and anterior transposition yield comparable results. PMID- 23026464 TI - Evaluation and treatment of failed ulnar nerve release at the elbow. AB - Failure after ulnar nerve decompression at the elbow can be defined as either no change in the patient's symptoms or an initial improvement with recurrence, making the patient history essential in the work-up. Failure may be due to diagnostic, technical, or biologic factors. Technical errors and the development of perineural fibrosis necessitate revision surgery, while nerve damage due to chronic severe compression should be observed. We do not believe any one procedure is superior in the revision setting as long as a complete decompression is achieved with a compression free, stable transposition of the surgeon's choice. PMID- 23026465 TI - Late reconstruction of ulnar nerve palsy. AB - Ulnar nerve palsy results in significant loss of sensation and profound weakness, leading to a dysfunctional hand. Typical clinical findings include loss of key pinch, clawing, loss of normal flexion sequence of the digits, loss of the metacarpal arch, and abduction of the small finger. Further deficits in hand/wrist function are seen in high-level ulnar nerve palsy, including loss of ring- and small-finger distal interphalangeal flexion, decreased wrist flexion, and loss of dorsal sensory innervation. This article reviews the clinical findings seen in low and high ulnar nerve palsies, and reviews surgical options for correcting certain motor and sensory deficits. PMID- 23026466 TI - Ulnar neuropathy following distal humerus fracture fixation. AB - Ulnar nerve dysfunction is a well-recognized phenomenon following distal humerus fractures. Its fixed anatomic position predisposes the nerve to injury. Injury can occur at the time of injury, during closed-fracture manipulation, intraoperatively during fracture fixation (when it is routinely identified), or during fracture healing. Intraoperative management varies widely and can include in situ decompression or anterior transposition. This article reviews the literature and presents 24 patient cases. A 38% incidence of late ulnar neuropathy following open reduction and internal fixation is identified. There is no statistical difference between an in situ release and all anterior transpositions, except for submuscular. PMID- 23026467 TI - Carpal tunnel syndrome in pregnancy. AB - During pregnancy, hormonal fluctuations, fluid shifts, and musculoskeletal changes predispose women to carpal tunnel syndrome. While the clinical presentation is similar to other patients, the history obtained must include information regarding the pregnancy itself. Currently, the indication for electrodiagnostic testing is not clearly defined. Given that symptoms often improve with conservative treatment and abate after delivery, EMG/NCV testing can often be avoided. However, if symptoms are severe or persist, carpal tunnel release is indicated and is considered a safe procedure for both mother and fetus. PMID- 23026468 TI - Carpal tunnel syndrome after distal radius fracture. AB - Carpal tunnel syndrome is a common condition and is a well-recognized phenomenon following a distal radius fracture. The treating surgeon should be vigilant in noticing the signs and symptoms. If acute carpal tunnel syndrome is noted, then surgical release of the carpal tunnel and fracture fixation should be performed urgently. If early carpal tunnel syndrome findings are noted during distal radius fracture management, all potential causes should be evaluated. Delayed carpal tunnel syndrome presenting after a distal radius fracture has healed is best managed in standard fashion. There is no role for prophylactic carpal tunnel release at the time of distal radius fixation in a patient who is asymptomatic. PMID- 23026469 TI - Radial tunnel syndrome. AB - Radial tunnel syndrome is a pain syndrome resulting from compression of the posterior interosseous nerve at the proximal forearm. It has no specific radiologic or electrodiagnostic findings. Treatment should be started conservatively; if not successful, surgical treatment is indicated. The posterior interosseous nerve may be explored through dorsal or anterior approaches. All the potential sites of entrapment should be released, including complete release of the superficial head of the supinator muscle. Surgical treatment is generally successful, but patients who have associated lateral epicondylitis or those who are involved in workers' compensation claims have less successful outcomes. PMID- 23026470 TI - Orthopedic Clinics of North America. Management of compressive neuropathies of the upper extremity. Preface. PMID- 23026471 TI - Micro-punch technique for treatment of Fordyce spots: a surgical approach for an unpleasant condition of the male genital. AB - Fordyce spots are ectopic sebaceous glands, ranging between 2 and 3 mm in diameter. These benign lesions are most frequently located in the oral mucosa and the genital skin. Especially in the male genital region they can cause itching, discomfort during sexual activities and are aesthetically unpleasant. So far, a variety of therapeutic procedures have been reported with varying success and recurrence rates. In the present retrospective study (n = 23 patients between 2003 and 2011), we present our surgical approach by means of the micro-punch technique. Using this effective method, we achieved very satisfactory functional and cosmetic results. There were no signs of recurrence during postoperative observations from 12 up to 84 months (median = 51.3 months). PMID- 23026472 TI - Congenital symmastia revisited. AB - BACKGROUND: Symmastia is defined as medial confluence of the breast. The term 'symmastia' is modified from Greek (syn meaning 'together', and mastos meaning 'breast') and was first presented by Spence et al. in 1983. Two forms of symmastia exist: an iatrogenic and a congenital version. Congenital symmastia is a rare condition in which web-like soft tissue traverses the sternum to connect the breasts medially. The literature on congenital symmastia is limited, few cases have been published, and knowledge about ideal treatment is still insufficient. MATERIAL AND METHODS: Congenital symmastia was identified as a distinct deformation using a review of the literature and a theoretical model. We analysed the malady using a three-step principle, formulated by Blondeel, which describes the breast as a 'footprint', 'conus' and 'skin-envelope'. To date, few papers on congenital symmastia have been published, most of which focus on the application of various surgical approaches. We examined the literature and evaluated the procedures used, and are presenting two recent cases of congenital symmastia as examples. By combining review and analysis we offer a rational treatment practice. RESULTS: The analysis showed that the optimal treatment begins by correcting the 'footprint', removing the excess 'conus' over the sternum, and finally reattaching the 'skin-envelope' to the sternum to recreate the normal medial border of the 'footprint'. Thus far, the two most common approaches used to treat congenital symmastia are: reduction mammaplasty and liposuction. CONCLUSION: By combining the Blondeel analysis with a procedural review, we developed a flow chart to offer a possible treatment practice. PMID- 23026473 TI - Free partial latissimus dorsi myocutaneous flap for coverage of severe achilles contracture in children. AB - Achilles tendon and soft-tissue contractures caused by trauma to the foot and ankle are complex injuries. An array of techniques, including local and distant flaps, has been used and described to reconstruct these challenging wounds. However, the management of these injuries in a growing child who develops abnormal gait due to equinus deformity has not been categorically reported. The latissimus dorsi myocutaneous flap has the advantage of a rich blood supply making specific partial muscle harvest possible. In this case series, we report on five paediatric patients with severe contracture of the Achilles tendon and posterior ankle, who were reconstructed with free partial latissimus dorsi myocutaneous flaps. All flaps survived and satisfactory form and function of the ankle joint were achieved with minimal donor morbidity. We believe that the free partial latissimus dorsi myocutaneous flap is an excellent option for the soft tissue reconstruction of severe Achilles tendon contracture in children. PMID- 23026474 TI - Management of atrial fibrillation by Canadian electrophysiologists after early termination of the PALLAS study. PMID- 23026475 TI - Fold-increase in antibody titer upon vaccination with pneumococcal unconjugated polysaccharide vaccine. PMID- 23026476 TI - ESC/EACTS Guidelines on the management of valvular heart disease. PMID- 23026477 TI - Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. AB - OBJECTIVES: The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. BACKGROUND: A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. METHODS AND RESULTS: Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, the Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC 2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. CONCLUSIONS: This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavours of applying definitions to other transcatheter valve therapies (for example, mitral valve repair). PMID- 23026478 TI - Protective effect of planarian DJ-1 against 6-hydroxydopamine-induced neurotoxicity. AB - DJ-1/PARK7 has multiple functions as an antioxidant, an oncogene, and a molecular chaperone in vertebrates, and loss-of-function mutations in DJ-1 cause early onset of Parkinson's disease. However, the function of invertebrate DJ-1 remains unknown. In order to investigate the function of planarian DJ-1, we isolated the planarian DJ-1 gene Dugesia japonica DJ-1 (DjDJ-1) and analyzed its expression and function. In situ hybridization analysis revealed that DjDJ-1 mRNA was expressed throughout the body, including the central nervous system, cells surrounding the pharynx, and stem cells. Planarian DjDJ-1 protein exhibited antioxidant function, similar to human DJ-1, as evidenced by the fact that recombinant DjDJ-1 protein reduced reactive oxygen species and protected human neuroblastoma SH-SY5Y cells from cell death. In addition, dopaminergic neurons in DjDJ-1(RNAi) planarians became susceptible to 6-hydroxydopamine, a dopaminergic neurotoxin. These results suggest that planarians have a DJ-1 ortholog, which has conserved antioxidant and neuroprotective functions. PMID- 23026479 TI - Channelrhodopsins-Their potential in gene therapy for neurological disorders. AB - Recently, channelrhodopsins (ChRs) have begun to be used to manipulate the neuronal activity, since they can be targeted to specific neurons or neural circuits using genetic methods. To advance the potential applications in the investigation and treatment of neurological disorders, the following types of basic research should receive extensive financial support. The spectral and kinetic properties of ChRs should be optimized according to the application by generating variants of ChRs or exploring new rhodopsins from other species. These ChRs should be targeted to the specific types of neurons involved in the neurological disorders through a gene expression system using cell- or tissue specific promoters/enhancers as well as gene delivery systems with modified virus vectors. The methods have to be developed to apply the genes of interest with safety and long-term effectiveness. Sophisticated opto-electrical devices should be developed. Appropriate primate animal model systems should be established to minimize the structural differences between small animals such as rodents and human beings. In this paper, we will review the current progress in the basic research concerned with the potential clinical application of ChRs and discuss the future directions of research on ChRs so that they could be applied for human welfare. PMID- 23026480 TI - Rethinking hopelessness and the role of spiritual care when cure is no longer an option. AB - Increasingly in the U.S., health care clinicians fail to recognize and accept when curative goals are no longer realistic. At this point, futile efforts at cure can fuel false hopes in patients and their loved ones. The clinician's need to be "doing something" may result in treatment that violates the dignity and well-being of the patient and this can lead to the patient's ultimate hopelessness and despair. This article uses a personal narrative to explore the hopelessness of a patient diagnosed with nonresectable pancreatic cancer and the challenge it raised for the author, who was a friend and a nurse to the patient. Hope is described as a virtue that takes as its object "a future good, difficult but possible to obtain," and that sits squarely between false hopes and despair. Spiritual care that addresses three universal spiritual needs (meaning and purpose, love and relatedness, and forgiveness) is recommended as a valuable intervention to address hopelessness. PMID- 23026483 TI - Emerging opioid alternatives to nebulized fentanyl for improving exercise capacity in patients with COPD. PMID- 23026484 TI - Comment on the ARCTIC hypothermia protocol and prognostication. PMID- 23026485 TI - Asking the right questions: how early-life exposures influence later development of disease. PMID- 23026486 TI - Infant behaviors are predictive of functional somatic symptoms at ages 5-7 years: results from the Copenhagen Child Cohort CCC2000. AB - OBJECTIVE: To investigate infancy predictors of impairing functional somatic symptoms (FSS) at child ages 5-7 years with a focus on problems with feeding, sleep, and tactile reactivity. STUDY DESIGN: This study is part of a longitudinal birth cohort study, Copenhagen Child Cohort CCC2000. Child health, development, and functioning were assessed by community health nurses at 4 home visits from birth to age 10 months. FSS at ages 5-7 years were measured by the Soma Assessment Interview in 1327 children. Sociodemographic data and information on maternal psychiatric illness were obtained from the Danish National Registers. RESULTS: Multiple logistic regression analysis controlled for maternal psychiatric illness and annual household income revealed that combined infancy regulatory problems (ie, at least 2 of 3 problems of feeding, sleeping, or tactile reactivity during the first 10 months of living) predicted impairing FSS at 5-7 years (aOR = 2.9, 95% CI: 1.3-6.6). Maternal psychiatric illness during the child's first year of living was also associated with later child FSS (aOR = 7.1, 95% CI: 1.8-27.8). CONCLUSION: Regulatory problems may be an early marker of disturbed sensory reactivity in young children, which together with maternal psychiatric problems, point to possible early risk mechanisms of impairing FSS in childhood. PMID- 23026487 TI - Invasive giant prolactinoma presenting as a nasal polyp. PMID- 23026488 TI - Meconium peritonitis with intestinal atresia mimicking huge tumor in a preterm neonate. PMID- 23026489 TI - Mesoporous bioactive scaffolds prepared with cerium-, gallium- and zinc containing glasses. AB - Mesoporous bioactive glass scaffolds (MBG_Scs), based on 80% SiO(2)-15% CaO-5% P(2)O(5) (in mol.%) mesoporous sol-gel glasses substituted with Ce(2)O(3), Ga(2)O(3) (both 0.2% or 1.0%) and ZnO (0.4% or 2.0%), were synthesized by combination of evaporation-induced self-assembly and rapid prototyping techniques. Cerium, gallium and zinc trace elements were selected because of their inherent beneficial biological properties. Fabricated scaffolds were characterized and compared with unsubstituted scaffold (B_Sc). All of them contained well interconnected ultralarge pores (pores >400 MUm) ideal for vascular ingrowth and proliferation of cells. Macropores of size 100-400 MUm were present inside the scaffolds. In addition, low-angle X-ray diffraction showed that B_Sc and scaffolds with substituent contents up to 0.4% exhibited ordered mesoporosity useful for hosting molecules with biological activity. The textural properties of B_Sc were a surface area of 398 m(2) g(-1), a pore diameter of 4.3 nm and a pore volume of 0.43 cm(3) g(-1). A slight decrease in surface area and pore volume was observed upon substitution with no distinct effect on pore diameter. In addition, all the MBG_Scs except 2.0% ZnO_Sc showed quite quick in vitro bioactive response. Hence, the present study is a positive addition to ongoing research into preparing bone tissue engineering scaffolds from bioceramics containing elements of therapeutic significance. PMID- 23026490 TI - Mammary tumor development is directly inhibited by lifelong n-3 polyunsaturated fatty acids. AB - INTRODUCTION: Despite the advocacy that diet may be a significant contributor to cancer prevention, there is a lack of direct evidence from epidemiological and experimental studies to substantiate such claims. Experimental studies suggest that n-3 polyunsaturated fatty acids (n-3 PUFA) from marine oils may reduce breast cancer risk, however, findings are equivocal. Thus, in this study, novel transgenic mouse models were employed to provide, for the first time, direct evidence for an anti-cancer role of n-3 PUFA in mammary tumorigenesis. METHODS: fat-1 Mice, which are capable of endogenous n-3 PUFA synthesis, were bred with mouse mammary tumor virus (MMTV)-neu(ndl)-YD5 mice, an aggressive breast cancer model. The resultant offspring, including novel hybrid progeny, were assessed for tumor onset, size and multiplicity as well as n-3 PUFA composition in mammary gland and tumor tissue. A complementary group of MMTV-neu(ndl)-YD5 mice were fed n-3 PUFA in the diet. RESULTS: Mice expressing MMTV-neu(ndl)-YD5 and fat-1 displayed significant (P<.05) reductions in tumor volume (~30%) and multiplicity (~33%), as well as reduced n-6 PUFA and enriched n-3 PUFA in tumor phospholipids relative to MMTV-neu(ndl)-YD5 control mice. The effect observed in hybrid progeny was similarly observed in n-3 PUFA diet fed mice. CONCLUSION: Using complementary genetic and conventional dietary approaches we provide, for the first time, unequivocal experimental evidence that n-3 PUFA is causally linked to tumor prevention. PMID- 23026491 TI - Regulation of hepatic suppressor of cytokine signaling 3 by zinc. AB - Promoter analysis of the family of suppressors of cytokine signaling (SOCS) revealed that the human SOCS3 gene contains four binding sites for the metal regulatory transcription factor 1 (MTF-1) located within 1600 bp relative to the transcription start site. A series of experiments were carried out with human hepatoma cells (HepG2) and C57BL/6 mice to examine the effect of zinc on the regulation of SOCS3. In addition, we tested the role of MTF-1 in the regulation of SOCS3 expression using EMSA, chromatin immunoprecipitation assay and siRNA. Lastly, the role of the zinc transporter SLC39A14 on the basal expression of SOCS3 was evaluated. Results indicate that SOCS3 expression is regulated by zinc through an MTF-1-dependent mechanism. In addition, results from siRNA experiments suggest that SLC39A14 is required for basal expression of SOCS3. Further studies are needed to determine whether zinc status affects SOCS3 function. PMID- 23026492 TI - Effects of ALA, EPA and DHA in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. AB - We compared the cardiovascular, hepatic and metabolic responses to individual dietary n-3 fatty acids (alpha-linolenic acid, ALA; eicosapentaenoic acid, EPA; and docosahexaenoic acid, DHA) in a high-carbohydrate, high-fat diet-induced model of metabolic syndrome in rats. Additionally, we measured fatty acid composition of plasma, adipose tissue, liver, heart and skeletal muscle in these rats. The same dosages of ALA and EPA/DHA produced different physiological responses to decrease the risk factors for metabolic syndrome. ALA did not reduce total body fat but induced lipid redistribution away from the abdominal area and favorably improved glucose tolerance, insulin sensitivity, dyslipidemia, hypertension and left ventricular dimensions, contractility, volumes and stiffness. EPA and DHA increased sympathetic activation, reduced the abdominal adiposity and total body fat and attenuated insulin sensitivity, dyslipidemia, hypertension and left ventricular stiffness but not glucose tolerance. However, ALA, EPA and DHA all reduced inflammation in both the heart and the liver, cardiac fibrosis and hepatic steatosis. These effects were associated with complete suppression of stearoyl-CoA desaturase 1 activity. Since the physiological responses to EPA and DHA were similar, it is likely that the effects are mediated by DHA with EPA serving as a precursor. Also, ALA supplementation increased DHA concentrations but induced different physiological responses to EPA and DHA. This result strongly suggests that ALA has independent effects in metabolic syndrome, not relying on its metabolism to DHA. PMID- 23026493 TI - Zinc inhibits magnesium-dependent migration of human breast cancer MDA-MB-231 cells on fibronectin. AB - Metastasis is the major cause of breast cancer mortality. The strength of cell adhesion to extracellular matrix is critical to cancer cell migration. Integrins, the primary mediators of cell to extra-cellular matrix adhesion, contain distinct divalent cation-binding sites. Binding of manganese and magnesium is vital to integrin-mediated cancer cell adhesion and migration. We hypothesized that zinc, a divalent cation, can modulate breast cancer metastasis through interfering with these divalent cation-dependent integrin-mediated cancer cell adhesion and migration. MDA-MB-231 cells were cultured in a zinc-depleted medium supplemented with 0 (control), 2.5, 5, 10, 25 and 50 MUM of zinc to mimic severe zinc deficiency, moderate zinc-deficiency, adequate zinc and three levels of zinc supplementation: low-, moderate- and high-levels of zinc-supplementation, respectively. Zinc treatments had no effect on cellular zinc concentration, cell number and cell viability. Zinc at 5-50 MUM reduced migration distance of MDA-MB 231 cells on fibronectin by 43-86% and migration rate on fibronectin by 72-90%. Zinc induced a dose-dependent inhibition of cell adhesion to fibronectin (R(2)= 0.98). Zinc at 10-50 MUM reduced magnesium-facilitated cell adhesion to fibronectin in a dose-dependent manner (R(2)=-0.90). However, zinc had no effect on manganese-facilitated cell adhesion to fibronectin. Zinc at 5-50 MUM caused rounding of the normally elongated, irregular-shaped MDA-MB-231 cells and disappearance of F-actin. Anti-integrin alpha5- and beta1-subunit blocking antibodies inhibited magnesium-facilitated cell adhesion to fibronectin by 95 and 99%, respectively. In summary, zinc inhibited MDA-MB-231 cell migration on fibronectin by interfering with magnesium-dependent integrin-, likely integrin alpha5/beta1-, mediated adhesion. PMID- 23026494 TI - Capsiate improves glucose metabolism by improving insulin sensitivity better than capsaicin in diabetic rats. AB - Red peppers and red pepper paste are reported to have anti-obesity, analgesic and anti-inflammatory effects in animals and humans due to the capsaicin in red pepper. We investigated whether consuming capsaicin and capsiate, a nonpungent capsaicin analogue, modifies glucose-stimulated insulin secretion, pancreatic beta-cell survival and insulin sensitivity in 90% pancreatectomized (Px) diabetic rats, a moderate and non-obese type 2 diabetic animal model. Px diabetic rats were divided into 3 treatment groups: 1) capsaicin (Px-CPA), 2) capsiate (Px-CPI) or 3) dextrose (Px-CON) and provided high fat diets (40 energy % fat) containing assigned components (0.025% capsaicin, capsiate, or dextrose) for 8 weeks. Both capsaicin and capsiate reduced body weight gain, visceral fat accumulation, serum leptin levels and improved glucose tolerance without modulating energy intake in diabetic rats. In comparison to the control, both capsaicin and capsiate potentiated first and second and phase insulin secretion during hyperglycemic clamp. Both also increased beta-cell mass by increasing proliferation and decreasing apoptosis of beta-cells by potentiating insulin/IGF-1 signaling. However, only capsiate enhanced hepatic insulin sensitivity during euglycemic hyperinuslinemic clamp. Capsiate reduced hepatic glucose output and increased triglyceride accumulation in the hyperinsulinemic state and capsiate alone significantly increased glycogen storage. This was related to enhanced pAkt >PEPCK and pAMPK signaling. Capsaicin and capsiate reduced triglyceride storage through activating pAMPK. In conclusion, capsaicin and capsiate improve glucose homeostasis but they differently enhance insulin sensitivity in the liver, insulin secretion patterns, and islet morphometry in diabetic rats. Capsiate has better anti-diabetic actions than capsaicin. PMID- 23026496 TI - The neuropeptide transcriptome of a model echinoderm, the sea urchin Strongylocentrotus purpuratus. AB - Neuronal secretion of peptide signaling molecules (neuropeptides) is an evolutionarily ancient feature of nervous systems. Here we report the identification of 20 cDNAs encoding putative neuropeptide precursors in the sea urchin Strongylocentrotus purpuratus (Phylum Echinodermata), providing new insights on the evolution and diversity of neuropeptides. Identification of a gonadotropin-releasing hormone-like peptide precursor (SpGnRHP) is consistent with the widespread phylogenetic distribution of GnRH-type neuropeptides in the bilateria. A protein (SpTRHLP) comprising multiple copies of peptides that share structural similarity with thyrotropin-releasing hormone (TRH) is the first TRH like precursor to be identified in an invertebrate. SpCTLP is the first calcitonin-like peptide with two N-terminally located cysteine residues to be found in a non-chordate species. Discovery of two proteins (SpPPLNP1, SpPPLNP2) comprising homologs of molluscan pedal peptides and arthropod orcokinins indicates the existence of a bilaterian family of pedal peptide/orcokinin-type neuropeptides. Other proteins identified contain peptides that do not share apparent sequence similarity with known neuropeptides. These include Spnp5, which comprises multiple copies of C-terminally amidated peptides that have an N terminal Ala-Asn motif (AN peptides), and Spnp9, Spnp10 and Spnp12, which contain putative neuropeptides with a C-terminal Phe-amide, Ser-amide or Pro-amide, respectively. Several proteins (Spnp11, 14, 15, 16, 17, 18, 19 and 20) contain putative neuropeptides with multiple cysteine residues (2, 6 or 8), which may mediate formation of intramolecular or intermolecular disulphide bridges. Looking ahead, the identification of these neuropeptide precursors in S. purpuratus has provided a strong basis for a comprehensive analysis of neuropeptide function in this model echinoderm species. PMID- 23026495 TI - Hypothalamic-pituitary-adrenal (HPA) axis function in the California mouse (Peromyscus californicus): Changes in baseline activity, reactivity, and fecal excretion of glucocorticoids across the diurnal cycle. AB - The California mouse, Peromyscus californicus, is an increasingly popular animal model in behavioral, neural, and endocrine studies, but little is known about its baseline hypothalamic-pituitary-adrenal (HPA) axis activity or HPA responses to stressors. We characterized plasma corticosterone (CORT) concentrations in P. californicus under baseline conditions across the diurnal cycle, in response to pharmacological manipulation of the HPA axis, and in response to a variety of stressors at different times of day. In addition, we explored the use of fecal samples to monitor adrenocortical activity non-invasively. California mice have very high baseline levels of circulating CORT that change markedly over 24h, but that do not differ between the sexes. This species may be somewhat glucocorticoid resistant in comparison to other rodents as a relatively high dose of dexamethasone (5mg/kg, s.c.) was required to suppress plasma CORT for 8h post injection. CORT responses to stressors and ACTH injection differed with time of day, as CORT concentrations were elevated more readily during the morning (inactive period) than in the evening (active period) when compared to time matched control. Data from (3)H-CORT injection studies show that the time course for excretion of fecal CORT, or glucocorticoid metabolites, differs with time of injection. Mice injected in the evening excreted the majority of fecal radioactivity 2-4h post-injection whereas mice injected during the morning did so at 14-16h post-injection. Unfortunately, the antibody we used does not adequately bind the most prevalent fecal glucocorticoid metabolites and therefore we could not validate its use for fecal assays. PMID- 23026497 TI - The diagnostic value of specific IgE to Ara h 2 to predict peanut allergy in children is comparable to a validated and updated diagnostic prediction model. AB - BACKGROUND: A diagnostic prediction model for peanut allergy in children was recently published, using 6 predictors: sex, age, history, skin prick test, peanut specific immunoglobulin E (sIgE), and total IgE minus peanut sIgE. OBJECTIVES: To validate this model and update it by adding allergic rhinitis, atopic dermatitis, and sIgE to peanut components Ara h 1, 2, 3, and 8 as candidate predictors. To develop a new model based only on sIgE to peanut components. METHODS: Validation was performed by testing discrimination (diagnostic value) with an area under the receiver operating characteristic curve and calibration (agreement between predicted and observed frequencies of peanut allergy) with the Hosmer-Lemeshow test and a calibration plot. The performance of the (updated) models was similarly analyzed. RESULTS: Validation of the model in 100 patients showed good discrimination (88%) but poor calibration (P < .001). In the updating process, age, history, and additional candidate predictors did not significantly increase discrimination, being 94%, and leaving only 4 predictors of the original model: sex, skin prick test, peanut sIgE, and total IgE minus sIgE. When building a model with sIgE to peanut components, Ara h 2 was the only predictor, with a discriminative ability of 90%. Cutoff values with 100% positive and negative predictive values could be calculated for both the updated model and sIgE to Ara h 2. In this way, the outcome of the food challenge could be predicted with 100% accuracy in 59% (updated model) and 50% (Ara h 2) of the patients. CONCLUSIONS: Discrimination of the validated model was good; however, calibration was poor. The discriminative ability of Ara h 2 was almost comparable to that of the updated model, containing 4 predictors. With both models, the need for peanut challenges could be reduced by at least 50%. PMID- 23026499 TI - Asthma symptom utility index: reliability, validity, responsiveness, and the minimal important difference in adult asthmatic patients. AB - BACKGROUND: The evaluation of asthma symptoms is a core outcome measure in asthma clinical research. The Asthma Symptom Utility Index (ASUI) was developed to assess the frequency and severity of asthma symptoms. The psychometric properties of the ASUI are not well characterized, and a minimal important difference (MID) is not established. OBJECTIVES: We assessed the reliability, validity, and responsiveness to change of the ASUI in a population of adult asthmatic patients. We also sought to determine the MID for the ASUI. METHODS: Adult asthmatic patients (n = 1648) from 2 previously completed multicenter randomized trials were included. Demographic information, spirometric results, ASUI scores, and other asthma questionnaire scores were obtained at baseline and during follow-up visits. Participants also kept a daily asthma diary. RESULTS: The internal consistency reliability of the ASUI was 0.74 (Cronbach alpha). Test-retest reliability was 0.76 (intraclass correlation). Construct validity was demonstrated by significant correlations between ASUI scores and Asthma Control Questionnaire scores (Spearman correlation r = -0.79; 95% CI, -0.85 to -0.75; P < .001) and Mini Asthma Quality of Life Questionnaire scores (r = 0.59; 95% CI, 0.51-0.61; P < .001). Responsiveness to change was demonstrated, with significant differences between mean changes in ASUI scores across groups of participants differing by 10% in percent predicted FEV(1) (P < .001) and by 0.5 points in Asthma Control Questionnaire scores (P < .001). Anchor-based and statistical methods support an MID for the ASUI of 0.09 points. CONCLUSIONS: The ASUI is reliable, valid, and responsive to changes in asthma control over time. The MID of the ASUI (range of scores, 0-1) is 0.09. PMID- 23026498 TI - Epigenetic mechanisms and the development of asthma. AB - Asthma is heritable, influenced by the environment, and modified by in utero exposures and aging; all of these features are also common to epigenetic regulation. Furthermore, the transcription factors that are involved in the development of mature T cells that are critical to the T(H)2 immune phenotype in asthmatic patients are regulated by epigenetic mechanisms. Epigenetic marks (DNA methylation, modifications of histone tails, and noncoding RNAs) work in concert with other components of the cellular regulatory machinery to control the spatial and temporal levels of expressed genes. Technology to measure epigenetic marks on a genomic scale and comprehensive approaches to data analysis have recently emerged and continue to improve. Alterations in epigenetic marks have been associated with exposures relevant to asthma, particularly air pollution and tobacco smoke, as well as asthma phenotypes, in a few population-based studies. On the other hand, animal studies have begun to decipher the role of epigenetic regulation of gene expression associated with the development of allergic airway disease. Epigenetic mechanisms represent a promising line of inquiry that might, in part, explain the inheritance and immunobiology of asthma. PMID- 23026501 TI - Severe renal osteodystrophy in a pediatric patient with end-stage renal disease: Sagliker syndrome? AB - Renal osteodystrophy (ROD) is a multifactorial disorder of bone metabolism in chronic kidney disease (CKD). As CKD progresses, ensuing abnormalities in vitamin D metabolism and parathyroid hormone (PTH) secretion result in distortions in trabecular microarchitecture, thinning of the cortical shell, and increased cortical porosity. The recently described Sagliker syndrome (SS) might be an exaggerated version of ROD and is a very striking and prominent feature of secondary hyperparathyroidism in patients with end-stage renal disease (ESRD). It includes a distorted facial appearance, short stature, extremely severe maxillary and mandibulary changes, soft tissue tumors in the mouth, teeth/dental abnormalities, fingertip changes, knee and scapula deformities, hearing abnormalities, and neurologic and psychological problems. We herein describe an affected 14-year-old girl with severe ROD resulting from ESRD, who had severe peripheral and central neurologic problems caused by bone deformities, mimicking the features of Sagliker syndrome. PMID- 23026500 TI - Conceptions of daily life in men living with a woman suffering from chronic obstructive pulmonary disease. AB - AIM: To describe conceptions of daily life in men living with a woman suffering from chronic obstructive pulmonary disease (COPD) in different stages of the disease. BACKGROUND: A chronic disease like COPD affects not only the person living with the illness, but also the spouse. Significant tasks and demands are placed on husbands. COPD has for a long time been considered more a man's disease than a woman's disease, but according to new evidence COPD is a vast problem in women, which requires support from their spouses. The literature review did not reveal any previous studies concerning conceptions of daily life in men living with women suffering from COPD in different stages. METHODS: A phenomenographic study was conducted. Data were collected from October 2008 to October 2009 through semi-structured interviews with 19 men living with a woman suffering from COPD. FINDINGS: Two main descriptive categories were found: (1) unchanged life situation where no support was needed; (2) changed life situation related to severity of COPD, where support was needed. The categories were described from the perspective 'ME and my spouse'. Even in their caregiving situation, the men continued with their own life and activities and did not put themselves in second place. No support was needed from healthcare or municipality when the women had mild COPD, but this changed when the COPD progressed. The men felt that daily life was burdened, restricted and the partner relationship was affected, even if the disease had not reached the final stage. The COPD forced them gradually into a caregiving role, and their daily life changed. They become more of a caregiver than a spouse. The men experienced lack of knowledge and support, and they felt that health professionals and municipality did not care about them. PMID- 23026502 TI - Role of nutrition impact symptoms in predicting nutritional status and clinical outcome in hemodialysis patients: a potential screening tool. AB - OBJECTIVE: This study aims to establish the utility of the Nutrition Impact Symptoms (NIS), a part of the Patient-Generated Subjective Global Assessment (PG SGA) as a nutritional screening tool in patients receiving hemodialysis (HD). DESIGN: This was a prospective observational study. SETTING: The study took place in a single public tertiary in-center dialysis facility in Australia. SUBJECTS: Patients included 213 individuals receiving maintenance HD for at least 3 months who were older than 18 years of age (mean age, 58.9 +/- 16.3 years; 55.4% [n = 118] male patients). MAIN OUTCOME MEASURE: Malnutrition, which was classified by the Subjective Global Assessment rating (SGA, B or C) and the nutrition-related clinical outcome (decline in weight [>5%], SGA, reduction in serum albumin [>5 g/L]), or 12-month mortality. RESULTS: Patients assessed as malnourished totaled 23.5% (n = 50). Total PG-SGA and NIS scores showed a comparable ability to predict malnutrition (area under the curve, 0.93 [95% confidence interval {CI}, 0.90-0.97] and 0.86 [95% CI, 0.80-0.93], respectively). NIS (score >=2) was independently related to poor nutrition-related clinical outcome (odds ratio [OR], 3.03; 95% CI, 1.47-6.20) and mortality (OR, 1.11; 95% CI, 1.03-1.20) adjusted for age, dialysis vintage, serum albumin level, and comorbidities. CONCLUSIONS: NIS score is a promising nutritional screening tool for the identification of patients receiving hemodialysis who are at risk of malnutrition and poor clinical outcome. Further research is required to investigate the reliability and utility of this tool in a larger population group. PMID- 23026503 TI - The burden of narcolepsy with cataplexy: how disease history and clinical features influence socio-economic outcomes. AB - OBJECTIVE: To investigate in narcolepsy with cataplexy (NC) patients of working age (18-65 years) the influence of age at onset, age at diagnosis and clinical features on socio-occupational conditions, disease-related economic burden, and quality of life. METHODS: One hundred consecutive patients underwent a semistructured interview on socio-occupational aspects, NC-related direct and indirect costs, and NC history. Questionnaires were used to evaluate excessive daytime sleepiness, cataplexy, depressive symptoms, and quality of life. RESULTS: NC patients (51 males, mean age 37+/-11.5 years) had educational and occupational levels similar to those of the Italian population of the same age range, but married less often, especially if NC onset occurred at a young age. Total annual NC-related costs were ?9814 +/- 10,372 per patient. Multivariate analyses showed that patients with NC onset before the age of 30 years had a higher educational level, married less frequently, and were less frequently unemployed or inactive (retired, housewife). Patients diagnosed before the age of 30 years were less frequently unemployed or inactive, had fewer work changes, and had a better general health perception. Irresistible sleepiness was associated with work absences and higher indirect costs. Depressive symptoms were strongly associated with lower quality-of-life scores. CONCLUSIONS: NC age at onset and at diagnosis modulates the disease-related burden. A diagnosis at a young age could improve patients' occupational prognosis, and their general health perception. PMID- 23026504 TI - Teenage sleep-disordered breathing: recurrence of syndrome. AB - OBJECTIVES: The study aims to better understand the reappearance of sleep apnoea in adolescents considered cured of obstructive sleep apnoea (OSA) following adenotonsillectomy and orthodontic treatment. STUDY DESIGN: The study employs a retrospective analysis of 29 adolescents (nine girls and 20 boys) with OSA previously treated with adenotonsillectomy and orthodontia at a mean age of 7.5years. During follow-up at 11 and 14years of age, patients were clinically evaluated, filled the Pediatric Sleep Questionnaire (PSQ) and had systematic cephalometric X-rays performed by orthodontists. Polysomnographic (PSG) data were compared at the time of OSA diagnosis, following surgical and orthodontic treatment and during pubertal follow-up evaluation. RESULTS: Following the diagnosis of OSA and treatment with adenotonsillectomy and rapid maxillary expansion (Apnea-Hypopnea Index (AHI) 0.4+/-0.4), children were re-evaluated at a mean age of 11years. During follow-up at 14years, all children had normal body mass indices (BMIs). Teenagers were subdivided into two groups based on complaints: Nine asymptomatic subjects (seven girls and two boys) and 20 subjects with decline in school performance, presence of fatigue, indicators of sleep phase delays and, less frequently, specific symptoms of daytime sleepiness and snoring. Presence of mouth breathing, abnormal AHI and RDI and significant reduction of posterior airway space (PAS) was demonstrated during repeat polysomnography and cephalometry. Compared to cephalometry obtained at a mean of 11years of age, there was a significant reduction of PAS of 2.3+/-0.4mm at a mean age of 14years. CONCLUSION: Previously suggested recurrence of OSA during teenage years has again been demonstrated in this small group of subjects. Prospective investigations are needed to establish frequency of risk, especially in non orthodontically treated children. PMID- 23026505 TI - How smoking affects sleep: a polysomnographical analysis. AB - OBJECTIVE: Subjective quality of sleep is impaired in smokers compared with non smokers, but there is only limited evidence from methodologically sound studies about differences in polysomnography (PSG) sleep characteristics. Therefore, this study used PSG to evaluate sleep in smokers and non-smokers while controlling for other parameters that affect sleep. METHODS: After an adaptation night, PSG sleep laboratory data were obtained from 44 smokers (29 men and 15 women, median age 29.6 years) and compared with PSG data from 44 healthy, sex- and age-matched never smokers. Exclusion criteria were alcohol or other substance abuse, psychiatric or endocrine diseases, and treatment with any kind of psychotropic medication. Nicotine and cotinine plasma levels were measured (in the smoking group) and subjective sleep quality assessed in both groups. RESULTS: The smokers had a Fagerstrom tolerance score of 6.4, consumed an average of 21.2 cigarettes per day and had been smoking for 13.1 years (median). Smokers had a shorter sleep period time, longer sleep latency, higher rapid eye movement sleep density, more sleep apneas and leg movements in sleep than non-smokers. There were no differences regarding parameters of spectral analysis of the sleep electroencephalogram as well as in the sleep efficiency measured by PSG. Nevertheless smokers rated their sleep efficiency lower on the Pittsburgh Sleep Quality Index compared with non-smoking individuals, but no differences were detected on the SF-A. Plasma cotinine level correlated negatively with slow wave sleep in the smoking group. CONCLUSIONS: Smokers showed a number of insomnia-like sleep impairments. The findings suggest that it is important for sleep researchers to control smoking status in their analyses. Further research should focus on the causes and consequences of impaired sleep during tobacco cessation, as sleep disturbances are a known risk factor for early relapse after initial tobacco abstinence. PMID- 23026506 TI - Longitudinal studies of insomnia: current state and future challenges. PMID- 23026507 TI - Numismatic support for a case of snoring secondary to retrognathia. PMID- 23026508 TI - Development of a health information technology acceptance model using consumers' health behavior intention. AB - BACKGROUND: For effective health promotion using health information technology (HIT), it is mandatory that health consumers have the behavioral intention to measure, store, and manage their own health data. Understanding health consumers' intention and behavior is needed to develop and implement effective and efficient strategies. OBJECTIVE: To develop and verify the extended Technology Acceptance Model (TAM) in health care by describing health consumers' behavioral intention of using HIT. METHODS: This study used a cross-sectional descriptive correlational design. We extended TAM by adding more antecedents and mediating variables to enhance the model's explanatory power and to make it more applicable to health consumers' behavioral intention. Additional antecedents and mediating variables were added to the hypothetical model, based on their theoretical relevance, from the Health Belief Model and theory of planned behavior, along with the TAM. We undertook structural equation analysis to examine the specific nature of the relationship involved in understanding consumers' use of HIT. Study participants were 728 members recruited from three Internet health portals in Korea. Data were collected by a Web-based survey using a structured self administered questionnaire. RESULTS: The overall fitness indices for the model developed in this study indicated an acceptable fit of the model. All path coefficients were statistically significant. This study showed that perceived threat, perceived usefulness, and perceived ease of use significantly affected health consumers' attitude and behavioral intention. Health consumers' health status, health belief and concerns, subjective norm, HIT characteristics, and HIT self-efficacy had a strong indirect impact on attitude and behavioral intention through the mediators of perceived threat, perceived usefulness, and perceived ease of use. CONCLUSIONS: An extended TAM in the HIT arena was found to be valid to describe health consumers' behavioral intention. We categorized the concepts in the extended TAM into 3 domains: health zone, information zone, and technology zone. PMID- 23026509 TI - Vitamin D status and the Cdx-2 polymorphism of the vitamin D receptor gene are determining factors of bone mineral density in young healthy postmenopausal women. AB - Bone mineral density (BMD) is a main determinant of osteoporotic fractures. A cross-sectional study was conducted in 229 young, healthy postmenopausal women (PMW) to evaluate the contribution of the vitamin D endocrine system and other clinical, biochemical and genetic parameters. Clinical risk factors for osteoporosis were obtained by a questionnaire. Serum concentrations of 25OHD, 1,25(OH)2D, PTH, and bone turnover markers were measured. The BsmI, FokI and Cdx 2 polymorphisms of the vitamin D receptor (VDR) gene were determined. DXA and the WHO criteria were applied for the diagnosis of osteoporosis. Univariate logistic and multivariate logistic regression analyses were carried out. RESULTS: The prevalence of vitamin D deficiency (<50nmol/l) was 50%. Age increased osteoporosis risk; whereas body mass index (BMI), number of reproductive years, 25OHD level and the Cdx-2 polymorphism in the VDR gene (when allele A is present) were found to be protective. Therefore, both serum 25OHD and VDR polymorphism should be taken into account in the evaluation and implementation of therapeutic strategies concerning PMW, especially as the prevalence of vitamin D deficiency is still alarmingly high even at Southern latitudes. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23026510 TI - Differential response to 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) in non small cell lung cancer cells with distinct oncogene mutations. AB - We previously demonstrated that non-small cell lung cancer (NSCLC) cells and primary human lung tumors aberrantly express the vitamin D3-catabolizing enzyme, CYP24, and that CYP24 restricts transcriptional regulation and growth control by 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) in NSCLC cells. To ascertain the basis for CYP24 dysregulation, we assembled a panel of cell lines that represent distinct molecular classes of lung cancer: cell lines were selected which harbored mutually exclusive mutations in either the K-ras or the Epidermal Growth Factor Receptor (EGFR) genes. We observed that K-ras mutant lines displayed a basal vitamin D receptor (VDR)(low)CYP24(high) phenotype, whereas EGFR mutant lines had a VDR(high)CYP24(low) phenotype. A mutation-associated difference in CYP24 expression was also observed in clinical specimens. Specifically, K-ras mutation was associated with a median 4.2-fold increase in CYP24 mRNA expression (p=4.8*10(-7)) compared to EGFR mutation in a series of 147 primary lung adenocarcinoma cases. Because of their differential basal expression of VDR and CYP24, we hypothesized that NSCLC cells with an EGFR mutation would be more responsive to 1,25(OH)2D3 treatment than those with a K-ras mutation. To test this, we measured the ability of 1,25(OH)2D3 to increase reporter gene activity, induce transcription of endogenous target genes, and suppress colony formation. In each assay, the extent of 1,25(OH)2D3 response was greater in EGFR mutation positive HCC827 and H1975 cells than in K-ras mutation-positive A549 and 128.88T cells. We subsequently examined the effect of combining 1,25(OH)2D3 with erlotinib, which is used clinically in the treatment of EGFR mutation-positive NSCLC. 1,25(OH)2D3/erlotinib combination resulted in significantly greater growth inhibition than either single agent in both the erlotinib-sensitive HCC827 cell line and the erlotinib-resistant H1975 cell line. These data are the first to suggest that EGFR mutations may identify a lung cancer subset which remains responsive to and is likely to benefit from 1,25(OH)2D3 administration. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23026511 TI - 1alpha,25(OH)2-dihydroxyvitamin D3/VDR protects the skin from UVB-induced tumor formation by interacting with the beta-catenin pathway. AB - Ultra violet (UV) irradiation, in particular UVB, is the single most important carcinogen for skin tumor formation. UVB induces genetic mutations and immune suppression, which lead to abnormal cell proliferation and eventually tumor formation. Previously studies from our group and others demonstrated that both global and epidermal specific VDR knock out mice are predisposed to either chemical (DMBA)- or long-term UVB-induced skin tumor formation, paralleled by an increase in beta-catenin signaling. Using primary cultured human keratinocytes, we further demonstrated that 1,25(OH)2-dihydroxyvitamin D3 (1,25(OH)2D3) suppresses cyclin D1 and Gli1 which are regulated by beta-catenin/TCF signaling and have a critical role in epidermal carcinogenesis. Blockage of VDR by siRNA resulted in hyperproliferation of keratinocytes, and increased expression of cyclin D1 and Gli1. In addition, we also showed that 1,25(OH)2D3/VDR directly regulates transcriptional activity of beta-catenin/TCF signaling using the catenin reporter TopGlow. Using K14 driven tamoxifen-induced cre recombinase to delete both VDR and beta-catenin in keratinocytes of mice following the first hair follicle cycle, we found that ablation of epidermal specific beta-catenin cannot rescue VDR null mice from UVB-induced skin tumor formation. Further study using VDR or beta-catenin single null mice is necessary to compare with the data from double null mice. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23026512 TI - Validation of the association between PSMA6 -8 C/G polymorphism and type 2 diabetes mellitus in Chinese Dongxiang and Han populations. AB - OBJECTIVE: The aim of our study was to validate association between -8 C/G variant of PSMA6 gene and T2DM in Chinese Dongxiang and Han populations. METHOD: We genotyped PSMA6 gene -8 C/G polymorphism in the control groups and T2DM groups in two populations from China using PCR-RFLP technique. Phenotypes and biochemical indicators were measured by biochemical technique. RESULT: The frequencies of CG+GG genotype were observably different from CC genotype in the T2DM groups and control groups (for Dongxiang population: OR = 1.341, 95% CI: 1.101-1.632, P = 0.004; for Han population: OR = 1.313, 95% CI: 1.085-1.569, P = 0.006 after adjusting for gender, age, and BMI, respectively). In the Dongxiang population, the FPG, HOMA-IR, SBP and TG levels of CG+GG genotype were markedly higher than those of the CC genotype in control group (all P < 0.05). However, in the Han population, we only found that the FPI level of the CC genotype was significantly higher than that of the CG+GG genotype in control group (P < 0.05). CONCLUSION: Our investigation suggests that -8 C/G variant of PSMA6 gene may be associated with T2DM and diabetes-related metabolic traits in Chinese Dongxiang and Han populations. PMID- 23026513 TI - Human umbilical cord blood-derived mesenchymal stem cells prevent diabetic renal injury through paracrine action. AB - AIMS: The present study examined renoprotective effect of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) in diabetes. NRK-52E cells were utilized to determine the paracrine effect of hUCB-MSC. METHODS: hUCB was harvested with the mother's consent. MSC obtained from the hUCB were injected through the tail vein. Growth arrested and synchronized NRK-52E cells were stimulated with transforming growth factor-beta1 (TGF-beta1) in the presence of hUCB-MSC conditioned media. RESULTS: At 4 weeks after the streptozotocin (STZ) injection, diabetic rats showed significantly increased urinary protein excretion, renal and glomerular hypertrophy, fractional mesangial area, renal expression of TGF-beta1 and alpha-smooth muscle actin, and collagen accumulation but decreased renal E-cadherin and bone morphogenic protein-7 expression, confirming diabetic renal injury. hUCB-MSC effectively prevented diabetic renal injury except renal and glomerular hypertrophy without a significant effect on blood glucose. CM-DiI-labeled hUCB-MSC and immunostaining of PKcs, a human nuclei antigen, confirmed a few engraftment of hUCB-MSC in diabetic kidneys. hUCB-MSC conditioned media inhibited TGF-beta1-induced extracellular matrix upregulation and epithelial-to-mesenchymal transition in NRK-52E cells in a concentration dependent manner. CONCLUSIONS: These results demonstrate the renoprotective effect of hUCB-MSC in STZ-induced diabetic rats possibly through secretion of humoral factors and suggest hUCB-MSC as a possible treatment modality for diabetic renal injury. PMID- 23026514 TI - Increased thiamine intake may be required to maintain thiamine status during weight loss in patients with type 2 diabetes. AB - During weight loss, erythrocyte thiamine pyrophosphate (TPP) decreased (221+/-52 to 195+/-39 nmol/L, P<0.05) on a diet with adequate thiamine (1.1 mg/day) but was unchanged (217+/-55 vs 218+/-52 nmol/L, NS) on a high thiamine diet (2.8 mg/day). Attention to thiamine status may be required in patients with diabetes after weight loss. PMID- 23026515 TI - Metal exposure in child workers: assessing hazards in surgical instrument manufacturing workshops. PMID- 23026516 TI - Association between high fat-low carbohydrate diet score and newly diagnosed type 2 diabetes in Chinese population. AB - OBJECTIVE: To study the association between high fat-low carbohydrate diet score and newly diagnosed type 2 diabetes in Chinese population. METHODS: Data about 20 717 subjects aged 45-59 years from the cross-sectional 2002 China National Nutrition and Health Survey were analyzed. High fat-low carbohydrate diet was scored according to the energy of carbohydrate, fat, and protein. RESULTS: Of the 20 717 subjects, 1 332 were diagnosed with hyperglycemia and 662 were newly diagnosed with type 2 diabetes. Multivariate adjusted analysis showed that the highest score of type 2 diabetes patients was 2.75 (95% CI: 2.09-3.61). The score of type 2 diabetes patients was 1.87 (95% CI: 1.35-2.58) after further adjustment for their socioeconomic status and physical activity. No significant difference was found in the odds ratio after further adjustment for BMI, blood pressure, lipid level, and energy intake. No evidence was observed for the relation between high fat-low carbohydrate-diet score in type 2 diabetes patients due to high family income, less education, physical activity, overweight, hypertension, high TG, or low HDL level. CONCLUSION: High fat-low carbohydrate diets, far different from traditional Chinese diets, are associated with the high incidence of type 2 diabetes in Chinese population. PMID- 23026517 TI - The prevalence of nonalcoholic fatty liver disease and its association with lifestyle/dietary habits among university faculty and staff in Chengdu. AB - OBJECTIVE: To investigate the prevalence of nonalcoholic fatty liver disease (NAFLD) in different university categories and its association with lifestyle/dietary habits. METHODS: A cross-sectional study was carried out on 9 378 faculty members and staff who participated in an annual health checkup at three universities selected by random cluster sampling. Demographic, anthropometric, biochemical indices and abdominal ultrasound measurements were collected. A nested case-control study was conducted with 200 NAFLD cases and 200 controls matched by gender, age (+/-3 years), and university. RESULTS: The overall prevalence of NAFLD was 10.3% (13.7% in males and 6.8% in females). The prevalence was significantly higher in the science and engineering university (22.1%) than in the comprehensive universities with (6.4%) and without (10.9%) medical colleges. Obesity/overweight, hyperlipidemia, diabetes mellitus, and family history of NAFLD were independently associated with higher risk of NAFLD, as were frequent consumption of desserts and salty/spicy foods. Using nutritional supplements was a protective factor against NAFLD. Intake of coarse cereals, potatoes, vegetables, fruits, and milk was significantly lower, and intake of red meat, viscera, candies and pastries, cooking oil, and total energy was significantly higher in participants with NAFLD than in controls. CONCLUSION: Science and engineering university faculty and staff are key targets for NAFLD prevention. NAFLD is closely associated with age, gender, university type, metabolic diseases, and lifestyle/dietary habits. PMID- 23026518 TI - Dietary calcium decreases plasma cholesterol level only in female but not in male hamster fed a high cholesterol diet. AB - OBJECTIVE: To investigate the effect of dietary calcium on plasma lipoprotein profile in castrated and ovariectomized hamsters. METHODS: Male, castrated, female and ovariectomized hamsters (n=36 each group) were randomly divided into three sub-groups (n=12) and fed one of the three diets containing 0, 2, and 8 g calcium per kg diet for a period of six weeks. Changes in plasma lipoprotein profile were monitored at the end of week 0, 3 and 6. RESULTS: Plasma total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C), triacylglycerols (TG) and TC/HDL-C were decreased only in intact female and ovariectomized hamsters. In contrast, three levels of dietary calcium had no effect on lipoprotein profiles in both intact male and castrated hamsters. CONCLUSION: Beneficial modification of lipoprotein profile by dietary calcium was gender-dependent at least in hamsters. PMID- 23026519 TI - Association between vitamin D insufficiency and the risk for gestational diabetes mellitus in pregnant Chinese women. AB - OBJECTIVE: To investigate the association between vitamin D deficiency and risk of gestational diabetes mellitus (GDM) in pregnant Chinese women. METHODS: A nested case-control study was conducted. Clinical and biochemical data were analyzed for 200 subjects with GDM and 200 subjects with normal glucose tolerance (NGT). RESULTS: The median (interquartile range) serum 25-hydroxyvitamin D (25OHD) levels were 22.39 (17.67, 29.38) and 25.86 (19.09, 34.88) nmol/L in the GDM and NGT groups, respectively. Rates of 25OHD deficiency or insufficiency were significantly higher in the GDM group than in the NGT group. Subjects with 25OHD levels <25 nmol/L had a 1.8-fold higher risk of GDM compared with subjects with higher vitamin D levels. In the GDM group, serum 25OHD was independently associated with HbA1c and insulin resistance after adjusting for confounding factors. In the NGT group, serum 25OHD was independently associated with fasting plasma glucose and systolic blood pressure after adjusting for maternal age and other confounding factors. CONCLUSION: 25OHD insufficiency is very common in Chinese women. Low 25OHD status may be associated with insulin resistance and act as a risk factor for GDM. PMID- 23026520 TI - Epidemiological survey of the prevalence of non-fatal injury among children aged 5-14 years in China. AB - OBJECTIVE: To determine the prevalence of non-fatal injuries among children aged 5-14 years in China. METHODS: Data of 21 973 children aged 5-14 years were extracted from the Fourth National Health Service Survey of China carried out between June 15 and July 10, 2008. Injury-related indicators included: history of ever having had an injury, and injury frequency, cause, location and severity. RESULTS: The overall prevalence of non-fatal injuries among the children in the previous 12 months was 17.0 per 1000 subjects. The leading causes of non-fatal injuries were falls, animal bites, traffic accidents, falling objects and burns. The majority of children sustained only one injury. The main place of injury was at home in 40% and 54% of urban boys and girls, respectively, at school in 48% of rural boys, and at home and at school each in 33% of rural girls. Medical treatment for one day was the main option for 80% of urban boys and girls, 84% of rural boys, and 72% of rural girls. CONCLUSION: Nonfatal injuries among children aged 5-14 years are a serious public health concern in China. PMID- 23026521 TI - An evaluation of the investment for child development in China. AB - OBJECTIVE: This study estimated the investment in child development from three aspects-public health, public education, and family investment to establish the level of investment, to provide reference information for government decision making and to provide international comparisons. METHODS: Public investment in health was measured with macro data related to public health spending and child development in government expenditure. Public education investment was based on basic education data. Family investment evaluation was based on per capita family consumer spending data in different age groups to estimate the input for child development. RESULTS: Both public health investment level and the proportion of GDP rose for all age groups over time, but the overall investment level was still insufficient. Public investment in children's education has increased year by year, but the trends in all age groups are unbalanced with much lower investment in early childhood education. Private investment in children has increased over the period, but has declined as a percentage of GDP. International comparisons show that Chinas investment in child development is much lower than OECD countries. CONCLUSION: The private investment in child development was the main way in China, with public finance contributing only a small proportion. Given the poor international comparisons, the government needs to review the balance of public investment to redirect more towards the development of children under the age of six to their health and education. PMID- 23026522 TI - Risk factors of low back pain among the Chinese occupational population: a case control study. AB - OBJECTIVE: To explore the risk factors of low back pain among the Chinese occupational population in several major industries. METHODS: A total of 7200 subjects (3600 cases and 3600 controls) were randomly sampled from a cross sectional study, and they were investigated for individual and occupational factors of low back pain. The potential risk factors were first selected by using chi-square tests. Secondly, collinearity diagnosis proceeded by using the Kendall's rank correlation. Finally, binary logistic regression model was used for multi-factor analysis. RESULTS: Collinearity diagnosis showed that there was a severe collinearity problem among the potential risk factors of low back pain. Logistic regression model included 20 variables with statistical significance. Bending neck forward or holding neck in a forward posture for long periods (OR=1.408) was the most important risk factor inducing low back pain in this study, followed by bending heavily with the trunk (OR=1.402), carrying out identical work almost for the whole day (OR=1.340). Additionally, sufficient normal break was a protective factor of low back pain. CONCLUSION: Low back pain among the Chinese occupational population was associated with body height, occupation, work organization, physical work, working posture, and others. All these risk factors could be regarded as the indicators of low back pain, and some relevant preventive measures should be taken to reduce low back pain risk. PMID- 23026523 TI - Study on the method of quantitative analysis of serum ferritin and soluble transferrin receptor with protein microarray technology. AB - OBJECTIVE: To establish and evaluate a protein microarray method for combined measurement of serum ferritin (SF) and soluble transferrin receptor (sTfR). METHODS: Microarrayer was used to print both anti-SF antibodies I and anti-sTfR antibodies I on each protein microarray. Anti-SF antibodies II and anti-sTfR antibodies II were used as detection antibodies and goat antibodies coupled to Cy3 were used as antibodies III. The detection conditions of the quantitative analysis method for simultaneous measurement of SF and sTfR with protein microarray were optimized and evaluated. The protein microarray was compared with commercially available traditional tests with 26 serum samples. RESULTS: By comparison experiment, mouse monoclonal antibodies were chosen as the probes and contact printing was chosen as the printing method. The concentrations of SF and sTfR probes were 0.5 mg/mL and 0.5 mg/mL respectively, while those of SF and sTfR detection antibodies were 5 MUg/mL and 0.36 MUg/mL respectively. Intra- and inter assay variability was between 3.26% and 18.38% for all tests. The regression coefficients comparing protein microarray with traditional test assays were better than 0.81 for SF and sTfR. CONCLUSION: The present study has established a protein microarray method for combined measurement of SF and sTfR. PMID- 23026524 TI - Comparative genomic analysis of gene variations of two Chinese Yersinia pestis isolates from vaccine strain EV76. AB - OBJECTIVE: To investigate genomic variations of two Chinese Yersinia pestis isolates that were isolated from different plague foci obtained from vaccine strain EV76 from the Yunnan province of China. METHODS: A microarray containing 12 000 probes covering the entire genome of seven Yersinia pestis and two Yersinia pseudotuberculosis strains, was used. PCR assays were performed to confirm microarray results. RESULTS: The gene variations detected included the absence of five genes related to the synthesis of betaine in both EV76 and another sequenced attenuated strain, KIM D27. Several genes related to phage related membrane proteins were found to be absent in the Antiqua biovar Yunnan strain, 485, which was isolated from a rodent plague foci. CONCLUSION: These findings provide initial insight into the distinct strains isolated from natural foci, within their genomic context, including Yunnan Y. pestis strains. This information will be used therefore to establish subsequent comparisons of these sequences with published complete genomes of other strains. PMID- 23026525 TI - Development of an enzyme-linked immunosorbent assay for determination of the furaltadone etabolite, 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ) in animal tissues. AB - OBJECTIVE: To determine 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ) residues released from protein bound AMOZ in animal tissues. METHODS: Polyclonal and monoclonal antibodies were produced in this study. A rapid, sensitive, and specific competitive direct enzyme-linked immunosorbent assay (cdELISA) was developed. RESULTS: Rabbit polyclonal antibodies were used in the optimized cdELISA method, and exhibited negligible cross-reactivity with other compounds structurally related to AMOZ. The IC(50) of the polyclonal antibody was 0.16 ng/mL. The method limit of detection in four different types of animal and fish tissues was less than 0.06 MUg/kg. Recoveries ranged from 80% to 120% for fortified samples with the coefficient of variation values less than 15%. The results of the cdELISA method were in good agreement with the results from an established liquid chromatography-tandem mass spectrometry confirmatory method used for AMOZ residues. CONCLUSION: The cdELISA method developed in the present study is a convenient practical tool for screening large numbers of animal and fish tissue samples for the the detection of released protein bound AMOZ residues. PMID- 23026526 TI - Assessing heat-related mortality risks in Beijing, China. AB - OBJECTIVE: To obtain the exposure-response relationship for temperature and mortality, and assess the risk of heat-related premature death. METHODS: A statistical model was developed using a Poisson generalized linear regression model with Beijing mortality and temperature data from October 1st, 2006 to September 30th, 2008. We calculated the exposure-response relationship for temperature and mortality in the central city, and inner suburban and outer suburban regions. Based on this relationship, a health risk model was used to assess the risk of heat-related premature death in the summer (June to August) of 2009. RESULTS: The population in the outer suburbs had the highest temperature related mortality risk. People in the central city had a mid-range risk, while people in the inner suburbs had the lowest risk. Risk assessment predicted that the number of heat-related premature deaths in the summer of 2009 was 1581. The city areas of Chaoyang and Haidian districts had the highest number of premature deaths. The number of premature deaths in the southern areas of Beijing (Fangshan, Fengtai, Daxing, and Tongzhou districts) was in the mid-range. CONCLUSION: Ambient temperature significantly affects human mortality in Beijing. People in the city and outer suburban area have a higher temperature-related mortality risk than people in the inner suburban area. This may be explained by a temperature-related vulnerability. PMID- 23026527 TI - S100A4 siRNA inhibits human pancreatic cancer cell invasion in vitro. AB - OBJECTIVE: Pancreatic cancer is one of the most deadly cancers, which is characterized by its high metastatic potential. S100A4 is a major prometastatic protein involved in tumor invasion and metastasis which precise role in pancreatic cancer has not been fully investigated. We knocked down the S100A4 gene in the Bxpc-3 pancreatic cancer cell line via RNA interference to study the changes in cell behavior. METHODS: Real-time polymerase chain reaction and western blotting were used to detect mRNA and protein expression levels of S100A4, matrix metalloproteinase (MMP)-2, E-cadherin and thrombospondin (TSP)-1. Transwell chambers were used to detect the migration and invasion abilities; a cell adhesion assay was used to detect adhesion ability; colony forming efficiency was used to detect cell proliferation; flow cytometry was used to detect apoptosis. RESULTS: S100A4 mRNA expression was reduced to 17% after transfection with S100A4-siRNA, and protein expression had a similar trend. mRNA and protein expression of MMP-2 was reduced and that of E-cadherin and TSP-1 was elevated, indicating that S100A4 affects their expression. S100A4-silenced cells exhibited a marked decrease in migration and invasiveness and increased adhesion, whereas overall proliferation and apoptosis were not overtly altered. CONCLUSION: S100A4 and its downstream factors play important roles in pancreatic cancer invasion, and silencing A100A4 can significantly contain the invasiveness of pancreatic cancer. PMID- 23026528 TI - Clinical and familial characteristics of ten chinese patients with fatal family insomnia. AB - OBJECTIVE: Fatal familial insomnia (FFI) is an autosomal dominant prion disease characterized clinically by inattention, sleep loss, dysautonomia, and motor signs. This study is aimed to investigate clinical and familial characteristics of ten Chinese Patients with FFI. METHODS: We identified ten FFI cases from the surveillance network for Creutafeldt-Jakob disease (CJD) in China. Final diagnosis of FFI cases was made in accordance with the WHO criteria for CJD. The main clinical features and family histories of these ten FFI cases were analyzed. RESULTS: The median age of ten cases at onset was 38 years (from 19 to 55). The foremost symptoms seemed to be various, including sleep disturbances, vision disorder, dizziness and anorexia. Sleep disturbances appeared in all cases and lasted in the whole clinical courses. Progressive sympathetic symptoms, memory loss, movement disturbances, myoclonus and hypertension were also frequently observed. The median duration of the disease was 9.5 months. EEG and MRI did not figure out special abnormality. 14-3-3 protein in CSF was positive in five out of eight tested patients. Clear family histories were identified in 8 patients. CONCLUSION: The data from our study confirm that the Chinese FFI cases have similar clinical characteristics as that of the Caucasian cases. Compared with other genetic CJD associated mutations, the genetic frequencies of D178N in PRNP are apparently high among the Chinese cases. PMID- 23026529 TI - The effect of some boron derivatives on kanamycin resistance and survival of E. coli and P. aeruginosa in lake water. AB - OBJECTIVE: To study MIC value of 7 boron derivatives namely [Boric acid (H(3)BO(3)), Anhydrous Borax (Na(2)B(4)O(7)), Sodium Borate (NaBO(2)), Diammonium Tetraborate (NH(4))(2)B(4)O(7), Sodium Perborate (NaBO(3)), Boron Trioxide (B(2)O(3)), Potassium Tetraborate (K(2)B(4)O(7))] on E. coli and P. aeruginosa and their effects on survival of bacteria in lake water and resistance against kanamycin antibiotic. METHODS: MIC values of Boron derivatives and antibiotic were studied by broth microdilution method. The effect of boron derivatives on survival of bacteria in lake water were also determined with plate count. RESULTS: Sodium perborate was determined as the most effective substance among the studied substances. Effectiveness increased as temperature increased. E. coli was more affected from P. aeruginosa in 8 mg/mL sodium perborate concentration in lake water. Moreover, it was determined that MIC value of kanamycin antibiotic decreased 200 times by especially treating P. aeruginosa with sodium perborate in lake water. However, it can be stated that this change in resistance did not arise from microorganisms. CONCLUSION: Sodium perborate solution can be used supportedly in kanamycin antibiotic applications for P. aeruginosa. Future studies are necessary to explore the relation between sodium perborate and kanamycin which is effective on P. aeruginosa in lake water. PMID- 23026530 TI - Estimates of tuberculosis mortality rates in China using the disease surveillance point system, 2004-2010. AB - OBJECTIVE: To understand the current status and trends of tuberculosis mortality rates in China. METHODS: In 2010, 161 National Disease Surveillance Points representing all 31 mainland provinces, municipalities, and autonomous regions of China collected tuberculosis mortality surveillance data, including age, sex, region, and type of tuberculosis (all, pulmonary, and extra-pulmonary). The mortality rates of the three types of tuberculosis were compared between 2004 and 2010. RESULTS: In 2010, the mortality rates due to all tuberculosis, pulmonary tuberculosis, and extra-pulmonary tuberculosis were 4.69 (95% CI 4.54-4.84), 4.38 (4.23-4.52), and 0.31 (0.27-0.35) per 100 000 population, respectively. Mortality rates due to all tuberculosis and pulmonary tuberculosis were higher in males, the elderly, and those living in western and rural areas. From 2004 to 2010, the mortality rates due to all tuberculosis and pulmonary tuberculosis decreased by 36.02% and 37.70%, respectively, with an average annual rate of decline of 7.20% and 7.61%, respectively. CONCLUSION: Mortality rates due to tuberculosis have declined rapidly in China. The target of reducing the 1990 mortality rate by 50% by 2015 has already been achieved. However, the tuberculosis control program should pay more attention to high-risk groups, including the elderly and those living in underdeveloped areas. PMID- 23026531 TI - Estimation of population-size changes and HIV prevalence among female sex workers from 2006 to 2009 in Kaiyuan, Yunnan, China. AB - OBJECTIVE: This study is to estimate the population size and prevalence of HIV and herpes simplex virus type 2 (HSV-2) infections among female sex workers (FSWs) in Kaiyuan, Yunnan Province, China. METHODS: Eight cross-sectional studies were conducted among FSWs in Kaiyuan from 2006 to 2009. Based on the data from two study time points each year, the total numbers of FSWs and HIV positive FSWs were estimated by using the capture-recapture technique (CR). RESULTS: Estimated sizes of FSWs in Kaiyuan were 1 629, 1 672, 1 186, and 1 014 in the respective years from 2006 to 2009. Although the crude prevalence rates of HIV and HSV-2 varied over time, the adjusted prevalence among this population was relatively stable at 10%-12% and the adjusted HSV-2 prevalence ranged from 67% to72%. CONCLUSION: The reason for the slight decrease of the size of the FSW population is unknown. The adjusted prevalence rates of HIV and HSV-2 among them were stable over the course of this study. PMID- 23026532 TI - INF-beta1b therapy modulates L-arginine and nitric oxide metabolism in patients with relapse remittent multiple sclerosis. AB - OBJECTIVE: The scope of this study is the examination of NO(2)+NO(3), 3 nitrotyrosine (3-NT), S-nitrosothiols (RSNO), arginase activity and asymmetric (ADMA) and symmetric (SDMA) dimethyl-L-arginine concentrations in plasma of MS patients during interferon-beta1b therapy. METHODS: The study population included 15 (12 women, 3 men) untreated MS patients and 12 (10 women, 2 men) interferon beta1b treated MS patients with clinically definite relapsing MS (McDonalds criteria) for at least 1 year and a baseline EDSS score of 1.0 to 3.5 inclusive. Patients were treated with 250 MUg IU interferon-beta1b s.c. every second day during 30 months. The disease course was evaluated using correlations between baseline EDSS score and relapse rates in both groups. RESULTS: During interferon beta1b treatment, EDSS scores in treated patients were decreased compared to untreated ones - after 18 and 30 months (p<0.05). In interferon-beta1b treated MS patients, NO(2)+NO(3), 3-NT and RSNO plasma concentrations were significantly lower (p<0.05), while arginase activity, ADMA and SDMA levels were significantly increased (p<0.05) during the therapy, compared to the baseline levels in treated patients. CONCLUSION: The investigated parameters may be the new biomarkers, providing information for the therapeutic approach and valuable in clinical monitoring. PMID- 23026533 TI - Objective characterization of the relative afferent pupillary defect in MS. AB - OBJECTIVE: To develop an objective and precise neurophysiologic method from which to identify and characterize the presence and magnitude of relative afferent pupillary defects (RAPD) in patients with MS. METHODS: Binocular infrared pupillometry was performed in 40 control subjects and 32 MS patients with RAPDs, using two precisely defined sequences of alternating light flashes (right-left and left-right). We analyzed three distinct pupillary metrics in response to light stimulation. These included percent diameter change (DC), constriction curve area (CCA), which measures change in diameter over time, and the phase plane curve area (PCA) which measures change in diameter with change in velocity. Direct and consensual response ratios (for each eye) were computed and analyzed for each metric in response to both the first flash (i.e. first phase) and second flash (i.e. second phase) of the 'swinging flashlight' test. RESULTS: Second flash pupillary response metric asymmetry ratios yielded the highest discriminatory power for RAPD detection. Receiver operating characteristic areas under the curve for each of the pupillary metric response asymmetry ratios were as follows: diameter change: 0.97; constriction curve area: 0.96; phase-plane curve area: 0.95 (p<0.0001 for all comparisons compared to normal subjects). The sum of these three squared ratios (SSR) yielded a combined metric with the greatest discriminatory power (receiver operator characteristic area under the curve=0.99). CONCLUSIONS: Second flash (i.e. the second phase of the swinging light test) pupillary metric response asymmetry ratios are highly sensitive and specific for the confirmation and characterization of an RAPD in patients with MS. This objective neurophysiologic method may be useful for studying the relationship between a stereotyped reflex, and nervous system architecture, with potential ramifications for detecting and monitoring neuroprotective and restorative effects of novel agents in MS treatment trials. PMID- 23026534 TI - Vascular factors and epigenetic modifications in the pathogenesis of Alzheimer's disease. AB - Alzheimer's disease (AD) is a debilitating illness with no known cure. Nowadays accumulating evidence suggested that the vascular endothelium and chronic hypoperfusion may play important role in pathobiology of AD. The vascular endothelium which regulates the passage of macromolecules and circulating cells from blood to tissue, is a major target of oxidative stress, playing a critical role in the pathophysiology of vascular diseases. Since the vascular endothelium, neurons and glia are all able to synthesize, store and release reactive oxygen species (ROS) and vascular active substances in response to certain stimuli, their contribution to the pathophysiology of AD can be very important. New evidence indicates that continuous formation of free ROS induces cellular damage and decreases antioxidant defenses. Specifically, oxidative stress increases vascular endothelial permeability and promotes leukocyte adhesion. We summarize the reports that sporadic, late-onset of AD results from vascular etiology. Recently an involvement of epigenetic alterations in the etiology of AD is also intensively investigated. Gaining a more complete understanding of the essential components and underlying mechanisms involved in epigenetic regulation could lead to novel treatments for a number of neurological and psychiatric conditions. PMID- 23026535 TI - The independent association of hypertension with cognitive function among older adults with heart failure. AB - OBJECTIVE: Hypertension is the most common comorbidity among heart failure (HF) patients and has been independently linked with cognitive impairment. Cognitive impairment is prevalent among HF patients, though the extent to which hypertension contributes to cognitive function in this population is unclear. METHODS: 116 HF patients (31.0% women, 67.68 +/- 11.16 years) completed neuropsychological testing and impedance cardiography. History of physician diagnosed hypertension, along with other medical characteristics, was ascertained through a review of participants' medical charts. RESULTS: 69.8% of the HF patients had a diagnostic history of hypertension. After adjustment for demographic and medical characteristics (i.e., cardiac index, medication status, and resting blood pressure), hypertension was independently associated with attention/executive function/psychomotor speed (DeltaF(1,103)=10.85, DeltaR(2)=.07, p<.01) and motor functioning (DeltaF(1,103)=4.46, DeltaR(2)=.04, p<.05). HF patients with a diagnosed history of hypertension performed worse in these domains than those without such history. CONCLUSION: The current findings indicate that diagnostic history of hypertension is an important contributor to cognitive impairment in HF. Hypertension frequently precedes HF and future studies should examine whether sustained hypertension compromises cerebral autoregulatory mechanisms to produce brain damage and exacerbate cognitive impairment in this population. PMID- 23026537 TI - Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking parkinsonism, gaze palsy, aphasia, or dementia. AB - We report an autopsy case of progressive supranuclear palsy (PSP) that clinically showed only slowly progressive and symmetric upper motor neuron syndrome over a disease course of 12 years. A female patient initially exhibited dysarthria at the age of 65, followed by gait disturbance and dysphagia. Neurological examination at age 67 disclosed pseudobulbar palsy, spastic gait, hyperreflexia, and presence of bilateral Hoffmann and Babinski signs. However, muscle atrophy, weakness, evidence of denervation on electromyography, vertical gaze palsy, parkinsonism, gait freezing, aphasia, speech apraxia, or dementia was not noted throughout the course. She was clinically diagnosed as having motor neuron disease consistent with so-called primary lateral sclerosis. Pathological examination disclosed histopathological features of PSP, including argyrophilic and tau-positive tufted astrocytes, neurofibrillary tangles, coiled bodies, and thread-like processes in the motor cortex and superior frontal gyrus, and to a lesser degree, in the basal ganglia and brain stem nuclei. In addition, severe fibrillary gliosis was noted in the precentral gyrus and corticospinal tract, being consistent with upper motor neuron syndrome observed in this case. No TAR DNA binding protein 43-positive lesion, FUS pathology, Bunina body, or Lewy body like hyaline inclusion was noted in the motor cortex or lower motor neurons. These findings suggest that when tau pathology is prominent in the motor cortex but is minimal in the basal ganglia and brain stem nuclei, a PSP case can lack all classic clinical features of PSP and show only slowly progressive upper motor syndrome, consistent with clinical picture of primary lateral sclerosis. PMID- 23026536 TI - Lack of association between BST1 polymorphisms and sporadic Parkinson's disease in a Japanese population. AB - Several genome-wide association studies and case-control studies have investigated the relationships between single nucleotide polymorphisms (SNPs) in the BST1 gene and Parkinson's disease (PD), but the results have been inconsistent. We examined the relationships between SNPs rs11931532, rs12645693, and rs11724635 and the risk of sporadic PD in Japan. Included were 229 cases within 6years of onset of PD as defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. SNPs rs11931532 and rs12645693 were not significantly related to sporadic PD. Compared with a reference group of subjects with the CC genotype of SNP rs11724635, those with the AA genotype had a marginally significantly increased risk of sporadic PD: the adjusted OR was 1.57 (95% CI: 0.95-2.61, P=0.08). No significant interactions were found between BST1 SNP rs11724635 and smoking or caffeine intake with respect to sporadic PD. The current study failed to detect significant relationships between BST1 SNPs rs11931532, rs12645693, and rs11724635 and sporadic PD; however, the relationship between SNP rs11724635 and sporadic PD was of borderline significance. We do not find evidence for interactions between smoking or caffeine intake and SNP rs11724635 affecting sporadic PD. PMID- 23026538 TI - Investigation of SCA10 in the Cypriot population: further exclusion of SCA dynamic repeat mutations. AB - Autosomal dominant cerebellar ataxias (ADCAs) encompass a heterogeneous group of rare diseases that affect the cerebellum and its connections. The most common forms have been associated with dynamic mutations while some rarer forms with conventional mutations. Studies in different populations revealed differences in their relative frequencies both within and between the studied populations, showing that the frequencies are depended on ethnic and geographical factors. Previous investigation of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in the Cypriot population, revealed no pathogenic expansion in the Cypriot SCA patients. We hereby present our recent investigation of the SCA10 pentanucleotide repeat expansion. Forty-two ascertained Cypriot sporadic ataxia patients, the index case from 1 ADCA and 14 ARCA families and a cohort of normal population individuals were included in the study. All our patients have normal range ATXN10 gene ATTCT repeat numbers (10 19). In the normal population group, repeat lengths ranged from 11 to 20 with the 14 repeats allele being the most frequent. Therefore, all currently established dynamic repeat SCA mutations are absent from the Cypriot population, indicating distinct genetic causes. PMID- 23026539 TI - Chronic melatonin administration mitigates behavioral dysfunction induced by gamma-irradiation. AB - Melatonin, a 'hormone of darkness,' has been reported to play a role in a wide variety of physiological responses including reproduction, circadian homeostasis, sleep, retinal neuromodulation, and vasomotor responses. Our recent studies reported a prophylactic effect of exogenous melatonin against radiation-induced neurocognitive changes. However, there is no reported evidence for a mitigating effect of chronic melatonin administration against radiation-induced behavioral alterations. In the present study, C57BL/6 mice were given either whole day chronic melatonin administration (CMA) or chronic night-time melatonin administration (CNMA) by a low dose of melatonin in drinking water for a period of 2 weeks and 1 month following exposure to 6 Gy of gamma-radiation. Various behavioral endpoints, such as locomotor activities, gross behavioral traits, basal anxiety level, and depressive tendencies were scored at different time points. Radiation exposure significantly impaired gross behavioral traits as observed in the open field exploratory paradigms and forced swim test. Both the CMA and CNMA significantly ameliorated the radiation-induced changes in exploratory tendencies, risk-taking behavior and gross behavior traits, such as rearing and grooming. Melatonin administration afforded anxiolytic function against radiation in terms of center exploration tendencies. The radiation induced augmentation of immobility time in the forced swim test, indices of depression-like behavior was also inhibited by chronic melatonin administration. The results demonstrated the mitigating effect of chronic melatonin administration on radiation-induced affective disorders in mice. PMID- 23026541 TI - Review and meta-analysis of the association between self-reported sharing of needles/syringes and hepatitis C virus prevalence and incidence among people who inject drugs in Europe. AB - BACKGROUND: Although sharing needles/syringes (N/S) is a recognised risk factor for the hepatitis C virus (HCV), epidemiological studies have shown inconsistent associations between self-reported N/S sharing and biological markers of HCV infection. This review aims to summarise, and explore factors that may explain the variation in, the measure of association between self-reported sharing of N/S and HCV prevalence/incidence among people who inject drugs (PWID). METHODS: Studies undertaken in Europe during 1990-2011 were identified through an electronic literature search. Eligible studies reported HCV prevalence (or incidence) among those who reported ever/never (or recent/non-recent) sharing of N/S. Meta-analysis was undertaken to generate a pooled estimate of the association and heterogeneity was explored using stratified analyses. RESULTS: Sixteen cross-sectional studies and four longitudinal studies were included. Pooled prevalence and incidence of HCV was 59% and 11% among PWID who reported never and not recently sharing N/S, respectively. Random effects meta-analysis generated a pooled odds ratio (OR) of 3.3 (95% CI 2.4-4.6), comparing HCV infection among those who ever (or recently) shared N/S relative to those who reported never (or not recently) sharing. There was substantial heterogeneity between the study effect sizes (I(2)=72.8%). Differences in pooled ORs were found when studies were stratified by recruitment setting (prison vs. drug treatment sites), recruitment method (outreach vs. non-outreach), sample HCV prevalence and sample mean/median time since onset of injecting. CONCLUSION: We found high incidence/prevalence rates among those who did not report sharing N/S during the risk period, which may be due to a combination of unmeasured risk factors and reporting bias. Study design and population are likely to be important modifiers of the size and strength of association between HCV and N/S sharing. PMID- 23026540 TI - Serotonin modulates anxiety-like behaviors during withdrawal from adolescent anabolic-androgenic steroid exposure in Syrian hamsters. AB - From the U.S. to Europe and Australia anabolic steroid abuse remains high in the adolescent population. This is concerning given that anabolic steroid use is associated with a higher incidence of pathological anxiety that often appears during withdrawal from use. This study uses pubertal Syrian hamsters (Mesocricetus auratus) to investigate the hypothesis that adolescent anabolic/androgenic steroid (AAS) exposure predisposes hamsters to heightened levels of anxiety during AAS withdrawal that is modulated by serotonin (5HT) neural signaling. In the first two sets of experiments, adolescent AAS-treated hamsters were tested for anxiety 21 days after the cessation of AAS administration (i.e., during AAS withdrawal) using the elevated plus maze (EPM), dark/light (DL), and seed finding (SF) tests and then examined for differences in 5HT afferent innervation to select areas of the brain important for anxiety. In the EPM and DL tests, adolescent AAS exposure leads to significant increases in anxiety-like response during AAS withdrawal. AAS-treated hamsters showed long term reductions in 5HT innervation within several areas of the hamster brain implicated in anxiety, most notably the anterior hypothalamus and the central and medial amygdala. However, no differences in 5HT were found in other anxiety areas, e.g., frontal cortex and lateral septum. In the last experiment, adolescent AAS-treated hamsters were scored for anxiety on the 21st day of AAS withdrawal following the systemic administration of saline or one of three doses of fluoxetine, a selective serotonin reuptake inhibitor. Saline-treated hamsters showed high levels of AAS withdrawal-induced anxiety, while treatment with fluoxetine reduced AAS withdrawal-induced anxiety. These findings indicate that early AAS exposure has potent anxiogenic effects during AAS withdrawal that are modulated, in part, by 5HT signaling. PMID- 23026542 TI - Organic UV filters in personal care products in Switzerland: a survey of occurrence and concentrations. AB - Organic ultraviolet (UV) filters are a group of compounds designed to absorb UV radiation and hence protect our skin against UV-induced damage. Apart from traditional sunscreens, they can be found in many other categories of personal care products (PCPs). These include skin care, facial makeup and lip care products, which are often used simultaneously, and on a regular basis. The frequency of occurrence as well as concentrations of organic UV filters contained in PCPs change over time. Furthermore, in Switzerland the exact UV filter concentrations are confidential. To date, only limited data are available for the levels of organic UV filters in PCPs, and these data refer mainly to sunscreens. In this paper, we provide an up-to-date frequency of occurrence and concentrations of organic UV filters in PCPs, including for the first time PCPs used in everyday life. A total of 116 PCPs was selected on the basis of a product use questionnaire and distributed among seven PCP categories: lip care products, lipsticks, face creams, liquid makeup foundations, aftershaves, hand creams, and sunscreens. Concentrations of 22 organic UV filters were measured in the selected PCPs. The most frequently occurring UV filters were butyl methoxydibenzoylmethane (BMBM) detected in 82 products (71%), ethylhexyl methoxycinnamate (EHMC) in 59 products (51%) and octocrylene (OCT) in 50 products (43%). BMBM, EHMC and OCT concentrations averaged 2.6%, 4.0%, and 6.0%, respectively. Overall, UV filter concentrations in PCPs applied regularly throughout the year can be as high as those in sunscreens that are primarily used for sun protection and hence applied only on selected days. PCPs that are used on a regular basis, and often simultaneously, thus represent an important and, as yet, unquantified source of UV filter exposure. This study provides essential information for aggregate exposure assessments that combine data on concentrations of individual UV filters widely used in a variety of PCP categories. PMID- 23026544 TI - Continuous sedation (CS) until death: mapping the literature by bibliometric analysis. AB - CONTEXT: Sedation at the end of life, regardless of the nomenclature, is an increasingly debated practice at both clinical and bioethical levels. However, little is known about the characteristics and trends in scientific publications in this field of study. OBJECTIVES: This article presents a bibliometric analysis of the scientific publications on continuous sedation until death. METHODS: Four electronic databases (MEDLINE, PubMed, Embase, and PsycINFO(r)) were searched for the indexed material published between 1945 and 2011. This search resulted in bibliographic data of 273 published outputs that were analyzed using bibliometric techniques. RESULTS: Data revealed a trend of increased scientific publication from the early 1990s. Published outputs, diverse in type (comments/letters, articles, reviews, case reports, editorials), were widely distributed across 94 journals of varying scientific disciplines (medicine, nursing, palliative care, law, ethics). Most journals (72.3%) were classified under Medical and Health Sciences, with the Journal of Pain and Symptom Management identified as the major journal in the field covering 12.1% of the total publications. Empirical research articles, mostly of a quantitative design, originated from 17 countries. Although Japan and The Netherlands were found to be the leaders in research article productivity, it was the U.K. and the U.S. that ranked top in terms of the quantity of published outputs. CONCLUSION: This is the first bibliometric analysis on continuous sedation until death that can be used to inform future studies. Further research is needed to refine controversies on terminology and ethical acceptability of the practice, as well as conditions and modalities of its use. PMID- 23026545 TI - Overcoming barriers to recruitment in care of the dying research in hospitals. AB - CONTEXT: Approximately 40% of the U.S. and 60% of the U.K. population die in hospital. Many reports have highlighted variability in the care received by these patients and national initiatives have proposed strategies to improve this care. No studies have demonstrated whether any improvements in end-of-life care have been achieved, as research in this area is challenging. OBJECTIVES: We designed a study to assess the feasibility of a novel method of identifying patients likely to die during an acute hospital admission and a model of prior consent from patients and/or assent from their relatives. METHODS: A study for collecting data on patients' symptoms before and after the introduction of an end-of-life tool (comprising medical and nursing checklists, prescribing guidance, and a symptom observation chart) within five wards in a major U.K. teaching hospital was conducted. We asked the screening question to a senior member of staff, "Is this patient so unwell that you feel they could die on this admission?" to identify appropriate patients, and recruited using the consent procedure. Patients were enrolled in the study if they became more unwell and data were then collected until they died. RESULTS: In total, 6642 patients were screened. The ward staff answered "yes" to the screening question for 327 of 6642 (4.9%) patients. Patient's prior consent or relative's assent to enroll in the study was obtained for 117 of 327 (35.8%) patients, of whom 70 of 117 (59.8%) enrolled for the study and died within the study period. The staff found that the methods used were appropriate. CONCLUSION: We have shown that identifying and involving dying patients in research is possible and acceptable to patients and carers. PMID- 23026547 TI - Changes over time in occurrence, severity, and distress of common symptoms during and after radiation therapy for breast cancer. AB - CONTEXT: Little is known about changes over time in multiple dimensions of the symptom experience in patients with breast cancer undergoing radiation therapy (RT). OBJECTIVES: This study evaluated for changes in and predictors of occurrence, severity, and distress of six common symptoms (lack of energy, worrying, difficulty sleeping, feeling drowsy, sweats, and pain) during RT for breast cancer. METHODS: Patients (n = 188) completed the Memorial Symptom Assessment Scale before, during, and after the completion of RT, over a six-month period. Changes in symptom occurrence were evaluated using multilevel logistic regression analysis. Changes in severity and distress scores were evaluated using multilevel proportional odds ordinal logistic regression. The impact of five demographic and clinical characteristics (age, functional status, comorbidities, axillary lymph node dissection, and previous chemotherapy) was evaluated in these analyses. RESULTS: The trajectories for occurrence, severity, and distress for the six symptoms followed similar patterns. For three of the six symptoms (lack of energy, feeling drowsy, and worrying), all three dimensions changed over time. For the other three symptoms (difficulty sleeping, sweats, and pain), no changes over time occurred for any of the symptom dimensions. The overall effect of the five covariates was to increase symptom burden across all three dimensions. CONCLUSION: Findings from this study provide a more complete picture of the symptom experience of women who undergo RT for breast cancer. These findings can be used to identify patients at higher risk for more severe symptoms before, during, and after RT. PMID- 23026546 TI - Undertreatment of pain in HIV+ adults in Thailand. AB - CONTEXT: Chronic pain remains prevalent in HIV+ adults despite widespread antiretroviral use. Pain continues to be underrecognized and undertreated in this population. In Thailand, similar to the West, HIV care is transitioning toward chronic disease management. Despite the importance of pain management in chronic HIV, the prevalence of pain and adequacy of pain management is unknown in HIV+ adults in Thailand. OBJECTIVES: This cross-sectional study aimed to determine the prevalence of chronic pain, the burden of inadequate analgesia, and risk factors for chronic pain in HIV+ adults in Thailand. METHODS: A total of 254 HIV+ adults were recruited from an outpatient clinic in Thailand. Interviewers obtained information on demographics, clinical data, and pain characteristics. The burden of inadequate analgesia was assessed using the Brief Pain Inventory. Risk factors were identified with logistic regression analysis. RESULTS: Frequent pain was reported by 27% of participants; 22% reported chronic pain. Pain was significantly associated with education less than primary school, a positive depression screen, and the number of years on combined antiretroviral therapy. Eighty-six percent of patients with frequent pain were inadequately treated. Of 34 patients with moderate or severe pain, none received adequate analgesia. Inadequate analgesia was a significant risk factor for poorer quality of life. CONCLUSION: Despite widespread antiretroviral use, pain remains common and undertreated in HIV+ adults in Thailand. Undertreated pain negatively impacts quality of life. It is imperative that policy makers and HIV caregivers address this treatment gap to advance the care of people living with HIV in Thailand. PMID- 23026548 TI - Once-weekly transdermal buprenorphine application results in sustained and consistent steady-state plasma levels. AB - CONTEXT: Transdermal formulations of buprenorphine offer controlled delivery of buprenorphine for sustained analgesic efficacy with reduced adverse events (AEs) compared with the other modes of administration. A buprenorphine transdermal system (BTDS) delivering 5, 10, or 20 mcg/hour for seven days is now marketed in the U.S. as Butrans((r)) (Lohmann Therapie-System AG, Andernach Germany), a Schedule III single-entity opioid analgesic indicated for the management of moderate and chronic pain in patients requiring continuous around-the-clock analgesia for an extended period. OBJECTIVES: This was a randomized open-label study in healthy subjects to characterize the steady-state buprenorphine pharmacokinetics after the delivery of three consecutive seven-day BTDS applications. METHODS: Thirty-seven subjects were randomized to receive three consecutive BTDS 10 mcg/hour (BTDS 10) patches applied to the deltoid or upper back for seven days each. Blood samples for buprenorphine concentration measurements were taken. Safety was assessed using recorded AEs, clinical laboratory test results, vital signs, pulse oximetry, physical examinations, and electrocardiograms. Patch adhesion assessments were taken. RESULTS: Analysis of Cmin demonstrated that steady state was reached during the first BTDS 10 application. No significant difference in Cmin was observed across the three applications. Total and peak plasma buprenorphine exposures were similar after each of the seven-day administrations of BTDS. CONCLUSION: Three consecutive once weekly applications of BTDS 10 provided consistent and sustained delivery of buprenorphine. Steady-state plasma concentrations were reached within 48 hours of the first application of BTDS 10. Patch adhesion analysis confirmed the appropriateness of the seven-day application period. Overall, BTDS 10 was safe and well tolerated. PMID- 23026549 TI - Identification of antigenic proteins of Toxoplasma gondii RH strain recognized by human immunoglobulin G using immunoproteomics. AB - Toxoplasma gondii, a ubiquitous intracellular protozoan, infects one third of the world human population. It is of great medical significance, especially for pregnant women and immune-compromised patients. Accurate and early detection of T. gondii infection is crucial in the management of this disease. To obtain potential diagnostic markers, immunoproteomics was employed to identify immunodominant proteins separated by 2-D immunobloting and probed with sera collected from Toxoplasma-positive pregnant women. MALDI-TOF MS and MS/MS analyses identified a total of 18 immunoreactive proteins that were recognized by Toxoplasma-positive sera, whereas none was reactive with the negative-control sera from healthy, Toxoplasma-negative volunteers. Pregnant women showed a diverse immunoreactivity pattern with each serum recognizing one to eight identified tachyzoite proteins. The identified proteins were localized in the membrane, cytoplasm and specific organelles of T. gondii, and are involved in host cell invasion, metabolism and cell structure. Among these 18 proteins, actin, catalase, GAPDH, and three hypothetical proteins had a broad reactivity with Toxoplasma-positive sera, indicating their potential as diagnostic markers for toxoplasmosis. Each of several combinations of the identified proteins offered 100% detection of Toxoplasma infections of all 28 Toxoplasma-positive women. The study findings suggest that Toxoplasma tachyzoites are highly immunogenic and highlights the heterogeneity of host responses to Toxoplasma infection and the importance of using combinations of immunogens as diagnostic antigens. The findings have significant implications to the development of diagnostic reagents with high sensitivity and specificity. PMID- 23026550 TI - Differential proteomic analysis of drought stress response in leaves of common bean (Phaseolus vulgaris L.). AB - The majority of common bean plants are cultivated under drought conditions. Maintaining crop yields under drought stress is thus one of the biggest challenges facing bean production. In order to improve our understanding of the complex mechanisms involved in the response of common bean (Phaseolus vulgaris) to drought stress, a proteomic approach was used to identify drought-responsive proteins in leaves of two cultivars differing in their response to drought, Tiber and more sensitive Starozagorski cern. 2D-DIGE was used to compare differences in protein abundance between control and stressed plants. Fifty-eight proteins whose abundance changed significantly were identified by LC-MS/MS in Tiber and 64 in Starozagorski cern. The majority of identified proteins were classified into functional categories that include energy metabolism, photosynthesis, ATP interconversion, protein synthesis and proteolysis, stress and defence related proteins. Details of the function of the identified proteins and their abundance profiles in Tiber and Starozagorski are discussed. Interactions between identified proteins were demonstrated by bioinformatics analysis, enabling a more complete insight into biological pathways and molecular functions affected by drought stress. The results form the basis for a further understanding of the biochemical mechanisms of drought response in common bean. PMID- 23026551 TI - Characterization of alpha-l-Iduronidase (Aldurazyme(r)) and its complexes. AB - Alpha-l-Iduronidase(IDUA) was the first enzyme replacement therapy approved for mucopolysaccharidosis type I and the corresponding recombinant protein drug, Aldurazyme(r), is commercially available. In the frame of gel-based mass spectrometrical characterization of protein drugs, we intended to identify protein sequence and possible protein modifications. Moreover, we were interested in which aggregation/complex form Aldurazyme(r) would exist, which complexes were enzymatically active and in which form the naturally occurring enzyme would be present in the brain. Aldurazyme(r) was run on 2DE gel electrophoresis, spots were excised, in-gel digested with several proteases and identified by nano-LC ESI-MS/MS on an ion trap. IDUA-activity was determined by a fluorometric principle. Blue-native gel electrophoresis with subsequent immunoblotting was carried out to show the presence of protein complexes. The protein was unambiguously identified by 100% sequence coverage; several amino acid substitutions were detected and protein modifications were novel phosphorylations on S59 and S482, histidine methylation at H572 and provide evidence for already known N-glycosylations. Four Aldurazyme(r) complexes that all were enzymatically active, were observed while a single complex was observed for the physiologically occurring IDUA in the brain. The findings are relevant for understanding chemistry, physiology, pharmacology and medicine of IDUA, design of further and interpretation of previous work. PMID- 23026553 TI - Expression and production of recombinant cis-epoxysuccinate hydrolase in Escherichia coli under the control of temperature-dependent promoter. AB - cis-Epoxysuccinate hydrolase (ESH) from Nocardia tartaricans CAS-52 could catalyze the stereospecific hydrolysis of cis-epoxysuccinate to L-(+)-tartrate. The ESH gene of 762 bp was cloned and its open reading frame (ORF) sequence predicted a protein of 253 amino acids. An expression plasmid carrying the ESH gene under the control of the P(L)P(R) promoter was introduced into Escherichia coli, and the ESH gene was successfully expressed in the recombinant strain. The expression conditions and scale-up production were also studied. Fed-batch fermentation of E. coli Trans 1-T1 transformant was carried out in a 2000 L fermentor to product recombinant ESH. The results showed that wet cell concentration reached to 62.45 g L(-1), and the specific activity of ESH was 380.17 U mg(-1), which could meet the requirements of industrial production of L (+)-tartaric acid. PMID- 23026554 TI - Co-metabolic degradation activities of trichloroethylene by phenol-grown aerobic granules. AB - Aerobic granule, a novel form of microbial aggregation, was explored for its potential in a co-metabolic degradation process using trichloroethylene (TCE) as the model compound and phenol as the primary substrate. Granulation process was conducted with phenol as the sole carbon and energy source, and phenol-acclimated sludge as seed sludge. TCE and phenol degradation activity of the biomass was monitored during granulation, together with other sludge characteristics. The biomass' settling ability improved significantly with granulation, and the mean size increased from 100 to 600 MUm. The biomass showed efficient and robust TCE co-metabolism activity, but the phenol-dependent specific oxygen utilization rate (SOUR), TCE instant transformation rate (T(r)) and ultimate transformation capacity (T(C)) all exhibited decreasing trends during granulation. Compared to the seed sludge, stable granules retained most of the SOUR and T(r), but lost half of the original T(C). Phenol and TCE degradation kinetic parameters of the granules were determined to be V(max) 1.59 mg g SS(-1) min(-1), K(S) 37.2 mg L( 1), K(I) 461.8 mg L(-1) for phenol; and V(max) 0.0142 mg g SS(-1) min(-1), K(S) 1.02 mg L(-1) for TCE. 2.5 mol Cl(-) was released per mol TCE transformed, and the T(C) was approximately 0.011 g TCE g granule(-1). PMID- 23026552 TI - Strategies for discovering novel pancreatic cancer biomarkers. AB - Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in both men and women in Canada and the United States and has the most dismal survival rates among any solid malignancy. Most patients are diagnosed with pancreatic cancer once the disease has progressed into an advanced or metastatic stage, making the only curative approach of resection surgery impossible. The persistent delayed or missed diagnosis of pancreatic cancer can be attributed to the absence of early symptoms and the lack of efficient non invasive screening or diagnostic tests in clinical practice. Given that earlier diagnosis is critical for ameliorating patients' survival rates, there is an urgent need for biomarkers with enough sensitivity and specificity to help diagnose pancreatic cancer early. Serological biomarkers provide a minimally invasive and efficient way of detecting pancreatic cancer, however, there is currently no marker with sufficient diagnostic sensitivity and specificity to identify early cancer patients. This review focuses on the classical tumor markers for PDAC as well as emerging markers. In addition, we will discuss an integrative proteomic approach used in our lab to identify a panel of biomarkers that have the potential to allow the early detection of PDAC.This article is part of a Special Issue entitled: From protein structures to clinical applications. PMID- 23026555 TI - MetaSAMS--a novel software platform for taxonomic classification, functional annotation and comparative analysis of metagenome datasets. AB - Metagenomics aims at exploring microbial communities concerning their composition and functioning. Application of high-throughput sequencing technologies for the analysis of environmental DNA-preparations can generate large sets of metagenome sequence data which have to be analyzed by means of bioinformatics tools to unveil the taxonomic composition of the analyzed community as well as the repertoire of genes and gene functions. A bioinformatics software platform is required that allows the automated taxonomic and functional analysis and interpretation of metagenome datasets without manual effort. To address current demands in metagenome data analyses, the novel platform MetaSAMS was developed. MetaSAMS automatically accomplishes the tasks necessary for analyzing the composition and functional repertoire of a given microbial community from metagenome sequence data by implementing two software pipelines: (i) the first pipeline consists of three different classifiers performing the taxonomic profiling of metagenome sequences and (ii) the second functional pipeline accomplishes region predictions on assembled contigs and assigns functional information to predicted coding sequences. Moreover, MetaSAMS provides tools for statistical and comparative analyses based on the taxonomic and functional annotations. The capabilities of MetaSAMS are demonstrated for two metagenome datasets obtained from a biogas-producing microbial community of a production scale biogas plant. The MetaSAMS web interface is available at https://metasams.cebitec.uni-bielefeld.de. PMID- 23026557 TI - First report of fipronil resistance in Rhipicephalus (Boophilus) microplus of Mexico. AB - Five strains of Rhipicephalus (Boophilus) microplus collected from Tamaulipas Mexico were tested for resistance against several classes of acaricides commonly used. All were resistant to fipronil. Four of five were co-resistant to permethrin and coumaphos in addition to being resistant to fipronil. One strain, El Zamora was found multi-resistant to permethrin, coumaphos, fipronil, and amitraz. Selection with fipronil for 3 generations produced a resistance ratio of 8.3 and 9.4 at the LC(50) and the LC(99) estimates, respectively. Permethrin resistance in El Zamora was possibly linked to elevated esterase (CZEST9) and could be a contributing factor of resistance to fipronil. The implications of resistance for the control of the southern cattle tick in the future are discussed. PMID- 23026556 TI - Staphylococcus haemolyticus prophage PhiSH2 endolysin relies on cysteine, histidine-dependent amidohydrolases/peptidases activity for lysis 'from without'. AB - Staphylococcus aureus is an important pathogen, with methicillin-resistant (MRSA) and multi-drug resistant strains becoming increasingly prevalent in both human and veterinary clinics. S. aureus causing bovine mastitis yields high annual losses to the dairy industry. Conventional treatment of mastitis by broad range antibiotics is often not successful and may contribute to development of antibiotic resistance. Bacteriophage endolysins present a promising new source of antimicrobials. The endolysin of prophage PhiSH2 of Staphylococcus haemolyticus strain JCSC1435 (PhiSH2 lysin) is a peptidoglycan hydrolase consisting of two catalytic domains (CHAP and amidase) and an SH3b cell wall binding domain. In this work, we demonstrated its lytic activity against live staphylococcal cells and investigated the contribution of each functional module to bacterial lysis by testing a series of deletion constructs in zymograms and turbidity reduction assays. The CHAP domain exhibited three-fold higher activity than the full length protein and optimum activity in physiological saline. This activity was further enhanced by the presence of bivalent calcium ions. The SH3b domain was shown to be required for full activity of the complete PhiSH2 lysin. The full length enzyme and the CHAP domain showed activity against multiple staphylococcal strains, including MRSA strains, mastitis isolates, and CoNS. PMID- 23026558 TI - Comparative efficacy of a spot-on formulation containing emodepside and praziquantel (Profender (r), Bayer) and praziquantel and pyrantel oral tablets (Drontal (r) for Cats) against experimental Ancylostoma ceylanicum infections in cats. AB - Ancylostoma ceylanicum is a common zoonotic hookworm of dogs and cats throughout Asia and has also been reported to occur within the Australasian region. The aim of this study to was to determine the efficacy of a spot-on formulation containing emodepside and praziquantel (Profender((r)), Bayer) and praziquantel and pyrantel oral tablets (Drontal((r)) for Cats, Bayer) against experimental A. ceylanicum infections in cats. Twenty-four kittens were each subcutaneously injected with 100 infective third-stage larvae of A. ceylanicum. Kittens were stratified by egg count and randomly allocated equally into control and two treatment groups. The first group were treated with emodepside 2.1%/praziquantel 8.6% (Profender(r), Bayer) at the recommended label dose. The second group was treated with 80 mg pyrantel and 20mg praziquantel (Drontal((r)) for Cats, Bayer) at the recommended label dose. The kittens in the control group were not treated. Egg counts were performed daily until the end of the study period and compared for the treated and control groups. No eggs were detected in the treated group of kittens within 4 days of treatment and faecal samples from this group remained negative throughout the rest of the study, resulting in a treatment efficacy (egg reduction) of 100% (P<0.0001). The egg counts remained high (993 +/- 666 epg) in the untreated control group for the rest of the study period. This study demonstrated that both combination products containing topical emodepside/praziquantel (Profender((r)), Bayer) and praziquantel/pyrantel oral tablets (Drontal((r)) for Cats, Bayer) given at the recommended dose is highly effective against infection with A. ceylanicum in cats. PMID- 23026559 TI - Genome-wide mRNA profiling and multiplex quantitative RT-PCR for forensic body fluid identification. AB - In forensic science, identifying a tissue where a forensic specimen was originated is one of the principal challenges. Messenger RNA (mRNA) profile clearly reveals tissue-specific gene expression patterns that many attempts have been made to use RNA for forensic tissue identification. To systematically investigate the body-fluid-specific expression of mRNAs and find novel mRNA markers for forensic body fluid identification, we performed DNA microarray experiment with 24 Korean body fluid samples. Shannon entropy and Q-values were calculated for each gene, and 137 body-fluid-specific candidate genes were selected. By applying more stringent criteria, we further selected 28 candidate genes and validated them by RT-PCR and qRT-PCR. As a result, we suggest a novel combination of four body-fluid-specific mRNA makers: PPBP for blood, FDCSP for saliva, MSMB for semen and MSLN for vaginal secretion. Multiplex qRT-PCR assay was designed using the four mRNA markers and DNA/RNA co-extraction method was tested for forensic use. This study will provide a thorough examination of body fluid-specifically expressed mRNAs, which will enlarge the possibility of practical use of RNA for forensic purpose. PMID- 23026560 TI - Facilitating pharmacometric workflow with the metrumrg package for R. AB - metrumrg is an R package that facilitates workflow for the discipline of pharmacometrics. Support is provided for data preparation, modeling, simulation, diagnostics, and reporting. Existing tools and techniques are emphasized where available; original solutions are provided for otherwise unmet needs. In particular, metrumrg implements an R interface for the NONMEM((r)) modeling software, optionally run in a distributed computing environment. The paradigm allows start-to-finish analyses in a single scripting language. Emphasis on text based formats promotes traceability of results. PMID- 23026561 TI - Inhibition of mitochondrial cytochrome c oxidase potentiates Abeta-induced ER stress and cell death in cortical neurons. AB - Previously we reported that amyloid-beta (Abeta) leads to endoplasmic reticulum (ER) stress in cultured cortical neurons and that ER-mitochondria Ca(2+) transfer is involved in Abeta-induced apoptotic neuronal cell death. In cybrid cells which recreate the defect in mitochondrial cytochrome c oxidase (COX) activity observed in platelets from Alzheimer's disease (AD) patients, we have shown that mitochondrial dysfunction affects the ER stress response triggered by Abeta. Here, we further investigated the impact of COX inhibition on Abeta-induced ER dysfunction using a neuronal model. Primary cultures of cortical neurons were challenged with toxic concentrations of Abeta upon chemical inhibition of COX with potassium cyanide (KCN). ER Ca(2+) homeostasis was evaluated under these conditions, together with the levels of ER stress markers, namely the chaperone GRP78 and XBP-1, a mediator of the ER unfolded protein response (UPR). We demonstrated that COX inhibition potentiates the Abeta-induced depletion of ER Ca(2+) content. KCN pre-treatment was also shown to enhance the rise of cytosolic Ca(2+) levels triggered by Abeta and thapsigargin, a widely used ER stressor. This effect was reverted in the presence of dantrolene, an inhibitor of ER Ca(2+) release through ryanodine receptors. Similarly, the increase in GRP78 and XBP-1 protein levels was shown to be higher in neurons treated with Abeta or thapsigargin in the presence of KCN in comparison with levels determined in neurons treated with the neurotoxins alone. Although the decrease in cell survival, the activation of caspase-9- and -3-mediated apoptotic cell death observed in Abeta- and thapsigargin-treated neurons were also potentiated by KCN, this effect is less pronounced than that observed in Ca(2+) signalling and UPR. Furthermore, in neurons treated with Abeta, the potentiating effect of the COX inhibitor in cell survival and death was not prevented by dantrolene. These results show that inhibition of mitochondrial COX activity potentiates Abeta induced ER dysfunction and, to a less extent, neuronal cell death. Furthermore, data supports that the effect of impaired COX on Abeta-induced cell death occurs independently of Ca(2+) release through ER ryanodine receptors. Together, our data demonstrate that mitochondria dysfunction in AD enhances the neuronal susceptibility to toxic insults, namely to Abeta-induced ER stress, and strongly suggest that the close communication between ER and mitochondria can be a valuable future therapeutic target in AD. PMID- 23026562 TI - Systemic immune activation shapes stroke outcome. AB - Stroke is a major cause of morbidity and mortality, and activation of the immune system can impact on stroke outcome. Although the majority of research has focused on the role of the immune system after stroke there is increasing evidence to suggest that inflammation and immune activation prior to brain injury can influence stroke risk and outcome. With the high prevalence of co-morbidities in the Western world such as obesity, hypertension and diabetes, pre-existing chronic 'low-grade' systemic inflammation has become a customary characteristic of stroke pathophysiology that needs to be considered in the search for new therapies. The importance of the immune system in stroke has been demonstrated in a number of ways, both experimentally and in the clinical setting. This review will focus on the effect of immune activation arising from systemic inflammatory conditions and infection, how it affects the incidence and outcomes of stroke, and the possible underlying mechanisms involved. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'. PMID- 23026563 TI - C-terminal processing of the teneurin proteins: independent actions of a teneurin C-terminal associated peptide in hippocampal cells. AB - Many neuropsychiatric conditions have a common set of neurological substrates associated with the integration of sensorimotor processing. The teneurins are a recently described family of proteins that play a significant role in visual and auditory development. Encoded on the terminal exon of the teneurin genes is a family of bioactive peptides, termed teneurin C-terminal associated peptides (TCAP), which regulate mood-disorder associated behaviors. Thus, the teneurin TCAP system could represent a novel neurological system underlying the origins of a number of complex neuropsychiatric conditions. However, it is not known if TCAP 1 exerts its effects as part of a direct teneurin function, whereby TCAP represents a functional region of the larger teneurin protein, or if it has an independent role, either as a splice variant or post-translational proteolytic cleavage product of teneurin. In this study, we show that TCAP-1 can be transcribed as a smaller mRNA transcript. After translation, further processing yields a smaller 15 kDa protein containing the TCAP-1 region. In the mouse hippocampus, immunoreactive (ir) TCAP-1 is exclusively localized to the pyramidal layers of the CA1, CA2 and CA3 regions. Although the localization of TCAP and teneurin in hippocampal regions is similar, they are distinct within the cell as most ir-teneurin is found at the plasma membrane, whereas ir-TCAP-1 is predominantly found in the cytosol. Moreover, in mouse embryonic hippocampal cell culture, FITC-labeled TCAP-1 binds to the plasma membrane and is taken up into the cytosol via dynamin-dependent caveolae-mediated endocytosis. Our data provides novel evidence that TCAP-1 is structurally and functionally distinct from the larger teneurins. PMID- 23026564 TI - The transition state analog inhibitor of Purine Nucleoside Phosphorylase (PNP) Immucillin-H arrests bone loss in rat periodontal disease models. AB - Purine nucleoside phosphorylase (PNP) is a purine-metabolizing enzyme that catalyzes the reversible phosphorolysis of 6-oxypurine (deoxy)nucleosides to their respective bases and (deoxy)ribose-1-phosphate. It is a key enzyme in the purine salvage pathway of mammalian cells. The present investigation sought to determine whether the PNP transition state analog inhibitor (Immucillin-H) arrests bone loss in two models of induced periodontal disease in rats. Periodontal disease was induced in rats using ligature or LPS injection followed by administration of Immucillin-H for direct analysis of bone loss, histology and TRAP staining. In vitro osteoclast differentiation and activation of T CD4+ cells in the presence of Immucillin-H were carried out for assessment of RANKL expression, PNP and Cathepsin K activity. Immucillin-H inhibited bone loss induced by ligatures and LPS, leading to a reduced number of infiltrating osteoclasts and inflammatory cells. In vitro assays revealed that Immucillin-H could not directly abrogate differentiation of osteoclast precursor cells, but affected lymphocyte-mediated osteoclastogenesis. On the other hand, incubation of pre-activated T CD4+ with Immucillin-H decreased RANKL secretion with no compromise of cell viability. The PNP transition state analog Immucillin-H arrests bone loss mediated by T CD4+ cells with no direct effect on osteoclasts. PNP inhibitor may have an impact in the treatment of diseases characterized by the presence of pathogens and imbalances of bone metabolism. PMID- 23026565 TI - Radiation induces osteogenesis in human aortic valve interstitial cells. AB - OBJECTIVE: Irradiation of the chest or chest wall has been shown to cause calcific aortic stenosis. However, the mechanisms are unknown. Aortic valve interstitial cells have been implicated in the pathogenesis of aortic stenosis; they have been shown to change from the phenotype of a myofibroblast to an osteoblastlike cell. We therefore hypothesized that irradiation of human aortic valve interstitial cells induces an osteogenic phenotype. In isolated human aortic valve interstitial cells, our purpose was to determine the effect of irradiation on the production of osteogenic factors: (1) bone morphogenetic protein 2, (2) osteopontin, (3) alkaline phosphatase, and (4) the transcription factor Runx2. METHODS: Human aortic valve interstitial cells were isolated from normal aortic valves obtained from explanted hearts of patients undergoing cardiac transplantation (n = 4) and were grown in culture. The cells were grown to confluence, irradiated with 10 Gy using a cesium-137 irradiator, and then lysed 24 hours after irradiation. Cell lysates were analyzed via immunoblot and densitometry for bone morphogenetic protein 2, osteopontin, alkaline phosphatase, and Runx2. Statistical analysis was performed using analysis of variance, with P < .05 indicating significance. RESULTS: Irradiation induced an osteogenic phenotype in human aortic valve interstitial cells. Irradiation induced a 2-fold increase in bone morphogenetic protein 2, a 7-fold increase in osteopontin, a 3 fold increase in alkaline phosphatase, and a 2-fold increase in Runx2. CONCLUSIONS: Radiation induces an osteogenic phenotype in human aortic valve interstitial cells. The irradiated cells had a significantly increased expression of the osteogenic factors bone morphogenetic protein 2, osteopontin, alkaline phosphatase, and Runx2. These data offer mechanistic insight into the pathogenesis of radiation-induced valvular heart disease. PMID- 23026567 TI - Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition-mediated cell death in K-ras mutant lung cancer cells. AB - OBJECTIVE: There are currently no targeted therapies against lung tumors with oncogenic K-ras mutations that are found in 25% to -40% of lung cancers and are characterized by their resistance to epidermal growth factor receptor inhibitors. The isozyme group IIa secretory phospholipase A(2) (sPLA(2)IIa) is a potential biomarker and regulator of lung cancer cell invasion; however, the relationship between K-ras mutations and sPLA(2)IIa has yet to be investigated. We hypothesize that sPLA(2)IIa modulates lung cancer cell growth in K-ras mutant cells and that sPLA(2)IIa expression in human lung tumors is increased in K-ras mutant tumors. METHODS: Baseline sPLA(2)IIa expression in K-ras mutant lung cancer cell lines (A549, SW1573, H358, H2009) was assessed. Cells were treated with a specific sPLA(2)IIa inhibitor and evaluated for apoptosis and cell viability. Nuclear factor kappa-b (NF-kappaB) and extracellular signal-regulated kinase 1/2 activity were detected by Western blot. Human tumor samples were evaluated for sPLA(2)IIa mRNA expression by quantitative reverse-transcription polymerase chain reaction. RESULTS: Cytotoxicity of sPLA(2)IIa inhibition correlates with sPLA(2)IIa expression. Apoptosis in response to sPLA(2) inhibition parallels attenuation in NF-kappaB activity. In addition, sPLA(2)IIa expression in human tumors correlates with squamous cell pathology and increasing stage of K-ras mutant lung tumors. CONCLUSIONS: Baseline sPLA(2)IIa expression predicts response to sPLA(2)IIa inhibition in some K-ras mutant lung cancer cells. This finding is independent of p53 mutation status. Furthermore, squamous tumors and advanced-stage K-ras mutant tumors express more sPLA(2)IIa. These data support a role for sPLA(2)IIa as a potential global therapeutic target in the treatment of lung cancer. PMID- 23026566 TI - Detection of human telomerase reverse transcriptase mRNA in cells obtained by lavage of the pleura is not associated with worse outcome in patients with stage I/II non-small cell lung cancer: results from Cancer and Leukemia Group B 159902. AB - OBJECTIVE: Previous studies suggest that cytologic analysis of cells obtained by lavage of the pleural surfaces at the time of resection of non-small cell lung cancer can identify patients at risk for recurrence. Because telomerase gene expression has been associated with worse outcome in non-small cell lung cancer, we hypothesized that identification of cells obtained from pleural lavage that express telomerase would identify patients at risk for recurrent disease. METHODS: Patients with presumed non-small cell lung cancer underwent thoracotomy with curative intent. Cells obtained by lavage of the pleural surfaces were analyzed for telomerase catalytic subunit human telomerase reverse transcriptase mRNA expression using reverse transcriptase polymerase chain reaction. RESULTS: A total of 194 patients with stage I/II non-small cell lung cancer had adequate samples, and median follow-up was 60 months (17-91 months). By using Cox models, no statistical differences were found between human telomerase reverse transcriptase-negative and positive patients in disease-free survival (hazard ratio, 1.28; 95% confidence interval, 0.85-1.94; log-rank test, P = .2349) or overall survival (hazard ratio, 1.13; 95% confidence interval, 0.72-1.79; log rank test, P = .5912) CONCLUSIONS: Detection of human telomerase reverse transcriptase in cells obtained from pleural lavage of patients with stage I/II non-small cell lung cancer does not identify patients at risk for recurrent disease. PMID- 23026569 TI - Guidelines for maintenance of adult patients with brain death and potential for multiple organ donations: the Task Force of the Brazilian Association of Intensive Medicine the Brazilian Association of Organs Transplantation, and the Transplantation Center of Santa Catarina. AB - INTRODUCTION: The organ shortage for transplantation, the principal factor that increases waiting lists, has become a serious public health problem. In this scenario, the intensivist occupies a prominent position as one of the professionals that first has a chance to identify brain death and to be responsible for the maintenance of the potential deceased donor. OBJECTIVE: This report attempts to establish guidelines for care and maintenance of adult deceased donor organs guiding and standardizing care provided to patients with brain death. METHOD: These guidelines were composed by intensivists, transplant coordinators, professionals from various transplant teams, and used transplant center. The formulated questions were forwarded to all members and recommendations were constructed after an extensive literature review selecting articles with the highest degree of evidence. RESULTS: Guidelines were developed in the form of questions reflecting frequent experiences in clinical intensive care practices. The main questions were: Is there an optimal interval for keeping organs of deceased donors viable? What actions are considered essential for maintaining deceased donors in this period? What are the limits of body temperature? How should the patient be warmed? Which laboratory tests should be performed? What is the collection interval? What are the limits in the laboratory and the capture scenario? What are the limits of blood pressure? When and how should one use catecholamines? CONCLUSIONS: This pioneer project involved a multidisciplinary team working in organ transplantation seeking to provide treatment guidance to increase the number of viable organs from deceased adult donors. PMID- 23026570 TI - Families who previously refused organ donation would agree to donate in a new situation: a cross-sectional study. AB - BACKGROUND: The limited supply of organs restricts the number of transplantations. Studying the families who refuse donation may help to increase the number of transplantations. METHODS: This descriptive cross-sectional study used a questionnaire to obtain information from 61 family members who had refused to donate organs from January 1997 to December 2004. The exclusion criterion was donor death less than 1 year from the study. The mean age of subjects was 41 +/- 12.7 years (range, 18 to 79 years) with 66% women. RESULTS: More than half (36 of 69; 52%) of the families who refused donation would agree to donate in a new situation. The primary reasons for refusing donation were: disagreement among family members (25 of 128; 19%), lack of knowledge regarding the deceased's wishes (22 of 128; 17%), and previous request from the deceased not to be a donor (17 of 128; 13%). The most frequent suggestions to increase organ donation were to provide families with more information (43 of 149; 29%), initiate contact among the families (36 of 149; 24%), and involve a trusted physician (30 of 149; 20%). CONCLUSION: Most family members who refused organ donation changed their minds and would agree to donate in a few situation. Most of the reasons for refusing to donate reflected a lack of information and discussion on the topic. PMID- 23026571 TI - Intentionality of organ/tissues donation for transplantation within a Brazilian hospital complex. AB - OBJECTIVE: Considering the challenges faced by members of the Intrahospital Committee of Organ and Tissue Donation for Transplantation (CIHDOTT) of a Brazilian hospital complex in Santa Casa of Belo Horizonte in the execution of multiple donations of organs and tissues, this study aimed to investigate the issues involved in the intention to donate within this population. This research sought to promote the work of CIHDOTT by planning strategies for conducting of family interviews to best meet the needs of this population, thereby contributing to reduce the wait-list for transplantations in this state hospital of Minas Gerais. METHODS: The survey was performed by applying a standard questionnaire to 602 respondents comprising patients and families/caregivers. The analysis of the collected data was developed from studies of contingency tables based on chi- square and Fisher exact tests. RESULTS: The analysis revealed that 94% of the population to be favorable to donation. It also showed a significant influence of the following factors to determining the likelihood of organ donation: knowledge of religion (35%), spouse's opinion (17%), as well as belief in the possibility of interference or delay of the funeral as a result of donation (6%). CONCLUSION: Although the population expressed a willingness to donate, there were significant contravening factors that may be addressed by professional training and informational activities. PMID- 23026572 TI - New law of renal transplantation in Portugal associated with more acute rejection episodes and higher costs. AB - The new law implemented in August 2007 changed the criteria to select renal transplantation (RT) candidates in Portugal, favoring hyperimmunized subjects and those on the waiting list for a longer time, making human leukocyte antigen (HLA) compatibilities less important. The authors compared patients who received a deceased donor kidney between 2005 and 2010. Patients were divided in group A who underwent transplantation before August 2007 (n = 132) and group B (n = 125) after that date. We considered a value of P < .05. Overall mean age at RT was 46.6 +/- 13.9 years with 58.8% men, 88% on hemodialysis (HD), with a mean dialysis time of 82.8 +/- 119 months. Also, 10.5% of patients underwent a previous transplantation. The mean follow-up was 35 +/- 17.1 months. Group B showed significant adverse differences, including dialysis time (50.9 vs. 117 months), length of hospitalization (14.4 vs. 23.2 days), need for HD (1 vs. 3.4 days), HLA match (3.3 vs. 1.4 compatibilities), previous sensitization (4.4% vs. 21.7%), acute rejection episodes in the 1st year (23% vs. 37%), greater use of immunosuppressive drugs, higher costs of induction therapy (2790 vs 4360epsilon), and greater costs of drugs during first hospitalization (3456 vs. 7144epsilon). Among the 16 subjects who lost their grafts, 7 were in group A (3 in the first year) and 9 in group B all in the first year. There was a 5.1% decrease in graft survival at 12 months (P = .07). Univariate analysis showed an association of acute rejection episodes with HLA mismatches, hyperimmunized patients, absence of immediate graft function, hospitalization time, longer HD need, and higher creatinine level at months 1, 2, 3, and 6. Multivariate analysis revealed acute rejection episodes to be associated with a lower number of HLA compatibilities (odds ratio = 0.65; 95% confidence interval, [0.46-0.9]). Application of the law has led to a greater number of acute rejection episodes in the first year and increased costs. PMID- 23026573 TI - Causes of organ donation failure in Brazil. AB - INTRODUCTION: There has been a great improvement in transplantation medicine in Brazil in the last 2 decades. However, there remain several barriers regarding notification of brain and cardiac death as well as completion of the donation process. METHODS: This retrospective study was performed between January 2008 and December 2010. We reviewed all deaths in a University Hospital, observing the causes of non-notification to the State Transplantation Authority and non donations. RESULTS: There were 41 notifications of brain death resulting in donation in only 19.5% of those cases. Cardiac death was diagnosed in 21 patients, resulting in 52.4% donations. The main cause for non-donation were family refusal (37.2%), infectious diseases (30.2%), and clinical contraindications (32.6%). Most of the missed possible donors occurred during the night (54.8%) and in the emergency room (80.9%). CONCLUSION: There is an urgent need for better education of the Brazilian population about organ donation and brain death definitions. Other identified problems include lack of uniformity in brain death determinations among hospitals, rigid contraindications to donation in the State of Parana, physician unawareness or disbelief about brain death diagnostic criteria, and lack of structure of our Hospital. PMID- 23026574 TI - Testing liver allocation in Sao Paulo, Brazil: the relationship of model for end stage liver disease implementation with a reduction in waiting-list mortality. AB - INTRODUCTION: In 2006, the model for end-stage liver disease (MELD) was launched as a new liver allocation system in Sao Paulo, Brazil. We designed this study to assess the results of the new allocation policy on waiting list mortality. METHODS: We reviewed the state of Sao Paulo liver transplant database from July 2003 through July 2009. Patients were divided in those who were transplanted before (pre-MELD group) and those who were transplanted after (post-MELD group) the implementation of the MELD system. Included were adult liver transplant candidates. Waiting list mortality was the primary endpoint. RESULTS: The unadjusted death rate in patients on the waiting list decreased significantly after the implementation of the MELD system (from 91.2 to 33.5/1000 patients/year, P < .0001). Multivariate analysis has shown a significant drop of the risk of waiting list death for post-MELD patients (odds ration 0.34, P < .0001). CONCLUSION: There was a reduction in waiting time and list mortality after the implementation of the MELD system in Brazil. Patients listed in the post-MELD era had a significant reduction of death risk on the waiting list. Future studies should assess posttransplant outcomes. PMID- 23026575 TI - Increasing the donor pool reduces the severity of liver disease: lessons learned from Sao Paulo, Brazil. AB - INTRODUCTION: A new liver allocation system driven by the model for end-stage liver disease (MELD) score was implemented in Brazil in 2006. In association with the new allocation policy, there was a concomitant expansion of the number of donors. We designed this study to assess whether a potential expansion of the donor pool with these educational campaigns had reduced the severity of liver disease at transplantation. METHODS: We retrospectively reviewed the state of Sao Paulo liver transplant database from July 2003 through July 2009. Patients were divided into groups: those who were transplanted before (pre-MELD group) and those who were transplanted after (post-MELD group) the implementation of the MELD system. The number of transplantations and the severity of liver disease were the endpoints of the study. RESULTS: There has been a significant shift towards an older donor population, mainly those who are dying of cerebrovascular accidents. The average MELD score has changed over time. Approximately one quarter of the patients have been transplanted with a MELD score of more than 30 in the post-MELD era. However, this number has decreased over the past 3 years (P = .012). Currently, it has been possible to transplant patients with a MELD score from 25 to 30. The number of transplantations due to hepatocarcinoma (HCC) has increased 8-fold. CONCLUSION: An aggressive educational campaign has successfully expanded the donor pool with a concomitant yearly reduction of the average MELD score at the time of transplantation. Patients with HCC have been benefited tremendously with the new allocation system. PMID- 23026576 TI - Kidney transplantation using donors over 70 years old: are the criteria for organ allocation too expanded? AB - BACKGROUND: The scarcity of organs available for transplantation has led to the use of kidneys from old deceased donors including those >=70 years of age. The results of kidney transplants performed using such "limit" organs warrent further study. METHODS: We retrospectively evaluated all cadaveric heart-beating renal transplants performed from September 1996 to June 2010 using expanded-criteria donors: Group 1 included 302 transplants performed with kidneys from expanded criteria donors aged 50-69 years; group 2 included 60 recipients of kidneys from donors aged >=70 years. All patients were prescribed an immunossupressive regimen based on mycophenolate mofetil or mycophenolic acid, a calcineurin inhibitor, and corticosteroids, with or without monoclonal/polyclonal antibodies. RESULTS: The baseline recipient characteristics were similar except for age, which was higher in group 2; history of previous transplantation was absent in group 2, and there was more use of induction with monoclonal or polyclonal antibodies in group 2 (65% vs 49%; P = .02). There was no significant difference in the rate of nonfunctioning grafts, delayed graft function, or acute rejection episodes in the first 6 months. There was no significant difference between groups regarding graft or patient survival. CONCLUSIONS: The use of kidneys from donors aged >=70 older than or years yielded generally satisfactory results. PMID- 23026577 TI - Liver grafts procured by other transplant teams do not affect posttransplantation outcomes. AB - BACKGROUND: Transplant surgeons have one the riskiest jobs in medicine. Multiple reports have described fatalities involving transplant team members who were traveling to recover organs for transplantation. There are few initiatives to use allografts recovered by local teams. We tested the impact of local organ procurement on posttransplantation survival. METHODS: This single-center retrospective study included primary deceased-donor liver grafts transplanted under the Model for End-stage Liver Disease system. Multivariate analysis was performed to evaluate whether liver allografts procured outside of the organ procurement organization (OPO) region were related to allograft loss. We also studied posttransplantation survival according to local procurement. RESULTS: There were 271 transplantations performed with local donors, 19 from other states, and 54 from within our state but outside of our OPO. Recipient demographic data were similar among the groups. There were more male (P = .007), slim (P = .01), and younger (P = .008) donors among allografts from other states (national group). Local or regional donors had brain death more often related to cerebrovascular accidents. National donors had brain death related to trauma (P = .01). Multivariate analysis confirmed that local organ retrieval was not related to posttransplantation survival. Kaplan-Meier curves showed no difference in patient and graft survivals among the groups. CONCLUSIONS: Local procurement did not affect posttransplantation survival. Liver allografts procured by other teams showed equivalent posttransplantation outcomes. Policies that stimulate the training of local teams to procure liver allografts for distant transplant centers should be launched to increase job safety for transplant surgeons. PMID- 23026578 TI - Noninvasive analyses of kidney injury molecule-1 messenger RNA in kidney transplant recipients with graft dysfunction. AB - BACKGROUND: Kidney graft fibrosis is a major factor related to chronic loss of kidney function. At present, the finding of fibrosis depends on the analysis of tissue in the renal biopsy, which has important limitations. In this study, we evaluated the messenger mRNA transcription and gene expression of kidney injury molecule-1 (KIM-1) in kidney tissue and in urinary sediment cells of kidney transplant patients with graft dysfunction aiming at the development of techniques that may allow the noninvasive diagnosis of interstitral fibrosis/tubular atrophy (IF/TA). PATIENTS AND METHODS: RNA extracted from cells in tissue and urine of 77 renal transplant patients whose biopsies were classified according to the Banff scheme-2007. Four diagnostic groups were established: (1) acute tubular necrosis (n = 9); (2) acute rejection (n = 49); (3) acute calcineurin inhibitors nephrotoxicity (n = 10); and (4) interstitial fibrosis and tubular atrophy (IFTA, n = 29). Tissue and urine cell RNA was amplified and quantification were made by real-time polymerase chain reactron. Data from the quantification of gene expression are presented as median and 25th to 75th percentiles. RESULTS: Messenger RNA levels of the KIM-1 gene were higher in the biopsies (26.17; 3.38-294.53) and urinary sediment cells (0.09; 0-5.81) of the patients classified as having IF/TA as compared with all others groups. A significant correlation between gene expression in samples of urine and tissue cells was found (P < .01). CONCLUSION: These initial data suggests that KIM-1 gene mRNA quantification can be used as a noninvasive biomarker of IF/TA. PMID- 23026579 TI - Study of heparin in intestinal ischemia and reperfusion in rats: morphologic and functional evaluation. AB - To study whether treatment with heparin (HEP) attenuates intestinal dysfunction caused by ischemia (I) and reperfusion (R), rats were treated with HEP (100 U/kg intravenously) or saline solution (SS) before I (60 min), which was produced by occlusion of the superior mesenteric artery, and R (120 min). After I or I/R, we mounted 2-cm jejunal segment in an organ bath to study neurogenic contractions stimulated by electrical pulses or KCl, using a digital recording system. Thin jejunal slices were stained with hematoxylin and eosin for optical microscopy. Compared with the sham group, jejunal contractions were similar in the I + HEP and the I/R + HEP groups, but reduced in the I + SS and the I/R + SS groups. The jejunal enteric nerves were damaged in the I + SS and the I/R + SS, but not in the I + HEP and the I/R + HEP cohorts. These results suggested that HEP attenuated intestinal dysfunction caused by I and I/R. PMID- 23026580 TI - Effect of ischemic preconditioning on injuries caused by ischemia and reperfusion in rat intestine. AB - To study whether ischemic preconditioning (IPC) attenuated intestinal dysfunction caused by ischemia (I) and reperfusion (R), rats were underwent 60 minutes of I which was produced by occlusion of the superior mesenteric artery, and/or 120 minutes R. The IPC group had the I procedure previously stimulated for 5 minutes and the R for 10 minutes. IPC and sham groups were injected with saline solution (SS) via the femoral vein 5 minutes before the I and R, and for R. After I or I/R, 2-cm jejunal segments were mounted in an organ bath to study neurogenic contractions stimulated by electrical pulses or KCl using a digital recording system. Thin jejunal slices were stained with hematoxylin and eosin for optical microscopy. Compared with the sham group, jejunal contractions were similar in the IPC + I and the IPC + I/R groups, but reduced in the I + SS and the I/R + SS groups. The jejunal enteric nerves were damaged in the I + SS and the I/R + SS groups, but not in the IPC groups. These results suggested that ischemic preconditioning attenuated intestinal dysfunction caused by I and I/R. PMID- 23026581 TI - Study of L-arginine in intestinal lesions caused by ischemia-reperfusion in rats. AB - To examine whether treatment with L-arginine (ARG), a substrate of nitric oxide biosynthesis, attenuated intestinal dysfunction caused by ischemia (I) and reperfusion (R), we treated rats with ARG (100 mg/kg intravenously) or saline solution (SS) before 60 minutes of I produced by occlusion of the superior mesenteric artery and/or during 120 minutes of R. After I or I/R, we isolated 2 cm jejunal segments for mounting in an organ bath to study neurogenic contractions stimulated by electrical pulses or KCl with the use of a digital recording system. Thin jejunal slices were stained with hematoxylin and eosin for optical microscopy. Jejunal contractions were similar in the sham and I+ARG, but reduced in I+SS, I/R+SS, and I/R+ARG groups. Jejunal enteric nerves were damaged in I+SS, IR+SS, and IR+ARG, but not in the I+ARG group, suggesting that ARG attenuate intestinal dysfunctions due to I but not to R. PMID- 23026582 TI - Atenolol to treat intestinal ischemia and reperfusion in rats. AB - To study whether treatment with the beta-blocker atenolol (AT) attenuates intestinal dysfunction caused by ischemia (I) and reperfusion (R), rats were treated with AT (1.5 mg . kg(-1), intravenously) or saline solution (SS) prior to I (60 minutes), which was produced by occlusion of the superior mesenteric artery, and/or R (120 minutes). After I or I/R, 2-cm jejunal segments were mounted in an organ bath to study neurogenic contractions stimulated by electrical pulses or KCl using a digital recording system. Thin jejunal slices were stained with hematoxylin and eosin for optical microscopy analysis. Compared to the sham group, jejunal contractions were similar in the I + AT and the I/R + AT groups, but reduced in the I + SS and the I/R + SS groups. The jejunal enteric nerves were damaged in the I + SS and the I/R + SS groups, but not in the I + AT and the I/R + AT. These results suggest that AT may attenuate intestinal dysfunction caused by I and I/R. PMID- 23026583 TI - Effect of adenosine on injury caused by ischemia and reperfusion in rats: functional and morphologic study. AB - To study whether treatment with adenosine (ADO), an agonist of adenosine receptors, attenuates intestinal dysfunction caused by ischemia (I) and reperfusion (R), we treated rats with ADO (15 mg/kg or saline solution (SS) intravenously before 60 minutes occlusion of the superior mesenteric artery (I) and/or 120 minutes after its release (R). After I or I/R, isolated jejunal segments (2 cm) were mounted in an organ bath to study nerve-mediated contractions stimulated by electrical pulses or KCI with the use of a digital recording system. Thin jejunal slices were stained with hematoxylin and eosin for optical microscopy. Compared with the sham group, jejunal contractions were reduced in I+SS and IR+SS but similar after treatment with ADO (I+ADO and IR+ADO groups). We concluded that rat jejunal enteric nerves were damaged in I+SS and IR+SS but not in the I+ADO and IR+ADO groups. These results suggested that ADO attenuated intestinal dysfunction due to I and R. PMID- 23026584 TI - Proliferative activity in ischemia/reperfusion injury in hepatectomized mice: effect of N-acetylcysteine. AB - BACKGROUND: Dysfunction of the liver after transplantation may be related to the graft size and ischemia/reperfusion (I/R) injury. N-Acetylcysteine (NAC) exerts beneficial effects on livers undergoing ischemia reperfusion. We sought to evaluate NAC modulation on reduced livers associated with I/R injury. METHODS: Male C57BL/6 mice of 8 weeks of age were divided into groups: 50% hepatectomy (G Hep); NAC (G-Hep + NAC [150 mg/kg]) via vena cava 15 minutes before hepatectomy; ischemia (G-Hep + IR); NAC with hepatectomy (G-IR + Hep + Nac); and IR using 30 minutes selective hepatic occlusion and reperfusion for 24 hours. After 24 hours, the remaining liver was removed, for staining with hematoxylin and eosin or labeling by proliferating cell nuclear antigen. Blood was collected for biochemical evaluations. Significance was considered for P <= .05. RESULTS: Aspartate aminotransferase was high in all studied groups reflecting the hepatectomy and intervention. injuries. However, when assessing alanine aminotransferase, which depicts liver function, induction of IR promoted a greater increase than hepatectomy (P = .0003). NAC decreased ALT activity in all groups, even in association with I/R (P < .05), reflecting a modulation of the injury. Necrosis resulting from IR was mitigated by NAC. The experimental model of 50% reduced live promoted regeneration of the hepatic remnant, which was accentuated by NAC, according to the total number of hepatocytes and PCNA values. CONCLUSION: NAC preserved the remnant liver in mice and stimulates regeneration even after IR injury. PMID- 23026585 TI - Deleterious effect of hypothermia in myocardial protection against cold ischemia: a comparative study in isolated rat hearts. AB - BACKGROUND: There is a growing need to improve heart preservation benefit the performance of cardiac operations, decrease morbidity, and more important, increase the donor pool. Therefore, the objective of this study was to evaluate the cardioprotective effects of Krebs-Henseleit buffer (KHB), Bretschneider-HTK (HTK), St. Thomas No. 1 (STH-1), and Celsior (CEL) solutions infused at 10 degrees C and 20 degrees C. METHODS: Hearts isolated from male albino Wistar rats and prepared according to Langendorff were randomly divided equally into 8 groups according to the temperature of infusion (10 degrees C or 20 degrees C) and cardioprotective solutions (KHB, HTK, STH-1, and CEL). After stabilization with KHB at 37 degrees C, baseline values were collected (control) for heart rate (HR), left ventricle systolic pressure (LVSP), coronary flow (CF), maximum rate of rise of left ventricular pressure during ventricular contraction (+dP/dt) and maximum rate of fall of left ventricular pressure during left ventricular relaxation (-dP/dt). The hearts were then perfused with cardioprotective solutions for 5 minutes and kept for 2 hours in static ischemia at 20 degrees C. Data evaluation used analysis of variance (ANOVA) in all together randomized 2 way ANOVA and Tukey's test for multiple comparisons. The level of significance chosen was P < .05. RESULTS: We observed that all 4 solutions were able to recover HR, independent of temperature. Interestingly, STH-1 solution at 20 degrees C showed HR above baseline throughout the experiment. An evaluation of the corresponding hemodynamic values (LVSP, +dP/dt, and -dP/dt) indicated that treatment with CEL solution was superior at both temperatures compared with the other solutions, and had better performance at 20 degrees C. When analyzing performance on CF maintenance, we observed that it was temperature dependent. However, when applying both HTK and CEL, at 10 degrees C and 20 degrees C respectively, indicated better protection against development of tissue edema. Multiple comparisons between treatments and hemodynamic variable outcomes showed that using CEL solution resulted in significant improvement compared with the other solutions at both temperatures. CONCLUSION: The solutions investigated were not able to fully suppress the deleterious effects of ischemia and reperfusion of the heart. However, these results allow us to conclude that temperature and the cardioprotective solution are interdependent as far as myocardial protection. Although CEL solution is the best for in myocardial protection, more studies are needed to understand the interaction between temperature and perfusion solution used. This will lead to development of better and more efficient cardioprotective methods. PMID- 23026586 TI - Hyperbaric oxygen therapy induces kidney protection in an ischemia/reperfusion model in rats. AB - Ischemia/reperfusion (I/R) injury remains a major cause of graft dysfunction, which impacts short- and long-term follow-up. Hyperbaric oxygen therapy (HBO), through plasma oxygen transport, has been currently used as an alternative treatment for ischemic tissues. The aim of this study was to analyze the effects of HBO on kidney I/R injury model in rats, in reducing the harmful effect of I/R. The renal I/R model was obtained by occluding bilateral renal pedicles with nontraumatic vascular clamps for 45 minutes, followed by 48 hours of reperfusion. HBO therapy was delivered an hypebaric chamber (2.5 atmospheres absolute). Animals underwent two sessions of 60 minutes each at 6 hours and 20 hours after initiation of reperfusion. Male Wistar rats (n = 38) were randomized into four groups: sham, sham operated rats; Sham+HBO, sham operated rats exposed to HBO; I/R, animals submitted to I/R; and I/R+HBO, I/R rats exposed to HBO. Blood, urine, and kidney tissue were collected for biochemical, histologic, and immunohistochemical analyses. The histopathological evaluation of the ischemic injury used a grading scale of 0 to 4. HBO attenuated renal dysfunction after ischemia characterized by a significant decrease in blood urea nitrogen (BUN), serum creatinine, and proteinuria in the I/R+HBO group compared with I/R alone. In parallel, tubular function was improved resulting in significantly lower fractional excretions of sodium and potassium. Kidney sections from the I/R plus HBO group showed significantly lower acute kidney injury scores compared with the I/R group. HBO treatment significantly diminished proliferative activity in I/R (P < .05). There was no significant difference in macrophage infiltration or hemoxygenase-1 expression. In conclusion, HBO attenuated renal dysfunction in a kidney I/R injury model with a decrease in BUN, serum creatinine, proteinuria, and fractional excretion of sodium and potassium, associated with reduced histological damage. PMID- 23026587 TI - Cardiovascular risk estimated in renal transplant recipients with the Framingham score. AB - BACKGROUND: Cardiovascular disease is responsible for much of the mortality and morbidity observed in the renal transplant population. Some studies have applied the Framingham score mainly to the chronic kidney disease (CKD) on renal replacement therapy in an attempt to predict cardiovascular events, but the results underestimated the risk. It became evident at the participation of so called nontraditional factors, such as anemia and inflammatory markers among others, were important predictors of risk in this population. OBJECTIVE: The aim of this study was to apply the Framingham score to a population of renal transplant subjects to assess its quality to predict cardiovascular events among a population without the theoretically nontraditional risk factors. METHODS: We retrospectively evaluated the medical records of patients transplanted from 2005 to 2010 for the score as determined by sex, age, blood pressure, low-density lipoprotein cholesterol, smoking history, and presence of diabetes mellitus. The final results expressed the risk for absolute development of cardiovascular diseases at the end of 10 years. RESULTS: Among 126 patients including 44 women and, 82 men of mean age 45 +/- 16 years were 64 living-related and 62 deceased donor grafts. The etiology of CKD was hypertension (58%), diabetes (37%), and other causes (5%). Fifty-nine percent of patients had a low risk of developing coronary artery diseases at the end of 10 years, 30% medium risk, and only 11% high risk when measured by the Framingham score. CONCLUSIONS: The assessment of cardiovascular risk using the Framingham risk score did not reflect the observations in the literature of both high mortality and high morbidity. Therefore, this was not a good method to assess the risk of cardiovascular disease, probably because it does not include cardiovascular risk factors in addition to traditional ones that are important in this population. PMID- 23026588 TI - Social diagnosis of chronic kidney disease patients in preparation for living donor renal transplantation. AB - BACKGROUND: The relationship between socioeconomic status and clinical outcome in health and disease is complex and multifactorial. An association between low socioeconomic status and shorter patient survival in renal replacement therapy, dialysis, and transplantation, has been reported, implicating individual and environmental factors. We sought to analyze the socioeconomic and demographic characteristics of chronic kidney disease (CKD) patients in preparation for living kidney transplantation. METHODS: We evaluated 60 patients with CKD-V, on hemodialysis or peritoneal dialysis and who were being prepared in our public service between July 2008 and January 2010. Socioeconomic data were collected from the records. RESULTS: The mean age was 44.8 +/- 13.3 years and 51% were male. Sixty-three percent were married, most of them with children, with a family size of 3.5 +/- 1.45 members. They were taken a mean of 5.8 +/- 2.8 drugs; only half of them were dispensed by public health insurance. Almost all--93%--did not work regularly, and the majority reported some limitation in daily activities. The mean monthly income was US $1,535.70 and 76.2% reported a monthly income <= US $1,810.60. The mean of school years was 7.91 +/- 4.19. CONCLUSION: Low-income patients are gaining access to preparing for renal transplantation; we believe that is inherent to the universal structure of Brazil's public health system. Besides the low income, this population showed a considerable educational level, suggesting this characteristic made the patient more active to search the living transplant as an alternative for their CKD treatment. Knowledge about social status is essential for design strategies in minimizing its potential undesirable effects after transplantation. PMID- 23026589 TI - Advantages of kidney transplant precocity in graft long-term survival. AB - BACKGROUND: Preemptive kidney transplantation (KT) or KT after a brief period on dialysis (<6 months) has been associated with better graft survival. Our study aimed to analyze the effect of an early KT on graft survival censored for patient death with functioning graft. METHODS: A total of 1,373 kidney-only transplantations, from both living and deceased donors, performed from 1983 to 2010 were retrospectively studied. We defined 2 groups: those with early KT (preemptive or within 6 months after dialysis initiation; n = 131) and non-early KT (n = 1,242). Survival curves for each group were calculated by Kaplan-Meier analysis and compared by log-rank test. The independent effect of early KT on censored graft survival was analyzed by a multivariate-adjusted Cox proportional regression model. RESULTS: The 5-, 10-, 15-, and 20-year censored graft survival rates were, respectively, 96%, 89%, 79%, and 79% among the early KT group, and 91%, 81%, 68%, and 49% among the non-early KT group (P = .024). Multivariate analysis showed the following to be independent predictors for censored graft failure: non-early KT (hazard ratio [HR] 2.58; P = .028), recipient age (HR 0.97; P < .001), donor age (HR 1.03; P < .001), recipient negative status for cytomegalovirus IgG (HR 1.44; P = .032), delayed graft function (HR 1.48; P = .013), and acute rejection event (HR 1.68; P = .002). CONCLUSIONS: Our results show that early KT can be an approach for the improvement of long-term graft survival. PMID- 23026590 TI - Sirolimus in renal transplantation: analysis of safety and efficacy in a nonprotocol conversion group. AB - BACKGROUND: Conversion to sirolimus (SRL)-based immunosuppression in renal transplant recipients is an alternative for chronic allograft dysfunction (CAD), cancer and viral infections. We sought to analyze the indications for and safety and efficacy of conversion to SRL among renal transplant patients. METHODS/MATERIALS: We examined a retrospective cohort, using medical records of renal transplant recipients >18 years old who had their immunosuppressive regimen converted to a SRL-based treatment. Data analysis included the indication for conversion, time posttransplant, as well as urine protein and serum creatinine at conversion and 6 months thereafter. The end points included death, graft loss and/or discontinuation of SRL. RESULTS: We included 112 patients in this series who had indications for conversion: fungal, polyomavirus, or cytomegalovirus infection (n = 32), CAD (n = 30), cancer (n = 21), immunologic (n = 3), and other reasons (n = 26). Changes in immunosuppression were performed at 41 +/- 57 months posttransplant or later in cancer patients. SRL was discontinued in 9 patients owing to adverse events such as edema, proteinuria, mucositis, or pneumonitis. Graft loss was observed in 19 patients, and death in 6. In 87 patients with functioning grafts, protein/creatinine ratios increased from 0.28 +/- 0.03 (conversion) to 0.63 +/- 0.09 (after 6 months; P < .001). Serum creatinine decreased from 2.24 +/- 0.13 (conversion) to 1.89 +/- 0.75 mg/dL (after 6 months; P < .001). Graft survival was 88% at 1 and 80% at 3 years after conversion. CONCLUSION: In, SRL was well tolerated; conversion to SRL improved graft function with a slight increase in proteinuria. PMID- 23026591 TI - A comparison between serum creatinine and cystatin C-based equations for estimation of graft function. AB - BACKGROUND: Accurate monitoring of estimated glomerular filtration rate (GFR) is essential for an optimal management of kidney transplant (KT) patients. We aimed to compare the predictive performance of creatinine- and cystatin C-based GFR with creatinine clearance (CCr) in a 24-hour urine collection as the reference test. METHODS: GFR was calculated using cystatin C-based equations (Le Bricon, Stevens) and two creatinine-based equations [Cockcroft-Gault (CG), modification of diet in renal disease (MDRD)]. We enrolled 173 KT recipients. Bias, precision, and accuracy of each equation were determined. Kappa statistics evaluated the concordance between the reference test and GFR formulas in classifying patients according graft function (CCr <60 or >=60 mL/min/1.73 m2). RESULTS: Patients (108 males) had a mean age of 48.6 +/- 12.2 years and a median posttransplant time of 6.8 years. Mean CCr was 69.3 +/- 19.9 (range: 32.1-105.2) mL/min/1.73 m2. The cystatin C-based equations estimates (Le Bricon, Stevens) had the highest accuracy (83.8% and 87.9% within 30% of CCr result, respectively). Precision of Le Bricon, Stevens, and MDRD was similar (around 13.5 mL/min/1.73 m2)) and much better than CG (22.5 mL/min/1.73 m2). The lowest bias was seen in Le Bricon (-1.2 mL/min/1.73 m2), followed by CG, Stevens, and MDRD (-2.6, -9.5, -16.5 mL/min/1.73 m(2), respectively). Kappa coefficient was higher in cystatin C-based equations (0.53) in contrast with CG (0.48) and MDRD (0.40). Stevens had a high sensitivity (90.8%) and low specificity (66.7%) and, conversely, Le Bricon had 64.6% sensitivity and 87.0% specificity. CONCLUSIONS: Cystatin C-based equations showed a better predictive performance of graft function than creatinine-based equations. The role of cystatin C in graft function monitoring deserves further investigation. PMID- 23026592 TI - Comparison of cystatin C- and creatinine-based glomerular filtration rate formulas with inulin clearance in pediatric renal transplantation. AB - BACKGROUND: It has been suggested that plasma cystatin C (Cyst-C) concentrations provide better indicators of changes in glomerular filtration rate (GFR) than plasma creatinine concentration (PCr). METHODS: We compared the performance of five equations--2009 Schwartz, Local Schwartz, Larsson, Le Bricon, and Schwartz Combined--in 60 renal transplant children by calculating the mean bias, Pearson correlation coefficient (R) and determination (R2), 10% (P10) and 30% (P30) accuracies, and Bland-Altman plots. GFR was measured by inulin clearance. RESULTS: For the whole population, R2 was slightly lower for formulas based on Cyst-C or PCr, but the mean bias was lower, and P10 and P30 were greater, than using combined Schwartz equation. However, the mean estimated GFR by Schwartz 2009, Local Schwartz, and Schwartz combined equations was not statistically different from the mean inulin clearance measurement. CONCLUSIONS: In our pediatric transplant population, the combined Schwartz formula exhibited better performance to estimate GFR than formulae based on Cyst-C or combined PCr. PMID- 23026593 TI - C4d deposits in acute "cell-mediated" rejection: a marker for renal prognosis? AB - BACKGROUND: Accumulation of C4d along peritubular capillaries (PTC) of renal allografts is normally attributed to antibody-mediated rejection. The prognostic implication of these deposits associated with "cell-mediated" rejection on graft survival remains uncertain. Our study aims to evaluate the impact of C4d deposits along PTC of patients with acute cell- mediated rejection on graft function and survival. METHODS: We retrospectively analyzed patients transplanted between 2005 and 2010 with histopathologic diagnosis of acute rejection (AR). Eleven patients with "pure" antibody-mediated rejection were excluded. The remaining 79 patients were divided into two groups according to type of AR by Banff 2003 criteria: type I (69.6%) versus type II (30.4%). In each group, comparisons were made between C4d-negative (-) and C4d-positive (+) biopsies. RESULTS: Fifty-five patients presented with type I AR: 35 (63.6%) C4d- and 20 (36.4%) C4d+. Twenty-four patients presented with type II AR: 13 (54.2%) C4d- and 11 (45.8%) C4d+. In the type I AR group, graft survival at the first and second years was similar in C4d- and C4d+ patients (94% and 91% versus 75% and 75%, respectively, log-rank P = .26). No differences were encountered in estimated glomerular filtration rate (eGFR) between subgroups at the first, second, and final years of follow-up. Graft loss occurred in 14.7% of C4d- patients versus 25% in C4d+ patients (P = NS). In the type II AR group, graft survival at the first and second years was similar in C4d- and C4d+ patients (85% and 85% versus 72% and 61%, respectively, log-rank P = .50). No differences were encountered in eGFR between subgroups at the first, second, and final years of follow-up. Graft loss occurred in 30.8% of C4d- patients versus 45.5% in C4d+ patients (P = NS). CONCLUSION: Our results suggest that detection of C4d staining in acute "cell-mediated" rejection does not imply a worse renal prognosis. PMID- 23026594 TI - Nutritional status and body composition in patients early after renal transplantation. AB - INTRODUCTION: After renal transplantation recovery in nutritional status occurs during the first year. We assessed the changes in nutritional status after transplantation in 145 transplant recipients (94 males, 51 females). METHODS: Patients were evaluated immediately after renal transplant (baseline data) and at 6 months' follow-up. Analysis included body mass index (BMI), body composition (skin fold and arm circumference), and estimated body composition (calculated percent of fat, arm circumference, arm muscle circumference, and arm muscle area). Other data obtained from medical records included renal function (MDRD) serum albumin and lipid profile. RESULTS: At baseline evaluation (21 +/- 15 days posttransplant), mean BMI was 23.9 +/- 3.9 kg/m(2), serum albumin was 3.7 +/- 0.7 g/dL, and lipid profile showed (cholesterol 158.5 +/- 52.7 mg% and triglycerides 135.9 +/- 91.8 mg%. Body composition analysis showed better adaptation of muscle mass in females [AC (91 +/- 10.2 * 98 +/- 14.6; male * female, P < .05) arm muscle circumference (92.6 +/- 1.4 * 102.3% +/- 2.9%, male * female, P < .05) and arm muscle area (87.1 +/- 22.3 * 105.5% +/- 25.9%, male * female, P < .05)]. Body fat was above the recommended levels in 80% of patients, especially females. After 6 months we divided the groups according to BMI, observing better renal function in the normal weight group compared with obese subjects (60 +/- 17.2 * 39.5 +/- 19.8 mL/min MDRD, P < .05), despite comparable estimated glomerular filtration rate at baseline. CONCLUSION: The nutritional assessment of patients with end-stage renal disease early after renal transplantation, showed inadequate body composition, with increased fat and reduced lean body mass. The lower glomerular filtration rate after 6 months may be attributed to relatively inadequate renal mass or to obesity-induced hyperfiltration. PMID- 23026595 TI - Hyperuricemia in adult renal allograft recipients: prevalence and predictors. AB - BACKGROUND: Hyperuricemia is a common complication after kidney transplantation that may adversely affect graft survival. OBJECTIVE: Our aim was to determine the prevalence of hyperuricemia in a sample of adult kidney graft recipients and to investigate its predictors. METHODS: A total of 302 patients were included in the study. We used univariate analyses to compare clinical characteristics between the hyper-and normouricemic groups. We used multivariate adjusted logistic regression to detect independent predictors of hyperuricemia. Hyperuricemia was defined as serum uric acid >=6.5 mg/dL in women and >=7.0 mg/dL in men or allopurinol use. RESULTS: The patients had a mean age of 49.6 +/- 13.4 years, a median posttransplantation time of 7.6 years, and a mean estimated glomerular filtration rate (eGFR) of 51.9 +/- 18.46 mL/min. The prevalence of hyperuricemia was 42.1% (n = 127). Hyperuricemic patients were predominately male (P = .004), older (P = .038), and with lower eGFR (P < .001). They also had a higher prevalence of hypertension (P = .001), dyslipidemia (P = .004) and proteinuria (P = .001). Multivariate adjusted regression model showed as significant predictors of hyperuricemia: male gender (odds ratio [OR], 2.46; P = .002); impaired renal function (OR 1.33 for every 10 mL/min reduction in eGFR; P < .001), higher body weight (OR 1.09 for every 1 kg/m(2) increase of body mass index; P = .044), prednisolone use (OR 2.12; P = .035), and cyclosporine versus tacrolimus use (OR 2.44; P = .039). CONCLUSIONS: The prevalence of posttransplant hyperuricemia was high, particularly in patients with classical cardiovascular risk factors and lower eGFR. However, our findings suggest that modifiable immunosuppression options could play a role in its management. PMID- 23026596 TI - Lithiasis in 1,313 kidney transplants: incidence, diagnosis, and management. AB - BACKGROUND: Renal transplantation remains the optimal treatment of patients with end-stage renal disease. Urinary lithiasis represents an unusual urologic complication in renal transplantation, with an incidence of <1%. Today, recipients of kidneys from deceased donors are more likely to receive grafts with undiagnosed lithiasis, which does not occur in patients from living donors, owing to screening with computerized tomography. OBJECTIVE: The aim of this study was to evaluate the incidence, diagnosis, and therapeutic management of renal lithiasis in transplanted kidneys at a single institution. METHODS: We reviewed the medical records for 1,313 patients who underwent kidney transplantation from February 1968 to February 2011. RESULTS: Among the grafts, 17 patients (1.29%) had nephrolithiasis: 9 women and 8 men. Ages ranged from 32 to 63 years (mean = 45.6 years). Fifteen patients received kidneys from cadaveric and only 2 from living related donors. Two stones, both located inside the ureter, were identified during transplant surgery (11.7%). Three instances of lithiasis were incidentally diagnosed by ultrasound during graft evaluation, within 7 days after surgery (17.6%); all 3 were in the calyces. The 12 remaining patients had the stones diagnosed later (70.58%): 6 in the calyces, 3 in the renal pelvis, and 3 inside the ureter. CONCLUSIONS: Urinary lithiasis is a rare complication in renal transplantation. In most patients the condition occurs without pain. The diagnosis and treatment options for graft urolithiasis are similar to those patients with nephrolithiasis in the general population. Extracorporeal shock wave lithotripsy (ESWL) was the most common treatment method. PMID- 23026597 TI - Cinacalcet de novo in persistent hypercalcemia after kidney transplantation secondary to hyperparathyroidism: long-term follow-up and effect of withdrawal. AB - BACKGROUND: Secondary hyperparathyroidism that persists after kidney transplantation (KT), is the main cause of hypercalcemia. Cinacalcet has been used to control hypercalcemia in KT patients. OBJECTIVE: The aim of this study was to evaluate the effect of de novo cinacalcet in KT patients with hypercalcemia and the evolution after its withdrawal. METHODS: This observational study included 41 KT patients (17 men) with persistent hypercalcemia (>6 months), defined as serum calcium (sCa) >=10.5 mg/dL, and a mean age of 51.1 +/- 13.3 years with a functional allograft for >12 months. The time after surgery to begin cinacalcet was 33 months (range, 12.5-81.3). The initial dose of cinacalcet was 30 mg/d. In a subgroup of 14 patients cinacalcet was stopped after 1 year. We studied the evolution of serum levels of calcium, phosphorus, intact pathyroid hormone (iPTH), and serum creatinine. RESULTS: Calcemia normalized in all patients (sCa <10.2 mg/dL). iPTH decreased (basal 267 +/- 212 pg/mL vs final: 219 +/- 160 pg/mL; P = ns) Serum phosphorus increased (basal 2.85 +/- 0.48 mg/dL vs final 3.16 +/- 0.50 mg/dL; P = ns). Renal function remained stable (basal creatinine 1.49 +/- 0.48 vs final 1.47 +/- 0.32 mg/dL; P = ns). After stopping cinacalcet, in group 1 calcemia persisted at normal levels in 50% (n = 7), but the drug had to be reintroduced in the other 50% after 10 +/- 7.9 months. No adverse events were documented. CONCLUSIONS: Cinacalcet is an effective alternative for the treatment of hypercalcemia in patients with persistent hyperparathyroidism after KT. Once the treatment is started, there is presently no invice to disclose to who tolerate its withdrawal or the time to do so. PMID- 23026598 TI - Withdrawal of cinacalcet at the time of renal transplantation is not a risk factor for allograft calcifications in the early posttransplantation period. AB - BACKGROUND: Secondary hyperparathyroidism is a relevant problem in patients on dialysis. Cinacalcet in regular clinical practice increases the percentage of patients achieving treatment targets for PTH, Ca and P. We evaluated allograft calcification in serial protocol biopsies after transplantation among patients receiving Cinacalcet on dialysis but discontinued after surgery. METHODS: This retrospective single-centre study included kidney allograft recipients who were receiving Cinacalcet for more than 6 months before surgery and had it withdrawn thereafter. The 46 patients including 17 women showed a mean overall age of 54 +/ 30 years. Protocol graft biopsy was performed at 3 and at 12 months. Biochemical analyses at the time of biopsy included blood levels of creatinine, phosphorus, calcium, alkaline phosphatases, iPTH, and proteinuria. RESULTS: Any biopsy showed nephrocalcinosis either intratubular calcifications, or in the parenchyma. There were no changes in calcemia (10.22 +/- 0.7 to 10.27 +/- 0.7 mg/dL), in alkaline phosphatase (259 +/- 119.6 to 255 +/- 122.3 mg/dL) nor in iPTH (317 +/- 220.2 to 320 +/- 168.8 pg/mL) between 3 and 12 months respectively. There was a slight but non-significant increase in serum phosphorus (2.79 +/- 0.8 to 3.22 +/- 0.9 mg/dL), serum creatinine (1.53 +/- 0.6 to 1.84 +/- 1.2 mg/dL) and proteinuria (528 +/- 603 to 879 +/- 1398 mg/24h) between 3 and 12 months respectively. CONCLUSIONS: Withdrawal of Cinacalcet at the time of renal transplantation was not a risk factor for allograft calcifications in the early post-transplant period. PMID- 23026599 TI - Excessive immunosuppression in kidney transplant patients: prevalence and outcomes. AB - BACKGROUND: Death with a functioning graft is currently one of the main causes of kidney graft loss. A large proportion of cases is attributed to infectious complications that can be related to overimmunosuppression. We retrospectively studied 80 kidney transplant patients, grafted from January 2005 to December 2009, to assess the prevalence of excessive immunosuppression, and its possible correlation with infections and infection-related death. METHODS: Excessive immunosuppression was defined by a prescribed dosage above the expected to the time point or an elevated drug blood level according to the Kidney Disease: Improving Global Outcomes (2009) recommendations at 1, 3, 6, and 12 months, and then annually. RESULTS: Death with a functioning graft accounted for 76.5% of losses. Overall, 53.8% of deaths were from infections, and 38.5% from cardiovascular causes. Acute rejection episodes were noted in 8.8% of patients. Only 10% of patients had adequate immunosuppression throughout the follow-up. Seventy-two percent of patients showed adequate immunosuppression at least half of the 18 evaluated points, although 50% showed between 1 and 3 drugs administered above recommended dosages during the whole period. Infections were recorded in 78.8% patients, with a median of 3 episodes per patient. Any level of excessive immunosuppression was associated with infections (odds ratio, 11.2; P < .001), but not with death caused thereby. CONCLUSION: Excessive immunosuppression among this cohort was associated with a greater incidence of infections, but not with death from this cause. PMID- 23026600 TI - Assessment of gastrointestinal motility in renal transplant recipients by alternate current biosusceptometry. AB - BACKGROUND: Gastrointestinal (GI) complications are common after renal transplantation, mainly owing to immunosuppressive therapy. Assessment of GI transit time can facilitate rational management of these disorders. OBJECTIVE: We evaluate the GI transit parameters in renal transplant recipients taking tacrolimus, azathioprine, and prednisone with the use of the alternate current biosusceptometry (ACB) technique and compared them with healthy volunteers. METHODS: Ten renal transplant recipients and 10 healthy volunteers were enrolled in this study. After an overnight fast, patients and volunteers ingested a standard meal containing magnetic markers. The biomagnetic monitoring was performed at 10-minute intervals for at least 8 hours to obtain gastric emptying as well as the colonic arrival time-intensity curves. Mean gastric emptying time (MGET), mean colon arrival time (MCAT), and mean small intestinal transit time (MSITT) were quantified and compared between control and patient groups with results expressed as mean +/- SD. RESULTS: The MGET measured by the ACB technique was 48 +/- 31 minutes and 197 +/- 50 minutes for patients and healthy subjects, respectively. MSITT and MCAT values calculated for patients versus volunteers were 171 +/- 71 minutes versus 197 +/- 71 minutes and 219 +/- 83 minutes versus 373 +/- 52 minutes, respectively. Renal transplant recipients showed significantly faster; gastric emptying and colon arrival times (P < .001) compared with normal volunteers; however, small intestinal transit time was not significantly different (P = .44). CONCLUSIONS: In stable renal transplant recipients, the GI transit parameters were significantly faster than in normal healthy volunteers. ACB sensors are versatile technologies that can be used for clinical research, because they offer an excellent opportunity to evaluate GI transit in a noninvasive manner without the use of ionizing radiation. PMID- 23026601 TI - De novo thrombotic microangiopathy after kidney transplantation: clinical features, treatment, and long-term patient and graft survival. AB - INTRODUCTION: Posttransplant thrombotic microangiopathy (TMA)/hemolytic uremic syndrome (HUS) can occur as a recurrent or de novo disease. METHODS: A retrospective single-center observational study was applied in order to examine the incidence and outcomes of de novo TMA/HUS among transplantations performed between 2000 and 2010. Recurrent HUS or antibody-mediated rejections were excluded. RESULTS: Seventeen (1.1%) among 1549 kidney transplant recipients fulfilled criteria for de novo TMA. The mean follow-up was 572 days (range, 69 1769). Maintenance immunosuppression was prednisone, tacrolimus (TAC), and mycophenolic acid in 14 (82%) patients. Mean age at onset was 40 +/- 15 years, and serum creatinine was 6.1 +/- 4.1 mg/dL. TMA occurred at a median of 25 days (range, 1-1755) after transplantation. Nine (53%) patients developed TMA within 1 month of transplantation and only 12% after 1 year. Clinical features were anemia (hemoglobin < 10 g/dL) in 9 (53%) patients, thrombocytopenia in 7 (41%), and increased lactate dehydrogenase in 12 (70%). Decreased haptoglobin was observed in 64% and schistocytes in 35%. Calcineurin inhibitor (CNI) withdrawal or reduction was the first step in the management of 10/15 (66%) patients, and 6 (35%) received fresh frozen plasma (FFP) and/or plasmapheresis. TAC was successfully reintroduced in six patients after a median of 17 days. Eight (47%) patients needed dialytic support after TMA diagnosis and 75% remained on dialysis. At 4 years of follow-up, death-censored graft survival was worse for TMA group (43.0% versus 85.6%, log-rank = 0.001; hazard ratio = 3.74) and there was no difference in patient survival (53.1% versus 82.2%, log-rank = 0.24). CONCLUSION: De novo TMA after kidney transplantation is a rare but severe condition with poor graft outcomes. This syndrome may not be fully manifested, and clinical suspicion is essential for early diagnosis and treatment, based mainly in CNI withdrawal and FFP infusions and/or plasmapheresis. PMID- 23026602 TI - Evaluation of adherence to immunosuppressive drugs in kidney transplantation by control of medication dispensing. AB - Nonadherence to immunosuppressive medications represents a burden to organ transplantation being associated with rejection episodes and graft loss. In this cross-sectional study we evaluated the prevalence and risk factors for nonadherence in kidney transplant patients by measuring the retrieval of the immunosuppressive drugs in the registry kept by the state Rio Grande do Sul public health system. We considered nonadherence the failure to retrieval of medication at least one time over a 1-year period of evaluation. In 288 patients evaluated, the frequency of failure to retrieve was 58.7%. Being fully employed (66.4% * 33.6%, P = .008) and younger age at transplantation (39 +/- 13 * 46 +/- 11, P = .011) were associated with nonadherence. Multivariate analysis showed a greater prevalence ratio (PR) of non- adherence in patients using tacrolimus. Estimated glomerular filtration rate was significantly lower in the nonadherence groups as compared with adherent groups (45.3 +/- 21.6 * 51.3 +/- 19.4, P = .016). In conclusion, we found a high prevalence of nonadherence to immunosuppressive drugs with association to active working situation and use of tacrolimus. Importantly, glomerular filtration rate was found to be lower in nonadherent patients. PMID- 23026603 TI - Prevalence of urinary decoy cells and associated risk factors in a Brazilian kidney, pancreas, and kidney-pancreas transplant population. AB - BACKGROUND: Polyomavirus BK (BKV) is currently considered one of the most important infectious diseases in kidney transplants recipients. The prevalence of decoy cells (viral containing shed urothelial cells) in these patients varies between 20% and 60%. Of decoy-positive patients, 1%-8% develop BKV nephropathy, a finding that may be associated with graft failure in up to 80% of affected individuals. METHODS: Decoy cells cytology is an easily performed and inexpensive assay useful for poliomavirus infection screening. Data on the prevalence of decoy cells in simultaneous pancreas-kidney or isolated pancreas recipients remains largely unreported. In the present study, we evaluated 221 patients >=18 years old with >1 month follow-up after transplantation who had attended the outpatient clinic between September and December 2006. RESULTS: The total prevalence of decoy cells was 16% (16.9% in kidney recipients, 5.9% in simultaneous kidney-pancreas recipients and 20% in pancreas alone recipients). There were no differences between patients with either positive or negative urinary cytology for decoy cells, regarding demographic (gender, age, race) or clinical (time posttransplantation, donor type [deceased vs living donation], and presence of delayed graft function or rejection, other associated viral infections and type of immunosuppressive drugs variables. PMID- 23026604 TI - Aortic clamping in pancreas transplantation: is there any harm to the transplanted kidney graft? AB - INTRODUCTION: Some special situations may require aortic clamping during pancreas transplantation (PT). The most important problem is ischemic injury to a previous transplanted kidney. We sought to demonstrate experience with aortic clamping in PT without special kidney allograft protection measures and its impact on kidney function. METHODS: Retrospective study that analyzed 6 patients who underwent PT (5 pancreas after kidney and 1 simultaneous pancreas-kidney) with aortic clamping. In all cases, the pancreas graft was placed on the right with retrocolic portal-enteric drainage. Serum creatinine was evaluated pre- and posttransplantation. RESULTS: The average clamping time was 19 minutes. The mean serum creatinine was 1.1, 1.15, 0.95, and 1.0, respectively, at pre and postoperative days 1 and 7 and at hospital discharge. Patient, kidney, and pancreatic graft survivals were 100%, 100%, and 83%, respectively. CONCLUSION: The need for aortic clamping in selected cases of PT did not seem to affect the transplanted kidney, even without protective measures, provided that the ischemic time was short. PMID- 23026605 TI - Clinical profile and liver explant findings in patients with and without pretransplant downstaging for hepatocellular carcinoma. AB - INTRODUCTION: Since August 2010, The Brazilian National Transplantation System has allowed performance of liver transplantation (OLT) for patients with hepatocellular carcinoma (HCC) beyond the Milan criteria (MC) who have been successfully treated with preoperative downstaging (DS). Herein we sought to compare the clinical profiles and liver explant findings among patients with versus without preoperative DS. METHODOLOGY: Prospective cohort of patients with HCC within and beyond the MC undergoing OLT. Patients were considered for DS if they were beyond the MC without evidence of vascular invasion or extrahepatic disease. Transcatheter arterial chemoembolization was used for DS, which was considered to be successful if the MC were achieved at any moment during the follow-up. RESULTS: Between May 2006 and May 2010, we performed 130 OLTs in HCC patients, among whom 10 received preoperative DS. Both groups were comparable for gender, age, viral etiology, serum levels of alpha fetoprotein, and Child-Pugh and Model for End-Stage Liver Disease (MELD) scores (P > .05). The liver explants were within the MC in 80% of patients with preoperative DS and 90% of those without preoperative DS. They were comparable for the number of HCC nodules, total tumor size, histologic grade, and presence of microvascular invasion. Patients with pretransplant DS showed larger HCC nodules (33.3 +/- 9.65 vs 26.3 +/- 9.62 mm; P .029) and more frequent macrovascular invasion (1 vs 1 patient, P = .024). CONCLUSION: Preoperative DS for unresectable HCC may provide a curative treatment for patients who would otherwise be candidates for palliative therapy only. The baseline characteristics and liver explant findings were similar in both groups. We have yet to determine whether the differences observed regarding the size of the largest nodule and the higher frequency of macrovascular invasion have an impact on outcome. PMID- 23026606 TI - Profile of respiratory evaluation through surface electromyography, manovacuometry, and espirometry in candidates on the liver transplant waiting list. AB - INTRODUCTION: Electromyography (EMG) is the examination of skeletal muscle membrane electrical activity in response to physiologic activation. In healthy muscles, the square root (root mean square [RMS] is related to the amplitude of the obtained signal. Respiratory muscles are studied, especially those important for compliance, the diaphragm and the rectus abdominis. An evaluation to detect respiratory muscle deficits among liver disease patients on the waiting list for transplantation may serve as an alternative to providing specific treatments reducing the possibility of respiratory complications after transplantation. OBJECTIVE: To study muscle activity by evaluating respiratory and surface EMG of the right diaphragm and right rectus abdominis muscles in patients on the liver transplant waiting list. METHOD: Respiratory evaluation of muscle strength (maximum inspiratory pressure [MIP] and maximum expiratory pressure [MEP]) with a manometer -300, +300 from Gen-air; spirometry with Easyware Spirometer version 2.20; pulse oximetry with Nonim oximeter; Model for End-Stage Liver Disease (MELD) score as well as surface EMG of the diaphragm and rectus abdominis muscles from EMG/Brazil were applied in healthy and liver diseased subjects. RESULTS: The 87 liver disease patients showed a mean age of 53.9 +/- 7.3 years, mean body mass index of 28.21 +/- 5.04 kg/m2 with 24.14% smokers (n = 21) and 43.68% physically active (n = 38 p) showing Diaphragm RMS of 61.05 +/- 68.48 MUV; rectus abdominis RMS of 45.28 +/- 53.82 MUV; MEP of 100.28 +/- 27.85 cm H(2)O; and MIP of 92.41 +/ 29.77 cm H2O. The average MELD of studied patients was 16.5 +/- 0.71. CONCLUSION: The respiratory profiles of patients on the liver transplant waiting list concerning muscle support were precarious owing to ascites and motor adynamia. PMID- 23026607 TI - Is isoniazid safe for liver transplant candidates with latent tuberculosis? AB - Isoniazid (INH) is recommended for tuberculosis prophylaxis in non-liver transplant recipients. However, there is a great reluctance to prescribe this agent for liver transplant candidates and recipients due to the risk of precipitating further hepatic decompensation. We analyzed the records of liver transplantation candidates undergoing a purified protein derivative (PPD) test (tuberculosis skin test) between 2008 and 2010. Patients with no respiratory symptoms, PPD test > 10 mm, and normal chest radiography were diagnosed as latent tuberculosis and prescribed INH (300 mg) per day for 6 months. The 191 patients submitted to a PPD test and those on tuberculosis prophylaxis underwent blood tests and clinical evaluations monthly to detect hepatotoxicity of patients The 33 subjects (17.2%) with a PPD test >= 10 mm displayed an average model for end stage liver disease score of 20 (range: 9-29) and child-Pugh A/B score. The main causes for liver disease were chronic hepatitis C, hepatocellular carcinoma, and alcohol abuse. Among 27 patients who received INH, 18 (66.6%) completed 6 months of prophylaxis. Eight who had shorter treatment courses of 2 to 4 months had undergone transplantation. One patient had to stop treatment because of clinical decompensation due to spontaneous bacterial peritonitis without a transaminases elevation. Six patients did not receive INH: previous tuberculosis treatment, transplantation before initiating prophylaxis, or removal from the liver candidacy list. No patient showed clinical decompensation or laboratory abnormalities associated with use of INH. The average values of alanine aminotransferase pre- and posttreatment were similar (69 and 72 U/l respectively), demonstrating that tuberculosis prophylaxis with INH was safe for liver transplant candidates. PMID- 23026608 TI - Pre- and posttransplant monitoring of alloantibodies by complement-dependent cytotoxicity and luminex methodologies in liver transplantation. AB - BACKGROUND: This study evaluated the influence of circulating anti-HLA antibodies on outcomes of 97 liver allografts from deceased donors. METHODS: Human leukocyte antigen (HLA) antibody screening was performed by both complement-dependent cytotoxicity (CDC) and multiparameter Luminex microsphere-based assays (Luminex assay). RESULTS: The agreements between T- and B- cell CDC and Luminex assays were 67% and 77% for pre- and posttransplant specimens, respectively. Graft dysfunction was not associated with either positive pretransplant CDC or Luminex panel-reactive antibody (PRA) values. Likewise, positive posttransplant T- or B- cell CDC PRA values were not associated with graft dysfunction. In contrast, posttransplant Luminex PRA values were significantly higher among patients with graft dysfunction compared with subjects with good outcomes (P = .017). CONCLUSION: Posttransplant monitoring of HLA antibodies with Luminex methodology allowed identification of patients at high-risk for poor graft outcomes. PMID- 23026610 TI - Orthotopic liver transplantation without venovenous bypass: 125 cases from a single center. AB - AIM: This study analyzed a 10-year single-center experience in orthotopic liver transplantation (OLT) without venovenous bypass (VVB). METHODS: We retrospectively analysed a nonrandomized series (1999-2008) of 125 adult OLT patients without VVB. RESULTS: The main causes of liver failure were viral hepatitis (n = 39), alcoholic liver disease (n = 22), and liver cancer (n = 17). One-year survival was 76.4%. The most common postoperative complications were bile duct stenosis (n = 12), postoperative bleeding (n = 8), hepatic artery thrombosis (n = 7), and primary liver failure (n = 6). Twelve patients required hemodialysis and four underwent retransplantations of the liver. Fourteen patients died before postoperative day 30(th). Univariate analysis showed significant differences between patients who did and did not survive 30 days among donor death diagnoses (P = .05), red blood cell units transfused (P = .03), aspartate aminotranferase on the first postoperative day (P = .002), ABO type (P = .04), time of orotracheal intubation (P = .001), hemodialysis (P = .001), and period of postoperative vasoactive drug use (P = .006). The total length of orotracheal tube intubation showed a significant independent association with mortality before 30 days (P < .001). CONCLUSION: OLT without VVB can be safely performed even in severe cases of chronic liver failure. PMID- 23026609 TI - Quality of life, depression, and psychosocial characteristics of patients awaiting liver transplants. AB - BACKGROUND: The identification of the psychological issues that impair the quality of life and the adherence to treatment in transplant candidates are important. OBJECTIVE: This study evaluated the presence of symptoms of depression and the quality of life of liver transplant candidates. METHODS: One hundred liver transplant candidates underwent a psychological analysis using the following instruments: the short form-36 (SF-36) quality of life questionnaire, the Beck depression inventory (BDI), and Structured Interviews for liver transplant candidates. RESULTS: Seventy-three (73%) of the patients were males. Interestingly, 63% of the patients were in a domestic partnership. At the time of the evaluation, 55 patients were not working due to illness, 27 patients were actively working, and 11 patients were retired. Importantly, fears related to the transplant (e.g., fear the surgery and of death) were identified in 38% of the patients. The data from this study demonstrated a significant negative correlation between depressive scores (BDI) and seven of the eight areas of quality of life (SF-36), such as functional capacity (r = .317, P = .0013), social aspects (r = -.469, P < .0001), economic aspects (r = -.319, P = .0012), and mental health (r = -.3832, P < .0001). CONCLUSION: The data indicated that the psychological aspects related to transplants require psychological intervention because they can affect the recuperation process, the quality of life, and the adherence to treatment for potential transplant patients. PMID- 23026611 TI - Impact of model for end-stage liver disease score on long-term survival following liver transplantation for hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Survival rates after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) have significantly increased after Milan criteria and Model for End-Stage Liver Disease (MELD) score implementation. However, few studies have reported this survival in countries with organ donor shortages over a period of 10 years and long waiting lists. METHODS: This retrospective analysis of clinical data from 93 consecutive HCC patients who underwent OLT from June 2001 to September 2011 excluded 22 who underwent living donor liver transplantation (LDLT). Seventy-one deceased donor liver transplantations (DDLT) were evaluated before and after the MELD era. Kaplan Meier analysis was used to plot survival rates. The follow-up was 2 months to 10 years. RESULTS: The overall survival and recurrence rates at 10 years were 67% and 12.2%, respectively. After MELD, patient survival at 5 years decreased from 70% to 64% and the recurrence rate decreased from 15.3% to 12.5%. The most frequent recurrence sites were lung and liver. CONCLUSION: In our center MELD score implementation had a small impact on long-term survival post OLT for HCC. PMID- 23026613 TI - Sirolimus as rescue therapy after liver transplantation. AB - Sirolimus has immunosuppressive properties and antitumor effects. It was prescribed in liver transplantation initially in association with calcineurin inhibitors because of its lower nephrotoxic and neurotoxic effects and its potential antitumor effects. The aim of this study was to analyze the use of sirolimus as rescue therapy for liver transplant patients. METHODS: We retrospectively analyzed all 15 patients treated with sirolimus from 2009 to 2011 among 150 liver transplantations. We analyzed pre- and postconversion data. With statistical analysis using the Student's t-test. RESULTS: Sirolimus was the immunosuppressant therapy in 15 of 150 (10%) patients. Their average age was 56.2 years (range, 42-69) including 9 men (60%). The mean time between liver transplantation and the introduction of sirolimus was 24.6 months (range, 1-120). Sirolimus remained as the sole medication for 4 patients (26.6%). The overall time of sirolimus thereby averaged 14.3 months (range, 1-18). The reasons for the introduction of sirolimus were acute rejection (n = 8; 53.3%), chronic rejection (n = 2; 13.3%), development of malignancy (n = 3; 20%) or prior hepatocellular carcinoma (n = 2; 13.3%). Among 9 patients who initiated sirolimus because of rejection, 7 (77.7%) showed improvement in serum liver enzymes. Among the 3 (33.3%) patients who displayed renal insufficiency before the introduction of sirolimus (creatinine level > 1.5 mg/dL) 1 showed improvement with a decrease of >=50%. The average follow-up was 18 months (range, 1-36). The average sirolimus level during the first 3 months was 10.3 ng/mL (range, 6.1-19.3). All patients developed side effects such as anemia, hypertriglyceridemia, hypercholesterolemia, and infection. In conclusion, sirolimus was useful as rescue therapy. PMID- 23026612 TI - Comparison of long-term effect of thymoglobulin treatment in patients with a high risk of delayed graft function. AB - BACKGROUND: T-lymphocyte depletion is a strategy to reverse the impact of ischemia-reperfusion injury (IRI) in progression to chronic allograft dysfunction, especially among patients at high risk for delayed graft function (DGF). METHODS: The present work assessed the effect of thymoglobulin among a population with a high incidence of DGF. We analyzed 209 transplanted patients: 97 in the thymoglobulin and 112 in the control group. RESULTS: The main complication was DGF (59.3%), with a similar incidence in both groups (63.9% vs. 55.3%; P = .36). Acute rejection episodes (ARE) were decreased with thymoglobulin (8.2% vs. 28.5%; P < .001), but cytomegalovirus viremia was 3.4-fold more frequent (58.3% vs. 17.1%; P < .001). One-year graft function was significantly better in the thymoglobulin group (59.2 +/- 17.2 vs. 51.8 +/- 15.3 mL/min; P = .004), even when censored by ARE (59.7 +/- 17.5 vs. 53.3 +/- 14.4; P = .023). The same difference was observed at the 2-year follow-up (P = .024), even when censored for ARE (P = .045). A multivariate analysis showed thymoglobulin to be a factor strongly associated with protection of graft function (P = .039). CONCLUSION: Despite not reducing the incidence of DGF, thymoglobulin induction significantly reduced the incidence of ARE and showed a long-term profile of protection of renal graft function, independent of the reduction in ARE. PMID- 23026614 TI - Predicting survival after liver transplantation using up-to-seven criteria in patients with hepatocellular carcinoma. AB - BACKGROUND: Liver transplantation is a controversial issue in the initial management of hepatocellular carcinoma (HCC). The aim of this study was to demonstrate that up-to-seven could be useful as a model in evaluating potential candidates for liver transplantation for HCC. METHODS: Between January 1997 and December 2010, 84 patients undergoing liver transplantation were analyzed for HCC. Pathologic variables included the number of lesions, maximal tumor diameter, vascular invasion, and tumor grade. The following variables were recorded: Age, gender, recurrence of HCC, survival, donor age, incidental, Milan criteria, Model for End-Stage Liver Disease score, and alpha-fetoprotein (AFP) levels. To evaluate variables we used the Kaplan-Meier method, Cox regression and Kolmogorov Smirnov test. RESULTS: There were 68 (80.9%) patients within up-to-seven criteria and 16 (19.1%) beyond this criteria. AFP levels were 96.4 versus 464.3 ng/dL in patients within versus beyond up-to-seven criteria. The median diameter of the largest nodule was 22.2 versus 32.0 mm in patients within versus beyond up-to seven criteria, respectively. The median sum of nodules was 1.8 and 5.6 nodules in patients within versus beyond up-to-seven criteria. Vascular invasion was present in 11 (13.0%) patients within versus 7 (8.3%) beyond. Recurrence was observed in 9 (10.7%) patients and only 3 were beyond up-to-seven criteria, 2 had vascular invasion, and another showed poor differentiation. Post liver transplantation survival rates were 87.7%, 74.5%, and 65.3% at 1, 3, and 5 years in patients within up-to-seven versus 80.7%, 51.7%, and 32.1% beyond (P = .03). Similar results were observed when we applied Milan criteria or expanded Milan criteria. The largest nodule was the only predictive factor after proportional hazard Cox regression application (Beta = 0.037; exponent = 1.0377; Wald = 4.542; P = .03). In the present study, up-to-seven criteria could be useful to evaluate potential liver transplant candidates due to HCC. PMID- 23026615 TI - Detection of cytomegalovirus and human herpesvirus-6 DNA in liver biopsy specimens and their correlation with rejection after liver transplantation. AB - Cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6) reactivation after transplantation put patients at an increased risk of graft rejection mainly among those who receive organs that are positive in their donor biopsies. The aim of this study was to investigate the presence of CMV and HHV-6 DNA in liver biopsy specimens from the donors and from their grafts for correlation with rejection after transplantation. We followed 41 liver transplantation patients whose samples were evaluated using nested-polymerase chain reactions (N-PCR). Twenty one (51%) of the 41 studied patients experienced rejection; 4/21 (19%) were CMV positive in the donor biopsy specimens and remained positive; another 5 subjects became positive. The patients who received organs from donors with biopsies positive for CMV demonstrated a trend to develop graft rejection after transplantation (Fisher's exact test [P = .0591] with significant results on univariate and multivariate analysis [P = .042]). Eight of the 21 who experienced rejection episodes were HHV-6 positive in the donor biopsy but there was no statistical significance CMV DNA diagnosed in liver donor biopsies remained positive posttransplantation in liver biopsy recipients; it was considered a tendency to develop acute cellular rejection after transplantation. PMID- 23026616 TI - Intestinal and multivisceral transplantation immunosuppression protocols- literature review. AB - INTRODUCTION: Currently the most used techniques for small bowel transplant are isolated intestinal transplantation, multivisceral transplantation (MVT), and modified multivisceral transplantation. One important factor is early diagnosis of acute cellular rejection (ACR). In addition, improvements in immunosuppression have recently reduced the number and enhanced treatment of ACR episodes, enabling graft recovery. OBJECTIVE: We analyzed immunosuppression protocols of leading transplantation centers in the last 5 years. METHOD: We reviewed papers published in PubMed from major multivisceral and intestinal transplantation centers from 2006 to 2010 in adult recipients. The 211 adults transplanted in seven centers were divided into three groups according to the immunosuppression protocol used: protocol 1: daclizumab induction with tacrolimus and steroid maintenance; protocol 2: alemtuzumab and tacrolimus; and protocol 3: thymoglobulin and rituximab and tacrolimus. RESULTS: Protocol 2 showed the lowest rate of ACR (34%). Protocols 1 and 3 displayed 54% and 48% ACR rates; respectively. However, protocol 1 patients developed only mild ACR, whereas those in protocols 2 and 3 developed moderate ACR in 26.3% and 11.7%, and severe ACR in 7.9% and 47% of cases, respectively. The infection rate was considerably lower in protocol 3 (7.4%). Protocols 1 and 2 showed infection rates of 62.5% and 52%, respectively. One-year patient survival rates were 70%, 79% and 81%, respectively. Three-year patient survival rates were 62%, 56%, and 78% for protocols 1, 2 and 3, respectively. CONCLUSION: Protocol 2 was the strongest immunosuppressive regimen capable of reducing ACR rates when compared with the other protocols, but the strong effect resulted in high infection rate that impacts 1-year patient survival. Protocol 3 seems to be the best available one balancing ACR and infection rates. PMID- 23026617 TI - Early allograft dysfunction and liver transplant outcomes: a single center retrospective study. AB - BACKGROUND: Early allograft dysfunction (EAD) had been related to poor transplant outcomes during the early years of liver transplantation. We sought to determine the incidence of EAD at our unit and to evaluate its impact on posttransplant outcomes. METHODS: This single-center retrospective study included primary deceased donor liver grafts transplanted under the model for end-stage liver disease system. EAD was defined as a peak values of aminotransferase >2000 IU/mL during the first week or an international normalized ratio of >=1.6 and/or bilirubin >=10 mg/dL at day 7. The main endpoints were patient and graft survivals. RESULTS: Patients with versus without EAD showed similar recipient characteristics. Donors who experienced EAD who comprises 56% of recipients were heavier with larger body mass indices. EAD was an independent risk factor for allograft loss. Most retransplants were performed early due to nonfunction. The primary nonfunction rate among subjects with versus without EAD were 7% and 12% respectively (P < .05). Patient survival among those with EAD was 87.4%, while without EAD it was 90% (P = NS) with graft survivals of 81.4% and 88.7% respectively (P < .05). CONCLUSION: Patients with EAD show a significantly higher risk for allograft loss, but with a comparable survival after transplantation. Despite their worse outcomes, it seems that not all of these recipients behave equally. PMID- 23026618 TI - Can pre-liver transplantation renal insufficiency using a creatinine clearance calculator predict long-term survival? AB - INTRODUCTION: Renal insufficiency can be associated with poor long-term survival of liver transplant recipients. OBJECTIVE: The objective of this study was to study renal insufficiency observed pretransplantation and its long-term impact after liver transplantation. METHODS: We analyzed retrospectively an electronic database collected prospectively including transplant records from June 1994 to October 2010 using piggyback venous reconstruction. The exclusion criteria were chronic kidney disease, acute hepatic failure, children up to 12 years of age, and retransplantations. Renal insufficiency was defined by the creatinine clearance (CCr) calculated using the Cockcroft-Gault method. Patients were distributed into 3 groups: CCr >90, between 90 and 60, and >60 mL/min/1.73 m(2). The survival rate was calculated using the Kaplan-Meier method and proportional hazards Cox regression analysis using death and CCr as stratifying variables evaluated predictive factors for survival. The groups were compared using the Kruskal-Wallis test with significant differences at P < .05. RESULTS: Among the 305 patients those who showed preoperative and postoperative CCR of >90 were 187/59.9% and 82/26.3%, 60 to 90 were 77/24.7% and 74/23.7%, or <60 mL/min/1.73 m(2) were (41/13.1% and 149 (47.7%). Patients with preoperative CCr <60 mL/min/1.73 m(2) showed worse short- and long-term survivals as well as the longest intensive care unit and hospital stays (P = .034). The only predictive donor factor was age older than 40 years namely, the greatest hemotransfusion needs and postoperative liver and renal dysfunction (Chi square = 100.6064; P = .00001). The area under the curve (AUC) obtained using an receiver operating characteristic (ROC) analysis was 0.563 (95% CI 0.498-0.627) with a cut off of 30.25. CONCLUSION: Pre-liver transplantation renal insufficiency seemed to be a predictive factor for long-term survival. PMID- 23026619 TI - Co-infection and clinical impact of human herpesvirus 5 and 6 in liver transplantation. AB - BACKGROUND: Human herpesvirus (HHV) 5 and 6 remain latent after primary infection and can be reactivated after immunosuppression for organ transplantation. An association between HHV-5 and HHV-6 has been reported in liver transplant patients. The coinfection is associated with clinical manifestations and graft dysfunction. OBJECTIVE: The aim of this study was to monitor herpesviruses in liver transplant recipients to better understand issues involving coinfection with HHV-5/6 and correlations with acute cellular rejection episodes and bacterial infections. METHODS: Forty-five adult liver transplant patients of median age 47 years (range, 18-66), gave blood samples and liver biopsies in the first 6 months after their surgeries. Viremia was detected with the use of nested PCR and antigenemia; the Banff classification was used to detect allograft rejection. RESULTS: IgG positive for HHV-5 was observed in 94% of subjects whose main indication (67%) for transplantation was hepatitis C. Twenty-three (51.1%) displayed cytomeg virus (CMV) infections and 12 (26.7%) HHV-6 infection. There were 6 patients (13.3%) with HHV-5/6 coinfections. Eighteen of the 23 patients had CMV disease, showing a strong correlation between a positive test and CMV disease; 6 displayed an acute cellular rejection episode in the same period (chi(2) = 6.62; P < .03). Four out of 6 patients who displayed coinfections (HHV 5/6) had concomitant bacterial infections; 3/6 experienced graft rejection episodes. During follow-up, 1 patient had HHV-6 infection diagnosed as encephalitis followed by fever on the 24th day after surgery. The median 32 days for HHV-6 detection by nested PCR positivity was shorter than 38 days for HHV-5. CONCLUSIONS: HHV-5/6-infected patients displayed more allograft rejection episodes, coinfections, and concomitant bacterial infections, besides an higher risk for CMV disease. PMID- 23026620 TI - Hepatocellular carcinoma recurrence among liver transplant recipients within the Milan criteria. AB - INTRODUCTION: Orthotopic liver transplantation (OLT) is an excellent option for patients with unresectable hepatocellular carcinoma (HCC) within the Milan criteria. Recurrence of HCC has a severe impact on post-OLT survival. In this study, we performed an analysis of post-OLT recurrence pattern of HCC. METHODS: The prospective cohort of OLT patients included those with unresectable HCC within the Milan criteria, and those beyond the Milan criteria who were downstaged with transcatheter arterial embolization until they achieved the Milan criteria. RESULTS: Between May 2006 and May 2011, we performed 130 OLT for unresectable HCC within the Milan Criteria among whom 9 patients (6.9%) experienced tumor recurrence. Two (22.2%) had undergone preoperative downstaging. At the time of OLT, mean serum alpha-fetoprotein levels were 623.8 +/- 682.9 ng/mL. The liver explants showed 7 (77.8%) subjects were within the Milan criteria, with an average 2.6 +/- 2.2 tumors, most of which (89%) were moderately differentiated. Microvascular and macrovascular invasion were observed in 5 (55.6%) and 2 (22.2%) cases, respectively. Liver explants were beyond the Milan criteria in both patients who had undergone preoperative downstaging. Recurrence occurred 23.1 +/- 14.3 months after OLT, having been detected in the liver (n = 3; 33.3%), lung (n = 3; 33.3%), brain, peritoneum, and adrenal gland (n = 1 each; 11.1% each). Mean survival after detection of recurrence was 137.4 +/- 96.4 days. CONCLUSIONS: Despite strict candidate selection criteria, HCC recurrence may occur after OLT, bearing a significant impact on posttransplant outcomes to optimize results requires refinements in candidate selection, as well as well defined cost-effective post-OLT surveillance protocols. PMID- 23026621 TI - Risk factors and survival impact of primary graft dysfunction after lung transplantation in a single institution. AB - BACKGROUND: Lung transplantation has become a standard procedure for some end stage lung diseases, but primary graft dysfunction (PGD) is an inherent problem that impacts early and late outcomes. The aim of this study was to define the incidence, risk factors, and impact of mechanical ventilation time on mortality rates among a retrospective cohort of lung transplantations performed in a single institution. METHODS: We performed a retrospective study of 118 lung transplantations performed between January 2003 and July 2010. The most severe form of PGD (grade III) as defined at 48 and 72 hours was examined for risk factors by multivariable logistic regression models using donor, recipient, and transplant variables. RESULTS: The overall incidence of PGD at 48 hours was 19.8%, and 15.4% at 72 hours. According multivariate analysis, risk factors associated with PGD were donor smoking history for 48 hours (adjusted odds ratio [OR], 4.83; 95% confidence interval [CI], 1.236-18.896; P = .022) and older donors for 72 hours (adjusted OR, 1.046; 95% CI, 0.997-1.098; P = .022). The operative mortality was 52.9% among patients with PGD versus 20.3% at 48 hours (P = .012). At 72 hours, the mortality rate was 58.3% versus 21.2% (P = .013). The 90-days mortality was also higher among patients with PGD. The mechanical ventilation time was longer in patients with PGD III at 48 hours namely, a mean time of 72 versus 24 hours (P = .001). When PGD was defined at 72 hours, the mean ventilation time was even longer, namely 151 versus 24 hours (P < .001). The mean overall survival for patients who developed PGD at 48 hours was 490.9 versus 1665.5 days for subjects without PGD (P = .001). Considering PGD only at 72 hours, the mean survival was 177.7 days for the PGD group and 1628.9 days for the other patients (P < .001). CONCLUSION: PGD showed an important impacts on operative and 90-day mortality rates, mechanical ventilation time, and overall survival among lung transplant patients. PGD at 72 hours was a better predictor of lung transplant outcomes than at 48 hours. The use of donors with a smoking history or of advanced age were risk factors for the development of PGD. PMID- 23026622 TI - Risk factor analysis of late survival after heart transplantation according to donor profile: a multi-institutional retrospective study of 512 transplants. AB - INTRODUCTION: Patients with terminal heart failure have increased more than the available organs leading to a high mortality rate on the waiting list. Use of Marginal and expanded criteria donors has increased due to the heart shortage. OBJECTIVE: We analyzed all heart transplantations (HTx) in Sao Paulo state over 8 years for donor profile and recipient risk factors. METHOD: This multi institutional review collected HTx data from all institutions in the state of Sao Paulo, Brazil. From 2002 to 2008 (6 years), only 512 (28.8%) of 1777 available heart donors were accepted for transplantation. All medical records were analyzed retrospectively; none of the used donors was excluded, even those considered to be nonstandard. RESULTS: The hospital mortality rate was 27.9% (n = 143) and the average follow-up time was 29.4 +/- 28.4 months. The survival rate was 55.5% (n = 285) at 6 years after HTx. Univariate analysis showed the following factors to impact survival: age (P = .0004), arterial hypertension (P = .4620), norepinephrine (P = .0450), cardiac arrest (P = .8500), diabetes mellitus (P = .5120), infection (P = .1470), CKMB (creatine kinase MB) (P = .8694), creatinine (P = .7225), and Na+ (P = .3273). On multivariate analysis, only age showed significance; logistic regression showed a significant cut-off at 40 years: organs from donors older than 40 years showed a lower late survival rates (P = .0032). CONCLUSIONS: Donor age older than 40 years represents an important risk factor for survival after HTx. Neither donor gender nor norepinephrine use negatively affected early survival. PMID- 23026623 TI - Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single center study. AB - INTRODUCTION: Endomyocardial biopsy (EMB) plays an important role in allograft surveillance to screen an acute rejection episode after heart transplantation (HT), to diagnose an unknown cause of cardiomyopathies (CMP) or to reveal a cardiac tumor. However, the procedure is not risk free. OBJECTIVE: The main objective of this research was to describe our experience with EMB during the last 33 years comparing surgical risk between HT versus no-HT patients. METHOD: We analyzed retrospectively the data of 5347 EMBs performed from 1978 to 2011 (33 years). For surveillance of acute rejection episodes after HT we performed 3564 (66.7%), whereas 1777 (33.2%) for CMP diagnosis, and 6 (1.0%) for cardiac tumor identification. RESULTS: The main complications due to EMB were divided into 2 groups to facilitate analysis: major complications associated with potential death risk, and minor complications. The variables that showed a significant difference in the HT group were as follows: tricuspid injury (.0490) and coronary fistula (.0000). Among the no-HT cohort they were insufficient fragment (.0000), major complications (.0000) and total complications (.0000). CONCLUSIONS: EMB can be accomplished with a low risk of complications and high effectiveness to diagnose CMP and rejection after HT. However, the risk is great among patients with CMP due to their anatomic characteristics. Children also constitute a risk group for EMB due to their small size in addition to the heart disease. The risk of injury to the tricuspid valve was higher among the HT group. PMID- 23026624 TI - Tricuspid valve injury after heart transplantation due to endomyocardial biopsy: an analysis of 3550 biopsies. AB - INTRODUCTION: Tricuspid regurgitation (TR) is the most commonly valvular dysfunction found after heart transplantation (HTx). It may be related to endomyocardial biopsy (EMB) performed for allograft rejection surveillance. OBJECTIVE: This investigation evaluated the presence of tricuspid valve tissue fragments obtained during routine EMB performed after HTx and its possible effect on short-term and long-term hemodynamic status. METHOD: This single-center review included prospectively collected and retrospectively analyzed data. From 1985 to 2010, 417 patients underwent 3550 EMB after HTx. All myocardial specimens were reviewed to identify the presence of tricuspid valve tissue by 2 observers initially and in doubtful cases by a third observer. The echocardiographic and hemodynamic parameters were only considered for valvular functional damage analysis in cases of tricuspid tissue inadvertently removed during EMB. RESULTS: The 417 HTx patients to 3550 EMB, including 17,550 myocardial specimens. Tricuspid valve tissue was observed in 12 (2.9%) patients corresponding to 0.07% of the removed fragments. The echocardiographic and hemodynamic parameters of these patients before versus after the biopsy showed increased TR in 2 cases (2/12; 16.7%) quantified as moderate without progression in the long term. Only the right atrial pressure showed a significant increase (P = .0420) after tricuspid injury; however, the worsening of the functional class was not significant enough in any of the subjects. Thus, surgical intervention was not required. CONCLUSIONS: Histological evidence of chordal tissue in EMB specimens is a real-world problem of relatively low frequency. Traumatic tricuspid valve injury due to EMB rarely leads to severe valvular regurgitation; only a minority of patients develop significant clinical symptoms. Hemodynamic and echocardiographic alterations are also less often observed in most patients. PMID- 23026625 TI - The impact of tacrolimus as rescue therapy in children using a double immunosuppressive regimen after heart transplantation. AB - BACKGROUND: Organ transplant recipients with refractory rejection or intolerance to the prescribed immunosuppressant may respond to rescue therapy with tacrolimus. We sought to evaluate the clinical outcomes of children undergoing heart transplantation who required conversion from a cyclosporine-based, steroid free therapy to a tacrolimus-based regimen. METHODS: We performed a prospective, observational, cohort study of 28 children who underwent conversion from cyclosporine-based, steroid-free therapy to a tacrolimus-based therapy for refractory or late rejection or intolerance to cyclosporine. RESULTS: There was complete resolution of refractory rejection episodes and adverse side effects in all patients. The incidence rate (*100) of rejection episodes before and after conversion was 7.98 and 2.11, respectively (P <= .0001). There was a 25% mortality rate in patients using tacrolimus after a mean period of 60 months after conversion. CONCLUSION: Tacrolimus is effective as rescue therapy for refractory rejection and is a therapeutic option for pediatric patients. PMID- 23026626 TI - Effects of prednisone on mucociliary clearance in a murine model. AB - All transplant patients are at increased risk of developing pulmonary infections, a significant cause of morbidity and mortality. Immunosuppressants increase the incidence of lung infection by acting not only directly on the inflammatory cells, but also on the native immune system. Experimental studies have shown corticosteroid therapy, which is used in most immunosuppressive protocols after transplantation, to suppress mucus production by inhibiting calceiform. The objective of this study was to evaluate the effects of prednisone on mucociliary clearance. A total of 120 male Wistar rats were distributed into 4 groups. Animals in P1, P2, and P3 groups received daily doses of prednisone (0.625, 1.25, and 2.5 mg/kg/d), and hosts in the Sal group underwent gavage with saline solution (2.5 mL/d). After 7, 15, and 30 days, treatment, animals were killed. We assessed ciliary beating frequency (CBF), mucociliary transport velocity (MCTV), and mucus transportability (MT). There was no significant difference for CBF regarding dose (P = .089) or treatment duration (P = .175). MCTV values of 0.60 +/- 0.14 in group P1, 0.59 +/- 0.13 in group P2, 0.51 +/- 0.19 in group P3, and 0.61 +/- 0.08 Group Sal, showed P3 to significantly differ from P1 (P = .048) and Sal (P = .007) groups. Regardless of the prednisone dose, all groups displayed impaired MT compared with the Sal group: P1 (P = .02); P2 (P = .02) P3 (P = .03). There was no interaction between the therapy and the treatment time for CBF (P = .10), MCTV (P = .71), and MT (P = .64). Prednisone reduced the transportability of mucus even when administered at low doses; however, this change was not sufficient to alter the mucociliary clearance. Only high doses of prednisone impaired mucociliary clearance. PMID- 23026627 TI - Protective effects of human amniotic fluid stem cells in a model of aorta allograft vasculopathy in rats. AB - BACKGROUND: Chronic allograft vasculopathy (CAV) is an important cause of graft loss. Considering the immune inflammatory events involved in the development of CAV, therapeutic approaches to target this process are of relevance. Human amniotic fluid-derived stem cells (hAFSCs), a class of fetal, pluripotent stem cells with intermediate characteristics between embryonic and adult stem cells, display immunomodulatory properties. hAFSCs express mesenchymal and embryonic markers, show high proliferation rates; however, they do not induce tumor formation, and their use does not raise ethical issues. Thus, we sought to investigate the effect of hAFSC on CAV in a model of aorta transplantation. METHODS: Orthotopic aorta transplantation was performed using Fisher (F344) rats as donors and Lewis rats as recipients. Rats were divided into three groups: syngeneic (SYNG), untreated F344 receiving aorta from F344 (n = 8); allogeneic (ALLO), Lewis rats receiving allogeneic aorta from F344 (n = 8); and ALLO + hAFSC, ALLO rats treated with hAFSC (10(6) cells; n = 8). Histological analysis and immunohistochemistry were performed 30 days posttransplantation. RESULTS: The ALLO group developed a robust aortic neointimal formation (208.7 +/- 25.4 MUm) accompanied by a significant high number of ED1+ (4845 +/- 841 cells/mm2) and CD43+ cells (4064 +/- 563 cells/mm2), and enhanced expression of alpha-smooth muscle actin in the neointima (25 +/- 6%). Treatment with hAFSC diminished neointimal thickness (180.7 +/- 23.7 MUm) and induced a significant decrease of ED1+ (1100 +/- 276 cells/mm2), CD43+ cells (1080 +/- 309 cells/MUm2), and alpha smooth muscle actin expression 8 +/- 3% in the neointima. CONCLUSIONS: These preliminary results showed that hAFSC suppressed inflammation and myofibroblast migration to the intima, which may contribute to ameliorate vascular changes in CAV. PMID- 23026628 TI - Expression of pancreatic endocrine markers by mesenchymal stem cells from human adipose tissue. AB - Mesenchymal stem cells (MSCs) from human adipose tissue have a great potential for use in cell therapy due to their ease of isolation, expansion, and differentiation, besides the relative acceptance from the ethical point of view. Our intention was to isolate and promote in vitro expansion and differentiation of MSCs from human adipose tissue into cells with a pancreatic endocrine phenotype. Human adipose tissue obtained from patients undergoing abdominal dermolipectomy was digested with type I collagenase. MSCs isolated by plastic adherence and characterized by cytochemistry and FACS were expanded in vitro. MSC differentiation into an endocrine phenotype was induced over 2 to 4 months with high glucose (25 mmol/L) media containing nicotinamide, exendin-4, and 2 mercaptoethanol. Insulin and glucagon expressions were analyzed by immunofluorescence. Cells isolated from human adipose tissue and expanded in vitro expressed MSC markers as confirmed by FACS and cytochemistry. Insulin but not glucagon production by differentiated cells was demonstrated by immunofluorescence. MSCs isolated from human adipose tissue were induced to differentiate in vitro into an endocrine phenotype that expressed insulin. PMID- 23026629 TI - Stress-induced cardiomyopathy (takotsubo cardiomyopathy) after liver transplantation-report of two cases. AB - Cardiac complications after liver transplantation are a common cause of death. Stress-induced cardiomyopathy, also called takotsubo cardiomyopathy, is a special form of cardiomyopathy that is precipitated by a stress situation. It can occur after a surgical procedure that results in acute heart failure. Herein we have presented 2 cases of reversible stress-induced cardiac dysfunction early in the period after liver transplantation. Before surgery, cardiac evaluation was normal, with both patients classified as low risk for cardiovascular events during the proposed procedure. Both patients experienced cardiac arrest after graft reperfusion with return of spontaneous circulation after resuscitation. Their early periods after transplantation were characterized by cardiogenic shock secondary to important ventricular dysfunction requiring vasoactive drugs. Subsequent investigations excluded coronary disease. The diagnosis of takotsubo cardiomyopathy was established based on the clinical features and ancillary tests, particularly echocardiography showing apical ballooning. In both cases, ventricular function recovered completely. In conclusion, stress-induced cardiomyopathy, an underestimated cause of heart complications, should be considered as a possible cause of cardiac failure in liver transplant patients. PMID- 23026630 TI - Case report of hepatic mucormycosis after liver transplantation: successful treatment with liposomal amphotericin B followed by posaconazole sequential therapy. AB - Mucormycosis is a rare but emerging fungal infection complicating solid organ transplantation (SOT), with a cumulative incidence of around 2% during the first year after SOT. The associated mortality rate is high, and surgical debridement is frequently required as part of the treatment along with antifungal therapy based mostly on amphotericin B formulations, We describe here an unusual case of hepatic mucormycosis in a liver transplant recipient that was successfully treated with clinical therapy based on liposomal amphotericin B followed by posaconazole, without surgical resection. PMID- 23026631 TI - Single-balloon enteroscopy for treating Roux-en-Y choledochojejunostomy stenosis after liver transplantation: a case report. AB - Endoscopic treatment of biliary tract complications after Roux-en-Y surgery is still a challenge. With balloon enteroscopy, we can reach previously inaccessible areas changing the management of biliopancreatic diseases in patients with surgically altered anatomy. We report a case of single-balloon enteroscopy plus endoscopic retrograde cholangiopancreatography for the treatment of a pinpoint stricture in a hepaticojejunal anastomosis after liver transplantation. PMID- 23026632 TI - Use of enteroscopy for treating pancreatitis in a pancreas and kidney transplantation patient with Roux-en-Y portoenteric derivation--a case report. AB - In pancreas and kidney transplantations, the donor duodenum and pancreas are frequently anastomosed to the jejunum to allow exocrine drainage by creation of a Roux-en-Y jejunal loop. In this situation, those organs are relatively inaccessible using standard endoscopes. We present a case of the use of single balloon enteroscopy in the treatment of cronic pancreatitis in the donor pancreas. PMID- 23026633 TI - Uncommon cause of chest pain in a renal transplantation patient with autosomal dominant polycystic kidney disease: a case report. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of end stage renal disease (ESRD) and, because of its intrinsic systemic involvement, its treatment can be a medical and surgical challenge. This condition is often associated with the presence of hepatic cysts and their prevalence generally increases with age. Most patients remain asymptomatic, but some of these will develop complications associated with enlargement and infection of their cysts. Chest pain is a rare manifestation of these complications and, after exclusion of more common cardiovascular and pulmonary causes, should raise the suspicion of an infected hepatic cyst in these patients. We report the case of a 62-year-old male who underwent a kidney transplantation from a cadaveric donor in 1997 (etiology of the ESRD was ADPKD), and was admitted to the emergency department with complaints of chest pain radiating to both shoulders and the interscapular region. An echocardiogram was showed compression of the right atrium by a large liver cyst without associated ventricular dysfunction. Computer tomography-guided drainage of the cyst was performed and an Enterobacter aerogenes sensitive to carbamapenemes was isolated from respective cultures. The patient presented a favorable clinical outcome with prolonged administration of antibiotic therapy according to the antibiotic susceptibility testing. There was no need for surgical intervention. PMID- 23026634 TI - Pain syndrome induced by calcineurin inhibitor and resolved by conversion to sirolimus in a child after kidney transplantation: a case report. AB - Pain induced by calcineurin inhibitors is a rare complication of unknown pathogenesis. We have reported herein a 7-year-old child who presented with abdominal pain, vomiting, and weight loss showing no significant findings after an extensive laboratory and imaging workup. After conversion from tacrolimus to sirolimus, there was complete resolution of the gastrointestinal symptoms and pain; the patient displays excellent renal function. Calcineurin inhibitor induced pain syndrome is diagnosis of exclusion but must be considered because the withdrawal of this immunosuppressive agent is associated with improvement in symptoms and quality of life. PMID- 23026638 TI - The use of the Meek technique in conjunction with cultured epithelial autograft in the management of major paediatric burns. AB - BACKGROUND: The management of major paediatric burns remains challenging, in part due to limited donor sites. Skin graft expansion facilitates rapid closure of the burn wound, reducing the risk of sepsis. We reviewed our unit's experience with a combined modified Meek technique and cultured epithelial autograft (CEA). METHODS: A retrospective chart review over a seven year period from April 2004 to April 2011 was conducted of patients whose burns were treated with Meek and CEA. RESULTS: The Meek technique was combined with meshed split skin grafts and CEA to either donor, graft site or both in 7 cases. One case had Meek skin grafts alone with cultured cells applied to both donor and graft sites. There were two scald burns and five flame burns, with total body surface area ranging from 30% to 70%. Mean length of stay was 51 days (range 41-74 days). The average number of surgical procedures undergone to obtain good coverage was 3.3. There were small (1-3%) areas of breakdown in six cases which received regrafting. Two of these patients had confirmed wound infections. All patients had varying degrees of hypertrophic scarring (HTS) but remained well at follow up. CONCLUSIONS: The Meek technique facilitates high expansion ratios, allowing for a greater area of skin coverage. Epithelialisation in the burn wound appeared to be enhanced by the application of CEA. The Meek technique in combination with CEA would appear a useful additional option in achieving wound closure in the severely burned paediatric patient. PMID- 23026637 TI - Fusion protein linkers: property, design and functionality. AB - As an indispensable component of recombinant fusion proteins, linkers have shown increasing importance in the construction of stable, bioactive fusion proteins. This review covers the current knowledge of fusion protein linkers and summarizes examples for their design and application. The general properties of linkers derived from naturally-occurring multi-domain proteins can be considered as the foundation in linker design. Empirical linkers designed by researchers are generally classified into 3 categories according to their structures: flexible linkers, rigid linkers, and in vivo cleavable linkers. Besides the basic role in linking the functional domains together (as in flexible and rigid linkers) or releasing the free functional domain in vivo (as in in vivo cleavable linkers), linkers may offer many other advantages for the production of fusion proteins, such as improving biological activity, increasing expression yield, and achieving desirable pharmacokinetic profiles. PMID- 23026639 TI - Incidence and predictors of venous thromboembolism (VTE) among ambulatory patients with lung cancer. AB - BACKGROUND: The incidence and economic impact of lung cancer-associated venous thromboembolic (VTE) events in a contemporary ambulatory setting is unknown. PATIENTS AND METHODS: We conducted a retrospective cohort analysis utilizing the IMS Patient-Centric database of US healthcare claims and recorded VTE events occurring 3-12 months after chemotherapy initiation. RESULTS: Lung cancer (n=6732) and control (n=17 284) cohorts had 51% women, with a mean age of 64 years. VTE occurred in 13.9% of the lung cancer cohort (odds ratio [OR], 3.15; 95% confidence interval [CI] 2.55, 3.89), and 1.4% of the control cohort (P<0.0001). Charlson Comorbidity Index >= 5 (CCI; OR, 2.56; 95% CI 1.02, 6.39; P=0.045), the use of erythropoiesis-stimulating agents (ESAs; OR, 1.63; 95% CI 1.40, 1.89; P<0.0001), and congestive heart failure (CHF; OR, 1.29; 95% CI 1.01, 1.66; P=0.045) were associated with VTE. Bleeding occurred in 22.1% of the lung cancer cohort and 7.0% of the control cohort (P<0.0001). Among lung cancer patients the average total healthcare payment was $84,187 in patients with VTE compared to $56,818 in patients without VTE (P<0.0001). CONCLUSIONS: VTE is common among lung cancer patients receiving chemotherapy and is associated with increased healthcare utilization. PMID- 23026640 TI - An accurate and rapid detection of lymph node metastasis in non-small cell lung cancer patients based on one-step nucleic acid amplification assay. AB - A sublobar resection is currently recognized as an option for early small-sized non-small cell lung cancer (NSCLC), and intraoperative rapid and accurate lymph node assessment is required for a complete resection. To solve this issue, we investigated the clinical utility of one-step nucleic acid amplification (OSNA) assay, an automated rapid molecular diagnostic method and its optimal mRNA marker for detection of lymph node metastasis in lung cancer. We extracted 16 target candidate mRNA markers with high expression in lung cancer from a genetic database, and then quantified their expression levels by quantitative RT-PCR using surgically dissected lymph nodes with or without metastasis. Cytokeratin 19 (CK19), cytokeratin 7 (CK7), stratifin (SFN), and anterior gradient homolog 2 (AGR2) showed significant differences for mRNA expression between metastasis negative and -positive lymph nodes in quantitative-RT-PCR screening. CK19 and CK7 were finally selected as potential target markers and were quantified using OSNA assay findings of 165 dissected lymph nodes obtained from 49 lung cancer patients. The OSNA assay with CK19 and CK7 were completed within 40 min and their positive predictive value, negative predictive value, and accuracy comparing to pathological diagnosis with hematoxylin-eosin staining and immunohistochemistry were shown to be 95.0%, 99.3%, and 98.8%, and 85.0%, 97.9%, and 96.4%, respectively, using a cut-off value of 250 copies/MUL. Among the 165 lymph nodes tested, 1 false negative result was due to massive necrosis of cancer cells and 1 false positive was caused by the allocation bias of cancer cells in the sampling in patient with pleural dissemination. The best performance was observed when CK19 was used as a marker, while the addition of CK7 mRNA as a marker did not increase sensitivity or specificity. In conclusion, an OSNA assay using CK19 could be effective for molecular diagnosis of lymph node metastasis in lung cancer. This is the first report suggesting the potential clinical utility of OSNA assay for intraoperative rapid diagnosis of nodal status in lung cancer. PMID- 23026641 TI - Analysis of EGFR, KRAS and P53 mutations in lung cancer using cells in the curette lavage fluid obtained by bronchoscopy. AB - Histopathological samples are commonly used for molecular testing to detect both oncogenes and tumor-suppressor genes in lung cancer. The purpose of this study was to determine the efficacy of using curette lavage fluid for molecular testing to detect EGFR, KRAS and P53 mutations in lung cancer patients. Samples were obtained from 77 lung cancer patients by bronchoscopy at the time of diagnosis, collected by scraping the site of the primary tumor lesion with a curette. DNA was extracted from cells in the curette lavage fluid, and PCRs were performed to amplify mutation hot spot regions in the EGFR, KRAS and P53 genes. The PCR products were direct-sequenced to detect mutations of each gene. The reference sequence of each gene was obtained from GenBank. Overall, 27% (21 of 77) were found with EGFR mutations, 1% (1 of 77) with KRAS mutations, and 36% (28 of 77) with P53 mutations. KRAS mutations were not detected in patients harboring mutations in either EGFR or P53. P53 mutations were identified in 38% (8 of 21) of the patients with EGFR mutations, all of who had advanced lung cancer. Of these patients, a 62-year-old female current smoker was given EGFR-TKI as third line therapy, with no improvement in clinical symptoms or results of radiographic examination. Multivariate analysis indicated that P53 mutation rates in advanced stage lung cancer were significantly higher than those in early-stage lung cancer (P=.017). In contrast, EGFR mutation rates were not significantly associated with staging. L747S in EGFR, described as a mutation associated with secondary resistance to EGFR-TKI, was detected in three patients who had never received EGFR-TKI, including one SCLC patient. It is possible to analyze EGFR, KRAS and P53 mutations using curette lavage fluid collected from lung cancer patients. This is useful when sufficient amounts of tumor samples cannot be obtained. Data from the current study suggest that EGFR mutations in concert with P53 mutations accelerate cancer development and lead to evolution of therapeutic resistance. PMID- 23026642 TI - Shake, rattle, and roll: the impact of undiagnosed concussions in pediatrics. PMID- 23026644 TI - Effects of effluent organic matter characteristics on the removal of bulk organic matter and selected pharmaceutically active compounds during managed aquifer recharge: Column study. AB - Soil column experiments were conducted to investigate the effects of effluent organic matter (EfOM) characteristics on the removal of bulk organic matter (OM) and pharmaceutically active compounds (PhACs) during managed aquifer recharge (MAR) treatment processes. The fate of bulk OM and PhACs during an MAR is important to assess post-treatment requirements. Biodegradable OM from EfOM, originating from biological wastewater treatment, was effectively removed during soil passage. Based on a fluorescence excitation-emission matrix (F-EEM) analysis of wastewater effluent-dominated (WWE-dom) surface water (SW), protein-like substances, i.e., biopolymers, were removed more favorably than fluorescent humic like substances under oxic compared to anoxic conditions. However, there was no preferential removal of biopolymers or humic substances, determined as dissolved organic carbon (DOC) observed via liquid chromatography with online organic carbon detection (LC-OCD) analysis. Most of the selected PhACs exhibited removal efficiencies of greater than 90% in both SW and WWE-dom SW. However, the removal efficiencies of bezafibrate, diclofenac and gemfibrozil were relatively low in WWE-dom SW, which contained more biodegradable OM than did SW (copiotrophic metabolism). Based on this study, low biodegradable fractions such as humic substances in MR may have enhanced the degradation of diclofenac, gemfibrozil and bezafibrate by inducing an oligotrophic microbial community via long term starvation. Both carbamazepine and clofibric acid showed persistent behaviors and were not influenced by EfOM. PMID- 23026643 TI - Simulating an exclusion zone for vapour intrusion of TCE from groundwater into indoor air. AB - This paper is an extension of the work by Yu et al. (2009) to examine exposure pathways of volatile organic compounds (VOCs) originating from a NAPL source zone located below the water table, and their potential impact on multiple residential dwellings down-gradient of the source zone. The three-dimensional problem geometry is based on the Rivett (1995) field experiment in the Borden aquifer, and contains houses located both above and adjacent to the groundwater plume in order to define an exclusion zone. Simulation results using the numerical model CompFlow Bio indicate that houses which are laterally offset from the groundwater plume are less affected by vapour intrusion than those located directly above the plume due to limited transverse horizontal flux of TCE within the groundwater plume, in agreement with the ASTM (2008) guidance. Uncertainty in the simulated indoor air concentration is sensitive to heterogeneity in the permeability structure of a stratigraphically continuous aquifer, with uncertainty defined as the probability of simulated indoor air concentrations exceeding the NYSDOH (2005) regulatory limit. Within this uncertainty framework, this work shows that the Johnson and Ettinger (1991), ASTM (2008) and CompFlow Bio models all delineate an identical exclusion zone at a 99.9% confidence interval of indoor air concentrations based on the probability of exceedence. PMID- 23026636 TI - Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances. AB - Targeting of drugs and their carrier systems by using receptor-mediated endocytotic pathways was in its nascent stages 25 years ago. In the intervening years, an explosion of knowledge focused on design and synthesis of nanoparticulate delivery systems as well as elucidation of the cellular complexity of what was previously-termed receptor-mediated endocytosis has now created a situation when it has become possible to design and test the feasibility of delivery of highly specific nanoparticle drug carriers to specific cells and tissue. This review outlines the mechanisms governing the major modes of receptor-mediated endocytosis used in drug delivery and highlights recent approaches using these as targets for in vivo drug delivery of nanoparticles. The review also discusses some of the inherent complexity associated with the simple shift from a ligand-drug conjugate versus a ligand-nanoparticle conjugate, in terms of ligand valency and its relationship to the mode of receptor-mediated internalization. PMID- 23026647 TI - Photoperiodic regulation of life-history traits before and after eclosion: egg-to adult development time, juvenile body mass and reproductive diapause in Drosophila montana. AB - Photoperiod is the main environmental cue used by northern insects to predict the forthcoming seasonal changes and to adjust their life-history traits to fit these changes. We studied the effects of photoperiod on egg-to-adult development time, juvenile body mass and female reproductive diapause in two northern Drosophila montana populations with different patterns of voltinism. The most interesting findings were consistent between the populations: (1) when maintained before eclosion in short day conditions, representing early autumn, the flies developed faster and were lighter than when maintained in long day conditions, representing early summer, (2) photoperiodic time measurement is apparently reset after eclosion, adjusting the flies' development according to post eclosion conditions, (3) the sensitive period for diapause induction took place after eclosion and (4) there was no direct connection between females' egg-to-adult development time and their reproductive state at adulthood, which suggests that these traits can be determined by photoperiodic cues through different time measurement systems. Independence of photoperiodic regulation of life-history traits before and after eclosion enable D. montana flies to respond to changing photoperiods on a short time scale and match their life-history traits according to seasons. PMID- 23026648 TI - Micropatterned silica thin films with nanohydroxyapatite micro-aggregates for guided tissue regeneration. AB - Surface modification of biomaterials has been shown to improve the biological response to dental implants. The ability to create a controlled micro-texture on the implant via additive surface modification techniques with bioactive nanohydroxyapatite (nanoHA) may positively influence guided tissue regeneration. OBJECTIVE: The main goal of this study was to produce micro-fabricated SiO(2) surfaces modified with nanohydroxyapatite particles and to characterize their influence on the biological response of Human Dental-Pulp Mesenchymal Stem Cells (hDP-MSCs) and Streptococcus mutans. MATERIALS AND METHODS: A combined methodology of sol-gel and soft-lithography was used to produce micropatterned SiO(2) thin films with different percentages of nanoHA micro-aggregates. The surfaces were characterized by SEM/EDS, FT-IR/ATR, AFM, XPS quantitative elemental percentage and contact angle measurements. Biological characterization was performed using hDP-MSCs cultures, while Streptococcus mutans was the selected microorganism to evaluate the bacterial adhesion on the thin films. RESULTS: Micropatterned SiO(2) surfaces with 0%, 1% and 5% of nanoHA micro aggregates were successfully produced using a combination of sol-gel and soft lithography. These surfaces controlled the biological response, triggering alignment and oriented proliferation of hDP-MSCs and significant differences in the adhesion of S. mutans to the different surfaces. SIGNIFICANCE: The micropatterned surfaces exhibited biocompatible behavior that induced an oriented adhesion and proliferation of hDP-MSCs while SiO(2) presented low bacterial adhesion. These results show that the combination of sol-gel with soft lithography is a good approach to create micropatterned surfaces with bioactive nanoparticles for guided tissue regeneration. PMID- 23026649 TI - Clinical approach to splanchnic vein thrombosis: risk factors and treatment. AB - Splanchnic vein thrombosis (SVT) is an unusual manifestation of venous thromboembolism which involves one or more abdominal veins (portal, splenic, mesenteric and supra-hepatic veins). SVT may be associated with different underlying disorders, either local (abdominal cancer, liver cirrhosis, intra abdominal inflammation or surgery) or systemic (hormonal treatment, thrombophilic conditions). In the last decades, myeloproliferative neoplasm (MPN) emerged as the leading systemic cause of SVT. JAK2 mutation, even in the absence of known MPN, showed a strong association with the development of SVT, and SVT was suggested to be the first clinical manifestation of MPN. Recently, an association between SVT, in particular supra-hepatic vein thrombosis, and paroxysmal nocturnal hemoglobinuria has also been reported. SVT occurs with heterogeneous clinical presentations, ranging from incidentally detected events to extensive thrombosis associated with overt gastrointestinal bleeding, thus representing a clinical challenge for treatment decisions. In the absence of major contraindications, anticoagulant therapy is generally recommended for all patients presenting with acute symptomatic SVT, but there is no consensus about the use of anticoagulant drugs in chronic or incidentally detected SVT. High quality evidence on the acute and long-term management is substantially lacking and the risk to benefit-ratio of anticoagulant therapy in SVT still needs to be better assessed. PMID- 23026650 TI - Circulating biomarkers. AB - Cardiovascular diseases (CVD) remain a leading cause of death worldwide. In the past years new biomarkers have drawn the clinician's attention for their use in primary prevention and in the identification of individuals at cardiovascular risk. Biomarkers also provide information on the progression and possible recurrence of cardiovascular events, and include inflammatory markers (C-reactive protein and interleukin-18), endothelial dysfunction markers (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), neurohormonal markers (brain natriuretic peptide and copeptine), ischemia biomarkers (apolipoprotein J) and necrosis markers (troponins). Although biomarkers provide utility for predicting cardiovascular risk, the identification and characterization of new biomarkers to achieve increasing diagnosis and prognostic efficiency in CVD prevention is of high clinical interest. In this review we will discuss on recently discovered biomarkers and their clinical applications. PMID- 23026651 TI - Oral contraception in women with mild thrombophilia: what have we learned recently? AB - Mild thrombophilias include heterozygous forms of Factor V Leiden and prothrombin G20210A mutation and high levels of factor VIII. These defects are responsible for only a moderate increase of venous thromboembolism (VTE) risk compared with strong thrombophilias (antithrombin III, protein C and protein S deficiencies and homozygous forms of factor V Leiden and G20210A prothrombin mutation). Combined oral contraceptives increase the VTE risk in women in a fertile age, and in a far more important way in thrombophilia carrier women. Universal screening of thrombophilia test before the use of combined oral contraceptives is not recommended. However, selective VTE-history based screening is associated with a better cost-effectiveness, especially in asymptomatic relatives of carriers of strong thrombophilia. Currently, combined oral contraceptives are discouraged in women with any thrombophilic defects. The VTE risk is higher during pregnancy and postpartum period compared to hormonal contraceptive use period in women with mil thrombophilia. For this reason, a careful election of an alternative birth control method is necessary in these women. PMID- 23026652 TI - Cerebral venous thrombosis, pregnancy and oral contraceptives. AB - Cerebral venous thrombosis (CVT) is a rare variety of cerebro-vascular disease accounting for 0.5% of all stroke. It can occur at any age. It has a 3/1 female preponderance with a peak in young women due to gender specific risk factors, especially oral contraceptives and to lesser extent pregnancy, post-partum, and in vitro fertilization. Despite a wide variety of clinical presentations, early diagnosis, mostly based on MRI/MRA, is crucial but often difficult particularly during post-partum because of the numerous causes of headache that may occur after delivery. Antithrombotic treatment based on low molecular weight heparin and symptomatic treatment should be started as rapidly as possible. The overall prognosis of CVT is much better than that of arterial stroke and it is even better in women with gender specific risk factors, with a complete recovery in 80% of patients. Future pregnancy is not contra-indicated, but contraception with oestro-progestogens is definitely contra-indicated. PMID- 23026653 TI - Surgery in patients with hemophilia: is thromboprophylaxis mandatory? AB - Patients with hemophilia are considered low risk for thromboembolic complications. However, in the presence of risk factors for thrombosis, such as surgical procedures, and intensive replacement therapy this complication has been reported. Major orthopedic surgeries are often required in patients with hemophilia, due to the presence of hemophiliac arthropathy. In individuals that do not have hemophilia, orthopedic surgeries are particularly well recognized as high risk for venous thromboembolism, and the use of thromboprophylaxis for this condition is recommended. However, for hemophilia patients the use of venous thrombosis prophylaxis during major surgeries, including orthopedic procedures remains controversial. For the majority of the patients the use of gradated compression stockings and early mobilization can be sufficient to prevent venous thromboembolism. The use of anticoagulant prophylaxis should be considered just for patients with relevant additional risk factor for thrombosis. However, for hemophilia patients with inhibitor, pharmacologic thromboprophylaxis is not recommended. For patients with von Willebrand disease receiving factor concentrates replacement therapy undergoing surgical procedures, the FVIII plasma levels should be monitored and thromboprophylaxis should be considered if any other thrombosis risk factor is present. It is important for the future to establish risk assessment tools that can help to determine the most effective and safe practice to prevent venous thrombosis in patients with hemophilia and other bleeding disorders who undergo surgical procedures. PMID- 23026655 TI - Antipsychotic drugs and venous thromboembolism. AB - Since preliminary case reports suggesting a possible association between first generation of antipsychotics and venous thromboembolism (VTE), consistent epidemiological data is now available suggesting a moderate association between antipsychotics and VTE. However, despite several hypotheses, the underlying mechanisms remain unknown or uncertain. In addition, if the association between antipsychotics and VTE is plausible, the intensity of this risk and the dose effect relationship do not have yet been determined. Prospective data is therefore needed in order to confirm and to quantify this association. Because of the level of uncertainty, the clinical impact on the prevention and the treatment of VTE in patients with a psychiatric illness appears to be low. PMID- 23026654 TI - Mechanisms of variability in antiplatelet agents response. AB - Inter-individual variability in the response to antiplatelet drugs has been reported. Suboptimal response to aspirin, as determined by specific tests, is rare and, in most instances, caused by poor compliance. In contrast, it is well established that the pharmacological response to clopidogrel is widely variable, with a significant proportion of subjects (about 1/3) being very poor responders. Inter-individual difference in the extent of metabolism of clopidogrel to its active metabolite is the most plausible mechanism for the observed inter individual variability in platelet inhibition. Tailored treatment based on laboratory monitoring of platelet function has been proposed as a solution to poor responsiveness to clopidogrel. However, we still need to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost effectiveness, before monitoring clopidogrel therapy can be recommended in clinical practice. PMID- 23026656 TI - Bleeding definitions in orthopaedic VTE prophylaxis trials: a real need for standardization. PMID- 23026657 TI - Antiphospholipid antibodies: evaluation of the thrombotic risk. AB - The laboratory diagnosis of the antiphospholipid syndrome (APS) via antiphospholipid antibody (aPL) tests, including lupus anticoagulant (LAC), anti cardiolipin (aCL), or anti-beta2 glycoprotein I (abeta2GPI) antibodies remains a challenge. Coagulation tests for LAC as well as solid phase assays for aCL and abeta2GPI have methodological shortcomings, although for LAC large progress have been made in standardization. All assays are associated with clinical APS criteria (thrombotic and/or pregnancy complications) but with limited specificity. Besides, clinical studies demonstrating the association between the presence of aPL and thrombosis are not always well designed and result in wide ranges of odds ratio with large variation between studies. The best association between thrombotic complications and aPL is found for LAC. The association between thrombosis and aCL or abeta2GPI is at least inconsistent. The inclusion of more specific assays, such as the domain-I-beta2GPI.antibodies is too premature and depends on further investigation in large clinical studies and the commercial availability. The search for new assays should proceed to identify patients with aPL with increased risk for thrombosis, preferable in large prospective studies. Meanwhile, with the current available LAC, aCL and abeta2GPI assays it is strongly recommended to make antibody profiles. Multiple positivity of tests seems clinically more relevant. The strengths and weaknesses of the current laboratory criteria for APS are discussed in view of their role in risk stratification of patients with thrombotic events. PMID- 23026658 TI - Should we follow the 9th ACCP guidelines for VTE prevention in surgical patients? AB - The 9th edition of the American College of Chest Physicians (ACCP) guidelines on antithrombotic therapy and prevention, includes relevant changes compared to previous versions. In the 9th ACCP, leadership of most chapters was given to methodologists who were familiar with the GRADE methodology. All topic panelists underwent a selection process paying particular attention to their financial and intellectual conflicts of interests. In the 9th ACCP guidelines, evidence has been explicitly presented in many evidence profiles and summary of evidence tables. In order to get a more balanced trade-off between desirable and undesirable effects of the alternative prevention and therapeutic interventions, there has been an increased emphasis on clinically relevant events, as opposed to previous surrogate asymptomatic outcomes. In addition, there has been a systematic review and survey on patient values and preferences for thrombotic and bleeding outcomes. As a result of the above changes, the strength of most recommendations has been downgraded compared to previous editions. The main changes regarding prevention on nonorthopedic surgical patients include the adoption of two risk assessment models. The only recommendation that has been upgraded is to extend prophylaxis with low molecular weight heparins (LMWH) for four weeks after abdominal or pelvic cancer surgery. A controversial modification in orthopedic patients is recommendation in favor of the use of aspirin after hip or knee arthroplasty. New oral anticoagulants are recommended, but LMWH are suggested as the preferred option. Extending pharmacological prophylaxis for up to 35days rather than 10-14days is now suggested for patients undergoing major orthopedic surgery. PMID- 23026659 TI - What did we learn from new oral anticoagulant treatment? AB - Orally active direct inhibitors of thrombin and factor Xa have now been approved for treatment or prevention of deep vein thrombosis,and stroke associated with atrial fibrillation. The factor Xa inhibitor, rivaroxaban, has shown promising results in the treatment of acute coronary syndrome but is not yet approved for that indication. These agents share a rapid onset and are cleared with half lives of approximately 10 hours. At present there is no approved antidote for either class of anticoagulant, making the treatment of life-threatening bleeding episodes problematic. These agents have fewer drug interactions than warfarin, have a predictable clearance, and hence do not require monitoring. Patients with renal insufficiency have delayed clearance and hence may have elevated levels of the drug leading to increased risk of bleeding. PMID- 23026660 TI - Formation of the clot. AB - An electron transport system regulates the initiation of thrombus formation through the activation of critical receptors involved in hemostasis and thrombosis. Protein disulfide isomerase along with other thiol isomerases, important for intracellular protein synthesis, are responsible for this extracellular activity during thrombus formation. Inhibition of these thiol isomerases blocks platelet aggregation and fibrin generation. Pharmaceuticals directed against these thiol isomerases offers a novel approach to antithrombotic therapy. PMID- 23026661 TI - Is the coexistence of thromboembolic events and Factor VII deficiency fortuitous? AB - Over 30 thromboembolic events have been reported in factor VII (FVII) deficiency either associated with previously asymptomatic forms or bleeding diathesis. Whether this coexistence is fortuitous or not is still a mater of debate. Nevertheless, it is well admitted that (i) thrombotic events occurring in FVII deficient patients with any apparent triggering factors are very rare, (ii) surgical procedures, replacement therapy (especially containing activated factors) but also the presence of an antiphospholipid syndrome are frequently associated with these particular thrombotic events, (iii) in the same way, R304Q and A294V FVII variants appear to be more prevalent than other FVII equally frequent mutations and finally (iv) low FVII coagulant activity levels do not protect against thrombosis. Therefore, peri-operative thrombotic prophylaxis should be relevant for these particular FVII-deficient patients. However, safety, treatment modalities and specific indications of such an antithrombotic prophylaxis remain to be established. PMID- 23026662 TI - Venous thromboembolic disease in patients with haemophilia. AB - With the availability of efficient and safe clotting factor replacement therapy, elective total joint arthroplasty is increasingly performed in subjects with haemophilia suffering from chronic haemophilic arthropathy. Little has been published addressing the prevalence and the specific risk factors of thromboembolic complications and the role of thromboembolic prophylaxis in this specific population. While the risk of thrombosis in hemophilic patients following hip or knee arthroplasty is considered to be low and probably mitigated by the clotting factor deficiency, cases have been reported of pulmonary embolism and deep vein thrombosis in hemophilic patients. Although most guidelines advocate thromboembolic prophylaxis in the general population undergoing major orthopaedic surgery, no such standard of care is in place for hemophilic patients. This paper discusses the scope of the problem of venous thromboembolism in patients with haemophilia undergoing major orthopaedic surgery and reviews the published approaches to the use of prophylactic anticoagulation in this setting. PMID- 23026663 TI - New anti-platelet agents: the end of resistance? AB - Despite improved clinical outcomes from dual anti-platelet therapy with aspirin plus the CYP12 ADP receptor antagonist clopidogrel in patients undergoing coronary revascularisation, ex-vivo platelet function testing consistently reveals a proportion of patients with apparent resistance or non-response to clopidogrel loading and maintenance therapy who are at increased risk of coronary thrombosis. Treatment regimens using the newer CYP12 antagonists prasugrel and ticagrelor demonstrate improved ex-vivo platelet inhibition and superior clinical efficacy in large-scale clinical trials-even in patients demonstrating clopidogrel resistance. However, improved efficacy comes at the cost of an increased overall risk of bleeding for both drugs. Further analysis of the outcomes from large scale clinical studies suggests that individual patient sub groups differ both in their liklehood of bleeding with newer anti-platelet agents and with regard to efficacy outcomes. Therefore when deciding anti-platelet regimens in suspected acute coronary syndrome, particular consideration must be given to patient's risk of thrombosis (STEMI, previous stent thrombosis), the procedure (complex PCI, thrombus in-situ, strategy of pre-treatment), and factors affecting safety (patient age, patient weight, previous stroke, liklehood of surgical revascularisation). Placing the focus on individualised patient risk benefit assessment with appropriate use of platelet function testing when indicated, in combination with the ongoing assessment of prasugrel and ticagrelor in larger numbers of patients should be the key strategies governing use of dual anti-platelet therapy. PMID- 23026664 TI - Mondor's disease: what's new since 1939? AB - Mondor's disease (MD) is a rare and self-limited benign disease first described in 1939. Originally its clinical presentation was a superficial vein thrombosis (SVT) without contiguous skin inflammation of the chest wall veins. Over time its definition has evolved and now also includes subcutaneous thrombosis of the dorsal vein of the penis but also retractile scarring of the fascia after breast surgery without concomitant SVT. In all cases clinical examination constitutes the first step of diagnostic management. It is followed by an ultrasound exploration (US) to search for a thrombus. In about half of all cases the disease is considered as idiopathic and cancer is rare. Whatever the location considered, the follow-up is usually uneventful with low rates of recurrence and of subsequent cancer. Treatment is debated and ranges from therapeutic abstention to anticoagulants or even surgery. It is likely that the new locations and mechanisms (without thrombosis) of the MD have lead to the constitution of a heterogeneous entity precluding from a consensual mode of care. PMID- 23026665 TI - Antithrombotic treatment of atrial fibrillation: new insights. AB - The incidence and prevalence of atrial fibrillation are quickly increasing, mainly due to the ageing of the population. Atrial fibrillation is, to date, a problem of public health. Atrial fibrillation is associated to a five-fold risk of stroke, which may be identified by score risks, such as CHADS(2) score. The classical antithrombotic treatment of atrial fibrillation is based on vitamin K antagonists. Trials made in the 90's have clearly shown that vitamin K antagonists were able to decrease stroke risk by about 60%. New oral anticoagulants are now available on the market to treat patients with atrial fibrillation. These drugs are dabigatran which has demonstrated an interest in the RE-LY trial. Two doses may be prescribed, 110 mg bid and 150 mg bid. Anti Xa have also demonstrated an interest : rivaroxaban in the ROCKET AF trial and apixaban in the AVERROES (versus aspirin) and ARISTOTLE trials. In the future these drugs will have a major place in the armamentarium used to treat patients with atrial fibrillation. In all these trials a decrease in intra cranial haemorrhages has been demonstrated. In the everyday practice it will be necessary to be very cautious in patients with impaired renal function, as all these drugs are eliminated by kidneys. PMID- 23026666 TI - Antithrombotic agents and invasive procedures--hematologist point of view. AB - The management of a patient treated with an antithrombotic agent who requires an invasive procedure remains challenging. There are antidotes neither for the antiplatelet agents nor the new anticoagulants. A good knowledge of basic pharmacology of these drugs and the help of a hematologist within a multidisciplinary approach are essential. The potential interest of laboratory tests and the use of reversal agents, and the transfusion of plasma and platelets will be discussed. PMID- 23026667 TI - Thrombosis in myeloma treated with IMiDs. AB - Survival of myeloma patients has improved since the introduction of novel agents in the armamentorium, especially with the Immunomodulator drugs (IMiDs). However, this substantial benefit has been counterbalanced by the dramatic increase of the incidence rate of thromboembolic events, either venous and/or arterial. This observation has made compulsory a prophylactic treatment in myeloma treated with IMiDs. Although guidelines were proposed since, it is clear that several unanswered questions remain, starting with the choice of the thromboprophylaxis and the definition of risk factors. Further studies are warranted to help decide the optimal thromboprophylaxis. PMID- 23026668 TI - Adjuvant therapy in breast cancer and venous thromboembolism. AB - Breast cancer patients are considered to be at relatively low risk of developing a TEE. The highest incidence of VTE events occurs in metastatic breast cancer patients likely due to extension of disease, immobility for pathologic bone fractures, cancer cachexia and venous compression by the tumour mass. Although thrombosis is less common in patients with early stage cancer compared to those with more advanced disease, it does occur and is clinically challenging. The adjuvant setting is of particular interest in order to assess the specific thrombogenic potential of systemic chemotherapy, because of the low tumor burden with only microscopic tumor foci at the time of treatment administration. This review summarizes risk factors, incidence and strategies to avoid VTE in breast cancer patients receiving adjuvant therapy. PMID- 23026669 TI - Structure-function relationship of estrogen receptors in cardiovascular pathophysiological models. AB - The ancestral status of estrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of estrogens, and in particular of 17beta-estradiol (E2). Indeed, in addition to their well described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes several highly beneficial effects such as prevention of osteoporosis, atheroma and type 2 diabetes,... However, estrogens also promotes two deleterious actions : the stimulation of the proliferation of the epithelium of two sex targets : uterus and breast, favoring an increase in risk of epithelial cancer in these two tissues. These actions are mediated by the activation of ER alpha (ERalpha) and beta (ERbeta), which regulate target gene transcription (genomic action) through two independent activation functions AF-1 and AF-2, but can also elicit rapid membrane initiated steroid signals. Although ERbeta plays an important role in the central nervous system and in the heart, ERalpha appears to play a prominent role in most of the other tissues. One major challenge consists in uncoupling some beneficial actions from other deleterious ones, i.e. selective ER modulation. Tamoxifen and raloxifen are beneficial to prevent the recurrence of breast cancer, and mimic estrogen action mainly on bone, but their effets on atheroma and on type 2 diabetes are if any marginal. These last years, several labs, and in particular our lab, have attempted: 1) To perform an in vivo molecular "dissection" of ER alpha, allowing the uncoupling of some of its actions, and potentially paving the way to optimized selective ER modulators. (reviewed in Arnal JF, et al. Br J Pharmacol. 2012;165:57-66). 2) To describe an unexpected action of E2 treatment at the level of platelet responses in mice, that protects the animals from thromboembolism through the haematopoietic ER alpha. (Valera MC et al. Blood. 2012, in press). PMID- 23026670 TI - Microparticles in vascular disorders: how tissue factor-exposing vesicles contribute to pathology and physiology. AB - Coagulation is initiated by tissue factor (TF). Coagulant TF is constitutively expressed by extravascular cells, but there is increasing evidence that TF can also be present within the blood, in particular during pathological conditions. Such TF is exposed on circulating cell-derived vesicles, and its presence has been associated with development of disseminated intravascular coagulation and venous thrombosis. For example, the presence of TF-exposing vesicles in the blood of cancer patients may be associated with their high risk of developing venous thromboembolism. Remarkably, high levels of coagulant TF-exposing vesicles are present in other body fluids such as saliva and urine of healthy persons, suggesting that these vesicles play a physiological role. We postulate that the presence of TF-exposing vesicles in body fluids as saliva and urine provides an additional source of coagulant TF that promotes coagulation, thereby reducing blood loss and contributing to host defence by reducing the risk of microorganisms entering the "milieu interieur". PMID- 23026671 TI - Thrombosis in patients with primary chronic immune thrombocytopenia. AB - Patients with primary chronic immune thrombocytopenia (ITP) have immune-mediated platelet destruction and/or suppressed platelet production. ITP patients are, due to the thrombocytopenia, at increased risk of severe bleeding episodes. Paradoxically, these patients also seem to have an increased risk of venous thromboembolism (VTE). Findings from a Danish study including 391 patients with chronic ITP and 3,128 comparisons from the general population have suggested a more than twofold higher risk of VTE in patients with chronic ITP compared with the general population. VTEs may occur even in patients with low platelet count. The conclusion is therefore that clinicians should keep VTE in mind as a potential diagnosis in patients with chronic ITP. PMID- 23026672 TI - ISTH guidelines on lupus anticoagulant testing. PMID- 23026673 TI - Crosstalk of the plasma contact system with bacteria. AB - Activation of the plasma contact system triggers several cascade systems such as the kallikrein-kinin system, the intrinsic pathway of coagulation, the classical complement cascade and the fibrinolytic system. Recent studies have shown a critical role of the contact system for arterial and venous thrombus formation and thromboembolic disease. In contrast, the function of the contact system for host-defense reactions and its physiological functions have remained enigmatic. Experimental animal studies and clinical data have linked the contact system to bacterial infections with implications for sepsis disease. The present review summarizes the role of the contact system and its activation for bacterial infections. PMID- 23026675 TI - Do new oral anticoagulants require laboratory monitoring? The clinician point of view. AB - Although no laboratory monitoring is needed for new anticoagulants, the measurement of their activity is required in special clinical situations. Standardised tests have been developed for rivaroxaban and dabigatran which allow the measurement of the patient's response to the drug at Cmax (2 to 3 hours after intake) or at trough (before repeated administration). The results can be expressed in mg per ml of plasma and compared to the expected concentrations. The influence of the new anticoagulants of coagulation assays has been determined. Several clinical cases of major bleeding have been reported and a severe coagulopathy was found in these patients (prolonged PT and aPTT, increased drug concentration in plasma). These observations raise the question regarding the potential benefit of laboratory coagulation monitoring from time to time. Trials are needed to determine the relationship of assay results with bleeding or thrombotic complications. Pros and Cons laboratory measurements are discussed. PMID- 23026674 TI - Tissue factor and cancer. AB - The hemostatic system is involved in multiple interactions with transformed cells that progress from a dormant, non-vascularized tumor to highly metastatic phenotypes. Oncogenic transformations up regulate not only the initiator of the coagulation cascade, tissue factor (TF), but also induce other molecules that are required for TF's direct cell signaling activity, including the protease activated receptor (PAR) 2 and factor VIIa. TF-dependent signaling is a major driver for primary tumor progression, whereas TF-initiated coagulation and other components of the hemostatic system support metastasis. Basic research continues to identify pivotal molecular interactions in these processes and provides potential leads for targeting specific tumor promoting pathways associated with hemostasis and thrombosis. PMID- 23026676 TI - Pro-angiogenic cell-based therapy for the treatment of ischemic cardiovascular diseases. AB - Pro-angiogenic cell therapy has emerged as a promising option to treat patients with acute myocardial infarction or with critical limb ischemia. Exciting pre clinical studies have prompted the initiation of numerous clinical trials based on administration of stem/progenitor cells with pro-angiogenic potential. Most of the clinical studies performed so far have used bone marrow-derived or peripheral blood-derived mononuclear cells and showed, overall, a modest but significant benefit on tissue remodeling and function in patients with ischemic diseases. These mixed results pave the way for the development of strategies to overcome the limitation of autologous cell therapy and to propose more efficient approaches. Such strategies include pretreatment of cells with activators to augment cell recruitment and survival in the ischemic target area and/or the improvement of cell functions such as their paracrine ability to release proangiogenic factors and vasoactive molecules. In addition, efforts should be directed towards stimulation of both angiogenesis and vessel maturation, the development of a composite product consisting of stem/progenitor cells encapsulated in a biomaterial and the use of additional sources of regenerative cells. PMID- 23026677 TI - Laboratory tests and the new oral anticoagulants. AB - New oral anticoagulants are ready to enter the scene on a massive basis for the treatment/prophylaxis of many cardiovascular diseases. Although they can be prescribed without dose-adjustment based on laboratory testing, the laboratory is still an essential partner that may assist clinicians for the management of anticoagulated patients. In principle, there are many tests that can be used to evaluate the anticoagulant effect of the new drugs, but the choice should be made among those that are more readily available in emergency and that are easy to run. Linearity of dose-response and responsiveness to increasing dose in addition to standardization are other important issues to consider. This article is aimed at reviewing the current tests, their characteristics and the most appropriate choice. PMID- 23026678 TI - Involvement of platelet derived microparticles in tumor metastasis and tissue regeneration. AB - Platelets play a major role in hemostasis, but are also involved in vascular biology processes such as angiogenesis and tumor metastasis. Activated platelets release many proteins favoring wound healing and promoting angiogenesis. Microparticles (MP) are small plasma membrane vesicles shed from cells upon their activation or apoptosis. Platelet-derived microparticles (PMP) constitute the majority of the pool of MP circulating in the blood. PMP express and may transfer functional receptors, stimulate the release of cytokines, activate intracellular signaling pathways, promote angiogenesis, and are involved in tissue regeneration and cancer metastasis. We investigated the effect of PMP on cancer cells metastasis and their potential beneficial effect in an ischemic stroke model. PMID- 23026679 TI - Purification of a recombinant plant peroxidase produced in Pichia pastoris by a simple 2-step strategy. AB - The enzyme horseradish peroxidase (HRP), which is frequently applied in industry and medicine, is primarily isolated from plant. This purification procedure is costly and the obtainable amount of HRP from the horseradish root is low. However, recombinant HRP (rHRP) produced in yeast is hyperglycosylated rendering the subsequent purification cumbersome and the recombinant production of HRP in yeast not competitive. In this study, we screened different common techniques to develop a fast and efficient purification strategy for hyperglycosylated rHRP expressed in Pichia pastoris. We demonstrated that the extensive glycosylation pattern on the surface of rHRP masked its physico-chemical properties, which is why standard purification strategies were rather unsuccessful. Only switching the strategies to a flowthrough mode gave satisfactory results. After determining the optimal operation conditions in a multivariate Design of Experiments approach, we present a simple 2-step strategy for the purification of hyperglycosylated rHRP. Combining a hydrophobic charge induction chromatography operated in flowthrough mode and a size-exclusion chromatography, we were able to purify rHRP more than 12-fold from a specific activity of 80U/mg to more than 1000U/mg. PMID- 23026680 TI - The substance P/neurokinin-1 receptor system in lung cancer: focus on the antitumor action of neurokinin-1 receptor antagonists. AB - The last decades have seen no significant progress in extending the survival of lung cancer patients and there is an urgent need to improve current therapies. The substance P (SP)/neurokinin-1 receptor (NK-1R) system plays an important role in the development of cancer: SP and NK-1R antagonists respectively induce cell proliferation and inhibition in human cancer cell lines. No study of the involvement of this system in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells has been carried out in depth. Here, we demonstrate the involvement of the SP/NK-1R system in human H-69 (SCLC) and COR-L23 (NSCLC) cell lines: (1) they express isoforms of the NK-1R and mRNA for the NK-1R; (2) they overexpress the tachykinin 1 gene; (3) the NK-1R is involved in their viability; (4) SP induces their proliferation; (5) NK-1R antagonists (Aprepitant (Emend), L 733,060, L-732,138) inhibit the growth of both cell lines in a concentration dependent manner; (6) the specific antitumor action of these antagonists against such cells occurs through the NK-1R; and (7) lung cancer cell death is due to apoptosis. We also demonstrate the presence of NK-1Rs and SP in all the human SCLC and NSCLC samples studied. Our findings indicate that the NK-1R may be a promising new target in the treatment of lung cancer and that NK-1R antagonists could be new candidate antitumor drugs in the treatment of SCLC and NSCLC. PMID- 23026681 TI - Improving muscular endurance with the MVe Fitness ChairTM in breast cancer survivors: a feasibility and efficacy study. AB - OBJECTIVES: To assess the feasibility and efficacy of delivering Pilates exercises for resistance training to breast cancer survivors using the MVe Fitness ChairTM. DESIGN: Pilot randomized controlled trial. METHODS: Twenty-six female breast cancer survivors were randomized to use the MVe Fitness ChairTM (n=8), traditional resistance training (n=8), or a control group (no exercise) (CO) (n=10). The MVe Fitness ChairTM and traditional resistance training groups completed 8 weeks of exercise. Muscular endurance was assessed pre and post-test for comparisons within and between groups using push ups, curl ups, and the Dynamic Muscular Endurance Test Battery for Cancer Patients of Various Ages. RESULTS: Feasibility of the MVe Fitness ChairTM was good, evidenced by over 80% adherence for both exercise groups and positive narrative feedback. Significant improvements in muscular endurance were observed in the MVe Fitness ChairTM (p<0.002) and traditional resistance training groups (p<0.001), but there were no differences in improvement between the MVe Fitness ChairTM and traditional resistance training groups (p<0.711) indicating that Pilates and traditional resistance training may be equally effective at improving muscular endurance in this population. CONCLUSIONS: The MVe Fitness ChairTM is feasible for use in breast cancer survivors. It appears to promote similar improvements in muscular endurance when compared to traditional resistance training, but has several advantages over traditional resistance training, including cost, logistics, enjoyment, and ease of learning. PMID- 23026685 TI - "On-off" switchable electrochemical affinity nanobiosensor based on graphene oxide for ultrasensitive glucose sensing. AB - A novel "smart" electrochemical affinity nanobiosensor with "on-off" switchable property was designed for the ultrasensitive determination of glucose. The sensing approach was based on the glucose-ConA-dextran competitive system induced charge evolution in the use of graphene oxide (GO) as transducer element, resulting in the enhancement of interfacial electron transfer kinetics between the redox probe and the electrode. As concanavalin A (ConA) constituent was pH sensitive, when the ConA-DexP/GO film electrode switched in probe Fe(CN)(6)(3-/4 ) solution between pH 4.0 and 8.0, the film was cycled between the "on" and "off" states by the electrostatic attraction and repulsion of Fe(CN)(6)(3-/4-) to and from the electrode surface. Upon introduction of glucose into the ConA-DexP/GO complex at the "off" state, glucose competed with DexP for ConA and displaced ConA from the GO platform, resulting in gradual decrease of the surface negative charge as well as the resistance of probe for electron communication on the sensor surface, and making the switching from "off" state to "on" state simultaneously. This ultrasensitive glucose nanobiosensor had a broad linearity between the decrease in electron transfer resistance (DeltaR) and the glucose concentration over a range from 5.0 MUM to 9.0 mM with a detection limit as low as 0.34 MUM. The proposed method showed potential application for fabricating novel biosensors and bioelectronic devices. PMID- 23026686 TI - Re: cost-effectiveness of pertussis booster vaccination in the Netherlands. PMID- 23026687 TI - Evaluation of protective effect of DNA vaccines encoding the BAB1_0263 and BAB1_0278 open reading frames of Brucella abortus in BALB/c mice. AB - The immunogenicity of two DNA vaccines encoding open reading frames (ORFs) of genomic island 3 (GI-3), specific for Brucella abortus and Brucella melitensis, has been examined. Intramuscular injection of plasmid DNA carrying the BAB1_0263 and BAB1_0278 genes (pVF263 and pVF278, respectively) into BALB/c mice elicited both humoral and cellular immune responses. Mice injected with pVF263 or pVF278 had a dominant immunoglobulin G2a (IgG2a) response. In addition, both DNA vaccines elicited a T-cell-proliferative response, but only pVF263 induced significant levels of interferon gamma (INF-gamma) upon restimulation with recombinant 263 protein. Neither DNA vaccine induced interleukin (IL)-10, nor IL 4, upon stimulation with an appropriate recombinant protein or crude Brucella protein, suggesting the induction of a typical T-helper 1 (Th1)-dominated immune response. Furthermore, the pVF278 DNA vaccines induced protection in BALB/c mice against challenge with the virulent strain B. abortus 2308. Taken together, these data suggest that DNA vaccination offers an improved delivery strategy for the BAB1_0278 antigen, and provide the first evidence of a protective effect of this antigen. PMID- 23026688 TI - The status of live viral vaccination in early life. AB - The need for neonatal vaccines is supported by the high disease burden during the first year of life particularly in the first month. Two-thirds of childhood deaths are attributable to infectious diseases of which viruses represent key pathogens. Many infectious diseases have the highest incidence, severity and mortality in the first months of life, and therefore early life vaccination would provide significant protection and life savings. For some childhood viral diseases successful vaccines exist, such as against measles, mumps, rubella, varicella, influenza poliovirus, and rotavirus, but their use in the first year particularly at birth is not yet practiced. Vaccines against other key pathogens continue to elude scientists such as against respiratory syncytial virus. The obstacles for early and neonatal vaccination are complex and include host factors, such as a developing immune system and the interference of passively acquired antibodies, as well vaccine-specific issues, such as optimal route of administration, titer and dosing requirements. Importantly, additional host and infrastructure barriers also present obstacles to neonatal vaccination in the developing world where morbidity and mortality rates are highest. This review will highlight the current live viral vaccines and their use in the first year of life, focusing on efficacy and entertaining the barriers that exist. It is important to understand the successes of current vaccines and use this knowledge to determine strategies that are successful in young infants and for the development of new vaccines for use in early life. PMID- 23026689 TI - The potential economic value of a human norovirus vaccine for the United States. AB - Vaccines against human norovirus are currently under development. We developed a simulation model to determine their potential economic value. Vaccination prevented 100-6125 norovirus gastroenteritis cases per 10,000 vaccinees. Low vaccine cost (<=$50) garnered cost-savings and a more expensive vaccine led to costs per case averted comparable to other vaccines. In the US, vaccination could avert approximately 1.0-2.2 million cases (efficacy 50%, 12 month duration), costing an additional $400 million to $1.0 billion, but could save <=$2.1 billion (48 month duration). Human norovirus vaccination can offer economic value while averting clinical outcomes, depending on price, efficacy, and protection duration. PMID- 23026690 TI - Translating vaccine policy into action: a report from the Bill & Melinda Gates Foundation Consultation on the prevention of maternal and early infant influenza in resource-limited settings. AB - Immunization of pregnant women against influenza is a promising strategy to protect the mother, fetus, and young infant from influenza-related diseases. The burden of influenza during pregnancy, the vaccine immunogenicity during this period, and the robust influenza vaccine safety database underpin recommendations that all pregnant women receive the vaccine to decrease complications of influenza disease during their pregnancies. Recent data also support maternal immunization for the additional purpose of preventing disease in the infant during the first six months of life. In April 2012, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization recommended revisions to the WHO position paper on influenza vaccines. For the first time, SAGE recommended pregnant women should be made the highest priority for inactivated seasonal influenza vaccination. However, the variable maternal influenza vaccination coverage in countries with pre-existing maternal influenza vaccine recommendations underscores the need to understand and to address the discrepancy between recommendations and implementation success. We present the outcome of a multi stakeholder expert consultation on inactivated influenza vaccination in pregnancy. The creation and implementation of vaccine policies and regulations require substantial resources and capacity. As with all public health interventions, the existence of perceived and real risks of vaccination will necessitate effective and transparent risk communication. Potential risk allocation and sharing mechanisms should be addressed by governments, vaccine manufacturers, and other stakeholders. In resource-limited settings, vaccine related issues concerning supply, formulation, regulation, evidence evaluation, distribution, cost-utility, and post-marketing safety surveillance need to be addressed. Lessons can be learned from the Maternal and Neonatal Tetanus Elimination Initiative as well as efforts to increase vaccine coverage among pregnant women during the 2009 influenza pandemic. We conclude with an analysis of data gaps and necessary activities to facilitate implementation of maternal influenza immunization programs in resource-limited settings. PMID- 23026691 TI - Investigation of a small-diameter decellularised artery as a potential scaffold for vascular tissue engineering; biomechanical evaluation and preliminary cell seeding. AB - The development of a small-diameter tissue engineered blood vessel (TEBV), with equivalent mechanical properties to the vessel being replaced, may provide a potential solution to the limitations associated with natural and synthetic bypass grafts of small-diameter vessels. This study presents the biomechanical properties of small-diameter (<4mm) porcine coronary arteries (PCA) and the corresponding natural matrix scaffold of the artery achieved through short-term decellularisation. Tubular segments, up to 50mm in length, of PCA were perfused with 0.1M sodium hydroxide (NaOH) for 3 to 12h to achieve the natural matrix scaffold. Uniaxial tensile, inflation and permeability tests were performed on non-decellularised and decellularised sections within 24h of slaughter to determine the alteration in mechanical properties as a result of decellularisation. A treatment time of 9h achieved decellularisation as all cell nuclei were appropriately disrupted and there was an absence of smooth muscle in the vascular wall. Uniaxial tensile and inflation tests confirmed the scaffold maintains its non-linear response, however a less stiff, more distensible low load response and stiffer high-load response was found compared to non decellularised sections. Vascular smooth muscle cells were successfully seeded to the lumen, abluminal side and lateral edges of decellularised sections and attachment and infiltration of the xenogeneic cells after 15 days confirmed the viability of the PCA scaffold as a suitable environment for cell growth and infiltration. An extended decellularisation treatment time increased the porosity whilst maintaining the mechanical integrity of the scaffold and this may optimise the repopulation of the scaffold. This study provides valuable information for the development of an optimum TEBV, while also establishing the potential of this natural matrix scaffold to be used as a graft or vascular tissue engineering scaffold. PMID- 23026692 TI - Numerical investigation of the active role of the actin cytoskeleton in the compression resistance of cells. AB - Numerous in-vitro studies have established that cells react to their physical environment and to applied mechanical loading. However, the mechanisms underlying such phenomena are poorly understood. Previous modelling of cell compression considered the cell as a passive homogenous material, requiring an artificial increase in the stiffness of spread cells to replicate experimentally measured forces. In this study, we implement a fully 3D active constitutive formulation that predicts the distribution, remodelling, and contractile behaviour of the cytoskeleton. Simulations reveal that polarised and axisymmetric spread cells contain stress fibres which form dominant bundles that are stretched during compression. These dominant fibres exert tension; causing an increase in computed compression forces compared to round cells. In contrast, fewer stress fibres are computed for round cells and a lower resistance to compression is predicted. The effect of different levels of cellular contractility associated with different cell phenotypes is also investigated. Highly contractile cells form more dominant circumferential stress fibres and hence provide greater resistance to compression. Computed predictions correlate strongly with published experimentally observed trends of compression resistance as a function of cellular contractility and offer an insight into the link between cell geometry, stress fibre distribution and contractility, and cell deformability. Importantly, it is possible to capture the behaviour of both round and spread cells using a given, unchanged set of material parameters for each cell type. Finally, it is demonstrated that stress distributions in the cell cytoplasm and nucleus computed using the active formulation differ significantly from those computed using passive material models. PMID- 23026693 TI - On the efficiency of attachment methods of biological soft tissues in shear experiments. AB - Sandpaper and glue are commonly used to prevent slip of the sample in rheometric measurements of soft biological tissues. We show in this paper that the best attachment method is to glue the sample to the plates of the test device. Whereas no significant difference was observed at small strain, sandpaper proved to be less efficient than glue in preventing slip at large strain, leading to a significant underestimation of the tissue stiffness. PMID- 23026694 TI - Determination of friction coefficient in unconfined compression of brain tissue. AB - Unconfined compression tests are more convenient to perform on cylindrical samples of brain tissue than tensile tests in order to estimate mechanical properties of the brain tissue because they allow homogeneous deformations. The reliability of these tests depends significantly on the amount of friction generated at the specimen/platen interface. Thus, there is a crucial need to find an approximate value of the friction coefficient in order to predict a possible overestimation of stresses during unconfined compression tests. In this study, a combined experimental-computational approach was adopted to estimate the dynamic friction coefficient MU of porcine brain matter against metal platens in compressive tests. Cylindrical samples of porcine brain tissue were tested up to 30% strain at variable strain rates, both under bonded and lubricated conditions in the same controlled environment. It was established that MU was equal to 0.09+/-0.03, 0.18+/-0.04, 0.18+/-0.04 and 0.20+/-0.02 at strain rates of 1, 30, 60 and 90/s, respectively. Additional tests were also performed to analyze brain tissue under lubricated and bonded conditions, with and without initial contact of the top platen with the brain tissue, with different specimen aspect ratios and with different lubricants (Phosphate Buffer Saline (PBS), Polytetrafluoroethylene (PTFE) and Silicone). The test conditions (lubricant used, biological tissue, loading velocity) adopted in this study were similar to the studies conducted by other research groups. This study will help to understand the amount of friction generated during unconfined compression of brain tissue for strain rates of up to 90/s. PMID- 23026695 TI - An analytical calculation of the fluid load support fraction in a biphasic material: an alternative technique. AB - BACKGROUND: The fluid load support fraction (W(F)/W(T)) can be used to define the mechanical contribution of the interstitial fluid (W(F)) to the total force (W(T)) in the deformation of cartilage. Traditionally, W(F)/W(T) is calculated using complex experimental setups or time-consuming micromechanical poroelastic Finite Element (FE) simulations. AIM: To define and validate a fast and efficient technique to predict W(F)/W(T) using an analytical approach that can be applied without micromechanical detail or experimental measurement. METHODOLOGY: Poroelastic FE simulations defined accurate values of W(F)/W(T) for a range of loading configurations and were used to validate subsequent predictions. The analytical prediction of W(F)/W(T) used elastic contact mechanics to calculate W(F), and viscoelastic FE representation to calculate W(T). Subsequently, these independent calculations of W(F) and W(T) provided values of W(F)/W(T) that were compared with the poroelastic FE calculations. RESULTS AND DISCUSSION: The analytical prediction of W(F)/W(T) proved effective and suitably accurate (mean difference S<0.05). This technique demonstrated how W(F) and W(T) can be determined independently, without a biphasic constitutive model. Here we used viscoelasticity to calculate W(T) as an example, however, W(T) could be measured experimentally or predicted computationally. PMID- 23026696 TI - Characterization of PLGA based composite nerve guidance conduits: effect of F127 content on modulus over time in simulated physiological conditions. AB - PLGA/pluronic F127 based nerve guidance conduits (NGCs) for peripheral nerve regeneration offer excellent potential for clinical use. To date, little emphasis has been directed towards the effect of pluronic F127 on their subsequent mechanical properties as a function of degradation time or the physiological environment. This report was designed to redress the balance. This study synthesised 5 groups of 20wt% PLGA NGCs with varied additions of pluronic F127 (range 0-5wt%) to obtain Young's Moduli (E) in the range of 7-107MPa, depending on degradation conditions and pluronic F127 content. PMID- 23026697 TI - Full-field optical deformation measurement in biomechanics: digital speckle pattern interferometry and 3D digital image correlation applied to bird beaks. AB - In this paper two easy-to-use optical setups for the validation of biomechanical finite element (FE) models are presented. First, we show an easy-to-build Michelson digital speckle pattern interferometer (DSPI) setup, yielding the out of-plane displacement. We also introduce three-dimensional digital image correlation (3D-DIC), a stereo photogrammetric technique. Both techniques are non contact and full field, but they differ in nature and have different magnitudes of sensitivity. In this paper we successfully apply both techniques to validate a multi-layered FE model of a small bird beak, a strong but very light biological composite. DSPI can measure very small deformations, with potentially high signal to-noise ratios. Its high sensitivity, however, results in high stability requirements and makes it hard to use it outside an optical laboratory and on living samples. In addition, large loads have to be divided into small incremental load steps to avoid phase unwrapping errors and speckle de correlation. 3D-DIC needs much larger displacements, but automatically yields the strains. It is more flexible, does not have stability requirements, and can easily be used as an optical strain gage. PMID- 23026698 TI - Contribution of actin filaments to the global compressive properties of fibroblasts. AB - Actin filaments are often regarded as tension-bearing components. Here, we examined the effects of actin filaments on global compressive properties of cells experimentally and numerically. Fibroblasts were harvested from the patellar tendon of a mature Japanese white rabbit and treated with cytochalasin D to depolymerize the actin filaments. Intact cells and cells with disrupted actin filaments were subjected to the compressive tests. Each floating cell was held between the cantilever and compressive plates and compressed by moving the compressive plate with a linear actuator to obtain a load-deformation curve under quasi-static conditions. The experimental results demonstrated that the initial stiffness of a cell with disrupted actin filaments decreased by 51%. After the experiments, we simulated the compressive test of cells with/without bundles of actin filaments. A bundle of actin filaments was modeled as a tension-bearing component that generates a force based on Hooke's law only when it was elongated. By contrast, if it was shortened, it was assumed to exert no force. The computational results revealed that the alignment of bundles of actin filaments significantly affected the cell stiffness. In addition, the passive reorientation of bundles of actin filaments perpendicular to the compression induced an increase in the resistance to the vertical elongation of a cell and thereby increased the cell stiffness. These results clearly indicated that bundles of actin filaments contribute to the compressive properties of a cell, even if they are tension-bearing components. PMID- 23026699 TI - Interactions of sulforaphane and dimethyl sulfoxide with methyl methanesulfonate, urethane, 4-nitroquinoline-1-oxide and hydrogen peroxide in the Drosophila melanogaster wing spot test. AB - Sulforaphane (SF) is an isothiocyanate present in Brassicaceae, vegetables that induce the detoxification of electrophiles and reactive oxygen species. SF has been correlated with chemoprevention mechanisms against degenerative diseases. We tested if the SF had an effect against methyl methanesulfonate (MMS), urethane (URE), 4-NQO and H(2)O(2). SF (>95% purity, 0.14, 0.28, 0.56 mM) was diluted in a DMSO/Tw80/EtOH mixture (DTE) corresponding to 25, 50, 100% of lyophilized broccoli. The SF treatment (0.14 mM) was positive for small spots in the ST cross and negative in the HB cross. In the HB cross, SF (0.28 mM) was genotoxic. In the ST cross, the SF treatments showed a tendency to reduce the genotoxic damage caused by MMS, which could be explained by the radical scavenging action of the DTE mixture. In the ST cross, the frequency of small spots in the SF 0.14 mM/URE treatment was similar to that of Water/URE, which can be explained by a DTE and SF scavenger action. In both crosses, the results for the direct oxidants, 4-NQO and H(2)O(2), were different and must be related to differential modulation of CYPs expression and the SF and DTE scavenger properties. PMID- 23026700 TI - Cassia tora (Leguminosae) seed extract alleviates high-fat diet-induced nonalcoholic fatty liver. AB - The aim of this study was to examine the effects of Cassia tora seeds on high-fat diet (HFD)-induced hepatic steatosis, and elucidate the molecular mechanisms behind its effects. After being fed a HFD for two weeks, rats were orally dosed with Cassia seed ethanol extract (CSEE) (100, 200, or 300mg/kg) once daily for 8weeks. CSEE induced dose-dependent reductions in plasma lipid levels, as well as decreased the over hepatic lipid accumulation. Furthermore, CSEE treatment improved HFD-induced hepatic histological lesions. CSEE enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated the gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in the livers of HFD-fed rats. AMPK inhibition by compound C retarded CSEE-induced reduction in triglyceride accumulation in HepG2 cells stimulated by insulin. Our findings suggest that CSEE may regulate hepatic lipid homeostasis related with an AMPK dependent signaling pathway. Targeting AMPK activation with CSEE may represent a promising approach for the prevention and treatment of obesity-related non alcoholic fatty liver disease. PMID- 23026701 TI - [Groenouw type II macular corneal dystrophy: case report]. AB - Corneal dystrophies are relatively rare diseases of the young adult. We report a case of a Groenouw type II macular corneal dystrophy. A 34-year-old woman with no prior history was referred by her ophthalmologist for bilateral corneal dystrophy developing for several years. Physical examination revealed decreased visual acuity related to bilateral rounded corneal deposits. The patient underwent penetrating keratoplasty. The diagnosis of Groenouw type II macular corneal dystrophy was confirmed by pathological examination of the recipient cornea. The clinical, pathologic and therapeutic features are discussed. PMID- 23026702 TI - Histological survey of symbionts and other conditions of pod razor clam Ensis siliqua (Linnaeus, 1758) in Galicia (NW Spain). AB - The aim of the present study was to carry out a survey of parasites and other conditions affecting pod razor clam populations, Ensis siliqua, in two beds from Galicia (NW Spain). In Galicia, the production of E. siliqua has increased in recent years due to the development of specific plans for its exploitation, however few and quite recent pathological studies have been carried out in this species. The results of this study showed the presence of different protozoa as the more prevalent group, especially Nematopsis sp. gregarines, unidentified branchial protozoa, renal coccidia and Trichodina sp. ciliates. Larval stages of trematodes and neoplastic disorders were also observed with lower prevalences. Furthermore, an ultrastructural analysis of two types of unidentified basophilic inclusions, both found in the digestive gland, revealed the presence of icosahedral viral particles and prokaryotic organisms, respectively. None of the parasites detected in E. siliqua from this study was notifiable to the World Organisation for Animal Health (OIE) and the majority of the symbionts and conditions observed in their tissues did not cause host damage. Nevertheless, parasites like bucephalid digenean sporocysts, viral inclusions, prokaryotic infections, disseminated neoplasm or germinoma detected in some samples could cause moderate or severe damage to the host depending on the intensity of infection. PMID- 23026703 TI - Silkworm plasmatocytes are more resistant than other hemocyte morphotypes to Bombyx mori nucleopolyhedrovirus infection. AB - Differences in the viral susceptibility of multiple insect hemocyte morphotypes have not been investigated to date. In this study, a Bombyx mori nucleopolyhedrovirus (BmNPV) derivative possessing a Drosophila hsp70 promoter driven green fluorescent protein (GFP) gene was used to observe NPV tropism of B. mori larval hemocytes. The experiments clearly revealed that there were fewer GFP positive plasmatocytes than those observed in other types of hemocytes, such as granulocytes, oenocytoids, and spherulocytes, when infected via the intrahemocoelic or oral route. Our results indicate that silkworm plasmatocytes are more resistant than other hemocyte morphotypes to BmNPV infection. PMID- 23026704 TI - Is amyotrophic lateral sclerosis a primary astrocytic disease? AB - Amyotrophic lateral sclerosis (ALS) is thought to be due to primary involvement of motor neurons. Pathogenic mechanisms underlying its appearance are relatively well known and include inflammation, excitotoxicity, oxidative stress, endoplasmic reticulum stress, protein damage, genetic abnormalities and type of neuronal death. Although these processes have been investigated in detail in the past two decades none of them appear to be the cause of the illness. In addition several possible environmental agents have been investigated but the results, in every case, were conflicting and therefore inconclusive. However, since the motor neurons display the features of apoptosis in this illness, the possibility remains that the motor neurons die because of a hostile environment, one that is unable to sustain their health, rather than being directly targeted themselves. The above considerations lead to an examination of astrocytes, for these cells play a key role in controlling the environment of neurons. It is known that astrocytes are exquisitely plastic, adapting their metabolism and behaviour to the needs of the neurons they contact. Each population of astrocytes is therefore unique and, were one to be adversely affected at the start of a disease process, the consequences would extend to the neurons that it normally chaperoned. The disturbed relationship might involve inappropriate production and secretion of astrocytic neurotransmitters, defective transport of glutamate and impaired trophic and metabolic support of the motor neurons. In order to explain the spread of weakness and pyramidal signs in ALS patients, which is very often from one group of muscles to a neighbouring one, it is postulated that, within the spinal cord, the brainstem and the motor cortex, the disease-causing process is also spreading-in this case, from one group of astrocytes to its neighbours. A misfolded protein, possibly a prion-like protein, would be a candidate for this type of transmission. PMID- 23026705 TI - Leptin - a novel pharmacological agent for treatment of women with overactive bladder symptoms? AB - Overactive bladder is a common condition and is significantly known to affect quality of life in both men and women. It is usually associated with urinary urgency, frequency, nocturia with or without urinary incontinence. The exact aetiology of overactive bladder is unknown. The two main theories put forward include (a) disruption of central control of the bladder by excessive suprapontine excitation or reduced suprapontine inhibition (b) Peripheral abnormality due to excessive cholinergic excitation (increases release of acetylcholine which is calcium dependent) or reduced neuropeptidergic inhibition. The other factors which contribute to its cause include increase in caffeine intake and behavioural problems. Therefore the initial treatments are based on excluding pathology and implementing behavioural changes, bladder training and caffeine reduction. Anticholinergic drugs are the main pharmacological agents used in the treatment of overactive bladder and they are usually used in conjunction with the above treatment methods. Recently, an increase in serum leptin levels has been associated with overactive bladder symptoms. This possibly is not true because leptin actually reduces Ca2+ influx in the smooth muscle. The addition of increasing doses of leptin on uterine smooth muscle (in vitro) has shown to inhibit spontaneous as well as induced uterine contractions (myometrial biopsies taken from obese women) by reducing Ca2+ influx in obese women compared to normal weight women. We believe it may have similar action on the bladder and therefore expect inhibition of the bladder detrusor smooth muscle contraction rather than stimulation which may lead to overactive bladder symptoms. This action can be considered anticholinergic rather than cholinergic and therefore should improve overactive bladder symptoms. So could this hormone (leptin) be used as a new novel agent for treating women suffering with overactive bladder symptoms? PMID- 23026707 TI - Factors modifying transcriptional regulation of signaling genes have putative role in tumor development and progression in humans. AB - Genes involved in signaling are highly regulated at the level of transcription. Several factors have been known to play role in transcriptional modification of genes. Among these DNA sequence variations present in the regulatory region and aberrant methylation of CpG Iceland in promoter region are the most important factors modifying transcriptional regulation of genes. DNA sequence variation interferes with assembling of regulatory protein TF (transcription factor) on the cis elements TFBS (transcription factor binding site). Presence of variations in regulatory region may alter the level of gene product via interaction of TF to TFBS (transcriptional modification). Promoter hypermethylation causes gene silencing and responsible for transcriptional dysregulation of gene. JAK-1, STAT 3, IL-6, MAPK and AR genes participate in signaling pathway and are tightly regulated. Overexpression of IL-6 and activated STAT3 may contribute to the development of prostate cancer and possibly other human cancers. Indeed, constitutively activated STAT3 have been found in a growing number of human tumors. In the present work, we have predicted 34 regulatory polymorphisms that lies in TFBS of 5 (JAK-1, STAT-3, IL-6, MAPK and AR) signaling genes and compare the methylation of CpG Iceland in promoter region of above motioned genes. On the basis of these predictions, it has been hypothesized that transcriptional modification of gene resulting from the DNA sequence variations in regulatory region or promoter hypermethylation increases the susceptibility to diseases such as cancer by alteration in the level of signaling genes product. Presence of DNA sequence variations may also influence the response to a particular drug. PMID- 23026706 TI - Systemic and local ACTH produced during inflammatory states promotes osteochondrogenic mesenchymal cell differentiation contributing to the pathologic progression of calcified atherosclerosis. AB - There are many well-known roles for the proopiomelanocortin (POMC) derived peptides and their receptors, the melanocortin receptors (MC-R). The focus here is on the evolving role of the melanocortin system in inflammation. Chronic inflammatory states such as those occurring in diabetes and obesity are associated with both a hyperactive hypothalamic-pituitary-adrenal (HPA) axis as well as increased incidence of atherosclerosis. An inflammation-induced hyperactive HPA axis along with increased leukocyte infiltration can lead to significant exposure to melanocortin peptides, particularly ACTH, in an inflamed vasculature. Mesenchymal progenitor cells are present throughout the vasculature, express receptors for the melanocortin peptides, and respond to ACTH with increased osteochondrogenic differentiation. Coupled to the increased exposure to ACTH during HPA hyperactivity is increased glucocorticoid (GC) exposure. GCs also promote chondrogenic differentiation of mesenchymal progenitors and increase their expression of MC-R as well as their expression of POMC and its cleavage products. It is hypothesized that during inflammatory states systemically produced ACTH and glucocorticoid as well as ACTH produced locally by macrophage and other immune cells, can influence and potentiate mesenchymal progenitor cell differentiation along the osteochondrogenic lineages. In turn the increase in osteochondrogenic matrix contributes to the pathophysiological progression of the calcified atherosclerotic plaque. The roles of the melanocortin system in inflammation and its resolution have just begun to be explored. Investigations into the ACTH-induced matrix changes among mesenchymal cell populations are warranted. ACTH signaling through the MC-R represents a new therapeutic target for the prevention and treatment of calcified atherosclerosis. PMID- 23026708 TI - Gadolinium chelate with DO3A conjugated 2-(diphenylphosphoryl) ethyldiphenylphosphonium cation as potential tumor-selective MRI contrast agent. AB - A series of organic cations, such as triphenylphosphonium (TPP), 2 (diphenylphosphoryl)-ethyldiphenylphosphonium (TPEP), represent molecular probes for imaging tumors. These organic cations have been labeled with 64Cu radioisotope for imaging tumors by positron emission tomograghy (PET). Among these organic cation ligands, TPEP was selected for extensive evaluation using magnetic resonance imaging (MRI) based on its higher tumor uptake and better Tumor/Background (T/B) ratios. This report presents the development of a new Gd(III) chelate [Gd(DO3A-xy-TPEP)]+ as a cationic MRI contrast agent. The contrast agent was synthesized and characterized in vitro and in vivo. In vitro cell viability showed low cytotoxicity at low [Gd] concentrations. Cell uptake experiment shows that the [Gd(DO3A-xy-TPEP)]+ has high affinity for tumor cells. The in vitro T1 relaxivity measured at 9.4 T is about 50% higher than those of contrast agents in clinical use: Gd-DTPA (Magnevist) and Gd-DOTA (Dotarem). In vivo imaging studies in tumor-bearing mice at 7.0 T demonstrated significant signal enhancement at the site of the tumors. [Gd(DO3A-xy-TPEP)]+ is a promising tumor-targeting MRI contrast agent for diagnostic imaging. PMID- 23026709 TI - Controlled delivery of recombinant adeno-associated virus serotype 2 using pH sensitive poly(ethylene glycol)-poly-L-histidine hydrogels. AB - Loading of viral vectors in synthetic polymers is a promising strategy for overcoming hurdles associated with viral gene delivery. For enhanced gene expression at a specific site, gene transfer by using hydrogels represents a versatile approach. In this study, adeno-associated virus serotype 2 containing the green fluorescent protein gene (rAAV2-GFP) were loaded into poly(ethylene glycol) (PEG) hydrogels, with and without incorporation of poly-L-hisditine (polyHis). Inclusion of polyHis created pH responsive hydrogels in a physiological range of tissues, containing the damaged vasculature and activated phagocytosis. The fraction of polyHis used controlled the degree of swelling, water uptake and subsequent degradation of the hydrogels and release rate of rAAV2-GFP. The swelling ratio of the PEG-polyHis hydrogels increased inversely with environment pH. As pH declined from 7.4 to 6.0, PEG-polyHis hydrogel swelling ratio and degradation rate increased 875% and 135%, respectively. As a result, release and transduction efficiency of the rAAV2-GFP from PEG-polyHis hydrogel in human HT-1080 fibrosarcoma cells increased significantly compared to a PEG hydrogel. Transduction rate can be controlled by the hydrogels' polyHis concentration and is sensitive to localized decreases in pH consistent with inflammation. This is relevant to optimizing parameters for wound care and regenerative medicine applications. PMID- 23026710 TI - Stereocontrolled synthesis of four diastereomeric C-aryl manno- and talofuranosides. AB - In a chiral-pool synthesis starting from D-mannono-1,4-lactone 1a, the four diastereomeric C-aryl furanosides (1S,4R)-4a, (1S,4S)-4b, (1R,4R)-4c, and (1R,4S) 4d were obtained in a stereocontrolled manner. The key steps of the synthetic pathway comprise a stereoselective reduction of the diastereomeric hemiketals (4R)-2a and (4S)-2b as well as a stereospecific cycloetherification of the resulting diols (1R,4R)-5a, (1S,4R)-5c, and (1S,4S)-5d. This ring closure which led to the desired C-glycosides was achieved by a Mitsunobu reaction or by preparing the 1-O-benzoyl-4-O-methylsulfonyl derivative 7 which was then treated with sodium methoxide. Final hydrolysis of the 5,6-O-isopropylidene protecting group led to the diastereomeric diols (1S,4R)-4a, (1S,4S)-4b, (1R,4R)-4c, and (1R,4S)-4d, representing versatile building blocks for further synthetic transformations. PMID- 23026711 TI - Biochemical characterization of a recombinant plant class III chitinase from the pitcher of the carnivorous plant Nepenthes alata. AB - A class III chitinase belonging to the GH18 family from Nepenthes alata (NaCHIT3) was expressed in Escherichia coli. The enzyme exhibited hydrolytic activity toward colloidal chitin, ethylene glycol chitin, and (GlcNAc)(n) (n=5 and 6). The enzyme hydrolyzed the fourth glycosidic linkage from the non-reducing end of (GlcNAc)(6). The anomeric form of the products indicated it was a retaining enzyme. The colloidal chitin hydrolytic reaction displayed high activity between pH 3.9 and 6.9, but the pH optimum of the (GlcNAc)(6) hydrolytic reaction was 3.9 at 37 degrees C. The optimal temperature for activity was 65 degrees C in 50 mM sodium acetate buffer (pH 3.9). The pH optima of NaCHIT3 and NaCHIT1 might be related to their roles in chitin degradation in the pitcher fluid. PMID- 23026712 TI - Methylation dependent enhancement of trehalose production in Candida utilis. AB - Trehalose metabolism plays a central role in various stress responses in yeasts. Methylation dependant enhancement of trehalose synthesis has been reported from yeast Saccharomyces cerevisiae. In order to establish the role of methylation on trehalose metabolism in yeast, it was further investigated in Candida utilis. Universal methyl group donor, S-adenosyl-l-methionine (AdoMet) and its inhibitor, oxidized adenosine (Adox) were used to study the effect of methylation on trehalose metabolism in C. utilis. Treatment of early stationary phase cells of C. utilis with AdoMet and Adox exhibited increase in both intracellular metabolite levels and activities of the trehalose synthesizing enzymes, trehalose 6-phosphate synthase (TPS) and trehalose phosphate phosphatase (TPP). Among the intracellular metabolites studied, trehalose levels were enhanced in presence of AdoMet which correlated with the increasing levels of trehalose synthesizing enzymes. TPS was purified in presence of AdoMet and Adox, following an established protocol reported from this laboratory. Differences in the mobility of control TPS, methylated TPS, and methylation-inhibited TPS during acidic native gel electrophoresis confirmed the occurrence of induced methylation. MALDI TOF analysis of trypsin-digested samples of the same further strengthened the presence of methylation in TPS. The data presented in this paper strongly indicate a positive role of methylation on trehalose synthesis which finally leads to enhanced trehalose production during the stationary growth phase of C. utilis. PMID- 23026713 TI - Conformational behavior of peracetylated beta-D-mannopyranosyl methanesulfonamide: implications for the mechanism of sulfonamidoglycosylation of carbohydrate derivatives. AB - The conformational behavior of 2,3,4,6-tetra-O-acetyl-beta-D-mannopyranosyl methanesulfonamide has been investigated from a combined theoretical and experimental point of view. The study of the conformational space of the glycosyl sulfonamide revealed that the beta anomer is thermodynamically more stable than the alpha one. This fact suggests that the synthesis reaction could take place mainly under thermodynamic control as the main experimental product is the beta anomeric form of the sulfonamide. Several intramolecular hydrogen bonds were found in the stable conformers of the N-mannopyranosyl sulfonamide under study. A relationship was found to exist between them and the relative stability of the conformers. A detailed analysis of geometrical parameters shed light into the nature of the solid state structure of the novel 2,3,4,6-tetra-O-acetyl-beta-D mannopyranosyl methanesulfonamide in terms of exo- and endo-anomeric effects and antiperiplanar relationships. NBO calculations confirmed those findings. Calculated (1)H and (13)C NMR chemical shifts support previous findings concerning configuration and conformation assignments of the title sulfonamide. Finally, an explanation of the stereochemical outcome of sulfonamidoglycosylations, was given in terms of exo- and endo-anomeric effects and steric factors. PMID- 23026714 TI - Study of carbohydrate-protein interactions using glyco-QDs with different fluorescence emission wavelengths. AB - QDs with different fluorescence emission wavelengths were coated with galactose, glucose, and lactose respectively. The formulas of glyco-QDs were determined by NMR and ICP-OES, and the interactions between glyco-QDs and PNA lectin were investigated by SPR. The results showed that multivalent presentation achieved by using QDs as the scaffold is an effective way to enhance the carbohydrate-protein interactions. The K(D) for the interaction of PNA with multivalent glyco-QDs is over 3 * 10(6)-fold lower than those with the same free sugars. The specific recognition for the sugar coated on the QDs by lectin is maintained. These sugar coated QDs could be used as a fluorescent probe to label and identify glycoproteins. PMID- 23026715 TI - Schmallenberg virus: responding to the challenge. PMID- 23026716 TI - The challenge of Schmallenberg virus emergence in Europe. AB - The large-scale outbreak of disease across Northern Europe caused by a new orthobunyavirus known as Schmallenberg virus has caused considerable disruption to lambing and calving. Although advances in technology and collaboration between veterinary diagnostic and research institutes have enabled rapid identification of the causative agent and the development and deployment of tests, much remains unknown about this virus and its epidemiology that make predictions of its future impact difficult to assess. This review outlines current knowledge of the virus, drawing comparisons with related viruses, then explores possible scenarios of its impact in the near future, and highlights some of the urgent research questions that need to be addressed to allow the development of appropriate control strategies. PMID- 23026717 TI - Socially disadvantaged parents of children treated with allogeneic haematopoietic stem cell transplantation (HSCT): report from a supportive intervention study, Denmark. AB - PURPOSE: This study was undertaken to test a daily Family Navigator Nurse (FNN) conducted intervention program, to support parents during the distressful experience of their child's Allogeneic Haematopoietic Stem Cell Transplantation (HSCT). METHODS: A qualitative analysis of the supportive intervention program for parents whose child is under HSCT treatment while hospitalized. Parents to 25 children were included in the intervention group. Twenty-five parents were included in a participant observational study and 21 of these completed a semi structured interview 100 days following HSCT. RESULTS: Three main problems faced by all parents included 1) the emotional strain of the child's HSCT; 2) re organizing of the family's daily life to include hospitalization with the child; and 3) the financial strain of manoeuvring within the Danish welfare system. The FNN performed daily intervention rounds to ease each of these problems during the study period. Having the following pre-existing risk factors, negatively influenced the parents' ability to address these problems: 1) being a single parents; 2) low-level income; 3) low-level education; 4) low-level network support: 5) being a student or unemployed; 6) physical/psychiatric illness; and 7) ethnicity. Six families with 4 or more risk factors had complex emotional, social and financial problems that required extensive intervention by the FNN and that impacted their ability to provide care for the child. CONCLUSION: The parents' pre-existing risk factors were further complicated by their children's HSCT. A recommendation for clinical practice is to identify families with multiple interrelated problems and allocate resources to support these families. PMID- 23026718 TI - Comparison between intestinal and non-mucosal immune functions of rainbow trout, Oncorhynchus mykiss. AB - Since mucosal surfaces represent major portals of entry for pathogens, its associated immune system is important to protect the organism. In this paper, we compared at the cellular and molecular levels intestinal leukocyte suspensions with their head kidney (HK) or peripheral blood (PBL) counterparts to highlight characteristics of intestinal immune functions in healthy rainbow trout. These studies show that intestinal phagocytes are less activated by yeast cells but when they are activated they can ingest as many yeast cells as their HK counterparts. A natural cytotoxic activity could be detected which is twice higher in intestinal than in HK leukocyte preparations. This natural cytotoxic activity is correlated with the expression of transcripts encoding the natural killer enhancement factor (NKEF). Intestinal leukocytes did not respond to an in vitro mitogenic stimulation performed under classical culture conditions. And finally, a high expression of CD8alpha transcripts was observed in gut leukocyte preparations, suggesting that the intestine could contain a high proportion of T cells expressing the alphaalpha homodimeric form of CD8. This kind of comparison on nonimmunized fish provides better knowledge on basal immune functions in the intestine to, analyze later on, immune responses induced by an antigenic stimulation. PMID- 23026719 TI - Structure and partial protein profiles of the peritrophic membrane (PM) from the gut of the shrimp Litopenaeus vannamei. AB - Peritrophic membrane (PM) is a non-cellular structure surrounding the food bolus in invertebrate's midgut. In this study, the shrimp Litopenaeus vannamei was found continuously secreting a tube-like PM enclosing the fecal pellets. The PM structure was membranous in this penaeid shrimp which was similar to that in Sicyonia ingentis studied and was primarily composed of chitin and proteins. Chitin was detected along the whole PM. By using the approach of gel electrophoresis and mass spectrometry of tryptic peptides, the most extracted proteins from the shrimp PMs were identified mainly including digestion-related, immune-related, antioxidant proteins and proteins related to PM structure. This suggests that PM may participate in modulating its permeability and immobilizating the digestive enzymes, actively protect the gut from pathogen contact, and play an important role in the gut immune system. PMID- 23026720 TI - [Nutritional assessment with Mini Nutritional Assessment]. PMID- 23026721 TI - [Flecainide intoxication]. PMID- 23026722 TI - [Ramsay Hunt syndrome]. PMID- 23026723 TI - [Pyoderma gangrenosum mimicking surgical wound infection]. PMID- 23026724 TI - Phenotypic models of evolution and development: geometry as destiny. AB - Quantitative models of development that consider all relevant genes typically are difficult to fit to embryonic data alone and have many redundant parameters. Computational evolution supplies models of phenotype with relatively few variables and parameters that allows the patterning dynamics to be reduced to a geometrical picture for how the state of a cell moves. The clock and wavefront model, that defines the phenotype of somitogenesis, can be represented as a sequence of two discrete dynamical transitions (bifurcations). The expression time to space map for Hox genes and the posterior dominance rule are phenotypes that naturally follow from computational evolution without considering the genetics of Hox regulation. PMID- 23026725 TI - Infiltrative hepatocellular carcinoma: comparison of MRI sequences for lesion conspicuity. AB - AIM: To characterize the magnetic resonance imaging (MRI) features of infiltrative hepatocellular carcinoma (I-HCC), with emphasis on its relative conspicuity on different sequences. MATERIALS AND METHODS: Nineteen patients exhibiting HCC with non-mass-like appearance and ill-defined margins, and who died within 1 year following diagnosis of I-HCC, were included. For each sequence, two observers independently assessed the lesion's signal intensity relative to benign liver as well as subjective visual conspicuity. The observers also selected the sequence exhibiting the greatest visual conspicuity. A separate radiologist placed regions of interest to measure tumour-to-liver contrast for each lesion. Tumour size and clinical features were also assessed. RESULTS: Eighteen of the 19 patients exhibited central portal vein tumour thrombus; eight of the 19 patients had metastatic disease. All I-HCC measured over 5 cm. The two observers identified hyperintensity on T2-weighted imaging (WI) in 19 and 19 cases, hyperintensity on high b-value diffusion-weighted imaging (DWI) in 18 and 19 cases, arterial-phase hyperintensity in six and 10 cases, and venous-phase hypo-intensity in 17 and 16 cases. T2WI, DWI, and venous-phase images exhibited significantly greater subjective visual conspicuity than arterial-phase images for both observers (all p <= 0.040). Also, T2WI and DWI tended to exhibit greater tumour-to-liver contrast than arterial- and venous-phase images (all p <= 0.055). The arterial-phase was not selected as having greatest conspicuity for any case by either reader. CONCLUSION: I-HCC is an aggressive form of HCC that is often less conspicuous on arterial-phase images than typical mass-forming HCC; T2WI and DWI may be more useful sequences for its diagnosis. Awareness of the distinct imaging features of I-HCC may be important for proper diagnosis. PMID- 23026726 TI - Autologous chondrocyte implantation for traumatic full-thickness cartilage defects of the knee in 14 patients: 6-year functional outcomes. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) was introduced in 1987 in Sweden by Brittberg and Peterson for the treatment of severe chondral defects of the knee. Here, our objective was to evaluate mid-term outcomes of ACI in young athletic patients with deep chondral defects of the knee after trauma. HYPOTHESIS: ACI is effective in filling full-thickness chondral defects of the knee. PATIENTS AND METHODS: We prospectively monitored 14 patients, with International Cartilage Repair Society grade III or IV lesions, who underwent ACI between 2001 and 2006. Standard evaluation measurements were used. Mean age at surgery was 37.7 years (range, 30-45). A history of surgery on the same knee was noted in ten (67%) patients. The defect was on the medial femoral condyle in 11 patients, lateral femoral condyle in two patients, and both femoral condyles in one patient. Mean defect surface area after debridement was 2.1cm(2) (1-6.3). RESULTS: After a mean follow-up of six years, improvements were noted in 12 (86%) patients, with an International Knee Documentation Committee (IKDC) score increase from 40 (27.6-65.5) to 60.2 (35.6-89.6) (P=0.003) and a Brittberg Perterson score decrease from 54.4 (11.8-98.2) to 32.9 (0-83.9) (P=0.02), between the preoperative assessment and last follow-up. The visual analogic scale pain score decreased from 66.3 (44-89) to 23.2 (0-77) (P=0.0006). In two (14%) patients, no improvements were detectable at last follow-up. The remaining 12 patients were satisfied and able to resume sporting activities, albeit at a less strenuous level. Two ACI-specific complications occurred, namely, periosteal hypertrophy treated with debridement in one patient and transplant delamination in another. DISCUSSION: Our findings are consistent with previous reports but cover a longer follow-up period. Although the outcomes are promising, longer follow-ups are needed to confirm the long-term effectiveness of ACI. LEVEL OF EVIDENCE: IV, prospective therapeutic study. PMID- 23026727 TI - Femur malunion treated with open osteotomy and intramedullary nailing in developing countries. AB - INTRODUCTION: In developing countries, malunion, after diaphyseal femur fractures initially untreated by internal fixation, is not rare. Their difficult management contrasts with the deficiency of the technical operating room facilities. PATIENTS AND METHODS: Our prospective study, conducted over a 1-year period, reports 16 open osteotomies fixed using Kuntscher intramedullary nailing in patients who presented malunion of the femoral diaphysis. Twelve males and four females (mean age, 34.5 years; range, 18-67 years) were managed with a mean time to surgery of 8 months (range, 4-14 months). All had initially consulted a bonesetter. The mean length inequality was 3 cm (range, 2-6 cm); the mean knee flexion limitation was 90 degrees (range, 10 degrees -120 degrees ). Locking of the rotation was obtained by the obliquity of the osteotomy line. No bone filling was added but reaming and decortications were systematic. The patients were clinically and radiographically assessed at D21, D45, D90, and D120, based on the evaluation of the length inequality, mobility, and bone union. Rotational malunion or deformity were not analyzed. RESULTS: Fifteen patients had achieved union in 90 days. In one case, secondary incurvation of the nail led to changing the nail, allowing union with no axis deformity at D120. The mean postoperative knee flexion was 120 degrees (range, 45 degrees -130 degrees ). The mean gain in length was 2 cm (range, 1.5-4 cm). DISCUSSION: This open technique using non interlocking material allowed us to obtain bone union while improving joint mobility and length inequality. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 23026729 TI - Small intestine mucosal adhesivity to in vivo capsule robot materials. AB - Multiple research groups are investigating the feasibility of miniature, swallowable, in vivo, untethered robots that are capable of traversing the small intestine for the purpose of acquiring biometrics and performing simple surgical procedures. A mathematical model of the intraluminal environment will speed the development of these so-called Robotic Capsule Endoscopes (RCEs), and to this end, the authors, in previous work, initiated a comprehensive program for characterizing both the active and passive forces exerted by the small intestine on an RCE-sized solid bolus. In this work, forces due to adhesivity between RCE materials and the mucosa are investigated. The experimental factors are adhesive modality (peel and tack), material (polycarbonate, micropatterned polydimethylsiloxane, stainless steel, and mucosa), and bowel region (proximal, middle, and distal). The mucosa is excised from a fasting pig, stored in lactated ringer's solution at 3 degrees C, and then tested at room temperature within 43 h of excision. The results show the mean tack strength of the mucosa to engineering materials was 0.198+/-0.070 mJ cm-2. The mean peel strength was 0.055+/-0.016 mJ cm-2. This study marks the first time, to the authors' knowledge, that adhesivity between small intestinal mucosa and RCE engineering materials has been measured. The adhesivity values acquired from this study will provide a valuable input into analytical and numerical models of the gastrointestinal tract, specifically models that account for the interfacial properties of the tissue. PMID- 23026728 TI - Decoding myocardial Ca2+ signals across multiple spatial scales: a role for sensitivity analysis. AB - Numerous studies have employed mathematical modeling to quantitatively understand release of Ca(2+) from the sarcoplasmic reticulum (SR) in the heart. Models have been used to investigate physiologically important phenomena such as triggering of SR Ca(2+) release by Ca(2+) entry across the cell membrane and spontaneous leak of Ca(2+) from the SR in quiescent heart cells. In this review we summarize studies that have modeled myocardial Ca(2+) at different spatial scales: the sub cellular level, the cellular level, and the multicellular level. We discuss each category of models from the standpoint of parameter sensitivity analysis, a common simulation procedure that can generate quantitative, comprehensive predictions about how changes in conditions influence model output. We propose that this is a useful perspective for conceptualizing models, in part because a sensitivity analysis requires the investigator to define the relevant parameters and model outputs. This procedure therefore helps to illustrate the capabilities and limitations of each model. We further suggest that in future studies, sensitivity analyses will aid in simplifying complex models and in suggesting experiments to differentiate between competing models built with different assumptions. We conclude with a discussion of unresolved questions that are likely to be addressed over the next several years. PMID- 23026730 TI - Mechanical behaviour of pressed and sintered titanium alloys obtained from master alloy addition powders. AB - The fabrication of the workhorse Ti-6Al-4V alloy and of the Ti-3Al-2.5V alloy was studied considering the master alloy addition variant of the blending elemental approach conventionally used for titanium powder metallurgy. The powders were characterised by means thermal analysis and X-ray diffraction and shaped by means of uniaxial pressing. The microstructural evolution with the sintering temperature (900-1400 degrees C) was evaluated by SEM and EDS was used to study the composition. XRD patterns as well as the density by Archimedes method were also obtained. The results indicate that master alloy addition is a suitable way to fabricate well developed titanium alloy but also to produce alloy with the desired composition, not available commercially. Density of 4.3 g/cm3 can be obtained where a temperature higher than 1200 degrees C is needed for the complete diffusion of the alloying elements. Flexural properties comparable to those specified for wrought Ti-6Al-4V medical devices are, generally, obtained. PMID- 23026731 TI - Computational modeling and stress analysis of columellar biomechanics. AB - The open approach for rhinoplasty offers excellent exposure of the various components of the nose in situ. The biggest advantage of the external approach is the complete anatomic exposure, which allows the surgeon to inspect the osteo cartilagineous framework, while the biggest disadvantage is represented by the transcolumellar scar. The goal of this study is to numerically quantify the stress induced on the scar of a human columella by a constant load, through a fine tuned finite elasticity continuum model. Specifically we want to determine the best shape of incision which would minimize this stress. The columellar portion of the nose, together with the various constituting tissues, has been modeled in a first approximation as a hyperelastic body and seven types of scars have been studied. The determination of the best incision must be a compromise among different factors: shape and size primarily, but also position with respect to the internal structures and external loads. From this point of view, the best class of scar appears to be, both at simulated and real levels, the V-shaped one, inducing a maximum logarithmic von Mises stress in tissue of 4.67 Pa, and an absolute minimum stress distribution on the scar of 4.17 Pa. Numerical simulations appear to be in agreement with the evidence-based results coming from surgical practice, thus confirming the necessity to minimize local stresses on the tissue. A parameters' sensitivity analysis further highlighted our optimal choice. The proposed mathematical model can be applied both to theoretically designed and numerically verified new non-conventional scar geometries. PMID- 23026732 TI - GRBAS and Cape-V scales: high reliability and consensus when applied at different times. AB - OBJECTIVES: To evaluate whether the overall dysphonia grade, roughness, breathiness, asthenia, and strain (GRBAS) scale, and the Consensus Auditory Perceptual Evaluation-Voice (CAPE-V) scale show the same reliability and consensus when applied to the same vocal sample at different times. STUDY DESIGN: Observational cross-sectional study. METHODS: Sixty subjects had their voices recorded according to the tasks proposed in the CAPE-V scale. Vowels /a/ and /i/ were sustained between 3 and 5 seconds. Reproduction of six sentences and spontaneous speech from the request "Tell me about your voice" were analyzed. For the analysis of the GRBAS scale, the sustained vowel and reading tasks of the sentences was used. Auditory-perceptual voice analyses were conducted by three expert speech therapists with more than 5 years of experience and familiar with both the scales. RESULTS: A strong correlation was observed in the intrajudge consensus analysis, both for the GRBAS scale as well as for CAPE-V, with intraclass coefficient values ranging from 0.923 to 0.985. A high degree of correlation between the general GRBAS and CAPE-V grades (coefficient=0.842) was observed, with similarities in the grades of dysphonia distribution in both scales. The evaluators indicated a mild difficulty in applying the GRBAS scale and low to mild difficulty in applying the CAPE-V scale. The three evaluators agreed when indicating the GRBAS scale as the fastest and the CAPE-V scale as the most sensitive, especially for detecting small changes in voice. CONCLUSIONS: The two scales are reliable and are indicated for use in analyzing voice quality. PMID- 23026734 TI - Editorial comment: Adenosine in heart transplants: have we finally found the good indication? PMID- 23026733 TI - Multi-walled carbon nanotube directed gene and protein expression in cultured human aortic endothelial cells is influenced by suspension medium. AB - The use and production of multi-walled carbon nanotubes (MWCNTs) have significantly increased over the last decade due to their versatility in numerous applications. Their unique physical and chemical properties make them desirable for various biomedical applications, but the same properties also raise concerns about their safety to human health, particularly at the cellular level. The vascular endothelium could be exposed to nanomaterials either by direct intravenous administration in nanomedicine or by translocation following inhalational exposure in an occupational setting. We hypothesized that direct exposure to MWCNTs will increase the expression of inflammatory markers in human aortic endothelial cells (HAEC). We also investigated the effect of the route of exposure on activation by changing the suspension medium of the MWCNTs. HAEC were treated in vitro with MWCNTs (1 or 10 MUg/cm(2)) suspended in either cell culture medium [(M)-MWCNTs] or 10% clinical grade pulmonary surfactant [(S)-MWCNTs]. The zeta potential of the (S)-MWCNTs was significantly more negative than the (M) MWCNTs suggesting a more stable suspension. Treatment of HAEC with (S)-MWCNTs; as compared to (M)-MWCNTs resulted in a significantly higher up-regulation of mRNA transcripts for cell adhesion molecules VCAM1, SELE, ICAM1 and the chemokine CCL2. Time dependent changes in VCAM1 and CCL2 protein levels were confirmed by immunofluorescence, flow cytometry and ELISA. A label free quantitative mass spectrometry proteomic analysis was utilized to compare protein expression patterns between the two suspensions of MWCNTs. We identified significant expression changes in >200 unique proteins in MWCNT treated HAEC. However, the two suspensions of MWCNTs resulted in different protein expression patterns with the eIF2 pathway as the only common pathway identified between the two suspensions. These data suggest that direct exposure to MWCNTs induces acute inflammatory and protein expression changes in HAEC, which is influenced by the type of media used for suspension of MWCNTs and their resulting zeta potential. PMID- 23026735 TI - The elephant in the room. PMID- 23026736 TI - Diagnosis of infection in paediatric veno-arterial cardiac extracorporeal membrane oxygenation: role of procalcitonin and C-reactive protein. AB - OBJECTIVES: Plasma concentration of procalcitonin (PCT) and its value in the diagnosis of infection in paediatric patients treated with extracorporeal membrane oxygenation (ECMO) are undefined. This study aimed to define the levels of PCT and C-reactive protein (CRP) in paediatric cardiac ECMO patients and to determine their role in predicting infection, severity of organ dysfunction and clinical outcome. METHODS: PCT and CRP plasma concentrations were measured daily in 20 consecutive infants and young children treated with veno-arterial ECMO. Each patient was examined daily for signs of infection and multiple organ dysfunction syndrome (MODS). A total of 139 patient days were classified for infection and MODS. RESULTS: The median PCT and CRP plasma concentrations were not increased during infection: 2.4 vs 8.8 ng/ml and 223.8 vs 240.6 mg/l, in patients with vs without infection, respectively. PCT, but not CRP, was significantly elevated during MODS (10.9 vs 1.85 ng/ml) (P = 0.001). The area under the receiver operating characteristic (ROC) curve was 0.984 for PCT (95% confidence interval [CI], 0.962-1.000) compared with 0.347 for CRP (95% CI, 0.211 0.484) (P = 0.001). Only PCT differed significantly in patients weaned from ECMO who survived (2.6 ng/ml) vs patients not weaned from ECMO (10.5 ng/ml) (P = 0.001). The area under the ROC curve was 0.871 (95% CI, 0.786-0.956) compared with 0.261 for CRP (95% CI, 0.145-0.377) (P = 0.001). CONCLUSIONS: Neither PCT nor CRP are reliable markers of infection in paediatric cardiac ECMO patients. However, high levels of PCT are associated with MODS. PCT may be used as a prognostic indicator of clinical outcome in this high-risk population. PMID- 23026737 TI - A modified protocol for retrograde cerebral perfusion: magnetic resonance spectroscopy in pigs. AB - OBJECTIVES: Retrograde cerebral perfusion (RCP) has been employed to protect the brain during cardiovascular surgery, requiring temporary hypothermic circulatory arrest (HCA). However, the protocol used for RCP remains to be modified if prolonged HCA is expected. The aim of this study was to determine the efficacy of a modified protocol for this purpose. METHODS: After establishment of HCA at 15 degrees C, 14 pigs were subjected to 90-min RCP using either the conventional protocol (i.e. alpha-stat strategy, 25-mmHg perfusion pressure and occluded inferior vena cava, Group I, n = 7) or the new protocol (i.e. pH-stat strategy, 40-mmHg perfusion pressure and unoccluded inferior vena cava, Group II, n = 7). After being rewarmed to 37 degrees C, pigs were perfused for another 60 min. Phosphorus-31 magnetic resonance spectroscopy was used to track the changes of brain high-energy phosphates [i.e. adenosine triphosphate and phosphocreatine (PCr)] and intracellular pH (pHi). At the end, brain water content was measured. RESULTS: During RCP, high-energy phosphates decreased in both groups, whereas adenosine triphosphate decreased much faster in Group I (10.4 +/- 4.3 vs 30.4 +/- 4.4% of the baseline, P = 0.007, 60-min RCP). After rewarming, the recovery of high-energy phosphates and pHi was much slower in Group I (PCr: 55.7 +/- 9.1 vs 78.4 +/- 5.1% of the baseline, P = 0.046; adenosine triphosphate: 26.6 +/- 10.6 vs 64.8 +/- 4.6% of the baseline, P = 0.007; pHi: 6.5 +/- 0.4 vs 7.1 +/- 0.1, P = 0.021 at 30-min normothermic perfusion after rewarming). Brain tissue water content was significantly higher in Group I (81.1 +/- 0.4 vs 79.5 +/- 0.4%, P = 0.016). CONCLUSIONS: Application of the modified RCP protocol significantly improved cerebral energy conservation during HCA and accelerated energy recovery after rewarming. PMID- 23026738 TI - Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document (VARC 2). AB - OBJECTIVES: The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. BACKGROUND: A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. METHODS AND RESULTS: Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. CONCLUSIONS: This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavours of applying definitions to other transcatheter valve therapies (for example, mitral valve repair). PMID- 23026740 TI - Myeloid-derived suppressor cells accumulate in the liver site after sepsis to induce immunosuppression. AB - Myeloid-derived suppressor cells (MDSCs) play a major role in modulating immune response, but only a few reports focused on MDSCs in the liver of sepsis states. Here, we investigated the changes in MDSCs in liver of the cecal ligation and puncture (CLP) mice. The results of flow cytometry showed that MDSCs accumulate in the liver site of mice after CLP for 7days (CLP7d model mice) and settled to the livers of both normal and LPS stimulated mice. In vitro experiment showed a strong suppressive effect of MDSCs on the proliferation of CD4+ T lymphocytes of spleen. Furthermore, adoptive transfer of the liver MDSCs from CLP7d miceincreased the survival rate of acute hepatic failure (AHF) model mice in vivo. In conclusion, our data suggest that sepsis-induced liver MDSCs may have exert a key role in maintaining the immune homoeostasis in liver during the sepsis state. PMID- 23026739 TI - Effect of dietary supplementation with either red wine extract or vitamin E on the volatile profile of lamb meat fed with omega-3 sources. AB - The effect of dietary supplementation with either vitamin E (300 ppm) or a red wine extract rich in polyphenols (900 ppm) in an omega-3 enriched concentrate on the volatile fraction of lamb meat was assessed. The effect of refrigerated storage (0 and 6 days) under high-oxygen atmospheres (70% O(2)/30% CO(2)) was also studied. Extraction and analysis of the volatile compounds was carried out by headspace solid-phase microextraction (HS-SPME) and GC-MS, respectively. Vitamin E supplementation led to lower levels of lipo-oxidation compounds, such as 2-heptanone and 1-penten-3-ol. The red wine extract was less efficient against lipid oxidation than vitamin E but more efficient than the control (no added antioxidants). The levels of numerous lipid-derived compounds were found to be lower after 6 days of storage which could be due to further interactions with protein-related compounds. PMID- 23026741 TI - Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases. AB - The rising median age of our population and the age-dependent risk of neurodegeneration translate to exponentially increasing numbers of afflicted individuals in the coming years. Although symptomatic treatments are available for some neurodegenerative diseases, most are only moderately efficacious and are often associated with significant side effects. The development of small molecule, disease-modifying drugs has been hindered by complex pathogenesis and a failure to clearly define the rate-limiting steps in disease progression. An alternative approach is to directly target the mutant gene product or a defined causative protein. Antisense oligonucleotides (ASOs) - with their diverse functionality, high target specificity, and relative ease of central nervous system (CNS) delivery - are uniquely positioned as potential therapies for neurological diseases. Here we review the development of ASOs for the treatment of inherited neurodegenerative diseases. PMID- 23026742 TI - Revisiting the housekeeping genes of human placental development and insufficiency syndromes. AB - Gene expression analysis using semi-quantitative RT-PCR is a common tool in placental research. However the comparison of steady-state gene transcription between different clinical groups is dependent upon comparison of target mRNA data with mRNA obtained from so-called housekeeping (HK) genes whose steady-state transcription does not differ significantly between the groups. In this communication, we evaluated the performance of candidate HK genes across nine clinical groups commonly used in placental research. We used the GeNorm method to evaluate qRT-PCR data to determine the performance of candidate HKs. PMID- 23026744 TI - Factors involved in health-related transitions after curative resection for pancreatic cancer. 10-years experience: a multi state model. AB - BACKGROUND: Pancreatic cancer is one of the least common tumours, nevertheless it is one of the most lethal. This lethality is mainly due to the fact that the vast majority of patients are diagnosed in an advanced stage. The purpose of this study was to investigate how different covariates affect the transition to death or discharge with and without complications after pancreatic resection. METHODS: We analyse the impact of different factors on transitions after pancreatic resection based on a multi state model. RESULTS: Transitions of interest include the transition to death/discharge with/without complications after pancreatic resection. We consider presence of comorbidities, higher age (>60), gender-male, lower hospital volume (<10 cases per year), type of surgery, localization of tumour and transfusion received as covariates with a potentially negative effect on the transition intensities to death with or without complications. CONCLUSIONS: The multi-state model allows for a very detailed analysis of the impact of covariates on each transition, since effects of covariates may change depending on the current state of the patient, thus helping surgeons and patients throughout the surgical process and counselling patients if needed. PMID- 23026743 TI - Neural dynamics and circuit mechanisms of decision-making. AB - In this review, I briefly summarize current neurobiological studies of decision making that bear on two general themes. The first focuses on the nature of neural representation and dynamics in a decision circuit. Experimental and computational results suggest that ramping-to-threshold in the temporal domain and trajectory of population activity in the state space represent a duality of perspectives on a decision process. Moreover, a decision circuit can display several different dynamical regimes, such as the ramping mode and the jumping mode with distinct defining properties. The second is concerned with the relationship between biologically-based mechanistic models and normative-type models. A fruitful interplay between experiments and these models at different levels of abstraction have enabled investigators to pose increasingly refined questions and gain new insights into the neural basis of decision-making. In particular, recent work on multi-alternative decisions suggests that deviations from rational models of choice behavior can be explained by established neural mechanisms. PMID- 23026745 TI - The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ. AB - Nephronophthisis (NPH) is a genetically heterogenous kidney disease and represents the most common genetic cause for end-stage renal disease in children. It is caused by the mutation of genes encoding for the nephrocystin proteins (NPHPs) which localize to primary cilia or centrosomes, classifying this disease as a 'ciliopathy'. Recently, it has been shown that NPHP4 acts as a potent negative regulator of mammalian Hippo signalling by interacting with the Lats protein kinase and controlling the phosphorylation of the oncogenic transcriptional activator TAZ. Here, we demonstrate that NPHP9, another NPH family member, also controls TAZ activity by a distinct mechanism. NPHP9, which is also called NEK8, directly interacted with TAZ and induced nuclear translocation of the TAZ/NPHP9 protein complex. Binding of NPHP9 to TAZ was enhanced in a TAZ mutant that lost its ability to bind 14-3-3, suggesting that 14 3-3 and NPHP9 may compete for TAZ binding, with 14-3-3 favouring cytoplasmic retention and NPHP9 mediating nuclear delivery. Consistently, co-expression of NPHP4, which inhibits TAZ phosphorylation at the 14-3-3 binding site through the inhibition of Lats kinase activity, induced efficient nuclear delivery of the TAZ/NPHP9 protein pair. Consistent with a role for TAZ in controlling proliferation and tumorigenesis, the downregulation of NPHP9 inhibited the TAZ dependent proliferation of hippo-responsive normal epithelial and also breast cancer cells. As NPHP9 has been shown to be upregulated in breast cancer, these data do not only support a critical role for TAZ/hippo signalling in the pathogenesis of NPH but may also imply a possible role for NPHP9 in TAZ-mediated tumorigenesis. PMID- 23026746 TI - Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis. AB - A common cause of amyotrophic lateral sclerosis (ALS) is mutations in the gene encoding superoxide dismutase-1. There is evolving circumstantial evidence that the wild-type protein can also be neurotoxic and that it may more generally be involved in the pathogenesis of ALS. To test this proposition more directly, we generated mice that express wild-type human superoxide dismutase-1 at a rate close to that of mutant superoxide dismutase-1 in the commonly studied G93A transgenic model. These mice developed an ALS-like syndrome and became terminally ill after around 370 days. The loss of spinal ventral neurons was similar to that in the G93A and other mutant superoxide dismutase-1 models, and large amounts of aggregated superoxide dismutase-1 were found in spinal cords, but also in the brain. The findings show that wild-type human superoxide dismutase-1 has the ability to cause ALS in mice, and they support the hypothesis of a more general involvement of the protein in the disease in humans. PMID- 23026747 TI - The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia. AB - Hedgehog (Hh) signaling is involved in patterning and morphogenesis of most organs in the developing mammalian embryo. Despite many advances in understanding core components of the pathway, little is known about how the activity of the Hh pathway is adjusted in organ- and tissue-specific developmental processes. Mutations in EVC or EVC2 disrupt Hh signaling in tooth and bone development. Using mouse models, we show here that Evc and Evc2 are mutually required for localizing to primary cilia and also for maintaining their normal protein levels. Consistent with Evc and Evc2 functioning as a complex, the skeletal phenotypes in either single or double homozygous mutant mice are virtually indistinguishable. Smo translocation to the cilium was normal in Evc2-deficient chondrocytes following Hh activation with the Smo-agonist SAG. However, Gli3 recruitment to cilia tips was reduced and Sufu/Gli3 dissociation was impaired. Interestingly, we found Smo to co-precipitate with Evc/Evc2, indicating that in some cells Hh signaling requires direct interaction of Smo with the Evc/Evc2 complex. Expression of a dominantly acting Evc2 mutation previously identified in Weyer's acrodental dysostosis (Evc2Delta43) caused mislocalization of Evc/Evc2Delta43 within the cilium and also reproduced the Gli3-related molecular defects observed in Evc2(-/-) chondrocytes. Moreover, Evc silencing in Sufu(-/-) cells attenuated the output of the Hh pathway, suggesting that Evc/Evc2 also promote Hh signaling in the absence of Sufu. Together our data reveal that the Hh pathway involves Evc/Evc2-dependent modulations that are necessary for normal endochondral bone formation. PMID- 23026748 TI - L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome. AB - Phosphorylated creatine (Cr) serves as an energy buffer for ATP replenishment in organs with highly fluctuating energy demand. The central role of Cr in the brain and muscle is emphasized by severe neurometabolic disorders caused by Cr deficiency. Common symptoms of inborn errors of creatine synthesis or distribution include mental retardation and muscular weakness. Human mutations in l-arginine:glycine amidinotransferase (AGAT), the first enzyme of Cr synthesis, lead to severely reduced Cr and guanidinoacetate (GuA) levels. Here, we report the generation and metabolic characterization of AGAT-deficient mice that are devoid of Cr and its precursor GuA. AGAT-deficient mice exhibited decreased fat deposition, attenuated gluconeogenesis, reduced cholesterol levels and enhanced glucose tolerance. Furthermore, Cr deficiency completely protected from the development of metabolic syndrome caused by diet-induced obesity. Biochemical analyses revealed the chronic Cr-dependent activation of AMP-activated protein kinase (AMPK), which stimulates catabolic pathways in metabolically relevant tissues such as the brain, skeletal muscle, adipose tissue and liver, suggesting a mechanism underlying the metabolic phenotype. In summary, our results show marked metabolic effects of Cr deficiency via the chronic activation of AMPK in a first animal model of AGAT deficiency. In addition to insights into metabolic changes in Cr deficiency syndromes, our genetic model reveals a novel mechanism as a potential treatment option for obesity and type 2 diabetes mellitus. PMID- 23026750 TI - Design principles for life. PMID- 23026749 TI - Female Mecp2(+/-) mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies. AB - Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Typical RTT primarily affects girls and is characterized by a brief period of apparently normal development followed by the loss of purposeful hand skills and language, the onset of anxiety, hand stereotypies, autistic features, seizures and autonomic dysfunction. Mecp2 mouse models have extensively been studied to demonstrate the functional link between MeCP2 dysfunction and RTT pathogenesis. However, the majority of studies have focused primarily on the molecular and behavioral consequences of the complete absence of MeCP2 in male mice. Studies of female Mecp2(+/-) mice have been limited because of potential phenotypic variability due to X chromosome inactivation effects. To determine whether reproducible and reliable phenotypes can be detected Mecp2(+/-) mice, we analyzed Mecp2(+/-) mice of two different F1 hybrid isogenic backgrounds and at young and old ages using several neurobehavioral and physiological assays. Here, we report a multitude of phenotypes in female Mecp2(+/-) mice, some presenting as early as 5 weeks of life. We demonstrate that Mecp2(+/-) mice recapitulate several aspects of typical RTT and show that mosaic expression of MeCP2 does not preclude the use of female mice in behavioral and molecular studies. Importantly, we uncover several behavioral abnormalities that are present in two genetic backgrounds and report on phenotypes that are unique to one background. These findings provide a framework for pre-clinical studies aimed at improving the constellation of phenotypes in a mouse model of RTT. PMID- 23026751 TI - Insight into DEG/ENaC channel gating from genetics and structure. AB - The founding members of the superfamily of DEG/ENaC ion channel proteins are C. elegans proteins that form mechanosensitive channels in touch and pain receptors. For more than a decade, the research community has used mutagenesis to identify motifs that regulate gating. This review integrates insight derived from unbiased in vivo mutagenesis screens with recent crystal structures to develop new models for activation of mechanically gated DEGs. PMID- 23026753 TI - Regulation of metabolism: a cross talk between gut microbiota and its human host. AB - The recent epidemic of obesity and diabetes and the diversity at the individual level could be explained by the intestinal microbiota-to-host relationship. More than four million gene products from the microbiome could interact with the immune system to induce a tissue metabolic infection, which is the molecular origin of the low-grade inflammation that characterizes the onset of obesity and diabetes. PMID- 23026754 TI - No rest for the weary: diastolic calcium homeostasis in the normal and failing myocardium. AB - Following contraction of the heart, efficient relaxation (diastole) is essential for refilling the ventricles with blood. This review describes how ventricular relaxation is controlled by Ca(2+) homeostasis in cardiac muscle cells and how alterations in Ca(2+) cycling affect diastolic function in the normal and failing heart. These discussions illustrate that the diastolic phase is not simply a period of rest but rather involves highly regulated and dynamic Ca(2+) fluxes. PMID- 23026752 TI - The WNK/SPAK and IRBIT/PP1 pathways in epithelial fluid and electrolyte transport. AB - Fluid and electrolyte homeostasis is a fundamental physiological function required for survival and is associated with a plethora of diseases when aberrant. Systemic fluid and electrolyte composition is regulated by the kidney, and all secretory epithelia generate biological fluids with defined electrolyte composition by vectorial transport of ions and the obligatory water. A major regulatory pathway that immerged in the last several years is regulation of ion transporters by the WNK/SPAK kinases and IRBIT/PP1 pathways. The IRBIT/PP1 pathway functions to reverse the effects of the WNK/SPAK kinases pathway, as was demonstrated for NBCe1-B and CFTR. Since many transporters involved in fluid and electrolyte homeostasis are affected by PP1 and/or calcineurin, it is possible that WNK/SPAK and IRBIT/PP1 form a common regulatory pathway to tune the activity of fluid and electrolyte transport in response to physiological demands. PMID- 23026755 TI - Peptidylarginine deiminase expression and activity in PAD2 knock-out and PAD4-low mice. AB - Citrullination, the conversion of peptidylarginine to peptidylcitrulline is catalyzed by peptidylarginine deiminases (PAD). The expression of PAD isoforms displays great variation among different tissues as demonstrated by PAD mRNA analyses. Here we have analyzed the differential expression of PAD2, PAD4 and PAD6 in mouse tissues at the protein level and by enzymatic activity assays using PAD2 and PAD4 knock-out strains. As expected, no PAD2 expression was detected in the PAD2-/- mice. In contrast, the PAD4 protein was observed in several tissues of the PAD4 knock-out mice, albeit at reduced levels in most tissues, and are therefore referred to as PAD4-low mice. In material from PAD2-/- mice, except for leukocyte lysates, hardly any PAD activity was found and no citrullinated proteins were detected after incubation in the presence of calcium. PAD activity in the PAD4-low mice was similar to that in wild-type mice. In both PAD knock-out strains the expression of PAD6 appeared to be up-regulated in all tissues analyzed, with the exception of spleen and testis. Our data demonstrate that the PAD2 protein is expressed in brain, spinal cord, spleen, skeletal muscle and leukocytes, but not detectably in liver, lung, kidney and testis. PAD4 was detected in each of these tissues, although the expression levels varied. In all tissues where PAD2 was detected, except for blood cells, this PAD isoform appeared to be responsible for virtually all peptidylarginine deiminase activity. PMID- 23026756 TI - The mineralocorticoid signaling pathway throughout development: expression, regulation and pathophysiological implications. AB - The mineralocorticoid signaling pathway has gained interest over the past few years, considering not only its implication in numerous pathologies but also its emerging role in physiological processes during kidney, brain, heart and lung development. This review aims at describing the setting and regulation of aldosterone biosynthesis and the expression of the mineralocorticoid receptor (MR), a nuclear receptor mediating aldosterone action in target tissues, during the perinatal period. Specificities concerning MR expression and regulation during the development of several major organs are highlighted. We provide evidence that MR expression is tightly controlled in a tissue-specific manner during development, which could have major pathophysiological implications in the neonatal period. PMID- 23026758 TI - Neuroimaging resolution of the altered state hypothesis. AB - A controversy in the field of hypnosis has centered on the question of whether there is a uniquely hypnotic state of consciousness and, if so, whether it is causally related to responsiveness to suggestion. Evidence from brain imaging studies has been used to support claims for various altered state hypotheses, without resolving the debate. The designs of many neuroimaging studies confound the induction of hypnosis with the suggestions that can be given in or out of hypnosis, thus rendering them incapable of resolving the controversy. Brain imaging studies that do not have this confound support the hypothesis that hypnotic inductions produce changes in brain activity, but also indicate that these changes are not required for the experience of hypnotic suggestions or their neural correlates. The data remain equivocal as to whether there is a causal relation between the changes in brain activity produced by hypnotic inductions and those produced by other suggestions. It also remains uncertain whether the changes in activation produced by hypnotic inductions reflect a uniquely hypnotic state as opposed to more mundane processes. PMID- 23026757 TI - Behavioral and neural evidence for masked conceptual priming of recollection. AB - Previous research has found that masked repetition primes, presented immediately prior to the test item in a recognition memory test, increase the likelihood that participants think that the item was present in a previous study phase, even if it was not. This memory illusion is normally associated with a feeling of familiarity, rather than recollection (e.g., as indexed by Remember/Know judgments), and has been explained in terms of an increased fluency of processing the test item, which, in the absence of awareness of the cause of that fluency (i.e., the masked prime), is attributed instead to prior exposure in the study phase. Recently however, we have found that masked conceptual primes (semantically rather than associatively related to the test item) have the opposite effect of increasing Remember but not Know judgments. This result appears difficult to explain in terms of existing theories of recollection and familiarity. Here we report data from a functional magnetic resonance imaging study using the same design, in which we replicate our previous behavioral findings, and find converging evidence for increased activity following conceptual primes in brain regions associated with recollection. This neural evidence supports an account in terms of "true" recollection (for example, conceptual primes reactivating semantically related information that was generated at encoding), rather than an artifact of the mutually-exclusive nature of the Remember/Know procedure. PMID- 23026760 TI - Are tool properties always processed automatically? The role of tool use context and task complexity. AB - Previous work with healthy adults supports the idea that perception of the orientation of a tool's handle may automatically activate cognitive components for grasping and use. An important source of evidence for this automatic activation view comes from studies showing interference when automatically activated action representations are inconsistent with the behaviors demanded by a task (e.g., Tucker and Ellis, 1998). Here, we evaluated whether such effects occur in a grip selection task in which responses were chosen based on a learned rule (Rule task) versus anticipatory planning (Plan task). Participants were asked to pantomime grasping horizontally presented objects with handles. In the Rule task, a color cue indicated on which side of the tool's handle the thumb had to be placed. In the Plan task, participants had to choose the most comfortable way to grasp and rotate the object into a specific end-position. Across three experiments we found evidence of interference on grip selection exclusively during the Rule task, and only when it was preceded by a prime task that involved tool use. These findings suggest that prior activation of cognitive components through use of tools can be effective over time and interferes with grip selection based on use of a pre-learned rule. Absence of interference effects during the plan task, even when preceded by the Use task, suggest that engagement of similar mechanisms during active planning overwrites this automatic activation of previously effective components. Possible cognitive and neural mechanisms are discussed. PMID- 23026759 TI - Shielding cognition from nociception with working memory. AB - Because pain often signals the occurrence of potential tissue damage, nociceptive stimuli have the capacity to capture attention and interfere with ongoing cognitive activities. Working memory is known to guide the orientation of attention by maintaining goal priorities active during the achievement of a task. This study investigated whether the cortical processing of nociceptive stimuli and their ability to capture attention are under the control of working memory. Event-related brain potentials (ERPs) were recorded while participants performed primary tasks on visual targets that required or did not require rehearsal in working memory (1-back vs 0-back conditions). The visual targets were shortly preceded by task-irrelevant tactile stimuli. Occasionally, in order to distract the participants, the tactile stimuli were replaced by novel nociceptive stimuli. In the 0-back conditions, task performance was disrupted by the occurrence of the nociceptive distracters, as reflected by the increased reaction times in trials with novel nociceptive distracters as compared to trials with standard tactile distracters. In the 1-back conditions, such a difference disappeared suggesting that attentional capture and task disruption induced by nociceptive distracters were suppressed by working memory, regardless of task demands. Most importantly, in the conditions involving working memory, the magnitude of nociceptive ERPs, including ERP components at early latency, were significantly reduced. This indicates that working memory is able to modulate the cortical processing of nociceptive input already at its earliest stages, and could explain why working memory reduces consequently ability of nociceptive stimuli to capture attention and disrupt performance of the primary task. It is concluded that protecting cognitive processing against pain interference is best guaranteed by keeping out of working memory pain-related information. PMID- 23026761 TI - Multispectral opto-acoustic tomography (MSOT) of the brain and glioblastoma characterization. AB - Brain research depends strongly on imaging for assessing function and disease in vivo. We examine herein multispectral opto-acoustic tomography (MSOT), a novel technology for high-resolution molecular imaging deep inside tissues. MSOT illuminates tissue with light pulses at multiple wavelengths and detects the acoustic waves generated by the thermoelastic expansion of the environment surrounding absorbing molecules. Using spectral unmixing analysis of the data collected, MSOT can then differentiate the spectral signatures of oxygenated and deoxygenated hemoglobin and of photo-absorbing agents and quantify their concentration. By being able to detect absorbing molecules up to centimeters deep in the tissue it represents an ideal modality for small animal brain imaging, simultaneously providing anatomical, hemodynamic, functional, and molecular information. In this work we examine the capacity of MSOT in cross-sectional brain imaging of mice. We find unprecedented optical imaging performance in cross sectional visualization of anatomical and physiological parameters of the mouse brain. For example, the potential of MSOT to characterize ischemic brain areas was demonstrated through the use of a carbon dioxide challenge. In addition, indocyanine green (ICG) was injected intravenously, and the kinetics of uptake and clearance in the vasculature of the brain was visualized in real-time. We further found that multiparameter, multispectral imaging of the growth of U87 tumor cells injected into the brain could be visualized through the intact mouse head, for example through visualization of deoxygenated hemoglobin in the growing tumor. We also demonstrate how MSOT offers several compelling features for brain research and allows time-dependent detection and quantification of brain parameters that are not available using other imaging methods without invasive procedures. PMID- 23026762 TI - Stop early to travel fast: modelling risk-averse scheduling among nocturnally migrating birds. AB - Many migrating birds divide their journeys into nocturnal flights interspersed by stopovers where they build up energy reserves (fuel) for subsequent flights. Given the difficulty in monitoring fuel loads of individual migrants over long distances, theoretical models are often used to interpret observed relations between departure fuel loads (DFLs) and fuel deposition rates (FDRs) in the context of time-minimised migration. Models applicable to nocturnal migration have hitherto considered only the departure decision, i.e. ignored interim stopover possibilities before fuel loads are depleted. This results in 'risk prone' migratory schedules in terms of choice of stopover. In this study we assess 'risk-averse' behaviour, whereby nocturnal migrants minimise migration time by adjusting not only DFLs to experienced and expected FDRs, but also stopping fuel loads (SFLs), below which they stop to refuel at high-quality sites. We developed analytical formulae to solve for maximal risk-prone and risk averse migration speeds in modelled environments comprised of two stopover qualities (high- and low-quality), and a constant probability of encountering a high-quality site (encounter probability). Risk-aversion was beneficial to migration speeds in over 99% of the modelled environments, with median ratios of risk-averse to risk-prone migration speeds ranging from 1.5 to 2.8. Among modelled environments, this benefit increased with increasing FDRs at high quality sites, and was highest with low probabilities of encountering high quality sites. Time-minimising risk-averse DFLs at low-quality sites were minimal in nearly all modelled environments, and whenever encounter probabilities were low, risk-averse SFLs typically indicated that migrants should stop immediately on encountering high-quality sites. Modelled fuel loads in environments with high and low encounter probabilities resembled observed fuel loads of migratory populations with ubiquitous and scarce food availability, respectively. This study demonstrates the benefits of risk-averse exploitation of variable resources, presents a new approach to model time-minimised migration in heterogeneous environments and emphasises the importance of premium stopover sites to nocturnally migrating birds. PMID- 23026763 TI - Start/stop codon like trinucleotides extensions in primate alpha satellites. AB - The centromeres remain "the final frontier" in unexplored segments of genome landscape in primate genomes, characterized by 2-5 Mb arrays of evolutionary rapidly evolving alpha satellite (AS) higher order repeats (HORs). Alpha satellites as specific noncoding sequences may be also significant in light of regulatory role of noncoding sequences. Using the Global Repeat Map (GRM) algorithm we identify in NCBI assemblies of chromosome 5 the species-specific alpha satellite HORs: 13mer in human, 5mer in chimpanzee, 14mer in orangutan and 3mers in macaque. The suprachromosomal family (SF) classification of alpha satellite HORs and surrounding monomeric alpha satellites is performed and specific segmental structure was found for major alpha satellite arrays in chromosome 5 of primates. In the framework of our novel concept of start/stop Codon Like Trinucleotides (CLTs) as a "new DNA language in noncoding sequences", we find characteristics and differences of these species in CLT extensions, in particular the extensions of stop-TGA CLT. We hypothesize that these are regulators in noncoding sequences, acting at a distance, and that they can amplify or weaken the activity of start/stop codons in coding sequences in protein genesis, increasing the richness of regulatory phenomena. PMID- 23026764 TI - Mathematical model of colitis-associated colon cancer. AB - As a result of chronic inflammation of their colon, patients with ulcerative colitis or Crohn's disease are at risk of developing colon cancer. In this paper, we consider the progression of colitis-associated colon cancer. Unlike normal colon mucosa, the inflammed colon mucosa undergoes genetic mutations, affecting, in particular, tumor suppressors TP53 and adenomatous polyposis coli (APC) gene. We develop a mathematical model that involves these genes, under chronic inflammation, as well as NF-kappaB, beta-catenin, MUC1 and MUC2. The model demonstrates that increased level of cells with TP53 mutations results in abnormal growth and proliferation of the epithelium; further increase in the epithelium proliferation results from additional APC mutations. The model may serve as a conceptual framework for further data-based study of the early stage of colon cancer. PMID- 23026765 TI - The role of auxin and cytokinin signalling in specifying the root architecture of Arabidopsis thaliana. AB - Auxin and cytokinin are key hormonal signals that control the cellular architecture of the primary root and the initiation of new lateral root organs in the plant Arabidopsis thaliana. Both developmental processes are regulated by cross-talk between these hormones and their signalling pathways. In this paper, sub-cellular and multi-cellular mathematical models are developed to investigate how interactions between auxin and cytokinin influence the size and location of regions of division and differentiation within the primary root, and describe how their cross-regulation may cause periodic branching of lateral roots. We show how their joint activity may influence tissue-specific oscillations in gene expression, as shown in Moreno-Risueno et al. (2010) and commented upon in Traas and Vernoux (2010), and we propose mechanisms that may generate synchronisation of such periodic behaviours inside a cell and with its neighbours. Using a multi cellular model, we also analyse the roles of cytokinin and auxin in specifying the three main regions of the primary root (elongation, transition and division zones), our simulation results being in good agreement with independent experimental observations. We then use our model to generate testable predictions concerning the effect of varying the concentrations of the auxin efflux transporters on the sizes of the different root regions. In particular, we predict that over-expression of the transporters will generate a longer root with a longer elongation zone and a smaller division zone than that of a wild type root. This root will contain fewer cells than its wild type counterpart. We conclude that our model can provide a useful tool for investigating the response of cell division and elongation to perturbations in hormonal signalling. PMID- 23026766 TI - Dynamics of tRNA occupancy and dissociation during translation by the ribosome. AB - Repetitive cycles of protein elongation by the ribosome involve dynamic changes in tRNA occupancy and the deacylated-tRNA dissociation plays an important role in the process. Here we present a detailed analysis of the dynamics for the complicated process. We study analytically the dynamic tRNA occupancy and, specifically, the mean time for occupancy of one tRNA molecule, two tRNA molecules and three tRNA molecules during one cycle of protein elongation. The deacylated-tRNA dissociation probability at each state of the elongation cycle is analytically studied. The analyses give quantitative explanations of the available experimental data and provide interesting results: for example, the deacylated tRNA in hybrid P/E state can also be dissociated from the ribosome, as in post-translocation E/E state, but with a dissociation rate in the former being only about 1/20-fold of that in the latter; at low EF-G.GTP concentration, large fractions of the deacylated tRNA molecules are dissociated before the codon recognition in the A site and the ribosome is most of the time occupied by only one tRNA molecule, while at high and in vivo near EF-G.GTP concentration the ribosome is most of the time occupied by two tRNA molecules and the release of a third tRNA occurs mainly after the decoding step; even at high concentrations of EF-G.GTP and aminoacyl-tRNA.EF-Tu.GTP complex, the mean time for occupancy of three tRNA molecules is in the order of milliseconds in one translation cycle, which is much shorter than the in vitro mean translation time of about 1s. PMID- 23026767 TI - A new scale-free network model for simulating and predicting epidemics. AB - The course of epidemics often resembles a scale-free network, but some specific elements should be considered in developing a new model. This study introduces a time-shifting and discontinuous forcing function H into the scale-free network model to fit the specific period and intensity of the infection, and redefines the probability p as abortive infection rate. For the non-human vectors or hosts, three new factors (new connectivity K(i)(t), new links M, and time delay tau) were introduced in the proposed model of this study. The simulation results of six types of epidemic transmissions show that the proposed Scale-Free Epidemic Models, SFE-1 and SFE-2, are accurate. SFE-1 model and SFE-2 model are useful for the transmission categories from human and insects/vertebrates, respectively. Further comparisons of different races/ethnicities and different transmission categories of AIDS cases in the United States were also analyzed. Both SFE models can be used to predict epidemics and can suggest the results more clearly, irrespective of whether the epidemics are under control. Therefore, the proposed SFE models can help the government determine the level of caution required and predict the results of policy decisions, thus helping to balance socioeconomic and health concerns. PMID- 23026769 TI - Comparing subcutaneous and sublingual immunotherapy: what do we know? AB - PURPOSE OF REVIEW: Although allergen-specific sublingual (SLIT) and subcutaneous immunotherapy (SCIT) have been demonstrated to be clinically effective with similar immunological responses, head-to-head studies comparing those two modes of allergen administration in terms of onset of clinical improvement along with simultaneous immunological responses and underlying mechanisms of preventive effect are scarce. The present review will update current data on this issue. RECENT FINDINGS: Compared with SLIT, SCIT provides a rapid onset of clinical improvement by eliciting a simultaneous surge in production of T helper 1 (Th1) and T regulatory cell (Treg) cytokines and blocking antibodies. Similar immunological and clinical responses are evoked quite later, with no effect on Immunoglobulin G (IgG)4 levels during SLIT. Increases in TGFbeta secretion due to nonrelevant allergens during SLIT may explain the preventive effect on new sensitizations. SUMMARY: SLIT and SCIT are both clinically effective in the treatment of respiratory allergic diseases with slight differences in the early phase in terms of onset of clinical efficacy and simultaneous immunological responses. Both SLIT and SCIT induce similar T-cell responses in time, but specific IgG4-blocking antibody responses are more prevalent following SCIT. Further head-to-head studies addressing the preventive effect of monotherapy and the efficacy and immunological responses of nonrelated multiallergen immunotherapy in polysensitized patients are warranted. PMID- 23026770 TI - The many faces of the clinical picture of common variable immune deficiency. AB - PURPOSE OF REVIEW: To summarize the recent advancements in common variable immune deficiency (CVID), specifically CVID genetics, clinical discoveries and treatment implications. RECENT FINDINGS: Large genomic studies have implicated new genes in the pathogenesis of CVID, and basic science studies have contributed to our knowledge of potential mechanisms. Cohort studies have further defined the immunologic parameters and clinical presentation of CVID, as well as the factors that contribute to morbidity and mortality in this disease. Immunoglobulin remains the mainstay of treatment, although there may be a role for immunosuppression and other therapies. SUMMARY: CVID is a genotypically and phenotypically heterogeneous primary immune deficiency, the genetic and clinical characteristics of which are under active investigation. Further, discovery may yield important new treatment protocols that can continue to reduce the morbidity and mortality from this disease. PMID- 23026768 TI - Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. AB - PURPOSE OF REVIEW: Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent symptomatic infection of the nails, skin and mucosae mostly by Candida albicans. CMC is common in patients with profound primary T cell immunodeficiency, who often display multiple infectious and autoimmune diseases. Patients with syndromic CMC, including autosomal dominant hyper IgE syndrome (AD-HIES) and autosomal recessive autoimmune polyendocrinopathy syndrome type I (APS-I), display fewer other infections. Patients with isolated CMC (CMCD) rarely display any other severe disease. We review here recent progress in the genetic dissection of these three types of inherited CMC. RECENT FINDINGS: Low IL 17 T-cell proportions were reported in patients with AD-HIES bearing heterozygous STAT3 mutations, prone to CMC and staphylococcal diseases, and in a kindred with autosomal recessive CARD9 deficiency, prone to CMC and other fungal infections. High levels of neutralizing autoantibodies against IL-17 cytokines were documented in patients with APS-I presenting with CMC as their only infectious disease. The first three genetic causes of CMCD were then reported: autosomal recessive IL-17RA and autosomal dominant IL-17F deficiencies and autosomal dominant STAT1 gain-of-function, impairing IL-17-producing T-cell development. SUMMARY: Inborn errors of human IL-17 immunity underlie CMC. Impaired IL-17 immunity may therefore account for CMC in other settings, including patients with acquired immunodeficiency. PMID- 23026771 TI - The 10 warning signs: a time for a change? AB - PURPOSE OF REVIEW: It is 20 years since the 10 Warning Signs of primary immunodeficiency (PID) were first published and with over 180 PIDs now identified it is timely to evaluate their effectiveness, given the broadening clinical spectrum of PID. RECENT FINDINGS: Two recent studies have sought to define the features that best identify patients with PID and compare these with the 10 Warning Signs. They suggest the 10 Warning Signs discriminate poorly between those with and without PID, and that other features identify about one-third of patients with PID in whom none of the 10 Warning Signs was present. Recent literature describes the diverse presenting features that may assist in more accurately identifying those with PID. SUMMARY: Further development and refinement of early warning signs in light of the growing knowledge of how PIDs manifest clinically may allow relatively simple yet effective guidelines targeted at different groups to better detect PID. PMID- 23026772 TI - IgA deficiency: what is new? AB - PURPOSE OF REVIEW: To summarize recent publications on clinical and genetic aspects of IgA deficiency (IgAD). RECENT FINDINGS: Both major histocompatibility complex (MHC) and non-MHC genes contribute to susceptibility to the disease. The former genes appear to be located in different parts of the MHC region depending on the HLA haplotype. The latter show a marked overlap with genes associated with a variety of autoimmune disorders including Graves' disease, systemic lupus erythematosus, type 1 diabetes and celiac disease, suggesting common pathophysiological mechanisms. Various cytokines, recently shown to include interleukin 21, can induce IgA synthesis in vitro in cells from patients with IgAD, suggesting a regulatory basis of the disease. SUMMARY: IgAD is the most common primary immunodeficiency in the Western world with a prevalence of approximately 1 : 600 in the general population. It appears to be a polygenic disorder and several of the genes involved have recently been identified. The involvement of genes associated with autoimmunity may suggest that IgAD in itself is an autoimmune disease. PMID- 23026774 TI - Spatial scales of pollution from variable resolution satellite imaging. AB - The Moderate Resolution Imaging Spectroradiometer (MODIS) provides daily global coverage, but the 10 km resolution of its aerosol optical depth (AOD) product is not adequate for studying spatial variability of aerosols in urban areas. Recently, a new Multi-Angle Implementation of Atmospheric Correction (MAIAC) algorithm was developed for MODIS which provides AOD at 1 km resolution. Using MAIAC data, the relationship between MAIAC AOD and PM(2.5) as measured by the EPA ground monitoring stations was investigated at varying spatial scales. Our analysis suggested that the correlation between PM(2.5) and AOD decreased significantly as AOD resolution was degraded. This is so despite the intrinsic mismatch between PM(2.5) ground level measurements and AOD vertically integrated measurements. Furthermore, the fine resolution results indicated spatial variability in particle concentration at a sub-10 km scale. Finally, this spatial variability of AOD within the urban domain was shown to depend on PM(2.5) levels and wind speed. PMID- 23026775 TI - Angioimmunoblastic T-cell lymphoma mice model. AB - We established an angioimmunoblastic T-cell lymphoma (AITL) mouse model using NOD/Shi-scid, IL-2Rgamma(null) mice as recipients. The immunohistological findings of the AITL mice were almost identical to those of patients with AITL. In addition, substantial amounts of human immunoglobulin G/A/M were detected in the sera of the AITL mice. This result indicates that AITL tumor cells helped antibody production by B cells or plasma cells. This is the first report of reconstituting follicular helper T (TFH) function in AITL cells in an experimental model, and this is consistent with the theory that TFH cell is the cell of origin of AITL tumor cells. PMID- 23026776 TI - New method for discovery of starch phenotypes in growing microalgal colonies. AB - To identify algal strains with altered starch metabolism from a large pool of candidates of growing algal colonies, we have developed a novel, high-throughput screening tool by combining gaseous bleaching of replica transferred colonies and subsequent iodine staining to visualize starch. Screening of healthy growing colonies of microalgae has not been possible previously because high levels of chlorophyll make the detection of starch with an iodine stain impossible. We demonstrated that chlorine dioxide (ClO(2)) removes essentially all chlorophyll from the colonies and enables high-throughput screening of, for example, a population of mutagenized cells or a culture collection isolated in a bioprospecting project. PMID- 23026777 TI - High-throughput work flow for IgG Fc-glycosylation analysis of biotechnological samples. AB - Immunoglobulin G (IgG) fragment crystallizable (Fc) glycosylation is crucial for antibody effector functions such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. To monitor IgG Fc glycosylation, high throughput techniques for glycosylation analysis are needed in the biotechnology industry. Here we describe the development of a fully automated high-throughput method based on glycopeptide analysis. Samples are prepared in 96-well plates. The IgG's are purified directly from fermentation broths by means of immobilized protein A followed by trypsin digestion. Glycopeptides are purified by hydrophilic interaction solid-phase extraction and analyzed by electrospray mass spectrometry in the positive-ion mode. Data are automatically processed and relative intensities of the various IgG glycopeptides are obtained. The intermediate precision of the method is below 5% for the five major glycoforms of an IgG1 antibody. The newly developed method is suitable for glycosylation profiling of IgG's from fermentation broths. We compared the developed method to other glycoanalytical methods and successfully applied it to analyze the fermentation time course of two different clones of the same therapeutic antibody. PMID- 23026779 TI - Facile construction of a random protein domain insertion library using an engineered transposon. AB - Insertional fusion between multiple protein domains represents a novel means of creating integrated functionalities. Currently, there is no robust guideline for selection of insertion sites ensuring the desired functional outcome of insertional fusion. Therefore, construction and testing of random domain insertion libraries, in which a host protein domain is randomly inserted into a guest protein domain, significantly benefit extensive exploration of sequence spaces for insertion sites. Short peptide residues are usually introduced between protein domains to alleviate structural conflicts, and the interdomain linker residues may affect the functional outcome of protein insertion complexes. Unfortunately, optimal control of interdomain linker residues is not always available in conventional methods used to construct random domain insertion libraries. Moreover, most conventional methods employ blunt-end rather than sticky-end ligation between host and guest DNA fragments, thus lowering library construction efficiency. Here, we report the facile construction of random domain insertion libraries using an engineered transposon. We show that random domain insertion with optimal control of interdomain linker residues was possible with our engineered transposon-based method. In addition, our method employs sticky end rather than blunt-end ligation between host and guest DNA fragments, thus allowing for facile construction of relatively large sized libraries. PMID- 23026780 TI - Gene expression analysis by real-time PCR: experimental demonstration of PCR detection limits. AB - Reverse transcription followed by real-time PCR (RT-qPCR) is the gold standard for quantifying gene expression. However, because of PCR detection limits, theorized to be three template copies, the quantification of genes exhibiting great expression variability is challenging. Using genes with high to low expression in rat tissues we experimentally demonstrated this limit and found it to be applicable only for describing reactions in which stochastic events and the Monte Carlo effect are present. We also determined the lower limits of RNA input that should be used to prevent artifactual template quantification and we propose a methodology to assess RT-qPCR detection limits in any qPCR platform. PMID- 23026778 TI - Immobilization of unraveled immunoglobulin G using well-oriented ZZ-His protein on functionalized microtiter plate for sensitive immunoassay. AB - Highly efficient protein immobilization is extremely crucial for solid-phase immunoassays. We present a strategy for oriented immobilization of functionally intact immunoglobulin G (IgG) on a polystyrene microtiter plate via iminodiacetic acid (IDA)-Ni(2+) and ZZ-His protein interaction. We immobilized a ZZ-EAP (Escherichia coli alkaline phosphatase)-His fusion protein, which exhibits Fc binding, His tag, and intrinsic AP activities, and analyzed it against the interaction between rabbit IgG anti-horseradish peroxidase (anti-HRP) and its binding partner HRP to investigate the specificity and efficacy of this method. We compared the IDA-Ni(2+)-(ZZ-His) method with ZZ-EAP random immobilization using sandwich enzyme-linked immunosorbent assay, and the results showed that the former method had an enhanced signal, 10-fold higher sensitivity, and a wider linear range. Thus, the proposed method allows a broad range of oriented immobilized functionally intact IgG antibodies on polystyrene plates using only one type of IDA-Ni(2+) chelate surface because the ZZ protein can bind to the Fc region of various IgGs. PMID- 23026773 TI - A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance. AB - Treatment with partial (p)MHC class II-beta1alpha1 constructs (also referred to as recombinant T-cell receptor ligands - RTL) linked to antigenic peptides can induce T-cell tolerance, inhibit recruitment of inflammatory cells and reverse autoimmune diseases. Here we demonstrate a novel regulatory pathway that involves RTL binding to CD11b(+) mononuclear cells through a receptor comprised of MHC class II invariant chain (CD74), cell-surface histones and MHC class II itself for treatment of experimental autoimmune encephalomyelitis (EAE). Binding of RTL constructs with CD74 involved a previously unrecognized MHC class II-alpha1/CD74 interaction that inhibited CD74 expression, blocked activity of its ligand, macrophage migration inhibitory factor, and reduced EAE severity. These findings implicate binding of RTL constructs to CD74 as a key step in both antigen-driven and bystander T-cell tolerance important in treatment of inflammatory diseases. PMID- 23026781 TI - MRI of the bowel: the future of gastrointestinal imaging? PMID- 23026782 TI - Reflective practice as a tool to teach digital professionalism. AB - RATIONALE AND OBJECTIVES: Digital professionalism is increasingly being integrated into postgraduate medical education. We developed a small-group, reflective practice-based session incorporating radiology-specific cases to heighten residents' awareness about digital professionalism. MATERIALS AND METHODS: Case-based, radiology-specific scenarios were created for a small-group, reflective practice-based session on digital professionalism. Anonymous pre- and postsession surveys evaluating residents' use of social media and their thoughts about the session were administered to the radiology residents. RESULTS: Twenty five of 38 (66%) residents responded to the presession survey with 40% (10/25) reporting daily social media use; 50% (12/24) witnessing an unprofessional posting on Facebook; and 8% (2/25) posting something unprofessional themselves. Of the 21 residents who attended the session, 13 (62%) responded to the postsession survey. Residents reported that the session added to their understanding of professionalism 3.92, 95% CI (3.57-4.27). As a result of the session, residents stated that they were more aware of protecting patient privacy and confidentiality on social media sites 3.92, 95% CI (3.47-4.37), and would take a more active role in ensuring professional use of social media as it relates to patient care 4.00, 95% CI (3.66-4.34). CONCLUSION: Residents favorably viewed the reflective case-based session on digital professionalism as a means to be more aware of ways to avoid unprofessional interactions on the internet. Our results suggest that such reflective sessions are an effective method to educate residents on key concepts regarding digital professionalism. PMID- 23026783 TI - Ishrad, I am a member. PMID- 23026785 TI - Point-of-care testing may reduce length of stay but not emergency department crowding. PMID- 23026784 TI - Is emergency department closure resulting in increased distance to the nearest emergency department associated with increased inpatient mortality? AB - STUDY OBJECTIVE: We seek to determine whether patients living in areas affected by emergency department (ED) closure, with subsequent increased distance to the nearest ED, have a higher risk of inpatient death from time-sensitive conditions. METHODS: Using the California Office of Statewide Health and Planning Development database, we performed a nonconcurrent cohort study of hospital admissions in California between 1999 and 2009 for patients admitted for acute myocardial infarction, stroke, sepsis and asthma or chronic obstructive pulmonary disease. We used generalized linear mixed-effects models comparing adjusted inpatient mortality for patients experiencing increased distance to the nearest ED versus no change in distance. RESULTS: Of 785,385 patient admissions, 67,577 (8.6%) experienced an increase in distance to ED care because of an ED closure. The median change for patients experiencing an increase in distance to the nearest ED was only 0.8 miles, with a range of 0.1 to 33.4 miles. Patients with an increase did not have a significantly higher mortality (adjusted odds ratio 1.04; 95% confidence interval 0.99 to 1.09). In subgroups, we also observed no statistically significant differences in adjusted mortality among patients with acute myocardial infarction, stroke, asthma or chronic obstructive pulmonary disease, and sepsis. We did not observe any significant variations in mortality for time-sensitive conditions in sensitivity analyses that incorporated a lag effect of time after change in distance, allowance for a larger affected population, or removal of ST-segment elevation myocardial infarction from the acute myocardial infarction subgroup. CONCLUSION: In this large population-based sample, less than 10% of the patients experienced an increase in distance to the nearest ED, and of that group, the majority had less than a 1-mile increase. These small increased distances to the nearest ED were not associated with higher inpatient mortality among time-sensitive conditions. PMID- 23026786 TI - Apparent life-threatening event: multicenter prospective cohort study to develop a clinical decision rule for admission to the hospital. AB - STUDY OBJECTIVE: We identify factors in emergency department (ED) patients presenting with apparent life-threatening events that distinguish those safe for discharge from those warranting hospitalization. METHODS: Data were prospectively collected on all subjects presenting to 4 EDs with apparent life-threatening events. Patients were observed for subsequent events or interventions, defined a priori, which would have mandated hospital admission (eg, hypoxia, apnea, bradycardia that is not self-resolving, or serious bacterial infection). For patients discharged from the ED, telephone follow-up was arranged. Classification and regression tree analysis was performed to delineate admission predictors. RESULTS: A total of 832 subjects were enrolled. The overall median age was 31.5 days (interquartile range 10 to 90 days); 427 (51.3%) were male patients, and 513 (61.7%) arrived by emergency medical services. One hundred ninety-one (23.0%) infants had a significant intervention warranting hospitalization. One hundred thirty-seven patients (16.5%) met predetermined criteria that would obviously mandate hospital admission (eg, persistent hypoxia requiring oxygen) by the end of their ED stay. In addition to these patients for whom it was obvious that admission would be necessary in the ED, classification and regression tree analysis (receiver operating curve=0.90) yielded 2 factors predictive of hospitalization: having a significant medical history and having greater than 1 apparent life-threatening event in 24 hours. The sensitivity was 89.0% (95% confidence interval 83.5% to 92.9%); specificity was 61.9% (95% confidence interval 58.0% to 65.7%). CONCLUSION: We found 3 variables (obvious need for admission, significant medical history, >1 apparent life-threatening event in 24 hours) that identified most but not all infants with apparent life-threatening events necessitating admission. These variables require external validation and reliability assessment before clinical implementation. PMID- 23026787 TI - Vasopressors for hypotensive shock. PMID- 23026789 TI - Comparing LEA numbers low vision book and Feinbloom visual acuity charts. AB - PURPOSE: This study aims to determine the accuracy and repeatability of visual acuity measurements taken with the LEA numbers low vision book (LNLVB) and the Feinbloom chart in visually impaired subjects. METHODS: Distance visual acuities were taken with the LNLVB, the Feinbloom chart, and the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart, then repeated 15 to 30 min later to evaluate for inter-test repeatability. To determine threshold, participants were encouraged to guess until they could not identify any optotypes. The total number of correctly identified optotypes was recorded and extrapolated to logMAR on all three charts. The Feinbloom chart and LNLVB were evaluated for correlation to ETDRS. Nine visually impaired children and nine visually impaired adults participated in the study. RESULTS: In comparing the LNLVB to ETDRS, the 95% limits of agreement were +0.099/-0.240, and the correlation coefficient (R) was 0.953 (p < 0001). The same comparison for the Feinbloom chart vs. ETDRS was +0.169/-0.322 with r = 0.905 (p < 0.0001). On test-retest comparisons, the ETDRS was highest with the 95% limits of agreement of +0.117/-0.128. LNLVB and Feinbloom were nearly identical at +0.159/-0.200 and +0.184/-0.202, respectively. The R value for ETDRS was 0.976, LNLVB was 0.954, and Feinbloom was 0.942 (p < 0.0001 on all three). CONCLUSIONS: The results of our study indicate that there is a slight advantage, in terms of agreement with ETDRS, of LNLVB over the Feinbloom chart when testing visually impaired patients. The two tests proved nearly identical in terms of repeatability in a low-vision setting. Both handheld charts measured slightly worse acuity than the ETDRS chart, but overall proved to be suitable alternatives when the ETDRS chart is not available or practical in certain clinical situations. PMID- 23026788 TI - Nontraumatic subarachnoid hemorrhage in the setting of negative cranial computed tomography results: external validation of a clinical and imaging prediction rule. AB - STUDY OBJECTIVE: Clinical variables can reliably exclude a diagnosis of nontraumatic subarachnoid hemorrhage in patients with negative cranial computed tomography (CT) results. We externally validated 2 decision rules with 100% reported sensitivity for a diagnosis of subarachnoid hemorrhage, among patients undergoing lumbar puncture after a negative cranial CT result: (1) clinical rule: presence of any combination of age 40 years and older, neck pain or stiffness, loss of consciousness, or headache onset during exertion; and (2) imaging rule: cranial CT performed within 6 hours of headache onset. METHODS: This was a matched case-control study of patients presenting to 21 emergency departments between 2000 and 2011. Patients with a diagnosis of subarachnoid hemorrhage as determined by lumbar puncture after a negative cranial CT result were screened for inclusion. A matched control cohort was selected among patients with a diagnosis of headache after negative cranial CT and lumbar puncture results. RESULTS: Fifty-five cases of subarachnoid hemorrhage meeting inclusion criteria were identified, 34 (62%) of which were attributed to cerebral aneurysms. External validation of the clinical rule demonstrated a sensitivity of 97.1% (95% confidence interval [CI] 88.6% to 99.7%), a specificity of 22.7% (95% CI 16.6% to 29.8%), and a negative likelihood ratio of 0.13 (95% CI 0.03 to 0.61) for a diagnosis of subarachnoid hemorrhage. External validation of the imaging rule revealed that 11 of 55 subarachnoid hemorrhage cases (20%) had negative cranial CT results for tests performed within 6 hours of headache onset. CONCLUSION: The clinical rule demonstrated useful Bayesian test characteristics when retrospectively validated against this patient cohort. The imaging rule, however, failed to identify 20% of subarachnoid hemorrhage patients with a negative cranial CT result. PMID- 23026790 TI - Progressive visual and hearing loss secondary to neurosyphilis. AB - PURPOSE: There is a rising incidence of syphilis in economically advanced countries. Early diagnosis can spare the patient devastating vision and hearing loss, as well as other significant morbidity. Ocular presentations of neurosyphilis are varied and numerous, requiring syphilis to be considered in many clinical situations, even if a negative medical history is reported. Features of Argyll Robertson pupils, however, are virtually pathognomonic of syphilis; therefore, careful pupil testing can be the key to making a correct and timely diagnosis. CASE REPORT: A 51-year-old woman with a history of unexplained hearing loss presented for a third opinion for progressive vision loss OU, which was previously labeled as functional loss. A review of records indicated significant worsening of visual acuity and visual fields over 6 months, with minimal remaining visual function. She exhibited features of optic neuropathy as well as 2 mm miotic pupils, with evident light-near dissociation bilaterally. Evaluation showed a reactive fluorescent treponemal antibody absorption and rapid plasma reagin (1:8 titer) and positive cerebral spinal fluid venereal disease research laboratory test. A diagnosis of neurosyphilis was made, and a 2-week course of intravenous penicillin treatment was completed. Despite treatment, her vision decreased to no light perception OU owing to the advanced course of the disease at the time of treatment. CONCLUSIONS: Neurosyphilis can occur at any stage of infection and needs to be considered in the differential diagnosis for many visual and ocular problems, especially in the setting of other systemic signs and symptoms. In this case, the combination of light-near dissociation and optic neuropathy with hearing loss was instrumental in dismissing the past diagnosis of functional vision loss and in pursuing the diagnosis of neurosyphilis. A timely diagnosis of neurosyphilis needs to be made to prevent devastating vision loss as seen in this case. PMID- 23026791 TI - Impact of pupil diameter on axial growth in orthokeratology. AB - PURPOSE: To compare axial elongation between myopic orthokeratology (OK) contact lens and spectacle wearers, and to investigate the impact of pupil diameter on axial growth in myopic children after OK treatment. METHODS: Fifty-two Chinese children aged 9 to 14 years were enrolled in this study, 27 for the OK group and 25 for the single vision spectacle lenses (SVL) group. Subjects in each group were further divided into two subcategories according to their baseline scotopic pupil diameters. Axial length (AL) was measured at baseline and at every 6-month visit through to 24 months. Linear mixed-effect model was used to determine myopia progression (AL changes from baseline). In this model, repeated visits were taken as within-subject effect, and treatment group as well as pupil size were taken as between-subject effects. The interaction of treatment group*pupil size was analyzed. Relationships between axial growth at 24 months and baseline pupil area were analyzed in both lens groups. RESULTS: Twenty-five subjects in the OK group and 22 subjects in the SVL group completed the 24-month study. AL increased significantly throughout the observed 24-month period (F = 32.09, p < 0.001). Pupil size significantly affected axial growth (F = 15.95, p < 0.001) and different treatment modalities (OK vs. SVL) interacted with the effect of pupil size on axial growth (F = 24.66, p < 0.001). To be more specific, axial growth was significantly slower in subjects with above average pupil sizes than those with below average pupil sizes in the OK group (F = 25.04, p < 0.001). Contrarily, pupil size did not affect axial growth in the SVL group (F = 0.46, p = 0.50). Baseline scotopic pupil area was significantly correlated to axial growth in the OK group (r = 0.405, p < 0.001) but not in the SVL group (r = 0.171, p = 0.056). CONCLUSIONS: Large pupil diameters facilitate the effect of OK to slow axial growth in myopia. We speculate that this is because of enhancement of the myopic shift in the peripheral retina. PMID- 23026793 TI - Erratum: An Optimized Procedure for Fluorescence-activated Cell Sorting (FACS) Isolation of Autonomic Neural Progenitors from Visceral Organs of Fetal Mice. AB - The authors middle initials were omitted from the publication of An Optimized Procedure for Fluorescence-activated Cell Sorting (FACS) Isolation of Autonomic Neural Progenitors from Visceral Organs of Fetal Mice. PMID- 23026792 TI - pdFVIII/VWF may be an alternative treatment for old medical patient with acquired haemophilia A and systemic vascular disease? AB - Acquired Haemophilia is a severe, rare and potentially life-threatening bleeding that affects both males and females with an incidence of 1.5 cases/million/year. Mucocutaneous haemorrhages or haematomas are the typical expression of this disease as a consequence of a decrease in FVIII activity and the presence of a FVIII inhibitor, which differs from congenital haemophilia. We report a case of a 71 year-old-man who presented with spontaneous haematomas and severe anaemia and suffered from vascular disease. At admission, all haemostatic and laboratory data were diagnostic for idiopathic AHA. Treatment with by-passing agents such as rFVIIa was contraindicated because of the risk of thromboembolic events. Despite the fact that administration of FVIII concentrates in AHA is recommended only in patients with an inhibitor titre<5.0 BU, the physicians decided to use pdFVIII/vWF with corticosteroids in this patient. One month later, the FVIII was within the normal range and the inhibitors had disappeared. In our case, pdFVIII/vWF resulted in a safe and effective alternative for the treatment of acquired haemophilia A in a patient at high thromboembolic risk. PMID- 23026798 TI - Semantic memory recognition is supported by intrinsic recollection-like processes: "The butcher on the bus" revisited. AB - Dual-process models suggest that recognition memory is independently supported by recollection and familiarity. Current theories attribute recollection solely to hippocampally mediated episodic memory (EM), and familiarity to both episodic and semantic memory (SM) supported by medial temporal lobe cortex (MTLC) and prefrontal cortex. We tested whether, contrary to this view, recollection-like processes also intrinsically support SM recognition and whether MTL structures are involved in their execution. A semantic process dissociation procedure (PDP) with famous and non-famous names was used in three experiments. Experiment 1 revealed that recollection-like processes in semantic memory were not associated with episodic memory for the public events, were predicted by performance on standard SM tasks and were independent of EM tasks, suggesting they are intrinsic to SM. Experiment 2 demonstrated the independence of the two process estimates by showing only familiarity was affected by shifting response criterion while only recollection estimates were significantly altered under divided-attention. Finally experiment 3 tested amnesic patients with varying degrees of hippocampal and MTLC damage. Despite normal overall fame recognition performance, recollection estimates were specifically affected by MTL damage. When damage was primarily hippocampal, only retrograde recollection estimates were reduced, while more extensive MTLC damage led to both retrograde and anterograde recollection deficits. We conclude that recognition of semantic information is supported by at least two independent processes akin to the ones that support EM recognition. Recollection-like processes are intrinsic to SM and likely do not reflect EM contribution to SM performance. Together with previous studies of recollection in remote memory, these data suggest that recollection is not a unitary phenomenon. In EM it involves autonoetic re-experiencing, and is supported by interaction of fronto-temporal networks; in EM and SM it supports retrieval of contextual/associative information regardless of consciousness type, and is dependent on intact MTL function. Familiarity processes and neural substrates may also differ between lifetime familiarity and within-session familiarity. PMID- 23026799 TI - Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells. AB - We have previously shown that elevated expression of mitotic kinase aurora kinase A (AURKA) in cancer cells promotes the development of metastatic phenotypes and is associated clinically with adverse prognosis. Here, we first revealed a clinically positive correlation between AURKA and autophagy-associated protein SQSTM1 in breast cancer and further demonstrated that AURKA regulated SQSTM1 through autophagy. Indeed, depletion by siRNA or chemical inhibition of AURKA by the small molecule VX-680 increased both the level of microtubule-associated protein 1 light chain 3-II (LC3-II) and the number of autophagosomes, along with decreased SQSTM1. Conversely, overexpression of AURKA inhibited autophagy, as assessed by decreased LC3-II and increased SQSTM1 either upon nutrient deprivation or normal conditions. In addition, phosphorylated forms of both RPS6KB1 and mechanistic target of rapamycin (MTOR) were elevated by overexpression of AURKA whereas they were suppressed by depletion or inhibition of AURKA. Moreover, inhibition of MTOR by PP242, an inhibitor of MTOR complex1/2, abrogated the changes in both LC3-II and SQSTM1 in AURKA-overexpressing BT-549 cells, suggesting that AURKA-suppressed autophagy might be associated with MTOR activation. Lastly, repression of autophagy by depletion of either LC3 or ATG5, sensitized breast cancer cells to VX-680-induced apoptosis. Similar findings were observed in cells treated with the autophagy inhibitors chloroquine (CQ) and bafilomycin A 1 (BAF). Our data thus revealed a novel role of AURKA as a negative regulator of autophagy, showing that AURKA inhibition induced autophagy, which may represent a novel mechanism of drug resistance in apoptosis-aimed therapy for breast cancer. PMID- 23026800 TI - Mortality after exposure to polychlorinated biphenyls and dibenzofurans: 30 years after the "Yucheng accident". AB - BACKGROUND: In 1979, approximately 2,000 people in central Taiwan were accidentally exposed to polychlorinated biphenyls and dibenzofurans due to ingestion of contaminated cooking oil. This event was called Yucheng, "oil syndrome" in Chinese. We followed the exposed persons and compared their cause specific mortality with that of neighborhood referents 30 years after the accident. METHODS: We obtained age- and gender-matched referents from the 1979 neighborhoods of the exposed people. Cause-specific mortality was compared between exposed subjects (N=1803) and their neighborhood referents (N=5170) using standardized mortality ratios (SMR). Total person-years for the Yucheng subjects and neighborhood referents were 48,751 and 141,774, respectively. RESULTS: The SMR for all causes (SMR=1.2, 95% CI: 1.1-1.3), diseases of the circulatory system (SMR=1.3, 95% CI: 1.0-1.6), and diseases of the musculoskeletal system and connective tissue (SMR=6.4, 95% CI: 2.8-12.7) were elevated in Yucheng subjects. Among Yucheng males, the SMRs for diseases of the digestive system (SMR=1.9, 95% CI: 1.2-2.8), malignant neoplasm of stomach (SMR=3.5, 95% CI: 1.5-7.0), and malignant neoplasm of lymphatic and hematopoietic tissue (SMR=3.0, 95% CI: 1.1 6.6) were increased. The SMR for total neoplasms was increased (SMR=1.3, 95% CI: 0.9-1.7). CONCLUSION: We conclude that exposure to PCBs/PCDFs at levels that produced symptoms in many affects mortality patterns 3 decades after exposure. PMID- 23026801 TI - Spatiotemporal model or time series model for assessing city-wide temperature effects on mortality? AB - Most studies examining the temperature-mortality association in a city used temperatures from one site or the average from a network of sites. This may cause measurement error as temperature varies across a city due to effects such as urban heat islands. We examined whether spatiotemporal models using spatially resolved temperatures produced different associations between temperature and mortality compared with time series models that used non-spatial temperatures. We obtained daily mortality data in 163 areas across Brisbane city, Australia from 2000 to 2004. We used ordinary kriging to interpolate spatial temperature variation across the city based on 19 monitoring sites. We used a spatiotemporal model to examine the impact of spatially resolved temperatures on mortality. Also, we used a time series model to examine non-spatial temperatures using a single site and the average temperature from three sites. We used squared Pearson scaled residuals to compare model fit. We found that kriged temperatures were consistent with observed temperatures. Spatiotemporal models using kriged temperature data yielded slightly better model fit than time series models using a single site or the average of three sites' data. Despite this better fit, spatiotemporal and time series models produced similar associations between temperature and mortality. In conclusion, time series models using non-spatial temperatures were equally good at estimating the city-wide association between temperature and mortality as spatiotemporal models. PMID- 23026802 TI - Syntheses and structures of lanthanoid(II) complexes featuring Sn-M (M = Al, Ga, In) bonds. AB - The reactions of the tris(pyridyl)tin(II) derivative [Li(thf)Sn(2-py(R))(3)] (py(R) = C(5)H(3)N-5-Me) (1) with the heavier group 13 alkyl compounds MEt(3), M = Ga or In, have been carried out. These led to formation of [{Li(thf)Sn(2 py(R))(3)}MEt(3)] adducts, which exhibit long Sn-M bonds and can be used for further lanthanoid metal coordination via the salt metathesis reaction with [Eu(Cp*)(2)(OEt(2))] (Cp* = eta(5)-C(5)Me(5)) to give complexes [Eu{Sn(2 py(R))(3)MEt(3)}(2)]. In contrast, addition of the lighter group 13 analogue, (AlMe(3))(2), to 1 resulted in a pyridyl transfer reaction, yielding dimeric [AlMe(2)(2-py(R))](2). For comparison, the reaction of (AlMe(3))(2) with [Yb{Sn(2 py(R))(3)}(2)] (py(R) = C(5)H(3)N-3-Me) was explored, affording complex [Yb{Sn(2 py(R))(3)AlMe(3)}(2)]. All complexes have been characterised by NMR spectroscopy and X-ray crystallographic studies. PMID- 23026803 TI - Understanding anesthesia training and trainees. AB - PURPOSE OF REVIEW: Patient safety is topical today. Competent professionals are necessary to keep anesthesia care safe, and teaching trainees is an important element in safety work. The purpose of this review is to present the latest research on anesthesia training and trainees. RECENT FINDINGS: Most trainees of today aim for excellence, for which personal qualities are as important as knowledge and skills. The definition of excellence is the first subject covered here. Trainees of today can train many procedural skills in a simulators setting, a step forward for patient safety. Several studies about simulator training are reported. A dimension of competence that has received much attention during the last years is anesthesiologists' nontechnical skills. Studies on anesthesiologists' nontechnical skills as a valuable tool for assessing trainees' progress in nontechnical skills are presented. SUMMARY: Much research about anesthesia training concerns simulator training and assessment of trainees' competence. More research is needed to understand the process of learning anesthesia. PMID- 23026804 TI - Dilemmas in biomedical research publication: are we losing the plot? AB - PURPOSE OF REVIEW: Some recent and very controversial developments in the sphere of scientific publication, with significant implications for biomedical research, are posing a significant threat to traditional publication models. Many of these developments appear to be the result of a vicious circle that has developed from publication pressure on researchers, corporate financial exploitation of those pressures, and an apparent perception that individual and institutional reputations are to be promoted at all cost. RECENT FINDINGS: The detrimental effects of these developments have led to a groundswell of academic discontent and a 'researcher uprising' that may result in precipitous changes. SUMMARY: In many different respects, biomedical research publication is now in an unprecedented state of flux. Traditional models are being strongly challenged, probably with good reason, and alternative models of both funding and delivery need to be settled upon with some urgency. While individuals, institutions and corporate bodies who resist the current evolution may find themselves in line for extinction, at the same time it is important for the entire 'industry' to revert to some more traditional values and not allow self-interest to prevail. PMID- 23026806 TI - Difficult airway management in an ambulatory surgical center? AB - PURPOSE OF REVIEW: This review will focus on two key aspects of difficult airway management in an ambulatory surgical center (ASC). First, the selection process of patients with known difficult airways suitable for this environment, and second, the requirements of a difficult airway cart to manage unexpected airway problems. RECENT FINDINGS: The decision whether to manage a patient with a previously documented difficult airways in an ASC requires a multidisciplinary approach. Many factors will influence this decision including the cause and severity of the airway problem, the type of procedure, the experience of the perioperative staff, and the availability of difficult airway management devices.Unexpected difficult airways will always occur in anesthesia. Difficult airway carts are, therefore, a requirement for any area in which anesthesia is to be conducted. The contents of these carts should reflect the need to maintain patient oxygenation to avoid morbidity and mortality. Regular training sessions should include both technical training in the use of equipment and nontechnical training to improve interpersonal communication during crises. SUMMARY: The management of ambulatory surgical practices must provide suitable difficult airway management equipment as well as technical and nontechnical training. Patients may present to an ASC with expected and unexpected difficult airways. Appropriate management of these patients requires advance planning to avoid poor outcomes. PMID- 23026807 TI - Exploring new frontiers in anesthesia education. PMID- 23026805 TI - Patient safety and office-based anesthesia. AB - PURPOSE OF REVIEW: Office-based anesthesia is a new and growing subspecialty within ambulatory anesthesia. We examine major developments in office-based anesthesia and how patient safety can be maintained. RECENT FINDINGS: The emergence of office-based anesthesia as a subspecialty of ambulatory anesthesia is a result of economic and social factors, and is also due to the development of better surgical techniques and anesthestic drugs. There is still a dearth of primary literature that addresses patient safety in the office-based setting. Some existing literature points to increased risk in the office, although others suggest that proper provider credentialing, qualifications, and appropriate facility accreditation can improve patient outcomes compared to surgicenters and inpatient facilities. There is a lack of state and federal oversight of office based facilities. Increased regulation and standardization of care, such as the use of check lists and professional society guidelines, can help promote safer practices. SUMMARY: There is no uniform standard of care for performing procedures in the office-based setting. Healthcare providers are facing the challenge of creating a safer, efficient, cost-effective and patient-centered environment. Available data show that the office-based practice can be as safe as any ambulatory surgicenter or hospital, as long as patients, regulators, and physicians become educated advocates of safer practices. In addition, procedures can be performed safely with general anesthesia or conscious sedation, provided that there are properly trained personnel and adequate equipment and facilities. Moreover, physicians should be credentialed to perform the same procedure in a hospital that they perform in an office. PMID- 23026808 TI - Plumage evolution in relation to light environment in a novel clade of Neotropical tanagers. AB - Molecular phylogenetic analyses have greatly changed Neotropical avian systematics in the past couple of decades. These new phylogenies provide the necessary framework to study the ecology and natural history of species in the region in an evolutionary context. This study addresses the systematics of Poospiza, Compsospiza, Hemispingus, Thlypopsis, and eight monotypic genera, which form a strongly supported and novel clade within the tanagers. We find Poospiza, Hemispingus, and Thlypopsis to be polyphyletic, confirm or reject relationships proposed based on morphology and life history, and describe novel relationships among these and the monotypic genera. The diversity of plumage, habitat, and geography throughout the clade allows us to test hypotheses of plumage evolution in relation to light environment. We find that overall plumage brightness best fits a model that includes selective regimes based on open versus closed habitats and foraging strata, while plumage measures describing color diversity and chroma best fit a model that only includes selective regimes based on open and closed habitats. PMID- 23026809 TI - Overlooked cryptic endemism in copepods: systematics and natural history of the calanoid subgenus Occidodiaptomus Borutzky 1991 (Copepoda, Calanoida, Diaptomidae). AB - Our comprehension of the phylogeny and diversity of most inland-water crustaceans is currently hampered by their pronounced morphological bradytely, which contributed to the affirmation of the "Cosmopolitanism Paradigm" of freshwater taxa. However, growing evidence of the existence of cryptic diversity and molecular regionalism is available for calanoid copepods, thus stressing the need for careful morphological and molecular studies in order to soundly investigate the systematics, diversity and distribution patterns of the group. Diaptomid copepods were here chosen as model taxa, and the morphological and molecular diversity of the species belonging to the west-Mediterranean diaptomid subgenus Occidodiaptomus were investigated with the aim of comparing the patterns of morphological and molecular evolution in freshwater copepods. Three species currently lumped under the binomen Hemidiaptomus (Occidodiaptomus) ingens and two highly divergent clades within H. (O.) roubaui were distinguished, thus showing an apparent discordance between the molecular distances recorded and Occidodiaptomus morphological homogeneity, and highlighting a noteworthy decoupling between the morphological and molecular diversity in the subgenus. Current Occidodiaptomus diversity pattern is ascribed to a combined effect of ancient vicariance and recent dispersal events. It is stressed that the lack of sound calibration points for the molecular clock makes it difficult to soundly temporally frame the diversification events of interest in the taxon studied, and thus to asses the role of morphological bradytely and of accelerated molecular evolutionary rates in shaping the current diversity of the group. PMID- 23026810 TI - Global phylogeny and new classification of the Rapaninae (Gastropoda: Muricidae), dominant molluscan predators on tropical rocky seashores. AB - The monophyly of the muricid subfamily Rapaninae has recently been confirmed with molecular techniques, but its composition and the relationships among its constituent genera remain unclear. We use four genes (28S rRNA, 12S rRNA, 16S rRNA and cytochrome c oxidase subunit I, COI) to construct a Bayesian phylogeny of 80 rapanine species (73% of the approximately 109 currently accepted), representing 27 of the 31 nominal genera. This is the most complete phylogeny of this taxonomically confusing subfamily yet produced. We propose a revised phylogenetic classification of the Rapaninae, assigning the recognized species to 28 genera. Most of the morphologically-defined rapanine genera are considered valid, including Purpura, Drupa, Thais and Nassa, but many of them are here restricted or redefined so that they are monophyletic. In particular the familiar genus Thais is narrowly restricted to a single species. Many groups previously accepted as subgenera, including Mancinella, Vasula, Thalessa and Thaisella, are here accorded full generic rank. We describe one new genus, Indothais. While we do not formally alter species-level taxonomy, we show molecular evidence for two cryptic species and several instances of probable species synonymy. We estimate the age of diversification of the Rapaninae as Late Cretaceous (75.9 Ma) and of many of its genera as Miocene. PMID- 23026811 TI - Multilocus phylogeny and recent rapid radiation of the viviparous sea snakes (Elapidae: Hydrophiinae). AB - The viviparous sea snakes (Hydrophiinae: Hydrophiini) comprise a young but morphologically and ecologically diverse clade distributed throughout the Indo Pacific. Despite presenting a very promising model for marine diversification studies, many relationships among the 62 species and 16 genera in Hydrophiini remain unresolved. Here, we extend previous taxonomic and genomic sampling for Hydrophiini using three mitochondrial fragments and five nuclear loci for multiple individuals of 39 species in 15 genera. Our results highlight many of the impediments to inferring phylogenies in recent rapid radiations, including low variation at all five nuclear markers, and conflicting relationships supported by mitochondrial and nuclear trees. However, concatenated Bayesian and likelihood analyses, and a multilocus coalescent tree, recovered concordant support for primary clades and several previously unresolved inter-specific groupings. The Aipysurus group is monophyletic, with egg-eating specialists forming separate, early-diverging lineages. All three monotypic semi-aquatic genera (Ephalophis, Parahydrophis and Hydrelaps) are robustly placed as early diverging lineages along the branch leading to the Hydrophis group, with Ephalophis recovered as sister to Parahydrophis. The molecular phylogeny implies extensive evolutionary convergence in feeding adaptations within the Hydrophis group, especially the repeated evolution of small-headed (microcephalic) forms. Microcephalophis (Hydrophis) gracilis is robustly recovered as a relatively distant sister lineage to all other sampled Hydrophis group species, here termed the 'core Hydrophis group'. Within the 'core Hydrophis group', Hydrophis is recovered as broadly paraphyletic, with several other genera nested within it (Pelamis, Enhydrina, Astrotia, Thalassophina, Acalyptophis, Kerilia, Lapemis, Disteira). Instead of erecting multiple new genera, we recommend dismantling the latter (mostly monotypic) genera and recognising a single genus, Hydrophis Latreille 1802, for the core Hydrophis group. Estimated divergence times suggest that all Hydrophiini last shared a common ancestor ~6million years ago, but that the majority of extant lineages diversified over the last ~3.5million years. The core Hydrophis group is a young and rapidly speciating clade, with 26 sampled species and 9 genera and dated at only ~1.5-3million years old. PMID- 23026812 TI - Antidepressant-dependent mRNA changes in mouse associated with hippocampal neurogenesis in a mouse model of depression. AB - RATIONALE: Monoaminergic imbalances play a role in the pathogenesis of depression and most common antidepressant drugs act on monoamine neurotransmitters. However, the lag time between restoring neurochemical balance and symptom improvement suggests that the response to drugs involves complex biological events downstream of primary targets that have not yet been fully characterized. Here, we report a mouse mRNA expression study to evaluate the effect of escitalopram (a serotonergic antidepressant) and nortriptyline (a noradrenergic antidepressant) on genes that are involved in the pathogenesis of depression and to assess the similarities and differences between two drugs on gene expression levels. METHODS: Genome-wide RNA expression data from the hippocampal tissues of four inbred mouse strains (129S1/SvlmJ, C57LB/6J, DBA/2J and FVB/NJ) were treated with varying doses of either nortriptyline (NRI) or escitalopram (SSRI) and subjected to two different depressogenic protocols. Following robust multichip average normalization, we applied the nonparametric RankProd approach to identify differentially expressed genes in response to drugs across the four strains. Pathway analysis was subsequently carried out on top-ranking genes to gain further biological insights. RESULTS: A total of 371 genes were significantly differentially expressed in response to nortriptyline, whereas 383 were altered by escitalopram. Genes involved in the pathways of integrin signalling (Fnlb, Mapk1, Mapk8), synaptic transmission (Cacnb1, Dnajc5, Kcnma1, Slc1a2) or Huntington disease (Crebbp, Dlg4, Ncor1) were altered by both nortriptyline and escitalopram. Several biological processes and pathways were identified, which could explain the divergence between the molecular mechanisms of nortriptyline and escitalopram. CONCLUSION: From a large-scale animal study, we obtain gene sets comprised of commonly and differentially expressed genes in response to different antidepressant drug treatments. The results may help to characterize the response to antidepressant treatment, shed further light on the neurobiology of depressive disorders and inform future animal and human studies. Finally, the top-ranking pathways from Ingenuity provide further evidence for the hippocampal neurogenesis hypothesis of major depressive disorders. PMID- 23026813 TI - ABCC10 rs2125739 polymorphism and nevirapine-induced hepatotoxicity: lack of association in a population from Mozambique. PMID- 23026814 TI - Impulsivity in adult ADHD patients with and without cocaine dependence. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is present in about a quarter of patients with a substance use disorder (SUD) and impulsivity is a key feature of both disorders. However, very little is known about differences in impulse control and other cognitive functions between ADHD patients with and without SUD. METHODS: In adult male medication-naive ADHD patients with and without comorbid cocaine dependence and healthy controls (matched on gender, age and IQ), we measured motor impulsivity (stop signal task), cognitive impulsivity (delay discounting task), divided attention (trail making test), interference (Stroop task), working memory (n-back task), and time reproduction (time reproduction task). Additionally, self-reported ADHD symptoms (using the ADHD Symptom Rating Scale; ASRS) and self-reported impulsivity (Barratt Impulsivity Scale; BIS) were assessed. RESULTS: Significantly higher levels of motor and cognitive impulsivity were found in ADHD patients with comorbid cocaine dependence compared to ADHD patients without cocaine dependence and controls, and both measures of impulsivity were highly correlated. No significant group differences were found on other cognitive measures. With regard to the self report measures, only BIS attention subscores differed significantly between ADHD patients with and without cocaine dependence. ASRS and BIS scores were not significantly correlated. CONCLUSION: This is the first study showing that ADHD patients with cocaine dependence are a distinctly more impulsive subpopulation compared to ADHD patients without cocaine dependence on objective measures of impulsivity. These findings are relevant to optimize psycho-education and treatment of ADHD patients with comorbid SUD. PMID- 23026816 TI - Minimal mimicry: mere effector matching induces preference. AB - Both mimicking and being mimicked induces preference for a target. The present experiments investigate the minimal sufficient conditions for this mimicry preference link to occur. We argue that mere effector matching between one's own and the other person's movement is sufficient to induce preference, independent of which movement is actually performed. In Experiments 1 and 2, participants moved either their arms or legs, and watched avatars that moved either their arms or legs, respectively, without any instructions to mimic. The executed movements themselves and their pace were completely different between participants (fast circular movements) and targets (slow linear movements). Participants preferred avatars that moved the same body part as they did over avatars that moved a different body part. In Experiment 3, using human targets and differently paced movements, movement similarity was manipulated in addition to effector overlap (moving forward-backward or sideways with arms or legs, respectively). Only effector matching, but not movement matching, influenced preference ratings. These findings suggest that mere effector overlap is sufficient to trigger preference by mimicry. PMID- 23026815 TI - Salivary hexosaminidase in smoking alcoholics with bad periodontal and dental states. AB - BACKGROUND: A sensitive alcohol marker, beta-hexosaminidase (HEX), in the saliva of alcoholics, is investigated for the first time. METHODS: The activity, specific-activity and output of total HEX and its isoenzymes HEX A and HEX B were measured in the saliva of healthy controls (C), alcohol-dependent non-smokers (ANS), and alcohol-dependent smokers (AS). RESULTS: We observed a significantly increased activity/specific-activity and output of HEX A in the ANS and AS groups, due to the inflammatory state of the oral-cavity/salivary-glands. Significantly increased activity of HEX A contributed to an increase in the salivary activity of the total HEX in the ANS group. A significant decrease in the activity/specific-activity of HEX B in AS seemed to be due to HEX B inactivation by cigarette smoke. We noticed a tendency for deteriorated dental state (lower decayed-missing-filled-teeth index - DMFT), worse periodontal state (higher gingival index - GI and papilla-bleeding index - PBI) in AS, and worse periodontal state (higher GI) in ANS, as compared to the controls. We found no differences in the salivary protein concentrations between all groups and decreased salivary flow in both alcoholic groups as compared to the controls. In alcoholics, the area under the curve (AUC) for HEX A activity/specific-activity was significantly greater than for HEX and HEX B. The salivary HEX A activity/specific-activity had good/excellent sensitivity and specificity in smoking and non-smoking alcoholics, whereas salivary HEX and HEX B had poor/fair sensitivity and specificity. CONCLUSIONS: Salivary HEX A may be helpful in the diagnosis of chronic alcohol intoxication, even in smokers. PMID- 23026817 TI - Sequential monitoring of transgene expression following Agrobacterium-mediated transformation of rice. AB - Although Agrobacterium-mediated transformation technology is now used widely in rice, many varieties of indica-type rice are still recalcitrant to Agrobacterium mediated transformation. It was reported recently that T-DNA integration into the rice genome could be the limiting step in this method. Here, we attempted to establish an efficient sequential monitoring system for stable transformation events by visualizing stable transgene expression using a non-destructive and highly sensitive visible marker. Our results demonstrate that click beetle luciferase (ELuc) is an excellent marker allowing the observation of transformed cells in rice callus, exhibiting a sensitivity >30-fold higher than that of firefly luciferase. Since we have previously shown that green fluorescent protein (GFP) is a useful visual marker with which to follow transient and/or stable expression of transgenes in rice, we constructed an enhancer trap vector using both the gfbsd2 (GFP fused to the N-terminus of blasticidin S deaminase) and eluc genes. In this vector, the eluc gene is under the control of the Cauliflower mosaic virus 35S minimal promoter, while the gfbsd2 gene is under the control of the full-length rice elongation factor gene promoter. Observation of transformed callus under a dissecting microscope demonstrated that the level of ELuc luminescence reflected exclusively stable transgene expression, and that both transient and stable expression could be monitored by the level of GFP fluorescence. Moreover, we show that our system enables sequential quantification of transgene expression via differential measurement of ELuc luminescence and GFP fluorescence. PMID- 23026820 TI - The evolution of radioembolisation. PMID- 23026818 TI - The KAC family of kinesin-like proteins is essential for the association of chloroplasts with the plasma membrane in land plants. AB - Chloroplasts require association with the plasma membrane for movement in response to light and for appropriate positioning within the cell to capture photosynthetic light efficiently. In Arabidopsis, CHLOROPLAST UNUSUAL POSITIONING 1 (CHUP1), KINESIN-LIKE PROTEIN FOR ACTIN-BASED CHLOROPLAST MOVEMENT 1 (KAC1) and KAC2 are required for both the proper movement of chloroplasts and the association of chloroplasts with the plasma membrane, through the reorganization of short actin filaments located on the periphery of the chloroplasts. Here, we show that KAC and CHUP1 orthologs (AcKAC1, AcCHUP1A and AcCHUP1B, and PpKAC1 and PpKAC2) play important roles in chloroplast positioning in the fern Adiantum capillus-veneris and the moss Physcomitrella patens. The knockdown of AcKAC1 and two AcCHUP1 genes induced the aggregation of chloroplasts around the nucleus. Analyses of A. capillus-veneris mutants containing perinuclear-aggregated chloroplasts confirmed that AcKAC1 is required for chloroplast-plasma membrane association. In addition, P. patens lines in which two KAC genes had been knocked out showed an aggregated chloroplast phenotype similar to that of the fern kac1 mutants. These results indicate that chloroplast positioning and movement are mediated through the activities of KAC and CHUP1 proteins, which are conserved in land plants. PMID- 23026821 TI - EGFR mutations in circulating tumour DNA. PMID- 23026822 TI - Unprovoked venous thromboembolism: assess for cancer. PMID- 23026823 TI - Trametinib for patients with advanced melanoma. PMID- 23026825 TI - Dickkopf-1 and hepatocellular carcinoma. PMID- 23026827 TI - Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. AB - Squamous-cell carcinomas of the lung (SQCLCs) are defined by unique clinicopathological and molecular characteristics that have evolved substantially over time. Historically, these neoplasms were the most common subtype of non small-cell lung cancers and were regarded as central tumours with high molecular complexity without targetable genetic abnormalities. Today, the incidence of SQCLCs is surpassed by adenocarcinomas of the lung with a shift towards peripheral squamous tumours. Differential responses to cytotoxic and biological treatments have reshaped our approach to standard therapies. Additionally, evidence of unique biology has emerged with the discovery of SOX2 amplification, NFE2L2 and KEAP1 mutations, PI3K pathway changes, FGFR1 amplification, and DDR2 mutations. These discoveries have ushered in a new era of targeted therapeutic agents for patients with this disease. This Review draws attention to the distinct clinical and pathological characteristics of SQCLCs, summarises present experience with existing cytotoxic and targeted therapies, and discusses emerging treatments based on new insights into the biology of this disease. PMID- 23026828 TI - Pharmacogenetic biomarkers for the prediction of response to antiangiogenic treatment. AB - Antiangiogenic treatments have shown activity across multiple tumour types and in various settings. Despite having been approved on the basis of efficacy, the therapeutic index varies substantially in different settings for many of these agents. A major limitation is the current inability to personalise treatment a priori according to findings on measurement of a predictive biomarker. The roles of germline single-nucleotide polymorphisms have been investigated as potential biomarkers for antiangiogenic treatments. The rationale is founded on the understanding that the drugs target the vasculature rather than the tumour, which could mean that much of the variability is regulated by the host. Several single nucleotide polymorphisms have been associated with differential outcomes and toxic effects in clinical trials. In this Review we provide an overview of available data with particular attention paid to the pitfalls and strengths of potential biomarkers. We also highlight continuing work and plans for confirmatory studies. PMID- 23026829 TI - Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. AB - Comprehensive geriatric assessment (CGA) is done to detect vulnerability in elderly patients with cancer so that treatment can be adjusted accordingly; however, this process is time-consuming and pre-screening is often used to identify fit patients who are able to receive standard treatment versus those in whom a full CGA should be done. We aimed to assess which of the frailty screening methods available show the best sensitivity and specificity for predicting the presence of impairments on CGA in elderly patients with cancer. We did a systematic search of Medline and Embase, and a hand-search of conference abstracts, for studies on the association between frailty screening outcome and results of CGA in elderly patients with cancer. Our search identified 4440 reports, of which 22 publications from 14 studies, were included in this Review. Seven different frailty screening methods were assessed. The median sensitivity and specificity of each screening method for predicting frailty on CGA were as follows: Vulnerable Elders Survey-13 (VES-13), 68% and 78%; Geriatric 8 (G8), 87% and 61%; Triage Risk Screening Tool (TRST 1+; patient considered frail if one or more impairments present), 92% and 47%, Groningen Frailty Index (GFI) 57% and 86%, Fried frailty criteria 31% and 91%, Barber 59% and 79%, and abbreviated CGA (aCGA) 51% and 97%. However, even in case of the highest sensitivity, the negative predictive value was only roughly 60%. G8 and TRST 1+ had the highest sensitivity for frailty, but both had poor specificity and negative predictive value. These findings suggest that, for now, it might be beneficial for all elderly patients with cancer to receive a complete geriatric assessment, since available frailty screening methods have insufficient discriminative power to select patients for further assessment. PMID- 23026830 TI - Delays in diagnosis of paediatric cancers: a systematic review and comparison with expert testimony in lawsuits. AB - Delayed diagnosis of paediatric cancers is reported regularly and is a source of remorse for physicians and parents and a leading cause of malpractice claims. We did a systematic review of information about the distribution, determinants, and consequences of time to diagnosis of paediatric malignancies and compared these findings with those of court-appointed expert witnesses in malpractice claims in Canada and France. Time to diagnosis varied widely between tumour types in the 98 relevant studies (medians ranged from 2-260 weeks) without any significant decrease with time. Determinants of a long delay in diagnosis included older age, qualification of the first physician contacted, non-specific symptoms, histological type, and tumour localisation. Delayed diagnosis was associated with poor outcome for retinoblastoma and possibly for leukaemia, nephroblastoma, and rhabdomyosarcoma (data were insufficient for definitive conclusions). It was not associated with an adverse outcome for most CNS tumours, osteosarcoma or Ewing's sarcoma, and, paradoxically, was frequently associated with better outcomes than was short time to diagnosis in these cancers. A third of the court-appointed experts provided testimony concordant with the medical literature. The relations between delay in diagnosis and outcome are complex and probably depend more on tumour biology than on parental or medical factors. PMID- 23026833 TI - Evaluation and use of childhood lung function tests in cystic fibrosis. AB - PURPOSE OF REVIEW: Lung disease begins early in life in cystic fibrosis (CF), yet our understanding of CF lung abnormalities in the first years of life remains limited. By facilitating earlier diagnosis, newborn screening for CF provides the opportunity to understand and characterize presymptomatic lung disease in infants and young children. This could lead to earlier interventions to mitigate disease progression at a time when therapeutic intervention or prevention may be most effective. This article reviews lung function tests that can be used during the first 5 years of life and discusses their potential applications as objective outcomes for clinical monitoring or research. RECENT FINDINGS: During the past decade, commercial equipment for assessing a wide range of lung function tests in infants and preschool children has become available together with international guidelines and improved reference equations with which to interpret results. The lung clearance index, derived from multiple breath washout, has been shown to be far more sensitive to early CF lung disease than conventional spirometric assessments. SUMMARY: Although limited evidence exists as to whether incorporating lung function tests into routine clinical care can improve patient outcomes during the early years, this is likely to be helpful in preschool children if more sensitive tests such as the multiple breath washout become more widely available. There is an urgent need to assess which infant and preschool lung function outcomes will provide the most robust outcome measures in collaborative multicenter studies, so that they can be incorporated into early therapeutic intervention studies. PMID- 23026831 TI - Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. AB - Acrolein is a common environmental, food and water pollutant and a major component of cigarette smoke. Also, it is produced endogenously via lipid peroxidation and cellular metabolism of certain amino acids and drugs. Acrolein is cytotoxic to many cell types including hepatocytes; however the mechanisms are not fully understood. We examined the molecular mechanisms underlying acrolein hepatotoxicity in primary human hepatocytes and hepatoma cells. Acrolein, at pathophysiological concentrations, caused a dose-dependent loss of viability of hepatocytes. The death was apoptotic at moderate and necrotic at high concentrations of acrolein. Acrolein exposure rapidly and dramatically decreased intracellular glutathione and overall antioxidant capacity, and activated the stress-signaling MAP-kinases JNK, p42/44 and p38. Our data demonstrate for the first time in human hepatocytes, that acrolein triggered endoplasmic reticulum (ER) stress and activated eIF2alpha, ATF-3 and -4, and Gadd153/CHOP, resulting in cell death. Notably, the protective/adaptive component of ER stress was not activated, and acrolein failed to up-regulate the protective ER-chaperones, GRP78 and GRP94. Additionally, exposure to acrolein disrupted mitochondrial integrity/function, and led to the release of pro-apoptotic proteins and ATP depletion. Acrolein-induced cell death was attenuated by N-acetyl cysteine, phenyl-butyric acid, and caspase and JNK inhibitors. Our data demonstrate that exposure to acrolein induces a variety of stress responses in hepatocytes, including GSH depletion, oxidative stress, mitochondrial dysfunction and ER stress (without ER-protective responses) which together contribute to acrolein toxicity. Our study defines basic mechanisms underlying liver injury caused by reactive aldehyde pollutants such as acrolein. PMID- 23026832 TI - Isoorientin induces apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cancer cells. AB - Isoorientin (ISO) is a flavonoid compound that can be extracted from several plant species, such as Phyllostachys pubescens, Patrinia, and Drosophyllum lusitanicum; however, its biological activity remains poorly understood. The present study investigated the effects and putative mechanism of apoptosis induced by ISO in human hepatoblastoma cancer (HepG2) cells. The results showed that ISO induced cell death in a dose-dependent manner in HepG2 cells, but no toxicity in human liver cells (HL-7702) and buffalo rat liver cells (BRL-3A) treated with ISO at the indicated concentrations. ISO-induced cell death included apoptosis which characterized by the appearance of nuclear shrinkage, the cleavage of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. ISO significantly (p<0.01) increased the Bax/Bcl-2 ratio, disrupted the mitochondrial membrane potential (MMP), increased the release of cytochrome c, activated caspase-3, and enhanced intracellular levels of reactive oxygen species (ROS) and nitric oxide (NO). In addition, ISO effectively inhibited the phosphorylation of Akt and increased FoxO4 expression. The PI3K/Akt inhibitor LY294002 enhanced the apoptosis-inducing effect of ISO. However, LY294002 markedly quenched ROS and NO generation and diminished the protein expression of heme peroxidase enzyme (HO-1) and inducible nitric oxide synthase (iNOS). Furthermore, the addition of a ROS inhibitor (N-acetyl cysteine, NAC) or iNOS inhibitor (N-[3-(aminomethyl) benzyl] acetamidine, dihydrochloride, 1400W) significantly diminished the apoptosis induced by ISO and also blocked the phosphorylation of Akt. These results demonstrated for the first time that ISO induces apoptosis in HepG2 cells and indicate that this apoptosis might be mediated through mitochondrial dysfunction and PI3K/Akt signaling pathway, and has no toxicity in normal liver cells, suggesting that ISO may have good potential as a therapeutic and chemopreventive agent for liver cancer. PMID- 23026834 TI - Bibliography. Sleep and respiratory neurobiology. Current world literature. PMID- 23026836 TI - Abdominal segment reduction: development and evolution of a deeply fixed trait. AB - When a new student first begins to push flies, an immediate skill that must be learned is sorting the sexes. In Drosophila melanogaster several sexually dimorphic characters can be used to readily distinguish males from females including abdominal pigmentation, male sex combs and genital morphology. Another, often-overlooked, sexual dimorphism is adult abdominal segment number. Externally, adult Drosophila males possess one fewer abdominal segment than females; the terminal pre-genital segment apparently either absent or fused with the next-most anterior segment. Beyond known roles for the homeotic protein Abdominal-B (Abd-B) and the sex-determining transcription factor Doublesex (Dsx) as key regulators of this trait, surprisingly little is known about either the morphogenetic processes or the downstream genetics responsible for patterning these events. We have explored both and found that rapid epithelial reorganization during pupation eliminates a nascent terminal male segment. We found this Abd-B-dependent process results from sex- and segment-specific regulation of diverse developmental targets including the wingless gene and surprisingly, dsx itself. ( 1) (,) ( 2) Here, I review our observations and discuss this trait as a model to explore both dynamics of epithelial morphogenesis as well as the evolution of developmental mechanisms. PMID- 23026837 TI - The promise of primary care-based screening for diabetic retinopathy: the devil will be in the details. PMID- 23026839 TI - Dinitrogen metal complexes with a strongly activated N-N bond: a computational investigation of [(Cy2N)3Nb-(MU-NN)-Nb(NCy2)3] and related [Nb-(MU-NN)-Nb] systems. AB - The structural and bonding properties of the dinitrogen-bridged diniobium [(Cy(2)N)(3)Nb(MU-NN)Nb(NCy(2))(3)] complex experimentally characterized by Berno and Gambarotta, which exhibits a strongly activated N-N bond of 134 pm, have been explored using density functional methods and compared with those of a series of related [(R(2)N)(3)Nb(MU-NN)Nb(NR(2))(3)] (R = H, Me, (i)Pr, (t)Bu, Cy) model species and other experimentally relevant [Nb(MU-NN)Nb] systems, in order to rationalize the unusually long N-N distance. Geometry optimizations of [(Cy(2)N)(3)Nb(MU-NN)Nb(NCy(2))(3)] and three other known systems indicate that the most favourable N-N distance lies within the range of commonly reported results for end-on bound dinitrogen-diniobium complexes, between 123 and 128 pm. However, structures exhibiting appreciably longer N-N distances, close to 134 pm, are found to be only weakly disfavoured, and may represent the preferred geometry in cases where lengthening of the N-N bond counteracts the effects of highly repulsive steric interactions between terminal fragments. Calculations on model complexes, in which small-sized [R = H, Me] terminal groups are involved, support the finding that N-N bond lengths within the 123-128 pm range are most favoured, whereas calculations on larger [R = (i)Pr, (t)Bu] model species indicate that the presence of excessively repulsive intramolecular interactions can lead to substantial changes in the geometric properties of the [Nb-NN-Nb] core, including significant increase in N-N bond length and activation. The preference for N-N distances ranging between 123 and 128 pm, irrespective of ligand size and identity, can be understood on the basis that the principal bonding mechanisms across the central [Nb-NN-Nb] core are largely unaffected by changes in the chemical composition and properties of terminal fragments. However, the balance between repulsive (steric) and attractive (electrostatic plus orbital) bonding contributions can be altered by the presence of geometrically rigid and oversized peripheral groups and, in these cases, the interplay between repulsive and attractive bonding effects is dominated by the former and can result in abnormally elongated N-N distances. The present calculations thus provide a rationale for the observed structural properties of the [(Cy(2)N)(3)Nb(MU NN)Nb(NCy(2))(3)] system on the basis of the interplay between electronic and steric factors. PMID- 23026838 TI - The effect of race-ethnicity and geography on adoption of innovations in the treatment of schizophrenia. AB - OBJECTIVE: This study evaluated the effect of race-ethnicity and geography on the adoption of a pharmacological innovation (long-acting injectable risperidone [LAIR]) among Medicaid beneficiaries with schizophrenia as well as the contribution of geographic location to observed racial-ethnic disparities. METHODS: The data source was a claims data set from the Florida Medicaid program for the 2.5-year period that followed the launch of LAIR in the U.S. market. Study participants were beneficiaries with schizophrenia who had filled at least one antipsychotic prescription during the study period. The outcome variable was any use of LAIR; model variables were need indicators and random effects for 11 Medicaid areas, which are multicounty units used by the Medicaid program to administer benefits. Adjusted probability of use of LAIR for blacks and Latinos versus whites was estimated with logistic regression models. RESULTS: The study cohort included 13,992 Medicaid beneficiaries: 25% of the cohort was black, 37% Latino, and 38% white. Unadjusted probability of LAIR use was lower for Latinos than whites, and use varied across the state's geographic areas. Adjustment for need confirmed the unadjusted finding of a disparity between Latinos and whites (odds ratio=.58, 95% confidence interval=.49-.70). The inclusion of geographic location in the model eliminated the Latino-white disparity but confirmed the unadjusted finding of geographic variation in adoption. CONCLUSIONS: Within a state Medicaid program, the initial finding of a disparity between Latinos and whites in adopting LAIR was driven by geographic disparities in adoption rates and the geographic concentration of Latinos in a low-adoption area. Possible contributors and implications of these results are discussed. PMID- 23026841 TI - Significant correlation between the acceleration of platelet aggregation and phosphorylation of HSP27 at Ser-78 in diabetic patients. AB - To clarify the mechanism underlying a high risk of thrombotic complications in diabetic patients, we investigated the relationship between HSP27 phosphorylation and the platelet activation induced by adenosine diphosphate (ADP) in diabetic patients. Platelet-rich plasma was prepared from the blood of type 2 diabetes mellitus (DM) patients. By measuring the dose response of platelet aggregation to ADP, an individual ED50 was determined. Based on the normal range identified in non-DM controls, the subjects were divided into a hyper-aggregate (Group 1) and a normo- or hypo-aggregate group (Group 2). The protein phosphorylation was analyzed by western blotting. The release of PDGF-AB and sCD40 ligand (sCD40L) was measured by ELISA. In both groups, ADP induced HSP27 phosphorylation at Ser 78 and Ser-82. The phosphorylation at Ser-78 and the release of both PDGF-AB and sCD40L induced by a low dose of ADP (1 uM) in Group 1 were significantly higher than these values in Group 2. There was a significant relationship between the ADP-induced HSP27 phosphorylation level at Ser-78 and the ADP ED50 value of platelet aggregation. The ADP (1 uM)-induced phosphorylation of HSP at Ser-78 observed in the platelets from Group 1 was inhibited by PD98059 or SB203580. The use of aspirin ameliorated the accelerated microaggregation of platelets in Group 1, and the low-dose ADP-induced phosphorylation of HSP27 at Ser-78 was no longer observed. These results strongly suggest that the phosphorylation of HSP27 at Ser 78 is correlated with the acceleration of platelet aggregation induced by ADP in type 2 DM patients. PMID- 23026842 TI - Tailored Li4Ti5O12 nanofibers with outstanding kinetics for lithium rechargeable batteries. AB - We report on the synthesis of one-dimensional (1D) Li(4)Ti(5)O(12) nanofibers through electrospinning and their outstanding electrochemical performances. Li(4)Ti(5)O(12) with a spinel structure is a promising candidate anode material for lithium rechargeable batteries due to its well-known zero-strain merits. In order to improve the electronic properties of spinel Li(4)Ti(5)O(12), which are intrinsically poor, we processed the material into a nanofiber type of architecture to shorten the Li(+) and electron transport distance using a versatile electrospinning approach. The electrospun Li(4)Ti(5)O(12) nanofiber showed significantly enhanced discharging/charging properties, even at high rates that exceeded 10 C, demonstrating that the nanofiber offers an attractive architecture for enhanced kinetics. PMID- 23026843 TI - Comparative pharmacokinetics/pharmacodynamics of clopidogrel besylate and clopidogrel bisulfate in healthy Korean subjects. AB - BACKGROUND: Clopidogrel selectively inhibits platelet aggregation. Clopidogrel bisulfate (Plavix((r))) was first developed for atherothrombosis prevention and is commonly prescribed for this indication. A new clopidogrel formulation, clopidogrel besylate (KOVIX((r))), has recently been developed. OBJECTIVE: This study was designed to compare the multiple-dose pharmacokinetics/pharmacodynamics and tolerability of clopidogrel besylate with those of clopidogrel bisulfate in 40 healthy male subjects. METHODS: This was an open-label, randomized-sequence, multiple-dose, two-period, two-treatment crossover study. The subjects were randomly assigned to a sequence group that received two treatments: clopidogrel besylate 75 mg followed by clopidogrel bisulfate 75 mg, or vice versa. The subjects received a 300-mg loading dose on day 1 followed by 75 mg daily for the next 4 days. Serial blood samples were collected to determine the concentrations of clopidogrel and its carboxylic acid metabolite, SR26334. Platelet aggregation and bleeding times were measured. Tolerability was evaluated throughout the study. RESULTS: The clopidogrel plasma concentration-time profiles of the formulations were similar. The measured pharmacokinetic parameters did not differ significantly between the clopidogrel besylate and clopidogrel bisulfate groups. The geometric mean ratios of the clopidogrel besylate group to the clopidogrel bisulfate group with respect to the maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUC(last)) were 0.96 (90 % confidence interval [CI] 0.82, 1.12) and 0.95 (0.81, 1.11), respectively. Moreover, the pharmacokinetic parameters of SR26334 did not differ significantly between the two treatment groups. Furthermore, the areas under the platelet aggregation inhibition-time curves (AUIC) and the maximum inhibitory effects (I(max)) did not differ significantly between the two groups. The geometric mean ratios (clopidogrel besylate to clopidogrel bisulfate) were 1.01 (90 % CI 0.95, 1.08) for the I(max) and 0.98 (0.89, 1.07) for the AUIC. Both formulations were well tolerated and exhibited comparable safety profiles. CONCLUSION: This study demonstrated that the pharmacokinetic/pharmacodynamic profiles of clopidogrel besylate were not significantly different from those of clopidogrel bisulfate. Both formulations were well tolerated in healthy subjects. PMID- 23026844 TI - Lifetime cost-utility analyses of deferasirox in beta-thalassaemia patients with chronic iron overload: a UK perspective. AB - BACKGROUND AND OBJECTIVES: Regular blood transfusions for beta-thalassaemia patients lead to the accumulation of iron deposits in the body. In order to remove such deposits, iron chelation therapy is required. Subcutaneously administered deferoxamine has been the gold standard chelation therapy for over 40 years. Deferasirox is a newer chelation therapy that is taken orally once daily. The objective of this study was to estimate the long-term costs and quality-adjusted life-years (QALYs) associated with deferoxamine and deferasirox in a cohort of transfusion-dependent beta-thalassaemia patients from a UK health service perspective. METHODS: A 50-year annual cycle state transition model comprised three core health states: alive without cardiac complications, alive with cardiac complications, and dead, as well as representing other chronic complications of iron overload: diabetes, hypogonadism, hypoparathyroidism and hypothyroidism. The model was calibrated to identify sets of convergent input parameter values that predicted observed overall survival by mean lifetime compliance with chelation therapy. A pivotal non-inferiority trial informed the main estimates of the effectiveness of deferasirox, which were applied to the calibrated model. Using cost values for the year 2011, costs and utilities were summed over patients' lifetimes to estimate lifetime costs and QALY gains. RESULTS: Mean lifetime treatment costs for patients receiving deferoxamine were L70,000 higher than deferasirox. Drug acquisition costs were L100,000 higher for deferasirox, but administration costs associated with deferoxamine were L170,000 higher. Higher compliance associated with oral deferasirox administration led to fewer complications. Combined with the quality-of-life effects of an oral mode of administration, an average gain of 4.85 QALYs for deferasirox was estimated. In the base case, deferasirox dominates deferoxamine, i.e., costs less and patients gain more QALYs. The key parameter is the proportion of deferoxamine patients using balloon infusers. Sensitivity analyses showed that even when the proportion of patients using balloon infusers is decreased from 79 to 25 %, the incremental cost per QALY gained remains well under L20,000. CONCLUSION: Higher drug acquisition costs for deferasirox are offset by the avoidance of infusion-related equipment costs. Combined with health benefits derived from an oral mode of administration and improved compliance, deferasirox has a high probability of being a cost-effective intervention compared with deferoxamine. PMID- 23026845 TI - Achieving and sustaining remission in bipolar I disorder with ziprasidone : a post hoc analysis of a 24-week, double-blind, placebo-controlled study. AB - BACKGROUND AND OBJECTIVE: A number of operational definitions have been proposed to describe outcomes in bipolar disorders; the criteria used to define terms such as recurrence, relapse, response, remission and recovery have varied both in observational studies and in clinical trials. We carried out a post hoc analysis of rates of symptomatic point remission and sustained remission using four different remission criteria that had been evaluated in a previously published 24 week, double-blind, placebo-controlled study. METHODS: After stabilization for 8 consecutive weeks on open-label ziprasidone plus lithium or valproate, stabilized subjects were randomized to two groups, ziprasidone with lithium or valproate (ziprasidone group), or placebo with lithium or valproate (placebo group) for 16 weeks. Four remission criteria included (i) Mania Rating Scale (MRS) score <=7, (ii) MRS <=7 + Montgomery-Asberg Depression Rating Scale (MADRS) score <=10, (iii) MRS <=7 + Clinical Global Impression-Improvement (CGI-I) = 1, (iv) MRS score <=7 + MADRS score <=10 + CGI-I score = 1. We examined the percentages of subjects in each treatment group achieving symptomatic point (i.e. at each visit) and sustained (i.e. for >=8 weeks) remission during the double-blind phase. RESULTS: At week 24, symptomatic point remission based on the above two more stringent criteria was achieved by 48.0 and 24.4% of the ziprasidone group versus 36.9 and 18.0% of placebo recipients, respectively (p = 0.04 and 0.14). Sustained remission rates at 24 weeks were 42.5 and 18.1% for ziprasidone, respectively (vs 33.3 and 14.4% for placebo, p = 0.04 and 0.21, respectively). CONCLUSION: This analysis indicates that ziprasidone plus lithium or valproate treatment showed modest to moderate remission rates at week 24 based on four different remission criteria in terms of symptomatic and sustained remission, despite the stringent criteria. Our findings indicate that ziprasidone may be effective in achieving sustained remission in bipolar I disorder and propose that a better understanding regarding the definition of remission in bipolar disorders should be required in clinical practice since our results showed different remission rates with different remission criteria. PMID- 23026846 TI - Effect of intravitreal triamcinolone acetonide on healing of retinal photocoagulation lesions. AB - PURPOSE: To evaluate the effect of intravitreal triamcinolone acetonide (TA) on healing of retinal photocoagulation lesions using drug and laser dosing typically employed in clinical practice. METHODS: Laser burns with a 267-MUm retinal beam size at 532-nm wavelength were applied to 40 eyes of Dutch belted rabbits. Barely visible to intense lesions were produced with pulses of 5, 10, 20, and 50 milliseconds and power of 175 mW. Eyes received intravitreal injections of either 2 mg TA/50 MUL or balanced salt solution administered either 1 week before or immediately after laser treatment. Lesion grades were assessed acutely ophthalmoscopically and by a masked observer histologically at 1, 3, 7, 30, and 60 days. RESULTS: Both TA groups demonstrated significant reduction in retinal thickness throughout follow-up compared with balanced salt solution groups (P < 0.001). The width of the lesions at 1 day after injection was not significantly different between groups. However, by 7 days, the lesions in balanced salt solution groups contracted much more than in the TA groups, especially the more intense burns, and this difference persisted to 2 months. The healing rate of the barely visible burns was not significantly affected by TA compared with the balanced salt solution control eyes. CONCLUSION: Triamcinolone acetonide injection previously or concurrently with photocoagulation significantly decreases laser-induced edema but interferes with lesions healing, thereby leaving wider residual scarring, especially persistent in more intense burns. PMID- 23026847 TI - Open globe ocular trauma: functional outcome of eyes with no light perception at initial presentation. AB - PURPOSE: To evaluate characteristics and prognostic factors for functional success in eyes that present with no light perception (NLP) after open globe trauma. METHODS: The medical records of all subjects presenting to a single university referral center with visual acuity (VA) of NLP after sustaining an open globe eye injury from January 1, 2001, through June 30, 2010, were retrospectively analyzed to determine epidemiologic and clinical factors associated with visual outcomes. RESULTS: Of the 73 NLP eyes (73 patients) that underwent primary repair and were included in the study, final VA was 20/100 in 1 eye (1%), counting fingers in 2 eyes (3%), hand motion in 9 eyes (12%), light perception in 5 eyes (7%), and NLP in 56 eyes (77%). Recovery of some vision on postoperative Day 1, pars plana vitrectomy operation, and Zone 2 injury were significantly associated with an improvement in final VA. Zone 3 injuries were the most likely to result in NLP final VA, although this difference was not statistically significant. CONCLUSION: Visual recovery to light perception or better on postoperative Day 1 increases the likelihood of having a long-term improvement in VA. Pars plana vitrectomy may be beneficial in such eyes if posterior segment abnormalities are noted. PMID- 23026848 TI - Diagnostic and therapeutic challenges. PMID- 23026849 TI - Idiopathic multifocal choroiditis: a comment on present and past nomenclature. PMID- 23026850 TI - Aligning prognosis, patient goals, policy, and care models for palliative care in nursing homes. PMID- 23026851 TI - Synthesis and structures of transition metal pacman complexes of heteroditopic Schiff-base pyrrole macrocycles. AB - A series of polydentate dual-compartment, Schiff-base pyrrole macrocycles has been prepared through the straightforward Lewis acid catalysed [1 + 1] condensation reactions between ONO or O(5)-linked aryldiamines and dipyrromethane dialdehydes. These macrocycles display hydrogen-bond acceptor and donor properties and provide distinct N(4) and O(5)/ONO donor sets for metallation reactions, so forming alkali, alkaline earth, and transition metal complexes that were characterised spectroscopically and crystallographically. While the conformationally flexible O(5) donor set allows the formation of helical potassium salt structures, the transition metal complexes of all variants of these macrocycles invariably adopt wedged, Pacman-shaped structures in which the metal is bound in the pyrrole-imine N(4) donor set, so leaving the ONO/O(5) donor set pendant and apical. In some cases (V, Cr, and Co), this proximate combination of Lewis acid binding site and hydrogen bond acceptor facilitates the coordination of water within the molecular cleft; alternatively, direct interaction between the pendant arm and the metal is seen (e.g. Ti). Higher order [2 + 2] macrocycles were also prepared as minor, inseparable by-products of cyclisation, and Fe(2), Mn(2), and Co(2) complexes of these larger macrocycles were found to adopt binuclear helical structures by X-ray crystallography. PMID- 23026853 TI - Grape seed proanthocyanidins inhibit colon cancer-induced angiogenesis through suppressing the expression of VEGF and Ang1. AB - Tumor cells trigger angiogenesis through overexpression of various angiogenic factors including vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1). Therefore, inhibition of the expression of both VEGF and Ang1, the initial step of tumor angiogenesis, is a promising strategy for cancer chemoprevention and therapy. Grape seed proanthocyanidins (GSPs) are widely consumed dietary supplements that have antitumor activity. Due to their polymeric structure, GSPs are poorly absorbed along the gastrointestinal tract and can reach the colon at high concentrations, allowing these chemicals to act as chemopreventive agents for colon cancer. In the present study, we found that GSPs inhibited colon tumor-induced angiogenesis and, thus, the growth of colon tumor xenografts on the chick chorioallantoic membranes. The mechanisms of their action were related to inhibiting the expression of both VEGF and Ang1 through scavenging reactive oxygen species. Previous studies have demonstrated that the chemopreventive effects of GSPs on colon cancer are associated with their growth inhibitory and apoptosis-inducing effects. Our results demonstrate another mechanism by which GSPs inhibit colon tumor growth, which will be helpful for developing GSPs as a pharmacologically safe angiopreventive agent against colorectal cancer. PMID- 23026854 TI - Use of standard Webcam and Internet equipment for telepsychiatry treatment of depression among underserved Hispanics. AB - OBJECTIVE: Depression affects nearly one in five Americans at some time in their life, causing individual suffering and financial cost. The Internet has made it possible to deliver telemedicine care economically to areas and populations with limited access to specialist or culturally and linguistically congruent care. METHODS: This study compared the effectiveness for Hispanic patients of depression treatment provided by a psychiatrist through Internet videoconferencing (Webcam intervention) and treatment as usual by a primary care provider. Adults (N=167) with a diagnosis of depression were recruited from a community clinic and were randomly assigned to treatment condition. Webcam participants met remotely each month with the psychiatrist, and treatment-as usual patients received customary care from their primary care providers, all for six months. At baseline and three and six months, analyses of variance tested differences between conditions in scores on depression rating scales and quality of-life and functional ability measures. RESULTS: All participants experienced an improvement in depression symptoms. Ratings on the Montgomery-Asberg Depression Rating Scale by clinicians blind to treatment group and self-ratings on the nine item Patient Health Questionnaire, Quality of Life Enjoyment and Satisfaction Questionnaire, and Sheehan Disability Scale showed a significant main effect of time. On all four measures, a significant interaction of time by intervention favoring the Webcam group was noted. DISCUSSION: Results suggest that telepsychiatry delivered through the Internet utilizing commercially available domestic Webcams and standard Internet and computer equipment is effective and acceptable. Use of this technology may help close the gap in access to culturally and linguistically congruent specialists. PMID- 23026855 TI - Visual test of subparts per billion-level copper(II) by Fe3O4 magnetic nanoparticle-based solid phase extraction coupled with a functionalized gold nanoparticle probe. AB - By combining Fe(3)O(4) magnetic nanoparticle-based solid phase extraction with a gold nanoparticle-based visual test, a novel method was developed for the field assay of Cu(ii) in environmental water at subparts per billion-levels within 30 min. When a 200 mL water sample was treated with 12.5 mg L(-1) Fe(3)O(4) nanoparticles by the proposed procedure, the detection limit with the naked eye was 0.2 MUg L(-1) Cu(ii). The proposed method is very specific to Cu(ii), with tolerance against at least 100-fold amounts of other environmentally relevant metal ions except for Hg(ii) (25-fold), and was successfully applied to the detection of trace Cu(ii) in tap water, river water, and treated wastewater, and results agreed well with that determined by inductively coupled plasma-mass spectrometry (ICP-MS). PMID- 23026857 TI - The genetics of scleroderma: looking into the postgenomic era. AB - PURPOSE OF REVIEW: The last decade has seen enormous progress in understanding genetic associations of systemic sclerosis to explain the observed heritability. This review highlights the most recent findings and places them in the context of proposed functional roles. RECENT FINDINGS: Over 30 genes and gene regions have now been identified as scleroderma susceptibility loci. These include both human leukocyte antigen (HLA) and non-HLA genes, most of which involve immune-related pathways and modifiers of immune function. Many of these associations have also been reported in other systemic autoimmune diseases and suggest that there are multiple autoimmunity genes resulting in disease occurrence. SUMMARY: In spite of these advances, only a small proportion of the heritability of systemic sclerosis has been explained. Ongoing studies include fine mapping and sequencing studies to identify causal variants, whereas other studies focus on functional consequences of these variants in order to identify the link between these genetic variants and disease susceptibility. Such knowledge should lead to more targeted and effective treatment in this disease. PMID- 23026858 TI - Cerebrospinal fluid biomarkers in neurological diseases in children. AB - Analysis of cerebrospinal fluid (CSF) biomarkers is an integral part of neurology. Basic CSF biomarkers, such as CSF/serum albumin ratio and CSF cell counts, have been used to diagnose inflammatory and infectious CNS disorders in adults and children for decades. During recent years, however, numerous biomarkers for neuronal and astroglial injury, as well as disease-specific protein inclusions, have been developed for neurodegenerative disorders in adults. The overall aim of this paper is to give an updated overview of some of these biomarkers with special focus on their possible relevance to neurological disorders in children and adolescents. PMID- 23026859 TI - Rapid synthesis of arylgold compounds using dielectric heating. AB - Dielectric heating has been successfully used in the preparation of a range of arylgold compounds. The approach is tolerant of a number of functional groups and rapidly generates the organometallic complexes in moderate to excellent yields. PMID- 23026861 TI - Heterogeneous nanoclusters assembled by PNA-templated double-stranded DNA. AB - Heterogeneous nanoclusters with trimeric and core-shell architectures containing nanoparticles of different size and composition have been fabricated via site specific PNA-"invasion" of DNA double helix. This novel strategy facilitates the incorporation of double-stranded DNA into the nanoparticle assembly design. PMID- 23026862 TI - Recognition of Lyme in time. PMID- 23026864 TI - Is defibrillation testing of ICDs necessary? AB - Defibrillation testing during implantation of cardioverter-defibrillators is controversial because of potential safety concerns and a lack of evidence for the effectiveness of the procedure. New data from the SAFE-ICD study is helpful, but does not completely resolve the issue. PMID- 23026863 TI - Topographic and quantitative relationship between prostate inflammation, proliferative inflammatory atrophy and low-grade prostate intraepithelial neoplasia: a biopsy study in chronic prostatitis patients. AB - Inflammatory processes are important components in the pathogenesis of many human cancers. According to the 'injury and regeneration' model for prostate carcinogenesis, injury caused by pathogens or pro-inflammatory cytotoxic agents would trigger proliferation of prostatic glandular cells, leading to the appearance of epithelial lesions named 'Proliferative Inflammatory Atrophy' (PIA). Inflammatory cells infiltrating the prostate would release genotoxic reactive oxygen species, leading atrophic cells to neoplastic progression. The hypothesis pointing to PIA as risk-lesion for prostate cancer has been extensively investigated at the cellular and molecular levels, but few morphological data are available linking PIA or prostatic intraepithelial neoplasia (PIN) to inflammation or clinical prostatitis. We investigated at the morphological level 1367 prostate biopsies from 98 patients with a recent history of chronic prostatitis, and 32 patients with biopsies positive for carcinoma. Our results show that i) PIA is found more frequently in biopsy cores containing a severe or moderate inflammatory focus, compared to NON-PIA lesions (partial or cystic atrophy); ii) the PIA lesion post-atrophic hyperplasia is more frequently found in tissues showing mild or no inflammation; iii) the extent of PIA per patient correlates with the burden of moderate or severe inflammation, whereas NON-PIA lesions do not; iv) low-grade PIN is in over 90% of cases emerging from normal, non-atrophic glands and is more frequently found in biopsy cores with absent or mild inflammatory burden; v) the inverse relationship between the prevalence of low-grade PIN and the extent of PIA lesions per patient is described by a power law function, suggesting the low likelihood of the concomitant presence of these lesions in the same tissue; vi) NON-PIA lesions correlate inversely with neoplasia in patients with prostate cancer; vii) the total scores of the NIH-CPSI questionnaire correlate with both PIA and inflammation burdens at diagnosis of prostatitis but not after pharmacological intervention. These results point to a positive association between tissue inflammation, clinical prostatitis and the putative cancer risk-lesion PIA, but do not support a model whereby low-grade PIN would arise from PIA. PMID- 23026865 TI - Pros and cons of high-sensitivity assays for cardiac troponin. AB - A 3-h algorithm using high-sensitivity assays for cardiac troponin to rule out myocardial infarction (MI) is recommended in current ESC guidelines. Whether faster rule-out algorithms can discriminate between MI and other conditions that elevate the troponin level, or be safely implemented across the whole spectrum of patient risk, is unclear. PMID- 23026866 TI - Heterogeneity in aripiprazole diffusion for bipolar disorder treatment in the Veterans Health Administration. AB - OBJECTIVES: The objectives of this study were to ascertain the relative importance of scientific "approval" versus U.S. Food and Drug Administration (FDA) regulatory approval regarding changes in aripiprazole prescribing rates for treating bipolar disorder and to identify system-level covariates associated with faster regional uptake of aripiprazole. METHODS: Medication use data for 2002 2009 were obtained from the Veterans Health Administration (VHA) National Psychosis Registry for 106,547 patients with diagnoses of bipolar disorder, aggregated at the level of the Veterans Integrated Service Network (VISN). VISN level independent variables were obtained from several VHA organizational databases. Interrupted time-series analysis was used to examine changes in rates of prescribing aripiprazole, and logistic regression was used to model above- versus below-median growth in aripiprazole prescribing across VISNs. RESULTS: Three inflections were observed, corresponding to the publication of two positive studies and FDA approval of aripiprazole for the treatment of bipolar mania. No significant VISN-level policy, administrative, or staffing predictors of the growth rate in aripiprazole prescribing were identified. Exploratory analyses showed that access to care may play a role in uptake, whereas competing demands, such as substance abuse treatment needs, may retard adoption. CONCLUSIONS: Early published evidence may have a strong impact on practice for low-barrier innovations, such as newly marketed medications or changes in indication for approved medications. Regional targeting of prescriber behavior interventions may maximize efficiency in efforts to change prescribing; further delineation of factors associated with regional heterogeneity in prescribing would support such efforts. PMID- 23026867 TI - Radiation exposure to the surgeon during percutaneous endoscopic lumbar discectomy: a prospective study. AB - STUDY DESIGN: A prospective study. OBJECTIVE: The purpose of this study was to determine the radiation dose to which the surgeons are exposed during percutaneous endoscopic lumbar discectomy (PELD) and to calculate the allowable number of cases per year. SUMMARY OF BACKGROUND DATA: Transforaminal PELD is a minimally invasive technique for soft disc herniation. Minimal invasiveness can be achieved through the use of fluoroscopy and endoscopy. The radiation dose to the surgeon during PELD is unknown. METHODS: The occupational radiation dose absorbed by 3 spinal surgeons performing 30 consecutive PELDs (33 levels) during a 3-month period was evaluated. Transforaminal PELDs were performed according to the standard technique. The radiation exposure of the neck, chest, arm, and both hands of the surgeons was measured. Occupational exposure guidelines of National Council on Radiation Protection & Measurements were used to calculate the allowable number of procedures per year. RESULTS: The mean operation time was 49.8 minutes, and the mean fluoroscopy time was 2.5 minutes. No significant correlations were found between operation time and fluoroscopy time. The calculated radiation doses per operated level were as follows: neck, 0.0785 mSv; chest, 0.1718 mSv; right upper arm, 0.0461 mSv; left ring finger, 0.7318 mSv; and right ring finger, 0.6694 mSv. The protective effects of a lead collar and lead apron were demonstrated by the reduction of the radiation dose by 96.9% and 94.2%, respectively. Therefore, with regard to whole-body radiation, 5379 operations can be performed per year using a lead apron, whereas only 291 operations can be performed without using a lead apron. Moreover, 1910 operations can be performed within the occupational exposure limit for the eyes (150 mSv), and 683 operations can be performed within the occupational exposure limit for the hands (500 mSv). CONCLUSION: Without radiation shielding, a surgeon performing 291 PELDs annually would be exposed to the maximum allowable radiation dose. Given the measurable lifetime radiation hazards to the surgeon, the use of adequate protective equipment is essential to reducing exposure during PELD. PMID- 23026868 TI - Improving the best available evidence component of evidence-based medicine: it's all in the question! PMID- 23026869 TI - Spinal high-velocity low amplitude manipulation in acute nonspecific low back pain: a double-blinded randomized controlled trial in comparison with diclofenac and placebo. AB - STUDY DESIGN: A randomized, double-blinded, placebo-controlled, parallel trial with 3 arms. OBJECTIVE: To investigate in acute nonspecific low back pain (LBP) the effectiveness of spinal high-velocity low-amplitude (HVLA) manipulation compared with the nonsteroidal anti-inflammatory drug diclofenac and with placebo. SUMMARY OF BACKGROUND DATA: LBP is an important economical factor in all industrialized countries. Few studies have evaluated the effectiveness of spinal manipulation in comparison to nonsteroidal anti-inflammatory drugs or placebo regarding satisfaction and function of the patient, off-work time, and rescue medication. METHODS: A total of 101 patients with acute LBP (for <48 hr) were recruited from 5 outpatient practices, exclusion criteria were numerous and strict. The subjects were randomized to 3 groups: (1) spinal manipulation and placebo-diclofenac; (2) sham manipulation and diclofenac; (3) sham manipulation and placebo-diclofenac. Outcomes registered by a second and blinded investigator included self-rated physical disability, function (SF-12), off-work time, and rescue medication between baseline and 12 weeks after randomization. RESULTS: Thirty-seven subjects received spinal manipulation, 38 diclofenac, and 25 no active treatment. The placebo group with a high number of dropouts for unsustainable pain was closed praecox. Comparing the 2 active arms with the placebo group the intervention groups were significantly superior to the control group. Ninety subjects were analyzed in the collective intention to treat. Comparing the 2 intervention groups, the manipulation group was significantly better than the diclofenac group (Mann-Whitney test: P = 0.0134). No adverse effects or harm was registered. CONCLUSION: In a subgroup of patients with acute nonspecific LBP, spinal manipulation was significantly better than nonsteroidal anti-inflammatory drug diclofenac and clinically superior to placebo. PMID- 23026870 TI - Acupuncture for chronic low back pain: a multicenter, randomized, patient assessor blind, sham-controlled clinical trial. AB - STUDY DESIGN: Multicenter, randomized, patient-assessor blind, sham-controlled clinical trial. OBJECTIVE: To investigate the efficacy of acupuncture treatment with individualized setting for reduction of bothersomeness in participants with chronic low back pain (cLBP). SUMMARY OF BACKGROUND DATA: Low back pain is one of the main reasons of disability among adults of working age. Acupuncture is known as an effective treatment of cLBP, but it remains unclear whether acupuncture is superior to placebo. METHODS: One hundred thirty adults aged 18 to 65 years with nonspecific LBP lasting for at least last 3 months prior to the trial participated in the study from 3 Korean medical hospitals. Participants received individualized real acupuncture treatments or sham acupuncture treatments for more than 6 weeks (twice a week) from Korean Medicine doctors. Primary outcome was change of visual analogue scale (VAS) score for bothersomeness of cLBP. Secondary outcomes included VAS score for pain intensity and questionnaires including Oswestry Disability Index, general health status (Short Form-36), and Beck Depression Inventory (BDI). RESULTS: There were no baseline differences observed between the 2 groups, except in the Oswestry Disability Index. One hundred sixteen participants finished the treatments and 3- and 6-month follow ups, with 14 subjects dropping out. Significant difference in VAS score for bothersomeness and pain intensity score of cLBP has been found between the 2 groups (P < 0.05) at the primary end point (8 wk). In addition, those 2 scores improved continuously until 3-month follow-up (P = 0.011, P = 0.005, respectively). Oswestry Disability Index, the Beck Depression Inventory, and Short Form-36 scores were also improved in both groups without group difference. CONCLUSION: This randomized sham-controlled trial suggests that acupuncture treatment shows better effect on the reduction of the bothersomeness and pain intensity than sham control in participants with cLBP. PMID- 23026871 TI - Paulus aegineta: review of spine-related chapters in "Epitomoe medicoe libri septem". AB - STUDY DESIGN: Analysis of chapters related to spinal fractures and dislocations of an important medical book from medieval age. A historical study. OBJECTIVE: To present the sections on spinal fractures and dislocations in the treatise of Paulus Aegineta or Paul of Aegina, and to discuss their relationship with preceding and subsequent literature. SUMMARY OF BACKGROUND DATA: Paul of Aegina was influenced by precedent great authors and provided a significant link in the transmission of the surgical knowledge to present day via the prominent physicians of Islamic golden age. METHODS: The edition on which this study is based was translated from Greek into English by Francis Adams and was published in 1846 by The Sydenham Society in London in 3 volumes. The related sections were examined and compared with the treatises of earlier and subsequent writers. RESULTS: Although Paul of Aegina was influenced by Hippocrates, Celsus, and Galen, he also put forward his own opinions. The most prominent representatives of the Islamic Golden Age, Rhazes, Albucasis, Avicenna, and Haly Abas were influenced by Paul of Aegina. CONCLUSION: Paul of Aegina, who was the last representative of the Byzantine School, compiled approximately 1000 years of medical knowledge up to his own era. By taking on this task, he provided a significant link in the transmission of ancient knowledge to later generations. He is also considered as a bridge between Western and Eastern medicines as he conveyed medical knowledge of the ancient era to Islamic authors. PMID- 23026873 TI - Irradiated allograft bone in spine surgery: to culture or not? A single center retrospective study. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVE: We aimed to document the rate of infection in our institution after the use of irradiated cancellous allograft or iliac crest bone autograft in vertebral fusion procedures. We also reviewed the pertinence of microbiological culture of cadaveric allograft bone prior to its implantation. SUMMARY OF BACKGROUND DATA: Recent studies have shown similar postoperative infection rates between allograft and autograft. The pertinence of microbiological culture of allograft bone prior to its implantation is currently controversial. METHODS: Retrospectively, we identified 338 patients who underwent spine fusion procedures for which there was a minimum of a 1-year follow-up. Files from both the neurosurgery and orthopedics divisions of the Centre hospitalier universitaire de Sherbrooke were reviewed during 1999 to 2009. Irradiated allografts were used in 164 patients and autografts were used in 174 patients. Of the 164 allografts implanted, 53 were cultured peroperatively. Postoperative spinal infection was based on documented positive spine cultures at the time of re-exploration for presumed infection. Infection rates were compared using Fisher exact test. RESULTS: From the 53 peroperative cultures, 5 were positive (9.4%) and none of them led to antibiotherapy or surgical revision at 1 year. No significant difference was observed in the rate of surgical site infection at 1 year, after the use of irradiated allografts (1.8%) or autografts (1.7%), P = 1.0. CONCLUSION: Perceived association with infection should not influence the surgeon in bone graft choice for spinal fusion. There is a lack of scientific evidence to recommend for or against routine cultures on allograft implantation in the literature. Our results strongly underline the pertinence of larger multicenter clinical trials to assess the pertinence of peroperative allograft bone culture. PMID- 23026874 TI - Upconversion polymeric nanofibers containing lanthanide-doped nanoparticles via electrospinning. AB - Flexible and freestanding poly(methyl methacrylate) nanofibers containing the upconversion nanoparticles (UCNPs) of lanthanide-doped sodium yttrium fluoride have been successfully fabricated via an electrospinning process. The UCNPs in nanofibers commonly formed chain-like aggregates aligned along the fiber axes. The effect of the electrospinning process on the upconversion properties of the embedded UCNPs was explored by characterizing the time evolution of the upconversion emission following pulsed near-infrared excitation. Our study revealed that there is only a slight reduction of upconversion efficiency for the UCNPs in electrospun nanofibers, indicating that upconversion properties of the UCNPs are largely preserved in the nanofibrous films. The prepared upconversion nanocomposites (in the form of nanofibrous films) with controlled morphologies, structures, and properties could be useful for broad photonic applications. PMID- 23026875 TI - Paraneoplastic rheumatologic syndromes. AB - PURPOSE OF REVIEW: To describe rheumatic syndromes that can be a paraneoplastic manifestation of an underlying malignancy. The pathogenesis of paraneoplastic rheumatologic diseases is complex and not fully understood in the majority of instances. In the absence of a defined pathogenic link between the malignancy and the rheumatic syndrome, the association between these diseases has been based on concurrence and a parallel clinical course. RECENT FINDINGS: This is an updated review of paraneoplastic presentations of synovitis, bone disease, myositis, and vasculitis. SUMMARY: Although paraneoplastic rheumatic syndromes are rare, clinicians should be aware that they can be the first sign of an occult malignancy and that early recognition is vital for early cancer diagnosis and treatment. PMID- 23026876 TI - Haematological cancer: European LeukemiaNet AML genetic classification works. PMID- 23026879 TI - Particle chain display--an optofluidic electronic paper. AB - A particle-based display medium and a driving mechanism insensitive to the charge polarity of those particles, based on the transformation of particle chains, are developed for reflective electronic paper displays. Particle chains are formed by dipole-dipole interactions between polarized particles with an appropriate electric field applied across the tested display medium, i.e. the solution that regulates the light in the field of display technology, containing neutral polystyrene (PS) particles dispersed in water. Formation of the particle chains results in a large change in optical transmittance and reflectance of the display medium. The performance of the particle chain displays (PCD) was evaluated according to macroscopic (device), microscopic (particle) and optical (reflectance) points of view. A display medium (thickness 100 MUm) containing colored PS particles (3 MUm, 2.5% w/v) was polarized to display the fixed images of the directly driven electrodes and programmable images of arrayed (5 * 5) electrodes with electric fields (0.48 MV m(-1) and 0.09 MV m(-1), 500 kHz, respectively). The formation of particle chains under electric fields (0.2 MV m( 1) and 0.4 MV m(-1), 500 kHz) was observed in the microscopic images of a display medium (thickness 100 MUm) with fluorescent PS particles (5 MUm, 1%). Images recorded with a confocal microscope demonstrated the particle chains. The opacity, a common parameter serving to characterize a display medium, was derived by measuring the reflectance ratio of a black background to a white background of the display medium with varied thickness and particle concentration. The temporal response of a display medium (thickness 50 MUm) with black PS particles (3 MUm, 5%) was tested. When an electric field (0.6 MV m(-1), 500 kHz) was applied, the reflectance increased twice at the first data point in 0.7 s, attaining a contrast ratio of 2. Application of a voltage (20 s) yielded a contrast ratio of 10. The performance of a tested display medium, composed of simple PS particles and water and driven to form particle chains by polarization, is reported. PMID- 23026880 TI - [Cancer immunotherapy - novel perspectives]. AB - The concept of cancer immune surveillance dates back decades and is based on the hypothesis that the immune system can suppress the development or progression of spontaneous malignancies. Immunotherapy strategies include antitumor monoclonal antibodies, cancer vaccines, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies that either costimulate immune cells or block immune inhibitory pathways. Sipuleucel-T is the first anticancer vaccine that improved overall survival in a randomized clinical study in patients with metastatic castration-resistant prostate cancer. Similarly, ipilimumab, a monoclonal antibody blocking cytotoxic T-lymphocyte antigen 4 (CTLA-4), showed an overall survival benefit and durable tumor responses in pretreated and previously untreated patients with metastatic melanoma. In Switzerland, ipilimumab is approved for second line treatment in metastatic melanoma. These recent positive results of clinical trials with novel immunoactive drugs raised expectations that immunotherapy will play a crucial role in the anticancer treatment of the next decade. PMID- 23026881 TI - [Lung cancer - on the way to a molecular classification]. AB - Treatment options for patients with advanced lung cancer have greatly improved in recent years. New molecular-targeted drugs are avaliable based on predictive biomarkers. Molecular diagnostics are key to successful therapy. Guidelines and recommendations for lung cancer testing and treatment are evolving, and it is increasingly challenging to stay up-to-date. In view of the rapid development in the lung cancer field, the current article discusses the current evidence for lung cancer classification and testing, and illustrates new perspectives in modern oncology. PMID- 23026882 TI - [Current diagnostics and therapy of B cell Non Hodgkin Lymphoma]. AB - New diagnostic tools and therapeutic options for Non Hodgkin Lymphoma (NHL) contributed to several improvements in the understanding and treatment of this hematological malignancies. In diffuse large cell lymphoma (DLBCL) gene expression profiling and molecular analyses of myc and bcl-2 gene rearrangements resulted in the description of new DLBCL entities with significant differences in outcome. Combination immunochemotherapy according to the R-CHOP protocol remains the mainstay for treatment of DLBCL in younger and older patients. Mantle cell lymphoma is characterised by the overexpression of cyclin D1. While older patients should be treated with R-CHOP with rituximab maintenance therapy, first line treatment of younger patients should also include AraC containing regimens and autologous stem cell transplantation. Cases with follicular lymphoma very often show the t(14; 18) translocation resulting in overexpression of BCL2 and diminished apoptosis. Compared to R-CHOP treatment new combinations with R Bendamustin have shown high efficacy with reduced toxicity and should therefore be regarded as standard in patients in need for therapy. PMID- 23026883 TI - [Breast cancer - Treatment guidelines and new treatment options in 2012, a medical oncology prospective]. AB - Breast cancer is the leading cancer in women with an annual incidence rate of 110/100.000 women in all age groups in Europe. The incidence rate increases in older women. Treatment includes surgery, radiotherapy, chemotherapy with or without antibody therapy and hormonal treatment. During the last 40 years the survival rate has significantly improved. From the 1970ies to 2010 the five year survival rate has risen from 85% to 98% early breast cancer. Similarly, in metastatic breast cancer 5-year survival has increased from below 10% in 1970 to 26% in 2010. This was possible because of better treatment options and better screening causing earlier diagnosis of breast cancer. This article reviews the standard treatment of breast cancer according to ESMO/ASCO guidelines and discusses new treatment options and new therapeutic strategies for breast cancer. PMID- 23026884 TI - [Advances in the treatment of prostate cancer - dawn of a new era]. AB - Over the recent years we have seen a rapid increase in published research both in the preclinical and clinical field regarding the treatment of prostate cancer. Only within the last two years the results of four positive phase III trials, all showing improved survival for patients with metastatic castration resistant prostate cancer (mCRPC), have been presented. In this article the basis of treatment of localized and advanced prostate cancer is discussed with a focus on new treatment options. Due to the rapid evolution of options an interdisciplinary management of patients with prostate cancer has become crucial in order to offer the best treatment to the patients. PMID- 23026885 TI - [Gastroenteropancreatic neuro-endocrine neoplasms]. AB - Neuroendocrine neoplasms (NEN) occur in the entire gastrointestinal tract. The updated classification of the WHO (2010) and current TNM-classification provide a basis for the therapeutic decision and assess the prognosis. Endoscopy and different imaging techniques are important for the localization of the primary tumor as well as local and distant metastases. The most important diagnostic imaging technique is somatostatin receptor scintigraphy. Therapeutic strategy should be discussed within the scope of a multidisciplinary tumor board. Surgery of NEN is the sole curative option. The treatment options for liver metastases include surgical resection as well as radiofrequency ablation and hepatic artery embolization. In advanced stage, systemic therapy should be used. Recent studies demonstrated a significantly prolonged progression-free survival using octreotide in well differentiated NEN. Besides the well established steptozotocine based chemotherapy regimens for pancreatic NEN, novel agents such as the mTOR-inhibitor everolimus and multityrosine kinase inhibitor sunitinib have recently also shown a prolonged progression-free survival. Moreover, temozolomide-based chemotherapy appears to be effective in pancreatic NEN. Finally, somatostatin receptor targeted radionuclide therapy can be effective in progressing gastroenteropancreatic NEN. PMID- 23026886 TI - [Current concepts in Neuro-Oncology]. AB - Over the last decade, understanding of gliomas on a molecular level has greatly expanded This update briefly reviews the potential utility of molecular markers in refining diagnosis, prognosis, and treatment decisions, focussing on 1p/19q co deletion, MGMT promoter methylation, EGFR mutations, and IDH 1/2 mutation. In the past, clinicians relied primarily on clinical factors such as age, Karnofsky performance status and extent of resection to inform prognosis. These para-meters and others have been used to identify prognostically distinct classes using recursive partitioning analysis (RPA) for patients with anaplastic astrocytomas and glioblastomas. They have been proven useful and were validated by subsequent glioma trials both at dia-gnosis and recurrence. Today clinical trials incorporate molecular information, either as stratification factors to balance treatment arms in randomized studies, or as eligibility criteria. Currently two markers are recommended to guide a clinician in deciding treatment: LOH 1p 19q in WHO III glioma defines a subgroup which should be treated with postoperative chemotherapy and radiation therapy and the methylation of the MGMT gene promoter is predictive for chemotherapy in elderly patients with a glioblastoma. Neuroimaging as the basic tool to diagnose a glioma and monitor treatment response during the course of the disease has markedly evolved. Conventional T1 sequences with and without contrast and T2/FLAIR sequences still remain the gold standard to delineate a new lesion and inform about criteria of malignancy. During treatment, advanced MRI techniques and PET imaging are being incorporated and explored to reflect metabolic activity of a lesion. PMID- 23026887 TI - Phosphorus concentration and loading reductions following changes in fertilizer application and formulation on managed turf. AB - Excess phosphorus, particularly in surface waters can lead to severe eutrophication. Identifying source areas, quantifying contributions, and evaluating management practices are required to address current and future water quality concerns. A before-after study was conducted from 2003-2010 on a sub watershed of Northland Country Club Golf Course in Duluth, MN to demonstrate the impacts of two different phosphorus management approaches (Period 1: traditional application and timing using commercially available synthetic blends; Period 2: reduced rate, low dose applications, and organic formulations). Outflow median dissolved reactive phosphorus (DRP) and total phosphorus (TP) stream concentrations were significantly less in Period 2 compared to Period 1. There was no statistical difference in the mean TP loading in Period 1 (0.25 kg ha(-1) year(-1)) compared to Period 2 (0.20 kg ha(-1) year(-1)) or between the DRP loading in Period 1 (0.15 kg ha(-1) year(-1)) compared to Period 2 (0.09 kg ha( 1) year(-1)). However, by switching to organic phosphorus formulations and reducing application rates by greater than 75%, substantial reduction in DRP and TP concentrations was achieved. Based on these findings it is recommended that turf managers (parks and recreation to golf courses) explore the feasibility of altering their fertility management related to phosphorus by including organic formulations, low dose applications, and overall rate reductions. Additionally, it is recommended that the fertilizer industry develop and make more readily available commercial blends with lesser to zero amounts of phosphorus. PMID- 23026888 TI - High resolution melting analysis of the MMAA gene in patients with cblA and in those with undiagnosed methylmalonic aciduria. AB - The gene product of MMAA is required for the intracellular metabolism of cobalamin (Cbl). Mutations in this gene lead to the cblA class of disorders, characterized by isolated methylmalonic aciduria. We have been concerned that somatic cell methods of diagnosis may miss patients with mild cellular phenotypes. A high resolution melting analysis (HRMA) assay was developed to rapidly scan the coding exons and flanking intronic regions of the MMAA gene for variants. DNA was scanned by HRMA from 96 unaffected reference individuals, 72 cblA patients confirmed by complementation, and 181 patients with isolated elevated methylmalonic acid, who could not be diagnosed using complementation analysis. Suspected variants were confirmed by Sanger sequencing. In the cblA cohort, HRMA correctly identified all previously known mutations as well as an additional 22 variants, 10 of which had not been previously reported. Novel variants included one duplication (c.551dupG, p.C187LfsX3), one deletion (c.387delC, p.Y129YfsX13), one splice site mutation (c.440-2A>G, splice site), 4 missense mutations (c.748G>A, p.E520K; c.820G>A, p.G274S; c.627G>T, p.R209S; c.826A>G, p.K276E), and 3 nonsense mutations (c.960G>A, p.W320X; c.1075C>T, p.E359X; c.1084C>T, p.Q362X). All novel missense variants affect highly conserved residues and are predicted to be damaging. Scanning of MMAA in the 181 undiagnosed samples revealed a single novel heterozygous missense change (c.821G>A, p.G274D). PMID- 23026889 TI - From perception to functional outcome in schizophrenia: modeling the role of ability and motivation. AB - CONTEXT Schizophrenia remains a highly disabling disorder, but the specific determinants and pathways that lead to functional impairment are not well understood. It is not known whether these key determinants of outcome lie on 1 or multiple pathways. OBJECTIVE To evaluate theoretically based models of pathways to functional outcome starting with early visual perception. The intervening variables were previously established determinants of outcome drawn from 2 general categories: ability (ie, social cognition and functional capacity) and beliefs/motivation (ie, defeatist beliefs, expressive and experiential negative symptoms). We evaluated an integrative model in which these intervening variables formed a single pathway to poor outcome. DESIGN This was a cross-sectional study that applied structural equation modeling to evaluate the relationships among determinants of functional outcome in schizophrenia. SETTING Assessments were conducted at a Veterans Administration Medical Center. PARTICIPANTS One hundred ninety-one clinically stable outpatients with schizophrenia or schizoaffective disorder were recruited from the community. RESULTS A measurement model showed that the latent variables of perception, social cognition, and functional outcome were well reflected by their indicators. An initial untrimmed structural model with functional capacity, defeatist beliefs, and expressive and experiential negative symptoms had good model fit. A final trimmed model was a single path running from perception to ability to motivational variables to outcome. It was more parsimonious and had better fit indices than the untrimmed model. Further, it could not be improved by adding or dropping connections that would change the single path to multiple paths. The indirect effect from perception to outcome was significant. CONCLUSIONS The final structural model was a single pathway running from perception to ability to beliefs/motivation to outcome. Hence, both ability and motivation appear to be needed for community functioning and can be modeled effectively on the same pathway. PMID- 23026890 TI - Circulating microRNAs: new biomarkers in diagnosis, prognosis and treatment of cancer (review). AB - MicroRNAs (miRNAs) are small non-coding, endogenous, single-stranded RNAs. MiRNAs have been implicated in different areas such as the immune response, neural development, DNA repair, apoptosis, oxidative stress response and cancer. However, while the majority of miRNAs are found intracellularly, a significant number of miRNAs have been observed outside of cells, including various body fluids. Circulating miRNAs function as 'extracellular communication RNAs' that play an important role in cell proliferation and differentiation. MiRNA regulation is essential to many cellular processes, and escape from this regulatory network seems to be a common characteristic of several disease processes and malignant transformation. The interest in circulating miRNAs reflects in fact their central role in regulation of gene expression and the implication of miRNA-specific aberrant expression in the pathogenesis of cancer, cardiac, metabolic, neurologic, immune-related diseases as well as others. In our review we aimed to summarize the data related to the action of cellular miRNAs on the onset of various diseases, thus bringing together some of the latest information available on the role of circulating miRNAs. Additionally, the role of circulating miRNAs could be particularly relevant in the context of neoplastic diseases. At least 79 miRNAs have been reported as plasma or serum miRNA biomarkers of solid and hematologic tumors. Circulating miRNA profiling could improve the diagnosis of cancer, and could predict outcome for cancer patients, while the profiling of alterations in circulating miRNA that may signal a predisposition to cancer, could also be a therapeutic target in these patients. PMID- 23026891 TI - Oxygen-deficient metal oxide nanostructures for photoelectrochemical water oxidation and other applications. AB - This review presents highlights of the latest results of studies directed at developing oxygen-deficient metal oxides, including TiO(2), WO(3), and alpha Fe(2)O(3), nanostructures as electrode materials, which show significantly enhanced performance in applications for photoelectrochemical water oxidation. The enhanced photoelectrochemical performance is attributed to improved electrical conductivities by controlled incorporation of oxygen vacancies as shallow donors for metal oxides. We also discuss the potential of these oxygen deficient metal oxides for other energy conversion and storage applications, such as photocatalytic reactions and charge storage. PMID- 23026892 TI - Hypospadias. AB - PURPOSE OF REVIEW: Hypospadias is one of the most common congenital anomalies in men. We searched the recent literature (since 1 January 2011) using the following keywords in the title or abstract: hypospadia or hypospadias, in order to provide the reader with an updated view of the subject. RECENT FINDINGS: Early repair is recommended; distal forms are mainly treated by the tubularized incised plate technique; however, meatal stricture concerns are still noticed, limiting its use on proximal forms. The debate of proximal primary repair in either one or two stages is still ongoing. Minor modifications for preparing the distal bed for the urethroplasty in two stages are presented. One-stage repairs, either with reconstruction of the urethral plate (three-in-one concept) or simply with the onlay to tunica albuginea (Rigamonti), is a viable option with over 70% success in one surgery. The importance of barriers, such as tunica vaginalis and dartos flap, was reassessed and flow rates may indicate obstructive voiding patterns after 1-year follow-up. SUMMARY: Further experience and comparative studies for distal and proximal hypospadias are required. Long-term data may indicate the appropriate procedure selected for primary repair. PMID- 23026893 TI - Urethral 'cripples': two-staged procedures. AB - PURPOSE OF REVIEW: To review the current literature on staged procedures in patients with previous urethral interventions ('urethral cripples'). RECENT FINDINGS: Five studies published during the past 18 months could be identified, the majority with short-term follow-up and small patient numbers. Four studies investigated the outcome after redo surgery in hypospadias patients, one study after urethral stricture disease. SUMMARY: The few data published suggest acceptable complication rate and success rate for surgical outcome. Long-term and prospective data with special respect to sexual function, patient satisfaction, and quality of life are still lacking. PMID- 23026894 TI - Varicocele repair for low testosterone. AB - PURPOSE OF REVIEW: Several recent clinical studies have added to the existing literature on the impact of varicocelectomy on serum testosterone levels. These studies were not included in the most recent previous review of this topic and strengthen considerably the evidence base supporting the claim that varicocele repair can reliably restore below-normal testosterone levels. RECENT FINDINGS: Three studies were published in 2011 on the effect of varicocele repair on testosterone levels. These studies were all adequately powered to detect statistically significant changes in testosterone preprocedure and postprocedure, and all demonstrated significant increases in testosterone levels in patients who had low preprocedure testosterone levels. SUMMARY: Varicocele repair can restore testosterone to the eugonadal range in hypogonadal patients with either unilateral or bilateral varicocele. PMID- 23026895 TI - Varicocele repair for infertility: what is the evidence? AB - PURPOSE OF REVIEW: Considering the persistent controversy concerning the impact of varicocele repair on fertility, we decided to perform an update of the review of the literature with the aim to evaluate whether the most recent research in this field gives us more evidence about the indications to treat or not to treat varicocele in dyspermic or infertile men. RECENT FINDINGS: Randomized controlled trials (RCTs) and prospective studies evaluating semen parameters before and after varicocelectomy clearly demonstrate that varicocele repair is associated with a significant improvement of sperm concentration, motility and normal morphology. Moreover, some recent studies highlighted the potential role of varicocelectomy in reduction of seminal oxidative stress and sperm DNA damage. One recent RCT showed a statistically significant advantage in favor of varicocelectomy in comparison with observations in terms of spontaneous pregnancy rate. Meta-analysis including this study confirmed the heterogeneity of pooled studies and showed a significant trend in favor of varicocele repair. This trend has become statistically significant when an 'as-treated' analysis is performed (odds ratio 2.69, 95% confidence interval 1.16-6.24). The advantages in favor of varicocele treatment were also observed in a recent RCT analyzing couples with first-term recurrent miscarriage. CONCLUSION: Varicocele repair must be proposed in young adult men with impairment of seminal parameters and not yet interested in pregnancy. Men of infertile couples should be adequately counselled concerning the high possibility of attaining a significant improvement in seminal parameters after varicocele repair. This condition can be associated with a spontaneous pregnancy rate of 30%. The main alternative remains the use of artificial reproductive techniques. PMID- 23026896 TI - Varicocele repair in the era of modern assisted reproductive techniques. AB - PURPOSE OF REVIEW: This review looks at the literature on varicocele repair and its effect on assisted reproductive techniques. The effects of varicocele correction on improved sperm production have been well documented with semen analysis data. What remain to be elucidated are the causes of the varicocele effect and how correction of the resultant pathophysiology may affect the outcomes of modern assisted reproductive technology. RECENT FINDINGS: Basic science research shows us that varicoceles exert deleterious effects on Leydig cells, Sertoli cells, and germ cells via very different mechanisms. The effects of varicocele correction on the reproductive potential of sperm are less well understood. Clinical research has shown improved semen parameters, DNA integrity, and assisted reproductive technology outcomes after varicocele repair. SUMMARY: Varicocele correction presents a possible method to optimize a couples' reproductive potential or decrease the need for complex assisted reproductive technology. PMID- 23026897 TI - Varicocele: standard and alternative indications for repair. AB - PURPOSE OF REVIEW: This review provides timely and relevant information to address the indications for repair of the adolescent varicocele. In this review, we summarize the most recent available evidence and provide clinical guidelines. RECENT FINDINGS: The indications for adolescent varicocelectomy commonly include testicular hypotrophy and pain but become confusing and contradictory when discussing potential infertility as an indication for repair. The preponderance of patients with varicocele in the infertile population leads to the search for causality and reversibility. However, in the era of assisted reproduction, the question of early prevention of infertility is brought to the forefront of discussion. Recent attempts have been made to determine the patient parameters that predict future infertility. Current publications have focused on predictors for clinically significant varicoceles that would benefit from intervention, such as hormonal profile and peak retrograde flow. Contradictory evidence exists regarding the significance of testicular asymmetry in adolescence. SUMMARY: Substantial effort has been made to tease out the clinically significant adolescent varicocele. However, definitive evidence regarding fertility outcomes and adolescent varicocele repair remains limited and controversial. Large-scale, long-term follow-up studies are necessary to determine the true benefit of adolescent varicocele repair on decreasing the risk of fertility problems in adulthood. PMID- 23026901 TI - Biopsy and personalized medicine. PMID- 23026902 TI - Diagnosis of hepatitis E. AB - Hepatitis E, caused by infection with hepatitis E virus (HEV), is a common cause of enterically-transmitted acute hepatitis in developing countries. Occasional cases of sporadic hepatitis E have been increasingly recognized in developed countries over the past decade. These cases differ from those in developing countries in being possibly caused by zoonotic transmission, often affecting people with a suppressed immune system and occasionally leading to persistent HEV infection. The commonly used tests for HEV infection include detection of IgM and IgG anti-HEV antibodies and detection of HEV RNA. IgM anti-HEV antibodies can be detected during the first few months after HEV infection, whereas IgG anti-HEV antibodies represent either recent or remote exposure. The presence of HEV RNA indicates current infection, whether acute or chronic. Although several diagnostic assays for anti-HEV antibodies are available, they have undergone fairly limited testing and often provide discordant results, particularly for IgG antibodies. Thus, although the available antibody assays might be useful for case diagnosis in areas with high disease endemicity, their use for case diagnosis in areas with low endemicity and for seroprevalence studies remains problematic. Improved validation of existing anti-HEV antibody assays or development of new assays with superior performance characteristics is urgently needed. PMID- 23026904 TI - IBS: Linaclotide approved for constipation-predominant IBS. PMID- 23026905 TI - Pancreatic cancer: Image enhancement by endoscopic ultrasonography-elastography. PMID- 23026906 TI - Surgery: Aftercare for elective colectomy--coffee to go? PMID- 23026903 TI - Ghrelin, the proglucagon-derived peptides and peptide YY in nutrient homeostasis. AB - Dysregulation of nutrient homeostasis is implicated in the current epidemics of obesity and type 2 diabetes mellitus. The maintenance of homeostasis in the setting of repeated cycles of feeding and fasting occurs through complex interactions between metabolic, hormonal and neural factors. Although pancreatic islets, the liver, muscle, adipocytes and the central nervous system are all key players in this network, the gastrointestinal tract is the first tissue exposed to ingested nutrients and thus has an important role. This Review focuses on several of the endocrine hormones released by the gastrointestinal tract prior to or during nutrient ingestion that have key roles in maintaining energy balance. These hormones include the gastric orexigenic hormone, ghrelin, and the distal L cell anorexigenic and metabolic hormones, glucagon-like peptide (GLP)-1, GLP-2, oxyntomodulin and peptide YY. Each of these hormones exerts a distinct set of biological actions to maintain nutrient homeostasis, the properties of which are currently, or might soon be, exploited in the clinic for the treatment of obesity and type 2 diabetes mellitus. PMID- 23026907 TI - Engineering designer transcription activator-like effector nucleases (TALENs) by REAL or REAL-Fast assembly. AB - Engineered transcription activator-like effector nucleases (TALENs) are broadly useful tools for performing targeted genome editing in a wide variety of organisms and cell types including plants, zebrafish, C. elegans, rat, human somatic cells, and human pluripotent stem cells. Here we describe detailed protocols for the serial, hierarchical assembly of TALENs that require neither PCR nor specialized multi-fragment ligations and that can be implemented by any laboratory. These restriction enzyme and ligation (REAL)-based protocols can be practiced using plasmid libraries and user-friendly, Web-based software that both identifies target sites in sequences of interest and generates printable graphical guides that facilitate assembly of TALENs. With the described platform of reagents, protocols, and software, researchers can easily engineer multiple TALENs within 2 weeks using standard cloning techniques. PMID- 23026908 TI - Using Cell-ID 1.4 with R for microscope-based cytometry. AB - This unit describes a method for quantifying various cellular features (e.g., volume, total and subcellular fluorescence localization) from sets of microscope images of individual cells. It includes procedures for tracking cells over time. One purposely defocused transmission image (sometimes referred to as bright-field or BF) is acquired to segment the image and locate each cell. Fluorescence images (one for each of the color channels to be analyzed) are then acquired by conventional wide-field epifluorescence or confocal microscopy. This method uses the image-processing capabilities of Cell-ID and data analysis by the statistical programming framework R, which is supplemented with a package of routines for analyzing Cell-ID output. Both Cell-ID and the analysis package are open-source. PMID- 23026910 TI - Carbohydrate recognition and photodegradation by an anthracene-Kemp's acid hybrid. AB - Selective recognition and photodegradation of a monosaccharide, octyl beta-D glucopyranoside, was achieved without any additives under neutral conditions using an anthracene-Kemp's acid hybrid and long-wavelength UV irradiation. PMID- 23026909 TI - ChIP-exo method for identifying genomic location of DNA-binding proteins with near-single-nucleotide accuracy. AB - This unit describes the ChIP-exo methodology, which combines chromatin immunoprecipitation (ChIP) with lambda exonuclease digestion followed by high throughput sequencing. ChIP-exo allows identification of a nearly complete set of the binding locations of DNA-binding proteins at near-single-nucleotide resolution with almost no background. The process is initiated by cross-linking DNA and associated proteins. Chromatin is then isolated from nuclei and subjected to sonication. Subsequently, an antibody against the desired protein is used to immunoprecipitate specific DNA-protein complexes. ChIP DNA is purified, sequencing adaptors are ligated, and the adaptor-ligated DNA is then digested by lambda exonuclease, generating 25- to 50-nucleotide fragments for high-throughput sequencing. The sequences of the fragments are mapped back to the reference genome to determine the binding locations. The 5' ends of DNA fragments on the forward and reverse strands indicate the left and right boundaries of the DNA protein binding regions, respectively. PMID- 23026911 TI - Pancreatic cancer cells surviving gemcitabine treatment express markers of stem cell differentiation and epithelial-mesenchymal transition. AB - Objective response rates to standard chemotherapeutic regimens remain low in pancreatic cancer. Subpopulations of cells have been identified in various solid tumors which express stem cell-associated markers and are associated with increased resistance against radiochemotherapy. We investigated the expression of stem cell genes and markers of epithelial-mesenchymal transition in pancreatic cancer cells that survived high concentrations of gemcitabine treatment. Capan-1 and Panc-1 cells were continuously incubated with 1 and 10 uM gemcitabine. Surviving cells were collected after 1, 3 and 6 days. Expression of PDX-1, SHH, CD24, CD44, CD133, EpCAM, CBX7, OCT4, SNAIL, SLUG, TWIST, Ki-67, E-cadherin, beta catenin and vimentin were quantified by qPCR or immunocytochemistry. Migration was assessed by wound-healing assay. SHH was knocked down using RNA interference. Five primary pancreatic cancer cell lines were used to validate the qPCR results. All investigated genes were upregulated after 6 days of gemcitabine incubation. Highest relative expression levels were observed for OCT4 (13.4-fold), CD24 (47.3 fold) and EpCAM (15.9-fold) in Capan-1 and PDX-1 (13.3-fold), SHH (24.1-fold), CD44 (17.4-fold), CD133 (20.2-fold) and SLUG (15.2-fold) in Panc-1 cells. Distinct upregulation patterns were observed in the primary cells. Migration was increased in Panc-1 cells and changes in the expression of E-cadherin and beta catenin were typical of epithelial-mesenchymal transition in both cell lines. SHH knockdown reduced IC(50) from 30.1 to 27.6 nM in Capan-1 while it strongly inhibited proli-feration in Panc-1 cells. Cells surviving high-dose gemcitabine treatment express increased levels of stem cell genes, show characteristics associated with epithelial-mesenchymal transition and retain their proliferative capacity. PMID- 23026912 TI - Parametric modulation of neural activity by emotion in youth with bipolar disorder, youth with severe mood dysregulation, and healthy volunteers. AB - CONTEXT Youth with bipolar disorder (BD) and those with severe, nonepisodic irritability (severe mood dysregulation [SMD]) exhibit amygdala dysfunction during facial emotion processing. However, studies have not compared such patients with each other and with comparison individuals in neural responsiveness to subtle changes in facial emotion; the ability to process such changes is important for social cognition. To evaluate this, we used a novel, parametrically designed faces paradigm. OBJECTIVE To compare activation in the amygdala and across the brain in BD patients, SMD patients, and healthy volunteers (HVs). DESIGN Case-control study. SETTING Government research institute. PARTICIPANTS Fifty-seven youths (19 BD, 15 SMD, and 23 HVs). MAIN OUTCOME MEASURE Blood oxygenation level-dependent data. Neutral faces were morphed with angry and happy faces in 25% intervals; static facial stimuli appeared for 3000 milliseconds. Participants performed hostility or nonemotional facial feature (ie, nose width) ratings. The slope of blood oxygenation level-dependent activity was calculated across neutral-to-angry and neutral-to-happy facial stimuli. RESULTS In HVs, but not BD or SMD participants, there was a positive association between left amygdala activity and anger on the face. In the neutral-to-happy whole-brain analysis, BD and SMD participants modulated parietal, temporal, and medial frontal areas differently from each other and from that in HVs; with increasing facial happiness, SMD patients demonstrated increased, and BD patients decreased, activity in the parietal, temporal, and frontal regions. CONCLUSIONS Youth with BD or SMD differ from HVs in modulation of amygdala activity in response to small changes in facial anger displays. In contrast, individuals with BD or SMD show distinct perturbations in regions mediating attention and face processing in association with changes in the emotional intensity of facial happiness displays. These findings demonstrate similarities and differences in the neural correlates of facial emotion processing in BD and SMD, suggesting that these distinct clinical presentations may reflect differing dysfunctions along a mood disorders spectrum. PMID- 23026914 TI - The role of acute care surgery in the treatment of severe, complicated Clostridium difficile-associated disease. AB - Clostridium difficile associated disease (CDAD) is the result of colonic bacterial overgrowth with this gram positive anaerobic organism and the production of toxins that typically induce diarrhea. Most patients with CDAD respond to treatment with oral metronidazole or vancomycin, but a subset of patients will develop a severe systemic illness, multiple organ failure, and death. There are no reliable combinations of clinical or laboratory findings that will distinguish patients who will respond to medical therapy and those who will progress to a more complicated state. Early surgical consultation should be considered in patients with ileus, severe abdominal pain, significant tenderness, immunosuppression, advanced age, high white blood cell or band counts, acute renal failure, mental status changes, or cardiopulmonary compromise. The standard operation for fulminant colitis is subtotal colectomy but the high mortality of the operation, and the long-term morbidity even in survivors combine to act as deterrents to early surgical consultation and operation. Novel operative approaches that preserve the colon and minimize operative morbidity may prove to remove the barriers to earlier surgical treatment for fulminant CDAD and improve outcomes. PMID- 23026916 TI - Four serum microRNAs identified as diagnostic biomarkers of sepsis. AB - BACKGROUND: Serum microRNAs (miRNAs) can be used as biomarkers for many kinds of diseases, and some are even better than current indicators. The aim of this study was to investigate a diagnostic role for serum miRNAs in sepsis patients. METHODS: We recruited 166 patients with sepsis and 24 normal controls. Blood samples for these patients were obtained upon their admission in intensive care units of the Chinese PLA General Hospital. The expression levels of miR-223, miR 15b, miR-483-5p, miR-499-5p, miR-122, and miR-193b* were determined by quantitative reverse transcriptase polymerase chain reaction assays. RESULTS: Expression levels of miR-223 were significantly higher in patients with mild sepsis (p < 0.001) and patients with severe sepsis and septic shock (p < 0.001) than in normal controls, and levels of miR-499-5p, miR-122, and miR-193b* were significantly lower than in normal controls. In addition, only miR-223 (p = 0.035) and miR-499-5p (p < 0.001) were significantly different between patients with mild sepsis and patients with severe sepsis and septic shock. miR-499-5p had the highest area under a receiver operating characteristic curve of 0.686 (95% confidence interval, 0.592-0.779). In addition, Sequential Organ Failure Assessment scores (p < 0.001), Acute Physiology and Chronic Health Evaluation II scores (p < 0.001), and procalcitonin levels (p < 0.001) also could distinguish a mild sepsis group from a severe sepsis and septic shock group. In a binary logistic regression model, only miR-499-5p and Sequential Organ Failure Assessment scores had good diagnostic values to distinguish between mild sepsis and severe sepsis and septic shock. CONCLUSION: Four serum miRNAs were identified as novel biomarkers of sepsis. LEVEL OF EVIDENCE: II, diagnostic study. PMID- 23026915 TI - Hypothermia and hemostasis in severe trauma: A new crossroads workshop report. AB - OBJECTIVE: The hypothermia and hemostasis in severe trauma (HYPOSTAT): a new crossroads workshop was convened to evaluate the interplay among hypothermia, hemostasis, and severe trauma/hemorrhage. Trauma is the major cause of death in young individuals in the United States, with uncontrolled hemorrhage representing the major cause of preventable deaths. DATA SOURCES: This workshop organized by the National Heart, Lung, and Blood Institute and the US Army Medical Research and Material Command as a forum for exchange of ideas among experts from diverse fields. The specific workshop goals were to (1) identify state-of-the-art and needs in knowledge of biology of hypothermia and hemostasis in the setting of significant traumatic injury; (2) provide an interdisciplinary forum to enhance knowledge regarding early detection of traumatic shock and monitoring of the level and effect of controlled hypothermia in severe trauma settings; and (3) identify future research directions of the role of therapeutic-oriented hypothermia and hemostasis in trauma with severe blood loss. STUDY SELECTION: Not applicable. DATA EXTRACTION: Expert opinion and literature review. CONCLUSION: This document provides a summary of the expert opinion and highlights the recommendations that came out of the discussions at this workshop to guide scientific efforts in basic, translational, and clinical research in this area. PMID- 23026917 TI - Esophageal stenting for spontaneous esophageal perforation. AB - BACKGROUND: Stenting has proven to be a promising treatment of spontaneous esophageal perforation, but currently, the scientific background to treatment of this condition is limited. METHODS: Fourteen consecutive patients with spontaneous esophageal perforation were treated with coated self-expandable stent and a debridement procedure (three patients by thoracotomy, four by thoracoscopy, three by tube drainage, and two patients with no drainage). Eight patients had one stent, while six patients needed one or more additional stents to achieve source control. RESULTS: Patients were treated for a mean period of 9 days in the intensive care unit. Patients who had definitive source control with primary stent were treated for a mean of 3 days in the intensive care unit, while those who needed more stents were treated for a mean of 15 days (p = 0.009). Two patients (14%) died during the in-hospital stay, both of them having received more than one stent. Eight patients had one stent, while six patients needed one or more additional stents to achieve source control. The mean estimated time from rupture to stenting was 58 hours (median, 27 hours). Fourteen percent of patients who underwent stenting within 24 hours to stent placement were in septic shock compared with 86% of patients with a delay of more than 24 hours. CONCLUSION: Stent placement with thoracic debridement seems to be effective as a primary treatment of spontaneous esophageal perforation. According to our findings, it is of utmost importance to achieve source control with the first stent. Additional debridement procedures are still invariably needed. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 23026918 TI - Delayed abdominal wall reconstruction of giant ventral hernias using the anterolateral thigh free flap for skin coverage. AB - Delayed abdominal wall reconstruction for extremely large ventral hernias can be exceedingly difficult if there is a concomitant skin deficiency. In the past decade, six such patients after restoration of the integrity of the musculofascial layer required vascularized tissues to accomplish closure of huge mid-abdominal defects using in all cases the anterolateral thigh free flap. As with all perforator flaps, this ensures function preservation of the intrinsic abdominal muscles to provide a reliable solution to a difficult challenge. PMID- 23026919 TI - Re: Is bougie-aided cricothyrotomy really "extremely fast and safe" in the morbidly obese patient? PMID- 23026920 TI - Abbreviated Injury Scale mapping between 1998 and 2008 versions: Multiple maps, but no destination yet. PMID- 23026921 TI - Infections and tourniquet application in severe open tibia fractures from combat. PMID- 23026922 TI - The assessment of blunt trauma patients at risk for significant intrathoracic injury. PMID- 23026925 TI - C-reactive protein is a useful predictor of metronidazole treatment failure in mild-to-moderate Clostridium difficile infection. AB - OBJECTIVE: To assess the ability of C-reactive (CRP) protein, against the other commonly used metrics, to predict metronidazole treatment failure in Clostridium difficile infection. METHODS: We retrospectively reviewed the case notes of 65 patients with C. difficile infection initially treated with metronidazole. Patients were grouped on the basis of outcome: those who responded to metronidazole within 6 days (cut-off as used by previous authors) versus those who required vancomycin. Individual predictor variables were examined between groups (using a t-test, Kruskal-Wallis test, or Fisher's exact test), and the strength of associations was assessed by logistic regression. RESULTS: Of the 65 patients reviewed, 48 (74%) resolved with metronidazole alone. Regression analysis found that (CRP) white cell count and creatinine levels were significantly different across the metronidazole success/failure groups (P<0.01, P=0.01 and P=0.03, respectively). CONCLUSION: (CRP) is a useful predictor of metronidazole treatment failure in mild-to-moderate C. difficile infection. PMID- 23026926 TI - Enhanced photooxidation sensitizers: the first examples of cyclometalated pyrene complexes of iridium(III). AB - The iridium(III) cyclometalation of alkylated pyrene-benzimidazole ligands proceeds in an unprecedented manner. The resultant complexes display remarkably enhanced photooxidation capabilities using 1,5-dihydroxynaphthalene as a substrate. PMID- 23026927 TI - Diagnosing lyme disease: getting the details right. PMID- 23026928 TI - Objective quantification of the Ki67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system: a comparison of digital image analysis with manual methods. AB - Pathologic grading for prognostic stratification of neuroendocrine tumors (NETs) is critical but presents a challenging interpretive dilemma. Tumor cell proliferative rate is an important factor in the determination of prognosis, and immunohistochemical analysis with Ki67 is becoming more widely used to quantify the proliferative rate. However, Ki67 assessment has limitations due to lack of uniformity and consistency in quantification. These limitations are accentuated in well-differentiated NETs, as differences in the range of 1% to 5% can alter tumor grade, with potential implications for treatment. We therefore performed a concordance study to assess different Ki67 quantification techniques including: (a) digital image analysis (DIA); (b) manual counting (MC) of >2000 cells; and (c) "eyeballed" estimate (EE) of labeling percentage by pathologists (n=18), including individuals experienced in evaluating Ki67 labeling as well as others who had little prior experience assessing Ki67 percentages. Forty-five Ki67 images were selected and analyzed using the 3 methods. On the basis of the recommendations of the World health Organization (WHO) for grading NETs, MC of 2000 cells was used as the "gold standard" reference against which the other techniques were compared. Three images were presented twice, the second being inverted, to assess intraobserver consistency. Statistical analyses were performed to evaluate: (a) the concordance between methods; (b) intraobserver and interobserver consistency; and (c) correlation of NET grades on the basis of Ki67 scores by EE versus the gold standard. Agreement between scores was assessed by intraclass correlation (ICC). DIA and MC were highly concordant (ICC=0.98). The ICC between DIA and the mean EE of all observers was 0.88. However, there was discordance among individual observers on all cases quantified by EE (ICC=0.13). The ICC for intraobserver consistency was 0.39+/-0.26. With Ki67 in the ranges of <1%, 2% to 3%, and >20%, the mean of Ki67 by EE was, respectively, 93%+/-2%, 55%+/-7%, and 55%+/-15% correct against the gold standard. The kappa statistics for EE exhibited low agreement (kappa=0.24; 95% confidence interval, 0.23-0.25) for all WHO NET grades. Incorrect assessment by EE resulted in upgrading of all WHO G1 group tumors (n=14); in the WHO G2 group, downgrading of 41% cases occurred (n=11) when Ki67 was <5% (by DIA or MC), and upgrading of 59% cases occurred (n=16) when Ki67 was >5%. We conclude that DIA and MC are the acceptable standards for Ki67 assessment. Given the inherent discordance in determining the grade, the use of an approximate EE of the Ki67-labeling index requires critical reevaluation, especially for NETs with a labeling index straddling the cut-points between grades. Consequently, determination of therapeutic strategies should be guided by an amalgamation of clinicopathologic characteristics, including but not limited to the Ki67 index. PMID- 23026929 TI - Clinicopathologic study of 62 acinar cell carcinomas of the pancreas: insights into the morphology and immunophenotype and search for prognostic markers. AB - Acinar cell carcinoma (ACC) of the pancreas is a very rare tumor that has various morphologic features, which may give rise to diagnostic difficulties. Because of its rarity, many clinicopathologic characteristics remain to be further elucidated, and prognostic factors are yet to be well established. With the aim of better characterizing this carcinoma and searching for prognostic indicators, we collected 62 ACCs and investigated the following parameters: site, size, local infiltration, node and distant metastases, architectural pattern, nuclear atypia, presence of necrosis, lymphovascular and perineural invasion, proliferation, BCL10, trypsin, carboxyl ester lipase, amylase, lipase, PDX1, cytokeratin 19 (CK19), CK7, p53, and beta-catenin expression. Twelve cases showing >30% of endocrine cells were reclassified as mixed acinar-neuroendocrine carcinomas, whereas 1 tumor was reclassified as a mixed ductal-acinar carcinoma and was excluded from the statistical prognostic evaluations. BCL10 and trypsin were the most reliable immunohistochemical markers, whereas amylase and lipase were not. Surgery was statistically correlated with a better prognosis (P=0.0008). Among resected tumors there was no difference in survival between ACCs and mixed acinar neuroendocrine carcinomas, and factors that significantly correlated with poor prognosis were size >6.5 cm (P=0.004), lymph node (P=0.0039) and distant (P=0.008) metastases, and UICC stage (P=0.009). Stage was the only independent prognostic factor at multivariable analysis, and the best prognostic discrimination was observed on grouping together stages I and II and grouping together stages III and IV, suggesting a simplification of the UICC staging for such cancers. In addition, vascular and perineural invasion and CK19 and p53 expression showed a trend for poor prognosis, not reaching statistical significance. PMID- 23026930 TI - Multilocular thymic cyst associated with thymoma: a clinicopathologic study of 20 cases with an emphasis on the pathogenesis of cyst formation. AB - Multilocular thymic cysts (MTCs) are considered to be acquired lesions associated with various inflammatory conditions and/or malignant tumors. MTCs associated with thymomas are rare, with only 11 cases having been reported. On reviewing 110 consecutive patients with thymomas, we found 20 cases of MTCs. The patients included 18 men and 2 women aged 32 to 65 years (median 52 y). Eleven of the patients were symptomatic, and 6 presented with symptoms associated with inflammation. Computed tomography images were available for 11 patients, and cystic lesions were identified in 4 patients. The histologic subtypes of thymoma observed were: 3 tumors of type AB, 4 tumors of type B1, 9 tumors of type B2, and 4 tumors of type B3. In addition, 2 tumors were in advanced stages. Multilocular cystic structures accompanied by acute and chronic inflammation were observed in the remnant thymic tissues. Immunohistochemically, CK13 was diffusely expressed in the inner surface cells lining the cysts, whereas CK5/6 and p63 were primarily expressed in the basal cells of the cysts. D2-40 was weakly expressed in a small number of basal epithelial cells. The immunohistochemical profiles of the cysts were similar to those of Hassall corpuscles of normal thymi. A clinical follow-up showed that 15 patients continued to be alive without any evidence of disease, 1 patient with tumor recurrence continued to be alive, and 3 patients had died of other diseases. Our results suggest that MTCs associated with thymomas are not as uncommon as thought and may develop from the promotion of differentiation of increased numbers of epithelial cells into Hassall corpuscles by inflammatory processes. Our data also suggest a better clinical behavior for patients with thymomas accompanied by MTCs than patients with thymomas unaccompanied by those cysts, although further investigation is needed. PMID- 23026931 TI - Cutaneous digital papillary adenocarcinoma: a clinicopathologic study of 31 cases of a rare neoplasm with new observations. AB - Aggressive digital papillary adenocarcinoma is a rare tumor predominantly involving the distal end of digits. We examined 31 cases of this distinctive tumor for clinicopathologic, immunohistochemical, and follow-up data where available. Males were predominantly affected (n=29), with a mean age of 43 years (range, 14 to 67 y). Three lesions were reported in patients below the age of 20 years. All cases involved a finger (n=26) or a toe (n=5), with most involving the distal portion of the digit (n=29). Two lesions involved the base of the digit/webspace. Histopathologically, all tumors involved the dermis with subcutaneous extension in 14 cases. The lesions demonstrated a multinodular solid and/or cystic pattern, with focally infiltrative architecture in 21 cases. Papillary projections were: prominent (n=10), focal (n=15), or not identified (n=6). Within the solid component, tubular structures were present at least focally in all cases. Cytologic atypia ranged from mild (n=8) to moderate (n=20), but was focally severe in 3 cases. Mitotic count ranged from <1 to 18 per mm. Focal necrosis was seen in 6 cases. Immunohistochemically stained sections were available for review in 8 cases. Tumor cells were diffusely positive for MNF116 (3 of 3). Carcinoembryonic antigen and epithelial membrane antigen highlighted the luminal border of tubules (8 of 8). Smooth muscle actin (5 of 6) and calponin (6 of 6) highlighted a myoepithelial layer around tubular/glandular structures, as did p63 (2 of 2) and podoplanin (5 of 5). Follow-up after excision or amputation (n=23; range, 2 mo- to 21 y) revealed local recurrence (n=5) and metastatic disease (n=6; lymph node in 1, lungs in 4, and both lymph node and lung in 1). Metastases were noted at presentation in 2 cases (lymph node in 1 and lung in 1), but presented as late as 14 and 20 years in lymph node and lung, respectively. Only 1 patient died of metastatic disease 6 years after initial diagnosis, after multiple recurrences and lung metastases. Three patients were alive with progressive disease up to 24 months after developing lung metastases. Histopathologic features were not found to be predictive of outcome. The presence of tumor-associated myoepithelial cells histologically and immunohistochemically was not synonymous with benignity. Wide excision and partial digit amputation significantly reduced recurrence and metastatic rates. Delayed occurrence of metastases and a protracted course despite metastatic disease, necessitates long term follow-up. As the name implies a malignant neoplasm, the rubric "aggressive" is unnecessary. PMID- 23026932 TI - Combined BRAF(V600E)-positive melanocytic lesions with large epithelioid cells lacking BAP1 expression and conventional nevomelanocytes. AB - Recently a group of spitzoid melanocytic proliferations with loss of BAP1 expression has been reported. The lesions may occur sporadically or as part of a familial cancer syndrome. They have distinct histopathologic features characterized by a nevus-like silhouette and cytologic composition of large epithelioid melanocytes with oval vesicular nuclei, distinct nucleoli, and abundant cytoplasm with well-defined cytoplasmic borders. A characteristic immunohistochemical finding is loss of nuclear labeling for BAP1. In contrast to classic Spitz nevi, the lesions carry the BRAF mutation. They may present as a pure large epithelioid cell proliferation or as a combined lesion in association with a conventional nevus. Here we report a series of 8 combined melanocytic lesions, in which a dominant large epithelioid cell proliferation with loss of BAP1 expression was associated and intimately admixed with a BAP1-positive conventional nevus. These biphenotypic lesions were from 6 patients, 3 female and 3 male, ranging in age from 16 to 59 years. Immunohistochemical analysis for BAP1 showed loss of nuclear labeling confined to the large epithelioid melanocyte subpopulation. The conventional melanocytes retained BAP1 expression. Both large epithelioid and conventional melanocytes were immunoreactive with the monoclonal antibody VE1, which recognizes the protein encoded by mutant BRAF. In 6 cases the conventional nevus component was a compound nevus of small "type B" melanocytes. In 2 cases, the nevus remnant was entirely intradermal. The lesions described herein may represent a peculiar combined melanocytic nevus variant. However, longer follow-up and more studies are needed to determine the biological potential of the BAP1-negative melanocyte proliferations. PMID- 23026933 TI - Histology of intestinal allografts: lymphocyte apoptosis and phagocytosis of lymphocytic apoptotic bodies are diagnostic findings of acute rejection in addition to crypt apoptosis. AB - Acute rejection of a small-bowel transplant is often difficult to diagnose due to complicated immune responses. The present study aimed to elucidate the specific immune responses involved in intestinal transplant rejection. We correlated immunohistologic findings with an increase in crypt apoptosis, which has been commonly accepted as a criterion for the diagnosis of acute cellular rejection (ACR). Of 8 patients who received an intestinal allograft at Kyoto University Hospital, biopsy specimens from 7 patients were assessed immunohistologically with antibodies against 20 types of lymphocytic antigens including CD3, CD4, CD8, CD79a, CD20, IgG, and T-cell receptor, along with assessment of the patients' clinical courses. It was revealed that, in addition to apoptotic crypts, T lymphocyte apoptosis and phagocytosis of apoptotic bodies in the lamina propria of villi were findings of ACR; both were observed in all cases. Immunostaining of the Fas ligand, one of the apoptosis-inducing molecules, was useful for the identification of the apoptotic bodies in the lamina propria of villi. Apoptotic body phagocytosis may be a surrogate diagnostic finding of grafts undergoing ACR. PMID- 23026934 TI - Ampullary region carcinomas: definition and site specific classification with delineation of four clinicopathologically and prognostically distinct subsets in an analysis of 249 cases. AB - Ampullary (AMP) carcinomas comprise a heterogeneous group of cancers lacking adequate subcategorization. In the present study, 249 strictly defined primary AMP carcinomas (ACs) identified in 1469 malignant pancreatoduodenectomy specimens were analyzed for defining features. Gross and microscopic findings were used to determine tumor epicenter and extent of preinvasive component. ACs were classified into 4 distinct subtypes based on location: (1) Intra-AMP (25%): Invasive carcinomas arising in intra-ampullary papillary-tubular neoplasms with zero to minimal, duodenal surface involvement (<25% of the tumor). These tumors were more commonly found in men, they had a relatively large overall size (mean, 2.9 cm) but had smaller invasive component (mean, 1.5 cm), and were predominantly of a lower TNM stage (85%, T1/2; and 72% N0). They carried the best prognosis among the 4 groups (3-y survival, 73%). (2) AMP-ductal (15%): These were tumors forming constrictive, sclerotic, plaque-like thickening of the walls of the common bile duct and/or pancreatic duct resulting in mucosa-covered, button-like elevations of the papilla into the duodenal lumen. There was no significant exophytic (preinvasive) growth. These were the smallest tumors (mean overall size, 1.9 cm; mean invasion size 1.7 cm), but carried the worst prognosis (3-y survival, 41%), presumably due to the pancreatobiliary histology/origin (in 86%); however, even this group had significantly better prognosis when compared with 113 ordinary pancreatic ductal adenocarcinomas (3 y, 11%; P<0.0001). (3) Peri-AMP duodenal (5%): Massive exophytic, ulcero-fungating tumors growing into the duodenal lumen and eccentrically encasing the ampullary orifice with only minimal intra-ampullary luminal involvement. These were mostly of intestinal phenotype (75%) and some had mucinous features. Although these tumors were the largest (mean overall size 4.7 cm; and mean invasion size 3.4 cm), and had the highest incidence of lymph node metastasis (50%), they carried an intermediate prognosis (3-y survival, 69%) to that seen among a group of 55 nonampullary duodenal carcinoma controls. (4) AC-not otherwise specified ("papilla of Vater"; 55%): Ulcero-nodular tumors located at the papilla of Vater, which do not show the specific characteristics identified among the other 3 subtypes. In conclusion, ACs comprise 4 clinicopathologic subtypes that are prognostically distinct. PMID- 23026935 TI - Coexisting high-grade vulvar intraepithelial neoplasia (VIN) and condyloma acuminatum: independent lesions due to different HPV types occurring in immunocompromised patients. AB - The majority of vulvar intraepithelial neoplasia (VIN) is high-grade and is related to high-risk human papillomavirus (HRHPV) (most commonly HPV 16). It is considered to be the precursor of HRHPV-related vulvar squamous cell carcinoma. Vulvar condyloma acuminatum is low-risk HPV (LRHPV)-related (most commonly types 6 and 11) and has virtually no risk of neoplastic progression. While infection with multiple LRHPV and HRHPV types has been reported for cervical squamous intraepithelial lesions, coexisting vulvar condyloma and adjacent high-grade VIN have not been well characterized. Eleven cases of concurrent condyloma acuminatum and adjacent flat high-grade VIN and 3 cases of high-grade VIN with prominent condylomatous architecture were analyzed using immunohistochemical analysis of p16 expression, in situ hybridization (ISH) for HPV detection [HPV 6/11, HPV 16, HPV 18, and HPV wide spectrum (types 6, 11, 16, 18, 31, 33, 35, 45, 51, 52) probes], and HPV typing by a polymerase chain reaction (PCR)-based method (in select cases). All patients had underlying immunosuppressive conditions (human immunodeficiency virus infection or posttransplant therapy). Among the 11 cases of concurrent high-grade VIN and condyloma, the lesions were directly adjacent to one another in 5 cases (with 2 of these demonstrating an intimate admixture of lesions), and in 6 cases the lesions were found in separate tissue sections from the same specimen. Diffuse/strong p16 expression was seen in all high-grade VIN lesions, whereas patchy/weak staining was found in all condylomata. All condylomata contained HPV 6 or 11 as detected by ISH. HRHPV was detected in all of the accompanying high-grade VIN lesions. Ten contained HPV 16 (9 by ISH, 1 by PCR), with the remaining case containing multiple HPV types by PCR. All condylomatous high-grade VIN lesions demonstrated diffuse/strong p16 expression and had evidence of HRHPV (1 with HPV 16 by ISH, 1 with HPV 18 by ISH, and 1 with multiple HPV types by PCR), with no detection of HPV 6 or 11 by ISH. The restriction of LRHPV to condylomatous components and HRHPV to high-grade VIN components of adjacent lesions suggests these are independent lesions caused by different HPV types. Diffuse p16 expression can highlight small foci of high grade VIN, which may be overlooked in more abundant condylomatous tissue from immunosuppressed patients. The presence of only HRHPV in those VIN lesions with high-grade cytologic features but prominent condylomatous architecture supports their classification as forms of pure high-grade VIN and distinguishes them from condyloma acuminatum. PMID- 23026936 TI - Angioinvasive lymphomatoid papulosis: a new variant simulating aggressive lymphomas. AB - Lymphomatoid papulosis (LyP) belongs to the spectrum of primary cutaneous CD30 positive lymphoproliferative disorders. Clinically, LyP is characterized by a variable number of self-healing papulo-nodular lesions, with the typical waxing and waning course. Histologically, 4 types (A, B, C, and D) have been delineated. Angioinvasive growth and large ulcers are rare findings in LyP and simulate aggressive lymphoma. We retrospectively analyzed the clinicopathologic and molecular features of angioinvasive LyP in a series of 16 patients. This new form of LyP is characterized by oligolesional papules that rapidly ulcerate and evolve into large necrotic eschar-like lesions with a diameter of 1 to 4 cm and an angiocentric and angiodestructive infiltrate of small-sized to medium-sized atypical lymphocytes expressing CD30 and frequently CD8. As in other forms of LyP, the lesions underwent spontaneous regression after a few weeks. Recurrences were common, but the prognosis was excellent with no extracutaneous spread or disease-related deaths. Complete remission occurred in 9 of 16 patients (56%). This LyP variant should be distinguished from aggressive forms of angiocentric and angiodestructive and cytotoxic T-cell lymphomas. We propose the term LyP type E for this clinically and histologically unusual variant. PMID- 23026937 TI - Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma. AB - This study investigated the sensitivity and specificity of immunohistochemical (IHC) analysis using an anti-BRAF antibody to detect the presence of the BRAF V600E mutation in patients with metastatic melanoma. A total of 100 patients with American Joint Committee on Cancer stage IIIC unresectable or stage IV melanoma and who underwent tumor DNA BRAF mutation testing were selected. Paraffin embedded, formalin-fixed melanoma biopsies were analyzed for the BRAF mutation status by independent, blinded observers using both conventional DNA molecular techniques and IHC with the novel BRAF V600E mutant-specific antibody, VE1. The antibody had a sensitivity of 97% (37/38) and a specificity of 98% (58/59) for detecting the presence of a BRAF V600E mutation. Of the BRAF-mutated cases, none of the non-V600E cases (including V600K) stained positive with the antibody (0/11). There were 5 cases with discordant BRAF mutation results. Additional molecular analysis confirmed the immunohistochemically obtained BRAF result in 3 cases, suggesting that the initial molecular testing results were incorrect. Two of these patients would not have received a BRAF inhibitor on the basis of the initial false-negative mutation testing result. Two cases remained discordant. The reported IHC method is an accurate, rapid, and cost-effective method for detecting V600E BRAF mutations in melanoma patients. Clinical use of the V600E BRAF antibody should be a valuable supplement to conventional mutation testing and allow V600E mutant metastatic melanoma patients to be triaged rapidly into appropriate treatment pathways. PMID- 23026938 TI - Primary renal neuroblastoma. PMID- 23026939 TI - SPP tomography: a simple wide-field nanoscope. AB - We explore the wide-field optical nanoimaging capabilities of the surface plasmon polariton (SPP) tomography technique. We show that nanofeatures with lateral dimensions smaller than lambda/20 can be observed in the surface emission (SE) images of plasmonic crystals with a period of 300 nm. Moreover, as a proof-of concept, we demonstrate that SPP tomography permits to resolve two single objects with a center-to-center separation of 200 nm and edge-to-edge separation as small as lambda/7. We present a comprehensive discussion about the nanoimaging capabilities of the SPP tomography technique. In contrast to other optical subwavelength resolution techniques, in our approach for imaging nanosize features, enhanced evanescent waves are coupled to the far-field via leakage radiation associated with SPPs excited by near-field fluorescence; therefore wide field images, which are not out-of-plane diffraction-limited, are formed directly in the microscope's camera. We also discuss additional imaging processing capabilities associated with the fact that SPP tomography SE images are formed by the microscope lenses through an analog tomography process. PMID- 23026940 TI - Mutation of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) at the 3'-untranslated region is associated with adrenocortical insufficiency. AB - In the present study, we report the mutation of the 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene in a family suffering from adrenocortical insufficiency. The index patient was clinically diagnosed with adrenocortical insufficiency. Peripheral venous blood (5 ml) was collected from the proband and 5 members of his family, and genomic DNA was extracted. Exons 1, 2, 3 and 4 of the 3beta-HSD gene and their flanking sequences were amplified by polymerase chain reaction (PCR). Some of the family members were examined by amplifying only exon 4. The PCR products were then purified and sequenced. The C to T homozygous mutation at nucleotide 1088 and C to G homozygous mutation at nucleotide 1132 within exon 4 of the 3beta-HSD gene were found in the family members with abnormal phenotype. In the family members with normal phenotype, heterozygous mutations at the sites mentioned above were identified in the parents and Aunt 1, but not in Aunt 2 of the proband. In conclusion, a family with 3beta-HSD deficiency was identified in the present study. The cause of the disease in the studied family appears to be two novel homozygous mutations in the 3beta-HSD gene. PMID- 23026941 TI - Contributions of international nursing research. PMID- 23026942 TI - The role of complement in antibody-mediated rejection in kidney transplantation. AB - Over the past decade, several studies have suggested that the complement system has an active role in both acute and chronic allograft rejection. These studies have been facilitated by improved techniques to detect antibody-mediated organ rejection, including immunohistological staining for C4d deposition in the allograft and solid-phase assays that identify donor-specific alloantibodies (DSAs) in the serum of transplant recipients. Studies with eculizumab, a humanized monoclonal antibody directed against complement component C5, have shown that activation of the terminal complement pathway is necessary for the development of acute antibody-mediated rejection in recipients of living-donor kidney allografts who have high levels of DSAs. The extent to which complement activation drives chronic antibody-mediated injury leading to organ rejection is less clear. In chronic antibody-mediated injury, early complement activation might facilitate chemotaxis of inflammatory cells into the allograft in a process that later becomes somewhat independent of DSA levels and complement factors. In this Review, we discuss the different roles that the complement system might have in antibody-mediated allograft rejection, with specific emphasis on renal transplantation. PMID- 23026947 TI - Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. AB - Until recently, membranoproliferative glomerulonephritis (MPGN) was clinically classified as either primary, idiopathic MPGN or as secondary MPGN when an underlying aetiology was identifiable. Primary MPGN was further classified into three types--type I, type II, and type III--based principally on the ultrastructural appearance and location of electron-dense deposits. Both the clinical and histopathologic schemes presented problems, however, as neither was based on disease pathogenesis. An improved understanding of the role of complement in the pathogenesis of MPGN has led to a proposed reclassification into immunoglobulin-mediated disease (driven by the classical complement pathway) and non-immunoglobulin-mediated disease (driven by the alternative complement pathway). This reclassification has led to improved diagnostic clinical algorithms and the emergence of a new grouping of diseases known as the C3 glomerulopathies, best represented by dense deposit disease and C3 glomerulonephritis. In this Review, we re-examine the previous and current classification schemes of MPGN, focusing on the role of complement. We survey current data about the pathogenesis of the C3 glomerulopathies, including familial studies and patient cohorts from the USA and Europe. In addition, we discuss the diagnosis, treatment, and prognosis of the C3 glomerulopathies. PMID- 23026948 TI - Transplantation: Sirolimus for secondary SCC prevention in renal transplantation. PMID- 23026952 TI - Olive trees in a mountainous landscape. PMID- 23026949 TI - Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. AB - In the past decade, a large body of evidence has accumulated in support of the critical role of dysregulation of the alternative complement pathway in atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathies. These findings have paved the way for innovative therapeutic strategies based on complement blockade, and eculizumab, a monoclonal antibody targeting the human complement component 5, is now widely used to treat aHUS. In this article, we review 28 case reports and preliminary data from 37 patients enrolled in prospective trials of eculizumab treatment for episodes of aHUS involving either native or transplanted kidneys. Eculizumab may be considered as an optimal first-line therapy when the diagnosis of aHUS is unequivocal and this treatment has the potential to rescue renal function when administered early after onset of the disease. However, a number of important issues require further study, including the appropriate duration of treatment according to an individual's genetic background and medical history, the optimal strategy to prevent post-transplantation recurrence of aHUS and a cost-efficacy analysis. Data regarding the efficacy of eculizumab in the control of C3 glomerulopathies are more limited and less clear, but several observations suggest that eculizumab may act on the most inflammatory forms of this disorder. PMID- 23026953 TI - Prevalence and persistence of psychiatric disorders in youth after detention: a prospective longitudinal study. AB - CONTEXT: Psychiatric disorders are prevalent among incarcerated juveniles. Most juveniles eventually return to their communities, where they become the responsibility of the community mental health system. However, no large-scale study has examined psychiatric disorders after youth leave detention. OBJECTIVE: To examine changes in the prevalence and persistence of psychiatric disorders during the 5 years after detention, focusing on sex and racial/ethnic differences. DESIGN: Prospective longitudinal study with up to 5 interviews (1829 youth: 1172 males and 657 females). To ensure representation of key demographic subgroups, the randomly selected sample was stratified by sex, race/ethnicity (African American, non-Hispanic white, and Hispanic), age, and legal status (juvenile or adult court). SETTING: The Northwestern Juvenile Project, sampling youth from the Cook County Juvenile Temporary Detention Center, Chicago, Illinois. PARTICIPANTS: Detained youth, aged 10 to 18 years at baseline interview. MAIN OUTCOME MEASURES: At baseline, the Diagnostic Interview Schedule for Children Version 2.3. At follow-up interviews, the Diagnostic Interview Schedule for Children Version IV (Child and Young Adult versions) and the Diagnostic Interview Schedule Version IV (substance use disorders and antisocial personality disorder). RESULTS: Five years after baseline, more than 45% of males and nearly 30% of females had 1 or more psychiatric disorders with associated impairment. More than 50% of males and more than 40% of females had 1 or more psychiatric disorders without impairment. Substance use disorders were the most common; males, however, had higher rates over time (5 years after baseline, adjusted odds ratio [AOR], 2.61; 95% CI, 1.96-3.47). Non-Hispanic whites and Hispanics also had higher rates of substance use disorders vs African Americans (AOR, 1.96; 95% CI, 1.54-2.49 and AOR, 1.59; 95% CI, 1.24-2.03). Females had higher rates of major depression over time (AOR, 1.59; 95% CI, 1.22-2.08). CONCLUSIONS: Although prevalence rates of most psychiatric disorders declined as youth aged, a substantial proportion of delinquent youth continue to have disorders. There are notable sex and racial/ethnic differences in the prevalence and persistence of psychiatric disorders in this population. PMID- 23026954 TI - Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. AB - CONTEXT: Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function. OBJECTIVES: To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior. DESIGN: Cross-sectional and longitudinal studies. SETTING: Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia. PATIENTS: Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment. MAIN OUTCOME MEASURES: Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa-induced depression, anhedonia, fatigue, and neurotoxicity. RESULTS: Patients with HCV receiving interferon alfa for 4 to 6 weeks (n = 14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n = 14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n = 12) exhibited significantly increased 18F dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration. CONCLUSIONS: These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release. PMID- 23026955 TI - The associations of insomnia with costly workplace accidents and errors: results from the America Insomnia Survey. AB - CONTEXT: Insomnia is a common and seriously impairing condition that often goes unrecognized. OBJECTIVES: To examine associations of broadly defined insomnia (ie, meeting inclusion criteria for a diagnosis from International Statistical Classification of Diseases, 10th Revision, DSM-IV, or Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition) with costly workplace accidents and errors after excluding other chronic conditions among workers in the America Insomnia Survey (AIS). DESIGN/SETTING: A national cross-sectional telephone survey (65.0% cooperation rate) of commercially insured health plan members selected from the more than 34 million in the HealthCore Integrated Research Database. PARTICIPANTS: Four thousand nine hundred ninety-one employed AIS respondents. MAIN OUTCOME MEASURES: Costly workplace accidents or errors in the 12 months before the AIS interview were assessed with one question about workplace accidents "that either caused damage or work disruption with a value of $500 or more" and another about other mistakes "that cost your company $500 or more." RESULTS: Current insomnia with duration of at least 12 months was assessed with the Brief Insomnia Questionnaire, a validated (area under the receiver operating characteristic curve, 0.86 compared with diagnoses based on blinded clinical reappraisal interviews), fully structured diagnostic interview. Eighteen other chronic conditions were assessed with medical/pharmacy claims records and validated self-report scales. Insomnia had a significant odds ratio with workplace accidents and/or errors controlled for other chronic conditions (1.4). The odds ratio did not vary significantly with respondent age, sex, educational level, or comorbidity. The average costs of insomnia-related accidents and errors ($32 062) were significantly higher than those of other accidents and errors ($21 914). Simulations estimated that insomnia was associated with 7.2% of all costly workplace accidents and errors and 23.7% of all the costs of these incidents. These proportions are higher than for any other chronic condition, with annualized US population projections of 274 000 costly insomnia-related workplace accidents and errors having a combined value of US $31.1 billion. CONCLUSION: Effectiveness trials are needed to determine whether expanded screening, outreach, and treatment of workers with insomnia would yield a positive return on investment for employers. PMID- 23026956 TI - Functional brain basis of hypnotizability. AB - CONTEXT: Focused hypnotic concentration is a model for brain control over sensation and behavior. Pain and anxiety can be effectively alleviated by hypnotic suggestion, which modulates activity in brain regions associated with focused attention, but the specific neural network underlying this phenomenon is not known. OBJECTIVE: To investigate the brain basis of hypnotizability. DESIGN: Cross-sectional, in vivo neuroimaging study performed from November 2005 through July 2006. SETTING: Academic medical center at Stanford University School of Medicine. PATIENTS: Twelve adults with high and 12 adults with low hypnotizability. MAIN OUTCOME MEASURES: Functional magnetic resonance imaging to measure functional connectivity networks at rest, including default-mode, salience, and executive-control networks; structural T1 magnetic resonance imaging to measure regional gray and white matter volumes; and diffusion tensor imaging to measure white matter microstructural integrity. RESULTS: High compared with low hypnotizable individuals had greater functional connectivity between the left dorsolateral prefrontal cortex, an executive-control region of the brain, and the salience network composed of the dorsal anterior cingulate cortex, anterior insula, amygdala, and ventral striatum, involved in detecting, integrating, and filtering relevant somatic, autonomic, and emotional information using independent component analysis. Seed-based analysis confirmed elevated functional coupling between the dorsal anterior cingulate cortex and the dorsolateral prefrontal cortex in high compared with low hypnotizable individuals. These functional differences were not due to any variation in brain structure in these regions, including regional gray and white matter volumes and white matter microstructure. CONCLUSIONS: Our results provide novel evidence that altered functional connectivity in the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex may underlie hypnotizability. Future studies focusing on how these functional networks change and interact during hypnosis are warranted. PMID- 23026957 TI - Twenty-year depressive trajectories among older women. AB - CONTEXT: Despite the frequent occurrence of depressive symptoms among older adults, especially women, little is known about the long-term course of late-life depressive symptoms. OBJECTIVE: To characterize the natural course of depressive symptoms among older women (from the young old to the oldest old) followed up for almost 20 years. DESIGN: Using latent-class growth-curve analysis, we analyzed women enrolled in an ongoing prospective cohort study (1988 through 2009). SETTING: Clinic sites in Baltimore, Maryland; Minneapolis, Minnesota; the Monongahela Valley near Pittsburgh, Pennsylvania; and Portland, Oregon. PARTICIPANTS: We studied 7240 community-dwelling women 65 years or older. MAIN OUTCOME MEASURE: The Geriatric Depression Scale short form (score range, 0-15) was used to routinely assess depressive symptoms during the follow-up period. RESULTS: Among older women, we identified 4 latent classes during 20 years, with the predicted probabilities of group membership totaling 27.8% with minimal depressive symptoms, 54.0% with persistently low depressive symptoms, 14.8% with increasing depressive symptoms, and 3.4% with persistently high depressive symptoms. In an adjusted model for latent class membership, odds ratios (ORs) for belonging in the increasing depressive symptoms and persistently high depressive symptoms classes, respectively, compared with a group having minimal depressive symptoms were substantially and significantly (P < .05) elevated for the following variables: baseline smoking (ORs, 4.69 and 7.97), physical inactivity (ORs, 2.11 and 2.78), small social network (ORs, 3.24 and 6.75), physical impairment (ORs, 8.11 and 16.43), myocardial infarction (ORs, 2.09 and 2.41), diabetes mellitus (ORs, 2.98 and 3.03), and obesity (ORs, 1.86 and 2.90). CONCLUSIONS: During 20 years, almost 20% of older women experienced persistently high depressive symptoms or increasing depressive symptoms. In addition, these women had more comorbidities, physical impairment, and negative lifestyle factors at baseline. These associations support the need for intervention and prevention strategies to reduce depressive symptoms into the oldest-old years. PMID- 23026958 TI - Amygdala volume in combat-exposed veterans with and without posttraumatic stress disorder: a cross-sectional study. AB - CONTEXT: Data from animal models demonstrate a link between stress exposure and hypertrophic changes in the amygdala; however, studies of adults with posttraumatic stress disorder (PTSD) have failed to find analogous structural alterations. OBJECTIVES: To compare amygdala volumes between a sample of combat veterans with and without PTSD (analysis 1) and examine whether our observation of larger amygdala volume in individuals with PTSD could be accounted for by the presence of trauma exposure in childhood and the severity of combat exposure in adulthood (analysis 2). DESIGN: Cross-sectional magnetic resonance imaging. SETTING: Veterans Affairs Palo Alto Health Care System Inpatient Trauma Recovery Program and Veterans Affairs New England Health Care System Outpatient PTSD program. PARTICIPANTS: Ninety-nine combat-exposed veterans from the Vietnam Conflict or the Persian Gulf War who had been exposed to substantial military operational stress. MAIN OUTCOME MEASURES: Amygdala volume adjusted for total cerebral volume, Life Events Checklist, and the Combat Exposure Scale. RESULTS: Analysis 1 indicated that combat-exposed individuals with PTSD exhibited larger total amygdala volume compared with their non-PTSD counterparts (99 individuals, P = .047). Analysis 2 indicated that greater severity of combat exposure (87 individuals, P = .02), as well as the interaction between the presence of early life trauma and the severity of combat exposure (87 individuals, P = .008), were significantly associated with smaller total amygdala volume. The PTSD diagnosis continued to explain larger amygdala volume (87 individuals, P = .006). CONCLUSIONS: Posttraumatic stress disorder is associated with enlarged amygdala volume, above the variance accounted for by a history of early life trauma and severity of adult trauma exposure. The discrepancy between our and prior findings may be explained by variability in these trauma indices in previous investigations. These findings support additional study of amygdala structure in human stress disorders and further delineation of the role of early and adult trauma on associated neurologic changes. PMID- 23026959 TI - Editor's foreword. PMID- 23026960 TI - Injury-related hospital admissions of military dependents compared with similarly aged nonmilitary insured infants, children, and adolescents. AB - BACKGROUND: Military deployment of one or both parents is associated with declines in school performance, behavioral difficulties, and increases in reported mental health conditions, but less is known regarding injury risks in pediatric military dependents. METHODS: Kid Health Care Cost and Utilization Project 2006 (KID) was used to identify military dependents aged 0.1 year to 17 years through expected insurance payer being CHAMPUS, Tricare, or CHAMPVA (n = 12,310) and similarly aged privately insured nonmilitary in CHAMPUS, Tricare, or CHAMPVA states (n = 730,065). Mental health diagnoses per 1,000 hospitalizations and mechanisms of injury per 1,000 injury-related hospitalizations are reported. Unweighted univariate analyses used Fisher's exact, chi(2), and analysis of variance tests for significance. Odds ratios are age and sex adjusted with 95% confidence intervals. RESULTS: Injury-related admissions were higher in military than in nonmilitary dependents (15.5% vs. 13.2%, p < 0.0001). Age- and sex adjusted motor vehicle occupant and pedestrian injuries were significantly lower in all-age military dependents but not in age-stratified categories. Very young military dependents had higher all-cause injury admissions (p < 0.0001), drowning/near drowning (p < 0.0001), and intracranial injury (p < 0.0001) and showed a tendency toward higher suffocation (p = 0.055) and crushing injury (p = 0.065). Military adolescents and teenagers had higher suicide/suicide attempts (p = 0.0001) and poisonings from medicinal substances (p = 0.0001). Mental health diagnoses were significantly higher in every age category of military dependents. All-cause in-hospital mortality tended to be greater in military than in nonmilitary dependents (p = 0.052). CONCLUSION: This study suggests that military dependents are a vulnerable population with special needs and provides clues to areas where injury prevention professionals might begin to address their needs. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level II. PMID- 23026961 TI - Can a youth violence screening tool be used in a Pediatric Emergency Department setting? AB - BACKGROUND: Youth violence is a significant public health concern. Many children and adolescents are treated in emergency departments (EDs), which may be a location to identify at-risk youth for interventions by administering a screening instrument. METHODS: A prospective convenience study of youth (ages 8-17 years) presenting to the ED was conducted to evaluate a second-generation violence questionnaire. The 14 items of the Violence Prevention Emergency Tool 2 (VPET 2) was developed from a previously described tool (VPET 1). VPET 2 asked the frequency of physical or verbal violence events witnessed or experienced by the subject and was administered in the ED by research assistants. RESULTS: Of the 211 youths, 200 were enrolled (95% participation rate); 3 were ineligible, and 8 declined (<4%). The youths had a mean age 13.3 years, 52.5% males, 39% Hispanic, and 17% black. Seventy-six percent of the legal guardians were mothers, 62.5% had at least a high school education, and 55% were working full time. Sixty-six percent of the subjects reported seeing a person slap another person "really hard;" 8.5% were threatened by someone with a weapon; 28% were physically harmed by another person; 10% reported drug/alcohol use; 32.5% had failed a class in the past year. Adolescents (13-17 years) compared with preadolescents (8-12 years) were more likely to report being threatened and/or physically harmed (p < 0.05). No significant sex differences were identified. CONCLUSION: VPET 2 was administered in an ED with a high rate of enrollment and completion. This may be a feasible screening tool for use in the ED for determining which youth have the highest levels of violence exposure. A brief validated version of VPET 2 could be a valuable tool in ensuring that youth most at-risk are identified and provided appropriate referrals and services. LEVEL OF EVIDENCE: Diagnostic study, level IV. PMID- 23026962 TI - Clinical predictors of outcome following inflicted traumatic brain injury in children. AB - BACKGROUND: The study aimed to determine which acute injury variables were predictors of long-term functional outcome following inflicted traumatic brain injury (iTBI). METHODS: A retrospective case review of 35 children with iTBI was performed. After controlling for age at injury and time since injury, the generalized estimation equations method was used to identify acute injury variables that were significantly related to the Glasgow Outcome Scale scores at the initial follow-up assessments. When available, functional sequelae at these and longer-term follow-ups were also examined. RESULTS: In bivariate generalized estimation equations analyses, a low Glasgow Coma Scale (GCS) eye component score, a low GCS motor component score, a low GCS verbal component score, need for neurosurgical intervention, seizures in the first week after injury, need for mechanical ventilation for more than 10 days, length of intensive care unit stay of more than 10 days, initial hyperglycemia, and neuroimaging findings of cerebral edema or loss of gray-white matter differentiation were significantly (p <= 0.05) related to having a poor outcome, as defined by their Glasgow Outcome Scale score at the initial follow-up. In multivariable analyses, considering the significant predictors while controlling for age at injury and time since injury, the presence of cerebral edema on neuroimaging (odds ratio, 27.21; 95% confidence interval, 4.40-168.22), and length of intensive care unit stay of more than 10 days (odds ratio, 21.57; 95% confidence interval, 3.09-150.48) were significantly related to having a poor outcome. CONCLUSION: Early clinical data following iTBI help predict long-term functional outcome. Further research to support these findings may help delineate acutely after injury which children with iTBI are at risk for a poor prognosis and should be more closely followed up over time. LEVEL OF EVIDENCE: Prognostic study, level IV. PMID- 23026963 TI - Falls in children birth to 5 years: different mechanisms lead to different injuries. AB - BACKGROUND: Falls are the most common cause of injury-related hospitalization in children younger than 5 years old. Most anticipatory guidance surrounding falls is around falls from windows or stairs; however, falls from furniture also are important causes of morbidity. The purpose of this study was to compare the number of children injured, ages of injured children, and injuries sustained in falls from furniture and falls from stairs in hospitalized children younger than 5 years. METHODS: All records of individuals from 0 year through 4 years, hospitalized at our institution for a fall from furniture or stairs between January 1, 1996, and December 31, 2006, were retrospectively reviewed. A standard data set was abstracted from each chart. Frequencies were used to characterize the study population. chi and t tests were used to determine differences between groups. RESULTS: A total of 171 patients were hospitalized for falls from stairs and 318 for falls from furniture. There were no differences between the groups with regard to age, sex, race, type of insurance, length of stay, Injury Severity Score, or total cost. The most common pieces of furniture from which children fell were beds (33.0%), couches (18.9%), and chairs (17.9%). Children who fell from stairs were significantly more likely to have injuries to their head (64.3% vs. 38.1%); those that fell from furniture were more likely to sustain arm injuries (33.3% vs. 9.9%). There were significantly more skull fractures in those that fell from stairs (39.8% vs. 20.1%) and humerus fractures in those that fell from furniture (30.8% vs. 9.4%) (p < 0.001). Falls from furniture increased during the study period, while falls from stairs fell; the difference was not statistically significant, however. CONCLUSION: Falls from furniture and stairs are important causes of morbidity in children. More children were hospitalized for falls from furniture than from stairs. Falls down stairs are decreasing while falls off furniture are increasing. More anticipatory guidance should be developed and given to families regarding falls from furniture to help prevent these injuries. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 23026964 TI - Is an emergency department encounter for a motor vehicle collision truly a teachable moment? AB - BACKGROUND: Some have suggested that a pediatric emergency department (PED) visit for an injury represents a "teachable moment." Our aim was to determine if a motor vehicle collision (MVC) instigates greater change in booster seat use compared with children presenting for non-injury-related complaints. METHODS: A prospective pilot study of children 4 years to 8 years who never used a booster seat and were in a minor MVC were compared with children presenting to the PED for non-injury-related complaints. After completing a survey of demographics and knowledge about booster seats, all parents received brief, standardized counseling about booster seats. Two weeks after the PED visit, follow-up telephone calls were made to assess behavior change. RESULTS: Sixty-seven youth were enrolled (37 MVC group, 30 controls). Initially, 65 (97%) used a seat belt alone (36 MVC, 29 controls); the rest were unrestrained. There was no difference between the groups in mean age, sex of child, or insurance type. Significantly more families in the MVC group claimed that they would get a booster seat after their PED encounter (46% vs. 19%, p = 0.02) and their child would consistently use a booster seat (54% vs. 23%, p = 0.01). At follow-up, 45 families (67%) were reached (25 cases [68%] and 20 controls [67%]). There was no significant difference between the groups in having a booster seat at follow-up (12 cases [48%] and 9 controls [45%]) and reports of booster seat use more than 75% of the time (9 cases [36%] and 7 controls [35%]). CONCLUSION: A minor MVC did not serve as a teachable moment to entice families to consistently use a booster seat more than families presenting to a PED for non-injury-related complaints. However, more than one third of the families who learned about booster seats in the PED reported using a booster seat regularly. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 23026965 TI - Wishful thinking: safe transportation of newborns at hospital discharge. AB - BACKGROUND: Motor vehicle occupant injury is a significant source of morbidity and mortality among children. Correctly used child safety seats (CSSs) substantially reduce injury morbidity and mortality. The objective of this study was to describe how parents learn to use and install CSS at newborn discharge. METHODS: We prospectively enrolled maternal/newborn infant dyads at discharge from a large urban teaching hospital. Survey data included maternal demographics and parental knowledge on CSS installation. After survey completion, a certified child passenger safety technician observed and recorded CSS information, infant placement in CSS, and CSS placement in vehicle. Nine specific misuse categories were recorded. RESULTS: A total of 101 mothers were enrolled, with mean age 29.4 years (15-45 years); 52% were white, 18% were black, and 27% were Hispanic; 50% had college degree or higher; and 41% were privately insured. We observed 254 CSS errors (range, 0-7; mean, 2.5). There were 52% infant placement in CSS misuse errors (range 0-4; mean, 1.3), and 48% CSS placement in vehicle misuse errors (range, 0-4; mean, 1.2). The CSS placement misuse included 29% CSS not attached to vehicle. More frequent misuse occurred among non-white, non-college-educated mothers (p < 0.01).There was no difference in misuse related to how, when, and where mothers learned about CSS installation. CONCLUSION: Despite national, state, and hospital policies that require newborns to be transported in a CSS, we found a significant number of concerning CSS misuse in our study population. These results highlight the need for improved CSS education starting with the first ride home. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 23026966 TI - The reality of teenage driving: the results of a driving educational experience for teens in the juvenile court system. AB - BACKGROUND: In the United States, one third of all deaths in teens are a result of motor vehicle crashes, accounting for 6,000 deaths annually. Injury Free Coalition for Kids-Worcester in collaboration with Worcester Juvenile Court has developed an interactive program for first-time teenaged driving offenders, Reality Intensive Driver Education (Teen RIDE). This full-day program at the trauma center provides a realistic exposure to the consequences of risky driving behaviors. This article examined the driving offense recidivism rates for Teen RIDE participants versus a comparison group (CG). METHODS: The intervention group (IG) consists of teenagers between 13 years and 17 years who have been arrested for the first time for a serious driving offense and are sentenced by a Worcester Juvenile Court Judge or Magistrate to the Teen RIDE program. They are required to attend the program as a condition of probation, so attendance is mandatory. Each participant in the IG completed the program and was tracked for driving reoffenses for 6 months after completion of the course. The CG consists of also first-time driving offenders. The CG was matched with the IG with respect to age (13-17 years), sex, and offense type. Springfield, Massachusetts, serves as the site for recruitment of the CG, since it is demographically similar to Worcester but 60 mi away. Students in the CG had no exposure to this program. Each CG member was also tracked for 6 months after arrest. RESULTS: The recidivism rate for Teen RIDE participants 6 months after the course is 6% with 0% reoffending more than once. The CG has a recidivism rate of 56% 6 months after the arrest and 14% have more than one reoffense. The CG is 13.062 (4.296-39.713) times more likely to reoffend, and this is significant (p < 0.001). CONCLUSION: The Teen RIDE program provides an impactful exposure of the consequences of risky driving behaviors to teenaged participants. In addition, Teen RIDE participants are significantly less likely to reoffend after completion of the course. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 23026967 TI - Safety factors related to all-terrain vehicle injuries in children. AB - BACKGROUND: All-terrain vehicle (ATV)-related injuries are a significant source of pediatric trauma. We hypothesized that these injuries are caused by poor safety behavior. To test this hypothesis, we surveyed both injured and uninjured ATV riders. METHODS: A prospective convenience sample-based survey was initiated at Children's Hospital of Pittsburgh, a Level I pediatric trauma center. Patients with an ATV-related injury were asked to complete the survey for the study group (INJ), while uninjured pediatric ATV-riders completed the survey for the control group (UnINJ). The Fisher's exact probability test was used for data analysis. RESULTS: There were 38 surveys completed for INJ and 11 for UnINJ. Both groups had similar demographics. ATVs in both groups were mostly used for recreation, and most of the INJ patients were in a rural setting. Half of the ATVs were purchased second hand, and less than half were purchased from a dealer. Most dealers reviewed age recommendations for ATV use; however, many safety recommendations were not followed. INJ group had a higher percentage of children riding inappropriately sized ATVs and a lower rate of helmet use when compared with UnINJ group. In addition, there were a significant number of regulatory violations in the INJ group, including nine children (24%) riding as passengers and 5 (13%) driving on a road. CONCLUSION: These data suggest that there may be decreased safety behavior among injured pediatric ATV-riders; however, uninjured riders also demonstrate poor safety habits. The study showed that dealers do review safety regulations with consumers; however, most of the ATVs are not purchased through dealers. Therefore, we may need to shift our safety and educational focus to reach these families. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 23026969 TI - Telemedicine and retinal imaging for improving diabetic retinopathy evaluation. PMID- 23026968 TI - Analysis of pediatric all-terrain vehicle trauma data in Middle Tennessee: implications for injury prevention. AB - BACKGROUND: Trauma registries capture data about injuries that can be used to objectively guide injury prevention initiatives. This article analyzes trauma registry data to describe the nature and distribution of all-terrain vehicle (ATV) injuries in Middle Tennessee. A community injury prevention effort, based on this analysis, is also presented. METHODS: A retrospective analysis of data (2007-2009) from the trauma registry of a Level I pediatric trauma center in Middle Tennessee was conducted. Patients younger than 16 years with ATV-related injuries were included in the analysis (n = 163). The key variables examined were demographics, injury severity, helmet use, injury mechanism, length of stay, and patient's county of residence. In addition, Geographic Information Systems software was used to examine the distribution of injuries and graphically represent counties with highest injury rates in the youth population. RESULTS: ATV injuries were more prevalent among boys than girls (66% vs. 34%; p < 0.001). Approximately 64% of the ATV injuries were in the age group 10 years to 15 years. Most injuries were either moderately severe (44%) or severe (30%). Injury mechanism varied by age; younger children experienced more rollovers while older children tended to be injured from ejections (p < 0.05). Helmet use was low (33%). Data from this study suggest that helmet use resulted in fewer injuries to the head, neck, and face. Counties with high rates of ATV injuries were targeted for ATV training programs. 4-H agents trained by the ATV Safety Institute provided ATV training classes. CONCLUSION: Rural youth are clearly at greater risk for ATV injuries than urban populations. Young ATV riders are often self taught and lack the knowledge to ride ATVs safely. Organizations such as the 4-H, provide effective injury prevention outreach. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 23026971 TI - Designing, implementing, and conducting a web-based radiation safety training program to meet Texas standards for radiation protection. AB - The implementation of a web-based radiation safety training program for a large biomedical research institution has the capability of increasing the knowledge of proper use of radionuclides in the laboratories in a more cost effective and efficient way of demonstrating this material. The design and implementation of the web-based course for the University of Texas Health Science Center at San Antonio must meet Texas radioactive material regulations while ensuring that the content engages and challenges the student's health physics knowledge. The implementation of this course required updating the existing course to reflect current regulatory requirements for radiation safety training, emergency response, and biological effects risk coefficients. The final web-based radiation safety training program was evaluated by a standard examination that it is equivalent to the knowledge gained in the classroom course. The results of the scores for the standard examination were equivalent for both the classroom and the web-based course. However, the web-based version with 1 h in the classroom has saved 5,407 h total throughout the institution. PMID- 23026972 TI - How the University of Texas system responded to the need for interim storage of low-level radioactive waste materials. AB - Faced with the prospect of being unable to permanently dispose of low-level radioactive wastes (LLRW) generated from teaching, research, and patient care activities, component institutions of the University of Texas System worked collaboratively to create a dedicated interim storage facility to be used until a permanent disposal facility became available. Located in a remote section of West Texas, the University of Texas System Interim Storage Facility (UTSISF) was licensed and put into operation in 1993, and since then has provided safe and secure interim storage for up to 350 drums of dry solid LLRW at any given time. Interim storage capability provided needed relief to component institutions, whose on-site waste facilities could have possibly become overburdened. Experiences gained from the licensing and operation of the site are described, and as a new permanent LLRW disposal facility emerges in Texas, a potential new role for the storage facility as a surge capacity storage site in times of natural disasters and emergencies is also discussed. PMID- 23026973 TI - Radiological safety at a broad scope radioactive materials license: Texas A&M University. AB - Operating a radiological safety program under a broad-scope license at a major research university introduces many elements not encountered by general or industrial licenses. This article outlines elements of the radiological safety program in place at Texas A&M University. PMID- 23026974 TI - Long-lived impurities of 90Y-labeled microspheres, TheraSphere and SIR-spheres, and the impact on patient dose and waste management. AB - Yittrium-90 microsphere brachytherapy procedures have increased in number due to their efficacy in treating some unresectable metastatic liver tumors. The discovery of long-lived impurities in two microsphere products, first reported between 2006 and 2007, has resulted in some radiation safety concerns. Since then, microsphere production processes have been refined, which reportedly lead to a reduction in detectable by-products. In this study unused vials of TheraSphere and SIR-Spheres, manufactured in early January 2011, were analyzed to identify and quantify the low-level radioactive impurities. Absorbed dose calculations were performed to assess the potential increased dose to the patient due to long-lived impurities. Results showed that while the SIR-Spheres vials contained no detectable impurities (contrary to other published results in the literature), the TheraSphere vials contained 17 radionuclides in one sample and 15 in the other. The dominant impurities were Y and Y, with specific activities ranging from 0.99 +/- 3.40 * 10 kBq mg to 6.30 +/- 0.40 kBq mg at vendor assay date. Other impurities were on the order of Bq mg. Based on Medical Internal Radiation Dose (MIRD) liver and lung dose estimates, the long-lived impurities would be expected to increase an administered dose by less than 0.1% from the prescribed dose. PMID- 23026975 TI - Radiological safety concerns for the accelerator production of diagnostic and therapeutic radionuclides in a university setting. AB - Accelerator production of radionuclides for diagnostic and therapeutic research at a university has many advantages. Radionuclides not commonly available through commercial suppliers may be readily produced for innovative research applications. Loss of material due to decay in transit is minimized, and product lead times may be significantly reduced. Furthermore, graduate students and research assistants have the opportunity to gain considerable hands-on experience during the production, extraction, and processing operations. However, the benefits of implementing accelerator production into an existing radiological protection program must be balanced against increased safety procedures and maintenance of as-low-as-reasonably-achievable work practices. This article outlines the basics for radioactive material production and corresponding issues in radiological protection associated with the production, use, and disposal on a college campus. PMID- 23026976 TI - Determining the applicability of the Landauer nanoDot as a general public dosimeter in a research imaging facility. AB - The Research Imaging Institute (RII) building at the University of Texas Health Science Center at San Antonio (UTHSCSA) houses two cyclotron particle accelerators, positron emission tomography (PET) machines, and a fluoroscopic unit. As part of the radiation protection program (RPP) and meeting the standard for achieving ALARA (as low as reasonably achievable), it is essential to minimize the ionizing radiation exposure to the general public through the use of controlled areas and area dose monitoring. Currently, thirty-four whole body Luxel+ dosimeters, manufactured by Landauer, are being used in various locations within the RII to monitor dose to the general public. The intent of this research was to determine if the nanoDot, a single point dosimeter, can be used as a general public dosimeter in a diagnostic facility. This was tested by first verifying characteristics of the nanoDot dosimeter including dose linearity, dose rate dependence, angular dependence, and energy dependence. Then, the response of the nanoDot dosimeter to the Luxel+ dosimeter when placed in a continuous, low dose environment was investigated. Finally, the nanoDot was checked for appropriate response in an acute, high dose environment. Based on the results, the current recommendation is that the nanoDot should not replace the Luxel+ dosimeter without further work to determine the energy spectra in the RII building and without considering the limitation of the microStar reader, portable on-site OSL reader, at doses below 0.1 mGy (10 mrad). PMID- 23026977 TI - Decreased plasma decorin levels following acute ischemic stroke: correlation with MMP-2 and differential expression in TOAST subtypes. AB - Accumulating evidence suggests that extracellular matrix (ECM) remodeling plays a significant role following acute ischemic stroke (AIS). Decorin (DCN) is a well recognized molecule present in the ECM; however, the role of DCN in AIS remains unknown. The present study aimed to investigate whether plasma concentrations of DCN are altered in patients following an AIS and whether they are correlated with matrix metalloproteinase-2 (MMP-2) levels and other laboratory and clinical variables. Plasma concentrations of DCN were assessed in 102 patients with AIS (less than 7 days) and 120 control subjects using ELISA assays. The correlation between DCN concentrations and MMP-2 levels, Trial of Org 10172 in Acute Stroke Treatment (TOAST) subtypes, stroke severity and risk factors were evaluated. The expression of DCN was significantly decreased in patients with AIS (P<0.001), particularly in the large-artery atherosclerosis (LAAS) group. The levels of DCN were positively correlated with MMP-2 (R=0.332; P<0.001), thus MMP-2 is an independent predictor of DCN concentration (P<0.001). DCN levels below 8,500 pg/ml had sensitivity and specificity values of AIS of 79.4 and 62.8%, respectively and DCN below 8,500 pg/ml was associated with AIS (OR=4.8; 95% CI: 2.1-11.1; P<0.001) following adjustment for potential confounders. In conclusion, for the first time, a reduction in DCN was detected in patients following AIS and these altered plasma concentrations were correlated with MMP-2. Larger studies are required to further investigate whether DCN is involved in the pathogenesis of ischemic stroke. PMID- 23026978 TI - Multidisciplinary team care in rehabilitation: an overview of reviews. AB - OBJECTIVES: To systematically investigate current scientific evidence about the effectiveness of multidisciplinary team rehabilitation for different health problems. DATA SOURCES: A comprehensive literature search was conducted in Cochrane, Medline, DARE, Embase, and Cinahl databases, and research from existing systematic reviews was critically appraised and summarized. STUDY SELECTION: Using the search terms "rehabilitation", "multidisciplinary teams" or "team care", references were identified for existing studies published after 2000 that examined multidisciplinary rehabilitation team care for adults, without restrictions in terms of study population or outcomes. The most recent reviews examining a study population were selected. DATA EXTRACTION: Two reviewers independently extracted information about study populations, sample sizes, study designs, rehabilitation settings, the team, interventions, and findings. DATA SYNTHESIS: A total of 14 reviews were included to summarize the findings of 12 different study populations. Evidence was found to support improved functioning following multidisciplinary rehabilitation team care for 10 of 12 different study population: elderly people, elderly people with hip fracture, homeless people with mental illness, adults with multiple sclerosis, stroke, acquired brain injury, chronic arthropathy, chronic pain, low back pain, and fibromyalgia. Whereas evidence was not found for adults with amyetrophic lateral schlerosis, and neck and shoulder pain. CONCLUSION: Although these studies included heterogeneous patient groups the overall conclusion was that multidisciplinary rehabilitation team care effectively improves rehabilitation intervention. However, further research in this area is needed. PMID- 23026979 TI - Neuroprotection and repair in multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease that is considered by many people to have an autoimmune aetiology. In recent years, new data emerging from histopathology, imaging and other studies have expanded our understanding of the disease and may change the way in which it is treated. Conceptual shifts have included: first, an appreciation of the extent to which the neuron and its axon are affected in MS, and second, elucidation of how the neurobiology of axon-glial and, particularly, axon-myelin interaction may influence disease progression. In this article, we review advances in both areas, focusing on the molecular mechanisms underlying axonal loss in acute inflammation and in chronic demyelination, and discussing how the restoration of myelin sheaths via the regenerative process of remyelination might prevent axon degeneration. An understanding of these processes could lead to better strategies for the prevention and treatment of axonal loss, which will ultimately benefit patients with MS. PMID- 23026981 TI - Use of the Medicare posthospitalization skilled nursing benefit in the last 6 months of life. AB - BACKGROUND: In the last 6 months of life, many older adults will experience a hospitalization, followed by a transfer to a skilled nursing facility (SNF) for additional care. We sought to examine patterns of Medicare posthospitalization SNF use in the last 6 months of life. METHODS: We used data from the Health and Retirement Study, a longitudinal survey of older adults, linked to Medicare claims (January 1994 through December 2007). We determined the number of individuals 65 years or older at death who had used the SNF benefit in the last 6 months of life. We report demographic, social, and clinical correlates of SNF use. We examined the relationship between place of death and hospice use for those residing in nursing homes and the community before the last 6 months of life. RESULTS: The mean age at death among 5163 individuals was 82.8 years; 54.5% of the cohort were female, and 23.2% had resided in a nursing home. In total, 30.5% had used the SNF benefit in the last 6 months of life, and 9.2% had died while enrolled in the SNF benefit. The use of the SNF benefit was greater among patients who were 85 years or older, had at least a high school education, did not have cancer, resided in a nursing home, used home health services, and were expected to die soon (P < .01 for all). Of community dwellers who had used the SNF benefit, 42.5% died in a nursing home, 10.7% died at home, 38.8% died in the hospital, and 8.0% died elsewhere. In contrast, of community dwellers who did not use the SNF benefit, 5.3% died in a nursing home, 40.6% died at home, 44.3% died in the hospital, and 9.8% died elsewhere. CONCLUSIONS: Almost one-third of older adults receive care in a SNF in the last 6 months of life under the Medicare posthospitalization benefit, and 1 in 11 elders will die while enrolled in the SNF benefit. Palliative care services should be incorporated into SNF-level care. PMID- 23026982 TI - Celecoxib desensitization: continued temozolomide/celecoxib chemotherapy after a celecoxib-induced hypersensitivity reaction. AB - Cox-2 inhibitors have been identified as promising candidates for cancer therapy. Several studies have recently proposed the use of celecoxib in long-term low intensity chemotherapy protocols for recurrent tumors. However, drug-induced hypersensitivity reactions may force discontinuation of the medication and, thus, significantly complicate successful care. Here, we report on celecoxib desensitization after a celecoxib-induced skin reaction, thereby allowing the continuation of temozolomide/celecoxib chemotherapy in a young patient with recurrent astrocytoma. PMID- 23026983 TI - Focus on safety at home and getting to that more primary care and preventative care model. PMID- 23026985 TI - Infusion therapy in the home care setting: a clinical competency program at work. AB - Infusion therapy is a growing need in the home care setting, and clinicians need to be not only competent with the hands-on skills involved but also able to provide education and troubleshooting to support patients in the home. Improvements in technology, earlier discharge of sicker people, and the expanding range of skills that can be performed in the home have led to the expansion of infusion therapy in this setting. Preparing clinicians to practice infusion therapy based on standards of practice will provide quality outcomes. This article will describe how an infusion therapy clinical competency program was developed and implemented for the home care setting. PMID- 23026980 TI - The influence of nutritional factors on the prognosis of multiple sclerosis. AB - The effect of nutrition and dietary supplements on the course of multiple sclerosis (MS) is a topic of great interest to both patients and clinicians. In particular, vitamin D status has been shown to influence both the incidence and the course of MS. High vitamin D levels are probably protective against the development of MS, although the efficacy of vitamin D supplementation in slowing progression of MS remains to be established. The influence of polyunsaturated fatty acids (PUFAs) on the development and course of MS has also long been under investigation. Small clinical trials suggest a modest reduction in the severity and duration of relapses in patients with MS receiving PUFA supplements. Other nutritional factors have been evaluated for their effect on MS disease progression, including milk proteins, gluten, probiotics, antioxidants (uric acid, vitamins A, C and E, lipoic acid), polyphenols, Ginkgo biloba extracts and curcumin. However, further studies are needed to evaluate the effects of these dietary components on the relapse rate and progression of MS. This Review gives an overview of the literature on the nutritional factors most commonly implicated as having an effect on MS and discusses the biological rationale that is thought to underlie their influence. PMID- 23026986 TI - Falls risk assessment begins with hello: lessons learned from the use of one home health agency's fall risk tool. AB - Identifying older adults at risk for falls is a challenge all home healthcare agencies (HHAs) face. The process of assessing for falls risk begins with the initial home visit. One HHA affiliated with an academic medical center describes its experience in development and use of a Falls Risk Assessment (FRA) tool over a 10-year period. The FRA tool has been modified since initial development to clarify elements of the tool based on research and to reflect changes in the Outcome and Assessment Information Set (OASIS) document. The primary purpose of this article is to share a validated falls risk assessment tool to facilitate identification of fall-related risk factors in the homebound population. A secondary purpose is to share lessons learned by the HHA during the 10 years using the FRA. PMID- 23026987 TI - Orthostatic hypotension: pathophysiology, problems, and prevention. AB - Orthostatic hypotension (OH) has traditionally been associated with falls (). However, data has been inconsistent, and some believe that more research in the area is needed before a true link can be made (A. ). OH, a drop in systolic pressure of >= 20 points or in diastolic pressure of >= 10 points within 3 minutes of standing as compared to the reading while supine may be accompanied by tachycardia, syncope, dizziness, visual changes, and death. Pathophysiological causes of OH include the dependent pooling of blood in organs and the periphery, compromised venous return and stroke volume, and changes in cardiac and baroreceptor function. Hypertension, diet, mobility, and medications may also contribute to the disorder. The treatment goal is to educate the patient, eliminate physiological causes, omit contributing medications, and resort to pharmacologic means as needed (). Thorough knowledge about OH can assist home care nurses in assessing for and educating patients about the disorder. This manuscript will discuss the pathophysiology, contributing diagnoses and drug classes, signs and symptoms, treatment, and implications for home care and hospice nurses related to orthostatic hypotension. PMID- 23026989 TI - Evidence about the prevention and management of constipation: implications for comfort part 1. AB - Constipation remains a challenging problem for patients and caregivers in home health. In Part 1 of this 2-part series, the scope, physiology, and evidence based practice for nonpharmacological interventions for constipation are discussed. Part 2 will focus on pharmacological management of constipation, including medication cost, prevention of occurrence, and implications for palliative care. PMID- 23026991 TI - Alcoholism & depression. AB - One out of 2 Americans report drinking on a routine basis, making the excessive consumption of alcohol the third leading cause of preventable death in America (). Alcoholism and depression are common comorbidities that home healthcare professionals frequently encounter. To achieve the best patient outcomes, alcoholism should be addressed initially. Although all age groups are at risk, alcoholism and depression occur in more than 8 percent of older adults. Prevention through identifying alcohol use early in adolescence is vital to reduce the likelihood of alcohol dependence. This article provides an overview of the long-term effects of alcohol abuse, including alcoholic cirrhosis and hepatic encephalopathy. The diagnostic criteria for substance dependence and ideas for nonthreatening screening questions to use with patients who are adolescent or older are discussed. While providing patient care, home healthcare nurses share the patient's intimate home environment. This environment is perceived as a safe haven by the patient and home care nurses can take advantage of counseling and treatment opportunities in this nonthreatening environment. PMID- 23026993 TI - Research on culturally tailored interventions aimed at improving chronic disease risk factors and management. AB - High blood pressure (HBP) is a worldwide epidemic with health and economic consequences. Although there is a growing body of knowledge, treatment options, and clinical guidelines, a small percentage of people with hypertension (HTN) achieve optimal control. In addition, HBP disproportionately affects racial and ethnic minorities. Strategies to address the management of HTN among specific populations remain scarce. Evidence shows that successful management of HTN requires pharmacological, educational, and self-care approaches. The first 3 summaries here profile research addressing this issue. The research focuses on the tailoring of interventions for racial and ethnic minority groups, specifically African Americans and Korean Americans. The fourth summary profiles an intervention targeted at a low-literacy group to improve diet. Readers are encouraged to access the full articles to learn more details about the intervention strategies and outcomes of these initiatives. PMID- 23026994 TI - VNAA takes the lead on stopping waste, fraud, and abuse. PMID- 23026995 TI - Digital images are data: and should be treated as such. AB - The scientific community has become very concerned about inappropriate image manipulation. In journals that check figures after acceptance, 20-25% of the papers contained at least one figure that did not comply with the journal's instructions to authors. The scientific press continues to report a small, but steady stream of cases of fraudulent image manipulation. Inappropriate image manipulation taints the scientific record, damages trust within science, and degrades science's reputation with the general public. Scientists can learn from historians and photojournalists, who have provided a number of examples of attempts to alter or misrepresent the historical record. Scientists must remember that digital images are numerically sampled data that represent the state of a specific sample when examined with a specific instrument. These data should be carefully managed. Changes made to the original data need to be tracked like the protocols used for other experimental procedures. To avoid pitfalls, unexpected artifacts, and unintentional misrepresentation of the image data, a number of image processing guidelines are offered. PMID- 23026997 TI - Live-cell migration and adhesion turnover assays. AB - Fluorescence microscopy has revolutionized the way live-cell imaging is achieved. At the same time, it is also potentially harmful to a living specimen. Therefore, the specimen must be monitored for viability and health before, during, and after imaging sessions. Methods for monitoring cell viability and health will be discussed in this chapter. Another key to successful live-cell imaging is to minimize light exposure as much as possible. A summary of strategies for minimizing light exposure including maximizing the light throughput of the microscope and the sensitivity of light detection is presented. Various fluorescence microscopy techniques are presented with a focus on how the light is delivered to the sample (i.e., light density) and pros and cons for use with living specimens. The reader is also directed to other publications that go into these topics in more detail. Methods are described on how to prepare samples for single cell migration assays, how to measure cell migration rates (e.g., bright field, semi-automated, and automated), and how to measure focal adhesion turnover rates. Details of how to correct images for background intensity and field illumination uniformity artifacts for quantitative imaging are also described. Overall, this chapter will be helpful to scientists who are interested in imaging live specimens using fluorescence microscopy techniques. It will be of particular interest to anyone wanting to perform quantitative fluorescence imaging, and wanting to measure cell migration rates, and focal adhesion dynamics. PMID- 23026996 TI - Epi-fluorescence microscopy. AB - Epi-fluorescence microscopy is available in most life sciences research laboratories, and when optimized can be a central laboratory tool. In this chapter, the epi-fluorescence light path is introduced and the various components are discussed in detail. Recommendations are made for incident lamp light sources, excitation and emission filters, dichroic mirrors, objective lenses, and charge-coupled device (CCD) cameras in order to obtain the most sensitive epi fluorescence microscope. The even illumination of metal-halide lamps combined with new "hard" coated filters and mirrors, a high resolution monochrome CCD camera, and a high NA objective lens are all recommended for high resolution and high sensitivity fluorescence imaging. Recommendations are also made for multicolor imaging with the use of monochrome cameras, motorized filter turrets, individual filter cubes, and corresponding dyes being the best choice for sensitive, high resolution multicolor imaging. Images should be collected using Nyquist sampling and images should be corrected for background intensity contributions and nonuniform illumination across the field of view. Photostable fluorescent probes and proteins that absorb a lot of light (i.e., high extinction co-efficients) and generate a lot of fluorescence signal (i.e., high quantum yields) are optimal. A neuronal immune-fluorescence labeling protocol is also presented. Finally, in order to maximize the utility of sensitive wide-field microscopes and generate the highest resolution images with high signal-to-noise, advice for combining wide-field epi-fluorescence imaging with restorative image deconvolution is presented. PMID- 23026998 TI - Multifluorescence confocal microscopy: application for a quantitative analysis of hemostatic proteins in human venous valves. AB - Confocal laser scanning microscopy is commonly used to visualize and quantify protein expression. Visualization of the expression of multiple proteins in the same region via multifluorescence allows for the analysis of differential protein expression. The defining step of multifluorescence labeling is the selection of primary antibodies from different host species. In addition, species-appropriate secondary antibodies must also be conjugated to different fluorophores so that each protein can be visualized in separate channels. Quantitative analysis of proteins labeled via multifluorescence can be used to compare relative changes in protein expression. Multifluoresecence labeling and analysis of fluorescence intensity within and among human venous specimens, for example, allowed us to determine that the anticoagulant phenotype of the venous valve is defined not by increased anticoagulant expression, but instead by significantly decreased procoagulant protein expression (Blood 114:1276-1279, 2009 and Histochem Cell Biol 135:141-152, 2011). PMID- 23026999 TI - Colocalization analysis in fluorescence microscopy. AB - The measurement of colocalization requires images of two fluorophores that are aligned, with no cross talk, and that the intensities remain within the response range of the microscope. Quantitation depends upon differentiating between the presence and absence of fluorescence, and measurements should be made within biologically relevant regions of interest. Co-occurrence can be measured simply by area or with the M1 and M2 coefficients, and should be compared to random distributions. Correlation analysis should use the Pearson and Spearman coefficients, which need to be measured by replicate based noise corrected correlation to eliminate errors arising from differences in image quality. Ideally, both co-occurrence and correlation should be reported. PMID- 23027000 TI - A time-lapse imaging assay to study nuclear envelope breakdown. AB - Real-time imaging coupled with a permeabilized cell system presents a very versatile platform to visualize the dynamic and intricate nature of nuclear envelope breakdown, one of the major morphological changes of mitosis. Here, we describe such a strategy in which the plasma membrane of cells expressing fluorescently tagged nucleoporin POM121 and Histone H2B is permeabilized with digitonin. These cells are then incubated with mitotic Xenopus egg extract to create conditions that recapitulate the major events of mitotic nuclear remodeling seen in live-cell imaging, providing the opportunity to probe mechanisms and pathways that coordinate nuclear disassembly. PMID- 23027001 TI - Light sheet microscopy in cell biology. AB - Light sheet-based fluorescence microscopy (LSFM) is emerging as a powerful imaging technique for the life sciences. LSFM provides an exceptionally high imaging speed, high signal-to-noise ratio, low level of photo-bleaching, and good optical penetration depth. This unique combination of capabilities makes light sheet-based microscopes highly suitable for live imaging applications. Here, we provide an overview of light sheet-based microscopy assays for in vitro and in vivo imaging of biological samples, including cell extracts, soft gels, and large multicellular organisms. We furthermore describe computational tools for basic image processing and data inspection. PMID- 23027002 TI - Image-based high-throughput screening for inhibitors of angiogenesis. AB - Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling. PMID- 23027003 TI - Intravital microscopy to image membrane trafficking in live rats. AB - Intravital microscopy is a powerful tool that enables imaging various biological processes in live animals. Here, we describe a series of procedures designed to image subcellular structures, such as endosomes and secretory vesicles in the salivary glands (SGs) of live rats. To this aim, we used fluorescently labeled molecules and/or fluorescently tagged proteins that were transiently transfected in the live animal. PMID- 23027004 TI - Imaging non-fluorescent nanoparticles in living cells with wavelength-dependent differential interference contrast microscopy and planar illumination microscopy. AB - Optical microscopy is a simple yet robust strategy to study live cellular processes. By changing the wavelength of the illumination light, different non fluorescent nanoparticle probes can be identified and tracked dynamically inside crowded living cells with either differential interference contrast (DIC) microscopy or planar illumination microscopy (PIM). The translational and rotational dynamics of anisotropic nanoparticles can be readily extracted via the modified DIC microscope and the home-built PIM. In this protocol, the optimization procedures for DIC microscopy and PIM imaging are explained, and the sample preparation procedures to image non-fluorescent nanoparticles in living cells are described. PMID- 23027005 TI - Laser scanning cytometry: principles and applications-an update. AB - Laser scanning cytometer (LSC) is the microscope-based cytofluorometer that offers a plethora of unique analytical capabilities, not provided by flow cytometry (FCM). This review describes attributes of LSC and covers its numerous applications derived from plentitude of the parameters that can be measured. Among many LSC applications the following are emphasized: (a) assessment of chromatin condensation to identify mitotic, apoptotic cells, or senescent cells; (b) detection of nuclear or mitochondrial translocation of critical factors such as NF-kappaB, p53, or Bax; (c) semi-automatic scoring of micronuclei in mutagenicity assays; (d) analysis of fluorescence in situ hybridization (FISH) and use of the FISH analysis attribute to measure other punctuate fluorescence patterns such as gammaH2AX foci or receptor clustering; (e) enumeration and morphometry of nucleoli and other cell organelles; (f) analysis of progeny of individual cells in clonogenicity assay; (g) cell immunophenotyping; (h) imaging, visual examination, or sequential analysis using different probes of the same cells upon their relocation; (i) in situ enzyme kinetics, drug uptake, and other time-resolved processes; (j) analysis of tissue section architecture using fluorescent and chromogenic probes; (k) application for hypocellular samples (needle aspirate, spinal fluid, etc.); and (l) other clinical applications. Advantages and limitations of LSC are discussed and compared with FCM. PMID- 23027007 TI - Viewing dynamic interactions of proteins and a model lipid membrane with atomic force microscopy. AB - The information covered in this chapter will present a model homogenous membrane preparation technique and dynamic imaging procedure that can be successfully applied to more than one type of lipid study and atomic force microscope (AFM) instrument setup. The basic procedural steps have been used with an Asylum Research MFP-3D BIO and the Bruker (formerly, Veeco) BioScope. The AFM imaging protocol has been supplemented by procedures (not to be presented in this chapter) of ellipsometry, standardized western blotting, and dot-blots to verify appropriate purity and activity of all experimental molecular components; excellent purity and activity level of the lipids, proteins, and drug(s) greatly influence the success of imaging experiments in the scanning probe microscopy field. The major goal of the chapter is to provide detailed procedures for sample preparation and operation of the Asylum Research MFP-3D BIO AFM. In addition, one should be cognizant that our comprehensive description in the use of the MFP-3D BIO's functions for successful image acquisitions and analyses is greatly enhanced by Asylum Research's (AR's) accompanying extensive manual(s), technical notes, and AR's users forum. Ultimately, the stepwise protocol and information will allow novice personnel to begin acquiring quality images for processing and analysis with minimal supervision. PMID- 23027006 TI - Laser capture microdissection for protein and NanoString RNA analysis. AB - Laser capture microdissection (LCM) allows the precise procurement of enriched cell populations from a heterogeneous tissue, or live cell culture, under direct microscopic visualization. Histologically enriched cell populations can be procured by harvesting cells of interest directly or isolating specific cells by ablating unwanted cells. The basic components of laser microdissection technology are (a) visualization of cells via light microscopy, (b) transfer of laser energy to a thermolabile polymer with either the formation of a polymer-cell composite (capture method) or transfer of laser energy via an ultraviolet laser to photovolatize a region of tissue (cutting method), and (c) removal of cells of interest from the heterogeneous tissue section. The capture and cutting methods (instruments) for laser microdissection differ in the manner by which cells of interest are removed from the heterogeneous sample. Laser energy in the capture method is infrared (810 nm), while in the cutting mode the laser is ultraviolet (355 nm). Infrared lasers melt a thermolabile polymer that adheres to the cells of interest, whereas ultraviolet lasers ablate cells for either removal of unwanted cells or excision of a defined area of cells. LCM technology is applicable to an array of applications including mass spectrometry, DNA genotyping and loss-of-heterozygosity analysis, RNA transcript profiling, cDNA library generation, proteomics discovery, and signal kinase pathway profiling. This chapter describes LCM using an Arcturus(XT) instrument for downstream protein sample analysis and using an mmi CellCut Plus(r) instrument for RNA analysis via NanoString technology. PMID- 23027009 TI - Measuring the elastic properties of living cells with atomic force microscopy indentation. AB - Atomic force microscopy (AFM) is a powerful and versatile tool for probing the mechanical properties of biological samples. This chapter describes the procedures for using AFM indentation to measure the elastic moduli of living cells. We include step-by-step instructions for cantilever calibration and data acquisition using a combined AFM/optical microscope system, as well as a detailed protocol for data analysis. Our protocol is written specifically for the BioScopeTM CatalystTM AFM system (Bruker AXS Inc.); however, most of the general concepts can be readily translated to other commercial systems. PMID- 23027010 TI - Atomic force microscopy functional imaging on vascular endothelial cells. AB - One of the challenging tasks in molecular cell biology is to identify and localize specific binding sites on biological samples with high spatial accuracy (in order of several nm). During the past 5 years, simultaneous topography and recognition imaging (TREC) has become a powerful AFM-based technique for quick and easy high-resolution receptor mapping. In this chapter, we provide a flavor of TREC application on vascular endothelial cells by describing the detailed procedures for all stages of the experiment from tip and sample preparations through the operating principles and visualization. PMID- 23027008 TI - Mica functionalization for imaging of DNA and protein-DNA complexes with atomic force microscopy. AB - Surface preparation is a key step for reliable and reproducible imaging of DNA and protein-DNA complexes with atomic force microscopy (AFM). This article describes the approaches for chemical functionalization of the mica surface. One approach utilizes 3-aminopropyl-trietoxy silane (APTES), enabling one to obtain a smooth surface termed AP-mica. This surface binds nucleic acids and nucleoprotein complexes in a wide range of ionic strengths, in the absence of divalent cations and in a broad range of pH. Another method utilizes aminopropyl silatrane (APS) to yield an APS-mica surface. The advantage of APS-mica compared with AP-mica is the ability to obtain reliable and reproducible time-lapse images in aqueous solutions. The chapter describes the methodologies for the preparation of AP-mica and APS-mica surfaces and the preparation of samples for AFM imaging. The protocol for synthesis and purification of APS is also provided. The applications are illustrated with a number of examples. PMID- 23027011 TI - Porosome: the secretory NanoMachine in cells. AB - Cells synthesize and store within membranous sacs products such as hormones, growth factors, neurotransmitters, or digestive enzymes, for release on demand. As recently as just 15 years ago, it was believed that during cell secretion, membrane-bound secretory vesicles completely merge at the cell plasma membrane resulting in the diffusion of intravesicular contents to the cell exterior and the compensatory retrieval of the excess membrane by endocytosis. This explanation, however, failed to explain the generation of partially empty vesicles observed in electron micrographs following secretion. Logically therefore, in a 1993 News and Views article in the journal Nature, Prof. Erwin Neher wrote "It seems terribly wasteful that, during the release of hormones and neurotransmitters from a cell, the membrane of a vesicle should merge with the plasma membrane to be retrieved for recycling only seconds or minutes later." The discovery of permanent secretory portals or nanomachines at the cell plasma membrane called POROSOMES, where membrane-bound secretory vesicles transiently dock and fuse to release intravesicular contents to the cell exterior, has finally resolved this conundrum. Following this discovery, the composition of the porosome, its structure and dynamics visualized with high-resolution imaging techniques atomic force and electron microscopy, and its functional reconstitution into artificial lipid membrane have provided a molecular understanding of cell secretion. In agreement, it has been demonstrated that "secretory granules are recaptured largely intact after stimulated exocytosis in cultured endocrine cells" (Proc Natl Acad Sci U S A 100:2070-2075, 2003); that "single synaptic vesicles fuse transiently and successively without loss of identity" (Nature 423:643-647, 2003); and that "zymogen granule exocytosis is characterized by long fusion pore openings and preservation of vesicle lipid identity" (Proc Natl Acad Sci U S A 101:6774-6779, 2004). It made no sense all these years to argue that mammalian cells possess an "all or none" mechanism of cell secretion resulting from complete vesicle merger at the cell plasma membrane, when even single-cell organisms have developed specialized and sophisticated secretory machinery, such as the secretion apparatus of Toxoplasma gondii, contractile vacuoles in paramecium, and different types of secretory structures in bacteria. The discovery of the porosome and its functional reconstitution in artificial lipid membrane, and an understanding of its morphology, composition, and dynamics, has resulted in a paradigm shift in our understanding of the secretory process in cells. PMID- 23027012 TI - Stereology and morphometry of lung tissue. AB - This chapter deals with the stereological quantification of structural characteristics of the lung. The aim of design-based stereological methods is the unbiased and efficient estimation of structural features without making any assumptions on the underlying nature of the biological sample. The methods are based on rigorous sampling of location and orientation, the application of appropriate test systems, and the controlling of the precision of the estimates. Here, we describe the workflow from the fixation of the lung over the processing of the tissue samples to gaining estimates on the structural properties of the lung. Specifically, this chapter deals with methods for estimating the reference volume, sampling location, and sampling orientation, estimating volumes and surface areas of alveolar compartments, estimating total alveolar number, performing stereology at light and electron microscopic level, and dealing with technical problems such as tissue shrinkage. The procedures are illustrated using a worked example from the authors' own laboratory. PMID- 23027013 TI - A novel combined imaging/morphometrical method for the analysis of human sural nerve biopsies for clinical diagnosis. AB - Nerve Morphometry is one tool employed in the clinical assessment of peripheral sural nerve pathological abnormalities. A new method is presented in this chapter incorporating an unbiased approach to quantitative sural nerve evaluation. Using conventional epoxy embedded nerves processed for electron microscopy, confocal microscopy, and interactive digital assessment, this method produces a rigorous, accurate reproducible record for use in clinical diagnosis. PMID- 23027014 TI - Correlative light-electron microscopy as a tool to study in vivo dynamics and ultrastructure of intracellular structures. AB - Correlative light-electron microscopy (CLEM) is a very effective technique that combines live-cell imaging and immuno-electron microscopy for ultrastructural morphological characterization of dynamic intracellular organelles. The use of green fluorescent protein (GFP)-tagged chimeras allows the user to follow the movements and/or behavior of intracellular structures in a live cell and to fix it at the moment of interest. The subsequent immuno-electron microscopy processing can then reveal the three-dimensional architecture of the same structure, together with precise recognition of the GFP-labeled protein. The process resembles the taking of a high-resolution snapshot of an interesting live scene. Considering that CLEM is a very useful but technically demanding and time consuming technique, accurate protocols will be helpful to simplify the work of scientists who are willing to apply this method for their own purposes. Here, we present a detailed protocol that describes all of the "tricks" and know-hows involved in carrying out the crucial steps of a CLEM experiment. PMID- 23027015 TI - Photooxidation technology for correlative light and electron microscopy. AB - Correlative microscopic approaches combine the advantages of both light and electron microscopy. Here we show a correlative approach that uses the photooxidation capacity of fluorescent dyes. Through illumination with high energetic light, the chromogen diaminobenzidine is oxidized and stable deposits are formed at the sites of the former fluorescent signals, which after osmification are then visible in the electron microscope. The potential of the method is illustrated by tracing the endocytic pathway of three different ligands: the lipid ceramide, high density lipoproteins, and the lectin wheat germ agglutinin. The ligands were labeled either with BODIPY or Alexa dyes. Following cell surface binding, uptake, and time-dependent intracellular progression, the route taken by these molecules together with the organelles that have been visited is characterized. Correlative microscopic data are recorded at various levels. First, by fluorescence and phase contrast illumination with the light microscope, followed by the analysis of semithin sections after photooxidation, and finally of thin sections at the ultrastructural level. PMID- 23027016 TI - Electron microscopy of endocytic pathways. AB - Detailed insight into the fine structure and 3D-architecture of the complex and dynamic compartments of the endocytic system is essential for a morpho-functional analysis of retrograde traffic from the cell surface to different intracellular destinations. Here, we describe a cytochemical approach for electron microscopic exploration of endocytic pathways with the use of wheat germ agglutinin (WGA) in combination with either conventional chemical fixation or ultrafast physical fixation of the cells by high pressure-freezing. Horseradish peroxidase-labeled WGA endocytozed by human hepatoma cells for various periods of time served as a marker. Its intracellular routes were visualized by means of diaminobenzidine oxidation either done conventionally after chemical fixation or in living cells prior to physical fixation. The latter protocol permits the combination of peroxidase-catalyzed cytochemistry with high pressure-freezing (HPF), which is state of the art for ultrastructural studies of complex and dynamic organelles at high spatial and temporal resolutions. The technique yields distinct cytochemical reactions and excellently preserved fine structures well qualified for detailed electron microscopic and 3D-studies of the complex endocytic architectures. PMID- 23027017 TI - Morphological analysis of autophagy. AB - Autophagy is a bulk intracellular degradation process that is ubiquitous in eukaryotic cells and helps to recycle nutrients from catabolites by degrading proteins, lipids, and glycans, including organelles. Since autophagy has divergent physiological roles in cancer, infection, immunity, and other processes, it is important to accurately analyze autophagic activity. In this chapter, we describe methods that can be used to monitor autophagy in cultured mammalian cells by immunostaining and using fluorescently tagged autophagy related proteins such as GFP- or mRFP-GFP-tandem-tagged proteins as well as electron microscopic methods, including electron tomography and immuno-electron microscopy. PMID- 23027019 TI - Histochemical detection of lipid droplets in cultured cells. AB - Cells store excess lipid as esters in the form of triglycerides and cholesterol esters. Most lipid esters are compartmentalized in globular structures called lipid droplets. Here we describe several methods of detecting lipid droplets by fluorescence microscopy. Lipid droplets can be visualized either by staining the lipid ester core using fluorescent dyes or by labeling lipid droplet-specific proteins using antibodies. The intracellular distribution of lipid droplets can be analyzed without much difficulty by these methods, but care must be taken to avoid certain pitfalls. PMID- 23027018 TI - Cytochemical detection of peroxisomes and mitochondria. AB - Peroxisomes and mitochondria are essential subcellular organelles in mammals. Interestingly, recent studies have elucidated that these highly dynamic and plastic organelles exhibit a much closer interrelationship than previously assumed. Peroxisomes and mitochondria are metabolically linked organelles, which are cooperating and cross-talking. They share key components of their division machinery and cooperate in antiviral signaling and defense. As peroxisomal alterations in metabolism, biogenesis, dynamics, and proliferation have the potential to influence mitochondrial morphology and functions (and vice versa), there is currently great interest in the detection of both organelles under different experimental conditions. Here, we present protocols used successfully in our laboratory for the dual detection of peroxisomes and mitochondria in cultured mammalian cells. We address double immunofluorescence and fluorescence based techniques as well as reagents to investigate organelle dynamics, morphological alterations, and organelle-specific targeting of proteins. In addition, we describe the application of diaminobenzidine cytochemistry on cultured cells to specifically label peroxisomes in ultrastructural studies. PMID- 23027020 TI - Environmental scanning electron microscopy in cell biology. AB - Environmental scanning electron microscopy (ESEM) (1) is an imaging technique which allows hydrated, insulating samples to be imaged under an electron beam. The resolution afforded by this technique is higher than conventional optical microscopy but lower than conventional scanning electron microscopy (CSEM). The major advantage of the technique is the minimal sample preparation needed, making ESEM quick to use and the images less susceptible to the artifacts that the extensive sample preparation usually required for CSEM may introduce. Careful manipulation of both the humidity in the microscope chamber and the beam energy are nevertheless essential to prevent dehydration and beam damage artifacts. In some circumstances it is possible to image live cells in the ESEM (2).In the following sections we introduce the fundamental principles of ESEM imaging before presenting imaging protocols for plant epidermis, mammalian cells, and bacteria. In the first two cases samples are imaged using the secondary electron (topographic) signal, whereas a transmission technique is employed to image bacteria. PMID- 23027021 TI - Environmental scanning electron microscopy gold immunolabeling in cell biology. AB - Immunogold labeling (IGL) technique has been utilized by many authors in combination with scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to obtain the identification/localization of receptors and antigens, both in cells and tissues. Environmental scanning electron microscopy (ESEM) represents an important tool in biomedical research, since it does not require any severe processing of the sample, lowering the risk of generating artifacts and interfere with the IGL procedure. The absence of metal coating could yield further advantages for our purpose as the labeling detection is based on the atomic number difference between nanogold spheres and the biological material. Using the gaseous secondary electron detector, compositional contrast is easily revealed by the backscattered electron component of the signal. In spite of this fact, only few published papers present a combination of ESEM and IGL. Hereby we present our method, optimized to improve the intensity and the specificity of the labeling signal, in order to obtain a semiquantitative evaluation of the labeling signal.In particular, we used a combination of IGL and ESEM to detect the presence of a protein on the cell surface. To achieve this purpose, we chose as an experimental system 3T3 Swiss albino mouse fibroblasts and galectin-3. PMID- 23027022 TI - High-pressure freezing for scanning transmission electron tomography analysis of cellular organelles. AB - Using an electron microscope's scanning transmission mode (STEM) for collection of tomographic datasets is advantageous compared to bright field transmission electron microscopic (TEM). For image formation, inelastic scattering does not cause chromatic aberration, since in STEM mode no image forming lenses are used after the beam has passed the sample, in contrast to regular TEM. Therefore, thicker samples can be imaged. It has been experimentally demonstrated that STEM is superior to TEM and energy filtered TEM for tomography of samples as thick as 1 MUm. Even when using the best electron microscope, adequate sample preparation is the key for interpretable results. We adapted protocols for high-pressure freezing of cultivated cells from a physiological state. In this chapter, we describe optimized high-pressure freezing and freeze substitution protocols for STEM tomography in order to obtain high membrane contrast. PMID- 23027023 TI - MALDI imaging mass spectrometry for direct tissue analysis. AB - MALDI (Matrix-Assisted Laser Desorption/Ionization) Imaging mass spectrometry is a powerful new method for analyzing the spatial distribution of molecules in tissues. Several different classes of cellular constituents such as proteins, peptides, lipids, and small molecules can be analyzed in situ while maintaining the morphological integrity of the tissue. This allows a correlation of the morphology with the previously acquired molecular patterns. By this, specific molecules can be clearly assigned to their cellular origin. Here, we will present a protocol for the analysis of proteins in tissues which are either native or alcohol-fixed and paraffin-embedded. PMID- 23027024 TI - Construction of a DNA vaccine based on the Mycobacterium tuberculosis Ag85A/MPT64 fusion gene and evaluation of its immunogenicity. AB - The aim of this study was to construct a DNA vaccine based on the Ag85A/MPT64 gene of Mycobacterium tuberculosis (MTB) and analyze its immunogenicity by enzyme linked immunospot (ELISPOT) assay. The fusion gene encoding Ag85A/MPT64 was amplified by PCR from the genome of the MTB H37Rv strain and cloned into a eukaryotic expression vector followed by confirmation using restriction endonuclease digestion and DNA sequencing. The immunogenicity of the recombinant vector was tested in vivo in BALB/c mice. The serum antibody titers against Ag85A/MPT64 were detected by ELISPOT assay. The number of ELISPOT spots for the mice following immunization with Ag85A/MPT64 was significantly greater than for the negative and blank controls. A DNA vaccine based on the gene encoding the Ag85A/MPT64 fusion protein of MTB was successfully constructed and expressed. Our data may serve as a foundation for further research into the prevention and treatment of tuberculosis and carcinomas. PMID- 23027027 TI - Paediatric rheumatic disease: Defining clinically inactive disease in juvenile dermatomyositis. PMID- 23027025 TI - Alternating current cloud point extraction on a microchip: a comprehensive study. AB - We present a comprehensive study of alternating current cloud point extraction (ACPE) on a microchip. ACPE is an extraction technique for preconcentration of membrane-associated biomolecules. To characterize and optimize ACPE, we carried out ACPE experiments under various experimental conditions including amplitude and frequency of applied voltages, flow velocity, and concentration of surfactant, analyte, and salt. We found that ACPE has an amplitude threshold (15 V(p-p)), above which the extraction was more efficient. The dependence of the extraction on frequency (>5 MHz) was insignificant. Efficient extraction was achieved when the velocity of the test solution was 0.10~0.67 mm s-1 and the concentration of surfactant was 0.10~1.0%. In contrast, the extraction was independent of the concentration of analytes (0.20~20 MUmol dm-3). The technique was applicable to solutions with a salt concentration of 0.050~0.15 mol dm-3 under temperature control of the devices. Solution temperature in ACPE was also studied. These results provide guidelines for use of the ACPE technique in microfluidic chemical and biochemical analyses. PMID- 23027029 TI - Immunology: Zoster vaccine and biologic agents: time to question a paradigm? PMID- 23027031 TI - Bone research: Autophagy is central to joint destruction in arthritis. PMID- 23027033 TI - Municipal waste management and energy recovery in an Italian region. AB - Diverting waste from landfill is one of the basic priorities on improving the use of resources and reducing the environmental impacts of waste management. In order to achieve this goal it is necessary to limit the amount of materials sent to final disposal and promote energy recovery. In Italy the use of recycling is registering a growing trend but the recourse to landfill is still too high with respect to European Commission targets. The aim of the paper was to analyse the financial and economic benefits that energy recovery could produce by diverting waste from landfills in an Italian region, as landfilling cannot be a solution in the long term because of its finite capacity and for various other ecological reasons. A sensitivity analysis on the critical variables of this plan and a risk analysis are also provided. PMID- 23027034 TI - Analysis of total copper, cadmium and lead in refuse-derived fuels (RDF): study on analytical errors using synthetic samples. AB - Components with extraordinarily high analyte contents, for example copper metal from wires or plastics stabilized with heavy metal compounds, are presumed to be a crucial source of errors in refuse-derived fuel (RDF) analysis. In order to study the error generation of those 'analyte carrier components', synthetic samples spiked with defined amounts of carrier materials were mixed, milled in a high speed rotor mill to particle sizes <1 mm, <0.5 mm and <0.2 mm, respectively, and analyzed repeatedly. Copper (Cu) metal and brass were used as Cu carriers, three kinds of polyvinylchloride (PVC) materials as lead (Pb) and cadmium (Cd) carriers, and paper and polyethylene as bulk components. In most cases, samples <0.2 mm delivered good recovery rates (rec), and low or moderate relative standard deviations (rsd), i.e. metallic Cu 87-91% rec, 14-35% rsd, Cd from flexible PVC yellow 90-92% rec, 8-10% rsd and Pb from rigid PVC 92-96% rec, 3-4% rsd. Cu from brass was overestimated (138-150% rec, 13-42% rsd), Cd from flexible PVC grey underestimated (72-75% rec, 4-7% rsd) in <0.2 mm samples. Samples <0.5 mm and <1 mm spiked with Cu or brass produced errors of up to 220% rsd (<0.5 mm) and 370% rsd (<1 mm). In the case of Pb from rigid PVC, poor recoveries (54-75%) were observed in spite of moderate variations (rsd 11-29%). In conclusion, time consuming milling to <0.2 mm can reduce variation to acceptable levels, even given the presence of analyte carrier materials. Yet, the sources of systematic errors observed (likely segregation effects) remain uncertain. PMID- 23027035 TI - Modified gluteal fold V-Y advancement flap for vulvovaginal reconstruction. AB - The gluteal fold V-Y advancement flap is a good option for the reconstruction of a vulvovaginal defect because it is thin, sensate, reliable, and has matched local skin quality. However, in situations where wider and deeper vulvovaginal reconstruction is needed, advancement of the flap alone may not be sufficient to create tension-free closure. To overcome these limitations, we designed a modified gluteal V-Y advancement flap, which has 1 or 2 additional transposition flaps at the base of the conventional advancement flap.This study includes a total number of 16 patients who had received vulvovaginal reconstruction with our new technique between March 2008 and April 2011. The causes of the defects were vulvar cancer in 13 patients and extramammary Paget disease in 3 patients. We examined the location and size of the defect, the flap design, and postoperative clinical courses. The mean follow-up period was 10.6 months, and the defect sizes ranged from 8 * 6 to 15 * 12 cm. Overall, 11 of 16 patients were reconstructed with bilateral modified gluteal fold V-Y advancement flaps, and 5 patients were treated with a unilateral flap. All flaps survived without major complications, and the aesthetic and functional results were satisfactory. The modified gluteal fold V-Y advancement flap is useful and reliable for the reconstruction of wide and deep vulvovaginal defects. It can cover the defect without tension, and the complications associated with it are rare. PMID- 23027036 TI - Motion of the drawing hand induces a progressive increase in muscle activity of the non-dominant hand in Ramachandran's mirror-box therapy. AB - OBJECTIVE: To observe the real-time muscle activity of bilateral hands while subjects draw circles under 2 conditions: with and without using Ramachandran's mirror-box. SUBJECTS: A total of 24 healthy volunteers. METHODS: Subjects drew 4 circles sequentially using their dominant hand with the other hand at rest, both with and without looking at a mirror image. Circles were marked by 8 dots on the paper, which subjects connected up to draw the shape. The activity of the bilateral first dorsal interosseus muscles was recorded using surface electromyography. RESULTS: Muscle activity of the dominant hand remained constant during each task. In contrast, muscle activity of the non-dominant hand increased under the condition of watching the image in the mirror, but was low under the non-watching condition. Furthermore, muscle activity of the non-dominant hand increased over the duration of the task. However, wide variation between subjects was observed under the mirror-image condition. CONCLUSION: Increased muscle action potential of the non-dominant hand may be induced by the circle drawing task of the dominant hand during Ramachandran's mirror-box therapy, which supports previous observations of increased brain activity caused by watching a mirror image. PMID- 23027037 TI - Reviewing the role of parametrial boost in patients with cervical cancer with clinically involved parametria and staged with positron emission tomography. AB - OBJECTIVE: Primary objective was to validate the practice of not treating clinically involved parametria by parametrial boost. Secondary objective was to validate the adequacy of nodal boost in node-positive patients regardless of parametrial status. MATERIAL AND METHODS: A retrospective analysis of 193 patients with locoregionally advanced cervical cancer treated with curative intent using external beam radiotherapy and brachytherapy. All patients were staged clinically (International Federation of Gynecology and Obstetrics) and radiologically using magnetic resonance imaging and positron emission tomography. The positron emission tomography positive nodes were boosted to an additional dose of 6 to 10 Gy after 40 Gy to the whole pelvis. Parametrial boost was not used. Patients with stages IB to IIa and stages IIB to IIIB disease were allocated to groups A and B, respectively. RESULTS: The pelvic failure (P = 0.430) and extrapelvic failure (P = 0.437) did not differ significantly between groups A and B. In multifactor analysis, tumor volume was significantly associated with pelvic failure (P = 0.009) and node positivity was significantly associated with extrapelvic failure (P = 0.002). Clinical parametrial involvement in the absence of parametrial boost was not related to either pelvic or extrapelvic failure. None of the node-positive patients had isolated pelvic nodal failure. CONCLUSION: Cervical cancer with clinically involved parametria can be adequately treated without parametrial boost. A dose of 46 to 50 Gy was adequate to avoid isolated pelvic nodal failure. PMID- 23027038 TI - The MBD4 Glu346Lys polymorphism is associated with the risk of cervical cancer in a Chinese population. AB - OBJECTIVE: Methyl-CpG binding domain 4 (MBD4) protein functions as a DNA repair enzyme and plays an important role in maintaining genome integrity and carcinogenesis. The polymorphisms in the MBD4 gene may be associated with differences in DNA repair capacity and thereby influence an individual's susceptibility to cervical cancer. To verify this hypothesis, we examined the potential association between the MBD4 Glu346Lys polymorphism (rs140693, G>A) and the risk of cervical cancer in a Chinese population. METHODS: We genotyped the MBD4 Glu346Lys polymorphism in 146 cervical cancer cases and 320 healthy female subjects using polymerase chain reaction-based restriction fragment length polymorphism method. Unconditional logistic regression analysis was used to estimate the association between the genotypes and the risk of cervical cancer. RESULTS: We observed a significantly decreased risk of cervical cancer associated with the heterozygous Lys/Glu genotype (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.36-0.99; P = 0.046) and the homozygous Glu/Glu genotype (OR, 0.52; 95% CI, 0.30-0.89; P = 0.018), compared with the Lys/Lys homozygotes. Moreover, the reduced cervical cancer risk was more predominant among younger subjects or human papillomavirus-positive individuals carrying Glu/Glu genotypes (OR, 0.33; 95% CI, 0.14-0.78, P = 0.011; and OR, 0.27; 95% CI, 0.09-0.75, P = 0.013, respectively). CONCLUSIONS: The MBD4 codon 346 polymorphism may play a role in cervical cancer susceptibility in the Chinese population. Further larger case-control and functional studies are needed to validate these findings. PMID- 23027039 TI - Erythropoietin is detectable in the ascitic fluid in patients with ovarian tumors. AB - BACKGROUND AND OBJECTIVE: Erythropoietin (Epo) is a glycoprotein that stimulates proliferation and migration of human endothelial cells and promotes angiogenesis, which are crucial phenomena in cancer biology. The objective of this study was to investigate whether Epo is detectable in the ascitic fluid of patients with ovarian tumors. PATIENTS AND METHODS: We investigated the presence of Epo in the ascitic fluid of 100 women undergoing laparotomy for an ovarian tumor. Epo concentration was quantitated with an immunochemiluminometric assay. RESULTS: Ten women had a benign tumor, 13 women had a borderline tumor, and 77 women had ovarian cancer. Epo was detected in all ascitic fluid samples, in similar amounts as in corresponding serum samples. Ascitic fluid Epo concentration did not differ between the 3 study groups (P = 0.081), but in multiple comparisons, ascitic fluid Epo was higher in the women with cancer than in the women with a benign tumor (P = 0.006). Ascitic fluid Epo concentration correlated positively with serum Epo (P < 0.0001) and the volume of ascites (P < 0.0001). In regression analyses, serum Epo, volume of ascites, blood hemoglobin, plasma CA125, tumor stage, tumor grade, and the presence of residual tumor after surgery had no significant independent effect on ascitic fluid Epo. CONCLUSION: Considerable amounts of Epo are present in the ascitic fluid of women with ovarian tumors. The origin of Epo in the ascitic fluid of women with ovarian tumors as well as the clinical relevance of our finding remain to be clarified. PMID- 23027040 TI - Expected benefits of topotecan combined with lapatinib in recurrent ovarian cancer according to biological profile: a phase 2 trial. AB - OBJECTIVE: Lapatinib, a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), also inhibits breast cancer resistance protein (BCRP) involved in resistance to topotecan. The aim of this multicenter study was to assess the efficacy of the combination topotecan-lapatinib in epithelial ovarian cancer relapsing after a first line of chemotherapy. METHODS: Patients having relapsed within 6 months (n = 20) or between 6 and 12 months (n = 19) received weekly topotecan (3.2 mg/m given intravenously on days 1, 8, and 15) and daily oral lapatinib (1250 mg). Translational studies were performed on tumor and serum. RESULTS: An objective (partial) response was observed for 5 patients (14%), all with late relapse. The rates of overall benefits, including responses and stabilizations, were 37% and 62% in patients having relapsed within or after 6 months, respectively. Corresponding median time to progression were 58 and 94 days. The most frequent toxicity was hematological, including grade 4 neutropenia (18%) and thrombocytopenia (3%). None of the tumors overexpressed HER2 or EGFR, and no mutation was found. Two Kras mutations were identified. Positive expressions of BCRP and cyclin A (median, 70% and 40%) were not correlated to the response to treatment. CONCLUSIONS: This study failed to demonstrate a clinical benefit of lapatinib-topotecan compared to previously described activity with topotecan alone in a context of low levels of EGFR and HER2 expressions, and no biomarkers could be identified. The absence of correlation between BCRP expression and clinical outcomes suggests that other mechanisms of resistance to topotecan could predominate. PMID- 23027041 TI - IGF-1 activates the P13K/AKT signaling pathway via upregulation of secretory clusterin. AB - Secretory clusterin (sCLU) is a type of stress-induced, pro-survival glycoprotein elevated in early-stage cancer. It enhances cancer cell survival and is associated with several types of cancer progression. In this study, we measured the PI3K/AKT signaling activity by determining the phosphorylation level of the AKT protein, namely pAKT. A549 human non-small cell lung carcinoma (NSCLC) cells were treated with insulin-like growth factor-1 (IGF-1) for various periods of time. The results showed that IGF-1 activated the PI3K/AKT signaling pathway in the A549 cells in a time-dependent manner. Western blot analysis was performed to determine the expression of sCLU protein in A549 cells treated with IGF-1. IGF-1 elevated the expression of sCLU. To determine whether sCLU is required for the IGF-1 activation of the PI3K/AKT signaling pathway, the A549 cells were treated with IGF-1 and sCLU antisense oligonuleotide (sCLU ASO). sCLU ASO blocked the IGF 1 activation of the PI3K/AKT signaling pathway. These results demonstrate that IGF-1 activates the P13K/AKT signaling pathway via the upregulation of sCLU. The present study implies that this pathway may uncover a new mechanism for cancer progression and reveal new targets for drug development in the treatment of NSCLC. PMID- 23027042 TI - Electric field gradient focusing using a variable width polyaniline electrode. AB - A new approach for electric field gradient focusing (EFGF) based on the use of a variable-width polyaniline (PANI) electrode is demonstrated. The electrode was created by patterning a PANI nanofibre film using a 635-nm laser and a computer controlled XY stage. The electrode consisted of 16 segments of varying width, ranging from 200 to 5000 MUm in 320 MUm increments, with the resistance changing approximately 20-fold from 3881 to 198 kOmega at each extreme, respectively. Application of a voltage across the electrode established a voltage gradient resulting in a non-linear distribution of electrophoretic velocities along the microchannel. When balanced with a combination of hydrodynamic flow and EOF, the variable-width PANI electrode could be used for the concentration and separation of two cationic dyes, rhodamine 6G and quinine, which were concentrated by at least threefold within 10 min. PMID- 23027043 TI - What parameters to consider and which software tools to use for target selection and molecular design of small interfering RNAs. AB - The design of small gene silencing RNAs with a high probability of being efficient still has some elements of an art, especially when the lowest concentration of small molecules needs to be utilized. The design of highly target-specific small interfering RNAs or short hairpin RNAs is even a greater challenging task. Some logical schemes and software tools that can be used for simplifying both tasks are presented here. In addition, sequence motifs and sequence composition biases of small interfering RNAs that have to be avoided because of specificity concerns are also detailed. PMID- 23027044 TI - Methods for selecting effective siRNA target sequences using a variety of statistical and analytical techniques. AB - Short interfering RNA (siRNA) has been widely used for studying gene function in mammalian cells but varies markedly in its gene silencing efficacy. Although many design rules/guidelines for effective siRNAs based on various criteria have been reported recently, there are only a few consistencies among them. This makes it difficult to select effective siRNA sequences in mammalian genes. This chapter first reviews the recently reported siRNA design guidelines and then proposes new methods for selecting effective siRNA sequences from many possible candidates by using decision tree learning, Bayes' theorem, and average silencing probability on the basis of a large number of known effective siRNAs. These methods differ from the previous score-based siRNA design techniques and can predict the probability that a candidate siRNA sequence will be effective. Evaluation of these methods by applying them to recently reported effective and ineffective siRNA sequences for a number of genes indicates that they would be useful for many other genes. They should, therefore, be of general utility for selecting effective siRNA sequences for mammalian genes. The chapter also describes another method using a hidden Markov model to select the optimal functional siRNAs and discusses the frequencies of combinations of two successive nucleotides as an important characteristic of effective siRNA sequences. PMID- 23027045 TI - Designing functional siRNA with reduced off-target effects. AB - RNA interference (RNAi) mediated by small interfering RNA (siRNA) is now widely used to knock down gene expression in a sequence-specific manner, making it a powerful tool not only for studying gene functions but also for therapeutic applications. siRNA decreases the expression level of the intended target gene with complete complementarity by cleaving its mRNA. However, the efficacy of each siRNA widely varies depending on its sequence in mammalian cells; only a limited fraction of randomly designed siRNAs is functional. Moreover, off-target silencing effects arise when the siRNA has partial complementarity in the seed region with unintended genes. Here, we describe the rational designing of functional, off-target effect-reduced siRNAs using siDirect 2.0 Web server (http://siDirect2.RNAi.jp/). By using the default parameters, siDirect 2.0 can design at least one qualified siRNA for >94% of human mRNA sequences in the RefSeq database. PMID- 23027046 TI - Design and screening of siRNAs against highly structured RNA targets. AB - RNA silencing is an invaluable tool to interrogate gene function. The cytoplasmic delivery of small interfering RNAs (siRNAs) complementary to a gene of interest results in cleavage and degradation of the target mRNA. Given the potential to target virtually any RNA, siRNA-based therapeutics may revolutionize the treatment of disease. Target site accessibility is a significant barrier to the design and efficacy of siRNAs, particularly against highly structured targets such as the genomes of positive-sense RNA viruses. Here, we describe a bead-based approach to screen for target site accessibility of siRNAs designed against highly structured target RNAs and demonstrate that this approach can be used to assess target site accessibility in vitro and predict potent target sites for siRNAs in cell culture against a highly structured RNA target. PMID- 23027047 TI - Engineering small interfering RNAs by strategic chemical modification. AB - Synthetic small interfering RNAs (siRNAs) have revolutionized functional genomics in mammalian cell cultures due to their reliability, efficiency, and ease of use. This success, however, has not fully translated into siRNA applications in vivo and in siRNA therapeutics where initial optimism has been dampened by a lack of efficient delivery strategies and reports of siRNA off-target effects and immunogenicity. Encouragingly, most aspects of siRNA behavior can be addressed by careful engineering of siRNAs incorporating beneficial chemical modifications into discrete nucleotide positions during siRNA synthesis. Here, we review the literature (Subheadings 1 -3) and provide a quick guide (Subheading 4) to how the performance of siRNA can be improved by chemical modification to suit specific applications in vitro and in vivo. PMID- 23027048 TI - The design, selection, and evaluation of highly specific and functional siRNA incorporating unlocked nucleobase analogs. AB - The efficient and specific silencing of genes via RNA interference (RNAi) for functional genomics and therapeutics depends on careful consideration of the factors that affect the functionality of small interfering RNA (siRNA). These factors include (1) the length of sequence available for siRNA targeting of an mRNA, (2) the structural and thermodynamic properties of target and siRNA sequences, (3) the mechanisms of siRNA off-target effects, and (4) the susceptibility of siRNA degradation when exposed to nucleases in serum and inside cells. Incorporation of Unlocked Nucleobase analogs (UNAs) in the siRNA design offers an attractive approach to design highly efficacious siRNAs with dramatically reduced off-target activity. Here, we describe methods and principles pertaining to the design, selection and screening of optimal siRNAs containing UNA. PMID- 23027049 TI - The design, preparation, and evaluation of asymmetric small interfering RNA for specific gene silencing in mammalian cells. AB - RNA interference (RNAi) is a highly efficient endogenous gene silencing mechanism mediated by short double-stranded RNAs termed small interfering RNAs (siRNAs). The current standard siRNA structure, which is used by most researchers to trigger sequence-specific target gene silencing, consists of a double strand region of 19 bp with 2 nt 3'-overhangs at both ends. However, in addition to the desired target gene silencing, this conventional siRNA structure also exhibits several unintended effects that constitute obstacles to the use of siRNA in gene function studies and therapeutics development. Here, we provide protocols for designing and preparing an alternative structure for RNAi trigger, termed asymmetric shorter-duplex RNA (asiRNA). The asiRNA structure has a duplex region shorter than 19 bp and has an asymmetric 3'-overhang structure. Importantly, the asiRNA structure not only triggers efficient target gene silencing comparable to that of the 19 bp standard siRNA structure but also significantly reduces nonspecific effects triggered by 19 bp siRNAs such as sense-strand-mediated off target silencing and the saturation of RNAi machinery. Procedures are described for verifying that asiRNA activates gene silencing through an Ago2-dependent pathway and for assessing the miRNA pathway competition potency and specific and nonspecific silencing abilities of asiRNAs. We propose that asiRNA, an improved RNAi trigger that can overcome the nonspecific effects evoked by standard siRNA structures, can be developed as a precise and effective tool for both functional genomics and therapeutic applications. PMID- 23027050 TI - Design of nuclease-resistant fork-like small interfering RNA (fsiRNA). AB - Small interfering RNAs (siRNAs) are potent inducers of RNA interference--the conservative cellular process of posttranscriptional gene silencing. The silencing activity of siRNAs depends on the thermodynamic asymmetry of the siRNA duplex. Here, we describe the design of chemically modified fork-like siRNA (fsiRNAs) containing mismatches at the 3'-end region of the sense strand and 2'-O methyl modifications in nuclease-sensitive sites, capable of silencing of thermodynamically unfavorable targets. PMID- 23027052 TI - Strategies for designing and validating immunostimulatory siRNAs. AB - Specific clinical applications of RNA interference (RNAi) can benefit from a concurrent activation of the immune system. This is the case for small interfering RNAs (siRNAs) with antitumor or antiviral activities. This chapter provides a brief overview of the strategies reported to date to design siRNAs with gene silencing and immune activating properties, as well as methods for the validation of immunostimulatory activities. PMID- 23027051 TI - Designing dual-targeting siRNA duplexes having two active strands that combine siRNA and microRNA-like targeting. AB - Short interfering RNAs (siRNAs) have become valued tools for knocking down specific genes. As such, siRNAs are routinely used to study gene function and are also being explored as therapeutic agents. Traditionally, siRNAs are designed to target one specific gene, but this chapter describes a procedure for designing dual-targeting siRNAs where the two strands in the siRNA duplex are both active and down-regulate different target genes through both siRNA and miRNA-like effects. The procedure can be used to create siRNAs that robustly target pairs of genes. PMID- 23027053 TI - Designing efficient and specific endoribonuclease-prepared siRNAs. AB - RNA interference (RNAi) has grown to be one of the main techniques for loss-of function studies, leading to the elucidation of biological function of genes in various cellular systems and model organisms. While for many invertebrates such as Drosophila melanogaster (D. melanogaster) and Caenorhabditis elegans (C. elegans) long double-stranded RNA (dsRNA) can directly be used to induce a RNAi response, chemically synthesized small interfering RNAs (siRNAs) are typically employed in mammalian cells to avoid an interferon-like response triggered by long dsRNA (Reynolds et al., RNA 12:988-993, 2006). However, siRNAs are expensive and beset with unintentional gene targeting effects (off-targets) confounding the analysis of results from such studies. We, and others, have developed an alternative technology for RNAi in mammalian cells, termed endoribonuclease prepared siRNA (esiRNA), which is based on the enzymatic generation of siRNA pools by digestion of long dsRNAs with recombinant RNase III in vitro (Yang et al., Proc Natl Acad Sci USA 99: 9942-9947, 2002; Myers et al., Nat Biotechnol 21:324-328; 2003). This technology has proven to be cost-efficient and reliable. Furthermore, several studies have demonstrated that complex pools of siRNAs, as inherent in esiRNAs, which target one transcript reduce off-target effects (Myers et al., J RNAi Gene Silencing 2:181, 2006; Kittler et al., Nat Methods 4:337-344, 2007). Within this chapter we describe design criteria for the generation of target-optimized esiRNAs. PMID- 23027054 TI - Short hairpin RNA-mediated gene silencing. AB - Since the first application of RNA interference (RNAi) in mammalian cells, the expression of short hairpin RNAs (shRNAs) for targeted gene silencing has become a benchmark technology. Using plasmid and viral vectoring systems, the transcription of shRNA precursors that are effectively processed by the RNAi pathway can lead to potent gene knockdown. The past decade has seen continual advancement and improvement to the various strategies that can be used for shRNA delivery, and the use of shRNAs for clinical applications is well underway. Driving these developments has been the many benefits afforded by shRNA technologies, including the stable integration of expression constructs for long term expression, infection of difficult-to-target cell lines and tissues using viral vectors, and the temporal control of shRNA transcription by inducible promoters. The use of different effector molecule formats, promoters, and vector types, has meant that experiments can be tailored to target specific cell types and minimize cellular toxicities. Through the application of combinatorial RNAi (co-RNAi), multiple shRNA delivery strategies can improve gene knockdown, permit multiple transcripts to be targeted simultaneously, and curtail the emergence of viral escape mutants. This chapter reviews the history, cellular processing, and various applications of shRNAs in mammalian systems, including options for effector molecule design, vector and promoter types, and methods for multiple shRNA delivery. PMID- 23027055 TI - Design of lentivirally expressed siRNAs. AB - RNA interference (RNAi) has been widely used as a tool for gene knockdown in fundamental research and for the development of new RNA-based therapeutics. The RNAi pathway is typically induced by expression of ~22 base pair (bp) small interfering RNAs (siRNAs), which can be transfected into cells. For long-term gene silencing, short hairpin RNA (shRNA), or artificial microRNA (amiRNA) expression constructs have been developed that produce these RNAi inducers inside the cell. Currently, these types of constructs are broadly applied to knock down any gene of interest. Besides mono RNAi strategies that involve single shRNAs or amiRNAs, combinatorial RNAi approaches have been developed that allow the simultaneous expression of multiple siRNAs or amiRNAs by using polycistrons, extended shRNAs (e-shRNAs), or long hairpin RNAs (lhRNAs). Here, we provide practical information for the construction of single shRNA or amiRNA vectors, but also multi-shRNA/amiRNA constructs. Furthermore, we summarize the advantages and limitations of the most commonly used viral vectors for the expression of RNAi inducers. PMID- 23027056 TI - Bifunctional short hairpin RNA (bi-shRNA): design and pathway to clinical application. AB - The discovery of RNA interference (RNAi) engendered great excitement and raised expectations regarding its potential applications in biomedical research and clinical usage. Over the ensuing years, expanded understanding of RNAi and preliminary results from early clinical trials tempered enthusiasm with realistic appraisal resulting in cautious optimism and a better understanding of necessary research and clinical directions. As a result, data from more recent trials are beginning to show encouraging positive clinical outcomes. The capability of delivering a pharmacologically effective dose to the target site while avoiding adverse host reactions still remains a challenge although the delivery technology continues to improve. We have developed a novel vector-driven bifunctional short hairpin RNA (bi-shRNA) technology that harnesses both cleavage-dependent and cleavage-independent RISC loading pathways to enhance knockdown potency. Consequent advantages provided by the bi-shRNA include a lower effective systemic dose than comparator siRNA/shRNA to minimize the potential for off-target side effects, due to its ability to induce both a rapid (inhibition of protein translation) and delayed (mRNA cleavage and degradation) targeting effect depending on protein and mRNA kinetics, and a longer duration of effectiveness for clinical applications. Here, we provide an overview of key molecular methods for the design, construction, quality control, and application of bi-shRNA that we believe will be useful for others interested in utilizing this technology. PMID- 23027057 TI - Design and chemical modification of synthetic short shRNAs as potent RNAi triggers. AB - Synthetic shRNAs that are too short to be Dicer substrates (short shRNAs or sshRNAs) can be highly potent RNAi effectors when properly designed, with activities similar to or more potent than the more commonly used siRNAs targeting the same sequences. sshRNAs can be designed in two possible orientations: left- or right-hand loop, designated L-sshRNAs and R-sshRNAs, respectively. Because L- and R-sshRNAs are processed by the RNAi machinery in different ways, optimal designs for the two formats diverge in several key aspects. Here, we describe the principles of design and chemical modification of highly effective L- and R sshRNAs. PMID- 23027058 TI - Production and application of long dsRNA in mammalian cells. AB - Double-stranded RNA (dsRNA) is involved in different biological processes. At least three different pathways can respond to dsRNA in mammals. One of these pathways is RNA interference (RNAi) where long dsRNA induces sequence-specific degradation of transcripts carrying sequences complementary to dsRNA. Long dsRNA is also a potent trigger of the interferon pathway, a sequence-independent response that leads to global suppression of translation and global RNA degradation. In addition, dsRNA can be edited by adenosine deamination, which may result in nuclear retention and degradation of dsRNA or in alteration of RNA coding potential. Here, we provide a technical review summarizing different strategies of long dsRNA usage. While the review is largely focused on long dsRNA induced RNAi in mammalian cells, it also provides helpful information on both the in vitro production and in vivo expression of dsRNAs. We present an overview of currently available vectors for dsRNA expression and provide the latest update on oocyte-specific transgenic RNAi approaches. PMID- 23027059 TI - Design of RNAi reagents for invertebrate model organisms and human disease vectors. AB - RNAi has become a very versatile tool to silence gene expression in a variety of organisms, in particular when classical genetic methods are missing. However, the application of this method in functional studies has raised new challenges in order to design RNAi reagents that minimize false positives and false negatives. Because the performance of reagents cannot be validated on a genome-wide scale, improved computational methods are required that consider experimentally derived quality measures. In this chapter, we describe computational methods for the design of RNAi reagents for invertebrate model organisms and human disease vectors, such as Anopheles. We describe procedures for designing short and long double-stranded RNAs for single genes, and evaluate their predicted specificity and efficiency. Using a bioinformatics pipeline we also describe how to design a genome-wide RNAi library for Anopheles gambiae. PMID- 23027060 TI - Construction of shRNA expression plasmids for silkworm cell lines using single stranded DNA and Bst DNA polymerase. AB - Transfection of short hairpin RNA (shRNA) expression plasmids is conventionally performed for gene-specific knockdown in cultured mammalian and insect cells. Here, I describe a simple method to synthesize an inverted repeat DNA in a U6 small nuclear RNA promoter-based parent vector using a single-stranded inverted repeat DNA and Bst DNA polymerase. The shRNA expression plasmids constructed by this method were confirmed to promote efficient RNA interference knockdown in silkworm cell lines. This method may be useful for constructing a relatively large number of shRNA expression plasmids. PMID- 23027061 TI - Designing effective amiRNA and multimeric amiRNA against plant viruses. AB - RNA-mediated virus resistance is increasingly becoming a method of choice for antiviral defense in plants when effective natural resistance is unavailable. In this chapter we discuss the design principles of artificial micro RNA (amiRNA), in which a natural miRNA precursor gene is modified to target a different species of RNA, in particular viral RNA. In addition, we explore the advantages and effectiveness of multiple amiRNAs within one polycistronic amiRNA precursor against a virus, as illustrated with Wheat streak mosaic virus, WSMV. The judicious selection of amiRNAs, which are sequences of short length as compared to other related methodologies of RNA interference, greatly assists in avoiding unintended off-targets in the host plant. The viral sequences targeted can be genomic or replicative and should be derived from conserved regions of the published WSMV genome. In short, using published folding and miRNA selection rules and algorithms, candidate miRNA sequences are selected from conserved regions between a number of WSMV genomes, and are BLASTed against wheat TIGR ESTs. Five miRNAs are selected that are least likely to interfere with the expression of transcripts from the wheat host. Then, the natural miRNA in each of the five arms of the polycistronic rice miR395 is replaced in silico with the chosen artificial miRNAs. This artificial precursor is transformed into wheat behind a ubiquitin promoter, and its integration into transformed wheat plants is confirmed by PCR and Southern blot analysis. We have demonstrated the effectiveness of this methodology using an amiRNA precursor that we have termed Fanguard. The processing of amiRNAs in transgenic leaves is verified through splinted ligation assay, and the functionality of the transgene in preventing viral replication is verified by virus bioassay. Resistance is confirmed using mechanical virus inoculation over two subsequent generations. This example demonstrates the potential of polycistronic amiRNA to achieve stable immunity to economically important viruses. PMID- 23027063 TI - In praise of practitioners. PMID- 23027062 TI - Downregulation of plant genes with miRNA-induced gene silencing. AB - In plants, some microRNAs (miRNAs) can trigger the production of secondary small interfering RNAs (siRNAs) from their targets. miRNA-induced gene silencing (MIGS) exploits this unique feature to efficiently downregulate gene expression. The simple flanking of a sequence of interest with the target site for the miR173 (an miRNA able to trigger transitivity) is sufficient to start the production of secondary siRNAs and, consequently, silencing of the target gene. This technique can be easily adapted to promote gene silencing of more than one gene, even with those that share no sequence similarities. This chapter describes the necessary steps for designing and implementing the use of MIGS in plants. PMID- 23027064 TI - Correlation between vitamin D binding protein expression and angiographic-proven coronary artery disease. AB - AIM: Proteomics is considered a promising tool in the discovery of new biomarkers and/or therapeutic targets. The aim of this study was to identify proteins expressed in the plasma of survivors of myocardial infarction and possible correlations between expression of some proteins and the severity of coronary artery disease (CAD) in this population. METHODS: The study included 17 survivors (15 men; age=53+/-9 years) of myocardial infarction at young age (age<60 years) classified for the severity of CAD graded according to angiography and 10 healthy volunteers (nine men; age=54+/-9 years). Proteomic analysis was carried out using a high-throughput technology and MALDI TOF/TOF mass spectrometry. RESULTS: Compared with the healthy population, 14 proteins were differentially expressed in patients, and were classified in three principal categories: contraction, inflammation, and coagulation. Results show a correlation between the angiographic severity, the extension of CAD, and the expression of some proteins. In particular decreased levels of vitamin D binding protein (VDBP) in the plasma of patients statistically correlated with the number of affected coronary arteries. Enzyme-linked immunosorbent assay test confirmed modulation of VDBP. CONCLUSION: Our results suggest that some proteins are differentially expressed in atherosclerotic patients and their disregulation is strongly dependent on the severity of the artery disease. The down regulation of VDBP is confirmed and marked in multivessel disease patients. PMID- 23027066 TI - Male factor infertility: testis explantation for spermatogenic failure. PMID- 23027065 TI - Treatment options for intrinsic sphincter deficiency. AB - Type III stress urinary incontinence (SUI) is generally defined as a condition that involves intrinsic sphincter deficiency (ISD). Although the clinical parameters for ISD are loosely defined as a Valsalva leak-point pressure <60 cmH(2)O or a maximal urethral closure pressure <20 cmH(2)O, consensus is lacking. As a result, studies evaluating the success of any treatment for ISD are difficult to interpret. Regardless, several studies over the past 20 years have evaluated a number of surgical and nonsurgical treatments specifically for SUI caused by ISD. Surgical options include retropubic suspension, needle suspensions, various types of suburethral slings and the artificial urinary sphincter, whereas nonsurgical options include urethral bulking agents. Assessing urethral function (specifically, leak-point pressure or maximal urethral closure pressure) and urethral hypermobility will enable treating physicians to determine the ideal solution for individual patients, especially as no standardized treatment for ISD exists. PMID- 23027067 TI - Prostate cancer-from steroid transformations to clinical translation. AB - The survival benefit conferred by two hormonal agents in phase III trials has clinically validated the long suspected and now widely recognized phenomenon of castration-resistant prostate cancer (CRPC) hormone dependence. Abiraterone inhibits steroid 17alpha-hydroxylase/17,20-lyase (CYP17A1) and blocks androgen synthesis, whereas enzalutamide directly binds and antagonizes the androgen receptor. Both agents are highly effective against CRPC and significantly prolong survival following docetaxel treatment. However, this clinical validation of the androgen pathway has led to questions regarding the fundamental mechanisms of CRPC, as well as resistance to abiraterone and enzalutamide. Our understanding of the predominant steroid transformation pathways that lead to dihydrotestosterone synthesis in CRPC is evolving. The role of steroidogenesis in the development of resistance to abiraterone and enzalutamide remains uncertain. The specific roles of candidate enzyme targets in the development of resistance to these agents must be defined if we are to identify novel targets for improved pharmacologic therapies. PMID- 23027068 TI - Efficacy of a land-based home exercise programme for patients with juvenile idiopathic arthritis: a randomized, controlled, single-blind study. AB - OBJECTIVE: To investigate the effects of a land-based home exercise programme on pain, functional ability and quality of life in patients with juvenile idiopathic arthritis. DESIGN: A randomized, controlled, single-blind study. PATIENTS: Eighty one patients with juvenile idiopathic arthritis participated in this study. METHODS: Functional ability, pain, and quality of life were assessed with a 6 minute walk test, Childhood Health Assessment Questionnaire, visual analogue scale, and the Pediatric Quality of Life Inventory. The patients were randomly assigned to an exercise or control group. The exercise group (n = 43) completed a 12-week individually planned land-based home exercise programme once a week at the hospital for 4 days per week. The control group (n = 38) was placed on the waiting list until the end of the study. RESULTS: Statistically significant improvements (p < 0.001) were found in all the outcome measures in the exercise group. The visual analogue scale score decreased significantly (p < 0.01) in the control group after 12 weeks. Other than the visual analogue scale score (P > 0.05), the changes in the other outcome measures (P < 0.001) were significant in favour of the exercise group. CONCLUSION: The study demonstrated that participating in a 12-week individually planned land-based home exercise programme may result in improved physical function and quality of life in patients with juvenile idiopathic arthritis. PMID- 23027069 TI - Systematic review and meta-analysis of safety of laparoscopic versus open appendicectomy for suspected appendicitis in pregnancy (Br J Surg 2012; 99: 1470 1478). PMID- 23027070 TI - Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases (Br J Surg 2012; 99: 1480-1486). PMID- 23027071 TI - Effects of hybrid minimally invasive oesophagectomy on major postoperative pulmonary complications. AB - BACKGROUND: Morbidity after oesophageal cancer surgery remains high, mainly due to major postoperative pulmonary complications (MPPCs). The aim of this study was to test the hypothesis that hybrid minimally invasive oesophagectomy (HMIO) decreases the 30-day MPPC rate without compromising oncological outcomes. METHODS: Consecutive patients undergoing curative oesophagectomy for cancer by laparoscopic gastric mobilization and open thoracotomy (HMIO) between January 2004 and December 2009 were matched to randomly selected patients undergoing a totally open approach during the same study interval. Matching variables were age, sex, cancer stage, location of the primary tumour, histological subtype, American Society of Anesthesiologists grade, malnutrition, neoadjuvant chemoradiation and epidural analgesia. RESULTS: MPPCs at 30 days were significantly less frequent after HMIO compared with open surgery (15.7 versus 42.9 per cent; P < 0.001). Postoperative in-hospital mortality and overall morbidity rates were 4.3 and 47.5 per cent respectively, again significantly lower in the HMIO group: 1.4 versus 7.1 per cent (P = 0.018) and 35.7 versus 59.3 per cent (P < 0.001). In multivariable analysis, HMIO, adenocarcinoma subtype, epidural analgesia and surgery after 2006 were independent protective factors against MPPCs, and HMIO was independently protective against acute respiratory distress syndrome (ARDS). Lymph node yields and survival were similar in the two groups. CONCLUSION: HMIO for oesophageal cancer, using laparoscopic gastric mobilization and open right thoracotomy, offered a substantial and independent protective effect against MPPCs, including ARDS, without compromising oncological outcomes. PMID- 23027072 TI - Surgical stress after robot-assisted distal gastrectomy and its economic implications. AB - BACKGROUND: There is a lack of reports evaluating the outcomes of robotic gastrectomy and conventional laparoscopic surgery. The aim of this study was to compare the surgical stress response and costs of robot-assisted distal gastrectomy (RADG) with those of laparoscopy-assisted distal gastrectomy (LADG). METHODS: This prospective study compared a cohort of patients who had RADG with a cohort that underwent conventional LADG for early gastric cancer between March 2010 and May 2011. The surgical outcomes including Eastern Cooperative Oncology Group performance status and complications, surgical stress response and overall costs were compared between the two groups. RESULTS: Thirty patients were enrolled in the RADG group and 120 in the LADG group. There were no conversions. Median duration of operation was longer in the RADG group (218 (interquartile range 200-254) versus 140 (118-175) min; P < 0.001). Postoperative abdominal drain production was less (P = 0.001) and postoperative performance status was worse (P < 0.001) in the RADG group. C-reactive protein (CRP) levels on postoperative days 1 and 3, and interleukin (IL) 6 level on the third postoperative day, were lower in the LADG compared with the RADG group (CRP: P = 0.002 and P = 0.014 respectively; IL-6: P < 0.001). Costs for robotic surgery were much higher than for laparoscopic surgery (difference ?3189). CONCLUSION: RADG did not reduce surgical stress compared with LADG. The substantial RADG costs due to robotic system expenses may not be justified. PMID- 23027073 TI - Surgical strategies for non-functioning pancreatic neuroendocrine tumours. AB - BACKGROUND: The purpose of this study was to identify management strategies for non-functioning pancreatic neuroendocrine tumours (NF-PNETs) by analysis of surgical outcomes at a single institution. METHODS: Archived records of patients with NF-PNETs who underwent surgery between 1994 and 2010 were reviewed. RESULTS: Among 125 patients, the median tumour size was 2.5 (range 0.15-20.5) cm. Of the 51 NF-PNETs with a diameter of no more than 2 cm, 12 (24 per cent) were diagnosed as carcinoma. Overall 20 patients (16.0 per cent) had metastases to the lymph nodes. The minimum size of the tumour with lymph node metastasis was 1.2 cm. Having a NF-PNET of 2 cm or larger significantly increased the probability of a poorly differentiated carcinoma (P = 0.006), and having a NF-PNET of at least 2.5 cm significantly increased the probability of lymph node metastasis (P = 0.048). The 5-year cumulative survival rate after curative resection was 89.7 per cent. During a median follow-up of 31.5 months, there were 27 recurrences (23.1 per cent) and 13 disease-specific deaths (11.1 per cent) among the 117 patients who had an R0 resection. All patients who underwent repeat operations were alive without additional recurrence after a mean(s.d.) follow-up of 27.1(18.0) months. CONCLUSION: Curative surgery should be performed for control of primary NF-PNETs. Lymph node dissection for NF-PNETs of 2.5 cm or larger and at least node sampling for tumours with a diameter of 1 cm or more are recommended. Debulking surgery should be considered for advanced tumours. PMID- 23027074 TI - External biliary drainage and liver regeneration after major hepatectomy. AB - BACKGROUND: Bile acid signalling and farnesoid X receptor activation are assumed to be essential for liver regeneration. This study was designed to investigate the association between serum bile acid levels and extent of liver regeneration after major hepatectomy. METHODS: Patients who underwent left- or right-sided hemihepatectomy between 2006 and 2009 at the authors' institution were eligible for inclusion. Patients were divided into two groups: those undergoing hemihepatectomy with external bile drainage by cystic duct tube (group 1) and those having hemihepatectomy without drainage (group 2). Serum bile acid levels were measured before and after hepatectomy. Computed tomography was used to calculate liver volume before hepatectomy and remnant liver volume on day 7 after surgery. RESULTS: A total of 46 patients were enrolled. Mean(s.d.) serum bile acid levels on day 3 after hemihepatectomy were significantly higher in group 2 than in group 1 (11.6(13.5) versus 2.7(2.1) umol/l; P = 0.003). Regenerated liver volumes on day 7 after hepatectomy were significantly greater in group 2 138.1(135.9) ml versus 40.0(158.8) ml in group 1; P = 0.038). Liver regeneration volumes and rates on day 7 after hemihepatectomy were positively associated with serum bile acid levels on day 3 after hemihepatectomy (P = 0.006 and P < 0.001 respectively). The incidence of bile leakage was similar in the two groups. CONCLUSION: Initial liver regeneration after major hepatectomy was less after biliary drainage and was associated with serum bile acid levels. External biliary drainage should be used judiciously after liver resection. PMID- 23027075 TI - KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab. AB - BACKGROUND: The prognostic value of KRAS mutation in patients with colorectal cancer liver metastases (CLM) receiving neoadjuvant chemotherapy including bevacizumab before liver resection is unclear. METHODS: The KRAS and BRAF status of resected CLM was assessed in prospectively studied patients. Mutations were correlated with recurrence-free and overall survival. Only patients with remaining vital tumour cells in the resected specimen and those without disease progression were analysed; those with progressive disease did not undergo resection. RESULTS: A total of 60 patients were enrolled. Fifteen (25 per cent) had a KRAS mutation, but none of the 60 patients had a BRAF mutation. The radiological response to neoadjuvant chemotherapy including bevacizumab, assessed according to the Response Evaluation Criteria In Solid Tumours, was partial in 52 patients (87 per cent) and the remaining eight had stable disease. The partial response rate was similar in patients with a KRAS mutation and those with the wild-type gene (12 of 15 versus 40 of 45 patients; P = 0.400). KRAS mutation had a negative prognostic effect on recurrence-free survival (hazard ratio (HR) 2.48, 95 per cent confidence interval 1.26 to 4.89; P = 0.009) and overall survival (HR 3.51, 1.30 to 9.45; P = 0.013). CONCLUSION: This study provided further evidence for the prognostic importance of KRAS status in terms of recurrence-free and overall survival. Neoadjuvant chemotherapy including bevacizumab elicited a response, irrespective of KRAS status, in this selected group of patients with CLM. PMID- 23027076 TI - KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab (Br J Surg 2012; 99: 1575-1582). PMID- 23027077 TI - Criteria for drain removal following liver resection. AB - BACKGROUND: Abdominal drains have been placed prophylactically and removed in liver resection without robust evidence. The present study was designed to establish the optimal time for removal of such drains. METHODS: Data on abdominal prophylactic drains were analysed in a consecutive series of patients who underwent liver resection for malignancy between 2006 and 2009. Bilirubin levels in drain fluid were measured and bacteriological cultures were taken on days 1, 3, 5 and 7 after surgery. Drains were removed on day 3 if the drain-fluid bilirubin level was less than 5 mg/dl and bacteriological cultures were negative. Drains remained in situ until these conditions were met. RESULTS: A total of 514 abdominal drains were placed in 316 patients operated on in the study period. Fifty-eight patients (18.4 per cent) had positive drain-fluid cultures and 14 (4.4 per cent) had bile leakage (drain-fluid bilirubin level 5 mg/dl or more). Only one patient required ultrasound-guided abdominal drainage. On multivariable analysis, drain-fluid bilirubin level on day 3 after surgery was the strongest predictor of infection (odds ratio 15.11, 95 per cent confidence interval 3.04 to 92.11; P < 0.001). The area under the receiver operating characteristic curve on day 3 had the highest predictive value: 83.6 per cent accuracy and 3.9 per cent false-positive rate for a drain-fluid bilirubin level of 3.01 mg/dl (51.5 umol/l). CONCLUSION: The '3 * 3 rule' (drain-fluid bilirubin level below 3 mg/dl on day 3 after operation) is an accurate criterion for removal of prophylactically placed abdominal drains in liver resection. PMID- 23027079 TI - Altered leucocyte progenitor profile in human bone marrow from patients with major trauma during the recovery phase (Br J Surg 2012; 99: 1591-1599). PMID- 23027078 TI - Altered leucocyte progenitor profile in human bone marrow from patients with major trauma during the recovery phase. AB - BACKGROUND: Changes in human bone marrow associated with the systemic inflammatory response to injury are little understood. It was hypothesized that major trauma results in an altered bone marrow leucocyte progenitor profile, with either uniform depletion or the balance between multipotent and committed progenitors varying, depending on whether self-renewal is favoured over differentiation. METHODS: Bone marrow aspirate and peripheral blood samples were obtained at definitive surgery in adults with pelvic fractures from blunt trauma (major trauma with Injury Severity Score (ISS) at least 18, or isolated fractures) and control patients undergoing iliac crest bone grafting. ISS, interval to surgery and transfusion in the first 24 h were recorded. Bone marrow aspirate flow cytometry was used to identify haemopoietic progenitor cells (CD34(+) ), multipotent cells (CD34(+) CD45(+) CD38(-) ) and oligopotent cells (CD34(+) CD45(+) CD38(lo/+) and CD34(+) CD45(+) CD38(BRIGHT(++ +)) subsets). Peripheral blood levels of inflammatory markers were measured, and the ratio of immature to mature (CD35(-) /CD35(+) ) granulocytes was determined. RESULTS: The median (range) interval between injury and sampling was 7 (1-21) and 5 (1-21) days in the major trauma and isolated fracture groups respectively. The CD34(+) pool was significantly depleted in the major trauma group (P = 0.017), particularly the CD34(+) CD45(+) CD38(BRIGHT(++ +)) oligopotent pool (P = 0.003). Immature CD35(-) granulocytes increased in bone marrow with increasing injury severity (P = 0.024) and massive transfusion (P = 0.019), and in peripheral blood with increasing interval to surgery (P = 0.005). CONCLUSION: Major blunt trauma resulted in changes in the bone marrow CD34(+) progenitor pool. At the point in recovery when these samples were obtained, oligopotent progenitors were lost from the bone marrow, with continued release of immature cells. PMID- 23027080 TI - The surgical significance of residual mucosal abnormalities in rectal cancer following neoadjuvant chemoradiotherapy (Br J Surg 2012; 99: 993-1001). PMID- 23027083 TI - Comparison of 30-day, 90-day and in-hospital postoperative mortality for eight different cancer types (Br J Surg 2012; 99: 1149-1154). PMID- 23027085 TI - Cytokine expression and the role of Th17 cells in a mouse model of colitis. AB - The aim of this study was to explore the expression of cytokines by Th17 cells and their mechanisms of action in a mouse model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced inflammatory bowel disease (IBD). ELISA was used to detect the expression of the Th17 cytokine interleukin, (IL)-17, and that of the Th1 cytokine, interferon-gamma (IFN-gamma), in colon tissues. Western blot analysis was used to detect IL-17 expression in the peripheral blood mononuclear cells (PBMCs), spleen mononuclear cells (SMCs), mesenteric lymph node cells and colon tissues of the colitic mice. RT-PCR analysis was used to detect the effect of anti-IL-17 antibody application on the tumor necrosis factor (TNF)-alpha, IFN gamma and IL-6 mRNA levels in the SMCs of the colitic mice. The Th17 cytokine, IL 17, and the Th1 cytokine, IFN-gamma, were expressed at high levels in the TNBS induced colitic mice. In addition, the expression of the Th17 cytokine appeared earlier than that of the Th1 cytokine. The IL-17 levels in the SMCs, mesenteric lymph node cells and colon tissues of the disease model group were significantly different from those of the normal control group (p<0.01), while the IL-17 levels in the PBMCs of the disease model group were not significantly different (p>0.05) from those of the control group. Following the application of 10 ug/ml anti-IL-7 antibody, the TNF-alpha, IL-6 and IFN-gamma mRNA levels in the SMCs of the model group demonstrated no significant differences from those of the non-antibody treated control group (p>0.05). In conclusion, Th17 and Th1 cells are involved in TNBS-induced IBD and the effect of the Th17 cells may be mediated through the induction of the secretion of pro-inflammatory cytokines. PMID- 23027087 TI - Interstitial fluid pressure and associated lymph node metastasis revealed in tumors by dynamic contrast-enhanced MRI. AB - Elevated interstitial fluid pressure (IFP) in tumors can cause metastatic dissemination and treatment resistance, but its study poses a challenge because of a paucity of noninvasive imaging strategies. In this study, we address this issue by reporting the development of a noninvasive tool to assess tumor IFP and interstitial hypertension-induced lymph node metastasis. Using mouse xenograft models of several types of human cancer, we used gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) as a contrast agent for dynamic contrast-enhanced MRI (DCE-MRI). Immediately after Gd-DTPA administration, a high-signal-intensity rim was observed in the tumor periphery, which moved outward with time. Assuming the velocity of Gd-DTPA to be equal to the fluid flow velocity, we used a simple model of peritumoral interstitial fluid flow to calculate the fluid flow velocity at the tumor surface (v(0)) based on the rim movement. Significant positive correlations were found between v(0) and IFP in all tumor xenografts. Moreover, the primary tumors of metastasis-positive mice displayed higher IFP and v(0) than the primary tumors of metastasis-negative mice. Findings were confirmed in cervical cancer patients with pelvic lymph node metastases, where we found v(0) to be higher compared with patients without lymph node involvement (P < 0.00001). Together, these findings establish that Gd-DTPA-based DCE-MRI can noninvasively visualize tumor IFP, and they reveal the potential for v(0) determined by this method to serve as a novel general biomarker of tumor aggressiveness. PMID- 23027088 TI - A comment on the use of stochastic character maps to estimate evolutionary rate variation in a continuously valued trait. PMID- 23027089 TI - Millimeter scale separation of DNA with a replaceable polymer matrix. AB - Electrophoresis is a powerful method that has seen a wide range of applications, often in automated genetic diagnostic instruments that require the use of a replaceable sieving matrix. The power and simplicity of electrophoresis as an analysis technique would be ideal for highly integrated and low-cost analysis systems if the method could be implemented in microfluidics on the scale of several mm. We demonstrate the electrophoretic analysis of DNA with separation lengths as small as 2 mm and with a resolution adequate for the analysis of PCR products, i.e. resolutions of 10-20 base pairs. Such small-scale separations enable analysis systems consisting of microfluidics and microelectronics integrated into a single inexpensive package, thereby overcoming a key challenge facing the development of the lab on chip technologies. PMID- 23027090 TI - The electroclinical spectrum of epilepsy. PMID- 23027091 TI - Mesial temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is the most common form of adult localization related epilepsy. Hippocampal onset accounts for at least 80% of all temporal lobe seizures. The electroencephalogram (EEG) of mesial TLE contains interictal features often associated with anterior temporal epileptiform discharges with a maximal voltage over the basal temporal electrodes. Localized ictal patterns on scalp EEGs characteristically reveal unilateral 5- to 9-Hz rhythmic ictal theta or alpha epileptiform activity maximal in the anterior temporal scalp electrodes. Invasive-scalp EEG comparisons have yielded direct information about mesial temporal sources and their corresponding electrical fields. Refinement of macroscopic spatial and the temporal resolution suggest that a more precise seizure localization may exist beyond 1- to 35-Hz frequencies observed in routine scalp recording. Defining the focal areas of ictogenesis within the medial temporal lobe demonstrates a rich connection to a broad network that goes beyond the medial structures and even the temporal lobe itself. Advanced electrophysiologic application in TLE may further our understanding of ictogenesis to perfect surgical treatment and to elucidate the neurophysiologic corollaries of epileptogensis itself. PMID- 23027092 TI - Neocortical temporal lobe epilepsy. AB - Neocortical temporal lobe epilepsy (NTLE) comprises a heterogeneous group of epilepsies with focal seizures characterized by auditory, somatosensory, or psychic auras followed by motionless staring, early contralateral clonic activity often secondarily generalizing. Neurophysiologic findings in NTLE are typically a predominance of lateral temporal interictal epileptiform activity (IEA) and an ictal onset pattern consisting of irregular, hemispheric delta slowing. Advanced neurophysiologic techniques such as EEG and magnetoencephalography source imaging can help to determine the area generating the initial and propagated interictal and ictal activities and may limit the number of patients requiring long-term invasive recordings before epilepsy surgery. PMID- 23027093 TI - Mesial frontal lobe epilepsy. AB - Mesial frontal lobe epilepsies can be divided into epilepsies arising from the anterior cingulate gyrus and those of the supplementary sensorimotor area. They provide diagnostic challenges because they often lack lateralizing or localizing features on clinical semiology and interictal and ictal scalp electroencephalographic (EEG) recordings. A number of unique semiologic features have been described over the last decade in patients with mesial frontal lobe epilepsy (FLE). There are few reports of applying advanced neurophysiologic techniques such as electrical source imaging, magnetoencephalography, EEG/functional magnetic resonance imaging, or analysis of high-frequency oscillations in patients with mesial FLE. Despite these diagnostic challenges, it seems that patients with mesial FLE benefit from epilepsy surgery to the same extent or even better than patients with FLE do, as a whole. PMID- 23027095 TI - Orbitofrontal and insular epilepsy. AB - PURPOSE: Orbitofrontal and insular epilepsy are difficult to recognize because clinical presentations are variable and surgical approaches remain difficult. METHODS: Literature review and review of our own case series including selected cases regarding the clinical manifestation and diagnostic utility of diagnostic tests in orbitofrontal and insular epilepsy. RESULTS: Orbitofrontal epilepsy presents with either frontal lobe type seizures with hypermotor automatism or temporal lobe type seizures with oroalimentary and manual automatisms depending on the spread pattern. Ictal single photon emission computed tomography (SPECT) and other functional imaging can be helpful, but intracranial electroencephalograms (EEGs) are still required to identify orbitofrontal seizure onset. Insular epilepsy presents with throat constriction and unilateral paresthesias. Preoperative functional imaging methods can be helpful, but exploration of the insula is required to identify unequivocal insular onset. Intracranial EEG in the insula can be performed safely and should be considered in atypical temporal lobe cases. CONCLUSIONS: Intracranial EEG remains the main diagnostic modality to identify orbitofrontal and insular epilepsy. Newer diagnostic modalities such as high-frequency oscillations, EEG, functional magnetic resonance imaging (fMRI), magnet resonance spectroscopy, and magnet source imaging need to be examined further to establish their diagnostic utility. PMID- 23027094 TI - Dorsolateral frontal lobe epilepsy. AB - Dorsolateral frontal lobe seizures often present as a diagnostic challenge. The diverse semiologies may not produce lateralizing or localizing signs and can appear bizarre and suggest psychogenic events. Unfortunately, scalp electroencephalographic (EEG) and magnetic resonance imaging (MRI) are often unsatisfactory. It is not uncommon that these traditional diagnostic studies are either unhelpful or even misleading. In some cases, SPECT and positron emission tomography imaging can be an effective tool to identify the origin of seizures. However, these techniques and other emerging techniques all have limitations, and new approaches are needed to improve source localization. PMID- 23027096 TI - Parietal lobe epilepsy. AB - Patients with parietal lobe epilepsy (PLE) exhibit an electroclinical epilepsy syndrome that is rarely seen even at large epilepsy centers. Clinically, most patients with PLE exhibit a somatosensory aura that may include painful dysesthesias, though vertigo, aphasia, disturbances of one's body image also occur, when ictal propagation occurs from the parietal lobe to the supplementary motor area, hypermotor manifestations are noted. When temporolimbic propagation occurs, complex visual or auditory hallucinations and automatisms may appear. Scalp electroencephalogram (EEG) is often nonlocalizing. Ictal EEG is rarely localizing in PLE, and invasive EEG is often required for definitive localization and functional mapping. Recent advances in clinical neurophysiology during the evaluation of patients with refractory partial epilepsy include Ictal magnetic source imaging (MSI). Combined EEG and functional magnetic resonance imaging (EEG fMRI) may be useful for patients with PLE to refine the localization in patients undergoing a presurgical evaluation. High-frequency oscillations (HFOs) are more concentrated inside the seizure onset zone (SOZ), indicating that they may be used as interictal scalp EEG biomarker for the SOZ. When medical therapy fails, resective epilepsy surgery can result in seizure freedom or significant reduction especially when a lesion is present. PMID- 23027097 TI - Occipital lobe seizures and epilepsies. AB - Occipital lobe epilepsies (OLEs) manifest with occipital seizures from an epileptic focus within the occipital lobes. Ictal clinical symptoms are mainly visual and oculomotor. Elementary visual hallucinations are common and characteristic. Postictal headache occurs in more than half of patients (epilepsy migraine sequence). Electroencephalography (EEG) is of significant diagnostic value, but certain limitations should be recognized. Occipital spikes and/or occipital paroxysms either spontaneous or photically induced are the main interictal EEG abnormalities in idiopathic OLE. However, occipital epileptiform abnormalities may also occur without clinical relationship to seizures particularly in children. In cryptogenic/symptomatic OLE, unilateral posterior EEG slowing is more common than occipital spikes. In neurosurgical series of symptomatic OLE, interictal EEG abnormalities are rarely strictly occipital. The most common localization is in the posterior temporal regions and less than one fifth show occipital spikes. In photosensitive OLE, intermittent photic stimulation elicits (1) spikes/polyspikes confined in the occipital regions or (2) generalized spikes/polyspikes with posterior emphasis. In ictal EEG, a well localized unifocal rhythmic ictal discharge during occipital seizures is infrequent. A bioccipital field spread to the temporal regions is common. Frequency, severity, and response to treatment vary considerably from good to intractable and progressive mainly depending on underlying causes. PMID- 23027098 TI - Genetic generalized epilepsies. AB - In the International League Against Epilepsy's most recent revision of classification and terminology, the term idiopathic epilepsy, previously used to describe those epilepsies whose cause was unknown, but presumed genetic, has been removed. It has been replaced by the term genetic epilepsy, only to be used to describe epilepsy in which the etiology has a known or presumed genetic defect in which seizures are the core symptom of the disorder. The purpose of this article was to review the electroclinical spectrum of those epilepsies that would fall under this new designation of genetic epilepsies in the context of specific generalized epilepsy syndromes providing an update in the clinical, electroencephalographic, and genetic findings in these syndromes. PMID- 23027099 TI - Epileptic encephalopathies in infants and children. AB - The term epileptic encephalopathy is used to describe diffuse brain dysfunction that is caused, at least in part, by some aspect of epilepsy. Early-infantile epileptic encephalopathy (EIEE), West syndrome, late infantile epileptic encephalopathy, and Lennox-Gastaut are four epilepsy syndromes. These epilepsies are also among the most severe with dire consequences including intractable seizures and severe cognitive dysfunction. These epilepsies share several important characteristics: diverse causes; severe and frequent seizures; diffusely abnormal background activity on electroencephalograms that is often profound; medical intractability; and severe consequences for a normal development. Ohtahara proposed that these epilepsies exist on an electroclinical spectrum and that the clinical and electroencephalogram features are dependent on the maturation of the nervous system. One can now add Late Infantile Epileptogenic Encephalopathy (LIEE) or epilepsy with late-onset of epileptic spasms. Recently, similar gene mutations have been found in several different epilepsy syndromes, reinforcing the notion that these epilepsies are not likely to be distinguished based on cause alone. Recognition and accurate classification of these severe epilepsies is important as the first step toward improving treatment and outcomes. PMID- 23027100 TI - Pediatric focal epilepsy syndromes. AB - Benign epilepsy with centrotemporal spikes, early-onset childhood occipital epilepsy (Panayiotopoulos syndrome [PS]) and late-onset childhood occipital epilepsy (Gastaut type [LOCE-G]) are the principal pediatric focal epilepsy syndromes. They share major common characteristics: the appearance and resolution of electroclinical features are age related, there is a strong genetic predisposition, the clinical course is often mild with infrequent and easy to control seizures, interictal epileptiform activity is disproportionately abundant when compared with the clinical correlate, and tends to potentiate and generalize during sleep. In this review, we outline the relevant pathophysiology underlying this electroclinical spectrum. Then, the initial description of individual syndromes is followed by a summary of overlapping features and intermediate presentations that question the boundaries between these entities and provide the basis for the concept of a childhood seizure susceptibility syndrome. Additionally, we outline the main features of the related epileptic encephalopathies. An outlook on potential future lines of research completes this review. PMID- 23027101 TI - Neonatal seizures and status epilepticus. AB - Neonatal seizures are common, often require EEG monitoring for diagnosis and management, may be associated with worse neurodevelopmental outcome, and can often be treated with existing anticonvulsants. A neonatal electrographic seizure is defined as a sudden, repetitive, evolving, and stereotyped event of abnormal electrographic pattern with amplitude of at least 2 MUV and a minimum duration of 10 seconds. The diagnosis of neonatal seizures relies heavily on the neurophysiologist's interpretation of EEG. Consideration of specific criteria for the definition of a neonatal seizure, including seizure duration, location, morphology, evolution, semiology, and overall seizure burden, has utility for both the clinician and the researcher. The importance of EEG in the diagnosis and management of neonatal seizures, the electrographic characteristics of neonatal seizures, the impact of neonatal seizures on outcome, and tools to aid in the identification of neonatal seizures are reviewed. PMID- 23027102 TI - Increased ictal discharge frequency and neocortex gliosis in lateral temporal lobe epilepsy. AB - PURPOSE: Medial temporal lobe epilepsy (TLE) with hippocampal sclerosis has both a scalp EEG initial ictal discharge frequency, which is faster, and also an intracranial EEG onset site that is more restricted to the hippocampus, than lateral TLE without hippocampal sclerosis. This study was performed to determine if lateral TLE patients have either intracranial EEG neocortical initial ictal frequencies or measures of lateral neocortex (LNC) histopathology that differ from patients whose seizures start in medial or multiple temporal lobe areas. METHODS: Thirty-six TLE patients undergoing ictal depth and subdural strip electrode recordings were studied to determine the initial ictal discharge site (epileptogenic zone) within the temporal lobe and neocortical ictal frequency. In 25 patients, the number of reactive astrocytes in the neocortex and other measures of pathologic assessment of LNC were assessed. RESULTS: The initial neocortical ictal frequency was significantly faster when the initial ictal discharge was in the LNC +/- medial paleocortex than either when it was in the hippocampus +/- medial paleocortex or when it occurred simultaneously over the entire temporal lobe. Intracortical and Chaslin gliosis were both significantly greater when the initial ictal discharge was limited to the LNC than when it was in the hippocampus and/or medial paleocortex. CONCLUSIONS: Temporal lobe seizures originating in neocortex had a faster initial neocortical ictal frequency than seizures arising either medially in the hippocampus or widely over the whole temporal lobe. Epileptogenic zones limited to temporal neocortex were associated with greater intraneocortical and Chaslin gliosis compared with zones confined to medial structures. PMID- 23027103 TI - Comparison of triphasic waves and epileptic discharges in one patient with genetic epilepsy. AB - Genetic epilepsies with generalized spike-wave complexes (GSWCs) and encephalopathy triphasic waves (TWs) may resemble each other and have three phases per complex. Electroencephalographic (EEG) interpretation is subjective, and EEGers have noted "TWs" in cases labeled nonconvulsive status epilepticus (NCSE). Direct comparison of both wave forms under the same conditions is rarely possible. In a single patient with generalized spike waves who developed hepatic TWs, morphologic characteristics of both were compared, and it was found that GSWCs have higher frequency first, second, and third phases; steeper phase 2 slope; and briefer after-going slow waves maximal at F3 to F4. Total complex duration was approximately 0.12 seconds. The TWs had dominant high-voltage phases 2 and 3 located more posteriorly, in the frontocentral region, lasting an average of approximately 0.32 seconds. These morphologic distinctions may help differentiate TWs from GSWCs. PMID- 23027104 TI - Predictors of clamp-induced electroencephalographic changes during carotid endarterectomies. AB - OBJECTIVE: Electroencephalograms (EEGs) detect clamp-induced cerebral ischemia during carotid endarterectomy (CEA) and thus impact management and minimize the risk of perioperative stroke. We hypothesized that age, preoperative neurologic symptoms, >=70% contralateral carotid and bilateral vertebral stenosis increase the probability of clamp-induced EEG changes, whereas >=70% unilateral carotid stenosis does not. METHODS: This is an observational cohort study of 299 patients who underwent CEA with EEG monitoring at a single large urban academic medical center in 2009. Univariate and multivariate logistic regression were used. RESULTS: Seventy percent or greater ipsilateral carotid stenosis decreases the odds of clamp-induced neurophysiologic dysfunction (odds ratio [OR] = 0.43, 95% confidence interval [CI] [0.18, 0.99], P = 0.04) after adjustment for symptomatic status, degree contralateral carotid or vertebral stenosis, and age. Preoperative neurologic symptoms, >=70% contralateral carotid stenosis, and bilateral extracranial vertebral stenosis independently increase these odds (OR 2.62, 95% CI [1.32, 5.18], P = 0.005; OR 2.84, 95% CI [1.27, 6.34], P = 0.01; and OR 3.58, 95% CI [1.02, 12.53], P = 0.04, respectively), after adjustment for the other factors. Age >=70 years has no significant impact. CONCLUSIONS: Preoperative neurologic symptoms, >=70% contralateral carotid, and bilateral vertebral stenosis increase the probability of clamp-induced ischemia as detected by intraoperative EEG, while >=70% ipsilateral carotid stenosis decreases it. PMID- 23027105 TI - Quantitative electromyography in dengue-associated muscle dysfunction. AB - PURPOSE: This study was undertaken to document the muscle involvement in dengue virus infection using quantitative electromyography (QEMG). METHODS: The patients with dengue myopathy were subjected to clinical examination including muscle power, tone, reflex, and sensations. Blood counts, hemoglobin, hematocrit, serum creatine kinase (CK), and electrolytes were determined. The QEMG was performed in the biceps using multimotor unit potential analysis program. Muscle biopsy was done in two patients. At 1 month, their clinical and QEMG analyses were repeated. RESULTS: Thirteen patients whose median age was 34 years were included. Seven patients had severe and six had mild weakness, which was more marked in proximal lower limb muscles. The median CK level was 480 (300-2,477) U/L. Needle EMG did not reveal any spontaneous activity. The motor unit potentials (MUPs) were of normal to short duration, polyphasic with normal interference pattern. The QEMG revealed a significant change in the duration of MUP at 1 month compared with that of baseline. All the patients clinically and biochemically improved after 1 month. Muscle biopsy revealed interstitial hemorrhage with occasional myonecrosis and myophagocytosis without inflammation or vasculitis. CONCLUSIONS: The QEMG in dengue myopathy revealed improvement in the duration of MUP at 1-month follow-up, which paralleled with clinical and CK improvement. PMID- 23027106 TI - Facilitation from hand muscles innervated by the ulnar nerve to the extensor carpi radialis motoneurone pool in humans: a study with an electromyogram averaging technique. AB - Effects of low-threshold afferents of hand muscles innervated by the ulnar nerve on an excitability of the extensor carpi radialis (ECR) motoneurone pool in humans were examined using an electromyogram-averaging (EMG-A) technique. Changes of EMG-A of ECR exhibiting 10% of the maximum contraction by electrical stimulation to the ulnar nerve at the wrist (ES-UN) and mechanical stimulation to the hypothenar muscles (MS-HTM) and first dorsal interosseus (MS-FDI) were evaluated in eight normal human subjects. The ES-UN with the intensity immediately below the motor threshold and MS-HTM and -FDI with the intensity below the threshold of the tendon(T)-reflex were delivered. Early and significant peaks in EMG-A were produced by ES-UN, MS-HTM, and MS-FDI in eight of eight subjects. The mean amplitudes of the peaks by ES-UN, MS-HTM, and MS-FDI were, respectively, 121.9%, 139.3%, and 149.9% of the control EMG (100%). The difference between latencies of the peaks by ES-UN and MS-HTM, and ES-UN and MS FDI was almost equivalent to that of the Hoffmann(H)- and T-reflexes of HTM and FDI, respectively. The peaks by ES-UN, MS-HTM, and MS-FDI diminished with tonic vibration stimulation (TVS) to HTM and FDI, respectively. These findings suggest that group Ia afferents of the hand muscles facilitate the ECR motoneurone pool. PMID- 23027107 TI - The role of EEG in patients with syncope. PMID- 23027111 TI - Narrative medicine and narrative writing. PMID- 23027109 TI - Intraoperative neurophysiologic monitoring: can we be better? PMID- 23027112 TI - Publication productivity by family medicine faculty: 1999 to 2009. AB - BACKGROUND AND OBJECTIVES: Scholarly work is an important part of all medical specialties. A decline in publications by academic family medicine faculty during the 1990s was documented. The purpose of this study was to compare the publication productivity of family medicine academicians during the 2000s to that in the 1990s. METHODS: A random sample of 1,500 individuals was drawn from the 2009 Society of Teachers of Family Medicine (STFM) membership. We then performed a PubMed search to identify publications by each of the subjects for the year 2009. Publications by STFM members in 1999 were identified from results of a previous study. We then compared differences between 1999 and 2009 in the percentage of STFM members publishing papers, the number of published papers per member, and the number of journals in which publications appeared. RESULTS: The percentage of STFM members publishing at least one article increased from 8.5% (95% confidence interval [CI]=7.2%--10.0%) in 1999 to 20.9% (95% CI=18.9%--23.0%) in 2009. The mean number of publications by those who published increased from 1.73 (95% CI=1.68--1.78) to 2.22 (95% CI=2.13--2.31). STFM members were 2.85 (95% CI=2.29--3.55) times more likely to publish at least one paper in 2009 than in 1999. Publications appeared in 202 different journals in 2009 compared to 75 in 1999. CONCLUSIONS: A higher percentage of family medicine academicians published papers in 2009 than in 1999. There were also more papers published per individual, and publications appeared in a wider range of journals. PMID- 23027113 TI - Interdisciplinary direct observation: impact on precepting, residents, and faculty. AB - BACKGROUND: Direct observation of residents for training and assessment is a core recommendation in medical education policy initiatives. Limited research exists about the impact of direct observation on precepting, and we are unaware of any research examining the impact of interdisciplinary precepting on trainees or preceptors. Over the past 3 years we have implemented an Interdisciplinary Direct Observation Precepting Model (IDOPM). Residents are directly observed via closed circuit television by a behavioral scientist and family physician team. METHODS: Surveys and focus groups were used to examine the impact of the IDOPM. Authors analyzed survey responses and focus group transcripts using an immersion/crystallization approach to arrive at themes. RESULTS: Between February and June 2009, 24 residents, 14 physician faculty, and eight behavioral science faculty members participated in 19 IDOPM clinics. Eighty-two percent of residents and 95% of faculty responded to surveys. Key findings were (1) Residents and faculty report addressing topics that are not usually discussed in traditional precepting, including communication skills, time management, electronic medical record use, responding to emotional complexity, and physical exam skills, (2) The model reinforced a biopsychosocial approach to care, (3) Residents report ambivalent feelings about being observed, and (4) Faculty value the team approach to strengthen training and promote faculty development. CONCLUSIONS: The IDOPM addresses many core skills that are overlooked in traditional precepting encounters. Interdisciplinary direct observation may strengthen faculty ability to provide formative competency assessment in preparing residents to work in the complex world of primary care. PMID- 23027114 TI - Do gifts from the pharmaceutical industry affect trust in physicians? AB - BACKGROUND AND OBJECTIVES: Gifts to physicians from the pharmaceutical industry are receiving increased scrutiny, but no previous research has evaluated the effect of such gifts on trust. The goal of this study is to determine patient awareness of interactions between physicians and the pharmaceutical industry and to learn whether those interactions impact trust and the doctor-patient relationship. METHODS: A cross-sectional, self-administered 61-item survey was administered in five outpatient clinic waiting rooms at a US medical center in 2008. A total of 220 consecutive English-speaking adults were invited to participate. Main outcome measures included: (1) Awareness of physician relationship with the pharmaceutical industry, (2) Attitudes about physician acceptance of gifts, (3) Perceived impact of gifts on trust in physicians, and (4) Effect of gifts on intent to adhere to physician recommendations. RESULTS: A total of 192 individuals participated (87% response rate). While most were unaware of particular interactions between physicians and the pharmaceutical industry (12% to 60%, depending on activity), approximately half (51%) wanted to know if their physician accepted gifts >$100. A majority indicated they would have less trust in their physician if they learned he or she: accepted gifts >$100 (59%) or went on industry-sponsored trips (58%) or sporting events (54%). Further, 25% said they would be less likely to take a prescribed medication if their physician had recently accepted a gift in return for listening to a pharmaceutical representative's presentation about that drug. CONCLUSIONS: Accepting gifts from the pharmaceutical industry has implications for the doctor patient relationship. Doing so can undermine trust and affect patients' intent to adhere to medical recommendations. PMID- 23027115 TI - An ecological model for family violence prevention across the life cycle. AB - BACKGROUND AND OBJECTIVES: Family violence (FV) impacts individuals and their families, their communities, their physical health, and the economic health of society. The origins of FV are complex, and relationships among historical, cultural, interpersonal, and intrapersonal components are poorly understood. The morbidity, mortality, and cost of FV are enormous. This paper introduces an ecological model for FV prevention through the life cycle-from child abuse through interpersonal violence and to elder abuse. The model incorporates medical as well as social, justice, and educational literature about violence prevention efforts and programs. Health care professionals, particularly in family medicine, are on the front line of preventing family violence. The responsibilities and competencies related to preventing/addressing family violence include (1) identifying risk factors, (2) noting early signs and symptoms, (3) assessing for violence within families, (4) managing sequelae to minimize morbidity and mortality, (5) knowing/using referral and community resources, and (6) advocating for changes that promote a violence-free society. The model presented in this article provides a holistic approach to FV. This model can be applied to the Patient-centered Medical Home to promote educational initiatives, inter-professional collaborations, and community and population based efforts to prevent and to decrease violence. PMID- 23027116 TI - Walking and neighborhood environments for obese and overweight patients: perspectives from family physicians. AB - BACKGROUND AND OBJECTIVES: Primary care practitioners can play a significant role in helping patients adopt healthy behaviors such as physical activity (PA). The aim of this qualitative study was to assess family physicians' understanding and perception of the personal and environmental factors influencing PA, especially walking, and factors affecting their counseling of obese patients about environmental motivators and barriers to PA. METHODS: We conducted five focus groups with 35 family physicians and 14 family medicine residents in four clinics and a residency program affiliated with CenTexNet, a primary care practice-based research network in central Texas. Data were transcribed and analyzed using thematic content analysis. RESULTS: Physicians were aware of the PA guidelines, but not many actually brought up PA during their counseling of patients. Physicians agreed that neighborhood environments are important for walking and reported that their patients often brought up environmental barriers. Physicians recommended walking as an ideal type of PA for obese patients and sidewalks, parks, and trails/tracks with smooth and soft surfaces as ideal places to engage in walking. However, they rarely talked about these factors with their patients due to a perceived ineffectiveness in counseling, an inability to address environmental factors, and time constraints in the medical encounter. CONCLUSIONS: While physicians believe neighborhood environments often present many barriers to PA, they still believe that environmental factors are secondary to personal motivation in promoting PA among obese patients. Physicians, if better informed of the growing evidence on the environment-PA links, may be able to facilitate patients' behavior change more effectively. PMID- 23027117 TI - Internet use by primary care patients: where is the digital divide? AB - BACKGROUND AND OBJECTIVES: Internet-based technologies such as personal health records and patient portals are increasingly viewed as essential for enhancing patient-provider communication and patient-centered care. We examined how primary care patients use the Internet, particularly patient characteristics associated with Internet use. METHODS: We surveyed patients in five primary care clinic waiting rooms. Patients who had used email or the Internet in the past month (Internet users) were asked how often they used a computer for a variety of tasks. Participants who reported not using the Internet were asked about several potential barriers to Internet use. RESULTS: We approached 713 patients, and 638 (89.6%) completed questionnaires; 499 (78%) were Internet users and 139 (22%) were non-users. Lack of computer access and not knowing how to use email or the Internet were the most common barriers to Internet use. Younger age, higher education and income, better health, and absence of a chronic illness were associated with Internet use. After controlling for age and other variables, chronic illness was no longer associated with Internet use. CONCLUSIONS: Internet use was high among our primary care patients. The major factor associated with Internet use among patients with chronic conditions was their age. If older adults with chronic illness are to reap the benefits of health information technology, their Internet access will need to be improved. Institutions that are planning to offer consumer health information technology should be aware of groups with lower Internet access. PMID- 23027118 TI - A patient-centered telephone intervention using the asthma action plan. AB - BACKGROUND AND OBJECTIVES: Application of the patient-centered medical home (PCMH) practice model requires managing patients with chronic diseases, such as asthma, with patient-centered approaches that ensure appropriate ongoing assessment and treatment for all patients. The Asthma Control Score (ACS) and the Asthma Action Plan (AAP) are validated tools for assessment and management of asthma. ACS use by phone has been shown to accurately assess patients' asthma control; however, no studies to date demonstrate the utility of AAP implementation by phone to improve asthma control. This study tested the effectiveness of AAP implementation by phone to improve asthma control. METHODS: Adult patients with asthma (n=48) participating in a managed care insurance plan at a university-based family medicine residency clinic were enrolled in the study. Patients were contacted by phone, and an initial ACS was assessed. Patients with an ACS <20 (uncontrolled asthma) had their medication adjusted and a new AAP implemented by phone. Uncontrolled patients were reassessed by phone monthly and management was adjusted until control was achieved. RESULTS: Of 48 patients, 42 (87.5%) were reached by phone. On initial assessment, 33 (69%) were controlled. After implementation of the new AAP by phone, seven of nine (78%) initially uncontrolled patients were controlled, for a total of 40 (83%) patients controlled by the end of the study. CONCLUSIONS: Asthma management using the ACS and AAP by phone is a feasible strategy that is acceptable to patients and can improve asthma control without the need for an office visit. PMID- 23027119 TI - Using a learning coach to teach residents evidence-based medicine. AB - BACKGROUND AND OBJECTIVES: Medical educators have used multiple interventions to teach evidence-based medicine (EBM) and information mastery. Most of these interventions are applied uniformly to a group of residents. We developed a curriculum to increase residents' EBM and information mastery skills that would meet individual learning needs. METHODS: Two cohorts of second year residents (n=26) in the Family Medicine Residency Program at Brown University participated in the intervention. We delivered the curriculum through monthly individual meetings with a learning coach over 1 year. Before and after participating, residents completed a survey assessing their attitudes toward EBM and a quiz assessing their knowledge of EBM. Semi-structured interviews with each resident were done after the intervention and analyzed using qualitative methods. RESULTS: At the conclusion of our intervention, residents' attitudes toward EBM and information mastery were overwhelmingly positive, EBM knowledge quiz scores increased by 31.8%, and reported use of EBM in real time during patient encounters increased. CONCLUSIONS: An intervention using a learning coach to provide one-on-one EBM and information mastery instruction to residents improved residents' attitudes, knowledge, and use of both in the clinical setting. PMID- 23027120 TI - The shaman told me so! PMID- 23027122 TI - The family medicine chief resident: a national survey of leadership development. PMID- 23027121 TI - Monsters at the window: cure brings terror for a child. PMID- 23027124 TI - Variable compliance with clinical practice guidelines identified in a 1-day audit at 66 French adult intensive care units. AB - OBJECTIVE: Clinical guidelines should provide a framework for managing patients hospitalized in intensive care units. Little is known about guideline compliance in real-life practice. To evaluate compliance rates for a large bundle of intensive care unit practice guidelines and determine factors associated with noncompliance to these guidelines. DESIGN, SETTING, AND PATIENTS: A bundle of 13 clinical guidelines was elaborated by a group of senior physicians. Four external consultants validated the process. Then, a 1-day audit was performed at 66 participating adult intensive care units in 39 institutions by a group of 64 junior investigators supervised by senior intensivists. At the bedside, investigators collected data from 625 patients hospitalized in those units. INTERVENTIONS AND MEASUREMENTS: The eligibility and compliance rates were determined for each clinical recommendation. The rate of full compliance to each eligible clinical guideline was calculated. Mortality data were requested 28 days after the completion of the audit. MAIN RESULTS: The eligibility rate ranged from 11% (sepsis bundle) to 80% (identified closest relative). The median compliance rate was 75% (60-100), ranging from 24% (sedation monitoring) to 96% (identified closest relative and bacteriological sampling before initiating antibiotics). Our results showed that only 24% (20-27) of patients in our cohort received fully compliant care. The 28-day survival probability was .77 (.73-.80). CONCLUSIONS: At the bedside, clinical guidelines are fully applied in 24% of patients. Our study underlines the need to both improve the process of implementation and become cognizant of excessive proliferation of clinical guidelines. PMID- 23027125 TI - HER2 stabilizes EGFR and itself by altering autophosphorylation patterns in a manner that overcomes regulatory mechanisms and promotes proliferative and transformation signaling. AB - One of the causes of breast cancer is overexpression of the human epidermal growth factor receptor 2 (HER2). Enhanced receptor autophosphorylation and resistance to activation-induced downregulation have been suggested as mechanisms for HER2-induced sustained signaling and cell transformation. However, the molecular mechanisms underlying these possibilities remain incompletely understood. In the current report, we present evidence that show that HER2 overexpression does not lead to receptor hyper-autophosphorylation, but alters patterns in a manner that favors receptor stability and sustained signaling. Specifically, HER2 overexpression blocks epidermal growth factor receptor (EGFR) tyrosine phosphorylation on Y1045 and Y1068, the known docking sites of c-Cbl and Grb2, respectively, whereas promoting phosphorylation on Y1173, the known docking site of the Gab adaptor proteins and phospholipase C gamma. Under these conditions, HER2 itself is phosphorylated on Y1221/1222, with no known role, and on Y1248 that corresponds to Y1173 of EGFR. Interestingly, suppressed EGFR autophosphorylation on the Grb2 and c-Cbl-binding sites correlated with receptor stability and sustained signaling, suggesting that HER2 accomplishes these tasks by altering autophosphorylation patterns. In conformity with these findings, mutation of the Grb2-binding site on EGFR (Y1068F-EGFR) conferred resistance to ligand-induced degradation, which in turn induced sustained signaling, and increased cell proliferation and transformation. These findings suggest that the Grb2-binding site on EGFR is redundant for signaling, but critical for receptor regulation. On the other hand, mutation of the putative Grb2-binding site in HER2 (Y1139) did not affect stability, signaling or transformation, suggesting that Y1139 in HER2 may not serve as a Grb2-binding site. In agreement with the role of EGFR in HER2 signaling, inhibition of EGFR expression reduced HER2-induced anchorage-independent growth and tumorigenesis. These results imply that complementing HER2-targeted therapies with anti-EGFR drugs may be beneficial in HER2-positive breast cancer. PMID- 23027126 TI - Effect of a natural mutation in the 5' untranslated region on the translational control of p53 mRNA. AB - Tumor-suppressor protein p53, the 'guardian of the genome', is critical in maintaining cellular homeostasis and genomic stability. Earlier, we have reported the discovery of internal ribosome entry sites (IRESs) within the p53 mRNA that regulate the translation of the full length and its N-terminal-truncated isoform, DeltaN-p53. Polypyrimidine tract-binding protein (PTB) is an IRES trans-acting factor that positively regulates the IRES activities of both p53 isoforms by relocating from nucleus to the cytoplasm during stress conditions. Here we have demonstrated the putative contact points of PTB on the p53 IRES RNA. Studies on mutations that occur naturally in the 5' untranslated region (5' UTR) in p53 mRNA were lacking. We have investigated a naturally occurring C-to-T single-nucleotide polymorphism (SNP) first reported in human melanoma tumors. This SNP is at position 119 in the 5' UTR of p53 mRNA and we demonstrate that it has consequences on the translational control of p53. Introduction of this SNP has led to decrease in cap-independent translation from p53 5' UTR in bicistronic reporter assay. Further, the effects of this SNP on cap-independent translation have been studied in the context of p53 cDNA as well. Interestingly, the 5' UTR with this SNP has shown reduced binding to PTB that can be corroborated to its weaker IRES activity. Previously, it has been shown that G2-M checkpoint, DNA damaging stress and oncogenic insult favor IRES-mediated translation. Under similar conditions, we demonstrate that this SNP interferes with the enhancement of the IRES activity of the 5' UTR. Taken together, the results demonstrate for the first time that SNP in the 5' UTR of the p53 mRNA might have a role in translational control of this critical tumor-suppressor gene. PMID- 23027127 TI - LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap. AB - The liver kinase B1 (LKB1) tumor suppressor inhibits cell growth through its regulation of cellular metabolism and apical-basal polarity. The best understood mechanism whereby LKB1 limits cell growth is through activation of the AMP activated-protein-kinase/mammalian-target-of-rapamycin (AMPK/mTOR) pathway to control metabolism. As LKB1 is also required for polarized epithelial cells to resist hyperplasia, it is anticipated to function through additional mechanisms. Recently, Yes-associated protein (Yap) has emerged as a transcriptional co activator that modulates tissue homeostasis in response to cell-cell contact. Thus this study examined a possible connection between Yap and LKB1. Restoration of LKB1 expression in HeLa cells, which lack this tumor suppressor, or short hairpin RNA knockdown of LKB1 in NTERT immortalized keratinocytes, demonstrated that LKB1 promotes Yap phosphorylation, nuclear exclusion and proteasomal degradation. The ability of phosphorylation-defective Yap mutants to rescue LKB1 phenotypes, such as reduced cell proliferation and cell size, suggest that Yap inhibition contributes to LKB1 tumor suppressor function(s). However, failure of Lats1/2 knockdown to suppress LKB1-mediated Yap regulation suggested that LKB1 signals to Yap via a non-canonical pathway. Additionally, LKB1 inhibited Yap independently of either AMPK or mTOR activation. These findings reveal a novel mechanism whereby LKB1 may restrict cancer cell growth via the inhibition of Yap. PMID- 23027129 TI - RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance. AB - Chemotherapeutic drug resistance is one of the major causes for treatment failure in high-risk neuroblastoma (NB), the most common extra cranial solid tumor in children. Poor prognosis is typically associated with MYCN amplification. Here, we utilized a loss-of-function kinome-wide RNA interference screen to identify genes that cause cisplatin sensitization. We identified fibroblast growth factor receptor 2 (FGFR2) as an important determinant of cisplatin resistance. Pharmacological inhibition of FGFR2 confirmed the importance of this kinase in NB chemoresistance. Silencing of FGFR2 sensitized NB cells to cisplatin-induced apoptosis, which was regulated by the downregulation of the anti-apoptotic proteins BCL2 and BCLXL. Mechanistically, FGFR2 was shown to activate protein kinase C-delta to induce BCL2 expression. FGFR2, as well as the ligand fibroblast growth factor-2, were consistently expressed in primary NB and NB cell lines, indicating the presence of an autocrine loop. Expression analysis revealed that FGFR2 correlates with MYCN amplification and with advanced stage disease, demonstrating the clinical relevance of FGFR2 in NB. These findings suggest a novel role for FGFR2 in chemoresistance and provide a rational to combine pharmacological inhibitors against FGFR2 with chemotherapeutic agents for the treatment of NB. PMID- 23027130 TI - TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior. AB - Treatment options for adenoid cystic carcinoma (ACC) of the salivary gland, a slowly growing tumor with propensity for neuroinvasion and late recurrence, are limited to surgery and radiotherapy. Based on expression analysis performed on clinical specimens of salivary cancers, we identified in ACC expression of the neurotrophin-3 receptor TrkC/NTRK3, neural crest marker SOX10, and other neurologic genes. Here, we characterize TrkC as a novel ACC marker, which was highly expressed in 17 out of 18 ACC primary-tumor specimens, but not in mucoepidermoid salivary carcinomas or head and neck squamous cell carcinoma. Expression of the TrkC ligand NT-3 and Tyr-phosphorylation of TrkC detected in our study suggested the existence of an autocrine signaling loop in ACC with potential therapeutic significance. NT-3 stimulation of U2OS cells with ectopic TrkC expression triggered TrkC phosphorylation and resulted in Ras, Erk 1/2 and Akt activation, as well as VEGFR1 phosphorylation. Without NT-3, TrkC remained unphosphorylated, stimulated accumulation of phospho-p53 and had opposite effects on p-Akt and p-Erk 1/2. NT-3 promoted motility, migration, invasion, soft-agar colony growth and cytoskeleton restructuring in TrkC-expressing U2OS cells. Immunohistochemical analysis demonstrated that TrkC-positive ACC specimens also show high expression of Bcl2, a Trk target regulated via Erk 1/2, in agreement with activation of the TrkC pathway in real tumors. In normal salivary gland tissue, both TrkC and Bcl2 were expressed in myoepithelial cells, suggesting a principal role for this cell lineage in the ACC origin and progression. Sub micromolar concentrations of a novel potent Trk inhibitor AZD7451 completely blocked TrkC activation and associated tumorigenic behaviors. Pre-clinical studies on ACC tumors engrafted in mice showed efficacy and low toxicity of AZD7451, validating our in vitro data and stimulating more research into its clinical application. In summary, we describe in ACC a previously unrecognized pro-survival neurotrophin signaling pathway and link it with cancer progression. PMID- 23027128 TI - Protein tyrosine kinase 6 protects cells from anoikis by directly phosphorylating focal adhesion kinase and activating AKT. AB - Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase expressed in epithelial cancers. Disruption of Ptk6 decreases azoxymethane-induced colon tumorigenesis in mice by preventing signal transducer and activator of transcription 3 activation. Relocalization of PTK6 in prostate cancers contributes to increased growth. Although not expressed in normal breast or ovary, PTK6 promotes anchorage-independent survival of breast and ovarian tumor cells. We identified several potential PTK6 substrates in the human SW620 colon cancer cell line using mass spectrometry, including FAK (focal adhesion kinase). We show that FAK is a direct substrate of PTK6 in vitro and in vivo. Expression of membrane-targeted active PTK6 (Palm-PTK6-YF) induces constitutive activation of FAK and cell morphology changes, which are independent of SRC family kinases in Src-/-, Yes-/-, Fyn-/- (SYF) mouse embryonic fibroblasts (MEFs). Palm-PTK6-YF expressing SYF cells are transformed and overcome contact inhibition, form colonies in transformation assays, proliferate in suspension and form tumors in a xenograft model. Expression of FAK and Palm-PTK6-YF in Fak-/- MEFs synergistically activates AKT and protects cells against anoikis. However, expression of Palm-PTK6-YF in Akt1/2-/- MEFs fails to protect cells from anoikis, indicating AKT is critical in PTK6 and FAK-mediated survival signaling. In a conditional Pten knockout murine prostate cancer model, we identify prostate epithelial cells with enhanced activation of endogenous PTK6 and FAK at the plasma membrane. Knockdown of PTK6 in the PC3 human prostate cancer cell line disrupts FAK and AKT activation and promotes anoikis, which can be rescued by exogenous expression of FAK. Our data reveal important roles for a PTK6-FAK-AKT signaling axis in promoting anchorage-independent cell survival. PMID- 23027131 TI - Wnt4 inhibits cell motility induced by oncogenic Ras. AB - Aberrant motility and invasive ability are relevant hallmarks of malignant tumor cells. Pathways regulating the movement of cancer cells from the site of primary tumor toward adjacent and/or distant tissues are not entirely defined. By using a model of malignant transformation induced by Ras, we identified Wnt4 as an early target of Ras oncogenic signaling. Here we show that Wnt4 is repressed by Ras and that forced Wnt4 expression inhibits Ras-induced cell motility. Accordingly, we found that Wnt4 is downregulated in human anaplastic thyroid carcinomas, the most malignant and metastatic thyroid cancer histotype. Wnt4 interferes with Ras induced actin cytoskeleton reorganization through non-canonical pathways, by altering the balance between the activation of different Rho-family small guanosine triphosphatases (GTPases). Finally, we demonstrate that Wnt4 is post transcriptionally repressed by miR-24, a Ras-induced micro RNA (miRNA) targeting the 3'-untranslated region (UTR) of Wnt4. Taken together our data highlight a novel Ras-regulated miRNA-dependent circuitry regulating the motile phenotype of cancer cells. PMID- 23027133 TI - The development of opposition-defiance during toddlerhood: a population-based cohort study. AB - OBJECTIVE: There is now emerging epidemiological evidence that a substantial proportion of toddlers in the general population may be experiencing a significant opposition-defiance problem before 2 years of age. This article describes the continuity and discontinuity in boys' and girls' opposition defiance statuses during toddlerhood. METHOD: Data came from The Quebec Longitudinal Study of Child Development, a survey of a representative birth cohort of children from the Canadian province of Quebec. A time-specific latent variables (Markov) model was used to estimate the proportion of toddlers who cease or start to exhibit oppositional-defiant behaviors (ODBs) on a frequent basis between 17 and 29 months of age and to test for gender differences therein. RESULTS: A majority of toddlers who had exhibited ODBs on a frequent basis at 17 months of age were still doing so 1 year later. Also, a majority of toddlers who did exhibit ODBs on a frequent basis at 29 months of age had done so 1 year earlier. The results also show that there are more toddlers who start than stop exhibiting ODBs on a frequent basis during this period. Further, the continuity and discontinuity in toddlers' opposition-defiance statuses during this period did not vary between boys and girls, suggesting that gender differences in opposition-defiance have not yet emerged by the second half of the third year of life. CONCLUSION: The predictive accuracy of early opposition-defiance is very good, with a substantial proportion of toddlers experiencing a significant opposition-defiance problem throughout toddlerhood. PMID- 23027132 TI - Ethnic differences in caregiver quality of life in pediatric asthma. AB - OBJECTIVE: The aim of this study was to determine ethnic and site differences in quality of life (QOL) in a sample of Latino (Puerto Rican [PR] and Dominican) and non-Latino white caregivers of children with asthma in mainland US and Island PR. We also investigated ethnic and site differences in associations between caregiver QOL and indicators of asthma morbidity. METHOD: Seven hundred and eighty-seven children with asthma (7-16 years of age) and their primary caregivers participated in the study. Primary caregivers completed a measure of QOL, child asthma control, and emergency department utilization, among other measures. RESULTS: Ethnic and site differences were found on total QOL scores (DeltaF(1,783) = 29.46, p < .001). Island PR caregivers reported worse QOL scores than Rhode Island (Rl) Latino and non-Latino white caregivers; Rl Latino caregivers reported significantly worse QOL scores than non-Latino white caregivers. In Rl Latino and Island PR children, worse caregiver QOL was associated with asthma that was not in control and with one or more emergency department visits. CONCLUSION: Latino caregivers may be experiencing a greater level of burden related to their child's asthma than non-Latino white caregivers. Caregiver QOL in pediatric asthma may be a reflection of broader contextual stress that some Latino caregivers experience on a daily basis (e.g., cultural beliefs, acculturation). Future research should continue to investigate mechanisms that explain the burden associated with pediatric asthma in Latino families, as well as whether QOL assessments should consider the impact of everyday stressors on caregiver QOL in pediatric asthma. PMID- 23027134 TI - Nutrition, physical activity, and bone mineral density in youth with autistic spectrum disorders. AB - OBJECTIVE: Fractures and pain, secondary to low bone mineral density (BMD), have been reported in pediatric patients with autistic spectrum disorders (ASD). The purpose of this study was to assess the BMD of a clinical sample of 10- to 18 year olds with ASD, and the nutrition and physical activity correlates of skeletal health in this population. METHODS: Twenty-six patients with ASD were recruited from an outpatient multidisciplinary child-development clinic. Lumbar bone density was measured using dual-energy x-ray absorptiometry. Data collection included anthropometries, serum nutrient levels, parent interview, and 72-hour diet, screen-time, and physical activity records. RESULTS: Four patients (15%) met criteria for pediatric low BMD with z scores less than or equal to -2.0; another 4 were at risk with z scores less than or equal to -1.0. Approximately 54% of participants had insufficient serum 25-hydroxy vitamin D. Mean electronic media use was 251 minutes/day; mean physical activity 69 minutes/day. Fewer than 50% of participants met daily reference intake of vitamins A, B3, D, E, K, zinc, calcium, folate, potassium, and fiber. Bone density correlated positively with body mass (r = .47), calcium intake (r = .46), and calorie intake (r = .58). CONCLUSIONS: Children aged 10 to 18 years old with ASD are at risk for occult low bone density. In this study, those with low body mass index and insufficient calcium and calorie intake were at greater risk. Other unhealthy behaviors in this population included a high screen-time to physical activity ratio and multiple nutrient deficiencies. PMID- 23027135 TI - Identity dynamics and peer relationship quality in adolescents with a chronic disease: the sample case of congenital heart disease. AB - OBJECTIVE: Identity formation has been found to relate to psychosocial and disease-specific functioning in chronically ill adolescents. Therefore, examining antecedent factors of identity formation in this population is needed. The main goal of the present longitudinal study was to examine how peer relationship quality influenced identity formation in adolescents with congenital heart disease (CHD). METHOD: Adolescents with CHD were selected from the database of pediatric and congenital cardiology of the University Hospitals Leuven. A total of 429 adolescents (14-18 years) with CHD participated at time 1; 401 were matched on gender and age with community controls recruited at secondary schools. Adolescents completed questionnaires on identity and peer relationship quality. Nine months later, at time 2, 382 patients again completed these questionnaires. RESULTS: Adolescents with CHD were generally found to be as competent as controls in addressing the task of identity formation. Moreover, the importance of peer relationships for identity formation was demonstrated. Supportive peer relationships positively influenced the process of identifying with the identity commitments made. Furthermore, such relationships protected adolescents from getting stuck in the exploration process. Finally, reciprocal pathways were uncovered; a maladaptive exploration process was also found to negatively affect peer relationships. CONCLUSION: The present study found peer relationship quality to be an important antecedent factor of identity formation in adolescents with CHD. Future research should investigate how changes in peer relationships and identity relate to well-being in these patients. PMID- 23027136 TI - Evaluation of cognitive and motor development in toddlers with congenital hypothyroidism diagnosed by neonatal screening. AB - OBJECTIVE: The Dutch neonatal congenital hypothyroidism (CH) screening procedure and treatment modality has been adapted several times since its national institution in 1981. These changes enabled us to investigate whether earlier treatment has resulted in improved cognitive and motor outcomes. The present study examined whether the advancement of treatment modality has resulted in improved cognitive and motor outcomes. METHODS: In 95 toddlers with thyroidal CH (CH-T), born in 2002 through 2004 and treated at a median age of 9 days, cognitive and motor outcomes were assessed with the Bayley Scales of Infant Development-II-NL at 1 and 2 years of age. This outcome was also analyzed in relation to treatment variables. RESULTS: The mean mental developmental index (MDI) scores of the severe (initial free thyroxine [FT4] <=0.4 ng/dL (<=5 pmol/L), moderate (0.4 < initial FT4 <= 0.8 ng/dL (5.0 < initial FT4 <= 10.0 pmol/L), and mild (initial FT4 > 0.8 ng/dL (>10.0 pmol/l) CH-T groups at 1 year and the moderate and mild CH-T groups at 2 years were similar to the population mean. The mean MDI scores of the total CH-T group and severe CH-T group at 2 years were significantly lower than the population mean (p < .0001). In all 3 severity subgroups, significant lower psychomotor developmental index scores (p < .0001) were observed. No correlations were found between starting day of treatment and developmental outcome. Initial T4 concentration and initial T4 dose were weak predictors for developmental outcome. CONCLUSION: Essentially, comparable with our earlier findings, children with CH, especially those with severe CH, are still at risk for motor and cognitive problems, which are probably due to the consequence of the prenatal hypothyroid state or the thyroid hormone deficiency in early life. PMID- 23027139 TI - Health-related physical fitness in Dutch children with developmental coordination disorder. AB - OBJECTIVE: To compare components of health-related physical fitness between Dutch children with clinically diagnosed developmental coordination disorder (DCD) and typically developing children (TDC), and to examine associations between motor performance problems and components of health-related fitness in children with DCD. METHODS: A multicenter case-control study was used to compare health-related physical fitness in children with DCD (N = 38; age, 7-12 years; 10 girls and 28 boys) with that in age- and gender-matched TDC. Motor coordination problems (manual dexterity, ball and balance skills) were assessed using the movement assessment battery for children. Health-related physical fitness was indicated by (1) cardiorespiratory fitness, (2) muscle strength, and (3) body mass index. RESULTS: Significantly lower values of cardiorespiratory fitness (6.7% lower maximal cardiorespiratory fitness) were found in children with DCD compared with TDC. Extension and flexion of the elbow and flexion of the knee were also significantly lower (by 15.3%, 16.7%, and 18.4%, respectively) in DCD children compared with TDC. A significant negative and large association was found between cardiorespiratory fitness and balance performance. CONCLUSION: Lower cardiorespiratory fitness and muscle strength in children with clinically diagnosed DCD compared with TDC support the importance of examining and training cardiorespiratory fitness and muscle strength, besides the regular attention for motor coordination problems. PMID- 23027138 TI - Relation of emotional and behavioral problems with body mass index in preschool children: the Generation R study. AB - OBJECTIVE: Although problem behavior in children and adolescents has frequently been associated with overweight, it is unclear whether this relationship is already present in early childhood. We hypothesized that problem behavior is positively related to body mass index (BMI) in children of preschool age and that eating behavior explains part of this relation. METHODS: The study was embedded in the Generation R Study, a population-based cohort with data available on BMI and problem behavior for 3137 children aged 3 to 4 years. Problem behavior was measured with the child behavior checklist (CBCI), and eating behavior was assessed using the child eating behaviour questionnaire (CEBQ). Linear regression analyses were conducted to assess the association between the CBCI (expressed as z-scores). CEBQ, and BMI standard deviation scores (BMI-SDS), Bootstrapping was used to formally test mediation. RESULTS: Children with higher levels of emotional problems had a lower BMI-SDS after adjustment for relevant covariates (e.g., beta [95% confidence interval {Cl}] for mother report of emotional problems = -0.04 [-0.07, -0.001], father report = -0.04 [-0.08, -0.001]). Behavioral problems were not associated with BMI. Emotional and behavioral problems were not associated with underweight or overweight if studied categorically. The effect estimate for the relation of emotional problems with BMI-SDS attenuated to nonsignificance after adjustment for specific eating behaviors, i.e., they were accounted for by satiety responsiveness, fussiness, and emotional undereating. CONCLUSION: In this population-based study, emotional problems in preschoolers were negatively related to BMI, and this relation was fully explained by food avoidant eating behaviors. PMID- 23027140 TI - Telehealth in developmental-behavioral pediatrics. AB - Developmental-behavioral pediatrics (DBP) is recognized as one of the fields with the greatest shortages of pediatric subspecialists. Families who access care often must travel great distances to tertiary academic medical centers or endure long waiting lists. While the shortages are likely to persist due to limited provider availability and an increasing number of children with developmental and behavioral disorders being identified, our field must look to innovative ways to reduce the barriers to access. One such way is telehealth, the use of videoconferencing to deliver DBP services to underserved populations. We aim to describe the practical uses of telehealth for the delivery of diagnostic and management clinical services in a variety of settings and for the additional educational and research benefits of the modality. We will highlight the obstacles to setting up a successful DBP telehealth practice and direct readers to resources to address these in their communities. Most of all, we will demonstrate the benefit to families and children, practitioners, and health care systems of supplementing traditional in-person DBP services with telehealth modalities to enhance outreach and engagement with communities. PMID- 23027141 TI - Choosing the best child assessment instrument for a specific context: a methodology for engaging local experts applied in Chile. AB - OBJECTIVE: Chile is considering expanding its system for early childhood development to include 5- to 7-year olds, but it has no consensus about how to identify at-risk children. This study facilitated a process for incorporating local priorities and best practices to choose a child assessment instrument. METHODS: Using the priority-setting method of the Child Health and Nutrition Research Initiative (CHNRI), 21 Chilean experts defined and weighted ideal assessment instrument characteristics; 130 instruments were scored according to how closely they matched experts' ideal definitions. Instruments were ranked by score under different inclusion criteria. RESULTS: Experts weighted instrument quality highest (95 on 1-100 scale), followed by administration site (87), domains assessed (82), cost (80), administrator (76), Spanish version (75), time (75), and prior use in Chile (53). Experts agreed that an ideal instrument (1) would reliably assess language, socioemotional well-being, mental health, and parenting abilities, (2) could be administered at schools or home, and (3) could be administered by teachers or parents. No single instrument matched all Chilean priorities. Three instruments met 11 of 13 priorities (age; quality; administration at school, home, or waiting rooms; assess language and socioemotional domains; administered by teachers, parents, or psychologists; time <=30 minutes). Including mental health or parenting abilities ranked instruments whose composite scores were 35% lower. CONCLUSION: Decisions about how to assess children at developmental risk should be informed by local context. The CHNRI method provided a useful process that made explicit mutually exclusive priorities, quantified trade-offs of different assessment strategies, and identified 3 of the instruments that best met local needs and priorities. PMID- 23027142 TI - Significant weight loss with cognitive and communication limitations in an adolescent. AB - CASE: Mark is a 17-year-old adolescent with an unknown dysmorphic syndrome associated with intellectual disability. His food intake was limited for at least 3 months. He refused all foods, while he lost 12 pounds in 9 months. His mother said that he has been in a good mood and performing at his baseline level in school. Mark has a limited expressive verbal capacity; he uses some single words, he can express pain, but he has minimal understanding of conversation. He has an appointment at the primary care pediatric clinic for a weight check. PMID- 23027144 TI - Thinking ethically about professional practice in adapted physical activity. AB - There has been little critical exploration of the ethical issues that arise in professional practice common to adapted physical activity. We cannot avoid moral issues as we inevitably will act in ways that will negatively affect the well being of others. We will make choices, which in our efforts to support others, may hurt by violating dignity or infringing on rights. The aim of this paper is to open a dialogue on what constitutes ethical practice in adapted physical activity. Ethical theories including principlism, virtue ethics, ethics of care, and relational ethics provide a platform for addressing questions of right and good and wrong and bad in the field of adapted physical activity. Unpacking of stories of professional practice (including sacred, secret, and cover stories) against the lived experiences of persons experiencing disability will create a knowledge landscape in adapted physical activity that is sensitive to ethical reflection. PMID- 23027145 TI - Disability in physical education textbooks: an analysis of image content. AB - The aim of this paper is to show how images of disability are portrayed in physical education textbooks for secondary schools in Spain. The sample was composed of 3,316 images published in 36 textbooks by 10 publishing houses. A content analysis was carried out using a coding scheme based on categories employed in other similar studies and adapted to the requirements of this study with additional categories. The variables were camera angle, gender, type of physical activity, field of practice, space, and level. Univariate and bivariate descriptive analyses were also carried out. The Pearson chi-square statistic was used to identify associations between the variables. Results showed a noticeable imbalance between people with disabilities and people without disabilities, and women with disabilities were less frequently represented than men with disabilities. People with disabilities were depicted as participating in a very limited variety of segregated, competitive, and elite sports activities. PMID- 23027146 TI - Enhancing physical activity guidelines: a needs survey of adults with spinal cord injury and health care professionals. AB - The purpose of this study was to determine preferences of people with spinal cord injury (SCI) and health care professionals (HCP) regarding the content and format of a SCI physical activity guide to support recently released SCI physical activity guidelines. Seventy-eight people with SCI and 80 HCP completed a survey questionnaire. Participants with SCI identified desired content items and their preferences for format. HCP rated the helpfulness of content items to prescribe physical activity. All content items were rated favorably by participants with SCI and useful by HCP. The risks and benefits of activity and inactivity, and strategies for becoming more active, were rated high by both samples. Photographs and separate information for those with paraplegia versus tetraplegia were strongly endorsed. These data were used to guide the development of an SCI physical activity guide to enhance the uptake of physical activity guidelines for people with SCI. The guide was publically released November 11, 2011. PMID- 23027147 TI - Examining rater effects of the TGMD-2 on children with intellectual disability. AB - The purpose of this study was to investigate rater effects on the TGMD-2 when it applied to children with intellectual disability. A total of 22 children with intellectual disabilities participated in this study. Children's performances in each of 12 subtests of the TGMD-2 were recorded via video and scored by three adapted physical activity specialists who have expertise in the TGMD-2. Two advanced measurement theories, Generalizability-theory (G-theory) and many-facet Rasch model (MFRM), were applied in data analyses. There were relatively large variances attributed to rater effects on the scores of the TGMD-2 awarded to children with intellectual disabilities. The severity of each rater significantly differed across all subtests of the TGMD-2. There was a set of biased ratings interacted with measurement conditions of the TGMD-2. PMID- 23027148 TI - Reliability and validity of the Paediatric Volitional Questionnaire - Chinese version. AB - OBJECTIVE: The purpose of this study is to examine the psychometric properties of the Chinese version of the Paediatric Volitional Questionnaire (PVQ-C) for use amongst preschoolers in Taiwan. METHODS: Forty preschoolers with developmental delays were randomly selected from northern Taiwan, along with another 40 typically developing preschoolers. The data was analysed using Rasch measurement model for construct validity and classical test theory for item reliability, intra- and inter-rater reliability, and convergent validity. RESULTS: The results indicated the PVQ items of PVQ-C fit into a unidimensional continuum of volition (logit -6.63~3.05) with 2 items representing differential item functioning for diagnostic group. The person-fit statistics showed that 83% participants' response could be appropriately estimated and stratified (separation index = 1.86). Using a modified 3-point rating scale resulted in acceptable item reliability (0.97), intra-rater reliability (0.412-1.0), 86% PVQ items in test retest reliability > 0.4, and convergent validity (r = 0.562-0.656). CONCLUSIONS: The PVQ-C is regarded as a reliable and valid instrument for assessing the volitional status of children, as a reference for subsequent clinical judgement, and for client-centred intervention programmes and treatment effects. PMID- 23027149 TI - Angiogenesis in a rat model following myocardial infarction induced by hypoxic regulation of VEGF165 gene-transfected EPCs. AB - Hypoxia-response elements (HREs) regulate the expression of the vascular endothelial growth factor 165 (VEGF165) gene and enhance the safety and efficacy of therapeutic angiogenesis. However, the role of hypoxic regulation of VEGF165 gene-modified stem cells in promoting angiogenesis in the ischemic myocardium remains unclear. In this study, the effects of the hypoxic regulation of genetically modified endothelial progenitor cells (EPCs) on angiogenesis in the ischemic myocardium and on changes in cardiac function following acute myocardial infarction (AMI) were investigated through the transplantation of hypoxia regulated VEGF165 gene-modified EPCs into the ischemic myocardium. Rat bone marrow-derived EPCs transfected with plasmid p6HRE-CMV-VEGF165 (6HRE-VEGF165-E), and plasmid pCMV-VEGF165 (VEGF165-E) were injected into rats with a successfully established model of AMI. The levels of VEGF165 mRNA and protein expression in the EPCs and ischemic myocardium were determined using reverse transcription polymerase chain reaction and western blot assay, respectively, and the capillary density in the ischemic myocardium and the cardiac function of the rats were detected using immunohistochemistry and echocardiography, respectively. We found that the hypoxia promoter 6HRE-CMV effectively regulated the expression of the VEGF165 gene in the EPCs and the ischemic myocardium. In rats of the 6HRE-VEGF165 E-transplanted group, the levels of VEGF165 gene expression and capillary density in the ischemic myocardium were significantly higher than those in the other experimental groups. Moreover, cardiac function was also improved compared with that in other groups. VEGF165 gene-modified EPCs are able to significantly promote angiogenesis in the ischemic myocardium and markedly ameliorate the cardiac function of rats following AMI, especially under 6HRE regulation. PMID- 23027151 TI - Medical school graduates entering family medicine: increasing the overall number. PMID- 23027152 TI - Results of the 2012 National Resident Matching Program: family medicine. AB - BACKGROUND: The percentage of US seniors choosing primary care careers remains well below the nation's future workforce needs. Data in this article are collected from the 2012 National Resident Matching Program (NRMP) Main Residency Match and the 2012 American Academy of Family Physicians (AAFP) Medical Education Residency Census, which had a response rate of 100%. The census verified residents who entered training July 2012 from all medical schools. The information provided includes the number of applicants to graduate medical education programs for the 2012--2013 academic year, specialty choice, and trends in specialty selection. Compared with the 2011 Match, family medicine residency programs filled 35 more positions (with 18 more US seniors) through the NRMP in 2012. In other primary care fields, 31 more primary care internal medicine positions (20 more US seniors), two fewer positions in pediatrics-primary care (one less US senior), and 18 fewer positions in internal medicine-pediatrics programs (33 fewer US seniors) filled. The 2012 NRMP results indicate a small increase in medical students choosing primary care careers for the third year in a row; however, students continue to show an overall preference for subspecialty careers. PMID- 23027153 TI - Entry of US medical school graduates into family medicine residencies: 2011- 2012. AB - BACKGROUND: This study reports on the number of graduates entering family medicine residencies in 2011 from allopathic, osteopathic, and international medical schools. Allopathic graduate data come from medical school registrars or the American Medical Association Masterfile. The 2012 family medicine residency program director census, with a response rate of 100%, verified residents who entered training July 2011 from all medical schools. Approximately 8.4% allopathic medical school's graduates of the 17,478 graduates (July 2010 to June 2011) were first-year family medicine residents in 2011, compared with 8.0% in 2010 and 7.5% in 2009. The percent of medical school graduates entering family medicine from each of the allopathic schools was calculated and averaged over 3 years to diminish 1-year fluctuations. Allopathic medical schools' 3-year average percentage of graduates who entered family medicine residency programs in 2011 ranged from 0.6% to 21.4%. Compared to 2010, osteopathic graduates in Accreditation Council for Graduate Medical Education-accredited family medicine residencies (21.5%) increased 2.8% from 2010, whereas international medical graduates (32.1%) decreased 3.4%. An increasing trend is seen in the number of allopathic graduates entering family medicine residencies. Osteopathic and international graduates' entry to residency appears inversely related. As medical schools emphasize social accountability to improve the health of communities, higher family medicine graduation rates may occur. Initiatives in medical school admissions may increase the number of medical students more likely to select family medicine careers. PMID- 23027154 TI - Impact of a 3-day OSCE workshop on Iraqi physicians. AB - BACKGROUND AND OBJECTIVES: Following a severe hardship for the past 4 decades, the Iraqi Ministry of Health initiated many activities to enhance the knowledge and skills of health professionals. The American University of Beirut was approached to deliver a workshop to update the skills of Iraqi physicians in constructing an Objective Structured Clinical Examination (OSCE). METHODS: This is a descriptive study of the 3-day workshop delivered to Iraqi physicians as train the trainer. The participants were given reading material and participated in interactive hands-on exercises. Performance was determined by direct observation of participants performing a mock OSCE. Pretests and posttests were conducted to assess change in knowledge. RESULTS: The participants demonstrated a significant improvement in their mean score of the posttest in comparison to pretest (8.6 versus 6.4, respectively). Moreover, they revealed mastery of the OSCE in the final mock OSCE activity. The participants highly evaluated the workshop and were positive in their future ability to conduct an OSCE. CONCLUSIONS: Adopting an interactive hands-on workshop to train the trainer is feasible and appears to be effective. PMID- 23027155 TI - What could family income be if health insurance were more affordable? AB - BACKGROUND AND OBJECTIVES: Adjusted for inflation, household income has been relatively flat since the mid-1990s, but the inflation rate of employer-sponsored health insurance has been greater than both household income growth and general inflation for 50 years. We estimated the effect on average family income if health insurance inflation matched the general inflation rate since 1996, and those savings were given to employees as income. METHODS: We used data from the Medical Expenditure Panel Survey, the Milliman Medical Index, and other federal sources to model the relationship between private health insurance costs and household income over the last 15 years. RESULTS: If the cost of family health care costs had kept pace with the Consumer Price Index (CPI) rate since 1996, the average family income could have been $8,410 higher in 2010 ($68,805 versus $60,395), 13.9% more than actual earnings. CONCLUSIONS: If health care costs had not exceeded the CPI rate since 1996 and if all the excess costs were converted into employee wages, median family income could be substantially higher today. PMID- 23027156 TI - Evidence-based IUD practice: family physicians and obstetrician-gynecologists. AB - BACKGROUND AND OBJECTIVES: Family physicians and obstetrician-gynecologists provide much of contraceptive care in the United States and have a shared goal in preventing unintended pregnancy among patients. We assessed their competency to offer women contraceptives of the highest efficacy levels. METHODS: We conducted a national probability survey of family physicians and obstetrician-gynecologists (n=1,192). We measured counseling and provision practices of intrauterine contraception and used multivariable regression analysis to evaluate the importance of evidence-based knowledge to contraceptive care. RESULTS: Family physicians reported seeing fewer contraceptive patients per week than did obstetrician-gynecologists and were less likely to report sufficient time for counseling. While 95% of family physicians believed patients were receptive to learning about intrauterine contraception, fewer than half offered counseling or the method. Only half were trained to competence to offer intrauterine contraception, while virtually all obstetrician-gynecologists were. Both family physicians and obstetrician-gynecologists were unlikely to have adequate knowledge of the women who would be good candidates for intrauterine contraception-as gauged by the Centers for Disease Control and Prevention Medical Eligibility Criteria for contraception-and consequently did not offer the method to a wide range of eligible patients. CONCLUSIONS: Most family physicians providing contraceptive care were not offering methods with top-tier effectiveness, although they reported interest in updating contraceptive skills through training. Obstetrician-gynecologists had technical skills to offer intrauterine contraception but still required education on patient selection. Greater hands-on training opportunities for family physicians, and complementary education on eligible method candidates for obstetrician-gynecologists, can increase access to intrauterine contraception by women seeking contraceptive care. PMID- 23027157 TI - Medical student perceptions of the educational value of a student-run free clinic. AB - BACKGROUND AND OBJECTIVES: Many medical schools have student-run free clinics (SRFCs), yet their educational value has not been well studied. We performed a one-time cross-sectional survey to assess medical student perceptions of the educational value of an SRFC at their institution. METHODS: The authors designed and validated a survey instrument including six statements on a 5-point Likert scale. The questionnaire was distributed from February through May 2010 to all students enrolled at the University of California San Diego (UCSD) School of Medicine as part of a larger yearly, anonymous, internet-based survey regarding their experiences at the institution. RESULTS: The response rate was 66.5% with 347 of 522 eligible students participating. Ninety percent agreed or strongly agreed that the SRFC was a valuable educational experience, mean score: 4.51 on a scale of 5. Eighty-two percent agreed or strongly agreed that the teaching was excellent, mean score: 4.23. Students agreed or strongly agreed that the SRFC improved attitudes toward working with underserved patients (72%, mean score 3.99), helped students stay connected to sense of purpose, (71%, mean score 3.98), improved overall sense of well-being (67%, mean score 3.88), and influenced their decision to come to UCSD (52%, mean score 3.37). Eighty-four percent of qualitative responses in a free text comment box were positive (46 of 55). CONCLUSIONS: To the authors' knowledge, this is the first study to report the perceptions of an entire medical student body of a SRFC at their institution. The majority felt that this was a valuable educational experience. PMID- 23027158 TI - The influence of ASCCP guideline changes on family medicine residency colposcopy training. AB - BACKGROUND AND OBJECTIVES: The study objective was to determine the influence of the 2001 and 2006 American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines changes on colposcopy training at one family medicine residency. METHODS: We conducted a retrospective chart review from January 1, 2000 to October 31, 2009. The 2001 ASCCP guidelines were fully implemented into our practice in June 2002 and the 2006 guidelines in June 2008. Data were extracted from our electronic medical records and delineated into three groups: 2000-2002 (pre-2001 guideline changes), 2003-2007 (post-2001 and pre-2006 update), and 2008 2009 (post 2006 changes) for total female patient visits aged 18-75 years, pap smears, and colposcopies. An ANOVA post-hoc comparison test was performed on the three data groups to test significance. RESULTS: After the 2001 guidelines, there was a 28.6% significant decrease in colposcopies (CI=0.20-0.37). An additional, 16.5% significant decrease occurred after the 2006 revisions (CI=0.06-0.28). Consequently, residents performed 45.1% fewer colposcopies. The total number of pap smears remained relatively unchanged. CONCLUSIONS: Implementation of the 2001 and 2006 ASCCP guidelines significantly reduced the number colposcopies performed, resulting in greater difficulty training competent family medicine residents in colposcopy. PMID- 23027159 TI - Probability and the black cloud. PMID- 23027160 TI - Heart failure in Vietnam. AB - BACKGROUND: Students are increasingly participating in international health experiences during their medical training. This essay explores one student's perspective on the importance of relationship development with both patients and health care systems in global settings. The essay also reflects on the unique learning experiences available in resource-limited areas. PMID- 23027162 TI - Geographic patterns in primary care visits provided by osteopathic physicians. PMID- 23027163 TI - Incidence of serious injuries due to physical abuse in the United States: 1997 to 2009. AB - BACKGROUND AND OBJECTIVE: Although US child protective services data showed a 55% decrease in the national incidence of substantiated physical abuse from 1992 to 2009, no study has tracked the occurrence of serious injuries due to physical abuse. This study examined changes in the incidence of serious injuries due to physical abuse in hospitalized children from 1997 to 2009. METHODS: The Kids' Inpatient Database, a sample of discharges from hospitals in the United States, includes International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and external cause of injury codes; it was prepared every 3 years from 1997 to 2009. Cases of serious physical abuse (eg, abusive head injury) were identified by using injury codes (800-959) and codes for abuse (995.50, 0.54, 0.55, and 0.59), selected assault codes (E960-966, 968), or perpetrator of abuse (E967). The weighted number of hospitalizations due to serious physical abuse was used to calculate the national incidence, and chi(2) for linear trend compared over time the incidence for children <18 years and <1 year of age. RESULTS: The incidence per 100,000 children <18 years of age increased 4.9%: 6.1 (95% confidence interval = 5.4-6.8) for 1997, 6.0 (5.2-6.7) for 2000, 6.0 (5.3-6.7) for 2003, 6.1 (5.3-6.8) for 2006, and 6.4 (5.7-7.2) for 2009 (P < .01). The incidence for children <1 year of age increased 10.9% (P < .05). CONCLUSIONS: Over 12 years, when substantiated physical abuse was declining, there was a small increase in the incidence of serious physical abuse in children <18 and <1 year of age. PMID- 23027164 TI - Hot flashes in a young girl: a wake-up call concerning Serenoa repens use in children. AB - Extracts of the plant Serenoa repens are widely used in male adults for the treatment of benign prostatic hyperplasia. Recently, therapy with S repens has been proposed as a "natural" alternative to conventional treatments for male androgenetic alopecia as well as for other hair disorders. Telogen effluvium is a form of alopecia characterized by abnormality of hair cycling, resulting in excessive loss of telogen hair. We report the case of an 11-year-old girl presenting hot flashes that appeared after treatment of telogen effluvium with a food supplement containing S repens that lasted for ~2 months. When use of the product was discontinued, the hot flashes no longer occurred. Four months after the start of S repens intake and 45 days from the cessation of therapy, the girl experienced menarche at the age of 11 years. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the appearance of hot flashes and the intake of S repens. A correlation between exposure to S repens and the onset of menarche is not certain, but it cannot be excluded. Medicinal products or food supplements containing S repens are generally well tolerated in male adults, but we believe that their use in pediatric patients should be better evaluated. PMID- 23027165 TI - Depressive symptoms and neurocardiogenic syncope in children: a 2-year prospective study. AB - OBJECTIVE: To evaluate prospectively the relationship between neurocardiogenic syncope (NCS) and depressive symptoms in pediatric patients. METHODS: Forty-five patients (aged 12.3 +/- 2.9 years) with NCS (diagnosed as >= 1 syncopal episodes with typical symptoms, reproduced by tilt-table testing, in the absence of structural or primary electrical heart disease) were compared with 45 age- and gender-matched control subjects. Assessment was performed at baseline and 2 years thereafter. Depressive symptoms and self-perception profile of participants were evaluated, along with their parents' psychological distress, defensive profile and hostility. Family cohesion and adaptability, as well as the opinion of parents and teachers on children's strengths and difficulties, were also examined. RESULTS: At baseline, patients showed more (P = .008) depressive symptoms than controls, correlating with the number of syncopal episodes, impaired relationship with parents and poor family cohesion. A conservative management strategy of NCS was adopted and psychological counseling was offered, focusing on patients with clinically significant depressive symptoms and their families. During follow-up, depressive symptoms decreased in patients (P < .001), but remained stable in controls. Child-parent relationship, family cohesion and family adaptability improved at follow-up in patients. No recurrent syncope was noted during follow-up and this along with improvement in child-parent relationship were associated with depressive symptoms improvement. CONCLUSIONS: Depressive symptomatology is common in pediatric patients with NCS. Our findings call for additional investigation in larger controlled clinical interventional studies that will enhance understanding of the possible pathophysiological association between depressive symptomatology and NCS in pediatric populations. PMID- 23027166 TI - Background television in the homes of US children. AB - OBJECTIVE: US parents were surveyed to determine the amount of background television that their children are exposed to as well as to isolate demographic factors associated with increased exposure to background television. After this, we ask how certain home media practices are linked to children's background television exposure. METHODS: US parents/caregivers (N = 1454) with 1 child between the ages of 8 months and 8 years participated in this study. A nationally representative telephone survey was conducted. Parents were asked to report on their child's exposure to background television via a 24-hour time diary. Parents were also asked to report relevant home media behaviors related to their child: bedroom television ownership, number of televisions in the home, and how often a television was on in the home. RESULTS: The average US child was exposed to 232.2 minutes of background television on a typical day. With the use of multiple regression analysis, we found that younger children and African American children were exposed to more background television. Leaving the television on while no one is viewing and children's bedroom television ownership were associated with increased background television exposure. CONCLUSIONS: Although recent research has shown the negative consequences associated with background television, this study provides the first nationally representative estimates of that exposure. The amount of exposure for the average child is startling. This study offers practitioners potential pathways to reduce exposure. PMID- 23027167 TI - Posterior rib fractures in a young infant who received chiropractic care. AB - We report on a 21-day-old infant with healing posterior rib fractures that were noted after a chiropractic visit for colic. Chiropractors are the third largest group of health care professionals in the United States, and colic is the leading complaint for pediatric chiropractic care. Rib fractures, specifically when posterior, are traditionally considered to be secondary to nonaccidental trauma. Thorough investigation is necessary to rule out bone fragility and genetic disorders, but patient history is key when evaluating unexplained fractures. PMID- 23027168 TI - Preservation of renal function in atypical hemolytic uremic syndrome by eculizumab: a case report. AB - Genetic mutations in complement components are associated with the development of atypical hemolytic uremic syndrome (aHUS), a rare disease with high morbidity rate triggered by infections or unidentified factors. The uncontrolled activation of the alternative pathway of complement results in systemic endothelial damage leading to progressive development of renal failure. A previously healthy 8-month old boy was referred to our hospital because of onset of fever, vomiting, and a single episode of nonbloody diarrhea. Acute kidney injury with preserved diuresis, hemolytic anemia, and thrombocytopenia were detected, and common protocols for management of HUS were followed without considerable improvement. The persistent low levels of complement component C3 led us to hypothesize the occurrence of aHUS. In fact, the child carried a specific mutation in complement factor H (Cfh; nonsense mutation in 3514G>T, serum levels of Cfh 138 mg/L, normal range 350-750). Given the lack of response to therapy and the occurrence of kidney failure requiring dialysis, we used eculizumab as rescue therapy, a monoclonal humanized antibody against the complement component C5. One week from the first administration, we observed a significant improvement of all clinical and laboratory parameters with complete recovery from hemodialysis, even in the presence of systemic infections. Our case report shows that complement inhibiting treatment allows the preservation of renal function and avoids disease relapses during systemic infections. PMID- 23027169 TI - Physician attitudes regarding school-located vaccinations. AB - OBJECTIVE: To assess physician attitudes regarding school-located adolescent vaccination and influenza vaccination. METHODS: From July through September 2010, a 20-item survey was mailed to 1337 practicing Colorado family physicians and pediatricians. Standard statistical methods were used to examine unadjusted and adjusted odds ratios of factors associated with physician support for school located vaccination programs. RESULTS: Overall, 943 physicians were survey eligible, and 584 (62%) responded. More than half of physicians supported both school-located influenza and adolescent vaccination. However, fewer physicians supported school-located adolescent vaccination compared with influenza vaccination. More physicians supported school-located vaccination for their publicly insured patients compared with their privately insured patients. Some family physicians (32%) and pediatricians (39%) believed that school-located vaccination would make their patients less likely to attend well-child visits, and half of respondents believed that school-located vaccination would have a negative financial impact on their practice. In multivariate analyses, physicians concerned about the financial impact of school-located vaccination were less likely to support such programs. CONCLUSIONS: Although a majority of Colorado physicians supported influenza and adolescent vaccination at school, they expressed concerns regarding the implications on their practice. Lesser support for vaccination of their privately insured patients and concerns regarding attendance at well-child visits suggests the perceived financial impact from school-located vaccination is a barrier and merits additional examination. PMID- 23027170 TI - Long-term outcomes of infant behavioral dysregulation. AB - OBJECTIVES: To determine whether maternal report of infant behavioral dysregulation at 6 months is associated with a higher prevalence of behavioral concerns at 5, 14, and 21 years of age; and to assess the extent to which maternal and social factors may affect reported child behavior outcomes. METHODS: From the Mater-University of Queensland Study of Pregnancy cohort of 7223 live singleton babies, information on dysregulation was available for 6389 children at 6 months. Of those children, behavior data were available for 4836 at 5 years by using a modified Child Behavior Checklist, 4746 at 14 years by using a full Child Behavior Checklist and Youth Self-Report, and 3558 at 21 years by using a Young Adult Self-Report. Of the youth with dysregulation data at 6 months, 2308 completed the Composite International Diagnostic Interview at 21 years. Potential confounding and mediating factors were analyzed by using logistic regression. RESULTS: Maternal-reported behavioral dysregulation at 6 months was associated with a significantly higher prevalence of maternal-reported behavior problems at 5 and 14 years (P < .001), but not youth self-reported problems at 14 or 21 years, or Composite International Diagnostic Interview-Diagnostic and Statistical Manual diagnoses at 21 years. The strength of association between infant dysregulation and maternal-reported behaviors was greater at 5 years than at 14 years, and was substantially reduced by adjusting for maternal, social, and infant factors, especially potentially the mediating factors of maternal anxiety and depression. CONCLUSIONS: Infant behavioral dysregulation was a risk factor for maternal-reported behavior concerns at 5 and 14 years, although was unrelated to young adult mental health. PMID- 23027171 TI - Prevalence and correlates of exergaming in youth. AB - OBJECTIVES: Less than 15% of children and adolescents participate regularly in physical activity (PA) and, with ever-increasing obesity, strategies to improve PA levels in youth are urgently needed. Exergaming offers a PA alternative that may be especially attractive in our increasingly technophilic society. However, there are no observational studies of exergaming in population-based samples of adolescents. The purpose of this study was to investigate potential sociodemographic, lifestyle, psychosocial, weight-related, and mental health correlates of exergaming as well as describe the type, timing, and intensity of exergaming in a population-based sample of adolescents. METHODS: Data on exergame use and potential sociodemographic, lifestyle, psychosocial, weight-related, and mental health correlates of exergaming were collected in mailed self-report questionnaires completed by 1241 grade 10 and 11 students from the Montreal area with a mean age of 16.8 years (SD = 0.05 years; 43% male) participating in the AdoQuest study. The independent correlates of exergaming were identified in multivariable logistic regression models. RESULTS: Nearly one-quarter (24%) of participants reported exergaming. Exergamers played 2 days per week on average, for ~50 minutes each bout; 73% of exergamers played at a moderate or vigorous intensity. Exergamers were more likely than nonexergamers to be girls, to play nonactive video games, to watch >=2 hours of television per day, to be stressed about weight, and to be nonsmokers. CONCLUSIONS: Many adolescents exergame at intensity levels that could help them achieve current moderate-to-vigorous PA recommendations. Interventions that encourage exergaming may increase PA and decrease sedentary behavior in select youth subgroups, notably in girls. PMID- 23027172 TI - Status of the pediatric clinical trials enterprise: an analysis of the US ClinicalTrials.gov registry. AB - BACKGROUND AND OBJECTIVES: Clinical trials are the gold standard for generating evidence-based knowledge in medicine. Recent legislation requiring trials to be registered at ClinicalTrials.gov has enabled evaluation of the clinical trial enterprise as a whole, which was previously not possible. The purpose of this study was to create a snapshot of the pediatric clinical trial portfolio. METHODS: All interventional trials registered at ClinicalTrials.gov from July 2005 to September 2010 were included. Pediatric (ie, enrolling patients aged 0-18 years) trial characteristics, therapeutic area, location, and funding were described. Secondary objectives included describing pediatric trials over time and comparison with nonpediatric trials. RESULTS: During this time, 5035 pediatric trials were registered compared with >10 times as many nonpediatric trials. Neonates/infants were eligible for enrollment in 46.6% of trials versus children (77.9%) and adolescents (45.2%). Nearly one-half of pediatric trials enrolled <100 subjects, and more pediatric trials versus nonpediatric trials evaluated preventive therapies. The proportion of pediatric trials evaluating a drug intervention declined over time, and there were fewer Phase 0 to II versus Phase III to IV trials. Infectious disease/vaccine studies (23%) were the most common, followed by psychiatric/mental health (13%) studies. Many trials enrolled patients outside the United States, and <15% of trials were sponsored by the National Institutes of Health or other US federal agencies. CONCLUSIONS: Analysis of the ClinicalTrials.gov data set allows description of the current scope of pediatric trials. These data may be useful to stakeholders in informing decisions regarding the conduct of trials in children and provide insight into mechanisms to advance pediatric trial infrastructure and methodology toward improving child health. PMID- 23027173 TI - Improvement in adolescent screening and counseling rates for risk behaviors and developmental tasks. AB - BACKGROUND: High-quality preventive services for youth aged 11 to 18 include assessment and counseling regarding health behavior risks and developmental tasks/strengths of adolescence. Nationally, primary care health behavior risk screening and counseling rates lag considerably behind other preventive health services. The purpose of this project was to assist pediatric and family medicine practices to make office systems-based changes that promote comprehensive screening and counseling for risks and developmental tasks/strengths during adolescent preventive services visits. METHODS: Over a 9-month period, 7 pediatric and 1 family medicine primary care practices (13 physicians and 3 nurse practitioners) participated in a modified Breakthrough Series Collaborative. This project was designed to support primary care practitioner efforts to implement comprehensive screening and counseling for risk behaviors and developmental tasks/strengths for their adolescent patients and increase the rate of brief office intervention and referral. Composite variables were designed to reflect whether screening and counseling were documented for risks and developmental tasks. Statistical comparisons were made by using the nonparametric Wilcoxon matched-pairs signed rank test. RESULTS: There were increases in the composite measures of screening and counseling for risk behaviors (all 6 risks: 26%-50%, P = .01) and 3 of 4 developmental tasks/strengths (32%-66%, P = .01). Documentation of office interventions for identified risks and out-of office referral rates did not change. CONCLUSIONS: With the use of an office systems-based approach, screening and counseling for all critical risk behaviors and developmental tasks/strengths during adolescent preventive services visits can be improved in primary care practices. PMID- 23027174 TI - Transition and sickle cell disease. AB - Sickle cell disease (SCD), the most common genetic disease screened for in the newborn period, occurs in ~1 in 2400 newborns in the general population and 1 in 400 individuals of African descent in the United States. Despite the relative high prevalence and low pediatric mortality rate of SCD when compared with other genetic diseases or chronic diseases in pediatrics, few evidence-based guidelines have been developed to facilitate the transition from pediatrics to an internal medicine or family practice environment. As with any pediatric transition program, common educational, social, and health systems themes exist to prepare for the next phase of health care; however, unique features characterizing the experience of adolescents with SCD must also be addressed. These challenges include, but are not limited to, a higher proportion of SCD adolescents receiving public health insurance when compared with any other pediatric genetic or chronic diseases; the high proportion of overt strokes or silent cerebral infarcts (~30%) affecting cognition; risk of low high school graduation; and a high rate of comorbid disease, including asthma. Young adults with SCD are living longer; consequently, the importance of transitioning from a pediatric primary care provider to adult primary care physician has become a critical step in the health care management plan. We identify how the primary care physicians in tandem with the pediatric specialist can enhance transition interventions for children and adolescents with SCD. PMID- 23027175 TI - Sleep duration and adiposity during adolescence. AB - BACKGROUND AND OBJECTIVE: The association between sleep and obesity has been described in different age groups. However, there are not sufficient data to clarify the inconsistent results reported in adolescents. Our objective was to study the associations between sleep duration and adiposity at 13 and at 17 years of age, with both cross-sectional and longitudinal approaches. METHODS: We evaluated, as part of an urban population-based cohort (EPITeen), 1171 adolescents at both 13 and 17 years of age. Sleep duration was estimated by self reported bedtimes and wake-up times. Age- and gender-specific BMI z scores were calculated based on Centers for Disease Control and Prevention references. Body fat percentage (BF%) was assessed by bioelectrical impedance. Regression coefficients (beta) and respective 95% confidence intervals (CIs) were used to estimate the association between sleep and BMI z scores and BF%. Additionally, a cross-lagged analysis was performed to investigate the causal relations. RESULTS: In the cross-sectional analysis, at 13 years, sleep duration was inversely associated with BMI z score only in boys (beta = -0.155, 95% CI: -0.267 to 0.043); at 17 years, a positive association was found among girls but was only significant for BF% (beta = 0.510, 95% CI: 0.061-0.958). In the longitudinal approach, sleep duration at age 13 was inversely associated with BMI z score (beta = -0.123, 95% CI: -0.233 to -0.012) and BF% (beta = -0.731, 95% CI: -1.380 to -0.081) at 17 years only in boys. These significant associations disappeared after adjustment for adiposity at 13 years. These results were corroborated by those from cross-lagged analysis. CONCLUSIONS: Our results showed an effect of sleep duration in adiposity at younger ages of adolescence and suggested gender differences in this association. PMID- 23027176 TI - Impact of neonatal intensive care on late preterm infants: developmental outcomes at 3 years. AB - BACKGROUND: Late preterm infants (LPIs) (34-36 weeks' gestation) account for up to 75% of preterm births and constitute a significant proportion of all neonatal admissions. This study assessed the impact of neonatal intensive or high dependency care (IC) on developmental outcomes of LPIs at 3 years of age. METHODS: This cohort study included 225 children born late preterm in Northern Ireland during 2006. Children born late preterm who received IC were compared with children born late preterm who did not receive IC. Cognitive, motor, and language skills were assessed by using the Bayley Scales of Infant and Toddler Development, Third Edition. Growth was assessed by using anthropometric measures of height and weight. RESULTS: LPIs who received IC were more often less mature (34 weeks' gestation), with lower birth weight (<= 2500 g) and Apgar scores (<7 at 5 minutes) compared with the control group. They were more often born by cesarean delivery and more likely to have received resuscitation at birth. At 3 years of age, children born late preterm who received IC demonstrated similar cognitive, motor, and language skills compared with children in the control group. Measurements of growth also did not differ significantly between groups. CONCLUSIONS: Despite having increased maternal, perinatal, and neonatal risk factors, there were no significant differences in early childhood development between LPIs who received IC and those who did not. LPIs do not receive routine follow-up after IC and this study provides useful and reassuring data for parents and clinicians on the longer-term outcome of this infant group. PMID- 23027178 TI - CD66c is a novel marker for colorectal cancer stem cell isolation, and its silencing halts tumor growth in vivo. AB - BACKGROUND: Despite the well recognized expression of the cell surface markers cluster of differentiation 44 (homing cell adhesion molecule) and CD133 (Prominin 1) on human colorectal cancer stem cells (CCSCs), these molecules do not appear to be effective targets for stem cell-directed therapies. Because the surface marker CD66c (also known as carcinoembryonic antigen-related cell adhesion molecule 6) has demonstrated promise as a therapeutic target in pancreatic malignancy, the authors evaluated its potential as a target for stem cell directed treatment of colorectal cancer. METHODS: First, the authors characterized CD66c expression by flow cytometry and immunohistochemistry in colon cancer samples and in normal colon tissues. Then, the coexpression of CD66c and CD133 was evaluated on putative CCSCs. CD66c expression also was measured in stem cell-enriched colon spheres. Finally, the effects of small-interfering RNA mediated CD66c silencing on the in vitro and in vivo growth of Caco2 colon cancer cells were evaluated. RESULTS: CD66c expression was significantly higher in colon cancers than in contiguous normal colon tissues and paralleled cancer stage. CD66c was absent in CD133-positive cells that were isolated from normal colon, whereas its expression was brightest (CD66c(bright) ) in CD133-positive cells from colon cancer samples. In vitro experiments demonstrated that colon spheres were considerably enriched in a CD66c(bright) population in a fashion comparable to the enrichment observed in fresh liver metastases. In vitro proliferation and clonogenic potential were hampered when CD66c was silenced in Caco2 cells. Finally, in vivo xenograft experiments demonstrated that CD66c silencing almost completely abrogated the tumorigenic potential of Caco2 cells. CONCLUSIONS: CD66c(bright) expression was associated with colon cancer stem cells and CD66c silencing blocked tumor growth, thereby opening the way to a potential new treatment for colon cancer. PMID- 23027179 TI - A cross-national comparative study of blood pressure levels and hypertension prevalence in Canada and Hungary. AB - PURPOSE: Hungary has one of the highest cardiovascular (CV) mortality and stroke rates compared to other countries in Europe and North America. Data from two recent blood pressure (BP) screening projects in Hungary and Canada provided us with the opportunity to compare potential differences in the prevalence of hypertension between these countries. METHODS: From the Ontario Blood Pressure Survey, 880 white Canadians between 20 and 62 years old with white-collar occupation were selected and compared with a total of 1000 Hungarian bank employees in the same age range. Identical methods were employed for CV risk factor screening and BP measurements using the BpTRU instrument. Hypertension was defined by elevated BP measurement (SBP >=140 mmHg and/or DBP >=90 mmHg) or current intake of antihypertensive medication. RESULTS: Canadian participants were on average 10 years older with a higher rate of obesity, diabetes and high cholesterol. Smoking was more prevalent among Hungarians (29.4 vs. 22.5%, P < 0.001). Despite being younger, Hungarians exhibited significantly higher SBP (121.3 +/- 4.3 vs. 111.6 +/- 14.1, P < 0.001) and DBP (78.5 +/- 10.5 vs. 70.8 +/- 9.5, P < 0.001), which remained significant after adjustment for age and use of antihypertensive medication as well as sex and CV risk factors. Age adjusted prevalence of hypertension was significantly higher and poorly controlled among Hungarians (P < 0.001). CONCLUSION: The increased prevalence of hypertension among young and middle-aged Hungarians compared with Canadians could represent an essential contributor to the high CV mortality and stroke rates in Hungary. BP awareness, treatment and control require improved medical attention and should be addressed early among young Hungarians. PMID- 23027180 TI - Does home blood pressure allow for a better assessment of the white-coat effect than ambulatory blood pressure? AB - BACKGROUND: The difference between clinic and ambulatory blood pressure (BP) is a poor estimate of the true white-coat effect (WCE) measured with beat-to-beat recording. METHOD: We investigated whether the difference between clinic and home BP (home WCE) was a better estimate of true WCE than ambulatory WCE. In 73 young hypertensives, ambulatory WCE was calculated as the difference between clinic BP and the mean of two 24-h BP recordings, and home WCE as the difference between clinic and home BP (HBP) measured over 6 months. All individuals underwent beat to-beat BP monitoring with the Finometer. During the recording, a white-coat test (true WCE) and a public speaking test were performed. RESULTS: Ambulatory WCE correlated with home WCE (P < 0.001 for systolic and diastolic BPs). However, both surrogate WCEs were unrelated to true WCE (P = 0.93/0.36 and P = 0.11/0.36, respectively). True WCE correlated with the BP reaction to public speaking (P < 0.001/P < 0.001), whereas both surrogate WCEs were unrelated to the BP response to this test (all P > 0.21). Individuals were divided into two groups according to whether BP response to the doctor's visit was above (WCH+) or below (WCH-) the median. WCH+ patients had similar clinic and ambulatory BPs to WCH- but showed a higher BP response to public speaking. CONCLUSION: As previously observed for ambulatory WCE, home WCE does not reflect the true BP reaction to doctor's visit. BP response to psychosocial stressors is increased in individuals with hyperreactivity to doctor's measurement but not in individuals with white-coat hypertension identified with either ambulatory or HBP measurement. PMID- 23027181 TI - Angiotensin-converting enzyme inhibitors enhance the effect of cyclooxygenase inhibitors on breast cancer: a nationwide case-control study. AB - OBJECTIVES: Angiotensin-converting enzyme (ACE) inhibitors are first-line antihypertensive and potential cancer preventive agents. Interest in breast cancer prevention is growing, and more clinical evidence is needed regarding the effects of preventive therapy, alone or in combination. METHODS: This was a nationwide case-control analysis from the Taiwan National health Insurance Research Database. We analyzed 16,847 female breast cancer patients (diagnosed between 1 January 2002 and 31 December 2008) and 50,541 matched individuals. Longitudinal exposure to ACE inhibitors and cyclooxygenase inhibitors was compared. RESULTS: The risk of developing breast cancer among patients taking both aspirin and an ACE inhibitor decreased as the ACE inhibitor dose increased. Among patients receiving between 28 and 364 cumulative defined daily doses (cDDDs) of aspirin, the adjusted odds ratios (ORs) were 0.97 (0.90-1.06), 0.91 (0.82-1.03), and 0.79 (0.68-0.92) for women taking ACE inhibitors for 0-27, 28 364, and more than 365 cDDD, respectively. Among women receiving more than 365 cDDD of aspirin, the adjusted ORs were 0.91 (0.80-1.03), 0.81 (0.70-0.94), and 0.81 (0.71-0.92) as the ACE inhibitor dose increased, respectively. Women taking nonaspirin NSAIDs along with an ACE inhibitor had the same finding. Among women taking 28-364 cDDD of NSAIDs, the adjusted ORs were 0.85 (0.81-0.89), 0.87 (0.81 0.94), and 0.80 (0.73-0.88); for women receiving more than 365 cDDD of NSAIDs, the adjusted ORs were 0.68 (0.62-0.74), 0.61 (0.53-0.70), and 0.60 (0.52-0.70) as the ACE inhibitor dose increased, respectively. CONCLUSION: The findings of this nationwide analysis support the hypothesis that ACE inhibitors enhance the antitumor effect of cyclooxygenase inhibitors on breast cancer. PMID- 23027182 TI - Gender differences in lower limb kinematics during stair descent. AB - The purpose of this study was to compare lower limb kinematics between genders during stair descent. Fifteen females and fifteen males who were healthy and active were included in this study. The lower limb kinematics (pelvis, femur and knee) in the coronal and transversal planes were assessed during stair descent at 30 degrees , 40 degrees , 50 degrees and 60 degrees of knee flexion. The study found that females showed greater knee medial rotation for all the knee flexion angles (P = .02-.001), greater femoral adduction (P = .01 for all variables), with exception for 30 degrees (P = .13), and greater femoral lateral rotation at 60 degrees (P = .04). Females also showed a trend to have greater knee valgus at all the knee flexion angles (P = .06-.11) as well as less contralateral pelvis elevation at 50 degrees and 60 degrees (P = .10 and .12, respectively). This study showed that females carry out the stair descent with a lower limb alignment that might predispose them to develop overuse knee injuries, such as the iliotibial band syndrome and patellofemoral pain syndrome. Further prospective investigations should be carried out to verify whether these variables are factors that could predict these knee injuries. PMID- 23027183 TI - Insulin upregulates the expression of zinc finger and BTB domain-containing 7A in HepG2 cells. AB - Zinc finger and BTB domain-containing 7A (Zbtb7A) is a proto-oncogene overexpressed in numerous cancers. In this study, we explored the mechanism of insulin-induced Zbtb7A expression. Real-time PCR and western blotting were used to detect Zbtb7A expression. Zbtb7A promoter activity was monitored by Luciferase reporter assay. It was shown that insulin elevates the mRNA and protein levels of the Zbtb7A gene in HepG2 cells. Using chemical inhibitors of insulin downstream pathways, we demonstrated that the insulin-induced Zbtb7A gene expression was completely blocked by LY294002, a PI3K/AKT inhibitor, and partially attenuated by the MAPK inhibitor PD98059. Transfection of HepG2 cells with a 1 kb Zbtb7A promoter-luciferase reporter construct revealed a dose-dependent activation of the Zbtb7A promoter by insulin, while mutation of the Sp1 binding site within the Zbtb7A promoter resulted in the failure of insulin-induced promoter activation, suggesting that insulin increases Zbtb7A expression through transcriptional regulation mediated by Sp1 in HepG2 cells. PMID- 23027184 TI - Repetitive step training with preparatory signals improves stability limits in patients with Parkinson's disease. AB - OBJECTIVE: To examine the effects of repetitive volitional and compensatory step training with preparatory signals on the limits of stability, postural and gait skills, and spatiotemporal gait characteristics in patients with Parkinson's disease with no falls during the previous 12 months. DESIGN: Randomized clinical trial with assessor blinded to group assignment. SUBJECTS: Twenty-eight patients with Parkinson's disease with no falls during the previous 12 months. METHODS: Eligible patients were randomly assigned to an experimental group, which undertook repetitive step training with preparatory visual cues, or a control group, which undertook lower limb strength training for 4 weeks. Outcome measures included limits of stability test, postural and gait sub-scores from Unified Parkinson's Disease Rating Scale motor score (UPDRS-PG), and spatiotemporal gait characteristics. All tests were conducted before and after training at patients' peak medication cycle. RESULTS: The experimental group showed significant improvements in reaction time, movement velocity, and endpoint excursion of limits of stability, as well as UPDRS-PG score and stride length (p < 0.05), compared with the control group. Both groups significantly increased gait velocity (p < 0.05). CONCLUSION: Repetitive step training with preparatory cues can enhance limits of stability, postural and gait skills and spatiotemporal gait characteristics in patients with Parkinson's disease with no falls during the previous 12 months. PMID- 23027185 TI - Fks1 and Fks2 are functionally redundant but differentially regulated in Candida glabrata: implications for echinocandin resistance. AB - The echinocandins caspofungin, micafungin, and anidulafungin, inhibitors of cell wall beta-1,3-glucan synthesis, were recently elevated to first-line agents for treating infections due to the azole-refractory yeast Candida glabrata. In Candida albicans, echinocandin resistance is strictly associated with mutations in Fks1, a large integral membrane protein and putative beta-1,3-glucan synthase, while mutations in both Fks1 and its paralog Fks2 (but not Fks3) have been associated with resistance in C. glabrata. To further explore their function, regulation, and role in resistance, C. glabrata fks genes were disrupted and subjected to mutational analysis, and their differential regulation was explored. An fks1Delta fks2Delta double disruptant was not able to be generated; otherwise, all three single and remaining two double disruptants displayed normal growth and echinocandin susceptibility, indicating Fks1-Fks2 redundancy. Selection on echinocandin-containing medium for resistant mutants was dependent on strain background: only fks1Delta and fks1Delta fks3Delta strains consistently yielded mutants exhibiting high-level resistance, all with Fks2 hot spot 1 mutations. Thus, Fks1-Fks2 redundancy attenuates the rate of resistance; further analysis showed that it also attenuates the impact of resistance-conferring mutations. Growth of the fks1Delta and, especially, fks1Delta fks3Delta strains was specifically susceptible to the calcineurin inhibitor FK506. Relatedly, FK506 addition or calcineurin gene CMP2 disruption specifically reversed Fks2-mediated resistance of laboratory mutants and clinical isolates. RNA analysis suggests that transcriptional control is not the sole mechanism by which calcineurin modulates Fks2 activity. PMID- 23027186 TI - Interaction of the echinocandin caspofungin with amphotericin B or voriconazole against Aspergillus biofilms in vitro. AB - Aspergillus biofilms were prepared from 22 strains of Aspergillus spp. via a 96 well plate-based method. Using a broth microdilution checkerboard technique with the XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5 carboxanilide] colorimetric assay, we demonstrated a synergistic antifungal activity against 18 of 22 Aspergillus biofilm strains with a combination of caspofungin and amphotericin B and against 13 of 22 strains with a combination of caspofungin and voriconazole. We did not observe antagonism. PMID- 23027187 TI - A case of daptomycin-induced immune thrombocytopenia. AB - We report a case of severe daptomycin-induced immune thrombocytopenia in a patient treated for methicillin-resistant Staphylococcus epidermidis and ampicillin-resistant Enterococcus faecalis bacteremia acquired in an intensive care unit. Serum antibodies bound to platelets in the presence of daptomycin on flow cytometry. There was no evidence of other causes of thrombocytopenia. The patient died of brain herniation complicating extensive cerebral hemorrhage. To our knowledge, this is the first described case of daptomycin-induced thrombocytopenia. PMID- 23027188 TI - Two clinical isolates of Candida glabrata exhibiting reduced sensitivity to amphotericin B both harbor mutations in ERG2. AB - Two novel isolates of Candida glabrata exhibiting reduced sensitivity to amphotericin B (MIC, 8 MUg ml(-1)) were found to be ERG2 mutants, wherein Delta(8)-sterol intermediates comprised >90% of the total cellular sterol fraction. Both harbored an alteration at Thr(121) in ERG2; the corresponding residue (Thr(119)) in Saccharomyces cerevisiae is essential for sterol Delta8 Delta7 isomerization. This constitutes the first report of C. glabrata harboring mutations in ERG2 and exhibiting reduced sensitivity to amphotericin B. PMID- 23027189 TI - In vitro synergy between clofazimine and amikacin in treatment of nontuberculous mycobacterial disease. AB - Disease caused by nontuberculous mycobacteria (NTM) is increasing in frequency. The outcome of treatment for NTM lung disease is poor, particularly lung disease caused by Mycobacterium simiae and M. abscessus. Exploring synergy between active available drugs is a sensible way forward given the lack of new active drugs. We tested for synergy between amikacin and clofazimine, using standardized methods, in 564 consecutive clinical isolates identified as 21 species of rapidly growing mycobacteria, 16 clinical M. avium complex isolates, and 10 M. simiae isolates. Clofazimine and amikacin are each active in vitro against NTM; 97% (n = 548) of the rapid growers revealed MICs of clofazimine of <=1 MUg/ml, and 93% (n = 524) proved susceptible to amikacin. The combination showed significant synergistic activity in 56 of 68 (82%) eligible M. abscessus isolates, 4 of 5 M. chelonae isolates, and 1 M. fortuitum and 1 M. cosmeticum isolate, with 4- to 8-fold decreases in MICs to both drugs. Significant synergy could also be demonstrated against all M. avium complex and M. simiae isolates, with fractional inhibitory concentrations of <0.5. Clofazimine and amikacin show significant synergistic activity against both rapidly and slowly growing nontuberculous mycobacteria. The safety and tolerability of adding clofazimine to amikacin-containing regimens should be tested in clinical trials, and the results of susceptibility tests for these two compounds and their combination merit clinical validation. Synergy between clofazimine and other antibiotics with intracellular targets should be explored. PMID- 23027190 TI - ICESp1116, the genetic element responsible for erm(B)-mediated, inducible resistance to erythromycin in Streptococcus pyogenes. AB - ICESp1116, responsible for erm(B)-mediated, inducible erythromycin resistance in Streptococcus pyogenes, was comprehensively characterized, and its chromosomal integration site was determined. It displayed a unique mosaic organization consisting of a scaffold, related to TnGallo1 from Streptococcus gallolyticus, with two inserted fragments separated by IS1216. One fragment, containing erm(B), displayed high-level identity to a portion of the S. pyogenes plasmid pSM19035; the other, containing a truncated tet(M) gene, displayed high-level identity to the right-hand portion of Clostridium difficile Tn5397. PMID- 23027191 TI - Full and broad-spectrum in vivo eradication of catheter-associated biofilms using gentamicin-EDTA antibiotic lock therapy. AB - Biofilms that develop on indwelling devices are a major concern in clinical settings. While removal of colonized devices remains the most frequent strategy for avoiding device-related complications, antibiotic lock therapy constitutes an adjunct therapy for catheter-related infection. However, currently used antibiotic lock solutions are not fully effective against biofilms, thus warranting a search for new antibiotic locks. Metal-binding chelators have emerged as potential adjuvants due to their dual anticoagulant/antibiofilm activities, but studies investigating their efficiency were mainly in vitro or else focused on their effects in prevention of infection. To assess the ability of such chelators to eradicate mature biofilms, we used an in vivo model of a totally implantable venous access port inserted in rats and colonized by either Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, or Pseudomonas aeruginosa. We demonstrate that use of tetrasodium EDTA (30 mg/ml) as a supplement to the gentamicin (5 mg/ml) antibiotic lock solution associated with systemic antibiotics completely eradicated Gram-positive and Gram-negative bacterial biofilms developed in totally implantable venous access ports. Gentamicin-EDTA lock was able to eliminate biofilms with a single instillation, thus reducing length of treatment. Moreover, we show that this combination was effective for immunosuppressed rats. Lastly, we demonstrate that a gentamicin EDTA lock is able to eradicate the biofilm formed by a gentamicin-resistant strain of methicillin-resistant S. aureus. This in vivo study demonstrates the potential of EDTA as an efficient antibiotic adjuvant to eradicate catheter associated biofilms of major bacterial pathogens and thus provides a promising new lock solution. PMID- 23027192 TI - Effect of posaconazole on cyclosporine blood levels and dose adjustment in allogeneic blood and marrow transplant recipients. AB - The posaconazole prescribing information recommends an upfront cyclosporine dose reduction upon initiation of posaconazole prophylaxis. We examined this recommendation in the early phase of allogeneic transplantation, where cyclosporine levels potentially becoming subtherapeutic following upfront dose reduction would be deleterious to transplant outcome. Our data show that while posaconazole leads to an increase in cyclosporine levels, subsequent cyclosporine dose reduction can be safely guided by therapeutic drug monitoring and is not required upfront. Therefore, the current recommendation may be modified. PMID- 23027193 TI - Ceftaroline versus isolates from animal bite wounds: comparative in vitro activities against 243 isolates, including 156 Pasteurella species isolates. AB - More than 5 million Americans are bitten by animals, usually dogs, annually. Bite patients comprise ~1% of all patients who visit emergency departments (300,000/year), and approximately 10,000 require hospitalization and intravenous antibiotics. Ceftaroline is the bioactive component of the prodrug ceftaroline fosamil, which is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs), including those containing methicillin-resistant Staphylococcus aureus (MRSA). There are no in vitro data about the activity of ceftaroline against Pasteurella multocida subsp. multocida and Pasteurella multocida subsp. septica, other Pasteurella spp., or other bite wound isolates. We therefore studied the in vitro activity of ceftaroline against 243 animal bite isolates. MICs were determined using the broth microdilution method according to CLSI guidelines. Comparator drugs included cefazolin, ceftriaxone, ertapenem, ampicillin-sulbactam, azithromycin, doxycycline, and sulfamethoxazole trimethoprim (SMX-TMP). Ceftaroline was the most active agent against all 5 Pasteurella species, including P. multocida subsp. multocida and P. multocida subsp. septica, with a maximum MIC of <=0.008 MUg/ml; more active than ceftriaxone and ertapenem (MIC(90)s, <=0.015 MUg/ml); and more active than cefazolin (MIC(90), 0.5 MUg/ml) doxycycline (MIC(90), 0.125 MUg/ml), azithromycin (MIC(90), 0.5 MUg/ml), ampicillin-sulbactam (MIC(90), 0.125 MUg/ml), and SMX-TMP (MIC(90), 0.125 MUg/ml). Ceftaroline was also very active against all S. aureus isolates (MIC(90), 0.125 MUg/ml) and other Staphylococcus and Streptococcus species, with a maximum MIC of 0.125 MUg/ml against all bite isolates tested. Ceftaroline has potential clinical utility against infections involving P. multocida, other Pasteurella species, and aerobic Gram-positive isolates, including S. aureus. PMID- 23027194 TI - Exacerbation of influenza virus infections in mice by intranasal treatments and implications for evaluation of antiviral drugs. AB - Compounds lacking oral activity may be delivered intranasally to treat influenza virus infections in mice. However, intranasal treatments greatly enhance the virulence of such virus infections. This can be partially compensated for by giving reduced virus challenge doses. These can be 100- to 1,000-fold lower than infections without such treatment and still cause equivalent mortality. We found that intranasal liquid treatments facilitate virus production (probably through enhanced virus spread) and that lung pneumonia was delayed by only 2 days relative to a 1,000-fold higher virus challenge dose not accompanied by intranasal treatments. In one study, zanamivir was 90 to 100% effective at 10 mg/kg/day by oral, intraperitoneal, and intramuscular routes against influenza A/California/04/2009 (H1N1) virus in mice. However, the same compound administered intranasally at 20 mg/kg/day for 5 days gave no protection from death although the time to death was significantly delayed. A related compound, Neu5Ac2en (N-acetyl-2,3-dehydro-2-deoxyneuraminic acid), was ineffective at 100 mg/kg/day. Intranasal zanamivir and Neu5Ac2en were 70 to 100% protective against influenza A/NWS/33 (H1N1) virus infections at 0.1 to 10 and 30 to 100 mg/kg/day, respectively. Somewhat more difficult to treat was A/Victoria/3/75 virus that required 10 mg/kg/day of zanamivir to achieve full protection. These results illustrate that treatment of influenza virus infections by the intranasal route requires consideration of both virus challenge dose and virus strain in order to avoid compromising the effectiveness of a potentially useful antiviral agent. In addition, the intranasal treatments were shown to facilitate virus replication and promote lung pathology. PMID- 23027195 TI - Clinically relevant Gram-negative resistance mechanisms have no effect on the efficacy of MC-1, a novel siderophore-conjugated monocarbam. AB - The incidence of hospital-acquired infections with multidrug-resistant (MDR) Gram negative pathogens is increasing at an alarming rate. Equally alarming is the overall lack of efficacious therapeutic options for clinicians, which is due primarily to the acquisition and development of various antibiotic resistance mechanisms that render these drugs ineffective. Among these mechanisms is the reduced permeability of the outer membrane, which prevents many marketed antibiotics from traversing this barrier. To circumvent this, recent drug discovery efforts have focused on conjugating a siderophore moiety to a pharmacologically active compound that has been designed to hijack the bacterial siderophore transport system and trick cells into importing the active drug by recognizing it as a nutritionally beneficial compound. MC-1, a novel siderophore conjugated beta-lactam that promotes its own uptake into bacteria, has exquisite activity against many Gram-negative pathogens. While the inclusion of the siderophore was originally designed to facilitate outer membrane penetration into Gram-negative cells, here we show that this structural moiety also renders other clinically relevant antibiotic resistance mechanisms unable to affect MC-1 efficacy. Resistance frequency determinations and subsequent characterization of first-step resistant mutants identified PiuA, a TonB-dependent outer membrane siderophore receptor, as the primary means of MC-1 entry into Pseudomonas aeruginosa. While the MICs of these mutants were increased 32-fold relative to the parental strain in vitro, we show that this resistance phenotype is not relevant in vivo, as alternative siderophore-mediated uptake mechanisms compensated for the loss of PiuA under iron-limiting conditions. PMID- 23027196 TI - Adenylate kinase release as a high-throughput-screening-compatible reporter of bacterial lysis for identification of antibacterial agents. AB - Adenylate kinase (AK) is a ubiquitous intracellular enzyme that is released into the extracellular space upon cell lysis. We have shown that AK release serves as a useful reporter of bactericidal agent activity and can be exploited for antimicrobial screening purposes. The AK assay exhibits improved sensitivity over that of growth-based assays and can detect agents that are active against bacteria in clinically relevant growth states that are difficult to screen using conventional approaches, such as small colony variants (SCV) and bacteria within established biofilms. The usefulness of the AK assay was validated by screening a library of off-patent drugs for agents that exhibit antimicrobial properties toward a variety of bacterial species, including Escherichia coli and all members of the "ESKAPE" pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). The assay detected antibiotics within the library that were expected to be active against the organism screened. Moreover, 38 drugs with no previously reported antibacterial activity elicited AK release. Four of these were acquired, and all were verified to exhibit antimicrobial activity by standard susceptibility testing. Two of these molecules were further characterized. The antihistamine, terfenadine, was active against S. aureus planktonic, SCV population, and biofilm-associated cells. Tamoxifen, an estrogen receptor antagonist, was active toward E. faecium in vitro and also reduced E. faecium pathogenesis in a Galleria mellonella infection model. Our data demonstrate that the AK assay provides an attractive screening approach for identifying new antimicrobial agents. Further, terfenadine and tamoxifen may represent novel antimicrobial drug development scaffolds. PMID- 23027197 TI - Ceftobiprole efficacy in vitro against Panton-Valentine leukocidin production and in vivo against community-associated methicillin-resistant Staphylococcus aureus osteomyelitis in rabbits. AB - Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected. In vitro sub-MIC antibiotic effects on growth and PVL production by 11 PVL(+) MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL(+) methicillin-susceptible S. aureus (MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 * 10(7) CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days. In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log(10)-CFU-count decrease. In vivo, the mean log(10) CFU/g of bone for ceftobiprole (1.44 +/- 0.40) was significantly lower than that for vancomycin (2.37 +/- 1.22) (P = 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 +/- 0.04 CFU/g of bone [P = 0.056], 11/11 sterile bones) and vancomycin (1.23 +/- 0.06 CFU/g [P = 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA MRSA osteomyelitis. PMID- 23027198 TI - Therapeutic drug monitoring of posaconazole in patients with acute myeloid leukemia or myelodysplastic syndrome. AB - Posaconazole is a broad-spectrum triazole antifungal available as an oral suspension. Pharmacokinetic data showed a high variability of plasma posaconazole concentrations (PPCs) in patients, suggesting a potential interest in drug monitoring. The aim of our prospective study was to measure the PPCs in prophylactically treated patients to evaluate the impact of different factors on these concentrations. In 40 patients treated prophylactically with posaconazole for acute myeloid leukemia or myelodysplastic syndrome between February 2009 and August 2010, PPCs were measured at day 7 of treatment and then twice weekly. Demographic data, clinical data (including gastrointestinal disorders, comedications, and treatment compliance), caloric and fat intake, and biological data were collected and evaluated. We obtained 275 measurements of PPCs, with a median of 430 ng/ml. PPCs were significantly lower in patients with mucositis (P < 0.001), nausea (P = 0.03), diarrhea (P = 0.03), or vomiting (P = 0.05). PPCs were higher in patients with a higher caloric intake (P = 0.02), while the proportion of fat intake had no influence on PPCs (P = 0.84). The concomitant use of proton pump inhibitors decreased the PPCs (P = 0.02), while the use of tacrolimus increased the PPC (P = 0.03). In the multivariate analysis, the factors influencing the PPCs independently were the concomitant use of tacrolimus (P < 0.001), the presence of mucositis (P = 0.01), and food intake (P = 0.02). Our study confirmed the high variability of posaconazole bioavailability and showed the significant influence of gastrointestinal disorders, food intake, and concomitant medication on the PPCs. However, the optimal PPCs still remain to be defined and correlated with clinical efficacy. PMID- 23027200 TI - A viscoelastic constitutive model can accurately represent entire creep indentation tests of human patella cartilage. AB - Cartilage material properties provide important insights into joint health, and cartilage material models are used in whole-joint finite element models. Although the biphasic model representing experimental creep indentation tests is commonly used to characterize cartilage, cartilage short-term response to loading is generally not characterized using the biphasic model. The purpose of this study was to determine the short-term and equilibrium material properties of human patella cartilage using a viscoelastic model representation of creep indentation tests. We performed 24 experimental creep indentation tests from 14 human patellar specimens ranging in age from 20 to 90 years (median age 61 years). We used a finite element model to reproduce the experimental tests and determined cartilage material properties from viscoelastic and biphasic representations of cartilage. The viscoelastic model consistently provided excellent representation of the short-term and equilibrium creep displacements. We determined initial elastic modulus, equilibrium elastic modulus, and equilibrium Poisson's ratio using the viscoelastic model. The viscoelastic model can represent the short-term and equilibrium response of cartilage and may easily be implemented in whole joint finite element models. PMID- 23027201 TI - Sexual function in a traumatic spinal cord injured population 10-45 years after injury. AB - OBJECTIVE: To examine sexual function at least 10 years after traumatic spinal cord injury. STUDY DESIGN: Cross-sectional questionnaire plus retrospective and prospective data from medical files. SUBJECTS: A total of 279 individuals with traumatic spinal cord injury. RESULTS: For spinal cord injured women: 94% had no problems with impaired vaginal lubrication; 22% had given birth after the injury; and 69% reported being satisfied with their sexual life. The women who were satisfied with their sexual life were younger than those who were not, and were younger at the time of injury. For spinal cord injured men: 75% could achieve erection, and they were younger than those who could not achieve erection; 35% used aid(s) for erection; 78-94% had positive reported effect of penile vibration, drugs and intracavernous injection for erection; 44% could achieve ejaculation, and they were younger than those who could not; 56% used aid(s) for ejaculation; 19% had made a woman pregnant, and a higher frequency of these men could achieve erection and ejaculation; 54% reported being satisfied with their sexual life; and significantly more men who had made a woman pregnant were satisfied with their sexual life. For both genders problems regarding bladder and bowel management, pressure ulcers, spasticity or pain correlated with lower satisfaction with sexual life. PMID- 23027199 TI - Toxicology and carcinogenesis studies of N,N-dimethyl-p-toluidine (CAS No. 99-97 8) in F344/N rats and B6C3F1/N mice (gavage studies). AB - N,N-dimethyl-p-toluidine was nominated for toxicology and carcinogenesis studies by the National Cancer Institute based on the potential for human exposure through its use in dental materials and bone cements and the lack of toxicity and carcinogenicity data. Male and female F344/N rats and B6C3F1/N mice were administered N,N-dimethyl-p-toluidine (greater than 99% pure) in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, mouse peripheral blood, and mouse and rat liver. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg N,N-dimethyl-p-toluidine/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 25 days. On day 88, blood was collected from core study rats for hemoglobin and methemoglobin analyses only. All 1,000 mg/kg male and female rats and one 500 mg/kg male rat died by study day 3. Mean body weights of all surviving dosed groups of males and females were significantly less than those of the vehicle controls. Clinical findings associated with exposure to N,N dimethyl-p-toluidine included cyanosis, abnormal breathing, and lethargy in groups administered 250 mg/kg or greater. Methemoglobinemia appeared to be the primary hematologic toxic response, and many other lesions could be explained as secondary to methemoglobin formation including Heinz body formation; a macrocytic, hypochromic, responsive anemia; and increased hematopoietic cell proliferation in the spleen and bone marrow. In general, hematologic changes were dose-related and occurred at both evaluated timepoints in all dosed groups. Anemia was evidenced by decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts; erythrocyte macrocytosis was characterized by increases in mean cell volume and mean cell hemoglobin values; erythrocyte hypochromia was evidenced by decreases in mean cell hemoglobin concentration values; and an erythropoietic response to the anemia was characterized by substantially increased reticulocyte and nucleated erythrocyte counts. Liver weights of all surviving dosed groups of males and females were significantly greater than those of the vehicle controls. Kidney weights of all surviving dosed groups of females were significantly greater than those of the vehicle controls. There were significant decreases in left cauda epididymis and left epididymis weights in 250 mg/kg males. There was a dose-related decrease in the number of cycling females, with only four females in the 250 mg/kg group having regular cycles and females in the 125 and 250 mg/kg groups spending a significantly higher proportion of time in extended diestrus compared to the vehicle control group. In the surviving groups of rats, there were significantly increased incidences of pigmentation in the liver of all dosed groups, hepatocyte hypertrophy in groups administered 125 mg/kg or greater, and hepatocyte necrosis in 62.5, 250, and 500 mg/kg females. In the olfactory epithelium of the nose, there were dose-related increases in the incidences and severities of degeneration in all dosed groups and significantly increased incidences of metaplasia in the 250 and 500 mg/kg groups. In the respiratory epithelium of the nose, there were significantly increased incidences of hyperplasia and squamous metaplasia in all of the groups administered 125 mg/kg or greater. The incidences of glandular hyperplasia of the nose were significantly increased in males and females administered 125, 250, or 500 mg/kg. In the spleen, there were significantly increased incidences of capsule fibrosis, congestion, mesothelial hypertrophy, and lymphoid follicle atrophy primarily in groups administered 125 mg/kg or greater. Hematopoietic cell proliferation and pigmentation were increased in severity in treated groups. In the kidney, there were significantly increased incidences of nephropathy (females), pigmentation (males and females), papillary necrosis (males and females), and mineralization (males). Other treatment-related lesions included inflammation of the forestomach in males, mesenteric lymph node atrophy in females, and bone marrow hyperplasia in males and females. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 15, 30, 60, 125, or 250 mg N,N-dimethyl-p-toluidine/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All 250 mg/kg male and female mice (except for one male mouse) died before day 10, and three males and two females administered 125 mg/kg died before the end of the study. The final mean body weight of 125 mg/kg males and the mean body weight gains of 125 mg/kg males and females were significantly less than those of the vehicle controls. Clinical findings associated with administration of N,N-dimethyl-p toluidine included abnormal breathing, thinness, lethargy, cyanosis, and ruffled fur in 125 and 250 mg/kg males and females. Methemoglobinemia appeared to be the primary hematologic toxic response; however there were less severe erythron changes compared to the 3-month study in rats. In females, no erythron changes were detected up to 125 mg/kg. In males, inconsistent and minor decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts, and increased reticulocyte counts occurred in groups administered 60 mg/kg or greater. Methemoglobin values were minimally increased in males and females administered 30 mg/kg or greater. Heinz bodies were slightly increased in 60 mg/kg females, 125 mg/kg males and females, and the one surviving 250 mg/kg male; Heinz body formation was considered secondary to methemoglobin formation. Liver weights of all dosed groups of mice were significantly greater than those of the vehicle controls. In the surviving groups of mice, there were significantly increased incidences of bronchiolar epithelium degeneration, bronchiolar epithelium regeneration, and peribronchiolar chronic active inflammation in the lung of 125 mg/kg groups, and histiocytic infiltrates of the alveoli in 125 mg/kg females. In the nose, there were significantly increased incidences of glandular hyperplasia and olfactory epithelium metaplasia in the 125 mg/kg groups and olfactory epithelium degeneration in 60 mg/kg females and 125 mg/kg males and females. In the thymus, the incidences of thymocyte necrosis in the 125 mg/kg groups were significantly increased. In the liver, the severities of cytoplasmic vacuolization of the hepatocytes were increased in dosed groups of males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 6, 20, or 60 mg N,N-dimethyl-p-toluidine/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses for 86 days. Survival of 60 mg/kg males was significantly less than that of the vehicle controls. Mean body weights of 60 mg/kg males and females were more than 10% less than those of the vehicle controls after week 61 and week 33, respectively. Clinical findings included signs of pallor in 60 mg/kg females and hyperactivity and boxing behavior in 20 mg/kg females and 60 mg/kg males and females. The hematology findings at the 3-month timepoint were consistent with those in the 3-month study in rats which indicated that methemoglobinemia was the primary hematologic toxic response. In the 20 and 60 mg/kg groups, there were dose-related decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts. There were similar trends toward erythrocyte macrocytosis and hypochromia and increased erythropoiesis as seen in the 3-month study. While the magnitudes of the erythron decreases were not sufficient to classify the responses as anemias, the patterns of the erythron changes were identical to those in the 3-month study. In the liver of 60 mg/kg males and females, there were significantly increased incidences of hepatocellular carcinoma and hepatocellular adenoma or hepatocellular carcinoma (combined). Numerous nonneoplastic liver lesions occurred in dosed males and females primarily in the 20 and 60 mg/kg groups. In the nose, there were significantly increased incidences of transitional epithelium adenoma and transitional epithelium adenoma or carcinoma (combined) in 60 mg/kg males; transitional epithelium adenoma also occurred in female rats administered 6 or 60 mg/kg. In the nose, there were significantly increased incidences of nonneoplastic lesions in the olfactory, respiratory, and transitional epithelia of dosed rats. These lesions occurred with the greatest incidence and severity in the 60 mg/kg groups. The incidences of inflammation and nerve atrophy were significantly increased in males and females administered 60 mg/kg. There were increased incidences of follicular cell adenoma or carcinoma (combined) of the thyroid gland in all dosed groups of males, and an increased incidence of follicular cell adenoma in 20 mg/kg females. In the spleen, there were significantly increased incidences of hematopoietic cell proliferation in all dosed groups of males and females. The incidences of congestion and mesothelial hypertrophy of the capsule were significantly increased in 60 mg/kg males and all dosed groups of females. There were also significantly increased incidences of capsular fibrosis and atrophy of the lymphoid follicle in the 60 mg/kg groups. The incidences of pigmentation were significantly increased in all dosed groups of males and in 60 mg/kg females. In all dosed groups of female rats, there were significantly increased incidences of nephropathy. (ABSTRACT TRUNCATED) PMID- 23027202 TI - Mitochondrial DNA damage and its effect on mitochondrial function in rats with obstructive jaundice. AB - This study investigated mitochondrial DNA (mtDNA) damage in rats with obstructive jaundice (OJ) and to explore its effect on mitochondrial and hepatic function. Forty-eight male Wistar rats were randomly divided into two groups: sham-operated (Sham) and bile duct ligation (BDL). Blood and tissue samples were collected from the two groups on days 1, 4, 7 and 14 following surgery. Hepatic and mitochondrial function were measured. Long and accurate PCR, restriction enzyme digestion and gene sequencing were used to analyze the locations of mtDNA deletions. In addition, quantitative fluorescent PCR was used to measure the relative amounts of total DNA in hepatocytes and mtDNA deletions. Results showed that the hepatic and mitochondrial function was compromised in the BDL group compared to the Sham group. Notably, a novel 11,194-bp mtDNA deletion (nucleotide positions 4101-15294) and fewer mtDNA copies were found compared to the Sham group. With prolonged ligation time, there was a decrease in the copy number, while the ratio of mtDNA deletions to total mtDNA levels increased in the BDL group. These changes were consistent with damage to hepatic and mitochondrial function. A novel 11,194-bp mtDNA deletion and fewer mtDNA copies were detected in hepatocytes of rats with OJ. The mtDNA deletions may therefore be an important factor leading to mitochondrial and hepatic dysfunction. PMID- 23027203 TI - (89)Sr imaging with bremsstrahlung in patients with metastatic breast cancer. AB - PURPOSE: In this study, we investigated the clinical and laboratory factors that may enhance (89)Sr uptake to strengthen its tumoricidal effect. METHODS: We enrolled 21 patients with multiple bone metastases (n = 23) from breast cancer and classified them into 2 groups according to their zoledronic acid (ZOL) treatment history. (89)Sr imaging with bremsstrahlung was performed 2 to 6 weeks after administration and (89)Sr index was measured using combined imaging with bone scintigraphy. We compared the Sr index with the levels of alkaline phosphatase, bone-specific alkaline phosphatase, serum cross-linked N telopeptides, carboxy-terminal telopeptide of type 1 collagen, C-reactive protein, calcium, and hemoglobin on administration and evaluated the differences among the groups. RESULTS: The (89)Sr index ranged from 0.01 to 2.0 and was significantly correlated with C-reactive protein and alkaline phosphatase and moderately correlated with carboxy-terminal telopeptide of type 1 collagen, serum cross-linked N-telopeptides, and bone-specific alkaline phosphatase. The (89)Sr index was not significantly correlated with calcium or hemoglobin. The group with less than 1 year of ZOL treatment demonstrated a mean (SD) (89)Sr index of 1.11 (0.59), and the group with 1 or more years of ZOL treatment showed a mean (89)Sr index of 0.36 (0.26). The Wilcoxon signed-rank test demonstrated a significant difference between the 2 groups (P < 0.001). CONCLUSIONS: (89)Sr accumulation seemed to be associated with bone turnover, in particular bone resorption, and vascularization due to inflammation or tumor growth. Long-term ZOL treatment may reduce bone resorption and vascularization. To enhance the tumoricidal effect and palliation of bone pain by (89)Sr, combined therapy must be established. PMID- 23027204 TI - Pulmonary carcinosarcoma: 18F-FDG PET/CT imaging. AB - We present a case of pulmonary carcinosarcoma. The patient is a 31-year-old man with a history of infectious mononucleosis in whom a right lung mass was found. His age is lower than the mean age at which pulmonary carcinosarcoma is usually reported. Chest CT scan showed a lobulated 29-mm mass in the right upper lung and multiple hypervascular liver nodules. FDG PET/CT showed increased FDG uptake in the right upper lung nodule (SUVmax, 4.1). However, the hepatic radiouptake showed only background activity. The liver nodules were stable at the 1-year follow-up period and were suggestive of hemangiomas. PMID- 23027205 TI - Three-dimensional lymphoscintigraphy using SPECT/CT and 123I-BMIPP for the preoperative detection of anatomical anomalies of the thoracic duct. AB - PURPOSE: Orally administered I-labeled 15-(4-iodophenyl)-3(R,S) methylpentadecanoic acid (BMIPP), a fatty acid analog, is absorbed from the intestine and ascends to the venous angle through the thoracic duct (TD). The objective of this study was to evaluate the clinical feasibility of 3-dimensional (3D) TD scintigraphy using SPECT/CT and BMIPP for the detection of anatomical anomalies of TD. PATIENTS AND METHODS: This study included 35 consecutive patients with esophageal cancer who underwent tumor resection after TD scintigraphy. For scintigraphy, 111 MBq of BMIPP was orally administered, and static images and SPECT/CT images were obtained. On the basis of the SPECT/CT fusion images, TD was divided into the following 4 segments: cervical, upper thoracic, middle thoracic, and lower thoracic. The TD visualization was categorized into 5 grades, from grade 1 (poor) to 5 (excellent). In addition, the diagnostic accuracy of 3D TD scintigraphy for the detection of anatomical anomalies of TD was calculated using the intraoperative finding as a criterion standard. RESULTS: The TD visualization grades for the cervical, upper, middle, and lower thoracic segments were 4.4 +/- 0.6, 3.7 +/- 1.0, 3.1 +/- 0.8, and 2.1 +/- 0.9, respectively. The TD scintigraphy demonstrated an uncommon accumulation including that in the right- or bilateral-sided mediastinum or venous angle in 6 (17%) of the 35 patients. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of 3D TD scintigraphy for the detection of anatomical anomalies of TD were 0.75, 0.90, 0.5, 0.97, and 0.89, respectively. CONCLUSIONS: Three-dimensional TD scintigraphy by BMIPP is a simple and minimally invasive method for imaging the anatomical configuration of the TD and for detecting any anatomical anomalies, except in the lower thoracic segment. PMID- 23027206 TI - Iatrogenic chyloma in the neck: lymphoscintigraphic findings. AB - Iatrogenic chyle leak with chyloma formation in the neck is a rare complication of neck dissection resulting from injury to the thoracic duct. We present the case of a 37-year-old woman who complained of left-sided neck swelling within days after total thyroidectomy and lateral neck dissection for papillary thyroid cancer. Lymphoscintigraphy demonstrated the chyle leak in the left cervical region, and subsequent aspiration of the left neck swelling showed radioactivity in the aspirate. After successful operative repair of the thoracic duct, the patient was able to undergo radioactive ablative thyroid treatment. PMID- 23027208 TI - Quantitative myocardial perfusion-SPECT: algorithm-specific influence of reorientation on calculation of summed stress score. AB - PURPOSE: Myocardial perfusion SPECT (MPS) with software-assisted determination of summed stress score (SSS) is of established importance for diagnosis/therapy planning in coronary artery disease. Differences in contour finding suggest algorithm-specific influence on quantification if heart axes are chosen incorrectly. Thus, this study quantified the influence of heart-axis tilt on SSS calculation using Quantitative Perfusion SPECT and 4D-MSPECT. PATIENTS AND METHODS: Stress MPS of 50 men acquired on a triple-head gamma camera were correctly reoriented by experienced technologists (R0) and then tilted by 5 degrees/10 degrees/15 degrees/20 degrees/30 degrees/45 degrees along both long axes (R5-R45). SPECT images were quantified for SSS using QPS and 4D-MSPECT. SSS values for R0 and R5-R45 were analyzed using correlation analysis. Weighted kappa values (kappa) were calculated to measure agreement regarding perfusion abnormality severity (4-step SSS rating: 0-3, 4-8, 9-13, and >=14). RESULTS: For QPS SSS correlation, R0 vs. tilted datasets remained very high (R > 0.97) up to 20 degrees, but degraded for higher tilts (R = 0.895/0.780 for 30 degrees/45 degrees). 4D-MSPECT showed comparable SSS correlation only up to 10 degrees (R > 0.95) and strong deterioration thereafter (R = 0.863-0.347 for 15-45 degrees). Deviation in severity class from R0 increased from 6/50 (R5; kappa = 0.914) to 25/50 (R45; kappa = 0.252) using QPS and from 7/50 (R5; kappa = 0.899) to 33/50 (R45; kappa = 0.065) using 4D-MSPECT. CONCLUSION: For tilted MPS datasets, considerable differences in SSS calculation emerge using QPS and 4D-MSPECT. QPS showed more stable results than 4D-MSPECT. PMID- 23027207 TI - Tumor lesion glycolysis and tumor lesion proliferation for response prediction and prognostic differentiation in patients with advanced non-small cell lung cancer treated with erlotinib. AB - PURPOSE: The aim was to assess the value of tumor lesion glycolysis (TLG) and tumor lesion proliferation (TLP) determined by FDG and 3'-deoxy-3'-F fluorothymidine (FLT) PET for response prediction and prognostic differentiation in patients with advanced non-small cell lung cancer (NSCLC) treated with erlotinib. PATIENTS AND METHODS: FDG-PET and FLT-PET were performed in 30 patients with untreated Stage IV NSCLC before start of therapy, 1 (early) and 6 (late) weeks after erlotinib treatment. Functional tumor volume parameters including TLG in FDG-PET and TLP in FLT-PET were measured in the sum of up to 5 lesions per scan. Metabolic response was assessed using different cutoff values for percentage changes of TLG and TLP. Absolute baseline and residual levels of TLG and TLP were used for dichotomizing the patients into 2 groups. Kaplan-Meier analysis and the log-rank test were performed to analyze the association with progression-free survival (PFS). RESULTS: Patients with a metabolic response measured by early changes of TLP and late changes of TLG and TLP showed a significantly better PFS than metabolically nonresponding patients. A lower cutoff value of 20% or 30% for definition of metabolic response showed better differentiation between metabolically responding and nonresponding patients in cases where the 45% cutoff value revealed no significant results. Furthermore, patients with lower absolute early and late residual TLG and TLP levels had a significantly prolonged PFS. In contrast, absolute baseline TLG and TLP levels showed no significant association with PFS. CONCLUSIONS: In patients with advanced NSCLC, percentage changes of TLG and TLP and absolute residual TLG and TLP levels under erlotinib treatment emerged as strong predictive factors for PFS. Our findings indicate that a cutoff value of 20% or 30% for definition of metabolic response measured by percentage changes of TLG and TLP provides suitable results for response prediction, which should be further validated. PMID- 23027212 TI - Scar revision in the 21st century. PMID- 23027213 TI - Principles to minimize scars. AB - Principles to minimize scars include attention to a multitude of intrinsic and extrinsic patient factors preoperatively, operatively, and postoperatively. Preoperatively the goal is to maximize the treatment of patient specific comorbidities and limit the usage of medications that can have negative effects on healing. Operatively, the focus is on proper incisional planning, meticulous surgical technique and hemostasis, judicious use of prophylactic antibiotics, and focus on tensionless closures. Postoperatively, we must maximize the healing environment by keeping the wound well hydrated and closely monitoring and intervening early in high-risk wounds. We also have the responsibility to provide evidence-based recommendations, to the best of our ability, regarding the myriad of over-the-counter products. The field of scar prevention is ever changing and the new frontier focuses on controlling the microenvironment of wounds and altering signaling molecules to promote near scarless healing. PMID- 23027214 TI - Scar revision techniques-pearls and pitfalls. AB - Although scars are a normal part of the healing process, facial scars have significant implications on a patient's well-being, both physically and psychologically. Facial scars are one of the most common reasons a patient presents to the facial plastic and reconstructive surgeon. The ability to evaluate facial scars and choose the most appropriate technique for revision is of paramount importance to obtain the best result. A thorough understanding of superficial facial anatomy and principles of wound healing is equally as important as meticulous technical execution. Above all, the expectations of the patient must be assessed and considered when formulating a surgical plan. PMID- 23027215 TI - Revising large scars. AB - Large scars in the head and neck are often the cause of significant emotional distress to patients, and often present unique challenges to the plastic and reconstructive surgeon undertaking their revision. The primary goal of scar revision is to eliminate compromise of function that may have resulted from scar contracture; a secondary goal is to improve the appearance of the scar. Special techniques for the revision of large scars include serial partial excision, rapid intraoperative or prolonged tissue expansion, split- and full-thickness skin grafting, regional flaps, and free microvascular tissue transfer. Recent research has investigated the use of artificial skin and autologous fat grafting for large scar revision. PMID- 23027216 TI - Scars after second intention healing. AB - Second intention healing (SIH) is useful for many defects after skin cancer removal. SIH decreases intraoperative morbidity and reduces procedure costs. Granulating wounds are rarely infected, have minimal pain or bleeding, and care is simple. Location is the key determinant in cosmetic outcomes of SIH. Concavities of the face including the medial canthus and conchal bowl often heal imperceptibly. Defects on convex surfaces such as the nasal tip and malar cheek can heal poorly with depressed scars. Flat areas of the cheeks, forehead, and chin heal favorably but cosmesis can be unpredictable. These regions are often described by NEET (concavities of the nose, eyes, ears, and temple), NOCH (convexities of nose, oral lips, cheek, chin, and helix), and FAIR (flat areas of the forehead, antihelix of the ear, eyelids, and rest of the nose, lips, and cheeks). We review the limited literature describing SIH based on regional anatomy of the face. Complications of SIH include exuberant granulation tissue, hypopigmented or telangiectatic scars, and distortion of free lid margins. SIH should be an integral part of the surgeon's reconstructive algorithm after skin cancer removal. PMID- 23027217 TI - Current concepts in the etiology and treatment of keloids. AB - Keloids are benign, fibroproliferative growths that occur as a result of dermal injury in ~15% of the population. They are characterized by their extension beyond the confines of the original injury and often present with pain and pruritus. Additionally, these growths may result in cosmetic deformities and contribute to significant emotional distress. It is thought that keloids form as a result of aberrancies in the normal wound-healing process, which is complex and involves an elegant interplay between multiple cell types, cytokines, and proteins. The exact etiology is unknown, but significant research efforts have been made. These efforts have revealed that various cell types in keloids are either hyperresponsive and/or overproductive of various growth factors. Additionally, keloid cell types respond differently to mechanical strain than skin cells in patients who do not form keloids. This lack of understanding of keloid pathophysiology has left the care provider with a lack of a single definitive treatment strategy. Instead, a multitude of therapies exist ranging from surgery to injectables to lasers and any combination thereof. This purpose of this article is to highlight our current knowledge and emerging scientific understanding of keloid pathology and the current management strategies. PMID- 23027218 TI - Utilizing topical therapies and mitomycin to reduce scars. AB - Minimizing scar size, width, and contour of elevation is a common goal for the facial plastic surgeon. Various standard techniques are employed to reduce tension and enhance the rapid and uneventful healing of incisions. In some cases, these routine measures are not judged to be adequate, and additional intraoperative and postsurgical measures are employed to control the body's innate healing processes. Mitomycin C and self-drying silicone gel have been particularity useful in our practice. PMID- 23027219 TI - Laser treatment of scars. AB - Recent advances in optical technologies have produced laser systems capable of optimizing the appearance of scars from various etiologies. Laser treatment can commence as early as the time of the initial injury and as late as several years after the injury. Optimal results can now be attained with minimal down time. Herein, we review several available optical technologies for treatment of surgical, traumatic, and inflammatory scars, based upon our clinical experience. PMID- 23027220 TI - Botulinum toxin to minimize facial scarring. AB - Chemoimmobilization with botulinum toxin A is an ideal biochemical agent that allows near-total elimination of muscle pull on the healing facial wound. The goal of chemoimmobilization of facial cutaneous wounds is to eliminate dynamic tension on the healing tissues to improve wound healing and minimize scarring for optimal aesthetic results. PMID- 23027221 TI - Medical makeup for concealing facial scars. AB - Surgical, laser, and pharmacological therapies are all used to correct scars and surgical incisions, though have limits with respect to how well facial skin can be restored or enhanced. The use of cosmetics has long been a relevant adjunct to all scar treatment modalities. In recent years, technical advancements in the chemistry and composition of cosmetic products have provided the patient with a broader range of products to employ for concealing scars. This review will provide an overview of contemporary methods for concealing facial scars, birthmarks, and pigmentary changes without the use of traditional/dated, heavy appearing camouflage products. Additionally, general guidelines and information will be provided with respect to identifying competent makeup artists for care of the medical patient. The article by no means is meant to be a tutorial, but rather serves as a starting point in this allied field of medicine. PMID- 23027222 TI - The cross-running intradermal suture: a novel method for incision closure. PMID- 23027224 TI - Image-guided transcranial Doppler sonography for monitoring of defined segments of intracranial arteries. AB - BACKGROUND: Transcranial Doppler sonography (TCD) is widely used in neurointensive care. Image guidance (IG) could simplify secure vessel identification and reduce interinvestigator and intrainvestigator variability. The present study was purposed to investigate the precision and reproducibility of image-guided TCD. METHODS: The Kolibri IG system (Brainlab AG, Feldkirchen, Germany) was used to track a hand-held Doppler probe of a DWL Multi-Dop(r) T digital device (Compumedics Germany GmbH, Singen, Germany). The patient's head was registered noninvasively to the IG system. Distance between predefined vascular target and optimal Doppler signal was evaluated to assess spatial accuracy of image-guided TCD. To investigate reproducibility, spatial accuracy of trajectories acquired during an initial examination using the IG system was analyzed in serial examinations. Furthermore, stability of noninvasive registration of the patient's head to the IG system was analyzed. Data are presented as mean+/-SD for descriptive statistics. Twelve patients were included. RESULTS: Using IG, a Doppler signal was recorded immediately in all cases for middle cerebral artery (MCA) (29 examinations), in 81% for carotid-T (27 examinations), and in 90% for basilar tip (29 examinations). The optimal Doppler signal was found within 2.64+/-1.15 mm (94 preplanned targets). At serial examinations, a spatial deviation of 2.75+/-1.20 mm was found (56 trajectories acquired in 19 serial examinations). Examination time did not influence accuracy of noninvasive patient registration. CONCLUSIONS: Data suggest that image-guided TCD allows for accurate examinations with high intraprocedural and high interprocedural reproducibility. It facilitates identification of specific vessel segments and generation of standardized examination protocols for serial examinations. PMID- 23027225 TI - A combination of sevoflurane postconditioning and albumin increases Bcl-2 expression after transient global cerebral ischemia compared with either sevoflurane postconditioning or albumin alone. AB - BACKGROUND: The aim of this study was to determine whether a combination of sevoflurane postconditioning and albumin provides additive neuroprotective effects after transient global cerebral ischemia in rats. METHODS: Forty-three rats were assigned to 4 groups: the control group (group C; n=13; 3 died) received no treatment. The albumin group (group A; n=10) received 2 g/kg of albumin for 5 minutes after ischemia. The sevoflurane postconditioning group (group P; n=10) underwent 2 sevoflurane inhalations after ischemia. Each inhalation consisted of 5 minutes of 2.5% sevoflurane and a subsequent washout time of 5 minutes. The sevoflurane postconditioning plus albumin group (group PA; n=10) received additional albumin during sevoflurane postconditioning after ischemia. In all groups, ischemia was induced by a bilateral common carotid artery occlusion along with hemorrhagic hypotension and was maintained for 10 minutes. Histologic and neurobehavioral outcomes were measured 7 days after ischemia in CA1 pyramidal cells of the rat hippocampus. RESULTS: Groups A, P, and PA showed an improved neurological outcome and contained more viable cells in the hippocampal CA1 area compared with group C (P<0.05). The number of apoptotic cells was significantly reduced in group PA compared with group C (P<0.01). There was a significant difference in the Bcl-2, an antiapoptotic protein, expression between group C and other groups (P<0.01) and between group A or P and group PA (P<0.05). CONCLUSIONS: A combination of sevoflurane postconditioning and albumin increased the level of Bcl-2 expression compared with sevoflurane postconditioning or albumin alone, suggesting their combination might provide additional neuroprotection by decreasing apoptosis. PMID- 23027226 TI - BIS-guided anesthesia decreases postoperative delirium and cognitive decline. AB - BACKGROUND: Previous clinical trials and animal experiments have suggested that long-lasting neurotoxicity of general anesthetics may lead to postoperative cognitive dysfunction (POCD). Brain function monitoring such as the bispectral index (BIS) facilitates anesthetic titration and has been shown to reduce anesthetic exposure. In a randomized controlled trial, we tested the effect of BIS monitoring on POCD in 921 elderly patients undergoing major noncardiac surgery. METHODS: Patients were randomly assigned to receive either BIS-guided anesthesia or routine care. The BIS group had anesthesia adjusted to maintain a BIS value between 40 and 60 during maintenance of anesthesia. Routine care group had BIS measured but not revealed to attending anesthesiologists. Anesthesia was adjusted according to traditional clinical signs and hemodynamic parameters. A neuropsychology battery of tests was administered before and at 1 week and 3 months after surgery. Results were compared with matched control patients who did not have surgery during the same period. Delirium was measured using the confusion assessment method criteria. RESULTS: The median (interquartile range) BIS values during the maintenance period of anesthesia were significantly lower in the control group, 36 (31 to 49), compared with the BIS-guided group, 53 (48 to 57), P<0.001. BIS-guided anesthesia reduced propofol delivery by 21% and that for volatile anesthetics by 30%. There were fewer patients with delirium in the BIS group compared with routine care (15.6% vs. 24.1%, P=0.01). Although cognitive performance was similar between groups at 1 week after surgery, patients in the BIS group had a lower rate of POCD at 3 months compared with routine care (10.2% vs. 14.7%; adjusted odds ratio 0.67; 95% confidence interval, 0.32-0.98; P=0.025). CONCLUSIONS: BIS-guided anesthesia reduced anesthetic exposure and decreased the risk of POCD at 3 months after surgery. For every 1000 elderly patients undergoing major surgery, anesthetic delivery titrated to a range of BIS between 40 and 60 would prevent 23 patients from POCD and 83 patients from delirium. PMID- 23027227 TI - Reversible shortness of breath caused by the antiplatelet agent, clopidogrel. PMID- 23027228 TI - Mindfulness, movement control, and attentional focus strategies: effects of mindfulness on a postural balance task. AB - We examined whether the momentary induction of state mindfulness benefited subsequent balance performance, taking into consideration the effects of dispositional mindfulness. We also tested whether our mindfulness induction, grounded in sustaining moment-to-moment attention, influenced the attentional focus strategies that were adopted by the participants during the balancing task. Balance performance was ascertained based on approximate entropy (ApEn) of the center of pressure (COP) data. The study involved 32 males (age: M = 22.8, SD = 1.94) who were randomly assigned to the mindfulness or control group. Using difference in pretest to posttest performance based on the medio-lateral movements as the dependent variable, the test for interaction showed that the mindfulness induction was more effective for participants with higher dispositional mindfulness. Participants who underwent mindfulness induction also reported greater use of external focus strategies than those in the control group. Results suggest that momentary mindful attention could benefit balance performance and affect the use of attentional focus strategies during movement control. PMID- 23027229 TI - Anxiety, ego depletion, and sports performance. AB - In the present article, we analyzed the role of self-control strength and state anxiety in sports performance. We tested the hypothesis that self-control strength and state anxiety interact in predicting sports performance on the basis of two studies, each using a different sports task (Study 1: performance in a basketball free throw task, N = 64; Study 2: performance in a dart task, N = 79). The patterns of results were as expected in both studies: Participants with depleted self-control strength performed worse in the specific tasks as their anxiety increased, whereas there was no significant relation for participants with fully available self-control strength. Furthermore, different degrees of available self-control strength did not predict performance in participants who were low in state anxiety, but did in participants who were high in state anxiety. Thus increasing self-control strength could reduce the negative anxiety effects in sports and improve athletes' performance under pressure. PMID- 23027230 TI - Train in vain: the role of the self in claimed self-handicapping strategies. AB - Two field studies investigate the role of self in the tendency of athletes to engage in claimed handicapping strategies during training (anticipatively claiming that handicaps may interfere with their performance). Study 1 tested the relationship between trait self-esteem and athletes' engagement in claimed self handicapping. As hypothesized, low physical self-esteem athletes claimed more handicaps than high physical self-esteem athletes. For stronger evidence for the causal role of the self, Study 2 tested whether securing athletes' self-worth through self-affirmation would lead to decreased claimed self-handicapping by using a mixed model design that allows for both between-subjects (affirmation vs. control condition) and within-subject comparisons (before vs. after self affirmation intervention). Self-affirmed athletes had decreased levels of claimed self-handicapping. Studies 1 and 2 also demonstrate that athletes engage in claimed self-handicapping during training, which could have deleterious effects on subsequent performance. Discussion centers on theoretical implications and applications for coaches, sport teachers, and sport psychologists. PMID- 23027231 TI - Further validation and development of the movement imagery questionnaire. AB - This research validated and extended the Movement Imagery Questionnaire- Revised (MIQ-R; Hall & Martin, 1997). Study 1 (N = 400) examined the MIQ-R's factor structure via multitrait-multimethod confirmatory factor analysis. The questionnaire was then modified in Study 2 (N = 370) to separately assess the ease of imaging external visual imagery and internal visual imagery, as well as kinesthetic imagery (termed the Movement Imagery Questionnaire-3; MIQ-3). Both Studies 1 and 2 found that a correlated-traits correlated-uniqueness model provided the best fit to the data, while displaying gender invariance and no significant differences in latent mean scores across gender. Study 3 (N = 97) demonstrated the MIQ-3's predictive validity revealing the relationships between imagery ability and observational learning use. Findings highlight the method effects that occur by assessing each type of imagery ability using the same four movements and demonstrate that better imagers report greater use of observational learning. PMID- 23027233 TI - Transcontextual development of motivation in sport injury prevention among elite athletes. AB - The present study investigated the transcontextual process of motivation in sport injury prevention. We examined whether general causality orientation, perceived autonomy support from coaches (PAS), self-determined motivation (SD-Mtv), and basic need satisfaction in a sport context predicted SD-Mtv, beliefs, and adherence with respect to sport injury prevention. Elite athletes (N = 533) completed self-report measures of the predictors (Week 1) and the dependent variables (Week 2). Variance-based structural equation modeling supported hypotheses: SD-Mtv in a sport context was significantly predicted by PAS and basic need satisfaction and was positively associated with SD-Mtv for sport injury prevention when controlling for general causality orientation. SD-Mtv for sport injury prevention was a significant predictor of adherence to injury preventive behaviors and beliefs regarding safety in sport. In conclusion, the transcontextual mechanism of motivation may explain the process by which distal motivational factors in sport direct the formation of proximal motivation, beliefs, and behaviors of sport injury prevention. PMID- 23027232 TI - Exercise identity and attribution properties predict negative self-conscious emotions for exercise relapse. AB - Research on exercise identity (EXID) indicates that it is related to negative affect when exercisers are inconsistent or relapse. Although identity theory suggests that causal attributions about this inconsistency elicit negative self conscious emotions of shame and guilt, no EXID studies have examined this for exercise relapse. Weiner's attribution-based theory of interpersonal motivation (2010) offers a means of testing the attribution-emotion link. Using both frameworks, we examined whether EXID and attributional properties predicted negative emotions for exercise relapse. Participants (n = 224) read an exercise relapse vignette, and then completed EXID, attributions, and emotion measures. Hierarchical multiple regression models using EXID and the attributional property of controllability significantly predicted each of shame and guilt, R2 adjusted = .09, ps <= .001. Results support identity theory suggestions and Weiner's specific attribution-emotion hypothesis. This first demonstration of an interlinking of EXID, controllability, and negative self-conscious emotions offers more predictive utility using complementary theories than either theory alone. PMID- 23027234 TI - Circular common-path point diffraction interferometer. AB - A simple and compact point-diffraction interferometer with circular common-path geometry configuration is developed. The interferometer is constructed by a beam splitter, two reflection mirrors, and a telescope system composed by two lenses. The signal and reference waves travel along the same path. Furthermore, an opaque mask containing a reference pinhole and a test object holder or test window is positioned in the common focal plane of the telescope system. The object wave is divided into two beams that take opposite paths along the interferometer. The reference wave is filtered by the reference pinhole, while the signal wave is transmitted through the object holder. The reference and signal waves are combined again in the beam-splitter and their interference is imaged in the CCD. The new design is compact, vibration insensitive, and suitable for the measurement of moving objects or dynamic processes. PMID- 23027235 TI - Discrete solitons in arrays of positive and negative index waveguides. AB - We report on existence and properties of discrete solitons in arrays of alternating waveguides with positive and negative refractive indices. When the nonlinearities of all waveguides are focusing, we found solitons only in the semi infinite gaps. Finite gap solitons found for waveguides having nonlinearities of different types reveal the symmetry breaking in the Fourier space. It is found that there exist more than one soliton families bifurcating from the gap edges of the linear spectrum. The field distribution in such multichannel couplers reveals nonexponential decay and nonmonotonic dependence of the energy growth in the positive index waveguides on the strength of losses in the negative index waveguides. PMID- 23027236 TI - Control of nonlinear spectral phase induced by ultra-broadband optical parametric amplification. AB - Optical parametric amplifiers (OPAs) impose an optical parametric phase (OPP) onto the amplified signal. It manifests itself as a spectral phase in the case of broadband signals and, therefore, hampers pulse compression. Here we present, for the first time, a complete experimental characterization of this OPP for different ultra-broadband noncollinear OPA configurations. This measurement allows us to compensate the OPP and to achieve Fourier-limited pulses as short as 1.9 optical cycles. A numerical model is in excellent agreement with our measurements and reveals the importance of high order phase compensation in the case of noncollinear phase matching. In contrast, operation at degeneracy enables almost complete compensation of the OPP by second-order dispersion only. PMID- 23027238 TI - Continuously variable long microwave-photonic delay of arbitrary frequency chirped signals. AB - A generic method for the continuously variable, long microwave-photonic delay of the impulse response of arbitrarily chirped waveforms is proposed and demonstrated. Nonlinear-frequency-modulated waveforms of 500 MHz bandwidth are delayed by tens of nanoseconds. The principle relies on the specific phase-time relations of the waveforms, and is applicable to chirped pulses of arbitrary durations, central radio frequencies, and bandwidths. The approach is suitable for beam steering in large phased-array antennas. PMID- 23027237 TI - Distributed birefringence measurement with beat period detection of homodyne Brillouin optical time-domain reflectometry. AB - We report a distributed optical fiber birefringence measurement method based on homodyne Brillouin optical time-domain reflectometry (BOTDR). Unlike conventional BOTDR, which requires scanning of the local oscillator to get the Brillouin spectrum, instead we propose the beat period measurement of fast and slow components of the backscattered Brillouin signal in single-mode fibers using homodyne detection. The beat period is measured by detecting the envelope of the Brillouin beat signal, which gives the beat length at different fiber locations, so that birefringence can be calculated accordingly. The distributed birefringence of a 1.7 km SMF-28 and a 4.3 km large-effective-area fiber were measured with 0.6 m spatial resolution without frequency scanning of the Brillouin spectrum. PMID- 23027239 TI - Demonstration of reconfigurable electro-optical logic with silicon photonic integrated circuits. AB - We demonstrate a scalable and reconfigurable optical directed-logic architecture consisting of a regular array of integrated optical switches based on microring resonators. The switches are controlled by electrical input logic signals through embedded p-i-n junctions. The circuit can be reconfigured to perform any combinational logic operation by thermally tuning the operation modes of the switches. Here we show experimentally a directed logic circuit based on a 2*2 array of switches. The circuit is reconfigured to perform arbitrary two-input logic functions. PMID- 23027240 TI - Cylindrical interferometric out-of-focus imaging for the analysis of droplets in a volume. AB - We propose an original cylindrical interferometric out-of-focus imaging setup to realize the characterization of spherical droplets in a volume. The longitudinal position of the droplets is determined through the orientation of the fringes while the diameter of the droplets is obtained from the frequency of the fringes. The experiments agree with the simulations. PMID- 23027241 TI - Optical limiting as result a of photoinduced electron transfer in hybrid systems with CdSe/ZnS quantum dots, C60, and Perylene. AB - We investigated the interaction of an intense laser radiation with colloidal solutions containing CdSe/ZnS core shell quantum dots (QDs; mean size 3.4 nm), fullerene C(60), and Perylene. These materials would give rise to the photoinduced electron transfer and charge separation on the QDs and thus the optical limiting effect. Results confirm the intended aim, obtained by means of intermediate metastable products of reversible photochemical reactions, i.e., ion radicals of hybrid systems containing semiconductor nanoparticles. PMID- 23027242 TI - Innovative method to investigate how the spatial correlation of the pump beam affects the purity of polarization entangled states. AB - We present an innovative method to address the relation between the purity of type-I polarization entangled states and the spatial properties of the pump laser beam. Our all-optical apparatus is based on a spatial light modulator, and it offers unprecedented control on the spatial phase function of the entangled states. In this way, we demonstrate quantitatively the relation between the purity of the generated state and the spatial field correlation function of the pump beam. PMID- 23027243 TI - Tunable optical frequency comb enabled scalable and cost-effective multiuser orthogonal frequency-division multiple access passive optical network with source free optical network units. AB - We propose and experimentally demonstrate a multiuser orthogonal frequency division multiple access passive optical network (OFDMA-PON) with source-free optical network units (ONUs), enabled by tunable optical frequency comb generation technology. By cascading a phase modulator (PM) and an intensity modulator and dynamically controlling the peak-to-peak voltage of a PM driven signal, a tunable optical frequency comb source can be generated. It is utilized to assist the configuration of a multiple source-free ONUs enhanced OFDMA-PON where simultaneous and interference-free multiuser upstream transmission over a single wavelength can be efficiently supported. The proposed multiuser OFDMA-PON is scalable and cost effective, and its feasibility is successfully verified by experiment. PMID- 23027245 TI - Quantum-confined Stark effect at 1.3 MUm in Ge/Si(0.35)Ge(0.65) quantum-well structure. AB - Room-temperature quantum-confined Stark effect in a Ge/SiGe quantum-well structure is reported at the wavelength of 1.3 MUm. The operating wavelength is tuned by the use of strain engineering. Low-energy plasma-enhanced chemical vapor deposition is used to grow 20 periods of strain-compensated quantum wells (8 nm Ge well and 12 nm Si(0.35)Ge(0.65) barrier) on Si(0.21)Ge(0.79) virtual substrate. The fraction of light absorbed per well allows for a strong modulation around 1.3 MUm. The half-width at half-maximum of the excitonic peak of only 12 meV allows for a discussion on physical mechanisms limiting the performances of such devices. PMID- 23027244 TI - Laser speckle imaging using a consumer-grade color camera. AB - Laser speckle imaging (LSI) is a noninvasive optical imaging technique able to provide wide-field two-dimensional maps of moving particles. Raw laser speckle images are typically taken with a scientific-grade monochrome camera. We demonstrate that a digital single-lens reflex (dSLR) camera with a Bayer filter is able to provide similar sensitivity despite taking information only from a specific pixel color. Here we demonstrate the effect of changing three primary dSLR exposure settings (i.e., aperture, exposure time/shutter speed, and gain/sensitivity (ISO)) on speckle contrast. In addition, we present data from an in vivo reactive hyperemia experiment that demonstrates the qualitative similarity in blood-flow dynamics visualized with a color dSLR and a scientific grade monochrome camera. PMID- 23027246 TI - Er-doped high-aspect-ratio core rectangular fiber producing 5 mJ, 13 ns pulses at 1572 nm. AB - We have produced 5 mJ, 13 ns pulses using a very large-mode-area rectangular fiber containing a high-aspect-ratio core with dimensions of ~30 MUm*580 MUm. The rectangular fiber design retains a thin cladding dimension ~0.5 mm, which is compatible with a compact coiled package. We have developed a theoretical model that achieves good agreement with the experimental data. This model indicates that an optimized fiber design can be scaled to pulse energies of several tens of millijoules. We also discuss a strategy for maintaining good beam quality in both transverse dimensions of this fiber. PMID- 23027247 TI - Infrared imaging using arrays of SiO2 micromechanical detectors. AB - In this Letter, we describe the fabrication of an array of bimaterial detectors for infrared (IR) imaging that utilize SiO(2) as a structural material. All the substrate material underneath the active area of each detector element was removed. Each detector element incorporates an optical resonant cavity layer in the IR-absorbing region of the sensing element. The simplified microfabrication process requires only four photolithographic steps with no wet etching or sacrificial layers. The thermomechanical deflection sensitivity was 7.9*10(-3) rad/K, which corresponds to a noise equivalent temperature difference (NETD) of 2.9 mK. In the present work, the array was used to capture IR images while operating at room temperature and atmospheric pressure without the need for vacuum packaging. The average measured NETD of our IR detector system was approximately 200 mK, but some sensing elements exhibited an NETD of 50 mK. PMID- 23027249 TI - Generation of sub-7-cycle optical pulses from a mode-locked ytterbium-doped single-mode fiber oscillator pumped by polarization-combined 915 nm laser diodes. AB - We report on a passively mode-locked ytterbium-doped fiber oscillator pumped by polarization-combined diodes emitting at a wavelength of 915 nm instead of 976 nm. Stable mode-locked operation based on nonlinear polarization evolution generated a broad spectrum of 140 nm, spanning from 950 to 1090 nm. The output power was 16.3 mW at a repetition rate of 93.1 MHz. External compression using a pair of transmission gratings resulted in pulse durations as short as 21.6 fs, which is equivalent to 6.6 cycle optical pulses at a wavelength of around 1000 nm. PMID- 23027248 TI - Multiple resonance fiber-optic sensor with time division multiplexing for multianalyte detection. AB - A proof-of-concept multiwindow fiber-optic sensor utilizing multiple particle plasmon resonance (PPR) of silver nanoparticles and gold nanorods separately on two unclad portions of the fiber for multianalyte detection is demonstrated. The detection is based on intensity interrogation of multiple wavelengths by a single detector. Time division multiplexing is employed to modulate the illumination of dual-wavelength LEDs to induce PPRs for simultaneous real-time and label-free monitoring of two types of biomolecular interactions. Preliminary results reveal that a refractive index resolution of 9 *10(-6) RIU is achieved. Moreover, the measured intensities of two windows independently respond to their respective binding events. The potential of the sensor architecture with multiple sensing windows for cascaded, higher throughput, and multianalyte biochemical detection can be expected. PMID- 23027250 TI - Demonstration of channel-spacing-tunable demultiplexing of optical orthogonal frequency-division-multiplexed subcarriers utilizing reconfigurable all-optical discrete Fourier transform. AB - We experimentally demonstrate a tunable and reconfigurable optical discrete Fourier transform (DFT) to demultiplex orthogonal-frequency-division-multiplexed subcarriers with 2/3/4 subcarriers at 20/40 GHz frequency spacing. An average power penalty of ~5 dB (~3.5) at bit error ratio of 10(-9) is achieved for 4*20 Gbit/s (4*10 Gbit/s) OFDM signal with 20 GHz frequency spacing. PMID- 23027251 TI - Active coherent beam combining of a five-element, 800 W nanosecond fiber amplifier array. AB - Coherent beam combining of an 800 W nanosecond single-frequency fiber amplifier array has been demonstrated. Five high-power all-fiberized Yb-fiber amplifiers were tiled into a crisscross array, and the laser beams were actively phase locked by using the stochastic parallel gradient descent algorithm. The contrast of the far-field intensity pattern of the combined beam was more than 91.6%. The combined pulsed laser has a pulse width of ~3.5 ns and a peak power of 21.5 kW. PMID- 23027252 TI - Time-frequency conversion, temporal filtering, and temporal imaging using graded index time lenses. AB - We propose several applications of graded-index (GRIN) time lenses including time frequency conversion (time-to-frequency conversion and frequency-to-time conversion simultaneously), temporal filtering, and temporal imaging. The evolution of the signal pulses in these systems is demonstrated. As two important parameters, the focal length and the time-frequency conversion factors of time frequency conversion based on GRIN time lenses are evaluated. PMID- 23027253 TI - Femtosecond Yb:CaGdAlO4 thin-disk oscillator. AB - A mode-locked thin-disk laser based on Yb:CALGO is demonstrated for the first time. At an average output power of 28 W we obtained pulses with a duration of 300 fs and a pulse energy of 1.3 MUJ. 197 fs pulses with 0.9 MUJ of energy were achieved at an average output power of 20 W. The shortest pulse duration measured in our experiments was 135 fs with a spectrum centered at 1043 nm. The experiments also revealed a very broad tunability from 1032 to 1046 nm with sub 200 fs pulses. PMID- 23027254 TI - Suppression for dispersion induced phase noise of an optically generated millimeter wave employing optical spectrum processing. AB - A phase adjustment technique employing optical spectrum processing is proposed to suppress the dispersion induced phase noise (PN) in optically generated millimeter-wave (MMW) and fiber transmission. A phase shift between the two beating optical tones in an optical MMW link is introduced by an optical spectrum processor (OSP) to compensate the phase mismatch between them, which results from fiber dispersion and deteriorates the PN of optically generated MMW signals. A MMW PN amelioration of 12.63 dB at 10 kHz offset and 11.23 dB at 100 kHz offset is achieved in a 40 GHz, 25 km optical MMW link thanks to this OSP. PMID- 23027255 TI - Mode-selective couplers for few-mode optical fiber networks. AB - The excitation and separation of individual modes in a few-mode optical fiber network can be realized using mode-selective couplers. For excitation at the beginning of the fiber, two-core mode-selective couplers can be used, while at the end of the fiber, either two- or three-core mode-selective couplers are required for demultiplexing of the field symmetric or field asymmetric modes, respectively. Both analytical and numerical solutions are presented to quantify the mode-selective functionality. PMID- 23027256 TI - Simultaneous broadband microwave downconversion and programmable complex filtering by optical frequency comb shaping. AB - High-repetition-rate optical frequency combs can act as broadband photonic mixers and downconvert a microwave signal to an intermediate frequency (IF) band so that it becomes accessible with high-speed electronics. In this Letter, we show that with line-by-line pulse shaping and dispersive propagation, the photonic mixer can simultaneously perform programmable multitap complex-coefficient-filtering within the IF band. This solution opens new possibilities for microwave signal processing by combining the flexibility of optoelectronic frequency comb technology with high-speed analog-to-digital converters. PMID- 23027257 TI - Chip-scale parametric amplifier with 11 dB gain at 1550 nm based on a slow-light GaInP photonic crystal waveguide. AB - We report on a chip scale parametric amplifier based on a GaInP photonic crystal waveguide. The amplifier operates with both pump and signal in the 1550 nm wavelength range and offers an on-chip gain of 11 dB (5 dB including the 6 dB coupling losses) when pumped at only 800 mW. It enables us, therefore, to incorporate the many advantages of parametric amplification within photonic chips for optical communication applications. PMID- 23027258 TI - Femtosecond direct-write uberstructure waveguide Bragg gratings in ZBLAN. AB - Strong waveguide Bragg gratings (10.5 dB transmission dip) were fabricated using the femtosecond (fs) laser direct-write technique in ZBLAN glass. The Bragg gratings are based on depressed cladding waveguides and consist of planes, periodic according to the Bragg condition, which are constructed from a transverse hexagonal lattice of smaller point features. Such gratings are a key step toward the realization of mid-infrared monolithic waveguide lasers using the fs laser direct-write technique. PMID- 23027259 TI - Single-shot dual-illumination phase unwrapping using a single wavelength. AB - We propose a single-shot phase unwrapping technique using a single wavelength. In the proposed technique, an object is illuminated by two laser beams, which are emitted from the same laser, whose illumination angles and polarizations are different. Then two types of the object waves generated by the two beams are separately and simultaneously recorded by a polarization imaging camera. We conducted an experiment and a 2.5 mm height object, which was 9400 times height of the wavelength of the laser, was reconstructed without wrapping. PMID- 23027261 TI - One-way transmission of linearly polarized light in plasmonic subwavelength metallic grating cascaded with dielectric grating. AB - We show that optical transmission of linearly polarized light through a plasmonic subwavelength metallic grating cascaded with a dielectric grating at a 45 degrees angle to each other is asymmetric in opposite directions. A key characteristic of this asymmetric transmission is that the polarization of the transmitted light is changed. Simulation results reveal that transmission of 0.92 in one direction and 10(-5) in the opposite direction can be obtained at normal incidence at a wavelength of 1550 nm. Because of their high optical performance and loose fabrication requirements, the structures may provide practical applications in the control of light transmission. PMID- 23027260 TI - Fast synchronized dual-wavelength laser speckle imaging system for monitoring hemodynamic changes in a stroke mouse model. AB - In this Letter, we describe a newly developed synchronized dual-wavelength laser speckle contrast imaging system, which contains two cameras that are synchronously triggered to acquire data. The system can acquire data at a high spatiotemporal resolution (up to 500 Hz for ~1000*1000 pixels). A mouse model of stroke is used to demonstrate the capability for imaging the fast changes (within tens of milliseconds) in oxygenated and deoxygenated hemoglobin concentration, and the relative changes in blood flow in the mouse brain, through an intact cranium. This novel imaging technology will enable the study of fast hemodynamics and metabolic changes in vascular diseases. PMID- 23027262 TI - Optical detection of potassium chloride vapor using collinear photofragmentation and atomic absorption spectroscopy. AB - A sensitive and selective optical technique to detect potassium chloride (KCl) vapor is introduced. The technique is based on the photofragmentation of KCl molecules, using a pulsed UV laser, and optical probing of the temporarily increased amount of potassium atoms with a near-infrared laser. The two laser beams are aligned to go through the sample volume along the same optical path. The performance of the technique is demonstrated by detecting KCl concentrations from 25 ppb to 30 ppm in a temperature-controlled cell. PMID- 23027263 TI - Multicore fiber distributed feedback lasers. AB - We demonstrate parallel fabrication of seven fiber distributed feedback (DFB) lasers in a hexagonally arrayed multicore core Er doped fiber with 40 MUm core spacing. DFB grating cavities 8 cm long and operating near 1545 nm were fabricated with a single UV inscription exposure. We observed dual polarization, single longitudinal mode operation with a linewidth below 300 kHz for each laser. PMID- 23027265 TI - Anderson localization in Bragg-guiding arrays with negative defects. AB - We show that Anderson localization is possible in waveguide arrays with periodically spaced defect waveguides having a lower refractive index. Such localization is mediated by Bragg reflection, and it takes place even if diagonal or off-diagonal disorder affects only defect waveguides. For off-diagonal disorder the localization degree of the intensity distributions monotonically grows with increasing disorder. In contrast, under appropriate conditions, increasing diagonal disorder may result in weaker localization. PMID- 23027264 TI - Optical fiber tip for field-enhanced second harmonic generation. AB - We propose a simple optical fiber tip for field-enhanced second harmonic generation (SHG). The tip shows nonlinear phenomena of SHG over a wide range of sources, at least from 630 to 830 nm. The optical field corresponding to the second harmonic appears as a nondiffracting bottle beam with voids due to the surface curvature of the tip. The field-enhanced second harmonic can also induce surface plasmons, converting the tip to a plasmonic probe with reduced background signal. The tip can be useful in nanophotonics characterization. As an example, we demonstrate the tip's response as a surface-enhanced Raman spectroscopy probe. PMID- 23027266 TI - Correspondence between entanglement and Fano resonance of surface plasmons. AB - We investigate the Fano resonance of the scattering spectra in a system consisting of a metal nanowire coupled to two colloidal quantum dots. By varying the coupling strengths and the energy spacings of the quantum dot qubits, we find that both the line shapes and the presence of the Fano resonance can be controlled. Furthermore, the degree of two-qubit entanglement can vary from unity to zero when the Fano resonance occurs. This indicates that there exists correlations between the two-qubit entanglement and the Fano resonance. PMID- 23027267 TI - Comparing resonant photon tunneling via cavity modes and Tamm plasmon polariton modes in metal-coated Bragg mirrors. AB - Resonant photon tunneling was investigated experimentally in multilayer structures containing a high-contrast (TiO(2)/SiO(2)) Bragg mirror capped with a semitransparent gold film. Transmission via a fundamental cavity resonance was compared with transmission via the Tamm plasmon polariton resonance that appears at the interface between a metal film and a one-dimensional photonic bandgap structure. The Tamm-plasmon-mediated transmission exhibits a smaller dependence on the angle and polarization of the incident light for similar values of peak transmission, resonance wavelength, and finesse. Implications for transparent electrical contacts based on resonant tunneling structures are discussed. PMID- 23027268 TI - Broadband, diode pumped Yb:SiO2 multicomponent glass laser. AB - Fabrication, spectroscopic properties, and laser performance of a Yb:SiO(2) multicomponent glass have been investigated in this paper. The glass system composed of SiO(2), Al(2)O(3), and La(2)O(3) excels in terms of a high thermal stress resistance compared to other laser glasses. The laser experiments were conducted with a 3.4 mm thick and 0.9 mol. % Y(2)O(3) doped sample. A maximum slope efficiency of 51%, a maximum optical to optical efficiency of 42%, and a tuning range from 1010-1090 nm was realized. Due to the promising laser properties and a straightforward fabrication technique it may well qualify as an alternative gain medium in high-energy, ultrashort pulse laser systems. PMID- 23027269 TI - Tm:LiYF4 planar waveguide laser at 1.9 MUm. AB - Continuous wave laser operation at 1.87 MUm of liquid-phase epitaxially (LPE) grown Tm(3+)-doped YLiF(4) (Tm:YLF) layers is demonstrated. The waveguide laser delivers 560 mW by pumping with a Ti:Sapphire laser at 780 nm leading to an efficiency of 76% with respect to the absorbed pump power. This constitutes the first Tm(3+)-doped crystalline fluoride waveguide laser ever demonstrated as well as a record in efficiency and output power for an LPE grown waveguide laser operating in the 2 MUm spectral range. PMID- 23027270 TI - Epitaxial III-V-on-silicon waveguide butt-coupled photodetectors. AB - We report silicon waveguide butt-coupled p-i-n InGaAs photodetectors epitaxially grown on silicon-on-insulator substrates by metalorganic chemical vapor deposition. The InGaAs absorption layer that is lattice-matched to InP is selectively grown on patterned SOI substrates, employing metamorphic growth of GaAs and InP buffer layers. We measure a dark current of 2.5 MUA and a responsivity of 0.17 A/W at 1550 nm wavelength upon -1 V bias voltage, with a 20 MUm * 20 MUm InGaAs photodetector area. This device exhibits a 3 dB bandwidth of 9 GHz upon -4 V bias voltage. We demonstrate an open-eye diagram at 10 Gb/s data rate upon -4 V bias voltage. PMID- 23027271 TI - Optical lift from dielectric semicylinders. AB - A wave optics numerical analysis of the force and torque on a semicylindrical optical wing is presented. Comparisons with a recently reported ray optics analysis indicate good agreement when the radius is large compared with the wavelength of light, as expected. Surprisingly, we find that the dominant rotationally stable angle of attack at alpha~-15 degrees is relatively invariant to changes in radius and refractive index. However, the torsional stiffness at the equilibrium point is found to increase, approximately, as the cubic power of the radius. Quasi-resonant internal modes of light produce complex size-dependent variations of the angle and magnitude of the optical lift force. PMID- 23027272 TI - Gouy phase of optical beams in anisotropic indefinite metamaterials. AB - The Gouy phase shift of optical beams in anisotropic indefinite metamaterials displays extraordinary characteristics because of the presence of anisotropic magnetic and electric responses. We propose a simple interpretation of these characteristics from the unusual dispersion relation of the optical waves in the metamaterials, which influences the expectation value of the axial propagation constant of the focused beam. PMID- 23027273 TI - Terahertz single-shot quadrature phase-shifting interferometry. AB - A single-shot quadrature phase-shifting interferometry architecture is presented that is applicable to antenna coupled detector technologies. The method is based on orthogonally polarized object and reference beams and on linear and circular polarization sensitive antennas in space-division multiplexing. The technique can be adapted to two-, three-, and four-step and Gabor holography recordings. It is also demonstrated that the space-division multiplexing does not necessarily cause sparse sampling. A sub-THz detector array is presented containing multiple on chip antennas and FET plasma wave detectors implemented in a 90 nm complementary metal-oxide semiconductor technology. As an example, two-step phase-shifting reconstruction results are given at 360 GHz. PMID- 23027274 TI - Electromagnetic shock wave in nonlinear vacuum: exact solution. AB - An analytical approach to the theory of electromagnetic waves in nonlinear vacuum is developed. The evolution of the pulse is governed by a system of nonlinear wave vector equations. An exact solution with its own angular momentum in the form of a shock wave is obtained. PMID- 23027275 TI - Simplified coherent receiver with heterodyne detection of eight-channel 50 Gb/s PDM-QPSK WDM signal after 1040 km SMF-28 transmission. AB - We propose and experimentally demonstrate a simplified coherent receiver based on heterodyne detection with only two balanced photodetectors and two analog-to digital converters. The polarization diversity hybrid can be simplified relative to the conventional one. The detected intermediate frequency signals are first downconverted to baseband with inphase and quadrature separation. Using this scheme, we successfully demonstrated the eight-channel 50 Gb/s polarization division multiplexed quadrature phase shift keying WDM signal with heterodyne detection based on digital signal processing over 1040 km single-mode fiber 28 with erbium-doped fiber amplifier only amplification. PMID- 23027276 TI - Terahertz emission from surface-immobilized gold nanospheres. AB - Electromagnetic wave emission based on optical rectification at terahertz (THz) wavelengths was observed from surface-immobilized gold nanospheres (SIGNs) above a gold surface. Although the excitation wavelength is off-resonant with the localized surface plasmons, the THz emission field was observed to be approximately 4.8 times greater than that from a percolated gold thin film of 10 nm thickness. A theoretical calculation predicts that the light electric field is enhanced in the SIGN system, even at off-resonance wavelengths. The observed THz field amplitude was quadratic with the illumination light field, suggesting that the THz generation is due to a second-order nonlinear optical process. PMID- 23027277 TI - Study of disklike microdroplet cavities directly coupled to liquid-core waveguides. AB - A design of microfluidic devices is presented to integrate single-mode, liquid core waveguides with microfluidic channels that generate and deliver disklike emulsion microdroplet cavities doped with an organic dye. The microcavity modes can be directly coupled to the liquid waveguide. Cavity-enhanced spontaneous emission was observed at the waveguide with low pump pulse energy. PMID- 23027278 TI - Nonlinear optical filter with ultranarrow bandwidth approaching the natural linewidth. AB - We demonstrate a nonlinear optical filter with ultranarrow bandwidth in cesium vapor. The optical filter operates on the 6S(1/2)->7P(3/2) transition at 455 nm. The single peak transmission at the 6S(1/2), F=4->7P(31/2), F'=5 transition is 9.7% with a bandwidth of 6.2 MHz, whereas at the 6S(1/2), F=3->7P(3/2), F'=2, 3 (cross-over) transition is 6.1% with a bandwidth of 3.9 MHz. The bandwidth approaching the natural linewidth is improved at least two orders of magnitude compared with conventional Faraday anomalous dispersion optical filters. This technique can also be applied to other alkali atoms. PMID- 23027279 TI - Quantitative phase imaging using a partitioned detection aperture. AB - We present a technique to quantitatively image the phase of thin quasi transparent samples using extended source incoherent illumination and off-axis detection apertures. Our technique is achromatic and polarization independent, requires no active elements, and can be readily adapted to standard bright-field microscopes. We demonstrate our technique by quantitatively reconstructing the phase of cheek cells and a microlens. The light efficient, single-shot nature of our technique enables phase imaging at frame rates that are camera limited. PMID- 23027280 TI - Self-diffraction from two-photon absorption gratings in Sn2P2S6. AB - Self-diffraction with the appearance of higher diffraction orders is discovered when writing a grating with a single sub-100 fs pulse in a nominally undoped Sn(2)P(2)S(6) sample. The short time of grating development, dependence of diffraction efficiency on the recording light intensity, correlation of wavelength dependence of efficiency with the spectrum of the two-photon absorption (TPA) constant, and a pi phase shift of the diffracted beam allow for attributing the recorded grating to a dynamic amplitude grating of TPA. PMID- 23027281 TI - Cascaded Raman microlaser in air and buffer. AB - Optical microcavities provide an intriguing platform for the development of low threshold microlasers based on nonlinear effects. Long photon lifetimes within the cavity translate to high circulating optical intensities, thereby reducing the lasing threshold. It is therefore possible to create lasers that can operate in complex environments. In the present work, we use a silica microsphere to demonstrate a cascaded Raman microlaser that operates in air and buffer with the first emission peak around 800 nm in both environments. As expected, the threshold in air is significantly lower than in buffer. PMID- 23027282 TI - High-brightness 1.3 MUm InAs/GaAs quantum dot tapered laser with high temperature stability. AB - We demonstrate high-brightness 1.3 MUm tapered lasers with high temperature stability by using p-doped InAs/GaAs quantum dots (QDs) as the active region. It is found that the beam quality factor M(2) for the devices is almost unchanged as the light power and temperature increase. The almost constant M(2) results from the p-doped QD active region. PMID- 23027283 TI - Four-wave interference and perfect blaze. AB - The recently calculated high diffraction efficiencies for TE- and TM-polarized light (perfect blaze) for echelette gratings are explained by four-wave interference, which is formed as a double periodical pattern in the cross section of the grating plane. The blazed grating profile should match this interference pattern for a single reference light wavelength. The recently published data are the special case of a general design. The prognoses of the model are connected with large grating constants in comparison with the light wavelength, where short grating constants need comparison with numerical methods. PMID- 23027284 TI - Quantum-optical coherence tomography with collinear entangled photons. AB - Quantum-optical coherence tomography (QOCT) combines the principles of classical OCT with the correlation properties of entangled photon pairs [Phys. Rev. A 65, 053817 (2002)]. The standard QOCT configuration is based on the Hong-Ou-Mandel interferometer, which uses entangled photons propagating in separate interferometer arms. This noncollinear configuration imposes practical limitations, e.g., misalignment due to drift and low signal-to-noise. Here, we introduce and implement QOCT based on collinear entangled photons. It makes use of a two-photon Michelson interferometer and offers several advantages, such as simplicity, robustness, and adaptability. PMID- 23027285 TI - Model-based optoacoustic imaging using focused detector scanning. AB - Optoacoustic (photoacoustic) mesoscopic and microscopic imaging is often implemented by linearly scanning a spherically focused ultrasound transducer. In this case, the resolution and sensitivity along the scan direction are limited by diffraction and therefore degrade rapidly for imaging depths away from the focal point. Partial restoration of the lost resolution can be achieved by using data processing techniques, such as the virtual detector delay-and-sum method. However, these techniques are based on an approximate description of the detector properties, which limits the improvement in image quality they achieve. Herein we propose a reconstruction method based on an exact model of the optoacoustic generation and propagation that incorporates the spatial response of the sensor. The proposed method shows superior imaging performance over previously considered techniques. PMID- 23027286 TI - Coherent phase lock of a 9 MUm quantum cascade laser to a 2 MUm thulium optical frequency comb. AB - We demonstrate coherent phase locking of a room-temperature continuous-wave quantum cascade laser (QCL) at 9.1 MUm to a Tm-fiber laser frequency comb centered at 2 MUm, with an integrated residual phase error of 0.9 rad (30 mHz to 1.5 MHz). This resulted in a QCL linewidth reduction from 525 to 25 kHz at 1 ms observation time, limited by the linewidth of the free-running frequency comb. PMID- 23027287 TI - Athermal silicon nitride ring resonator by photobleaching of Disperse Red 1-doped poly(methyl methacrylate) polymer. AB - To fabricate athermal silicon nitride waveguides, the dimensions of both the core and cladding, refractive index, and thermo-optic coefficients must be controlled precisely. We present a simple and effective method for the postfabrication trimming of silicon nitride ring resonators that overcomes the highly demanding fabrication. In order to manipulate the polymer's refractive index and thermo optic coefficient, we bleached the Disperse Red 1-doped poly(methyl methacrylate) (DR1/PMMA) top cladding using UV irradiation. After a suitable bleaching time, the temperature-dependent wavelength shift of the ring resonator was reduced from -9.8 to -0.018 pm/ degrees C, which is the lowest shift that we are aware of for an athermal waveguide realized by overlaying a polymer cladding to date. PMID- 23027288 TI - Reflective interferometry for optical metamaterial phase measurements. AB - The unambiguous determination of optical refractive indices of metamaterials is a challenging task for device applications and the study of new optical phenomena. We demonstrate here simple broadband phase measurements of metamaterials using spectrally and spatially resolved interferometry. We study the phase response of a pi-shaped metamaterial known to be an analog to electromagnetically induced transparency. The measured broadband interferograms give the phase delay or advance produced by the metamaterial in a single measurement. The presented technique offers an effective way of characterizing optical metamaterials including nonlinear and gain-metamaterial systems. PMID- 23027289 TI - Measuring the reflectance of hidden color objects with acoustically modulated laser speckle. AB - We demonstrate a technique to measure the reflectance of colored objects, including blue, green, and yellow, hidden behind an opaque slab based on acoustically modulated laser speckle. One colored paper at a time was placed behind a 1 cm thick opaque slab with an air gap of 5 mm. Small periodic movements (nanometer scale) at 200 Hz were induced in the colored paper. A coherent red He Ne laser illuminated the front of the slab, producing acoustically modulated speckle patterns, which were captured by a CCD camera. The magnitude of the time varying speckle intensity is indicative of the hidden colored paper's reflectance. PMID- 23027290 TI - Fluoroalkyl-grafted mesoporous silica antireflective films with enhanced stability in vacuum. AB - A new antireflective silica film with closed mesopores was successfully prepared for the optical elements used in vacuum of a high-power laser system. The ordered cagelike mesopores were formed with the direction of surfactant F127 and then closed by long-chain fluoroalkylsilane. The grazing incident x-ray diffraction and grazing incident small-angle x-ray scattering results indicated that the mesopores in film constructed a body-center cubic structure. The films exhibited excellent transmittance as high as 99.98% on quartz substrate. After a 1-month antipollution test with polydimethylsiloxane in vacuum, the decrease of transmittance was small as 0.02%. This film had a high laser-induced damage threshold of above 28 J/cm(2) at 1 ns laser pulse of 1053 nm wavelength. PMID- 23027292 TI - Gigantic dispersive wave emission from dual concentric core microstructured fiber. AB - We achieved efficient frequency conversion from a 1064 nm subnanosecond pulse pump to a dispersive wave (DW) centered around 1535 nm in a microstructured double core fiber. We experimentally observed that at the output of a 4 m span of fiber almost half of the input pump power was transferred to a 100 nm band around the peak of the DW. Such outstanding conversion efficiency is an outcome of the fiber dispersion curve exhibiting a large normal peak around 1515 nm, which allows for the resonant energy transfer into the DW directly from the solitons which are generated nearby the pump wavelength. PMID- 23027291 TI - Molecular layer detection on a diffractive optical balance. AB - Diffraction-based molecular detection is achieved by etching optical gratings into thermal oxide on silicon. The gratings perform as a stable common-path diffractive optical balance (DOB) designed to operate near a missing diffraction order. The biosensor is operated in an off-null condition with a phase bias to produce a high-contrast responsivity that is linear in accumulated molecules but with a low background. The DOB linear responsivity is a factor of 20 larger than the reflectometric responsivity of planar thermal oxide. PMID- 23027293 TI - 20 nJ 200 fs all-fiber highly chirped dissipative soliton oscillator. AB - The dissipative solitons (DS) generated in fiber oscillators with mode-locking mechanism based on nonlinear polarization evolution in a single-mode fiber exhibit stability and energy limits at the cavity lengthening. We demonstrate an alternative approach that enables us to increase the cavity length of the DS oscillator up to 30 m, namely, by the use of a long section of polarization maintaining (PM) fiber in an all-fiber cavity configuration. We have also identified the next limit of energy scaling related to the onset of Raman conversion of the DS spectrum. The maximum energy of the stable highly chirped DS realized with a 5.5 MUm core PM fiber, amounts to ~20 nJ in ~200 fs pulses after a grating compressor. As a next step, energy scaling by means of a fiber core enlargement is discussed. PMID- 23027294 TI - Improving the room-temperature confinement of light by miniaturizing mode sizes into a deep subwavelength scale using dielectric spheres in metal cavities. AB - The confinement of light within nanometer-scale regions may result in the significant enhancement of light-matter interactions. However, light confinement to nanometers is hindered by the diffraction limit of a dielectric material. For a dielectric cavity, if the material loss is negligible, reducing the cavity size usually causes a significantly increase in radiation loss. Surface plasmons show great promise for potential subwavelength light confinement. However, in most circumstances, light confinement by dissipative metallic materials can cause ohmic losses at optical frequencies. In such cases, the realization of light confinement with deep subwavelength mode sizes results in great losses and thus has low quality factors. In the present study, a three-dimensional light confinement with deep subwavelength mode sizes is achieved using dielectric spheres in metal cavities. Contrary to other mechanisms for subwavelength light confinement that are based on the use of dielectric or metal cavities, the nanometer-scale regions ensure that most of the light energy is confined away from the metal-dielectric interfaces, thereby decreasing light absorption in the metal cavity. In turn, the metal cavity decreases the radiation loss of light. Thus, high quality factors ranging from 2*10(2) to 6*10(2) can be obtained at room temperature. An effective electrical mode volume ranging from 7*10( 5)lambda(0)(3) to 2*10(-4)lambda(0)(3) (where lambda(0) is the resonant wavelength in a vacuum) can be achieved. Therefore, this method of three dimensional light confinement with deep subwavelength mode sizes using dielectric spheres in metal cavities may have potential applications in the design of nanolasers, nanophoton detectors, nonlinear optical switches, and so on. PMID- 23027295 TI - One-way edge mode in a gyromagnetic photonic crystal slab. AB - We demonstrate that one-way electromagnetic modes could be sustained by the edge of a gyromagnetic photonic crystal slab of triangular lattice under an external dc magnetic field. The applied magnetic field breaks the time-reversal symmetry of the three-dimensional system, and thus the original degeneracy point in k space, at which two dispersion surfaces intersect, is lifted, resulting in a photonic band gap below the light cone. At this band gap, the one-way mode is localized horizontally to the slab edge, while confined by the index contrast in the vertical direction. PMID- 23027296 TI - Simultaneous dual-wavelength operation of Nd:YVO4 self-Raman laser at 1524 nm and undoped GdVO4 Raman laser at 1522 nm. AB - A diode-pumped, actively Q-switched dual-wavelength laser employing Nd:YVO(4) self-Raman emission at 1524 nm and undoped GdVO(4) Raman emission at 1522 nm is demonstrated. With a pump power of 21.5 W and pulse repetition frequency of 20 kHz, a maximum dual-wavelength output power of 1.62 W was obtained, comprising a 0.54 W, 1522 nm Raman component and 1.08 W, 1524 nm self-Raman component. The corresponding dual-wavelength Raman pulse width was 5.6 ns. The experimental results indicate that this laser, with quite small wavelength separation, was effective by virtue of simultaneous self-Raman and Raman shifts. PMID- 23027297 TI - Directionally selective optical limiting of femtosecond pulses in simple transparent two-layer systems. AB - Directionally selective nonlinear transmission behavior has been observed for simple glass-based two-layer systems in Z-scan experiments employing femtosecond pulses at a wavelength of lambda=800 nm. Glass sheets of 1 mm thickness with a very thin surface layer (~2 MUm) containing spherical Ag nanoparticles have been studied. In these samples, irradiating from the substrate side causes a strong transmission decrease via self-focusing of the beam and subsequent two-photon absorption in the thin layer, whereas the reverse direction may pass the sample without loss. This anisotropic optical limiting is discussed in terms of a numerical model in the limit of thin samples with respect to the Rayleigh range of the laser beam. PMID- 23027298 TI - Digital holographic microscope with low-frequency attenuation filter for position measurement of a nanoparticle. AB - We propose a new method for three-dimensional (3D) position measurement of nanoparticles using an in-line digital holographic microscope. The method improves the signal-to-noise ratio of the amplitude of the interference fringes to achieve higher accuracy in the position measurement by increasing weak scattered light from a nanoparticle relative to the reference light by using a low spatial frequency attenuation filter. We demonstrated the improvements of signal-to-noise ratio of the optical system and contrast of the interference fringes, allowing the 3D positions of nanoparticles to be determined more precisely. PMID- 23027299 TI - Bandwidth reduction in a multistage Brillouin system. AB - We investigate the gain bandwidth of stimulated Brillouin scattering (SBS) in multistage systems. As we will show, the bandwidth is reduced significantly by the number of stages, which can increase the distortions in cascaded slow-light systems, for instance. However, other applications, which are limited by the minimum bandwidth achievable with SBS, can benefit from the reduced bandwidth. Since the peak value of the SBS gain spectrum is not reduced by this method, the reduced bandwidth can drastically enhance the performance of many different applications, such as the quasi-light storage (QLS). The minimum bandwidth of 10.3 MHz for a one-stage system was reduced down to 5.8 MHz for three stages. With this reduced bandwidth, we achieved a storage time advancement of the QLS method by 60%. PMID- 23027300 TI - Three-dimensional imaging with axially distributed sensing using electronically controlled liquid crystal lens. AB - In this Letter, we present a three-dimensional (3D) imaging system with axially distributed sensing (ADS) using an electronically controlled liquid crystal (LC) lens. The proposed system performed an optical image acquisition by varying the focal lengths of the LC lens without mechanical movements of an image sensor. Multiple images with slightly different perspectives were experimentally recorded, and the 3D images were reconstructed according to the ray backprojection algorithm. To the best of our knowledge, this is the first report on 3D ADS using a LC lens. The proposed system is attractive for compact 3D sensing camera systems. PMID- 23027301 TI - Scaled angular spectrum method. AB - The angular spectrum method (ASM) calculates diffraction calculation in a high numerical aperture, unlike Fresnel diffraction. However, this method does not allow us to calculate at different sampling rates on source and destination planes. In this Letter, we propose a scaled ASM that calculates diffraction at different sampling rates on source and destination planes using the nonuniform fast Fourier transform. PMID- 23027302 TI - Nonlinear diffusion regularization for transport of intensity phase imaging. AB - We demonstrate a nonlinear diffusion (NLD) regularization method to solve the transport of intensity equation (TIE). A novel NLD regularization function is proposed to enforce piecewise-constant priors and to remove low-frequency artifacts in the TIE solution. PMID- 23027303 TI - Detection of sub-10 nm emission profile features in organic light-emitting diodes using destructive interference. AB - The position of light-emitting molecules can be identified using interferometric approaches. Standard schemes utilize constructive interference to obtain a sectioned area of interest with high detection efficiency. The examination of organic light-emitting diodes (OLED) removes the common constraint of low light levels and enables a more generalized analysis. The OLED emitters are located in the front of a metal mirror, giving rise to an approximate two-wave fringe pattern in the far field. It is demonstrated theoretically and experimentally that positions around the field nodes enable the extraction of emitter distribution details within an electroluminescent layer of only 10 nm thickness. PMID- 23027304 TI - Level coding technique for a wavelength-division-multiplexed optical access system using a remodulation scheme. AB - In the wavelength-division-multiplexed optical access network, the system architecture based on remodulating the downstream (DS) signal for upstream transmission resolves the issues of wavelength management and hardware cost . However, this amplitude remodulation scheme introduces intensity noise in the uplink and leads to a system performance penalty. Therefore, the DS extinction ratio (ER(d)) has to be optimized in order to balance the performance of up- and down- links. In this Letter, a novel technique is presented to overcome the restrictions on ER(d) by introducing correlations into the levels of the DS signal to alter its spectrum. 4 dB improved tolerance to ER(d) is achieved in the proposed system. The level-correlation coding technique is also able to mitigate the in-band crosstalk induced by Rayleigh backscattering. It is demonstrated that the system reach is extended by 40 km with the proposed approach. PMID- 23027305 TI - Evaluation algorithms for multistep measurement of spatially varying linear polarization and phase. AB - Optical components manipulating both polarization and phase of wave fields find more and more applications in today's optical systems. In particular, the polarization orientation may vary across the aperture. New measurement techniques and evaluation algorithms are needed to simultaneously characterize the properties of such elements. In this Letter, a general measurement algorithm for locally linear polarization distributions is presented, extending the methods of phase shifting interferometry to the simultaneous determination of polarization and phase. A class of evaluation algorithms is derived, and some example algorithms are described and tested for their resilience against systematic and stochastic stepping errors. PMID- 23027306 TI - Bit-error-rate performance of non-line-of-sight UV transmission with spatial diversity reception. AB - In non-line-of-sight (NLOS) UV communication links using intensity modulation with direct detection, atmospheric turbulence-induced intensity fluctuations can significantly impair link performance. To mitigate turbulence-induced fading and, therefore, to improve the bit error rate (BER) performance, spatial diversity reception can be used over NLOS UV links, which involves the deployment of multiple receivers. The maximum-likelihood (ML) spatial diversity scheme is derived for spatially correlated NLOS UV links, and the influence of various fading correlation at different receivers on the BER performance is investigated. For the dual-receiver case, ML diversity detection is compared with equal gain combining and optimal combining schemes under different turbulence intensity conditions. PMID- 23027307 TI - Midinfrared optical parametric oscillator based on the wide-bandgap BaGa4S7 nonlinear crystal. AB - The orthorhombic biaxial crystal BaGa(4)S(7) has been employed in a 1064 nm pumped optical parametric oscillator generating <6 ns long idler pulses with energies as high as 0.5 mJ at 6.217 MUm and average power of ~50 mW at 100 Hz. Notwithstanding the relatively low nonlinearity, ~3 times above threshold operation has been achieved at pump intensities more than 5 times below the crystal surface damage limit. PMID- 23027308 TI - Versatile offset-free 16-QAM single dual-drive IQ modulator driven by binary signals. AB - A customized IQ modulator driven by equal-amplitude binary signals for generating offset-free 16-quadrature amplitude modulation (QAM) is proposed and validated through simulations. The incorporation of tunable splitters demonstrates the feasibility of the transmitter and enables more efficient constellations such as hexagonal 16-QAM. PMID- 23027309 TI - Giant sensitivity of long period gratings in transition mode near the dispersion turning point: an integrated design approach. AB - We report an original design approach based on the modal dispersion curves for the development of long period gratings in transition mode near the dispersion turning point exhibiting ultrahigh refractive index sensitivity. The theoretical model predicting a giant sensitivity of 9900 nm per refractive index unit in a watery environment was experimentally validated with a result of approximately 9100 nm per refractive index unit around an ambient index of 1.3469. This result places thin film coated LPGs as an alternative to other fiber-based technologies for high-performance chemical and biological sensing applications. PMID- 23027310 TI - Terahertz generation in quasi-phase-matching structure formed by a phase mask. AB - It is theoretically shown that application of a phase mask in optical rectification scheme is equivalent to spatial modulation of the crystal's nonlinear coefficient in cross-section plane of the laser beam. It allows using the technique of quasi-phase-matching for efficient noncollinear terahertz (THz) generation by using high-power wide-aperture optical beam. According to calculations, the linewidth of THz generation can be varied from 10 GHz to a few THz by changing the optical beam size. It is shown that the frequency of THz generation can be also tuned by building the image of the phase mask in the crystal with variable magnification. PMID- 23027311 TI - Spatially modulated light source obliquely incident on a semi-infinite scattering medium. AB - The three-dimensional radiative transfer equation is solved in the spatial frequency domain for modeling the light propagation due to a spatially modulated light source obliquely incident on a semi-infinite uniform medium. The dependence of the derived solution on the spatial frequencies as well as on position and direction is found analytically. The main computational procedure arises from the determination of several constants obtained by a system of linear equations. The obtained equations are verified and illustrated by comparisons with Monte Carlo simulations and the diffusion approximation, respectively. PMID- 23027312 TI - Fourier transform light scattering angular spectroscopy using digital inline holography. AB - A simple and practical method for measuring the angle-resolved light scattering (ARLS) from individual objects is reported. Employing the principle of inline holography and a Fourier transform light scattering technique, both the static and dynamic scattering patterns from individual micrometer-sized objects can be effectively and quantitatively obtained. First, the light scattering measurements were performed on individual polystyrene beads, from which the refractive index and diameter of each bead were retrieved. Also, the measurements of the static and dynamic light scattering from intact human red blood cells are demonstrated. Using the present method, an existing microscope can be directly transformed into a precise instrument for ARLS measurements. PMID- 23027313 TI - Improving depth-of field in broadband THz beams using nondiffractive Bessel beams. AB - We report new results related to imaging using broadband Bessel-like beams at the terahertz (THz) domain that were generated by use of axicons and pulsed THz radiation emitting at a bandwidth 0.1 to 1 THz. Such Bessel-like beams exhibit an invariant line of focus with an extended length compared to Gaussian-beams Rayleigh range, which enables imaging through the extended length. We demonstrate this imaging property using a resolution target illuminated by broadband-THz beams and show an improvement by a factor of 3.5 in imaging depth while using Bessel-like beams over Gaussian beams. Our results highlight the potential in using broadband THz radiation together with nondiffractive Bessel beams to significantly improve spatial separation over deep view. PMID- 23027314 TI - Cormack-Jolly-Seber model with environmental covariates: a P-spline approach. AB - In capture-recapture models, survival and capture probabilities can be modelled as functions of time-varying covariates, such as temperature or rainfall. The Cormack-Jolly-Seber (CJS) model allows for flexible modelling of these covariates; however, the functional relationship may not be linear. We extend the CJS model by semi-parametrically modelling capture and survival probabilities using a frequentist approach via P-splines techniques. We investigate the performance of the estimators by conducting simulation studies. We also apply and compare these models with known semi-parametric Bayesian approaches on simulated and real data sets. PMID- 23027315 TI - In vivo and in vitro evidence of the neurotoxic effects of ropivacaine: the role of the Akt signaling pathway. AB - There is a growing body of evidence that suggests common complications in regional anesthesia, including transient neurological syndrome, are caused by the neurotoxicity of local anesthetics (LAs). Ropivacaine is thought to be one of the safest LAs, however, there have been several studies detailing possible neurotoxic effects. At present, the exact molecular mechanism of ropivacaine mediated neurotoxicity is unknown. The present study was designed to explore the possible mechanisms underlying the neurotoxicity of ropivacaine. The neurotoxic effects of ropivacaine were assessed in spinal cord by TUNEL staining for apoptosis and in cultured PC12 cells by cell viability assays. Protein kinase B (Akt) activation was evaluated by immunoblotting. Ropivacaine promoted apoptosis and caused cell death in a treatment group compared with a sham-operated group. Furthermore, ropivacaine significantly diminished Akt activation. There were significantly lower Akt levels in cells exposed to ropivacaine compared with controls. The present study demonstrated ropivacaine neurotoxicity in vivo and in vitro, mediated by the Akt signaling pathway. The neurotoxicity of apoptosis with concomitant cell death, mediated by ropivacaine, may offer an explanation for its adverse effects (e.g., transient neurological syndrome). PMID- 23027316 TI - Supporting family members of people with traumatic brain injury using telehealth: a systematic review. AB - OBJECTIVE: To describe the effectiveness of using telehealth programs to provide training or support to family members of people with traumatic brain injury. DESIGN: Systematic review. DATA SOURCES: Intervention studies were identified by searching Medline, CINAHL, PsycINFO, Web of Science, Scopus, the Cochrane library, Embase, PsycBITE and ProQUEST. STUDY SELECTION: Studies included in the review reported an intervention involving family members of adults or children with traumatic brain injury, delivered at a distance through use of technology (including telephone, websites or video-conferencing). Reliability of inclusion of studies in the review was high (Kappa = 0.816) based on a second reviewer evaluating a random sample of 25% of the 830 references originally identified from the database search. DATA EXTRACTION: Data describing the participants, interventions and outcomes were extracted from each study. The quality of studies was evaluated using the PEDro-P scale. DATA SYNTHESIS: The review identified 7 randomised controlled trials, 4 non-randomised controlled trials and 5 case series studies. The studies involved a variety of program formats and intervention targets. All but one study reported positive outcomes of the telehealth programs, however very few studies used blinded assessors. CONCLUSIONS: Telehealth programs for family members of people with traumatic brain injury are feasible, with positive outcomes reported. Further research is needed to strengthen the evidence for the use of telehealth in comparison to face to-face interventions, and to provide information to guide clinical decision making. PMID- 23027317 TI - Inviting patients to read their doctors' notes: a quasi-experimental study and a look ahead. AB - BACKGROUND: Little information exists about what primary care physicians (PCPs) and patients experience if patients are invited to read their doctors' office notes. OBJECTIVE: To evaluate the effect on doctors and patients of facilitating patient access to visit notes over secure Internet portals. DESIGN: Quasi experimental trial of PCPs and patient volunteers in a year-long program that provided patients with electronic links to their doctors' notes. SETTING: Primary care practices at Beth Israel Deaconess Medical Center (BIDMC) in Massachusetts, Geisinger Health System (GHS) in Pennsylvania, and Harborview Medical Center (HMC) in Washington. PARTICIPANTS: 105 PCPs and 13,564 of their patients who had at least 1 completed note available during the intervention period. MEASUREMENTS: Portal use and electronic messaging by patients and surveys focusing on participants' perceptions of behaviors, benefits, and negative consequences. RESULTS: 11,155 [corrected] of 13,564 patients with visit notes available opened at least 1 note (84% at BIDMC, 82% [corrected] at GHS, and 47% at HMC). Of 5219 [corrected] patients who opened at least 1 note and completed a postintervention survey, 77% to 59% [corrected] across the 3 sites reported that open notes helped them feel more in control of their care; 60% to 78% of those taking medications reported increased medication adherence; 26% to 36% had privacy concerns; 1% to 8% reported that the notes caused confusion, worry, or offense; and 20% to 42% reported sharing notes with others. The volume of electronic messages from patients did not change. After the intervention, few doctors reported longer visits (0% to 5%) or more time addressing patients' questions outside of visits (0% to 8%), with practice size having little effect; 3% to 36% of doctors reported changing documentation content; and 0% to 21% reported taking more time writing notes. Looking ahead, 59% to 62% of patients believed that they should be able to add comments to a doctor's note. One out of 3 patients believed that they should be able to approve the notes' contents, but 85% to 96% of doctors did not agree. At the end of the experimental period, 99% of patients wanted open notes to continue and no doctor elected to stop. LIMITATIONS: Only 3 geographic areas were represented, and most participants were experienced in using portals. Doctors volunteering to participate and patients using portals and completing surveys may tend to offer favorable feedback, and the response rate of the patient surveys (41%) may further limit generalizability. CONCLUSION: Patients accessed visit notes frequently, a large majority reported clinically relevant benefits and minimal concerns, and virtually all patients wanted the practice to continue. With doctors experiencing no more than a modest effect on their work lives, open notes seem worthy of widespread adoption. PRIMARY FUNDING SOURCE: The Robert Wood Johnson Foundation, the Drane Family Fund, the Richard and Florence Koplow Charitable Foundation, and the National Cancer Institute. PMID- 23027318 TI - Two novel equations to estimate kidney function in persons aged 70 years or older. AB - BACKGROUND: In older adults, current equations to estimate glomerular filtration rate (GFR) are not validated and may misclassify elderly persons in terms of their stage of chronic kidney disease. OBJECTIVE: To derive the Berlin Initiative Study (BIS) equation, a novel estimator of GFR in elderly participants. DESIGN: Cross-sectional. Data were split for analysis into 2 sets for equation development and internal validation. SETTING: Random community-based population of a large insurance company. PARTICIPANTS: 610 participants aged 70 years or older (mean age, 78.5 years). INTERVENTION: Iohexol plasma clearance measurement as gold standard. MEASUREMENTS: GFR, measured as the plasma clearance of the endogenous marker iohexol, to compare performance of existing equations of estimated GFR with measured GFR of the gold standard; estimation of measured GFR from standardized creatinine and cystatin C levels, sex, and age in the learning sample; and comparison of the BIS equations (BIS1: creatinine-based; BIS2: creatinine- and cystatin C-based) with other estimating equations and determination of bias, precision, and accuracy in the validation sample. RESULTS: The new BIS2 equation yielded the smallest bias followed by the creatinine-based BIS1 and Cockcroft-Gault equations. All other equations considerably overestimated GFR. The BIS equations confirmed a high prevalence of persons older than 70 years with a GFR less than 60 mL/min per 1.73 m2 (BIS1, 50.4%; BIS2, 47.4%; measured GFR, 47.9%). The total misclassification rate for this criterion was smallest for the BIS2 equation (11.6%), followed by the cystatin C equation 2 (15.1%) proposed by the Chronic Kidney Disease Epidemiology Collaboration. Among the creatinine-based equations, BIS1 had the smallest misclassification rate (17.2%), followed by the Chronic Kidney Disease Epidemiology Collaboration equation (20.4%). LIMITATION: There was no validation by an external data set. CONCLUSION: The BIS2 equation should be used to estimate GFR in persons aged 70 years or older with normal or mild to moderately reduced kidney function. If cystatin C is not available, the BIS1 equation is an acceptable alternative. PRIMARY FUNDING SOURCE: Kuratorium fur Dialyse und Nierentransplatation (KfH) Foundation of Preventive Medicine. PMID- 23027319 TI - Outpatient electronic health records and the clinical care and outcomes of patients with diabetes mellitus. AB - BACKGROUND: Physicians can receive federal payments for meaningful use of complete certified electronic health records (EHRs). Evidence is limited on how EHR use affects clinical care and outcomes. OBJECTIVE: To examine the association between use of a commercially available certified EHR and clinical care processes and disease control in patients with diabetes. DESIGN: Quasi-experimental design with outpatient EHR implementation sequentially across 17 medical centers. Multivariate analyses adjusted for patient characteristics, medical center, time trends, and facility-level clustering. SETTING: Kaiser Permanente Northern California, an integrated delivery system. PATIENTS: 169 711 patients with diabetes mellitus. INTERVENTION: Use of a commercially available certified EHR. MEASUREMENTS: Drug treatment intensification and hemoglobin A(1c) (HbA(1c)) and low-density lipoprotein cholesterol (LDL-C) testing and values. RESULTS: Use of an EHR was associated with statistically significant improvements in treatment intensification after HbA(1c) values of 9% or greater (odds ratio, 1.10 [95% CI, 1.05 to 1.15]) or LDL-C values of 2.6 to 3.3 mmol/L (100 to 129 mg/dL) (odds ratio, 1.06 [CI, 1.00 to 1.12]); increases in 1-year retesting for HbA(1c) and LDL-C levels among all patients, with the most dramatic change among patients with the worst disease control (HbA(1c) levels >=9% or LDL-C levels >=3.4 mmol/L [>=130 mg/dL]); and decreased 90-day retesting among patients with HbA(1c) levels less than 7% or LDL-C levels less than 2.6 mmol/L (<100 mg/dL). The EHR was also associated with statistically significant reductions in HbA(1c) and LDL-C levels, with the largest reductions among patients with the worst control (0.06-mmol/L [2.19-mg/dL] reduction among patients with baseline LDL-C levels >=3.4 mmol/L [>=130 mg/dL]; P < 0.001). LIMITATION: The EHR was implemented in a setting with strong baseline performance on cardiovascular care quality measures. CONCLUSION: Use of a commercially available certified EHR was associated with improved drug treatment intensification, monitoring, and physiologic control among patients with diabetes, with greater improvements among patients with worse control and less testing in patients already meeting guideline-recommended glycemic and lipid targets. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases. PMID- 23027321 TI - A patient's view of OpenNotes. PMID- 23027322 TI - Pushing the envelope of electronic patient portals to engage patients in their care. PMID- 23027324 TI - Once upon a time, a "Family Doc". PMID- 23027325 TI - Risk factors for breast cancer for women aged 40 to 49 years. PMID- 23027327 TI - A comprehensive care management program to prevent chronic obstructive pulmonary disease hospitalizations. PMID- 23027329 TI - Supraventricular tachycardia induced by swallowing. PMID- 23027331 TI - In the Clinic. Contraception. PMID- 23027332 TI - [Writing for the HaMiPla]. AB - This paper describes from the editors' perspective step-by-step how to configure and write a manuscript for the Handchirurgie Mikrochirurgie Plastische Chirurgie with the goal to make a successful and quick publication easier. PMID- 23027333 TI - [Photography in Hand Surgery. Basic knowledge and standards]. AB - Photo documentation plays an important role in hand surgery. Pre- and postoperative documentation, planning of interventions, patient information as well as publications and presentations all require high quality images. Last but not least an accurate documentation is necessary for legal reasons. We present basic knowledge of equipment, photo and processing methods and illustrate imaging techniques and photographic standards for professional work flows in daily hand surgery. PMID- 23027334 TI - [Proximal interphalangeal (PIP) finger prosthesis - what have we learnt? Experiences over 10 years]. AB - PURPOSE: In the following article we evaluate the clinical and radiological results after PIP joint replacement to answer the question if the outcome improved over the last years. PATIENTS AND METHODS: In a retrospective clinical study 53 patients with 66 PIP joint implants (SBI-Avanta, Small Bone Innovations, Inc.) were assessed on the basis of clinical and radiological parameters. We examined the patients' range of motion, their grip strength, the rate of radiological loosening, the development of pain and the patients' satisfaction. 2 groups were included in the study. Patients operated from 2001 to 2007 (group A) were compared with patients operated from 2008 to 2011 (group B). To facilitate a standardized examination, we developed a score providing a comprehensive representation of the outcome after PIP joint replacement. RESULTS: Group B showed significant improvement in the rate of loosening of the prosthesis (44-4%) in the last follow-up examination. Further improvement was demonstrated in pain reduction, range of motion (77 degrees /67 degrees ), the patients' satisfaction and development of swan neck deformity (11%/18%). There was no significant improvement in the patients' grip strength and the rate of revision surgery. CONCLUSION: Overall, the results after PIP joint replacement are very good. All patients reported a marked improvement in pain reduction. In group B a significant reduction in the rate of loosening of the prosthesis was shown. Moreover, the rate of swan neck deformity, the range of motion, the reduction of pain and the patient's satisfaction improved over the last years. The application of a new PIP-joint-score for a standardized evaluation of the outcome indicated a good correlation with patient satisfaction over time. The experience of the past years enabled improvements in PIP joint replacement. We consider cementing the prosthesis, a large contact area between the prosthesis and the bone and an emphasis on easy intraoperative flexion/extension as factors which can improve the results after PIP joint replacement. However, some problems could not been solved to date. In this respect, prospective clinical and biomechanical studies are necessary. PMID- 23027335 TI - [Comparative biomechanical studies on implant systems for the treatment of distal radius fractures: what are the conclusions for clinical practice?]. AB - AIM: This review evaluates which conclusions can be drawn for the clinical daily routine in operative treatment of distal radius fractures, regarding the published biomechanical studies concerning implant systems within the last 10 years. METHOD: After identification of 21 articles about biomechanical studies of implant systems for the treatment of distal radius fractures from a literature search, these articles were analysed concerning the specimens, the fracture model as well as the implants used. The quintessence was reviewed with regard to their clinical relevance. RESULTS: All tested palmar angular stable plate systems showed sufficient stiffness for holding the load transmission from the hand to the forearm also within active fist closure. There was no advantage of palmar angular stable plates concerning stiffness compared to dorsal angular stable plates. Angular stable plates are superior over non-angular stable plates in treatment of distal radius extension fractures. Locking screws should be preferred over locking pegs. Subchondrally placed screws have a higher stability than more proximal localised screws. When palmar plates with 2 rows of distal screw holes are used, the highest stability can be achieved by filling all screw holes. However using 2 screws in each row is sufficient. CONCLUSION: There were clinically relevant implications from the published biomechanical studies concerning implant systems for treatment of distal radius fractures in the last 10 years and their considerations provide a safer therapy of distal radius fractures. These are to be respected accordingly. PMID- 23027336 TI - [Development of length of stay and reimbursement in elective hand surgery after the introduction of DRGs in Germany]. AB - BACKGROUND: Since its introduction in Germany, the DRG (Diagnosis-Related Groups) system is often fraught with negative connotations. Frequent points of criticism are a deterioration of patient care by decreasing length of stay (LOS) in hospital and a decline in reimbursement. The following investigation analyzes and compares the development of length of stay and reimbursement in hand surgery based on the 3 most common elective procedures. MATERIAL AND METHODS: The main diagnoses scaphoid nonunion (PSA), Dupuytren's contracture (DK) and rhizarthrosis (RIA) were evaluated for number of cases, length of stay, reimbursement per day and total reimbursement in 2000 as well as 2010 based on the data of our clinic. Patients covered by the Employers' Liability Insurance were not included. Only inpatient cases were considered. RESULTS: In PSA and RIA an increase in the number of cases is reported (PSA: +11 cases; RIA: +26 cases) and a decrease in DK ( - 7 cases). The sum of the total hospital days declined despite rising case numbers predominantly between 65 (RIA) and 260 days (DK). The average LOS decreased by 3.1 days at DK (48.4%) to 4.1 days at PSA (52.6%). Average revenues per day in 2000 amounted to 379 ?, which corresponds to 442 ? adjusted for inflation in 2010. Average revenue per day in 2010 was 755 ? (RIA), 797 ? (PSA) and 876 ? (DK). Revenue per case in 2010 were only higher than in 2000, when 5 (RIA) or 6 hospital days (DK and PSA) were not exceeded. CONCLUSION: With declining revenue per case, the average income per day increased by a reduction in hospital days. A positive or at least equivalent revenue situation can thus only be achieved by a distinct concentration of labor and reduction of hospital days under the DRG-system. PMID- 23027337 TI - [Quality rating of MRI regarding TFCC lesions in the clinical practice]. AB - BACKGROUND: MRI diagnostic is used for wrist pain diagnostic frequently. Clinical studies in specialized centers show high sensitivity and specificity concerning TFCC lesions. The aim of this study is a comparison of MRI and arthroscopy regarding TFCC lesions not in a specialized but in a common medical environment. PATIENTS/MATERIAL AND METHODS: We retrospectively recorded all patients between January 2004 and April 2012 who went through a wrist arthroscopy and had a preoperative MRI. 401 patients were identified, 218 males and 183 females. The average age was 42.4 (12-84) years. 88 examiners of radiological practices in the region of our hospital reported the MRI results used for this research. RESULTS: In 334 cases TFCC lesions could be identified during arthroscopy. MRI showed an average sensitivity of 69% and a specificity of 60%. A Palmer classification was reported through MRI in 58 cases. Most frequently, the MRI examiners reported a Palmer 1b lesion. That result could only be verified by arthroscopy in 11 cases. CONCLUSION: Although MRI has an acceptable degree of diagnostic test accuracy in controlled clinical studies, we do not recommend the general use of MRI in diagnosis of ulnocarpal wrist pain. PMID- 23027338 TI - [Artificial synostosis for traumatic metacarpal defect: a case report]. AB - Reconstruction of traumatic metacarpal defects is still challenging because of the key function of the architecture of the metacarpus for the function of the entire hand. Especially the exact restoration of the rotation for a parallel finger movement plays an important role. There are less information on this topic in the literature. We present a 28-year old patient with a traumatic almost complete defect of the fourth metacarpal. Reconstruction of the metacarpal arch was achieved with an artificial synostosis between the intact head of the 4th metacarpal and the 3rd metacarpal. PMID- 23027339 TI - [Do we need a curriculum "nerve surgery"?]. PMID- 23027340 TI - Clinical features and treatment outcome of primary systemic light-chain amyloidosis in Korea: results of multicenter analysis. AB - Primary systemic light-chain (AL) amyloidosis a disorder characterized by accumulation of monoclonal light chains as aggregated amyloid fibrils in tissues of multiple organs to cause organ dysfunction and death (Kyle and Gertz, Semin Hematol 1995;32:45-59; Merlini and Bellotti, N Engl J Med 2003;349:583-596). Although there are quite a number of data regarding clinical features and treatment outcomes of AL amyloidosis, most of them are from western countries except for a couple of reports from Japan (Kyle and Gertz, Semin Hematol 1995;32:45-59; Yamazaki et al., Clin Exp Nephrol 2009;13:522-525; Goodman et al., Br J Haematol 2006;134:417-425; Michael et al., Clin Lymphoma Myeloma Leuk 2010;10:56-61; Palladini et al., Blood 2004;103:2936-2938). Considering the effect of ethnic difference on the clinical course and outcomes of AL amyloidosis, the analysis of Asian patients may help better understanding of this disease entity. Therefore, we conducted retrospective analysis of clinical features and treatment outcomes of 84 newly diagnosed AL amyloidosis patients in six referral centers in Korea between 1995 and 2010. PMID- 23027341 TI - Role of beta-catenin expression in paediatric mesenchymal lesions: a tissue microarray-based immunohistochemical study. AB - Beta-catenin is a major protein in the Wnt signalling pathway. Although it has been studied in various types of carcinoma, little is known about its expression in mesenchymal tumours. In this study 41 specimens of a variety of mesenchymal childhood tumours were compared to 24 samples of the corresponding adult tumours to assess the diagnostic value of nuclear beta-catenin expression using tissue microarray-based immunohistochemistry. Similar to adult sarcoma and fibromatosis, beta-catenin was not expressed in the majority of childhood sarcomas, and its nuclear translocation was detected in paediatric fibromatosis; non-negligible levels of nuclear staining in other tumour types demonstrate Wnt pathway activation in mesenchymal neoplasms of childhood and adolescence. PMID- 23027342 TI - CM2 antigen, a potential novel molecule participating in glucuronide transport on rat hepatocyte canalicular membrane. AB - The polarized molecules predominately distributing at hepatocyte canalicular surface play a vital role in disclosing the process of bile formation and etiopathogenisis of cholestatic live diseases. Therefore, it is important to find novel polarized molecules on hepatocyte canalicular membrane. In the present study, canalicular membrane vesicles (CMVs) isolated from rat hepatocyte by density gradient centrifugation were used as immunogens to produce hybridoma and 46 strains of monoclonal antibodies (mAb) against CMVs were obtained. With a series of morphological assay methods, including immunohistochemistry, immunofluorescence and immuno-electron microscope, the antigens recognized by canalicular mAb1 (CM1) and canalicular mAb2 (CM2) were confirmed to predominately distribute at hepatocyte canalicular membrane. Transport activity assay revealed that CM2 could inhibit ATP-dependent E217betaG uptake of rat hepatocyte CMVs. Meanwhile, Western blotting analysis showed that the molecular mass of CM2 antigen was approximately 110kDa, which was much less than Mr 180kDa of multidrug resistance-associated protein 2 (MRP2) involved in glucuronide transport. These data indicated that CM2 antigen might be a potential novel molecule participating in glucuronide transport on the hepatocyte canalicular membrane. PMID- 23027343 TI - Uneven distribution of NG2 cells in the rat cerebellar vermis and changes in aging. AB - We describe by NG2 (neuron-glia chondroitin sulphate proteoglycan 2) immunocytochemistry an uneven distribution of NG2 glial cells in the rat cerebellum, being them more represented in the central lobules of the cerebellar vermis, belonging to the cerebrocerebellum. The cerebellar distribution of NG2 cells changes in aging rats, in which the area where the cells appear to be densely scattered throughout all cerebellar layers involves also more rostral and caudal lobules. In addition, in aging rats, in the most rostral and caudal lobules belonging to the spinocerebellum, punctate reaction product is present at the apical pole of Purkinje cells, i.e. in the area where the majority of synapses between olivary climbing fibers and Purkinje cells occur. Data suggest that the different distribution of NG2 cells is correlated to differences in physiology among cerebellar areas and reflects changes during aging. PMID- 23027344 TI - Immunohistochemical localization and morphometry of somatotrophs and lactotrophs in protein, probiotic and symbiotic supplemented molted layers. AB - Two-hundred Single Comb White Leg-Horn spent hens at the age of 70 weeks were purchased from a commercial layer farm. The birds were shifted to the Poultry Research Station, Department of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan. High dietary zinc (3g/kg feed/day) was used to induce molting in all the birds after one week of acclimatization. Thereafter, birds were divided in groups of 50 birds each, with the following treatments: G1 [control; crude protein (CP)16%, no other supplement], G2 (CP18%, no other supplement), G3 (CP16%, Symbiotic, 85 mg/L drinking water) and G4 (CP16%, Probiotic, 85mg/L in drinking water). Fifteen birds were slaughtered at 5% of peak of production each to collect their pituitary glands. The better egg production was seen in all the supplemented groups as compared to the control. Especially an earlier post molt production recovery and delayed decline was seen in the G2 as compared to all other groups. The immunohistochemistry of the pituitary gland reveals the decrease (P<=0.01) in the cell and nucleus size as well as area of somatotrophs in G2 and G4 as compared to G1. The cell and nucleus size as well as area of lactotrophs decreased (P<=0.01) in G2, G3 and G4 as compared to G1. The better and earlier post molt production in G2 highlights the potential role of protein supplementation in connection with the decreased lactotroph size and area in molted birds. PMID- 23027345 TI - Proteoglycan and collagen expression during human air conducting system development. AB - The lung is formed from a bud that grows and divides in a dichotomous way. A bud is a new growth center which is determined by epithelial-mesenchymal interactions where proteins of the extracellular matrix (ECM) might be involved. To understand this protein participation during human lung development, we examined the expression and distribution of proteoglycans in relation to the different types of collagens during the period in which the air conducting system is installed. Using light microscopy and immunohistochemistry we evaluate the expression of collagens (I, III and VI) and proteoglycans (decorin, biglycan and lumican) between 8 to 10 weeks post fertilization and 11 to 14 weeks of gestational age of human embryo lungs. We show that decorin, lumican and all the collagen types investigated were expressed at the epithelium mesenchymal interface, forming a sleeve around the bronchiolar ducts. In addition, biglycan was expressed in both the endothelial cells and the smooth muscle of the blood vessels. Thus, the similar distribution pattern of collagen and proteoglycans in the early developmental stages of the human lung may be closely related to the process of dichotomous division of the bronchial tree. This study provides a new insight concerning the participation of collagens and proteoglycans in the epithelial-mesenchymal interface during the period in which the air conducting system is installed in the human fetal lung. PMID- 23027346 TI - Secretion of immunomodulating neuropeptides (VIP, SP) and nitric oxide synthase in porcine small intestine during postnatal development. AB - Immunohistological identification/localization of immunomodulating neuropeptides [vasoactive intestinal polypeptide (VIP) and substance P (SP)] and enzyme nitric oxide synthase (NOS) as well as histomorphometric analyses of kinetics of their release and development of respective nerve fibers density during postnatal ontogenesis of porcine intestinal mucosal immune system (IMIS), were performed in order to assess the role of these molecules involved in maturation of the IMIS. The kinetcs of reactions to VIP, SP and NOS were demonstrated in the samples of jejunum and ileum from conventionally reared pigs. The samples were obtained at 0, 7, 14, 21, 28, 35, 42 and 49 days of age and processed for immunohistological staining. The VIP+ reaction was prevalently visible in the epithelial layer, lamina propria and Lieberkuhn crypts (Lc) but also in the submucosa and lamina muscularis along blood and lymphatic vessels. The SP+ fibers were regularily distributed along enteric neurons in the muscular layer. The reaction to NOS was demonstrated in both mucosa and submucosa of ileum and jejunum and in the ileal Peyer's patches (PP). Intensity of the reaction was more pronounced in the epithelial layer and numerous NOS+ cells were observed around the Lc and inside the follicles of the PP. Also, we have noticed NOS+ blood vessels, particular neurons and nerve fibers in the submucosa and muscular layer of the small intestine. By analyzing quantitative patterns of SP+, VIP+ fibers and release of NOS we have concluded that intensity of their reactions gradually increases with age, except a short period of stagnation after weaning (at age of 28 days), reaching the highest values in the pigs aged between 42 and 49 days. The values obtained by Sperman rank order correlation test (rs) between days of age of pigs and intensity of the reactions in their jejunum/ileum to VIP (rs=0.97/0.95), SP (rs=0.97/0.97) and NOS (rs=0.98/0.95), respectively, showed positive correlations (P<0.05) according to Roemer Orphal scale. Current study showed that postnatal development of porcine IMIS was accompanied by a substantial increase in the secretion of neuropeptides/enzyme tested and that these molecules may participate in the functional maturation of immunoregulatory/bactericidal mechanisms of the local (intestinal) immune defense in young pigs. PMID- 23027347 TI - Phenotypic alterations of neuropeptide Y and calcitonin gene-related peptide containing neurons innervating the rat temporomandibular joint during carrageenan induced arthritis. AB - The aim of this study was to identify immunoreactive neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) neurons in the autonomic and sensory ganglia, specifically neurons that innervate the rat temporomandibular joint (TMJ). A possible variation between the percentages of these neurons in acute and chronic phases of carrageenan-induced arthritis was examined. Retrograde neuronal tracing was combined with indirect immunofluorescence to identify NPY immunoreactive (NPY-IR) and CGRP-immunoreactive (CGRP-IR) neurons that send nerve fibers to the normal and arthritic temporomandibular joint. In normal joints, NPY IR neurons constitute 78+/-3%, 77+/-6% and 10+/-4% of double-labeled nucleated neuronal profile originated from the superior cervical, stellate and otic ganglia, respectively. These percentages in the sympathetic ganglia were significantly decreased in acute (58+/-2% for superior cervical ganglion and 58+/ 8% for stellate ganglion) and chronic (60+/-2% for superior cervical ganglion and 59+/-15% for stellate ganglion) phases of arthritis, while in the otic ganglion these percentages were significantly increased to 19+/-5% and 13+/-3%, respectively. In the trigeminal ganglion, CGRP-IR neurons innervating the joint significantly increased from 31+/-3% in normal animals to 54+/-2% and 49+/-3% in the acute and chronic phases of arthritis, respectively. It can be concluded that NPY neurons that send nerve fibers to the rat temporomandibular joint are located mainly in the superior cervical, stellate and otic ganglia. Acute and chronic phases of carrageenan-induced arthritis lead to an increase in the percentage of NPY-IR parasympathetic and CGRP-IR sensory neurons and to a decrease in the percentage of NPY-IR sympathetic neurons related to TMJ innervation. PMID- 23027348 TI - Unusual localization and translocation of TRPV4 protein in cultured ventricular myocytes of the neonatal rat. AB - TRPV4 protein forms a Ca2+-permeable channel that is sensitive to osmotic and mechanical stimuli and responds to warm temperatures, and expresses widely in various kinds of tissues. As for cardiac myocytes, TRPV4 has been detected only at the mRNA level and there were few reports about subcellular localization of the protein. The purpose of the present study was to investigate the expression profile of TRPV4 protein in cultured neonatal rat ventricular myocytes. Using Western blots, immunofluorescence, confocal microscopy and immuno-electron microscopy, we have shown that TRPV4 protein was predominantly located in the nucleus of cultured neonatal myocytes. Furthermore, cardiac myocytes responded to hypotonic stimulation by translocating TRPV4 protein out of the nucleus. The significance and mechanism concerning the unusual distribution and translocation of TRPV4 protein in cardiac myocytes remain to be clarified. PMID- 23027349 TI - Isolation and biological characterization of chicken amnion epithelial cells. AB - Amniotic epithelial cells (AECs) express Oct4, Nanog and Sox-2, which are necessary for maintaining the undifferentiated state of pluripotent stem cells. AECs additionally express CK19, which is a specific marker of epithelial cells, both in vivo and in vitro. In this research, we investigated the biological characteristics and potential for cell therapy of AECs from 6-day-old chicken embryos. We induced the AECs to differentiate into pancreatic islet-like cells (endoderm), adipocytes and osteoblasts (mesoderm) and neural-like cells (ectoderm), and used immunofluorescence and RT-PCR to detect the expression of AECs specific markers. To assess the differentiation capacity of AECs, passage 3 cells were induced to differentiate into adipocytes, osteoblasts, pancreatic islet-like cells and neural-like cells. The AEC markers, Oct4, Nanog, Sox-2 and CK19, were all positively expressed. Cloning efficiency decreased with increasing passage number. Passage 3 AECs were successfully induced to differentiate into pancreatic islet-like cells, osteoblasts, adipocytes, and neural-like cells. These results suggested that AECs isolated from chicken embryos exhibited the characteristics of the multipotent stem cells. AECs may therefore be ideal candidates for cellular transplantation therapy and tissue engineering. PMID- 23027350 TI - Immunolocalization of choline acetyltransferase of common type in the central brain mass of Octopus vulgaris. AB - Acetylcholine, the first neurotransmitter to be identified in the vertebrate frog, is widely distributed among the animal kingdom. The presence of a large amount of acetylcholine in the nervous system of cephalopods is well known from several biochemical and physiological studies. However, little is known about the precise distribution of cholinergic structures due to a lack of a suitable histochemical technique for detecting acetylcholine. The most reliable method to visualize the cholinergic neurons is the immunohistochemical localization of the enzyme choline acetyltransferase, the synthetic enzyme of acetylcholine. Following our previous study on the distribution patterns of cholinergic neurons in the Octopus vulgaris visual system, using a novel antibody that recognizes choline acetyltransferase of the common type (cChAT), now we extend our investigation on the octopus central brain mass. When applied on sections of octopus central ganglia, immunoreactivity for cChAT was detected in cell bodies of all central brain mass lobes with the notable exception of the subfrontal and subvertical lobes. Positive varicosed nerves fibers where observed in the neuropil of all central brain mass lobes. PMID- 23027351 TI - Expression of SP-C and Ki67 in lungs of preterm infants dying from respiratory distress syndrome. AB - This study aimed at exploring the expression of Surfactant protein-C (SP-C) and Ki67 in autopsy lung tissues of premature infants dying from respiratory distress syndrome (RDS) who were exposed to mechanical ventilation and elevated oxygen concentrations. The possible influence of pulmonary surfactant (PS) on the expression of SP-C and Ki67 was also investigated. Thirty preterm infants were selected who were histologically and clinically diagnosed as RDS. Preterm infants with RDS were divided into 4 groups, according to the time of death: infants ventilated for 1-3 days, 4-8 days, 9-16 days and >6 days. Five premature infants died within 1 day after delivery for non- pulmonary reasons served as controls. The expression of SP-C and Ki67 in lungs was detected by immunohistochemistry. Compared with the control group, the expression of SP-C and Ki67 in RDS infants decreased significantly after 1-3 days of ventilation, but increased after 4 days and reached peak value after 9-16 days. No significant difference in the expression of SP-C and Ki67 was found between infants treated with PS and those without. Thus our results suggest SP-C and Ki67 may have participated in the pulmonary pathological process in ventilated/oxygen treated preterm infants with RDS, and exogenous surfactant had no effect on the expression of SP-C and Ki67 in the lungs of ventilated/oxygen treated preterm infants with RDS. PMID- 23027352 TI - Skeletal muscle features in myotonic dystrophy and sarcopenia: do similar nuclear mechanisms lead to skeletal muscle wasting? AB - In the cell nucleus, the gene primary transcripts undergo molecular processing to generate mature RNAs, which are finally exported to the cytoplasm. These mRNA maturation events are chronologically and spatially ordered, and mostly occur on distinct ribonucleoprotein (RNP)-containing structures. Defects in the mRNA maturation pathways have been demonstrated in myotonic dystrophy type 1 (DM1) and type 2 (DM2) whose characteristic multisystemic features are caused by the expansion of two distinct nucleotide sequences: (CTG)n in the DMPK gene on chromosome 19q13 in DM1, and (CCTG)n in the ZNF9 gene on chromosome 3q21 in DM2. By combining biomolecular and cytochemical techniques, it has been shown that the basic mechanisms of DMs reside in the accumulation of CUG- or CCUG-containing transcripts in intranuclear foci where several RNA-binding proteins necessary for the physiological processing of pre-mRNA are sequestered. Moreover, a nucleoplasmic accumulation of splicing and cleavage factors has been found in DMs. This suggests that the dystrophic phenotype could depend on a general alteration of the pre-mRNA post-transcriptional pathway. Interestingly, the accumulation of pre-mRNA processing factors in the myonuclei of DM1 and DM2 patients is reminiscent of the nuclear alterations typical of sarcopenia, i.e., the loss of muscle mass and function which physiologically occurs during ageing. Consistently, in an in vitro study, we observed that satellite-cell-derived DM2 myoblasts show cell senescence alterations and impairment of the pre-mRNA maturation pathways earlier than the myoblasts from healthy patient. These results suggest possible common cellular mechanisms responsible for skeletal muscle wasting in sarcopenia and in myotonic dystrophy. PMID- 23027353 TI - Large-scale chromatin morpho-functional changes during mammalian oocyte growth and differentiation. AB - Mammalian oocyte development is characterized by impressive changes in chromatin structure and function within the germinal vesicle (GV). These changes are crucial to confer the oocyte with meiotic and developmental competencies. In cow, oocytes collected from early and middle antral follicles present four patterns of chromatin configuration, from GV0 to GV3, and its progressive condensation has been related to the achievement of developmental potential. During oogenesis, follicular cells are essential for the acquisition of meiotic and developmental competencies and communicate with the oocyte by paracrine and gap junction mediated mechanisms. We recently analyzed the role of gap junction communications (GJC) on chromatin remodeling process during the specific phase of folliculogenesis that coincides with the transcriptional silencing and sequential acquisition of meiotic and developmental capabilities. Our studies demonstrated that GJC between germinal and somatic compartments plays a fundamental role in the regulation of chromatin remodeling and transcription activities during the final oocyte differentiation, throughout cAMP dependent mechanism(s). PMID- 23027354 TI - Ultrastructure of human mature oocytes after vitrification. AB - Since the introduction of human assisted reproduction, oocyte cryopreservation has been regarded as an attractive option to capitalize the reproductive potential of surplus oocytes and preserve female fertility. However, for two decades the endeavor to store oocytes has been limited by the not yet optimized methodologies, with the consequence of poor clinical outcome or of uncertain reproducibility. Vitrification has been developed as the promising technology of cryopreservation even if slow freezing remains a suitable choice. Nevertheless, the insufficiency of clinical and correlated multidisciplinary data is still stirring controversy on the impact of this technique on oocyte integrity. Morphological studies may actually provide a great insight in this debate. Phase contrast microscopy and other light microscopy techniques, including cytochemistry, provided substantial morphofunctional data on cryopreserved oocyte, but are unable to unraveling fine structural changes. The ultrastructural damage is one of the most adverse events associated with cryopreservation, as an effect of cryo-protectant toxicity, ice crystal formation and osmotic stress. Surprisingly, transmission electron microscopy has attracted only limited attention in the field of cryopreservation. In this review, the subcellular structure of human mature oocytes following vitrification is discussed at the light of most relevant ultrastructural studies. PMID- 23027360 TI - Predictive factors for removal of percutaneous endoscopic gastrostomy tube in post-stroke dysphagia. AB - OBJECTIVE: To investigate predictive factors for percutaneous endoscopic gastrostomy (PEG) removal, thereby minimizing unnecessary PEG insertion in post stroke dysphagia. DESIGN: Retrospective cohort study. PATIENTS: A total of 49 patients who undertook PEG tube insertion for post-stroke dysphagia. METHODS: Patients were divided into a removal group (n = 8) and a sustaining group (n = 41) depending on the presence of a PEG tube. Patients' demographic data, nutritional status, Charlson's Comorbidity Index (CCI), and video-fluoroscopic swallowing study findings at the time of PEG insertion were compared between the 2 groups. RESULTS: Eight out of 49 patients (16.3%) removed the PEG tube at a mean of 4.8 months after the insertion. Demographic data, nutritional status, and CCI were comparable between the 2 groups before tube insertion. Video fluoroscopic swallowing study findings in the removal group showed a lower prevalence of premature bolus loss (50.0% vs 73.2%; p = 0.032), aspiration (37.5% vs 80.6%; p = 0.012) and pharyngeal trigger delay (12.5% vs 74.2%; p = 0.010) than those in the sustaining group. CONCLUSION: The absence of aspiration or pharyngeal trigger delay in video-fluoroscopic swallowing study findings at the time of PEG insertion may be a predictive factor for eventual removal of PEG tubes. Identification of removal factors will assist in determining PEG insertion. PMID- 23027359 TI - Hyperthermia reduces migration of osteosarcoma by suppression of autocrine motility factor. AB - Autocrine motility factor (AMF) plays an important role in the development of metastasis by regulating tumor cell motility. The expression of AMF is associated with metastasis in malignant musculoskeletal tumors including osteosarcoma. Recent studies indicated that hyperthermia contributes to the improvement of the prognosis of patients with soft tissue sarcomas; however, few reports have evaluated the impact of hyperthermia on tumor cell motility, which is an important factor of metastasis. The purpose of this study was to evaluate the effect of hyperthermia with or without heat shock protein (HSP) inhibitors on the motility and AMF expression in an osteosarcoma cell line. Hyperthermia was carried out at 41C for 24 h. According to microarray results, HSP90, HSP70 and HSP27 expression was upregulated in osteosarcoma cells under hyperthermia. The intracellular, secreted AMF, mRNA of AMF and cell motility were evaluated by western blotting, ELISA, RT-PCR, wound healing and phagokinetic track assays, respectively. The protein secretion and mRNA levels of AMF and tumor cell motility were significantly decreased by hyperthermia. Of note, the downregulated AMF expression and motility were recovered by the addition of an HSP27 inhibitor. By contrast, the HSP90 and HSP70/72/105 inhibitors had no effect on AMF expression and motility downregulated by hyperthermia. In conclusion, hyperthermia reduced AMF expression and tumor cell motility via HSP27 and may therefore be applied as osteosarcoma treatment. PMID- 23027361 TI - Clinical examination, spondylolysis and adolescent athletes. AB - Symptomatic spondylolysis is a stress reaction caused by microtrauma during physical exercise, an imaging diagnostic subgroup of Adolescent Low Back Pain (ALBP), found in adolescent athletes. Early diagnosis increases the possibility of healing. Thus, it is important to divide ALBP into subgroups. The aim of this study was to evaluate clinical tests that can distinguish symptomatic spondylolysis from other forms of ALBP in order to facilitate early referral for diagnostic imaging. The investigation subjects were a prospective case series with a control group, 25 subjects with ALBP and 13 subjects that had no history of LBP. The 2 groups were examined using the same clinical protocol. MRI of the whole lumbar spine was performed in both the case and control groups and CT investigations of the L4 and L5 vertebrae were performed in the case group. Significant differences between the 2 groups were found in 8 of our clinical tests. No clinical test, alone or in combination, could distinguish between spondylolysis and other forms of ALBP. As 88% of the subjects in the case group had MRI findings and almost 50% had spondylolysis, MRI should be performed at an early age in young athletes with ALBP. PMID- 23027362 TI - Risk factors for new osteoporotic vertebral compression fractures after vertebroplasty: a systematic review and meta-analysis. AB - STUDY DESIGN: Literature review and meta-analysis. OBJECTIVE: To perform a systematic review and meta-analysis of risk factors for new osteoporotic vertebral compression fracture (VCF) after vertebroplasty. SUMMARY OF BACKGROUND DATA: New osteoporotic VCF is one of the serious complications of vertebroplasty, and it is important to investigate the risk factors for such VCFs. The risk factors for new VCFs reported so far remain controversial because of limited data and lack of uniform measurements and evaluation. METHODS: We searched the electronic database of PubMed for case-control studies about the risk of new osteoporotic VCFs after vertebroplasty. RESULTS: A total of 116 studies were identified, of which 16 studies including 559 cases and 1736 controls met the inclusion criteria. The significant risk factors for new VCFs were low bone mineral density [BMD; standardized mean difference (SMD), -0.73; 95% confidence interval (CI), -1.26 to -0.20], low body mass index (BMI; SMD, -0.30; 95% CI, 0.51 to -0.10), and intradiscal cement leakage [odds ratio (OR), 2.13; 95% CI, 1.40-2.36]. The significant risk factors for new VCFs adjacent to the treated VCF were low BMD (SMD, -0.43; 95% CI, -0.76 to -0.09), low BMI (SMD, -0.52; 95% CI, 0.81 to -0.22), and intradiscal cement leakage (OR, 2.61; 95% CI, 1.63-4.17). Low BMD, low BMI, intradiscal cement leakage, cement volume, surgical approach, age, sex, and thoracolumbar junction fracture were all not significant risk factors for new VCFs away from the original VCF. Only one study reported dynamic characteristics as risk factors for new VCFs. CONCLUSIONS: The results of this meta-analysis strongly suggested that patients with low BMD, low BMI, and intradiscal cement leakage were at high risk for new VCFs after vertebroplasty, and risk-reduction options should be considered for such patients. PMID- 23027363 TI - Comparative analysis of 3 different construct systems for single-level anterior cervical discectomy and fusion: stand-alone cage, iliac graft plus plate augmentation, and cage plus plating. AB - STUDY DESIGN: A retrospective cohort-nested longitudinal study. OBJECTIVE: To evaluate radiologic and clinically functional outcomes after single-level anterior cervical discectomy and fusion (ACDF) using 3 different fusion construct systems applying an accurate and reliable methodology. SUMMARY OF BACKGROUND DATA: ACDF is an established procedure that uses 3 different fusion construct systems: cage alone (CA), iliac tricortical bone block with plate (IP), and cage with plate construct (CP). The outcome of a previous study is quite different and did not correlate with experimental studies. METHODS: ACDF was performed on 158 patients (90 male and 68 female), who were followed up for >12 months. The patients were divided into the following 3 treatment groups: CA, IP, and CP. Factors related to outcome were also evaluated. Fusion rate, subsidence rate, and cervical angles were used to measure radiologic outcome. The Odom criteria and the visual analog scale were used to evaluate the clinical outcome. RESULTS: The fusion rate was higher for patients in the IP (87.1%) and CP (79.5%) groups than for those in the CA group (63.2%) after 12 months of follow-up (P=0.019). The subsidence rate was lower for patients in the IP (28.1%) and CP (38.5%) groups than for those in the CA group (58.6%) (P=0.010). Subsidence occurred for the anterior height regardless of constructs. Radiating arm pain showed greater relief in the CP group than in the CA group (P=0.015). It improved more in the CP group than in the IP group, but the differences were not statistically significant (P=0.388). Other clinical outcomes did not show significant differences. CONCLUSIONS: The trend of excellent radiologic outcome was observed for IP>=CP>CA. Plating may play a key role in the support of anterior height. As a result, plating prevents segmental kyphosis and subsidence and promotes bone fusion. Although the overall clinical outcomes were not different among the 3 groups, except for arm pain, more favorable trends regarding clinical outcome were observed for CP>=IP>CA. PMID- 23027364 TI - Instrumented Minimally Invasive Spinal-Transforaminal Lumbar Interbody Fusion (MIS-TLIF): Minimum 5-Year Follow-Up With Clinical and Radiologic Outcomes. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To determine the clinical and radiologic outcomes of the long-term results of instrumented minimally invasive spinal-transforaminal lumbar interbody fusion (MIS-TLIF) in unstable, single level, low-grade, isthmic spondylolisthesis (IS) or degenerative spondylosis (DS) including degenerative spondylolisthesis, foraminal stenosis with central stenosis, degenerative disk disease, and recurrent disk herniation. SUMMARY OF BACKGROUND DATA: MIS-TLIF is a common surgical procedure to treat lumbar spondylolisthesis. However, there are no studies that have documented the long term results of MIS-TLIF. METHODS: Forty-four patients who had undergone instrumented MIS-TLIF between July 2003 and January 2005 were retrospectively reviewed. The visual analog scale, Oswestry Disability Index, patient satisfaction rate, and the patient's return-to-work status were used to assess clinical and functional outcomes. Radiologic follow-up were carried out in patients to check for adjacent segmental degeneration (ASD). The plain radiographs, computed tomography and magnetic resonance imaging, were used in all patients in last follow-up period. RESULTS: The mean visual analog scale scores for back and leg pain decreased from 5.8 and 7 to 3.5 and 3.7, respectively, in the DS group (n=19) and from 6.8 and 6.9 to 1.8 and 2.0, respectively, in the IS group (n=25) (P<0.001). The mean Oswestry Disability Index scores improved from 61.7% to 21.5% in the DS group and from 53.9% to 16% in the IS group (P<0.001). Patient satisfaction rate was 80% and 81% in the DS and IS groups, respectively. Evidence of fusion was observed radiologically in 24 (96%) and 19 (100%) of the patients in the IS and the DS group, respectively, giving an overall fusion rate of 97.7% (43/44). The final ASD rate, observed using radiography, was 68.4% (13/19) in the DS and 40% (10/25) in the IS group. However, 15.8% (3/19) in the DS and 4% (1/25) in the IS group had symptoms associated with ASD. CONCLUSIONS: The long-term clinical and radiologic outcomes after instrumented MIS-TLIF in patients with unstable single-level spine are favorable. PMID- 23027365 TI - Assessment of rib hump deformity correction in adolescent idiopathic scoliosis with or without costoplasty using the double rib contour sign. AB - STUDY DESIGN: Level III-therapeutic study. OBJECTIVE: The purpose of this study was to determine whether the addition of costoplasty in adolescent idiopathic scoliosis surgery improved correction of the rib hump deformity. BACKGROUND: Trunk deformity is comprised of vertebral rotation, posterior vertebral element, and rib deformities. Surgical correction of the rotational deformity has been performed by segmental spinal instrumentation with vertebral derotation, but complete correction of the rib hump by derotation is rarely achieved. METHODS: A multicenter registry database for adolescent idiopathic scoliosis was reviewed with the inclusion criteria of Lenke type I curves treated with posterior spinal fusion with or without costoplasty, instrumented with pedicle screws or hybrid constructs, with a minimum follow-up of 2 years. The first group (group I) was treated with pedicle screws, direct vertebral rotation, and no costoplasty, whereas the second group (group II) was treated with pedicle screws, vertebral rotation, and costoplasty. The rib index (RI), calculated from the double rib contour sign, and Cobb angle were measured radiographically and compared between groups. RESULTS: The groups comprised 36 subjects in group I and 40 subjects in group II. The mean preoperative Cobb angles for groups I and II were 49.7 and 49.8 degrees, respectively, whereas the mean postoperative Cobb angles were 10.2 and 10.9 degrees, respectively. There was no difference in preoperative and postoperative values when comparing both groups (P=0.48 and 0.96, respectively). Before spine surgery, RI for groups I and II was 1.61 and 1.80, respectively. Postoperatively, the rib indices were 1.39 for group I and 1.29 for group II. These differences were found to be statistically significant (P=0.002 and 0.006, respectively). The amounts of correction of RI were 0.23 and 0.51 for groups I and II, respectively. This difference was found to be statistically significant (P<0.0001). The correction percentages were 13.7% and 28.3%, respectively. This difference was also found to be statistically significant (P<0.0001). CONCLUSIONS: Costoplasty combined with pedicle screws and vertebral derotation may significantly improve rib hump deformity as opposed to pedicle screws and vertebral derotation alone. PMID- 23027366 TI - Minimally Invasive Percutaneous Iliac Screws: Initial 24 Case Experiences With CT Confirmation. AB - OF BACKGROUND DATA: Percutaneous pedicle screws have become accepted as an effective method for segmental fixation in a variety of settings. However, fixation to the pelvis, which offers unique biomechanical advantages, had remained elusive from a minimally invasive approach. OBJECTIVE: To ascertain the safety of percutaneous iliac screws implanted placement using fluoroscopic guidance. METHODS: In an effort to verify the accuracy of a fluoroscopically guided technique for safe iliosacral screw placement, we reviewed the imaging results from 24 consecutive patients undergoing this procedure. Percutaneous iliac screw placement was accomplished using primarily x-ray-guided screw insertion (obturator outlet view technique) without frameless image-guidance and with limited exposure of bony landmarks or tactile feedback. Indications for surgery included infection, neoplasia, trauma, and deformity. All patients underwent early postoperative computed tomography scanning to determine the accuracy of screw positioning. RESULTS: A total of 24 patients had 47 screws placed for fixation at the lumbosacral junction. No cases required abortion of the procedure or conversion to an open operation. All of the percutaneous screws were placed appropriately as verified by postoperative computed tomography scanning with 3-dimensional reconstruction. There were no hardware-related complications. However, one 75-year-old patient suffering a sacral fracture died of medical comorbidities on postoperative day 10. CONCLUSIONS: A minimally invasive technique for iliac screw placement can be performed safely with a low likelihood of bony violation. This technique offers the unique biomechanical advantages of iliac fixation without the soft-tissue exposure traditionally needed for safe hardware insertion. The technique relies on high-quality intraoperative fluoroscopic imaging. PMID- 23027367 TI - Anion recognition by coordinative interactions: metal-amine complexes as receptors. AB - Alfred Werner's complexes of formula [M(III)(NH(3))(6-n)X(n)]X(3-n) involved inert metal centres (M = Cr, Co), and anions X(-)'frozen' in the coordination sphere, a circumstance which allowed the isolation of a variety of isomers. Amine complexes of labile transition metal ions, studied later, do not form isomers, yet they allow the investigation of the fast and reversible interaction of the anion X(-) with the metal-amine core. On these bases, anion receptors of varying degrees of sophistication have been synthesised, which consist of coordinatively unsaturated polyamine metal complexes and whose vacant coordination sites can be occupied by anion donor atoms. A thoughtful design of the polyamine framework may introduce geometrical selectivity, resulting from the matching between anion shape and size and the geometrical features of receptor's cavity. Compared to their purely organic counterparts, metal containing receptors display several advantages: (i) metal-anion interactions are strong enough to more than compensate anion dehydration energy, which allows recognition studies to be carried out in water; (ii) transition metal ions of different electronic configurations exhibit different geometrical preferences, which addresses anion binding and introduces a further element of selectivity. Chosen examples of polyamine metal complexes, including macrocycles and cages, displaying selective binding tendencies towards anions will be illustrated in this tutorial review. PMID- 23027368 TI - Study of active ingredients in black soybean sprouts and their safety in cosmetic use. AB - Active ingredients in different lengths of black soybean sprouts were extracted with water. Concentrations of the main proteins and polysaccharides were determined by the Forint phenol assay and phenol-sulfuric acid assay, respectively. Anti-oxidizing capacities of the extracts were measured in vitro using the DPPH scavenging test and whitening capacity was measured in vitro using the tyrosinase inhibition test. The effects of the bean sprout extracts on human skin fibroblasts damnified by H2O2 were studied using an MTT colorimetric assay. The safety of the extracts was determined using the red blood cell (RBC) test, chick chorioallantoic membrane (CAM) assay and human patch test. Results show that DPPH radical scavenging rates at different shoot lengths were all greater than 95%, while the tyrosinase inhibition capacity of the extracts reached 98%. Hemolysis rate in all extracts were lower than 10%, below the 20% regulatory limit for the RBC test. No signs of allergic reactions were observed in the human patch tests. The optimum extract was obtained from bean sprouts grown to 0.5 cm. Extracts of black bean sprouts are safe and can be used as additives in anti aging and whitening cosmetic products. PMID- 23027369 TI - Cytoprotective effects of beta-melanocortin in the rat gastrointestinal tract. AB - Recently discovered anti-inflammatory and immunomodulatory properties of melanocortin peptides led to the conclusion that they might serve as new anti inflammatory therapeutics. The purpose of this work was to examine the effectiveness of beta-melanocortin (beta-MSH) in two experimental models: ethanol induced gastric lesions and TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced colitis in male Wistar rats. Three progressive doses of beta-MSH were used: 0.125, 0.250 and 0.500 mg/kg. Our results suggest that beta-MSH acts as a protective substance in the gastric lesions model, which can be seen as a statistically significant reduction of hemorrhagic lesions at all three doses, compared to the control group. The most efficient dose was 0.250 mg/kg. Statistically significant reduction in mucosal surface affected by necrosis and the reduction of overall degree of inflammation in the colitis model indicates an anti-inflammatory effect of beta-MSH at a dose of 0.250 mg/kg. The results justify further research on beta-MSH peptide and its derivates in the inflammatory gastrointestinal diseases, and point out the possibility of using beta-MSH in studies of digestive system pharmacology. PMID- 23027370 TI - Synthetic flavanones augment the anticancer effect of tumor necrosis factor related apoptosis-inducing ligand (TRAIL). AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as the most promising anticancer agent in the TNF superfamily because of its selective cytotoxicity against tumor cells versus normal primary cells. However, as more tumor cells are reported to be resistant to TRAIL-mediated death, it is important to develop new therapeutic strategies to overcome this resistance. Flavonoids have been shown to sensitize cancer cells to TRAIL-induced apoptosis. The aim of this study was to examine the cytotoxic and apoptotic activities of TRAIL on HeLa cancer cells in combination with two synthetic compounds: 6 hydroxyflavanone (6-HF) and its derivative 6-propionoxy-flavanone (6-PF) and to determine the mechanism by which the flavanones overcome the TRAIL-resistance. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected by annexin V-FITC fluorescence staining in flow cytometry and microscopy. Death receptor (TRAIL-R1/DR4 and TRAIL-R2/DR5) expression were analysed using flow cytometry. Mitochondrial membrane potential was evaluated using DePsipher staining by fluorescence microscopy. The synthetic flavanones enhanced TRAIL induced apoptosis in HeLa cells through increased expression of TRAIL-R2 death receptor and reduction of mitochondrial membrane potential. Our study indicates that the 6-HF and 6-PF augmented the anticancer effects of TRAIL and confirm a potential use of flavanones in TRAIL-based anticancer therapy and prevention. PMID- 23027371 TI - Identification of three new N-demethylated and O-demethylated bisbenzylisoquinoline alkaloid metabolites of isoliensinine from dog hepatic microsomes. AB - Isoliensinine, a natural phenolic bisbenzyltetrahydroisoquinoline alkaloid, has received considerable attention for its potential biological effects such as antioxidant and anti-HIV activities. From the dog hepatic microsomes of isoliensinine, three new N-demethylated and O-demethylated metabolites, 2-N desmethyl-isoliensinine (M1), 2'-N-desmethylisoliensinine (M2), and 2'-N-6-O didesmethylisoliensinine (M3), were identified by high-performance liquid chromatography and data-dependent electrospray ionization tandem mass spectrometry. Possible metabolic pathways for isoliensinine have been proposed. The result should prove very helpful for evaluation of the drug-like properties of isoliensinine and other bisbenzylisoquinoline alkaloids. PMID- 23027372 TI - A new saponin from tea seed pomace (Camellia oleifera Abel) and its protective effect on PC12 cells. AB - A new triterpenoid saponin, oleiferasaponin A1, was isolated from tea seed pomace (Camellia oleifera Abel). The structure of oleiferasaponin A1 was elucidated on the basis of chemical and physicochemical evidence and was found to be 22-O-cis-2 hexenoyl-A1-barrigenol 3-O-[beta-D-galactopyranosyl(1->2)] [beta-D glucopyranosyl(1->2)-alpha-L-arabinopyranosyl(1->3)]-beta-D-glucopyranosiduronic acid. PC12 cells injured with H2O2 were used as the model to test the protective effects of oleiferasaponin A1. The results indicated that oleiferasaponin A1 can potentially prevent the H2O2-induced cell death of PC12 cells. PMID- 23027373 TI - Accessory splenules in autoimmune hemolytic anemia. PMID- 23027374 TI - Pien Tze Huang suppresses IL-6-inducible STAT3 activation in human colon carcinoma cells through induction of SOCS3. AB - IL-6/STAT3 is one of the most critical cellular signal transduction pathways known to malfunction in colorectal cancer (CRC). As a target gene of signal transducer and activator of transcription 3 (STAT3) signaling, suppressor of cytokine signaling 3 (SOCS3) can be quickly induced by interleukin-6 (IL-6) stimulation but it then strongly inhibits IL-6-mediated STAT3 activation, functioning as a negative feedback regulator of the IL-6/STAT3 pathway. Aberrant activation of STAT3 and/or reduced expression of SOCS are strongly correlated with carcinogenesis, which therefore becomes a promising target for the development of novel anticancer chemotherapies. Pien Tze Huang (PZH) is a well known traditional Chinese formula that was first prescribed by a royal physician 450 years ago in the Ming Dynasty. It has been used in China and Southeast Asia for centuries as a folk remedy for various types of cancer including CRC. However, the precise mechanism of its antitumor activity remains largely unclear. In the present study, we found that PZH could significantly and dose-dependently inhibit IL-6-mediated increase of STAT3 phosphorylation levels and transcriptional activity in the human colon carcinoma HT-29 cells, resulting in the suppression of cell proliferation and the induction of apoptosis. In addition, PZH treatment profoundly inhibited IL-6-induced upregulation of cyclin D1 and Bcl-2, two key target genes of the STAT3 pathway. Moreover, PZH treatment increased the expression of SOCS3. These results suggest that PZH could effectively inhibit proliferation and promote apoptosis of human colon carcinoma cells via modulation of the IL-6/STAT3 signaling pathway and its target genes. PMID- 23027375 TI - The Work Ability Index as a screening tool to identify the need for rehabilitation: longitudinal findings from the Second German Sociomedical Panel of Employees. AB - OBJECTIVE: To evaluate the predictive value of the Work Ability Index (WAI) for different indicators of the need for rehabilitation at 1-year follow-up. DESIGN: Cohort study. METHODS: Data were obtained from the Second German Sociomedical Panel of Employees, a large-scale cohort study with postal surveys in 2009 and 2010. RESULTS: A total of 457 women and 579 men were included. Confirmatory factor analysis confirmed the one-dimensionality of the WAI. Regression analyses showed that poor and moderate baseline WAI scores were associated with lower health-related quality of life and more frequent use of primary healthcare 1 year later. Subjects with poor baseline work ability had 4.6 times higher odds of unemployment and 12.2 times higher odds of prolonged sick leave than the reference group with good or excellent baseline work ability. Moreover, the odds of subjectively perceived need for rehabilitation, intention to request rehabilitation and actual use of rehabilitation services were 9.7, 5.7 and 3 times higher in the poor baseline WAI group and 5.5, 4 and 1.8 times higher in the moderate baseline WAI group, respectively. A WAI score <= 37 was identified as the optimal cut-off to predict the need for rehabilitation. CONCLUSION: The WAI is a valid screening tool for identifying the need for rehabilitation. PMID- 23027376 TI - Actin cytoskeleton-dependent pathways for ADMA-induced NF-kappaB activation and TGF-beta high expression in human renal glomerular endothelial cells. AB - Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is considered to be an independent risk factor in the progression of chronic kidney diseases (CKD). It can induce kidney fibrosis by increasing transforming growth factor (TGF)-beta1 expression, but its molecular mechanism is unclear. The aim of the present study was to investigate the role of actin cytoskeleton in ADMA-induced TGF-beta1 high expression in human renal glomerular endothelial cells (HRGECs). The structure of stress fibers was visualized by immunofluorescence, nuclear factor-kappaB (NF-kappaB) DNA-binding activity was assessed by an electrophoretic mobility shift assay and TGF-beta1 expression was assessed by western blot analysis. Results showed that ADMA induced the assembly of stress fibers, DNA binding of NF-kappaB, and increasing expression of TGF beta1. When the dynamics of actin cytoskeleton was perturbed by the actin depolymerizing agent cytochalasin D and the actin-stabilizing agent jasplakinolide, or ablation of stress fiber bundles by the nicotineamide adenine dinucleotide phosphate oxidase inhibitor apocynin and p38 mitogen-activated protein kinase inhibitor SB203580, ADMA-induced DNA binding of NF-kappaB and TGF beta1 expression were inhibited. These results revealed an actin cytoskeleton dependent mechanism in ADMA-induced NF-kappaB activation and TGF-beta1 high expression in HRGECs. The specific targeting of the actin cytoskeleton may be a useful strategy to prevent ADMA-activated kidney fibrosis in CKD. PMID- 23027377 TI - Exogenous nerve growth factor supplementation elevates myocardial immunoreactivity and attenuates cardiac remodeling in pressure-overload rats. AB - It is postulated that supplementation of exogenous nerve growth factor (NGF) might mediate improvement of the cardiac sympathetic nerve function in heart failure (HF). Local intramuscular injection of NGF near the cardiac sympathetic ganglia could influence the innervation pattern, norepinephrine transporter (NET) gene expression, and improve the cardiac remodeling in experimental HF animals. In this study, we injected NGF into the scalenus medius muscles of Sprague-Dawley rats with abdominal aortic constriction (AC). The nerve innervated pattern, left ventricular morphology, and function following injection in rats with AC were investigated respectively by immunohistochemistry and echocardiography. Levels of mRNA expression of NET, growth associated protein 43 (GAP 43), NGF and its receptors TrkA and p75(NTR), and brain natriuretic peptide (BNP) were measured by real-time polymerase chain reaction. The results showed that myocardial NGF mRNA levels were comparable in rats with AC. Short-term supplementation of exogenous NGF raised the myocardial NGF immunoreactivity, but did not cause hyperinnervation and NET mRNA upregulation in the AC rats. Furthermore, myocardial TrkA mRNA was found to be remarkably decreased and p75(NTR) mRNA was increased. Myocardial TrkA downregulation may play a beneficial effect for avoiding the hyperinnervation, and it is reasonable to postulate that p75(NTR) can function as an NGF receptor in the absence of TrkA. Interestingly, local NGF administration into the neck muscles near the ganglia could attenuate cardiac remodeling and downregulate BNP mRNA. These results suggest that exogenous NGF can reach the target tissue along the axons anterogradely, and improve the cardiac remodeling. PMID- 23027378 TI - Poly(ADP-ribose) polymerase 1 inhibition protects human aortic endothelial cells against LPS-induced inflammation response. AB - Atherosclerosis is a chronic inflammatory disease. Toll-like receptor 4 (TLR4) is an important signaling receptor and plays a critical role in the inflammatory response. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that can regulate the expression of various inflammatory genes. In this study, we investigated the role and the underlying mechanisms of PARP1 on lipopolysaccharide (LPS)-induced inflammation in human aortic endothelial cells. Compared with the control, LPS stimulation increased the protein expression of TLR4 and PARP1. TLR4 inhibition reduced LPS-induced upregulation of inducible nitric oxide synthase (iNOS) and ICAM-1 as well as PARP1. Nuclear factor kappaB (NF-kappaB) inhibition decreased ICAM-1 and iNOS expression. Inhibition of PARP1 decreased protein expression of inflammatory cytokines induced by LPS stimulation, probably through preventing NF-kappaB nuclear translocation. Our study demonstrated that LPS increased ICAM-1 and iNOS expression via TLR4/PARP1/NF-kappaB pathway. PARP1 might be an indispensable factor in TLR4 mediated inflammation after LPS stimulation. PARP1 inhibition might shed light on the treatment of LPS-induced inflammatory cytokines expression during atherosclerosis. PMID- 23027379 TI - Intersection of Hippo/YAP and Wnt/beta-catenin signaling pathways. AB - Traditionally, signaling pathways have been perceived to act in an autonomous manner to regulate tissue morphology, size, differentiation, and development. Recent evidence suggests that these pathways often intersect and regulate one another to elicit an appropriate response to a complex set of stimuli. Two pathways known to be important for development, growth, and homeostasis are the Wnt/beta-catenin and the Hippo/YAP pathways. Growing data indicate that these two pathways influence each other in a number of ways to properly regulate tissue growth and repair. Deregulation of these pathways often contributes to tumorigenesis. In this review, we will discuss the points of intersection between the Wnt/beta-catenin and Hippo/YAP pathways and how these interactions contribute to homeostasis, organ repair, and tumorigenesis. PMID- 23027380 TI - Dermal pharmacokinetics of Terpinen-4-ol following topical administration of Zingiber cassumunar (plai) oil. AB - The purpose of this study was to investigate dermal pharmacokinetics of terpinen 4-ol in rats following topical administration of plai oil derived from the rhizomes of Zingiber cassumunar Roxb. Unbound terpinen-4-ol concentrations in dermal tissue were measured by microdialysis. The dermal pharmacokinetic study of terpinen-4-ol was performed under non-occlusive conditions. The oil was topically applied at a dose of 2, 4, and 8 mg/cm2 plai oil corresponding to the amount of 1.0, 1.9, and 3.8 mg/cm2 terpinen-4-ol, respectively. Following topical application of the oil, terpinen-4-ol rapidly distributed into the dermis and demonstrated linear pharmacokinetics with no changes in the dose-normalized area under the concentration-time curves across the investigated dosage range. The mean percentages of free terpinen-4-ol distributed in the dermis per amount of administered were 0.39 +/- 0.06 %, 0.41 +/- 0.08 %, and 0.30 +/- 0.03 % for 2, 4, and 8 mg/cm2 doses, respectively. The dermal pharmacokinetics of terpinen-4-ol could provide information for its further formulation development and therapy schedules. PMID- 23027381 TI - The profile and practice of nuclear medicine technologists in Portugal: findings from a nationwide survey. AB - OBJECTIVES: Nuclear medicine (NM) is a rapidly developing field. In Portugal, no occupational study has been conducted yet that characterizes the professional profile of NM technologists (NMTs). We investigated the clinical tasks performed by NMTs in Portugal, analysing their practices with regard to radiation protection matters and their compliance with established international guidelines for best practice. METHODS: A questionnaire targeted at NMTs was constructed and distributed among 105 NMTs working in Portugal (an estimated 88% of the NMT population in Portugal). Questions addressed the demographic profile, academic background and professional profile of NMTs, with emphasis on practices adopted in NM tasks and radiation protection. RESULTS: In all, 51.4% of the 105 NMTs responded. The majority (70.4%) of the NMTs studied were women, with an average age of 34.3 (+/- 10.4) years and 11.6 (+/- 10.6) years of professional experience. The reported NM tasks included radiopharmaceutical preparation (96.3%), PET (44.4%), intravenous administration (74.1%), administration with dose containers (97.7%) and administration with syringe shields (76.9%). The use of a protective lead apron was rare (2.7%). The average individual dose recorded was 3.8 (+/- 2.7%) mSv/year. CONCLUSION: NMTs in Portugal are generally young women with specialized academic education, consistent with the developments in NM technology and education in Portugal since the past decade. The majority of NMT activities are focused on conventional NM. The estimated annual average individual dose is below the established legal limit. However, radiation protection practices related to staff protection are not harmonized, revealing key aspects to be considered in future education and training. PMID- 23027382 TI - An investigation into truncation artefacts experienced in cardiac imaging using a dedicated cardiac SPECT gamma camera with transmission attenuation correction. AB - BACKGROUND: In SPECT images truncation artefacts may occur when the object does not remain in the field of view (FOV). This truncation may lead to distortions in the transmission map (MU map), which would affect the attenuation correction (AC) and possibly the final image. Our aim was to investigate this distortion on our dedicated small FOV cardiac camera and evaluate the efficacy of the truncation correction. METHODS: Using a phantom, transmission data were acquired with our cardiac camera using arrays of (153)Gd sources. The width of the phantom was varied by adding attenuating material. AC and non-AC images were analysed. RESULTS: The results showed that distorted u maps were produced, which remained distorted even after the application of correction algorithms for chest width measurements greater than 43 +/- 1 cm. This distortion was observed to worsen with increasing chest width measurements. Artefacts were not seen for chest width measurements smaller than 43 cm, even when significant anterior attenuation was modelled. CONCLUSION: Our findings demonstrate that AC-corrected images acquired with our dedicated small FOV cardiac camera are not suitable for patients with chest width measurements greater than 43 cm. PMID- 23027383 TI - Quantitative Tc-99m DTPA renal transplant scintigraphy predicts graft survival in the very early postoperative period. AB - BACKGROUND: Early evaluation of renal allograft prognosis is important for identification and targeted management of 'at-risk' grafts but is difficult in the absence of established tests. Tc-99m diethylene triamine pentaacetic acid renal transplant scintigraphy is a useful noninvasive method for assessing graft function. We aimed to assess the relative role of quantitative scintigraphic parameters in the immediate postoperative period for the assessment of short-term and long-term prognoses. METHODS: Data from 290 dynamic renal transplant scintigraphy procedures, performed on 161 recipients on day 1 (D1) or day 4 (D4) after transplantation, were analysed to derive various perfusion parameters [Kirchner's Index, Hilson's Index (HI), kidney-to-aorta ratio and DeltaP] as well as nonperfusion parameters (graft washout t (1/2), P : PI ratio, P : U ratio, R20/3, T10 and T20) using regions of interest within the whole renal graft and iliac artery. Information on graft survival up to 1 year (as a measure of short term prognosis) and serum creatinine at 1 year (regarded as a predictor for longer-term prognosis) was collected. Mann-Whitney tests, receiver-operating characteristic curve analyses and odds ratios were used to assess the utility of each parameter in stratifying the risk for graft failure within 1 year. Correlations between each parameter and 1-year serum creatinine were tested using Spearman's rank correlation. RESULTS: Eleven grafts failed within 1 year. All perfusion parameters on both D1 and D4 showed significant differences between the failure and survival groups (P=0.026-0.0005). No significant between-group differences were observed for nonperfusion parameters except for R20/3 on D1 (P=0.0298). Receiver-operating characteristic analysis showed moderate accuracy for HI and DeltaP on both D1 and D4 (area under the curve: 0.73-0.84); DeltaP of longer than 6.0 s on D4 was associated with 24.9 times higher relative risk for graft failure within 1 year (sensitivity 88% and specificity 83%). For the assessment of long-term prognosis, a moderate correlation was found between most perfusion parameters (Kirchner's Index, HI and kidney-to-aorta ratio on both D1 and D4) and 1-year serum creatinine (rho=0.40-0.50; P <= 0.0001). The nonperfusion parameters showed only weak correlation. CONCLUSION: Perfusion assessment using HI and DeltaP is useful in the assessment of graft prognosis. This can be achieved as early as D1 and D4 after transplantation. PMID- 23027384 TI - Potential for truncating the scan length of restaging 18F-FDG PET/CT after chemoradiotherapy in head and neck squamous cell carcinoma. PMID- 23027385 TI - The organometallic chemistry of cycloheptatrienyl zirconium complexes. AB - This tutorial review summarizes the organometallic chemistry derived from the half-sandwich complex [(eta(7)-C(7)H(7))ZrCl(tmeda)], which was used as an efficient and versatile starting material for the incorporation of monoanionic ligands into the cycloheptatrienyl zirconium coordination sphere by conventional salt metathesis reactions. A broad variety of ligands was employed, affording novel and previously inaccessible cycloheptatrienyl (sandwich) complexes of the type [(eta(7)-C(7)H(7))Zr(Y)]; Y comprises pentadienyl, cyclopentadienyl, allyl, phospholyl, boratabenzene, imidazolin-2-iminato and amido systems. The cycloheptatrienyl ring in these systems usually acts as an "innocent spectator ligand", but reactivity can arise from the second ligand Y or the Lewis acidity of the, formally, Zr(+iv) center, which was probed in selected examples and put in perspective to related studies. The corresponding results emphasize why the use of [(eta(7)-C(7)H(7))ZrCl(tmeda)] is clearly an advancement in the chemistry of the still fairly unexplored area of cycloheptatrienyl transition metal complexes. PMID- 23027387 TI - [Also involved - relatives of acutely and chronically ill patients]. PMID- 23027386 TI - Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury. AB - Chondroitin sulfate proteoglycans (CSPGs) found in perineuronal nets and in the glial scar after spinal cord injury have been shown to inhibit axonal growth and plasticity. Since we have previously identified SOX9 as a transcription factor that upregulates the expression of a battery of genes associated with glial scar formation in primary astrocyte cultures, we predicted that conditional Sox9 ablation would result in reduced CSPG expression after spinal cord injury and that this would lead to increased neuroplasticity and improved locomotor recovery. Control and Sox9 conditional knock-out mice were subject to a 70 kdyne contusion spinal cord injury at thoracic level 9. One week after injury, Sox9 conditional knock-out mice expressed reduced levels of CSPG biosynthetic enzymes (Xt-1 and C4st), CSPG core proteins (brevican, neurocan, and aggrecan), collagens 2a1 and 4a1, and Gfap, a marker of astrocyte activation, in the injured spinal cord compared with controls. These changes in gene expression were accompanied by improved hind limb function and locomotor recovery as evaluated by the Basso Mouse Scale (BMS) and rodent activity boxes. Histological assessments confirmed reduced CSPG deposition and collagenous scarring at the lesion of Sox9 conditional knock-out mice, and demonstrated increased neurofilament-positive fibers in the lesion penumbra and increased serotonin immunoreactivity caudal to the site of injury. These results suggest that SOX9 inhibition is a potential strategy for the treatment of SCI. PMID- 23027388 TI - [Fear of progression in partners of chronically ill patients]. AB - Fear of progression (FoP) is one of the most prevalent symptoms in patients with chronic diseases. Little is known about FoP in partners of chronically ill patients. Therefore, this study assessed FoP in 332 partners of lung, colon cancer, migraine and rheumatism patients. Objectives were to ascertain the influence of individual, dyadic and disease related factors on FoP. 49% of partners were experiencing high levels of FoP varied according to the nature of the disease (highest FoP in spouses of lung cancer patients, lowest in partners of migraine patients). As significant predictors emerged more medical consultations of the patient, high avoidance symptoms, and own dyadic coping nor dyadic coping of the patient. FoP seems to impact the psychological functioning of the partner as well. Therefore, investigating FoP in partners of chronically ill patients is a promising approach to extending a program of care for patients to their partners. PMID- 23027389 TI - [Evaluation of a cognitive-behavioral group intervention for family caregivers of persons with dementia]. AB - International studies have revealed that dementia caregivers' health deteriorates as a result of intensive at-home care. A cognitive-behavioral group intervention concept was therefore tailored to the needs of dementia caregivers and aimed at an increase in psychological well-being and the prevention of adverse effects on psychological health. The group concept was evaluated with an intervention control group design (N=86 IG; N=92 CG) in a prospective longitudinal study. Outcome variables, assessed at 3 point of measurement, were depressive symptoms, symptoms of anxiety, health-related quality of life, and physical health. Compared to caregivers in the control group, caregivers in the intervention group showed significantly lower symptoms of depression and anxiety at follow-up, which was consistent with the hypotheses. Furthermore, nursing home placement was delayed. PMID- 23027390 TI - [Caregiving relatives of people with dementia: which factors influence the transfer from home-care to nursing home?]. AB - Recent research on institutionalization of family members with dementia has shown caregiving-need, caregiver's burden and role conflicts as important influence factors. However, current knowledge is still superficial because most studies used highly aggregated indicators. Logistic regression was used to explore whether differentiated measures of caregiving-needs, caregiver-burden and role conflicts were risk factors for institutionalization of demented elderly people (N=373). A greater distance between households, increased need in housekeeping, a higher income, increased caregiver-burden and low self-evaluation of caregiving quality are related to an increase in chance for institutionalization. A constant need for supervision and lack of social appreciation are associated with a smaller chance. The results illustrate the dilemma of many caregiving relatives. A future enhancement of the given regression model by including prior decline in caregiving-burden is discussed. PMID- 23027391 TI - [Problem-solving counselling for caregivers of stroke survivors - an analysis of the addressed topics]. AB - Problem-solving therapies for family caregivers have been described for different dyads and care recipients with various chronic conditions. Only little attention is directed to the specific topics worked on with informal caregivers. This study focuses on the intensive intervention period of 3 months of an individualized mainly telephone-based problem-solving training for informal carers of stroke survivors (TIPS-Study). We present data of 47 strained caregivers who cared for their spouses and partners (n=42) or (grand-)parents (n=5). Results show that effective changes in burden can be achieved with only few contacts concentrating on problems that can be controlled by problem-focused coping mechanisms. Problems that require emotion-focused coping were processed rarely. Future perspectives of the approach are discussed. PMID- 23027392 TI - [It's not only the gamblers who need help - a pilot study on a family training programme]. AB - Relatives of problematic and pathological gamblers are seriously affected by the illness comparable to relatives of substance abusers. Therefore they might need support. Hence the psycho-educational training programme ETAPPE was developed and tested in an explorative pilot study in cooperation with counselling services. The participants got several questionnaires concerning amongst others: self assessment of stress, psychological distress and taxing subjects. Results show that families of problematic and pathological gamblers are highly stressed. ETAPPE addresses the topics that are a burden for families. Taking into consideration the limitations, there are positive trends: Through this training, self-assessment of stress, psychological distress and actual situative perceived stress are reduced significantly. Chronic stress remains unchanged. A conclusive evaluation of the effectiveness of this manualized programme is still pending. PMID- 23027393 TI - World War I and my mother's jaw. PMID- 23027394 TI - Chk1 knockdown confers radiosensitization in prostate cancer stem cells. AB - Radioresistance is responsible for treatment failure after radiotherapy in localized prostate cancer, while prostate cancer stem cells promote radioresistance by preferential activation of the DNA damage response. Chk1 inhibition has been shown to sensitize many tumor cells to radiation. However, whether Chk1 inhibition can potentiate the cytotoxic effects of radiation on prostate cancer stem cells remains to be elucidated. In this study, CD133+CD44+ cells were isolated using microbeads and were found to possess cancer stem cell properties. Using shRNA, Chk1 was knocked down in the sorted CD133+CD44+ cells. Our results demonstrated that Chk1 knockdown abrogated the radiation-induced G2/M arrest, inhibited DNA damage repair and promoted premature mitosis, leading to increased apoptosis in the radiated sorted CD133+CD44+ cells. Moreover, these effects were accompanied by caspase-2 activation and the inactivation of phosphorylated Cdc25C and Cdc2. Our results suggest that Chk1 knockdown increases the radiosensitivity of CD133+CD44+ prostate cancer stem cells. Chk1 knockdown in prostate cancer stem cells may be an effective therapeutic strategy against prostate cancer. PMID- 23027399 TI - [Acute effects of fast dynamic stretching on rate of force development in ice hockey players: a pilot study]. AB - BACKGROUND: Fast dynamic stretching has a positive effect on rate of force development in ice hockey players. The aim of this pilot study was to evaluate the influence of fast dynamic stretching (FDS) of the gluteus maximus muscle on rate of force development. SUBJECTS/METHODS: This study included 12 healthy ice hockey players. The intervention was based on a fast dynamic stretching of the gluteus maximus muscle. For quantification, measurements were performed before and after the intervention. The rate of force development was determined by using the drop jump (DJ) for ground contact time and jump height, and sprint time was measured on ice over 20 meters. RESULTS: The intervention showed significant extension of the ground reaction time. The jump height and the sprint time showed no significant differences after FDS intervention. CONCLUSION: The data in this present randomised controlled pilot study showed that FDS interventions on the gluteus maximus muscle have no influence on rate of force development. For future studies, it is recommended that the study protocol should be modified with regard to determining the stretched muscle groups. Furthermore, the FDS intervention on the gluteus maximus muscle showed no positive influence on DJ and sprint. PMID- 23027400 TI - [Frequency, nature and distribution of school sport injuries at different types of schools]. AB - BACKGROUND: A high percentage of all sports injuries occur during school sports. It was analysed whether there are differences in frequency, nature and distribution of school sport injuries at two different types of schools. METHODOLOGY: School sport injuries of all secondary modern schools (n = 106) and in lower classes of grammar Schools (n = 17) in the federal state of Tyrol, Austria, from the ten school years 2001/02 to 2010/11 were analysed. All physical injuries occurring during school sports and resulting in the consultation of a medical doctor and therefore being reported to the general accident department (Allgemeine Unfallversicherungsanstalt [AUVA]) were assessed. RESULTS: During the evaluation period an average number of 32,935 (+/-1584) school children attended the two types of schools in Tyrol per year. The average incidence of school sports injuries in this ten-year period in both types of schools was 36.4/1,000 (mean) with a standard deviation of 4.4/1,000 per school child per year. The incidence increased from 30.3 in the school year 2001/02 to 40.4 in the school year 2010/11 (r = 0.91; b = 1.34; p < 0.0001). The incidence of school sport injuries at secondary modern schools (37.4 +/- 4.9 per 1,000 school children per year) was higher than at the lower classes of grammar schools (32.9 +/- 4.0 per 1,000 school children per year; relative risk 1.138; 95% CI = 1.09-1.19; p = 1.8 * 10-8). In addition, the sports injuries of the school year 2010/11 were analysed in detail and a comparison was made between the two types of schools. The distribution pattern of school sports injuries did not show any significant differences between both school types. At the secondary modern schools, as well as in the lower classes of grammar schools, injuries to the upper extremities prevailed (>50%). Ball sports were responsible for every second injury. Secondary modern school pupils had a significantly higher risk of suffering a school sports injury than pupils in the lower classes of grammar schools. The injury pattern did not show differences between the two types of schools. CONCLUSION: The consistently higher frequency of injuries at secondary modern schools compared to the lower classes of grammar schools indicates the need for school type-specific accident research and prevention efforts. PMID- 23027401 TI - Phenotype of entero-endocrine L cells becomes restricted during development. AB - BACKGROUND: Glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are hormones secreted by L and K cells, respectively, and by LK cells. To characterize L and K cells during development, we examined ileum from embryonic (e)- 12 to e-17. RESULTS: GLP-1 cells were first seen at e-15 and their number increased at e-17. At e-17, most GLP-1 cells co-expressed GIP. The transcription factors Pax6 and Pdx-1 are required for GIP expression, while Pax6 activates the expression of GLP-1. At e-17, the mucosa has GIP+ Pax6+, GIP+ Pdx 1+, GLP-1+ Pax6+, and GLP-1+ Pdx-1+ cells. Unlike ileal L cells of postnatal and adult mice, a subset of ileal L cells of e-17 embryos co-expressed GLP-1 and glucagon (Glu). Glu-positive cells contain proprotein-convertase 2 (PC2) and PC3/1, the enzymes responsible for Glu and GLP-1 synthesis, respectively. CONCLUSIONS: Our findings indicate that most GLP-1+ cells of ileum of e-17 embryos co-express GIP and, therefore, are LK cells. In addition, a subset of GLP 1+ cells of embryos but not of neonates co-express glucagon, indicating that the expression of Glu in GLP-1+ cells disappears after birth. PMID- 23027402 TI - Determinants of central nervous system adult neurogenesis are sex, hormones, mouse strain, age, and brain region. AB - Multiple sclerosis is a sexually dimorphic (SD) disease that causes oligodendrocyte death, but SD of glial cells is poorly studied. Here, we analyze SD of neural progenitors in 6-8 weeks and 6-8 months normal C57BL/6, SJL/J, and BALB/c mice in the subventricular zone (SVZ), dorsolateral horn (DLC), corpus callosum (CC), and parenchyma. With a short 2-h bromodeoxyuridine (BrdU) pulse, no gender and strain differences are present at 6-8 weeks. At 6-8 months, the number of BrdU(+) cells decreases twofold in each sex, strain, and region, indicating that a common aging mechanism regulates BrdU incorporation. Strikingly, 2* more BrdU(+) cells are found in all brain regions in 6-8 months C57BL/6 females versus males, no gender differences in 6-8 months SJL/J, and fewer BrdU(+) cells in females versus males in BALB/cs. The number of BrdU(+) cells modestly fluctuates throughout the estrous cycle in C57BL/6 and SJLs. Castration causes a dramatic increase in BrdU(+) cells in SVZ and DLC. These findings indicate that testosterone is a major regulator of adult neural proliferation. At 6-8 months, the ratio of PDGFRalpha(+) cells in the CC to BrdU(+) cells in the DLC of both strains, sexes, estrous cycle, and castrated mice was essentially the same, suggesting that BrdU(+) cells in the DLC differentiate into CC oligodendrocytes. The ratio of TUNEL(+) to BrdU(+) cells does not match proliferation, indicating that these events are differentially regulated. Differential regulation of these two processes leads to the variation in glial numbers between gender and strain. Explanations of neural proliferation based upon data from one sex or strain may be very misleading. PMID- 23027403 TI - Proteomic analysis of formalin-fixed paraffin-embedded renal tissue samples by label-free MS: assessment of overall technical variability and the impact of block age. AB - PURPOSE: Protein profiling of formalin-fixed paraffin-embedded (FFPE) tissues has enormous potential for the discovery and validation of disease biomarkers. The aim of this study was to systematically characterize the effect of length of time of storage of such tissue blocks in pathology archives on the quality of data produced using label-free MS. EXPERIMENTAL DESIGN: Normal kidney and clear cell renal cell carcinoma tissues routinely collected up to 10 years prior to analysis were profiled using LC-MS/MS and the data analyzed using MaxQuant. Protein identities and quantification data were analyzed to examine differences between tissue blocks of different ages and assess the impact of technical and biological variability. RESULTS: An average of over 2000 proteins was seen in each sample with good reproducibility in terms of proteins identified and quantification for normal kidney tissue, with no significant effect of block age. Greater biological variability was apparent in the renal cell carcinoma tissue, possibly reflecting disease heterogeneity, but again there was good correlation between technical replicates and no significant effect of block age. CONCLUSIONS AND CLINICAL RELEVANCE: These results indicate that archival storage time does not have a detrimental effect on protein profiling of FFPE tissues, supporting the use of such tissues in biomarker discovery studies. PMID- 23027404 TI - Assembly of a phospho-molybdic Wells-Dawson-based silver coordination polymer derived from Keggin polyoxoanion cluster. AB - A 2D Wells-Dawson-based silver(I) coordination polymer was achieved based on silver-Schiff base building blocks and [P(2)Mo(18)O(62)](6-) clusters using AgNO(3), N,N'-bis(furan-2-ylmethylene)hydrazine and Keggin [PMo(12)O(40)](3-) as original materials at room temperature. It is structurally characterized by IR spectroscopy, (31)P NMR, XRPD, thermogravimetric (TG) analyses and X-ray crystallography. The structure of 1 exhibits a novel crystalline 2D coordination polymer constructed by the coordination interaction between the Wells-Dawson polyoxoanion [P(2)Mo(18)O(62)](6-) and Ag-L species. The luminescent property of 1 in the solid state is investigated. PMID- 23027406 TI - Dietary modification of metabolic pathways via nuclear hormone receptors. AB - Nuclear hormone receptors (NHRs), as ligand-dependent transcription factors, have emerged as important mediators in the control of whole body metabolism. Because of the promiscuous nature of several members of this superfamily that have been found to bind ligand with lower affinity than the classical steroid NHRs, they consequently display a broader ligand selectivity. This promiscuous nature has facilitated various bioactive dietary components being able to act as agonist ligands for certain members of the NHR superfamily. By binding to these NHRs, bioactive dietary components are able to mediate changes in various metabolic pathways, including, glucose, cholesterol and triglyceride homeostasis among others. This review will provide a general overview of the nuclear hormone receptors that have been shown to be activated by dietary components. The physiological consequences of such receptor activation by these dietary components will then be discussed in more detail. PMID- 23027407 TI - Mild traumatic brain injuries and their sequelae. I: the need for screening. PMID- 23027408 TI - Reply to the influence of Hispanic ethnicity on nonsmall cell lung cancer histology and patient survival: an analysis of the survival, epidemiology, and end results database. PMID- 23027409 TI - Prioritization of comparative effectiveness research topics in hospital pediatrics. AB - OBJECTIVE: To use information about prevalence, cost, and variation in resource utilization to prioritize comparative effectiveness research topics in hospital pediatrics. DESIGN: Retrospective analysis of administrative and billing data for hospital encounters. SETTING: Thirty-eight freestanding US children's hospitals from January 1, 2004, through December 31, 2009. PARTICIPANTS: Children hospitalized with conditions that accounted for either 80% of all encounters or 80% of all charges. MAIN OUTCOME MEASURES: Condition-specific prevalence, total standardized cost, and interhospital variation in mean standardized cost per encounter, measured in 2 ways: (1) intraclass correlation coefficient, which represents the fraction of total variation in standardized costs per encounter due to variation between hospitals; and (2) number of outlier hospitals, defined as having more than 30% of encounters with standardized costs in either the lowest or highest quintile across all encounters. RESULTS: Among 495 conditions accounting for 80% of all charges, the 10 most expensive conditions accounted for 36% of all standardized costs. Among the 50 most prevalent and 50 most costly conditions (77 in total), 26 had intraclass correlation coefficients higher than 0.10 and 5 had intraclass correlation coefficients higher than 0.30. For 10 conditions, more than half of the hospitals met outlier hospital criteria. Surgical procedures for hypertrophy of tonsils and adenoids, otitis media, and acute appendicitis without peritonitis were high cost, were high prevalence, and displayed significant variation in interhospital cost per encounter. CONCLUSIONS: Detailed administrative and billing data can be used to standardize hospital costs and identify high-priority conditions for comparative effectiveness research--those that are high cost, are high prevalence, and demonstrate high variation in resource utilization. PMID- 23027410 TI - Clinical instruments to evaluate and guide treatment in schizophrenia. AB - Treatment research in schizophrenia is focused on the development of pharmacological agents that are effective for improving community functioning and decreasing disability. As a result of this recent focus, there has been substantial activity for developing instruments that can measure functioning as well as the psychopathological domains that are related to functioning. Issues in selecting measures of real-world functioning include ensuring that the instrument measures the full range of possible outcomes and differentiating symptoms from functioning. For many treatment studies it is unrealistic to expect a change in actual functioning. Most treatment trials are too brief to permit subjects to change their level of vocational or social functioning. In addition, real-world functioning is influenced by factors such as an individual's financial status or the availability of community services. This has led to the use of functional capacity measures which monitor an individual's ability to perform functionally meaningful tasks even if they do not complete these tasks. Attention has also focused on interview-based measures of cognition and negative symptoms. Both of these psychopathological domains are related to functioning and both are the focus of drug development.Recent drug development has focused on the development of agents that target domains of psychopathology that may lead to improved functioning. This focus contrasts with the development of first and second generation antipsychotics; these drugs were considered effective when they treated psychotic symptoms such as auditory hallucinations, suspiciousness, delusions, and disorganized behaviors. Treating these symptoms was important for reducing suffering and for allowing many patients to live in their communities. On the other hand, these agents had relatively modest effects on the ability of patients to function in their communities. This new focus on functioning has led to the development of new instruments for measuring functioning as well as the psychopathological domains that appear to be related to impaired functioning. This review will discuss the challenges that instrument developers have faced in designing these new instruments as well as the current state of the field. The measurement of typical psychopathology-particularly psychosis will not be discussed. PMID- 23027411 TI - Cognitive impairment in schizophrenia. AB - Cognitive functioning is moderately to severely impaired in patients with schizophrenia. This impairment is the prime driver of the significant disabilities in occupational, social, and economic functioning in patients with schizophrenia and an important treatment target. The profile of deficits in schizophrenia includes many of the most important aspects of human cognition: attention, memory, reasoning, and processing speed. While various efforts are under way to identify specific aspects of neurocognition that may lie closest to the neurobiological etiology and pathophysiology of the illness, and may provide relevant convergence with animal models of cognition, standard neuropsychological measures continue to demonstrate the greatest sensitivity to functionally relevant cognitive impairment.The effects of antipsychotic medications on cognition in schizophrenia and first-episode psychosis appear to be minimal. Important work on the effects of add-on pharmacologic treatments is ongoing. Very few of the studies completed to date have had sufficient statistical power to generate firm conclusions; recent studies examining novel add-on treatments have produced some encouraging findings. Cognitive remediation programs have generated considerable interest as these methods are far less costly than pharmacologic treatment and are likely to be safer. A growing consensus suggests that these interventions produce modest gains for patients with schizophrenia, but the efficacy of the various methods used has not been empirically investigated. PMID- 23027412 TI - Behavioral animal models to assess pro-cognitive treatments for schizophrenia. AB - Cognitive dysfunction is a core aspect of schizophrenia that constitutes a major obstacle toward reintegration of patients into society. Although multiple cognitive deficits are evident in schizophrenia patients, no medication is currently approved for their amelioration. Although consensus clinical test batteries have been developed for the assessment of putative cognition enhancers in patients with schizophrenia, parallel animal tests remain to be validated. Having no approved treatment for cognitive symptoms means no positive control can be used to examine pharmacological predictive validity of animal models. Thus, focus has been placed on animal paradigms that have demonstrable construct validity for the cognitive domain being assessed.This review describes the growing arsenal of animal paradigms under development that have putative construct validity to cognitive domains affected in schizophrenia. We discuss (1) the construct validity of the paradigms; (2) compounds developed to investigate putative treatment targets; and (3) manipulations used to first impair task performance. Focus is placed on the paradigm design, including how the use of multivariate assessments can provide evidence that main effects of treatment are not confounded by extraneous effects. PMID- 23027414 TI - Mutant mouse models in evaluating novel approaches to antipsychotic treatment. AB - In this review we consider the application of mutant mouse phenotypes to the study of psychotic illness in general and schizophrenia in particular, as they relate to behavioral, psychopharmacological, and cellular phenotypes of putative import for antipsychotic drug development. Mutant models appear to be heuristic at two main levels; firstly, by indicating the functional roles of neuronal components thought to be of relevance to the putative pathobiology of psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those neuronal components; secondly, by indicating the functional roles of genes associated with risk for psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those risk genes. We focus initially on models of dopaminergic and glutamatergic dysfunction. Then, we consider advances in the genetics of schizophrenia and mutant models relating to replicable risk genes. Lastly, we extend this discussion by exemplifying two new variant approaches in mutant mice that may serve as prototypes for advancing antipsychotic drug development. There is continuing need not only to address numerous technical challenges but also to develop more "real-world" paradigms that reflect the milieu of gene * environment and gene * gene interactions that characterize psychotic illness and its response to antipsychotic drugs. PMID- 23027415 TI - 5-HT(2C) agonists as therapeutics for the treatment of schizophrenia. AB - The 5-HT(2C) receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT(2C) receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT(2C) receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT(2C) agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT(2C) agonists in schizophrenia. To this end, the preclinical profile of 5-HT(2C) agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT(2C) agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT(2C) agonists are potential therapeutics for the treatment of psychiatric disorders. PMID- 23027416 TI - The role of dopamine D(3) receptors in antipsychotic activity and cognitive functions. AB - Dopamine D(3) receptors have a pre- and postsynaptic localization in brain stem nuclei, limbic parts of the striatum, and cortex. Their widespread influence on dopamine release, on dopaminergic function, and on several other neurotransmitters makes them attractive targets for therapeutic intervention. The signaling pathways of D(3) receptors are distinct from those of other members of the D(2)-like receptor family. There is increasing evidence that D(3) receptors can form heteromers with dopamine D(1), D(2), and probably other G-protein coupled receptors. The functional consequences remain to be characterized in more detail but might open new interesting pharmacological insight and opportunities. In terms of behavioral function, D(3) receptors are involved in cognitive, social, and motor functions, as well as in filtering and sensitization processes. Although the role of D(3) receptor blockade for alleviating positive symptoms is still unsettled, selective D(3) receptor antagonism has therapeutic features for schizophrenia and beyond as demonstrated by several animal models: improved cognitive function, emotional processing, executive function, flexibility, and social behavior. D(3) receptor antagonism seems to contribute to atypicality of clinically used antipsychotics by reducing extrapyramidal motor symptoms; has no direct influence on prolactin release; and does not cause anhedonia, weight gain, or metabolic dysfunctions. Unfortunately, clinical data with new, selective D(3) antagonists are still incomplete; their cognitive effects have only been communicated in part. In vitro, virtually all clinically used antipsychotics are not D(2)-selective but also have affinity for D(3) receptors. The exact D(3) receptor occupancies achieved in patients, particularly in cortical areas, are largely unknown, mainly because only nonselective or agonist PET tracers are currently available. It is unlikely that a degree of D(3) receptor antagonism optimal for antipsychotic and cognitive function can be achieved with existing antipsychotics. Therefore, selective D(3) antagonism represents a promising mechanism still to be fully exploited for the treatment of schizophrenia, cognitive deficits in schizophrenia, and comorbid conditions such as substance abuse. PMID- 23027413 TI - Towards medication-enhancement of cognitive interventions in schizophrenia. AB - Current antipsychotic medications do little to improve real-life function in most schizophrenia patients. A dispassionate view of the dispersed and variable neuropathology of schizophrenia strongly suggests that it is not currently, and may never be, correctable with drugs. In contrast, several forms of cognitive therapy have been demonstrated to have modest but lasting positive effects on cognition, symptoms, and functional outcomes in schizophrenia patients. To date, attempts to improve clinical outcomes in schizophrenia by adding pro-cognitive drugs to antipsychotic regimens have had limited success, but we propose that a more promising strategy would be to pair drugs that enhance specific neurocognitive functions with cognitive therapies that challenge and reinforce those functions. By using medications that engage spared neural resources in the service of cognitive interventions, it might be possible to significantly enhance the efficacy of cognitive therapies. We review and suggest several laboratory measures that might detect potential pro-neurocognitive effects of drugs in individual patients, using a "test dose" design, aided by specific biomarkers predicting an individual's drug sensitivity. Lastly, we argue that drug classes viewed as "counter-intuitive" based on existing models for the pathophysiology of schizophrenia-including pro-catecholaminergic and NMDA-antagonistic drugs-might be important candidate "pro-cognitive therapy" drugs. PMID- 23027418 TI - Muscarinic mechanisms in psychotic disorders. AB - Schizophrenia is a devastating disease with several broad symptom clusters and the current monoamine-based treatments do not adequately treat the disease, especially negative and cognitive symptoms. A proposed alternative approach for treating schizophrenia is through the use of compounds that activate certain muscarinic receptor subtypes, the so-called muscarinic cholinergic hypothesis theory. This theory has been revitalized with a number of recent and provocative findings including postmortem reports in schizophrenia patients showing decreased numbers of muscarinic M(1) and M(4) receptors in brain regions associated with schizophrenia as well as decreased muscarinic receptors in an in vivo imaging study. Studies with M(4) knockout mice have shown that there is a reciprocal relationship between M(4) and dopamine receptor function, and a number of muscarinic agonists have shown antidopaminergic activity in a variety of preclinical assays predictive of antipsychotic efficacy in the clinic. Furthermore, the M(1)/M(4) preferring partial agonist xanomeline has been shown to have antipsychotic-like and pro-cognitive activity in preclinical models and in clinical trials to decrease psychotic-like behaviors in Alzheimer's patients and positive, negative, and cognitive symptoms in patients with schizophrenia. Therefore, we propose that an agonist with M(1) and M(4) interactions would effectively treat core symptom clusters associated with schizophrenia. Currently, research is focused on developing subtype-selective muscarinic agonists and positive allosteric modulators that have reduced propensity for parasympathetic side-effects, but retain the therapeutic benefit observed with their less selective predecessors. PMID- 23027417 TI - Nicotinic mechanisms in the treatment of psychotic disorders: a focus on the alpha7 nicotinic receptor. AB - Nicotine is heavily abused by persons with schizophrenia. Nicotine better enables people with schizophrenia to filter out extraneous auditory stimuli. Nicotine also improves prepulse inhibition when compared to placebo. Nicotine similarly increases the amplitude of patients' duration mismatch negativity. The 15q13-14 region of the genome coding for the alpha7 nicotinic receptor is linked to schizophrenia. Multiple single nucleotide polymorphisms have been identified in this 15q13-14 gene promoter region that are more frequently present in people with schizophrenia than in normal controls. Abnormalities in expression and regulation of central nicotinic cholinoceptors with decreased alpha7 binding in multiple brain regions are also present. Nicotine enhances cognition in schizophrenia. Alternative agents that activate the nicotinic receptor have been tested including 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB-A). This compound improved attention, working memory, and negative symptoms in an add-on study in nonsmoking patients with schizophrenia. There are multiple other nicotinic agents, including positive allosteric modulators, in the preclinical stages of development. Finally, the effects of varenicline and clozapine and their relation to smoking cessation are discussed. PMID- 23027420 TI - Metabotropic glutamate receptors for new treatments in schizophrenia. AB - Metabotropic glutamate receptors (mGluRs) represent exciting targets for the development of novel therapeutic agents for schizophrenia. Recent studies indicate that selective activation of specific mGluR subtypes may provide potential benefits for not only the positive symptoms, but also the negative symptoms and cognitive impairments observed in individuals with schizophrenia. Although optimization of traditional orthosteric agonists may still offer a feasible approach for the activation of mGluRs, important progress has been made in the discovery of novel subtype-selective allosteric ligands, including positive allosteric modulators (PAMs) of mGluR2 and mGluR5. These allosteric mGluR ligands have improved properties for clinical development and have served as key preclinical tools for a more in-depth understanding of the potential roles of these different mGluR subtypes for the treatment of schizophrenia. PMID- 23027421 TI - Glycine transport inhibitors in the treatment of schizophrenia. AB - Schizophrenia is a severe neuropsychiatric disorder without adequate current treatment. Recent theories of schizophrenia focus on disturbances of glutamatergic neurotransmission particularly at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors are regulated in vivo by the amino acids glycine and D-serine. Glycine levels, in turn, are regulated by glycine type I (GlyT1) transporters, which serve to maintain low subsaturating glycine levels in the vicinity of the NMDA receptor. A proposed approach to treatment of schizophrenia, therefore, is inhibition of GlyT1-mediated transport. Over the past decade, several well tolerated, high affinity GlyT1 inhibitors have been developed and shown to potentiate NMDA receptor-mediated neurotransmission in animal models relevant to schizophrenia. In addition, clinical trials have been conducted with sarcosine (N-methylglycine), a naturally occurring GlyT1 inhibitor, and with the high affinity compound RG1678. Although definitive trials remain ongoing, encouraging results to date have been reported. PMID- 23027422 TI - Nicotinic receptors and functional regulation of GABA cell microcircuitry in bipolar disorder and schizophrenia. AB - Studies of the hippocampus in postmortem brains from patients with schizophrenia and bipolar disorder have provided evidence for a defect of GABAergic interneurons. Significant decreases in the expression of GAD67, a marker for GABA cell function, have been found repeatedly in several different brain regions that include the hippocampus. In this region, nicotinic receptors are thought to play an important role in modulating the activity of GABAergic interneurons by influences of excitatory cholinergic afferents on their activity. In bipolar disorder, this influence appears to be particularly prominent in the stratum oriens of sectors CA3/2 and CA1, two sites where these cells constitute the exclusive neuronal cell type. In sector CA3/2, this layer receives a robust excitatory projection from the basolateral amygdala (BLA) and this is thought to play a central role in regulating GABA cells at this locus. Using laser microdissection, recent studies have focused selectively on these two layers and their associated GABA cells using microarray technology. The results have provided support for the idea that nicotinic cholinergic receptors play a particularly important role in regulating the activity of GABA neurons at these loci by regulating the progression of cell cycle and the repair of damaged DNA. In bipolar disorder, there is a prominent reduction in the expression of mRNAs for several different nicotinic subunit isoforms. These decreases could reflect a diminished influence of this receptor system on these GABA cells, particularly in sector CA3/2 where a preponderance of abnormalities have been observed in postmortem studies. In patients with bipolar disorder, excitatory nicotinic cholinergic fibers from the medial septum may converge with glutamatergic fibers from the BLA on GABAergic interneurons in the stratum oriens of CA3/2 and result in disturbances of their genomic and functional integrity, ones that may induce disruptions of the integration of microcircuitry within this region. PMID- 23027423 TI - Development of disease-modifying treatment of schizophrenia. AB - Development of disease-modifying therapies requires an innovative approach to drug development where novel drugs are designed to target mechanisms of interest rather than to produce preclinical effects similar to those of currently used antipsychotics. Application of such novel strategy will undoubtedly require a very deep understanding of the disease biology that is just starting to emerge. Alternatively, one may let environmental experiences of the diseased individual guide the repair process and use drugs only to facilitate the effects of experience. Such an approach would bring together functional experience that is age-, environment- and disease-dependent with the plasticity resources that may otherwise not be available. There are currently no preclinical drug-environment interaction models that can be claimed to have significant degrees of validity. Therefore, from a drug development perspective, principles that combine acute symptomatic and disease-modifying properties are clearly preferred. The question arises then how such treatments can be differentiated from those that have only symptomatic effects (i.e., most currently used antipsychotic medications). One expectation is that the former will show superior and broader efficacy (especially with longer treatment duration). Another possibility is that disease modifying drugs will be particularly useful at the very earliest stages of the disease. Society and medical communities may not be ready yet to initiate the treatment as early as during the prodromal phase, but the situation may change by the time the science advances enough to bring a convincing case of a drug with disease-modification potential. PMID- 23027419 TI - Glutamatergic synaptic dysregulation in schizophrenia: therapeutic implications. AB - Schizophrenia affects approximately 1% of the population and continues to be associated with poor outcome because of the limited efficacy of and noncompliance with existing antipsychotic medications. An alternative hypothesis invoking the excitatory neurotransmitter, glutamate, arose out of clinical observations that NMDA receptor antagonists, the dissociative anesthetics like ketamine, can replicate in normal individuals the full range of symptoms of schizophrenia including psychosis, negative symptoms, and cognitive impairments. Low dose ketamine can also re-create a number of physiologic abnormalities characteristic of schizophrenia. Postmortem studies have revealed abnormalities in endogenous modulators of NMDA receptors in schizophrenia as well as components of a postsynaptic density where NMDA receptors are localized. Gene association studies have revealed several genes that affect NMDA receptor function whose allelic variants are associated with increased risk for schizophrenia including genes encoding D-amino acid oxidase, its modulator G72, dysbindin, and neuregulin. The parvalbumin-positive, fast-firing GABAergic interneurons that provide recurrent inhibition to cortical-limbic pyramidal neurons seem to be most sensitive to NMDA receptor hypofunction. As a consequence, disinhibition of glutamatergic efferents disrupts cortical processing, causing cognitive impairments and negative symptoms, and drives subcortical dopamine release, resulting in psychosis. Drugs designed to correct the cortical-limbic dysregulated glutamatergic neurotransmission show promise for reducing negative and cognitive symptoms of schizophrenia as well as its positive symptoms. PMID- 23027424 TI - Spin-polarized semiconductors: tuning the electronic structure of graphene by introducing a regular pattern of sp3 carbons on the graphene plane. AB - First-principles calculations (generalized gradient approximation, density functional therory (DFT) with dispersion corrections, and DFT plus local atomic potential) are carried out on the stability and electronic structures of superlattice configurations of nitrophenyl diazonium functionalized graphene with different coverage. In the calculations, the stabilities of these structures are strengthened significantly since van der Waals interactions between nitrophenyl groups are taken into account. Furthermore, spin-polarized and wider-bandgap electronic structures are obtained when the nitrophenyl groups break the sublattice symmetry of the graphene. The unpaired quasi-localized p electrons are responsible for this itinerant magnetism. The results provide a novel approach to tune graphene's electronic structures as well as to form ferromagnetic semiconductive graphene. PMID- 23027425 TI - The roots of cancer: stem cells and the basis for tumor heterogeneity. AB - Recent studies of prostate cancer and other tumor types have revealed significant support, as well as unexpected complexities, for the application of concepts from normal stem cell biology to cancer. In particular, the cell of origin and cancer stem cell models have been proposed to explain the heterogeneity of tumors during the initiation, propagation, and evolution of cancer. Thus, a basis of intertumor heterogeneity has emerged from studies investigating whether stem cells and/or non-stem cells can serve as cells of origin for cancer and give rise to tumor subtypes that vary in disease outcome. Furthermore, analyses of putative cancer stem cells have revealed the genetically diverse nature of cancers and expanded our understanding of intratumor heterogeneity and clonal evolution. Overall, the principles that have emerged from these stem cell studies highlight the challenges to be surmounted to develop effective treatment strategies for cancer. PMID- 23027426 TI - Functional redundancy between Cdc14 phosphatases in zebrafish ciliogenesis. AB - BACKGROUND: Cyclin-dependent kinases (Cdks) and their counteracting phosphatases are key regulators of cell cycle progression. In yeasts, the Cdc14 family of phosphatases promotes exit from mitosis and progression through cytokinesis by reversing phosphorylation of Cdk1 substrates. In vertebrates, CDC14 paralogs, CDC14A and CDC14B, have so far been implicated in processes ranging from DNA damage repair, meiosis, centrosome duplication to ciliogenesis. However, the question of whether CDC14 paralogs can functionally compensate for each other has yet to be addressed. RESULTS: Here, using antisense morpholino oligonucleotides to inhibit Cdc14A1 function, we observed that Cdc14A1 depleted zebrafish embryos displayed ventrally curved body and left-right asymmetry defects, similar to Cdc14B deficient embryos and zebrafish mutants with cilia defects. Accordingly, we found that Cdc14A1, like Cdc14B, plays a role in ciliogenesis in the Kupffer's vesicle (KV) and other ciliated tissues, and can do so independently of its function in cell cycle. Furthermore, we observed reciprocal suppression of KV cilia length defects of Cdc14A1 and Cdc14B deficient embryos by cdc14b and cdc14a1 RNAs, respectively. CONCLUSIONS: Together, these studies demonstrate for the first time that Cdc14A and Cdc14B have overlapping functions in the ciliogenesis process during zebrafish development. PMID- 23027427 TI - Prophylactic and therapeutic efficacy of an attenuated Listeria monocytogenes based vaccine delivering HPV16 E7 in a mouse model. AB - Listeria monocytogenes (L. monocytogenes) has been developed as a cancer vaccine vector due to its ability to elicit strong innate and adaptive immune responses. For clinical application, it is necessary to exploit a Listeria platform strain that is safe and that also retains its immunogenicity to develop vaccine candidates against cancer. In this study, a highly attenuated strain with a deletion of actA/plcB was employed as a vector to deliver the human papillomavirus type 16 (HPV16) E7 antigen, which was stably inserted into the chromosome of L. monocytogenes. The prophylactic and therapeutic efficacy of the recombinant L. monocytogenes strain expressing E7 (LM1-2-E7) were evaluated in C57BL/6 mice. In prophylactic tumor challenge assays, immunization with the recombinant strain LM1-2-E7 was able to protect against tumor formation in 87.5% of the mice, even after a second challenge, suggesting that this prophylactic immunization can provide long-lasting immunity. In the therapeutic setting, immunization with LM1-2-E7 led to tumor regression in 50% of the mice and suppressed tumor growth in the remaining mice. The results showed that the recombinant strain was cleared by the immune system within 5 days after immunization and induced a Th1 immune response against E7 peptide and E7-specific cytotoxic T-lymphocyte (CTL) killing activity without severe inflammatory responses in the spleen and liver. Markedly, recombinant Listeria strain resulted in preferential accumulation within tumor tissues and induced higher numbers of CD8+ T cells that infiltrated into the tumor, which were associated with retardation of tumor growth. Collectively, these data indicate that LM1-2-E7 is a possible vaccine candidate against cervical cancer. PMID- 23027428 TI - Assessment of the health status of wild fish from the Wheatley Harbour Area of Concern, Ontario, Canada. AB - The overall health and endocrine function of wild brown bullhead (Ameiurus nebulosus) and goldfish (Carassius auratus) from the Wheatley Harbour Area of Concern (Lake Erie, Ontario, Canada) was assessed using a suite of physiological and biochemical endpoints. Smaller gonads were detected in female brown bullhead and goldfish from Wheatley Harbour compared with Hillman Marsh (Ontario, Canada) reference fish. Female brown bullhead exhibited decreased in vitro synthesis of 17beta-estradiol. Female goldfish had decreased plasma vitellogenin concentrations. Plasma testosterone and 11-ketotestosterone were significantly depressed in males of both species. Perturbations in the thyroid status were detected, but varied between sexes and species. Observed differences included lower plasma concentrations of thyroid hormones and/or elevated liver deiodinase activity. Histological evaluation of the thyroid tissue indicated that in the case of female goldfish, those perturbations stimulated the thyroid (as indicated by increased thyroid epithelial cell height) and partially depleted the thyroxine reserves, as indicated by decreased colloid and elevated thyroid activation index. Increased mixed-function oxygenase activity in brown bullhead from Wheatley Harbour was consistent with exposure to planar aromatic contaminants. A principal component analysis of selected variables showed the separation of fish by collection site. The endpoints most strongly associated with the separation were generally those exhibiting significant differences between sites. The results of the present study indicate that the health of fish populations within Wheatley Harbour warrants continued attention. PMID- 23027429 TI - Ask Suicide-Screening Questions (ASQ): a brief instrument for the pediatric emergency department. AB - OBJECTIVE: To develop a brief screening instrument to assess the risk for suicide in pediatric emergency department patients. DESIGN: A prospective, cross sectional instrument-development study evaluated 17 candidate screening questions assessing suicide risk in young patients. The Suicidal Ideation Questionnaire served as the criterion standard. SETTING: Three urban, pediatric emergency departments associated with tertiary care teaching hospitals. PARTICIPANTS: A convenience sample of 524 patients aged 10 to 21 years who presented with either medical/surgical or psychiatric chief concerns to the emergency department between September 10, 2008, and January 5, 2011. MAIN EXPOSURES: Participants answered 17 candidate questions followed by the Suicidal Ideation Questionnaire. MAIN OUTCOME MEASURES: Sensitivity, specificity, predictive values, likelihood ratios, and area under the receiver operating characteristic curves of the best fitting combinations of screening questions for detecting elevated risk for suicide. RESULTS: A total of 524 patients were screened (344 medical/surgical and 180 psychiatric). Fourteen of the medical/surgical patients (4%) and 84 of the psychiatric patients (47%) were at elevated suicide risk on the Suicidal Ideation Questionnaire. Of the 17 candidate questions, the best-fitting model comprised 4 questions assessing current thoughts of being better off dead, current wish to die, current suicidal ideation, and past suicide attempt. This model had a sensitivity of 96.9% (95% CI, 91.3-99.4), specificity of 87.6% (95% CI, 84.0 90.5), and negative predictive values of 99.7% (95% CI, 98.2-99.9) for medical/surgical patients and 96.9% (95% CI, 89.3-99.6) for psychiatric patients. CONCLUSIONS: A 4-question screening instrument, the Ask Suicide-Screening Questions (ASQ), with high sensitivity and negative predictive value, can identify the risk for suicide in patients presenting to pediatric emergency departments. PMID- 23027430 TI - Synthesis, crystal structure and physical properties of the clathrate-I phase Ba(8)Rh(x)Si(46-x-y?y). AB - The new clathrate-I phase Ba(8)Rh(x)Si(46-x-y?y) (2.36 < x < 2.74; y = 0.65 for x = 2.74), Pearson symbol cP54, space group Pm3[combining macron]n, was prepared as a single phase and characterized. For these compositions, the lattice parameter does not change significantly and was found to be a = 10.347(1) A. Phase relations were investigated by means of metallographic and thermal analyses. The incongruently melting phase Ba(8)Rh(x)Si(46-x-y?y) was obtained by annealing a solidified melt of the stoichiometric composition at 1000 degrees C for five days. Below 850 degrees C, the clathrate phase slowly decomposes to BaSi(2), Si and the new compound BaRh(2)Si(9). Crystal structure and vacancy concentration were investigated by means of single crystal and powder X-ray diffraction and wavelength dispersive X-ray spectroscopy analyses. Quantum chemical calculations show that the Rh 4d states hybridize with Si 3p states so that the DOS structure cannot be simply deduced in a rigid band approach from that of the binary Ba(8)Si(46). Analysis of the chemical bonding applying the ELI-D approach yielded covalent two-center two-electron bonds between Rh and Si atoms. For the composition Ba(8)Rh(2.74)Si(42.61?0.65), a temperature dependent diamagnetic susceptibility and an almost temperature independent electrical resistivity (rho~ 5 MUOmegam) were observed. The magnitude of the negative Seebeck coefficient is increasing linearly with temperature from 0 MUV K(-1) at 2 K to -35 MUV K(-1) at 850 K indicating n-type electrical conductivity. PMID- 23027431 TI - Modulation of Golgi-associated microtubule nucleation throughout the cell cycle. AB - A microtubule (MT) subpopulation that emanates from Golgi membrane has been recently shown to comprise a significant part of MT network in interphase cells. In this study, we address whether Golgi membrane, which is being extensively remodeled throughout the cell cycle, retains its ability to nucleate MTs at diverse cell cycle stages. Live cell imaging and immunofluorescence microscopy reveals that Golgi-derived MTs form at multiple stages of the cell cycle, including G(1), G(2), and distinct phases of mitosis. However, the capacity of Golgi to nucleate MTs in mitosis is strongly down-regulated as compared with interphase, indicating that this property is cell cycle regulated. We demonstrate that Golgi-derived MTs are indispensable for efficient Golgi assembly in telophase, and speculate that these noncentrosomal MTs may hold specific functions at other cell cycle stages. PMID- 23027432 TI - The influence of Hispanic ethnicity on nonsmall cell lung cancer histology and patient survival : an analysis of the surveillance, epidemiology, and end results database. PMID- 23027433 TI - Endoscopic endonasal versus open repair of anterior skull base CSF leak, meningocele, and encephalocele: a systematic review of outcomes. AB - BACKGROUND: Repair of anterior skull base cerebrospinal fluid (CSF) leaks, encephaloceles, and meningoceles can prevent meningitis, intracranial abscess, and pneumocephalus. Various surgical techniques have been employed for repair, including open transcranial and transfacial methods. The endoscopic endonasal approach represents a minimal access but equally aggressive alternative. We conducted a systematic review of case series and case reports to assess the role of endoscopy in the management of these lesions. METHODS: We performed a MEDLINE search of the literature (1950-2010) to identify open and endoscopic surgical series for repair of anterior skull base CSF leaks, encephaloceles, and meningoceles. Comparisons were made for patient and defect characteristics as well as success of repair, morbidity, and outcome. RESULTS: Seventy-one studies, involving 1178 patients, were included. There was no significant difference in the rate of successful repair (~90%) between the open and endoscopic cohorts. Compared with open approaches, complications were significantly lower in the endoscopic group, including meningitis (3.9% versus 1.1%, p = 0.034), abscess/wound infection (6.8% versus 0.7%, p < 0.001), and sepsis (3.8% versus 0%, p = 0.003). Perioperative mortality was also lower in the endoscopic group (0%) compared with the open group (1.4%) (p < 0.001). CONCLUSION: Our systematic review supports the endoscopic endonasal approach as a safe and effective alternative for the treatment of anterior skull base defects, which may be preferable in select patients. PMID- 23027434 TI - Purely neuroendoscopic resection of an intraventricular cavernous angioma: case report. AB - BACKGROUND: Intraventricular cavernomas are rare and generally treated by microsurgical approach. With the advances in neuroendoscopy, intraventricular lesions have been managed by this technique. However, tumor size and vascular nature are considered restrictive factors. As far as we are concerned, there are two cases in the literature of intraventricular cavernoma resection done by neuroendoscopy. CASE: We describe a case of a man who presented with hydrocephalus secondary to a mesencephalic cavernoma and a second cavernous angioma located at the dorsum thalamus. This second lesion was successfully removed using a pure neuroendoscopic technique at the same time as a third ventriculostomy was performed. CONCLUSION: As neuroendoscopy evolves, we see that lesions considered impossible to be managed by neuroendoscopy before today are being treated with the advantages that the minimally invasive surgery offers. PMID- 23027435 TI - The trans-frontal-sinus subcranial approach for removal of large olfactory groove meningiomas: surgical technique and comparison to other approaches. AB - BACKGROUND AND STUDY OBJECTIVE: Several surgical approaches have been previously reported for the treatment of olfactory groove meningiomas (OGM).The trans frontal-sinus subcranial approach (TFSSA) for the removal of large OGMs is described, comparing it with other reported approaches in terms of advantages and drawbacks. MATERIAL AND METHODS: The TFSSA was performed on cadaveric specimens to illustrate the surgical technique. RESULTS: The surgical steps of the TFSSA and the related anatomical pictures are reported. The approach was adopted in a clinical setting; a case illustration is reported to demonstrate the feasibility of the described approach and to provide intraoperative pictures. CONCLUSION: The TFSSA represents a possible route to treat large OGMs. The subcranial approach provides early devascularization of the tumor, direct tumor access from the base without traction on the frontal lobes, good overview of dissection of the optic nerves and anterior cerebral arteries, and dural reconstruction with pedicled pericranial flap. PMID- 23027436 TI - Transdural imaging of meningiomas by indocyanine green videography: the eclipse sign. AB - BACKGROUND: Indocyanine green videography has been introduced into neurosurgical fields for minimally invasive neurosurgery. To establish a new intraoperative imaging modality, we performed transdural indocyanine green videography during the surgery of meningiomas. METHOD: A dose of 12.5 mg of indocyanine green was injected transvenously in two cases of meningiomas just before the dural opening. Transdural indocyanine green videography was monitored. RESULTS: The cortical arteries and veins and the venous sinus were identified by the indocyanine green videography transdurally in both cases. The projection of meningiomas was identified as the shadow and signal negative regions, and was visualized as "the Eclipse." CONCLUSION: Transdural observation of the cortical arteries and veins and the venous sinus was successfully performed followed by the visualization of the projection of meningiomas as the shadow. We propose this sign as "the Eclipse sign." This transdural imaging method was of value in terms of precise and minimal dural incision. PMID- 23027440 TI - Conducting research with non-clinical healthy undergraduates: does effort play a role in neuropsychological test performance? AB - Poor effort by examinees during neuropsychological testing has a profound effect on test performance. Although neuropsychological experiments often utilize healthy undergraduate students, the test-taking effort of this population has not been investigated previously. The purpose of the present study was to determine whether undergraduate students exercise variable effort in neuropsychological testing. During two testing sessions, participants (N = 36) were administered three Symptom Validity Tests (SVTs), the Test of Memory Malingering, the Dot Counting Test, and the Victoria Symptom Validity Test (VSVT), along with various neuropsychological tests. Analyses revealed 55.6% of participants in Session 1 and 30.8% of participants in Session 2 exerted poor effort on at least one SVT. Poor effort on the SVTs was significantly correlated with poor performance on various neuropsychological tests and there was support for the temporal stability of effort. These preliminary results suggest that the base rate of suboptimal effort in a healthy undergraduate population is quite high. Accordingly, effort may serve as a source of variance in neuropsychological research when using undergraduate students. PMID- 23027441 TI - Czech version of the Trail Making Test: normative data and clinical utility. AB - The Trail Making Test (TMT) comprises two psychomotor tasks that measure a wide range of visual-perceptual and executive functions. The purpose of this study was to provide Czech normative data and to examine the relationship between derived TMT indices and demographic variables. The TMT was administered to 421 healthy adults. Two clinical groups (n = 126) were evaluated to investigate the clinical utility of the TMT-derived scores: amnestic mild cognitive impairment (n = 90) and Alzheimer's disease (n = 36). Statistical analyses showed that age and education, but not gender, were significantly associated with TMT completion times and derived scores. Of all the indices, only the TMT ratio score was insensitive to age. We present normative values for the Czech version of the TMT, providing a reference for measuring individual performance in native Czech speakers. Moreover, we found that accuracy on the TMT was improved with the attenuation of age. PMID- 23027439 TI - Functional protein microarray as molecular decathlete: a versatile player in clinical proteomics. AB - Functional protein microarrays were developed as a high-throughput tool to overcome the limitations of DNA microarrays and to provide a versatile platform for protein functional analyses. Recent years have witnessed tremendous growth in the use of protein microarrays, particularly functional protein microarrays, to address important questions in the field of clinical proteomics. In this review, we will summarize some of the most innovative and exciting recent applications of protein microarrays in clinical proteomics, including biomarker identification, pathogen-host interactions, and cancer biology. PMID- 23027443 TI - Sex and gender differences in clinical medicine. AB - Sex and gender differences in frequent diseases are more widespread than one may assume. In addition, they have significant yet frequently underestimated consequences on the daily practice of medicine, on outcomes and effects of therapies. Gender medicine is a novel medical discipline that takes into account the effects of sex and gender on the health of women and men. The major goal is to improve health and health care for both, for women as well as for men. We give in this chapter an overview on sex and gender differences in a number of clinical areas, in cardiovascular diseases, pulmonary diseases, gastroenterology and hepatology, in nephrology, autoimmune diseases, endocrinology, hematology, neurology. We discuss the preferential use of male animals in drug development, the underrepresentation of women in early and cardiovascular clinical trials, sex and gender differences in pharmacology, in pharmacokinetics and pharmacodynamics, in management and drug use. Most guidelines do not include even well-known sex and gender differences. European guidelines for the management of cardiovascular diseases in pregnancy have only recently been published. Personalized medicine cannot replace gender-based medicine. Large databases reveal that gender remains an independent risk factor after ethnicity, age, comorbidities, and scored risk factors have been taken into account. Some genetic variants carry a different risk in women and men. The sociocultural dimension of gender integrating lifestyle, environment, stress, and other variables cannot be replaced by a sum of biological parameters. Because of this prominent role of gender, clinical care algorithms must include gender-based assessment. PMID- 23027442 TI - Structural disorganization of pronephric glomerulus in zebrafish mpp5a/nagie oko mutant. AB - BACKGROUND: The podocyte slit diaphragm (SD) is an essential component of the selective filtration barrier in the glomerulus. Several structural proteins required for formation and maintenance of SD have been identified; however, molecular mechanisms regulating these proteins are still limited. RESULTS: Here, we demonstrate that MAGUK p55 subfamily member 5a (Mpp5a)/Nagie oko, a component of the Crb multi-protein complex, was colocalized with an SD-associated protein ZO-1 in the zebrafish pronephric glomerulus. To characterize the function of Mpp5a, zebrafish mpp5a(m520) mutant embryos, which are known to have defects in cardiac and neuronal morphogenesis, were analyzed. These mutants failed to merge the bilateral glomerular primordia and to form the glomerular capillary and mesangium, but the foot processes and SD showed normal appearance. The structural disorganization in the mpp5a(m520) mutant glomerulus was quite similar to that of a cardiac troponin T2a/tnnt2a/silent heart knockdown zebrafish, which exhibited circulatory failure due to lack of heart beating. CONCLUSIONS: Mpp5a is not prerequisite to form podocyte slit diaphragm in the pronephric glomerular development in zebrafish. The structural disorganization of the pronephric glomerulus in the mpp5a(m520) mutant is likely to result from circulatory failure, rather than the anomaly of Mpp5a protein in the glomerulus. PMID- 23027444 TI - Sex differences in animal models for cardiovascular diseases and the role of estrogen. AB - Clinical findings show sex differences in the manifestation of a number of cardiovascular diseases (CVD). However, the underlying molecular mechanisms are incompletely understood. Multiple animal models suggest sex differences in the manifestation of CVD, and provide strong experimental evidence that different major pathways are regulated in a sex-specific manner. In most animal studies females display a lower mortality, less severe hypertrophy, and better preserved cardiac function compared with male counterparts. The data support the hypothesis that female sex and/or the sex hormone estrogen (17beta-estradiol; E2) may contribute to the sexual dimorphism in the heart and to a better outcome of cardiac diseases in females. To improve our understanding of the sex-based molecular and cellular mechanisms of CVD and to develop new therapeutic strategies, the use of appropriate animal models is essential. This review highlights recent findings from animal models relevant for studying the mechanisms of sexual dimorphisms in the healthy and diseased heart, focusing on physiological hypertrophy (exercise), pathological hypertrophy (volume and pressure overload induced hypertrophy), and heart failure (myocardial infarction). Furthermore, the potential effects of E2 in these models will be discussed. PMID- 23027445 TI - Sex differences at cellular level: "cells have a sex". AB - Different pathways involved in the complex machinery implicated in determining cell fate have been investigated in the recent years. Different forms of cell death have been described: apart from the "classical" form of death known as necrosis, a well characterized traumatic injury of the cell, several additional forms of cell death have been identified. Among these, apoptosis has been characterized in detail. These studies stem from the implication that the apoptotic process plays a key role in a plethora of human pathologies, including cardiovascular diseases. In fact, defects in the mechanisms of cell death, i.e., both an increase or a decrease of apoptosis, have been associated with the pathogenesis of vessel and myocardial diseases. Some new insights also derived from the study of autophagy, a less characterized form of cell damage mainly associated with cell survival strategies but that also leads, as final event, to the death of the cell. Interestingly, very recently, a gender difference has been found in this respect: cells from males and females can behave differently. In fact, they seem to display several different features, including those determining their fate. These gender cytology differences are briefly described here. The study of this gender disparity is of great relevance in cardiovascular disease pathogenesis and pharmacology. The comprehension of the gender-related mechanisms of cell demise can in fact disclose new scenarios in preclinical and clinical management of cardiovascular diseases. PMID- 23027447 TI - Sex differences in drug effects: interaction with sex hormones in adult life. AB - In recent years, it has become clear that women and men may differ for drug response. Also, there is an increasing recognition on the role of sex hormones on pharmacokinetics and pharmacodynamics as mechanism accounting for sex differences in drug effects.In women, the phases of menstrual cycle, of reproductive life and fluctuations in the concentrations of sexual steroids on pharmacokinetics and pharmacodynamics must be considered. Furthermore, the use of oral contraceptives or hormonal replacement therapy, the sex hormone-related changes in total body water or in the amount of fat influence the overall effect of drugs.On the contrary, the influence of androgens on drug effects is minimal because of the even plasma levels of these hormones in adult males.Nevertheless, since women have been scarcely included in the early phases of clinical trials, the results obtained in men have been often translated to women and their exact response to drugs is still not well known.The available evidence suggests that sex hormones influence drug absorption, distribution, metabolism, pharmacodynamics, and adverse effects. For instance, many cardiovascular drugs are metabolized by enzymes of the cytochrome P450 mono-oxygenases system, which is more expressed in females than in males, showing sex differences in drug response.Upcoming pharmacological research should aim to further clarify the influence of sex hormones on drug effects and, for this purpose, to increase the number of women enrolled in all phases of clinical trials. An evidence-based pharmacotherapy in women is therefore auspicable for women's health. PMID- 23027448 TI - Sex and gender in adverse drug events, addiction, and placebo. AB - Sex-gender-based differences in response to pharmaceutical treatments are still under evaluation but evidence already exists regarding the impact of sex-gender related differences on drug safety profile, drug abuse/addiction, and placebo effects. For a number of drugs it is well recognized that a sex-gender dimorphic profile in terms of drug adverse effects exists and appears to be more frequent and severe in women than in men. However, it is not well known whether this is due to pharmacodynamic or pharmacokinetic differences. Indeed the optimization of therapy requires that attention is paid to single sex-gender. Numerous pharmacokinetic, pharmacodynamic, and sociocultural differences between women and men in drug abuse have been described. Here we focus on sex-gender differences in alcoholism and nicotine addiction. The relevance of sex and gender differences in addiction appear to be relevant. Specific programs aimed to address addicted women's specific needs (child care, pregnancy, housing, and violence and others) are recommended. Finally, this article discusses the possible effect of sex gender on placebo response in the light of the more significant recent literature evidencing that studies are urgently required in order to better understand the role of sex-gender on placebo mechanism and its impact on randomized clinical trials outcomes. PMID- 23027450 TI - "Gender-specific drug prescription in Germany" results from prescriptions analyses. AB - There are still considerable differences in the medication supply for men and women. While the prescription volumes for both men and women have, for some time, been similar or have even risen for the men, there are still characteristic differences between the sexes when it comes to the prescription of certain indication groups. Women are still prescribed clearly more drugs in the field of psychotropic medication, especially antidepressants, hypnotic drugs, and tranquilisers. As the American Beers criteria for quite some time now and, more recently, the German PRISCUS list have shown, the effects of such drugs are potentially dangerous, particularly for older women. The known adverse effects are, apart from dependence problems, restricted cognitive capacities, insecure or instable walking, and badly healing wounds from falling accidents that are followed by patient's nursing care dependency. In secondary prophylaxis after acute myocardial infarction, the characteristic prescription features of the various medicinal products that are used for both men and women (such as platelet aggregation inhibitors, beta-receptor blockers, ACE-inhibitors, statins) have become similar; women's still higher mortality risk appears to go back to the fact that too much time is spent before proper hospital treatment commences. In general, more attention should be paid to the right medication, the right length of treatment, and the right dosage of the medication prescribed to women; the evidence concerning women's supply of medicinal products should also be improved. PMID- 23027449 TI - Considerations of sex and gender differences in preclinical and clinical trials. AB - Women continue to be underrepresented in clinical trials, particularly in Phases I and II of experimental drug studies in spite of legislative guidelines in the USA, Canada, the European Union, Australia, and Japan requiring the inclusion of women in clinical trials. As such, women remain a vulnerable population subject to the adverse effects of pharmacological therapies. Thus, women experience higher rates of adverse drug reactions than do men and for women of reproductive age or who may be pregnant, therapeutic options may be limited. This chapter provides a brief history of inclusion of sex and gender as variables in clinical trials, summarizes governmental legislation for consideration of sex and gender in clinical trials and provides specific examples of drugs which have been withdrawn from the market because of side effects in women. Additional information related to sex and gender in preclinical testing, trial design, challenges to recruitment of women for clinical trials and statistical methods for analysis of data also is considered. PMID- 23027446 TI - What a difference an X or Y makes: sex chromosomes, gene dose, and epigenetics in sexual differentiation. AB - A modern general theory of sex determination and sexual differentiation identifies the factors that cause sexual bias in gene networks, leading to sex differences in physiology and disease. The primary sex-biasing factors are those encoded on the sex chromosomes that are inherently different in the male and female zygotes. These factors, and downstream factors such as gonadal hormones, act directly on tissues to produce sex differences and antagonize each other to reduce sex differences. Recent studies of mouse models such as the four core genotypes have begun to distinguish between the direct effects of sex chromosome complement (XX vs. XY) and hormonal effects. Several lines of evidence implicate epigenetic processes in the control of sex differences, although a great deal of information is needed about sex differences in the epigenome. PMID- 23027451 TI - Gender and polypharmacotherapy in the elderly: a clinical challenge. AB - Polypharmacotherapy is a major concern in the elderly and especially in older women after the age of 80. It results from the intake of prescription and non prescription drugs, being often a problem of evidence-based therapy. Besides the fact that women live longer than men and outnumber them, reasons for polypharmacy in women are diverse and include a different attitude towards intake of drugs between men and women, the propensity of women to rather see a physician and talk about their problems, the load of family responsibility as women are the main caregivers within a family, the influence of physician sex on patient care, the level of education, social deprivation and self-rated health. Women are more often prescribed potentially inappropriate medication and more often become victims of adverse drug reactions. This is not only due to the number and quality of drugs prescribed but also to differences in pharmacokinetics and - dynamics which make them more vulnerable to drug exposure. Thus, inappropriate prescribing contributes to hospitalization, poor quality of life, costs, compliance issues and poor outcomes. More preclinical and clinical studies with elderly patients and especially elderly women are needed to study the underlying mechanisms of the pharmacologic differences and obtain more insight into the difference in risk between men and women. Attention to prescribing of medications, consistent review of medication lists, and reevaluation of indications and outcomes of prescribing are essential to ensure that drugs are used appropriately in elderly women, polypharmacy is minimized and safety for patients is maximized. PMID- 23027452 TI - Role of physician gender in drug therapy. AB - There is evidence that female patients receive less intensified drug therapy in many medical conditions than male patients. However, there are only limited data regarding the influence of physician gender on drug therapy. It has been shown, for example, that female physicians tend to adhere more closely to guideline recommended pharmacotherapy compared to their male counterparts. In some medical conditions where drug therapy is only one among various components of a complex interplay of therapeutic regimes (e.g., diabetes, cardiovascular diseases, depression, pain management), female physicians seem to achieve better overall intermediate outcomes and some studies suggest that "better" drug therapy is provided by female compared to male physicians. The reasons for the overall better outcomes may be superior communication skills of female physicians, participatory decision making, and consequently improved drug adherence in addition to or in combination with more effective non-pharmacologic treatment results. It is impossible to distinguish between the individual contributions of drug- and nondrug-related influence on such improved outcomes and thus to determine whether they are due to unconfounded physician gender effects on drug therapy. There is until now in no area of medicine evidence to suggest that a patient will consistently receive higher quality of drug therapy by switching to a physician of a specific gender. PMID- 23027453 TI - Sex and gender differences in cardiovascular drug therapy. AB - This chapter outlines sex differences in pharmacokinetics and pharmacodynamics of the most frequently used drugs in cardiovascular diseases, e.g., coronary artery disease, hypertension, heart failure. Retrospective analysis of previously published drug trials revealed marked sex differences in efficacy and adverse effects in a number of cardiovascular drugs. This includes a higher mortality among women taking digoxin for heart failure, more torsade de pointes arrhythmia in QT prolonging drugs and more cough with ACE inhibitors. Trends towards a greater benefit for women and/or female animals have been observed in some studies for endothelin receptor antagonists, the calcium channel blocker amlodipine, the ACE-inhibitor ramipril and the aldosterone antagonist eplerenone. However, reproduction of these results in independent studies and solid statistical evidence is still lacking. Some drugs require a particularly careful dose adaptation in women: the beta-blocker metoprolol, the calcium channel blocker verapamil, loop-, and thiazide diuretics. In conclusion, sex differences in pharmacokinetics and pharmacodynamics have to be taken into account for cardiovascular drug therapy in women. PMID- 23027454 TI - Sex and gender aspects in antiarrhythmic therapy. AB - Although cardiac arrhythmia had long been considered a predominantly male syndrome, it is now clear that arrhythmia is also a primary cause of mortality in women. Notably, the manifestation of specific arrhythmia syndromes appears to be gender specific. In particular, female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes which occur as adverse effects of existing drugs. Males, on the other hand, are more likely to develop Brugada syndrome. Recent clinical and experimental studies suggest that these differences may stem from intrinsic sex differences in cardiac tissue. These include fundamental electrical differences resulting from variable ion channel expression and diverse sex hormonal regulation via long-term genomic and acute nongenomic pathways, and sex differences in drug responses and metabolisms. Undoubtedly, determining the effect of gender on cardiac function will be difficult and require sophisticated methodologies. However, gender differences underlying predilection to distinct arrhythmia syndromes must be revealed so that new therapeutic strategies that take gender into account can be applied to at risk patients. PMID- 23027455 TI - Sex and gender aspects in anesthetics and pain medication. AB - The influence of sex and gender on anesthesia and analgesic therapy remains poorly understood, nevertheless the numerous physiological and pharmacological differences present between men and women. Although in anesthesiology sex-gender aspects have attracted little attention, it has been reported that women have a greater sensitivity to the non-depolarizing neuroblocking agents, whereas males are more sensitive than females to propofol. It has been suggested that men wake slower than women after general anesthesia and have less postoperative nausea and vomiting. Sexual hormones seem to be of importance in the onset of differences. Nevertheless, in the last years, sex-gender influences on pain and analgesia have become a hot topic and data regarding sex-gender differences in response to pharmacologic and non-pharmacologic pain treatments are still scanty, inconsistent, and non-univocal. In particular, females seem to be more sensitive than males to opioid receptor agonists. Women may experience respiratory depression and other adverse effects more easily if they are given the same doses as males. Evidently, there is an obvious need for more research, which should include psychological and social factors in experimental preclinical and clinical paradigms in view of their importance on pain mechanism, in order to individualize analgesia to optimize pain relief. PMID- 23027456 TI - Psychopharmacological treatment of mood and anxiety disorders during pregnancy. AB - Many women with psychiatric disorders want to become mothers and only a minority seek advise prior to becoming pregnant. In those women, in whom pregnancy can be planned, the decision, if a medication is required for stabilisation and which one to choose if this is the case, is easier to make than in women in whom pregnancy occurs unplanned. The physician has to weigh the risk that a relapse of the psychiatric disorder during pregnancy poses to the foetus against the reproductive risk of psychotropic drugs. This presentation is intended to assist in understanding the general principles of pharmacotherapy during pregnancy as well as the morphological, perinatal and neurobehavioural toxicity of antidepressants, antipsychotics, benzodiazepines and mood stabilisers. PMID- 23027457 TI - Obesity and diabetes. PMID- 23027458 TI - Adrenal disorders. PMID- 23027459 TI - Thyroid disorders. AB - All forms of thyroid diseases are much more frequently observed in women than men, although the reasons are still not completely elucidated.Hyperthyroidism is defined by elevated circulating free thyroid hormones. The prevalence is about 2 % in women and 0.2 % in men. The most frequent causes are various forms of thyroid autonomy in elderly women and Graves' disease, which occurs mostly in younger women.Hypothyroidism is defined by a lack of thyroid hormones. It is a common endocrine disorder caused by autoimmune thyroiditis (Hashimoto thyroiditis), iodine deficiency or following surgery or radioiodine therapy. Thyroxine requirements depend on fat-free mass and are, therefore, somewhat higher in males who are more often undersubstituted. In pregnancy lower TSH reference ranges have to be considered and thyroid function should be monitored throughout pregnancy to avoid harm to the foetus caused by maternal thyroid dysfunctions. If overtreated women more often feature fractures, whereas males more often develop atrial fibrillation. PMID- 23027460 TI - Sex-specific differences in Type 2 Diabetes Mellitus and dyslipidemia therapy: PPAR agonists. AB - The influence of sex on the development of obesity, Type 2 Diabetes Mellitus (T2DM), and dyslipidemia is well documented, although the molecular mechanism underlying those differences reminds elusive. Ligands of peroxisome proliferator activated receptors (PPARs) are used as oral antidiabetics (PPARgamma agonists: thiazolidinediones, TZDs), or for the treatment of dyslipidemia and cardiovascular diseases, due to their lipid-lowering properties (PPARalpha agonists: fibrates), as PPARs control transcription of a set of genes involved in the regulation of lipid and carbohydrate metabolism. Given a high prevalence of those metabolic disorders, and thus a broad use of PPAR agonists, the present review will discuss distinct aspects of sex-specific differences in antiobesity treatment using those groups of PPAR ligands. PMID- 23027461 TI - Sex differences in the drug therapy for oncologic diseases. AB - There are clear gender-dependent differences in response rates and the probability of side effects in patients treated with chemotherapy. Sex-biased expression levels of metabolic enzymes and transporters in liver and kidney leading to different pharmacokinetics have been described for most common anti cancer drugs. In women, half-life is often longer, which is associated with improved survival, but also increased toxicity.Some chemotherapy protocols lead to a better response rate in women without increasing toxicity (e.g., cisplatin and irinotecan), while others only increase toxicity, but do not improve response rates in women (e.g., 5-fluorouracil). The increased toxicity often correlates with different pharmacokinetics, but women also show a higher sensitivity to some agents with shorter half-life (e.g., steroids). Organ-specific toxicities like cardiac toxicity after doxorubicin treatment or neurotoxicity associated with ifosfamide are more severe in women due to gender-specific changes in gene expression. Novel therapies like tyrosine kinase inhibitors or monoclonal antibodies show very complex, but clinical significant differences depending on gender. Antibodies often have a longer half-life in women, which is associated with an improved response to therapy.Side effects appear to be highly dependent on different tissue properties, as women have a higher incidence of oral mucositis, but lower rates of gut toxicity. Nausea and vomiting is a greater problem in females during therapy due to the lower activity of anti-emetic drugs. Nausea and vomiting pose a bigger challenge in female patients, as anti-emetic drugs seem to be less effective. PMID- 23027462 TI - Sex differences in effects and use of anti-inflammatory drugs. AB - Gender accounts for important differences in the incidence, prevalence, and course of many immunoinflammatory diseases. However, similar treatment strategies, such as the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and tumor necrosis factor-alpha (TNF-alpha) inhibitors, have been advocated for both genders. Experimental studies found that molecular mechanisms of inflammation differ in males and females. In our chapter we summarize the data concerning gender-specific aspects about prevalence of use, drug survival, responsiveness, and adverse drug effects of NSAIDs and TNF-alpha inhibitors. Gender-related differences in the prevalence and course of many autoimmune diseases as well as differences in effects of anti-inflammatory drugs should be considered for the tailored treatment options for these patients. PMID- 23027463 TI - Treatment of irritable bowel syndrome: sex and gender specific aspects. AB - Patients with functional gastrointestinal disorders constitute the majority of patients seeking healthcare for gastrointestinal symptoms in primary and secondary care. Of these disorders irritable bowel syndrome (IBS) is one of the most common and affects 10-20% in the Western world. IBS is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. Sex and gender aspects are important in understanding differences between men and women in their risk and experience of IBS. Relative to men, women are diagnosed more frequently with IBS. Female patients are more likely to be constipated, complain of abdominal distension and of certain extracolonic symptoms. Given the variability of IBS, the most successful treatment will be comprehensive, involving multiple strategies. Efficacy, safety and tolerability are important in the evaluation of IBS therapies, as patients are likely to require long-term treatment. Laxatives, antidiarrheals or antispasmodics are common in the treatment of IBS but the majority of patients receive antispasmodics followed by prokinetic agents. In treatment of IBS there appears to be a greater clinical response to serotonergic agents developed for IBS in women compared to men. There is an absence of drugs licensed specifically for the treatment of IBS. Further studies with novel agents are needed, to evaluate new approaches to IBS management including gender specific behavioral therapies and better characterization of patient subgroups with regard to drug therapy so that personalized therapy can be tested. PMID- 23027465 TI - Gender differences in anticoagulation and antithrombotic therapy. AB - Cardiovascular disease is the main cause of mortality and morbidity worldwide. The rate of thromboembolic events has increased in women but not in men. Large clinical studies support the use of a variety of antithrombotic drugs for the treatment of patients with different cardiovascular diseases. The heterogeneous patient population included in these trials affects the attempt to generalize the study results to subgroups, which are not sufficiently represented in the study population, such as women and other minorities. Gender-related differences in the clinical presentation and outcome seem to relate to differences in platelet biology and coagulation reactions, resulting in different rates of thromboembolic and bleeding events. The effectiveness of antithrombotic therapies and the occurrence of adverse events define the clinical benefit of the treatment for each patient. This chapter gives an overview of the currently available data on gender-differences in anticoagulation and antithrombotic therapy. PMID- 23027464 TI - Sex differences in prophylaxis and therapeutic treatments for viral diseases. AB - The intensity and prevalence of viral infections are typically higher in males than in females. In contrast, disease outcome can be worse for females. Males and females also differ in their responses to prophylaxis and therapeutic treatments for viral diseases. In response to vaccines against herpes viruses, hepatitis viruses, influenza viruses, and others, females consistently mount higher humoral immune responses and experience more frequent and severe adverse reactions than males. Males and females also differ in the absorption, metabolism, and clearance of antiviral drugs. The pharmacological effects, including toxicity and adverse reactions, of antiviral drugs are typically greater in females than males. The efficacy of antiviral drugs at reducing viral load also differs between the sexes, with antiviral treatments being better at clearing HIV and hepatitis C virus in females, but showing greater reduction of herpes simplex virus and influenza A virus loads in males. Biological variables, including hormone and genes, as well as gender-specific factors related to access and compliance to drug regimens must be considered when evaluating male-female differences in responses to treatments for viral diseases. Clinicians, epidemiologists, and basic biomedical scientists should design experiments that include both males and females, develop a priori hypotheses that the sexes will differ in their responses to and the outcome of vaccines and antiviral treatments, and statistically analyze outcome data by sex. Knowledge that the sexes differ in response to prophylaxis and therapeutic treatments for viral diseases should influence the recommended course of treatment differently for males and females. PMID- 23027466 TI - Pharmacology and clinical use of sex steroid hormone receptor modulators. AB - Sex steroid receptors are ligand-triggered transcription factors. Oestrogen, progesterone and androgen receptors form, together with the glucocorticoid and mineralocorticoid receptors, a subgroup of the superfamily of nuclear receptors. They share a common mode of action, namely translating a hormone-i.e. a small molecule signal-from outside to changes in gene expression and cell fate, and thereby represent "natural" pharmacological targets.For pharmacological therapy, these receptors have originally been addressed by hormones and synthetic hormone analogues in order to overcome pathologies related to deficiencies in the natural ligands. Another major use for female sex hormone receptor modulators is oral contraception, i.e. birth control.On the other side, blocking the activity of sex steroid receptors has become an established way to treat hormone-dependent malignancies, such as breast and prostate cancer.In this review, we will discuss how the experience gained from the classical pharmacology of these receptors and their molecular similarities led to new options for the treatment of gender specific diseases and highlight recent progress in medicinal chemistry of sex hormone-modulating drugs. PMID- 23027467 TI - Polychlorinated biphenyls and their hydroxylated metabolites in wild fish from Wheatley Harbour Area of Concern, Ontario, Canada. AB - Whole-body polychlorinated biphenyls (SigmaPCBs) and plasma hydroxylated PCBs (OH PCBs) concentrations were determined in brown bullhead (Ameiurus nebulosus) from Wheatley Harbour, Ontario, Canada. Elevated SigmaPCBs in Wheatley Harbour are suspected to have originated from industrial waste disposal and/or discharges from nearby fish processing through discarding of fish remains. Mean SigmaPCB concentrations in brown bullhead from Wheatley Harbour were approximately 250 ng/g wet weight compared with approximately 40 ng/g wet weight for brown bullhead from the reference sites, Hillman Marsh and Turkey Creek (both in Ontario, Canada). A significant relationship was found between the concentrations of non ortho and mono-ortho PCB concentrations (toxic equivalents) and liver mixed function oxygenase in brown bullhead (r = 0.74, p < 0.001). Plasma OH-PCB concentrations were greater in Wheatley Harbour brown bullhead than in those from Hillman Marsh (3.6 vs 1.5 ng/g wet wt, p < 0.01), and were detected infrequently in those from Turkey Creek (0.1 ng/g wet wt, n = 2). The OH-PCB congeners most frequently detected were 4'-OH-CB172, 3'-OH-CB180, 4-OH-CB187, 4-OH-CB146, 3-OH CB138, and 4-OH-CB130, which are structurally similar to the thyroid hormones. To test the hypothesis of fish waste as the cause of the observed PCB contamination of Wheatley Harbour brown bullhead, a principal component analysis (PCA) was used to compare the brown bullhead PCB congener data with equivalent data for Lake Erie walleye, Lake Erie sediment, and industrial Aroclor mixtures. The relative proportions of each Aroclor mixture were estimated using the conjugated gradient method. The high similarity between the congener signatures for Lake Erie walleye and Wheatley Harbour brown bullhead supports the hypothesis of contamination from the fish processing industry. PMID- 23027468 TI - MMP-9 inhibition suppresses wear debris-induced inflammatory osteolysis through downregulation of RANK/RANKL in a murine osteolysis model. AB - Wear debris-induced osteolysis in periprosthetic tissue with aseptic loosening is a serious problem after total joint arthroplasty. Matrix metalloproteinase-9 (MMP 9) is expressed in osteoclast cells that surround loosening peri-implant tissue, but the molecular mechanism of MMP-9 action in wear debris-induced osteolysis remains ambiguous. We used a murine osteolysis model to examine the hypothesis that administration of an MMP-9 inhibitor reduces the expression of receptor activator of nuclear factor-kappaB (RANK) and nuclear factor-kappaB ligand (RANKL) and, thereby, suppressesdebris-induced inflammatory osteolysis. Experiments were performed in 3 groups of 15 mice: a control, a titanium (Ti) and a Ti plus tetracycline group. To provoke inflammatory osteolysis, calvarial bone was implanted from syngeneic littermates, followed by injection of Ti particles into established air pouches for all groups except the control. Tetracycline was administered daily by intraperitoneal (i.p.) injection, and PBS was administered by i.p. injection to the control and Ti groups. Mice were sacrificed 14 days after bone-Ti implantation. Pouch membranes with the intact bone implants were collected for histological and molecular analysis. Tetracycline had minimum effect on the expression of MMP-9 and tumor necrosis factor-alpha (TNF-alpha) but it decreased gene activation and inhibited the expression of RANK and RANKL, thereby inhibiting Ti-particle-induced inflammatory osteolysis. Tetracycline decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive cells in the pouch tissues. Our results in the murine osteolysis model suggest that through the downregulation of RANK/RANKL, tetracycline significantly inhibits debris-induced inflammatory osteolysis. Its use in clinical practice may help prevent complications experienced by patients who have undergone total joint arthroplasty. PMID- 23027469 TI - Safety of quadrivalent human papillomavirus vaccine administered routinely to females. AB - OBJECTIVE: To assess the safety of the quadrivalent human papillomavirus vaccine (HPV4) in females following routine administration. DESIGN: In a cohort of vaccinated females, we compared the risk of emergency department visits and hospitalizations during the interval soon after vaccination with risk during a comparison interval more remote from vaccination. SETTING: Kaiser Permanente in California. PARTICIPANTS: All females who received the HPV4 vaccine. MAIN EXPOSURE: One or more doses of HPV4 between August 2006 and March 2008. MAIN OUTCOME MEASURES: Outcomes were emergency department visits and hospitalizations, grouped into predefined diagnostic categories. Within diagnostic groups, we used odds ratios (ORs) to estimate whether each subject had any outcome in postvaccination risk intervals (days 1-60, days 1-14, and day 0), compared with a control interval distant in time from vaccination. RESULTS: One hundred eighty nine thousand six hundred twenty-nine females received at least 1 dose and 44 001 received 3 HPV4 doses. Fifty categories had significantly elevated ORs during at least 1 risk interval. Medical record review revealed that most diagnoses were present before vaccination or diagnostic workups were initiated at the vaccine visit. Only skin infections during days 1 to 14 (OR, 1.8; 95% CI, 1.3-2.4) and syncope on day of vaccination (OR, 6.0; 95% CI, 3.9-9.2) were noted by an independent Safety Review Committee as likely associations with HPV4. CONCLUSIONS: The quadrivalent human papillomavirus vaccine was associated with same-day syncope and skin infections in the 2 weeks after vaccination. This study did not detect evidence of new safety concerns among females 9 to 26 years of age secondary to vaccination with HPV4. PMID- 23027470 TI - Radiologic case study. PMID- 23027471 TI - Reflections on the aurora mass shooting. PMID- 23027472 TI - Centromedullary manipulation and stabilization of completely displaced proximal humerus fractures in adolescents. AB - Completely displaced metaphyseal fractures of the proximal humerus in older children may need reduction and stabilization. The authors describe a technique for closed reduction and intramedullary stabilization of these fractures using a centromedullary pin inserted from the distal humerus through a small distal incision. This technique was used successfully in 2 adolescents. Retrograde elastic nails avoid scars in front of the shoulder, impingement problems from prominent extramedullary metal work, and further surgery of a similar magnitude to remove the metalwork. Based on the authors' experience, they recommend this method for reduction and stabilization of displaced irreducible metaphyseal fractures of the proximal humerus in older children and adolescents. PMID- 23027473 TI - Flipping method of a RetroButton during ACL reconstruction with outside-in femoral drilling using a FlipCutter. AB - Little information exists on the intraoperative difficulties and complications of using a RetroButton (Arthrex, Inc, Naples, Florida), which is a new suspensory device. However, some difficulties are encountered, such as incomplete sitting, pulling at the outside portion of the iliotibial band, or slipping during distal pulling due to incomplete transverse flipping. These problems can be avoided if the mechanism can be understood and some technical tips are practiced. The goal of this study was to determine the difficulties encountered during RetroButton femoral fixation and prevent iatrogenic complications with the RetroButton devices by offering some technical tips. PMID- 23027474 TI - Shoulder replacement surgery. An interview with T. Bradley Edwards. PMID- 23027475 TI - Contact pressure in the wrist during computer mouse work. AB - This study investigated the relationship between computer mouse work and contact pressure around the pisiform. Commonly performed mouse work was simulated using 3 different-shaped mice with 3 forearm positions. When typical mouse work was performed, the contact pressure on the pisiform area was evaluated using a digital pressure sensor and compared with that of the thenar area. Six mouse tasks were simulated. Results indicate that mouse users should avoid wrist-snap dragging and resting their wrist on the edge of the desk to minimize the pressure concentration on the pisiform area. PMID- 23027476 TI - Getting under the skin of adverse drug reactions. AB - Cutaneous drug reactions are among the most commonly reported adverse drug reactions. Drugs prescribed by orthopedic surgeons, such as antibiotics, opiates, and nonsteroidal anti-inflammatory drugs, are common offenders. Cutaneous drug reactions can range from those that are common, mild nuisances to those that are rare, severe, and life-threatening. Medications should be considered part of a differential diagnosis for any dermatologic condition. It is important to recognize the different clinical features and common drugs that are related to each type of reaction. This review characterizes the different forms of cutaneous drug reactions and the clinical features, proposed mechanisms, and drugs frequently associated with each. PMID- 23027477 TI - Acute management of open fractures: proposal of a new multidisciplinary algorithm. AB - Despite the frequency of open fractures, their management remains one of the greatest and most debated orthopedic challenges. The current challenges that health care faces financially and clinically offer an opportunity to develop a universal reliable, reproducible, evidence-based protocol. The authors review the current evidence concerning the acute management of open fractures and suggest a modern treatment algorithm. PMID- 23027479 TI - Hematogenous pyogenic spinal infection: current perceptions. AB - EDUCATIONAL OBJECTIVES: As a result of reading this article, physicians should be able to:1.Understand the importance of early diagnosis and treatment of spinal infection in an effort to avoid devastating and crippling complications such as paralysis, painful deformity, and death.2.Understand current perceptions in the ongoing debate of whether operative or conventional treatment should be preferred and in which cases.3.Understand the latest advances in the surgical treatment of spinal infection, their indications, and their effectiveness.4.Understand the change in the traditionally held belief that in the presence of infection, the use of metal implants or grafts is not indicated. Controversy exists regarding optimal treatment for pyogenic spinal infection. The authors systematically reviewed peer-reviewed published clinical trials in the English language through 2009 on the clinical presentation, complications, and conservative and operative treatments of pyogenic spinal infection. The cornerstone of therapy for uncomplicated spondylodiskitis is intravenous antibiotics followed by oral antibiotics and bracing. Surgery is effective in complicated cases and improves sagittal balance, restores neurological impairment, and relieves severe pain. In cases of delayed diagnosis or surgery, potential early devastating and late crippling complications may occur. To the authors' knowledge, no Level I studies compare operative vs conservative treatment of pyogenic spinal infection. PMID- 23027480 TI - Cost comparison of cementless versus cemented hemiarthroplasty for displaced femoral neck fractures. AB - Hip hemiarthroplasties are frequently performed for displaced femoral neck fractures. The purpose of this study was to identify the costs associated with cementless and cemented hemiarthroplasties, compare operative times, and identify complications. The hypothesis was that cementless hemiarthroplasties cost less than cemented hemiarthroplasties, require less operative time, and have fewer perioperative complications. A retrospective review was conducted of 2 surgeons' patients admitted for displaced femoral neck fractures between 2006 and 2010. Group 1 included 45 patients who underwent monopolar hemiarthroplasties with cementless femoral components via a standard posterior approach by a single surgeon. Group 2 included 49 patients who underwent monopolar hemiarthroplasties with cemented femoral components via a modified lateral approach by a single surgeon. Surgical and anesthesia times and the cost of implants and accessories were recorded. The cost for cementless components was $3275.60 (femoral stem, $2800; monopolar head, $400; sleeve, $75.60), whereas the cost of cemented components was $3694.47 (femoral stem, $1800; monopolar head, $400; sleeve, $75.60, 3 Simplex with tobramycin cement packets, $1221; cement mixer/irrigator with tip/centralizer and plug/pressurizer, $197.87), a cost savings of 12.7% ($418.87). Operative time was significantly reduced in group 1 vs group 2 (mean, 32.9 vs 56.1 minutes, respectively; P<.01). Anesthesia time was also significantly reduced in group 1 (mean, 82.3 vs 102.9 minutes, respectively; P<.01). The difference in mean anesthetic times demonstrates an overall cost savings of 18.6%, or $1161.30. No difference in complications was noted between the groups perioperatively. Regional cost variances, vendor-hospital contracts, and surgeons' operative times are factors that may influence cost savings. This study demonstrates significantly lower operative and anesthetic times and observable cost savings with cementless femoral implants. PMID- 23027481 TI - Estimating the transfusion risk following total knee arthroplasty. AB - Patients undergoing total knee arthroplasty (TKA) are likely to receive a blood transfusion, which may increase the risk of complications and prolong hospital stay. Considerable variation exists in transfusion practice among orthopedic surgeons following elective TKA. Previous studies have investigated the relationship between preoperative risk factors and the requirement for blood transfusions in patients undergoing a total hip or knee arthroplasty, but few have focused on transfusion risk in those specifically undergoing TKA.The authors performed a retrospective review of a prospectively collected database of 2281 patients undergoing unilateral TKA in a district general hospital over a 10-year period. Multiple regression analysis models were used to identify risk factors associated with postoperative blood transfusion. A predictive model was created based on the regression coefficients and factor levels. The risk of transfusion was independently predicted by the patients' age at surgery (P<.001), preoperative hemoglobin (P<.001), weight (P=.009) and lateral retinacular release (P<.001). The preoperative variables of age, hemoglobin, and weight were incorporated into a model to provide an estimation of the transfusion risk. The area under the receiver operating characteristic curve was 74% (95% confidence interval, 70%-77.5%). This study identifies risk factors independently associated with the risk of requiring a blood transfusion following TKA. The predictive model stratifies the risk according to the individual patient in the preoperative setting, allowing preventative measures to take place preoperatively. It also helps in the counseling of patients at high risk of requiring a postoperative blood transfusion. PMID- 23027482 TI - Measured flexion following total knee arthroplasty. AB - Postoperative flexion is an important factor in the outcome of total knee arthroplasty. Although normal activities of daily living require a minimum of 105 degrees to 110 degrees of flexion, patients from non-Western cultures often engage in activities such as kneeling and squatting that require higher flexion. The desire to achieve greater flexion serves as the driving force for prosthetic modifications, including high-flexion designs. Techniques used to measure knee flexion and knee position during measurement are not often described or are different depending on the examiner. The purpose of this study was to compare active (self) and passive (assisted) flexion after successful total knee arthroplasty for 5 prostheses (2 standard and 3 high-flexion) using clinical (goniometer) and radiographic (true lateral radiograph) measurement techniques by different independent examiners.At a mean follow-up of 2.7 years (range, 1-5.6 years), a total of 108 patients (144 total knee arthroplasties) had completed the study. Mean postoperative active flexion was 111 degrees clinically and 109 degrees radiographically for the standard designs and 114 degrees clinically and 117 degrees radiographically for the high-flexion designs. Adding passive flexion increased flexion to 115 degrees clinically and 117 degrees radiographically for the standard designs and 119 degrees clinically and 124 degrees radiographically for the high-flexion designs. Flexion differences between the 2 measurement techniques (active vs passive and clinically vs radiographically) were statistically significant (P<.05). These findings demonstrate the importance of describing how flexion is measured in studies and understanding how the method of measurement can affect the findings. PMID- 23027483 TI - Incidence of venous thromboembolism in fractures around and below the knee with physical prophylaxis. AB - Fractures occurring at the distal part of the lower extremities are recognized to have a relatively lower risk of venous thromboembolism (VTE); however, few detailed reports exist on the subject. The purpose of this study was to investigate the incidence of VTE in fractures around and below the knee. Overall, 109 consecutive patients with fractures around and below the knee who were surgically treated at the authors' hospital were analyzed retrospectively. Physical prophylaxis was performed in all patients. Until April 2009, VTE screening was performed by contrast-enhanced computed tomography or ultrasonography when the D-dimer value did not decline predictably, exceeded 20 MUg/mL 5 days after trauma and surgery, or increased above 20 MUg/mL after a period of decline. After April 2009, ultrasonography was routinely performed pre- and postoperatively irrespective of the D-dimer value. The patients were divided into 2 groups based on the absence or presence of accompanying injuries, including head, chest, abdominal, or spinal injury and other fractures of the pelvis and lower extremities. Overall, VTE and pulmonary thromboembolism were detected in 28 (25.7%) patients and 5 (4.6%) patients, respectively. All cases were asymptomatic. The VTE incidence rates were 8.6% (former screening) and 40% (newer screening) in patients with isolated fractures and 25% (former screening) and 41.7% (newer screening) in patients with accompanying injuries. The pulmonary thromboembolism incidence rates were 2.9% (former screening) and 0% (newer screening) in patients with isolated fractures and 3.2% (former screening) and 25.0% (newer screening) in patients with accompanying injuries. Surgeons should be vigilant for symptoms of VTE in patients with fractures occurring at the distal part of the lower extremities. PMID- 23027484 TI - Inter- and intraobserver reliability of the radiographic diagnosis and treatment of acromioclavicular joint separations. AB - The management of acromioclavicular joint separations, in particular Rockwood types III and V, remains controversial. The purpose of this study was to investigate the observer reliability of shoulder surgeons when presented with the same cases of acromioclavicular joint separations. The authors retrospectively identified 28 patients who were diagnosed with a type III, IV, or V acromioclavicular joint separation. A PowerPoint presentation was compiled that contained an anteroposterior and axial radiograph from each patient prior to treatment. Radiographs were sent to surgeons, who diagnosed each injury according to the Rockwood classification and stated whether they recommended operative or nonoperative treatment for each patient.Inter- and intraobserver reliability were calculated from the surgeons' reviews. Repeat diagnoses were returned by 8 surgeons. A single-measure intraclass correlation coefficient (ICC) was used to determine interobserver reliability for the surgeons' Rockwood classifications (ICC=0.602) and their decision to operate (ICC=0.469). Intraobserver reliability also was calculated for Rockwood classifications (rho=0.694) and decision to operate (kappa=0.366). Two (25%) of 8 surgeons stated that they would have used open and arthroscopic techniques for repairing the dislocations, whereas the remaining (75%) surgeons would have performed open techniques. Individual surgeons were consistent in their grading of acromioclavicular joint dislocations, but less observer agreement existed among the surgeons. Poor agreement among surgeons for the decision to operate indicates that this decision is heavily influenced by clinical factors and the radiographic classification. PMID- 23027485 TI - Excision of radial head fractures with medially displaced fragments using 2 incisions: the nutcracker effect. AB - Marginal radial head fractures with displaced fragments are relatively common, especially when associated with a concomitant posterior elbow dislocation. The separated fragments are usually displaced forward and outward into the lateral part of the elbow or proximally in the elbow joint. Ulnar displacement of the separated fragments has been described in few cases, and in most of them treatment consisted of excision of the entire radial head.This article present a case series of 4 Mason type 3 radial head fractures with medially displaced fragments that had to be excised via a separate medial incision. Surgery was performed using 2 incisions, the standard Kocher and a medial incision; complete radial head excision was performed. Clinical and radiological assessment was done for all cases. Pain and range of motion at 2 years and any evidence of heterotrophic ossification were assessed. All patients had some degree of flexion deformity at final follow-up. One patient had some loss of rotation. No heterotrophic ossification existed in any patient. The authors postulate that the medial displacement may have been due to a nutcracker effect that caused the medial portion of the radial head to be compressed between the capitellum and the radial shaft and lateral part of the radial head. Such injuries are rare, and postoperative loss of flexion should be expected. Posterior elbow dislocation may not be present in all cases. PMID- 23027486 TI - Risk factors for failed closed reduction of pediatric supracondylar humerus fractures. AB - The purpose of this retrospective study was to examine pediatric supracondylar humerus fractures at a Level I trauma center. Data were analyzed to identify risk factors associated with closed reduction failure. Closed pediatric supracondylar humerus fractures that were treated at the authors' trauma center between October 1997 and January 2009 were reviewed. The main outcome variable was necessity of open reduction. To determine which factors were independently associated with a failed closed reduction, a multivariate logistic model was fit predicting open reduction status.A total of 174 patients required operative treatment. Of these, 23 underwent open reduction and 151 underwent with closed reduction and percutaneous pinning. For patients who required open reduction, 39.1% had an associated injury compared with 14.6% of patients treated with closed reduction (P=.008). Average time from presentation to surgery was 4.1 hours in the open reduction and 6.3 hours in the closed reduction group (P=.049). Risk factors that significantly predicted failure of closed reduction were the presence of an associated injury, initial fracture displacement, and Gartland type III fracture (P=.008, .03, and .023, respectively).Associated injury, large initial fracture displacement, and Gartland type III factures were statistically significant independent risk factors for closed reduction failure. Increased time from injury to presentation demonstrated a trend toward open reduction. Consideration should be given to the expedient transfer of patients with type III supracondylar humerus fractures with associated injuries when definitive care will be provided at another institution. PMID- 23027487 TI - Outcome of a dynamic neutralization system for the spine. AB - One hundred fourteen patients (66 men and 48 women; mean age, 49 years) underwent spine stabilization using a dynamic neutralization system between January 1999 and August 2010 for degenerative disk disease, spinal instability, or spinal stenosis. Mean follow-up was 6.8 years (range, 1-11 years). Seven patients were lost to follow-up. Radiological examination and clinical evaluation, including the Oswestry Disability Index, the Roland-Morris Disability Questionnaire, and patient satisfaction, were performed.Mean Oswestry Disability Index score improved from 57% (severe disability) preoperatively to 22% (moderate disability) postoperatively. Mean Roland-Morris Disability Questionnaire score improved from 52% preoperatively to 35% postoperatively; 79 (74%) patients declared themselves very satisfied with the end result of the operation. Postoperatively, 27 (25%) patients experienced complications, including screw loosening (n=22), infection (n=2), back (n=5) and leg (n=2) pain, and endplate vertebral fracture (n=1). Three patients with screw loosening, 2 with deep infection, and 1 with severe persistent back and leg pain underwent rigid spine arthrodesis.Dynamic neutralization systems can be considered for degenerative disk disease, spinal instability, and stenosis. Patient satisfaction with the procedure is excellent. However, in the long term, the complication rate, most commonly screw loosening, is high and reoperations are common. In this setting, long-term follow-up is recommended, and the use of this system should be reconsidered. PMID- 23027488 TI - Stand-alone anchored spacer versus anterior plate for multilevel anterior cervical diskectomy and fusion. AB - The purpose of this study was to compare the clinical outcomes and radiological changes of 3- and 4-level anterior cervical diskectomy and fusion with stand alone anchored spacers and with traditional anterior plates. A total of 51 consecutive patients with cervical spondylotic myelopathy who underwent 3- or 4 level anterior cervical diskectomy and fusion were divided into 2 groups: group A (n=23) received anchored spacers and group B (n=28) received an anterior plate. Mean follow-up was 14.6 months. Solid fusion was achieved in all patients at final follow-up. No significant difference existed between multilevel anterior cervical diskectomy and fusion with stand-alone anchored implants and with an anterior cervical plate in achieving clinical symptomatic improvement, fusion rate, and lordotic curvature improvement. The dysphagia rate of group A at 2 month follow-up was significantly lower than that of group B. No statistically significant difference existed between the 2 groups at the other time points. Swallowing Quality of Life of group A at 48 hours and 2 months postoperatively were significantly higher than those of group B. The thickness of the prevetebral soft tissue at 48 hours and 2 months postoperatively were significantly lower in group A than in group B. Compared with using an anterior plate, anterior cervical diskectomy and fusion with a stand-alone anchored spacer achieved a similar clinical outcome with less irritation to the prevertebral soft tissue and a lower dysphagia rate in the first 2 months. PMID- 23027489 TI - Fixation strength of PMMA-augmented pedicle screws after depth adjustment in a synthetic bone model of osteoporosis. AB - The purpose of this study was to determine the change of fixation strength after adjusting the height of polymethylmethacrylate (PMMA)-augmented pedicle screws.Cement-augmented cannulated pedicle screws with or without PMMA augmentation with a radial hole in the distal third of the screw thread were inserted into synthetic bone blocks used to model osteoporosis. Screws were left unchanged (in situ), screwed in 3 threads, or screwed out 3 threads. The change in screw height was made 24 hours after cement placement. Radiographs of the samples were taken before and after screw adjustment, and pullout strength testing was performed. In the cement group, a radiolucent cavity was present after screwing in due to the screw-cement complex migrating downward, whereas no obvious change in the boneicement complex existed after screwing out. Mean pullout strength was significantly higher in the groups with cement as compared to those without cement. However, in the cement groups, the screw-in group had the lowest mean pullout strength among 3 groups, and the mean pullout strength in the screw-out group was also significantly lower than that in the in situ group (P<.05).Adjustment of pedicle screw height after cement augmentation in a severely osteoporotic spine can significantly reduce the pullout strength of the screw. PMID- 23027490 TI - Comparative study of unilateral and bilateral pedicle screw fixation in posterior lumbar interbody fusion. AB - A prospective, randomized clinical study was performed to determine whether unilateral pedicle screw fixation was comparable with bilateral fixation in 1- or 2-segment lumbar interbody fusion. One hundred eight patients with lumbar degenerative diseases were randomly assigned to the unilateral (n=56) or bilateral (n=52) pedicle screw fixation group. Interbody fusion was performed in 1 or 2 levels with 1 cage. Operative time, blood loss, duration of hospital stay, functional outcome, fusion rate, and complication rate were recorded and compared statistically. The patients were followed for 3 years postoperatively.Successful radiographic fusion was documented in all patients. No flexion-extension hypermobility or pedicle screw loosening or breakage occurred during the follow up period. No significant difference existed between the 2 groups when comparing the union rate, complication rate, and functional outcome scores (P>.05). However, compared with the bilateral pedicle screw group, a significant decrease occurred in operative time, duration of hospital stay, and blood loss in the unilateral group (P<.01). Unilateral pedicle screw fixation was as effective as bilateral fixation when performed in addition to 1- or 2-level lumbar interbody fusion. The authors recommend the use of unilateral fixation in lumbar interbody fusion with 1 cage for lumbar degenerative diseases without major instability. PMID- 23027491 TI - Parameters for lateral extent of dissection during anterior cervical decompression and fusion. AB - The purpose of this anatomic study was to determine the extent of lateral dissection that can be performed during anterior cervical decompression and fusion to maximize decompression without compromising the vertebral arteries. Although vertebral artery injury is rare, it is sometimes catastrophic and leads to significant morbidity and mortality. Previous studies have attempted to establish standards for surgical anatomy during anterior cervical decompression and fusion; however, none have accounted for significant degenerative changes that occur with increased age.The uncus-to-uncus distance, representing part of the vertebral endplate, of 500 cervical spine specimens was measured at each vertebral level from C3 to C7. The corresponding femoral head diameter (a correlate of body mass index) was also measured. These values were used to determine whether a specific uncus-to-uncus distance exists per vertebral level regardless of age, and whether the uncus-to-uncus distance becomes more specific when correlated with body mass index. According to the data, uncus-to-uncus distance increases between each vertebral level, and each level has a range of approximately 6 mm. The range does not decrease when compared with femoral head diameter. Although a statistically significant, positive correlation existed between uncus-to-uncus distance and femoral head diameter, the correlation coefficient was not large enough to suggest that uncus-to-uncus distance varies greatly from femoral head diameter. Although anatomical markers such as the distance between the uncinate processes can aid surgeons in safe decompression of the cervical vertebrae, vertebral artery injury is best avoided by thorough pre- and intraoperative radiological and anatomical analysis. PMID- 23027492 TI - Biomechanical comparison of endplate forces generated by uniaxial screws and monoaxial pedicle screws. AB - Current surgical treatment of idiopathic scoliosis involves the use of various segmental instrumentation. Various pedicle screws have allowed for improved correction. Although monoaxial screws have improved rotational control compared with polyaxial screws, their use may increase screw-bone interface or vertebral endplate forces if not inserted in an exactly straight trajectory. Uniaxial screws potentially decrease these forces while retaining the advantages of monoaxial screws with respect to better rotational control. The purpose of this study was to compare the vertebral endplate forces with monoaxial or uniaxial screws when being reduced to a rod. Thirty-two plastic, surrogate T11 vertebrae were prepared with monoaxial (n=16) or uniaxial (n=16) screws. Screw angles relative to inferior vertebral endplates were assessed with lateral radiographs. The vertebrae were fixed to a load cell, and loads were measured as the screw was reduced to a rod. Monoaxial screws demonstrated a linear progression of endplate force with increasing screw angle. Uniaxial screws demonstrated minimal endplate force until approximately 20 degrees , coinciding with screwhead excursion angle. As this maximum excursion angle was passed, uniaxial screws demonstrated a force slope similar to the monoaxial screws.The measured endplate forces should be equivalent to forces at the screw-bone interface. The reduced force with uniaxial screws is expected to have less cranial-caudal plow potential as the screw is coupled to a rod for deformity correction. This could have potential implications for screw failure, especially in less dense bone. PMID- 23027493 TI - Bone impaction grafting of the lateral femoral condyle in a pediatric patient. AB - Avascular necrosis of the femoral condyle is an uncommon but serious sequela in patients who have received chemotherapy or corticosteroid treatment. The optimal treatment of avascular necrosis of the femoral condyles in pediatric patients is not well established. Nonoperative management has had limited long-term success, and many of the surgical procedures available for adults, including core decompression, osteotomy, and femur resurfacing, are undesirable in skeletally immature patients with open physes.This article describes a case of a 7-year-old girl with acute lymphocytic leukemia who developed avascular necrosis of the lateral femoral condyle that was treated with bone impaction grafting. The patient experienced right knee pain and swelling shortly after the initiation of chemotherapy. The radiological studies obtained showed subchondral collapse of the lateral femoral condyle. After a course of nonoperative management failed to improve symptoms, she underwent bone impaction allografting of the lateral femoral condyle using a physis-sparing approach. More than 5 years postoperatively, she has achieved excellent clinical results. Postoperative imaging of the knee has also confirmed good integration of the bone graft, an open physis, and preservation of the articular surface. This technique is a relatively less invasive surgical procedure for the treatment of avascular necrosis of the femoral condyle in a pediatric patient. PMID- 23027494 TI - Bilateral neglected posterior fracture-dislocation of the shoulders. AB - Posterior dislocation of the shoulder is an uncommon injury. Diagnosis is difficult and often missed. Once diagnosed, management must be individualized depending on the amount of the defect of the humeral head and the time from injury. This article presents a case of a 40-year-old man with a 4-month history of bilateral locked posterior fracture-dislocation of the shoulders after a grand mal seizure. Imaging showed loss of the glenohumeral joint lines congruency, reverse Hill-Sachs lesions, and articular defects of 35% and 40% of the humeral heads. A modified McLaughlin technique was performed in both shoulders in a single stage. Through the standard deltopectoral approach, the lesser tuberosity was osteotomized with the subscapularis and capsule attached and elevated to expose the humeral head and glenoid. The shape of the humeral head was restored by packing the defect with morselized bone allograft. Before packing the allograft into the defect, 2 absorbable suture anchors were inserted at the bottom of the defect; the lesser tuberosity was transferred into the defect, and fixed with 2 transosseous horizontal mattress sutures. Stable fixation was evaluated intraoperatively, and the wound was closed in layers. Postoperatively, both shoulders were immobilized with external rotation braces for 6 weeks, followed by passive, active-assisted, and progressively active range of shoulder motion and rotator cuff strengthening exercises for the next 6 weeks. At 12 weeks postoperatively, full range of motion was accomplished, and full activity was allowed. At 22-month follow-up, the patient was satisfied with his level of function; both shoulder joints were painless and stable without apprehension or recurrence of instability. Radiographs showed congruent joints and complete incorporation of the allograft into the defect with restoration of the shape of the humeral head. PMID- 23027495 TI - Posterior sternoclavicular dislocation presenting with upper-extremity deep vein thrombosis. AB - Posterior sternoclavicular dislocation is an uncommon injury and often remains initially undiagnosed due to variable clinical presentation and inadequate visualization of the joint on plain radiographs. It is frequently associated with serious and life-threatening injuries involving the trachea, esophagus, or great vessels. A 15-year-old boy was knocked to the ground during wrestling and landed on his left shoulder. He presented 6 days after trauma with increasing arm swelling and pain. A Doppler ultrasound revealed deep vein thrombosis involving the left shoulder and arm. Contrast-enhanced computed tomography of the chest confirmed the diagnosis of left posterior sternoclavicular dislocation with the medial end of left clavicle compressing the underlying brachiocephalic vein. Venous duplex scan confirmed acute venous thrombosis of the left jugular and subclavian veins. Open reduction of the left posterior sternoclavicular dislocation was performed under general anesthesia with cardiothoracic surgery backup. The reduced joint was stable, negating the need for internal fixation. Postoperatively, the pain and arm swelling gradually subsided, and patient recovered well with no complications. Deep vein thrombosis has not been reported as a presenting symptom for posterior sternoclavicular dislocation. Orthopedic, trauma, and thoracic surgeons should be aware of this presentation and obtain a chest computed tomography scan with 3-dimensional reconstruction to confirm the diagnosis. In cases of posterior sternoclavicular dislocation with vascular compromise, patients should immediately undergo open reduction with or without internal fixation. PMID- 23027496 TI - Malignant soft tissue tumors of the biceps muscle mistaken for proximal biceps tendon rupture. AB - Tears of the proximal long head of the biceps tendon are among the most common tendon tears in the body. In most cases, the diagnosis is easily determined based on the history and physical examination. However, malignant soft tissue tumors can simulate proximal biceps tendon tears. Although tumors simulating tears of the distal biceps tendon at the elbow have been reported, to the authors' knowledge, no previous cases of tumors simulating or being mistaken for proximal biceps tendon tears have been reported.This article describes 2 cases of malignant sarcomas initially mistaken for tears of the long head of the biceps tendon. In the first case, a 62-year-old woman developed swelling in her arm after feeling a twinge in her shoulder. A magnetic resonance imaging scan was misread as a biceps tendon tear and not treated by the examining physician. In the second case, a mass appeared with little trauma in the brachium of a 70-year old man. On physical examination, the mass was hard to palpation. In each case, biopsy revealed a soft tissue sarcoma. Both patients underwent wide excision with radiation and are currently disease free. These 2 cases emphasize the importance of obtaining a good history and of performing a thorough shoulder and arm examination in patients with deformities consistent with tears of the long head of the biceps tendon. PMID- 23027497 TI - Bilateral carpal tunnel syndrome in a 9-year-old boy with acromicric dysplasia. AB - Acromicric dysplasia is a skeletal dysplasia that is characterized by short stature, short hands and feet, typical facial dysmorphism, normal mental development, and characteristic hand radiology. Carpal tunnel syndrome may be seen in adults with acromicric dysplasia; however, to the authors' knowledge, it has not been reported in pediatric patients. This article describes a 9-year old boy with bilateral carpal tunnel syndrome and acromicric dysplasia treated operatively. No recurrences occurred during 1 year of postoperative follow up.Carpal tunnel syndrome is a rare disease in childhood. The etiologic factors of carpal tunnel syndrome include trauma (especially distal radius epiphysealis), overuse, genetic or metabolic disorders, space-occupying lesions in the carpal tunnel, hemophilia, congenital anomalies, adverse effect of growth hormone replacement therapy, and idiopathic carpal tunnel syndrome. Acromicric dysplasia should be considered in the etiology of childhood carpal tunnel syndrome.The surgical outcome of carpal tunnel syndrome is good with early diagnosis and treatment. However, in the case of skeletal dysplasia, the diagnosis of carpal tunnel syndrome may be delayed due to anomalies of the hand and due to the child's difficulty in expressing symptoms. Because of the delay in diagnosis of carpal tunnel syndrome in patients with skeletal dysplasia, the treatment outcomes may not be promising. Electrophysiologic studies should be performed early when the clinical signs are positive. PMID- 23027499 TI - Magnetic resonance imaging of a cystic pilomatricoma in an ankle joint. AB - Pilomatricoma, also known as calcifying epithelioma of Malherbe, is an asymptomatic, slow-growing, benign dermal neoplasm that originates from hair cortex cells. The most common sites are the head and neck (68.2%), followed by the trunk (14.4%) and the upper (15.3%) and lower (2%) extremities. The majority (60%-70%) of tumors develop in the first 2 decades of life. A typical pilomatricoma presents as a firm, calcified, dermal nodule appearing as a solid mass in subcutaneous tissue on computed tomography or magnetic resonance imaging.This article describes the case of a 42-year-old man who presented with nontender soft tissue swelling in the right ankle joint. Radiographs and magnetic resonance imaging findings showed an inflamed cystic mass with calcification in the lateral malleolar area of the right ankle joint. These atypical magnetic resonance imaging features around the ankle joint led to confusion with other disease entities, including chronic bursitis, pigmented villonodular synovitis, rheumatoid nodules, and gout. After complete excision of the mass, histological examination revealed a cystic pilomatricoma.Although rare, a cystic pilomatricoma should be considered in the differential diagnosis of soft tissue masses with calcification. PMID- 23027498 TI - Successful surgical and medical treatment of rhizopus osteomyelitis following hematopoietic cell transplantation. AB - Mucormycosis has been reported in otherwise healthy individuals; however, it is primarily seen in immunocompromised patients, such as those with diabetes mellitus, malignancy, or chronic graft-versus-host disease, and has a high mortality rate. Because most cases of mucormycosis are associated with contiguous rhinocerebral infection, only 5 cases of isolated musculoskeletal Rhizopus infection have been reported in the literature. One patient underwent hematopoietic cell transplant, which resulted in a fatal outcome.This article describes the successful treatment of isolated Rhizopus osteomyelitis in a patient who underwent hematopoietic cell transplant using a combined surgical and medical approach. A 33-year-old woman with pre-B cell acute lymphoblastic leukemia underwent hematopoietic cell transplant with few complications but developed chronic graft-versus-host disease 8 months posttransplant. She was treated with high-dose steroids for 6 weeks before she was admitted for severe right tibial pain in the absence of trauma. Early detection, aggressive therapies, and a multidisciplinary surgical and medical team allowed for the microbiologically confirmed resolution of the infection. Treatment included multiagent antimicrobial therapy with amphotericin B, daptomycin, and ertapenem. Several surgical irrigation and debridement procedures were also performed, with the eventual placement of amphotericin-impregnated polymethylmethacrylate cement beads and small fragment titanium screws. The patient continued taking postoperative antifungal treatment for 7 months after discharge. Six months following the discontinuation of antifungal therapy, the team's multidisciplinary approach achieved a continued resolution of the patient's infection and a return to a fully ambulatory and radiographically proven recovery without limb loss. PMID- 23027500 TI - Late malignant transformation of giant cell tumor of bone 41 years after primary surgery. AB - Giant cell tumor of bone is an uncommon benign tumor that frequently recurs locally. Spontaneous malignant transformation of conventional giant cell tumor of bone is rare and usually occurs with irradiation.This article describes a case of malignant transformation of a giant cell tumor 41 years after initial curettage and subsequent resection. A 68-year-old man presented with a 6-month history of left hip pain. He had been diagnosed 41 years previously with giant cell tumor in the left femoral neck treated by simple curettage and bone grafting, followed by resection of the femoral head 1 year later for local recurrence. On presentation, radiographs revealed a destructive lesion in the left proximal femur. Incisional biopsy revealed recurrence of giant cell tumor with suspected malignant transformation. The patient underwent en bloc resection of the proximal femur with adequately wide margins and reconstruction of the hip joint with a prosthesis. Pathological findings showed malignant transformation of a giant cell tumor to osteosarcoma and leiomyosarcoma. No recurrence or metastasis developed during 2-year follow-up. Benign local recurrences usually arise in the first 3 postoperative years, whereas malignant transformation tends to take longer than 3 years. To the authors' knowledge, the 41-year interval from primary surgery to diagnosis of malignancy for the current patient is the longest interval reported among cases in which patients received no radiation therapy. PMID- 23027501 TI - Lumbar spinal stenosis induced by rare chronic tophaceous gout in a 29-year-old man. AB - Spinal gout is rare in patients younger than 45 years, occurring most commonly between ages 45 and 80 years. This article describes a 29-year-old man with a history of gout initially observed more than 20 years previously who presented with lower back pain and left lower limb weakness. Computed tomography and magnetic resonance imaging revealed severely damaged facet joints and laminae surrounding L4-S1, and materials with a granular, yellow, cheese-like appearance were observed under direct vision. Postoperative histological examination confirmed spinal gout. Complete posterior decompression was performed concurrently with interbody fusion at L4-L5 and L5-S1. Seventeen-month follow-up revealed good recovery.The mechanism by which urate crystals form preferentially in the spine as opposed to more common soft tissue sites is not well understood. Most reported spinal gout cases were located at L4-S1, which were believed to be the segments with high stresses. These cases occurred in older patients with degenerative spinal diseases and had trauma as indicators. The current authors presume that gout is more likely to exist in the mobile regions with high pressure, such as L4-S1, even in individuals with an initially healthy spine, especially with a long period of abnormal renal dysfunction. Although it is often overlooked in young patients, this condition may be more common than the literature suggests due to the high potential for misdiagnosis in relatively young patients. PMID- 23027502 TI - Vertebral osteomyelitis complicated by iliopsoas muscle abscess in an immunocompetent adolescent: successful conservative treatment. AB - Vertebral osteomyelitis is rare in children. The lumbar spine is the most commonly involved region. Vertebral osteomyelitis occurs more frequently in the vertebral body, and involvement of posterior element is rare. Vertebral osteomyelitis results from hematogenous seeding, spread from contiguous infections, and direct inoculation from spinal surgery. Initial symptoms include low back pain, difficulty standing, limping gait, and fever. Blood cultures should be obtained for children with vertebral osteomyelitis because it is the definite guide for providing accurate treatment. Computed tomographyi-guided abscess aspiration should be considered for patients with negative blood cultures. Staphylococcus aureus is the most common microorganism in vertebral osteomyelitis, and the incidence of methicillin-resistant S aureus has increased in recent years. Plain radiographs, bone scintigraphy, and magnetic resonance imaging are useful for making the diagnosis. Antimicrobial therapy for 6 weeks is usually successful, and an early transition to oral form does not increase the risk of treatment failure. Debridement with implant removal is required, especially for late-onset infections associated with previous spinal surgery. Vertebral osteomyelitis can cause motor weakness and paralysis. Because of the involvement of spinal development, spinal deformities, including scoliosis and loss of normal lumbar lordosis, should be a concern in pediatric patients. Early diagnosis and adequate treatment for vertebral osteomyelitis are important to prevent severe complications and lifelong disabilities.This article describes the case of a 14-year-old boy with spontaneous lumbar vertebral osteomyelitis who initially presented with low back pain and was successfully treated nonoperatively. PMID- 23027503 TI - Curium(III) citrate speciation in biological systems: a europium(III) assisted spectroscopic and quantum chemical study. AB - Citrate complexes are the dominant binding form of trivalent actinides and lanthanides in human urine at pH < 6. Hence, an accurate prediction of the speciation of these elements in the presence of citrate is crucial for the understanding of their impact on the metabolism of the human organism and the corresponding health risks. We studied the complexation of Cm(III) and Eu(III), as representatives of trivalent actinides and lanthanides, respectively, in aqueous citrate solution over a wide pH range using time-resolved laser-induced fluorescence spectroscopy. Four distinct citrate complexes were identified and their stability constants were determined, which are MHCit(0), M(HCitH)HCit(2-), M(HCit)(2)(3-), and M(Cit)(2)(5-) (M = Cm, Eu). Additionally, there were also indications for the formation of MCit(-) complexes. Structural details on the EuHCit(0) and EuCit(-) complexes were obtained with FT-IR spectroscopy in combination with density functional theory calculations. IR spectroscopic evidence for the deprotonation of the hydroxyl group of the citrate ion in the EuCit(-) complex is presented, which also revealed that the complexation of the Eu(3+) ion takes place not only through the carboxylate groups, like in EuHCit(0), but additionally via the hydroxylate group. In both EuHCit(0) and EuCit(-) the carboxylate binding mode is mono-dentate. Under a very low metal : citrate ratio that is typical for human body fluids, the Cm(III) and Eu(III) speciation was found to be strongly pH-dependent. The Cm(III) and Eu(III) citrate complexes dominant in human urine at pH < 6 were identified to be Cm(HCitH)HCit(2 ) and a mixture of Eu(HCitH)HCit(2-) and EuHCit(0). The results specify our previous in vitro study using natural human urine samples (Heller et al., Chem. Res. Toxicol., 2011, 24, 193-203). PMID- 23027504 TI - Inherently slow and weak forward forces of neuronal growth cones measured by a drift-stabilized atomic force microscope. AB - Previous results have shown that glial cells provide a soft environment for the neurons of the mammalian central nervous system (CNS). This raises the question whether neurons are confined to the CNS and cannot wander off into more rigid tissues, such as brain capillary walls. We investigated the mechanical properties and force generation of extending mouse retinal ganglion cells and NG108-15 growth cones (GCs) using different atomic force microscope (AFM)-based methods. For the first time, to our knowledge, we were able to measure the forward pushing forces at the leading edge of outgrowing neuronal GCs with our drift-stabilized AFM. Our results demonstrate that these GCs have neither the required stability nor the ability to produce forces necessary to penetrate tissues that are at least an order of magnitude stiffer. PMID- 23027505 TI - Nanostructured superhydrophobic substrates trigger the development of 3D neuronal networks. AB - The generation of 3D networks of primary neurons is a big challenge in neuroscience. Here, a novel method is presented for a 3D neuronal culture on superhydrophobic (SH) substrates. How nano-patterned SH devices stimulate neurons to build 3D networks is investigated. Scanning electron microscopy and confocal imaging show that soon after plating neurites adhere to the nanopatterned pillar sidewalls and they are subsequently pulled between pillars in a suspended position. These neurons display an enhanced survival rate compared to standard cultures and develop mature networks with physiological excitability. These findings underline the importance of using nanostructured SH surfaces for directing 3D neuronal growth, as well as for the design of biomaterials for neuronal regeneration. PMID- 23027506 TI - A sensitive LC-MS/MS method for the simultaneous determination of amoxicillin and ambroxol in human plasma with segmental monitoring. AB - Amoxicillin (AMO) degrades in plasma at room temperature and readily undergoes hydrolysis by the plasma amidase. In this paper, a novel, rapid and sensitive LC MS/MS method operated in segmental and multiple reaction monitoring has been developed for the simultaneous determination of amoxicillin and ambroxol in human plasma. The degradation of amoxicillin in plasma was well prevented by immediate addition of 20 MUL glacial acetic acid to 200 MUL aliquot of freshly collected plasma samples before storage at -80 degrees C. The sensitivity of the method was improved with segmental monitoring of the analytes, and lower limits of quantitation of 0.5 ng/mL for ambroxol and 5 ng/mL for amoxicillin were obtained. The sensitivity of our method was five times better than those of the existing methods. Furthermore, the mass response saturation problem with amoxicillin was avoided by diluting the deproteinized plasma samples with water before injection into the LC-MS/MS system. The method was successfully employed in a pharmacokinetic study of the compound amoxicillin and ambroxol hydrochloride tablets. PMID- 23027507 TI - [Forward]. PMID- 23027508 TI - [Postweaning multisystemic wasting syndrome (PMWS) and porcine dermatitis and nephropathy syndrome (PDNS) in Switzerland in the years 2003 - 2006]. AB - In Switzerland postweaning multisystemic wasting syndrome (PMWS), caused by porcine circovirus type 2, was detected for the first time in 2001. To comprise the PMWS epizooty in 2003 - 2006 retrospectively, individual animals were diagnosed according to internationally accepted criteria and temporal and regional patterns of the epizooty were reconstructed. Occurrence of PMWS was predominantly in regions with a high frequency of swine farms (central and eastern Switzerland). Apparently it was spread to other, less affected regions, through trade of infected fattening pigs. Concurrently, disease was found in different establishments of production. Affected were mainly weaners or fattening pigs. In 40 % of the breeding farms and in 25 % of the fattening farms mortality rate was higher than 5 %. Starting in 2003, also a higher frequency of porcine dermatitis and nephropathy syndrome (PDNS) diseased pigs was diagnosed. In the years 2004 to 2006 they accounted for about 10 % of the diagnosed PCV2-associated diseases. Besides the characteristic skin- and kidney lesions approximately half of the PDNS cases showed wasting and lymphoid lesions with high quantities of PCV2 antigen. We termed these mixed forms PMWS-PDNS-hybrid forms. PMID- 23027509 TI - Risk factors causing postweaning multisystemic wasting syndrome (PMWS) onset in Swiss pig farms. AB - Postweaning multisystemic wasting syndrome (PMWS) was epizoozic between 2003 and 2008 in Switzerland. Nevertheless, infectious risk factors including porcine reproductive and respiratory syndrome virus (PRRSV) were missing at all or were seen only sporadically (enzootic pneumonia and actinobazillosis). In a case control study, 30 farms with PMWS affected pigs were compared to 30 inconspicious farms ("matched pairs"). The case-control allocation was verified by PCV2 DNA measurements of 5 healthy weaned pigs in each control farm, 5 healthy and 5 PMWS affected weaners in each PMWS affected farm. Diseased pigs showed in average 1.8x10(8) DNA templates per ml serum significantly higher than healthy pigs from control farms with 1x10(6) DNA templates per ml serum. Virus load in healthy pigs did not differ between control- and PMWS affected farms. PMWS mainly emerged among affected pigs in the 5th to 8th week of age. In a logistic regression model risk factors were identified such as high occupancy in weaning pens (p = 0.002), large groups in gestation facilities (p = 0.03) as well as reduced birth weight < 1.3 kg (p = 0.04). We suggest these factors might have lead to chronic stress e.g. through influencing negatively social interaction in pigs or disturbances of the maturing immune system. Heavy fly and rodent infestation might not only be viewed as a vector for disease transmission, but, also as a stress factor. PMID- 23027510 TI - [Infection related fertility disorders in Swiss pig breeding farms at the end of the postweaning multisystemic wasting syndrome (PMWS) epizooty]. AB - Porcine Circovirus type 2 (PCV2) is able to induce reproductive failures. 286 fetuses from 113 sows of 59 farms with increased reproductive disorders which included abortions, mummies, stillborn and weak born piglets were studied six years after the beginning of the epizooty of postweaning multisystemic wasting syndrome (PMWS) in Switzerland. 14 % of the cases were bacterial infections based on histological signs of inflammation and pathogen isolation. 12 % further cases showed inflammatory reactions by histology without pathogen identification. PCV2 was identified in only 4 % of cases by immunohistochemistry (IHC). Thus, PCV2 infections are of minor importance in respect to pig reproductive failures in Switzerland. Porcine parvovirus (PPV) infections were found in 3 % of the cases and seem to occur more infrequently compared to former findings. Hitherto, Enteroviruses/Teschovirus were marginally studied in etiologically undefined cases with a prevalence of 11 %. To our knowledge this is the first identification of Enteroviruses/Teschovirus in fetal tissue from reproductive failures in Switzerland. The etiology remained unclear in more than 50 % of all cases in spite of modern diagnostic methods. PMID- 23027511 TI - Efficacy of simultaneous vaccination with Enterisol(r) Ileitis and Ingelvac(r) CircoFLEXTM in a Swiss breeding farm. AB - This study explores administration of two piglet vaccines as compared to the mono and adjuvant-application. A vaccine against the Porcine Circovirus Type 2 (PCV2) cap protein subunit and a vaccine with attenuated live culture against Lawsonia (L.) intracellularis were applied to piglets aged 23.5 days on average. 1'405 animals were divided randomly into four groups. One piglet group was immunized with both vaccines while two other groups were immunized with a combination of one vaccine and adjuvants of alternate vaccination protocol and vice versa. These piglet groups were also compared to a control group supplemented with both adjuvants only. During fattening, pigs, which were simultaneously immunized with Enterisol((r)) Ileitis and Ingelvac((r)) CircoFLEX(TM) vaccine, gained significantly more weight (792 g/day) when compared to piglet groups mono vaccinated with Ingelvac(r) CircoFLEXTM (772 g/day) or either with Enterisol(r) Ileitis (774 g/day). Moreover, immunized piglet groups showed significantly higher daily weight gain when compared to adjuvants only inoculated control group (751 g/day). Additionally, during fattening the control group displayed higher mortality (6,3 %) than the three vaccinated groups (Ingelvac((r)) CircoFLEX(TM) 2,5 %, Enterisol((r)) Ileitis 2,3 % and the combination of both vaccines 1,1 %). These data imply that simultaneous immunization with PCV2- and L. intracellularis specific vaccines positively benefit piglet growth observed by an additive effect on growth parameters in farms harboring both pathogens. Return of investment was calculated of 2.10 on the additional Enterisol((r)) Ileitis vaccination. PMID- 23027512 TI - [Economic impact of Circovac(r) - vaccination in a PCV2 subclinically infected farm in Switzerland on performance parameters]. AB - Vaccination of dams in a PCV2 subclinically infected farm 2 and 4 weeks before insemination, with a booster at 12 weeks of gestation did not influence fertility parameters of the dams. However, growth parameters of offspring of vaccinated sows improved significantly (+ 51 g/d), resulting in a shorter growing period of 9 days and a massively improved economy. Mortality of weaners and fattening pigs was not significantly influenced by dam vaccination. Nevertheless, compared to a period of 6 months before vaccination, the mortality rate declined in the weaning period by 0,3 % and in the fattening period by 5,5 %. The Return on Investment (ROI) was calculated with 1:9.5. Even, the historically low pork prices in 2011 led to a ROI of 1:7. PMID- 23027515 TI - [Disclosure of documents to the successor practice]. PMID- 23027516 TI - [Trends- Veterinary Phytotherapy in Switzerland]. PMID- 23027517 TI - Light induced nanowire assembly: the electrostatic alignment of semiconductor nanowires into functional macroscopic yarns. AB - The electrostatic alignment and directed assembly of semiconductor nanowires into macroscopic, centimeter-long yarns is demonstrated. Different morphologies can be produced, including longitudinally segmented/graded yarns or mixed composition fibers. Nanowire yarns display long range photoconductivities and open up exciting opportunities for potential use in future nanowire-based textiles or in solar photovoltaics. PMID- 23027518 TI - The influence of Hispanic ethnicity on nonsmall cell lung cancer histology and patient survival : an analysis of the Survival, epidemiology, and end results database. PMID- 23027519 TI - Geriatric medicine: services and training in Africa. AB - BACKGROUND: the population is ageing globally and developing countries are experiencing the most rapid increase in the number of older persons. By 2045 the United Nations estimate that for the first time in history more people will be over 65, than under 15, years of age. The World Health Organization predicts that deaths from non-communicable diseases will rise by 24% in Africa in the next decade. The aim of this survey was to determine the specialist medical services available for older persons and the undergraduate and postgraduate training systems in place for geriatrics in each African country. METHODS: a short survey was developed and sent to representatives from every country. Where appropriate, French and Portuguese translations were available. RESULTS: responses were received from 40/54 countries (74%). Data were obtained via an internet search for a further three countries. Out of 43, 25 countries had no geriatricians. Out of 40, 35 countries had no formal undergraduate training for medical students on geriatrics and 33 of 40 countries reported no national postgraduate training scheme for geriatrics. Having at least one geriatrician in the country was associated with a World Bank upper middle-income status (P = 0.04), but there was no significant association with the population size (P = 0.395). CONCLUSION: despite increasing numbers of older people and the increasing burden of chronic disease there are few geriatricians in Africa. Without undergraduate training, even general medical physicians will have limited knowledge of specialist geriatric needs. This is an area that will require development and investment in the future. PMID- 23027521 TI - Baby whisperers--knowing when to stay quiet and when to intervene. PMID- 23027520 TI - A versatile protein microarray platform enabling antibody profiling against denatured proteins. AB - PURPOSE: We aim to develop a protein microarray platform capable of presenting both natural and denatured forms of proteins for antibody biomarker discovery. We will further optimize plasma screening protocols to improve detection. EXPERIMENTAL DESIGN: We developed a new covalent capture protein microarray chemistry using HaloTag fusion proteins and ligand. To enhance protein yield, we used HeLa cell lysate as an in vitro transcription translation (IVTT) system. Escherichia coli lysates were added to the plasma blocking buffer to reduce nonspecific background. These protein microarrays were probed with plasma samples and autoantibody responses were quantified and compared with or without denaturing buffer treatment. RESULTS: We demonstrated that protein microarrays using the covalent attachment chemistry endured denaturing conditions. Blocking with E. coli lysates greatly reduced the background signals and expression with IVTT based on HeLa cell lysates significantly improved the antibody signals on protein microarrays probed with plasma samples. Plasma samples probed on denatured protein arrays produced autoantibody profiles distinct from those probed on natively displayed proteins. CONCLUSIONS AND CLINICAL RELEVANCE: This versatile protein microarray platform allows the display of both natural and denatured proteins, offers a new dimension to search for disease-specific antibodies, broadens the repertoire of potential biomarkers, and will potentially yield clinical diagnostics with greater performance. PMID- 23027522 TI - Ascertaining children's wishes and feelings about hospital life. AB - It is increasingly accepted that children have the right to have their views taken into consideration by healthcare providers. Children's opinions and experiences of hospitalisation are essential for monitoring and evaluating the effectiveness of health services provision. In this paper we report on children's views and wishes about hospital and healthcare professionals. The children held both positive and negative views of hospital and healthcare professionals. Dissatisfaction was caused by insufficient information, lack of involvement, and inadequate play facilities. Their wishes were mainly concerned with the need for more information and more involvement in communication interactions with doctors and nurses. They wished to express their opinions, ask questions and receive information about care and procedures. They recommended that healthcare professionals make a better effort to listen and to take account of their views. PMID- 23027523 TI - 'Making the bad things seem better': coping in children receiving healthcare. AB - The focus of children's healthcare literature has been the delivery of services to children and their parents, little attention has been paid to how children cope with receiving such care. In this paper we use a literature scoping method to bring together the literature on how medical talk can engage or isolate children, consider the environmental factors which can help children to be engaged and discuss an ethical symmetry approach. We propose that an ethical symmetry approach would provide a framework for healthcare teams to explore how to optimize children's engagement with their healthcare. PMID- 23027524 TI - Hormone symphony during root growth and development. AB - Hormones regulate plant growth and development in response to external environmental stimuli via complex signal transduction pathways, which in turn form complex networks of interaction. Several classes of hormones have been reported, and their activity depends on their biosynthesis, transport, conjugation, accumulation in the vacuole, and degradation. However, the activity of a given hormone is also dependent on its interaction with other hormones. Indeed, there is a complex crosstalk between hormones that regulates their biosynthesis, transport, and/or signaling functionality, although some hormones have overlapping or opposite functions. The plant root is a particularly useful system in which to study the complex role of plant hormones in the plastic control of plant development. Physiological, cellular, and molecular genetic approaches have been used to study the role of plant hormones in root meristem homeostasis. In this review, we discuss recent findings on the synthesis, signaling, transport of hormones and role during root development and examine the role of hormone crosstalk in maintaining homeostasis in the apical root meristem. PMID- 23027525 TI - Sediment contact tests as a tool for the assessment of sediment quality in German waters. AB - A sediment contact test (SCT) battery consisting of five ecotoxicological test systems was applied to 21 native freshwater sediments characterized by a broad variety of geochemical properties and anthropogenic contamination. Higher plants (Myriophyllum aquaticum), nematodes (Caenorhabditis elegans), oligochaetes (Lumbriculus variegatus), zebrafish embryos (Danio rerio), and bacteria (Arthrobacter globiformis), representing various trophic levels and exposure pathways, were used as test organisms. The test battery detected sediment toxicity caused by anthropogenic pollution, whereas the various tests provided site-specific, nonredundant information to the overall toxicity assessment. Based on the toxicity pattern derived from the test battery, the sediments were classified according to a newly proposed classification system for sediment toxicity assessment. The SCT-derived classification generally agreed well with the application of consensus-based sediment quality guidelines (SQGs), especially with regard to sediments with high toxic potential. For sediments with low to medium toxic potential, the SQGs often underestimated the toxicity that was detected by the SCTs, underpinning the need for toxicity tests in sediment quality assessment. PMID- 23027526 TI - Changing the conversation regarding pediatric cholesterol screening: the rare disease paradigm. PMID- 23027527 TI - [Fe(III)(dmbpy)(CN)4]-: a new building block for designing single-chain magnets. AB - We herein present the synthesis and magneto-structural study of a new family of heterobimetallic chains of general formula {[Fe(III)(dmbpy)(CN)(4)](2)M(II)(H(2)O)(2)}(n).pnH(2)O [dmbpy = 4,4'-dimethyl 2,2'-bipyridine; M = Mn (2), Cu (3), Ni (4) and Co (5) with p = 4 (2), 3 (3), 9 (4) and 3.5 (5)] which were prepared by using the mononuclear PPh(4)[Fe(III)(dmbpy)(CN)(4)].3H(2)O (1) building block (PPh(4)(+) = tetraphenylphosphonium) as a ligand toward fully solvated M(II) ions. The structure of 1 consists of discrete [Fe(III)(dmbpy)(CN)(4)](-) anions, tetraphenylphosphonium cations and noncoordinated water molecules. Complexes 2-5 are isostructural compounds whose structure consists of neutral 4,2-wave like heterobimetallic chains of formula {[Fe(III)(dmbpy)(CN)(4)](2)M(II)(H(2)O)(2)}(n) where the [Fe(III)(dmbpy)(CN)(4)](-) entity adopts a bis-monodentate coordination mode toward trans-[M(II)(H(2)O)(2)] units through two of its four cyanide groups in cis positions. 1 exhibits the magnetic behaviour of magnetically isolated six coordinate low-spin Fe(III) complexes with an important orbital contribution. 2 behaves as ferrimagnetic Fe(III)(2)Mn(II) chains, whereas 3-5 exhibit intrachain ferromagnetic couplings between the low-spin Fe(III) and either Cu(II) (3), Ni (4) or Co(II) (5) as well as frequency-dependence of the out-of-phase ac susceptibility signals below 3.0 (3), 5.5 (4) and 5.0 K (5). The relaxation time and the energy to reverse the magnetization of 3-5 are related to the anisotropy of the M(II) center and to the intra- and interchain magnetic interactions. Unprecedentedly in the world of cyanide-bearing complexes, 5 exhibits a double slow relaxation of the magnetization. PMID- 23027528 TI - Bordetella parapertussis survives the innate interaction with human neutrophils by impairing bactericidal trafficking inside the cell through a lipid raft dependent mechanism mediated by the lipopolysaccharide O antigen. AB - Whooping cough is a reemerging disease caused by two closely related pathogens, Bordetella pertussis and Bordetella parapertussis. The incidence of B. parapertussis in whooping cough cases has been increasing since the introduction of acellular pertussis vaccines containing purified antigens that are common to both strains. Recently published results demonstrated that these vaccines do not protect against B. parapertussis due to the presence of the O antigen on the bacterial surface that impairs antibody access to shared antigens. We have investigated the effect of the lack of opsonization of B. parapertussis on the outcome of its interaction with human neutrophils (polymorphonuclear leukocytes [PMNs]). In the absence of opsonic antibodies, PMN interaction with B. parapertussis resulted in nonbactericidal trafficking upon phagocytosis. A high percentage of nonopsonized B. parapertussis was found in nonacidic lysosome marker (lysosome-associated membrane protein [LAMP])-negative phagosomes with access to the host cell-recycling pathway of external nutrients, allowing bacterial survival as determined by intracellular CFU counts. The lipopolysaccharide (LPS) O antigen was found to be involved in directing B. parapertussis to PMN lipid rafts, eventually determining the nonbactericidal fate inside the PMN. IgG opsonization of B. parapertussis drastically changed this interaction by not only inducing efficient PMN phagocytosis but also promoting PMN bacterial killing. These data provide new insights into the immune mechanisms of hosts against B. parapertussis and document the crucial importance of opsonic antibodies in immunity to this pathogen. PMID- 23027529 TI - Pertussis toxin exacerbates and prolongs airway inflammatory responses during Bordetella pertussis infection. AB - Throughout infection, pathogenic bacteria induce dramatic changes in host transcriptional repertoires. An understanding of how bacterial factors influence host reprogramming will provide insight into disease pathogenesis. In the human respiratory pathogen Bordetella pertussis, the causative agent of whooping cough, pertussis toxin (PT) is a key virulence factor that promotes colonization, suppresses innate immune responses during early infection, and causes systemic disease symptoms. To determine the full extent of PT-associated gene regulation in the airways through the peak of infection, we measured global transcriptional profiles in the lungs of BALB/c mice infected with wild-type (WT) or PT-deficient (DeltaPT) B. pertussis. DeltaPT bacteria were inoculated at a dose equivalent to the WT dose and at a high dose (DeltaPT(high)) to distinguish effects caused by higher bacterial loads achieved in WT infection from effects associated with PT. The results demonstrated that PT was associated with a significant upregulation of immune and inflammatory response genes as well as several other genes implicated in airway pathology. In contrast to the early, transient responses observed for DeltaPT(high) infection, WT infection induced a prolonged expression of inflammatory genes and increased the extent and duration of lung histopathology. In addition, the administration of purified PT to DeltaPT(high) infected mice 1 day after bacterial inoculation exacerbated and prolonged inflammatory responses and airway pathology. These data indicate that PT not only is associated with exacerbated host airway responses during peak B. pertussis infection but also may inhibit host mechanisms of attenuating and resolving inflammation in the airways, suggesting possible links between PT and pertussis disease symptoms. PMID- 23027530 TI - Impaired innate immunity in mice deficient in interleukin-1 receptor-associated kinase 4 leads to defective type 1 T cell responses, B cell expansion, and enhanced susceptibility to infection with Toxoplasma gondii. AB - Interleukin-1 receptor (IL1R)-associated kinase 4 (IRAK4) is a member of the IRAK family and has an important role in inducing the production of inflammatory mediators. This kinase is downstream of MyD88, an adaptor protein essential for Toll-like receptor (TLR) function. We investigated the role of this kinase in IRAK4-deficient mice orally infected with the cystogenic ME49 strain of Toxoplasma gondii. IRAK4(-/-) mice displayed higher morbidity, tissue parasitism, and accelerated mortality than the control mice. The lymphoid follicles and germinal centers from infected IRAK4(-/-) mice were significantly smaller. We consistently found that IRAK4(-/-) mice showed a defect in splenic B cell activation and expansion as well as diminished production of gamma interferon (IFN-gamma) by T lymphocytes. The myeloid compartment was also affected. Both the frequency and ability of dendritic cells (DCs) and monocytes/macrophages to produce IL-12 were significantly decreased, and resistance to infection with Toxoplasma was rescued by treating IRAK4(-/-) mice with recombinant IL-12 (rIL 12). Additionally, we report the association of IRAK4 haplotype-tagging single nucleotide polymorphisms (tag-SNPs) with congenital toxoplasmosis in infected individuals (rs1461567 and rs4251513, P < 0.023 and P < 0.045, respectively). Thus, signaling via IRAK4 is essential for the activation of innate immune cells, development of parasite-specific acquired immunity, and host resistance to infection with T. gondii. PMID- 23027531 TI - Thiol peroxidase is an important component of Streptococcus pneumoniae in oxygenated environments. AB - Streptococcus pneumoniae is an aerotolerant gram-positive bacterium that causes an array of diseases, including pneumonia, otitis media, and meningitis. During aerobic growth, S. pneumoniae produces high levels of H(2)O(2). Since S. pneumoniae lacks catalase, the question of how it controls H(2)O(2) levels is of critical importance. The psa locus encodes an ABC Mn(2+)-permease complex (psaBCA) and a putative thiol peroxidase, tpxD. This study shows that tpxD encodes a functional thiol peroxidase involved in the adjustment of H(2)O(2) homeostasis in the cell. Kinetic experiments showed that recombinant TpxD removed H(2)O(2) efficiently. However, in vivo experiments revealed that TpxD detoxifies only a fraction of the H(2)O(2) generated by the pneumococcus. Mass spectrometry analysis demonstrated that TpxD Cys(58) undergoes selective oxidation in vivo, under conditions where H(2)O(2) is formed, confirming the thiol peroxidase activity. Levels of TpxD expression and synthesis in vitro were significantly increased in cells grown under aerobic versus anaerobic conditions. The challenge with D39 and TIGR4 with H(2)O(2) resulted in tpxD upregulation, while psaBCA expression was oppositely affected. However, the challenge of DeltatpxD mutants with H(2)O(2) did not affect psaBCA, implying that TpxD is involved in the regulation of the psa operon, in addition to its scavenging activity. Virulence studies demonstrated a notable difference in the survival time of mice infected intranasally with D39 compared to that of mice infected intranasally with D39DeltatpxD. However, when bacteria were administered directly into the blood, this difference disappeared. The findings of this study suggest that TpxD constitutes a component of the organism's fundamental strategy to fine-tune cellular processes in response to H(2)O(2). PMID- 23027532 TI - Interplay between the QseC and QseE bacterial adrenergic sensor kinases in Salmonella enterica serovar Typhimurium pathogenesis. AB - The bacterial adrenergic sensor kinases QseC and QseE respond to epinephrine and/or norepinephrine to initiate a complex phosphorelay regulatory cascade that modulates virulence gene expression in several pathogens. We have previously shown that QseC activates virulence gene expression in Salmonella enterica serovar Typhimurium. Here we report the role of QseE in S. Typhimurium pathogenesis as well as the interplay between these two histidine sensor kinases in gene regulation. An S. Typhimurium qseE mutant is hampered in the invasion of epithelial cells and intramacrophage replication. The DeltaqseC strain is highly attenuated for intramacrophage survival but has only a minor defect in invasion. However, the DeltaqseEC strain has only a slight attenuation in invasion, mirroring the DeltaqseC strain, and has an intermediary intramacrophage replication defect in comparison to the DeltaqseE and DeltaqseC strains. The expressions of the sipA and sopB genes, involved in the invasion of epithelial cells, are activated by epinephrine via QseE. The expression levels of these genes are still decreased in the DeltaqseEC double mutant, albeit to a lesser extent, congruent with the invasion phenotype of this mutant. The expression level of the sifA gene, important for intramacrophage replication, is decreased in the qseE mutant and the DeltaqseEC double mutant grown in vitro. However, as previously reported by us, the epinephrine-dependent activation of this gene occurs via QseC. In the systemic model of S. Typhimurium infection of BALB/c mice, the qseC and qseE mutants are highly attenuated, while the double mutant has an intermediary phenotype. Altogether, these data suggest that both adrenergic sensors play an important role in modulating several aspects of S. Typhimurium pathogenesis. PMID- 23027533 TI - Genotypic and phenotypic characterization of Clostridium perfringens isolates from Darmbrand cases in post-World War II Germany. AB - Clostridium perfringens type C strains are the only non-type-A isolates that cause human disease. They are responsible for enteritis necroticans, which was termed Darmbrand when occurring in post-World War II Germany. Darmbrand strains were initially classified as type F because of their exceptional heat resistance but later identified as type C strains. Since only limited information exists regarding Darmbrand strains, this study genetically and phenotypically characterized seven 1940s era Darmbrand-associated strains. Results obtained indicated the following. (i) Five of these Darmbrand isolates belong to type C, carry beta-toxin (cpb) and enterotoxin (cpe) genes on large plasmids, and express both beta-toxin and enterotoxin. The other two isolates are cpe-negative type A. (ii) All seven isolates produce highly heat-resistant spores with D(100) values (the time that a culture must be kept at 100 degrees C to reduce its viability by 90%) of 7 to 40 min. (iii) All of the isolates surveyed produce the same variant small acid-soluble protein 4 (Ssp4) made by type A food poisoning isolates with a chromosomal cpe gene that also produce extremely heat-resistant spores. (iv) The Darmbrand isolates share a genetic background with type A chromosomal-cpe-bearing isolates. Finally, it was shown that both the cpe and cpb genes can be mobilized in Darmbrand isolates. These results suggest that C. perfringens type A and C strains that cause human food-borne illness share a spore heat resistance mechanism that likely favors their survival in temperature-abused food. They also suggest possible evolutionary relationships between Darmbrand strains and type A strains carrying a chromosomal cpe gene. PMID- 23027534 TI - Systemic macrophage depletion inhibits Helicobacter bilis-induced proinflammatory cytokine-mediated typhlocolitis and impairs bacterial colonization dynamics in a BALB/c Rag2-/- mouse model of inflammatory bowel disease. AB - Helicobacter bilis, an enterohepatic helicobacter, is associated with chronic hepatitis in aged immunocompetent inbred mice and inflammatory bowel disease (IBD) in immunodeficient mice. To evaluate the role of macrophages in H. bilis induced IBD, Rag2(-/-) BALB/c or wild-type (WT) BALB/c mice were either sham dosed or infected with H. bilis Missouri strain under specific-pathogen-free conditions, followed by an intravenous injection of a 0.2-ml suspension of liposomes coated with either phosphate-buffered saline (control) or clodronate (a macrophage depleting drug) at 15 weeks postinfection (wpi). At 16 wpi, the ceca of H. bilis-infected Rag2(-/-) mice treated with control liposomes had significantly higher histopathological lesional scores (for cumulative typhlitis index, inflammation, edema, epithelial defects, and hyperplasia) and higher counts of F4/80(+) macrophages and MPO(+) neutrophils compared to H. bilis infected Rag2(-/-) mice treated with clodronate liposomes. In addition, cecal quantitative PCR analyses revealed a significant suppression in the expression of macrophage-related cytokine genes, namely, Tnfa, Il-1beta, Il-10, Cxcl1, and iNos, in the clodronate-treated H. bilis-infected Rag2(-/-) mice compared to the H. bilis-infected Rag2(-/-) control mice. Finally, cecal quantitative PCR analyses also revealed a significant reduction in bacterial colonization in the clodronate-treated Rag2(-/-) mice. Taken together, our results suggest that macrophages are critical inflammatory cellular mediators for promoting H. bilis induced typhlocolitis in mice. PMID- 23027535 TI - Bacillus anthracis lethal toxin reduces human alveolar epithelial barrier function. AB - The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness. PMID- 23027536 TI - Haemophilus ducreyi-induced interleukin-10 promotes a mixed M1 and M2 activation program in human macrophages. AB - During microbial infection, macrophages are polarized to classically activated (M1) or alternatively activated (M2) cells in response to microbial components and host immune mediators. Proper polarization of macrophages is critical for bacterial clearance. To study the role of macrophage polarization during Haemophilus ducreyi infection, we analyzed a panel of macrophage surface markers in skin biopsy specimens of pustules obtained from experimentally infected volunteers. Lesional macrophages expressed markers characteristic of both M1 and M2 polarization. Monocyte-derived macrophages (MDM) also expressed a mixed M1 and M2 profile of surface markers and cytokines/chemokines upon infection with H. ducreyi in vitro. Endogenous interleukin 10 (IL-10) produced by infected MDM downregulated and enhanced expression of several M1 and M2 markers, respectively. Bacterial uptake, mediated mainly by class A scavenger receptors, and activation of mitogen-activated protein kinase and phosphoinositide 3-kinase signaling pathways were required for H. ducreyi-induced IL-10 production in MDM. Compared to M1 cells, IL-10-polarized M2 cells displayed enhanced phagocytic activity against H. ducreyi and similar bacterial killing. Thus, IL-10-modulated macrophage polarization may contribute to H. ducreyi clearance during human infection. PMID- 23027537 TI - Enterotoxigenic Escherichia coli prevents host NF-kappaB activation by targeting IkappaBalpha polyubiquitination. AB - The NF-kappaB pathway regulates innate immune responses to infection. NF-kappaB is activated after pathogen-associated molecular patterns are detected, leading to the induction of proinflammatory host responses. As a countermeasure, bacterial pathogens have evolved mechanisms to subvert NF-kappaB signaling. Enterotoxigenic Escherichia coli (ETEC) causes diarrheal disease and significant morbidity and mortality for humans in developing nations. The extent to which this important pathogen subverts innate immune responses by directly targeting the NF-kappaB pathway is an understudied topic. Here we report that ETEC secretes a heat-stable, proteinaceous factor that blocks NF-kappaB signaling normally induced by tumor necrosis factor (TNF), interleukin-1beta, and flagellin. Pretreating intestinal epithelial cells with ETEC supernatant significantly blocked the degradation of the NF-kappaB inhibitor IkappaBalpha without affecting IkappaBalpha phosphorylation. Data from immunoprecipitation experiments suggest that the ETEC factor functions by preventing IkappaBalpha polyubiquitination. Inhibiting clathrin function blocked the activity of the secreted ETEC factor, suggesting that this yet-uncharacterized activity may utilize clathrin-dependent endocytosis to enter host cells. These data suggest that ETEC evades the host innate immune response by directly modulating NF-kappaB signaling. PMID- 23027538 TI - Insulin treatment directly restores neutrophil phagocytosis and bactericidal activity in diabetic mice and thereby improves surgical site Staphylococcus aureus infection. AB - Bacterial infections, including surgical site infections (SSI), are a common and serious complication of diabetes. Staphylococcus aureus, which is eliminated mainly by neutrophils, is a major cause of SSI in diabetic patients. However, the precise mechanisms by which diabetes predisposes to staphylococcal infection are not fully elucidated. The effect of insulin on this infection is also not well understood. We therefore investigated the effect of insulin treatment on SSI and neutrophil function in diabetic mice. S. aureus was inoculated into the abdominal muscle in diabetic db/db and high-fat-diet (HFD)-fed mice with or without insulin treatment. Although the diabetic db/db mice developed SSI, insulin treatment ameliorated the infection. db/db mice had neutrophil dysfunction, such as decreased phagocytosis, superoxide production, and killing activity of S. aureus; however, insulin treatment restored these functions. Ex vivo treatment (coincubation) of neutrophils with insulin and euglycemic control by phlorizin suggest that insulin may directly activate neutrophil phagocytic and bactericidal activity independently of its euglycemic effect. However, insulin may indirectly restore superoxide production by neutrophils through its euglycemic effect. HFD fed mice with mild hyperglycemia also developed more severe SSI by S. aureus than control mice and had impaired neutrophil phagocytic and bactericidal activity, which was improved by insulin treatment. Unlike db/db mice, in HFD mice, superoxide production was increased in neutrophils and subsequently suppressed by insulin treatment. Glycemic control by insulin also normalized the neutrophil superoxide-producing capability in HFD mice. Thus, insulin may restore neutrophil phagocytosis and bactericidal activity, thereby ameliorating SSI. PMID- 23027539 TI - In vivo sequence variation in HopZ, a phase-variable outer membrane protein of Helicobacter pylori. AB - The Helicobacter pylori outer membrane protein HopZ is regulated by a phase variable CT repeat and occurs in two distinct allelic variants. Whole-genome comparisons of isolates from one human volunteer recently provided evidence for in vivo selection for the hopZ ON status. We explored the frequency of sequence variation in hopZ during acute and chronic human infection and studied the association of hopZ with the phylogeographic population structure of H. pylori. hopZ ON variants were cultured from 24 out of 33 volunteers challenged with the hopZ OFF strain BCS 100. Transmission of H. pylori within families was also frequently associated with a status change of hopZ. In contrast, hopZ sequences obtained from 26 sets of sequential isolates from chronically infected individuals showed no changes of status, suggesting that the hopZ status selected during early infection is subsequently stable. Mutations leading to amino acid changes in HopZ occurred more frequently in ON than in OFF status isolates during chronic infection, indicating that sequence changes are more likely the result of positive selection in ON isolates than of a loss of negative selection pressure in OFF isolates. Analysis of 63 isolates from chronically infected individuals revealed no significant correlation of hopZ status with chronic atrophic gastritis. hopZ sequences were obtained from a globally representative collection of 54 H. pylori strains. All H. pylori populations contained hopZ-positive isolates. The data suggest that hopZ has been acquired and split into the two variants before the human migration out of Africa. PMID- 23027541 TI - Quantification of MAP and molecular motor activities on geometrically controlled microtubule networks. AB - The spatial organization of the microtubule (MT) network directs cell polarity and mitosis. It is finely regulated by hundreds of different types of microtubule associated proteins and molecular motors whose specific functions are difficult to investigate directly in cells. Here, we have investigated their functions using geometrically controlled MT networks in vitro in cell-free assay. This was achieved by developing a new method to spatially define MT nucleation using MT microseeds adsorbed on a micropatterned glass substrate. This method could be used to control MT growth and the induction of complex MT networks. We selected the interaction of two radial arrays of dynamic and polarized MTs to analyze the formation of the central antiparallel MT bundle. We investigated the effects of the MT cross-linker anaphase spindle elongation 1 (Ase1) and the kinesin motor Klp2, which are known to regulate MT organization in the spindle midzone. We thus identified the respective roles of each protein and revealed their synergy on the establishment of stable antiparallel MT bundles by quantifying MT interactions over hundreds of comparable MT networks. PMID- 23027540 TI - Microbial amyloids induce interleukin 17A (IL-17A) and IL-22 responses via Toll like receptor 2 activation in the intestinal mucosa. AB - The Toll-like receptor 2 (TLR2)/TLR1 receptor complex responds to amyloid fibrils, a common component of biofilm material produced by members of the phyla Firmicutes, Bacteroidetes, and Proteobacteria. To determine whether this TLR2/TLR1 ligand stimulates inflammatory responses when bacteria enter intestinal tissue, we investigated whether expression of curli amyloid fibrils by the invasive enteric pathogen Salmonella enterica serotype Typhimurium contributes to T helper 1 and T helper 17 responses by measuring cytokine production in the mouse colitis model. A csgBA mutant, deficient in curli production, elicited decreased expression of interleukin 17A (IL-17A) and IL-22 in the cecal mucosa compared to the S. Typhimurium wild type. In TLR2-deficient mice, IL-17A and IL 22 expression was blunted during S. Typhimurium infection, suggesting that activation of the TLR2 signaling pathway contributes to the expression of these cytokines. T cells incubated with supernatants from bone marrow-derived dendritic cells (BMDCs) treated with curli fibrils released IL-17A in a TLR2-dependent manner in vitro. Lower levels of IL-6 and IL-23 production were detected in the supernatants of the TLR2-deficient BMDCs treated with curli fibrils. Consistent with this, three distinct T-cell populations-CD4(+) T helper cells, cytotoxic CD8(+) T cells, and gammadelta T cells-produced IL-17A in response to curli fibrils in the intestinal mucosa during S. Typhimurium infection. Notably, decreased IL-6 expression by the dendritic cells and decreased IL-23 expression by the dendritic cells and macrophages were observed in the cecal mucosa of mice infected with the curli mutant. We conclude that TLR2 recognition of bacterial amyloid fibrils in the intestinal mucosa represents a novel mechanism of immunoregulation, which contributes to the generation of inflammatory responses, including production of IL-17A and IL-22, in response to bacterial entry into the intestinal mucosa. PMID- 23027545 TI - Quantifying and imaging engineered nanomaterials in vivo: challenges and techniques. AB - Quantifying and imaging the engineered nanomaterials (ENMs) in vivo can provide information on the bio-distribution and fate of ENMs in living systems. A necessary amount of in vivo quantitative data is indispensable to verify the extrapolation from in vitro tests, to modify the predictive models of ENM exposure, and to underpin the risk management strategy for ENMs. However, it remains a challenge to quantitatively assess the bio-distribution of ENMs under realistic exposure, their long-term deposition (especially in non-targeted tissues), their passage across the natural barriers, and the impacts of nano-bio interactions on their in vivo behaviors. Some commonly used techniques for in vivo ENM quantification, such as electron microscopy, fluorescence-based detection, atomic spectroscopy, radiotracing, and techniques basing on synchrotron radiation are reviewed, and their technical characteristics, the state of the art, limitations, and future prospects are addressed. PMID- 23027546 TI - Enhancement by Glycyrrhizae Radix of hepatic metabolism of hypaconitine, a major bioactive and toxic component of Aconiti Laterlis Radix, evaluated by HPLC-TQ MS/MS analysis. AB - Glycyrrhizae Radix (GR) is often prescribed together with Aconiti Laterlis Radix (ALR) (a so-called compatible drug pair) in traditional Chinese medicinal practice to reduce toxicity of ALR. However, the mechanisms involved remain to be addressed. In this study, the metabolic interactions between GR-ALR drug pair were investigated for the first time. First, an HPLC-TQ-MS/MS method was developed to analyze hypaconitine, a major bioactive and toxic component of ALR, in rat liver S9. Then the in vitro metabolic rates of hypaconitine by different rat liver S9 were compared using the established method. The experiments were designed in four groups: pure hypaconitine (group I) and ALR extract (group II) incubated with liver S9 of normal rats, and pure hypaconitine (group III) and ALR extract (group IV) incubated with liver S9 of GR-pretreated rats. When incubated for more than 4 h, the metabolic rates of hypaconitine in group III were significantly higher than those in group I, and when incubated for more than 2 h, the metabolic rates of hypaconitine in group IV were significantly higher than those in group II, suggesting that GR can enhance metabolic rate of hypaconitine, the mechanism of which might be related to hepatic metabolizing enzyme induction by GR. PMID- 23027544 TI - Robust microarray production of freshly expressed proteins in a human milieu. AB - PURPOSE: In vitro transcription/translation (IVTT) systems are widely used in proteomics. For clinical applications, mammalian systems are preferred for protein folding and activity; however, the level of protein obtained is low. A new system extracted from human cells (1-Step Human Coupled IVT (HCIVT)) has the potential to overcome this problem and deliver high yields of protein expressed in a human milieu. EXPERIMENTAL DESIGN: Western blots and self-assembled protein microarrays were used to test the efficiency of protein synthesis by HCIVT compared to rabbit reticulocyte lysate (RRL). The arrays were also used to measure the immune response obtained from serum of patients exposed to pathogens or vaccine. RESULTS: HCIVT performed better than RRL in all experiments. The yield of protein synthesized in HCIVT is more than ten times higher than RRL, in both Western blot and protein microarrays. Moreover, HCIVT showed a robust lot-to lot reproducibility. In immune assays, the signals of many antigens were detected only in HCIVT-expressed arrays, mainly due to the reduction in the background signal and the increased levels of protein on the array. CONCLUSION AND CLINICAL RELEVANCE: HCIVT is a robust in vitro transcription and translation system that yields high levels of protein produced in a human milieu. It can be used in applications where protein expression in a mammalian system and high yields are needed. The increased immunogenic response of HCIVT-expressed proteins will be critical for biomarker discovery in many diseases, including cancer. PMID- 23027548 TI - Excitation enhancement of a quantum dot coupled to a plasmonic antenna. AB - Plasmonic antennas are key elements to control the luminescence of quantum emitters. However, the antenna's influence is often hidden by quenching losses. Here, the luminescence of a quantum dot coupled to a gold dimer antenna is investigated. Detailed analysis of the multiply excited states quantifies the antenna's influence on the excitation intensity and the luminescence quantum yield separately. PMID- 23027550 TI - Nesting phenology and clutch characteristics of captive Siamese crocodiles (Crocodylus siamensis) in Cambodia. AB - The Siamese crocodile (Crocodylus siamensis) is considered one of the least studied and most critically endangered crocodilians in the world. Although few wild populations remain, more than 700,000 C. siamensis are held on commercial crocodile farms in Southeast Asia. Despite conservation concerns, many aspects of C. siamensis life history remain poorly known, particularly with regards to its reproductive biology. We studied nesting phenology, clutch characteristics, and other aspects of C. siamensis reproductive biology on crocodile farms in Cambodia during 2000 and 2001. Oviposition among captive crocodiles began in February and continued into early June. The mean (+/-1 SD) oviposition date based on pooled data from 2000 and 2001 was 5 April +/- 24 days. Mean oviposition date differed significantly between 2000 and 2001, possibly as a result of annual variability among nesting cues. The mean incubation period was 72 +/- 3 days and eggs hatched from 5 May to 18 August. Mean clutch size (25.0 +/- 8.8 eggs; n = 183) differed significantly between years, possibly resulting from the >2.5-fold increase in sample size during 2001. There was no correlation between clutch size and oviposition date during either 2000 or 2001. A single female produced two clutches during 2001, complimenting previous reports of double-clutching among C. siamensis. The mean length and width of 515 eggs were 78.2 +/- 4.9 and 48.1 +/- 2.5 mm, respectively; mean egg mass was 90.8 +/- 16.5 g (n = 471). One unpipped egg contained a set of twins. PMID- 23027549 TI - Interactions between Drosophila IgCAM adhesion receptors and cindr, the Cd2ap/Cin85 ortholog. AB - BACKGROUND: Morphogenetic modeling of tissues requires coordinated regulation of adhesion. For its correct patterning, the Drosophila pupal eye requires several Immunoglobulin superfamily cell adhesion molecules (IgCAMs) and the adaptor protein Cindr. Orthologs of these proteins are essential components of specialized junctions of the vertebrate kidney; the Cindr ortholog Cd2ap is essential for the integrity of this structure. RESULTS: Reducing Cindr during fly eye development led to incorrect distribution of the IgCAMs Roughest (Rst) and Hibris (Hbs). Both bound Cindr. Disrupting endocytosis similarly led to Rst and Hbs mis-localization; our data suggests an additional early requirement for endocytosis in regulating Hbs localization or stability. Finally, Rst and Hbs localized correctly only when in stable membrane complexes and we propose that Cindr anchors these to the cytoskeleton. This regulation likely does not extend to IgCAMs Kin of irre (Kirre) and Sticks and stones (Sns) in the pupal eye; neither interacted with Cindr in in vitro assays. Nonetheless, Kirre and Sns partially mis-localized when Cindr was reduced, possibly due to interactions with Rst/Hbs. CONCLUSIONS: Our data suggests Cindr recapitulates both proposed functions of its mammalian orthologs Cd2ap and Cin85: targeting the IgCAMs Rst and Hbs for endocytosis and stabilizing these heterophilic IgCAM complexes. PMID- 23027551 TI - Neonatal milestones, behavior and growth rate of Sumatran rhinoceros (Dicerorhinus sumatrensis) calves born and bred in captivity. AB - The birth of Sumatran rhino calves at the Cincinnati Zoo and Botanical Garden offered a unique opportunity to study early development and cow-calf behavior in this elusive, critically endangered species. Study goals were to: (1) record developmental milestones of newborn calves; (2) characterize cow and calf behavior during the first year following birth; (3) compare trends in the behavioral development of a male vs. female calf; and (4) record weight gain and footprint size throughout the first year. In addition to recording eight neonatal milestones, more than 450 hr of behavioral data were collected on each of the two calves (one male and one female) and their dam during the first 12 months of life. Neonatal milestones were achieved within 24 hr of birth with the exception of first defecation, which occurred at 16-18 days. Although nursing bouts decreased slightly in the second half of the year (from once every 90 min to once every 2 hr), they continued to occur frequently throughout the day and night. Therefore, calves grew rapidly from approximately 33 kg at birth to 400 kg at 12 months. Average daily weight gain for the first week was approximately 2.0 kg, whereas average daily weight gain for the remaining 12 months was slight (<1 kg) and did not differ between calves. Eating and resting occupied 70-80% of the Sumatran rhino cow and calves' time and no gender biases in either maternal investment or developmental parameters were noted. Finally, footprint measurements proved valuable for estimating calf age. PMID- 23027555 TI - Impairment of adenosine A3 receptor activity disrupts neutrophil migratory capacity and impacts innate immune function in vivo. AB - Adenosine possesses potent anti-inflammatory properties which are partly mediated by G(i) -coupled adenosine A3 receptors (A3Rs). A3R agonists have shown clinical benefit in a number of inflammatory conditions although some studies in A3R deficient mice suggest a pro-inflammatory role. We hypothesised that, in addition to cell signalling effects, A3R compounds might inhibit neutrophil chemotaxis by disrupting the purinergic feedback loop controlling leukocyte migration. Human neutrophil activation triggered rapid upregulation of surface A3R expression which was disrupted by pre-treatment with either agonist (Cl-IB-MECA) or antagonist (MRS1220). Both compounds reduced migration velocity and neutrophil transmigration capacity without impacting the response to chemokines per se. Similar effects were observed in murine neutrophils, while cells from A3R deficient mice displayed a constitutively impaired migratory phenotype indicating compound-induced desensitisation and genetic ablation had the same functional outcome. In a dextran sodium sulphate-induced colitis model, A3R-deficient mice exhibited reduced colon pathology and decreased tissue myeloperoxidase levels at day 8 - consistent with reduced neutrophil recruitment. However, A3R-deficient mice were unable to resolve the dextran sodium sulphate-induced inflammation and had elevated numbers of tissue-associated bacteria by day 21. Our data indicate that A3Rs play a role in neutrophil migration and disrupting this function has the potential to adversely affect innate immune responses. PMID- 23027560 TI - Picture of the month. Congenital diaphragmatic hernia. PMID- 23027562 TI - Methodological concerns regarding cost-effectiveness analysis of palivizumab in Florida Medicaid. PMID- 23027564 TI - Children's environmental health. PMID- 23027565 TI - Thorium-mediated ring-opening of tetrahydrofuran and the development of a new thorium starting material: preparation and chemistry of ThI4(DME)2. AB - The thorium(IV) tetraiodide complex ThI(4)(DME)(2) (3) (DME = 1,2 dimethoxyethane) has been prepared in high yield by reacting the corresponding chloride complex ThCl(4)(DME)(2) with an excess of trimethylsilyl iodide (Me(3)SiI) in toluene. This new route avoids the use of thorium metal as a reagent. ThI(4)(DME)(2) (3) exhibits excellent thermal stability compared to ThI(4)(THF)(4) (1), which undergoes rapid ring-opening of THF at ambient temperature to yield the iodobutoxide complex ThI(3)[O(CH(2))(4)I](THF)(3) (2). Subsequent ligand-exchange between 2 and DME affords ThI(3)[O(CH(2))(4)I](DME)(2) (11), which can be converted to 3 with Me(3)SiI. Salt metathesis between 2 and K(L(Me)) (L(Me) = (2,6-(i)Pr(2)C(6)H(3))NC(Me)CHC(Me)N(2,6-(i)Pr(2)C(6)H(3))) cleanly gives (L(Me))ThI(2)[O(CH(2))(4)I](THF) (10), which is a rare example of a thorium beta-diketiminate complex. Complexes 2, 10, and 11 represent the first reported examples of THF ring-opening mediated by thorium. The synthetic utility of ThI(4)(DME)(2) (3) is demonstrated by preparation of thorium(IV) alkoxide, amide, and organometallic compounds. PMID- 23027575 TI - Artificial cytoskeletal structures within enzymatically active bio-inorganic protocells. AB - The fabrication of enzymatically active, semi-permeable bio-inorganic protocells capable of self-assembling a cytoskeletal-like interior and undergoing small molecule dephosphorylation reactions is described. Reversible disassembly of an amino acid-derived supramolecular hydrogel within the internalized reaction space is used to tune the enzymatic activity of the nanoparticle-bounded inorganic compartments. PMID- 23027576 TI - Comparing contractile apparatus-driven cytokinesis mechanisms across kingdoms. AB - Cytokinesis is the final stage of the cell cycle during which a cell physically divides into two daughters through the assembly of new membranes (and cell wall in some cases) between the forming daughters. New membrane assembly can either proceed centripetally behind a contractile apparatus, as in the case of prokaryotes, archaea, fungi, and animals or expand centrifugally, as in the case of higher plants. In this article, we compare the mechanisms of cytokinesis in diverse organisms dividing through the use of a contractile apparatus. While an actomyosin ring participates in cytokinesis in almost all centripetally dividing eukaryotes, the majority of bacteria and archaea (except Crenarchaea) divide using a ring composed of the tubulin-related protein FtsZ. Curiously, despite molecular conservation of the division machinery components, division site placement and its cell cycle regulation occur by a variety of unrelated mechanisms even among organisms from the same kingdom. While molecular motors and cytoskeletal polymer dynamics contribute to force generation during eukaryotic cytokinesis, cytoskeletal polymer dynamics alone appears to be sufficient for force generation during prokaryotic cytokinesis. Intriguingly, there are life forms on this planet that appear to lack molecules currently known to participate in cytokinesis and how these cells perform cytokinesis remains a mystery waiting to be unravelled. PMID- 23027578 TI - Interaction of peptides spanning the transmembrane domain of caveolin-1 with model membranes. AB - Caveolin-1 has an atypical membrane-spanning domain comprising of 34 residues. Caveolin-1 targets to lipid droplets under certain conditions, where they are involved in signaling and cholesterol balance. In the present study, membrane association of synthetic peptides corresponding to the membrane-spanning domain of caveolin-1 has been investigated to obtain an insight into the topology of transmembrane region in the lipid bilayer and the effect of truncations in this sequence, as observed in the targeting to lipid droplets, by using model membranes. Fluorescence studies revealed strong association of the peptide corresponding to the membrane-spanning domain of caveolin-1 with anionic lipids as compared with zwitterionic lipids, which is consistent with the location of this domain in the cytoplasmic side of the plasma membrane. Association of a short 9 residue peptide corresponding to the C-terminus of caveolin-1 membrane spanning domain with lipid vesicles revealed the importance of this region for association with model membranes. Our investigations indicate that the peptide corresponding to the membrane-spanning domain of caveolin-1 does not span the lipid bilayer. We propose that both caveolin scaffolding domain and transmembrane segment of caveolin-1 contribute to the strong association with the plasma membrane rendering the protein highly detergent resistant. PMID- 23027577 TI - Changes in chondrocyte gene expression following in vitro impaction of porcine articular cartilage in an impact injury model. AB - Our objective was to monitor chondrocyte gene expression at 0, 3, 7, and 14 days following in vitro impaction to the articular surface of porcine patellae. Patellar facets were either axially impacted with a cylindrical impactor (25 mm/s loading rate) to a load level of 2,000 N or not impacted to serve as controls. After being placed in organ culture for 0, 3, 7, or 14 days, total RNA was isolated from full thickness cartilage slices and gene expression measured for 17 genes by quantitative real-time RT-PCR. Targeted genes included those encoding proteins involved with biological stress, inflammation, or anabolism and catabolism of cartilage extracellular matrix. Some gene expression changes were detected on the day of impaction, but most significant changes occurred at 14 days in culture. At 14 days in culture, 10 of the 17 genes were differentially expressed with col1a1 most significantly up-regulated in the impacted samples, suggesting impacted chondrocytes may have reverted to a fibroblast-like phenotype. PMID- 23027579 TI - All-conjugated triblock polyelectrolytes. AB - All-conjugated triblock polyfluorenes with well-defined molecular weights and low polydispersities are synthesized via chain-growth Suzuki-Miyaura polymerization. Ionization of pendant alkylbromide chains by pyridine affords amphiphilic triblock polyelectrolytes with neutral/charged/neutral or charged/neutral/charged segments. The immiscible blocks lead to aggregation in polar and nonpolar solvents, and to complex surface morphologies depending on the polarity of the substrate. These triblock polyelectrolytes can also be used as interfacial layers in polymer light-emitting diodes to facilitate electron injection from aluminum. PMID- 23027581 TI - The role of nectins in different types of cell-cell adhesion. AB - Mammalian tissues and organs are composed of different types of cells that adhere to each other homotypically (i.e. interactions between cells of the same cell type) or heterotypically (i.e. interactions between different cell types), forming a variety of cellular patterns, including mosaic patterns. At least three types of cell-cell adhesion have been observed: symmetric homotypic, asymmetric homotypic and heterotypic cell adhesions. Cadherins and nectins, which are known cell-cell adhesion molecules, mediate these cell adhesions. Cadherins comprise a family of more than 100 members, but they are primarily involved in homophilic trans-interactions (i.e. interactions between the same cadherin members) between opposing cells. By contrast, the nectin family comprises only four members, and these proteins form both homophilic and heterophilic trans-interactions (i.e. interactions between the same and different nectin members on opposing cells). In addition, heterophilic trans-interactions between nectins are much stronger than homophilic trans-interactions. Because of these unique properties, nectins have crucial roles in asymmetric homotypic cell-cell adhesion at neuronal synapses and in various types of heterotypic cell-cell adhesions. We summarize recent progress in our understanding of the biology of nectins and discuss their roles in heterotypic cell-cell adhesions, whose formation cannot be solely explained by the action of cadherins. PMID- 23027580 TI - Integrin trafficking at a glance. PMID- 23027582 TI - Decomposition of fractionated local electrograms using an analytic signal model based on sigmoid functions. AB - Microstructural heterogeneities in cardiac tissue, such as embedded connective tissue secondary to fibrosis, may lead to complex patterns of electrical activation that are reflected in the fractionation of extracellularly recorded electrograms. The decomposition of such electrograms into non-fractionated components is expected to provide additional information to allow a more precise classification of the microstructural properties adjacent to a given recording site. For the sake of this, an analytic signal model is introduced in this study that is capable of reliably identifying extracellular waveforms associated with sites of initiating, free-running, and terminating or colliding activation wavefronts. Using this signal model as a template, a procedure is developed for the automatic decomposition of complex fractionated electrograms into non fractionated components. The decomposition method has been validated using electrograms obtained from one- and two-dimensional computer simulations in which all relevant intracellular and extracellular quantities are accessible at a very high spatiotemporal resolution and can be manipulated in a controlled manner. Fractionated electrograms were generated in these models by incorporating microstructural obstacles that mimicked inlays of connective tissue. Using this signal model, fractionated electrograms emerging from microstructural heterogeneities in the submillimeter range with latencies between components down to 0.6 ms can be decomposed. PMID- 23027583 TI - Pharmacovigilance in pregnancy: adverse drug reactions associated with fetal disorders. AB - OBJECTIVE: To provide the first update on drug safety profiles and adverse drug reactions (ADRs) associated with fetal disorders from the Swiss national ADR database. METHODS: We conducted a retrospective study using data from 202 pharmacovigilance reports on drug-associated fetal disorders from the Swiss national ADR database from 1990 to 2009. Evaluated aspects included administrative information on the report, drug exposure, and disorders. RESULTS: The ADR reporting frequency on the topic of fetal disorders has increased during the last 20 years, from only 1 report in 1991 to a maximum of 31 reports in 2008. Nervous system drugs were the most frequently reported drug group (40.2%) above all antidepressants and antiepileptics. The highest level of overall drug intake could be observed for the 1st trimester (85.4%), especially for the first 6 weeks of pregnancy. The most frequently reported types of fetal disorders were malformations (68.8%), especially those of the musculoskeletal and circulatory systems. A positive association was discovered between antiepileptics and malformations in general and in particular of the circulatory system and the eye, ear, face, and neck. CONCLUSIONS: The results suggest that the nervous system drug group bears an especially high risk for malformations. The most commonly identified drug exposures can help focus pharmacoepidemiologic efforts in drug induced birth defects. PMID- 23027584 TI - Discrepancy in lamellar body counts (LBCs) between the Sysmex XE-2100 and Sysmex XT-2000i instruments. PMID- 23027585 TI - Analytical goals for the determination of HbA2. AB - BACKGROUND: We present a study aimed to define the analytical goals for the determination of hemoglobin A2, a minor hemoglobin present in human blood normally accounting from 2.5 % to 3.3 % of total hemoglobin, and typically increased up to 6 % - 7 % in subjects carriers of beta-thalassemia. METHODS: The analytical goals have been derived using two approaches, the first one based on biologic variation, and the second one based on the opinion of experts. RESULTS: The data obtained by studying 17 adult non-carrier healthy subjects, from whom we took blood samples every 2 weeks for 2.0 months, indicated a small intraindividual biologic variation (CV I of 0.7 % ), with respect to a larger between-subject variation (CV G of 7.7 % ). The minimum levels for imprecision, bias and total error derived from the analysis of these data were: 0.5 % , 2.9 % and 4.5 % , respectively. The limits derived from the opinion of experts were based on a questionnaire with three clinical cases, which was circulated among two teams of international experts, and on a discussion about the clinical needs. The average total error derived from such surveys ranged between 7.0 % and 9.5 % . CONCLUSIONS: The various methods to derive analytical performance goals gave different limits, thus indicating the need for an increased communication between clinicians and laboratory professionals on this matter. PMID- 23027586 TI - Level of mental health intervention and clinical need among inmates with mental illness in five English jails. AB - OBJECTIVE: This study examined associations between clinical, demographic, and criminological characteristics of inmates with mental illness and level of mental health intervention received during early custody. METHODS: In a prospective study, 3,079 participants entering five English jails were recruited and screened for mental illness with a standardized tool. Individuals who screened positive were assessed for mental illness and symptom severity within one week of arrival. Clinical records of those who received a diagnosis of mental illness (N=409) were reviewed for one month (or until discharge, if sooner) to determine mental health care interventions received. Main outcomes were the level of mental health intervention received (none, primary, or secondary) and whether an intervention was received from substance misuse services. RESULTS: Compared with individuals who did not receive services, those who received primary mental health care were more likely to have a diagnosis of major depressive disorder than another mental illness (OR=2.01, CI=1.20-3.36). Compared with those who received primary care services, those who received secondary mental health care were more likely to have a diagnosis of psychosis (OR=3.34, CI=1.81-6.17). However, 23% of the sample received no intervention. Offenders with mental illness who misused drugs were more likely than those who misused alcohol alone to receive an intervention from substance misuse services (OR=3.67, CI=1.91-7.05). CONCLUSIONS: Level of intervention was not consistently linked with diagnoses or symptom severity among inmates with mental illness. Triage processes should be improved to ensure that mental health care resources in jails are appropriately matched to clinical need. PMID- 23027587 TI - Variable selection in multivariate modeling of drug product formula and manufacturing process. AB - Multivariate data analysis methods such as partial least square (PLS) modeling have been increasingly applied to pharmaceutical product development. This study applied the PLS modeling to analyze a product development dataset generated from a design of experiment and historical batch data. Attention was paid in particular to the assessment of the importance of predictor variables, and subsequently the variable selection in the PLS modeling. The assessment indicated that irrelevant and collinear predictors could be extensively present in the initial PLS model. Therefore, variable selection is an important step in the optimization of the pharmaceutical product process model. The variable importance for projections (VIP) and coefficient values can be employed to rank the importance of predictors. On the basis of this ranking, the irrelevant predictors can be removed. To further reduce collinear predictors, multiple rounds of PLS modeling on different combinations of predictors may be necessary. To this end, stepwise reduction of predictors based on their VIP/coefficient ranking was introduced and was proven to be an effective approach to identify and remove redundant collinear predictors. Overall, the study demonstrated that the variable selection procedure implemented herein can effectively evaluate the importance of variables and optimize models of drug product processes. PMID- 23027588 TI - Well-defined alkylpalladium complexes with pyridine-carboxylate ligands as catalysts for the aerobic oxidation of alcohols. AB - Neophylpalladium complexes of the type [Pd(CH(2)CMe(2)Ph)(N-O)(L)], where N-O is picolinate or a related bidentate, monoanionic ligand (6-methylpyridine-2 carboxylate, quinoline-2-carboxylate, 2-pyridylacetate or pyridine-2-sulfonate) and L is pyridine or a pyridine derivative, efficiently catalyze the oxidation of a range of aliphatic, benzylic and allylic alcohols with oxygen, without requiring any additives. A versatile method is described which allows the synthesis of the above-mentioned complexes with a minimum synthetic effort from readily available materials. Comparison of the rates of oxidation of 1 phenylethanol with different catalysts reveals the influence of the structure of the bidentate N-O chelate and the monodentate ligand L on the catalytic performance of these complexes. PMID- 23027589 TI - Implementation of a multidisciplinary approach to solve complex nano EHS problems by the UC Center for the Environmental Implications of Nanotechnology. AB - UC CEIN was established with funding from the US National Science Foundation and the US Environmental Protection Agency in 2008 with the mission to study the impact of nanotechnology on the environment, including the identification of hazard and exposure scenarios that take into consideration the unique physicochemical properties of engineered nanomaterials (ENMs). Since its inception, the Center has made great progress in assembling a multidisciplinary team to develop the scientific underpinnings, research, knowledge acquisition, education and outreach that is required for assessing the safe implementation of nanotechnology in the environment. In this essay, the development of the infrastructure, protocols, and decision-making tools that are required to effectively integrate complementary scientific disciplines allowing knowledge gathering in a complex study area that goes beyond the traditional safety and risk assessment protocols of the 20th century is outlined. UC CEIN's streamlined approach, premised on predictive hazard and exposure assessment methods, high throughput discovery platforms and environmental decision-making tools that consider a wide range of nano/bio interfaces in terrestrial and aquatic ecosystems, demonstrates the implementation of a 21st-century approach to the safe implementation of nanotechnology in the environment. PMID- 23027590 TI - Changes in in vivo knee contact forces through gait modification. AB - Knee osteoarthritis (OA) commonly occurs in the medial compartment of the knee and has been linked to overloading of the medial articular cartilage. Gait modification represents a non-invasive treatment strategy for reducing medial compartment knee force. The purpose of this study was to evaluate the effectiveness of a variety of gait modifications that were expected to alter medial contact force. A single subject implanted with a force-measuring knee replacement walked using nine modified gait patterns, four of which involved different hiking pole configurations. Medial and lateral contact force at 25, 50, and 75% of stance phase, and the average value over all of stance phase (0-100%), were determined for each gait pattern. Changes in medial and lateral contact force values relative to the subject's normal gait pattern were determined by a Kruskal-Wallis test. Apart from early stance (25% of stance), medial contact force was most effectively reduced by walking with long hiking poles and wide pole placement, which significantly reduced medial and lateral contact force during stance phase by up to 34% (at 75% of stance) and 26% (at 50% of stance), respectively. Although this study is based on data from a single subject, the results provide important insight into changes in medial and lateral contact forces through gait modification. The results of this study suggest that an optimal configuration of bilateral hiking poles may significantly reduce both medial and lateral compartment knee forces in individuals with medial knee osteoarthritis. PMID- 23027591 TI - A critical reevaluation of the stationary axonal cytoskeleton hypothesis. AB - Neurofilaments are transported along axons in a rapid intermittent and bidirectional manner but there is a long-standing controversy about whether this applies to all axonal neurofilaments. Some have proposed that only a small proportion of axonal neurofilaments are mobile and that most are deposited into a persistently stationary and extensively cross-linked cytoskeleton that remains fixed in place for many months without movement, turning over very slowly. In contrast, others have proposed that this hypothesis is based on a misinterpretation of the experimental data and that, in fact, all axonal neurofilaments move. These contrary perspectives have distinct implications for our understanding of how neurofilaments are organized and reorganized in axons both in health and disease. Here, we discuss the history and substance of this controversy. We show that the published data on the kinetics and distribution of neurofilaments along axons favor a simple "stop and go" transport model in which axons contain a single population of neurofilaments that all move in a stochastic, bidirectional and intermittent manner. Based on these considerations, we propose a dynamic view of the neuronal cytoskeleton in which all neurofilaments cycle repeatedly between moving and pausing states throughout their journey along the axon. The filaments move infrequently, but the average pause duration is on the order of hours rather than weeks or months. Against this fluid backdrop, the action of molecular motors on neurofilaments can have dramatic effects on neurofilament organization that would not be possible if the neurofilaments were extensively cross-linked into a truly stationary network. PMID- 23027593 TI - Clinical relevance of frailty trajectory post myocardial infarction. AB - BACKGROUND: Frailty describes the heterogeneity of vulnerability in older people and has been shown to predict mortality, disability, and institutionalization. Little is known about the clinical relevance of frailty post myocardial infarction (MI). DESIGN: The Rockwood frailty index, based on accumulation of deficits, was adapted in a cohort of MI survivors followed up for 20 years, in order to assess trajectory and predictive value for clinical outcomes. METHODS: Participants were 1521 patients aged <=65 years admitted to one of eight Israeli hospitals with first acute MI between 1992 and 1993. A frailty index (on a 0-1 continuous scale) was developed comprising 32 variables, including self-rated health, functional limitations, comorbidity, weight loss, and physical activity. Frailty was assessed at baseline and 10-13 years after MI. RESULTS: Median frailty score increased from 0.08 to 0.19 during follow up. Participants in the frailest group (>=0.25) at baseline had twice the multivariable-adjusted mortality risk of those in the least frail group (<0.10) (hazard ratio, HR, 2.02, 95% CI 1.46-2.79). Frailty index modelled as a time-dependent variable showed a substantially stronger association (HR 3.61, 95% CI 2.82-4.63) and provided incremental value in risk discrimination beyond clinical and socio-demographic variables (p < 0.001 for improvement in c-statistic). The frailest patients were more than twice as likely to be hospitalized during follow up compared to the least frail (adjusted rate ratio 2.14, 95% CI 1.63-2.81). CONCLUSIONS: Frailty, calculated via an index of deficits, was associated with mortality and hospitalizations following MI. Beyond predictive value, accurate identification of frailty may indicate which individuals will benefit most from preventive interventions. PMID- 23027592 TI - Associations between a parental history of premature cardiovascular disease and coronary artery calcium and carotid intima-media thickness: the Coronary Artery Risk Development In Young Adults (CARDIA) study. AB - BACKGROUND: It is unclear if associations between a parental history of premature CVD (pCVD) and subclinical atherosclerosis are attenuated by adjustment for long term risk factor levels through middle adulthood. DESIGN: Prospective community based cohort study. METHODS: CARDIA participants who attended the year-20 exam (n = 2283, mean age 45 years) were grouped by pCVD status: maternal only, paternal only, any parental, and no parental history (referent). We used separate logistic regression models, adjusted for average risk factor levels over a 20-year follow up to assess associations of parental pCVD and subclinical atherosclerosis in offspring. RESULTS: White participants with any parental history of pCVD had a higher odds of coronary artery calcium (CAC) >0 than participants with no parental history (OR 1.55, 95% CI 1.01-2.37). This was largely driven by the association of a paternal history of pCVD with CAC >0 (OR 2.15, 95% CI 1.42 3.23), which was minimally attenuated by multivariable adjustment (OR 2.09, 95% CI 1.31-3.32). Similarly, adjusted associations between parental pCVD and intima media thickness (IMT) >90% were observed in white participants with a paternal history of pCVD (OR 1.93, 95% CI 1.10-3.39) and any parental history pCVD (OR 1.67, 95% CI 1.02-2.74). No significant associations between a parental history of pCVD and the odds of subclinical atherosclerosis were observed in black participants. CONCLUSIONS: Parental pCVD is independently associated with early development of subclinical atherosclerosis; these associations may be race specific for participants in their fifth decade of life. PMID- 23027594 TI - Ultralow voltage, OTFT-based sensor for label-free DNA detection. AB - An organic ultralow voltage field effect transistor for DNA hybridization detection is presented. The transduction mechanism is based on a field-effect modulation due to the electrical charge of the oligonucleotides, so label-free detection can be performed. The device shows a sub-nanometer detection limit and unprecedented selectivity with respect to single nucleotide polymorphism. PMID- 23027595 TI - Is surgery the gold standard in the treatment of obstructive hypertrophic cardiomyopathy? AB - OBJECTIVES: Hypertrophic cardiomyopathy is a complex and relatively common genetic cardiac disease and has been the subject of intensive scrutiny and investigation for over 40 years. The aim of this non-randomized cohort study was to compare subjective and objective outcomes in hypertrophic cardiomyopathy patients undergoing drug therapy, surgical myotomy-myectomy, dual-chamber pacing and alcohol septal ablation. METHODS: We examined 194 patients: 103 with non obstructive hypertrophic cardiomyopathy and 91 with obstructive hypertrophic cardiomyopathy. All the patients with a non-obstructive form were on drug therapy. Ninety-one consecutive patients with drug-refractory obstructive hypertrophic cardiomyopathy were treated invasively. Dual-chamber pacemaker implantation was performed for 49 patients with previous positive temporary pacing test (Group 1). In 28 patients with massive left ventricle hypertrophy and obliteration of its cavities, extensive myotomy-myectomy was performed (Group 2). In 14 patients with midventricular obstruction and appropriate coronary anatomy, alcohol septal ablation was performed (Group 3). RESULTS: The peak left ventricle outflow tract gradient was 84.1 +/- 15.2 mmHg in Group 1, 113.3 +/- 14.9 mmHg in Group 2 and 97.5 +/- 8.9 mmHg in Group 3. Dual-chamber pacing in Group 1 with optimal atrio-ventricular delay (85-180 ms for atrium pacing and 45-120 ms for atrial sensing) leads to dramatic decreases in left ventricle outflow tract gradient to 17.6 +/- 11.8 mmHg and degree of mitral regurgitation. After extensive myectomy in Group 2, we observed a reduction of left ventricle outflow tract gradient to 17.3 +/- 10.2 mmHg. Septal alcohol ablation in Group 3 leads to a left ventricle outflow tract gradient decrease from 97.5 +/- 8.9 to 25.3 +/- 5.8 mmHg. CONCLUSIONS: Surgical myectomy, dual-chamber pacing and alcohol septal ablation are equally effective in reducing obstruction in case of correct indications. Dual-chamber pacing is indicated in functional reversible states characterized by excitation delay. Alcohol septal ablation is preferable in cases with midventricular obstruction and appropriate coronary anatomy. Surgical methods are indicated in anatomical irreversible changes and remain the gold standard for obstructive hypertrophic cardiomyopathy treatment. PMID- 23027596 TI - Preservation versus non-preservation of mitral valve apparatus during mitral valve replacement: a meta-analysis of 3835 patients. AB - Resection of the chordopapillary apparatus during mitral valve replacement has been associated with a negative impact on survival. Mitral valve replacement with the preservation of the mitral valve apparatus has been associated with better outcomes, but surgeons remain refractory to its use. To determine if there is any real difference in preservation vs non-preservation of mitral valve apparatus during mitral valve replacement in terms of outcomes, we performed a systematic review and meta-analysis using MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles to search for clinical studies that compared outcomes (30-day mortality, postoperative low cardiac output syndrome or 5-year mortality) between preservation vs non-preservation during mitral valve replacement from 1966 to 2011. The principal summary measures were odds ratios (ORs) with 95% confidence interval and P-values (that will be considered statistically significant when <0.05). The ORs were combined across studies using a weighted DerSimonian-Laird random-effects model. The meta analysis was completed using the software Comprehensive Meta-Analysis version 2 (Biostat Inc., Englewood, NJ, USA). Twenty studies (3 randomized and 17 non randomized) were identified and included a total of 3835 patients (1918 for mitral valve replacement preservation and 1917 for mitral valve replacement non preservation). There was significant difference between mitral valve replacement preservation and mitral valve replacement non-preservation groups in the risk of 30-day mortality (OR 0.418, P <0.001), postoperative low cardiac output syndrome (OR 0.299, P <0.001) or 5-year mortality (OR 0.380, P <0.001). No publication bias or important heterogeneity of effects on any outcome was observed. In conclusion, we found evidence that argues in favour of the preservation of mitral valve apparatus during mitral valve replacement. PMID- 23027597 TI - Cellular localization of PACAP and its receptors in the ovary of the spotted ray Torpedo marmorata Risso 1880 (Elasmobranchii: Torpediniformes). AB - The pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the glucagon-related family and occurs in two amidated forms, PACAP38 and PACAP27, with 38 and 27 amino acids, respectively. PACAP acts by binding to three different receptors, that are classified by their binding affinity for PACAP and VIP (vasoactive intestinal polypeptide): PAC(1)R (PACAP-specific receptor) exclusively binds PACAP, while VPAC(1)R (VIP/PACAP receptor, subtype 1) and VPAC(2)R (VIP/PACAP receptor, subtype 2) bind both PACAP and VIP. PACAP, first discovered in the brain, was then localized in several peripheral tissues of mammals, including the ovary. Besides mammals, PACAP and its receptors have been reported in fish too; however, less is known about the presence of PACAP in the fish ovary and the studies are limited to teleosts. The aim of our work was to study the distribution of the PACAP/PACAP-Rs system in the ovary of the cartilaginous fish Torpedo marmorata. Using in situ hybridization (ISH) and immunohistochemistry techniques, we demonstrated that PACAP and its receptors are widely represented in the Torpedo ovary in a stage-dependent manner. Moreover, our findings suggest an involvement of this peptide in the whole follicologenesis, probably influencing steroidogenesis, follicle development, and oocyte growth. PMID- 23027598 TI - Rotavirus. PMID- 23027599 TI - Understanding developmental-behavioral screening measures. PMID- 23027600 TI - Metabolic syndrome. PMID- 23027602 TI - Spirometry. PMID- 23027603 TI - Quantifying associations: understanding relative risks and odds ratios. PMID- 23027604 TI - Index of suspicion. Case 1: Palpitations and dizziness in a teenage boy. Case 2: Arthritis in a 4-year-old girl. Case 3: Seizures, hallucinations, hyponatremia, and red urine in a teenage boy in India. PMID- 23027605 TI - Chronic immunosuppression. PMID- 23027606 TI - Fever and petechial rash in a 9-year-old boy. PMID- 23027607 TI - Shape-controlled synthesis and catalytic application of ceria nanomaterials. AB - Because of their excellent properties and extensive applications, ceria nanomaterials have attracted much attention in recent years. This perspective provides a comprehensive review of current research activities that focus on the shape-controlled synthesis methods of ceria nanostructures. We elaborate on the synthesis strategies in the following four sections: (i) oriented growth directed by the crystallographic structure of cerium-based materials; (ii) oriented growth directed by the use of an appropriate capping reagent; (iii) growth confined or dictated by various templates; (iv) other potential methods for generating CeO(2) nanomaterials. In this perspective, we also discuss the catalytic applications of ceria nanostructures. They are often used as active components or supports in many catalytic reactions and their catalytic activities show morphology dependence. We review the morphology dependence of their catalytic performances in carbon monoxide oxidation, water-gas shift, nitric oxide reduction, and reforming reactions. At the end of this review, we give a personal perspective on the probable challenges and developments of the controllable synthesis of CeO(2) nanomaterials and their catalytic applications. PMID- 23027608 TI - Interferon-gamma inhibits integrin-mediated adhesion to fibronectin and survival signaling in thyroid cells. AB - Hashimoto's thyroiditis is the most frequent autoimmune disorder, characterized by the presence of a large lymphocytic infiltration and secretion of inflammatory cytokines in the thyroid. Infiltrating lymphocytes and cytokines play a pivotal role in the progression of HT, characterized by the progressive destruction of the normal follicular architecture of the gland and death of follicular cells, ending with loss of thyroid function. Integrins are plasma membrane receptors for the cell-extra-cellular matrix components, with both structural and signaling functions. Integrin-mediated fibronectin (FN) binding is necessary for the correct function and survival of thyroid follicular cells. The purpose of this study was to determine the effect of interferon-gamma (IFN-gamma) stimulation on integrin expression and signaling in the thyroid cell. Cytotoxicity, integrin expression, cell adhesion to FN, and FN-stimulated ERK and AKT phosphorylation were determined in a normal human thyroid cell line treated with IFN-gamma. IFN gamma induced apoptosis and reduced the expression of the integrin alphavbeta3. Integrin-mediated cell adhesion to FN was strongly impaired. Similarly, FN stimulated ERK and AKT phosphorylation were inhibited. In conclusion, our study in a thyroid cell model demonstrates that IFN-gamma induces apoptosis and inhibits the expression of the integrin alphavbeta3, reducing cell adhesion to FN and the succeeding outside-in signaling. These results suggest that integrins mediate the cytotoxic effect of IFN-gamma and are involved in the destructive mechanism of autoimmune thyroiditis. PMID- 23027609 TI - Sugars, ascorbic acid, total phenolic content and total antioxidant activity in passion fruit (Passiflora) cultivars. AB - BACKGROUND: The levels of sugars, ascorbic acid, total phenolic content (TPC) and total antioxidant activity (TAA) were determined in fruit juices from seven passion fruit (Passiflora spp.) cultivars: P. edulis cultivars Purple, Frederick, Yellow, Pink, P. edulis f. flavicarpa, P. maliformis and P. quadrangularis (we also tested this cultivar's mesocarp). RESULTS: Purple and Yellow P. edulis had significantly higher total sugar, 142.85 +/- 0.17 g kg-1 and 139.69 +/- 0.12 g kg 1, respectively, than other cultivars. Glucose and fructose content were higher in juice from vine-ripened fruits of Purple, Frederick and Yellow P. edulis, P. quadrangularis and P. maliformis. Sucrose content was significantly higher in juice of non-vine-ripened fruits of P. edulis (Pink) and P. edulis f. flavicarpa. Ascorbic acid, TPC and TAA were significantly higher in vine-ripened Purple and Yellow P. edulis; ranges were 0.22-0.33 g kg-1, 342.80-382.00 mg gallic acid equivalent L-1 and 409.13-586.70 umol Trolox L-1, respectively. Based on principal component analysis (PCA) and cluster analysis, the main variables - degrees Brix, total sugar, glucose, fructose, ascorbic acid, TPC and TAA - formed the characteristics for the group comprising Purple and Yellow P. edulis. CONCLUSIONS: Glucose, fructose, sucrose, ascorbic acid, TAA and TPC were quantified in passion fruit juices. Variation of the above variables in juices of Passiflora depends on the cultivar and ripeness. PMID- 23027610 TI - Chemical differences between voided and bladder urine in the aye-aye (Daubentonia madagascariensis): implications for olfactory communication studies. AB - Urine serves a communicative function in many mammalian species. In some species, the signaling function of urine can be enhanced by the addition of chemical compounds from glands along the distal portion of the urogenital tract. Although urine marking is the main mode of chemical communication in many primate species, there has been no study of the contribution of urogenital secretions to the chemical complexity of primate urine. Here, we compared the chemical composition of bladder urine versus voided urine in the aye-aye, Daubentonia madagascariensis, a strepsirrhine primate that relies on urine in intraspecific communication. Both types of urine, collected from each of 11 aye-ayes representing both sexes of varying adult ages, underwent headspace analysis via gas chromatography and mass spectrometry. Although the average number of compounds was similar in bladder and voided urine, 17% of the compounds detected occurred exclusively in voided urine (but only in a subset of individuals). An overall measure of chemical complexity (using a nonmetric multidimensional scaling analysis) showed that both types of urine were chemically different at the individual level. There was no apparent sex or age differences in the chemical components found in aye-aye urine. Nonetheless, the individual dissimilarities between bladder urine and voided urine indicate chemical contributions from structures along the urogenital tract and offer further support for the relevance of urinary communication in the aye-aye. PMID- 23027611 TI - 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. AB - Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5-HT(6) receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5-HT(6) receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5-HT(6) receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5-HT(6) agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post-weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5-HT(6) antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5 HT(6) receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control. PMID- 23027612 TI - Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. AB - Atherosclerotic lesions are characterized by the accumulation of oxidized LDL (OxLDL) and the infiltration of macrophages and T cells. Cytokine expression in the microenvironment of evolving lesions can profoundly contribute to plaque development. While the pro-atherogenic effect of T helper (Th) 1 cytokines, such as IFN-gamma, is well established, the role of Th2 cytokines is less clear. Therefore, we characterized the role of the Th2 cytokine interleukin (IL)-13 in murine atherosclerosis. Here, we report that IL-13 administration favourably modulated the morphology of already established atherosclerotic lesions by increasing lesional collagen content and reducing vascular cell adhesion molecule 1 (VCAM-1)-dependent monocyte recruitment, resulting in decreased plaque macrophage content. This was accompanied by the induction of alternatively activated (M2) macrophages, which exhibited increased clearance of OxLDL compared to IFN-gamma-activated (M1) macrophages in vitro. Importantly, deficiency of IL 13 results in accelerated atherosclerosis in LDLR(-/-) mice without affecting plasma cholesterol levels. Thus, IL-13 protects from atherosclerosis and promotes a favourable plaque morphology, in part through the induction of alternatively activated macrophages. PMID- 23027613 TI - A guanidine-rich regulatory oligodeoxynucleotide improves type-2 diabetes in obese mice by blocking T-cell differentiation. AB - T lymphocytes exhibit pro-inflammatory or anti-inflammatory activities in obesity and diabetes, depending on their subtypes. Guanidine-rich immunosuppressive oligodeoxynucleotides (ODNs) effectively control Th1/Th2-cell counterbalance. This study reveals a non-toxic regulatory ODN (ODNR01) that inhibits Th1- and Th17-cell polarization by binding to STAT1/3/4 and blocking their phosphorylation without affecting Th2 and regulatory T cells. ODNR01 improves glucose tolerance and insulin sensitivity in both diet-induced obese (DIO) and genetically generated obese (ob/ob) mice. Mechanistic studies show that ODNR01 suppresses Th1 and Th17-cell differentiation in white adipose tissue, thereby reducing macrophage accumulation and M1 macrophage inflammatory molecule expression without affecting M2 macrophages. While ODNR01 shows no effect on diabetes in lymphocyte-free Rag1-deficient DIO mice, it enhances glucose tolerance and insulin sensitivity in CD4(+) T-cell-reconstituted Rag1-deficient DIO mice, suggesting its beneficial effect on insulin resistance is T-cell-dependent. Therefore, regulatory ODNR01 reduces obesity-associated insulin resistance through modulation of T-cell differentiation. PMID- 23027614 TI - The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice. AB - Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti leishmanial agent. The compound induces topoisomerase I-mediated DNA-protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topoisomerase of L. donovani and acts as a non competitive inhibitor interacting with both subunits of the enzyme. Niranthin interacts with DNA-protein binary complexes and thus stabilizes the 'cleavable complex' formation and subsequently inhibits the religation of cleaved strand. The compound inhibits the proliferation of Leishmania amastigotes in infected cultured murine macrophages with limited cytotoxicity to the host cells and is effective against antimony-resistant Leishmania parasites by modulating upregulated P-glycoprotein on host macrophages. Importantly, besides its in vitro efficacy, niranthin treatment leads to a switch from a Th2- to a Th1-type immune response in infected BALB/c mice. The immune response causes production of nitric oxide, which results in almost complete clearance of the liver and splenic parasite burden after intraperitoneal or intramuscular administration of the drug. These findings can be exploited to develop niranthin as a new drug candidate against drug-resistant leishmaniasis. PMID- 23027616 TI - Identification and characterization of two sensory neuron membrane proteins from Cnaphalocrocis medinalis (Lepidoptera: Pyralidae). AB - Sensory neuron membrane proteins (SNMPs), which are located on the dendritic membrane of olfactory neurons, were considered as important components involved in pheromone reception in insects. In Drosophila melanogaster, mutants without SNMP are unable to evoke neuronal activities in the presence of pheromone cis vaccenyl acetate (cVA). So deeply understanding the SNMPs functions may help to develop pheromone-mediated insect pest management tactics. The present study reports the identification and characterization of CmedSNMP1 and CmedSNMP2, two candidate SNMPs in the rice leaffolder, Cnaphalocrocis medinalis, one of the serious rice insect pests in Asia. The comparison of amino acid sequences shows that CmedSNMP1 and CmedSNMP2 are very similar to the previously reported SNMPs isolated from moths such as Ostrinia nubilalis and O. furnacalis, respectively, but the two CmedSNMPs share low identity with each other. The distribution patterns of two CmedSNMPs in different tissues of adult moths were examined using RT-PCR and quantitative real-time PCR. Although the two genes are expressed not only in antennae but also in nonolfactory tissues such as wings, legs, and body; the relative transcription level shows both CmedSNMP1 and CmedSNMP2 are highly enriched in antennae. The dN/dS ratios of the two CmedSNMPs indicate that the two genes are all subject to purifying selection and evolved to be functional genes. This work presents for the first time a study on the SNMPs of C. medinalis, which may help in providing guidance to future functional research of moth SNMPs. PMID- 23027617 TI - Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice. AB - Obesity and its associated disorders, such as non-alcoholic steatohepatitis, increase the risk of hepatocellular carcinoma. Branched-chain amino acids (BCAA), which improve protein malnutrition in patients with liver cirrhosis, reduce the risk of hepatocellular carcinoma in these patients with obesity. In the present study, the effects of BCAA supplementation on the spontaneous development of hepatic premalignant lesions, foci of cellular alteration, in db/db obese mice were examined. Male db/db mice were given a basal diet containing 3.0% of either BCAA or casein, a nitrogen-content-matched control of BCAA, for 36 weeks. On killing the mice, supplementation with BCAA significantly inhibited the development of foci of cellular alteration when compared with casein supplementation by inhibiting cell proliferation, but inducing apoptosis. BCAA supplementation increased the expression levels of peroxisome proliferator activated receptor-gamma, p21(CIP1) and p27(KIP1) messenger RNA and decreased the levels of c-fos and cyclin D1 mRNA in the liver. BCAA supplementation also reduced both the amount of hepatic triglyceride accumulation and the expression of interleukin (IL)-6, IL-1beta, IL-18 and tumor necrosis factor-alpha mRNA in the liver. Increased macrophage infiltration was inhibited and the expression of IL-6, TNF-alpha, and monocyte chemoattractant protein-1 mRNA in the white adipose tissue were each decreased by BCAA supplementation. BCAA supplementation also reduced adipocyte size while increasing the expression of peroxisome proliferator activated receptor-alpha, peroxisome proliferator-activated receptor-gamma and adiponectin mRNA in the white adipose tissue compared with casein supplementation. These findings indicate that BCAA supplementation inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. BCAA supplementation may be useful in the chemoprevention of liver tumorigenesis in obese individuals. PMID- 23027618 TI - DNA repair gene variants in relation to overall cancer risk: a population-based study. AB - The hypothesis that germ-line polymorphisms in DNA repair genes influence cancer risk has previously been tested primarily on a cancer site-specific basis. The purpose of this study was to test the hypothesis that DNA repair gene allelic variants contribute to globally elevated cancer risk by measuring associations with risk of all cancers that occurred within a population-based cohort. In the CLUE II cohort study established in 1989 in Washington County, MD, this study was comprised of all 3619 cancer cases ascertained through 2007 compared with a sample of 2296 with no cancer. Associations were measured between 759 DNA repair gene single nucleotide polymorphisms (SNPs) and risk of all cancers. A SNP in O(6)-methylguanine-DNA methyltransferase, MGMT, (rs2296675) was significantly associated with overall cancer risk [per minor allele odds ratio (OR) 1.30, 95% confidence interval (CI) 1.19-1.43 and P-value: 4.1 * 10(-8)]. The association between rs2296675 and cancer risk was stronger among those aged <=54 years old than those who were >=55 years at baseline (P-for-(interaction) = 0.021). OR were in the direction of increased risk for all 15 categories of malignancies studied (P < 0.0001), ranging from 1.22 (P = 0.42) for ovarian cancer to 2.01 (P = 0.008) for urinary tract cancers; the smallest P-value was for breast cancer (OR 1.45, P = 0.0002). The results indicate that the minor allele of MGMT SNP rs2296675, a common genetic marker with 37% carriers, was significantly associated with increased risk of cancer across multiple tissues. Replication is needed to more definitively determine the scientific and public health significance of this observed association. PMID- 23027619 TI - Transcriptional regulation of the interleukin-11 gene by oncogenic Ras. AB - Interleukin-11 (IL-11), which belongs to a class of IL6-type cytokines, plays an important role in inflammation, motility and invasion in cancer. The ras mutation is frequently found in human cancer, but little is known regarding the transcriptional activation of the IL-11 gene by the Ras signal pathway in tumour cells. In this study, we investigated the role of Ras in the regulation of IL-11 using two different cell model systems: mouse NIH3T3 cells over-expressing oncogenic Ras with a tet-on system and Capan-1 human pancreatic carcinoma cells harbouring a K-ras mutation. We found that IL-11 expression was up-regulated at the transcriptional level by oncogenic Ras. Activation of the AP-1 response element, located between -153 and -30 in the 5'-regulatory region of the IL-11 gene, was necessary for oncogenic Ras-induced IL-11 promoter activation. AP-1 proteins, including Fra-1 and Fra-2, were up-regulated through the Raf/MEK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways by oncogenic Ras. Knockdown of Fra-1 by siRNA in NIH3T3 or Capan-1 cells strongly attenuated oncogenic Ras induced IL-11 expression. Additionally, inhibition of JNK, p38 and Stat3 abrogated oncogenic Ras-induced IL-11 expression. These results suggest that both the PI3K and Raf pathways are necessary for the expression of IL-11 in oncogenic Ras-mutated cells, and that JNK, p38 and Stat3 also contribute to oncogenic Ras induced IL-11 expression. PMID- 23027620 TI - CXCL1/GROalpha increases cell migration and invasion of prostate cancer by decreasing fibulin-1 expression through NF-kappaB/HDAC1 epigenetic regulation. AB - Inflammatory tumor microenvironments play pivotal roles in the development of cancer. Inflammatory cytokines such as CXCL1/GROalpha exert cancer-promoting activities by increasing tumor angiogenesis. However, whether CXCL1/GROalpha also plays a role in the progression of prostate cancer, particularly in highly invasive castration-resistant prostate cancer (CRPC), has not been investigated. We explored whether CXCL1/GROalpha enhances cell migration and invasion in PC-3 and DU145 CRPC. Induction of PC-3 and DU145 cancer progression by CXCL1/GROalpha is associated with increased AKT activation and IkappaB kinase alpha (IKKalpha) phosphorylation, resulting in nuclear factor-kappaB (NF-kappaB) activation. Activated NF-kappaB interacts with histone deacetylase 1 (HDAC1) to form a gene silencing complex, which represses the expression of fibulin-1D by decreasing the acetylation of histone H3 and H4 on the NF-kappaB-binding site of the fibulin-1D promoter. Blockade of AKT2 by small hairpin RNA (shRNA) decreases IKKalpha phosphorylation, NF-kappaB nuclear translocation and cell migration, indicating that AKT is required in CXCL1/GROalpha-mediated NF-kappaB activation and cell migration. In addition, NF-kappaB and HDAC1 shRNA decrease the effect of CXCL1/GROalpha on fibulin-1D downregulation, migration and invasion, suggesting that the NF-kappaB/HDAC1 complex is also involved in CXCL1/GROalpha-mediated cancer progression. Our findings provide the first evidence that CXCL1/GROalpha decreases fibulin-1D expression in prostate cancer cells and also reveals novel insights into the mechanism by which CXCL1/GROalpha regulates NF-kappaB activation through the AKT pathway. Our results also clearly establish that co operation of NF-kappaB and HDAC1 regulates fibulin-1D expression by epigenetic modification. Our study suggests that inhibition of CXCL1/GROalpha-mediated AKT/NF-kappaB signaling may be an attractive therapeutic target for CRPC. PMID- 23027621 TI - Alaska Native smokers and smokeless tobacco users with slower CYP2A6 activity have lower tobacco consumption, lower tobacco-specific nitrosamine exposure and lower tobacco-specific nitrosamine bioactivation. AB - Nicotine, the psychoactive ingredient in tobacco, is metabolically inactivated by CYP2A6 to cotinine. CYP2A6 also activates procarcinogenic tobacco-specific nitrosamines (TSNA). Genetic variation in CYP2A6 is known to alter smoking quantity and lung cancer risk in heavy smokers. Our objective was to investigate how CYP2A6 activity influences tobacco consumption and procarcinogen levels in light smokers and smokeless tobacco users. Cigarette smokers (n = 141), commercial smokeless tobacco users (n = 73) and iqmik users (n = 20) were recruited in a cross-sectional study of Alaska Native people. The participants' CYP2A6 activity was measured by both endophenotype and genotype, and their tobacco and procarcinogen exposure biomarker levels were also measured. Smokers, smokeless tobacco users and iqmik users with lower CYP2A6 activity had lower urinary total nicotine equivalents (TNE) and (methylnitrosamino)-1-(3)pyridyl-1 butanol (NNAL) levels (a biomarker of TSNA exposure). Levels of N nitrosonornicotine (NNN), a TSNA metabolically bioactivated by CYP2A6, were higher in smokers with lower CYP2A6 activities. Light smokers and smokeless tobacco users with lower CYP2A6 activity reduce their tobacco consumption in ways (e.g. inhaling less deeply) that are not reflected by self-report indicators. Tobacco users with lower CYP2A6 activity are exposed to lower procarcinogen levels (lower NNAL levels) and have lower procarcinogen bioactivation (as indicated by the higher urinary NNN levels suggesting reduced clearance), which is consistent with a lower risk of developing smoking-related cancers. This study demonstrates the importance of CYP2A6 in the regulation of tobacco consumption behaviors, procarcinogen exposure and metabolism in both light smokers and smokeless tobacco users. PMID- 23027622 TI - DNA damage response in peritumoral regions of oesophageal cancer microenvironment. AB - Oesophageal cancer is a highly aggressive disease, ranking among the 10 most common cancers in the world. Oesophageal cancer patients often suffer from multi origin tumours, and therefore, it is important to improve our understanding of the complex biology, which underpins microenvironmental interactions in this disease. Extensive evidence indicates that the interaction of tumours with their microenvironment may play a crucial role in tumour initiation and progression. In this study, we analysed DNA damage response (DDR), immune cell invasion and cancer progression in 47 patients with oesophageal cancer from three different regions (tumour tissue, tumour-proximal non-malignant tissue and distant non malignant tissue). Accumulated DDR (positive staining for gammaH2AX and phospho ATM) was evident within tumour tissue and significantly increased in non malignant tissue surrounding the tumour cells although activation of p53 by phosphorylation at serine 15 was observed only in tumour tissue. The level of DDR detected in cancer microenvironment depended largely on the distance from the tumour, as stronger DDR was observed in tumour-proximal areas compared with that in tumour-distant tissue. Induction of DDR in non-malignant tissues correlated with increased invasion of lymphocytes and macrophages and with precancerous progression. Our results support that DDR is induced in oesophageal cancer surrounding non-malignant epithelial cells, via activation of an inflammatory process, which in turn contributes to the progression of precancerous lesions. These findings provide novel pathological evidence for inflammation and DDR in influencing non-metastatic progression of cancer in its microenvironment. PMID- 23027623 TI - MAP kinase genes and colon and rectal cancer. AB - Mitogen-activated protein kinase (MAPK) pathways regulate many cellular functions including cell proliferation, differentiation, migration and apoptosis. We evaluate genetic variation in the c-Jun-N-terminal kinases, p38, and extracellular regulated kinases 1/2 MAPK-signaling pathways and colon and rectal cancer risk using data from population-based case-control studies (colon: n = 1555 cases, 1956 controls; rectal: n = 754 cases, 959 controls). We assess 19 genes (DUSP1, DUSP2, DUSP4, DUSP6, DUSP7, MAP2K1, MAP3K1, MAP3K2, MAP3K3, MAP3K7, MAP3K9, MAP3K10, MAP3K11, MAPK1, MAPK3, MAPK8, MAPK12, MAPK14 and RAF1). MAP2K1 rs8039880 [odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.38, 0.83; GG versus AA genotype] and MAP3K9 rs11625206 (OR = 1.41, 95% CI = 1.14, 1.76; recessive model) were associated with colon cancer (P (adj) value < 0.05). DUSP1 rs322351 (OR = 1.43, 95% CI = 1.09, 1.88; TT versus CC) and MAPK8 rs10857561 (OR = 1.48, 95% CI 1.08, 2.03; AA versus GG/GA) were associated with rectal cancer (P (adj) < 0.05). Aspirin/non-steroidal anti-inflammatory drug, cigarette smoking and body mass index interacted with several genes to alter cancer risk. Genetic variants had unique associations with KRAS, TP53 and CIMP+ tumors. DUSP2 rs1724120 [hazard rate ratio (HRR) = 0.72, 95%CI = 0.54, 0.96; AA versus GG/GA), MAP3K10 rs112956 (HRR = 1.40, 95% CI = 1.10, 1.76; CT/TT versus CC) and MAP3K11 (HRR = 1.76, 95% CI 1.18, 2.62 TT versus GG/GT) influenced survival after diagnosis with colon cancer; MAP2K1 rs8039880 (HRR = 2.53, 95% CI 1.34, 4.79 GG versus AG/GG) and Raf1 rs11923427 (HRR = 0.59 95% CI = 0.40, 0.86; AA versus TT/TA) were associated with rectal cancer survival. These data suggest that genetic variation in the MAPK-signaling pathway influences colorectal cancer risk and survival after diagnosis. Associations may be modified by lifestyle factors that influence inflammation and oxidative stress. PMID- 23027625 TI - Tectorigenin sensitizes paclitaxel-resistant human ovarian cancer cells through downregulation of the Akt and NFkappaB pathway. AB - Paclitaxel (Taxol) is currently used as the front-line chemotherapeutic agent for several cancers including ovarian carcinoma; however, the drug frequently induces drug resistance through multiple mechanisms. The new strategy of using natural compounds in combination therapies is highly attractive because those compounds may enhance the efficacy of chemotherapy. In this study, we found that tectorigenin, an isoflavonoid isolated from flower of Pueraria thunbergiana, enhanced the growth-inhibitory effect of paclitaxel in paclitaxel-resistant ovarian cancer cells (MPSC1(TR), A2780(TR) and SKOV3(TR)) as well as their naive counterparts. The combination of tectorigenin with paclitaxel resulted in a synergistic apoptosis compared with either agent alone through activation of caspases-3, -8 and -9. Treatment with tectorigenin inhibited the nuclear translocation of NFkappaB and the expression of NFkappaB-dependent genes such as FLIP, XIAP, Bcl-2, Bcl-xL and COX-2, which are known to be associated with chemoresistance. In addition, the tectorigenin-paclitaxel combination inhibited the phosphorylation of IkappaB and IKK and the activation of Akt in paclitaxel resistant cancer cells. Moreover, tectorigenin-paclitaxel-induced cell growth inhibition was enhanced by pretreatment with the Akt inhibitor LY294002 or overexpression of the dominant negative Akt (Akt-DN), but reduced by overexpression of constitutively activated Akt (Akt-Myr). Furthermore, we found that Akt-Myr, at least in part, reversed tectorigenin-paclitaxel-induced nuclear translocation of NFkappaB and the phosphorylation of IkappaB and IKK. These data suggest that tectorigenin could sensitize paclitaxel-resistant human ovarian cancer cells through inactivation of the Akt/IKK/IkappaB/NFkappaB signaling pathway, and promise a new intervention to chemosensitize paclitaxel-induced cytotoxicity in ovarian cancer. PMID- 23027624 TI - Superoxide dismutase 3 is induced by antioxidants, inhibits oxidative DNA damage and is associated with inhibition of estrogen-induced breast cancer. AB - Epidemiological data and studies in rodent models strongly support the role of estrogens in the development of breast cancers. Oxidative stress has been implicated in this carcinogenic process. We have recently demonstrated that antioxidants vitamin C or butylated hydroxyanisole (BHA) severely inhibit 17beta estradiol (E2)-induced breast tumor development in female ACI rats. The objective of this study was to characterize the mechanism of antioxidant-mediated prevention of breast cancer. Female August Copenhagen Irish (ACI) rats were treated with E2, vitamin C, vitamin C + E2, BHA and BHA + E2 for up to 8 months. Superoxide dismutase 3 (SOD3) was suppressed in E2-exposed mammary tissues and in mammary tumors of rats treated with E2. This suppression was overcome by co treatment of rats with E2 and vitamin C or BHA. 8-Hydroxydeoxyguanosine (8-OHdG) levels determined as a marker of oxidative DNA damage were higher in E2-exposed mammary tissues and in mammary tumors compared with age-matched controls. Vitamin C or BHA treatment significantly decreased E2-mediated increase in 8-OHdG levels in the mammary tissues and in MCF-10A cells. Increased DNA damage, colony and mammosphere formation, and migration in SOD3 knocked down MCF-10A cells, and nuclear translocation of SOD3 in vitamin C-treated mammary tissues and in MCF-10A cells suggest protective role of SOD3 against DNA damage and mammary carcinogenesis. Our studies further demonstrate that SOD3, but not SOD2 and SOD1, is induced by antioxidants and is regulated through NRF2. SOD3 may thus be an important gene in defense against oxidative stress and in the prevention of estrogen-mediated breast cancer. PMID- 23027626 TI - Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models. AB - Approximately half of prostate cancers (PCa) carry TMPRSS2-ERG translocations; however, the clinical impact of this genomic alteration remains enigmatic. Expression of v-ets erythroblastosis virus E26 oncogene like (avian) gene (ERG) promotes prostatic epithelial dysplasia in transgenic mice and acquisition of epithelial-to-mesenchymal transition (EMT) characteristics in human prostatic epithelial cells (PrECs). To explore whether ERG-induced EMT in PrECs was associated with therapeutically targetable transformation characteristics, we established stable populations of BPH-1, PNT1B and RWPE-1 immortalized human PrEC lines that constitutively express flag-tagged ERG3 (fERG). All fERG-expressing populations exhibited characteristics of in vitro and in vivo transformation. Microarray analysis revealed >2000 commonly dysregulated genes in the fERG-PrEC lines. Functional analysis revealed evidence that fERG cells underwent EMT and acquired invasive characteristics. The fERG-induced EMT transcript signature was exemplified by suppressed expression of E-cadherin and keratins 5, 8, 14 and 18; elevated expression of N-cadherin, N-cadherin 2 and vimentin, and of the EMT transcriptional regulators Snail, Zeb1 and Zeb2, and lymphoid enhancer-binding factor-1 (LEF-1). In BPH-1 and RWPE-1-fERG cells, fERG expression is correlated with increased expression of integrin-linked kinase (ILK) and its downstream effectors Snail and LEF-1. Interfering RNA suppression of ERG decreased expression of ILK, Snail and LEF-1, whereas small interfering RNA suppression of ILK did not alter fERG expression. Interfering RNA suppression of ERG or ILK impaired fERG-PrEC Matrigel invasion. Treating fERG-BPH-1 cells with the small molecule ILK inhibitor, QLT-0267, resulted in dose-dependent suppression of Snail and LEF-1 expression, Matrigel invasion and reversion of anchorage-independent growth. These results suggest that ILK is a therapeutically targetable mediator of ERG-induced EMT and transformation in PCa. PMID- 23027627 TI - Association of genetic variants for colorectal cancer differs by subtypes of polyps in the colorectum. AB - Most colorectal cancers originate from polyps, however, only a small proportion of polyps progress to carcinomas. Genome-wide association studies have identified multiple single-nucleotide polymorphisms (SNPs) in relation to colorectal cancer. Using these genetic risk variants, we evaluated whether colorectal cancer genetic factors may determine certain polyp phenotypes with different malignant potential. We analyzed 20 SNPs in 15 colorectal cancer susceptibility loci in a case-control study including 2473 cases (1831 with adenomas and 642 with hyperplastic polyps only) and 4019 controls. These patients were recruited from participants who received colonoscopy at two major hospitals in Nashville. A weighted genetic risk score (wGRS) was created to measure the cumulative association of multiple SNPs with polyp subtypes. Thirteen SNPs in 10 loci showed a statistically significant (P < 0.05, n = 9) or marginally significant (P < 0.10, n = 4) association with the risk of adenomas or hyperplastic polyps in the same direction as reported previously for colorectal cancer. A dose-response relation was observed between the wGRS and adenoma risk [per-allele odds ratio (OR) = 1.15, 95 confidence interval (CI): 1.10-1.20, P (trend) = 7.3*10(-10)], with the association stronger for advanced than non-advanced adenomas (P (heterogeneity) = 0.038), for multiple adenomas than a single adenoma (P (heterogeneity) = 0.039), and for proximal than distal adenomas (P (heterogeneity) = 0.038) and for adenomas diagnosed at younger than older age (P (heterogeneity) = 0.031). A similar, but weak association between the wGRS and hyperplastic polyps was also observed (OR = 1.11, 95% CI: 1.04-1.18, P (trend) = 0.002). These findings suggest that genetic factors play a significant role in the development of polyps with different malignant potential. PMID- 23027628 TI - 53BP1 functions as a tumor suppressor in breast cancer via the inhibition of NF kappaB through miR-146a. AB - p53-binding protein-1 (53BP1) plays a critical role in cell cycle checkpoint and DNA repair activities. Recently, 53BP1 was recognized as a potential tumor suppressor gene. In this study, we investigated its tumor suppressor function in breast cancer. In clinical samples, we observed a lower level of 53BP1 expression in the cancer lesions than in the matched non-tumor tissues. Furthermore, the 53BP1 level showed a gradual decrease during the progression from precancerous to cancer lesion. Ectopic expression of 53BP1 can significantly inhibit cell proliferation and curb the invasiveness in breast cancer cell lines, whereas knockdown of 53BP1 by RNA interference had the opposite effects. Additionally, 53BP1 markedly inhibited xenograft formation and metastasis of breast cancer cells in nude mice. Both in vitro and in vivo studies revealed that the 53BP1 expression level was inversely correlated to the function of nuclear factor kappaB (NF-kappaB), which contributes to the invasion and metastasis of breast cancer. Importantly, the inhibitory effect of 53BP1 on NF-kappaB activity was shown to be mediated by the upregulation of miR-146a. Together, our findings demonstrated that 53BP1 has a potent tumor suppressor activity in breast cancer, and it may serve as a novel target for breast cancer prevention and treatment. PMID- 23027629 TI - Mid-infrared HgTe/As2S3 field effect transistors and photodetectors. AB - HgTe colloidal quantum dots (CQD) in an inorganic As(2)S(3) matrix allow 100-fold higher mobility with optimized transport properties compared to HgTe-organic CQD film while remaining intrinsic. The material's electronic properties are measured by field effect transistors as a function of temperature and the responsivity and detectivity of the mid-IR photoconductors are discussed. PMID- 23027630 TI - Computational and numerical modelling in neuromechanics and biomechanics. PMID- 23027631 TI - Review and perspective: neuromechanical considerations for predicting muscle activation patterns for movement. AB - Muscle coordination may be difficult or impossible to predict accurately based on biomechanical considerations alone because of redundancy in the musculoskeletal system. Because many solutions exist for any given movement, the role of the nervous system in further constraining muscle coordination patterns for movement must be considered in both healthy and impaired motor control. On the basis of computational neuromechanical analyses of experimental data combined with modeling techniques, we have demonstrated several such neural constraints on the temporal and spatial patterns of muscle activity during both locomotion and postural responses to balance perturbations. We hypothesize that subject-specific and trial-by-trial differences in muscle activation can be parameterized and understood by a hierarchical and low-dimensional framework that reflects the neural control of task-level goals. In postural control, we demonstrate that temporal patterns of muscle activity may be governed by feedback control of task level variables that represent the overall goal-directed motion of the body. These temporal patterns then recruit spatially-fixed patterns of muscle activity called muscle synergies that produce the desired task-level biomechanical functions that require multijoint coordination. Moreover, these principles apply more generally to movement, and in particular to locomotor tasks in both healthy and impaired individuals. Overall, understanding the goals and organization of the neural control of movement may provide useful reduced dimension parameter sets to address the degrees-of-freedom problem in musculoskeletal movement control. More importantly, however, neuromechanical analyses may lend insight and provide a framework for understanding subject-specific and trial-by-trial differences in movement across both healthy and motor-impaired populations. PMID- 23027632 TI - Neuromechanic: a computational platform for simulation and analysis of the neural control of movement. AB - Neuromusculoskeletal models solve the basic problem of determining how the body moves under the influence of external and internal forces. Existing biomechanical modeling programs often emphasize dynamics with the goal of finding a feed forward neural program to replicate experimental data or of estimating force contributions or individual muscles. The computation of rigid-body dynamics, muscle forces, and activation of the muscles are often performed separately. We have developed an intrinsically forward computational platform (Neuromechanic, www.neuromechanic.com) that explicitly represents the interdependencies among rigid body dynamics, frictional contact, muscle mechanics, and neural control modules. This formulation has significant advantages for optimization and forward simulation, particularly with application to neural controllers with feedback or regulatory features. Explicit inclusion of all state dependencies allows calculation of system derivatives with respect to kinematic states and muscle and neural control states, thus affording a wealth of analytical tools, including linearization, stability analyses and calculation of initial conditions for forward simulations. In this review, we describe our algorithm for generating state equations and explain how they may be used in integration, linearization, and stability analysis tools to provide structural insights into the neural control of movement. PMID- 23027633 TI - Inspiration from nature: dynamic modelling of the musculoskeletal structure of the seahorse tail. AB - Technological advances are often inspired by nature, considering that engineering is frequently faced by the same challenges as organisms in nature. One such interesting challenge is creating a structure that is at the same time stiff in a certain direction, yet flexible in another. The seahorse tail combines both radial stiffness and bending flexibility in a particularly elegant way: even though the tail is covered in a protective armour, it still shows sufficient flexibility to fully function as a prehensile organ. We therefore study the complex mechanics and dynamics of the musculoskeletal system of the seahorse tail from an engineering point of view. The seahorse tail derives its combination of flexibility and resilience from a chain of articulating skeletal segments. A versatile dynamic model of those segments was constructed, on the basis of automatic recognition of joint positions and muscle attachments. Both muscle structures that are thought to be responsible for ventral and ventral-lateral tail bending, namely the median ventral muscles and the hypaxial myomere muscles, were included in the model. Simulations on the model consist mainly of dynamic multi-body simulations. The results show that the sequential structure of uniformly shaped bony segments can remain flexible because of gliding joints that connect the corners of the segments. Radial stiffness on the other hand is obtained through the support that the central vertebra provides to the tail plating. Such insights could help in designing biomedical instruments that specifically require both high bending flexibility and radial stiffness (e.g. flexible stents and steerable catheters). PMID- 23027634 TI - Evaluation of carotid stent scaffolding through patient-specific finite element analysis. AB - After carotid artery stenting, the plaque remains contained between the stent and the vessel wall, moving consequently physicians' concerns toward the stent capability of limiting the plaque protrusion, that is, toward vessel scaffolding, to avoid that some debris is dislodged after the procedure. Vessel scaffolding is usually measured as the cell area of the stent in free-expanded configuration, neglecting thus the actual stent configuration within the vascular anatomy. In the present study, we measure the cell area of four different stent designs deployed in a realistic carotid artery model through patient-specific finite element analysis. The results suggest that after deployment, the cell area change along the stent length and the related reduction with respect to the free expanded configuration are functions of the vessel tapering. Hence, the conclusions withdrawn from the free-expanded configuration appear to be qualitatively acceptable for comparative purposes, but they should be carefully handled because they neglect the post-implant variability, which seems to be more pronounced in open-cell designs, especially at the bifurcation segment. Even though the investigation is limited to few stent designs and one vascular anatomy, our study confirms the capability of dedicated computer-based simulations to provide useful information about complex stent features as vessel scaffolding. PMID- 23027635 TI - Mechanics of the foot Part 1: a continuum framework for evaluating soft tissue stiffening in the pathologic foot. AB - Soft tissue stiffening is a common mechanical observation reported in foot pathologies including diabetes mellitus and gout. These material changes influence the spatial distribution of stress and affect blood flow, which is essential to nutrient entry and waste removal. An anatomically-based subject specific foot model was developed to explore the influence of tissue stiffening on plantar pressure and internal von Mises stress at heel-strike, midstance and toe-off. This work draws on the model database developed for the Physiome project consisting of muscles, bones, soft tissue and other structures such as sensory nerves. The anisotropic structure of soft tissue was embedded in a single continuum as an efficient model for finite soft tissue deformation, and customisation methods were used to capture the unique foot profile. The model was informed by kinetics from an instrumented treadmill and kinematics from motion capture, synchronised together. Foot sole pressure predictions were evaluated against a commercial pressure platform. Key outcomes showed that internal stress can be up to 1.6 times the surface pressure with implications for internal soft tissue damage not observed at the surface. The main nerve branch stimulated during gait was the lateral plantar nerve. This subject-specific modelling framework can play an integral part in therapeutic treatments by informing assistive strategies such as mechanical noise stimulation and orthotics. PMID- 23027636 TI - Mechanics of the foot Part 2: A coupled solid-fluid model to investigate blood transport in the pathologic foot. AB - A coupled computational model of the foot consisting of a three-dimensional soft tissue continuum and a one-dimensional (1D) transient blood flow network is presented in this article. The primary aim of the model is to investigate the blood flow in major arteries of the pathologic foot where the soft tissue stiffening occurs. It has been reported in the literature that there could be up to about five-fold increase in the mechanical stiffness of the plantar soft tissues in pathologic (e.g. diabetic) feet compared with healthy ones. The increased stiffness results in higher tissue hydrostatic pressure within the plantar area of the foot when loaded. The hydrostatic pressure acts on the external surface of blood vessels and tend to reduce the flow cross-section area and hence the blood supply. The soft tissue continuum model of the foot was modelled as a tricubic Hermite finite element mesh representing all the muscles, skin and fat of the foot and treated as incompressible with transversely isotropic properties. The details of the mechanical model of soft tissue are presented in the companion paper, Part 1. The deformed state of the soft tissue continuum because of the applied ground reaction force at three foot positions (heel-strike, midstance and toe-off) was obtained by solving the Cauchy equations based on the theory of finite elasticity using the Galerkin finite element method. The geometry of the main arterial network in the foot was represented using a 1D Hermite cubic finite element mesh. The flow model consists of 1D Navier-Stokes equations and a nonlinear constitutive equation to describe vessel radius-transmural pressure relation. The latter was defined as the difference between the fluid and soft tissue hydrostatic pressure. Transient flow governing equations were numerically solved using the two-step Lax-Wendroff finite difference method. The geometry of both the soft tissue continuum and arterial network is anatomically-based and was developed using the data derived from visible human images and magnetic resonance images of a healthy male volunteer. Simulation results reveal that a two-fold increase in tissue stiffness leads to about 28% reduction in blood flow to the affected region. PMID- 23027639 TI - Impact of high dose chemoimmunotherapy after surgery on the overall and disease free survivals in advanced stage malignant melanoma. AB - BACKGROUND: To investigate the impact of high dose chemoimmunotherapy in addition to surgery on the cumulative survival and disease-free survey of malignant melanoma patients. METHODS: A total of 86 malignant melanoma patients [35 females (40.7%), 51 males (59.3%), mean age: 55.5] were treated according to their stages between Februrary 1997 and June 2007. After surgery, adjuvant immunotherapy was applied to patients in Stage 2, while adjuvant chemotherapy and adjuvan immunotherapy were administered to those at Stages 3 and 4. RESULTS: Overall rate of mortality was 31.4% (27/86). The most frequent postoperative complications were wound infection (n=8, 9.3%) in the early period and lymphedema in lower extremities (n=4, 4.6%) in the late period. Temporary and tolerable complications ensourcing from chemoimmunotherapy were encountered in 9 (10.4%) patients. The survival rates and disease-free periods of combined treatment protocol were found to be similar to those in ECOG 1684 and ECOG 1690 studies. CONCLUSION: Adjuvant immunotherapy and chemoimmunotherapy seem to improve overall survival and disease free survey in malignant melanoma. Further clinical studies are necessary to demonstrate the actual effectivity of this promising protocol in the management of malignant melanoma. PMID- 23027640 TI - A comparative evaluation of NB30, NB54 and PTC124 in translational read-through efficacy for treatment of an USH1C nonsense mutation. AB - Translational read-through-inducing drugs (TRIDs) promote read-through of nonsense mutations, placing them in the spotlight of current gene-based therapeutic research. Here, we compare for the first time the relative efficacies of new-generation aminoglycosides NB30, NB54 and the chemical compound PTC124 on retinal toxicity and read-through efficacy of a nonsense mutation in the USH1C gene, which encodes the scaffold protein harmonin. This mutation causes the human Usher syndrome, the most common form of inherited deaf-blindness. We quantify read-through efficacy of the TRIDs in cell culture and show the restoration of harmonin function. We do not observe significant differences in the read-through efficacy of the TRIDs in retinal cultures; however, we show an excellent biocompatibility in retinal cultures with read-through versus toxicity evidently superior for NB54 and PTC124. In addition, in vivo administration of NB54 and PTC124 induced recovery of the full-length harmonin a1 with the same efficacy. The high biocompatibilities combined with the sustained read-through efficacies of these drugs emphasize the potential of NB54 and PTC124 in treating nonsense mutation-based retinal disorders. PMID- 23027642 TI - Effect of low temperature upon vitality of Saccharomyces cerevisiae phospholipid mutants. AB - The phospholipid metabolism of Saccharomyces cerevisiae plays a central role in its adaptation to low temperatures. In order to detect the key genes in this adaptation, various phospholipid mutants from the EUROSCARF collection of Saccharomyces cerevisiae BY4742 were tested to ascertain whether the suppression of some genes could improve the fermentation vitality of the cells at low temperature. The cell vitality and phospholipid composition of these mutants were analysed. Some knockouts improved (hmn1Delta) or impaired (cho2Delta and psd1Delta) their vitality at low temperature (13 degrees C) but were not affected at optimum temperature (25 degrees C). A common trait of the mutants that had some defect in vitality was a lower concentration of phosphatidylcholine and/or phosphatidylethanolamine. The supplementation with choline allowed them to recover viability, probably by synthesis through the Kennedy pathway. Hmn1Delta showed a lower concentration of phosphatidylcholine, which explains the dominant role of the de novo pathway in cellular phosphatidylethanolamine and phosphatidylcholine vs the Kennedy pathway. The absence of such genes as CRD1 or OPI3 produced important changes in phospholipid composition. Cardiolipin was not detected in crd1Delta but phosphatidylglycerol circumvents most of the functions assigned to CL. The considerable reduction in PC diminished the cell vitality of opi3Delta at both temperatures, although the decrease at 13 degrees C was more marked. PMID- 23027641 TI - Localization of gonadotropin-releasing hormone (GnRH), gonadotropin-inhibitory hormone (GnIH), kisspeptin and GnRH receptor and their possible roles in testicular activities from birth to senescence in mice. AB - The changes in distribution and concentration of neuropeptides, gonadotropin releasing hormone (GnRH), gonadotropin-inhibitory hormone (GnIH), kisspeptin, and gonadotropin-releasing hormone receptor (GnRH-R) were evaluated and compared with reproductive parameters, such as cytochrome P450 side-chain cleavage (P450 SCC) enzyme activity, androgen receptors (AR) in the testis and serum testosterone levels, from birth to senescence in mice. The results showed the localization of these molecules mainly in the interstitial and germ cells as well as showed significant variations in immunostatining from birth to senescence. It was found that increased staining of testicular GnRH-R coincided with increased steroidogenic activity during pubertal and adult stages, whereas decreased staining coincides with decreased steroidogenic activity during senescence. Similar changes in immunostaining were confirmed by Western/slot blot analysis. Thus, these results suggest a putative role of GnRH during testicular pubertal development and senescence. Treatment with a GnRH agonist ([DTrp(6), Pro(9)-NEt] GnRH) to mice from prepubertal to pubertal period showed a significant increase in steroidogenic activity of the mouse testis and provided further support to the role of GnRH in testicular pubertal maturation. The significant decline in GnRH-R during senescence may be due to a significant increase in GnIH synthesis during senescence causing the decrease in GnRH-R expression. It is considered that significant changes in the levels of GnRH-R may be responsible for changes in steroidogenesis that causes either pubertal activation or senescence in testis of mice. Furthermore, changes in the levels of GnRH-R may be modulated by interactions among GnRH, GnIH, and kisspeptin in the testis. PMID- 23027643 TI - Quinocetone triggers oxidative stress and induces cytotoxicity and genotoxicity in human peripheral lymphocytes of both genders. AB - BACKGROUND: Quinocetone has been widely used as an animal growth promoter in China. However, available data showed that QCT has potential genotoxicity. This study was conducted to investigate the cytotoxicity and genotoxicity of QCT in human lymphocytes. RESULTS: CCK-8 assay demonstrated the severe inhibitory effects by QCT in a dose- and time-dependent manner. DNA damage analysis using alkalic Comet assay revealed a pronounced increase of DNA fragmentation in cells. In contrast, DNA damage was significantly decreased after incubation with S9 mix. This finding demonstrated that the intermediate metabolites of this drug exerted lower genotoxicity than its parent drugs. We further described chromosomal damage induced by this drug employing cytokinesis-block micronucleus assay. The micronucleus frequency was significantly increased in quinocetone groups as compared to controls. Similar to the observation in Comet assay, incorporation of S9 mix in the cytokinesis-block micronucleus assay could markedly alleviate the chromosomal damage. Moreover, QCT could invoke increase of reactive oxygen species generation in cells. Intriguingly, the toxicity of QCT was more prominent in samples from males than those from females under the same conditions. CONCLUSION: QCT could induce potential cytotoxicity and genotoxicity in human lymphocytes. PMID- 23027644 TI - All-in-fiber chemical sensing. AB - A new all-in-fiber trace-level chemical sensing approach is demonstrated. Photoconductive structures, embedded directly into the fiber cladding along its entire length, capture light emitted anywhere within the fiber's hollow core and transform it directly into an electrical signal. Localized signal transduction circumvents problems associated with conventional fiber-optics, including limited signal collection efficiency and optical losses. This approach facilitates a new platform for remote and distributed photosensing. PMID- 23027645 TI - Experiences of healthcare provision for foot ulceration occurring in people with rheumatoid arthritis. AB - BACKGROUND: Participants with rheumatoid arthritis (RA) report that foot ulceration has an impact on their health-related quality of life (HRQL) across physical, social and psychological domains. What is not known is how experiences of healthcare provision influence HRQL. The present study set out to map the patent journey while integrating the impact on HRQL. METHODS: A purposive sample of RA patients with open foot ulceration was recruited from podiatry clinics in West Yorkshire (UK) between May 2008 and June 2009. Patients with diabetes were excluded (the impact of foot ulceration in this group is well established). In depth interviews were taped and transcribed. A framework approach to data management was used to facilitate a case- and theme-based analysis. RESULTS: Twenty-three RA patients (18 female, five male; aged 45-88 years) participated. Two themes and five sub-themes were identified. The patient journey theme comprised the following sub-themes: access to care; knowledge acquisition; care pathways and continuity of care. Patient-professional relationships comprised the sub-themes: therapeutic patient-professional relationships and task-orientated care. The journey took a highly variable course that was influenced by patient specific factors (past experience of ulceration; symptomology; knowledge and self efficacy); service-specific factors (access to care and care pathways) and professional-specific factors (knowing and trusting someone; holism). CONCLUSIONS: The present study highlights the need for clearer care pathways for patients affected by foot ulceration improved patient education and better coordination of care. PMID- 23027646 TI - Participant characteristics and study features associated with high retention rates in a longitudinal investigation of type 1 diabetes mellitus. AB - BACKGROUND: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study has sustained an extraordinarily high level of participant involvement for over two decades. PURPOSE: In order to identify specific characteristics of EDIC that contributed most strongly to retention, study-designed questionnaires were distributed to 1334 participants. METHODS: Confidential questionnaires were completed during EDIC Years 15-17. Participants were classified as Completely Adherent (completed all visits), Partly Adherent (missed >1 visit or major portion of a visit), or Inactive (did not participate for >5 years). Questionnaire items addressed specific aspects of clinic visits, evaluation procedures, staff-participant relationships, and medical/health-care support provided by EDIC. RESULTS: The most commonly cited reasons for continuing participation were Cutting Edge Tests to assess diabetes complications (79.3%), Annual Evaluations (67.7%), a desire to Help Others (65.2%), and Better Care for Diabetes (61.6%). Women chose Cutting Edge Tests as their first or second most important reason significantly more often than men, whereas men chose Better Care for Diabetes more frequently. Individuals with at least three diabetes-related complications were more likely than those with fewer complications to choose Annual Evaluations as their first or second reason for continued involvement. LIMITATIONS: The small proportion of individuals who discontinued participation restricted our ability to identify factors associated with suspended involvement. In addition, our analysis is limited to a cohort with type 1 diabetes followed in an observational study after an average participation time of 6.5 years in a randomized trial. CONCLUSIONS: The primary reasons identified by respondents for their long-term commitment are consistent with shorter-term studies and underscore the importance of expert medical care, supportive staff-participant relationships, and involvement with clinically and scientifically meaningful research. PMID- 23027647 TI - Does the sliding dichotomy result in higher powered clinical trials for stroke and traumatic brain injury research? AB - BACKGROUND: Recent research has proposed a new method for defining a favorable outcome in traumatic brain injury and stroke research. PURPOSE: This new method is called the sliding dichotomy, and it is suggested as a potential solution to the problem of underpowered clinical trials. METHODS: We present a brief simulation study and graphical comparison of the power of each method to detect varying treatment effect sizes. RESULTS: Simulations of a patient population similar to the National Acute Brain Injury Study: Hypothermia (NABISH) study indicate that the sliding dichotomy method does not result in higher power than traditional methods. CONCLUSIONS: Although the sliding dichotomy may present gains in power in some cases, several aspects of the patient population need to be considered in choosing between sliding dichotomy and traditional definitions of favorable outcomes. PMID- 23027648 TI - Regulation of nonsense-mediated mRNA decay. AB - Nonsense-mediated mRNA decay (NMD) is a highly conserved pathway that was originally identified as a RNA surveillance mechanism that degrades aberrant mRNAs harboring premature termination (nonsense) codons. Recently, it was discovered that NMD also regulates normal gene expression. Genome-wide studies showed that ablation of NMD alters the expression of ~10% of transcripts in a wide variety of eukaryotes. In general, NMD specifically targets normal transcripts that harbor a stop codon in a premature context. The finding that NMD regulates normal gene expression raises the possibility that NMD itself is subject to regulation. Indeed, recent studies have shown that NMD efficiency varies in different cell types and tissues. NMD is also subject to developmental control in both higher and lower eukaryotic species. Molecular mechanisms have been defined-including those involving microRNAs and other RNA decay pathways that regulate the magnitude of NMD in some developmental settings. This developmental regulation of NMD appears to have physiological roles, at least in some model systems. In addition to mechanisms that modulate the efficiency of NMD, mechanisms have recently been identified that serve the opposite purpose: to maintain the efficiency of NMD in the face of insults. This 'buffering' is achieved by feedback networks that serve to regulate the stability of NMD factors. The discovery of NMD homeostasis and NMD regulatory mechanisms has important implications for how NMD acts in biological processes and how its magnitude could potentially be manipulated for clinical benefit. PMID- 23027649 TI - Controlling proteome degradation in Daphnia pulex. AB - An attempted proteomic study of Daphnia pulex response to sodium chloride exposure revealed an unexpected result: very strong proteome degradation previously observed in D. pulex is halted when animals have been exposed to elevated salinity prior to protein extraction. Further characterization of conditions controlling proteome degradation shows that the proteolytic factor(s) is/are present in an active form under chemically denaturing conditions in extract from control "normal/healthy" animals, and can be negatively regulated by prior in vivo salinity exposure of animals or inhibited by post-homogenization heating of samples. We interpret these data as evidence for salinity-induced inhibition of proteolysis in Daphnia. PMID- 23027650 TI - Rapid drinking is associated with increases in driving-related risk-taking. AB - OBJECTIVE: The rate of alcohol drinking has been shown to predict impairment on cognitive and behavioral tasks. The current study assessed the influence of speed of alcohol consumption within a laboratory-administered binge on self-reported attitudes toward driving and simulated driving ability. METHOD: Forty moderate drinkers (20 female, 20 male) were recruited from the local community via advertisements for individuals who drank alcohol at least once per month. The equivalent of four standard alcohol drinks was consumed at the participant's desired pace within 2-h session. RESULTS: Correlation analyses revealed that, after alcohol drinking, mean simulated driving speed, time in excess of speed limit, collisions, and reported confidence in driving were all associated with rapid alcohol drinking. CONCLUSION: Fast drinking may coincide with increased driving confidence because of the extended latency between the conclusion of drinking and the commencement of driving. However, this latency did not reduce alcohol-related driving impairment, as fast drinking was also associated with risky driving. PMID- 23027651 TI - Antibiotic resistance in hospitals: a ward-specific random effect model in a low antibiotic consumption environment. AB - Association between previous antibiotic use and emergence of antibiotic resistance has been reported for several microorganisms. The relationship has been extensively studied, and although the causes of antibiotic resistance are multi-factorial, clear evidence of antibiotic use as a major risk factor exists. Most studies are carried out in countries with high consumption of antibiotics and corresponding high levels of antibiotic resistance, and currently, little is known whether and at what level the associations are detectable in a low antibiotic consumption environment. We conduct an ecological, retrospective study aimed at determining the impact of antibiotic consumption on antibiotic-resistant Pseudomonas aeruginosa in three hospitals in Norway, a country with low levels of antibiotic use. We construct a sophisticated statistical model to capture such low signals. To reduce noise, we conduct our study at hospital ward level. We propose a random effect Poisson or binomial regression model, with a reparametrisation that allows us to reduce the number of parameters. Inference is likelihood based. Through scenario simulation, we study the potential effects of reduced or increased antibiotic use. Results clearly indicate that the effects of consumption on resistance are present under conditions with relatively low use of antibiotic agents. This strengthens the recommendation on prudent use of antibiotics, even when consumption is relatively low. PMID- 23027652 TI - Tocopherol retention and vitamin E activity in frozen and canned immature seeds of five cultivars of common bean. AB - BACKGROUND: This paper investigates tocopherol retention and vitamin E activity in the seeds of five bean cultivars (flageolet type and grown mostly for their dry seeds) harvested at the wax stage of maturity. Seeds were analyzed raw, cooked and in three products prepared for consumption after 0 and 12 months of storage. These comprised frozen products obtained using the traditional method (blanching-freezing-frozen storage-boiling) and a modified method (boiling freezing-frozen storage-defrosting and heating in a microwave oven), and canned products. RESULT: Total tocopherols in fresh bean seeds were within the range 18.53-25.98 mg kg(-1) of edible portion. The most abundant form of tocopherol found in fresh seeds was gamma-T isomer (87-91% of the total), followed by the alpha-T (5-7%) and delta-T (3-5%) forms; the beta-T form was not detected. Cooking resulted in a 13-28% decrease in total tocopherols and a 17-31% reduction in vitamin E activity. In products prepared for consumption after 12 months' storage, total tocopherols and vitamin E activity were 13-53% and 23-60% lower, respectively, than in fresh seeds, with the highest losses being mainly in alpha T content. CONCLUSION: The variety and cultivar or method of preservation had no effect on either tocopherol retention or vitamin E activity. PMID- 23027653 TI - High-contrast photoswitching of nonlinear optical response in crosslinked ferroelectric liquid-crystalline polymers. AB - A conceptually novel materials design, based on crosslinked ferroelectric liquid crystalline polymers, is demonstrated for efficient switching of a second-order nonlinear optical (NLO) response in the solid state. By controlling the molecular alignment of the NLO moieties through two-photon isomerization of azobenzene molecules, reversible isothermal photocontrol of second-harmonic generation is achieved with contrast of up to 20. PMID- 23027656 TI - Rac1 signalling mediates doxorubicin-induced cardiotoxicity through both reactive oxygen species-dependent and -independent pathways. AB - AIMS: Doxorubicin causes damage to the heart, often leading to irreversible cardiomyopathy, which is fatal. Reactive oxygen species (ROS) or oxidative stress is involved in cardiomyocyte death, contributing to doxorubicin-induced cardiotoxicity. This study investigated the role of Rac1, an important subunit of NADPH oxidase, in doxorubicin-induced cardiotoxicity and the underlying mechanisms. METHODS AND RESULTS: In a mouse model of acute doxorubicin-induced cardiotoxicity, cardiomyocyte-specific deletion of Rac1 inhibited NADPH oxidase activation and ROS production, prevented cardiac cell death, and improved myocardial function in Rac1 knockout mice. Therapeutic administration of the specific Rac1 inhibitor NSC23766 achieved similar cardio-protective effects in doxorubicin-stimulated mice. In rat cardiomyoblasts (H9c2 cells) and cultured neonatal mouse cardiomyocytes, Rac1 inhibition attenuated apoptosis as evidenced by decreases in caspase-3 activity and DNA fragmentation in response to doxorubicin, which correlated with a reduction in ROS production and down regulation of p53 acetylation and histone H2AX phosphorylation. In contrast, overexpression of Rac1 enhanced apoptosis. Doxorubicin also inhibited the activity of classical histone deacetylases (HDAC), which was preserved by Rac1 inhibition and further decreased by Rac1 overexpression. Interestingly, scavenging ROS mitigated apoptosis but did not change HDAC activity and p53 acetylation stimulated by doxorubicin, suggesting both ROS-dependent and independent pathways are involved in Rac1-mediated cardiotoxicity. Furthermore, the HDAC inhibitor trichostatin A enhanced apoptosis, p53 acetylation and H2AX phosphorylation in doxorubicin-treated cardiomyocytes. CONCLUSIONS: Rac1 signalling contributes to doxorubicin-induced cardiotoxicity through both a ROS dependent mechanism and ROS-independent HDAC/p53 signalling in cardiomyocytes. Thus, inhibition of Rac1 may be a useful therapy for doxorubicin-induced cardiotoxicity. PMID- 23027657 TI - The effect of a clinically effective and non-effective dose of lorazepam on 7.5% CO2-induced anxiety. AB - Symptoms of anxiety induced by 7.5% CO2 inhalation can be attenuated by acute administration of GABA(A) receptor anxiolytics such as lorazepam and alprazolam. This study investigated if these effects are dose-related, by comparing a 0.5 mg dose (considered non-clinically effective) and a 2 mg dose of lorazepam (clinically effective) on 7.5% CO2 inhalation. Eighteen healthy males (mean age 20.6 years, SD 1.29), judged physically and mentally fit, attended three visits, each one week apart, to take each treatment in a randomised double-blind crossover design. Drugs were given 60 min prior to 20 min air inhalation, followed by 20 min 7.5% CO2 inhalation. The order of gas presentation was single blind. Subjective ratings using visual analogue scales (VAS) and questionnaires were recorded before and after each inhalation. Blood pressure (BP), heart rate (HR), respiration rate (RR) and expired CO2 were recorded during each inhalation. Inhalation of 7.5% CO2 significantly raised BP, HR, RR and expired CO2. Ratings of feeling like leaving the room were significantly lower on 2 mg compared with 0.5 mg and placebo, and dose-dependent trends were seen in scores for VAS fearful, anxious, stressed, tense, and worried. Results may be indicative of dose dependent effects of lorazepam in a CO2 model of anxiety. PMID- 23027658 TI - "Salt templating": a simple and sustainable pathway toward highly porous functional carbons from ionic liquids. AB - A facile method to fabricate high-surface area functional carbons via convenient "salt templating" is presented. Exemplarily, nitrogen- as well as nitrogen-/boron co-doped carbons were synthesized using ionic liquids as precursors and eutectics as porogen. The porogen is easily removable with water and the porosities can be adjusted from micro- to mesoporous depending on the salt nature and amount. PMID- 23027659 TI - A novel green analytical procedure for monitoring of azoxystrobin in water samples by a flow injection chemiluminescence method with off-line ultrasonic treatment. AB - A simple and green flow injection chemiluminescence (FI-CL) method for determination of the fungicide azoxystrobin was described for the first time. CL signal was generated when azoxystrobin was injected into a mixed stream of luminol and KMnO4 . The CL signal of azoxystrobin could be greatly improved when an off-line ultrasonic treatment was adopted. Meanwhile, the signal intensity increases with the analyte concentration proportionally. Several variables, such as the ultrasonic parameters, flow rate of reagents, concentrations of sodium hydroxide solution and CL reagents (potassium permanganate, luminol) were investigated, and the optimal CL conditions were obtained. Under optimal conditions, the linear range of 1-100 ng/mL for azoxystrobin was obtained and the detection limit (3sigma) was determined as 0.13 ng/mL. The relative standard deviation was 1.5% for 10 consecutive measurements of 20 ng/mL azoxystrobin. The method has been applied to the determination of azoxystrobin residues in water samples. PMID- 23027660 TI - Minimizing immunogenicity of biopharmaceuticals by controlling critical quality attributes of proteins. AB - Adverse immune responses severely hamper the success of biopharmaceutical therapies. Possible clinical consequences include anaphylaxis, reduced drug half life and neutralization of the therapeutic protein as well as the endogenous human homologue. Controlling potential triggers of the immune system helps to minimize the immunogenicity of biopharmaceuticals, a crucial consideration in biopharmaceutical manufacturing. This review summarizes the latest advancements that have been made towards insight into the impact of structural characteristics on the immunogenicity of therapeutic proteins. Examples are given to illustrate the role of critical quality attributes, such as protein conformation, glycosylation, chemical modifications and aggregation, in immunogenicity. During the development of biopharmaceutical products, it is important to not just assess the risk for immunogenicity in clinical trials, but to ensure product quality throughout drug design, cell-line selection, upstream and downstream processing, all the way to to the final product. PMID- 23027661 TI - Effects of dietary sweet potato leaf meal on the growth, non-specific immune responses, total phenols and antioxidant capacity in channel catfish (Ictalurus punctatus). AB - BACKGROUND: Traditional energy sources in catfish diets have become costly, and economical alternatives are needed. Sweet potato leaves are underutilised agricultural by-products that provide energy and substantial amounts of phenols, which affect animal and human health. There is little information on the effects of these compounds on catfish, or the capacity of catfish to accumulate dietary phenols. Catfish enriched with phenols have marketing potential as functional foods. This study investigated the effects of diets with sweet potato leaf meal (SPLM) on growth performance, health and total phenolic compounds in catfish. RESULTS: SPLM was substituted for wheat middlings in three diets fed to groups of juvenile catfish for 10 weeks. Weight gain, feed conversion, survival, alternative complement activity and lysozyme activity were similar among diets. Haematocrit was lower in fish fed diets with SPLM, but within the normal range. Total phenols and antioxidant capacity in the whole body were similar among treatments. CONCLUSION: SPLM was an effective energy source for catfish up to the maximum level tested (230 g kg(-1) diet). SPLM did not enhance total phenols in catfish, but there were no apparent antinutritional effects of the meal on catfish growth, health or survival. PMID- 23027662 TI - Empirical likelihood-based confidence intervals for length-biased data. AB - Logistic or other constraints often preclude the possibility of conducting incident cohort studies. A feasible alternative in such cases is to conduct a cross-sectional prevalent cohort study for which we recruit prevalent cases, that is, subjects who have already experienced the initiating event, say the onset of a disease. When the interest lies in estimating the lifespan between the initiating event and a terminating event, say death for instance, such subjects may be followed prospectively until the terminating event or loss to follow-up, whichever happens first. It is well known that prevalent cases have, on average, longer lifespans. As such, they do not constitute a representative random sample from the target population; they comprise a biased sample. If the initiating events are generated from a stationary Poisson process, the so-called stationarity assumption, this bias is called length bias. The current literature on length-biased sampling lacks a simple method for estimating the margin of errors of commonly used summary statistics. We fill this gap by using the empirical likelihood-based confidence intervals by adapting this method to right censored length-biased survival data. Both large and small sample behaviors of these confidence intervals are studied. We illustrate our method by using a set of data on survival with dementia, collected as part of the Canadian Study of Health and Aging. PMID- 23027663 TI - Control of Tobacco mosaic virus movement protein fate by CELL-DIVISION-CYCLE protein48. AB - Like many other viruses, Tobacco mosaic virus replicates in association with the endoplasmic reticulum (ER) and exploits this membrane network for intercellular spread through plasmodesmata (PD), a process depending on virus-encoded movement protein (MP). The movement process involves interactions of MP with the ER and the cytoskeleton as well as its targeting to PD. Later in the infection cycle, the MP further accumulates and localizes to ER-associated inclusions, the viral factories, and along microtubules before it is finally degraded. Although these patterns of MP accumulation have been described in great detail, the underlying mechanisms that control MP fate and function during infection are not known. Here, we identify CELL-DIVISION-CYCLE protein48 (CDC48), a conserved chaperone controlling protein fate in yeast (Saccharomyces cerevisiae) and animal cells by extracting protein substrates from membranes or complexes, as a cellular factor regulating MP accumulation patterns in plant cells. We demonstrate that Arabidopsis (Arabidopsis thaliana) CDC48 is induced upon infection, interacts with MP in ER inclusions dependent on the MP N terminus, and promotes degradation of the protein. We further provide evidence that CDC48 extracts MP from ER inclusions to the cytosol, where it subsequently accumulates on and stabilizes microtubules. We show that virus movement is impaired upon overexpression of CDC48, suggesting that CDC48 further functions in controlling virus movement by removal of MP from the ER transport pathway and by promoting interference of MP with microtubule dynamics. CDC48 acts also in response to other proteins expressed in the ER, thus suggesting a general role of CDC48 in ER membrane maintenance upon ER stress. PMID- 23027664 TI - Buffering capacity explains signal variation in symbiotic calcium oscillations. AB - Legumes form symbioses with rhizobial bacteria and arbuscular mycorrhizal fungi that aid plant nutrition. A critical component in the establishment of these symbioses is nuclear-localized calcium (Ca(2+)) oscillations. Different components on the nuclear envelope have been identified as being required for the generation of the Ca(2+) oscillations. Among these an ion channel, Doesn't Make Infections1, is preferentially localized on the inner nuclear envelope and a Ca(2+) ATPase is localized on both the inner and outer nuclear envelopes. Doesn't Make Infections1 is conserved across plants and has a weak but broad similarity to bacterial potassium channels. A possible role for this cation channel could be hyperpolarization of the nuclear envelope to counterbalance the charge caused by the influx of Ca(2+) into the nucleus. Ca(2+) channels and Ca(2+) pumps are needed for the release and reuptake of Ca(2+) from the internal store, which is hypothesized to be the nuclear envelope lumen and endoplasmic reticulum, but the release mechanism of Ca(2+) remains to be identified and characterized. Here, we develop a mathematical model based on these components to describe the observed symbiotic Ca(2+) oscillations. This model can recapitulate Ca(2+) oscillations, and with the inclusion of Ca(2+)-binding proteins it offers a simple explanation for several previously unexplained phenomena. These include long periods of frequency variation, changes in spike shape, and the initiation and termination of oscillations. The model also predicts that an increase in buffering capacity in the nucleoplasm would cause a period of rapid oscillations. This phenomenon was observed experimentally by adding more of the inducing signal. PMID- 23027665 TI - UDP-glycosyltransferases from the UGT73C subfamily in Barbarea vulgaris catalyze sapogenin 3-O-glucosylation in saponin-mediated insect resistance. AB - Triterpenoid saponins are bioactive metabolites that have evolved recurrently in plants, presumably for defense. Their biosynthesis is poorly understood, as is the relationship between bioactivity and structure. Barbarea vulgaris is the only crucifer known to produce saponins. Hederagenin and oleanolic acid cellobioside make some B. vulgaris plants resistant to important insect pests, while other, susceptible plants produce different saponins. Resistance could be caused by glucosylation of the sapogenins. We identified four family 1 glycosyltransferases (UGTs) that catalyze 3-O-glucosylation of the sapogenins oleanolic acid and hederagenin. Among these, UGT73C10 and UGT73C11 show highest activity, substrate specificity and regiospecificity, and are under positive selection, while UGT73C12 and UGT73C13 show lower substrate specificity and regiospecificity and are under purifying selection. The expression of UGT73C10 and UGT73C11 in different B. vulgaris organs correlates with saponin abundance. Monoglucosylated hederagenin and oleanolic acid were produced in vitro and tested for effects on P. nemorum. 3-O-beta-d-Glc hederagenin strongly deterred feeding, while 3-O-beta d-Glc oleanolic acid only had a minor effect, showing that hydroxylation of C23 is important for resistance to this herbivore. The closest homolog in Arabidopsis thaliana, UGT73C5, only showed weak activity toward sapogenins. This indicates that UGT73C10 and UGT73C11 have neofunctionalized to specifically glucosylate sapogenins at the C3 position and demonstrates that C3 monoglucosylation activates resistance. As the UGTs from both the resistant and susceptible types of B. vulgaris glucosylate sapogenins and are not located in the known quantitative trait loci for resistance, the difference between the susceptible and resistant plant types is determined at an earlier stage in saponin biosynthesis. PMID- 23027669 TI - Stem cells and the future of regenerative medicine: from basic research, to translational aspects and upcoming therapies. Abstracts of TERM STEM 2012. October 9-13, 2012. Guimaraes, Portugal. PMID- 23027666 TI - The atypical short-chain dehydrogenases HCF173 and HCF244 are jointly involved in translational initiation of the psbA mRNA of Arabidopsis. AB - The related proteins D1 and D2 together build up the photosystem II reaction center. Synthesis of D1 (PsbA) is highly regulated in all photosynthetic organisms. The mechanisms and specific protein factors involved in controlled expression of the psbA gene in higher plants are highly elusive. Here, we report on the identification of a chloroplast-located protein, HCF244 (for high chlorophyll fluorescence244), which is essentially required for translational initiation of the psbA messenger RNA in Arabidopsis (Arabidopsis thaliana). The factor is highly conserved between land plants, algae, and cyanobacteria. HCF244 was identified by coexpression analysis of HCF173, which encodes a protein that is also necessary for psbA translational initiation and in addition for stabilization of this messenger RNA. Phenotypic characterization of the mutants hcf244 and hcf173 suggests that the corresponding proteins operate cooperatively during psbA translation. Immunolocalization studies detected the majority of the two proteins at the thylakoid membrane. Both HCF244 and HCF173 are members of the atypical short-chain dehydrogenase/reductase superfamily, a modified group, which has lost enzyme activity but acquires new functions in the metabolism of the cell. PMID- 23027667 TI - Common and specific protein accumulation patterns in different albino/pale-green mutants reveals regulon organization at the proteome level. AB - Research interest in proteomics is increasingly shifting toward the reverse genetic characterization of gene function at the proteome level. In plants, several distinct gene defects perturb photosynthetic capacity, resulting in the loss of chlorophyll and an albino or pale-green phenotype. Because photosynthesis is interconnected with the entire plant metabolism and its regulation, all albino plants share common characteristics that are determined by the switch from autotrophic to heterotrophic growth. Reverse genetic characterizations of such plants often cannot distinguish between specific consequences of a gene defect from generic effects in response to perturbations in photosynthetic capacity. Here, we set out to define common and specific features of protein accumulation in three different albino/pale-green plant lines. Using quantitative proteomics, we report a common molecular phenotype that connects the loss of photosynthetic capacity with other chloroplast and cellular functions, such as protein folding and stability, plastid protein import, and the expression of stress-related genes. Surprisingly, we do not find significant differences in the expression of key transcriptional regulators, suggesting that substantial regulation occurs at the posttranscriptional level. We examine the influence of different normalization schemes on the quantitative proteomics data and report all identified proteins along with their fold changes and P values in albino plants in comparison with the wild type. Our analysis provides initial guidance for the distinction between general and specific adaptations of the proteome in photosynthesis-impaired plants. PMID- 23027672 TI - Supramolecular alternate co-assembly through a non-covalent amphiphilic design: conducting nanotubes with a mixed D-A structure. AB - Mixing it up! The supramolecular alternate co-assembly of extended pi-conjugated donor (D) and acceptor (A) molecules (i.e., oligo(phenylenevinylene) and perylenebisimide, respectively), to 1-D nanotubes with an unprecedented mixed stack D-A molecular structure is presented, through a non-covalent amphiphilic design strategy, which results in the formation of hydrogels with remarkable mechanical properties (see scheme). PMID- 23027671 TI - Prescribing patterns of antidepressants, antipsychotics and mood stabilizers in bipolar patients misdiagnosed with major depressive disorder in China. AB - OBJECTIVE: Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD), which may lead to inappropriate treatment and poor outcomes. This study aimed to examine prescribing patterns of antidepressants, antipsychotics and mood stabilizers in BD patients misdiagnosed with MDD in China. METHODS: A total of 1487 patients originally diagnosed with MDD were consecutively screened for diagnostic revision in 13 psychiatric hospitals or psychiatric units of general hospitals in China nationwide. The patients' sociodemographic and clinical characteristics were recorded using a standardized protocol and data collection procedure. The Mini International Neuropsychiatric Interview (MINI) was used to establish DSM-IV diagnoses. Data on psychotropic prescriptions were collected by a review of medical records. RESULTS: Three hundred and nine of the 1487 patients (20.8%) fulfilled DSM-IV criteria for BD; 118 (7.9%) for BD-I and 191 (12.8%) for BD-II on the MINI. Of the BD patients (n = 309), 227 (73.5%) received any use of antidepressants, 73 (23.6%) antipsychotics and 33 (10.7%) mood stabilizers. In multiple logistic regression analyses, compared with those with MDD, patients with BD-I were more likely to receive antidepressants (OR 1.7, 95% CI 1.1-2.8, p = 0.02), antipsychotics (OR 1.6, 95% CI 1.04-2.5, p = 0.04) and mood stabilizers (OR 3.9, 95% CI 2.1-7.2, p < 0.001), whereas patients with BD-II were more likely to receive mood stabilizers (OR 2.4, 95% CI 1.3-4.4, p = 0.003). There was no difference in the use of antidepressants (OR 1.1, 95% CI 0.8-1.5, p = 0.7) and antipsychotics (OR 1.3, 95% CI 0.9-1.9, p = 0.2) between BD-II and MDD. In addition, there was no difference between BD-I and BD-II in any use of antidepressants, antipsychotics and mood stabilizers. CONCLUSIONS: The prescription of antidepressants for BD patients misdiagnosed with MDD is very common, and only a very small proportion of patients received guideline concordant treatment. Considering the potentially hazardous effects of inappropriate pharmacotherapy in this population, continuing education and training addressing the correct diagnosis of BD and rational use of psychotropic medications are needed in China. PMID- 23027673 TI - Short-term effects of social exclusion at work and worries on sleep. AB - The present study investigated short-term effects of daily social exclusion at work on various indicators of sleep quality and tested the mediating role of work related worries using a time-based diary study with ambulatory assessments of sleep quality. Ninety full-time employees participated in a 2-week data collection. Multilevel analyses revealed that daily workplace social exclusion and work-related worries were positively related to sleep fragmentation in the following night. Daily social exclusion, however, was unrelated to sleep onset latency, sleep efficiency and self-reported sleep quality. Moreover, worries did not mediate the effect of social exclusion at work on sleep fragmentation. Theoretical and practical implications of the results are discussed. PMID- 23027674 TI - Effects of simultaneous speech and sign on infants' attention to spoken language. AB - OBJECTIVES: To examine the hypothesis that infants receiving a degraded auditory signal have more difficulty segmenting words from fluent speech if familiarized with the words presented in both speech and sign compared to familiarization with the words presented in speech only. STUDY DESIGN: Experiment utilizing an infant controlled visual preference procedure. METHODS: Twenty 8.5-month-old normal hearing infants completed testing. Infants were familiarized with repetitions of words in either the speech + sign (n = 10) or the speech only (n = 10) condition. Infants were then presented with four six-sentence passages using an infant controlled visual preference procedure. Every sentence in two of the passages contained the words presented in the familiarization phase, whereas none of the sentences in the other two passages contained familiar words. RESULTS: Infants exposed to the speech + sign condition looked at familiar word passages for 15.3 seconds and at nonfamiliar word passages for 15.6 seconds, t (9) = -0.130, p = .45. Infants exposed to the speech only condition looked at familiar word passages for 20.9 seconds and to nonfamiliar word passages for 15.9 seconds. This difference was statistically significant, t (9) = 2.076, p = .03. CONCLUSIONS: Infants' ability to segment words from degraded speech is negatively affected when these words are initially presented in simultaneous speech and sign. The current study suggests that a decreased ability to segment words from fluent speech may contribute towards the poorer performance of pediatric cochlear implant recipients in total communication settings on a wide range of spoken language outcome measures. PMID- 23027675 TI - A "do-it-yourself" interactive bone structure module: development and evaluation of an online teaching resource. AB - A stand-alone online teaching module was developed to cover an area of musculoskeletal anatomy (structure of bone) found to be difficult by students. The material presented in the module was not formally presented in any other way, thus providing additional time for other curriculum components, but it was assessed in the final examination. The module was developed using "in-house" software designed for academics with minimal computer experience. The efficacy and effectiveness of the module was gauged via student surveys, testing student knowledge before and after module introduction, and analysis of final examination results. At least 74% of the class used the module and student responses were positive regarding module usability (navigation, interaction) and utility (learning support). Learning effectiveness was demonstrated by large significant improvements in the post-presentation test scores for "users" compared with "non users" and by the percentage of correct responses to relevant multiple choice questions in the final examination. Performance on relevant short answer questions in the final examination was, on average, comparable to that for other components. Though limited by study structure, it was concluded that the module produced learning outcomes equivalent to those generated by more traditional teaching methods. This "Do-It-Yourself" e-learning approach may be particularly useful for meeting specific course needs not catered for by commercial applications or where there are cost limitations for generation of online learning material. The specific approaches used in the study can assist in development of effective online resources in anatomy. PMID- 23027676 TI - Modelling the hierarchical structure in datasets with very small clusters: a simulation study to explore the effect of the proportion of clusters when the outcome is continuous. AB - In cluster-randomised trials, the problem of non-independence within clusters is well known, and appropriate statistical analysis documented. Clusters typically seen in cluster trials are large in size and few in number, whereas datasets of preterm infants incorporate clusters of size two (twins), size three (triplets) and so on, with the majority of infants being in 'clusters' of size one. In such situations, it is unclear whether adjustment for clustering is needed or even possible. In this paper, we compared analyses allowing for clustering (linear mixed model) with analyses ignoring clustering (linear regression). Through simulations based on two real datasets, we explored estimation bias in predictors of a continuous outcome in different size datasets typical of preterm samples, with varying percentages of twins. Overall, the biases for estimated coefficients were similar for linear regression and mixed models, but the standard errors were consistently much less well estimated when using a linear model. Non-convergence was rare but was observed in approximately 5% of mixed models for samples below 200 and percentage of twins 2% or less. We conclude that in datasets with small clusters, mixed models should be the method of choice irrespective of the percentage of twins. If the mixed model does not converge, a linear regression can be fitted, but standard error will be underestimated, and so type I error may be inflated. PMID- 23027677 TI - A process-based approach to characterizing the effect of acute alprazolam challenge on visual paired associate learning and memory in healthy older adults. AB - OBJECTIVE: Alprazolam is a benzodiazepine that, when administered acutely, results in impairments in several aspects of cognition, including attention, learning, and memory. However, the profile (i.e., component processes) that underlie alprazolam-related decrements in visual paired associate learning has not been fully explored. METHODS: In this double-blind, placebo-controlled, randomized cross-over study of healthy older adults, we used a novel, "process based" computerized measure of visual paired associate learning to examine the effect of a single, acute 1-mg dose of alprazolam on component processes of visual paired associate learning and memory. RESULTS: Acute alprazolam challenge was associated with a large magnitude reduction in visual paired associate learning and memory performance (d = 1.05). Process-based analyses revealed significant increases in distractor, exploratory, between-search, and within search error types. Analyses of percentages of each error type suggested that, relative to placebo, alprazolam challenge resulted in a decrease in the percentage of exploratory errors and an increase in the percentage of distractor errors, both of which reflect memory processes. CONCLUSIONS: Results of this study suggest that acute alprazolam challenge decreases visual paired associate learning and memory performance by reducing the strength of the association between pattern and location, which may reflect a general breakdown in memory consolidation, with less evidence of reductions in executive processes (e.g., working memory) that facilitate visual paired associate learning and memory. PMID- 23027678 TI - Effects of aqueous extracts of raw pu-erh tea and ripened pu-erh tea on proliferation and differentiation of 3T3-L1 preadipocytes. AB - Pu-erh tea has shown anti-obesity effects but little is known about its effect on proliferation and differentiation of preadipocytes. This study investigated the effects of the aqueous extracts of raw pu-erh tea and ripened pu-erh tea on proliferation and differentiation of murine 3T3-L1 preadiopocytes. We examined dose and time effects of both aqueous extracts on proliferation of 3T3-L1 preadipocytes. The contents of triglycerides in cytoplasm and the mRNA expression of critical transcriptional factors involved in differentiation were determined. Cytotoxicity and apoptosis rate of preadipocytes by pu-erh tea extracts treatment were test for toxic and pro-apoptotic effects. Both aqueous extracts of pu-erh tea inhibited the proliferation of 3T3-L1 preadipocytes at the selected time points. At lower concentration of raw pu-erh tea extracts (less than 300 ug/ml) and ripened pu-erh tea extracts (less than 350 ug/ml), no significant cytotoxic and pro-apoptotic were observed. Ripened pu-erh tea was more effective with lower IC50 than raw pu-erh tea. Both extracts suppressed the differentiation and down regulated the gene expression of peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer binding proteins-alpha. Therefore, these results indicate that both aqueous extracts of pu-erh tea can inhibit proliferation and differentiation with ripened pu-erh tea more potent. Polyphenol rich in both extracts may play a role in the inhibition of proliferation and differentiation of 3T3-L1 preadipocytes. PMID- 23027679 TI - Measurement invariance of the perceived stress scale and latent mean differences across gender and time. AB - Measurement invariance of the 2-factor model of the Perceived Stress Scale--10 item version (Cohen & Williamson, 1988) was tested across men and women at two time points and in the combined total sample over a 2-year time frame (n = 871). Measurement invariance results indicated that the scale measured the latent factors, stress and counter-stress, equivalently in men and women and over time. With measurement invariance demonstrated, differences in latent means were tested. Results indicated that men had lower levels of frequencies of stressors, and at one time point, higher levels of counter-stress, when compared with women. When examining change in frequencies of stressors and counter-stress over 2 years with the combined male and female sample, stressors remained stable, yet counter stress increased over time. These findings may aid in the interpretation of results when examining stressors and counter-stress in clinical samples where one would expect stress to increase, whereas positive psychological states decrease. PMID- 23027680 TI - Relationship between carbohydrate-deficient transferrin, gamma-glutamyl transferase, and mean corpuscular volume levels and alcohol-related brain volume decreases in male drinkers. AB - OBJECTIVE: We investigated the association between mean corpuscular volume (MCV), carbohydrate-deficient transferrin (CDT), and gamma-glutamyl transferase (GGT) levels and gray and white brain matter in male drinkers to find out which if any of these biomarkers of alcohol consumption is indicative for alcohol-related differences in brain volume. METHOD: Plasma levels of CDT, GGT, and MCV and magnetic resonance imaging-determined brain gray and white matter volumes were assessed in 55 male drinkers. Current alcohol intake and lifetime alcohol intake were determined by self-report measures. The relationship between MCV, CDT, and GGT and brain volumes was explored using multiple linear regression analyses. RESULTS: There was a significant negative relationship between plasma GGT and MCV levels and gray matter volumes. Middle-aged male drinkers with highly elevated GGT and MCV levels (twice the standard deviation above the mean) have 4-12% less parietal and occipital gray matter than males with average GGT and MCV levels. There was no association between CDT levels and brain gray or white matter. CONCLUSIONS: Elevated GGT and MCV levels may be indicative of alcohol-related gray-matter decline in male drinkers. The link with GGT may reflect that elevated GGT levels are a sign of increased oxidative stress. The link with MCV levels may reflect a decreased oxygen transport to the brain. PMID- 23027681 TI - Clay modeling versus written modules as effective interventions in understanding human anatomy. AB - The effectiveness of clay modeling to written modules is examined to determine the degree of improvement in learning and retention of anatomical 3D relationships among students with different learning preferences. Thirty-nine undergraduate students enrolled in a cadaver dissection course completed a pre assessment examination and the VARK questionnaire, classifying learning preference as visual, auditory, read/write, or kinesthetic. Students were divided into clay, module, and control groups with preference for learning style distributed among groups. The clay and module groups participated in weekly one hour classes using either clay models or answering written questions (modules) about anatomical relationships, respectively. The control group received no intervention. Post-assessment and retention examinations were administered at the end of the semester, and three months later, respectively. Two variables (Delta1, Delta2) represented examination score differences between pre- and post assessment and between post-assessment and retention examinations, respectively. The Delta1 for clay and module groups were each significantly higher than controls (21.46 +/- 8.2 vs. 15.70 +/- 7.5, P <= 0.05; and 21.31 +/- 6.9 vs. 15.70 +/- 7.5, P <=0.05, respectively). The Delta2 for clay and module groups approached but did not achieve significance over controls (-6.09 +/- 5.07 vs. 8.80 +/- 4.60, P = 0.16 and -5.73 +/- 4.47 vs. -8.80 +/- 4.60, P = 0.12, respectively). No significant differences were seen between interventions or learning preferences in any group. However, students of some learning styles tended to perform better when engaging in certain modalities. Multiple teaching modalities may accommodate learning preferences and improve understanding of anatomy. PMID- 23027682 TI - Paraganglioma of the skull base presenting as nasal polyps. AB - The authors report a case of paraganglioma of the skull base presenting as nasal polyps. A 29-year-old patient presented with epistaxis and was found to have nasal polyps. The patient underwent a nasal polypectomy. After pathology showed an unusual appearance, the mass was subsequently excised endoscopically using radiofrequency coblation, and it was found to be originating from the skull base. The diagnosis was made using a combination of clinical findings, radiology, and histopathology examination. It is important to consider paraganglioma in the differential diagnosis of unusual tumors of the nose and skull base. PMID- 23027683 TI - Clinical heterogeneity of de novo 11q deletion chronic lymphocytic leukaemia: prognostic relevance of extent of 11q deleted nuclei inside leukemic clone. AB - Deletion on the long arm of chromosome 11 occurs in 5-20% of chronic lymphocytic leukaemia (CLL) patients. We analysed clinical-biological characteristics of 131 CLL patients carrying 11q deletion documented before therapy (de novo 11q deleted CLL). De novo 11q deleted CLL were characterized by high frequencies of unmutated immunoglobulin variable heavy genes, multiple fluorescence in situ hybridization aberrations and lymph node involvement. Factors significantly associated with shorter time to first treatment (TTFT) were advanced Binet stages, high white blood cell count, increased beta2 -microglobulin levels, 17p in addition, splenomegaly and more extensive lymphadenopathy. We found that patients with <25% 11q deleted nuclei (n = 22) experienced longer TTFT compared with patients with >=25% 11q deleted nuclei (n = 87; median TTFT, 40 vs. 14 months, p = 0.011) and also showed better response to treatments (complete response, 50% vs. 21%, p = 0.016). The variables identified by multivariate analysis as independently associated with reduced TTFT were advanced Binet stages [hazard ratio (HR) 4.69; p < 0.001] and >=25% 11q deleted nuclei (HR 4.73; p = 0.004). De novo 11q deleted CLLs exhibit variable clinical outcome. The percentage of deleted nuclei inside leukemic clone should be included in the prognostic definition of therapy-naive 11q deleted CLL patients. PMID- 23027684 TI - Anti-inflammatory effects of the Zingiber officinale roscoe constituent 12 dehydrogingerdione in lipopolysaccharide-stimulated Raw 264.7 cells. AB - Ginger has long been used worldwide as a spice, seasoning, and wine and is also used as a traditional medicine. There have been no previous studies of the potential beneficial effects of the ginger constituent 12-dehydrogingerdione (12 DHGD). We investigated the anti-inflammatory effect of 12-DHGD on lipopolysaccharide (LPS)-stimulated Raw 264.7 cells. The cytotoxicity of 12-DHGD was measured using the MTT assay, and production of prostaglandin E2 (PGE2 ) and the inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha was measured by ELISA. Production of nitric oxide (NO) was measured using Griess reagent and expression of cyclooxygenase-2 (COX-2) and inducible NO (iNOS) enzymes was assessed by reverse transcriptase-polymerase chain reaction. Treatment of Raw 264.7 cells with 12-DHGD significantly inhibited LPS-stimulated production of NO (at 12-DHGD concentrations of 150 and 200 ng/ml), IL-6 (at 50, 100, 150, and 200 ng/ml), and PGE2 (at 200 ng/ml). Consistent with the effects on NO and PGE2 production, 12-DHGD treatment also inhibited the LPS stimulated increase in iNOS and COX-2 mRNA levels. However, 12-DHGD did not affect production of IL-1beta or TNF-alpha in response to LPS. 12-DHGD, a constituent of ginger, is a potent inhibitor of proinflammatory mediator production in Raw 264.7 macrophage cells. PMID- 23027685 TI - OMIP-013: differentiation of human T-cells. PMID- 23027686 TI - Anticipatory smooth eye movements with random-dot kinematograms. AB - Anticipatory smooth eye movements were studied in response to expectations of motion of random-dot kinematograms (RDKs). Dot lifetime was limited (52-208 ms) to prevent selection and tracking of the motion of local elements and to disrupt the perception of an object moving across space. Anticipatory smooth eye movements were found in response to cues signaling the future direction of global RDK motion, either prior to the onset of the RDK or prior to a change in its direction of motion. Cues signaling the lifetime of the dots were not effective. These results show that anticipatory smooth eye movements can be produced by expectations of global motion and do not require a sustained representation of an object or set of objects moving across space. At the same time, certain properties of global motion (direction) were more sensitive to cues than others (dot lifetime), suggesting that the rules by which prediction operates to influence pursuit may go beyond simple associations between cues and the upcoming motion of targets. PMID- 23027688 TI - The impact of stressor patterns on clinical features in patients with tako-tsubo cardiomyopathy: experiences of two tertiary cardiovascular centers. AB - BACKGROUND: Tako-tsubo cardiomyopathy (TTC) is typically triggered by an acute emotional or physical stress event. The aim of this study was to investigate the impact of stressor patterns on clinical features, laboratory parameters, and electrocardiographic and echocardiographic findings in patients with TTC. HYPOTHESIS: Clinical features are different according to stressor patterns. METHODS: Of 137 patients enrolled from the TTC registry database, 14 patients had emotional triggers (E group), 96 had physical triggers (P group), and 27 had no triggers (N group). RESULTS: Most clinical presentations and in-hospital courses were similar among the groups. However, the E group had a higher prevalence of chest pain (P = 0.006) and palpitation (P = 0.006), whereas the P group had a higher prevalence of cardiogenic shock (P = 0.040), than other groups. The P group had a significantly higher heart rate (P = 0.001); higher high-sensitivity C-reactive protein (P = 0.006), creatine kinase MB fraction (P = 0.045), and N terminal-probrain natriuretic peptide (P = 0.036) levels; higher left ventricular end-diastolic pressure (P = 0.019) and left ventricular end-systolic diameter (P = 0.002); but lower left ventricular ejection fraction (P = 0.018). The E group had lesser prevalence of apical ballooning pattern (P = 0.038) than other groups. The P group required more frequent use of inotropics (P = 0.041) and diuretics (P = 0.047) and had significantly longer intensive care unit (P = 0.014) and in hospital stays (P = 0.001). CONCLUSIONS: The clinical features of TTC are different according to preceding stressor patterns. The TTC group with preceding physical stressors was less likely to have preserved cardiovascular reserve and more likely to require hemodynamic support than other groups. The overall prognosis of TTC is excellent, regardless of triggering stressors. PMID- 23027687 TI - The Importance of astrocyte-derived purines in the modulation of sleep. AB - Sleep is an evolutionarily conserved phenomenon that is clearly essential for survival, but we have limited understanding of how and why it is so important. Adenosine triphosphate (ATP)/adenosine signaling has been known to be important in the regulation of sleep and recent evidence suggests a critical role for gliotransmission in the modulation of sleep homeostasis. Herein, we review the regulation of ATP/adenosine in the nervous system and provide evidence of a critical role for astrocyte-derived adenosine in the regulation of sleep homeostasis and the modulation of synaptic transmission. Further understanding of the role of glial cells in the regulation of sleep may provide new targets for pharmaceutical intervention in the treatment of brain dysfunctions, specifically those that are comorbid with sleep disruptions. PMID- 23027689 TI - Risk factors for impaired gonadal function in female Hodgkin lymphoma survivors: final analysis of a retrospective multicenter joint study from Italian and Brazilian Institutions. AB - Hodgkin lymphoma (HL) is one of the most common types of cancer in the young and one of the most curable forms of cancer. Therefore, there has been an increasing interest in the study of long-term morbidities. The aims of the present study were to evaluate the prevalence and risk factors for impaired gonadal function in a retrospective cohort of 238 HL female survivors from Italy and Brazil and to analyse the role of oral contraceptives (OC) and GnRH-analogues. Besides data collection from HL databases, a specific questionnaire was administered to collect data on gonadal function. The median age at diagnosis was 25 years and the median follow-up was 7 years. Overall, 25% of the patients developed impaired gonadal function. Older age at diagnosis, front-line therapies containing alkylating agents and more than one treatment were independent risk factors, whereas the use of OC or GnRH-a reduced independently the risk of impaired gonadal function. The fertility rate among fertile survivors was low when compared with the general population. We confirmed that older age, type of front line chemotherapy and a higher number of therapies are associated with gonadal function impairment in terms of infertility and premature menopause in female HL survivors. Also, the use of GnRH-a or OC was independently identified as a protective factor. Further prospective studies are needed to better understand the barriers to parenthood in HL survivors. PMID- 23027691 TI - Shoulder dislocation in the older patient. AB - Approximately 20% of all shoulder dislocations occur in patients aged >60 years. Older patients who sustain a primary shoulder dislocation are much less likely than younger patients to suffer from recurrence. However, older patients are more likely than younger patients to sustain injuries to the rotator cuff, axillary nerve, or brachial plexus. Rotator cuff tears are significantly more common than nerve palsies, and rotator cuff tears can be mistaken for nerve palsies. Older patients with persistent shoulder pain and dysfunction after dislocation should be carefully evaluated for rotator cuff pathology. Although dislocation is a common injury in the older population, these concomitant injuries-especially of the rotator cuff-are often missed. PMID- 23027690 TI - Stability of T cell phenotype and functional assays following heparinized umbilical cord blood collection. AB - Umbilical cord blood has been used for a wide variety of immunologic investigations including assessments of developmental perturbations by antenatal exposures. Recent advances in multiparameter flow cytometry have allowed finer characterization of lymphocyte phenotype and function, revealing important differences between the fetal and adult immune systems. The degree of variability between human subjects confounds the ability to draw firm conclusions. Artifacts resulting from processing techniques exacerbate this variability. The unpredictable nature of deliveries, especially of premature infants, makes it difficult to control variables such as timing of umbilical cord mononuclear cell (UCMC) isolation and method of collection. Additionally, in multicenter studies dependent on central processing, delays are inevitable. However, little available literature describes systematic testing of the degree to which processing variations affect UCMC phenotype and function. Using multiparameter flow cytometry, we tested the effect of collection technique and length of time prior to UCMC isolation on T cell phenotype and function, with the goal of creating a standardized operating procedure for a multicenter investigation. The study also provides a benchmark data set including extensive surface and functional phenotyping of umbilical cord T cells. UCMC isolation delay of up to 24 h produced similar T cell phenotype and function as tested by in vitro SEB stimulation. There were few statistically significant differences between time points based on data medians. We conclude that, for the purpose of immunologic investigations, a 24-h time delay from sample collection to mononuclear cell isolation does not introduce a significant degree of variation in T cell phenotype and function when adhering to strict standard operating procedures. PMID- 23027692 TI - Arthritis of the distal radioulnar joint: from Darrach to total joint arthroplasty. AB - The distal radioulnar joint (DRUJ) is a complex structure that contributes to full, painless forearm rotation and weight bearing. Stability requires adequate bony architecture and robust soft-tissue support. Arthritis of the DRUJ between the sigmoid notch of the distal radius and the ulnar head can be caused by traumatic, inflammatory, congenital, and degenerative processes. Initial management of symptomatic DRUJ arthritis is nonsurgical. Surgery is reserved for patients with refractory pain. Although outcomes typically are positive following excision of the distal ulna, serious potential postoperative complications include instability and potentially painful impingement of the residual distal ulnar stump. Procedures used to manage the unstable residual ulna include soft tissue stabilization techniques and DRUJ implant arthroplasty. PMID- 23027693 TI - Graft tensioning during knee ligament reconstruction: principles and practice. AB - Failure to correctly tension grafts may overconstrain or underconstrain the knee, potentially predisposing the patient to deteriorating clinical and/or radiographic results over time. Knee ligament reconstruction requires a fundamental understanding of native anatomy, ligament biomechanics, and principles of graft tensioning. A successful strategy for graft tensioning takes into account the specific biomechanics of the ligament or ligaments in question, the mechanical properties of the graft selected, the chosen fixation method, the selected tensioning method (ie, manual or mechanical), and the overall goal of the reconstruction (ie, isometry versus anisometry). PMID- 23027694 TI - Malignant osseous tumors of the pediatric spine. AB - In the pediatric population, malignant osseous tumors of the spine include osteosarcoma, Ewing sarcoma, lymphoma, and metastatic neuroblastoma. Although these tumors are rare, prompt diagnosis and recognition are critical to the overall prognosis. Improved understanding of the natural history of spine deformity, combined with advances in imaging, surgical technology, radiation therapy, and chemotherapeutic regimens, has improved survival rates and decreased rates of local recurrence-especially recurrence of low-grade lesions. Prognosis for patients with high-grade lesions with distant metastasis on presentation remains exceedingly poor. Recognition of these spine tumors and prompt referral to a tertiary care center that specializes in oncology can optimize patient outcomes. PMID- 23027695 TI - Principles of rotationplasty. AB - Rotationplasty is a reconstructive, limb-sparing option for management of lower extremity bone deficiency. This technique involves an intercalary resection, followed by 180 degrees rotation of the distal limb to allow the ankle to function as a knee joint when it is fitted with a modified below-knee prosthesis. Gait analysis and functional outcome studies have reported favorable results with rotationplasty compared with those of above-knee amputation. Moreover, patient satisfaction with rotationplasty is higher than with other limb salvage procedures. The primary drawback of this procedure is patient acceptance of the limb's appearance. PMID- 23027696 TI - Sex differences in osteoarthritis of the knee. PMID- 23027697 TI - The roles of osteocyte signaling in bone. PMID- 23027698 TI - Endothelial progenitor cells: a novel cell-based therapy in orthopaedic surgery. PMID- 23027699 TI - Chemical composition and biological activities of polar extracts and essential oil of rose-scented geranium, Pelargonium graveolens. AB - Pelargonium graveolens (Geraniaceae) was characterized with respect to its chemical composition, antioxidant potential and antimicrobial activities. This is the first investigation focusing on the comparison of both essential oil and polar extracts from this species. The chemical composition of the essential oil of the aerial parts of P. graveolens was analyzed by gas chromatography/mass spectrometry. The main constituents of the oil were found to be beta-citronellol (21.9%), citronellyl formate (13.2%), geraniol (11.1%), 10-epi-gamma-eudesmol (7.9%), geranyl formate (6.2%) and (l)-linalool (5.6%). Nine flavonoids were identified by high-performance liquid chromatography-MS in leaf and flower extracts. Kaempferol 3-O-rhamnoside-glucoside, isorhamnetin aglycone, quercetin 3 O-glucoside, kaempferol 3,7-di-O-glucoside, quercetin 3-O-pentose and kaempferol 3-O-glucoside, quercetin 3-O-rhamnoside-glucoside, quercetin 3-O-pentoside glucoside, myrisetin 3-O-glucoside-rhamnoside flavonoids were detected in methanolic and aqueous extracts, respectively. The total flavonoids ranged between 29.9 and 78.2 mg QE/g in flower water and methanol extracts, respectively, and 22.5 and 71.2 mg QE/g dry weight in leaf water and methanol extracts, respectively. The highest antioxidant activities using two methods of free radical scavenging capacities were obtained with the essential oil (9.16 mM of Trolox and 2.68 ug/ml). All P. graveolens essential oil and polar extracts were active against at least one bacterium. PMID- 23027700 TI - Nanoscale structure of type I collagen fibrils: quantitative measurement of D spacing. AB - This article details a quantitative method to measure the D-periodic spacing of type I collagen fibrils using atomic force microscopy coupled with analysis using a two-dimensional fast fourier transform approach. Instrument calibration, data sampling and data analysis are discussed and comparisons of the data to the complementary methods of electron microscopy and X-ray scattering are made. Examples of the application of this new approach to the analysis of type I collagen morphology in disease models of estrogen depletion and osteogenesis imperfecta (OI) are provided. We demonstrate that it is the D-spacing distribution, not the D-spacing mean, that showed statistically significant differences in estrogen depletion associated with early stage osteoporosis and OI. The ability to quantitatively characterize nanoscale morphological features of type I collagen fibrils will provide important structural information regarding type I collagen in many research areas, including tissue aging and disease, tissue engineering, and gene knockout studies. Furthermore, we also envision potential clinical applications including evaluation of tissue collagen integrity under the impact of diseases or drug treatments. PMID- 23027701 TI - Prediction of Contrast-Induced Nephropathy With Persistent Renal Dysfunction and Adverse Long-term Outcomes in Patients With Acute Myocardial Infarction Using the Mehran Risk Score. AB - BACKGROUND: Contrast-induced nephropathy (CIN) has been generally considered to be transient and associated with unfavorable clinical outcomes. HYPOTHESIS: The aim of this study was to investigate whether Mehran risk score could predict CIN with persistent renal dysfunction and long-term clinical outcomes in acute myocardial infarction (AMI) patients undergoing percutaneous coronary intervention (PCI). METHODS: We analyzed the clinical data of 1041 AMI patients. The primary end point was defined as major adverse cardiovascular and cerebrovascular event (MACCE) including death, reinfarction, target vessel revascularization, heart failure requiring hospital admission, and stroke. Patients were categorized into 4 groups according to risk scores: low (<= 5, n = 596), moderate (6-10, n = 265), high (11-15, n = 111), and very high (>=16, n = 69). RESULTS: Among the 148 patients (14.2%) who developed CIN, persistent renal dysfunction was observed in 68 patients. Presence in high- or very high-risk groups was the most important independent risk factor of CIN with persistent renal dysfunction (odds ratio: 3.35, 95 confidence interval [CI]: 1.89-5.92, P < 0.001). Furthermore, patients in higher-risk groups experienced significantly more MACCE and mortality 2 years after PCI. Using multivariate analysis, significant increase in the hazard ratio (HR) for MACCE was noted in moderate- (HR: 1.40, 95% CI: 0.97-2.03, P = 0.075), high- (HR 1.96, 95% CI: 1.22-3.15, P = 0.006), and very high-risk (HR 2.40, 95% CI: 1.36-4.21, p = 0.002) groups, compared with the low-risk group. The very high-risk group had approximately 6 fold increase in mortality over the low-risk group (HR: 6.22, 95% CI: 2.77-13.95, P < 0.001). CONCLUSIONS: Mehran risk score predicted CIN with persistent renal dysfunction and long-term clinical outcomes in patients with AMI. PMID- 23027702 TI - Regulation of organization and function of microtubules by the mitogen-activated protein kinase cascade during plant cytokinesis. AB - Cytokinesis in eukaryotes involves specific arrays of microtubules (MTs), which are known as the central spindle in animals, the anaphase spindle in yeasts, and the phragmoplast in plants. In plants, a mitogen-activated protein kinase (MAPK) cascade stimulates the turnover of phragmoplast MTs, which allows the expansion of the phragmoplast that is essential for cytokinesis including the formation of cell plates. A prerequisite for activation of this cascade is the interaction between mitotic kinesin NACK1 in tobacco (HINKEL in Arabidopsis) and MAPK kinase kinase NPK1 (ANP1, 2, 3 in Arabidopsis). Other members of this cascade are NQK1 MAPK kinase and NRK1/NTF6 MAPK in tobacco and the respective orthologs in Arabidopsis. All the components in the pathway (designated the NACK-PQR pathway) concentrate at the midzone of the phragmoplast in plant cells during cytokinesis. Downstream MAPKs in both plant species phosphorylate microtubule-associated protein 65 (MAP65). Interestingly, activities of components in the NACK-PQR pathway are downregulated by depolymerization of MTs. In the present review, we summarize current views on the mechanisms involved in activating the kinase cascade, a role of MAP65 phosphorylation by MAPK during cytokinesis, and the feedback mechanism for regulating inactivation of the kinase cascade. PMID- 23027703 TI - Human mesenchymal stem cells: from immunophenotyping by flow cytometry to clinical applications. AB - Modern medicine will unequivocally include regenerative medicine as a major breakthrough in the re-establishment of damaged or lost tissues due to degenerative diseases or injury. In this scenario, millions of patients worldwide can have their quality of life improved by stem cell implantation coupled with endogenous secretion or administration of survival and differentiation promoting factors. Large efforts, relying mostly on flow cytometry and imaging techniques, have been put into cell isolation, immunophenotyping, and studies of differentiation properties of stem cells of diverse origins. Mesenchymal stem cells (MSCs) are particularly relevant for therapy due to their simplicity of isolation. A minimal phenotypic pattern for the identification of MSCs cells requires them to be immunopositive for CD73, CD90, and CD105 expression, while being negative for CD34, CD45, and HLA-DR and other surface markers. MSCs identified by their cell surface marker expression pattern can be readily purified from patient's bone marrow and adipose tissues. Following expansion and/or predifferentiation into a desired tissue type, stem cells can be reimplanted for tissue repair in the same patient, virtually eliminating rejection problems. Transplantation of MSCs is subject of almost 200 clinical trials to cure and treat a very broad range of conditions, including bone, heart, and neurodegenerative diseases. Immediate or medium term improvements of clinical symptoms have been reported as results of many clinical studies. PMID- 23027704 TI - Photoluminescence and optical waveguiding characteristics of bisalkoxy tin(IV) porphyrin microcrystals. AB - Guide me: Laser confocal microscope photoluminescence (LCM-PL) and optical waveguiding characteristics for tin(IV) porphyrin-based microcrystalline rods and plates were investigated. The efficiency of optical waveguiding for the rods (0.04 MUm(-1)) was five times better than for the plate, due to stronger pi-pi interaction and a short layer distance (3.035 vs. 3.328 A). PMID- 23027705 TI - Graphical analysis of flow cytometer data for characterizing controlled fluorescent protein display on lambda phage. AB - As native virus particles typically cannot be resolved using a flow cytometer, the general practice is to use fluorescent dyes to label the particles. In this work, an attempt was made to use a common commercial flow cytometer to characterize a phage display strategy that allows for controlled levels of protein display, in this case, eGFP. To achieve this characterization, a number of data processing steps were needed to ensure that the observed phenomena were indeed capturing differences in the phages produced. Phage display of eGFP resulted in altered side scatter and fluorescence profile, and sub-populations could be identified within what would otherwise be considered uniform populations. Surprisingly, this study has found that side scatter may be used in the future to characterize the display of nonfluorescent proteins. PMID- 23027706 TI - Cytokinesis in trypanosomes. AB - Cytokinesis is a crucial step in the cell division cycle whereby the cell membrane and underlying cortex is remodelled and drawn together to create two new daughter cells. While in many eukaryotic systems this process is accomplished by an actomyosin contractile ring, the protozoan parasite Trypanosoma brucei displays an unusual mechanism for cytokinesis, with an increased reliance on microtubules. There are a number of crucial preparatory steps involving the replication and segregation of organelles that must be undertaken in order for cytokinesis to occur. In this review, we will discuss the cellular architecture of the trypanosome and its importance within cytokinesis, and the recent progress in understanding the regulatory systems involved. Recent advances in three dimensional imaging techniques have improved our understanding of the mechanisms driving cytokinesis and are likely to yield further insights in the future. PMID- 23027707 TI - Methodologies for the detection of adverse drug reactions: comparison of hospital databases, chart review and spontaneous reporting. AB - PURPOSE: To evaluate a methodology for adverse drug reactions (ADRs) detection through hospital databases. METHODS: A retrospective analysis was conducted to identify ADRs using diagnostic codes from databases, later validated by chart review. An independent chart review was performed for comparison, as well as assessment of spontaneous reports. RESULTS: 325 ADRs were identified (prevalence of 2.41%, positive predictive value of 87.6%). Independent chart review identified 9% of ADRs at a cost of 35 person-hours (versus two person-hours in databases). There were seven spontaneous reports of ADRs. CONCLUSIONS: Although not frequently used, the detection of ADRs through databases is a relatively less expensive, fast and effective methodology that can improve current pharmacovigilance systems. PMID- 23027710 TI - Astral microtubules physically redistribute cortical actin filaments to the incipient contractile ring. AB - Prior to cell cleavage, cytokinetic proteins are recruited into the nascent actomyosin contractile ring, paving the way for formation of a functional cleavage furrow. Interactions between spindle microtubules and the cell cortex may play a critical role in this recruitment, since microtubules have been shown to affect distribution and activation of cytokinetic proteins within the cortex. However, direct evidence for physical interaction between microtubules and the cortex has been lacking. Here, we probed the physical connection between astral microtubules and cortical actin filaments, by micromanipulating the fluorescently tagged cytoskeleton in living spermatocytes of the grasshopper Melanoplus femurrubrum. When microtubules were tugged with a microneedle, they in turn pulled on cortical actin filaments, interrupting the filaments' journey toward the equator. Further displacement of the actin dragged the cell membrane inward, demonstrating that the cortical actin network physically linked spindle microtubules to the cell membrane. Regional disruption of the connection by breaking spindle microtubules prevented actin accumulation in a segment of the ring, which locally inhibited furrowing. We propose a model in which dynamic astral microtubules physically redistribute cortical actin into the incipient contractile ring. PMID- 23027709 TI - Expression of immune inhibitory receptor ILT3 in acute myeloid leukemia with monocytic differentiation. AB - BACKGROUND: The diagnosis of AML with monocytic differentiation is limited by the lack of highly sensitive and specific monocytic markers. Immunoglobulin-like transcript 3 (ILT3) is an immune inhibitory receptor expressed by myelomonocytic cells and at high levels by tolerogenic dendritic cells. METHODS: Using flow cytometry, we analyzed the expression of ILT3 in 37 patients with AML and 20 patients with no detectable disease. RESULTS: We showed that ILT3 was expressed in all cases of AML displaying monocytic differentiation (FAB M4/M5; N = 18), but not in AML M1/M2 and M3 (N = 19; P < 0.0001). Co-expression of ILT3 and immature cell markers, such as CD34 and CD117, was observed in monoblastic leukemia. ILT3 expression was preserved after treatment in M4/M5 patients with refractory or relapsed disease. ILT3 expression was associated with the presence of cytogenetic abnormalities linked to an intermediate prognosis (P = 0.001). Rare CD45dimCD34+CD117+ILT3+ cells were identified in noninvolved bone marrow, suggesting that ILT3 expression is acquired at an early stage by normal myelomonocytic precursors. CONCLUSIONS: ILT3 is a highly sensitive and specific marker which distinguishes AML with monocytic differentiation from other types of AML. Testing of ILT3 expression should be incorporated into the initial diagnostic work-up and monitoring of patients with AML. PMID- 23027708 TI - Apolipoprotein A-I: insights from redox proteomics for its role in neurodegeneration. AB - Proteomics has a wide range of applications, including determination of differences in the proteome in terms of expression and post-translational protein modifications. Redox proteomics allows the identification of specific targets of protein oxidation in a biological sample. Using proteomic techniques, apolipoprotein A-I (ApoA-I) has been found at decreased levels in subjects with a variety of neurodegenerative disorders including in the serum and cerebrospinal fluid (CSF) of Alzheimer disease (AD), Parkinson disease (PD), and Down syndrome (DS) with gout subjects. ApoA-I plays roles in cholesterol transport and regulation of inflammation. Redox proteomics further showed ApoA-I to be highly oxidatively modified and particularly susceptible to modification by 4-hydroxy-2 trans-nonenal (HNE), a lipid peroxidation product. In the current review, we discuss the consequences of oxidation of ApoA-I in terms of neurodegeneration. ROS-associated chemotherapy related ApoA-I oxidation leads to elevation of peripheral levels of tumor necrosis factor-alpha (TNF-alpha) that can cross the blood-brain barrier (BBB) causing a signaling cascade that can contribute to neuronal death, likely a contributor to what patients refer to as "chemobrain." Current evidence suggests ApoA-I to be a promising diagnostic marker as well as a potential target for therapeutic strategies in these neurodegenerative disorders. PMID- 23027711 TI - Parallel imports and innovation in an emerging economy: the case of Indian pharmaceuticals. AB - This paper studies the impact of the re-importation of imitated pharmaceuticals as a by-product of an open policy toward parallel import (PI) on process innovation. Foreign investment by a firm to exploit a new unregulated market with weak intellectual property rights can give rise to imitation. These products can potentially re-enter the original country when PI is allowed influencing research and development (R&D) incentives. In an emerging economy with technologically heterogeneous firms, trade costs shift PI-related market share losses from the more to the less R&D efficient firm, inducing the former to strategically increase R&D. PI accompanied by tariffs also induces higher R&D effort by the technologically inferior firm when it results in an expansion of its sales abroad. A tariff on PI is most likely to increase welfare when the technological gap between the two firms at home is sufficiently large. PMID- 23027712 TI - Impact of pre-analytical factors on the proteomic analysis of formalin-fixed paraffin-embedded tissue. AB - Formalin-fixed paraffin-embedded (FFPE) tissue samples represent a tremendous potential resource for biomarker discovery, with large numbers of samples in hospital pathology departments and links to clinical information. However, the cross-linking of proteins and nucleic acids by formalin fixation has hampered analysis and proteomic studies have been restricted to using frozen tissue, which is more limited in availability as it needs to be collected specifically for research. This means that rare disease subtypes cannot be studied easily. Recently, improved extraction techniques have enabled analysis of FFPE tissue by a number of proteomic techniques. As with all clinical samples, pre-analytical factors are likely to impact on the results obtained, although overlooked in many studies. The aim of this review is to discuss the various pre-analytical factors, which include warm and cold ischaemic time, size of sample, fixation duration and temperature, tissue processing conditions, length of storage of archival tissue and storage conditions, and to review the studies that have considered these factors in more detail. In those areas where investigations are few or non existent, illustrative examples of the possible importance of specific factors have been drawn from studies using frozen tissue or from immunohistochemical studies of FFPE tissue. PMID- 23027714 TI - Association of ertapenem and antipseudomonal carbapenem usage and carbapenem resistance in Pseudomonas aeruginosa among 12 hospitals in Queensland, Australia. AB - OBJECTIVES: The objective of this study was to determine the association between ertapenem and antipseudomonal carbapenem use and carbapenem resistance in Pseudomonas aeruginosa in 12 hospitals in Queensland, Australia. METHODS: Data on usage of ertapenem and other antipseudomonal carbapenems, measured in defined daily doses per 1000 occupied bed-days, were collated using statewide pharmacy dispensing and distribution software from January 2007 until June 2011. The prevalence of unique carbapenem-resistant P. aeruginosa isolates derived from statewide laboratory information systems was collected for the same time period. Mixed-effects models were used to determine any relationship between ertapenem and antipseudomonal carbapenem usage and carbapenem resistance among P. aeruginosa isolates in the 12 hospitals analysed. RESULTS: No relationship between ertapenem usage and P. aeruginosa carbapenem resistance was observed. The introduction of ertapenem did not replace antipseudomonal carbapenem prescribing to any significant extent. However, an association between greater usage of antipseudomonal carbapenems and greater P. aeruginosa carbapenem resistance was demonstrated. CONCLUSIONS: It is likely that the only mechanism by which ertapenem can improve P. aeruginosa resistance patterns is by being used as a substitute for, rather than in addition to, antipseudomonal carbapenems. PMID- 23027713 TI - Decreasing population selection rates of resistance mutation K65R over time in HIV-1 patients receiving combination therapy including tenofovir. AB - OBJECTIVES: The use of tenofovir is highly associated with the emergence of mutation K65R, which confers broad resistance to nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs), especially when tenofovir is combined with other NRTIs also selecting for K65R. Although recent HIV-1 treatment guidelines discouraging these combinations resulted in reduced K65R selection with tenofovir, updated information on the impact of currently recommended regimens on the population selection rate of K65R is presently lacking. METHODS: In this study, we evaluated changes over time in the selection rate of resistance mutation K65R in a large population of 2736 HIV-1-infected patients failing combination antiretroviral treatment between 2002 and 2010. RESULTS: The K65R resistance mutation was detected in 144 patients, a prevalence of 5.3%. A large majority of observed K65R cases were explained by the use of tenofovir, reflecting its wide use in clinical practice. However, changing patterns over time in NRTIs accompanying tenofovir resulted in a persistent decreasing probability of K65R selection by tenofovir-based therapy. The currently recommended NRTI combination tenofovir/emtricitabine was associated with a low probability of K65R emergence. For any given dual NRTI combination including tenofovir, higher selection rates of K65R were consistently observed with a non nucleoside reverse transcriptase inhibitor than with a protease inhibitor as the third agent. DISCUSSION: Our finding of a stable time trend of K65R despite elevated use of tenofovir illustrates increased potency of current HIV-1 therapy including tenofovir. PMID- 23027715 TI - A mosaic transposon encoding OXA-48 and CTX-M-15: towards pan-resistance. PMID- 23027716 TI - Evaluation of FMH QuikQuant for the detection and quantification of fetomaternal hemorrhage. AB - BACKGROUND: The Kleihauer-Betke test (KBT) is the most widely used assay for fetomaternal hemorrhage (FMH) detection in rhesus D negative women. In the current study, we sought to evaluate the performance of a flow cytometry (FCM) kit (FMH QuikQuant) using an anti-HbF antibody. METHODS: Eighty-three pregnant women, 58 umbilical cord blood (UCB) dilutions in adult blood, and 6 control samples were tested in parallel with FCM and KBT. RESULTS: Firstly, we compared for each assay, on the 58 UCB preparations, results obtained to dilutions prepared. FCM results showed an excellent correlation (r = 0.97), a high reproducibility with a coefficient of variation lower than 20% for values reaching 10 fetal RBCs. KBT values were correlated (r = 0.94) but exhibited a poor reproducibility. Then, we compared both techniques on all samples. FCM showed a good correlation with KBT (r = 0.87) but the KBT exhibited a systematic overestimation of the FMH. For 8 out of 83 pregnant women, KBT was positive. Five were concordant with FCM results (KBT+/FCM+). On the three discordant (KBT+/FCM ), 2 were finally classified as false positive of the KBT because a second control sample was negative and additionally, FCM identified an increased rate of F cells. One discordant case (KBT+/FCM-) remained unexplained. By receiver operating characteristic analysis, we found a threshold at 4.5 RBCs for FCM with a sensitivity of 89.8% and a specificity of 93.2%. CONCLUSIONS: The FMH QuikQuant kit is a reliable and highly reproductive FCM method for FMH quantification. PMID- 23027717 TI - Insights into cell division using Listeria monocytogenes infections of PtK2 renal epithelial cells. AB - The assembly of actin into a cleavage furrow is accompanied by disassembly of the interphase actin cytoskeleton. A variation of this actin filament disassembly/assembly cycle is seen during cell division in PtK2 cells infected with the intracellular pathogen, Listeria monocytogenes, where F-actin associates with the bacteria either as a halo surrounding nonmoving bacteria, or as an array of filaments that encases the sides of moving baceteria and extends behind them like a tail. The moving Listeria are found both in the cytoplasm and in the distal ends of undulating filopodia. When infected cells enter mitosis, the distribution of moving and stationary bacteria changes. In the transition from prophase to metaphase, there is a decrease in the number of bacteria with tails of actin in the cytoplasm. The nonmoving bacteria surrounded with F-actin are excluded from the mitotic spindle and moving bacteria are seldom seen in the cytoplasm during mitosis, although small thin filopodia cluster at the edges of the cells. After completion of cytokinesis, strong tail reformation first becomes obvious in the filopodia with Listeria moving back into the cytoplasm as the daughter cells spread. In summary, the disassembly and reassembly of actin tails extending from Listeria in dividing cells is a variation of the changes in actin organization produced by stress fiber and myofibril disassembly/assembly cycles during cell division. We suggest that the same unknown factors that regulate the disassembly/assembly of stress fibers and myofibrils during mitosis and post cytokinesis also affect the movement of Listeria inside mitotic cells. PMID- 23027718 TI - Abdominal pain and health related quality of life in pediatric inflammatory bowel disease. AB - OBJECTIVE: To summarize rates of abdominal pain in pediatric inflammatory bowel disease, and to examine associations of abdominal pain, disease activity, and health-related quality of life (HRQoL). METHODS: 44 youths aged 11-18 years completed ratings of abdominal pain, whereas youths and mothers provided ratings of HRQoL at Time 1 (T1) and Time 2 (T2; 6 months later). Disease activity was rated by physicians at T1. RESULTS: At T1, 55% of participants reported pain in the past week, with most in clinical remission. Approximately one-third reported abdominal pain at neither (absent), either (transient), or both (chronic) T1 and T2, respectively. T1 abdominal pain did not contribute significant variance to T1 HRQoL beyond disease activity. However, pain group uniquely predicted T2 HRQoL, with chronic abdominal pain associated with lower HRQoL. CONCLUSIONS: Abdominal pain is prevalent in pediatric inflammatory bowel disease, even during clinical remission. Interventions to address abdominal pain also may enhance HRQoL. PMID- 23027719 TI - Disclosure and self-report of emotional, social, and physical health in children and adolescents with chronic pain--a qualitative study of PROMIS pediatric measures. AB - OBJECTIVES: To examine the content validity of the Patient-Reported Outcomes Measurement Information System pediatric measures, including the pain interference scale, among children and adolescents (aged 8-18 years) who experience chronic pain. To describe children's understandings of the health domain constructs and elucidate verbal and conceptual aspects of self-reported pain-related functioning, which shape disclosure and reporting. METHODS: 34 children and youth with diagnoses of juvenile idiopathic arthritis or noninflammatory chronic pain completed semistructured and cognitive interviews exploring the meaning, experience, and expression of up to 4 of the Patient Reported Outcomes Measurement Information System pediatric domains: anger, anxiety, depressive symptoms, fatigue, pain interference, and peer relationships. Team-based thematic and content analyses were conducted. RESULTS: Clear verbal and social-cognitive differences were observed in representations and accounts of the domain-experiences across age-groups, but we noted little, if any, evidence of problems with content validity. CONCLUSIONS: Findings suggest the importance of a rigorous developmental approach for understanding the verbal and cognitive dimensions of pediatric self-reports and patient-reported outcomes. PMID- 23027720 TI - Changes in executive functioning and self-management in adolescents with type 1 diabetes: a growth curve analysis. AB - OBJECTIVE: To investigate the relation of changes in executive functioning to changes in diabetes self-management in a 2-year prospective study of a sample of youth aged 9-11 years at baseline (n = 239) with type 1 diabetes and their maternal caregivers. RESEARCH DESIGN AND METHODS: Youth and maternal caregivers completed the Diabetes Self-Management Profile (DSMP) at baseline, 12 months, and 24 months. Maternal caregivers completed the Behavioral Rating Inventory of Executive Functioning (BRIEF) at the same time points to assess global executive functioning, and the domains of behavioral regulation and metacognition. RESULTS: Youth reported self-management decreased over time (p < .01) while behavioral regulation (e.g., the child's ability to shift cognitive set and moderate emotions and behaviors via emotional control) increased (p < .05). Changes in behavioral regulation significantly predicted rate of change in youth-reported self-management (p < .01). Global executive functioning and metacognition (e.g., the child's ability to monitor, initiate, plan, organize, and sustain future oriented problem solving and working memory) did not change over time and did not predict changes in self-management. Moreover, executive functioning and self management did not predict changes in HbA1c. CONCLUSIONS: Positive changes in behavioral regulation may enhance self-management of type 1 diabetes during the transition to adolescence. PMID- 23027721 TI - The effects of aerobic exercise on psychosocial functioning of adolescents who are overweight or obese. AB - OBJECTIVES: To evaluate effects of stationary cycling to music versus interactive video game cycling on psychosocial functioning in obese adolescents. METHODS: 30 obese adolescents aged 12-17 years were randomized to twice weekly laboratory based sessions of stationary cycling to music or interactive video game cycling for a 10-week trial. Participant's self-reported measures of scholastic competence, social competence, athletic competence, body image, and self-esteem were obtained. Aerobic fitness and body composition were directly measured. RESULTS: Although no differences emerged between exercise groups over time, when collapsed across exercise modality, significant pre-post improvements were found for body image, perceived scholastic competence and social competence. Changes in aerobic fitness, but not body composition, were positively associated with psychosocial functioning. CONCLUSIONS: Aerobic exercise was associated with improvements in body image, perceived academic performance, and social competence in obese adolescents, and these psychological benefits were related to improved aerobic fitness but not changes in body composition. PMID- 23027722 TI - Quantitative mass spectrometry for colorectal cancer proteomics. AB - This review documents the uses of quantitative MS applied to colorectal cancer (CRC) proteomics for biomarker discovery and molecular pathway profiling. Investigators are adopting various labeling and label-free MS approaches to quantitate differential protein levels in cells, tumors, and plasma/serum. We comprehensively review recent uses of this technology to examine mouse models of CRC, CRC cell lines, their secretomes and subcellular fractions, CRC tumors, CRC patient plasma/serum, and stool samples. For biomarker discovery these approaches are uncovering proteins with potential diagnostic and prognostic utility, while in vitro cell culture experiments are characterizing proteomic and phosphoproteomic responses to disrupted signaling pathways due to mutations or to inhibition of drugable enzymes. PMID- 23027723 TI - Psychosocial care in cancer: an overview of psychosocial programmes and national cancer plans of countries within the International Federation of Psycho-Oncology Societies. AB - We report data from representatives of national professional psycho-oncology societies on the integration of psychosocial care into national cancer programmes or cancer plans. To date information on how, or whether, psychosocial care has been recognized and integrated into comprehensive cancer care internationally has been extremely limited. The value of the current survey, whilst not comprehensive, lies with the fact that it is the first to report on the current status of psychosocial care for cancer patients and their families from a global perspective. Representatives of 29 countries that are members of the Federation of National Psycho-Oncology Societies, coordinated under the aegis of the International Psycho-Oncology Society (IPOS), participated in a survey aimed at clarifying access to psychosocial care. Results indicate that while psychosocial oncology has grown over the last decade, it is either not established or not completely established, or not an integral part of care in some countries, especially developing countries, where basic care is sometimes not provided to cancer patients. Future targets need to focus on the integration of psychosocial oncology programmes into comprehensive cancer care and their coordination within multidisciplinary teams. PMID- 23027724 TI - Home testing: the metamorphosis of attitudes about HIV infection. PMID- 23027725 TI - V(1): the most important lead in inferior STEMI. PMID- 23027726 TI - A 60-year-old man with abdominal bruising. PMID- 23027727 TI - Chronic lymphocytic leukemia and apparent hyperkalemia. PMID- 23027728 TI - Hypertension in the elderly: some practical considerations. AB - Data from randomized controlled trials suggest that treating hypertension in the elderly, including octogenarians, may substantially reduce the risk of cardiovascular disease and death. However, treatment remains challenging because of comorbidities and aging-related changes. We present common case scenarios encountered while managing elderly patients with hypertension, including secondary hypertension, adverse effects of drugs, labile hypertension, orthostatic hypotension, and dementia. PMID- 23027729 TI - Cognitive impairment in ICU survivors: assessment and therapy. AB - Cognitive impairment occurs in up to one-third of intensive care patients and may affect one or more cognitive domains. Because data are scarce on therapies for this complication, prevention remains the prevailing strategy. In this review, we discuss the clinical approach to cognitive impairment after an intensive care unit (ICU) stay. PMID- 23027730 TI - Home testing for HIV: hopefully, a step forward. AB - An over-the-counter at-home test for human immunodeficiency virus (HIV) infection has been approved and will likely be available soon. It is intended to decrease the percentage of HIV-infected people unaware of their infection (estimated at 18% of the 1.2 million people infected in the United States). Since early and continued treatment prevents disease progression and reduces HIV transmission, testing is the first step toward effective care. PMID- 23027731 TI - Male hypogonadism: more than just a low testosterone. AB - Confronted with a low serum testosterone level, physicians should not jump to the diagnosis of hypogonadism, as confirmation and thorough evaluation are warranted before making the diagnosis or starting therapy. This review discusses how to approach the finding of a low testosterone value, stressing the need to confirm the finding, the underlying pathophysiologic processes, drugs that can be responsible, and the importance of determining whether the cause is primary (testicular) or secondary (hypothalamic-pituitary). PMID- 23027732 TI - Hypertensive chronic kidney disease in African Americans: strategies for improving care. AB - African Americans have a disproportionate burden of chronic kidney disease (CKD), which tends to have an earlier onset and a more rapid progression in this population. Many of the factors responsible for the rapid progression of CKD in African Americans are detectable by screening and are modifiable with prompt therapy. PMID- 23027734 TI - An economic evaluation of screening 60- to 70-year-old adults for hearing loss. AB - BACKGROUND: Hearing loss is common among older adults and has consequences for sufferers, families and society, but there is substantial unmet need for intervention. Screening could expedite intervention and improve outcomes. METHODS: We use Markov models to estimate the incremental cost-effectiveness ratio (ICER) of potential screening programmes compared with current provision (GP-referral), from a health service perspective. Alternative options are investigated through scenario analysis. One-way and probabilistic sensitivity analyses are undertaken. RESULTS: All modelled screens are cost-effective and reduce unmet need for hearing aids. The most cost-effective option identified is a one-stage audiometric screen for bilateral hearing loss >=30 dB hearing level (HL) at age 60, repeated at ages 65 and 70. This option has an ICER of L1461 compared to GP-referral and would mean an additional 15 437 adults benefiting from hearing intervention per 100 000 population aged 60. The cost-effectiveness acceptability curve shows that screening is more cost-effective than GP-referral provided a Quality Adjusted Life Year is valued at L2000 or more. CONCLUSIONS: Adult hearing screening would provide a cost-effective way to improve quality of life for older adults. We recommend piloting an audiometric screen offered to all adults age 60, 65 and 70 years to identify bilateral hearing loss of at least 30 dB HL. PMID- 23027733 TI - Targeted proteomic dissection of Toxoplasma cytoskeleton sub-compartments using MORN1. AB - The basal complex in Toxoplasma functions as the contractile ring in the cell division process. Basal complex contraction tapers the daughter cytoskeleton toward the basal end and is required for daughter segregation. We have previously shown that the protein MORN1 is essential for basal complex assembly and likely acts as a scaffolding protein. To further our understanding of the basal complex, we combined subcellular fractionation with an affinity purification of the MORN1 complex and identified its protein composition. We identified two new components of the basal complex, one of which uniquely associated with the basal complex in mature parasites, the first of its kind. In addition, we identified several other novel cytoskeleton proteins with different spatiotemporal dynamics throughout cell division. Since many of these proteins are unique to Apicomplexa this study significantly contributes to the annotation of their unique cytoskeleton. Furthermore, we show that G-actin binding protein TgCAP is localized at the apical cap region in intracellular parasites, but quickly redistributes to a cytoplasmic localization pattern upon egress. (c) 2012 Wiley Periodicals, Inc. PMID- 23027735 TI - Polar expansion during cytokinesis. AB - Vesicle trafficking and new membrane addition at the cleavage furrow have been extensively documented. However, less clear is the old idea that expansion at the cell poles occurs during cytokinesis. We find that new membrane is added to the cell poles during anaphase, causing the plasma membrane to expand coincident with the constriction of the contractile ring and may provide a pushing force for membrane ingression at the furrow. This membrane addition occurs earlier during mitosis than membrane addition at the furrow and is dependent on actin and astral microtubules. The membrane that is added at the polar regions is compositionally distinct from the original cell membrane in that it is devoid of GM(1) , a component of lipid rafts. These findings suggest that the growth of the plasma membrane at the cell poles during cell division is not due to stretching as previously thought, but due to the addition of compositionally unique new membrane. PMID- 23027737 TI - Cloning, expression, purification, crystallization and X-ray analysis of inositol monophosphatase from Mus musculus and Homo sapiens. AB - Inositol monophosphatase (IMPase) catalyses the hydrolysis of inositol monophosphate to inositol and is crucial in the phosphatidylinositol (PI) signalling pathway. Lithium, which is the drug of choice for bipolar disorder, inhibits IMPase at therapeutically relevant plasma concentrations. Both mouse IMPase 1 (MmIMPase 1) and human IMPase 1 (HsIMPase 1) were cloned into pRSET5a, expressed in Escherichia coli, purified and crystallized using the sitting-drop method. The structures were solved at resolutions of 2.4 and 1.7 A, respectively. Comparison of MmIMPase 1 and HsIMPase 1 revealed a core r.m.s. deviation of 0.516 A. PMID- 23027736 TI - High-resolution structures of Thermus thermophilus enoyl-acyl carrier protein reductase in the apo form, in complex with NAD+ and in complex with NAD+ and triclosan. AB - Enoyl-acyl carrier protein reductase (ENR; the product of the fabI gene) is an important enzyme that is involved in the type II fatty-acid-synthesis pathway of bacteria, plants, apicomplexan protozoa and mitochondria. Harmful pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum use the type II fatty acid-synthesis system, but not mammals or fungi, which contain a type I fatty acid-synthesis pathway consisting of one or two multifunctional enzymes. For this reason, specific inhibitors of ENR are attractive antibiotic candidates. Triclosan, a broad-range antibacterial agent, binds to ENR, inhibiting fatty-acid synthesis. As humans do not have an ENR enzyme, they are not affected. Here, high resolution structures of Thermus thermophilus (Tth) ENR in the apo form, bound to NAD(+) and bound to NAD(+) plus triclosan are reported. Differences from and similarities to other known ENR structures are reported; in general, the structures are very similar. The cofactor-binding site is also very similar to those of other ENRs and, as reported for other species, triclosan leads to greater ordering of the loop that covers the cofactor-binding site, which, together with the presence of triclosan itself, presumably provides tight binding of the dinucleotide, preventing cycling of the cofactor. Differences between the structures of Tth ENR and other ENRs are the presence of an additional beta-sheet at the N-terminus and a larger number of salt bridges and side-chain hydrogen bonds. These features may be related to the high thermal stability of Tth ENR. PMID- 23027738 TI - Structure of the [NiFe]-hydrogenase maturation protein HypF from Thermococcus kodakarensis KOD1. AB - HypF is involved in the biosynthesis of the CN ligand of the NiFe(CN)(2)CO centre of [NiFe]-hydrogenases. Here, the full-length structure of HypF from Thermococcus kodakarenesis is reported at 4.5 A resolution. The N-terminal acylphosphatase like (ACP) domain interacts with the zinc-finger domain with some flexibility in its relative position. Molecular-surface analysis shows that a deep pocket formed between the ACP and zinc-finger domains is highly conserved and has positive potential. These results suggest that the positively charged pocket identified is involved in the hydrolysis of carbamoyl phosphate and the formation of a carbamoyl intermediate. PMID- 23027739 TI - Structure of the HECT C-lobe of the UBR5 E3 ubiquitin ligase. AB - UBR5 ubiquitin ligase (also known as EDD, Rat100 or hHYD) is a member of the E3 protein family of HECT (homologous to E6-AP C-terminus) ligases as it contains a C-terminal HECT domain. In ubiquitination cascades involving E3s of the HECT class, ubiquitin is transferred from an associated E2 ubiquitin-conjugating enzyme to the acceptor cysteine of the HECT domain, which consists of structurally distinct N- and C-lobes connected by a flexible linker. Here, the high-resolution crystal structure of the C-lobe of the HECT domain of human UBR5 is presented. The structure reveals important features that are unique compared with other HECT domains. In particular, a distinct four-residue insert in the second helix elongates this helix, resulting in a strikingly different orientation of the preceding loop. This protruding loop is likely to contribute to specificity towards the E2 ubiquitin-conjugating enzyme UBCH4, which is an important functional partner of UBR5. Ubiquitination assays showed that the C lobe of UBR5 is able to form a thioester-linked E3-ubiquitin complex, although it does not physically interact with UBCH4 in NMR experiments. This study contributes to a better understanding of UBR5 ubiquitination activity. PMID- 23027740 TI - Structure of beta-1,4-mannanase from the common sea hare Aplysia kurodai at 1.05 A resolution. AB - beta-1,4-Mannanase (EC 3.2.1.78) catalyzes the hydrolysis of beta-1,4-glycosidic bonds within mannan, a major constituent group of the hemicelluloses. Bivalves and gastropods possess beta-1,4-mannanase and may degrade mannan in seaweed and/or phytoplankton to obtain carbon and energy using the secreted enzymes in their digestive systems. In the present study, the crystal structure of AkMan, a gastropod beta-1,4-mannanase prepared from the common sea hare Aplysia kurodai, was determined at 1.05 A resolution. This is the first report of the three dimensional structure of a gastropod beta-1,4-mannanase. The structure was compared with bivalve beta-1,4-mannanase and the roles of residues in the catalytic cleft were investigated. No obvious binding residue was found in subsite +1 and the substrate-binding site was exposed to the molecular surface, which may account for the enzymatic properties of mannanases that can digest complex substrates such as glucomannan and branched mannan. PMID- 23027741 TI - Structure of d(CCGGGACCGG)4 as a four-way junction at 1.6 A resolution: new insights into solvent interactions. AB - The crystal structure of the decamer sequence d(CCGGGACCGG)(4) has previously been reported at 2.16 A resolution as a four-way junction. Here, the structure of this sequence is reported at the significantly higher resolution of 1.6 A, which is the highest resolution reported for a four-way junction. This allowed the unambiguous identification of an extensive hydration network with distinct patterns and solvent-mediated interactions that shed new light on the role of water in the formation and stabilization of junction structures. PMID- 23027742 TI - Structures of a gamma-aminobutyrate (GABA) transaminase from the s-triazine degrading organism Arthrobacter aurescens TC1 in complex with PLP and with its external aldimine PLP-GABA adduct. AB - Two complex structures of the gamma-aminobutyrate (GABA) transaminase A1R958 from Arthrobacter aurescens TC1 are presented. The first, determined to a resolution of 2.80 A, features the internal aldimine formed by reaction between the E-amino group of Lys295 and the cofactor pyridoxal phosphate (PLP); the second, determined to a resolution of 2.75 A, features the external aldimine adduct formed between PLP and GABA in the first half-reaction. This is the first structure of a microbial GABA transaminase in complex with its natural external aldimine and reveals the molecular determinants of GABA binding in this enzyme. PMID- 23027743 TI - Crystallization and preliminary X-ray diffraction analysis of tau protein microtubule-binding motifs in complex with Tau5 and DC25 antibody Fab fragments. AB - The Alzheimer's disease-associated protein tau is an intrinsically disordered protein with no preferred structure in solution. Under physiological conditions, tau binds to microtubules and regulates their dynamics, whereas during the development of neurodegeneration tau dissociates from microtubules, misfolds and creates highly insoluble deposits. To elucidate the determinants of tau-protein misfolding, tau peptides from microtubule-binding motifs were crystallized in complexes with Fab fragments of specific monoclonal antibodies. The crystals diffracted to 1.69 A resolution and gave complete data sets using a synchrotron X ray source. Molecular replacement was used to solve the phase problem. PMID- 23027744 TI - Crystallization and preliminary X-ray diffraction analysis of two peptides from Alzheimer PHF in complex with the MN423 antibody Fab fragment. AB - The major constituent of the Alzheimer's disease paired helical filaments (PHF) core is the intrinsically disordered protein (IDP) tau. Globular binding partners, e.g. monoclonal antibodies, can stabilize the fold of disordered tau in complexes. A previously published structure of a proteolytically generated tau fragment in a complex with the PHF-specific monoclonal antibody MN423 revealed a turn-like structure of the PHF core C-terminus [Sevcik et al. (2007). FEBS Lett. 581, 5872-5878]. To examine the structures of longer better-defined PHF segments, crystals of the MN423 Fab fragment were grown in the presence of two synthetic peptides derived from the PHF core C-terminus. For each, X-ray diffraction data were collected at 100 K at a synchrotron source and initial phases were obtained by molecular replacement. PMID- 23027745 TI - Crystallization and preliminary crystallographic studies of CbsA, a secretory exoglucanase from Xanthomonas oryzae pv. oryzae. AB - The bacterial pathogen Xanthomonas oryzae pv. oryzae causes bacterial leaf blight, a serious disease of rice. The secreted exoglucanase CbsA is an important virulence factor of this pathogen. It belongs to the glycosyl hydrolase 6 family of proteins based on the carbohydrate-active enzyme (CAZY) classification. In this study, CbsA has been overexpressed, purified and crystallized. The crystal diffracted to a resolution of 1.86 A and belonged to space group P2(1)2(1)2(1). It contained one monomer per asymmetric unit, with a solvent content of 45.8%. PMID- 23027746 TI - Expression, purification, crystallization and preliminary X-ray analysis of ribitol-5-phosphate cytidylyltransferase from Bacillus subtilis. AB - TarI is a ribitol-5-phosphate cytidylyltransferase that catalyzes the formation of CDP-ribitol, which is involved in the biosynthesis of wall teichoic acids, from CTP and ribitol 5-phosphate. TarI from Bacillus subtilis (BsTarI) was purified and crystallized using the sitting-drop vapour-diffusion method. The crystals diffracted to a resolution of 1.78 A and belonged to the monoclinic space group C2, with unit-cell parameters a = 103.74, b = 60.97, c = 91.80 A, beta = 113.48 degrees . The initial structural model indicated that the crystals of BsTarI contained a dimer in the asymmetric unit. PMID- 23027747 TI - Purification, crystallization and preliminary crystallographic analysis of the CBS-domain pair of cyclin M2 (CNNM2). AB - This work describes the purification and preliminary crystallographic analysis of the CBS-domain pair of the murine CNNM2 magnesium transporter (formerly known as ancient domain protein 2; ACDP2), which consists of a pair of cystathionine beta synthase (CBS) motifs and has 100% sequence identity to its human homologue. CNNM proteins represent the least-studied members of the eight different types of magnesium transporters identified to date in mammals. In humans, the CNNM family is encoded by four genes: CNNM1-4. CNNM1 acts as a cytosolic copper chaperone, whereas CNNM2 and CNNM4 have been associated with magnesium handling. Interestingly, mutations in the CNNM2 gene cause familial dominant hypomagnesaemia (MIM:607803), a rare human disorder characterized by renal and intestinal magnesium (Mg(2+)) wasting, which may lead to symptoms of Mg(2+) depletion such as tetany, seizures and cardiac arrhythmias. This manuscript describes the preliminary crystallographic analysis of two different crystal habits of a truncated form of the protein containing its regulatory CBS-domain pair, which has been reported to host the pathological mutation T568I in humans. The crystals belonged to space groups P2(1)2(1)2 and I222 (or I2(1)2(1)2(1)) and diffracted X-rays to 2.0 and 3.6 A resolution, respectively, using synchrotron radiation. PMID- 23027748 TI - Cloning, purification, crystallization and preliminary X-ray analysis of two low molecular-weight protein tyrosine phosphatases from Vibrio cholerae. AB - Low-molecular-weight protein tyrosine phosphatases (LMWPTPs) are small cytoplasmic enzymes of molecular weight ~18 kDa that belong to the large family of protein tyrosine phosphatases (PTPs). Despite their wide distribution in both prokaryotes and eukaryotes, their exact biological role in bacterial systems is not yet clear. Two low-molecular-weight protein tyrosine phosphatases (VcLMWPTP-1 and VcLMWPTP-2) from the Gram-negative bacterium Vibrio cholerae have been cloned, overexpressed, purified by Ni(2+)-NTA affinity chromatography followed by gel filtration and used for crystallization. Crystals of VcLMWPTP-1 were grown in the presence of ammonium sulfate and glycerol and diffracted to a resolution of 1.6 A. VcLMWPTP-2 crystals were grown in PEG 4000 and diffracted to a resolution of 2.7 A. Analysis of the diffraction data showed that the VcLMWPTP-1 crystals had symmetry consistent with space group P3(1) and that the VcLMWPTP-2 crystals had the symmetry of space group C2. Assuming the presence of four molecules in the asymmetric unit, the Matthews coefficient for the VcLMWPTP-1 crystals was estimated to be 1.97 A(3) Da(-1), corresponding to a solvent content of 37.4%. The corresponding values for the VcLMWPTP-2 crystals, assuming the presence of two molecules in the asymmetric unit, were 2.77 A(3) Da(-1) and 55.62%, respectively. PMID- 23027749 TI - Production and crystallization of the C-propeptide trimer from human procollagen III. AB - The C-propeptide domains of the fibrillar procollagens, which are present throughout the Metazoa in the form of ~90 kDa trimers, play crucial roles in both intracellular molecular assembly and extracellular formation of collagen fibrils. The first crystallization of a C-propeptide domain, that from human procollagen III, is described. Following transient expression in mammalian 293T cells of both the native protein and a selenomethionine derivative, two crystal forms of the homotrimer were obtained: an orthorhombic form (P2(1)2(1)2(1)) that diffracted to 1.7 A resolution and a trigonal form (P321) that diffracted to 3.5 A resolution. Characterization by MALDI-TOF mass spectrometry allowed the efficiency of selenomethionine incorporation to be determined. PMID- 23027750 TI - Crystallization and preliminary X-ray studies of MutT1 (MSMEG_2390) from Mycobacterium smegmatis. AB - MutT1 (MSMEG_2390) from Mycobacterium smegmatis has been crystallized and the crystals have been characterized using X-ray diffraction. The crystals belonged to space group P2(1)2(1)2(1). The Matthews coefficient suggested the possibility of one protein molecule in the asymmetric unit of the orthorhombic unit cell. Solution of the structure using the known three-dimensional structure of a bacterial MutT1 is anticipated. PMID- 23027751 TI - Purification, crystallization and X-ray diffraction analysis of human dynamin related protein 1 GTPase-GED fusion protein. AB - The mechano-enzyme dynamin-related protein 1 plays an important role in mitochondrial fission and is implicated in cell physiology. Dysregulation of Drp1 is associated with abnormal mitochondrial dynamics and neuronal damage. Drp1 shares structural and functional similarities with dynamin 1 with respect to domain organization, ability to self-assemble into spiral-like oligomers and GTP cycle-dependent membrane scission. Structural studies of human dynamin-1 have greatly improved the understanding of this prototypical member of the dynamin superfamily. However, high-resolution structural information for full-length human Drp1 covering the GTPase domain, the middle domain and the GTPase effector domain (GED) is still lacking. In order to obtain mechanistic insights into the catalytic activity, a nucleotide-free GTPase-GED fusion protein of human Drp1 was expressed, purified and crystallized. Initial X-ray diffraction experiments yielded data to 2.67 A resolution. The hexagonal-shaped crystals belonged to space group P2(1)2(1)2, with unit-cell parameters a = 53.59, b = 151.65, c = 43.53 A, one molecule per asymmetric unit and a solvent content of 42%. Expression of selenomethionine-labelled protein is currently in progress. Here, the expression, purification, crystallization and X-ray diffraction analysis of the Drp1 GTPase-GED fusion protein are presented, which form a basis for more detailed structural and biophysical analysis. PMID- 23027752 TI - Purification, crystallization and preliminary X-ray diffraction analysis of a class P-III metalloproteinase (BmMP-III) from the venom of Bothrops moojeni. AB - Snake-venom metalloproteinases (SVMPs) comprise a family of haemostatically active toxins which can cause haemorrhage, coagulopathy, inhibition of platelet aggregation and inflammatory response. These effects are attributed to the proteolytic action of SVMPs on extracellular matrix components, plasma proteins and cell-surface proteins. SVMPs are classified into four classes (P-I to P-IV) based on their domain structures. In order to understand the multiple roles played by the domains of P-III SVMPs, a P-III SVMP (BmMP-III) from the venom of Bothrops moojeni was purified, characterized and crystallized. The crystals belonged to space group I4(1)22, with unit-cell parameters a = b = 108.16, c = 196.09 A. Initially, flash-cooled crystals diffracted poorly to a resolution of about 10 A. However, a significant improvement in the diffraction resolution was observed upon annealing and a complete data set was collected to 3.3 A resolution. The asymmetric unit contained one molecule and the structure was determined and partially refined to an R factor of 34%. Structural comparisons indicated that the cysteine-rich domain can adopt different conformations in relation to the catalytic domain, which may modulate the enzyme activity. PMID- 23027753 TI - Crystallization and preliminary diffraction studies of GIM-1, a class B carbapenem-hydrolyzing beta-lactamase. AB - GIM-1 is a member of the class B carbapenemases (metallo-beta-lactamases; MBLs) and has a wide spectrum of activity against carbapenems, penicillins and extended spectrum cephalosporins, but not aztreonam. GIM-1 presents an enormous challenge to infection control, particularly in the eradication of Gram-negative pathogens including Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii and nonfermenters. There are presently few or no drugs in late-stage development for these pathogens and GIM-1 is a potential target for the development of antimicrobial agents against pathogens producing MBLs. In this study, GIM-1 was cloned, overexpressed and crystallized. The GIM-1 crystals diffracted to 1.4 A resolution and belonged to the orthorhombic space group P2(1)2(1)2(1), with unit cell parameters a = 38.5, b = 67.6, c = 72.8 A. One molecule is present in the asymmetric unit, with a corresponding V(M) of 1.69 A(3) Da(-1) and a solvent content of 27.1%. PMID- 23027754 TI - Improved crystallization of Escherichia coli ATP synthase catalytic complex (F1) by introducing a phosphomimetic mutation in subunit epsilon. AB - The bacterial ATP synthase (F(O)F(1)) of Escherichia coli has been the prominent model system for genetics, biochemical and more recently single-molecule studies on F-type ATP synthases. With 22 total polypeptide chains (total mass of ~529 kDa), E. coli F(O)F(1) represents nature's smallest rotary motor, composed of a membrane-embedded proton transporter (F(O)) and a peripheral catalytic complex (F(1)). The ATPase activity of isolated F(1) is fully expressed by the alpha(3)beta(3)gamma 'core', whereas single delta and epsilon subunits are required for structural and functional coupling of E. coli F(1) to F(O). In contrast to mitochondrial F(1)-ATPases that have been determined to atomic resolution, the bacterial homologues have proven very difficult to crystallize. In this paper, we describe a biochemical strategy that led us to improve the crystallogenesis of the E. coli F(1)-ATPase catalytic core. Destabilizing the compact conformation of epsilon's C-terminal domain with a phosphomimetic mutation (epsilonS65D) dramatically increased crystallization success and reproducibility, yielding crystals of E. coli F(1) that diffract to ~3.15 A resolution. PMID- 23027755 TI - Expression, purification, crystallization and preliminary X-ray analysis of the RecQ helicase catalytic core from Deinococcus radiodurans. AB - The RecQ proteins are a highly conserved group of DNA helicases which play crucial roles in the maintenance of genome stability. DrRecQ from the radioresistant bacterium Deinococcus radiodurans is a special member of the RecQ family because it contains three Helicase-and-RNase-D-C-terminal (HRDC) domains at the C-terminus. The helicase catalytic core is essential for ATPase and DNA unwinding activities. In this work, the helicase catalytic core of DrRecQ was expressed in Escherichia coli, purified and crystallized. Crystals were obtained using the sitting-drop vapour diffusion method and X-ray diffraction data were collected to 2.9 A resolution. The crystals belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 84.75, b = 95.61, c = 183.83 A. PMID- 23027756 TI - Expression, purification, crystallization and X-ray analysis of 3-quinuclidinone reductase from Agrobacterium tumefaciens. AB - (R)-3-Quinuclidinol is a useful chiral building block for the synthesis of various pharmaceuticals and can be produced from 3-quinuclidinone by asymmetric reduction. A novel 3-quinuclidinone reductase from Agrobacterium tumefaciens (AtQR) catalyzes the stereospecific reduction of 3-quinuclidinone to (R)-3 quinuclidinol with NADH as a cofactor. Recombinant AtQR was overexpressed in Escherichia coli, purified and crystallized with NADH using the sitting-drop vapour-diffusion method at 293 K. Crystals were obtained using a reservoir solution containing PEG 3350 as a precipitant. X-ray diffraction data were collected to 1.72 A resolution on beamline BL-5A at the Photon Factory. The crystal belonged to space group P2(1), with unit-cell parameters a = 62.0, b = 126.4, c = 62.0 A, beta = 110.5 degrees , and was suggested to contain four molecules in the asymmetric unit (V(M) = 2.08 A(3) Da(-1)). PMID- 23027757 TI - Crystallization and preliminary X-ray diffraction analysis of alanine racemase from Pseudomonas putida YZ-26. AB - A recombinant form of alanine racemase (Alr) from Pseudomonas putida YZ-26 has been crystallized by the sitting-drop vapour diffusion method. X-ray diffraction data were collected to 2.4 A resolution. The crystals belong to the space group C222(1), with unit-cell parameters a = 118.08, b = 141.86, c = 113.83 A, and contain an Alr dimer in the asymmetric unit. The Matthews coefficient and the solvent content were calculated to be 2.8 A(3) Da(-1) and approximately 50%, respectively. PMID- 23027758 TI - Crystallization and preliminary X-ray diffraction analysis of PsaA, the adhesive pilin subunit that forms the pH 6 antigen on the surface of Yersinia pestis. AB - Yersinia pestis has been responsible for a number of high-mortality epidemics throughout human history. Like all other bacterial infections, the pathogenesis of Y. pestis begins with the attachment of bacteria to the surface of host cells. At least five surface proteins from Y. pestis have been shown to interact with host cells. Psa, the pH 6 antigen, is one of them and is deployed on the surface of bacteria as thin flexible fibrils that are the result of the polymerization of a single PsaA pilin subunit. Here, the crystallization of recombinant donor strand complemented PsaA by the hanging-drop vapor-diffusion method is reported. X-ray diffraction data sets were collected to 1.9 A resolution from a native crystal and to 1.5 A resolution from a bromide-derivatized crystal. These crystals displayed the symmetry of the orthorhombic space group P222(1), with unit-cell parameters a = 26.3, b = 54.6, c = 102.1 A. Initial phases were derived from single isomorphous replacement with anomalous scattering experiments, resulting in an electron-density map that showed a single molecule in the crystallographic asymmetric unit. Sequence assignment was aided by residues binding to bromide ions of the heavy-atom derivative. PMID- 23027759 TI - Crystallization and preliminary X-ray diffraction studies of Xanthomonas campestris PNPase in the presence of c-di-GMP. AB - Bacterial polynucleotide phosphorylase (PNPase) is a 3'-5' processive exoribonuclease that participates in mRNA turnover and quality control of rRNA precursors in many bacterial species. It also associates with the RNase E scaffold and other components to form a multi-enzyme RNA degradasome machinery that performs a wider regulatory role in degradation, quality control and maturation of mRNA and noncoding RNA. Several crystal structures of bacterial PNPases, as well as some biological activity studies, have been published. However, how the enzymatic activity of PNPase is regulated is less well understood. Recently, Escherichia coli PNPase was found to be a direct c-di-GMP binding target, raising the possibility that c-di-GMP may participate in the regulation of RNA processing. Here, the successful cloning, purification and crystallization of S1-domain-truncated Xanthomonas campestris PNPase (XcPNPaseDeltaS1) in the presence of c-di-GMP are reported. The crystals belonged to the monoclinic space group C2, with unit-cell parameters a = 132.76, b = 128.38, c = 133.01 A, gamma = 93.3 degrees , and diffracted to a resolution of 2.00 A. PMID- 23027760 TI - Purification, crystallization and preliminary crystallographic analysis of Kar9p from Saccharomyces cerevisiae. AB - Kar9p is required for correct positioning of the mitotic spindle in Saccharomyces cerevisiae. The in vivo function of Kar9p is well understood, but no structural information is available. Additionally, molecular details of how Kar9p interacts with other proteins are scarce. Full-length Kar9p was expressed in Escherichia coli, purified and crystallized. Diffraction data were collected and processed at 7 A resolution. One crystal showed diffraction to 3 A resolution. The crystals that diffracted to 7 A resolution belonged to space group P3, with unit-cell parameters a = b = 195.02, c = 257.15 A, alpha = beta = 90, gamma = 120 degrees . The crystal that diffracted to 3 A resolution belonged to space group P222, with unit-cell parameters a = 46.37, b = 74.64, c = 133.63 A, alpha = beta = gamma = 90 degrees . PMID- 23027761 TI - Expression, purification and crystallization of the outer membrane lipoprotein GumB from Xanthomonas campestris. AB - GumB is a predicted outer membrane lipoprotein that is involved in the synthesis and/or secretion of xanthan gum. This exopolysaccharide, produced by Xanthomonas campestris, is valuable in industry because of its important rheological properties. Solution of the GumB structure will provide insight into the polymerization and/or secretion mechanisms of xanthan gum. GumB was overexpressed and purified and diffraction-quality crystals of native GumB were obtained. A complete data set was collected to 2.54 A resolution with an R(p.i.m.) of 0.034. The crystals belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 84.4, b = 90.5, c = 120.7 A. PMID- 23027762 TI - Use of a repetitive seeding protocol to obtain diffraction-quality crystals of a putative human D-xylulokinase. AB - In mammals, the enzyme D-xylulokinase (XK; EC 2.7.1.17) catalyses the last step of the glucuronate-xylulose pathway, in which the ketopentose sugar D-xylulose is phosphorylated to yield D-xylulose 5-phosphate (Xu5P). Xu5P is also a metabolite of the pentose phosphate pathway and acts as a signalling molecule that regulates lipogenesis and glycolysis in the liver. To date, no eukaryotic XK has been structurally characterized. A putative human XK was expressed in Escherichia coli aided by molecular chaperones, purified and crystallized. A seeding procedure involving repeated rounds of seeding was developed and proved to be essential for obtaining diffraction-quality crystals. Preliminary X-ray diffraction analysis was performed using synchrotron radiation. This resulted in the collection of a complete diffraction data set to 2.7 A resolution from a crystal belonging to the trigonal space group P3(1) or P3(2) with unit-cell parameters a = b = 101.87, c = 158.85 A. PMID- 23027763 TI - Purification, crystallization and preliminary X-ray diffraction analysis of the RNA-dependent RNA polymerase from Thosea asigna virus. AB - Thosea asigna virus (TaV) is a positive-sense, single-stranded RNA (ssRNA) virus that belongs to the Permutotetravirus genera within the recently created Permutotetraviridae family. The genome of TaV consists of an RNA segment of about 5.700 nucleotides with two open reading frames, encoding for the replicase and capsid protein. The particular TaV replicase does not contain N7-methyl transferase and helicase domains but includes a structurally unique RNA-dependent RNA polymerase (RdRp) with a sequence permutation in the domain where the active site is anchored. This architecture is also found in double-stranded RNA viruses of the Birnaviridae family. Here we report the purification and preliminary crystallographic studies TaV RdRp. The enzyme was crystallized by the sitting drop vapour diffusion method using PEG 8K and lithium sulfate as precipitants. Two different crystal forms were obtained: native RdRp crystallized in space group P2(1)2(1)2 and diffracts up to 2.1 A and the RdRp-Lu(3+) derivative co crystals belong to the C222(1) space group, diffracting to 3.0 A resolution. The structure of TaV RdRp represents the first structure of a non-canonical RdRp from ssRNA viruses. PMID- 23027764 TI - Recombinant portal protein from Staphylococcus epidermidis bacteriophage CNPH82 is a 13-subunit oligomer. AB - The portal protein cn3 of bacteriophage CNPH82 is predicted to serve as a gateway for translocation of viral genome into preformed pro-capsid, like portal proteins from other double-stranded DNA tailed bacteriophages. The host of bacteriophage CNPH82 is the opportunistic human pathogenic bacterium Staphylococcus epidermidis, a major cause of nosocomial infections. The portal protein of this phage has been cloned, overexpressed and purified. Size-exclusion chromatography multi-angle laser light scattering analysis has indicated that the portal protein contains ~13 subunits. Crystals of the portal protein, diffracting to 4.2 A, have been obtained. These crystals belong to the space group C222(1) with the unit cell parameters of a = 252.4, b = 367.0, c = 175.5 A. The self-rotation function revealed the presence of a single 13-subunit oligomer in the asymmetric unit. PMID- 23027765 TI - Low body weight and menstrual dysfunction are common findings in both elite and amateur ballet dancers. AB - BACKGROUND: Several studies have reported that low body weight and menstrual alterations are very frequent findings in elite dancers, suggesting they could be at risk for associated medical problems. However, it is still largely unknown whether these alterations are also common in the very large number of young amateur dancers. AIM: The aim of this study was to assess whether there is an increased prevalence of menstrual dysfunction also in amateur dancers. MATERIAL/SUBJECTS AND METHODS: Ninety-two professional ballet dancers, 93 non professional ballet dancers, and 293 (160 sedentary, 133 physically active) control women, ranging in age 14-23 yr, were included in the study. In these subjects, a detailed questionnaire that included questions on weight, height, age at menarche, training profile and menstrual alterations was administered. RESULTS: BMI was lower in both professional and non-professional dancers than in controls. Frequency of menstrual dysfunction was 51%, 34% and 21% in professional dancers, non-professional dancers and controls, respectively (p<0.0001). Amenorrhea was reported by 23% of professional dancers, vs 1-7% in the other groups (p<0.0001). Age at menarche occurred later in professional dancers than in the other groups. Logistic regression analyses showed that menstrual dysfunction was associated with the training profile in professional dancers, and with BMI in non-professional dancers. Age at menarche was associated with menstrual dysfunction in both groups. CONCLUSIONS: This study shows that low body weight and menstrual dysfunction are frequent findings also in amateur ballet dancers. PMID- 23027766 TI - A perfect storm: a window of opportunity for revolution in nurse practitioner education. PMID- 23027767 TI - Virtual clinical rounds in a multiuser virtual environment. PMID- 23027768 TI - Evaluating student learning in an undergraduate pharmacology nursing course using pharmacology timed tables. PMID- 23027771 TI - Steps for strengthening the health education profession. AB - Since its founding in 1950, the Society for Public Health Education (SOPHE) has evolved in response to the changing needs of both the public and the profession. This SOPHE Presidential Address provides a brief review of SOPHE's history and the legacy of its achievements over some 60 years. It also describes how new challenges being created by the pending organizational realignment between SOPHE and the American Association for Health Education, which promises to further unify the profession, along with changing American community demographics, can provide an opportunity for SOPHE to strengthen the health education profession by becoming more inclusive and further redefining Dorothy Nyswander's concept of the "Open Society" and the role health educators play as agents of change. PMID- 23027769 TI - Phalangeal quantitative ultrasound and metabolic control in pre-menopausal women with type 1 diabetes mellitus. AB - BACKGROUND: Several studies have reported increased fracture risk in Type 1 diabetes mellitus (T1DM). Quantitative Ultrasound (QUS) provides information on the structure and elastic properties of bone, which are important determinants of fracture risk, along with bone mineral density. AIM: To study phalangeal sites by QUS, examine bone turnover markers and analyze association between these factors with metabolic control in a population of pre-menopausal women with T1DM. MATERIAL AND METHODS: Thirty-five T1DM pre-menopausal women (mean age 34.5 +/- 6.8 yr) attending the Diabetic Outpatients Clinic in the Department of Internal Medicine, University of Messina, were consecutively enrolled and divided into two groups, taking into account the mean value of glycated hemoglobin in the last three years. Twenty healthy age-matched women served as controls. Phalangeal ultrasound measurements [Amplitude Dependent Speed of Sound (AD-SoS), Ultrasound Bone Profile Index (UBPI), TScore, Z-Score] were performed using a DBM Sonic Bone Profiler. Osteocalcin and deoxypyridinoline served as markers of bone formation and bone resorption, respectively. RESULTS: T1DM women with poor metabolic control showed lower phalangeal QUS values compared to healthy controls (p<0.01) and T1DM women with good metabolic control (p<0.05). No significant differences in QUS measurements were detected between T1DM women with good metabolic control and healthy controls. Lower bone formation and increased bone resorption, although not statistically significant, were observed in patients with poor metabolic control in comparison to patients with good metabolic control. CONCLUSIONS: Poor metabolic control may worsen the quality of bone in T1DM. Phalangeal QUS could be considered as a tool to screen T1DM women for osteoporosis in pre-menopausal age. PMID- 23027772 TI - Integrating health promotion in the national agenda: the perspective of a grassroots advocate. PMID- 23027770 TI - Growth hormone variants: a potential avenue for a better diagnostic characterization of growth hormone deficiency in children. AB - Human GH (hGH) is a heterogeneous protein hormone consisting of several isoforms. This heterogeneity is the consequence of multiple hGH genes, mRNA splicing, post translational modifications, and peripheral metabolism, and it represents one important reason for the disparity among GH assay results from different laboratories. However, other factors are involved: a) interference from endogenous GH binding proteins; b) different specificities of anti- GH (monoclonal and polyclonal) antibodies; c) different matrix effects among the calibrators; d) the use of different calibrators. The measurement of GH levels in response to provocative testing is an essential part of the diagnosis of GH deficiency. For this purpose, an accurate, reproducible and universally valid GH measurement would be highly desirable, but, despite a huge number of efforts in clinical biochemistry, this goal remains elusive. PMID- 23027773 TI - Interface-induced crystalline ordering and favorable morphology for efficient annealing-free poly(3-hexylthiophene): fullerene derivative solar cells. AB - A simple approach to fabricate high-efficiency annealing-free poly(3 hexylthiophene): [6,6]-phenyl C(61)-butyric acid methyl ester (P3HT:PCBM) solar cells is reported by using p-type CuI to substitute PEDOT:PSS as anode buffer layer. It is found that the P3HT:PCBM blend films deposited on CuI surface show different orientation of crystalline P3HT domains and phase separation from those deposited on PEDOT:PSS surface. A nanoscale phase separation of P3HT and PCBM with domain sizes about 10-30 nm is formed for the P3HT:PCBM blend films deposited on CuI surface. Absorption and grazing incidence X-ray diffraction (GIXRD) experiments indicate that the CuI layer not only induces the self organization of P3HT chains into well-ordered structure but also results in the vertical orientation of pi-pi stacking planes of P3HT with respect to the substrate which is favorable for the hole collection in polymer solar cells. Hole transport investigation discloses that hole mobility of the as-spincast P3HT:PCBM blend film on CuI surface is increased with 3 orders of magnitude compared to the P3HT:PCBM film deposited on PEDOT:PSS. A power conversion efficiency of 3.1% for the as-spincast P3HT:PCBM solar cell with CuI buffer layer is about 4-fold enhancement compared to 0.83% of the control device with PEDOT:PSS, and is comparable to the reported P3HT:PCBM solar cells subjected to post thermal treatments. This work implies that interfacial engineering is a promising approach for manipulating morphology of active layer and can potentially simplify the process and shorten the fabrication time of polymer solar cells in low-cost roll-to-roll manufacturing. PMID- 23027774 TI - Mutational characterization of congenital adrenal hyperplasia due to 21 hydroxylase deficiency in Malaysia. AB - BACKGROUND AND AIM: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder. Our objective was to identify the 21-hydroxylase active gene, CYP21A2 mutations in Malaysian 21-OHD patients using different techniques. MATERIALS AND METHODS: Blood samples were obtained from 97 Malaysian 21-OHD patients, which included 40 siblings from 19 families. We used various techniques which include restriction enzyme digestion, Southern blot, multiple ligation-dependent probe amplification (MLPA) and sequencing to elucidate CYP21A2 mutations. RESULTS: Homozygous and compound heterozygous mutations were identified in 95 of the 97 patients (98%). Deletions of CYP21A2 were found in 43 patients (44.3%). Deletions identified in CYP21A2 gene were the usual 30-kb deletion comprising 3'UTR CYP21A1P, C4B and 5'CYP21A2, complete deletion of CYP21A2 gene, deletion in exons 1-3, exons 1-6 and exons 1-8 of CYP21A2. The common mutations identified in CYP21A2 gene were deletion/conversion (22.6%), p.R356W (22%), IVS2-13A/C>G (21.3%), p.I172N (5.3%), p.Q318X (5.3%), and p.P30L (1.03%). This is the first report of the mutation frequency in CYP21A2 gene among the Malay ethnic group. Two novel mutations, c.Y97insT and p.L345P were identified in our patients. Our results show good phenotype-genotype correlation in most of the cases, although clinical variations were identified in some patients. CONCLUSIONS: The study has found various mutations including deletions in CYP21A2 gene in Malaysian patients with 21 hydroxylase deficiency using the MLPA technique that is being widely used in present laboratory settings. PMID- 23027775 TI - A pronounced dispersion effect of crystalline silicon nanoparticles on the performance and stability of polymer:fullerene solar cells. AB - We investigated the dispersion effect of crystalline silicon nanoparticles (SiNP) on the performance and stability of organic solar cells with the bulk heterojunction (BHJ) films of poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl C(61)-butyric acid methyl ester (PC(61)BM). To improve the dispersion of SiNP in the BHJ films, we attached octanoic acid (OA) to the SiNP surface via esterification reaction and characterized it with Raman spectroscopy and high resolution transmission electron microscopy. The OA-attached SiNP (SiNP-OA) showed improved dispersion in chlorobenzene without change of optical absorption, ionization potential and crystal nanostructure of SiNP. The device performance was significantly deteriorated upon high loading of SiNP (10 wt %), whereas relatively good performance was maintained without large degradation in the case of SiNP-OA. Compared to the control device (P3HT:PC(61)BM), the device performance was improved by adding 2 wt % SiNP-OA, but it was degraded by adding 2 wt % SiNP. In particular, the device stability (lifetime under short time exposure to 1 sun condition) was improved by adding 2 wt % SiNP-OA even though it became significantly decreased by adding 2 wt % SiNP. This result suggests that the dispersion of nanoparticles greatly affects the device performance and stability (lifetime). PMID- 23027780 TI - The importance of illness perceptions, quality of life and psychological status in patients with ulcerative colitis and Crohn's disease. AB - The present study investigates illness perceptions of inflammatory bowel disease patients in an outpatient population, examining whether these illness perceptions are related to disease severity, quality of life and psychological adjustment. A cohort of 102 inflammatory bowel disease outpatients was prospectively enrolled on the study. The participants completed a questionnaire assessing illness perceptions, anxiety, depression and disease-specific symptoms. The study has identified specific illness perceptions of inflammatory bowel disease sufferers that are strongly associated with patients' quality of life. By raising and addressing these issues, clinicians may be able to allay these significant and often unexpressed concerns, and improve quality of life for patients with inflammatory bowel disease. PMID- 23027776 TI - Interferon-gamma inhibits integrin-mediated extracellular signal-regulated kinase activation stimulated by fibronectin binding in thyroid cells. AB - Hashimoto's thyroiditis (HT) is an autoimmune disorder characterized by the presence of specific antibodies and by a lymphocytic infiltration of the thyroid secreting inflammatory cytokines. Macrophages, lymphocytes, and cytokines play a pivotal role in both development and progression of Th1-mediated autoimmune diseases, and a direct role in the destruction of thyroid follicles and follicular cell function in autoimmune thyroiditis. Integrins are integral membrane receptors involved in cell-extra-cellular matrix (ECM) interaction with both structural and signaling functions. The integrin- ECM interaction is necessary for the correct function and survival of thyroid follicular cells. The purpose of this study was to determine the effect of cytokine stimulation on integrin expression and signaling in the thyroid cell. Primary cultures from normal thyroids were treated with interferon-gamma (IFN-gamma), INF-alpha, tumor necrosis factor-alpha, interleukin 1a or these cytokines all together. Integrin expression, cell adhesion to fibronectin (FN) and FN-stimulated extracellular signal-regulated kinase (ERK) phosphorylation were determined after cytokine treatment. IFN-gamma and IFN-alpha were the most effective, reducing the expression of the integrin alphavbeta3 and slightly increasing the alpha3beta1. Cell treatment with IFN-gamma strongly impaired cell adhesion to FN. At the same time, the treatment with IFN-gamma dramatically inhibited the stimulation of ERK phosphorylation induced by cell adhesion to FN. In conclusion, IFN-gamma inhibits the expression of the integrin alphavbeta3, reducing the cell adhesion to FN and the following intracellular signaling in thyroid cells in culture. These results suggest that integrins may be a target of the infiltrating lymphocytes and have a role in the pathogenesis of autoimmune thyroiditis. PMID- 23027781 TI - A non-randomised trial of an art therapy intervention for patients with haematological malignancies to support post-traumatic growth. AB - The aim of this study was to determine the effect of art therapy on post traumatic growth in patients with haematological malignancies in a non-randomised trial (n = 36, intervention group; n = 129, control group). Art therapy was administered over a period of 22 weeks in small groups. Post-traumatic growth was measured with the Stress-Related Growth Scale. After controlling for the effect of potential confounders, no difference in post-traumatic growth was observed between the intervention and control groups after 22 weeks. There was no evidence for an effect of weekly group sessions with art therapy on post-traumatic growth in patients with haematological malignancies. PMID- 23027782 TI - Healthy Eating for Life English as a second language curriculum: primary outcomes from a nutrition education intervention targeting cancer risk reduction. AB - We conducted a pre-post feasibility trial of Healthy Eating for Life, a theory based, multimedia English as a second language curriculum that integrates content about healthy nutrition into an English language learning program to decrease cancer health disparities. Teachers in 20 English as a second language classrooms delivered Healthy Eating for Life to 286 adult English as a second language students over one semester. Postintervention data are available for 227 students. The results indicated that Healthy Eating for Life is effective for increasing fruit and vegetable intake as well as knowledge, action planning, and coping planning related to healthy eating. Participants also achieved higher reading scores compared to the state average. PMID- 23027783 TI - Judgments about illegal performance-enhancing substances: reasoned, reactive, or both? AB - This study applied aspects of the Theory of Reasoned Action and the Prototype/Willingness model to understand cognitions associated with the use of illegal performance-enhancing substances. There were two study objectives. One was to investigate whether the illegal-is-effective heuristic (i.e. belief that illegal performance-enhancing substances are more effective than legal performance-enhancing substances) affects willingness to use illegal performance enhancing substances. The second was to examine whether attitudes, norms, and prototypes influence the willingness and intentions to use illegal performance enhancing substances. The illegal-is-effective heuristic was a significant predictor of willingness but was not a significant predictor of intentions. Implications for future research and prevention efforts are discussed. PMID- 23027784 TI - Gendering attention deficit hyperactivity disorder: a discursive analysis of UK newspaper stories. AB - Discursive psychology is used to study the gendering of attention deficit hyperactivity disorder in UK national newspapers in the period of 2009-2011. The analysis examines how gendering is embedded in causal attributions and identity constructions. Attention deficit hyperactivity disorder is portrayed as a predominantly male phenomenon with representations of attention deficit hyperactivity disorder being gendered through extreme stories about victims, villains or heroes that depict boys and men as marginalised, exceptional or dangerous. There is also a focus on mothers as the spokespersons and caretakers for parenting and family health while fathers are rendered more invisible. This contributes to our understanding of how attention deficit hyperactivity disorder is constructed in the media using a range of gendered representations that draw on cultural stereotypes familiar in Western societies. PMID- 23027786 TI - The drug shortage: what Critical Care Nurse readers report. PMID- 23027787 TI - Experiencing the Synergy Model on a personal level. PMID- 23027788 TI - Managing risk of complications at femoral vascular access sites in percutaneous coronary intervention. AB - Percutaneous coronary intervention for acute coronary syndrome or non-ST elevation myocardial infarction requires the use of potent oral and intravenous anti-platelet and antithrombin medications. Although these potent antithrombotic agents and regimens may increase the effectiveness of percutaneous coronary intervention, they are also generally associated with an increased risk of vascular access complications such as hematoma, retroperitoneal hematoma, pseudoaneurysm, arterial occlusion, and arteriovenous fistula, which in turn are associated with increased morbidity, mortality, and costs. Risk factors predisposing patients to these complications are both modifiable (procedure technique, medications, hemostasis method) and nonmodifiable (sex, age, body mass index, blood pressure, renal function). Patients' risks can be reduced by nurses who are knowledgeable about these risk factors and identify complications before they become problematic. PMID- 23027789 TI - Acquired long QT syndrome: frequency, onset, and risk factors in intensive care patients. AB - BACKGROUND: Acquired long QT syndrome is a reversible condition that can lead to torsades de pointes and sudden cardiac death. OBJECTIVE: To determine the frequency, onset, frequency of medications, and risk factors for the syndrome in intensive care patients. METHODS: In a retrospective chart review of 88 subjects, hourly corrected QT intervals calculated by using the Bazett formula were collected. Acquired long QT syndrome was defined as a corrected QT of 500 milliseconds or longer or an increase in corrected QT of 60 milliseconds or greater from baseline level. Risk factors and medications administered were collected from patients' medical records. RESULTS: The syndrome occurred in 46 patients (52%); mean time of onset was 7.4 hours (SD, 9.4) from time of admission. Among the 88 patients, 52 (59%) received a known QTc-prolonging medication. Among the 46 with the syndrome, 23 (50%) received a known QT prolonging medication. No other risk factor studied was significantly predictive of the syndrome. CONCLUSIONS: Acquired long QT syndrome occurs in patients not treated with a known QT-prolonging medication, indicating the importance of frequent QT monitoring of all intensive care patients. PMID- 23027790 TI - Beyond the bloody mess: hematologic assessment. AB - Hematologic assessment is part of the routine assessment of acute and critically ill patients. Nurses must be aware of the reference ranges for complete blood cell counts and common coagulation profiles. A case study is presented of an elderly patient, taking warfarin for atrial fibrillation, who falls and sustains a head laceration. The subsequent assessment, hospital course, and treatments required are outlined. PMID- 23027791 TI - Coagulopathy in the intensive care unit. AB - Coagulopathy is a potential problem for many critically ill patients, placing them at risk for hemorrhage. Critical illness activates both hemostasis and the inflammatory-immune system, leading to both physiological and potentially pathophysiological responses. Following complex surgery or trauma, patients are at high risk for development of problems such as thrombocytopenia and postoperative bleeding, challenging nurses to recognize and manage these problems. The clinical manifestations of coagulopathy may be obvious or occult, and correlation with the coagulation panel results is a complex process. Transfusion of blood and components has long been an important part of patient management, but is known to put patients at risk for transfusion-related complications. Current clinical practice guidelines provide blood conservation strategies and criteria to guide decisions on transfusion therapy. PMID- 23027792 TI - Patients' confidentiality. AB - Critical care providers are often privy to confidential information in the course of clinical practice. A dilemma can arise when confidential information is requested by family members or friends of the patient. Critical care nurses must be aware of the regulations regarding confidentiality, as well as situations where the use and disclosure of protected health information are permitted. PMID- 23027793 TI - Normal saline and mucous plugging. PMID- 23027794 TI - Showing we care with hugs and kisses. PMID- 23027796 TI - I am a critical care nurse. PMID- 23027798 TI - Flavonoid insertion into cell walls improves wood properties. AB - Wood has an excellent mechanical performance, but wider utilization of this renewable resource as an engineering material is limited by unfavorable properties such as low dimensional stability upon moisture changes and a low durability. However, some wood species are known to produce a wood of higher quality by inserting mainly phenolic substances in the already formed cell walls- a process so-called heartwood formation. In the present study, we used the heartwood formation in black locust (Robinia pseudoacacia) as a source of bioinspiration and transferred principles of the modification in order to improve spruce wood properties (Picea abies) by a chemical treatment with commercially available flavonoids. We were able to effectively insert hydrophobic flavonoids in the cell wall after a tosylation treatment for activation. The chemical treatment reduced the water uptake of the wood cell walls and increased the dimensional stability of the bulk spruce wood. Further analysis of the chemical interaction of the flavonoid with the structural cell wall components revealed the basic principle of this bioinspired modification. Contrary to established modification treatments, which mainly address the hydroxyl groups of the carbohydrates with hydrophilic substances, the hydrophobic flavonoids are effective by a physical bulking in the cell wall most probably stabilized by pi pi interactions. A biomimetic transfer of the underlying principle may lead to alternative cell wall modification procedures and improve the performance of wood as an engineering material. PMID- 23027797 TI - Mechanisms of human atrial fibrillation initiation: clinical and computational studies of repolarization restitution and activation latency. AB - BACKGROUND: Mechanisms of atrial fibrillation (AF) initiation are incompletely understood. We hypothesized that rate-dependent changes (restitution) in action potential duration (APD) and activation latency are central targets for clinical interventions that induce AF. We tested this hypothesis using clinical experiments and computer models. METHODS AND RESULTS: In 50 patients (20 persistent, 23 paroxysmal AF, 7 controls), we used monophasic action potential catheters to define left atrial APD restitution, activation latency, and AF incidence from premature extrastimuli. Isoproterenol (n=14), adenosine (n=10), or rapid pacing (n=36) was then initiated to determine impact on these parameters. Compared with baseline in AF patients, isoproterenol and rapid pacing decreased activation latency (64+/-14 versus 31+/-13 versus 24+/-14 ms; P<0.05), steepened maximum APD restitution slope (0.8+/-0.7 versus 1.7+/-0.5 versus 1.1+/-0.5; P<0.05), and increased AF incidence (12% versus 64% versus 84%; P<0.05). Conversely, adenosine shortened APD (P<0.05), yet increased activation latency (86+/-27 ms; P=0.002) so that maximum APD restitution slope did not steepen (1.0+/-0.5; P=NS), and AF incidence was unchanged (10%; P=NS). In controls, no intervention steepened APD restitution or initiated AF. Computational modeling revealed that isoproterenol steepened APD restitution by increased L-type calcium current and decreased activation latency via enhanced rapid delayed potassium reactifier current inactivation, whereas rapid pacing steepened APD restitution via increased cardiac inward potassium rectifier current. CONCLUSIONS: Steep APD restitution is a common pathway for AF initiation by isoproterenol and tachycardia via reduced activation latency that enables engagement of steep APD restitution at rapid rates. Modeling suggests that AF initiation from each intervention uses distinct ionic mechanisms. This insight may help design interventions to prevent AF. PMID- 23027799 TI - Diffusion of Ag into organic semiconducting materials: a combined analytical study using transmission electron microscopy and X-ray reflectivity. AB - This study shows that the morphology of organic/metal interfaces strongly depends on process parameters and the involved materials. The interface between organic n type blocking layer materials and the top Ag cathode within an organic photodiode was investigated. Ag was deposited on either amorphous tris-8-hydroxyquinolinato aluminum (Alq(3)) or crystalline 4,7-diphenyl-1,10-phenanthroline (Bphen) using different deposition techniques such as electron beam deposition, ion beam sputtering, and vacuum thermal evaporation at various deposition rates. The interfaces were studied by transmission electron microscopy and X-ray reflectivity. It was found that Bphen does not show any Ag diffusion no matter which deposition technique was used, whereas the Ag diffusion into Alq(3) depends on the deposition technique and the deposition rate. The highest amount of Ag diffusion into Alq(3) occurred by using thermal vacuum deposition at low deposition rates. PMID- 23027800 TI - Improving the management of warfarin may be easier than we think. PMID- 23027801 TI - Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: an analysis of patients receiving warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. AB - BACKGROUND: The outcome of atrial fibrillation patients on warfarin partially depends on maintaining adequate time in therapeutic International Normalized Ratio range (TTR). Large differences in TTR have been reported between centers and countries. The association between warfarin dosing practice, TTR, and clinical outcomes was evaluated in Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial patients receiving warfarin. METHODS AND RESULTS: RE-LY provided an algorithm for warfarin dosing, recommending no change for in-range, and 10% to 15% weekly dose changes for out-of-range International Normalized Ratio values. We determined whether dose adjustments were consistent with algorithm recommendations but could not verify whether providers used the algorithm. Using multilevel regression models to adjust for patient, center, and country characteristics, we assessed whether algorithm-consistent warfarin dosing could predict patient TTR and the composite outcome of stroke, systemic embolism, or major hemorrhage. We included 6022 nonvalvular atrial fibrillation patients from 912 centers in 44 countries. We found a strong association between the proportion of algorithm-consistent warfarin doses and mean country TTR (R(2)=0.65). The degree of algorithm-consistency accounted for 87% of the between center and 55% of the between-country TTR variation. Each 10% increase in center algorithm-consistent dosing independently predicted a 6.12% increase in TTR (95% confidence interval, 5.65-6.59) and an 8% decrease in rate of the composite clinical outcome (hazard ratio, 0.92; 95% confidence interval, 0.85-1.00). CONCLUSIONS: Adherence, intentional or not, to a simple warfarin dosing algorithm predicts improved TTR and accounts for considerable TTR variation between centers and countries. Systems facilitating algorithm-based warfarin dosing could optimize anticoagulation quality and improve clinical outcomes in atrial fibrillation on a global scale. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600. PMID- 23027802 TI - Molecular simulation for gas adsorption at NiO (100) surface. AB - Density functional theory (DFT) calculations have been employed to explore the gas-sensing mechanisms of NiO (100) surface on the basis of energetic and electronic properties. We have calculated the adsorption energies of NO(2), H(2)S, and NH(3) molecules on NiO (100) surface using GGA+U method. The calculated results suggest that the interaction of NO(2) molecule with NiO surface becomes stronger and contributes more extra peaks within the band gap as the coverage increases. The band gap of H(2)S-adsorbed systems decrease with the increase in coverage up to 0.5 ML and the band gap does not change at 1 ML because H(2)S molecules are repelled from the surface. In case of NH(3) molecular adsorption, the adsorption energy has been increased with the increase in coverage and the band gap is directly related to the adsorption energy. Charge transfer mechanism between the gas molecule and the NiO surface has been illustrated by the Bader analysis and plotting isosurface charge distribution. It is also found that that work function of the surfaces shows different behavior with different adsorbed gases and their coverage. The work function of NO(2) gas adsorption has a hill-shaped behavior, whereas H(2)S adsorption has a valley shaped behavior. The work function of NH(3) adsorption decreases with the increase in coverage. On the basis of our calculations, we can have a better understanding of the gas-sensing mechanism of NiO (100) surface toward NO(2), H(2)S, and NH(3) gases. PMID- 23027803 TI - Ross-Konno procedure in infants: mid-term results. AB - OBJECTIVES: The aim of study was to analyse the mid-term results of the Ross Konno procedure in infants. METHODS: Between 2000 and 2011, 16 infants, including five newborns, with complex left ventricular outflow tract (LVOT) obstruction underwent the Ross-Konno procedure. Twelve patients (75%) required multiple concomitant procedures such as: mitral valve (MV) surgery (four patients), resection of endocardial fibroelastosis (EFE) and myectomy (six patients), closure of ventricular septal defect (four patients) and aortic arch reconstruction (three patients). The median age at operation was 4.2 months (from 6 to 333 days). RESULTS: There was one late death with a median follow-up of 6.2 years. Actuarial survival is 93.3% at 5 years follow-up (95% confidence interval: 61.2-99.0). Postoperatively, two patients required extracorporeal membrane oxygenation support and one MV replacement. The median length of stay in hospital was 30 days (from 11 to 77 days). At 5 years of follow-up, seven patients had no aortic regurgitation (AR) and nine patients (56%) had trivial AR with no gradient in LVOT. Freedom from mitral regurgitation (MR) >= moderate or MV replacement was 70%. MR was associated with either structural abnormalities of MV or with development of EFE. Freedom from redo was 81 and 53% at 1 and 5 years of follow up. Sixty percent of patients are without medication. All patients are in sinus rhythm. CONCLUSIONS: With the technical aspects of this procedure well accomplished, the risk of surgery is minimal and functional outcome is encouraging. However, early postoperative morbidity is significant. At the mid term follow-up, there was no residual or recurrent outflow tract obstruction and excellent function of the neoaortic valve. A high incidence of MR associated with the development of EFE and structural abnormalities of the MV is worrisome; however, concomitant MV surgery is not associated with increased mortality. In the case of the development of EFE, an early indication for operation might protect MV function. The reoperation rate is high due to early conduit failure. PMID- 23027804 TI - Mechanisms in endocrinology. Role of emotional stress in the pathophysiology of Graves' disease. AB - The role of stress in the pathophysiology of Graves' disease is suggested by several clinical observations, by recent advances in immunology and by better understanding of autoimmune diseases which provides new insights into potential effects of stress hormones on T helper cell imbalance involved in the pathogenesis of autoimmune diseases. Stress management should therefore be an important part of the treatment of Graves' disease, as stress reduction may improve the effect of therapy. However, this field still requires interventional data to support stress management in the treatment of Graves' disease. PMID- 23027806 TI - Mammary gland morphology and gene expression differ in female rats treated with 17beta-estradiol or fed soy protein isolate. AB - Soy foods have been suggested to have both positive health benefits and potentially adverse effects as a result of their content of phytoestrogens. However, studies on the estrogenicity of soy foods are lacking. Here we directly compared the effects of soy protein isolate (SPI), the protein in soy infant formula, with those of 17beta-estradiol (E2), on global gene expression profiles and morphology in the female rat mammary gland. Rats were fed AIN-93G diets containing casein or SPI beginning on postnatal d 30. Rats were ovariectomized on postnatal d 50 and treated with 5 MUg/kg/d E2 or vehicle for 14 d. Microarray analysis revealed that E2 treatment altered expression of 780 genes more than or equal to 2-fold (P < 0.05), whereas SPI feeding altered expression of only 53 genes more than or equal to 2-fold. Moreover, the groups had only 10 genes in common to increase more than or equal to 2-fold. The combination of SPI feeding and E2 altered expression of 422 genes and reversed E2 effects on many mRNAs, including those involved in the c-myc signaling pathway, cyclin D1, and Ki67. ERalpha binding to its response element on the Tie-2/Tek and progesterone receptor promoters was increased by E2, but not SPI, and this promoter binding was suppressed by the combination of E2 + SPI for the Tie-2/Tek promoter but increased for the progesterone receptor promoter (P < 0.05). SPI reduced the ratio of epithelial to fat pad area and E2 + SPI reduced both epithelial and fat pad area (P < 0.05). These data suggest that SPI is only minimally estrogenic in the rat mammary gland even in the absence of endogenous estrogens. PMID- 23027805 TI - Apolipoprotein AIV requires cholecystokinin and vagal nerves to suppress food intake. AB - Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are gastrointestinal satiation signals that are stimulated by fat consumption. Previous studies have demonstrated that peripheral apo AIV cannot cross the blood-brain barrier. In the present study, we hypothesized that peripheral apo AIV uses a CCK-dependent system and intact vagal nerves to relay its satiation signal to the hindbrain. To test this hypothesis, CCK-knockout (CCK-KO) mice and Long-Evan rats that had undergone subdiaphragmatic vagal deafferentation (SDA) were used. Intraperitoneal administration of apo AIV at 100 or 200 MUg/kg suppressed food intake of wild type (WT) mice at 30, 60, and 90 min. In contrast, the same dose did not reduce food intake in the CCK-KO mice. Blockade of the CCK 1 receptor by lorglumide, a CCK 1 receptor antagonist, attenuated apo AIV-induced satiation. Apo AIV at 100 MUg/kg reduced food intake in SHAM rats but not in SDA rats. Furthermore, apo AIV elicited an increase in c-Fos-positive cells in the nucleus of the solitary tract (NTS), area postrema, dorsal motor nucleus of the vagus, and adjacent areas of WT mice but elicited only an attenuated increase in these same regions in CCK-KO mice. Apo AIV-induced c-Fos positive cells in the NTS and area postrema of WT mice were reduced by lorglumide. Lastly, apo AIV increased c-Fos positive cells in the NTS of SHAM rats but not in SDA rats. These observations imply that peripheral apo AIV requires an intact CCK system and vagal afferents to activate neurons in the hindbrain to reduce food intake. PMID- 23027807 TI - Oxidant stress and mitochondrial signaling regulate reversible changes of ERalpha expression and apoptosis in aging mouse glomeruli and mesangial cells. AB - Estrogen actions are largely dependent on the intracellular estrogen receptor (ER) levels. During aging the decline of estrogens or ER leads to a loss in antiinflammatory protection and an increase in oxidant stress due to changes in mitochondrial function. Estrogens/ER may also coordinate signaling between the nucleus and mitochondria through ERK activation, which paradoxically decreases ER expression. The changes in ER expression and transcriptional activation that occur with aging as well as the mitochondria-to-nuclear signaling pathways have not been studied in the glomerulus. We found that ER expression and transcriptional activation decreased with age. Whereas ER levels decreased by greater than 90%, serum 17beta-estradiol levels decreased by less than 30%, suggesting alternative mechanisms for ER decrease. Because we postulated that this was due in part to age-related oxidant stress, we treated mesangial cells (MCs) with ethidium bromide (EtBr) to deplete mitochondria. EtBr treatment resulted in decreased ERK activation and reactive oxygen species, which were associated with increased ERalpha expression and transcriptional activation in old MCs. EtBr treatment also decreased apoptosis and caspase-9 protein expression in old MCs. These data suggest that loss of several of the functions of 17beta estradiol during aging could be mainly due to decreased ERalpha expression, that the ER loss is reversible by reducing reactive oxygen species, and that mitochondrial retrograde signaling plays a role in this regulation. PMID- 23027808 TI - Chronic administration of the metastin/kisspeptin analog KISS1-305 or the investigational agent TAK-448 suppresses hypothalamic pituitary gonadal function and depletes plasma testosterone in adult male rats. AB - Metastin/kisspeptin, a hypothalamic peptide, plays a pivotal role in controlling GnRH neurons. Here we studied the effect of chronic sc administration of two kisspeptin analogs, KISS1-305 and TAK-448, on hypothalamic-pituitary-gonadal function in male rats in comparison with a GnRH analogue leuprolide or bilateral orchiectomy (ORX). The prototype polypeptide, KISS1-305 (1-4 nmol/h), caused substantial elevations of plasma LH and testosterone, followed by abrupt reductions of both hormone levels. Notably, testosterone levels were reduced to castrate levels within 3 d and remained depleted throughout the 4-wk dosing period, an effect that was faster and more pronounced than leuprolide (1 nmol/h) dosing. KISS1-305 also reduced genital organ weight more profoundly than leuprolide. In mechanistic studies, chronic KISS1-305 administration only transiently induced c-Fos expression in GnRH neurons, suggesting that GnRH-neural response was attenuated over time. Hypothalamic GnRH content was reduced to 10 20% of control at 3 wk without any changes in Gnrh mRNA expression. Dosing with the investigational peptide TAK-448 was also studied to extend our understanding of hypothalamic-pituitary functions. Similar to ORX, TAK-448 (0.1 nmol/h) depleted testosterone and decreased GnRH content by 4 wk. However, in contrast to ORX, TAK-448 decreased gonadotropin levels in pituitary and plasma samples, implying the suppression of GnRH pulses. These results suggest that chronic administration of kisspeptin analogs disrupts endogenous kisspeptin signals to suppress intrinsic GnRH pulses, perhaps by attenuating GnRH-neural response and inducing continuous GnRH leakage from the hypothalamus. The potential utility of kisspeptin analogs as novel agents to treat hormone-related diseases, including prostate cancer, is discussed. PMID- 23027809 TI - Vascular disease in a dish: all the right ingredients? PMID- 23027810 TI - Directing TRAF-ic: cell-specific TRAF6 signaling in chronic inflammation and atherosclerosis. PMID- 23027811 TI - Epicardial interventions in electrophysiology. PMID- 23027813 TI - Invasive aspergillosis: extensive cardiac involvement demonstrated by cardiac magnetic resonance. PMID- 23027812 TI - Childhood obesity. PMID- 23027814 TI - Early diagnosis of abscess in aortic bioprosthetic valve by 18F fluorodeoxyglucose positron emission tomography-computed tomography. PMID- 23027817 TI - Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain. AB - In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca(2+) indicator in the MBs, we investigated synaptic transmission and plasticity at the AL-MB synapse. Following stimulation with a glass micro-electrode, AL induced Ca(2+) responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca(2+) responses were mediated through Drosophila NMDA receptors (dNRs). AL-MB synaptic transmission was enhanced more than 2 h after the simultaneous 'associative-stimulation' of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL MB synapses but not at the AFV-MB synapses. AL-MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL-MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL-MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL-MB LTE might be a relevant cellular model for olfactory memory. PMID- 23027816 TI - Blood pressure and water regulation: understanding sex hormone effects within and between men and women. AB - Cardiovascular disease remains the leading cause of death for both men and women. Hypertension is less prevalent in young women compared with young men, but menopausal women are at greater risk for hypertension compared with men of similar age. Despite these risks, women do not consistently receive first line treatment for the early stages of hypertension, and the greater morbidity in menopause reflects this neglect. This review focuses on ovarian hormone effects on the cardiovascular and water regulatory systems that are associated with blood pressure control in women. The study of ovarian hormones within young women is complex because these hormones fluctuate across the menstrual cycle, and these fluctuations can complicate conclusions regarding sex differences. To better isolate the effects of oestrogen and progesterone on the cardiovascular and water regulation systems, we developed a model to transiently suppress reproductive function followed by controlled hormone administration. Sex differences in autonomic regulation of blood pressure appear related to ovarian hormone exposure, and these hormonal differences contribute to sex differences in hypertension and orthostatic tolerance. Oestrogen and progesterone exposure are also associated with plasma volume expansion, and a leftward shift in the osmotic operating point for body fluid regulation. In young, healthy women, the shift in osmoregulation appears to have only a minor effect on overall body water balance. Our overarching conclusion is that ovarian hormone exposure is the important underlying factor contributing to differences in blood pressure and water regulation between women and men, and within women throughout the lifespan. PMID- 23027818 TI - Quantifying Ca2+ release and inactivation of Ca2+ release in fast- and slow twitch muscles. AB - The aims of this study were to quantify the Ca(2+) release underlying twitch contractions of mammalian fast- and slow-twitch muscle and to comprehensively describe the transient inactivation of Ca(2+) release following a stimulus. Experiments were performed using bundles of fibres from mouse extensor digitorum longus (EDL) and soleus muscles. Ca(2+) release was quantified from the amount of ATP used to remove Ca(2+) from the myoplasm following stimulation. ATP turnover by crossbridges was blocked pharmacologically (N-benzyl-p-toluenesulphonamide for EDL, blebbistatin for soleus) and muscle heat production was used as an index of Ca(2+) pump ATP turnover. At 20 degrees C, Ca(2+) release in response to a single stimulus was 34 and 84 MUmol (kg muscle)(-1) for soleus and EDL, respectively, and increased with temperature (30 degrees C: soleus, 61 MUmol kg(-1); EDL, 168 MUmol kg(-1)). Delivery of another stimulus within 100 ms of the first produced a smaller Ca(2+) release. The maximum magnitude of the decrease in Ca(2+) release was greater in EDL than soleus. Ca(2+) release recovered with an exponential time course which was faster in EDL (mean time constant at 20 degrees C, 32.1 ms) than soleus (65.6 ms) and faster at 30 degrees C than at 20 degrees C. The amounts of Ca(2+) released and crossbridge cycles performed are consistent with a scheme in which Ca(2+) binding to troponin-C allowed an average of ~1.7 crossbridge cycles in the two muscles. PMID- 23027819 TI - Progressive limb ataxia following inferior olive lesions. AB - Cerebellar climbing fibres originate in the inferior olive (IO). Temporary IO inactivation produces movement deficits. Does permanent inactivation produce similar deficits and, if so, do they recover? The excitotoxin, kainic acid, was injected into the rostral IO of three cats. Behaviour was measured during reaching and locomotion. Two cats were injected during the reaching task. Within minutes, grasping became difficult and the trajectories of the reaches showed higher arcing than normally seen. During locomotion, both cats showed head and trunk deviation to the injected side, walking paths curved to the injected side, and the paws were lifted higher than normal. Limbs contralateral to the injections became rigid. Within 1 day, posture had normalized, locomotion was unsteady and high lifting of the paws had reversed to a tendency to drag the dorsum of the paws. Passive body movement produced vestibular signs. Over a few days, locomotion normalized and vestibular signs disappeared. Reach trajectories were normal but grasping deficits persisted. Over the first week, the amplitude of limb lift during reaching and locomotion began to increase. The increase continued over time and, after several months, limb movements became severely ataxic. The effects followed the somatotopy of the rostral IO: a loss of cells in medial rostral IO only affected the forelimb, whereas a loss of cells in medial and lateral IO affected both forelimb and hindlimb. Deficits produced by IO lesions involve multiple mechanisms; some recover rapidly, some appear stable, and some worsen over time. The nature of the progressive deficit suggests a gradual loss of Purkinje cell inhibition on cerebellar nuclear cells. PMID- 23027820 TI - Skeletal muscle vasodilatation during maximal exercise in health and disease. AB - Maximal exercise vasodilatation results from the balance between vasoconstricting and vasodilating signals combined with the vascular reactivity to these signals. During maximal exercise with a small muscle mass the skeletal muscle vascular bed is fully vasodilated. During maximal whole body exercise, however, vasodilatation is restrained by the sympathetic system. This is necessary to avoid hypotension since the maximal vascular conductance of the musculature exceeds the maximal pumping capacity of the heart. Endurance training and high-intensity intermittent knee extension training increase the capacity for maximal exercise vasodilatation by 20-30%, mainly due to an enhanced vasodilatory capacity, as maximal exercise perfusion pressure changes little with training. The increase in maximal exercise vascular conductance is to a large extent explained by skeletal muscle hypertrophy and vascular remodelling. The vasodilatory capacity during maximal exercise is reduced or blunted with ageing, as well as in chronic heart failure patients and chronically hypoxic humans; reduced vasodilatory responsiveness and increased sympathetic activity (and probably, altered sympatholysis) are potential mechanisms accounting for this effect. Pharmacological counteraction of the sympathetic restraint may result in lower perfusion pressure and reduced oxygen extraction by the exercising muscles. However, at the same time fast inhibition of the chemoreflex in maximally exercising humans may result in increased vasodilatation, further confirming a restraining role of the sympathetic nervous system on exercise-induced vasodilatation. This is likely to be critical for the maintenance of blood pressure in exercising patients with a limited heart pump capacity. PMID- 23027821 TI - Altered neurovascular control of the resting circulation in human metabolic syndrome. AB - Young healthy adults exhibit an inverse linear relationship between muscle sympathetic nerve activity (MSNA) and alpha-adrenergic responsiveness. This balance may be reversed in metabolic syndrome (MetSyn) as animal models exhibit increased sympathetic activity and alpha-mediated vasoconstriction. We hypothesized humans with MetSyn would demonstrate increased alpha-adrenergic vasoconstriction and the inverse relationship between MSNA and adrenergic responsiveness would be lost. We measured MSNA (microneurography of the peroneal nerve) and forearm blood flow (FBF, Doppler ultrasound) in 16 healthy control subjects (31 +/- 3 years) and 14 adults with MetSyn (35 +/- 3 years; P > 0.05) during local administration of alpha-adrenergic agonists (phenylephrine (PE), alpha(1); clonidine (CL), alpha(2)). MSNA was greater in MetSyn subjects than in healthy controls (P < 0.05). A group difference in vasoconstriction to PE was not detected (P = 0.08). The level of alpha(1)-mediated vasoconstriction was inversely related to MSNA in control subjects (r = 0.5, P = 0.04); this balance between MSNA and alpha(1) responsiveness was lost in adults with MetSyn. MetSyn subjects exhibited greater vasoconstriction to CL infusion as compared with healthy controls (P < 0.01). A relationship between MSNA and alpha(2)-mediated vasoconstriction was not detected in either group. In summary, altered neurovascular control in human MetSyn is receptor specific. The observed uncoupling between MSNA and alpha(1)-adrenergic responsiveness and increased alpha(2) vasoconstriction may lead to reduced FBF, altered flow distribution, and/or severe hypertension with the progression toward diabetes and cardiovascular disease. PMID- 23027822 TI - Structural tuning and plasticity of the axon initial segment in auditory neurons. AB - The axon initial segment (AIS) that separates axonal and somato-dendritic compartments is a highly specialised neuronal structure enriched with voltage gated Na(+) channels and functions as the site of spike initiation in neurons. The AIS was once thought to be uniform and static in structure, but has been found to be organised in a manner specific to the function of individual neurons and to exhibit plasticity with changes in synaptic inputs. Such structural specialisations are found in the avian auditory system. In the nucleus magnocellularis (NM), which is involved in a precise relay of timing information, the length of the AIS differs depending on sound frequency and increases with decreasing frequencies to accommodate frequency-specific variations in synaptic inputs. In the nucleus laminaris, which integrates the timing information from both NMs for sound localisation, the length and the location of the AIS vary depending on sound frequency: AISs are shorter and more remote for higher frequency. Furthermore, the AISs of NM neurons elongate to increase their excitability when synaptic inputs are removed by cochlea ablation, suggesting their contribution to the homeostatic control of neural activity. These structural tunings and plasticities of the AIS are thus indispensable for the function of the auditory circuits in both normal and pathological conditions. PMID- 23027823 TI - The information content of physiological and epileptic brain activity. AB - Cerebral cortex is a highly sophisticated computing machine, feeding on information provided by the senses, which is integrated with other, internally generated patterns of neural activity, to trigger behavioural outputs. Bit by bit, we are coming to understand how this may occur, but still, the nature of the 'cortical code' remains one of the greatest challenges in science. As with other great scientific challenges of the past, fresh insights have come from a coalescence of different experimental and theoretical approaches. These theoretical considerations are typically reserved for cortical function rather than cortical pathology. This approach, though, may also shed light on cortical dysfunction. The particular focus of this review is epilepsy; we will argue that the information capacity of different brain states provides a means of understanding, and even assessing, the impact and locality of the epileptic pathology. Epileptic discharges, on account of their all-consuming and stereotyped nature, represent instances where the information capacity of the network is massively compromised. These intense discharges also prevent normal processing in surrounding territories, but in a different way, through enhanced inhibition in these territories. Information processing is further compromised during the period of post-ictal suppression, during interictal bursts, and also at other times, through more subtle changes in synaptic function. We also comment on information processing in other more physiological brain states. PMID- 23027825 TI - Challenges for health psychology: theorizing belief and beyond. AB - We are supportive of Cromby's challenge to further develop 'belief' as a concept relevant for health psychology. Drawing on the wider "affective turn" in the social sciences, Cromby demonstrates the importance of theorising the sociality of thinking and feeling for fundamental health psychology conceptualisations. These theorisations might usefully be applied to key health psychology topics, such as social cogntion models, beliefs about adherence, medications, diagnoses, and illness perceptions. Cromby's approach to beliefs might also be beneficial for fostering a more contextual and culturally oriented health psychology, as well as a greater (and much needed) engagement with notions of embodiment. Cromby's arguments raise many questions for health psychology research practice and deserve close attention and consideration by health psychologists. PMID- 23027824 TI - Residues in the pore region of Drosophila transient receptor potential A1 dictate sensitivity to thermal stimuli. AB - The capacity to sense temperature is essential for the survival of all animals. At the molecular level, ion channels belonging to the transient receptor potential (TRP) family of channels function as temperature sensors in animals across several phyla. TRP channels are opened directly by changes in temperature and show pronounced sensitivity at their activation range. To determine how temperature activates these channels, we analysed channels belonging to the TRPA family, which detect heat in insects and cold in mammals. By constructing chimeric proteins consisting of human and Drosophila TRPA1 channels, we mapped regions that regulate thermal activation and identified residues in the pore helix that invert temperature sensitivity of TRPA1. From analysis of individual channels we defined the gating reaction of Drosophila TRPA1 and determined how mutagenesis alters the energy landscape for channel opening. Our results reveal specific molecular requirements for thermal activation of TRPA1 and provide mechanistic insight into this process. PMID- 23027826 TI - Commentaries on Viewpoint: Are there valid concerns for completing a marathon at 39 weeks of pregnancy? PMID- 23027827 TI - Last Word on Viewpoint: Are there valid concerns for completing a marathon at 39 weeks of pregnancy? PMID- 23027828 TI - The optimal hematocrit increases during exercise. PMID- 23027830 TI - Fermentation product of soybean, black bean, and green bean mixture induces apoptosis in a wide variety of cancer cells. AB - Previous studies have shown that soybean fermentation products can act as cancer chemoprevention or therapeutic agents. In this study, the anticancer activities of a fermentation product of soybean, black bean, and green bean mixture (BN999) were investigated. We found that BN999 inhibited the growth of human breast cancer AU565 cells and prostate adenocarcinoma PC-3 cells but not that of normal human cells. BN999 induced apoptosis in various human cancer cells but not in normal human cells. BN999 treatment of AU565 cancer cells resulted in activation of calpain and caspase-8, -9, and -3, suggesting that BN999 induces apoptosis via receptor-, mitochondria-, and endoplasmic reticulum-mediated pathways. Finally, we showed that BN999 inhibited the growth of mouse CT-26 colon cancer xenografts in syngenic BALB/c mice without causing obvious side effects. Together, these data suggest that BN999 has potential to be used as a cancer chemoprevention or therapeutic agent. PMID- 23027831 TI - Heterogeneity in drug abuse among juvenile offenders: is mixture regression more informative than standard regression? AB - Research on juvenile offenders has largely treated this population as a homogeneous group. However, recent findings suggest that this at-risk population may be considerably more heterogeneous than previously believed. This study compared mixture regression analyses with standard regression techniques in an effort to explain how known factors such as distress, trauma, and personality are associated with drug abuse among juvenile offenders. Researchers recruited 728 juvenile offenders from Missouri juvenile correctional facilities for participation in this study. Researchers investigated past-year substance use in relation to the following variables: demographic characteristics (gender, ethnicity, age, familial use of public assistance), antisocial behavior, and mental illness symptoms (psychopathic traits, psychiatric distress, and prior trauma). Results indicated that standard and mixed regression approaches identified significant variables related to past-year substance use among this population; however, the mixture regression methods provided greater specificity in results. Mixture regression analytic methods may help policy makers and practitioners better understand and intervene with the substance-related subgroups of juvenile offenders. PMID- 23027832 TI - Owner-assessed indices of quality of life in cats and the relationship to the presence of degenerative joint disease. AB - This study evaluated the types of items owners consider important to their cats' quality of life (QoL). We hypothesized that items contributing to QoL in cats are predominantly items requiring mobility. The objectives of the study were to describe the types of items considered important by owners for their cats' QoL; to describe the proportion of these items that involve mobility; to evaluate what patient factors, including severity of degenerative joint disease (DJD), affect this distribution; and to evaluate whether the proportion of QoL items involving mobility chosen by owners is different in cats presenting for a DJD study compared with a randomly selected population. A total of 830 client-generated items were evaluated. Regardless of DJD status, 40% of items listed by owners involved mobility, while 60% were 'inactive' items, rejecting our hypothesis. This highlights the need to assess non-active items that owners consider to constitute QoL to fully assess the impact of diseases like DJD and, therefore, the success of therapeutic interventions. PMID- 23027833 TI - Correspondence between clinical presentation and electrophysiological testing for potential carpal tunnel syndrome. AB - The diagnosis of carpal tunnel syndrome (CTS) is often applied in the absence of objectively verifiable pathophysiology (i.e. electrophysiologically normal carpal tunnel syndrome). The primary purpose of this study was to determine whether depressive symptoms, heightened illness concern, and pain catastrophizing are associated with an absence of electrophysiological abnormalities. The secondary purpose was to examine the correspondence between the Levine scale, the CTS-6, and electrophysiological abnormalities. Ninety-eight participants completed validated questionnaires assessing psychosocial factors at the initial visit, and surgeons recorded clinical data and their confidence that the diagnosis was carpal tunnel syndrome. Symptoms and signs that are characteristic of carpal tunnel syndrome (e.g. the CTS-6 and Levine scale) significantly, but incompletely coincided with electrophysiological testing. Psychological factors did not help distinguish patients with normal and abnormal objective testing and it remains unclear if symptoms that do not coincide with abnormal tests represent very mild, immeasurable median nerve dysfunction or a different illness altogether. Future studies should address whether outcomes are superior and resource utilization is optimized when surgery is offered based on symptoms and signs (e.g. the CTS-6) or when surgery is offered on the basis of measurable pathophysiology. PMID- 23027834 TI - Long-term aesthetic outcome of fingertip reconstruction in complete syndactyly release. AB - An aesthetically pleasing fingertip is an important but often under evaluated goal in syndactyly release. We assessed the aesthetic fingertip outcome in 26 patients with complete syndactylies, with a total of 84 separated digits, using a four-grade scale based on the quality of the lateral nail fold, nail plate definition, symmetry and pulp fullness. Fingertips with complete simple syndactylies released with the use of full-thickness skin grafts achieved a significantly better aesthetic result then fingertips with complete complex syndactylies released with the use of Buck-Gramcko pulp flaps. Fingertips involved in complex syndactylies achieved significantly better aesthetic results when reconstructed using Buck-Gramcko flaps in comparison with those reconstructed with full-thickness skin grafts. We recommend the use of Buck Gramcko flaps in complete complex syndactylies, while reserve the traditional zig zag and full-thickness skin graft closure for cases of complete simple syndactylies. We also propose a grading system for the aesthetic outcome of the fingertip following syndactyly release. PMID- 23027835 TI - Examining the roles of victim-perpetrator relationship and emotional closeness in judgments toward a depicted child sexual abuse case. AB - The current study investigated the impact that respondent gender, victim perpetrator relationship, and the level of emotional closeness had on attributions in a hypothetical child sexual abuse case. A total of 160 university students read a hypothetical scenario depicting a female child sexually abused by an adult male. The perpetrator was either the victim's biological father or her stepfather, with this relationship described as being either emotionally close or emotionally distant. Respondents read one of four (2 victim-perpetrator relationship * 2 emotional closeness) scenarios before completing 26 attribution items pertaining to credibility, blame, and severity. Principle components analysis yielded five factors, namely victim credibility, mother culpability, perpetrator culpability, assault severity, and victim culpability. Multivariate analysis of covariance--controlling for respondent (Caucasian vs. non-Caucasian) ethnicity--revealed, as predicted, significant main effects for respondent gender, victim-perpetrator relationship, and emotional closeness. In general, females assigned more provictim/ antiperpetrator/antimother attributions than males. Results were also suggested that both victim-perpetrator relationship and emotional closeness influence attributions made toward the victim, perpetrator, and nonoffending mother. Methodological issues and suggestions for future work are also discussed. PMID- 23027836 TI - Parental competence and maltreatment: the curvilinear influence of plan complexity. AB - A parent's ability to plan for child behavior problems was proposed to influence the relationship between parental competence and attitudes/beliefs about parenting behaviors. One hundred and one parents from three community sites completed questionnaires measuring parental competence, plan complexity, and attitudes/beliefs about parenting. Results indicated that plan complexity significantly influenced the relationship between parental competence and judgments about corporal punishment. The same influence existed between parental competence and power independence. We discuss these results with regard to forwarding theoretical work on planning processes, as well as practical implications for enhancing parent education curricula to better address the constructive management of difficult child behaviors. PMID- 23027837 TI - Health of ageing people with intellectual disability and the role of the nurse in Ireland. AB - The number of people with intellectual disability living into old age continues to increase. As one ages, generally, functional ability decreases and health issues increase, with recognising and responding to the health needs of the person with intellectual disability of great importance and the responsibility of the intellectual disability nurse. The nurse must review and adjust the way they deliver care to ageing people with intellectual disability, not only in terms of responding to their health needs but also through collaborative working within teams and other services. As Ireland has specifically trained nurses in intellectual disability, it has a prime opportunity to address the health needs and concerns of people with intdisability and actively advocate for how services develop and responds to the changing health needs of ageing people with intellectual disability. PMID- 23027839 TI - Genome sequence of Pichia kudriavzevii M12, a potential producer of bioethanol and phytase. AB - A draft genome sequence of Pichia kudriavzevii M12 is presented here. The genome reveals the presence of genes encoding enzymes involved in xylose utilization and the pentose phosphate pathway for bioethanol production. Strain M12 is also a potential producer of phytases, enzymes useful in food processing and agriculture. PMID- 23027840 TI - Listening to Npas4: a transcription factor is the prescription for restoring youthful plasticity in the mature brain. PMID- 23027841 TI - Juvenile mossy fibres: two pipers in the same pub? PMID- 23027842 TI - Risk stratification after myocardial infarction: it is time for intervention. PMID- 23027843 TI - Leadless pacing using induction technology: impact of pulse shape and geometric factors on pacing efficiency. AB - AIMS: Leadless pacing can be done by transmitting energy by an alternating magnetic field from a subcutaneous transmitter unit (TU) to an endocardial receiver unit (RU). Safety and energy consumption are key issues that determine the clinical feasibility of this new technique. The aims of the study were (i) to evaluate the stimulation characteristics of the non-rectangular pacing pulses induced by the alternating magnetic field, (ii) to determine the extent and impact of RU movement caused by the beating heart, and (iii) to evaluate the influence of the relative position between TU and RU on pacing efficiency and energy consumption. METHODS AND RESULTS: In the first step pacing efficiency and energy consumption for predefined positions were determined by bench testing. Subsequently, in a goat at five different ventricular sites (three in the right ventricle, two in the left ventricle) pacing thresholds using non-rectangular induction pulses were compared with conventional pulses. Relative position, defined by parallel distance, radial distance, and angulation between TU and RU, were determined in vivo by X-ray and an inclination angle measurement system. Bench testing showed that by magnetic induction for every alignment between TU and RU appropriate pulses can be produced up to a distance of 100 mm. In the animal experiment pacing thresholds were similar for non-rectangular pulses as compared with conventional pulse shapes. In all five positions with distances between 62 and 102 mm effective pacing was obtained in vivo. Variations in distance, displacement and angle caused by the beating heart did not cause loss of capture. At pacing threshold energy consumptions between 0.28 and 5.36 mJ were measured. Major determinants of energy consumption were distance and pacing threshold. CONCLUSION: For any given RU position up to a distance of 100 mm reliable pacing using induction can be obtained. In anatomically crucial distances, up to 60 mm energy consumption is within a reasonable range. PMID- 23027844 TI - Imagine ... imaging. PMID- 23027845 TI - T-wave integral: an electrocardiographic marker discriminating patients with arrhythmogenic right ventricular cardiomyopathy from patients with right ventricular outflow tract tachycardia. AB - AIMS: Clinical and electrocardiographic (ECG) presentation of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic right ventricular outflow-tract tachycardia (RVOT) may be similar. The aim of the study was to assess the validity and utility of T-wave integral measurement as an ECG discriminator of patients with ARVC and RVOT using a body surface mapping (BSM). METHODS AND RESULTS: A 120-channel BSM with quantitative signal analysis of the T wave integral was performed in 10 patients with ARVC. Results were compared with those obtained from 13 patients with RVOT and a control group of 12 healthy subjects (controls). Age, body mass index, and QRS-axis on surface ECG were not significantly different between the groups. Arrhythmogenic right ventricular cardiomyopathy patients showed a significantly negative T-wave integral in the right lower anterior region of the torso when compared with RVOT (P < 0.001). There was no statistically significant difference between RVOT patients and controls. At a cut-off level of -0.3 mV ms, sensitivity and specificity were 83% [area under curve (AUC) 0.85 +/- 0.04 for the comparison of ARVC and RVOT]. These differences were pronounced in ARVC patients with a plakophlin-2 mutation (P < 0.001). CONCLUSION: Quantitative analysis of the BSM T-wave integral in distinct anatomical regions discriminates ARVC patients from RVOT patients and controls and may serve as an additional diagnostic tool. PMID- 23027846 TI - On the value of portfolio diversity in heart, lung, and blood research. PMID- 23027847 TI - The mechanism of the exercise hyperpnea: the ultrasecret revisited. PMID- 23027848 TI - Accelerated lung function decline in smokers: spotlight on vitamin D deficiency. PMID- 23027849 TI - Limitations at the end of life. PMID- 23027850 TI - The paradox of carbon monoxide and the heart. PMID- 23027851 TI - Growing research evidence for continuous positive airway pressure treatment for sleepy patients with milder obstructive sleep apnea. PMID- 23027852 TI - Host susceptibility or environmental exposure in Mycobacterium avium complex lung disease: it takes two to tango. PMID- 23027853 TI - It's not asthma. PMID- 23027854 TI - Is warfarin the right anticoagulant in idiopathic pulmonary fibrosis? PMID- 23027855 TI - A young Hispanic with c.1646G>A mutation exhibits severe cystic fibrosis lung disease: is ivacaftor an option for therapy? PMID- 23027856 TI - Rod-like bacteria and recurrent venous thromboembolism. PMID- 23027857 TI - Proposed alternative scoring for SAQLI domain D. PMID- 23027858 TI - Diffuse talc granulomatosis in a patient with Crohn's disease. PMID- 23027859 TI - Men: the missing client in family planning. PMID- 23027860 TI - Regulatory subunit myristoylation antagonizes calcineurin phosphatase activation in yeast. AB - The Ca(2+)/calmodulin-stimulated protein phosphatase calcineurin is a critical component of Ca(2+) signaling cascades in eukaryotic cells. Myristoylation of the regulatory subunit of calcineurin (CNB) is conserved from yeast to humans. Here, we show that CNB myristoylation antagonizes phosphatase activation in yeast. Disruption of CNB myristoylation by mutation of the myristoylated glycine triggered constitutive expression of a calcineurin-dependent reporter gene and enhanced calcineurin-dependent phenotypes. Basal phosphatase activity was also increased in nmt1-181 yeast with reduced N-myristoyltransferase activity. Our findings are the first demonstration of a functional role for CNB myristoylation and reveal the importance of Nmt1 in modulating cellular calcineurin activation. PMID- 23027861 TI - Interplay between menin and K-Ras in regulating lung adenocarcinoma. AB - MEN1, which encodes the nuclear protein menin, acts as a tumor suppressor in lung cancer and is often inactivated in human primary lung adenocarcinoma. Here, we show that the inactivation of MEN1 is associated with increased DNA methylation at the MEN1 promoter by K-Ras. On one hand, the activated K-Ras up-regulates the expression of DNA methyltransferases and enhances the binding of DNA methyltransferase 1 to the MEN1 promoter, leading to increased DNA methylation at the MEN1 gene in lung cancer cells; on the other hand, menin reduces the level of active Ras-GTP at least partly by preventing GRB2 and SOS1 from binding to Ras, without affecting the expression of GRB2 and SOS1. In human lung adenocarcinoma samples, we further demonstrate that reduced menin expression is associated with the enhanced expression of Ras (p < 0.05). Finally, excision of the Men1 gene markedly accelerates the K-Ras(G12D)-induced tumor formation in the Men1(f/f);K Ras(G12D/+);Cre ER mouse model. Together, these findings uncover a previously unknown link between activated K-Ras and menin, an important interplay governing tumor activation and suppression in the development of lung cancer. PMID- 23027862 TI - Golgi phosphoprotein 3 determines cell binding properties under dynamic flow by controlling Golgi localization of core 2 N-acetylglucosaminyltransferase 1. AB - Core 2 N-acetylglucosaminyltransferase 1 (C2GnT1) is a key enzyme participating in the synthesis of core 2-associated sialyl Lewis x (C2-O-sLe(x)), a ligand involved in selectin-mediated leukocyte trafficking and cancer metastasis. To accomplish that, C2GnT1 needs to be localized to the Golgi and this step requires interaction of its cytoplasmic tail (CT) with a protein that has not been identified. Employing C2GnT1 CT as the bait to perform a yeast two-hybrid screen, we have identified Golgi phosphoprotein 3 (GOLPH3) as a principal candidate protein that interacts with C2GnT1 and demonstrated that C2GnT1 binds to GOLPH3 via the LLRRR(9) sequence in the CT. Confocal fluorescence microscopic analysis shows substantial Golgi co-localization of C2GnT1 and GOLPH3. Upon GOLPH3 knockdown, C2GnT1 is found mainly in the endoplasmic reticulum and decorated with complex-type N-glycans, indicating that the enzyme has been transported to the Golgi but is not retained. Also, we have found that a recombinant protein consisting of C2GnT1 CT(1-16)-Leu(17-32)-Gly(33-42)-GFP is localized to the Golgi although the same construct with mutated CT (AAAAA(9)) is not. The data demonstrate that the C2GnT1 CT is necessary and sufficient for Golgi localization of C2GnT1. Furthermore, GOLPH3 knockdown results in reduced synthesis of C2-O sLe(x) associated with P-selectin glycoprotein ligand-1, reduced cell tethering to and rolling on immobilized P- or E-selectin, and compromised E-selectin induced activation of spleen tyrosine kinase and cell adhesion to intercellular adhesion molecule-1 under dynamic flow. Our results reveal that GOLPH3 can regulate cell-cell interaction by controlling Golgi retention of C2GnT1. PMID- 23027863 TI - The matricellular protein CCN1/Cyr61 is a critical regulator of Sonic Hedgehog in pancreatic carcinogenesis. AB - CCN1 is a matricellular protein and a member of the CCN family of growth factors. CCN1 is associated with the development of various cancers including pancreatic ductal adenocarcinoma (PDAC). Our recent studies found that CCN1 plays a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. CCN1 mRNA and protein were detected in the early precursor lesions, and their expression intensified with disease progression. However, biochemical activity and the molecular targets of CCN1 in pancreatic cancer cells are unknown. Here we show that CCN1 regulates the Sonic Hedgehog (SHh) signaling pathway, which is associated with the PDAC progression and poor prognosis. SHh regulation by CCN1 in pancreatic cancer cells is mediated through the active Notch-1. Notably, active Notch-1is recruited by CCN1 in these cells via the inhibition of proteasomal degradation results in stabilization of the receptor. We find that CCN1-induced activation of SHh signaling might be necessary for CCN1-dependent in vitro pancreatic cancer cell migration and tumorigenicity of the side population of pancreatic cancer cells (cancer stem cells) in a xenograft in nude mice. Moreover, the functional role of CCN1 could be mediated through the interaction with the alphavbeta3 integrin receptor. These extensive studies propose that targeting CCN1 can provide a new treatment option for patients with pancreatic cancer since blocking CCN1 simultaneously blocks two critical pathways (i.e. SHh and Notch1) associated with the development of the disease as well as drug resistance. PMID- 23027864 TI - Botulinum neurotoxin serotype C associates with dual ganglioside receptors to facilitate cell entry. AB - BACKGROUND: How botulinum neurotoxin serotype C (BoNT/C) enters neurons is unclear. RESULTS: BoNT/C utilizes dual gangliosides as host cell receptors. CONCLUSION: BoNT/C accesses gangliosides on the plasma membrane. SIGNIFICANCE: Plasma membrane accessibility of the dual ganglioside receptors suggests synaptic vesicle exocytosis may not be necessary to expose BoNT/C receptors. Botulinum neurotoxins (BoNTs) cleave SNARE proteins in motor neurons that inhibits synaptic vesicle (SV) exocytosis, resulting in flaccid paralysis. There are seven BoNT serotypes (A-G). In current models, BoNTs initially bind gangliosides on resting neurons and upon SV exocytosis associate with the luminal domains of SV associated proteins as a second receptor. The entry of BoNT/C is less clear. Characterizing the heavy chain receptor binding domain (HCR), BoNT/C was shown to utilize gangliosides as dual host receptors. Crystallographic and biochemical studies showed that the two ganglioside binding sites, termed GBP2 and Sia-1, were independent and utilized unique mechanisms to bind complex gangliosides. The GBP2 binding site recognized gangliosides that contained a sia5 sialic acid, whereas the Sia-1 binding site recognized gangliosides that contained a sia7 sialic acid and sugars within the backbone of the ganglioside. Utilizing gangliosides that uniquely recognized the GBP2 and Sia-1 binding sites, HCR/C entry into Neuro-2A cells required both functional ganglioside binding sites. HCR/C entered cells differently than the HCR of tetanus toxin, which also utilizes dual gangliosides as host receptors. A point-mutated HCR/C that lacked GBP2 binding potential retained the ability to bind and enter Neuro-2A cells. This showed that ganglioside binding at the Sia-1 site was accessible on the plasma membrane, suggesting that SV exocytosis may not be required to expose BoNT/C receptors. These studies highlight the utility of BoNT HCRs as probes to study the role of gangliosides in neurotransmission. PMID- 23027865 TI - Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-beta (CaMKK-beta). AB - Autophagy is the main lysosomal catabolic process that becomes activated under stress conditions, such as amino acid starvation and cytosolic Ca(2+) upload. However, the molecular details on how both conditions control autophagy are still not fully understood. Here we link essential amino acid starvation and Ca(2+) in a signaling pathway to activate autophagy. We show that withdrawal of essential amino acids leads to an increase in cytosolic Ca(2+), arising from both extracellular medium and intracellular stores, which induces the activation of adenosine monophosphate-activated protein kinase (AMPK) via Ca(2+)/calmodulin dependent kinase kinase-beta (CaMKK-beta). Furthermore, we show that autophagy induced by amino acid starvation requires AMPK, as this induction is attenuated in its absence. Subsequently, AMPK activates UNC-51-like kinase (ULK1), a mammalian autophagy-initiating kinase, through phosphorylation at Ser-555 in a process that requires CaMKK-beta. Finally, the mammalian target of rapamycin complex C1 (mTORC1), a negative regulator of autophagy downstream of AMPK, is inhibited by amino acid starvation in a Ca(2+)-sensitive manner, and CaMKK-beta appears to be important for mTORC1 inactivation, especially in the absence of extracellular Ca(2+). All these results highlight that amino acid starvation regulates autophagy in part through an increase in cellular Ca(2+) that activates a CaMKK-beta-AMPK pathway and inhibits mTORC1, which results in ULK1 stimulation. PMID- 23027867 TI - Alterations of mitochondrial protein assembly and jasmonic acid biosynthesis pathway in Honglian (HL)-type cytoplasmic male sterility rice. AB - It has been suggested that the mitochondrial chimeric gene orfH79 is the cause for abortion of microspores in Honglian cytoplasmic male sterile rice, yet little is known regarding its mechanism of action. In this study, we used a mass spectrometry-based quantitative proteomics strategy to compare the mitochondrial proteome between the sterile line Yuetai A and its fertile near-isogenic line Yuetai B. We discovered a reduced quantity of specific proteins in mitochondrial complexes in Yuetai A compared with Yuetai B, indicating a defect in mitochondrial complex assembly in the sterile line. Western blotting showed that ORFH79 protein and ATP1 protein, an F(1) sector component of complex V, are both associated with large protein complexes of similar size. Respiratory complex activity assays and transmission electron microscopy revealed functional and morphological defects in the mitochondria of Yuetai A when compared with Yuetai B. In addition, we identified one sex determination TASSELSEED2-like protein increased in Yuetai A, leading to the discovery of an aberrant variation of the jasmonic acid pathway during the development of microspores. PMID- 23027866 TI - 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential. AB - The chemotherapeutic agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a potent inducer of type I IFNs and other cytokines. This ability is essential for its chemotherapeutic benefit in a mouse cancer model and suggests that it might also be useful as an antiviral agent. However, the mechanism underlying DMXAA induced type I IFNs, including the host proteins involved, remains unclear. Recently, it was reported that the antioxidant N-acetylcysteine (NAC) decreased DMXAA-induced TNF-alpha and IL-6, suggesting that oxidative stress may play a role. The goal of this study was to identify host proteins involved in DMXAA dependent signaling and determine how antioxidants modulate this response. We found that expression of IFN-beta in response to DMXAA in mouse macrophages requires the mitochondrial and endoplasmic reticulum resident protein STING. Addition of the antioxidant diphenylene iodonium (DPI) diminished DMXAA-induced IFN-beta, but this decrease was independent of both the NADPH oxidase, Nox2, and de novo generation of reactive oxygen species. Additionally, IFN-beta up regulation by DMXAA was inhibited by agents that target the mitochondrial electron transport chain and, conversely, loss of mitochondrial membrane potential correlated with diminished innate immune signaling in response to DMXAA. Up-regulation of Ifnb1 gene expression mediated by cyclic dinucleotides was also impaired by DPI, whereas up-regulation of Ifnb1 mRNA due to cytosolic double-stranded DNA was not. Although both stimuli signal through STING, cyclic dinucleotides interact directly with STING, suggesting that recognition of DMXAA by STING may also be mediated by direct interaction. PMID- 23027868 TI - The redox-sensing transcriptional regulator RexT controls expression of thioredoxin A2 in the cyanobacterium Anabaena sp. strain PCC 7120. AB - BACKGROUND: Thioredoxins (Trxs) play a crucial role in the oxidative stress response. RESULTS: A redox-sensing transcriptional regulator, RexT, controls expression of TrxA2, and TrxA2 regulates the DNA binding activity of RexT. CONCLUSION: The RexT-TrxA2 regulatory system regulates gene expression in response to redox state. SIGNIFICANCE: This is the first report on a transcriptional regulator of the trx gene in cyanobacteria. Thioredoxins are ubiquitous proteins that catalyze thiol-disulfide redox reactions. They have a crucial role in the oxidative stress response as well as the redox regulation of metabolic enzymes. In cyanobacteria, little is known about the regulation of trx gene expression despite the importance of thioredoxins in cellular functions. In the present study, transcriptional regulation of the trx genes under oxidative stress conditions was investigated in the heterocystous cyanobacterium Anabaena sp. strain PCC 7120. When cells were exposed to H(2)O(2), only the trxA2 gene (all1866) of seven trx genes was induced. Disruption of the rexT gene (alr1867), encoding a transcriptional regulator of the ArsR family, resulted in increased expression of trxA2. RexT bound to the region downstream of the transcription initiation site of trxA2. The DNA binding activity of RexT was impaired by H(2)O(2) through the formation of an intramolecular disulfide bond, which induced expression of the trxA2 gene. The inactivated DNA binding activity of RexT was restored by reduced TrxA2. Hence, RexT is considered as a redox-sensing transcriptional repressor of trxA2. These results support the idea that the RexT TrxA2 regulatory system is important for the oxidative stress response in this cyanobacterium. PMID- 23027869 TI - A photochromic histidine kinase rhodopsin (HKR1) that is bimodally switched by ultraviolet and blue light. AB - Rhodopsins are light-activated chromoproteins that mediate signaling processes via transducer proteins or promote active or passive ion transport as ion pumps or directly light-activated channels. Here, we provide spectroscopic characterization of a rhodopsin from the Chlamydomonas eyespot. It belongs to a recently discovered but so far uncharacterized family of histidine kinase rhodopsins (HKRs). These are modular proteins consisting of rhodopsin, a histidine kinase, a response regulator, and in some cases an effector domain such as an adenylyl or guanylyl cyclase, all encoded in a single protein as a two component system. The recombinant rhodopsin fragment, Rh, of HKR1 is a UVA receptor (lambda(max) = 380 nm) that is photoconverted by UV light into a stable blue light-absorbing meta state Rh-Bl (lambda(max) = 490 nm). Rh-Bl is converted back to Rh-UV by blue light. Raman spectroscopy revealed that the Rh-UV chromophore is in an unusual 13-cis,15-anti configuration, which explains why the chromophore is deprotonated. The excited state lifetime of Rh-UV is exceptionally stable, probably caused by a relatively unpolar retinal binding pocket, converting into the photoproduct within about 100 ps, whereas the blue form reacts 100 times faster. We propose that the photochromic HKR1 plays a role in the adaptation of behavioral responses in the presence of UVA light. PMID- 23027870 TI - Hyperactivity of the Ero1alpha oxidase elicits endoplasmic reticulum stress but no broad antioxidant response. AB - Oxidizing equivalents for the process of oxidative protein folding in the endoplasmic reticulum (ER) of mammalian cells are mainly provided by the Ero1alpha oxidase. The molecular mechanisms that regulate Ero1alpha activity in order to harness its oxidative power are quite well understood. However, the overall cellular response to oxidative stress generated by Ero1alpha in the lumen of the mammalian ER is poorly characterized. Here we investigate the effects of overexpressing a hyperactive mutant (C104A/C131A) of Ero1alpha. We show that Ero1alpha hyperactivity leads to hyperoxidation of the ER oxidoreductase ERp57 and induces expression of two established unfolded protein response (UPR) targets, BiP (immunoglobulin-binding protein) and HERP (homocysteine-induced ER protein). These effects could be reverted or aggravated by N-acetylcysteine and buthionine sulfoximine, respectively. Because both agents manipulate the cellular glutathione redox buffer, we conclude that the observed effects of Ero1alpha C104A/C131A overexpression are likely caused by an oxidative perturbation of the ER glutathione redox buffer. In accordance, we show that Ero1alpha hyperactivity affects cell viability when cellular glutathione levels are compromised. Using microarray analysis, we demonstrate that the cell reacts to the oxidative challenge caused by Ero1alpha hyperactivity by turning on the UPR. Moreover, this analysis allowed the identification of two new targets of the mammalian UPR, CRELD1 and c18orf45. Interestingly, a broad antioxidant response was not induced. Our findings suggest that the hyperoxidation generated by Ero1alpha-C104A/C131A is addressed in the ER lumen and is unlikely to exert oxidative injury throughout the cell. PMID- 23027871 TI - Tollip, an intracellular trafficking protein, is a novel modulator of the transforming growth factor-beta signaling pathway. AB - Upon activation, TGF-beta type I receptor (TbetaRI) undergoes active ubiquitination via recruitment of E3 ligases to the receptor complex by Smad7. However, how ubiquitination of TbetaRI is coupled to intracellular trafficking, and protein degradation remains unclear. We report here that Tollip, an adaptor protein that contains both ubiquitin-associated domains and endosome-targeting domain, plays an important role in modulating trafficking and degradation of TbetaRI. Tollip was previously demonstrated to possess a functional role in modulating the signaling of interleukin-1 and Toll-like receptors. We identify here that Tollip interacts with Smad7, a major modulatory protein involved in the negative regulation of TGF-beta signaling. Overexpression of Tollip antagonizes TGF-beta-stimulated transcriptional response, Smad2 phosphorylation, and epithelial-mesenchymal transition. Tollip also interacts with ubiquitinated TbetaRI, and such interaction requires ubiquitin-associated domains of Tollip. The interaction and intracellular colocalization of Tollip with TbetaRI is enhanced by Smad7. Overexpression of Tollip accelerates protein degradation of activated TbetaRI. In addition, Tollip alters subcellular compartmentalization and endosomal trafficking of activated TbetaRI. Collectively, our studies reveal that Tollip cooperates with Smad7 to modulate intracellular trafficking and degradation of ubiquitinated TbetaRI, whereby negatively regulates TGF-beta signaling pathway. PMID- 23027872 TI - Conservation of functional sites on interleukin-6 and implications for evolution of signaling complex assembly and therapeutic intervention. AB - A number of secreted cytokines, such as interleukin-6 (IL-6), are attractive targets for the treatment of inflammatory diseases. We have determined the solution structure of mouse IL-6 to assess the functional significance of apparent differences in the receptor interaction sites (IL-6Ralpha and gp130) suggested by the fairly low degree of sequence similarity with human IL-6. Structure-based sequence alignment of mouse IL-6 and human IL-6 revealed surprising differences in the conservation of the two distinct gp130 binding sites (IIa and IIIa), which suggests a primacy for site III-mediated interactions in driving initial assembly of the IL-6/IL-6Ralpha/gp130 ternary complex. This is further supported by a series of direct binding experiments, which clearly demonstrate a high affinity IL-6/IL-6Ralpha-gp130 interaction via site III but only weak binding via site II. Collectively, our findings suggest a pathway for the evolution of the hexameric, IL-6/IL-6Ralpha/gp130 signaling complex and strategies for therapeutic targeting. We propose that the signaling complex originally involved specific interactions between IL-6 and IL-6Ralpha (site I) and between the D1 domain of gp130 and IL-6/IL-6Ralpha (site III), with the later inclusion of interactions between the D2 and D3 domains of gp130 and IL-6/IL 6Ralpha (site II) through serendipity. It seems likely that IL-6 signaling benefited from the evolution of a multipurpose, nonspecific protein interaction surface on gp130, now known as the cytokine binding homology region (site II contact surface), which fortuitously contributes to stabilization of the IL-6/IL 6Ralpha/gp130 signaling complex. PMID- 23027873 TI - Cross-talk among RNA polymerase II kinases modulates C-terminal domain phosphorylation. AB - The RNA polymerase II (Pol II) C-terminal domain (CTD) serves as a docking site for numerous proteins, bridging various nuclear processes to transcription. The recruitment of these proteins is mediated by CTD phospho-epitopes generated during transcription. The mechanisms regulating the kinases that establish these phosphorylation patterns on the CTD are not known. We report that three CTD kinases, CDK7, CDK9, and BRD4, engage in cross-talk, modulating their subsequent CTD phosphorylation. BRD4 phosphorylates PTEFb/CDK9 at either Thr-29 or Thr-186, depending on its relative abundance, which represses or activates CDK9 CTD kinase activity, respectively. Conversely, CDK9 phosphorylates BRD4 enhancing its CTD kinase activity. The CTD Ser-5 kinase CDK7 also interacts with and phosphorylates BRD4, potently inhibiting BRD4 kinase activity. Additionally, the three kinases regulate each other indirectly through the general transcription factor TAF7. An inhibitor of CDK9 and CDK7 CTD kinase activities, TAF7 also binds to BRD4 and inhibits its kinase activity. Each of these kinases phosphorylates TAF7, affecting its subsequent ability to inhibit the other two. Thus, a complex regulatory network governs Pol II CTD kinases. PMID- 23027874 TI - Profibrotic effect of interleukin-18 in HK-2 cells is dependent on stimulation of the Toll-like receptor 4 (TLR4) promoter and increased TLR4 expression. AB - BACKGROUND: IL-18 induces profibrotic changes in TECs independent of TGF-beta1 activity. RESULTS: IL-18 stimulates the TLR4 promoter via AP-1 activation to increase TLR4 expression in TECs and stimulates profibrotic changes in TECs through increased TLR4 expression/signaling. CONCLUSION: The profibrotic effect of IL-18 in TECs is mediated through stimulation of TLR4 expression via activation of AP-1. SIGNIFICANCE: This represents a novel fibrotic signaling pathway in TECs independent of TGF-beta1. IL-18 is an important mediator of obstruction-induced renal fibrosis and tubular epithelial cell injury independent of TGF-beta1 activity. We sought to determine whether the profibrotic effect of IL-18 is mediated through Toll-like receptor 4 (TLR4). Male C57BL6 wild type and mice transgenic for human IL-18-binding protein were subjected to left unilateral ureteral obstruction versus sham operation. The kidneys were harvested 1 week postoperatively and analyzed for IL-18 production and TLR4 expression. In a separate arm, renal tubular epithelial cells (HK-2) were directly stimulated with IL-18 in the presence or absence of a TLR4 agonist, TLR4 antagonist, or TLR4 siRNA knockdown. Cell lysates were analyzed for TLR4, alpha-smooth muscle actin, and E-cadherin expression. TLR4 promotor activity, as well as AP-1 activation and the effect of AP-1 knockdown on TLR4 expression, was evaluated in HK-2 cells in response to IL-18 stimulation. The results demonstrate that IL-18 induces TLR4 expression during unilateral ureteral obstruction and induces TLR4 expression in HK-2 cells via AP-1 activation. Inhibition of TLR4 or knockdown of TLR4 gene expression in turn prevents IL-18-induced profibrotic changes in HK-2 cells. These results suggest that IL-18 induces profibrotic changes in tubular epithelial cells via increased TLR4 expression/signaling. PMID- 23027875 TI - Tic22 is an essential chaperone required for protein import into the apicoplast. AB - Most plastids proteins are post-translationally imported into organelles through multisubunit translocons. The TIC and TOC complexes perform this role in the two membranes of the plant chloroplast and in the inner two membranes of the apicoplasts of the apicomplexan parasites, Toxoplasma gondii and Plasmodium falciparum. Tic22 is a ubiquitous intermembrane translocon component that interacts with translocating proteins. Here, we demonstrate that T. gondii Tic22 is an apicoplast-localized protein, essential for parasite survival and protein import into the apicoplast stroma. The structure of Tic22 from P. falciparum reveals a fold conserved from cyanobacteria to plants, which displays a non-polar groove on each side of the molecule. We show that these grooves allow Tic22 to act as a chaperone. General chaperones are common components of protein translocation systems where they maintain cargo proteins in an unfolded conformation during transit. Such a chaperone had not been identified in the intermembrane space of plastids and we propose that Tic22 fulfills this role. PMID- 23027876 TI - The role of secretory immunoglobulin A in the natural sensing of commensal bacteria by mouse Peyer's patch dendritic cells. AB - The mammalian gastrointestinal (GI) tract harbors a diverse population of commensal species collectively known as the microbiota, which interact continuously with the host. From very early in life, secretory IgA (SIgA) is found in association with intestinal bacteria. It is considered that this helps to ensure self-limiting growth of the microbiota and hence participates in symbiosis. However, the importance of this association in contributing to the mechanisms ensuring natural host-microorganism communication is in need of further investigation. In the present work, we examined the possible role of SIgA in the transport of commensal bacteria across the GI epithelium. Using an intestinal loop mouse model and fluorescently labeled bacteria, we found that entry of commensal bacteria in Peyer's patches (PP) via the M cell pathway was mediated by their association with SIgA. Preassociation of bacteria with nonspecific SIgA increased their dynamics of entry and restored the reduced transport observed in germ-free mice known to have a marked reduction in intestinal SIgA production. Selective SIgA-mediated targeting of bacteria is restricted to the tolerogenic CD11c(+)CD11b(+)CD8(-) dendritic cell subset located in the subepithelial dome region of PPs, confirming that the host is not ignorant of its resident commensals. In conclusion, our work supports the concept that SIgA-mediated monitoring of commensal bacteria targeting dendritic cells in the subepithelial dome region of PPs represents a mechanism whereby the host mucosal immune system controls the continuous dialogue between the host and commensal bacteria. PMID- 23027877 TI - Skp1-Cul1-F-box ubiquitin ligase (SCF(betaTrCP))-mediated destruction of the ubiquitin-specific protease USP37 during G2-phase promotes mitotic entry. AB - Ubiquitin-mediated proteolysis is a key regulatory process in cell cycle progression. The Skp1-Cul1-F-box (SCF) and anaphase-promoting complex (APC) ubiquitin ligases target numerous components of the cell cycle machinery for destruction. Throughout the cell cycle, these ligases cooperate to maintain precise levels of key regulatory proteins, and indirectly, each other. Recently, we have identified the deubiquitinase USP37 as a regulator of the cell cycle. USP37 expression is cell cycle-regulated, being expressed in late G(1) and ubiquitinated by APC(Cdh1) in early G(1). Here we report that in addition to destruction at G(1), a major fraction of USP37 is degraded at the G(2)/M transition, prior to APC substrates and similar to SCF(betaTrCP) substrates. Consistent with this hypothesis, USP37 interacts with components of the SCF in a betaTrCP-dependent manner. Interaction with betaTrCP and subsequent degradation is phosphorylation-dependent and is mediated by the Polo-like kinase (Plk1). USP37 is stabilized in G(2) by depletion of betaTrCP as well as chemical or genetic manipulation of Plk1. Similarly, mutation of the phospho-sites abolishes betaTrCP binding and renders USP37 resistant to Plk1 activity. Expression of this mutant hinders the G(2)/M transition. Our data demonstrate that tight regulation of USP37 levels is required for proper cell cycle progression. PMID- 23027878 TI - The intrinsically disordered N-terminal region of AtREM1.3 remorin protein mediates protein-protein interactions. AB - The longstanding structure-function paradigm, which states that a protein only serves a biological function in a structured state, had to be substantially revised with the description of intrinsic disorder in proteins. Intrinsically disordered regions that undergo a stimulus-dependent disorder-to-order transition are common to a large number of signaling proteins. However, little is known about the functionality of intrinsically disordered regions in plant proteins. Here we investigated intrinsic disorder in a plant-specific remorin protein that has been described as a signaling component in plant-microbe interactions. Using bioinformatic, biochemical, and biophysical approaches, we characterized the highly abundant remorin AtREM1.3, showing that its N-terminal region is intrinsically disordered. Although only the AtREM1.3 C-terminal domain is essential for stable homo-oligomerization, the N-terminal region facilitates this interaction. Furthermore, we confirmed the stable interaction between AtREM1.3 and four isoforms of the importin alpha protein family in a yeast two-hybrid system and by an in planta bimolecular fluorescent complementation assay. Phosphorylation of Ser-66 in the intrinsically disordered N-terminal region decreases the interaction strength with the importin alpha proteins. Hence, the N terminal region may constitute a regulatory domain, stabilizing these interactions. PMID- 23027879 TI - Susceptibility-weighted imaging in the experimental autoimmune encephalomyelitis model of multiple sclerosis indicates elevated deoxyhemoglobin, iron deposition and demyelination. AB - BACKGROUND: Susceptibility-weighted imaging (SWI) is an iron-sensitive magnetic resonance imaging (MRI) method that has shown iron-related lesions in multiple sclerosis (MS) patients. The contribution of deoxyhemoglobin to the signals seen in SWI has not been well characterized in MS. OBJECTIVES: To determine if SWI lesions (seen as focal hypointensities) exist in the experimental autoimmune encephalomyelitis (EAE) animal model of MS, and to determine whether the lesions relate to iron deposits, inflammation, demyelination, and/or deoxyhemoglobin in the vasculature. METHODS: We performed SWI on the lumbar spinal cord and cerebellum of EAE and control mice (both complete Freund's adjuvant/pertussis toxin (CFA/PTX)-immunized and naive). We also performed SWI on mice before and after perfusion (to remove blood from vessels). SWI lesions were counted and their locations were compared to histology for iron, myelin and inflammation. RESULTS: SWI lesions were found to exist in the EAE model. Many lesions seen by SWI were not present after perfusion, especially at the grey/white matter boundary of the lumbar spinal cord and in the cerebellum, indicating that these lesion signals were associated with deoxyhemoglobin present in the lumen of vessels. We also observed SWI lesions in the white matter of the lumbar spinal cord that corresponded to iron deposition, inflammation and demyelination. In the cerebellum, SWI lesions were present in white matter tracts, where we found histological evidence of inflammatory perivascular cuffs. CONCLUSIONS: SWI lesions exist in EAE mice. Many lesions seen in SWI were a result of deoxyhemoglobin in the blood, and so may indicate areas of hypoxia. A smaller number of SWI lesions coincided with parenchymal iron, demyelination, and/or inflammation. PMID- 23027880 TI - EDSS variability before randomization may limit treatment discovery in primary progressive MS. AB - BACKGROUND: Baseline Expanded Disability Status Scale (EDSS) is usually based on a single measurement. Here we evaluated whether using a baseline EDSS derived from two pre-treatment measurements improves the detection of progression events and the ability to demonstrate a therapeutic effect in delaying MS disability progression. METHODS: Real data from OLYMPUS, a phase II/III randomized, placebo controlled trial of rituximab in patients with primary progressive multiple sclerosis (PPMS), as well as simulated data were analyzed. Several definitions of baseline EDSS were used to capture sustained disability progression (SDP) events. Variations in the EDSS were estimated by linear mixed-effect models. RESULTS: Selecting the higher of two baseline EDSS scores lowered the number of SDP events in both treatment groups, so decreasing sensitivity, and reduced the number of false SDP events, so increasing specificity. Conversely, selecting the lower of two baseline scores increased sensitivity but decreased specificity. Increased power (~7% based on the simulation study) was observed when the average of screening and Week 0 EDSS scores was used for baseline. CONCLUSION: Baseline EDSS derived from two pre-treatment EDSS measurements may enhance the ability of detecting a therapeutic effect in slowing disability progression in PPMS. This strategy could be implemented in future clinical trials of patients with MS. PMID- 23027881 TI - Multiple sclerosis and inflammatory bowel diseases: what we know and what we would need to know! AB - Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) but the causes have not been defined. The disease process appears to involve interplay between environmental factors and certain susceptibility genes. It is likely that the identification of the exact etiological mechanisms will permit the development of preventive and curative treatments. Evaluation of several diseases found to be more often associated than by chance alone may reveal clues to the etiology of those disorders. An association between MS and inflammatory bowel diseases (IBD) was suggested by the observation of an increased incidence of IBD among MS patients. A problem in the interpretation of the data rests, in part, with the observation that abnormal findings in brain magnetic resonance imaging (MRI) may be reported as MS in IBD patients. Defining the limits between incidental MRI findings and findings compatible with MS has resulted in further exploration of this possible association. PMID- 23027882 TI - Implications of infant cognition for executive functions at age 11. AB - Recent work suggests that executive functions, the cornerstone of higher-level cognitive operations, are driven by basic information processing abilities. Using structural equation modeling, with latent variables, the present study provides the first evidence that this driving force begins in infancy, such that abilities in infancy predict executive functions at age 11. Information processing abilities in three domains (attention, processing speed, and memory) were assessed when participants were infants (7 and 12 months) and toddlers (24 and 36 months) and were used to predict three executive functions (working memory, inhibition, and shifting) when participants were 11 years old. A model relating infant abilities to age-11 executive functions fit well, and accounted for 9% to 19% of the variance in the executive functions. Paths from both speed and memory in infancy to age-11 working memory were significant, as was the path from Speed in infancy to age-11 Shifting. A model using abilities in toddlerhood as predictors fit similarly. These findings implicate early basic cognitive abilities in the development of executive functions. PMID- 23027884 TI - Transitions. PMID- 23027885 TI - Annual medical costs and healthcare resource use in patients with systemic sclerosis in an insured population. AB - OBJECTIVE: Systemic sclerosis (SSc) is a chronic autoimmune disease. The objective of our study was to estimate the medical costs and healthcare resource use of subjects with SSc in a large US managed care plan. METHODS: Subjects at least 18 years of age and with claims-based evidence of SSc (ICD-9-CM code 710.1x) were identified from a health plan database from 2003 through 2008. Subjects were matched to unaffected controls, based on index date, age, sex, geographic region, time on insurance, and comorbidity score. Costs and resource use were identified during the 12-month postindex period. A generalized linear model (GLM) was used to estimate costs, controlling for demographic and clinical characteristics. RESULTS: In this study, 1648 subjects with SSc were matched to 4944 controls. Mean overall annual medical costs were higher among SSc subjects than controls ($17,365 vs $5,508; p < 0.001). A GLM model supported these results. Evidence of lung disease, gastrointestinal bleeding, or renal disease increased costs (all p < 0.001). Compared to controls, significantly higher proportions of SSc subjects had postindex ambulatory visits, emergency department visits, and inpatient hospital stays (all p < 0.001). CONCLUSION: Our findings suggest that the medical costs and resource use associated with treating SSc are high (compared to matched controls), and as expected, subjects with serious disease complications experience the highest costs. PMID- 23027886 TI - Orofacial symptoms related to temporomandibular joint arthritis in juvenile idiopathic arthritis: smallest detectable difference in self-reported pain intensity. AB - OBJECTIVE: Temporomandibular joint (TMJ) inflammation in patients with juvenile idiopathic arthritis (JIA) may lead to mandibular growth disturbances and interfere with optimal joint and muscle function. Orofacial symptoms are common clinical findings in relation to TMJ arthritis in adolescence. Knowledge about their clinical manifestation is important for TMJ arthritis diagnosis, treatment choice, and outcome evaluation. The aim of our prospective observational study was to evaluate and describe the frequency, the main complaints, and the localization of TMJ arthritis-related orofacial symptoms. The smallest detectable differences (SDD) for minimal, average, and maximal pain were estimated. METHODS: Thirty-three patients with JIA and arthritis-related orofacial symptoms in relation to 55 affected TMJ were included in our questionnaire study (mean age 14.11 yrs). Calculation of the SDD was based on a duplicate assessment 45 min after the first questionnaire was completed. RESULTS: The majority of the patients had common orofacial symptoms during mastication and maximal mouth opening procedures. Persistent orofacial symptoms were rare. The TMJ area in combination with the masseter muscle region was the orofacial region where symptoms were most common. The SDD for minimal, average, and maximal pain were between 10 and 14 mm on a visual analog scale. CONCLUSION: Our study offers new knowledge about TMJ arthritis-related orofacial symptoms that may aid diagnosis and clinical decision-making. We suggest that TMJ arthritis-related orofacial symptoms could be understood as products of the primary TMJ inflammation in combination with secondary myogenic and functional issues. PMID- 23027887 TI - Multiple courses of rituximab produce sustained clinical and radiographic efficacy and safety in patients with rheumatoid arthritis and an inadequate response to 1 or more tumor necrosis factor inhibitors: 5-year data from the REFLEX study. AB - OBJECTIVE: This 5-year observational posthoc analysis of the REFLEX study and its open-label extension assessed clinical efficacy, radiographic response, and safety of rituximab (RTX) in patients with rheumatoid arthritis (RA) who had an inadequate response to tumor necrosis factor (TNF) inhibitors. METHODS: Patients in REFLEX were originally randomized to placebo (PBO) + methotrexate (MTX; PBO randomized) or RTX + MTX (RTX-randomized). PBO-randomized patients were rescued with RTX as appropriate. Patients responding to initial RTX treatment could receive further RTX courses. For clinical efficacy and safety analyses, PBO randomized patients were re-baselined prior to first RTX treatment and the data were pooled with RTX-randomized patient data. Efficacy outcomes 24 weeks after each course were calculated relative to first RTX pretreatment baseline. Radiographic outcomes were assessed relative to randomization baseline for both PBO-randomized and RTX-randomized groups. RESULTS: A total of 480 patients received >= 1 RTX course. At 24 weeks, American College of Rheumatology 20/50/70 responses were 62.0%, 30.8%, and 13.0%, respectively at course 1 (n = 400) and 70.3%, 41.8%, and 22.0% at course 5 (n = 91). European League Against Rheumatism good/moderate responses were 77.2% and 84.4% at courses 1 (n = 390) and 5 (n = 90). Rates of adverse events (AE), serious AE, and infections generally remained stable. Rate of progressive joint damage (PJD; change in mean Total Sharp Score) decreased over time in both PBO-randomized (n = 79) and RTX-randomized (n = 105) groups. Mean change from baseline in PJD over 5 years was greater in PBO randomized versus RTX-randomized patients (5.51 vs 3.21). CONCLUSION: RTX re treatment over 5 years is associated with maintained or improved efficacy, continued inhibition of PJD, and a safety profile consistent with that previously reported. A delay in initiating RTX treatment may result in increased PJD. PMID- 23027888 TI - Familial Mediterranean fever in siblings. AB - OBJECTIVE: Genetic and environmental factors have been implicated in disease severity and development of amyloidosis in familial Mediterranean fever (FMF). We investigated similarities in clinical characteristics, disease severity, and treatment response within siblings with FMF. METHODS: The study group consisted of 2 or more siblings who were followed in our center with the diagnosis of FMF. Siblings were evaluated for demographic data, clinical and laboratory disease features, genetic analysis of MEFV mutations, and disease severity score. The intraclass correlation coefficient (ICC), which can be interpreted as the expected correlation between 2 siblings, was used to reflect within-family similarity. RESULTS: The study included 67 pediatric patients from 31 different families. When we investigated the similarity of siblings after adjusting for genetic effects, we found very low ICC with p > 0.05 in the majority of clinical features, disease severity, and colchicine dosages. However, age at disease onset, age at onset of therapy, attack-free acute-phase reactant levels, and presence of amyloidosis were found to be similar within siblings (relatively high ICC with p < 0.05). CONCLUSION: Siblings with FMF had different clinical findings and disease severity. They had similar amyloidogenic potential, proven by both similar presence of amyloid and increased levels of acute-phase reactants between attacks. Our findings strongly support that genetic factors may be more dominant in the development of amyloidosis. PMID- 23027889 TI - Semiquantified noncalcified coronary plaque in systemic lupus erythematosus. AB - OBJECTIVE: A major cause of morbidity and mortality in systemic lupus erythematosus (SLE) is accelerated coronary atherosclerosis. New technology (computed tomographic angiography) can measure noncalcified coronary plaque (NCP), which is more prone to rupture. We report on a study of semiquantified NCP in SLE. METHODS: Patients with SLE (n = 147) with no history of cardiovascular disease underwent 64-slice coronary multidetector computed tomography (MDCT). The MDCT scans were evaluated quantitatively by a radiologist, using dedicated software. RESULTS: The group of 147 patients with SLE was 86% female, 70% white, 29% African American, and 3% other ethnicity. The mean age was 51 years. In our univariate analysis, the major traditional cardiovascular risk factors associated with noncalcified plaque were age (p = 0.007), obesity (p = 0.03; measured as body mass index), homocysteine (p = 0.05), and hypertension (p = 0.04). Anticardiolipin (p = 0.026; but not lupus anticoagulant) and anti-dsDNA (p = 0.03) were associated with higher noncalcified plaque. Prednisone and hydroxychloroquine therapy had no effect, but methotrexate (MTX) use was associated with higher noncalcified plaque (p = 0.0001). In the best multivariate model, age, current MTX use, and history of anti-dsDNA remained significant. CONCLUSION: Our results suggest that serologic SLE (anti-dsDNA) and traditional cardiovascular risk factors contribute to semiquantified noncalcified plaque in SLE. The association with MTX is not understood, but should be replicated in larger studies and in multiple centers. PMID- 23027891 TI - Different type of carotid arterial wall remodeling in rheumatoid arthritis compared with healthy subjects: a case-control study. AB - OBJECTIVE: Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) risk, but mechanisms behind this increased risk have not been fully elucidated. Carotid arterial remodeling is the change of structural properties in response to hemodynamic or metabolic factors aimed at keeping wall stress within certain limits. This process might become maladaptive when stress on the arterial wall increases beyond these limits. We investigated whether maladaptive carotid arterial remodeling is present in RA compared with control subjects. METHODS: The 2 cohorts were 96 patients with RA and 274 healthy subjects, who were investigated cross-sectionally. Carotid intima-media thickness (cIMT) and interadventitial diameter (IAD) were assessed by B-mode carotid ultrasonography. Lumen diameter (LD), circumferential wall stress (CWS), and circumferential wall tension (CWT) were calculated. Linear regression analyses were used to investigate the association between presence of RA and carotid arterial remodeling. RESULTS: Compared with healthy subjects, RA was associated with a 0.40 mm (9.3%) greater LD, 0.41 mm (7.8%) greater IAD, 10% higher CWS, and 8% higher CWT. The groups had comparable cIMT. Associations remained similar after exclusion of patients with prior CV disease and after adjustment for demographic factors and CV risk factors. CONCLUSION: RA is associated with maladaptive outward carotid arterial remodeling. These results are relevant because maladaptive outward remodeling is associated with plaque instability and rupture. These results indicate an alternative pathway, beyond the traditional CV risk factors, in RA that amplifies the CV risk. PMID- 23027890 TI - Influence of the IL6 gene in susceptibility to systemic sclerosis. AB - OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan((r)) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795 rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression. PMID- 23027892 TI - Prevalence and risk factors of anterior atlantoaxial subluxation in ankylosing spondylitis. AB - OBJECTIVE: In ankylosing spondylitis (AS), the cervical spine, like other sections of the spine and sacroiliac joints, is vulnerable during the disease process. Atlantoaxial subluxation (AAS) has been studied in connection with AS, but its risk factors and progression have not been clarified. Therefore, this study assessed the prevalence and risk factors of AAS in patients with AS. METHODS: A total of 819 patients with AS who fulfilled the modified New York criteria and were examined with a full-flexion lateral view of the cervical spine by radiograph were enrolled from an outpatient clinic. The medical records of the patients were retrospectively reviewed and the anterior atlantodental interval (AADI) in the lateral flexion view of the cervical spine radiograph was investigated by 2 experienced musculoskeletal radiologists. We defined the AAS as an AADI of > 3 mm, and progression of AADI as a progression rate > 0.5 mm/year. RESULTS: AAS was found in 14.1% (116/819) of patients. Progression of AADI occurred in 32.1% (26/81) patients with AAS and 5.0% (16/320) patients without AAS (p < 0.001). The development of AAS was significantly associated with elevated C-reactive protein [CRP; OR 2.19 (1.36-3.53)], peripheral arthritis [OR 2.05 (1.36-3.07)], use of anti-tumor necrosis factor antagonists because of failure of nonsteroidal antiinflammatory drugs/disease-modifying antirheumatic drugs [NSAID/DMARD; OR 2.28 (1.52-3.42)], and uveitis [OR 1.71 (1.13-2.59)]. These factors were adjusted for age, sex, and disease duration by logistic regression analysis. No clear association was found for HLA-B27, seropositivity, or smoking status with AAS. CONCLUSION: AAS is a frequent complication, and the progression of AADI was more rapid in cases with AAS. The presence of peripheral arthritis, or high disease activity with elevated CRP level or refractory to conventional NSAID/DMARD, independently increased the risk of AAS, suggesting that clinicians should focus on the detection and monitoring of AAS, especially in cases with associated risk factors. PMID- 23027893 TI - Clinical consequences following regulatory changes in respect to reimbursement of statins cost by the Icelandic Social Insurance Administration. AB - INTRODUCTION: On 1 March 2009, a new reimbursement system was introduced by the Ministry of Health of Iceland regarding drugs to treat hyperlipidaemia. The Social Insurance Administration was only authorised to reimburse 10 and 20 mg simvastatin unless patients were eligible to receive a medical card from the Social Insurance Administration. The purpose of this study was to evaluate the influence of this reimbursement regulation on the clinical outcome. MATERIALS AND METHODS: Patients that received hyperlipidaemia treatment and were admitted to the cardiac ward were enrolled. The criteria were that the patients had been admitted 1 year prior to the regulation change and were using other statins than simvastatin. RESULTS: Out of 233 eligible patients 170 (73%) reached the treatment goal before the switch. After the switch, only 126 (54%) reached their goal (p<0.05). Total cholesterol was found to be increased after the switch by a mean of 0.48 mmol/l (range 3.90-5.53 mmol/l, p<0.001). Low-density lipoprotein cholesterol increased by a mean of 0.48 mmol/l (range 1.62-3.11, p<0.001). The level of triglycerides did not change significantly. Before the introduction of the new regulations, 73% of subjects were well controlled, but after 1 March 2009, this figure dropped to 46% (37% decrease). CONCLUSIONS: In order to lower costs for subsidising drugs, a switch to simvastatin from other cholesterol lowering drugs was implemented (by the Ministry of Health of Iceland). The result was a significant and unwanted increase in cholesterol levels among patients with heart disease. The reason seems to be inaccurate prescriptions due to lack of competence among physicians and pharmacists. The use of "one drug fits all" does not comply here. PMID- 23027894 TI - "No alcohol, no party": an explorative study of young Danish moderate drinkers. AB - BACKGROUND: Danish youth has for years had the highest alcohol consumption in Europe, however recent surveys show that consumption levels have diminished slightly and that the age of first intoxication has been raised. AIM: To explore young moderate drinkers' attitudes, values, and behaviour in relation to alcohol consumption. DESIGN, SETTING, AND PARTICIPANTS: Data consists of 10 individual semi-structured interviews with 16-17-year-old moderate drinkers attending high school in Copenhagen, Denmark. RESULTS: The study shows that the respondents perceive drinking as a necessity for feeling included at parties, but also that they do not feel a need to drink large amounts of alcohol in order to feel this social inclusion. The study finds that respondents employ a number of different behavioural and cognitive strategies aimed at controlling their own and close friends' drinking behaviour, and that short-term negative social implications are of much greater concern than long-term health consequences. In addition, the study shows that parents have a limited direct influence in this group. CONCLUSIONS: The study identifies a group of young people who have clearly defined restrictions as to what they consider positive drinking behaviour. As parents and long-term health consequences only have an limited influence on the respondents' drinking behaviour, these elements should not have primary focus in future interventions. In stead, interventions should take into account the social dynamics involved in drinking and recognise that the social qualities surrounding alcohol weighs higher among this group of young people than the quantity of alcohol consumed. PMID- 23027895 TI - Gender difference in wellbeing during school lessons among 10-12-year-old children: the importance of school subjects and student-teacher relationships. AB - AIMS: The aim of the study was to examine gender difference in self-reported wellbeing during school lessons among Icelandic 10-12-year-old boys and girls, in grades 5-7 in elementary schools. Also, to examine whether factors related to attitudes towards school subjects, student-teacher relationships and student-peer relationships mediated the associations between gender and wellbeing during school lessons. METHODS: A cross-sectional anonymous survey was conducted among 88% (in total 11,387 participants) of all registered students aged 10-12 attending grades 5-7 in Iceland. Multivariate logistic regression was used to test main, mediation, and interaction effects. RESULTS: Boys reported significantly less wellbeing during school lessons than girls. Not finding the subjects taught at school fun fully mediated the relationship between gender and self-reported wellbeing during school lessons. Furthermore, when not considering other school-related factors, finding the subjects at school to hard, not liking the teachers, not being praised by teachers, and being bullied in recess partially mediated the relationship between gender and self-reported wellbeing during school lessons. CONCLUSIONS: The results suggest that to improve boy's wellbeing during school lessons, making school subject more appealing to boys is of importance. Furthermore, fostering teacher-student relationships and decreasing bullying of boys in recess should be emphasised. PMID- 23027896 TI - Deep venous thrombosis and pulmonary embolism caused by an intravascular synovial sarcoma of the common femoral vein. AB - Malignant tumors arising in deep veins of the lower extremities are very uncommon. To our best knowledge, this is the seventh case of a primary venous intravascular synovial sarcoma (SS) reported in literature. A 32-year-old woman was admitted with a second episode of deep venous thrombosis of the right lower limb and pulmonary embolism. Physical and radiological examinations showed besides the thrombosis a tumor arising from the right common femoral vein involving the bifurcation of the common femoral artery. At surgery, en block resection of the tumor including the deep femoral vein and arterial bifurcation was done with an arterial reconstruction using a synthetic graft. Histopathological examination revealed an intravascular SS of the common femoral vein. The mainstay of curative therapy is complete surgical resection of all tumor manifestations with negative histological margins. PMID- 23027897 TI - Cedric Blanpain: the stories stem cells tell. Interview by Caitlin Sedwick. PMID- 23027898 TI - Cell biology: at the center of modern biomedicine. AB - How does basic cell biology contribute to biomedicine? A new series of Features in JCB provides a cross section of compelling examples of how basic cell biology findings can lead to therapeutics. These articles highlight the fruitful, essential, and increasingly prominent bridge that exists between cell biology and the clinic. PMID- 23027899 TI - Progeria: translational insights from cell biology. AB - Cell biologists love to think outside the box, pursuing many surprising twists and unexpected turns in their quest to unravel the mysteries of how cells work. But can cell biologists think outside the bench? We are certain that they can, and clearly some already do. To encourage more cell biologists to venture into the realm of translational research on a regular basis, we would like to share a handful of the many lessons that we have learned in our effort to develop experimental treatments for Hutchinson-Gilford progeria syndrome (HGPS), an endeavor that many view as a "poster child" for how basic cell biology can be translated to the clinic. PMID- 23027900 TI - The genesis of Zelboraf: targeting mutant B-Raf in melanoma. AB - The protein kinase B-Raf is a critical component of the Ras/MAPK signaling pathway. An oncogenic B-Raf mutation that constitutively activates the kinase was identified in ~50% of melanoma patients and in other cancers. A structure-guided drug discovery approach enabled the development of Zelboraf, a targeted inhibitor of oncogenic B-Raf. This drug has been used successfully in the clinic to treat metastatic melanoma patients harboring B-Raf mutations. PMID- 23027901 TI - Antisense-based therapy for the treatment of spinal muscular atrophy. AB - One of the greatest thrills a biomedical researcher may experience is seeing the product of many years of dedicated effort finally make its way to the patient. As a team, we have worked for the past eight years to discover a drug that could treat a devastating childhood neuromuscular disease, spinal muscular atrophy (SMA). Here, we describe the journey that has led to a promising drug based on the biology underlying the disease. PMID- 23027902 TI - S-nitrosylation of B23/nucleophosmin by GAPDH protects cells from the SIAH1-GAPDH death cascade. AB - B23/nucleophosmin is a multifunctional protein that participates in cell survival signaling by shuttling between the nucleolus/nucleoplasm and nucleus/cytoplasm. In this paper, we report a novel neuroprotective function of B23 through regulation of the SIAH1-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) death cascade. B23 physiologically bound to both SIAH1 and GAPDH, disrupting the SIAH1 GAPDH complex in the nucleus in response to nitrosative stress. S-nitrosylation of B23 at cysteine 275 by trans-nitrosylation from GAPDH dramatically reduced the interaction between SIAH1 and GAPDH. S-nitrosylation of B23 enhanced B23-SIAH1 binding and mediated the neuroprotective actions of B23 by abrogating the E3 ligase activity of SIAH1. In mice, overexpression of B23 notably inhibited N methyl-d-aspartate-mediated neurotoxicity, whereas expression of the C275S mutant, which is defective in binding to SIAH1, did not prevent neurotoxicity. Thus, B23 regulates neuronal survival by preventing SIAH1-GAPDH death signaling under stress-induced conditions in the brain. PMID- 23027903 TI - Differentiation-associated microRNAs antagonize the Rb-E2F pathway to restrict proliferation. AB - The cancer-associated loss of microRNA (miRNA) expression leads to a proliferative advantage and aggressive behavior through largely unknown mechanisms. Here, we exploit a model system that recapitulates physiological terminal differentiation and its reversal upon oncogene expression to analyze coordinated mRNA/miRNA responses. The cell cycle reentry of myotubes, forced by the E1A oncogene, was associated with a pattern of mRNA/miRNA modulation that was largely reciprocal to that induced during the differentiation of myoblasts into myotubes. The E1A-induced mRNA response was preponderantly Retinoblastoma protein (Rb)-dependent. Conversely, the miRNA response was mostly Rb-independent and exerted through tissue-specific factors and Myc. A subset of these miRNAs (miR-1, miR-34, miR-22, miR-365, miR-29, miR-145, and Let-7) was shown to coordinately target Rb-dependent cell cycle and DNA replication mRNAs. Thus, a dual level of regulation-transcriptional regulation via Rb-E2F and posttranscriptional regulation via miRNAs-confers robustness to cell cycle control and provides a molecular basis to understand the role of miRNA subversion in cancer. PMID- 23027904 TI - Cortical dynein is critical for proper spindle positioning in human cells. AB - Correct spindle positioning is fundamental for proper cell division during development and in stem cell lineages. Dynein and an evolutionarily conserved ternary complex (nuclear mitotic apparatus protein [NuMA]-LGN-Galpha in human cells and LIN-5-GPR-1/2-Galpha in Caenorhabditis elegans) are required for correct spindle positioning, but their relationship remains incompletely understood. By analyzing fixed specimens and conducting live-imaging experiments, we uncovered that appropriate levels of ternary complex components are critical for dynein-dependent spindle positioning in HeLa cells and C. elegans embryos. Moreover, using mutant versions of Galpha in both systems, we established that dynein acts at the membrane to direct spindle positioning. Importantly, we identified a region within NuMA that mediates association with dynein. By using this region to target dynein to the plasma membrane, we demonstrated that the mere presence of dynein at that location is sufficient to direct spindle positioning in HeLa cells. Overall, we propose a model in which the ternary complex serves to anchor dynein at the plasma membrane to ensure correct spindle positioning. PMID- 23027905 TI - Structural insights into WHAMM-mediated cytoskeletal coordination during membrane remodeling. AB - The microtubule (MT) and actin cytoskeletons drive many essential cellular processes, yet fairly little is known about how their functions are coordinated. One factor that mediates important cross talk between these two systems is WHAMM, a Golgi-associated protein that utilizes MT binding and actin nucleation activities to promote membrane tubulation during intracellular transport. Using cryoelectron microscopy and other biophysical and biochemical approaches, we unveil the underlying mechanisms for how these activities are coordinated. We find that WHAMM bound to the outer surface of MT protofilaments via a novel interaction between its central coiled-coil region and tubulin heterodimers. Upon the assembly of WHAMM onto MTs, its N-terminal membrane-binding domain was exposed at the MT periphery, where it can recruit vesicles and remodel them into tubular structures. In contrast, MT binding masked the C-terminal portion of WHAMM and prevented it from promoting actin nucleation. These results give rise to a model whereby distinct MT-bound and actin-nucleating populations of WHAMM collaborate during membrane tubulation. PMID- 23027906 TI - The role of retrograde intraflagellar transport in flagellar assembly, maintenance, and function. AB - The maintenance of flagellar length is believed to require both anterograde and retrograde intraflagellar transport (IFT). However, it is difficult to uncouple the functions of retrograde transport from anterograde, as null mutants in dynein heavy chain 1b (DHC1b) have stumpy flagella, demonstrating solely that retrograde IFT is required for flagellar assembly. We isolated a Chlamydomonas reinhardtii mutant (dhc1b-3) with a temperature-sensitive defect in DHC1b, enabling inducible inhibition of retrograde IFT in full-length flagella. Although dhc1b-3 flagella at the nonpermissive temperature (34 degrees C) showed a dramatic reduction of retrograde IFT, they remained nearly full-length for many hours. However, dhc1b-3 cells at 34 degrees C had strong defects in flagellar assembly after cell division or pH shock. Furthermore, dhc1b-3 cells displayed altered phototaxis and flagellar beat. Thus, robust retrograde IFT is required for flagellar assembly and function but is dispensable for the maintenance of flagellar length. Proteomic analysis of dhc1b-3 flagella revealed distinct classes of proteins that change in abundance when retrograde IFT is inhibited. PMID- 23027907 TI - Cecal volvulus. PMID- 23027909 TI - Postobstructive pulmonary edema associated with a substernal goitre. PMID- 23027910 TI - Alcohol consumption and the risk of incident atrial fibrillation among people with cardiovascular disease. AB - BACKGROUND: Moderate alcohol consumption may reduce cardiovascular events, but little is known about its effect on atrial fibrillation in people at high risk of such events. We examined the association between moderate alcohol consumption and the risk of incident atrial fibrillation among older adults with existing cardiovascular disease or diabetes. METHODS: We analyzed data for 30 433 adults who participated in 2 large antihypertensive drug treatment trials and who had no atrial fibrillation at baseline. The patients were 55 years or older and had a history of cardiovascular disease or diabetes with end-organ damage. We classified levels of alcohol consumption according to median cut-off values for low, moderate and high intake based on guidelines used in various countries, and we defined binge drinking as more than 5 drinks a day. The primary outcome measure was incident atrial fibrillation. RESULTS: A total of 2093 patients had incident atrial fibrillation. The age- and sex-standardized incidence rate per 1000 person-years was 14.5 among those with a low level of alcohol consumption, 17.3 among those with a moderate level and 20.8 among those with a high level. Compared with participants who had a low level of consumption, those with higher levels had an increased risk of incident atrial fibrillation (adjusted hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.04-1.26, for moderate consumption; 1.32, 95% CI 0.97-1.80, for high consumption). Results were similar after we excluded binge drinkers. Among those with moderate alcohol consumption, binge drinkers had an increased risk of atrial fibrillation compared with non binge drinkers (adjusted HR 1.29, 95% CI 1.02-1.62). INTERPRETATION: Moderate to high alcohol intake was associated with an increased incidence of atrial fibrillation among people aged 55 or older with cardiovascular disease or diabetes. Among moderate drinkers, the effect of binge drinking on the risk of atrial fibrillation was similar to that of habitual heavy drinking. PMID- 23027911 TI - African traditional medicine struggles to find its place within health care. PMID- 23027912 TI - Science and patient safety. PMID- 23027914 TI - Needling toward essential health benefits. PMID- 23027916 TI - Management of borderline personality disorder. PMID- 23027918 TI - Playing in the big leagues. PMID- 23027917 TI - Sleep disturbance and cardiovascular risk in adolescents. AB - BACKGROUND: Evidence suggests that inadequate or disturbed sleep is associated with increased cardiovascular risk in adults. There are limited data on sleep quality and associated cardiovascular risk in children. METHODS: We obtained data on adolescents from the 2009/10 cycle of the Healthy Heart Schools' Program, a population-based cross-sectional study in the Niagara region of Ontario. Participants underwent measurements of cardiometabolic risk factors, including body mass index (BMI), lipid profile and blood pressure, and they completed questionnaires measuring sleeping habits and nutritional status. We assessed sleep disturbance using the sleep disturbance score derived from the Pittsburgh Sleep Quality Index. We explored associations between sleeping habits and cardiovascular risk factors. RESULTS: Among 4104 adolescents (51% male), the mean hours of sleep per night (+/- standard deviation) were 7.9 +/- 1.1 on weeknights and 9.4 +/- 1.6 on weekends. In total, 19% of participants reported their sleep quality as fairly bad or very bad on weeknights and 10% reported it as fairly bad or very bad on weekends. In the multivariable regression models, a higher sleep disturbance score was associated with increased odds of being at high cardiovascular risk (highest v. lowest tertile odds ratio [OR] 1.43 [95% confidence interval (CI) 1.16-1.77], p < 0.001), increased odds of hypertension (highest v. lowest tertile OR 1.44 [95% CI 1.02-2.05], p = 0.05) and increased odds of elevated non-high density lipoprotein cholesterol (highest v. lowest tertile OR 1.28 [95% CI 1.00-1.64], p = 0.05). The mean duration of sleep was not associated with these outcomes. INTERPRETATION: In healthy adolescents, sleep disturbance is associated with cardiovascular risk factor abnormalities. Intervention strategies to optimize sleep hygiene early in life may be important for the prevention of cardiovascular disease. PMID- 23027919 TI - Europe proposes laxer regulation of clinical trials. PMID- 23027921 TI - Alkaline salts to counteract bone resorption and protein wasting induced by high salt intake: results of a randomized controlled trial. AB - High sodium chloride (NaCl) intake can induce low-grade metabolic acidosis (LGMA) and may thus influence bone and protein metabolism. We hypothesized that oral potassium bicarbonate (KHCO(3)) supplementation may compensate for NaCl-induced, LGMA-associated bone resorption and protein losses. Eight healthy male subjects participated in a randomized trial with a crossover design. Each of two study campaigns consisted of 5 d of dietary and environmental adaptation followed by 10 d of intervention and 1.5 d of recovery. In one study campaign, 90 mmol KHCO(3)/d were supplemented to counteract NaCl-induced LGMA, whereas the other campaign served as a control with only high NaCl intake. When KHCO(3) was ingested during high NaCl intake, postprandial buffer capacity ([HCO(3)(-)]) increased (P = 0.002). Concomitantly, urinary excretion of free potentially bioactive glucocorticoids [urinary free cortisol (UFF) and urinary free cortisone (UFE)] was reduced by 14% [?(UFF,UFE); P = 0.024]. Urinary excretion of calcium and bone resorption marker N-terminal telopeptide of type I collagen was reduced by 12 and 8%, respectively (calcium, P = 0.047; N-terminal bone collagen telopeptide, P = 0.044). There was a trend of declining net protein catabolism when high NaCl was combined with KHCO(3) (P = 0.052). We conclude that during high salt intake, the KHCO(3)-induced postprandial shift to a more alkaline state reduces metabolic stress. This leads to decreased bone resorption and protein degradation, which in turn might initiate an anticatabolic state for the musculoskeletal system in the long run. PMID- 23027922 TI - Parathyroid hormone and insulin resistance in distinct phenotypes of severe obesity: a cross-sectional analysis in middle-aged men and premenopausal women. AB - CONTEXT: High levels of PTH are reported in obese individuals and related to increased cardiometabolic risk. OBJECTIVE: Our objective was to evaluate whether the relationship between PTH, insulin resistance, and related metabolic parameters differ between metabolically healthy obese (MHO) and insulin-resistant obese (IRO) subjects. DESIGN AND SETTING: We conducted a cross-sectional study among patients evaluated for bariatric surgery in our University Hospital. PATIENTS: Patients initially included were 174 severely obese subjects (114 women, aged 40 +/- 5 yr, body mass index of 45 +/- 6 kg/m(2)) without diabetes, chronic kidney disease, or hyperparathyroidism. MHO (n = 43) and IRO (n = 86) subjects were identified according to quartiles of insulin resistance. MAIN OUTCOME MEASURES: Fasting and postload glucose, insulin, total and high-density lipoprotein cholesterol, triglycerides, creatinine, calcium, phosphorus, PTH, 25 hydroxyvitamin D (25OHD), fibrinogen, and high-sensitivity C-reactive protein were assessed. Insulin sensitivity index was derived from a 75-g oral glucose tolerance test. Fat distribution and bone mineral density were assessed with dual energy x-ray absorptiometry. RESULTS: Although 25OHD levels were higher in MHO than in IRO subjects [72.23 (59.41-80.36) vs. 52.36 (41.98-62.57) nmol/liter, P = 0.002], PTH levels were comparable between groups (74.4 +/- 13.2 vs. 72.1 +/- 15.1 ng/liter, P = 0.34). No differences in serum calcium, phosphorus, bone mineral density, and renal function were detected. An independent inverse association between 25OHD and insulin resistance was seen in both groups. In contrast to IRO subjects, after adjusting for covariates, PTH levels were unrelated to insulin sensitivity index, fasting and postload glucose, insulin, and high-sensitivity C-reactive protein in MHO subjects. CONCLUSIONS: MHO and IRO subjects show comparably high levels of circulating PTH, which are not associated with insulin resistance and related metabolic parameters in MHO subjects. Most of the associations observed in IRO subjects appear to be mediated by greater truncal fat mass. PMID- 23027923 TI - Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma. AB - Kaposi's sarcoma (KS), a multifocal vascular neoplasm linked to human herpesvirus 8 (HHV-8/KS-associated herpesvirus [KSHV]) infection, is the most common AIDS associated malignancy. Clinical management of KS has proven to be challenging because of its prevalence in immunosuppressed patients and its unique vascular and inflammatory nature that is sustained by viral and host-derived paracrine acting factors primarily released under hypoxic conditions. We show that interactions between the regulatory lectin galectin-1 (Gal-1) and specific target N-glycans link tumor hypoxia to neovascularization as part of the pathogenesis of KS. Expression of Gal-1 is found to be a hallmark of human KS but not other vascular pathologies and is directly induced by both KSHV and hypoxia. Interestingly, hypoxia induced Gal-1 through mechanisms that are independent of hypoxia-inducible factor (HIF) 1alpha and HIF-2alpha but involved reactive oxygen species-dependent activation of the transcription factor nuclear factor kappaB. Targeted disruption of Gal-1-N-glycan interactions eliminated hypoxia-driven angiogenesis and suppressed tumorigenesis in vivo. Therapeutic administration of a Gal-1-specific neutralizing mAb attenuated abnormal angiogenesis and promoted tumor regression in mice bearing established KS tumors. Given the active search for HIF-independent mechanisms that serve to couple tumor hypoxia to pathological angiogenesis, our findings provide novel opportunities not only for treating KS patients but also for understanding and managing a variety of solid tumors. PMID- 23027925 TI - Human lymphoma mutations reveal CARD11 as the switch between self-antigen-induced B cell death or proliferation and autoantibody production. AB - Self-tolerance and immunity are actively acquired in parallel through a poorly understood ability of antigen receptors to switch between signaling death or proliferation of antigen-binding lymphocytes in different contexts. It is not known whether this tolerance-immunity switch requires global rewiring of the signaling apparatus or if it can arise from a single molecular change. By introducing individual CARD11 mutations found in human lymphomas into antigen activated mature B lymphocytes in mice, we find here that lymphoma-derived CARD11 mutations switch the effect of self-antigen from inducing B cell death into T cell-independent proliferation, Blimp1-mediated plasmablast differentiation, and autoantibody secretion. Our findings demonstrate that regulation of CARD11 signaling is a critical switch governing the decision between death and proliferation in antigen-stimulated mature B cells and that mutations in this switch represent a powerful initiator for aberrant B cell responses in vivo. PMID- 23027926 TI - Role for urea in nitrification by polar marine Archaea. AB - Despite the high abundance of Archaea in the global ocean, their metabolism and biogeochemical roles remain largely unresolved. We investigated the population dynamics and metabolic activity of Thaumarchaeota in polar environments, where these microorganisms are particularly abundant and exhibit seasonal growth. Thaumarchaeota were more abundant in deep Arctic and Antarctic waters and grew throughout the winter at surface and deeper Arctic halocline waters. However, in situ single-cell activity measurements revealed a low activity of this group in the uptake of both leucine and bicarbonate (<5% Thaumarchaeota cells active), which is inconsistent with known heterotrophic and autotrophic thaumarchaeal lifestyles. These results suggested the existence of alternative sources of carbon and energy. Our analysis of an environmental metagenome from the Arctic winter revealed that Thaumarchaeota had pathways for ammonia oxidation and, unexpectedly, an abundance of genes involved in urea transport and degradation. Quantitative PCR analysis confirmed that most polar Thaumarchaeota had the potential to oxidize ammonia, and a large fraction of them had urease genes, enabling the use of urea to fuel nitrification. Thaumarchaeota from Arctic deep waters had a higher abundance of urease genes than those near the surface suggesting genetic differences between closely related archaeal populations. In situ measurements of urea uptake and concentration in Arctic waters showed that small-sized prokaryotes incorporated the carbon from urea, and the availability of urea was often higher than that of ammonium. Therefore, the degradation of urea may be a relevant pathway for Thaumarchaeota and other microorganisms exposed to the low-energy conditions of dark polar waters. PMID- 23027927 TI - Profile of Charles Stanish. PMID- 23027928 TI - Collective mesendoderm migration relies on an intrinsic directionality signal transmitted through cell contacts. AB - Collective cell migration is key to morphogenesis, wound healing, or cancer cell migration. However, its cellular bases are just starting to be unraveled. During vertebrate gastrulation, axial mesendoderm migrates in a group, the prechordal plate, from the embryonic organizer to the animal pole. How this collective migration is achieved remains unclear. Previous work has suggested that cells migrate as individuals, with collective movement resulting from the addition of similar individual cell behavior. Through extensive analyses of cell trajectories, morphologies, and polarization in zebrafish embryos, we reveal that all prechordal plate cells show the same behavior and rely on the same signaling pathway to migrate, as expected if they do so individually. However, by using cell transplants, we demonstrate that prechordal plate migration is a true collective process, as isolated cells do not migrate toward the animal pole. They are still polarized and motile but lose directionality. Directionality is restored upon contact with the endogenous prechordal plate. This contact dependent orientation relies on E-cadherin, Wnt-PCP signaling, and Rac1. Importantly, groups of cells also need contact with the endogenous plate to orient correctly, showing an instructive role of the plate in establishing directionality. Overall, our results lead to an original model of collective migration in which directional information is contained within the moving group rather than provided by extrinsic cues, and constantly maintained in cells by contacts with their neighbors. This self-organizing model could account for collective invasion of new territories, as observed in cancer strands, without requirement for any attractant in the colonized tissue. PMID- 23027929 TI - Protein kinase WNK3 regulates the neuronal splicing factor Fox-1. AB - We report an action of the protein kinase WNK3 on the neuronal mRNA splicing factor Fox-1. Fox-1 splices mRNAs encoding proteins important in synaptic transmission and membrane excitation. WNK3, implicated in the control of neuronal excitability through actions on ion transport, binds Fox-1 and inhibits its splicing activity in a kinase activity-dependent manner. Phosphorylation of Fox-1 by WNK3 does not change its RNA binding capacity; instead, WNK3 increases the cytoplasmic localization of Fox-1, thereby suppressing Fox-1-dependent splicing. These findings demonstrate a role of WNK3 in RNA processing. Considering the implication of WNK3 and Fox-1 in disorders of neuronal development such as autism, WNK3 may offer a target for treatment of Fox-1-induced disease. PMID- 23027924 TI - Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory. AB - One component of memory in the antibody system is long-lived memory B cells selected for the expression of somatically mutated, high-affinity antibodies in the T cell-dependent germinal center (GC) reaction. A puzzling observation has been that the memory B cell compartment also contains cells expressing unmutated, low-affinity antibodies. Using conditional Bcl6 ablation, we demonstrate that these cells are generated through proliferative expansion early after immunization in a T cell-dependent but GC-independent manner. They soon become resting and long-lived and display a novel distinct gene expression signature which distinguishes memory B cells from other classes of B cells. GC-independent memory B cells are later joined by somatically mutated GC descendants at roughly equal proportions and these two types of memory cells efficiently generate adoptive secondary antibody responses. Deletion of T follicular helper (Tfh) cells significantly reduces the generation of mutated, but not unmutated, memory cells early on in the response. Thus, B cell memory is generated along two fundamentally distinct cellular differentiation pathways. One pathway is dedicated to the generation of high-affinity somatic antibody mutants, whereas the other preserves germ line antibody specificities and may prepare the organism for rapid responses to antigenic variants of the invading pathogen. PMID- 23027930 TI - Cell-type homologies and the origins of the neocortex. AB - The six-layered neocortex is a uniquely mammalian structure with evolutionary origins that remain in dispute. One long-standing hypothesis, based on similarities in neuronal connectivity, proposes that homologs of the layer 4 input and layer 5 output neurons of neocortex are present in the avian forebrain, where they contribute to specific nuclei rather than to layers. We devised a molecular test of this hypothesis based on layer-specific gene expression that is shared across rodent and carnivore neocortex. Our findings establish that the layer 4 input and the layer 5 output cell types are conserved across the amniotes, but are organized into very different architectures, forming nuclei in birds, cortical areas in reptiles, and cortical layers in mammals. PMID- 23027931 TI - Functional anatomy of neural circuits regulating fear and extinction. AB - The memory of fear extinction is context dependent: fear that is suppressed in one context readily renews in another. Understanding of the underlying neuronal circuits is, therefore, of considerable clinical relevance for anxiety disorders. Prefrontal cortical and hippocampal inputs to the amygdala have recently been shown to regulate the retrieval of fear memories, but the cellular organization of these projections remains unclear. By using anterograde tracing in a transgenic rat in which neurons express a dendritically-targeted PSD-95:Venus fusion protein under the control of a c-fos promoter, we found that, during the retrieval of extinction memory, the dominant input to active neurons in the lateral amygdala was from the infralimbic cortex, whereas the retrieval of fear memory was associated with greater hippocampal and prelimbic inputs. This pattern of retrieval-related afferent input was absent in the central nucleus of the amygdala. Our data show functional anatomy of neural circuits regulating fear and extinction, providing a framework for therapeutic manipulations of these circuits. PMID- 23027932 TI - Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis. AB - We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the hippocampal dentate gyrus. We have further found that chemicals having efficacy in this in vivo screening assay also protect dopaminergic neurons of the substantia nigra following exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, a mouse model of Parkinson disease. Here, we provide evidence that an active analog of P7C3, known as P7C3A20, protects ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of amyotrophic lateral sclerosis (ALS). P7C3A20 is efficacious in this model when administered at disease onset, and protection from cell death correlates with preservation of motor function in assays of walking gait and in the accelerating rotarod test. The prototypical member of this series, P7C3, delays disease progression in G93A-SOD1 mice when administration is initiated substantially earlier than the expected time of symptom onset. Dimebon, an antihistaminergic drug with significantly weaker proneurogenic and neuroprotective efficacy than P7C3, confers no protection in this ALS model. We propose that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS. PMID- 23027933 TI - Variation in personality and fitness in wild female baboons. AB - Studies of personality in nonhuman primates have usually relied on assessments by humans and seldom considered the function of the resulting "trait" classifications. In contrast, we applied exploratory principal component analysis to seven behaviors among 45 wild female baboons over 7 y to determine whether the personality dimensions that emerged were associated with measures of reproductive success. We identified three relatively stable personality dimensions, each characterized by a distinct suite of behaviors that were not redundant with dominance rank or the availability of kin. Females scoring high on the "Nice" dimension were friendly to all females and often grunted to lower-ranking females to signal benign intent. "Aloof" females were aggressive, less friendly, and grunted primarily to higher-ranking females. "Loner" females were often alone, relatively unfriendly, and also grunted most often to higher-ranking females. Aloof and Loner females were rarely approached by others. Personality dimensions were correlated in different ways with three measures previously shown to be associated with fitness: stress levels and two behavioral indices reflecting the closeness of dyadic bonds formed by individuals. Females who scored high on Nice had high composite sociality indices (CSI) and stable partner preferences, whereas females who scored high on Aloof had lower CSI scores but significantly more stable partner preferences. Loner females had significantly lower CSI scores, less stable partner preferences, and significantly higher glucocorticoid levels. It remains to be determined which of the Nice or Aloof personality dimensions is more adaptive, or whether variation is maintained by contrasting effects on fitness. PMID- 23027934 TI - Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of Parkinson disease. AB - We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the dentate gyrus. Here, we provide evidence that P7C3 also protects mature neurons in brain regions outside of the hippocampus. P7C3 blocks 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated cell death of dopaminergic neurons in the substantia nigra of adult mice, a model of Parkinson disease (PD). Dose-response studies show that the P7C3 analog P7C3A20 blocks cell death with even greater potency and efficacy, which parallels the relative potency and efficacy of these agents in blocking apoptosis of newborn neural precursor cells of the dentate gyrus. P7C3 and P7C3A20 display similar relative effects in blocking 1-methyl-4-phenylpyridinium (MPP(+))-mediated death of dopaminergic neurons in Caenorhabditis elegans, as well as in preserving C. elegans mobility following MPP(+) exposure. Dimebon, an antihistaminergic drug that is weakly proneurogenic and neuroprotective in the dentate gyrus, confers no protection in either the mouse or the worm models of PD. We further demonstrate that the hippocampal proneurogenic efficacy of eight additional analogs of P7C3 correlates with their protective efficacy in MPTP-mediated neurotoxicity. In vivo screening of P7C3 analogs for proneurogenic efficacy in the hippocampus may thus provide a reliable means of predicting neuroprotective efficacy. We propose that the chemical scaffold represented by P7C3 and P7C3A20 provides a basis for optimizing and advancing pharmacologic agents for the treatment of patients with PD. PMID- 23027935 TI - Assessment of morphometry of pulmonary acini in mouse lungs by nondestructive imaging using multiscale microcomputed tomography. AB - Establishing the 3D architecture and morphometry of the intact pulmonary acinus is an essential step toward a more complete understanding of the relationship of lung structure and function. We combined a special fixation method with a unique volumetric nondestructive imaging technique and image processing tools to separate individual acini in the mouse lung. Interior scans of the parenchyma at a resolution of 2 um enabled the reconstruction and quantitative study of whole acini by image analysis and stereologic methods, yielding data characterizing the 3D morphometry of the pulmonary acinus. The 3D reconstructions compared well with the architecture of silicon rubber casts of mouse acini. The image-based segmentation of individual acini allowed the computation of acinar volume and surface area, as well as estimation of the number of alveoli per acinus using stereologic methods. The acinar morphometry of male C57BL/6 mice age 12 wk and 91 wk was compared. Significant increases in all parameters as a function of age suggest a continuous change of the lung morphometry, with an increase in alveoli beyond what has been previously viewed as the maturation phase of the animals. Our image analysis methods open up opportunities for defining and quantitatively assessing the acinar structure in healthy and diseased lungs. The methods applied here to mice can be adjusted for the study of similarly prepared human lungs. PMID- 23027936 TI - Structure of the primed paramyxovirus fusion protein. PMID- 23027937 TI - Regulation of memory CD4 T-cell pool size and function by natural killer T cells in vivo. AB - To develop more effective vaccines and strategies to regulate chronic inflammatory diseases, it is important to understand the mechanisms of immunological memory. Factors regulating memory CD4(+) T helper (Th)-cell pool size and function remain unclear, however. We show that activation of type I invariant natural killer T (iNKT) cells with glycolipid ligands and activation of type II natural killer T (NKT) cells with the endogenous ligand sulfatide induced dramatic proliferation and expansion of memory, but not naive, CD4 T cells. NKT cell-induced proliferation of memory Th1 and Th2 cells was dependent largely on the production of IL-2, with Th2-cell proliferation also affected by loss of IL 4. Type II NKT cells were also required for efficient maintenance of memory CD4 T cells in vivo. Activation of iNKT cells resulted in up-regulation of IFN-gamma expression by memory Th2 cells. These IFN-gamma-producing memory Th2 cells showed a decreased capability to induce Th2 cytokines and eosinophilic airway inflammation. Thus, activated NKT cells directly regulate memory CD4 T-cell pool size and function via the production of cytokines in vivo. PMID- 23027938 TI - Transcriptional repressor PRR5 directly regulates clock-output pathways. AB - The circadian clock is an endogenous time-keeping mechanism that enables organisms to adapt to external daily cycles. The clock coordinates biological activities with these cycles, mainly through genome-wide gene expression. However, the exact mechanism underlying regulation of circadian gene expression is poorly understood. Here we demonstrated that an Arabidopsis PSEUDO-RESPONSE REGULATOR 5 (PRR5), which acts in the clock genetic circuit, directly regulates expression timing of key transcription factors involved in clock-output pathways. A transient expression assay and ChIP-quantitative PCR assay using mutated PRR5 indicated that PRR5 associates with target DNA through binding at the CCT motif in vivo. ChIP followed by deep sequencing coupled with genome-wide expression profiling revealed the direct-target genes of PRR5. PRR5 direct-targets include genes encoding transcription factors involved in flowering-time regulation, hypocotyl elongation, and cold-stress responses. PRR5-target gene expression followed a circadian rhythm pattern with low, basal expression from noon until midnight, when PRR9, PRR7, and PRR5 were expressed. ChIP-quantitative PCR assays indicated that PRR7 and PRR9 bind to the direct-targets of PRR5. Genome-wide expression profiling using a prr9 prr7 prr5 triple mutant suggests that PRR5, PRR7, and PRR9 repress these targets. Taken together, our results illustrate a genetic network in which PRR5, PRR7, and PRR9 directly regulate expression timing of key transcription factors to coordinate physiological processes with daily cycles. PMID- 23027939 TI - Alphaherpesvirus axon-to-cell spread involves limited virion transmission. AB - The spread of viral infection within a host can be restricted by bottlenecks that limit the size and diversity of the viral population. An essential process for alphaherpesvirus infection is spread from axons of peripheral nervous system neurons to cells in peripheral epithelia (anterograde-directed spread, ADS). ADS is necessary for the formation of vesicular lesions characteristic of reactivated herpesvirus infections; however, the number of virions transmitted is unknown. We have developed two methods to quantitate ADS events using a compartmentalized neuronal culture system. The first method uses HSV-1 and pseudorabies virus recombinants that express one of three different fluorescent proteins. The fluorescence profiles of cells infected with the virus mixtures are used to quantify the number of expressed viral genomes. Strikingly, although epithelial or neuronal cells express 3-10 viral genomes after infection by free virions, epithelial cells infected by HSV-1 or pseudorabies virus following ADS express fewer than two viral genomes. The second method uses live-cell fluorescence microscopy to track individual capsids involved in ADS. We observed that most ADS events involve a single capsid infecting a target epithelial cell. Together, these complementary analyses reveal that ADS events are restricted to small numbers of viral particles, most often a single virion, resulting in a single viral genome initiating infection. PMID- 23027941 TI - Noncoding transcription within the Igh distal V(H) region at PAIR elements affects the 3D structure of the Igh locus in pro-B cells. AB - Noncoding sense and antisense germ-line transcription within the Ig heavy chain locus precedes V(D)J recombination and has been proposed to be associated with Igh locus accessibility, although its precise role remains elusive. However, no global analysis of germ-line transcription throughout the Igh locus has been done. Therefore, we performed directional RNA-seq, demonstrating the locations and extent of both sense and antisense transcription throughout the Igh locus. Surprisingly, the majority of antisense transcripts are localized around two Pax5 activated intergenic repeat (PAIR) elements in the distal IghV region. Importantly, long-distance loops measured by chromosome conformation capture (3C) are observed between these two active PAIR promoters and EMU, the start site of IMU germ-line transcription, in a lineage- and stage-specific manner, even though this antisense transcription is EMU-independent. YY1(-/-) pro-B cells are greatly impaired in distal V(H) gene rearrangement and Igh locus compaction, and we demonstrate that YY1 deficiency greatly reduces antisense transcription and PAIR EMU interactions. ChIP-seq shows high level YY1 binding only at EMU, but low levels near some antisense promoters. PAIR-EMU interactions are not disrupted by DRB, which blocks transcription elongation without disrupting transcription factories once they are established, but the looping is reduced after heat-shock treatment, which disrupts transcription factories. We propose that transcription mediated interactions, most likely at transcription factories, initially compact the Igh locus, bringing distal V(H) genes close to the DJ(H) rearrangement which is adjacent to EMU. Therefore, we hypothesize that one key role of noncoding germ line transcription is to facilitate locus compaction, allowing distal V(H) genes to undergo efficient rearrangement. PMID- 23027940 TI - Modification of RelA by O-linked N-acetylglucosamine links glucose metabolism to NF-kappaB acetylation and transcription. AB - The molecular mechanisms linking glucose metabolism with active transcription remain undercharacterized in mammalian cells. Using nuclear factor-kappaB (NF kappaB) as a glucose-responsive transcription factor, we show that cells use the hexosamine biosynthesis pathway and O-linked beta-N-acetylglucosamine (O-GlcNAc) transferase (OGT) to potentiate gene expression in response to tumor necrosis factor (TNF) or etoposide. Chromatin immunoprecipitation assays demonstrate that, upon induction, OGT localizes to NF-kappaB-regulated promoters to enhance RelA acetylation. Knockdown of OGT abolishes p300-mediated acetylation of RelA on K310, a posttranslational mark required for full NF-kappaB transcription. Mapping studies reveal T305 as an important residue required for attachment of the O GlcNAc moiety on RelA. Furthermore, p300 fails to acetylate a full-length RelA(T305A) mutant, linking O-GlcNAc and acetylation events on NF-kappaB. Reconstitution of RelA null cells with the RelA(T305A) mutant illustrates the importance of this residue for NF-kappaB-dependent gene expression and cell survival. Our work provides evidence for a unique regulation where attachment of the O-GlcNAc moiety to RelA potentiates p300 acetylation and NF-kappaB transcription. PMID- 23027942 TI - Mental time travel and default-mode network functional connectivity in the developing brain. AB - A core brain network is engaged in remembering the past and envisioning the future. This network overlaps with the so-called default-mode network, the activity of which increases when demands for focused attention are low. Because of their shared brain substrates, an intriguing hypothesis is that default-mode activity, measured at rest, is related to performance in separate attention focused recall and imagination tasks. However, we do not know how functional connectivity of the default-mode network is related to individual differences in reconstruction of the past and imagination of the future. Here, we show that functional connectivity of the default-mode network in children and adolescents is related to the quality of past remembering and marginally to future imagination. These results corroborate previous findings of a common neuronal substrate for memory and imagination and provide evidence suggesting that mental time travel is modulated by the task-independent functional architecture of the default-mode network in the developing brain. A further analysis showed that local cortical arealization also contributed to explain recall of the past and imagination of the future, underscoring the benefits of studying both functional and structural properties to understand the brain basis for complex human cognition. PMID- 23027943 TI - XAX1 from glycosyltransferase family 61 mediates xylosyltransfer to rice xylan. AB - Xylan is the second most abundant polysaccharide on Earth and represents an immense quantity of stored energy for biofuel production. Despite its importance, most of the enzymes that synthesize xylan have yet to be identified. Xylans have a backbone of beta-1,4-linked xylose residues with substitutions that include alpha-(1->2)-linked glucuronosyl, 4-O-methyl glucuronosyl, and alpha-1,2- and alpha-1,3-arabinofuranosyl residues. The substitutions are structurally diverse and vary by taxonomy, with grass xylan representing a unique composition distinct from dicots and other monocots. To date, no enzyme has yet been identified that is specific to grass xylan synthesis. We identified a xylose-deficient loss-of function rice mutant in Os02g22380, a putative glycosyltransferase in a grass specific subfamily of family GT61. We designate the mutant xax1 for xylosyl arabinosyl substitution of xylan 1. Enzymatic fingerprinting of xylan showed the specific absence in the mutant of a peak, which was isolated and determined by (1)H-NMR to be (beta-1,4-Xyl)(4) with a beta-Xylp-(1->2)-alpha-Araf-(1->3). Rice xax1 mutant plants are deficient in ferulic and coumaric acid, aromatic compounds known to be attached to arabinosyl residues in xylan substituted with xylosyl residues. The xax1 mutant plants exhibit an increased extractability of xylan and increased saccharification, probably reflecting a lower degree of diferulic cross links. Activity assays with microsomes isolated from tobacco plants transiently expressing XAX1 demonstrated xylosyltransferase activity onto endogenous acceptors. Our results provide insight into grass xylan synthesis and how substitutions may be modified for increased saccharification for biofuel generation. PMID- 23027944 TI - Structural basis for TetM-mediated tetracycline resistance. AB - Ribosome protection proteins (RPPs) confer tetracycline resistance by binding to the ribosome and chasing the drug from its binding site. The current model for the mechanism of action of RPPs proposes that drug release is indirect and achieved via conformational changes within the drug-binding site induced upon binding of the RPP to the ribosome. Here we report a cryo-EM structure of the RPP TetM in complex with the 70S ribosome at 7.2-A resolution. The structure reveals the contacts of TetM with the ribosome, including interaction between the conserved and functionally critical C-terminal extension of TetM and the decoding center of the small subunit. Moreover, we observe direct interaction between domain IV of TetM and the tetracycline binding site and identify residues critical for conferring tetracycline resistance. A model is presented whereby TetM directly dislodges tetracycline to confer resistance. PMID- 23027945 TI - Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity. AB - Continual and rapid mutation of seasonal influenza viruses by antigenic drift necessitates the almost annual reformulation of flu vaccines, which may offer little protection if the match to the dominant circulating strain is poor. S139/1 is a cross-reactive antibody that neutralizes multiple HA strains and subtypes, including those from H1N1 and H3N2 viruses that currently infect humans. The crystal structure of the S139/1 Fab in complex with the HA from the A/Victoria/3/1975 (H3N2) virus reveals that the antibody targets highly conserved residues in the receptor binding site and contacts antigenic sites A, B, and D. Binding and plaque reduction assays show that the monovalent Fab alone can protect against H3 strains, but the enhanced avidity from binding of bivalent IgG increases the breadth of neutralization to additional strains from the H1, H2, H13, and H16 subtypes. Thus, antibodies making relatively low affinity Fab interactions with the receptor binding site can have significant antiviral activity when enhanced by avidity through bivalent interactions of the IgG, thereby extending the breadth of binding and neutralization to highly divergent influenza virus strains and subtypes. PMID- 23027946 TI - Cognitive signals for brain-machine interfaces in posterior parietal cortex include continuous 3D trajectory commands. AB - Cortical neural prosthetics extract command signals from the brain with the goal to restore function in paralyzed or amputated patients. Continuous control signals can be extracted from the motor cortical areas, whereas neural activity from posterior parietal cortex (PPC) can be used to decode cognitive variables related to the goals of movement. Because typical activities of daily living comprise both continuous control tasks such as reaching, and tasks benefiting from discrete control such as typing on a keyboard, availability of both signals simultaneously would promise significant increases in performance and versatility. Here, we show that PPC can provide 3D hand trajectory information under natural conditions that would be encountered for prosthetic applications, thus allowing simultaneous extraction of continuous and discrete signals without requiring multisite surgical implants. We found that limb movements can be decoded robustly and with high accuracy from a small population of neural units under free gaze in a complex 3D point-to-point reaching task. Both animals' brain control performance improved rapidly with practice, resulting in faster target acquisition and increasing accuracy. These findings disprove the notion that the motor cortical areas are the only candidate areas for continuous prosthetic command signals and, rather, suggests that PPC can provide equally useful trajectory signals in addition to discrete, cognitive variables. Hybrid use of continuous and discrete signals from PPC may enable a new generation of neural prostheses providing superior performance and additional flexibility in addressing individual patient needs. PMID- 23027947 TI - Secreted Vago restricts West Nile virus infection in Culex mosquito cells by activating the Jak-STAT pathway. AB - Although West Nile virus (WNV) and other arthropod-borne viruses are a major public health problem, the mechanisms of antiviral immunity in mosquitoes are poorly understood. Dicer-2, responsible for the RNAi-mediated response through the C-terminal RNase-III domain, also contains an N-terminal DExD/H-box helicase domain similar to mammalian RIG-I/MDA5 which, in Drosophila, was found to be required for activation of an antiviral gene, Vago. Here we show that the Culex orthologue of Vago (CxVago) is up-regulated in response to WNV infection in a Dicer-2-dependent manner. Further, our data show that CxVago is a secreted peptide that restricts WNV infection by activation of the Jak-STAT pathway. Thus, Vago appears to function as an IFN-like antiviral cytokine in mosquitoes. PMID- 23027948 TI - CIRCADIAN CLOCK-ASSOCIATED 1 regulates ROS homeostasis and oxidative stress responses. AB - Organisms have evolved endogenous biological clocks as internal timekeepers to coordinate metabolic processes with the external environment. Here, we seek to understand the mechanism of synchrony between the oscillator and products of metabolism known as Reactive Oxygen Species (ROS) in Arabidopsis thaliana. ROS responsive genes exhibit a time-of-day-specific phase of expression under diurnal and circadian conditions, implying a role of the circadian clock in transcriptional regulation of these genes. Hydrogen peroxide production and scavenging also display time-of-day phases. Mutations in the core-clock regulator, CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), affect the transcriptional regulation of ROS-responsive genes, ROS homeostasis, and tolerance to oxidative stress. Mis-expression of EARLY FLOWERING 3, LUX ARRHYTHMO, and TIMING OF CAB EXPRESSION 1 affect ROS production and transcription, indicating a global effect of the clock on the ROS network. We propose CCA1 as a master regulator of ROS homeostasis through association with the Evening Element in promoters of ROS genes in vivo to coordinate time-dependent responses to oxidative stress. We also find that ROS functions as an input signal that affects the transcriptional output of the clock, revealing an important link between ROS signaling and circadian output. Temporal coordination of ROS signaling by CCA1 and the reciprocal control of circadian output by ROS reveal a mechanistic link that allows plants to master oxidative stress responses. PMID- 23027949 TI - In vitro reconstitution of the ordered assembly of the endosomal sorting complex required for transport at membrane-bound HIV-1 Gag clusters. AB - Most membrane-enveloped viruses depend on host proteins of the endosomal sorting complex required for transport (ESCRT) machinery for their release. HIV-1 is the prototypic ESCRT-dependent virus. The direct interactions between HIV-1 and the early ESCRT factors TSG101 and ALIX have been mapped in detail. However, the full pathway of ESCRT recruitment to HIV-1 budding sites, which culminates with the assembly of the late-acting CHMP4, CHMP3, CHMP2, and CHMP1 subunits, is less completely understood. Here, we report the biochemical reconstitution of ESCRT recruitment to viral assembly sites, using purified proteins and giant unilamellar vesicles. The myristylated full-length Gag protein of HIV-1 was purified to monodispersity. Myr-Gag forms clusters on giant unilamellar vesicle membranes containing the plasma membrane lipid PI(4,5)P(2). These Gag clusters package a fluorescent oligonucleotide, and recruit early ESCRT complexes ESCRT-I or ALIX with the appropriate dependence on the Gag PTAP and LYP(X)(n)L motifs. ALIX directly recruits the key ESCRT-III subunit CHMP4. ESCRT-I can only recruit CHMP4 when ESCRT-II and CHMP6 are present as intermediary factors. Downstream of CHMP4, CHMP3 and CHMP2 assemble synergistically, with the presence of both subunits required for efficient recruitment. The very late-acting factor CHMP1 is not recruited unless the pathway is completed through CHMP3 and CHMP2. These findings define the minimal sets of components needed to complete ESCRT assembly at HIV-1 budding sites, and provide a starting point for in vitro structural and biophysical dissection of the system. PMID- 23027950 TI - Identification of cation-binding sites on actin that drive polymerization and modulate bending stiffness. AB - The assembly of actin monomers into filaments and networks plays vital roles throughout eukaryotic biology, including intracellular transport, cell motility, cell division, determining cellular shape, and providing cells with mechanical strength. The regulation of actin assembly and modulation of filament mechanical properties are critical for proper actin function. It is well established that physiological salt concentrations promote actin assembly and alter the overall bending mechanics of assembled filaments and networks. However, the molecular origins of these salt-dependent effects, particularly if they involve nonspecific ionic strength effects or specific ion-binding interactions, are unknown. Here, we demonstrate that specific cation binding at two discrete sites situated between adjacent subunits along the long-pitch helix drive actin polymerization and determine the filament bending rigidity. We classify the two sites as "polymerization" and "stiffness" sites based on the effects that mutations at the sites have on salt-dependent filament assembly and bending mechanics, respectively. These results establish the existence and location of the cation binding sites that confer salt dependence to the assembly and mechanics of actin filaments. PMID- 23027951 TI - Biochemical evidence for superior correction of neuronal storage by chemically modified enzyme in murine mucopolysaccharidosis VII. AB - Enzyme replacement therapy has been used successfully in many lysosomal storage diseases. However, correction of brain storage has been limited by the inability of infused enzyme to cross the blood-brain barrier (BBB). We recently reported that PerT-GUS, a form of beta-glucuronidase (GUS) chemically modified to eliminate its uptake and clearance by carbohydrate-dependent receptors, crossed the BBB and cleared neuronal storage in an immunotolerant model of murine mucopolysaccharidosis (MPS) type VII. In this respect, the chemically modified enzyme was superior to native beta-glucuronidase. Chemically modified enzyme was also delivered more effectively to heart, kidney, and muscle. However, liver and spleen, which express high levels of carbohydrate receptors, received nearly fourfold lower levels of PerT-GUS compared with native GUS. A recent report on PerT-treated sulfamidase in murine MPS IIIA confirmed enhanced delivery to other tissues but failed to observe clearance of storage in neurons. To confirm and extend our original observations, we compared the efficacy of 12 weekly i.v. infusions of PerT-GUS versus native GUS on (i) delivery of enzyme to brain; (ii) improvement in histopathology; and (iii) correction of secondary elevations of other lysosomal enzymes. Such correction is a recognized biomarker for correction of neuronal storage. PerT-GUS was superior to native GUS in all three categories. These results provide additional evidence that long-circulating enzyme, chemically modified to escape carbohydrate-mediated clearance, may offer advantages in treating MPS VII. The relevance of this approach to treat other lysosomal storage diseases that affect brain awaits confirmation. PMID- 23027952 TI - Chlamydia trachomatis protein GrgA activates transcription by contacting the nonconserved region of sigma66. AB - The bacterial RNA polymerase holoenzyme consists of a catalytic core enzyme in complex with a sigma factor that is required for promoter-specific transcription initiation. Primary, or housekeeping, sigma factors are responsible for most of the gene expression that occurs during the exponential phase of growth. Primary sigma factors share four regions of conserved sequence, regions 1-4, which have been further subdivided. Many primary sigma factors also contain a nonconserved region (NCR) located between subregions 1.2 and 2.1, which can vary widely in length. Interactions between the NCR of the primary sigma factor of Escherichia coli, sigma(70), and the beta' subunit of the E. coli core enzyme have been shown to influence gene expression, suggesting that the NCR of primary sigma factors represents a potential target for transcription regulation. Here, we report the identification and characterization of a previously undocumented Chlamydia trachomatis transcription factor, designated GrgA (general regulator of genes A). We demonstrate in vitro that GrgA is a DNA-binding protein that can stimulate transcription from a range of sigma(66)-dependent promoters. We further show that GrgA activates transcription by contacting the NCR of the primary sigma factor of C. trachomatis, sigma(66). Our findings suggest GrgA serves as an important regulator of sigma(66)-dependent transcription in C. trachomatis. Furthermore, because GrgA is present only in chlamydiae, our findings highlight how nonconserved regions of the bacterial RNA polymerase can be targets of regulatory factors that are unique to particular organisms. PMID- 23027953 TI - Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. AB - Innate sensing of microbial components is well documented to occur at many cellular sites, including at the cell surface, in the cytosol, and in intracellular vesicles, but there is limited evidence of nuclear innate signaling. In this study we have defined the mechanisms of interferon regulatory factor-3 (IRF-3) signaling in primary human foreskin fibroblasts (HFF) infected with herpes simplex virus 1 (HSV-1) in the absence of viral gene expression. We found that the interferon inducible protein 16 (IFI16) DNA sensor, which is required for induction of IRF-3 signaling in these cells, is nuclear, and its localization does not change detectably upon HSV-1 d109 infection and induction of IRF-3 signaling. Consistent with the IFI16 sensor being nuclear, conditions that block viral DNA release from incoming capsids inhibit IRF-3 signaling. An unknown factor must be exported from the nucleus to activate IRF-3 through cytoplasmic STING, which is required for IRF-3 activation and signaling. However, when the viral ICP0 protein is expressed in the nucleus, it causes the nuclear relocalization and degradation of IFI16, inhibiting IRF-3 signaling. Therefore, HSV-1 infection is sensed in HFF by nuclear IFI16 upon release of encapsidated viral DNA into the nucleus, and the viral nuclear ICP0 protein can inhibit the process by targeting IFI16 for degradation. Together these results define a pathway for nuclear innate sensing of HSV DNA by IFI16 in infected HFF and document a mechanism by which a virus can block this nuclear innate response. PMID- 23027954 TI - Fine-tuning synaptic plasticity by modulation of Ca(V)2.1 channels with Ca2+ sensor proteins. AB - Modulation of P/Q-type Ca(2+) currents through presynaptic voltage-gated calcium channels (Ca(V)2.1) by binding of Ca(2+)/calmodulin contributes to short-term synaptic plasticity. Ca(2+)-binding protein-1 (CaBP1) and Visinin-like protein-2 (VILIP-2) are neurospecific calmodulin-like Ca(2+) sensor proteins that differentially modulate Ca(V)2.1 channels, but how they contribute to short-term synaptic plasticity is unknown. Here, we show that activity-dependent modulation of presynaptic Ca(V)2.1 channels by CaBP1 and VILIP-2 has opposing effects on short-term synaptic plasticity in superior cervical ganglion neurons. Expression of CaBP1, which blocks Ca(2+)-dependent facilitation of P/Q-type Ca(2+) current, markedly reduced facilitation of synaptic transmission. VILIP-2, which blocks Ca(2+)-dependent inactivation of P/Q-type Ca(2+) current, reduced synaptic depression and increased facilitation under conditions of high release probability. These results demonstrate that activity-dependent regulation of presynaptic Ca(V)2.1 channels by differentially expressed Ca(2+) sensor proteins can fine-tune synaptic responses to trains of action potentials and thereby contribute to the diversity of short-term synaptic plasticity. PMID- 23027955 TI - Efficient TALEN-mediated gene knockout in livestock. AB - Transcription activator-like effector nucleases (TALENs) are programmable nucleases that join FokI endonuclease with the modular DNA-binding domain of TALEs. Although zinc-finger nucleases enable a variety of genome modifications, their application to genetic engineering of livestock has been slowed by technical limitations of embryo-injection, culture of primary cells, and difficulty in producing reliable reagents with a limited budget. In contrast, we found that TALENs could easily be manufactured and that over half (23/36, 64%) demonstrate high activity in primary cells. Cytoplasmic injections of TALEN mRNAs into livestock zygotes were capable of inducing gene KO in up to 75% of embryos analyzed, a portion of which harbored biallelic modification. We also developed a simple transposon coselection strategy for TALEN-mediated gene modification in primary fibroblasts that enabled both enrichment for modified cells and efficient isolation of modified colonies. Coselection after treatment with a single TALEN pair enabled isolation of colonies with mono- and biallelic modification in up to 54% and 17% of colonies, respectively. Coselection after treatment with two TALEN pairs directed against the same chromosome enabled the isolation of colonies harboring large chromosomal deletions and inversions (10% and 4% of colonies, respectively). TALEN-modified Ossabaw swine fetal fibroblasts were effective nuclear donors for cloning, resulting in the creation of miniature swine containing mono- and biallelic mutations of the LDL receptor gene as models of familial hypercholesterolemia. TALENs thus appear to represent a highly facile platform for the modification of livestock genomes for both biomedical and agricultural applications. PMID- 23027956 TI - Making gene circuits sing. PMID- 23027957 TI - Evidence for the respiration of ancient terrestrial organic C in northern temperate lakes and streams. AB - Northern rivers and lakes process large quantities of organic and inorganic carbon from the surrounding terrestrial ecosystems. These external carbon inputs fuel widespread CO(2) supersaturation in continental waters, and the resulting CO(2) emissions from lakes and rivers are now recognized as a globally significant loss of terrestrial production to the atmosphere. Whereas the magnitude of emissions has received much attention, the pathways of C delivery and processing that generate these emissions are still not well-understood. CO(2) outgassing in aquatic systems has been unequivocally linked to microbial degradation and respiration of terrestrial organic carbon (OC), but the nature (i.e., age and source) of this OC respired in surface waters is largely unknown. We present direct radiocarbon measurements of OC respired by bacteria in freshwater aquatic systems, specifically temperate lakes and streams in Quebec. Terrestrial OC fuels much of the respiration in these systems, and our results show that a significant fraction of the respired terrestrial OC is old (in the range of 1,000-3,000 y B.P.). Because the bulk OC pools in these lakes is relatively young, our results also suggest selective removal of an old but highly bioreactive terrestrial OC pool and its conversion to CO(2) by bacteria. The respiration of ancient (14)C-depleted terrestrial C in northern lakes and rivers provides a biological link between contemporary aquatic carbon biogeochemistry and paleo-conditions in the watershed, and it implies the aquatic-mediated return to the atmosphere of C putatively considered permanently stored, thus challenging current models of long-term C storage in terrestrial reservoirs. PMID- 23027958 TI - Targeted microRNA expression in dairy cattle directs production of beta lactoglobulin-free, high-casein milk. AB - Milk from dairy cows contains the protein beta-lactoglobulin (BLG), which is not present in human milk. As it is a major milk allergen, we wished to decrease BLG levels in milk by RNAi. In vitro screening of 10 microRNAs (miRNAs), either individually or in tandem combinations, identified several that achieved as much as a 98% knockdown of BLG. One tandem construct was expressed in the mammary gland of an ovine BLG-expressing mouse model, resulting in 96% knockdown of ovine BLG in milk. Following this in vivo validation, we produced a transgenic calf, engineered to express these tandem miRNAs. Analysis of hormonally induced milk from this calf demonstrated absence of BLG and a concurrent increase of all casein milk proteins. The findings demonstrate miRNA-mediated depletion of an allergenic milk protein in cattle and validate targeted miRNA expression as an effective strategy to alter milk composition and other livestock traits. PMID- 23027959 TI - Activity-dependent BDNF release and TRPC signaling is impaired in hippocampal neurons of Mecp2 mutant mice. AB - Dysfunction of the neurotrophin brain-derived neurotrophic factor (BDNF) is implicated in Rett syndrome (RTT), but the state of its releasable pool and downstream signaling in mice lacking methyl-CpG-binding protein-2 (Mecp2) is unknown. Here, we show that membrane currents and dendritic Ca(2+) signals evoked by recombinant BDNF or an activator of diacylglycerol (DAG)-sensitive transient receptor potential canonical (TRPC) channels are impaired in CA3 pyramidal neurons of symptomatic Mecp2 mutant mice. TRPC3 and TRPC6 mRNA and protein levels are lower in Mecp2 mutant hippocampus, and chromatin immunoprecipitation (ChIP) identified Trpc3 as a target of MeCP2 transcriptional regulation. BDNF mRNA and protein levels are also lower in Mecp2 mutant hippocampus and dentate gyrus granule cells, which is reflected in impaired activity-dependent release of endogenous BDNF estimated from TRPC currents and dendritic Ca(2+) signals in CA3 pyramidal neurons. These results identify the gene encoding TRPC3 channels as a MeCP2 target and suggest a potential therapeutic strategy to boost impaired BDNF signaling in RTT. PMID- 23027960 TI - Oxygen isotopes in tree rings are a good proxy for Amazon precipitation and El Nino-Southern Oscillation variability. AB - We present a unique proxy for the reconstruction of variation in precipitation over the Amazon: oxygen isotope ratios in annual rings in tropical cedar (Cedrela odorata). A century-long record from northern Bolivia shows that tree rings preserve the signal of oxygen isotopes in precipitation during the wet season, with weaker influences of temperature and vapor pressure. Tree ring delta(18)O correlates strongly with delta(18)O in precipitation from distant stations in the center and west of the basin, and with Andean ice core delta(18)O showing that the signal is coherent over large areas. The signal correlates most strongly with basin-wide precipitation and Amazon river discharge. We attribute the strength of this (negative) correlation mainly to the cumulative rainout processes of oxygen isotopes (Rayleigh distillation) in air parcels during westward transport across the basin. We further find a clear signature of the El Nino-Southern Oscillation (ENSO) in the record, with strong ENSO influences over recent decades, but weaker influence from 1925 to 1975 indicating decadal scale variation in the controls on the hydrological cycle. The record exhibits a significant increase in delta(18)O over the 20th century consistent with increases in Andean delta(18)O ice core and lake records, which we tentatively attribute to increased water vapor transport into the basin. Taking these data together, our record reveals a fresh path to diagnose and improve our understanding of variation and trends of the hydrological cycle of the world's largest river catchment. PMID- 23027961 TI - The 27-year decline of coral cover on the Great Barrier Reef and its causes. AB - The world's coral reefs are being degraded, and the need to reduce local pressures to offset the effects of increasing global pressures is now widely recognized. This study investigates the spatial and temporal dynamics of coral cover, identifies the main drivers of coral mortality, and quantifies the rates of potential recovery of the Great Barrier Reef. Based on the world's most extensive time series data on reef condition (2,258 surveys of 214 reefs over 1985-2012), we show a major decline in coral cover from 28.0% to 13.8% (0.53% y( 1)), a loss of 50.7% of initial coral cover. Tropical cyclones, coral predation by crown-of-thorns starfish (COTS), and coral bleaching accounted for 48%, 42%, and 10% of the respective estimated losses, amounting to 3.38% y(-1) mortality rate. Importantly, the relatively pristine northern region showed no overall decline. The estimated rate of increase in coral cover in the absence of cyclones, COTS, and bleaching was 2.85% y(-1), demonstrating substantial capacity for recovery of reefs. In the absence of COTS, coral cover would increase at 0.89% y(-1), despite ongoing losses due to cyclones and bleaching. Thus, reducing COTS populations, by improving water quality and developing alternative control measures, could prevent further coral decline and improve the outlook for the Great Barrier Reef. Such strategies can, however, only be successful if climatic conditions are stabilized, as losses due to bleaching and cyclones will otherwise increase. PMID- 23027963 TI - Economics of nuclear power and climate change mitigation policies. AB - The events of March 2011 at the nuclear power complex in Fukushima, Japan, raised questions about the safe operation of nuclear power plants, with early retirement of existing nuclear power plants being debated in the policy arena and considered by regulators. Also, the future of building new nuclear power plants is highly uncertain. Should nuclear power policies become more restrictive, one potential option for climate change mitigation will be less available. However, a systematic analysis of nuclear power policies, including early retirement, has been missing in the climate change mitigation literature. We apply an energy economy model framework to derive scenarios and analyze the interactions and tradeoffs between these two policy fields. Our results indicate that early retirement of nuclear power plants leads to discounted cumulative global GDP losses of 0.07% by 2020. If, in addition, new nuclear investments are excluded, total losses will double. The effect of climate policies imposed by an intertemporal carbon budget on incremental costs of policies restricting nuclear power use is small. However, climate policies have much larger impacts than policies restricting the use of nuclear power. The carbon budget leads to cumulative discounted near term reductions of global GDP of 0.64% until 2020. Intertemporal flexibility of the carbon budget approach enables higher near-term emissions as a result of increased power generation from natural gas to fill the emerging gap in electricity supply, while still remaining within the overall carbon budget. Demand reductions and efficiency improvements are the second major response strategy. PMID- 23027962 TI - Modified SH2 domain to phototrap and identify phosphotyrosine proteins from subcellular sites within cells. AB - Spatial regulation of tyrosine phosphorylation is important for many aspects of cell biology. However, phosphotyrosine accounts for less than 1% of all phosphorylated substrates, and it is typically a very transient event in vivo. These factors complicate the identification of key tyrosine kinase substrates, especially in the context of their extraordinary spatial organization. Here, we describe an approach to identify tyrosine kinase substrates based on their subcellular distribution from within cells. This method uses an unnatural amino acid-modified Src homology 2 (SH2) domain that is expressed within cells and can covalently trap phosphotyrosine proteins on exposure to light. This SH2 domain based photoprobe was targeted to cellular structures, such as the actin cytoskeleton, mitochondria, and cellular membranes, to capture tyrosine kinase substrates unique to each cellular region. We demonstrate that RhoA, one of the proteins associated with actin, can be phosphorylated on two tyrosine residues within the switch regions, suggesting that phosphorylation of these residues might modulate RhoA signaling to the actin cytoskeleton. We conclude that expression of SH2 domains within cellular compartments that are capable of covalent phototrapping can reveal the spatial organization of tyrosine kinase substrates that are likely to be important for the regulation of subcellular structures. PMID- 23027964 TI - Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome. AB - Joubert syndrome (JS) and Meckel syndrome (MKS) are pleiotropic ciliopathies characterized by severe defects of the cerebellar vermis, ranging from hypoplasia to aplasia. Interestingly, ciliary conditional mutant mice have a hypoplastic cerebellum in which the proliferation of cerebellar granule cell progenitors (GCPs) in response to Sonic hedgehog (SHH) is severely reduced. This suggests that Shh signaling defects could contribute to the vermis hypoplasia observed in the human syndromes. As existing JS/MKS mutant mouse models suggest apparently contradictory hypotheses on JS/MKS etiology, we investigated Shh signaling directly on human fetal samples. First, in an examination of human cerebellar development, we linked the rates of GCP proliferation to the different levels and localizations of active Shh signaling and showed that the GCP possessed a primary cilium with CEP290 at its base. Second, we found that the proliferation of GCPs and their response to SHH were severely impaired in the cerebellum of subjects with JS/MKS and Jeune syndrome. Finally, we showed that the defect in GCP proliferation was similar in the cerebellar vermis and hemispheres in all patients with ciliopathy analyzed, suggesting that the specific cause of vermal hypo-/aplasia precedes this defect. Our results, obtained from the analysis of human samples, show that the hemispheres and the vermis are affected in JS/MKS and provide evidence of a defective cellular mechanism in these pathologic processes. PMID- 23027965 TI - Adolescents' risk-taking behavior is driven by tolerance to ambiguity. AB - Adolescents engage in a wide range of risky behaviors that their older peers shun, and at an enormous cost. Despite being older, stronger, and healthier than children, adolescents face twice the risk of mortality and morbidity faced by their younger peers. Are adolescents really risk-seekers or does some richer underlying preference drive their love of the uncertain? To answer that question, we used standard experimental economic methods to assess the attitudes of 65 individuals ranging in age from 12 to 50 toward risk and ambiguity. Perhaps surprisingly, we found that adolescents were, if anything, more averse to clearly stated risks than their older peers. What distinguished adolescents was their willingness to accept ambiguous conditions--situations in which the likelihood of winning and losing is unknown. Though adults find ambiguous monetary lotteries undesirable, adolescents find them tolerable. This finding suggests that the higher level of risk-taking observed among adolescents may reflect a higher tolerance for the unknown. Biologically, such a tolerance may make sense, because it would allow young organisms to take better advantage of learning opportunities; it also suggests that policies that seek to inform adolescents of the risks, costs, and benefits of unexperienced dangerous behaviors may be effective and, when appropriate, could be used to complement policies that limit their experiences. PMID- 23027966 TI - Boolean modeling of gene regulatory networks: Driesch redux. PMID- 23027967 TI - Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids. AB - Staphylococcus aureus peptidoglycan (PG) is densely functionalized with anionic polymers called wall teichoic acids (WTAs). These polymers contain three tailoring modifications: d-alanylation, alpha-O-GlcNAcylation, and beta-O GlcNAcylation. Here we describe the discovery and biochemical characterization of a unique glycosyltransferase, TarS, that attaches beta-O-GlcNAc (beta-O-N-acetyl D-glucosamine) residues to S. aureus WTAs. We report that methicillin resistant S. aureus (MRSA) is sensitized to beta-lactams upon tarS deletion. Unlike strains completely lacking WTAs, which are also sensitive to beta-lactams, DeltatarS strains have no growth or cell division defects. Because neither alpha-O-GlcNAc nor beta-O-Glucose modifications can confer resistance, the resistance phenotype requires a highly specific chemical modification of the WTA backbone, beta-O GlcNAc residues. These data suggest beta-O-GlcNAcylated WTAs scaffold factors required for MRSA resistance. The beta-O-GlcNAc transferase identified here, TarS, is a unique target for antimicrobials that sensitize MRSA to beta-lactams. PMID- 23027968 TI - Solar UV radiation reduces the barrier function of human skin. AB - The ubiquitous presence of solar UV radiation in human life is essential for vitamin D production but also leads to skin photoaging, damage, and malignancies. Photoaging and skin cancer have been extensively studied, but the effects of UV on the critical mechanical barrier function of the outermost layer of the epidermis, the stratum corneum (SC), are not understood. The SC is the first line of defense against environmental exposures like solar UV radiation, and its effects on UV targets within the SC and subsequent alterations in the mechanical properties and related barrier function are unclear. Alteration of the SC's mechanical properties can lead to severe macroscopic skin damage such as chapping and cracking and associated inflammation, infection, scarring, and abnormal desquamation. Here, we show that UV exposure has dramatic effects on cell cohesion and mechanical integrity that are related to its effects on the SC's intercellular components, including intercellular lipids and corneodesmosomes. We found that, although the keratin-controlled stiffness remained surprisingly constant with UV exposure, the intercellular strength, strain, and cohesion decreased markedly. We further show that solar UV radiation poses a double threat to skin by both increasing the biomechanical driving force for damage while simultaneously decreasing the skin's natural ability to resist, compromising the critical barrier function of the skin. PMID- 23027969 TI - Aberrant expression of c-Jun in glioblastoma by internal ribosome entry site (IRES)-mediated translational activation. AB - Although the protooncogene c-Jun plays a critical role in cell proliferation, cell death, and malignant transformation, DNA microarray screens have identified only a few human cancer types with aberrant expression of c-Jun. Here, we show that c-Jun accumulation is robustly elevated in human glioblastoma and that this increase contributes to the malignant properties of the cells. Most importantly, the increase in c-Jun protein accumulation occurs with no corresponding increase in c-Jun mRNA or the half-life of the c-Jun protein but, rather, in the translatability of the transcript. The c-Jun 5'UTR harbors a potent internal ribosomal entry site (IRES) with a virus-like IRES domain that directs cap independent translation in glioblastoma cells. Accumulation of c-Jun is not dependent on MAPK activity but can be stimulated by a cytoskeleton-dependent pathway. Our findings provide evidence that human c-Jun is an IRES-containing cellular transcript that contributes to cancer development through translational activation. This previously undescribed mechanism of c-Jun regulation might also be relevant to other types of human cancer and offers unique potential targets for therapy. PMID- 23027970 TI - High-resolution imaging of expertise reveals reliable object selectivity in the fusiform face area related to perceptual performance. AB - The fusiform face area (FFA) is a region of human cortex that responds selectively to faces, but whether it supports a more general function relevant for perceptual expertise is debated. Although both faces and objects of expertise engage many brain areas, the FFA remains the focus of the strongest modular claims and the clearest predictions about expertise. Functional MRI studies at standard-resolution (SR-fMRI) have found responses in the FFA for nonface objects of expertise, but high-resolution fMRI (HR-fMRI) in the FFA [Grill-Spector K, et al. (2006) Nat Neurosci 9:1177-1185] and neurophysiology in face patches in the monkey brain [Tsao DY, et al. (2006) Science 311:670-674] reveal no reliable selectivity for objects. It is thus possible that FFA responses to objects with SR-fMRI are a result of spatial blurring of responses from nonface-selective areas, potentially driven by attention to objects of expertise. Using HR-fMRI in two experiments, we provide evidence of reliable responses to cars in the FFA that correlate with behavioral car expertise. Effects of expertise in the FFA for nonface objects cannot be attributed to spatial blurring beyond the scale at which modular claims have been made, and within the lateral fusiform gyrus, they are restricted to a small area (200 mm(2) on the right and 50 mm(2) on the left) centered on the peak of face selectivity. Experience with a category may be sufficient to explain the spatially clustered face selectivity observed in this region. PMID- 23027971 TI - Misconduct accounts for the majority of retracted scientific publications. AB - A detailed review of all 2,047 biomedical and life-science research articles indexed by PubMed as retracted on May 3, 2012 revealed that only 21.3% of retractions were attributable to error. In contrast, 67.4% of retractions were attributable to misconduct, including fraud or suspected fraud (43.4%), duplicate publication (14.2%), and plagiarism (9.8%). Incomplete, uninformative or misleading retraction announcements have led to a previous underestimation of the role of fraud in the ongoing retraction epidemic. The percentage of scientific articles retracted because of fraud has increased ~10-fold since 1975. Retractions exhibit distinctive temporal and geographic patterns that may reveal underlying causes. PMID- 23027973 TI - A noncoding RNA regulates the neurogenin1 gene locus during mouse neocortical development. AB - The proneural basic helix-loop-helix (bHLH) transcription factor neurogenin1 (Neurog1) plays a pivotal role in neuronal differentiation during mammalian development. The spatiotemporal control of the Neurog1 gene expression is mediated by several specific enhancer elements, although how these elements regulate the Neurog1 locus has remained largely unclear. Recently it has been shown that a large number of enhancer elements are transcribed, but the regulation and function of the resulting transcripts have been investigated for only several such elements. We now show that an enhancer element located 5.8-7.0 kb upstream of the mouse Neurog1 locus is transcribed. The production of this transcript, designated utNgn1, is highly correlated with that of Neurog1 mRNA during neuronal differentiation. Moreover, knockdown of utNgn1 by a corresponding short interfering RNA inhibits the production of Neurog1 mRNA in response to induction of neuronal differentiation. We also found that production of utNgn1 is suppressed by polycomb group (PcG) proteins, which inhibit the expression of Neurog1. Our results thus suggest that a noncoding RNA transcribed from an enhancer element positively regulates transcription at the Neurog1 locus. PMID- 23027972 TI - Using intein catalysis to probe the origin of major histocompatibility complex class I-presented peptides. AB - All vertebrate nucleated cells generate peptides from their expressed gene products and then display them at the cell surface bound to MHC class I molecules. This allows CD8(+) T cells to detect and eliminate abnormal cells that are synthesizing foreign proteins, e.g., from viruses or mutations. To permit the immune system to more uniformly monitor a cell's proteins, regardless of their half-life or location, it has been thought that the products of rapid degradation of the mistakes of protein synthesis (defective ribosomal products, DRiPs) preferentially contribute to the class I-presented peptides. However, using intein catalysis to generate peptide sequences exclusively by posttranslational splicing of mature proteins, we show here that presented peptides can be generated from fully folded and functional proteins. Remarkably, the presentation of peptides from two model mature proteins is just as efficient as from newly synthesized proteins subject to errors in translation or folding. These results indicate that for the constructs we have analyzed, DRiPs are not a more efficient source of class I peptides for antigen presentation than the turnover of mature functional proteins. Accordingly, our data suggest that one of the major ways the immune system evaluates the health of cells is by monitoring the breakdown products of the proteome. PMID- 23027974 TI - Triggering the measles virus membrane fusion machinery. AB - Paramyxoviruses contain glycoprotein fusion machineries that mediate membrane merger for infection. The molecular framework and mechanistic principles governing receptor-induced triggering of the machinery remain unknown. Using measles virus (MeV) fusion complexes, we demonstrate that receptor binding to only one dimer of the tetrameric attachment protein (H) dimer-of-dimers induces fusion-protein (F) triggering; receptor binding and F triggering can be communicated across the dimer-dimer interface of H; and the physical integrity of the tetramer is maintained during fusion. The central MeV H ectodomain stalk region requires structural flexibility for activation of F, and alanine substitutions in this section, physical stress, or exposure of H to soluble ligands trigger conformational rearrangements in native H tetramers. Binding of soluble receptor to H is sufficient to initiate refolding of F, underscoring the physiological significance of this rearrangement of the H tetramer. These data outline a model of the triggering of the physiological MeV fusion machinery in which unilateral receptor binding to one dimer pair in the H tetramer is sufficient to induce a reorganization of H that affects the conformation of the central stalk section, severing interactions between H and the F trimer and activating refolding of F. PMID- 23027975 TI - Pathogen-Related Yeast (PRY) proteins and members of the CAP superfamily are secreted sterol-binding proteins. AB - Sterols and related membrane-perturbing agents are subject to a quality control cycle. Compounds that fail to pass this control are acetylated and secreted into the culture media, whereas lipids that pass the cycle are deacetylated and retained within the cell. Here we describe the identification of a family of conserved proteins, the Pathogen-Related Yeast (PRY) proteins, as a class of sterol-binding proteins. Saccharomyces cerevisiae has three members of this family, two of which, Pry1 and Pry2, are secreted, whereas Pry3 is a cell wall associated protein. Cells lacking both PRY1 and PRY2 have a complete block in secretion of the acetylated lipid and Pry1 and Pry2 proteins bind free cholesterol and cholesteryl acetate in vitro. PRY proteins belong to a large protein superfamily of unknown mode of action, the CAP protein superfamily [i.e. cysteine-rich secretory proteins (CRISP), antigen 5, and pathogenesis related 1 proteins]. The conserved CAP domain of Pry1 is necessary and sufficient for lipid export and sterol binding. Expression of a human CAP superfamily member, the cysteine-rich secretory protein 2 (CRISP2), rescues the phenotype of yeast mutants lacking Pry function and purified CRISP2 binds cholesterol in vitro, indicating that lipid binding is a conserved function of the CAP superfamily proteins. PMID- 23027976 TI - Bacillus cereus iron uptake protein fishes out an unstable ferric citrate trimer. AB - Citrate is a common biomolecule that chelates Fe(III). Many bacteria and plants use ferric citrate to fulfill their nutritional requirement for iron. Only the Escherichia coli ferric citrate outer-membrane transport protein FecA has been characterized; little is known about other ferric citrate-binding proteins. Here we report a unique siderophore-binding protein from the gram-positive pathogenic bacterium Bacillus cereus that binds multinuclear ferric citrate complexes. We have demonstrated that B. cereus ATCC 14579 takes up (55)Fe radiolabeled ferric citrate and that a protein, BC_3466 [renamed FctC (ferric citrate-binding protein C)], binds ferric citrate. The dissociation constant (K(d)) of FctC at pH 7.4 with ferric citrate (molar ratio 1:50) is 2.6 nM. This is the tightest binding observed of any B. cereus siderophore-binding protein. Nano electrospray ionization-mass spectrometry (nano ESI-MS) analysis of FctC and ferric citrate complexes or citrate alone show that FctC binds diferric di-citrate, and triferric tricitrate, but does not bind ferric di-citrate, ferric monocitrate, or citrate alone. Significantly, the protein selectively binds triferric tricitrate even though this species is naturally present at very low equilibrium concentrations. PMID- 23027977 TI - Crystal structure of Enpp1, an extracellular glycoprotein involved in bone mineralization and insulin signaling. AB - Enpp1 is a membrane-bound glycoprotein that regulates bone mineralization by hydrolyzing extracellular nucleotide triphosphates to produce pyrophosphate. Enpp1 dysfunction causes human diseases characterized by ectopic calcification. Enpp1 also inhibits insulin signaling, and an Enpp1 polymorphism is associated with insulin resistance. However, the precise mechanism by which Enpp1 functions in these cellular processes remains elusive. Here, we report the crystal structures of the extracellular region of mouse Enpp1 in complex with four different nucleotide monophosphates, at resolutions of 2.7-3.2 A. The nucleotides are accommodated in a pocket formed by an insertion loop in the catalytic domain, explaining the preference of Enpp1 for an ATP substrate. Structural mapping of disease-associated mutations indicated the functional importance of the interdomain interactions. A structural comparison of Enpp1 with Enpp2, a lysophospholipase D, revealed marked differences in the domain arrangements and active-site architectures. Notably, the Enpp1 mutant lacking the insertion loop lost the nucleotide-hydrolyzing activity but instead gained the lysophospholipid hydrolyzing activity of Enpp2. Our findings provide structural insights into how the Enpp family proteins evolved to exert their diverse cellular functions. PMID- 23027978 TI - Profile of Pamela J. Fraker. Interview by Tinsley H. Davis. PMID- 23027981 TI - The effects of childhood sexual abuse on women's lives and their attitudes to cervical screening. PMID- 23027979 TI - Correlating microbial community profiles with geochemical data in highly stratified sediments from the Arctic Mid-Ocean Ridge. AB - Microbial communities and their associated metabolic activity in marine sediments have a profound impact on global biogeochemical cycles. Their composition and structure are attributed to geochemical and physical factors, but finding direct correlations has remained a challenge. Here we show a significant statistical relationship between variation in geochemical composition and prokaryotic community structure within deep-sea sediments. We obtained comprehensive geochemical data from two gravity cores near the hydrothermal vent field Loki's Castle at the Arctic Mid-Ocean Ridge, in the Norwegian-Greenland Sea. Geochemical properties in the rift valley sediments exhibited strong centimeter-scale stratigraphic variability. Microbial populations were profiled by pyrosequencing from 15 sediment horizons (59,364 16S rRNA gene tags), quantitatively assessed by qPCR, and phylogenetically analyzed. Although the same taxa were generally present in all samples, their relative abundances varied substantially among horizons and fluctuated between Bacteria- and Archaea-dominated communities. By independently summarizing covariance structures of the relative abundance data and geochemical data, using principal components analysis, we found a significant correlation between changes in geochemical composition and changes in community structure. Differences in organic carbon and mineralogy shaped the relative abundance of microbial taxa. We used correlations to build hypotheses about energy metabolisms, particularly of the Deep Sea Archaeal Group, specific Deltaproteobacteria, and sediment lineages of potentially anaerobic Marine Group I Archaea. We demonstrate that total prokaryotic community structure can be directly correlated to geochemistry within these sediments, thus enhancing our understanding of biogeochemical cycling and our ability to predict metabolisms of uncultured microbes in deep-sea sediments. PMID- 23027985 TI - The independence of private versus public abortion providers: implications for abortion stigma. PMID- 23027982 TI - Barriers to cervical screening in women who have experienced sexual abuse: an exploratory study. AB - OBJECTIVES: To explore self-reported cervical screening history and barriers to attendance among women who have been sexually abused and to identify measures to improve the experience of cervical screening for these women. METHODS: Women visiting the website of the National Association for People Abused in Childhood (NAPAC), who had been sexually abused, were invited to complete a survey of their views and experiences of cervical screening. This included closed questions on demographic characteristics and cervical screening attendance, open questions on barriers to screening, and the opportunity to submit suggestions to improve this experience for women who have been sexually abused. Content analysis was used to code responses to the open questions. Four women also participated in a discussion group. RESULTS: Overall, 135 women completed the closed questions and 124 provided open-ended responses. 77.5% of responding women who were eligible for cervical screening in England had ever attended, 48.5% at least once in the previous 5 years, but 42.1% of women aged 25-49 within 3 years. A total of nine higher order themes were identified related to barriers to screening, one related to intention to attend screening and five related to suggestions to improve screening. CONCLUSIONS: This study supports the idea that women who have experienced sexual abuse are less likely to attend for regular cervical screening, with under half screened in the last 5 years compared to the National Health Service Cervical Screening Programme figure of 78.6%. Suggestions to improve the experience for abused women focused on communication, safety, trust and sharing control. Further research in this area is warranted to ensure that this at-risk population is appropriately served by cervical screening. PMID- 23027986 TI - "Will I be asked to have sex in the therapy room?". PMID- 23027988 TI - Gay sex crimes in Europe 1500-1790. PMID- 23027989 TI - Menstrual suppression among female Nigerian pilgrims during Hajj. PMID- 23027990 TI - Pitfalls of adapting emergency contraception CEU guidance. PMID- 23027991 TI - Entonox(r) analgesia for IUD insertions and removals. PMID- 23027992 TI - Licensing of mifepristone in New Zealand and Australia. PMID- 23027993 TI - Implanon(r) removal technique. PMID- 23027994 TI - Allergy to nexplanon(r). PMID- 23027995 TI - An innovative training for nurses in sexual and reproductive health. PMID- 23027996 TI - Training for nurses working in SRH. PMID- 23027997 TI - Innovative training for nurses in SRH. PMID- 23027999 TI - Does prevention of risk behaviour in primary care require a gender-specific approach? A cross-sectional study. AB - BACKGROUND: In planning a prevention programme, it is important to know to what extent gender, risk behaviour and GP consultation need to be taken into account. OBJECTIVE: To determine whether gender plays a role in the relation between risk behaviour and use of GP services. METHODS: The data used in this study originate from the Second Dutch National Survey of General Practice of 2000-02. We used respondent interviews in three age groups: 555 respondents aged 18-22; 1005 respondents aged 45-49; and 536 respondents aged 70-74. We studied smoking, alcohol abuse, excessive alcohol intake, use of soft drugs, overweight and insufficient physical exercise in relation to use of primary care and gender. RESULTS: Almost all risk behaviours were more prevalent in men. Of all studied risk behaviours, only smoking was related to yearly GP contact and consultation frequency in relation to gender. Smoking men consulted their GP significantly less frequently than non-smoking men, whereas in women, the opposite was the case. CONCLUSIONS: Both rates of consultation and yearly contact were significantly lower in smoking men than in smoking women. Preventive actions by means of case-finding, therefore, are less attainable in men than in women. This outcome may create a double setback for Dutch men, as smoking is a major cause of lower life expectancy in men. Recent data show that under-representation of men among consulters in general practice and excess of smoking men still exist in the Netherlands. This confirms the actual relevance of our findings although these were obtained 10years ago. PMID- 23028000 TI - Advance care planning and interpersonal relationships: a two-way street. AB - BACKGROUND: Advance care planning (ACP) has been gaining prominence for its perceived benefits for patients in enhancing patient autonomy and ensuring high quality end-of-life-care. Moreover, it has been postulated that ACP has positive effects on families and health professionals and their relationship with the patient. However, there is a paucity of studies examining the views of GPs on this issue. OBJECTIVE: To explore GP views on the impact that ACP has on interpersonal relationships among those involved in the patient's care. METHOD: Semi-structured, open-ended interviews of a purposive sample of 17 GPs. Interview transcripts were analysed using constructionist grounded theory methodology with QSR NVivo 9 software. RESULTS: ACP was seen as having both positive and negative impacts on interpersonal relationships. It was thought to enhance family relationships, help resolve conflicts between families and health professionals and improve trust and understanding between patients and health professionals. Negatively, it could take the family's attention away from patient care. The link between ACP and interpersonal relationships was perceived to be bidirectional-the nature of interpersonal relationship that patients have with their families and health professionals has a profound impact on what form of ACP is likely to be useful. CONCLUSION: Our study highlights the importance that GPs place on the link between ACP and the patient's interpersonal context. This has implications on how ACP is conducted in primary care settings that are considerably different from other care settings in their emphasis on continuity of care and long-term nature of relationships. PMID- 23028001 TI - Microsatellite markers for Amborella (Amborellaceae), a monotypic genus endemic to New Caledonia. AB - PREMISE OF THE STUDY: Informative markers are required for assessing the diversity of Amborella trichopoda, the only species of its order, endemic to New Caledonia and considered to be the sister species to all flowering plants. Therefore, expressed sequence tag (EST)-based microsatellite markers were developed. * METHODS AND RESULTS: Fifty-five microsatellite loci were characterized in 14896 putative unigenes, which were generated by assembling A. trichopoda ESTs from the public sequence database. Seventeen markers revealed polymorphism in 80 adult shrubs from three populations. The number of alleles per locus ranged from two to 12, with a total of 132 alleles scored. The mean expected heterozygosity per population ranged from 0.336 to 0.567. * CONCLUSIONS: These markers offer an appropriate amount of variation to investigate genetic diversity structure, gene flow, and other conservation issues. PMID- 23028002 TI - Development and characterization of 110 novel EST-SSR markers for Dendrobium officinale (Orchidaceae). AB - PREMISE OF THE STUDY: Expressed sequence tag (EST)-derived simple sequence repeat (SSR) markers were developed in Dendrobium officinale by screening a cDNA library. The loci were verified by sequencing and explored for polymorphism among 19 genotypes and transferability among 30 other distantly related Dendrobium species. * METHODS AND RESULTS: One hundred ten EST-SSRs were developed, and a set of 20 amplified two to six nucleotide repeats with a mean number of 2.5 alleles per locus and with an observed heterozygosity and polymorphism information content per locus ranging from 0.3463 to 0.9003 and 0.0997 to 0.6537 in 19 D. officinale genotypes, respectively. Furthermore, 92 of these markers have cross-taxa transferability, ranging from 6.45% to 100% among 30 other distantly related Dendrobium species. * CONCLUSIONS: The developed markers have potential for application in germplasm appraisal, genetic diversity study, genetic mapping, and molecular breeding in D. officinale and other congeneric species. PMID- 23028003 TI - Development of 161 novel EST-SSR markers from Lathyrus sativus (Fabaceae). AB - PREMISE OF THE STUDY: Expressed sequence tag (ESTs)-derived microsatellite markers were developed in Lathyrus sativus by screening the National Center for Biotechnology Information (NCBI) database. The usefulness of these novel markers was validated for size polymorphism among grasspea accessions. * METHODS AND RESULTS: Three hundred EST-simple sequence repeat (SSR) primer pairs were identified and loci characterized for size polymorphism among 24 grasspea accessions from worldwide sources. Among them 139 SSR loci produced no PCR product, 117 SSR loci were monomorphic, and 44 SSR loci were polymorphic. The mean number of alleles per locus ranged from two to 11. The observed heterozygosity and expected heterozygosity ranged from 0.000 to 1.000 and 0.042 to 0.836, respectively. * CONCLUSIONS: These novel markers will be useful and convenient to study genetic mapping and molecular breeding in grasspea. PMID- 23028004 TI - Isolation and characterization of 13 novel polymorphic microsatellite markers for Pinus koraiensis (Pinaceae). AB - PREMISE OF THE STUDY: Thirteen polymorphic microsatellite markers were developed to investigate the genetic diversity and population structure of Pinus koraiensis. * METHODS AND RESULTS: Using the Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) method with three specific PCR primers for screening the positive clones, 13 loci were found to be polymorphic in 78 individuals of P. koraiensis. Across all of the P. koraiensis samples, the number of alleles per locus ranged from two to 11. * CONCLUSIONS: These polymorphic markers will be useful for conservation genetics studies of this species and to inform the development of effective P. koraiensis conservation programs. PMID- 23028005 TI - Short seed longevity, variable germination conditions, and infrequent establishment events provide a narrow window for Yucca brevifolia (Agavaceae) recruitment. AB - PREMISE OF THE STUDY: The future of long-lived stand-forming desert plants such as Yucca brevifolia (Joshua tree) has come into question in light of climate variation and landscape-scale disturbances such as wildfire. Understanding plant establishment dynamics is important for mitigating the impacts of disturbances and promoting revegetation. * METHODS: We placed Y. brevifolia seeds in shallow caches and manipulated granivore access, nurse shrub effects, and the season of cache placement to determine conditions for seed germination and seedling establishment. * KEY RESULTS: Greatest seedling emergence occurred during spring and summer, when increased soil moisture was accompanied by warm soil temperatures. Late winter-spring emergence for cached seeds was enhanced beneath shrub canopies, but seedling survival declined beneath shrubs as temperatures increased in spring. Germinability of seed remaining in the soil was reduced from 50-68% after 12 mo residence time in soil and declined to <3% after 40 mo. Following dispersal from parent plants, seeds are either removed by granivores or lose germinability, imposing substantial losses of potential germinants. * CONCLUSIONS: Specific germination and establishment requirements impose stringent limits on recruitment rates for Y. brevifolia. Coupled with infrequent seed availability, the return rates to prefire densities and demographic structure may require decades to centuries, especially in light of potential changes to regional desert climate in combination with the potential for fire recurrence. Demographic patterns are predicted to vary spatially in response to environmental variability that limits recruitment and may already be apparent among extant populations. PMID- 23028006 TI - Isolation and characterization of polymorphic microsatellite loci in the endangered plant Dipteronia sinensis (Sapindaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed in Dipteronia sinensis to investigate the population genetics of this endangered plant. * METHODS AND RESULTS: Using the Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) protocol, 19 microsatellite loci were developed in D. sinensis and evaluated for their variability in 29 samples from a natural population. For the 15 polymorphic loci, the number of alleles ranged from nine to 33, while the observed and expected heterozygosities ranged from 0.3793 to 0.9655 and from 0.6029 to 0.9609, respectively. Their cross-taxa transferability was also investigated in Acer miaotaiense, A. palmatum, and A. pictum subsp. mono, and 10 to 15 loci proved amplifiable in these species. * CONCLUSIONS: These microsatellite markers could be employed to investigate the population genetics of D. sinensis and may potentially be applicable to other related species. PMID- 23028007 TI - Clinical year in review I: quality improvement for pulmonary and critical care medicine, lung transplantation, rehabilitation for pulmonary and critically ill patients, and sleep medicine. PMID- 23028008 TI - Clinical year in review II: mechanical ventilation, acute respiratory distress syndrome, critical care, and lung cancer. PMID- 23028009 TI - Clinical year in review III: asthma, chronic obstructive pulmonary disease, environmental and occupational lung disease, and ethics and end-of-life care. PMID- 23028010 TI - Clinical year in review IV: HIV, mycobacterial disease, pulmonary hypertension, and interstitial lung disease. PMID- 23028012 TI - The association between irregular menstruations and acne with asthma and atopy phenotypes. AB - Earlier menarche and irregular periods, among other markers of sex-hormone levels, have been associated with a higher risk of asthma and allergic diseases. This has suggested an etiologic role of sex hormones in the development of these conditions. The authors investigated the association of age at menarche, irregular periods, duration of menstruation, and acne with reported medical history of asthma and/or atopy (hay fever and/or eczema/urticaria) in a historical cohort of students born before the rise in asthma prevalence in the United Kingdom and attending university in 1948-1968. Finding consistent associations in a cohort that has experienced different life-course exposures and has different confounding structure can help to identify causal associations. In the Glasgow Alumni Cohort, irregular periods were associated with atopic asthma (multinomial odds ratio (MOR) = 2.79, 95% confidence interval (CI): 1.33, 5.83) and atopy alone (MOR = 1.40, 95% CI: 1.06, 1.84) but not with nonatopic asthma (MOR = 1.02, 95% CI: 0.45, 2.30), compared with students reporting no asthma and no atopy. The authors found no association with acne, a marker of high testosterone levels, that they hypothesized could point to polycystic ovary syndrome underpinning these associations. In summary, the authors found evidence for a potentially etiologic role of irregular menstruations with some specific asthma phenotypes, namely, atopic asthma and atopy, but not with nonatopic asthma. PMID- 23028013 TI - Number size distribution of fine and ultrafine fume particles from various welding processes. AB - Studies in the field of environmental epidemiology indicate that for the adverse effect of inhaled particles not only particle mass is crucial but also particle size is. Ultrafine particles with diameters below 100 nm are of special interest since these particles have high surface area to mass ratio and have properties which differ from those of larger particles. In this paper, particle size distributions of various welding and joining techniques were measured close to the welding process using a fast mobility particle sizer (FMPS). It turned out that welding processes with high mass emission rates (manual metal arc welding, metal active gas welding, metal inert gas welding, metal inert gas soldering, and laser welding) show mainly agglomerated particles with diameters above 100 nm and only few particles in the size range below 50 nm (10 to 15%). Welding processes with low mass emission rates (tungsten inert gas welding and resistance spot welding) emit predominantly ultrafine particles with diameters well below 100 nm. This finding can be explained by considerably faster agglomeration processes in welding processes with high mass emission rates. Although mass emission is low for tungsten inert gas welding and resistance spot welding, due to the low particle size of the fume, these processes cannot be labeled as toxicologically irrelevant and should be further investigated. PMID- 23028014 TI - Personal exposure to dust and endotoxin in Robusta and Arabica coffee processing factories in Tanzania. AB - INTRODUCTION: Endotoxin exposure associated with organic dust exposure has been studied in several industries. Coffee cherries that are dried directly after harvest may differ in dust and endotoxin emissions to those that are peeled and washed before drying. The aim of this study was to measure personal total dust and endotoxin levels and to evaluate their determinants of exposure in coffee processing factories. METHODS: Using Sidekick Casella pumps at a flow rate of 2l/min, total dust levels were measured in the workers' breathing zone throughout the shift. Endotoxin was analyzed using the kinetic chromogenic Limulus amebocyte lysate assay. Separate linear mixed-effects models were used to evaluate exposure determinants for dust and endotoxin. RESULTS: Total dust and endotoxin exposure were significantly higher in Robusta than in Arabica coffee factories (geometric mean 3.41 mg/m(3) and 10 800 EU/m(3) versus 2.10 mg/m(3) and 1400 EU/m(3), respectively). Dry pre-processed coffee and differences in work tasks explained 30% of the total variance for total dust and 71% of the variance for endotoxin exposure. High exposure in Robusta processing is associated with the dry pre processing method used after harvest. CONCLUSIONS: Dust and endotoxin exposure is high, in particular when processing dry pre-processed coffee. Minimization of dust emissions and use of efficient dust exhaust systems are important to prevent the development of respiratory system impairment in workers. PMID- 23028015 TI - The cyanobacterial CCM as a source of genes for improving photosynthetic CO2 fixation in crop species. AB - Crop yields need to nearly double over the next 35 years to keep pace with projected population growth. Improving photosynthesis, via a range of genetic engineering strategies, has been identified as a promising target for crop improvement with regard to increased photosynthetic yield and better water-use efficiency (WUE). One approach is based on integrating components of the highly efficient CO(2)-concentrating mechanism (CCM) present in cyanobacteria (blue green algae) into the chloroplasts of key C(3) crop plants, particularly wheat and rice. Four progressive phases towards engineering components of the cyanobacterial CCM into C(3) species can be envisaged. The first phase (1a), and simplest, is to consider the transplantation of cyanobacterial bicarbonate transporters to C(3) chloroplasts, by host genomic expression and chloroplast targeting, to raise CO(2) levels in the chloroplast and provide a significant improvement in photosynthetic performance. Mathematical modelling indicates that improvements in photosynthesis as high as 28% could be achieved by introducing both of the single-gene, cyanobacterial bicarbonate transporters, known as BicA and SbtA, into C(3) plant chloroplasts. Part of the first phase (1b) includes the more challenging integration of a functional cyanobacterial carboxysome into the chloroplast by chloroplast genome transformation. The later three phases would be progressively more elaborate, taking longer to engineer other functional components of the cyanobacterial CCM into the chloroplast, and targeting photosynthetic and WUE efficiencies typical of C(4) photosynthesis. These later stages would include the addition of NDH-1-type CO(2) pumps and suppression of carbonic anhydrase and C(3) Rubisco in the chloroplast stroma. We include a score card for assessing the success of physiological modifications gained in phase 1a. PMID- 23028016 TI - Engineering photosynthesis in plants and synthetic microorganisms. AB - Photosynthetic organisms, such as cyanobacteria, algae, and plants, sustain life on earth by converting light energy, water, and CO(2) into chemical energy. However, due to global change and a growing human population, arable land is becoming scarce and resources, including water and fertilizers, are becoming exhausted. It will therefore be crucial to design innovative strategies for sustainable plant production to maintain the food and energy bases of human civilization. Several different strategies for engineering improved photosynthesis in crop plants and introducing novel photosynthetic capacity into microorganisms have been reviewed. PMID- 23028017 TI - ALLENE OXIDE CYCLASE (AOC) gene family members of Arabidopsis thaliana: tissue- and organ-specific promoter activities and in vivo heteromerization. AB - Jasmonates are important signals in plant stress responses and plant development. An essential step in the biosynthesis of jasmonic acid (JA) is catalysed by ALLENE OXIDE CYCLASE (AOC) which establishes the naturally occurring enantiomeric structure of jasmonates. In Arabidopsis thaliana, four genes encode four functional AOC polypeptides (AOC1, AOC2, AOC3, and AOC4) raising the question of functional redundancy or diversification. Analysis of transcript accumulation revealed an organ-specific expression pattern, whereas detailed inspection of transgenic lines expressing the GUS reporter gene under the control of individual AOC promoters showed partially redundant promoter activities during development: (i) In fully developed leaves, promoter activities of AOC1, AOC2, and AOC3 appeared throughout all leaf tissue, but AOC4 promoter activity was vascular bundle-specific; (ii) only AOC3 and AOC4 showed promoter activities in roots; and (iii) partially specific promoter activities were found for AOC1 and AOC4 in flower development. In situ hybridization of flower stalks confirmed the GUS activity data. Characterization of single and double AOC loss-of-function mutants further corroborates the hypothesis of functional redundancies among individual AOCs due to a lack of phenotypes indicative of JA deficiency (e.g. male sterility). To elucidate whether redundant AOC expression might contribute to regulation on AOC activity level, protein interaction studies using bimolecular fluorescence complementation (BiFC) were performed and showed that all AOCs can interact among each other. The data suggest a putative regulatory mechanism of temporal and spatial fine-tuning in JA formation by differential expression and via possible heteromerization of the four AOCs. PMID- 23028018 TI - Nutrient enrichment affects the mechanical resistance of aquatic plants. AB - For many plant species, nutrient availability induces important anatomical responses, particularly the production of low-density tissues to the detriment of supporting tissues. Due to the contrasting biomechanical properties of plant tissues, these anatomical responses may induce important modifications in the biomechanical properties of plant organs. The aim of this study was to determine the effects of nutrient enrichment on the anatomical traits of two freshwater plant species and its consequences on plant biomechanical performance. Two plant species were grown under controlled conditions in low versus high nutrient levels. The anatomical and biomechanical traits of the plant stems were measured. Both species produced tissues with lower densities under nutrient-rich conditions, accompanied by modifications in the structure of the aerenchyma for one species. As expected, nutrient enrichment also led to important modifications in the biomechanical properties of the stem for both species. In particular, mechanical resistance (breaking force and strength) and stiffness of stems were significantly reduced under nutrient rich conditions. The production of weaker stem tissues as a result of nutrient enrichment may increase the risk of plants to mechanical failure, thus challenging plant maintenance in mechanically stressful or disturbed habitats. PMID- 23028020 TI - On the move: induced resistance in monocots. AB - Although plants possess an arsenal of constitutive defences such as structural barriers and preformed antimicrobial defences, many attackers are able to overcome the pre-existing defence layers. In response, a range of inducible plant defences is set up to battle these pathogens. These mechanisms, commonly integrated as induced resistance (IR), control pathogens and pests by the activation of specific defence pathways. IR mechanisms have been extensively studied in the Dicotyledoneae, whereas knowledge of IR in monocotyledonous plants, including the globally important graminaceous crop plants, is elusive. Considering the potential of IR for sustainable agriculture and the recent advances in monocot genomics and biotechnology, IR in monocots is an emerging research field. In the following, current facts and trends concerning basal immunity, and systemic acquired/induced systemic resistance in the defence of monocots against pathogens and herbivores will be summarized. PMID- 23028019 TI - Phylogeny and structure of the cinnamyl alcohol dehydrogenase gene family in Brachypodium distachyon. AB - Cinnamyl alcohol dehydrogenase (CAD) catalyses the final step of the monolignol biosynthesis, the conversion of cinnamyl aldehydes to alcohols, using NADPH as a cofactor. Seven members of the CAD gene family were identified in the genome of Brachypodium distachyon and five of these were isolated and cloned from genomic DNA. Semi-quantitative reverse-transcription PCR revealed differential expression of the cloned genes, with BdCAD5 being expressed in all tissues and highest in root and stem while BdCAD3 was only expressed in stem and spikes. A phylogenetic analysis of CAD-like proteins placed BdCAD5 on the same branch as bona fide CAD proteins from maize (ZmCAD2), rice (OsCAD2), sorghum (SbCAD2) and Arabidopsis (AtCAD4, 5). The predicted three-dimensional structures of both BdCAD3 and BdCAD5 resemble that of AtCAD5. However, the amino-acid residues in the substrate binding domains of BdCAD3 and BdCAD5 are distributed symmetrically and BdCAD3 is similar to that of poplar sinapyl alcohol dehydrogenase (PotSAD). BdCAD3 and BdCAD5 expressed and purified from Escherichia coli both showed a temperature optimum of about 50 degrees C and molar weight of 49 kDa. The optimal pH for the reduction of coniferyl aldehyde were pH 5.2 and 6.2 and the pH for the oxidation of coniferyl alcohol were pH 8 and 9.5, for BdCAD3 and BdCAD5 respectively. Kinetic parameters for conversion of coniferyl aldehyde and coniferyl alcohol showed that BdCAD5 was clearly the most efficient enzyme of the two. These data suggest that BdCAD5 is the main CAD enzyme for lignin biosynthesis and that BdCAD3 has a different role in Brachypodium. All CAD enzymes are cytosolic except for BdCAD4, which has a putative chloroplast signal peptide adding to the diversity of CAD functions. PMID- 23028021 TI - N-fertilization has different effects on the growth, carbon and nitrogen physiology, and wood properties of slow- and fast-growing Populus species. AB - To investigate how N-fertilization affects the growth, carbon and nitrogen (N) physiology, and wood properties of poplars with contrasting growth characteristics, slow-growing (Populus popularis, Pp) and fast-growing (P. alba*P. glandulosa, Pg) poplar saplings were exposed to different N levels. Above ground biomass, leaf area, photosynthetic rates (A), instantaneous photosynthetic nitrogen use efficiency (PNUE (i)), chlorophyll and foliar sugar concentrations were higher in Pg than in Pp. Foliar nitrate reductase (NR) activities and root glutamate synthase (GOGAT) activities were higher in Pg than in Pp as were the N amount and NUE of new shoots. Lignin contents and calorific values of Pg wood were less than that of Pp wood. N-fertilization reduced root biomass of Pg more than of Pp, but increased leaf biomass, leaf area, A, and PNUE(i) of Pg more than of Pp. Among 13 genes involved in the transport of ammonium or nitrate or in N assimilation, transcripts showed more pronounced changes to N-fertilization in Pg than in Pp. Increases in NR activities and N contents due to N-fertilization were larger in Pg than in Pp. In both species, N-fertilization resulted in lower calorific values as well as shorter and wider vessel elements/fibres. These results suggest that growth, carbon and N physiology, and wood properties are more sensitive to increasing N availability in fast-growing poplars than in slow growing ones, which is probably due to prioritized resource allocation to the leaves and accelerated N physiological processes in fast-growing poplars under higher N levels. PMID- 23028023 TI - A new physical interpretation of plant root capacitance. AB - Capacitance has been used as a non-destructive measure of root system size for 30 years. The equipment required is cheap and simple to apply in both field and laboratory. Good linear correlations have been reported between capacitance and root mass. A model by F. N. Dalton, predicting a linear relationship between these two variables, has become accepted widely. This model was tested for barley (Hordeum vulgare) grown hydroponically using treatments that included: raising roots out of solution, cutting roots at positions below the solution surface, and varying the distance between plant electrode and the solution surface. Although good linear correlations were found between capacitance and mass for whole root systems, when roots were raised out of solution capacitances were not linearly related to submerged root mass. Excision of roots in the solution had negligible effect on the measured capacitance. These latter observations conflict with Dalton's model. Capacitance correlated linearly with the sum of root cross sectional areas at the solution surface and inversely with distance between plant electrode and solution surface. A new model for capacitance is proposed that is consistent with these observations. PMID- 23028022 TI - Early gene expression events in the laminar abscission zone of abscission promoted citrus leaves after a cycle of water stress/rehydration: involvement of CitbHLH1. AB - Leaf abscission is a common response of plants to drought stress. Some species, such as citrus, have evolved a specific behaviour in this respect, keeping their leaves attached to the plant body during water stress until this is released by irrigation or rain. This study successfully reproduced this phenomenon under controlled conditions (24h of water stress followed by 24h of rehydration) and used it to construct a suppression subtractive hybridization cDNA library enriched in genes involved in the early stages of rehydration-promoted leaf abscission after water stress. Sequencing of the library yielded 314 unigenes, which were spotted onto nylon membranes. Membrane hybridization with petiole (Pet)- and laminar abscission zone (LAZ)-enriched RNA samples corresponding to early steps in leaf abscission revealed an almost exclusive preferential gene expression programme in the LAZ. The data identified major processes such as protein metabolism, cell-wall modification, signalling, control of transcription and vesicle production, and transport as the main biological processes activated in LAZs during the early steps of rehydration-promoted leaf abscission after water stress. Based on these findings, a model for the early steps of citrus leaf abscission is proposed. In addition, it is suggested that CitbHLH1, the putative citrus orthologue of Arabidopsis BIGPETAL, may play major roles in the control of abscission-related events in citrus abscission zones. PMID- 23028024 TI - Genetic variability of an unusual apomictic triploid cactus--Haageocereus tenuis Ritter--from the Coast of Central Peru. AB - Haageocereus tenuis is a prostrate cactus restricted to a small area of 2 km(2) near the city of Lima, Peru. The species is triploid and propagates mainly through stem fragmentation. In addition, propagation via agamospermy is documented and adventitious embryony is also inferred as a mechanism. Although seedling recruitment has not been observed in nature, we have shown that asexually produced seeds are viable. About 45 adult individuals, plus 9 individuals obtained from seeds, were sampled and 5 microsatellite markers were used to assess genetic variability. Microsatellite analysis confirms that individuals from the only existing population are genetically identical and that the population likely represents a single clone. The absence of mutations in any individual, even in highly variable microsatellite loci, may indicate that the species is also of recent origin. Other prostrate species of Haageocereus are suspected to be occasional apomicts. This phenomenon has significant implications for the evolutionary biology and ecology of Haageocereus and other clonal Cactaceae. PMID- 23028025 TI - Positron emission tomography/computed tomography for the diagnosis and assessment of giant cell arteritis: when to consider it and why. PMID- 23028026 TI - Palindromic rheumatism: a pre-rheumatoid arthritis state? PMID- 23028027 TI - Spermatic pedicle inflammation as the initial sign of henoch-schonlein purpura. PMID- 23028028 TI - Infected calcinosis of the knee in limited cutaneous systemic sclerosis. PMID- 23028029 TI - Psoriatic arthritis and sonographic entheseal index. PMID- 23028031 TI - Genetic markers of immunoglobulin G as potential risk factors for IgG4-related disease. PMID- 23028030 TI - Obesity-related adipokines and shoulder osteoarthritis. PMID- 23028032 TI - Failure to control progression of rheumatoid arthritis after a decade of biologic therapy. PMID- 23028033 TI - A remarkable pattern of subcortical vessel wall enhancement in granulomatous angiitis of the central nervous system. PMID- 23028034 TI - Renal involvement in antimyeloperoxidase antineutrophil cytoplasmic antibody positive granulomatosis with polyangiitis with chronic hypertrophic pachymeningitis. PMID- 23028035 TI - Tumor necrosis factor-associated palmoplantar pustular psoriasis treated with interleukin 6 blocker. PMID- 23028037 TI - Genomic grade adds prognostic value in invasive lobular carcinoma. AB - BACKGROUND: The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC. METHODS: Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS). RESULTS: A total of 166 patients were classified by GG. HG classified 33 (20%) tumors as HG1, 120 (73%) as HG2 and 12 (7%) as HG3. GG classified 106 (64%) tumors as GG low (GG1), 29 (17%) as GG high (GG3) and 31 (19%) as equivocal (cases not classified as GG1 or GG3). The median follow-up time was 6.5 years. In multivariate analyses, GG was associated with IDFS [HR(GG3 vs GG1) 5.6 (2.1-15.3); P < 0.001] and OS [HR(GG3 vs GG1) 7.2, 95% CI (1.6-32.2); P = 0.01]. CONCLUSIONS: GG outperformed HG in ILC and added prognostic value to classic clinicopathologic variables, including nodal status. PMID- 23028038 TI - Prognosticating in patients with advanced cancer--observational study comparing the accuracy of clinicians' and patients' estimates of survival. AB - BACKGROUND: Clinicians' prognoses in patients with advanced cancer are imprecise. The aim of this study was to compare doctors', nurses' and patients' survival predictions and to identify factors which influence accuracy. PATIENTS AND METHODS: Some 1018 patients with advanced cancer were recruited. Survival estimates were obtained from the attending doctor, nurse, multidisciplinary team (MDT) and patient (n = 829, 954, 987 and 290 estimates, respectively) and were compared with actual survival. Clinician and patient characteristics were recorded. RESULTS: MDTs', doctors' and nurses' predictions were accurate 57.5%, 56.3% and 55.5% of occasions, respectively. Nurses were less accurate than the MDT (P = 0.007) but were no worse than doctors (P = 0.284). Estimates of clinicians and patients were more optimistic (doctors: 31%; nurses: 34%; MDT: 31.1%; patients: 45.1%) than pessimistic (12.7%, 11%, 11.4% and 2.7%). Nurses' accuracy increased if they had reviewed the patient within 24 h. Most patients (61.4%) wanted to know their prognosis. Only 37.1% were willing to offer an estimate regarding their own survival. Patients' prognostic estimates were less accurate than health care professionals' (P < 0.001). CONCLUSIONS: MDTs were better at predicting survival than doctors' or nurses' alone. Patients were substantially worse. Among nurses, recency of review was related to improved prognostic accuracy. PMID- 23028039 TI - Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole. AB - BACKGROUND: MA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen. PATIENTS AND METHODS: Exploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis. RESULTS: At diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13-0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51-0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03-0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22-0.94; P = 0.03). CONCLUSIONS: Extended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen. PMID- 23028040 TI - Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer. AB - BACKGROUND: We previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival. PATIENTS AND METHODS: Patients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value >= 10 ng/ml and CEA measurements within +/- 30 days of the CTC collection were included. RESULTS: We included 217 patients with mCRC who had a CEA value of >= 10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of >= 25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (>= 3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3-5- and 6-12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6-12 weeks. CONCLUSIONS: This study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC. PMID- 23028041 TI - The running of the Buls: control of permease trafficking by alpha-arrestins Bul1 and Bul2. PMID- 23028042 TI - Casein kinase 1alpha regulates an MDMX intramolecular interaction to stimulate p53 binding. AB - MDMX is an important regulator of p53 during embryonic development and malignant transformation. Previous studies showed that casein kinase 1alpha (CK1alpha) stably associates with MDMX, stimulates MDMX-p53 binding, and cooperates with MDMX to inactivate p53. However, the mechanism by which CK1alpha stimulates MDMX p53 interaction remains unknown. Here, we present evidence that p53 binding by the MDMX N-terminal domain is inhibited by the central acidic region through an intramolecular interaction that competes for the p53 binding pocket. CK1alpha binding to the MDMX central domain and phosphorylation of S289 disrupts the intramolecular interaction, allowing the N terminus to bind p53 with increased affinity. After DNA damage, the MDMX-CK1alpha complex is disrupted by Chk2 mediated phosphorylation of MDMX at S367, leading to reduced MDMX-p53 binding. Therefore, CK1alpha is an important functional partner of MDMX. DNA damage activates p53 in part by disrupting CK1alpha-MDMX interaction and reducing MDMX p53 binding affinity. PMID- 23028043 TI - The nuclear receptor TLX is required for gliomagenesis within the adult neurogenic niche. AB - Neural stem cells (NSCs) continually generate functional neurons in the adult brain. Due to their ability to proliferate, deregulated NSCs or their progenitors have been proposed as the cells of origin for a number of primary central nervous system neoplasms, including infiltrating gliomas. The orphan nuclear receptor TLX is required for proliferation of adult NSCs, and its upregulation promotes brain tumor formation. However, it is unknown whether TLX is required for gliomagenesis. We examined the genetic interactions between TLX and several tumor suppressors, as well as the role of TLX-dependent NSCs during gliomagenesis, using mouse models. Here, we show that TLX is essential for the proliferation of adult NSCs with a single deletion of p21, p53, or Pten or combined deletion of Pten and p53. While brain tumors still form in Tlx mutant mice, these tumors are less infiltrative and rarely associate with the adult neurogenic niches, suggesting a non-stem-cell origin. Taken together, these results indicate a critical role for TLX in NSC-dependent gliomagenesis and implicate TLX as a therapeutic target to inhibit the development of NSC-derived brain tumors. PMID- 23028044 TI - Cell autonomous lipin 1 function is essential for development and maintenance of white and brown adipose tissue. AB - Through analysis of mice with spatially and temporally restricted inactivation of Lpin1, we characterized its cell autonomous function in both white (WAT) and brown (BAT) adipocyte development and maintenance. We observed that the lipin 1 inactivation in adipocytes of aP2(Cre/+)/Lp(fEx2)(-)(3/fEx2)(-)(3) mice resulted in lipodystrophy and the presence of adipocytes with multilocular lipid droplets. We further showed that time-specific loss of lipin 1 in mature adipocytes in aP2(Cre-ERT2/+)/Lp(fEx2)(-)(3/fEx2)(-)(3) mice led to their replacement by newly formed Lpin1-positive adipocytes, thus establishing a role for lipin 1 in mature adipocyte maintenance. Importantly, we observed that the presence of newly formed Lpin1-positive adipocytes in aP2(Cre-ERT2/+)/Lp(fEx2)(-)(3/fEx2)(-)(3) mice protected these animals against WAT inflammation and hepatic steatosis induced by a high-fat diet. Loss of lipin 1 also affected BAT development and function, as revealed by histological changes, defects in the expression of peroxisome proliferator-activated receptor alpha (PPARalpha), PGC-1alpha, and UCP1, and functionally by altered cold sensitivity. Finally, our data indicate that phosphatidic acid, which accumulates in WAT of animals lacking lipin 1 function, specifically inhibits differentiation of preadipocytes. Together, these observations firmly demonstrate a cell autonomous role of lipin 1 in WAT and BAT biology and indicate its potential as a therapeutical target for the treatment of obesity. PMID- 23028045 TI - Reciprocal interaction between TRAF6 and notch signaling regulates adult myofiber regeneration upon injury. AB - Skeletal muscle is a postmitotic tissue that repairs and regenerates through activation of a population of stem-cell-like satellite cells. However, signaling mechanisms governing adult skeletal muscle regeneration remain less understood. In the present study, we have investigated the role of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein involved in receptor-mediated activation of multiple signaling pathways in regeneration of adult myofibers. Skeletal muscle-specific depletion of TRAF6 in mice (TRAF6(mko)) improved regeneration of myofibers upon injury with a concomitant increase in the number of satellite cells and activation of the Notch signaling pathway. Ex vivo cultures of TRAF6(mko) myofiber explants demonstrated an increase in the proliferative capacity of myofiber-associated satellite cells accompanied by an upregulation of Notch ligands. Deletion of TRAF6 also inhibited the activity of transcription factor NF-kappaB and the expression of inflammatory cytokines and augmented the M2c macrophage phenotype in injured muscle tissues. Collectively, our study demonstrates that specific inhibition of TRAF6 improves satellite cell activation and skeletal muscle regeneration through upregulation of Notch signaling and reducing the inflammatory repertoire. PMID- 23028047 TI - Transcriptional regulation of the human tumor suppressor DOK1 by E2F1. AB - The expression of the tumor suppressor DOK1 is repressed in a variety of human tumors as a result of hypermethylation of its promoter region. However, the molecular mechanisms by which DOK1 expression is regulated have been poorly investigated. Here, we show that the expression of DOK1 is regulated mainly by the transcription factor E2F1. We identified three putative E2F1 response elements (EREs) in the DOK1 promoter region. E2F1 had a relatively higher binding affinity for the ERE located between bp -498 and -486 compared with the other two EREs. E2F1 gene silencing strongly inhibited DOK1 expression. E2F1-driven DOK1 transcription occurred in the presence of cellular stresses, such as accumulation of DNA damage induced by etoposide. DOK1 silencing promoted cell proliferation and protected against etoposide-induced apoptosis, indicating that DOK1 acts as a key mediator of cellular stress-induced cell death. Most importantly, we observed that DNA methylation of the DOK1 core promoter region found in head and neck cancer cell lines hampered the recruitment of E2F1 to the DOK1 promoter and compromised DOK1 expression. In summary, our data show that E2F1 is a key factor in DOK1 expression and provide novel insights into the regulation of these events in cancer cells. PMID- 23028046 TI - Cellular adaptation to anthrax lethal toxin-induced mitochondrial cholesterol enrichment, hyperpolarization, and reactive oxygen species generation through downregulating MLN64 in macrophages. AB - Cellular adaptation to different stresses related to survival and function has been demonstrated in several cell types. Anthrax lethal toxin (LeTx) induces rapid cell death, termed "pyroptosis," by activating NLRP1b/caspase-1 in murine macrophages. We and others (S. D. Ha et al., J. Biol. Chem. 282:26275-26283, 2007; I. I. Salles et al., Proc. Natl. Acad. Sci. U. S. A. 100:12426 -12431, 2003) have shown that RAW264.7 cells preexposed to sublethal doses of LeTx become resistant to subsequent high cytolytic doses of LeTx, termed toxin-induced resistance (TIR). To date, the cellular mechanisms of pyroptosis and TIR are largely unknown. We found that LeTx caused NLRP1b/caspase-1-dependent mitochondrial dysfunction, including hyperpolarization and generation of reactive oxygen species, which was distinct from that induced by stimuli such as NLRP3 activating ATP. In TIR cells, these mitochondrial events were not detected, although caspase-1 was activated, in response to LeTx. We identified that downregulation of the late endosomal cholesterol-transferring protein MLN64 in TIR cells was involved in TIR. The downregulation of MLN64 in TIR cells was at least in part due to DNA methyltransferase 1-mediated DNA methylation. In wild type RAW264.7 cells and primary bone marrow-derived macrophages, LeTx caused NLRP1b/caspase-1-dependent mitochondrial translocation of MLN64, resulting in cholesterol enrichment, membrane hyperpolarization, reactive oxygen species (ROS) generation, and depletion of free glutathione (GSH). This study demonstrates for the first time that MLN64 plays a key role in LeTx/caspase-1-induced mitochondrial dysfunction. PMID- 23028048 TI - Involvement of histone demethylase LSD1 in short-time-scale gene expression changes during cell cycle progression in embryonic stem cells. AB - The histone demethylase LSD1, a component of the CoREST (corepressor for element 1-silencing transcription factor) corepressor complex, plays an important role in the downregulation of gene expression during development. However, the activities of LSD1 in mediating short-time-scale gene expression changes have not been well understood. To reveal the mechanisms underlying these two distinct functions of LSD1, we performed genome-wide mapping and cellular localization studies of LSD1 and its dimethylated histone 3 lysine 4 (substrate H3K4me2) in mouse embryonic stem cells (ES cells). Our results showed an extensive overlap between the LSD1 and H3K4me2 genomic regions and a correlation between the genomic levels of LSD1/H3K4me2 and gene expression, including many highly expressed ES cell genes. LSD1 is recruited to the chromatin of cells in the G(1)/S/G(2) phases and is displaced from the chromatin of M-phase cells, suggesting that LSD1 or H3K4me2 alternatively occupies LSD1 genomic regions during cell cycle progression. LSD1 knockdown by RNA interference or its displacement from the chromatin by antineoplastic agents caused an increase in the levels of a subset of LSD1 target genes. Taken together, these results suggest that cell cycle-dependent association and dissociation of LSD1 with chromatin mediates short-time-scale gene expression changes during embryonic stem cell cycle progression. PMID- 23028049 TI - The corepressor NCoR1 antagonizes PGC-1alpha and estrogen-related receptor alpha in the regulation of skeletal muscle function and oxidative metabolism. AB - Skeletal muscle exhibits a high plasticity and accordingly can quickly adapt to different physiological and pathological stimuli by changing its phenotype largely through diverse epigenetic mechanisms. The nuclear receptor corepressor 1 (NCoR1) has the ability to mediate gene repression; however, its role in regulating biological programs in skeletal muscle is still poorly understood. We therefore studied the mechanistic and functional aspects of NCoR1 function in this tissue. NCoR1 muscle-specific knockout mice exhibited a 7.2% higher peak oxygen consumption (VO(2peak)), a 11% reduction in maximal isometric force, and increased ex vivo fatigue resistance during maximal stimulation. Interestingly, global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) overexpression on oxidative metabolism in muscle. Importantly, PPARbeta/delta and estrogen-related receptor alpha (ERRalpha) were identified as common targets of NCoR1 and PGC-1alpha with opposing effects on the transcriptional activity of these nuclear receptors. In fact, the repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1alpha-mediated coactivation of ERRalpha. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases. PMID- 23028050 TI - The alternative complement pathway propagates inflammation and injury in murine ischemic stroke. AB - There is mounting evidence indicating an important role for complement in the pathogenesis of cerebral ischemia-reperfusion injury, or ischemic stroke. The role of the alternative complement pathway in ischemic stroke has not been investigated, and there is conflicting data on the role of the terminal pathway. In this study, we show that compared with wild-type mice, mice deficient in the alternative pathway protein factor B or mice treated with the alternative pathway inhibitor CR2-fH have improved outcomes after 60-min middle cerebral artery occlusion and 24-h reperfusion. Factor B-deficient or CR2-fH-treated mice were protected in terms of improved neurologic function and reduced cerebral infarct, demyelination, P-selectin expression, neutrophil infiltration, and microthrombi formation. Mice deficient in both the classical and lectin pathways (C1q/MBL deficient) were also protected from cerebral ischemia-reperfusion injury, and there was no detectable C3d deposition in the ipsilateral brain of these mice. These data demonstrate that the alternative pathway is not alone sufficient to initiate complement activation and indicate that the alternative pathway propagates cerebral injury via amplification of the cascade. Deficiency of C6, a component of the terminal cytolytic membrane attack complex, had no effect on outcome after ischemic stroke, indicating that the membrane attack complex is not involved in mediating injury in this model. We additionally show that the protective effect of factor B deficiency and CR2-fH treatment is sustained in the subacute stage of infarct development, adding to the clinical relevance of these findings. PMID- 23028053 TI - Stomatin-like protein 2 deficiency in T cells is associated with altered mitochondrial respiration and defective CD4+ T cell responses. AB - Stomatin-like protein 2 (SLP-2) is a mostly mitochondrial protein that regulates mitochondrial biogenesis and function and modulates T cell activation. To determine the mechanism of action of SLP-2, we generated T cell-specific SLP-2 deficient mice. These mice had normal numbers of thymocytes and T cells in the periphery. However, conventional SLP-2-deficient T cells had a posttranscriptional defect in IL-2 production in response to TCR ligation, and this translated into reduced CD4(+) T cell responses. SLP-2 deficiency was associated with impaired cardiolipin compartmentalization in mitochondrial membranes, decreased levels of the NADH dehydrogenase (ubiquinone) iron-sulfur protein 3, NADH dehydrogenase (ubiquinone) 1beta subcomplex subunit 8, and NADH dehydrogenase (ubiquinone) 1alpha subcomplex subunit 9 of respiratory complex I, and decreased activity of this complex as well as of complex II plus III of the respiratory chain. In addition, SLP-2-deficient T cells showed a significant increase in uncoupled mitochondrial respiration and a greater reliance on glycolysis. Based on these results, we propose that SLP-2 organizes the mitochondrial membrane compartmentalization of cardiolipin, which is required for optimal assembly and function of respiratory chain complexes. This function, in T cells, helps to ensure proper metabolic response during activation. PMID- 23028051 TI - Anaphylatoxin C5a creates a favorable microenvironment for lung cancer progression. AB - The complement system contributes to various immune and inflammatory diseases, including cancer. In this study, we investigated the capacity of lung cancer cells to activate complement and characterized the consequences of complement activation on tumor progression. We focused our study on the production and role of the anaphylatoxin C5a, a potent immune mediator generated after complement activation. We first measured the capacity of lung cancer cell lines to deposit C5 and release C5a. C5 deposition, after incubation with normal human serum, was higher in lung cancer cell lines than in nonmalignant bronchial epithelial cells. Notably, lung malignant cells produced complement C5a even in the absence of serum. We also found a significant increase of C5a in plasma from patients with non-small cell lung cancer, suggesting that the local production of C5a is followed by its systemic diffusion. The contribution of C5a to lung cancer growth in vivo was evaluated in the Lewis lung cancer model. Syngeneic tumors of 3LL cells grew slower in mice treated with an antagonist of the C5a receptor. C5a did not modify 3LL cell proliferation in vitro but induced endothelial cell chemotaxis and blood-vessels formation. C5a also contributed to the immunosuppressive microenvironment required for tumor growth. In particular, blockade of C5a receptor significantly reduced myeloid-derived suppressor cells and immunomodulators ARG1, CTLA-4, IL-6, IL-10, LAG3, and PDL1 (B7H1). In conclusion, lung cancer cells have the capacity to generate C5a, a molecule that creates a favorable tumor microenvironment for lung cancer progression. PMID- 23028052 TI - Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3. AB - IFN regulatory factor 3 (IRF3) regulates early type I IFNs and other genes involved in innate immunity. We have previously shown that cells undergoing an endoplasmic reticulum (ER) stress response called the unfolded protein response produce synergistically augmented IFN-beta when stimulated with pattern recognition receptor agonists such as LPS. Concomitant ER stress and LPS stimulation resulted in greater recruitment of the IRF3 transcription factor to ifnb1 gene regulatory elements. In this study, we used murine cells to demonstrate that both oxygen-glucose deprivation and pharmacologic unfolded protein response inducers trigger phosphorylation and nuclear translocation of IRF3, even in the absence of exogenous LPS. Different ER stressors used distinct mechanisms to activate IRF3: IRF3 phosphorylation due to calcium-mobilizing ER stress (thapsigargin treatment, oxygen-glucose deprivation) critically depended upon stimulator of IFN gene, an ER-resident nucleic acid-responsive molecule. However, calcium mobilization alone by ionomycin was insufficient for IRF3 phosphorylation. In contrast, other forms of ER stress (e.g., tunicamycin treatment) promote IRF3 phosphorylation independently of stimulator of IFN gene and TANK-binding kinase 1. Rather, IRF3 activation by tunicamycin and 2 deoxyglucose was inhibited by 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, a serine protease inhibitor that blocks activating transcription factor 6 processing. Interfering with ER stress-induced IRF3 activation abrogated IFN-beta synergy. Together, these data suggest ER stress primes cells to respond to innate immune stimuli by activating the IRF3 transcription factor. Our results also suggest certain types of ER stress accomplish IRF3 phosphorylation by co opting existing innate immune pathogen response pathways. These data have implications for diseases involving ER stress and type I IFN. PMID- 23028055 TI - Ras oncoproteins transfer from melanoma cells to T cells and modulate their effector functions. AB - Lymphocytes establish dynamic cell-cell interactions with the cells they scan. Previous studies show that upon cell contact, various membrane-associated proteins, such as Ras-family proteins, transfer from B to T and NK lymphocytes. Mutations in RAS genes that encode constitutively active, GTP-bound, oncoproteins are rather common in human cancers; for instance, melanoma. Cancer immunoediting has been postulated to contribute to the elimination of malignant melanoma. Thus, we asked whether Ras oncoproteins can transfer from melanoma to T cells, including tumor-infiltrating lymphocytes (TILs), and subsequently induce functional effects in the adopting T cells. To explore this issue, we genetically engineered an HLA-A2(+) melanoma cell line, MEL526, to express GFP or GFP-tagged H-Ras mutants stably. In this study, we show by an in vitro coculture system that GFP-tagged H-Ras, but not GFP, transfers from MEL526 to T cells and localizes to the inner aspect of their plasma membrane. This cell-contact-dependent process was increased by TCR stimulation and did not require strict Ag specificity. Importantly, we found a positive correlation between the levels of the acquired constitutively active H-RasG12V and ERK1/2 phosphorylation within the adopting TILs. We also show a significant increase in IFN-gamma production and cytotoxic activity in TILs that acquired H-RasG12V compared to TILs that acquired a different H-Ras mutant. In conclusion, our findings demonstrate a hitherto unknown phenomenon of intercellular transfer of Ras oncoproteins from melanoma to TILs that consequently augments their effector functions. PMID- 23028054 TI - IL-1 family members IL-18 and IL-33 upregulate the inflammatory potential of differentiated human Th1 and Th2 cultures. AB - The IL-1 family members IL-1beta, IL-18, and IL-33 are potent cytokines in relationship to amplifying the CD4(+) T cell cytokine production. To evaluate their impact on in vitro-differentiated human Th1 and Th2 cultures, such cultures were established from naive T cells, purified from healthy blood donors, and reactivated in the presence of IL-1beta, IL-18, or IL-33. Interestingly, we observe modifying responses in Th1 and Th2 cultures induced by IL-18 or IL-33 but not by IL-1beta, both contributing to amplify production of IL-5, IL-13, and IFN gamma. IL-18 or IL-33 stimulation of Th1 cultures resulted in increased IFN-gamma and IL-13 production concurrent with reduced IL-10 gene transcription and secretion even though Th1 cultures, in contrast to IL-18Ralpha, had low ST2L expression. Furthermore, adding IL-18 to Th1 cultures promoted Tbet mRNA expression and production. Th2 cultures stimulated with IL-18 or IL-33 had an increased IL-5 secretion. Interestingly, E4BP4 gene expression and the percentage of E4BP4(+) cells of the recently shown IL-10 transcriptional regulator E4BP4 correlated with IL-10 gene expression and protein secretion in Th1 cultures. Taken together, we report that the IL-1 family "alarmins" IL-18 and IL-33 in addition to amplifying both Th1- and Th2-associated cytokines block production of the regulatory cytokine IL-10 in Th1 cultures. PMID- 23028056 TI - An antibody to the sixth Ig-like domain of VCAM-1 inhibits leukocyte transendothelial migration without affecting adhesion. AB - VCAM-1 plays a key role in leukocyte trafficking during inflammatory responses. However, molecular mechanisms underlying this function have not been clearly elucidated. In this study, using phage display technology, we developed a rabbit/human chimeric VCAM-1 Ab, termed VCAM-1 domain 6 (VCAM-1-D6), which specifically recognizes aa 511-599 within the sixth Ig-like domain. We report that the VCAM-1-D6 Ab blocked U937 cell transmigration across activated HUVECs but did not alter adhesion of U937 cells to the HUVECs. We also demonstrate that VCAM-1-D6 does not alter TNF-alpha-stimulated endothelial cell chemokine or cytokine production. Furthermore, through in vivo efficacy testing using a mouse islet allograft model, we demonstrate that VCAM-1-D6 significantly alleviates allograft rejection by blocking leukocyte infiltration to the grafted islets. Taken together, our results suggest that the VCAM-1-D6 Ab may block VCAM-1 mediated inflammation and could be a useful tool in treating inflammatory diseases. PMID- 23028057 TI - Maintenance of peripheral T cell responses during Mycobacterium tuberculosis infection. AB - Fully functional T cells are necessary for the maintenance of protective immunity during chronic infections. However, activated T cells often undergo apoptosis or exhaustion upon chronic stimulation mediated by Ag or inflammation. T cell attrition can be compensated for by the production of thymus-derived T cells, although the new naive T cells must undergo T cell priming and differentiation under conditions different from those encountered during acute infection. We used a murine model of Mycobacterium tuberculosis infection to address how the activation and differentiation of new thymic emigrants is affected by chronic inflammation, as well as whether the newly developed effector T cells help to maintain peripheral T cell responses. Although new thymic emigrants contributed to the peripheral T cell response early during acute M. tuberculosis infection, the relative contribution of new effector T cells to the peripheral CD4 and CD8 T cell pools declined during chronic infection. The decline in new T cell recruitment was a consequence of quantitative and/or qualitative changes in Ag presentation, because during chronic infection both the priming and expansion of naive T cells were inefficient. Thus, although thymic tolerance is not a major factor that limits protective T cell responses, the chronic environment does not efficiently support naive T cell priming and accumulation during M. tuberculosis infection. These studies support our previous findings that long-term protective T cell responses can be maintained indefinitely in the periphery, but also suggest that the perturbation of homeostasis during chronic inflammatory responses may elicit immune pathology mediated by new T cells. PMID- 23028058 TI - Immunity to the conserved influenza nucleoprotein reduces susceptibility to secondary bacterial infections. AB - Influenza causes >250,000 deaths annually in the industrialized world, and bacterial infections frequently cause secondary illnesses during influenza outbreaks, including pneumonia, bronchitis, sinusitis, and otitis media. In this study, we demonstrate that cross-reactive immunity to mismatched influenza strains can reduce susceptibility to secondary bacterial infections, even though this fails to prevent influenza infection. Specifically, infecting mice with H3N2 influenza before challenging with mismatched H1N1 influenza reduces susceptibility to either Gram-positive Streptococcus pneumoniae or Gram-negative Klebsiella pneumoniae. Vaccinating mice with the highly conserved nucleoprotein of influenza also reduces H1N1-induced susceptibility to lethal bacterial infections. Both T cells and Abs contribute to defense against influenza-induced bacterial diseases; influenza cross-reactive T cells reduce viral titers, whereas Abs to nucleoprotein suppress induction of inflammation in the lung. These findings suggest that nonneutralizing influenza vaccines that fail to prevent influenza infection may nevertheless protect the public from secondary bacterial diseases when neutralizing vaccines are not available. PMID- 23028059 TI - Adora2b adenosine receptor signaling protects during acute kidney injury via inhibition of neutrophil-dependent TNF-alpha release. AB - Renal ischemia is among the leading causes of acute kidney injury (AKI). Previous studies have shown that extracellular adenosine is a prominent tissue-protective cue elicited during ischemia, including signaling events through the adenosine receptor 2b (Adora2b). To investigate the functional role of Adora2b signaling in cytokine-mediated inflammatory pathways, we screened wild-type and Adora2b deficient mice undergoing renal ischemia for expression of a range of inflammatory cytokines. These studies demonstrated a selective and robust increase of TNF-alpha levels in Adora2b-deficient mice following renal ischemia and reperfusion. Based on these findings, we next sought to understand the contribution of TNF-alpha on ischemic AKI through a combination of loss- and gain of-function studies. Loss of TNF-alpha, through either Ab blockade or study of Tnf-alpha-deficient animals, resulted in significantly attenuated tissue injury and improved kidney function following renal ischemia. Conversely, transgenic mice with overexpression of TNF-alpha had significantly pronounced susceptibility to AKI. Furthermore, neutrophil depletion or reconstitution of Adora2b(-/-) mice with Tnf-alpha-deficient neutrophils rescued their phenotype. In total, these data demonstrate a critical role of adenosine signaling in constraining neutrophil-dependent production of TNF-alpha and implicate therapies targeting TNF-alpha in the treatment of ischemic AKI. PMID- 23028060 TI - High-definition de novo sequencing of crustacean hyperglycemic hormone (CHH) family neuropeptides. AB - A complete understanding of the biological functions of large signaling peptides (>4 kDa) requires comprehensive characterization of their amino acid sequences and post-translational modifications, which presents significant analytical challenges. In the past decade, there has been great success with mass spectrometry-based de novo sequencing of small neuropeptides. However, these approaches are less applicable to larger neuropeptides because of the inefficient fragmentation of peptides larger than 4 kDa and their lower endogenous abundance. The conventional proteomics approach focuses on large-scale determination of protein identities via database searching, lacking the ability for in-depth elucidation of individual amino acid residues. Here, we present a multifaceted MS approach for identification and characterization of large crustacean hyperglycemic hormone (CHH)-family neuropeptides, a class of peptide hormones that play central roles in the regulation of many important physiological processes of crustaceans. Six crustacean CHH-family neuropeptides (8-9.5 kDa), including two novel peptides with extensive disulfide linkages and PTMs, were fully sequenced without reference to genomic databases. High-definition de novo sequencing was achieved by a combination of bottom-up, off-line top-down, and on line top-down tandem MS methods. Statistical evaluation indicated that these methods provided complementary information for sequence interpretation and increased the local identification confidence of each amino acid. Further investigations by MALDI imaging MS mapped the spatial distribution and colocalization patterns of various CHH-family neuropeptides in the neuroendocrine organs, revealing that two CHH-subfamilies are involved in distinct signaling pathways. PMID- 23028061 TI - A simple and effective cleavable linker for chemical proteomics applications. AB - The study of metabolically labeled or probe-modified proteins is an important area in chemical proteomics. Isolation and purification of the protein targets is a necessary step before MS identification. The biotin-streptavidin system is widely used in this process, but the harsh denaturing conditions also release natively biotinylated proteins and non-selectively bound proteins. A cleavable linker strategy is a promising approach for solving this problem. Though several cleavable linkers have been developed and tested, an efficient, easily synthesized, and inexpensive cleavable linker is a desirable addition to the proteomics toolbox. Here, we describe the chemical proteomics application of a vicinal diol cleavable linker. Through easy-to-handle chemistry we incorporate this linker into an activity-based probe and a biotin alkyne tag amenable for bioorthogonal ligation. With these reagents, background protein identifications are significantly reduced relative to standard on-bead digestion. PMID- 23028062 TI - Estrogen modulates metabolic pathway adaptation to available glucose in breast cancer cells. AB - Most cancers use glucose as substrate for aerobic glycolysis in preference to oxidative phosphorylation. However, variable glucose concentrations within the in vivo tumor microenvironment may necessitate metabolic plasticity. Furthermore, little information exists on a role for estrogen receptors in modulating possible metabolic adaptations in breast cancer cells. Here we find that MCF-7 cells switch between metabolic pathways depending on glucose availability and 17beta estradiol (E(2)) potentiates adaptation. In high glucose conditions E(2) up regulates glycolysis via enhanced AKT kinase activity and suppresses tricarboxylic acid cycle activity. After a decrease in extracellular glucose, mitochondrial pathways are activated in preference to glycolysis. In this setting, E(2) suppresses glycolysis and rescues cell viability by stimulating the tricarboxylic acid cycle via the up-regulation of pyruvate dehydrogenase (PDH) activity. E(2) also increases ATP in low glucose-cultured cells, and the novel phosphorylation of PDH by AMP kinase is required for these metabolic compensations. Capitalizing on metabolic vulnerability, knockdown of PDH in the low-glucose state strongly potentiates ionizing radiation-induced apoptosis and reverses the cell survival effects of E(2). We propose that lowering glucose substrate and inhibiting PDH may augment adjuvant therapies for estrogen receptor positive breast cancer. PMID- 23028063 TI - Estrogen receptors beta1 and beta2 have opposing roles in regulating proliferation and bone metastasis genes in the prostate cancer cell line PC3. AB - The estrogen receptor (ER)beta1 is successively lost during cancer progression, whereas its splice variant, ERbeta2, is expressed in advanced prostate cancer. The latter form of cancer often metastasizes to bone, and we wanted to investigate whether the loss of ERbeta1 and/or the expression of ERbeta2 affect such signaling pathways in prostate cancer. Using PC3 and 22Rv1 prostate cancer cell lines that stably express ERbeta1 or ERbeta2, we found that the ERbeta variants differentially regulate genes known to affect tumor behavior. We found that ERbeta1 repressed the expression of the bone metastasis regulator Runx2 in PC3 cells. By contrast, RUNX2 expression was up-regulated at the mRNA level by ERbeta2 in PC3 cells, whereas Slug was up-regulated by ERbeta2 in both PC3 and 22Rv1 cells. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade prostate carcinoma, was increased by ERbeta2. In agreement with the increased Twist1 expression, we found increased expression of Dickkopf homolog 1; Dickkopf homolog 1 is a factor that has been shown to increase the RANK ligand/osteoprotegerin ratio and enhance osteoclastogenesis, indicating that the expression of ERbeta2 can cause osteolytic cancer. Furthermore, we found that only ERbeta1 inhibited proliferation, whereas ERbeta2 increased proliferation. The expression of the proliferation markers Cyclin E, c-Myc, and p45(Skp2) was differentially affected by ERbeta1 and ERbeta2 expression. In addition, nuclear beta-catenin protein and its mRNA levels were reduced by ERbeta1 expression. In conclusion, we found that ERbeta1 inhibited proliferation and factors known to be involved in bone metastasis, whereas ERbeta2 increased proliferation and up-regulated factors involved in bone metastasis. Thus, in prostate cancer cells, ERbeta2 has oncogenic abilities that are in strong contrast to the tumor-suppressing effects of ERbeta1. PMID- 23028065 TI - Preparation of Drosophila specimens for examination by transmission electron microscopy. AB - There is no single, simple procedure for fixing and embedding all tissues for transmission electron microscopy (TEM). The chemistry of different cell types is to some extent unique, and this affects the way each cell type reacts to the wide array of fixatives, buffers, organic solvents, and resins used in TEM specimen preparation. A recurring theme in those organisms or cell types that are difficult to fix is the presence of a diffusion barrier that prevents the free diffusion of fixative and other chemicals in and out of the cell or tissue. This in turn means that fixation takes a relatively long time (measured in minutes or tens of minutes in some cases), during which the cells begin autolysis or are otherwise degraded from their original state. Drosophila requires specific preparation methods for TEM because most fly tissues are surrounded by significant diffusion barriers. In the embryo, it is the vitelline envelope, and in larvae and adults, it is the cuticle. In this article, we discuss methods that have evolved to cope with these barriers to achieve reasonable preservation of ultrastructure. PMID- 23028066 TI - Transmission electron microscopy of thin sections of Drosophila: preparation of embryos using n-heptane and glutaraldehyde. AB - This protocol describes the simultaneous permeabilization of Drosophila embryos with n-heptane and initial fixation with glutaraldehyde. Even though the vitelline membrane around the embryo is chemically permeabilized, it must be manually removed to achieve infiltration with embedding resins. Once the embryo is embedded, it can be sectioned for transmission electron microscopy (TEM). This procedure can produce excellent preservation for ultrastructural analysis, and is useful for situations where optimal preservation (e.g., by high-pressure freezing) is not required or is not feasible. PMID- 23028064 TI - Orphan nuclear receptor NR4A1 is a negative regulator of DHT-induced rat preantral follicular growth. AB - Nuclear receptor subfamily 4 group A member1 (NR4A1), an orphan nuclear receptor, is involved in the transcriptional regulation of thecal cell androgen biosynthesis and paracrine factor insulin-like 3 (INSL3) expression. Androgens are known to play an important regulatory role in ovarian follicle growth. Using a chronically androgenized rat model, a preantral follicle culture model and virus-mediated gene delivery, we examined the role and regulation of NR4A1 in the androgenic control of preantral follicular growth. In the present study, Ki67 staining was increased in preantral follicles on ovarian sections from 5alpha dihydrotestosterone (DHT)-treated rats. Preantral follicles from DHT-treated rats cultured for 4 d exhibited increased growth and up-regulation of mRNA abundance of G(1)/S-specific cyclin-D2 (Ccnd2) and FSH receptor (Fshr). Similarly, DHT (1 MUm) increased preantral follicular growth and Ccnd2 and Fshr mRNA abundance in vitro. The NR4A1 expression was high in theca cells and was down-regulated by DHT in vivo and in vitro. Forced expression of NR4A1 augmented preantral follicular growth, androstenedione production, and Insl3 expression in vitro. Inhibiting the action of androgen (with androgen receptor antagonist flutamide) or INSL3 (with INSL3 receptor antagonist INSL3 B-chain) reduced NR4A1-induced preantral follicular growth. Furthermore, NR4A1 overexpression enhanced DHT-induced preantral follicular growth, a response attenuated by inhibiting INSL3. In conclusion, DHT promotes preantral follicular growth and attenuates thecal NR4A1 expression in vivo and in vitro. Our findings are consistent with the notion that NR4A1 serves as an important point of negative feedback to minimize the excessive preantral follicle growth in hyperandrogenism. PMID- 23028067 TI - Estimating object number in biological structures. AB - The number of cells and subcellular structures can often be readily related to quantitative evaluations of organ and tissue function. Neurons and synapses, for example, are directly involved in the integration and transfer of information in neural systems. Their numbers are consequently important parameters in the evaluations of the functional capacity of neural systems. Only information regarding the total number of objects, such as synapses and neurons, can be used to draw conclusions regarding changes or differences in the number of these structural entities. The large numbers of neurons and synapses in the vast majority of neural systems preclude absolute determinations of their total number, that is, counting each and every neuron or synapse. However, estimates or approximations based on limited sampling can be useful if the estimates are unbiased and if the individual estimates have an acceptable amount of precision. This article discusses the estimation of object number, including sampling, indirect and direct counting techniques, sources and types of bias, and the disector counting technique. An example is also given. PMID- 23028068 TI - Preparation of small RNA libraries for high-throughput sequencing. AB - This protocol details the process of small RNA cloning for sequencing on the Illumina/Solexa sequencing platform, but it can be easily modified for use on other next-generation platforms (e.g., SOLiD, 454). This procedure is designed to clone canonical small RNA molecules with 5'-monophosphate and 3'-hydroxyl termini. Modifications, such as the presence of a 2'-O-methyl group, can reduce efficiency, although not sufficiently to negate the utility of the approach. Other termini modifications, such as a 5' triphosphate or a 3' phosphate, can be altered by enzymatic treatment before cloning. PMID- 23028069 TI - Filter-binding assay for analysis of RNA-protein interactions. AB - One of the oldest and simplest (and still very useful) methods for detecting RNA protein interactions is the filter-binding assay. If a mixture of RNA and protein is passed through a nitrocellulose filter, the protein will be retained and the RNA will pass through. But if the protein is capable of binding RNA, then RNA will be retained on the filter as well. This protocol requires a purified protein (or chromatographic fractions) of interest and (32)P-labeled RNA. To perform the assay, the protein sample is serially diluted to several concentrations. It is then mixed with a fixed amount of radioactive RNA and allowed to bind under desired conditions for 30-60 min. The binding reactions are then applied to a 96 well dot-blot apparatus with low vacuum to trap the complexes on three membranes: The top membrane traps aggregates, the middle membrane (nitrocellulose) binds proteins and RNA-protein complexes, and the bottom membrane (which is charged) collects free RNA. After washing and drying, the membranes are exposed to phosphor-imaging screens for quantitation. Alternatively, single, larger filters (that can be counted in a scintillation counter) and a filter manifold can be used. PMID- 23028070 TI - Isolation of total RNA from yeast cell cultures. AB - This article describes two procedures for isolating total RNA from yeast cell cultures. The first allows the convenient isolation of total RNA from early log phase cultures (vegetative cells). RNA isolated in this way is intact and sufficiently pure for use in microarray experiments, primer extension, and RNase protection mapping. With additional treatment to remove contaminating genomic DNA, the preparation is suitable for reverse transcription-polymerase chain reaction (RT-PCR), quantitative PCR (qPCR), cDNA library construction, high throughput sequencing of RNA, or other manipulations. However, compared to vegetative cells, the isolation of RNA from cells late in meiosis (asci and ascospores) requires additional effort. This is because a tough cell wall composed of heavily cross-linked polysaccharides and proteins is built around the four spores during meiosis and ascospore development. Therefore, an alternative protocol is presented for extracting RNA from cells late in meiosis. This alternative may also be preferable for cells from stationary cultures or from yeast strains and other fungal species isolated from the environment. PMID- 23028071 TI - In vivo optical microendoscopy for imaging cells lying deep within live tissue. AB - Although in vivo microscopy has been pivotal in enabling studies of neuronal structure and function in the intact mammalian brain, conventional intravital microscopy has generally been limited to superficial brain areas such as the olfactory bulb, the neocortex, or the cerebellar cortex. For imaging cells in deeper areas, this article discusses in vivo optical microendoscopy using gradient refractive index (GRIN) microlenses that can be inserted into tissue. Our general methodology is broadly applicable to many deep brain regions and areas of the body. Microendoscopes are available in a wide variety of optical designs, allowing imaging across a range of spatial scales and with spatial resolution that can now closely approach that offered by standard water-immersion microscope objectives. The incorporation of microendoscope probes into portable miniaturized microscopes allows imaging in freely behaving animals. When combined with the broad sets of available fluorescent markers, animal preparations, and genetically modified mice, microendoscopic methods enable sophisticated experimental designs for probing how cellular characteristics may underlie or reflect animal behavior and life experience, in healthy animals and animal models of disease. PMID- 23028072 TI - In vivo microendoscopy of the hippocampus. AB - Conventional intravital microscopy has generally been limited to superficial brain areas such as the olfactory bulb, the neocortex, or the cerebellar cortex. In vivo optical microendoscopy uses gradient refractive index (GRIN) microlenses that can be inserted into tissue to image cells in deeper areas. This protocol describes in vivo microendoscopy of the mouse hippocampus. The general methodology can be applied to many deep brain regions and other areas of the body. PMID- 23028073 TI - Imaging calcium waves and sparks in central neurons. AB - Here we describe the use of wide-field charge-coupled device (CCD) camera-based imaging methods to detect the spatial and temporal aspects of calcium release from internal stores in dendrites of neurons in brain slice preparations. This approach is useful for revealing aspects of this signaling system, which is generally invisible to electrical recording. The changes in intracellular calcium ion concentrations, [Ca(2+)](i), sometimes occur as large-amplitude, propagating Ca(2+) waves or as much smaller, localized events (sparks). In this protocol, a cell is loaded with an indicator that responds to Ca(2+), waves or sparks are stimulated in the cell, and the spatial and temporal characteristics of calcium release from internal stores in the cell are detected using wide-field CCD camera based imaging. Such camera systems have some advantages for detecting and analyzing these [Ca(2+)](i) changes because the waves are spatially extended and the sparks do not always occur at the same locations. PMID- 23028074 TI - Imaging mouse embryonic cardiovascular development. AB - Early development of the mammalian cardiovascular system is a highly dynamic process. Live imaging is an essential tool for analyzing normal and abnormal cardiovascular development and dynamics. This article describes two optical approaches for live dynamic imaging of mouse embryonic cardiovascular development: confocal microscopy and optical coherence tomography (OCT). Confocal microscopy, used in combination with fluorescent protein reporter lines, enables visualization of the developing and remodeling cardiovascular system with submicron resolution and even allows visualization of subcellular details of labeled structures. We describe mouse transgenic lines that can be used to image the developing vasculature and characterize hemodynamics by tracking individual blood cells. Confocal microscopy of vital fluorescent markers reveals unique details about cell morphogenesis and movement; however, the imaging depth of this method is limited to ~200 um. This limitation can be addressed by using OCT, which allows three-dimensional (3D) imaging millimeters into tissue, although this is achieved at the expense of lower spatial resolution (2-10 um). We describe here how OCT can be applied to the structural analysis of developing mouse embryos and hemodynamic analysis in deep embryonic vessels. These complementary approaches can be used to analyze cardiovascular defects in mutant animals to understand genetic signaling pathways regulating human development. PMID- 23028075 TI - Mammary fat pad chamber preparation in mice. AB - This protocol describes a procedure to implant mammary fat pad chambers in mice. These chambers can then be used for studying breast cancer. In comparison to the classical mammary fat pad flap model, the chamber described here has the advantage of allowing multiple observation time points in the same animal with simple anesthesia. PMID- 23028076 TI - Mammary fat pad tumor preparation in mice. AB - The host microenvironment influences tumor biology, affecting parameters such as gene expression, angiogenesis, growth, invasion, metastasis, and responses to therapy. Consequently, the use of tumor models growing in appropriate orthotopic locations is necessary to obtain a rigorous understanding of tumor pathophysiology and to correctly study antitumor treatments. The mouse mammary fat pad serves as an orthotopic site for breast cancer and can be used to study various aspects of this disease, including the effect of host-tumor interactions on tumor biology and therapeutic response. This protocol describes mammary fat pad tumor preparation in mice. PMID- 23028077 TI - Preparation of hyaluronan-DNA matrices and films. AB - Natural carbohydrate is a class of underexplored polymers for gene delivery. The noninflammatory and nonimmunogenic properties of hyaluronan (hyaluronic acid, HA) are important in clinical situations. It has a role in wound repair and has great lubricating ability. Moreover, the presence of hyaluronidase in vivo enables any vehicle fabricated from HA to be degraded by enzyme-mediated erosion. When DNA is entrapped in a cross-linked HA vehicle, HA-DNA fragments are released on digestion by hyaluronidase. These fragments could serve both as microcarriers of DNA and its protective mechanism. This protocol describes preparation of water insoluble HA-DNA matrices and films designed for clinical applications, and assays for verification of their bioactivities. Plasmid DNA (pDNA) encoding platelet-derived growth factor (PDGF) is coupled to the matrices that could be implanted into chronic wounds to accelerate their healing. pDNA encoding hyaluronan synthase 2 (HAS2) is coupled to the film that could initially serve as a physical barrier and subsequently a pDNA reservoir for sustaining HAS2 transfection. This would lead to continual HA production for preventing postsurgical adhesion. PMID- 23028078 TI - Preparing sample chambers for single-molecule FRET. AB - Single-molecule (sm) fluorescence detection is a powerful method for studying biological events without time and population averaging. Forster (fluorescence) resonance energy transfer (FRET) is a spectroscopic technique in which the efficiency of energy transfer from donor to acceptor molecules is used to determine distances between molecules in the 30-80 A range. Structural changes in biological molecules or relative motion between two interacting molecules can be detected by a change in FRET. A variant of smFRET is based on total internal reflection (TIR) microscopy, which can be set up in two ways, either using an oil immersion (objective-type) or a water-immersion (prism-type) lens. To study the conformational changes of individual molecules over extended time periods, molecules must be localized in space. This protocol describes the preparation of sample chambers with either bovine serum albumin (BSA)- or polyethylene glycol (PEG)-coated slides to which single molecules can be tethered for use in FRET studies. PMID- 23028080 TI - Hysteria, conversion and functional disorders: a neurological contribution to classification issues. AB - Proposals by psychiatrists to reclassify conversion disorder in DSM-5 and ICD-11 are proving difficult and controversial. Patients with conversion disorder usually present initially to neurologists, who often use different concepts and terminology. History and clinical practice suggest that the way forward is to seek agreed principles and a common understanding between the two disciplines, preferably in a single universal classification. PMID- 23028079 TI - Imaging and identifying impurities in single-molecule FRET studies. AB - Single-molecule (sm) Forster (fluorescence) resonance energy transfer (FRET) is a spectroscopic technique in which the efficiency of energy transfer from donor to acceptor molecules is used to determine distances between molecules in the 30-80 A range. Structural changes in biological molecules or relative motion between two interacting molecules can be detected by a change in FRET. To study the conformational changes of individual molecules over extended time periods, the molecules must be immobilized on a coated surface that allows highly specific tethering of DNA, RNA, or protein. Nevertheless, there are always some fluorescent impurities on the surface and, without experience in sm imaging, it is often difficult to distinguish molecules of interest from impurities. This protocol describes the use of an imaging buffer that enhances the photostability of cyanine dyes used for smFRET, with emphasis on distinguishing molecules of interest from impurities. PMID- 23028081 TI - Do conflict-affected societies need psychiatrists? AB - Symptoms of post-traumatic stress disorder (PTSD), anxiety and depression are prevalent among post-conflict populations worldwide but controversy about the cultural meaning of these symptoms, particularly in relation to PTSD, adds to the challenge for psychiatry in mounting appropriate intervention programmes. Accumulating scientific evidence assists in guiding the focus and scope of emergency mental health programmes, initiatives that can become the vanguard of mental health development and reform for countries recovering from conflict. PMID- 23028082 TI - Psychotic experiences: disadvantaged and different from the norm. AB - Stress-induced alterations in how a person attributes meaning to internal and external stimuli may represent the first step in explaining how population ethnic minority-majority interactions affect mental health. Cross-context and diagnostic assumption-free research is required to elucidate how the wider social environment interacts with personal characteristics to increase expression of psychosis. PMID- 23028083 TI - Psychological interventions for difficult-to-treat depression. AB - Mindfulness-based cognitive therapy (MBCT) may be helpful in preventing relapse in those with three or more depressive episodes. Recent research suggests it may also benefit those who have experienced fewer previous episodes of depression. If confirmed, this raises challenges of how MBCT is offered, accessed and supported. PMID- 23028084 TI - Measuring patient-reported outcomes in psychosis: conceptual and methodological review. AB - BACKGROUND: There are calls to use patient-reported outcomes (PROs) routinely across mental health services. However, the use of PROs in patients with psychosis has been questioned. AIMS: To examine the concepts and measures of four widely used PROs: treatment satisfaction, subjective quality of life, needs for care and the quality of the therapeutic relationship. METHOD: We conducted a literature search of academic databases on concepts, characteristics and psychometric properties of the four PROs in patients with psychosis. RESULTS: Although numerous concepts and measures have been published, evidence on the methodological quality of existing PROs is limited. Measures designed to assess distinct PROs showed a considerable conceptual, operational and empirical overlap, and some of them also included specific aspects. The impact of symptoms and cognitive deficits appears unlikely to be of clinical significance. CONCLUSIONS: The popularity of PROs has not been matched with progress in their conceptualisation and measurement. Based on current evidence, some recommendations can be made. Distinct and short measures with clinical relevance and sufficient psychometric properties should be preferred. Future research should optimise the validity and measurement precision of PROs, while reducing assessment burden. PMID- 23028085 TI - Is alcohol consumption irrelevant to outcome in anxiety and depression? PMID- 23028086 TI - Depression in the workplace: what is depression? PMID- 23028087 TI - Severe mental illness in prisoners worldwide. PMID- 23028088 TI - The future is now for rare genetic diseases. PMID- 23028089 TI - The 5A model for the management of obesity. PMID- 23028091 TI - Contrasting coroners. PMID- 23028094 TI - EGFR 3'UTR 774T>C polymorphism contributes to bladder cancer risk. AB - Much evidence show that over-expression of epidermal growth factor receptor (EGFR) plays an important role in regulating carcinogenesis. Genetic variations in 3' untranslated region (3'UTR) of gene have been reported to affect gene expression by interfering with microRNAs (miRNAs), which are thought to function as either tumour suppressors or oncogenes by binding to their target mRNA. In this study, we investigated the association between the EGFR 3'UTR 774T>C polymorphism and bladder cancer risk. We used the TaqMan technology to genotype this genetic variant in a hospital-based case-control study of 908 bladder cancer patients and 1239 controls in a Chinese population. We found that the 774CC genotype was associated with a statistically significantly increased risk of bladder cancer [adjusted odds ratio = 1.29, 95% confidence interval = 1.05-1.58], compared with the 774TT/TC genotype, and this increased risk was more pronounced among subgroups of age > 65 years, non-smokers and patients' tumour invasive stage. Furthermore, luciferase assays in T24 cell showed that EGFR 3'UTR 774 T to C substitution could increase the expression of EGFR, which was consistent with the association study finding. Additionally, we also provide evidence that 774T>C polymorphism increasing EGFR expression was not regulated by hsa-miR-214 binding. These findings suggested that EGFR 3'UTR 774T>C polymorphism may contribute to susceptibility to bladder cancer. PMID- 23028095 TI - Hirschsprung's disease. PMID- 23028093 TI - Identification and characterization of poly(I:C)-induced molecular responses attenuated by nicotine in mouse macrophages. AB - To further our understanding of the effects of nicotine on the molecular responses of macrophages during virus or virus-like infections, poly(I:C) stimulated macrophage-like RAW264.2 cells or mouse primary peritoneal macrophages were challenged with nicotine; and their molecular responses were evaluated using a qRT-PCR array, antibody array, ELISA, Western blotting, and Ca(2+) imaging. Of 51 genes expressed in the Toll-like receptor (TLR) and RIG-I-like receptor (RLR) pathways, mRNA expression of 15 genes in RAW264.7 cells was attenuated by nicotine, of which mRNA expression of IL-6, TNF-alpha, and IL-1beta was confirmed to be attenuated in peritoneal macrophages. Concurrently, nicotine treatment attenuated the release of IL-6 and TNF-alpha from poly(I:C)-stimulated macrophages. However, when poly(I:C)-stimulated macrophages were challenged with nicotine plus alpha-bungarotoxin (alpha-BTX), secretion of IL-6 and TNF-alpha was found to be in a level seen with poly(I:C) stimulation only, indicating that alpha7-nAChR, a highly Ca(2+) permeable ion channel sensitive to blockade by alpha-BTX, is involved in this process. Furthermore, results from an antibody array indicated that nicotine treatment attenuated the phosphorylation of 82 sites, including Thr286 on CaMKIIalpha, from poly(I:C)-stimulated RAW264.7 cells, of which 28 are expressed in the downstream cascade of Ca(2+) signaling. Coincidentally, poly(I:C)-stimulated macrophages showed attenuated expression of phosphorylated CaMKIIalpha when pretreated with nicotine. In addition, nicotine attenuated intracellular Ca(2+) signal from poly(I:C)-stimulated RAW264.7 cells. Collectively, these results indicate that poly(I:C)-induced molecular responses of macrophages could be significantly attenuated by nicotine. PMID- 23028096 TI - Laxatives for chronic constipation in adults. PMID- 23028097 TI - Axial computed tomography of a male pelvis in the portal venous phase post contrast. PMID- 23028098 TI - What accountable care organizations will mean for physicians. PMID- 23028099 TI - Lack of money and poor security are barriers to global eradication of polio. PMID- 23028100 TI - A BMJ for the United States. PMID- 23028101 TI - Doctor is arrested in transit in United Arab Emirates for a 10 year old conviction passed in his absence. PMID- 23028102 TI - Taking ecstasy on television: a show trial. PMID- 23028103 TI - Protocol adherence and the progression of cardiovascular calcification in the ADVANCE study. AB - BACKGROUND: The ADVANCE study assessed the progression of vascular and cardiac valve calcification in 360 hemodialysis patients with secondary hyperparathyroidism (sHPT) assigned randomly to treatment either with cinacalcet plus low-dose vitamin D (<= 6 ug/week of intravenous paricalcitol equivalent) or with varying doses of vitamin D alone for 52 weeks. The primary efficacy endpoint was progression of coronary artery calcification (CAC). METHODS: In this post-hoc analysis, we compared CAC progression among 70 protocol-adherent subjects given cinacalcet and low doses of vitamin D (CPA) as specified in the study protocol and 120 control subjects given vitamin D sterols. RESULTS: Baseline patient characteristics did not differ between CPA and control subjects. The mean (standard error of the mean, SEM) doses of vitamin D at week 2 were 4.7 (0.3) and 12.8 (1.0) ug/week in CPA and control subjects, respectively, and the corresponding mean cumulative doses of vitamin D over 52 weeks in each group were 225 (22) and 671 (47) ug. The median change in Agatston CAC score after 52 weeks was less in CPA subjects than in controls (17.8% versus 31.3%, P = 0.02). The median increase in calcification scores in the aortic valve also was less in CPA subjects than in controls (6.0% versus 51.5% P = 0.02). Reductions in serum parathyroid hormone, calcium and phosphorus levels were significantly greater in CPA subjects than in controls (P < 0.05). CONCLUSIONS: The progression of cardiovascular calcification was attenuated among cinacalcet-treated subjects with sHPT given low doses of vitamin D per protocol compared with control subjects in whom sHPT was treated with higher doses of vitamin D sterols alone. PMID- 23028104 TI - Experimental diabetic nephropathy is accelerated in matrix metalloproteinase-2 knockout mice. AB - BACKGROUND: Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice. METHODS: Diabetes was induced by the injection of STZ in 6 week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone. RESULTS: Compared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-beta-D-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal alpha-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice. CONCLUSIONS: Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy. PMID- 23028106 TI - Hyperkalemia: getting to the heart of the matter. PMID- 23028105 TI - Reduced survival and quality of life following return to dialysis after transplant failure: the Dialysis Outcomes and Practice Patterns Study. AB - BACKGROUND: Although dialysis after kidney transplant failure (TF) is common, the outcomes of these patients remain unclear. We compared outcomes of TF patients with transplant-naive (TN) patients wait-listed for kidney transplantation. METHODS: We used data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), including laboratory markers and health-related quality of life (HR QOL). Mortality and hospitalization of participants with one prior TF versus TN patients were compared using the Cox regression analysis. HR-QOL physical and mental component summary scores (PCS and MCS) were examined using linear mixed models, and clinical practices were compared using logistic regression. RESULTS: Compared with TN patients (n = 2806), TF patients (n = 1856) were younger (48 versus 51 years, P = 0.003), less likely to be diabetic (18 versus 27%, P < 0.0001) and to use a permanent surgical vascular access {adjusted odds ratio (AOR): 0.85 [95% confidence interval (CI): 0.70-1.03], P = 0.10}, particularly within the first 3 months after TF [AOR 0.45 (0.32-0.62), P < 0.0001]. TF patients also had lower PCS [mean difference -2.56 (-3.36, -1.75), P < 0.0001] but not MCS [-0.42 (-1.34, 0.50), P = 0.37]. All-cause mortality [adjusted hazard ratio (AHR): 1.32 (95% CI: 1.05-1.66), P = 0.02], especially infection-related [AHR 2.45 (95% CI: 1.36-4.41), P = 0.01], was higher among TF patients. CONCLUSIONS: TF patients have reduced QOL and higher mortality, particularly due to infections, than TN patients. Interventions to optimize care before and after starting dialysis remain to be identified and applied in clinical practice. PMID- 23028107 TI - Expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in infiltrating inflammatory cells is associated with chronic allograft dysfunction and predicts long-term graft survival. AB - BACKGROUND: In chronic kidney failure, a hypoxic state, infiltrating inflammatory cells play a crucial role in the progression to end-stage renal disease. No studies have evaluated the influence of hypoxia and infiltrating inflammatory cells on chronic allograft dysfunction. METHODS: Renal transplant recipients who underwent renal allograft biopsy with interstitial fibrosis/tubular atrophy (IF/TA) were enrolled and renal allograft tissue sections were processed for immunohistochemical staining including hypoxia-inducible factor-1alpha (HIF 1alpha), nitrotyrosine, alpha-smooth muscle actin and e-cadherin. Patients with total renal tissue HIF score >=1 were defined as positive for HIF-1alpha. To assess the phenotype of the infiltrating cells, dual staining of HIF-1alpha with CD45, CD68 and CD3 was performed. The correlation between HIF-1alpha score and Banff's score was analysed. Clinical parameters including renal survival among patients with or without an expression of HIF-1alpha were compared. RESULTS: Out of 55 patients enrolled, 23 patients (41.8%) had an HIF-1alpha score >=1 (Group B). Compared with Group A (total renal HIF score <1), Group B had a significantly higher Banff score of interstitial infiltrates (i) (P = 0.029), vascular fibrous intimal thickening (cv) (P = 0.007) and arteriolar hyaline thickening (ah) (P = 0.026). Clinically, patients with an HIF-1alpha score were associated with a poor graft survival. Significantly inferior allograft survival was noted in Group B. HIF scores had an adjusted hazard ratio of 3.25 (95% confidence inteval: 1.71 6.16, P = 0.0003) in allograft failure. CONCLUSIONS: We first demonstrated the expression of HIF-1alpha protein among infiltrating inflammatory cells in areas with IF/TA in patients with chronic allograft dysfunction. PMID- 23028108 TI - Hip resurfacing offers no benefits over total hip replacement in some patients, finds study. PMID- 23028109 TI - Novel use of optical coherence tomography. AB - Currently in use by interventional cardiology for the intravascular evaluation of coronary arteries, optical coherence tomography (OCT) has proven to be effective in the evaluation of atherosclerotic disease and further therapeutic management. We report a novel use of OCT technology in the case of a 46-year-old man with sudden onset blurred vision and greater than 70% stenosis of his left vertebral artery. To date, no detailed descriptions or case reports have previously been reported regarding the use of neuroendovascular OCT in diseased arteries. PMID- 23028110 TI - Estimate of HIV prevalence and number of people living with HIV in India 2008 2009. AB - OBJECTIVES: To update the estimation of the adult HIV prevalence and number of people living with HIV (PLHIV) in India for the year 2008-2009 with the combination of improved data and methods. DESIGN: Based on HIV sentinel surveillance (HSS) data and a set of epidemiological assumptions, estimates of HIV prevalence and burden in India have been derived. SETTING: HSS sites spread over all the States of India. PARTICIPANTS: Secondary data from HSS sites which include attendees of antenatal clinics and sites under targeted interventions of high-risk groups, namely, female sex workers (FSW), intravenous drug users (IDU) and men having sex with men (MSM). PRIMARY AND SECONDARY OUTCOME MEASURES: Estimates of adult HIV prevalence and PLHIV in India and its states. RESULTS: The adult HIV prevalence in India has declined to an estimated 0.31% (0.25-0.39%) in 2009 against 0.36% (0.29-0.45%) in 2006. Among the high prevalence states, the HIV prevalence has declined in Tamil Nadu to 0.33% in 2009 and other states show either a plateau or a slightly declining trend over the time period 2006-2009. There are states in the low prevalence states where the adult HIV prevalence has risen over the last 4 years. The estimated number of PLHIV in India is 2.4 million (1.93-3.04 million) in 2009. Of which, 39% are women, children under 15 years of age account for 4.4% of all infections, while people aged 15-49 years account for 82.4% of all infections. CONCLUSIONS: The estimated adult prevalence has declined in few states, a plateau or a slightly declining trend over the time. In future, efforts may be made to examine the implications of the emerging trend of the HIV prevalence on the recent infections in the study population. PMID- 23028111 TI - Editorial: Sticking it to fibrocytes with serum amyloid P. PMID- 23028112 TI - Editorial: natural killer cell-mediated augmentation of autoantibody production? PMID- 23028114 TI - Anti-dope testing in sport: the history and the science. PMID- 23028113 TI - Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization. AB - Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. Identifying novel regulators of mitochondrial bioenergetics will broaden our understanding of regulatory checkpoints that coordinate complex metabolic pathways. We previously showed that Nur77, an orphan nuclear receptor of the NR4A family, regulates the expression of genes linked to glucose utilization. Here we demonstrate that expression of Nur77 in skeletal muscle also enhances mitochondrial function. We generated MCK-Nur77 transgenic mice that express wild-type Nur77 specifically in skeletal muscle. Nur77-overexpressing muscle had increased abundance of oxidative muscle fibers and mitochondrial DNA content. Transgenic muscle also exhibited enhanced oxidative metabolism, suggestive of increased mitochondrial activity. Metabolomic analysis confirmed that Nur77 transgenic muscle favored fatty acid oxidation over glucose oxidation, mimicking the metabolic profile of fasting. Nur77 expression also improved the intrinsic respiratory capacity of isolated mitochondria, likely due to the increased abundance of complex I of the electron transport chain. These changes in mitochondrial metabolism translated to improved muscle contractile function ex vivo and improved cold tolerance in vivo. Our studies outline a novel role for Nur77 in the regulation of oxidative metabolism and mitochondrial activity in skeletal muscle. PMID- 23028116 TI - Signaling pathways that regulate cell division. AB - Cell division requires careful orchestration of three major events: entry into mitosis, chromosomal segregation, and cytokinesis. Signaling within and between the molecules that control these events allows for their coordination via checkpoints, a specific class of signaling pathways that ensure the dependency of cell-cycle events on the successful completion of preceding events. Multiple positive- and negative-feedback loops ensure that a cell is fully committed to division and that the events occur in the proper order. Unlike other signaling pathways, which integrate external inputs to decide whether to execute a given process, signaling at cell division is largely dedicated to completing a decision made in G1 phase-to initiate and complete a round of mitotic cell division. Instead of deciding if the events of cell division will take place, these signaling pathways entrain these events to the activation of the cell-cycle kinase cyclin-dependent kinase 1 (CDK1) and provide the opportunity for checkpoint proteins to arrest cell division if things go wrong. PMID- 23028117 TI - Molecular control of neurogenesis: a view from the mammalian cerebral cortex. AB - The mammalian nervous system is the most complex organ of any living organism. How this complexity is generated during neural development is just beginning to be elucidated. This article discusses the signaling, transcriptional, and epigenetic mechanisms that are involved in neural development. The first part focuses on molecules that control neuronal numbers through regulation of the timing of onset of neurogenesis, the timing of the neuronal-to-glial switch, and the rate of progenitor proliferation. The second part focuses on molecules that control neuronal diversity by generating spatially or temporally distinct populations of neuronal progenitors. Most of the studies discussed in this article are focused on the developing mammalian cerebral cortex, because this is one of the main model systems for neural developmental studies and many of the mechanisms identified in this tissue also operate elsewhere in the developing brain and spinal cord. PMID- 23028119 TI - Notch signaling. PMID- 23028118 TI - Apoptotic and nonapoptotic caspase functions in animal development. AB - A developing animal is exposed to both intrinsic and extrinsic stresses. One stress response is caspase activation. Caspase activation not only controls apoptosis but also proliferation, differentiation, cell shape, and cell migration. Caspase activation drives development by executing cell death or nonapoptotic functions in a cell-autonomous manner, and by secreting signaling molecules or generating mechanical forces, in a noncell autonomous manner. PMID- 23028121 TI - Nonvesicular lipid transfer from the endoplasmic reticulum. AB - The transport of lipids from their synthesis site at the endoplasmic reticulum (ER) to different target membranes could be mediated by both vesicular and nonvesicular transport mechanisms. Nonvesicular lipid transport appears to be the major transport route of certain lipid species, and could be mediated by either spontaneous lipid transport or by lipid-transfer proteins (LTPs). Although nonvesicular lipid transport has been extensively studied for more than four decades, its underlying mechanism, advantage and regulation, have not been fully explored. In particular, the function of LTPs and their involvement in intracellular lipid movement remain largely controversial. In this article, we describe the pathways by which lipids are synthesized at the ER and delivered to different cellular membranes, and discuss the role of LTPs in lipid transport both in vitro and in intact cells. PMID- 23028120 TI - Mechanisms of protein sorting in mitochondria. AB - A protein's function is intimately linked to its correct subcellular location, yet the machinery required for protein synthesis is predominately cytosolic. How proteins are trafficked through the confines of the cell and integrated into the appropriate cellular compartments has puzzled and intrigued researchers for decades. Indeed, studies exploring this premise revealed elaborate cellular protein translocation and sorting systems, which ensure that all proteins are shuttled to the appropriate cellular destination, where they fulfill their specific functions. This holds true for mitochondria, where sophisticated molecular machines serve to recognize incoming precursor proteins and integrate them into the functional framework of the organelle. We summarize the recent progress in our understanding of mitochondrial protein sorting and the machineries and mechanisms that mediate and regulate this highly dynamic cellular process essential for survival of virtually all eukaryotic cells. PMID- 23028123 TI - Evidence of 5-HT components in human sperm: implications for protein tyrosine phosphorylation and the physiology of motility. AB - Serotonin (5-hydroxytryptamine; C(10)H(12)N(2)O (5-HT)) is produced in the CNS and in some cells of peripheral tissues. In the mammalian male reproductive system, both 5-HT and tryptophan hydroxylase (TPH) have been described in Leydig cells of the testis and in principal cells of the caput epididymis. In capacitated hamster sperm, it has been shown that 5-HT promotes the acrosomal reaction. The aim of this work was to explore the existence of components of the serotoninergic system and their relevance in human sperm physiology. We used both immunocytochemistry and western blot to detect serotoninergic markers such as 5 HT, TPH1, MAO(A), 5-HT(1B), 5-HT(3), and 5HT(T); HPLC for TPH enzymatic activity; Computer Assisted Semen Analysis assays to measure sperm motility parameters and pharmacological approaches to show the effect of 5-HT in sperm motility and tyrosine phosphorylation was assessed by western blot. We found the presence of serotoninergic markers (5-HT, TPH1, MAO(A), 5-HT(1B), 5-HT(2A), 5-HT(3), 5-HT(T), and TPH enzymatic activity) in human sperm. In addition, we observed a significant increase in tyrosine phosphorylation and changes in sperm motility after 5-HT treatment. In conclusion, our data demonstrate the existence of components of a serotoninergic system in human sperm and support the notion for a functional role of 5-HT in mammalian sperm physiology, which can be modulated pharmacologically. PMID- 23028124 TI - Na+/K+-ATPase alpha1 isoform mediates ouabain-induced expression of cyclin D1 and proliferation of rat sertoli cells. AB - Novel roles for the interaction of cardiotonic steroids to Na(+)/K(+)-ATPase have been established in recent years. The aim of this study was to investigate the intracellular signaling events downstream the action of ouabain on Na(+)/K(+) ATPase in Sertoli cell obtained from immature rats. Treatment of Sertoli cells with ouabain (1 MUM) induced a rapid and transient increase in the extracellular signal-regulated kinase (ERK1/2 or MAPK3/1) and phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase (AKT) phosphorylation. Also, ouabain upregulated the expression of cyclin D1 and incorporation of [methyl (3)H]thymidine, both of which were dependent on MAPK3/1 but not AKT intracellular cascade, as shown by pretreatment with MEK (MAP2K1/2) inhibitor U0126 and PI3K inhibitor wortmannin respectively. Moreover, the effect of ouabain on these proliferation parameters was completely prevented by phospho-cAMP response element-binding protein (CREB)/CREB-binding protein complex inhibitor KG501 and only partially by nuclear factor kappaB nuclear translocation inhibitor SN50. Pretreatment with estrogen receptor antagonist ICI 182780 showed that MAPK3/1 activation by ouabain does not involve this receptor. The Na(+)/K(+)-ATPase alpha1 isoform, but not alpha4, was detected in Sertoli cells, suggesting that ouabain effects in Sertoli cells are mediated via alpha1. Taken together, these results show a rapid ouabain action in the Sertoli cells, which in turn can modulate nuclear transcriptional events essential for Sertoli cell proliferation in a critical period of testicular development. Our findings are important to understand the role of ouabain in the testis and its possible implications in male infertility. PMID- 23028125 TI - Endometrial inflammation and effect on implantation improvement and pregnancy outcome. AB - Implantation failure, which is presently the major barrier in human fertility, is attributed, in many cases, to the failure of the uterus to acquire receptivity. The transition into a receptive uterus includes cellular changes in the endometrium and the modulated expression of different cytokines, growth factors, transcription factors, and prostaglandins. These molecules partake in the generation of an inflammatory response followed by the recruitment of immune cells. These cells have shown to be involved in the maternal immune tolerance toward the implanted embryo as well as in the maternal-fetus interaction during pregnancy. Most of the accumulated evidence indicates that embryo implantation is associated with an active Th1 inflammatory response while a Th2-humoral inflammation is required for pregnancy maintenance. Yet, recent findings suggest that a Th1 inflammatory response is also necessary for the acquisition of uterine receptivity. This notion was originally suggested by reports from our and other clinical centers worldwide that IVF patients with repeated implantation failure subjected to endometrial biopsy exhibit a substantial improvement in their chances to conceive. These findings, followed by the demonstration of an elevated pro-inflammatory cytokine/chemokine expression, as well as an increased abundance of immune cells, in the endometrium of these patients, raised the idea that acquisition of uterine receptivity is closely associated with an inflammatory response. This review summarizes the molecular and biochemical evidence that confirm this notion and proposes a mechanism by which injury-induced inflammation improves uterine receptivity and the subsequent pregnancy outcome. PMID- 23028122 TI - Roles of the oviduct in mammalian fertilization. AB - The oviduct or Fallopian tube is the anatomical region where every new life begins in mammalian species. After a long journey, the spermatozoa meet the oocyte in the specific site of the oviduct named ampulla and fertilization takes place. The successful fertilization depends on several biological processes that occur in the oviduct some hours before this rendezvous and affect both gametes. Estrogen and progesterone, released from the ovary, orchestrate a series of changes by genomic and nongenomic pathways in the oviductal epithelium affecting gene expression, proteome, and secretion of its cells into the fluid bathing the oviductal lumen. In addition, new regulatory molecules are being discovered playing important roles in oviductal physiology and fertilization. The present review tries to describe these processes, building a comprehensive map of the physiology of the oviduct, to better understand the importance of this organ in reproduction. With this purpose, gamete transport, sperm and oocyte changes in the oviductal environment, and other interactions between gametes and oviduct are discussed in light of recent publications in the field. PMID- 23028126 TI - The genetics of Alzheimer disease. AB - Family history is the second strongest risk factor for Alzheimer disease (AD) following advanced age. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 virtually guarantee early-onset (<60 years) familial AD, which represents ~5% of AD. On the other hand, common gene polymorphisms, such as the epsilon4 and epsilon2 variants of the APOE gene, can influence susceptibility for ~50% of the common late-onset AD. These four genes account for 30%-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of 11 additional AD candidate genes. This paper reviews the past, present, and future attempts to elucidate the complex and heterogeneous genetic underpinnings of AD. PMID- 23028127 TI - Endothelial cell-to-cell junctions: adhesion and signaling in physiology and pathology. AB - Besides intercellular recognition and adhesion, which are primarily performed by the transmembrane components, many of the molecules associated in endothelial cell-to-cell junctions initiate or regulate signal transmission. Clustering of molecules at junctions has the consequence of allowing new local interactions to direct specific cellular responses with crucial effects on the physiology and pathology of the endothelium and, more generally, of the vascular system. The implication is that cell-to-cell junctions could be envisaged as molecular targets for different types of therapeutic intervention. These could be directed to "cure" the defects of endothelial junctions that accompany several pathologies or to reversibly open them in a controlled way for the efficient delivery of drugs to the tissues. These aims can become more and more approachable as the knowledge of the molecular organization and function of endothelial junctions increases and their organ and tissue specificities become understood. PMID- 23028128 TI - Anti-VEGF therapies in the clinic. AB - The development and use of antiangiogenesis agents, particularly those targeting vascular endothelial growth factor (VEGF), has become an integral component of anticancer regimens for many tumor types. This review is intended to highlight some of the most important clinical successes and failures of anti-VEGF therapies, and where possible, to suggest important lessons that have been learned. This review emphasizes data from agents that have been FDA approved and/or have completed phase III studies. PMID- 23028130 TI - Novel cell and gene therapies for HIV. AB - Highly active antiretroviral therapy dramatically improves survival in HIV infected patients. However, persistence of HIV in reservoirs has necessitated lifelong treatment that can be complicated by cumulative toxicities, incomplete immune restoration, and the emergence of drug-resistant escape mutants. Cell and gene therapies offer the promise of preventing progressive HIV infection by interfering with HIV replication in the absence of chronic antiviral therapy. Individuals homozygous for a deletion in the CCR5 gene (CCR5Delta32) are largely resistant to infection from R5-topic HIV-1 strains, which are most commonly transmitted. A recent report that an HIV-infected patient with relapsed acute myelogenous leukemia was effectively cured from HIV infection after transplantation of hematopoietic stem/progenitor cells (HSC) from a CCR5Delta32 homozygous donor has generated renewed interest in developing treatment strategies that target viral reservoirs and generate HIV resistance in a patient's own cells. Although the development of cell-based and gene transfer therapies has been slow, progress in a number of areas is evident. Advances in the fields of gene-targeting strategies, T-cell-based approaches, and HSCs have been encouraging, and a series of ongoing and planned trials to establish proof of concept for strategies that could lead to successful cell and gene therapies for HIV are under way. The eventual goal of these studies is to eliminate latent viral reservoirs and the need for lifelong antiretroviral therapy. PMID- 23028129 TI - HIV-1 reverse transcription. AB - Reverse transcription and integration are the defining features of the Retroviridae; the common name "retrovirus" derives from the fact that these viruses use a virally encoded enzyme, reverse transcriptase (RT), to convert their RNA genomes into DNA. Reverse transcription is an essential step in retroviral replication. This article presents an overview of reverse transcription, briefly describes the structure and function of RT, provides an introduction to some of the cellular and viral factors that can affect reverse transcription, and discusses fidelity and recombination, two processes in which reverse transcription plays an important role. In keeping with the theme of the collection, the emphasis is on HIV-1 and HIV-1 RT. PMID- 23028131 TI - Transepithelial bicarbonate secretion: lessons from the pancreas. AB - Many cystic fibrosis transmembrane conductance regulator (CFTR)-expressing epithelia secrete bicarbonate (HCO(3)(-))-containing fluids. Recent evidence suggests that defects in epithelial bicarbonate secretion are directly involved in the pathogenesis of cystic fibrosis, in particular by building up hyperviscous mucus in the ductal structures of the lung and pancreas. Pancreatic juice is one of the representative fluids that contain a very high concentration of bicarbonate among bodily fluids that are secreted from CFTR-expressing epithelia. We introduce up-to-date knowledge on the basic principles of transepithelial bicarbonate transport by showing the mechanisms involved in pancreatic bicarbonate secretion. The model of pancreatic bicarbonate secretion described herein may also apply to other exocrine epithelia. As a central regulator of bicarbonate transport at the apical membrane, CFTR plays an essential role in both direct and indirect bicarbonate secretion. The major role of CFTR in bicarbonate secretion would be variable depending on the tissue and cell type. For example, in epithelial cells that produce a low concentration of bicarbonate containing fluid (up to 80 mm), either CFTR-dependent Cl(-)/HCO(3)(-) exchange or CFTR anion channel with low bicarbonate permeability would be sufficient to generate such fluid. However, in cells that secrete high-bicarbonate-containing fluids, a highly selective CFTR bicarbonate channel activity is required. Therefore, understanding the molecular mechanism of transepithelial bicarbonate transport and the role of CFTR in each specific epithelium will provide therapeutic strategies to recover from epithelial defects induced by hyposecretion of bicarbonate in cystic fibrosis. PMID- 23028133 TI - alpha-Thalassemia, mental retardation, and myelodysplastic syndrome. AB - This article describes three rare syndromes in which the presence of alpha thalassemia provided an important clue to the molecular basis of the underlying condition. It exemplifies how rare diseases allied with careful clinical observation can lead to important biological principles. Two of the syndromes, ATR-16 and ATR-X, are characterized by alpha-thalassemia in association with multiple developmental abnormalities including mental retardation. The third condition, ATMDS, is an acquired disorder in which alpha-thalassemia arises in the context of myelodysplasia. Intriguingly, mutations in the chromatin remodeling factor, ATRX, are common to both ATR-X syndrome and ATMDS. PMID- 23028132 TI - Neurovascular dysfunction and faulty amyloid beta-peptide clearance in Alzheimer disease. AB - Neurovascular dysfunction is an integral part of Alzheimer disease (AD). Changes in the brain vascular system may contribute in a significant way to the onset and progression of cognitive decline and the development of a chronic neurodegenerative process associated with accumulation of amyloid beta-peptide (Abeta) in brain and cerebral vessels in AD individuals and AD animal models. Here, we review the role of the neurovascular unit and molecular mechanisms in cerebral vascular cells behind the pathogenesis of AD. In particular, we focus on blood-brain barrier (BBB) dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Abeta from brain. The data reviewed here support an essential role of the neurovascular and BBB mechanisms in AD pathogenesis. PMID- 23028134 TI - The neurobiology of opiate motivation. AB - Opiates are a highly addictive class of drugs that have been reported to possess both dopamine-dependent and dopamine-independent rewarding properties. The search for how, if at all, these distinct mechanisms of motivation are related is of great interest in drug addiction research. Recent electrophysiological, molecular, and behavioral work has greatly improved our understanding of this process. In particular, the signaling properties of GABA(A) receptors located on GABA neurons in the ventral tegmental area (VTA) appear to be crucial to understanding the interplay between dopamine-dependent and dopamine-independent mechanisms of opiate motivation. PMID- 23028136 TI - The search for genetic modifiers of disease severity in the beta hemoglobinopathies. AB - Sickle cell disease (SCD) and beta-thalassemia, two monogenic diseases caused by mutations in the beta-globin gene, affect millions of individuals worldwide. These hemoglobin disorders are characterized by extreme clinical heterogeneity, complicating patient management and treatment. A better understanding of this patient-to-patient clinical variability would dramatically improve care and might also guide the development of novel therapies. Studies of the natural history of these beta-hemoglobinopathies have identified fetal hemoglobin levels and concomitant alpha-thalassemia as important modifiers of disease severity. Several small-scale studies have attempted to identify additional genetic modifiers of SCD and beta-thalassemia, without much success. Fortunately, improved knowledge of the human genome and the development of new genomic tools, such as genome-wide genotyping arrays and next-generation DNA sequencers, offer new opportunities to use genetics to better understand the causes of the many complications observed in beta-hemoglobinopathy patients. Here I discuss the most important factors to consider when planning an experiment to find associations between beta hemoglobinopathy-related complications and DNA sequence variants, with a focus on how to successfully perform a genome-wide association study. I also review the literature and explain why most published findings in the field of SCD modifier genetics are likely to be false-positive reports, with the goal to draw lessons allowing investigators to design better genetic experiments. PMID- 23028135 TI - Humoral autoimmunity in type 1 diabetes: prediction, significance, and detection of distinct disease subtypes. AB - Type 1 diabetes mellitus (T1D) is an autoimmune disease encompassing the T-cell mediated destruction of pancreatic beta cells and the production of autoantibodies against islet proteins. In humoral autoimmunity in T1D, the detection of islet autoantibodies and the examination of their associations with genetic factors and cellular autoimmunity constitute major areas in both basic research and clinical practice. Although insulin is a key autoantigen and may be primus inter pares in importance among T1D autoantigens, an abundant body of research has also revealed other autoantigens associated with the disease process. Solid evidence indicates that autoantibodies against islet targets serve as key markers to enroll newly diagnosed T1D patients and their family members in intervention trials aimed at preventing or halting the disease process. The next challenge is perfecting mechanistic bioassays to be used as end points for disease amelioration following immunomodulatory therapies aimed at blocking immune-mediated beta-cell injury and, in turn, preserving beta-cell function in type 1 diabetes mellitus. PMID- 23028137 TI - Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high fructose-fed dogs. AB - The cellular events mediating the pleiotropic actions of portal vein glucose (PoG) delivery on hepatic glucose disposition have not been clearly defined. Likewise, the molecular defects associated with postprandial hyperglycemia and impaired hepatic glucose uptake (HGU) following consumption of a high-fat, high fructose diet (HFFD) are unknown. Our goal was to identify hepatocellular changes elicited by hyperinsulinemia, hyperglycemia, and PoG signaling in normal chow-fed (CTR) and HFFD-fed dogs. In CTR dogs, we demonstrated that PoG infusion in the presence of hyperinsulinemia and hyperglycemia triggered an increase in the activity of hepatic glucokinase (GK) and glycogen synthase (GS), which occurred in association with further augmentation in HGU and glycogen synthesis (GSYN) in vivo. In contrast, 4 weeks of HFFD feeding markedly reduced GK protein content and impaired the activation of GS in association with diminished HGU and GSYN in vivo. Furthermore, the enzymatic changes associated with PoG sensing in chow-fed animals were abolished in HFFD-fed animals, consistent with loss of the stimulatory effects of PoG delivery. These data reveal new insight into the molecular physiology of the portal glucose signaling mechanism under normal conditions and to the pathophysiology of aberrant postprandial hepatic glucose disposition evident under a diet-induced glucose-intolerant condition. PMID- 23028138 TI - Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes. AB - To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome wide in skeletal muscle from individuals with (FH(+)) or without (FH(-)) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P <= 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH(+) compared with FH(-) men. We further validated our findings from FH(+) men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH(+) men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH(+) and FH(-) individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 * 10(-6)) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome. PMID- 23028139 TI - GLP-1 and GLP-2 as yin and yang of intestinal lipoprotein production: evidence for predominance of GLP-2-stimulated postprandial lipemia in normal and insulin resistant states. AB - The glucagon-like peptides (GLP-1 and GLP-2) are processed from the proglucagon polypeptide and secreted in equimolar amounts but have opposite effects on chylomicron (CM) production, with GLP-1 significantly reducing and GLP-2 increasing postprandial chylomicronemia. In the current study, we evaluated the apparent paradoxical roles of GLP-1 and GLP-2 under physiological conditions in the Syrian golden hamster, a model with close similarity to humans in terms of lipoprotein metabolism. A short (30-min) intravenous infusion of GLP-2 resulted in a marked increase in postprandial apolipoprotein B48 (apoB48) and triglyceride (TG) levels in the TG-rich lipoprotein (TRL) fraction, whereas GLP-1 infusion decreased lipid absorption and levels of TRL-TG and apoB48. GLP-1 and GLP-2 coinfusion resulted in net increased lipid absorption and an increase in TRL-TG and apoB48. However, prolonged (120-min) coinfusion of GLP-1 and GLP-2 decreased postprandial lipemia. Blocking dipeptidyl peptidase-4 activity resulted in decreased postprandial lipemia. Interestingly, fructose-fed, insulin-resistant hamsters showed a more pronounced response, including possible hypersensitivity to GLP-2 or reduced sensitivity to GLP-1. In conclusion, under normal physiological conditions, the actions of GLP-2 predominate; however, when GLP-1 activity is sustained, the hypolipidemic action of GLP-1 predominates. Pharmacological inhibition of GLP-1 degradation tips the balance toward an inhibitory effect on intestinal production of atherogenic CM particles. PMID- 23028140 TI - Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metabolism: variability in CYP2C8 activity may alter plasma concentrations and response. AB - Recent data suggest that the role of CYP3A4 in imatinib metabolism is smaller than presumed. This study aimed to evaluate the quantitative importance of different cytochrome P450 (P450) enzymes in imatinib pharmacokinetics. First, the metabolism of imatinib was investigated using recombinant P450 enzymes and human liver microsomes with P450 isoform-selective inhibitors. Thereafter, an in silico model for imatinib was constructed to perform pharmacokinetic simulations to assess the roles of P450 enzymes in imatinib elimination at clinically used imatinib doses. In vitro, CYP2C8 inhibitors and CYP3A4 inhibitors inhibited the depletion of 0.1 uM imatinib by 45 and 80%, respectively, and the formation of the main metabolite of imatinib, N-desmethylimatinib, by >50%. Likewise, recombinant CYP2C8 and CYP3A4 metabolized imatinib extensively, whereas other isoforms had minor effect on imatinib concentrations. In the beginning of imatinib treatment, the fractions of its hepatic clearance mediated by CYP2C8 and CYP3A4 were predicted to approximate 40 and 60%, respectively. During long-term treatment with imatinib 400 mg once or twice daily, up to 65 or 75% of its hepatic elimination was predicted to occur via CYP2C8, and only about 35 or 25% by CYP3A4, due to dose- and time-dependent autoinactivation of CYP3A4 by imatinib. Thus, although CYP2C8 and CYP3A4 are the main enzymes in imatinib metabolism in vitro, in silico predictions indicate that imatinib inhibits its own CYP3A4-mediated metabolism, assigning a key role for CYP2C8. During multiple dosing, pharmacogenetic polymorphisms and drug interactions affecting CYP2C8 activity may cause marked interindividual variation in the exposure and response to imatinib. PMID- 23028142 TI - Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. AB - Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr) Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl(-/-), Prlr(-/-), and Stat5(-/-) mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1(-/-);Akt2(+/-) mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway. PMID- 23028143 TI - Promoter-proximal polyadenylation sites reduce transcription activity. AB - Gene expression relies on the functional communication between mRNA processing and transcription. We previously described the negative impact of a point-mutated splice donor (SD) site on transcription. Here we demonstrate that this mutation activates an upstream cryptic polyadenylation (CpA) site, which in turn causes reduced transcription. Functional depletion of U1 snRNP in the context of the wild-type SD triggers the same CpA event accompanied by decreased RNA levels. Thus, in accordance with recent findings, U1 snRNP can shield premature pA sites. The negative impact of unshielded pA sites on transcription requires promoter proximity, as demonstrated using artificial constructs and supported by a genome wide data set. Importantly, transcription down-regulation can be recapitulated in a gene context devoid of splice sites by placing a functional bona fide pA site/transcription terminator within ~500 base pairs of the promoter. In contrast, promoter-proximal positioning of a pA site-independent histone gene terminator supports high transcription levels. We propose that optimal communication between a pA site-dependent gene terminator and its promoter critically depends on gene length and that short RNA polymerase II-transcribed genes use specialized termination mechanisms to maintain high transcription levels. PMID- 23028141 TI - The RNA polymerase II CTD coordinates transcription and RNA processing. AB - The C-terminal domain (CTD) of the RNA polymerase II largest subunit consists of multiple heptad repeats (consensus Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7), varying in number from 26 in yeast to 52 in vertebrates. The CTD functions to help couple transcription and processing of the nascent RNA and also plays roles in transcription elongation and termination. The CTD is subject to extensive post translational modification, most notably phosphorylation, during the transcription cycle, which modulates its activities in the above processes. Therefore, understanding the nature of CTD modifications, including how they function and how they are regulated, is essential to understanding the mechanisms that control gene expression. While the significance of phosphorylation of Ser2 and Ser5 residues has been studied and appreciated for some time, several additional modifications have more recently been added to the CTD repertoire, and insight into their function has begun to emerge. Here, we review findings regarding modification and function of the CTD, highlighting the important role this unique domain plays in coordinating gene activity. PMID- 23028144 TI - miR-26a is required for skeletal muscle differentiation and regeneration in mice. AB - Multiple microRNAs are known to be induced during the differentiation of myoblasts to myotubes. Yet, experiments in animals have not provided clear evidence for the requirement of most of these microRNAs in myogenic differentiation in vivo. miR-26a is induced during skeletal muscle differentiation and is predicted to target a well-known inhibitor of differentiation, the transforming growth factor beta/bone morphogenetic protein (TGF-beta/BMP) signaling pathway. Here we show that exogenous miR-26a promotes differentiation of myoblasts, while inhibition of miR-26a by antisense oligonucleotides or by Tough-Decoys delays differentiation. miR-26a targets the transcription factors Smad1 and Smad4, critical for the TGF-beta/BMP pathway, and expression of microRNA-resistant forms of these transcription factors inhibits differentiation. Injection of antagomirs specific to miR-26a into neonatal mice derepressed both Smad expression and activity and consequently inhibited skeletal muscle differentiation. In addition, miR-26a is induced during skeletal muscle regeneration after injury. Inhibiting miR-26a in the tibialis anterior muscles through the injection of adeno-associated virus expressing a Tough-Decoy targeting miR-26a prevents Smad down-regulation and delays regeneration. These findings provide evidence for the requirement of miR-26a for skeletal muscle differentiation and regeneration in vivo. PMID- 23028146 TI - The extracellular matrix proteoglycan perlecan facilitates transmembrane semaphorin-mediated repulsive guidance. AB - The Drosophila transmembrane semaphorin-1a (Sema-1a) is a repulsive guidance cue that uses the Plexin A (PlexA) receptor during neural development. Sema-1a is required in axons to facilitate motor axon defasciculation at guidance choice points. We found that mutations in the trol gene strongly suppress Sema-1a mediated repulsive axon guidance. trol encodes the phylogenetically conserved secreted heparan sulfate proteoglycan (HSPG) perlecan, a component of the extracellular matrix. Motor axon guidance defects in perlecan mutants resemble those observed in Sema-1a- and PlexA-null mutant embryos, and perlecan mutants genetically interact with PlexA and Sema-1a. Perlecan protein is found in both the CNS and the periphery, with higher expression levels in close proximity to motor axon trajectories and pathway choice points. Restoring perlecan to mutant motor neurons rescues perlecan axon guidance defects. Perlecan augments the reduction in phospho-focal adhesion kinase (phospho-FAK) levels that result from treating insect cells in vitro with Sema-1a, and genetic interactions among integrin, Sema-1a, and FAK in vivo support an antagonistic relationship between Sema-1a and integrin signaling. Therefore, perlecan is required for Sema-1a-PlexA mediated repulsive guidance, revealing roles for extracellular matrix proteoglycans in modulating transmembrane guidance cue signaling during neural development. PMID- 23028149 TI - Progress in calculating the potential energy surface of H3+. AB - The most accurate electronic structure calculations are performed using wave function expansions in terms of basis functions explicitly dependent on the inter electron distances. In our recent work, we use such basis functions to calculate a highly accurate potential energy surface (PES) for the H(3)(+) ion. The functions are explicitly correlated Gaussians, which include inter-electron distances in the exponent. Key to obtaining the high accuracy in the calculations has been the use of the analytical energy gradient determined with respect to the Gaussian exponential parameters in the minimization of the Rayleigh-Ritz variational energy functional. The effective elimination of linear dependences between the basis functions and the automatic adjustment of the positions of the Gaussian centres to the changing molecular geometry of the system are the keys to the success of the computational procedure. After adiabatic and relativistic corrections are added to the PES and with an effective accounting of the non adiabatic effects in the calculation of the rotational/vibrational states, the experimental H(3)(+) rovibrational spectrum is reproduced at the 0.1 cm(-1) accuracy level up to 16,600 cm(-1) above the ground state. PMID- 23028148 TI - Chemistry, astronomy and physics of H3+. AB - The great developments in the chemistry, astronomy and physics of H(3)(+) since 2006, which have led to this Royal Society Theo Murphy Meeting, are reviewed. PMID- 23028147 TI - Polycomb repressive complex 1 activities determine the columnar organization of motor neurons. AB - Polycomb repressive complexes (PRCs) establish and maintain gene repression through chromatin modifications, but their specific roles in cell fate determination events are poorly understood. Here we show an essential role for the PRC1 component Bmi1 in motor neuron (MN) subtype differentiation through dose dependent effects on Hox gene expression. While Bmi1 is dispensable for generating MNs as a class, it has an essential role in specifying and determining the position of Hox-dependent MN columnar and pool subtypes. These actions are mediated through limiting anterior Hox expression boundaries, functions deployed in post-mitotic MNs, temporally downstream from morphogen gradients. Within the HoxC gene cluster, we found a progressive depletion of PRC-associated marks from rostral to caudal levels of the spinal cord, corresponding to major demarcations of MN subtypes. Selective ablation of Bmi1 elicits a derepression of more posterior Hox genes, leading to a switch in MN fates. Unexpectedly, Hox patterns and MN fates appear to be sensitive to absolute PRC1 activity levels; while reducing Bmi1 switches forelimb lateral motor column (LMC) MNs to a thoracic preganglionic (PGC) identity, elevating Bmi1 expression at thoracic levels converts PGC to LMC MNs. These results suggest that graded PRC1 activities are essential in determining MN topographic organization. PMID- 23028145 TI - Synaptic vesicle clustering requires a distinct MIG-10/Lamellipodin isoform and ABI-1 downstream from Netrin. AB - The chemotrophic factor Netrin can simultaneously instruct different neurodevelopmental programs in individual neurons in vivo. How neurons correctly interpret the Netrin signal and undergo the appropriate neurodevelopmental response is not understood. Here we identify MIG-10 isoforms as critical determinants of individual cellular responses to Netrin. We determined that distinct MIG-10 isoforms, varying only in their N-terminal motifs, can localize to specific subcellular domains and are differentially required for discrete neurodevelopmental processes in vivo. We identified MIG-10B as an isoform uniquely capable of localizing to presynaptic regions and instructing synaptic vesicle clustering in response to Netrin. MIG-10B interacts with Abl-interacting protein-1 (ABI-1)/Abi1, a component of the WAVE complex, to organize the actin cytoskeleton at presynaptic sites and instruct vesicle clustering through SNN 1/Synapsin. We identified a motif in the MIG-10B N-terminal domain that is required for its function and localization to presynaptic sites. With this motif, we engineered a dominant-negative MIG-10B construct that disrupts vesicle clustering and animal thermotaxis behavior when expressed in a single neuron in vivo. Our findings indicate that the unique N-terminal domains confer distinct MIG-10 isoforms with unique capabilities to localize to distinct subcellular compartments, organize the actin cytoskeleton at these sites, and instruct distinct Netrin-dependent neurodevelopmental programs. PMID- 23028150 TI - Spectroscopy of H3+ based on a new high-accuracy global potential energy surface. AB - The molecular ion H(3)(+) is the simplest polyatomic and poly-electronic molecular system, and its spectrum constitutes an important benchmark for which precise answers can be obtained ab initio from the equations of quantum mechanics. Significant progress in the computation of the ro-vibrational spectrum of H(3)(+) is discussed. A new, global potential energy surface (PES) based on ab initio points computed with an average accuracy of 0.01 cm(-1) relative to the non-relativistic limit has recently been constructed. An analytical representation of these points is provided, exhibiting a standard deviation of 0.097 cm(-1). Problems with earlier fits are discussed. The new PES is used for the computation of transition frequencies. Recently measured lines at visible wavelengths combined with previously determined infrared ro-vibrational data show that an accuracy of the order of 0.1 cm(-1) is achieved by these computations. In order to achieve this degree of accuracy, relativistic, adiabatic and non adiabatic effects must be properly accounted for. The accuracy of these calculations facilitates the reassignment of some measured lines, further reducing the standard deviation between experiment and theory. PMID- 23028151 TI - Visible transitions from ground state H3+ measured with high-sensitivity action spectroscopy. AB - We report on the recent observation of new spectral lines of cold H(3)(+) ions lying well in the visible spectral region. Transitions from the two lowest ro vibrational levels to final levels up to 16,700 cm(-1), almost half way to the dissociation limit, have been measured, involving up to eight vibrational quanta. The observed transitions are more than six orders of magnitude less intense than the v(2)(1) fundamental band and yet another order of magnitude weaker than reached by previous sensitive action spectroscopy in the near-infrared region. The measurements were carried out in a cryogenic 22-pole ion trap with H(3)(+) ions cooled to their lowest rotational levels by helium buffer gas. Laser-induced chemical reactions lead to the formation of ArH(+) ions detected with single-ion sensitivity. These visible measurements, together with the previous near-infrared measurements, have helped to further develop empirically corrected calculations and have provided essential benchmarks for new ab initio calculations that now reach a spectroscopic accuracy of 0.1 cm(-1) on average up to the highest observed transition. Highly sensitive action spectroscopy and the attained high accuracy predictions will enable us to find and measure transitions even further into the visible region of H(3)(+), paving the way towards the dissociation limit. PMID- 23028152 TI - Transfer of a proton between H2 and O2. AB - The proton affinities of hydrogen and oxygen are very similar. Therefore, it has been discussed that the proton transfer from the omnipresent H(3)(+) to molecular oxygen in the near thermoneutral reaction H(3)(+) + O(2) <--> O(2)H(+) + H(2) effectively binds the interstellar oxygen in O(2)H(+). In this work, the proton transfer reaction has been investigated in a low-temperature 22-pole ion trap from almost room temperature (280 K) down to the lowest possible temperature limited by freeze out of oxygen gas (about 40 K at a low pressure). The Arrhenius behaviour of the rate coefficient for the forward reaction shows that it is subject to an activation energy of E(A)/k=113 K. Thus, the forward reaction can proceed only in higher temperature molecular clouds. Applying laser-induced reactions to the given reaction (in the backward direction), a preliminary search for spectroscopic signatures of O(2)H(+) in the infrared was unsuccessful, whereas the forward reaction has been successfully used to probe the population of the lowest ortho and para levels of H(3)(+). PMID- 23028153 TI - The ortho : para ratio of H3+ in laboratory and astrophysical plasmas. AB - In diffuse molecular clouds, the nuclear spin temperature of H(3)(+) (approx. 30 K) is much lower than the cloud kinetic temperature (approx. 70 K). To understand this temperature discrepancy, we have measured the ratio of the hop to exchange pathways (alpha) in the H(3)(+) + H(2) --> H(2) + H(3)(+) reaction (which interconverts ortho- and para-H(3)(+)) using high-resolution spectroscopy of the nu(2) fundamental band of H(3)(+) in a hydrogenic plasma. We find that alpha decreases from 1.6+/-0.1 at 350 K to its statistical value of 0.5+/-0.1 at 135 K. We use this result to model the steady-state chemistry of diffuse molecular clouds, finding good agreement with astronomical data provided the dissociative recombination rates of ortho- and para-H(3)(+) are equal and the identity branching fraction for the H(3)(+) + H(2) reaction is large. Our results highlight the need for further studies of the H(3)(+) + H(2) reaction as well as state-selective measurements of H(3)(+) dissociative recombination. PMID- 23028154 TI - Stabilization of H+-H2 collision complexes between 11 and 28 K. AB - Formation of H(3)(+) via association of H(+) with H(2) has been studied at low temperatures using a 22-pole radiofrequency trap. Operating at hydrogen number densities from 10(11) to 10(14) cm(-3), the contributions of radiative, k(r), and ternary, k(3), association have been extracted from the measured apparent binary rate coefficients, k*=k(r)+k(3)[H(2)]. Surprisingly, k(3) is constant between 11 and 22 K, (2.6+/-0.8)*10(-29) cm(6) s(-1), while radiative association decreases from k(r)(11 K)=(1.6+/-0.3)*10(-16) cm(3) s(-1) to k(r)(28 K)=(5+/-2)*10(-17) cm(3) s(-1). These results are in conflict with simple association models in which formation and stabilization of the complex are treated separately. Tentative explanations are based on the fact that, at low temperatures, only few partial waves contribute to the formation of the collision complex and that ternary association with H(2) may be quite inefficient because of the 'shared proton' structure of H(5)(+). PMID- 23028155 TI - The Jahn-Teller effect in the 3pe' Rydberg state of H3: review of experimental and ab initio determinations. AB - The dissociative recombination (DR) of H(3)(+) ions with electrons, producing neutral atomic and molecular fragments, is driven primarily by the vibronic Jahn Teller (JT) interaction between the electronic components of the pe' e(-)-H(3)(+) collision (Rydberg) channel. The JT parameters characterizing this interaction are therefore of great interest as they are required for the theoretical predictions of the DR cross section. In this contribution, we review various determinations of these quantities that have been made previously, based both on spectroscopic studies of 3pe' Rydberg-excited H(3) states, and on the analysis of the corresponding ab initio H(3) Rydberg potential surfaces near the conical intersection (D(3h) symmetry) for n=3-5. The highly correlated theoretical 3pe' potential surfaces of Mistrik et al. are used for a new determination of both the linear and quadratic JT terms. PMID- 23028156 TI - Storage ring measurements of the dissociative recombination of H3+. AB - The dissociative recombination (DR) of H(3)(+) is a key process in interstellar chemistry. More than 30 experimental studies of the DR process have been published in the literature. The H(3)(+) DR rate coefficient results obtained from these measurements, however, have not always been consistent. The outcome seems to depend on the experimental method, on the exact measurement procedure and sometimes even on the interpretation of the experimental data. In the past two decades, heavy-ion storage rings have become the working horse for DR measurements, as they provide a direct measurement of the DR products. Furthermore, storage ring measurements yield energy-resolved rate coefficients with unprecedented resolution that allow for detailed comparison with theory. DR results from different storage ring facilities have shown a remarkable consistency throughout the years and they provide additional information on break up dynamics and internal excitation. In this study, we will review the storage ring DR measurements that have been carried out for H(3)(+). PMID- 23028157 TI - Binary recombination of para- and ortho-H3+ with electrons at low temperatures. AB - Results of an experimental study of binary recombination of para- and ortho H(3)(+) ions with electrons are presented. Near-infrared cavity-ring-down absorption spectroscopy was used to probe the lowest rotational states of H(3)(+) ions in the temperature range of 77-200 K in an H(3)(+)-dominated afterglow plasma. By changing the para/ortho abundance ratio, we were able to obtain the binary recombination rate coefficients for pure and para-H(3)(+) and ortho H(3)(+). The results are in good agreement with previous theoretical predictions. PMID- 23028158 TI - Kinetic processes in recombining H3+ plasmas. AB - Recombination in plasmas containing H(3)(+) ions occurs not only by binary recombination but also by third-body-assisted mechanisms, the principal subject of this contribution. Third-body effects on recombination are of interest for model calculations of hydrogen discharges, their spectral emissions and the inference of binary recombination coefficients from plasma afterglow data. PMID- 23028159 TI - Dissociative recombination of H3+: 10 years in retrospect. AB - The dissociative recombination of H(3)(+) has been an intriguing problem for more than half a century. The early experiments on H(3)(+) during the first 20 years were carried out without mass analysis in decaying plasma afterglows, and thus the measured rates pertained to an uncontrolled mixture of H(3)(+) and impurity ions. When mass analysis was used, the rate coefficient was determined to be an uneventful value of about 10(-7) cm(3) s(-1), a very common rate coefficient for many molecular ions. But this was not the end of the story, not even the beginning of the end; it marked only the end of the beginning. The story I will tell in this article started about 10 years ago, when the dissociative recombination of H(3)(+) was approaching its deepest crisis. Today, owing to an extensive experimental and theoretical effort, the state of affairs has reached a historically unique level of harmony, although there still remains many things to sort out. PMID- 23028160 TI - H3+ at the interface between astrochemistry and astroparticle physics. AB - The H(3)(+) molecular ion has been used by Oka and collaborators to trace the rate of ionization by cosmic rays in the interstellar medium. More energetic cosmic rays also produce diffuse gamma-radiation. Now that several supernova remnants (SNRs) have been identified as gamma-ray sources, it is possible to use spectroscopy of molecular ions to search for enhanced ionization rates that would pinpoint the SNRs as the accelerators of cosmic rays. It is proposed that the warm, dilute molecular gas revealed by H(3)(+) absorption in the central molecular zone of the Galaxy can also be investigated via radio recombination lines of atoms and possibly triatomic hydrogen. PMID- 23028161 TI - The distribution of cosmic-ray ionization rates in diffuse molecular clouds as probed by H3+. AB - Owing to its simple chemistry, H(3)(+) is widely regarded as the most reliable tracer of the cosmic-ray ionization rate in diffuse interstellar clouds. At present, H(3)(+) observations have been made in over 50 sight lines that probe the diffuse interstellar medium (ISM) throughout the Galaxy. This small survey presents the opportunity to investigate the distribution of cosmic-ray ionization rates in the ISM, as well as any correlations between the ionization rate and line-of-sight properties. Some of the highest inferred ionization rates are about 25 times larger than the lowest upper limits, suggesting variations in the underlying low-energy cosmic-ray flux across the Galaxy. Most likely, such variations are caused predominantly by the distance between an observed cloud and the nearest site of particle acceleration. PMID- 23028162 TI - Exploring the central molecular zone of the Galaxy using spectroscopy of H3+ and CO. AB - The central 400 parsecs of the Milky Way, a region known as the central molecular zone (CMZ), contains interstellar gas in a wide range of physical environments, from ultra-hot, rarified and highly ionized to warm, dense and molecular. The combination of infrared spectroscopy of H(3)(+) and CO is a powerful way to determine the basic properties of molecular interstellar gas, because the abundance ratio of H(3)(+) to CO in 'dense' clouds is quite different from that in 'diffuse' clouds. Moreover, the energy-level structure and the radiative properties of H(3)(+) combined with the unusually warm temperatures of molecular gas in the CMZ make H(3)(+) a unique probe of the physical conditions there. This paper describes how, using infrared absorption spectroscopy of H(3)(+) and CO, it has been discovered that a large fraction of the volume of the CMZ is filled with warm, diffuse and partially molecular gas moving at speeds of up to approximately 200 km s(-1) and that the mean cosmic ray ionization rate in the CMZ exceeds by roughly an order of magnitude values found in diffuse molecular clouds elsewhere in the Galaxy. PMID- 23028163 TI - Hot, metastable hydronium ion in the Galactic centre: formation pumping in X-ray irradiated gas? AB - With a 3.5 m diameter telescope passively cooled to approximately 80 K, and a science payload comprising two direct detection cameras/medium resolution imaging spectrometers (PACS and SPIRE) and a very high spectral resolution heterodyne spectrometer (HIFI), the Herschel Space Observatory is providing extraordinary observational opportunities in the 55-670 MUm spectral range. HIFI has opened for the first time to high-resolution spectroscopy the submillimetre band that includes the fundamental rotational transitions of interstellar hydrides, the basic building blocks of astrochemistry. We discuss a recent HIFI discovery of metastable rotational transitions of the hydronium ion (protonated water, H(3)O(+)), with rotational level energies up to 1200 K above the ground state, in absorption towards Sagittarius B2(N) in the Galactic centre. Hydronium is an important molecular ion in the oxygen chemical network. Earlier HIFI observations have indicated a general deficiency of H(3)O(+) in the diffuse gas in the Galactic disc. The presence of hot H(3)O(+) towards Sagittarius B2(N) thus appears to be related to the unique physical conditions in the central molecular zone, manifested, for example, by the widespread presence of abundant H(3)(+). One intriguing theory for the high rotational temperature characterizing the population of the H(3)O(+) metastable levels may be formation pumping in molecular gas irradiated by X-rays emitted by the Galactic centre black hole. Alternatively, the pervasive presence of enhanced turbulence in the central molecular zone may give rise to shocks in the lower-density medium that is exposed to energetic radiation. PMID- 23028164 TI - Hydride spectroscopy of the diffuse interstellar medium: new clues on the gas fraction in molecular form and cosmic ray ionization rate in relation to H3+. AB - The Herschel-guaranteed time key programme PRobing InterStellar Molecules with Absorption line Studies (PRISMAS)(1) is providing a survey of the interstellar hydrides containing the elements C, O, N, F and Cl. As the building blocks of interstellar molecules, hydrides provide key information on their formation pathways. They can also be used as tracers of important physical and chemical properties of the interstellar gas that are difficult to measure otherwise. This paper presents an analysis of two sight-lines investigated by the PRISMAS project, towards the star-forming regions W49N and W51. By combining the information extracted from the detected spectral lines, we present an analysis of the physical properties of the diffuse interstellar gas, including the electron abundance, the fraction of gas in molecular form, and constraints on the cosmic ray ionization rate and the gas density. PMID- 23028165 TI - Using deuterated H3+ and other molecular species to understand the formation of stars and planets. AB - The H(3)(+) ion plays a key role in the chemistry of dense interstellar gas clouds where stars and planets are forming. The low temperatures and high extinctions of such clouds make direct observations of H(3)(+) impossible, but lead to large abundances of H(2)D(+) and D(2)H(+) that are very useful probes of the early stages of star and planet formation. Maps of H(2)D(+) and D(2)H(+) pure rotational line emission towards star-forming regions show that the strong deuteration of H(3)(+) is the result of near-complete molecular depletion of CNO bearing molecules onto grain surfaces, which quickly disappears as cores warm up after stars have formed. In the warmer parts of interstellar gas clouds, H(3)(+) transfers its proton to other neutrals such as CO and N(2), leading to a rich ionic chemistry. The abundances of such species are useful tracers of physical conditions such as the radiation field and the electron fraction. Recent observations of HF line emission towards the Orion Bar imply a high electron fraction, and we suggest that observations of OH(+) and H(2)O(+) emission may be used to probe the electron density in the nuclei of external galaxies. PMID- 23028166 TI - H2, H3+ and the age of molecular clouds and prestellar cores. AB - Measuring the age of molecular clouds and prestellar cores is a difficult task that has not yet been successfully accomplished although the information is of paramount importance to help in understanding and discriminating between different formation scenarios. Most chemical clocks suffer from unknown initial conditions and are therefore difficult to use. We propose a new approach based on a subset of deuterium chemistry that takes place in the gas phase and for which initial conditions are relatively well known. It relies primarily on the conversion of H(3)(+) into H(2)D(+) to initiate deuterium enrichment of the molecular gas. This conversion is controlled by the ortho/para ratio of H(2) that is thought to be produced with the statistical ratio of 3 and subsequently slowly decays to an almost pure para-H(2) phase. This slow decay takes approximately 1 Myr and allows us to set an upper limit on the age of molecular clouds. The deuterium enrichment of the core takes longer to reach equilibrium and allows us to estimate the time necessary to form a dense prestellar core, i.e. the last step before the collapse of the core into a protostar. We find that the observed abundance and distribution of DCO(+) and N(2)D(+) argue against quasi-static core formation and favour dynamical formation on time scales of less than 1 Myr. Another consequence is that ortho-H(2) remains comparable to para-H(2) in abundance outside the dense cores. PMID- 23028167 TI - Temperature changes and energy inputs in giant planet atmospheres: what we are learning from H3+. AB - Since its discovery at Jupiter in 1988, emission from H(3)(+) has been used as a valuable diagnostic tool in our understanding of the upper atmospheres of the giant planets. One of the lasting questions we have about the giant planets is why the measured upper atmosphere temperatures are always consistently hotter than the temperatures expected from solar heating alone. Here, we describe how H(3)(+) forms across each of the planetary disks of Jupiter, Saturn and Uranus, presenting the first observations of equatorial H(3)(+) at Saturn and the first profile of H(3)(+) emission at Uranus not significantly distorted by the effects of the Earth's atmosphere. We also review past observations of variations in temperature measured at Uranus and Jupiter over a wide variety of time scales. To this, we add new observations of temperature changes at Saturn, using observations by Cassini. We conclude that the causes of the significant level of thermal variability observed over all three planets is not only an important question in itself, but that explaining these variations could be the key to answering the more general question of why giant planet upper atmospheres are so hot. PMID- 23028168 TI - To be or not to be: the early history of H3 and H3+. AB - Triatomic hydrogen became a major research area only after 1980, but its history goes back to J. J. Thomson's discovery in 1911. In fact, the possible existence of H(3) was suggested as early as 1895. This paper outlines the history of H(3) and H(3)(+) up to the mid-1930s, when chemists and physicists ceased to believe in the existence of the H(3) molecule. In the intervening years, there was a great deal of interest in 'active hydrogen' and also in the configuration of H(3), which was examined by Bohr in 1919. While H(3) was abandoned, H(3)(+) was not. Although the properties of H(3)(+) were largely unknown, the existence of the ion was firmly established, and its structure studied by means of the new methods of quantum chemistry. PMID- 23028169 TI - Dissection and ruptured pseudoaneurysm of a renal artery: a non-described complication during transcatheter aortic-valve implantation. PMID- 23028170 TI - Towards improved risk scores: the quest for the grail continues. PMID- 23028171 TI - Does EuroSCORE II perform better than its original versions? A multicentre validation study. AB - AIMS: The European system for cardiac operation risk evaluation (EuroSCORE) is widely used for predicting in-hospital mortality after cardiac surgery. A new score (EuroSCORE II) has been recently developed to update the previously released versions. This study was undertaken to validate EuroSCORE II, to compare its performance with the original EuroSCOREs and to evaluate the effects of the removal of those factors that were included in the score even if they were statistically non-significant. METHODS AND RESULTS: Data on 12,325 consecutive patients who underwent major cardiac surgery in a 6-year period were retrieved from three prospective institutional databases. Discriminatory power was assessed using the c-index and comparison among the scores' performances was performed with Delong, bootstrap, and Venkatraman methods. Calibration was evaluated with calibration curves and associated statistics. The in-hospital mortality rate was 2.2%. The discriminatory power was high and similar in all algorithms (area under the curve 0.82, 95% CI: 0.79-0.84 for additive EuroSCORE; 0.82, 95% CI: 0.79-0.84 for logistic EuroSCORE; 0.82, 95% CI: 0.80-0.85 for EuroSCORE II). The EuroSCORE II had a fair calibration till 30%-predicted values and over-predicted beyond. The removal of non-significant factors from EuroSCORE II did not affect performance, being both the calibration and discrimination comparable. CONCLUSION: This validation study demonstrated that EuroSCORE II is a good predictor of perioperative mortality. It showed an optimal calibration until 30% predicted mortality. Nonetheless, it does not seem to significantly improve the performance of older versions in the higher tertiles of risk. Moreover, it could be simplified, as the removal from the algorithm of non-significant factors does not alter its performance. PMID- 23028172 TI - Radio-opacity and incidental identified mechanical complications of totally implantable venous access devices placed in the chest. AB - BACKGROUND: Totally implantable venous access devices (TIVAD) may be associated with different complications. Certain mechanical port disorders can easily be diagnosed on chest radiographs if the implanted systems are radiopaque and well visible. There are no reports regarding the visibility of TIVAD on chest X-rays. PURPOSE: To assess the radio opacity of TIVAD implanted in the chest as well as type and frequency of mechanical complications of ports on chest X-ray images. MATERIAL AND METHODS: Chest X-rays of 985 patients from the time period 2007-2009 were analyzed retrospectively. In these patients 1190 TIVAD were inserted. All parts of the TIVAD, i.e. port chamber, connection, and port catheter, were checked for their visibility on chest radiographs. An opacity score was used here as follows: ++ well visible; + visible; - partly or completely invisible. Mechanical complications of TIVAD incidentally detected on chest X-ray were also analyzed retrospectively. RESULTS: Nineteen TIVAD models with diverse configuration and visibility of port chambers, connections, and catheters were identified in our study. Eighty-eight percent of the analyzed port systems were well visible or visible on chest radiographs. Twelve percent of the port chambers and catheters were partly visible or completely invisible. In 9% of the TIVAD, different mechanical complications were diagnosed on chest X-ray images. CONCLUSION: TIVADs should be evaluated carefully on every chest X-ray. Ideally, they should be radio-opaque and well visible on thoracic X-ray images. Unfortunately, this is not always the case. Therefore, manufacturers of TIVAD should take into consideration to use exclusively radio-opaque materials that allow sufficient visibility of each port component on chest radiographs. PMID- 23028173 TI - Delay in diagnosis of Churg-Strauss syndrome: a case report. AB - Churg-Strauss syndrome (CSS) is a well established disorder of the blood vessels. However, it is still sometimes not diagnosed early enough to avoid serious complications. It is the later stage that carries the more serious complications. Therefore, we emphasize the ways in which the diagnosis can be made early enough to avoid this stage of the disease. We report a case of CSS that was not diagnosed early and so the patient went on to develop severe cardiac and neurological manifestations. In this report we discuss the techniques and the methods to diagnose CSS and discuss their effectiveness in establishing the diagnosis. We also explore late cardiac and neurological complications because these are particularly serious complications later in the disease. We conclude that the criteria established by the American College of Rheumatology for CSS is the best tool available for early diagnosis and that late stage manifestations of CSS carry high rates of morbidity and mortality. PMID- 23028174 TI - Preoperative assessment in the elderly: evaluation of a new clinical service. AB - Older people represent the fastest growing sector of society and a growing proportion of those undergoing elective surgery. Older people are at the highest risk of increased length of stay and postoperative complications. We evaluated the development of a nurse-led multidimensional preoperative assessment for older people. An older people's preassessment nurse reviewed consecutive patients undergoing elective surgery who met the inclusion criteria. In the first five months control phase, assessment was not acted on. Following the intervention, patients were referred to appropriate specialties for input. A total of 141 patients were reviewed before and 172 patients reviewed after the introduction of the pilot. Length of stay was reduced from 8.9 to 4.9 days after the introduction of the pilot (P < 0.001). Delays were reduced from 9.9% to 2.3% (P = 0.004) and fewer procedures were cancelled at pre-assessment (17.7% before, 5.2% after; P < 0.001). Serious postoperative complications were reduced from 8.5% to 2.3% (P = 0.01). Coordinated multidisciplinary preoperative assessment in the elderly may reduce complications and length of stay. PMID- 23028175 TI - Fat future for firefighters? Changes in prevalence of obesity in Scottish local authority firefighters. AB - There has been a dramatic increase in adult obesity in the Scotland during the past two decades, but little research has been undertaken into populations defined specifically by occupation. The aim of this study was to examine changes in the prevalence of obesity in a group of local authority firefighters arising early in their careers, between enlistment and initial examination for a large goods vehicle (LGV) licence. The body mass index (BMI) from initial LGV medical examinations of firefighters during a 30-month period up to the end of September 2005 was compared with that at enlistment. Enlistment and LGV BMI data were available for 114 firefighters, all men. Of 114, 77 (68%) of LGV examinations took place within five years of enlistment. None were obese (BMI >=30) at enlistment, but by LGV medical the BMI of 88 (84%) had increased, and nine (8%) were obese. Assuming uniform accrual, BMI increased annually at rates varying between 0.06% and 2.25% (mean, 0.56; standard deviation [SD], 0.42). For the nine obese, this was 0.29-2.25% (mean, 1.06; SD, 0.61). In a population for which fitness is an essential selection criterion, the implied decline of fitness as measured by rising BMI in a short period should be cause for concern. PMID- 23028176 TI - Management of acute poststroke blood pressure and detection of atrial fibrillation: a postal questionnaire of UK stroke physicians' current clinical practice. AB - The aim of this study was to determine the current clinical practice of UK stroke physicians with regard to the early management of blood pressure (BP) and arrhythmia detection following acute stroke. Postal service evaluation questionnaires were sent to the lead physicians for stroke in UK hospitals. Hospitals were identified by their inclusion in the 2008 Scottish Stroke Care Audit and the 2006 Royal College of Physicians Sentinel Stroke Audit. A total of 259 questionnaires were sent with a 33% response rate. Current practice regarding acute post-stroke BP management varied considerably. Approximately one-third of respondents lowered systolic BP within the first 72 hours of stroke, but the majority (65%) delayed intervening for at least seven days. Most would not intervene until systolic BP exceeded 180 mmHg. Of those who intervene, the most commonly quoted target systolic BP was 160 +/- 5 mmHg. Post-stroke arrhythmia investigation was similarly varied; 12-lead electrocardiogram recording was frequent, with further investigation being more individualized. Of all respondents, 87% expressed interest in participating in future trials of complex interventions for stroke. Current practice of UK stroke physicians regarding acute BP intervention is diverse, reflecting conflicting evidence. There is interest in the stroke community for further research aiming to answer these important clinical questions. PMID- 23028177 TI - Secular trends, treatments, and outcomes of Middle Eastern Arab and South Asian patients hospitalized with atrial fibrillation: insights from a 20-year registry in Qatar (1991-2010). AB - A prospective registry was made of all patients hospitalized with atrial fibrillation (AF) in the State of Qatar from 1991 to 2010. Clinical characteristics, management, and outcomes were compared according to ethnicity (Middle Eastern Arab vs South Asian). During this 20-year period, 2857 Arabs and 548 Asians were hospitalized for AF. Arabs were 9 years older and more likely to have hypertension, diabetes mellitus (DM), chronic renal impairment, and dyslipidemia than the Asians. Valvular heart disease and acute coronary syndromes were more common among Asians, while congestive heart failure was more common in Arabs. The overall inhospital mortality was lower in Asians than that of Arabs, while stroke rates were comparable. There was an increase in the prevalence of DM and hypertension in both the groups in the latter years of the study period, but there was no change in mortality trends. Our findings underscore the need to study AF according to ethnicity. PMID- 23028178 TI - Mean platelet volume and extent and complexity of coronary artery disease in diabetic and nondiabetic patients with ST elevation myocardial infarction. AB - We investigated whether the mean platelet volume (MPV) is associated with the extent and complexity of coronary artery disease in patients with ST elevation myocardial infarction (STEMI). We prospectively included 912 STEMI patients (663 male and 249 female; mean age 58.7 +/- 12.4 years) who underwent primary percutaneous coronary intervention. The patients were divided into 3 groups according to MPV tertiles. Highest SYNTAX score (SS) was observed in MPVhigh group compared with MPVmid and MPVlow groups (P < .001 for all). The SS of MPVmid group was higher than MPVlow group (P = .036). The MPV in diabetic STEMI patients was higher than in nondiabetic STEMI patients (P < .001). Multivariate linear regression analysis showed that the MPV was associated with diabetes (beta = .115, P = .001), troponin level (beta = .131, P = .001), platelet count (beta = .241, P < .001), and SS (beta = .216, P < .001). The relation between MPV and SS in diabetic STEMI patients was stronger than for nondiabetic STEMI patients (r = .473, P < .001 vs r = .129, P = .001). PMID- 23028179 TI - Long-term stability of acute and transient psychotic disorders. AB - OBJECTIVE: To examine the temporal stability of the category 'acute and transient psychotic disorders' (ATPDs), ICD-10 Classification of Mental and Behavioural Disorders, including subtypes characterised by polymorphic, schizophrenic and predominantly delusional features. METHOD: We checked the readmission patterns of all patients aged 15-64 years (n = 5426), whether admitted to hospital or treated as outpatients, who were enrolled for the first time in the Danish Psychiatric Register with a diagnosis of ATPDs between 1995 and 2008. RESULTS: An increasing number of cases with ATPDs changed diagnosis in subsequent admissions after 1, 2 and 5 years, mainly either to schizophrenia and related disorders or affective disorders. In their last admission, on average after 7.3 years, there were 2429 patients listed with ATPDs, accounting for an overall stability of 44.8%. Females were less likely than males to develop another diagnosis. Among the ATPD subtypes, polymorphic psychotic disorder without schizophrenic symptoms had a higher stability than those featuring schizophrenic or predominantly delusional features. CONCLUSIONS: The low diagnostic stability of ATPDs reflects the lack of clearly defining features and argues against their validity as a distinct category. PMID- 23028180 TI - 2012 SNM highlights lecture: general clinical specialties. PMID- 23028181 TI - SNM 2012 image of the year. PMID- 23028187 TI - Haplotype-based profiling of subtle allelic imbalance with SNP arrays. AB - Due to limitations of surgical dissection and tumor heterogeneity, tumor samples collected for cancer genomics studies are often heavily diluted with normal tissue or contain subpopulations of cells harboring important aberrations. Methods for profiling tumor-associated allelic imbalance in such scenarios break down at aberrant cell proportions of 10%-15% and below. Here, we present an approach that offers a vast improvement for detection of subtle allelic imbalance, or low proportions of cells harboring aberrant allelic ratio among nonaberrant cells, in unpaired tumor samples using SNP microarrays. We leverage the expected pattern of allele-specific intensity ratios determined by an individual's germline haplotypes, information that has been ignored in existing approaches. We demonstrate our method on real and simulated data from the CRL 2324 breast cancer cell line genotyped on the Illumina 370K array. Assuming a 5 million SNP array, we can detect the presence of aberrant cells in proportions lower than 0.25% in the breast cancer sample, approaching the sensitivity of some minimal residual disease assays. Further, we apply a hidden Markov model to identify copy-neutral LOH (loss of heterozygosity) events as short as 11 Mb in mixtures of only 4% tumor using 370K data. We anticipate our approach will offer a new paradigm for genomic profiling of heterogeneous samples. PMID- 23028189 TI - Debates, disputes, discussions and deliberations. PMID- 23028184 TI - Response to hyperosmotic stress. AB - An appropriate response and adaptation to hyperosmolarity, i.e., an external osmolarity that is higher than the physiological range, can be a matter of life or death for all cells. It is especially important for free-living organisms such as the yeast Saccharomyces cerevisiae. When exposed to hyperosmotic stress, the yeast initiates a complex adaptive program that includes temporary arrest of cell cycle progression, adjustment of transcription and translation patterns, and the synthesis and retention of the compatible osmolyte glycerol. These adaptive responses are mostly governed by the high osmolarity glycerol (HOG) pathway, which is composed of membrane-associated osmosensors, an intracellular signaling pathway whose core is the Hog1 MAP kinase (MAPK) cascade, and cytoplasmic and nuclear effector functions. The entire pathway is conserved in diverse fungal species, while the Hog1 MAPK cascade is conserved even in higher eukaryotes including humans. This conservation is illustrated by the fact that the mammalian stress-responsive p38 MAPK can rescue the osmosensitivity of hog1Delta mutations in response to hyperosmotic challenge. As the HOG pathway is one of the best understood eukaryotic signal transduction pathways, it is useful not only as a model for analysis of osmostress responses, but also as a model for mathematical analysis of signal transduction pathways. In this review, we have summarized the current understanding of both the upstream signaling mechanism and the downstream adaptive responses to hyperosmotic stress in yeast. PMID- 23028188 TI - Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer. AB - Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the "sensor" cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease. PMID- 23028191 TI - Treatment of refugees at the crossroads: the need for an evidence base. PMID- 23028190 TI - Understanding disproportionately high cardiometabolic risk in Australians treated for psychosis. PMID- 23028192 TI - Healthy Kids Check: lack of transparency and misplaced faith in the benefits of screening. PMID- 23028193 TI - The three year old social and emotional well-being check is good news. PMID- 23028194 TI - Playing the ferryman: psychiatry's role in end-of-life decision-making. PMID- 23028195 TI - Assisted dying in liberalised jurisdictions and the role of psychiatry: a clinician's view. AB - OBJECTIVE: Assisted dying is a contentious and topical issue. Mental disorder is a relevant influence on requests of hastened death. The psychiatry of dying is not a prominent component in the assessment of euthanasia and physician-assisted suicide (PAS) in jurisdictions with liberalised assisted dying laws. The literature on the assessment processes, with particular reference to mental status, involved in euthanasia requests is considered. METHODS: An experienced palliative medicine specialist and psychiatrist selectively reviewed the recent literature published about the mental health issues involved in euthanasia and PAS. RESULTS: Assessments of competency, sustained wish to die prematurely, depressive disorder, demoralisation and 'unbearable suffering' in the terminally ill are clinically uncertain and difficult tasks. There is a growing psychiatric and psychological literature on the mental status of the terminally ill. As yet psychiatry does not have the expertise to 'select' those whose wish for hastened death is rational, humane and 'healthy'. Rarely in those societies with liberalised assisted dying laws are psychiatrists involved in the decision-making for individuals requesting early death. This role is fulfilled by non specialists. CONCLUSIONS: There remain significant concerns about the accuracy of psychiatric assessment in the terminally ill. Mental processes are more relevant influences on a hastened wish to die than are the physical symptoms of terminal malignant disease. Psychiatric review of persons requesting euthanasia is relevant. It is not obligatory or emphasised in those legislations allowing assisted dying. Psychiatry needs to play a greater role in the assessment processes of euthanasia and PAS. PMID- 23028196 TI - The truth, the whole truth and nothing but the truth about early intervention. PMID- 23028197 TI - Clozapine-induced myocarditis and baseline echocardiograms. PMID- 23028198 TI - Clozapine-induced myocarditis and baseline echocardiography. PMID- 23028185 TI - The ubiquitin-proteasome system of Saccharomyces cerevisiae. AB - Protein modifications provide cells with exquisite temporal and spatial control of protein function. Ubiquitin is among the most important modifiers, serving both to target hundreds of proteins for rapid degradation by the proteasome, and as a dynamic signaling agent that regulates the function of covalently bound proteins. The diverse effects of ubiquitylation reflect the assembly of structurally distinct ubiquitin chains on target proteins. The resulting ubiquitin code is interpreted by an extensive family of ubiquitin receptors. Here we review the components of this regulatory network and its effects throughout the cell. PMID- 23028199 TI - It's a typical case of clozapine toxicity. PMID- 23028200 TI - Self-perception in a clinical sample of gender variant children. AB - BACKGROUND: Gender variance (GV) in childhood has a negative impact on the self concept of children in the general population and can lead to mental health problems and even suicidal ideation in adulthood. This study explored the self concept of clinically referred gender variant children and examined potential risk factors. METHOD: The Self-Perception Profile for Children was administered to 147 children, who were referred to a gender identity clinic. Their parents completed the Child Behaviour Checklist and the Gender Identity Questionnaire to assess the degree of GV. RESULTS: The referred children were at risk of developing a negative self-concept; more specifically gender variant girls had low scores on 'global self-worth', 'physical appearance' and 'behavioural conduct' compared to Dutch norms for girls. Gender variant boys had low scores on 'global self-worth', 'scholastic competence', 'athletic competence' and 'physical appearance' compared to Dutch norms for boys. Within the group of referred children, sex differences, but no age effects, were found. The referred girls felt more competent than the referred boys on 'athletic competence' and 'scholastic functioning'. For both boys and girls poor peer relations had a significant negative relationship with self-concept and more GV was related to a lower global self-worth. CONCLUSIONS: Clinically referred gender variant children seemed vulnerable to developing a negative self-concept. Poor peer relations and extreme GV might be mediating variables. Interventions might focus on enhancing acceptance of the environment and improving social skills of gender variant children. PMID- 23028201 TI - Behaviorally based adherence program for pediatric patients treated with positive airway pressure. AB - OBJECTIVES: Positive Airway Pressure (PAP) devices are being increasingly used in pediatric populations for problems including Obstructive Sleep Apnea. There is limited literature regarding pediatric adherence with PAP treatment or successful interventions that improve adherence. This paper describes a clinical program for pediatric PAP users which was designed to improve adherence of patients prescribed PAP therapy and involves intensive assessment and behavioral intervention. METHOD: The design and implementation of the program is described, including the purpose, goals, programmatic structure, clinical content, type and training of personnel, strengths and limitations and financial concerns as well as the challenges with the development and application of the program's protocol. RESULTS: Preliminary outcome data show short-term improvements in consistent usage for many of the patients. CONCLUSIONS: The program shows some promise and provides a framework for future program development and research. PMID- 23028202 TI - The principal fucosylated oligosaccharides of human milk exhibit prebiotic properties on cultured infant microbiota. AB - Breast-fed infant microbiota is typically rich in bifidobacteria. Herein, major human milk oligosaccharides (HMOS) are assessed for their ability to promote the growth of bifidobacteria and to acidify their environment, key features of prebiotics. During in vitro anaerobic fermentation of infant microbiota, supplementation by HMOS significantly decreased the pH even greater than supplementation by fructooligosaccharide (FOS), a prebiotic positive control. HMOS elevated lactate concentrations, increased the proportion of Bifidobacterium spp. in culture, and through their fermentation into organic acids, decreased the proportion of Escherichia and Clostridium perfringens. Three principal components of HMOS, 2'-fucosyllactose, lactodifucotetraose and 3-fucosyllactose, were consumed in these cultures. These three principal oligosaccharides of human milk were then individually tested as supplements for in vitro growth of four individual representative strains of infant gut microbes. Bifidobacterium longum JCM7007 and B. longum ATCC15697 efficiently consumed oligosaccharides and produced abundant lactate and short-chain fatty acids, resulting in significant pH reduction. The specificity of fermentation differed by microbe species and strain and by oligosaccharide structure. Escherichia coli K12 and C. perfringens did not utilize appreciable fucosylated oligosaccharides, and a typical mixture of organic acid fermentation products inhibited their growth. In summary, 2' fucosyllactose, lactodifucotetraose, and 3-fucosyllactose, when cultured with B. longum JCM7007 and B. longum ATCC15697, exhibit key characteristics of a prebiotic in vitro. If these bifidobacteria are representative of pioneering or keystone species for human microbiota, fucosylated HMOS could strongly promote colonization and maintenance of a mutualist symbiotic microbiome. Thus, these simple glycans could mediate beneficial effects of human milk on infant health. PMID- 23028203 TI - Therapeutic interventions against inflammatory and angiogenic mediators in proliferative diabetic retinopathy. AB - The global prevalence of diabetes is estimated to be 336 million people, with diabetic complications contributing to significant worldwide morbidity and mortality. Diabetic retinopathy results from cumulative microvascular damage to the retina and inflammation is recognized as a critical driver of this disease process. This paper outlines the pathophysiology leading to proliferative diabetic retinopathy and highlights many of the inflammatory, angiogenic, and cytokine mediators implicated in the development and progression of this disease. We focus a detailed discussion on the current targeted therapeutic interventions used to treat diabetic retinopathy. PMID- 23028204 TI - Usefulness of the vitreous fluid analysis in the translational research of diabetic retinopathy. AB - Diabetic retinopathy (DR) is the major cause of acquired blindness in working-age adults. Current treatments for DR (laser photocoagulation, intravitreal corticosteroids, intravitreal antivascular endothelial growth factor (VEGF) agents, and vitreo-retinal surgery) are applicable only at advanced stages of the disease and are associated with significant adverse effects. Therefore, new pharmacological treatments for the early stages of the disease are needed. Vitreous fluid obtained from diabetic patients undergoing vitreoretinal surgery is currently used to explore the events that are taking place in the retina for clinical research. However, several confounding factors such as vitreous haemorrhage and concentration of vitreous proteins should be considered in the analysis of the results. In this paper we will focus on the vitreous fluid as a tool for exploring the mediators of DR and in particular the molecules related to inflammatory pathways. In addition, their role in the pathogenesis of DR will be discussed. The usefulness of new technologies such as flow cytometry and proteomics in identifying new candidates involved in the inflammatory process that occurs in DR will be overviewed. Finally, a more personalized treatment based on vitreous fluid analysis aiming to reduce the burden associated with DR is suggested. PMID- 23028206 TI - Stability of Polyphenols Epigallocatechin Gallate and Pentagalloyl Glucose in a Simulated Digestive System. AB - Polyphenols found in foods and beverages are under intense scrutiny for their potential beneficial effects on human health. We examined the stability of two bioactive polyphenols, epigallocatechin-O-gallate (EGCg) and 1,2,3,4,6-penta-O galloyl-beta-D-glucopyranose (PGG), in a model digestive system at low oxygen tension with and without added digestive components and foods. Both compounds were stable at pH values of 5-6 and below, indicating gastric stability. Both compounds decomposed at pH 7.0. PGG was stabilized in a model system containing pepsin, pancreatin, bile and lipase, and/or baby food, but was not stabilized by dry cereal. EGCg was not stabilized by the addition of any biomolecule. The effects of polyphenols on human health should be evaluated in the context of their stability in the digestive tract with and without added digestive components and/or food. PMID- 23028205 TI - Systemic treatment of vitreous inflammation. AB - Non infectious vitreous inflammation is often vision threatening and can be associated with potentially life-threatening systemic conditions. Treatment is often challenging as it involves systemic medications that can be associated with adverse effects. The classes of drugs are ever expanding and include corticosteroids, antimetabolites, alkylating agents, T-cell and calcineurin agents, biologic agents, and interferons. Each class of systemic therapy for non infectious vitreous inflammation is reviewed. We discuss the mechanisms of action, usual clinical dosages, the specific conditions that are treated, the adverse effects, and usual course of treatment for each class of therapy. PMID- 23028207 TI - An N-glycosylation Analysis of Human Alpha-2-Macroglobulin Using an Integrated Approach. AB - Assignment of glycosylation sites and site microheterogeneity is of both biological and clinical significance. Herein, the detailed N-glycosylation pattern of human serum alpha-2-macroglobulin was studied using an integrative approach, including permethylation of N-glycans, collision induced dissociation (CID) and electron transfer dissociation (ETD) of chymotryptic N-glycopeptides, and partial deglycosylation of chymotryptic N-glycopeptides with endo-beta-N acetylglucosaminidase F3 (Endo F3). Three N-glycosylation sites were found to be occupied by four biantennary complex type N-glycans using N-glycan analysis and the ETD/CID method. Endo F3 assisted mass spectrometric analysis yielded five N glycosylation sites with and without core fucosylation. In total, six out of eight potential N-glycosylation sites were identified using this approach. This integrative approach was performed using only 10 MUL of human serum for both N glycosylation site assignment and site microheterogeneity determination. PMID- 23028208 TI - Multi-domain, Higher Order Level Set Scheme for 3D Image Segmentation on the GPU. AB - Level set method based segmentation provides an efficient tool for topological and geometrical shape handling. Conventional level set surfaces are only C(0) continuous since the level set evolution involves linear interpolation to compute derivatives. Bajaj et al. present a higher order method to evaluate level set surfaces that are C(2) continuous, but are slow due to high computational burden. In this paper, we provide a higher order GPU based solver for fast and efficient segmentation of large volumetric images. We also extend the higher order method to multi-domain segmentation. Our streaming solver is efficient in memory usage. PMID- 23028209 TI - Exposure to mebendazole and pyrvinium during pregnancy: a Danish nationwide cohort study. AB - PURPOSE: Families with children are frequently exposed to pinworm infection and treatment involves the whole family. Information on consequences of exposure during, pregnancy is limited. The aim of this study was to investigate the exposure to pyrvinium and mebendazole before, during, and after pregnancy in a Danish nationwide cohort. METHODS: From nationwide administrative registers, we identified 718,900 births in Denmark between January 1997 and December 2007 as well as maternal prescription data of anthelmintics and maternal characteristics. Redemption of a prescription for pyrvinium or mebendazole was used to identify exposure. RESULTS: 4715 women redeemed a prescription for pyrvinium or mebendazole during pregnancy; 1606 for pyrvinium, 2575 for mebendazole, and 534 for both drugs. Having >2 children compared to having no previous children was associated with exposure to pyrvinium (OR: 7.1, 95% CI: 5.8-8.7) and mebendazole (OR: 20.8, 95% CI: 17.3-24.9). CONCLUSION: 4715 pregnant women redeemed a prescription for either mebendazole or pyrvinium. We believe the exposure to be even higher since pyrvinium is also sold over-the-counter. Limited information on birth outcomes is available at present time, and considering the number of exposed pregnancies, we recommend that studies are to be undertaken to assess the safety of pyrvinium and mebendazole during pregnancy. PMID- 23028210 TI - Robot-Assisted Needle Steering. AB - Needle insertion is a critical aspect of many medical treatments, diagnostic methods, and scientific studies, and is considered to be one of the simplest and most minimally invasive medical procedures. Robot-assisted needle steering has the potential to improve the effectiveness of existing medical procedures and enable new ones by allowing increased accuracy through more dexterous control of the needle tip path and acquisition of targets not accessible by straight-line trajectories. In this article, we describe a robot-assisted needle steering system that uses three integrated controllers: a motion planner concerned with guiding the needle around obstacles to a target in a desired plane, a planar controller that maintains the needle in the desired plane, and a torsion compensator that controls the needle tip orientation about the axis of the needle shaft. Experimental results from steering an asymmetric-tip needle in artificial tissue demonstrate the effectiveness of the system and its sensitivity to various environmental and control parameters. In addition, we show an example of needle steering in ex vivo biological tissue to accomplish a clinically relevant task, and highlight challenges of practical needle steering implementation. PMID- 23028211 TI - Direct patterning of coplanar polyethylene glycol alkylsilane monolayers by deep ultraviolet photolithography as a general method for high fidelity, long-term cell patterning and culture. AB - This manuscript details a general method for patterning coplanar alkylsilane monolayers using deep-ultraviolet photolithography that has broad application for high fidelity patterning of cells of varying phenotype in long-term cultures. A polyethylene glycol monolayer was formed on a silica substrate and then patterned using 193 nm light from an ArF excimer laser. The regions of photoablation were then rederivatized with (3-trimethoxysilyl propyl) diethyltriamine (DETA), yielding high contrast cytophilic islands that promoted cell adhesion and growth. Rat hippocampal neurons, motoneurons, and myoblasts were then cultured in a defined, serum-free medium on the patterned surfaces for periods in excess of 40 days. This approach has been shown to be useful as a general method for the long term culture of multiple cell types in highly defined spatial patterns and can be used for supporting complex cocultures for creating in vitro models for biological systems. PMID- 23028212 TI - Rapid serial prototyping of magnet-tipped attonewton-sensitivity cantilevers by focused ion beam manipulation. AB - The authors report a method for rapidly prototyping attonewton-sensitivity cantilevers with custom-fabricated tips and illustrate the method by preparing tips consisting of a magnetic nanorod overhanging the leading edge of the cantilevers. Micron-long nickel nanorods with widths of 120-220 nm were fabricated on silicon chips by electron beam lithography, deposition, and lift off. Each silicon chip, with its integral nanomagnet, was attached serially to a custom-fabricated attonewton-sensitivity cantilever using focused ion beam manipulation. The magnetic nanorod tips were prepared with and without an alumina capping layer, and the minimum detectable force and tip magnetic moment of the resulting cantilevers was characterized by cantilever magnetometry. The results indicate that this serial but high-yield approach is an effective way to rapidly prepare and characterize magnetic tips for the proposed single-electron-spin and single-proton magnetic resonance imaging experiments. The approach also represents a versatile route for affixing essentially any vacuum-compatible sample to the leading edge of an attonewton-sensitivity cantilever. PMID- 23028213 TI - Adding thiazide to a rennin-angiotensin blocker regimen to improve left ventricular relaxation in diabetes and nondiabetes patients with hypertension. AB - The urinary albumin to creatinine ratio (UACR) is an independent predictor of outcomes in patients with diastolic dysfunction. Thus, we investigated the relationship between diastolic dysfunction, UACR, and diabetes mellitus (DM) in the EDEN study. We investigated the effect of switching from an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) to a combination of losartan and hydrochlorothiazide on left ventricular (LV) relaxation in patients with hypertension and diastolic dysfunction. We enrolled 106 patients with and 265 patients without DM. All patients had diastolic dysfunction and had not achieved their treatment goals with an ACEi or ARB. The measurements of e' velocity and E/e' ratio was performed with echocardiography as markers of LV diastolic function. We switched the ACEi or ARB to losartan/hydrochlorothiazide and followed these patients for 24 weeks. UACR was decreased in patients with DM (123.4 +/- 288.4 to 66.5 +/- 169.2 mg/g creatinine; P = 0.0024), but not in patients without DM (51.2 +/- 181.8 to 39.2 +/- 247.9 mg/g creatinine; P = 0.1051). Among DM patients, there was a significant relationship between changes in UACR and changes in e' velocity (r = -0.144; P = 0.0257) and between changes in estimated glomerular filtration rate and changes in the E/e' ratio (r = -0.130; P = 0.0436). Among patients without DM, there was a significant relationship between changes in high-sensitivity C-reactive protein (hs-CRP) and changes in E/e' (r = 0.205; P = 0.0010). Multivariate analysis demonstrated changes in hemoglobin A(1c) levels as one of the determinants of change of e' and E/e' in patients with DM, whereas hs-CRP was the determinant of change of e' among patients without DM. These data suggest that improvement in LV diastolic function is associated with an improvement of DM and a concomitant reduction in UACR among DM patients, and with a reduction of hs-CRP in patients without DM when thiazide is added to a renin-angiotensin blocker treatment regimen. PMID- 23028214 TI - Differentiation of human stem cells is promoted by amphiphilic pluronic block copolymers. AB - Stem cell usage provides novel avenues of tissue regeneration and therapeutics across disciplines. Apart from ethical considerations, the selection and amplification of donor stem cells remain a challenge. Various biopolymers with a wide range of properties have been used extensively to deliver biomolecules such as drugs, growth factors and nucleic acids, as well as to provide biomimetic surface for cellular adhesion. Using human tooth germ stem cells with high proliferation and transformation capacity, we have investigated a range of biopolymers to assess their potential for tissue engineering. Tolerability, toxicity, and their ability to direct differentiation were evaluated. The majority of pluronics, consisting of both hydrophilic and hydrophobic poly(ethylene oxide) chains, either exerted cytotoxicity or had no significant effect on human tooth germ stem cells; whereas F68 increased the multi-potency of stem cells, and efficiently transformed them into osteogenic, chondrogenic, and adipogenic tissues. The data suggest that differentiation and maturation of stem cells can be promoted by selecting the appropriate mechanical and chemical properties of polymers. It has been shown for the first time that F68, with its unique molecular characteristics, has a great potential to increase the differentiation of cells, which may lead to the development of new tissue engineering strategies in regenerative medicine. PMID- 23028215 TI - Influence of charge on FITC-BSA-loaded chondroitin sulfate-chitosan nanoparticles upon cell uptake in human Caco-2 cell monolayers. AB - BACKGROUND AND METHODS: Chondroitin sulfate-chitosan (ChS-CS) nanoparticles and positively and negatively charged fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA)-loaded ChS-CS nanoparticles were prepared and characterized. The properties of ChS-CS nanoparticles, including cellular uptake, cytotoxicity, and transepithelial transport, as well as findings on field emission-scanning electron microscopy, transmission electron microscopy, and confocal laser scanning microscopy were evaluated in human epithelial colorectal adenocarcinoma (Caco-2) fibroblasts. ChS-CS nanoparticles with a mean particle size of 250 nm and zeta potentials ranging from -30 to +18 mV were prepared using an ionic gelation method. RESULTS: Standard cell viability assays demonstrated that cells incubated with ChS-CS and FITC-BSA-loaded ChS-CS nanoparticles remained more than 95% viable at particle concentrations up to 0.1 mg/mL. Endocytosis of nanoparticles was confirmed by confocal laser scanning microscopy and measured by flow cytometry. Ex vivo transepithelial transport studies using Caco-2 cells indicated that the nanoparticles were effectively transported into Caco-2 cells via endocytosis. The uptake of positively charged FITC-BSA-loaded ChS-CS nanoparticles across the epithelial membrane was more efficient than that of the negatively charged nanoparticles. CONCLUSION: The ChS-CS nanoparticles fabricated in this study were effectively endocytosed by Caco-2 fibroblasts without significant cytotoxicity at high nanoparticle concentrations. ChS-CS nanoparticles represent a potential novel delivery system for the transport of hydrophilic macromolecules. PMID- 23028216 TI - In vitro and in vivo studies of surface-structured implants for bone formation. AB - BACKGROUND AND METHODS: Micronanoscale topologies play an important role in implant osteointegration and determine the success of an implant. We investigated the effect of three different implant surface topologies on osteoblast response and bone regeneration. In this study, implants with nanotubes and micropores were used, and implants with flat surfaces were used as the control group. RESULTS: Our in vitro studies showed that the nanostructured topologies improved the proliferation, differentiation, and development of the osteoblastic phenotype. Histological analysis further revealed that the nanotopology increased cell aggregation at the implant-tissue interfaces and enhanced bone-forming ability. Pushout testing indicated that the nanostructured topology greatly increased the bone-implant interfacial strength within 4 weeks of implantation. CONCLUSION: Nanotopography may improve regeneration of bone tissue and shows promise for dental implant applications. PMID- 23028217 TI - Characterization of drug-release kinetics in trabecular bone from titania nanotube implants. AB - PURPOSE: The aim of this study was to investigate the application of the three dimensional bone bioreactor for studying drug-release kinetics and distribution of drugs in the ex vivo cancellous bone environment, and to demonstrate the application of nanoengineered titanium (Ti) wires generated with titania nanotube (TNT) arrays as drug-releasing implants for local drug delivery METHODS: Nanoengineered Ti wires covered with a layer of TNT arrays implanted in bone were used as a drug-releasing implant. Viable bovine trabecular bone was used as the ex vivo bone substrate embedded with the implants and placed in the bone reactor. A hydrophilic fluorescent dye (rhodamine B) was used as the model drug, loaded inside the TNT-Ti implants, to monitor drug release and transport in trabecular bone. The distribution of released model drug in the bone was monitored throughout the bone structure, and concentration profiles at different vertical (0-5 mm) and horizontal (0-10 mm) distances from the implant surface were obtained at a range of release times from 1 hour to 5 days. RESULTS: Scanning electron microscopy confirmed that well-ordered, vertically aligned nanotube arrays were formed on the surface of prepared TNT-Ti wires. Thermogravimetric analysis proved loading of the model drug and fluorescence spectroscopy was used to show drug-release characteristics in-vitro. The drug release from implants inserted into bone ex vivo showed a consistent gradual release of model drug from the TNT-Ti implants, with a characteristic three-dimensional distribution into the surrounding bone, over a period of 5 days. The parameters including the flow rate of bone culture medium, differences in trabecular microarchitecture between bone samples, and mechanical loading were found to have the most significant influence on drug distribution in the bone. CONCLUSION: These results demonstrate the utility of the ZetosTM system for ex vivo drug-release studies in bone, which can be applied to optimize the delivery of specific therapies and to assist in the design of new drug delivery systems. This method has the potential to provide new knowledge to understand drug distribution in the bone environment and to considerably improve existing technologies for local administration in bone, including solving some critical problems in bone therapy and orthopedic implants. PMID- 23028218 TI - Injectable hydrogel as stem cell scaffolds from the thermosensitive terpolymer of NIPAAm/AAc/HEMAPCL. AB - A series of biodegradable thermosensitive copolymers was synthesized by free radical polymerization with N-isopropylacrylamide (NIPAAm), acrylic acid (AAc) and macromer 2-hydroxylethyl methacrylate-poly(E-caprolactone) (HEMAPCL). The structure and composition of the obtained terpolymers were confirmed by proton nuclear magnetic resonance spectroscopy, while their molecular weight was measured using gel permeation chromatography. The copolymers were dissolved in phosphate-buffered saline (PBS) solution (pH = 7.4) with different concentrations to prepare hydrogels. The lower critical solution temperature (LCST), cloud point, and rheological property of the hydrogels were determined by differential scanning calorimetry, ultraviolet-visible spectrometry, and rotational rheometry, respectively. It was found that LCST of the hydrogel increased significantly with the increasing NIPAAm content, and hydrogel with higher AAc/HEMAPCL ratio exhibited better storage modulus, water content, and injectability. The hydrogels were formed by maintaining the copolymer solution at 37 degrees C. The degradation experiment on the formed hydrogels was conducted in PBS solution for 2 weeks and demonstrated a less than 20% weight loss. Scanning electron microscopy was also used to study the morphology of the hydrogel. The copolymer with NIPAAm/AAc/HEMAPCL ratio of 88:9.6:2.4 was bioconjugated with type I collagen for the purpose of biocompatibility enhancement. In-vitro cytotoxicity of the hydrogels both with and without collagen was also addressed. PMID- 23028219 TI - Preparation of a nanoscale baohuoside I-phospholipid complex and determination of its absorption: in vivo and in vitro evaluations. AB - BACKGROUND: Baohuoside I is a potential anticancer drug for a variety of malignancies and has been approved for in vitro use. However, baohuoside I has very poor oral absorption. METHODS: In the present study, we prepared baohuoside I-phospholipid complexes of different diameters and determined their physicochemical properties using transmission electron microscopy, ultraviolet spectroscopy, and differential scanning calorimetry. The in vitro absorption of baohuoside I and baohuoside I-phospholipid complexes of different sizes were compared using the Caco-2 cell culture model, and subsequently, the bioavailability of baohuosidel and its complexes were estimated in vivo. RESULTS: Compared with the large-sized phospholipid complexes, a nanoscale phospholipid complex improved the oral bioavailability of baohuoside I. In addition, our results suggest that the smaller the particle size, the faster the complexes crossed the Caco-2 monolayer and the faster they were resorbed after oral administration in rats. The relative oral bioavailability of a nanoscale size 81 +/- 10 nm baohuoside I-phospholipid complex (area under the concentration-time curve [AUC](0-infinity)) was 342%, while that of baohuoside I and a 227.3 +/- 65.2 MUm baohuoside I-phospholipid complex was 165%. CONCLUSION: We enhanced the oral bioavailability of baohuoside I by reducing the particle size of the phospholipid complex to the nanometer range, thereby improving its potential for clinical application. PMID- 23028220 TI - Influence of polymer size, liposomal composition, surface charge, and temperature on the permeability of pH-sensitive liposomes containing lipid-anchored poly(2 ethylacrylic acid). AB - BACKGROUND: Liposomes containing pH-sensitive polymers are promising candidates for the treatment of tumors and localized infection. This study aimed to identify parameters influencing the extent of contents release from poly(ethylacrylic acid) (PEAA) vesicles, focusing on the effects of polymer size, lipid composition, vesicle surface charge, and temperature. METHODS: Anchored lipid pH sensitive PEAA was synthesized using PEAA with a molecular weight of 8.4 kDa. PEAA vesicles were prepared by insertion of the lipid-anchored PEAA into preformed large unilamellar vesicles. The preformed liposomes were manipulated by varying the phosphocholine and cholesterol content, and by adding negative or positive charges to the liposomes. A calcein release assay was used to evaluate the effects of polymer size, liposome composition, surface charge, and temperature on liposomal permeability. RESULTS: The release efficiency of the calcein-entrapped vesicles was found to be dependent on the PEAA polymer size. PEAA vesicles containing a phosphatidylcholine to cholesterol ratio of 60:40 (mol/mol) released more than 80% of their calcein content when the molecular weight of PEAA was larger than 8.4 kDa. Therefore, the same-sized polymer of 8.4 kDa was used for the rest of study. The calcein release potential was found to decrease as the percentage of cholesterol increased and with an increase in the phosphocholine acyl chain length (DMPC DPPC DSPC). Negatively charged and neutral vesicles released similar amounts of calcein, whereas positively charged liposomes released a significant amount of their contents. pH-sensitive release was dependent on temperature. Dramatic content release was observed at higher temperatures. CONCLUSION: The observed synergistic effect of pH and temperature on release of the contents of PEAA vesicles suggests that this pH-sensitive liposome might be a good candidate for intracellular drug delivery in the treatment of tumors or localized infection. PMID- 23028221 TI - Indomethacin-loaded lipid-core nanocapsules reduce the damage triggered by Abeta1 42 in Alzheimer's disease models. AB - Neuroinflammation, characterized by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of Alzheimer's disease (AD). Epidemiological studies suggesting that nonsteroidal anti-inflammatory drugs decrease the risk of developing AD have encouraged further studies elucidating the role of inflammation in AD. Nanoparticles have become an important focus of neurotherapeutic research because they are an especially effective form of drug delivery. Here, we investigate the potential protective effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNCs) against cell damage and neuroinflammation induced by amyloid beta (Abeta)1-42 in AD models. Our results show that IndOH-LNCs attenuated Abeta-induced cell death and were able to block the neuroinflammation triggered by Abeta1-42 in organotypic hippocampal cultures. Additionally, IndOH-LNC treatment was able to increase interleukin-10 release and decrease glial activation and c-jun N terminal kinase phosphorylation. As a model of Abeta-induced neurotoxicity in vivo, animals received a single intracerebroventricular injection of Abeta1-42 (1 nmol/site), and 1 day after Abeta1-42 infusion, they were administered either free IndOH or IndOH-LNCs (1 mg/kg, intraperitoneally) for 14 days. Only the treatment with IndOH-LNCs significantly attenuated the impairment of this behavior triggered by intracerebroventricular injection of Abeta1-42. Further, treatment with IndOH-LNCs was able to block the decreased synaptophysin levels induced by Abeta1-42 and suppress glial and microglial activation. These findings might be explained by the increase of IndOH concentration in brain tissue attained using drug-loaded lipid-core NCs. All these findings support the idea that blockage of neuroinflammation triggered by Abeta is involved in the neuroprotective effects of IndOH-LNCs. These data provide strong evidence that IndOH-LNC treatment may represent a promising approach for treating AD. PMID- 23028222 TI - Liposomes and nanotechnology in drug development: focus on oncotargets. AB - Nanotechnology is the development of an engineered device at the atomic, molecular, and macromolecular level in the nanometer range. Advances in nanotechnology have proven beneficial in therapeutic fields such as drug-delivery and gene/protein delivery. Antigen delivery systems are important for inducing and modifying immune responses. In cellular immunity, cytotoxic T lymphocytes (CTLs) are important in the host defense against tumors. Key to the development of CTL-inducible vaccines is the ability to deliver antigens to antigen presenting cells efficiently and to induce the subsequent activation of T cell mediated immunity without adjuvants, as they can induce excessive inflammation leading to systemic febrile disease. Since expression and cloning methods for tumor-associated antigens have been reported, cancer vaccines that induce effective cell immunity may be promising therapeutic candidates, but Th2 cells are undesirable for use in cancer immunotherapy. Peptide vaccines have immunological and economic advantages as cancer vaccines because CTL epitope peptides from tumor-associated antigens have high antigen-specificity. However, cancer vaccines have had limited effectiveness in clinical responses due to the ability of cancer cells to "escape" from cancer immunity and a low efficiency of antigen-specific CTL induction due to immunogenic-free synthetic peptides. In contrast, carbohydrate-decorated particles such as carbohydrate-coated liposomes with encapsulated antigens might be more suitable as antigen delivery vehicles to antigen-presenting cells. Oligomannose-coated liposomes (OML) can eliminate established tumors in mouse cancer models. In addition, OMLs with an encased antigen can induce antigen-specific CTLs from peripheral blood mononuclear cells obtained from patients. Feasibility studies of OML-based vaccines have revealed their potential for clinical use as vaccines for diseases where CTLs act as effector cells. Furthermore, use of the hepatitis B core particle, in which tumor antigen epitopes are set, has consistently been shown to induce strong CTL responses without the use of an adjuvant. Thus, nanoparticles may provide a new prophylactic strategy for infectious disease and therapeutic approaches for cancer via the induction of T-cell immunity. PMID- 23028223 TI - A sandwich-type DNA electrochemical biosensor for hairpin-stem-loop structure based on multistep temperature-controlling method. AB - A highly sensitive and selective method for amplified electrochemical detection for hairpin-stem-loop structured target sequences was developed based on the temperature regulation of DNA hybrids on a sandwich-type electrochemical DNA sensor. Multistep hybridization was applied to promote the hybridization efficiency of each section of sandwich structure. The results showed that both multistep and temperature-controlling hybridization techniques were both especially made to fabricate the sensor for the tendency of internal hybridization of target gene sequences. This strategy provides significantly enhanced hybridization efficiency and sequence specificity of electrochemical detection. PMID- 23028224 TI - Amphiphilic graft copolymer based on poly(styrene-co-maleic anhydride) with low molecular weight polyethylenimine for efficient gene delivery. AB - BACKGROUND AND METHODS: A new amphiphilic comb-shaped copolymer (SP) was synthesized by conjugating poly(styrene-co-maleic anhydride) with low molecular weight polyethyleneimine for gene delivery. Fourier transform infrared spectrum, (1)H nuclear magnetic resonance, and gel permeation chromatography were used to characterize the graft copolymer. RESULTS: The buffering capability of SP was similar to that of polyethyleneimine within the endosomal pH range. The copolymer could condense DNA effectively to form complexes with a positive charge (13-30 mV) and a small particle size (130-200 nm) at N/P ratios between 5 and 20, and protect DNA from degradation by DNase I. In addition, SP showed much lower cytotoxicity than polyethyleneimine 25,000. Importantly, the gene transfection activity and cellular uptake of SP-DNA complexes were all markedly higher than that of complexes of polyethyleneimine 25,000 and DNA in MCF-7 and MCF-7/ADR cell lines. CONCLUSION: This work highlights the promise of SP as a safe and efficient synthetic vector for DNA delivery. PMID- 23028225 TI - Biocompatibility of magnetic Fe3O4 nanoparticles and their cytotoxic effect on MCF-7 cells. AB - BACKGROUND: The objective of this study was to evaluate the synthesis and biocompatibility of Fe3O4 nanoparticles and investigate their therapeutic effects when combined with magnetic fluid hyperthermia on cultured MCF-7 cancer cells. METHODS: Magnetic Fe3O4 nanoparticles were prepared using a coprecipitation method. The appearance, structure, phase composition, functional groups, surface charge, magnetic susceptibility, and release in vitro were characterized by transmission electron microscopy, x-ray diffraction, scanning electron microscopy energy dispersive x-ray spectroscopy, and a vibrating sample magnetometer. Blood toxicity, in vitro toxicity, and genotoxicity were investigated. Therapeutic effects were evaluated by MTT [3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide] and flow cytometry assays. RESULTS: Transmission electron microscopy revealed that the shapes of the Fe3O4 nanoparticles were approximately spherical, with diameters of about 26.1 +/- 5.2 nm. Only the spinel phase was indicated in a comparison of the x-ray diffraction data with Joint Corporation of Powder Diffraction Standards (JCPDS) X-ray powder diffraction files. The O-to-Fe ratio of the Fe3O4was determined by scanning electron microscopy-energy dispersive x-ray spectroscopy elemental analysis, and approximated pure Fe3O4. The vibrating sample magnetometer hysteresis loop suggested that the Fe3O4nanoparticles were superparamagnetic at room temperature. MTT experiments showed that the toxicity of the material in mouse fibroblast (L-929) cell lines was between Grade 0 to Grade 1, and that the material lacked hemolysis activity. The acute toxicity (LD(50)) was 8.39 g/kg. Micronucleus testing showed no genotoxic effects. Pathomorphology and blood biochemistry testing demonstrated that the Fe3O4 nanoparticles had no effect on the main organs and blood biochemistry in a rabbit model. MTT and flow cytometry assays revealed that Fe3O4 nano magnetofluid thermotherapy inhibited MCF-7 cell proliferation, and its inhibitory effect was dose-dependent according to the Fe3O4 nano magnetofluid concentration. CONCLUSION: The Fe3O4 nanoparticles prepared in this study have good biocompatibility and are suitable for further application in tumor hyperthermia. PMID- 23028226 TI - A silica-based pH-sensitive nanomatrix system improves the oral absorption and efficacy of incretin hormone glucagon-like peptide-1. AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) (7-36) is a peptide incretin hormone released from the endocrine L-cells of the intestinal mucosa with unique antidiabetic potential. Due to low absorption efficiency and instability in the gastrointestinal tract, the introduction of orally active GLP-1 is a large challenge. Here we developed a novel silica-based pH-sensitive nanomatrix of GLP 1 (SPN-GLP-1) in order to provide a strategy for oral peptide delivery. METHODS: SPN-GLP-1 composed of silica nanoparticles and pH-sensitive Eudragit((r)) was prepared and characterized by dynamic light scattering, scanning electron microscope, transmission electron microscope, high-performance liquid chromatography, surface analysis, drug release, and so on. Its permeability across the Caco-2 cell monolayer and intestinal mucosa, proteolytic stability against the intestinal enzymes, pharmacokinetics, hypoglycemic effect in the intraperitoneal glucose tolerance test (IPGTT), and primary toxicity were then evaluated. RESULTS: It was indicated that the nanomatrix system obtained had a unique nanoscale structure and pH-sensitivity in drug release. It displayed a five-fold intestinal mucosa permeability and significantly higher proteolytic stability compared to native GLP-1 (P < 0.001). A longer half-life was observed after oral administration of SPN-GLP-1, and its relative bioavailability was 35.67% in comparison to intraperitoneal GLP-1. Oral delivery of SPN-GLP-1 significantly reduced the blood glucose level and its hypoglycemic effect over intraperitoneal GLP-1 reached 77%. There was no evident toxicity of SPN-GLP-1 found from both animal status and histochemical analysis of gastrointestinal tissues. CONCLUSION: The silica-based pH-sensitive nanomatrix designed and prepared here might be considered as a potential oral delivery system not only for GLP-1, but also for other peptide or macromolecular drugs. PMID- 23028228 TI - Reducing serum cholesterol levels in women. PMID- 23028227 TI - A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer. AB - Pancreatic cancer is a highly lethal disease with a 5-year survival rate less than 5% due to the lack of an early diagnosis method and effective therapy. To provide a novel early diagnostic method and targeted therapy for pancreatic cancer, a multifunctional nanoimmunoliposome with high loading of ultrasmall superparamagnetic iron oxides (USPIOs) and doxorubicin (DOX) was prepared by transient binding and reverse-phase evaporation method, and was conjugated with anti-mesothelin monoclonal antibody by post-insertion method to target anti mesothelin-overexpressed pancreatic cancer cells. The in vitro and in vivo properties of this anti-mesothelin antibody-conjugated PEGlyated liposomal DOX and USPIOs (M-PLDU; and PEGlyated nanoimmunoliposome without antibody conjugation [PLDU]) were evaluated both in human pancreatic cancer cell line Panc-1 cell and in a pancreatic cancer xenograft animal model. Results showed that M-PLDUs were spherical and uniform with a diameter about ~180 nm, with a zeta potential of about -28~-30 mV, and had good efficacy encapsulating DOX and USPIOs. The in vitro study demonstrated that M-PLDUs possessed good magnetic resonance imaging (MRI) capability with a transverse relaxivity (r(2)) of about 58.5 mM(-1) . s( 1). Confocal microscopy showed more efficient uptake of M-PLDU in Panc-1 cells by antibody-mediated targeting. Methyl thiazolyl tetrazolium assay results showed significant inhibitory effect of M-PLDU against Panc-1 cells (half-maximal inhibitory concentration, 1.95 MUM). The in vivo imaging study showed that the tumor signal intensity (SI) dropped significantly about 4 hours after intravenous injection of M-PLDU. The decrease in tumor SI induced by M-PLDUs (DeltaSI = 145.98 +/- 20.45) or PLDUs (DeltaSI = 75.69 +/- 14.53) was much more significant than that by free USPIOs (DeltaSI = 42.78 +/- 22.12; P < 0.01). The in vivo antitumor study demonstrated that compared with FD (free DOX) and PLDU, M-PLDU possessed higher inhibitory effect on tumor growth and the tissue distribution assay further proved that M-PLDUs could selectively accumulate in the tumor xenograft. These results indicated that M-PLDU not only well retained the inherent MRI capability of USPIOs, but significantly improved the targeting distribution of USPIOs and therapeutic agents in pancreatic tumor tissues. They may serve as a promising theranostic nanomedicine not only for early detection but also for MRI-monitored targeting therapy of human pancreatic cancer. PMID- 23028229 TI - Oxybutynin reduces sweating in depressed patients treated with sertraline: a double-blind, placebo-controlled, clinical study. AB - BACKGROUND: Selective serotonin reuptake inhibitors are primarily used in the pharmacological treatment of patients experiencing a major depressive disorder. However, one of the common unwanted effects is excessive sweating or hyperhidrosis. Oxybutynin is an anticholinergic medication which reduces sweating. The aim of this double-blind study was to examine the effect of administration of oxybutynin on subjective sweating in patients treated with sertraline. METHODS: A total of 140 patients experiencing a major depressive disorder (mean age 37.69 +/- 10.44 years, 86 females [61.4%]) treated with sertraline (mean dose 83 mg/day) were consecutively enrolled in the study, and all reported excessive sweating as a side effect. Thereafter, the patients were randomly assigned to either an oxybutynin 5 mg/day group or to a placebo group. At the beginning and end of the 2-week trial, the patients completed questionnaires related to sweating and medication-related side effects. RESULTS: Over time, subjective sweating reduced significantly in the treatment group as compared with the control group. Oxybutynin-induced side effects were uncommon. Relative to male patients, female patients reported less subjective sweating. CONCLUSION: Administration of oxybutynin successfully reduced excessive sweating in patients experiencing a major depressive disorder and treated with sertraline. However, possible gender effects should be taken into account. PMID- 23028230 TI - Cost-effectiveness analysis of HIV treatment in the clinical practice of a public hospital in northern Italy. AB - INTRODUCTION: We carried out an economic analysis to assess the cost effectiveness of highly active antiretroviral therapy (HAART) regimens in Italy for the management of human immunodeficiency virus (HIV)-infected patients according to clinical practice in the Infectious Diseases Department of "L. Sacco" Hospital, Milan, Italy. PATIENTS AND METHODS: The incremental cost effectiveness analysis was completed by means of a Markov model. Through a decision-analytic approach, this enabled us to compare the studied antiretroviral regimens. The model considered a population of adult HIV subjects who received HAART therapy for the first time according to clinical practice in the Infectious Diseases Department of "L. Sacco" Hospital, Milan. Data were investigated from the standpoint of the Lombardy Regional Health Service. We considered the following outcome measures: quality-adjusted life-years (QALYs), and direct health costs calculated for the years 2008 and 2009. The time horizon adopted in the model was 2 years. RESULTS: The model revealed that, in terms of cost per gained QALY, the tenofovir disoproxil fumarate + emtricitabine + efavirenz (TDF+FTC+EFV) once-a-day treatment strategy seems to be the most cost-effective therapeutic choice (?34,965); the incremental cost-effectiveness ratio (ICER) values for the remaining strategies ranged from ?53,000 to around ?62,000 per QALY. The validity of the base case scenario was then confirmed by means of a sensitivity analysis on the main variables. CONCLUSION: The TDF+FTC+EFV treatment strategy (TDF/FTC+EFV fixed-dose combination then switched to single-tablet regimen [STR]) in this setting is the most cost-effective treatment strategy compared with the other therapeutic regimens. The ICER value for the TDF+FTC+EFV once-a-day then switched to STR treatment was lower than the internationally generally accepted threshold value of ?50,000. The developed model is a tool for policy makers and health care professionals for creating short- and long-term cost projections, with the aim of assessing their impact on the available budgets for HIV patients. PMID- 23028231 TI - Glimepiride: evidence-based facts, trends, and observations (GIFTS). [corrected]. AB - Type 2 diabetes mellitus is characterized by insulin resistance and progressive beta cell failure; therefore, beta cell secretagogues are useful for achieving sufficient glycemic control. Glimepiride is a second-generation sulfonylurea that stimulates pancreatic beta cells to release insulin. Additionally, is has been shown to work via several extra pancreatic mechanisms. It is administered as monotherapy in patients with type 2 diabetes mellitus in whom glycemic control is not achieved by dietary and lifestyle modifications. It can also be combined with other antihyperglycemic agents, including metformin and insulin, in patients who are not adequately controlled by sulfonylureas alone. The effective dosage range is 1 to 8 mg/day; however, there is no significant difference between 4 and 8 mg/day, but it should be used with caution in the elderly and in patients with renal or hepatic disease. In clinical studies, glimepiride was generally associated with lower risk of hypoglycemia and less weight gain compared to other sulfonylureas. Glimepiride use may be safer in patients with cardiovascular disease because of its lack of detrimental effects on ischemic preconditioning. It is effective in reducing fasting plasma glucose, post-prandial glucose, and glycosylated hemoglobin levels and is a useful, cost-effective treatment option for managing type 2 diabetes mellitus. PMID- 23028233 TI - Calcipotriol and betamethasone dipropionate in the treatment of mild-to-moderate psoriasis: a cost-effectiveness analysis of the ointment versus gel formulation. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease with a major impact on the quality of life of affected individuals. Topical therapy has an important role in the treatment of psoriasis. Poor treatment outcomes from topical therapy regimens likely result from poor adherence and ineffective use of medication. METHODS: A cost-minimization analysis was performed with the purpose of assessing the use of a gel containing calcipotriol and betamethasone dipropionate (Dovobet((r)) gel) versus the ointment formulation (Dovobet ointment) in the treatment of psoriasis. The analysis was carried out using a Markov model with a one-year time horizon in a hypothetical cohort of patients with a Psoriasis Area and Severity Index score < 10. The model simulates different therapy adherence scenarios for the two different formulations. RESULTS: The Dovobet gel strategy allows a 5% reduction in the number of patients who could potentially be treated with more expensive therapies (biologics and conventional systemic drugs) in comparison with the Dovobet ointment strategy, with a consequent impact on costs for the National Healthcare Service. The total annual cost of Dovobet gel is about ?407.00 per patient, ie, 19% less that the total cost of about ?500.00 of the Dovobet ointment strategy. The base case results were then examined by sensitivity analysis and budget impact analysis to correlate the various scenarios of Dovobet gel use with cost savings to the National Healthcare Service. CONCLUSION: The Dovobet gel strategy seems more acceptable to patients, shows better overall adherence, and appears to be favorable from the pharmacoeconomic point of view than the ointment formulation for treatment of patients with mild-to-moderate psoriasis. PMID- 23028234 TI - Maintenance erlotinib in advanced nonsmall cell lung cancer: cost-effectiveness in EGFR wild-type across Europe. AB - BACKGROUND: First-line maintenance erlotinib in patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) has demonstrated significant overall survival and progression-free survival benefits compared with best supportive care plus placebo, irrespective of epidermal growth factor receptor (EGFR) status (SATURN trial). The cost-effectiveness of first-line maintenance erlotinib in the overall SATURN population has been assessed and published recently, but analyses according to EGFR mutation status have not been performed yet, which was the rationale for assessing the cost-effectiveness of first-line maintenance erlotinib specifically in EGFR wild-type metastatic NSCLC. METHODS: The incremental cost per life-year gained of first-line maintenance erlotinib compared with best supportive care in patients with EGFR wild-type stable metastatic NSCLC was assessed for five European countries (the United Kingdom, Germany, France, Spain, and Italy) with an area-under-the-curve model consisting of three health states (progression-free survival, progressive disease, death). Log-logistic survival functions were fitted to Phase III patient-level data (SATURN) to model progression-free survival and overall survival. The first-line maintenance erlotinib therapy cost (modeled for time to treatment cessation), medication cost in later lines, and cost for the treatment of adverse events were included. Deterministic and probabilistic sensitivity analyses using Monte Carlo simulation (1000 iterations) were performed. RESULTS: According to the model simulations, first-line maintenance erlotinib compared with best supportive care in EGFR wild-type stable metastatic NSCLC resulted in 4.57 months of life gained (17.82 months for erlotinib versus 13.24 months for best supportive care) and 1.14 months of life without progression gained (erlotinib 4.29 versus best supportive care 3.15), and incremental total costs of erlotinib from ?7897 (UK) to ?9580 (Germany). The corresponding mean incremental cost per life-year gained of erlotinib ranged between ?20,711 (UK) and ?25,124 (Germany). Sensitivity analyses confirmed these results. CONCLUSION: First-line erlotinib maintenance treatment is cost-effective compared with best supportive care in EGFR wild-type stable metastatic NSCLC, irrespective of the country setting. PMID- 23028232 TI - The complex regulation of TGF-beta in cardiovascular disease. AB - Transforming growth factor beta (TGF-beta1) is a pleiotropic cytokine with many and complex effects in cell and tissue physiology. This is made possible by a very complex and interwoven signaling system, whose regulation continues to be the focus of a growing line of research. This complex regulation translates to a key role in cardiovascular physiology, hemostasis, and the blood-vessel interface. In accordance with this, the TGF-beta1 pathway appears to be deregulated in related disorders, such as atherosclerotic vascular disease and myeloproliferative syndromes. It is expected that the growing amount of experimental and clinical research will yield medical advances in the applications of knowledge of the TGF-beta1 pathway to diagnosis and therapeutics. PMID- 23028235 TI - Update on triple therapy for eradication of Helicobacter pylori: current status of the art. AB - With the rising prevalence of antimicrobial resistance, the treatment success of standard triple therapy has recently declined to unacceptable levels (ie, 80% or less). Following the failure of conventional triple therapy, novel eradication regimens have been developed including sequential therapy, concomitant quadruple therapy, hybrid (dual-concomitant) therapy, bismuth-containing quadruple therapy, and a therapy with administration of N-acetylcysteine before a culture-guided antibiotic regimen. This article reviews the literature published on Helicobacter pylori eradication in the last year, focusing on the development of alternative strategies for first-, second-, and third-line rescue therapy for the eradication of H. pylori. PMID- 23028236 TI - Retrospective analysis of KRAS status in metastatic colorectal cancer patients: a single-center feasibility study. AB - BACKGROUND: The occurrence of KRAS mutations and their association with prognosis in metastatic colorectal cancer patients is not well documented in population based studies. OBJECTIVES: To examine the feasibility of identifying archived colorectal cancer specimens, and through linkage with nationwide Danish population-based databases to investigate the prevalence of KRAS mutations and their association with colorectal cancer survival. METHODS: We used the Danish Pathology Database to identify the physical location of primary (or in some cases secondary) tumor specimens from selected metastatic colorectal cancer patients referred to our hospital for palliative chemotherapy between November 1, 2008 and September 30, 2009. Routinely stored paraffin tissue blocks were obtained from the pathology archives of the originating hospital. KRAS mutation tumor status was assessed for each patient using the commercialized TheraScreen KRAS Mutation Kit. Using the unique identifier number, we linked the patients to the Danish National Registry of Patients and the Danish Civil Registration System to obtain data on date of first colorectal cancer diagnosis and follow-up status. We estimated prevalence of KRAS mutations and the 1-, 2-, and 5-year survival after colorectal cancer diagnosis using the Kaplan-Meier technique. RESULTS: We identified 106 metastatic colorectal cancer patients (64% males). All were successfully linked to the registries, and archived tumor-tissue samples were obtained and analyzed in each case. The overall prevalence of KRAS mutations was 55%, and 1-, 2-, and 5-year overall survival after colorectal cancer diagnosis was 91%, 68%, and 25%, respectively. CONCLUSION: It is feasible to use Danish population-based registries to obtain archived tissue samples from metastatic colorectal cancer patients, and to estimate prevalence of KRAS mutation and subsequently evaluate the association with colorectal cancer survival. PMID- 23028237 TI - Radiation dose reduction in CT-guided sacroiliac joint injections to levels of pulsed fluoroscopy: a comparative study with technical considerations. AB - BACKGROUND: The sacroiliac (SI) joint is frequently the primary source of low back pain. Over the past decades, a number of different SI injection techniques have been used in its diagnosis and therapy. Despite the concerns regarding exposure to radiation, image-guided injection techniques are the preferred method to achieve safe and precise intra-articular needle placement. The following study presents a comparison of radiation doses, calculated for fluoroscopy and CT guided SI joint injections in standard and low-dose protocol and presents the technical possibility of CT-guidance with maximum radiation dose reduction to levels of fluoroscopic-guidance for a precise intra-articular injection technique. OBJECTIVE: To evaluate the possibility of dose reduction in CT-guided sacroiliac joint injections to pulsed-fluoroscopy-guidance levels and to compare the doses of pulsed-fluoroscopy-, CT-guidance, and low-dose CT-guidance for intra articular SI joint injections. STUDY DESIGN: Comparative study with technical considerations. METHODS: A total of 30 CT-guided intra-articular SI joint injections were performed in January 2012 in a developed low-dose mode and the radiation doses were calculated. They were compared to 30 pulsed-fluoroscopy guided SI joint injections, which were performed in the month before, and to five injections, performed in standard CT-guided biopsy mode for spinal interventions. The statistical significance was calculated with the SPSS software using the Mann Whitney U-Test. Technical details and anatomical considerations were provided. RESULTS: A significant dose reduction of average 94.01% was achieved using the low-dose protocol for CT-guided SI joint injections. The radiation dose could be approximated to pulsed-fluoroscopy- guidance levels. CONCLUSION: Radiation dose of CT-guided SI joint injections can be decreased to levels of pulsed fluoroscopy with a precise intra-articular needle placement using the low-dose protocol. The technique is simple to perform, fast, and reproducible. PMID- 23028238 TI - NGF - the TrkA to successful pain treatment. AB - Chronic pain arising from various pathological conditions such as osteoarthritis, low back or spinal injuries, cancer, and urological chronic pelvic pain syndromes presents significant challenges in diagnosis and treatment. Specifically, since the underlying cause of these pain syndromes is unknown or heterogeneous, physicians diagnose and treat patients based on the symptoms presented. Nerve growth factor (NGF) has been recognized as an important mediator of chronic pain in many pathological conditions, and has been shown to be upregulated in a subset of individuals suffering from such pain syndromes. These findings have led to the development of anti-NGF monoclonal antibodies such as tanezumab as potentially effective therapeutics for chronic pain. Although tanezumab has reached Phase II and III clinical trials, the trials of anti-NGF antibodies were halted due to safety concerns. Some of these trials of anti-NGF treatment have had statistically significant decreases in pain, while others have yielded inconclusive results. These findings are suggestive of, though do not prove, target (NGF) neutralization in chronic pain syndromes. A biomarker-driven anti NGF clinical study layout is proposed that incorporates NGF measurements in the relevant samples before and after treatment, in addition to collecting the pain scores. This approach might not only confirm the mechanism of tanezumab's action in these chronic pain patients, but should establish NGF levels as a predictive biomarker for patients who can benefit from anti-NGF treatment, thereby creating a personalized approach to pain treatment. PMID- 23028239 TI - Optimal management of pernicious anemia. AB - Pernicious anemia (also known as Biermer's disease) is an autoimmune atrophic gastritis, predominantly of the fundus, and is responsible for a deficiency in vitamin B12 (cobalamin) due to its malabsorption. Its prevalence is 0.1% in the general population and 1.9% in subjects over the age of 60 years. Pernicious anemia represents 20%-50% of the causes of vitamin B12 deficiency in adults. Given its polymorphism and broad spectrum of clinical manifestations, pernicious anemia is a great pretender. Its diagnosis must therefore be evoked and considered in the presence of neurological and hematological manifestations of undetermined origin. Biologically, it is characterized by the presence of anti intrinsic factor antibodies. Treatment is based on the administration of parenteral vitamin B12, although other routes of administration (eg, oral) are currently under study. In the present update, these various aspects are discussed with special emphasis on data of interest to the clinician. PMID- 23028240 TI - The toronto extremity salvage score in unoperated controls: an age, gender, and country comparison. AB - The Toronto Extremity Salvage Score (TESS) is widely used for the functional assessment of patients following surgery for musculoskeletal tumours. The aim of this study was to determine if there are gender and/or age-specific changes, unrelated to surgery, that may influence this score and the appropriateness of the questions. The TESS for lower limb was carried out in two different countries to see if there was variation between them. There were no statistically significant differences between the scores obtained between the respondents from Australia or Britain either in total or between the corresponding age groups. There were statistically significant differences in the TESS obtained between age groups with a lower score at older age groups but there was no difference between the sexes. Patients in the age group 70+ were more likely to record activities as "not applicable" and also have a lower score. This study has shown that age is the major factor in determining the TESS in both an Australian and British populations of otherwise healthy people. As there were no differences between the two populations, it supports the TESS as an international scoring system. There may be also an argument for age-specific questions. PMID- 23028241 TI - Fluoroscopic caudal epidural injections in managing post lumbar surgery syndrome: two-year results of a randomized, double-blind, active-control trial. AB - STUDY DESIGN: A randomized, active control, double-blind trial. OBJECTIVE: To evaluate the effectiveness of fluoroscopically directed caudal epidural injections with or without steroids in managing chronic low back and lower extremity pain secondary to post lumbar surgery syndrome. SUMMARY OF BACKGROUND DATA: There is a paucity of evidence concerning caudal epidural injections for managing chronic persistent low back pain with or without lower extremity pain caused by post lumbar surgery syndrome. METHODS: This active control randomized study included 140 patients with 70 patients in each group. Group I received 0.5% lidocaine, 10 mL; Group II received 9 mL of 0.5% lidocaine mixed with 1 mL of 6 mg of nonparticulate betamethasone. The multiple outcome measures included the numeric rating scale, the Oswestry Disability Index 2.0, employment status, and opioid intake with assessments at 3, 6, 12, 18, and 24 months posttreatment. Primary outcome was defined as at least 50% improvement in pain and Oswestry Disability Index scores. Patients with a positive response to the first 2 procedures with at least 3 weeks of relief were considered to be successful. All others were considered as failures. RESULTS: Overall in Group I, 53% and 47% of the patients and in Group II, 59% and 58% of the patients, showed significant improvement with reduction in pain scores and disability index at 12 months and 24 months. In contrast, in the successful groups, significant pain relief and improvement in function were observed in 70% and 62% of Group I at one and 2 years; in 75% and 69% of Group II at one and 2 years. The results in the successful group showed that at the end of the first year patients experienced approximately 38 weeks of relief and at the end of 2 years Group I had 62 weeks and Group II had 68 weeks of relief. Overall total relief for 2 years was 48 weeks in Group I and 54 weeks in Group II. The average procedures in the successful groups were at 4 in one year and 6 at the end of 2 years. CONCLUSION: Caudal epidural injections of local anesthetic with or without steroid might be effective in patients with chronic persistent low back and/or lower extremity pain in patients with post lumbar surgery syndrome. PMID- 23028242 TI - CD44+/CD105+ human amniotic fluid mesenchymal stem cells survive and proliferate in the ovary long-term in a mouse model of chemotherapy-induced premature ovarian failure. AB - OBJECTIVES: Stem cell transplantation has been reported to rescue ovarian function in a preclinical mouse model of chemotherapy-induced premature ovarian failure (POF); however, maintaining the survival and self-renewal of transplanted seed cells in ovarian tissues over the long-term remains a troublesome issue. In this study we aimed to determine whether the CD44+/CD105+ human amniotic fluid cell (HuAFCs) subpopulation represent potential seed cells for stem cell transplantation treatments in POF. MATERIALS AND METHODS: The CD44+/CD105+ subpopulation were isolated from HuAFCs, cultured in vitro, and injected into a cyclophosphamide-induced mouse model of POF. RESULTS: Under continuous subculture in vitro, CD44+/CD105+ cells proliferated rapidly and expressed high levels of the proliferative markers Ki67 and survivin, as well as high levels of a number of mesenchymal stem cell biomarkers. Moreover, when red fluorescence protein (RFP)-transduced CD44+/CD105+ HuAFCs were transplanted into the ovaries of POF mice, the cells could be detected by fluorescence microscopy up to three weeks after injection. Furthermore, the BrdUrd incorporation assay and immunofluorescent staining demonstrated that CD44+/CD105+ HuAFCs underwent normal cycles of cell proliferation and self-renewal in the ovarian tissues of POF mice over the long-term. CONCLUSIONS: The mesenchymal stem cell properties and long term in vivo survival of CD44+/CD105+ HuAFCs make them ideal seed cells for stem cell transplantation to treat POF. PMID- 23028243 TI - Is Helicobacter pylori infection associated with asthma risk? A meta-analysis based on 770 cases and 785 controls. AB - OBJECTIVE: Helicobacter pylori (H. pylori) infection has been thought to play a critical role in disorders such as gastric and lung cancer. A number of studies have been devoted to the relationship between H. pylori infection and asthma risk, which have generated inconclusive results. In this study we aimed to derive a more precise estimation of the relationship. METHODS: Meta-analyses evaluating the association of H. pylori infection and asthma risk were conducted and subgroup analyses on ethnicity and source of controls as well as CagA status were further conducted. Eligible studies were identified for the period up to Jul 2012. RESULTS: A total of five case-control studies comprising 770 cases and 785 controls were lastly selected for analysis. The overall data failed to indicate a significant association of H. pylori infection and asthma risk (OR=1.01; 95%CI=0.82-1.24). Likewise, in the subgroup analysis regarding ethnicity, source of controls and CagA status, no associations could be observed. CONCLUSIONS: The pooled data failed to suggest a marked association between H. pylori infection and asthma risk. Future studies are needed to confirm this conclusion. PMID- 23028244 TI - Pre-operative serum alkaline phosphatase as a predictor for hypocalcemia post parathyroid adenectomy. AB - BACKGROUND: Post-operative hypocalcemia (POH) may complicate parathyroidectomy for primary hyperparathyroidism. This study investigates the relationship between POH and pre-operative risk factors to identify a simple method to predict POH risk. METHODS: Retrospective data on risk factors for 29 patients was collected for age, pre-operative serum calcium, alkaline phosphatase (ALP), parathyroid hormone (PTH), adenoma size, gender, and bisphosphonate pre-treatment. These were screened to exclude those with small effect sizes, and analyzed using Univariate General Linear Modeling (GLM) with trough serum calcium (TSC) as the dependent variable. The regression function of the significant variables against TSC was plotted with 95% CI fit lines. The cut-off regression value was read from the lower fit line for the threshold TSC of 2.0 mmol/L. RESULTS: After screening, log transformed age (r=0.600), ALP (r=-0.415), and PTH (r=-0.433) were entered into GLM analysis, which showed that only ALP was significant (p=0.016 Eta squared=0.220). The GLM model had a partial Eta-squared of 0.559 with 98% observed power. The plot of TSC against log-ALP gave an ALP cut-off of 340 U/L. CONCLUSIONS: The study shows that there is a strong relationship between ALP and TSC, and that patients with a pre-operative ALP less than 340 U/L are unlikely to have symptomatic POH (100% sensitivity, 95% specificity). While vitamin D was not analyzed in this study, the ALP cut-off is conservative and should still screen out cases with severe vitamin D deficiency. We therefore recommend that pre operative ALP be utilized to complement clinical protocols for POH management in parathyroid adenomectomy patients. PMID- 23028245 TI - The evaluation of the distribution of yeast like fungi 'Candida Species' at a tertiary care center in western Turkey. AB - OBJECTIVE: Candida infections have increased due to transplant patients, prolonged ICU stay and invasive procedures. The most common isolated strain is C. albicans. The aim of this study was to evaluate the distribution of Candida isolates at Tepecik Education and Research Hospital. MATERIALS AND METHODS: Yeast like fungi were isolated between 13.01.2010 and 19.08.2011 at Mycology Laboratory. The identification was done by conventional methods and carbohydrate assimilation profile using the ID32C identification system (Biomerieux, France). RESULTS: Yeast like fungi were isolated from 337 clinical specimens. They consisted of urine, blood culture, respiratory specimen and wound. The most isolated yeast strains were C.albicans (38.6%), C.tropicalis (13.9%), C. parapsilosis (28.4%), C.glabrata (7.4%), C.krusei (3.8%). CONCLUSION: Recently there is an increment in Candida infections. In this study the most common strain was C.albicans and the rate C. glabrata and C. krusei isolates were lower than expected. C. parapsilosis was the most isolated strain in blood cultures and this may be due to invasive procedures and the use of indwelling catheters. PMID- 23028246 TI - On physical properties of tetraether lipid membranes: effects of cyclopentane rings. AB - This paper reviews the recent findings related to the physical properties of tetraether lipid membranes, with special attention to the effects of the number, position, and configuration of cyclopentane rings on membrane properties. We discuss the findings obtained from liposomes and monolayers, composed of naturally occurring archaeal tetraether lipids and synthetic tetraethers as well as the results from computer simulations. It appears that the number, position, and stereochemistry of cyclopentane rings in the dibiphytanyl chains of tetraether lipids have significant influence on packing tightness, lipid conformation, membrane thickness and organization, and headgroup hydration/orientation. PMID- 23028247 TI - In the search for the treatment of compensatory sweating. AB - BACKGROUND: Despite success of thoracic sympathectomy (ETS), there are patients that develop postoperatively intensive sweating of the trunk. The aim of the study was to present outcomes of three of those methods: removal of the clips, clipping of T6-9, and regional abdomino-lumbar iontophoresis (RALI). METHODS: Out of the group of 229 patients treated with ETS, there were 9 that requested removal of the clips, 3 were treated with T6-9 video thoracoscopic block, and 5 were treated with RALI. The intensity of the side effect has been evaluated subjectively (with overall and localized perception of intensity of sweating) and objectively (with gravimetry). RESULTS: The removal of the clips resulted in slow (about 12 months) diminishing of the intensity of sweating of the trunk; but the symptom did not disappear to the degree satisfactory for the patients. The T6-9 block resulted in partial and transient diminishing of the symptom. The iontophoresis resulted in very promising short-term results. CONCLUSION: Removal of the clips from the sympathetic trunk does not provide resolution of compensatory sweating in 1 year of observation. T6-9 block does not provide remedy for compensatory hyperhidrosis. Regional abdomino-lumbar iontophoresis seems to be very promising, but further research and followup are mandatory. PMID- 23028248 TI - Treatment of superficial cutaneous vascular lesions: experience with the long pulsed 1064 nm Nd:YAG laser. AB - Recent published studies evaluating the long-pulsed 1064 nm Nd:YAG laser for superficial cutaneous vascular lesions have limited subjects and optimal treatment parameters have not been established. To determine the efficacy and safety of the long-pulsed 1064 nm Nd:YAG laser on superficial cutaneus vascular lesions and analyse retrospectively our experience of a 3-year period are the aims of this study. Over the 3-year period, 255 patients were treated [189 female and 66 male; median age 35 (range 7-65) years; Fitzpatrick skin types II-V]. Twenty-six patients with spider angioma, 130 with facial telangiectasia, and 99 with leg telangiectasia were treated. A long-pulsed 1064 nm Nd:YAG laser was used. A test dose was performed at the initial consultation and thereafter patients were reviewed and treated at 4-week intervals for 5 months. Of those patients who completed treatment and followup, 26/26 (100%) of spider angiomas, 125/130 (97%) of facial telangiectasia, and 80/99 (80,8%) of leg telangiectasia markedly improved or cleared. We suggest that the long pulsed Nd:YAG laser is a safe and effective treatment for common superficial cutaneous vascular lesions. However, it is not the first choise to use to treat superficial vessels on the face where depth is not the concern. PMID- 23028249 TI - Maternal aerobic exercise during pregnancy can increase spatial learning by affecting leptin expression on offspring's early and late period in life depending on gender. AB - Maternal exercise during pregnancy has been suggested to exert beneficial effects on brain functions of the offspring. Leptin is an adipocytokine which is secreted from adipose tissues and has positive effects on learning, memory, and synaptic plasticity. In this study, pregnant rats were moderately exercised and we observed the effects of this aerobic exercise on their prepubertal and adult offsprings' spatial learning, hippocampal neurogenesis, and expression of leptin. All the pups whose mothers exercised during pregnancy learned the platform earlier and spent longer time in the target quadrant. Their thigmotaxis times were shorter than those measured in the control group. It is shown that hippocampal CA1, CA3 neuron numbers increased in both prepubertal and adult pups, in addition that GD neuron numbers increased in adult pups. Leptin receptor expression significantly increased in the prepubertal male, adult male, and adult female pups. In our study, maternal running during pregnancy resulted in significant increase in the expression of leptin receptor but not in prepubertal female pups, enhanced hippocampal cell survival, and improved learning memory capability in prepubertal and adult rat pups, as compared to the control group. In conclusion, maternal exercise during pregnancy may regulate spatial plasticity in the hippocampus of the offspring by increasing the expression of leptin. PMID- 23028250 TI - A synchronized multipoint vision-based system for displacement measurement of civil infrastructures. AB - This study presents an advanced multipoint vision-based system for dynamic displacement measurement of civil infrastructures. The proposed system consists of commercial camcorders, frame grabbers, low-cost PCs, and a wireless LAN access point. The images of target panels attached to a structure are captured by camcorders and streamed into the PC via frame grabbers. Then the displacements of targets are calculated using image processing techniques with premeasured calibration parameters. This system can simultaneously support two camcorders at the subsystem level for dynamic real-time displacement measurement. The data of each subsystem including system time are wirelessly transferred from the subsystem PCs to master PC and vice versa. Furthermore, synchronization process is implemented to ensure the time synchronization between the master PC and subsystem PCs. Several shaking table tests were conducted to verify the effectiveness of the proposed system, and the results showed very good agreement with those from a conventional sensor with an error of less than 2%. PMID- 23028252 TI - Diffuse alveolar damage of the lungs in forensic autopsies: assessment of histopathological stages and causes of death. AB - INTRODUCTION: Diffuse alveolar damage (DAD) is a morphological prototype of acute interstitial pneumonia. Hospital autopsies or open-lung biopsies are used to monitor common alveolar damage and hyaline membrane (HM) development histopathologically. The aim of this study was to detect histopathological profiles and frequency of DAD and HM in adult forensic autopsies. MATERIALS AND METHODS: In total, 6813 reports with histopathological samples in 12,504 cases on which an autopsy was performed between 2006 and 2008 were investigated. Sixty-six individuals >18 years of age who were diagnosed with DAD were included. Hematoxylin- and eosin-stained lung preparations were reexamined in line with the 2002 American Thoracic Society/European Respiratory Society idiopathic interstitial pneumonia consensus criteria. RESULTS: Histopathological examination revealed that 50 cases (75.7%) were in the exudative phase and 16 (24.2%) were in the proliferative phase. Only the rate of alveolar exudate/oedema in exudative phase cases (P = 0.003); those of alveolar histiocytic desquamation (P = 0.037), alveolar fibrosis (P = 0.017), chronic inflammation (P = 0.02), and alveolar fibrin (P = 0.001) in proliferative cases were significantly higher. The presence of alveolar fibrin was the only independent variable in favour of proliferative cases (P = 0.016). CONCLUSION: The detection of all DAD morphological criteria with the same intensity is not always possible in each case. Forensic autopsies may provide a favourable means for expanding our knowledge about acute lung damage, DAD, and interstitial lung disease. PMID- 23028254 TI - Geographical gradients in Argentinean terrestrial mammal species richness and their environmental correlates. AB - We analysed the main geographical trends of terrestrial mammal species richness (SR) in Argentina, assessing how broad-scale environmental variation (defined by climatic and topographic variables) and the spatial form of the country (defined by spatial filters based on spatial eigenvector mapping (SEVM)) influence the kinds and the numbers of mammal species along these geographical trends. We also evaluated if there are pure geographical trends not accounted for by the environmental or spatial factors. The environmental variables and spatial filters that simultaneously correlated with the geographical variables and SR were considered potential causes of the geographic trends. We performed partial correlations between SR and the geographical variables, maintaining the selected explanatory variables statistically constant, to determine if SR was fully explained by them or if a significant residual geographic pattern remained. All groups and subgroups presented a latitudinal gradient not attributable to the spatial form of the country. Most of these trends were not explained by climate. We used a variation partitioning procedure to quantify the pure geographic trend (PGT) that remained unaccounted for. The PGT was larger for latitudinal than for longitudinal gradients. This suggests that historical or purely geographical causes may also be relevant drivers of these geographical gradients in mammal diversity. PMID- 23028253 TI - Brain metastases research 1990-2010: pattern of citation and systematic review of highly cited articles. AB - BACKGROUND: High and continuously increasing research activity related to different aspects of prevention, prediction, diagnosis and treatment of brain metastases has been performed between 1990 and 2010. One of the major databases contains 2695 scientific articles that were published during this time period. Different measures of impact, visibility, and quality of published research are available, each with its own pros and cons. For this overview, article citation rate was chosen. RESULTS: Among the 10 most cited articles, 7 reported on randomized clinical trials. Nine covered surgical or radiosurgical approaches and the remaining one a widely adopted prognostic score. Overall, 30 randomized clinical trials were published between 1990 and 2010, including those with phase II design and excluding duplicate publications, for example, after longer followup or with focus on secondary endpoints. Twenty of these randomized clinical trials were published before 2008. Their median number of citations was 110, range 13-1013, compared to 5-6 citations for all types of publications. Annual citation rate appeared to gradually increase during the first 2-3 years after publication before reaching high levels. CONCLUSIONS: A large variety of preclinical and clinical topics achieved high numbers of citations. However, areas such as quality of life, side effects, and end-of-life care were underrepresented. Efforts to increase their visibility might be warranted. PMID- 23028251 TI - A comprehensive review on pharmacotherapeutics of herbal bioenhancers. AB - In India, Ayurveda has made a major contribution to the drug discovery process with new means of identifying active compounds. Recent advancement in bioavailability enhancement of drugs by compounds of herbal origin has produced a revolutionary shift in the way of therapeutics. Thus, bibliographic investigation was carried out by analyzing classical text books and peer-reviewed papers, consulting worldwide-accepted scientific databases from last 30 years. Herbal bioenhancers have been shown to enhance bioavailability and bioefficacy of different classes of drugs, such as antibiotics, antituberculosis, antiviral, antifungal, and anticancerous drugs at low doses. They have also improved oral absorption of nutraceuticals like vitamins, minerals, amino acids, and certain herbal compounds. Their mechanism of action is mainly through absorption process, drug metabolism, and action on drug target. This paper clearly indicates that scientific researchers and pharmaceutical industries have to give emphasis on experimental studies to find out novel active principles from such a vast array of unexploited plants having a role as a bioavailability and bioefficacy enhancer. Also, the mechanisms of action by which bioenhancer compounds exert bioenhancing effects remain to be explored. PMID- 23028255 TI - Lateral surgical approach to lumbar intervertebral discs in an ovine model. AB - The sheep is becoming increasingly used as a large animal model for preclinical spine surgery studies. Access to the ovine lumbar intervertebral discs has traditionally been via an anterior or anterolateral approach, which requires larger wound incisions and, at times, significant abdominal retraction. We present a new minimally invasive operative technique for a far-lateral approach to the ovine lumbar spine that allows for smaller incisions, excellent visualisation of intervertebral discs, and minimal abdominal retraction and is well tolerated by animals with minimal morbidity. PMID- 23028256 TI - "It Takes a Village:" Familial Messages Regarding Dating Among African American Adolescents. AB - There is a dearth of research regarding the influence of family members on adolescent dating. This study explored messages that African American adolescents received from family members regarding dating attitudes, norms and behaviors. Qualitative interviews were conducted with sexually experienced urban African American heterosexual adolescents (N = 51) between the ages of 15-17. Analyses revealed that participants received a diversity of messages from a range of both nuclear and extended family members, and that these messages were organized around three temporal phases of dating: initiation, maintenance, and termination. Types and sources of messages are discussed, as well as implications for intervention development. PMID- 23028258 TI - Addressing HIV/AIDS in South African Classrooms. PMID- 23028260 TI - ASCO beyond McCormick: perseverance, collaboration, mentorship. PMID- 23028261 TI - Effect of statins on venous thromboembolic events: a meta-analysis of published and unpublished evidence from randomised controlled trials. AB - BACKGROUND: It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins. METHODS AND FINDINGS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78-1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72-1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76-1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82-1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80-1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out. Please see later in the article for the Editors' Summary. CONCLUSIONS: The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out. PMID- 23028262 TI - Statins and venous thrombosis: a story too good to be true? AB - Frits Rosendaal comments on new findings from a meta-analysis conducted by Kazem Rahimi and colleagues, evaluating whether statins can prevent venous thromboembolism. PMID- 23028263 TI - The effect of adding ready-to-use supplementary food to a general food distribution on child nutritional status and morbidity: a cluster-randomized controlled trial. AB - BACKGROUND: Recently, operational organizations active in child nutrition in developing countries have suggested that blanket feeding strategies be adopted to enable the prevention of child wasting. A new range of nutritional supplements is now available, with claims that they can prevent wasting in populations at risk of periodic food shortages. Evidence is lacking as to the effectiveness of such preventive interventions. This study examined the effect of a ready-to-use supplementary food (RUSF) on the prevention of wasting in 6- to 36-mo-old children within the framework of a general food distribution program. METHODS AND FINDINGS: We conducted a two-arm cluster-randomized controlled pragmatic intervention study in a sample of 1,038 children aged 6 to 36 mo in the city of Abeche, Chad. Both arms were included in a general food distribution program providing staple foods. The intervention group was given a daily 46 g of RUSF for 4 mo. Anthropometric measurements and morbidity were recorded monthly. Adding RUSF to a package of monthly household food rations for households containing a child assigned to the intervention group did not result in a reduction in cumulative incidence of wasting (incidence risk ratio: 0.86; 95% CI: 0.67, 1.11; p = 0.25). However, the intervention group had a modestly higher gain in height for-age (+0.03 Z-score/mo; 95% CI: 0.01, 0.04; p<0.001). In addition, children in the intervention group had a significantly higher hemoglobin concentration at the end of the study than children in the control group (+3.8 g/l; 95% CI: 0.6, 7.0; p = 0.02), thereby reducing the odds of anemia (odds ratio: 0.52; 95% CI: 0.34, 0.82; p = 0.004). Adding RUSF also resulted in a significantly lower risk of self reported diarrhea (-29.3%; 95% CI: 20.5, 37.2; p<0.001) and fever episodes ( 22.5%; 95% CI: 14.0, 30.2; p<0.001). Limitations of this study include that the projected sample size was not fully attained and that significantly fewer children from the control group were present at follow-up sessions. CONCLUSIONS: Providing RUSF as part of a general food distribution resulted in improvements in hemoglobin status and small improvements in linear growth, accompanied by an apparent reduction in morbidity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01154595 Please see later in the article for the Editors' Summary. PMID- 23028264 TI - Lipid-based nutrient supplements: how can they combat child malnutrition? AB - Kathryn Dewey and Mary Arimond discuss new research in PLOS Medicine that assesses the effect of blanket provision of ready-to-use supplementary food to children at high risk of malnutrition in Chad, and highlight some of the challenges of investigating the efficacy of supplementary foods for malnourished children. PMID- 23028265 TI - Thermodynamic Cycle Without Turning Off Self-Interactions: Formal Discussion and a Numerical Example. AB - The efficiency and accuracy of thermodynamic cycle calculations are considered. It is rigorously shown that the energy of the mutated part (MP) need not be scaled in a thermodynamic cycle computed with dual topology. Hence, there is no need to scale to zero any of the self-interactions (i.e. the interactions involving only particles of the same MP) regardless of whether the MP is bound or not to the main system. This observation carries a promise to lower computational resources and increase accuracy. A numerical test of a complete thermodynamic cycle illustrates cost and accuracy considerations. PMID- 23028266 TI - Micron: an Actively Stabilized Handheld Tool for Microsurgery. AB - We describe the design and performance of a hand-held actively stabilized tool to increase accuracy in micro-surgery or other precision manipulation. It removes involuntary motion such as tremor by actuating the tip to counteract the effect of the undesired handle motion. The key components are a three-degree-of-freedom piezoelectric manipulator that has 400 MUm range of motion, 1 N force capability, and bandwidth over 100 Hz, and an optical position measurement subsystem that acquires the tool pose with 4 MUm resolution at 2000 samples/s. A control system using these components attenuates hand motion by at least 15 dB (a fivefold reduction). By considering the effect of the frequency response of Micron on the human visual feedback loop, we have developed a filter that reduces unintentional motion, yet preserves intuitive eye-hand coordination. We evaluated the effectiveness of Micron by measuring the accuracy of the human/machine system in three simple manipulation tasks. Handheld testing by three eye surgeons and three non-surgeons showed a reduction in position error of between 32% and 52%, depending on the error metric. PMID- 23028267 TI - Predicting the extension of biomedical ontologies. AB - Developing and extending a biomedical ontology is a very demanding task that can never be considered complete given our ever-evolving understanding of the life sciences. Extension in particular can benefit from the automation of some of its steps, thus releasing experts to focus on harder tasks. Here we present a strategy to support the automation of change capturing within ontology extension where the need for new concepts or relations is identified. Our strategy is based on predicting areas of an ontology that will undergo extension in a future version by applying supervised learning over features of previous ontology versions. We used the Gene Ontology as our test bed and obtained encouraging results with average f-measure reaching 0.79 for a subset of biological process terms. Our strategy was also able to outperform state of the art change capturing methods. In addition we have identified several issues concerning prediction of ontology evolution, and have delineated a general framework for ontology extension prediction. Our strategy can be applied to any biomedical ontology with versioning, to help focus either manual or semi-automated extension methods on areas of the ontology that need extension. PMID- 23028268 TI - Ten simple rules for online learning. PMID- 23028269 TI - An online bioinformatics curriculum. AB - Online learning initiatives over the past decade have become increasingly comprehensive in their selection of courses and sophisticated in their presentation, culminating in the recent announcement of a number of consortium and startup activities that promise to make a university education on the internet, free of charge, a real possibility. At this pivotal moment it is appropriate to explore the potential for obtaining comprehensive bioinformatics training with currently existing free video resources. This article presents such a bioinformatics curriculum in the form of a virtual course catalog, together with editorial commentary, and an assessment of strengths, weaknesses, and likely future directions for open online learning in this field. PMID- 23028270 TI - What evidence is there for the homology of protein-protein interactions? AB - The notion that sequence homology implies functional similarity underlies much of computational biology. In the case of protein-protein interactions, an interaction can be inferred between two proteins on the basis that sequence similar proteins have been observed to interact. The use of transferred interactions is common, but the legitimacy of such inferred interactions is not clear. Here we investigate transferred interactions and whether data incompleteness explains the lack of evidence found for them. Using definitions of homology associated with functional annotation transfer, we estimate that conservation rates of interactions are low even after taking interactome incompleteness into account. For example, at a blastp E-value threshold of 10( 70), we estimate the conservation rate to be about 11 % between S. cerevisiae and H. sapiens. Our method also produces estimates of interactome sizes (which are similar to those previously proposed). Using our estimates of interaction conservation we estimate the rate at which protein-protein interactions are lost across species. To our knowledge, this is the first such study based on large scale data. Previous work has suggested that interactions transferred within species are more reliable than interactions transferred across species. By controlling for factors that are specific to within-species interaction prediction, we propose that the transfer of interactions within species might be less reliable than transfers between species. Protein-protein interactions appear to be very rarely conserved unless very high sequence similarity is observed. Consequently, inferred interactions should be used with care. PMID- 23028271 TI - High-throughput computer method for 3D neuronal structure reconstruction from the image stack of the Drosophila brain and its applications. AB - Drosophila melanogaster is a well-studied model organism, especially in the field of neurophysiology and neural circuits. The brain of the Drosophila is small but complex, and the image of a single neuron in the brain can be acquired using confocal microscopy. Analyzing the Drosophila brain is an ideal start to understanding the neural structure. The most fundamental task in studying the neural network of Drosophila is to reconstruct neuronal structures from image stacks. Although the fruit fly brain is small, it contains approximately 100,000 neurons. It is impossible to trace all the neurons manually. This study presents a high-throughput algorithm for reconstructing the neuronal structures from 3D image stacks collected by a laser scanning confocal microscope. The proposed method reconstructs the neuronal structure by applying the shortest path graph algorithm. The vertices in the graph are certain points on the 2D skeletons of the neuron in the slices. These points are close to the 3D centerlines of the neuron branches. The accuracy of the algorithm was verified using the DIADEM data set. This method has been adopted as part of the protocol of the FlyCircuit Database, and was successfully applied to process more than 16,000 neurons. This study also shows that further analysis based on the reconstruction results can be performed to gather more information on the neural network. PMID- 23028273 TI - Spontaneous excitation patterns computed for axons with injury-like impairments of sodium channels and Na/K pumps. AB - In injured neurons, "leaky" voltage-gated sodium channels (Nav) underlie dysfunctional excitability that ranges from spontaneous subthreshold oscillations (STO), to ectopic (sometimes paroxysmal) excitation, to depolarizing block. In recombinant systems, mechanical injury to Nav1.6-rich membranes causes cytoplasmic Na(+)-loading and "Nav-CLS", i.e., coupled left-(hyperpolarizing) shift of Nav activation and availability. Metabolic injury of hippocampal neurons (epileptic discharge) results in comparable impairment: left-shifted activation and availability and hence left-shifted I(Na-window). A recent computation study revealed that CLS-based I(Na-window) left-shift dissipates ion gradients and impairs excitability. Here, via dynamical analyses, we focus on sustained excitability patterns in mildly damaged nodes, in particular with more realistic Gaussian-distributed Nav-CLS to mimic "smeared" injury intensity. Since our interest is axons that might survive injury, pumps (sine qua non for live axons) are included. In some simulations, pump efficacy and system volumes are varied. Impacts of current noise inputs are also characterized. The diverse modes of spontaneous rhythmic activity evident in these scenarios are studied using bifurcation analysis. For "mild CLS injury", a prominent feature is slow pump/leak-mediated E(Ion) oscillations. These slow oscillations yield dynamic firing thresholds that underlie complex voltage STO and bursting behaviors. Thus, Nav-CLS, a biophysically justified mode of injury, in parallel with functioning pumps, robustly engenders an emergent slow process that triggers a plethora of pathological excitability patterns. This minimalist "device" could have physiological analogs. At first nodes of Ranvier and at nociceptors, e.g., localized lipid-tuning that modulated Nav midpoints could produce Nav-CLS, as could co-expression of appropriately differing Nav isoforms. PMID- 23028272 TI - Evolutionary dynamics on protein bi-stability landscapes can potentially resolve adaptive conflicts. AB - Experimental studies have shown that some proteins exist in two alternative native-state conformations. It has been proposed that such bi-stable proteins can potentially function as evolutionary bridges at the interface between two neutral networks of protein sequences that fold uniquely into the two different native conformations. Under adaptive conflict scenarios, bi-stable proteins may be of particular advantage if they simultaneously provide two beneficial biological functions. However, computational models that simulate protein structure evolution do not yet recognize the importance of bi-stability. Here we use a biophysical model to analyze sequence space to identify bi-stable or multi-stable proteins with two or more equally stable native-state structures. The inclusion of such proteins enhances phenotype connectivity between neutral networks in sequence space. Consideration of the sequence space neighborhood of bridge proteins revealed that bi-stability decreases gradually with each mutation that takes the sequence further away from an exactly bi-stable protein. With relaxed selection pressures, we found that bi-stable proteins in our model are highly successful under simulated adaptive conflict. Inspired by these model predictions, we developed a method to identify real proteins in the PDB with bridge-like properties, and have verified a clear bi-stability gradient for a series of mutants studied by Alexander et al. (Proc Nat Acad Sci USA 2009, 106:21149-21154) that connect two sequences that fold uniquely into two different native structures via a bridge-like intermediate mutant sequence. Based on these findings, new testable predictions for future studies on protein bi-stability and evolution are discussed. PMID- 23028274 TI - The spatial structure of stimuli shapes the timescale of correlations in population spiking activity. AB - Throughout the central nervous system, the timescale over which pairs of neural spike trains are correlated is shaped by stimulus structure and behavioral context. Such shaping is thought to underlie important changes in the neural code, but the neural circuitry responsible is largely unknown. In this study, we investigate a stimulus-induced shaping of pairwise spike train correlations in the electrosensory system of weakly electric fish. Simultaneous single unit recordings of principal electrosensory cells show that an increase in the spatial extent of stimuli increases correlations at short (~ 10 ms) timescales while simultaneously reducing correlations at long (~ 100 ms) timescales. A spiking network model of the first two stages of electrosensory processing replicates this correlation shaping, under the assumptions that spatially broad stimuli both saturate feedforward afferent input and recruit an open-loop inhibitory feedback pathway. Our model predictions are experimentally verified using both the natural heterogeneity of the electrosensory system and pharmacological blockade of descending feedback projections. For weak stimuli, linear response analysis of the spiking network shows that the reduction of long timescale correlation for spatially broad stimuli is similar to correlation cancellation mechanisms previously suggested to be operative in mammalian cortex. The mechanism for correlation shaping supports population-level filtering of irrelevant distractor stimuli, thereby enhancing the population response to relevant prey and conspecific communication inputs. PMID- 23028275 TI - Inferring the structure of social contacts from demographic data in the analysis of infectious diseases spread. AB - Social contact patterns among individuals encode the transmission route of infectious diseases and are a key ingredient in the realistic characterization and modeling of epidemics. Unfortunately, the gathering of high quality experimental data on contact patterns in human populations is a very difficult task even at the coarse level of mixing patterns among age groups. Here we propose an alternative route to the estimation of mixing patterns that relies on the construction of virtual populations parametrized with highly detailed census and demographic data. We present the modeling of the population of 26 European countries and the generation of the corresponding synthetic contact matrices among the population age groups. The method is validated by a detailed comparison with the matrices obtained in six European countries by the most extensive survey study on mixing patterns. The methodology presented here allows a large scale comparison of mixing patterns in Europe, highlighting general common features as well as country-specific differences. We find clear relations between epidemiologically relevant quantities (reproduction number and attack rate) and socio-demographic characteristics of the populations, such as the average age of the population and the duration of primary school cycle. This study provides a numerical approach for the generation of human mixing patterns that can be used to improve the accuracy of mathematical models in the absence of specific experimental data. PMID- 23028276 TI - Speeded reaching movements around invisible obstacles. AB - We analyze the problem of obstacle avoidance from a Bayesian decision-theoretic perspective using an experimental task in which reaches around a virtual obstacle were made toward targets on an upright monitor. Subjects received monetary rewards for touching the target and incurred losses for accidentally touching the intervening obstacle. The locations of target-obstacle pairs within the workspace were varied from trial to trial. We compared human performance to that of a Bayesian ideal movement planner (who chooses motor strategies maximizing expected gain) using the Dominance Test employed in Hudson et al. (2007). The ideal movement planner suffers from the same sources of noise as the human, but selects movement plans that maximize expected gain in the presence of that noise. We find good agreement between the predictions of the model and actual performance in most but not all experimental conditions. PMID- 23028277 TI - Deciphering interactions in moving animal groups. AB - Collective motion phenomena in large groups of social organisms have long fascinated the observer, especially in cases, such as bird flocks or fish schools, where large-scale highly coordinated actions emerge in the absence of obvious leaders. However, the mechanisms involved in this self-organized behavior are still poorly understood, because the individual-level interactions underlying them remain elusive. Here, we demonstrate the power of a bottom-up methodology to build models for animal group motion from data gathered at the individual scale. Using video tracks of fish shoal in a tank, we show how a careful, incremental analysis at the local scale allows for the determination of the stimulus/response function governing an individual's moving decisions. We find in particular that both positional and orientational effects are present, act upon the fish turning speed, and depend on the swimming speed, yielding a novel schooling model whose parameters are all estimated from data. Our approach also leads to identify a density-dependent effect that results in a behavioral change for the largest groups considered. This suggests that, in confined environment, the behavioral state of fish and their reaction patterns change with group size. We debate the applicability, beyond the particular case studied here, of this novel framework for deciphering interactions in moving animal groups. PMID- 23028278 TI - Analysis of surface protein expression reveals the growth pattern of the gram negative outer membrane. AB - The outer membrane (OM) of Gram-negative bacteria is a complex bilayer composed of proteins, phospholipids, lipoproteins, and lipopolysaccharides. Despite recent advances revealing the molecular pathways underlying protein and lipopolysaccharide incorporation into the OM, the spatial distribution and dynamic regulation of these processes remain poorly understood. Here, we used sequence-specific fluorescent labeling to map the incorporation patterns of an OM porin protein, LamB, by labeling proteins only after epitope exposure on the cell surface. Newly synthesized LamB appeared in discrete puncta, rather than evenly distributed over the cell surface. Further growth of bacteria after labeling resulted in divergence of labeled LamB puncta, consistent with a spatial pattern of OM growth in which new, unlabeled material was also inserted in patches. At the poles, puncta remained relatively stationary through several rounds of division, a salient characteristic of the OM protein population as a whole. We propose a biophysical model of growth in which patches of new OM material are added in discrete bursts that evolve in time according to Stokes flow and are randomly distributed over the cell surface. Simulations based on this model demonstrate that our experimental observations are consistent with a bursty insertion pattern without spatial bias across the cylindrical cell surface, with approximately one burst of ~ 10(-2) um(2) of OM material per two minutes per um(2). Growth by insertion of discrete patches suggests that stochasticity plays a major role in patterning and material organization in the OM. PMID- 23028279 TI - Stress-induced impairment of a working memory task: role of spiking rate and spiking history predicted discharge. AB - Stress, pervasive in society, contributes to over half of all work place accidents a year and over time can contribute to a variety of psychiatric disorders including depression, schizophrenia, and post-traumatic stress disorder. Stress impairs higher cognitive processes, dependent on the prefrontal cortex (PFC) and that involve maintenance and integration of information over extended periods, including working memory and attention. Substantial evidence has demonstrated a relationship between patterns of PFC neuron spiking activity (action-potential discharge) and components of delayed-response tasks used to probe PFC-dependent cognitive function in rats and monkeys. During delay periods of these tasks, persistent spiking activity is posited to be essential for the maintenance of information for working memory and attention. However, the degree to which stress-induced impairment in PFC-dependent cognition involves changes in task-related spiking rates or the ability for PFC neurons to retain information over time remains unknown. In the current study, spiking activity was recorded from the medial PFC of rats performing a delayed-response task of working memory during acute noise stress (93 db). Spike history-predicted discharge (SHPD) for PFC neurons was quantified as a measure of the degree to which ongoing neuronal discharge can be predicted by past spiking activity and reflects the degree to which past information is retained by these neurons over time. We found that PFC neuron discharge is predicted by their past spiking patterns for nearly one second. Acute stress impaired SHPD, selectively during delay intervals of the task, and simultaneously impaired task performance. Despite the reduction in delay-related SHPD, stress increased delay-related spiking rates. These findings suggest that neural codes utilizing SHPD within PFC networks likely reflects an additional important neurophysiological mechanism for maintenance of past information over time. Stress-related impairment of this mechanism is posited to contribute to the cognition-impairing actions of stress. PMID- 23028280 TI - Binding of two intrinsically disordered peptides to a multi-specific protein: a combined Monte Carlo and molecular dynamics study. AB - The unique ability of intrinsically disordered proteins (IDPs) to fold upon binding to partner molecules makes them functionally well-suited for cellular communication networks. For example, the folding-binding of different IDP sequences onto the same surface of an ordered protein provides a mechanism for signaling in a many-to-one manner. Here, we study the molecular details of this signaling mechanism by applying both Molecular Dynamics and Monte Carlo methods to S100B, a calcium-modulated homodimeric protein, and two of its IDP targets, p53 and TRTK-12. Despite adopting somewhat different conformations in complex with S100B and showing no apparent sequence similarity, the two IDP targets associate in virtually the same manner. As free chains, both target sequences remain flexible and sample their respective bound, natively [Formula: see text] helical states to a small extent. Association occurs through an intermediate state in the periphery of the S100B binding pocket, stabilized by nonnative interactions which are either hydrophobic or electrostatic in nature. Our results highlight the importance of overall physical properties of IDP segments, such as net charge or presence of strongly hydrophobic amino acids, for molecular recognition via coupled folding-binding. PMID- 23028281 TI - Structural investigation of MscL gating using experimental data and coarse grained MD simulations. AB - The mechanosensitive channel of large conductance (MscL) has become a model system in which to understand mechanosensation, a process involved in osmoregulation and many other physiological functions. While a high resolution closed state structure is available, details of the open structure and the gating mechanism remain unknown. In this study we combine coarse grained simulations with restraints from EPR and FRET experiments to study the structural changes involved in gating with much greater level of conformational sampling than has previously been possible. We generated a set of plausible open pore structures that agree well with existing open pore structures and gating models. Most interestingly, we found that membrane thinning induces a kink in the upper part of TM1 that causes an outward motion of the periplasmic loop away from the pore centre. This previously unobserved structural change might present a new mechanism of tension sensing and might be related to a functional role in osmoregulation. PMID- 23028282 TI - Stochastic simulations suggest that HIV-1 survives close to its error threshold. AB - The use of mutagenic drugs to drive HIV-1 past its error threshold presents a novel intervention strategy, as suggested by the quasispecies theory, that may be less susceptible to failure via viral mutation-induced emergence of drug resistance than current strategies. The error threshold of HIV-1, MU c, however, is not known. Application of the quasispecies theory to determine MU c poses significant challenges: Whereas the quasispecies theory considers the asexual reproduction of an infinitely large population of haploid individuals, HIV-1 is diploid, undergoes recombination, and is estimated to have a small effective population size in vivo. We performed population genetics-based stochastic simulations of the within-host evolution of HIV-1 and estimated the structure of the HIV-1 quasispecies and MU c. We found that with small mutation rates, the quasispecies was dominated by genomes with few mutations. Upon increasing the mutation rate, a sharp error catastrophe occurred where the quasispecies became delocalized in sequence space. Using parameter values that quantitatively captured data of viral diversification in HIV-1 patients, we estimated MU c to be 7 x 10(-5)-1 x 10(-4) substitutions/site/replication, ~ 2-6 fold higher than the natural mutation rate of HIV-1, suggesting that HIV-1 survives close to its error threshold and may be readily susceptible to mutagenic drugs. The latter estimate was weakly dependent on the within-host effective population size of HIV-1. With large population sizes and in the absence of recombination, our simulations converged to the quasispecies theory, bridging the gap between quasispecies theory and population genetics-based approaches to describing HIV-1 evolution. Further, MU c increased with the recombination rate, rendering HIV-1 less susceptible to error catastrophe, thus elucidating an added benefit of recombination to HIV-1. Our estimate of MU c may serve as a quantitative guideline for the use of mutagenic drugs against HIV-1. PMID- 23028283 TI - Mechanism of bacterial signal transduction revealed by molecular dynamics of Tsr dimers and trimers of dimers in lipid vesicles. AB - Bacterial chemoreceptors provide an important model for understanding signalling processes. In the serine receptor Tsr from E. coli, a binding event in the periplasmic domain of the receptor dimer causes a shift in a single transmembrane helix of roughly 0.15 nm towards the cytoplasm. This small change is propagated through the ~ 22 nm length of the receptor, causing downstream inhibition of the kinase CheA. This requires interactions within a trimer of receptor dimers. Additionally, the signal is amplified across a 53,000 nm(2) array of chemoreceptor proteins, including ~ 5,200 receptor trimers-of-dimers, at the cell pole. Despite a wealth of experimental data on the system, including high resolution structures of individual domains and extensive mutagenesis data, it remains uncertain how information is communicated across the receptor from the binding event to the downstream effectors. We present a molecular model of the entire Tsr dimer, and examine its behaviour using coarse-grained molecular dynamics and elastic network modelling. We observe a large bending in dimer models between the linker domain HAMP and coiled-coil domains, which is supported by experimental data. Models of the trimer of dimers, built from the dimer models, are more constrained and likely represent the signalling state. Simulations of the models in a 70 nm diameter vesicle with a biologically realistic lipid mixture reveal specific lipid interactions and oligomerisation of the trimer of dimers. The results indicate a mechanism whereby small motions of a single helix can be amplified through HAMP domain packing, to initiate large changes in the whole receptor structure. PMID- 23028285 TI - Inferring correlation networks from genomic survey data. AB - High-throughput sequencing based techniques, such as 16S rRNA gene profiling, have the potential to elucidate the complex inner workings of natural microbial communities - be they from the world's oceans or the human gut. A key step in exploring such data is the identification of dependencies between members of these communities, which is commonly achieved by correlation analysis. However, it has been known since the days of Karl Pearson that the analysis of the type of data generated by such techniques (referred to as compositional data) can produce unreliable results since the observed data take the form of relative fractions of genes or species, rather than their absolute abundances. Using simulated and real data from the Human Microbiome Project, we show that such compositional effects can be widespread and severe: in some real data sets many of the correlations among taxa can be artifactual, and true correlations may even appear with opposite sign. Additionally, we show that community diversity is the key factor that modulates the acuteness of such compositional effects, and develop a new approach, called SparCC (available at https://bitbucket.org/yonatanf/sparcc), which is capable of estimating correlation values from compositional data. To illustrate a potential application of SparCC, we infer a rich ecological network connecting hundreds of interacting species across 18 sites on the human body. Using the SparCC network as a reference, we estimated that the standard approach yields 3 spurious species-species interactions for each true interaction and misses 60% of the true interactions in the human microbiome data, and, as predicted, most of the erroneous links are found in the samples with the lowest diversity. PMID- 23028284 TI - Determinants of brain cell metabolic phenotypes and energy substrate utilization unraveled with a modeling approach. AB - Although all brain cells bear in principle a comparable potential in terms of energetics, in reality they exhibit different metabolic profiles. The specific biochemical characteristics explaining such disparities and their relative importance are largely unknown. Using a modeling approach, we show that modifying the kinetic parameters of pyruvate dehydrogenase and mitochondrial NADH shuttling within a realistic interval can yield a striking switch in lactate flux direction. In this context, cells having essentially an oxidative profile exhibit pronounced extracellular lactate uptake and consumption. However, they can be turned into cells with prominent aerobic glycolysis by selectively reducing the aforementioned parameters. In the case of primarily oxidative cells, we also examined the role of glycolysis and lactate transport in providing pyruvate to mitochondria in order to sustain oxidative phosphorylation. The results show that changes in lactate transport capacity and extracellular lactate concentration within the range described experimentally can sustain enhanced oxidative metabolism upon activation. Such a demonstration provides key elements to understand why certain brain cell types constitutively adopt a particular metabolic profile and how specific features can be altered under different physiological and pathological conditions in order to face evolving energy demands. PMID- 23028286 TI - Modeling phenotypic metabolic adaptations of Mycobacterium tuberculosis H37Rv under hypoxia. AB - The ability to adapt to different conditions is key for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), to successfully infect human hosts. Adaptations allow the organism to evade the host immune responses during acute infections and persist for an extended period of time during the latent infectious stage. In latently infected individuals, estimated to include one-third of the human population, the organism exists in a variety of metabolic states, which impedes the development of a simple strategy for controlling or eradicating this disease. Direct knowledge of the metabolic states of M. tuberculosis in patients would aid in the management of the disease as well as in forming the basis for developing new drugs and designing more efficacious drug cocktails. Here, we propose an in silico approach to create state-specific models based on readily available gene expression data. The coupling of differential gene expression data with a metabolic network model allowed us to characterize the metabolic adaptations of M. tuberculosis H37Rv to hypoxia. Given the microarray data for the alterations in gene expression, our model predicted reduced oxygen uptake, ATP production changes, and a global change from an oxidative to a reductive tricarboxylic acid (TCA) program. Alterations in the biomass composition indicated an increase in the cell wall metabolites required for cell-wall growth, as well as heightened accumulation of triacylglycerol in preparation for a low-nutrient, low metabolic activity life style. In contrast, the gene expression program in the deletion mutant of dosR, which encodes the immediate hypoxic response regulator, failed to adapt to low-oxygen stress. Our predictions were compatible with recent experimental observations of M. tuberculosis activity under hypoxic and anaerobic conditions. Importantly, alterations in the flow and accumulation of a particular metabolite were not necessarily directly linked to differential gene expression of the enzymes catalyzing the related metabolic reactions. PMID- 23028287 TI - Spike-timing dependence of structural plasticity explains cooperative synapse formation in the neocortex. AB - Structural plasticity governs the long-term development of synaptic connections in the neocortex. While the underlying processes at the synapses are not fully understood, there is strong evidence that a process of random, independent formation and pruning of excitatory synapses can be ruled out. Instead, there must be some cooperation between the synaptic contacts connecting a single pre- and postsynaptic neuron pair. So far, the mechanism of cooperation is not known. Here we demonstrate that local correlation detection at the postsynaptic dendritic spine suffices to explain the synaptic cooperation effect, without assuming any hypothetical direct interaction pathway between the synaptic contacts. Candidate biomolecular mechanisms for dendritic correlation detection have been identified previously, as well as for structural plasticity based thereon. By analyzing and fitting of a simple model, we show that spike-timing correlation dependent structural plasticity, without additional mechanisms of cross-synapse interaction, can reproduce the experimentally observed distributions of numbers of synaptic contacts between pairs of neurons in the neocortex. Furthermore, the model yields a first explanation for the existence of both transient and persistent dendritic spines and allows to make predictions for future experiments. PMID- 23028288 TI - Enhancing the prioritization of disease-causing genes through tissue specific protein interaction networks. AB - The prioritization of candidate disease-causing genes is a fundamental challenge in the post-genomic era. Current state of the art methods exploit a protein protein interaction (PPI) network for this task. They are based on the observation that genes causing phenotypically-similar diseases tend to lie close to one another in a PPI network. However, to date, these methods have used a static picture of human PPIs, while diseases impact specific tissues in which the PPI networks may be dramatically different. Here, for the first time, we perform a large-scale assessment of the contribution of tissue-specific information to gene prioritization. By integrating tissue-specific gene expression data with PPI information, we construct tissue-specific PPI networks for 60 tissues and investigate their prioritization power. We find that tissue-specific PPI networks considerably improve the prioritization results compared to those obtained using a generic PPI network. Furthermore, they allow predicting novel disease-tissue associations, pointing to sub-clinical tissue effects that may escape early detection. PMID- 23028289 TI - Spike-based decision learning of Nash equilibria in two-player games. AB - Humans and animals face decision tasks in an uncertain multi-agent environment where an agent's strategy may change in time due to the co-adaptation of others strategies. The neuronal substrate and the computational algorithms underlying such adaptive decision making, however, is largely unknown. We propose a population coding model of spiking neurons with a policy gradient procedure that successfully acquires optimal strategies for classical game-theoretical tasks. The suggested population reinforcement learning reproduces data from human behavioral experiments for the blackjack and the inspector game. It performs optimally according to a pure (deterministic) and mixed (stochastic) Nash equilibrium, respectively. In contrast, temporal-difference(TD)-learning, covariance-learning, and basic reinforcement learning fail to perform optimally for the stochastic strategy. Spike-based population reinforcement learning, shown to follow the stochastic reward gradient, is therefore a viable candidate to explain automated decision learning of a Nash equilibrium in two-player games. PMID- 23028290 TI - Convergent transmission of RNAi guide-target mismatch information across Argonaute internal allosteric network. AB - In RNA interference, a guide strand derived from a short dsRNA such as a microRNA (miRNA) is loaded into Argonaute, the central protein in the RNA Induced Silencing Complex (RISC) that silences messenger RNAs on a sequence-specific basis. The positions of any mismatched base pairs in an miRNA determine which Argonaute subtype is used. Subsequently, the Argonaute-guide complex binds and silences complementary target mRNAs; certain Argonautes cleave the target. Mismatches between guide strand and the target mRNA decrease cleavage efficiency. Thus, loading and silencing both require that signals about the presence of a mismatched base pair are communicated from the mismatch site to effector sites. These effector sites include the active site, to prevent target cleavage; the binding groove, to modify nucleic acid binding affinity; and surface allosteric sites, to control recruitment of additional proteins to form the RISC. To examine how such signals may be propagated, we analyzed the network of internal allosteric pathways in Argonaute exhibited through correlations of residue residue interactions. The emerging network can be described as a set of pathways emanating from the core of the protein near the active site, distributed into the bulk of the protein, and converging upon a distributed cluster of surface residues. Nucleotides in the guide strand "seed region" have a stronger relationship with the protein than other nucleotides, concordant with their importance in sequence selectivity. Finally, any of several seed region guide target mismatches cause certain Argonaute residues to have modified correlations with the rest of the protein. This arises from the aggregation of relatively small interaction correlation changes distributed across a large subset of residues. These residues are in effector sites: the active site, binding groove, and surface, implying that direct functional consequences of guide-target mismatches are mediated through the cumulative effects of a large number of internal allosteric pathways. PMID- 23028292 TI - Substrate-specific reorganization of the conformational ensemble of CSK implicates novel modes of kinase function. AB - Protein kinases use ATP as a phosphoryl donor for the posttranslational modification of signaling targets. It is generally thought that the binding of this nucleotide induces conformational changes leading to closed, more compact forms of the kinase domain that ideally orient active-site residues for efficient catalysis. The kinase domain is oftentimes flanked by additional ligand binding domains that up- or down-regulate catalytic function. C-terminal Src kinase (Csk) is a multidomain tyrosine kinase that is up-regulated by N-terminal SH2 and SH3 domains. Although the X-ray structure of Csk suggests the enzyme is compact, X ray scattering studies indicate that the enzyme possesses both compact and open conformational forms in solution. Here, we investigated whether interactions with the ATP analog AMP-PNP and ADP can shift the conformational ensemble of Csk in solution using a combination of small angle x-ray scattering and molecular dynamics simulations. We find that binding of AMP-PNP shifts the ensemble towards more extended rather than more compact conformations. Binding of ADP further shifts the ensemble towards extended conformations, including highly extended conformations not adopted by the apo protein, nor by the AMP-PNP bound protein. These ensembles indicate that any compaction of the kinase domain induced by nucleotide binding does not extend to the overall multi-domain architecture. Instead, assembly of an ATP-bound kinase domain generates further extended forms of Csk that may have relevance for kinase scaffolding and Src regulation in the cell. PMID- 23028291 TI - Tissue-specific functional networks for prioritizing phenotype and disease genes. AB - Integrated analyses of functional genomics data have enormous potential for identifying phenotype-associated genes. Tissue-specificity is an important aspect of many genetic diseases, reflecting the potentially different roles of proteins and pathways in diverse cell lineages. Accounting for tissue specificity in global integration of functional genomics data is challenging, as "functionality" and "functional relationships" are often not resolved for specific tissue types. We address this challenge by generating tissue-specific functional networks, which can effectively represent the diversity of protein function for more accurate identification of phenotype-associated genes in the laboratory mouse. Specifically, we created 107 tissue-specific functional relationship networks through integration of genomic data utilizing knowledge of tissue-specific gene expression patterns. Cross-network comparison revealed significantly changed genes enriched for functions related to specific tissue development. We then utilized these tissue-specific networks to predict genes associated with different phenotypes. Our results demonstrate that prediction performance is significantly improved through using the tissue-specific networks as compared to the global functional network. We used a testis-specific functional relationship network to predict genes associated with male fertility and spermatogenesis phenotypes, and experimentally confirmed one top prediction, Mbyl1. We then focused on a less-common genetic disease, ataxia, and identified candidates uniquely predicted by the cerebellum network, which are supported by both literature and experimental evidence. Our systems-level, tissue-specific scheme advances over traditional global integration and analyses and establishes a prototype to address the tissue-specific effects of genetic perturbations, diseases and drugs. PMID- 23028293 TI - Modeling the seasonal adaptation of circadian clocks by changes in the network structure of the suprachiasmatic nucleus. AB - The dynamics of circadian rhythms needs to be adapted to day length changes between summer and winter. It has been observed experimentally, however, that the dynamics of individual neurons of the suprachiasmatic nucleus (SCN) does not change as the seasons change. Rather, the seasonal adaptation of the circadian clock is hypothesized to be a consequence of changes in the intercellular dynamics, which leads to a phase distribution of electrical activity of SCN neurons that is narrower in winter and broader during summer. Yet to understand this complex intercellular dynamics, a more thorough understanding of the impact of the network structure formed by the SCN neurons is needed. To that effect, we propose a mathematical model for the dynamics of the SCN neuronal architecture in which the structure of the network plays a pivotal role. Using our model we show that the fraction of long-range cell-to-cell connections and the seasonal changes in the daily rhythms may be tightly related. In particular, simulations of the proposed mathematical model indicate that the fraction of long-range connections between the cells adjusts the phase distribution and consequently the length of the behavioral activity as follows: dense long-range connections during winter lead to a narrow activity phase, while rare long-range connections during summer lead to a broad activity phase. Our model is also able to account for the experimental observations indicating a larger light-induced phase-shift of the circadian clock during winter, which we show to be a consequence of higher synchronization between neurons. Our model thus provides evidence that the variations in the seasonal dynamics of circadian clocks can in part also be understood and regulated by the plasticity of the SCN network structure. PMID- 23028294 TI - Risk-sensitivity in Bayesian sensorimotor integration. AB - Information processing in the nervous system during sensorimotor tasks with inherent uncertainty has been shown to be consistent with Bayesian integration. Bayes optimal decision-makers are, however, risk-neutral in the sense that they weigh all possibilities based on prior expectation and sensory evidence when they choose the action with highest expected value. In contrast, risk-sensitive decision-makers are sensitive to model uncertainty and bias their decision-making processes when they do inference over unobserved variables. In particular, they allow deviations from their probabilistic model in cases where this model makes imprecise predictions. Here we test for risk-sensitivity in a sensorimotor integration task where subjects exhibit Bayesian information integration when they infer the position of a target from noisy sensory feedback. When introducing a cost associated with subjects' response, we found that subjects exhibited a characteristic bias towards low cost responses when their uncertainty was high. This result is in accordance with risk-sensitive decision-making processes that allow for deviations from Bayes optimal decision-making in the face of uncertainty. Our results suggest that both Bayesian integration and risk sensitivity are important factors to understand sensorimotor integration in a quantitative fashion. PMID- 23028295 TI - Multistationary and oscillatory modes of free radicals generation by the mitochondrial respiratory chain revealed by a bifurcation analysis. AB - The mitochondrial electron transport chain transforms energy satisfying cellular demand and generates reactive oxygen species (ROS) that act as metabolic signals or destructive factors. Therefore, knowledge of the possible modes and bifurcations of electron transport that affect ROS signaling provides insight into the interrelationship of mitochondrial respiration with cellular metabolism. Here, a bifurcation analysis of a sequence of the electron transport chain models of increasing complexity was used to analyze the contribution of individual components to the modes of respiratory chain behavior. Our algorithm constructed models as large systems of ordinary differential equations describing the time evolution of the distribution of redox states of the respiratory complexes. The most complete model of the respiratory chain and linked metabolic reactions predicted that condensed mitochondria produce more ROS at low succinate concentration and less ROS at high succinate levels than swelled mitochondria. This prediction was validated by measuring ROS production under various swelling conditions. A numerical bifurcation analysis revealed qualitatively different types of multistationary behavior and sustained oscillations in the parameter space near a region that was previously found to describe the behavior of isolated mitochondria. The oscillations in transmembrane potential and ROS generation, observed in living cells were reproduced in the model that includes interaction of respiratory complexes with the reactions of TCA cycle. Whereas multistationarity is an internal characteristic of the respiratory chain, the functional link of respiration with central metabolism creates oscillations, which can be understood as a means of auto-regulation of cell metabolism. PMID- 23028296 TI - The p7 protein of hepatitis C virus forms structurally plastic, minimalist ion channels. AB - Hepatitis C virus (HCV) p7 is a membrane-associated oligomeric protein harboring ion channel activity. It is essential for effective assembly and release of infectious HCV particles and an attractive target for antiviral intervention. Yet, the self-assembly and molecular mechanism of p7 ion channelling are currently only partially understood. Using molecular dynamics simulations (aggregate time 1.2 us), we show that p7 can form stable oligomers of four to seven subunits, with a bias towards six or seven subunits, and suggest that p7 self-assembles in a sequential manner, with tetrameric and pentameric complexes forming as intermediate states leading to the final hexameric or heptameric assembly. We describe a model of a hexameric p7 complex, which forms a transiently-open channel capable of conducting ions in simulation. We investigate the ability of the hexameric model to flexibly rearrange to adapt to the local lipid environment, and demonstrate how this model can be reconciled with low resolution electron microscopy data. In the light of these results, a view of p7 oligomerization is proposed, wherein hexameric and heptameric complexes may coexist, forming minimalist, yet robust functional ion channels. In the absence of a high-resolution p7 structure, the models presented in this paper can prove valuable as a substitute structure in future studies of p7 function, or in the search for p7-inhibiting drugs. PMID- 23028297 TI - Coupling between catalytic loop motions and enzyme global dynamics. AB - Catalytic loop motions facilitate substrate recognition and binding in many enzymes. While these motions appear to be highly flexible, their functional significance suggests that structure-encoded preferences may play a role in selecting particular mechanisms of motions. We performed an extensive study on a set of enzymes to assess whether the collective/global dynamics, as predicted by elastic network models (ENMs), facilitates or even defines the local motions undergone by functional loops. Our dataset includes a total of 117 crystal structures for ten enzymes of different sizes and oligomerization states. Each enzyme contains a specific functional/catalytic loop (10-21 residues long) that closes over the active site during catalysis. Principal component analysis (PCA) of the available crystal structures (including apo and ligand-bound forms) for each enzyme revealed the dominant conformational changes taking place in these loops upon substrate binding. These experimentally observed loop reconfigurations are shown to be predominantly driven by energetically favored modes of motion intrinsically accessible to the enzyme in the absence of its substrate. The analysis suggests that robust global modes cooperatively defined by the overall enzyme architecture also entail local components that assist in suitable opening/closure of the catalytic loop over the active site. PMID- 23028298 TI - Why open drug discovery needs four simple rules for licensing data and models. AB - When we look at the rapid growth of scientific databases on the Internet in the past decade, we tend to take the accessibility and provenance of the data for granted. As we see a future of increased database integration, the licensing of the data may be a hurdle that hampers progress and usability. We have formulated four rules for licensing data for open drug discovery, which we propose as a starting point for consideration by databases and for their ultimate adoption. This work could also be extended to the computational models derived from such data. We suggest that scientists in the future will need to consider data licensing before they embark upon re-using such content in databases they construct themselves. PMID- 23028299 TI - Ten simple rules to commercialize scientific research. PMID- 23028300 TI - Confidence-based somatic mutation evaluation and prioritization. AB - Next generation sequencing (NGS) has enabled high throughput discovery of somatic mutations. Detection depends on experimental design, lab platforms, parameters and analysis algorithms. However, NGS-based somatic mutation detection is prone to erroneous calls, with reported validation rates near 54% and congruence between algorithms less than 50%. Here, we developed an algorithm to assign a single statistic, a false discovery rate (FDR), to each somatic mutation identified by NGS. This FDR confidence value accurately discriminates true mutations from erroneous calls. Using sequencing data generated from triplicate exome profiling of C57BL/6 mice and B16-F10 melanoma cells, we used the existing algorithms GATK, SAMtools and SomaticSNiPer to identify somatic mutations. For each identified mutation, our algorithm assigned an FDR. We selected 139 mutations for validation, including 50 somatic mutations assigned a low FDR (high confidence) and 44 mutations assigned a high FDR (low confidence). All of the high confidence somatic mutations validated (50 of 50), none of the 44 low confidence somatic mutations validated, and 15 of 45 mutations with an intermediate FDR validated. Furthermore, the assignment of a single FDR to individual mutations enables statistical comparisons of lab and computation methodologies, including ROC curves and AUC metrics. Using the HiSeq 2000, single end 50 nt reads from replicates generate the highest confidence somatic mutation call set. PMID- 23028301 TI - The mechanistic basis of Myxococcus xanthus rippling behavior and its physiological role during predation. AB - Myxococcus xanthus cells self-organize into periodic bands of traveling waves, termed ripples, during multicellular fruiting body development and predation on other bacteria. To investigate the mechanistic basis of rippling behavior and its physiological role during predation by this Gram-negative soil bacterium, we have used an approach that combines mathematical modeling with experimental observations. Specifically, we developed an agent-based model (ABM) to simulate rippling behavior that employs a new signaling mechanism to trigger cellular reversals. The ABM has demonstrated that three ingredients are sufficient to generate rippling behavior: (i) side-to-side signaling between two cells that causes one of the cells to reverse, (ii) a minimal refractory time period after each reversal during which cells cannot reverse again, and (iii) physical interactions that cause the cells to locally align. To explain why rippling behavior appears as a consequence of the presence of prey, we postulate that prey associated macromolecules indirectly induce ripples by stimulating side-to-side contact-mediated signaling. In parallel to the simulations, M. xanthus predatory rippling behavior was experimentally observed and analyzed using time-lapse microscopy. A formalized relationship between the wavelength, reversal time, and cell velocity has been predicted by the simulations and confirmed by the experimental data. Furthermore, the results suggest that the physiological role of rippling behavior during M. xanthus predation is to increase the rate of spreading over prey cells due to increased side-to-side contact-mediated signaling and to allow predatory cells to remain on the prey longer as a result of more periodic cell motility. PMID- 23028303 TI - Retraction. Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PMID- 23028304 TI - Cryptococcus and beyond--inositol utilization and its implications for the emergence of fungal virulence. PMID- 23028305 TI - The human cytomegalovirus assembly compartment: a masterpiece of viral manipulation of cellular processes that facilitates assembly and egress. PMID- 23028306 TI - Copper at the front line of the host-pathogen battle. PMID- 23028307 TI - Deep sequencing of antiviral T-cell responses to HCMV and EBV in humans reveals a stable repertoire that is maintained for many years. AB - CD8(+) T-cell responses against latent viruses can cover considerable portions of the CD8(+) T-cell compartment for many decades, yet their initiation and maintenance remains poorly characterized in humans. A key question is whether the clonal repertoire that is raised during the initial antiviral response can be maintained over these long periods. To investigate this we combined next generation sequencing of the T-cell receptor repertoire with tetramer-sorting to identify, quantify and longitudinally follow virus-specific clones within the CD8(+) T-cell compartment. Using this approach we studied primary infections of human cytomegalovirus (hCMV) and Epstein Barr virus (EBV) in renal transplant recipients. For both viruses we found that nearly all virus-specific CD8(+) T cell clones that appeared during the early phase of infection were maintained at high frequencies during the 5-year follow-up and hardly any new anti-viral clones appeared. Both in transplant recipients and in healthy carriers the clones specific for these latent viruses were highly dominant within the CD8(+) T-cell receptor Vbeta repertoire. These findings suggest that the initial antiviral response in humans is maintained in a stable fashion without signs of contraction or changes of the clonal repertoire. PMID- 23028308 TI - A population genomics perspective on the emergence and adaptation of new plant pathogens in agro-ecosystems. PMID- 23028309 TI - The battle over mTOR: an emerging theatre in host-pathogen immunity. PMID- 23028310 TI - Vector-borne transmission imposes a severe bottleneck on an RNA virus population. AB - RNA viruses typically occur in genetically diverse populations due to their error prone genome replication. Genetic diversity is thought to be important in allowing RNA viruses to explore sequence space, facilitating adaptation to changing environments and hosts. Some arboviruses that infect both a mosquito vector and a mammalian host are known to experience population bottlenecks in their vectors, which may constrain their genetic diversity and could potentially lead to extinction events via Muller's ratchet. To examine this potential challenge of bottlenecks for arbovirus perpetuation, we studied Venezuelan equine encephalitis virus (VEEV) enzootic subtype IE and its natural vector Culex (Melanoconion) taeniopus, as an example of a virus-vector interaction with a long evolutionary history. Using a mixture of marked VEEV clones to infect C. taeniopus and real-time RT-PCR to track these clones during mosquito infection and dissemination, we observed severe bottleneck events that resulted in a significant drop in the number of clones present. At higher initial doses, the midgut was readily infected and there was a severe bottleneck at the midgut escape. Following a lower initial dose, the major bottleneck occurred at initial midgut infection. A second, less severe bottleneck was identified at the salivary gland infection stage following intrathoracic inoculation. Our results suggest that VEEV consistently encounters bottlenecks during infection, dissemination and transmission by its natural enzootic vector. The potential impacts of these bottlenecks on viral fitness and transmission, and the viral mechanisms that prevent genetic drift leading to extinction, deserve further study. PMID- 23028311 TI - PDGF receptor-alpha does not promote HCMV entry into epithelial and endothelial cells but increased quantities stimulate entry by an abnormal pathway. AB - Epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-alpha (PDGFRalpha) were reported to mediate entry of HCMV, including HCMV lab strain AD169. AD169 cannot assemble gH/gL/UL128-131, a glycoprotein complex that is essential for HCMV entry into biologically important epithelial cells, endothelial cells, and monocyte-macrophages. Given this, it appeared incongruous that EGFR and PDGFRalpha play widespread roles in HCMV entry. Thus, we investigated whether PDGFRalpha and EGFR could promote entry of wild type HCMV strain TR. EGFR did not promote HCMV entry into any cell type. PDGFRalpha transduction of epithelial and endothelial cells and several non-permissive cells markedly enhanced HCMV TR entry and surprisingly, promoted entry of HCMV mutants lacking gH/gL/UL128-131 into epithelial and endothelial cells. Entry of HCMV was not blocked by a panel of PDGFRalpha antibodies or the PDGFR ligand in fibroblasts, epithelial, or endothelial cells or by shRNA silencing of PDGFRalpha in epithelial cells. Moreover, HCMV glycoprotein induced cell-cell fusion was not increased when PDGFRalpha was expressed in cells. Together these results suggested that HCMV does not interact directly with PDGFRalpha. Instead, the enhanced entry produced by PDGFRalpha resulted from a novel entry pathway involving clathrin-independent, dynamin-dependent endocytosis of HCMV followed by low pH-independent fusion. When PDGFRalpha was expressed in cells, an HCMV lab strain escaped endosomes and tegument proteins reached the nucleus, but without PDGFRalpha virions were degraded. By contrast, wild type HCMV uses another pathway to enter epithelial cells involving macropinocytosis and low pH-dependent fusion, a pathway that lab strains (lacking gH/gL/UL128-131) cannot follow. Thus, PDGFRalpha does not act as a receptor for HCMV but increased PDGFRalpha alters cells, facilitating virus entry by an abnormal pathway. Given that PDGFRalpha increased infection of some cells to 90%, PDGFRalpha may be very useful in overcoming inefficient HCMV entry (even of lab strains) into the many difficult to-infect cell types. PMID- 23028312 TI - The Legionella IcmSW complex directly interacts with DotL to mediate translocation of adaptor-dependent substrates. AB - Legionella pneumophila is a Gram-negative bacterium that replicates within human alveolar macrophages by evasion of the host endocytic pathway through the formation of a replicative vacuole. Generation of this vacuole is dependent upon the secretion of over 275 effector proteins into the host cell via the Dot/Icm type IVB secretion system (T4SS). The type IV coupling protein (T4CP) subcomplex, consisting of DotL, DotM, DotN, IcmS and IcmW, was recently defined. DotL is proposed to be the T4CP of the L. pneumophila T4SS based on its homology to known T4CPs, which function as inner-membrane receptors for substrates. As a result, DotL is hypothesized to play an integral role(s) in the L. pneumophila T4SS for the engagement and translocation of substrates. To elucidate this role, a genetic approach was taken to screen for dotL mutants that were unable to survive inside host cells. One mutant, dotLY725Stop, did not interact with the type IV adaptor proteins IcmS/IcmW (IcmSW) leading to the identification of an IcmSW-binding domain on DotL. Interestingly, the dotLY725Stop mutant was competent for export of one class of secreted effectors, the IcmSW-independent substrates, but exhibited a specific defect in secretion of IcmSW-dependent substrates. This differential secretion illustrates that DotL requires a direct interaction with the type IV adaptor proteins for the secretion of a major class of substrates. Thus, by identifying a new target for IcmSW, we have discovered that the type IV adaptors perform an additional role in the export of substrates by the L. pneumophila Dot/Icm T4SS. PMID- 23028313 TI - Molecular basis for nucleotide conservation at the ends of the dengue virus genome. AB - The dengue virus (DV) is an important human pathogen from the Flavivirus genus, whose genome- and antigenome RNAs start with the strictly conserved sequence pppAG. The RNA-dependent RNA polymerase (RdRp), a product of the NS5 gene, initiates RNA synthesis de novo, i.e., without the use of a pre-existing primer. Very little is known about the mechanism of this de novo initiation and how conservation of the starting adenosine is achieved. The polymerase domain NS5Pol(DV) of NS5, upon initiation on viral RNA templates, synthesizes mainly dinucleotide primers that are then elongated in a processive manner. We show here that NS5Pol(DV) contains a specific priming site for adenosine 5'-triphosphate as the first transcribed nucleotide. Remarkably, in the absence of any RNA template the enzyme is able to selectively synthesize the dinucleotide pppAG when Mn(2+) is present as catalytic ion. The T794 to A799 priming loop is essential for initiation and provides at least part of the ATP-specific priming site. The H798 loop residue is of central importance for the ATP-specific initiation step. In addition to ATP selection, NS5Pol(DV) ensures the conservation of the 5' adenosine by strongly discriminating against viral templates containing an erroneous 3'-end nucleotide in the presence of Mg(2+). In the presence of Mn(2+), NS5Pol(DV) is remarkably able to generate and elongate the correct pppAG primer on these erroneous templates. This can be regarded as a genomic/antigenomic RNA end repair mechanism. These conservational mechanisms, mediated by the polymerase alone, may extend to other RNA virus families having RdRps initiating RNA synthesis de novo. PMID- 23028314 TI - H1N1 2009 pandemic influenza virus: resistance of the I223R neuraminidase mutant explained by kinetic and structural analysis. AB - Two classes of antiviral drugs, neuraminidase inhibitors and adamantanes, are approved for prophylaxis and therapy against influenza virus infections. A major concern is that antiviral resistant viruses emerge and spread in the human population. The 2009 pandemic H1N1 virus is already resistant to adamantanes. Recently, a novel neuraminidase inhibitor resistance mutation I223R was identified in the neuraminidase of this subtype. To understand the resistance mechanism of this mutation, the enzymatic properties of the I223R mutant, together with the most frequently observed resistance mutation, H275Y, and the double mutant I223R/H275Y were compared. Relative to wild type, K(M) values for MUNANA increased only 2-fold for the single I223R mutant and up to 8-fold for the double mutant. Oseltamivir inhibition constants (K(I)) increased 48-fold in the single I223R mutant and 7500-fold in the double mutant. In both cases the change was largely accounted for by an increased dissociation rate constant for oseltamivir, but the inhibition constants for zanamivir were less increased. We have used X-ray crystallography to better understand the effect of mutation I223R on drug binding. We find that there is shrinkage of a hydrophobic pocket in the active site as a result of the I223R change. Furthermore, R223 interacts with S247 which changes the rotamer it adopts and, consequently, binding of the pentoxyl substituent of oseltamivir is not as favorable as in the wild type. However, the polar glycerol substituent present in zanamivir, which mimics the natural substrate, is accommodated in the I223R mutant structure in a similar way to wild type, thus explaining the kinetic data. Our structural data also show that, in contrast to a recently reported structure, the active site of 2009 pandemic neuraminidase can adopt an open conformation. PMID- 23028315 TI - Slc15a4, a gene required for pDC sensing of TLR ligands, is required to control persistent viral infection. AB - Plasmacytoid dendritic cells (pDCs) are the major producers of type I IFN in response to viral infection and have been shown to direct both innate and adaptive immune responses in vitro. However, in vivo evidence for their role in viral infection is lacking. We evaluated the contribution of pDCs to acute and chronic virus infection using the feeble mouse model of pDC functional deficiency. We have previously demonstrated that feeble mice have a defect in TLR ligand sensing. Although pDCs were found to influence early cytokine secretion, they were not required for control of viremia in the acute phase of the infection. However, T cell priming was deficient in the absence of functional pDCs and the virus-specific immune response was hampered. Ultimately, infection persisted in feeble mice. We conclude that pDCs are likely required for efficient T cell priming and subsequent viral clearance. Our data suggest that reduced pDC functionality may lead to chronic infection. PMID- 23028316 TI - Marburg virus VP35 can both fully coat the backbone and cap the ends of dsRNA for interferon antagonism. AB - Filoviruses, including Marburg virus (MARV) and Ebola virus (EBOV), cause fatal hemorrhagic fever in humans and non-human primates. All filoviruses encode a unique multi-functional protein termed VP35. The C-terminal double-stranded (ds)RNA-binding domain (RBD) of VP35 has been implicated in interferon antagonism and immune evasion. Crystal structures of the VP35 RBD from two ebolaviruses have previously demonstrated that the viral protein caps the ends of dsRNA. However, it is not yet understood how the expanses of dsRNA backbone, between the ends, are masked from immune surveillance during filovirus infection. Here, we report the crystal structure of MARV VP35 RBD bound to dsRNA. In the crystal structure, molecules of dsRNA stack end-to-end to form a pseudo-continuous oligonucleotide. This oligonucleotide is continuously and completely coated along its sugar phosphate backbone by the MARV VP35 RBD. Analysis of dsRNA binding by dot-blot and isothermal titration calorimetry reveals that multiple copies of MARV VP35 RBD can indeed bind the dsRNA sugar-phosphate backbone in a cooperative manner in solution. Further, MARV VP35 RBD can also cap the ends of the dsRNA in solution, although this arrangement was not captured in crystals. Together, these studies suggest that MARV VP35 can both coat the backbone and cap the ends, and that for MARV, coating of the dsRNA backbone may be an essential mechanism by which dsRNA is masked from backbone-sensing immune surveillance molecules. PMID- 23028317 TI - Phase variable O antigen biosynthetic genes control expression of the major protective antigen and bacteriophage receptor in Vibrio cholerae O1. AB - The Vibrio cholerae lipopolysaccharide O1 antigen is a major target of bacteriophages and the human immune system and is of critical importance for vaccine design. We used an O1-specific lytic bacteriophage as a tool to probe the capacity of V. cholerae to alter its O1 antigen and identified a novel mechanism by which this organism can modulate O antigen expression and exhibit intra-strain heterogeneity. We identified two phase variable genes required for O1 antigen biosynthesis, manA and wbeL. manA resides outside of the previously recognized O1 antigen biosynthetic locus, and encodes for a phosphomannose isomerase critical for the initial step in O1 antigen biosynthesis. We determined that manA and wbeL phase variants are attenuated for virulence, providing functional evidence to further support the critical role of the O1 antigen for infectivity. We provide the first report of phase variation modulating O1 antigen expression in V. cholerae, and show that the maintenance of these phase variable loci is an important means by which this facultative pathogen can generate the diverse subpopulations of cells needed for infecting the host intestinal tract and for escaping predation by an O1-specific phage. PMID- 23028318 TI - Very long O-antigen chains enhance fitness during Salmonella-induced colitis by increasing bile resistance. AB - Intestinal inflammation changes the luminal habitat for microbes through mechanisms that have not been fully resolved. We noticed that the FepE regulator of very long O-antigen chain assembly in the enteric pathogen Salmonella enterica serotype Typhimurium (S. Typhimurium) conferred a luminal fitness advantage in the mouse colitis model. However, a fepE mutant was not defective for survival in tissue, resistance to complement or resistance to polymyxin B. We performed metabolite profiling to identify changes in the luminal habitat that accompany S. Typhimurium-induced colitis. This analysis suggested that S. Typhimurium-induced colitis increased the luminal concentrations of total bile acids. A mutation in fepE significantly reduced the minimal inhibitory concentration (MIC) of S. Typhimurium for bile acids in vitro. Oral administration of the bile acid sequestrant cholestyramine resin lowered the concentrations of total bile acids in colon contents during S. Typhimurium infection and significantly reduced the luminal fitness advantage conferred by the fepE gene in the mouse colitis model. Collectively, these data suggested that very long O-antigen chains function in bile acid resistance of S. Typhimurium, a property conferring a fitness advantage during luminal growth in the inflamed intestine. PMID- 23028319 TI - Structural organization of pregenomic RNA and the carboxy-terminal domain of the capsid protein of hepatitis B virus. AB - The Hepatitis B Virus (HBV) double-stranded DNA genome is reverse transcribed from its RNA pregenome (pgRNA) within the virus core (or capsid). Phosphorylation of the arginine-rich carboxy-terminal domain (CTD) of the HBV capsid protein (Cp183) is essential for pgRNA encapsidation and reverse transcription. However, the structure of the CTD remains poorly defined. Here we report sub-nanometer resolution cryo-EM structures of in vitro assembled empty and pgRNA-filled Cp183 capsids in unphosphorylated and phosphorylation-mimic states. In empty capsids, we found unexpected evidence of surface accessible CTD density partially occluding pores in the capsid surface. We also observed that CTD organization changed substantively as a function of phosphorylation. In RNA-filled capsids, unphosphorylated CTDs favored thick ropes of RNA, while the phosphorylation-mimic favored a mesh of thin, high-density strands suggestive of single stranded RNA. These results demonstrate that the CTD can regulate nucleic acid structure, supporting the hypothesis that the HBV capsid has a functional role as a nucleic acid chaperone. PMID- 23028320 TI - AID activity in B cells strongly correlates with polyclonal antibody affinity maturation in-vivo following pandemic 2009-H1N1 vaccination in humans. AB - The role of Activation-Induced Cytidine Deaminase (AID) in somatic hypermutation and polyclonal antibody affinity maturation has not been shown for polyclonal responses in humans. We investigated whether AID induction in human B cells following H1N1pdm09 vaccination correlated with in-vivo antibody affinity maturation against hemagglutinin domains in plasma of young and elderly individuals. AID was measured by qPCR in B cells from individuals of different ages immunized with the H1N1pdm09 influenza vaccine. Polyclonal antibody affinity in human plasma for the HA1 and HA2 domains of the H1N1pdm09 hemagglutinin was measured by antibody-antigen complex dissociation rates using real time kinetics in Surface Plasmon Resonance. Results show an age-related decrease in AID induction in B cells following H1N1pdm09 vaccination. Levels of AID mRNA before vaccination and fold-increase of AID mRNA expression after H1N1pdm09 vaccination directly correlated with increase in polyclonal antibody affinity to the HA1 globular domain (but not to the conserved HA2 stalk). In the younger population, significant affinity maturation to the HA1 globular domain was observed, which associated with initial levels of AID and fold-increase in AID after vaccination. In some older individuals (>65 yr), higher affinity to the HA1 domain was observed before vaccination and H1N1pdm09 vaccination resulted in minimal change in antibody affinity, which correlated with low AID induction in this age group. These findings demonstrate for the first time a strong correlation between AID induction and in-vivo antibody affinity maturation in humans. The ability to generate high affinity antibodies could have significant impact on the elucidation of age-specific antibody responses following vaccination and eventual clinical efficacy and disease outcome. PMID- 23028321 TI - A cell-based screen reveals that the albendazole metabolite, albendazole sulfone, targets Wolbachia. AB - Wolbachia endosymbionts carried by filarial nematodes give rise to the neglected diseases African river blindness and lymphatic filariasis afflicting millions worldwide. Here we identify new Wolbachia-disrupting compounds by conducting high throughput cell-based chemical screens using a Wolbachia-infected, fluorescently labeled Drosophila cell line. This screen yielded several Wolbachia-disrupting compounds including three that resembled Albendazole, a widely used anthelmintic drug that targets nematode microtubules. Follow-up studies demonstrate that a common Albendazole metabolite, Albendazole sulfone, reduces intracellular Wolbachia titer both in Drosophila melanogaster and Brugia malayi, the nematode responsible for lymphatic filariasis. Significantly, Albendazole sulfone does not disrupt Drosophila microtubule organization, suggesting that this compound reduces titer through direct targeting of Wolbachia. Accordingly, both DNA staining and FtsZ immunofluorescence demonstrates that Albendazole sulfone treatment induces Wolbachia elongation, a phenotype indicative of binary fission defects. This suggests that the efficacy of Albendazole in treating filarial nematode-based diseases is attributable to dual targeting of nematode microtubules and their Wolbachia endosymbionts. PMID- 23028322 TI - Structure and assembly of a trans-periplasmic channel for type IV pili in Neisseria meningitidis. AB - Type IV pili are polymeric fibers which protrude from the cell surface and play a critical role in adhesion and invasion by pathogenic bacteria. The secretion of pili across the periplasm and outer membrane is mediated by a specialized secretin protein, PilQ, but the way in which this large channel is formed is unknown. Using NMR, we derived the structures of the periplasmic domains from N. meningitidis PilQ: the N-terminus is shown to consist of two beta-domains, which are unique to the type IV pilus-dependent secretins. The structure of the second beta-domain revealed an eight-stranded beta-sandwich structure which is a novel variant of the HSP20-like fold. The central part of PilQ consists of two alpha/beta fold domains: the structure of the first of these is similar to domains from other secretins, but with an additional alpha-helix which links it to the second alpha/beta domain. We also determined the structure of the entire PilQ dodecamer by cryoelectron microscopy: it forms a cage-like structure, enclosing a cavity which is approximately 55 A in internal diameter at its largest extent. Specific regions were identified in the density map which corresponded to the individual PilQ domains: this allowed us to dock them into the cryoelectron microscopy density map, and hence reconstruct the entire PilQ assembly which spans the periplasm. We also show that the C-terminal domain from the lipoprotein PilP, which is essential for pilus assembly, binds specifically to the first alpha/beta domain in PilQ and use NMR chemical shift mapping to generate a model for the PilP:PilQ complex. We conclude that passage of the pilus fiber requires disassembly of both the membrane-spanning and the beta-domain regions in PilQ, and that PilP plays an important role in stabilising the PilQ assembly during secretion, through its anchorage in the inner membrane. PMID- 23028324 TI - Relacin, a novel antibacterial agent targeting the Stringent Response. AB - Finding bacterial cellular targets for developing novel antibiotics has become a major challenge in fighting resistant pathogenic bacteria. We present a novel compound, Relacin, designed to inhibit (p)ppGpp production by the ubiquitous bacterial enzyme RelA that triggers the Stringent Response. Relacin inhibits RelA in vitro and reduces (p)ppGpp production in vivo. Moreover, Relacin affects entry into stationary phase in Gram positive bacteria, leading to a dramatic reduction in cell viability. When Relacin is added to sporulating Bacillus subtilis cells, it strongly perturbs spore formation regardless of the time of addition. Spore formation is also impeded in the pathogenic bacterium Bacillus anthracis that causes the acute anthrax disease. Finally, the formation of multicellular biofilms is markedly disrupted by Relacin. Thus, we establish that Relacin, a novel ppGpp analogue, interferes with bacterial long term survival strategies, placing it as an attractive new antibacterial agent. PMID- 23028323 TI - A novel rhabdovirus associated with acute hemorrhagic fever in central Africa. AB - Deep sequencing was used to discover a novel rhabdovirus (Bas-Congo virus, or BASV) associated with a 2009 outbreak of 3 human cases of acute hemorrhagic fever in Mangala village, Democratic Republic of Congo (DRC), Africa. The cases, presenting over a 3-week period, were characterized by abrupt disease onset, high fever, mucosal hemorrhage, and, in two patients, death within 3 days. BASV was detected in an acute serum sample from the lone survivor at a concentration of 1.09 * 10(6) RNA copies/mL, and 98.2% of the genome was subsequently de novo assembled from ~ 140 million sequence reads. Phylogenetic analysis revealed that BASV is highly divergent and shares less than 34% amino acid identity with any other rhabdovirus. High convalescent neutralizing antibody titers of >1:1000 were detected in the survivor and an asymptomatic nurse directly caring for him, both of whom were health care workers, suggesting the potential for human-to-human transmission of BASV. The natural animal reservoir host or arthropod vector and precise mode of transmission for the virus remain unclear. BASV is an emerging human pathogen associated with acute hemorrhagic fever in Africa. PMID- 23028325 TI - Kaposi's sarcoma herpesvirus K15 protein contributes to virus-induced angiogenesis by recruiting PLCgamma1 and activating NFAT1-dependent RCAN1 expression. AB - Kaposi's Sarcoma (KS), caused by Kaposi's Sarcoma Herpesvirus (KSHV), is a highly vascularised angiogenic tumor of endothelial cells, characterized by latently KSHV-infected spindle cells and a pronounced inflammatory infiltrate. Several KSHV proteins, including LANA-1 (ORF73), vCyclin (ORF72), vGPCR (ORF74), vIL6 (ORF-K2), vCCL-1 (ORF-K6), vCCL-2 (ORF-K4) and K1 have been shown to exert effects that can lead to the proliferation and atypical differentiation of endothelial cells and/or the secretion of cytokines with angiogenic and inflammatory properties (VEGF, bFGF, IL6, IL8, GROalpha, and TNFbeta). To investigate a role of the KSHV K15 protein in KSHV-mediated angiogenesis, we carried out a genome wide gene expression analysis on primary endothelial cells infected with KSHV wildtype (KSHVwt) and a KSHV K15 deletion mutant (KSHVDeltaK15). We found RCAN1/DSCR1 (Regulator of Calcineurin 1/Down Syndrome critical region 1), a cellular gene involved in angiogenesis, to be differentially expressed in KSHVwt- vs KSHVDeltaK15-infected cells. During physiological angiogenesis, expression of RCAN1 in endothelial cells is regulated by VEGF (vascular endothelial growth factor) through a pathway involving the activation of PLCgamma1, Calcineurin and NFAT1. We found that K15 directly recruits PLCgamma1, and thereby activates Calcineurin/NFAT1-dependent RCAN1 expression which results in the formation of angiogenic tubes. Primary endothelial cells infected with KSHVwt form angiogenic tubes upon activation of the lytic replication cycle. This effect is abrogated when K15 is deleted (KSHVDeltaK15) or silenced by an siRNA targeting the K15 expression. Our study establishes K15 as one of the KSHV proteins that contribute to KSHV-induced angiogenesis. PMID- 23028326 TI - Loss of effector and anti-inflammatory natural killer T lymphocyte function in pathogenic simian immunodeficiency virus infection. AB - Chronic immune activation is a key determinant of AIDS progression in HIV infected humans and simian immunodeficiency virus (SIV)-infected macaques but is singularly absent in SIV-infected natural hosts. To investigate whether natural killer T (NKT) lymphocytes contribute to the differential modulation of immune activation in AIDS-susceptible and AIDS-resistant hosts, we compared NKT function in macaques and sooty mangabeys in the absence and presence of SIV infection. Cynomolgus macaques had significantly higher frequencies of circulating invariant NKT lymphocytes compared to both rhesus macaques and AIDS-resistant sooty mangabeys. Despite this difference, mangabey NKT lymphocytes were functionally distinct from both macaque species in their ability to secrete significantly more IFN-gamma, IL-13, and IL-17 in response to CD1d/alpha-galactosylceramide stimulation. While NKT number and function remained intact in SIV-infected mangabeys, there was a profound reduction in NKT activation-induced, but not mitogen-induced, secretion of IFN-gamma, IL-2, IL-10, and TGF-beta in SIV infected macaques. SIV-infected macaques also showed a selective decline in CD4(+) NKT lymphocytes which correlated significantly with an increase in circulating activated memory CD4(+) T lymphocytes. Macaques with lower pre infection NKT frequencies showed a significantly greater CD4(+) T lymphocyte decline post SIV infection. The disparate effect of SIV infection on NKT function in mangabeys and macaques could be a manifestation of their differential susceptibility to AIDS. Alternately, these data also raise the possibility that loss of anti-inflammatory NKT function promotes chronic immune activation in pathogenic SIV infection, while intact NKT function helps to protect natural hosts from developing immunodeficiency and aberrant immune activation. PMID- 23028327 TI - Complexes of vesicular stomatitis virus matrix protein with host Rae1 and Nup98 involved in inhibition of host transcription. AB - Vesicular stomatitis virus (VSV) suppresses antiviral responses in infected cells by inhibiting host gene expression at multiple levels, including transcription, nuclear cytoplasmic transport, and translation. The inhibition of host gene expression is due to the activity of the viral matrix (M) protein. Previous studies have shown that M protein interacts with host proteins Rae1 and Nup98 that have been implicated in regulating nuclear-cytoplasmic transport. However, Rae1 function is not essential for host mRNA transport, raising the question of how interaction of a viral protein with a host protein that is not essential for gene expression causes a global inhibition at multiple levels. We tested the hypothesis that there may be multiple M protein-Rae1 complexes involved in inhibiting host gene expression at multiple levels. Using size exclusion chromatography and sedimentation velocity analysis, it was determined that Rae1 exists in high, intermediate, and low molecular weight complexes. The intermediate molecular weight complexes containing Nup98 interacted most efficiently with M protein. The low molecular weight form also interacted with M protein in cells that overexpress Rae1 or cells in which Nup98 expression was silenced. Silencing Rae1 expression had little if any effect on nuclear accumulation of host mRNA in VSV-infected cells, nor did it affect VSV's ability to inhibit host translation. Instead, silencing Rae1 expression reduced the ability of VSV to inhibit host transcription. M protein interacted efficiently with Rae1-Nup98 complexes associated with the chromatin fraction of host nuclei, consistent with an effect on host transcription. These results support the idea that M protein-Rae1 complexes serve as platforms to promote the interaction of M protein with other factors involved in host transcription. They also support the idea that Rae1-Nup98 complexes play a previously under-appreciated role in regulation of transcription. PMID- 23028328 TI - Identification of alternatively translated Tetherin isoforms with differing antiviral and signaling activities. AB - Tetherin (BST-2/CD317/HM1.24) is an IFN induced transmembrane protein that restricts release of a broad range of enveloped viruses. Important features required for Tetherin activity and regulation reside within the cytoplasmic domain. Here we demonstrate that two isoforms, derived by alternative translation initiation from highly conserved methionine residues in the cytoplasmic domain, are produced in both cultured human cell lines and primary cells. These two isoforms have distinct biological properties. The short isoform (s-Tetherin), which lacks 12 residues present in the long isoform (l-Tetherin), is significantly more resistant to HIV-1 Vpu-mediated downregulation and consequently more effectively restricts HIV-1 viral budding in the presence of Vpu. s-Tetherin Vpu resistance can be accounted for by the loss of serine threonine and tyrosine motifs present in the long isoform. By contrast, the l Tetherin isoform was found to be an activator of nuclear factor-kappa B (NF kappaB) signaling whereas s-Tetherin does not activate NF-kappaB. Activation of NF-kappaB requires a tyrosine-based motif found within the cytoplasmic tail of the longer species and may entail formation of l-Tetherin homodimers since co expression of s-Tetherin impairs the ability of the longer isoform to activate NF kappaB. These results demonstrate a novel mechanism for control of Tetherin antiviral and signaling function and provide insight into Tetherin function both in the presence and absence of infection. PMID- 23028329 TI - Myeloid infection links epithelial and B cell tropisms of Murid Herpesvirus-4. AB - Gamma-herpesviruses persist in lymphocytes and cause disease by driving their proliferation. Lymphocyte infection is therefore a key pathogenetic event. Murid Herpesvirus-4 (MuHV-4) is a rhadinovirus that like the related Kaposi's Sarcoma associated Herpesvirus persists in B cells in vivo yet infects them poorly in vitro. Here we used MuHV-4 to understand how virion tropism sets the path to lymphocyte colonization. Virions that were highly infectious in vivo showed a severe post-binding block to B cell infection. Host entry was accordingly an epithelial infection and B cell infection a secondary event. Macrophage infection by cell-free virions was also poor, but improved markedly when virion binding improved or when macrophages were co-cultured with infected fibroblasts. Under the same conditions B cell infection remained poor; it improved only when virions came from macrophages. This reflected better cell penetration and correlated with antigenic changes in the virion fusion complex. Macrophages were seen to contact acutely infected epithelial cells, and cre/lox-based virus tagging showed that almost all the virus recovered from lymphoid tissue had passed through lysM(+) and CD11c(+) myeloid cells. Thus MuHV-4 reached B cells in 3 distinct stages: incoming virions infected epithelial cells; infection then passed to myeloid cells; glycoprotein changes then allowed B cell infection. These data identify new complexity in rhadinovirus infection and potentially also new vulnerability to intervention. PMID- 23028330 TI - A role for microRNA-155 modulation in the anti-HIV-1 effects of Toll-like receptor 3 stimulation in macrophages. AB - HIV-1 infection of macrophages plays a key role in viral pathogenesis and progression to AIDS. Polyinosine-polycytidylic acid (poly(I:C); a synthetic analog of dsRNA) and bacterial lipopolysaccharide (LPS), the ligands for Toll like receptors (TLR) TLR3 and TLR4, respectively, are known to decrease HIV-1 infection in monocyte-derived macrophages (MDMs), but the mechanism(s) are incompletely understood. We found that poly(I:C)- and LPS-stimulation of MDMs abrogated infection by CCR5-using, macrophage-tropic HIV-1, and by vesicular stomatitis virus glycoprotein-pseudotyped HIV-1 virions, while TLR2, TLR7 or TLR9 agonists only partially reduced infection to varying extent. Suppression of infection, or lack thereof, did not correlate with differential effects on CD4 or CCR5 expression, type I interferon induction, or production of pro-inflammatory cytokines or beta-chemokines. Integrated pro-viruses were readily detected in unstimulated, TLR7- and TLR9-stimulated cells, but not in TLR3- or TLR4 stimulated MDMs, suggesting the alteration of post-entry, pre-integration event(s). Using microarray analysis and quantitative reverse transcription (RT) PCR, we found increased microRNA (miR)-155 levels in MDMs upon TLR3/4- but not TLR7-stimulation, and a miR-155 specific inhibitor (but not a scrambled control) partially restored infectivity in poly(I:C)-stimulated MDMs. Ectopic miR-155 expression remarkably diminished HIV-1 infection in primary MDMs and cell lines. Furthermore, poly(I:C)-stimulation and ectopic miR-155 expression did not alter detection of early viral RT products, but both resulted in an accumulation of late RT products and in undetectable or extremely low levels of integrated pro viruses and 2-LTR circles. Reduced mRNA and protein levels of several HIV-1 dependency factors involved in trafficking and/or nuclear import of pre integration complexes (ADAM10, TNPO3, Nup153, LEDGF/p75) were found in poly(I:C) stimulated and miR-155-transfected MDMs, and a reporter assay suggested they are authentic miR-155 targets. Our findings provide evidence that miR-155 exerts an anti-HIV-1 effect by targeting several HIV-1 dependency factors involved in post entry, pre-integration events, leading to severely diminished HIV-1 infection. PMID- 23028331 TI - Acid-induced type VI secretion system is regulated by ExoR-ChvG/ChvI signaling cascade in Agrobacterium tumefaciens. AB - The type VI secretion system (T6SS) is a widespread, versatile protein secretion system in pathogenic Proteobacteria. Several T6SSs are tightly regulated by various regulatory systems at multiple levels. However, the signals and/or regulatory mechanisms of many T6SSs remain unexplored. Here, we report on an acid induced regulatory mechanism activating T6SS in Agrobacterium tumefaciens, a plant pathogenic bacterium causing crown gall disease in a wide range of plants. We monitored the secretion of the T6SS hallmark protein hemolysin-coregulated protein (Hcp) from A. tumefaciens and found that acidity is a T6SS-inducible signal. Expression analysis of the T6SS gene cluster comprising the imp and hcp operons revealed that imp expression and Hcp secretion are barely detected in A. tumefaciens grown in neutral minimal medium but are highly induced with acidic medium. Loss- and gain-of-function analysis revealed that the A. tumefaciens T6SS is positively regulated by a chvG/chvI two-component system and negatively regulated by exoR. Further epistasis analysis revealed that exoR functions upstream of the chvG sensor kinase in regulating T6SS. ChvG protein levels are greatly increased in the exoR deletion mutant and the periplasmic form of overexpressed ExoR is rapidly degraded under acidic conditions. Importantly, ExoR represses ChvG by direct physical interaction, but disruption of the physical interaction allows ChvG to activate T6SS. The phospho-mimic but not wild-type ChvI response regulator can bind to the T6SS promoter region in vitro and activate T6SS with growth in neutral minimal medium. We present the first evidence of T6SS activation by an ExoR-ChvG/ChvI cascade and propose that acidity triggers ExoR degradation, thereby derepressing ChvG/ChvI to activate T6SS in A. tumefaciens. PMID- 23028332 TI - Primary and secondary siRNAs in geminivirus-induced gene silencing. AB - In plants, RNA silencing-based antiviral defense is mediated by Dicer-like (DCL) proteins producing short interfering (si)RNAs. In Arabidopsis infected with the bipartite circular DNA geminivirus Cabbage leaf curl virus (CaLCuV), four distinct DCLs produce 21, 22 and 24 nt viral siRNAs. Using deep sequencing and blot hybridization, we found that viral siRNAs of each size-class densely cover the entire viral genome sequences in both polarities, but highly abundant siRNAs correspond primarily to the leftward and rightward transcription units. Double stranded RNA precursors of viral siRNAs can potentially be generated by host RDR dependent RNA polymerase (RDR). However, genetic evidence revealed that CaLCuV siRNA biogenesis does not require RDR1, RDR2, or RDR6. By contrast, CaLCuV derivatives engineered to target 30 nt sequences of a GFP transgene by primary viral siRNAs trigger RDR6-dependent production of secondary siRNAs. Viral siRNAs targeting upstream of the GFP stop codon induce secondary siRNAs almost exclusively from sequences downstream of the target site. Conversely, viral siRNAs targeting the GFP 3'-untranslated region (UTR) induce secondary siRNAs mostly upstream of the target site. RDR6-dependent siRNA production is not necessary for robust GFP silencing, except when viral siRNAs targeted GFP 5'-UTR. Furthermore, viral siRNAs targeting the transgene enhancer region cause GFP silencing without secondary siRNA production. We conclude that the majority of viral siRNAs accumulating during geminiviral infection are RDR1/2/6-independent primary siRNAs. Double-stranded RNA precursors of these siRNAs are likely generated by bidirectional readthrough transcription of circular viral DNA by RNA polymerase II. Unlike transgenic mRNA, geminiviral mRNAs appear to be poor templates for RDR-dependent production of secondary siRNAs. PMID- 23028333 TI - Mycobacterium marinum causes a latent infection that can be reactivated by gamma irradiation in adult zebrafish. AB - The mechanisms leading to latency and reactivation of human tuberculosis are still unclear, mainly due to the lack of standardized animal models for latent mycobacterial infection. In this longitudinal study of the progression of a mycobacterial disease in adult zebrafish, we show that an experimental intraperitoneal infection with a low dose (~ 35 bacteria) of Mycobacterium marinum, results in the development of a latent disease in most individuals. The infection is characterized by limited mortality (25%), stable bacterial loads 4 weeks following infection and constant numbers of highly organized granulomas in few target organs. The majority of bacteria are dormant during a latent mycobacterial infection in zebrafish, and can be activated by resuscitation promoting factor ex vivo. In 5-10% of tuberculosis cases in humans, the disease is reactivated usually as a consequence of immune suppression. In our model, we are able to show that reactivation can be efficiently induced in infected zebrafish by gamma-irradiation that transiently depletes granulo/monocyte and lymphocyte pools, as determined by flow cytometry. This immunosuppression causes reactivation of the dormant mycobacterial population and a rapid outgrowth of bacteria, leading to 88% mortality in four weeks. In this study, the adult zebrafish presents itself as a unique non-mammalian vertebrate model for studying the development of latency, regulation of mycobacterial dormancy, as well as reactivation of latent or subclinical tuberculosis. The possibilities for screening for host and pathogen factors affecting the disease progression, and identifying novel therapeutic agents and vaccine targets make this established model especially attractive. PMID- 23028334 TI - The single-nucleotide resolution transcriptome of Pseudomonas aeruginosa grown in body temperature. AB - One of the hallmarks of opportunistic pathogens is their ability to adjust and respond to a wide range of environmental and host-associated conditions. The human pathogen Pseudomonas aeruginosa has an ability to thrive in a variety of hosts and cause a range of acute and chronic infections in individuals with impaired host defenses or cystic fibrosis. Here we report an in-depth transcriptional profiling of this organism when grown at host-related temperatures. Using RNA-seq of samples from P. aeruginosa grown at 28 degrees C and 37 degrees C we detected genes preferentially expressed at the body temperature of mammalian hosts, suggesting that they play a role during infection. These temperature-induced genes included the type III secretion system (T3SS) genes and effectors, as well as the genes responsible for phenazines biosynthesis. Using genome-wide transcription start site (TSS) mapping by RNA-seq we were able to accurately define the promoters and cis-acting RNA elements of many genes, and uncovered new genes and previously unrecognized non-coding RNAs directly controlled by the LasR quorum sensing regulator. Overall we identified 165 small RNAs and over 380 cis-antisense RNAs, some of which predicted to perform regulatory functions, and found that non-coding RNAs are preferentially localized in pathogenicity islands and horizontally transferred regions. Our work identifies regulatory features of P. aeruginosa genes whose products play a role in environmental adaption during infection and provides a reference transcriptional landscape for this pathogen. PMID- 23028335 TI - Global assessment of genomic regions required for growth in Mycobacterium tuberculosis. AB - Identifying genomic elements required for viability is central to our understanding of the basic physiology of bacterial pathogens. Recently, the combination of high-density mutagenesis and deep sequencing has allowed for the identification of required and conditionally required genes in many bacteria. Genes, however, make up only a part of the complex genomes of important bacterial pathogens. Here, we use an unbiased analysis to comprehensively identify genomic regions, including genes, domains, and intergenic elements, required for the optimal growth of Mycobacterium tuberculosis, a major global health pathogen. We found that several proteins jointly contain both domains required for optimal growth and domains that are dispensable. In addition, many non-coding regions, including regulatory elements and non-coding RNAs, are critical for mycobacterial growth. Our analysis shows that the genetic requirements for growth are more complex than can be appreciated using gene-centric analysis. PMID- 23028336 TI - A unique protein phosphatase with kelch-like domains (PPKL) in Plasmodium modulates ookinete differentiation, motility and invasion. AB - Protein phosphorylation and dephosphorylation (catalysed by kinases and phosphatases, respectively) are post-translational modifications that play key roles in many eukaryotic signalling pathways, and are often deregulated in a number of pathological conditions in humans. In the malaria parasite Plasmodium, functional insights into its kinome have only recently been achieved, with over half being essential for blood stage development and another 14 kinases being essential for sexual development and mosquito transmission. However, functions for any of the plasmodial protein phosphatases are unknown. Here, we use reverse genetics in the rodent malaria model, Plasmodium berghei, to examine the role of a unique protein phosphatase containing kelch-like domains (termed PPKL) from a family related to Arabidopsis BSU1. Phylogenetic analysis confirmed that the family of BSU1-like proteins including PPKL is encoded in the genomes of land plants, green algae and alveolates, but not in other eukaryotic lineages. Furthermore, PPKL was observed in a distinct family, separate to the most closely related phosphatase family, PP1. In our genetic approach, C-terminal GFP fusion with PPKL showed an active protein phosphatase preferentially expressed in female gametocytes and ookinetes. Deletion of the endogenous ppkl gene caused abnormal ookinete development and differentiation, and dissociated apical microtubules from the inner-membrane complex, generating an immotile phenotype and failure to invade the mosquito mid-gut epithelium. These observations were substantiated by changes in localisation of cytoskeletal tubulin and actin, and the micronemal protein CTRP in the knockout mutant as assessed by indirect immunofluorescence. Finally, increased mRNA expression of dozi, a RNA helicase vital to zygote development was observed in ppkl(-) mutants, with global phosphorylation studies of ookinete differentiation from 1.5-24 h post-fertilisation indicating major changes in the first hours of zygote development. Our work demonstrates a stage specific essentiality of the unique PPKL enzyme, which modulates parasite differentiation, motility and transmission. PMID- 23028337 TI - Comparative pathogenomics reveals horizontally acquired novel virulence genes in fungi infecting cereal hosts. AB - Comparative analyses of pathogen genomes provide new insights into how pathogens have evolved common and divergent virulence strategies to invade related plant species. Fusarium crown and root rots are important diseases of wheat and barley world-wide. In Australia, these diseases are primarily caused by the fungal pathogen Fusarium pseudograminearum. Comparative genomic analyses showed that the F. pseudograminearum genome encodes proteins that are present in other fungal pathogens of cereals but absent in non-cereal pathogens. In some cases, these cereal pathogen specific genes were also found in bacteria associated with plants. Phylogenetic analysis of selected F. pseudograminearum genes supported the hypothesis of horizontal gene transfer into diverse cereal pathogens. Two horizontally acquired genes with no previously known role in fungal pathogenesis were studied functionally via gene knockout methods and shown to significantly affect virulence of F. pseudograminearum on the cereal hosts wheat and barley. Our results indicate using comparative genomics to identify genes specific to pathogens of related hosts reveals novel virulence genes and illustrates the importance of horizontal gene transfer in the evolution of plant infecting fungal pathogens. PMID- 23028338 TI - Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. AB - Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families. PMID- 23028339 TI - Variation in genes related to cochlear biology is strongly associated with adult onset deafness in border collies. AB - Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3-5 years) than typically expected for aging dogs (8-10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p value = 1.09 * 10(-13)). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-kappaB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS-guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders. PMID- 23028340 TI - A genetic basis for a postmeiotic X versus Y chromosome intragenomic conflict in the mouse. AB - Intragenomic conflicts arise when a genetic element favours its own transmission to the detriment of others. Conflicts over sex chromosome transmission are expected to have influenced genome structure, gene regulation, and speciation. In the mouse, the existence of an intragenomic conflict between X- and Y-linked multicopy genes has long been suggested but never demonstrated. The Y-encoded multicopy gene Sly has been shown to have a predominant role in the epigenetic repression of post meiotic sex chromatin (PMSC) and, as such, represses X and Y genes, among which are its X-linked homologs Slx and Slxl1. Here, we produced mice that are deficient for both Sly and Slx/Slxl1 and observed that Slx/Slxl1 has an opposite role to that of Sly, in that it stimulates XY gene expression in spermatids. Slx/Slxl1 deficiency rescues the sperm differentiation defects and near sterility caused by Sly deficiency and vice versa. Slx/Slxl1 deficiency also causes a sex ratio distortion towards the production of male offspring that is corrected by Sly deficiency. All in all, our data show that Slx/Slxl1 and Sly have antagonistic effects during sperm differentiation and are involved in a postmeiotic intragenomic conflict that causes segregation distortion and male sterility. This is undoubtedly what drove the massive gene amplification on the mouse X and Y chromosomes. It may also be at the basis of cases of F1 male hybrid sterility where the balance between Slx/Slxl1 and Sly copy number, and therefore expression, is disrupted. To the best of our knowledge, our work is the first demonstration of a competition occurring between X and Y related genes in mammals. It also provides a biological basis for the concept that intragenomic conflict is an important evolutionary force which impacts on gene expression, genome structure, and speciation. PMID- 23028341 TI - Genome-wide association study for serum complement C3 and C4 levels in healthy Chinese subjects. AB - Complement C3 and C4 play key roles in the main physiological activities of complement system, and their deficiencies or over-expression are associated with many clinical infectious or immunity diseases. A two-stage genome-wide association study (GWAS) was performed for serum levels of C3 and C4. The first stage was conducted in 1,999 healthy Chinese men, and the second stage was performed in an additional 1,496 subjects. We identified two SNPs, rs3753394 in CFH gene and rs3745567 in C3 gene, that are significantly associated with serum C3 levels at a genome-wide significance level (P = 7.33 * 10(-11) and P = 1.83 * 10(-9), respectively). For C4, one large genomic region on chromosome 6p21.3 is significantly associated with serum C4 levels. Two SNPs (rs1052693 and rs11575839) were located in the MHC class I area that include HLA-A, HLA-C, and HLA-B genes. Two SNPs (rs2075799 and rs2857009) were located 5' and 3' of C4 gene. The other four SNPs, rs2071278, rs3763317, rs9276606, and rs241428, were located in the MHC class II region that includes HLA-DRA, HLA-DRB, and HLA-DQB genes. The combined P-values for those eight SNPs ranged from 3.19 * 10(-22) to 5.62 * 10(-97). HBsAg-positive subjects have significantly lower C3 and C4 protein concentrations compared with HBsAg-negative subjects (P<0.05). Our study is the first GWAS report which shows genetic components influence the levels of complement C3 and C4. Our significant findings provide novel insights of their related autoimmune, infectious diseases, and molecular mechanisms. PMID- 23028342 TI - New susceptibility loci associated with kidney disease in type 1 diabetes. AB - Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 * 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 * 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF beta1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 * 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN. PMID- 23028343 TI - Vsx2 controls eye organogenesis and retinal progenitor identity via homeodomain and non-homeodomain residues required for high affinity DNA binding. AB - The homeodomain and adjacent CVC domain in the visual system homeobox (VSX) proteins are conserved from nematodes to humans. Humans with missense mutations in these regions of VSX2 have microphthalmia, suggesting both regions are critical for function. To assess this, we generated the corresponding mutations in mouse Vsx2. The homeodomain mutant protein lacked DNA binding activity and the knock-in mutant phenocopied the null mutant, ocular retardation J. The CVC mutant protein exhibited weakened DNA binding; and, although the corresponding knock-in allele was recessive, it unexpectedly caused the strongest phenotype, as indicated by severe microphthalmia and hyperpigmentation of the neural retina. This occurred through a cryptic transcriptional feedback loop involving the transcription factors Mitf and Otx1 and the Cdk inhibitor p27(Kip1). Our data suggest that the phenotypic severity of the CVC mutant depends on the weakened DNA binding activity elicited by the CVC mutation and a previously unknown protein interaction between Vsx2 and its regulatory target Mitf. Our data also suggest that an essential function of the CVC domain is to assist the homeodomain in high-affinity DNA binding, which is required for eye organogenesis and unhindered execution of the retinal progenitor program in mammals. Finally, the genetic and phenotypic behaviors of the CVC mutation suggest it has the characteristics of a recessive neomorph, a rare type of genetic allele. PMID- 23028344 TI - Cadm1 is a metastasis susceptibility gene that suppresses metastasis by modifying tumor interaction with the cell-mediated immunity. AB - Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors, including cellular immunity. We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms. However, how metastasis susceptibility genes interact with the tumor stroma is incompletely understood. Here, we employ a complex genetic screen to identify Cadm1 as a novel modifier of metastasis. We demonstrate that Cadm1 can specifically suppress metastasis without affecting primary tumor growth. Unexpectedly, Cadm1 did not alter tumor-cell-autonomous properties such as proliferation or invasion, but required the host's adaptive immune system to affect metastasis. The metastasis-suppressing effect of Cadm1 was lost in mice lacking T cell-mediated immunity, which was partially phenocopied by depleting CD8(+) T cells in immune-competent mice. Our data show a novel function for Cadm1 in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms, and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors. PMID- 23028345 TI - Genomics of adaptation during experimental evolution of the opportunistic pathogen Pseudomonas aeruginosa. AB - Adaptation is likely to be an important determinant of the success of many pathogens, for example when colonizing a new host species, when challenged by antibiotic treatment, or in governing the establishment and progress of long-term chronic infection. Yet, the genomic basis of adaptation is poorly understood in general, and for pathogens in particular. We investigated the genetics of adaptation to cystic fibrosis-like culture conditions in the presence and absence of fluoroquinolone antibiotics using the opportunistic pathogen Pseudomonas aeruginosa. Whole-genome sequencing of experimentally evolved isolates revealed parallel evolution at a handful of known antibiotic resistance genes. While the level of antibiotic resistance was largely determined by these known resistance genes, the costs of resistance were instead attributable to a number of mutations that were specific to individual experimental isolates. Notably, stereotypical quinolone resistance mutations in DNA gyrase often co-occurred with other mutations that, together, conferred high levels of resistance but no consistent cost of resistance. This result may explain why these mutations are so prevalent in clinical quinolone-resistant isolates. In addition, genes involved in cyclic di-GMP signalling were repeatedly mutated in populations evolved in viscous culture media, suggesting a shared mechanism of adaptation to this CF-like growth environment. Experimental evolutionary approaches to understanding pathogen adaptation should provide an important complement to studies of the evolution of clinical isolates. PMID- 23028346 TI - Convergence of the transcriptional responses to heat shock and singlet oxygen stresses. AB - Cells often mount transcriptional responses and activate specific sets of genes in response to stress-inducing signals such as heat or reactive oxygen species. Transcription factors in the RpoH family of bacterial alternative sigma factors usually control gene expression during a heat shock response. Interestingly, several alpha-proteobacteria possess two or more paralogs of RpoH, suggesting some functional distinction. We investigated the target promoters of Rhodobacter sphaeroides RpoH(I) and RpoH(II) using genome-scale data derived from gene expression profiling and the direct interactions of each protein with DNA in vivo. We found that the RpoH(I) and RpoH(II) regulons have both distinct and overlapping gene sets. We predicted DNA sequence elements that dictate promoter recognition specificity by each RpoH paralog. We found that several bases in the highly conserved TTG in the -35 element are important for activity with both RpoH homologs; that the T-9 position, which is over-represented in the RpoH(I) promoter sequence logo, is critical for RpoH(I)-dependent transcription; and that several bases in the predicted -10 element were important for activity with either RpoH(II) or both RpoH homologs. Genes that are transcribed by both RpoH(I) and RpoH(II) are predicted to encode for functions involved in general cell maintenance. The functions specific to the RpoH(I) regulon are associated with a classic heat shock response, while those specific to RpoH(II) are associated with the response to the reactive oxygen species, singlet oxygen. We propose that a gene duplication event followed by changes in promoter recognition by RpoH(I) and RpoH(II) allowed convergence of the transcriptional responses to heat and singlet oxygen stress in R. sphaeroides and possibly other bacteria. PMID- 23028347 TI - A genome-wide association study identifies five loci influencing facial morphology in Europeans. AB - Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes--PRDM16, PAX3, TP63, C5orf50, and COL17A1--in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications. PMID- 23028348 TI - H4K20me1 contributes to downregulation of X-linked genes for C. elegans dosage compensation. AB - The Caenorhabditis elegans dosage compensation complex (DCC) equalizes X chromosome gene dosage between XO males and XX hermaphrodites by two-fold repression of X-linked gene expression in hermaphrodites. The DCC localizes to the X chromosomes in hermaphrodites but not in males, and some subunits form a complex homologous to condensin. The mechanism by which the DCC downregulates gene expression remains unclear. Here we show that the DCC controls the methylation state of lysine 20 of histone H4, leading to higher H4K20me1 and lower H4K20me3 levels on the X chromosomes of XX hermaphrodites relative to autosomes. We identify the PR-SET7 ortholog SET-1 and the Suv4-20 ortholog SET-4 as the major histone methyltransferases for monomethylation and di/trimethylation of H4K20, respectively, and provide evidence that X-chromosome enrichment of H4K20me1 involves inhibition of SET-4 activity on the X. RNAi knockdown of set-1 results in synthetic lethality with dosage compensation mutants and upregulation of X-linked gene expression, supporting a model whereby H4K20me1 functions with the condensin-like C. elegans DCC to repress transcription of X-linked genes. H4K20me1 is important for mitotic chromosome condensation in mammals, suggesting that increased H4K20me1 on the X may restrict access of the transcription machinery to X-linked genes via chromatin compaction. PMID- 23028349 TI - Citrullination of histone H3 interferes with HP1-mediated transcriptional repression. AB - Multiple Sclerosis (MS) is an autoimmune disease associated with abnormal expression of a subset of cytokines, resulting in inappropriate T-lymphocyte activation and uncontrolled immune response. A key issue in the field is the need to understand why these cytokines are transcriptionally activated in the patients. Here, we have examined several transcription units subject to pathological reactivation in MS, including the TNFalpha and IL8 cytokine genes and also several Human Endogenous RetroViruses (HERVs). We find that both the immune genes and the HERVs require the heterochromatin protein HP1alpha for their transcriptional repression. We further show that the Peptidylarginine Deiminase 4 (PADI4), an enzyme with a suspected role in MS, weakens the binding of HP1alpha to tri-methylated histone H3 lysine 9 by citrullinating histone H3 arginine 8. The resulting de-repression of both cytokines and HERVs can be reversed with the PADI-inhibitor Cl-amidine. Finally, we show that in peripheral blood mononuclear cells (PBMCs) from MS patients, the promoters of TNFalpha, and several HERVs share a deficit in HP1alpha recruitment and an augmented accumulation of histone H3 with a double citrulline 8 tri-methyl lysine 9 modifications. Thus, our study provides compelling evidence that HP1alpha and PADI4 are regulators of both immune genes and HERVs, and that multiple events of transcriptional reactivation in MS patients can be explained by the deficiency of a single mechanism of gene silencing. PMID- 23028350 TI - An essential role of variant histone H3.3 for ectomesenchyme potential of the cranial neural crest. AB - The neural crest (NC) is a vertebrate-specific cell population that exhibits remarkable multipotency. Although derived from the neural plate border (NPB) ectoderm, cranial NC (CNC) cells contribute not only to the peripheral nervous system but also to the ectomesenchymal precursors of the head skeleton. To date, the developmental basis for such broad potential has remained elusive. Here, we show that the replacement histone H3.3 is essential during early CNC development for these cells to generate ectomesenchyme and head pigment precursors. In a forward genetic screen in zebrafish, we identified a dominant D123N mutation in h3f3a, one of five zebrafish variant histone H3.3 genes, that eliminates the CNC derived head skeleton and a subset of pigment cells yet leaves other CNC derivatives and trunk NC intact. Analyses of nucleosome assembly indicate that mutant D123N H3.3 interferes with H3.3 nucleosomal incorporation by forming aberrant H3 homodimers. Consistent with CNC defects arising from insufficient H3.3 incorporation into chromatin, supplying exogenous wild-type H3.3 rescues head skeletal development in mutants. Surprisingly, embryo-wide expression of dominant mutant H3.3 had little effect on embryonic development outside CNC, indicating an unexpectedly specific sensitivity of CNC to defects in H3.3 incorporation. Whereas previous studies had implicated H3.3 in large-scale histone replacement events that generate totipotency during germ line development, our work has revealed an additional role of H3.3 in the broad potential of the ectoderm-derived CNC, including the ability to make the mesoderm like ectomesenchymal precursors of the head skeleton. PMID- 23028351 TI - Transcriptional repression of Hox genes by C. elegans HP1/HPL and H1/HIS-24. AB - Elucidation of the biological role of linker histone (H1) and heterochromatin protein 1 (HP1) in mammals has been difficult owing to the existence of a least 11 distinct H1 and three HP1 subtypes in mice. Caenorhabditis elegans possesses two HP1 homologues (HPL-1 and HPL-2) and eight H1 variants. Remarkably, one of eight H1 variants, HIS-24, is important for C. elegans development. Therefore we decided to analyse in parallel the transcriptional profiles of HIS-24, HPL-1/-2 deficient animals, and their phenotype, since hpl-1, hpl-2, and his-24 deficient nematodes are viable. Global transcriptional analysis of the double and triple mutants revealed that HPL proteins and HIS-24 play gene-specific roles, rather than a general repressive function. We showed that HIS-24 acts synergistically with HPL to allow normal reproduction, somatic gonad development, and vulval cell fate decision. Furthermore, the hpl-2; his-24 double mutant animals displayed abnormal development of the male tail and ectopic expression of C. elegans HOM C/Hox genes (egl-5 and mab-5), which are involved in the developmental patterning of male mating structures. We found that HPL-2 and the methylated form of HIS-24 specifically interact with the histone H3 K27 region in the trimethylated state, and HIS-24 associates with the egl-5 and mab-5 genes. Our results establish the interplay between HPL-1/-2 and HIS-24 proteins in the regulation of positional identity in C. elegans males. PMID- 23028352 TI - Hominoid-specific de novo protein-coding genes originating from long non-coding RNAs. AB - Tinkering with pre-existing genes has long been known as a major way to create new genes. Recently, however, motherless protein-coding genes have been found to have emerged de novo from ancestral non-coding DNAs. How these genes originated is not well addressed to date. Here we identified 24 hominoid-specific de novo protein-coding genes with precise origination timing in vertebrate phylogeny. Strand-specific RNA-Seq analyses were performed in five rhesus macaque tissues (liver, prefrontal cortex, skeletal muscle, adipose, and testis), which were then integrated with public transcriptome data from human, chimpanzee, and rhesus macaque. On the basis of comparing the RNA expression profiles in the three species, we found that most of the hominoid-specific de novo protein-coding genes encoded polyadenylated non-coding RNAs in rhesus macaque or chimpanzee with a similar transcript structure and correlated tissue expression profile. According to the rule of parsimony, the majority of these hominoid-specific de novo protein coding genes appear to have acquired a regulated transcript structure and expression profile before acquiring coding potential. Interestingly, although the expression profile was largely correlated, the coding genes in human often showed higher transcriptional abundance than their non-coding counterparts in rhesus macaque. The major findings we report in this manuscript are robust and insensitive to the parameters used in the identification and analysis of de novo genes. Our results suggest that at least a portion of long non-coding RNAs, especially those with active and regulated transcription, may serve as a birth pool for protein-coding genes, which are then further optimized at the transcriptional level. PMID- 23028353 TI - Characterization of inducible models of Tay-Sachs and related disease. AB - Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid beta-N acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb-/- (Sandhoff) mice that lack beta-hexosaminidases A and B. To define determinants of therapeutic efficacy and establish a dynamic experimental platform to systematically investigate cellular pathogenesis of GM2 gangliosidosis, we generated two inducible experimental models. Reversible transgenic expression of beta-hexosaminidase directed by two promoters, mouse Hexb and human Synapsin 1 promoters, permitted progression of GM2 gangliosidosis in Sandhoff mice to be modified at pre-defined ages. A single auto-regulatory tetracycline-sensitive expression cassette controlled expression of transgenic Hexb in the brain of Hexb /- mice and provided long-term rescue from the acute neuronopathic disorder, as well as the accompanying pathological storage of glycoconjugates and gliosis in most parts of the brain. Ultimately, late-onset brainstem and ventral spinal cord pathology occurred and was associated with increased tone in the limbs. Silencing transgenic Hexb expression in five-week-old mice induced stereotypic signs and progression of Sandhoff disease, including tremor, bradykinesia, and hind-limb paralysis. As in germline Hexb-/- mice, these neurodegenerative manifestations advanced rapidly, indicating that the pathogenesis and progression of GM2 gangliosidosis is not influenced by developmental events in the maturing nervous system. PMID- 23028354 TI - Co-evolution of mitochondrial tRNA import and codon usage determines translational efficiency in the green alga Chlamydomonas. AB - Mitochondria from diverse phyla, including protozoa, fungi, higher plants, and humans, import tRNAs from the cytosol in order to ensure proper mitochondrial translation. Despite the broad occurrence of this process, our understanding of tRNA import mechanisms is fragmentary, and crucial questions about their regulation remain unanswered. In the unicellular green alga Chlamydomonas, a precise correlation was found between the mitochondrial codon usage and the nature and amount of imported tRNAs. This led to the hypothesis that tRNA import might be a dynamic process able to adapt to the mitochondrial genome content. By manipulating the Chlamydomonas mitochondrial genome, we introduced point mutations in order to modify its codon usage. We find that the codon usage modification results in reduced levels of mitochondrial translation as well as in subsequent decreased levels and activities of respiratory complexes. These effects are linked to the consequential limitations of the pool of tRNAs in mitochondria. This indicates that tRNA mitochondrial import cannot be rapidly regulated in response to a novel genetic context and thus does not appear to be a dynamic process. It rather suggests that the steady-state levels of imported tRNAs in mitochondria result from a co-evolutive adaptation between the tRNA import mechanism and the requirements of the mitochondrial translation machinery. PMID- 23028355 TI - C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. AB - FoxO transcription factors and sirtuin family deacetylases regulate diverse biological processes, including stress responses and longevity. Here we show that the Caenorhabditis elegans sirtuin SIR-2.4--homolog of mammalian SIRT6 and SIRT7 proteins--promotes DAF-16-dependent transcription and stress-induced DAF-16 nuclear localization. SIR-2.4 is required for resistance to multiple stressors: heat shock, oxidative insult, and proteotoxicity. By contrast, SIR-2.4 is largely dispensable for DAF-16 nuclear localization and function in response to reduced insulin/IGF-1-like signaling. Although acetylation is known to regulate localization and activity of mammalian FoxO proteins, this modification has not been previously described on DAF-16. We find that DAF-16 is hyperacetylated in sir-2.4 mutants. Conversely, DAF-16 is acetylated by the acetyltransferase CBP-1, and DAF-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. Surprisingly, a SIR-2.4 catalytic mutant efficiently rescues the DAF 16 localization defect in sir-2.4 null animals. Acetylation of DAF-16 by CBP-1 in vitro is inhibited by either wild-type or mutant SIR-2.4, suggesting that SIR-2.4 regulates DAF-16 acetylation indirectly, by preventing CBP-1-mediated acetylation under stress conditions. Taken together, our results identify SIR-2.4 as a critical regulator of DAF-16 specifically in the context of stress responses. Furthermore, they reveal a novel role for acetylation, modulated by the antagonistic activities of CBP-1 and SIR-2.4, in modulating DAF-16 localization and function. PMID- 23028356 TI - Functional variants in NFKBIE and RTKN2 involved in activation of the NF-kappaB pathway are associated with rheumatoid arthritis in Japanese. AB - Rheumatoid arthritis is an autoimmune disease with a complex etiology, leading to inflammation of synovial tissue and joint destruction. Through a genome-wide association study (GWAS) and two replication studies in the Japanese population (7,907 cases and 35,362 controls), we identified two gene loci associated with rheumatoid arthritis susceptibility (NFKBIE at 6p21.1, rs2233434, odds ratio (OR) = 1.20, P = 1.3 * 10(-15); RTKN2 at 10q21.2, rs3125734, OR = 1.20, P = 4.6 * 10( 9)). In addition to two functional non-synonymous SNPs in NFKBIE, we identified candidate causal SNPs with regulatory potential in NFKBIE and RTKN2 gene regions by integrating in silico analysis using public genome databases and subsequent in vitro analysis. Both of these genes are known to regulate the NF-kappaB pathway, and the risk alleles of the genes were implicated in the enhancement of NF-kappaB activity in our analyses. These results suggest that the NF-kappaB pathway plays a role in pathogenesis and would be a rational target for treatment of rheumatoid arthritis. PMID- 23028357 TI - The NDR kinase scaffold HYM1/MO25 is essential for MAK2 map kinase signaling in Neurospora crassa. AB - Cell communication is essential for eukaryotic development, but our knowledge of molecules and mechanisms required for intercellular communication is fragmentary. In particular, the connection between signal sensing and regulation of cell polarity is poorly understood. In the filamentous ascomycete Neurospora crassa, germinating spores mutually attract each other and subsequently fuse. During these tropic interactions, the two communicating cells rapidly alternate between two different physiological states, probably associated with signal delivery and response. The MAK2 MAP kinase cascade mediates cell-cell signaling. Here, we show that the conserved scaffolding protein HYM1/MO25 controls the cell shape regulating NDR kinase module as well as the signal-receiving MAP kinase cascade. HYM1 functions as an integral part of the COT1 NDR kinase complex to regulate the interaction with its upstream kinase POD6 and thereby COT1 activity. In addition, HYM1 interacts with NRC1, MEK2, and MAK2, the three kinases of the MAK2 MAP kinase cascade, and co-localizes with MAK2 at the apex of growing cells. During cell fusion, the three kinases of the MAP kinase module as well as HYM1 are recruited to the point of cell-cell contact. hym-1 mutants phenocopy all defects observed for MAK2 pathway mutants by abolishing MAK2 activity. An NRC1-MEK2 fusion protein reconstitutes MAK2 signaling in hym-1, while constitutive activation of NRC1 and MEK2 does not. These data identify HYM1 as a novel regulator of the NRC1-MEK2-MAK2 pathway, which may coordinate NDR and MAP kinase signaling during cell polarity and intercellular communication. PMID- 23028358 TI - A response regulator interfaces between the Frz chemosensory system and the MglA/MglB GTPase/GAP module to regulate polarity in Myxococcus xanthus. AB - How cells establish and dynamically change polarity are general questions in cell biology. Cells of the rod-shaped bacterium Myxococcus xanthus move on surfaces with defined leading and lagging cell poles. Occasionally, cells undergo reversals, which correspond to an inversion of the leading-lagging pole polarity axis. Reversals are induced by the Frz chemosensory system and depend on relocalization of motility proteins between the poles. The Ras-like GTPase MglA localizes to and defines the leading cell pole in the GTP-bound form. MglB, the cognate MglA GTPase activating protein, localizes to and defines the lagging pole. During reversals, MglA-GTP and MglB switch poles and, therefore, dynamically localized motility proteins switch poles. We identified the RomR response regulator, which localizes in a bipolar asymmetric pattern with a large cluster at the lagging pole, as important for motility and reversals. We show that RomR interacts directly with MglA and MglB in vitro. Furthermore, RomR, MglA, and MglB affect the localization of each other in all pair-wise directions, suggesting that RomR stimulates motility by promoting correct localization of MglA and MglB in MglA/RomR and MglB/RomR complexes at opposite poles. Moreover, localization analyses suggest that the two RomR complexes mutually exclude each other from their respective poles. We further show that RomR interfaces with FrzZ, the output response regulator of the Frz chemosensory system, to regulate reversals. Thus, RomR serves at the functional interface to connect a classic bacterial signalling module (Frz) to a classic eukaryotic polarity module (MglA/MglB). This modular design is paralleled by the phylogenetic distribution of the proteins, suggesting an evolutionary scheme in which RomR was incorporated into the MglA/MglB module to regulate cell polarity followed by the addition of the Frz system to dynamically regulate cell polarity. PMID- 23028359 TI - Two distinct repressive mechanisms for histone 3 lysine 4 methylation through promoting 3'-end antisense transcription. AB - Histone H3 di- and trimethylation on lysine 4 are major chromatin marks that correlate with active transcription. The influence of these modifications on transcription itself is, however, poorly understood. We have investigated the roles of H3K4 methylation in Saccharomyces cerevisiae by determining genome-wide expression-profiles of mutants in the Set1 complex, COMPASS, that lays down these marks. Loss of H3K4 trimethylation has virtually no effect on steady-state or dynamically-changing mRNA levels. Combined loss of H3K4 tri- and dimethylation results in steady-state mRNA upregulation and delays in the repression kinetics of specific groups of genes. COMPASS-repressed genes have distinct H3K4 methylation patterns, with enrichment of H3K4me3 at the 3'-end, indicating that repression is coupled to 3'-end antisense transcription. Further analyses reveal that repression is mediated by H3K4me3-dependent 3'-end antisense transcription in two ways. For a small group of genes including PHO84, repression is mediated by a previously reported trans-effect that requires the antisense transcript itself. For the majority of COMPASS-repressed genes, however, it is the process of 3'-end antisense transcription itself that is the important factor for repression. Strand-specific qPCR analyses of various mutants indicate that this more prevalent mechanism of COMPASS-mediated repression requires H3K4me3 dependent 3'-end antisense transcription to lay down H3K4me2, which seems to serve as the actual repressive mark. Removal of the 3'-end antisense promoter also results in derepression of sense transcription and renders sense transcription insensitive to the additional loss of SET1. The derepression observed in COMPASS mutants is mimicked by reduction of global histone H3 and H4 levels, suggesting that the H3K4me2 repressive effect is linked to establishment of a repressive chromatin structure. These results indicate that in S. cerevisiae, the non-redundant role of H3K4 methylation by Set1 is repression, achieved through promotion of 3'-end antisense transcription to achieve specific rather than global effects through two distinct mechanisms. PMID- 23028360 TI - Role of transposon-derived small RNAs in the interplay between genomes and parasitic DNA in rice. AB - RNA silencing is a defense system against "genomic parasites" such as transposable elements (TE), which are potentially harmful to host genomes. In plants, transcripts from TEs induce production of double-stranded RNAs (dsRNAs) and are processed into small RNAs (small interfering RNAs, siRNAs) that suppress TEs by RNA-directed DNA methylation. Thus, the majority of TEs are epigenetically silenced. On the other hand, most of the eukaryotic genome is composed of TEs and their remnants, suggesting that TEs have evolved countermeasures against host mediated silencing. Under some circumstances, TEs can become active and increase in copy number. Knowledge is accumulating on the mechanisms of TE silencing by the host; however, the mechanisms by which TEs counteract silencing are poorly understood. Here, we show that a class of TEs in rice produces a microRNA (miRNA) to suppress host silencing. Members of the microRNA820 (miR820) gene family are located within CACTA DNA transposons in rice and target a de novo DNA methyltransferase gene, OsDRM2, one of the components of epigenetic silencing. We confirmed that miR820 negatively regulates the expression of OsDRM2. In addition, we found that expression levels of various TEs are increased quite sensitively in response to decreased OsDRM2 expression and DNA methylation at TE loci. Furthermore, we found that the nucleotide sequence of miR820 and its recognition site within the target gene in some Oryza species have co-evolved to maintain their base-pairing ability. The co-evolution of these sequences provides evidence for the functionality of this regulation. Our results demonstrate how parasitic elements in the genome escape the host's defense machinery. Furthermore, our analysis of the regulation of OsDRM2 by miR820 sheds light on the action of transposon-derived small RNAs, not only as a defense mechanism for host genomes but also as a regulator of interactions between hosts and their parasitic elements. PMID- 23028362 TI - The conflict within and the escalating war between the sex chromosomes. PMID- 23028361 TI - Enrichment of HP1a on Drosophila chromosome 4 genes creates an alternate chromatin structure critical for regulation in this heterochromatic domain. AB - Chromatin environments differ greatly within a eukaryotic genome, depending on expression state, chromosomal location, and nuclear position. In genomic regions characterized by high repeat content and high gene density, chromatin structure must silence transposable elements but permit expression of embedded genes. We have investigated one such region, chromosome 4 of Drosophila melanogaster. Using chromatin-immunoprecipitation followed by microarray (ChIP-chip) analysis, we examined enrichment patterns of 20 histone modifications and 25 chromosomal proteins in S2 and BG3 cells, as well as the changes in several marks resulting from mutations in key proteins. Active genes on chromosome 4 are distinct from those in euchromatin or pericentric heterochromatin: while there is a depletion of silencing marks at the transcription start sites (TSSs), HP1a and H3K9me3, but not H3K9me2, are enriched strongly over gene bodies. Intriguingly, genes on chromosome 4 are less frequently associated with paused polymerase. However, when the chromatin is altered by depleting HP1a or POF, the RNA pol II enrichment patterns of many chromosome 4 genes shift, showing a significant decrease over gene bodies but not at TSSs, accompanied by lower expression of those genes. Chromosome 4 genes have a low incidence of TRL/GAGA factor binding sites and a low T(m) downstream of the TSS, characteristics that could contribute to a low incidence of RNA polymerase pausing. Our data also indicate that EGG and POF jointly regulate H3K9 methylation and promote HP1a binding over gene bodies, while HP1a targeting and H3K9 methylation are maintained at the repeats by an independent mechanism. The HP1a-enriched, POF-associated chromatin structure over the gene bodies may represent one type of adaptation for genes embedded in repetitive DNA. PMID- 23028363 TI - The Kcnq1ot1 long non-coding RNA affects chromatin conformation and expression of Kcnq1, but does not regulate its imprinting in the developing heart. AB - Although many of the questions raised by the discovery of imprinting have been answered, we have not yet accounted for tissue- or stage-specific imprinting. The Kcnq1 imprinted domain exhibits complex tissue-specific expression patterns co existing with a domain-wide cis-acting control element. Transcription of the paternally expressed antisense non-coding RNA Kcnq1ot1 silences some neighboring genes in the embryo, while others are unaffected. Kcnq1 is imprinted in early cardiac development but becomes biallelic after midgestation. To explore this phenomenon and the role of Kcnq1ot1, we used allele-specific assays and chromosome conformational studies in wild-type mice and mice with a premature termination mutation for Kcnq1ot1. We show that Kcnq1 imprinting in early heart is established and maintained independently of Kcnq1ot1 expression, thus excluding a role for Kcnq1ot1 in repressing Kcnq1, even while silencing other genes in the domain. The exact timing of the mono- to biallelic transition is strain-dependent, with the CAST/EiJ allele becoming activated earlier and acquiring higher levels than the C57BL/6J allele. Unexpectedly, Kcnq1ot1 itself also switches to biallelic expression specifically in the heart, suggesting that tissue-specific loss of imprinting may be common during embryogenesis. The maternal Kcnq1ot1 transcript is shorter than the paternal ncRNA, and its activation depends on an alternative transcriptional start site that bypasses the maternally methylated promoter. Production of Kcnq1ot1 on the maternal chromosome does not silence Cdkn1c. We find that in later developmental stages, however, Kcnq1ot1 has a role in modulating Kcnq1 levels, since its absence leads to overexpression of Kcnq1, an event accompanied by an aberrant three-dimensional structure of the chromatin. Thus, our studies reveal regulatory mechanisms within the Kcnq1 imprinted domain that operate exclusively in the heart on Kcnq1, a gene crucial for heart development and function. We also uncover a novel mechanism by which an antisense non-coding RNA affects transcription through regulating chromatin flexibility and access to enhancers. PMID- 23028365 TI - Genetic modifiers of chromatin acetylation antagonize the reprogramming of epi polymorphisms. AB - Natural populations are known to differ not only in DNA but also in their chromatin-associated epigenetic marks. When such inter-individual epigenomic differences (or "epi-polymorphisms") are observed, their stability is usually not known: they may or may not be reprogrammed over time or upon environmental changes. In addition, their origin may be purely epigenetic, or they may result from regulatory variation encoded in the DNA. Studying epi-polymorphisms requires, therefore, an assessment of their nature and stability. Here we estimate the stability of yeast epi-polymorphisms of chromatin acetylation, and we provide a genome-by-epigenome map of their genetic control. A transient epi drug treatment was able to reprogram acetylation variation at more than one thousand nucleosomes, whereas a similar amount of variation persisted, distinguishing "labile" from "persistent" epi-polymorphisms. Hundreds of genetic loci underlied acetylation variation at 2,418 nucleosomes either locally (in cis) or distantly (in trans), and this genetic control overlapped only partially with the genetic control of gene expression. Trans-acting regulators were not necessarily associated with genes coding for chromatin modifying enzymes. Strikingly, "labile" and "persistent" epi-polymorphisms were associated with poor and strong genetic control, respectively, showing that genetic modifiers contribute to persistence. These results estimate the amount of natural epigenomic variation that can be lost after transient environmental exposures, and they reveal the complex genetic architecture of the DNA-encoded determinism of chromatin epi-polymorphisms. Our observations provide a basis for the development of population epigenetics. PMID- 23028364 TI - Tetraspanin is required for generation of reactive oxygen species by the dual oxidase system in Caenorhabditis elegans. AB - Reactive oxygen species (ROS) are toxic but essential molecules responsible for host defense and cellular signaling. Conserved NADPH oxidase (NOX) family enzymes direct the regulated production of ROS. Hydrogen peroxide (H(2)O(2)) generated by dual oxidases (DUOXs), a member of the NOX family, is crucial for innate mucosal immunity. In addition, H(2)O(2) is required for cellular signaling mediated by protein modifications, such as the thyroid hormone biosynthetic pathway in mammals. In contrast to other NOX isozymes, the regulatory mechanisms of DUOX activity are less understood. Using Caenorhabditis elegans as a model, we demonstrate that the tetraspanin protein is required for induction of the DUOX signaling pathway in conjunction with the dual oxidase maturation factor (DUOXA). In the current study, we show that genetic mutation of DUOX (bli-3), DUOXA (doxa 1), and peroxidase (mlt-7) in C. elegans causes the same defects as a tetraspanin tsp-15 mutant, represented by exoskeletal deficiencies due to the failure of tyrosine cross-linking of collagen. The deficiency in the tsp-15 mutant was restored by co-expression of bli-3 and doxa-1, indicating the involvement of tsp 15 in the generation of ROS. H(2)O(2) generation by BLI-3 was completely dependent on TSP-15 when reconstituted in mammalian cells. We also demonstrated that TSP-15, BLI-3, and DOXA-1 form complexes in vitro and in vivo. Cell-fusion based analysis suggested that association with TSP-15 at the cell surface is crucial for BLI-3 activation to release H(2)O(2). This study provides the first evidence for an essential role of tetraspanin in ROS generation. PMID- 23028366 TI - Determinants of human adipose tissue gene expression: impact of diet, sex, metabolic status, and cis genetic regulation. AB - Weight control diets favorably affect parameters of the metabolic syndrome and delay the onset of diabetic complications. The adaptations occurring in adipose tissue (AT) are likely to have a profound impact on the whole body response as AT is a key target of dietary intervention. Identification of environmental and individual factors controlling AT adaptation is therefore essential. Here, expression of 271 transcripts, selected for regulation according to obesity and weight changes, was determined in 515 individuals before, after 8-week low calorie diet-induced weight loss, and after 26-week ad libitum weight maintenance diets. For 175 genes, opposite regulation was observed during calorie restriction and weight maintenance phases, independently of variations in body weight. Metabolism and immunity genes showed inverse profiles. During the dietary intervention, network-based analyses revealed strong interconnection between expression of genes involved in de novo lipogenesis and components of the metabolic syndrome. Sex had a marked influence on AT expression of 88 transcripts, which persisted during the entire dietary intervention and after control for fat mass. In women, the influence of body mass index on expression of a subset of genes persisted during the dietary intervention. Twenty-two genes revealed a metabolic syndrome signature common to men and women. Genetic control of AT gene expression by cis signals was observed for 46 genes. Dietary intervention, sex, and cis genetic variants independently controlled AT gene expression. These analyses help understanding the relative importance of environmental and individual factors that control the expression of human AT genes and therefore may foster strategies aimed at improving AT function in metabolic diseases. PMID- 23028367 TI - Rif2 promotes a telomere fold-back structure through Rpd3L recruitment in budding yeast. AB - Using a genome-wide screening approach, we have established the genetic requirements for proper telomere structure in Saccharomyces cerevisiae. We uncovered 112 genes, many of which have not previously been implicated in telomere function, that are required to form a fold-back structure at chromosome ends. Among other biological processes, lysine deacetylation, through the Rpd3L, Rpd3S, and Hda1 complexes, emerged as being a critical regulator of telomere structure. The telomeric-bound protein, Rif2, was also found to promote a telomere fold-back through the recruitment of Rpd3L to telomeres. In the absence of Rpd3 function, telomeres have an increased susceptibility to nucleolytic degradation, telomere loss, and the initiation of premature senescence, suggesting that an Rpd3-mediated structure may have protective functions. Together these data reveal that multiple genetic pathways may directly or indirectly impinge on telomere structure, thus broadening the potential targets available to manipulate telomere function. PMID- 23028369 TI - A comparison of brain gene expression levels in domesticated and wild animals. AB - Domestication has led to similar changes in morphology and behavior in several animal species, raising the question whether similarities between different domestication events also exist at the molecular level. We used mRNA sequencing to analyze genome-wide gene expression patterns in brain frontal cortex in three pairs of domesticated and wild species (dogs and wolves, pigs and wild boars, and domesticated and wild rabbits). We compared the expression differences with those between domesticated guinea pigs and a distant wild relative (Cavia aperea) as well as between two lines of rats selected for tameness or aggression towards humans. There were few gene expression differences between domesticated and wild dogs, pigs, and rabbits (30-75 genes (less than 1%) of expressed genes were differentially expressed), while guinea pigs and C. aperea differed more strongly. Almost no overlap was found between the genes with differential expression in the different domestication events. In addition, joint analyses of all domesticated and wild samples provided only suggestive evidence for the existence of a small group of genes that changed their expression in a similar fashion in different domesticated species. The most extreme of these shared expression changes include up-regulation in domesticates of SOX6 and PROM1, two modulators of brain development. There was almost no overlap between gene expression in domesticated animals and the tame and aggressive rats. However, two of the genes with the strongest expression differences between the rats (DLL3 and DHDH) were located in a genomic region associated with tameness and aggression, suggesting a role in influencing tameness. In summary, the majority of brain gene expression changes in domesticated animals are specific to the given domestication event, suggesting that the causative variants of behavioral domestication traits may likewise be different. PMID- 23028368 TI - Coevolution within and between regulatory loci can preserve promoter function despite evolutionary rate acceleration. AB - Phenotypes that appear to be conserved could be maintained not only by strong purifying selection on the underlying genetic systems, but also by stabilizing selection acting via compensatory mutations with balanced effects. Such coevolution has been invoked to explain experimental results, but has rarely been the focus of study. Conserved expression driven by the unc-47 promoters of Caenorhabditis elegans and C. briggsae persists despite divergence within a cis regulatory element and between this element and the trans-regulatory environment. Compensatory changes in cis and trans are revealed when these promoters are used to drive expression in the other species. Functional changes in the C. briggsae promoter, which has experienced accelerated sequence evolution, did not lead to alteration of gene expression in its endogenous environment. Coevolution among promoter elements suggests that complex epistatic interactions within cis regulatory elements may facilitate their divergence. Our results offer a detailed picture of regulatory evolution in which subtle, lineage-specific, and compensatory modifications of interacting cis and trans regulators together maintain conserved gene expression patterns. PMID- 23028370 TI - UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. AB - UTX (KDM6A) and UTY are homologous X and Y chromosome members of the Histone H3 Lysine 27 (H3K27) demethylase gene family. UTX can demethylate H3K27; however, in vitro assays suggest that human UTY has lost enzymatic activity due to sequence divergence. We produced mouse mutations in both Utx and Uty. Homozygous Utx mutant female embryos are mid-gestational lethal with defects in neural tube, yolk sac, and cardiac development. We demonstrate that mouse UTY is devoid of in vivo demethylase activity, so hemizygous X(Utx-) Y(+) mutant male embryos should phenocopy homozygous X(Utx-) X(Utx-) females. However, X(Utx-) Y(+) mutant male embryos develop to term; although runted, approximately 25% survive postnatally reaching adulthood. Hemizygous X(+) Y(Uty-) mutant males are viable. In contrast, compound hemizygous X(Utx-) Y(Uty-) males phenocopy homozygous X(Utx-) X(Utx-) females. Therefore, despite divergence of UTX and UTY in catalyzing H3K27 demethylation, they maintain functional redundancy during embryonic development. Our data suggest that UTX and UTY are able to regulate gene activity through demethylase independent mechanisms. We conclude that UTX H3K27 demethylation is non-essential for embryonic viability. PMID- 23028371 TI - Tethering of the conserved piggyBac transposase fusion protein CSB-PGBD3 to chromosomal AP-1 proteins regulates expression of nearby genes in humans. AB - The CSB-PGBD3 fusion protein arose more than 43 million years ago when a 2.5-kb piggyBac 3 (PGBD3) transposon inserted into intron 5 of the Cockayne syndrome Group B (CSB) gene in the common ancestor of all higher primates. As a result, full-length CSB is now coexpressed with an abundant CSB-PGBD3 fusion protein by alternative splicing of CSB exons 1-5 to the PGBD3 transposase. An internal deletion of the piggyBac transposase ORF also gave rise to 889 dispersed, 140-bp MER85 elements that were mobilized in trans by PGBD3 transposase. The CSB-PGBD3 fusion protein binds MER85s in vitro and induces a strong interferon-like innate antiviral immune response when expressed in CSB-null UVSS1KO cells. To explore the connection between DNA binding and gene expression changes induced by CSB PGBD3, we investigated the genome-wide DNA binding profile of the fusion protein. CSB-PGBD3 binds to 363 MER85 elements in vivo, but these sites do not correlate with gene expression changes induced by the fusion protein. Instead, CSB-PGBD3 is enriched at AP-1, TEAD1, and CTCF motifs, presumably through protein-protein interactions with the cognate transcription factors; moreover, recruitment of CSB PGBD3 to AP-1 and TEAD1 motifs correlates with nearby genes regulated by CSB PGBD3 expression in UVSS1KO cells and downregulated by CSB rescue of mutant CS1AN cells. Consistent with these data, the N-terminal CSB domain of the CSB-PGBD3 fusion protein interacts with the AP-1 transcription factor c-Jun and with RNA polymerase II, and a chimeric CSB-LacI construct containing only the N-terminus of CSB upregulates many of the genes induced by CSB-PGBD3. We conclude that the CSB-PGBD3 fusion protein substantially reshapes the transcriptome in CS patient CS1AN and that continued expression of the CSB-PGBD3 fusion protein in the absence of functional CSB may affect the clinical presentation of CS patients by directly altering the transcriptional program. PMID- 23028372 TI - SWI/SNF-like chromatin remodeling factor Fun30 supports point centromere function in S. cerevisiae. AB - Budding yeast centromeres are sequence-defined point centromeres and are, unlike in many other organisms, not embedded in heterochromatin. Here we show that Fun30, a poorly understood SWI/SNF-like chromatin remodeling factor conserved in humans, promotes point centromere function through the formation of correct chromatin architecture at centromeres. Our determination of the genome-wide binding and nucleosome positioning properties of Fun30 shows that this enzyme is consistently enriched over centromeres and that a majority of CENs show Fun30 dependent changes in flanking nucleosome position and/or CEN core micrococcal nuclease accessibility. Fun30 deletion leads to defects in histone variant Htz1 occupancy genome-wide, including at and around most centromeres. FUN30 genetically interacts with CSE4, coding for the centromere-specific variant of histone H3, and counteracts the detrimental effect of transcription through centromeres on chromosome segregation and suppresses transcriptional noise over centromere CEN3. Previous work has shown a requirement for fission yeast and mammalian homologs of Fun30 in heterochromatin assembly. As centromeres in budding yeast are not embedded in heterochromatin, our findings indicate a direct role of Fun30 in centromere chromatin by promoting correct chromatin architecture. PMID- 23028373 TI - The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation. AB - TNF expression of macrophages is under stringent translational control that depends on the p38 MAPK/MK2 pathway and the AU-rich element (ARE) in the TNF mRNA. Here, we elucidate the molecular mechanism of phosphorylation-regulated translation of TNF. We demonstrate that translation of the TNF-precursor at the ER requires expression of the ARE-binding and -stabilizing factor human antigen R (HuR) together with either activity of the p38 MAPK/MK2 pathway or the absence of the ARE-binding and -destabilizing factor tristetraprolin (TTP). We show that phosphorylation of TTP by MK2 decreases its affinity to the ARE, inhibits its ability to replace HuR, and permits HuR-mediated initiation of translation of TNF mRNA. Since translation of TTP's own mRNA is also regulated by this mechanism, an intrinsic feedback control of the inflammatory response is ensured. The phosphorylation-regulated TTP/HuR exchange at target mRNAs provides a reversible switch between unstable/non-translatable and stable/efficiently translated mRNAs. PMID- 23028374 TI - De novo CNV formation in mouse embryonic stem cells occurs in the absence of Xrcc4-dependent nonhomologous end joining. AB - Spontaneous copy number variant (CNV) mutations are an important factor in genomic structural variation, genomic disorders, and cancer. A major class of CNVs, termed nonrecurrent CNVs, is thought to arise by nonhomologous DNA repair mechanisms due to the presence of short microhomologies, blunt ends, or short insertions at junctions of normal and de novo pathogenic CNVs, features recapitulated in experimental systems in which CNVs are induced by exogenous replication stress. To test whether the canonical nonhomologous end joining (NHEJ) pathway of double-strand break (DSB) repair is involved in the formation of this class of CNVs, chromosome integrity was monitored in NHEJ-deficient Xrcc4(-/-) mouse embryonic stem (ES) cells following treatment with low doses of aphidicolin, a DNA replicative polymerase inhibitor. Mouse ES cells exhibited replication stress-induced CNV formation in the same manner as human fibroblasts, including the existence of syntenic hotspot regions, such as in the Auts2 and Wwox loci. The frequency and location of spontaneous and aphidicolin-induced CNV formation were not altered by loss of Xrcc4, as would be expected if canonical NHEJ were the predominant pathway of CNV formation. Moreover, de novo CNV junctions displayed a typical pattern of microhomology and blunt end use that did not change in the absence of Xrcc4. A number of complex CNVs were detected in both wild-type and Xrcc4(-/-) cells, including an example of a catastrophic, chromothripsis event. These results establish that nonrecurrent CNVs can be, and frequently are, formed by mechanisms other than Xrcc4-dependent NHEJ. PMID- 23028375 TI - Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding. AB - A causative role for single nucleotide polymorphisms (SNPs) in many genetic disorders has become evident through numerous genome-wide association studies. However, identification of these common causal variants and the molecular mechanisms underlying these associations remains a major challenge. Differential transcription factor binding at a SNP resulting in altered gene expression is one possible mechanism. Here we apply PWAS ("proteome-wide analysis of SNPs"), a methodology based on quantitative mass spectrometry that enables rapid screening of SNPs for differential transcription factor binding, to 12 SNPs that are highly associated with type 1 diabetes at the IL2RA locus, encoding the interleukin-2 receptor CD25. We report differential, allele-specific binding of the transcription factors RUNX1, LEF1, CREB, and TFAP4 to IL2RA SNPs rs12722508*A, rs12722522*C, rs41295061*A, and rs2104286*A and demonstrate the functional influence of RUNX1 at rs12722508 by reporter gene assay. Thus, PWAS may be able to contribute to our understanding of the molecular consequences of human genetic variability underpinning susceptibility to multi-factorial disease. PMID- 23028376 TI - The non-flagellar type III secretion system evolved from the bacterial flagellum and diversified into host-cell adapted systems. AB - Type 3 secretion systems (T3SSs) are essential components of two complex bacterial machineries: the flagellum, which drives cell motility, and the non flagellar T3SS (NF-T3SS), which delivers effectors into eukaryotic cells. Yet the origin, specialization, and diversification of these machineries remained unclear. We developed computational tools to identify homologous components of the two systems and to discriminate between them. Our analysis of >1,000 genomes identified 921 T3SSs, including 222 NF-T3SSs. Phylogenomic and comparative analyses of these systems argue that the NF-T3SS arose from an exaptation of the flagellum, i.e. the recruitment of part of the flagellum structure for the evolution of the new protein delivery function. This reconstructed chronology of the exaptation process proceeded in at least two steps. An intermediate ancestral form of NF-T3SS, whose descendants still exist in Myxococcales, lacked elements that are essential for motility and included a subset of NF-T3SS features. We argue that this ancestral version was involved in protein translocation. A second major step in the evolution of NF-T3SSs occurred via recruitment of secretins to the NF-T3SS, an event that occurred at least three times from different systems. In rhizobiales, a partial homologous gene replacement of the secretin resulted in two genes of complementary function. Acquisition of a secretin was followed by the rapid adaptation of the resulting NF-T3SSs to multiple, distinct eukaryotic cell envelopes where they became key in parasitic and mutualistic associations between prokaryotes and eukaryotes. Our work elucidates major steps of the evolutionary scenario leading to extant NF-T3SSs. It demonstrates how molecular evolution can convert one complex molecular machine into a second, equally complex machine by successive deletions, innovations, and recruitment from other molecular systems. PMID- 23028377 TI - Factors that promote H3 chromatin integrity during transcription prevent promiscuous deposition of CENP-A(Cnp1) in fission yeast. AB - Specialized chromatin containing CENP-A nucleosomes instead of H3 nucleosomes is found at all centromeres. However, the mechanisms that specify the locations at which CENP-A chromatin is assembled remain elusive in organisms with regional, epigenetically regulated centromeres. It is known that normal centromeric DNA is transcribed in several systems including the fission yeast, Schizosaccharomyces pombe. Here, we show that factors which preserve stable histone H3 chromatin during transcription also play a role in preventing promiscuous CENP-A(Cnp1) deposition in fission yeast. Mutations in the histone chaperone FACT impair the maintenance of H3 chromatin on transcribed regions and promote widespread CENP A(Cnp1) incorporation at non-centromeric sites. FACT has little or no effect on CENP-A(Cnp1) assembly at endogenous centromeres where CENP-A(Cnp1) is normally assembled. In contrast, Clr6 complex II (Clr6-CII; equivalent to Rpd3S) histone deacetylase function has a more subtle impact on the stability of transcribed H3 chromatin and acts to prevent the ectopic accumulation of CENP-A(Cnp1) at specific loci, including subtelomeric regions, where CENP-A(Cnp1) is preferentially assembled. Moreover, defective Clr6-CII function allows the de novo assembly of CENP-A(Cnp1) chromatin on centromeric DNA, bypassing the normal requirement for heterochromatin. Thus, our analyses show that alterations in the process of chromatin assembly during transcription can destabilize H3 nucleosomes and thereby allow CENP-A(Cnp1) to assemble in its place. We propose that normal centromeres provide a specific chromatin context that limits reassembly of H3 chromatin during transcription and thereby promotes the establishment of CENP A(Cnp1) chromatin and associated kinetochores. These findings have important implications for genetic and epigenetic processes involved in centromere specification. PMID- 23028378 TI - TCF7L2 modulates glucose homeostasis by regulating CREB- and FoxO1-dependent transcriptional pathway in the liver. AB - Peripheral insulin resistance contributes to the development of type 2 diabetes. TCF7L2 has been tightly associated with this disease, although the exact mechanism was largely elusive. Here we propose a novel role of TCF7L2 in hepatic glucose metabolism in mammals. Expression of medium and short isoforms of TCF7L2 was greatly diminished in livers of diet-induced and genetic mouse models of insulin resistance, prompting us to delineate the functional role of these isoforms in hepatic glucose metabolism. Knockdown of hepatic TCF7L2 promoted increased blood glucose levels and glucose intolerance with increased gluconeogenic gene expression in wild-type mice, in accordance with the PCR array data showing that only the gluconeogenic pathway is specifically up-regulated upon depletion of hepatic TCF7L2. Conversely, overexpression of a nuclear isoform of TCF7L2 in high-fat diet-fed mice ameliorated hyperglycemia with improved glucose tolerance, suggesting a role of this factor in hepatic glucose metabolism. Indeed, we observed a binding of TCF7L2 to promoters of gluconeogenic genes; and expression of TCF7L2 inhibited adjacent promoter occupancies of CREB, CRTC2, and FoxO1, critical transcriptional modules in hepatic gluconeogenesis, to disrupt target gene transcription. Finally, haploinsufficiency of TCF7L2 in mice displayed higher glucose levels and impaired glucose tolerance, which were rescued by hepatic expression of a nuclear isoform of TCF7L2 at the physiological level. Collectively, these data suggest a crucial role of TCF7L2 in hepatic glucose metabolism; reduced hepatic expression of nuclear isoforms of this factor might be a critical instigator of hyperglycemia in type 2 diabetes. PMID- 23028379 TI - A mimicking-of-DNA-methylation-patterns pipeline for overcoming the restriction barrier of bacteria. AB - Genetic transformation of bacteria harboring multiple Restriction-Modification (R M) systems is often difficult using conventional methods. Here, we describe a mimicking-of-DNA-methylation-patterns (MoDMP) pipeline to address this problem in three difficult-to-transform bacterial strains. Twenty-four putative DNA methyltransferases (MTases) from these difficult-to-transform strains were cloned and expressed in an Escherichia coli strain lacking all of the known R-M systems and orphan MTases. Thirteen of these MTases exhibited DNA modification activity in Southwestern dot blot or Liquid Chromatography-Mass Spectrometry (LC-MS) assays. The active MTase genes were assembled into three operons using the Saccharomyces cerevisiae DNA assembler and were co-expressed in the E. coli strain lacking known R-M systems and orphan MTases. Thereafter, results from the dot blot and restriction enzyme digestion assays indicated that the DNA methylation patterns of the difficult-to-transform strains are mimicked in these E. coli hosts. The transformation of the Gram-positive Bacillus amyloliquefaciens TA208 and B. cereus ATCC 10987 strains with the shuttle plasmids prepared from MoDMP hosts showed increased efficiencies (up to four orders of magnitude) compared to those using the plasmids prepared from the E. coli strain lacking known R-M systems and orphan MTases or its parental strain. Additionally, the gene coding for uracil phosphoribosyltransferase (upp) was directly inactivated using non-replicative plasmids prepared from the MoDMP host in B. amyloliquefaciens TA208. Moreover, the Gram-negative chemoautotrophic Nitrobacter hamburgensis strain X14 was transformed and expressed Green Fluorescent Protein (GFP). Finally, the sequence specificities of active MTases were identified by restriction enzyme digestion, making the MoDMP system potentially useful for other strains. The effectiveness of the MoDMP pipeline in different bacterial groups suggests a universal potential. This pipeline could facilitate the functional genomics of the strains that are difficult to transform. PMID- 23028380 TI - GWAS of diabetic nephropathy: is the GENIE out of the bottle? PMID- 23028381 TI - Heterozygous mutations in DNA repair genes and hereditary breast cancer: a question of power. PMID- 23028382 TI - Biosorption of Mercury (II) from Aqueous Solutions onto Fungal Biomass. AB - The biosorption of mercury (II) on 14 fungal biomasses, Aspergillus flavus I-V, Aspergillus fumigatus I-II, Helminthosporium sp., Cladosporium sp., Mucor rouxii mutant, M. rouxii IM-80, Mucor sp 1 and 2, and Candida albicans, was studied in this work. It was found that the biomasses of the fungus M. rouxii IM-80, M. rouxii mutant, Mucor sp1, and Mucor sp 2 were very efficient removing the metal in solution, using dithizone, reaching the next percentage of removals: 95.3%, 88.7%, 80.4%, and 78.3%, respectively. The highest adsorption was obtained at pH 5.5, at 30 degrees C after 24 hours of incubation, with 1 g/100 mL of fungal biomass. PMID- 23028383 TI - PPARs Signaling and Cancer in the Gastrointestinal System. AB - Nowadays, the study of the peroxisome proliferators activated receptors (PPARs) as potential targets for cancer prevention and therapy has gained a strong interest. From a biological point of view, the overall responsibility of PPARs in cancer development and progression is still controversial since several studies report both antiproliferative and tumor-promoting actions for these signaling molecules in human cancer cells and animal models. In this paper, we discuss PPARs functions in the context of different types of gastrointestinal cancer. PMID- 23028384 TI - Leptin Antagonizes Peroxisome Proliferator-Activated Receptor-gamma Signaling in Growth Plate Chondrocytes. AB - Leptin is an obesity-associated cytokine-like hormone encoded by the ob gene. Recent studies reveal that leptin promotes proliferation and differentiation of chondrocytes, suggesting a peripheral role of leptin in regulating growth plate function. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcriptional regulator of adipogenesis. Locally, PPARgamma negatively regulates chondrogenic differentiation and terminal differentiation in the growth plate. The aim of this study was to test the hypothesis that leptin may suppress the inhibitory effects of PPARgamma on growth plate chondrocytes. Chondrocytes were collected from distal femoral growth plates of newborn rats and were cultured in monolayer or cell pellets in the presence or absence of leptin and the PPARgamma agonist ciglitazone. The results show that leptin attenuates the suppressive effects of PPARgamma on chondrogenic differentiation and T3-mediated chondrocyte hypertrophy. Leptin treatment also leads to a mild downregulation of PPAR mRNA expression and a significant MAPK/ERK-dependent PPARgamma phosphorylation at serine 112/82. Blocking MAPK/ERK function with PD98059 confirmed that leptin antagonizes PPARgamma function in growth plate chondrocytes through the MAPK/ERK signaling pathway. Furthermore, leptin signaling in growth plate cells is also negatively modulated by activation of PPARgamma, implying that these two signaling pathways are mutually regulated in growth plate chondrocytes. PMID- 23028385 TI - Social Determinants of Active Aging: Differences in Mortality and the Loss of Healthy Life between Different Income Levels among Older Japanese in the AGES Cohort Study. AB - We examined the relationship between income, mortality, and loss of years of healthy life in a sample of older persons in Japan. We analyzed 22,829 persons aged 65 or older who were functionally independent at baseline as a part of the Aichi Gerontological Evaluation Study (AGES). Two outcome measures were adopted, mortality and loss of healthy life. Independent variables were income level and age. The occurrence of mortality and need for care during these 1,461 days were tracked. Cox regressions were used to calculate the hazard ratio for mortality and loss of healthy life by income level. We found that people with lower incomes were more likely than those with higher incomes to report worse health. For the overall sample, using the governmental administrative data, the hazard ratios of mortality and loss of healthy life-years comparing the lowest to the highest income level were 3.50 for men and 2.48 for women for mortality and 3.71 for men and 2.27 for women for loss of healthy life. When only those who responded to questions about income on the mail survey were included in the analysis, the relationships became weaker and lost statistical significance. PMID- 23028387 TI - Exploring risk factors for follicular lymphoma. AB - Follicular lymphoma (FL) is an indolent malignancy of germinal center B cells with varied incidence across racial groups and geographic regions. Improvements in the classification of non-Hodgkin lymphoma subtypes provide an opportunity to explore associations between environmental exposures and FL incidence. Our paper found that aspects of Western lifestyle including sedentary lifestyle, obesity, and diets high in meat and milk are associated with an increased risk of FL. Diets rich in fruits and vegetables, polyunsaturated fatty acids, vitamin D, and certain antioxidants are inversely associated with FL risk. A medical history of Sjogren's syndrome, influenza vaccination, and heart disease may be associated with FL incidence. Associations between FL and exposure to pesticides, industrial solvents, hair dyes, and alcohol/tobacco were inconsistent. Genetic risk factors include variants at the 6p21.32 region of the MHC II locus, polymorphisms of the DNA repair gene XRCC3, and UV exposure in individuals with certain polymorphisms of the vitamin D receptor. Increasing our understanding of risk factors for FL must involve integrating epidemiological studies of genetics and exposures to allow for the examination of risk factors and interactions between genes and environment. PMID- 23028388 TI - A balance test for chronic perilymph fistula. AB - Perilymph fistula is defined as a leak of perilymph at the oval or round window. It excludes other conditions with "fistula" tests due to a dehiscent semicircular canal from cholesteotoma and the superior canal dehiscence syndrome. First recognized as a complication of stapedectomy, it then became apparent that head trauma and barotraumatic trauma from flying or diving could be a cause. Descriptions of "spontanenous" perilymph fistulas with no trauma history followed. It is likely that most perilymph fistula patients have a congential potential weakness of the otic capsule at the round or oval window. The vestibular symptoms have been assumed to be due to endolymphatic hydrops, but there is poor evidence. Their unilateral disequilibrium, nausea, and subtle cognitive problems suggest they are due to otolith disfunction and that these patients have a specific balance abnormality, unlike subjects with unilateral vestibular hypofuction. In this series of twenty patients with a confirmed fistula a logical simplification of Singleton's "eyes-closed turning" test predicted a PLF in twelve with a trauma history. In four no cause was found. In three a prior traumatic event was later recalled, but one patient had concealed it. PMID- 23028389 TI - Bench to bedside of neural stem cell in traumatic brain injury. AB - Traumatic brain injury (TBI) is one of the leading causes of major disability and death worldwide. Neural stem cells (NSCs) have recently been shown to contribute to the cellular remodelling that occurs following TBI and attention has been drawn to the area of neural stem cell as possible therapy for TBI. The NSCs may play an important role in the treatment of TBI by replacing the damaged cells and eventual remyelination. This paper summarized a critical assessment of recent data and developed a view comprising of six points to possible quality translation of NSCs in TBI. PMID- 23028390 TI - Nestin protein is phosphorylated in adult neural stem/progenitor cells and not endothelial progenitor cells. AB - An intermediate filament protein, Nestin, is known as a neural stem/progenitor cell marker. It was shown to be required for the survival and self-renewal of neural stem cells according to the phenotypes of Nestin knockout mice. Nestin expression has also been reported in vascular endothelial cells, and we recently reported Nestin expression in proliferating endothelial progenitor cells, but not in mature endothelial cells. Using quantitative phosphoproteome analysis, we studied differences in phosphorylation levels between CNS Nestin in adult neural stem cells and vascular Nestin in adult bone-marrow-derived endothelial progenitor cells. We detected 495 phosphopeptides in the cell lysates of adult CNS stem/progenitor cells and identified 11 significant phosphorylated amino acid residues in the Nestin protein. In contrast, endothelial progenitor cells showed no significant phosphorylation of Nestin. We also measured neoplastic endothelial cells of the mouse brain and identified 13 phosphorylated amino acid residues in the Nestin protein. Among the 11 phosphorylated amino acids of adult CNS Nestin, five (S565, S570, S819, S883, and S886) were CNS Nestin-specific phosphorylation sites. Detection of the CNS-specific phosphorylation sites in Nestin, for example, by a phospho-specific Nestin antibody, may allow the expression of CNS Nestin to be distinguished from vascular Nestin. PMID- 23028391 TI - Evolution and development of dual ingestion systems in mammals: notes on a new thesis and its clinical implications. AB - Traditionally, the development of oral feeding is viewed as a continuous, unitary process in which reflex-dominated sucking behavior gives rise to a more varied and volitional feeding behavior. In contrast, we consider the thesis that the infant develops two separable ingestive systems, one for suckling and one for feeding. First, we apply an evolutionary perspective, recognizing that suckling feeding is a universal, mammalian developmental sequence. We find that in mammalian evolution, feeding systems in offspring were established prior to the evolution of lactation, and therefore suckling is a separable feature that was added to feeding. We next review an experimental literature that characterizes suckling and feeding as separable in terms of their topography, sensory controls, physiological controls, neural substrates, and experience-based development. Together, these considerations constitute a view of "dual ingestive systems." The thesis, then, is that suckling is not a simple precursor of feeding but is a complete behavior that emerges, forms, and then undergoes a dissolution that overlaps with the emergence of independent feeding. This thesis guides us to focus differently on the challenges of properly managing and facilitating oral ingestion in infants, especially those born preterm, prior to the developmental onset of suckling. PMID- 23028392 TI - Mucosal immunity and sublingual immunotherapy in respiratory disorders. PMID- 23028394 TI - Evaluation of Safety and Protective Effect of Combined Extract of Cissampelos pareira and Anethum graveolens (PM52) against Age-Related Cognitive Impairment. AB - The present study aimed to determine acute toxicity, the protective effect, and underlying mechanism of PM52, a combined extract of Cissampelos pareira and Anethum graveolens, against age-related cognitive impairment in animal model of age-related cognitive impairment. PM52 was determined as acute toxicity according to OECD guideline. Male Wistar rats, weighing 180-220 g, were orally given PM52 at doses of 2, 10, and 50 mg/kg at a period of 14 days before and 7 days after the bilateral administration of AF64A via intracerebroventricular route. All animals were assessed according to spatial memory, neuron density, MDA level, the activities of SOD, CAT, GSH-Px, and AChEI effect in hippocampus. It was found that all doses of PM52 could attenuate memory impairment and neurodegeneration in hippocampus. The possible mechanisms might occur via the suppression of AChE and the decreased oxidative stress in hippocampus. Therefore, our data suggest that PM52 may serve as food supplement to protect against age-related cognitive impairment such as mild cognitive impairment (MCI) and early phase of Alzheimer's disease. However, further researches are still essential. PMID- 23028393 TI - Health and the built environment: exploring foundations for a new interdisciplinary profession. AB - The supportive role of the built environment for human health is a growing area of interdisciplinary research, evidence-based policy development, and related practice. Nevertheless, despite closely linked origins, the contemporary professions of public health and urban planning largely operate within the neoliberal framework of academic, political, and policy silos. A reinvigorated relationship between the two is fundamental to building and sustaining an effective "healthy built environment profession." A recent comprehensive review of the burgeoning literature on healthy built environments identified an emergent theme which we have termed "Professional Development." This literature relates to the development of relationships between health and built environment professionals. It covers case studies illustrating good practice models for policy change, as well as ways professionals can work to translate research into policy. Intertwined with this empirical research is a dialogue on theoretical tensions emerging as health and built environment practitioners and researchers seek to establish mutual understanding and respect. The nature of evidence required to justify policy change, for example, has surfaced as an area of asynchrony between accepted disciplinary protocols. Our paper discusses this important body of research with a view to initiating and supporting the ongoing development of an interdisciplinary profession of healthy planning. PMID- 23028395 TI - Combining forces to target bacteria. PMID- 23028396 TI - Birds in space and time: genetic changes accompanying anthropogenic habitat fragmentation in the endangered black-capped vireo (Vireo atricapilla). AB - Anthropogenic alterations in the natural environment can be a potent evolutionary force. For species that have specific habitat requirements, habitat loss can result in substantial genetic effects, potentially impeding future adaptability and evolution. The endangered black-capped vireo (Vireo atricapilla) suffered a substantial contraction of breeding habitat and population size during much of the 20th century. In a previous study, we reported significant differentiation between remnant populations, but failed to recover a strong genetic signal of bottlenecks. In this study, we used a combination of historical and contemporary sampling from Oklahoma and Texas to (i) determine whether population structure and genetic diversity have changed over time and (ii) evaluate alternate demographic hypotheses using approximate Bayesian computation (ABC). We found lower genetic diversity and increased differentiation in contemporary samples compared to historical samples, indicating nontrivial impacts of fragmentation. ABC analysis suggests a bottleneck having occurred in the early part of the 20th century, resulting in a magnitude decline in effective population size. Genetic monitoring with temporally spaced samples, such as used in this study, can be highly informative for assessing the genetic impacts of anthropogenic fragmentation on threatened or endangered species, as well as revealing the dynamics of small populations over time. PMID- 23028397 TI - Genetic monitoring and complex population dynamics: insights from a 12-year study of the Rio Grande silvery minnow. AB - The endangered Rio Grande silvery minnow persists as a remnant population in a highly fragmented and regulated arid-land river system. The species is subject to dramatic annual fluctuations in density. Since 2003, the wild population has been supplemented by hatchery-reared fish. We report on a 12-year (1999-2010) monitoring study of genetic diversity and effective population size (N(e)) of wild and hatchery stocks. Our goals were to evaluate how genetic metrics responded to changes in wild fish density and whether they corresponded to the number and levels of diversity of hatchery-reared repatriates. Genetic diversity and all measures of N(e) in the wild population did not correlate with wild fish density until hatchery supplementation began in earnest. Estimates of variance and inbreeding effective size were not correlated. Our results suggest source sink dynamics where captive stocks form a genetically diverse source and the wild population behaves as a sink. Nevertheless, overall genetic diversity of silvery minnow has been maintained over the last decade, and we attribute this to a well designed and executed propagation management plan. When multiple factors like environmental fluctuation and hatchery supplementation act simultaneously on a population, interpretation of genetic monitoring data may be equally complex and require considerable ecological data. PMID- 23028398 TI - Phages limit the evolution of bacterial antibiotic resistance in experimental microcosms. AB - The evolution of multi-antibiotic resistance in bacterial pathogens, often resulting from de novo mutations, is creating a public health crisis. Phages show promise for combating antibiotic-resistant bacteria, the efficacy of which, however, may also be limited by resistance evolution. Here, we suggest that phages may be used as supplements to antibiotics in treating initially sensitive bacteria to prevent resistance evolution, as phages are unaffected by most antibiotics and there should be little cross-resistance to antibiotics and phages. In vitro experiments using the bacterium Pseudomonas fluorescens, a lytic phage, and the antibiotic kanamycin supported this prediction: an antibiotic phage combination dramatically decreased the chance of bacterial population survival that indicates resistance evolution, compared with antibiotic treatment alone, whereas the phage alone did not affect bacterial survival. This effect of the combined treatment in preventing resistance evolution was robust to immigration of bacteria from an untreated environment, but not to immigration from environment where the bacteria had coevolved with the phage. By contrast, an isogenic hypermutable strain constructed from the wild-type P. fluorescens evolved resistance to all treatments regardless of immigration, but typically suffered very large fitness costs. These results suggest that an antibiotic-phage combination may show promise as an antimicrobial strategy. PMID- 23028399 TI - Evolutionary dynamics of separate and combined exposure of Pseudomonas fluorescens SBW25 to antibiotics and bacteriophage. AB - The use of bacteriophages against pathogenic bacteria in health care and in the food industry is now being advocated as an alternative to the use of antibiotics. But what is the evolutionary response for a bacterial population if both antibiotics and phages are used in combination? We employ an experimental evolution approach to address these questions and exposed Pseudomonas fluorescens SBW25 and a related hypermutator strain (mutS-) to the action of the antibiotic rifampicin and the lytic bacteriophage SBW25phi2. We then compared the densities, growth rates, and the mutations at the rpoB locus leading to rifampicin resistance of the evolved bacterial populations. We observed that the evolutionary response of populations under different treatments varied depending on the order in which the antimicrobials were added and whether the bacterium was a hypermutator. We found that wild-type rifampicin-resistant populations involved in biofilm formation often reverted to rifampicin sensitivity when stresses were added sequentially. In contrast, when the mortality agents were added simultaneously, phage populations frequently went extinct and the bacteria evolved antibiotic resistance. However, populations of the hypermutator mutS- converged to a single genotype at the rpoB locus. Future investigation on other bacteria and using different antibiotics and bacteriophage are needed to evaluate the generality of our findings. PMID- 23028400 TI - Phylogeny meets ecotoxicology: evolutionary patterns of sensitivity to a common insecticide. AB - Pesticides commonly occur in aquatic systems and pose a substantial challenge to the conservation of many taxa. Ecotoxicology has traditionally met this challenge by focusing on short-term, single-species tests and conducting risk assessments based on the most sensitive species tested. Rarely have ecotoxicology data been examined from an evolutionary perspective, and to our knowledge, there has never been a phylogenetic analysis of sensitivity, despite the fact that doing so would provide insights into patterns of sensitivity among species and identify which clades are the most sensitive to a particular pesticide. We examined phylogenetic patterns of pesticide sensitivity in amphibians, a group of conservation concern owing to global population declines. Using the insecticide endosulfan, we combined previously published results across seven species of tadpoles and added eight additional species from the families Bufonidae, Hylidae, and Ranidae. We found significant phylogenetic signal in the sensitivity to the insecticide and in the existence of time lag effects on tadpole mortality. Bufonids were less sensitive than hylids, which were less sensitive than the ranids. Moreover, mortality time lags were common in ranids, occasional in hylids, and rare in bufonids. These results highlight the importance of an evolutionary perspective and offer important insights for conservation. PMID- 23028401 TI - Life history and demographic determinants of effective/census size ratios as exemplified by brown trout (Salmo trutta). AB - A number of demographic factors, many of which related to human-driven encroachments, are predicted to decrease the effective population size (N(e)) relative to the census population size (N), but these have been little investigated. Yet, it is necessary to know which factors most strongly impact N(e), and how to mitigate these effects through sound management actions. In this study, we use parentage analysis of a stream-living brown trout (Salmo trutta) population to quantify the effect of between-individual variance in reproductive success on the effective number of breeders (N(b)) relative to the census number of breeders (N(i)). Comprehensive estimates of the N(b)/N ratio were reduced to 0.16-0.28, almost entirely due to larger than binomial variance in family size. We used computer simulations, based on empirical estimates of age-specific survival and fecundity rates, to assess the effect of repeat spawning (iteroparity) on N(e) and found that the variance in lifetime reproductive success was substantially higher for repeat spawners. Random family-specific survival, on the other hand, acts to buffer these effects. We discuss the implications of these findings for the management of small populations, where maintaining high and stable levels of N(e) is crucial to extenuate inbreeding and protect genetic variability. PMID- 23028402 TI - Demographic history of an elusive carnivore: using museums to inform management. AB - Elusive carnivores present a challenge to managers because traditional survey methods are not suitable. We applied a genetic approach using museum specimens to examine how historical and recent conditions influenced the demographic history of Puma concolor in western and southern Texas, USA. We used 10 microsatellite loci and indexed population trends by estimating historical and recent genetic diversity, genetic differentiation and effective population size. Mountain lions in southern Texas exhibited a 9% decline in genetic diversity, whereas diversity remained stable in western Texas. Genetic differentiation between western and southern Texas was minimal historically (F(ST) = 0.04, P < 0.01), but increased 2 2.5 times in our recent sample. An index of genetic drift for southern Texas was seven to eight times that of western Texas, presumably contributing to the current differentiation between western and southern Texas. Furthermore, southern Texas exhibited a >50% temporal decline in effective population size, whereas western Texas showed no change. Our results illustrate that population declines and genetic drift have occurred in southern Texas, likely because of contemporary habitat loss and predator control. Population monitoring may be needed to ensure the persistence of mountain lions in the southern Texas region. This study highlights the utility of sampling museum collections to examine demographic histories and inform wildlife management. PMID- 23028403 TI - Genomic regions in crop-wild hybrids of lettuce are affected differently in different environments: implications for crop breeding. AB - Many crops contain domestication genes that are generally considered to lower fitness of crop-wild hybrids in the wild environment. Transgenes placed in close linkage with such genes would be less likely to spread into a wild population. Therefore, for environmental risk assessment of GM crops, it is important to know whether genomic regions with such genes exist, and how they affect fitness. We performed quantitative trait loci (QTL) analyses on fitness(-related) traits in two different field environments employing recombinant inbred lines from a cross between cultivated Lactuca sativa and its wild relative Lactuca serriola. We identified a region on linkage group 5 where the crop allele consistently conferred a selective advantage (increasing fitness to 212% and 214%), whereas on linkage group 7, a region conferred a selective disadvantage (reducing fitness to 26% and 5%), mainly through delaying flowering. The probability for a putative transgene spreading would therefore depend strongly on the insertion location. Comparison of these field results with greenhouse data from a previous study using the same lines showed considerable differences in QTL patterns. This indicates that care should be taken when extrapolating experiments from the greenhouse, and that the impact of domestication genes has to be assessed under field conditions. PMID- 23028404 TI - Scanning SNPs from a large set of expressed genes to assess the impact of artificial selection on the undomesticated genetic diversity of white spruce. AB - A scan involving 1134 single-nucleotide polymorphisms (SNPs) from 709 expressed genes was used to assess the potential impact of artificial selection for height growth on the genetic diversity of white spruce. Two case populations of different sizes simulating different family selection intensities (K = 13% and 5%, respectively) were delineated from the Quebec breeding program. Their genetic diversity and allele frequencies were compared with those of control populations of the same size and geographic origin to assess the effect of increasing the selection intensity. The two control populations were also compared to assess the effect of reducing the sampling size. On one hand, in all pairwise comparisons, genetic diversity parameters were comparable and no alleles were lost in the case populations compared with the control ones, except for few rare alleles in the large case population. Also, the distribution of allele frequencies did not change significantly (P <= 0.05) between the populations compared, but ten and nine SNPs (0.8%) exhibited significant differences in frequency (P <= 0.01) between case and control populations of large and small sizes, respectively. Results of association tests between breeding values for height at 15 years of age and these SNPs supported the hypothesis of a potential effect of selection on the genes harboring these SNPs. On the other hand, contrary to expectations, there was no evidence that selection induced an increase in linkage disequilibrium in genes potentially affected by selection. These results indicate that neither the reduction in the sampling size nor the increase in selection intensity was sufficient to induce a significant change in the genetic diversity of the selected populations. Apparently, no loci were under strong selection pressure, confirming that the genetic control of height growth in white spruce involves many genes with small effects. Hence, selection for height growth at the present intensities did not appear to compromise background genetic diversity but, as predicted by theory, effects were detected at a few gene SNPs harboring intermediate allele frequencies. PMID- 23028405 TI - A Foilized Polyethylene Pouch for the Prevention of Transmission of HIV from Mother to Child. AB - Many children become HIV+ due to mother-to-child transmission, a risk that can be largely eliminated if infants ingest antiretroviral (ARV) medications immediately after birth. As most mothers in Africa deliver at home, the ARV must be provided at their last antenatal visit, sometimes months before birth. No current drug delivery system allows the mother to store the medication at home long enough to be effective. We propose a preserving, foilized, polyethylene pouch to be pre dosed and sealed by a pharmacist for later delivery to the newborn.Pouches were filled with 0.6 ml of Nevirapine (NVP). Thirty-three pouches were immediately studied to measure the impact of medication handling (oxygen, light, filling and sealing the pouches). The remaining samples were stored for up to one year at three storage conditions (25 degrees C/60%RH, 30 degrees C/65%RH, and 40 degrees C/75%RH). Every two months, moisture loss, preservative concentration, impurity concentrations and NVP concentration were measured. Flora and fauna challenges were conducted.THE POUCH NEARLY ELIMINATED MOISTURE LOSS: pouches lost less than 0.7% of their weight over twelve months. As expected, exposing the medication to light, oxygen, and handling significantly affected the sacrificial preservative concentrations (Propyl paraben dropped 38%, Methyl paraben dropped 12% at time point zero). However, after the initial time point, preservative levels were stable in the package over twelve months under all storage conditions (4.1% average concentration drop), leaving sufficient preservatives to protect the medication. The concentration of NVP changed an average of only 1.3% over all storage conditions and times points (maximum 1.4%).We conclude that the foilized polyethylene pouch can preserve NVP, and perhaps other ARV's, for up to one year. PMID- 23028406 TI - The p38 MAPK Pathway in Rheumatoid Arthritis: A Sideways Look. AB - The p38 mitogen-activated protein kinase (MAPK) signaling pathway has been strongly implicated in many of the processes that underlie the pathology of rheumatoid arthritis (RA). For many years it has been considered a promising target for development of new anti-inflammatory drugs with which to treat RA and other chronic immune-mediated inflammatory diseases. However, several recent clinical trials have concluded in a disappointing manner. Why is this so, if p38 MAPK clearly contributes to the excessive production of inflammatory mediators, the destruction of bone and cartilage? We argue that, to explain the apparent failure of p38 inhibitors in the rheumatology clinic, we need to understand better the complexities of the p38 pathway and its many levels of communication with other cellular signaling pathways. In this review we look at the p38 MAPK pathway from a slightly different perspective, emphasising its role in post transcriptional rather than transcriptional control of gene expression, and its contribution to the off-phase rather than the on-phase of the inflammatory response. PMID- 23028407 TI - c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases. AB - The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are activated by environmental stress. JNK is also activated by proinflammatory cytokines, such as TNF and IL-1, and Toll-like receptor ligands. This pathway, therefore, can act as a critical convergence point in immune system signaling for both adaptive and innate responses. Like other MAPKs, the JNKs are activated via the sequential activation of protein kinases that includes two dual-specificity MAP kinase kinases (MKK4 and MKK7) and multiple MAP kinase kinase kinases. MAPKs, including JNKs, can be deactivated by a specialized group of phosphatases, called MAP kinase phosphatases. JNK phosphorylates and regulates the activity of transcription factors other than c Jun, including ATF2, Elk-1, p53 and c-Myc and non-transcription factors, such as members of the Bcl-2 family. The pathway plays a critical role in cell proliferation, apoptosis, angiogenesis and migration. In this review, an overview of the functions that are related to rheumatic diseases is presented. In addition, some diseases in which JNK participates will be highlighted. PMID- 23028408 TI - JAK Kinases in Health and Disease: An Update. AB - Janus kinases (Jaks) are critical signaling elements for a large subset of cytokines. As a consequence they play pivotal roles in the patho-physiology of many diseases including neoplastic and autoimmune diseases. Small molecule Jak inhibitors as therapeutic agents have become a reality and the palette of such inhibitors will likely expand. This review will summarize our current knowledge on these key enzymes and their associated pharmaceutical inhibitors. PMID- 23028409 TI - The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases. AB - The class 1 PI3Ks are lipid kinases with key roles in cell surface receptor triggered signal transduction pathways. Two isoforms of the catalytic subunits, p110gamma and p110delta, are enriched in leucocytes in which they promote activation, cellular growth, proliferation, differentiation and survival through the generation of the second messenger PIP3. Genetic inactivation or pharmaceutical inhibition of these PI3K isoforms in mice result in impaired immune responses and reduced susceptibility to autoimmune and inflammatory conditions. We review the PI3K signal transduction pathways and the effects of inhibition of p110gamma and/or p110delta on innate and adaptive immunity. Focusing on rheumatoid arthritis and systemic lupus erythematosus we discuss the preclinical evidence and prospects for small molecule inhibitors of p110gamma and/or p110delta in autoimmune disease. PMID- 23028414 TI - Role of toll like receptors in irritable bowel syndrome: differential mucosal immune activation according to the disease subtype. AB - BACKGROUND: The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose pathogenesis is not completely understood. Its high prevalence and the considerable effects on quality of life make IBS a disease with high social cost. Recent studies suggest that low grade mucosal immune activation, increased intestinal permeability and the altered host-microbiota interactions that modulate innate immune response, contribute to the pathophysiology of IBS. However, the understanding of the precise molecular pathophysiology remains largely unknown. METHODOLOGY AND FINDINGS: In this study our objective was to evaluate the TLR expression as a key player in the innate immune response, in the colonic mucosa of IBS patients classified into the three main subtypes (with constipation, with diarrhea or mixed). TLR2 and TLR4 mRNA expression was assessed by real time RT-PCR while TLRs protein expression in intestinal epithelial cells was specifically assessed by flow cytometry and immunofluorescence. Mucosal inflammatory cytokine production was investigated by the multiplex technology. Here we report that the IBS-Mixed subgroup displayed a significant up-regulation of TLR2 and TLR4 in the colonic mucosa. Furthermore, these expressions were localized in the epithelial cells, opening new perspectives for a potential role of epithelial cells in host-immune interactions in IBS. In addition, the increased TLR expression in IBS-M patients elicited intracellular signaling pathways resulting in increased expression of the mucosal proinflammatory cytokines IL-8 and IL1beta. CONCLUSIONS: Our results provide the first evidence of differential expression of TLR in IBS patients according to the disease subtype. These results offer further support that microflora plays a central role in the complex pathophysiology of IBS providing novel pharmacological targets for this chronic gastrointestinal disorder according to bowel habits. PMID- 23028410 TI - Signal transduction pathways in chronic inflammatory autoimmune disease: small GTPases. AB - Ras superfamily small GTPases represent a wide and diverse class of intracellular signaling proteins that are highly conserved during evolution. These enzymes serve as key checkpoints in coupling antigen receptor, growth factor, cytokine and chemokine stimulation to cellular responses. Once activated, via their ability to regulate multiple downstream signaling pathways, small GTPases amplify and diversify signaling cascades which regulate cellular proliferation, survival, cytokine expression, trafficking and retention. Small GTPases, particularly members of the Ras, Rap, and Rho family, critically coordinate the function and interplay of immune and stromal cells during inflammatory respones, and increasing evidence indicates that alterations in small GTPase signaling contribute to the pathological behavior of these cell populations in human chronic inflammatory diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Here, we review how Ras, Rap, and Rho family GTPases contribute to the biology of cell populations relevant to human chronic inflammatory disease, highlight recent advances in understanding how alterations in these pathways contribute to pathology in RA and SLE, and discuss new therapeutic strategies that may allow specific targeting of small GTPases in the clinic. PMID- 23028415 TI - Kamin blocking is associated with reduced medial-frontal gyrus activation: implications for prediction error abnormality in schizophrenia. AB - The following study used 3-T functional magnetic resonance imaging (fMRI) to investigate the neural signature of Kamin blocking. Kamin blocking is an associative learning phenomenon seen where prior association of a stimulus (A) with an outcome blocks subsequent learning to an added stimulus (B) when both stimuli are later presented together (AB) with the same outcome. While there are a number of theoretical explanations of Kamin blocking, it is widely considered to exemplify the use of prediction error in learning, where learning occurs in proportion to the difference between expectation and outcome. In Kamin blocking as stimulus A fully predicts the outcome no prediction error is generated by the addition of stimulus B to form the compound stimulus AB, hence learning about it is "blocked". Kamin blocking is disrupted in people with schizophrenia, their relatives and healthy individuals with high psychometrically-defined schizotypy. This disruption supports suggestions that abnormal prediction error is a core deficit that can help to explain the symptoms of schizophrenia. The present study tested 9 healthy volunteers on an f-MRI adaptation of Oades' "mouse in the house task", the only task measuring Kamin blocking that shows disruption in schizophrenia patients that has been independently replicated. Participant's Kamin blocking scores were found to inversely correlate with Kamin-blocking related activation within the prefrontal cortex, specifically the medial frontal gyrus. The medial frontal gyrus has been associated with the psychological construct of uncertainty, which we suggest is consistent with disrupted Kamin blocking and demonstrated in people with schizophrenia. These data suggest that the medial frontal gyrus merits further investigation as a potential locus of reduced Kamin blocking and abnormal prediction error in schizophrenia. PMID- 23028417 TI - Universal natural shapes: from unifying shape description to simple methods for shape analysis and boundary value problems. AB - Gielis curves and surfaces can describe a wide range of natural shapes and they have been used in various studies in biology and physics as descriptive tool. This has stimulated the generalization of widely used computational methods. Here we show that proper normalization of the Levenberg-Marquardt algorithm allows for efficient and robust reconstruction of Gielis curves, including self-intersecting and asymmetric curves, without increasing the overall complexity of the algorithm. Then, we show how complex curves of k-type can be constructed and how solutions to the Dirichlet problem for the Laplace equation on these complex domains can be derived using a semi-Fourier method. In all three methods, descriptive and computational power and efficiency is obtained in a surprisingly simple way. PMID- 23028418 TI - FSH modulates PKAI and GPR3 activities in mouse oocyte of COC in a gap junctional communication (GJC)-dependent manner to initiate meiotic resumption. AB - Many studies have shown that cyclic adenosine-5'-monophosphate (cAMP)-dependent protein kinase A (PKA) and G-protein-coupled receptor 3 (GPR3) are crucial for controlling meiotic arrest in oocytes. However, it is unclear how gonadotropins modulate these factors to regulate oocyte maturation, especially by gap junctional communication (GJC). Using an in vitro meiosis-arrested mouse cumulus oocyte complex (COC) culture model, we showed that there is a close relationship between follicle-stimulating hormone (FSH) and the PKA type I (PKAI) and GPR3. The effect of FSH on oocyte maturation was biphasic, initially inhibitory and then stimulatory. During FSH-induced maturation, rapid cAMP surges were observed in both cumulus cells and oocyte. Most GJC between cumulus cells and oocyte ceased immediately after FSH stimulation and recommenced after the cAMP surge. FSH-induced maturation was blocked by PKAI activator 8-AHA-cAMP. Levels of PKAI regulatory subunits and GPR3 decreased and increased, respectively, after FSH stimulation. In the presence of the GJC inhibitor carbenoxolone (CBX), FSH failed to induce the meiotic resumption and the changes in PKAI, GPR3 and cAMP surge in oocyte were no longer detected. Furthermore, GPR3 was upregulated by high cAMP levels, but not by PKAI activation. When applied after FSH stimulation, the specific phosphodiesterase 3A (PDE3A) inhibitor cilostamide immediately blocked meiotic induction, regardless of when it was administered. PKAI activation inhibited mitogen-activated protein kinase (MAPK) phosphorylation in the oocytes of COCs, which participated in the initiation of FSH-induced meiotic maturation in vitro. Just before FSH-induced meiotic maturation, cAMP, PKAI, and GPR3 returned to basal levels, and PDE3A activity and MAPK phosphorylation increased markedly. These experiments show that FSH induces a transient increase in cAMP levels and regulates GJC to control PKAI and GPR3 activities, thereby creating an inhibitory phase. After PDE3A and MAPK activities increase, meiosis resumes. PMID- 23028419 TI - Predictors of appropriate ICD therapy in patients with arrhythmogenic right ventricular cardiomyopathy: long term experience of a tertiary care center. AB - INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetically transmitted disease prone to ventricular arrhythmias. We therefore investigated the clinical, echocardiographical and electrophysiological predictors of appropriate implantable cardioverter defibrillator (ICD) therapy in patients with ARVC. METHODS: A retrospective analysis was performed in 26 patients (median age of 40 years at diagnosis, 21 males and 5 females) with ARVC who underwent ICD implantation. RESULTS: Over a median (range) follow-up period of 10 (2.7, 37) years, appropriate ICD therapy for ventricular arrhythmias was documented in 12 (46%) out of 26 patients. In all patients with appropriate ICD therapy the ICD was originally inserted for secondary prevention. Median time from ICD implantation to ICD therapy was 9 months (range 3.6, 54 months). History of heart failure was a significant predictor of appropriate ICD therapy (p = 0.033). Left ventricular disease involvement (p = 0.059) and age at implantation (p = 0.063) were borderline significant predictors. Patients with syncope at time of diagnosis were significantly less likely to receive ICD therapy (p = 0.02). Invasive electrophysiological testing was not significantly associated with appropriate ICD therapy. CONCLUSION: In our cohort of patients with ARVC, history of heart failure was a significant predictor of appropriate ICD therapy, whereas left ventricular involvement and age at time of ICD implantation were of borderline significance. These predictors should be tested in larger prospective cohorts to optimize ICD therapy in this rare cardiomyopathy. PMID- 23028420 TI - Pronounced peramorphosis in lissamphibians--Aviturus exsecratus (Urodela, Cryptobranchidae) from the Paleocene-Eocene Thermal Maximum of Mongolia. AB - BACKGROUND: The oldest and largest member of giant salamanders (Cryptobranchidae) Aviturus exsecratus appears in the latest Paleocene (near the Paleocene-Eocene Thermal Maximum) of Mongolia. Based on femoral and vertebral morphology and metrics, a terrestrial adaptation has been supposed for this species. METHODOLOGY/PRINCIPAL FINDINGS: A detailed morphological reinvestigation of published as well as unpublished material reveals that this salamander shows a vomerine dentition that is posteriorly shifted and arranged in a zigzag pattern, a strongly developed olfactory region within the cranial cavity, and the highest bone ossification and relatively longest femur among all fossil and recent cryptobranchids. CONCLUSIONS/SIGNIFICANCE: The presence of these characteristics indicates a peramorphic developmental pattern for Aviturus exsecratus. Our results from Av. exsecratus indicate for the first time pronounced peramorphosis within a crown-group lissamphibian. Av. exsecratus represents a new developmental trajectory within both fossil and recent lissamphibian clades characterized by extended ontogeny and large body size, resembling the pattern known from late Paleozoic eryopines. Moreover, Av. exsecratus is not only a cryptobranchid with distinctive peramorphic characters, but also the first giant salamander with partially terrestrial (amphibious) lifestyle. The morphology of the vomers and dentaries suggests the ability of both underwater and terrestrial feeding. PMID- 23028421 TI - Bacteria in crude oil survived autoclaving and stimulated differentially by exogenous bacteria. AB - Autoclaving of crude oil is often used to evaluate the hydrocarbon-degrading abilities of bacteria. This may be potentially useful for bioaugmentation and microbial enhanced oil recovery (MEOR). However, it is not entirely clear if "endogenous" bacteria (e.g., spores) in/on crude oil survive the autoclaving process, or influence subsequent evaluation of the hydrocarbon-degradation abilities of the "exogenous" bacterial strains. To test this, we inoculated autoclaved crude oil medium with six exogenous bacterial strains (three Dietzia strains, two Acinetobacter strains, and one Pseudomonas strain). The survival of the spore-forming Bacillus and Paenibacillus and the non-spore-forming mesophilic Pseudomonas, Dietzia, Alcaligenes, and Microbacterium was detected using a 16S rRNA gene clone library and terminal restriction fragment length polymorphism (T RFLP) analysis. However, neither bacteria nor bacterial activity was detected in three controls consisting of non-inoculated autoclaved crude oil medium. These results suggest that detection of endogenous bacteria was stimulated by the six inoculated strains. In addition, inoculation with Acinetobacter spp. stimulated detection of Bacillus, while inoculation with Dietzia spp. and Pseudomonas sp. stimulated the detection of more Pseudomonas. In contrast, similar exogenous bacteria stimulated similar endogenous bacteria at the genus level. Based on these results, special emphasis should be applied to evaluate the influence of bacteria capable of surviving autoclaving on the hydrocarbon-degrading abilities of exogenous bacteria, in particular, with regard to bioaugmentation and MEOR. Bioaugmentation and MEOR technologies could then be developed to more accurately direct the growth of specific endogenous bacteria that may then improve the efficiency of treatment or recovery of crude oil. PMID- 23028422 TI - Gene expression profiling identifies HOXB4 as a direct downstream target of GATA 2 in human CD34+ hematopoietic cells. AB - Aplastic anemia is characterized by a reduced hematopoietic stem cell number. Although GATA-2 expression was reported to be decreased in CD34-positive cells in aplastic anemia, many questions remain regarding the intrinsic characteristics of hematopoietic stem cells in this disease. In this study, we identified HOXB4 as a downstream target of GATA-2 based on expression profiling with human cord blood derived CD34-positive cells infected with control or GATA-2 lentiviral shRNA. To confirm the functional link between GATA-2 and HOXB4, we conducted GATA-2 gain-of function and loss-of-function experiments, and HOXB4 promoter analysis, including luciferase assay, in vitro DNA binding analysis and quantitative ChIP analysis, using K562 and CD34-positive cells. The analyses suggested that GATA-2 directly regulates HOXB4 expression through the GATA sequence in the promoter region. Furthermore, we assessed GATA-2 and HOXB4 expression in CD34-positive cells from patients with aplastic anemia (n = 10) and idiopathic thrombocytopenic purpura (n = 13), and demonstrated that the expression levels of HOXB4 and GATA-2 were correlated in these populations (r = 0.6573, p<0.01). Our results suggested that GATA-2 directly regulates HOXB4 expression in hematopoietic stem cells, which may play an important role in the development and/or progression of aplastic anemia. PMID- 23028423 TI - Cell elasticity determines macrophage function. AB - Macrophages serve to maintain organ homeostasis in response to challenges from injury, inflammation, malignancy, particulate exposure, or infection. Until now, receptor ligation has been understood as being the central mechanism that regulates macrophage function. Using macrophages of different origins and species, we report that macrophage elasticity is a major determinant of innate macrophage function. Macrophage elasticity is modulated not only by classical biologic activators such as LPS and IFN-gamma, but to an equal extent by substrate rigidity and substrate stretch. Macrophage elasticity is dependent upon actin polymerization and small rhoGTPase activation, but functional effects of elasticity are not predicted by examination of gene expression profiles alone. Taken together, these data demonstrate an unanticipated role for cell elasticity as a common pathway by which mechanical and biologic factors determine macrophage function. PMID- 23028425 TI - Population expanding with the phalanx model and lineages split by environmental heterogeneity: a case study of Primula obconica in subtropical China. AB - BACKGROUND: Current and historical events have both affected the current distribution patterns and intraspecific divergence of plants. While numerous studies have focused on the Qinghai-Tibetan Plateau (QTP), the impacts of such events on the flora of subtropical China remain poorly understood. Subtropical China is famous for its highly complex topography and the limited impact from glaciation during the Pleistocene; this may have resulted in a different genetic legacy for species in this region compared to fully glaciated areas. METHODOLOGY/PRINCIPAL FINDINGS: We used plastid and nuclear DNA sequence data and distribution modeling to analyze the divergence patterns and demographic history of Primula obconica Hance, a widespread herbaceous montane species in subtropical China. The phylogenetic analysis revealed two major lineages (lineage A and lineage B), representing a west-east split into the Yunnan and Eastern groups, and the Sichuan and Central groups, respectively. The Eastern and Central groups comprised relatively new derived haplotypes. Nested Clade Analysis and Bayesian Skyline Plot analyses both indicated that P. obconica mainly experienced a gradual expansion of populations. In addition, the simulated distribution of P. obconica during the Last Glacial Maximum was slightly larger than its present-day distribution. CONCLUSION/SIGNIFICANCE: Our results are the first to identify a west-east migration of P. obconica. The gradual expansion pattern and a larger potential distribution range in cold periods detected for P. obconica indicate that the population expansion of this species is consistent with the phalanx model. In addition, the current patterns of genetic differentiation have persisted as a result of the extensive environmental heterogeneity that exists in subtropical China. PMID- 23028424 TI - Proteomic and systems biology analysis of monocytes exposed to securinine, a GABA(A) receptor antagonist and immune adjuvant. AB - Securinine, a GABA(A) receptor antagonist, has been reported to enhance monocyte cell killing of Coxiella burnetii without obvious adverse effects in vivo. We employed multiplex 2D gel electrophoresis using Zdyes, a new generation of covalently linked fluorescent differential protein detection dyes to analyze changes in the monocyte proteome in response to Securinine. Securinine antagonism of GABA(A) receptors triggers the activation of p38. We used the differential protein expression results to guide a search of the literature and network analysis software to construct a systems biology model of the effect of Securinine on monocytes. The model suggests that various metabolic modulators (fatty acid binding protein 5, inosine 5'-monophosphate dehydrogenase, and thioredoxin) are at least partially reshaping the metabolic landscape within the monocytes. The actin bundling protein L-plastin, and the Ca(2+) binding protein S100A4 also appear to have important roles in the immune response stimulated by Securinine. Fatty acid binding protein 5 (FABP5) may be involved in effecting lipid raft composition, inflammation, and hormonal regulation of monocytes, and the model suggests that FABP5 may be a central regulator of metabolism in activated monocytes. The model also suggests that the heat shock proteins have a significant impact on the monocyte immune response. The model provides a framework to guide future investigations into the mechanisms of Securinine action and with elaboration may help guide development of new types of immune adjuvants. PMID- 23028426 TI - Finite element study of the mechanical response in spinal cord during the thoracolumbar burst fracture. AB - BACKGROUND: The mechanical response of the spinal cord during burst fracture was seldom quantitatively addressed and only few studies look into the internal strain of the white and grey matters within the spinal cord during thoracolumbar burst fracture (TLBF). The aim of the study is to investigate the mechanical response of the spinal cord during TLBF and correlate the percent canal compromise (PCC) with the strain in the spinal cord. METHODOLOGY/PRINCIPAL FINDINGS: A three-dimensional (3D) finite element (FE) model of human T12-L1 spinal cord with visco-elastic property was generated based on the transverse sections images of spinal cord, and the model was validated against published literatures under static uniaxial tension and compression. With the validated model, a TLBF simulation was performed to compute the mechanical strain in the spinal cord with the PCC. Linear regressions between PCC and strain in the spinal cord show that at the initial stage, with the PCC at 20%, and 45%, the corresponding mechanical strains in ventral grey, dorsal grey, ventral white, dorsal white matters were 0.06, 0.04, 0.12, 0.06, and increased to 0.14, 0.12, 0.23, and 0.13, respectively. At the recoiled stage, when the PCC was decreased from 45% to 20%, the corresponding strains were reduced to 0.03, 0.02, 0.04 and 0.03. The strain was correlated well with PCC. CONCLUSIONS/SIGNIFICANCE: The simulation shows that the strain in the spinal cord correlated well with the PCC, and the mechanical strains in the ventral regions are higher than those in the dorsal regions of spinal cord tissue during burst fracture, suggesting that the ventral regions of the spinal cord may susceptible to injury than the dorsal regions. PMID- 23028427 TI - Reductions in inpatient mortality following interventions to improve emergency hospital care in Freetown, Sierra Leone. AB - BACKGROUND: The demand for high quality hospital care for children in low resource countries is not being met. This paper describes a number of strategies to improve emergency care at a children's hospital and evaluates the impact of these on inpatient mortality. In addition, the cost-effectiveness of improving emergency care is estimated. METHODS AND FINDINGS: A team of local and international staff developed a plan to improve emergency care for children arriving at The Ola During Children's Hospital, Freetown, Sierra Leone. Following focus group discussions, five priority areas were identified to improve emergency care; staff training, hospital layout, staff allocation, medical equipment, and medical record keeping. A team of international volunteers worked with local staff for six months to design and implement improvements in these five priority areas. The improvements were evaluated collectively rather than individually. Before the intervention, the inpatient mortality rate was 12.4%. After the intervention this improved to 5.9%. The relative risk of dying was 47% (95% CI 0.369-0.607) lower after the intervention. The estimated number of lives saved in the first two months after the intervention was 103. The total cost of the intervention was USD 29 714, the estimated cost per death averted was USD 148. There are two main limitation of the study. Firstly, the brevity of the study and secondly, the assumed homogeneity of the clinical cases that presented to the hospital before and after the intervention. CONCLUSIONS: This study demonstarted a signficant reductuion in inpatient mortality rate after an intervention to improve emergency hospital care If the findings of this paper could be reproduced in a larger more rigorous study, improving the quality of care in hospitals would be a very cost effective strategy to save children's lives in low resource settings. PMID- 23028428 TI - A flow cytometry-based assay for quantifying non-plaque forming strains of yellow fever virus. AB - Primary clinical isolates of yellow fever virus can be difficult to quantitate by standard in vitro methods because they may not form discernable plaques or induce a measurable cytopathic effect (CPE) on cell monolayers. In our hands, the Dakar strain of yellow fever virus (YFV-Dakar) could not be measured by plaque assay (PA), focus-forming assay (FFA), or by measurement of CPE. For these reasons, we developed a YFV-specific monoclonal antibody (3A8.B6) and used it to optimize a highly sensitive flow cytometry-based tissue culture limiting dilution assay (TC LDA) to measure levels of infectious virus. The TC-LDA was performed by incubating serial dilutions of virus in replicate wells of C6/36 cells and stained intracellularly for virus with MAb 3A8.B6. Using this approach, we could reproducibly quantitate YFV-Dakar in tissue culture supernatants as well as from the serum of viremic rhesus macaques experimentally infected with YFV-Dakar. Moreover, the TC-LDA approach was >10-fold more sensitive than standard plaque assay for quantitating typical plaque-forming strains of YFV including YFV-17D and YFV-FNV (French neurotropic vaccine). Together, these results indicate that the TC-LDA technique is effective for quantitating both plaque-forming and non plaque-forming strains of yellow fever virus, and this methodology may be readily adapted for the study and quantitation of other non-plaque-forming viruses. PMID- 23028429 TI - Microarray analysis of microRNA expression during axolotl limb regeneration. AB - Among vertebrates, salamanders stand out for their remarkable capacity to quickly regrow a myriad of tissues and organs after injury or amputation. The limb regeneration process in axolotls (Ambystoma mexicanum) has been well studied for decades at the cell-tissue level. While several developmental genes are known to be reactivated during this epimorphic process, less is known about the role of microRNAs in urodele amphibian limb regeneration. Given the compelling evidence that many microRNAs tightly regulate cell fate and morphogenetic processes through development and adulthood by modulating the expression (or re-expression) of developmental genes, we investigated the possibility that microRNA levels change during limb regeneration. Using two different microarray platforms to compare the axolotl microRNA expression between mid-bud limb regenerating blastemas and non-regenerating stump tissues, we found that miR-21 was overexpressed in mid-bud blastemas compared to stump tissue. Mature A. mexicanum ("Amex") miR-21 was detected in axolotl RNA by Northern blot and differential expression of Amex-miR-21 in blastema versus stump was confirmed by quantitative RT-PCR. We identified the Amex Jagged1 as a putative target gene for miR-21 during salamander limb regeneration. We cloned the full length 3'UTR of Amex Jag1, and our in vitro assays demonstrated that its single miR-21 target recognition site is functional and essential for the response of the Jagged1 gene to miR-21 levels. Our findings pave the road for advanced in vivo functional assays aimed to clarify how microRNAs such as miR-21, often linked to pathogenic cell growth, might be modulating the redeployment of developmental genes such as Jagged1 during regenerative processes. PMID- 23028430 TI - Infection-related declines in chill coma recovery and negative geotaxis in Drosophila melanogaster. AB - Studies of infection in Drosophila melanogaster provide insight into both mechanisms of host resistance and tolerance of pathogens. However, research into the pathways involved in these processes has been limited by the relatively few metrics that can be used to measure sickness and health throughout the course of infection. Here we report measurements of infection-related declines in flies' performance on two different behavioral assays. D. melanogaster are slower to recover from a chill-induced coma during infection with either Listeria monocytogenes or Streptococcus pneumoniae. L. monocytogenes infection also impacts flies' performance during a negative geotaxis assay, revealing a decline in their rate of climbing as part of their innate escape response after startle. In addition to providing new measures for assessing health, these assays also suggest pathological consequences of and metabolic shifts that may occur over the course of an infection. PMID- 23028431 TI - Generation and characterization of the Western Regional Research Center Brachypodium T-DNA insertional mutant collection. AB - The model grass Brachypodium distachyon (Brachypodium) is an excellent system for studying the basic biology underlying traits relevant to the use of grasses as food, forage and energy crops. To add to the growing collection of Brachypodium resources available to plant scientists, we further optimized our Agrobacterium tumefaciens-mediated high-efficiency transformation method and generated 8,491 Brachypodium T-DNA lines. We used inverse PCR to sequence the DNA flanking the insertion sites in the mutants. Using these flanking sequence tags (FSTs) we were able to assign 7,389 FSTs from 4,402 T-DNA mutants to 5,285 specific insertion sites (ISs) in the Brachypodium genome. More than 29% of the assigned ISs are supported by multiple FSTs. T-DNA insertions span the entire genome with an average of 19.3 insertions/Mb. The distribution of T-DNA insertions is non uniform with a larger number of insertions at the distal ends compared to the centromeric regions of the chromosomes. Insertions are correlated with genic regions, but are biased toward UTRs and non-coding regions within 1 kb of genes over exons and intron regions. More than 1,300 unique genes have been tagged in this population. Information about the Western Regional Research Center Brachypodium insertional mutant population is available on a searchable website (http://brachypodium.pw.usda.gov) designed to provide researchers with a means to order T-DNA lines with mutations in genes of interest. PMID- 23028432 TI - An integrated pipeline for de novo assembly of microbial genomes. AB - Remarkable advances in DNA sequencing technology have created a need for de novo genome assembly methods tailored to work with the new sequencing data types. Many such methods have been published in recent years, but assembling raw sequence data to obtain a draft genome has remained a complex, multi-step process, involving several stages of sequence data cleaning, error correction, assembly, and quality control. Successful application of these steps usually requires intimate knowledge of a diverse set of algorithms and software. We present an assembly pipeline called A5 (Andrew And Aaron's Awesome Assembly pipeline) that simplifies the entire genome assembly process by automating these stages, by integrating several previously published algorithms with new algorithms for quality control and automated assembly parameter selection. We demonstrate that A5 can produce assemblies of quality comparable to a leading assembly algorithm, SOAPdenovo, without any prior knowledge of the particular genome being assembled and without the extensive parameter tuning required by the other assembly algorithm. In particular, the assemblies produced by A5 exhibit 50% or more reduction in broken protein coding sequences relative to SOAPdenovo assemblies. The A5 pipeline can also assemble Illumina sequence data from libraries constructed by the Nextera (transposon-catalyzed) protocol, which have markedly different characteristics to mechanically sheared libraries. Finally, A5 has modest compute requirements, and can assemble a typical bacterial genome on current desktop or laptop computer hardware in under two hours, depending on depth of coverage. PMID- 23028433 TI - Evidence for cohesive dispersal in the sea. AB - As with many marine species, the vast majority of coral-reef fishes have a bipartite life cycle consisting of a dispersive larval stage and a benthic adult stage. While the potentially far-reaching demographic and ecological consequences of marine dispersal are widely appreciated, little is known of the structure of the larval pool and of the dispersive process itself. Utilizing Palindrome Sequence Analysis of otolith micro-chemistry (PaSA;) we show that larvae of Neopomacentrus miryae (Pomacentridae) appear to remain in cohesive cohorts throughout their entire pelagic larval duration (PLD; ~28 days). Genetically, we found cohort members to be maternally (mtDNA) unrelated. While physical forcing cannot be negated as contributing to initial cohort formation, the small scale of the observed spatial structure suggests that some behavioral modification may be involved from a very early age. This study contributes to our ongoing re evaluation of the processes that structure marine populations and communities and the spatial scales at which they operate. PMID- 23028434 TI - Regulation to create environments conducive to physical activity: understanding the barriers and facilitators at the Australian state government level. AB - INTRODUCTION: Policy and regulatory interventions aimed at creating environments more conducive to physical activity (PA) are an important component of strategies to improve population levels of PA. However, many potentially effective policies are not being broadly implemented. This study sought to identify potential policy/regulatory interventions targeting PA environments, and barriers/facilitators to their implementation at the Australian state/territory government level. METHODS: In-depth interviews were conducted with senior representatives from state/territory governments, statutory authorities and non government organisations (n = 40) to examine participants': 1) suggestions for regulatory interventions to create environments more conducive to PA; 2) support for preselected regulatory interventions derived from a literature review. Thematic and constant comparative analyses were conducted. RESULTS: POLICY INTERVENTIONS MOST COMMONLY SUGGESTED BY PARTICIPANTS FELL INTO TWO AREAS: 1) urban planning and provision of infrastructure to promote active travel; 2) discouraging the use of private motorised vehicles. Of the eleven preselected interventions presented to participants, interventions relating to walkability/cycling and PA facilities received greatest support. Interventions involving subsidisation (of public transport, PA-equipment) and the provision of more public transport infrastructure received least support. These were perceived as not economically viable or unlikely to increase PA levels. Dominant barriers were: the powerful 'road lobby', weaknesses in the planning system and the cost of potential interventions. Facilitators were: the provision of evidence, collaboration across sectors, and synergies with climate change/environment agendas. CONCLUSION: This study points to how difficult it will be to achieve policy change when there is a powerful 'road lobby' and government investment prioritises road infrastructure over PA-promoting infrastructure. It highlights the pivotal role of the planning and transport sectors in implementing PA promoting policy, however suggests the need for clearer guidelines and responsibilities for state and local government levels in these areas. Health outcomes need to be given more direct consideration and greater priority within non-health sectors. PMID- 23028435 TI - Association between common allergic symptoms and cancer in the NHANES III female cohort. AB - BACKGROUND: Previous epidemiological studies have investigated the association between allergic symptoms and cancer occurrence. However, the role of allergy in cancer has been elusive, especially for the female population. METHODS: We examined the relationship between cancer prevalence and common allergic symptoms of rhinoconjunctivitis (RC) and wheezing (WZ) among NHANES III female participants. RESULTS: Among 4600 people, 36.3% (n = 1669) did not have any allergic symptoms (NO), while 47.6% (n = 2188) reported RC, and 16.2% (n = 743), WZ. The proportion of cancer among NO groups was 5.43% (91/1669), among RC group, 7.63% (167/2188), and among WZ group, 11.23% (83/743) (RC group- OR 1.44 with 95% CI 1.00-2.08; p = 0.05 while for WZ group- OR 2.20 with 95%CI 1.27-3.80; p = 0.01). After adjusting for all the possible confounding variables including age, smoking, or COPD, having symptoms of RC (AOR 1.49 with 95%CI 1.12-2.36; p = 0.01) or WC (AOR 2.08 with 95%CI 1.11-3.89; p = 0.02) demonstrated consistent strong association with cancer. Among nonsmokers (n = 2505, 54.5%) only symptoms of RC showed association with cancer (AOR 1.51 with 95%CI 1.00-2.28; p = 0.05). Among former or current smokers (n = 2094, 45.5%), only symptoms of WZ demonstrated association with cancer (AOR 2.38 with 95%CI 1.16-4.87; p = 0.02). Among different types of cancers, odds of having breast cancer among participants with symptoms of RC or WZ were approximately twice the odds of having breast cancer among participants without any of these symptoms. AOR for RC group was 1.89 with 95%CI 1.04-3.42 and p = 0.04 while AOR for WC group was 2.08 with 95%CI 0.90-4.78 and p = 0.08. CONCLUSIONS: In summary, we found associations between common allergic symptoms like rhinitis/conjunctivitis and wheezing and prevalence of cancer, specifically between rhinitis/conjunctivitis and breast cancer that were not found in previous studies. Larger prospective studies are required to validate our findings. PMID- 23028436 TI - Comparative effectiveness of cognitive therapies delivered face-to-face or over the telephone: an observational study using propensity methods. AB - OBJECTIVES: To compare the clinical and cost-effectiveness of face-to-face (FTF) with over-the-telephone (OTT) delivery of low intensity cognitive behavioural therapy. DESIGN: Observational study following SROBE guidelines. Selection effects were controlled using propensity scores. Non-inferiority comparisons assessed effectiveness. SETTING: IAPT (improving access to psychological therapies) services in the East of England. PARTICIPANTS: 39,227 adults referred to IAPT services. Propensity score strata included 4,106 individuals; 147 pairs participated in 1:1 matching. INTERVENTION: Two or more sessions of computerised cognitive behavioural therapy (CBT). MAIN OUTCOME MEASURES: Patient-reported outcomes: Patient Health Questionnaire (PHQ-9) for depression; Generalised Anxiety Disorder questionnaire (GAD-7); Work and Social Adjustment Scale (WSAS). Differences between groups were summarised as standardised effect sizes (ES), adjusted mean differences and minimally important difference for PHQ-9. Cost per session for OTT was compared with FTF. RESULTS: Analysis of covariance controlling for number of assessments, provider site, and baseline PHQ-9, GAD-7 and WSAS indicated statistically significantly greater reductions in scores for OTT treatment with moderate (PHQ-9: ES: 0.14; GAD-7: ES: 0.10) or small (WSAS: ES: 0.03) effect sizes. Non-inferiority in favour of OTT treatment for symptom severity persisted as small to moderate effects for all but individuals with the highest symptom severity. In the most stringent comparison, the one-to-one propensity matching, adjusted mean differences in treatment outcomes indicated non-inferiority between OTT versus FTF treatments for PHQ-9 and GAD-7, whereas the evidence was moderate for WSAS. The per-session cost for OTT was 36.2% lower than FTF. CONCLUSIONS: The clinical effectiveness of low intensity CBT-based interventions delivered OTT was not inferior to those delivered FTF except for people with more severe illness where FTF was superior. This provides evidence for better targeting of therapy, efficiencies for patients, cost savings for services and greater access to psychological therapies for people with common mental disorders. PMID- 23028437 TI - Moving the weber fraction: the perceptual precision for moment of inertia increases with exploration force. AB - How does the magnitude of the exploration force influence the precision of haptic perceptual estimates? To address this question, we examined the perceptual precision for moment of inertia (i.e., an object's "angular mass") under different force conditions, using the Weber fraction to quantify perceptual precision. Participants rotated a rod around a fixed axis and judged its moment of inertia in a two-alternative forced-choice task. We instructed different levels of exploration force, thereby manipulating the magnitude of both the exploration force and the angular acceleration. These are the two signals that are needed by the nervous system to estimate moment of inertia. Importantly, one can assume that the absolute noise on both signals increases with an increase in the signals' magnitudes, while the relative noise (i.e., noise/signal) decreases with an increase in signal magnitude. We examined how the perceptual precision for moment of inertia was affected by this neural noise. In a first experiment we found that a low exploration force caused a higher Weber fraction (22%) than a high exploration force (13%), which suggested that the perceptual precision was constrained by the relative noise. This hypothesis was supported by the result of a second experiment, in which we found that the relationship between exploration force and Weber fraction had a similar shape as the theoretical relationship between signal magnitude and relative noise. The present study thus demonstrated that the amount of force used to explore an object can profoundly influence the precision by which its properties are perceived. PMID- 23028438 TI - Manipulating fatty acid biosynthesis in microalgae for biofuel through protein protein interactions. AB - Microalgae are a promising feedstock for renewable fuels, and algal metabolic engineering can lead to crop improvement, thus accelerating the development of commercially viable biodiesel production from algae biomass. We demonstrate that protein-protein interactions between the fatty acid acyl carrier protein (ACP) and thioesterase (TE) govern fatty acid hydrolysis within the algal chloroplast. Using green microalga Chlamydomonas reinhardtii (Cr) as a model, a structural simulation of docking CrACP to CrTE identifies a protein-protein recognition surface between the two domains. A virtual screen reveals plant TEs with similar in silico binding to CrACP. Employing an activity-based crosslinking probe designed to selectively trap transient protein-protein interactions between the TE and ACP, we demonstrate in vitro that CrTE must functionally interact with CrACP to release fatty acids, while TEs of vascular plants show no mechanistic crosslinking to CrACP. This is recapitulated in vivo, where overproduction of the endogenous CrTE increased levels of short-chain fatty acids and engineering plant TEs into the C. reinhardtii chloroplast did not alter the fatty acid profile. These findings highlight the critical role of protein-protein interactions in manipulating fatty acid biosynthesis for algae biofuel engineering as illuminated by activity-based probes. PMID- 23028439 TI - Association of the DYX1C1 dyslexia susceptibility gene with orthography in the Chinese population. AB - Several independent studies have supported the association of DYX1C1 with dyslexia, but its role in general reading development remains unclear. Here, we investigated the contribution of this gene to reading, with a focus on orthographic skills, in a sample of 284 unrelated Chinese children aged 5 to 11 years who were participating in the Chinese Longitudinal Study of Reading Development. We tested this association using a quantitative approach for Chinese character reading, Chinese character dictation, orthographic judgment, and visual skills. Significant or marginally significant associations were observed at the marker rs11629841 with children's orthographic judgments at ages 7 and 8 years (all P values<0.020). Significant associations with Chinese character dictation (all P values<0.013) were also observed for this single-nucleotide polymorphism (SNP) at ages 9, 10, and 11 years. Further analyses revealed that the association with orthographic skills was specific to the processing of specific components of characters (P values<0.046). No association was found at either SNP of rs3743205 or rs57809907. Our findings suggest that DYX1C1 influences reading development in the general Chinese population and supports a universal effect of this gene. PMID- 23028440 TI - Mutation in Phex gene predisposes BALB/c-Phex(Hyp-Duk)/Y mice to otitis media. AB - Genetic susceptibility underlying otitis media (OM) remains to be understood. We show in this study that mutation in Phex gene predisposes the BALB/c-Phex(Hyp Duk)/Y (abbreviated Hyp-Duk/Y) mice to OM, which occurs at post-natal day 21 (P21) with an average penetrance of 73%. The OM was identified by effusion in the middle ear cavity and/or thickening of middle ear mucosae, and was characterised by increase in goblet cells, deformity of epithelial cilia and higher expression of proliferating cell nuclear antigen (PCNA) in cells of the middle ear mucosae. Moreover, the transcription levels of Tlr2, Tlr4, Nfkb1, Ccl4, Il1b and Tnfalpha in the ears of the Hyp-Duk/Y mice at P35 were significantly upregulated, compared to those of the controls. Higher expression levels of TLR2, TLR4, NF-kappaB and TNF-alpha in the middle ears were demonstrated by immunohistochemistry (IHC). However, the OM in the mice was not prevented by azithromycin administration from gestational day 18 to P35. Further study showed that, in contrast to the low mRNA levels of Phex gene in the ears of the Hyp-Duk/Y mice, the mRNA level of Fgf23 was significantly elevated at P9, P14, P21 and P35. Meanwhile, mRNA levels of EP2 (PGE2 receptor), which expressed in the middle ear epithelia as demonstrated by IHC, were already increased at P14 even before the occurrence of OM, indicating that PGE2, an inflammatory mediator, is involved in the OM development in the mutants. Taking together, Phex mutation primarily up-regulates gene expression levels in FGF23 mediated pathways in the middle ears, resulting in cell proliferation and defence impairment at the mucosae and subsequently bacterial infection. The Hyp-Duk/Y mouse is a new genetic mouse model of OM. PMID- 23028441 TI - Born in an alien nest: how do social parasite male offspring escape from host aggression? AB - Social parasites exploit the colony resources of social insects. Some of them exploit the host colony as a food resource or as a shelter whereas other species also exploit the brood care behavior of their social host. Some of these species have even lost the worker caste and rely completely on the host's worker force to rear their offspring. To avoid host defenses and bypass their recognition code, these social parasites have developed several sophisticated chemical infiltration strategies. These infiltration strategies have been highly studied in several hymenopterans. Once a social parasite has successfully entered a host nest and integrated its social system, its emerging offspring still face the same challenge of avoiding host recognition. However, the strategy used by the offspring to survive within the host nest without being killed is still poorly documented. In cuckoo bumblebees, the parasite males completely lack the morphological and chemical adaptations to social parasitism that the females possess. Moreover, young parasite males exhibit an early production of species specific cephalic secretions, used as sexual pheromones. Host workers might thus be able to recognize them. Here we used a bumblebee host-social parasite system to test the hypothesis that social parasite male offspring exhibit a chemical defense strategy to escape from host aggression during their intranidal life. Using behavioral assays, we showed that extracts from the heads of young cuckoo bumblebee males contain a repellent odor that prevents parasite males from being attacked by host workers. We also show that social parasitism reduces host worker aggressiveness and helps parasite offspring acceptance. PMID- 23028442 TI - Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis. AB - BACKGROUND: Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. METHODOLOGY/PRINCIPAL FINDINGS: Eight-week-old C57BL/6 mice were fed a methionine- and choline deficient plus high fat (MCD+HF) diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH. CONCLUSIONS/SIGNIFICANCE: These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance. PMID- 23028443 TI - Ten-m3 is required for the development of topography in the ipsilateral retinocollicular pathway. AB - BACKGROUND: The alignment of ipsilaterally and contralaterally projecting retinal axons that view the same part of visual space is fundamental to binocular vision. While much progress has been made regarding the mechanisms which regulate contralateral topography, very little is known of the mechanisms which regulate the mapping of ipsilateral axons such that they align with their contralateral counterparts. RESULTS: Using the advantageous model provided by the mouse retinocollicular pathway, we have performed anterograde tracing experiments which demonstrate that ipsilateral retinal axons begin to form terminal zones (TZs) in the superior colliculus (SC), within the first few postnatal days. These appear mature by postnatal day 11. Importantly, TZs formed by ipsilaterally-projecting retinal axons are spatially offset from those of contralaterally-projecting axons arising from the same retinotopic location from the outset. This pattern is consistent with that required for adult visuotopy. We further demonstrate that a member of the Ten-m/Odz/Teneurin family of homophilic transmembrane glycoproteins, Ten-m3, is an essential regulator of ipsilateral retinocollicular topography. Ten-m3 mRNA is expressed in a high-medial to low-lateral gradient in the developing SC. This corresponds topographically with its high-ventral to low dorsal retinal gradient. In Ten-m3 knockout mice, contralateral ventrotemporal axons appropriately target rostromedial SC, whereas ipsilateral axons exhibit dramatic targeting errors along both the mediolateral and rostrocaudal axes of the SC, with a caudal shift of the primary TZ, as well as the formation of secondary, caudolaterally displaced TZs. In addition to these dramatic ipsilateral-specific mapping errors, both contralateral and ipsilateral retinocollicular TZs exhibit more subtle changes in morphology. CONCLUSIONS: We conclude that important aspects of adult visuotopy are established via the differential sensitivity of ipsilateral and contralateral axons to intrinsic guidance cues. Further, we show that Ten-m3 plays a critical role in this process and is particularly important for the mapping of the ipsilateral retinocollicular pathway. PMID- 23028444 TI - In situ identification of CD44+/CD24- cancer cells in primary human breast carcinomas. AB - Breast cancer cells with the CD44+/CD24- phenotype have been reported to be tumourigenic due to their enhanced capacity for cancer development and their self renewal potential. The identification of human tumourigenic breast cancer cells in surgical samples has recently received increased attention due to the implications for prognosis and treatment, although limitations exist in the interpretation of these studies. To better identify the CD44+/CD24- cells in routine surgical specimens, 56 primary breast carcinoma cases were analysed by immunofluorescence and confocal microscopy, and the results were compared using flow cytometry analysis to correlate the amount and distribution of the CD44+/CD24- population with clinicopathological features. Using these methods, we showed that the breast carcinoma cells displayed four distinct sub-populations based on the expression pattern of CD44 and CD24. The CD44+/CD24- cells were found in 91% of breast tumours and constituted an average of 6.12% (range, 0.11% 21.23%) of the tumour. A strong correlation was found between the percentage of CD44+/CD24- cells in primary tumours and distant metastasis development (p = 0.0001); in addition, there was an inverse significant association with ER and PGR status (p = 0.002 and p = 0.001, respectively). No relationship was evident with tumour size (T) and regional lymph node (N) status, differentiation grade, proliferative index or HER2 status. In a multivariate analysis, the percentage of CD44+/CD24- cancer cells was an independent factor related to metastasis development (p = 0.004). Our results indicate that confocal analysis of fluorescence-labelled breast cancer samples obtained at surgery is a reliable method to identify the CD44+/CD24- tumourigenic cell population, allowing for the stratification of breast cancer patients into two groups with substantially different relapse rates on the basis of CD44+/CD24- cell percentage. PMID- 23028445 TI - PHYMYCO-DB: a curated database for analyses of fungal diversity and evolution. AB - BACKGROUND: In environmental sequencing studies, fungi can be identified based on nucleic acid sequences, using either highly variable sequences as species barcodes or conserved sequences containing a high-quality phylogenetic signal. For the latter, identification relies on phylogenetic analyses and the adoption of the phylogenetic species concept. Such analysis requires that the reference sequences are well identified and deposited in public-access databases. However, many entries in the public sequence databases are problematic in terms of quality and reliability and these data require screening to ensure correct phylogenetic interpretation. METHODS AND PRINCIPAL FINDINGS: To facilitate phylogenetic inferences and phylogenetic assignment, we introduce a fungal sequence database. The database PHYMYCO-DB comprises fungal sequences from GenBank that have been filtered to satisfy stringent sequence quality criteria. For the first release, two widely used molecular taxonomic markers were chosen: the nuclear SSU rRNA and EF1-alpha gene sequences. Following the automatic extraction and filtration, a manual curation is performed to remove problematic sequences while preserving relevant sequences useful for phylogenetic studies. As a result of curation, ~20% of the automatically filtered sequences have been removed from the database. To demonstrate how PHYMYCO-DB can be employed, we test a set of environmental Chytridiomycota sequences obtained from deep sea samples. CONCLUSION: PHYMYCO-DB offers the tools necessary to: (i) extract high quality fungal sequences for each of the 5 fungal phyla, at all taxonomic levels, (ii) extract already performed alignments, to act as 'reference alignments', (iii) launch alignments of personal sequences along with stored data. A total of 9120 SSU rRNA and 672 EF1-alpha high quality fungal sequences are now available. The PHYMYCO-DB is accessible through the URL http://phymycodb.genouest.org/. PMID- 23028446 TI - Collapse of a marine mammal species driven by human impacts. AB - Understanding historical roles of species in ecosystems can be crucial for assessing long term human impacts on environments, providing context for management or restoration objectives, and making conservation evaluations of species status. In most cases limited historical abundance data impedes quantitative investigations, but harvested species may have long-term data accessible from hunting records. Here we make use of annual hunting records for Caspian seals (Pusa caspica) dating back to the mid-19(th) century, and current census data from aerial surveys, to reconstruct historical abundance using a hind casting model. We estimate the minimum numbers of seals in 1867 to have been 1 1.6 million, but the population declined by at least 90% to around 100,000 individuals by 2005, primarily due to unsustainable hunting throughout the 20(th) century. This collapse is part of a broader picture of catastrophic ecological change in the Caspian over the 20(th) Century. Our results combined with fisheries data show that the current biomass of top predators in the Caspian is much reduced compared to historical conditions. The potential for the Caspian and other similar perturbed ecosystems to sustain natural resources of much greater biological and economic value than at present depends on the extent to which a number of anthropogenic impacts can be harnessed. PMID- 23028447 TI - Effects of psychological stress on innate immunity and metabolism in humans: a systematic analysis. AB - Stress is perhaps easiest to conceptualize as a process which allows an organism to accommodate for the demands of its environment such that it can adapt to the prevailing set of conditions. Psychological stress is an important component with the potential to affect physiology adversely as has become evident from various studies in the area. Although these studies have established numerous effects of psychological stress on physiology, a global strategy for the correlation of these effects has yet to begin. Our comparative and systematic analysis of the published literature has unraveled certain interesting molecular mechanisms as clues to account for some of the observed effects of psychological stress on human physiology. In this study, we attempt to understand initial phase of the physiological response to psychological stress by analyzing interactions between innate immunity and metabolism at systems level by analyzing the data available in the literature. In light of our gene association-networks and enrichment analysis we have identified candidate genes and molecular systems which might have some associative role in affecting psychological stress response system or even producing some of the observed terminal effects (such as the associated physiological disorders). In addition to the already accepted role of psychological stress as a perturbation that can disrupt physiological homeostasis, we speculate that it is potentially capable of causing deviation of certain biological processes from their basal level activity after which they can return back to their basal tones once the effects of stress diminish. Based on the derived inferences of our comparative analysis, we have proposed a probabilistic mechanism for how psychological stress could affect physiology such that these adaptive deviations are sometimes not able to bounce back to their original basal tones, and thus increase physiological susceptibility to metabolic and immune imbalance. PMID- 23028448 TI - Transcriptional differences between rhesus embryonic stem cells generated from in vitro and in vivo derived embryos. AB - Numerous studies have focused on the transcriptional signatures that underlie the maintenance of embryonic stem cell (ESC) pluripotency. However, it remains unclear whether ESC retain transcriptional aberrations seen in in vitro cultured embryos. Here we report the first global transcriptional profile comparison between ESC generated from either in vitro cultured or in vivo derived primate embryos by microarray analysis. Genes involved in pluripotency, oxygen regulation and the cell cycle were downregulated in rhesus ESC generated from in vitro cultured embryos (in vitro ESC). Significantly, several gene differences are similarly downregulated in preimplantation embryos cultured in vitro, which have been associated with long term developmental consequences and disease predisposition. This data indicates that prior to derivation, embryo quality may influence the molecular signature of ESC lines, and may differentially impact the physiology of cells prior to or following differentiation. PMID- 23028449 TI - Focal adhesion kinase plays a role in osteoblast mechanotransduction in vitro but does not affect load-induced bone formation in vivo. AB - A healthy skeleton relies on bone's ability to respond to external mechanical forces. The molecular mechanisms by which bone cells sense and convert mechanical stimuli into biochemical signals, a process known as mechanotransduction, are unclear. Focal adhesions play a critical role in cell survival, migration and sensing physical force. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that controls focal adhesion dynamics and can mediate reparative bone formation in vivo and osteoblast mechanotransduction in vitro. Based on these data, we hypothesized that FAK plays a role in load-induced bone formation. To test this hypothesis, we performed in vitro fluid flow experiments and in vivo bone loading studies in FAK-/- clonal lines and conditional FAK knockout mice, respectively. FAK-/- osteoblasts showed an ablated prostaglandin E(2) (PGE(2)) response to fluid flow shear. This effect was reversed with the re-expression of wild-type FAK. Re-expression of FAK containing site-specific mutations at Tyr-397 and Tyr-925 phosphorylation sites did not rescue the phenotype, suggesting that these sites are important in osteoblast mechanotransduction. Interestingly, mice in which FAK was conditionally deleted in osteoblasts and osteocytes did not exhibit altered load-induced periosteal bone formation. Together these data suggest that although FAK is important in mechanically-induced signaling in osteoblasts in vitro, it is not required for an adaptive response in vivo, possibly due to a compensatory mechanism that does not exist in the cell culture system. PMID- 23028450 TI - Growth dynamics explain the development of spatiotemporal burst activity of young cultured neuronal networks in detail. AB - A typical property of isolated cultured neuronal networks of dissociated rat cortical cells is synchronized spiking, called bursting, starting about one week after plating, when the dissociated cells have sufficiently sent out their neurites and formed enough synaptic connections. This paper is the third in a series of three on simulation models of cultured networks. Our two previous studies [26], [27] have shown that random recurrent network activity models generate intra- and inter-bursting patterns similar to experimental data. The networks were noise or pacemaker-driven and had Izhikevich-neuronal elements with only short-term plastic (STP) synapses (so, no long-term potentiation, LTP, or depression, LTD, was included). However, elevated pre-phases (burst leaders) and after-phases of burst main shapes, that usually arise during the development of the network, were not yet simulated in sufficient detail. This lack of detail may be due to the fact that the random models completely missed network topology .and a growth model. Therefore, the present paper adds, for the first time, a growth model to the activity model, to give the network a time dependent topology and to explain burst shapes in more detail. Again, without LTP or LTD mechanisms. The integrated growth-activity model yielded realistic bursting patterns. The automatic adjustment of various mutually interdependent network parameters is one of the major advantages of our current approach. Spatio-temporal bursting activity was validated against experiment. Depending on network size, wave reverberation mechanisms were seen along the network boundaries, which may explain the generation of phases of elevated firing before and after the main phase of the burst shape.In summary, the results show that adding topology and growth explain burst shapes in great detail and suggest that young networks still lack/do not need LTP or LTD mechanisms. PMID- 23028451 TI - Tumor selective cytotoxic action of a thiomorpholin hydroxamate inhibitor (TMI-1) in breast cancer. AB - BACKGROUND: Targeted therapies, associated with standard chemotherapies, have improved breast cancer care. However, primary and acquired resistances are frequently observed and the development of new concepts is needed. High throughput approaches to identify new active and safe molecules with or without an "a priori" are currently developed. Also, repositioning already-approved drugs in cancer therapy is of growing interest. The thiomorpholine hydroxamate compound TMI-1 has been previously designed to inhibit metalloproteinase activity for the treatment of rheumatoid arthritis. We present here the repositioning of TMI-1 drug in breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: We tested the effect of TMI-1 on luminal, basal and ERBB2-overexpressing breast tumor cell lines and on MMTV-ERBB2/neu tumor evolution. We measured the effects on i) cell survival, ii) cell cycle, iii) extrinsic and intrinsic apoptotic pathways, iv) association with doxorubicin, docetaxel and lapatinib, v) cancer stem cells compartment. In contrast with conventional cytotoxic drugs, TMI-1 was highly selective for tumor cells and cancer stem cells at submicromolar range. All non-malignant cells tested were resistant even at high concentration. TMI-1 was active on triple negative (TN) and ERBB2-overexpressing breast tumor cell lines, and was also highly efficient on human and murine "primary" ERBB2-overexpressing cells. Treatment of transgenic MMTV-ERBB2/neu mice with 100 mg/kg/day TMI-1 alone induced tumor apoptosis, inhibiting mammary gland tumor occurrence and development. No adverse effects were noticed during the treatment. This compound had a strong synergistic effect in association with docetaxel, doxorubicin and lapatinib. We showed that TMI-1 mediates its selective effects by caspase dependent apoptosis. TMI-1 was efficient in 34/40 tumor cell lines of various origins (ED50: 0.6 uM to 12.5 uM). CONCLUSIONS/SIGNIFICANCE: This is the first demonstration of the tumor selective cytotoxic action of a thiomorpholin hydroxamate compound. TMI-1 is a novel repositionable drug not only for the treatment of adverse prognosis breast cancers but also for other neoplasms. PMID- 23028452 TI - Addressing health inequalities in the delivery of the human papillomavirus vaccination programme: examining the role of the school nurse. AB - BACKGROUND: HPV immunisation of adolescent girls is expected to have a significant impact in the reduction of cervical cancer. UK The HPV immunisation programme is primarily delivered by school nurses. We examine the role of school nurses in delivering the HPV immunisation programme and their impact on minimising health inequalities in vaccine uptake. METHODS AND FINDINGS: A rapid evidence assessment (REA) and semi-structured interviews with health professionals were conducted and analysed using thematic analysis. 80 health professionals from across the UK are interviewed, primarily school nurses and HPV immunisation programme coordinators. The REA identified 2,795 articles and after analysis and hand searches, 34 relevant articles were identified and analysed. Interviews revealed that health inequalities in HPV vaccination uptake were mainly related to income and other social factors in contrast to published research which emphasises potential inequalities related to ethnicity and/or religion. Most school nurses interviewed understood local health inequalities and made particular efforts to target girls who did not attend or missed doses. Interviews also revealed maintaining accurate and consistent records influenced both school nurses' understanding and efforts to target inequalities in HPV vaccination uptake. CONCLUSIONS: Despite high uptake in the UK, some girls remain at risk of not being vaccinated with all three doses. School nurses played a key role in reducing health inequalities in the delivery of the HPV programme. Other studies identified religious beliefs and ethnicity as potentially influencing HPV vaccination uptake but interviews for this research found this appeared not to have occurred. Instead school nurses stated girls who were more likely to be missed were those not in education. Improving understanding of the delivery processes of immunisation programmes and this impact on health inequalities can help to inform solutions to increase uptake and address health inequalities in childhood and adolescent vaccination programmes. PMID- 23028453 TI - The effect of XPD/ERCC2 polymorphisms on gastric cancer risk among different ethnicities: a systematic review and meta-analysis. AB - BACKGROUND: Potential xeroderma pigmentosum group D (XPD), also called excision repair cross-complimentary group two (ERCC2), Lys751Gln and Asp312Asn polymorphisms have been implicated in gastric cancer risk among different ethnicities. METHODS: We aimed to explore the effect of XPD Lys751Gln and Asp312Asn polymorphisms on the susceptibility to gastric cancer among different ethnicities through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. 13 studies were ultimately eligible for the meta analysis of Lys751Gln polymorphism and 9 studies for the meta-analysis of Asp312Asn polymorphism. We adopted the most probably appropriate genetic model (recessive model) for both Lys751Gln and Asp312Asn polymorphisms. Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication biases were estimated. RESULTS: Statistically significant findings were apparently noted in Asians but not in Caucasians for both XPD Lys751Gln and XPD Asp312Asn polymorphisms. A statistically significant finding could be seen in noncardia-type gastric cancer for XPD Lys751Gln polymorphism. A statistically significant finding could also be seen in high quality subgroup, small-and-moderate sample size subgroup, articles published after 2007, or PCR RFLP genotyping subgroup for XPD Asp312Asn polymorphism. CONCLUSIONS: Our meta analysis indicates that XPD Gln751Gln (CC) genotype and Asn312Asn (AA) genotype may seem to be more susceptible to gastric cancer in Asian populations but not in Caucasian populations, suggesting that the two genotypes may be important biomarkers of gastric cancer susceptibility for Asian populations, the assumption that needs to be further confirmed in well-designed studies among different ethnicities. Gln751Gln (CC) genotype may also be associated with noncardia-type gastric cancer risk, which should also be confirmed among different ethnicities in the future. PMID- 23028454 TI - Gene network revealed involvements of Birc2, Birc3 and Tnfrsf1a in anti-apoptosis of injured peripheral nerves. AB - Crush injury or axotomy of peripheral nerves results in the rapid production of the inflammatory cytokines, which were confirmed in various models, to some extent, to be noxious to the myelin sheath or Schwann cells (SCs). TNF-alpha is one of the primary initiators of the inflammatory cascade and exerts pleiotropic functions in the physiological conditions by binding to its receptors, type I (TNFRI) and type II (TNFRII). The pathway molecules TNFRI, Birc2 and Birc3 play key roles during the activation of the signaling. Injured peripheral nerves, preventing them from TNF-alpha-mediated destruction and proceeding to successful regeneration, might initiate an anti-apoptotic mechanism. To identity the exact functions of TNFRI, Birc2 and Birc3, as well as its involved pathways in the cellular events, we inferred a dynamic gene regulatory network from short time series measurements of the proximal nerve segment cDNA microarray following rat sciatic nerve transection. TNFRI family member Tnfrsf1a, Birc2 and Birc3 were mined out integrating as master regulators to mediate inflammatory responses. Experiments revealed that Tnfrsf1a, Birc2 and Birc3 proteins colocalized with S100 in the rat peripheral nerve tissues, and the expression levels increased with the time extension. Knockdown of the proteins induced the apoptotic formation of primary cultured SCs by upregulation of caspase 3 and caspase 6. Our systematic analysis indicated that Tnfrsf1a, Birc2 and Birc3 of SCs, not originally regarded as XIAP, were mainly responsible for the inflammation mediated anti-apoptosis of peripheral nerves. Birc2 and Birc3 might be the most potential targets for anti-apoptotic protection mediated by inflammatory cytokines. PMID- 23028456 TI - Heterozygosity in an isolated population of a large mammal founded by four individuals is predicted by an individual-based genetic model. AB - BACKGROUND: Within-population genetic diversity is expected to be dramatically reduced if a population is founded by a low number of individuals. Three females and one male white-tailed deer Odocoileus virginianus, a North American species, were successfully introduced in Finland in 1934 and the population has since been growing rapidly, but remained in complete isolation from other populations. METHODOLOGY/PRINCIPAL FINDINGS: Based on 14 microsatellite loci, the expected heterozygosity H was 0.692 with a mean allelic richness (AR) of 5.36, which was significantly lower than what was found in Oklahoma, U.S.A. (H = 0.742; AR = 9.07), demonstrating that a bottleneck occurred. Observed H was in line with predictions from an individual-based model where the genealogy of the males and females in the population were tracked and the population's demography was included. CONCLUSION: Our findings provide a rare within-population empirical test of the founder effect and suggest that founding a population by a small number of individuals need not have a dramatic impact on heterozygosity in an iteroparous species. PMID- 23028455 TI - Reduced BMP signaling results in hindlimb fusion with lethal pelvic/urogenital organ aplasia: a new mouse model of sirenomelia. AB - Sirenomelia, also known as mermaid syndrome, is a developmental malformation of the caudal body characterized by leg fusion and associated anomalies of pelvic/urogenital organs including bladder, kidney, rectum and external genitalia. Most affected infants are stillborn, and the few born alive rarely survive beyond the neonatal period. Despite the many clinical studies of sirenomelia in humans, little is known about the pathogenic developmental mechanisms that cause the complex array of phenotypes observed. Here, we provide new evidences that reduced BMP (Bone Morphogenetic Protein) signaling disrupts caudal body formation in mice and phenocopies sirenomelia. Bmp4 is strongly expressed in the developing caudal body structures including the peri-cloacal region and hindlimb field. In order to address the function of Bmp4 in caudal body formation, we utilized a conditional Bmp4 mouse allele (Bmp4(flox/flox)) and the Isl1 (Islet1)-Cre mouse line. Isl1-Cre is expressed in the peri-cloacal region and the developing hindimb field. Isl1Cre;Bmp4(flox/flox) conditional mutant mice displayed sirenomelia phenotypes including hindlimb fusion and pelvic/urogenital organ dysgenesis. Genetic lineage analyses indicate that Isl1 expressing cells contribute to both the aPCM (anterior Peri-Cloacal Mesenchyme) and the hindlimb bud. We show Bmp4 is essential for the aPCM formation independently with Shh signaling. Furthermore, we show Bmp4 is a major BMP ligand for caudal body formation as shown by compound genetic analyses of Bmp4 and Bmp7. Taken together, this study reveals coordinated development of caudal body structures including pelvic/urogenital organs and hindlimb orchestrated by BMP signaling in Isl1-expressing cells. Our study offers new insights into the pathogenesis of sirenomelia. PMID- 23028457 TI - Identifying the preferred subset of enzymatic profiles in nonlinear kinetic metabolic models via multiobjective global optimization and Pareto filters. AB - Optimization models in metabolic engineering and systems biology focus typically on optimizing a unique criterion, usually the synthesis rate of a metabolite of interest or the rate of growth. Connectivity and non-linear regulatory effects, however, make it necessary to consider multiple objectives in order to identify useful strategies that balance out different metabolic issues. This is a fundamental aspect, as optimization of maximum yield in a given condition may involve unrealistic values in other key processes. Due to the difficulties associated with detailed non-linear models, analysis using stoichiometric descriptions and linear optimization methods have become rather popular in systems biology. However, despite being useful, these approaches fail in capturing the intrinsic nonlinear nature of the underlying metabolic systems and the regulatory signals involved. Targeting more complex biological systems requires the application of global optimization methods to non-linear representations. In this work we address the multi-objective global optimization of metabolic networks that are described by a special class of models based on the power-law formalism: the generalized mass action (GMA) representation. Our goal is to develop global optimization methods capable of efficiently dealing with several biological criteria simultaneously. In order to overcome the numerical difficulties of dealing with multiple criteria in the optimization, we propose a heuristic approach based on the epsilon constraint method that reduces the computational burden of generating a set of Pareto optimal alternatives, each achieving a unique combination of objectives values. To facilitate the post optimal analysis of these solutions and narrow down their number prior to being tested in the laboratory, we explore the use of Pareto filters that identify the preferred subset of enzymatic profiles. We demonstrate the usefulness of our approach by means of a case study that optimizes the ethanol production in the fermentation of Saccharomyces cerevisiae. PMID- 23028458 TI - Multi-level opinion dynamics under bounded confidence. AB - Opinion dynamics focuses on the opinion evolution in a social community. Recently, some models of continuous opinion dynamics under bounded confidence were proposed by Deffuant and Krause, et al. In the literature, agents were generally assumed to have a homogeneous confidence level. This paper proposes an extended model for a group of agents with heterogeneous confidence levels. First, a social differentiation theory is introduced and a social group is divided into opinion subgroups with distinct confidence levels. Second, a multi-level heterogeneous opinion formation model is formulated under the framework of bounded confidence. Finally, computer simulations are conducted to study the collective opinion evolution, focusing on three key factors: the fractions of heterogeneous agents, the initial opinions, and the group size. The simulation results demonstrate that the number of final opinions depends on the fraction of close-minded agents when the group size and the initial opinions are fixed; the final opinions converge more easily when the initial opinions are closer; and the number of final opinions can be approximately modeled by a linear increasing function of the group size and the increasing rate is the fraction of close minded agents. PMID- 23028459 TI - Exploiting protein-protein interaction networks for genome-wide disease-gene prioritization. AB - Complex genetic disorders often involve products of multiple genes acting cooperatively. Hence, the pathophenotype is the outcome of the perturbations in the underlying pathways, where gene products cooperate through various mechanisms such as protein-protein interactions. Pinpointing the decisive elements of such disease pathways is still challenging. Over the last years, computational approaches exploiting interaction network topology have been successfully applied to prioritize individual genes involved in diseases. Although linkage intervals provide a list of disease-gene candidates, recent genome-wide studies demonstrate that genes not associated with any known linkage interval may also contribute to the disease phenotype. Network based prioritization methods help highlighting such associations. Still, there is a need for robust methods that capture the interplay among disease-associated genes mediated by the topology of the network. Here, we propose a genome-wide network-based prioritization framework named GUILD. This framework implements four network-based disease-gene prioritization algorithms. We analyze the performance of these algorithms in dozens of disease phenotypes. The algorithms in GUILD are compared to state-of-the-art network topology based algorithms for prioritization of genes. As a proof of principle, we investigate top-ranking genes in Alzheimer's disease (AD), diabetes and AIDS using disease-gene associations from various sources. We show that GUILD is able to significantly highlight disease-gene associations that are not used a priori. Our findings suggest that GUILD helps to identify genes implicated in the pathology of human disorders independent of the loci associated with the disorders. PMID- 23028460 TI - The Aspergillus fumigatus dihydroxyacid dehydratase Ilv3A/IlvC is required for full virulence. AB - Dihydroxyacid dehydratase (DHAD) is a key enzyme in the branched-chain amino acid biosynthetic pathway that exists in a variety of organisms, including fungi, plants and bacteria, but not humans. In this study we identified four putative DHAD genes from the filamentous fungus Aspergillus fumigatus by homology to Saccharomyces cerevisiae ILV3. Two of these genes, AFUA_2G14210 and AFUA_1G03550, initially designated AfIlv3A and AfIlv3B for this study, clustered in the same group as S. cerevisiae ILV3 following phylogenetic analysis. To investigate the functions of these genes, AfIlv3A and AfIlv3B were knocked out in A. fumigatus. Deletion of AfIlv3B gave no apparent phenotype whereas the Deltailv3A strain required supplementation with isoleucine and valine for growth. Thus, AfIlv3A is required for branched-chain amino acid synthesis in A. fumigatus. A recombinant AfIlv3A protein derived from AFUA_2G14210 was shown to have DHAD activity in an in vitro assay, confirming that AfIlv3A is a DHAD. In addition we show that mutants lacking AfIlv3A and ilv3B exhibit reduced levels of virulence in murine infection models, emphasising the importance of branched-chain amino acid biosynthesis in fungal infections, and hence the potential of targeting this pathway with antifungal agents. Here we propose that AfIlv3A/AFUA_2G2410 be named ilvC. PMID- 23028461 TI - Using activity-related behavioural features towards more effective automatic stress detection. AB - This paper introduces activity-related behavioural features that can be automatically extracted from a computer system, with the aim to increase the effectiveness of automatic stress detection. The proposed features are based on processing of appropriate video and accelerometer recordings taken from the monitored subjects. For the purposes of the present study, an experiment was conducted that utilized a stress-induction protocol based on the stroop colour word test. Video, accelerometer and biosignal (Electrocardiogram and Galvanic Skin Response) recordings were collected from nineteen participants. Then, an explorative study was conducted by following a methodology mainly based on spatiotemporal descriptors (Motion History Images) that are extracted from video sequences. A large set of activity-related behavioural features, potentially useful for automatic stress detection, were proposed and examined. Experimental evaluation showed that several of these behavioural features significantly correlate to self-reported stress. Moreover, it was found that the use of the proposed features can significantly enhance the performance of typical automatic stress detection systems, commonly based on biosignal processing. PMID- 23028462 TI - Mining the Sinorhizobium meliloti transportome to develop FRET biosensors for sugars, dicarboxylates and cyclic polyols. AB - BACKGROUND: Forster resonance energy transfer (FRET) biosensors are powerful tools to detect biologically important ligands in real time. Currently FRET bisosensors are available for twenty-two compounds distributed in eight classes of chemicals (two pentoses, two hexoses, two disaccharides, four amino acids, one nucleobase, two nucleotides, six ions and three phytoestrogens). To expand the number of available FRET biosensors we used the induction profile of the Sinorhizobium meliloti transportome to systematically screen for new FRET biosensors. METHODOLOGY/PRINCIPAL FINDINGS: Two new vectors were developed for cloning genes for solute-binding proteins (SBPs) between those encoding FRET partner fluorescent proteins. In addition to a vector with the widely used cyan and yellow fluorescent protein FRET partners, we developed a vector using orange (mOrange2) and red fluorescent protein (mKate2) FRET partners. From the sixty nine SBPs tested, seven gave a detectable FRET signal change on binding substrate, resulting in biosensors for D-quinic acid, myo-inositol, L-rhamnose, L fucose, beta-diglucosides (cellobiose and gentiobiose), D-galactose and C4 dicarboxylates (malate, succinate, oxaloacetate and fumarate). To our knowledge, we describe the first two FRET biosensor constructs based on SBPs from Tripartite ATP-independent periplasmic (TRAP) transport systems. CONCLUSIONS/SIGNIFICANCE: FRET based on orange (mOrange2) and red fluorescent protein (mKate2) partners allows the use of longer wavelength light, enabling deeper penetration of samples at lower energy and increased resolution with reduced back-ground auto fluorescence. The FRET biosensors described in this paper for four new classes of compounds; (i) cyclic polyols, (ii) L-deoxy sugars, (iii) beta-linked disaccharides and (iv) C4-dicarboxylates could be developed to study metabolism in vivo. PMID- 23028464 TI - A complex interaction between Rickettsia conorii and Dickkopf-1--potential role in immune evasion mechanisms in endothelial cells. AB - The pathophysiological hallmark of spotted fever group rickettsioses comprises vascular inflammation. Based on the emerging importance of the wingless (Wnt) pathways in inflammation and vascular biology, we hypothesized that Dickkopf-1 (DKK-1), as a major modulator of Wnt signaling, could be involved in the pathogenesis in rickettsial infections. Our major findings were: (i) While baseline concentration of DKK-1 in patients with R. conorii infection (n = 32) were not different from levels in controls (n = 24), DKK-1 rose significantly from presentation to first follow-up sample (median 7 days after baseline). (ii) In vitro experiments in human umbilical vein endothelial cells (HUVECs) showed that while heat-inactivated R. conorii enhanced the release of interleukin-6 (IL 6) and IL-8, it down-regulated the release of endothelial-derived DKK-1 in a time and dose-dependent manner. (iii) Silencing of DKK-1 attenuated the release of IL 6, IL-8 and growth-related oncogene (GRO)alpha in R. conorii-exposed HUVECs, suggesting inflammatory effects of DKK-1. (iv) Silencing of DKK-1 attenuated the expression of tissue factor and enhanced the expression of thrombomodulin in R. conorii-exposed HUVECs suggesting pro-thrombotic effects of DKK-1. The capacity of R. conorii to down-regulate endothelial-derived DKK-1 and the ability of silencing DKK-1 to attenuate R. conorii-induced inflammation in endothelial cells could potentially reflect a novel mechanism by which R. conorii escapes the immune response at the site of infection. PMID- 23028465 TI - The breeding ranges of Central European and Arctic bird species move poleward. AB - BACKGROUND: Climatic warming predicts that species move their entire distribution poleward. Poleward movement of the 'cold' side of the distribution of species is empirically supported, but evidence of poleward movement at the 'warm' distributional side is relatively scarce. METHODOLOGY/PRINCIPAL FINDING: Finland has, as the first country in the world, completed three national atlas surveys of breeding birds, which we here use to calculate the sizes and weighted mean latitudes of the national range of 114 southern and 34 northern bird species during three periods (1974-1979; 1986-1989; 2006-2010), each denoting species presence in approximately 3 800 10 * 10 km2 squares. We find strong evidence that southern species (breeding predominantly in central Europe) showed a latitudinal shift of 1.1-1.3 km/year poleward during all three pairwise comparisons between these atlases (covering 11, 20.5 and 31.5 years respectively). We find evidence of a latitudinal shift of 0.7-0.8 km/year poleward of northern boreal and Arctic species, but this shift was not found in all study periods and may have been influenced by increased effort put into the more recent surveys. Species showed no significant correlation in changes in range size and weighted mean latitude between the first (11 year) and second (20.5 year) period covered by consecutive atlases, suggesting weak phylogenetic signal and little scope of species characteristics in explaining latitudinal avian range changes. CONCLUSIONS: Extinction-driven avian range changes (at the 'warm' side) of a species' distribution occur at approximately half the rate of colonisation-driven range changes (at the 'cold' side), and its quantification therefore requires long-term monitoring data, possibly explaining why evidence for such changes is currently rare. A clear latitudinal shift in an assemblage of species may still harbour considerable temporal inconsistency in latitudinal movement on the species level. Understanding this inconsistency is important for predictive modelling of species composition in a changing world. PMID- 23028463 TI - The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury. AB - The extent of damage following spinal cord injury (SCI) can be reduced by various neuroprotective regimens that include maintaining levels of cyclic adenosine monophosphate (cyclic AMP), via administration of the phosphodiesterase 4 (PDE4) inhibitor Rolipram. The current study sought to determine the optimal neuroprotective dose, route and therapeutic window for Rolipram following contusive SCI in rat as well as its prominent PDE target and putative mechanism of protection. Rolipram or vehicle control (10% ethanol) was given subcutaneously (s.c.) daily for 2 wk post-injury (PI) after which the preservation of oligodendrocytes, neurons and central myelinated axons was stereologically assessed. Doses of 0.1 mg/kg to 1.0 mg/kg (given at 1 h PI) increased neuronal survival; 0.5 mg to 1.0 mg/kg protected oligodendrocytes and 1.0 mg/kg produced optimal preservation of central myelinated axons. Ethanol also demonstrated significant neuronal and oligo-protection; though the preservation provided was significantly less than Rolipram. Subsequent use of this optimal Rolipram dose, 1.0 mg/kg, via different routes (i.v., s.c. or oral, 1 h PI), demonstrated that i.v. administration produced the most significant and consistent cyto- and axo- protection, although all routes were effective. Examination of the therapeutic window for i.v. Rolipram (1.0 mg/kg), when initiated between 1 and 48 h after SCI, revealed maximal neuroprotection at 2 h post-SCI, although the protective efficacy of Rolipram could still be observed when administration was delayed for up to 48 h PI. Importantly, use of the optimal Rolipram regimen significantly improved locomotor function after SCI as measured by the BBB score. Lastly we show SCI-induced changes in PDE4A, B and D expression and phosphorylation as well as cytokine expression and immune cell infiltration. We demonstrate that Rolipram abrogates SCI-induced PDE4B1 and PDE4A5 production, PDE4A5 phosphorylation, MCP-1 expression and immune cell infiltration, while preventing post-injury reductions in IL-10. This work supports the use of Rolipram as an acute neuroprotectant following SCI and defines an optimal administration protocol and target for its therapeutic application. PMID- 23028466 TI - Valproic acid downregulates RBP4 and elicits hypervitaminosis A-teratogenesis--a kinetic analysis on retinol/retinoic acid homeostatic system. AB - BACKGROUND: Valproic acid (VPA) is an antiepileptic and anti-migraine prophylactic drug. VPA exhibits two severe side effects, namely acute liver toxicity and teratogenicity. These side effects are usually seen at the genetic and somatic levels. The cited action mechanisms involve inhibition of histone deacetylase, hypofolatenemia, hyperhomocysteinemia, and reactive oxidative stress. The proteomic information associated with VPA teratogenicity is still unavailable. We hypothesized that proteomic analysis might help us identify functional proteins that could be relevantly affected by VPA, and this phenomenon could be very sensitive in early embryonic stage, resulting in VPA teratogenicity. METHODOLOGY/PRINCIPAL FINDINGS: Proteomic analysis on the chicken embryos at Hamburger and Hamilton (HH) stage 28 showed that there were significant downregulations of ovotransferrins, carbonic anhydrase-2, retinol binding protein-4 (RBP4), NADH cytochrome b5 reductase 2 (CYB5R2), apolipoprotein A1, and protein SET, together with upregulation of 60S ribosomal protein L22. Among these, RBP4 was the most significantly downregulated (-32%). Kinetic analysis suggested that this situation could trigger hypervitaminosis A (+39.3%), a condition that has been well known to induce teratogenesis.. CONCLUSIONS/SIGNIFICANCE: This is the first report showing that VPA dowregulates RBP4. Our finding not only has led to a possible mechanism of VPA teratogenesis, but also has initiated new preventive strategies for avoiding VPA teratogeneis. PMID- 23028467 TI - Comparison of venous and capillary differential leukocyte counts using a standard hematology analyzer and a novel microfluidic impedance cytometer. AB - Capillary blood sampling has been identified as a potentially suitable technique for use in diagnostic testing of the full blood count (FBC) at the point-of-care (POC), for which a recent need has been highlighted. In this study we assess the accuracy of capillary blood counts and evaluate the potential of a miniaturized cytometer developed for POC testing. Differential leukocyte counts in the normal clinical range from fingerprick (capillary) and venous blood samples were measured and compared using a standard hematology analyzer. The accuracy of our novel microfluidic impedance cytometer (MIC) was then tested by comparing same site measurements to those obtained with the standard analyzer. The concordance between measurements of fingerprick and venous blood samples using the standard hematology analyzer was high, with no clinically relevant differences observed between the mean differential leukocyte counts. Concordance data between the MIC and the standard analyzer on same-site measurements presented significantly lower leukocyte counts determined by the MIC. This systematic undercount was consistent across the measured (normal) concentration range, suggesting that an internal correction factor could be applied. Differential leukocyte counts obtained from fingerprick samples accurately reflect those from venous blood, which confirms the potential of capillary blood sampling for POC testing of the FBC. Furthermore, the MIC device demonstrated here presents a realistic technology for the future development of FBC and related tests for use at the site of patient care. PMID- 23028468 TI - Local polynomial estimation of heteroscedasticity in a multivariate linear regression model and its applications in economics. AB - Multivariate local polynomial fitting is applied to the multivariate linear heteroscedastic regression model. Firstly, the local polynomial fitting is applied to estimate heteroscedastic function, then the coefficients of regression model are obtained by using generalized least squares method. One noteworthy feature of our approach is that we avoid the testing for heteroscedasticity by improving the traditional two-stage method. Due to non-parametric technique of local polynomial estimation, it is unnecessary to know the form of heteroscedastic function. Therefore, we can improve the estimation precision, when the heteroscedastic function is unknown. Furthermore, we verify that the regression coefficients is asymptotic normal based on numerical simulations and normal Q-Q plots of residuals. Finally, the simulation results and the local polynomial estimation of real data indicate that our approach is surely effective in finite-sample situations. PMID- 23028469 TI - NEMO binds ubiquitinated TANK-binding kinase 1 (TBK1) to regulate innate immune responses to RNA viruses. AB - RIG-I-like receptors (RLR) are intracellular sensors utilized by nearly all cell types for recognition of viral RNA, initiation of antiviral defense, and induction of type I interferons (IFN). TBK1 is a critical kinase implicated in RLR-dependent IFN transcription. Posttranslational modification of TBK1 by K63 linked ubiquitin is required for RLR driven signaling. However, the TBK1 ubiquitin acceptor sites and the function of ubiquitinated TBK1 in the signaling cascade are unknown. We now show that TBK1 is ubiquitinated on residues K69, K154, and K372 in response to infection with RNA virus. The K69 and K154 residues are critical for innate antiviral responses and IFN production. Ubiquitinated TBK1 recruits the downstream adaptor NEMO through ubiquitin binding domains. The assembly of the NEMO/TBK1 complex on the mitochondrial protein MAVS leads to activation of TBK1 kinase activity and phosphorylation of the transcription factor, interferon response factor 3. The combined results refine current views of RLR signaling, define the role of TBK1 polyubiquitination, and detail the mechanisms involved in signalosome assembly. PMID- 23028470 TI - Light evokes melanopsin-dependent vocalization and neural activation associated with aversive experience in neonatal mice. AB - Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are the only functional photoreceptive cells in the eye of newborn mice. Through postnatal day 9, in the absence of functional rods and cones, these ipRGCs mediate a robust avoidance behavior to a light source, termed negative phototaxis. To determine whether this behavior is associated with an aversive experience in neonatal mice, we characterized light-induced vocalizations and patterns of neuronal activation in regions of the brain involved in the processing of aversive and painful stimuli. Light evoked distinct melanopsin dependent ultrasonic vocalizations identical to those emitted under stressful conditions, such as isolation from the litter. In contrast, light did not evoke the broad-spectrum calls elicited by acute mechanical pain. Using markers of neuronal activation, we found that light induced the immediate-early gene product Fos in the posterior thalamus, a brain region associated with the enhancement of responses to mechanical stimulation of the dura by light, and thought to be the basis for migrainous photophobia. Additionally, light induced the phosphorylation of extracellular-related kinase (pERK) in neurons of the central amygdala, an intracellular signal associated with the processing of the aversive aspects of pain. However, light did not activate Fos expression in the spinal trigeminal nucleus caudalis, the primary receptive field for painful stimulation to the head. We conclude that these light-evoked vocalizations and the distinct pattern of brain activation in neonatal mice are consistent with a melanopsin-dependent neural pathway involved in processing light as an aversive but not acutely painful stimulus. PMID- 23028471 TI - Gene regulatory network inference from multifactorial perturbation data using both regression and correlation analyses. AB - An important problem in systems biology is to reconstruct gene regulatory networks (GRNs) from experimental data and other a priori information. The DREAM project offers some types of experimental data, such as knockout data, knockdown data, time series data, etc. Among them, multifactorial perturbation data are easier and less expensive to obtain than other types of experimental data and are thus more common in practice. In this article, a new algorithm is presented for the inference of GRNs using the DREAM4 multifactorial perturbation data. The GRN inference problem among [Formula: see text] genes is decomposed into [Formula: see text] different regression problems. In each of the regression problems, the expression level of a target gene is predicted solely from the expression level of a potential regulation gene. For different potential regulation genes, different weights for a specific target gene are constructed by using the sum of squared residuals and the Pearson correlation coefficient. Then these weights are normalized to reflect effort differences of regulating distinct genes. By appropriately choosing the parameters of the power law, we constructe a 0-1 integer programming problem. By solving this problem, direct regulation genes for an arbitrary gene can be estimated. And, the normalized weight of a gene is modified, on the basis of the estimation results about the existence of direct regulations to it. These normalized and modified weights are used in queuing the possibility of the existence of a corresponding direct regulation. Computation results with the DREAM4 In Silico Size 100 Multifactorial subchallenge show that estimation performances of the suggested algorithm can even outperform the best team. Using the real data provided by the DREAM5 Network Inference Challenge, estimation performances can be ranked third. Furthermore, the high precision of the obtained most reliable predictions shows the suggested algorithm may be helpful in guiding biological experiment designs. PMID- 23028472 TI - Blood glutathione S-transferase-pi as a time indicator of stroke onset. AB - BACKGROUND: Ability to accurately determine time of stroke onset remains challenging. We hypothesized that an early biomarker characterized by a rapid increase in blood after stroke onset may help defining better the time window during which an acute stroke patient may be candidate for intravenous thrombolysis or other intravascular procedures. METHODS: The blood level of 29 proteins was measured by immunoassays on a prospective cohort of stroke patients (N = 103) and controls (N = 132). Mann-Whitney U tests, ROC curves and diagnostic odds ratios were applied to evaluate their clinical performances. RESULTS: Among the 29 molecules tested, GST-pi concentration was the most significantly elevated marker in the blood of stroke patients (p<0.001). More importantly, GST-pi displayed the best area under the curve (AUC, 0.79) and the best diagnostic odds ratios (10.0) for discriminating early (N = 22, <3 h of stroke onset) vs. late stroke patients (N = 81, >3 h after onset). According to goal-oriented distinct cut-offs (sensitivity(Se)-oriented: 17.7 or specificity(Sp)-oriented: 65.2 ug/L), the GST-pi test obtained 91%Se/50%Sp and 50%Se/91%Sp, respectively. Moreover, GST pi showed also the highest AUC (0.83) and performances for detecting patients treated with tPA (N = 12) compared to ineligible patients (N = 103). CONCLUSIONS: This study demonstrates that GST-pi can accurately predict the time of stroke onset in over 50% of early stroke patients. The GST-pi test could therefore complement current guidelines for tPA administration and potentially increase the number of patients accessing thrombolysis. PMID- 23028473 TI - Age-associated hyper-methylated regions in the human brain overlap with bivalent chromatin domains. AB - Recent associations between age-related differentially methylated sites and bivalently marked chromatin domains have implicated a role for these genomic regions in aging and age-related diseases. However, the overlap between such epigenetic modifications has so far only been identified with respect to age associated hyper-methylated sites in blood. In this study, we observed that age associated differentially methylated sites characterized in the human brain were also highly enriched in bivalent domains. Analysis of hyper- vs. hypo-methylated sites partitioned by age (fetal, child, and adult) revealed that enrichment was significant for hyper-methylated sites identified in children and adults (child, fold difference = 2.28, P = 0.0016; adult, fold difference = 4.73, P = 4.00 * 10( 5)); this trend was markedly more pronounced in adults when only the top 100 most significantly hypo- and hyper-methylated sites were considered (adult, fold difference = 10.7, P = 2.00 * 10(-5)). Interestingly, we found that bivalently marked genes overlapped by age-associated hyper-methylation in the adult brain had strong involvement in biological functions related to developmental processes, including neuronal differentiation. Our findings provide evidence that the accumulation of methylation in bivalent gene regions with age is likely to be a common process that occurs across tissue types. Furthermore, particularly with respect to the aging brain, this accumulation might be targeted to loci with important roles in cell differentiation and development, and the closing off of these developmental pathways. Further study of these genes is warranted to assess their potential impact upon the development of age-related neurological disorders. PMID- 23028474 TI - Comparison of human and animal surveillance data for H5N1 influenza A in Egypt 2006-2011. AB - BACKGROUND: The majority of emerging infectious diseases are zoonotic (transmissible between animals and humans) in origin, and therefore integrated surveillance of disease events in humans and animals has been recommended to support effective global response to disease emergence. While in the past decade there has been extensive global surveillance for highly pathogenic avian influenza (HPAI) infection in both animals and humans, there have been few attempts to compare these data streams and evaluate the utility of such integration. METHODOLOGY: We compared reports of bird outbreaks of HPAI H5N1 in Egypt for 2006-2011 compiled by the World Organisation for Animal Health (OIE) and the UN Food and Agriculture Organization (FAO) EMPRESi reporting system with confirmed human H5N1 cases reported to the World Health Organization (WHO) for Egypt during the same time period. PRINCIPAL FINDINGS: Both human cases and bird outbreaks showed a cyclic pattern for the country as a whole, and there was a statistically significant temporal correlation between the data streams. At the governorate level, the first outbreak in birds in a season usually but not always preceded the first human case, and the time lag between events varied widely, suggesting regional differences in zoonotic risk and/or surveillance effectiveness. In a multivariate risk model, lower temperature, lower urbanization, higher poultry density, and the recent occurrence of a bird outbreak were associated with increased risk of a human case of HPAI in the same governorate, although the positive predictive value of a bird outbreak was low. CONCLUSIONS: Integrating data streams of surveillance for human and animal cases of zoonotic disease holds promise for better prediction of disease risk and identification of environmental and regional factors that can affect risk. Such efforts can also point out gaps in human and animal surveillance systems and generate hypotheses regarding disease transmission. PMID- 23028475 TI - Genome wide analysis of differentially expressed genes in HK-2 cells, a line of human kidney epithelial cells in response to oxalate. AB - Nephrolithiasis is a multi-factorial disease which, in the majority of cases, involves the renal deposition of calcium oxalate. Oxalate is a metabolic end product excreted primarily by the kidney. Previous studies have shown that elevated levels of oxalate are detrimental to the renal epithelial cells; however, oxalate renal epithelial cell interactions are not completely understood. In this study, we utilized an unbiased approach of gene expression profiling using Affymetrix HG_U133_plus2 gene chips to understand the global gene expression changes in human renal epithelial cells [HK-2] after exposure to oxalate. We analyzed the expression of 47,000 transcripts and variants, including 38,500 well characterized human genes, in the HK2 cells after 4 hours and 24 hours of oxalate exposure. Gene expression was compared among replicates as per the Affymetrix statistical program. Gene expression among various groups was compared using various analytical tools, and differentially expressed genes were classified according to the Gene Ontology Functional Category. The results from this study show that oxalate exposure induces significant expression changes in many genes. We show for the first time that oxalate exposure induces as well as shuts off genes differentially. We found 750 up-regulated and 2276 down-regulated genes which have not been reported before. Our results also show that renal cells exposed to oxalate results in the regulation of genes that are associated with specific molecular function, biological processes, and other cellular components. In addition we have identified a set of 20 genes that is differentially regulated by oxalate irrespective of duration of exposure and may be useful in monitoring oxalate nephrotoxicity. Taken together our studies profile global gene expression changes and provide a unique insight into oxalate renal cell interactions and oxalate nephrotoxicity. PMID- 23028476 TI - Caesarean delivery in South Italy: women without choice. A cross sectional survey. AB - BACKGROUND: In spite of the World Health Organization's recommendations to maintain caesarean delivery (CD) between 5% and 15% of total births, the rates of CD continue to rise in countries with routine access to medical services. As in Italy CD rate reached 38% in 2008, the highest at EU level, we evaluated socioeconomic and clinical correlates of "elective" and "non programmed" CD in the Country. We performed a stratified analysis in order to verify whether the effect of such correlates differed among women with an "a priori" preference for natural and caesarean delivery respectively. METHODS AND FINDINGS: We analyzed cross-sectional data from the Italian National Statistics Institute (ISTAT) survey on health condition. Socio-demographic variables, information on maternal care services use and health conditions during pregnancy, as well as maternal preferences on delivery, were available for a representative sample of 2,474 primiparous women. After an initial bivariate analysis, we used logistic regressions to evaluate factors associated to the study outcomes. Overall CD accounted for 35.5% of the total births in our sample (CI 33.6-37.4%); moreover, 30.7% (CI 28.6-32.6%) of women preferring natural delivery actually delivered with a CD. Elective CD rate is higher among women over 35 years (22.9%, CI 18.8 27.4%), and those living in the South (26.2%, CI 23.0-29.6%). The multivariate analysis showed that, even adjusting for several confounders, women in the South, receiving care in the private sector had higher chances of CD, also in case of preference for natural delivery. CONCLUSION: Policy interventions are required to reduce the rate of undesired CD, e.g. increasing women knowledge regarding delivery in order to favour aware choices. An effective strategy to reduce CD rate should address the Southern Regions, as women here appear to have a very limited control over the delivery, in spite of a widespread preference for natural delivery. PMID- 23028477 TI - Dynamical behaviors of Rb-E2F pathway including negative feedback loops involving miR449. AB - MiRNAs, which are a family of small non-coding RNAs, regulate a broad array of physiological and developmental processes. However, their regulatory roles have remained largely mysterious. E2F is a positive regulator of cell cycle progression and also a potent inducer of apoptosis. Positive feedback loops in the regulation of Rb-E2F pathway are predicted and shown experimentally. Recently, it has been discovered that E2F induce a cluster of miRNAs called miR449. In turn, E2F is inhibited by miR449 through regulating different transcripts, thus forming negative feedback loops in the interaction network. Here, based on the integration of experimental evidence and quantitative data, we studied Rb-E2F pathway coupling the positive feedback loops and negative feedback loops mediated by miR449. Therefore, a mathematical model is constructed based in part on the model proposed in Yao-Lee et al. (2008) and nonlinear dynamical behaviors including the stability and bifurcations of the model are discussed. A comparison is given to reveal the implication of the fundamental differences of Rb-E2F pathway between regulation and deregulation of miR449. Coherent with the experiments it predicts that miR449 plays a critical role in regulating the cell cycle progression and provides a twofold safety mechanism to avoid excessive E2F induced proliferation by cell cycle arrest and apoptosis. Moreover, numerical simulation and bifurcation analysis shows that the mechanisms of the negative regulation of miR449 to three different transcripts are quite distinctive which needs to be verified experimentally. This study may help us to analyze the whole cell cycle process mediated by other miRNAs more easily. A better knowledge of the dynamical behaviors of miRNAs mediated networks is also of interest for bio engineering and artificial control. PMID- 23028478 TI - Morphology and molecules reveal unexpected cryptic diversity in the enigmatic genus Sinobirma Bryk, 1944 (Lepidoptera: Saturniidae). AB - The wild silkmoth genus Sinobirma Bryk, 1944 is a poorly known monotypic taxon from the eastern end of the Himalaya Range. It was convincingly proposed to be closely related to some members of an exclusively Afro-tropical group of Saturniidae, but its biogeographical and evolutionary history remains enigmatic. After examining recently collected material from Tibet, northern India, and northeastern Myanmar, we realized that this unique species, S. malaisei Bryk, 1944 only known so far from a few specimens and from a very restricted area near the border between north-eastern Myanmar and the Yunnan province of China, may in fact belong to a group of closely related cryptic species. In this work, we combined morphological comparative study, DNA barcoding, and the sequences of a nuclear marker (D2 expansion segment of the 28S rRNA gene) to unequivocally delimit three distinct species in the genus Sinobirma, of which two are described as new to science: S. myanmarensis sp. n. and S. bouyeri sp. n. An informative DNA barcode sequence was obtained from the female holotype of S. malaisei- collected in 1934--ensuring the proper assignation of this name to the newly collected and studied specimens. Our findings represent another example of the potential of coupling traditional taxonomy and DNA barcoding for revealing and solving difficult cases of cryptic diversity. This approach is now being generalized to the world fauna of Saturniidae, with the participation of most of the taxonomists studying these moths. PMID- 23028479 TI - Epidermal growth factor receptor tyrosine kinase defines critical prognostic genes of stage I lung adenocarcinoma. AB - PURPOSE: To identify stage I lung adenocarcinoma patients with a poor prognosis who will benefit from adjuvant therapy. PATIENTS AND METHODS: Whole gene expression profiles were obtained at 19 time points over a 48-hour time course from human primary lung epithelial cells that were stimulated with epidermal growth factor (EGF) in the presence or absence of a clinically used EGF receptor tyrosine kinase (RTK)-specific inhibitor, gefitinib. The data were subjected to a mathematical simulation using the State Space Model (SSM). "Gefitinib-sensitive" genes, the expressional dynamics of which were altered by addition of gefitinib, were identified. A risk scoring model was constructed to classify high- or low risk patients based on expression signatures of 139 gefitinib-sensitive genes in lung cancer using a training data set of 253 lung adenocarcinomas of North American cohort. The predictive ability of the risk scoring model was examined in independent cohorts of surgical specimens of lung cancer. RESULTS: The risk scoring model enabled the identification of high-risk stage IA and IB cases in another North American cohort for overall survival (OS) with a hazard ratio (HR) of 7.16 (P = 0.029) and 3.26 (P = 0.0072), respectively. It also enabled the identification of high-risk stage I cases without bronchioalveolar carcinoma (BAC) histology in a Japanese cohort for OS and recurrence-free survival (RFS) with HRs of 8.79 (P = 0.001) and 3.72 (P = 0.0049), respectively. CONCLUSION: The set of 139 gefitinib-sensitive genes includes many genes known to be involved in biological aspects of cancer phenotypes, but not known to be involved in EGF signaling. The present result strongly re-emphasizes that EGF signaling status in cancer cells underlies an aggressive phenotype of cancer cells, which is useful for the selection of early-stage lung adenocarcinoma patients with a poor prognosis. TRIAL REGISTRATION: The Gene Expression Omnibus (GEO) GSE31210. PMID- 23028480 TI - Comparison of two commercial PCR methods for methicillin-resistant Staphylococcus aureus (MRSA) screening in a tertiary care hospital. AB - Nose/throat-swabs from 1049 patients were screened for MRSA using CHROMagar MRSA, LightCycler Advanced MRSA, and Detect-Ready MRSA. Results were compared to the CHROMagar MRSA results, which was set as reference system. MRSA was detected in 3.05% of the patients with CHROMagar MRSA. LightCycler MRSA Advanced showed a higher clinical sensitivity (84.38%) than Detect-Ready MRSA (57.69%).The negative predictive values were high for both tests (>98%). The specificity and the positive predictive value were higher for the Detect-Ready MRSA test than for the LightCycler MRSA test (99.59% and 78.95% versus 98.52% and 64.29%). For routine screening LightCycler MRSA Advanced proved to be more efficient in our clinical setting as the clinical sensitivity was much higher than the sensitivity of Detect-Ready MRSA. CHROMagar MRSA detected more MRSA positive samples than both PCR methods, leading to the conclusion that the combination of PCR with cultural screening is still the most reliable way for the detection of MRSA. LightCycler MRSA Advanced was faster and needed less hands-on time. The advantage of Detect Ready MRSA was the additional identification of methicillin-sensitive S.aureus (here in 34.63% of the samples), an information which can be possibly used for reducing the risk of postoperative infections in surgical patients in future. PMID- 23028481 TI - (-)-Epigallocatechin-3-gallate protects against NO-induced ototoxicity through the regulation of caspase- 1, caspase-3, and NF-kappaB activation. AB - Excessive nitric oxide (NO) production is toxic to the cochlea and induces hearing loss. However, the mechanism through which NO induces ototoxicity has not been completely understood. The aim of this study was to gain further insight into the mechanism mediating NO-induced toxicity in auditory HEI-OC1 cells and in ex vivo analysis. We also elucidated whether and how epigallocatechin-3-gallate (EGCG), the main component of green tea polyphenols, regulates NO-induced auditory cell damage. To investigate NO-mediated ototoxicity, S-nitroso-N acetylpenicillamine (SNAP) was used as an NO donor. SNAP was cytotoxic, generating reactive oxygen species, releasing cytochrome c, and activating caspase-3 in auditory cells. NO-induced ototoxicity also mediated the nuclear factor (NF)-kappaB/caspase-1 pathway. Furthermore, SNAP destroyed the orderly arrangement of the 3 outer rows of hair cells in the basal, middle, and apical turns of the organ of Corti from the cochlea of Sprague-Dawley rats at postnatal day 2. However, EGCG counteracted this ototoxicity by suppressing the activation of caspase-3/NF-kappaB and preventing the destruction of hair cell arrays in the organ of Corti. These findings may lead to the development of a model for pharmacological mechanism of EGCG and potential therapies against ototoxicity. PMID- 23028482 TI - Cch1p mediates Ca2+ influx to protect Saccharomyces cerevisiae against eugenol toxicity. AB - Eugenol has antifungal activity and is recognised as having therapeutic potential. However, little is known of the cellular basis of its antifungal activity and a better understanding of eugenol tolerance should lead to better exploitation of eugenol in antifungal therapies. The model yeast, Saccharomyces cerevisiae, expressing apoaequorin was used to show that eugenol induces cytosolic Ca(2+) elevations. We investigated the eugenol Ca(2+) signature in further detail and show that exponentially growing cells exhibit Ca(2+) elevation resulting exclusively from the influx of Ca(2+) across the plasma membrane whereas in stationary growth phase cells Ca(2+) influx from intracellular and extracellular sources contribute to the eugenol-induced Ca(2+) elevation. Ca(2+) channel deletion yeast mutants were used to identify the pathways mediating Ca(2+) influx; intracellular Ca(2+) release was mediated by the vacuolar Ca(2+) channel, Yvc1p, whereas the Ca(2+) influx across the plasma membrane could be resolved into Cch1p-dependent and Cch1p-independent pathways. We show that the growth of yeast devoid the plasma membrane Ca(2+) channel, Cch1p, was hypersensitive to eugenol and that this correlated with reduced Ca(2+) elevations. Taken together, these results indicate that a cch1p-mediated Ca(2+) influx is part of an intracellular signal which protects against eugenol toxicity. This study provides fresh insight into the mechanisms employed by fungi to tolerate eugenol toxicity which should lead to better exploitation of eugenol in antifungal therapies. PMID- 23028483 TI - Genome-wide association studies of asthma in population-based cohorts confirm known and suggested loci and identify an additional association near HLA. AB - RATIONALE: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. OBJECTIVES: To test if population-based cohorts with self reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. METHODS: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5 x 10(-8)) and three variants reported as suggestive (P<5* 10( 7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. MAIN RESULTS: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4 * 10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P(Stage1+Stage2) = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P(Stage1+Stage2) = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. CONCLUSIONS: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma. PMID- 23028484 TI - Trajectories of quality of life among Chinese patients diagnosed with nasopharynegeal cancer. AB - OBJECTIVE: This secondary longitudinal analysis describes distinct quality of life trajectories during eight months of radiation therapy (RT) among patients with nasopharyngeal cancer (NPC) and examines factors differentiating these trajectories. METHODS: 253 Chinese patients with NPC scheduled for RT were assessed at pre-treatment, and 4 months and 8 months later on QoL (Chinese version of the FACT-G), optimism, pain, eating function, and patient satisfaction. Latent growth mixture modelling identified different trajectories within each of four QoL domains: Physical, Emotional, Social/family, and Functional well-being. Multinomial logistic regression compared optimism, pain, eating function, and patient satisfaction by trajectories adjusted for demographic and medical characteristics. RESULTS: We identified three distinct trajectories for physical and emotional QoL domains, four trajectories for social/family, and two trajectories for functional domains. Within each domain most patients (physical (77%), emotional (85%), social/family (55%) and functional (63%)) experienced relatively stable high levels of well-being over the 8-month period. Different Physical trajectory patterns were predicted by pain and optimism, whereas for Emotion-domain trajectories pain, optimism, eating enjoyment, patient satisfaction with information, and gender were predictive. Age, appetite, optimism, martial status, and household income predicted Social/family trajectories; household income, eating enjoyment, optimism, and patient satisfaction with information predicted Functional trajectories. CONCLUSION: Most patients with NPC showed high stable QoL during radiotherapy. Optimism predicted good QoL. Symptom impacts varied by QoL domain. Information satisfaction was protective in emotional and functional well-being, reflecting the importance in helping patients to establish a realistic expectation of treatment impacts. PMID- 23028485 TI - Lack or inhibition of dopaminergic stimulation induces a development increase of striatal tyrosine hydroxylase-positive interneurons. AB - We examined the role of endogenous dopamine (DA) in regulating the number of intrinsic tyrosine hydroxylase-positive (TH(+)) striatal neurons using mice at postnatal day (PND) 4 to 8, a period that corresponds to the developmental peak in the number of these neurons. We adopted the strategy of depleting endogenous DA by a 2-day treatment with alpha-methyl-p-tyrosine (alphaMpT, 150 mg/kg, i.p.). This treatment markedly increased the number of striatal TH(+) neurons, assessed by stereological counting, and the increase was highly correlated to the extent of DA loss. Interestingly, TH(+) neurons were found closer to the clusters of DA fibers after DA depletion, indicating that the concentration gradient of extracellular DA critically regulates the distribution of striatal TH(+) neurons. A single i.p. injection of the D1 receptor antagonist, SCH23390 (0.1 mg/kg), the D2/D3 receptor antagonist, raclopride (0.1 mg/kg), or the D4 receptor antagonist, L-745,870 (5 mg/kg) in mice at PND4 also increased the number of TH(+) neurons after 4 days. Treatment with the D1-like receptor agonist SKF38393 (10 mg/kg) or with the D2-like receptor agonist, quinpirole (1 mg/kg) did not change the number of TH(+) neurons. At least the effects of SCH23390 were prevented by a combined treatment with SKF38393. Immunohistochemical analysis indicated that striatal TH(+) neurons expressed D2 and D4 receptors, but not D1 receptors. Moreover, treatment with the alpha4beta2 receptor antagonist dihydro-beta-erythroidine (DHbetaE) (3.2 mg/kg) also increased the number of TH(+) neurons. The evidence that DHbetaE mimicked the action of SCH23390 in increasing the number of TH(+) neurons supports the hypothesis that activation of D1 receptors controls the number of striatal TH(+) neurons by enhancing the release of acetylcholine. These data demonstrate for the first time that endogenous DA negatively regulates the number of striatal TH(+) neurons by direct and indirect mechanisms mediated by multiple DA receptor subtypes. PMID- 23028486 TI - The mental representation of social connections: generalizability extended to Beijing adults. AB - Social connections are essential for the survival of a social species like humans. People differ in the degree to which they are sensitive to perceived deficits in their social connections, but evidence suggests that they nevertheless construe the nature of their social connections similarly. This construal can be thought of as a mental representation of a multi-faceted social experience. A three-dimensional mental representation has been identified with the UCLA Loneliness Scale and consists of Intimate, Relational, and Collective Connectedness reflecting beliefs about one's individual, dyadic, and collective (group) social value, respectively. Moreover, this mental representation has been replicated with other scales and validated across age, gender, and racial/ethnic lines in U.S. samples. The purpose of this study is to evaluate the extent to which this three-dimensional representation applies to people whose social lives are experienced in a collectivistic rather than individualistic culture. To that end, we used confirmatory factor analyses to assess the fit of the three dimensional mental structure to data collected from Chinese people living in China. Two hundred sixty-seven young adults (16-25 yrs) and 250 older adults (50 65 yrs) in Beijing completed the revised UCLA Loneliness Scale and demographic and social activity questionnaires. Results revealed adequate fit of the structure to data from young and older Chinese adults. Moreover, the structure exhibited equivalent fit in young and older Chinese adults despite changes in the Chinese culture that exposed these two generations to different cultural experiences. Social activity variables that discriminated among the three dimensions in the Chinese samples corresponded well with variables that discriminated among the three dimensions in the U.S.-based samples, indicating cultural commonalities in the factors predicting dimensions of people's representations of their social connections. Equivalence of the three-dimensional structure is relevant for an understanding of cultural differences in the sources of loneliness and social connectedness. PMID- 23028487 TI - Elevated urine heparanase levels are associated with proteinuria and decreased renal allograft function. AB - Heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate side chains, leading to structural modifications that loosen the extracellular matrix barrier and associated with tumor metastasis, inflammation and angiogenesis. In addition, the highly sulfated heparan sulfate proteoglycans are important constituents of the glomerular basement membrane and its permselective properties. Recent studies suggest a role for heparanase in several experimental and human glomerular diseases associated with proteinuria such as diabetes, minimal change disease, and membranous nephropathy. Here, we quantified blood and urine heparanase levels in renal transplant recipients and patients with chronic kidney disease (CKD), and assessed whether alterations in heparanase levels correlate with proteinuria and renal function. We report that in transplanted patients, urinary heparanase was markedly elevated, inversely associated with estimated glomerular filtration rate (eGFR), suggesting a relationship between heparanase and graft function. In CKD patients, urinary heparanase was markedly elevated and associated with proteinuria, but not with eGFR. In addition, urinary heparanase correlated significantly with plasma heparanase in transplanted patients. Such a systemic spread of heparanase may lead to damage of cells and tissues alongside the kidney.The newly described association between heparanase, proteinuria and decreased renal function is expected to pave the way for new therapeutic options aimed at attenuating chronic renal allograft nephropathy, leading to improved graft survival and patient outcome. PMID- 23028488 TI - Continuity of visual and auditory rhythms influences sensorimotor coordination. AB - People often coordinate their movement with visual and auditory environmental rhythms. Previous research showed better performances when coordinating with auditory compared to visual stimuli, and with bimodal compared to unimodal stimuli. However, these results have been demonstrated with discrete rhythms and it is possible that such effects depend on the continuity of the stimulus rhythms (i.e., whether they are discrete or continuous). The aim of the current study was to investigate the influence of the continuity of visual and auditory rhythms on sensorimotor coordination. We examined the dynamics of synchronized oscillations of a wrist pendulum with auditory and visual rhythms at different frequencies, which were either unimodal or bimodal and discrete or continuous. Specifically, the stimuli used were a light flash, a fading light, a short tone and a frequency modulated tone. The results demonstrate that the continuity of the stimulus rhythms strongly influences visual and auditory motor coordination. Participants' movement led continuous stimuli and followed discrete stimuli. Asymmetries between the half-cycles of the movement in term of duration and nonlinearity of the trajectory occurred with slower discrete rhythms. Furthermore, the results show that the differences of performance between visual and auditory modalities depend on the continuity of the stimulus rhythms as indicated by movements closer to the instructed coordination for the auditory modality when coordinating with discrete stimuli. The results also indicate that visual and auditory rhythms are integrated together in order to better coordinate irrespective of their continuity, as indicated by less variable coordination closer to the instructed pattern. Generally, the findings have important implications for understanding how we coordinate our movements with visual and auditory environmental rhythms in everyday life. PMID- 23028489 TI - Metabolomic profiling to identify predictors of response to vitamin E for non alcoholic steatohepatitis (NASH). AB - Vitamin E was recently shown to improve hepatic histology in a randomized controlled trial of pioglitazone or vitamin E for nonalcoholic steatohepatitis (PIVENS). The current study utilized samples collected in the PIVENS trial to identify: (1) baseline metabolomic profiles that could identify who would respond to vitamin E treatment and (2) end of treatment metabolomic profiles reflective of histologic improvement. A comprehensive analysis of metabolomics profiles (n = 547) quantified by mass spectrometry was performed in vitamin E responders (n = 16), vitamin E non-responders (n = 15), and placebo responders (n = 15). At baseline, phenyl-propionic acid (Odds ratio: 29.4, p<0.01), indole-propionic acid levels (Odds ratio: 16.2, p<0.01) were directly associated with a subsequent histologic response to vitamin E treatment whereas gamma carboxyethylhydroxychroman (CEHC) levels were inversely related to histologic response. Adjusting for baseline values by analysis of covariance, the end of treatment levels of gamma-glutamyl leucine (Fold change: 0.82, p<0.02) and gamma glutamyl valine (Fold change: 0.8, p<0.03) were significantly lower in vitamin E responders compared to non-responders. The levels of gamma-glutamyl transpeptidase were not significantly different across the two groups. Subjects receiving placebo who demonstrated a histologic improvement also demonstrated lower levels of gamma-glutamylated amino acids (leucine, valine and isoleucine) compared to vitamin E non-responders. These data provide exploratory proof that there are measurable differences in the metabolic profile of subjects who are likely (vs unlikely) to respond to vitamin E treatment for NASH and in those experiencing histologic improvement (vs no improvement) on treatment and support further studies to validate these biomarkers. PMID- 23028490 TI - In vitro and in vivo antitumor activity of a novel pH-activated polymeric drug delivery system for doxorubicin. AB - BACKGROUND: Conventional chemotherapy agent such as doxorubicin (DOX) is of limited clinical use because of its inherently low selectivity, which can lead to systemic toxicity in normal healthy tissue. METHODS: A pH stimuli-sensitive conjugate based on polyethylene glycol (PEG) with covalently attachment doxorubicin via hydrazone bond (PEG-hyd-DOX) was prepared for tumor targeting delivery system. While PEG-DOX conjugates via amid bond (PEG-ami-DOX) was synthesized as control. RESULTS: The synthetic conjugates were confirmed by proton nuclear magnetic resonance (NMR) spectroscopy, the release profile of DOX from PEG-hyd-DOX was acid-liable for the hydrazone linkage between DOX and PEG, led to different intracellular uptake route; intracellular accumulation of PEG hyd-DOX was higher than PEG-ami-DOX due to its pH-triggered profile, and thereby more cytotoxicity against MCF-7, MDA-MB-231 (breast cancer models) and HepG2 (hepatocellular carcinoma model) cell lines. Following the in vitro results, we xenografted MDA-MB-231 cell onto SCID mice, PEG-hyd-DOX showed stronger antitumor efficacy than free DOX and was tumor-targeting. CONCLUSIONS: Results from these in vivo experiments were consistent with our in vitro results; suggested this pH triggered PEG-hyd-DOX conjugate could target DOX to tumor tissues and release free drugs by acidic tumor environment, which would be potent in antitumor drug delivery. PMID- 23028491 TI - Non-listening and self centered leadership--relationships to socioeconomic conditions and employee mental health. AB - BACKGROUND: The way in which leadership is experienced in different socioeconomic strata is of interest per se, as well as how it relates to employee mental health. METHODS: Three waves of SLOSH (Swedish Longitudinal Occupational Survey of Health, a questionnaire survey on a sample of the Swedish working population) were used, 2006, 2008 and 2010 (n = 5141). The leadership variables were: "Non listening leadership" (one question: "Does your manager listen to you?"--four response categories), "Self centered leadership" (sum of three five-graded questions--"non-participating", "asocial" and "loner"). The socioeconomic factors were education and income. Emotional exhaustion and depressive symptoms were used as indicators of mental health. RESULTS: Non-listening leadership was associated with low income and low education whereas self-centered leadership showed a weaker relationship with education and no association at all with income. Both leadership variables were significantly associated with emotional exhaustion and depressive symptoms. "Self centered" as well as "non-listening" leadership in 2006 significantly predicted employee depressive symptoms in 2008 after adjustment for demographic variables. These predictions became non-significant when adjustment was made for job conditions (demands and decision latitude) in the "non-listening" leadership analyses, whereas predictions of depressive symptoms remained significant after these adjustments in the "self-centered leadership" analyses. CONCLUSIONS: Our results show that the leadership variables are associated with socioeconomic status and employee mental health. "Non listening" scores were more sensitive to societal change and more strongly related to socioeconomic factors and job conditions than "self-centered" scores. PMID- 23028492 TI - Salinomycin induces autophagy in colon and breast cancer cells with concomitant generation of reactive oxygen species. AB - BACKGROUND: Salinomycin is a polyether ionophore antibiotic that has recently been shown to induce cell death in human cancer cells displaying multiple mechanisms of drug resistance. The underlying mechanisms leading to cell death after salinomycin treatment have not been well characterized. We therefore investigated the role of salinomycin in caspase dependent and independent cell death in colon cancer (SW480, SW620, RKO) and breast cancer cell lines (MCF-7, T47D, MDA-MB-453). METHODOLOGY/PRINCIPAL FINDINGS: We detected features of apoptosis in all cell lines tested, but the executor caspases 3 and 7 were only strongly activated in RKO and MDA-MB-453 cells. MCF-7 and SW620 cells instead presented features of autophagy such as cytoplasmic vacuolization and LC3 processing. Caspase proficient cell lines activated autophagy at lower salinomycin concentrations and before the onset of caspase activation. Salinomycin also led to the formation of reactive oxygen species (ROS) eliciting JNK activation and induction of the transcription factor JUN. Salinomycin mediated cell death could be partially inhibited by the free radical scavenger N acetyl-cysteine, implicating ROS formation in the mechanism of salinomycin toxicity. CONCLUSIONS: Our data indicate that, in addition to its previously reported induction of caspase dependent apoptosis, the initiation of autophagy is an important and early effect of salinomycin in tumor cells. PMID- 23028493 TI - Enhanced solubilisation of six PAHs by three synthetic cyclodextrins for remediation applications: molecular modelling of the inclusion complexes. AB - Solubilisation of six polycyclic aromatic hydrocarbons (PAHs) (acenaphthene, anthracene, fluoranthene, fluorene, phenanthrene and pyrene) by three synthetic cyclodextrins (CDs) (2-hydroxypropyl-beta-CD, hydroxypropyl-gamma-CD and randomly methylated-beta-CD) was investigated in order to select the CD which presents the greatest increase in solubility and better complexation parameters for its use in contaminated scenarios. The presence of the three cyclodextrins greatly enhanced the apparent water solubility of all the PAHs through the formation of inclusion complexes of 1:1 stoichiometry. Anthracene, fluoranthene, fluorene and phenanthrene clearly presented a higher solubility when beta-CD derivatives were used, and especially the complexes with the randomly methylated-beta-CD were favoured. On the contrary, pyrene presented its best solubility results when using 2-hydroxypropyl-gamma-CD, but for acenaphthene the use of any of the three CDs gave the same results. Complementary to experimental phase-solubility studies, a more in-depth estimation of the inclusion process for the different complexes was carried out using molecular modelling in order to find a correlation between the degree of solubilisation and the fit of PAH molecules within the cavity of the different CDs and to know the predominant driving forces of the complexation. PMID- 23028494 TI - Investigating gaze of children with ASD in naturalistic settings. AB - BACKGROUND: Visual behavior is known to be atypical in Autism Spectrum Disorders (ASD). Monitor-based eye-tracking studies have measured several of these atypicalities in individuals with Autism. While atypical behaviors are known to be accentuated during natural interactions, few studies have been made on gaze behavior in natural interactions. In this study we focused on i) whether the findings done in laboratory settings are also visible in a naturalistic interaction; ii) whether new atypical elements appear when studying visual behavior across the whole field of view. METHODOLOGY/PRINCIPAL FINDINGS: Ten children with ASD and ten typically developing children participated in a dyadic interaction with an experimenter administering items from the Early Social Communication Scale (ESCS). The children wore a novel head-mounted eye-tracker, measuring gaze direction and presence of faces across the child's field of view. The analysis of gaze episodes to faces revealed that children with ASD looked significantly less and for shorter lapses of time at the experimenter. The analysis of gaze patterns across the child's field of view revealed that children with ASD looked downwards and made more extensive use of their lateral field of view when exploring the environment. CONCLUSIONS/SIGNIFICANCE: The data gathered in naturalistic settings confirm findings previously obtained only in monitor based studies. Moreover, the study allowed to observe a generalized strategy of lateral gaze in children with ASD when they were looking at the objects in their environment. PMID- 23028495 TI - Interplay between cytoskeletal stresses and cell adaptation under chronic flow. AB - Using stress sensitive FRET sensors we have measured cytoskeletal stresses in alpha-actinin and the associated reorganization of the actin cytoskeleton in cells subjected to chronic shear stress. We show that long-term shear stress reduces the average actinin stress and this effect is reversible with removal of flow. The flow-induced changes in cytoskeletal stresses are found to be dynamic, involving a transient decrease in stress (phase-I), a short-term increase (3-6 min) (Phase-II), followed by a longer-term decrease that reaches a minimum in ~20 min (Phase-III), before saturating. These changes are accompanied by reorganization of the actin cytoskeleton from parallel F-actin bundles to peripheral bundles. Blocking mechanosensitive ion channels (MSCs) with Gd(3+) and GsMTx4 (a specific inhibitor) eliminated the changes in cytoskeletal stress and the corresponding actin reorganization, indicating that Ca(2+) permeable MSCs participate in the signaling cascades. This study shows that shear stress induced cell adaptation is mediated via MSCs. PMID- 23028496 TI - MyDas, an extensible Java DAS server. AB - A large number of diverse, complex, and distributed data resources are currently available in the Bioinformatics domain. The pace of discovery and the diversity of information means that centralised reference databases like UniProt and Ensembl cannot integrate all potentially relevant information sources. From a user perspective however, centralised access to all relevant information concerning a specific query is essential. The Distributed Annotation System (DAS) defines a communication protocol to exchange annotations on genomic and protein sequences; this standardisation enables clients to retrieve data from a myriad of sources, thus offering centralised access to end-users.We introduce MyDas, a web server that facilitates the publishing of biological annotations according to the DAS specification. It deals with the common functionality requirements of making data available, while also providing an extension mechanism in order to implement the specifics of data store interaction. MyDas allows the user to define where the required information is located along with its structure, and is then responsible for the communication protocol details. PMID- 23028497 TI - Sequencing and characterization of striped venus transcriptome expand resources for clam fishery genetics. AB - BACKGROUND: The striped venus Chamelea gallina clam fishery is among the oldest and the largest in the Mediterranean Sea, particularly in the inshore waters of northern Adriatic Sea. The high fishing pressure has lead to a strong stock abundance decline, enhanced by several irregular mortality events. The nearly complete lack of molecular characterization limits the available genetic resources for C. gallina. We achieved the first transcriptome of this species with the aim of identifying an informative set of expressed genes, potential markers to assess genetic structure of natural populations and molecular resources for pathogenic contamination detection. METHODOLOGY/PRINCIPAL FINDINGS: The 454-pyrosequencing of a normalized cDNA library of a pool C. gallina adult individuals yielded 298,494 raw reads. Different steps of reads assembly and filtering produced 36,422 contigs of high quality, one half of which (18,196) were annotated by similarity. A total of 111 microsatellites and 20,377 putative SNPs were identified. A panel of 13 polymorphic transcript-linked microsatellites was developed and their variability assessed in 12 individuals. Remarkably, a scan to search for contamination sequences of infectious origin indicated the presence of several Vibrionales species reported to be among the most frequent clam pathogen's species. Results reported in this study were included in a dedicated database available at http://compgen.bio.unipd.it/chameleabase. CONCLUSIONS/SIGNIFICANCE: This study represents the first attempt to sequence and de novo annotate the transcriptome of the clam C. gallina. The availability of this transcriptome opens new perspectives in the study of biochemical and physiological role of gene products and their responses to large and small-scale environmental stress in C. gallina, with high throughput experiments such as custom microarray or targeted re-sequencing. Molecular markers, such as the already optimized EST-linked microsatellites and the discovered SNPs will be useful to estimate effects of demographic processes and to detect minute levels of population structuring. PMID- 23028498 TI - Temporal percolation of the susceptible network in an epidemic spreading. AB - In this work, we study the evolution of the susceptible individuals during the spread of an epidemic modeled by the susceptible-infected-recovered (SIR) process spreading on the top of complex networks. Using an edge-based compartmental approach and percolation tools, we find that a time-dependent quantity PhiS(t), namely, the probability that a given neighbor of a node is susceptible at time t, is the control parameter of a node void percolation process involving those nodes on the network not-reached by the disease. We show that there exists a critical time t(c) above which the giant susceptible component is destroyed. As a consequence, in order to preserve a macroscopic connected fraction of the network composed by healthy individuals which guarantee its functionality, any mitigation strategy should be implemented before this critical time t(c). Our theoretical results are confirmed by extensive simulations of the SIR process. PMID- 23028499 TI - Human antibody response to Anopheles saliva for comparing the efficacy of three malaria vector control methods in Balombo, Angola. AB - Human antibody (Ab) response to Anopheles whole saliva, used as biomarker of Anopheles exposure, was investigated over a period of two years (2008-2009), in children between 2 to 9 years old, before and after the introduction of three different malaria vector control methods; deltamethrin treated long lasting impregnated nets (LLIN) and insecticide treated plastic sheeting (ITPS)--Zero Fly(r)) (ITPS-ZF), deltamethrin impregnated Durable (Wall) Lining (ITPS-DL- Zerovector(r)) alone, and indoor residual spraying (IRS) with lambdacyhalothrin alone. These different vector control methods resulted in considerable decreases in all three entomological (82.4%), parasitological (54.8%) and immunological criteria analyzed. The highest reductions in the number of Anopheles collected and number of positive blood smears, respectively 82.1% and 58.3%, were found in Capango and Canjala where LLIN and ITPS-ZF were implemented. The immunological data based on the level of anti-saliva IgG Ab in children of all villages dropped significantly from 2008 to 2009, except in Chissequele. These results indicated that these three vector control methods significantly reduced malaria infections amongst the children studied and IRS significantly reduced the human-Anopheles contact. The number of Anopheles, positive blood smears, and the levels of anti saliva IgG Ab were most reduced when LLIN and ITPS-ZF were used in combination, compared to the use of one vector control method alone, either ITPS-DL or IRS. Therefore, as a combination of two vector control methods is significantly more effective than one control method only, this control strategy should be further developed at a more global scale. PMID- 23028500 TI - Comparative genomics of CytR, an unusual member of the LacI family of transcription factors. AB - CytR is a transcription regulator from the LacI family, present in some gamma proteobacteria including Escherichia coli and known not only for its cellular role, control of transport and utilization of nucleosides, but for a number of unusual structural properties. The present study addressed three related problems: structure of CytR-binding sites and motifs, their evolutionary conservation, and identification of new members of the CytR regulon. While the majority of CytR-binding sites are imperfect inverted repeats situated between binding sites for another transcription factor, CRP, other architectures were observed, in particular, direct repeats. While the similarity between sites for different genes in one genome is rather low, and hence the consensus motif is weak, there is high conservation of orthologous sites in different genomes (mainly in the Enterobacteriales) arguing for the presence of specific CytR-DNA contacts. On larger evolutionary distances candidate CytR sites may migrate but the approximate distance between flanking CRP sites tends to be conserved, which demonstrates that the overall structure of the CRP-CytR-DNA complex is gene specific. The analysis yielded candidate CytR-binding sites for orthologs of known regulon members in less studied genomes of the Enterobacteriales and Vibrionales and identified a new candidate member of the CytR regulon, encoding a transporter named NupT (YcdZ). PMID- 23028501 TI - Three-dimensional genome architecture influences partner selection for chromosomal translocations in human disease. AB - Chromosomal translocations are frequent features of cancer genomes that contribute to disease progression. These rearrangements result from formation and illegitimate repair of DNA double-strand breaks (DSBs), a process that requires spatial colocalization of chromosomal breakpoints. The "contact first" hypothesis suggests that translocation partners colocalize in the nuclei of normal cells, prior to rearrangement. It is unclear, however, the extent to which spatial interactions based on three-dimensional genome architecture contribute to chromosomal rearrangements in human disease. Here we intersect Hi-C maps of three dimensional chromosome conformation with collections of 1,533 chromosomal translocations from cancer and germline genomes. We show that many translocation prone pairs of regions genome-wide, including the cancer translocation partners BCR-ABL and MYC-IGH, display elevated Hi-C contact frequencies in normal human cells. Considering tissue specificity, we find that translocation breakpoints reported in human hematologic malignancies have higher Hi-C contact frequencies in lymphoid cells than those reported in sarcomas and epithelial tumors. However, translocations from multiple tissue types show significant correlation with Hi-C contact frequencies, suggesting that both tissue-specific and universal features of chromatin structure contribute to chromosomal alterations. Our results demonstrate that three-dimensional genome architecture shapes the landscape of rearrangements directly observed in human disease and establish Hi-C as a key method for dissecting these effects. PMID- 23028503 TI - Simple and highly discriminatory VNTR-based multiplex PCR for tracing sources of Aspergillus flavus isolates. AB - Aspergillus flavus is second only to A. fumigatus in causing invasive aspergillosis and it is the major agent responsible for fungal sinusitis, keratitis and endophthalmitis in many countries in the Middle East, Africa and Southeast Asia. Despite the growing challenge due to A. flavus, data on the molecular epidemiology of this fungus remain scarce. The objective of the present study was to develop a new typing method based on the detection of VNTR (Variable number tandem repeat) markers. Eight VNTR markers located on 6 different chromosomes (1, 2, 3, 5, 7 and 8) of A. flavus were selected, combined by pairs for multiplex amplifications and tested on 30 unrelated isolates and six reference strains. The Simpson index for individual markers ranged from 0.398 to 0.818. A combined loci index calculated with all the markers yielded an index of 0.998. The MLVA (Multiple Locus VNTR Analysis) technique proved to be specific and reproducible. In a second time, a total of 55 isolates from Chinese avian farms and from a Tunisian hospital have been evaluated. One major cluster of genotypes could be defined by using the graphing algorithm termed Minimum Spanning Tree. This cluster comprised most of the isolates collected in an avian farm in southern China. The MLVA technique should be considered as an excellent and cost-effective typing method that could be used in many laboratories without the need for sophisticated equipment. PMID- 23028502 TI - Rapid intraspecific evolution of miRNA and siRNA genes in the mosquito Aedes aegypti. AB - RNA silencing, or RNA interference (RNAi) in metazoans mediates development, reduces viral infection and limits transposon mobility. RNA silencing involves 21 30 nucleotide RNAs classified into microRNA (miRNA), exogenous and endogenous small interfering RNAs (siRNA), and Piwi-interacting RNA (piRNA). Knock-out, silencing and mutagenesis of genes in the exogenous siRNA (exo-siRNA) regulatory network demonstrate the importance of this RNAi pathway in antiviral immunity in Drosophila and mosquitoes. In Drosophila, genes encoding components for processing exo-siRNAs are among the fastest evolving 3% of all genes, suggesting that infection with pathogenic RNA viruses may drive diversifying selection in their host. In contrast, paralogous miRNA pathway genes do not evolve more rapidly than the genome average. Silencing of exo-siRNA pathway genes in mosquitoes orally infected with arboviruses leads to increased viral replication, but little is known about the comparative patterns of molecular evolution among the exo-siRNA and miRNA pathways genes in mosquitoes. We generated nearly complete sequences of all exons of major miRNA and siRNA pathway genes dicer-1 and dicer-2, argonaute-1 and argonaute-2, and r3d1 and r2d2 in 104 Aedes aegypti mosquitoes collected from six distinct geographic populations and analyzed their genetic diversity. The ratio of replacement to silent amino acid substitutions was 1.4 fold higher in dicer-2 than in dicer-1, 27.4 fold higher in argonaute-2 than in argonaute-1 and similar in r2d2 and r3d1. Positive selection was supported in 32% of non-synonymous sites in dicer-1, in 47% of sites in dicer-2, in 30% of sites in argonaute-1, in all sites in argonaute-2, in 22% of sites in r3d1 and in 55% of sites in r2d2. Unlike Drosophila, in Ae. aegypti, both exo siRNA and miRNA pathway genes appear to be undergoing rapid, positive, diversifying selection. Furthermore, refractoriness of mosquitoes to infection with dengue virus was significantly positively correlated for nucleotide diversity indices in dicer-2. PMID- 23028504 TI - Cyclohexyl ketone inhibitors of Pin1 dock in a trans-diaxial cyclohexane conformation. AB - Cyclohexyl ketone substrate analogue inhibitors (Ac-pSer-Psi[C = OCH]-Pip tryptamine) of Pin1, the cell cycle regulatory peptidyl-prolyl isomerase (PPIase), were designed and synthesized as potential electrophilic acceptors for the Pin1 active site Cys113 nucleophile to test a proposed nucleophilic addition isomerization mechanism. Because they were weak inhibitors, models of all three stereoisomers were docked into the active site of Pin1. Each isomer consistently minimized to a trans-diaxial cyclohexane conformation. From this, we hypothesize that Pin1 stretches substrates into a trans-pyrrolidine conformation to lower the barrier to isomerization. Our reduced amide inhibitor of Pin1 adopted a similar trans-pyrrolidine conformation in the crystal structure. The molecular model of 1, which mimics the l-Ser-l-Pro stereochemistry, in the Pin1 active site showed a distance of 4.4 A, and an angle of 31 degrees between Cys113-S and the ketone carbon. The computational models suggest that the mechanism of Pin1 PPIase is not likely to proceed through nucleophilic addition. PMID- 23028505 TI - Centromere architecture breakdown induced by the viral E3 ubiquitin ligase ICP0 protein of herpes simplex virus type 1. AB - The viral E3 ubiquitin ligase ICP0 protein has the unique property to temporarily localize at interphase and mitotic centromeres early after infection of cells by the herpes simplex virus type 1 (HSV-1). As a consequence ICP0 induces the proteasomal degradation of several centromeric proteins (CENPs), namely CENP-A, the centromeric histone H3 variant, CENP-B and CENP-C. Following ICP0-induced centromere modification cells trigger a specific response to centromeres called interphase Centromere Damage Response (iCDR). The biological significance of the iCDR is unknown; so is the degree of centromere structural damage induced by ICP0. Interphase centromeres are complex structures made of proximal and distal protein layers closely associated to CENP-A-containing centromeric chromatin. Using several cell lines constitutively expressing GFP-tagged CENPs, we investigated the extent of the centromere destabilization induced by ICP0. We show that ICP0 provokes the disappearance from centromeres, and the proteasomal degradation of several CENPs from the NAC (CENP-A nucleosome associated) and CAD (CENP-A Distal) complexes. We then investigated the nucleosomal occupancy of the centromeric chromatin in ICP0-expressing cells by micrococcal nuclease (MNase) digestion analysis. ICP0 expression either following infection or in cell lines constitutively expressing ICP0 provokes significant modifications of the centromeric chromatin structure resulting in higher MNase accessibility. Finally, using human artificial chromosomes (HACs), we established that ICP0-induced iCDR could also target exogenous centromeres. These results demonstrate that, in addition to the protein complexes, ICP0 also destabilizes the centromeric chromatin resulting in the complete breakdown of the centromere architecture, which consequently induces iCDR. PMID- 23028506 TI - Bifidobacterium asteroides PRL2011 genome analysis reveals clues for colonization of the insect gut. AB - Bifidobacteria are known as anaerobic/microaerophilic and fermentative microorganisms, which commonly inhabit the gastrointestinal tract of various animals and insects. Analysis of the 2,167,301 bp genome of Bifidobacterium asteroides PRL2011, a strain isolated from the hindgut of Apis mellifera var. ligustica, commonly known as the honey bee, revealed its predicted capability for respiratory metabolism. Conservation of the latter gene clusters in various B. asteroides strains enforces the notion that respiration is a common metabolic feature of this ancient bifidobacterial species, which has been lost in currently known mammal-derived Bifidobacterium species. In fact, phylogenomic based analyses suggested an ancient origin of B. asteroides and indicates it as an ancestor of the genus Bifidobacterium. Furthermore, the B. asteroides PRL2011 genome encodes various enzymes for coping with toxic products that arise as a result of oxygen-mediated respiration. PMID- 23028507 TI - Fungal diversity is not determined by mineral and chemical differences in serpentine substrates. AB - The physico-chemical properties of serpentine soils lead to strong selection of plant species. Whereas many studies have described the serpentine flora, little information is available on the fungal communities dwelling in these sites. Asbestos minerals, often associated with serpentine rocks, can be weathered by serpentine-isolated fungi, suggesting an adaptation to this substrate. In this study, we have investigated whether serpentine substrates characterized by the presence of rocks with distinct mineral composition could select for different fungal communities. Both fungal isolation and 454 pyrosequencing of amplicons obtained from serpentine samples following direct DNA extraction revealed some fungal taxa shared by the four ophiolitic substrates, but also highlighted several substrate-specific taxa. Bootstrap analysis of 454 OTU abundances indicated weak clustering of fungal assemblages from the different substrates, which did not match substrate classification based on exchangeable macronutrients and metals. Intra-substrate variability, as assessed by DGGE profiles, was similar across the four serpentine substrates, and comparable to inter-substrate variability. These findings indicate the absence of a correlation between the substrate (mineral composition and available cations) and the diversity of the fungal community. Comparison of culture-based and culture-independent methods supports the higher taxonomic precision of the former, as complementation of the better performance of the latter. PMID- 23028508 TI - Absence of antiretroviral therapy and other risk factors for morbidity and mortality in Malaysian compulsory drug detention and rehabilitation centers. AB - BACKGROUND: Throughout Asia, people who use drugs are confined in facilities referred to as compulsory drug detention and rehabilitation centers. The limited transparency and accessibility of these centers has posed a significant challenge to evaluating detainees and detention conditions directly. Despite HIV being highly prevalent in this type of confined setting, direct evaluation of detainees with HIV and their access to medical care has yet to be reported in the literature. METHODS: We evaluated the health status of 100 adult male detainees with HIV and their access to medical care in the two largest Malaysian compulsory drug detention and rehabilitation centers holding HIV-infected individuals. RESULTS: Approximately 80% of all detainees with HIV were surveyed in each detention center. Most participants reported multiple untreated medical conditions. None reported being able to access antiretroviral therapy during detention and only 9% reported receiving any HIV-related clinical assessment or care. Nearly a quarter screened positive for symptoms indicative of active tuberculosis, yet none reported having been evaluated for tuberculosis. Although 95% of participants met criteria for opioid dependence prior to detention, none reported being able to access opioid substitution therapy during detention, with 86% reporting current cravings for opioids and 87% anticipating relapsing to drug use after release. Fourteen percent of participants reported suicidal ideation over the previous two weeks. CONCLUSION: We identified a lack of access to antiretroviral therapy in two of the six compulsory drug detention and rehabilitation centers in Malaysia designated to hold HIV-infected individuals and found significant, unmet health needs among detainees with HIV. Individuals confined under such conditions are placed at considerably high risk for morbidity and mortality. Our findings underscore the urgent need for evidence-based drug policies that respect the rights of people who use drugs and seek to improve, rather than undermine, their health. PMID- 23028509 TI - System wide analysis of the evolution of innate immunity in the nematode model species Caenorhabditis elegans and Pristionchus pacificus. AB - The evolution of genetic mechanisms used to combat bacterial infections is critical for the survival of animals and plants, yet how these genes evolved to produce a robust defense system is poorly understood. Studies of the nematode Caenorhabditis elegans have uncovered a plethora of genetic regulators and effectors responsible for surviving pathogens. However, comparative studies utilizing other free-living nematodes and therefore providing an insight into the evolution of innate immunity have been lacking. Here, we take a systems biology approach and use whole genome microarrays to profile the transcriptional response of C. elegans and the necromenic nematode Pristionchus pacificus after exposure to the four different pathogens Serratia marcescens, Xenorhabdus nematophila, Staphylococcus aureus and Bacillus thuringiensis DB27. C. elegans is susceptible to all four pathogens whilst P. pacificus is only susceptible to S. marcescens and X. nematophila. We show an unexpected level of specificity in host responses to distinct pathogens within and across species, revealing an enormous complexity of effectors of innate immunity. Functional domains enriched in the transcriptomes on different pathogens are similar within a nematode species but different across them, suggesting differences in pathogen sensing and response networks. We find translation inhibition to be a potentially conserved response to gram-negative pathogens in both the nematodes. Further computational analysis indicates that both nematodes when fed on pathogens up-regulate genes known to be involved in other stress responses like heat shock, oxidative and osmotic stress, and genes regulated by DAF-16/FOXO and TGF-beta pathways. This study presents a platform for comparative systems analysis of two nematode model species, and a catalog of genes involved in the evolution of nematode immunity and identifies both pathogen specific and pan-pathogen responses. We discuss the potential effects of ecology on evolution of downstream effectors and upstream regulators on evolution of nematode innate immunity. PMID- 23028510 TI - Anti-cancer activity of a novel small molecule compound that simultaneously activates p53 and inhibits NF-kappaB signaling. AB - The p53 and NF-kappaB pathways play important roles in diverse cellular functions, including cell growth, apoptosis, and tumorigenesis. Mutations that inactivate the p53 gene and constitutive NF-kappaB pathway activation are common occurrences in human cancers. Although many drugs are being developed that selectively activate p53 or inhibit NF-kappaB, there are few drug candidates that can do both. Simultaneous activation of p53 and inhibition of the NF-kappaB pathway is therefore a prime target for new cancer drug development. This study is the first report of a high-throughput approach with mass compounds that concurrently target both pathways. Using a cell-based screening assay and a library of 200,000 synthetic compounds, we identified 9 small molecules that simultaneously inhibit NF-kappaB and activate p53. One of these compounds, N-2, increased the expression of p53 target genes, including p21 and GADD45a. In addition, N-2 inhibited the transcriptional activity of NF-kappaB, concomitantly repressing interleukin-6 and monocyte chemotactic protein-1 (MCP-1) expression. When cell lines derived from a diverse range of cancers were treated in vitro with N-2, we observed increased cell death. N-2 also significantly inhibited allograft growth in murine models of melanoma and lung carcinoma. Our findings suggest that N-2 may act as a bivalent anti-cancer agent through simultaneous modulation of NF-kappaB and p53 activities. PMID- 23028512 TI - Fast feedback in active sensing: touch-induced changes to whisker-object interaction. AB - Whisking mediated touch is an active sense whereby whisker movements are modulated by sensory input and behavioral context. Here we studied the effects of touching an object on whisking in head-fixed rats. Simultaneous movements of whiskers C1, C2, and D1 were tracked bilaterally and their movements compared. During free-air whisking, whisker protractions were typically characterized by a single acceleration-deceleration event, whisking amplitude and velocity were correlated, and whisk duration correlated with neither amplitude nor velocity. Upon contact with an object, a second acceleration-deceleration event occurred in about 25% of whisk cycles, involving both contacting (C2) and non-contacting (C1, D1) whiskers ipsilateral to the object. In these cases, the rostral whisker (C2) remained in contact with the object throughout the double-peak phase, which effectively prolonged the duration of C2 contact. These "touch-induced pumps" (TIPs) were detected, on average, 17.9 ms after contact. On a slower time scale, starting at the cycle following first touch, contralateral amplitude increased while ipsilateral amplitude decreased. Our results demonstrate that sensory induced motor modulations occur at various timescales, and directly affect object palpation. PMID- 23028513 TI - The mechanics of metastasis: insights from a computational model. AB - Although it may seem obvious that mechanical forces are required to drive metastatic cell movements, understanding of the mechanical aspects of metastasis has lagged far behind genetic and biochemical knowledge. The goal of this study is to learn about the mechanics of metastasis using a cell-based finite element model that proved useful for advancing knowledge about the forces that drive embryonic cell and tissue movements. Metastasis, the predominant cause of cancer related deaths, involves a series of mechanical events in which one or more cells dissociate from a primary tumour, migrate through normal tissue, traverse in and out of a multi-layer circulatory system vessel and resettle. The present work focuses on the dissemination steps, from dissociation to circulation. The model shows that certain surface tension relationships must be satisfied for cancerous cells to dissociate from a primary tumour and that these equations are analogous to those that govern dissociation of embryonic cells. For a dissociated cell to then migrate by invadopodium extension and contraction and exhibit the shapes seen in experiments, the invadopodium must generate a contraction equal to approximately twice that produced by the interfacial tension associated with surrounding cells. Intravasation through the wall of a vessel is governed by relationships akin to those in the previous two steps, while release from the vessel wall is governed by equations that involve surface and interfacial tensions. The model raises a number of potential research questions. It also identifies how specific mechanical properties and the sub-cellular structural components that give rise to them might be changed so as to thwart particular metastatic steps and thereby block the spread of cancer. PMID- 23028514 TI - Enhancement and distortion in the temporal representation of sounds in the ventral cochlear nucleus of chinchillas and cats. AB - A subset of neurons in the cochlear nucleus (CN) of the auditory brainstem has the ability to enhance the auditory nerve's temporal representation of stimulating sounds. These neurons reside in the ventral region of the CN (VCN) and are usually known as highly synchronized, or high-sync, neurons. Most published reports about the existence and properties of high-sync neurons are based on recordings performed on a VCN output tract--not the VCN itself--of cats. In other species, comprehensive studies detailing the properties of high-sync neurons, or even acknowledging their existence, are missing.Examination of the responses of a population of VCN neurons in chinchillas revealed that a subset of those neurons have temporal properties similar to high-sync neurons in the cat. Phase locking and entrainment--the ability of a neuron to fire action potentials at a certain stimulus phase and at almost every stimulus period, respectively- have similar maximum values in cats and chinchillas. Ranges of characteristic frequencies for high-sync neurons in chinchillas and cats extend up to 600 and 1000 Hz, respectively. Enhancement of temporal processing relative to auditory nerve fibers (ANFs), which has been shown previously in cats using tonal and white-noise stimuli, is also demonstrated here in the responses of VCN neurons to synthetic and spoken vowel sounds.Along with the large amount of phase locking displayed by some VCN neurons there occurs a deterioration in the spectral representation of the stimuli (tones or vowels). High-sync neurons exhibit a greater distortion in their responses to tones or vowels than do other types of VCN neurons and auditory nerve fibers.Standard deviations of first-spike latency measured in responses of high-sync neurons are lower than similar values measured in ANFs' responses. This might indicate a role of high-sync neurons in other tasks beyond sound localization. PMID- 23028515 TI - A stochastic model of DNA fragments rejoining. AB - When cells are exposed to ionizing radiation, DNA damages in the form of single strand breaks (SSBs), double strand breaks (DSBs), base damage or their combinations are frequent events. It is known that the complexity and severity of DNA damage depends on the quality of radiation, and the microscopic dose deposited in small segments of DNA, which is often related to the linear transfer energy (LET) of the radiation. Experimental studies have suggested that under the same dose, high LET radiation induces more small DNA fragments than low-LET radiation, which affects Ku efficiently binding with DNA end and might be a main reason for high-LET radiation induced RBE [1] since DNA DSB is a major cause for radiation-induced cell death. In this work, we proposed a mathematical model of DNA fragments rejoining according to non-homologous end joining (NHEJ) mechanism. By conducting Gillespie's stochastic simulation, we found several factors that impact the efficiency of DNA fragments rejoining. Our results demonstrated that aberrant DNA damage repair can result predominantly from the occurrence of a spatial distribution of DSBs leading to short DNA fragments. Because of the low efficiency that short DNA fragments recruit repair protein and release the protein residue after fragments rejoining, Ku-dependent NHEJ is significantly interfered with short fragments. Overall, our work suggests that inhibiting the Ku-dependent NHEJ may significantly contribute to the increased efficiency for cell death and mutation observed for high LET radiation. PMID- 23028511 TI - Plasma based markers of [11C] PiB-PET brain amyloid burden. AB - Changes in brain amyloid burden have been shown to relate to Alzheimer's disease pathology, and are believed to precede the development of cognitive decline. There is thus a need for inexpensive and non-invasive screening methods that are able to accurately estimate brain amyloid burden as a marker of Alzheimer's disease. One potential method would involve using demographic information and measurements on plasma samples to establish biomarkers of brain amyloid burden; in this study data from the Alzheimer's Disease Neuroimaging Initiative was used to explore this possibility. Sixteen of the analytes on the Rules Based Medicine Human Discovery Multi-Analyte Profile 1.0 panel were found to associate with [(11)C]-PiB PET measurements. Some of these markers of brain amyloid burden were also found to associate with other AD related phenotypes. Thirteen of these markers of brain amyloid burden--c-peptide, fibrinogen, alpha-1-antitrypsin, pancreatic polypeptide, complement C3, vitronectin, cortisol, AXL receptor kinase, interleukin-3, interleukin-13, matrix metalloproteinase-9 total, apolipoprotein E and immunoglobulin E--were used along with co-variates in multiple linear regression, and were shown by cross-validation to explain >30% of the variance of brain amyloid burden. When a threshold was used to classify subjects as PiB positive, the regression model was found to predict actual PiB positive individuals with a sensitivity of 0.918 and a specificity of 0.545. The number of APOE [Symbol: see text] 4 alleles and plasma apolipoprotein E level were found to contribute most to this model, and the relationship between these variables and brain amyloid burden was explored. PMID- 23028516 TI - Dynamic sounds capture the boundaries of peripersonal space representation in humans. AB - BACKGROUND: We physically interact with external stimuli when they occur within a limited space immediately surrounding the body, i.e., Peripersonal Space (PPS). In the primate brain, specific fronto-parietal areas are responsible for the multisensory representation of PPS, by integrating tactile, visual and auditory information occurring on and near the body. Dynamic stimuli are particularly relevant for PPS representation, as they might refer to potential harms approaching the body. However, behavioural tasks for studying PPS representation with moving stimuli are lacking. Here we propose a new dynamic audio-tactile interaction task in order to assess the extension of PPS in a more functionally and ecologically valid condition. METHODOLOGY/PRINCIPAL FINDINGS: Participants vocally responded to a tactile stimulus administered at the hand at different delays from the onset of task-irrelevant dynamic sounds which gave the impression of a sound source either approaching or receding from the subject's hand. Results showed that a moving auditory stimulus speeded up the processing of a tactile stimulus at the hand as long as it was perceived at a limited distance from the hand, that is within the boundaries of PPS representation. The audio-tactile interaction effect was stronger when sounds were approaching compared to when sounds were receding. CONCLUSION/SIGNIFICANCE: This study provides a new method to dynamically assess pps representation: The function describing the relationship between tactile processing and the position of sounds in space can be used to estimate the location of PPS boundaries, along a spatial continuum between far and near space, in a valuable and ecologically significant way. PMID- 23028518 TI - Phylogeny, histology and inferred body size evolution in a new rhabdodontid dinosaur from the Late Cretaceous of Hungary. AB - BACKGROUND: Rhabdodontid ornithopod dinosaurs are characteristic elements of Late Cretaceous European vertebrate faunas and were previously collected from lower Campanian to Maastrichtian continental deposits. Phylogenetic analyses have placed rhabdodontids among basal ornithopods as the sister taxon to the clade consisting of Tenontosaurus, Dryosaurus, Camptosaurus, and Iguanodon. Recent studies considered Zalmoxes, the best known representative of the clade, to be significantly smaller than closely related ornithopods such as Tenontosaurus, Camptosaurus, or Rhabdodon, and concluded that it was probably an island dwarf that inhabited the Maastrichtian Hateg Island. METHODOLOGY/PRINCIPAL FINDINGS: Rhabdodontid remains from the Santonian of western Hungary provide evidence for a new, small-bodied form, which we assign to Mochlodon vorosi n. sp. The new species is most similar to the early Campanian M. suessi from Austria, and the close affinities of the two species is further supported by the results of a global phylogenetic analysis of ornithischian dinosaurs. Bone histological studies of representatives of all rhabdodontids indicate a similar adult body length of 1.6-1.8 m in the Hungarian and Austrian species, 2.4-2.5 m in the subadults of both Zalmoxes robustus and Z. shqiperorum and a much larger, 5-6 m adult body length in Rhabdodon. Phylogenetic mapping of femoral lengths onto the results of the phylogenetic analysis suggests a femoral length of around 340 mm as the ancestral state for Rhabdodontidae, close to the adult femoral lengths known for Zalmoxes (320-333 mm). CONCLUSIONS/SIGNIFICANCE: Our analysis of body size evolution does not support the hypothesis of autapomorhic nanism for Zalmoxes. However, Rhabdodon is reconstructed as having undergone autapomorphic giantism and the reconstructed small femoral length (245 mm) of Mochlodon is consistent with a reduction in size relative to the ancestral rhabdodontid condition. Our results imply a pre-Santonian divergence between western and eastern rhabdodontid lineages within the western Tethyan archipelago. PMID- 23028517 TI - Characterization of a novel phenol hydroxylase in indoles biotransformation from a strain Arthrobacter sp. W1 [corrected]. AB - BACKGROUND: Indigoids, as popular dyes, can be produced by microbial strains or enzymes catalysis. However, the new valuable products with their transformation mechanisms, especially inter-conversion among the intermediates and products have not been clearly identified yet. Therefore, it is necessary to investigate novel microbial catalytic processes for indigoids production systematically. FINDINGS: A phenol hydroxylase gene cluster (4,606 bp) from Arthrobacter sp. W1 (PH(w1)) was obtained. This cluster contains six components in the order of KLMNOP, which exhibit relatively low sequence identities (37-72%) with known genes. It was suggested that indole and all the tested indole derivatives except for 3 methylindole were transformed to various substituted indigoid pigments, and the predominant color products derived from indoles were identified by spectrum analysis. One new purple product from indole, 2-(7-oxo-1H-indol-6(7H)-ylidene) indolin-3-one, should be proposed as the dimerization of isatin and 7 hydroxylindole at the C-2 and C-6 positions. Tunnel entrance and docking studies were used to predict the important amino acids for indoles biotransformation, which were further proved by site-directed mutagenesis. CONCLUSIONS/SIGNIFICANCE: We showed that the phenol hydroxylase from genus Arthrobacter could transform indoles to indigoids with new chemical compounds being produced. Our work should show high insights into understanding the mechanism of indigoids bio-production. PMID- 23028519 TI - Tracking the quality of care for sick children using lot quality assurance sampling: targeting improvements of health services in Jigawa, Nigeria. AB - BACKGROUND: In Nigeria, 30% of child deaths are due to malaria. The National Malaria Control Program of Nigeria (NMCP) during 2009 initiated a program to improve the quality of paediatric malaria services delivered in health facilities (HF). This study reports a rapid approach used to assess the existing quality of services in Jigawa state at decentralised levels of the health system. METHODS: NMCP selected Lot Quality Assurance Sampling (LQAS) to identify the variation in HF service quality among Senatorial Districts (SD). LQAS was selected because it was affordable and could be used by local health workers (HW) in a population based survey. NMCP applied a 2-stage LQAS using a structured Rapid Health Facility Assessment (R-HFA) tool to identify high and low performing SD for specified indicators. FINDINGS: LQAS identified variations in HF performance (n = 21) and enabled resources to be targeted to address priorities. All SD exhibited deficient essential services, supplies and equipment. Only 9.7% of HF had Artemisinin-based Combination Therapies and other first-line treatments for childhood illnesses. No SD and few HF exhibited adequate HW performance for the assessment, treatment or counselling of sick children. Using the IMCI algorithm, 17.5% of HW assessed the child's vaccination status, 46.8% assessed nutritional status, and 65.1% assessed children for dehydration. Only 5.1% of HW treatments were appropriate for the assessment. Exit interviews revealed that 5.1% of caregivers knew their children's illness, and only 19.9% could accurately describe how to administer the prescribed drug. CONCLUSION: This R-HFA, using LQAS principles, is a rapid, simple tool for assessing malaria services and can be used at scale. It identified technical deficiencies that could be corrected by improved continuing medical education, targeted supervision, and recurrent R-HFA assessments of the quality of services. PMID- 23028521 TI - Combined, sequential intravenous and intra-arterial chemotherapy (bridge chemotherapy) for young infants with retinoblastoma. AB - BACKGROUND: Intra-arterial (i.a.) chemotherapy has more risks of procedural complications in neonates and young infants. For these reasons, we have developed a strategy of bridge intravenous single agent chemotherapy to postpone i.a. chemotherapy in these children PROCEDURE: Neonates and young infants with retinoblastoma who required chemotherapy were treated with systemic carboplatin chemotherapy (18.7 mg/kg i.v. every 3-4 weeks) until they reached the age of 3 months and a weight of 6 Kg. If necessary, i.a. chemotherapy was subsequently performed at 4 weeks intervals. Efficacy was judged by tumor regression on ophthalmological examination. Retinal toxicity was judged by electroretinography. RESULTS: Eleven children (19 eyes) were treated. All patients are alive and no patient has developed metastatic disease or second malignancies (mean follow-up 27 months, range 9-46 months). Intravenous carboplatin (median 2 cycles, range 1 5) combined with cryotherapy and laser was given to all children. This was effective for five eyes, which did not require i.a. chemotherapy. I.a. chemotherapy was administered to 14 eyes (median 3.5 cycles per eye, range 1 to 6). No radiation therapy was required. The Kaplan Meier estimate of ocular radiation-free survival was 94.7% at one year (95% confidence interval 68.1 99.2%). One eye was enucleated due to tumor progression. ERG showed no deterioration of retinal function. CONCLUSION: Bridge i.v.-i.a. chemotherapy was feasible and safe, and is a promising strategy to treat retinoblastoma in neonates and young infants. PMID- 23028520 TI - The C-terminal domains of NF-H and NF-M subunits maintain axonal neurofilament content by blocking turnover of the stationary neurofilament network. AB - Newly synthesized neurofilaments or protofilaments are incorporated into a highly stable stationary cytoskeleton network as they are transported along axons. Although the heavily phosphorylated carboxyl-terminal tail domains of the heavy and medium neurofilament (NF) subunits have been proposed to contribute to this process and particularly to stability of this structure, their function is still obscure. Here we show in NF-H/M tail deletion [NF-(H/M)(tailDelta)] mice that the deletion of both of these domains selectively lowers NF levels 3-6 fold along optic axons without altering either rates of subunit synthesis or the rate of slow axonal transport of NF. Pulse labeling studies carried out over 90 days revealed a significantly faster rate of disappearance of NF from the stationary NF network of optic axons in NF-(H/M)(tailDelta) mice. Faster NF disappearance was accompanied by elevated levels of NF-L proteolytic fragments in NF (H/M)(tailDelta) axons. We conclude that NF-H and NF-M C-terminal domains do not normally regulate NF transport rates as previously proposed, but instead increase the proteolytic resistance of NF, thereby stabilizing the stationary neurofilament cytoskeleton along axons. PMID- 23028522 TI - Effect of solar particle event radiation and hindlimb suspension on gastrointestinal tract bacterial translocation and immune activation. AB - The environmental conditions that could lead to an increased risk for the development of an infection during prolonged space flight include: microgravity, stress, radiation, disturbance of circadian rhythms, and altered nutritional intake. A large body of literature exists on the impairment of the immune system by space flight. With the advent of missions outside the Earth's magnetic field, the increased risk of adverse effects due to exposure to radiation from a solar particle event (SPE) needs to be considered. Using models of reduced gravity and SPE radiation, we identify that either 2 Gy of radiation or hindlimb suspension alone leads to activation of the innate immune system and the two together are synergistic. The mechanism for the transient systemic immune activation is a reduced ability of the GI tract to contain bacterial products. The identification of mechanisms responsible for immune dysfunction during extended space missions will allow the development of specific countermeasures. PMID- 23028523 TI - Comparison of intact Arabidopsis thaliana leaf transcript profiles during treatment with inhibitors of mitochondrial electron transport and TCA cycle. AB - Plant mitochondria signal to the nucleus leading to altered transcription of nuclear genes by a process called mitochondrial retrograde regulation (MRR). MRR is implicated in metabolic homeostasis and responses to stress conditions. Mitochondrial reactive oxygen species (mtROS) are a MRR signaling component, but whether all MRR requires ROS is not established. Inhibition of the cytochrome respiratory pathway by antimycin A (AA) or the TCA cycle by monofluoroacetate (MFA), each of which initiates MRR, can increase ROS production in some plant cells. We found that for AA and MFA applied to leaves of soil-grown Arabidopsis thaliana plants, ROS production increased with AA, but not with MFA, allowing comparison of transcript profiles under different ROS conditions during MRR. Variation in transcript accumulation over time for eight nuclear encoded mitochondrial protein genes suggested operation of both common and distinct signaling pathways between the two treatments. Consequences of mitochondrial perturbations for the whole transcriptome were examined by microarray analyses. Expression of 1316 and 606 genes was altered by AA and MFA, respectively. A subset of genes was similarly affected by both treatments, including genes encoding photosynthesis-related proteins. MFA treatment resulted in more down regulation. Functional gene category (MapMan) and cluster analyses showed that genes with expression levels affected by perturbation from AA or MFA inhibition were most similarly affected by biotic stresses such as pathogens. Overall, the data provide further evidence for the presence of mtROS-independent MRR signaling, and support the proposed involvement of MRR and mitochondrial function in plant responses to biotic stress. PMID- 23028525 TI - Habitat selection and reproductive success of Lewis's Woodpecker (Melanerpes lewis) at its northern limit. AB - Lewis's Woodpecker (Melanerpes lewis) has experienced population declines in both Canada and the United States and in 2010 was assigned a national listing of threatened in Canada. We conducted a two-year study (2004-2005) of this species at its northern range limit, the South Okanagan Valley in British Columbia, Canada. Our main objective was to determine whether the habitat features that influenced nest-site selection also predicted nest success, or whether other factors (e.g. cavity dimensions, clutch initiation date or time of season) were more important. Nest tree decay class, density of suitable cavities and total basal area of large trees were the best predictors of nest-site selection, but these factors were unrelated to nesting success. Estimates of demographic parameters (mean +/- SE) included daily nest survival rate (0.988+/-0.003, years combined), nest success (0.52+/-0.08), clutch size (5.00+/-0.14 eggs), female fledglings per successful nest (1.31+/-0.11), and annual productivity (0.68+/ 0.12 female fledglings per nest per year). Although higher nest survival was associated with both early and late initiated clutches, early-initiated clutches allowed birds to gain the highest annual productivity as early clutches were larger. Nests in deep cavities with small entrances experienced lower predation risk especially during the peak period of nest predation. We concluded that nest site selection can be predicted by a number of easily measured habitat variables, whereas nest success depended on complicated ecological interactions among nest predators, breeding behaviors, and cavity features. Thus, habitat-based conservation strategies should also consider ecological factors that may not be well predicted by habitat. PMID- 23028524 TI - GPR54-dependent stimulation of luteinizing hormone secretion by neurokinin B in prepubertal rats. AB - Kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn) are coexpressed within KNDy neurons that project from the hypothalamic arcuate nucleus (ARC) to GnRH neurons and numerous other hypothalamic targets. Each of the KNDy neuropeptides has been implicated in regulating pulsatile GnRH/LH secretion. In isolation, kisspeptin is generally known to stimulate, and Dyn to inhibit LH secretion. However, the NKB analog, senktide, has variously been reported to inhibit, stimulate or have no effect on LH secretion. In prepubertal mice, rats and monkeys, senktide stimulates LH secretion. Furthermore, in the monkey this effect is dependent on kisspeptin signaling through its receptor, GPR54. The present study tested the hypotheses that the stimulatory effects of NKB on LH secretion in intact rats are mediated by kisspeptin/GPR54 signaling and are independent of a Dyn tone. To test this, ovarian-intact prepubertal rats were subjected to frequent automated blood sampling before and after intracerebroventricular injections of KNDy neuropeptide analogs. Senktide robustly induced single LH pulses, while neither the GPR54 antagonist, Kp-234, nor the Dyn agonist and antagonist (U50488 and nor-BNI, respectively) had an effect on basal LH levels. However, Kp-234 potently blocked the senktide-induced LH pulses. Modulation of the Dyn tone by U50488 or nor-BNI did not affect the senktide-induced LH pulses. These data demonstrate that the stimulatory effect of NKB on LH secretion in intact female rats is dependent upon kisspeptin/GPR54 signaling, but not on Dyn signaling. PMID- 23028526 TI - Adverse drug reactions in hospitalised children in Germany are decreasing: results of a nine year cohort-based comparison. AB - BACKGROUND: In recent years, efforts have been made to improve paediatric drug therapy. The aim of this research was to investigate any changes regarding the frequency and nature of adverse drug reactions (ADRs) in hospitalized children in one paediatric general medical ward over a 9-year period. METHODOLOGY: Two prospective observational cohort studies were conducted at a large University hospital in Germany in 1999 and 2008, respectively. Children aged 0-18 years admitted to the study ward during the study periods were included. ADRs were identified using intensive chart review. Uni- and multivariable regression has been used for data analysis. RESULTS: A total of 520 patients (574 admissions) were included [1999: n = 144 (167); 2008: n = 376 (407)]. Patients received a total of 2053 drugs [median 3, interquartile range (IQR) 2-5]. 19% of patients did not receive any medication. Median length of stay was 4 days (IQR 3-7; range 1-190 days) with a significantly longer length of stay in 1999. The overall ADR incidence was 13.1% (95% CI, 9.8-16.3) varying significantly between the two study cohorts [1999: 21.9%, 95% CI, 14.7-29.0; 2008: 9.2%, 95% CI, 5.9-12.5 (p<0.001)]. Antibacterials and corticosteroids for systemic use caused most of the ADRs in both cohorts (1999; 2008). Exposure to systemic antibacterials decreased from 62.9% to 43.5% whereas exposure to analgesics and anti inflammatory drugs increased from 17.4% to 45.2%, respectively. The use of high risk drugs decreased from 75% to 62.2%. In 1999, 45.7% and in 2008 96.2% of ADRs were identified by treating clinicians (p<0.001). CONCLUSIONS: Between 1999 and 2008, the incidence of ADRs decreased significantly. Improved treatment strategies and an increased awareness of ADRs by physicians are most likely to be the cause for this positive development. Nevertheless further research on ADRs particularly in primary care and the establishment of prospective pharmacovigilance systems are still needed. PMID- 23028527 TI - Antitumor and angiostatic activities of the antimicrobial peptide dermaseptin B2. AB - Recently, we have found that the skin secretions of the Amazonian tree frog Phyllomedusa bicolor contains molecules with antitumor and angiostatic activities and identified one of them as the antimicrobial peptide dermaseptin (Drs) B2. In the present study we further explored the in vitro and in vivo antitumor activity of this molecule and investigated its mechanism of action. We showed that Drs B2 inhibits the proliferation and colony formation of various human tumor cell types, and the proliferation and capillary formation of endothelial cells in vitro. Furthermore, Drs B2 inhibited tumor growth of the human prostate adenocarcinoma cell line PC3 in a xenograft model in vivo. Research on the mechanism of action of Drs B2 on tumor PC3 cells demonstrated a rapid increasing amount of cytosolic lactate dehydrogenase, no activation of caspase-3, and no changes in mitochondrial membrane potential. Confocal microscopy analysis revealed that Drs B2 can interact with the tumor cell surface, aggregate and penetrate the cells. These data together indicate that Drs B2 does not act by apoptosis but possibly by necrosis. In conclusion, Drs B2 could be considered as an interesting and promising pharmacological and therapeutic leader molecule for the treatment of cancer. PMID- 23028528 TI - Molecular characterization of circulating plasma cells in patients with active systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a generalized autoimmune disease characterized by abnormal B cell activation and the occurrence of increased frequencies of circulating plasma cells (PC). The molecular characteristics and nature of circulating PC and B cells in SLE have not been completely characterized. Microarray analysis of gene expression was used to characterize circulating PC in subjects with active SLE. Flow cytometry was used to sort PC and comparator B cell populations from active SLE blood, normal blood and normal tonsil. The gene expression profiles of the sorted B cell populations were then compared. SLE PC exhibited a similar gene expression signature as tonsil PC. The differences in gene expression between SLE PC and normal tonsil PC and tonsil plasmablasts (PB) suggest a mature Ig secreting cell phenotype in the former population. Despite this, SLE PC differed in expression of about half the genes from previously published gene expression profiles of normal bone marrow PC, indicating that these cells had not achieved a fully mature status. Abnormal expression of several genes, including CXCR4 and S1P(1), suggests a mechanism for the persistence of SLE PC in the circulation. All SLE B cell populations revealed an interferon (IFN) gene signature previously only reported in unseparated SLE peripheral blood mononuclear cells. These data indicate that SLE PC are a unique population of Ig secreting cells with a gene expression profile indicative of a mature, but not fully differentiated phenotype. PMID- 23028529 TI - Interferon-gamma induced by in vitro re-stimulation of CD4+ T-cells correlates with in vivo FMD vaccine induced protection of cattle against disease and persistent infection. AB - The immune defense against FMDV has been correlated to the antibody mediated component. However, there are occasions when some animals with high virus neutralising (VN) antibody are not protected following challenge and some with low neutralising antibody which do not succumb to disease. The importance of cell mediated immunity in clinical protection is less clear and so we investigated the source and production of interferon-gamma (IFN-gamma) in re-stimulated whole blood of FMDV immunized cattle and its correlation to vaccine induced protection and FMDV persistence. We were able to show a positive correlation between IFN gamma response and vaccine induced protection as well as reduction of long term persistence of FMD virus. When combining this IFN-gamma response in re-stimulated blood with virus neutralizing antibody titer in serum on the day of challenge, a better correlation of vaccine-induced protection with IFN-gamma and VN antibody was predicted. Our investigations also showed that CD4+ T-cells are the major proliferating phenotype and IFN-gamma producing cells. PMID- 23028530 TI - MRN1 implicates chromatin remodeling complexes and architectural factors in mRNA maturation. AB - A functional relationship between chromatin structure and mRNA processing events has been suggested, however, so far only a few involved factors have been characterized. Here we show that rsc nhp6DeltaDelta mutants, deficient for the function of the chromatin remodeling factor RSC and the chromatin architectural proteins Nhp6A/Nhp6B, accumulate intron-containing pre-mRNA at the restrictive temperature. In addition, we demonstrate that rsc8-ts16 nhp6DeltaDelta cells contain low levels of U6 snRNA and U4/U6 di-snRNA that is further exacerbated after two hours growth at the restrictive temperature. This change in U6 snRNA and U4/U6 di-snRNA levels in rsc8-ts16 nhp6DeltaDelta cells is indicative of splicing deficient conditions. We identify MRN1 (multi-copy suppressor of rsc nhp6DeltaDelta) as a growth suppressor of rsc nhp6DeltaDelta synthetic sickness. Mrn1 is an RNA binding protein that localizes both to the nucleus and cytoplasm. Genetic interactions are observed between 2 um-MRN1 and the splicing deficient mutants snt309Delta, prp3, prp4, and prp22, and additional genetic analyses link MRN1, SNT309, NHP6A/B, SWI/SNF, and RSC supporting the notion of a role of chromatin structure in mRNA processing. PMID- 23028531 TI - Effects of fiber type and size on the heterogeneity of oxygen distribution in exercising skeletal muscle. AB - The process of oxygen delivery from capillary to muscle fiber is essential for a tissue with variable oxygen demand, such as skeletal muscle. Oxygen distribution in exercising skeletal muscle is regulated by convective oxygen transport in the blood vessels, oxygen diffusion and consumption in the tissue. Spatial heterogeneities in oxygen supply, such as microvascular architecture and hemodynamic variables, had been observed experimentally and their marked effects on oxygen exchange had been confirmed using mathematical models. In this study, we investigate the effects of heterogeneities in oxygen demand on tissue oxygenation distribution using a multiscale oxygen transport model. Muscles are composed of different ratios of the various fiber types. Each fiber type has characteristic values of several parameters, including fiber size, oxygen consumption, myoglobin concentration, and oxygen diffusivity. Using experimentally measured parameters for different fiber types and applying them to the rat extensor digitorum longus muscle, we evaluated the effects of heterogeneous fiber size and fiber type properties on the oxygen distribution profile. Our simulation results suggest a marked increase in spatial heterogeneity of oxygen due to fiber size distribution in a mixed muscle. Our simulations also suggest that the combined effects of fiber type properties, except size, do not contribute significantly to the tissue oxygen spatial heterogeneity. However, the incorporation of the difference in oxygen consumption rates of different fiber types alone causes higher oxygen heterogeneity compared to control cases with uniform fiber properties. In contrast, incorporating variation in other fiber type-specific properties, such as myoglobin concentration, causes little change in spatial tissue oxygenation profiles. PMID- 23028534 TI - Unexpected demography in the recovery of an endangered primate population. AB - Assessments of the status of endangered species have focused on population sizes, often without knowledge of demographic and behavioral processes underlying population recovery. We analyzed demographic data from a 28-year study of a critically endangered primate, the northern muriqui, to investigate possible changes in demographic rates as this population recovered from near extirpation. As the population increased from 60 to nearly 300 individuals, its growth rate declined due to increased mortality and male-biased birth sex ratios; the increased mortality was not uniform across ages and sexes, and there has been a recent increase in mortality of prime-aged males. If not for a concurrent increase in fertility rates, the population would have stabilized at 200 individuals instead of continuing to grow. The unexpected increase in fertility rates and in adult male mortality can be attributed to the muriquis' expansion of their habitat by spending more time on the ground. The demographic consequences of this behavioral shift must be incorporated into management tactics for this population and emphasize the importance of understanding demographic rates in the recovery of endangered species. PMID- 23028532 TI - Obese rats exhibit high levels of fat necrosis and isoprostanes in taurocholate induced acute pancreatitis. AB - BACKGROUND: Obesity is a prognostic factor for severity in acute pancreatitis in humans. Our aim was to assess the role of oxidative stress and abdominal fat in the increased severity of acute pancreatitis in obese rats. METHODOLOGY: Taurocholate-induced acute pancreatitis was performed in lean and obese Zucker rats. Levels of reduced glutathione, oxidized glutathione, L-cysteine, cystine, and S-adenosylmethionine were measured in pancreas as well as the activities of serine/threonine protein phosphatases PP1 and PP2A and tyrosin phosphatases. Isoprostane, malondialdehyde, triglyceride, and free fatty acid levels and lipase activity were measured in plasma and ascites. Lipase activity was measured in white adipose tissue with and without necrosis and confirmed by western blotting. FINDINGS: Under basal conditions obese rats exhibited lower reduced glutathione levels in pancreas and higher triglyceride and free fatty acid levels in plasma than lean rats. S-adenosyl methionine levels were markedly increased in pancreas of obese rats. Acute pancreatitis in obese rats led to glutathione oxidation and lower reduced glutathione levels in pancreas together with decreased activities of redox-sensitive phosphatases PP1, and PP2A. S-adenosyl methionine levels decreased but cystine levels increased markedly in pancreas upon pancreatitis. Acute pancreatitis triggered an increase in isoprostane levels in plasma and ascites in obese rats. Free fatty acid levels were extremely high in pancreatitis associated ascitic fluid from obese rats and lipase was bound with great affinity to white adipose tissue, especially to areas of necrosis. CONCLUSIONS: Our results show that oxidative stress occurs locally and systemically in obese rats with pancreatitis favouring inactivation of protein phosphatases in pancreas, which would promote up-regulation of pro-inflammatory cytokines, and the increase of isoprostanes which might cause powerful pulmonary and renal vasoconstriction. Future studies are needed to confirm the translational relevance of the present findings obtained in a rat model of taurocholate-induced pancreatic damage and necrosis. PMID- 23028533 TI - Pyrosequencing-based analysis of the microbiome associated with the horn fly, Haematobia irritans. AB - The horn fly, Haematobia irritans, is one of the most economically important pests of cattle. Insecticides have been a major element of horn fly management programs. Growing concerns with insecticide resistance, insecticide residues on farm products, and non-availability of new generation insecticides, are serious issues for the livestock industry. Alternative horn fly control methods offer the promise to decrease the use of insecticides and reduce the amount of insecticide residues on livestock products and give an impetus to the organic livestock farming segment. The horn fly, an obligatory blood feeder, requires the help of microflora to supply additional nutrients and metabolize the blood meal. Recent advancements in DNA sequencing methodologies enable researchers to examine the microflora diversity independent of culture methods. We used the bacterial 16S tag-encoded FLX-titanium amplicon pyrosequencing (bTEFAP) method to carry out the classification analysis of bacterial flora in adult female and male horn flies and horn fly eggs. The bTEFAP method identified 16S rDNA sequences in our samples which allowed the identification of various prokaryotic taxa associated with the life stage examined. This is the first comprehensive report of bacterial flora associated with the horn fly using a culture-independent method. Several rumen, environmental, symbiotic and pathogenic bacteria associated with the horn fly were identified and quantified. This is the first report of the presence of Wolbachia in horn flies of USA origin and is the first report of the presence of Rikenella in an obligatory blood feeding insect. PMID- 23028535 TI - Transcriptional analysis of prebiotic uptake and catabolism by Lactobacillus acidophilus NCFM. AB - The human gastrointestinal tract can be positively modulated by dietary supplementation of probiotic bacteria in combination with prebiotic carbohydrates. Here differential transcriptomics and functional genomics were used to identify genes in Lactobacillus acidophilus NCFM involved in the uptake and catabolism of 11 potential prebiotic compounds consisting of alpha- and beta linked galactosides and glucosides. These oligosaccharides induced genes encoding phosphoenolpyruvate-dependent sugar phosphotransferase systems (PTS), galactoside pentose hexuronide (GPH) permease, and ATP-binding cassette (ABC) transporters. PTS systems were upregulated primarily by di- and tri-saccharides such as cellobiose, isomaltose, isomaltulose, panose and gentiobiose, while ABC transporters were upregulated by raffinose, Polydextrose, and stachyose. A single GPH transporter was induced by lactitol and galactooligosaccharides (GOS). The various transporters were associated with a number of glycoside hydrolases from families 1, 2, 4, 13, 32, 36, 42, and 65, involved in the catabolism of various alpha- and beta-linked glucosides and galactosides. Further subfamily specialization was also observed for different PTS-associated GH1 6-phospho-beta glucosidases implicated in the catabolism of gentiobiose and cellobiose. These findings highlight the broad oligosaccharide metabolic repertoire of L. acidophilus NCFM and establish a platform for selection and screening of both probiotic bacteria and prebiotic compounds that may positively influence the gastrointestinal microbiota. PMID- 23028537 TI - Combined micro-PET/micro-CT imaging of lung tumours in SPC-raf and SPC-myc transgenic mice. AB - INTRODUCTION: SPC-raf and SPC-myc transgenic mice develop disseminated and circumscribed lung adenocarcinoma respectively, allowing for assessment of carcinogenesis and treatment strategies. The purpose of this study was to investigate the technical feasibility, the correlation of initial findings to histology and the administered radiation dose of combined micro-PET/micro-CT in these animal models. MATERIAL AND METHODS: 14 C57BL/6 mice (4 nontransgenic, 4 SPC-raf transgenic, 6 SPC-myc transgenic) were examined using micro-CT and (18)F Fluoro-deoxyglucose micro-PET in-vivo. Micro-PET data was corrected for random events and scatter prior to reconstruction with a 3D-FORE/2D-OSEM iterative algorithm. Rigid micro-PET/micro-CT registration was performed. Tumour-to-non tumour ratios were calculated for different lung regions and focal lesions. Diffuse tumour growth was quantified using a semiautomated micro-CT segmentation routine reported earlier. Regional histologic tumour load was assessed using a 4 point rating scale. Gamma radiation dose was determined using thermoluminescence dosimeters. RESULTS: Micro-CT allowed visualisation of diffuse and circumscribed tumours in SPC-raf and SPC-myc transgenic animals along with morphology, while micro-PET provided information on metabolism, but lacked morphologic detail. Mean tumour-to-non-tumour ratio was 2.47 for circumscribed lesions. No significant correlation could be shown between histological tumour load and tumour-to nontumour ratio for diffuse tumours in SPC-raf transgenic animals. Calculation of the expected dose based on gamma dosimetry yielded approximately 140 mGy/micro PET examination additional to approximately 200 mGy due to micro-CT. CONCLUSIONS: Combined micro-PET/micro-CT imaging allows for in-vivo assessment of lung tumours in SPC-raf and SPC-myc transgenic mice. The technique has potential for the evaluation of carcinogenesis and treatment strategies in circumscribed lung tumours. PMID- 23028536 TI - Age-related changes in task related functional network connectivity. AB - Aging has a multi-faceted impact on brain structure, brain function and cognitive task performance, but the interaction of these different age-related changes is largely unexplored. We hypothesize that age-related structural changes alter the functional connectivity within the brain, resulting in altered task performance during cognitive challenges. In this neuroimaging study, we used independent components analysis to identify spatial patterns of coordinated functional activity involved in the performance of a verbal delayed item recognition task from 75 healthy young and 37 healthy old adults. Strength of functional connectivity between spatial components was assessed for age group differences and related to speeded task performance. We then assessed whether age-related differences in global brain volume were associated with age-related differences in functional network connectivity. Both age groups used a series of spatial components during the verbal working memory task and the strength and distribution of functional network connectivity between these components differed across the age groups. Poorer task performance, i.e. slower speed with increasing memory load, in the old adults was associated with decreases in functional network connectivity between components comprised of the supplementary motor area and the middle cingulate and between the precuneus and the middle/superior frontal cortex. Advancing age also led to decreased brain volume; however, there was no evidence to support the hypothesis that age-related alterations in functional network connectivity were the result of global brain volume changes. These results suggest that age-related differences in the coordination of neural activity between brain regions partially underlie differences in cognitive performance. PMID- 23028539 TI - Structural design principles of complex bird songs: a network-based approach. AB - Bird songs are acoustic communication signals primarily used in male-male aggression and in male-female attraction. These are often monotonous patterns composed of a few phrases, yet some birds have extremely complex songs with a large phrase repertoire, organized in non-random fashion with discernible patterns. Since structure is typically associated with function, the structures of complex bird songs provide important clues to the evolution of animal communication systems. Here we propose an efficient network-based approach to explore structural design principles of complex bird songs, in which the song networks--transition relationships among different phrases and the related structural measures--are employed. We demonstrate how this approach works with an example using California Thrasher songs, which are sequences of highly varied phrases delivered in succession over several minutes. These songs display two distinct features: a large phrase repertoire with a 'small-world' architecture, in which subsets of phrases are highly grouped and linked with a short average path length; and a balanced transition diversity amongst phrases, in which deterministic and non-deterministic transition patterns are moderately mixed. We explore the robustness of this approach with variations in sample size and the amount of noise. Our approach enables a more quantitative study of global and local structural properties of complex bird songs than has been possible to date. PMID- 23028538 TI - Molecular interrogation of the feeding behaviour of field captured individual insects for interpretation of multiple host plant use. AB - The way in which herbivorous insect individuals use multiple host species is difficult to quantify under field conditions, but critical to understanding the evolutionary processes underpinning insect-host plant relationships. In this study we developed a novel approach to understanding the host plant interactions of the green mirid, Creontiades dilutus, a highly motile heteropteran bug that has been associated with many plant species. We combine quantified sampling of the insect across its various host plant species within particular sites and a molecular comparison between the insects' gut contents and available host plants. This approach allows inferences to be made as to the plants fed upon by individual insects in the field. Quantified sampling shows that this "generalist" species is consistently more abundant on two species in the genus Cullen (Fabaceae), its primary host species, than on any other of its numerous listed hosts. The chloroplast intergenic sequences reveal that C. dilutus frequently feeds on plants additional to the one from which it was collected, even when individuals were sampled from the primary host species. These data may be reconciled by viewing multiple host use in this species as an adaptation to survive spatiotemporally ephemeral habitats. The methodological framework developed here provides a basis from which new insights into the feeding behaviour and host plant relationships of herbivorous insects can be derived, which will benefit not only ecological interpretation but also our understanding of the evolution of these relationships. PMID- 23028540 TI - Minimizing manual image segmentation turn-around time for neuronal reconstruction by embracing uncertainty. AB - The ability to automatically segment an image into distinct regions is a critical aspect in many visual processing applications. Because inaccuracies often exist in automatic segmentation, manual segmentation is necessary in some application domains to correct mistakes, such as required in the reconstruction of neuronal processes from microscopic images. The goal of the automated segmentation tool is traditionally to produce the highest-quality segmentation, where quality is measured by the similarity to actual ground truth, so as to minimize the volume of manual correction necessary. Manual correction is generally orders-of magnitude more time consuming than automated segmentation, often making handling large images intractable. Therefore, we propose a more relevant goal: minimizing the turn-around time of automated/manual segmentation while attaining a level of similarity with ground truth. It is not always necessary to inspect every aspect of an image to generate a useful segmentation. As such, we propose a strategy to guide manual segmentation to the most uncertain parts of segmentation. Our contributions include 1) a probabilistic measure that evaluates segmentation without ground truth and 2) a methodology that leverages these probabilistic measures to significantly reduce manual correction while maintaining segmentation quality. PMID- 23028542 TI - Control centrality and hierarchical structure in complex networks. AB - We introduce the concept of control centrality to quantify the ability of a single node to control a directed weighted network. We calculate the distribution of control centrality for several real networks and find that it is mainly determined by the network's degree distribution. We show that in a directed network without loops the control centrality of a node is uniquely determined by its layer index or topological position in the underlying hierarchical structure of the network. Inspired by the deep relation between control centrality and hierarchical structure in a general directed network, we design an efficient attack strategy against the controllability of malicious networks. PMID- 23028541 TI - Aqueous cytokine changes associated with Posner-Schlossman syndrome with and without human cytomegalovirus. AB - AIM: To study the differences in aqueous cytokines in Posner-Schlossman Syndrome (PSS) patients with and without human cytomegalovirus (CMV) DNA in the aqueous humor. METHODS: This is a prospective study. Fifty-three uveitis patients with clinical signs of PSS were enrolled and aqueous humor samples were collected. Fourteen PSS patients were positive of CMV DNA in the aqueous by polymerase chain reaction (PCR) analysis. These eyes were negative of common ocular pathogens such as herpes simplex virus, varicella-zoster virus, rubella virus and toxoplasma. Twenty-five otherwise healthy cataract patients were enrolled as controls. Cytokine concentration was measured by a magnetic color-bead-based multiplex assay and analyzed using statistical and classification approaches. RESULTS: The average age of 53 PSS patients was 48.74+/-13.43 years (yrs) (mean +/- standard deviation) and 66.3+/-15.0 yrs for the controls. The median CMV viral DNA copy number was 26000/mL aqueous (range 1400 to 85000 copies/mL) in 14 CMV positive patients as determined by quantitative PCR. PSS aqueous had significantly higher Interleukin (IL)-8 (CXCL8), monocyte chemotactic protein-1 (CCL2), macrophage inhibitory protein 1-beta (CCL4), granulocyte colony-stimulating factor (GCSF) and transforming growth factor-beta (TGF-beta) levels than controls after adjusted by age and gender. IL-2, IL-12, tumor necrosis factor-alpha (TNF-alpha) and interferon-alpha (IFN-alpha) levels were significantly lower in PSS aqueous than controls. No difference between CMV positive PSS and CMV negative PSS aqueous was observed. Over 97% of PSS samples were distinguished from controls by elevated CXCL10 (>500 ng/mL), CXCL8 (>30 ng/mL) and CCL2 (>60 ng/mL) levels. CONCLUSION: PSS eyes were characterized by elevated aqueous chemokine concentration. The presence of CMV viral DNA was not associated with significant change of the type of cytokine expression in PSS patients. PMID- 23028543 TI - LabPush: a pilot study of providing remote clinics with laboratory results via short message service (SMS) in Swaziland, Africa. AB - BACKGROUND: Turnaround time (TAT) is an important indicator of laboratory performance. It is often difficult to achieve fast TAT for blood tests conducted at clinics in developing countries. This is because clinics where the patient is treated are often far away from the laboratory, and transporting blood samples and test results between the two locations creates significant delay. Recent efforts have sought to mitigate this problem by using Short Message Service (SMS) to reduce TAT. Studies reporting the impact of this technique have not been published in scientific literature however. In this paper we present a study of LabPush, a system developed to test whether SMS delivery of HIV related laboratory results to clinics could shorten TAT time significantly. METHOD: LapPush was implemented in six clinics of the Kingdom of Swaziland. SMS results were sent out from the laboratory as a supplement to normal transport of paper results. Each clinic was equipped with a mobile phone to receive SMS results. The laboratory that processes the blood tests was equipped with a system for digital input of results, and transmission of results via SMS to the clinics. RESULTS: Laboratory results were received for 1041 different clinical cases. The total number of SMS records received (1032) was higher than that of paper records (965), indicating a higher loss rate for paper records. A statistical comparison of TAT for SMS and paper reports indicates a statistically significant improvement for SMS. Results were more positive for more rural clinics, and an urban clinic with high workload. CONCLUSION: SMS can be used to reduce TAT for blood tests taken at clinics in developing countries. Benefits are likely to be greater at clinics that are further away from laboratories, due to the difficulties this imposes on transport of paper records. PMID- 23028544 TI - Characterization and robust classification of EEG signal from image RSVP events with independent time-frequency features. AB - This paper considers the problem of automatic characterization and detection of target images in a rapid serial visual presentation (RSVP) task based on EEG data. A novel method that aims to identify single-trial event-related potentials (ERPs) in time-frequency is proposed, and a robust classifier with feature clustering is developed to better utilize the correlated ERP features. The method is applied to EEG recordings of a RSVP experiment with multiple sessions and subjects.The results show that the target image events are mainly characterized by 3 distinct patterns in the time-frequency domain, i.e., a theta band (4.3 Hz) power boosting 300-700 ms after the target image onset, an alpha band (12 Hz) power boosting 500-1000 ms after the stimulus onset, and a delta band (2 Hz) power boosting after 500 ms. The most discriminant time-frequency features are power boosting and are relatively consistent among multiple sessions and subjects.Since the original discriminant time-frequency features are highly correlated, we constructed the uncorrelated features using hierarchical clustering for better classification of target and non-target images. With feature clustering, performance (area under ROC) improved from 0.85 to 0.89 on within-session tests, and from 0.76 to 0.84 on cross-subject tests. The constructed uncorrelated features were more robust than the original discriminant features and corresponded to a number of local regions on the time-frequency plane. AVAILABILITY: The data and code are available at: http://compgenomics.cbi.utsa.edu/rsvp/index.html. PMID- 23028545 TI - Association between one-hour post-load plasma glucose levels and vascular stiffness in essential hypertension. AB - OBJECTIVES: Pulse wave velocity (PWV) is a surrogate end-point for cardiovascular morbidity and mortality. A plasma glucose value >=155 mg/dl for the 1-hour post load plasma glucose during an oral glucose tolerance test (OGTT) is able to identify subjects with normal glucose tolerance (NGT) at high-risk for type-2 diabetes (T2D) and for subclinical organ damage. Thus, we addressed the question if 1-hour post-load plasma glucose levels, affects PWV and its central hemodynamic correlates, as augmentation pressure (AP) and augmentation index (AI). METHODS: We enrolled 584 newly diagnosed hypertensives. All patients underwent OGTT and measurements of PWV, AP and AI. Insulin sensitivity was assessed by Matsuda-index. RESULTS: Among participants, 424 were NGT and 160 had impaired glucose tolerance (IGT). Of 424 NGT, 278 had 1-h post-load plasma glucose <155 mg/dl (NGT<155) and 146 had 1-h post-load plasma glucose >=155 mg/dl (NGT>=155). NGT>=155 had a worse insulin sensitivity and higher hs-CRP than NGT<155, similar to IGT subjects. In addition, NGT >=155 in comparison with NGT<155 had higher central systolic blood pressure (134+/-12 vs 131+/-10 mmHg), as well as PWV (8.4+/-3.7 vs 6.7+/-1.7 m/s), AP (12.5+/-7.1 vs 9.8+/-5.7 mmHg) and AI (29.4+/-11.9 vs 25.1+/-12.4%), and similar to IGT. At multiple regression analysis, 1-h post-load plasma glucose resulted the major determinant of all indices of vascular stiffness. CONCLUSION: Hypertensive NGT>=155 subjects, compared with NGT<155, have higher PWV and its hemodynamic correlates that increase their cardiovascular risk profile. PMID- 23028546 TI - FragIt: a tool to prepare input files for fragment based quantum chemical calculations. AB - Near linear scaling fragment based quantum chemical calculations are becoming increasingly popular for treating large systems with high accuracy and is an active field of research. However, it remains difficult to set up these calculations without expert knowledge. To facilitate the use of such methods, software tools need to be available to support these methods and help to set up reasonable input files which will lower the barrier of entry for usage by non experts. Previous tools relies on specific annotations in structure files for automatic and successful fragmentation such as residues in PDB files. We present a general fragmentation methodology and accompanying tools called FragIt to help setup these calculations. FragIt uses the SMARTS language to locate chemically appropriate fragments in large structures and is applicable to fragmentation of any molecular system given suitable SMARTS patterns. We present SMARTS patterns of fragmentation for proteins, DNA and polysaccharides, specifically for D galactopyranose for use in cyclodextrins. FragIt is used to prepare input files for the Fragment Molecular Orbital method in the GAMESS program package, but can be extended to other computational methods easily. PMID- 23028547 TI - An IL12-IL2-antibody fusion protein targeting Hodgkin's lymphoma cells potentiates activation of NK and T cells for an anti-tumor attack. AB - Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30(+) Hodgkin/Reed Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-gamma and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer. PMID- 23028548 TI - An early reduction in Treg cells correlates with enhanced local inflammation in cutaneous leishmaniasis in CCR6-deficient mice. AB - Resistance to Leishmania major infection is dependent on the development of a cell-mediated Th1 immune response in resistant C57BL/6 mice whereas Th2-prone BALB/c mice develop non-healing lesions after infection. The chemokine receptor CCR6 is shared by anti-inflammatory regulatory T cells and pro-inflammatory Th17 cells. In a recent study we showed that C57BL/6 mice deficient in CCR6 exhibited enhanced footpad swelling and impaired T helper cell migration indicated by reduced recruitment of total T helper cells into the skin after infection and a reduced delayed type hypersensitivity reaction. Based on these findings we tested whether the lack of CCR6 alters Treg or Th17 cell responses during the course of Leishmania major infection. When we analyzed T cell subsets in the lymph nodes of CCR6-deficient mice, Th17 cell numbers were not different. However, reduced numbers of Treg cells paralleled with a stronger IFNgamma response. Furthermore, the early increase in IFNgamma-producing cells correlated with increased local tissue inflammation at later time points. Our data indicate an important role of CCR6 for Treg cells and a redundant role for Th17 cells in a Th1 cell-driven anti parasitic immune response against Leishmania major parasites in resistant C57BL/6 mice. PMID- 23028549 TI - Limit allogeneic blood use with routine re-use of patient's own blood: a prospective, randomized, controlled trial in total hip surgery. AB - BACKGROUND: There are risks related to blood incompatibility and blood-borne diseases when using allogeneic blood transfusion. Several alternatives exist today, one of which, used for autologous blood salvage perioperatively, is the Sangvia Blood Management System. This study was designed to investigate the efficacy of the system and to add data to previously reported safety results. METHODOLOGY/PRINCIPAL FINDINGS: Two hundred sixteen patients undergoing primary or revision total hip arthroplasty (THA) were enrolled in this randomized, controlled, assessor-blinded multicenter study. Randomization was either autologous blood transfusion (Sangvia group) or no use of autologous blood (Control group), both in combination with a transfusion protocol for allogeneic transfusion. Patients were followed during hospital stay and at two months after discharge. The primary outcome was allogeneic blood transfusion frequency. Data on blood loss, postoperative hemoglobin/hematocrit, safety and quality of life were also collected. The effectiveness analysis including all patients showed an allogeneic blood transfusion rate of 14% in both groups. The efficacy analysis included 197 patients and showed a transfusion rate of 9% in the Sangvia group as compared to 13% in the Control group (95%CI -0.05-0.12, p = 0.5016). A mean of 522 mL autologous blood was returned in the Sangvia group and lower calculated blood loss was seen. 1095 mL vs 1285 mL in the Control group (95%CI 31-346, p = 0.0175). No differences in postoperative hemoglobin was detected but a lower hematocrit reduction after surgery was seen among patients receiving autologous blood. No relevant differences were found for safety parameters or quality of life. CONCLUSIONS/SIGNIFICANCE: General low use of allogeneic blood in THA is seen in the current study of the Sangvia system used together with a transfusion protocol. The trial setting is under-powered due to premature termination and therefore not able to verify efficacy for the system itself but contributes with descriptive data on safety. TRIAL REGISTRATION: Clinicaltrials.gov NCT00822588. PMID- 23028550 TI - Effect of different fertilizer application on the soil fertility of paddy soils in red soil region of southern China. AB - Appropriate fertilizer application is an important management practice to improve soil fertility and quality in the red soil regions of China. In the present study, we examined the effects of five fertilization treatments [these were: no fertilizer (CK), rice straw return (SR), chemical fertilizer (NPK), organic manure (OM) and green manure (GM)] on soil pH, soil organic carbon (SOC), total nitrogen (TN), C/N ratio and available nutrients (AN, AP and AK) contents in the plowed layer (0-20 cm) of paddy soil from 1998 to 2009 in Jiangxi Province, southern China. Results showed that the soil pH was the lowest with an average of 5.33 units in CK and was significantly higher in NPK (5.89 units) and OM (5.63 units) treatments (P<0.05). The application of fertilizers have remarkably improved SOC and TN values compared with the CK, Specifically, the OM treatment resulted in the highest SOC and TN concentrations (72.5% and 51.2% higher than CK) and NPK treatment increased the SOC and TN contents by 22.0% and 17.8% compared with CK. The average amounts of C/N ratio ranged from 9.66 to 10.98 in different treatments, and reached the highest in OM treatment (P<0.05). During the experimental period, the average AN and AP contents were highest in OM treatment (about 1.6 and 29.6 times of that in the CK, respectively) and second highest in NPK treatment (about 1.2 and 20.3 times of that in the CK). Unlike AN and AP, the highest value of AK content was observed in NPK treatments with 38.10 mg.kg(-1). Thus, these indicated that organic manure should be recommended to improve soil fertility in this region and K fertilizer should be simultaneously applied considering the soil K contents. Considering the long-term fertilizer efficiency, our results also suggest that annual straw returning application could improve soil fertility in this trial region. PMID- 23028551 TI - Comparing deep-sea fish fauna between coral and non-coral "megahabitats" in the Santa Maria di Leuca cold-water coral province (Mediterranean Sea). AB - Two experimental longline surveys were carried out in the Santa Maria di Leuca (SML) cold-water coral province (Mediterranean Sea) during May-June and September October 2010 to investigate the effect of corals on fish assemblages. Two types of "megahabitat" characterized by the virtual absence of fishing were explored. One was characterized by complex topography including mesohabitats with carbonate mounds and corals. The other type of megahabitat, although characterized by complex topographic features, lacks carbonate mounds and corals. The fishing vessel was equipped with a 3,000 m monofilament longline with 500 hooks and snoods of 2.5 m in length. A total of 9 hauls, using about 4,500 hooks, were carried out both in the coral megahabitat and in the non-coral megahabitat during each survey. The fish Leucoraja fullonica and Pteroplatytrygon violacea represent new records for the SML coral province. The coral by-catch was only obtained in the coral megahabitat in about 55% of the stations investigated in both surveys. The total catches and the abundance indices of several species were comparable between the two habitat typologies. The species contributing most to the dissimilarity between the two megahabitat fish assemblages were Pagellus bogaraveo, Galeus melastomus, Etmopterus spinax and Helicolenus dactylopterus for density and P. bogaraveo, Conger conger, Polyprion americanus and G. melastomus for biomass. P. bogaraveo was exclusively collected in the coral megahabitat, whereas C. conger, H. dactylopterus and P. americanus were found with greater abundance in the coral than in the non-coral megahabitat. Differences in the sizes between the two megahabitats were detected in E. spinax, G. melastomus, C. conger and H. dactylopterus. Although these differences most probably related to the presence-absence of corals, both megahabitats investigated play the role of attraction-refuge for deep-sea fish fauna, confirming the important role of the whole SML coral province as a refuge area from fishing. PMID- 23028552 TI - Using networks to understand medical data: the case of Class III malocclusions. AB - A system of elements that interact or regulate each other can be represented by a mathematical object called a network. While network analysis has been successfully applied to high-throughput biological systems, less has been done regarding their application in more applied fields of medicine; here we show an application based on standard medical diagnostic data. We apply network analysis to Class III malocclusion, one of the most difficult to understand and treat orofacial anomaly. We hypothesize that different interactions of the skeletal components can contribute to pathological disequilibrium; in order to test this hypothesis, we apply network analysis to 532 Class III young female patients. The topology of the Class III malocclusion obtained by network analysis shows a strong co-occurrence of abnormal skeletal features. The pattern of these occurrences influences the vertical and horizontal balance of disharmony in skeletal form and position. Patients with more unbalanced orthodontic phenotypes show preponderance of the pathological skeletal nodes and minor relevance of adaptive dentoalveolar equilibrating nodes. Furthermore, by applying Power Graphs analysis we identify some functional modules among orthodontic nodes. These modules correspond to groups of tightly inter-related features and presumably constitute the key regulators of plasticity and the sites of unbalance of the growing dentofacial Class III system. The data of the present study show that, in their most basic abstraction level, the orofacial characteristics can be represented as graphs using nodes to represent orthodontic characteristics, and edges to represent their various types of interactions. The applications of this mathematical model could improve the interpretation of the quantitative, patient specific information, and help to better targeting therapy. Last but not least, the methodology we have applied in analyzing orthodontic features can be applied easily to other fields of the medical science. PMID- 23028553 TI - Excess body mass index and risk of liver cancer: a nonlinear dose-response meta analysis of prospective studies. AB - BACKGROUND: Excess body weight measured as body mass index (BMI) has a positive association with risk of common cancers. However, previous meta-analyses related to BMI and liver cancer had inconsistent results. The purpose of the current study is to establish a nonlinear dose-response relationship between BMI and incidence risk of liver cancer. METHODS: A systematic literature search for relevant articles published from 1966 to November 2011 was conducted in PUBMED and EMBASE digital databases. Additional articles were manually searched by using the reference lists of identified papers. Restricted cubic splines and generalized least-squares regression methods were used to model a potential curvilinear relationship and to make a dose-response meta-analysis. Stratified analysis, sensitivity analysis and assessment of bias were performed in our meta analysis. RESULTS: 8 articles including 1,779,471 cohort individuals were brought into meta-analysis. A non-linear dose-response association between BMI and risk of liver cancer was visually significant (P for nonlinearity<0.001), besides, the point value of BMI also enhanced the results quantitatively, where relative risks were 1.02 (95%CI = 1.02-1.03), 1.35 (95%CI = 1.24-1.47) and 2.22-fold (95%CI = 1.74-2.83) when BMI was at the point of 25, 30 and 35 kg/m(2) compared with reference (the median value of the lowest category), respectively. The ethnicity of the population was found as the main source of heterogeneity. In subsequent stratified analysis, no evidence of heterogeneity was showed in Asian and White populations (P for heterogeneity>0.1), and all value of BMI still presented significantly increased risk of cancer. CONCLUSIONS: The findings from meta analysis provided that excess BMI had significant increased association with risk of liver cancer, although the biological mechanisms underlying the obesity-cancer link still need to be clarified. PMID- 23028554 TI - Developmental pathways of Psammotermes hybostoma (Isoptera: Rhinotermitidae): old pseudergates make up a new sterile caste. AB - BACKGROUND: Ergonomic efficiency is in termites maximized by task partitioning among specialized castes. The isopteran caste systems can be classified as either (i) linear, when tasks are performed by pluripotent immatures (pseudergates), retaining the ability to develop into winged imagoes or (ii) bifurcated, with the presence of a true worker caste, which diverges early and permanently from the sexual (nymph/alate) line. PRINCIPAL FINDINGS: Here, we report on the ontogenetic potentialities of the highly polymorphic sand termite Psammotermes hybostoma. Beside numerous pluripotent pseudergates, constituting the main work force, some larger non-feeding apterous immatures, also occur. These individuals are unable to proceed to the winged imago stage, but store large amounts of fat and also give rise to large soldiers. Soldiers therefore originate from a wide range of apterous instars, consequently being highly polymorphic. CONCLUSIONS: The caste system of P. hybostoma is essentially linear, as in other basal Rhinotermitidae, but is distinguished by the late bifurcation leading to large apterous immatures. Because these large worker-like individuals deviate late and do not perform worker tasks, they cannot be considered homologous to the true workers of Termitidae and advanced Rhinotermitidae, but they provide a novel example of the evolution of sterile immatures in termites. PMID- 23028555 TI - Case-control study of the etiology of infant diarrheal disease in 14 districts in Madagascar. AB - BACKGROUND: Acute diarrhea is a major cause of childhood morbidity and mortality worldwide. Its microbiological causes and clinico-epidemiological aspects were examined during the rainy seasons from 2008 to 2009 in 14 districts in Madagascar. METHODS: Stool specimens of 2196 children with acute diarrhea and 496 healthy children were collected in a community setting. Intestinal parasites were diagnosed by microscopy and bacteria by culturing methods. Rota-, astro and adenoviruses were identified using commercially available ELISA kits and rotaviruses were confirmed using reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Intestinal microorganisms were isolated from 54.6% of diarrheal patients and 45.9% of healthy subjects (p = <0.01). The most common pathogens in diarrheic patients were intestinal parasites (36.5%). Campylobacter spp. and Rotavirus were detected in 9.7% and 6.7% of diarrheic patients. The detection rates of Entamoeba histolytica, Trichomonas intestinalis and Giardia lamblia were much greater in diarrheal patients than in non diarrheal subjects (odds ratios of 5.1, 3.2, 1.7 respectively). The abundance of other enteropathogens among the non diarrheal group may indicate prolonged excretion or limited pathogenicity. CONCLUSION: In developing countries, where the lack of laboratory capacities is great, cross sectional studies of enteropathogens and their spatial distribution, including diarrheal and non diarrheal subjects, are interesting tools in order to advise regional policies on treatment and diarrheic patient management. PMID- 23028556 TI - Application of the asthma phenotype algorithm from the Severe Asthma Research Program to an urban population. AB - RATIONALE: Identification and characterization of asthma phenotypes are challenging due to disease complexity and heterogeneity. The Severe Asthma Research Program (SARP) used unsupervised cluster analysis to define 5 phenotypically distinct asthma clusters that they replicated using 3 variables in a simplified algorithm. We evaluated whether this simplified SARP algorithm could be used in a separate and diverse urban asthma population to recreate these 5 phenotypic clusters. METHODS: The SARP simplified algorithm was applied to adults with asthma recruited to the New York University/Bellevue Asthma Registry (NYUBAR) to classify patients into five groups. The clinical phenotypes were summarized and compared. RESULTS: Asthma subjects in NYUBAR (n = 471) were predominantly women (70%) and Hispanic (57%), which were demographically different from the SARP population. The clinical phenotypes of the five groups generated by the simplified SARP algorithm were distinct across groups and distributed similarly to those described for the SARP population. Groups 1 and 2 (6 and 63%, respectively) had predominantly childhood onset atopic asthma. Groups 4 and 5 (20%) were older, with the longest duration of asthma, increased symptoms and exacerbations. Group 4 subjects were the most atopic and had the highest peripheral eosinophils. Group 3 (10%) had the least atopy, but included older obese women with adult-onset asthma, and increased exacerbations. CONCLUSIONS: Application of the simplified SARP algorithm to the NYUBAR yielded groups that were phenotypically distinct and useful to characterize disease heterogeneity. Differences across NYUBAR groups support phenotypic variation and support the use of the simplified SARP algorithm for classification of asthma phenotypes in future prospective studies to investigate treatment and outcome differences between these distinct groups. TRIAL REGISTRATION: Clinicaltrials.gov NCT00212537. PMID- 23028557 TI - Gavialis from the Pleistocene of Thailand and its relevance for drainage connections from India to Java. AB - BACKGROUND: The genus Gavialis comprises a single living but endangered species, G. gangeticus, as well as fossil species recorded in the Miocene to Pleistocene deposits of the Indian subcontinent. The genus is also represented in the Pleistocene deposits of Java by the species G. bengawanicus, which was recently recognized to be valid. Surprisingly, no detailed report of the genus exists between these two provinces and the recent evolutionary history of Gavialis is not understood. METHODOLOGY/PRINCIPAL FINDINGS: We report new material consisting of skull and mandibular remains of Gavialis from the Early Pleistocene of Khok Sung, Nakhon Ratchasima Province, northeastern Thailand. The Gavialis material described herein is attributed to Gavialis cf. bengawanicus and sheds new light on the occurrence of the genus in mainland SE Asia. CONCLUSIONS/SIGNIFICANCE: Comparison of this new material with other species referred to the genus Gavialis led us to preliminary restrict the content of the genus to three species, namely G. gangeticus Gmelin, G. bengawanicus Dubois and G. lewisi Lull. The occurrence of G. cf. bengawanicus in Thailand allows us to propose a scenario for the dispersal of Gavialis from Indo-Pakistan to Indonesia, thus bridging a geographical gap between these two provinces. Dispersal by sea appears a less likely possibility than dispersal through fluvial drainages. PMID- 23028558 TI - Cross tissue trait-pathway network reveals the importance of oxidative stress and inflammation pathways in obesity-induced diabetes in mouse. AB - Complex disorders often involve dysfunctions in multiple tissue organs. Elucidating the communication among them is important to understanding disease pathophysiology. In this study we integrate multiple tissue gene expression and quantitative trait measurements of an obesity-induced diabetes mouse model, with databases of molecular interaction networks, to construct a cross tissue trait pathway network. The animals belong to two strains of mice (BTBR or B6), of two obesity status (obese or lean), and at two different ages (4 weeks and 10 weeks). Only 10 week obese BTBR animals are diabetic. The expression data was first utilized to determine the state of every pathway in each tissue, which is subsequently utilized to construct a pathway co-expression network and to define trait-relevant and trait-linking pathways. Among the six tissues profiled, the adipose contains the largest number of trait-linking pathways. Among the eight traits measured, the body weight and plasma insulin level possess the most number of relevant and linking pathways. Topological analysis of the trait-pathway network revealed that the glycolysis/gluconeogenesis pathway in liver and the insulin signaling pathway in muscle are of top importance to the information flow in the network, with the highest degrees and betweenness centralities. Interestingly, pathways related to metabolism and oxidative stress actively interact with many other pathways in all animals, whereas, among the 10 week animals, the inflammation pathways were preferentially interactive in the diabetic ones only. In summary, our method offers a systems approach to delineate disease trait relevant intra- and cross tissue pathway interactions, and provides insights to the molecular basis of the obesity-induced diabetes. PMID- 23028559 TI - Defining disease heterogeneity to guide the empirical treatment of febrile illness in resource poor settings. AB - BACKGROUND: Malaria incidence is in decline in many parts of SE Asia leading to a decreasing proportion of febrile illness that is attributable to malaria. However in the absence of rapid, affordable and accurate diagnostic tests, the non malaria causes of these illnesses cannot be reliably identified. Studies on the aetiology of febrile illness have indicated that the causes are likely to vary by geographical location within countries (i.e. be spatially heterogeneous) and that national empirical treatment policies based on the aetiology measured in a single location could lead to inappropriate treatment. METHODS: Using data from Vientiane as a reference for the incidence of major febrile illnesses in the Lao People's Democratic Republic (Laos) and estimated incidences, plausible incidence in other Lao provinces were generated using a mathematical model for a range of national and local scale variations. For a range of treatment protocols, the mean number of appropriate treatments was predicted and the potential impact of a spatially explicit national empirical treatment protocol assessed. FINDINGS: The model predicted a negative correlation between number of appropriate treatments and the level of spatial heterogeneity. A spatially explicit national treatment protocol was predicted to increase the number of appropriate treatments by 50% for intermediate levels of spatial heterogeneity. CONCLUSIONS: The results suggest that given even only moderate spatial variation, a spatially explicit treatment algorithm will result in a significant improvement in the outcome of undifferentiated fevers in Laos and other similar resource poor settings. PMID- 23028561 TI - The genomic signature of human rhinoviruses A, B and C. AB - Human rhinoviruses are single stranded positive sense RNA viruses that are presented in more than 50% of acute upper respiratory tract infections. Despite extensive studies on the genetic diversity of the virus, little is known about the forces driving it. In order to explain this diversity, many research groups have focused on protein sequence requirements for viable, functional and transmissible virus but have missed out an important aspect of viral evolution such as the genomic ontology of the virus. This study presents for the first time the genomic signature of 111 fully sequenced HRV strains from all three groups HRV-A, HRV-B and HRV-C. We observed an HRV genome tendency to eliminate CpG and UpA dinucleotides, coupling with over-representation of UpG and CpA. We propose a specific mechanism which describes how rapid changes in the HRV genomic sequence can take place under the strict control of conservation of the polypeptide backbone. Moreover, the distribution of the observed under- and over-represented dinucleotides along the HRV genome is presented. Distance matrice tables based on CpG and UpA odds ratios were constructed and viewed as heatmaps and distance trees. None of the suppressions can be attributed to codon usage or in RNA secondary structure requirements. Since viral recognition is dependent on RNA motifs rich in CpG and UpA, it is possible that the overall described genome evolution mechanism acts in order to protect the virus from host recognition. PMID- 23028560 TI - Relations between BOLD fMRI-derived resting brain activity and cerebral blood flow. AB - Consistent resting brain activity patterns have been repeatedly demonstrated using measures derived from resting BOLD fMRI data. While those metrics are presumed to reflect underlying spontaneous brain activity (SBA), it is challenging to prove that association because resting BOLD fMRI metrics are purely model-free and scale-free variables. Cerebral blood flow (CBF) is typically closely coupled to brain metabolism and is used as a surrogate marker for quantifying regional brain function, including resting function. Assessing the correlations between resting BOLD fMRI measures and CBF correlation should provide a means of linking of those measures to the underlying SBA, and a means to quantify those scale-free measures. The purpose of this paper was to examine the CBF correlations of 3 widely used neuroimaging-based SBA measures, including seed-region based functional connectivity (FC), regional homogeneity (ReHo), and amplitude of low frequency fluctuation (ALFF). Test-retest data were acquired to check the stability of potential correlations across time. Reproducible posterior cingulate cortex (PCC) FC vs regional CBF correlations were found in much of the default mode network and visual cortex. Dorsal anterior cingulate cortex (ACC) FC vs CBF correlations were consistently found in bilateral prefrontal cortex. Both ReHo and ALFF were found to be reliably correlated with CBF in most of brain cortex. None of the assessed SBA measures was correlated with whole brain mean CBF. These findings suggest that resting BOLD fMRI-derived measures are coupled with regional CBF and are therefore linked to regional SBA. PMID- 23028563 TI - At limits of life: multidisciplinary insights reveal environmental constraints on biotic diversity in continental Antarctica. AB - Multitrophic communities that maintain the functionality of the extreme Antarctic terrestrial ecosystems, while the simplest of any natural community, are still challenging our knowledge about the limits to life on earth. In this study, we describe and interpret the linkage between the diversity of different trophic level communities to the geological morphology and soil geochemistry in the remote Transantarctic Mountains (Darwin Mountains, 80 degrees S). We examined the distribution and diversity of biota (bacteria, cyanobacteria, lichens, algae, invertebrates) with respect to elevation, age of glacial drift sheets, and soil physicochemistry. Results showed an abiotic spatial gradient with respect to the diversity of the organisms across different trophic levels. More complex communities, in terms of trophic level diversity, were related to the weakly developed younger drifts (Hatherton and Britannia) with higher soil C/N ratio and lower total soluble salts content (thus lower conductivity). Our results indicate that an increase of ion concentration from younger to older drift regions drives a succession of complex to more simple communities, in terms of number of trophic levels and diversity within each group of organisms analysed. This study revealed that integrating diversity across multi-trophic levels of biotic communities with abiotic spatial heterogeneity and geological history is fundamental to understand environmental constraints influencing biological distribution in Antarctic soil ecosystems. PMID- 23028562 TI - Drosophila Ninjurin A induces nonapoptotic cell death. AB - Ninjurins are conserved transmembrane proteins that are upregulated across species in response to injury and stress. Their biological functions are not understood, in part because there have been few in vivo studies of their function. We analyzed the expression and function of one of three Drosophila Ninjurins, NijA. We found that NijA protein is redistributed to the cell surface in larval immune tissues after septic injury and is upregulated by the Toll pathway. We generated a null mutant of NijA, which displayed no detectable phenotype. In ectopic expression studies, NijA induced cell death, as evidenced by cell loss and acridine orange staining. These dying cells did not display hallmarks of apoptotic cells including TUNEL staining and inhibition by p35, indicating that NijA induced nonapoptotic cell death. In cell culture, NijA also induced cell death, which appeared to be cell autonomous. These in vivo studies identify a new role for the Ninjurin family in inducing nonapoptotic cell death. PMID- 23028564 TI - Brain-derived neurotrophic factor from bone marrow-derived cells promotes post injury repair of peripheral nerve. AB - Brain-derived neurotrophic factor (BDNF) stimulates peripheral nerve regeneration. However, the origin of BNDF and its precise effect on nerve repair have not been clarified. In this study, we examined the role of BDNF from bone marrow-derived cells (BMDCs) in post-injury nerve repair. Control and heterozygote BDNF knockout mice (BDNF+/-) received a left sciatic nerve crush using a cerebral blood clip. Especially, for the evaluation of BDNF from BMDCs, studies with bone marrow transplantation (BMT) were performed before the injury. We evaluated nerve function using a rotarod test, sciatic function index (SFI), and motor nerve conduction velocity (MNCV) simultaneously with histological nerve analyses by immunohistochemistry before and after the nerve injury until 8 weeks. BDNF production was examined by immunohistochemistry and mRNA analyses. After the nerve crush, the controls showed severe nerve dysfunction evaluated at 1 week. However, nerve function was gradually restored and reached normal levels by 8 weeks. By immunohistochemistry, BDNF expression was very faint before injury, but was dramatically increased after injury at 1 week in the distal segment from the crush site. BDNF expression was mainly co-localized with CD45 in BMDCs, which was further confirmed by the appearance of GFP-positive cells in the BMT study. Variant analysis of BDNF mRNA also confirmed this finding. BDNF+/- mice showed a loss of function with delayed histological recovery and BDNF+/+->BDNF+/- BMT mice showed complete recovery both functionally and histologically. These results suggested that the attenuated recovery of the BDNF+/- mice was rescued by the transplantation of BMCs and that BDNF from BMDCs has an essential role in nerve repair. PMID- 23028565 TI - Readthrough acetylcholinesterase is increased in human liver cirrhosis. AB - BACKGROUND & AIMS: There have been many studies on plasma butyrylcholinesterase in liver dysfunction. However, no data is available about acetylcholinesterase in human cirrhosis, although profound changes have been described in cirrhotic rat models. METHODS: Human serum and liver acetylcholinesterase and its molecular forms were determined enzymatically, after butyrylcholinesterase immunodepletion. The distinct species of acetylcholinesterase, with a distinct C-terminus, were determined by western blotting, and the level of liver transcripts by real-time PCR. Liver acetylcholinesterase was also evaluated by immunocytochemistry. RESULTS: In patients with liver cirrhosis, the activity of plasma acetylcholinesterase (rich in light species), appeared to be apparently unaffected. However, the levels of the soluble readthrough (R) acetylcholinesterase form, an acetylcholinesterase species usually associated with stress and pathology, was increased compared to controls. Human liver acetylcholinesterase activity levels were also unchanged, but protein levels of the acetylcholinesterase-R and other acetylcholinesterase subunit species were increased in the cirrhotic liver. This increase in acetylcholinesterase protein expression in the cirrhotic liver was confirmed by PCR analysis. Immunohistological examination confirmed that acetylcholinesterase immunoreactivity is increased in parenchymal cells of the cirrhotic liver. CONCLUSIONS: We demonstrate significant changes in acetylcholinesterase at the protein and mRNA levels in liver cirrhosis, with no difference in enzymatic activity. The altered expression of acetylcholinesterase protein may reflect changes in its pathophysiological role. PMID- 23028566 TI - Gene expression and physiological changes of different populations of the long lived bivalve Arctica islandica under low oxygen conditions. AB - The bivalve Arctica islandica is extremely long lived (>400 years) and can tolerate long periods of hypoxia and anoxia. European populations differ in maximum life spans (MLSP) from 40 years in the Baltic to >400 years around Iceland. Characteristic behavior of A. islandica involves phases of metabolic rate depression (MRD) during which the animals burry into the sediment for several days. During these phases the shell water oxygen concentrations reaches hypoxic to anoxic levels, which possibly support the long life span of some populations. We investigated gene regulation in A. islandica from a long-lived (MLSP 150 years) German Bight population and the short-lived Baltic Sea population, experimentally exposed to different oxygen levels. A new A. islandica transcriptome enabled the identification of genes important during hypoxia/anoxia events and, more generally, gene mining for putative stress response and (anti-) aging genes. Expression changes of a) antioxidant defense: Catalase, Glutathione peroxidase, manganese and copper-zinc Superoxide dismutase; b) oxygen sensing and general stress response: Hypoxia inducible factor alpha, Prolyl hydroxylase and Heat-shock protein 70; and c) anaerobic capacity: Malate dehydrogenase and Octopine dehydrogenase, related transcripts were investigated. Exposed to low oxygen, German Bight individuals suppressed transcription of all investigated genes, whereas Baltic Sea bivalves enhanced gene transcription under anoxic incubation (0 kPa) and, further, decreased these transcription levels again during 6 h of re-oxygenation. Hypoxic and anoxic exposure and subsequent re oxygenation in Baltic Sea animals did not lead to increased protein oxidation or induction of apoptosis, emphasizing considerable hypoxia/re-oxygenation tolerance in this species. The data suggest that the energy saving effect of MRD may not be an attribute of Baltic Sea A. islandica chronically exposed to high environmental variability (oxygenation, temperature, salinity). Contrary, higher physiological flexibility and stress hardening may predispose these animals to perform a pronounced stress response at the expense of life span. PMID- 23028568 TI - Connection between genetic and clinical data in bipolar disorder. AB - Complex diseases may be associated with combinations of changes in DNA, where the single change has little impact alone. In a previous study of patients with bipolar disorder and controls combinations of SNP genotypes were analyzed, and four large clusters of combinations were found to be significantly associated with bipolar disorder. It has now been found that these clusters may be connected to clinical data. PMID- 23028567 TI - Hepcidin regulation by BMP signaling in macrophages is lipopolysaccharide dependent. AB - Hepcidin is an antimicrobial peptide, which also negatively regulates iron in circulation by controlling iron absorption from dietary sources and iron release from macrophages. Hepcidin is synthesized mainly in the liver, where hepcidin is regulated by iron loading, inflammation and hypoxia. Recently, we have demonstrated that bone morphogenetic protein (BMP)-hemojuvelin (HJV)-SMAD signaling is central for hepcidin regulation in hepatocytes. Hepcidin is also expressed by macrophages. Studies have shown that hepcidin expression by macrophages increases following bacterial infection, and that hepcidin decreases iron release from macrophages in an autocrine and/or paracrine manner. Although previous studies have shown that lipopolysaccharide (LPS) can induce hepcidin expression in macrophages, whether hepcidin is also regulated by BMPs in macrophages is still unknown. Therefore, we examined the effects of BMP signaling on hepcidin expression in RAW 264.7 and J774 macrophage cell lines, and in primary peritoneal macrophages. We found that BMP4 or BMP6 alone did not have any effect on hepcidin expression in macrophages although they stimulated Smad1/5/8 phosphorylation and Id1 expression. In the presence of LPS, however, BMP4 and BMP6 were able to stimulate hepcidin expression in macrophages, and this stimulation was abolished by the NF-kappaB inhibitor Ro1069920. These results suggest that hepcidin expression is regulated differently in macrophages than in hepatocytes, and that BMPs regulate hepcidin expression in macrophages in a LPS NF-kappaB dependent manner. PMID- 23028569 TI - Birth timing for mountain lions (Puma concolor); testing the prey availability hypothesis. AB - We investigated potential advantages in birth timing for mountain lion (Puma concolor) cubs. We examined cub body mass, survival, and age of natal dispersal in relation to specific timing of birth. We also investigated the role of maternal age relative to timing of births. We captured mountain lion cubs while in the natal den to determine birth date, which allowed for precise estimates of the population birth pulse and age of natal dispersal. A birth pulse occurred during June-August. Body mass of cubs was related to litter size and timing of birth; heaviest cubs occurred in litters of 2, and those born after 1 July. Cubs born within pulse months exhibited similar survival to those born out of the pulse. We found that cubs born April-June dispersed at younger ages than those born after 1 July. There was less variation in birth timing for 1(st) litters of females than older females. We hypothesize that cubs born after the peak in births of neonate prey are advantaged by the abundance of vulnerable prey and those cubs and mothers realize an evolutionary advantage. PMID- 23028570 TI - Altitudinal variation in leaf nitrogen concentration on the eastern slope of Mount Gongga on the Tibetan Plateau, China. AB - Mount Gongga spans 6500 m in elevation and has intact and continuous vertical vegetation belts, ranging from subtropical evergreen broad-leaved vegetation to an alpine frigid sparse grass and desert zone. Investigating the altitudinal trends in leaf nitrogen (N) on Mount Gongga can increase our understanding of the global biogeography of foliar N. In this study, 460 leaf samples from mosses, ferns, and seed plants were collected along an altitudinal gradient on the eastern slope of Mount Gongga, and the variation in leaf N concentration (mass basis) with elevation was analyzed. There are considerable differences in leaf N between mosses and ferns, mosses and seed plants, C(4) and C(3) plants, and evergreen and deciduous woody plants. The general altitudial pattern of leaf N in Mount Gongga plants was that leaf N kept increasing until an elevation of about 2200 m above sea level, with a corresponding mean annual temperature (MAT) of 8.5 degrees C, and then decreased with increasing elevation. However, the evergreen woody plants displayed a decline trend in leaf N across the altitude gradient. Our findings provide an insight into the altitudinal variation in leaf N. PMID- 23028571 TI - Time-delayed mutual information of the phase as a measure of functional connectivity. AB - We propose a time-delayed mutual information of the phase for detecting nonlinear synchronization in electrophysiological data such as MEG. Palus already introduced the mutual information as a measure of synchronization. To obtain estimates on small data-sets as reliably as possible, we adopt the numerical implementation as proposed by Kraskov and colleagues. An embedding with a parametric time-delay allows a reconstruction of arbitrary nonstationary connective structures--so-called connectivity patterns--in a wide class of systems such as coupled oscillatory or even purely stochastic driven processes. By using this method we do not need to make any assumptions about coupling directions, delay times, temporal dynamics, nonlinearities or underlying mechanisms. For verifying and refining the methods we generate synthetic data sets by a mutual amplitude coupled network of Rossler oscillators with an a priori known connective structure. This network is modified in such a way, that the power-spectrum forms a 1/f power law, which is also observed in electrophysiological recordings. The functional connectivity measure is tested on robustness to additive uncorrelated noise and in discrimination of linear mixed input data. For the latter issue a suitable de-correlation technique is applied. Furthermore, the compatibility to inverse methods for a source reconstruction in MEG such as beamforming techniques is controlled by dedicated dipole simulations. Finally, the method is applied on an experimental MEG recording. PMID- 23028572 TI - Cortico-cardio-respiratory network interactions during anesthesia. AB - General anesthetics are used during medical and surgical procedures to reversibly induce a state of total unconsciousness in patients. Here, we investigate, from a dynamic network perspective, how the cortical and cardiovascular systems behave during anesthesia by applying nonparametric spectral techniques to cortical electroencephalography, electrocardiogram and respiratory signals recorded from anesthetized rats under two drugs, ketamine-xylazine (KX) and pentobarbital (PB). We find that the patterns of low-frequency cortico-cardio-respiratory network interactions may undergo significant changes in network activity strengths and in number of network links at different depths of anesthesia dependent upon anesthetics used. PMID- 23028573 TI - A predictive framework for integrating disparate genomic data types using sample specific gene set enrichment analysis and multi-task learning. AB - Understanding the root molecular and genetic causes driving complex traits is a fundamental challenge in genomics and genetics. Numerous studies have used variation in gene expression to understand complex traits, but the underlying genomic variation that contributes to these expression changes is not well understood. In this study, we developed a framework to integrate gene expression and genotype data to identify biological differences between samples from opposing complex trait classes that are driven by expression changes and genotypic variation. This framework utilizes pathway analysis and multi-task learning to build a predictive model and discover pathways relevant to the complex trait of interest. We simulated expression and genotype data to test the predictive ability of our framework and to measure how well it uncovered pathways with genes both differentially expressed and genetically associated with a complex trait. We found that the predictive performance of the multi-task model was comparable to other similar methods. Also, methods like multi-task learning that considered enrichment analysis scores from both data sets found pathways with both genetic and expression differences related to the phenotype. We used our framework to analyze differences between estrogen receptor (ER) positive and negative breast cancer samples. An analysis of the top 15 gene sets from the multi-task model showed they were all related to estrogen, steroids, cell signaling, or the cell cycle. Although our study suggests that multi-task learning does not enhance predictive accuracy, the models generated by our framework do provide valuable biological pathway knowledge for complex traits. PMID- 23028574 TI - A targeted library screen reveals a new inhibitor scaffold for protein kinase D. AB - Protein kinase D (PKD) has emerged as a potential therapeutic target in multiple pathological conditions, including cancer and heart diseases. Potent and selective small molecule inhibitors of PKD are valuable for dissecting PKD mediated cellular signaling pathways and for therapeutic application. In this study, we evaluated a targeted library of 235 small organic kinase inhibitors for PKD1 inhibitory activity at a single concentration. Twenty-eight PKD inhibitory chemotypes were identified and six exhibited excellent PKD1 selectivity. Five of the six lead structures share a common scaffold, with compound 139 being the most potent and selective for PKD vs PKC and CAMK. Compound 139 was an ATP-competitive PKD1 inhibitor with a low double-digit nanomolar potency and was also cell active. Kinase profiling analysis identified this class of small molecules as pan PKD inhibitors, confirmed their selectivity again PKC and CAMK, and demonstrated an overall favorable selectivity profile that could be further enhanced through structural modification. Furthermore, using a PKD homology model based on similar protein kinase structures, docking modes for compound 139 were explored and compared to literature examples of PKD inhibition. Modeling of these compounds at the ATP-binding site of PKD was used to rationalize its high potency and provide the foundation for future further optimization. Accordingly, using biochemical screening of a small number of privileged scaffolds and computational modeling, we have identified a new core structure for highly potent PKD inhibition with promising selectivity against closely related kinases. These lead structures represent an excellent starting point for the further optimization and the design of selective and therapeutically effective small molecule inhibitors of PKD. PMID- 23028575 TI - On the applicability of temperature and precipitation data from CMIP3 for China. AB - Global Circulation Models (GCMs) contributed to the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) and are widely used in global change research. This paper assesses the performance of the AR4 GCMs in simulating precipitation and temperature in China from 1960 to 1999 by comparison with observed data, using system bias (B), root-mean-square error (RMSE), Pearson correlation coefficient (R) and Nash-Sutcliffe model efficiency (E) metrics. Probability density functions (PDFs) are also fitted to the outputs of each model. It is shown that the performance of each GCM varies to different degrees across China. Based on the skill score derived from the four metrics, it is suggested that GCM 15 (ipsl_cm4) and GCM 3 (cccma_cgcm_t63) provide the best representations of temperature and precipitation, respectively, in terms of spatial distribution and trend over 10 years. The results also indicate that users should apply carefully the results of annual precipitation and annual temperature generated by AR4 GCMs in China due to poor performance. At a finer scale, the four metrics are also used to obtain best fit scores for ten river basins covering mainland China. Further research is proposed to improve the simulation accuracy of the AR4 GCMs regarding China. PMID- 23028576 TI - A systematic review on renal and bladder dysfunction after endoscopic treatment of infravesical obstruction in boys. AB - BACKGROUND: Posterior urethral valves (PUV) may cause subtle to severe obstruction of the urethra, resulting in a broad clinical spectrum. PUV are the most common cause of chronic renal disease in boys. Our purpose was to report the incidences of kidney and bladder dysfunction in boys treated with endoscopic valve resection for PUV. METHODOLOGY: We searched MEDLINE and EMBASE databases until 1st of July 2011, to identify original papers that described outcome of endoscopic valve resection (EVR) in boys. We extracted information on (1) patient characteristics and clinical presentation of PUV related to outcomes and (2) the post-treatment absolute risks for kidney and bladder dysfunction. PRINCIPAL FINDINGS: Thirty-four studies describing renal function, vesicoureteral reflux (VUR), incontinence, and urodynamic bladder function after EVR in 1474 patients were retrieved. Patients treated for PUV show high percentages of chronic kidney disease (CKD) or end stage renal disease (ESRD), 22% (0-32%) and 11% (0-20%), respectively. Elevated nadir serum creatinine was the only independent factor associated with renal failure. Before treatment, VUR was present in 43% of boys and after EVR, VUR was present in 22%. Post treatment, 19% (0-70%) was reported to suffer from urinary incontinence. Urodynamic bladder dysfunction was seen in many patients (55%, 0-72%) after treatment of PUV. CONCLUSIONS: The reported cumulative incidence of renal and bladder dysfunction in patients with PUV after endoscopic PUV treatment varies widely. This may reflect a broad clinical spectrum, which relates to the lack of a standardised quantification of obstruction and its severity. Moreover, the risk of bias is rather high, and therefore we put little confidence in the reported estimates of effect. We found elevated nadir serum creatinine as a predictor for renal dysfunction. In order to be able to predict outcomes for patients with PUV, an objective classification of severity of obstruction is mandatory. PMID- 23028577 TI - Reconstructing the history of Mesoamerican populations through the study of the mitochondrial DNA control region. AB - The study of genetic information can reveal a reconstruction of human population's history. We sequenced the entire mtDNA control region (positions 16.024 to 576 following Cambridge Reference Sequence, CRS) of 605 individuals from seven Mesoamerican indigenous groups and one Aridoamerican from the Greater Southwest previously defined, all of them in present Mexico. Samples were collected directly from the indigenous populations, the application of an individual survey made it possible to remove related or with other origins samples. Diversity indices and demographic estimates were calculated. Also AMOVAs were calculated according to different criteria. An MDS plot, based on FST distances, was also built. We carried out the construction of individual networks for the four Amerindian haplogroups detected. Finally, barrier software was applied to detect genetic boundaries among populations. The results suggest: a common origin of the indigenous groups; a small degree of European admixture; and inter-ethnic gene flow. The process of Mesoamerica's human settlement took place quickly influenced by the region's orography, which development of genetic and cultural differences facilitated. We find the existence of genetic structure is related to the region's geography, rather than to cultural parameters, such as language. The human population gradually became fragmented, though they remained relatively isolated, and differentiated due to small population sizes and different survival strategies. Genetic differences were detected between Aridoamerica and Mesoamerica, which can be subdivided into "East", "Center", "West" and "Southeast". The fragmentation process occurred mainly during the Mesoamerican Pre-Classic period, with the Otomi being one of the oldest groups. With an increased number of populations studied adding previously published data, there is no change in the conclusions, although significant genetic heterogeneity can be detected in Pima and Huichol groups. This result may be explained because populations historically assigned as belonging to the same group were, in fact, different indigenous populations. PMID- 23028578 TI - The insect pathogen Serratia marcescens Db10 uses a hybrid non-ribosomal peptide synthetase-polyketide synthase to produce the antibiotic althiomycin. AB - There is a continuing need to discover new bioactive natural products, such as antibiotics, in genetically-amenable micro-organisms. We observed that the enteric insect pathogen, Serratia marcescens Db10, produced a diffusible compound that inhibited the growth of Bacillis subtilis and Staphyloccocus aureus. Mapping the genetic locus required for this activity revealed a putative natural product biosynthetic gene cluster, further defined to a six-gene operon named alb1-alb6. Bioinformatic analysis of the proteins encoded by alb1-6 predicted a hybrid non ribosomal peptide synthetase-polyketide synthase (NRPS-PKS) assembly line (Alb4/5/6), tailoring enzymes (Alb2/3) and an export/resistance protein (Alb1), and suggested that the machinery assembled althiomycin or a related molecule. Althiomycin is a ribosome-inhibiting antibiotic whose biosynthetic machinery had been elusive for decades. Chromatographic and spectroscopic analyses confirmed that wild type S. marcescens produced althiomycin and that production was eliminated on disruption of the alb gene cluster. Construction of mutants with in frame deletions of specific alb genes demonstrated that Alb2-Alb5 were essential for althiomycin production, whereas Alb6 was required for maximal production of the antibiotic. A phosphopantetheinyl transferase enzyme required for althiomycin biosynthesis was also identified. Expression of Alb1, a predicted major facilitator superfamily efflux pump, conferred althiomycin resistance on another, sensitive, strain of S. marcescens. This is the first report of althiomycin production outside of the Myxobacteria or Streptomyces and paves the way for future exploitation of the biosynthetic machinery, since S. marcescens represents a convenient and tractable producing organism. PMID- 23028579 TI - Double stranded sperm DNA breaks, measured by Comet assay, are associated with unexplained recurrent miscarriage in couples without a female factor. AB - It is known that sperm samples from recurrent pregnancy loss (RPL) couples have an increase in their sperm DNA fragmentation (SDF), but no studies have been performed in order to identify differences between single stranded SDF (ssSDF) and double stranded SDF (dsSDF) in these patients. This could be relevant because the type of DNA damage could have different effects. Semen samples were classified attending their clinical status: 25 fertile donors and 20 RPL patients with at least two unexplained first trimester miscarriages. SDF was analysed using alkaline and neutral Comet assay, SCD test and pulsed-field gel electrophoresis (PFGE), and ROC analysis including data from 105 more infertile patients (n = 150) was performed to establish predictive threshold values. SDF for alkaline and neutral Comet, and the SCD test was analysed in these categories of individuals. Data revealed the presence of two subgroups within fertile donors. The values obtained were 21.10+/-9.13, 23.35+/-10.45 and 12.31+/-4.31, respectively, for fertile donors with low values for both ssSDF and dsSDF; 27.86+/-12.64, 80.69+/-12.67 and 12.43+/-5.22, for fertile donors with low ssSDF and high dsSDF; and 33.61+/-15.50, 84.64+/-11.28 and 19.28+/-6.05, for unexplained RPL patients, also showing a low ssSDF and high dsSDF profile. This latter profile was seen in 85% of unexplained RPL and 33% of fertile donors, suggesting that it may be associated to a male risk factor for undergoing RPL. ROC analysis regarding recurrent miscarriage set the cut-off value at 77.50% of dsDNA SDF. PFGE for low ssSDF and high dsSDF profile samples and positive controls treated with DNase, to induce dsDNA breaks, showed a more intense band of about 48 kb, which fits the toroid model of DNA compaction in sperm, pointing out that some nuclease activity may be affecting their sperm DNA in RPL patients. This work identifies a very specific SDF profile related to the paternal risk of having RPL. PMID- 23028580 TI - Evidence of public engagement with science: visitor learning at a zoo-housed primate research centre. AB - Primate behavioural and cognitive research is increasingly conducted on direct public view in zoo settings. The potential of such facilities for public engagement with science is often heralded, but evidence of tangible, positive effects on public understanding is rare. Here, the effect of a new zoo-based primate research centre on visitor behaviour, learning and attitudes was assessed using a quasi-experimental design. Zoo visitors approached the primate research centre more often when a scientist was present and working with the primates, and reported greater awareness of primates (including conservation) compared to when the scientist was not present. Visitors also reported greater perceived learning when the scientist was present. Installation of information signage had no main effect on visitor attitudes or learning. Visitors who interacted with the signage, however, demonstrated increased knowledge and understanding when asked about the specific information present on the signs (which was related to the ongoing facial expression research at the research centre). The findings show that primate behaviour research centres on public view can have a demonstrable and beneficial effect on public understanding of science. PMID- 23028581 TI - Increased urine and serum nerve growth factor levels in interstitial cystitis suggest chronic inflammation is involved in the pathogenesis of disease. AB - OBJECTIVE: Interstitial cystitis/bladder pain syndrome (IC/BPS) is considered a bladder disorder due to localized chronic inflammation. This study investigated the nerve growth factor (NGF) levels in serum and urine in patients with IC/BPS. MATERIALS AND METHODS: Thirty patients with IC/BPS and 28 normal subjects without lower urinary tract symptoms were recruited from an outpatient clinic. IC/BPS was diagnosed by frequency, bladder pain, and the presence of glomerulations during cystoscopic hydrodistention. Serum and urine were collected before any treatment was given. Serum NGF and urinary NGF/Cr levels were compared between IC/BPS and the controls. RESULTS: Urinary NGF levels were significantly higher in patients with IC/PBS (26.3+/-11.2 pg/ml) than in controls (1.40+/-0.63 pg) (p = 0.014). After normalization, the urinary NGF/Cr levels were significantly greater in IC/BPS (0.69+/-0.38 pg/mg) than controls (0.20+/-0.01, p = 0.011). Relative to the levels in control subjects (1.90+/-0.38 pg/mL), the mean serum NGF levels were higher in patients IC/BPS patients (3.48+/-0.55 pg/mL) (p = 0.015). No significant correlation was found between the serum and urinary NGF levels in IC/BPS patients. However, the clinical characteristics and medical co-morbidities did not show significant difference between IC/BPS patients with a higher and lower serum NGF level. CONCLUSIONS: Increased urinary NGF levels in IC/BPS patients suggest that chronic inflammation is involved in this bladder disorder. Increased circulating serum NGF levels were noted in over half of patients with IC/BPS, however, the urinary and serum NGF were not inter-correlated and elevated serum NGF did not relate with clinical features. PMID- 23028582 TI - Cardiac regeneration from activated epicardium. AB - In contrast to lower vertebrates, the mammalian heart has a very limited regenerative capacity. Cardiomyocytes, lost after ischemia, are replaced by fibroblasts. Although the human heart is able to form new cardiomyocytes throughout its lifespan, the efficiency of this phenomenon is not enough to substitute sufficient myocardial mass after an infarction. In contrast, zebrafish hearts regenerate through epicardial activation and initiation of myocardial proliferation. With this study we obtain insights into the activation and cellular contribution of the mammalian epicardium in response to ischemia. In a mouse myocardial infarction model we analyzed the spatio-temporal changes in expression of embryonic epicardial, EMT, and stem cell markers and the contribution of cells of the Wt1-lineage to the infarcted area. Though the integrity of the epicardial layer overlaying the infarct is lost immediately after the induction of the ischemia, it was found to be regenerated at three days post infarction. In this regenerated epicardium, the embryonic gene program is transiently re-expressed as well as proliferation. Concomitant with this activation, Wt1-lineage positive subepicardial mesenchyme is formed until two weeks post-infarction. These mesenchymal cells replace the cardiomyocytes lost due to the ischemia and contribute to the fibroblast population, myofibroblasts and coronary endothelium in the infarct, and later also to the cardiomyocyte population. We show that in mice, as in lower vertebrates, an endogenous, epicardium-dependent regenerative response to injury is induced. Although this regenerative response leads to the formation of new cardiomyocytes, their number is insufficient in mice but sufficient in lower vertebrates to replace lost cardiomyocytes. These molecular and cellular analyses provide basic knowledge essential for investigations on the regeneration of the mammalian heart aiming at epicardium-derived cells. PMID- 23028583 TI - Identification of conserved and novel microRNAs from Liriodendron chinense floral tissues. AB - BACKGROUND: Liriodendron chinense (L. chinense) is an endangered basal angiosperm plant in China because of its low reproductive efficiency. Recently, miRNAs have obtained great attention because they can play important roles. Through high throughput sequencing technique, large amount of miRNAs were identified from different plant species. But there were few studies about the miRNAs in the basal angiosperms especially in the sexual reproduction process. RESULTS: Deep sequencing technology was applied to discover miRNAs in L. chinense flowers at different stages. After bioinformatic analysis, 496 putative conserved miRNAs representing 97 families and 2 novel miRNAs were found. Among them, one is previously regarded as gymnosperm specific. Their expressions were further validated by Real-time PCR for 13 selected miRNAs. Putative targeting genes were predicted and categorized with gene ontology (GO) analysis. About ten percents of the targets are involved in the reproduction process. Further expressional analysis showed that many of these miRNAs were highly related to the reproductive growth. CONCLUSIONS: This is the first comprehensive identification of conserved and novel miRNAs in L. chinense. The data presented here might not only help to fill the gap of miRNA registered about basal angiosperm plants but also contribute to understanding the evolution of miRNAs. The differential expression of some of the miRNAs and the prediction of their target genes are also helpful in understanding the regulation of L. chinense sexual reproduction. PMID- 23028584 TI - Puzzling findings in studying the outcome of "real world" adolescent mental health services: the TRAILS study. AB - BACKGROUND: The increased use and costs of specialist child and adolescent mental health services (MHS) urge us to assess the effectiveness of these services. The aim of this paper is to compare the course of emotional and behavioural problems in adolescents with and without MHS use in a naturalistic setting. METHOD AND FINDINGS: Participants are 2230 (pre)adolescents that enrolled in a prospective cohort study, the TRacking Adolescents' Individual Lives Survey (TRAILS). Response rate was 76%, mean age at baseline 11.09 (SD 0.56), 50.8% girls. We used data from the first three assessment waves, covering a six year period. Multiple linear regression analysis, propensity score matching, and data validation were used to compare the course of emotional and behavioural problems of adolescents with and without MHS use. The association between MHS and follow-up problem score (beta 0.20, SE 0.03, p-value<0.001) was not confounded by baseline severity, markers of adolescent vulnerability or resilience nor stressful life events. The propensity score matching strategy revealed that follow-up problem scores of non MHS-users decreased while the problem scores of MHS users remained high. When taking into account future MHS (non)use, it appeared that problem scores decreased with limited MHS use, albeit not as much as without any MHS use, and that problem scores with continuous MHS use remained high. Data validation showed that using a different outcome measure, multiple assessment waves and multiple imputation of missing values did not alter the results. A limitation of the study is that, although we know what type of MHS participants used, and during which period, we lack information on the duration of the treatment. CONCLUSIONS: The benefits of MHS are questionable. Replication studies should reveal whether a critical examination of everyday care is necessary or an artefact is responsible for these results. PMID- 23028585 TI - Increased metallothionein I/II expression in patients with temporal lobe epilepsy. AB - In the central nervous system, zinc is released along with glutamate during neurotransmission and, in excess, can promote neuronal death. Experimental studies have shown that metallothioneins I/II (MT-I/II), which chelate free zinc, can affect seizures and reduce neuronal death after status epilepticus. Our aim was to evaluate the expression of MT-I/II in the hippocampus of patients with temporal lobe epilepsy (TLE). Hippocampi from patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and patients with TLE associated with tumor or dysplasia (TLE-TD) were evaluated for expression of MT-I/II, for the vesicular zinc levels, and for neuronal, astroglial, and microglial populations. Compared to control cases, MTLE group displayed widespread increase in MT-I/II expression, astrogliosis, microgliosis and reduced neuronal population. In TLE-TD, the same changes were observed, except that were mainly confined to fascia dentata. Increased vesicular zinc was observed only in the inner molecular layer of MTLE patients, when compared to control cases. Correlation and linear regression analyses indicated an association between increased MT-I/II and increased astrogliosis in TLE. MT-I/II levels did not correlate with any clinical variables, but MTLE patients with secondary generalized seizures (SGS) had less MT-I/II than MTLE patients without SGS. In conclusion, MT-I/II expression was increased in hippocampi from TLE patients and our data suggest that it is associated with astrogliosis and may be associated with different seizure spread patterns. PMID- 23028586 TI - Saturated alanine scanning mutagenesis of the pneumococcus competence stimulating peptide identifies analogs that inhibit genetic transformation. AB - Antibiotic resistance is a major challenge to modern medicine. Intraspecies and interspecies dissemination of antibiotic resistance genes among bacteria can occur through horizontal gene transfer. Competence-mediated gene transfer has been reported to contribute to the spread of antibiotic resistance genes in Streptococcus pneumoniae. Induction of the competence regulon is mediated by a 17 amino acid peptide pheromone called the competence stimulating peptide (CSP). Thus, synthetic analogs that competitively inhibit CSPs may reduce horizontal gene transfer. We performed saturated alanine scanning mutagenesis and other amino acid substitutions on CSP1 to screen for analogs that disable genetic transformation in S. pneumoniae. Substitution of the glutamate residue at the first position created analogs that could competitively inhibit CSP1-mediated competence development in a concentration-dependent manner. Additional substitutions of the negatively-charged glutamate residue with amino acids of different charge, acidity and hydrophobicity, as well as enantiomeric D glutamate, generated analogs that efficiently outcompeted CSP1, suggesting the importance of negative charge and enantiomericity of the first glutamate residue for the function of CSP1. Collectively, these results indicate that glutamate residue at the first position is important for the ability of CSP1 to induce ComD, but is dispensable for the peptide to bind the receptor. Furthermore, these results demonstrate the potential applicability of competitive CSP analogs to control horizontal transfer of antibiotic resistance genes in S. pneumoniae. PMID- 23028587 TI - Activation of myocardial phosphoinositide-3-kinase p110alpha ameliorates cardiac dysfunction and improves survival in polymicrobial sepsis. AB - Phosphoinositide-3-kinase (PI3K)/Akt dependent signaling has been shown to improve outcome in sepsis/septic shock. There is also ample evidence that PI3K/Akt dependent signaling plays a crucial role in maintaining normal cardiac function. We hypothesized that PI3K/Akt signaling may ameliorate septic shock by attenuating sepsis-induced cardiac dysfunction. Cardiac function and survival were evaluated in transgenic mice with cardiac myocyte specific expression of constitutively active PI3K isoform, p110alpha (caPI3K Tg). caPI3K Tg and wild type (WT) mice were subjected to cecal ligation/puncture (CLP) induced sepsis. Wild type CLP mice showed dramatic cardiac dysfunction at 6 hrs. Septic cardiomyopathy was significantly attenuated in caPI3K CLP mice. The time to 100% mortality was 46 hrs in WT CLP mice. In contrast, 80% of the caPI3K mice survived at 46 hrs after CLP (p<0.01) and 50% survived >30 days (p<0.01). Cardiac caPI3K expression prevented expression of an inflammatory phenotype in CLP sepsis. Organ neutrophil infiltration and lung apoptosis were also effectively inhibited by cardiac PI3k p110alpha expression. Cardiac high mobility group box-1 (HMGB-1) translocation was also inhibited by caPI3K p110alpha expression. We conclude that cardiac specific activation of PI3k/Akt dependent signaling can significantly modify the morbidity and mortality associated with sepsis. Our data also indicate that myocardial function/dysfunction plays a prominent role in the pathogenesis of sepsis and that maintenance of cardiac function during sepsis is essential. Finally, these data suggest that modulation of the PI3K/p110alpha signaling pathway may be beneficial in the prevention and/or management of septic cardiomyopathy and septic shock. PMID- 23028588 TI - Global renal gene expression profiling analysis in B2-kinin receptor null mice: impact of diabetes. AB - Diabetic nephropathy (DN), the leading cause of end-stage renal failure, is clinically manifested by albuminuria and a progressive decline in glomerular filtration rate. The risk factors and mechanisms that contribute to the development and progression of DN are still incompletely defined. To address the involvement of bradykinin B(2)-receptors (B(2)R) in DN, we used a genome wide approach to study the effects of diabetes on differential renal gene expression profile in wild type and B(2)R knockout (B(2)R(-/-)) mice. Diabetes was induced with streptozotocin and plasma glucose levels and albumin excretion rate (AER) were measured at predetermined times throughout the 23 week study period. Longitudinal analysis of AER indicated that diabetic B(2)R(-/-)D null mice had a significantly decreased AER levels compared to wild type B(2)R(+/+)D mice (P = 0.0005). Results from the global microarray study comparing gene expression profiles among four groups of mice respectively: (B(2)R(+/+)C, B(2)R(+/+)D, B(2)R(-/-)C and B(2)R(-/-)D) highlighted the role of several altered pathological pathways in response to disruption of B(2)R and to the diabetic state that included: endothelial injury, oxidative stress, insulin and lipid metabolism and inflammatory process with a marked alteration in the pro-apoptotic genes. The findings of the present study provide a global genomics view of biomarkers that highlight the mechanisms and putative pathways involved in DN. PMID- 23028589 TI - The antiestrogens tamoxifen and fulvestrant abolish estrogenic impacts of 17alpha ethinylestradiol on male calling behavior of Xenopus laevis. AB - Various synthetic chemicals released to the environment can interfere with the endocrine system of vertebrates. Many of these endocrine disrupting compounds (EDCs) exhibit estrogenic activity and can interfere with sexual development and reproductive physiology. More recently, also chemicals with different modes of action (MOAs), such as antiestrogenic, androgenic and antiandrogenic EDCs, have been shown to be present in the environment. However, to date EDC-research primarily focuses on exposure to EDCs with just one MOA, while studies examining the effects of simultaneous exposure to EDCs with different MOAs are rare, although they would reflect more real, natural exposure situations. In the present study the combined effects of estrogenic and antiestrogenic EDCs were assessed by analyzing the calling behavior of short-term exposed male Xenopus laevis. The estrogenic 17alpha-ethinylestradiol (EE2), and the antiestrogenic EDCs tamoxifen (TAM) and fulvestrant (ICI) were used as model substances. As previously demonstrated, sole EE2 exposure (10-10 M) resulted in significant alterations of the male calling behavior, including altered temporal and spectral parameters of the advertisement calls. Sole TAM (10-7 M, 10-8 M, 10-10 M) or ICI (10-7 M) exposure, on the other hand, did not affect any of the measured parameters. If frogs were co-exposed to EE2 (10-10 M) and TAM (10-7 M) the effects of EE2 on some parameters were abolished, but co-exposure to EE2 and ICI (10-7 M) neutralized all estrogenic effects. Thus, although EDCs with antiestrogenic MOA might not exhibit any effects per se, they can alter the estrogenic effects of EE2. Our observations demonstrate that there is need to further investigate the combined effects of EDCs with various, not only opposing, MOAs as this would reflect realistic wildlife situations. PMID- 23028590 TI - Step-wise assembly, maturation and dynamic behavior of the human CENP-P/O/R/Q/U kinetochore sub-complex. AB - Kinetochores are multi-protein megadalton assemblies that are required for attachment of microtubules to centromeres and, in turn, the segregation of chromosomes in mitosis. Kinetochore assembly is a cell cycle regulated multi-step process. The initial step occurs during interphase and involves loading of the 15 subunit constitutive centromere associated complex (CCAN), which contains a 5 subunit (CENP-P/O/R/Q/U) sub-complex. Here we show using a fluorescent three hybrid (F3H) assay and fluorescence resonance energy transfer (FRET) in living mammalian cells that CENP-P/O/R/Q/U subunits exist in a tightly packed arrangement that involves multifold protein-protein interactions. This sub complex is, however, not pre-assembled in the cytoplasm, but rather assembled on kinetochores through the step-wise recruitment of CENP-O/P heterodimers and the CENP-P, -O, -R, -Q and -U single protein units. SNAP-tag experiments and immuno staining indicate that these loading events occur during S-phase in a manner similar to the nucleosome binding components of the CCAN, CENP-T/W/N. Furthermore, CENP-P/O/R/Q/U binding to the CCAN is largely mediated through interactions with the CENP-N binding protein CENP-L as well as CENP-K. Once assembled, CENP-P/O/R/Q/U exchanges slowly with the free nucleoplasmic pool indicating a low off-rate for individual CENP-P/O/R/Q/U subunits. Surprisingly, we then find that during late S-phase, following the kinetochore-binding step, both CENP-Q and -U but not -R undergo oligomerization. We propose that CENP P/O/R/Q/U self-assembles on kinetochores with varying stoichiometry and undergoes a pre-mitotic maturation step that could be important for kinetochores switching into the correct conformation necessary for microtubule-attachment. PMID- 23028591 TI - Killer immunoglobulin-like receptor (KIR) and HLA genotypes affect the outcome of allogeneic kidney transplantation. AB - BACKGROUND: Recipient NK cells may detect the lack of recipient's (i.e., self) HLA antigens on donor renal tissue by means of their killer cell immunoglobulin like receptors (KIRs). KIR genes are differently distributed in individuals, possibly contributing to differences in response to allogeneic graft. METHODOLOGY/PRINCIPAL FINDINGS: We compared frequencies of 10 KIR genes by PCR SSP in 93 kidney graft recipients rejecting allogeneic renal transplants with those in 190 recipients accepting grafts and 690 healthy control individuals. HLA matching results were drawn from medical records. We observed associations of both a full-length KIR2DS4 gene and its variant with 22-bp deletion with kidney graft rejection. This effect was modulated by the HLA-B,-DR matching, particularly in recipients who did not have glomerulonephritis but had both forms of KIR2DS4 gene. In contrast, in recipients with glomerulonephritis, HLA compatibility seemed to be much less important for graft rejection than the presence of KIR2DS4 gene. Simultaneous presence of both KIR2DS4 variants strongly increased the probability of rejection. Interestingly, KIR2DS5 seemed to protect the graft in the presence of KIR2DS4fl but in the absence of KIR2DS4del. CONCLUSIONS/SIGNIFICANCE: Our results suggest a protective role of KIR2DS5 in graft rejection and an association of KIR2DS4 with kidney rejection, particularly in recipients with glomerulonephritis. PMID- 23028592 TI - Expressional analysis of immunoglobulin D in cattle (Bos taurus), a large domesticated ungulate. AB - For decades, it has remained unknown whether artiodactyls, such as cattle, pigs, and sheep, express immunoglobulin D (IgD), although the delta gene was identified in these species nearly 10 years ago. By developing a mouse anti-bovine IgD heavy chain monoclonal antibody (13C2), we show that secreted bovine IgD was present mainly as a monomer in serum and was heavily glycosylated by N-linked saccharides. Nonetheless, IgD was detectable in some but not all of the Holstein cattle examined. Membrane-bound IgD was detected in the spleen by western blotting. Flow cytometric analysis demonstrated that IgD-positive B cells constituted a much lower percentage of B cells in the bovine spleen (~6.8% of total B cells), jejunal Peyer's patches (~0.8%), and peripheral blood leukocytes (~1.2%) than in humans and mice. Furthermore, IgD-positive B cells were almost undetectable in bovine bone marrow and ileal Peyer's patches. We also demonstrated that the bovine delta gene can be expressed via class switch recombination. Accordingly, bovine delta germline transcription, which involves an Idelta exon and is highly homologous to IMU, was confirmed. However, we could not identify an Idelta promoter, despite bovine EMU demonstrating both enhancer and promoter activity. This study has answered a long-standing question in cattle B cell biology and significantly contributes to our understanding of B cell development in this species. PMID- 23028593 TI - The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration. AB - Recent studies have implicated the hypocretin/orexinergic system in reward seeking behavior. Almorexant, a dual orexin/hypocretin R(1) and R(2) receptor antagonist, has proven effective in preclinical studies in promoting sleep in animal models and was in Phase III clinical trials for sleep disorders. The present study combines behavioral assays with in vitro biochemical and electrophysiological techniques to elucidate the role of almorexant in ethanol and sucrose intake. Using an operant self-administration paradigm, we demonstrate that systemic administration of almorexant decreased operant self-administration of both 20% ethanol and 5% sucrose. We further demonstrate that intra-ventral tegmental area (VTA) infusions, but not intra-substantia nigra infusions, of almorexant reduced ethanol self-administration. Extracellular recordings performed in VTA neurons revealed that orexin-A increased firing and this enhancement of firing was blocked by almorexant. The results demonstrate that orexin/hypocretin receptors in distinct brain regions regulate ethanol and sucrose mediated behaviors. PMID- 23028594 TI - Foxp3+ regulatory T cells among tuberculosis patients: impact on prognosis and restoration of antigen specific IFN-gamma producing T cells. AB - CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) and programmed death-1 (PD-1) molecules have emerged as pivotal players in immune suppression of chronic diseases. However, their impact on the disease severity, therapeutic response and restoration of immune response in human tuberculosis remains unclear. Here, we describe the possible role of Treg cells, their M. tuberculosis driven expansion and contribution of PD-1 pathway to the suppressive function of Treg cells among pulmonary tuberculosis (PTB) patients. Multicolor flow cytometry, cell culture, cells sorting and ELISA were employed to execute the study. Our results showed significant increase in frequency of antigen-reactive Treg cells, which gradually declined during successful therapy and paralleled with decline of M. tuberculosis specific IL-10 along with elevation of IFN-gamma production, and raising the IFN gamma/IL-4 ratio. Interestingly, persistence of Treg cells tightly correlated with MDR tuberculosis. Also, we show that blocking PD-1/PD-L1 pathway abrogates Treg-mediated suppression, suggesting that the PD-1/PD-L1 pathway is required for Treg-mediated suppression of the antigen-specific T cells. Treg cells possibly play a role in dampening the effector immune response and abrogating PD-1 pathway on Treg cells significantly rescued protective T cell response, suggesting its importance in immune restoration among tuberculosis patients. PMID- 23028595 TI - First evidence and predictions of Plasmodium transmission in Alaskan bird populations. AB - The unprecedented rate of change in the Arctic climate is expected to have major impacts on the emergence of infectious diseases and host susceptibility to these diseases. It is predicted that malaria parasites will spread to both higher altitudes and latitudes with global warming. Here we show for the first time that avian Plasmodium transmission occurs in the North American Arctic. Over a latitudinal gradient in Alaska, from 61 degrees N to 67 degrees N, we collected blood samples of resident and migratory bird species. We found both residents and hatch year birds infected with Plasmodium as far north as 64 degrees N, providing clear evidence that malaria transmission occurs in these climates. Based on our empirical data, we make the first projections of the habitat suitability for Plasmodium under a future-warming scenario in Alaska. These findings raise new concerns about the spread of malaria to naive host populations. PMID- 23028596 TI - Effects of pre-meal drinks with protein and amino acids on glycemic and metabolic responses at a subsequent composite meal. AB - BACKGROUND: Whey proteins have insulinogenic properties and the effect appears to originate from a specific postprandial plasma amino acid pattern. The insulinogenic effect can be mimicked by a specific mixture of the five amino acids iso, leu, lys, thr and val. OBJECTIVE: The objective was to evaluate the efficacy of pre-meal boluses of whey or soy protein with or without added amino acids on glycaemia, insulinemia as well as on plasma responses of incretins and amino acids at a subsequent composite meal. Additionally, plasma ghrelin and subjective appetite responses were studied. DESIGN: In randomized order, fourteen healthy volunteers were served a standardized composite ham sandwich meal with either water provided (250 ml) during the time course of the meal, or different pre-meal protein drinks (PMPD) (100 ml provided as a bolus) with additional water (150 ml) served to the meal. The PMPDs contained 9 g protein and were based on either whey or soy protein isolates, with or without addition of the five amino acids (iso, leu, lys, thr and val) or the five amino acids + arg. RESULTS: All PMPD meals significantly reduced incremental area for plasma glucose response (iAUC) during the first 60 min. All whey based PMPD meals displayed lower glycemic indices compared to the reference meal. There were no significant differences for the insulinemic indices. The early insulin response (iAUC 0-15 min) correlated positively to plasma amino acids, GIP and GLP-1 as well as to the glycemic profile. Additionally, inverse correlations were found between insulin iAUC 0-15 min and the glucose peak. CONCLUSION: The data suggests that a pre-meal drink containing specific proteins/amino acids significantly reduces postprandial glycemia following a composite meal, in absence of elevated insulinemic excursions. An early phase insulinemic response induced by plasma amino acids and incretins appears to mediate the effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT01586780 PMID- 23028597 TI - Describing the situational contexts of sweetened product consumption in a Middle Eastern Canadian community: application of a mixed method design. AB - Little is known about the situational contexts in which individuals consume processed sources of dietary sugars. This study aimed to describe the situational contexts associated with the consumption of sweetened food and drink products in a Catholic Middle Eastern Canadian community. A two-stage exploratory sequential mixed-method design was employed with a rationale of triangulation. In stage 1 (n = 62), items and themes describing the situational contexts of sweetened food and drink product consumption were identified from semi-structured interviews and were used to develop the content for the Situational Context Instrument for Sweetened Product Consumption (SCISPC). Face validity, readability and cultural relevance of the instrument were assessed. In stage 2 (n = 192), a cross sectional study was conducted and exploratory factor analysis was used to examine the structure of themes that emerged from the qualitative analysis as a means of furthering construct validation. The SCISPC reliability and predictive validity on the daily consumption of sweetened products were also assessed. In stage 1, six themes and 40-items describing the situational contexts of sweetened product consumption emerged from the qualitative analysis and were used to construct the first draft of the SCISPC. In stage 2, factor analysis enabled the clarification and/or expansion of the instrument's initial thematic structure. The revised SCISPC has seven factors and 31 items describing the situational contexts of sweetened product consumption. Initial validation of the instrument indicated it has excellent internal consistency and adequate test-retest reliability. Two factors of the SCISPC had predictive validity for the daily consumption of total sugar from sweetened products (Snacking and Energy demands) while the other factors (Socialization, Indulgence, Constraints, Visual Stimuli and Emotional needs) were rather associated to occasional consumption of these products. PMID- 23028598 TI - Association between change in normal appearing white matter metabolites and intrathecal inflammation in natalizumab-treated multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is associated not only with focal inflammatory lesions but also diffuse pathology in the central nervous system (CNS). Since there is no firm association between the amount of focal inflammatory lesions and disease severity, diffuse pathology in normal appearing white matter (NAWM) may be crucial for disease progression. Immunomodulating treatments for MS reduce the number of focal lesions, but possible effects on diffuse white matter pathology are less studied. Furthermore, it is not known whether intrathecal levels of inflammatory or neurodegenerative markers are associated with development of pathology in NAWM. METHODS: Quantitative proton magnetic resonance spectroscopy ((1)H-MRS) was used to investigate NAWM in 27 patients with relapsing MS before and after one year of treatment with natalizumab as well as NAWM in 20 healthy controls at baseline. Changes in (1)H MRS metabolite concentrations during treatment were also correlated with a panel of intrathecal markers of inflammation and neurodegeneration in 24 of these 27 patients. RESULTS: The group levels of (1)H-MRS metabolite concentrations were unchanged pre- to posttreatment, but a pattern of high magnitude correlation coefficients (r = 0.43-0.67, p<0.0005-0.03) were found between changes in individual metabolite concentrations (total creatine and total choline) and levels of pro-inflammatory markers (IL-1beta and CXCL8). CONCLUSIONS: Despite a clinical improvement and a global decrease in levels of inflammatory markers in cerebrospinal fluid during treatment, high levels of pro-inflammatory CXCL8 and IL-1beta were associated with an increase in (1)H-MRS metabolites indicative of continued gliosis development and membrane turnover in NAWM. PMID- 23028599 TI - Retinoic acid signalling is activated in the postischemic heart and may influence remodelling. AB - BACKGROUND: All-trans retinoic acid (atRA), an active derivative of vitamin A, regulates cell differentiation, proliferation and cardiac morphogenesis via transcriptional activation of retinoic acid receptors (RARs) acting on retinoic acid response elements (RARE). We hypothesized that the retinoic acid (RA) signalling pathway is activated in myocardial ischemia and postischemic remodelling. METHODS AND FINDINGS: Myocardial infarction was induced through ligating the left coronary artery in mice. In vivo cardiac activation of the RARs was measured by imaging RARE-luciferase reporter mice, and analysing expression of RAR target genes and proteins by real time RT-PCR and western blot. Endogenous retinoids in postinfarcted hearts were analysed by triple-stage liquid chromatography/tandem mass spectrometry. Cardiomyocytes (CM) and cardiofibroblasts (CF) were isolated from infarcted and sham operated RARE luciferase reporter hearts and monitored for RAR activity and expression of target genes. The effect of atRA on CF proliferation was evaluated by EdU incorporation. Myocardial infarction increased thoracic RAR activity in vivo (p<0.001), which was ascribed to the heart through ex vivo imaging (p = 0.002) with the largest signal 1 week postinfarct. This was accompanied by increased cardiac gene and protein expression of the RAR target genes retinol binding protein 1 (p = 0.01 for RNA, p = 0,006 for protein) and aldehyde dehydrogenase 1A2 (p = 0.04 for RNA, p = 0,014 for protein), while gene expression of cytochrome P450 26B1 was downregulated (p = 0.007). Concomitantly, retinol accumulated in the infarcted zone (p = 0.02). CM and CF isolated from infarcted hearts had higher luminescence than those from sham operated hearts (p = 0.02 and p = 0.008). AtRA inhibited CF proliferation in vitro (p = 0.02). CONCLUSION: The RA signalling pathway is activated in postischemic hearts and may play a role in regulation of damage and repair during remodelling. PMID- 23028600 TI - Immunoglobulin kappa C predicts overall survival in node-negative breast cancer. AB - BACKGROUND: Biomarkers of the immune system are currently not used as prognostic factors in breast cancer. We analyzed the association of the B cell/plasma cell marker immunoglobulin kappa C (IGKC) and survival of untreated node-negative breast cancer patients. MATERIAL AND METHODS: IGKC expression was evaluated by immunostaining in a cohort of 335 node-negative breast cancer patients with a median follow-up of 152 months. The prognostic significance of IGKC for disease free survival (DFS) and breast cancer-specific overall survival (OS) was evaluated with Kaplan-Meier survival analysis as well as univariate and multivariate Cox analysis adjusted for age at diagnosis, pT stage, histological grade, estrogen receptor (ER) status, progesterone receptor (PR) status, Ki-67 and human epidermal growth factor receptor 2 (HER-2) status. RESULTS: 160 patients (47.7%) showed strong expression of IGKC. Univariate analysis showed that IGKC was significantly associated with DFS (P = 0.017, hazard ratio [HR] = 0.570, 95% confidence interval [CI] = 0.360-0.903) and OS (P = 0.011, HR = 0.438, 95% CI = 0.233-0.822) in the entire cohort. The significance of IGKC was especially strong in ER negative and in luminal B carcinomas. In multivariate analysis IGKC retained its significance independent of established clinical factors for DFS (P = 0.004, HR = 0.504, 95% CI = 0.315-0.804) as well as for OS (P = 0.002, HR = 0.371, 95% CI = 0.196-0.705). CONCLUSION: Expression of IGKC has an independent protective impact on DFS and OS in node-negative breast cancer. PMID- 23028601 TI - Empathy moderates the effect of repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex on costly punishment. AB - Humans incur considerable costs to punish unfairness directed towards themselves or others. Recent studies using repetitive transcranial magnetic stimulation (rTMS) suggest that the right dorsolateral prefrontal cortex (DLPFC) is causally involved in such strategic decisions. Presently, two partly divergent hypotheses are discussed, suggesting either that the right DLPFC is necessary to control selfish motives by implementing culturally transmitted social norms, or is involved in suppressing emotion-driven prepotent responses to perceived unfairness. Accordingly, we studied the role of the DLPFC in costly (i.e. third party) punishment by applying rTMS to the left and right DLPFC before playing a Dictator Game with the option to punish observed unfair behavior (DG-P). In addition, sham stimulation took place. Individual differences in empathy were assessed with the German version of the Interpersonal Reactivity Index. Costly punishment increased (non-significantly) upon disruption of the right--but not the left--DLPFC as compared to sham stimulation. However, empathy emerged as a highly significant moderator variable of the effect of rTMS over the right, but not left, DLPFC, suggesting that the right DLPFC is involved in controlling prepotent emotional responses to observed unfairness, depending on individual differences in empathy. PMID- 23028602 TI - Lactase persistence and lipid pathway selection in the Maasai. AB - The Maasai are a pastoral people in Kenya and Tanzania, whose traditional diet of milk, blood and meat is rich in lactose, fat and cholesterol. In spite of this, they have low levels of blood cholesterol, and seldom suffer from gallstones or cardiac diseases. Field studies in the 1970s suggested that the Maasai have a genetic adaptation for cholesterol homeostasis. Analysis of HapMap 3 data using Fixation Index (Fst) and two metrics of haplotype diversity: the integrated Haplotype Score (iHS) and the Cross Population Extended Haplotype Homozygosity (XP-EHH), identified genomic regions and single nucleotide polymorphisms (SNPs) as strong candidates for recent selection for lactase persistence and cholesterol regulation in 143-156 founder individuals from the Maasai population in Kinyawa, Kenya (MKK). The non-synonmous SNP with the highest genome-wide Fst was the TC polymorphism at rs2241883 in Fatty Acid Binding Protein 1(FABP1), known to reduce low density lipoprotein and tri-glyceride levels in Europeans. The strongest signal identified by all three metrics was a 1.7 Mb region on Chr2q21. This region contains the genes LCT (Lactase) and MCM6 (Minichromosome Maintenance Complex Component) involved in lactase persistence, and the gene Rab3GAP1 (Rab3 GTPase-activating Protein Catalytic Subunit), which contains polymorphisms associated with total cholesterol levels in a genome-wide association study of >100,000 individuals of European ancestry. Sanger sequencing of DNA from six MKK samples showed that the GC-14010 polymorphism in the MCM6 gene, known to be associated with lactase persistence in Africans, is segregating in MKK at high frequency (~58%). The Cytochrome P450 Family 3 Subfamily A (CYP3A) cluster of genes, involved in cholesterol metabolism, was identified by Fst and iHS as candidate loci under selection. Overall, our study identified several specific genomic regions under selection in the Maasai which contain polymorphisms in genes associated with lactase persistence and cholesterol regulation. PMID- 23028603 TI - MR angiography, MR imaging and proton MR spectroscopy in-vivo assessment of skeletal muscle ischemia in diabetic rats. AB - To prospectively evaluate the feasibility of using magnetic resonance (MR) techniques for in-vivo assessing a rat diabetic model of limb ischemia. Unilateral hind limb ischemia was induced by ligation of the iliac-femoral artery in male streptozotocin-treated and non-diabetic control rats. Four weeks after ligation, rats underwent MR Angiography (MRA), T(1)-weighted and Short Time Inversion Recovery (STIR) sequences and muscle Proton MR Spectroscopy ((1)H-MRS) on both hind limbs. After MR examinations, immunoblotting and immunofluorescence analysis were performed. MRA showed a signal void due to flow discontinuation distal to the artery ligation. T(1)-weighted and STIR images showed, respectively, the presence of tissue swelling (p = 0.018 for non-diabetic; p = 0.027 for diabetic rats) and signal hyperintensity in tissue affected by occlusion. Mean total creatine/water for the occluded limb was significantly lower than for the non-occluded limbs in both non-diabetic (5.46*10(-4) vs 1.14*10(-3), p = 0.028) and diabetic rats (1.37*10(-4) vs 1.10*10(-3); p = 0.018). MR Imaging and (1)H-MRS changes were more pronounced in diabetic than in non-diabetic occluded limbs (p = 0.032). MR findings were confirmed by using histological findings. Combined MR techniques can be used to demonstrate the presence of structural and metabolic changes produced by iliac-femoral artery occlusion in rat diabetic model of limb ischemia. PMID- 23028604 TI - Impact of two common xeroderma pigmentosum group D (XPD) gene polymorphisms on risk of prostate cancer. AB - BACKGROUND: DNA repair genes (EG: xeroderma pigmentosum group D, XPD) may affect the capacity of encoded DNA repair enzymes to effectively remove DNA adducts or lesions, which may result in enhanced cancer risk. The association between XPD gene polymorphisms and the susceptibility of prostate cancer (PCa) was inconsistent in previous studies. METHODOLOGY/PRINCIPAL FINDINGS: A meta-analysis based on 9 independent case-control studies involving 3165 PCa patients and 3539 healthy controls for XPD Gln751Lys SNP (single nucleotide polymorphism) and 2555 cases and 3182 controls for Asn312Asp SNP was performed to address this association. Meanwhile, odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate this relationship. Statistical analysis was performed with STATA10.0. No significant association was found between XPD Gln751Lys SNP and PCa risk. On the other hand, in subgroup analysis based on ethnicity, associations were observed in Asian (eg. Asn vs. Asp: OR = 1.34, 95%CI = 1.16-1.55; Asn/Asn+Asn/Asp vs. Asp/Asp: OR = 1.23, 95%CI = 1.07-1.42) and African (eg. Asn vs. Asp: OR = 1.31, 95%CI = 1.01-1.70; Asn/Asn vs. Asp/Asp: OR = 1.71, 95%CI = 1.03-7.10) populations for Asn312Asp SNP. Moreover, similar associations were detected in hospital-based controls studies; the frequency of Asn/Asn genotype in early stage of PCa men was poorly higher than those in advanced stage of PCa men (OR = 1.45, 95%CI = 1.00-2.11). CONCLUSION/SIGNIFICANCE: Our investigations demonstrate that XPD Asn312Asp SNP not the Gln751Lys SNP, might poorly increase PCa risk in Asians and Africans, moreover, this SNPs may associate with the tumor stage of PCa. Further studies based on larger sample size and gene-environment interactions should be conducted to determine the role of XPD gene polymorphisms in PCa risk. PMID- 23028605 TI - Molecular survey of hepatitis C virus in the touristic city of Mar del Plata, Argentina. AB - The global epidemiology of hepatitis C virus (HCV) may be roughly described by two groups of genotypes: the worldwide distributed ones (subtypes 1a, 1b, 2a and 3a, among others) and the endemic ones (subtypes 4a, 5a, 6a, among others). Epidemiological and population dynamic studies of the worldwide distributed genotypes have shown that subtypes 1a and 3a are common among intravenous drug users (IDUs) and that they are also in expansion in some countries. The molecular survey of HCV provides some clues about the epidemiological status of the infections in a local scale and the phylogenetic and demographic reconstruction analyses complement this study by inferring whether the infections of certain subtypes are in a steady state or expanding. Here, a molecular survey of the HCV variants that circulate in the touristic city of Mar del Plata (Buenos Aires, Argentina) was performed in samples obtained from 42 patients. The subtypes detected were 1a (32 patients), 3a (8 patients) and 1b (2 patients). The demographic history of subtype 1a inferred using the sequence data showed an exponential growth in the 1990's. The period of viral expansion was delayed compared with that observed for the same genotype in other countries where the transmission was associated with IDUs. Also, the phylogeographic analysis of HCV 1a showed a statistically significant association between the location of the samples and the phylogeny, which may be the result of the local transmission of HCV in the city. The molecular analysis helped in the description of the complex epidemiological context of a touristic city, and pointed out that some sanitary measures should be taken in order to reduce the transmission of HCV (and maybe of HIV) among IDUs. PMID- 23028606 TI - Structural and functional changes in subcortical vascular mild cognitive impairment: a combined voxel-based morphometry and resting-state fMRI study. AB - The present study aimed to investigate changes in structural gray matter (GM) volume and functional amplitude of spontaneous low-frequency oscillations (LFO) and functional connectivity density in patients with subcortical vascular mild cognitive impairment (svMCI). Structural MRI and resting-sate functional MRI data were collected from 26 svMCI patients and 28 age- and gender-matched healthy controls. Structurally, widespread GM atrophy was found in the svMCI patients that resided primarily in frontal (e.g., the superior and middle frontal gyri and medial prefrontal cortex) and temporal (the superior and inferior temporal gyri) brain regions as well as several subcortical brain sites (e.g., the thalamus and the caudate). Functionally, svMCI-related changes were predominantly found in the default mode network (DMN). Compared with the healthy controls, the svMCI patients exhibited decreased LFO amplitudes in the anterior part of the DMN (e.g., the medial prefrontal cortex), whereas increased LFO amplitudes in the posterior part of the DMN (e.g., the posterior cingulate/precuneus). As for functional connectivity density, the DMN regions (e.g., the posterior cingulate/precuneus, the medial prefrontal cortex and the middle temporal gyrus) consistently exhibited decreased functional connectivity. Finally, the overall patterns of functional alterations in LFO amplitudes and functional connectivity density remained little changed after controlling for structural GM volume losses, which suggests that functional abnormalities can be only partly explained by morphological GM volume changes. Together, our results indicate that svMCI patients exhibit widespread abnormalities in both structural GM volume and functional intrinsic brain activity, which have important implications in understanding the pathophysiological mechanism of svMCI. PMID- 23028607 TI - Movement coordination or movement interference: visual tracking and spontaneous coordination modulate rhythmic movement interference. AB - When an actor performs a rhythmic limb movement while observing a spatially incongruent movement he or she exhibits increased movement orthogonal to the instructed motion. Known as rhythmic movement interference, this phenomenon has been interpreted as a motor contagion effect, whereby observing the incongruent movement interferes with the intended movement and results in a motor production error. Here we test the hypothesis that rhythmic movement interference is an emergent property of rhythmic coordination. Participants performed rhythmic limb movements at a self-selected tempo while observing a computer stimulus moving in a congruent or incongruent manner. The degree to which participants visually tracked the stimulus was manipulated to influence whether participants became spontaneously entrained to the stimulus or not. Consistent with the rhythmic coordination hypothesis, participants only exhibited the rhythmic movement interference effect when they became spontaneously entrained to the incongruent stimulus. PMID- 23028608 TI - A remarkable new family of Jurassic insects (Neuroptera) with primitive wing venation and its phylogenetic position in Neuropterida. AB - BACKGROUND: Lacewings (insect order Neuroptera), known in the fossil record since the Early Permian, were most diverse in the Mesozoic. A dramatic variety of forms ranged in that time from large butterfly-like Kalligrammatidae to minute two winged Dipteromantispidae. PRINCIPAL FINDINGS: We describe the intriguing new neuropteran family Parakseneuridae fam. nov. with three new genera and 15 new species from the Middle Jurassic of Daohugou (Inner Mongolia, China) and the Early/Middle Jurassic of Sai-Sagul (Kyrgyzstan): Parakseneura undula gen. et sp. nov., P. albomacula gen. et sp. nov., P. curvivenis gen. et sp. nov., P. nigromacula gen. et sp. nov., P. nigrolinea gen. et sp. nov., P. albadelta gen. et sp. nov., P. cavomaculata gen. et sp. nov., P. inflata gen. et sp. nov., P. metallica gen. et sp. nov., P. emarginata gen. et sp. nov., P. directa gen. et sp. nov., Pseudorapisma jurassicum gen. et sp. nov., P. angustipenne gen. et sp. nov., P. maculatum gen. et sp. nov. (Daohugou); Shuraboneura ovata gen. et sp. nov. (Sai-Sagul). The family comprises large neuropterans with most primitive wing venation in the order indicated by the presence of ScA and AA1+2, and the dichotomous branching of MP, CuA, CuP, AA3+4, AP1+2. The phylogenetic position of Parakseneuridae was investigated using a phylogenetic analysis of morphological scoring for 33 families of extinct and extant Neuropterida combined with DNA sequence data for representatives of all extant families. Parakseneuridae were recovered in a clade with Osmylopsychopidae, Prohemerobiidae, and Ithonidae. CONCLUSIONS/SIGNIFICANCE: The presence of the presumed AA1+2 in wings of Parakseneuridae is a unique plesiomorphic condition hitherto unknown in Neuropterida, the clade comprising Neuroptera, Megaloptera, Raphidioptera. The relative uncertainty of phylogenetic position of Parakseneuridae and the majority of other families of Neuroptera reflects deficient paleontological data, especially from critical important periods for the order, earliest Triassic and latest Triassic/earliest Jurassic. PMID- 23028609 TI - Ontogeny of Toll-like receptor mediated cytokine responses of South African infants throughout the first year of life. AB - The first year of life represents a time of marked susceptibility to infections; this is particularly true for regions in sub-Saharan Africa. As innate immunity directs the adaptive immune response, the observed increased risk for infection as well as a suboptimal response to vaccination in early life may be due to less effective innate immune function. In this study, we followed a longitudinal cohort of infants born and raised in South Africa over the first year of life, employing the most comprehensive analysis of innate immune response to stimulation published to date. Our findings reveal rapid changes in innate immune development over the first year of life. This is the first report depicting dramatic differences in innate immune ontogeny between different populations in the world, with important implications for global vaccination strategies. PMID- 23028610 TI - Clinicopathological and prognostic significance of survivin over-expression in patients with esophageal squamous cell carcinoma: a meta-analysis. AB - BACKGROUND: The prognostic significance of survivin for survival of patients with esophageal squamous cell carcinoma (ESCC) remains controversial. Thus, meta analysis of the literatures was performed in order to demonstrate its expression impact on ESCC clinicopathological features and prognosis. METHODOLOGY: Relevant literatures were searched using PubMed, EMBASE and Medline Databases. Revman5.0 software was used to pool eligible studies and summary hazard ratio (HR). Correlation between survivin expression and clinicopathological features of ESCC was analyzed. PRINCIPAL FINDINGS: Final analysis of 523 patients from 7 eligible studies was performed. Combined HR of survivin location in nuclei suggested that survivin expression has an unfavorable impact on ESCC patients' survival (n = 277 in 3 studies; HR = 1.89, 95% CI: 1.45-2.96; Z = 4.69; P<0.0001). Nevertheless, combined HR of survivin location in cytoplasm displayed that survivin expression has no significance for prognosis of ESCC patients (n = 113 in 2 studies; HR = 0.96, 95% CI: 0.96-5.69; Z = 0.04; P = 0.97); Combined odds ratio (OR) of survivin location in cytoplasm indicated that survivin expression is associated with ESCC advanced stage (n = 113 in 2 studies; OR = 0.36, 95% CI: 0.14-0.93; Z = 2.10; P = 0.04). Whereas, combined OR of survivin location in nuclei exhibited that survivin over-expression has no correlation with cell differentiation grade, lymph node status, depth of invasion, stage, and metastasis of ESCC. CONCLUSIONS: This study showed that survivin expression detected by immunohistochemistry seems to be associated with a worse prognosis of ESCC patients. Survivin subcellular location may be an important factor impacting on ESCC development. Larger prospective studies should be performed to evaluate the status of survivin in predicting prognosis of patients with ESCC. PMID- 23028611 TI - Fibrin-Induced epithelial-to-mesenchymal transition of peritoneal mesothelial cells as a mechanism of peritoneal fibrosis: effects of pentoxifylline. AB - Excessive fibrin deposition in the peritoneum is thought to be involved in the development of encapsulating peritoneal sclerosis (EPS), an important cause of morbidity and mortality in peritoneal dialysis patients. We investigated fibrin induced epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) as a possible mechanism of fibrin involvement in EPS. In vitro, fibrin overlay of PMCs altered their morphology; increased alpha-smooth muscle actin, fibronectin, fibroblast specific protein-1, and alpha(v)beta(3) integrin expression; and decreased cytokeratin 18 and E-cadherin expression. Fibrin overlay also increased focal adhesion kinase and Src kinase phosphorylation. Fibrin-induced changes were inhibited by treating the cells with alpha(v)beta(3) integrin antibody or pentoxifylline (PTX). In a rat model, intraperitoneal injection of Staphylococcus aureus and fibrinogen induced severe EPS features, which were attenuated by PTX treatment. PTX-treated rats also showed preserved peritoneal ultrafiltration function and lower concentrations of cytokines than the untreated rats. S. aureus- and fibrinogen-injected rats had higher percentage of cytokeratin-positive cells in the omentum fibrotic tissue than controls; this was also reduced by PTX treatment. Our results suggest that fibrin induces EMT of PMCs by engaging alpha(v)beta(3) integrin and activating associated kinases. Our EPS animal model showed that fibrin-induced EMT was involved in the pathogenesis of peritoneal fibrosis and was inhibited by PTX. PMID- 23028612 TI - The redox-sensing regulator Rex modulates central carbon metabolism, stress tolerance response and biofilm formation by Streptococcus mutans. AB - The Rex repressor has been implicated in regulation of central carbon and energy metabolism in gram-positive bacteria. We have previously shown that Streptococcus mutans, the primary causative agent of dental caries, alters its transcriptome upon Rex-deficiency and renders S. mutans to have increased susceptibility to oxidative stress, aberrations in glucan production, and poor biofilm formation. In this study, we showed that rex in S. mutans is co-transcribed as an operon with downstream guaA, encoding a putative glutamine amidotransferase. Electrophoretic mobility shift assays showed that recombinant Rex bound promoters of target genes avidly and specifically, including those down-regulated in response to Rex-deficiency, and that the ability of recombinant Rex to bind to selected promoters was modulated by NADH and NAD(+). Results suggest that Rex in S. mutans can function as an activator in response to intracellular NADH/NAD(+) level, although the exact binding site for activator Rex remains unclear. Consistent with a role in oxidative stress tolerance, hydrogen peroxide challenge assays showed that the Rex-deficient mutant, TW239, and the Rex/GuaA double mutant, JB314, were more susceptible to hydrogen peroxide killing than the wildtype, UA159. Relative to UA159, JB314 displayed major defects in biofilm formation, with a decrease of more than 50-fold in biomass after 48-hours. Collectively, these results further suggest that Rex in S. mutans regulates fermentation pathways, oxidative stress tolerance, and biofilm formation in response to intracellular NADH/NAD(+) level. Current effort is being directed to further investigation of the role of GuaA in S. mutans cellular physiology. PMID- 23028613 TI - A nested case-control study of intrauterine exposure to persistent organochlorine pollutants and the risk of hypospadias. AB - BACKGROUND: Environmental exposures to endocrine disrupting chemicals have been suggested as a risk factor for male genital abnormalities such as hypospadias. The aim of this case-control study was to investigate the association between fetal exposure to persistent organochlorine pollutants (POP) and the risk for hypospadias. METHODOLOGY/PRINCIPAL FINDINGS: The Southern Sweden Maternity Cohort (SSMC) contains serum samples collected in early pregnancy among women in Southern Sweden. Linkages with the Medical Birth Register, the Malformation Register and the In-patient Register resulted in 390 SSMC mothers who had given birth to a boy with hypospadias in year 1986-2002 (mean 1995). For 237 of these (cases) sufficient amounts of serum for the chemical analyses were available. For each case, a control boy from the SSMC was randomly selected, matched for maternal age, birth year, parity and maternal smoking. PCB-153, p,p'-DDE and hexachlorbenzene (HCB) were used as biomarkers for POP exposure. The exposures were categorized into quartiles based on the distributions among the controls. There were no statistically significant trends between the a priori categorisation of the exposure variables and the risk for hypospadias. However, when the upper HCB quartile (>26 ng/ml) was compared to the other quartiles an odds ratio of 1.65 (95% CI 1.02 to 2.69) was obtained. p,p'-DDE levels above median (>1.0 ng/ml) compared to levels below 0.1 ng/ml gave an OR of 1.69 (95% CI 0.97 to 2.93). CONCLUSIONS: The present study suggests that fetal exposure to HCB and p,p'-DDE may be a risk factor for hypospadias. PMID- 23028614 TI - microRNA-222 targeting PTEN promotes neurite outgrowth from adult dorsal root ganglion neurons following sciatic nerve transection. AB - Dorsal root ganglia (DRG) neurons spontaneously undergo neurite growth after nerve injury. MicroRNAs (miRNAs), as small, non-coding RNAs, negatively regulate gene expression in a variety of biological processes. The roles of miRNAs in the regulation of responses of DRG neurons to injury stimuli, however, are not fully understood. Here, microarray analysis was performed to profile the miRNAs in L4 L6 DRGs following rat sciatic nerve transection. The 26 known miRNAs were differentially expressed at 0, 1, 4, 7, 14 d post injury, and the potential targets of the miRNAs were involved in nerve regeneration, as analyzed by bioinformatics. Among the 26 miRNAs, microRNA-222 (miR-222) was our research focus because its increased expression promoted neurite outgrowth while it silencing by miR-222 inhibitor reduced neurite outgrowth. Knockdown experiments confirmed that phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a major inhibitor of nerve regeneration, was a direct target of miR-222 in DRG neurons. In addition, we found that miR-222 might regulate the phosphorylation of cAMP response element binding protein (CREB) through PTEN, and c-Jun activation might enhance the miR-222 expression. Collectively, our data suggest that miR-222 could regulate neurite outgrowth from DRG neurons by targeting PTEN. PMID- 23028615 TI - Local effects of regulatory T cells in MUC1 transgenic mice potentiate growth of MUC1 expressing tumor cells in vivo. AB - MUC1 transgenic (MUC1.Tg) mice have widely been used as model recipients of cancer immunotherapy with MUC1. Although MUC1.Tg mice have previously been shown to be immunologically tolerant to MUC1, the involvement of regulatory T (Treg) cells in this phenotype remains unclear. Here, we showed that numbers of Treg cells in MUC1-expressing tumors were greater in MUC1.Tg mice than in control C57BL/6 (B6) mice, and that the growth of tumor cells expressing MUC1, but not that of control cells, in MUC1. Tg mice was faster than in B6 mice. The MUC1.Tg mice appeared to develop MUC1-specific peripheral tolerance, as transferred MUC1 specific T cells were unable to function in MUC1.Tg mice but were functional in control B6 mice. The suppressive function of CD4(+)CD25(high) cells from MUC1.Tg mice was more potent than that of cells from control B6 mice when Treg cell activity against MUC1-specific T cells was compared in vitro. Therefore, the enhanced growth of MUC1-expressing tumor cells in MUC1.Tg mice is likely due to the presence of MUC1-specific Treg cells. PMID- 23028616 TI - Keratinocyte growth factor improves epithelial structure and function in a mouse model of intestinal ischemia/reperfusion. AB - BACKGROUND: Intestinal ischemia/reperfusion (I/R) induces the desquamation of the intestinal epithelium, increases the intestinal permeability, and in patients often causes fatal conditions including sepsis and multiple organ failure. Keratinocyte growth factor (KGF) increases intestinal growth, although little is known about KGF activity on intestinal function after intestinal I/R. We hypothesized that KGF administration would improve the intestinal function in a mouse model of intestinal I/R. METHODS: Adult C57BL/6J mice were randomized to three groups: Sham, I/R group and I/R+KGF group. Mice were killed on day 5, and the small bowel was harvested for histology, wet weight, RNA and protein content analysis. Epithelial cell (EC) proliferation was detected by immunohistochemistry for PCNA, and apoptosis was determined by TUNEL staining. The expressions of Claudin-1 and ZO-1 were detected by immunohistochemistry. Epithelial barrier function was assessed with transepithelial resistance (TER). RESULTS: KGF significantly increased the intestinal wet weight, contents of intestinal protein and RNA, villus height, crypt depth and crypt cell proliferation, while KGF resulted in the decrease of epithelial apoptosis. KGF also stimulated the recovery of mucosal structures and attenuated the disrupted distribution of TJ proteins. Moreover, KGF attenuated the intestinal I/R-induced decrease in TER and maintained the intestinal barrier function. CONCLUSION: KGF administration improves the epithelial structure and barrier function in a mouse model of intestinal I/R. This suggests that KGF may have clinical applicability. PMID- 23028617 TI - Development of a fetal weight chart using serial trans-abdominal ultrasound in an East African population: a longitudinal observational study. AB - OBJECTIVE: To produce a fetal weight chart representative of a Tanzanian population, and compare it to weight charts from Sub-Saharan Africa and the developed world. METHODS: A longitudinal observational study in Northeastern Tanzania. Pregnant women were followed throughout pregnancy with serial trans abdominal ultrasound. All pregnancies with pathology were excluded and a chart representing the optimal growth potential was developed using fetal weights and birth weights. The weight chart was compared to a chart from Congo, a chart representing a white population, and a chart representing a white population but adapted to the study population. The prevalence of SGA was assessed using all four charts. RESULTS: A total of 2193 weight measurements from 583 fetuses/newborns were included in the fetal weight chart. Our chart had lower percentiles than all the other charts. Most importantly, in the end of pregnancy, the 10(th) percentiles deviated substantially causing an overestimation of the true prevalence of SGA newborns if our chart had not been used. CONCLUSIONS: We developed a weight chart representative for a Tanzanian population and provide evidence for the necessity of developing regional specific weight charts for correct identification of SGA. Our weight chart is an important tool that can be used for clinical risk assessments of newborns and for evaluating the effect of intrauterine exposures on fetal and newborn weight. PMID- 23028618 TI - Cost-effectiveness of the third-agent class in treatment-naive human immunodeficiency virus-infected patients in Portugal. AB - INTRODUCTION: Current Portuguese HIV treatment guidelines recommend initiating antiretroviral therapy with a regimen composed of two Nucleoside Reverse Transcriptase Inhibitors plus one Non-nucleoside Reverse Transcriptase Inhibitor (2NRTI+NNRTI) or two Nucleoside Reverse Transcriptase Inhibitors plus one boosted protease inhibitor (2NRTI+PI/r). Given the lower daily cost of NNRTI as the third agent when compared to the average daily costs of PI/r, it is relevant to estimate the long term impact of each treatment option in the Portuguese context. METHODS: We developed a microsimulation discrete events model for cost effectiveness analysis of HIV treatment, simulating individual paths from ART initiation to death. Four driving forces determine the course of events: CD4+ cell count, viral load, resistance and adherence. Distributions of time to event are conditional to individuals' characteristics and past history. Time to event was modeled using parametric survival analysis using Stata 11(r). Disease progression was structured according to therapy lines and the model was parameterized with cohort Portuguese observational data. All resources were valued at 2009 prices. The National Health Service's perspective was assumed considering a lifetime horizon and a 5% annual discount rate. RESULTS: In this analysis, initiating therapy with two Nucleoside Reverse Transcriptase Inhibitors plus one Non-nucleoside Reverse Transcriptase Inhibitor reduces the average number of switches by 17%, saves 19.573? per individual and increases life expectancy by 1.7 months showing to be a dominant strategy in 57% of the simulations when compared to two Nucleoside Reverse Transcriptase Inhibitors plus one boosted protease inhibitor. CONCLUSION: This study suggests that, when clinically valid, initiating therapy with two Nucleoside Reverse Transcriptase Inhibitors plus one Non-nucleoside Reverse Transcriptase Inhibitor is a cost saving strategy and equally effective when compared to two Nucleoside Reverse Transcriptase Inhibitors plus one boosted protease inhibitor as the first regimen. PMID- 23028620 TI - Whole genome duplication affects evolvability of flowering time in an autotetraploid plant. AB - Whole genome duplications have occurred recurrently throughout the evolutionary history of eukaryotes. The resulting genetic and phenotypic changes can influence physiological and ecological responses to the environment; however, the impact of genome copy number on evolvability has rarely been examined experimentally. Here, we evaluate the effect of genome duplication on the ability to respond to selection for early flowering time in lines drawn from naturally occurring diploid and autotetraploid populations of the plant Chamerion angustifolium (fireweed). We contrast this with the result of four generations of selection on synthesized neoautotetraploids, whose genic variability is similar to diploids but genome copy number is similar to autotetraploids. In addition, we examine correlated responses to selection in all three groups. Diploid and both extant tetraploid and neoautotetraploid lines responded to selection with significant reductions in time to flowering. Evolvability, measured as realized heritability, was significantly lower in extant tetraploids (^b(T) = 0.31) than diploids (^b(T) = 0.40). Neotetraploids exhibited the highest evolutionary response (^b(T) = 0.55). The rapid shift in flowering time in neotetraploids was associated with an increase in phenotypic variability across generations, but not with change in genome size or phenotypic correlations among traits. Our results suggest that whole genome duplications, without hybridization, may initially alter evolutionary rate, and that the dynamic nature of neoautopolyploids may contribute to the prevalence of polyploidy throughout eukaryotes. PMID- 23028619 TI - Biologically-directed modeling reflects cytolytic clearance of SIV-infected cells in vivo in macaques. AB - The disappointing outcomes of cellular immune-based vaccines against HIV-1 despite strong evidence for the protective role of CD8+ T lymphocytes (CTLs) has prompted revisiting the mechanisms of cellular immunity. Prior data from experiments examining the kinetics of Simian Immunodeficiency Virus (SIV) clearance in infected macaques with or without in vivo CD8 depletion were interpreted as refuting the concept that CTLs suppress SIV/HIV by direct killing of infected cells. Here we briefly review the biological evidence for CTL cytolytic activity in viral infections, and utilize biologically-directed modeling to assess the possibility of a killing mechanism for the antiviral effect of CTLs, taking into account the generation, proliferation, and survival of activated CD4+ and CD8+ T lymphocytes, as well as the life cycle of the virus. Our analyses of the published macaque data using these models support a killing mechanism, when one considers T lymphocyte and HIV-1 lifecycles, and factors such as the eclipse period before release of virions by infected cells, an exponential pattern of virion production by infected cells, and a variable lifespan for acutely infected cells. We conclude that for SIV/HIV pathogenesis, CTLs deserve their reputation as being cytolytic. PMID- 23028622 TI - Adolescent toluene inhalation in rats affects white matter maturation with the potential for recovery following abstinence. AB - Inhalant misuse is common during adolescence, with ongoing chronic misuse associated with neurobiological and cognitive abnormalities. While human imaging studies consistently report white matter abnormalities among long-term inhalant users, longitudinal studies have been lacking with limited data available regarding the progressive nature of such abnormalities, including the potential for recovery following periods of sustained abstinence. We exposed adolescent male Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (3,000 ppm) for 1 hour/day, 3 times/week for 8 weeks to model abuse patterns observed in adolescent and young adult human users. This dosing regimen resulted in a significant retardation in weight gain during the exposure period (p<0.05). In parallel, we performed longitudinal magnetic resonance imaging (T2-weighted) and diffusion tensor imaging prior to exposure, and after 4 and 8 weeks, to examine the integrity of white matter tracts, including the anterior commissure and corpus callosum. We also conducted imaging after 8 weeks of abstinence to assess for potential recovery. Chronic intermittent toluene exposure during adolescence and early adulthood resulted in white matter abnormalities, including a decrease in axial (p<0.05) and radial (p<0.05) diffusivity. These abnormalities appeared region-specific, occurring in the anterior commissure but not the corpus callosum and were not present until after at least 4 weeks of exposure. Toluene induced effects on both body weight and white matter parameters recovered following abstinence. Behaviourally, we observed a progressive decrease in rearing activity following toluene exposure but no difference in motor function, suggesting cognitive function may be more sensitive to the effects of toluene. Furthermore, deficits in rearing were present by 4 weeks suggesting that toluene may affect behaviour prior to detectable white matter abnormalities. Consequently, exposure to inhalants that contain toluene during adolescence and early adulthood appear to differentially affect white matter maturation and behavioural outcomes, although recovery can occur following abstinence. PMID- 23028621 TI - MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response. AB - Increasing evidence supports the involvement of microRNAs (miRNA) in the regulation of inflammation in human neurological disorders. In the present study we investigated the role of miR-146a, a key regulator of the innate immune response, in the modulation of astrocyte-mediated inflammation. Using Taqman PCR and in situ hybridization, we studied the expression of miR-146a in epilepsy associated glioneuronal lesions which are characterized by prominent activation of the innate immune response. In addition, cultured human astrocytes were used to study the regulation of miR-146a expression in response to proinflammatory cytokines. qPCR and western blot were used to evaluate the effects of overexpression or knockdown of miR-146a on IL-1beta signaling. Downstream signaling in the IL-1beta pathway, as well as the expression of IL-6 and COX-2 were evaluated by western blot and ELISA. Release several cytokines was evaluated using a human magnetic multiplex cytokine assay on a Luminex(r) 100TM/200TM platform. Increased expression of miR-146a was observed in glioneuronal lesions by Taqman PCR. MiR-146a expression in human glial cell cultures was strongly induced by IL-1beta and blocked by IL-1beta receptor antagonist. Modulation of miR-146a expression by transfection of astrocytes with anti-miR146a or mimic, regulated the mRNA expression levels of downstream targets of miR-146a (IRAK-1, IRAK-2 and TRAF-6) and the expression of IRAK-1 protein. In addition, the expression of IL-6 and COX-2 upon IL-1beta stimulation was suppressed by increased levels of miR-146a and increased by the reduction of miR-146a. Modulation of miR-146a expression affected also the release of several cytokines such as IL-6 and TNF-alpha. Our observations indicate that in response to inflammatory cues, miR-146a was induced as a negative-feedback regulator of the astrocyte-mediated inflammatory response. This supports an important role of miR 146a in human neurological disorders associated with chronic inflammation and suggests that this miR may represent a novel target for therapeutic strategies. PMID- 23028623 TI - Coadministration of lopinavir/ritonavir and rifampicin in HIV and tuberculosis co infected adults in South Africa. AB - BACKGROUND: In HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine--in routine practice--the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment. METHODOLOGY/PRINCIPLE FINDINGS: We conducted a retrospective review of HIV-infected patients who receiving second-line ART with a LPV/r-containing regimen who required concomitant TB treatment. We identified 29 patients; the median age was 36 years (IQR 29-40), 22 (76%) were female, the median CD4 cell count and viral load at first-line ART failure was 86 cells/mm3 (IQR 21-159) and 39,457 copies/mL (IQR 6,025-157,500), respectively. According to physician preference, 15 (52%) of 29 patients received super-boosted LPV/r (400 mg/400 mg) every 12 hours during TB treatment and 14 (48%) of 29 patients received standard dose LPV/r (400 mg/100 mg) twice daily during TB treatment. Among patients who received super-boosted LPV/r there was a trend towards a higher rate of symptomatic transaminitis (27% vs. 7%; p = 0.3), gastrointestinal toxicity (20% vs. 0%; p = 0.2) and a significantly increased need for treatment discontinuation (47% vs. 7%; p = 0.035. The durability of coadministered treatment was significantly shorter in patients who received super boosted lopinavir/ritonavir with TB treatment compared to patients who received standard lopinavir/ritonavir dosing (log rank, P = 0.036). The rate of virologic failure was not higher in patients with unadjusted LPV/r dosing. CONCLUSIONS/SIGNIFICANCE: We observed a high rate of toxicity and need for treatment discontinuation among patients on standard rifampicin-based TB treatment who received super-boosted LPV/r. PMID- 23028624 TI - Regulation of energy metabolism by the extracytoplasmic function (ECF) sigma factors of Arcobacter butzleri. AB - The extracytoplasmic function (ECF) sigma factors are fundamental for bacterial adaptation to distinct environments and for survival under different stress conditions. The emerging pathogen Arcobacter butzleri possesses seven putative pairs of sigma/anti-sigma factors belonging to the ECF family. Here, we report the identification of the genes regulated by five out of the seven A. butzleri ECF sigma factors. Three of the ECF sigma factors play an apparent role in transport, energy generation and the maintenance of redox balance. Several genes like the nap, sox and tct genes are regulated by more than one ECF sigma factor, indicating that the A. butzleri ECF sigma factors form a network of overlapping regulons. In contrast to other eubacteria, these A. butzleri ECF regulons appear to primarily regulate responses to changing environments in order to meet metabolic needs instead of an obvious role in stress adaptation. PMID- 23028625 TI - Influence of tryptophan contained in 1-Methyl-Tryptophan on antimicrobial and immunoregulatory functions of indoleamine 2,3-dioxygenase. AB - Indoleamine 2,3-dioxygenase (IDO) has been identified as an important antimicrobial and immunoregulatory effector molecule essential for the establishment of tolerance by regulating local tryptophan (Trp) concentrations. On the other hand, the immunosuppressive capacity of IDO can have detrimental effects for the host as it can lead to deleterious alterations of the immune response by promoting tolerance to some types of tumors. To suppress this disadvantageous IDO effect, the competitive inhibitor 1-Methyl-Tryptophan (1-MT) is being tested in clinical trials. However, it remains inconclusive which stereoisomer of 1-MT is the more effective inhibitor of IDO-mediated immunosuppression. While IDO enzyme activity is more efficiently inhibited by 1-L MT in cell-free or in vitro settings, 1-D-MT is superior to 1-L-MT in the enhancement of anti-tumor responses in vivo.Here, we present new data showing that commercially available 1-L-MT lots contain tryptophan in amounts sufficient to compensate for the IDO-mediated tryptophan depletion in vitro. The addition of 1-L-MT abrogated IDO-mediated antimicrobial effects and permitted the growth of the tryptophan-auxotroph microorganisms Staphylococcus aureus and Toxoplasma gondii. Consistent with this, the tryptophan within 1-L-MT lots was sufficient to antagonize IDO-mediated inhibition of T cell responses. Mass spectrometry (MS) analysis revealed not only tryptophan within 1-L-MT, but also the incorporation of this tryptophan in bacterial and human proteins that were generated in the presence of 1-L-MT in otherwise tryptophan-free conditions. In summary, these data reveal that tryptophan within 1-L-MT can affect the results of in vitro studies in an L-stereospecific and IDO-independent way. PMID- 23028626 TI - Combined therapy with cytokine-induced killer cells and oncolytic adenovirus expressing IL-12 induce enhanced antitumor activity in liver tumor model. AB - Both adoptive immunotherapy and gene therapy hold a great promise for treatment of malignancies. However, these strategies exhibit limited anti-tumor activity, when they are used alone. In this study, we explore whether combination of cytokine-induced killer (CIK) adoptive immunotherapy with oncolytic adenovirus mediated transfer of human interleukin-12 (hIL-12) gene induce the enhanced antitumor potency. Our results showed that oncolytic adenovirus carrying hIL-12 (AdCN205-IL12) could produce high levels of hIL-12 in liver cancer cells, as compared with replication-defective adenovirus expressing hIL-12 (Ad-IL12). AdCN205-IL12 could specifically induce cytotoxocity to liver cancer cells. Combination of CIK cells with AdCN205-IL12 could induce higher antitumor activity to liver cancer cells in vitro than that induced by either CIK or AdCN205-IL12 alone, or combination of CIK and control vector AdCN205-GFP. Furthermore, treatment of the established liver tumors with the combined therapy of CIK cells and AdCN205-IL12 resulted in tumor regression and long-term survival. High level expression of hIL-12 in tumor tissues could increase traffic of CIK cells to tumor tissues and enhance their antitumor activities. Our study provides a novel strategy for the therapy of cancer by the combination of CIK adoptive immunotherapy with oncolytic adenovirus-mediated transfer of immune stimulatory molecule hIL-12. PMID- 23028627 TI - Human hepatocyte growth factor (hHGF)-modified hepatic oval cells improve liver transplant survival. AB - Despite progress in the field of immunosuppression, acute rejection is still a common postoperative complication following liver transplantation. This study aims to investigate the capacity of the human hepatocyte growth factor (hHGF) in modifying hepatic oval cells (HOCs) administered simultaneously with orthotopic liver transplantation as a means of improving graft survival. HOCs were activated and isolated using a modified 2-acetylaminofluorene/partial hepatectomy (2 AAF/PH) model in male Lewis rats. A HOC line stably expressing the HGF gene was established following stable transfection of the pBLAST2-hHGF plasmid. Our results demonstrated that hHGF-modified HOCs could efficiently differentiate into hepatocytes and bile duct epithelial cells in vitro. Administration of HOCs at the time of liver transplantation induced a wider distribution of SRY-positive donor cells in liver tissues. Administration of hHGF-HOC at the time of transplantation remarkably prolonged the median survival time and improved liver function for recipients compared to these parameters in the other treatment groups (P<0.05). Moreover, hHGF-HOC administration at the time of liver transplantation significantly suppressed elevation of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) levels while increasing the production of IL-10 and TGF-beta1 (P<0.05). HOC or hHGF-HOC administration promoted cell proliferation, reduced cell apoptosis, and decreased liver allograft rejection rates. Furthermore, hHGF-modified HOCs more efficiently reduced acute allograft rejection (P<0.05 versus HOC transplantation only). Our results indicate that the combination of hHGF-modified HOCs with liver transplantation decreased host anti-graft immune responses resulting in a reduction of allograft rejection rates and prolonging graft survival in recipient rats. This suggests that HOC-based cell transplantation therapies can be developed as a means of treating severe liver injuries. PMID- 23028628 TI - Clinical analysis of 36 cases of autoimmune pancreatitis in China. AB - BACKGROUND: To improve the early identification of autoimmune pancreatitis in China by a retrospective analysis of clinical data from AIP patients. METHODOLOGY/PRINCIPAL FINDINGS: The analysis included 36 patients admitted by the surgery department of our hospital from January 2003 to October 2011 whose postoperative pathological confirmations were consistent with the histological criteria of Honolulu Consensus Document. The clinical phenotypes associated with the histopathologic patterns of LPSP and IDCP were referred to as type 1 and type 2 of AIP, respectively. A retrospective analysis of clinical features, serological data, pathological findings and imageological records was performed in line with the subtypes of AIP. Type 1 showing a sex predilection (males) was commonly more dominant than type 2 in all AIP. Type 2 without a gender predilection was, on average, a decade younger than type 1. Type 1 was inferior to type 2 in ALT, ALP and gamma-GT with statistical significance (P = 0.044, 0.025 and 0.013). Type 1 was inferior to type 2 in AST with difference close to statistical significance (P = 0.072). Histopathology revealed frequent lymphoplasmacytic infiltration with less frequent infiltration of neutrophils, eosinophils and fibroblasts. Diffuse and intensive interstitial fibrosis could be seen. The changes of pancreatic head were more frequently seen in type 2 than in type 1 (P = 0.05). Plasma cells staining of IgG4 at a density of over 30 or more cells per high-power field appeared to be a specific finding in China with type 1. Imageology found a diffusely or focally enlarged pancreas, most frequently a mass or enlargement in the pancreatic head, characteristic capsule-like rim, calcification or pancreatic calculus and cystic degeneration. CONCLUSIONS/SIGNIFICANCE: AIP is a unique type of chronic pancreatitis and has distinctive serological, pathological and imageological characteristics, which should be used for differentiation from pancreatic cancer. PMID- 23028629 TI - Quantitative measurements of autobiographical memory content. AB - Autobiographical memory (AM), subjective recollection of past experiences, is fundamental in everyday life. Nevertheless, characterization of the spontaneous occurrence of AM, as well as of the number and types of recollected details, remains limited. The CRAM (Cue-Recalled Autobiographical Memory) test (http://cramtest.info) adapts and combines the cue-word method with an assessment that collects counts of details recalled from different life periods. The SPAM (Spontaneous Probability of Autobiographical Memories) protocol samples introspection during everyday activity, recording memory duration and frequency. These measures provide detailed, naturalistic accounts of AM content and frequency, quantifying essential dimensions of recollection. AM content (~20 details/recollection) decreased with the age of the episode, but less drastically than the probability of reporting remote compared to recent memories. AM retrieval was frequent (~20/hour), each memory lasting ~30 seconds. Testable hypotheses of the specific content retrieved in a fixed time from given life periods are presented. PMID- 23028630 TI - Vagus nerve stimulation reduces body weight and fat mass in rats. AB - Among the manifold effects of vagus nerve stimulation (VNS) delivered as an add on treatment to patients with drug-resistant epilepsy, a moderate loss of body weight has been observed in some individuals. We have now investigated this effect in rats. Exposure of rats to VNS for 4 weeks reduced feed conversion efficiency as well as body weight gain (by ~25%) and the amount of mesenteric adipose tissue (by ~45%) in comparison with those in sham-operated control animals. A pair-fed experiment showed that both lower dietary intake and increase energy expenditure independently contributed to the reduction of body weight and mesenteric adipose tissue. Moreover, VNS increased the level of non-esterified fatty acids in plasma and mesenteric adipose tissue by ~50 and 80%, respectively, without affecting that in the liver. In addition, VNS reduced the amounts of endocannabinoids and increased N-palmitoylethanolamide, an endogenous ligand of the transcription factor PPARalpha (peroxisome proliferator-activated receptor alpha) in mesenteric adipose tissue but not in the hypothalamus. These effects were accompanied by increased expression of the gene for brain-derived neurotrophic factor (BDNF) in the hypothalamus and up-regulation of the abundance of PPARalpha in the liver. Our results suggest that the reduction in body fat induced by VNS in rats may result from the action of both central and peripheral mediators. The reduced feed conversion efficiency associated with VNS may be mediated by hypothalamic BDNF, down-regulation of endocannabinoid tone in mesenteric adipose tissue and a PPARalpha-dependent increase in fatty acid oxidation in the liver, which in concerted action may account for the anorexic effect and increased energy expenditure. PMID- 23028631 TI - L-selectin and skin damage in systemic sclerosis. AB - BACKGROUND: L-selectin ligands are induced on the endothelium of inflammatory sites. L-selectin expression on neutrophils and monocytes may mediate the primary adhesion of these cells at sites of inflammation by mediating the leukocyte leukocyte interactions that facilitate their recruitment. L-selectin retains functional activity in its soluble form. Levels of soluble L-selectin have been reported as both elevated and lowered in patients with systemic sclerosis (SSc). This preliminary study seeks to discern amongst these disparate results and to discover whether there is an association between L-selectin concentrations in plasma and skin damage in SSc patients. METHODOLOGY AND PRINCIPAL FINDINGS: Nineteen cases with limited systemic sclerosis (lSSc) and 11 cases with diffuse systemic sclerosis (dSSc) were compared on a pairwise basis to age- and sex matched controls. Criteria of the American College of Rheumatology were used to diagnose SSc. Skin involvement was assessed using the modified Rodnan skin score (mRSS). We find no association between mRSS and plasma L-selectin concentration in lSSc cases (p = 0.9944) but a statistically significant negative correlation in dSSc cases (R(2) = 73.11 per cent, p = 0.0008). The interpretation of the slope for dSSc cases is that for each increase of 100 ng/ml in soluble L-selectin concentration, the mRSS drops 4.22 (95 per cent CI: 2.29, 6.16). There was also a highly statistically significant negative correlation between sL-selectin and disease activity (p = 0.0007) and severity (p = 0.0007) in dSSc cases but not in lSSc cases (p = 0.2596, p = 0.7575, respectively). CONCLUSIONS AND SIGNIFICANCE: No effective treatments exist for skin damage in SSc patients. Nor is there a laboratory alternative to the modified Rodnan skin score as is the case for other organs within the body. Modulation of circulating L-selectin is a promising target for reducing skin damage in dSSc patients. Plasma levels of soluble L selectin could serve as an outcome measure for dSSc patients in clinical trials. PMID- 23028632 TI - The identification of a novel gene, MAPO2, that is involved in the induction of apoptosis triggered by O6-methylguanine. AB - O6-Methylguanine, one of alkylated DNA bases, is especially mutagenic. Cells containing this lesion are eliminated by induction of apoptosis, associated with the function of mismatch repair (MMR) proteins. A retrovirus-mediated gene-trap mutagenesis was used to isolate new genes related to the induction of apoptosis, triggered by the treatment with an alkylating agent, N-methyl-N-nitrosourea (MNU). This report describes the identification of a novel gene, MAPO2 (O6 methylguanine-induced apoptosis 2), which is originally annotated as C1orf201. The MAPO2 gene is conserved among a wide variety of multicellular organisms and encodes a protein containing characteristic PxPxxY repeats. To elucidate the function of the gene product in the apoptosis pathway, a human cell line derived from HeLa MR cells, in which the MAPO2 gene was stably knocked down by expressing specific miRNA, was constructed. The knockdown cells grew at the same rate as HeLa MR, thus indicating that MAPO2 played no role in the cellular growth. After exposure to MNU, HeLa MR cells and the knockdown cells underwent cell cycle arrest at G2/M phase, however, the production of the sub-G1 population in the knockdown cells was significantly suppressed in comparison to that in HeLa MR cells. Moreover, the activation of BAK and caspase-3, and depolarization of mitochondrial membrane, hallmarks for the induction of apoptosis, were also suppressed in the knockdown cells. These results suggest that the MAPO2 gene product might positively contribute to the induction of apoptosis triggered by O6 methylguanine. PMID- 23028633 TI - Loss of CCR7 expression on CD56(bright) NK cells is associated with a CD56(dim)CD16+ NK cell-like phenotype and correlates with HIV viral load. AB - NK cells are pivotal sentinels of the innate immune system and distinct subpopulations in peripheral blood have been described. A number of studies addressed HIV-induced alterations of NK cell phenotype and functionality mainly focusing on CD56(dim)CD16+ and CD56-CD16+ NK cells. However, the impact of HIV infection on CD56(bright) NK cells is less well understood. Here we report a rise of CD56(bright) NK cells in HIV-infected individuals, which lack CCR7-expression and strongly correlate with HIV viral load. CCR7-CD56(bright) NK cells were characterized by increased cytolytic potential, higher activation states and a more differentiated phenotype. These cells thus acquired a number of features of CD56(dim)CD16+ NK cells. Furthermore, CD56(bright) NK cells from HIV patients exhibited higher degranulation levels compared to uninfected individuals. Thus, chronic HIV-infection is associated with a phenotypic and functional shift of CD56(bright) NK cells, which provides a novel aspect of HIV-associated pathogenesis within the NK cell compartment. PMID- 23028634 TI - Women's roles in voluntary medical male circumcision in Nyanza Province, Kenya. AB - Women are an important audience for voluntary medical male circumcision (VMMC) communication messages so that they know that VMMC provides only partial protection against HIV. They may also be able to influence their male partners to get circumcised and practice other HIV protective measures after VMMC. This study was conducted in two phases of qualitative data collection. Phase 1 used in-depth interviews to explore women's understanding of partial protection and their role in VMMC. Phase 2 built on the findings from the Phase 1, using focus groups to test VMMC communication messages currently used in Nyanza Province and to further explore women's roles in VMMC. Sixty-four sexually active women between the ages of 18 and 35 participated. In Phase 1, all women said they had heard of partial protection, though some were not able to elaborate on what the concept means. When women in Phase 2 were exposed to messages about partial protection, however, participants understood the messages well and were able to identify the main points. In Phases 1 and 2, many participants said that they had discussed VMMC with their partner, and for several, it was a joint decision for the man to go for VMMC. These findings suggest that current VMMC messaging is reaching women, though communications could more effectively target women to increase their ability to communicate about partial HIV protection from VMMC. Also, women seem to be playing an important role in encouraging men to get circumcised, so reaching out to women could be a valuable intervention strategy for increasing VMMC uptake and promoting use of other HIV protective measures after VMMC. PMID- 23028635 TI - Crystal structures of human CaMKIalpha reveal insights into the regulation mechanism of CaMKI. AB - Human calcium/calmodulin-dependent protein kinase I (CaMKI) plays pivotal roles in the nervous system. The activity of human CaMKI is regulated by a regulatory region including an autoinhibitory segment and a CaM-binding segment. We report here four structures of three CaMKIalpha truncates in apo form and in complexes with ATP. In an apo, autoinhibited structure, the activation segment adopts a unique helical conformation which together with the autoinhibitory segment constrains helices alphaC and alphaD in inactive conformations, sequesters Thr177 from being phosphorylated, and occludes the substrate-binding site. In an ATP bound, inactive structure, the activation segment is largely disordered and the CaM-binding segment protrudes out ready for CaM binding. In an ATP-bound, active structure, the regulatory region is dissociated from the catalytic core and the catalytic site assumes an active conformation. Detailed structural analyses reveal the interplay of the regulatory region, the activation segment, and the nucleotide-binding site in the regulation of CaMKI. PMID- 23028636 TI - Host platelets and, in part, neutrophils mediate lung accumulation of transfused UVB-irradiated human platelets in a mouse model of acute lung injury. AB - We previously reported that ultraviolet light B (UVB)-treated human platelets (hPLTs) can cause acute lung injury (ALI) in a two-event SCID mouse model in which the predisposing event was Lipopolysaccharide (LPS) injection and the second event was infusion of UVB-treated hPLTs. To delineate contributions of host mouse platelets (mPLTs) and neutrophils in the pathogenesis of ALI in this mouse model, we depleted mPLTs or neutrophils and measured hPLT accumulation in the lung. We also assessed lung injury by protein content in bronchoalveolar lavage fluid (BALF). LPS injection followed by infusion of UVB-treated hPLTs resulted in sequestration of both mPLTs and hPLTs in the lungs of SCID mice, although the numbers of neutrophils in the lung were not significantly different from the control group. Depletion of mouse neutrophils caused only a mild reduction in UVB-hPLTs accumulation in the lungs and a mild reduction in protein content in BALF. In comparison, depletion of mPLTs almost completely abolished hPLTs accumulation in the lung and significantly reduced protein content in BALF. UVB-treated hPLTs bound to host mPLTs, but did not bind to neutrophils in the lung. Aspirin treatment of hPLTs in vitro abolished hPLT accumulation in the lung and protected mice from lung injury. Our data indicate that host mPLTs accumulated in the lungs in response to an inflammatory challenge and subsequently mediated the attachment of transfused UVB-hPLTs. Neutrophils also recruited a small percentage of platelets to the lung. These findings may help develop therapeutic strategies for ALI which could potentially result from transfusion of UV illuminated platelets. PMID- 23028638 TI - The chemokine receptor CCR5, a therapeutic target for HIV/AIDS antagonists, is critical for recovery in a mouse model of Japanese encephalitis. AB - Japanese encephalitis is a severe central nervous system (CNS) inflammatory disease caused by the mosquito-borne flavivirus, Japanese encephalitis virus (JEV). In the current study we have investigated the immune responses against JEV in mice lacking expression of the chemokine receptor CCR5, which functions in activation and chemotaxis of leukocytes during infection. We show that CCR5 serves as a host antiviral factor against Japanese encephalitis, with CCR5 deficiency markedly increasing mortality, and viral burden in the CNS. Humoral immune responses, which are essential in recovery from JEV infection, were of similar magnitude in CCR5 sufficient and deficient mice. However, absence of CCR5 resulted in a multifaceted deficiency of cellular immune responses characterized by reduced natural killer and CD8+ T cell activity, low splenic cellularity, and impaired trafficking of leukocytes to the brain. Interestingly, adoptive transfer of immune spleen cells, depleted of B lymphocytes, increased resistance of CCR5 deficient recipient mice against JEV regardless of whether the cells were obtained from CCR5-deficient or wild-type donor mice, and only when transferred at one but not at three days post-challenge. This result is consistent with a mechanism by which CCR5 expression enhances lymphocyte activation and thereby promotes host survival in Japanese encephalitis. PMID- 23028639 TI - Artificial regulation of water level and its effect on aquatic macrophyte distribution in Taihu Lake. AB - Management of water levels for flood control, water quality, and water safety purposes has become a priority for many lakes worldwide. However, the effects of water level management on the distribution and composition of aquatic vegetation has received little attention. Relevant studies have used either limited short term or discrete long-term data and thus are either narrowly applicable or easily confounded by the effects of other environmental factors. We developed classification tree models using ground surveys combined with 52 remotely sensed images (15-30 m resolution) to map the distributions of two groups of aquatic vegetation in Taihu Lake, China from 1989-2010. Type 1 vegetation included emergent, floating, and floating-leaf plants, whereas Type 2 consisted of submerged vegetation. We sought to identify both inter- and intra-annual dynamics of water level and corresponding dynamics in the aquatic vegetation. Water levels in the ten-year period from 2000-2010 were 0.06-0.21 m lower from July to September (wet season) and 0.22-0.27 m higher from December to March (dry season) than in the 1989-1999 period. Average intra-annual variation (CV(a)) decreased from 10.21% in 1989-1999 to 5.41% in 2000-2010. The areas of both Type 1 and Type 2 vegetation increased substantially in 2000-2010 relative to 1989-1999. Neither annual average water level nor CV(a) influenced aquatic vegetation area, but water level from January to March had significant positive and negative correlations, respectively, with areas of Type 1 and Type 2 vegetation. Our findings revealed problems with the current management of water levels in Taihu Lake. To restore Taihu Lake to its original state of submerged vegetation dominance, water levels in the dry season should be lowered to better approximate natural conditions and reinstate the high variability (i.e., greater extremes) that was present historically. PMID- 23028637 TI - A complex systems approach to evaluate HIV prevention in metropolitan areas: preliminary implications for combination intervention strategies. AB - BACKGROUND: HIV transmission among injecting and non-injecting drug users (IDU, NIDU) is a significant public health problem. Continuing propagation in endemic settings and emerging regional outbreaks have indicated the need for comprehensive and coordinated HIV prevention. We describe the development of a conceptual framework and calibration of an agent-based model (ABM) to examine how combinations of interventions may reduce and potentially eliminate HIV transmission among drug-using populations. METHODOLOGY/PRINCIPAL FINDINGS: A multidisciplinary team of researchers from epidemiology, sociology, geography, and mathematics developed a conceptual framework based on prior ethnographic and epidemiologic research. An ABM was constructed and calibrated through an iterative design and verification process. In the model, "agents" represent IDU, NIDU, and non-drug users who interact with each other and within risk networks, engaging in sexual and, for IDUs, injection-related risk behavior over time. Agents also interact with simulated HIV prevention interventions (e.g., syringe exchange programs, substance abuse treatment, HIV testing) and initiate antiretroviral treatment (ART) in a stochastic manner. The model was constructed to represent the New York metropolitan statistical area (MSA) population, and calibrated by comparing output trajectories for various outcomes (e.g., IDU/NIDU prevalence, HIV prevalence and incidence) against previously validated MSA-level data. The model closely approximated HIV trajectories in IDU and NIDU observed in New York City between 1992 and 2002, including a linear decrease in HIV prevalence among IDUs. Exploratory results are consistent with empirical studies demonstrating that the effectiveness of a combination of interventions, including syringe exchange expansion and ART provision, dramatically reduced HIV prevalence among IDUs during this time period. CONCLUSIONS/SIGNIFICANCE: Complex systems models of adaptive HIV transmission dynamics can be used to identify potential collective benefits of hypothetical combination prevention interventions. Future work will seek to inform novel strategies that may lead to more effective and equitable HIV prevention strategies for drug-using populations. PMID- 23028640 TI - Inverse regulation of the cytosolic Ca2+ buffer parvalbumin and mitochondrial volume in muscle cells via SIRT1/PGC-1alpha axis. AB - Skeletal muscles show a high plasticity to cope with various physiological demands. Different muscle types can be distinguished by the force, endurance, contraction/relaxation kinetics (fast-twitch vs. slow-twitch muscles), oxidative/glycolytic capacity, and also with respect to Ca2+-signaling components. Changes in Ca2+ signaling and associated Ca2+-dependent processes are thought to underlie the high adaptive capacity of muscle fibers. Here we investigated the consequences and the involved mechanisms caused by the ectopic expression of the Ca2+-binding protein parvalbumin (PV) in C2C12 myotubes in vitro, and conversely, the effects caused by its absence in in fast-twitch muscles of parvalbumin null-mutant (PV-/-) mice in vivo. The absence of PV in fast-twitch muscle tibialis anterior (TA) resulted in an increase in the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) and of its positive regulator, the deacetylase sirtuin 1 (SIRT1). TA muscles from PV-/- mice also have an increased mitochondrial volume. Mild ionophore treatment of control (PV-devoid) C2C12 myotubes causing a moderate elevation in [Ca2+](c) resulted in an increase in mitochondrial volume, together with elevated PGC 1alpha and SIRT1 expression levels, whilst it increased PV expression levels in myotubes stably transfected with PV. In PV-expressing myotubes the mitochondrial volume, PGC-1alpha and SIRT1 were significantly lower than in control C2C12 myotubes already at basal conditions and application of ionophore had no effect on either one. SIRT1 activation causes a down-regulation of PV in transfected myotubes, whilst SIRT1 inhibition has the opposite effect. We conclude that PV expression and mitochondrial volume in muscle cells are inversely regulated via a SIRT1/PGC-1alpha signaling axis. PMID- 23028641 TI - FRUIT, a scar-free system for targeted chromosomal mutagenesis, epitope tagging, and promoter replacement in Escherichia coli and Salmonella enterica. AB - Recombineering is a widely-used approach to delete genes, introduce insertions and point mutations, and introduce epitope tags into bacterial chromosomes. Many recombineering methods have been described, for a wide range of bacterial species. These methods are often limited by (i) low efficiency, and/or (ii) introduction of "scar" DNA into the chromosome. Here, we describe a rapid, efficient, PCR-based recombineering method, FRUIT, that can be used to introduce scar-free point mutations, deletions, epitope tags, and promoters into the genomes of enteric bacteria. The efficiency of FRUIT is far higher than that of the most widely-used recombineering method for Escherichia coli. We have used FRUIT to introduce point mutations and epitope tags into the chromosomes of E. coli K-12, Enterotoxigenic E. coli, and Salmonella enterica. We have also used FRUIT to introduce constitutive and inducible promoters into the chromosome of E. coli K-12. Thus, FRUIT is a versatile, efficient recombineering approach that can be applied in multiple species of enteric bacteria. PMID- 23028642 TI - Glucose tolerance during pulmonary exacerbations in children with cystic fibrosis. AB - BACKGROUND: Patients with Cystic Fibrosis (CF) are relatively insulinopenic and are at risk of diabetes, especially during times of stress. There is a paucity of data in the literature describing glucose tolerance during CF pulmonary exacerbations. We hypothesised that glucose tolerance would be worse during pulmonary exacerbations in children with CF than during clinical stability. METHODS: Patients with CF, 10 years or older, admitted with a pulmonary exacerbation underwent an OGTT within 48 hours of admission. A repeat OGTT was performed 4 to 6 weeks post discharge when the patients were well. RESULTS: Nine patients completed the study. Four patients were found to have normal glucose tolerance, 3 with impaired and 2 with CF related diabetes during the exacerbation. Mean change in 2-hour glucose was 1.1 mmol (SD = 0.77). At the follow up OGTT, 8 of 9 (89%) remained within their respective glucose tolerance status groupings. CONCLUSION: The findings of this study show that there is little difference in glucose tolerance during CF exacerbations compared to clinical stability in the majority of patients. PMID- 23028643 TI - Biomass production from electricity using ammonia as an electron carrier in a reverse microbial fuel cell. AB - The storage of renewable electrical energy within chemical bonds of biofuels and other chemicals is a route to decreasing petroleum usage. A critical challenge is the efficient transfer of electrons into a biological host that can covert this energy into high energy organic compounds. In this paper, we describe an approach whereby biomass is grown using energy obtained from a soluble mediator that is regenerated electrochemically. The net result is a separate-stage reverse microbial fuel cell (rMFC) that fixes CO2 into biomass using electrical energy. We selected ammonia as a low cost, abundant, safe, and soluble redox mediator that facilitated energy transfer to biomass. Nitrosomonas europaea, a chemolithoautotroph, was used as the biocatalyst due to its inherent capability to utilize ammonia as its sole energy source for growth. An electrochemical reactor was designed for the regeneration of ammonia from nitrite, and current efficiencies of 100% were achieved. Calculations indicated that overall bioproduction efficiency could approach 2.7+/-0.2% under optimal electrolysis conditions. The application of chemolithoautotrophy for industrial bioproduction has been largely unexplored, and results suggest that this and related rMFC platforms may enable biofuel and related biochemical production. PMID- 23028645 TI - Phylogenetic properties of RNA viruses. AB - A new word, phylodynamics, was coined to emphasize the interconnection between phylogenetic properties, as observed for instance in a phylogenetic tree, and the epidemic dynamics of viruses, where selection, mediated by the host immune response, and transmission play a crucial role. The challenges faced when investigating the evolution of RNA viruses call for a virtuous loop of data collection, data analysis and modeling. This already resulted both in the collection of massive sequences databases and in the formulation of hypotheses on the main mechanisms driving qualitative differences observed in the (reconstructed) evolutionary patterns of different RNA viruses. Qualitatively, it has been observed that selection driven by the host immune response induces an uneven survival ability among co-existing strains. As a consequence, the imbalance level of the phylogenetic tree is manifestly more pronounced if compared to the case when the interaction with the host immune system does not play a central role in the evolutive dynamics. While many imbalance metrics have been introduced, reliable methods to discriminate in a quantitative way different level of imbalance are still lacking. In our work, we reconstruct and analyze the phylogenetic trees of six RNA viruses, with a special emphasis on the human Influenza A virus, due to its relevance for vaccine preparation as well as for the theoretical challenges it poses due to its peculiar evolutionary dynamics. We focus in particular on topological properties. We point out the limitation featured by standard imbalance metrics, and we introduce a new methodology with which we assign the correct imbalance level of the phylogenetic trees, in agreement with the phylodynamics of the viruses. Our thorough quantitative analysis allows for a deeper understanding of the evolutionary dynamics of the considered RNA viruses, which is crucial in order to provide a valuable framework for a quantitative assessment of theoretical predictions. PMID- 23028644 TI - Resting-state functional connectivity patterns predict Chinese word reading competency. AB - Resting-state functional connectivity (RSFC) offers a novel approach to reveal the temporal synchronization of functionally related brain regions. Recent studies have identified several RSFCs whose strength was associated with reading competence in alphabetic languages. In the present study, we examined the role of intrinsic functional relations for reading a non-alphabetic language--Chinese--by correlating RSFC maps of nine Chinese reading-related seed regions and reaction time in the single-character reading task. We found that Chinese reading efficiency was positively correlated with the connection between left inferior occipital gyrus and left superior parietal lobule, between right posterior fusiform gyrus and right superior parietal lobule, and between left inferior temporal gyrus and left inferior parietal lobule. These results could not be attributed to inter-individual differences arising from the peripheral processes of the reading task such as visual input detection and articulation. The observed RSFC-reading correlation relationships are discussed in the framework of Chinese character reading, including visuospatial analyses and semantic/phonological processes. PMID- 23028646 TI - A novel type of colony formation in marine planktonic diatoms revealed by atomic force microscopy. AB - Diatoms have evolved a variety of colonial life forms in which cells are connected by organic threads, mucilage pads or silicate structures. In this study, we provide the first description of a novel strategy of colony formation among marine planktonic diatoms. Bacteriastrum jadranum forms loose but regular chains with distinct heterovalvate terminal cells. The colonial cells and their siliceous projections, the setae, are not in direct contact; instead, they are enclosed within the optically transparent organic matrix. This cell jacket structure was detected by staining procedure with Alcian Blue, which showed that the polysaccharides are predominant matrix constituents and revealed that the jacket reaches the span of the setae. The scanning electron microscopy (SEM) observations showed distinguishable fibrillar network firmly associated with cells. Using atomic force microscopy (AFM), we were able to visualise and characterise the cell jacket structure at molecular resolution. At nanoscale resolution, the cell jacket appears as a cross-linked fibrillar network organised into a recognisable structure. The circular patches of self-repeating pattern (hexagonal pores with openings of 8-100 nm) are connected through thicker surrounding fibrils and reinforced by branching fibrils. The pore-forming fibrils within the patches are only 0.6-1.6 nm high, the surrounding fibrils connecting patches are 2.0-2.8 nm high, and the branching fibrils are considerably wider but not higher than 4.0 nm. The discovered polysaccharide fibrillar network is highly organised and delicately structured with a monomolecular fibril height of 0.6 nm. We conclude that the Bacteriastrum polysaccharide jacket represents an essential part of the cell, as the conjunction of the polymer network with the frustule appears to be extremely tight and such specific and unique patterns have never been found in self-assembled polysaccharide gel networks, which are usually encountered in the marine environment. PMID- 23028647 TI - Clinical disorders in a post war British cohort reaching retirement: evidence from the First National Birth Cohort study. AB - BACKGROUND: The medical needs of older people are growing because the proportion of the older population is increasing and disease boundaries are widening. This study describes the distribution and clustering of 15 common clinical disorders requiring medical treatment or supervision in a representative British cohort approaching retirement, and how health tracked across adulthood. METHODS AND FINDINGS: The data come from a cohort of 2661 men and women, 84% of the target sample, followed since birth in England, Scotland and Wales in 1946, and assessed at 60-64 years for: cardio and cerebro-vascular disease, hypertension, raised cholesterol, renal impairment, diabetes, obesity, hypothyroidism, hyperthyroidism, anaemia, respiratory disease, liver disease, psychiatric problems, cancers, atrial fibrillation on ECG and osteoporosis. We calculated the proportions disorder-free, with one or more disorders, and the level of undiagnosed disorders; and how these disorders cluster into latent classes and relate to health assessed at 36 years. Participants had, on average, two disorders (range 0-9); only 15% were disorder-free. The commonest disorders were hypertension (54.3%, 95% CI 51.8%-56.7%), obesity (31.1%, 28.8%-33.5%), raised cholesterol (25.6%, 23.1-28.26%), and diabetes or impaired fasting glucose (25.0%, 22.6-27.5%). A cluster of one in five individuals had a high probability of cardio-metabolic disorders and were twice as likely than others to have been in the poorest health at 36 years. The main limitations are that the native born sample is entirely white, and a combination of clinical assessments and self reports were used. CONCLUSIONS: Most British people reaching retirement already have clinical disorders requiring medical supervision. Widening disease definitions and the move from a disease-based to a risk-based medical model will increase pressure on health services. The promotion of healthy ageing should start earlier in life and consider the individual's ability to adapt to and self manage changes in health. PMID- 23028648 TI - Macroalgal extracts induce bacterial assemblage shifts and sublethal tissue stress in Caribbean corals. AB - Benthic macroalgae can be abundant on present-day coral reefs, especially where rates of herbivory are low and/or dissolved nutrients are high. This study investigated the impact of macroalgal extracts on both coral-associated bacterial assemblages and sublethal stress response of corals. Crude extracts and live algal thalli from common Caribbean macroalgae were applied onto the surface of Montastraea faveolata and Porites astreoides corals on reefs in both Florida and Belize. Denaturing gradient gel electrophoresis (DGGE) of 16S rRNA gene amplicons was used to examine changes in the surface mucus layer (SML) bacteria in both coral species. Some of the extracts and live algae induced detectable shifts in coral-associated bacterial assemblages. However, one aqueous extract caused the bacterial assemblages to shift to an entirely new state (Lobophora variegata), whereas other organic extracts had little to no impact (e.g. Dictyota sp.). Macroalgal extracts more frequently induced sublethal stress responses in M. faveolata than in P. astreoides corals, suggesting that cellular integrity can be negatively impacted in selected corals when comparing co-occurring species. As modern reefs experience phase-shifts to a higher abundance of macroalgae with potent chemical defenses, these macroalgae are likely impacting the composition of microbial assemblages associated with corals and affecting overall reef health in unpredicted and unprecedented ways. PMID- 23028649 TI - Taxonomic identity of the invasive fruit fly pest, Bactrocera invadens: concordance in morphometry and DNA barcoding. AB - In 2003, a new fruit fly pest species was recorded for the first time in Kenya and has subsequently been found in 28 countries across tropical Africa. The insect was described as Bactrocera invadens, due to its rapid invasion of the African continent. In this study, the morphometry and DNA Barcoding of different populations of B. invadens distributed across the species range of tropical Africa and a sample from the pest's putative aboriginal home of Sri Lanka was investigated. Morphometry using wing veins and tibia length was used to separate B. invadens populations from other closely related Bactrocera species. The Principal component analysis yielded 15 components which correspond to the 15 morphometric measurements. The first two principal axes contributed to 90.7% of the total variance and showed partial separation of these populations. Canonical discriminant analysis indicated that only the first five canonical variates were statistically significant. The first two canonical variates contributed a total of 80.9% of the total variance clustering B. invadens with other members of the B. dorsalis complex while distinctly separating B. correcta, B. cucurbitae, B. oleae and B. zonata. The largest Mahalanobis squared distance (D(2) = 122.9) was found to be between B. cucurbitae and B. zonata, while the lowest was observed between B. invadens populations against B. kandiensis (8.1) and against B. dorsalis s.s (11.4). Evolutionary history inferred by the Neighbor-Joining method clustered the Bactrocera species populations into four clusters. First cluster consisted of the B. dorsalis complex (B. invadens, B. kandiensis and B. dorsalis s. s.), branching from the same node while the second group was paraphyletic clades of B. correcta and B. zonata. The last two are monophyletic clades, consisting of B. cucurbitae and B. oleae, respectively. Principal component analysis using the genetic distances confirmed the clustering inferred by the NJ tree. PMID- 23028650 TI - In silico investigations of the anti-catabolic effects of pamidronate and denosumab on multiple myeloma-induced bone disease. AB - It is unclear whether the new anti-catabolic agent denosumab represents a viable alternative to the widely used anti-catabolic agent pamidronate in the treatment of Multiple Myeloma (MM)-induced bone disease. This lack of clarity primarily stems from the lack of sufficient clinical investigations, which are costly and time consuming. However, in silico investigations require less time and expense, suggesting that they may be a useful complement to traditional clinical investigations. In this paper, we aim to (i) develop integrated computational models that are suitable for investigating the effects of pamidronate and denosumab on MM-induced bone disease and (ii) evaluate the responses to pamidronate and denosumab treatments using these integrated models. To achieve these goals, pharmacokinetic models of pamidronate and denosumab are first developed and then calibrated and validated using different clinical datasets. Next, the integrated computational models are developed by incorporating the simulated transient concentrations of pamidronate and denosumab and simulations of their actions on the MM-bone compartment into the previously proposed MM-bone model. These integrated models are further calibrated and validated by different clinical datasets so that they are suitable to be applied to investigate the responses to the pamidronate and denosumab treatments. Finally, these responses are evaluated by quantifying the bone volume, bone turnover, and MM-cell density. This evaluation identifies four denosumab regimes that potentially produce an overall improved bone-related response compared with the recommended pamidronate regime. This in silico investigation supports the idea that denosumab represents an appropriate alternative to pamidronate in the treatment of MM-induced bone disease. PMID- 23028651 TI - Multiparametric analyses of human PBMCs loaded ex vivo with a candidate idiotype vaccine for HCV-related lymphoproliferative disorders. AB - Hepatitis C virus (HCV) has been identified as one of the major risk factors for type II mixed cryoglobulinemia (MC), during the clinical evolution of chronic hepatitis, which may lead to development of B cell non-Hodgkin's lymphoma (NHL). We have previously shown that the candidate idiotype vaccine, based on the IGKV3 20 light chain protein, is able to induce activation and maturation of circulating antigen presenting cells (APCs) in both HCV-positive and HCV-negative healthy control subjects, with production of Th2-type cytokines. Here, the effect of the recombinant IGKV3-20 protein on human peripheral blood mononuclear cells (PBMCs) from HCV-positive subjects, with known blood levels of cryoglobulins, is shown via gene expression profiling analysis combined to multiparameter flow cytometry and multiplex analyses of cytokines. PMID- 23028653 TI - Systematic differences in signal emitting and receiving revealed by PageRank analysis of a human protein interactome. AB - Most protein PageRank studies do not use signal flow direction information in protein interactions because this information was not readily available in large protein databases until recently. Therefore, four questions have yet to be answered: A) What is the general difference between signal emitting and receiving in a protein interactome? B) Which proteins are among the top ranked in directional ranking? C) Are high ranked proteins more evolutionarily conserved than low ranked ones? D) Do proteins with similar ranking tend to have similar subcellular locations? In this study, we address these questions using the forward, reverse, and non-directional PageRank approaches to rank an information directional network of human proteins and study their evolutionary conservation. The forward ranking gives credit to information receivers, reverse ranking to information emitters, and non-directional ranking mainly to the number of interactions. The protein lists generated by the forward and non-directional rankings are highly correlated, but those by the reverse and non-directional rankings are not. The results suggest that the signal emitting/receiving system is characterized by key-emittings and relatively even receivings in the human protein interactome. Signaling pathway proteins are frequent in top ranked ones. Eight proteins are both informational top emitters and top receivers. Top ranked proteins, except a few species-related novel-function ones, are evolutionarily well conserved. Protein-subunit ranking position reflects subunit function. These results demonstrate the usefulness of different PageRank approaches in characterizing protein networks and provide insights to protein interaction in the cell. PMID- 23028652 TI - Nubp1 is required for lung branching morphogenesis and distal progenitor cell survival in mice. AB - The lung is a complex system in biology and medicine alike. Whereas there is a good understanding of the anatomy and histology of the embryonic and adult lung, less is known about the molecular details and the cellular pathways that ultimately orchestrate lung formation and affect its health. From a forward genetic approach to identify novel genes involved in lung formation, we identified a mutated Nubp1 gene, which leads to syndactyly, eye cataract and lung hypoplasia. In the lung, Nubp1 is expressed in progenitor cells of the distal epithelium. Nubp1(m1Nisw) mutants show increased apoptosis accompanied by a loss of the distal progenitor markers Sftpc, Sox9 and Foxp2. In addition, Nubp1 mutation disrupts localization of the polarity protein Par3 and the mitosis relevant protein Numb. Using knock-down studies in lung epithelial cells, we also demonstrate a function of Nubp1 in regulating centrosome dynamics and microtubule organization. Together, Nubp1 represents an essential protein for lung progenitor survival by coordinating vital cellular processes including cell polarity and centrosomal dynamics. PMID- 23028654 TI - Dyslexia impairs speech recognition but can spare phonological competence. AB - Dyslexia is associated with numerous deficits to speech processing. Accordingly, a large literature asserts that dyslexics manifest a phonological deficit. Few studies, however, have assessed the phonological grammar of dyslexics, and none has distinguished a phonological deficit from a phonetic impairment. Here, we show that these two sources can be dissociated. Three experiments demonstrate that a group of adult dyslexics studied here is impaired in phonetic discrimination (e.g., ba vs. pa), and their deficit compromises even the basic ability to identify acoustic stimuli as human speech. Remarkably, the ability of these individuals to generalize grammatical phonological rules is intact. Like typical readers, these Hebrew-speaking dyslexics identified ill-formed AAB stems (e.g., titug) as less wordlike than well-formed ABB controls (e.g., gitut), and both groups automatically extended this rule to nonspeech stimuli, irrespective of reading ability. The contrast between the phonetic and phonological capacities of these individuals demonstrates that the algebraic engine that generates phonological patterns is distinct from the phonetic interface that implements them. While dyslexia compromises the phonetic system, certain core aspects of the phonological grammar can be spared. PMID- 23028655 TI - Computational prediction of polycomb-associated long non-coding RNAs. AB - Among thousands of long non-coding RNAs (lncRNAs) only a small subset is functionally characterized and the functional annotation of lncRNAs on the genomic scale remains inadequate. In this study we computationally characterized two functionally different parts of human lncRNAs transcriptome based on their ability to bind the polycomb repressive complex, PRC2. This classification is enabled by the fact that while all lncRNAs constitute a diverse set of sequences, the classes of PRC2-binding and PRC2 non-binding lncRNAs possess characteristic combinations of sequence-structure patterns and, therefore, can be separated within the feature space. Based on the specific combination of features, we built several machine-learning classifiers and identified the SVM-based classifier as the best performing. We further showed that the SVM-based classifier is able to generalize on the independent data sets. We observed that this classifier, trained on the human lncRNAs, can predict up to 59.4% of PRC2-binding lncRNAs in mice. This suggests that, despite the low degree of sequence conservation, many lncRNAs play functionally conserved biological roles. PMID- 23028656 TI - Evaluating caveolin interactions: do proteins interact with the caveolin scaffolding domain through a widespread aromatic residue-rich motif? AB - Caveolins are coat proteins of caveolae, small flask-shaped pits of the plasma membranes of most cells. Aside from roles in caveolae formation, caveolins recruit, retain and regulate many caveolae-associated signalling molecules. Caveolin-protein interactions are commonly considered to occur between a ~20 amino acid region within caveolin, the caveolin scaffolding domain (CSD), and an aromatic-rich caveolin binding motif (CBM) on the binding partner (fXfXXXXf, fXXXXfXXf or fXfXXXXfXXf, where f is an aromatic and X an unspecified amino acid). The CBM resembles a typical linear motif--a short, simple sequence independently evolved many times in different proteins for a specific function. Here we exploit recent improvements in bioinformatics tools and in our understanding of linear motifs to critically examine the role of CBMs in caveolin interactions. We find that sequences conforming to the CBM occur in 30% of human proteins, but find no evidence for their statistical enrichment in the caveolin interactome. Furthermore, sequence- and structure-based considerations suggest that CBMs do not have characteristics commonly associated with true interaction motifs. Analysis of the relative solvent accessible area of putative CBMs shows that the majority of their aromatic residues are buried within the protein and are thus unlikely to interact directly with caveolin, but may instead be important for protein structural stability. Together, these findings suggest that the canonical CBM may not be a common characteristic of caveolin-target interactions and that interfaces between caveolin and targets may be more structurally diverse than presently appreciated. PMID- 23028657 TI - Deficiency of interleukin-15 enhances susceptibility to acetaminophen-induced liver injury in mice. AB - Hepatocytes have a direct necrotic role in acetaminophen (APAP)-induced liver injury (AILI), prolonged secondary inflammatory response through innate immune cells and cytokines also significantly contributes to APAP hepatotoxicity. Interleukin 15 (IL-15), a multifunction cytokine, regulates the adaptive immune system and influences development and function of innate immune cells. To better understand the role of IL-15 in liver injury, we treated wild-type (WT) and IL-15 knockout (Il15-/-) mice with a hepatotoxic dose of APAP to induce AILI and evaluated animal survival, liver damage, APAP metabolism in livers and the inflammatory response. Production of pro-inflammatory cytokines/chemokines was greater in Il15-/- than WT mice. Subanalysis of hepatic infiltrated monocytes revealed greater neutrophil influx, along with greater hepatic induction of inducible nitric oxide synthase (iNOS), in Il15-/- than WT mice. In addition, the level of hepatic hemeoxygenase 1 (HO-1) was partially suppressed in Il15-/- mice, but not in WT mice. Interestingly, elimination of Kupffer cells and neutrophils did not alter the vulnerability to excess APAP in Il15-/- mice. However, injection of galactosamine, a hepatic transcription inhibitor, significantly reduced the increased APAP sensitivity in Il15-/- mice but had minor effect on WT mice. We demonstrated that deficiency of IL-15 increased mouse susceptibility to AILI. Moreover, Kupffer cell might affect APAP hepatotoxicity through IL-15. PMID- 23028659 TI - KCN1, a novel synthetic sulfonamide anticancer agent: in vitro and in vivo anti pancreatic cancer activities and preclinical pharmacology. AB - The purpose of the present study was to determine the in vitro and in vivo anti cancer activity and pharmacological properties of 3,4-dimethoxy-N-[(2,2-dimethyl 2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1. In the present study, we investigated the in vitro activity of KCN1 on cell proliferation and cell cycle distribution of pancreatic cancer cells, using the MTT and BrdUrd assays, and flow cytometry. The in vivo anti-cancer effects of KCN1 were evaluated in two distinct xenograft models of pancreatic cancer. We also developed an HPLC method for the quantitation of the compound, and examined its stability in mouse plasma, plasma protein binding, and degradation by mouse S9 microsomal enzymes. Furthermore, we examined the pharmacokinetics of KCN1 following intravenous or intraperitoneal injection in mice. Results showed that, in a dose-dependent manner, KCN1 inhibited cell growth and induced cell cycle arrest in human pancreatic cancer cells in vitro, and showed in vivo anticancer efficacy in mice bearing Panc-1 or Mia Paca-2 tumor xenografts. The HPLC method provided linear detection of KCN1 in all of the matrices in the range from 0.1 to 100 uM, and had a lower limit of detection of 0.085 uM in mouse plasma. KCN1 was very stable in mouse plasma, extensively plasma bound, and metabolized by S9 microsomal enzymes. The pharmacokinetic studies indicated that KCN1 could be detected in all of the tissues examined, most for at least 24 h. In conclusion, our preclinical data indicate that KCN1 is a potential therapeutic agent for pancreatic cancer, providing a basis for its future development. PMID- 23028658 TI - Topological and functional properties of the small GTPases protein interaction network. AB - Small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) regulate key cellular processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. A great deal of experimental evidence supports the existence of signaling cascades and feedback loops within and among the small GTPase subfamilies suggesting that these proteins function in a coordinated and cooperative manner. The interplay occurs largely through association with bi-partite regulatory and effector proteins but can also occur through the active form of the small GTPases themselves. In order to understand the connectivity of the small GTPases signaling routes, a systems-level approach that analyzes data describing direct and indirect interactions was used to construct the small GTPases protein interaction network. The data were curated from the Search Tool for the Retrieval of Interacting Genes (STRING) database and include only experimentally validated interactions. The network method enables the conceptualization of the overall structure as well as the underlying organization of the protein-protein interactions. The interaction network described here is comprised of 778 nodes and 1943 edges and has a scale-free topology. Rac1, Cdc42, RhoA, and HRas are identified as the hubs. Ten sub-network motifs are also identified in this study with themes in apoptosis, cell growth/proliferation, vesicle traffic, cell adhesion/junction dynamics, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase response, transcription regulation, receptor-mediated endocytosis, gene silencing, and growth factor signaling. Bottleneck proteins that bridge signaling paths and proteins that overlap in multiple small GTPase networks are described along with the functional annotation of all proteins in the network. PMID- 23028660 TI - Cynoglossus semilaevis ISG15: a secreted cytokine-like protein that stimulates antiviral immune response in a LRGG motif-dependent manner. AB - ISG15 is an ubiquitin-like protein that is induced rapidly by interferon stimulation. Like ubiquitin, ISG15 forms covalent conjugates with its target proteins in a process called ISGylation, which in mammals is known to play a role in antiviral immunity. In contrast to mammalian ISG15, the function of teleost ISG15 is unclear. In this study, we identified and analyzed the function of an ISG15 homologue, CsISG15, from tongue sole (Cynoglossus semilaevis). CsISG15 is composed of 162 residues and possesses two tandem ubiquitin-like domains and the highly conserved LRGG motif found in all known ISG15. Expression of CsISG15 occurred in a wide range of tissues and was upregulated in kidney and spleen by viral and bacterial infection. In vitro study with primary head kidney (HK) lymphocytes showed that megalocytivirus infection caused induction of CsISG15 expression and extracellular release of CsISG15 protein. Purified recombinant CsISG15 (rCsISG15) activated HK macrophages and enhanced the expression of immune genes in HK lymphocytes, both these effects, however, were significantly reduced when the conserved LRGG sequence was mutated to LAAG. Further study showed that the presence of rCsISG15 during megalocytivirus infection of HK lymphocytes reduced intracellular viral load, whereas antibody blocking of CsISG15 enhanced viral infection. Likewise, interference with CsISG15 expression by RNAi promoted viral infection. Taken together, these results indicate that CsISG15, a teleost ISG15, promotes antiviral immune response and that, unlike mammalian ISG15, CsISG15 exerts its immunoregulatory effect in the form of an unconjugated extracellular cytokine. In addition, these results also suggest a role for the LRGG motif other than that in protein conjugation. PMID- 23028661 TI - Differential recruitment of brain networks following route and cartographic map learning of spatial environments. AB - An extensive neuroimaging literature has helped characterize the brain regions involved in navigating a spatial environment. Far less is known, however, about the brain networks involved when learning a spatial layout from a cartographic map. To compare the two means of acquiring a spatial representation, participants learned spatial environments either by directly navigating them or learning them from an aerial-view map. While undergoing functional magnetic resonance imaging (fMRI), participants then performed two different tasks to assess knowledge of the spatial environment: a scene and orientation dependent perceptual (SOP) pointing task and a judgment of relative direction (JRD) of landmarks pointing task. We found three brain regions showing significant effects of route vs. map learning during the two tasks. Parahippocampal and retrosplenial cortex showed greater activation following route compared to map learning during the JRD but not SOP task while inferior frontal gyrus showed greater activation following map compared to route learning during the SOP but not JRD task. We interpret our results to suggest that parahippocampal and retrosplenial cortex were involved in translating scene and orientation dependent coordinate information acquired during route learning to a landmark-referenced representation while inferior frontal gyrus played a role in converting primarily landmark-referenced coordinates acquired during map learning to a scene and orientation dependent coordinate system. Together, our results provide novel insight into the different brain networks underlying spatial representations formed during navigation vs. cartographic map learning and provide additional constraints on theoretical models of the neural basis of human spatial representation. PMID- 23028662 TI - The small GTPase Rheb affects central brain neuronal morphology and memory formation in Drosophila. AB - Mutations in either of two tumor suppressor genes, TSC1 or TSC2, cause tuberous sclerosis complex (TSC), a syndrome resulting in benign hamartomatous tumors and neurological disorders. Cellular growth defects and neuronal disorganization associated with TSC are believed to be due to upregulated TOR signaling. We overexpressed Rheb, an upstream regulator of TOR, in two different subsets of D. melanogaster central brain neurons in order to upregulate the Tsc-Rheb-TOR pathway. Overexpression of Rheb in either the mushroom bodies or the insulin producing cells resulted in enlarged axon projections and cell bodies, which continued to increase in size with prolonged Rheb expression as the animals aged. Additionally, Rheb overexpression in the mushroom bodies resulted in deficiencies in 3 hr but not immediate appetitive memory. Thus, Rheb overexpression in the central brain neurons of flies causes not only morphological phenotypes, but behavioral and aging phenotypes that may mirror symptoms of TSC. PMID- 23028664 TI - Production of Fibronectin Binding Protein A at the surface of Lactococcus lactis increases plasmid transfer in vitro and in vivo. AB - Lactococci are noninvasive lactic acid bacteria frequently used as protein delivery vectors and, more recently, as DNA delivery vehicles. We previously showed that Lactococcus lactis (LL) expressing the Fibronectin-Binding Protein A of Staphylococcus aureus (LL-FnBPA+) showed higher internalization rates in vitro in Caco-2 cells than the native (wt) lactococci and were able to deliver a eukaryotic Green Fluorescent Protein (GFP) expression plasmid in 1% of human Caco 2 cells. Here, using the bovine beta-lactoglobulin (BLG), one of the major cow's milk allergen, and GFP we characterized the potential of LL-FnBPA+ as an in vivo DNA vaccine delivery vehicle. We first showed that the invasive strain LL-FnBPA+ carrying the plasmid pValac:BLG (LL-FnBPA+ BLG) was more invasive than LL-BLG and showed the same invasivity as LL-FnBPA+. Then we demonstrated that the Caco-2 cells, co-incubated with LL-FnBPA+ BLG produced up to 30 times more BLG than the Caco-2 cells co-incubated with the non invasive LL-BLG. Using two different gene reporters, BLG and GFP, and two different methods of detection, EIA and fluorescence microscopy, we showed in vivo that: i) in order to be effective, LL FnBPA+ required a pre-coating with Fetal Calf Serum before oral administration; ii) plasmid transfer occurred in enterocytes without regard to the strains used (invasive or not); iii) the use of LL-FnBPA+ increased the number of mice producing BLG, but not the level of BLG produced. We thus confirmed the good potential of invasive recombinant lactic acid bacteria as DNA delivery vector in vivo. PMID- 23028665 TI - Impact of glucocorticoid receptor gene polymorphisms on the metabolic profile of adult patients with the classical form of 21-hydroxylase deficiency. AB - BACKGROUND: CAH patients have an increased risk of cardiovascular disease, and it remains unknown if lifelong glucocorticoid (GC) treatment is a contributing factor. In the general population, glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of CAH patients. METHODOLOGY: Sixty-eight adult patients (34SV/34SW) with a mean age of 28.4+/-9 years received dexamethasone (mean 0.27+/-0.11 mg/day) to obtain normal androgen levels. SW patients also received fludrocortisone (50 ug/day). Metabolic syndrome (MetS) was defined by the NCEP ATPIII criteria and obesity by BMI >=30 kg/m2. NR3C1 alleles were genotyped, and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis. RESULTS: Obesity and MetS were observed in 23.5% and 7.3% of patients, respectively, and were not correlated with GC doses and treatment duration. BMI was positively correlated with blood pressure (BP), triglycerides (TG), LDL-c levels and HOMA-IR and inversely correlated with HDL-c levels. BclI and A3669G variants were found in 26.4% and 9.6% of alleles, respectively. Heterozygotes for the BclI polymorphism presented with higher BMI (29 kg/m2+/-5.3 vs. 26 kg/m2+/ 5.3, respectively) and waist circumference (89 cm+/-12.7 vs. 81 cm+/-13, respectively) compared to wild-type subjects. Hypertension was found in 12% of patients and heterozygotes for the BclI polymorphism presented higher systolic BP than wild type subjects. Low HDL-c and high TG levels were identified in 30% and 10% of patients, respectively, and were not associated with the NR3C1 polymorphisms. A3669G carriers and non-carriers did not differ. CONCLUSION: In addition to GC therapy, the BclI GR variant might play an important role in obesity susceptibility in CAH patients. Genotyping of GR polymorphisms could result in the identification of a subgroup at risk patients, allowing for the establishment of personalized treatment and the avoidance of long-term adverse consequences. PMID- 23028663 TI - An anilinoquinazoline derivative inhibits tumor growth through interaction with hCAP-G2, a subunit of condensin II. AB - We screened 46 novel anilinoquinazoline derivatives for activity to inhibit proliferation of a panel of human cancer cell lines. Among them, Q15 showed potent in vitro growth-inhibitory activity towards cancer cell lines derived from colorectal cancer, lung cancer and multiple myeloma. It also showed antitumor activity towards multiple myeloma KMS34 tumor xenografts in lcr/scid mice in vivo. Unlike the known anilinoquinazoline derivative gefitinib, Q15 did not inhibit cytokine-mediated intracellular tyrosine phosphorylation. Using our mRNA display technology, we identified hCAP-G2, a subunit of condensin II complex, which is regarded as a key player in mitotic chromosome condensation, as a Q15 binding partner. Immunofluorescence study indicated that Q15 compromises normal segregation of chromosomes, and therefore might induce apoptosis. Thus, our results indicate that hCAP-G2 is a novel therapeutic target for development of drugs active against currently intractable neoplasms. PMID- 23028666 TI - Modelling sensory limitation: the role of tree selection, memory and information transfer in bats' roost searching strategies. AB - Sensory limitation plays an important role in the evolution of animal behaviour. Animals have to find objects of interest (e.g. food, shelters, predators). When sensory abilities are strongly limited, animals adjust their behaviour to maximize chances for success. Bats are nocturnal, live in complex environments, are capable of flight and must confront numerous perceptual challenges (e.g. limited sensory range, interfering clutter echoes). This makes them an excellent model for studying the role of compensating behaviours to decrease costs of finding resources. Cavity roosting bats are especially interesting because the availability of tree cavities is often limited, and their quality is vital for bats during the breeding season. From a bat's sensory point of view, cavities are difficult to detect and finding them requires time and energy. However, tree cavities are also long lasting, allowing information transfer among conspecifics. Here, we use a simple simulation model to explore the benefits of tree selection, memory and eavesdropping (compensation behaviours) to searches for tree cavities by bats with short and long perception range. Our model suggests that memory and correct discrimination of tree suitability are the basic strategies decreasing the cost of roost finding, whereas perceptual range plays a minor role in this process. Additionally, eavesdropping constitutes a buffer that reduces the costs of finding new resources (such as roosts), especially when they occur in low density. We conclude that natural selection may promote different strategies of roost finding in relation to habitat conditions and cognitive skills of animals. PMID- 23028667 TI - Selection for adaptation to dietary shifts: towards sustainable breeding of carnivorous fish. AB - Genetic adaptation to dietary environments is a key process in the evolution of natural populations and is of great interest in animal breeding. In fish farming, the use of fish meal and fish oil has been widely challenged, leading to the rapidly increasing use of plant-based products in feed. However, high substitution rates impair fish health and growth in carnivorous species. We demonstrated that survival rate, mean body weight and biomass can be improved in rainbow trout (Oncorhynchus mykiss) after a single generation of selection for the ability to adapt to a totally plant-based diet (15.1%, 35.3% and 54.4%, respectively). Individual variability in the ability to adapt to major diet changes can be effectively used to promote fish welfare and a more sustainable aquaculture. PMID- 23028668 TI - Triterpenoid dihydro-CDDO-trifluoroethyl amide protects against maladaptive cardiac remodeling and dysfunction in mice: a critical role of Nrf2. AB - BACKGROUND AND AIMS: Nuclear factor E2-related factor 2 (Nrf2) appears to be an attractive therapeutic target for the treatment of cardiac disease. We investigated whether a synthetic triterpenoid derivative of dihydro-CDDO trifluoroethylamide (dh404), a novel Nrf2 activator, protects against pathological cardiac responses to hemodynamic stress in mice. METHODS: Cardiac maladaptive remodeling and dysfunction were established by transverse aortic constriction (TAC) in mice. Hypertrophic growth of rat neonatal cardiomyocytes was induced by angiotensin II (Ang II). Cell death of rat neonatal cardiomyocytes was induced with hydrogen peroxide (H2O2). Cellular proliferation of rat neonatal cardiac fibroblasts was induced by Ang II, norepinephrine (NE) and phenylephrine (PE). Protein expression was assessed by immunochemical staining and Western blots. Gene expression was determined by real time reverse transcription polymerase chain reaction (Q-PCR). RESULTS: TAC suppressed myocardial Nrf2 expression, increased myocardial 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine levels, and induced cardiac hypertrophy, fibrosis and apoptosis, and overt heart failure and death in mice. Administration of dh404 inhibited the pathological cardiac remodeling and dysfunction, and reduced the mortality. Moreover, dhd404 elevated myocardial levels of Nrf2 and Nrf2 nuclear translocation with a dramatic suppression of the oxidative stress in the heart. Dh404 inhibited hypertrophic growth and death in primary culture of rat neonatal cardiomyocytes and suppressed proliferation in primary culture of rat neonatal cardiac fibroblasts. However, these effects of dh404 were blunted by knocking down of Nrf2. CONCLUSION: These findings demonstrate that dh404 prevents pathological cardiac remodeling and dysfunction by activating Nrf2, indicating a therapeutic potential of dh404 for cardiac disease. PMID- 23028670 TI - Beeswax as dental filling on a neolithic human tooth. AB - Evidence of prehistoric dentistry has been limited to a few cases, the most ancient dating back to the Neolithic. Here we report a 6500-year-old human mandible from Slovenia whose left canine crown bears the traces of a filling with beeswax. The use of different analytical techniques, including synchrotron radiation computed micro-tomography (micro-CT), Accelerator Mass Spectrometry (AMS) radiocarbon dating, Infrared (IR) Spectroscopy and Scanning Electron Microscopy (SEM), has shown that the exposed area of dentine resulting from occlusal wear and the upper part of a vertical crack affecting enamel and dentin tissues were filled with beeswax shortly before or after the individual's death. If the filling was done when the person was still alive, the intervention was likely aimed to relieve tooth sensitivity derived from either exposed dentine and/or the pain resulting from chewing on a cracked tooth: this would provide the earliest known direct evidence of therapeutic-palliative dental filling. PMID- 23028669 TI - Wnt activation by wild type and mutant myocilin in cultured human trabecular meshwork cells. AB - BACKGROUND: Myocilin is a gene linked to the most prevalent form of glaucoma, a major blinding disease. The trabecular meshwork (TM), a specialized eye tissue, is believed to be involved, at least in part, in the development of glaucoma. The Pro370 to Leu (P370L) mutation of myocilin is associated with severe glaucoma phenotypes and Gln368 stop (Q368X) is the most common myocilin mutation reported. Myocilin, upon overexpression, has been shown to induce phenotypes that include a loss of actin stress fibers, an increase in the cAMP level and protein kinase A (PKA) activity, as well as a reduction in the RhoA activity. We examined herein whether Wnt signaling pathway is involved in the myocilin phenotypes and whether P370L and Q368X mutants also display biological effects similar to those of the wild type myocilin. METHODOLOGY/PRINCIPAL FINDINGS: Wild type myocilin, when transfected into cultured human TM cells, induced a loss of actin stress fibers as judged by phalloidin staining. Such a loss was averted by treatment of secreted Frizzled-related protein 1 (sFRP1), an inhibitor of Wnt signaling. Consistent with the notion that Wnt pathway mediates the myocilin phenotype, Wnt activation was demonstrated by TOP/FOP-Flash reporter assays. Treatment of human TM cells of a Wnt activator, SB216763, as well as transfection of myocilin P370L and Q368X mutants all resulted in actin stress fiber loss, PKA activation and RhoA inactivation. The PKA elevation was obviated by the sFRP1 treatment, indicating that Wnt signaling was upstream that of PKA. CONCLUSIONS/SIGNIFICANCE: The present study demonstrated that following forced expression of wild type myocilin, Wnt was activated, triggering in turn other myocilin-related alterations. P370L and Q368X mutations induced similar phenotypes, suggesting one possible mechanism how the mutants may lead to TM cell damage and pathology. PMID- 23028671 TI - The expression levels of plasma micoRNAs in atrial fibrillation patients. AB - BACKGROUND: MicroRNA (miRNA) has been found in human blood. It has been increasingly suggested that miRNAs may serve as biomarkers for diseases. We examined the potential of circulating miRNA to serve as predictors of atrial fibrillation (AF). METHODOLOGY/PRINCIPAL FINDINGS: During the discovery stage of this project, we used massively parallel signature sequencing (MPSS) to carry out an in-depth analysis of the miRNA expression profile (miRNome) in 5 healthy controls, 5 patients with paroxysmal atrial fibrillation (PAF) alone, and 5 patients with persistent atrial fibrillation (PersAF) alone. Twenty-two specific miRNAs were found to be dysregulated in each PAF group, PersAF group, or control group. Four candidate microRNAs (miRNA-146a, miRNA-150, miRNA-19a, and miRNA-375) met our selection criteria and were evaluated in an independent cohort of 90 plasma samples using TaqMan miRNA quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). We found miRNA-150 levels to be reduced by a factor of approximately 17 in PAF relative to controls and a factor of approximately 20 in PersAF relative to controls (P<.0001). Logistic regression analyses were carried out to evaluate the reduced miRNA-150 expression levels (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.5 to 3.57, P<0.001), age (OR 1.1, 95% CI 1.36 to 2.73, P<0.001), and Left atrial diameter (LAD) (OR 1.5, 95% CI 1.36 to 1.8, P<0.001). Each was independently associated with AF. Much of the identified target genes related to AF were part of the inflammatory response system. We found that plasma levels of CRP were negatively correlated with the plasma levels of miRNA-150. CONCLUSIONS/SIGNIFICANCE: In summary, we firstly found that plasma miRNA-150 levels in from AF patients were substantially lower than that from healthy people. Circulating reduced miRNA-150 was significantly associated with AF. PMID- 23028672 TI - MicroRNA-145 protects cardiomyocytes against hydrogen peroxide (H2O2)-induced apoptosis through targeting the mitochondria apoptotic pathway. AB - MicroRNAs, a class of small and non-encoding RNAs that transcriptionally or post transcriptionally modulate the expression of their target genes, has been implicated as critical regulatory molecules in many cardiovascular diseases, including ischemia/reperfusion induced cardiac injury. Here, we report microRNA 145, a tumor suppressor miRNA, can protect cardiomyocytes from hydrogen peroxide H2O2-induced apoptosis through targeting the mitochondrial pathway. Quantitative real-time PCR (qPCR) demonstrated that the expression of miR-145 in either ischemia/reperfused mice myocardial tissues or H2O2-treated neonatal rat ventricle myocytes (NRVMs) was markedly down-regulated. Over-expression of miR 145 significantly inhibited the H2O2-induced cellular apoptosis, ROS production, mitochondrial structure disruption as well as the activation of key signaling proteins in mitochondrial apoptotic pathway. These protective effects of miR-145 were abrogated by over-expression of Bnip3, an initiation factor of the mitochondrial apoptotic pathway in cardiomyocytes. Finally, we utilized both luciferase reporter assay and western blot analysis to identify Bnip3 as a direct target of miR-145. Our results suggest miR-145 plays an important role in regulating mitochondrial apoptotic pathway in heart challenged with oxidative stress. MiR-145 may represent a potential therapeutic target for treatment of oxidative stress-associated cardiovascular diseases, such as myocardial ischemia/reperfusion injury. PMID- 23028673 TI - Highly efficient isolation of Populus mesophyll protoplasts and its application in transient expression assays. AB - BACKGROUND: Populus is a model woody plant and a promising feedstock for lignocellulosic biofuel production. However, its lengthy life cycle impedes rapid characterization of gene function. METHODOLOGY/PRINCIPAL FINDINGS: We optimized a Populus leaf mesophyll protoplast isolation protocol and established a Populus protoplast transient expression system. We demonstrated that Populus protoplasts are able to respond to hormonal stimuli and that a series of organelle markers are correctly localized in the Populus protoplasts. Furthermore, we showed that the Populus protoplast transient expression system is suitable for studying protein-protein interaction, gene activation, and cellular signaling events. CONCLUSIONS/SIGNIFICANCE: This study established a method for efficient isolation of protoplasts from Populus leaf and demonstrated the efficacy of using Populus protoplast transient expression assays as an in vivo system to characterize genes and pathways. PMID- 23028674 TI - Characterization of de novo synthesized GPCRs supported in nanolipoprotein discs. AB - The protein family known as G-protein coupled receptors (GPCRs) comprises an important class of membrane-associated proteins, which remains a difficult family of proteins to characterize because their function requires a native-like lipid membrane environment. This paper focuses on applying a single step method leading to the formation of nanolipoprotein particles (NLPs) capable of solubilizing functional GPCRs for biophysical characterization. NLPs were used to demonstrate increased solubility for multiple GPCRs such as the Neurokinin 1 Receptor (NK1R), the Adrenergic Receptor a2 (ADRB2) and the Dopamine Receptor D1 (DRD1). All three GPCRs showed affinity for their specific ligands using a simple dot blot assay. The NK1R was characterized in greater detail to demonstrate correct folding of the ligand pocket with nanomolar specificity. Electron paramagnetic resonance (EPR) spectroscopy validated the correct folding of the NK1R binding pocket for Substance P (SP). Fluorescence correlation spectroscopy (FCS) was used to identify SP-bound NK1R-containing NLPs and measure their dissociation rate in an aqueous environment. The dissociation constant was found to be 83 nM and was consistent with dot blot assays. This study represents a unique combinational approach involving the single step de novo production of a functional GPCR combined with biophysical techniques to demonstrate receptor association with the NLPs and binding affinity to specific ligands. Such a combined approach provides a novel path forward to screen and characterize GPCRs for drug discovery as well as structural studies outside of the complex cellular environment. PMID- 23028676 TI - mMass as a software tool for the annotation of cyclic peptide tandem mass spectra. AB - Natural or synthetic cyclic peptides often possess pronounced bioactivity. Their mass spectrometric characterization is difficult due to the predominant occurrence of non-proteinogenic monomers and the complex fragmentation patterns observed. Even though several software tools for cyclic peptide tandem mass spectra annotation have been published, these tools are still unable to annotate a majority of the signals observed in experimentally obtained mass spectra. They are thus not suitable for extensive mass spectrometric characterization of these compounds. This lack of advanced and user-friendly software tools has motivated us to extend the fragmentation module of a freely available open-source software, mMass (http://www.mmass.org), to allow for cyclic peptide tandem mass spectra annotation and interpretation. The resulting software has been tested on several cyanobacterial and other naturally occurring peptides. It has been found to be superior to other currently available tools concerning both usability and annotation extensiveness. Thus it is highly useful for accelerating the structure confirmation and elucidation of cyclic as well as linear peptides and depsipeptides. PMID- 23028675 TI - Differentiation and selection of hepatocyte precursors in suspension spheroid culture of transgenic murine embryonic stem cells. AB - Embryonic stem cell-derived hepatocyte precursor cells represent a promising model for clinical transplantations to diseased livers, as well as for establishment of in vitro systems for drug metabolism and toxicology investigations. This study aimed to establish an in vitro culture system for scalable generation of hepatic progenitor cells. We used stable transgenic clones of murine embryonic stem cells possessing a reporter/selection vector, in which the enhanced green fluorescent protein- and puromycin N-acetyltransferase-coding genes are driven by a common alpha-fetoprotein gene promoter. This allowed for "live" monitoring and puromycin selection of the desired differentiating cell type possessing the activated alpha-fetoprotein gene. A rotary culture system was established, sequentially yielding initially partially selected hepatocyte lineage-committed cells, and finally, a highly purified cell population maintained as a dynamic suspension spheroid culture, which progressively developed the hepatic gene expression phenotype. The latter was confirmed by quantitative RT-PCR analysis, which showed a progressive up-regulation of hepatic genes during spheroid culture, indicating development of a mixed hepatocyte precursor-/fetal hepatocyte-like cell population. Adherent spheroids gave rise to advanced differentiated hepatocyte-like cells expressing hepatic proteins such as albumin, alpha-1-antitrypsin, cytokeratin 18, E-cadherin, and liver-specific organic anion transporter 1, as demonstrated by fluorescent immunostaining. A fraction of adherent cells was capable of glycogen storage and of reversible up take of indocyanine green, demonstrating their hepatocyte-like functionality. Moreover, after transplantation of spheroids into the mouse liver, the spheroid derived cells integrated into recipient. These results demonstrate that large scale hepatocyte precursor-/hepatocyte-like cultures can be established for use in clinical trials, as well as in in vitro screening assays. PMID- 23028677 TI - Increases in pediatric antiretroviral treatment, South Africa 2005-2010. AB - BACKGROUND: In South Africa in 2010, about 340,000 children under the age of 15 were infected with HIV. We describe the increase in the treatment of South African pediatric HIV-infected patients assisted by the President's Emergency Plan for AIDS Relief (PEPFAR) from 2004 to 2010. METHODS: We reviewed routine program data from PEPFAR-funded implementing partners among persons receiving antiretroviral treatment age 15 years old and less. Data quality was assessed during the reporting period by program officials through routine analysis of trends and logic checks. Based on UNAIDS estimated mortality rates of untreated HIV-infected children, we calculated the number of deaths averted and life-years gained in children under five receiving PEPFAR-assisted antiretroviral treatment. RESULTS: From October 2004 through September 2010, the number of children newly initiated on antiretroviral treatment in PEPFAR-assisted programs increased from 154 to 2,641 per month resulting in an increase from 2,412 children on antiretroviral treatment in September 2005 to 79,416 children in September 2010. Of those children who initiated antiretroviral treatment before September 2009, 0 4 year olds were 1.4 (95% CI: 1.3-1.5) times as likely to transfer out of the program or die as 5-14 year olds; males were 1.3 (95% CI: 1.0-1.7) times as likely to stop treatment as females. Approximately 27,548 years of life were added to children under-five years old from PEPFAR-assisted antiretroviral treatment. CONCLUSIONS: Pediatric antiretroviral treatment in South Africa has increased substantially. However, additional case-finding and a further acceleration in the implementation of pediatric care and treatment services is required to meet the current treatment need. PMID- 23028678 TI - Predictive value of Sp1/Sp3/FLIP signature for prostate cancer recurrence. AB - Prediction of prostate cancer prognosis is challenging and predictive biomarkers of recurrence remain elusive. Although prostate specific antigen (PSA) has high sensitivity (90%) at a PSA level of 4.0 ng/mL, its low specificity leads to many false positive results and considerable overtreatment of patients and its performance at lower ranges is poor. Given the histopathological and molecular heterogeneity of prostate cancer, we propose that a panel of markers will be a better tool than a single marker. We tested a panel of markers composed of the anti-apoptotic protein FLIP and its transcriptional regulators Sp1 and Sp3 using prostate tissues from 64 patients with recurrent and non-recurrent cancer who underwent radical prostatectomy as primary treatment for prostate cancer and were followed with PSA measurements for at least 5 years. Immunohistochemical staining for Sp1, Sp3, and FLIP was performed on these tissues and scored based on the proportion and intensity of staining. The predictive value of the FLIP/Sp1/Sp3 signature for clinical outcome (recurrence vs. non-recurrence) was explored with logistic regression, and combinations of FLIP/Sp1/Sp3 and Gleason score were analyzed with a stepwise (backward and forward) logistic model. The discrimination of the markers was identified by sensitivity-specificity analysis and the diagnostic value of FLIP/Sp1/Sp3 was determined using area under the curve (AUC) for receiver operator characteristic curves. The AUCs for FLIP, Sp1, Sp3, and Gleason score for predicting PSA failure and non-failure were 0.71, 0.66, 0.68, and 0.76, respectively. However, this increased to 0.93 when combined. Thus, the "biomarker signature" of FLIP/Sp1/Sp3 combined with Gleason score predicted disease recurrence and stratified patients who are likely to benefit from more aggressive treatment. PMID- 23028679 TI - "Seed-Milarity" confers to hsa-miR-210 and hsa-miR-147b similar functional activity. AB - Specificity of interaction between a microRNA (miRNA) and its targets crucially depends on the seed region located in its 5'-end. It is often implicitly considered that two miRNAs sharing the same biological activity should display similarity beyond the strict six nucleotide region that forms the seed, in order to form specific complexes with the same mRNA targets. We have found that expression of hsa-miR-147b and hsa-miR-210, though triggered by different stimuli (i.e. lipopolysaccharides and hypoxia, respectively), induce very similar cellular effects in term of proliferation, migration and apoptosis. Hsa-miR-147b only shares a "minimal" 6-nucleotides seed sequence with hsa-miR-210, but is identical with hsa-miR-147a over 20 nucleotides, except for one base located in the seed region. Phenotypic changes induced after heterologous expression of miR 147a strikingly differ from those induced by miR-147b or miR-210. In particular, miR-147a behaves as a potent inhibitor of cell proliferation and migration. These data fit well with the gene expression profiles observed for miR-147b and miR 210, which are very similar, and the gene expression profile of miR-147a, which is distinct from the two others. Bioinformatics analysis of all human miRNA sequences indicates multiple cases of miRNAs from distinct families exhibiting the same kind of similarity that would need to be further characterized in terms of putative functional redundancy. Besides, it implies that functional impact of some miRNAs can be masked by robust expression of miRNAs belonging to distinct families. PMID- 23028680 TI - Glycyrrhetic acid synergistically enhances beta2-adrenergic receptor-Gs signaling by changing the location of Galphas in lipid rafts. AB - Glycyrrhetic acid (GA) exerts synergistic anti-asthmatic effects via a beta2 adrenergic receptor (beta2AR)-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the beta2AR-Gs-adenylate cyclase (AC)-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances beta2AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA) was synthesized and applied to human embryonic kidney 293 (HEK293) cells expressing fusion beta2AR, and the electron spin resonance (ESR) technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Galphas from lipid rafts to non-raft regions, resulting the binding of beta2AR and Galphas, as well as in reduced beta2AR internalization. Co-localization of beta2AR, Galphas, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane beta2AR-protein kinase A (PKA) signaling pathway was proposed. The enhanced efficacy of beta2AR agonists by this novel mechanism could prevent tachyphylaxis. PMID- 23028681 TI - Muscle cramps and neuropathies in patients with allogeneic hematopoietic stem cell transplantation and graft-versus-host disease. AB - OBJECTIVE: Graft-versus-host disease (GVHD) is an immune-mediated multisystemic disorder and the leading cause of morbidity after allogeneic hematopoietic stem cell transplantation. Peripheral nervous system manifestations of GVHD are rare but often disabling. Whereas immune-mediated neuropathies are an established feature of GVHD, muscle cramps are not well characterized. METHODS: In a single centre retrospective cohort we studied 27 patients (age 23 to 69 years) with GVHD (acute n = 6, chronic n = 21) who complained of symptoms suggestive of peripheral nervous system complications. Clinical, laboratory and neurophysiological findings were evaluated by descriptive statistics and regression analysis to detect factors associated with muscle cramps. Patient's sera were examined for anti-neuronal antibodies. RESULTS: Nine patients had polyneuropathy, 4 had muscle cramps, and 14 had both. Median onset of polyneuropathy and muscle cramps was 6 and 9 months after allogeneic hematopoietic stem cell transplantation, respectively. Neurophysiology revealed a predominantly axonal polyneuropathy in 20 of 26 patients. In 4 of 19 patients electromyography showed signs of myopathy or myositis. Muscle cramps were more frequent during chronic than acute GVHD and affected muscles other than calves in 15 of 18 patients. They typically occurred daily, lasted 1 to 10 minutes with medium to severe pain intensity, compromised daily activity or sleep in 12, and were refractory to therapy in 4 patients. Muscle cramps were less likely with tacrolimus treatment and signs of severe polyneuropathy, but more likely with myopathic changes in electromyography and with incipient demyelinating polyneuropathy, shown by increased high frequency attenuation of the tibial nerve. Serological studies revealed antinuclear or antimitochondrial antibodies in a subset of patients. Two of 16 patients had a serum reactivity against peripheral nervous tissue. CONCLUSION: Muscle cramps are associated with chronic GVHD, often compromise daily activity, and correlate negatively with axonal polyneuropathy and positively with myopathy and incipient demyelination. PMID- 23028682 TI - Phosphorylation of Rad9 at serine 328 by cyclin A-Cdk2 triggers apoptosis via interfering Bcl-xL. AB - Cyclin A-Cdk2, a cell cycle regulated Ser/Thr kinase, plays important roles in a variety of apoptoticprocesses. However, the mechanism of cyclin A-Cdk2 regulated apoptosis remains unclear. Here, we demonstrated that Rad9, a member of the BH3 only subfamily of Bcl-2 proteins, could be phosphorylated by cyclin A-Cdk2 in vitro and in vivo. Cyclin A-Cdk2 catalyzed the phosphorylation of Rad9 at serine 328 in HeLa cells during apoptosis induced by etoposide, an inhibitor of topoisomeraseII. The phosphorylation of Rad9 resulted in its translocation from the nucleus to the mitochondria and its interaction with Bcl-xL. The forced activation of cyclin A-Cdk2 in these cells by the overexpression of cyclin A,triggered Rad9 phosphorylation at serine 328 and thereby promoted the interaction of Rad9 with Bcl-xL and the subsequent initiation of the apoptotic program. The pro-apoptotic effects regulated by the cyclin A-Cdk2 complex were significantly lower in cells transfected with Rad9S328A, an expression vector that encodes a Rad9 mutant that is resistant to cyclin A-Cdk2 phosphorylation. These findings suggest that cyclin A-Cdk2 regulates apoptosis through a mechanism that involves Rad9phosphorylation. PMID- 23028683 TI - High-resolution microendoscopy for the detection of cervical neoplasia in low resource settings. AB - Cervical cancer is the second leading cause of cancer death among women in developing countries. Developing countries often lack infrastructure, cytotechnologists, and pathologists necessary to implement current screening tools. Due to their low cost and ease of interpretation at the point-of-care, optical imaging technologies may serve as an appropriate solution for cervical cancer screening in low resource settings. We have developed a high-resolution optical imaging system, the High Resolution Microendoscope (HRME), which can be used to interrogate clinically suspicious areas with subcellular spatial resolution, revealing changes in nuclear to cytoplasmic area ratio. In this pilot study carried out at the women's clinic of Princess Marina Hospital in Botswana, 52 unique sites were imaged in 26 patients, and the results were compared to histopathology as a reference standard. Quantitative high resolution imaging achieved a sensitivity and specificity of 86% and 87%, respectively, in differentiating neoplastic (>=CIN 2) tissue from non-neoplastic tissue. These results suggest the potential promise of HRME to assist in the detection of cervical neoplasia in low-resource settings. PMID- 23028684 TI - Adaptive evolution of the FADS gene cluster within Africa. AB - Long chain polyunsaturated fatty acids (LC-PUFAs) are essential for brain structure, development, and function, and adequate dietary quantities of LC-PUFAs are thought to have been necessary for both brain expansion and the increase in brain complexity observed during modern human evolution. Previous studies conducted in largely European populations suggest that humans have limited capacity to synthesize brain LC-PUFAs such as docosahexaenoic acid (DHA) from plant-based medium chain (MC) PUFAs due to limited desaturase activity. Population-based differences in LC-PUFA levels and their product-to-substrate ratios can, in part, be explained by polymorphisms in the fatty acid desaturase (FADS) gene cluster, which have been associated with increased conversion of MC PUFAs to LC-PUFAs. Here, we show evidence that these high efficiency converter alleles in the FADS gene cluster were likely driven to near fixation in African populations by positive selection ~85 kya. We hypothesize that selection at FADS variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60-80 kya. PMID- 23028685 TI - The anti-cancer IgM monoclonal antibody PAT-SM6 binds with high avidity to the unfolded protein response regulator GRP78. AB - The monoclonal IgM antibody PAT-SM6 derived from human tumours induces apoptosis in tumour cells and is considered a potential anti-cancer agent. A primary target for PAT-SM6 is the unfolded protein response regulator GRP78, over-expressed externally on the cell surface of tumour cells. Small angle X-ray scattering (SAXS) studies of human GRP78 showed a two-domain dumbbell-shaped monomer, while SAXS analysis of PAT-SM6 revealed a saucer-shaped structure accommodating five fold symmetry, consistent with previous studies of related proteins. Sedimentation velocity analysis of GRP78 and PAT-SM6 mixtures indicated weak complex formation characterized by dissociation constants in the high micromolar concentration range. In contrast, enzyme-linked immunosorbant assays (ELISAs) showed strong and specific interactions between PAT-SM6 and immobilized GRP78. The apparent binding constant estimated from a PAT-SM6 saturation curve correlated strongly with the concentration of GRP78 used to coat the microtiter tray. Experiments using polyclonal antiGRP78 IgG antibodies or a monoclonal IgG derivative of PAT-SM6 did not show a similar dependence. Competition experiments with soluble GRP78 indicated more effective inhibition of PAT-SM6 binding at low GRP78 coating concentrations. These observations suggest an avidity-based binding mechanism that depends on the multi-point attachment of PAT-SM6 to GRP78 clustered on the surface of the tray. Analysis of ELISA data at high GRP78 coating concentrations yielded an apparent dissociation constant of approximately 4 nM. We propose that the biological action of PAT-SM6 in tumour cell apoptosis may depend on the multivalent nature of PAT-SM6 and the high avidity of its interaction with multiple GRP78 molecules clustered on the tumour cell surface. PMID- 23028686 TI - ASPM and the evolution of cerebral cortical size in a community of New World monkeys. AB - The ASPM (abnormal spindle-like microcephaly associated) gene has been proposed as a major determinant of cerebral cortical size among primates, including humans. Yet the specific functions of ASPM and its connection to human intelligence remain controversial. This debate is limited in part by a taxonomic focus on Old World monkeys and apes. Here we expand the comparative context of ASPM sequence analyses with a study of New World monkeys, a radiation of primates in which enlarged brain size has evolved in parallel in spider monkeys (genus Ateles) and capuchins (genus Cebus). The primate community of Costa Rica is perhaps a model system because it allows for independent pairwise comparisons of smaller- and larger-brained species within two taxonomic families. Accordingly, we analyzed the complete sequence of exon 18 of ASPM in Ateles geoffroyi, Alouatta palliata, Cebus capucinus, and Saimiri oerstedii. As the analysis of multiple species in a genus improves phylogenetic reconstruction, we also analyzed eleven published sequences from other New World monkeys. Our exon-wide, lineage-specific analysis of eleven genera and the ratio of rates of nonsynonymous to synonymous substitutions (d(N)/d(S)) on ASPM revealed no detectable evidence for positive selection in the lineages leading to Ateles or Cebus, as indicated by d(N)/d(S) ratios of <1.0 (0.6502 and 0.4268, respectively). Our results suggest that a multitude of interacting genes have driven the evolution of larger brains among primates, with different genes involved in this process in different encephalized lineages, or at least with evidence for positive selection not readily apparent for the same genes in all lineages. The primate community of Costa Rica may serve as a model system for future studies that aim to elucidate the molecular mechanisms underlying cognitive capacity and cortical size. PMID- 23028687 TI - Antibiotics increase gut metabolism and antioxidant proteins and decrease acute phase response and necrotizing enterocolitis in preterm neonates. AB - BACKGROUND: The appropriate use of antibiotics for preterm infants, which are highly susceptible to develop necrotizing enterocolitis (NEC), is not clear. While antibiotic therapy is commonly used in neonates with NEC symptoms and sepsis, it remains unknown how antibiotics may affect the intestine and NEC sensitivity. We hypothesized that broad-spectrum antibiotics, given immediately after preterm birth, would reduce NEC sensitivity and support intestinal protective mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Preterm pigs were treated with antibiotics for 5 d (oral and systemic doses of gentamycin, ampicillin and metrodinazole; AB group) and compared with untreated pigs. Only the untreated pigs showed evidence of NEC lesions and reduced digestive function, as indicated by lowered villus height and activity of brush border enzymes. In addition, 53 intestinal and 22 plasma proteins differed in expression between AB and untreated pigs. AB treatment increased the abundance of intestinal proteins related to carbohydrate and protein metabolism, actin filaments, iron homeostasis and antioxidants. Further, heat shock proteins and the complement system were affected suggesting that all these proteins were involved in the colonization dependent early onset of NEC. In plasma, acute phase proteins (haptoglobin, complement proteins) decreased, while albumin, cleaved C3, ficolin and transferrin increased. CONCLUSIONS/SIGNIFICANCE: Depressed bacterial colonization following AB treatment increases mucosal integrity and reduces bacteria associated inflammatory responses in preterm neonates. The plasma proteins C3, ficolin, and transferrin are potential biomarkers of the colonization-dependent NEC progression in preterm neonates. PMID- 23028688 TI - Inequalities in advice provided by public health workers to women during antenatal sessions in rural India. AB - OBJECTIVES: Studies have widely documented the socioeconomic inequalities in maternal and child health related outcomes in developing countries including India. However, there is limited research on the inequalities in advice provided by public health workers on maternal and child health during antenatal visits. This paper investigates the inequalities in advice provided by public health workers to women during antenatal visits in rural India. METHODS AND FINDINGS: The District Level Household Survey (2007-08) was used to compute rich-poor ratios and concentration indices. Binary logistic regressions were used to investigate inequalities in advice provided by public health workers. The dependent variables comprised the advice provided on seven essential components of maternal and child health care. A significant proportion of pregnant women who attended at least four ANC sessions were not advised on these components during their antenatal sessions. Only 51%-72% of the pregnant women were advised on at least one of the components. Moreover, socioeconomic inequalities in providing advice were significant and the provision of advice concentrated disproportionately among the rich. Inequalities were highest in the case of advice on family planning methods. Advice on breastfeeding was least unequal. Public health workers working in lower level health facilities were significantly less likely than their counterparts in the higher level health facilities to provide specific advice. CONCLUSION: A significant proportion of women were not advised on recommended components of maternal and child health in rural India. Moreover, there were enormous socioeconomic inequalities. The findings of this study raise questions about the capacity of the public health care system in providing equitable services in India. The Government of India must focus on training and capacity building of the public health workers in communication skills so that they can deliver appropriate and recommended advice to all clients, irrespective of their socioeconomic status. PMID- 23028689 TI - Mechanistic insights into validoxylamine A 7'-phosphate synthesis by VldE using the structure of the entire product complex. AB - The pseudo-glycosyltransferase VldE catalyzes non-glycosidic C-N coupling between an unsaturated cyclitol and a saturated aminocyclitol with the conservation of the stereochemical configuration of the substrates to form validoxylamine A 7' phosphate, the biosynthetic precursor of the antibiotic validamycin A. To study the molecular basis of its mechanism, the three-dimensional structures of VldE from Streptomyces hygroscopicus subsp. limoneus was determined in apo form, in complex with GDP, in complex with GDP and validoxylamine A 7'-phosphate, and in complex with GDP and trehalose. The structure of VldE with the catalytic site in both an "open" and "closed" conformation is also described. With these structures, the preferred binding of the guanine moiety by VldE, rather than the uracil moiety as seen in OtsA could be explained. The elucidation of the VldE structure in complex with the entirety of its products provides insight into the internal return mechanism by which catalysis occurs with a net retention of the stereochemical configuration of the donated cyclitol. PMID- 23028690 TI - Search for cellular stress biomarkers in lymphocytes from patients with multiple sclerosis: a pilot study. AB - Multiple Sclerosis (MS) is a chronic disease of the central nervous system, the etiology of which, although not completely known, involves inflammation and autoimmunity. In the present study we aimed at identifying molecular markers of apoptosis, cellular stress and DNA damage in isolated peripheral blood mononuclear cells (PBMCs) of MS patients. The analysis was carried on 19 relapsing-remitting untreated MS patients and 13 healthy individuals. We investigated the emergency-driven synthesis of poly(ADP-ribose) (PAR), the expression level of the constitutive enzyme poly(ADP-ribose) polymerase-1 (PARP 1) and the DNA damage-induced phosphorylation of histone H2AX. PAR accumulation, PARP-1 and phosphorylated H2AX (gammaH2AX) were detected by immunofluorescence experiments on PBMCs isolated from 19 patients and 13 healthy volunteers. Our results show for the first time a net increased amount in PAR and gammaH2AX in MS patients compared to healthy individuals. Patients were further subdivided in three groups, according to the neuroimaging (MRI)-based classification of disease phase. Remarkably, we found a positive correlation between the level of gammaH2AX and MS aggressiveness. In addition, apoptosis in PBMCs was monitored by flow cytometry of both phosphatidylserine exposure (revealed by Annexin V-FITC labeling) and membrane permeability to propidium iodide. Our observations provide the evidence that the number of apoptotic cells was significantly higher in patients compared to healthy individuals, thus suggesting that apoptosis could affect MS lymphocyte function. PMID- 23028691 TI - Robust markers reflecting phylogeny and taxonomy of rhizobia. AB - Genomic ANI (Average Nucleotide Identity) has been found to be able to replace DNA-DNA hybridization in prokaryote taxonomy. The ANI of each of the core genes that has a phylogeny congruent with the reference species tree of rhizobia was compared to the genomic ANI. This allowed us to identify three housekeeping genes (SMc00019-truA-thrA) whose ANI reflected the intraspecies and interspecies genomic ANI among rhizobial strains, revealing an ANI gap (>=2%) between the inter- and intra-species comparisons. The intraspecies (96%) and interspecies (94%) ANI boundaries calculated from three genes (SMc00019-truA-thrA) provided a criterion for bacterial species definition and confirmed 621/629 of known interspecies relationships within Bradyrhizobium, Mesorhizobium, Sinorhizobium and Rhizobium. Some widely studied strains should be renamed. The SMc00019-truA thrA ANI also correlates well with the genomic ANI of strains in Agrobacterium, Methylobacterium, Ralstonia, Rhodopseudomonas, Cupriavidus and Burkholderia, suggesting their wide applicability in other bacteria. PMID- 23028692 TI - Enhanced PKCdelta and ERK signaling mediate cell migration of retinal pigment epithelial cells synergistically induced by HGF and EGF. AB - Proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR) are characterized by the development of epi-retinal membranes which may exert a tractional force on retina. A lot of inflammatory growth factors may disturb the local ocular cells such as retinal pigment epithelial (RPE) cells, causing them to migrate and proliferate in the vitreous cavity and ultimately forming the PVR membrane. In this study, the signal pathways mediating cell migration of RPE induced by growth factors were investigated. Hepatocyte growth factor (HGF), epidermal growth factor (EGF) or heparin-binding epidermal growth factor (HB-EGF) induced a greater extent of migration of RPE50 and ARPE19 cells, compared with other growth factors. According to inhibitor studies, migration of RPE cells induced by each growth factor was mediated by protein kinase C (PKC) and ERK (MAPK). Moreover, HGF coupled with EGF or HB-EGF had synergistic effects on cell migration and enhanced activation of PKC and ERK, which were attributed to cross activation of growth factor receptors by heterogeneous ligands. Furthermore, using the shRNA technique, PKCdelta was found to be the most important PKC isozyme involved. Finally, vitreous fluids from PVR and PDR patients with high concentration of HGF may induce RPE cell migration in PKCdelta and ERK- dependent manner. In conclusion, migration of RPE cells can be synergistically induced by HGF coupled with HB-EGF or EGF, which were mediated by enhanced PKCdelta activation and ERK phosphorylation. PMID- 23028693 TI - Therapeutic effects of astragaloside IV on myocardial injuries: multi-target identification and network analysis. AB - Astragaloside IV (AGS-IV) is a main active ingredient of Astragalus membranaceus Bunge, a medicinal herb used for cardiovascular diseases (CVD). In this work, we investigated the therapeutic mechanisms of AGS-IV at a network level by computer assisted target identification with the in silico inverse docking program (INVDOCK). Targets included in the analysis covered all signaling pathways thought to be implicated in the therapeutic actions of all CVD drugs approved by US FDA. A total of 39 putative targets were identified. Three of these targets, calcineurin (CN), angiotensin-converting enzyme (ACE), and c-Jun N-terminal kinase (JNK), were experimentally validated at a molecular level. Protective effects of AGS-IV were also compared with the CN inhibitor cyclosporin A (CsA) in cultured cardiomyocytes exposed to adriamycin. Network analysis of protein protein interactions (PPI) was carried out with reference to the therapeutic profiles of approved CVD drugs. The results suggested that the therapeutic effects of AGS-IV are based upon a combination of blocking calcium influx, vasodilation, anti-thrombosis, anti-oxidation, anti-inflammation and immune regulation. PMID- 23028694 TI - Opium addiction increases interleukin 1 receptor antagonist (IL-1Ra) in the coronary artery disease patients. AB - BACKGROUND: There is evidence that opium addiction has immunosuppressant effects. Coronary artery disease (CAD) is a condition resulted from atherosclerosis which is dependent on the immune response. PURPOSE: To evaluate plasma levels of interleukin-6 and interleukin-1Ra in 30 patients with three-vessel coronary artery disease, ejection fraction of more than 35% and to evaluate their changes after prognostic treadmill test in 15 opium addicted and 15 non-addicted patients. METHODS: The participants underwent prognostic treadmill test and plasma levels of interleukin-6 (IL-6) and interleukin-1Ra (IL-1Ra) were evaluated with ELISA method before, just after and 4 hours after the test. RESULTS: IL-1Ra (2183 pg/ml) tended to decrease over time in the opium addicted group (1372 pg/ml after prognostic treadmill test and 1034 pg/ml 4 hours after that), although such decrease did not reach the statistical significance. IL-1Ra levels were significantly higher in opium addicted than in non addicted patients. Opium addiction had no significant effect on IL-6 changes. CONCLUSION: Consumption of opium in CAD patients is associated with higher IL-1Ra levels. PMID- 23028695 TI - Different patterns of cytokines and chemokines combined with IFN-gamma production reflect Mycobacterium tuberculosis infection and disease. AB - BACKGROUND: IFN-gamma is presently the only soluble immunological marker used to help diagnose latent Mycobacterium tuberculosis (M.tb) infection. However, IFN gamma is not available to distinguish latent from active TB infection. Moreover, extrapulmonary tuberculosis, such as tuberculous pleurisy, cannot be properly diagnosed by IFN-gamma release assay. As a result, other disease- or infection related immunological biomarkers that would be more effective need to be screened and identified. METHODOLOGY: A panel of 41 soluble immunological molecules (17 cytokines and 24 chemokines) was tested using Luminex liquid array-based multiplexed immunoassays. Samples, including plasma and pleural effusions, from healthy donors (HD, n = 12) or patients with latent tuberculosis infection (LTBI, n = 20), pulmonary tuberculosis (TB, n = 12), tuberculous pleurisy (TP, n = 15) or lung cancer (LC, n = 15) were collected and screened for soluble markers. Peripheral blood mononuclear cells (PBMCs) and pleural fluid mononuclear cells (PFMCs) were also isolated to investigate antigen-specific immune factors. PRINCIPAL FINDINGS: For the 41 examined factors, our results indicated that three patterns were closely associated with infection and disease. (1) Significantly elevated plasma levels of IL-2, IP-10, CXCL11 and CXCL12 were present in both patients with tuberculosis and in a sub-group participant with latent tuberculosis infection who showed a higher level of IFN-gamma producing cells by ELISPOT assay compared with other latently infected individuals. (2) IL-6 and IL 9 were only significantly increased in plasma from active TB patients, and the two factors were consistently highly secreted after M.tb antigen stimulation. (3) When patients developed tuberculous pleurisy, CCL1, CCL21 and IL-6 were specifically increased in the pleural effusions. In particular, these three factors were consistently highly secreted by pleural fluid mononuclear cells following M.tb-specific antigen stimulation. In conclusion, our data imply that the specific secretion of soluble immunological factors, in addition to IFN gamma, may be used to evaluate M.tb infection and tuberculosis disease. PMID- 23028696 TI - Probing the dynamics of doxorubicin-DNA intercalation during the initial activation of apoptosis by fluorescence lifetime imaging microscopy (FLIM). AB - Doxorubicin is a potent anthracycline antibiotic, commonly used to treat a wide range of cancers. Although postulated to intercalate between DNA bases, many of the details of doxorubicin's mechanism of action remain unclear. In this work, we demonstrate the ability of fluorescence lifetime imaging microscopy (FLIM) to dynamically monitor doxorubicin-DNA intercalation during the earliest stages of apoptosis. The fluorescence lifetime of doxorubicin in nuclei is found to decrease rapidly during the first 2 hours following drug administration, suggesting significant changes in the doxorubicin-DNA binding site's microenvironment upon apoptosis initiation. Decreases in doxorubicin fluorescence lifetimes were found to be concurrent with increases in phosphorylation of H2AX (an immediate signal of DNA double-strand breakage), but preceded activation of caspase-3 (a late signature of apoptosis) by more than 150 minutes. Time dependent doxorubicin FLIM analyses of the effects of pretreating cells with either Cyclopentylidene-[4-(4-chlorophenyl)thiazol-2-yl)-hydrazine (a histone acetyltransferase inhibitor) or Trichostatin A (a histone deacetylase inhibitor) revealed significant correlation of fluorescence lifetime with the stage of chromatin decondensation. Taken together, our findings suggest that monitoring the dynamics of doxorubicin fluorescence lifetimes can provide valuable information during the earliest phases of doxorubicin-induced apoptosis; and implicate that FLIM can serve as a sensitive, high-resolution tool for the elucidation of intercellular mechanisms and kinetics of anti-cancer drugs that bear fluorescent moieties. PMID- 23028697 TI - Requirement of PML SUMO interacting motif for RNF4- or arsenic trioxide-induced degradation of nuclear PML isoforms. AB - PML, the organizer of nuclear bodies (NBs), is expressed in several isoforms designated PMLI to VII which differ in their C-terminal region due to alternative splicing of a single gene. This variability is important for the function of the different PML isoforms. PML NB formation requires the covalent linkage of SUMO to PML. Arsenic trioxide (As2O3) enhances PML SUMOylation leading to an increase in PML NB size and promotes its interaction with RNF4, a poly-SUMO-dependent ubiquitin E3 ligase responsible for proteasome-mediated PML degradation. Furthermore, the presence of a bona fide SUMO Interacting Motif (SIM) within the C-terminal region of PML seems to be required for recruitment of other SUMOylated proteins within PML NBs. This motif is present in all PML isoforms, except in the nuclear PMLVI and in the cytoplasmic PMLVII. Using a bioluminescence resonance energy transfer (BRET) assay in living cells, we found that As2O3 enhanced the SUMOylation and interaction with RNF4 of nuclear PML isoforms (I to VI). In addition, among the nuclear PML isoforms, only the one lacking the SIM sequence, PMLVI, was resistant to As2O3-induced PML degradation. Similarly, mutation of the SIM in PMLIII abrogated its sensitivity to As2O3-induced degradation. PMLVI and PMLIII-SIM mutant still interacted with RNF4. However, their resistance to the degradation process was due to their inability to be polyubiquitinated and to recruit efficiently the 20S core and the beta regulatory subunit of the 11S complex of the proteasome in PML NBs. Such resistance of PMLVI to As2O3-induced degradation was alleviated by overexpression of RNF4. Our results demonstrate that the SIM of PML is dispensable for PML SUMOylation and interaction with RNF4 but is required for efficient PML ubiquitination, recruitment of proteasome components within NBs and proteasome-dependent degradation of PML in response to As2O3. PMID- 23028698 TI - P. falciparum infection durations and infectiousness are shaped by antigenic variation and innate and adaptive host immunity in a mathematical model. AB - Many questions remain about P. falciparum within-host dynamics, immunity, and transmission-issues that may affect public health campaign planning. These gaps in knowledge concern the distribution of durations of malaria infections, determination of peak parasitemia during acute infection, the relationships among gametocytes and immune responses and infectiousness to mosquitoes, and the effect of antigenic structure on reinfection outcomes. The present model of intra-host dynamics of P. falciparum implements detailed representations of parasite and immune dynamics, with structures based on minimal extrapolations from first principles biology in its foundations. The model is designed to quickly and readily accommodate gains in mechanistic understanding and to evaluate effects of alternative biological hypothesis through in silico experiments. Simulations follow the parasite from the liver-stage through the detailed asexual cycle to clearance while tracking gametocyte populations. The modeled immune system includes innate inflammatory and specific antibody responses to a repertoire of antigens. The mechanistic focus provides clear explanations for the structure of the distribution of infection durations through the interaction of antigenic variation and innate and adaptive immunity. Infectiousness to mosquitoes appears to be determined not only by the density of gametocytes but also by the level of inflammatory cytokines, which harmonizes an extensive series of study results. Finally, pre-existing immunity can either decrease or increase the duration of infections upon reinfection, depending on the degree of overlap in antigenic repertoires and the strength of the pre-existing immunity. PMID- 23028700 TI - Full-sibs in cohorts of newly settled coral reef fishes. AB - Reef fishes exhibit a bipartite life cycle where a benthic adult stage is preceded by a pelagic dispersal phase during which larvae are presumed to be mixed and transported by oceanic currents. Genetic analyses based on twelve microsatellite loci of 181 three-spot dascyllus (Dascyllus trimaculatus) that settled concurrently on a small reef in French Polynesia revealed 11 groups of siblings (1 full sibs and 10 half-sibs). This is the first evidence that fish siblings can journey together throughout their entire planktonic dispersal phase (nearly a month long for three-spot dascyllus). Our findings have critical implications for the dynamics and genetic structure of fish populations, as well as for the design of marine protected areas and management of fisheries. PMID- 23028699 TI - Cysteine dioxygenase 1 is a tumor suppressor gene silenced by promoter methylation in multiple human cancers. AB - The human cysteine dioxygenase 1 (CDO1) gene is a non-heme structured, iron containing metalloenzyme involved in the conversion of cysteine to cysteine sulfinate, and plays a key role in taurine biosynthesis. In our search for novel methylated gene promoters, we have analyzed differential RNA expression profiles of colorectal cancer (CRC) cell lines with or without treatment of 5-aza-2' deoxycytidine. Among the genes identified, the CDO1 promoter was found to be differentially methylated in primary CRC tissues with high frequency compared to normal colon tissues. In addition, a statistically significant difference in the frequency of CDO1 promoter methylation was observed between primary normal and tumor tissues derived from breast, esophagus, lung, bladder and stomach. Downregulation of CDO1 mRNA and protein levels were observed in cancer cell lines and tumors derived from these tissue types. Expression of CDO1 was tightly controlled by promoter methylation, suggesting that promoter methylation and silencing of CDO1 may be a common event in human carcinogenesis. Moreover, forced expression of full-length CDO1 in human cancer cells markedly decreased the tumor cell growth in an in vitro cell culture and/or an in vivo mouse model, whereas knockdown of CDO1 increased cell growth in culture. Our data implicate CDO1 as a novel tumor suppressor gene and a potentially valuable molecular marker for human cancer. PMID- 23028702 TI - Phenotypic plasticity and population differentiation in an ongoing species invasion. AB - The ability to succeed in diverse conditions is a key factor allowing introduced species to successfully invade and spread across new areas. Two non-exclusive factors have been suggested to promote this ability: adaptive phenotypic plasticity of individuals, and the evolution of locally adapted populations in the new range. We investigated these individual and population-level factors in Polygonum cespitosum, an Asian annual that has recently become invasive in northeastern North America. We characterized individual fitness, life-history, and functional plasticity in response to two contrasting glasshouse habitat treatments (full sun/dry soil and understory shade/moist soil) in 165 genotypes sampled from nine geographically separate populations representing the range of light and soil moisture conditions the species inhabits in this region. Polygonum cespitosum genotypes from these introduced-range populations expressed broadly similar plasticity patterns. In response to full sun, dry conditions, genotypes from all populations increased photosynthetic rate, water use efficiency, and allocation to root tissues, dramatically increasing reproductive fitness compared to phenotypes expressed in simulated understory shade. Although there were subtle among-population differences in mean trait values as well as in the slope of plastic responses, these population differences did not reflect local adaptation to environmental conditions measured at the population sites of origin. Instead, certain populations expressed higher fitness in both glasshouse habitat treatments. We also compared the introduced-range populations to a single population from the native Asian range, and found that the native population had delayed phenology, limited functional plasticity, and lower fitness in both experimental environments compared with the introduced-range populations. Our results indicate that the future spread of P. cespitosum in its introduced range will likely be fueled by populations consisting of individuals able to express high fitness across diverse light and moisture conditions, rather than by the evolution of locally specialized populations. PMID- 23028701 TI - In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer. AB - XMRV, or xenotropic murine leukemia virus (MLV)-related virus, is a novel gammaretrovirus originally identified in studies that analyzed tissue from prostate cancer patients in 2006 and blood from patients with chronic fatigue syndrome (CFS) in 2009. However, a large number of subsequent studies failed to confirm a link between XMRV infection and CFS or prostate cancer. On the contrary, recent evidence indicates that XMRV is a contaminant originating from the recombination of two mouse endogenous retroviruses during passaging of a prostate tumor xenograft (CWR22) in mice, generating laboratory-derived cell lines that are XMRV-infected. To confirm or refute an association between XMRV and prostate cancer, we analyzed prostate cancer tissues and plasma from a prospectively collected cohort of 39 patients as well as archival RNA and prostate tissue from the original 2006 study. Despite comprehensive microarray, PCR, FISH, and serological testing, XMRV was not detected in any of the newly collected samples or in archival tissue, although archival RNA remained XMRV positive. Notably, archival VP62 prostate tissue, from which the prototype XMRV strain was derived, tested negative for XMRV on re-analysis. Analysis of viral genomic and human mitochondrial sequences revealed that all previously characterized XMRV strains are identical and that the archival RNA had been contaminated by an XMRV-infected laboratory cell line. These findings reveal no association between XMRV and prostate cancer, and underscore the conclusion that XMRV is not a naturally acquired human infection. PMID- 23028703 TI - Teaching the blind to find their way by playing video games. AB - Computer based video games are receiving great interest as a means to learn and acquire new skills. As a novel approach to teaching navigation skills in the blind, we have developed Audio-based Environment Simulator (AbES); a virtual reality environment set within the context of a video game metaphor. Despite the fact that participants were naive to the overall purpose of the software, we found that early blind users were able to acquire relevant information regarding the spatial layout of a previously unfamiliar building using audio based cues alone. This was confirmed by a series of behavioral performance tests designed to assess the transfer of acquired spatial information to a large-scale, real-world indoor navigation task. Furthermore, learning the spatial layout through a goal directed gaming strategy allowed for the mental manipulation of spatial information as evidenced by enhanced navigation performance when compared to an explicit route learning strategy. We conclude that the immersive and highly interactive nature of the software greatly engages the blind user to actively explore the virtual environment. This in turn generates an accurate sense of a large-scale three-dimensional space and facilitates the learning and transfer of navigation skills to the physical world. PMID- 23028704 TI - Sirenomelia phenotype in bmp7;shh compound mutants: a novel experimental model for studies of caudal body malformations. AB - Sirenomelia is a severe congenital malformation of the lower body characterized by the fusion of the legs into a single lower limb. This striking external phenotype consistently associates severe visceral abnormalities, most commonly of the kidneys, intestine, and genitalia that generally make the condition lethal. Although the causes of sirenomelia remain unknown, clinical studies have yielded two major hypotheses: i) a primary defect in the generation of caudal mesoderm, ii) a primary vascular defect that leaves the caudal part of the embryo hypoperfused. Interestingly, Sirenomelia has been shown to have a genetic basis in mice, and although it has been considered a sporadic condition in humans, recently some possible familial cases have been reported. Here, we report that the removal of one or both functional alleles of Shh from the Bmp7-null background leads to a sirenomelia phenotype that faithfully replicates the constellation of external and internal malformations, typical of the human condition. These mutants represent an invaluable model in which we have analyzed the pathogenesis of sirenomelia. We show that the signaling defect predominantly impacts the morphogenesis of the hindgut and the development of the caudal end of the dorsal aortas. The deficient formation of ventral midline structures, including the interlimb mesoderm caudal to the umbilicus, leads to the approximation and merging of the hindlimb fields. Our study provides new insights for the understanding of the mechanisms resulting in caudal body malformations, including sirenomelia. PMID- 23028705 TI - Gap junction enhancer increases efficacy of cisplatin to attenuate mammary tumor growth. AB - Cisplatin treatment has an overall 19% response rate in animal models with malignant tumors. Increasing gap junction activity in tumor cells provides the targets to enhance antineoplastic therapies. Previously, a new class of substituted quinolines (PQs) acts as gap junction enhancer, ability to increase the gap junctional intercellular communication, in breast cancer cells. We examined the effect of combinational treatment of PQs and antineoplastic drugs in an animal model, showing an increase in efficacy of antineoplastic drugs via the enhancement of gap junctions. Mice were implanted with estradiol-17beta (1.7 mg/pellet) before the injection of 1*107 T47D breast cancer cells subcutaneously into the inguinal region of mammary fat pad. Animals were treated intraperitoneally with DMSO (control), cisplatin (3.5 mg/kg), PQ (25 mg/kg), or a combining treatment of cisplatin and PQ. Cisplatin alone decreased mammary tumor growth by 85% while combinational treatment of cisplatin and PQ1 or PQ7 showed an additional reduction of 77% and 22% of tumor growth after 7 treatments at every 2 days, respectively. Histological results showed a significant increase of gap junction proteins, Cx43 and Cx26, in PQ-treated tissues compared to control or cisplatin. Furthermore, evidence of highly stained caspase 3 in tumors of combinational treatment (PQ and cisplatin) was seen compared to cisplatin alone. We have showed for the first time an increase in the efficacy of antineoplastic drugs through a combinational treatment with PQs, a specific class of gap junction enhancers. PMID- 23028706 TI - Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3. AB - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the best understood cause of dominantly inherited stroke and results from NOTCH3 mutations that lead to NOTCH3 protein accumulation and selective arterial smooth muscle degeneration. Previous studies show that NOTCH3 protein forms multimers. Here, we investigate protein interactions between NOTCH3 and other vascular Notch isoforms and characterize the effects of elevated NOTCH3 on smooth muscle gene regulation. We demonstrate that NOTCH3 forms heterodimers with NOTCH1, NOTCH3, and NOTCH4. R90C and C49Y mutant NOTCH3 form complexes which are more resistant to detergents than wild type NOTCH3 complexes. Using quantitative NOTCH3-luciferase clearance assays, we found significant inhibition of mutant NOTCH3 clearance. In coculture assays of NOTCH function, overexpressed wild type and mutant NOTCH3 significantly repressed NOTCH-regulated smooth muscle transcripts and potently impaired the activity of three independent smooth muscle promoters. Wildtype and R90C recombinant NOTCH3 proteins applied to cell cultures also blocked canonical Notch fuction. We conclude that CADASIL mutants of NOTCH3 complex with NOTCH1, 3, and 4, slow NOTCH3 clearance, and that overexpressed wild type and mutant NOTCH3 protein interfere with key NOTCH-mediated functions in smooth muscle cells. PMID- 23028707 TI - A cell culture adapted HCV JFH1 variant that increases viral titers and permits the production of high titer infectious chimeric reporter viruses. AB - The unique properties of the hepatitis C virus (HCV) JFH1 isolate have made it possible to produce and study HCV in an infectious cell culture system. However, relatively low virus titers restrict some of the uses of this system and preparing infectious chimeric reporter viruses have been difficult. In this study, we report cell culture-adapted mutations in wild-type JFH1 yielding higher titers of infectious particles of both JFH1 and chimeric JFH1 viruses carrying reporter genes. Sequencing analyses determined that ten of the sixteen nonsynonymous mutations were in the NS5A region. Individual viruses harboring specific adaptive mutations were prepared and studied. The mutations in the NS5A region, which included all three domains, were most effective in increasing infectious virus production. Insertion of two reporter genes in JFH1 without the adaptive mutations ablated the production of infectious HCV particles. However, the introduction of specific adaptive mutations in the NS5A region permitted reporter genes, Renilla luciferase (Rluc) and EGFP, to be introduced into JHF1 to produce chimeric HCV-NS5A-EGFP and HCV-NS5A-Rluc reporter viruses at relatively high titers of infectious virus. The quantity of hyperphosphorylated NS5A (p58) was decreased in the adapted JFH1 compared wild type JFH1 and is likely be involved in increased production of infectious virus based on previous studies of p58. The JFH1-derived mutant viruses and chimeric reporter viruses described here provide new tools for studying HCV biology, identifying HCV antivirals, and enable new ways of engineering additional infectious chimeric viruses. PMID- 23028708 TI - When the lowest energy does not induce native structures: parallel minimization of multi-energy values by hybridizing searching intelligences. AB - BACKGROUND: Protein structure prediction (PSP), which is usually modeled as a computational optimization problem, remains one of the biggest challenges in computational biology. PSP encounters two difficult obstacles: the inaccurate energy function problem and the searching problem. Even if the lowest energy has been luckily found by the searching procedure, the correct protein structures are not guaranteed to obtain. RESULTS: A general parallel metaheuristic approach is presented to tackle the above two problems. Multi-energy functions are employed to simultaneously guide the parallel searching threads. Searching trajectories are in fact controlled by the parameters of heuristic algorithms. The parallel approach allows the parameters to be perturbed during the searching threads are running in parallel, while each thread is searching the lowest energy value determined by an individual energy function. By hybridizing the intelligences of parallel ant colonies and Monte Carlo Metropolis search, this paper demonstrates an implementation of our parallel approach for PSP. 16 classical instances were tested to show that the parallel approach is competitive for solving PSP problem. CONCLUSIONS: This parallel approach combines various sources of both searching intelligences and energy functions, and thus predicts protein conformations with good quality jointly determined by all the parallel searching threads and energy functions. It provides a framework to combine different searching intelligence embedded in heuristic algorithms. It also constructs a container to hybridize different not-so-accurate objective functions which are usually derived from the domain expertise. PMID- 23028709 TI - Involvement of microRNA-mediated gene expression regulation in the pathological development of stem canker disease in Populus trichocarpa. AB - MicroRNAs (miRNAs), a type of short (21-23 nucleotides), non-coding RNA molecule, mediate repressive gene regulation through RNA silencing at the post transcriptional level, and play an important role in defense and response to abiotic and biotic stresses. In the present study, Affymetrix(r) miRNA Array, real-time quantitative PCR (qPCR) for miRNAs and their targets, and miRNA promoter analysis were used to validate the gene expression patterns of miRNAs in Populus trichocarpa plantlets induced with the poplar stem canker pathogen, Botryosphaeria dothidea. Twelve miRNAs (miR156, miR159, miR160, miR164, miR166, miR168, miR172, miR319, miR398, miR408, miR1448, and miR1450) were upregulated in the stem bark of P. trichocarpa, but no downregulated miRNAs were found. Based on analysis of the miRNAs and their targets, a potential co-regulatory network was developed to describe post-transcriptional regulation in the pathological development of poplar stem canker. There was highly complex cross-talk between diverse miRNA pathway responses to biotic and abiotic stresses. The results suggest that miR156 is probably an integral component of the miRNA response to all environmental stresses in plants. Cis-regulatory elements were binding sites for the transcription factors (TFs) on DNA. Promoter analysis revealed that TC rich repeats and a W1-box motif were both tightly related disease response motifs in Populus. Promoter analysis and target analysis of miRNAs also revealed that some TFs regulate their activation/repression. Furthermore, a feedback regulatory network in the pathological development of poplar stem canker is provided. The results confirm that miRNA pathways regulate gene expression during the pathological development of plant disease, and provide new insights into understanding the onset and development of poplar stem canker. PMID- 23028710 TI - Blue light acts as a double-edged sword in regulating sexual development of Hypocrea jecorina (Trichoderma reesei). AB - The industrially important cellulolytic filamentous fungus Trichoderma reesei is the anamorph of the pantropical ascomycete Hypocrea jecorina. H. jecorina CBS999.97 strain undergoes a heterothallic reproductive cycle, and the mating yields fertilized perithecia imbedded in stromata. Asci in the perithecia contain 16 linearly arranged ascospores. Here, we investigated H. jecorina sexual development under different light regimes, and found that visible light was dispensable for sexual development (stroma formation and ascospore discharge). By contrast, constant illumination inhibited stroma formation, and an interruption of the darkness facilitated timely stroma formation in a 12 h/12 h light-dark photoperiod. The results of genetic analyses further revealed that H. jecorina blue-light photoreceptors (BLR1, BLR2) and the photoadaptation protein ENV1 were not essential for sexual development in general. BLR1, BLR2 and ENV1 are orthologues of the conserved Neurospora crassa WC-1, WC-2 and VVD, respectively. Moreover, BLR1 and BLR2 mediate both positive and negative light-dependent regulation on sexual development, whereas ENV1 is required for dampening the light-dependent inhibitory effect in response to changes in illumination. Comparative genome-wide microarray analysis demonstrated an overview of light dependent gene expression versus sexual potency in CBS999.97 (MAT1-2) haploid cells. Constant illumination promotes abundant asexual conidiation and high levels of hpp1 transcripts. hpp1 encodes a h (hybrid)-type propheromone that exhibits features of both yeast a and a pheromone precursors. Deletion of hpp1 could rescue stroma formation but not ascospore generation under constant illumination. We inferred that the HPP1-dependent pheromone signaling system might directly prevent stroma formation or simply disallow the haploid cells to acquire sexual potency due to abundant asexual conidiation upon constant illumination. PMID- 23028711 TI - Transmission mode predicts specificity and interaction patterns in coral Symbiodinium networks. AB - Most reef-building corals in the order Scleractinia depend on endosymbiotic algae in the genus Symbiodinium for energy and survival. Significant levels of taxonomic diversity in both partners result in numerous possible combinations of coral-Symbiodinium associations with unique functional characteristics. We created and analyzed the first coral-Symbiodinium networks utilizing a global dataset of interaction records from coral reefs in the tropical Indo-Pacific and Atlantic Oceans for 1991 to 2010. Our meta-analysis reveals that the majority of coral species and Symbiodinium types are specialists, but failed to detect any one-to-one obligate relationships. Symbiont specificity is correlated with a host's transmission mode, with horizontally transmitting corals being more likely to interact with generalist symbionts. Globally, Symbiodinium types tend to interact with only vertically or horizontally transmitting corals, and only a few generalist types are found with both. Our results demonstrate a strong correlation between symbiont specificity, symbiont transmission mode, and community partitioning. The structure and dynamics of these network interactions underlie the fundamental biological partnership that determines the condition and resilience of coral reef ecosystems. PMID- 23028712 TI - Identification of novel human dipeptidyl peptidase-IV inhibitors of natural origin (Part II): in silico prediction in antidiabetic extracts. AB - BACKGROUND: Natural extracts play an important role in traditional medicines for the treatment of diabetes mellitus and are also an essential resource for new drug discovery. Dipeptidyl peptidase IV (DPP-IV) inhibitors are potential candidates for the treatment of type 2 diabetes mellitus, and the effectiveness of certain antidiabetic extracts of natural origin could be, at least partially, explained by the inhibition of DPP-IV. METHODOLOGY/PRINCIPAL FINDINGS: Using an initial set of 29,779 natural products that are annotated with their natural source and an experimentally validated virtual screening procedure previously developed in our lab (Guasch et al.; 2012) [1], we have predicted 12 potential DPP-IV inhibitors from 12 different plant extracts that are known to have antidiabetic activity. Seven of these molecules are identical or similar to molecules with described antidiabetic activity (although their role as DPP-IV inhibitors has not been suggested as an explanation for their bioactivity). Therefore, it is plausible that these 12 molecules could be responsible, at least in part, for the antidiabetic activity of these extracts through their inhibitory effect on DPP-IV. In addition, we also identified as potential DPP-IV inhibitors 6 molecules from 6 different plants with no described antidiabetic activity but that share the same genus as plants with known antidiabetic properties. Moreover, none of the 18 molecules that we predicted as DPP-IV inhibitors exhibits chemical similarity with a group of 2,342 known DPP-IV inhibitors. CONCLUSIONS/SIGNIFICANCE: Our study identified 18 potential DPP-IV inhibitors in 18 different plant extracts (12 of these plants have known antidiabetic properties, whereas, for the remaining 6, antidiabetic activity has been reported for other plant species from the same genus). Moreover, none of the 18 molecules exhibits chemical similarity with a large group of known DPP-IV inhibitors. PMID- 23028715 TI - Migrating giant honey bees (Apis dorsata) congregate annually at stopover site in Thailand. AB - Giant honey bees (Apis dorsata) of southern Asia are vital honey producers and pollinators of cultivated crops and wild plants. They are known to migrate seasonally up to 200 km. It has been assumed their migrations occur stepwise, with stops for rest and foraging, but bivouacking bees have rarely been seen by scientists. Here I report discovery of a site in northern Thailand where bivouacs appeared in large congregations during the wet seasons of 2009 and 2010. The bivouac congregation stopover site is a small mango orchard along the Pai River. Bivouacs rested in branches of mango and other tree species in the immediate vicinity. Departures were preceded by dances indicating approximate direction and apparently, distance of flights. Such consistent stopover sites likely occur throughout southern Asia and may support critical, vulnerable stages in the life history of giant honey bees that must be conserved for populations of the species to survive. PMID- 23028713 TI - Gene expression and functional annotation of the human ciliary body epithelia. AB - PURPOSE: The ciliary body (CB) of the human eye consists of the non-pigmented (NPE) and pigmented (PE) neuro-epithelia. We investigated the gene expression of NPE and PE, to shed light on the molecular mechanisms underlying the most important functions of the CB. We also developed molecular signatures for the NPE and PE and studied possible new clues for glaucoma. METHODS: We isolated NPE and PE cells from seven healthy human donor eyes using laser dissection microscopy. Next, we performed RNA isolation, amplification, labeling and hybridization against 44*k Agilent microarrays. For microarray conformations, we used a literature study, RT-PCRs, and immunohistochemical stainings. We analyzed the gene expression data with R and with the knowledge database Ingenuity. RESULTS: The gene expression profiles and functional annotations of the NPE and PE were highly similar. We found that the most important functionalities of the NPE and PE were related to developmental processes, neural nature of the tissue, endocrine and metabolic signaling, and immunological functions. In total 1576 genes differed statistically significantly between NPE and PE. From these genes, at least 3 were cell-specific for the NPE and 143 for the PE. Finally, we observed high expression in the (N)PE of 35 genes previously implicated in molecular mechanisms related to glaucoma. CONCLUSION: Our gene expression analysis suggested that the NPE and PE of the CB were quite similar. Nonetheless, cell-type specific differences were found. The molecular machineries of the human NPE and PE are involved in a range of neuro-endocrinological, developmental and immunological functions, and perhaps glaucoma. PMID- 23028714 TI - Investigating embryonic expression patterns and evolution of AHI1 and CEP290 genes, implicated in Joubert syndrome. AB - Joubert syndrome and related diseases (JSRD) are developmental cerebello-oculo renal syndromes with phenotypes including cerebellar hypoplasia, retinal dystrophy and nephronophthisis (a cystic kidney disease). We have utilised the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR), to perform in situ hybridisation studies on embryonic tissues, revealing an early onset neuronal, retinal and renal expression pattern for AHI1. An almost identical pattern of expression is seen with CEP290 in human embryonic and fetal tissue. A novel finding is that both AHI1 and CEP290 demonstrate strong expression within the developing choroid plexus, a ciliated structure important for central nervous system development. To test if AHI1 and CEP290 may have co-evolved, we carried out a genomic survey of a large group of organisms across eukaryotic evolution. We found that, in animals, ahi1 and cep290 are almost always found together; however in other organisms either one may be found independent of the other. Finally, we tested in murine epithelial cells if Ahi1 was required for recruitment of Cep290 to the centrosome. We found no obvious differences in Cep290 localisation in the presence or absence of Ahi1, suggesting that, while Ahi1 and Cep290 may function together in the whole organism, they are not interdependent for localisation within a single cell. Taken together these data support a role for AHI1 and CEP290 in multiple organs throughout development and we suggest that this accounts for the wide phenotypic spectrum of AHI1 and CEP290 mutations in man. PMID- 23028716 TI - Association test based on SNP set: logistic kernel machine based test vs. principal component analysis. AB - GWAS has facilitated greatly the discovery of risk SNPs associated with complex diseases. Traditional methods analyze SNP individually and are limited by low power and reproducibility since correction for multiple comparisons is necessary. Several methods have been proposed based on grouping SNPs into SNP sets using biological knowledge and/or genomic features. In this article, we compare the linear kernel machine based test (LKM) and principal components analysis based approach (PCA) using simulated datasets under the scenarios of 0 to 3 causal SNPs, as well as simple and complex linkage disequilibrium (LD) structures of the simulated regions. Our simulation study demonstrates that both LKM and PCA can control the type I error at the significance level of 0.05. If the causal SNP is in strong LD with the genotyped SNPs, both the PCA with a small number of principal components (PCs) and the LKM with kernel of linear or identical-by state function are valid tests. However, if the LD structure is complex, such as several LD blocks in the SNP set, or when the causal SNP is not in the LD block in which most of the genotyped SNPs reside, more PCs should be included to capture the information of the causal SNP. Simulation studies also demonstrate the ability of LKM and PCA to combine information from multiple causal SNPs and to provide increased power over individual SNP analysis. We also apply LKM and PCA to analyze two SNP sets extracted from an actual GWAS dataset on non-small cell lung cancer. PMID- 23028717 TI - Latexin is down-regulated in hematopoietic malignancies and restoration of expression inhibits lymphoma growth. AB - Latexin is a negative regulator of hematopoietic stem cell number in mice. Its dysregulated expression in other tumors led us to hypothesize that latexin may have tumor suppressor properties in hematological malignancies. We found that latexin was down-regulated in a variety of leukemia and lymphoma cell lines as well as in CD34+ cells from the blood and marrow of patients with these malignancies. 5-aza-2'-deoxycytodine treatment and bisulfite sequencing revealed hypermethylation of latexin promoter in tumor cells. Retrovirus-mediated latexin overexpression in A20 mouse lymphoma cells inhibited their in vitro growth by 16 fold and in vivo tumor volume by 2 fold. Latexin caused growth inhibition of lymphoma cells by significantly increasing apoptosis through the down-regulation of anti-apoptotic genes Bcl-2 and Pim-2. The molecular mechanism underlying latexin-mediated tumor inhibition was not through its canonical carboxypeptidase inhibitor activity. These results are consistent with a tumor suppressor role for latexin and suggest that latexin may have clinical efficacy in the treatment of malignancies. PMID- 23028718 TI - Socio economic position in TB prevalence and access to services: results from a population prevalence survey and a facility-based survey in Bangladesh. AB - BACKGROUND: In Bangladesh DOTS has been provided free of charge since 1993, yet information on access to TB services by different population group is not well documented. The objective of this study was to assess and compare the socio economic position (SEP) of actively detected cases from the community and the cases being routinely detected under National Tuberculosis Control Programme (NTP) in Bangladesh. METHODS AND FINDINGS: SEP was assessed by validated asset item for each of the 21,427 households included in the national tuberculosis prevalence survey 2007-2009. A principal component analysis generated household scores and categorized in quartiles. The distribution of 33 actively identified cases was compared with the 240 NTP cases over the identical SEP quartiles to evaluate access to TB services by different groups of the population. The population prevalence of tuberculosis was 5 times higher in the lowest quartiles of population (95.4, 95% CI: 48.0-189.7) to highest quartile population (19.5, 95% CI: 6.9-55.0). Among the 33 cases detected during survey, 25 (75.8%) were from lower two quartiles, and the rest 8 (24.3%) were from upper two quartiles. Among TB cases detected passively under NTP, more than half of them 137 (57.1%) were from uppermost two quartiles, 98 (41%) from the second quartile, and 5 (2%) in the lowest quartile of the population. This distribution is not affected when adjusted for other factors or interactions among them. CONCLUSIONS: The findings indicate that despite availability free of charge, DOTS is not equally accessed by the poorer sections of the population. However, these figures should be interpreted with caution since there is a need for additional studies that assess in-depth poverty indicators and its determinants in relation to access of the TB services provided in Bangladesh. PMID- 23028719 TI - Extensive phenotypic variation among allelic T-DNA inserts in Arabidopsis thaliana. AB - T-DNA insertion mutants are a tool used widely in Arabidopsis thaliana to disrupt gene function. We phenotyped multiple homozygous T-DNA A. thaliana mutants at each of two loci (AT1G11060 and AT4G00210). We measured life history traits, including germination, size at reproduction and fruit production. Allelic T-DNA lines differed for most traits at AT1G11060 but not at AT4G00210. However, insertions in exons differed from other insertion positions in AT4G00210 but not in AT1G11060. We found evidence for additional insertions in approximately half of the lines, but found few phenotypic consequences. In general, our results suggest that a cautious interpretation of T-DNA phenotypes is warranted. PMID- 23028720 TI - Met receptor acts uniquely for survival and morphogenesis of EGFR-dependent normal mammary epithelial and cancer cells. AB - Mammary gland development and breast cancer growth require multiple factors both of endocrine and paracrine origin. We analyzed the roles of Epidermal Growth Factor Receptor (EGFR) and Hepatocyte Growth Factor Receptor (Met) in mammary epithelial cells and mammary tumor cells derived from a mutated-ErbB2 transgenic mice. By using highly specific tyrosine kinase inhibitors we found that MCF-10A and NMuMG mammary epithelial cell lines are totally dependent on EGFR activation for their growth and survival. Proliferation and 3D-morphogenesis assays showed that HGF had no role in maintaining mammary cell viability, but was the only cytokine able to rescue EGFR-inhibited mammary cells. Insulin-Like Growth Factor I (IGF-I), basic-Fibroblast Growth Factor (b-FGF) and Neuregulin, which are well known mammary morphogenic factors, did not rescue proliferation or morphogenesis in these cell lines, following EGFR inhibition. Similarly, ErbB2-driven tumor cells are EGFR-dependent and also display HGF-mediated rescue. Western-blot analysis of the signaling pathways involved in rescue after EGFR inhibition indicated that concomitant ERK1/2 and AKT activation was exclusively driven by Met, but not by IGF-I or b-FGF. These results describe a unique role for EGFR and Met in mammary epithelial cells by showing that similar pathways can be used by tumorigenic cells to sustain growth and resist to EGFR-directed anti-tumorigenic drugs. PMID- 23028721 TI - Development of skewed functionality of HIV-1-specific cytotoxic CD8(+) T cells from primary to early chronic phase of HIV infection. AB - In recent years, the prevalence of HIV-1 infection has been rapidly increasing among men who have sex with men (MSM). However, it remains unknown how the host immune system responds to the infection in this population. We assessed the quantity of HIV-specific CD8(+) T-cell responses by using Elispot assay and their functionalities by measuring 5 CD8(+) T-cell evaluations (IL-2, MIP-1beta, CD107a, TNF-alpha, IFN-gamma) with flow cytometry assays among 18 primarily and 37 early chronically HIV-infected MSM. Our results demonstrated that subjects at early chronic phase developed HIV-specific CD8(+) T-cell responses with higher magnitudes and more diversified functionalities in comparison with those at primary infection. However, populations with IL-2(+) CD107a(+) or in combination with other functionality failed to develop in parallel. The multifunctional but not monofunctional HIV-specific CD8(+) T cells were associated with higher CD4(+) T -cell counts and lower viral loads. These data revealed that prolonged infection from primary to early chronic infection could selectively increase the functionalities of HIV-specific CD8(+) T cells in HIV-infected MSM population, the failure to develop IL-2 and cytotoxic functionalities in parallel may explain why the increased HIV-specific CD8(+) T cells were unable to enhance the containment of HIV-1 replication at the early chronic stage. PMID- 23028723 TI - The cranial osteology and feeding ecology of the metriorhynchid crocodylomorph genera Dakosaurus and Plesiosuchus from the late Jurassic of Europe. AB - BACKGROUND: Dakosaurus and Plesiosuchus are characteristic genera of aquatic, large-bodied, macrophagous metriorhynchid crocodylomorphs. Recent studies show that these genera were apex predators in marine ecosystems during the latter part of the Late Jurassic, with robust skulls and strong bite forces optimized for feeding on large prey. METHODOLOGY/PRINCIPAL FINDINGS: Here we present comprehensive osteological descriptions and systematic revisions of the type species of both genera, and in doing so we resurrect the genus Plesiosuchus for the species Dakosaurus manselii. Both species are diagnosed with numerous autapomorphies. Dakosaurus maximus has premaxillary 'lateral plates'; strongly ornamented maxillae; macroziphodont dentition; tightly fitting tooth-to-tooth occlusion; and extensive macrowear on the mesial and distal margins. Plesiosuchus manselii is distinct in having: non-amblygnathous rostrum; long mandibular symphysis; microziphodont teeth; tooth-crown apices that lack spalled surfaces or breaks; and no evidence for occlusal wear facets. Our phylogenetic analysis finds Dakosaurus maximus to be the sister taxon of the South American Dakosaurus andiniensis, and Plesiosuchus manselii in a polytomy at the base of Geosaurini (the subclade of macrophagous metriorhynchids that includes Dakosaurus, Geosaurus and Torvoneustes). CONCLUSIONS/SIGNIFICANCE: The sympatry of Dakosaurus and Plesiosuchus is curiously similar to North Atlantic killer whales, which have one larger 'type' that lacks tooth-crown breakage being sympatric with a smaller 'type' that has extensive crown breakage. Assuming this morphofunctional complex is indicative of diet, then Plesiosuchus would be a specialist feeding on other marine reptiles while Dakosaurus would be a generalist and possible suction feeder. This hypothesis is supported by Plesiosuchus manselii having a very large optimum gape (gape at which multiple teeth come into contact with a prey-item), while Dakosaurus maximus possesses craniomandibular characteristics observed in extant suction-feeding odontocetes: shortened tooth-row, amblygnathous rostrum and a very short mandibular symphysis. We hypothesise that trophic specialisation enabled these two large-bodied species to coexist in the same ecosystem. PMID- 23028722 TI - A genetic and pathologic study of a DENV2 clinical isolate capable of inducing encephalitis and hematological disturbances in immunocompetent mice. AB - Dengue virus (DENV) is the causative agent of dengue fever (DF), a mosquito-borne illness endemic to tropical and subtropical regions. There is currently no effective drug or vaccine formulation for the prevention of DF and its more severe forms, i.e., dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). There are two generally available experimental models for the study of DENV pathogenicity as well as the evaluation of potential vaccine candidates. The first model consists of non-human primates, which do not develop symptoms but rather a transient viremia. Second, mouse-adapted virus strains or immunocompromised mouse lineages are utilized, which display some of the pathological features of the infection observed in humans but may not be relevant to the results with regard to the wild-type original virus strains or mouse lineages. In this study, we describe a genetic and pathological study of a DENV2 clinical isolate, named JHA1, which is naturally capable of infecting and killing Balb/c mice and reproduces some of the symptoms observed in DENV-infected subjects. Sequence analyses demonstrated that the JHA1 isolate belongs to the American genotype group and carries genetic markers previously associated with neurovirulence in mouse-adapted virus strains. The JHA1 strain was lethal to immunocompetent mice following intracranial (i.c.) inoculation with a LD(50) of approximately 50 PFU. Mice infected with the JHA1 strain lost weight and exhibited general tissue damage and hematological disturbances, with similarity to those symptoms observed in infected humans. In addition, it was demonstrated that the JHA1 strain shares immunological determinants with the DENV2 NGC reference strain, as evaluated by cross-reactivity of anti-envelope glycoprotein (domain III) antibodies. The present results indicate that the JHA1 isolate may be a useful tool in the study of DENV pathogenicity and will help in the evaluation of anti-DENV vaccine formulations as well as potential therapeutic approaches. PMID- 23028724 TI - Pyrethroid resistance in Anopheles gambiae, in Bomi County, Liberia, compromises malaria vector control. AB - BACKGROUND: Long Lasting Insecticidal Nets (LLIN) and Indoor Residual Spraying (IRS) have both proven to be effective malaria vector control strategies in Africa and the new technology of insecticide treated durable wall lining (DL) is being evaluated. Sustaining these interventions at high coverage levels is logistically challenging and, furthermore, the increase in insecticide resistance in African malaria vectors may reduce the efficacy of these chemical based interventions. Monitoring of vector populations and evaluation of the efficacy of insecticide based control approaches should be integral components of malaria control programmes. This study reports on entomological survey conducted in 2011 in Bomi County, Liberia. METHODS: Anopheles gambiae larvae were collected from four sites in Bomi, Liberia, and reared in a field insectary. Two to five days old female adult An gambiae s.l. were tested using WHO tube (n=2027) and cone (n=580) bioassays in houses treated with DL or IRS. A sample of mosquitoes (n=169) were identified to species/molecular form and screened for the presence of knock down resistance (kdr) alleles associated with pyrethroid resistance. RESULTS: Anopheles gambiae s.l tested were resistant to deltamethrin but fully susceptible to bendiocarb and fenithrothion. The corrected mortality of local mosquitoes exposed to houses treated with deltamethrin either via IRS or DL was 12% and 59% respectively, suggesting that resistance may affect the efficacy of these interventions. The presence of pyrethroid resistance was associated with a high frequency of the 1014F kdr allele (90.5%) although this mutation alone cannot explain the resistance levels observed. CONCLUSION: High prevalence of resistance to deltamethrin in Bomi County may reduce the efficacy of malaria strategies relying on this class of insecticide. The findings highlight the urgent need to expand and sustain monitoring of insecticide resistance in Liberian malaria vectors, evaluate the effectiveness of existing interventions and develop appropriate resistance management strategies. PMID- 23028725 TI - Caring for caregivers of people living with HIV in the family: a response to the HIV pandemic from two urban slum communities in Pune, India. AB - INTRODUCTION: In low resource settings, the vast majority of 'Person/people Living with HIV' (PLHIV/s) and inadequate healthcare delivery systems to meet their treatment and care needs, caregivers play a vital role. Home based caregivers are often unrecognized with limited AIDS policies and programs focusing on them. We explored the perceptions and norms regarding care being provided by family caregivers of PLHIVs in India. METHODOLOGY: A community based qualitative study to understand the issues pertaining to home based care for PLHIV was conducted in urban settings of Pune city, in Maharashtra, India. Eight Focus Group Discussions (FGDs) among men, women and peer educators were carried out. A total of 44 in-depth Interviews (IDIs) with PLHIVs (20) and their caregivers (24), were conducted using separate guides respectively. Data was analyzed thematically. RESULTS: Home based care was perceived as economically viable option available for PLHIVs. 'Care' comprised of emotional, adherence, nursing and financial support to PLHIV. Home based care was preferred over hospital based care as it ensured confidentiality and patient care without hampering routine work at home. Women emerged as more vital primary caregivers compared to men. Home based care for men was almost unconditional while women had no such support. The natal family of women also abandoned. Their marital families seemed to provide support. Caregivers voiced the need for respite care and training. DISCUSSION: Gender related stigma and discrimination existed irrespective of women being the primary family caregivers. The support from marital families indicates a need to explore care and support issues at natal and marital homes of the women living with HIV respectively. Home based care training and respite care for the caregivers is recommended. Gender sensitive interventions addressing gender inequity and HIV related stigma should be modeled while designing interventions for PLHIVs and their family caregivers. PMID- 23028726 TI - Doxorubicin induces cytotoxicity through upregulation of pERK-dependent ATF3. AB - Although doxorubicin is commonly used in the treatment of many cancer types, its use in chemotherapy has been limited, largely because of its severe side effects, including cardiotoxicity and nephrotoxicity. In this study, we aimed to identify the mechanism of doxorubicin-induced cytotoxicity by using the human kidney proximal tubule cell line HK-2. Furthermore, we investigated the role of activating transcription factor 3 (ATF3) as a mediator of doxorubicin-induced cytotoxicity by using wild-type mouse embryonic fibroblasts (MEF) cells and ATF3 knockout (KO) cells. In HK-2 cells, doxorubicin decreased cell viability in a dose-dependent manner and induced an increase in cells in the sub G1 and G2/M phases at all doses. Doxorubicin treatment showed the following dose-dependent effects: increase in the secretion of tumor necrosis factor alpha; decrease in the expression of phosphorylated protein kinase A and Bcl-2; and increase in the expression of phosphorylated signal transducer and activator of transcription 3, phosphorylated extracellular signal-regulated kinase (ERK), and ATF3. Based on these results, we suggest that doxorubicin induces cytotoxicity through an ERK dependent pathway, and ATF3 plays a pivotal role as a transcriptional regulator in this process. PMID- 23028728 TI - Longitudinal study of spatially heterogeneous emphysema progression in current smokers with chronic obstructive pulmonary disease. AB - BACKGROUND: Cigarette smoke is the main risk factor for emphysema, which is a key pathology in chronic obstructive pulmonary disease (COPD). Low attenuation areas (LAA) in computed tomography (CT) images reflect emphysema, and the cumulative size distribution of LAA clusters follows a power law characterized by the exponent D. This property of LAA clusters can be explained by model simulation, where mechanical force breaks alveolar walls causing local heterogeneous lung tissue destruction. However, a longitudinal CT study has not investigated whether continuous smoking causes the spatially heterogeneous progression of emphysema. METHODS: We measured annual changes in ratios of LAA (LAA%), D and numbers of LAA clusters (LAN) in CT images acquired at intervals of >= 3 years from 22 current and 31 former smokers with COPD to assess emphysema progression. We constructed model simulations using CT images to morphologically interpret changes in current smokers. RESULTS: D was decreased in current and former smokers, whereas LAA% and LAN were increased only in current smokers. The annual changes in LAA%, D, and LAN were greater in current, than in former smokers (1.03 vs. 0.37%, p=0.008; 0.045 vs. -0.01, p=0.004; 13.9 vs. 1.1, p=0.007, respectively). When LAA% increased in model simulations, the coalescence of neighboring LAA clusters decreased D, but the combination of changes in D and LAN in current smokers could not be explained by the homogeneous emphysema progression model despite cluster coalescence. Conversely, a model in which LAAs heterogeneously increased and LAA clusters merged somewhat in relatively advanced emphysematous regions could reflect actual changes. CONCLUSIONS: Susceptibility to parenchymal destruction induced by continuous smoking is not uniform over the lung, but might be higher in local regions of relatively advanced emphysema. These could result in the spatially heterogeneous progression of emphysema in current smokers. PMID- 23028727 TI - Expression and activation by Epstein Barr virus of human endogenous retroviruses W in blood cells and astrocytes: inference for multiple sclerosis. AB - BACKGROUND: Proposed co-factors triggering the pathogenesis of multiple sclerosis (MS) are the Epstein Barr virus (EBV), and the potentially neuropathogenic MSRV (MS-associated retrovirus) and syncytin-1, of the W family of human endogenous retroviruses. METHODOLOGY/PRINCIPAL FINDINGS: In search of links, the expression of HERV-W/MSRV/syncytin-1, with/without exposure to EBV or to EBV glycoprotein350 (EBVgp350), was studied on peripheral blood mononuclear cells (PBMC) from healthy volunteers and MS patients, and on astrocytes, by discriminatory env-specific RT PCR assays, and by flow cytometry. Basal expression of HERV-W/MSRV/syncytin-1 occurs in astrocytes and in monocytes, NK, and B, but not in T cells. This uneven expression is amplified in untreated MS patients, and dramatically reduced during therapy. In astrocytes, EBVgp350 stimulates the expression of HERV W/MSRV/syncytin-1, with requirement of the NF-kappaB pathway. In EBVgp350-treated PBMC, MSRVenv and syncytin-1 transcription is activated in B cells and monocytes, but not in T cells, nor in the highly expressing NK cells. The latter cells, but not the T cells, are activated by proinflammatory cytokines. CONCLUSIONS/SIGNIFICANCE: In vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/syncytin-1, in cells deriving from blood and brain. In vivo, pathogenic outcomes would depend on abnormal situations, as in late EBV primary infection, that is often symptomatic, or/and in the presence of particular host genetic backgrounds. In the blood, HERV-Wenv activation might induce immunopathogenic phenomena linked to its superantigenic properties. In the brain, toxic mechanisms against oligodendrocytes could be established, inducing inflammation, demyelination and axonal damage. Local stimulation by proinflammatory cytokines and other factors might activate further HERV-Ws, contributing to the neuropathogenity. In MS pathogenesis, a possible model could include EBV as initial trigger of future MS, years later, and HERV W/MSRV/syncytin-1 as actual contributor to MS pathogenicity, in striking parallelism with disease behaviour. PMID- 23028729 TI - A portable chemotaxis platform for short and long term analysis. AB - Flow-based microfluidic systems have been widely utilized for cell migration studies given their ability to generate versatile and precisely defined chemical gradients and to permit direct visualization of migrating cells. Nonetheless, the general need for bulky peripherals such as mechanical pumps and tubing and the complicated setup procedures significantly limit the widespread use of these microfluidic systems for cell migration studies. Here we present a simple method to power microfluidic devices for chemotaxis assays using the commercially available ALZET(r) osmotic pumps. Specifically, we developed a standalone chemotaxis platform that has the same footprint as a multiwell plate and can generate well-defined, stable chemical gradients continuously for up to 7 days. Using this platform, we validated the short-term (24 hours) and long-term (72 hours) concentration dependent PDGF-BB chemotaxis response of human bone marrow derived mesenchymal stem cells. PMID- 23028730 TI - Model Hirano bodies protect against tau-independent and tau-dependent cell death initiated by the amyloid precursor protein intracellular domain. AB - The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP) and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has yet to be determined. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death mechanisms. Exogenous expression of APP and either of its c-terminal fragments c31 or Amyloid Precursor Protein Intracellular Domain c58 (AICDc58) enhance cell death. The presence of tau is not required for this enhanced cell death. However, the addition of a hyperphosphorylated tau mimic 352PHPtau significantly increases cell death in the presence of both APP and c31 or AICDc58 alone. The mechanism of cell death induced by APP and its c-terminal fragments and tau was investigated. Fe65, Tip60, p53, and caspases play a role in tau-independent and tau-dependent cell death. In addition, apoptosis was determined to contribute to cell death. The presence of model Hirano bodies protected against cell death, indicating Hirano bodies may play a protective role in neurodegeneration. PMID- 23028731 TI - An integrated genomic and expression analysis of 7q deletion in splenic marginal zone lymphoma. AB - Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterised by 7q32 deletion, but the target genes of this deletion remain unknown. In order to elucidate the genetic target of this deletion, we performed an integrative analysis of the genetic, epigenetic, transcriptomic and miRNomic data. High resolution array comparative genomic hybridization of 56 cases of SMZL delineated a minimally deleted region (2.8 Mb) at 7q32, but showed no evidence of any cryptic homozygous deletion or recurrent breakpoint in this region. Integrated transcriptomic analysis confirmed significant under-expression of a number of genes in this region in cases of SMZL with deletion, several of which showed hypermethylation. In addition, a cluster of 8 miRNA in this region showed under-expression in cases with the deletion, and three (miR-182/96/183) were also significantly under-expressed (P<0.05) in SMZL relative to other lymphomas. Genomic sequencing of these miRNA and IRF5, a strong candidate gene, did not show any evidence of somatic mutation in SMZL. These observations provide valuable guidance for further characterisation of 7q deletion. PMID- 23028732 TI - Hemoglobin may contribute to sex differences in mortality among HIV-infected persons in care. AB - BACKGROUND: Some retrospective studies have found that HIV-infected women have a higher mortality risk than men after adjusting for baseline characteristics, while others have not. Anemia is a known predictor of HIV-related mortality. We assessed whether anemia contributed to the sex difference in mortality in our cohort. METHODS: We conducted a retrospective cohort study among HIV-infected persons in care at the Comprehensive Care Center (Nashville, TN) between 1998 and 2009. Cox proportional hazards models compared time from first clinic visit to death and AIDS-defining events (ADE), adjusted for baseline characteristics with and without baseline hemoglobin. RESULTS: Of 3,633 persons, 879 (24%) were women. Women had lower median baseline hemoglobin compared to men: 12.4 g/dL (inter quartile range (IQR) 11.3-13.4) vs. 14.4 (IQR 13.1-15.5), respectively (P<0.001). In multivariable models without hemoglobin, the risk of death was higher among women: hazard ratio (HR) 1.46 (95% confidence interval (CI) 1.17, 1.82; P=0.001). In multivariable models with hemoglobin, the risk of death in women was diminished and no longer statistically significant: HR 1.2 (95% CI 0.93, 1.55; P=0.17). The risk of ADE was higher among women in both models, but not statistically significant: HR 1.1 (95% CI 0.85-1.42; P=0.46) in the model without hemoglobin and 1.11 (95% CI 0.82-1.48; P=0.50) in the model with hemoglobin. Hemoglobin was a strong predictor of death: HR 0.88 per 1 g/dL increase (95% CI 0.83, 0.93; P<0.001). CONCLUSION: In our study population of HIV-infected persons in care, women had lower baseline hemoglobin, and lower hemoglobin contributed to their higher risk of ADE and death. PMID- 23028733 TI - A technique for performing electrical impedance myography in the mouse hind limb: data in normal and ALS SOD1 G93A animals. AB - OBJECTIVE: To test a method for performing electrical impedance myography (EIM) in the mouse hind limb for the assessment of disease status in neuromuscular disease models. METHODS: An impedance measuring device consisting of a frame with electrodes embedded within an acrylic head was developed. The head was rotatable such that data longitudinal and transverse to the major muscle fiber direction could be obtained. EIM measurements were made with this device on 16 healthy mice and 14 amyotrophic lateral sclerosis (ALS) animals. Repeatability was assessed in both groups. RESULTS: The technique was easy to perform and provided good repeatability in both healthy and ALS animals, with intra-session repeatability (mean +/- SEM) of 5% +/- 1% and 12% +/- 2%, respectively. Significant differences between healthy and ALS animals were also identified (e.g., longitudinal mean 50 kHz phase was 18 +/- 0.6 degrees for the healthy animals and 14 +/- 1.0 degrees for the ALS animals, p=0.0025). CONCLUSIONS: With this simple device, the EIM data obtained is highly repeatable and can differentiate healthy from ALS animals. SIGNIFICANCE: EIM can now be applied to mouse models of neuromuscular disease to assess disease status and the effects of therapy. PMID- 23028734 TI - Solving a migration riddle using isoscapes: house martins from a Dutch village winter over West Africa. AB - BACKGROUND: The ability to connect breeding, stopover and wintering locations of populations of migratory birds greatly enhances our understanding of the phenomenon of migration and improves our chances of effectively conserving these species. Among Palearctic-Afrotropical migratory species, aerial insectivores like the house martin (Delichon urbicum) are sensitive to factors influencing the availability of flying insects, and have declined in recent decades. The strict aerial behaviour of martins severely limits ring recoveries on wintering grounds and so there is a dearth of information on where European breeding populations over-winter in Africa, and the relative effects of population regulation on breeding vs. wintering grounds. We used a newly developed multi-isotope (delta(2)H, delta(13)C, delta(15)N) feather isoscape for Africa together with inferences from summarized ring return data based on longitude, to assign winter origins to birds captured at a breeding colony in The Netherlands. PRINCIPAL FINDINGS: Based on isotopic analyses of winter-grown martin feathers, we used a likelihood-based assignment approach to describe potential wintering locations where molt occurred of individual house martins from a Dutch colony by assigning them to four potential isotopically distinct clusters in Africa. We found the overwhelming majority of Dutch martins were assigned to a geographical cluster associated with West Africa. CONCLUSIONS/SIGNIFICANCE: The existence of strong isotopic gradients and patterns in African foodwebs that support migratory wildlife allows for the spatial assignment of tissues grown there. The assignment of Dutch house martins to wintering grounds primarily in West Africa was in strong agreement with independent and indirect methods used to infer winter origins of this species based on the association between the Normalized Difference Vegetation Index (NDVI) in Africa and population patterns in Italy and the United Kingdom. These confirmatory data-sets underscore the importance of suitable habitats in West Africa to the conservation of migratory aerial insectivores and other species. PMID- 23028735 TI - Genetic diversity and ecosystem functioning in the face of multiple stressors. AB - Species diversity is important for a range of ecosystem processes and properties, including the resistance to single and multiple stressors. It has been suggested that genetic diversity may play a similar role, but empirical evidence is still relatively scarce. Here, we report the results of a microcosm experiment where four strains of the marine diatom Skeletonema marinoi were grown in monoculture and in mixture under a factorial combination of temperature and salinity stress. The strains differed in their susceptibility to the two stressors and no strain was able to survive both stressors simultaneously. Strong competition between the genotypes resulted in the dominance of one strain under both control and salinity stress conditions. The overall productivity of the mixture, however, was not related to the dominance of this strain, but was instead dependent on the treatment; under control conditions we observed a positive effect of genetic richness, whereas a negative effect was observed in the stress treatments. This suggests that interactions among the strains can be both positive and negative, depending on the abiotic environment. Our results provide additional evidence that the biodiversity-ecosystem functioning relationship is also relevant at the level of genetic diversity. PMID- 23028736 TI - In vivo detection of activated platelets allows characterizing rupture of atherosclerotic plaques with molecular magnetic resonance imaging in mice. AB - BACKGROUND: Early and non-invasive detection of platelets on micro atherothrombosis provides a means to identify unstable plaque and thereby allowing prophylactic treatment towards prevention of stroke or myocardial infarction. Molecular magnetic resonance imaging (mMRI) of activated platelets as early markers of plaque rupture using targeted contrast agents is a promising strategy. In this study, we aim to specifically image activated platelets in murine atherothrombosis by in vivo mMRI, using a dedicated animal model of plaque rupture. METHODS: An antibody targeting ligand-induced binding sites (LIBS) on the glycoprotein IIb/IIIa-receptor of activated platelets was conjugated to microparticles of iron oxide (MPIO) to form the LIBS-MPIO contrast agent causing a signal-extinction in T2*-weighted MRI. ApoE(-/-) mice (60 weeks-old) were fed a high fat diet for 5 weeks. Using a small needle, the surface of their carotid plaques was scratched under blood flow to induce atherothrombosis. In vivo 9.4 Tesla MRI was performed before and repetitively after intravenous injection of either LIBS-MPIO versus non-targeted-MPIO. RESULTS: LIBS-MPIO injected animals showed a significant signal extinction (p<0.05) in MRI, corresponding to the site of plaque rupture and atherothrombosis in histology. The signal attenuation was effective for atherothrombosis occupying >= 2% of the vascular lumen. Histology further confirmed significant binding of LIBS-MPIO compared to control-MPIO on the thrombus developing on the surface of ruptured plaques (p<0.01). CONCLUSION: in vivo mMRI detected activated platelets on mechanically ruptured atherosclerotic plaques in ApoE(-/-) mice with a high sensititvity. This imaging technology represents a unique opportunity for noninvasive detection of atherothrombosis and the identification of unstable atherosclerotic plaques with the ultimate promise to prevent strokes and myocardial infarctions. PMID- 23028737 TI - The diversity and biogeography of Western Indian Ocean reef-building corals. AB - This study assesses the biogeographic classification of the Western Indian Ocean (WIO) on the basis of the species diversity and distribution of reef-building corals. Twenty one locations were sampled between 2002 and 2011. Presence/absence of scleractinian corals was noted on SCUBA, with the aid of underwater digital photographs and reference publications for species identification. Sampling effort varied from 7 to 37 samples per location, with 15 to 45 minutes per dive allocated to species observations, depending on the logistics on each trip. Species presence/absence was analyzed using the Bray-Curtis similarity coefficient, followed by cluster analysis and multi-dimensional scaling. Total (asymptotic) species number per location was estimated using the Michaelis-Menten equation. Three hundred and sixty nine coral species were named with stable identifications and used for analysis. At the location level, estimated maximum species richness ranged from 297 (Nacala, Mozambique) to 174 (Farquhar, Seychelles). Locations in the northern Mozambique Channel had the highest diversity and similarity, forming a core region defined by its unique oceanography of variable meso-scale eddies that confer high connectivity within this region. A distinction between mainland and island fauna was not found; instead, diversity decreased radially from the northern Mozambique Channel. The Chagos archipelago was closely related to the northern Mozambique Channel region, and analysis of hard coral data in the IUCN Red List found Chagos to be more closely related to the WIO than to the Maldives, India and Sri Lanka. Diversity patterns were consistent with primary oceanographic drivers in the WIO, reflecting inflow of the South Equatorial Current, maintenance of high diversity in the northern Mozambique Channel, and export from this central region to the north and south, and to the Seychelles and Mascarene islands. PMID- 23028738 TI - NVX-412, a new oncology drug candidate, induces S-phase arrest and DNA damage in cancer cells in a p53-independent manner. AB - The new molecular entity quinoxalinhydrazide derivative NVX-412 was identified as a promising drug candidate for the treatment of various cancer types due to its strong cytotoxic activity and relative specificity. Here, we provide first data about the mechanisms of action of NVX-412. We show that NVX-412 exerts its anti neoplastic activity in a p53-independent manner and induces S-phase arrest and DNA damage as assessed by gammaH2AX staining. We suggest a bi-modal (dose dependent) mode of action of NVX-412, being primarily cytostatic at lower and predominantly cytotoxic at higher concentrations. Based on the broad and consistent anti-neoplastic activity observed, NVX-412 holds promise as an effective drug candidate for the treatment of various cancer types, especially for hematological malignancies with highly unmet medical need. PMID- 23028739 TI - Trail pheromone of the Argentine ant, Linepithema humile (Mayr) (Hymenoptera: Formicidae). AB - The Argentine ant (Linepithema humile) is recognized as one of the world's most damaging invasive species. One reason for the ecological dominance of introduced Argentine ant populations is their ability to dominate food and habitat resources through the rapid mobilization and recruitment of thousands of workers. More than 30 years ago, studies showed that (Z)-9-hexadecenal strongly attracted Argentine ant workers in a multi-choice olfactometer, suggesting that (Z)-9-hexadecenal might be the trail pheromone, or a component of a trail pheromone mixture. Since then, numerous studies have considered (Z)-9-hexadecenal as the key component of the Argentine ant trails. Here, we report the first chemical analyses of the trails laid by living Argentine ants and find that (Z)-9-hexadecenal is not present in a detectible quantity. Instead, two iridoids, dolichodial and iridomyrmecin, appear to be the primary chemical constituents of the trails. Laboratory choice tests confirmed that Argentine ants were attracted to artificial trails comprised of these two chemicals significantly more often than control trails. Although (Z)-9-hexadecenal was not detected in natural trails, supplementation of artificial dolichodial+iridomyrmecin trails with an extremely low concentraion of (Z)-9-hexadecenal did increase the efficacy of the trail following behavior. In stark contrast with previous dogma, our study suggests that dolichodial and iridomyrmecin are major components of the Argentine ant trail pheromone. (Z)-9-hexadecenal may act in an additive manner with these iridoids, but it does not occur in detectable quantities in Argentine ant recruitment trails. PMID- 23028740 TI - A prospective population study of resting heart rate and peak oxygen uptake (the HUNT Study, Norway). AB - OBJECTIVES: We assessed the prospective association of resting heart rate (RHR) at baseline with peak oxygen uptake (VO(2peak)) 23 years later, and evaluated whether physical activity (PA) could modify this association. BACKGROUND: Both RHR and VO(2peak) are strong and independent predictors of cardiovascular morbidity and mortality. However, the association of RHR with VO(2peak) and modifying effect of PA have not been prospectively assessed in population studies. METHODS: In 807 men and 810 women free from cardiovascular disease both at baseline (1984-86) and follow-up 23 years later, RHR was recorded at both occasions, and VO(2peak) was measured by ergospirometry at follow-up. We used Generalized Linear Models to assess the association of baseline RHR with VO(2peak), and to study combined effects of RHR and self-reported PA on later VO(2peak). RESULTS: There was an inverse association of RHR at baseline with VO(2peak) (p<0.01). Men and women with baseline RHR greater than 80 bpm had 4.6 mL.kg(-1).min(-1) (95% confidence interval [CI], 2.8 to 6.3) and 1.4 mL.kg( 1).min(-1) (95% CI, -0.4 to 3.1) lower VO(2peak) at follow-up compared with men and women with RHR below 60 bpm at baseline. We found a linear association of change in RHR with VO(2peak) (p=0.03), suggesting that a decrease in RHR over time is likely to be beneficial for cardiovascular fitness. Participants with low RHR and high PA at baseline had higher VO(2peak) than inactive people with relatively high RHR. However, among participants with relatively high RHR and high PA at baseline, VO(2peak) was similar to inactive people with relatively low RHR. CONCLUSION: RHR is an important predictor of VO(2peak), and serial assessments of RHR may provide useful and inexpensive information on cardiovascular fitness. The results suggest that high levels of PA may compensate for the lower VO(2peak) associated with a high RHR. PMID- 23028741 TI - Enamel formation genes influence enamel microhardness before and after cariogenic challenge. AB - There is evidence for a genetic component in caries susceptibility, and studies in humans have suggested that variation in enamel formation genes may contribute to caries. For the present study, we used DNA samples collected from 1,831 individuals from various population data sets. Single nucleotide polymorphism markers were genotyped in selected genes (ameloblastin, amelogenin, enamelin, tuftelin, and tuftelin interacting protein 11) that influence enamel formation. Allele and genotype frequencies were compared between groups with distinct caries experience. Associations with caries experience can be detected but they are not necessarily replicated in all population groups and the most expressive results was for a marker in AMELX (p=0.0007). To help interpret these results, we evaluated if enamel microhardness changes under simulated cariogenic challenges are associated with genetic variations in these same genes. After creating an artificial caries lesion, associations could be seen between genetic variation in TUFT1 (p=0.006) and TUIP11 (p=0.0006) with enamel microhardness. Our results suggest that the influence of genetic variation of enamel formation genes may influence the dynamic interactions between the enamel surface and the oral cavity. PMID- 23028742 TI - The natural anticancer agent plumbagin induces potent cytotoxicity in MCF-7 human breast cancer cells by inhibiting a PI-5 kinase for ROS generation. AB - Drug-induced haploinsufficiency (DIH) in yeast has been considered a valuable tool for drug target identification. A plant metabolite, plumbagin, has potent anticancer activity via reactive oxygen species (ROS) generation. However, the detailed molecular targets of plumbagin for ROS generation are not understood. Here, using DIH and heterozygous deletion mutants of the fission yeast Schizosaccharomyces pombe, we identified 1, 4-phopshatidylinositol 5-kinase (PI5K) its3 as a new molecular target of plumbagin for ROS generation. Plumbagin showed potent anti-proliferative activity (GI(50); 10 uM) and induced cell elongation and septum formation in wild-type S. pombe. Furthermore, plumbagin dramatically increased the intracellular ROS level, and pretreatment with the ROS scavenger, N-acetyl cysteine (NAC), protected against growth inhibition by plumbagin, suggesting that ROS play a crucial role in the anti-proliferative activity in S. pombe. Interestingly, significant DIH was observed in an its3 deleted heterozygous mutant, in which ROS generation by plumbagin was higher than that in wild-type cells, implying that its3 contributes to ROS generation by plumbagin in this yeast. In MCF7 human breast cancer cells, plumbagin significantly decreased the level of a human ortholog, 1, 4-phopshatidylinositol 5-kinase (PI5K)-1B, of yeast its3, and knockdown of PI5K-1B using siPI5K-1B increased the ROS level and decreased cell viability. Taken together, these results clearly show that PI5K-1B plays a crucial role in ROS generation as a new molecular target of plumbagin. Moreover, drug target screening using DIH in S. pombe deletion mutants is a valuable tool for identifying molecular targets of anticancer agents. PMID- 23028743 TI - Characterization of molecular determinants of the conformational stability of macrophage migration inhibitory factor: leucine 46 hydrophobic pocket. AB - Macrophage Migration Inhibitory Factor (MIF) is a key mediator of inflammatory responses and innate immunity and has been implicated in the pathogenesis of several inflammatory and autoimmune diseases. The oligomerization of MIF, more specifically trimer formation, is essential for its keto-enol tautomerase activity and probably mediates several of its interactions and biological activities, including its binding to its receptor CD74 and activation of certain signaling pathways. Therefore, understanding the molecular factors governing the oligomerization of MIF and the role of quaternary structure in modulating its structural stability and multifunctional properties is crucial for understanding the function of MIF in health and disease. Herein, we describe highly conserved intersubunit interactions involving the hydrophobic packing of the side chain of Leu46 onto the beta-strand beta3 of one monomer within a hydrophobic pocket from the adjacent monomer constituted by residues Arg11, Val14, Phe18, Leu19, Val39, His40, Val41, Val42, and Pro43. To elucidate the structural significance of these intersubunit interactions and their relative contribution to MIF's trimerization, structural stability and catalytic activity, we generated three point mutations where Leu46 was replaced by glycine (L46G), alanine (L46A) and phenylalanine (L46F), and their structural properties, stability, oligomerization state, and catalytic activity were characterized using a battery of biophysical methods and X-ray crystallography. Our findings provide new insights into the role of the Leu46 hydrophobic pocket in stabilizing the conformational state of MIF in solution. Disrupting the Leu46 hydrophobic interaction perturbs the secondary and tertiary structure of the protein but has no effect on its oligomerization state. PMID- 23028744 TI - Cyclooxygenase-2 expression in bladder cancer and patient prognosis: results from a large clinical cohort and meta-analysis. AB - Aberrant overexpression of cyclooxygenase-2 (COX2) is observed in urothelial carcinoma of the bladder (UCB). Studies evaluating COX2 as a prognostic marker in UCB report contradictory results. We determined the prognostic potential of COX2 expression in UCB and quantitatively summarize the results with those of the literature through a meta-analysis. Newly diagnosed UCB patients recruited between 1998-2001 in 18 Spanish hospitals were prospectively included in the study and followed-up (median, 70.7 months). Diagnostic slides were reviewed and uniformly classified by expert pathologists. Clinical data was retrieved from hospital charts. Tissue microarrays containing non-muscle invasive (n=557) and muscle invasive (n=216) tumours were analyzed by immunohistochemistry using quantitative image analysis. Expression was evaluated in Cox regression models to assess the risk of recurrence, progression and disease-specific mortality. Meta hazard ratios were estimated using our results and those from 11 additional evaluable studies. COX2 expression was observed in 38% (211/557) of non-muscle invasive and 63% (137/216) of muscle invasive tumors. Expression was associated with advanced pathological stage and grade (p<0.0001). In the univariable analyses, COX2 expression - as a categorical variable - was not associated with any of the outcomes analyzed. As a continuous variable, a weak association with recurrence in non-muscle invasive tumors was observed (p-value=0.048). In the multivariable analyses, COX2 expression did not independently predict any of the considered outcomes. The meta-analysis confirmed these results. We did not find evidence that COX2 expression is an independent prognostic marker of recurrence, progression or survival in patients with UCB. PMID- 23028745 TI - Information flow in networks and the law of diminishing marginal returns: evidence from modeling and human electroencephalographic recordings. AB - We analyze simple dynamical network models which describe the limited capacity of nodes to process the input information. For a proper range of their parameters, the information flow pattern in these models is characterized by exponential distribution of the incoming information and a fat-tailed distribution of the outgoing information, as a signature of the law of diminishing marginal returns. We apply this analysis to effective connectivity networks from human EEG signals, obtained by Granger Causality, which has recently been given an interpretation in the framework of information theory. From the distributions of the incoming versus the outgoing values of the information flow it is evident that the incoming information is exponentially distributed whilst the outgoing information shows a fat tail. This suggests that overall brain effective connectivity networks may also be considered in the light of the law of diminishing marginal returns. Interestingly, this pattern is reproduced locally but with a clear modulation: a topographic analysis has also been made considering the distribution of incoming and outgoing values at each electrode, suggesting a functional role for this phenomenon. PMID- 23028746 TI - Traveling and pinned fronts in bistable reaction-diffusion systems on networks. AB - Traveling fronts and stationary localized patterns in bistable reaction-diffusion systems have been broadly studied for classical continuous media and regular lattices. Analogs of such non-equilibrium patterns are also possible in networks. Here, we consider traveling and stationary patterns in bistable one-component systems on random Erdos-Renyi, scale-free and hierarchical tree networks. As revealed through numerical simulations, traveling fronts exist in network organized systems. They represent waves of transition from one stable state into another, spreading over the entire network. The fronts can furthermore be pinned, thus forming stationary structures. While pinning of fronts has previously been considered for chains of diffusively coupled bistable elements, the network architecture brings about significant differences. An important role is played by the degree (the number of connections) of a node. For regular trees with a fixed branching factor, the pinning conditions are analytically determined. For large Erdos-Renyi and scale-free networks, the mean-field theory for stationary patterns is constructed. PMID- 23028747 TI - Prediction of risk factors for coronary heart disease using Framingham Risk Score in Korean men. AB - BACKGROUND: Currently, there is sparse data available on the relationship between coronary heart disease (CHD) and its risk factors estimated by the Framingham Risk Score (FRS) in Korea. This is particularly true when looking at risk factors of CHD associated with the FRS after adjustment for other covariates especially in healthy subjects. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a prospective cohort study to examine the association between the risk factors of CHD and the risk for CHD estimated by FRS in 15,239 men in 2005 and 2010. The FRS is based on six coronary risk factors: gender, age, total cholesterol, high-density lipoprotein (HDL)-cholesterol, systolic blood pressure (BP), and smoking habit. Multiple linear regression analysis was used to analyze the relationships between the FRS and risk factors for CHD. This study reported that apolipoproetein B (apoB), apoA-I, apoB/apoA-I, alcohol intake, log-transformed TG, log-transformed hsCRP, LDL-cholesterol, hypertension, diabetes, regular exercise, and BMI were significantly associated with the FRS. Above all, the partial R-square of apoB was 14.77%, which was overwhelmingly bigger than that of other variables in model V. This indicated that apoB accounted for 14.77% of the variance in FRS. CONCLUSION/SIGNIFICANCE: In this study, apoB was found to be the most important determinant for the future development of CHD during a 5-year follow-up in healthy Korean men. PMID- 23028748 TI - Activation-induced cytidine deaminase alters the subcellular localization of Tet family proteins. AB - Activation-induced cytidine deminase (Aid), a unique enzyme that deaminates cytosine in DNA, shuttles between the nucleus and the cytoplasm. A recent study proposed a novel function of Aid in active DNA demethylation via deamination of 5 hydroxymethylcytosine, which is converted from 5-methylcytosine by the Ten-eleven translocation (Tet) family of enzymes. In this study, we examined the effect of simultaneous expression of Aid and Tet family proteins on the subcellular localization of each protein. We found that overexpressed Aid is mainly localized in the cytoplasm, whereas Tet1 and Tet2 are localized in the nucleus, and Tet3 is localized in both the cytoplasm and the nucleus. However, nuclear Tet proteins were gradually translocated to the cytoplasm when co-expressed with Aid. We also show that Aid-mediated translocation of Tet proteins is associated with Aid shuttling. Here we propose a possible role for Aid as a regulator of the subcellular localization of Tet family proteins. PMID- 23028749 TI - Highly efficient and specific genome editing in silkworm using custom TALENs. AB - Establishment of efficient genome editing tools is essential for fundamental research, genetic engineering, and gene therapy. Successful construction and application of transcription activator-like effector nucleases (TALENs) in several organisms herald an exciting new era for genome editing. We describe the production of two active TALENs and their successful application in the targeted mutagenesis of silkworm, Bombyx mori, whose genetic manipulation methods are parallel to those of Drosophila and other insects. We will also show that the simultaneous expression of two pairs of TALENs generates heritable large chromosomal deletion. Our results demonstrate that (i) TALENs can be used in silkworm and (ii) heritable large chromosomal deletions can be induced by two pairs of TALENs in whole organisms. The generation and the high frequency of TALENs-induced targeted mutagenesis in silkworm will promote the genetic modification of silkworm and other insect species. PMID- 23028751 TI - AmyR is a novel negative regulator of amylovoran production in Erwinia amylovora. AB - In this study, we attempted to understand the role of an orphan gene amyR in Erwinia amylovora, a functionally conserved ortholog of ybjN in Escherichia coli, which has recently been characterized. Amylovoran, a high molecular weight acidic heteropolymer exopolysaccharide, is a virulent factor of E. amylovora. As reported earlier, amylovoran production in an amyR knockout mutant was about eight-fold higher than that in the wild type (WT) strain of E. amylovora. When a multicopy plasmid containing the amyR gene was introduced into the amyR mutant or WT strains, amylovoran production was strongly inhibited. Furthermore, amylovoran production was also suppressed in various amylovoran-over-producing mutants, such as grrSA containing multicopies of the amyR gene. Consistent with amylovoran production, an inverse correlation was observed between in vitro expression of amyR and that of amylovoran biosynthetic genes. However, both the amyR knockout mutant and over-expression strains showed reduced levan production, another exopolysaccharide produced by E. amylovora. Virulence assays demonstrated that while the amyR mutant was capable of inducing slightly greater disease severity than that of the WT strain, strains over-expressing the amyR gene did not incite disease on apple shoots or leaves, and only caused reduced disease on immature pear fruits. Microarray studies revealed that amylovoran biosynthesis and related membrane protein-encoding genes were highly expressed in the amyR mutant, but down-regulated in the amyR over-expression strains in vitro. Down-regulation of amylovoran biosynthesis genes in the amyR over-expression strain partially explained why over-expression of amyR led to non-pathogenic or reduced virulence in vivo. These results suggest that AmyR plays an important role in regulating exopolysaccharide production, and thus virulence in E. amylovora. PMID- 23028750 TI - Novel multiple markers to distinguish melanoma from dysplastic nevi. AB - BACKGROUND: Distinguishing melanoma from dysplastic nevi can be challenging. OBJECTIVE: To assess which putative molecular biomarkers can be optimally combined to aid in the clinical diagnosis of melanoma from dysplastic nevi. METHODS: Immunohistochemical expressions of 12 promising biomarkers (pAkt, Bim, BRG1, BRMS1, CTHRC1, Cul1, ING4, MCL1, NQO1, SKP2, SNF5 and SOX4) were studied in 122 melanomas and 33 dysplastic nevi on tissue microarrays. The expression difference between melanoma and dysplastic nevi was performed by univariate and multiple logistic regression analysis, diagnostic accuracy of single marker and optimal combinations were performed by receiver operating characteristic (ROC) curve and artificial neural network (ANN) analysis. Classification and regression tree (CART) was used to examine markers simultaneous optimizing the accuracy of melanoma. Ten-fold cross-validation was analyzed for estimating generalization error for classification. RESULTS: Four (Bim, BRG1, Cul1 and ING4) of 12 markers were significantly differentially expressed in melanoma compared with dysplastic nevi by both univariate and multiple logistic regression analysis (p < 0.01). These four combined markers achieved 94.3% sensitivity, 81.8% specificity and attained 84.3% area under the ROC curve (AUC) and the ANN classified accuracy with training of 83.2% and testing of 81.2% for distinguishing melanoma from dysplastic nevi. The classification trees identified ING4, Cul1 and BRG1 were the most important classification parameters in ranking top-performing biomarkers with cross-validation error of 0.03. CONCLUSIONS: The multiple biomarkers ING4, Cul1, BRG1 and Bim described here can aid in the discrimination of melanoma from dysplastic nevi and provide a new insight to help clinicians recognize melanoma. PMID- 23028752 TI - Specific protein kinase C isoforms alpha and betaI are involved in follicle stimulating hormone-induced mouse follicle-enclosed oocytes meiotic resumption. AB - Protein kinase C (PKC) is involved in gonadotrophin-induced oocyte maturation. In the present study, we investigated the role of specific PKC isoforms in the process of follicle-stimulating hormone (FSH)-induced oocyte meiotic resumption. Small antral follicles (200-300 um in diameter) were isolated from immature mice and cultured in vitro. FSH significantly induced follicle-enclosed oocytes (FEOs) meiotic resumption after 8 hr culture. However, the induced effect of FSH was dose-dependently inhibited by the specific PKC alpha and betaI inhibitor Go6976, and 100 nM Go6976 completely blocked FSH function in oocyte meiotic resumption. Furthermore, FSH dramatically induced the expression of transcripts encoding epidermal growth factor (EGF)-like growth factors Areg, Btc, and Ereg mRNA levels, and up-regulated tyrosine phosphorylation level of EGF receptor (EGFR) in granulosa cells. Blocking the function of EGFR by AG1478 eliminated the effect of FSH-induced FEOs meiotic resumption, suggesting that FSH induced oocyte maturation through the activation of EGFR. FSH-induced phosphorylation of EGFR could also be inhibited by Go6976. Next, we examined the effect of FSH on the expression and phosphorylation PKC alpha and betaI. FSH induced the expression of PKC alpha at mRNA and protein level, and also up-regulated its phosphorylation level in granulosa cells after 8 hr culture. However, FSH had no effect on the expression of PKC betaI but down-regulated its phosphorylation level. In conclusion, FSH-induced activation of PKC alpha alone, or together with the inactivation of PKC betaI in granulosa cells, participates in mouse oocyte meiotic resumption, possibly by the activation of EGFR signaling pathway. PMID- 23028753 TI - Saccharomyces boulardii improves intestinal epithelial cell restitution by inhibiting alphavbeta5 integrin activation state. AB - Intestinal epithelial cell damage is frequently seen in the mucosal lesions of infectious or inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. Complete remission of these diseases requires both the disappearance of inflammation and the repair of damaged epithelium. Saccharomyces boulardii (Sb, Biocodex) is a non-pathogenic yeast widely used as a preventive and therapeutic probiotic for the prevention and treatment of diarrhea and other gastrointestinal disorders. We recently showed that it enhances the repair of intestinal epithelium through activation of alpha2beta1 integrin collagen receptors. In the present study, we demonstrated that alpha2beta1 integrin is not the sole cell extracellular matrix receptor involved during Sb-mediated intestinal restitution. Indeed, by using cell adhesion assays, we showed that Sb supernatant contains heat sensitive molecule(s), with a molecular weight higher than 9 kDa, which decreased alphavbeta5 integrin-mediated adhesion to vitronectin by competing with the integrin. Moreover, Sb-mediated changes in cell adhesion to vitronectin resulted in a reduction of the alphavbeta5signaling pathway. We used a monolayer wounding assay that mimics in vivo cell restitution to demonstrate that down modulation of the alphavbeta5 integrin-vitronectin interaction is related to Sb induced cell migration. We therefore postulated that Sb supernatant contains motogenic factors that enhance cell restitution through multiple pathways, including the dynamic fine regulation of alphavbeta5 integrin binding activity. This could be of major importance in diseases characterized by severe mucosal injury, such as inflammatory and infectious bowel diseases. PMID- 23028754 TI - Prevention of disuse muscle atrophy by dietary ingestion of 8-prenylnaringenin in denervated mice. AB - Flavonoids have attracted considerable attention in relation to their effects upon health. 8-Prenylnaringenin (8-PN) is found in the common hop (Humulus lupulus) and assumed to be responsible for the health impact of beer consumption. We wanted to clarify the effects of prenylation on the physiological functions of dietary flavonoids by comparing the effects of 8-PN with that of intact naringenin in the prevention of disuse muscle atrophy using a model of denervation in mice. Consumption of 8-PN (but not naringenin) prevented loss of weight in the gastrocnemius muscle further supported by the lack of induction of the protein content of a key ubiquitin ligase involved in muscle atrophy, atrogin 1, and by the activation of Akt phosphorylation. 8-PN content in the gastrocnemius muscle was tenfold higher than that of naringenin. These results suggested that, compared with naringenin, 8-PN was effectively concentrated into skeletal muscle to exert its preventive effects upon disuse muscle atrophy. It is likely that prenylation generates novel functions for 8-PN by enhancing its accumulation into muscle tissue through dietary intake. PMID- 23028755 TI - Asymmetry indices for analysis and prediction of replication origins in eukaryotic genomes. AB - DNA replication was recently shown to induce the formation of compositional skews in the genomes of the yeasts Saccharomyces cerevisiae and Kluyveromyces lactis. In this work, I have characterized further GC and TA skew variations in the vicinity of S. cerevisiae replication origins and termination sites, and defined asymmetry indices for origin analysis and prediction. The presence of skew jumps at some termination sites in the S. cerevisiae genome was established. The majority of S. cerevisiae replication origins are marked by an oriented consensus sequence called ACS, but no evidence could be found for asymmetric origin firing that would be linked to ACS orientation. Asymmetry indices related to GC and TA skews were defined, and a global asymmetry index I(GC,TA) was described. I(GC,TA) was found to strongly correlate with origin efficiency in S. cerevisiae and to allow the determination of sets of intergenes significantly enriched in origin loci. The generalized use of asymmetry indices for origin prediction in naive genomes implies the determination of the direction of the skews, i.e. the identification of which strand, leading or lagging, is enriched in G and which one is enriched in T. Recent work indicates that in Candida albicans and in several related species, centromeres contain early and efficient replication origins. It has been proposed that the skew jumps observed at these positions would reflect the activity of these origins, thus allowing to determine the direction of the skews in these genomes. However, I show here that the skew jumps at C. albicans centromeres are not related to replication and that replication associated GC and TA skews in C. albicans have in fact the opposite directions of what was proposed. PMID- 23028756 TI - Mortality burden of the 2009 A/H1N1 influenza pandemic in France: comparison to seasonal influenza and the A/H3N2 pandemic. AB - BACKGROUND: The mortality burden of the 2009 A/H1N1 pandemic remains unclear in many countries due to delays in reporting of death statistics. We estimate the age- and cause-specific excess mortality impact of the pandemic in France, relative to that of other countries and past epidemic and pandemic seasons. METHODS: We applied Serfling and Poisson excess mortality approaches to model weekly age- and cause-specific mortality rates from June 1969 through May 2010 in France. Indicators of influenza activity, time trends, and seasonal terms were included in the models. We also reviewed the literature for country-specific estimates of 2009 pandemic excess mortality rates to characterize geographical differences in the burden of this pandemic. RESULTS: The 2009 A/H1N1 pandemic was associated with 1.0 (95% Confidence Intervals (CI) 0.2-1.9) excess respiratory deaths per 100,000 population in France, compared to rates per 100,000 of 44 (95% CI 43-45) for the A/H3N2 pandemic and 2.9 (95% CI 2.3-3.7) for average inter pandemic seasons. The 2009 A/H1N1 pandemic had a 10.6-fold higher impact than inter-pandemic seasons in people aged 5-24 years and 3.8-fold lower impact among people over 65 years. CONCLUSIONS: The 2009 pandemic in France had low mortality impact in most age groups, relative to past influenza seasons, except in school age children and young adults. The historical A/H3N2 pandemic was associated with much larger mortality impact than the 2009 pandemic, across all age groups and outcomes. Our 2009 pandemic excess mortality estimates for France fall within the range of previous estimates for high-income regions. Based on the analysis of several mortality outcomes and comparison with laboratory-confirmed 2009/H1N1 deaths, we conclude that cardio-respiratory and all-cause mortality lack precision to accurately measure the impact of this pandemic in high-income settings and that use of more specific mortality outcomes is important to obtain reliable age-specific estimates. PMID- 23028757 TI - Aging effect on neurotrophic activity of human mesenchymal stem cells. AB - Clinical efficacy of stem cells for nerve repair is likely to be influenced by issues including donor age and in vitro expansion time. We isolated human mesenchymal stem cells (MSC) from bone marrow of young (16-18 years) and old (67 75 years) donors and analyzed their capacity to differentiate and promote neurite outgrowth from dorsal root ganglia (DRG) neurons. Treatment of MSC with growth factors (forskolin, basic fibroblast growth factor, platelet derived growth factor-AA and glial growth factor-2) induced protein expression of the glial cell marker S100 in cultures from young but not old donors. MSC expressed various neurotrophic factor mRNA transcripts. Growth factor treatment enhanced the levels of BDNF and VEGF transcripts with corresponding increases in protein release in both donor cell groups. MSC in co-culture with DRG neurons significantly enhanced total neurite length which, in the case of young but not old donors, was further potentiated by treatment of the MSC with the growth factors. Stem cells from young donors maintained their proliferation rate over a time course of 9 weeks whereas those from the old donors showed increased population doubling times. MSC from young donors, differentiated with growth factors after long-term culture, maintained their ability to enhance neurite outgrowth of DRG. Therefore, MSC isolated from young donors are likely to be a favourable cell source for nerve repair. PMID- 23028758 TI - Zinc finger binding motifs do not explain recombination rate variation within or between species of Drosophila. AB - In humans and mice, the Cys(2)His(2) zinc finger protein PRDM9 binds to a DNA sequence motif enriched in hotspots of recombination, possibly modifying nucleosomes, and recruiting recombination machinery to initiate Double Strand Breaks (DSBs). However, since its discovery, some researchers have suggested that the recombinational effect of PRDM9 is lineage or species specific. To test for a conserved role of PRDM9-like proteins across taxa, we use the Drosophila pseudoobscura species group in an attempt to identify recombination associated zinc finger proteins and motifs. We leveraged the conserved amino acid motifs in Cys(2)His(2) zinc fingers to predict nucleotide binding motifs for all Cys(2)His(2) zinc finger proteins in Drosophila pseudoobscura and identified associations with empirical measures of recombination rate. Additionally, we utilized recombination maps from D. pseudoobscura and D. miranda to explore whether changes in the binding motifs between species can account for changes in the recombination landscape, analogous to the effect observed in PRDM9 among human populations. We identified a handful of potential recombination-associated sequence motifs, but the associations are generally tenuous and their biological relevance remains uncertain. Furthermore, we found no evidence that changes in zinc finger DNA binding explains variation in recombination rate between species. We therefore conclude that there is no protein with a DNA sequence specific human PRDM9-like function in Drosophila. We suggest these findings could be explained by the existence of a different recombination initiation system in Drosophila. PMID- 23028759 TI - Buzzwords in females' ears? The use of buzz songs in the communication of nightingales (Luscinia megarhynchos). AB - Differences in individual male birds' singing may serve as honest indicators of male quality in male-male competition and female mate choice. This has been shown e.g. for overall song output and repertoire size in many bird species. More recently, differences in structural song characteristics such as the performance of physically challenging song components were analysed in this regard. Here we show that buzz elements in the song of nightingales (Luscinia megarhynchos) hold the potential to serve as indicators of male quality and may therefore serve a communicative function. Buzzes were produced with considerable differences between males. The body weight of the males was correlated with one measure of these buzzes, namely the repetition rate of the buzz subunits, and individuals with larger repertoires sang buzzes at higher subunit-rates. A model of buzz performance constraints suggested that buzzes were sung with different proficiencies. In playback experiments, female nightingales showed more active behaviour when hearing buzz songs. The results support the idea that performance differences in the acoustic fine structure of song components are used in the communication of a large repertoire species such as the nightingale. PMID- 23028760 TI - Quantifying transmission of highly pathogenic and low pathogenicity H7N1 avian influenza in turkeys. AB - Outbreaks of avian influenza in poultry can be devastating, yet many of the basic epidemiological parameters have not been accurately characterised. In 1999-2000 in Northern Italy, outbreaks of H7N1 low pathogenicity avian influenza virus (LPAI) were followed by the emergence of H7N1 highly pathogenic avian influenza virus (HPAI). This study investigates the transmission dynamics in turkeys of representative HPAI and LPAI H7N1 virus strains from this outbreak in an experimental setting, allowing direct comparison of the two strains. The fitted transmission rates for the two strains are similar: 2.04 (1.5-2.7) per day for HPAI, 2.01 (1.6-2.5) per day for LPAI. However, the mean infectious period is far shorter for HPAI (1.47 (1.3-1.7) days) than for LPAI (7.65 (7.0-8.3) days), due to the rapid death of infected turkeys. Hence the basic reproductive ratio, [Formula: see text] is significantly lower for HPAI (3.01 (2.2-4.0)) than for LPAI (15.3 (11.8-19.7)). The comparison of transmission rates and [Formula: see text] are critically important in relation to understanding how HPAI might emerge from LPAI. Two competing hypotheses for how transmission rates vary with population size are tested by fitting competing models to experiments with differing numbers of turkeys. A model with frequency-dependent transmission gives a significantly better fit to experimental data than density-dependent transmission. This has important implications for extrapolating experimental results from relatively small numbers of birds to the commercial poultry flock size, and for how control, including vaccination, might scale with flock size. PMID- 23028761 TI - Blunted behavioral and c Fos responses to acidic fumes in the African naked mole rat. AB - Acidosis in the skin triggers activation of pain pathways and behaviors indicative of pain in vertebrates. The exception is the naked mole-rat, the only known vertebrate to show physiological and behavioral insensitivity to acid pain in the skin. The goal of the present study was to determine behavioral and physiological responses of this species to airborne acidic fumes, which would be expected to affect the trigeminal pain pathway in other species. Behaviorally, naked mole-rats did not avoid fumes from moderately high concentrations of acetic acid (10 and 20%), and c Fos labeling showed no increase in activity in the trigeminal nuclei and nucleus tractus solitarius. In contrast, these concentrations triggered behavioral aversion and increased Fos activity in other laboratory rodents. For a very high concentration of acetic acid (50%), naked mole-rats showed significant avoidance behavior and increased Fos labeling in the nucleus tractus solitarius caudal region, which receives vagal chemosensory information. However, there was no increase in trigeminal labeling, and in fact, activity significantly decreased. This pattern is opposite of that associated with another irritant, ammonia fumes, which elicited an increase in trigeminal but not nucleus tractus solitarius Fos labeling, and no behavioral avoidance. Behavioral avoidance of acidic fumes, but no increased labeling in the trigeminal pain nucleus is consistent with the notion of adaptations to blunt acid pain, which would be advantageous for naked mole-rats as they normally live under chronically high levels of acidosis-inducing CO(2). PMID- 23028762 TI - Multiple metabolic alterations exist in mutant PI3K cancers, but only glucose is essential as a nutrient source. AB - Targeting tumour metabolism is becoming a major new area of pharmaceutical endeavour. Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating diverse cellular processes including cell proliferation and survival, but has also been associated with metabolic dysregulation. In this study, we sought to define how mutations within PI3KCA may affect the metabolic dependency of a cancer cell, using precisely engineered isogenic cell lines. Studies revealed gene expression signatures in PIK3CA mutant cells indicative of a consistent up-regulation of glycolysis. Interestingly, the genes up- and down-regulated varied between isogenic models suggesting that the primary node of regulation is not the same between models. Additional gene expression changes were also observed, suggesting that metabolic pathways other than glycolysis, such as glutaminolysis, were also affected. Nutrient dependency studies revealed that growth of PIK3CA mutant cells is highly dependent on glucose, whereas glutamine dependency is independent of PIK3CA status. In addition, the glucose dependency exhibited by PIK3CA mutant cells could not be overridden by supplementation with other nutrients. This specific dependence on glucose for growth was further illustrated by studies evaluating the effects of targeted disruption of the glycolytic pathway using siRNA and was also found to be present across a wider panel of cancer cell lines harbouring endogenous PIK3CA mutations. In conclusion, we have found that PIK3CA mutations lead to a shift towards a highly glycolytic phenotype, and that despite suggestions that cancer cells are adept at utilising alternative nutrient sources, PIK3CA mutant cells are not able to compensate for glucose withdrawal. Understanding the metabolic dependencies of PIK3CA mutant cancers will provide critical information for the design of effective therapies and tumour visualisation strategies. PMID- 23028763 TI - Breaking down complex Saproxylic communities: understanding sub-networks structure and implications to network robustness. AB - Saproxylic insect communities inhabiting tree hollow microhabitats correspond with large food webs which simultaneously are constituted by multiple types of plant-animal and animal-animal interactions, according to the use of trophic resources (wood- and insect-dependent sub-networks), or to trophic habits or interaction types (xylophagous, saprophagous, xylomycetophagous, predators and commensals). We quantitatively assessed which properties of specialised networks were present in a complex networks involving different interacting types such as saproxylic community, and how they can be organised in trophic food webs. The architecture, interacting patterns and food web composition were evaluated along sub-networks, analysing their implications to network robustness from random and directed extinction simulations. A structure of large and cohesive modules with weakly connected nodes was observed throughout saproxylic sub-networks, composing the main food webs constituting this community. Insect-dependent sub-networks were more modular than wood-dependent sub-networks. Wood-dependent sub-networks presented higher species degree, connectance, links, linkage density, interaction strength, and were less specialised and more aggregated than insect-dependent sub networks. These attributes defined high network robustness in wood-dependent sub networks. Finally, our results emphasise the relevance of modularity, differences among interacting types and interrelations among them in modelling the structure of saproxylic communities and in determining their stability. PMID- 23028764 TI - Effect of multimeric structure of CaMKII in the GluN2B-mediated modulation of kinetic parameters of ATP. AB - Interaction of GluN2B subunit of N-methyl-D-aspartate receptor with calcium/calmodulin dependent protein kinase II (CaMKII) is critical for the induction of long term potentiation at hippocampal CA3-CA1 synapses. We have previously reported that CaMKII binding to GluN2B increases its affinity but abolishes the cooperativity for ATP. In the present study, we demonstrate that the reduction in S(0.5) for ATP of an individual CaMKII subunit seems to be directly induced by the binding of GluN2B to the same subunit, while any GluN2B induced effects on the cooperativity and maximal velocity would additionally require the CaMKII holoenzyme structure. We measured the apparent kinetic parameters for ATP using an association domain truncated monomeric CaMKII and a heteromultimeric CaMKII (having subunits that are either GluN2B binding defective or ATP binding defective), in the presence of GluN2A or GluN2B substrates. The S(0.5) value for ATP of monomeric CaMKII is reduced ~ 3 fold by the presence of GluN2B suggesting that the induced change in affinity for ATP is independent of the holoenzyme structure. The heteromultimeric mutant of CaMKII, did not exhibit cooperativity of ATP binding probably because of the interspersing of ATP binding defective subunits in the holoenzyme. In contrast to the wild type holoenzyme, presence of GluN2B increased the V(max) of monomeric CaMKII which resulted in an approximately 4.0 fold increase in the apparent catalytic constant (V(max)/S(0.5)) as compared to GluN2A. The kinetic parameter values of the heteromultimeric CaMKII for ATP, on the other hand, did not show any significant difference between the phosphorylation of GluN2B and GluN2A suggesting that modulation requires binding of GluN2B to the same subunit. Overall, our present study provides insights into the role of multimeric structure of CaMKII in GluN2B mediated regulation. PMID- 23028765 TI - Natural or naturalized? Phylogeography suggests that the abundant sea urchin Arbacia lixula is a recent colonizer of the Mediterranean. AB - We present the global phylogeography of the black sea urchin Arbacia lixula, an amphi-Atlantic echinoid with potential to strongly impact shallow rocky ecosystems. Sequences of the mitochondrial cytochrome c oxidase gene of 604 specimens from 24 localities were obtained, covering most of the distribution area of the species, including the Mediterranean and both shores of the Atlantic. Genetic diversity measures, phylogeographic patterns, demographic parameters and population differentiation were analysed. We found high haplotype diversity but relatively low nucleotide diversity, with 176 haplotypes grouped within three haplogroups: one is shared between Eastern Atlantic (including Mediterranean) and Brazilian populations, the second is found in Eastern Atlantic and the Mediterranean and the third is exclusively from Brazil. Significant genetic differentiation was found between Brazilian, Eastern Atlantic and Mediterranean regions, but no differentiation was found among Mediterranean sub-basins or among Eastern Atlantic sub-regions. The star-shaped topology of the haplotype network and the unimodal mismatch distributions of Mediterranean and Eastern Atlantic samples suggest that these populations have suffered very recent demographic expansions. These expansions could be dated 94-205 kya in the Mediterranean, and 31-67 kya in the Eastern Atlantic. In contrast, Brazilian populations did not show any signature of population expansion. Our results indicate that all populations of A. lixula constitute a single species. The Brazilian populations probably diverged from an Eastern Atlantic stock. The present-day genetic structure of the species in Eastern Atlantic and the Mediterranean is shaped by very recent demographic processes. Our results support the view (backed by the lack of fossil record) that A. lixula is a recent thermophilous colonizer which spread throughout the Mediterranean during a warm period of the Pleistocene, probably during the last interglacial. Implications for the possible future impact of A. lixula on shallow Mediterranean ecosystems in the context of global warming trends must be considered. PMID- 23028766 TI - Ontogenetic and among-individual variation in foraging strategies of northeast Pacific white sharks based on stable isotope analysis. AB - There is growing evidence for individuality in dietary preferences and foraging behaviors within populations of various species. This is especially important for apex predators, since they can potentially have wide dietary niches and a large impact on trophic dynamics within ecosystems. We evaluate the diet of an apex predator, the white shark (Carcharodon carcharias), by measuring the stable carbon and nitrogen isotope composition of vertebral growth bands to create lifetime records for 15 individuals from California. Isotopic variations in white shark diets can reflect within-region differences among prey (most importantly related to trophic level), as well as differences in baseline values among the regions in which sharks forage, and both prey and habitat preferences may shift with age. The magnitude of isotopic variation among sharks in our study (>50/00 for both elements) is too great to be explained solely by geographic differences, and so must reflect differences in prey choice that may vary with sex, size, age and location. Ontogenetic patterns in delta(15)N values vary considerably among individuals, and one third of the population fit each of these descriptions: 1) delta(15)N values increased throughout life, 2) delta(15)N values increased to a plateau at ~5 years of age, and 3) delta(15)N values remained roughly constant values throughout life. Isotopic data for the population span more than one trophic level, and we offer a qualitative evaluation of diet using shark-specific collagen discrimination factors estimated from a 3+ year captive feeding experiment (Delta(13)C(shark-diet) and Delta(15)N(shark-diet) equal 4.20/00 and 2.50/00, respectively). We assess the degree of individuality with a proportional similarity index that distinguishes specialists and generalists. The isotopic variance is partitioned among differences between-individual (48%), within individuals (40%), and by calendar year of sub-adulthood (12%). Our data reveal substantial ontogenetic and individual dietary variation within a white shark population. PMID- 23028767 TI - Distance decay of similarity in neotropical diatom communities. AB - BACKGROUND: The regression of similarity against distance unites several ecological phenomena, and thus provides a highly useful approach for illustrating the spatial turnover across sites. Our aim was to test whether the rates of decay in community similarity differ between diatom growth forms suggested to show different dispersal ability. We hypothesized that the diatom group with lower dispersal ability (i.e. periphyton) would show higher distance decay rates than a group with higher dispersal ability (i.e. plankton). METHODS/PRINCIPAL FINDINGS: Periphyton and phytoplankton samples were gathered at sites distributed over an area of approximately 800 km length in the Negro River, Amazon basin, Brazil, South America (3 degrees 08'00"S; 59 degrees 54'30"W). Distance decay relationships were then estimated using distance-based regressions, and the coefficients of these regressions were compared among the groups with different dispersal abilities to assess our predictions. We found evidence that different tributaries and reaches of the Negro River harbor different diatom communities. As expected, the rates of distance decay in community similarity were higher for periphyton than for phytoplankton indicating the lower dispersal ability of periphytic taxa. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that the comparison of distance decay relationships among taxa with similar ecological requirements, but with different growth form and thus dispersal ability provides a sound approach to evaluate the effects of dispersal ability on beta diversity patterns. Our results are also in line with the growing body of evidence indicating that microorganisms exhibit biogeographic patterns. Finally, we underscore that clumbing all microbial taxa into one group may be a flawed approach to test whether microbes exhibit biogeographic patterns. PMID- 23028768 TI - Impaired chemosensitivity of mouse dorsal raphe serotonergic neurons overexpressing serotonin 1A (Htr1a) receptors. AB - BACKGROUND: Serotonergic system participates in a wide range of physiological processes and behaviors, but its role is generally considered as modulatory and noncrucial, especially concerning life-sustaining functions. We recently created a transgenic mouse line in which a functional deficit in serotonin homeostasis due to excessive serotonin autoinhibition was produced by inducing serotonin 1A receptor (Htr1a) overexpression selectively in serotonergic neurons (Htr1a raphe overexpressing or Htr1a(RO) mice). Htr1a(RO) mice exhibit episodes of autonomic dysregulation, cardiovascular crises and death, resembling those of sudden infant death syndrome (SIDS) and revealing a life-supporting role of serotonergic system in autonomic control. Since midbrain serotonergic neurons are chemosensitive and are implicated in arousal we hypothesized that their chemosensitivity might be impaired in Htr1a(RO) mice. PRINCIPAL FINDINGS: Loose-seal cell-attached recordings in brainstem slices revealed that serotonergic neurons in dorsal raphe nucleus of Htr1a(RO) mice have dramatically reduced responses to hypercapnic challenge as compared with control littermates. In control mice, application of 9% CO(2) produced an increase in firing rate of serotonergic neurons (0.260 +/- 0.041 Hz, n=20, p=0.0001) and application of 3% CO(2) decreased their firing rate (-0.142 +/- 0.025 Hz, n=17, p=0.0008). In contrast, in Htr1a(RO) mice, firing rate of serotonergic neurons was not significantly changed by 9% CO(2) (0.021 +/- 0.034 Hz, n=16, p=0.49) and by 3% CO(2) (0.012 +/- 0.046 Hz, n=12, p=0.97). CONCLUSIONS: Our findings support the hypothesis that chemosensitivity of midbrain serotonergic neurons provides a physiological mechanism for arousal responses to life-threatening episodes of hypercapnia and that functional impairment, such as excessive autoinhibition, of midbrain serotonergic neuron responses to hypercapnia may contribute to sudden death. PMID- 23028769 TI - Molecular basis for involvement of CYP1B1 in MYOC upregulation and its potential implication in glaucoma pathogenesis. AB - CYP1B1 has been implicated in primary congenital glaucoma with autosomal recessive mode of inheritance. Mutations in CYP1B1 have also been reported in primary open angle glaucoma (POAG) cases and suggested to act as a modifier of the disease along with Myocilin (MYOC). Earlier reports suggest that over expression of myocilin leads to POAG pathogenesis. Taken together, we propose a functional interaction between CYP1B1 and myocilin where 17beta estradiol acts as a mediator. Therefore, we hypothesize that 17beta estradiol can induce MYOC expression through the putative estrogen responsive elements (EREs) located in its promoter and CYP1B1 could manipulate MYOC expression by metabolizing 17beta estradiol to 4-hydroxy estradiol, thus preventing it from binding to MYOC promoter. Hence any mutation in CYP1B1 that reduces its 17beta estradiol metabolizing activity might lead to MYOC upregulation, which in turn might play a role in glaucoma pathogenesis. It was observed that 17beta estradiol is present in Human Trabecular Meshwork cells (HTM) and Retinal Pigment Epithelial cells (RPE) by immunoflouresence and ELISA. Also, the expression of enzymes related to estrogen biosynthesis pathway was observed in both cell lines by RT-PCR. Subsequent evaluation of the EREs in the MYOC promoter by luciferase assay, with dose and time dependent treatment of 17beta estradiol, showed that the EREs are indeed active. This observation was further validated by direct binding of estrogen receptors (ER) on EREs in MYOC promoter and subsequent upregulation in MYOC level in HTM cells on 17beta estradiol treatment. Interestingly, CYP1B1 mutants with less than 10% enzymatic activity were found to increase the level of endogenous myocilin in HTM cells. Thus the experimental observations are consistent with our proposed hypothesis that mutant CYP1B1, lacking the 17beta estradiol metabolizing activity, can cause MYOC upregulation, which might have a potential implication in glaucoma pathogenesis. PMID- 23028770 TI - Intraocular pressure-lowering effects of commonly used fixed-combination drugs with timolol: a systematic review and meta-analysis. AB - BACKGROUND: The first goal of medical therapy in glaucoma is to reduce intraocular pressure (IOP), and the fixed-combination medications are needed to achieve sufficiently low target IOP. The aim of this systematic review and meta analysis is to evaluate IOP-lowering effect of the commonly used fixed combination drugs containing 0.5% timolol. METHODS: Pertinent publications were identified through systematic searches. Over 85% of the patients had to be diagnosed with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). Forty-one randomized clinical trials were included in the meta-analysis. The main efficacy measures were the absolute and relative values of mean diurnal IOP reduction, and the highest and lowest IOP reductions on the diurnal IOP curve. The pooled 1- to 3-month IOP-lowering effects after a medicine-free washout period was calculated by performing meta-analysis using the random effects model, and relative treatment effects among different fixed combinations were assessed using a mixed-effects meta-regression model. RESULTS: The relative reductions for mean diurnal IOP were 34.9% for travoprost/timolol, 34.3% for bimatoprost/timolol, 33.9% for latanoprost/timolol, 32.7% for brinzolamide/timolol, 29.9% for dorzolamide/timolol, and 28.1% for brimonidine/timolol. For the highest IOP decrease, relative reductions ranged from 31.3% for dorzolamide/timolol to 35.5% for travoprost/timolol; for the lowest IOP decrease, those varied from 25.9% for dorzolamide/timolol to 33.1% for bimatoprost/timolol. Both latanoprost/timolol and travoprost/timolol were more effective in lowering mean diurnal IOP than brimonidine/timolol (WMD: 5.9 and 7.0) and dorzolamide/timolol (WMD: 3.8 and 3.3). CONCLUSIONS: All six commonly used fixed-combination drugs containing timolol can effectively lower IOP in patients with POAG and OHT, and both latanoprost/timolol and travoprost/timolol might achieve better IOP-lowering effects among the six fixed-combination agents. PMID- 23028771 TI - Accuracy and reliability of automated gray matter segmentation pathways on real and simulated structural magnetic resonance images of the human brain. AB - Automated gray matter segmentation of magnetic resonance imaging data is essential for morphometric analyses of the brain, particularly when large sample sizes are investigated. However, although detection of small structural brain differences may fundamentally depend on the method used, both accuracy and reliability of different automated segmentation algorithms have rarely been compared. Here, performance of the segmentation algorithms provided by SPM8, VBM8, FSL and FreeSurfer was quantified on simulated and real magnetic resonance imaging data. First, accuracy was assessed by comparing segmentations of twenty simulated and 18 real T1 images with corresponding ground truth images. Second, reliability was determined in ten T1 images from the same subject and in ten T1 images of different subjects scanned twice. Third, the impact of preprocessing steps on segmentation accuracy was investigated. VBM8 showed a very high accuracy and a very high reliability. FSL achieved the highest accuracy but demonstrated poor reliability and FreeSurfer showed the lowest accuracy, but high reliability. An universally valid recommendation on how to implement morphometric analyses is not warranted due to the vast number of scanning and analysis parameters. However, our analysis suggests that researchers can optimize their individual processing procedures with respect to final segmentation quality and exemplifies adequate performance criteria. PMID- 23028772 TI - Phyllostachys edulis compounds inhibit palmitic acid-induced monocyte chemoattractant protein 1 (MCP-1) production. AB - BACKGROUND: Phyllostachys edulis Carriere (Poaceae) is a bamboo species that is part of the traditional Chinese medicine pharmacopoeia. Compounds and extracts from this species have shown potential applications towards several diseases. One of many complications found in obesity and diabetes is the link between elevated circulatory free fatty acids (FFAs) and chronic inflammation. This study aims to present a possible application of P. edulis extract in relieving inflammation caused by FFAs. Monocyte chemoattractant protein 1 (MCP-1/CCL2) is a pro inflammatory cytokine implicated in chronic inflammation. Nuclear factor kappa light-chain-enhancer of activated B cells (NF-kappaB) and activator protein 1 (AP 1) are transcription factors activated in response to inflammatory stimuli, and upregulate pro-inflammatory cytokines such as MCP-1. This study examines the effect of P. edulis extract on cellular production of MCP-1 and on the NF-kappaB and AP-1 pathways in response to treatment with palmitic acid (PA), a FFA. METHODOLOGY/PRINCIPAL FINDINGS: MCP-1 protein was measured by cytometric bead assay. NF-kappaB and AP-1 nuclear localization was detected by colorimetric DNA binding ELISA. Relative MCP-1 mRNA was measured by real-time quantitative PCR. Murine cells were treated with PA to induce inflammation. PA increased expression of MCP-1 mRNA and protein, and increased nuclear localization of NF-kappaB and AP 1. Adding bamboo extract (BEX) inhibited the effects of PA, reduced MCP-1 production, and inhibited nuclear translocation of NF-kappaB and AP-1 subunits. Compounds isolated from BEX inhibited MCP-1 secretion with different potencies. CONCLUSIONS/SIGNIFICANCE: PA induced MCP-1 production in murine adipose, muscle, and liver cells. BEX ameliorated PA-induced production of MCP-1 by inhibiting nuclear translocation of NF-kappaB and AP-1. Two O-methylated flavones were isolated from BEX with functional effects on MCP-1 production. These results may represent a possible therapeutic application of BEX and its compounds toward alleviating chronic inflammation caused by elevated circulatory FFAs. PMID- 23028774 TI - Are autobiographical memories inherently social? Evidence from an fMRI study. AB - The story of our lifetime - our narrative self - is constructed from our autobiographical memories. A central claim of social psychology is that this narrative self is inherently social: When we construct our lives, we do so in a real or imagined interaction. This predicts that self-referential processes which are involved in recall of autobiographical memories overlap with processes involved in social interactions. Indeed, previous functional MRI studies indicate that regions in the medial prefrontal cortex (mPFC) are activated during autobiographical memory recall and virtual communication. However, no fMRI study has investigated recall of autobiographical memories in a real-life interaction. We developed a novel paradigm in which participants overtly reported self-related and other-related memories to an experimenter, whose non-verbal reactions were being filmed and online displayed to the participants in the scanner. We found that recall of autobiographical vs. non-autobiographical memories was associated with activation of the mPFC, as was recall in the social as compared to a non social control condition; however, both contrasts involved different non overlapping regions within the mPFC. These results indicate that self-referential processes involved in autobiographical memory recall are different from processes supporting social interactions, and argue against the hypothesis that autobiographical memories are inherently social. PMID- 23028773 TI - Identification of genes from the fungal pathogen Cryptococcus neoformans related to transmigration into the central nervous system. AB - BACKGROUND: A mouse brain transmigration assessment (MBTA) was created to investigate the central nervous system (CNS) pathogenesis of cryptococcal meningoencephalitis. METHODOLOGY/PRINCIPAL FINDINGS: Two cryptococcal mutants were identified from a pool of 109 pre-selected mutants that were signature tagged with the nourseothricin acetyltransferase (NAT) resistance cassette. These two mutants displayed abnormal transmigration into the central nervous system. One mutant displaying decreased transmigration contains a null mutation in the putative FNX1 gene, whereas the other mutant possessing a null mutation in the putative RUB1 gene exhibited increased transmigration into the brain. Two macrophage adhesion-defective mutants in the pool, 12F1 and 3C9, showed reduced phagocytosis by macrophages, but displayed no defects in CNS entry suggesting that transit within macrophages (the "Trojan horse" model of CNS entry) is not the primary mechanism for C. neoformans migration into the CNS in this MBTA. CONCLUSIONS/SIGNIFICANCE: This research design provides a new strategy for genetic impact studies on how Cryptococcus passes through the blood-brain barrier (BBB), and the specific isolated mutants in this assay support a transcellular mechanism of CNS entry. PMID- 23028775 TI - Argument structure and morphological factors in noun and verb processing: an fMRI study. AB - In a functional MRI (fMRI) study, we have investigated the grammatical categories of object noun, event noun and verb in order to assess the cortical regions of activation supporting their processing. Twelve Italian healthy participants performed a lexical decision task. They had to decide whether a string was an Italian word or not. Words could be objects like medaglia (medal), or events like the noun pianto (cry); or the verb dormire (to sleep). Noun and verb comparison shows differences in regions of activation in the left Inferior Frontal cortex and in the extent of the same areas. We have found specific areas of activation for object noun, and similarities in the pattern of activation for event noun and verb. The activations induced by pseudowords highly resembled the areas activated by the corresponding word category. The implications of the results are discussed in light of the recent debate on the role of grammatical category in the brain. PMID- 23028776 TI - I dare you to punish me-vendettas in games of cooperation. AB - Everybody has heard of neighbours, who have been fighting over some minor topic for years. The fight goes back and forth, giving the neighbours a hard time. These kind of reciprocal punishments are known as vendettas and they are a cross cultural phenomenon. In evolutionary biology, punishment is seen as a mechanism for maintaining cooperative behaviour. However, this notion of punishment excludes vendettas. Vendettas pose a special kind of evolutionary problem: they incur high costs on individuals, i.e. costs of punishing and costs of being punished, without any benefits. Theoretically speaking, punishment should be rare in dyadic relationships and vendettas would not evolve under natural selection. In contrast, punishment is assumed to be more efficient in group environments which then can pave the way for vendettas. Accordingly, we found that under the experimental conditions of a prisoner's dilemma game, human participants punished only rarely and vendettas are scarce. In contrast, we found that participants retaliated frequently in the group environment of a public goods game. They even engaged in cost-intense vendettas (i.e. continuous retaliation), especially when the first punishment was unjustified or ambiguous. Here, punishment was mainly targeted at defectors in the beginning, but provocations led to mushrooming of counter-punishments. Despite the counter-punishing behaviour, participants were able to enhance cooperation levels in the public goods game. Few participants even seemed to anticipate the outbreak of costly vendettas and delayed their punishment to the last possible moment. Overall, our results highlight the importance of different social environments while studying punishment as a cooperation-enhancing mechanism. PMID- 23028777 TI - A role for the CAL1-partner Modulo in centromere integrity and accurate chromosome segregation in Drosophila. AB - The relationship between the nucleolus and the centromere, although documented, remains one of the most elusive aspects of centromere assembly and maintenance. Here we identify the nucleolar protein, Modulo, in complex with CAL1, a factor essential for the centromeric deposition of the centromere-specific histone H3 variant, CID, in Drosophila. Notably, CAL1 localizes to both centromeres and the nucleolus. Depletion of Modulo, by RNAi, results in defective recruitment of newly-synthesized CAL1 at the centromere. Furthermore, depletion of Modulo negatively affects levels of CID at the centromere and results in chromosome missegregation. Interestingly, examination of Modulo localization during mitosis reveals it localizes to the chromosome periphery but not the centromere. Combined, the data suggest that rather than a direct regulatory role at the centromere, it is the nucleolar function of modulo which is regulating the assembly of the centromere by directing the localization of CAL1. We propose that a functional link between the nucleolus and centromere assembly exists in Drosophila, which is regulated by Modulo. PMID- 23028779 TI - No trade-off between learning speed and associative flexibility in bumblebees: a reversal learning test with multiple colonies. AB - Potential trade-offs between learning speed and memory-related performance could be important factors in the evolution of learning. Here, we test whether rapid learning interferes with the acquisition of new information using a reversal learning paradigm. Bumblebees (Bombus terrestris) were trained to associate yellow with a floral reward. Subsequently the association between colour and reward was reversed, meaning bees then had to learn to visit blue flowers. We demonstrate that individuals that were fast to learn yellow as a predictor of reward were also quick to reverse this association. Furthermore, overnight memory retention tests suggest that faster learning individuals are also better at retaining previously learned information. There is also an effect of relatedness: colonies whose workers were fast to learn the association between yellow and reward also reversed this association rapidly. These results are inconsistent with a trade-off between learning speed and the reversal of a previously made association. On the contrary, they suggest that differences in learning performance and cognitive (behavioural) flexibility could reflect more general differences in colony learning ability. Hence, this study provides additional evidence to support the idea that rapid learning and behavioural flexibility have adaptive value. PMID- 23028778 TI - PI3Kgamma drives priming and survival of autoreactive CD4(+) T cells during experimental autoimmune encephalomyelitis. AB - The class IB phosphoinositide 3-kinase gamma enzyme complex (PI3Kgamma) functions in multiple signaling pathways involved in leukocyte activation and migration, making it an attractive target in complex human inflammatory diseases including MS. Here, using pik3cg(-/-) mice and a selective PI3Kgamma inhibitor, we show that PI3Kgamma promotes development of experimental autoimmune encephalomyelitis (EAE). In pik3cg(-/-) mice, EAE is markedly suppressed and fewer leukocytes including CD4(+) and CD8(+) T cells, granulocytes and mononuclear phagocytes infiltrate the CNS. CD4(+) T cell priming in secondary lymphoid organs is reduced in pik3cg(-/-) mice following immunisation. This is attributable to defects in DC migration concomitant with a failure of full T cell activation following TCR ligation in the absence of p110gamma. Together, this results in suppressed autoreactive T cell responses in pik3cg(-/-) mice, with more CD4(+) T cells undergoing apoptosis and fewer cytokine-producing Th1 and Th17 cells in lymphoid organs and the CNS. When administered from onset of EAE, the orally active PI3Kgamma inhibitor AS605240 caused inhibition and reversal of clinical disease, and demyelination and cellular pathology in the CNS was reduced. These results strongly suggest that inhibitors of PI3Kgamma may be useful therapeutics for MS. PMID- 23028780 TI - Genome-wide prediction and validation of sigma70 promoters in Lactobacillus plantarum WCFS1. AB - BACKGROUND: In prokaryotes, sigma factors are essential for directing the transcription machinery towards promoters. Various sigma factors have been described that recognize, and bind to specific DNA sequence motifs in promoter sequences. The canonical sigma factor sigma(70) is commonly involved in transcription of the cell's housekeeping genes, which is mediated by the conserved sigma(70) promoter sequence motifs. In this study the sigma(70) promoter sequences in Lactobacillus plantarum WCFS1 were predicted using a genome wide analysis. The accuracy of the transcriptionally-active part of this promoter prediction was subsequently evaluated by correlating locations of predicted promoters with transcription start sites inferred from the 5'-ends of transcripts detected by high-resolution tiling array transcriptome datasets. RESULTS: To identify sigma(70)-related promoter sequences, we performed a genome-wide sequence motif scan of the L. plantarum WCFS1 genome focussing on the regions upstream of protein-encoding genes. We obtained several highly conserved motifs including those resembling the conserved sigma(70)-promoter consensus. Position weight matrices-based models of the recovered sigma(70)-promoter sequence motif were employed to identify 3874 motifs with significant similarity (p-value<10( 4)) to the model-motif in the L. plantarum genome. Genome-wide transcript information deduced from whole genome tiling-array transcriptome datasets, was used to infer transcription start sites (TSSs) from the 5'-end of transcripts. By this procedure, 1167 putative TSSs were identified that were used to corroborate the transcriptionally active fraction of these predicted promoters. In total, 568 predicted promoters were found in proximity (<= 40 nucleotides) of the putative TSSs, showing a highly significant co-occurrence of predicted promoter and TSS (p value<10(-263)). CONCLUSIONS: High-resolution tiling arrays provide a suitable source to infer TSSs at a genome-wide level, and allow experimental verification of in silico predicted promoter sequence motifs. PMID- 23028781 TI - Sirt5 deacylation activities show differential sensitivities to nicotinamide inhibition. AB - Sirtuins are protein deacylases regulating metabolism and aging processes, and the seven human isoforms are considered attractive therapeutic targets. Sirtuins transfer acyl groups from lysine sidechains to ADP-ribose, formed from the cosubstrate NAD(+) by release of nicotinamide, which in turn is assumed to be a general Sirtuin inhibitor. Studies on Sirtuin regulation have been hampered, however, by shortcomings of available assays. Here, we describe a mass spectrometry-based, quantitative deacylation assay not requiring any substrate labeling. Using this assay, we show that the deacetylation activity of human Sirt5 features an unusual insensitivity to nicotinamide inhibition. In contrast, we find similar values for Sirt5 and Sirt3 for the intrinsic NAD(+) affinity as well as the apparent NAD(+) affinity in presence of peptide. Structure comparison and mutagenesis identify an Arg neighboring to the Sirt5 nicotinamide binding pocket as a mediator of nicotinamide resistance, and statistical sequence analyses along with testing further Sirtuins reveal a network of coevolved residues likely defining a nicotinamide-insensitive Sirtuin deacetylase family. The same Arg was recently reported to render Sirt5 a preferential desuccinylase, and we find that this Sirt5 activity is highly sensitive to nicotinamide inhibition. Analysis of Sirt5 structures and activity data suggest that an Arg/succinate interaction is the molecular basis of the differential nicotinamide sensitivities of the two Sirt5 activities. Our results thus indicate a Sirtuin subfamily with nicotinamide-insensitive deacetylase activity and suggest that the molecular features determining nicotinamide sensitivity overlap with those dominating deacylation specificity, possibly suggesting that other subfamily members might also prefer other acylations than acetylations. PMID- 23028782 TI - A lentiviral gene therapy strategy for the in vitro production of feline erythropoietin. AB - Nonregenerative anemia due to chronic renal failure is a common problem in domestic cats. Unfortunately, administration of recombinant human erythropoietin often only improves anemia temporarily due to antibody development. In this in vitro study, feline erythropoietin cDNA was cloned from feline renal tissue and utilized in the construction of a replication-defective lentiviral vector. The native recombinant feline erythropoietin (rfEPO) sequence was confirmed by sequencing. Upon viral vector infection of human 293H cells, Crandall Renal Feline Kidney cell line and primary feline peripheral blood mononuclear cells, bioactive rfEPO protein was produced. The presence of cellular rfEPO cDNA was confirmed by standard PCR, production of abundant rfEPO mRNA was confirmed by real-time PCR, and secretion of rfEPO protein was demonstrated by Western blot analyses, while rfEPO protein bioactivity was confirmed via an MTT proliferation bioassay. This in vitro study demonstrates the feasibility of a replication defective lentiviral vector delivery system for the in vitro production of biologically active feline erythropoietin. Anemic cats with chronic renal failure represent a potential in vivo application of a lentiviral gene therapy system. PMID- 23028783 TI - Variable lengths of stay among ischemic stroke subtypes in Chinese general teaching hospitals. AB - BACKGROUND: Length of stay (LOS) is one of the most important quantitative indexes that measures health service utilization within a hospital. Many studies have examined the association of three major stroke categories with LOS. Our aim is to investigate the differences of LOS among ischemic stroke subtypes, results from which are helpful to healthcare providers and government agencies to improve health care delivery efficiency. METHODOLOGY/PRINCIPAL FINDINGS: Using the Beijing Municipal Health Bureau's hospitalization summary reports, we performed a retrospective study among first-ever in-hospital patients with ischemic stroke (ICD-10 I63) in three general teaching hospitals in Beijing, China, from 2006 to 2010 with generalized linear model. In our study, 5,559 patients (female, 36.0%; age, 64.4 +/- 12.9 years) were included. The estimated mean LOS of ischemic stroke was 17.4 +/- 1.8 days. After adjusting for confounders, LOS of lacunar infarction (14.7 days; p<0.001) and LOS of small cerebral infarction (17.0 days; p=0.393) were shorter than that of single cerebral infarction (17.9 days, p<0.001). LOS of multi-infarct (19.0 days; p=0.028), brainstem infarction (19.3 days; p=0.045), basal ganglia infarction (18.5 days; p=0.452) and other subtypes of ischemic stroke (18.9 days; p=0.327) were longer than that of single cerebral infarction. CONCLUSIONS: LOS of ischemic stroke patient differes across single cerebral infarction, lacunar infarction, multi-infarct and brainstem infarction patients. The ascending order of LOS was lacunar infarction, small cerebral infarction, single cerebral infarction, basal ganglia infarction, other subtypes of ischemic stroke, multi-infarct and brainstem infarction. PMID- 23028784 TI - Targeting viral antigens to CD11c on dendritic cells induces retrovirus-specific T cell responses. AB - Dendritic cells (DC) represent the most potent antigen presenting cells and induce efficient cytotoxic T lymphocyte (CTL) responses against viral infections. Targeting antigens (Ag) to receptors on DCs is a promising strategy to enhance antitumor and antiviral immune responses induced by DCs. Here, we investigated the potential of CD11c-specific single-chain fragments (scFv) fused to an immunodominant peptide of Friend retrovirus for induction of virus-specific T cell responses by DCs. In vitro CD11c-specific scFv selectively targeted viral antigens to DCs and thereby significantly improved the activation of virus specific T cells. In vaccination experiments DCs loaded with viral Ag targeted to CD11c provided improved rejection of FV-derived tumors and efficiently primed virus-specific CTL responses after virus challenge. Since the induction of strong virus-specific T cell responses is critical in viral infections, CD11c targeted protein vaccines might provide means to enhance the cellular immune response to prophylactic or therapeutic levels. PMID- 23028785 TI - Predicting statistical properties of open reading frames in bacterial genomes. AB - An analytical model based on the statistical properties of Open Reading Frames (ORFs) of eubacterial genomes such as codon composition and sequence length of all reading frames was developed. This new model predicts the average length, maximum length as well as the length distribution of the ORFs of 70 species with GC contents varying between 21% and 74%. Furthermore, the number of annotated genes is predicted with high accordance. However, the ORF length distribution in the five alternative reading frames shows interesting deviations from the predicted distribution. In particular, long ORFs appear more often than expected statistically. The unexpected depletion of stop codons in these alternative open reading frames cannot completely be explained by a biased codon usage in the +1 frame. While it is unknown if the stop codon depletion has a biological function, it could be due to a protein coding capacity of alternative ORFs exerting a selection pressure which prevents the fixation of stop codon mutations. The comparison of the analytical model with bacterial genomes, therefore, leads to a hypothesis suggesting novel gene candidates which can now be investigated in subsequent wet lab experiments. PMID- 23028786 TI - Dealing with illumination in visual scenes: effects of ageing and Alzheimer's disease. AB - Various visual functions decline in ageing and even more so in patients with Alzheimer's disease (AD). Here we investigated whether the complex visual processes involved in ignoring illumination-related variability (specifically, cast shadows) in visual scenes may also be compromised. Participants searched for a discrepant target among items which appeared as posts with shadows cast by light-from-above when upright, but as angled objects when inverted. As in earlier reports, young participants gave slower responses with upright than inverted displays when the shadow-like part was dark but not white (control condition). This is consistent with visual processing mechanisms making shadows difficult to perceive, presumably to assist object recognition under varied illumination. Contrary to predictions, this interaction of "shadow" colour with item orientation was maintained in healthy older and AD groups. Thus, the processing mechanisms which assist complex light-independent object identification appear to be robust to the effects of both ageing and AD. Importantly, this means that the complexity of a function does not necessarily determine its vulnerability to age- or AD-related decline.We also report slower responses to dark than light "shadows" of either orientation in both ageing and AD, in keeping with increasing light scatter in the ageing eye. Rather curiously, AD patients showed further slowed responses to "shadows" of either colour at the bottom than the top of items as if they applied shadow-specific rules to non-shadow conditions. This suggests that in AD, shadow-processing mechanisms, while preserved, might be applied in a less selective way. PMID- 23028787 TI - Comparison of microarray platforms for measuring differential microRNA expression in paired normal/cancer colon tissues. AB - BACKGROUND: Microarray technology applied to microRNA (miRNA) profiling is a promising tool in many research fields; nevertheless, independent studies characterizing the same pathology have often reported poorly overlapping results. miRNA analysis methods have only recently been systematically compared but only in few cases using clinical samples. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the inter-platform reproducibility of four miRNA microarray platforms (Agilent, Exiqon, Illumina, and Miltenyi), comparing nine paired tumor/normal colon tissues. The most concordant and selected discordant miRNAs were further studied by quantitative RT-PCR. Globally, a poor overlap among differentially expressed miRNAs identified by each platform was found. Nevertheless, for eight miRNAs high agreement in differential expression among the four platforms and comparability to qRT-PCR was observed. Furthermore, most of the miRNA sets identified by each platform are coherently enriched in data from the other platforms and the great majority of colon cancer associated miRNA sets derived from the literature were validated in our data, independently from the platform. Computational integration of miRNA and gene expression profiles suggested that anti-correlated predicted target genes of differentially expressed miRNAs are commonly enriched in cancer-related pathways and in genes involved in glycolysis and nutrient transport. CONCLUSIONS: Technical and analytical challenges in measuring miRNAs still remain and further research is required in order to increase consistency between different microarray-based methodologies. However, a better inter-platform agreement was found by looking at miRNA sets instead of single miRNAs and through a miRNAs - gene expression integration approach. PMID- 23028788 TI - Training the brain to survive stroke. AB - BACKGROUND: Presently, little can be done to repair brain tissue after stroke damage. We hypothesized that the mammalian brain has an intrinsic capacity to adapt to low oxygen which would improve outcome from a reversible hypoxic/ischemic episode. Acclimation to chronic hypoxia causes increased capillarity and tissue oxygen levels which may improve the capacity to survive ischemia. Identification of these adaptations will lead to protocols which high risk groups could use to improve recovery and reduce costs. METHODS AND FINDINGS: Rats were exposed to hypoxia (3 weeks living at 1/2 an atmosphere). After acclimation, capillary density was measured morphometrically and was increased by 30% in the cortex. Novel implantable oxygen sensors showed that partial pressure of oxygen in the brain was increased by 40% in the normal cortex. Infarcts were induced in brain with 1 h reversible middle cerebral artery occlusions. After ischemia (48 h) behavioural scores were improved and T2 weighted MRI lesion volumes were reduced by 52% in acclimated groups. There was a reduction in inflammation indicated by reduced lymphocytes (by 27-33%), and ED1 positive cells (by 35-45%). CONCLUSIONS: It is possible to stimulate a natural adaptive mechanism in the brain which will reduce damage and improve outcome for a given ischemic event. Since these adaptations occur after factors such as HIF-1alpha have returned to baseline, protection is likely related more to morphological changes such as angiogenesis. Such pre-conditioning, perhaps with exercise or pharmaceuticals, would not necessarily reduce the incidence of stroke, but the severity of damage could be reduced by 50%. PMID- 23028789 TI - Hsp90 is involved in apoptosis of Candida albicans by regulating the calcineurin caspase apoptotic pathway. AB - Candida albicans is the most common human fungal pathogen. Recent evidence has revealed the occurrence of apoptosis in C. albicans that is inducible by environmental stresses such as hydrogen peroxide, acetic acid, and amphotericin B. Apoptosis is regulated by the calcineurin-caspase pathway in C. albicans, and calcineurin is under the control of Hsp90 in echinocandin resistance. However, the role of Hsp90 in apoptosis of C. albicans remains unclear. In this study, we investigated the role of Hsp90 in apoptosis of C. albicans by using an Hsp90 compromised strain tetO-HSP90/hsp90 and found that upon apoptotic stimuli, including hydrogen peroxide, acetic acid or amphotericin B treatment, less apoptosis occurred, less ROS was produced, and more cells survived in the Hsp90 compromised strain compared with the Hsp90/Hsp90 wild-type strain. In addition, Hsp90-compromised cells were defective in up-regulating caspase-encoding gene CaMCA1 expression and activating caspase activity upon the apoptotic stimuli. Investigations on the relationship between Hsp90 and calcineurin revealed that activation of calcineurin could up-regulate apoptosis but could not further down regulate apoptosis in Hsp90-compromised cells, indicating that calcineurin was downstream of Hsp90. Hsp90 inhibitor geldanamycin (GdA) could further decrease the apoptosis in calcineurin-pathway-defect strains, indicating that compromising Hsp90 function had a stronger effect than compromising calcineurin function on apoptosis. Collectively, this study demonstrated that compromised Hsp90 reduced apoptosis in C. albicans, partially through downregulating the calcineurin caspase pathway. PMID- 23028790 TI - Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants. AB - Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (OMIM 201450) is the most common inherited disorder of fatty acid metabolism presenting with hypoglycaemia, hepatopathy and Reye-like symptoms during catabolism. In the past, the majority of patients carried the prevalent c.985A>G mutation in the ACADM gene. Since the introduction of newborn screening many other mutations with unknown clinical relevance have been identified in asymptomatic newborns. In order to identify functional effects of these mutant genotypes we correlated residual MCAD (OMIM 607008) activities as measured by octanoyl-CoA oxidation in lymphocytes with both genotype and relevant medical reports in 65 newborns harbouring mutant alleles. We identified true disease-causing mutations with residual activities of 0 to 20%. In individuals carrying the c.199T>C or c.127G>A mutation on one allele, residual activities were much higher and in the range of heterozygotes (31%-60%). Therefore, both mutations cannot clearly be associated with a clinical phenotype. This demonstrates a correlation between the octanoyl-CoA oxidation rate in lymphocytes and the clinical outcome. With newborn screening, the natural course of disease is difficult to assess. The octanoyl-CoA oxidation rate, therefore, allows a risk assessment at birth and the identification of new ACADM genotypes associated with asymptomatic disease variants. PMID- 23028791 TI - Multiple loci associated with renal function in African Americans. AB - The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a two-fold higher rate than European Americans. One of the two defining variables underlying staging of chronic kidney disease is the glomerular filtration rate. Meta-analysis in individuals of European ancestry has identified 23 genetic loci associated with the estimated glomerular filtration rate (eGFR). We conducted a follow-up study of these 23 genetic loci using a population-based sample of 1,018 unrelated admixed African Americans. We included in our follow-up study two variants in APOL1 associated with end-stage kidney disease discovered by admixture mapping in admixed African Americans. To address confounding due to admixture, we estimated local ancestry at each marker and global ancestry. We performed regression analysis stratified by local ancestry and combined the resulting regression estimates across ancestry strata using an inverse variance-weighted fixed effects model. We found that 11 of the 24 loci were significantly associated with eGFR in our sample. The effect size estimates were not significantly different between the subgroups of individuals with two copies of African ancestry vs. two copies of European ancestry for any of the 11 loci. In contrast, allele frequencies were significantly different at 10 of the 11 loci. Collectively, the 11 loci, including four secondary signals revealed by conditional analyses, explained 14.2% of the phenotypic variance in eGFR, in contrast to the 1.4% explained by the 24 loci in individuals of European ancestry. Our findings provide insight into the genetic basis of variation in renal function among admixed African Americans. PMID- 23028792 TI - Consistent condom use increases the regression rate of cervical intraepithelial neoplasia 2-3. AB - OBJECTIVE: Cervical intraepithelial neoplasia grades 2-3 (CIN2-3) are usually treated by cone excision, although only 30% progress to cancer and 6-50% regress spontaneously. The aim of this study was to examine the influence of clinical factors like smoking habits, number of lifetime sexual partners, age at first sexual intercourse, sexual activity span and hormonal versus non-hormonal contraception type on the regression rate of CIN2-3. METHODS: In this prospective population-based cohort study 170 women aged 25-40 with abnormal cytology and colposcopy-directed biopsies showing first time onset CIN2-3 were consecutively included. The interval between biopsy and cone excision was standardized to minimum 12 weeks. Regression was defined as <= CIN1 in the cone biopsy. RESULTS: The regression rate was 22%. Consistent condom use, defined as those women whose partners used condoms for all instances of sexual intercourse, was infrequent (n=20, 12%). In univariate analysis consistent condom use, hormonal contraception and age at first sexual intercourse significantly predicted regression. In a multivariate analysis only consistent condom use remained as an independent predictor of regression (regression rate 55%, p=0.001, hazard ratio=4.4). CONCLUSION: Consistent condom use between punch biopsy and cone excision in first time onset CIN2-3 patients significantly increases the regression rate. PMID- 23028793 TI - Pharmacokinetics and biodistribution of a human monoclonal antibody to oxidized LDL in cynomolgus monkey using PET imaging. AB - PURPOSE: Oxidized low-density lipoprotein (LDL) plays an essential role in the pathogenesis of atherosclerosis. The purpose of this study was to characterize the pharmacokinetics (PK) of a human recombinant IgG1 antibody to oxidized LDL (anti-oxLDL) in cynomolgus monkey. The tissue biodistribution of anti-oxLDL was also investigated using positron emission tomography (PET) imaging. METHODS: Anti oxLDL was conjugated with the N-hydroxysuccinimide ester of DOTA (1,4,7,10 tetraazacyclododecane 1,4,7,10-tetraacetic acid) and radiolabeled by chelation of radioactive copper-64 ((64)Cu) for detection by PET. Anti-oxLDL was administered as a single intravenous (IV) dose of 10 mg/kg (as a mixture of radiolabeled and non-labeled material) to two male and two female cynomolgus monkeys. Serum samples were collected over 29 days. Two ELISA methods were used to measure serum concentrations of anti-oxLDL; Assay A was a ligand binding assay that measured free anti-oxLDL (unbound and partially bound forms) and Assay B measured total anti-oxLDL. The biodistribution was observed over a 48-hour period following dose administration using PET imaging. RESULTS: Anti-oxLDL serum concentration-time profiles showed a biphasic elimination pattern that could be best described by a two-compartment elimination model. The serum concentrations obtained using the two ELISA methods were comparable. Clearance values ranged from 8 to 17 ml/day/kg, while beta half-life ranged from 8 to 12 days. The initial volume of distribution and volume of distribution at steady state were approximately 55 mL/kg and 150 mL/kg, respectively. PET imaging showed distribution predominantly to the blood pool, visible as the heart and great vessels in the trunk and limbs, plus diffuse signals in the liver, kidney, spleen, and bone marrow. CONCLUSIONS: The clearance of anti-oxLDL is slightly higher than typical IgG1 antibodies in cynomolgus monkeys. The biodistribution pattern appears to be consistent with an antibody that has no large, rapid antigen sink outside the blood space. PMID- 23028794 TI - Effects of the sigma-1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3 phenylpropyl)-piperazine dihydro-chloride on inflammation after stroke. AB - Activation of the sigma-1 receptor (Sig-1R) improves functional recovery in models of experimental stroke and is known to modulate microglia function. The present study was conducted to investigate if Sig-1R activation after experimental stroke affects mediators of the inflammatory response in the ischemic hemisphere. Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (MCAO) and injected with the specific Sig-1R agonist 1 (3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) or saline for 5 days starting on day 2 after MCAO. Treatment did not affect the increased levels of the pro-inflammatory cytokines interleukin 1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 13 (IL-13) in the infarct core and peri-infarct area after MCAO. In addition, treatment with SA4503 did not affect elevated levels of nitrite, TNF-alpha and IL-1beta observed in primary cultures of microglia exposed to combined Hypoxia/Aglycemia, while the unspecific sigma receptor ligand 1,3-di-o-tolylguanidine (DTG) significantly decreased the production of nitrite and levels of TNF-alpha. Analysis of the ischemic hemisphere also revealed increased levels of ionized calcium binding adaptor molecule 1 (Iba1) levels in the infarct core of SA4503 treated animals. However, no difference in Iba1 immunoreactivity was detected in the infarct core. Also, levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and OX-42 were not increased in the infarct core in rats treated with SA4503. Together, our results suggest that sigma-1 receptor activation affects Iba1 expression in microglia/macrophages of the ischemic hemisphere after experimental stroke but does not affect post-stroke inflammatory mediators. PMID- 23028795 TI - Foraging ecology of fall-migrating shorebirds in the Illinois River valley. AB - Populations of many shorebird species appear to be declining in North America, and food resources at stopover habitats may limit migratory bird populations. We investigated body condition of, and foraging habitat and diet selection by 4 species of shorebirds in the central Illinois River valley during fall migrations 2007 and 2008 (Killdeer [Charadrius vociferus], Least Sandpiper [Calidris minutilla], Pectoral Sandpiper [Calidris melanotos], and Lesser Yellowlegs [Tringa flavipes]). All species except Killdeer were in good to excellent condition, based on size-corrected body mass and fat scores. Shorebird diets were dominated by invertebrate taxa from Orders Diptera and Coleoptera. Additionally, Isopoda, Hemiptera, Hirudinea, Nematoda, and Cyprinodontiformes contribution to diets varied by shorebird species and year. We evaluated diet and foraging habitat selection by comparing aggregate percent dry mass of food items in shorebird diets and core samples from foraging substrates. Invertebrate abundances at shorebird collection sites and random sites were generally similar, indicating that birds did not select foraging patches within wetlands based on invertebrate abundance. Conversely, we found considerable evidence for selection of some diet items within particular foraging sites, and consistent avoidance of Oligochaeta. We suspect the diet selectivity we observed was a function of overall invertebrate biomass (51.2 +/- 4.4 [SE] kg/ha; dry mass) at our study sites, which was greater than estimates reported in most other food selection studies. Diet selectivity in shorebirds may follow tenants of optimal foraging theory; that is, at low food abundances shorebirds forage opportunistically, with the likelihood of selectivity increasing as food availability increases. Nonetheless, relationships between the abundance, availability, and consumption of Oligochaetes for and by waterbirds should be the focus of future research, because estimates of foraging carrying capacity would need to be revised downward if Oligochaetes are truly avoided or unavailable for consumption. PMID- 23028796 TI - The erythropoietin/erythropoietin receptor signaling pathway promotes growth and invasion abilities in human renal carcinoma cells. AB - Co-expression of erythropoietin (Epo) and erythropoietin receptor (EpoR) has been found in various non-hematopoietic cancers including hereditary and sporadic renal cell carcinomas (RCC), but the Epo/EpoR autocrine and paracrine mechanisms in tumor progression have not yet been identified. In this study, we used RNA interference method to down-regulate EpoR to investigate the function of Epo/EpoR pathway in human RCC cells. Epo and EpoR co-expressed in primary renal cancer cells and 6 human RCC cell lines. EpoR signaling was constitutionally phosphorylated in primary renal cancer cells, 786-0 and Caki-1 cells, and recombinant human Epo (rhEpo) stimulation had no significant effects on further phosphorylation of EpoR pathway, proliferation, and invasiveness of the cells. Down-regulation of EpoR expression in 786-0 cells by lentivirus-introduced siRNA resulted in inhibition of growth and invasiveness in vitro and in vivo, and promotion of cell apoptosis. In addition, rhEpo stimulation slightly antagonized the anti-tumor effect of Sunitinib on 786-0 cells. Sunitinib could induce more apoptotic cells in 786-0 cells with knockdown EpoR expression. Our results suggested that Epo/EpoR pathway was involved in cell growth, invasion, survival, and sensitivity to the multi-kinases inhibitor Sunitinib in RCC cells. PMID- 23028797 TI - Ocean acidification accelerates reef bioerosion. AB - In the recent discussion how biotic systems may react to ocean acidification caused by the rapid rise in carbon dioxide partial pressure (pCO(2)) in the marine realm, substantial research is devoted to calcifiers such as stony corals. The antagonistic process - biologically induced carbonate dissolution via bioerosion - has largely been neglected. Unlike skeletal growth, we expect bioerosion by chemical means to be facilitated in a high-CO(2) world. This study focuses on one of the most detrimental bioeroders, the sponge Cliona orientalis, which attacks and kills live corals on Australia's Great Barrier Reef. Experimental exposure to lowered and elevated levels of pCO(2) confirms a significant enforcement of the sponges' bioerosion capacity with increasing pCO(2) under more acidic conditions. Considering the substantial contribution of sponges to carbonate bioerosion, this finding implies that tropical reef ecosystems are facing the combined effects of weakened coral calcification and accelerated bioerosion, resulting in critical pressure on the dynamic balance between biogenic carbonate build-up and degradation. PMID- 23028798 TI - Overexpression of class III beta tubulin and amplified HER2 gene predict good response to paclitaxel and trastuzumab therapy. AB - Through this study, we aimed to validate several biomarkers that have been known to possibly predict the outcomes of the trastuzumab and paclitaxel (TP). Human epidermal growth factor 2 (HER2) positive metastatic breast cancer (MBC) patients who had been treated with TP in single institute from 2006 to 2009 were included in this study. For procured formalin fixed paraffin embedded tumor tissues, HER2 amplification index (AI) and polymorphisms of the immunoglobulin G fragment C receptors (FCGR) were assessed as biomarkers to the trastuzumab and expression of class III beta tubulin (bTubIII) was evaluated as a predictive factor to the paclitaxel. Of 46 patients treated with TP, 27 patients could be evaluated for HER2 AI, 31 for bTubIII, and 26 for FCGR gene polymorphism. The median of the HER2 AI was 5.0 (range, 1.4-15.5) and a higher HER2 AI (>= 5.0) was significantly correlated with better response rate (RR) (80% vs. 42%, P=0.049) and longer progression-free survival (PFS) (13.6 vs. 6.9 months, P=0.023). High bTubIII expression showed higher RRs than did low expression (81% vs. 40%, P=0.040) in addition to longer PFS (16.2 months vs. 8.8 months, P=0.04). However, polymorphisms in FCGR 2A-H131R or FCGR 3A-V158F were not predictive of RR or PFS. Our results suggest that a high HER2 AI and high bTubIII expression could be predictive of the outcomes to TP therapy but no evidence was found in terms of FCGR polymorphisms. PMID- 23028799 TI - Role of single nucleotide polymorphisms of KIF1B gene in HBV-associated viral hepatitis. AB - BACKGROUND/AIM: Kinesin family member 1B (KIF1B) gene resides in the chromosomal region 1p36.22 and has been reported to have frequent deletions in a variety of human cancers. A recent genome wide association study (GWAS) study conducted on a Chinese population has reported the involvement of a KIF1B genetic variant in Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). This study aims to investigate the significance of KIF1B genetic variations in HBV-associated hepatitis in patients of Saudi Arabian ethnicity. METHODS: TaqMan genotyping assay was used to investigate the association of three SNPs (rs17401966, rs12734551, and rs3748578) in 584 normal healthy controls and 660 HBV-infected patients. The patients were categorized into inactive carriers (Case I), active carriers (Case II), Cirrhosis (Case III) and Cirrhosis-HCC (Case IV) sub-groups. RESULTS: Since SNPs rs12734551 and rs3748578 are in strong linkage disequilibrium (LD) with rs17401966, only results for the latter SNP are reported. Therefore, the allele frequency of rs17401966 among HBV-infected patients and healthy controls were comparable and therefore, no significant association was observed (P=0.2811, Odds Ratio (OR) 0.897). A similar analysis was performed among the different sub-groups in order to determine whether KIF1B SNPs were associated with the advancement of the disease. No significant differences were observed in any of the comparisons performed. CONCLUSION: Polymorphisms at KIF1B gene locus investigated in this study showed no significant association with HBV infection or with HBV-associated diseases such as liver cirrhosis or HCC. PMID- 23028800 TI - p53 Stabilization induces cell growth inhibition and affects IGF2 pathway in response to radiotherapy in adrenocortical cancer cells. AB - Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. However, it is generally fatal, with an overall survival of 5 years from detection. Radiotherapy usefulness for ACC treatment has been widely debated and seems to be dependent on molecular alterations, which in turn lead to increased radio-resistance. Many studies have shown that p53 loss is an important risk factor for malignant adrenocortical tumour onset and it has been reported that somatic mutations in TP53 gene occur in 27 to 70% of adult sporadic ACCs. In this study, we investigated the role of somatic mutations of the TP53 gene in response to ionizing radiation (IR). We studied the status of p53 in two adrenocortical cell lines, H295R and SW-13, harbouring non-functioning forms of this protein, owing to the lack of exons 8 and 9 and a point mutation in exon 6, respectively. Moreover, these cell lines show high levels of p-Akt and IGF2, especially H295R. We noticed that restoration of p53 activity led to inhibition of growth after transient transfection of cells with wild type p53. Evaluation of their response to IR in terms of cell proliferation and viability was determined by means of cell count and TUNEL assay.(wt)p53 over-expression also increased cell death by apoptosis following radiation in both cell lines. Moreover, RT-PCR and Western blotting analysis of some p53 target genes, such as BCL2, IGF2 and Akt demonstrated that p53 activation following IR led to a decrease in IGF2 expression. This was associated with a reduction in the active form of Akt. Taken together, these results highlight the role of p53 in response to radiation of ACC cell lines, suggesting its importance as a predictive factor for radiotherapy in malignant adrenocortical tumours cases. PMID- 23028801 TI - Acetylation-mediated suppression of transcription-independent memory: bidirectional modulation of memory by acetylation. AB - Learning induced changes in protein acetylation, mediated by histone acetyl transferases (HATs), and the antagonistic histone deacetylases (HDACs) play a critical role in memory formation. The status of histone acetylation affects the interaction between the transcription-complex and DNA and thus regulates transcription-dependent processes required for long-term memory (LTM). While the majority of studies report on the role of elevated acetylation in memory facilitation, we address the impact of both, increased and decreased acetylation on formation of appetitive olfactory memory in honeybees. We show that learning induced changes in the acetylation of histone H3 at aminoacid-positions H3K9 and H3K18 exhibit distinct and different dynamics depending on the training strength. A strong training that induces LTM leads to an immediate increase in acetylation at H3K18 that stays elevated for hours. A weak training, not sufficient to trigger LTM, causes an initial increase in acetylation at H3K18, followed by a strong reduction in acetylation at H3K18 below the control group level. Acetylation at position H3K9 is not affected by associative conditioning, indicating specific learning-induced actions on the acetylation machinery. Elevating acetylation levels by blocking HDACs after conditioning leads to an improved memory. While memory after strong training is enhanced for at least 2 days, the enhancement after weak training is restricted to 1 day. Reducing acetylation levels by blocking HAT activity after strong training leads to a suppression of transcription-dependent LTM. The memory suppression is also observed in case of weak training, which does not require transcription processes. Thus, our findings demonstrate that acetylation-mediated processes act as bidirectional regulators of memory formation that facilitate or suppress memory independent of its transcription-requirement. PMID- 23028802 TI - Opc expression, LPS immunotype switch and pilin conversion contribute to serum resistance of unencapsulated meningococci. AB - Neisseria meningitidis employs polysaccharides and outer membrane proteins to cope with human serum complement attack. To screen for factors influencing serum resistance, an assay was developed based on a colorimetric serum bactericidal assay. The screening used a genetically modified sequence type (ST)-41/44 clonal complex (cc) strain lacking LPS sialylation, polysaccharide capsule, the factor H binding protein (fHbp) and MutS, a protein of the DNA repair mechanism. After killing of >99.9% of the bacterial cells by serum treatment, the colorimetric assay was used to screen 1000 colonies, of which 35 showed enhanced serum resistance. Three mutant classes were identified. In the first class of mutants, enhanced expression of Opc was identified. Opc expression was associated with vitronectin binding and reduced membrane attack complex deposition confirming recent observations. Lipopolysaccharide (LPS) immunotype switch from immunotype L3 to L8/L1 by lgtA and lgtC phase variation represented the second class. Isogenic mutant analysis demonstrated that in ST-41/44 cc strains the L8/L1 immunotype was more serum resistant than the L3 immunotype. Consecutive analysis revealed that the immunotypes L8 and L1 were frequently observed in ST-41/44 cc isolates from both carriage and disease. Immunotype switch to L8/L1 is therefore suggested to contribute to the adaptive capacity of this meningococcal lineage. The third mutant class displayed a pilE allelic exchange associated with enhanced autoaggregation. The mutation of the C terminal hypervariable region D of PilE included a residue previously associated with increased pilus bundle formation. We suggest that autoaggregation reduced the surface area accessible to serum complement and protected from killing. The study highlights the ability of meningococci to adapt to environmental stress by phase variation and intrachromosomal recombination affecting subcapsular antigens. PMID- 23028803 TI - TSA suppresses miR-106b-93-25 cluster expression through downregulation of MYC and inhibits proliferation and induces apoptosis in human EMC. AB - Histone deacetylase (HDAC) inhibitors are emerging as a novel class of anti-tumor agents and have manifested the ability to decrease proliferation and increase apoptosis in different cancer cells. A significant number of genes have been identified as potential effectors responsible for the anti-tumor function of HDAC inhibitor. However, the molecular mechanisms of these HDAC inhibitors in this process remain largely undefined. In the current study, we searched for microRNAs (miRs) that were affected by HDAC inhibitor trichostatin (TSA) and investigated their effects in endometrial cancer (EMC) cells. Our data showed that TSA significantly inhibited the growth of EMC cells and induced their apoptosis. Among the miRNAs that altered in the presence of TSA, the miR-106b-93-25 cluster, together with its host gene MCM7, were obviously down-regulated in EMC cells. p21 and BIM, which were identified as target genes of miR-106b-93-25 cluster, increased in TSA treated tumor cells and were responsible for cell cycle arrest and apoptosis. We further identified MYC as a regulator of miR-106b-93-25 cluster and demonstrated its down-regulation in the presence of TSA resulted in the reduction of miR-106b-93-25 cluster and up-regulation of p21 and BIM. More important, we found miR-106b-93-25 cluster was up-regulated in clinical EMC samples in association with the overexpression of MCM7 and MYC and the down regulation of p21 and BIM. Thus our studies strongly indicated TSA inhibited EMC cell growth and induced cell apoptosis and cell cycle arrest at least partially through the down-regulation of the miR-106b-93-25 cluster and up-regulation of it's target genes p21 and BIM via MYC. PMID- 23028804 TI - Mitochondrial genomic analysis of late onset Alzheimer's disease reveals protective haplogroups H6A1A/H6A1B: the Cache County Study on Memory in Aging. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain. METHODOLOGY/PRINCIPAL FINDINGS: We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p=0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status. CONCLUSIONS/SIGNIFICANCE: Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary. PMID- 23028805 TI - The interaction of dipole modifiers with polyene-sterol complexes. AB - Recently, we showed that the effect of dipole modifiers (flavonoids and styrylpyridinium dyes) on the conductance of single amphotericin B (AmB) channels in sterol-containing lipid bilayers primarily resulted from changes in the membrane dipole potential. The present study examines the effect of dipole modifiers on the AmB multi-channel activity. The addition of phloretin to cholesterol-containing membranes leads to a significant increase in the steady state AmB-induced transmembrane current. Quercetin significantly decreases and RH 421 increases the current through ergosterol-containing bilayers. Other tested flavonoids and styrylpyridinium dyes do not affect the channel-forming activity of AmB independently on the sterol composition of the bilayers. The effects obtained in these trials may instead be attributed to the direct interaction of dipole modifiers with AmB/sterol complexes and not to the effect of dipole potential changes. The presence of double bonds in the Delta7 and Delta22 positions of sterol molecules, the number of conjugated double bonds and amino sugar residues in polyene molecules, and the conformation and adsorption plane of dipole modifiers are important factors impacting this interaction. PMID- 23028806 TI - Foreign RNA induces the degradation of mitochondrial antiviral signaling protein (MAVS): the role of intracellular antiviral factors. AB - Mitochondrial antiviral signaling protein (MAVS) is an essential adaptor molecule that is responsible for antiviral signaling triggered by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), leading to the induction of type I interferon in innate immunity. Previous studies have shown that certain viruses evade the innate immune response by cleaving the MAVS protein. However, little is known about how MAVS is regulated in response to foreign RNA, including both single-stranded (ss) and double-stranded (ds) RNA, because most previous reports have shown that the cleavage of MAVS is executed by proteases that are induced or activated by the invading RNA viruses. Here, we report that MAVS mRNA is degraded in response to polyinosinic-polycytidylic acid (polyI:C), a synthetic dsRNA, in A549 cells. RNA interference (RNAi) experiments revealed that both ssRNA- and dsRNA-associated pattern-recognition receptors (PRRs) were not involved in the degradation of MAVS mRNA. Foreign RNA also induced the transient degradation of the MAVS protein. In the resting state, the MAVS protein was protected from degradation by interferon regulatory factor 3 (IRF3); moreover, the dimerization of IRF3 appeared to be correlated with the rescue of protein degradation in response to polyI:C. The overexpression of MAVS enhanced interferon-beta (IFN beta) expression in response to polyI:C, suggesting that the degradation of MAVS contributes to the suppression of the hyper-immune reaction in late-phase antiviral signaling. Taken together, these results suggest that the comprehensive regulation of MAVS in response to foreign RNA may be essential to antiviral host defenses. PMID- 23028807 TI - Archaeobotanical study of ancient food and cereal remains at the Astana Cemeteries, Xinjiang, China. AB - Starch grain, phytolith and cereal bran fragments were analyzed in order to identify the food remains including cakes, dumplings, as well as porridge unearthed at the Astana Cemeteries in Turpan of Xinjiang, China. The results suggest that the cakes were made from Triticum aestivum while the dumplings were made from Triticum aestivum, along with Setaria italica. The ingredients of the porridge remains emanated from Panicum miliaceum. Moreover, direct macrobotantical evidence of the utilization of six cereal crops, such as Triticum aestivum, Hordeum vulgare var. coeleste, Panicum miliaceum, Setaria italica, Cannabis sativa, and Oryza sativa in the Turpan region during the Jin and Tang dynasties (about 3(rd) to 9(th) centuries) is also presented. All of these cereal crops not only provided food for the survival of the indigenous people, but also spiced up their daily life. PMID- 23028808 TI - Extended spectrum beta-lactamase-producing Enterobacteriaceae in international travelers and non-travelers in New York City. AB - BACKGROUND: We performed this study 1) to determine the prevalence of community associated extended spectrum beta-lactamase producing Enterobacteriaceae (ESBLPE) colonization and infection in New York City (NYC); 2) to determine the prevalence of newly-acquired ESBLPE during travel; 3) to look for similarities in contemporaneous hospital-associated bloodstream ESBLPE and travel-associated ESBLPE. METHODS: Subjects were recruited from a travel medicine practice and consented to submit pre- and post-travel stools, which were assessed for the presence of ESBLPE. Pre-travel stools and stools submitted for culture were used to estimate the prevalence of community-associated ESBLPE. The prevalence of ESBLPE-associated urinary tract infections was calculated from available retrospective data. Hospital-associated ESBLPE were acquired from saved bloodstream isolates. All ESBLPE underwent multilocus sequence typing (MLST) and ESBL characterization. RESULTS: One of 60 (1.7%) pre- or non-travel associated stool was colonized with ESBLPE. Among community-associated urine specimens, 1.3% of Escherichia coli and 1.4% of Klebsiella pneumoniae were identified as ESBLPE. Seven of 28 travelers (25.0%) acquired a new ESBLPE during travel. No similarities were found between travel-associated ESBLPE and hospital-associated ESBLPE. A range of imported ESBL genes were found, including CTX-M-14 and CTX-15. CONCLUSION: ESBL colonization and infection were relatively low during the study period in NYC. A significant minority of travelers acquired new ESBLPE during travel. PMID- 23028810 TI - Peer support and exclusive breastfeeding duration in low and middle-income countries: a systematic review and meta-analysis. AB - OBJECTIVE: To examine the effect of peer support on duration of exclusive breastfeeding (EBF) in low and middle-income countries (LMICs). DATA SOURCES: Medline, EMBASE, and Cochrane Central Register for Controlled Trials were searched from inception to April 2012. METHODS: Two authors independently searched, reviewed, and assessed the quality of randomized controlled trials utilizing peer support in LMICs. Meta-analysis and metaregression techniques were used to produce pooled relative risks and investigate sources of heterogeneity in the estimates. RESULTS: Eleven randomized controlled trials conducted at 13 study sites met the inclusion criteria for systematic review. We noted significant differences in study populations, peer counselor training methods, peer visit schedule, and outcome ascertainment methods. Peer support significantly decreased the risk of discontinuing EBF as compared to control (RR: 0.71; 95% CI: 0.61 0.82; I(2) =92%). The effect of peer support was significantly reduced in settings with >10% community prevalence of formula feeding as compared to settings with <10% prevalence (p=0.048). There was no evidence of effect modification by inclusion of low birth weight infants (p=0.367) and no difference in the effect of peer support on EBF at 4 versus 6 months postpartum (p=0.398). CONCLUSIONS: Peer support increases the duration of EBF in LMICs; however, the effect appears to be reduced in formula feeding cultures. Future studies are needed to determine the optimal timing of peer visits, how to best integrate peer support into packaged intervention strategies, and the effectiveness of supplemental interventions to peer support in formula feeding cultures. PMID- 23028809 TI - The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors. AB - Primary osteoporosis is an age-related disease characterized by an imbalance in bone homeostasis. While the resorptive aspect of the disease has been studied intensely, less is known about the anabolic part of the syndrome or presumptive deficiencies in bone regeneration. Multipotent mesenchymal stem cells (MSC) are the primary source of osteogenic regeneration. In the present study we aimed to unravel whether MSC biology is directly involved in the pathophysiology of the disease and therefore performed microarray analyses of hMSC of elderly patients (79-94 years old) suffering from osteoporosis (hMSC-OP). In comparison to age matched controls we detected profound changes in the transcriptome in hMSC-OP, e.g. enhanced mRNA expression of known osteoporosis-associated genes (LRP5, RUNX2, COL1A1) and of genes involved in osteoclastogenesis (CSF1, PTH1R), but most notably of genes coding for inhibitors of WNT and BMP signaling, such as Sclerostin and MAB21L2. These candidate genes indicate intrinsic deficiencies in self-renewal and differentiation potential in osteoporotic stem cells. We also compared both hMSC-OP and non-osteoporotic hMSC-old of elderly donors to hMSC of ~30 years younger donors and found that the transcriptional changes acquired between the sixth and the ninth decade of life differed widely between osteoporotic and non-osteoporotic stem cells. In addition, we compared the osteoporotic transcriptome to long term-cultivated, senescent hMSC and detected some signs for pre-senescence in hMSC-OP.Our results suggest that in primary osteoporosis the transcriptomes of hMSC populations show distinct signatures and little overlap with non-osteoporotic aging, although we detected some hints for senescence-associated changes. While there are remarkable inter-individual variations as expected for polygenetic diseases, we could identify many susceptibility genes for osteoporosis known from genetic studies. We also found new candidates, e.g. MAB21L2, a novel repressor of BMP-induced transcription. Such transcriptional changes may reflect epigenetic changes, which are part of a specific osteoporosis-associated aging process. PMID- 23028811 TI - Glucose intolerance and the amount of visceral adipose tissue contribute to an increase in circulating triglyceride concentrations in Caucasian obese females. AB - CONTEXT: Lipotoxicity is a risk factor for developing obesity-related metabolic complications, including non-alcoholic fatty liver disease, type 2 diabetes (DM2), cardiovascular disease and stroke. Yet, the mechanisms underlying the development of lipotoxicity itself remain poorly understood. Here, we investigated whether glucose intolerance aggravates lipotoxicity by evaluating the association between triglyceride (TG) concentrations and glucose tolerance status in a cross-sectional study on obese Caucasian women at risk for DM2. METHODS: 913 obese females unknown to have diabetes were recruited (mean age: 41.2 +/- SD 12.3; median BMI: 36.2, IQR 32.9-40.2). Visceral (VAT) and subcutaneous abdominal adipose tissue volumes were quantified with computed tomography. Glucose, insulin, and triglyceride concentrations were determined in fasting state and following a 75 gram oral glucose tolerance test. RESULTS: Based on fasting and 2 h post-load glucose levels, 27% of the women had impaired glucose tolerance (IGT), and 8% had newly diagnosed DM2. Fasting TG concentrations were similar between the IGT- and DM2-groups, and increased as compared to women with normal glucose tolerance (NGT). Even when adjusting for age, hip circumference and VAT, fasting TG concentrations remained elevated as compared to NGT. Mixed modelling analysis of post-load responses showed that TG concentrations declined more slowly in the DM2-group as compared to IGT and NGT. However, when adjusting for VAT the difference in decline between the glucose tolerance groups disappeared. CONCLUSIONS: Glucose intolerance associates with elevated fasting TG concentrations in obese Caucasian women. We propose that glucose intolerance and increased VAT reduce lipid disposal mechanisms and may accelerate lipotoxicity. PMID- 23028812 TI - Western Australian marsupials are multiply infected with genetically diverse strains of Toxoplasma gondii. AB - Five different organs from 16 asymptomatic free-ranging marsupial macropods (Macropus rufus, M. fuliginosus, and M. robustus) from inland Western Australia were tested for infection with Toxoplasma gondii by multi-locus PCR-DNA sequencing. All macropods were infected with T. gondii, and 13 had parasite DNA in at least 2 organs. In total, 45 distinct T. gondii genotypes were detected. Fourteen of the 16 macropods were multiply infected with genetically distinct T. gondii genotypes that often partitioned between different organs. The presence of multiple T. gondii infections in macropods suggests that native mammals have the potential to promote regular cycles of sexual reproduction in the definitive felid host in this environment. PMID- 23028813 TI - Two goose-type lysozymes in Mytilus galloprovincialis: possible function diversification and adaptive evolution. AB - Two goose-type lysozymes (designated as MGgLYZ1 and MGgLYZ2) were identified from the mussel Mytilus galloprovincialis. MGgLYZ1 mRNA was widely expressed in the examined tissues and responded sensitively to bacterial challenge in hemocytes, while MGgLYZ2 mRNA was predominately expressed and performed its functions in hepatopancreas. However, immunolocalization analysis showed that both these lysozymes were expressed in all examined tissues with the exception of adductor muscle. Recombinant MGgLYZ1 and MGgLYZ2 could inhibit the growth of several Gram positive and Gram-negative bacteria, and they both showed the highest activity against Pseudomonas putida with the minimum inhibitory concentration (MIC) of 0.95-1.91 uM and 1.20-2.40 uM, respectively. Protein sequences analysis revealed that MGgLYZ2 had lower isoelectric point and less protease cutting sites than MGgLYZ1. Recombinant MGgLYZ2 exhibited relative high activity at acidic pH of 4 5, while MGgLYZ1 have an optimum pH of 6. These results indicated MGgLYZ2 adapted to acidic environment and perhaps play an important role in digestion. Genomic structure analysis suggested that both MGgLYZ1 and MGgLYZ2 genes are composed of six exons with same length and five introns, indicating these genes were conserved and might originate from gene duplication during the evolution. Selection pressure analysis showed that MGgLYZ1 was under nearly neutral selection while MGgLYZ2 evolved under positive selection pressure with three positively selected amino acid residues (Y(102), L(200) and S(202)) detected in the mature peptide. All these findings suggested MGgLYZ2 perhaps served as a digestive lysozyme under positive selection pressure during the evolution while MGgLYZ1 was mainly involved in innate immune responses. PMID- 23028814 TI - Sequences located within the N-terminus of the PD-linked LRRK2 lead to increased aggregation and attenuation of 6-hydroxydopamine-induced cell death. AB - Clinical symptoms of Parkinson's disease (PD) arise from the loss of substantia nigra neurons resulting in bradykinesia, rigidity, and tremor. Intracellular protein aggregates are a pathological hallmark of PD, but whether aggregates contribute to disease progression or represent a protective mechanism remains unknown. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been linked to PD in both familial cases and idiopathic cases and aggregates of the LRRK2 protein are present in postmortem PD brain samples. To determine whether LRRK2 contains a region of protein responsible for self-aggregation, two independent, bioinformatic algorithms were used to identify an N-terminal amino acid sequence as being aggregation-prone. Cells subsequently transfected with a construct containing this domain were found to have significantly increased protein aggregation compared to wild type protein or a construct containing only the last half of the molecule. Finally, in support of the hypothesis that aggregates represent a self-protection strategy, aggregated N-terminal LRRK2 constructs significantly attenuated cell death induced by the PD-mimetic, 6 hydroxydopamine (6-OHDA). PMID- 23028815 TI - RAI1 transcription factor activity is impaired in mutants associated with Smith Magenis Syndrome. AB - Smith-Magenis Syndrome (SMS) is a complex genomic disorder mostly caused by the haploinsufficiency of the Retinoic Acid Induced 1 gene (RAI1), located in the chromosomal region 17p11.2. In a subset of SMS patients, heterozygous mutations in RAI1 are found. Here we investigate the molecular properties of these mutated forms and their relationship with the resulting phenotype. We compared the clinical phenotype of SMS patients carrying a mutation in RAI1 coding region either in the N-terminal or the C-terminal half of the protein and no significant differences were found. In order to study the molecular mechanism related to these two groups of RAI1 mutations first we analyzed those mutations that result in the truncated protein corresponding to the N-terminal half of RAI1 finding that they have cytoplasmic localization (in contrast to full length RAI1) and no ability to activate the transcription through an endogenous target: the BDNF enhancer. Similar results were found in lymphoblastoid cells derived from a SMS patient carrying RAI1 c.3103insC, where both mutant and wild type products of RAI1 were detected. The wild type form of RAI1 was found in the chromatin bound and nuclear matrix subcellular fractions while the mutant product was mainly cytoplasmic. In addition, missense mutations at the C-terminal half of RAI1 presented a correct nuclear localization but no activation of the endogenous target. Our results showed for the first time a correlation between RAI1 mutations and abnormal protein function plus they suggest that a reduction of total RAI1 transcription factor activity is at the heart of the SMS clinical presentation. PMID- 23028817 TI - Changes in sedimentary redox associated with mussel (Mytilus edulis L.) farms on the west-coast of Scotland. AB - Aquaculture is growing rapidly in response to an increasing demand for protein and the over-exploitation of wild fisheries. Mussel (family Mytilidae) production has doubled over the last decade and currently stands at 1.5 million tones production per annum. Mussels produce organic biodeposits which are dispersed around the production site and, potentially, impact the receiving environment in a number of inter-linked ways. The reported benthic impacts that occur, primarily through the accumulation of these biodeposits and associated organic enrichment, vary widely between studies. The objectives of this research were to determine the nature of the relationship between sediment redox (a proxy for oxygenation) and farm-proximity and covariables whilst accounting for, and quantifying, differences in redox between sites. Sediment cores (N = 159) were taken remotely around a random sample of mussel farms, redox was measured at 10 mm sediment depth and linked to farm-distance and sediment organic/shell content and particle size, using an additive, mixed, weighted regression model. Redox varied considerably between sites and there was a highly significant reduction (50 mV) in redox adjacent to the mussel lines. Redox increased non-linearly with distance, rising rapidly at >7 m from the farm edge. The modest reduction in sediment oxygenation in close proximity to mussel farms reported here suggests that farms located over sediments characterised by pre-existing oxygen stress are likely to exacerbate benthic species impoverishment associated with reducing sedimentary conditions whilst those located over highly oxygenated sediments are likely to increase benthic productivity. PMID- 23028816 TI - A conserved motif in the ITK PH-domain is required for phosphoinositide binding and TCR signaling but dispensable for adaptor protein interactions. AB - Binding of the membrane phospholipid phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) to the Pleckstrin Homology (PH) domain of the Tec family protein tyrosine kinase, Inducible T cell Kinase (ITK), is critical for the recruitment of the kinase to the plasma membrane and its co-localization with the TCR-CD3 molecular complex. Three aromatic residues, termed the FYF motif, located in the inner walls of the phospholipid-binding pocket of the ITK PH domain, are conserved in the PH domains of all Tec kinases, but not in other PH-domain containing proteins, suggesting an important function of the FYF motif in the Tec kinase family. However, the biological significance of the FYF amino acid motif in the ITK-PH domain is unknown. To elucidate it, we have tested the effects of a FYF triple mutant (F26S, Y90F, F92S), henceforth termed FYF-ITK mutant, on ITK function. We found that FYF triple mutation inhibits the TCR-induced production of IL-4 by impairing ITK binding to PIP(3), reducing ITK membrane recruitment, inducing conformational changes at the T cell-APC contact site, and compromising phosphorylation of ITK and subsequent phosphorylation of PLCgamma(1). Interestingly, however, the FYF motif is dispensable for the interaction of ITK with two of its signaling partners, SLP-76 and LAT. Thus, the FYF mutation uncouples PIP(3)-mediated ITK membrane recruitment from the interactions of the kinase with key components of the TCR signalosome and abrogates ITK function in T cells. PMID- 23028818 TI - The unique GGA clathrin adaptor of Drosophila melanogaster is not essential. AB - The Golgi-localized, gamma-ear-containing, ARF binding proteins (GGAs) are a highly conserved family of monomeric clathrin adaptor proteins implicated in clathrin-mediated protein sorting between the trans-Golgi network and endosomes. GGA RNAi knockdowns in Drosophila have resulted in conflicting data concerning whether the Drosophila GGA (dGGA) is essential. The goal of this study was to define the null phenotype for the unique Drosophila GGA. We describe two independently derived dGGA mutations. Neither allele expresses detectable dGGA protein. Homozygous and hemizygous flies with each allele are viable and fertile. In contrast to a previous report using RNAi knockdown, GGA mutant flies show no evidence of age-dependent retinal degeneration or cathepsin missorting. Our results demonstrate that several of the previous RNAi knockdown phenotypes were the result of off-target effects. However, GGA null flies are hypersensitive to dietary chloroquine and to starvation, implicating GGA in lysosomal function and autophagy. PMID- 23028819 TI - Low bone strength is a manifestation of phenylketonuria in mice and is attenuated by a glycomacropeptide diet. AB - PURPOSE: Phenylketonuria (PKU), caused by phenylalanine (phe) hydroxylase loss of function mutations, requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP), a low-phe whey protein, provides a palatable alternative to AA formula. Skeletal fragility is a poorly understood chronic complication of PKU. We sought to characterize the impact of the PKU genotype and dietary protein source on bone biomechanics. PROCEDURES: Wild type (WT; Pah(+/+)) and PKU (Pah(enu2/enu2)) mice on a C57BL/6J background were fed high-phe casein, low-phe AA, and low-phe GMP diets between 3 to 23 weeks of age. Following euthanasia, femur biomechanics were assessed by 3-point bending and femoral diaphyseal structure was determined. Femoral ex vivo bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry. Whole bone parameters were used in principal component analysis. Data were analyzed by 3-way ANCOVA with genotype, sex, and diet as the main factors. FINDINGS: Regardless of diet and sex, PKU femora were more brittle, as manifested by lower post-yield displacement, weaker, as manifested by lower energy and yield and maximal loads, and showed reduced BMD compared with WT femora. Four principal components accounted for 87% of the variance and all differed significantly by genotype. Regardless of genotype and sex, the AA diet reduced femoral cross-sectional area and consequent maximal load compared with the GMP diet. CONCLUSIONS: Skeletal fragility, as reflected in brittle and weak femora, is an inherent feature of PKU. This PKU bone phenotype is attenuated by a GMP diet compared with an AA diet. PMID- 23028820 TI - Is telomere length a biomarker for aging: cross-sectional evidence from the west of Scotland? AB - BACKGROUND: The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure. METHODOLOGY/PRINCIPAL FINDINGS: Using data from a large population based study, we show that telomere length is associated with age, with several measures of physical and cognitive functioning that are related to normal aging, and with three measures of overall health. In the majority of cases, telomere length adds predictive power to that of age, although it was not nearly as good a predictor overall. We used principal components analysis to form two composites from the measures of functioning, one including telomere length and the other not including it. These composite BoAs were better predictors of the health outcomes than chronological age. There was little difference between the two composites. CONCLUSIONS: Telomere length does not satisfy the strict criteria for a BoA, but does add predictive power to that of chronological age. Equivocal results from previous studies might be due to lack of power or the choice of measures examined together with a focus on single biomarkers. Composite biomarkers of aging have the potential to outperform age and should be considered for future research in this area. PMID- 23028821 TI - An obligate role of oxytocin neurons in diet induced energy expenditure. AB - Oxytocin neurons represent one of the major subsets of neurons in the paraventricular hypothalamus (PVH), a critical brain region for energy homeostasis. Despite substantial evidence supporting a role of oxytocin in body weight regulation, it remains controversial whether oxytocin neurons directly regulate body weight homeostasis, feeding or energy expenditure. Pharmacologic doses of oxytocin suppress feeding through a proposed melanocortin responsive projection from the PVH to the hindbrain. In contrast, deficiency in oxytocin or its receptor leads to reduced energy expenditure without feeding abnormalities. To test the physiological function of oxytocin neurons, we specifically ablated oxytocin neurons in adult mice. Our results show that oxytocin neuron ablation in adult animals has no effect on body weight, food intake or energy expenditure on a regular diet. Interestingly, male mice lacking oxytocin neurons are more sensitive to high fat diet-induced obesity due solely to reduced energy expenditure. In addition, despite a normal food intake, these mice exhibit a blunted food intake response to leptin administration. Thus, our study suggests that oxytocin neurons are required to resist the obesity associated with a high fat diet; but their role in feeding is permissive and can be compensated for by redundant pathways. PMID- 23028822 TI - Accuracy and user-acceptability of HIV self-testing using an oral fluid-based HIV rapid test. AB - BACKGROUND: The United States FDA approved an over-the-counter HIV self-test, to facilitate increased HIV testing and earlier linkage to care. We assessed the accuracy of self-testing by untrained participants compared to healthcare worker (HCW) testing, participants' ability to interpret sample results and user acceptability of self-tests in Singapore. METHODOLOGY/PRINCIPAL FINDINGS: A cross sectional study, involving 200 known HIV-positive patients and 794 unknown HIV status at-risk participants was conducted. Participants (all without prior self test experience) performed self-testing guided solely by visual instructions, followed by HCW testing, both using the OraQuick ADVANCE Rapid HIV 1/2 Antibody Test, with both results interpreted by the HCW. To assess ability to interpret results, participants were provided 3 sample results (positive, negative, and invalid) to interpret. Of 192 participants who tested positive on HCW testing, self-testing was positive in 186 (96.9%), negative in 5 (2.6%), and invalid in 1 (0.5%). Of 794 participants who tested negative on HCW testing, self-testing was negative in 791 (99.6%), positive in 1 (0.1%), and invalid in 2 (0.3%). Excluding invalid tests, self-testing had sensitivity of 97.4% (95% CI 95.1% to 99.7%) and specificity of 99.9% (95% CI: 99.6% to 100%). When interpreting results, 96%, 93.1% and 95.2% correctly read the positive, negative and invalid respectively. There were no significant demographic predictors for false negative self-testing or wrongly interpreting positive or invalid sample results as negative. Eighty seven percent would purchase the kit over-the-counter; 89% preferred to take HIV tests in private. 72.5% and 74.9% felt the need for pre- and post-test counseling respectively. Only 28% would pay at least USD15 for the test. CONCLUSIONS/SIGNIFICANCE: Self-testing was associated with high specificity, and a small but significant number of false negatives. Incorrectly identifying model results as invalid was a major reason for incorrect result interpretation. Survey responses were supportive of making self-testing available. PMID- 23028823 TI - Rescue the failed half-ZFN by a sensitive mammalian cell-based luciferase reporter system. AB - ZFN technology is a powerful research tool and has been used for genome editing in cells lines, animals and plants. The generation of functional ZFNs for particular targets in mammalian genome is still challenging for an average research group. The modular-assembly method is relatively fast, easy-to-practice but has a high failure rate. Some recent studies suggested that a ZFP with low binding activity might be able to form a working ZFN pair with another binding active half-ZFP. In order to unveil the potential ZFP candidates among those with low binding activities, this paper established a highly sensitive mammalian cell based transcriptional reporter system to assess the DNA binding activities of ZFPs by inserting multiple copies of ZFN target sequence fragment (TSF) of an interested gene (e. g., hPGRN or hVEGF). Our results showed that this system increased the screening sensitivity up to 50-fold and markedly amplified the differences in the binding activities between different ZFPs. We also found that the targeted chromosomal gene repair efficiency of each hPGRN or hVEGF ZFN pair was in proportion with the combination of the binding activities of the ZFL (Left zinc finger) and ZFR (Right zinc finger). A hPGRN ZFR with low binding ability was able to form a biological active ZFN if combined with a hPGRN ZFL with relatively high binding ability. Lastly, site-specific genome editing by hPGRN ZFNs generated by this system was confirmed by sequencing, and the PGRN knock-out cell line showed significantly decreased cell growth compared with the control. Our system will provide a valuable tool for further optimizing the nucleases with regard to specificity and cytotoxicity. PMID- 23028824 TI - Sex bias in susceptibility to MCMV infection: implication of TLR9. AB - Toll-like receptor (TLR)-dependent pathways control the activation of various immune cells and the production of cytokines and chemokines that are important in innate immune control of viruses, including mouse cytomegalovirus (MCMV). Here we report that upon MCMV infection wild-type and TLR7(-/-) male mice were more resistant than their female counterparts, while TLR9(-/-) male and female mice showed similar susceptibility. Interestingly, 36 h upon MCMV infection TLR9 mRNA expression was higher in male than in female mouse spleens. MCMV infection led to stronger reduction of marginal zone (MZ) B cells, and higher infiltration of plasmacytoid dendritic cells and neutrophils in wild-type male than female mice, while no such sex differences were observed in TLR9(-/-) mice. In accordance, the serum levels of KC and MIP-2, major neutrophil chemoattractants, were higher in wild-type, but not in TLR9(-/-), male versus female mice. Wild-type MCMV-infected female mice showed more severe liver inflammation, necrosis and steatosis compared to infected male mice. Our data demonstrate sex differences in susceptibility to MCMV infection, accompanied by a lower activation of the innate immune system in female mice, and can be attributed, at least in a certain degree, to the lower expression of TLR9 in female than male mice. PMID- 23028826 TI - Stem cell selection in vivo using foamy vectors cures canine pyruvate kinase deficiency. AB - BACKGROUND: Hematopoietic stem cell (HSC) gene therapy has cured immunodeficiencies including X-linked severe combined immunodeficiency (SCID-X1) and adenine deaminase deficiency (ADA). For these immunodeficiencies corrected cells have a selective advantage in vivo, and low numbers of gene-modified cells are sufficient to provide therapeutic benefit. Strategies to efficiently transduce and/or expand long-term repopulating cells in vivo are needed for treatment of diseases that require higher levels of corrected cells, such as hemoglobinopathies. Here we expanded corrected stem cells in vivo in a canine model of a severe erythroid disease, pyruvate kinase deficiency. METHODOLOGY/PRINCIPAL FINDINGS: We used a foamy virus (FV) vector expressing the P140K mutant of methylguanine methyltransferase (MGMTP140K) for in vivo expansion of corrected hematopoietic repopulating cells. FV vectors are attractive gene transfer vectors for hematopoietic stem cell gene therapy since they efficiently transduce repopulating cells and may be safer than more commonly used gammaretroviral vectors. Following transplantation with HSCs transduced ex vivo using a tri-cistronic FV vector that expressed EGFP, R-type pyruvate kinase, and MGMTP140K, we were able to increase marking from approximately 3.5% to 33% in myeloid long-term repopulating cells resulting in a functional cure. CONCLUSIONS/SIGNIFICANCE: Here we describe in one affected dog a functional cure for a severe erythroid disease using stem cell selection in vivo. In addition to providing a potential cure for patients with pyruvate kinase deficiency, in vivo selection using foamy vectors with MGMTP140K has broad potential for several hematopoietic diseases including hemoglobinopathies. PMID- 23028825 TI - Plasma membrane phosphatidylinositol 4,5 bisphosphate is required for internalization of foot-and-mouth disease virus and vesicular stomatitis virus. AB - Phosphatidylinositol-4,5-bisphosphate, PI(4,5)P(2), is a phospholipid which plays important roles in clathrin-mediated endocytosis. To investigate the possible role of this lipid on viral entry, two viruses important for animal health were selected: the enveloped vesicular stomatitis virus (VSV) - which uses a well characterized clathrin mediated endocytic route - and two different variants of the non-enveloped foot-and-mouth disease virus (FMDV) with distinct receptor specificities. The expression of a dominant negative dynamin, a PI(4,5)P(2) effector protein, inhibited the internalization and infection of VSV and both FMDV isolates. Depletion of PI(4,5)P(2) from plasma membrane using ionomycin or an inducible system, and inhibition of its de novo synthesis with 1-butanol revealed that VSV as well as FMDV C-S8c1, which uses integrins as receptor, displayed a high dependence on PI(4,5)P(2) for internalization. Expression of a kinase dead mutant (KD) of phosphatidylinositol-4-phosphate-5-kinase Ialpha (PIP5K-Ialpha), an enzyme responsible for PI(4,5)P(2) synthesis that regulates clathrin-dependent endocytosis, also impaired entry and infection of VSV and FMDV C-S8c1. Interestingly FMDV MARLS variant that uses receptors other than integrins for cell entry was less sensitive to PI(4,5)P(2) depletion, and was not inhibited by the expression of the KD PIP5K-Ialpha mutant suggesting the involvement of endocytic routes other than the clathrin-mediated on its entry. These results highlight the role of PI(4,5)P(2) and PIP5K-Ialpha on clathrin-mediated viral entry. PMID- 23028827 TI - The zebrafish homologue of the human DYT1 dystonia gene is widely expressed in CNS neurons but non-essential for early motor system development. AB - DYT1 dystonia is caused by mutation of the TOR1A gene, resulting in the loss of a single glutamic acid residue near the carboxyl terminal of TorsinA. The neuronal functions perturbed by TorsinA[DeltaE] are a major unresolved issue in understanding the pathophysiology of dystonia, presenting a critical roadblock to developing effective treatments. We identified and characterized the zebrafish homologue of TOR1A, as a first step towards elucidating the functions of TorsinA in neurons, in vivo, using the genetically-manipulable zebrafish model. The zebrafish genome was found to contain a single alternatively-spliced tor1 gene, derived from a common ancestral locus shared with the dual TOR1A and TOR1B paralogues found in tertrapods. tor1 was expressed ubiquitously during early embryonic development and in multiple adult tissues, including the CNS. The 2.1 kb tor1 mRNA encodes Torsin1, which is 59% identical and 78% homologous to human TorsinA. Torsin1 was expressed as major 45 kDa and minor 47 kDa glycoproteins, within the cytoplasm of neurons and neuropil throughout the CNS. Similar to previous findings relating to human TorsinA, mutations of the ATP hydrolysis domain of Torsin1 resulted in relocalization of the protein in cultured cells from the endoplasmic reticulum to the nuclear envelope. Zebrafish embryos lacking tor1 during early development did not show impaired viability, overt morphological abnormalities, alterations in motor behavior, or developmental defects in the dopaminergic system. Torsin1 is thus non-essential for early development of the motor system, suggesting that important CNS functions may occur later in development, consistent with the critical time window in late childhood when dystonia symptoms usually emerge in DYT1 patients. The similarities between Torsin1 and human TorsinA in domain organization, expression pattern, and cellular localization suggest that the zebrafish will provide a useful model to understand the neuronal functions of Torsins in vivo. PMID- 23028829 TI - A symmetric region of the HIV-1 integrase dimerization interface is essential for viral replication. AB - HIV-1 integrase (IN) is an important target for contemporary antiretroviral drug design research. Historically, efforts at inactivating the enzyme have focused upon blocking its active site. However, it has become apparent that new classes of allosteric inhibitors will be necessary to advance the antiretroviral field in light of the emergence of viral strains resistant to contemporary clinically used IN drugs. In this study we have characterized the importance of a close network of IN residues, distant from the active site, as important for the obligatory multimerization of the enzyme and viral replication as a whole. Specifically, we have determined that the configuration of six residues within a highly symmetrical region at the IN dimerization interface, composed of a four-tiered aromatic interaction flanked by two salt bridges, significantly contributes to proper HIV-1 replication. Additionally, we have utilized a quantitative luminescence assay to examine IN oligomerization and have determined that there is a very low tolerance for amino acid substitutions along this region. Even conservative residue substitutions negatively impacted IN multimerization, resulting in an inactive viral enzyme and a non-replicative virus. We have shown that there is a very low tolerance for amino acid variation at the symmetrical dimeric interface region characterized in this study, and therefore drugs designed to target the amino acid network detailed here could be expected to yield a significantly reduced number of drug-resistant escape mutations compared to contemporary clinically-evaluated antiretrovirals. PMID- 23028828 TI - Cost effectiveness of screening strategies for early identification of HIV and HCV infection in injection drug users. AB - OBJECTIVE: To estimate the cost, effectiveness, and cost effectiveness of HIV and HCV screening of injection drug users (IDUs) in opioid replacement therapy (ORT). DESIGN: Dynamic compartmental model of HIV and HCV in a population of IDUs and non-IDUs for a representative U.S. urban center with 2.5 million adults (age 15 59). METHODS: We considered strategies of screening individuals in ORT for HIV, HCV, or both infections by antibody or antibody and viral RNA testing. We evaluated one-time and repeat screening at intervals from annually to once every 3 months. We calculated the number of HIV and HCV infections, quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). RESULTS: Adding HIV and HCV viral RNA testing to antibody testing averts 14.8 30.3 HIV and 3.7-7.7 HCV infections in a screened population of 26,100 IDUs entering ORT over 20 years, depending on screening frequency. Screening for HIV antibodies every 6 months costs $30,700/QALY gained. Screening for HIV antibodies and viral RNA every 6 months has an ICER of $65,900/QALY gained. Strategies including HCV testing have ICERs exceeding $100,000/QALY gained unless awareness of HCV-infection status results in a substantial reduction in needle-sharing behavior. DISCUSSION: Although annual screening for antibodies to HIV and HCV is modestly cost effective compared to no screening, more frequent screening for HIV provides additional benefit at less cost. Screening individuals in ORT every 3-6 months for HIV infection using both antibody and viral RNA technologies and initiating ART for acute HIV infection appears cost effective. PMID- 23028830 TI - An accurate prostate cancer prognosticator using a seven-gene signature plus Gleason score and taking cell type heterogeneity into account. AB - One of the major challenges in the development of prostate cancer prognostic biomarkers is the cellular heterogeneity in tissue samples. We developed an objective Cluster-Correlation (CC) analysis to identify gene expression changes in various cell types that are associated with progression. In the Cluster step, samples were clustered (unsupervised) based on the expression values of each gene through a mixture model combined with a multiple linear regression model in which cell-type percent data were used for decomposition. In the Correlation step, a Chi-square test was used to select potential prognostic genes. With CC analysis, we identified 324 significantly expressed genes (68 tumor and 256 stroma cell expressed genes) which were strongly associated with the observed biochemical relapse status. Significance Analysis of Microarray (SAM) was then utilized to develop a seven-gene classifier. The Classifier has been validated using two independent Data Sets. The overall prediction accuracy and sensitivity is 71% and 76%, respectively. The inclusion of the Gleason sum to the seven-gene classifier raised the prediction accuracy and sensitivity to 83% and 76% respectively based on independent testing. These results indicated that our prognostic model that includes cell type adjustments and using Gleason score and the seven-gene signature has some utility for predicting outcomes for prostate cancer for individual patients at the time of prognosis. The strategy could have applications for improving marker performance in other cancers and other diseases. PMID- 23028831 TI - Cardiovascular responses to chemical stimulation of the hypothalamic arcuate nucleus in the rat: role of the hypothalamic paraventricular nucleus. AB - The mechanism of cardiovascular responses to chemical stimulation of the hypothalamic arcuate nucleus (ARCN) was studied in urethane-anesthetized adult male Wistar rats. At the baseline mean arterial pressure (BLMAP) close to normal, ARCN stimulation elicited decreases in MAP and sympathetic nerve activity (SNA). The decreases in MAP elicited by ARCN stimulation were attenuated by either gamma aminobutyric acid (GABA), neuropeptide Y (NPY), or beta-endorphin receptor blockade in the ipsilateral hypothalamic paraventricular nucleus (PVN). Combined blockade of GABA-A, NPY1 and opioid receptors in the ipsilateral PVN converted the decreases in MAP and SNA to increases in these variables. Conversion of inhibitory effects on the MAP and SNA to excitatory effects following ARCN stimulation was also observed when the BLMAP was decreased to below normal levels by an infusion of sodium nitroprusside. The pressor and tachycardic responses to ARCN stimulation at below normal BLMAP were attenuated by blockade of melanocortin 3/4 (MC3/4) receptors in the ipsilateral PVN. Unilateral blockade of GABA-A receptors in the ARCN increased the BLMAP and heart rate (HR) revealing tonic inhibition of the excitatory neurons in the ARCN. ARCN stimulation elicited tachycardia regardless of the level of BLMAP. ARCN neurons projecting to the PVN were immunoreactive for glutamic acid decarboxylase 67 (GAD67), NPY, and beta endorphin. These results indicated that: 1) at normal BLMAP, decreases in MAP and SNA induced by ARCN stimulation were mediated via GABA-A, NPY1 and opioid receptors in the PVN, 2) lowering of BLMAP converted decreases in MAP following ARCN stimulation to increases in MAP, and 3) at below normal BLMAP, increases in MAP and HR induced by ARCN stimulation were mediated via MC3/4 receptors in the PVN. These results provide a base for future studies to explore the role of ARCN in cardiovascular diseases. PMID- 23028832 TI - Idebenone protects against retinal damage and loss of vision in a mouse model of Leber's hereditary optic neuropathy. AB - Leber's hereditary optic neuropathy (LHON) is an inherited disease caused by mutations in complex I of the mitochondrial respiratory chain. The disease is characterized by loss of central vision due to retinal ganglion cell (RGC) dysfunction and optic nerve atrophy. Despite progress towards a better understanding of the disease, no therapeutic treatment is currently approved for this devastating disease. Idebenone, a short-chain benzoquinone, has shown promising evidence of efficacy in protecting vision loss and in accelerating recovery of visual acuity in patients with LHON. It was therefore of interest to study suitable LHON models in vitro and in vivo to identify anatomical correlates for this protective activity. At nanomolar concentrations, idebenone protected the rodent RGC cell line RGC-5 against complex I dysfunction in vitro. Consistent with the reported dosing and observed effects in LHON patients, we describe that in mice, idebenone penetrated into the eye at concentrations equivalent to those which protected RGC-5 cells from complex I dysfunction in vitro. Consequently, we next investigated the protective effect of idebenone in a mouse model of LHON, whereby mitochondrial complex I dysfunction was caused by exposure to rotenone. In this model, idebenone protected against the loss of retinal ganglion cells, reduction in retinal thickness and gliosis. Furthermore, consistent with this protection of retinal integrity, idebenone restored the functional loss of vision in this disease model. These results support the pharmacological activity of idebenone and indicate that idebenone holds potential as an effective treatment for vision loss in LHON patients. PMID- 23028833 TI - The role of alpha-synuclein in melanin synthesis in melanoma and dopaminergic neuronal cells. AB - The relatively high co-occurrence of Parkinson's disease (PD) and melanoma has been established by a large number of epidemiological studies. However, a clear biological explanation for this finding is still lacking. Ultra-violet radiation (UVR)-induced skin melanin synthesis is a defense mechanism against UVR-induced damage relevant to the initiation of melanoma, whereas, increased neuromelanin (NM), the melanin synthesized in dopaminergic neurons, may enhance the susceptibility to oxidative stress-induced neuronal injury relevant to PD. SNCA is a PD-causing gene coding for alpha-Synuclein (alpha-Syn) that expresses not only in brain, but also in skin as well as in tumors, such as melanoma. The findings that alpha-Syn can interact with tyrosinase (TYR) and inhibit tyrosine hydroxylase (TH), both of which are enzymes involved in the biosynthesis of melanin and dopamine (DA), led us to propose that alpha-Syn may participate in the regulation of melanin synthesis. In this study, by applying ultraviolet B (UVB) light, a physiologically relevant stimulus of melanogenesis, we detected melanin synthesis in A375 and SK-MEL-28 melanoma cells and in SH-SY5Y and PC12 dopaminergic neuronal cells and determined effects of alpha-Syn on melanin synthesis. Our results showed that UVB light exposure increased melanin synthesis in all 4 cell lines. However, we found that alpha-Syn expression reduced UVB light-induced increase of melanin synthesis and that melanin content was lower when melanoma cells were expressed with alpha-Syn, indicating that alpha-Syn may have inhibitory effects on melanin synthesis in melanoma cells. Different from melanoma cells, the melanin content was higher in alpha-Syn-over-expressed dopaminergic neuronal SH-SY5Y and PC12 cells, cellular models of PD, than that in non-alpha-Syn-expressed control cells. We concluded that alpha-Syn could be one of the points responsible for the positive association between PD and melanoma via its differential roles in melanin synthesis in melanoma cells and in dopaminergic neuronal cells. PMID- 23028834 TI - Cellular plasticity enables adaptation to unforeseen cell-cycle rewiring challenges. AB - The fundamental dynamics of the cell cycle, underlying cell growth and reproduction, were previously found to be robust under a wide range of environmental and internal perturbations. This property was commonly attributed to its network structure, which enables the coordinated interactions among hundreds of proteins. Despite significant advances in deciphering the components and autonomous interactions of this network, understanding the interfaces of the cell cycle with other major cellular processes is still lacking. To gain insight into these interfaces, we used the process of genome-rewiring in yeast by placing an essential metabolic gene HIS3 from the histidine biosynthesis pathway, under the exclusive regulation of different cell-cycle promoters. In a medium lacking histidine and under partial inhibition of the HIS3p, the rewired cells encountered an unforeseen multitasking challenge; the cell-cycle regulatory genes were required to regulate the essential histidine-pathway gene in concert with the other metabolic demands, while simultaneously driving the cell cycle through its proper temporal phases. We show here that chemostat cell populations with rewired cell-cycle promoters adapted within a short time to accommodate the inhibition of HIS3p and stabilized a new phenotypic state. Furthermore, a significant fraction of the population was able to adapt and grow into mature colonies on plates under such inhibiting conditions. The adapted state was shown to be stably inherited across generations. These adaptation dynamics were accompanied by a non-specific and irreproducible genome-wide transcriptional response. Adaptation of the cell-cycle attests to its multitasking capabilities and flexible interface with cellular metabolic processes and requirements. Similar adaptation features were found in our previous work when rewiring HIS3 to the GAL system and switching cells from galactose to glucose. Thus, at the basis of cellular plasticity is the emergence of a yet-unknown general, non-specific mechanism allowing fast inherited adaptation to unforeseen challenges. PMID- 23028835 TI - Distinct licensing of IL-18 and IL-1beta secretion in response to NLRP3 inflammasome activation. AB - Inflammasome activation permits processing of interleukins (IL)-1beta and 18 and elicits cell death (pyroptosis). Whether these responses are independently licensed or are "hard-wired" consequences of caspase-1 (casp1) activity has not been clear. Here, we show that that each of these responses is independently regulated following activation of NLRP3 inflammasomes by a "non-canonical" stimulus, the secreted Listeria monocytogenes (Lm) p60 protein. Primed murine dendritic cells (DCs) responded to p60 stimulation with reactive oxygen species (ROS) production and secretion of IL-1beta and IL-18 but not pyroptosis. Inhibitors of ROS production inhibited secretion of IL-1beta, but did not impair IL-18 secretion. Furthermore, DCs from caspase-11 (casp11)-deficient 129S6 mice failed to secrete IL-1beta in response to p60 but were fully responsive for IL-18 secretion. These findings reveal that there are distinct licensing requirements for processing of IL-18 versus IL-1beta by NLRP3 inflammasomes. PMID- 23028836 TI - Survival of Vibrio cholerae in nutrient-poor environments is associated with a novel "persister" phenotype. AB - In response to antibiotic and/or environmental stress, some species of bacteria shift to a "persister" phenotype. Although toxigenic Vibrio cholerae, responsible for the disease cholera, can be found in nutrient-poor aquatic environments in endemic areas, the underlying mechanism(s) by which culturable cells persist in these environmental reservoirs is largely unknown. Here we report that introduction of V. cholerae into a nutrient-poor filter sterilized lake water (FSLW) microcosm promoted a shift to what we have defined as a "persister" phenotype (PP) which was culturable for >700 days. Direct transfer of PP of V. cholerae from original microcosms to freshly prepared FSLW resulted in the same pattern of persistence seen in the original microcosms. Scanning electron microscopy of cells persisting for over 700 days demonstrated cell morphologies that were very small in size, with a high degree of aggregation associated with flagella emanating from all aspects of the cell. V. cholerae PP cells reverted to a typical V. cholerae morphology when transferred to nutrient-rich L- broth. Cell free supernatants obtained from microcosms at 24 hours, 180 days, and 700 days all showed >2-fold increase in CAI-1 signaling molecules, consistent with quorum sensing activity, as has been described for Pseudomonas aeruginosa persister cells. Chitin and phosphate promoted cell growth. Our data suggest that nutrient stress can select a V. cholerae persister phenotype in environmental reservoirs, with these strains then seeding subsequent cholera epidemics in response to chitin and phosphate availability. PMID- 23028837 TI - Effect of pregnancy for females born small on later life metabolic disease risk. AB - There is a strong inverse relationship between a females own birth weight and her subsequent risk for gestational diabetes with increased risk of developing diabetes later in life. We have shown that growth restricted females develop loss of glucose tolerance during late pregnancy with normal pancreatic function. The aim of this study was to determine whether growth restricted females develop long term impairment of metabolic control after an adverse pregnancy adaptation. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham surgery (Control) in late pregnancy (E18) in F0 female rats. F1 Control and Restricted female offspring were mated with normal males and allowed to deliver (termed Ex-Pregnant). Age-matched Control and Restricted Virgins were also studied and glucose tolerance and insulin secretion were determined. Pancreatic morphology and hepatic glycogen and triacylglycerol content were quantified respectively. Restricted females were born lighter than Control and remained lighter at all time points studied (p<0.05). Glucose tolerance, first phase insulin secretion and liver glycogen and triacylglycerol content were not different across groups, with no changes in beta-cell mass. Second phase insulin secretion was reduced in Restricted Virgins (-34%, p<0.05) compared to Control Virgins, suggestive of enhanced peripheral insulin sensitivity but this was lost after pregnancy. Growth restriction was associated with enhanced basal hepatic insulin sensitivity, which may provide compensatory benefits to prevent adverse metabolic outcomes often associated with being born small. A prior pregnancy was associated with reduced hepatic insulin sensitivity with effects more pronounced in Controls than Restricted. Our data suggests that pregnancy ameliorates the enhanced peripheral insulin sensitivity in growth restricted females and has deleterious effects for hepatic insulin sensitivity, regardless of maternal birth weight. PMID- 23028838 TI - Retinitis pigmentosa reduces the risk of proliferative diabetic retinopathy: a nationwide population-based cohort study. AB - PURPOSE: To study the association between retinitis pigmentosa (RP) and the progression of diabetic retinopathy (DR). METHODS: Using the Longitudinal Health Insurance Database 2000 of Taiwan, we identified individuals with an initial diagnosis for RP during the period of 1997-2008. A non-RP comparison group, 10 fold frequency matched by sex, age, index year and the year of diabetes diagnosed, were randomly selected from the same database. The occurrence of DR was observed for all subjects until the end of 2009. The Kaplan-Meier curves were used to illustrate the cumulative probability of developing DR for the RP group and comparison groups. The hazard ratio (HR) of DR for the RP group relative to the comparison group was estimated using Cox proportional hazards model after adjusting for potential confounders. RESULTS: The Kaplan-Meier curves were not statistically significant different between the RP group and the comparison group. However, the RP group had a higher cumulative probability of developing DR during the first six to seven years. The cumulative probability kept increasing and became higher in the comparison group but remained unchanged in the RP group. The HR for the RP patients comparing with the comparison group was 0.96 (95% confidence interval (CI) = 0.43-2.14). Stratified by severity, RP was associated with a non-statistically significant reduced risk of proliferative DR (PDR) (HR = 0.70, 95% CI = 0.16-3.14). The HR for non-proliferative DR (NPDR) was 1.08 (95% CI = 0.40-2.86). CONCLUSION: In this study, RP was not statistically significant associated with the incidence of DR. PMID- 23028839 TI - Modulation of invasive phenotype by interstitial pressure-driven convection in aggregates of human breast cancer cells. AB - This paper reports the effect of elevated pressure on the invasive phenotype of patterned three-dimensional (3D) aggregates of MDA-MB-231 human breast cancer cells. We found that the directionality of the interstitial pressure profile altered the frequency of invasion by cells located at the surface of an aggregate. In particular, application of pressure at one end of an aggregate suppressed invasion at the opposite end. Experimental alteration of the configuration of cell aggregates and computational modeling of the resulting flow and solute concentration profiles revealed that elevated pressure inhibited invasion by altering the chemical composition of the interstitial fluid near the surface of the aggregate. Our data reveal a link between hydrostatic pressure, interstitial convection, and invasion. PMID- 23028840 TI - Effect of remifentanil on mitochondrial oxygen consumption of cultured human hepatocytes. AB - During sepsis, liver dysfunction is common, and failure of mitochondria to effectively couple oxygen consumption with energy production has been described. In addition to sepsis, pharmacological agents used to treat septic patients may contribute to mitochondrial dysfunction. This study addressed the hypothesis that remifentanil interacts with hepatic mitochondrial oxygen consumption. The human hepatoma cell line HepG2 and their isolated mitochondria were exposed to remifentanil, with or without further exposure to tumor necrosis factor-alpha (TNF-alpha). Mitochondrial oxygen consumption was measured by high-resolution respirometry, Caspase-3 protein levels by Western blotting, and cytokine levels by ELISA. Inhibitory kappaBalpha (IkappaBalpha) phosphorylation, measurement of the cellular ATP content and mitochondrial membrane potential in intact cells were analysed using commercial ELISA kits. Maximal cellular respiration increased after one hour of incubation with remifentanil, and phosphorylation of IkappaBalpha occurred, denoting stimulation of nuclear factor kappaB (NF-kappaB). The effect on cellular respiration was not present at 2, 4, 8 or 16 hours of incubation. Remifentanil increased the isolated mitochondrial respiratory control ratio of complex-I-dependent respiration without interfering with maximal respiration. Preincubation with the opioid receptor antagonist naloxone prevented a remifentanil-induced increase in cellular respiration. Remifentanil at 10* higher concentrations than therapeutic reduced mitochondrial membrane potential and ATP content without uncoupling oxygen consumption and basal respiration levels. TNF-alpha exposure reduced respiration of complex-I, -II and -IV, an effect which was prevented by prior remifentanil incubation. Furthermore, prior remifentanil incubation prevented TNF-alpha-induced IL-6 release of HepG2 cells, and attenuated fragmentation of pro-caspase-3 into cleaved active caspase 3 (an early marker of apoptosis). Our data suggest that remifentanil increases cellular respiration of human hepatocytes and prevents TNF-alpha-induced mitochondrial dysfunction. The results were not explained by uncoupling of mitochondrial respiration. PMID- 23028841 TI - Study of natural health product adverse reactions (SONAR): active surveillance of adverse events following concurrent natural health product and prescription drug use in community pharmacies. AB - BACKGROUND: Many consumers use natural health products (NHPs) concurrently with prescription medications. As NHP-related harms are under-reported through passive surveillance, the safety of concurrent NHP-drug use remains unknown. To conduct active surveillance in participating community pharmacies to identify adverse events related to concurrent NHP-prescription drug use. METHODOLOGY/PRINCIPAL FINDINGS: Participating pharmacists asked individuals collecting prescription medications about (i) concurrent NHP/drug use in the previous three months and (ii) experiences of adverse events. If an adverse event was identified and if the patient provided written consent, a research pharmacist conducted a guided telephone interview to gather additional information after obtaining additional verbal consent and documenting so within the interview form. Over a total of 112 pharmacy weeks, 2615 patients were screened, of which 1037 (39.7%; 95% CI: 37.8% to 41.5%) reported concurrent NHP and prescription medication use. A total of 77 patients reported a possible AE (2.94%; 95% CI: 2.4% to 3.7%), which represents 7.4% of those using NHPs and prescription medications concurrently (95%CI: 6.0% to 9.2%). Of 15 patients available for an interview, 4 (26.7%: 95% CI: 4.3% to 49.0%) reported an AE that was determined to be "probably" due to NHP use. CONCLUSIONS/SIGNIFICANCE: Active surveillance markedly improves identification and reporting of adverse events associated with concurrent NHP-drug use. Although not without challenges, active surveillance is feasible and can generate adverse event data of sufficient quality to allow for meaningful adjudication to assess potential harms. PMID- 23028842 TI - Loss of expression and function of SOCS3 is an early event in HNSCC: altered subcellular localization as a possible mechanism involved in proliferation, migration and invasion. AB - BACKGROUND: Suppressor of cytokine signaling 3 (SOCS3) is an inducible endogenous negative regulator of signal transduction and activator of transcription 3 (STAT3). Epigenetic silencing of SOCS3 has been shown in head and neck squamous cell carcinoma (HNSCC), which is associated with increased activation of STAT3. There is scarce information on the functional role of the reduction of SOCS3 expression and no information on altered subcellular localization of SOCS3 in HNSCC. METHODOLOGY/PRINCIPAL FINDINGS: We assessed endogenous SOCS3 expression in different HNSCC cell lines by RT-qPCR and western blot. Immunofluorescence and western blot were used to study the subcellular localization of endogenous SOCS3 induced by IL-6. Overexpression of SOCS3 by CMV-driven plasmids and siRNA mediated inhibition of endogenous SOCS3 were used to verify the role of SOCS3 on tumor cell proliferation, viability, invasion and migration in vitro. In vivo relevance of SOCS3 expression in HNSCC was studied by quantitative immunohistochemistry of commercially-available tissue microarrays. Endogenous expression of SOCS3 was heterogeneous in four HNSCC cell lines and surprisingly preserved in most of these cell lines. Subcellular localization of endogenous SOCS3 in the HNSCC cell lines was predominantly nuclear as opposed to cytoplasmic in non-neoplasic epithelial cells. Overexpression of SOCS3 produced a relative increase of the protein in the cytoplasmic compartment and significantly inhibited proliferation, migration and invasion, whereas inhibition of endogenous nuclear SOCS3 did not affect these events. Analysis of tissue microarrays indicated that loss of SOCS3 is an early event in HNSCC and was correlated with tumor size and histological grade of dysplasia, but a considerable proportion of cases presented detectable expression of SOCS3. CONCLUSION: Our data support a role for SOCS3 as a tumor suppressor gene in HNSCC with relevance on proliferation and invasion processes and suggests that abnormal subcellular localization impairs SOCS3 function in HNSCC cells. PMID- 23028843 TI - Abstract profiles of structural stability point to universal tendencies, family specific factors, and ancient connections between languages. AB - Language is the best example of a cultural evolutionary system, able to retain a phylogenetic signal over many thousands of years. The temporal stability (conservatism) of basic vocabulary is relatively well understood, but the stability of the structural properties of language (phonology, morphology, syntax) is still unclear. Here we report an extensive Bayesian phylogenetic investigation of the structural stability of numerous features across many language families and we introduce a novel method for analyzing the relationships between the "stability profiles" of language families. We found that there is a strong universal component across language families, suggesting the existence of universal linguistic, cognitive and genetic constraints. Against this background, however, each language family has a distinct stability profile, and these profiles cluster by geographic area and likely deep genealogical relationships. These stability profiles seem to show, for example, the ancient historical relationships between the Siberian and American language families, presumed to be separated by at least 12,000 years, and possible connections between the Eurasian families. We also found preliminary support for the punctuated evolution of structural features of language across families, types of features and geographic areas. Thus, such higher-level properties of language seen as an evolutionary system might allow the investigation of ancient connections between languages and shed light on the peopling of the world. PMID- 23028844 TI - Determinants of plant community assembly in a mosaic of landscape units in central Amazonia: ecological and phylogenetic perspectives. AB - The Amazon harbours one of the richest ecosystems on Earth. Such diversity is likely to be promoted by plant specialization, associated with the occurrence of a mosaic of landscape units. Here, we integrate ecological and phylogenetic data at different spatial scales to assess the importance of habitat specialization in driving compositional and phylogenetic variation across the Amazonian forest. To do so, we evaluated patterns of floristic dissimilarity and phylogenetic turnover, habitat association and phylogenetic structure in three different landscape units occurring in terra firme (Hilly and Terrace) and flooded forests (Igapo). We established two 1-ha tree plots in each of these landscape units at the Caparu Biological Station, SW Colombia, and measured edaphic, topographic and light variables. At large spatial scales, terra firme forests exhibited higher levels of species diversity and phylodiversity than flooded forests. These two types of forests showed conspicuous differences in species and phylogenetic composition, suggesting that environmental sorting due to flood is important, and can go beyond the species level. At a local level, landscape units showed floristic divergence, driven both by geographical distance and by edaphic specialization. In terms of phylogenetic structure, Igapo forests showed phylogenetic clustering, whereas Hilly and Terrace forests showed phylogenetic evenness. Within plots, however, local communities did not show any particular trend. Overall, our findings suggest that flooded forests, characterized by stressful environments, impose limits to species occurrence, whereas terra firme forests, more environmentally heterogeneous, are likely to provide a wider range of ecological conditions and therefore to bear higher diversity. Thus, Amazonia should be considered as a mosaic of landscape units, where the strength of habitat association depends upon their environmental properties. PMID- 23028845 TI - Transcriptomic assay of CD8+ T cells in treatment-naive HIV, HCV-mono-infected and HIV/HCV-co-infected Chinese. AB - BACKGROUND: Co-infection with HIV and HCV is very common. It is estimated that over 5 million people are co-infected with HIV and HCV worldwide. Accumulated evidence shows that each virus alters the course of infection of the other one. CD8+ T cells play a crucial role in the eradication of viruses and infected target cells. To the best of our knowledge, no one has investigated the gene expression profiles in HIV/HCV-co-infected individuals. METHODOLOGY: Genome-wide transcriptomes of CD8+ T cells from HIV/HCV-co-infected or mono-infected treatment-naive individuals were analyzed by microarray assays. Pairwise comparisons were performed and differentially expressed genes were identified followed by quantitative real-time PCR (qRT-PCR) validation. Directed Acyclic Graphs (DAG) from Web-based Gene SeT AnaLysis Toolkit (WebGestalt) and DAVID bioinformatics resources 6.7 (the Database for Annotation, Visualization, and Integrated Discovery) were used to discover the Gene Ontology (GO) categories with significantly enriched gene numbers. The enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were also obtained by using WebGestalt software. RESULTS AND CONCLUSIONS: A total of 110, 24 and 72 transcript IDs were shown to be differentially expressed (> 2-fold and p<0.05) in comparisons between HCV- and HIV-mono-infected groups, HIV/HCV-co-infected and HIV-mono-infected groups, and HIV/HCV-co-infected and HCV-mono-infected groups, respectively. In qRT-PCR assay, most of the genes showed similar expressing profiles with the observation in microarray assays. Further analysis revealed that genes involved in cell proliferation, differentiation, transcriptional regulation and cytokine responses were significantly altered. These data offer new insights into HIV/HCV co-infections, and may help to identify new markers for the management and treatment of HIV/HCV co-infections. PMID- 23028846 TI - Inhibition of glycogen synthase kinase 3beta ameliorates D-GalN/LPS-induced liver injury by reducing endoplasmic reticulum stress-triggered apoptosis. AB - BACKGROUND: Glycogen synthase kinase 3beta(GSK3beta) is a ubiquitous serine threonine protein kinase that participates in numerous cellular processes and disease pathophysiology. We aimed to determine therapeutic potential of GSK3beta inhibition and its mechanism in a well-characterized model of lipopolysaccharide (LPS)-induced model of acute liver failure (ALF). METHODOLOGY: In a murine ALF model induced by D-GalN(700 mg/kg)/LPS(10 ug/kg), we analyzed GSK3beta mechanisms using a specific chemical inhibitor, SB216763, and detected the role of endoplasmic reticulum stress (ERS). Mice were administered SB216763 at 2 h before or after D-GalN/LPS injection, respectively, and then sacrificed 6 h after D GalN/LPS treatment to evaluate its prophylactic and therapeutic function. The lethality rate, liver damage, ERS, cytokine expression, MAP kinase, hepatocyte apoptosis and expression of TLR 4 were evaluated, respectively. Whether the inhibition of GSK3beta activation protected hepatocyte from ERS-induced apoptosis was investigated in vitro. PRINCIPAL FINDINGS: GSK3beta became quickly activated (dephosphorylated) upon D-GalN/LPS exposure. Administration of SB216763 not only ameliorated liver injury, as evidenced by reduced transaminase levels, and well preserved liver architecture, but also decreased lethality. Moreover, GSK3beta inhibition resulted in down-regulation of pro-apoptotic proteins C/EBP-homologous protein(CHOP) and caspase-12, which are related to ERS. To further demonstrate the role of ERS, we found that GSK3beta inhibition protected hepatocyte from ERS induced cell death. GSK3beta inhibition down-regulated the MAPK pathways, reduced expression of inflammatory cytokines and decreased expression of TLR4. CONCLUSIONS: Our findings demonstrate the key function of GSK3beta signaling in the pathophysiology of ALF, especially in regulating the ERS, and provide a rationale for targeting GSK3beta as a potential therapeutic strategy to ameliorate ALF. PMID- 23028847 TI - A second soundly sleeping dragon: new anatomical details of the Chinese troodontid Mei long with implications for phylogeny and taphonomy. AB - A second nearly complete, articulated specimen of the basal troodontid Mei long (DNHM D2154) is reported from the Early Cretaceous (Hauterivian-Valanginian) lower Yixian Formation, Liaoning Province, China. New diagnostic features of Mei long are identified, including: a uniquely shaped maxilla, low with small, low maxillary fenestra; sacrum with an extremely wide caudal portion and elongate 4(th) and 5(th) sacral processes; and a large distal articular surface on the tibiotarsus which continues caudally on the tibia. A phylogenetic analysis including new data from the second specimen recovered Mei as a basal troodontid, in keeping with previous analyses. Although the skeleton exhibits several juvenile-like features including free cervical ribs, unfused frontals and nasals, and a short snouted skull, other attributes, full fusion of all neurocentral synostoses and the sacrum, and dense exteriors to cortical bone, suggest a small, mature individual. Microscopic examination of tibia and fibula histology confirms maturity and suggests an individual greater than two years old with slowed growth. Despite being one of the smallest dinosaurs, Mei long exhibits multi-year growth and cortical bone consisting largely of fibro-lamellar tissue marked by lines of arrested growth as in much larger and more basal theropods. This Mei long specimen lies in a similar but mirrored sleeping position to that of the holotype, strengthening the hypothesis that both specimens were preserved in a stereotypical life position. Like many Liaoning specimens, the new specimen also lacks extensive taphonomic and stratigraphic data, making further behavioral inference problematic. PMID- 23028848 TI - Water- and plant-mediated responses of ecosystem carbon fluxes to warming and nitrogen addition on the Songnen grassland in northeast China. AB - BACKGROUND: Understanding how grasslands are affected by a long-term increase in temperature is crucial to predict the future impact of global climate change on terrestrial ecosystems. Additionally, it is not clear how the effects of global warming on grassland productivity are going to be altered by increased N deposition and N addition. METHODOLOGY/PRINCIPAL FINDINGS: In-situ canopy CO(2) exchange rates were measured in a meadow steppe subjected to 4-year warming and nitrogen addition treatments. Warming treatment reduced net ecosystem CO(2) exchange (NEE) and increased ecosystem respiration (ER); but had no significant impacts on gross ecosystem productivity (GEP). N addition increased NEE, ER and GEP. However, there were no significant interactions between N addition and warming. The variation of NEE during the four experimental years was correlated with soil water content, particularly during early spring, suggesting that water availability is a primary driver of carbon fluxes in the studied semi-arid grassland. CONCLUSION/SIGNIFICANCE: Ecosystem carbon fluxes in grassland ecosystems are sensitive to warming and N addition. In the studied water-limited grassland, both warming and N addition influence ecosystem carbon fluxes by affecting water availability, which is the primary driver in many arid and semiarid ecosystems. It remains unknown to what extent the long-term N addition would affect the turn-over of soil organic matter and the C sink size of this grassland. PMID- 23028849 TI - Sound stabilizes locomotor-respiratory coupling and reduces energy cost. AB - A natural synchronization between locomotor and respiratory systems is known to exist for various species and various forms of locomotion. This Locomotor Respiratory Coupling (LRC) is fundamental for the energy transfer between the two subsystems during long duration exercise and originates from mechanical and neurological interactions. Different methodologies have been used to compute LRC, giving rise to various and often diverging results in terms of synchronization, (de-)stabilization via information, and associated energy cost. In this article, the theory of nonlinear-coupled oscillators was adopted to characterize LRC, through the model of the sine circle map, and tested it in the context of cycling. Our specific focus was the sound-induced stabilization of LRC and its associated change in energy consumption. In our experimental study, participants were instructed during a cycling exercise to synchronize either their respiration or their pedaling rate with an external auditory stimulus whose rhythm corresponded to their individual preferential breathing or cycling frequencies. Results showed a significant reduction in energy expenditure with auditory stimulation, accompanied by a stabilization of LRC. The sound-induced effect was asymmetrical, with a better stabilizing influence of the metronome on the locomotor system than on the respiratory system. A modification of the respiratory frequency was indeed observed when participants cycled in synchrony with the tone, leading to a transition toward more stable frequency ratios as predicted by the sine circle map. In addition to the classical mechanical and neurological origins of LRC, here we demonstrated using the sine circle map model that information plays an important modulatory role of the synchronization, and has global energetic consequences. PMID- 23028850 TI - Inhibition of HIV-1 infection by human alpha-defensin-5, a natural antimicrobial peptide expressed in the genital and intestinal mucosae. AB - BACKGROUND: alpha-defensin-5 (HD5) is a key effector of the innate immune system with broad anti-bacterial and anti-viral activities. Specialized epithelial cells secrete HD5 in the genital and gastrointestinal mucosae, two anatomical sites that are critically involved in HIV-1 transmission and pathogenesis. We previously found that human neutrophil defensins (HNP)-1 and -2 inhibit HIV-1 entry by specific bilateral interaction both with the viral envelope and with its primary cellular receptor, CD4. Despite low amino acid identity, human defensin-5 (HD5) shares with HNPs a high degree of structural homology. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that HD5 inhibits HIV-1 infection of primary CD4(+) T lymphocytes at low micromolar concentration under serum-free and low-ionic-strength conditions similar to those occurring in mucosal fluids. Blockade of HIV-1 infection was observed with both primary and laboratory-adapted strains and was independent of the viral coreceptor-usage phenotype. Similar to HNPs, HD5 inhibits HIV-1 entry into the target cell by interfering with the reciprocal interaction between the external envelope glycoprotein, gp120, and CD4. At high concentrations, HD5 was also found to downmodulate expression of the CXCR4 coreceptor, but not of CCR5. Consistent with its broad spectrum of activity, antibody competition studies showed that HD5 binds to a region overlapping with the CD4- and coreceptor-binding sites of gp120, but not to the V3 loop region, which contains the major determinants of coreceptor-usage specificity. CONCLUSION/SIGNIFICANCE: These findings provide new insights into the first line of immune defense against HIV-1 at the mucosal level and open new perspectives for the development of preventive and therapeutic strategies. PMID- 23028851 TI - The hepatic Raldh1 expression is elevated in Zucker fatty rats and its over expression introduced the retinal-induced Srebp-1c expression in INS-1 cells. AB - The roles of vitamin A (VA) in the development of metabolic diseases remain unanswered. We have reported that retinoids synergized with insulin to induce the expression of sterol-regulatory element-binding protein 1c gene (Srebp-1c) expression in primary rat hepatocytes. Additionally, the hepatic Srebp-1c expression is elevated in Zucker fatty (ZF) rats, and reduced in those fed a VA deficient diet. VA is metabolized to retinoic acid (RA) for regulating gene expression. We hypothesized that the expression of RA production enzymes contributes to the regulation of the hepatic Srebp-1c expression. Therefore, we analyzed their expression levels in Zucker lean (ZL) and ZF rats. The mRNA levels of retinaldehyde dehydrogenase family 1 gene (Raldh1) were found to be higher in the isolated and cultured primary hepatocytes from ZF rats than that from ZL rats. The RALDH1 protein level was elevated in the liver of ZF rats. Retinol and retinal dose- and time-dependently induced the expression of RA responsive Cyp26a1 gene in hepatocytes and hepatoma cells. INS-1 cells were identified as an ideal tool to study the effects of RA production on the regulation of gene expression because only RA, but not retinal, induced Srebp-1c mRNA expression in them. Recombinant adenovirus containing rat Raldh1 cDNA was made and used to infect INS-1 cells. The over-expression of RALDH1 introduced the retinal-mediated induction of Srebp-1c expression in INS-1 cells. We conclude that the expression levels of the enzymes for RA production may contribute to the regulation of RA responsive genes, and determine the responses of the cells to retinoid treatments. The elevated hepatic expression of Raldh1 in ZF rats may cause the excessive RA production from retinol, and in turn, result in higher Srebp-1c expression. This excessive RA production may be one of the factors contributing to the elevated lipogenesis in the liver of ZF rats. PMID- 23028852 TI - Multi-edge gene set networks reveal novel insights into global relationships between biological themes. AB - Curated gene sets from databases such as KEGG Pathway and Gene Ontology are often used to systematically organize lists of genes or proteins derived from high throughput data. However, the information content inherent to some relationships between the interrogated gene sets, such as pathway crosstalk, is often underutilized. A gene set network, where nodes representing individual gene sets such as KEGG pathways are connected to indicate a functional dependency, is well suited to visualize and analyze global gene set relationships. Here we introduce a novel gene set network construction algorithm that integrates gene lists derived from high-throughput experiments with curated gene sets to construct co enrichment gene set networks. Along with previously described co-membership and linkage algorithms, we apply the co-enrichment algorithm to eight gene set collections to construct integrated multi-evidence gene set networks with multiple edge types connecting gene sets. We demonstrate the utility of approach through examples of novel gene set networks such as the chromosome map co differential expression gene set network. A total of twenty-four gene set networks are exposed via a web tool called MetaNet, where context-specific multi edge gene set networks are constructed from enriched gene sets within user defined gene lists. MetaNet is freely available at http://blaispathways.dfci.harvard.edu/metanet/. PMID- 23028853 TI - Attenuated Mycobacterium tuberculosis SO2 vaccine candidate is unable to induce cell death. AB - It has been proposed that Mycobacterium tuberculosis virulent strains inhibit apoptosis and trigger cell death by necrosis of host macrophages to evade innate immunity, while non-virulent strains induce typical apoptosis activating a protective host response. As part of the characterization of a novel tuberculosis vaccine candidate, the M. tuberculosis phoP mutant SO2, we sought to evaluate its potential to induce host cell death. The parental M. tuberculosis MT103 strain and the current vaccine against tuberculosis Bacillus Calmette-Guerin (BCG) were used as comparators in mouse models in vitro and in vivo. Our data reveal that attenuated SO2 was unable to induce apoptotic events neither in mouse macrophages in vitro nor during lung infection in vivo. In contrast, virulent MT103 triggers typical apoptotic events with phosphatidylserine exposure, caspase-3 activation and nuclear condensation and fragmentation. BCG strain behaved like SO2 and did not induce apoptosis. A clonogenic survival assay confirmed that viability of BCG or SO2-infected macrophages was unaffected. Our results discard apoptosis as the protective mechanism induced by SO2 vaccine and provide evidence for positive correlation between classical apoptosis induction and virulent strains, suggesting apoptosis as a possible virulence determinant during M. tuberculosis infection. PMID- 23028854 TI - Biosynthesis and characterization of polyhydroxyalkanoates copolymers produced by Pseudomonas putida Bet001 isolated from palm oil mill effluent. AB - The biosynthesis and characterization of medium chain length poly-3 hydroxyalkanoates (mcl-PHA) produced by Pseudomonas putida Bet001 isolated from palm oil mill effluent was studied. The biosynthesis of mcl-PHA in this newly isolated microorganism follows a growth-associated trend. Mcl-PHA accumulation ranging from 49.7 to 68.9% on cell dry weight (CDW) basis were observed when fatty acids ranging from octanoic acid (C(8:0)) to oleic acid (C(18:1)) were used as sole carbon and energy source. Molecular weight of the polymer was found to be ranging from 55.7 to 77.7 kDa. Depending on the type of fatty acid used, the (1)H NMR and GCMSMS analyses of the chiral polymer showed a composition of even and odd carbon atom chain with monomer length of C4 to C14 with C8 and C10 as the principal monomers. No unsaturated monomer was detected. Thermo-chemical analyses showed the accumulated PHA to be semi-crystalline polymer with good thermal stability, having a thermal degradation temperature (T(d)) of 264.6 to 318.8 (+/- 0.2) (o)C, melting temperature (T(m)) of 43. (+/- 0.2) (o)C, glass transition temperature (T(g)) of -1.0 (+/- 0.2) (o)C and apparent melting enthalpy of fusion (DeltaH(f)) of 100.9 (+/- 0.1) J g(-1). PMID- 23028855 TI - Dissecting quantitative trait loci for boron efficiency across multiple environments in Brassica napus. AB - High yield is the most important goal in crop breeding, and boron (B) is an essential micronutrient for plants. However, B deficiency, leading to yield decreases, is an agricultural problem worldwide. Brassica napus is one of the most sensitive crops to B deficiency, and considerable genotypic variation exists among different cultivars in response to B deficiency. To dissect the genetic basis of tolerance to B deficiency in B. napus, we carried out QTL analysis for seed yield and yield-related traits under low and normal B conditions using the double haploid population (TNDH) by two-year and the BQDH population by three year field trials. In total, 80 putative QTLs and 42 epistatic interactions for seed yield, plant height, branch number, pod number, seed number, seed weight and B efficiency coefficient (BEC) were identified under low and normal B conditions, singly explaining 4.15-23.16% and 0.53-14.38% of the phenotypic variation. An additive effect of putative QTLs was a more important controlling factor than the additive-additive effect of epistatic interactions. Four QTL-by-environment interactions and 7 interactions between epistatic interactions and the environment contributed to 1.27-4.95% and 1.17-3.68% of the phenotypic variation, respectively. The chromosome region on A2 of SYLB-A2 for seed yield under low B condition and BEC-A2 for BEC in the two populations was equivalent to the region of a reported major QTL, BE1. The B. napus homologous genes of Bra020592 and Bra020595 mapped to the A2 region and were speculated to be candidate genes for B efficiency. These findings reveal the complex genetic basis of B efficiency in B. napus. They provide a basis for the fine mapping and cloning of the B efficiency genes and for breeding B-efficient cultivars by marker-assisted selection (MAS). PMID- 23028856 TI - Extrapancreatic autoantibody profiles in type I diabetes. AB - Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing beta-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-beta. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-beta (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ specific subgroup, there was minimal overlap among anti-gastric ATPase, anti thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together, these results suggest that autoantibody portraits derived from islet and organ-specific targets will likely be useful for enhancing the clinical management of T1D. PMID- 23028857 TI - Natural selection mediated association of the Duffy (FY) gene polymorphisms with Plasmodium vivax malaria in India. AB - The Duffy (Fy) antigens act as receptors for chemokines as well as for Plasmodium vivax to invade human RBCs. A recent study has correlated the occurrence of the FY*A allele of Duffy gene with decreased susceptibility to vivax malaria, but no epidemiological correlation between the distribution of FY*A allele and incidences of vivax malaria has been established so far. Furthermore, if such correlations exist, whether natural selection has mediated the association, is an important question. Since India is highly endemic to P. vivax malaria with variable eco-climatic and varying vivax malaria epidemiology across different regions, such a question could well be answered in Indians. For this, we have genotyped the FY gene at the -33(rd) and the 125(th) nucleotide positions in 250 Indians sampled from six different zonal plus one tribal population covering the whole of India and studied possible correlations with eco-climatic and vivax malaria incidences. No FY*O allele was found, however, both the FY*A and FY*B alleles forming FY*A/FY*A, FY*A/FY*B and FY*B/FY*B genotypes were widely distributed among Indians. Five out of seven population samples significantly deviated from the Hardy-Weinberg equilibrium expectation, and two alleles (FY*A and FY*B) and the homozygote genotype, FY*B/FY*B were clinically distributed over the population coordinates. Furthermore, vivax malaria incidences over the past five years were significantly negatively and positively associated with the frequencies of the FY*A and FY*B alleles, respectively. The Northern Indians were highly differentiated from the other zonal population samples at the FY gene, as evidenced from the reconstructed Neighbor-Joining phylogenetic tree. The results specify the role of natural selection in the distribution of FY gene polymorphism in India. Furthermore, the hypotheses on the part of the FY*A allele in conferring protection to vivax malaria could be validated following population genetic studies in a vivax malaria epidemiological setting, such as India. PMID- 23028858 TI - E-cadherin promotes incorporation of mouse epiblast stem cells into normal development. AB - Mouse epiblast stem cells (mEpiSCs) are pluripotent stem cells derived from epiblasts of postimplantation mouse embryos. Their pluripotency is distinct from that of mouse embryonic stem cells (mESCs) in several cell biological criteria. One of the distinctions is that mEpiSCs contribute either not at all or at much lower efficiency to chimeric embryos after blastocyst injection compared to mESCs. However, here we showed that mEpiSCs can be incorporated into normal development after blastocyst injection by forced expression of the E-cadherin transgene for 2 days in culture. Using this strategy, mEpiSCs gave rise to live born chimeras from 5% of the manipulated blastocysts. There were no obvious signs of reprogramming of mEpiSCs toward the mESC-like state during the 2 days after induction of the E-cadherin transgene, suggesting that mEpiSCs possess latent ability to integrate into the normal developmental process as its origin, epiblasts. PMID- 23028859 TI - Pigment epithelium derived factor inhibits the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro. AB - Angiogenesis is a prerequisite for the formation and development of endometriosis. Pigment epithelium derived factor (PEDF) is a natural inhibitor of angiogenesis. We previously demonstrated a reduction of PEDF in the peritoneal fluid, serum and endometriotic lesions from women with endometriosis compared with women without endometriosis. Here, we aim to investigate the inhibitory effect of PEDF on human endometriotic cells in vivo and in vitro. We found that PEDF markedly inhibited the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro by up-regulating PEDF expression and down-regulating vascular endothelial growth factor (VEGF) expression. Moreover, apoptotic index was significantly increased in endometriotic lesions in vivo and endometriotic stromal cells in vitro when treated with PEDF. In mice treated with PEDF, decreased microvessel density labeled by Von Willebrand factor but not by alpha-Smooth Muscle Actin was observed in endometriotic lesions. And it showed no increase in PEDF expression of the ovary and uterus tissues. These findings suggest that PEDF gene therapy may be a new treatment for endometriosis. PMID- 23028860 TI - A novel role of IGFBP7 in mouse uterus: regulating uterine receptivity through Th1/Th2 lymphocyte balance and decidualization. AB - Previously we have screened out Insulin-like Growth Factor Binding Protein 7 (IGFBP7) as a differentially expressed gene in post-implantation uterus versus pre-implantation uterus by suppressive subtractive hybridation. However its function in uterus was not clearly identified. In this research, the expression and function of IGFBP7 during post-implantation were studied. We found that IGFBP7 was mainly located in the glandular epithelium and the stroma, and was upregulated after embryo implantation. The vector pCR3.1-IGFBP7-t expressing partial IGFBP7 was constructed. Inhibition of IGFBP7 by specific DNA immunization induced significant reduction of implanted embryos and pregnancy rate. The number of implanted embryos (5.68 +/- 0.46) was significantly reduced after immunization with pCR3.1-IGFBP7-t, as compared with that of the mice immunized with the control vector (12.29 +/- 0.36) or saline (14.58 +/- 0.40) (p<0.01). After specific inhibition of IGFBP7, the T helper type 1 (Th1) cytokine IFNgamma, was significantly elevated (p<0.05) and the Th2 cytokines IL-4 and IL-10, were reduced in uteri (p<0.05). The increase of Tbet and the decrease of Gata3 were found in mice peripheral lymphocytes by flow cytometry. The expression of decidualization marker IGFBP1 and angiogenesis regulator VEGF were declined in uteri (p<0.05). The expression of apoptosis-associated proteins, caspase3 and Bcl 2, were also declined (p<0.05). These results showed that inhibition of IGFBP7 induced pregnancy failure by shifting uterine cytokines to Th1 type dominance and repressing uterine decidualization. PMID- 23028861 TI - Deletion of IL-33R (ST2) abrogates resistance to EAE in BALB/C mice by enhancing polarization of APC to inflammatory phenotype. AB - The administration of interleukin 33 and deletion of IL-33 receptor, ST2 molecule, affects the induction of autoimmunity in different experimental models of human autoimmune diseases. The aim of this study was to analyze the effect of ST2 deletion on the induction of experimental autoimmune encephalomyelitis (EAE) in resistant BALB/c mice. Mice were immunized with MOG(35-55) peptide or disease was induced by passive transfer of encephalitogenic singenic cells and EAE was clinically and histologically evaluated. Expression of intracellular inflammatory cytokines, markers of activation and chemokine receptors on lymphoid tissue and CNS infiltrating mononuclear cells was analyzed by flow cytometry. We report here that deletion of ST2(-/-) molecule abrogates resistance of BALB/c mice to EAE induction based on clinical and histopathological findings. Brain and spinal cord infiltrates of ST2(-/-) mice had significantly higher number of CD4(+) T lymphocytes containing inflammatory cytokines compared to BALB/c WT mice. Adoptive transfer of ST2(-/-) primed lymphocytes induced clinical signs of the disease in ST2(-/-) as well as in WT mice. MOG(35-55) restimulated ST2(-/-) CD4(+) cells as well as ex vivo analyzed lymph node cells had higher expression of T-bet and IL-17, IFN-gamma, TNF-alpha and GM-CSF in comparison with WT CD4(+) cells. ST2(-/-) mice had higher percentages of CD4(+) cells expressing chemokine receptors important for migration to CNS in comparison with WT CD4(+) cells. Draining lymph nodes of ST2(-/-) mice contained higher percentage of CD11c(+)CD11b(+)CD8(-) cells containing inflammatory cytokines IL-6 and IL-12 with higher expression of activation markers. Transfer of ST2(-/-) but not WT dendritic cells induced EAE in MOG(35-55) immunized WT mice. Our results indicate that ST2 deficiency attenuates inherent resistance of BALB/c mice to EAE induction by enhancing differentiation of proinflammatory antigen presenting cells and consecutive differentiation of encephalitogenic T cells in the draining lymph node rather than affecting their action in the target tissue. PMID- 23028862 TI - Modelling neuroinflammation in vitro: a tool to test the potential neuroprotective effect of anti-inflammatory agents. AB - Neuron-microglia co-cultures treated with pro-inflammatory agents are a useful tool to study neuroinflammation in vitro, where to test the potential neuroprotective effect of anti-inflammatory compounds. However, a great diversity of experimental conditions can be found in the literature, making difficult to select the working conditions when considering this approach for the first time. We compared the use of neuron-primary microglia and neuron-BV2 cells (a microglial cell line) co-cultures, using different neuron:microglia ratios, treatments and time post-treatment to induce glial activation and derived neurotoxicity. We show that each model requires different experimental conditions, but that both neuron-BV2 and neuron-primary microglia LPS/IFN-gamma treated co-cultures are good to study the potential neuroprotective effect of anti-inflammatory agents. The contribution of different pro-inflammatory parameters in the neurotoxicity induced by reactive microglial cells was determined. IL-10 pre-treatment completely inhibited LPS/IFN-gamma-induced TNF alpha and IL-6 release, and COX-2 expression both in BV2 and primary microglial cultures, but not NO production and iNOS expression. However, LPS/IFN-gamma induced neurotoxicity was not inhibited in IL-10 pre-treated co-cultures. The inhibition of NO production using the specific iNOS inhibitor 1400 W totally abolished the neurotoxic effect of LPS/IFN-gamma, suggesting a major role for NO in the neurotoxic effect of activated microglia. Consequently, among the anti inflammatory agents, special attention should be paid to compounds that inhibit NO production. PMID- 23028863 TI - HIF1-alpha expression predicts survival of patients with squamous cell carcinoma of the oral cavity. AB - BACKGROUND: Oral squamous cell carcinoma is an important cause of death and morbidity wordwide and effective prognostic markers are still to be discovered. HIF1alpha protein is associated with hypoxia response and neovascularization, essential conditions for solid tumors survival. The relationship between HIF1alpha expression, tumor progression and treatment response in head and neck cancer is still poorly understood. PATIENTS AND METHODS: In this study, we investigated HIF1alpha expression by immunohistochemistry in tissue microarrays and its relationship with clinical findings, histopathological results and survival of 66 patients with squamous cell carcinoma of the lower mouth. RESULTS: Our results demonstrated that high HIF1alpha expression is associated with local disease-free survival, independently from the choice of treatment. Furthermore, high expression of HIF1alpha in patients treated with postoperative radiotherapy was associated with survival, therefore being a novel prognostic marker in squamous cell carcinoma of the mouth. Additionally, our results showed that MVD was associated with HIF1alpha expression and local disease relapse. CONCLUSION: These findings suggest that HIF1alpha expression can be used as a prognostic marker and predictor of postoperative radiotherapy response, helping the oncologist choose the best treatment for each patient. PMID- 23028864 TI - Pregnancy and preeclampsia affect monocyte subsets in humans and rats. AB - INTRODUCTION: Both nonclassical and intermediate monocytes have been implicated in different inflammatory conditions. We hypothesized that these monocytes would increase during pregnancy, a condition associated with generalized activation of inflammatory responses and that they would increase even more during preeclampsia, in which inflammatory responses are further stimulated. In the present study we investigated changes in monocyte subsets during healthy pregnancy and preeclampsia in humans and rats. METHODS: Blood monocyte subsets of nonpregnant, preeclamptic and healthy pregnant women were identified with CD14 and CD16. In nonpregnant and pregnant rats, blood monocytes were identified with CD172a and CD43, as well as in rats infused with adenosine triphosphate (ATP), a pro-inflammatory stimulus known to induce preeclampsia-like symptoms. Total and CD206-positive macrophages were quantified in placentas of these animals. RESULTS: Lower percentages of classical monocytes were found in pregnant women (91%-[83-98%]) compared to nonpregnant women (94%-[90-98%]) and even less in preeclamptic patients (90%-[61-92%]). In contrast, the percentage of combined nonclassical/intermediate monocytes was higher in pregnant women (8.5%-[2.3 16.6%] vs. 5.6%-[1.9-9.5%]) and even higher in preeclamptic patients (9.9%-[7.8 38.7%]), which was caused by a selective increase of intermediate monocytes. In rats, we also found lower percentages of classical monocytes and higher percentages of nonclassical monocytes in pregnant versus nonpregnant rats. ATP infusion increased the percentage of nonclassical monocytes in pregnant rats even further but not in nonpregnant rats. These nonclassical monocytes showed a more activated phenotype in pregnant ATP-infused rats only. Mesometrial triangles of ATP-infused rats had less CD206-positive macrophages as compared to those of saline-infused rats. CONCLUSION: The higher percentage of nonclassical/intermediate monocytes found in pregnancy and preeclampsia confirms their association with inflammatory responses. The observation that ATP stimulated numbers/activation of nonclassical monocytes in pregnant rats only, suggests that nonclassical monocytes are specifically altered in pregnancy and may play a role in the pathophysiology of preeclampsia. PMID- 23028865 TI - Effects of consumer interactions on benthic resources and ecosystem processes in a neotropical stream. AB - The effect of consumers on their resources has been demonstrated in many systems but is often confounded by trophic interactions with other consumers. Consumers may also have behavioral and life history adaptations to each other and to co occurring predators that may additionally modulate their particular roles in ecosystems. We experimentally excluded large consumers from tile periphyton, leaves and natural benthic substrata using submerged electrified frames in three stream reaches with overlapping consumer assemblages in Trinidad, West Indies. Concurrently, we assessed visits to (non-electrified) control frames by the three most common large consumers-primarily insectivorous killifish (Rivulus hartii), omnivorous guppies (Poecilia reticulata) and omnivorous crabs (Eudaniela garmani). Consumers caused the greatest decrease in final chlorophyll a biomass and accrual rates the most in the downstream reach containing all three focal consumers in the presence of fish predators. Consumers also caused the greatest increase in leaf decay rates in the upstream reach containing only killifish and crabs. In the downstream reach where guppies co-occur with predators, we found significantly lower benthic invertebrate biomass in control relative to exclosure treatments than the midstream reach where guppies occur in the absence of predators. These data suggest that differences in guppy foraging, potentially driven by differences in their life history phenotype, may affect ecosystem structure and processes as much as their presence or absence and that interactions among consumers may further mediate their effects in these stream ecosystems. PMID- 23028866 TI - Ectonucleotidase CD38 demarcates regulatory, memory-like CD8+ T cells with IFN gamma-mediated suppressor activities. AB - Regulatory CD8(+) T cells are critical for self-tolerance and restricting excessive immune responses. The variety of immune functions they fulfill, the heterogeneity of their phenotype, and the mechanism of action are still poorly understood. Here we describe that regulatory CD8(+) T cells exhibiting immunosuppressive actions in vitro and in vivo are recognized as CD38(high) T cells and present in naive mice. CD38 is a glycosylated membrane protein with ectonucleotidase properties. CD8(+)CD38(high) (CD44(+)CD122(+)CD62L(high)) lymphocytes suppress CD4(+) effector T-cell proliferation in an antigen-non specific manner via IFN-gamma. While direct cell-to-cell contact is needed for this suppressor activity, it is independent of membrane-bound TGF-beta and granzyme B release. IL-15 potentiates the suppressive activity of CD8(+)CD38(high) T cells and controls their survival and expansion. In humans CD8(+)CD38(high) T cells inhibit CD4(+) effector T cell proliferation. In vivo, CD8(+)CD38(high), but not CD8(+)CD38(-) T cells mitigate murine experimental autoimmune encephalomyelitis (EAE) by reducing the clinical score and delaying disease occurrence. EAE suppression is enhanced by pre-treatment of CD8(+)CD38(high) T cells with IL-15. These findings add evidence that the expression of ectoenzyme receptor family members positively correlates with suppressor functions and identifies CD8(+)CD38(high) T cells as potential inhibitors of excessive immune responses. PMID- 23028867 TI - The CnuK9E H-NS complex antagonizes DNA binding of DicA and leads to temperature dependent filamentous growth in E. coli. AB - Cnu (an OriC-binding nucleoid protein) associates with H-NS. A variant of Cnu was identified as a key factor for filamentous growth of a wild-type Escherichia coli strain at 37 degrees C. This variant (CnuK9E) bears a substitution of a lysine to glutamic acid, causing a charge reversal in the first helix. The temperature dependent filamentous growth of E. coli bearing CnuK9E could be reversed by either lowering the temperature to 25 degrees C or lowering the CnuK9E concentration in the cell. Gene expression analysis suggested that downregulation of dicA by CnuK9E causes a burst of dicB transcription, which, in turn, elicits filamentous growth. In vivo assays indicated that DicA transcriptionally activates its own gene, by binding to its operator in a temperature-dependent manner. The antagonizing effect of CnuK9E with H-NS on DNA-binding activity of DicA was stronger at 37 degrees C, presumably due to the lower operator binding of DicA at 37 degrees C. These data suggest that the temperature-dependent negative effect of CnuK9E on DicA binding plays a major role in filamentous growth. The C-terminus of DicA shows significant amino acid sequence similarity to the DNA-binding domains of RovA and SlyA, regulators of pathogenic genes in Yersinia and Salmonella, respectively, which also show better DNA-binding activity at 25 degrees C. PMID- 23028868 TI - Viscoelastic properties of differentiating blood cells are fate- and function dependent. AB - Although cellular mechanical properties are known to alter during stem cell differentiation, understanding of the functional relevance of such alterations is incomplete. Here, we show that during the course of differentiation of human myeloid precursor cells into three different lineages, the cells alter their viscoelastic properties, measured using an optical stretcher, to suit their ultimate fate and function. Myeloid cells circulating in blood have to be advected through constrictions in blood vessels, engendering the need for compliance at short time-scales (minutes), compared to undifferentiated cells. These findings suggest that reduction in steady-state viscosity is a physiological adaptation for enhanced migration through tissues. Our results indicate that the material properties of cells define their function, can be used as a cell differentiation marker and could serve as target for novel therapies. PMID- 23028869 TI - Local breast cancer spatial patterning: a tool for community health resource allocation to address local disparities in breast cancer mortality. AB - Despite available demographic data on the factors that contribute to breast cancer mortality in large population datasets, local patterns are often overlooked. Such local information could provide a valuable metric by which regional community health resources can be allocated to reduce breast cancer mortality. We used national and statewide datasets to assess geographical distribution of breast cancer mortality rates and known risk factors influencing breast cancer mortality in middle Tennessee. Each county in middle Tennessee, and each ZIP code within metropolitan Davidson County, was scored for risk factor prevalence and assigned quartile scores that were used as a metric to identify geographic areas of need. While breast cancer mortality often correlated with age and incidence, geographic areas were identified in which breast cancer mortality rates did not correlate with age and incidence, but correlated with additional risk factors, such as mammography screening and socioeconomic status. Geographical variability in specific risk factors was evident, demonstrating the utility of this approach to identify local areas of risk. This method revealed local patterns in breast cancer mortality that might otherwise be overlooked in a more broadly based analysis. Our data suggest that understanding the geographic distribution of breast cancer mortality, and the distribution of risk factors that contribute to breast cancer mortality, will not only identify communities with the greatest need of support, but will identify the types of resources that would provide the most benefit to reduce breast cancer mortality in the community. PMID- 23028870 TI - Computational study of unfolding and regulation mechanism of preQ1 riboswitches. AB - Riboswitches are novel RNA regulatory elements. Each riboswitch molecule consists of two domains: aptamer and express platform. The three-dimensional (3D) structure of the aptamer domain, depending on ligand binding or not, controls that of the express platform, which then switches on or off transcriptional or translational process. Here we study the two types of preQ(1) riboswitch aptamers from T. Tengcongensis (denoted as Tte preQ(1) riboswitch for short below) and Bacillus subtilis (denoted as Bsu preQ(1) riboswitch for short below), respectively. The free-state 3D structure of the Tte preQ(1) riboswitch is the same as its bound state but the Bsu preQ(1) riboswitch is not. Therefore, it is very interesting to investigate how these riboswitches realize their different regulation functions. We simulated the unfolding of these two aptamers through all-atom molecular dynamic simulation and found that they have similar unfolding or folding pathways and ligand-binding processes. The main difference between them is the folding intermediate states. The similarity and difference of their unfolding or folding dynamics may suggest their similar regulation mechanisms and account for their different functions, respectively. These results are also useful to understand the regulation mechanism of other riboswitches with free state 3D structures similar to their bound states. PMID- 23028871 TI - An in vivo method to quantify lymphangiogenesis in zebrafish. AB - BACKGROUND: Lymphangiogenesis is a highly regulated process involved in the pathogenesis of disease. Current in vivo models to assess lymphangiogenesis are largely unphysiologic. The zebrafish is a powerful model system for studying development, due to its rapid growth and transparency during early stages of life. Identification of a network of trunk lymphatic capillaries in zebrafish provides an opportunity to quantify lymphatic growth in vivo. METHODS AND RESULTS: Late-phase microangiography was used to detect trunk lymphatic capillaries in zebrafish 2- and 3-days post-fertilization. Using this approach, real-time changes in lymphatic capillary development were measured in response to modulators of lymphangiogenesis. Recombinant human vascular endothelial growth factor (VEGF)-C added directly to the zebrafish aqueous environment as well as human endothelial and mouse melanoma cell transplantation resulted in increased lymphatic capillary growth, while morpholino-based knockdown of vegfc and chemical inhibitors of lymphangiogenesis added to the aqueous environment resulted in decreased lymphatic capillary growth. CONCLUSION: Lymphatic capillaries in embryonic and larval zebrafish can be quantified using late-phase microangiography. Human activators and small molecule inhibitors of lymphangiogenesis, as well as transplanted human endothelial and mouse melanoma cells, alter lymphatic capillary development in zebrafish. The ability to rapidly quantify changes in lymphatic growth under physiologic conditions will allow for broad screening of lymphangiogenesis modulators, as well as help define cellular roles and elucidate pathways of lymphatic development. PMID- 23028872 TI - Variables controlling entry into and exit from the steady-state, one of two modes of feeding in Aplysia. AB - BACKGROUND: Aplysia feeding is a model system for examining the neural mechanisms by which changes in motivational state control behavior. When food is intermittently present, Aplysia eat large meals controlled by a balance between food stimuli exciting feeding and gut stimuli inhibiting feeding. However, when food is continuously present animals are in a state in which feeding is relatively inhibited and animals eat little. We examined which stimuli provided by food and feeding initiate steady-state inhibition of feeding, and which stimuli maintain the inhibition. RESULTS: Multiple stimuli were found to control entry into the steady-state inhibition, and its maintenance. The major variable governing entry into the steady-state is fill of the gut with bulk provided by food, but this stimulus cannot alone cause entry into the steady-state. Food odor and nutritional stimuli such as increased hemolymph glucose and L-arginine concentrations also contribute to inhibition of feeding leading to entry into the steady-state. Although food odor can alone cause some inhibition of feeding, it does not amplify the effect of gut fill. By contrast, neither increased hemolymph glucose nor L-arginine alone inhibits feeding in hungry animals, but both amplify the inhibitory effects of food odor, and increased glucose also amplifies the effect of gut fill. The major variable maintaining the steady-state is the continued presence of food odor, which can alone maintain the steady-state for 48 72 hrs. Neither increased glucose nor L-arginine can alone preserve the steady state, although they partially preserve it. Glucose and arginine partially extend the effect of food odor after 72 hrs. CONCLUSIONS: These findings show that control of Aplysia feeding is more complex than was previously thought, in that multiple inhibitory factors interact in its control. PMID- 23028873 TI - Metastable differentially methylated regions within Arabidopsis inbred populations are associated with modified expression of non-coding transcripts. AB - Individual plants within a population may vary at both genetic and epigenetic levels. The rate of genetic divergence and its underlying mechanisms is well understood. Less is known about the factors contributing to epigenetic divergence among isogenic populations except that, despite the presence of mechanisms that faithfully maintain epigenetic marks, epigenetic differences are more frequent than genetic variation. Epigenetically divergent stretches of isogenic DNA sequence are called epialleles. Currently, it is not clear why certain regions exhibit variable epigenetic status. We identified and characterised two long RNA transcripts with altered expression and DNA methylation in an ago5 mutant. However, further investigation revealed that these changes were not dependent upon AGO5. Rather, the variable transcription of these loci in Arabidopsis mutant and wild-type populations corresponds to spontaneous differential methylated regions (DMRs) or epialleles. These two DMRs are delineated by RNAs which are highly expressed when the DMR is hypomethylated. Furthermore, they control the expression of 5' transcriptional start site mRNA variants of nearby protein coding genes. Our data support the recent observations that meiotically stable DMRs exist within inbred populations. We further demonstrate that DMR boundaries can be defined by putative non-coding promoter-associated transcripts. PMID- 23028874 TI - Anti-inflammatory and cardioprotective effects of tadalafil in diabetic mice. AB - BACKGROUND: Insulin resistance impairs nitric oxide (NO) bioavailability and obesity promotes a state of chronic inflammation and damages the vascular endothelium. Phosphodiesterase-5 inhibitors restore NO signaling and may reduce circulating inflammatory markers, and improve metabolic parameters through a number of mechanisms. We hypothesized that daily administration of the PDE-5 inhibitor, tadalafil (TAD) will attenuate inflammation, improve fasting plasma glucose and triglyceride levels, body weight, and reduce infarct size after ischemia/reperfusion injury in obese, diabetic mice. METHODS: Twenty leptin receptor null (db/db) mice underwent treatment with TAD (1 mg/Kg) or 10% DMSO for 28 days. Body weight and fasting plasma glucose levels were determined weekly. Upon completion, hearts were isolated and subjected to 30 min global ischemia followed by 60 min reperfusion in a Langendorff model. Plasma samples were taken for cytokine analysis and fasting triglyceride levels. Infarct size was measured using computer morphometry of tetrazolium stained sections. Additionally, ventricular cardiomyocytes were isolated and subjected to 40 min of simulated ischemia and reoxygenation. Necrosis was determined using trypan blue exclusion and LDH release assay and apoptosis was assessed by TUNEL assay after 1 h or 18 h of reoxygenation, respectively. RESULTS: Treatment with TAD caused a reduction in infarct size in the diabetic heart (23.2 +/- 1.5 vs. 47.8 +/- 3.7%, p<0.01, n = 6/group), reduced fasting glucose levels (292 +/- 31.8 vs. 511 +/- 19.3 mg/dL, p<0.001) and fasting triglycerides (43.3 +/- 21 vs. 129.7 +/- 29 mg/dL, p<0.05) as compared to DMSO, however body weight was not significantly reduced. Circulating tumor necrosis factor-alpha and interleukin-1beta were reduced after treatment compared to control (257 +/- 16.51 vs. 402.3 +/- 17.26 and 150.8 +/- 12.55 vs. 264 +/- 31.85 pg/mL, respectively; P<0.001) Isolated cardiomyocytes from TAD-treated mice showed reduced apoptosis and necrosis. CONCLUSION: We have provided the first evidence that TAD therapy ameliorates circulating inflammatory cytokines and chemokines in a diabetic animal model while improving fasting glucose levels and reducing infarct size following ischemia-reperfusion injury in the heart. PMID- 23028875 TI - Distinct motifs in the intracellular domain of human CD30 differentially activate canonical and alternative transcription factor NF-kappaB signaling. AB - The TNF-receptor superfamily member CD30 is expressed on normal and malignant lymphocytes, including anaplastic large cell lymphoma (ALCL) cells. CD30 transmits multiple effects, including activation of NF-kappaB signaling, cell proliferation, growth arrest and apoptosis. How CD30 generates these pleiotropic effects is currently unknown. Herein we describe ALCL cells expressing truncated forms of the CD30 intracellular domain that allowed us to identify the key regions responsible for transmitting its biological effects in lymphocytes. The first region (CD30(519-537)) activated both the alternative and canonical NF kappaB pathways as detected by p100 and IkappaBalpha degradation, IKKbeta dependent transcription of both IkappaBalpha and the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and induction of cell cycle arrest. In contrast, the second region of CD30 (CD30(538-595)) induced some aspects of canonical NF-kappaB activation, including transcription of IkappaBalpha, but failed to activate the alternative NF-kappaB pathway or drive p21(WAF1/CIP1)-mediated cell-cycle arrest. Direct comparison of canonical NF-kappaB activation by the two motifs revealed 4 fold greater p65 nuclear translocation following CD30(519-537) engagement. These data reveal that independent regions of the CD30 cytoplasmic tail regulate the magnitude and type of NF-kappaB activation and additionally identify a short motif necessary for CD30-driven growth arrest signals in ALCL cells. PMID- 23028877 TI - TNF-alpha rs1800629 polymorphism is not associated with HPV infection or cervical cancer in the Chinese population. AB - BACKGROUND: While HPV infection is the main cause of cervical cancer, genetic susceptibility to HPV infection is not well understood. Tumor necrosis factor alpha (TNF-alpha), involved in the defense against HPV infection, plays an important role in cervical cancer progression and regression. The aim of this study was to investigate the relationship between the TNF-alpha rs1800629 polymorphism and risk of HPV infection or cervical cancer. METHODS: Three groups were involved in this study of Chinese women. Group 1 consisted of 285 high risk HPV positive cervical cancer patients, Group 2, 225 high risk HPV positive patients without cervical cancer, and Group 3, 318 HPV negative women with no cervical cancer. Blood samples were obtained from all patients and genotyped by PCR-RLFP. Fifty randomly selected samples were further sequenced. RESULTS: The allele and genotype distributions of the TNF-alpha rs1800629 polymorphism were not significantly different between each of the groups (P>0.05). There are no significant relationship between rs1800629 polymorphism and high risk HPV infection (OR = 0.649, 95% CI: 0.253-1.670, P = 0.371), cervical cancer (OR = 0.993, 95% CI: 0.376-2.618, P = 0.988), or cervical cancer with HPV infection (OR = 0.663, 95% CI: 0.250-1.758, P = 0.409). CONCLUSIONS: We demonstrated that there is no association between TNF rs1800629 polymorphism and the HPV infection, or cervical cancer with HPV infection. PMID- 23028876 TI - A naturally occurring single nucleotide polymorphism in the Salmonella SPI-2 type III effector srfH/sseI controls early extraintestinal dissemination. AB - CD18 expressing phagocytes associated with the gastro-intestinal (GI) epithelium can shuttle Salmonella directly into the bloodstream within a few minutes following microbial ingestion. We have previously demonstrated that Salmonella controls the CD18 pathway to deeper tissue, manipulating the migratory properties of infected cells as an unappreciated component of its pathogenesis. We have observed that one type III effector, SrfH (also called SseI) that Salmonella secretes into infected phagocytes manipulates the host protein TRIP6 to stimulate their migration. Paradoxically, SrfH was shown in another study to subvert a different host protein, IQGAP1, in a manner that inhibits the productive motility of such cells, perhaps to avoid interactions with T cells. Here, we resolve the discrepancy. We report that one naturally occurring allele of srfH promotes the migration of infected phagocytes into the bloodstream, while another naturally occurring allele that differs by only a single nucleotide polymorphism (SNP) does not. This SNP determines if the protein contains an aspartic acid or a glycine residue at position 103 and may determine if SrfH binds TRIP6. SrfH Gly103 is a rare allele, but is present in the highly invasive strain Salmonella enterica serovar Typhimurium UK-1 (stands for universal killer). It is also present in the genome of the only sequenced strain belonging to the emerging pandemic Salmonella enterica serovar 4, [5],12,i:-, which is frequently associated with septicemia. Finally, we present evidence that suggests that Gifsy-2, the bacteriophage upon which srfH resides, is present in a clinical isolate of the human-specific pathogen, Salmonella enterica serovar Typhi. These observations may have interesting implications for our understanding of Salmonella pathogenesis. PMID- 23028878 TI - Accurate blood flow measurements: are artificial tracers necessary? AB - Imaging-based blood flow measurement techniques, such as particle image velocimetry, have become an important tool in cardiovascular research. They provide quantitative information about blood flow, which benefits applications ranging from developmental biology to tumor perfusion studies. Studies using these methods can be classified based on whether they use artificial tracers or red blood cells to visualize the fluid motion. We here present the first direct comparison in vivo of both methods. For high magnification cases, the experiments using red blood cells strongly underestimate the flow (up to 50% in the present case), as compared to the tracer results. For medium magnification cases, the results from both methods are indistinguishable as they give the same underestimation of the real velocities (approximately 33%, based on in vitro reference measurements). These results suggest that flow characteristics reported in literature cannot be compared without a careful evaluation of the imaging characteristics. A method to predict the expected flow averaging behavior for a particular facility is presented. PMID- 23028879 TI - EZN-2208 (PEG-SN38) overcomes ABCG2-mediated topotecan resistance in BRCA1 deficient mouse mammary tumors. AB - BRCA1 dysfunction in hereditary breast cancer causes defective homology-directed DNA repair and sensitivity towards DNA damaging agents like the clinically used topoisomerase I inhibitors topotecan and irinotecan. Using our conditional K14cre;Brca1(F/F);p53(F/F) mouse model, we showed previously that BRCA1;p53 deficient mammary tumors initially respond to topotecan, but frequently acquire resistance by overexpression of the efflux transporter ABCG2. Here, we tested the pegylated SN38 compound EZN-2208 as a novel approach to treat BRCA1-mutated tumors that express ABCG2. We found that EZN-2208 therapy resulted in more pronounced and durable responses of ABCG2-positive tumors than topotecan or irinotecan therapy. We also evaluated tumor-specific ABCG2 inhibition by Ko143 in Abcg2(-/-) host animals that carried tumors with topotecan-induced ABCG2 expression. Addition of Ko143 moderately increased overall survival of these animals, but did not yield tumor responses like those seen after EZN-2208 therapy. Our results suggest that pegylation of Top1 inhibitors may be a useful strategy to circumvent efflux transporter-mediated resistance and to improve their efficacy in the clinic. PMID- 23028880 TI - The neuron-astrocyte-microglia triad in normal brain ageing and in a model of neuroinflammation in the rat hippocampus. AB - Ageing is accompanied by a decline in cognitive functions; along with a variety of neurobiological changes. The association between inflammation and ageing is based on complex molecular and cellular changes that we are only just beginning to understand. The hippocampus is one of the structures more closely related to electrophysiological, structural and morphological changes during ageing. In the present study we examined the effect of normal ageing and LPS-induced inflammation on astroglia-neuron interaction in the rat hippocampus of adult, normal aged and LPS-treated adult rats. Astrocytes were smaller, with thicker and shorter branches and less numerous in CA1 Str. radiatum of aged rats in comparison to adult and LPS-treated rats. Astrocyte branches infiltrated apoptotic neurons of aged and LPS-treated rats. Cellular debris, which were more numerous in CA1 of aged and LPS-treated rats, could be found apposed to astrocytes processes and were phagocytated by reactive microglia. Reactive microglia were present in the CA1 Str. Radiatum, often in association with apoptotic cells. Significant differences were found in the fraction of reactive microglia which was 40% of total in adult, 33% in aged and 50% in LPS-treated rats. Fractalkine (CX3CL1) increased significantly in hippocampus homogenates of aged and LPS-treated rats. The number of CA1 neurons decreased in aged rats. In the hippocampus of aged and LPS-treated rats astrocytes and microglia may help clearing apoptotic cellular debris possibly through CX3CL1 signalling. Our results indicate that astrocytes and microglia in the hippocampus of aged and LPS infused rats possibly participate in the clearance of cellular debris associated with programmed cell death. The actions of astrocytes may represent either protective mechanisms to control inflammatory processes and the spread of further cellular damage to neighboring tissue, or they may contribute to neuronal damage in pathological conditions. PMID- 23028881 TI - Morphine decreases enteric neuron excitability via inhibition of sodium channels. AB - Gastrointestinal peristalsis is significantly dependent on the enteric nervous system. Constipation due to reduced peristalsis is a major side-effect of morphine, which limits the chronic usefulness of this excellent pain reliever in man. The ionic basis for the inhibition of enteric neuron excitability by morphine is not well characterized as previous studies have mainly utilized microelectrode recordings from whole mount myenteric plexus preparations in guinea pigs. Here we have developed a Swiss-Webster mouse myenteric neuron culture and examined their electrophysiological properties by patch-clamp techniques and determined the mechanism for morphine-induced decrease in neuronal excitability. Isolated neurons in culture were confirmed by immunostaining with pan-neuronal marker, beta-III tubulin and two populations were identified by calbindin and calretinin staining. Distinct neuronal populations were further identified based on the presence and absence of an afterhyperpolarization (AHP). Cells with AHP expressed greater density of sodium currents. Morphine (3 uM) significantly reduced the amplitude of the action potential, increased the threshold for spike generation but did not alter the resting membrane potential. The decrease in excitability resulted from inhibition of sodium currents. In the presence of morphine, the steady-state voltage dependence of Na channels was shifted to the left with almost 50% of channels unavailable for activation from hyperpolarized potentials. During prolonged exposure to morphine (two hours), action potentials recovered, indicative of the development of tolerance in single enteric neurons. These results demonstrate the feasibility of isolating mouse myenteric neurons and establish sodium channel inhibition as a mechanism for morphine-induced decrease in neuronal excitability. PMID- 23028882 TI - High resolution melt analysis (HRMA); a viable alternative to agarose gel electrophoresis for mouse genotyping. AB - Most mouse genetics laboratories maintain mouse strains that require genotyping in order to identify the genetically modified animals. The plethora of mutagenesis strategies and publicly available mouse alleles means that any one laboratory may maintain alleles with random or targeted insertions of orthologous or unrelated sequences as well as random or targeted deletions and point mutants. Many experiments require that different strains be cross bred conferring the need to genotype progeny at more than one locus. In contrast to the range of new technologies for mouse mutagenesis, genotyping methods have remained relatively static with alleles typically discriminated by agarose gel electrophoresis of PCR products. This requires a large amount of researcher time. Additionally it is susceptible to contamination of future genotyping experiments because it requires that tubes containing PCR products be opened for analysis. Progress has been made with the genotyping of mouse point mutants because a range of new high-throughput techniques have been developed for the detection of Single Nucleotide Polymorphisms. Some of these techniques are suitable for genotyping point mutants but do not detect insertion or deletion alleles. Ideally, mouse genetics laboratories would use a single, high-throughput platform that enables closed tube analysis to genotype the entire range of possible insertion and deletion alleles and point mutants. Here we show that High Resolution Melt Analysis meets these criteria, it is suitable for closed-tube genotyping of all allele types and current genotyping assays can be converted to this technology with little or no effort. PMID- 23028884 TI - Quantum entanglement and spin control in silicon nanocrystal. AB - Selective coherence control and electrically mediated exchange coupling of single electron spin between triplet and singlet states using numerically derived optimal control of proton pulses is demonstrated. We obtained spatial confinement below size of the Bohr radius for proton spin chain FWHM. Precise manipulation of individual spins and polarization of electron spin states are analyzed via proton induced emission and controlled population of energy shells in pure (29)Si nanocrystal. Entangled quantum states of channeled proton trajectories are mapped in transverse and angular phase space of (29)Si <100> axial channel alignment in order to avoid transversal excitations. Proton density and proton energy as impact parameter functions are characterized in single particle density matrix via discretization of diagonal and nearest off-diagonal elements. We combined high field and low densities (1 MeV/92 nm) to create inseparable quantum state by superimposing the hyperpolarizationed proton spin chain with electron spin of (29)Si. Quantum discretization of density of states (DOS) was performed by the Monte Carlo simulation method using numerical solutions of proton equations of motion. Distribution of gaussian coherent states is obtained by continuous modulation of individual spin phase and amplitude. Obtained results allow precise engineering and faithful mapping of spin states. This would provide the effective quantum key distribution (QKD) and transmission of quantum information over remote distances between quantum memory centers for scalable quantum communication network. Furthermore, obtained results give insights in application of channeled protons subatomic microscopy as a complete versatile scanning-probe system capable of both quantum engineering of charged particle states and characterization of quantum states below diffraction limit linear and in-depth resolution.PACS NUMBERS: 03.65.Ud, 03.67.Bg, 61.85.+p, 67.30.hj. PMID- 23028883 TI - The Plasmodium falciparum erythrocyte invasion ligand Pfrh4 as a target of functional and protective human antibodies against malaria. AB - BACKGROUND: Acquired antibodies are important in human immunity to malaria, but key targets remain largely unknown. Plasmodium falciparum reticulocyte-binding homologue-4 (PfRh4) is important for invasion of human erythrocytes and may therefore be a target of protective immunity. METHODS: IgG and IgG subclass specific responses against different regions of PfRh4 were determined in a longitudinal cohort of 206 children in Papua New Guinea (PNG). Human PfRh4 antibodies were tested for functional invasion-inhibitory activity, and expression of PfRh4 by P. falciparum isolates and sequence polymorphisms were determined. RESULTS: Antibodies to PfRh4 were acquired by children exposed to P. falciparum malaria, were predominantly comprised of IgG1 and IgG3 subclasses, and were associated with increasing age and active parasitemia. High levels of antibodies, particularly IgG3, were strongly predictive of protection against clinical malaria and high-density parasitemia. Human affinity-purified antibodies to the binding region of PfRh4 effectively inhibited erythrocyte invasion by P. falciparum merozoites and antibody levels in protected children were at functionally-active concentrations. Although expression of PfRh4 can vary, PfRh4 protein was expressed by most isolates derived from the cohort and showed limited sequence polymorphism. CONCLUSIONS: Evidence suggests that PfRh4 is a target of antibodies that contribute to protective immunity to malaria by inhibiting erythrocyte invasion and preventing high density parasitemia. These findings advance our understanding of the targets and mechanisms of human immunity and evaluating the potential of PfRh4 as a component of candidate malaria vaccines. PMID- 23028885 TI - A spirulina-enhanced diet provides neuroprotection in an alpha-synuclein model of Parkinson's disease. AB - Inflammation in the brain plays a major role in neurodegenerative diseases. In particular, microglial cell activation is believed to be associated with the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). An increase in microglia activation has been shown in the substantia nigra pars compacta (SNpc) of PD models when there has been a decrease in tyrosine hydroxylase (TH) positive cells. This may be a sign of neurotoxicity due to prolonged activation of microglia in both early and late stages of disease progression. Natural products, such as spirulina, derived from blue green algae, are believed to help reverse this effect due to its anti-inflammatory/anti oxidant properties. An adeno-associated virus vector (AAV9) for alpha-synuclein was injected in the substantia nigra of rats to model Parkinson's disease and to study the effects of spirulina on the inflammatory response. One month prior to surgeries, rats were fed either a diet enhanced with spirulina or a control diet. Immunohistochemistry was analyzed with unbiased stereological methods to quantify lesion size and microglial activation. As hypothesized, spirulina was neuroprotective in this alpha-synuclein model of PD as more TH+ and NeuN+ cells were observed; spirulina concomitantly decreased the numbers of activated microglial cells as determined by MHCII expression. This decrease in microglia activation may have been due, in part, to the effect of spirulina to increase expression of the fractalkine receptor (CX3CR1) on microglia. With this study we hypothesize that alpha-synuclein neurotoxicity is mediated, at least in part, via an interaction with microglia. We observed a decrease in activated microglia in the rats that received a spirulina- enhanced diet concomitant to neuroprotection. The increase in CX3CR1 in the groups that received spirulina, suggests a potential mechanism of action. PMID- 23028886 TI - Perlecan Domain V induces VEGf secretion in brain endothelial cells through integrin alpha5beta1 and ERK-dependent signaling pathways. AB - Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the alpha(5)beta(1) integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio modulatory activity outside of the brain, binds poorly to alpha(5)beta(1) and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction of DV with alpha(5)beta(1). Furthermore, we investigated the importance of AKT and ERK signaling in DV-induced VEGF expression and secretion. We show that DV increases the phosphorylation of ERK, which leads to subsequent activation and stabilization of eIF4E and HIF-1alpha. Inhibition of ERK activity by U0126 suppressed DV-induced expression and secretion of VEGR in BECs. While DV was capable of phosphorylating AKT we show that AKT phosphorylation does not play a role in DV's induction of VEGF expression or secretion using two separate inhibitors, LY294002 and Akt IV. Lastly, we demonstrate that VEGF activity is critical for DV increases in BEC proliferation, as well as angiogenesis in a BEC neuronal co-culture system. Collectively, our findings expand our understanding of DV's mechanism of action on BECs, and further support its potential as a novel stroke therapy. PMID- 23028887 TI - On-lattice simulation of T cell motility, chemotaxis, and trafficking in the lymph node paracortex. AB - Agent-based simulation is a powerful method for investigating the complex interplay of the processes occurring in a lymph node during an adaptive immune response. We have previously established an agent-based modeling framework for the interactions between T cells and dendritic cells within the paracortex of lymph nodes. This model simulates in three dimensions the "random-walk" T cell motility observed in vivo, so that cells interact in space and time as they process signals and commit to action such as proliferation. On-lattice treatment of cell motility allows large numbers of densely packed cells to be simulated, so that the low frequency of T cells capable of responding to a single antigen can be dealt with realistically. In this paper we build on this model by incorporating new numerical methods to address the crucial processes of T cell ingress and egress, and chemotaxis, within the lymph node. These methods enable simulation of the dramatic expansion and contraction of the T cell population in the lymph node paracortex during an immune response. They also provide a novel probabilistic method to simulate chemotaxis that will be generally useful in simulating other biological processes in which chemotaxis is an important feature. PMID- 23028888 TI - Use of fibrates and cancer risk: a systematic review and meta-analysis of 17 long term randomized placebo-controlled trials. AB - BACKGROUND: Fibrates comprise a class of well-established antilipidemic agents that significantly reduce cardiovascular events. Given the concerns of cancer with fibrate therapy, we undertook a systematic review and meta-analysis to investigate the effects of fibrates on cancer outcomes. METHODS: We systematically searched Medline, Scopus, SCI Expanded, and the Cochrane Library for studies published up to 2012. We included randomized controlled trials (RCTs) that evaluated a fibrate therapy compared with placebo, had a minimum duration of two years, and reported data on the incidence of and/or deaths from cancer during the trial. Reviews of each study were performed and the relative data were abstracted. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated using the inverse variance weighted approach. Subgroup, sensitivity and meta-regression analyses were also conducted. RESULTS: Seventeen RCTs, involving 44,929 participants with an average follow-up of 5.2 years, contributed to the analysis. The degree of variability between trials was consistent with what would be expected to occur by chance alone. The quantitative synthesis of data retrieved from the RCTs was not indicative of a fibrate effect on cancer incidence (780 [fibrate] vs 814 [control]; RR = 1.02, 95% CI 0.92-1.12) or cancer death (385 [fibrate] vs 377 [control]; RR = 1.06, 95% CI: 0.92-1.22). When the analysis was restricted to major RCTs, the results did not substantially change. Similarly, we found no evidence of differential effects by length of follow-up or type of fibrate. Insignificant results were also obtained for the role of fibrates in cancers of the respiratory tract, breast, colon, gastrointestinal tract, prostate, genitourinary tract, or in melanoma. CONCLUSION: Our findings demonstrate that fibrates have a neutral effect on cancer outcomes. However, it is important to continue monitoring their long-term safety profiles. PMID- 23028889 TI - NOD1 activation induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis. AB - The innate immune system is responsible for the initial response of an organism to potentially harmful stressors, pathogens or tissue injury, and accordingly plays an essential role in the pathogenesis of many inflammatory processes, including some cardiovascular diseases. Toll like receptors (TLR) and nucleotide binding oligomerization domain-like receptors (NLRs) are pattern recognition receptors that play an important role in the induction of innate immune and inflammatory responses. There is a line of evidence supporting that activation of TLRs contributes to the development and progression of cardiovascular diseases but less is known regarding the role of NLRs. Here we demonstrate the presence of the NLR member NOD1 (nucleotide-binding oligomerization domain containing 1) in the murine heart. Activation of NOD1 with the specific agonist C12-iEDAP, but not with the inactive analogue iE-Lys, induces a time- and dose-dependent cardiac dysfunction that occurs concomitantly with cardiac fibrosis and apoptosis. The administration of iEDAP promotes the activation of the NF-kappaB and TGF-beta pathways and induces apoptosis in whole hearts. At the cellular level, both native cardiomyocytes and cardiac fibroblasts expressed NOD1. The NLR activation in cardiomyocytes was associated with NF-kappaB activation and induction of apoptosis. NOD1 stimulation in fibroblasts was linked to NF-kappaB activation and to increased expression of pro-fibrotic mediators. The down-regulation of NOD1 by specific siRNAs blunted the effect of iEDAP on the pro-fibrotic TGF-beta pathway and cell apoptosis. In conclusion, our report uncovers a new pro-inflammatory target that is expressed in the heart, NOD1. The specific activation of this NLR induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis, pathological processes involved in several cardiac diseases such as heart failure. PMID- 23028891 TI - Directional migration of recirculating lymphocytes through lymph nodes via random walks. AB - Naive T lymphocytes exhibit extensive antigen-independent recirculation between blood and lymph nodes, where they may encounter dendritic cells carrying cognate antigen. We examine how long different T cells may spend in an individual lymph node by examining data from long term cannulation of blood and efferent lymphatics of a single lymph node in the sheep. We determine empirically the distribution of transit times of migrating T cells by applying the Least Absolute Shrinkage & Selection Operator (LASSO) or regularised S-LASSO to fit experimental data describing the proportion of labelled infused cells in blood and efferent lymphatics over time. The optimal inferred solution reveals a distribution with high variance and strong skew. The mode transit time is typically between 10 and 20 hours, but a significant number of cells spend more than 70 hours before exiting. We complement the empirical machine learning based approach by modelling lymphocyte passage through the lymph node insilico. On the basis of previous two photon analysis of lymphocyte movement, we optimised distributions which describe the transit times (first passage times) of discrete one dimensional and continuous (Brownian) three dimensional random walks with drift. The optimal fit is obtained when drift is small, i.e. the ratio of probabilities of migrating forward and backward within the node is close to one. These distributions are qualitatively similar to the inferred empirical distribution, with high variance and strong skew. In contrast, an optimised normal distribution of transit times (symmetrical around mean) fitted the data poorly. The results demonstrate that the rapid recirculation of lymphocytes observed at a macro level is compatible with predominantly randomised movement within lymph nodes, and significant probabilities of long transit times. We discuss how this pattern of migration may contribute to facilitating interactions between low frequency T cells and antigen presenting cells carrying cognate antigen. PMID- 23028890 TI - Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice. AB - Adrenomedullin (AM) and its receptor complexes, calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2/3, are highly expressed in lymphatic endothelial cells and are required for embryonic lymphatic development. To determine the role of Calcrl in adulthood, we used an inducible Cre-loxP system to temporally and ubiquitously delete Calcrl in adult mice. Following tamoxifen injection, Calcrl(fl/fl)/CAGGCre-ERTM mice rapidly developed corneal edema and inflammation that was preceded by and persistently associated with dilated corneoscleral lymphatics. Lacteals and submucosal lymphatic capillaries of the intestine were also dilated, while mesenteric collecting lymphatics failed to properly transport chyle after an acute Western Diet, culminating in chronic failure of Calcrl(fl/fl)/CAGGCre-ERTM mice to gain weight. Dermal lymphatic capillaries were also dilated and chronic edema challenge confirmed significant and prolonged dermal lymphatic insufficiency. In vivo and in vitro imaging of lymphatics with either genetic or pharmacologic inhibition of AM signaling revealed markedly disorganized lymphatic junctional proteins ZO-1 and VE cadherin. The maintenance of AM signaling during adulthood is required for preserving normal lymphatic permeability and function. Collectively, these studies reveal a spectrum of lymphatic defects in adult Calcrl(fl/fl)/CAGGCre ERTM mice that closely recapitulate the clinical symptoms of patients with corneal, intestinal and peripheral lymphangiectasia. PMID- 23028892 TI - Resting-state functional connectivity bias of middle temporal gyrus and caudate with altered gray matter volume in major depression. AB - Magnetic resonance imaging (MRI) studies have indicated that the structure deficits and resting-state functional connectivity (FC) imbalances in cortico limbic circuitry might underline the pathophysiology of MDD. Using structure and functional MRI, our aim is to investigate gray matter abnormalities in patients with treatment-resistant depression (TRD) and treatment-responsive depression (TSD), and test whether the altered gray matter is associated with altered FC. Voxel-based morphometry was used to investigate the regions with gray matter abnormality and FC analysis was further conducted between each gray matter abnormal region and the remaining voxels in the brain. Using one-way analysis of variance, we found significant gray matter abnormalities in the right middle temporal cortex (MTG) and bilateral caudate among the TRD, TSD and healthy controls. For the FC of the right MTG, we found that both the patients with TRD and TSD showed altered connectivity mainly in the default-mode network (DMN). For the FC of the right caudate, both patient groups showed altered connectivity in the frontal regions. Our results revealed the gray matter reduction of right MTG and bilateral caudate, and disrupted functional connection to widely distributed circuitry in DMN and frontal regions, respectively. These results suggest that the abnormal DMN and reward circuit activity might be biomarkers of depression trait. PMID- 23028893 TI - Prevalence of diabetic retinopathy in mainland China: a meta-analysis. AB - BACKGROUND: Although diabetic retinopathy (DR) is considered to be a major cause of blindness, this is the first meta-analysis to investigate the pooled prevalence of DR in mainland China. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a search of all English reports on population-based studies for the prevalence of DR using Medline, EMbase, Web of Science, Google (scholar), and all Chinese reports were identified manually and on-line using CBMDisc, Chongqing VIP database, and CNKI database. A meta-analysis was carried out. The fixed effects model or random effects model was used as a statistical test for homogeneity. Nineteen studies were included. The prevalence of DR, non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) in the pooled general population was 1.3% (95%CI: 0.5%-3.2%), 1.1% (95%CI: 0.6%-2.1%), and 0.1% (95%CI: 0.1%-0.3%), respectively, but was 23% (95%CI: 17.8%-29.2%), 19.1% (95%CI: 13.6%-26.3%), and 2.8% (95%CI: 1.9%-4.2%) in the diabetic group. The prevalence rate of DR in the pooled rural population was higher than that in the urban population, 1.6% (95%CI: 1.3%-2%), and the diabetic population, 29.1% (95%CI: 20.9%-38.9%). The prevalence of DR was higher in the Northern region compared with the Southern region. CONCLUSIONS/SIGNIFICANCE: The prevalence of DR in mainland China appeared a little high, and varied according to area. NPDR was more common. This study highlights the necessity for DR screening in the rural areas of China. PMID- 23028894 TI - Dynamic dyssynchrony and impaired contractile reserve of the left ventricle in beta-thalassaemia major: an exercise echocardiographic study. AB - BACKGROUND: Performance of the left ventricle during exercise stress in thalassaemia patients is uncertain. We aimed to explore the phenomenon of dynamic dyssynchrony and assess contractile reserve in patients with beta-thalassaemia major and determine their relationships with myocardial iron load. METHODS AND RESULTS: Thirty-two thalassaemia patients (16 males), aged 26.8 +/- 6.9 years, without heart failure and 17 healthy controls were studied. Their left ventricular (LV) volumes, ejection fraction, systolic dyssynchrony index (SDI), and myocardial acceleration during isovolumic LV contraction (IVA) were determined at rest and during submaximal bicycle exercise testing using 3 dimensional and tissue Doppler echocardiography. Myocardial iron load as assessed by T2* cardiac magnetic resonance in patients were further related to indices of LV dyssynchrony and contractile reserve. At rest, patients had significantly greater LV SDI (p<0.001) but similar IVA (p = 0.22) compared with controls. With exercise stress, the prevalence of mechanical dyssynchrony (SDI>4.6%, control+2SD) increased from baseline 25% to 84% in patients. Delta SDI(exercise baseline) correlated with exercise-baseline differences in LV ejection fraction (p<0.001) and stroke volume (p = 0.006). Compared with controls, patients had significantly less exercise-induced increase in LV ejection fraction, cardiac index, and IVA (interaction, all p<0.05) and had impaired contractile reserve as reflected by the gentler IVA-heart rate slope (p = 0.018). Cardiac T2* in patients correlated with baseline LV SDI (r = -0.44, p = 0.011) and IVA-heart rate slope (r = 0.36, p = 0.044). CONCLUSIONS: Resting LV dyssynchrony is associated with myocardial iron load. Exercise stress further unveils LV dynamic dyssynchrony and impaired contractile reserve in patients with beta-thalassaemia major. PMID- 23028895 TI - Broad and cross-clade CD4+ T-cell responses elicited by a DNA vaccine encoding highly conserved and promiscuous HIV-1 M-group consensus peptides. AB - T-cell based vaccine approaches have emerged to counteract HIV-1/AIDS. Broad, polyfunctional and cytotoxic CD4(+) T-cell responses have been associated with control of HIV-1 replication, which supports the inclusion of CD4(+) T-cell epitopes in vaccines. A successful HIV-1 vaccine should also be designed to overcome viral genetic diversity and be able to confer immunity in a high proportion of immunized individuals from a diverse HLA-bearing population. In this study, we rationally designed a multiepitopic DNA vaccine in order to elicit broad and cross-clade CD4(+) T-cell responses against highly conserved and promiscuous peptides from the HIV-1 M-group consensus sequence. We identified 27 conserved, multiple HLA-DR-binding peptides in the HIV-1 M-group consensus sequences of Gag, Pol, Nef, Vif, Vpr, Rev and Vpu using the TEPITOPE algorithm. The peptides bound in vitro to an average of 12 out of the 17 tested HLA-DR molecules and also to several molecules such as HLA-DP, -DQ and murine IA(b) and IA(d). Sixteen out of the 27 peptides were recognized by PBMC from patients infected with different HIV-1 variants and 72% of such patients recognized at least 1 peptide. Immunization with a DNA vaccine (HIVBr27) encoding the identified peptides elicited IFN-gamma secretion against 11 out of the 27 peptides in BALB/c mice; CD4(+) and CD8(+) T-cell proliferation was observed against 8 and 6 peptides, respectively. HIVBr27 immunization elicited cross-clade T-cell responses against several HIV-1 peptide variants. Polyfunctional CD4(+) and CD8(+) T cells, able to simultaneously proliferate and produce IFN-gamma and TNF-alpha, were also observed. This vaccine concept may cope with HIV-1 genetic diversity as well as provide increased population coverage, which are desirable features for an efficacious strategy against HIV-1/AIDS. PMID- 23028896 TI - Differential gene and microRNA expression between etoposide resistant and etoposide sensitive MCF7 breast cancer cell lines. AB - In order to develop targeted strategies for combating drug resistance it is essential to understand it's basic molecular mechanisms. In an exploratory study we have found several possible indicators of etoposide resistance operating in MCF7VP cells, including up-regulation of ABC transporter genes, modulation of miRNA, and alteration in copy numbers of genes. PMID- 23028897 TI - A randomized trial of selenium supplementation and risk of type-2 diabetes, as assessed by plasma adiponectin. AB - BACKGROUND: Evidence that selenium affects the risk of type-2 diabetes is conflicting, with observational studies and a few randomized trials showing both lower and higher risk linked to the level of selenium intake and status. We investigated the effect of selenium supplementation on the risk of type-2 diabetes in a population of relatively low selenium status as part of the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study. Plasma adiponectin concentration, a recognised independent predictor of type-2 diabetes risk and known to be correlated with circulating selenoprotein P, was the biomarker chosen. METHODS: In a randomized, double-blind, placebo-controlled trial, five hundred and one elderly volunteers were randomly assigned to a six month intervention with 100, 200 or 300 ug selenium/d as high-selenium or placebo yeast. Adiponectin concentration was measured by ELISA at baseline and after six months of treatment in 473 participants with one or both plasma samples available. RESULTS: Mean (SD) plasma selenium concentration was 88.5 ng/g (19.1) at baseline and increased significantly in the selenium-treatment groups. In baseline cross-sectional analyses, the fully adjusted geometric mean of plasma adiponectin was 14% lower (95% CI, 0-27%) in the highest than in the lowest quartile of plasma selenium (P for linear trend = 0.04). In analyses across randomized groups, however, selenium supplementation had no effect on adiponectin levels after six months of treatment (P = 0.96). CONCLUSIONS: These findings are reassuring as they did not show a diabetogenic effect of a six-month supplementation with selenium in this sample of elderly individuals of relatively low selenium status. PMID- 23028898 TI - Intracerebral hemorrhages in adults with community associated bacterial meningitis in adults: should we reconsider anticoagulant therapy? AB - OBJECTIVE: To study the incidence, clinical presentation and outcome of intracranial hemorrhagic complications in adult patients with community associated bacterial meningitis. METHODS: Nationwide prospective cohort study from all hospitals in the Netherlands, from 1 March 2006, through 31 December 2010. RESULTS: Of the 860 episodes of bacterial meningitis that were included, 24 were diagnosed with intracranial hemorrhagic complications: 8 upon presentation and 16 during clinical course. Clinical presentation between patients with or without intracranial hemorrhage was similar. Causative bacteria were Streptococcus pneumoniae in 16 patients (67%), Staphylococcus aureus in 5 (21%), Pseudomonas aeruginosa and Listeria monocytogenes both in 1 patient (4%). Occurrence of intracranial hemorrhage was associated with death (63% vs. 15%, P<0.001) and unfavorable outcome (94% vs. 34%, P<0.001). The use of anticoagulants on admission was associated with a higher incidence of intracranial hemorrhages (odds ratio 5.84, 95% confidence interval 2.17-15.76). CONCLUSION: Intracranial hemorrhage is a rare but devastating complication in patients with community-associated bacterial meningitis. Since anticoagulant therapy use is associated with increased risk for intracranial hemorrhage, physicians may consider reversing or temporarily discontinuing anticoagulation in patients with bacterial meningitis. PMID- 23028899 TI - Mesenchymal stem cells repress Th17 molecular program through the PD-1 pathway. AB - MSC display potent suppressive properties initially described a decade ago. More recently, MSC suppressive activities on T-cell effector pathways have been investigated. MSC modulate CD4 differentiation through different mechanisms depending on culture conditions and display disparate activities on T cells according to their differentiation status. A significant amount of evidence for MSC effects on Th17 cells revealed that MSC could be suppressive under diverse circumstances but also enhance Th17 cell activity under other conditions. In the present study, we investigated the suppressive effects of MSC on Th1 and Th17 subsets of T cells using T cells undergoing Th1 and Th17 polarization or mature Th1 and Th17 cells. MSC inhibited the proliferation of T cells during their differentiation toward Th1 cells and mature Th1 cells. This suppressive effect was maintained in a transwell cell culture insert demonstrating the major role played by soluble factors. Using the transwell cell separation barrier, we observed that MSC decrease the number of T cells undergoing Th17 differentiation whereas they did not affect IL-17 production by mature Th17, demonstrating the need for cell contact for suppressing Th17 cell function. Moreover, we reported that PD-L1 is highly expressed on MSC co-cultured with differentiating or polarized Th1 and Th17 cells. Using neutralizing antibodies specific for PD-L1 and PD-1 we showed that the mechanisms by which MSC mediate Th17 cell repolarization depend on PD-L1 expression on MSC. Taken together our results demonstrated a cell-to-cell contact depend mechanism in the selective immunosuppression of MSC on mature Th17 cells through up-regulation of PD-L1. PMID- 23028900 TI - Innate immunity and non-Hodgkin's lymphoma (NHL) related genes in a nested case control study for gastric cancer risk. AB - OBJECTIVE: Genetic variants regulating the host immune system may contribute to the susceptibility for the development of gastric cancer. Little is known about the role of the innate immunity- and non-Hodgkin's lymphoma (NHL)-related genes for gastric cancer risk. This nested case-control study was conducted to identify candidate genes for gastric cancer risk for future studies. METHODS: In the Discovery phase, 3,072 SNPs in 203 innate immunity- and 264 NHL-related genes using the Illumine GoldenGateTM OPA Panel were analyzed in 42 matched case control sets selected from the Korean Multi-center Cancer Cohort (KMCC). Six significant SNPs in four innate immunity (DEFA6, DEFB1, JAK3, and ACAA1) and 11 SNPs in nine NHL-related genes (INSL3, CHMP7, BCL2L11, TNFRSF8, RAD50, CASP7, CHUK, CD79B, and CLDN9) with a permutated p-value <0.01 were re-genotyped in the Replication phase among 386 cases and 348 controls. Odds ratios (ORs) for gastric cancer risk were estimated adjusting for age, smoking status, and H. pylori and CagA sero-positivity. Summarized ORs in the total study population (428 cases and 390 controls) are presented using pooled- and meta-analyses. RESULTS: Four SNPS had no heterogeneity across the phases: in the meta-analysis, DEFA6 rs13275170 and DEFB1 rs2738169 had both a 1.3-fold increased odds ratio (OR) for gastric cancer (95% CIs = 1.1-1.6; and 1.1-1.5, respectively). INSL3 rs10421916 and rs11088680 had both a 0.8-fold decreased OR for gastric cancer (95% CIs = 0.7 0.97; and 0.7-0.9, respectively). CONCLUSIONS: Our findings suggest that certain variants in the innate immunity and NHL-related genes affect the gastric cancer risk, perhaps by modulating infection-inflammation-immunity mechanisms that remain to be defined. PMID- 23028901 TI - Cyclosporine A enhances Th2 bias at the maternal-fetal interface in early human pregnancy with aid of the interaction between maternal and fetal cells. AB - Our previous study has demonstrated that cyclosporine A (CsA) administration in vivo induces Th2 bias at the maternal-fetal interface, leading to improved murine pregnancy outcomes. Here, we investigated how CsA treatment in vitro induced Th2 bias at the human maternal-fetal interface in early pregnancy. The cell co culture in vitro in different combination of component cells at the maternal fetal interface was established to investigate the regulation of CsA on cytokine production from the interaction of these cells. It was found that interferon (IFN)-gamma was produced only by decidual immune cells (DICs), and not by trophoblasts or decidual stromal cells (DSCs); all these cells secreted interleukin (IL)-4, IL-10, and tumor necrosis factor (TNF)-alpha. Treatment with CsA completely blocked IFN-gamma production in DICs and inhibited TNF-alpha production in all examined cells. CsA increased IL-10 and IL-4 production in trophoblasts co-cultured with DSCs and DICs although CsA treatment did not affect IL-10 or IL-4 production in any of the cells when cultured alone. These results suggest that CsA promotes Th2 bias at the maternal-fetal interface by increasing Th2-type cytokine production in trophoblasts with the aid of DSCs and DICs, while inhibiting Th1-type cytokine production in DICs and TNF-alpha production in all investigated cells. Our study might be useful in clinical therapeutics for spontaneous pregnancy wastage and other pregnancy complications. PMID- 23028902 TI - Characterization of in vivo Dlg1 deletion on T cell development and function. AB - BACKGROUND: The polarized reorganization of the T cell membrane and intracellular signaling molecules in response to T cell receptor (TCR) engagement has been implicated in the modulation of T cell development and effector responses. In siRNA-based studies Dlg1, a MAGUK scaffold protein and member of the Scribble polarity complex, has been shown to play a role in T cell polarity and TCR signal specificity, however the role of Dlg1 in T cell development and function in vivo remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the combined data from three independently-derived dlg1-knockout mouse models; two germline deficient knockouts and one conditional knockout. While defects were not observed in T cell development, TCR-induced early phospho-signaling, actin-mediated events, or proliferation in any of the models, the acute knockdown of Dlg1 in Jurkat T cells diminished accumulation of actin at the IS. Further, while Th1 type cytokine production appeared unaffected in T cells derived from mice with a dlg1 germline-deficiency, altered production of TCR-dependent Th1 and Th2-type cytokines was observed in T cells derived from mice with a conditional loss of dlg1 expression and T cells with acute Dlg1 suppression, suggesting a differential requirement for Dlg1 activity in signaling events leading to Th1 versus Th2 cytokine induction. The observed inconsistencies between these and other knockout models and siRNA strategies suggest that 1) compensatory upregulation of alternate gene(s) may be masking a role for dlg1 in controlling TCR-mediated events in dlg1 deficient mice and 2) the developmental stage during which dlg1 ablation begins may control the degree to which compensatory events occur. CONCLUSIONS/SIGNIFICANCE: These findings provide a potential explanation for the discrepancies observed in various studies using different dlg1-deficient T cell models and underscore the importance of acute dlg1 ablation to avoid the upregulation of compensatory mechanisms for future functional studies of the Dlg1 protein. PMID- 23028903 TI - Monitoring the cytoskeletal EGF response in live gastric carcinoma cells. AB - Altered cell motility is considered to be a key factor in determining tumor invasion and metastasis. Epidermal growth factor (EGF) signaling has been implicated in this process by affecting cytoskeletal organization and dynamics in multiple ways. To sort the temporal and spatial regulation of EGF-dependent cytoskeletal re-organization in relation to a cell's motile behavior time-lapse microscopy was performed on EGF-responsive gastric carcinoma-derived MKN1 cells co-expressing different fluorescently labeled cytoskeletal filaments and focal adhesion components in various combinations. The experiments showed that EGF almost instantaneously induces a considerable increase in membrane ruffling and lamellipodial activity that can be inhibited by Cetuximab EGF receptor antibodies and is not elicited in non-responsive gastric carcinoma Hs746T cells. The transient cell extensions are rich in actin but lack microtubules and keratin intermediate filaments. We show that this EGF-induced increase in membrane motility can be measured by a simple image processing routine. Microtubule plus ends subsequently invade growing cell extensions, which start to accumulate focal complexes at the lamellipodium-lamellum junction. Such paxillin-positive complexes mature into focal adhesions by tyrosine phosphorylation and recruitment of zyxin. These adhesions then serve as nucleation sites for keratin filaments which are used to enlarge the neighboring peripheral keratin network. Focal adhesions are either disassembled or give rise to stable zyxin-rich fibrillar adhesions which disassemble in the presence of EGF to support formation of new focal adhesion sites in the cell periphery. Taken together the results serve as a basis for modeling the early cytoskeletal EGF response as a tightly coordinated and step-wise process which is relevant for the prediction of the effectiveness of anti-EGF receptor-based tumor therapy. PMID- 23028904 TI - Longitudinal qPCR study of the dynamics of L. crispatus, L. iners, A. vaginae, (sialidase positive) G. vaginalis, and P. bivia in the vagina. AB - BACKGROUND: To obtain more detailed understanding of the causes of disturbance of the vaginal microflora (VMF), a longitudinal study was carried out for 17 women during two menstrual cycles. METHODS: Vaginal swabs were obtained daily from 17 non-pregnant, menarchal volunteers. For each woman, Gram stains were scored, the quantitative changes of 5 key vaginal species, i.e. Atopobium vaginae, Lactobacillus crispatus, L. iners, (sialidase positive) Gardnerella vaginalis and Prevotella bivia were quantified with qPCR and hydrogen-peroxide production was assessed on TMB+ agar. RESULTS: Women could be divided in 9 subjects with predominantly normal VMF (grades Ia, Ib and Iab, group N) and 8 with predominantly disturbed VMF (grades I-like, II, III and IV, group D). VMF was variable between women, but overall stable for most of the women. Menses were the strongest disturbing factor of the VMF. L. crispatus was present at log7-9 cells/ml in grade Ia, Iab and II VMF, but concentrations declined 100-fold during menses. L. crispatus below log7 cells/ml corresponded with poor H(2)O(2) production. L. iners was present at log 10 cells/ml in grade Ib, II and III VMF. Sialidase negative G. vaginalis strains (average log5 cells/ml) were detected in grade I, I-like and IV VMF. In grade II VMF, predominantly a mixture of both sialidase negative and positive G. vaginalis strains (average log9 cells/ml) were present, and predominantly sialidase positive strains in grade III VMF. The presence of A. vaginae (average log9 cells/ml) coincided with grade II and III VMF. P. bivia (log4-8 cells/ml) was mostly present in grade III vaginal microflora. L. iners, G. vaginalis, A. vaginae and P. bivia all increased around menses for group N women, and as such L. iners was considered a member of disturbed VMF. CONCLUSIONS: This qPCR-based study confirms largely the results of previous culture-based, microscopy-based and pyrosequencing-based studies. PMID- 23028905 TI - Use of postmortem human dura mater and scalp for deriving human fibroblast cultures. AB - Fibroblasts can be collected from deceased individuals, grown in culture, reprogrammed into induced pluripotent stem cells (iPSCs), and then differentiated into a multitude of cell types, including neurons. Past studies have generated iPSCs from somatic cell biopsies from either animal or human subjects. Previously, fibroblasts have only been successfully cultured from postmortem human skin in two studies. Here we present data on fibroblast cell cultures generated from 146 scalp and/or 53 dura mater samples from 146 postmortem human brain donors. In our overall sample, the odds of successful dural culture was almost two-fold compared with scalp (OR = 1.95, 95% CI: [1.01, 3.9], p = 0.047). Using a paired design within subjects for whom both tissues were available for culture (n = 53), the odds of success for culture in dura was 16-fold as compared to scalp (OR = 16.0, 95% CI: [2.1-120.6], p = 0.0007). Unattended death, tissue donation source, longer postmortem interval (PMI), and higher body mass index (BMI) were associated with unsuccessful culture in scalp (all p<0.05), but not in dura. While scalp cells proliferated more and grew more rapidly than dura cells [F (1, 46) = 12.94, p<0.008], both tissues could be generated and maintained as fibroblast cell lines. Using a random sample of four cases, we found that both postmortem scalp and dura could be successfully reprogrammed into iPSC lines. Our study demonstrates that postmortem dura mater, and to a lesser extent, scalp, are viable sources of living fibroblasts for culture that can be used to generate iPSCs. These tissues may be accessible through existing brain tissue collections, which is critical for studying disorders such as neuropsychiatric diseases. PMID- 23028906 TI - A comparative analysis of glomerulus development in the pronephros of medaka and zebrafish. AB - The glomerulus of the vertebrate kidney links the vasculature to the excretory system and produces the primary urine. It is a component of every single nephron in the complex mammalian metanephros and also in the primitive pronephros of fish and amphibian larvae. This systematic work highlights the benefits of using teleost models to understand the pronephric glomerulus development. The morphological processes forming the pronephric glomerulus are astoundingly different between medaka and zebrafish. (1) The glomerular primordium of medaka - unlike the one of zebrafish - exhibits a C-shaped epithelial layer. (2) The C shaped primordium contains a characteristic balloon-like capillary, which is subsequently divided into several smaller capillaries. (3) In zebrafish, the bilateral pair of pronephric glomeruli is fused at the midline to form a glomerulus, while in medaka the two parts remain unmerged due to the interposition of the interglomerular mesangium. (4) Throughout pronephric development the interglomerular mesangial cells exhibit numerous cytoplasmic granules, which are reminiscent of renin-producing (juxtaglomerular) cells in the mammalian afferent arterioles. Our systematic analysis of medaka and zebrafish demonstrates that in fish, the morphogenesis of the pronephric glomerulus is not stereotypical. These differences need be taken into account in future analyses of medaka mutants with glomerulus defects. PMID- 23028907 TI - Limited evidence for parent-of-origin effects in inflammatory bowel disease associated loci. AB - BACKGROUND: Genome-wide association studies of two main forms of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), have identified 99 susceptibility loci, but these explain only 23% of the genetic risk. Part of the 'hidden heritability' could be in transmissible genetic effects in which mRNA expression in the offspring depends on the parental origin of the allele (genomic imprinting), since children whose mothers have CD are more often affected than children with affected fathers. We analyzed parent-of-origin (POO) effects in Dutch and Indian cohorts of IBD patients. METHODS: We selected 28 genetic loci associated with both CD and UC, and tested them for POO effects in 181 Dutch IBD case-parent trios. Three susceptibility variants in NOD2 were tested in 111 CD trios and a significant finding was re-evaluated in 598 German trios. The UC-associated gene, BTNL2, reportedly imprinted, was tested in 70 Dutch UC trios. Finally, we used 62 independent Indian UC trios to test POO effects of five established Indian UC risk loci. RESULTS: We identified POO effects for NOD2 (L1007fs; OR = 21.0, P-value = 0.013) for CD; these results could not be replicated in an independent cohort (OR = 0.97, P-value = 0.95). A POO effect in IBD was observed for IL12B (OR = 3.2, P-value = 0.019) and PRDM1 (OR = 5.6, P-value = 0.04). In the Indian trios the IL10 locus showed a POO effect (OR = 0.2, P-value = 0.03). CONCLUSIONS: Little is known about the effect of genomic imprinting in complex diseases such as IBD. We present limited evidence for POO effects for the tested IBD loci. POO effects explain part of the hidden heritability for complex genetic diseases but need to be investigated further. PMID- 23028908 TI - Role of centrins 2 and 3 in organelle segregation and cytokinesis in Trypanosoma brucei. AB - Centrins are calcium binding proteins involved in cell division in eukaryotes. Previously, we have shown that depletion of centrin1 in Trypanosoma brucei (T. brucei) displayed arrested organelle segregation resulting in loss of cytokinesis. In this study we analyzed the role of T. brucei centrin2 (TbCen2) and T. brucei 3 (TbCen3) in the early events of T. brucei procyclic cell cycle. Both the immunofluorescence assay and electron microscopy showed that TbCen2 and 3-deficient cells were enlarged in size with duplicated basal bodies, multinuclei and new flagella that are detached along the length of the cell body. In both TbCen2 and TbCen3 depleted cells segregation of the organelles i.e. basal bodies, kinetoplast and nucleus was disrupted. Further analysis of the cells with defective organelle segregation identified three different sub configurations of organelle mis-segregations (Type 1-3). In addition, in majority of the TbCen2 depleted cells and in nearly half of the TbCen3 depleted cells, the kinetoplasts were enlarged and undivided. The abnormal segregations ultimately led to aborted cytokinesis and hence affected growth in these cells. Therefore, both centrin2 and 3 are involved in organelle segregation similar to centrin1 as was previously observed. In addition, we identified their role in kinetoplast division which may be also linked to overall mis-segregation. PMID- 23028909 TI - Preliminary insights into the phylogeography of six aquatic hyphomycete species. AB - Aquatic hyphomycetes occur worldwide on a wide range of plant substrates decomposing in freshwaters, and are known to play a key role in organic matter turnover. The presumed worldwide distribution of many aquatic hyphomycete species has been based on morphology-based taxonomy and identification, which may overlook cryptic species, and mask global-scale biogeographical patterns. This might be circumvented by using DNA sequence data. The internal transcribed spacer (ITS) region from rDNA was recently designated as the most suitable barcode for fungal identification. In this study, we generated ITS barcodes of 130 isolates belonging to 6 aquatic hyphomycete species (Anguillospora filiformis, Flagellospora penicillioides, Geniculospora grandis, Lunulospora curvula, Tetrachaetum elegans and Tricladium chaetocladium), and collected from streams of Southwest Europe (86 isolates) and East Australia (44 isolates). European and Australian populations of 4 species (A. filiformis, F. penicillioides, G. grandis and T. elegans) grouped into different clades, and molecular diversity indices supported significant differentiation. Continents did not share haplotypes, except for T. chaetocladium. Overall results show substantial population diversity for all tested species and suggests that the biogeography of aquatic hyphomycetes may be species-specific. PMID- 23028910 TI - Circulating heat shock protein 60 levels are elevated in HIV patients and are reduced by anti-retroviral therapy. AB - Circulating heat shock protein 60 (Hsp60) and heat shock protein 10 (Hsp10) have been associated with pro- and anti-inflammatory activity, respectively. To determine whether these heat shock proteins might be associated with the immune activation seen in HIV-infected patients, the plasma levels of Hsp60 and Hsp10 were determined in a cohort of 20 HIV-infected patients before and after effective combination anti-retroviral therapy (cART). We show for the first time that circulating Hsp60 levels are elevated in HIV-infected patients, with levels significantly reduced after cART, but still higher than those in HIV-negative individuals. Hsp60 levels correlated significantly with viral load, CD4 counts, and circulating soluble CD14 and lipopolysaccharide levels. No differences or correlations were seen for Hsp10 levels. Elevated circulating Hsp60 may contribute to the immune dysfunction and non-AIDS clinical events seen in HIV infected patients. PMID- 23028911 TI - Patterns and possible roles of LINE-1 methylation changes in smoke-exposed epithelia. AB - Tobacco smoking and reduced methylation of long interspersed element-1 (LINE-1) are crucial in oral carcinogenesis. 5'UTR of human LINE-1 sequence contains several CpG dinucleotides which are methylated in various proportions (0-100%). Methylation levels of many LINE-1s in cancer were reduced, hypomethylated. The hypomethylation of each LINE-1 locus can promote instability of genome and repress expression of a gene located on that same chromosome. This study investigated if cigarette smoking influences LINE-1 methylation of oral mucosal cells. The methylation of human LINE-1 in clinically normal oral mucosa of current smokers was compared to non-smokers. By using the combined bisulphite restriction analysis, each LINE-1 sequence was categorised into 4 patterns depending on the methylation status and location of the two 18-bp successive CpG from 5' to 3' including (m)C(m)C, (u)C(u)C, (m)C(u)C and (u)C(m)C. Of these, (m)C and (u)C represent methylated and unmethylated CpG, respectively. The DNA bisulphite sequence demonstrated that most CpGs of (m)C(m)C and (u)C(u)C were methylated and unmethylated, respectively. Nevertheless, some CpGs of each (m)C(u)C or (u)C(m)C allele were methylated. Imaging of the digestion products was used to generate %methylation value. No significant difference in the overall LINE-1 methylation level but the differences in percentages of some methylation patterns were discovered. The %(m)C(m)C and %(u)C(u)C increased, while the %(m)C(u)C decreased in current smokers (p = 0.002, 0.015, and <0.0001, respectively). Additionally, the lower %(m)C(u)C still persisted in persons who had stopped smoking for over 1 year (p = 0.001). The %(m)C(u)C also decreased in the higher pack-year smokers (p = 0.028). Smoking possibly altered (m)C(u)C to (m)C(m)C and (u)C(u)C forms, and changes (u)C(m)C to (u)C(u)C forms. In conclusion, smoking changes methylation levels of partial methylated LINE-1s and increased the number of hypo- and hypermethylated loci. These hypomethylated LINE 1s may possess carcinogenesis potential. Moreover, LINE-1 methylation patterns may be useful for monitoring oral carcinogenesis in smokers. PMID- 23028912 TI - Estimating additive and non-additive genetic variances and predicting genetic merits using genome-wide dense single nucleotide polymorphism markers. AB - Non-additive genetic variation is usually ignored when genome-wide markers are used to study the genetic architecture and genomic prediction of complex traits in human, wild life, model organisms or farm animals. However, non-additive genetic effects may have an important contribution to total genetic variation of complex traits. This study presented a genomic BLUP model including additive and non-additive genetic effects, in which additive and non-additive genetic relation matrices were constructed from information of genome-wide dense single nucleotide polymorphism (SNP) markers. In addition, this study for the first time proposed a method to construct dominance relationship matrix using SNP markers and demonstrated it in detail. The proposed model was implemented to investigate the amounts of additive genetic, dominance and epistatic variations, and assessed the accuracy and unbiasedness of genomic predictions for daily gain in pigs. In the analysis of daily gain, four linear models were used: 1) a simple additive genetic model (MA), 2) a model including both additive and additive by additive epistatic genetic effects (MAE), 3) a model including both additive and dominance genetic effects (MAD), and 4) a full model including all three genetic components (MAED). Estimates of narrow-sense heritability were 0.397, 0.373, 0.379 and 0.357 for models MA, MAE, MAD and MAED, respectively. Estimated dominance variance and additive by additive epistatic variance accounted for 5.6% and 9.5% of the total phenotypic variance, respectively. Based on model MAED, the estimate of broad sense heritability was 0.506. Reliabilities of genomic predicted breeding values for the animals without performance records were 28.5%, 28.8%, 29.2% and 29.5% for models MA, MAE, MAD and MAED, respectively. In addition, models including non additive genetic effects improved unbiasedness of genomic predictions. PMID- 23028913 TI - Compensatory feto-placental upregulation of the nitric oxide system during fetal growth restriction. AB - BACKGROUND: Fetal Growth Restriction is often associated with a feto-placental vascular dysfunction conceivably involving endothelial cells. Our study aimed to verify this pathogenic role for feto-placental endothelial cells and, coincidentally, demonstrate any abnormality in the nitric oxide system. METHODS: Prenatal assessment of feto-placental vascular function was combined with measurement of nitric oxide (in the form of S-nitrosohemoglobin) and its nitrite byproduct, and of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. Umbilical vein endothelial cells were also harvested to determine their gene profile. The study comprised term pregnancies with normal (n = 40) or small-for-gestational-age (n = 20) newborns, small-for-gestational-age preterm pregnancies (n = 15), and bi-chorial, bi-amniotic twin pregnancies with discordant fetal growth (n = 12). RESULTS: Umbilical blood nitrite (p<0.001) and S-nitrosohemoglobin (p = 0.02) rose with fetal growth restriction while asymmetric dimethylarginine decreased (p = 0.003). Nitrite rise coincided with an abnormal Doppler profile from umbilical arteries. Fetal growth restriction umbilical vein endothelial cells produced more nitrite and also exhibited reciprocal changes in vasodilator (upwards) and vasoconstrictor (downwards) transcripts. Elevation in blood nitrite and S-nitrosohemoglobin persisted postnatally in the fetal growth restriction offspring. CONCLUSION: Fetal growth restriction is typified by increased nitric oxide production during pregnancy and after birth. This response is viewed as an adaptative event to sustain placental blood flow. However, its occurrence may modify the endothelial phenotype and may ultimately represent an element of risk for cardiovascular disease in adult life. PMID- 23028914 TI - Interaural level differences do not suffice for restoring spatial release from masking in simulated cochlear implant listening. AB - Spatial release from masking refers to a benefit for speech understanding. It occurs when a target talker and a masker talker are spatially separated. In those cases, speech intelligibility for target speech is typically higher than when both talkers are at the same location. In cochlear implant listeners, spatial release from masking is much reduced or absent compared with normal hearing listeners. Perhaps this reduced spatial release occurs because cochlear implant listeners cannot effectively attend to spatial cues. Three experiments examined factors that may interfere with deploying spatial attention to a target talker masked by another talker. To simulate cochlear implant listening, stimuli were vocoded with two unique features. First, we used 50-Hz low-pass filtered speech envelopes and noise carriers, strongly reducing the possibility of temporal pitch cues; second, co-modulation was imposed on target and masker utterances to enhance perceptual fusion between the two sources. Stimuli were presented over headphones. Experiments 1 and 2 presented high-fidelity spatial cues with unprocessed and vocoded speech. Experiment 3 maintained faithful long-term average interaural level differences but presented scrambled interaural time differences with vocoded speech. Results show a robust spatial release from masking in Experiments 1 and 2, and a greatly reduced spatial release in Experiment 3. Faithful long-term average interaural level differences were insufficient for producing spatial release from masking. This suggests that appropriate interaural time differences are necessary for restoring spatial release from masking, at least for a situation where there are few viable alternative segregation cues. PMID- 23028915 TI - Cell visco-elasticity measured with AFM and optical trapping at sub-micrometer deformations. AB - The measurement of the elastic properties of cells is widely used as an indicator for cellular changes during differentiation, upon drug treatment, or resulting from the interaction with the supporting matrix. Elasticity is routinely quantified by indenting the cell with a probe of an AFM while applying nano Newton forces. Because the resulting deformations are in the micrometer range, the measurements will be affected by the finite thickness of the cell, viscous effects and even cell damage induced by the experiment itself. Here, we have analyzed the response of single 3T3 fibroblasts that were indented with a micrometer-sized bead attached to an AFM cantilever at forces from 30-600 pN, resulting in indentations ranging from 0.2 to 1.2 micrometer. To investigate the cellular response at lower forces up to 10 pN, we developed an optical trap to indent the cell in vertical direction, normal to the plane of the coverslip. Deformations of up to two hundred nanometers achieved at forces of up to 30 pN showed a reversible, thus truly elastic response that was independent on the rate of deformation. We found that at such small deformations, the elastic modulus of 100 Pa is largely determined by the presence of the actin cortex. At higher indentations, viscous effects led to an increase of the apparent elastic modulus. This viscous contribution that followed a weak power law, increased at larger cell indentations. Both AFM and optical trapping indentation experiments give consistent results for the cell elasticity. Optical trapping has the benefit of a lower force noise, which allows a more accurate determination of the absolute indentation. The combination of both techniques allows the investigation of single cells at small and large indentations and enables the separation of their viscous and elastic components. PMID- 23028916 TI - IL-15 augments TCR-induced CD4+ T cell expansion in vitro by inhibiting the suppressive function of CD25 High CD4+ T cells. AB - Due to its critical role in NK cell differentiation and CD8(+) T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4(+) T cells. The increased levels of IL-15 found in several CD4(+) T cell-driven (auto-) immune diseases prompted us to examine how IL-15 influences murine CD4(+) T cell responses to low dose TCR stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4(+) and CD8(+) T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4(+) T cells, IL-15 augmented initial IL-2-dependent expansion and once IL 15Ralpha was upregulated, IL-15 sustained the TCR-induced expression of IL 2/15Rbeta, supporting proliferation independently of secreted IL-2. Moreover, IL 15 counteracts CD4(+) T cell suppression by a gradually expanding CD25(High)CD4(+) T cell subset that expresses Foxp3 and originates from CD4(+)CD25(+) Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology. PMID- 23028917 TI - Identification of POMC exonic variants associated with substance dependence and body mass index. AB - BACKGROUND: Risk of substance dependence (SD) and obesity has been linked to the function of melanocortin peptides encoded by the proopiomelanocortin gene (POMC). METHODS AND RESULTS: POMC exons were Sanger sequenced in 280 African Americans (AAs) and 308 European Americans (EAs). Among them, 311 (167 AAs and 114 EAs) were affected with substance (alcohol, cocaine, opioid and/or marijuana) dependence and 277 (113 AAs and164 EAs) were screened controls. We identified 23 variants, including two common polymorphisms (rs10654394 and rs1042571) and 21 rare variants; 12 of which were novel. We used logistic regression to analyze the association between the two common variants and SD or body mass index (BMI), with sex, age, and ancestry proportion as covariates. The common variant rs1042571 in the 3'UTR was significantly associated with BMI in EAs (Overweight: P(adj) = 0.005; Obese: P(adj) = 0.018; Overweight+Obese: P(adj) = 0.002) but not in AAs. The common variant, rs10654394, was not associated with BMI and neither common variant was associated with SD in either population. To evaluate the association between the rare variants and SD or BMI, we collapsed rare variants and tested their prevalence using Fisher's exact test. In AAs, rare variants were nominally associated with SD overall and with specific SD traits (SD: P(FET,1df) = 0.026; alcohol dependence: P(FET,1df) = 0.027; cocaine dependence: P(FET,1df) = 0.007; marijuana dependence: P(FET,1df) = 0.050) (the P-value from cocaine dependence analysis survived Bonferroni correction). There was no such effect in EAs. Although the frequency of the rare variants did not differ significantly between the normal-weight group and the overweight or obese group in either population, certain rare exonic variants occurred only in overweight or obese subjects without SD. CONCLUSION: These findings suggest that POMC exonic variants may influence risk for both SD and elevated BMI, in a population-specific manner. However, common and rare variants in this gene may exert different effects on these two phenotypes. PMID- 23028918 TI - Perspective distortion from interpersonal distance is an implicit visual cue for social judgments of faces. AB - The basis on which people make social judgments from the image of a face remains an important open problem in fields ranging from psychology to neuroscience and economics. Multiple cues from facial appearance influence the judgments that viewers make. Here we investigate the contribution of a novel cue: the change in appearance due to the perspective distortion that results from viewing distance. We found that photographs of faces taken from within personal space elicit lower investments in an economic trust game, and lower ratings of social traits (such as trustworthiness, competence, and attractiveness), compared to photographs taken from a greater distance. The effect was replicated across multiple studies that controlled for facial image size, facial expression and lighting, and was not explained by face width-to-height ratio, explicit knowledge of the camera distance, or whether the faces are perceived as typical. These results demonstrate a novel facial cue influencing a range of social judgments as a function of interpersonal distance, an effect that may be processed implicitly. PMID- 23028919 TI - Incidence of chronic kidney disease and its risk factors, results of over 10 year follow up in an Iranian cohort. AB - To examine, the predictors of incident chronic kidney disease (CKD) in a community-based cohort of Middle East population, during a mean follow-up of 9.9 years. In a sample of 3313 non-CKD Iranian adults >=20 years the estimated glomerular filtration rate (eGFR) was calculated at baseline and at three year intervals during three consecutive phases. The eGFR <60 mL/min/1.73 m2 was defined as CKD. Multivariate Logistic regression analysis was used to determine the independent variables associated with incident CKD. The incidence density rates of CKD were 285.3 and 132.6 per 10,000 person-year, among women and men, respectively. Female gender per se was associated with higher risk of CKD, compared with males. Among women, age, eGFR, known diabetes, being single or divorced/widowed, hypertension (marginally significant) and current smoking were independent risk factors for CKD; however the intermediate degree of education and family history of diabetes decreased the risk by 40% (P<0.05). Among male subjects, independent predictors of developing CKD included aging and hypertension (with significantly higher risk than in women, P for interaction<0.05), eGFR, new diagnosed diabetes, high normal blood pressure; abdominal obesity decreased the risk of CKD about 30% which was marginally significant. In the Iranian population,>2% of individuals develops CKD each year. Our findings confirmed that sex- specific risk predictors should be considered in primary prevention for incident CKD. PMID- 23028920 TI - NOTCH1, HIF1A and other cancer-related proteins in lung tissue from uranium miners--variation by occupational exposure and subtype of lung cancer. AB - BACKGROUND: Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners. METHODOLOGY/PRINCIPAL FINDINGS: Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r(s)). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r(s) = 0.18, 95% CI 0.02-0.33; arsenic: r(s) = 0.23, 95% CI 0.07-0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%. CONCLUSIONS/SIGNIFICANCE: These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate. PMID- 23028921 TI - Genome dynamics explain the evolution of flowering time CCT domain gene families in the Poaceae. AB - Numerous CCT domain genes are known to control flowering in plants. They belong to the CONSTANS-like (COL) and PREUDORESPONSE REGULATOR (PRR) gene families, which in addition to a CCT domain possess B-box or response-regulator domains, respectively. Ghd7 is the most recently identified COL gene to have a proven role in the control of flowering time in the Poaceae. However, as it lacks B-box domains, its inclusion within the COL gene family, technically, is incorrect. Here, we show Ghd7 belongs to a larger family of previously uncharacterized Poaceae genes which possess just a single CCT domain, termed here CCT MOTIF FAMILY (CMF) genes. We molecularly describe the CMF (and related COL and PRR) gene families in four sequenced Poaceae species, as well as in the draft genome assembly of barley (Hordeum vulgare). Genetic mapping of the ten barley CMF genes identified, as well as twelve previously unmapped HvCOL and HvPRR genes, finds the majority map to colinear positions relative to their Poaceae orthologues. Combined inter-/intra-species comparative and phylogenetic analysis of CMF, COL and PRR gene families indicates they evolved prior to the monocot/dicot divergence ~200 mya, with Poaceae CMF evolution described as the interplay between whole genome duplication in the ancestral cereal, and subsequent clade specific mutation, deletion and duplication events. Given the proven role of CMF genes in the modulation of cereals flowering, the molecular, phylogenetic and comparative analysis of the Poaceae CMF, COL and PRR gene families presented here provides the foundation from which functional investigation can be undertaken. PMID- 23028922 TI - Human lung cancer cells grown in an ex vivo 3D lung model produce matrix metalloproteinases not produced in 2D culture. AB - We compared the growth of human lung cancer cells in an ex vivo three-dimensional (3D) lung model and 2D culture to determine which better mimics lung cancer growth in patients. A549 cells were grown in an ex vivo 3D lung model and in 2D culture for 15 days. We measured the size and formation of tumor nodules and counted the cells after 15 days. We also stained the tissue/cells for Ki-67, and Caspase-3. We measured matrix metalloproteinase (MMP) levels in the conditioned media and in blood plasma from patients with adenocarcinoma of the lung. Organized tumor nodules with intact vascular space formed in the ex vivo 3D lung model but not in 2D culture. Proliferation and apoptosis were greater in the ex vivo 3D lung model compared to the 2D culture. After 15 days, there were significantly more cells in the 2D culture than the 3D model. MMP-1, MMP-9, and MMP-10 production were significantly greater in the ex vivo 3D lung model. There was no production of MMP-9 in the 2D culture. The patient samples contained MMP 1, MMP-2, MMP-9, and MMP-10. The human lung cancer cells grown on ex vivo 3D model form perfusable nodules that grow over time. It also produced MMPs that were not produced in 2D culture but seen in human lung cancer patients. The ex vivo 3D lung model may more closely mimic the biology of human lung cancer development than the 2D culture. PMID- 23028923 TI - Microbial distribution and abundance in the digestive system of five shipworm species (Bivalvia: Teredinidae). AB - Marine bivalves of the family Teredinidae (shipworms) are voracious consumers of wood in marine environments. In several shipworm species, dense communities of intracellular bacterial endosymbionts have been observed within specialized cells (bacteriocytes) of the gills (ctenidia). These bacteria are proposed to contribute to digestion of wood by the host. While the microbes of shipworm gills have been studied extensively in several species, the abundance and distribution of microbes in the digestive system have not been adequately addressed. Here we use Fluorescence In-Situ Hybridization (FISH) and laser scanning confocal microscopy with 16S rRNA directed oligonucleotide probes targeting all domains, domains Bacteria and Archaea, and other taxonomic groups to examine the digestive microbiota of 17 specimens from 5 shipworm species (Bankia setacea, Lyrodus pedicellatus, Lyrodus massa, Lyrodus sp. and Teredo aff. triangularis). These data reveal that the caecum, a large sac-like appendage of the stomach that typically contains large quantities of wood particles and is considered the primary site of wood digestion, harbors only very sparse microbial populations. However, a significant number of bacterial cells were observed in fecal pellets within the intestines. These results suggest that due to low abundance, bacteria in the caecum may contribute little to lignocellulose degradation. In contrast, the comparatively high population density of bacteria in the intestine suggests a possible role for intestinal bacteria in the degradation of lignocellulose. PMID- 23028924 TI - Use of temperature for standardizing the progression of Francisella tularensis in mice. AB - The study of infectious agents, their pathogenesis, the host response and the evaluation of newly developed countermeasures often requires the use of a living system. Murine models are frequently used to undertake such investigations with the caveat that non-biased measurements to assess the progression of infection are underutilized. Instead, murine models predominantly rely on symptomology exhibited by the animal to evaluate the state of the animal's health and to determine when euthanasia should be performed. In this study, we used subcutaneous temperature as a non-subjective measurement to follow and compare infection in mice inoculated with Francisella tularensis, a Gram-negative pathogen that produces an acute and fatal illness in mice. A reproducible temperature pattern defined by three temperature phases (normal, febrile and hypothermic) was identified in all mice infected with F. tularensis, regardless of the infecting strain. More importantly and for the first time a non subjective, ethical, and easily determined surrogate endpoint for death based on a temperature, termed drop point, was identified and validated with statistical models. In comparative survival curve analyses for F. tularensis strains with differing virulence, the drop point temperature yielded the same results as those obtained using observed time to death. Incorporation of temperature measurements to evaluate F. tularensis was standardized based on statistical models to provide a new level of robustness for comparative analyses in mice. These findings should be generally applicable to other pathogens that produce acute febrile disease in animal models and offers an important tool for understanding and following the infection process. PMID- 23028925 TI - A pilot study to examine the effect of chronic treatment with immunosuppressive drugs on mucociliary clearance in a vagotomized murine model. AB - BACKGROUND: Previously, we have demonstrated that mucociliary clearance (MCC) is diminished within the first months after surgery in lung transplant patients and the explanation for the reduction in MCC is unknown. We hypothesized that chronic treatment with a commonly prescribed regimen of immunosuppressive drugs significantly impairs MCC. We tested this hypothesis in a murine model of lung transplantation. METHODS: Fifteen C57BL/6 mice underwent vagotomy on the right side to simulate denervation associated with lung transplantation in humans. For 6 days, seven mice (controls) were intraperitoneally injected with three 100 uL doses of phosphate buffered saline and eight mice (immunosuppressed) were injected with three 100 uL injections of tacrolimus (1 mg/kg), mycophenolate mofetil (30 mg/kg), and prednisone (2 mg/kg) once daily. Then, mice inhaled the radioisotope (99m)technetium and underwent gamma camera imaging of their lungs for 6.5 hrs. Counts in the right lung at 1-1.5 hrs and at 6-6.5 hrs were first background-corrected and then decay-corrected to time 0 counts. Decay-corrected counts were then divided by time 0 counts. Retention at each time point was subtracted from 1.00 and multiplied by 100% to obtain percent removed by mucociliary clearance. RESULTS: Although there was a slowing of MCC at 1-1.5 hrs for the immunosuppressed mice, there was no statistical difference in MCC measured at 1-1.5 hrs for the two groups of mice. At 6-6.5 hrs, MCC was significantly slower in the immunosuppressed mice, compared to controls, with 7.78+/-5.9% cleared versus 23.01+/-11.7% cleared, respectively (p = 0.006). CONCLUSIONS: These preliminary results suggest that chronic treatment with immunosuppressive medications significantly slows MCC in vagotomized C57BL/6 mice. These findings could shed light on why MCC is reduced in lung transplant patients whose lungs are denervated during surgery and who are chronically treated with immunosuppressive drugs post surgery. PMID- 23028926 TI - An intertwined evolutionary history of methanogenic archaea and sulfate reduction. AB - Hydrogenotrophic methanogenesis and dissimilatory sulfate reduction, two of the oldest energy conserving respiratory systems on Earth, apparently could not have evolved in the same host, as sulfite, an intermediate of sulfate reduction, inhibits methanogenesis. However, certain methanogenic archaea metabolize sulfite employing a deazaflavin cofactor (F(420))-dependent sulfite reductase (Fsr) where N- and C-terminal halves (Fsr-N and Fsr-C) are homologs of F(420)H(2) dehydrogenase and dissimilatory sulfite reductase (Dsr), respectively. From genome analysis we found that Fsr was likely assembled from freestanding Fsr-N homologs and Dsr-like proteins (Dsr-LP), both being abundant in methanogens. Dsr LPs fell into two groups defined by following sequence features: Group I (simplest), carrying a coupled siroheme-[Fe(4)-S(4)] cluster and sulfite-binding Arg/Lys residues; Group III (most complex), with group I features, a Dsr-type peripheral [Fe(4)-S(4)] cluster and an additional [Fe(4)-S(4)] cluster. Group II Dsr-LPs with group I features and a Dsr-type peripheral [Fe(4)-S(4)] cluster were proposed as evolutionary intermediates. Group III is the precursor of Fsr-C. The freestanding Fsr-N homologs serve as F(420)H(2) dehydrogenase unit of a putative novel glutamate synthase, previously described membrane-bound electron transport system in methanogens and of assimilatory type sulfite reductases in certain haloarchaea. Among archaea, only methanogens carried Dsr-LPs. They also possessed homologs of sulfate activation and reduction enzymes. This suggested a shared evolutionary history for methanogenesis and sulfate reduction, and Dsr-LPs could have been the source of the oldest (3.47-Gyr ago) biologically produced sulfide deposit. PMID- 23028927 TI - Boundary conditions for heat transfer and evaporative cooling in the trachea and air sac system of the domestic fowl: a two-dimensional CFD analysis. AB - Various parts of the respiratory system play an important role in temperature control in birds. We create a simplified computational fluid dynamics (CFD) model of heat exchange in the trachea and air sacs of the domestic fowl (Gallus domesticus) in order to investigate the boundary conditions for the convective and evaporative cooling in these parts of the respiratory system. The model is based upon published values for respiratory times, pressures and volumes and upon anatomical data for this species, and the calculated heat exchange is compared with experimentally determined values for the domestic fowl and a closely related, wild species. In addition, we studied the trachea histologically to estimate the thickness of the heat transfer barrier and determine the structure and function of moisture-producing glands. In the transient CFD simulation, the airflow in the trachea of a 2-dimensional model is evoked by changing the volume of the simplified air sac. The heat exchange between the respiratory system and the environment is simulated for different ambient temperatures and humidities, and using two different models of evaporation: constant water vapour concentration model and the droplet injection model. According to the histological results, small mucous glands are numerous but discrete serous glands are lacking on the tracheal surface. The amount of water and heat loss in the simulation is comparable with measured respiratory values previously reported. Tracheal temperature control in the avian respiratory system may be used as a model for extinct or rare animals and could have high relevance for explaining how gigantic, long-necked dinosaurs such as sauropoda might have maintained a high metabolic rate. PMID- 23028928 TI - Dynamic scaling in the growth of a non-branching plant, Cardiocrinum cordatum. AB - We investigated whole-plant leaf area in relation to ontogenetic variation in leaf-size for a forest perennial herb, Cardiocrinum cordatum. The 200-fold ontogenetic variability in C. cordatum leaf area followed a power-law dependence on total leaf number, a measure of developmental stage. When we normalized for plant size, the function describing the size of single leaves along the stem was similar among different-sized plants, implying that the different-sized canopies observed at different times in the growth trajectory were fundamentally similar to each other. We conclude that the growth trajectory of a population of C. cordatum plant leaves obeyed a dynamic scaling law, the first reported for a growth trajectory at the whole-plant level. PMID- 23028929 TI - Genomic integration and germline transmission of plasmid injected into crustacean Daphnia magna eggs. AB - The water flea, Daphnia, has been the subject of study in ecology, evolution, and environmental sciences for decades. Over the last few years, expressed sequence tags and a genome sequence have been determined. In addition, functional approaches of overexpression and gene silencing based on microinjection of RNAs into eggs have been established. However, the transient nature of these approaches prevents us from analyzing gene functions in later stages of development. To overcome this limitation, transgenesis would become a key tool. Here we report establishment of a transgenic line using microinjection of plasmid into Daphnia magna eggs. The green fluorescent protein (GFP) gene fused with the D. magna histone H2B gene under the control of a promoter/enhancer region of the elongation factor 1alpha-1 (EF1alpha-1) gene, EF1alpha-1::H2B-GFP, was used as a reporter providing high resolution visualization of active chromatin. Transgenic lines were obtained from 0.67% of the total fertile adults that survived the injections. One of the transgenic animals, which exhibited fluorescence in the nuclei of cells during embryogenesis and oogenesis, had two copies of EF1alpha 1::H2B-GFP in a head-to-tail array. This is the first report of a transgenesis technique in Daphnia and, together with emerging genome sequences, will be useful for advancing knowledge of the molecular biology of Daphnia. PMID- 23028930 TI - Defects in mitochondrial fission protein dynamin-related protein 1 are linked to apoptotic resistance and autophagy in a lung cancer model. AB - Evasion of apoptosis is implicated in almost all aspects of cancer progression, as well as treatment resistance. In this study, resistance to apoptosis was identified in tumorigenic lung epithelial (A549) cells as a consequence of defects in mitochondrial and autophagic function. Mitochondrial function is determined in part by mitochondrial morphology, a process regulated by mitochondrial dynamics whereby the joining of two mitochondria, fusion, inhibits apoptosis while fission, the division of a mitochondrion, initiates apoptosis. Mitochondrial morphology of A549 cells displayed an elongated phenotype-mimicking cells deficient in mitochondrial fission protein, Dynamin-related protein 1 (Drp1). A549 cells had impaired Drp1 mitochondrial recruitment and decreased Drp1 dependent fission. Cytochrome c release and caspase-3 and PARP cleavage were impaired both basally and with apoptotic stimuli in A549 cells. Increased mitochondrial mass was observed in A549 cells, suggesting defects in mitophagy (mitochondrial selective autophagy). A549 cells had decreased LC3-II lipidation and lysosomal inhibition suggesting defects in autophagy occur upstream of lysosomal degradation. Immunostaining indicated mitochondrial localized LC3 punctae in A549 cells increased after mitochondrial uncoupling or with a combination of mitochondrial depolarization and ectopic Drp1 expression. Increased inhibition of apoptosis in A549 cells is correlated with impeded mitochondrial fission and mitophagy. We suggest mitochondrial fission defects contribute to apoptotic resistance in A549 cells. PMID- 23028931 TI - Increased gamma-H2A.X intensity in response to chronic medium-dose-rate gamma-ray irradiation. AB - BACKGROUND: The molecular mechanisms of DNA repair following chronic medium-dose rate (MDR) gamma-ray-induced damage remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used a cell function imager to quantitatively measure the fluorescence intensity of gamma-H2A.X foci in MDR (0.015 Gy/h and 0.06 Gy/h) or high-dose-rate (HDR) (54 Gy/h) gamma-ray irradiated embryonic fibroblasts derived from DNA-dependent protein kinase mutated mice (scid/scid mouse embryonic fibroblasts (scid/scid MEFs)). The obtained results are as follows: (1) Automatic measurement of the intensity of radiation-induced gamma-H2A.X foci by the cell function imager provides more accurate results compared to manual counting of gamma-H2A.X foci. (2) In high-dose-rate (HDR) irradiation, gamma-H2A.X foci with high fluorescence intensity were observed at 1 h after irradiation in both scid/scid and wild-type MEFs. These foci were gradually reduced through de phosphorylation at 24 h or 72 h after irradiation. Furthermore, the fluorescence intensity at 24 h increased to a significantly greater extent in scid/scid MEFs than in wild-type MEFs in the G(1) phase, although no significant difference was observed in G(2)/M-phase MEFs, suggesting that DNA-PKcs might be associated with non-homologous-end-joining-dependent DNA repair in the G(1) phase following HDR gamma-ray irradiation. (3) The intensity of gamma-H2A.X foci for continuous MDR (0.06 Gy/h and 0.015 Gy/h) irradiation increased significantly and in a dose dependent fashion. Furthermore, unlike HDR-irradiated scid/scid MEFs, the intensity of gamma-H2A.X foci in MDR-irradiated scid/scid MEFs showed no significant increase in the G(1) phase at 24 h, indicating that DNA repair systems using proteins other than DNA-PKcs might induce cell functioning that are subjected to MDR gamma-ray irradiation. CONCLUSIONS: Our results indicate that the mechanism of phosphorylation or de-phosphorylation of gamma-H2A.X foci induced by chronic MDR gamma-ray irradiation might be different from those induced by HDR gamma-ray irradiation. PMID- 23028932 TI - Genetic inhibition of CaMKII in dorsal striatal medium spiny neurons reduces functional excitatory synapses and enhances intrinsic excitability. AB - Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is abundant in striatal medium spiny neurons (MSNs). CaMKII is dynamically regulated by changes in dopamine signaling, as occurs in Parkinson's disease as well as addiction. Although CaMKII has been extensively studied in the hippocampus where it regulates excitatory synaptic transmission, relatively little is known about how it modulates neuronal function in the striatum. Therefore, we examined the impact of selectively overexpressing an EGFP-fused CaMKII inhibitory peptide (EAC3I) in striatal medium spiny neurons (MSNs) using a novel transgenic mouse model. EAC3I expressing cells exhibited markedly decreased excitatory transmission, indicated by a decrease in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs). This decrease was not accompanied by changes in the probability of release, levels of glutamate at the synapse, or changes in dendritic spine density. CaMKII regulation of the AMPA receptor subunit GluA1 is a major means by which the kinase regulates neuronal function in the hippocampus. We found that the decrease in striatal excitatory transmission seen in the EAC3I mice is mimicked by deletion of GluA1. Further, while CaMKII inhibition decreased excitatory transmission onto MSNs, it increased their intrinsic excitability. These data suggest that CaMKII plays a critical role in setting the excitability rheostat of striatal MSNs by coordinating excitatory synaptic drive and the resulting depolarization response. PMID- 23028933 TI - Sip1, a conserved AP-1 accessory protein, is important for Golgi/endosome trafficking in fission yeast. AB - We had previously identified the mutant allele of apm1(+) that encodes a homolog of the mammalian MU 1A subunit of the clathrin-associated adaptor protein-1 (AP 1) complex and demonstrated that the AP-1 complex plays a role in Golgi/endosome trafficking, secretion, and vacuole fusion in fission yeast. Here, we isolated a mutant allele of its4(+)/sip1(+), which encodes a conserved AP-1 accessory protein. The its4-1/sip1-i4 mutants and apm1-deletion cells exhibited similar phenotypes, including sensitivity to the calcineurin inhibitor FK506, Cl(-) and valproic acid as well as various defects in Golgi/endosomal trafficking and cytokinesis. Electron micrographs of sip1-i4 mutants revealed vacuole fragmentation and accumulation of abnormal Golgi-like structures and secretory vesicles. Overexpression of Apm1 suppressed defective membrane trafficking in sip1-i4 mutants. The Sip1-green fluorescent protein (GFP) co-localized with Apm1 mCherry at Golgi/endosomes, and Sip1 physically interacted with each subunit of the AP-1 complex. We found that Sip1 was a Golgi/endosomal protein and the sip1 i4 mutation affected AP-1 localization at Golgi/endosomes, thus indicating that Sip1 recruited the AP-1 complex to endosomal membranes by physically interacting with each subunit of this complex. Furthermore, Sip1 is required for the correct localization of Bgs1/Cps1, 1,3-beta-D-glucan synthase to polarized growth sites. Consistently, the sip1-i4 mutants displayed a severe sensitivity to micafungin, a potent inhibitor of 1,3-beta-D-glucan synthase. Taken together, our findings reveal a role for Sip1 in the regulation of Golgi/endosome trafficking in coordination with the AP-1 complex, and identified Bgs1, required for cell wall synthesis, as the new cargo of AP-1-dependent trafficking. PMID- 23028934 TI - Arginine consumption by the intestinal parasite Giardia intestinalis reduces proliferation of intestinal epithelial cells. AB - In the field of infectious diseases the multifaceted amino acid arginine has reached special attention as substrate for the hosts production of the antimicrobial agent nitric oxide (NO). A variety of infectious organisms interfere with this part of the host immune response by reducing the availability of arginine. This prompted us to further investigate additional roles of arginine during pathogen infections. As a model we used the intestinal parasite Giardia intestinalis that actively consumes arginine as main energy source and secretes an arginine-consuming enzyme, arginine deiminase (ADI). Reduced intestinal epithelial cell (IEC) proliferation is a common theme during bacterial and viral intestinal infections, but it has never been connected to arginine-consumption. Our specific question was thereby, whether the arginine-consumption by Giardia leads to reduced IEC proliferation, in addition to NO reduction. In vitro cultivation of human IEC lines in arginine-free or arginine/citrulline complemented medium, as well as in interaction with different G. intestinalis isolates, were used to study effects on host cell replication by MTT assay. IEC proliferation was further analyzed by DNA content analysis, polyamine measurements and expressional analysis of cell cycle regulatory genes. IEC proliferation was reduced upon arginine-withdrawal and also in an arginine dependent manner upon interaction with G. intestinalis or addition of Giardia ADI. We show that arginine-withdrawal by intestinal pathogens leads to a halt in the cell cycle in IECs through reduced polyamine levels and upregulated cell cycle inhibitory genes. This is of importance with regards to intestinal tissue homeostasis that is affected through reduced cell proliferation. Thus, the slower epithelial cell turnover helps the pathogen to maintain a more stable niche for colonization. This study also shows why supplementation therapy of diarrhea patients with arginine/citrulline is helpful and that citrulline especially should gain further attention in future treatment strategies. PMID- 23028935 TI - Auditory nerve spike generator modeled as a variable attenuator based on a saddle node on invariant circle bifurcation. AB - Mammalian inner hair cells transduce the sound waves amplified by the cochlear amplifier (CA) into a graded neurotransmitter release that activates channels on auditory nerve fibers (ANF). These synaptic channels then charge its dendritic spike generator. While the outer hair cells of the CA employ positive feedback, poising on Andronov-Hopf type instabilities which make them extremely sensitive to faint sounds and make CA output strongly nonlinear, the ANF appears to be based on different principles and a different type of dynamical instability. Its spike generator "digitizes" CA output into trains of action potentials and behaves as a linear filter, rate-coding sound intensity across a wide dynamic range. Here we model the spike generator as a 3 dimensional version of a saddle node on invariant circle (SNIC) bifurcation. The generic 2d SNIC increases its spike rate as the square root of the input current above its spiking threshold. We add negative feedback in the form of a low voltage-threshold potassium conductance that slows down the generator's rate of increase of its spike rate. A Poisson random source simulates an inner hair cell, outputting a series of noisy periodic current pulses to the model ANF whose spikes phase lock to these pulses and have a linear frequency to current relation with a wide dynamic range. Also, the spike generator compartment has a cholinergic feedback connection from the olive and experiments show that such feedback is able to alter the amount of H conductance inside the generator compartment. We show that an olive able to decrease H would be able to shift the spike generator's dynamic range to higher sound intensities. In a quiet environment by increasing H the olive would be able to make spike trains similar to those caused by synaptic input. PMID- 23028936 TI - Caspase 2 activation and ER stress drive rapid Jurkat cell apoptosis by clofibrate. AB - Differently from the antiapoptotic action most commonly assigned to peroxisome proliferators (PPs), we demonstrated that some of them, clofibrate (CF) in particular, display clearcut apoptogenic properties on rat hepatoma cell lines. We and others could confirm that CF as well as various other PPs can induce apoptosis in a variety of cells, including human liver, breast and lung cancer cell lines. The present study was aimed at investigating the cytotoxic action of CF on a neoplastic line of different origin, the human T leukemia Jurkat cells. We observed that CF rapidly triggers an extensive and morphologically typical apoptotic process on Jurkat cells, though not in primary T cells, which is completely prevented by the polycaspase inhibitor zVADfmk. Gene silencing studies demonstrated that CF-induced apoptosis in Jurkat cells is partially dependent on activation of caspase 2. Looking for a possible trigger of caspase 2 activation, we observed increased levels of phosphorylated eIF2alpha and JNK in CF-treated cells. Moreover, intracellular Ca(2+) homeostasis was perturbed. Together, these findings are suggestive for the occurrence of ER stress, an event that is known to have the potential to activate caspase 2. The present observations demonstrate that CF induces in Jurkat cells a very fast and extensive apoptosis, that involves induction of ER stress and activation of caspases 2 and 3. Since apoptosis in Jurkat cells occurs at pharmacologically relevant concentrations of CF, the present findings encourage further in depth analysis in order to work out the potential implications of CF cytotoxcity on leukemic cells. PMID- 23028937 TI - The DMD locus harbours multiple long non-coding RNAs which orchestrate and control transcription of muscle dystrophin mRNA isoforms. AB - The 2.2 Mb long dystrophin (DMD) gene, the largest gene in the human genome, corresponds to roughly 0.1% of the entire human DNA sequence. Mutations in this gene cause Duchenne muscular dystrophy and other milder X-linked, recessive dystrophinopathies. Using a custom-made tiling array, specifically designed for the DMD locus, we identified a variety of novel long non-coding RNAs (lncRNAs), both sense and antisense oriented, whose expression profiles mirror that of DMD gene. Importantly, these transcripts are intronic in origin and specifically localized to the nucleus and are transcribed contextually with dystrophin isoforms or primed by MyoD-induced myogenic differentiation. Furthermore, their forced ectopic expression in both human muscle and neuronal cells causes a specific and negative regulation of endogenous dystrophin full length isoforms and significantly down-regulate the activity of a luciferase reporter construct carrying the minimal promoter regions of the muscle dystrophin isoform. Consistent with this apparently repressive role, we found that, in muscle samples of dystrophinopathic female carriers, lncRNAs expression levels inversely correlate with those of muscle full length DMD isoforms. Overall these findings unveil an unprecedented complexity of the transcriptional pattern of the DMD locus and reveal that DMD lncRNAs may contribute to the orchestration and homeostasis of the muscle dystrophin expression pattern by either selective targeting and down-modulating the dystrophin promoter transcriptional activity. PMID- 23028938 TI - The physical interaction of myoblasts with the microenvironment during remodeling of the cytoarchitecture. AB - Integrins, focal adhesions, the cytoskeleton and the extracellular matrix, form a structural continuum between the external and internal environment of the cell and mediate the pathways associated with cellular mechanosensitivity and mechanotransduction. This continuum is important for the onset of muscle tissue generation, as muscle precursor cells (myoblasts) require a mechanical stimulus to initiate myogenesis. The ability to sense a mechanical cue requires an intact cytoskeleton and strong physical contact and adhesion to the microenvironment. Importantly, myoblasts also undergo reorientation, alignment and large scale remodeling of the cytoskeleton when they experience mechanical stretch and compression in muscle tissue. It remains unclear if such dramatic changes in cell architecture also inhibit physical contact and adhesion with the tissue microenvironment that are clearly important to myoblast physiology. In this study, we employed interference reflection microscopy to examine changes in the close physical contact of myoblasts with a substrate during induced remodeling of the cytoarchitecture (de-stabilization of the actin and microtubule cytoskeleton and inhibition of acto-myosin contractility). Our results demonstrate that while each remodeling pathway caused distinct effects on myoblast morphology and sub cellular structure, we only observed a ~13% decrease in close physical contact with the substrate, regardless of the pathway inhibited. However, this decrease did not correlate well with changes in cell adhesion strength. On the other hand, there was a close correlation between cell adhesion and beta1-integrin expression and the presence of cell-secreted fibronectin, but not with the presence of intact focal adhesions. In this study, we have shown that myoblasts are able to maintain a large degree of physical contact and adhesion to the microenvironment, even during shot periods (<60 min) of large scale remodeling and physiological stress, which is essential to their in-vivo functionality. PMID- 23028939 TI - Sphingosine kinase 1 is required for mesothelioma cell proliferation: role of histone acetylation. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a devastating disease with an overall poor prognosis. Despite the recent advances in targeted molecular therapies, there is a clear and urgent need for the identification of novel mesothelioma targets for the development of highly efficacious therapeutics. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we report that the expression of Sphingosine Kinase 1 (SphK1) protein was preferentially elevated in MPM tumor tissues (49 epithelioid and 13 sarcomatoid) compared to normal tissue (n = 13). In addition, we also observed significantly elevated levels of SphK1 and SphK2 mRNA and SphK1 protein expression in MPM cell lines such as H2691, H513 and H2461 compared to the non-malignant mesothelial Met5 cells. The underlying mechanism appears to be mediated by SphK1 induced upregulation of select gene transcription programs such as that of CBP/p300 and PCAF, two histone acetyl transferases (HAT), and the down regulation of cell cycle dependent kinase inhibitor genes such as p27Kip1 and p21Cip1. In addition, using immunoprecipitates of anti acetylated histone antibody from SphK inhibitor, SphK-I2 treated Met5A and H2691 cell lysates, we also showed activation of other cell proliferation related genes, such as Top2A (DNA replication), AKB (chromosome remodeling and mitotic spindle formation), and suppression of p21 CIP1 and p27KIP1. The CDK2, HAT1 and MYST2 were, however, unaffected in the above study. Using SphK inhibitor and specific siRNA targeting either SphK1 or SphK2, we also unequivocally established that SphK1, but not SphK2, promotes H2691 mesothelioma cell proliferation. Using a multi-walled carbon nanotubes induced peritoneal mesothelioma mouse model, we showed that the SphK1-/- null mice exhibited significantly less inflammation and granulamatous nodules compared to their wild type counterparts. CONCLUSIONS/SIGNIFICANCE: The lipid kinase SphK1 plays a positive and essential role in the growth and development of malignant mesothelioma and is therefore a likely therapeutic target. PMID- 23028940 TI - SIRT1 regulates endothelial Notch signaling in lung cancer. AB - BACKGROUND: Sirtuin 1 (SIRT1) acts as a key regulator of vascular endothelial homeostasis, angiogenesis, and endothelial dysfunction. However, the underlying mechanism for SIRT1-mediated lung carcinoma angiogenesis remains unknown. Herein, we report that the nicotinamide adenine dinucleotide 1 (NAD1)-dependent deacetylase SIRT1 can function as an intrinsic negative modulator of Delta-like ligand 4 (DLL4)/Notch signaling in Lewis lung carcinoma (LLC) xenograft-derived vascular endothelial cells (lung cancer-derived ECs). PRINCIPAL FINDINGS: SIRT1 negatively regulates Notch1 intracellular domain (N1IC) and Notch1 target genes HEY1 and HEY2 in response to Delta-like ligand 4 (DLL4) stimulation. Furthermore, SIRT1 deacetylated and repressed N1IC expression. Quantitative chromatin immunoprecipitation (qChIP) analysis and gene reporter assay demonstrated that SIRT1 bound to one highly conserved region, which was located at approximately 500 bp upstream of the transcriptional start site of Notch1,and repressed Notch1 transcription. Inhibition of endothelial cell growth and sprouting angiogenesis by DLL4/Notch signaling was enhanced in SIRT1-silenced lung cancer-derived EC and rescued by Notch inhibitor DAPT. In vivo, an increase in proangiogenic activity was observed in Matrigel plugs from endothelial-specific SIRT1 knock-in mice. SIRT1 also enhanced tumor neovascularization and tumor growth of LLC xenografts. CONCLUSIONS: Our results show that SIRT1 facilitates endothelial cell branching and proliferation to increase vessel density and promote lung tumor growth through down-regulation of DLL4/Notch signaling and deacetylation of N1IC. Thus, targeting SIRT1 activity or/and gene expression may represent a novel mechanism in the treatment of lung cancer. PMID- 23028942 TI - Understanding long-term variations in an elephant piosphere effect to manage impacts. AB - Surface water availability is a key driver of elephant impacts on biological diversity. Thus, understanding the spatio-temporal variations of these impacts in relation to water is critical to their management. However, elephant piosphere effects (i.e. the radial pattern of attenuating impact) are poorly described, with few long-term quantitative studies. Our understanding is further confounded by the complexity of systems with elephant (i.e. fenced, multiple water points, seasonal water availability, varying population densities) that likely limit the use of conceptual models to predict these impacts. Using 31 years of data on shrub structure in the succulent thickets of the Addo Elephant National Park, South Africa, we tested elephant effects at a single water point. Shrub structure showed a clear sigmoid response with distance from water, declining at both the upper and lower limits of sampling. Adjacent to water, this decline caused a roughly 300-m radial expansion of the grass-dominated habitats that replace shrub communities. Despite the clear relationship between shrub structure and ecological functioning in thicket, the extent of elephant effects varied between these features with distance from water. Moreover, these patterns co-varied with other confounding variables (e.g. the location of neighboring water points), which limits our ability to predict such effects in the absence of long-term data. We predict that elephant have the ability to cause severe transformation in succulent thicket habitats with abundant water supply and elevated elephant numbers. However, these piosphere effects are complex, suggesting that a more integrated understanding of elephant impacts on ecological heterogeneity may be required before water availability is used as a tool to manage impacts. We caution against the establishment of water points in novel succulent thicket habitats, and advocate a significant reduction in water provisioning at our study site, albeit with greater impacts at each water point. PMID- 23028941 TI - Hedgehog pathway signaling regulates human colon carcinoma HT-29 epithelial cell line apoptosis and cytokine secretion. AB - The Hedgehog (Hh) pathway is involved in embryogenesis and physiologic processes including cell survival and proliferation. We used the HT-29 and other human colon carcinoma cell lines to investigate Hh signaling and biological functions in colonic epithelial cells. HT-29 cells were cultured under different conditions and exposed to various stimuli. The expression of Hh pathway components and related genes and proteins were assessed by real-time PCR and immunofluorescence. Viability, apoptosis and cell proliferation were measured by the MTT assay, Annexin-V/7-AAD staining and BrdU uptake, respectively. Chemokines production was measured by ELISA in culture supernatants. Indian and Sonic Hh mRNA levels and the downstream transcription factors Gli-1 and Gli-2 increased following treatment with Hh agonists and butyrate, but decreased upon exposure to cyclopamine or GANT61. BMP4 and BMP7 expression increased after stimulation with Hh agonists. Gli-1 protein expression increased after Hh agonists and decreased following cyclopamine. Exposure to Hh agonists promoted beta-catenin reduction and subcellular redistribution. Levels of IL-8 and MCP-1 decreased upon exposure to Hh agonists compared to Hh antagonists, LPS, IFN-gamma or EGF. Monocyte chemotaxis decreased upon exposure to supernatants of HT-29 cells treated with Shh compared to Hh antagonists, LPS and IFN-gamma. Cellular incorporation of BrdU and cell viability decreased following Hh blockade. Hh agonists abrogated the anti-CD95 induced apoptosis. Hh pathway is a key controller of colon cancer cells, as demonstrated by its effect in dampening inflammatory signals and antagonizing apoptosis. The differential expression of Hh components may underlie abnormalities in the local immune response and in epithelial barrier integrity, with potential homeostatic implications for the development of colonic inflammation and malignancies. PMID- 23028943 TI - Inferring foraging areas of nesting loggerhead turtles using satellite telemetry and stable isotopes. AB - In recent years, the use of intrinsic markers such as stable isotopes to link breeding and foraging grounds of migratory species has increased. Nevertheless, several assumptions still must be tested to interpret isotopic patterns found in the marine realm. We used a combination of satellite telemetry and stable isotope analysis to (i) identify key foraging grounds used by female loggerheads nesting in Florida and (ii) examine the relationship between stable isotope ratios and post-nesting migration destinations. We collected tissue samples for stable isotope analysis from 14 females equipped with satellite tags and an additional 57 untracked nesting females. Telemetry identified three post-nesting migratory pathways and associated non-breeding foraging grounds: (1) a seasonal continental shelf-constrained migratory pattern along the northeast U.S. coastline, (2) a non breeding residency in southern foraging areas and (3) a residency in the waters adjacent to the breeding area. Isotopic variability in both delta(13)C and delta(15)N among individuals allowed identification of three distinct foraging aggregations. We used discriminant function analysis to examine how well delta(13)C and delta(15)N predict female post-nesting migration destination. The discriminant analysis classified correctly the foraging ground used for all but one individual and was used to predict putative feeding areas of untracked turtles. We provide the first documentation that the continental shelf of the Mid and South Atlantic Bights are prime foraging areas for a large number (61%) of adult female loggerheads from the largest loggerhead nesting population in the western hemisphere and the second largest in the world. Our findings offer insights for future management efforts and suggest that this technique can be used to infer foraging strategies and residence areas in lieu of more expensive satellite telemetry, enabling sample sizes that are more representative at the population level. PMID- 23028944 TI - HuR is necessary for mammary epithelial cell proliferation and polarity at least in part via DeltaNp63. AB - HuR, a RNA binding protein, is known to function as a tumor maintenance gene in breast cancer and associated with tumor growth and poor prognosis. However, the cellular function of this protein remains largely unknown in normal mammary epithelial cells. Here, we showed that in immortalized MCF10A mammary epithelial cells, HuR knockdown inhibits cell proliferation and enhances premature senescence. We also showed that in three-dimensional culture, MCF10A cells with HuR knockdown form abnormal acini with filled lumen and an aberrant expression pattern of the extracellular matrix protein laminin V. In addition, we showed that HuR knockdown increases DeltaNp63, but decreases wild-type p53, expression in MCF10A cells. Moreover, we showed that DeltaNp63 knockdown partially rescues the proliferative defect induced by HuR knockdown in MCF10A cells. Consistent with this, we identified two U-rich elements in the 3'-untranslated region of p63 mRNA, to which HuR specifically binds. Finally, we showed that HuR knockdown enhances DeltaNp63 mRNA translation but has no effect on p63 mRNA turnover. Together, our data suggest that HuR maintains cell proliferation and polarity of mammary epithelial cells at least in part via DeltaNp63. PMID- 23028945 TI - Development of SCN connectivity and the circadian control of arousal: a diminishing role for humoral factors? AB - The suprachiasmatic nucleus (SCN) is part of a wake-promoting circuit comprising the dorsomedial hypothalamus (DMH) and locus coeruleus (LC). Although widely considered a "master clock," the SCN of adult rats is also sensitive to feedback regarding an animal's behavioral state. Interestingly, in rats at postnatal day (P)2, repeated arousing stimulation does not increase neural activation in the SCN, despite doing so in the LC and DMH. Here we show that, by P8, the SCN is activated by arousing stimulation and that selective destruction of LC terminals with DSP-4 blocks this activational effect. We next show that bidirectional projections among the SCN, DMH, and LC are nearly absent at P2 but present at P8. Despite the relative lack of SCN connectivity with downstream structures at P2, day-night differences in sleep-wake activity are observed, suggesting that the SCN modulates behavior at this age via humoral factors. To test this hypothesis, we lesioned the SCN at P1 and recorded sleep-wake behavior at P2: Day-night differences in sleep and wake were eliminated. We next performed precollicular transections at P2 and P8 that isolate the SCN and DMH from the brainstem and found that day-night differences in sleep-wake behavior were retained at P2 but eliminated at P8. Finally, the SCN or DMH was lesioned at P8: When recorded at P21, rats with either lesion exhibited similarly fragmented wake bouts and no evidence of circadian modulation of wakefulness. These results suggest an age related decline in the SCN's humoral influence on sleep-wake behavior that coincides with the emergence of bidirectional connectivity among the SCN, DMH, and LC. PMID- 23028946 TI - Aquaporin expression contributes to human transurothelial permeability in vitro and is modulated by NaCl. AB - It is generally considered that the bladder is impervious and stores urine in unmodified form on account of the barrier imposed by the highly-specialised uro epithelial lining. However, recent evidence, including demonstration of aquaporin (AQP) expression by human urothelium, suggests that urothelium may be able to modify urine content. Here we have we applied functional assays to an in vitro differentiated normal human urothelial cell culture system and examined both whether AQP expression was responsive to changes in osmolality, and the effects of blocking AQP channels on water and urea transport. AQP3 expression was up regulated by increased osmolality, but only in response to NaCl. A small but similar effect was seen with AQP9, but not AQP4 or AQP7. Differentiated urothelium revealed significant barrier function (mean TER 3862 Omega.cm(2)), with mean diffusive water and urea permeability coefficients of 6.33*10(-5) and 2.45*10(-5) cm/s, respectively. AQP blockade with mercuric chloride resulted in decreased water and urea flux. The diffusive permeability of urothelial cell sheets remained constant following conditioning in hyperosmotic NaCl, but there was a significant increase in water and urea flux across an osmotic gradient. Taken collectively with evidence emerging from studies in other species, our results support an active role for human urothelium in sensing and responding to hypertonic salt concentrations through alterations in AQP protein expression, with AQP channels providing a mechanism for modifying urine composition. These observations challenge the traditional concept of an impermeable bladder epithelium and suggest that the urothelium may play a modulatory role in water and salt homeostasis. PMID- 23028947 TI - Development and application of stereo camera-based upper extremity workspace evaluation in patients with neuromuscular diseases. AB - BACKGROUND: The concept of reachable workspace is closely tied to upper limb joint range of motion and functional capability. Currently, no practical and cost effective methods are available in clinical and research settings to provide arm function evaluation using an individual's three-dimensional (3D) reachable workspace. A method to intuitively display and effectively analyze reachable workspace would not only complement traditional upper limb functional assessments, but also provide an innovative approach to quantify and monitor upper limb function. METHODOLOGY/PRINCIPAL FINDINGS: A simple stereo camera-based reachable workspace acquisition system combined with customized 3D workspace analysis algorithm was developed and compared against a sub-millimeter motion capture system. The stereo camera-based system was robust, with minimal loss of data points, and with the average hand trajectory error of about 40 mm, which resulted to ~5% error of the total arm distance. As a proof-of-concept, a pilot study was undertaken with healthy individuals (n = 20) and a select group of patients with various neuromuscular diseases and varying degrees of shoulder girdle weakness (n = 9). The workspace envelope surface areas generated from the 3D hand trajectory captured by the stereo camera were compared. Normalization of acquired reachable workspace surface areas to the surface area of the unit hemi sphere allowed comparison between subjects. The healthy group's relative surface areas were 0.618+/-0.09 and 0.552+/-0.092 (right and left), while the surface areas for the individuals with neuromuscular diseases ranged from 0.03 and 0.09 (the most severely affected individual) to 0.62 and 0.50 (very mildly affected individual). Neuromuscular patients with severe arm weakness demonstrated movement largely limited to the ipsilateral lower quadrant of their reachable workspace. CONCLUSIONS/SIGNIFICANCE: The findings indicate that the proposed stereo camera-based reachable workspace analysis system is capable of distinguishing individuals with varying degrees of proximal upper limb functional impairments. PMID- 23028948 TI - Ultrastructural modifications in the mitochondria of hypoxia-adapted Drosophila melanogaster. AB - Chronic hypoxia (CH) occurs under certain physiological or pathological conditions, including in people who reside at high altitude or suffer chronic cardiovascular or pulmonary diseases. As mitochondria are the predominant oxygen consuming organelles to generate ATP through oxidative phosphorylation in cells, their responses, through structural or molecular modifications, to limited oxygen supply play an important role in the overall functional adaptation to hypoxia. Here, we report the adaptive mitochondrial ultrastructural modifications and the functional impacts in a recently generated hypoxia-adapted Drosophila melanogaster strain that survives severe, otherwise lethal, hypoxic conditions. Using electron tomography, we discovered increased mitochondrial volume density and cristae abundance, yet also cristae fragmentation and a unique honeycomb-like structure in the mitochondria of hypoxia-adapted flies. The homeostatic levels of adenylate and energy charge were similar between hypoxia-adapted and naive control flies and the hypoxia-adapted flies remained active under severe hypoxia as quantified by negative geotaxis behavior. The equilibrium ATP level was lower in hypoxia-adapted flies than those of the naive controls tested under severe hypoxia that inhibited the motion of control flies. Our results suggest that the structural rearrangement in the mitochondria of hypoxia-adapted flies may be an important adaptive mechanism that plays a critical role in preserving adenylate homeostasis and metabolism as well as muscle function under chronic hypoxic conditions. PMID- 23028949 TI - Palatability of selected alpine plant litters for the decomposer Lumbricus rubellus (Lumbricidae). AB - On alpine pastureland the decline in large-bodied earthworm numbers and biomass after abandonment of management might be the result of a shift from highly palatable grass litter to poorly digestible leaf litter of dwarf shrubs. To test this hypothesis, we analysed nitrogen, phosphorous and total phenolic contents of fresh and aged litter of eight commonly occuring alpine plant species and compared consumption rates of these food sources in a controlled feeding experiment with Lumbricus rubellus (Lumbricidae). Furthermore, we analysed the microbial community structure of aged litter materials to check for a relationship between the microbial characteristics of the different plant litter types and the food choice of earthworms. Plant litters differed significantly in their chemical composition, earthworms, however, showed no preference for any litter species, but generally rejected fresh litter material. Microbial community structures of the litter types were significantly different, but we could find no evidence for selective feeding of L. rubellus. We conclude that L. rubellus is a widespread, adaptable ubiquist, which is able to feed on a variety of food sources differing in quality and palatability, as long as they have been exposed to wheathering. PMID- 23028950 TI - Pan-genomic analysis provides insights into the genomic variation and evolution of Salmonella Paratyphi A. AB - Salmonella Paratyphi A (S. Paratyphi A) is a highly adapted, human-specific pathogen that causes paratyphoid fever. Cases of paratyphoid fever have recently been increasing, and the disease is becoming a major public health concern, especially in Eastern and Southern Asia. To investigate the genomic variation and evolution of S. Paratyphi A, a pan-genomic analysis was performed on five newly sequenced S. Paratyphi A strains and two other reference strains. A whole genome comparison revealed that the seven genomes are collinear and that their organization is highly conserved. The high rate of substitutions in part of the core genome indicates that there are frequent homologous recombination events. Based on the changes in the pan-genome size and cluster number (both in the core functional genes and core pseudogenes), it can be inferred that the sharply increasing number of pseudogene clusters may have strong correlation with the inactivation of functional genes, and indicates that the S. Paratyphi A genome is being degraded. PMID- 23028951 TI - Proteomic analysis of adrenocorticotropic hormone treatment of an infantile spasm model induced by N-methyl-D-aspartic acid and prenatal stress. AB - Infantile spasms is an age-specific epileptic syndrome associated with poor developmental outcomes and poor response to nearly all traditional antiepileptic drugs except adrenocorticotropic hormone (ACTH). We investigated the protective mechanism of ACTH against brain damage. An infantile spasm rat model induced by N methyl-D-aspartate (NMDA) in neonate rats was used. Pregnant rats were randomly divided into the stress-exposed and the non-stress exposed groups, and their offspring were randomly divided into ACTH-treated spasm model, untreated spasm model, and control groups. A proteomics-based approach was used to detect the proteome differences between ACTH-treated and untreated groups. Gel image analysis was followed by matrix-assisted laser desorption/ionization time-of flight mass spectrometric protein identification and bioinformatics analysis. Prenatal stress exposure resulted in more severe seizures, and ACTH treatment reduced and delayed the onset of seizures. The most significantly up-regulated proteins included isoform 1 of tubulin beta-5 chain, cofilin-1 (CFL1), synaptosomal-associated protein 25, malate dehydrogenase, N(G),N(G) dimethylarginine dimethylaminohydrolase 1, annexin A3 (ANXA3), and rho GDP dissociation inhibitor 1 (ARHGDIA). In contrast, tubulin alpha-1A chain was down regulated. Three of the identified proteins, ARHGDIA, ANXA3, and CFL1, were validated using western blot analysis. ARHGDIA expression was assayed in the brain samples of five infantile spasm patients. These proteins are involved in the cytoskeleton, synapses, energy metabolism, vascular regulation, signal transduction, and acetylation. The mechanism underlying the effects of ACTH involves the molecular events affected by these proteins, and protein acetylation is the mechanism of action of the drug treatment. PMID- 23028952 TI - Direct engagement of TLR4 in invariant NKT cells regulates immune diseases by differential IL-4 and IFN-gamma production in mice. AB - During interaction with APCs, invariant (i) NKT cells are thought to be indirectly activated by TLR4-dependently activated APCs. However, whether TLR4 directly activates iNKT cells is unknown. Therefore, the expression and function of TLR4 in iNKT cells were investigated. Flow cytometric and confocal microscopic analysis revealed TLR4 expression on the surface and in the endosome of iNKT cells. Upon LPS stimulation, iNKT cells enhanced IFN-gamma production, but reduced IL-4 production, in the presence of TCR signals, depending on TLR4, MyD88, TRIF, and the endosome. However, enhanced TLR4-mediated IFN-gamma production by iNKT cells did not affect IL-12 production or CD1d expression by DCs. Adoptive transfer of WT, but not TLR4-deficient, iNKT cells promoted antibody-induced arthritis in CD1d(-/-) mice, suggesting that endogenous TLR4 ligands modulate iNKT cell function in arthritis. Furthermore, LPS-pretreated WT, but not TLR4-deficient, iNKT cells suppressed pulmonary fibrosis, but worsened hypersensitivity pneumonitis more than untreated WT iNKT cells, indicating that exogenous TLR4 ligands regulate iNKT cell functions in pulmonary diseases. Taken together, we propose a novel direct activation pathway of iNKT cells in the presence of TCR signals via endogenous or exogenous ligand-mediated engagement of TLR4 in iNKT cells, which regulates immune diseases by altering IFN-gamma and IL 4 production. PMID- 23028953 TI - Persistence of hyperinvasive meningococcal strain types during global spread as recorded in the PubMLST database. AB - Neisseria meningitidis is a major cause of septicaemia and meningitis worldwide. Most disease in Europe, the Americas and Australasia is caused by meningococci expressing serogroup B capsules, but no vaccine against this polysaccharide exists. Potential candidates for 'serogroup B substitute' vaccines are outer membrane protein antigens including the typing antigens PorA and FetA. The web accessible PubMLST database (www.pubmlst.org) was used to investigate the temporal and geographical patterns of associations among PorA and FetA protein variants and lineages defined by combinations of housekeeping genes, known as clonal complexes. The sample contained 3460 isolates with genotypic information from 57 countries over a 74 year period. Although shifting associations among antigen variants and clonal complexes were evident, a subset of strain types associated with several serogroups persisted for decades and proliferated globally. Genetic stability among outer membrane proteins of serogroup A meningococci has been described previously, but here long-lived genetic associations were also observed among meningococci belonging to serogroups B and C. The patterns of variation were consistent with behaviour predicted by models that invoke inter-strain competition mediated by immune selection. There was also substantial geographic and temporal heterogeneity in antigenic repertoires, providing both opportunities and challenges for the design of broad coverage protein-based meningococcal vaccines. PMID- 23028954 TI - Nociceptin induces hypophagia in the perifornical and lateral hypothalamic area. AB - Nociceptin/orphanin FQ (N/OFQ) is known to induce food intake when administered into the lateral ventricle or certain brain areas. This is somewhat contradictory to its reward-suppressing role, as food is a strong rewarding stimulus. This discrepancy may be due to the functional diversity of N/OFQ's target brain areas. N/OFQ has been shown to inhibit orexin and melanin-concentrating hormone (MCH) neurons, both of which are appetite-inducing cells. As the expression of these neurons is largely confined to the lateral hypothalamus/perifornical area (LH/PFA), we hypothesized that N/OFQ inhibits food intake by acting in this area. To test this hypothesis, we examined the effect of local N/OFQ infusion within the LH/PFA on food intake in the rat and found that N/OFQ decreased sugar pellet as well as chow intake. This effect was not seen when the injection site was outside of the LH/PFA, suggesting a site-specific effect. Next, to determine a possible cellular mechanism of N/OFQ action on food intake, whole cell patch clamp recordings were performed on rat orexin neurons. As previously reported in mice, N/OFQ induced a strong and long lasting hyperpolarization. Pharmacological study indicated that N/OFQ directly inhibited orexin neurons by activating ATP sensitive potassium (KATP) channels. This effect was partially but significantly attenuated by the inhibitors of PI3K, PKC and PKA, suggesting that the N/OFQ signaling is mediated by these protein kinases. In summary, our results demonstrate a KATP channel-dependent N/OFQ signaling and that N/OFQ is a site specific anorexic peptide. PMID- 23028955 TI - Directional selection causes decanalization in a group I ribozyme. AB - A canalized genotype is robust to environmental or genetic perturbations. Canalization is expected to result from stabilizing selection on a well-adapted phenotype. Decanalization, the loss of robustness, might follow periods of directional selection toward a new optimum. The evolutionary forces causing decanalization are still unknown, in part because it is difficult to determine the fitness effects of mutations in populations of organisms with complex genotypes and phenotypes. Here, we report direct experimental measurements of robustness in a system with a simple genotype and phenotype, the catalytic activity of an RNA enzyme. We find that the robustness of a population of RNA enzymes decreases during a period of directional selection in the laboratory. The decrease in robustness is primarily caused by the selective sweep of a genotype that is decanalized relative to the wild-type, both in terms of mutational robustness and environmental robustness (thermodynamic stability). Our results experimentally demonstrate that directional selection can cause decanalization on short time scales, and demonstrate co-evolution of mutational and environmental robustness. PMID- 23028956 TI - OSBP-related proteins (ORPs) in human adipose depots and cultured adipocytes: evidence for impacts on the adipocyte phenotype. AB - Oxysterol-binding protein (OSBP) homologues, ORPs, are implicated in lipid homeostatic control, vesicle transport, and cell signaling. We analyzed here the quantity of ORP mRNAs in human subcutaneous (s.c.) and visceral adipose depots, as well as in the Simpson-Golabi-Behmel syndrome (SGBS) adipocyte cell model. All of the ORP mRNAs were present in the s.c and visceral adipose tissues, and the two depots shared an almost identical ORP mRNA expression pattern. SGBS adipocytes displayed a similar pattern, suggesting that the adipose tissue ORP expression pattern mainly derives from adipocytes. During SGBS cell adipogenic differentiation, ORP2, ORP3, ORP4, ORP7, and ORP8 mRNAs were down-regulated, while ORP11 was induced. To assess the impacts of ORPs on adipocyte differentiation, ORP3 and ORP8, proteins down-regulated during adipogenesis, were overexpressed in differentiating SGBS adipocytes, while ORP11, a protein induced during adipogenesis, was silenced. ORP8 overexpression resulted in reduced expression of the aP2 mRNA, while down-regulation of adiponectin and aP2 was observed in ORP11 silenced cells. Furthermore, ORP8 overexpression or silencing of ORP11 markedly decreased cellular triglyceride storage. These data identify the patterns of ORP expression in human adipose depots and SGBS adipocytes, and provide the first evidence for a functional impact of ORPs on the adipocyte phenotype. PMID- 23028957 TI - Differential effects of lovastatin on cisplatin responses in normal human mesothelial cells versus cancer cells: implication for therapy. AB - The cancer killing efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is limited by their side effects to normal tissues. Therefore, research efforts optimizing the safety and efficacy of those agents are clinically relevant. We did screen for agents that specifically protect normal human mesothelial cells against CDDP without reducing the cancer cell killing efficacy. Lovastatin was identified from the screen. Lovastatin at a pharmacologically relevant concentration strongly arrested the proliferation of normal cells, whereas cancer cells were less affected. CDDP-induced DNA damage response was not activated and normal cells showed enhanced tolerance to CDDP when normal cells were treated with the combination of CDDP and lovastatin. We demonstrate that interfering with protein geranylgeranylation is involved in the lovastatin mediated CDDP protective effect in normal cells. In contrast to normal cells, in cancer cells lovastatin did not change the CDDP-induced response, and cancer cells were not protected by lovastatin. Furthermore, lovastatin at the pharmacological relevant concentration per se induced DNA damage, oxidative stress and autophagy in cancer cells but not in normal mesothelial cells. Therefore, our data suggest that lovastatin has a potential to improve the therapeutic index of cisplatin-based therapy. PMID- 23028958 TI - A novel phytomyxean parasite associated with galls on the bull-kelp Durvillaea antarctica (Chamisso) Hariot. AB - Durvillaea antarctica (Fucales, Phaeophyceae) is a large kelp of high ecological and economic significance in the Southern Hemisphere. In natural beds along the central coast of Chile (Pacific Ocean), abnormal growth characterized by evident gall development and discolorations of the fronds/thallus was observed. Analysing these galls by light microscopy and scanning electron microscopy revealed the presence of endophytic eukaryotes showing typical characteristics for phytomyxean parasites. The parasite developed within enlarged cells of the subcortical tissue of the host. Multinucleate plasmodia developed into many, single resting spores. The affiliation of this parasite to the Phytomyxea (Rhizaria) was supported by 18S rDNA data, placing it within the Phagomyxida. Similar microorganisms were already reported once 23 years ago, indicating that these parasites are persistent and widespread in D. antarctica beds for long times. The symptoms caused by this parasite are discussed along with the ecological and economic consequences. Phytomyxean parasites may play an important role in the marine ecosystem, but they remain understudied in this environment. Our results demonstrate for the first time the presence of resting spores in Phagomyxida, an order in which resting spores were thought to be absent making this the first record of a phagomyxean parasite with a complete life cycle so far, challenging the existing taxonomic concepts within the Phytomyxea. The importance of the here described resting spores for the survival and ecology of the phagomyxid parasite will be discussed together with the impact this parasite may have on 'the strongest seaweed of the world', which is an important habitat forming and economic resource from the Southern Hemisphere. PMID- 23028959 TI - Hypervariable region polymorphism of mtDNA of recurrent oral ulceration in Chinese. AB - BACKGROUND: MtDNA haplogroups could have important implication for understanding of the relationship between the mutations of the mitochondrial genome and diseases. Distribution of a variety of diseases among these haplogroups showed that some of the mitochondrial haplogroups are predisposed to disease. To examine the susceptibility of mtDNA haplogroups to ROU, we sequenced the mtDNA HV1, HV2 and HV3 in Chinese ROU. METHODOLOGY/PRINCIPAL FINDINGS: MtDNA haplogroups were analyzed in the 249 cases of ROU patients and the 237 cases of healthy controls respectively by means of primer extension analysis and DNA sequencing. Haplogroups G1 and H were found significantly more abundant in ROU patients than in healthy persons, while haplogroups D5 and R showed a trend toward a higher frequency in control as compared to those in patients. The distribution of C stretch sequences polymorphism in mtDNA HV1, HV2 and HV3 regions was found in diversity. CONCLUSIONS/SIGNIFICANCE: For the first time, the relationship of mtDNA haplogroups and ROU in Chinese was investigated. Our results indicated that mtDNA haplogroups G1 and H might constitute a risk factor for ROU, which possibly increasing the susceptibility of ROU. Meanwhile, haplogroups D5 and R were indicated as protective factors for ROU. The polymorphisms of C-stretch sequences might being unstable and influence the mtDNA replication fidelity. PMID- 23028960 TI - A new dimension to Ras function: a novel role for nucleotide-free Ras in Class II phosphatidylinositol 3-kinase beta (PI3KC2beta) regulation. AB - The intersectin 1 (ITSN1) scaffold stimulates Ras activation on endocytic vesicles without activating classic Ras effectors. The identification of Class II phosphatidylinositol 3-kinase beta, PI3KC2beta, as an ITSN1 target on vesicles and the presence of a Ras binding domain (RBD) in PI3KC2beta suggests a role for Ras in PI3KC2beta activation. Here, we demonstrate that nucleotide-free Ras negatively regulates PI3KC2beta activity. PI3KC2beta preferentially interacts in vivo with dominant-negative (DN) Ras, which possesses a low affinity for nucleotides. PI3KC2beta interaction with DN Ras is disrupted by switch 1 domain mutations in Ras as well as RBD mutations in PI3KC2beta. Using purified proteins, we demonstrate that the PI3KC2beta-RBD directly binds nucleotide-free Ras in vitro and that this interaction is not disrupted by nucleotide addition. Finally, nucleotide-free Ras but not GTP-loaded Ras inhibits PI3KC2beta lipid kinase activity in vitro. Our findings indicate that PI3KC2beta interacts with and is regulated by nucleotide-free Ras. These data suggest a novel role for nucleotide free Ras in cell signaling in which PI3KC2beta stabilizes nucleotide-free Ras and that interaction of Ras and PI3KC2beta mutually inhibit one another. PMID- 23028961 TI - Maternal immunization affects in utero programming of insulin resistance and type 2 diabetes. AB - Maternal immunization with oxidized lipoproteins prior to pregnancy protects against atherogenic in utero programming by gestational hypercholesterolemia and enhances beneficial lymphocyte-dependent immune responses in offspring. To determine whether in utero programming and immunomodulation also affect insulin resistance (IR) and type 2 diabetes, we investigated the effects of immunization on glucose and insulin responses in LDL receptor-deficient mice fed regular or 60% sucrose diets, as well as in offspring fed 0.5% cholesterol or 60% sucrose diets. IR was assessed by fasting glucose and insulin levels, oral glucose tolerance tests, glucose clamps, pancreatic immunohistochemistry and plasma free fatty acid concentrations. Immunizations improved glucose responses in both genders and protected both immunized mice and their offspring against IR and type 2 diabetes. Protection occurred even under euglycemic conditions, but was greatest in obese males exposed to very obesogenic/diabetogenic conditions. Hyperinsulinemic euglycemic clamps confirmed that maternal immunization protected mainly by reducing IR, but pancreatic immunocytochemistry also indicated some protection against beta cell damage. Maternal immunization was associated with marked regulation in offspring of 4 genes relevant to diabetes and 19 genes of importance for oxidative stress, as well as increased hepatic activities of key antioxidant enzymes. These findings establish that targeted immunomodulation may be used to protect immunized subjects and their offspring against IR and type 2 diabetes, and thus to reduce cardiovascular risk. They also support the notion that in utero programming influences offspring disease not by a single mechanism, but by multiple systemic effects. PMID- 23028962 TI - High prevalence of shared international type 53 among Mycobacterium tuberculosis complex strains in retreated patients from Cote d'Ivoire. AB - BACKGROUND: Genotyping methods are useful tools to provide information on tuberculosis epidemic. They can allow a better response from health authorities and the implementation of measures for tuberculosis control. This study aimed to identify the main lineages and clades of Mycobacterium tuberculosis complex strains circulating in Cote d'Ivoire. METHODS/MAIN FINDINGS: Strains isolated from sputum samples of patients ongoing retreatment from all the country were characterized by spoligotyping and by MIRU-VNTR. Profiles obtained by spoligotyping were first compared to the SITVIT/SpolDB4 database for family assignment. Of 194 strains analysed, 146 (75.3%) belonged to the T lineage. The most predominant spoligotype was the shared international type 53 with 135 strains (69.6%). In contrast with neighbouring countries, LAM (11 strains, 5.7%) and H (9 strains 4.6%) lineages were slightly represented. Only 3 Beijing strains (1.5%) and 4 strains of Mycobacterium africanum (2%) were found. Analysis of the results obtained with MIRU-VNTR revealed also a high level of clustering. CONCLUSION/SIGNIFICANCE: The population of Mycobacterium tuberculosis complex strains among retreatment cases in Cote d'Ivoire exhibits a low diversity, allowing to assume recent transmission and locally based infection. PMID- 23028963 TI - 5-aza-2'-deoxycytidine leads to reduced embryo implantation and reduced expression of DNA methyltransferases and essential endometrial genes. AB - BACKGROUND: The DNA demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) incorporates into DNA and decreases DNA methylation, sparking interest in its use as a potential therapeutic agent. We aimed to determine the effects of maternal 5 aza-CdR treatment on embryo implantation in the mouse and to evaluate whether these effects are associated with decreased levels of DNA methyltransferases (Dnmts) and three genes (estrogen receptor alpha [Esr1], progesterone receptor [Pgr], and homeobox A10 [Hoxa10]) that are vital for control of endometrial changes during implantation. METHODS AND PRINCIPAL FINDINGS: Mice treated with 5 aza-CdR had a dose-dependent decrease in number of implantation sites, with defected endometrial decidualization and stromal cell proliferation. Western blot analysis on pseudo-pregnant day 3 (PD3) showed that 0.1 mg/kg 5-aza-CdR significantly repressed Dnmt3a protein level, and 0.5 mg/kg 5-aza-CdR significantly repressed Dnmt1, Dnmt3a, and Dnmt3b protein levels in the endometrium. On PD5, mice showed significantly decreased Dnmt3a protein level with 0.1 mg/kg 5-aza-CdR, and significantly decreased Dnmt1 and Dnmt3a with 0.5 mg/kg 5-aza-CdR. Immunohistochemical staining showed that 5-aza-CdR repressed DNMT expression in a cell type-specific fashion within the uterus, including decreased expression of Dnmt1 in luminal and/or glandular epithelium and of Dnmt3a and Dnmt3b in stroma. Furthermore, the 5' flanking regions of the Esr1, Pgr, and Hoxa10 were hypomethylated on PD5. Interestingly, the higher (0.5 mg/kg) dose of 5-aza-CdR decreased protein expression of Esr1, Pgr, and Hoxa10 in the endometrium on PD5 in both methylation-dependent and methylation-independent manners. CONCLUSIONS: The effects of 5-aza-CdR on embryo implantation in mice were associated with altered expression of endometrial Dnmts and genes controlling endometrial changes, suggesting that altered gene methylation, and not cytotoxicity alone, contributes to implantation defects induced by 5-aza-CdR. PMID- 23028964 TI - Detrimental effects of RNAi: a cautionary note on its use in Drosophila ageing studies. AB - RNA interference (RNAi) provides an important tool for gene function discovery. It has been widely exploited in Caenorhabditis elegans ageing research because it does not appear to have any non-specific effects on ageing-related traits in that model organism. We show here that ubiquitous, adult-onset activation of the RNAi machinery, achieved by expressing a double stranded RNA targeting GFP or lacZ for degradation, or by increasing expression of Dicer substantially reduces lifespan in Drosophila melanogaster. Induction of GFPRNAi construct also alters the response of lifespan to nutrition, exacerbating the lifespan-shortening effects of food containing a high quantity of yeast. Our study indicates that activation of the RNAi machinery may have sequence-independent side-effects on lifespan, and that caution needs to be exercised when employing ubiquitous RNAi in Drosophila ageing studies. However, we also show that RNAi restricted to certain tissues may not be detrimental to lifespan. PMID- 23028965 TI - Stability of the transthyretin molecule as a key factor in the interaction with a beta peptide--relevance in Alzheimer's disease. AB - Transthyretin (TTR) protects against A-Beta toxicity by binding the peptide thus inhibiting its aggregation. Previous work showed different TTR mutations interact differently with A-Beta, with increasing affinities correlating with decreasing amyloidogenecity of the TTR mutant; this did not impact on the levels of inhibition of A-Beta aggregation, as assessed by transmission electron microscopy. Our work aimed at probing differences in binding to A-Beta by WT, T119M and L55P TTR using quantitative assays, and at identifying factors affecting this interaction. We addressed the impact of such factors in TTR ability to degrade A-Beta. Using a dot blot approach with the anti-oligomeric antibody A11, we showed that A-Beta formed oligomers transiently, indicating aggregation and fibril formation, whereas in the presence of WT and T119M TTR the oligomers persisted longer, indicative that these variants avoided further aggregation into fibrils. In contrast, L55PTTR was not able to inhibit oligomerization or to prevent evolution to aggregates and fibrils. Furthermore, apoptosis assessment showed WT and T119M TTR were able to protect against A-Beta toxicity. Because the amyloidogenic potential of TTR is inversely correlated with its stability, the use of drugs able to stabilize TTR tetrameric fold could result in increased TTR/A-Beta binding. Here we showed that iododiflunisal, 3 dinitrophenol, resveratrol, [2-(3,5-dichlorophenyl)amino] (DCPA) and [4-(3,5 difluorophenyl)] (DFPB) were able to increase TTR binding to A-Beta; however only DCPA and DFPB improved TTR proteolytic activity. Thyroxine, a TTR ligand, did not influence TTR/A-Beta interaction and A-Beta degradation by TTR, whereas RBP, another TTR ligand, not only obstructed the interaction but also inhibited TTR proteolytic activity. Our results showed differences between WT and T119M TTR, and L55PTTR mutant regarding their interaction with A-Beta and prompt the stability of TTR as a key factor in this interaction, which may be relevant in AD pathogenesis and for the design of therapeutic TTR-based therapies. PMID- 23028966 TI - The homeobox transcription factor HOXA9 is a regulator of SHOX in U2OS cells and chicken micromass cultures. AB - The homeobox gene SHOX encodes for a transcription factor that plays an important role during limb development. Mutations or deletions of SHOX in humans cause short stature in Turner, Langer and Leri-Weill syndrome as well as idiopathic short stature. During embryonic development, SHOX is expressed in a complex spatio-temporal pattern that requires the presence of specific regulatory mechanisms. Up to now, it was known that SHOX is regulated by two upstream promoters and several enhancers on either side of the gene, but no regulators have been identified that can activate or repress the transcription of SHOX by binding to these regulatory elements. We have now identified the homeodomain protein HOXA9 as a positive regulator of SHOX expression in U2OS cells. Using luciferase assays, chromatin immunoprecipitation and electrophoretic mobility shift assays, we could narrow down the HOXA9 binding site to two AT-rich sequences of 31 bp within the SHOX promoter 2. Virus-induced Hoxa9 overexpression in a chicken micromass model validated the regulation of Shox by Hoxa9 (negative regulation). As Hoxa9 and Shox are both expressed in overlapping regions of the developing limb buds, a regulatory relationship of Hoxa9 and Shox during the process of limb development can be assumed. PMID- 23028967 TI - Bacterial neuraminidase rescues influenza virus replication from inhibition by a neuraminidase inhibitor. AB - Influenza virus neuraminidase (NA) cleaves terminal sialic acid residues on oligosaccharide chains that are receptors for virus binding, thus playing an important role in the release of virions from infected cells to promote the spread of cell-to-cell infection. In addition, NA plays a role at the initial stage of viral infection in the respiratory tract by degrading hemagglutination inhibitors in body fluid which competitively inhibit receptor binding of the virus. Current first line anti-influenza drugs are viral NA-specific inhibitors, which do not inhibit bacterial neuraminidases. Since neuraminidase producing bacteria have been isolated from oral and upper respiratory commensal bacterial flora, we posited that bacterial neuraminidases could decrease the antiviral effectiveness of NA inhibitor drugs in respiratory organs when viral NA is inhibited. Using in vitro models of infection, we aimed to clarify the effects of bacterial neuraminidases on influenza virus infection in the presence of the NA inhibitor drug zanamivir. We found that zanamivir reduced progeny virus yield to less than 2% of that in its absence, however the yield was restored almost entirely by the exogenous addition of bacterial neuraminidase from Streptococcus pneumoniae. Furthermore, cell-to-cell infection was severely inhibited by zanamivir but restored by the addition of bacterial neuraminidase. Next we examined the effects of bacterial neuraminidase on hemagglutination inhibition and infectivity neutralization activities of human saliva in the presence of zanamivir. We found that the drug enhanced both inhibitory activities of saliva, while the addition of bacterial neuraminidase diminished this enhancement. Altogether, our results showed that bacterial neuraminidases functioned as the predominant NA when viral NA was inhibited to promote the spread of infection and to inactivate the neutralization activity of saliva. We propose that neuraminidase from bacterial flora in patients may reduce the efficacy of NA inhibitor drugs during influenza virus infection. (295 words). PMID- 23028968 TI - Three main mutational pathways in HIV-2 lead to high-level raltegravir and elvitegravir resistance: implications for emerging HIV-2 treatment regimens. AB - Human immunodeficiency virus type 2 (HIV-2) is intrinsically resistant to non nucleoside reverse transcriptase inhibitors and exhibits reduced susceptibility to several of the protease inhibitors used for antiretroviral therapy of HIV-1. Thus, there is a pressing need to identify new classes of antiretroviral agents that are active against HIV-2. Although recent data suggest that the integrase strand transfer inhibitors raltegravir and elvitegravir may be beneficial, mutations that are known to confer resistance to these drugs in HIV-1 have been reported in HIV-2 sequences from patients receiving raltegravir-containing regimens. To examine the phenotypic effects of mutations that emerge during raltegravir treatment, we constructed a panel of HIV-2 integrase variants using site-directed mutagenesis and measured the susceptibilities of the mutant strains to raltegravir and elvitegravir in culture. The effects of single and multiple amino acid changes on HIV-2 replication capacity were also evaluated. Our results demonstrate that secondary replacements in the integrase protein play key roles in the development of integrase inhibitor resistance in HIV-2. Collectively, our data define three major mutational pathways to high-level raltegravir and elvitegravir resistance: i) E92Q+Y143C or T97A+Y143C, ii) G140S+Q148R, and iii) E92Q+N155H. These findings preclude the sequential use of raltegravir and elvitegravir (or vice versa) for HIV-2 treatment and provide important information for clinical monitoring of integrase inhibitor resistance in HIV-2 infected individuals. PMID- 23028969 TI - Transcriptome tomography for brain analysis in the web-accessible anatomical space. AB - Increased information on the encoded mammalian genome is expected to facilitate an integrated understanding of complex anatomical structure and function based on the knowledge of gene products. Determination of gene expression-anatomy associations is crucial for this understanding. To elicit the association in the three-dimensional (3D) space, we introduce a novel technique for comprehensive mapping of endogenous gene expression into a web-accessible standard space: Transcriptome Tomography. The technique is based on conjugation of sequential tissue-block sectioning, all fractions of which are used for molecular measurements of gene expression densities, and the block- face imaging, which are used for 3D reconstruction of the fractions. To generate a 3D map, tissues are serially sectioned in each of three orthogonal planes and the expression density data are mapped using a tomographic technique. This rapid and unbiased mapping technique using a relatively small number of original data points allows researchers to create their own expression maps in the broad anatomical context of the space. In the first instance we generated a dataset of 36,000 maps, reconstructed from data of 61 fractions measured with microarray, covering the whole mouse brain (ViBrism: http://vibrism.riken.jp/3dviewer/ex/index.html) in one month. After computational estimation of the mapping accuracy we validated the dataset against existing data with respect to the expression location and density. To demonstrate the relevance of the framework, we showed disease related expression of Huntington's disease gene and Bdnf. Our tomographic approach is applicable to analysis of any biological molecules derived from frozen tissues, organs and whole embryos, and the maps are spatially isotropic and well suited to the analysis in the standard space (e.g. Waxholm Space for brain-atlas databases). This will facilitate research creating and using open-standards for a molecular-based understanding of complex structures; and will contribute to new insights into a broad range of biological and medical questions. PMID- 23028970 TI - Peptide nanovesicles formed by the self-assembly of branched amphiphilic peptides. AB - Peptide-based packaging systems show great potential as safer drug delivery systems. They overcome problems associated with lipid-based or viral delivery systems, vis-a-vis stability, specificity, inflammation, antigenicity, and tune ability. Here, we describe a set of 15 & 23-residue branched, amphiphilic peptides that mimic phosphoglycerides in molecular architecture. These peptides undergo supramolecular self-assembly and form solvent-filled, bilayer delimited spheres with 50-200 nm diameters as confirmed by TEM, STEM and DLS. Whereas weak hydrophobic forces drive and sustain lipid bilayer assemblies, these all-peptide structures are stabilized potentially by both hydrophobic interactions and hydrogen bonds and remain intact at low micromolar concentrations and higher temperatures. A linear peptide lacking the branch point showed no self-assembly properties. We have observed that these peptide vesicles can trap fluorescent dye molecules within their interior and are taken up by N/N 1003A rabbit lens epithelial cells grown in culture. These assemblies are thus potential drug delivery systems that can overcome some of the key limitations of the current packaging systems. PMID- 23028972 TI - Diversities in virulence, antifungal activity, pigmentation and DNA fingerprint among strains of Burkholderia glumae. AB - Burkholderia glumae is the primary causal agent of bacterial panicle blight of rice. In this study, 11 naturally avirulent and nine virulent strains of B. glumae native to the southern United States were characterized in terms of virulence in rice and onion, toxofalvin production, antifungal activity, pigmentation and genomic structure. Virulence of B. glumae strains on rice panicles was highly correlated to virulence on onion bulb scales, suggesting that onion bulb can be a convenient alternative host system to efficiently determine the virulence of B. glumae strains. Production of toxoflavin, the phytotoxin that functions as a major virulence factor, was closely associated with the virulence phenotypes of B. glumae strains in rice. Some strains of B. glumae showed various levels of antifungal activity against Rhizoctonia solani, the causal agent of sheath blight, and pigmentation phenotypes on casamino acid-peptone-glucose (CPG) agar plates regardless of their virulence traits. Purple and yellow-green pigments were partially purified from a pigmenting strain of B. glumae, 411gr-6, and the purple pigment fraction showed a strong antifungal activity against Collectotrichum orbiculare. Genetic variations were detected among the B. glumae strains from DNA fingerprinting analyses by repetitive element sequence-based PCR (rep-PCR) for BOX-A1R-based repetitive extragenic palindromic (BOX) or enterobacterial repetitive intergenic consensus (ERIC) sequences of bacteria; and close genetic relatedness among virulent but pigment-deficient strains were revealed by clustering analyses of DNA fingerprints from BOX-and ERIC-PCR. PMID- 23028971 TI - Temporal feature perception in cochlear implant users. AB - For the perception of timbre of a musical instrument, the attack time is known to hold crucial information. The first 50 to 150 ms of sound onset reflect the excitation mechanism, which generates the sound. Since auditory processing and music perception in particular are known to be hampered in cochlear implant (CI) users, we conducted an electroencephalography (EEG) study with an oddball paradigm to evaluate the processing of small differences in musical sound onset. The first 60 ms of a cornet sound were manipulated in order to examine whether these differences are detected by CI users and normal-hearing controls (NH controls), as revealed by auditory evoked potentials (AEPs). Our analysis focused on the N1 as an exogenous component known to reflect physical stimuli properties as well as on the P2 and the Mismatch Negativity (MMN). Our results revealed different N1 latencies as well as P2 amplitudes and latencies for the onset manipulations in both groups. An MMN could be elicited only in the NH control group. Together with additional findings that suggest an impact of musical training on CI users' AEPs, our findings support the view that impaired timbre perception in CI users is at partly due to altered sound onset feature detection. PMID- 23028973 TI - Role of macrophage CCAAT/enhancer binding protein delta in the pathogenesis of rheumatoid arthritis in collagen-induced arthritic mice. AB - BACKGROUND: The up-regulation of CCAAT/enhancer binding protein delta (CEBPD) has frequently been observed in macrophages in age-associated disorders, including rheumatoid arthritis (RA). However, the role of macrophage CEBPD in the pathogenesis of RA is unclear. METHODOLOGY AND PRINCIPAL FINDINGS: We found that the collagen-induced arthritis (CIA) score and the number of affected paws in Cebpd(-/-) mice were significantly decreased compared with the wild-type (WT) mice. The histological analysis revealed an attenuated CIA in Cebpd(-/-) mice, as shown by reduced pannus formation and greater integrity of joint architecture in affected paws of Cebpd(-/-) mice compared with WT mice. In addition, immunohistochemistry analysis revealed decreased pannus proliferation and angiogenesis in Cebpd(-/-) mice compared with WT mice. CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. CCL20, IL23A, CXCL1 and TNFAIP6 contributed to the migration and proliferation of synoviocytes, and the latter two proteins were involved in tube formation of endothelial cells. Finally, two anti-inflammatory chemicals, inotilone and rosmanol, reduced the expression of CEBPD and its downstream targets and mitigated the above phenomena. CONCLUSIONS AND SIGNIFICANCE: Collectively, our findings suggest that CEBPD and its downstream effectors could be biomarkers for the diagnosis of RA and potentially serve as therapeutic targets for RA therapy. PMID- 23028974 TI - Two origins of blastemal progenitors define blastemal regeneration of zebrafish lower jaw. AB - Zebrafish possess a remarkable ability to regenerate complicated structures by formation of a mass of undifferentiated mesenchymal cells called blastema. To understand how the blastema retains the original structural form, we investigate cellular transitions and transcriptional characteristics of cell identity genes during all stages of regeneration of an amputated lower jaw. We find that mesenchymal blastema originates from multiple sources including nucleated blood cells, fibroblasts, damaged muscle cells and pigment cells. These cells are transformed into two populations of blastemal progenitors: foxi1-expression and isl1-expression, before giving rise to cartilage, bone, and muscle. Time point- based transcriptomal analysis of 45 annotated Hox genes reveal that five 3'-end Hox genes and an equal number of 5'-end Hox genes are activated largely at the stage of blastema reformation. RNA in situ hybridization shows that foxi1 and pax3a are respectively expressed in the presumptive mandible skeletal region and regenerating muscle at 5 dpa. In contrast, hoxa2b and hoxa11b are widely expressed with different domain in chondrogenic blastema and blastema mesenchyme. Knockdown foxi1 changes the expression patterns of sox9a and hoxa2b in chondrogenic blastema. From these results we propose that two origins of blastemal progenitors define blastema skeleton and muscle respecifications through distinct signaling pathways. Meanwhile, the positional identity of blastema reformation is implicated in mesenchymal segmentation and characteristic expression pattern of Hox genes. PMID- 23028975 TI - Melanoma-associated cancer-testis antigen 16 (CT16) regulates the expression of apoptotic and antiapoptotic genes and promotes cell survival. AB - Cancer-testis (CT) antigens are predominantly expressed in testis or placenta, but absent in most adult tissues. During malignant transformation CT genes are often activated. CT antigen 16 (CT16, PAGE5) is frequently expressed in advanced melanoma but its biological function has been unknown. To examine the role of CT16 in cell survival we knocked it down in A2058 melanoma cells using specific siRNAs and exposed the cells to cancer drug cisplatin known to induce apoptosis. As a result, cell survival was markedly decreased. To study the effects of CT16 on cell survival in more detail, the cellular gene expression profiles were investigated after CT16 silencing in CT16 positive A2058 melanoma cells, as well as after CT16 overexpression in CT16 negative WM-266-4 melanoma cells. Among the 11 genes both upregulated by CT16 silencing and downregulated by CT16 overexpression or vice versa, 4 genes were potentially apoptotic or antiapoptotic genes. CT16 was recognized as a positive regulator of antiapoptotic metallothionein 2A and interleukin 8 genes, whereas it inhibited the expression of apoptosis inducing dickkopf 1 (DKK1) gene. In addition CT16 enhanced the expression of fatty acid binding protein 7, a known promoter of melanoma progression. The effect of CT16 on DKK1 expression was p53 independent. Furthermore, CT16 did not regulate apoptotic genes via DNA methylation. In twenty melanoma metastasis tissue samples average DKK1 mRNA level was shown to be significantly (p<0.05) lower in high CT16 expressing tumors (n = 3) when compared to the tumors with low CT16 expression (n = 17). Thus, our results indicate that CT16 promotes the survival of melanoma cells and is therefore a potential target for future drug development. PMID- 23028976 TI - Targeting G with TAL effectors: a comparison of activities of TALENs constructed with NN and NK repeat variable di-residues. AB - The DNA binding domain of Transcription Activator-Like (TAL) effectors can easily be engineered to have new DNA sequence specificities. Consequently, engineered TAL effector proteins have become important reagents for manipulating genomes in vivo. DNA binding by TAL effectors is mediated by arrays of 34 amino acid repeats. In each repeat, one of two amino acids (repeat variable di-residues, RVDs) contacts a base in the DNA target. RVDs with specificity for C, T and A have been described; however, among RVDs that target G, the RVD NN also binds A, and NK is rare among naturally occurring TAL effectors. Here we show that TAL effector nucleases (TALENs) made with NK to specify G have less activity than their NN-containing counterparts: fourteen of fifteen TALEN pairs made with NN showed more activity in a yeast recombination assay than otherwise identical TALENs made with NK. Activity was assayed for three of these TALEN pairs in human cells, and the results paralleled the yeast data. The in vivo data is explained by in vitro measurements of binding affinity demonstrating that NK-containing TAL effectors have less affinity for targets with G than their NN-containing counterparts. On targets for which G was substituted with A, higher G-specificity was observed for NK-containing TALENs. TALENs with different N- and C-terminal truncations were also tested on targets that differed in the length of the spacer between the two TALEN binding sites. TALENs with C-termini of either 63 or 231 amino acids after the repeat array cleaved targets across a broad range of spacer lengths - from 14 to 33 bp. TALENs with only 18 aa after the repeat array, however, showed a clear optimum for spacers of 13 to 16 bp. The data presented here provide useful guidelines for increasing the specificity and activity of engineered TAL effector proteins. PMID- 23028977 TI - Dynamic formation of asexual diploid and polyploid lineages: multilocus analysis of Cobitis reveals the mechanisms maintaining the diversity of clones. AB - Given the hybrid genomic constitutions and increased ploidy of many asexual animals, the identification of processes governing the origin and maintenance of clonal diversity provides useful information about the evolutionary consequences of interspecific hybridization, asexuality and polyploidy. In order to understand the processes driving observed diversity of biotypes and clones in the Cobitis taenia hybrid complex, we performed fine-scale genetic analysis of Central European hybrid zone between two sexual species using microsatellite genotyping and mtDNA sequencing. We found that the hybrid zone is populated by an assemblage of clonally (gynogenetically) reproducing di-, tri- and tetraploid hybrid lineages and that successful clones, which are able of spatial expansion, recruit from two ploidy levels, i.e. diploid and triploid. We further compared the distribution of observed estimates of clonal ages to theoretical distributions simulated under various assumptions and showed that new clones are most likely continuously recruited from ancestral populations. This suggests that the clonal diversity is maintained by dynamic equilibrium between origination and extinction of clonal lineages. On the other hand, an interclonal selection is implied by nonrandom spatial distribution of individual clones with respect to the coexisting sexual species. Importantly, there was no evidence for sexually reproducing hybrids or clonally reproducing non-hybrid forms. Together with previous successful laboratory synthesis of clonal Cobitis hybrids, our data thus provide the most compelling evidence that 1) the origin of asexuality is causally linked to interspecific hybridization; 2) successful establishment of clones is not restricted to one specific ploidy level and 3) the initiation of clonality and polyploidy may be dynamic and continuous in asexual complexes. PMID- 23028978 TI - Sexual segregation in juvenile New Zealand sea lion foraging ranges: implications for intraspecific competition, population dynamics and conservation. AB - Sexual segregation (sex differences in spatial organisation and resource use) is observed in a large range of taxa. Investigating causes for sexual segregation is vital for understanding population dynamics and has important conservation implications, as sex differences in foraging ecology may affect vulnerability to area-specific human activities. Although behavioural ecologists have proposed numerous hypotheses for this phenomenon, the underlying causes of sexual segregation are poorly understood. We examined the size-dimorphism and niche divergence hypotheses as potential explanations for sexual segregation in the New Zealand (NZ) sea lion (Phocarctos hookeri), a nationally critical, declining species impacted by trawl fisheries. We used satellite telemetry and linear mixed effects models to investigate sex differences in the foraging ranges of juvenile NZ sea lions. Male trip distances and durations were almost twice as long as female trips, with males foraging over the Auckland Island shelf and in further locations than females. Sex was the most important variable in trip distance, maximum distance travelled from study site, foraging cycle duration and percent time at sea whereas mass and age had small effects on these characteristics. Our findings support the predictions of the niche divergence hypothesis, which suggests that sexual segregation acts to decrease intraspecific resource competition. As a consequence of sexual segregation in foraging ranges, female foraging grounds had proportionally double the overlap with fisheries operations than males. This distribution exposes female juvenile NZ sea lions to a greater risk of resource competition and bycatch from fisheries than males, which can result in higher female mortality. Such sex-biased mortality could impact population dynamics, because female population decline can lead to decreased population fecundity. Thus, effective conservation and management strategies must take into account sex differences in foraging behaviour, as well as differential threat-risk to external impacts such as fisheries bycatch. PMID- 23028979 TI - Does multimorbidity influence the occurrence rates of chronic conditions? A claims data based comparison of expected and observed prevalence rates. AB - OBJECTIVE: Multimorbidity is a complex phenomenon with an almost endless number of possible disease combinations with unclear implications. One important aspect in analyzing the clustering of diseases is to distinguish between random coexistence and statistical dependency. We developed a model to account for random coexistence based on stochastic distribution. We analyzed if the number of diseases of the patients influences the occurrence rates of chronic conditions. METHODS: We analyzed claims data of 121,389 persons aged 65+ using a list of 46 chronic conditions. Expected prevalences were simulated by drawing without replacement from all observed diseases using observed overall prevalences as initial probability weights. To determine if a disease occurs more or less frequently than expected by chance we calculated observed-minus-expected deltas for each disease. We defined clinical relevance as |delta| >= 5.0%. 18 conditions were excluded because of a prevalence < 5.0%. RESULTS: We found that (1) two chronic conditions (e.g. hypertension) were more frequent than expected in patients with a low number of comorbidities; (2) four conditions (e.g. renal insufficiency) were more frequent in patients with many comorbidities; (3) six conditions (e.g. cancer) were less frequent with many comorbidities; and (4) 16 conditions had an average course of prevalences. CONCLUSION: A growing extent of multimorbidity goes along with a rapid growth of prevalences. This is for the largest part merely a stochastic effect. If we account for this effect we find that only few diseases deviate from the expected prevalence curves. Causes for these deviations are discussed. Our approach also has methodological implications: Naive analyses of multimorbidity might easily be affected by bias, because the prevalence of all chronic conditions necessarily increases with a growing extent of multimorbidity. We should therefore always examine and discuss the stochastic interrelations between the chronic conditions we analyze. PMID- 23028980 TI - Longitudinal study of a human drug-induced model of autoantibody to cytoplasmic rods/rings following HCV therapy with ribavirin and interferon-alpha. AB - BACKGROUND: A novel pattern in the indirect immunofluorescence antinuclear antibody assay on HEp-2 cells (IIF-HEp-2) characterized by cytoplasmic rods and rings (RR) was reported in HCV patients, but stringent disease specificity studies and longitudinal analysis are lacking. We investigated the clinical significance of anti-RR in an HCV cohort with up to a 12-month treatment follow up. METHODOLOGY/RESULTS: 597 patients (342 HCV, 55 HCV/HIV, 200 non-HCV) were screened and titered for anti-RR. Serial samples were available from 78 of 176 treated and 27 of 166 untreated patients. Anti-RR was detected in 14.1% of 342 HCV patients, 9.1% of 55 HCV/HIV, 3.4% of 29 Hepatitis B, and none of 171 non-HCV (p<0.0001; HCV versus non-HCV). Anti-RR was present in 38% of 108 patients receiving interferon-alpha/ribavirin, but none in 26 receiving either interferon alpha or ribavirin, or 166 untreated patients (p<0.0001). Other IIF-HEp-2 patterns were more frequently associated with interferon-alpha treatment alone (52.2%) as compared to interferon-alpha/ribavirin (25%), ribavirin alone (33.3%), and no therapy (26.5%). Anti-RR frequency was not associated with sex, age, ethnicity, HCV genotype or viral load. Anti-RR occurred only after initiation of treatment, beginning as early as 1 month (6%), but by the sixth month >47% tested positive for anti-RR. The anti-RR titer generally increased with sustained treatment and remained high in 53% of patients. After treatment, anti-RR titer was negative in 41%. Non-responders to HCV therapy were 77% in anti-RR-positive versus 64% in anti-RR-negative patients. Response to treatment was not associated with anti-RR titer or the dynamics of anti-RR reactivity during and after treatment. CONCLUSIONS: The exquisite association of anti-RR reactivity with combined interferon-alpha/ribavirin therapy in HCV patients represents a unique model for drug-induced autoantibody generation in humans as demonstrated by the fact that a significant fraction of patients who have anti-RR during therapy becomes anti-RR-negative after completion of therapy. PMID- 23028981 TI - Heterodimeric barnase-barstar vaccine molecules: influence of one versus two targeting units specific for antigen presenting cells. AB - It is known that targeting of antigen to antigen presenting cells (APC) increases immune responses. However, it is unclear if more than one APC-specific targeting unit in the antigenic molecule will increase responses. To address this issue, we have here made heterodimeric vaccine molecules that each express four different fusion subunits. The bacterial ribonuclease barnase and its inhibitor barstar interact with high affinity, and the barnase-barstar complex was therefore used as a dimerization unit. Barnase and barstar were fused N-terminally with single chain fragment variable (scFv)s targeting units specific for either MHC class II molecules on APC or the hapten 5-iodo-4-hydroxy-3-nitrophenylacetyl (NIP). C terminal antigenic fusions were either the fluorescent protein mCherry or scFv(315) derived from myeloma protein M315. The heterodimeric vaccine molecules were formed both in vitro and in vivo. Moreover, the four different fused moieties appeared to fold correctly since they retained their specificity and function. DNA vaccination with MHC class II-targeted vaccine induced higher mCherry-specific IgG1 responses compared to non-targeted control. Since mCherry and MHC class II are in trans in this heterodimer, this suggests that heterodimeric proteins are formed in vivo without prior protein purification. Surprisingly, one targeting moiety was sufficient for the increased IgG1 response, and addition of a second targeting moiety did not increase responses. Similar results were found in in vitro T cell assays; vaccine molecules with one targeting unit were as potent as those with two. In combination with the easy cloning strategy, the heterodimeric barnase-barstar vaccine molecule could provide a flexible platform for development of novel DNA vaccines with increased potency. PMID- 23028982 TI - Loss of the V-ATPase B1 subunit isoform expressed in non-neuronal cells of the mouse olfactory epithelium impairs olfactory function. AB - The vacuolar proton-pumping ATPase (V-ATPase) is the main mediator of intracellular organelle acidification and also regulates transmembrane proton (H(+)) secretion, which is necessary for an array of physiological functions fulfilled by organs such as the kidney, male reproductive tract, lung, bone, and ear. In this study we characterize expression of the V-ATPase in the main olfactory epithelium of the mouse, as well as a functional role for the V-ATPase in odor detection. We report that the V-ATPase localizes to the apical membrane microvilli of olfactory sustentacular cells and to the basolateral membrane of microvillar cells. Plasma membrane V-ATPases containing the B1 subunit isoform are not detected in olfactory sensory neurons or in the olfactory bulb. This precise localization of expression affords the opportunity to ascertain the functional relevance of V-ATPase expression upon innate, odor-evoked behaviors in B1-deficient mice. This animal model exhibits diminished innate avoidance behavior (revealed as a decrease in freezing time and an increase in the number of sniffs in the presence of trimethyl-thiazoline) and diminished innate appetitive behavior (a decrease in time spent investigating the urine of the opposite sex). We conclude that V-ATPase-mediated H(+) secretion in the olfactory epithelium is required for optimal olfactory function. PMID- 23028983 TI - Life-history and spatial determinants of somatic growth dynamics in Komodo dragon populations. AB - Somatic growth patterns represent a major component of organismal fitness and may vary among sexes and populations due to genetic and environmental processes leading to profound differences in life-history and demography. This study considered the ontogenic, sex-specific and spatial dynamics of somatic growth patterns in ten populations of the world's largest lizard the Komodo dragon (Varanus komodoensis). The growth of 400 individual Komodo dragons was measured in a capture-mark-recapture study at ten sites on four islands in eastern Indonesia, from 2002 to 2010. Generalized Additive Mixed Models (GAMMs) and information-theoretic methods were used to examine how growth rates varied with size, age and sex, and across and within islands in relation to site-specific prey availability, lizard population density and inbreeding coefficients. Growth trajectories differed significantly with size and between sexes, indicating different energy allocation tactics and overall costs associated with reproduction. This leads to disparities in maximum body sizes and longevity. Spatial variation in growth was strongly supported by a curvilinear density dependent growth model with highest growth rates occurring at intermediate population densities. Sex-specific trade-offs in growth underpin key differences in Komodo dragon life-history including evidence for high costs of reproduction in females. Further, inverse density-dependent growth may have profound effects on individual and population level processes that influence the demography of this species. PMID- 23028984 TI - In vivo inhibition of c-MYC in myeloid cells impairs tumor-associated macrophage maturation and pro-tumoral activities. AB - Although tumor-associated macrophages (TAMs) are involved in tumor growth and metastasis, the mechanisms controlling their pro-tumoral activities remain largely unknown. The transcription factor c-MYC has been recently shown to regulate in vitro human macrophage polarization and be expressed in macrophages infiltrating human tumors. In this study, we exploited the predominant expression of LysM in myeloid cells to generate c-Myc(fl/fl) LysM(cre/+) mice, which lack c Myc in macrophages, to investigate the role of macrophage c-MYC expression in cancer. Under steady-state conditions, immune system parameters in c-Myc(fl/fl) LysM(cre/+) mice appeared normal, including the abundance of different subsets of bone marrow hematopoietic stem cells, precursors and circulating cells, macrophage density, and immune organ structure. In a model of melanoma, however, TAMs lacking c-Myc displayed a delay in maturation and showed an attenuation of pro-tumoral functions (e.g., reduced expression of VEGF, MMP9, and HIF1alpha) that was associated with impaired tissue remodeling and angiogenesis and limited tumor growth in c-Myc(fl/fl) LysM(cre/+) mice. Macrophage c-Myc deletion also diminished fibrosarcoma growth. These data identify c-Myc as a positive regulator of the pro-tumoral program of TAMs and suggest c-Myc inactivation as an attractive target for anti-cancer therapy. PMID- 23028985 TI - Interaction of species traits and environmental disturbance predicts invasion success of aquatic microorganisms. AB - Factors such as increased mobility of humans, global trade and climate change are affecting the range of many species, and cause large-scale translocations of species beyond their native range. Many introduced species have a strong negative influence on the new local environment and lead to high economic costs. There is a strong interest to understand why some species are successful in invading new environments and others not. Most of our understanding and generalizations thereof, however, are based on studies of plants and animals, and little is known on invasion processes of microorganisms. We conducted a microcosm experiment to understand factors promoting the success of biological invasions of aquatic microorganisms. In a controlled lab experiment, protist and rotifer species originally isolated in North America invaded into a natural, field-collected community of microorganisms of European origin. To identify the importance of environmental disturbances on invasion success, we either repeatedly disturbed the local patches, or kept them as undisturbed controls. We measured both short term establishment and long-term invasion success, and correlated it with species specific life-history traits. We found that environmental disturbances significantly affected invasion success. Depending on the invading species' identity, disturbances were either promoting or decreasing invasion success. The interaction between habitat disturbance and species identity was especially pronounced for long-term invasion success. Growth rate was the most important trait promoting invasion success, especially when the species invaded into a disturbed local community. We conclude that neither species traits nor environmental factors alone conclusively predict invasion success, but an integration of both of them is necessary. PMID- 23028986 TI - Adoptive immunotherapy with Cl-IB-MECA-treated CD8+ T cells reduces melanoma growth in mice. AB - Cl-IB-MECA is a selective A3 adenosine receptor agonist, which plays a crucial role in limiting tumor progression. In mice, Cl-IB-MECA administration enhances the anti-tumor T cell-mediated response. However, little is known about the activity of Cl-IB-MECA on CD8+ T cells. The aim of this study was to investigate the effect of ex vivo Cl-IB-MECA treatment of CD8+ T cells, adoptively transferred in melanoma-bearing mice. Adoptive transfer of Cl-IB-MECA-treated CD8+ T cells or a single administration of Cl-IB-MECA (20 ng/mouse) inhibited tumor growth compared with the control group and significantly improved mouse survival. This was associated with the release of Th1-type cytokines and a greater influx of mature Langerin+ dendritic cells (LCs) into the tumor microenvironment. CD8+ T cells treated with Cl-IB-MECA released TNF-alpha which plays a critical role in the therapeutic efficacy of these cells when injected to mice. Indeed, neutralization of TNF-alpha by a specific monoclonal Ab significantly blocked the anti-tumor activity of Cl-IB-MECA-treated T cells. This was due to the reduction in levels of cytotoxic cytokines and the presence of fewer LCs. In conclusion, these studies reveal that ex vivo treatment with Cl-IB MECA improves CD8+ T cell adoptive immunotherapy for melanoma in a TNF-alpha dependent manner. PMID- 23028988 TI - Neural correlates to food-related behavior in normal-weight and overweight/obese participants. AB - Two thirds of US adults are either obese or overweight and this rate is rising. Although the etiology of obesity is not yet fully understood, neuroimaging studies have demonstrated that the central nervous system has a principal role in regulating eating behavior. In this study, functional magnetic resonance imaging and survey data were evaluated for correlations between food-related problem behaviors and the neural regions underlying responses to visual food cues before and after eating in normal-weight individuals and overweight/obese individuals. In normal-weight individuals, activity in the left amygdala in response to high calorie food vs. nonfood object cues was positively correlated with impaired satiety scores during fasting, suggesting that those with impaired satiety scores may have an abnormal anticipatory reward response. In overweight/obese individuals, activity in the dorsolateral prefrontal cortex (DLPFC) in response to low-calorie food cues was negatively correlated with impaired satiety during fasting, suggesting that individuals scoring lower in satiety impairment were more likely to activate the DLPFC inhibitory system. After eating, activity in both the putamen and the amygdala was positively correlated with impaired satiety scores among obese/overweight participants. While these individuals may volitionally suggest they are full, their functional response to food cues suggests food continues to be salient. These findings suggest brain regions involved in the evaluation of visual food cues may be mediated by satiety-related problems, dependent on calorie content, state of satiation, and body mass index. PMID- 23028987 TI - Expression of TIP-1 confers radioresistance of malignant glioma cells. AB - BACKGROUND: Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combined with chemotherapeutic agents because of the intrinsic or acquired resistance. In this study, TIP-1 was identified as one novel protein that confers resistance of glioma cells to IR. METHODOLOGY/PRINCIPAL FINDINGS: Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosis of human malignant gliomas after radiotherapy. Studies with established human glioma cell lines demonstrated that TIP-1 depletion with specific shRNAs sensitized the cells to IR, whereas an ectopic expression of TIP-1 protected the glioma cells from the IR-induced DNA damage and cell death. Biochemical studies indicated that TIP-1 protein promoted p53 ubiquitination and resulted in a reduced p53 protein level. Furthermore, p53 and its ubiquitination are required for the TIP-1 regulated cellular response to IR. A yeast two-hybrid screening identified that TIP-1, through its single PDZ domain, binds to the carboxyl terminus of LZAP that has been studied as one tumor suppressor functioning through ARF binding and p53 activation. It was revealed that the presence of TIP-1 enhances the protein association between LZAP and ARF and modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depleting TIP-1 within D54 cells improved the tumor growth control with IR. CONCLUSIONS/SIGNIFICANCE: This study provided the first evidence showing that TIP 1 modulates p53 protein stability and is involved in the radioresistance of malignant gliomas, suggesting that antagonizing TIP-1 might be one novel approach to sensitize malignant gliomas to radiotherapy. PMID- 23028989 TI - Fingers crossed! An investigation of somatotopic representations using spatial directional judgements. AB - Processing of tactile stimuli requires both localising the stimuli on the body surface and combining this information with a representation of the current posture. When tactile stimuli are applied to crossed hands, the system first assumes a prototypical (e.g. uncrossed) positioning of the limbs. Remapping to include the crossed posture occurs within about 300 ms. Since fingers have been suggested to be represented in a mainly somatotopic reference frame we were interested in how the processing of tactile stimuli applied to the fingers would be affected by an unusual posture of the fingers. We asked participants to report the direction of movement of two tactile stimuli, applied successively to the crossed or uncrossed index and middle fingers of one hand at different inter stimulus intervals (15 to 700 ms). Participants almost consistently reported perceiving the stimulus direction as opposite to what it was in the fingers crossed condition, even with SOAs of 700 ms, suggesting that on average they did not incorporate the unusual relative finger positions. Therefore our results are in agreement with the idea that, by default, the processing of tactile stimuli assumes a prototypical positioning of body parts. However, in contrast to what is generally found with tactile perception with crossed hands, performance did not improve with SOAs as long as 700 ms. This suggests that the localization of stimuli in a somatotopic reference and the integration of this representation with postural information are two separate processes that apply differently to the hands and fingers. PMID- 23028990 TI - MicroRNAome comparison between intramuscular and subcutaneous vascular stem cell adipogenesis. AB - BACKGROUND: As an important factor affecting meat quality, intramuscular fat (IMF) content is a topic of worldwide concern. Emerging evidences indicate that microRNAs play important roles in adipocyte differentiation. However, miRNAome has neither been studied during porcine intramuscular preadipocyte differentiation, nor compared with subcutaneous preadipocytes. The objectives of this study were to identify porcine miRNAs involved in adipogenesis in primary preadipocytes, and to determine whether intramuscular and subcutaneous adipocytes differ in the expression and regulation of miRNAs. RESULTS: miRNAomes in primary intramuscular and subcutaneous adipocytes during differentiation were first sequenced using the Solexa deep sequencing method. The sequences and relative expression levels of 224 known (98.2% in miRbase 18.0) and 280 potential porcine miRNAs were identified. Fifty-four of them changed in similar pattern between intramuscular vascular stem cells (IVSC) and subcutaneous vascular stem cells (SVSC) differentiation, such as miR-210, miR-10b and miR-99a. Expression levels of 10 miRNAs were reversely up-or down-regulated between IVSC and SVSC differentiation, 19 were up-or down-regulated only during IVSC differentiation and 55 only during SVSC differentiation. Additionally, 30 miRNAs showed fat-depot specific expression pattern (24 in cells of intramuscular origin and 6 in cells of subcutaneous origin). These adipogenesis-related miRNAs mainly functioned by targeting similar pathways in adipogenesis, obesity and syndrome. CONCLUSION: Comparison of miRNAomes in IVSC and SVSC during differentiation revealed that many different miRNAs are involved in adipogenesis, and they regulate SVSC and IVSC differentiation through similar pathways. These miRNAs may serve as biomarkers or targets for enhancing IMF content, and uncovering their function in IMF development will be of great value in the near future. PMID- 23028991 TI - Characterization of clinical and environmental Mycobacterium avium spp. isolates and their interaction with human macrophages. AB - Members of the Mycobacterium avium complex (MAC) are naturally occurring bacteria in the environment. A link has been suggested between M. avium strains in drinking water and clinical isolates from infected individuals. There is a need to develop new screening methodologies that can identify specific virulence properties of M. avium isolates found in water that predict a level of risk to exposed individuals. In this work we have characterized 15 clinical and environmental M. avium spp. isolates provided by the US Environmental Protection Agency (EPA) to improve our understanding of the key processes involved in the binding, uptake and survival of these isolates in primary human macrophages. M. avium serovar 8 was predominant among the isolates studied. Different amounts and exposure of mannose-capped lipoarabinomannan (ManLAM) and glycopeptidolipids (GPLs), both major mycobacterial virulence factors, were found among the isolates studied. Reference clinical isolate 104 serovar 1 and clinical isolates 11 and 14 serovar 8 showed an increased association with macrophages. Serum opsonization increased the cell association and survival at 2 h post infection for all isolates. However, only the clinical isolates 104 and 3 among those tested showed an increased growth in primary human macrophages. The other isolates varied in their survival in these cells. Thus we conclude that the amounts of cell envelope ManLAM and GPL, as well as GPL serovar specificity are not the only important bacterial factors for dictating the early interactions of M. avium with human macrophages. PMID- 23028993 TI - Functional characterisation of the WW minimal domain for delivering therapeutic proteins by adenovirus dodecahedron. AB - Protein transduction offers a great therapeutic potential by efficient delivery of biologically active cargo into cells. The Adenovirus Dd (Dodecahedron) has recently been shown to deliver proteins fused to the tandem WW(2-3-4) structural domains from the E3 ubiquitin ligase Nedd4. In this study, we conclusively show that Dd is able to efficiently deliver cargo inside living cells, which mainly localize in fast moving endocytic vesicles, supporting active transport along the cytoskeleton. We further improve this delivery system by expressing a panel of 13 WW-GFP mutant forms to characterize their binding properties towards Dd. We identified the domain WW(3) and its mutant form WW(3)_10_13 to be sufficient for optimal binding to Dd. We greatly minimise the interacting WW modules from 20 to 6 kDa without compromising its efficient delivery by Dd. Using these minimal WW domains fused to the tumor suppressor p53 protein, we show efficient cellular uptake and distribution into cancer cells, leading to specific induction of apoptosis in these cells. Taken together, these findings represent a step further towards the development of a Dd-based delivery system for future therapeutic application. PMID- 23028992 TI - Brain activation patterns at exhaustion in rats that differ in inherent exercise capacity. AB - In order to further understand the genetic basis for variation in inherent (untrained) exercise capacity, we examined the brains of 32 male rats selectively bred for high or low running capacity (HCR and LCR, respectively). The aim was to characterize the activation patterns of brain regions potentially involved in differences in inherent running capacity between HCR and LCR. Using quantitative in situ hybridization techniques, we measured messenger ribonuclease (mRNA) levels of c-Fos, a marker of neuronal activation, in the brains of HCR and LCR rats after a single bout of acute treadmill running (7.5-15 minutes, 15 degrees slope, 10 m/min) or after treadmill running to exhaustion (15-51 minutes, 15 degrees slope, initial velocity 10 m/min). During verification of trait differences, HCR rats ran six times farther and three times longer prior to exhaustion than LCR rats. Running to exhaustion significantly increased c-Fos mRNA activation of several brain areas in HCR, but LCR failed to show significant elevations of c-Fos mRNA at exhaustion in the majority of areas examined compared to acutely run controls. Results from these studies suggest that there are differences in central c-Fos mRNA expression, and potential brain activation patterns, between HCR and LCR rats during treadmill running to exhaustion and these differences could be involved in the variation in inherent running capacity between lines. PMID- 23028994 TI - Pathogenicity of Salmonella enterica in Caenorhabditis elegans relies on disseminated oxidative stress in the infected host. AB - Feeding Caenorhabditis elegans with Salmonella enterica serovar Typhimurium significantly shortens the lifespan of the nematode. S. Typhimurium-infected C. elegans, stained with 2',7'-dichlorodihydrofluorescein diacetate which fluoresces upon exposure to reactive oxygen species, revealed intestinal luminal staining that along with the time of infection progressed to a strong staining in the hypodermal tissues of the nematode. Still, we could not detect invasion beyond the nematode's intestinal epithelium at any stage of the infection. A similar dispersion of oxidative response was also noted in nematodes infected with S. Dublin, but not with non-pathogenic Escherichia coli or the defined pathogen Burkholderia thailandensis. Addition of catalase or the reductant ascorbic acid significantly restored the lifespan of S. Typhimurium-infected nematodes. Mutational inactivation of the bacterial thioredoxin 1 resulted in total ablation of the hypodermal oxidative response to infection, and in a strong attenuation of virulence. Virulence of the thioredoxin 1 mutant was restored by trans complementation with redox-active variants of thioredoxin 1 or, surprisingly, by exposing the thioredoxin 1 mutant to sublethal concentrations of the disulphide catalyst copper chloride prior to infection. In summary, our observations define a new aspect in virulence of S. enterica that apparently does not involve the classical invasive or intracellular phenotype of the pathogen, but that depends on the ability to provoke overwhelming systemic oxidative stress in the host through the redox activity of bacterial thioredoxin 1. PMID- 23028995 TI - Prevalence and concomitants of arthritis in the elderly in Rio Grande do Sul, Brazil. AB - OBJECTIVES: Information on the prevalence and concomitants of arthritis in developing countries is sparse. It is unclear whether they are comparable to findings in developed countries. To ascertain the prevalence, demographic characteristics, and health-related concomitants of arthritis in older persons in the southern state of Rio Grande do Sul, Brazil, a middle income country. METHODS: The state of Rio Grande do Sul, Brazil, was subdivided into nine regions. Stratified random sampling was used to identify 880 community residents age >=60 years in each region. One region with suspect data was excluded. Of 7040 community residents contacted in eight regions, 6963 participated (1.1% refusal rate). In 1995, trained, monitored interviewers, using structured questionnaires, conducted in-home interviews gathering information on demographic characteristics (age, sex, race/ethnicity, education, income, living arrangements, employment status), health behaviors (physical activity, tobacco use, social activity), functional limitations, depression, and 15 self-reported health conditions, including arthritis. Data were analyzed using descriptive statistics and logistic regression. RESULTS: Arthritis, reported by 43% of the sample, was more prevalent in women, among the less educated, those with lower income, and higher age. Severity, but not prevalence, differed by race/ethnicity. Controlled analyses indicated significant association with female gender, lower education, and less social activity. Arthritis was associated with reduced odds of stroke, but increased odds of hypertension, varicosities, bronchitis, renal problems, headache, gastrointestinal disorders, and depression. Arthritis was not significantly associated with age or functional limitations, and associations did not differ by gender. CONCLUSIONS: The prevalence, demographic and health characteristics associated with self-reported arthritis in this southern state in Brazil are similar to findings elsewhere in Brazil, and in developed countries. PMID- 23028996 TI - Estimating the active space of male koala bellows: propagation of cues to size and identity in a Eucalyptus forest. AB - Examining how increasing distance affects the information content of vocal signals is fundamental for determining the active space of a given species' vocal communication system. In the current study we played back male koala bellows in a Eucalyptus forest to determine the extent that individual classification of male koala bellows becomes less accurate over distance, and also to quantify how individually distinctive acoustic features of bellows and size-related information degrade over distance. Our results show that the formant frequencies of bellows derived from Linear Predictive Coding can be used to classify calls to male koalas over distances of 1-50 m. Further analysis revealed that the upper formant frequencies and formant frequency spacing were the most stable acoustic features of male bellows as they propagated through the Eucalyptus canopy. Taken together these findings suggest that koalas could recognise known individuals at distances of up to 50 m and indicate that they should attend to variation in the upper formant frequencies and formant frequency spacing when assessing the identity of callers. Furthermore, since the formant frequency spacing is also a cue to male body size in this species and its variation over distance remained very low compared to documented inter-individual variation, we suggest that male koalas would still be reliably classified as small, medium or large by receivers at distances of up to 150 m. PMID- 23028997 TI - Globus Pallidus external segment neuron classification in freely moving rats: a comparison to primates. AB - Globus Pallidus external segment (GPe) neurons are well-characterized in behaving primates. Based on their firing properties, these neurons are commonly divided into two distinct groups: high frequency pausers (HFP) and low frequency bursters (LFB). However, no such characterization has been made for behaving rats. The current study characterizes and categorizes extracellularly recorded GPe neurons in freely moving rats, and compares these results to those obtained by extracellular recordings in behaving primates using the same analysis methods. Analysis of our data recorded in rats revealed two distinct neuronal populations exhibiting firing-pattern characteristics that are similar to those obtained in primates. These characteristic firing patterns are conserved between species although the firing rate is significantly lower in rats than in primates. Significant differences in waveform duration and shape were insufficient to create a reliable waveform-based classification in either species. The firing pattern analogy may emphasize conserved processing properties over firing rate per-se. Given the similarity in GPe neuronal activity between human and non-human primates in different pathologies, our results encourage information transfer using complementary studies across species in the GPe to acquire a better understanding of the function of this nucleus in health and disease. PMID- 23028998 TI - Interferon regulatory factor-8 is important for histone deacetylase inhibitor mediated antitumor activity. AB - The notion that epigenetic alterations in neoplasia are reversible has provided the rationale to identify epigenetic modifiers for their ability to induce or enhance tumor cell death. Histone deacetylase inhibitors (HDACi) represent one such class of anti-neoplastic agents. Despite great interest for clinical use, little is known regarding the molecular targets important for response to HDACi based cancer therapy. We had previously shown that interferon regulatory factor (IRF)-8, originally discovered as a leukemia suppressor gene by regulating apoptosis, also regulates Fas-mediated killing in non-hematologic tumor models. Furthermore, we and others have shown that epigenetic mechanisms are involved in repression of IRF-8 in tumors. Therefore, in our preclinical tumor model, we tested the hypothesis that IRF-8 expression is important for response to HDACi based antitumor activity. In the majority of experiments, we selected the pan HDACi, Trichostatin A (TSA), because it was previously shown to restore Fas sensitivity to tumor cells. Overall, we found that: 1) TSA alone and more so in combination with IFN-gamma enhanced both IRF-8 expression and Fas-mediated death of tumor cells in vitro; 2) TSA treatment enhanced IRF-8 promoter activity via a STAT1-dependent pathway; and 3) IRF-8 was required for this death response, as tumor cells rendered IRF-8 incompetent were significantly less susceptible to Fas mediated killing in vitro and to HDACi-mediated antitumor activity in vivo. Thus, IRF-8 status may underlie a novel molecular basis for response to HDACi-based antitumor treatment. PMID- 23028999 TI - Dysregulation of the autonomous nervous system in patients with temporomandibular disorder: a pupillometric study. AB - The role of the autonomic nervous system (ANS) was recently investigated in Temporomandibular disorders (TMD). Several authors argue that in subjects with TMD there is a dysregulation of ANS. Recent literature support that Pupillometry is a simple non-invasive tool to study ANS. The aim of this study was to investigate the relationship between TMD and ANS activity using pupillometry recording in Infrared light at rest Mandible Position (RP); Infrared light at Forced Habitual Occlusion (FHO); Yellow-green light at RP; Yellow-green light at FHO. Forty female subjects were enrolled: 20 case patients showed TMD based on the Research Diagnostic Criteria for TMD, and 20 control patients, aged matched, had no signs or symptoms of TMD. Statistical analysis was performed on average pupil size. Ratio between pupil size in FHO and RP (FHO/RP ratio) and yellow green and infrared (light/darkness ratio) lighting were carried out. Within group differences of pupil size and of "ratio" were analyzed using a paired t test, while differences of pupil size between groups were tested using an unpaired t test. Statistical comparisons between groups showed no significant differences of absolute values of pupil dimension in RP and FHO, both in yellow-green and in infrared lighting. In addition, there were no significant differences within groups comparing RP and FHO in yellow-green light. In within group comparison of pupil size, differences between RP and FHO were significant in infrared conditions. Control subjects increased, whereas TMD patients decreased pupil size at FHO in infrared lightening. FHO/RP ratio in darkness and light/darkness ratio in RP were significantly different between groups. Taken together, these data suggest that TMD subjects have an impairment of the sympathetic-adrenergic component of the ANS to be activated under stress. The present study provides preliminary pupillometric data confirming that adrenergic function is dysregulated in patients with TMD. PMID- 23029000 TI - VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation. AB - BACKGROUND: Signals generated by the inflammed intestine are thought to contribute to metabolic derangement. The intestinal microbiota contributes to instructing the immune system beyond the intestinal wall and its modulation is a potential target for treating systemic disorders. AIMS: To investigate the pathogenetic role of low grade intestinal inflammation in the development of steatohepatitis and atherosclerosis in a model of genetic dyslipidemia and to test the therapeutic potential of a probiotics intervention in protecting against development of these disorders. RESULTS: ApoE(-/-) mice were randomized to receive vehicle or VSL#3, a mixture of eight probiotics, at the dose of 20*10(9) colony-forming units/kg/day for three months alone or in combination with 0.2% of dextran sulfate sodium (DSS) in drinking water. Administering DSS to ApoE(-/-) mice failed to induce signs and symptoms of colitis but increased intestinal permeability to dextran FITC and, while had no effect on serum lipids, increased the blood levels of markers of liver injury and insulin resistance. DSS administration associated with low level inflammation of intestinal and mesenteric adipose tissues, caused liver histopathology features of steatohepatitis and severe atherosclerotic lesions in the aorta. These changes were prevented by VSL#3 intervention. Specifically, VSL#3 reversed insulin resistance, prevented development of histologic features of mesenteric adipose tissue inflammation, steatohepatitis and reduced the extent of aortic plaques. Conditioned media obtained from cultured probiotics caused the direct transactivation of peroxisome proliferator-activated receptor-gamma, Farnesoid-X receptors and vitamin D receptor. CONCLUSIONS: Low grade intestinal inflammation drives a transition from steatosis to steatohepatitis and worsens the severity of atherosclerosis in a genetic model of dyslipidemia. VSL#3 intervention modulates the expression of nuclear receptors, corrects for insulin resistance in liver and adipose tissues and protects against development of steatohepatitis and atherosclerosis. PMID- 23029001 TI - Expression analysis of taste signal transduction molecules in the fungiform and circumvallate papillae of the rhesus macaque, Macaca mulatta. AB - The molecular mechanisms of the mammalian gustatory system have been examined in many studies using rodents as model organisms. In this study, we examined the mRNA expression of molecules involved in taste signal transduction in the fungiform papillae (FuP) and circumvallate papillae (CvP) of the rhesus macaque, Macaca mulatta, using in situ hybridization. TAS1R1, TAS1R2, TAS2Rs, and PKD1L3 were exclusively expressed in different subsets of taste receptor cells (TRCs) in the FuP and CvP. This finding suggests that TRCs sensing different basic taste modalities are mutually segregated in macaque taste buds. Individual TAS2Rs exhibited a variety of expression patterns in terms of the apparent level of expression and the number of TRCs expressing these genes, as in the case of human TAS2Rs. GNAT3, but not GNA14, was expressed in TRCs of FuP, whereas GNA14 was expressed in a small population of TRCs of CvP, which were distinct from GNAT3- or TAS1R2-positive TRCs. These results demonstrate similarities and differences between primates and rodents in the expression profiles of genes involved in taste signal transduction. PMID- 23029002 TI - Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. AB - BACKGROUND: Sepsis is associated with systemic inflammatory responses and induction of coagulation system. Neutrophil extracellular traps (NETs) constitute an antimicrobial mechanism, recently implicated in thrombosis via platelet entrapment and aggregation. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrate for the first time the localization of thrombogenic tissue factor (TF) in NETs released by neutrophils derived from patients with gram-negative sepsis and normal neutrophils treated with either serum from septic patients or inflammatory mediators involved in the pathogenesis of sepsis. Localization of TF in acidified autophagosomes was observed during this process, as indicated by positive LC3B and LysoTracker staining. Moreover, phosphatidylinositol 3-kinase inhibition with 3-MA or inhibition of endosomal acidification with bafilomycin A1 hindered the release of TF-bearing NETs. TF present in NETs induced thrombin generation in culture supernatants, which further resulted in protease activated receptor-1 signaling. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the involvement of autophagic machinery in the extracellular delivery of TF in NETs and the subsequent activation of coagulation cascade, providing evidence for the implication of this process in coagulopathy and inflammatory response in sepsis. PMID- 23029003 TI - Biofortification and bioavailability of rice grain zinc as affected by different forms of foliar zinc fertilization. AB - BACKGROUND: Zinc (Zn) biofortification through foliar Zn application is an attractive strategy to reduce human Zn deficiency. However, little is known about the biofortification efficiency and bioavailability of rice grain from different forms of foliar Zn fertilizers. METHODOLOGY/PRINCIPAL FINDINGS: Four different Zn forms were applied as a foliar treatment among three rice cultivars under field trial. Zinc bioavailability was assessed by in vitro digestion/Caco-2 cell model. Foliar Zn fertilization was an effective agronomic practice to promote grain Zn concentration and Zn bioavailability among three rice cultivars, especially, in case of Zn-amino acid and ZnSO(4). On average, Zn-amino acid and ZnSO(4) increased Zn concentration in polished rice up to 24.04% and 22.47%, respectively. On average, Zn-amino acid and ZnSO(4) increased Zn bioavailability in polished rice up to 68.37% and 64.43%, respectively. The effectiveness of foliar applied Zn-amino acid and ZnSO(4) were higher than Zn-EDTA and Zn-Citrate on improvement of Zn concentration, and reduction of phytic acid, as a results higher accumulation of bioavailable Zn in polished rice. Moreover, foliar Zn application could maintain grain yield, the protein and minerals (Fe and Ca) quality of the polished rice. CONCLUSIONS: Foliar application of Zn in rice offers a practical and useful approach to improve bioavailable Zn in polished rice. According to current study, Zn-amino acid and ZnSO(4) are recommended as excellent foliar Zn forms to ongoing agronomic biofortification. PMID- 23029004 TI - IFN-gamma and TNF-alpha synergize to inhibit CTGF expression in human lung endothelial cells. AB - Connective tissue growth factor (CTGF/CCN2) is an angiogenetic and profibrotic factor, acting downstream of TGF-beta, involved in both airway- and vascular remodeling. While the T-helper 1 (Th1) cytokine interferon-gamma (IFN-gamma) is well characterized as immune-modulatory and anti-fibrotic cytokine, the role of IFN-gamma in lung endothelial cells (LEC) is less defined. Tumour necrosis factor alpha (TNF-alpha) is another mediator that drives vascular remodeling in inflammation by influencing CTGF expression. In the present study we investigated the influence of IFN-gamma and TNF-alpha on CTGF expression in human LEC (HPMEC ST1.6R) and the effect of CTGF knock down on human LEC. IFN-gamma and TNF-alpha down-regulated CTGF in human LEC at the promoter-, transcriptional- and translational-level in a dose- and time-dependent manner. The inhibitory effect of IFN-gamma on CTGF-expression could be almost completely compensated by the Jak inhibitor AG-490, showing the involvement of the Jak-Stat signaling pathway. Besides the inhibitory effect of IFN-gamma and TNF-alpha alone on CTGF expression and LEC proliferation, these cytokines had an additive inhibitory effect on proliferation as well as on CTGF expression when administered together. To study the functional role of CTGF in LEC, endogenous CTGF expression was down-regulated by a lentiviral system. CTGF silencing in LEC by transduction of CTGF shRNA reduced cell proliferation, but did not influence the anti-proliferative effect of IFN-gamma and TNF-alpha. In conclusion, our data demonstrated that CTGF was negatively regulated by IFN-gamma in LEC in a Jak/Stat signaling pathway dependent manner. In addition, an additive effect of IFN-gamma and TNF-alpha on inhibition of CTGF expression and cell proliferation could be found. The inverse correlation between IFN-gamma and CTGF expression in LEC could mean that screwing the Th2 response to a Th1 response with an additional IFN-gamma production might be beneficial to avoid airway remodeling in asthma. PMID- 23029005 TI - Urochordate ascidians possess a single isoform of Aurora kinase that localizes to the midbody via TPX2 in eggs and cleavage stage embryos. AB - Aurora kinases are key proteins found throughout the eukaryotes that control mitotic progression. Vertebrate Aurora-A and B kinases are thought to have evolved from a single Aurora-kinase isoform closest to that found in present day urochordates. In urochordate ascidians Aurora binds both TPX2 (a vertebrate AURKA partner) and INCENP (a vertebrate AURKB partner) and localizes to centrosomes and spindle microtubules as well as chromosomes and midbody during both meiosis and mitosis. Ascidian Aurora also displays this localization pattern during mitosis in echinoderms, strengthening the idea that non-vertebrate deuterostomes such as the urochordates and echinoderms possess a single form of Aurora kinase that has properties of vertebrate Aurora-kinase A and B. In the ascidian, TPX2 localizes to the centrosome and the spindle poles also as in vertebrates. However, we were surprised to find that TPX2 also localized strongly to the midbody in ascidian eggs and embryos. We thus examined more closely Aurora localization to the midbody by creating two separate point mutations of ascidian Aurora predicted to perturb binding to TPX2. Both forms of mutated Aurora behaved as predicted: neither localized to spindle poles where TPX2 is enriched. Interestingly, neither form of mutated Aurora localized to the midbody where TPX2 is also enriched, suggesting that ascidian Aurora midbody localization required TPX2 binding in ascidians. Functional analysis revealed that inhibition of Aurora kinase with a pharmacological inhibitor or with a dominant negative kinase dead form of Aurora caused cytokinesis failure and perturbed midbody formation during polar body extrusion. Our data support the view that vertebrate Aurora-A and B kinases evolved from a single non-vertebrate deuterostome ancestor. Moreover, since TPX2 localizes to the midbody in ascidian eggs and cleavage stage embryos it may be worthwhile re-assessing whether Aurora A kinase or TPX2 localize to the midbody in eggs and cleavage stage embryos. PMID- 23029006 TI - A conserved homeobox transcription factor Htf1 is required for phialide development and conidiogenesis in Fusarium species. AB - Conidia are primary means of asexual reproduction and dispersal in a variety of pathogenic fungi, and it is widely recognized that they play a critical role in animal and plant disease epidemics. However, genetic mechanisms associated with conidiogenesis are complex and remain largely undefined in numerous pathogenic fungi. We previously showed that Htf1, a homeobox transcription factor, is required for conidiogenesis in the rice pathogen Magnaporthe oryzae. In this study, our aim was to characterize how Htf1 homolog regulates common and also distinctive conidiogenesis in three key Fusarium pathogens: F. graminearm, F. verticillioides, and F. oxysporum. When compared to wild-type progenitors, the gene-deletion mutants in Fusarium species failed to form conventional phialides. Rather, they formed clusters of aberrant phialides that resembled elongated hyphae segments, and it is conceivable that this led to the obstruction of conidiation in phialides. We also observed that mutants, as well as wild-type Fusaria, can initiate alternative macroconidia production directly from hyphae through budding-like mechanism albeit at low frequencies. Microscopic observations led us to conclude that proper basal cell division and subsequent foot cell development of macroconidia were negatively impacted in the mutants. In F. verticillioides and F. oxysporum, mutants exhibited a 2- to 5- microconidia complex at the apex of monophialides resulting in a floral petal-like shape. Also, prototypical microconidia chains were absent in F. verticillioides mutants. F. graminearum and F. verticillioides mutants were complemented by introducing its native HTF1 gene or homologs from other Fusarium species. These results suggest that Fusarium Htf1 is functionally conserved homeobox transcription factor that regulates phialide development and conidiogenesis via distinct signaling pathways yet to be characterized in fungi. PMID- 23029008 TI - Generation of corneal epithelial cells from induced pluripotent stem cells derived from human dermal fibroblast and corneal limbal epithelium. AB - Induced pluripotent stem (iPS) cells can be established from somatic cells. However, there is currently no established strategy to generate corneal epithelial cells from iPS cells. In this study, we investigated whether corneal epithelial cells could be differentiated from iPS cells. We tested 2 distinct sources: human adult dermal fibroblast (HDF)-derived iPS cells (253G1) and human adult corneal limbal epithelial cells (HLEC)-derived iPS cells (L1B41). We first established iPS cells from HLEC by introducing the Yamanaka 4 factors. Corneal epithelial cells were successfully induced from the iPS cells by the stromal cell derived inducing activity (SDIA) differentiation method, as Pax6(+)/K12(+) corneal epithelial colonies were observed after prolonged differentiation culture (12 weeks or later) in both the L1B41 and 253G1 iPS cells following retinal pigment epithelial and lens cell induction. Interestingly, the corneal epithelial differentiation efficiency was higher in L1B41 than in 253G1. DNA methylation analysis revealed that a small proportion of differentially methylated regions still existed between L1B41 and 253G1 iPS cells even though no significant difference in methylation status was detected in the specific corneal epithelium related genes such as K12, K3, and Pax6. The present study is the first to demonstrate a strategy for corneal epithelial cell differentiation from human iPS cells, and further suggests that the epigenomic status is associated with the propensity of iPS cells to differentiate into corneal epithelial cells. PMID- 23029007 TI - Live attenuated S. Typhimurium vaccine with improved safety in immuno-compromised mice. AB - Live attenuated vaccines are of great value for preventing infectious diseases. They represent a delicate compromise between sufficient colonization-mediated adaptive immunity and minimizing the risk for infection by the vaccine strain itself. Immune defects can predispose to vaccine strain infections. It has remained unclear whether vaccine safety could be improved via mutations attenuating a vaccine in immune-deficient individuals without compromising the vaccine's performance in the normal host. We have addressed this hypothesis using a mouse model for Salmonella diarrhea and a live attenuated Salmonella Typhimurium strain (ssaV). Vaccination with this strain elicited protective immunity in wild type mice, but a fatal systemic infection in immune-deficient cybb(-/-)nos2(-/-) animals lacking NADPH oxidase and inducible NO synthase. In cybb(-/-)nos2(-/-) mice, we analyzed the attenuation of 35 ssaV strains carrying one additional mutation each. One strain, Z234 (ssaV SL1344_3093), was >1000-fold attenuated in cybb(-/-)nos2(-/-) mice and ~100 fold attenuated in tnfr1(-/-) animals. However, in wt mice, Z234 was as efficient as ssaV with respect to host colonization and the elicitation of a protective, O-antigen specific mucosal secretory IgA (sIgA) response. These data suggest that it is possible to engineer live attenuated vaccines which are specifically attenuated in immuno-compromised hosts. This might help to improve vaccine safety. PMID- 23029009 TI - Solution structure of MSL2 CXC domain reveals an unusual Zn3Cys9 cluster and similarity to pre-SET domains of histone lysine methyltransferases. AB - The dosage compensation complex (DCC) binds to single X chromosomes in Drosophila males and increases the transcription level of X-linked genes by approximately twofold. Male-specific lethal 2 (MSL2) together with MSL1 mediates the initial recruitment of the DCC to high-affinity sites in the X chromosome. MSL2 contains a DNA-binding cysteine-rich CXC domain that is important for X targeting. In this study, we determined the solution structure of MSL2 CXC domain by NMR spectroscopy. We identified three zinc ions in the CXC domain and determined the metal-to-cysteine connectivities from (1)H-(113)Cd correlation experiments. The structure reveals an unusual zinc-cysteine cluster composed of three zinc ions coordinated by six terminal and three bridging cysteines. The CXC domain exhibits unexpected structural homology to pre-SET motifs of histone lysine methyltransferases, expanding the distribution and structural diversity of the CXC domain superfamily. Our findings provide novel structural insight into the evolution and function of CXC domains. PMID- 23029010 TI - Tactile motion adaptation reduces perceived speed but shows no evidence of direction sensitivity. AB - INTRODUCTION: While the directionality of tactile motion processing has been studied extensively, tactile speed processing and its relationship to direction is little-researched and poorly understood. We investigated this relationship in humans using the 'tactile speed aftereffect' (tSAE), in which the speed of motion appears slower following prolonged exposure to a moving surface. METHOD: We used psychophysical methods to test whether the tSAE is direction sensitive. After adapting to a ridged moving surface with one hand, participants compared the speed of test stimuli on the adapted and unadapted hands. We varied the direction of the adapting stimulus relative to the test stimulus. RESULTS: Perceived speed of the surface moving at 81 mms(-1) was reduced by about 30% regardless of the direction of the adapting stimulus (when adapted in the same direction, Mean reduction = 23 mms(-1), SD = 11; with opposite direction, Mean reduction = 26 mms(-1), SD = 9). In addition to a large reduction in perceived speed due to adaptation, we also report that this effect is not direction sensitive. CONCLUSIONS: Tactile motion is susceptible to speed adaptation. This result complements previous reports of reliable direction aftereffects when using a dynamic test stimulus as together they describe how perception of a moving stimulus in touch depends on the immediate history of stimulation. Given that the tSAE is not direction sensitive, we argue that peripheral adaptation does not explain it, because primary afferents are direction sensitive with friction creating stimuli like ours (thus motion in their preferred direction should result in greater adaptation, and if perceived speed were critically dependent on these afferents' response intensity, the tSAE should be direction sensitive). The adaptation that reduces perceived speed therefore seems to be of central origin. PMID- 23029011 TI - Nutritional evaluation of commercially important fish species of Lakshadweep archipelago, India. AB - Estimation of nutrition profile of edible fishes is essential and thus a bio monitoring study was carried out to find out the nutritional composition of commonly available fishes in Agatti Island water of Lakshadweep Sea. Protein, carbohydrate, lipid, ash, vitamin, amino acid and fatty acid composition in the muscle of ten edible fish species were studied. Proximate analysis revealed that the protein, carbohydrate, lipid and ash contents were high in Thunnus albacares (13.69%), Parupeneus bifasciatus (6.12%), Hyporhamphus dussumieri (6.97%) and T. albacares (1.65%), respectively. Major amino acids were lysine, leucine and methionine, registering 2.84-4.56%, 2.67-4.18% and 2.64-3.91%, respectively. Fatty acid compositions ranged from 31.63% to 38.97% saturated (SFA), 21.99 26.30% monounsaturated (MUFAs), 30.32-35.11% polyunsaturated acids (PUFAs) and 2.86-7.79% branched fatty acids of the total fatty acids. The omega-3 and omega-6 PUFAs were ranged 13.05-21.14% and 6.88-9.82% of the total fatty acids, respectively. Hence, the fishes of Lakshadweep Sea are highly recommended for consumption, since these fishes are highly enriched with nutrition. The results can be used as a baseline data for comparing the various nutritional profiles of fishes in future. PMID- 23029013 TI - The mode of action of isocyanide in three aquatic organisms, Balanus amphitrite, Bugula neritina and Danio rerio. AB - Isocyanide is a potential antifouling compound in marine environments. In this study, we investigated its mode of action in three aquatic organisms. Two of them, the bryozoan Bugula neritina and the barnacle Balanus amphitrite, are major marine fouling invertebrates, and the other organism is the non-target species zebrafish Danio rerio. In the swimming larvae of B. neritina, isocyanide did not affect the total attachment rate (<=50 ug ml(-1)), but it did change the attachment site by increasing the percentage of attachment on the bottom of the container rather than on the wall or air-water inter-surface. Isocyanide binds several proteins in B. neritina as identified via SDS-PAGE-LC-MS/MS: 1) a 30 kD protein band containing two proteins similar to voltage dependent anion channels (VDAC), which control the direct coupling of the mitochondrial matrix to the energy maintenance of the cytosol and the release of apoptogenic factors from mitochondria of mammalian cells; and 2) an unknown 39 kD protein. In B. amphitrite cyprids, the isocyanide binding protein were 1) a protein similar to NADH-ubiquinone oxidoreductase, which is the "entry enzyme" of oxidative phosphorylation in mitochondria; and 2) cytochrome P450. In Danio rerio embryos, isocyanide caused "wavy" notochords, hydrocephalus, pericardial edema, poor blood circulation, and defects in pigmentation and hematopoiesis, which phenocopied copper deficiency. This is the first report on isocyanide binding proteins in fouling organisms, as well as the first description of its phenotype and potential toxicology in zebrafish. PMID- 23029012 TI - Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate. AB - Previous evidence from tooth agenesis studies suggested IRF6 and TGFA interact. Since tooth agenesis is commonly found in individuals with cleft lip/palate (CL/P), we used four large cohorts to evaluate if IRF6 and TGFA interaction contributes to CL/P. Markers within and flanking IRF6 and TGFA genes were tested using Taqman or SYBR green chemistries for case-control analyses in 1,000 Brazilian individuals. We looked for evidence of gene-gene interaction between IRF6 and TGFA by testing if markers associated with CL/P were overtransmitted together in the case-control Brazilian dataset and in the additional family datasets. Genotypes for an additional 142 case-parent trios from South America drawn from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), 154 cases from Latvia, and 8,717 individuals from several cohorts were available for replication of tests for interaction. Tgfa and Irf6 expression at critical stages during palatogenesis was analyzed in wild type and Irf6 knockout mice. Markers in and near IRF6 and TGFA were associated with CL/P in the Brazilian cohort (p<10(-6)). IRF6 was also associated with cleft palate (CP) with impaction of permanent teeth (p<10(-6)). Statistical evidence of interaction between IRF6 and TGFA was found in all data sets (p = 0.013 for Brazilians; p = 0.046 for ECLAMC; p = 10(-6) for Latvians, and p = 0.003 for the 8,717 individuals). Tgfa was not expressed in the palatal tissues of Irf6 knockout mice. IRF6 and TGFA contribute to subsets of CL/P with specific dental anomalies. Moreover, this potential IRF6-TGFA interaction may account for as much as 1% to 10% of CL/P cases. The Irf6-knockout model further supports the evidence of IRF6 TGFA interaction found in humans. PMID- 23029014 TI - Blood vessel adaptation with fluctuations in capillary flow distribution. AB - Throughout the life of animals and human beings, blood vessel systems are continuously adapting their structures - the diameter of vessel lumina, the thickness of vessel walls, and the number of micro-vessels - to meet the changing metabolic demand of the tissue. The competition between an ever decreasing tendency of luminal diameters and an increasing stimulus from the wall shear stress plays a key role in the adaptation of luminal diameters. However, it has been shown in previous studies that the adaptation dynamics based only on these two effects is unstable. In this work, we propose a minimal adaptation model of vessel luminal diameters, in which we take into account the effects of metabolic flow regulation in addition to wall shear stresses and the decreasing tendency of luminal diameters. In particular, we study the role, in the adaptation process, of fluctuations in capillary flow distribution which is an important means of metabolic flow regulation. The fluctuation in the flow of a capillary group is idealized as a switch between two states, i.e., an open-state and a close-state. Using this model, we show that the adaptation of blood vessel system driven by wall shear stress can be efficiently stabilized when the open time ratio responds sensitively to capillary flows. As micro-vessel rarefaction is observed in our simulations with a uniformly decreased open time ratio of capillary flows, our results point to a possible origin of micro-vessel rarefaction, which is believed to induce hypertension. PMID- 23029015 TI - Overexpression of CONSTANS homologs CO1 and CO2 fails to alter normal reproductive onset and fall bud set in woody perennial poplar. AB - CONSTANS (CO) is an important flowering-time gene in the photoperiodic flowering pathway of annual Arabidopsis thaliana in which overexpression of CO induces early flowering, whereas mutations in CO cause delayed flowering. The closest homologs of CO in woody perennial poplar (Populus spp.) are CO1 and CO2. A previous report showed that the CO2/FLOWERING LOCUS T1 (FT1) regulon controls the onset of reproduction in poplar, similar to what is seen with the CO/FLOWERING LOCUS T (FT) regulon in Arabidopsis. The CO2/FT1 regulon was also reported to control fall bud set. Our long-term field observations show that overexpression of CO1 and CO2 individually or together did not alter normal reproductive onset, spring bud break, or fall dormancy in poplar, but did result in smaller trees when compared with controls. Transcripts of CO1 and CO2 were normally most abundant in the growing season and rhythmic within a day, peaking at dawn. Our manipulative experiments did not provide evidence for transcriptional regulation being affected by photoperiod, light intensity, temperature, or water stress when transcripts of CO1 and CO2 were consistently measured in the morning. A genetic network analysis using overexpressing trees, microarrays, and computation demonstrated that a majority of functionally known genes downstream of CO1 and CO2 are associated with metabolic processes, which could explain their effect on tree size. In conclusion, the function of CO1 and CO2 in poplar does not appear to overlap with that of CO from Arabidopsis, nor do our data support the involvement of CO1 and CO2 in spring bud break or fall bud set. PMID- 23029016 TI - Blocking of connexin-mediated communication promotes neuroprotection during acute degeneration induced by mechanical trauma. AB - Accruing evidence indicates that connexin (Cx) channels in the gap junctions (GJ) are involved in neurodegeneration after injury. However, studies using KO animal models endowed apparently contradictory results in relation to the role of coupling in neuroprotection. We analyzed the role of Cx-mediated communication in a focal lesion induced by mechanical trauma of the retina, a model that allows spatial and temporal definition of the lesion with high reproducibility, permitting visualization of the focus, penumbra and adjacent areas. Cx36 and Cx43 exhibited distinct gene expression and protein levels throughout the neurodegeneration progress. Cx36 was observed close to TUNEL-positive nuclei, revealing the presence of this protein surrounding apoptotic cells. The functional role of cell coupling was assessed employing GJ blockers and openers combined with lactate dehydrogenase (LDH) assay, a direct method for evaluating cell death/viability. Carbenoxolone (CBX), a broad-spectrum GJ blocker, reduced LDH release after 4 hours, whereas quinine, a Cx36-channel specific blocker, decreased LDH release as early as 1 hour after lesion. Furthermore, analysis of dying cell distribution confirmed that the use of GJ blockers reduced apoptosis spread. Accordingly, blockade of GJ communication during neurodegeneration with quinine, but not CBX, caused downregulation of initial and effector caspases. To summarize, we observed specific changes in Cx gene expression and protein distribution during the progress of retinal degeneration, indicating the participation of these elements in acute neurodegeneration processes. More importantly, our results revealed that direct control of GJ channels permeability may take part in reliable neuroprotection strategies aimed to rapid, fast treatment of mechanical trauma in the retina. PMID- 23029017 TI - Normal hearing sensitivity at low-to-middle frequencies with 34% prestin-charge density. AB - The mammalian outer hair cells (OHCs) provide a positive mechanical feedback to enhance the cochlea's hearing sensitivity and frequency selectivity. Although the OHC-specific, somatic motor protein prestin is required for cochlear amplification, it remains unclear whether prestin can provide sufficient cycle-by cycle feedback. In cochlear mechanical modeling, varying amounts of OHC motor activity should provide varying degrees of feedback efficiency to adjust the gain of cochlear amplifier at resonant frequencies. Here we created and characterized two new prestin-hypomorphic mouse models with reduced levels of wild-type prestin. OHCs from these mice exhibited length, total elementary charge movement (Q(max)), charge density, and electromotility intermediate between those of wild type and prestin-null mice. Remarkably, measurements of auditory brainstem responses and distortion product otoacoustic emissions from these mice displayed wild-type like hearing sensitivities at 4-22 kHz. These results indicate that as low as 26.7% Q(max), 34.0% charge density and 44.0% electromotility in OHCs were sufficient for wild-type-like hearing sensitivity in mice at 4-22 kHz, and that these in vitro parameters of OHCs did not correlate linearly with the feedback efficiency for in vivo gain of the cochlear amplifier. Our results thus provide valuable data for modeling cochlear mechanics and will stimulate further mechanistic analysis of the cochlear amplifier. PMID- 23029018 TI - Supply-side constraints are insufficient to explain the ontogenetic scaling of metabolic rate in the tobacco Hornworm, Manduca sexta. AB - Explanations for the hypoallometric scaling of metabolic rate through ontogeny generally fall into two categories: supply-side constraints on delivery of oxygen, or decreased mass-specific intrinsic demand for oxygen. In many animals, supply and demand increase together as the body grows, thus making it impossible to tease apart the relative contributions of changing supply and demand to the observed scaling of metabolic rate. In larval insects, the large components of the tracheal system are set in size at each molt, but then remain constant in size until the next molt. Larvae of Manduca sexta increase up to ten-fold in mass between molts, leading to increased oxygen need without a concomitant increase in supply. At the molt, the tracheal system is shed and replaced with a new, larger one. Due to this discontinuous growth of the tracheal system, insect larvae present an ideal system in which to examine the relative contributions of supply and demand of oxygen to the ontogenetic scaling of metabolic rate. We observed that the metabolic rate at the beginning of successive instars scales hypoallometrically. This decrease in specific intrinsic demand could be due to a decrease in the proportion of highly metabolically active tissues (the midgut) or to a decrease in mitochondrial activity in individual cells. We found that decreased intrinsic demand, mediated by a decrease in the proportion of highly metabolically active tissues in the fifth instar, along with a decrease in the specific mitochondrial activity, contribute to the hypoallometric scaling of metabolic rate. PMID- 23029020 TI - Lifting the veil of morality: choice blindness and attitude reversals on a self transforming survey. AB - Every day, thousands of polls, surveys, and rating scales are employed to elicit the attitudes of humankind. Given the ubiquitous use of these instruments, it seems we ought to have firm answers to what is measured by them, but unfortunately we do not. To help remedy this situation, we present a novel approach to investigate the nature of attitudes. We created a self-transforming paper survey of moral opinions, covering both foundational principles, and current dilemmas hotly debated in the media. This survey used a magic trick to expose participants to a reversal of their previously stated attitudes, allowing us to record whether they were prepared to endorse and argue for the opposite view of what they had stated only moments ago. The result showed that the majority of the reversals remained undetected, and a full 69% of the participants failed to detect at least one of two changes. In addition, participants often constructed coherent and unequivocal arguments supporting the opposite of their original position. These results suggest a dramatic potential for flexibility in our moral attitudes, and indicates a clear role for self-attribution and post-hoc rationalization in attitude formation and change. PMID- 23029019 TI - PRAS40 is an integral regulatory component of erythropoietin mTOR signaling and cytoprotection. AB - Emerging strategies that center upon the mammalian target of rapamycin (mTOR) signaling for neurodegenerative disorders may bring effective treatment for a number of difficult disease entities. Here we show that erythropoietin (EPO), a novel agent for nervous system disorders, prevents apoptotic SH-SY5Y cell injury in an oxidative stress model of oxygen-glucose deprivation through phosphatidylinositol-3-kinase (PI 3-K)/protein kinase B (Akt) dependent activation of mTOR signaling and phosphorylation of the downstream pathways of p70 ribosomal S6 kinase (p70S6K), eukaryotic initiation factor 4E-binding protein 1 (4EBP1), and proline rich Akt substrate 40 kDa (PRAS40). PRAS40 is an important regulatory component either alone or in conjunction with EPO signal transduction that can determine cell survival through apoptotic caspase 3 activation. EPO and the PI 3-K/Akt pathways control cell survival and mTOR activity through the inhibitory post-translational phosphorylation of PRAS40 that leads to subcellular binding of PRAS40 to the cytoplasmic docking protein 14-3-3. However, modulation and phosphorylation of PRAS40 is independent of other protective pathways of EPO that involve extracellular signal related kinase (ERK 1/2) and signal transducer and activator of transcription (STAT5). Our studies highlight EPO and PRAS40 signaling in the mTOR pathway as potential therapeutic strategies for development against degenerative disorders that lead to cell demise. PMID- 23029021 TI - Mediterranean style diet and 12-year incidence of cardiovascular diseases: the EPIC-NL cohort study. AB - BACKGROUND: A recent meta-analysis showed that a Mediterranean style diet may protect against cardiovascular diseases (CVD). Studies on disease-specific associations are limited. We evaluated the Mediterranean Diet Score (MDS) in relation to incidence of total and specific CVDs. METHODS: The EPIC-NL Study is a cohort of 40,011 men and women aged 20-70 years, examined between 1993 and 1997, with 10-15 years of follow-up. Diet was assessed with a validated food frequency questionnaire and the MDS was based on the daily intakes of vegetables, fruits, legumes and nuts, grains, fish, fatty acids, meat, dairy, and alcohol. Cardiovascular morbidity and mortality were ascertained through linkage with national registries. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) adjusted for age, sex, cohort, smoking, physical activity, total energy intake, and educational level. RESULTS: In 34,708 participants free of CVD at baseline, 4881 CVD events occurred, and 487 persons died from CVD. A two unit increment in MDS (range 0-9) was inversely associated with fatal CVD (HR: 0.78; 95%CI: 0.69-0.88), total CVD (HR: 0.95 (0.91 0.98)), myocardial infarction (HR: 0.86 (0.79-0.93)), stroke (HR: 0.88 (0.78 1.00)), and pulmonary embolism (HR: 0.74 (0.59-0.92)). The MDS was not related to incident angina pectoris, transient ischemic attack and peripheral arterial disease. CONCLUSION: Better adherence to a Mediterranean style diet was more strongly associated with fatal CVD than with total CVD. Disease specific associations were strongest for incident myocardial infarction, stroke and pulmonary embolism. PMID- 23029022 TI - Mutational analysis of the respiratory nitrate transporter NarK2 of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis induces nitrate reductase activity in response to decreasing oxygen levels. This is due to regulation of both the transcription and the activity of the nitrate transporter NarK2. A model of NarK2 structure is proposed containing 12 membrane spanning regions consistent with other members of the major facilitator superfamily. The role of the proton gradient was determined by exposing M. tuberculosis to uncouplers. Nitrite production decreased indicating that the importation of nitrate involved an H(+)/nitrate symporter. The addition of nitrite before nitrate had no effect, suggesting no role for a nitrate/nitrite antiporter. In addition the NarK2 knockout mutant showed no defect in nitrite export. NarK2 is proposed to be a Type I H(+)/nitrate symporter. Site directed mutagenesis was performed changing 23 amino acids of NarK2. This allowed the identification of important regions and amino acids of this transporter. Five of these mutants were inactive for nitrate transport, seven produced reduced activity and eleven mutants retained wild type activity. NarK2 is inactivated in the presence of oxygen by an unknown mechanism. However none of the mutants, including those with mutated cysteines, were altered in their response to oxygen levels. The assimilatory nitrate transporter NasA of Bacillus subtilis was expressed in the M. tuberculosis NarK2 mutant. It remained active during aerobic incubation showing that the point of oxygen control is NarK2. PMID- 23029023 TI - Proteomic identification of plasma protein tyrosine phosphatase alpha and fibronectin associated with liver fluke, Opisthorchis viverrini, infection. AB - Opisthorchiasis caused by Opisthorchis viverrini induces periductal fibrosis via host immune/inflammatory responses. Plasma protein alteration during host parasite interaction-mediated inflammation may provide potential diagnostic and/or prognostic biomarkers. To search for target protein changes in O. viverrini-infected hamsters, a 1-D PAGE gel band was trypsin-digested and analyzed by a LC-MS/MS-based proteomics approach in the plasma profile of infected hamsters, and applied to humans. Sixty seven proteins were selected for further analysis based on at least two unique tryptic peptides with protein ID score >10 and increased expression at least two times across time points. These proteins have not been previously identified in O. viverrini-associated infection. Among those, proteins involved in structural (19%), immune response (13%), cell cycle (10%) and transcription (10%) were highly expressed. Western blots revealed an expression level of protein tyrosine phosphatase alpha (PTPalpha) which reached a peak at 1 month and subsequently tended to decrease. Fibronectin significantly increased at 1 month and tended to increase with time, supporting proteomic analysis. PTPalpha was expressed in the cytoplasm of inflammatory cells, while fibronectin was observed mainly in the cytoplasm of fibroblasts and the extracellular matrix at periductal fibrosis areas. In addition, these protein levels significantly increased in the plasma of O. viverrini-infected patients compared to healthy individuals, and significantly decreased at 2-months post-treatment, indicating their potential as disease markers. In conclusion, our results suggest that plasma PTPalpha and fibronectin may be associated with opisthorchiasis and the hamster model provides the basis for development of novel diagnostic markers in the future. PMID- 23029024 TI - Replication study in Chinese population and meta-analysis supports association of the 11q23 locus with colorectal cancer. AB - BACKGROUND: A common single nucleotide polymorphism (SNP), rs3802842, located at 11q23, was identified by genome-wide association studies (GWAS) to be significantly associated with the risk of colorectal cancer (CRC); however, the results of following replication studies were not always concordant. Thus, a case control study and a meta-analysis were performed to clearly discern the effect of this variant in CRC. METHOD AND FINDINGS: We determined the genotypes of rs3802842 in 641 unrelated Chinese patients with CRC and 1037 cancer-free controls. Additionally, a meta-analysis comprising current and previously published studies was conducted. In our case-control study, significant associations between the polymorphism and CRC risk were observed in all genetic models, with an additive OR being 1.45 (95% CI = 1.26-1.67). The meta-analysis of 38534 cases and 39446 controls further confirmed the significant associations in all genetic models but with obvious between-study heterogeneity. Nevertheless, ethnicity, study type and whether subjects affected by Lynch syndrome could synthetically accounted for the heterogeneity. Besides, the cumulative and sensitivity analyses indicated the robust stability of the results. CONCLUSION: The results from our case-control study and meta-analysis provided convincing evidence that rs3802842 significantly contributed to CRC risk. PMID- 23029025 TI - Activating mutations in beta-catenin in colon cancer cells alter their interaction with macrophages; the role of snail. AB - BACKGROUND: Tumor cells become addicted to both activated oncogenes and to proliferative and pro-survival signals provided by the abnormal tumor microenvironment. Although numerous soluble factors have been identified that shape the crosstalk between tumor cells and stroma, it has not been established how oncogenic mutations in the tumor cells alter their interaction with normal cells in the tumor microenvironment. PRINCIPAL FINDINGS: We showed that the isogenic HCT116 and Hke-3 cells, which differ only by the presence of the mutant kRas allele, both stimulate macrophages to produce IL1beta. In turn, macrophages enhanced Wnt signaling, proliferation and survival in both HCT116 and Hke-3 cells, demonstrating that signaling by oncogenic kRas in tumor cells does not impact their interaction with macrophages. HCT116 cells are heterozygous for beta catenin (HCT116(WT/MT)), harboring one wild type (WT) and one mutant (MT) allele, but isogenic lines that carry only the WT (HCT116(WT)) or MT beta-catenin allele (HCT116(MT)) have been generated. We showed that macrophages promoted Wnt signaling in cells that carry the MT beta-catenin allele, but not in HCT116(WT) cells. Consistent with this observation, macrophages and IL1beta failed to stabilize Snail in HCT116(WT) cells, and to protect these cells from TRAIL induced apoptosis. Finally, we demonstrated that HCT116 cells expressing dominant negative TCF4 (dnTCF4) or HCT116 cells with silenced Snail failed to stimulate IL1beta production in macrophages, demonstrating that tumor cells activate macrophages via a Wnt-dependent factor. SIGNIFICANCE: Our data demonstrate that oncogenic beta-catenin mutations in tumor cells, and subsequent activation of Wnt signaling, not only trigger cell-intrinsic alterations, but also have a significant impact on the crosstalk of tumor cells with the tumor associated macrophages. PMID- 23029026 TI - Embryonic IGF2 expression is not associated with offspring size among populations of a placental fish. AB - In organisms that provision young between fertilization and birth, mothers and their developing embryos are expected to be in conflict over embryonic growth. In mammalian embryos, the expression of Insulin-like growth factor II (IGF2) plays a key role in maternal-fetal interactions and is thought to be a focus of maternal fetal conflict. Recent studies have suggested that IGF2 is also a focus of maternal-fetal conflict in placental fish in the family Poeciliidae. However, whether the expression of IGF2 influences offspring size, the trait over which mothers and embryos are likely to be in conflict, has not been assessed in a poeciliid. We tested whether embryonic IGF2 expression varied among four populations of a placental poeciliid that display large and consistent differences in offspring size at birth. We found that IGF2 expression varied significantly among embryonic stages with expression being 50% higher in early stage embryos than late stage embryos. There were no significant differences among populations in IGF2 expression; small differences in expression between population pairs with different offspring sizes were comparable in magnitude to those between population pairs with the same offspring sizes. Our results indicate that variation in IGF2 transcript abundance does not contribute to differences in offspring size among H. formosa populations. PMID- 23029027 TI - A novel missense SNRNP200 mutation associated with autosomal dominant retinitis pigmentosa in a Chinese family. AB - The SNRNP200 gene encodes hBrr2, a helicase essential for pre-mRNA splicing. Six mutations in SNRNP200 have recently been discovered to be associated with autosomal dominant retinitis pigmentosa (adRP). In this work, we analyzed a Chinese family with adRP and identified a novel missense mutation in SNRNP200. To identify the genetic defect in this family, exome of the proband was captured and sequencing analysis was performed to exclude known genetic defects and find possible pathogenic mutations. Subsequently, candidate mutations were validated in affected family members using Sanger sequencing. A novel missense mutation, c.2653C>G transition (p.Q885E), in exon 20 of SNRNP200 was identified. The mutation co-segregated with the disease phenotype over four generations and was absent in 100 normal unaffected individuals. This mutation occurs at highly conserved position in hBrr2 and is predicted to have a functional impact, suggesting that hBrr2-dependent small nuclear riboproteins (snRNPs) unwinding and spliceosome activation is important in the pathogenesis of some variants of RP. PMID- 23029028 TI - Effects of paclitaxel on EGFR endocytic trafficking revealed using quantum dot tracking in single cells. AB - Paclitaxel (PTX), a chemotherapeutic drug, affects microtubule dynamics and influences endocytic trafficking. However, the mechanism and the dynamics of altered endocytic trafficking by paclitaxel treatment in single living cells still remain elusive. By labeling quantum dots (QDs) to the epidermal growth factor (EGF), we continuously tracked the endocytosis and post-endocytic trafficking of EGF receptors (EGFRs) in A549 cells for a long time interval. A single-cell analysis method was introduced to quantitatively study the dynamics of endocytic trafficking. Compared with the control cells, the velocity of directed motion was reduced by 30% due to the suppression of high speed movements of EGF-QDs along the microtubules in PTX-treated cells. The endocytic trafficking in PTX-treated cells was mainly via super-diffusive mode of motion, whereas in control cells, it was mostly via sub-diffusive mode of motion. Moreover, PTX shortened endosomal trafficking and prevented EGF-QDs from moving to the perinuclear area via the rapid delivery of EGF-QDs into the peripheral lysosomes. The present study may shed light on the mechanism of the effect of PTX on the treatment of lung cancer. PMID- 23029029 TI - High-resolution transcriptome of human macrophages. AB - Macrophages are dynamic cells integrating signals from their microenvironment to develop specific functional responses. Although, microarray-based transcriptional profiling has established transcriptional reprogramming as an important mechanism for signal integration and cell function of macrophages, current knowledge on transcriptional regulation of human macrophages is far from complete. To discover novel marker genes, an area of great need particularly in human macrophage biology but also to generate a much more thorough transcriptome of human M1- and M1-like macrophages, we performed RNA sequencing (RNA-seq) of human macrophages. Using this approach we can now provide a high-resolution transcriptome profile of human macrophages under classical (M1-like) and alternative (M2-like) polarization conditions and demonstrate a dynamic range exceeding observations obtained by previous technologies, resulting in a more comprehensive understanding of the transcriptome of human macrophages. Using this approach, we identify important gene clusters so far not appreciated by standard microarray techniques. In addition, we were able to detect differential promoter usage, alternative transcription start sites, and different coding sequences for 57 gene loci in human macrophages. Moreover, this approach led to the identification of novel M1-associated (CD120b, TLR2, SLAMF7) as well as M2-associated (CD1a, CD1b, CD93, CD226) cell surface markers. Taken together, these data support that high resolution transcriptome profiling of human macrophages by RNA-seq leads to a better understanding of macrophage function and will form the basis for a better characterization of macrophages in human health and disease. PMID- 23029030 TI - Pharmacokinetic analysis of 111 in-labeled liposomal Doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound. AB - The goal of this study was to evaluate the pharmacokinetics of targeted and untargeted (111)In-doxorubicin liposomes after these have been intravenously administrated to tumor-bearing mice in the presence of blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). An intracranial brain tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells was developed in this study. (111)In-labeled human atherosclerotic plaque specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (Lipo-Dox; AP-1 Lipo-Dox) were used as a microSPECT probe for radioactivity measurements in the GBM-bearing mice. Compared to the control tumors treated with an injection of (111)In-AP-1 Lipo-Dox or (111)In-Lipo-Dox, the animals receiving the drugs followed by FUS exhibited enhanced accumulation of the drug in the brain tumors (p<0.05). Combining sonication with drugs significantly increased the tumor-to normal brain doxorubicin ratio of the target tumors compared to the control tumors. The tumor-to-normal brain ratio was highest after the injection of (111)In-AP-1 Lipo-Dox with sonication. The (111)In-liposomes micro-SPECT/CT should be able to provide important information about the optimum therapeutic window for the chemotherapy of brain tumors using sonication. PMID- 23029031 TI - Patterns of spontaneous brain activity in amyotrophic lateral sclerosis: a resting-state FMRI study. AB - By detecting spontaneous low-frequency fluctuations (LFF) of blood oxygen level dependent (BOLD) signals, resting-state functional magnetic resonance imaging (rfMRI) measurements are believed to reflect spontaneous cerebral neural activity. Previous fMRI studies were focused on the examination of motor-related areas and little is known about the functional changes in the extra-motor areas in amyotrophic lateral sclerosis (ALS) patients. The aim of this study is to investigate functional cerebral abnormalities in ALS patients on a whole brain scale. Twenty ALS patients and twenty age- and sex-matched healthy volunteers were enrolled. Voxel-based analysis was used to characterize the alteration of amplitude of low frequency fluctuation (ALFF). Compared with the controls, the ALS patients showed significantly decreased ALFF in the visual cortex, fusiform gyri and right postcentral gyrus; and significantly increased ALFF in the left medial frontal gyrus, and in right inferior frontal areas after grey matter (GM) correction. Taking GM volume as covariates, the ALFF results were approximately consistent with those without GM correction. In addition, ALFF value in left medial frontal gyrus was negatively correlated with the rate of disease progression and duration. Decreased functional activity observed in the present study indicates the underlying deficits of the sensory processing system in ALS. Increased functional activity points to a compensatory mechanism. Our findings suggest that ALS is a multisystem disease other than merely motor dysfunction and provide evidence that alterations of ALFF in the frontal areas may be a special marker of ALS. PMID- 23029032 TI - The role of nucleus accumbens core/shell in sleep-wake regulation and their involvement in modafinil-induced arousal. AB - BACKGROUND: We have previously shown that modafinil promotes wakefulness via dopamine receptor D(1) and D(2) receptors; however, the locus where dopamine acts has not been identified. We proposed that the nucleus accumbens (NAc) that receives the ventral tegmental area dopamine inputs play an important role not only in reward and addiction but also in sleep-wake cycle and in mediating modafinil-induced arousal. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we further explored the role of NAc in sleep-wake cycle and sleep homeostasis by ablating the NAc core and shell, respectively, and examined arousal response following modafinil administration. We found that discrete NAc core and shell lesions produced 26.5% and 17.4% increase in total wakefulness per day, respectively, with sleep fragmentation and a reduced sleep rebound after a 6-hr sleep deprivation compared to control. Finally, NAc core but not shell lesions eliminated arousal effects of modafinil. CONCLUSIONS/SIGNIFICANCE: These results indicate that the NAc regulates sleep-wake behavior and mediates arousal effects of the midbrain dopamine system and stimulant modafinil. PMID- 23029033 TI - Panning of a phage display library against a synthetic capsule for peptide ligands that bind to the native capsule of Bacillus anthracis. AB - Bacillus anthracis is the causative agent of anthrax with the ability to not only produce a tripartite toxin, but also an enveloping capsule comprised primarily of gamma-D-glutamic acid residues. The purpose of this study was to isolate peptide ligands capable of binding to the native capsule of B. anthracis from a commercial phage display peptide library using a synthetic form of the capsule consisting of 12 gamma-D-glutamic acid residues. Following four rounds of selection, 80 clones were selected randomly and analysed by DNA sequencing. Four clones, each containing a unique consensus sequence, were identified by sequence alignment analysis. Phage particles were prepared and their derived 12-mer peptides were also chemically synthesized and conjugated to BSA. Both the phage particles and free peptide-BSA conjugates were evaluated by ELISA for binding to encapsulated cells of B. anthracis as well as a B. anthracis capsule extract. All the phage particles tested except one were able to bind to both the encapsulated cells and the capsule extract. However, the peptide-BSA conjugates could only bind to the encapsulated cells. One of the peptide-BSA conjugates, with the sequence DSSRIPMQWHPQ (termed G1), was fluorescently labelled and its binding to the encapsulated cells was further confirmed by confocal microscopy. The results demonstrated that the synthetic capsule was effective in isolating phage displayed peptides with binding affinity for the native capsule of B. anthracis. PMID- 23029034 TI - Mephedrone in adolescent rats: residual memory impairment and acute but not lasting 5-HT depletion. AB - Mephedrone (4-methylmethcathinone, MMC) is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days) injections of MMC (30 mg/kg) or the comparator drug methamphetamine (METH, 2.5 mg/kg). Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA) levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT) levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([(125)I]CLINDE ligand used as a marker for translocator protein (TSPO) expression) with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days) and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg) dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted. PMID- 23029035 TI - A simplified approach for the molecular classification of glioblastomas. AB - Glioblastoma (GBM) is the most common malignant primary brain tumors in adults and exhibit striking aggressiveness. Although GBM constitute a single histological entity, they exhibit considerable variability in biological behavior, resulting in significant differences in terms of prognosis and response to treatment. In an attempt to better understand the biology of GBM, many groups have performed high-scale profiling studies based on gene or protein expression. These studies have revealed the existence of several GBM subtypes. Although there remains to be a clear consensus, two to four major subtypes have been identified. Interestingly, these different subtypes are associated with both differential prognoses and responses to therapy. In the present study, we investigated an alternative immunohistochemistry (IHC)-based approach to achieve a molecular classification for GBM. For this purpose, a cohort of 100 surgical GBM samples was retrospectively evaluated by immunohistochemical analysis of EGFR, PDGFRA and p53. The quantitative analysis of these immunostainings allowed us to identify the following two GBM subtypes: the "Classical-like" (CL) subtype, characterized by EGFR-positive and p53- and PDGFRA-negative staining and the "Proneural-like" (PNL) subtype, characterized by p53- and/or PDGFRA-positive staining. This classification represents an independent prognostic factor in terms of overall survival compared to age, extent of resection and adjuvant treatment, with a significantly longer survival associated with the PNL subtype. Moreover, these two GBM subtypes exhibited different responses to chemotherapy. The addition of temozolomide to conventional radiotherapy significantly improved the survival of patients belonging to the CL subtype, but it did not affect the survival of patients belonging to the PNL subtype. We have thus shown that it is possible to differentiate between different clinically relevant subtypes of GBM by using IHC based profiling, a method that is advantageous in its ease of daily implementation and in large-scale clinical application. PMID- 23029036 TI - Reduced fractional anisotropy of corpus callosum modulates inter-hemispheric resting state functional connectivity in migraine patients without aura. AB - BACKGROUND: Diffusion tensor imaging (DTI) study revealed reduced fractional anisotropy (FA) values in the corpus callosum (CC) in migraine patients without aura. Abnormalities in white matter integrity, particularly in the CC, may affect inter-hemispheric resting state functional connectivity (RSFC). Unfortunately, relatively little is known about the alterations in functional interactions between the cerebral hemispheres during resting state in migraine patients without aura, and even less about how the inter-hemispheric RSFC are affected by the abnormalities of the CC. METHODS AND FINDINGS: Twenty-one migraine patients without aura and 21 healthy controls participated in this study, age-, sex-, and education-matched. Tract-based spatial statistics (TBSS) was employed to investigate the white matter alterations of the CC. Meanwhile, voxel-mirrored homotopic connectivity (VMHC) was used to compare the inter-hemispheric RSFC differences between the patients and controls. TBSS analysis revealed reduced FA values in the genu and the splenium of CC in patient group. VMHC analysis showed decreased inter-hemispheric RSFC of anterior cingulate cortex (ACC) in migraine patients without aura relative to that of the controls. Furthermore, in migraine patients without aura, the reduced FA values of the genu of CC correlated with the decreased inter-hemispheric RSFC of the ACC. CONCLUSIONS: Our findings demonstrated that the migraine patients without aura showed reduced FA values of the genu of CC and decreased inter-hemispheric RSFC of the ACC. The correlation between the above structural and functional changes suggested that the reduced fractional anisotropy (FA) of CC modulates inter-hemispheric VMHC in migraine patients without aura. Our results demonstrated that the VMHC alterations of ACC can reflect the FA changes of the genu of CC in migraine patients without aura. PMID- 23029037 TI - An in vitro and in vivo analysis of the correlation between susceptibility weighted imaging phase values and R2* in cirrhotic livers. AB - OBJECTIVE: To establish a baseline of susceptibility-weighted imaging (SWI) phase value as a means of detecting iron abnormalities in cirrhotic liver and to analyze its relationship with R2*. MATERIALS AND METHODS: Sixteen MnCl(2) phantoms, thirty-seven healthy individuals and 87 cirrhotic patients were performed SWI and multi-echo T2*-weighted imaging, and the signal processing in NMR (SPIN) software was used to measure the radian on SWI phase images and the R2* on T2* maps. The mean minus two times standard deviation (SD) of Siemens Phase Unit (SPU) in healthy individuals was designated as a threshold to separate the regions of interest (ROIs) into high- and low-iron areas in healthy participants and cirrhotic patients. The SWI phase values of high-iron areas were calculated. The R2* values was measured in the same ROI in both healthy participants and patients. RESULTS: SWI phase values correlated linearly with R2* values in cases of MnCl(2) concentrations lower than 2.3 mM in vitro (r = -0.996, P<0.001). The mean value and SD of 37 healthy participants were 2003 and 15 (SPU), respectively. A threshold of 1973 SPU (-0.115 radians) was determined. The SWI phase value and R2* values had a negative correlation in the cirrhotic patients (r = -0.742, P<0.001). However, no similar relationship was found in the healthy individuals (r = 0.096, P = 0.576). Both SWI phase values and R2* values were found to have significant correlations with serum ferritin concentrations in 42 patients with blood samples (r = -0.512, P = 0.001 and r = 0.641, P<0.001, respectively). CONCLUSION: SWI phase values had significant correlations with R2* after the establishment of a baseline on the phase image. SWI phase images may be used for non-invasive quantitative measurement of mild and moderate iron deposition in hepatic cirrhosis in vivo. PMID- 23029038 TI - An inflammation loop orchestrated by S100A9 and calprotectin is critical for development of arthritis. AB - OBJECTIVE: The S100A9 and S100A8 proteins are highly expressed by neutrophils and monocytes and are part of a group of damage-associated molecular pattern molecules that trigger inflammatory responses. Sera and synovial fluids of patients with rheumatoid arthritis (RA) contain high concentrations of S100A8/A9 that correlate with disease activity. METHODS: In this study, we investigated the importance of S100A9 in RA by using neutralizing antibodies in a murine lipopolysaccharide-synchronized collagen-induced arthritis model. We also used an in vitro model of stimulation of human immune cells to decipher the role played by S100A9 in leukocyte migration and pro-inflammatory cytokine secretion. RESULTS: Treatment with anti-S100A9 antibodies improved the clinical score by 50%, diminished immune cell infiltration, reduced inflammatory cytokines, both in serum and in the joints, and preserved bone/collagen integrity. Stimulation of neutrophils with S100A9 protein led to the enhancement of neutrophil transendothelial migration. S100A9 protein also induced the secretion by monocytes of proinflammatory cytokines like TNFalpha, IL-1beta and IL-6, and of chemokines like MIP-1alpha and MCP-1. CONCLUSION: The effects of anti-S100A9 treatment are likely direct consequences of inhibiting the S100A9-mediated promotion of neutrophil transmigration and secretion of pro-inflammatory cytokines from monocytes. Collectively, our results show that treatment with anti S100A9 may inhibit amplification of the immune response and help preserve tissue integrity. Therefore, S100A9 is a promising potential therapeutic target for inflammatory diseases like rheumatoid arthritis for which alternative therapeutic strategies are needed. PMID- 23029039 TI - Virological and serological findings in Rousettus aegyptiacus experimentally inoculated with vero cells-adapted hogan strain of Marburg virus. AB - The Egyptian fruit bat, Rousettus aegyptiacus, is currently regarded as a potential reservoir host for Marburg virus (MARV). However, the modes of transmission, the level of viral replication, tissue tropism and viral shedding pattern remains to be described. Captive-bred R. aegyptiacus, including adult males, females and pups were exposed to MARV by different inoculation routes. Blood, tissues, feces and urine from 9 bats inoculated by combination of nasal and oral routes were all negative for the virus and ELISA IgG antibody could not be demonstrated for up to 21 days post inoculation (p.i.). In 21 bats inoculated by a combination of intraperitoneal/subcutaneous route, viremia and the presence of MARV in different tissues was detected on days 2-9 p.i., and IgG antibody on days 9-21 p.i. In 3 bats inoculated subcutaneously, viremia was detected on days 5 and 8 (termination of experiment), with virus isolation from different organs. MARV could not be detected in urine, feces or oral swabs in any of the 3 experimental groups. However, it was detected in tissues which might contribute to horizontal or vertical transmission, e.g. lung, intestines, kidney, bladder, salivary glands, and female reproductive tract. Viremia lasting at least 5 days could also facilitate MARV mechanical transmission by blood sucking arthropods and infections of susceptible vertebrate hosts by direct contact with infected blood. All bats were clinically normal and no gross pathology was identified on post mortem examination. This work confirms the susceptibility of R. aegyptiacus to infection with MARV irrespective of sex and age and contributes to establishing a bat-filovirus experimental model. Further studies are required to uncover the mode of MARV transmission, and to investigate the putative role of R. aegyptiacus as a reservoir host. PMID- 23029040 TI - 15-lipoxygenase metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and survival. AB - A 15-LOX, it is proposed, suppresses the growth of prostate cancer in part by converting arachidonic, eicosatrienoic, and/or eicosapentaenoic acids to n-6 hydroxy metabolites. These metabolites inhibit the proliferation of PC3, LNCaP, and DU145 prostate cancer cells but only at >=1-10 uM. We show here that the 15 LOX metabolites of docosahexaenoic acid (DHA), 17-hydroperoxy-, 17-hydroxy-, 10,17-dihydroxy-, and 7,17-dihydroxy-DHA inhibit the proliferation of these cells at >=0.001, 0.01, 1, and 1 uM, respectively. By comparison, the corresponding 15 hydroperoxy, 15-hydroxy, 8,15-dihydroxy, and 5,15-dihydroxy metabolites of arachidonic acid as well as DHA itself require >=10-100 uM to do this. Like DHA, the DHA metabolites a) induce PC3 cells to activate a peroxisome proliferator activated receptor-gamma (PPARgamma) reporter, express syndecan-1, and become apoptotic and b) are blocked from slowing cell proliferation by pharmacological inhibition or knockdown of PPARgamma or syndecan-1. The DHA metabolites thus slow prostate cancer cell proliferation by engaging the PPARgamma/syndecan-1 pathway of apoptosis and thereby may contribute to the prostate cancer-suppressing effects of not only 15-LOX but also dietary DHA. PMID- 23029042 TI - An FD-LC-MS/MS proteomic strategy for revealing cellular protein networks: a conditional superoxide dismutase 1 knockout cells. AB - Systems biology aims to understand biological phenomena in terms of complex biological and molecular interactions, and thus proteomics plays an important role in elucidating protein networks. However, many proteomic methods have suffered from their high variability, resulting in only showing altered protein names. Here, we propose a strategy for elucidating cellular protein networks based on an FD-LC-MS/MS proteomic method. The strategy permits reproducible relative quantitation of differences in protein levels between different cell populations and allows for integration of the data with those obtained through other methods. We demonstrate the validity of the approach through a comparison of differential protein expression in normal and conditional superoxide dismutase 1 gene knockout cells and believe that beginning with an FD-LC-MS/MS proteomic approach will enable researchers to elucidate protein networks more easily and comprehensively. PMID- 23029041 TI - 4-1BB signaling breaks the tolerance of maternal CD8+ T cells that are reactive with alloantigens. AB - 4-1BB (CD137, TNFRSF9), a member of the activation-induced tumor necrosis factor receptor family, is a powerful T-cell costimulatory molecule. It generally enhances CD8(+) T responses and even breaks the tolerance of CD8(+) T cells in an antigen-specific manner. In the present study we found that it was expressed in the placentas of pregnant mice and that its expression coincided with that of the immunesuppressive enzyme indoleamine 2,3-dioxygenase (IDO). Therefore, we investigated whether 4-1BB signaling is involved in fetal rejection using agonistic anti-4-1BB mAb and 4-1BB-deficient mice. Treatment with agonistic anti 4-1BB mAb markedly increased the rate of rejection of allogeneic but not syngeneic fetuses, and this was primarily dependent on CD8(+) T cells. Complement component 3 (C3) seemed to be the effector molecule because 4-1BB triggering resulting in accumulation of C3 in the placenta, and this accumulation was also reversed by anti-CD8 mAb treatment. These findings demonstrate that 4-1BB triggering breaks the tolerance of CD8(+) T cells to alloantigens in the placenta. Moreover, triggering 4-1BB protected the pregnant mice from Listeria monocytogenes (LM) infection, but led to rejection of semi-allogeneic fetuses. Therefore, given the cross-recognition of alloantigen by pathogen-reactive CD8(+) T cells, the true function of 4-1BB may be to reverse the hypo-responsiveness of pathogen-reactive CD8(+) T cells in the placenta in cases of infection, even if that risks losing the fetus. PMID- 23029044 TI - Direct writing of flexible electronics through room temperature liquid metal ink. AB - BACKGROUND: Conventional approaches of making a flexible circuit are generally complex, environment unfriendly, time and energy consuming, and thus expensive. Here, we describe for the first time the method of using high-performance GaIn(10)-based electrical ink, a significantly neglected room temperature liquid metal, as both electrical conductors and interconnects, for directly writing flexible electronics via a rather easy going and cost effective way. METHODS: The new generation electric ink was made and its wettability with various materials was modified to be easily written on a group of either soft or rigid substrates such as epoxy resin board, glass, plastic, silica gel, paper, cotton, textiles, cloth and fiber etc. Conceptual experiments were performed to demonstrate and evaluate the capability of directly writing the electrical circuits via the invented metal ink. Mechanisms involved were interpreted through a series of fundamental measurements. RESULTS: The electrical resistivity of the fluid like GaIn(10)-based material was measured as 34.5 uOmega.cm at 297 K by four point probe method and increased with addition of the oxygen quantity, which indicates it as an excellent metal ink. The conductive line can be written with features that are approximately 10 um thick. Several functional devices such as a light emitting diode (LED) array showing designed lighting patterns and electrical fan were made to work by directly writing the liquid metal on the specific flexible substrates. And satisfactory performances were obtained. CONCLUSIONS: The present method opens the way to directly and quickly writing flexible electronics which can be as simple as signing a name or drawing a picture on the paper. The unique merit of the GaIn(10)-based liquid metal ink lies in its low melting temperature, well controlled wettability, high electrical conductivity and good biocompability. The new electronics writing strategy and basic principle has generalized purpose and can be extended to more industrial areas, even daily life. PMID- 23029043 TI - The genomic landscape of TP53 and p53 annotated high grade ovarian serous carcinomas from a defined founder population associated with patient outcome. AB - High-grade ovarian serous carcinomas (HGSC) are characterized by TP53 mutations and non-random patterns of chromosomal anomalies, where the nature of the TP53 mutation may correlate with clinical outcome. However, the frequency of common somatic genomic events occurring in HGSCs from demographically defined populations has not been explored. Whole genome SNP array, and TP53 mutation, gene and protein expression analyses were assessed in 87 confirmed HGSC samples with clinical correlates from French Canadians, a population exhibiting strong founder effects, and results were compared with independent reports describing similar analyses from unselected populations. TP53 mutations were identified in 91% of HGSCs. Anomalies observed in more than 50% of TP53 mutation-positive HGSCs involved gains of 3q, 8q and 20q, and losses of 4q, 5q, 6q, 8p, 13q, 16q, 17p, 17q, 22q and Xp. Nearly 400 regions of non-overlapping amplification or deletion were identified, where 178 amplifications and 98 deletions involved known genes. The subgroup expressing mutant p53 protein exhibited significantly prolonged overall and disease-free survival as compared with the p53 protein null subgroup. Interestingly, a comparative analysis of genomic landscapes revealed a significant enrichment of gains involving 1q, 8q, and 12p intervals in the subgroup expressing mutant p53 protein as compared with the p53 protein null subgroup. Although the findings show that the frequency of TP53 mutations and the genomic landscapes observed in French Canadian samples were similar to those reported for samples from unselected populations, there were differences in the magnitude of global gains/losses of specific chromosomal arms and in the spectrum of amplifications and deletions involving focal regions in individual samples. The findings from our comparative genomic analyses also support the notion that there may be biological differences between HGSCs that could be related to the nature of the TP53 mutation. PMID- 23029045 TI - WaveSeq: a novel data-driven method of detecting histone modification enrichments using wavelets. AB - BACKGROUND: Chromatin immunoprecipitation followed by next-generation sequencing is a genome-wide analysis technique that can be used to detect various epigenetic phenomena such as, transcription factor binding sites and histone modifications. Histone modification profiles can be either punctate or diffuse which makes it difficult to distinguish regions of enrichment from background noise. With the discovery of histone marks having a wide variety of enrichment patterns, there is an urgent need for analysis methods that are robust to various data characteristics and capable of detecting a broad range of enrichment patterns. RESULTS: To address these challenges we propose WaveSeq, a novel data-driven method of detecting regions of significant enrichment in ChIP-Seq data. Our approach utilizes the wavelet transform, is free of distributional assumptions and is robust to diverse data characteristics such as low signal-to-noise ratios and broad enrichment patterns. Using publicly available datasets we showed that WaveSeq compares favorably with other published methods, exhibiting high sensitivity and precision for both punctate and diffuse enrichment regions even in the absence of a control data set. The application of our algorithm to a complex histone modification data set helped make novel functional discoveries which further underlined its utility in such an experimental setup. CONCLUSIONS: WaveSeq is a highly sensitive method capable of accurate identification of enriched regions in a broad range of data sets. WaveSeq can detect both narrow and broad peaks with a high degree of accuracy even in low signal-to-noise ratio data sets. WaveSeq is also suited for application in complex experimental scenarios, helping make biologically relevant functional discoveries. PMID- 23029046 TI - Limited predator-induced dispersal in whiteflies. AB - Whereas prey are known to avoid habitats with their predators, it is less well established whether they are triggered to emigrate to new habitats when exposed to predators in their current habitat. We studied plant-to-plant dispersal of adult whiteflies in response to the presence of predatory mites on the plant on which the whiteflies were released. These predators attack whitefly eggs and crawlers, but not the adults, which can fly to other plants and can learn to avoid plants with predators. Being tiny and wingless, the predatory mites are slow dispersers compared to adult whiteflies. This offers the whiteflies the opportunity to escape from plants with predatory mites to plants without predators, thus avoiding predation of their offspring. To test for this escape response, a greenhouse experiment was carried out, where whiteflies were released on the first of a row of 5 cucumber plants, 0.6 m or 2 m apart, and predators either on the same plant, on the next plant, or nowhere (control). Adult whiteflies dispersed significantly faster from plants with predatory mites onto neighbouring plants when the plants were 0.6 m apart, but not when plants were 2 m apart. However, the final numbers of whiteflies that had successfully dispersed at the end of the experiments did not differ significantly for either of the two interplant distances. Overall, the proportion of whiteflies that did disperse was low, suggesting that adult whiteflies were apparently reluctant to disperse, even from plants with predators. Our results suggest that this reluctance increases with the distance between the plants, so most likely depends on the uncertainty to find a new plant. Thus, whiteflies do not always venture to fly even when they can easily bridge the distance to another plant. PMID- 23029048 TI - Influence of microsite disturbance on the establishment of two congeneric invasive thistles. AB - The successful establishment of invasive species has been shown to depend on aspects of the invaded community, such as gap characteristics. Biotic resistance may be particularly critical for stopping invaders at early life history stages, but new species can often invade following disturbances, which may create microsites with very different characteristics than are usually present. We examine the response of two invasive thistle species, Carduus nutans L. and C. acanthoides L., to three different microsite characteristics: disturbance type, size, and water availability. The two species initially responded differently to the type of disturbance: C. acanthoides had higher emergence and survival in plots with both above- and belowground disturbance, whereas C. nutans had better early performance in large microsites with above-ground disturbance only. Later in their life cycle, C. nutans performed better in plots that had been disturbed both above- and belowground, whereas C. acanthoides was largely unaffected by disturbance type. Increased emergence and survival, larger size and a higher proportion flowering were observed in larger gaps for both species throughout the life cycle. Watering had a negative impact on C. nutans emergence and fall survival and on C. acanthoides survival to the following summer. Overall, these results suggest that disturbance-generated microsite characteristics (disturbance type and size) may have large impacts on establishment of these two Carduus species, which in turn may persist well beyond the initial stages of growth. Studying invader responses to disturbance can help us to understand under what circumstances they are likely to establish and create persistent problems; avoiding or ameliorating such situations will have significant management benefits. PMID- 23029047 TI - The cardiac ventricular 5-HT4 receptor is functional in late foetal development and is reactivated in heart failure. AB - A positive inotropic responsiveness to serotonin, mediated by 5-HT(4) and 5 HT(2A) receptors, appears in the ventricle of rats with post-infarction congestive heart failure (HF) and pressure overload-induced hypertrophy. A hallmark of HF is a transition towards a foetal genotype which correlates with loss of cardiac functions. Thus, we wanted to investigate whether the foetal and neonatal cardiac ventricle displays serotonin responsiveness. Wistar rat hearts were collected day 3 and 1 before expected birth (days -3 and -1), as well as day 1, 3, 5 and 113 (age matched with Sham and HF) after birth. Hearts from post infarction HF and sham-operated animals (Sham) were also collected. Heart tissue was examined for mRNA expression of 5-HT(4), 5-HT(2A) and 5-HT(2B) serotonin receptors, 5-HT transporter, atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-alpha and MHC-beta (real-time quantitative RT-PCR) as well as 5-HT receptor-mediated increase in contractile function exvivo (electrical field stimulation of ventricular strips from foetal and neonatal rats and left ventricular papillary muscle from adult rats in organ bath). Both 5-HT(4) mRNA expression and functional responses were highest at day -3 and decreased gradually to day 5, with a further decrease to adult levels. In HF, receptor mRNA levels and functional responses reappeared, but to lower levels than in the foetal ventricle. The 5-HT(2A) and 5-HT(2B) receptor mRNA levels increased to a maximum immediately after birth, but of these, only the 5-HT(2A) receptor mediated a positive inotropic response. We suggest that the 5-HT(4) receptor is a representative of a foetal cardiac gene program, functional in late foetal development and reactivated in heart failure. PMID- 23029049 TI - Immune sculpting of norepinephrine on MHC-I, B7-1, IDO and B7-H1 expression and regulation of proliferation and invasion in pancreatic carcinoma cells. AB - BACKGROUND: The sympathetic neurotransmitter Norepinephrine (NE) contributes to tumorigenesis and cancer progression. This study aims to investigate the role of NE in modulating the immune phenotype and allowing pancreatic carcinoma (PC) cells to escape the immune response. METHODS: Varied concentrations of NE and interferon-gamma (IFN-gamma) were administrated to MIA PaCa-2 and BxPC-3 cell lines for 48 hours. Proliferation and invasion were then investigated using an MTT assay and a membrane invasion culture system respectively. MHC-I, B7-1, IDO and B7-H1 expression were measured using real-time quantitative RT-PCR, western blotting and immunocytochemistry. The synergistic and time-dependent effects of NE/IFN-gamma were also investigated. Adrenergic antagonists were used to identify the relevant target receptor of NE. RESULTS: The results showed that NE had dose dependent and time-dependent effects on cell biological processes as well as on the expression of MHC-I, B7-1, IDO and B7-H1. These effects occurred mainly via the beta(2)-adrenergic receptor. Long-term NE treatment was able to antagonize some of the effects of IFN-gamma (after 2 weeks of treatment), but NE and IFN gamma had significant synergistic stimulatory effects on IDO and B7-H1 expression. The residual effects on biological activities lasted for 2 weeks, while the immunophenotypic changes decreased at early time points after treatment. CONCLUSIONS: NE plays important roles in modulating PC cell biological activities and affecting MHC-I, B7-1, IDO and B7-H1 expression in vitro, mainly via the beta2-adrenergic receptor (beta2-AR) in a time- and dose-dependent fashion. Only at extended treatment durations could NE affect PC cell progression and immune evasion. PMID- 23029050 TI - Dacarbazine and the agonistic TRAIL receptor-2 antibody lexatumumab induce synergistic anticancer effects in melanoma. AB - Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of cancer cells. The potency of mapatumumab and lexatumumab was assessed in mono therapy protocols, and the ability to sensitize for dacarbazine (DTIC) treatment was explored in ten different melanoma cell lines. Our data indicated that melanoma cell lines tend to be resistant to mapatumumab, most likely due to low expression of DR4, while a dose dependent response to lexatumumab was observed. Combining DTIC and lexatumumab induced an additive or synergistic effect on cell death in the various melanoma cell lines. The synergistic effect observed in the FEMX-1 cell line was related to enhanced cleavage of Bid in parallel with elevated expression of the pro-apoptotic proteins Bim, Bax and Bak. Furthermore, the anti-apoptotic proteins Bcl-XL, cIAP 1, XIAP and livin were down regulated. Cleavage of Bid and down regulation of cIAP-2 and livin were observed in vivo. Altogether, these data suggest a change in the balance between pro- and anti-apoptotic proteins favoring induction of apoptosis. In the more therapy resistant cell line, HHMS, no changes in the pro- and anti-apoptotic proteins were observed. FEMX-1 xenografts treated with DTIC and lexatumumab showed reduced growth and increased level of apoptosis compared to the control groups, providing arguments for further evaluation of this combination in melanoma patients. PMID- 23029051 TI - Radiofrequency ablation versus resection for colorectal cancer liver metastases: a meta-analysis. AB - BACKGROUND: No randomized controlled trial (RCT) has yet been performed to provide the evidence to clarify the therapeutic debate on liver resection (LR) and radiofrequency ablation (RFA) in treating colorectal liver metastases (CLM). The meta-analysis was performed to summarize the evidence mostly from retrospective clinical trials and to investigate the effect of LR and RFA. METHODOLOGY/PRINCIPAL FINDINGS: Systematic literature search of clinical studies was carried out to compare RFA and LR for CLM in Pubmed, Embase and the Cochrane Library Central databases. The meta-analysis was performed using risk ratio (RR) and random effect model, in which 95% confidence intervals (95% CI) for RR were calculated. Primary outcomes were the overall survival (OS) and disease-free survival (DFS) at 3 and 5 years plus mortality and morbidity. 1 prospective study and 12 retrospective studies were finally eligible for meta-analysis. LR was significantly superior to RFA in 3 -year OS (RR 1.377, 95% CI: 1.246-1.522); 5 year OS (RR: 1.474, 95%CI: 1.284-1.692); 3-year DFS (RR 1.735, 95% CI: 1.483 2.029) and 5-year DFS (RR 2.227, 95% CI: 1.823-2.720). The postoperative morbidity was higher in LR (RR: 2.495, 95% CI: 1.881-3.308), but no significant difference was found in mortality between LR and RFA. The data from the 3 subgroups (tumor<3 cm; solitary tumor; open surgery or laparoscopic approach) showed significantly better OS and DFS in patients who received surgical resection. CONCLUSIONS/SIGNIFICANCES: Although multiple confounders exist in the clinical trials especially the bias in patient selection, LR was significantly superior to RFA in the treatment of CLM, even when conditions limited to tumor<3 cm, solitary tumor and open surgery or laparoscopic (lap) approach. Therefore, caution should be taken when treating CLM with RFA before more supportive evidences for RFA from RCTs are obtained. PMID- 23029053 TI - Regional scale high resolution delta18O prediction in precipitation using MODIS EVI. AB - The natural variation in stable water isotope ratio data, also known as water isoscape, is a spatiotemporal fingerprint and a powerful natural tracer that has been widely applied in disciplines as diverse as hydrology, paleoclimatology, ecology and forensic investigation. Although much effort has been devoted to developing a predictive water isoscape model, it remains a central challenge for scientists to generate high accuracy, fine scale spatiotemporal water isoscape prediction. Here we develop a novel approach of using the MODIS-EVI (the Moderate Resolution Imagining Spectroradiometer-Enhanced Vegetation Index), to predict delta(18)O in precipitation at the regional scale. Using a structural equation model, we show that the EVI and precipitated delta(18)O are highly correlated and thus the EVI is a good predictor of precipitated delta(18)O. We then test the predictability of our EVI-delta(18)O model and demonstrate that our approach can provide high accuracy with fine spatial (250*250 m) and temporal (16 days) scale delta(18)O predictions (annual and monthly predictabilities [r] are 0.96 and 0.80, respectively). We conclude the merging of the EVI and delta(18)O in precipitation can greatly extend the spatial and temporal data availability and thus enhance the applicability for both the EVI and water isoscape. PMID- 23029052 TI - Quercetin protects Saccharomyces cerevisiae against oxidative stress by inducing trehalose biosynthesis and the cell wall integrity pathway. AB - BACKGROUND: Quercetin is a naturally occurring flavonol with antioxidant, anticancer and anti-ageing properties. In this study we aimed to identify genes differentially expressed in yeast cells treated with quercetin and its role in oxidative stress protection. METHODS: A microarray analysis was performed to characterize changes in the transcriptome and the expression of selected genes was validated by RT-qPCR. Biological processes significantly affected were identified by using the FUNSPEC software and their relevance in H(2)O(2) resistance induced by quercetin was assessed. RESULTS: Genes associated with RNA metabolism and ribosome biogenesis were down regulated in cells treated with quercetin, whereas genes associated with carbohydrate metabolism, endocytosis and vacuolar proteolysis were up regulated. The induction of genes related to the metabolism of energy reserves, leading to the accumulation of the stress protectant disaccharide trehalose, and the activation of the cell wall integrity pathway play a key role in oxidative stress resistance induced by quercetin. CONCLUSIONS: These results suggest that quercetin may act as a modulator of cell signaling pathways related to carbohydrate metabolism and cell integrity to exert its protective effects against oxidative stress. PMID- 23029054 TI - Alteration of TEAD1 expression levels confers apoptotic resistance through the transcriptional up-regulation of Livin. AB - BACKGROUND: TEA domain (TEAD) proteins are highly conserved transcription factors involved in embryonic development and differentiation of various tissues. More recently, emerging evidences for a contribution of these proteins towards apoptosis and cell proliferation regulation have also been proposed. These effects appear to be mediated by the interaction between TEAD and its co activator Yes-Associated Protein (YAP), the downstream effector of the Hippo tumour suppressor pathway. METHODOLOGY/PRINCIPAL FINDINGS: We further investigated the mechanisms underlying TEAD-mediated apoptosis regulation and showed that overexpression or RNAi-mediated silencing of the TEAD1 protein is sufficient to protect mammalian cell lines from induced apoptosis, suggesting a proapoptotic function for TEAD1 and a non physiological cytoprotective effect for overexpressed TEAD1. Moreover we show that the apoptotic resistance conferred by altered TEAD1 expression is mediated by the transcriptional up-regulation of Livin, a member of the Inhibitor of Apoptosis Protein (IAP) family. In addition, we show that overexpression of a repressive form of TEAD1 can induce Livin up regulation, indicating that the effect of TEAD1 on Livin expression is indirect and favoring a model in which TEAD1 activates a repressor of Livin by interacting with a limiting cofactor that gets titrated upon TEAD1 up-regulation. Interestingly, we show that overexpression of a mutated form of TEAD1 (Y421H) implicated in Sveinsson's chorioretinal atrophy that strongly reduces its interaction with YAP as well as its activation, can induce Livin expression and protect cells from induced apoptosis, suggesting that YAP is not the cofactor involved in this process. CONCLUSIONS/SIGNIFICANCE: Taken together our data reveal a new, Livin-dependent, apoptotic role for TEAD1 in mammals and provide mechanistic insight downstream of TEAD1 deregulation in cancers. PMID- 23029055 TI - Pericytes regulate vascular basement membrane remodeling and govern neutrophil extravasation during inflammation. AB - During inflammation polymorphonuclear neutrophils (PMNs) traverse venular walls, composed of the endothelium, pericyte sheath and vascular basement membrane. Compared to PMN transendothelial migration, little is known about how PMNs penetrate the latter barriers. Using mouse models and intravital microscopy, we show that migrating PMNs expand and use the low expression regions (LERs) of matrix proteins in the vascular basement membrane (BM) for their transmigration. Importantly, we demonstrate that this remodeling of LERs is accompanied by the opening of gaps between pericytes, a response that depends on PMN engagement with pericytes. Exploring how PMNs modulate pericyte behavior, we discovered that direct PMN-pericyte contacts induce relaxation rather than contraction of pericyte cytoskeletons, an unexpected response that is mediated by inhibition of the RhoA/ROCK signaling pathway in pericytes. Taking our in vitro results back into mouse models, we present evidence that pericyte relaxation contributes to the opening of the gaps between pericytes and to the enlargement of the LERs in the vascular BM, facilitating PMN extravasation. Our study demonstrates that pericytes can regulate PMN extravasation by controlling the size of pericyte gaps and thickness of LERs in venular walls. This raises the possibility that pericytes may be targeted in therapies aimed at regulating inflammation. PMID- 23029056 TI - Characterization of PTPRG in knockdown and phosphatase-inactive mutant mice and substrate trapping analysis of PTPRG in mammalian cells. AB - Receptor tyrosine phosphatase gamma (PTPRG, or RPTPgamma) is a mammalian receptor like tyrosine phosphatase which is highly expressed in the nervous system as well as other tissues. Its function and biochemical characteristics remain largely unknown. We created a knockdown (KD) line of this gene in mouse by retroviral insertion that led to 98-99% reduction of RPTPgamma gene expression. The knockdown mice displayed antidepressive-like behaviors in the tail-suspension test, confirming observations by Lamprianou et al. 2006. We investigated this phenotype in detail using multiple behavioral assays. To see if the antidepressive-like phenotype was due to the loss of phosphatase activity, we made a knock-in (KI) mouse in which a mutant, RPTPgamma C1060S, replaced the wild type. We showed that human wild type RPTPgamma protein, expressed and purified, demonstrated tyrosine phosphatase activity, and that the RPTPgamma C1060S mutant was completely inactive. Phenotypic analysis showed that the KI mice also displayed some antidepressive-like phenotype. These results lead to a hypothesis that an RPTPgamma inhibitor could be a potential treatment for human depressive disorders. In an effort to identify a natural substrate of RPTPgamma for use in an assay for identifying inhibitors, "substrate trapping" mutants (C1060S, or D1028A) were studied in binding assays. Expressed in HEK293 cells, these mutant RPTPgammas retained a phosphorylated tyrosine residue, whereas similarly expressed wild type RPTPgamma did not. This suggested that wild type RPTPgamma might auto-dephosphorylate which was confirmed by an in vitro dephosphorylation experiment. Using truncation and mutagenesis studies, we mapped the auto dephosphorylation to the Y1307 residue in the D2 domain. This novel discovery provides a potential natural substrate peptide for drug screening assays, and also reveals a potential functional regulatory site for RPTPgamma. Additional investigation of RPTPgamma activity and regulation may lead to a better understanding of the biochemical underpinnings of human depression. PMID- 23029057 TI - Unlike physical exercise, modified environment increases the lifespan of SOD1G93A mice however both conditions induce cellular changes. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a gradual muscular paralysis resulting from progressive motoneurons death. ALS etiology remains unknown although it has been demonstrated to be a multifactorial disease involving several cellular partners. There is currently no effective treatment. Even if the effect of exercise is under investigation for many years, whether physical exercise is beneficial or harmful is still under debate. METHODS AND FINDINGS: We investigated the effect of three different intensities of running exercises on the survival of SOD1(G93A) mice. At the early-symptomatic stage (P60), males were isolated and randomly assigned to 5 conditions: 2 sedentary groups ("sedentary" and "sedentary treadmill" placed on the inert treadmill), and 3 different training intensity groups (5 cm/s, 10 cm/s and 21 cm/s; 15 min/day, 5days/week). We first demonstrated that an appropriate "control" of the environment is of the utmost importance since comparison of the two sedentary groups evidenced an 11.6% increase in survival in the "sedentary treadmill" group. Moreover, we showed by immunohistochemistry that this increased lifespan is accompanied with motoneurons survival and increased glial reactivity in the spinal cord. In a second step, we showed that when compared with the proper control, all three running-based training did not modify lifespan of the animals, but result in motoneurons preservation and changes in glial cells activation. CONCLUSIONS/SIGNIFICANCE: We demonstrate that increase in survival induced by a slight daily modification of the environment is associated with motoneurons preservation and strong glial modifications in the lumbar spinal cord of SOD1(G93A). Using the appropriate control, we then demonstrate that all running intensities have no effect on the survival of ALS mice but induce cellular modifications. Our results highlight the critical importance of the control of the environment in ALS studies and may explain discrepancy in the literature regarding the effect of exercise in ALS. PMID- 23029058 TI - Linear growth and final height characteristics in adolescent females with anorexia nervosa. AB - OBJECTIVE: Growth retardation is an established complication of anorexia nervosa (AN). However, findings concerning final height of AN patients are inconsistent. The aim of this study was to assess these phenomena in female adolescent inpatients with AN. METHODS: We retrospectively studied all 211 female adolescent AN patients hospitalized in an inpatient eating disorders department from 1/1/1987 to 31/12/99. Height and weight were assessed at admission and thereafter routinely during hospitalization and follow-up. Final height was measured in 69 patients 2-10 years after discharge. Pre-morbid height data was available in 29 patients. RESULTS: Patients' height standard deviation scores (SDS) on admission (-0.285+/-1.0) and discharge (-0.271+/-1.02) were significantly (p<0.001) lower than expected in normal adolescents. Patients admitted at age <=13 years, or less than 1 year after menarche, were more severely growth-impaired than patients admitted at an older age, (p = 0.03). Final height SDS, available for 69 patients, was -0.258+/-1.04, significantly lower than expected in a normal population (p = 0.04), and was more severely compromised in patients who were admitted less than 1 year from their menarche. In a subgroup of 29 patients with complete growth data (pre-morbid, admission, discharge, and final adult height), the pre-morbid height SDS was not significantly different from the expected ( 0.11+/-1.1), whereas heights at the other time points were significantly (p = 0.001) lower (-0.56+/-1.2, -0.52+/-1.2, and -0.6+/-1.2, respectively). CONCLUSIONS: Our findings suggest that whereas the premorbid height of female adolescent AN patients is normal, linear growth retardation is a prominent feature of their illness. Weight restoration is associated with catch-up growth, but complete catch-up is often not achieved. PMID- 23029059 TI - Framework for modelling economic impacts of invasive species, applied to pine wood nematode in Europe. AB - BACKGROUND: Economic impact assessment of invasive species requires integration of information on pest entry, establishment and spread, valuation of assets at risk and market consequences at large spatial scales. Here we develop such a framework and demonstrate its application to the pinewood nematode, Bursaphelenchus xylophilus, which threatens the European forestry industry. The effect of spatial resolution on the assessment result is analysed. METHODOLOGY/PRINCIPAL FINDINGS: Direct economic impacts resulting from wood loss are computed using partial budgeting at regional scale, while impacts on social welfare are computed by a partial equilibrium analysis of the round wood market at EU scale. Substantial impacts in terms of infested stock are expected in Portugal, Spain, Southern France, and North West Italy but not elsewhere in EU in the near future. The cumulative value of lost forestry stock over a period of 22 years (2008-2030), assuming no regulatory control measures, is estimated at ?22 billion. The greatest yearly loss of stock is expected to occur in the period 2014-2019, with a peak of three billion euros in 2016, but stabilizing afterwards at 300-800 million euros/year. The reduction in social welfare follows the loss of stock with considerable delay because the yearly harvest from the forest is only 1.8%. The reduction in social welfare for the downstream round wood market is estimated at ?218 million in 2030, whereby consumers incur a welfare loss of ?357 million, while producers experience a ?139 million increase, due to higher wood prices. The societal impact is expected to extend to well beyond the time horizon of the analysis, and long after the invasion has stopped. CONCLUSIONS/SIGNIFICANCE: Pinewood nematode has large economic consequences for the conifer forestry industry in the EU. A change in spatial resolution affected the calculated directed losses by 24%, but did not critically affect conclusions. PMID- 23029060 TI - Routine HIV testing in adolescents and young adults presenting to an outpatient clinic in Durban, South Africa. AB - OBJECTIVES: Although youth (12-24 years) in Sub-Saharan Africa have a high HIV risk, many have poor access to HIV testing services and are unaware of their status. Our objective was to evaluate the proportion of adolescents (12-17 years) and young adults (18-24 years) who underwent HIV testing and the prevalence among those tested in an urban adult outpatient clinic with a routine HIV testing program in Durban, South Africa. DESIGN: We conducted a retrospective cross sectional analysis of adolescent and young adult outpatient records between February 2008 and December 2009. METHODS: We determined the number of unique outpatient visitors, HIV tests, and positive rapid tests among those tested. RESULTS: During the study period, 956 adolescents registered in the outpatient clinic, of which 527 (55%) were female. Among adolescents, 260/527 (49%, 95% CI 45-54%) females underwent HIV testing compared to 129/429 (30%, 95% CI 26-35%) males (p<0.01). The HIV prevalence among the 389 (41%, 95% CI 38-44%) adolescents who underwent testing was 16% (95% CI 13-20%) and did not vary by gender (p = 0.99). During this period, there were 2,351 young adult registrations, and of these 1,492 (63%) were female. The proportion consenting for HIV testing was similar among females 980/1,492 (66%, 95% CI 63-68%) and males 543/859 (63%, 95% CI 60-66%, p = 0.25). Among the 1,523 (65%, 95% CI 63-67%) young adults who underwent testing, the HIV prevalence was 22% (95% CI 19-24%) in females versus 14% in males (95% CI 11-17%, p<0.01). CONCLUSIONS: Although the HIV prevalence is high among youth participating in an adult outpatient clinic routine HIV program, the uptake of testing is low, especially among 12-17 year old males. There is an urgent need to offer targeted, age-appropriate routine HIV testing to youth presenting to outpatient clinics in epidemic settings. PMID- 23029061 TI - Ecological complexity in a coffee agroecosystem: spatial heterogeneity, population persistence and biological control. AB - BACKGROUND: Spatial heterogeneity is essential for the persistence of many inherently unstable systems such as predator-prey and parasitoid-host interactions. Since biological interactions themselves can create heterogeneity in space, the heterogeneity necessary for the persistence of an unstable system could be the result of local interactions involving elements of the unstable system itself. METHODOLOGY/PRINCIPAL FINDINGS: Here we report on a predatory ladybird beetle whose natural history suggests that the beetle requires the patchy distribution of the mutualism between its prey, the green coffee scale, and the arboreal ant, Azteca instabilis. Based on known ecological interactions and the natural history of the system, we constructed a spatially-explicit model and showed that the clustered spatial pattern of ant nests facilitates the persistence of the beetle populations. Furthermore, we show that the dynamics of the beetle consuming the scale insects can cause the clustered distribution of the mutualistic ants in the first place. CONCLUSIONS/SIGNIFICANCE: From a theoretical point of view, our model represents a novel situation in which a predator indirectly causes a spatial pattern of an organism other than its prey, and in doing so facilitates its own persistence. From a practical point of view, it is noteworthy that one of the elements in the system is a persistent pest of coffee, an important world commodity. This pest, we argue, is kept within limits of control through a complex web of ecological interactions that involves the emergent spatial pattern. PMID- 23029062 TI - Annexin A10 in human oral cancer: biomarker for tumoral growth via G1/S transition by targeting MAPK signaling pathways. AB - BACKGROUND: Annexins are calcium and phospholipid binding proteins that form an evolutionary conserved multigene family. Considerable evidence indicates that annexin A10 (ANXA10) is involved in tumoral progression, although little is known about its role in human oral carcinogenesis. In this study, we investigated the involvement of ANXA10 in oral squamous cell carcinoma (OSCC). METHODOLOGY/PRINCIPAL FINDINGS: ANXA10 mRNA and protein expressions were assessed by quantitative reverse transcriptase polymerase chain reaction and immunoblotting, and we conducted a proliferation assay and cell-cycle analysis in ANXA10 knockdown cells in vitro. We evaluated the correlation between the ANXA10 expression status in 100 primary OSCCs and the clinicopathological features by immunohistochemistry. ANXA10 mRNA and protein expression levels were up-regulated in all cellular lines examined (n = 7, p<0.05). ANXA10 knockdown cells showed that cellular proliferation decreased by inactivation of extracellular regulated kinase (ERK) (p<0.05), and cell-cycle arrest at the G1 phase resulted from up regulation of cyclin-dependent kinase inhibitors. ANXA10 protein expression in primary OSCCs was also significantly greater than in normal counterparts (p<0.05), and higher expression was correlated with tumoral size (p = 0.027). CONCLUSIONS/SIGNIFICANCE: Our results proposed for the first time that ANXA10 is an indicator of cellular proliferation in OSCCs. Our results suggested that ANXA10 expression might indicate cellular proliferation and ANXA10 might be a potential therapeutic target for the development of new treatments for OSCCs. PMID- 23029063 TI - A national case-control study identifies human socio-economic status and activities as risk factors for tick-borne encephalitis in Poland. AB - BACKGROUND: Tick-borne encephalitis (TBE) is endemic to Europe and medically highly significant. This study, focused on Poland, investigated individual risk factors for TBE symptomatic infection. METHODS AND FINDINGS: In a nation-wide population-based case-control study, of the 351 TBE cases reported to local health departments in Poland in 2009, 178 were included in the analysis. For controls, of 2704 subjects (matched to cases by age, sex, district of residence) selected at random from the national population register, two were interviewed for each case and a total of 327 were suitable for the analysis. Questionnaires yielded information on potential exposure to ticks during the six weeks (maximum incubation period) preceding disease onset in each case. Independent associations between disease and socio-economic factors and occupational or recreational exposure were assessed by conditional logistic regression, stratified according to residence in known endemic and non-endemic areas. Adjusted population attributable fractions (PAF) were computed for significant variables. In endemic areas, highest TBE risk was associated with spending >=10 hours/week in mixed forests and harvesting forest foods (adjusted odds ratio 19.19 [95% CI: 1.72 214.32]; PAF 0.127 [0.064-0.193]), being unemployed (11.51 [2.84-46.59]; 0.109 [0.046-0.174]), or employed as a forester (8.96 [1.58-50.77]; 0.053 [0.011 0.100]) or non-specialized worker (5.39 [2.21-13.16]; 0.202 [0.090-0.282]). Other activities (swimming, camping and travel to non-endemic regions) reduced risk. Outside TBE endemic areas, risk was greater for those who spent >=10 hours/week on recreation in mixed forests (7.18 [1.90-27.08]; 0.191 [0.065-0.304]) and visited known TBE endemic areas (4.65 [0.59-36.50]; 0.058 [-0.007-0.144]), while travel to other non-endemic areas reduced risk. CONCLUSIONS: These socio-economic factors and associated human activities identified as risk factors for symptomatic TBE in Poland are consistent with results from previous correlational studies across eastern Europe, and allow public health interventions to be targeted at particularly vulnerable sections of the population. PMID- 23029064 TI - Transcriptional regulation of flotillins by the extracellularly regulated kinases and retinoid X receptor complexes. AB - Flotillin-1 and flotillin-2 are important regulators of signal transduction pathways such as growth factor signaling. Flotillin expression is increased under pathological conditions such as neurodegenerative disorders and cancer. Despite their importance for signal transduction, very little is known about the transcriptional regulation of flotillins. Here, we analyzed the expression of flotillins at transcriptional level and identified flotillins as downstream targets of the mitogen activated kinases ERK1/2. The promoter activity of flotillins was increased upon growth factor stimulation in a MAPK dependent manner. Overexpression of serum response factor or early growth response gene 1 resulted in increased flotillin mRNA and protein expression. Furthermore, both promoter activity and expression of endogenous flotillins were increased upon treatment with retinoic acid or by overexpression of the retinoid X receptor and its binding partners RARalpha and PPARgamma. Our data indicate that the expression of flotillins, which can be detected in all cultured cells, is fine tuned in response to various external stimuli. This regulation may be critical for the outcome of signaling cascades in which flotillins are known to be involved. PMID- 23029065 TI - A 10-year analysis of the effects of media coverage of regulatory warnings on antidepressant use in The Netherlands and UK. AB - BACKGROUND: In 2003-2004 and 2007-2008, the regulatory banning of SSRI use in pediatrics and young adults due to concerns regarding suicidality risk coincided with negative media coverage. SSRI use trends were analyzed from 2000-2010 in the Netherlands (NL) and the UK, and whether trend changes might be associated with media coverage of regulatory warnings. METHODS: Monthly SSRIs sales were presented as DDDs/1000 inhabitants/day. SSRI-use trends were studied using time series segmented regression analyses. Timing of trend changes was compared with two periods of media coverage of warnings. Annual Dutch SSRI prescription data were analyzed by age group. RESULTS: Trend changes in SSRI use largely corroborated with the periods of media coverage of warnings. British SSRI use declined from 3.9 to 0.7 DDDs/month (95%CI 3.3;4.5 & 0.5;0.9, respectively) before the first warning period (2003-2004). A small decrease of -0.6 DDDs/month (-1.2; -0.05) was observed in Dutch SSRI use shortly after 2003-2004. From 2007 2008, British SSRI use stabilized, whilst Dutch SSRI use diminished to -0.04 DDDs/month (-0.4;0.3). Stratified analyses showed a rapid decrease of -1.2 DDDs/month (-2.1; -1.7) in UK paroxetine use before 2003-2004, but only a minimal change in Dutch paroxetine use (-0.3 DDDs/month -0.8;0.2). Other SSRI use, especially (es)citalopram, increased during 2003-2004 in both countries. Significant reductions in Dutch paroxetine use were observed in pediatrics, adolescents, and young adults after 2003-2004. CONCLUSION: Changes in SSRI use (NL & UK) were associated with the timing of the combined effect of media coverage and regulatory warnings. Our long-term assessment illustrates that changes in SSRI use were temporal, drug-specific and more pronounced in pediatrics and young adults. The twofold increase in SSRI use over one decade indicates that regulatory warnings and media coverage may come and go, but they do not have a significant impact on the overall upward trend of SSRI use as a class in both countries. PMID- 23029066 TI - Recovered patients with Stevens-Johson syndrome and toxic epidermal necrolysis maintain long-lived IFN-gamma and sFasL memory response. AB - There is evidence that drug-specific T cells are involved in inducing keratinocyte apoptosis in acute stage of Steven-Johson syndrome (SJS) and Toxic epidermal necrolysis (TEN). However, there are few studies that have attempted to examine T cell memory responses over time. We sought to determine the duration of IFN-gamma and sFasL memory response to causal drugs in patients with SJS and TEN after remission. Eight patients with previous SJS and TEN were enrolled. Memory T cells were measured by 10-day cultured IFN-gamma enzyme-linked immunosorbent spot forming cell (ELISpot) assay. Effector T-cell responses were measured by ex vivo IFN-gamma ELISpot assay and sFasL ELISA. The sFasL-mediated toxicities of drug stimulated PBMC supernatants against keratinocyte line were further investigated by MTT proliferation assay and Annexin-V staining. We observed significant cultured and ex vivo IFN-gamma ELISpot responses against causal drugs in all 8 patients. In addition, the sFasL levels were specifically increased in the supernatant of PBMCs cultured with causal drugs from 6 of 8 patients. Drug stimulated PBMC supernatants were cytotoxic against keratinocyte line, which was inhibited by anti-FasL mAb in a dose-dependent manner. Our findings confirmed that drug-specific IFN-gamma and sFasL memory response against causal drugs could be sustained over several years and further suggest that patients should avoid causal drug re-exposure after the recovery of TEN and SJS. PMID- 23029067 TI - Isolation and characterization of multipotential mesenchymal cells from the mouse synovium. AB - The human synovium contains mesenchymal stem cells (MSCs), which are multipotential non-hematopoietic progenitor cells that can differentiate into a variety of mesenchymal lineages and they may therefore be a candidate cell source for tissue repair. However, the molecular mechanisms by which this can occur are still largely unknown. Mouse primary cell culture enables us to investigate the molecular mechanisms underlying various phenomena because it allows for relatively easy gene manipulation, which is indispensable for the molecular analysis. However, mouse synovial mesenchymal cells (SMCs) have not been established, although rabbit, cow, and rat SMCs are available, in addition to human MSCs. The aim of this study was to establish methods to harvest the synovium and to isolate and culture primary SMCs from mice. As the mouse SMCs were not able to be harvested and isolated using the same protocol for human, rat and rabbit SMCs, the protocol for humans was modified for SMCs from the Balb/c mouse knee joint. The mouse SMCs obtained showed superior proliferative potential, growth kinetics and colony formation compared to cells derived from muscle and bone marrow. They expressed PDGFRa and Sca-1 detected by flow cytometry, and showed an osteogenic, adipogenic and chondrogenic potential similar or superior to the cells derived from muscle and bone marrow by demonstrating in vitro osteogenesis, adipogenesis and chondrogenesis. In conclusion, we established a primary mouse synovial cell culture method. The cells derived from the mouse synovium demonstrated both the ability to proliferate and multipotentiality similar or superior to the cells derived from muscle and bone marrow. PMID- 23029068 TI - A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland. AB - Glucocorticoids produced in the adrenal cortex under the control of the hypothalamic-pituitary axis play a vital role in the maintenance of basal and stress-related homeostasis and influence health and well-being. To identify loci affecting regulation of the hypothalamic-pituitary-adrenal (HPA) axis in the pig we performed a genome-wide association study for two parameters of acute and long term adrenal activity: plasma cortisol level and adrenal weight. We detected a major quantitative trait locus at the position of the glucocorticoid receptor gene (NR3C1) - a key regulator of HPA axis activity. To determine the causal variant(s), we resequenced the coding region of NR3C1 and found three missense single nucleotide polymorphisms (SNPs). SNP c.1829C>T, leading to a p.Ala610Val substitution in the ligand binding domain, showed large (about 0.6* and 1.2* phenotypic standard deviations for cortisol level and adrenal weight, respectively), and highly significant (2.1E-39<=log10(1/p)<=1.7E+0) negative effects on both traits. We were able to replicate the association in three commercial pig populations with different breed origins. We analyzed effects of the p.Ala610Val substitution on glucocorticoid-induced transcriptional activity of porcine glucocorticoid receptor (GR) in vitro and determined that the substitution introduced by SNP c.1829C>T increased sensitivity of GR by about two fold. Finally, we found that non-coding polymorphisms in linkage disequilibrium with SNP c.1829C>T have only a minor effect on the expression of NR3C1 in tissues related to the HPA axis. Our findings provide compelling evidence that SNP c.1829C>T in porcine NR3C1 is a gain-of-function mutation with a major effect on the activity of the adrenal gland. Pigs carrying this SNP could provide a new animal model to study neurobiological and physiological consequences of genetically based GR hypersensitivity and adrenal hypofunction. PMID- 23029069 TI - High-density SNP genotyping of tomato (Solanum lycopersicum L.) reveals patterns of genetic variation due to breeding. AB - The effects of selection on genome variation were investigated and visualized in tomato using a high-density single nucleotide polymorphism (SNP) array. 7,720 SNPs were genotyped on a collection of 426 tomato accessions (410 inbreds and 16 hybrids) and over 97% of the markers were polymorphic in the entire collection. Principal component analysis (PCA) and pairwise estimates of F(st) supported that the inbred accessions represented seven sub-populations including processing, large-fruited fresh market, large-fruited vintage, cultivated cherry, landrace, wild cherry, and S. pimpinellifolium. Further divisions were found within both the contemporary processing and fresh market sub-populations. These sub populations showed higher levels of genetic diversity relative to the vintage sub population. The array provided a large number of polymorphic SNP markers across each sub-population, ranging from 3,159 in the vintage accessions to 6,234 in the cultivated cherry accessions. Visualization of minor allele frequency revealed regions of the genome that distinguished three representative sub-populations of cultivated tomato (processing, fresh market, and vintage), particularly on chromosomes 2, 4, 5, 6, and 11. The PCA loadings and F(st) outlier analysis between these three sub-populations identified a large number of candidate loci under positive selection on chromosomes 4, 5, and 11. The extent of linkage disequilibrium (LD) was examined within each chromosome for these sub populations. LD decay varied between chromosomes and sub-populations, with large differences reflective of breeding history. For example, on chromosome 11, decay occurred over 0.8 cM for processing accessions and over 19.7 cM for fresh market accessions. The observed SNP variation and LD decay suggest that different patterns of genetic variation in cultivated tomato are due to introgression from wild species and selection for market specialization. PMID- 23029070 TI - Identification of early biomarkers during acetaminophen-induced hepatotoxicity by fourier transform infrared microspectroscopy. AB - Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/-) mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfalpha and Ifngamma in sera are not significantly affected, Nos2(-/-) mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases. PMID- 23029071 TI - Neural correlates of processing negative and sexually arousing pictures. AB - Recent work has questioned whether the negativity bias is a distinct component of affective picture processing. The current study was designed to determine whether there are different neural correlates of processing positive and negative pictures using event-related brain potentials. The early posterior negativity and late positive potential were greatest in amplitude for erotic pictures. Partial Least Squares analysis revealed one latent variable that distinguished erotic pictures from neutral and positive pictures and another that differentiated negative pictures from neutral and positive pictures. The effects of orienting task on the neural correlates of processing negative and erotic pictures indicate that affective picture processing is sensitive to both stimulus-driven, and attentional or decision processes. The current data, together with other recent findings from our laboratory, lead to the suggestion that there are distinct neural correlates of processing negative and positive stimuli during affective picture processing. PMID- 23029072 TI - Evolutionary history of assassin bugs (insecta: hemiptera: Reduviidae): insights from divergence dating and ancestral state reconstruction. AB - Assassin bugs are one of the most successful clades of predatory animals based on their species numbers (~6,800 spp.) and wide distribution in terrestrial ecosystems. Various novel prey capture strategies and remarkable prey specializations contribute to their appeal as a model to study evolutionary pathways involved in predation. Here, we reconstruct the most comprehensive reduviid phylogeny (178 taxa, 18 subfamilies) to date based on molecular data (5 markers). This phylogeny tests current hypotheses on reduviid relationships emphasizing the polyphyletic Reduviinae and the blood-feeding, disease-vectoring Triatominae, and allows us, for the first time in assassin bugs, to reconstruct ancestral states of prey associations and microhabitats. Using a fossil calibrated molecular tree, we estimated divergence times for key events in the evolutionary history of Reduviidae. Our results indicate that the polyphyletic Reduviinae fall into 11-14 separate clades. Triatominae are paraphyletic with respect to the reduviine genus Opisthacidius in the maximum likelihood analyses; this result is in contrast to prior hypotheses that found Triatominae to be monophyletic or polyphyletic and may be due to the more comprehensive taxon and character sampling in this study. The evolution of blood-feeding may thus have occurred once or twice independently among predatory assassin bugs. All prey specialists evolved from generalist ancestors, with multiple evolutionary origins of termite and ant specializations. A bark-associated life style on tree trunks is ancestral for most of the lineages of Higher Reduviidae; living on foliage has evolved at least six times independently. Reduviidae originated in the Middle Jurassic (178 Ma), but significant lineage diversification only began in the Late Cretaceous (97 Ma). The integration of molecular phylogenetics with fossil and life history data as presented in this paper provides insights into the evolutionary history of reduviids and clears the way for in-depth evolutionary hypothesis testing in one of the most speciose clades of predators. PMID- 23029073 TI - Detection of S-nitrosothiol and nitrosylated proteins in Arachis hypogaea functional nodule: response of the nitrogen fixing symbiont. AB - To detect the presence of NO, ROS and RNS in nodules of crack entry legumes, we used Arachis hypogaea functional nodule. The response of two cognate partner rhizobia was compared towards NO and GSNO using S. meliloti and Bradyrhizobium sp NC921001. ROS, NO, nitrosothiol and bacteroids were detected by fluorescence microscopy. Redox enzymes and thiol pools were detected biochemically. Nitrosothiols were found to be present but ROS and NO were absent in A. hypogaea nodule. A number of S-nitrosylated proteins were also detected. The total thiol pool and most of the redox enzymes were low in nodule cytosolic extract but these were found to be high in the partner microorganisms indicating partner rhizobia could protect the nodule environment against the nitrosothiols. Both S. meliloti and Bradyrhizobium sp NC921001 were found to contain GSNO reductase. Interestingly, there was a marked difference in growth pattern between S. meliloti and Bradyrhizobium sp in presence of sodium nitroprusside (SNP) and S nitrosoglutathione (GSNO). Bradyrhizobium sp was found to be much more tolerant to NO donor compounds than the S. meliloti. In contrast, S. meliloti showed resistance to GSNO but was sensitive to SNP. Together our data indicate that nodule environment of crack entry legumes is different than the nodules of infection mode entry in terms of NO, ROS and RNS. Based on our biochemical characterization, we propose that exchange of redox molecules and reactive chemical species is possible between the bacteroid and nodule compartment. PMID- 23029074 TI - Puerarin suppresses proliferation of endometriotic stromal cells partly via the MAPK signaling pathway induced by 17beta-estradiol-BSA. AB - BACKGROUND: Puerarin is a major isoflavonoid compound extracted from Radix puerariae. It has a weak estrogenic action by binding to estrogen receptors (ERs). In our early clinical practice to treat endometriosis, a better therapeutic effect was achieved if the formula of traditional Chinese medicine included Radix puerariae. The genomic and non-genomic effects of puerarin were studied in our Lab. This study aims to investigate the ability of puerarin to bind competitively to ERs in human endometriotic stromal cells (ESCs), determine whether and how puerarin may influence phosphorylation of the non-genomic signaling pathway induced by 17beta-estradiol conjugated to BSA (E(2)-BSA). METHODOLOGY: ESCs were successfully established. Binding of puerarin to ERs was assessed by a radioactive competitive binding assay in ESCs. Activation of the signaling pathway was screened by human phospho-kinase array, and was further confirmed by western blot. Cell proliferation was analyzed according to the protocol of CCK-8. The mRNA and protein levels of cyclin D1, Cox-2 and Cyp19 were determined by real-time PCR and western blotting. Inhibitor of MEK1/2 or ER antagonist was used to confirm the involved signal pathway. PRINCIPAL FINDINGS: Our data demonstrated that the total binding ability of puerarin to ERs on viable cells is around 1/3 that of 17beta-estradiol (E(2)). E(2)-BSA was able to trigger a rapid, non-genomic, membrane-mediated activation of ERK1/2 in ESCs and this phenomenon was associated with an increased proliferation of ESCs. Treating ESCs with puerarin abrogated the phosphorylation of ERK and significantly decreased cell proliferation, as well as related gene expression levels enhanced by E(2) BSA. CONCLUSIONS/SIGNIFICANCE: Puerarin suppresses proliferation of ESCs induced by E(2)-BSA partly via impeding a rapid, non-genomic, membrane-initiated ERK pathway, and down-regulation of Cyclin D1, Cox-2 and Cyp19 are involved in the process. Our data further show that puerarin may be a new candidate to treat endometriosis. PMID- 23029075 TI - Cannabinoids inhibit acid-sensing ion channel currents in rat dorsal root ganglion neurons. AB - Local acidosis has been found in various pain-generating conditions such as inflammation and tissue injury. Cannabinoids exert a powerful inhibitory control over pain initiation via peripheral cognate receptors. However, the peripheral molecular targets responsible for the antinociceptive effects of cannabinoids are still poorly understood. Here, we have found that WIN55,212-2, a cannabinoid receptor agonist, inhibits the activity of native acid-sensing ion channels (ASICs) in rat dorsal root ganglion (DRG) neurons. WIN55,212-2 dose-dependently inhibited proton-gated currents mediated by ASICs. WIN55,212-2 shifted the proton concentration-response curve downwards, with an decrease of 48.6+/-3.7% in the maximum current response but with no significant change in the EC(50) value. The inhibition of proton-gated current induced by WIN55,212-2 was almost completely blocked by the selective CB1 receptor antagonist AM 281, but not by the CB2 receptor antagonist AM630. Pretreatment of forskolin, an AC activator, and the addition of cAMP also reversed the inhibition of WIN55,212-2. Moreover, WIN55,212 2 altered acid-evoked excitability of rat DRG neurons and decreased the number of action potentials induced by acid stimuli. Finally, WIN55,212-2 attenuated nociceptive responses to injection of acetic acid in rats. These results suggest that WIN55,212-2 inhibits the activity of ASICs via CB1 receptor and cAMP dependent pathway in rat primary sensory neurons. Thus, cannabinoids can exert their analgesic action by interaction with ASICs in the primary afferent neurons, which was novel analgesic mechanism of cannabinoids. PMID- 23029076 TI - Association between human prothrombin variant (T165M) and kidney stone disease. AB - We previously reported the association between prothrombin (F2), encoding a stone inhibitor protein - urinary prothrombin fragment 1 (UPTF1), and the risk of kidney stone disease in Northeastern Thai patients. To identify specific F2 variation responsible for the kidney stone risk, we conducted sequencing analysis of this gene in a group of the patients with kidney stone disease. Five intronic SNPs (rs2070850, rs2070852, rs1799867, rs2282687, and rs3136516) and one exonic non-synonymous single nucleotide polymorphism (nsSNP; rs5896) were found. The five intronic SNPs have no functional change as predicted by computer programs while the nsSNP rs5896 (c.494 C>T) located in exon 6 results in a substitution of threonine (T) by methionine (M) at the position 165 (T165M). The nsSNP rs5896 was subsequently genotyped in 209 patients and 216 control subjects. Genotypic and allelic frequencies of this nsSNP were analyzed for their association with kidney stone disease. The frequency of CC genotype of rs5896 was significantly lower in the patient group (13.4%) than that in the control group (22.2%) (P = 0.017, OR 0.54, 95% CI 0.32-0.90), and the frequency of C allele was significantly lower in the patient group (36.1%) than that in the control group (45.6%) (P = 0.005, OR 0.68, 95% CI 0.51-0.89). The significant differences of genotype and allele frequencies were maintained only in the female group (P = 0.033 and 0.003, respectively). The effect of amino-acid change on UPTF1 structure was also examined by homologous modeling and in silico mutagenesis. T165 is conserved and T165M substitution will affect hydrogen bond formation with E180. In conclusion, our results indicate that prothrombin variant (T165M) is associated with kidney stone risk in the Northeastern Thai female patients. PMID- 23029077 TI - MAGEB2 is activated by promoter demethylation in head and neck squamous cell carcinoma. AB - PURPOSE: Although promoter hypermethylation has been an accepted means of tumor suppressor gene inactivation, activation of otherwise normally repressed proto oncogenes by promoter demethylation has been infrequently documented. EXPERIMENTAL DESIGN: In this study we performed an integrative, whole-genome analysis for discovery of epigenetically activated proto-oncogenes in head and neck cancer tumors. We used the 47K GeneChip U133 Plus 2.0 Affymetrix expression microarray platform to obtain re-expression data from 5-aza treated normal cell line and expression data from primary head and neck squamous cell carcinoma (HNSCC) tumor tissues and normal mucosa tissues. We then investigated candidate genes by screening promoter regions for CpG islands and bisulfite sequencing followed by QUMSP and RT PCR for the best candidate genes. Finally, functional studies were performed on the top candidate gene. RESULTS: From the top 178 screened candidates 96 had CpG islands in their promoter region. Seven candidate genes showed promoter region methylation in normal mucosa samples and promoter demethylation in a small cohort of primary HNSCC tissues. We then studied the demethylation of the top 3 candidate genes in an expanded cohort of 76 HNSCC tissue samples and 17 normal mucosa samples. We identified MAGEB2 as having significant promoter demethylation in primary head and neck squamous cell carcinoma tissues. We then found significantly higher expression of MAGEB2 in tumors in a separate cohort of 73 primary HNSCC tissues and 31 normal tissues. Finally, we found that MAGEB2 has growth promoting effects on minimally transformed oral keratinocyte cell lines but not a definite effect on HNSCC cell lines. CONCLUSION: In conclusion, we identified MAGEB2 as activated by promoter demethylation in HNSCCand demonstrates growth promoting effects in a minimally transformed oral keratinocyte cell line. More studies are needed to evaluate MAGBE2's exact role in HNSCC. PMID- 23029078 TI - Unveiling clusters of RNA transcript pairs associated with markers of Alzheimer's disease progression. AB - BACKGROUND: One primary goal of transcriptomic studies is identifying gene expression patterns correlating with disease progression. This is usually achieved by considering transcripts that independently pass an arbitrary threshold (e.g. p<0.05). In diseases involving severe perturbations of multiple molecular systems, such as Alzheimer's disease (AD), this univariate approach often results in a large list of seemingly unrelated transcripts. We utilised a powerful multivariate clustering approach to identify clusters of RNA biomarkers strongly associated with markers of AD progression. We discuss the value of considering pairs of transcripts which, in contrast to individual transcripts, helps avoid natural human transcriptome variation that can overshadow disease related changes. METHODOLOGY/PRINCIPAL FINDINGS: We re-analysed a dataset of hippocampal transcript levels in nine controls and 22 patients with varying degrees of AD. A large-scale clustering approach determined groups of transcript probe sets that correlate strongly with measures of AD progression, including both clinical and neuropathological measures and quantifiers of the characteristic transcriptome shift from control to severe AD. This enabled identification of restricted groups of highly correlated probe sets from an initial list of 1,372 previously published by our group. We repeated this analysis on an expanded dataset that included all pair-wise combinations of the 1,372 probe sets. As clustering of this massive dataset is unfeasible using standard computational tools, we adapted and re-implemented a clustering algorithm that uses external memory algorithmic approach. This identified various pairs that strongly correlated with markers of AD progression and highlighted important biological pathways potentially involved in AD pathogenesis. CONCLUSIONS/SIGNIFICANCE: Our analyses demonstrate that, although there exists a relatively large molecular signature of AD progression, only a small number of transcripts recurrently cluster with different markers of AD progression. Furthermore, considering the relationship between two transcripts can highlight important biological relationships that are missed when considering either transcript in isolation. PMID- 23029079 TI - Only low frequency event-related EEG activity is compromised in multiple sclerosis: insights from an independent component clustering analysis. AB - Cognitive impairment (CI), often examined with neuropsychological tests such as the Paced Auditory Serial Addition Test (PASAT), affects approximately 65% of multiple sclerosis (MS) patients. The P3b event-related potential (ERP), evoked when an infrequent target stimulus is presented, indexes cognitive function and is typically compared across subjects' scalp electroencephalography (EEG) data. However, the clustering of independent components (ICs) is superior to scalp based EEG methods because it can accommodate the spatiotemporal overlap inherent in scalp EEG data. Event-related spectral perturbations (ERSPs; event-related mean power spectral changes) and inter-trial coherence (ITCs; event-related consistency of spectral phase) reveal a more comprehensive overview of EEG activity. Ninety-five subjects (56 MS patients, 39 controls) completed visual and auditory two-stimulus P3b event-related potential tasks and the PASAT. MS patients were also divided into CI and non-CI groups (n = 18 in each) based on PASAT scores. Data were recorded from 128-scalp EEG channels and 4 IC clusters in the visual, and 5 IC clusters in the auditory, modality were identified. In general, MS patients had significantly reduced ERSP theta power versus controls, and a similar pattern was observed for CI vs. non-CI MS patients. The ITC measures were also significantly different in the theta band for some clusters. The finding that MS patients had reduced P3b task-related theta power in both modalities is a reflection of compromised connectivity, likely due to demyelination, that may have disrupted early processes essential to P3b generation, such as orientating and signal detection. However, for posterior sources, MS patients had a greater decrease in alpha power, normally associated with enhanced cognitive function, which may reflect a compensatory mechanism in response to the compromised early cognitive processing. PMID- 23029080 TI - Pristine Early Eocene wood buried deeply in kimberlite from northern Canada. AB - We report exceptional preservation of fossil wood buried deeply in a kimberlite pipe that intruded northwestern Canada's Slave Province 53.3+/-0.6 million years ago (Ma), revealed during excavation of diamond source rock. The wood originated from forest surrounding the eruption zone and collapsed into the diatreme before resettling in volcaniclastic kimberlite to depths >300 m, where it was mummified in a sterile environment. Anatomy of the unpermineralized wood permits conclusive identification to the genus Metasequoia (Cupressaceae). The wood yields genuine cellulose and occluded amber, both of which have been characterized spectroscopically and isotopically. From cellulose delta(18)O and delta(2)H measurements, we infer that Early Eocene paleoclimates in the western Canadian subarctic were 12-17 degrees C warmer and four times wetter than present. Canadian kimberlites offer Lagerstatte-quality preservation of wood from a region with limited alternate sources of paleobotanical information. PMID- 23029081 TI - Myogenic potential of whole bone marrow mesenchymal stem cells in vitro and in vivo for usage in urinary incontinence. AB - Urinary incontinence, defined as the complaint of any involuntary loss of urine, is a pathological condition, which affects 30% females and 15% males over 60, often following a progressive decrease of rhabdosphincter cells due to increasing age or secondary to damage to the pelvic floor musculature, connective tissue and/or nerves. Recently, stem cell therapy has been proposed as a source for cell replacement and for trophic support to the sphincter. To develop new therapeutic strategies for urinary incontinence, we studied the interaction between mesenchymal stem cells (MSCs) and muscle cells in vitro; thereafter, aiming at a clinical usage, we analyzed the supporting role of MSCs for muscle cells in vitro and in in vivo xenotransplantation. MSCs can express markers of the myogenic cell lineages and give rise, under specific cell culture conditions, to myotube-like structures. Nevertheless, we failed to obtain mixed myotubes both in vitro and in vivo. For in vivo transplantation, we tested a new protocol to collect human MSCs from whole bone marrow, to get larger numbers of cells. MSCs, when transplanted into the pelvic muscles close to the external urethral sphincter, survived for a long time in absence of immunosuppression, and migrated into the muscle among fibers, and towards neuromuscular endplates. Moreover, they showed low levels of cycling cells, and did not infiltrate blood vessels. We never observed formation of cell masses suggestive of tumorigenesis. Those which remained close to the injection site showed an immature phenotype, whereas those in the muscle had more elongated morphologies. Therefore, MSCs are safe and can be easily transplanted without risk of side effects in the pelvic muscles. Further studies are needed to elucidate their integration into muscle fibers, and to promote their muscular transdifferentiation either before or after transplantation. PMID- 23029082 TI - The dynamics of natural Plasmodium falciparum infections. AB - BACKGROUND: Natural immunity to Plasmodium falciparum has been widely studied, but its effects on parasite dynamics are poorly understood. Acquisition and clearance rates of untreated infections are key elements of the dynamics of malaria, but estimating these parameters is challenging because of frequent super infection and imperfect detectability of parasites. Consequently, information on effects of host immune status or age on infection dynamics is fragmentary. METHODS: An age-stratified cohort of 347 individuals from Northern Ghana was sampled six times at 2 month intervals. High-throughput capillary electrophoresis was used to genotype the msp-2 locus of all P. falciparum infections detected by PCR. Force of infection (FOI) and duration were estimated for each age group using an immigration-death model that allows for imperfect detection of circulating parasites. RESULTS: Allowing for imperfect detection substantially increased estimates of FOI and duration. Effects of naturally acquired immunity on the FOI and duration would be reflected in age dependence in these indices, but in our cohort data FOI tended to increase with age in children. Persistence of individual parasite clones was characteristic of all age-groups. Duration peaked in 5-9 year old children (average duration 319 days, 95% confidence interval 318;320). CONCLUSIONS: The main age-dependence is on parasite densities, with only small age-variations in the FOI and persistence of infections. This supports the hypothesis that acquired immunity controls transmission mainly by limiting blood-stage parasite densities rather than changing rates of acquisition or clearance of infections. PMID- 23029083 TI - Diversity among macroalgae-consuming fishes on coral reefs: a transcontinental comparison. AB - Despite high diversity and abundance of nominally herbivorous fishes on coral reefs, recent studies indicate that only a small subset of taxa are capable of removing dominant macroalgae once these become established. This limited functional redundancy highlights the potential vulnerability of coral reefs to disturbance and stresses the need to assess the functional role of individual species of herbivores. However, our knowledge of species-specific patterns in macroalgal consumption is limited geographically, and there is a need to determine the extent to which patterns observed in specific reefs can be generalised at larger spatial scales. In this study, video cameras were used to quantify rates of macroalgae consumption by fishes in two coral reefs located at a similar latitude in opposite sides of Australia: the Keppel Islands in the Great Barrier Reef (eastern coast) and Ningaloo Reef (western coast). The community of nominally herbivorous fish was also characterised in both systems to determine whether potential differences in the species observed feeding on macroalgae were related to spatial dissimilarities in herbivore community composition. The total number of species observed biting on the dominant brown alga Sargassum myriocystum differed dramatically among the two systems, with 23 species feeding in Ningaloo, compared with just 8 in the Keppel Islands. Strong differences were also found in the species composition and total biomass of nominally herbivorous fish, which was an order of magnitude higher in Ningaloo. However, despite such marked differences in the diversity, biomass, and community composition of resident herbivorous fishes, Sargassum consumption was dominated by only four species in both systems, with Naso unicornis and Kyphosus vaigiensis consistently emerging as dominant feeders of macroalgae. PMID- 23029084 TI - Sunlight effects on the Osmotrophic uptake of DMSP-sulfur and leucine by polar phytoplankton. AB - Even though the uptake and assimilation of organic compounds by phytoplankton has been long recognized, very little is still known about its potential ecological role in natural marine communities and whether it varies depending on the light regimes the algae experience. We combined measurements of size-fractionated assimilation of trace additions of (3)H-leucine and (35)S dimethylsulfoniopropionate (DMSP) with microautoradiography to assess the extent and relevance of osmoheterotrophy in summer phytoplankton assemblages from Arctic and Antarctic waters, and the role of solar radiation on it was further investigated by exposing samples to different radiation spectra. Significant assimilation of both substrates occurred in the size fraction containing most phytoplankton (>5 um), sunlight exposure generally increasing (35)S-DMSP-sulfur assimilation and decreasing (3)H-leucine assimilation. Microautoradiography revealed that the capacity to take up both organic substrates seemed widespread among different polar algal phyla, particularly in pennate and centric diatoms, and photosynthetic dinoflagellates. Image analysis of the microautoradiograms showed for the first time interspecific variability in the uptakes of (35)S-DMSP and (3)H-leucine by phytoplankton depending on the solar spectrum. Overall, these results suggest that the role of polar phytoplankton in the utilization of labile dissolved organic matter may be significant under certain conditions and further confirm the relevance of solar radiation in regulating heterotrophy in the pelagic ocean. PMID- 23029085 TI - Keratinocyte-targeted expression of human laminin gamma2 rescues skin blistering and early lethality of laminin gamma2 deficient mice. AB - Laminin-332 is a heterotrimeric basement membrane component comprised of the alpha3, beta3, and gamma2 laminin chains. Laminin-332 modulates epithelial cell processes, such as adhesion, migration, and differentiation and is prominent in many embryonic and adult tissues. In skin, laminin-332 is secreted by keratinocytes and is a key component of hemidesmosomes connecting the keratinocytes to the underlying dermis. In mice, lack of expression of any of the three Laminin-332 chains result in impaired anchorage and detachment of the epidermis, similar to that seen in human junctional epidermolysis bullosa, and death occurs within a few days after birth. To bypass the early lethality of laminin-332 deficiency caused by the knockout of the mouse laminin gamma2 chain, we expressed a dox-controllable human laminin gamma2 transgene under a keratinocyte-specific promoter on the laminin gamma2 (Lamc2) knockout background. These mice appear similar to their wild-type littermates, do not develop skin blisters, are fertile, and survive >1.5 years. Immunofluorescence analyses of the skin showed that human laminin gamma2 colocalized with mouse laminin alpha3 and beta3 in the basement membrane zone underlying the epidermis. Furthermore, the presence of "humanized" laminin-332 in the epidermal basement membrane zone rescued the alterations in the deposition of hemidesmosomal components, such as plectin, collagen type XVII/BP180, and integrin alpha6 and beta4 chains, seen in conventional Lamc2 knockout mice, leading to restored formation of hemidesmosomes. These mice will be a valuable tool for studies of organs deficient in laminin-332 and the role of laminin-332 in skin, including wound healing. PMID- 23029086 TI - The influence of sulphate deposition on the seasonal variation of peat pore water methyl Hg in a boreal mire. AB - In this paper we investigate the hypothesis that long-term sulphate (SO(4) (2-)) deposition has made peatlands a larger source of methyl mercury (MeHg) to remote boreal lakes. This was done on experimental plots at a boreal, low sedge mire where the effect of long-term addition of SO(4) (2-) on peat pore water MeHg concentrations was observed weekly throughout the snow-free portion of 1999. The additions of SO(4) (2-) started in 1995. The seasonal mean of the pore water MeHg concentrations on the plots with 17 kg ha(-1) yr(-1) of sulphur (S) addition (1.3+/-0.08 ng L(-1), SE; n = 44) was significantly (p<0.0001) higher than the mean MeHg concentration on the plots with 3 kg ha(-1) yr(-1) of ambient S deposition (0.6+/-0.02 ng L(-1), SE; n = 44). The temporal variation in pore water MeHg concentrations during the snow free season was larger in the S addition plots, with an amplitude of >2 ng L(-1) compared to +/-0.5 ng L(-1) in the ambient S deposition plots. The concentrations of pore water MeHg in the S addition plots were positively correlated (r(2) = 0.21; p = 0.001) to the groundwater level, with the lowest concentrations of MeHg during the period with the lowest groundwater levels. The pore water MeHg concentrations were not correlated to total Hg, DOC concentration or pH. The results from this study indicate that the persistently higher pore water concentrations of MeHg in the S addition plots are caused by the long-term additions of SO(4) (2-) to the mire surface. Since these waters are an important source of runoff, the results support the hypothesis that SO(4) (2-) deposition has increased the contribution of peatlands to MeHg in downstream aquatic systems. This would mean that the increased deposition of SO(4) (2-) in acid rain has contributed to the modern increase in the MeHg burdens of remote lakes hydrologically connected to peatlands. PMID- 23029087 TI - Post-transplant immunosuppression: regulation of the efflux of allospecific effector T cells from lymphoid tissues. AB - A functional sphingosine-1-phosphate (S1P) receptor antagonist specifically inhibited the egress of activated allospecific T cells from draining popliteal lymph nodes in alloantigen-sensitised mice. The level of S1P receptor 1 (S1PR1) mRNA was similarly reduced 1 and 3 days after mitogenic activation of T cells. However, the response of these cells to the S1PR1-specific agonist SEW2871 was only reduced on the first day after T cell activation with normal receptor mediated Akt-phosphorylation restored by day 3. Longitudinal analysis of CD69 expression showed that almost all T cells expressed this antigen on days 1 and 3 after activation. However, the absolute level of cell-surface expression of CD69 peaked on undivided T cells and was then halved by each of the first 3 cycles of mitosis. CD69-specific small interfering RNA (siRNA) reduced the maximal level of CD69 expression by undivided, mitogen-stimulated T cells. These cells retained their capacity to phosphorylate Akt in response to stimulation with SEW2871. These data show that S1P receptors are involved in controlling the egress of activated T cells from lymph nodes, and that S1PR1 function is regulated by the level of T cell surface CD69. They suggest a potential for augmentation of this process to deplete alloreactive effector cells after organ transplantation. PMID- 23029088 TI - Development of peritoneal tumor-targeting vector by in vivo screening with a random peptide-displaying adenovirus library. AB - The targeting of gene transfer at the cell-entry level is one of the most attractive challenges in vector development. However, attempts to redirect adenovirus vectors to alternative receptors by engineering the capsid-coding region have shown limited success, because the proper targeting ligands on the cells of interest are generally unknown. To overcome this limitation, we have constructed a random peptide library displayed on the adenoviral fiber knob, and have successfully selected targeted vectors by screening the library on cancer cell lines in vitro. The infection of targeted vectors was considered to be mediated by specific receptors on target cells. However, the expression levels and kinds of cell surface receptors may be substantially different between in vitro culture and in vivo tumor tissue. Here, we screened the peptide display adenovirus library in the peritoneal dissemination model of AsPC-1 pancreatic cancer cells. The vector displaying a selected peptide (PFWSGAV) showed higher infectivity in the AsPC-1 peritoneal tumors but not in organs and other peritoneal tumors as compared with a non-targeted vector. Furthermore, the infectivity of the PFWSGAV-displaying vector for AsPC-1 peritoneal tumors was significantly higher than that of a vector displaying a peptide selected by in vitro screening, indicating the usefulness of in vivo screening in exploring the targeting vectors. This vector-screening system can facilitate the development of targeted adenovirus vectors for a variety of applications in medicine. PMID- 23029089 TI - Scaling proprioceptor gene transcription by retrograde NT3 signaling. AB - Cell-type specific intrinsic programs instruct neuronal subpopulations before target-derived factors influence later neuronal maturation. Retrograde neurotrophin signaling controls neuronal survival and maturation of dorsal root ganglion (DRG) sensory neurons, but how these potent signaling pathways intersect with transcriptional programs established at earlier developmental stages remains poorly understood. Here we determine the consequences of genetic alternation of NT3 signaling on genome-wide transcription programs in proprioceptors, an important sensory neuron subpopulation involved in motor reflex behavior. We find that the expression of many proprioceptor-enriched genes is dramatically altered by genetic NT3 elimination, independent of survival-related activities. Combinatorial analysis of gene expression profiles with proprioceptors isolated from mice expressing surplus muscular NT3 identifies an anticorrelated gene set with transcriptional levels scaled in opposite directions. Voluntary running experiments in adult mice further demonstrate the maintenance of transcriptional adjustability of genes expressed by DRG neurons, pointing to life-long gene expression plasticity in sensory neurons. PMID- 23029090 TI - Sheep wool delta13C reveals no effect of grazing on the C3/C4 ratio of vegetation in the inner Mongolia-Mongolia border region grasslands. AB - We tested whether the abundance of C(4) vegetation in grasslands of the Mongolian plateau is influenced by grazing conditions. The analysis exploited the politically originated contrast that exists between Mongolia (low stocking rate, transhumant system) and the district of Inner Mongolia, China (high stocking rate, sedentary system). We estimated the proportion of C(4) carbon (P(C4)) in grazed vegetation from the relative carbon isotope ratio (delta(13)C) of sheep wool sampled from 298 annual shearings originating from 1996 to 2007. Annual stocking rates varying over time and between the districts of both countries were taken from regional statistics. The P(C4) pattern within the 0.7 million km(2) sampling area was geostatistically analyzed and related to stocking rates and temperature gradients. For similar climatic conditions, P(C4) was the same in both countries. Further, a unique relationship was found between P(C4) and July temperature on both sides of the border, which explained 71% of the pattern. Stocking rate and grazing system had no significant influences on present-day C(3)/C(4) abundance ratio. This finding suggests that recent changes in the C(3)/C(4) ratio of these grasslands are mainly a consequence of regional warming, not overgrazing. PMID- 23029091 TI - High prevalence of Beijing and EAI4-VNM genotypes among M. tuberculosis isolates in northern Vietnam: sampling effect, rural and urban disparities. AB - A total of 221 isolates of M. tuberculosis were sampled from hospitals and the general population in the northern plain of Vietnam, one of the most populated region of the country. Genotypic composition and diversity were characterized, and we investigated how they are affected by sampling (hospital vs. general population), correcting for potential confounding effects (location, age and gender of the patients). Spoligotyping and 12 MIRU-VNTR typing were used as first line. Then 15 MIRU-VNTR standard set was used, making 21 MIRU-VNTR typing for the clustered isolates. Result showed that 8 lineages and 13 sub-lineages were circulating in the region. The most predominant lineages were Beijing (38.5%) and EAI (38.5%). Others appeared with small proportions H (1.4%), LAM (1.8%), T (8.1%), X (0.9%), MANU (2.3%), and Zero (0.4%). Higher clustering rate was found in the hospital samples (17.9% in urban and 19.2% in rural areas) compared to the population ones (0%). The typical Vietnamese EAI4-VNM sub-lineage of EAI lineage accounted for 67% of EAI strains and was associated with older ages. Beijing genotypes were associated with younger, urban population and were characterized by high clustering rates. These characteristics strongly suggest that Beijing strains are invading the population, replacing the local EAI-VNM4, thus predicting a more serious tuberculosis situation in the future in the absence of more effective control strategies. PMID- 23029092 TI - Is one sputum specimen as good as two during follow-up cultures for monitoring multi drug resistant tuberculosis patients in India? AB - BACKGROUND: In India, the Revised National Tuberculosis Control Programme (RNTCP) has adopted the strategy of examining two specimens during follow-up culture examinations to monitor the treatment response of multi-drug resistant tuberculosis (MDR-TB) patients. OBJECTIVES: To determine the incremental yield of the second sputum specimen during follow-up culture examinations among patients with MDR-TB and the effect on case management on changing from two to one specimen follow-up strategy. METHODS: A cross sectional record review of MDR-TB patients registered during 2008-09 under RNTCP was undertaken in three MDR-TB treatment sites of India. RESULTS: Of 1721 pairs of follow-up sputum culture examinations done among 220 MDR-TB patients, 451(26%) were positive with either of the two specimens; 29(1.7%) were culture positive only on the second specimen indicating the incremental yield. To detect one additional culture positive result on the second specimen, 59 specimens needed to be processed. If we had examined only one specimen, we would have missed 29 culture-positive results. By current RNTCP guidelines, however, a single specimen policy would have altered case management in only 3(0.2%) instances, where patients would have missed a one month extension of the intensive phase of MDR-TB treatment. There is no meaningful advantage in using two specimens for the monitoring of MDR-TB patients. A single specimen policy could be safely implemented with negligible clinical effect on MDR-TB patients and favourable resource implications for RNTCP. PMID- 23029093 TI - Comparing molecular variation to morphological species designations in the deep sea coral Narella reveals new insights into seamount coral ranges. AB - Recent studies have countered the paradigm of seamount isolation, confounding conservation efforts at a critical time. Efforts to study deep-sea corals, one of the dominant taxa on seamounts, to understand seamount connectivity, are hampered by a lack of taxonomic keys. A prerequisite for connectivity is species overlap. Attempts to better understand species overlap using DNA barcoding methods suggest coral species are widely distributed on seamounts and nearby features. However, no baseline has been established for variation in these genetic markers relative to morphological species designations for deep-sea octocoral families. Here we assess levels of genetic variation in potential octocoral mitochondrial barcode markers relative to thoroughly examined morphological species in the genus Narella. The combination of six markers used here, approximately 3350 bp of the mitochondrial genome, resolved 83% of the morphological species. Our results show that two of the markers, ND2 and NCR1, are not sufficient to resolve genera within Primnoidae, let alone species. Re-evaluation of previous studies of seamount octocorals based on these results suggest that those studies were looking at distributions at a level higher than species, possibly even genus or subfamily. Results for Narella show that using more markers provides haplotypes with relatively narrow depth ranges on the seamounts studied. Given the lack of 100% resolution of species with such a large portion of the mitochondrial genome, we argue that previous genetic studies have not resolved the degree of species overlap on seamounts and that we may not have the power to even test the hypothesis of seamount isolation using mitochondrial markers, let alone refute it. Thus a precautionary approach is advocated in seamount conservation and management, and the potential for depth structuring should be considered. PMID- 23029094 TI - Acceptability of rapid diagnostic test-based management of Malaria among caregivers of under-five children in rural Ghana. AB - INTRODUCTION: WHO now recommends test-based management of malaria (TBMM) across all age-groups. This implies artemisinin-based combination treatment (ACT) should be restricted to rapid diagnostic test (RDT)-positive cases. This is a departure from what caregivers in rural communities have been used to for many years. METHODS: We conducted a survey among caregivers living close to 32 health centres in six districts in rural Ghana and used logistic regression to explore factors likely to influence caregiver acceptability of RDT based case management and concern about the denial of ACT on account of negative RDT results. Focus group discussions were conducted to explain the quantitative findings and to elicit further factors. RESULTS: A total of 3047 caregivers were interviewed. Nearly all (98%) reported a preference for TBMM over presumptive treatment. Caregivers who preferred TBMM were less likely to be concerned about the denial of ACT to their test-negative children (O.R. 0.57, 95%C.I. 0.33-0.98). Compared with caregivers who had never secured national health insurance cover, caregivers who had valid (adjusted O.R. 1.30, 95% CI 1.07-1.61) or expired (adjusted O.R. 1.38, 95% CI 1.12-1.73) insurance cover were more likely to be concerned about the denial of ACT to their RDT-negative children. Major factors that promote TBMM acceptability include the perception that a blood test at health centre level represents improvement in the quality of care, leads to improvement in treatment outcomes, and offers opportunity for better communication between health workers and caregivers. Acceptability is also enhanced by engaging caregivers in the procedures of the test. Apprehensions about negative health worker attitude could however undermine acceptance. CONCLUSION: Test (RDT)-based management of malaria in under-five children is likely to be acceptable to caregivers in rural Ghana. The quality of caregiver-health worker interaction needs to be improved if acceptability is to be sustained. PMID- 23029095 TI - Pharmacogenetic analysis of pediatric patients with acute lymphoblastic leukemia: a possible association between survival rate and ITPA polymorphism. AB - Genetic polymorphisms are important factors in the effects and toxicity of chemotherapeutics. To analyze the pharmacogenetic and ethnic differences in chemotherapeutics, major genes implicated in the treatment of acute lymphoblastic leukemia (ALL) were analyzed. Eighteen loci of 16 genes in 100 patients with ALL were analyzed. The distribution of variant alleles were CYP3A4*1B (0%), CYP3A5*3 (0%), GSTM1 (21%), GSTP1 (21%), GSTT1 (16%), MDR1 exon 21 (77%), MDR1 exon 26 (61%), MTHFR 677 (63%), MTHFR 1298 (29%), NR3C1 1088 (0%), RFC1 80 (68%), TPMT combined genotype (7%), VDR intron 8 (11%), VDR FokI (83%), TYMS enhancer repeat (22%) and ITPA 94 (30%). The frequencies of single nucleotide polymorphisms (SNPs) of 10 loci were statistically different from those in Western Caucasians. Dose percents (actual/planned dose) or toxicity of mercaptopurine and methotrexate were not related to any SNPs. Event free survival (EFS) rate was lower in ITPA variants, and ITPA 94 AC/AA variant genotypes were the only independent risk factor for lower EFS in multivariate analysis, which was a different pharmacogenetic implication from Western studies. This study is the first pharmacogenetic study in Korean pediatric ALL. Our result suggests that there are other possible pharmacogenetic factors besides TPMT or ITPA polymorphisms which influence the metabolism of mercaptopurine in Asian populations. PMID- 23029097 TI - Plasticity of the injured human spinal cord: insights revealed by spinal cord functional MRI. AB - INTRODUCTION: While numerous studies have documented evidence for plasticity of the human brain there is little evidence that the human spinal cord can change after injury. Here, we employ a novel spinal fMRI design where we stimulate normal and abnormal sensory dermatomes in persons with traumatic spinal cord injury and perform a connectivity analysis to understand how spinal networks process information. METHODS: Spinal fMRI data was collected at 3 Tesla at two institutions from 38 individuals using the standard SEEP functional MR imaging techniques. Thermal stimulation was applied to four dermatomes in an interleaved timing pattern during each fMRI acquisition. SCI patients were stimulated in dermatomes both above (normal sensation) and below the level of their injury. Sub group analysis was performed on healthy controls (n = 20), complete SCI (n = 3), incomplete SCI (n = 9) and SCI patients who recovered full function (n = 6). RESULTS: Patients with chronic incomplete SCI, when stimulated in a dermatome of normal sensation, showed an increased number of active voxels relative to controls (p = 0.025). There was an inverse relationship between the degree of sensory impairment and the number of active voxels in the region of the spinal cord corresponding to that dermatome of abnormal sensation (R(2) = 0.93, p<0.001). Lastly, a connectivity analysis demonstrated a significantly increased number of intraspinal connections in incomplete SCI patients relative to controls suggesting altered processing of afferent sensory signals. CONCLUSIONS: In this work we demonstrate the use of spinal fMRI to investigate changes in spinal processing of somatosensory information in the human spinal cord. We provide evidence for plasticity of the human spinal cord after traumatic injury based on an increase in the average number of active voxels in dermatomes of normal sensation in chronic SCI patients and an increased number of intraspinal connections in incomplete SCI patients relative to healthy controls. PMID- 23029096 TI - Decorin protein core affects the global gene expression profile of the tumor microenvironment in a triple-negative orthotopic breast carcinoma xenograft model. AB - Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that decorin protein core modulated the differential expression of 374 genes within the stromal compartment of the tumor xenograft. Further, our top gene ontology classes strongly suggests an unexpected and preferential role for decorin protein core to inhibit genes necessary for immunomodulatory responses while simultaneously inducing expression of those possessing cellular adhesion and tumor suppressive gene properties. Rigorous verification of the top scoring candidates led to the discovery of three genes heretofore unlinked to malignant breast cancer that were reproducibly found to be induced in several models of tumor stroma. Collectively, our data provide highly novel and unexpected stromal gene signatures as a direct function of systemic administration of decorin protein core and reveals a fundamental basis of action for decorin to modulate the tumor stroma as a biological mechanism for the ascribed anti-tumorigenic properties. PMID- 23029098 TI - Stathmin is dispensable for tumor onset in mice. AB - The microtubule-destabilizing protein stathmin is highly expressed in several types of tumor, thus deserving the name of oncoprotein 18. High levels of stathmin expression and/or activity favor the metastatic spreading and mark the most aggressive tumors, thus representing a realistic marker of poor prognosis. Stathmin is a downstream target of many signaling pathways, including Ras-MAPK, PI3K and p53, involved in both tumor onset and progression. We thus hypothesized that stathmin could also play a role during the early stages of tumorigenesis, an issue completely unexplored. In order to establish whether stathmin expression is necessary for tumor initiation, we challenged wild type (WT), stathmin heterozygous and stathmin knock-out (KO) mice with different carcinogens. Using well-defined mouse models of carcinogenesis of skin, bladder and muscle by the means of 7,12-dimethylbenz[alpha]antracene (DMBA)/12-O-tetradecanoylphorbol-13 acetate (TPA), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) and 3 methylcholanthrylene (3MC) treatments, respectively, we demonstrated that knock out of stathmin has no impact on the onset of cancer in mice. No significant difference was noticed either when the Ras oncogene was mutated (skin carcinogenesis model) or when the p53 pathway was inactivated (bladder carcinomas and fibrosarcomas). Finally, we concomitantly impinged on p53 and Ras pathways, by generating WT and stathmin KO mouse embryo fibroblasts transformed with papilloma virus large T antigen (LgTAg) plus the K-Ras(G12V) oncogene. In vivo growth of xenografts from these transformed fibroblasts did not highlight any significant difference depending on the presence or absence of stathmin. Overall, our work demonstrates that stathmin expression is dispensable for tumor onset, at least in mice, thus making stathmin a virtually exclusive marker of aggressive disease and a promising therapeutic target for advanced cancers. PMID- 23029099 TI - Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2. AB - Glioblastoma constitutes the most aggressive and deadly of brain tumors. As yet, both conventional and molecular-based therapies have met with limited success in treatment of this cancer. Among other explanations, the heterogeneity of glioblastoma and the associated microenvironment contribute to its development, as well as resistance and recurrence in response to treatments. Increased vascularity suggests that tumor angiogenesis plays an important role in glioblastoma progression. However, the molecular crosstalk between endothelial and glioblastoma cells requires further investigation. To examine the effects of glioblastoma-derived signals on endothelial homeostasis, glioblastoma cell secretions were collected and used to treat brain endothelial cells. Here, we present evidence that the glioblastoma secretome provides pro-angiogenic signals sufficient to disrupt VE-cadherin-mediated cell-cell junctions and promote endothelial permeability in brain microvascular endothelial cells. An unbiased angiogenesis-specific antibody array screen identified the chemokine, interleukin 8, which was further demonstrated to function as a key factor involved in glioblastoma-induced permeability, mediated through its receptor CXCR2 on brain endothelia. This underappreciated interface between glioblastoma cells and associated endothelium may inspire the development of novel therapeutic strategies to induce tumor regression by preventing vascular permeability and inhibiting angiogenesis. PMID- 23029100 TI - 10'(Z),13'(E)-heptadecadienylhydroquinone inhibits swarming and virulence factors and increases polymyxin B susceptibility in Proteus mirabilis. AB - In this study, we demonstrated that 10'(Z), 13'(E)-heptadecadienylhydroquinone (HQ17-2), isolated from the lacquer tree, could decrease swarming motility and hemolysin activity but increase polymyxin B (PB) susceptibilityof Proteus mirabilis which is intrinsically highly-resistant to PB. The increased PB susceptibility induced by HQ17-2 was also observed in clinical isolates and biofilm-grown cells. HQ17-2 could inhibit swarming in the wild-type and rppA mutant but not in the rcsB mutant, indicating that HQ17-2 inhibits swarming through the RcsB-dependent pathway, a two-component signaling pathway negatively regulating swarming and virulence factor expression. The inhibition of hemolysin activity by HQ17-2 is also mediated through the RcsB-dependent pathway, because HQ17-2 could not inhibit hemolysin activity in the rcsB mutant. Moreover, the finding that HQ17-2 inhibits the expression of flhDC gene in the wild-type and rcsB-complemented strain but not in the rcsB mutant supports the notion. By contrast, HQ17-2 could increase PB susceptibility in the wild-type and rcsB mutant but not in the rppA mutant, indicating that HQ17-2 increases PB susceptibility through the RppA-dependent pathway, a signaling pathway positively regulating PB resistance. In addition, HQ17-2 could inhibit the promoter activities of rppA and pmrI, a gene positively regulated by RppA and involved in PB resistance, in the wild-type but not in the rppA mutant. The inhibition of rppA and pmrI expression caused lipopolysaccharide purified from HQ17-2-treated cells to have higher affinity for PB. Altogether, this study uncovers new biological effects of HQ17-2 and provides evidence for the potential of HQ17-2 in clinical applications. PMID- 23029101 TI - Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas or angiotensin type 2 receptor. AB - The counter-regulatory axis of the renin angiotensin system peptide angiotensin (1-7) [Ang-(1-7)] has been identified as a potential therapeutic target in cardiac remodelling, acting via the mas receptor. Furthermore, we recently reported that an alternative peptide, Ang-(1-9) also counteracts cardiac remodelling via the angiotensin type 2 receptor (AT(2)R). Here, we have engineered adenoviral vectors expressing fusion proteins which release Ang-(1-7) [RAdAng-(1-7)] or Ang-(1-9) [RAdAng-(1-9)] and compared their effects on cardiomyocyte hypertrophy in rat H9c2 cardiomyocytes or primary adult rabbit cardiomyocytes, stimulated with angiotensin II, isoproterenol or arg-vasopressin. RAdAng-(1-7) and RAdAng-(1-9) efficiently transduced cardiomyocytes, expressed fusion proteins and secreted peptides, as demonstrated by western immunoblotting and conditioned media assays. Furthermore, secreted Ang-(1-7) and Ang-(1-9) inhibited cardiomyocyte hypertrophy (Control = 168.7+/-8.4 um; AngII = 232.1+/ 10.7 um; AngII+RAdAng-(1-7) = 186+/-9.1 um, RAdAng-(1-9) = 180.5+/-9 um; P<0.05) and these effects were selectively reversed by inhibitors of their cognate receptors, the mas antagonist A779 for RAdAng-(1-7) and the AT(2)R antagonist PD123,319 for RAdAng-(1-9). Thus gene transfer of Ang-(1-7) and Ang-(1-9) produces receptor-specific effects equivalent to those observed with addition of exogenous peptides. These data highlight that Ang-(1-7) and Ang-(1-9) can be expressed via gene transfer and inhibit cardiomyocyte hypertrophy via their respective receptors. This supports applications for this approach for sustained peptide delivery to study molecular effects and potential gene therapeutic actions. PMID- 23029102 TI - Effect of Elodea nuttallii roots on bacterial communities and MMHg proportion in a Hg polluted sediment. AB - The objective of this study was to assess the effect of a rooted macrophyte Elodea nuttallii on rhizosphere bacterial communities in Hg contaminated sediments. Specimens of E. nuttallii were exposed to sediments from the Hg contaminated Babeni reservoir (Olt River, Romania) in our microcosm. Plants were allowed to grow for two months until they occupied the entirety of the sediments. Total Hg and MMHg were analysed in sediments where an increased MMHg percentage of the total Hg in pore water of rhizosphere sediments was found. E. nuttallii roots also significantly changed the bacterial community structure in rhizosphere sediments compared to bulk sediments. Deltaproteobacteria dominated the rhizosphere bacterial community where members of Geobacteraceae within the Desulfuromonadales and Desulfobacteraceae were identified. Two bacterial operational taxonomic units (OTUs) which were phylogenetically related to sulfate reducing bacteria (SRB) became abundant in the rhizosphere. We suggest that these phylotypes could be potentially methylating bacteria and might be responsible for the higher MMHg percentage of the total Hg in rhizosphere sediments. However, SRB were not significantly favoured in rhizosphere sediments as shown by qPCR. Our findings support the hypothesis that rooted macrophytes created a microenvironment favorable for Hg methylation. The presence of E. nuttallii in Hg contaminated sediments should therefore not be overlooked. PMID- 23029103 TI - A qualitative exploration of sexual risk and HIV testing behaviors among men who have sex with men in Beirut, Lebanon. AB - Men who have sex with men (MSM) may account for most new HIV infections in Lebanon, yet little is known about the factors that influence sexual risk behavior and HIV testing in this population. Qualitative interviews were conducted with 31 MSM living in Beirut, and content analysis was used to identify emergent themes. Mean age of the participants was 28.4 years, and all identified as either gay (77%) or bisexual (23%). Half reported not using condoms consistently and one quarter had not been HIV-tested. Many described not using condoms with a regular partner in the context of a meaningful relationship, mutual HIV testing, and a desire to not use condoms, suggesting that trust, commitment and intimacy play a role in condom use decisions. Condoms were more likely to be used with casual partners, partners believed to be HIV-positive, and with partners met online where men found it easier to candidly discuss HIV risk. Fear of infection motivated many to get HIV tested and use condoms, but such affect also led some to avoid HIV testing in fear of disease and social stigma if found to be infected. Respondents who were very comfortable with their sexual orientation and who had disclosed their sexuality to family and parents tended to be more likely to use condoms consistently and be tested for HIV. These findings indicate that similar factors influence the condom use and HIV testing of MSM in Beirut as those observed in studies elsewhere of MSM; hence, prevention efforts in Lebanon can likely benefit from lessons learned and interventions developed in other regions, particularly for younger, gay-identified men. Further research is needed to determine how prevention efforts may need to be tailored to address the needs of men who are less integrated into or do not identify with the gay community. PMID- 23029104 TI - Novel HRPT2/CDC73 gene mutations and loss of expression of parafibromin in Chinese patients with clinically sporadic parathyroid carcinomas. AB - OBJECTIVE: It is widely recognized that the diagnosis of parathyroid carcinoma (PC) is often difficult because of the overlap of characteristics between malignant and benign parathyroid tumors, especially at an early stage. Based on the identification of tumor suppressor gene HRPT2/CDC73 and its association with hereditary and sporadic PC, screening of gene mutations and detection of parafibromin immunoreactivity have been suggested as diagnostic instruments of PC in Whites. There is little information about HRPT2/CDC73 mutations and its corresponding protein expression in patients with sporadic PC in Chinese population, and the long-term follow-up data is scarce. METHODS: Paraffin embedded tissues were obtained from 13 patients with PC, 13 patients with parathyroid adenoma (PA) and 7 patients with parathyroid hyperplasia(PH), and 6 normal parathyroid (NP) tissues as controls. Peripheral blood from 11 patients with PC was collected. PCR products using Genomic DNA extracted from tumor tissues or blood as template was sequenced for HRPT2/CDC73 gene. Expression of parafibromin in tumor tissues was evaluated by immunohistochemical analysis. RESULTS: Six mutations in 6 of 13 patients with PC were identified, with three being novel. Four of them were germ-line mutations. Patients with mutations were susceptible to recurrence of the PC. Complete (8/13, 61.5%) or partial (5/13, 38.5%) loss of parafibromin expression was observed in PC tissues. All of tissue samples from normal parathyroid or benign parathyroid tumors displayed positive immunostaining of parafibromin except one adenoma. CONCLUSIONS: The present study supplies information on the mutations and protein expression of HRPT2/CDC73 gene and phenotypes of parathyroid carcinoma in Chinese population. And the expanded mutation database of this gene may benefit patients in the diagnosis and treatment of this disease. PMID- 23029105 TI - Overexpression of AtDREB1A causes a severe dwarf phenotype by decreasing endogenous gibberellin levels in soybean [Glycine max (L.) Merr]. AB - Gibberellic acids (GAs) are plant hormones that play fundamental roles in plant growth and developmental processes. Previous studies have demonstrated that three key enzymes of GA20ox, GA3ox, and GA2ox are involved in GA biosynthesis. In this study, the Arabidopsis DREB1A gene driven by the CaMV 35S promoter was introduced into soybean plants by Agrobacterium- mediated transformation. The results showed that the transgenic soybean plants exhibited a typical phenotype of GA-deficient mutants, such as severe dwarfism, small and dark-green leaves, and late flowering compared to those of the non-transgenic plants. The dwarfism phenotype was rescued by the application of exogenous GA(3) once a week for three weeks with the concentrations of 144 uM or three times in one week with the concentrations of 60 uM. Quantitative RT-PCR analysis revealed that the transcription levels of the GA synthase genes were higher in the transgenic soybean plants than those in controls, whereas GA-deactivated genes except GmGA2ox4 showed lower levels of expression. The transcript level of GmGA2ox4 encoding the only deactivation enzyme using C(20)-GAs as the substrates in soybean was dramatically enhanced in transgenic plants compared to that of wide type. Furthermore, the contents of endogenous bioactive GAs were significantly decreased in transgenic plants than those of wide type. The results suggested that AtDREB1A could cause dwarfism mediated by GA biosynthesis pathway in soybean. PMID- 23029106 TI - A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity. AB - Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles. Using cancer cell-based survivin reporter systems (US 7,569,221 B2) via high throughput screening (HTS) of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit lead compounds, we identified a novel anticancer compound (designated FL118). FL118 shows structural similarity to irinotecan. However, while the inhibition of DNA topoisomerase 1 activity by FL118 was no better than the active form of irinotecan, SN-38 at 1 uM, FL118 effectively inhibited cancer cell growth at less than nM levels in a p53 status-independent manner. Moreover, FL118 selectively inhibited survivin promoter activity and gene expression also in a p53 status independent manner. Although the survivin promoter-reporter system was used for the identification of FL118, our studies revealed that FL118 not only inhibits survivin expression but also selectively and independently inhibits three additional cancer-associated survival genes (Mcl-1, XIAP and cIAP2) in a p53 status-independent manner, while showing no inhibitory effects on control genes. Genetic silencing or overexpression of FL118 targets demonstrated a role for these targets in FL118's effects. Follow-up in vivo studies revealed that FL118 exhibits superior antitumor efficacy in human tumor xenograft models in comparison with irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin, and a majority of mice treated with FL118 showed tumor regression with a weekly * 4 schedule. FL118 induced favorable body weight-loss profiles (temporary and reversible) and was able to eliminate large tumors. Together, the molecular targeting features of FL118 plus its superior antitumor activity warrant its further development toward clinical trials. PMID- 23029107 TI - Lactobacillus rhamnosus accelerates zebrafish backbone calcification and gonadal differentiation through effects on the GnRH and IGF systems. AB - Endogenous microbiota play essential roles in the host's immune system, physiology, reproduction and nutrient metabolism. We hypothesized that a continuous administration of an exogenous probiotic might also influence the host's development. Thus, we treated zebrafish from birth to sexual maturation (2 months treatment) with Lactobacillus rhamnosus, a probiotic species intended for human use. We monitored for the presence of L. rhamnosus during the entire treatment. Zebrafish at 6 days post fertilization (dpf) exhibited elevated gene expression levels for Insulin-like growth factors -I and -II, Peroxisome proliferator activated receptors -alpha and -beta, VDR-alpha and RAR-gamma when compared to untreated-10 days old zebrafish. Using a gonadotropin-releasing hormone 3 GFP transgenic zebrafish (GnRH3-GFP), higher GnRH3 expression was found at 6, 8 and 10 dpf upon L. rhamnosus treatment. The same larvae exhibited earlier backbone calcification and gonad maturation. Noteworthy in the gonad development was the presence of first testes differentiation at 3 weeks post fertilization in the treated zebrafish population -which normally occurs at 8 weeks- and a dramatic sex ratio modulation (93% females, 7% males in control vs. 55% females, 45% males in the treated group). We infer that administration of L. rhamnosus stimulated the IGF system, leading to a faster backbone calcification. Moreover we hypothesize a role for administration of L. rhamnosus on GnRH3 modulation during early larval development, which in turn affects gonadal development and sex differentiation. These findings suggest a significant role of the microbiota composition on the host organism development profile and open new perspectives in the study of probiotics usage and application. PMID- 23029108 TI - IGF2BP2 alternative variants associated with glutamic acid decarboxylase antibodies negative diabetes in Malaysian subjects. AB - BACKGROUND: The association of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) common variants (rs4402960 and rs1470579) with type 2 diabetes (T2D) has been performed in different populations. The aim of this study was to evaluate the association of alternative variants of IGF2BP2; rs6777038, rs16860234 and rs7651090 with glutamic acid decarboxylase antibodies (GADA) negative diabetes in Malaysian Subjects. METHODS/PRINCIPAL FINDINGS: IGF2BP2; rs6777038, rs16860234 and rs7651090 single nucleotide polymorphisms (SNPs) were genotyped in 1107 GADA negative diabetic patients and 620 control subjects of Asian from Malaysia. The additive genetic model adjusted for age, race, gender and BMI showed that alternative variants; rs6777038, rs16860234 and rs7651090 of IGF2BP2 associated with GADA negative diabetes (OR = 1.21; 1.36; 1.35, P = 0.03; 0.0004; 0.0002, respectively). In addition, the CCG haplotype and diplotype CCG TCG increased the risk of diabetes (OR = 1.51, P = 0.01; OR = 2.36, P = 0.009, respectively). CONCLUSIONS/SIGNIFICANCE: IGF2BP2 alternative variants were associated with GADA negative diabetes. The IGF2BP2 haplotypes and diplotypes increased the risk of diabetes in Malaysian subject. PMID- 23029109 TI - Senegenin attenuates hepatic ischemia-reperfusion induced cognitive dysfunction by increasing hippocampal NR2B expression in rats. AB - BACKGROUND: The root of Polygala tenuifolia, a traditional Chinese medicine, has been used to improve memory and intelligence, while the underlying mechanisms remain largely unknown. In this study, we investigated the protective effects of senegenin, an component of Polygala tenuifolia root extracts, on cognitive dysfunction induced by hepatic ischemia-reperfusion. METHODOLOGY/PRINCIPAL FINDINGS: Initially, we constructed a rat model of hepatic ischemia-reperfusion (HIR) and found that the memory retention ability of rats in the step-down and Y maze test was impaired after HIR, paralleled by a decrease of N-methyl-D aspartate (NMDA) receptor NR2B subunit mRNA and protein expressions in hippocampus. Furthermore, we found that administration of senegenin by gavage attenuated HIR-induced cognitive impairment in a dose and time dependent manner, and its mechanisms might partly due to the increasing expression of NR2B in rat hippocampus. CONCLUSIONS/SIGNIFICANCE: Cognitive dysfunction induced by HIR is associated with reduction of NR2B expression. Senegenin plays a neuroprotective role in HIR via increasing NR2B expression in rat hippocampus. These findings suggest that senegenin might be a potential agent for prevention and treatment of postoperative cognitive dysfunction (POCD) or other neurodegenerative diseases. PMID- 23029110 TI - Immune phenotype and body condition in roe deer: individuals with high body condition have different, not stronger immunity. AB - An efficient immunity is necessary for host survival, but entails energetic costs. When energy is limited, immunocompetence and body condition should co-vary positively among individuals and, depending on body condition, individuals should allocate more either in innate immunity or in adaptive response. We tested whether immune phenotype depends on body condition in large mammals, using data from two contrasted populations of roe deer Capreolus capreolus in France. Roe deer living at Chize, a forest with poor habitat quality, were expected to show lower values for body condition and immune parameters than roe deer at Trois Fontaines, a forest with high habitat quality. From 285 blood samples collected between December 2009 and March 2011, we measured seven metabolic parameters and ten immunological parameters. A Principal Component Analysis showed that all indicators of body condition co-varied positively and were lowest at Chize. Several immunological indicators correlated to body condition and differed between Trois Fontaines and Chize. However, high body condition was not associated to a high average level of immunocompetence, but instead to high levels of indicators of acute inflammatory innate response, while low body condition was associated to high levels of monocytes and lymphocytes, possibly reflecting adaptive immunity. Limited data suggest that the difference between populations was not related to the presence of specific parasite species, however parasite exposure and stress have to be investigated to gain a more complete understanding of the determinants of immunity. PMID- 23029111 TI - let-7b and miR-126 are down-regulated in tumor tissue and correlate with microvessel density and survival outcomes in non--small--cell lung cancer. AB - Angiogenesis is a critical event in the development, progression, and spread of various human cancers, including lung cancer. Molecular mechanisms that underlie the complex regulation of angiogenic processes are poorly understood. However, an increasing body of evidence indicates miRNAs as important regulators of tumor angiogenesis. Forceps biopsies were collected from tumor tissue, surrounding tissue, and non-tumor tissue from 50 NSCLC patients. Lung tissue samples from individuals with no clinical evidence of a cancerous disease served as controls. Immunohistochemical staining for Factor VIII was used to evaluate microvessel density (MVD). TaqMan(r) primer-probe sets were used in quantitative real-time RT PCR reactions to determine expression levels of let-7b, miR-126, miR-9, and miR 19a. We demonstrated significantly higher MVD and decreased expression levels of let-7b and miR-126 in tumor tissue and surrounding tissue in comparison to corresponding non-tumor tissue or lung tissue from the control group. In addition, no differences in MVD and expression levels of both miRNAs between tumor tissue and surrounding tissue from NSCLC patients were observed. Low expression of both miRNAs correlated with high MVD and worse progression-free survival and overall survival. These observations strongly suggest similar molecular alternations within tumor tissue and surrounding tissue that comprise a specific microenvironment. Low expression of let-7b and miR-126 seems to have a possible anti-angiogenic role in lung tumor tissue and significantly correlates with worse survival outcomes for lung cancer patients. Moreover, the regulation of let-7b and miR-126 expression could have therapeutic potential because it could reduce tumor angiogenesis and therefore suppress tumor growth in lung cancer patients. PMID- 23029112 TI - Sensory dysfunction of bladder mucosa and bladder oversensitivity in a rat model of metabolic syndrome. AB - PURPOSE: To study the role of sensory dysfunction of bladder mucosa in bladder oversensitivity of rats with metabolic syndrome. MATERIALS AND METHODS: Female Wistar rats were fed a fructose-rich diet (60%) or a normal diet for 3 months. Based on cystometry, the fructose-fed rats (FFRs) were divided into a group with normal detrusor function or detrusor overactivity (DO). Acidic adenosine triphosphate (ATP) solution (5mM, pH 3.3) was used to elicit reflex micturition. Cystometric parameters were evaluated before and after drug administration. Functional proteins of the bladder mucosa were assessed by western blotting. RESULTS: Compared to the controls, intravesical acidic ATP solution instillation induced a significant increase in provoked phasic contractions in both FFR groups and a significant decrease in the mean functional bladder capacity of group DO. Pretreatment with capsaicin for C-fiber desentization, intravesical liposome for mucosal protection, or intravenous pyridoxal 5-phosphate 6-azophenyl-2',4' disulfonic acid for antagonized purinergic receptors can interfere with the urodynamic effects of intravesical ATP in FFRs and controls. Over-expression of TRPV1, P2X(3), and iNOS proteins, and down-regulation of eNOS proteins were observed in the bladder mucosa of both fructose-fed groups. CONCLUSIONS: Alterations of sensory receptors and enzymes in the bladder mucosa, including over-expression of TRPV1, P2X(3), and iNOS proteins, can precipitate the emergence of bladder phasic contractions and oversensitivity through the activation of C-afferents during acidic ATP solution stimulation in FFRs. The down-regulation of eNOS protein in the bladder mucosa of FFRs may lead to a failure to suppress bladder oversensitivity and phasic contractions. Sensory dysfunction of bladder mucosa and DO causing by metabolic syndrome are easier to elicit bladder oversensitivity to certain urothelium stimuli. PMID- 23029113 TI - Discrimination of low-frequency tones employs temporal fine structure. AB - An auditory neuron can preserve the temporal fine structure of a low-frequency tone by phase-locking its response to the stimulus. Apart from sound localization, however, much about the role of this temporal information for signal processing in the brain remains unknown. Through psychoacoustic studies we provide direct evidence that humans employ temporal fine structure to discriminate between frequencies. To this end we construct tones that are based on a single frequency but in which, through the concatenation of wavelets, the phase changes randomly every few cycles. We then test the frequency discrimination of these phase-changing tones, of control tones without phase changes, and of short tones that consist of a single wavelet. For carrier frequencies below a few kilohertz we find that phase changes systematically worsen frequency discrimination. No such effect appears for higher carrier frequencies at which temporal information is not available in the central auditory system. PMID- 23029114 TI - Monitoring performance degradation of cerebellar functions using computational neuroscience methods: implications on neurological diseases. AB - Neurodegeneration is a major cause of human disease. Within the cerebellum, neuronal degeneration and/or dysfunction has been associated with many diseases, including several forms of cerebellar ataxia, since normal cerebellar function is paramount for proper motor coordination, balance, and motor learning. The cerebellum represents a well-established neural circuit. Determining the effects of neuronal loss is of great importance for understanding the fundamental workings of the cerebellum and disease-associated dysfunctions. This paper presents computational modeling of cerebellar function in relation to neurodegeneration either affecting a specific cerebellar cell type, such as granule cells or Purkinje cells, or more generally affecting cerebellar cells and the implications on effects in relation to performance degradation throughout the progression of cell death. The results of the models show that the overall number of cells, as a percentage of the total cell number in the model, of a particular type and, primarily, their proximity to the circuit output, and not the neuronal convergence due to the relative number of cells of a particular type, is the main indicator of the gravity of the functional deficit caused by the degradation of that cell type. Specifically, the greater the percentage loss of neurons of a specific type and the closer proximity of those cells to the deep cerebellar neurons, the greater the deficit caused by the neuronal cell loss. These findings contribute to the understanding of the functional consequences of neurodegeneration and the functional importance of specific connectivity within a neuronal circuit. PMID- 23029116 TI - Separation of sensitized and non-sensitized RBCs: sephadex-based cell-affinity adsorbents. AB - INTRODUCTION: In transfusion medicine, antibodies that cause RBCs positive DATs, may interfere with patients' phenotyping. Traditionally, these antibodies were removed using various antibody elution methodologies. However, the elution agents and conditions used have been only partially successful; and no one method is superior. The purpose of this study was to develop a general and efficient method to separate non-sensitized from sensitized RBCs using Sephadex-based cell affinity adsorbents. METHODS: First, we coupled Sephadex support with Staphylococcal Protein G (SpG) with or without NHS. Then we simulated clinical conditions by mixing different ratios of sensitized and non-sensitized RBCs in vitro. Sensitized cells were prepared by mixing antibody with corresponding antigen-positive RBCs. Finally, we checked the sensitization status of absorbed RBCs after absorption with modified Sephadex support. RESULTS: The number of sensitized RBCs bound to Sephadex-based cell-affinity adsorbents is approximately 5*10(8) RBCs/mL support. Activated Sephadex could separate sensitized from non sensitized RBCs. Conclusion Sephadex-based cell-affinity adsorbents with an NHS spacer arm have bigger capacity for binding RBCs than unmodified Sephadex. The Sephadex-based cell-affinity adsorbents readily separate non-sensitized RBCs from sensitized RBCs, thus providing a new strategy to type the blood for transfused patients. PMID- 23029115 TI - Hemispherically-unified surface maps of human cerebral cortex: reliability and hemispheric asymmetries. AB - Understanding the anatomical and structural organization of the cerebral cortex is facilitated by surface-based analysis enabled by FreeSurfer, Caret, and related tools. Here, we examine the precision of FreeSurfer parcellation of the cortex and introduce a method to align FreeSurfer-registered left and right hemispheres onto a common template in order to characterize hemispheric asymmetries. The results are visualized using Mollweide projections, an area preserving map. The regional distribution, inter-hemispheric asymmetries and intersubject variability in cortical curvature, sulcal depth, cortical thickness, and cortical surface area of 138 young, right handed subjects were analyzed on the Mollweide projection map of the common spherical space. The results show that gyral and sulcal structures are aligned with high but variable accuracy in different cortical regions and show consistent hemispheric asymmetries that are maximal in posterior temporal regions. PMID- 23029117 TI - Direction of association between bite wounds and Mycobacterium bovis infection in badgers: implications for transmission. AB - BACKGROUND: Badgers are involved in the transmission to cattle of bovine tuberculosis (TB), a serious problem for the UK farming industry. Cross-sectional studies have shown an association between bite wounds and TB infection in badgers which may have implications for M. bovis transmission and control, although the sequence of these two events is unclear. Transmission during aggressive encounters could potentially reduce the effectiveness of policies which increase the average range of a badger and thus its opportunities for interaction with other social groups. METHODS: Data were obtained on badgers captured during a long term study at Woodchester Park, UK (1998-2006). Many badgers had multiple observations. At each observation, the badger was assigned a "state" depending on presence of bite wounds and/or TB infection. Hence each badger had a "transition" from the previous state to the current state. We calculated the numbers of each type of transition and the time spent in each state. Transition rates were calculated for each transition category, dividing the number of such transitions by the total time at risk. We compared the rate of bite wound acquisition in infected badgers with that for uninfected badgers and the rate of positive M.bovis test results in bitten badgers with that in unbitten badgers. RESULTS: The rate of bite wound acquisition in infected badgers (0.291 per year) was 2.09 (95% CI: 1.41, 3.08) times that in uninfected badgers (0.139 per year). The rate of positive M.bovis test results in bitten badgers (0.097 per year) was 2.45 (95% CI: 1.29, 4.65) times that in unbitten badgers (0.040 per year). CONCLUSIONS: We found strong evidence of both potential sequences of events consistent with transmission via bite wounds and distinctive behaviour in infected badgers. The complex relationship between behaviour and infection must be considered when planning TB control strategies. PMID- 23029118 TI - Early warnings of regime shift when the ecosystem structure is unknown. AB - Abrupt changes in dynamics of an ecosystem can sometimes be detected using monitoring data. Using nonparametric methods that assume minimal knowledge of the underlying structure, we compute separate estimates of the drift (deterministic) and diffusion (stochastic) components of a general dynamical process, as well as an indicator of the conditional variance. Theory and simulations show that nonparametric conditional variance rises prior to critical transition. Nonparametric diffusion rises also, in cases where the true diffusion function involves a critical transition (sometimes called a noise-induced transition). Thus it is possible to discriminate noise-induced transitions from other kinds of critical transitions by comparing time series for the conditional variance and the diffusion function. Monte Carlo analysis shows that the indicators generally increase prior to the transition, but uncertainties of the indicators become large as the ecosystem approaches the transition point. PMID- 23029119 TI - The monoamine re-uptake inhibitor UWA-101 improves motor fluctuations in the MPTP lesioned common marmoset. AB - BACKGROUND: The wearing-OFF phenomenon is a common motor complication of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for Parkinson's disease. We recently described the discovery of UWA-101, a dual serotonin (SERT) and dopamine (DAT) transporter inhibitor, which increases the duration of "good quality" ON time provided by L-DOPA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we further characterise the effects of UWA-101 on this extension of ON-time in terms of L-DOPA-induced side-effects in the MPTP lesioned common marmoset. METHODS: Marmosets were rendered parkinsonian by MPTP injection and "primed" by repeated L-DOPA administration, to exhibit dyskinesia and psychosis-like behaviours. Animals were then administered acute challenges of L-DOPA in combination with UWA-101 (1, 3, 6 and 10 mg/kg) or vehicle. RESULTS: In combination with L-DOPA, UWA-101 (3, 6 and 10 mg/kg) significantly increased duration of ON-time (by 28%, 28%, and 33%, respectively; all P<0.05). UWA-101 (10 mg/kg) significantly extended duration of ON-time without disabling dyskinesia (by 62%, P<0.01). UWA-101 did not exacerbate the severity of dyskinesia (P>0.05). However, at the highest doses (6 and 10 mg/kg), UWA-101 increased the severity of psychosis-like behaviours (P<0.05). CONCLUSIONS: Our results demonstrate that dual SERT/ DAT inhibitors can effectively enhance L-DOPA anti-parkinsonian action, without exacerbating dyskinesia and, as such, represent a promising new therapeutic class for wearing-OFF. However, at higher doses, dual SERT/ DAT inhibitors may exacerbate dopaminergic psychosis. PMID- 23029121 TI - Achieving high accuracy prediction of minimotifs. AB - The low complexity of minimotif patterns results in a high false-positive prediction rate, hampering protein function prediction. A multi-filter algorithm, trained and tested on a linear regression model, support vector machine model, and neural network model, using a large dataset of verified minimotifs, vastly improves minimotif prediction accuracy while generating few false positives. An optimal threshold for the best accuracy reaches an overall accuracy above 90%, while a stringent threshold for the best specificity generates less than 1% false positives or even no false positives and still produces more than 90% true positives for the linear regression and neural network models. The minimotif multi-filter with its excellent accuracy represents the state-of-the-art in minimotif prediction and is expected to be very useful to biologists investigating protein function and how missense mutations cause disease. PMID- 23029120 TI - Insulin-like growth factor-I E-peptide activity is dependent on the IGF-I receptor. AB - Insulin-like growth factor-I (IGF-I) is an essential growth factor that regulates the processes necessary for cell proliferation, differentiation, and survival. The Igf1 gene encodes mature IGF-I and a carboxy-terminal extension called the E peptide. In rodents, alternative splicing and post-translational processing produce two E-peptides (EA and EB). EB has been studied extensively and has been reported to promote cell proliferation and migration independently of IGF-I and its receptor (IGF-IR), but the mechanism by which EB causes these actions has not been identified. Further, the properties of EA have not been evaluated. Therefore, the goals of this study were to determine if EA and EB possessed similar activity and if these actions were IGF-IR independent. We utilized synthetic peptides for EA, EB, and a scrambled control to examine cellular responses. Both E-peptides increased MAPK signaling, which was blocked by pharmacologic IGF-IR inhibition. Although the E-peptides did not directly induce IGF-IR phosphorylation, the presence of either E-peptide increased IGF-IR activation by IGF-I, and this was achieved through enhanced cell surface bioavailability of the receptor. To determine if E-peptide biological actions required the IGF-IR, we took advantage of the murine C2C12 cell line as a platform to examine the key steps of skeletal muscle proliferation, migration and differentiation. EB increased myoblast proliferation and migration while EA delayed differentiation. The proliferation and migration effects were inhibited by MAPK or IGF-IR signaling blockade. Thus, in contrast to previous studies, we find that E-peptide signaling, mitogenic, and motogenic effects are dependent upon IGF-IR. We propose that the E-peptides have little independent activity, but instead affect growth via modulating IGF-I signaling, thereby increasing the complexity of IGF-I biological activity. PMID- 23029122 TI - Mesenchymal stem cell 1 (MSC1)-based therapy attenuates tumor growth whereas MSC2 treatment promotes tumor growth and metastasis. AB - BACKGROUND: Currently, there are many promising clinical trials using mesenchymal stem cells (MSCs) in cell-based therapies of numerous diseases. Increasingly, however, there is a concern over the use of MSCs because they home to tumors and can support tumor growth and metastasis. For instance, we established that MSCs in the ovarian tumor microenvironment promoted tumor growth and favored angiogenesis. In parallel studies, we also developed a new approach to induce the conventional mixed pool of MSCs into two uniform but distinct phenotypes we termed MSC1 and MSC2. METHODOLOGY/PRINCIPAL FINDINGS: Here we tested the in vitro and in vivo stability of MSC1 and MSC2 phenotypes as well as their effects on tumor growth and spread. In vitro co-culture of MSC1 with various cancer cells diminished growth in colony forming units and tumor spheroid assays, while conventional MSCs or MSC2 co-culture had the opposite effect in these assays. Co culture of MSC1 and cancer cells also distinctly affected their migration and invasion potential when compared to MSCs or MSC2 treated samples. The expression of bioactive molecules also differed dramatically among these samples. MSC1-based treatment of established tumors in an immune competent model attenuated tumor growth and metastasis in contrast to MSCs- and MSC2-treated animals in which tumor growth and spread was increased. Also, in contrast to these groups, MSC1 therapy led to less ascites accumulation, increased CD45+leukocytes, decreased collagen deposition, and mast cell degranulation. CONCLUSION/SIGNIFICANCE: These observations indicate that the MSC1 and MSC2 phenotypes may be convenient tools for the discovery of critical components of the tumor stroma. The continued investigation of these cells may help ensure that cell based-therapy is used safely and effectively in human disease. PMID- 23029124 TI - High-throughput 1,536-well fluorescence polarization assays for alpha(1)-acid glycoprotein and human serum albumin binding. AB - Two major plasma proteins in humans are primarily responsible for drug binding, the alpha(1)-acid-glycoprotein (AGP) and human serum albumin (HSA). The availability of at least a semiquantitative high-throughput assay for assessment of protein binding is expected to aid in bridging the current gap between high throughput screening and early lead discovery, where cell-based and biochemical assays are deployed routinely to test up to several million compounds rapidly, as opposed to the late-stage candidate drug profiling methods which test at most dozens of compounds at a time. Here, we describe the miniaturization of a pair of assays based on the binding- and displacement-induced changes in fluorescence polarization (FP) of fluorescent small molecule probes known to specifically target the drug-binding sites of these two proteins. A robust and reproducible assay performance was achieved in <=4 uL assay volume in 1,536-well format. The assays were tested against a validation set of 10 known protein binders, and the results compared favorably with data obtained using protein-coated beads with high-performance liquid chromatography analysis. The miniaturized assays were taken to a high-throughput level in a screen of the LOPAC(1280) collection of 1,280 pharmacologically active compounds. The adaptation of the AGP and HSA FP assays to a 1,536-well format should allow their use in early-stage profiling of large-size compound sets. PMID- 23029123 TI - Roles of dopamine 2 receptor isoforms and g proteins in ethanol regulated prolactin synthesis and lactotropic cell proliferation. AB - Alcohol consumption has been shown to increase prolactin (PRL) production and cell proliferation of pituitary lactotropes. It also causes a reduction in the lactotrope's response to dopaminergic agents and a differential expression of dopamine 2 receptor short (D2S) and long (D2L) isoforms in the pituitary. However, the role of each of these D2 receptor isoforms and its coupled G protein in mediation of ethanol actions on lactotropes is not known. We have addressed this issue by comparing ethanol effects on the level of PRL production gene transcription rate cellular protein, G proteins and cell proliferation in enriched lactotropes and lactotrope-derived PR1 cells containing various D2 receptor isoforms. Additionally, we determined the effects of G protein blockade on ethanol-induced PRL production and cell proliferation in these cells. We show here that the D2 receptor, primarily the D2S isoform, is critically involved in the regulation of ethanol actions on PRL production and cell proliferation in lactotropes. We also present data to elucidate that the presence of the pertussis toxin (PTX)-sensitive D2S receptor is critical to mediate the ethanol stimulatory action on Gs and the ethanol's inhibitory action on Gi3 protein in lactotropes. Additionally, we provide evidence for the existence of an inhibitory action of Gi3 on Gs that is under the control of the D2S receptor and is inhibited by ethanol. These results suggest that ethanol via the inhibitory action on D2S receptor activity suppresses Gi3 repression of Gs expression resulting in stimulation of PRL synthesis and cell proliferation in lactotropes. PMID- 23029125 TI - Src homology-2 domain-containing protein tyrosine phosphatase (SHP) 2 and p38 regulate the expression of chemokine CXCL8 in human astrocytes. AB - CXCL8, one of the first chemokines found in the brain, is upregulated in the brains and cerebrospinal fluid of HIV-1 infected individuals suggesting its potential role in human immune deficiency virus (HIV)-associated neuroinflammation. Astrocytes are known to be the major contributors to the CXCL8 pool. Interleukin (IL)-1beta activated astrocytes exhibit significant upregulation of CXCL8. In order to determine the signaling pathways involved in CXCL8 regulation in astrocytes, we employed pharmacological inhibitors for non receptor Src homology-2 domain-containing protein tyrosine phosphatase (SHP) 2 and mitogen-activated protein kinases (MAPK) pathway and observed reduced expression of CXCL8 following IL-1beta stimulation. Overexpression of SHP2 and p38 enzymes in astrocytes led to elevated CXCL8 expression; however, inactivating SHP2 and p38 with dominant negative mutants abrogated CXCL8 induction. Furthermore, SHP2 overexpression resulted in higher SHP2 and p38 enzyme activity whereas p38 overexpression resulted in higher p38 but not SHP2 enzyme activity. Phosphorylation of SHP2 was important for phosphorylation of p38, which in turn was critical for phosphorylation of extracellular signal regulated kinase (ERK). Thus, our findings suggest an important role for SHP2 in CXCL8 expression in astrocytes during inflammation, as SHP2, directly or indirectly, modulates p38 and ERK MAPK in the signaling cascade leading to CXCL8 production. This study provides detailed understanding of the mechanisms involved in CXCL8 production during neuroinflammation. PMID- 23029126 TI - X-ray phase contrast imaging of cell isolation with super-paramagnetic microbeads. AB - Super-paramagnetic microbeads are widely used for cell isolation. Evaluation of the binding affinity of microbeads to cells using optical microscopy has been limited by its small scope. Here, magnetic property of microbeads was first investigated by using synchrotron radiation (SR) in-line x-ray phase contrast imaging (PCI). The cell line mouse LLC (Lewis lung carcinoma) was selected for cell adhesion studies. Targeted microbeads were prepared by attaching anti-VEGFR2 (vascular endothelial growth factor receptor-2) antibody to the shell of the microbeads. The bound microbeads were found to better adhere to LLC cells than unbound ones. PCI dynamically and clearly showed the magnetization and demagnetization of microbeads in PE-50 tube. The cells incubated with different types of microbeads were imaged by PCI, which provided clear and real-time visualization of the cell isolation. Therefore, PCI might be considered as a novel and efficient tool for further cell isolation studies. PMID- 23029127 TI - Biogeographical divergence of the flora of Yunnan, southwestern China initiated by the uplift of Himalaya and extrusion of Indochina block. AB - The floral composition of Yunnan is conspicuously linked to the biogeographical history of this extremely species-rich province in southwestern China. The floristic compositions of three representative regions in Yunnan were compared to reveal their variation with geography. From southern Yunnan, 4150 native species (including subspecies and varieties) from 1240 genera and 183 families of seed plants were recognized. From central Yunnan 3389 native species from 1095 genera and 167 families of seed plants were recognized. From northwestern Yunnan 6807 native species from 1296 genera and 166 families of seed plants were recognized. Although these three floras across Yunnan are similar in familial composition, similarities between the floras of southern and northwestern Yunnan are low at the generic and specific levels. The flora of northwestern Yunnan is dominated by families and genera with cosmopolitan and north temperate distributions, while the flora of southern Yunnan is dominated by tropical families and genera. Northwestern Yunnan is composed largely of temperate genera, of which the highest proportion has a north temperate distribution. In contrast, southern Yunnan has mainly tropical genera, of which most have a tropical Asian distribution. The flora of central Yunnan is a combination of southern and northwestern Yunnan. These three floras might be derived from a common Tertiary tropical or subtropical East Asian flora, but the geological history of each region has influenced its flora, and they have remained divergent since the late Tertiary. The flora of northwestern Yunnan has evolved with the uplift of the Himalayas and by gradual proliferation of mainly cosmopolitan and north temperate floristic elements, while the flora of southern Yunnan has evolved with extrusion of the Indochina block and the influence of mainly tropical Asian elements. PMID- 23029128 TI - Ethnic differences in disability prevalence and their determinants studied over a 20-year period: a cohort study. AB - BACKGROUND: To compare disability prevalence rates in the major ethnic groups in the UK and understand the risk factors contributing to differences identified. It was hypothesised that Indian Asian and African Caribbean people would experience higher rates of disability compared with Europeans. METHODS: Data was collected from 888 European, 636 Indian Asian and 265 African Caribbean men and women, aged 58-88 years at 20-year follow-up of community-based cohort study, based in West London. Disability was measured using a performance-based locomotor function test and self-reported questionnaires on functional limitation, and instrumental (IADL) and basic activities of daily living (ADL). RESULTS: The mean (SD) age of participants at follow-up was 69.6 (6.2) years. Compared with Europeans, Indian Asian people were significantly more likely to experience all of the disability outcomes than Europeans; this persisted after adjustment for socioeconomic, behavioural, adiposity and chronic disease risk factors measured at baseline (locomotor dysfunction: adjusted odds ratio (OR) 2.20, 95% CI 1.56-3.11; functional limitation: OR 2.77, 2.01-3.81; IADL impairment: OR 3.12, 2.20-4.41; ADL impairment: OR 1.58, 1.11-2.24). In contrast, a modest excess risk of disability was observed in African Caribbeans, which was abolished after adjustment (e.g. locomotor dysfunction: OR 1.37, 0.90-1.91); indeed a reduced risk of ADL impairment appeared after multivariable adjustment (OR from 0.99, 0.68-1.45 to 0.59, 0.38-0.93), compared with Europeans. CONCLUSIONS: Substantially elevated risk of disability was observed among Indian Asian participants, unexplained by known factors. A greater understanding of determinants of disability and normative functional beliefs of healthy aging is required in this population to inform intervention efforts to prevent disability. PMID- 23029129 TI - Cost-minimization analysis favours intravenous ferric carboxymaltose over ferric sucrose for the ambulatory treatment of severe iron deficiency. AB - OBJECTIVE: Intravenous iron is widely used to treat iron deficiency in day-care units. Ferric carboxymaltose (FCM) allows administration of larger iron doses than iron sucrose (IS) in each infusion (1000 mg vs. 200 mg). As FCM reduces the number of infusions required but is more expensive, we performed a cost minimization analysis to compare the cost impact of the two drugs. MATERIALS AND METHODS: The number of infusions and the iron dose of 111 consecutive patients who received intravenous iron at a gastrointestinal diseases day-care unit from 8/2007 to 7/2008 were retrospectively obtained. Costs of intravenous iron drugs were obtained from the Spanish regulatory agencies. The accounting department of the Hospital determined hospital direct and indirect costs for outpatient iron infusion. Non-hospital direct costs were calculated on the basis of patient interviews. In the pharmacoeconomic model, base case mean costs per patient were calculated for administering 1000 mg of iron per infusion using FCM or 200 mg using IS. Sensitivity analysis and Monte Carlo simulation were performed. RESULTS: Under baseline assumptions, the estimated cost of iron infusion per patient and year was ?304 for IS and ?274 for FCM, a difference of ?30 in favour of FCM. Adding non-hospital direct costs to the model increased the difference to ?67 (?354 for IS vs. ?287 for FCM). A Monte Carlo simulation taking into account non-hospital direct costs favoured the use of FCM in 97% of simulations. CONCLUSION: In this pharmacoeconomic analysis, FCM infusion reduced the costs of iron infusion at a gastrointestinal day-care unit. PMID- 23029130 TI - Involvement of the tubular ClC-type exchanger ClC-5 in glomeruli of human proteinuric nephropathies. AB - Glomerular protein handling mechanisms have received much attention in studies of nephrotic syndrome. Histopathological findings in renal biopsies from severely proteinuric patients support the likelihood of protein endocytosis by podocytes. ClC-5 is involved in the endocytosis of albumin in the proximal tubule. AIM: To investigate whether ClC-5 is expressed in the glomerular compartment and whether it has a role in proteinuric nephropathies. ClC-5 expression was studied using Real-time PCR in manually- and laser-microdissected biopsies from patients with type 2 diabetes (n 37) and IgA nephropathy (n 10); in biopsies of membranous glomerulopathy (MG) (n 14) immunohistochemistry for ClC-5 (with morphometric analysis) and for WT1 was done. CONTROLS: cortical tissue (n 23) obtained from unaffected parts of tumor-related nephrectomy specimens. RESULTS: ClC-5 was expressed at glomerular level in all biopsies. Glomerular ClC-5 levels were significantly higher in diabetic nephropaty and MG at both mRNA and protein level (p<0.002; p<0.01). ClC-5 and WT1 double-staining analysis in MG showed that ClC-5 was localized in the podocytes. ClC-5 ultrastructural immunolocalization was demonstrated in podocytes foot processes. Our study is the first to demonstrate that ClC-5 is expressed in human podocytes. The ClC-5 overexpression found in biopsies of proteinuric patients suggests that proteinuria may play a part in its expression and that podocytes are likely to have a key role in albumin handling in proteinuric states. PMID- 23029131 TI - Temporal differential proteomes of Clostridium difficile in the pig ileal-ligated loop model. AB - The impact of Clostridium difficile infection (CDI) on healthcare is becoming increasingly recognized as it represents a major cause of nosocomial diarrhea. A rising number of CDI cases and outbreaks have been reported worldwide. Here, we developed the pig ileal-ligated loop model for semi-quantitative analysis comparing temporal differential proteomes in C. difficile following in vivo incubation with in vitro growth using isobaric tags for relative and absolute quantification (iTRAQ). Proteins retrieved from the in vitro cultures and the loop contents after 4, 8, and 12 h in vivo incubation were subjected to in solution digestion, iTRAQ labeling, two-dimensional liquid chromatography/tandem mass spectrometry and statistical analyses. From a total of 1152 distinct proteins identified in this study, 705 proteins were available for quantitative measures at all time points in both biological and technical replicates; 109 proteins were found to be differentially expressed. With analysis of clusters of orthologous group and protein-protein network interactions, we identified the proteins that might play roles in adaptive responses to the host environment, hence enhancing pathogenicity during CDI. This report represents the quantitative proteomic analysis of C. difficile that demonstrates time-dependent protein expression changes under conditions that mimic in vivo infection and identifies potential candidates for diagnostic or therapeutic measures. PMID- 23029132 TI - Molecular characterization of the viaB locus encoding the biosynthetic machinery for Vi capsule formation in Salmonella Typhi. AB - The Vi capsular polysaccharide (CPS) of Salmonella enterica serovar Typhi, the cause of human typhoid, is important for infectivity and virulence. The Vi biosynthetic machinery is encoded within the viaB locus composed of 10 genes involved in regulation of expression (tviA), polymer synthesis (tviB-tviE), and cell surface localization of the CPS (vexA-vexE). We cloned the viaB locus from S. Typhi and transposon insertion mutants of individual viaB genes were characterized in Escherichia coli DH5alpha. Phenotype analysis of viaB mutants revealed that tviB, tviC, tviD and tviE are involved in Vi polymer synthesis. Furthermore, expression of tviB-tviE in E. coli DH5alpha directed the synthesis of cytoplasmic Vi antigen. Mutants of the ABC transporter genes vexBC and the polysaccharide copolymerase gene vexD accumulated the Vi polymer within the cytoplasm and productivity in these mutants was greatly reduced. In contrast, de novo synthesis of Vi polymer in the export deficient vexA mutant was comparable to wild-type cells, with drastic effects on cell stability. VexE mutant cells exported the Vi, but the CPS was not retained at the cell surface. The secreted polymer of a vexE mutant had different physical characteristics compared to the wild-type Vi. PMID- 23029133 TI - TNF-alpha and temporal changes in sleep architecture in mice exposed to sleep fragmentation. AB - TNF-alpha plays critical roles in host-defense, sleep-wake regulation, and the pathogenesis of various disorders. Increases in the concentration of circulating TNF-alpha after either sleep deprivation or sleep fragmentation (SF) appear to underlie excessive daytime sleepiness in patients with sleep apnea (OSA). Following baseline recordings, mice were subjected to 15 days of SF (daily for 12 h/day from 07.00 h to 19.00 h), and sleep parameters were recorded on days1, 7 and 15. Sleep architecture and sleep propensity were assessed in both C57BL/6J and in TNF-alpha double receptor KO mice (TNFR KO). To further confirm the role of TNF-alpha, we also assessed the effect of treatment with a TNF- alpha neutralizing antibody in C57BL/6J mice. SF was not associated with major changes in global sleep architecture in C57BL/6J and TNFR KO mice. TNFR KO mice showed higher baseline SWS delta power. Further, following 15 days of SF, mice injected with TNF-alpha neutralizing antibody and TNFR KO mice showed increased EEG SWS activity. However, SWS latency, indicative of increased propensity to sleep, was only decreased in C57BL/6J, and was unaffected in TNFR KO mice as well as in C57BL/6J mice exposed to SF but treated with TNF-alpha neutralizing antibody. Taken together, our findings show that the excessive sleepiness incurred by recurrent arousals during sleep may be due to activation of TNF-alpha-dependent inflammatory pathways, despite the presence of preserved sleep duration and global sleep architecture. PMID- 23029134 TI - A lateral flow assay for quantitative detection of amplified HIV-1 RNA. AB - Although the accessibility of HIV treatment in developing nations has increased dramatically over the past decade, viral load testing to monitor the response of patients receiving therapy is often unavailable. Existing viral load technologies are often too expensive or resource-intensive for poor settings, and there is no appropriate HIV viral load test currently available at the point-of-care in low resource settings. Here, we present a lateral flow assay that employs gold nanoparticle probes and gold enhancement solution to detect amplified HIV RNA quantitatively. Preliminary results show that, when coupled with nucleic acid sequence based amplification (NASBA), this assay can detect concentrations of HIV RNA that match the clinically relevant range of viral loads found in HIV patients. The lateral flow test is inexpensive, simple and rapid to perform, and requires few resources. Our results suggest that the lateral flow assay may be integrated with amplification and sample preparation technologies to serve as an HIV viral load test for low-resource settings. PMID- 23029135 TI - Clonal evolution of a case of treatment refractory maxillary sinus carcinoma. AB - BACKGROUND: Maxillary sinus carcinoma (MSC) is a rare cancer of the head and neck region. Patients are treated with surgery, radiation therapy, and chemotherapy and the treatment regimen is based on patient's age, general health condition, disease stage, and its extent of spread. There is very little information available on the genetics of this disease. DNA content based flow sorting of tumor cells followed by array comparative genomic hybridization allows for high definition global assessment of distinct clonal changes within tumor populations. METHODS: We applied this technique to primary and metastatic samples collected from a patient with radio- and chemotherapy refractory maxillary sinus carcinoma to gauge the progression of this disease. RESULTS: A clonal KIT amplicon was present in aneuploid populations sorted from the primary tumor and in divergent subclones arising in metastatic foci found in the brain, lung, and jejunum. The evolution of these subclones was associated with distinct genetic aberrations and DNA ploidies. CONCLUSION: The information presented here paves the path to understanding the development and progression of this disease. PMID- 23029136 TI - The role of pre-operative and post-operative glucose control in surgical-site infections and mortality. AB - BACKGROUND AND OBJECTIVE: The impact of glucose control on surgical-site infection (SSI) and death remains unclear. We examined how pre- and post operative glucose levels and their variability are associated with the risk of SSI or in-hospital death. METHODS: This retrospective cohort study employed data on 13,800 hospitalized patients who underwent a surgical procedure at a large referral hospital in New York between 2006 and 2008. Over 20 different sources of electronic data were used to analyze how thirty-day risk of SSI and in-hospital death varies by glucose levels and variability. Maximum pre- and post-operative glucose levels were determined for 72 hours before and after the operation and glucose variability was defined as the coefficient of variation of the glucose measurements. We employed logistic regression to model the risk of SSI or death against glucose variables and the following potential confounders: age, sex, body mass index, duration of operation, diabetes status, procedure classification, physical status, emergency status, and blood transfusion. RESULTS: While association of pre- and post-operative hyperglycemia with SSI were apparent in the crude analysis, multivariate results showed that SSI risk did not vary significantly with glucose levels. On the other hand, in-hospital deaths were associated with pre-operative hypoglycemia (OR = 5.09, 95% CI (1.80, 14.4)) and glucose variability (OR = 1.14, 95% CI (1.03, 1.27) for 10% increase in coefficient of variation). CONCLUSION: In-hospital deaths occurred more often among those with pre-operative hypoglycemia and higher glucose variability. These findings warrant further investigation to determine whether stabilization of glucose and prevention of hypoglycemia could reduce post-operative deaths. PMID- 23029138 TI - Valproate alters dopamine signaling in association with induction of Par-4 protein expression. AB - Chromatin remodeling through histone modifications has emerged as a key mechanism in the pathophysiology of psychiatric disorders. Valproate (VPA), a first-line medication for bipolar disorder, is known to have histone deacetylase (HDAC) inhibitor activity, but the relationship between its efficacy as a mood stabilizer and HDAC inhibitory activity is unclear. Here we provide evidence that prostate apoptosis response-4 (Par-4), an intracellular binding partner of dopamine D2 receptors (DRD2), plays a role in mediating the effectiveness of VPA. We found that chronic VPA treatment enhanced the expression of Par-4 in cultured neurons and adult mouse brains. This Par-4 induction phenomenon occurred at the transcriptional level and was correlated with an increase in histone H3 and H4 acetylation of the Par-4 promoter regions. Furthermore, chronic VPA treatment potentiated the suppression of the cAMP signaling cascade upon dopamine stimulation, which was blocked by sulpiride treatment. These results indicate that VPA potentiates DRD2 activity by enhancing Par-4 expression via a chromatin remodeling mechanism. PMID- 23029137 TI - Inhibition of Tcf-4 induces apoptosis and enhances chemosensitivity of colon cancer cells. AB - Aberrant activation of beta-catenin/Tcf-4 signaling has been implicated in human carcinogenesis, including colorectal cancer. In this study, we compared the effects of Tcf-4 knockdown with beta-catenin knockdown on cell proliferation, apoptosis, and chemosensitivity in SW480 and HCT116 colon cancer cells using adenoviral vector-mediated short hairpin RNA (shRNA). Our results show that, compared to beta-catenin knockdown, Tcf-4 knockdown more effectively inhibited colony formation, induced apoptosis, and increased 5-FU and oxaliplatin-mediated cytotoxicity in colon cancer cells. We further investigated the mechanisms involved in the different efficacies observed with beta-catenin and Tcf-4 knockdown in colon cancer cells. FOXO4 is a member of the subfamily of mammalian FOXO forkhead transcription factors and plays a major role in controlling cellular proliferation, apoptosis, and DNA repair. Our data showed that the protein level of FOXO4 did not change after treatment with both beta-catenin and Tcf-4 shRNA. However, beta-catenin shRNA was found to increase the accumulation of phosphorylated FOXO4 S193 and decrease the expression of FOXO target genes p27Kip1 and MnSOD, whereas Tcf-4 shRNA showed the opposite effect. Therefore, compared to beta-catenin knockdown, Tcf-4 knockdown shows better efficacy for inhibiting proliferation and inducing apoptosis of colorectal cancer cells, which may be related to increased FOXO4 transcriptional activity. These results suggest that Tcf-4 is an attractive potential therapeutic target for colorectal cancer therapy. PMID- 23029139 TI - Junctional adhesion molecule (JAM)-C deficient C57BL/6 mice develop a severe hydrocephalus. AB - The junctional adhesion molecule (JAM)-C is a widely expressed adhesion molecule regulating cell adhesion, cell polarity and inflammation. JAM-C expression and function in the central nervous system (CNS) has been poorly characterized to date. Here we show that JAM-C(-/-) mice backcrossed onto the C57BL/6 genetic background developed a severe hydrocephalus. An in depth immunohistochemical study revealed specific immunostaining for JAM-C in vascular endothelial cells in the CNS parenchyma, the meninges and in the choroid plexus of healthy C57BL/6 mice. Additional JAM-C immunostaining was detected on ependymal cells lining the ventricles and on choroid plexus epithelial cells. Despite the presence of hemorrhages in the brains of JAM-C(-/-) mice, our study demonstrates that development of the hydrocephalus was not due to a vascular function of JAM-C as endothelial re-expression of JAM-C failed to rescue the hydrocephalus phenotype of JAM-C(-/-) C57BL/6 mice. Evaluation of cerebrospinal fluid (CSF) circulation within the ventricular system of JAM-C(-/-) mice excluded occlusion of the cerebral aqueduct as the cause of hydrocephalus development but showed the acquisition of a block or reduction of CSF drainage from the lateral to the 3(rd) ventricle in JAM-C(-/-) C57BL/6 mice. Taken together, our study suggests that JAM C(-/-) C57BL/6 mice model the important role for JAM-C in brain development and CSF homeostasis as recently observed in humans with a loss-of-function mutation in JAM-C. PMID- 23029140 TI - Moniliophthora perniciosa necrosis- and ethylene-inducing protein 2 (MpNep2) as a metastable dimer in solution: structural and functional implications. AB - Understanding how Nep-like proteins (NLPs) behave during the cell cycle and disease progression of plant pathogenic oomycetes, fungi and bacteria is crucial in light of compelling evidence that these proteins play a role in Witches' Broom Disease (WBD) of Theobroma cacao, one of the most important phytopathological problems to afflict the Southern Hemisphere. The crystal structure of MpNep2, a member of the NLP family and the causal agent of WBD, revealed the key elements for its activity. This protein has the ability to refold after heating and was believed to act as a monomer in solution, in contrast to the related homologs MpNep1 and NPP from the oomyceteous fungus Phytophthora parasitica. Here, we identify and characterize a metastable MpNep2 dimer upon over-expression in Escherichia coli using different biochemical and structural approaches. We found using ultra-fast liquid chromatography that the MpNep2 dimer can be dissociated by heating but not by dilution, oxidation or high ionic strength. Small-angle X ray scattering revealed a possible tail-to-tail interaction between monomers, and nuclear magnetic resonance measurements identified perturbed residues involved in the putative interface of interaction. We also explored the ability of the MpNep2 monomer to refold after heating or chemical denaturation. We observed that MpNep2 has a low stability and cooperative fold that could be an explanation for its structure and activity recovery after stress. These results can provide new insights into the mechanism for MpNep2's action in dicot plants during the progression of WBD and may open new avenues for the involvement of NLP- oligomeric species in phytopathological disorders. PMID- 23029141 TI - Adipose stromal cells amplify angiogenic signaling via the VEGF/mTOR/Akt pathway in a murine hindlimb ischemia model: a 3D multimodality imaging study. AB - Although adipose-derived stromal cell (ADSC) transplantation has been demonstrated as a promising therapeutic strategy for peripheral arterial disease (PAD), the mechanism of action behind the observed therapeutic efficacy of ADSCs remains unclear. This study was designed to investigate the long-term outcome and therapeutic behavior of engrafted ADSCs in a murine hindlimb ischemia model using multimodality molecular imaging approaches. ADSCs (1.0*10(7)) were isolated from Tg(Fluc-egfp) mice which constitutively express dual-reporter firefly luciferase and enhanced green fluorescent protein (Fluc(+)-eGFP(+), mADSCs(Fluc+GFP+)), then intramuscularly injected into the hindlimb of BALB/c-nu mice after unilateral femoral artery ligation and excision. Abbreviated survival (~5 weeks) of post transplant mADSCs within the ischemic hindlimb was longitudinally monitored using noninvasive bioluminescence imaging (BLI), fluorescence imaging (FRI), and bioluminescence tomography with micro-computed tomography (BLT/micro-CT). Use of the BLT/micro-CT system enabled quantitative 3-dimensional (3D) imaging of the cells' distribution and kinetics in vivo. Engrafted mADSCs improved blood perfusion recovery, ambulatory performance and prognosis of the ischemic hindlimb, probably by inducing angiogenesis and formation of collateral vessels, which could be visualized using laser Doppler perfusion imaging (LDPI), micro-CT angiography, vascular-cast imaging, and immunofluorescence. mADSCs augmented activation of the pro-angiogenic VEGF/mTOR/Akt pathway in vivo, even though the cells failed to incorporate into the host microvasculature as functional components. Downregulation of VEGF/mTOR/Akt signaling using small molecule inhibitors counteracted mADSC-induced angiogenesis and perfusion restoration. This study demonstrates for the first time the spatiotemporal kinetics and functional survival of transplanted mADSCs in a PAD model using in vivo 3D multimodality imaging. Our study indicates that mADSCs potentiate pro-angiogenic signal amplification via a VEGF/mTOR/Akt-dependent pathway, and thereby promote recovery from hindlimb ischemia. PMID- 23029142 TI - Multiple pathways of plasmid DNA transfer in Helicobacter pylori. AB - Many Helicobacter pylori (Hp) strains carry cryptic plasmids of different size and gene content, the function of which is not well understood. A subgroup of these plasmids (e.g. pHel4, pHel12), contain a mobilisation region, but no cognate type IV secretion system (T4SS) for conjugative transfer. Instead, certain H. pylori strains (e.g. strain P12 carrying plasmid pHel12) can harbour up to four T4SSs in their genome (cag-T4SS, comB, tfs3, tfs4). Here, we show that such indigenous plasmids can be efficiently transferred between H. pylori strains, even in the presence of extracellular DNaseI eliminating natural transformation. Knockout of a plasmid-encoded mobA relaxase gene significantly reduced plasmid DNA transfer in the presence of DNaseI, suggesting a DNA conjugation or mobilisation process. To identify the T4SS involved in this conjugative DNA transfer, each individual T4SS was consecutively deleted from the bacterial chromosome. Using a marker-free counterselectable gene deletion procedure (rpsL counterselection method), a P12 mutant strain was finally obtained with no single T4SS (P12DeltaT4SS). Mating experiments using these mutants identified the comB T4SS in the recipient strain as the major mediator of plasmid DNA transfer between H. pylori strains, both in a DNaseI-sensitive (natural transformation) as well as a DNaseI-resistant manner (conjugative transfer). However, transfer of a pHel12::cat plasmid from a P12DeltaT4SS donor strain into a P12DeltaT4SS recipient strain provided evidence for the existence of a third, T4SS-independent mechanism of DNA transfer. This novel type of plasmid DNA transfer, designated as alternate DNaseI-Resistant (ADR) mechanism, is observed at a rather low frequency under in vitro conditions. Taken together, our study describes for the first time the existence of three distinct pathways of plasmid DNA transfer between H. pylori underscoring the importance of horizontal gene transfer for this species. PMID- 23029143 TI - The schizophrenia-associated Kv11.1-3.1 isoform results in reduced current accumulation during repetitive brief depolarizations. AB - Recent genome wide association studies identified a brain and primate specific isoform of a voltage-gated potassium channel, referred to as Kv11.1-3.1, which is significantly associated with schizophrenia. The 3.1 isoform replaces the first 102 amino acids of the most abundant isoform (referred to as Kv11.1-1A) with six unique amino acids. Here we show that the Kv11.1-3.1 isoform has faster rates of channel deactivation but a slowing of the rates of inactivation compared to the Kv11.1-1A isoform. The Kv11.1-3.1 isoform also has a significant depolarizing shift in the voltage-dependence of steady-state inactivation. The consequence of the altered gating kinetics is that there is lower current accumulation for Kv11.1-3.1 expressing cells during repetitive action potential firing compared to Kv11.1-1A expressing cells, which in turn will result in longer lasting trains of action potentials. Increased expression of Kv11.1-3.1 channels in the brain of schizophrenia patients might therefore contribute to disorganized neuronal firing. PMID- 23029145 TI - A year in hypoxia: epibenthic community responses to severe oxygen deficit at a subsea observatory in a coastal inlet. AB - Changes in ocean ventilation driven by climate change result in loss of oxygen in the open ocean that, in turn, affects coastal areas in upwelling zones such as the northeast Pacific. Saanich Inlet, on the west coast of Canada, is a natural seasonally hypoxic fjord where certain continental shelf species occur in extreme hypoxia. One study site on the VENUS cabled subsea network is located in the hypoxic zone at 104 m depth. Photographs of the same 5 m(2) area were taken with a remotely-controlled still camera every 2/3 days between October 6(th) 2009 and October 18(th) 2010 and examined for community composition, species behaviour and microbial mat features. Instruments located on a near-by platform provided high resolution measurements of environmental variables. We applied multivariate ordination methods and a principal coordinate analysis of neighbour matrices to determine temporal structures in our dataset. Responses to seasonal hypoxia (0.1 1.27 ml/l) and its high variability on short time-scale (hours) varied among species, and their life stages. During extreme hypoxia, microbial mats developed then disappeared as a hippolytid shrimp, Spirontocaris sica, appeared in high densities (200 m(-2)) despite oxygen below 0.2 ml/l. The slender sole Lyopsetta exilis was abundant in severe hypoxia and diminished as oxygen increased in the summer. This planktivore may be responding to changes in the depth of the diurnal migration of zooplankton. While the squat lobster Munida quadrispina was common at all times, juveniles disappeared in fluctuating conditions. Despite low oxygen conditions, animal densities were high indicating that the risk from hypoxia is balanced by factors such as food availability and escape from less tolerant predators. As hypoxia increases on the continental shelf, we expect benthic communities to become dominated by low diversity, hypoxia-tolerant species of low commercial significance. PMID- 23029144 TI - Protection against Th17 cells differentiation by an interleukin-23 receptor cytokine-binding homology region. AB - Th17 cells have been reported to produce proinflammatory cytokines like Interleukin-17, IL-22, and regarded as important players in various inflammatory diseases. One of the IL-12 cytokine family cytokines, IL-23, composed of p19 and p40 subunit, is known for its potential to promote Th17 development and IL-17 producing, and the IL-23/IL-17 pathway is considered to be potential therapeutic target for autoimmune inflammation responses. Knockout mice deficient in either IL-23 or IL-17 related genes can suppress the allergic responses. Several IL-23 or IL-17 neutralizing agents are being evaluated in vitro or in vivo to disrupt the IL-23/IL-17 axis. Herein, we report that prokaryotically expressed soluble IL 23 receptor cytokine-binding homology region as an endogenous extracellular receptor analogue could be a natural antagonist against IL-23/IL-17 axis. We provide evidence that IL23R-CHR can bind to IL-23 in a dose-dependent manner in vitro, and block IL-23 signal by IL23R-CHR reducing the RORgammat expression, which in turn lowers the expression of IL-17/IL-22, thus protecting naive CD4+ T cells against Th17 development. Together, this study indicates the importance of IL-23 pathway in Th17 development and the negative regulation of Th17 development by IL23R-CHR, and highlights the important roles of the soluble receptor extracellular region in the therapeutic strategy of neutralizing IL-23. PMID- 23029146 TI - Risk and prognostic factors of inpatient mortality associated with unintentional insecticide and herbicide poisonings: a retrospective cohort study. AB - INTRODUCTION: Pesticide poisoning is an important public health problem worldwide. The study aimed to determine the risk of all-cause and cause-specific inpatient mortality and to identify prognostic factors for inpatient mortality associated with unintentional insecticide and herbicide pesticide poisonings. METHODS: We performed a retrospective cohort study of 3,986 inpatients recruited at hospitalization between 1999 and 2008 in Taiwan. We used the International Classification of Disease, 9th ed., Clinical Modification external causes of injury codes to classify poisoning agents into accidental poisoning by insecticides and herbicides. Comparisons in mortality rates were made between insecticide poisoning patients and herbicide poisoning patients by using the Cox proportional hazards models to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). RESULTS: There were 168 deaths during 21,583 person-days of follow-up evaluation (7.8 per 1,000 person-days). The major causes of mortality for insecticide poisonings were the toxic effect of organophosphate and coma, and the major causes of mortality for herbicide poisonings were the toxic effect of other pesticides and the toxic effect of organophosphate. The mortality for herbicide exposure was fourfold higher than that for insecticide exposure. The factors associated with inpatient mortality were herbicide poisonings (HR = 4.58, 95% CI 3.29 to 6.37) and receiving mechanical ventilation treatment (HR = 3.85, 95% CI 2.73 to 5.42). CONCLUSIONS: We demonstrated that herbicides stand out as the dominant agent for poisoning related fatalities. The control of and limiting access to herbicide agents and developing appropriate therapeutic regimens, including emergency care, should be priorities. PMID- 23029147 TI - Heterozygosity for fibrinogen results in efficient resolution of kidney ischemia reperfusion injury. AB - Fibrinogen (Fg) has been recognized to play a central role in coagulation, inflammation and tissue regeneration. Several studies have used Fg deficient mice (Fg(-/-)) in comparison with heterozygous mice (Fg(+/-)) to point the proinflammatory role of Fg in diverse pathological conditions and disease states. Although Fg(+/-) mice are considered 'normal', plasma Fg is reduced to ~75% of the normal circulating levels present in wild type mice (Fg(+/+)). We report that this reduction in Fg protein production in the Fg(+/-) mice is enough to protect them from kidney ischemia reperfusion injury (IRI) as assessed by tubular injury, kidney dysfunction, necrosis, apoptosis and inflammatory immune cell infiltration. Mechanistically, we observed binding of Fg to ICAM-1 in kidney tissues of Fg(+/+) mice at 24 h following IRI as compared to a complete absence of binding observed in the Fg(+/-) and Fg(-/-) mice. Raf-1 and ERK were highly activated as evident by significantly higher phosphorylation in the Fg(+/+) kidneys at 24 h following IRI as compared to Fg(+/-) and Fg(-/-) mice kidneys. On the other hand Cyclin D1 and pRb, indicating higher cell proliferation, were significantly increased in the Fg(+/-) and Fg(-/-) as compared to Fg(+/+) kidneys. These data suggest that Fg heterozygosity allows maintenance of a critical balance of Fg that enables regression of initial injury and promotes faster resolution of kidney damage. PMID- 23029148 TI - White matter reorganization and functional response after focal cerebral ischemia in the rat. AB - After stroke, the brain has shown to be able to achieve spontaneous functional recovery despite severe cerebral damage. This phenomenon is poorly understood. To address this issue, focal transient ischemia was induced by 60 min middle cerebral artery occlusion in Wistar rats. The evolution of stroke was followed using two magnetic resonance imaging modalities: diffusion spectrum imaging (acquired before, one and four weeks after stroke) and functional magnetic resonance imaging (acquired before and five weeks after stroke). To confirm the imaging observations, immunohistochemical staining for myelin, astrocytes and macrophages/microglia was added. At four weeks after stroke, a focal alteration of the diffusion anisotropy was observed between the ipsilesional ventricle and the lesion area. Using tractography this perturbation was identified as reorganization of the ipsilesional internal capsule. Functional imaging at five weeks after ischemia demonstrated activation of the primary sensorimotor cortex in both hemispheres in all rats except one animal lacking a functional response in the ipsilesional cortex. Furthermore, fiber tracking showed a transhemispheric fiber connection through the corpus callosum, which-in the rat without functional recovery-was lost. Our study shows the influence of the internal capsule reorganization, combined with inter-hemispheric connections though the corpus callosum, on the functional activation of the brain from stroke. In conclusion, tractography opens a new door to non-invasively investigate the structural correlates of lack of functional recovery after stroke. PMID- 23029149 TI - HCV and HIV infection among heroin addicts in methadone maintenance treatment (MMT) and not in MMT in Changsha and Wuhan, China. AB - OBJECTIVE: To compare HCV and HIV infection among heroin addicts in MMT and not in MMT in two large cities in central China. METHODS: A total of 541 heroin addicts were recruited from MMT clinics and voluntary detoxification centers in Changsha and Wuhan, China. Structured questionnaires collected data on their socio-demographics, clinical status, risk behaviors, and their knowledge of HIV. Their HIV serostatus and Hepatitis C virus (HCV) serostatus were determined by testing antibodies in blood serum. RESULTS: We observed a higher prevalence of HCV infection among MMT heroin addicts (82.3%) than that in the non-MMT group (50.6%). However, our findings indicated that the heroin addicts in MMT had less drug or sexual HIV/HCV risk behaviors and more knowledge about HIV than non-MMT addicts. The heroin addicts in MMT had a significantly higher percentage of individuals who always used condoms (44.9%) compared with patients in the non-MMT group (14.6%, p = 0.039), and they had more knowledge about HIV than non-MMT individuals (p<.001). The percentage of HIV-positive addicts in the MMT group (0.7%) and non-MMT group (0.8%) were almost same. CONCLUSION: Our study indicated that the rate of HCV infection among heroin addicts among MMT or non-MMT settings in central China is very high. The non-MMT heroin addicts have higher risk of becoming infected with HCV in the future, while at present they have lower rates of HCV infection than MMT heroin addicts. Although rates of HIV infection among MMT and non-MMT heroin addicts are low now, they are all at great risk of becoming infected with HIV in the future, especially for non-MMT heroin addicts. We should use the MMT sites as a platform to improve the control of HCV and HIV infection in heroin addicts. PMID- 23029150 TI - Sirtuin 1 facilitates generation of induced pluripotent stem cells from mouse embryonic fibroblasts through the miR-34a and p53 pathways. AB - Forced-expression of transcription factors can reprogram somatic cells into induced pluripotent stem cells (iPSC). Recent studies show that the reprogramming efficiency can be improved by inclusion of small molecules that regulate chromatin modifying enzymes. We report here that sirtuin 1 (SIRT1), a member of the sirtuin family of NAD(+)-dependent protein deacetylases, is involved in iPSC formation. By using an efficient mouse secondary fibroblast reprogramming system with doxycycline (DOX) inducible Yamanaka's transcription factors delivered by piggyBac (PB) transposition (2 degrees F/1B MEF), we show that SIRT1 knockdown decreased while resveratrol (RSV) increased the efficiency of iPSC formation. The treatments were associated with altered acetylated p53 and its downstream Nanog but not p21 expression. The stimulatory effect was also confirmed by SIRT1 over expression, which stimulated the formation of colonies with induced Nanog and reduced p21 expression. Furthermore, the effects of RSV and SIRT1 knockdown on reprogramming were most pronounced during the initiation phase of reprogramming. MicroRNA-34a is a known regulator of SIRT1. Its inhibitor increased, while its mimics reduced iPSC formation. The stimulatory effect of SIRT1 during reprogramming was also confirmed in the primary MEF. RSV increased while tenovin 6, a small molecule that activates p53 through SIRT1 inhibition, suppressed reprogramming. In conclusion, SIRT1 enhances iPSC generation, in part, through deacetylation of p53, inhibition of p21 and enhancement of Nanog expression. PMID- 23029151 TI - KDM2B is implicated in bovine lethal multi-organic developmental dysplasia. AB - In the last decade breeders of Romagnola cattle observed an outbreak of a new congenital anomaly. This lethal multi-organ developmental dysplasia is mainly characterized by facial deformities, ascites and hepatic fibrosis. Affected stillborn calves were inbred to a single founder sire suggesting autosomal monogenic recessive inheritance. We localized the causative mutation to a 1.2 Mb interval on BTA 17 by genome-wide association and identical by descent mapping. A solution-based method for targeted DNA capture combined with massively parallel sequencing was used to analyze the entire critical region containing 24 genes. Homozygosity for two non-synonymous coding sequence variants affecting the RNF34 and KDM2B genes was detected by evaluating one affected calf. Here we show that the disease phenotype is associated with a KDM2B missense mutation (c.2503G>A) leading to an amino acid exchange (p.D835N) in an evolutionary strongly conserved domain. In addition, the genetic makeup of three inbred cattle strongly supports the causality of the KDM2B mutation. This report of a naturally-occurring spontaneous mutation of a JmjC domain containing histone demethylase gene provides evidence for their important role in the endo- and mesodermal organ development. PMID- 23029153 TI - Annexin A1 N-terminal derived peptide Ac2-26 stimulates fibroblast migration in high glucose conditions. AB - Deficient wound healing in diabetic patients is very frequent, but the cellular and molecular causes are poorly defined. In this study, we have evaluated whether Annexin A1 derived peptide Ac2-26 stimulates fibroblast migration in high glucose conditions. Using normal human skin fibroblasts WS1 in low glucose (LG) or high glucose (HG) we observed the enrichment of Annexin A1 protein at cell movement structures like lamellipodial extrusions and interestingly, a significant decrease in levels of the protein in HG conditions. The analysis of the translocation of Annexin A1 to cell membrane showed lower levels of Annexin A1 in both membrane pool and supernatants of WS1 cells treated with HG. Wound-healing assays using cell line transfected with Annexin A1 siRNAs indicated a slowing down in migration speed of cells suggesting that Annexin A1 has a role in the migration of WS1 cells. In order to analyze the role of extracellular Annexin A1 in cell migration, we have performed wound-healing assays using Ac2-26 showing that peptide was able to increase fibroblast cell migration in HG conditions. Experiments on the mobilization of intracellular calcium and analysis of p-ERK expression confirmed the activity of the FPR1 following stimulation with the peptide Ac2-26. A wound-healing assay on WS1 cells in the presence of the FPR agonist fMLP, of the FPR antagonist CsH and in the presence of Ac2-26 indicated that Annexin A1 influences fibroblast cell migration under HG conditions acting through FPR receptors whose expression was slightly increased in HG. In conclusion, these data demonstrate that (i) Annexin A1 is involved in migration of WS1 cells, through interaction with FPRs; (ii) N- terminal peptide of Annexin A1 Ac2-26 is able to stimulate direct migration of WS1 cells in high glucose treatment possibly due to the increased receptor expression observed in hyperglycemia conditions. PMID- 23029152 TI - Multiscale modeling of metabolism and macromolecular synthesis in E. coli and its application to the evolution of codon usage. AB - Biological systems are inherently hierarchal and multiscale in time and space. A major challenge of systems biology is to describe biological systems as a computational model, which can be used to derive novel hypothesis and drive experiments leading to new knowledge. The constraint-based reconstruction and analysis approach has been successfully applied to metabolism and to the macromolecular synthesis machinery assembly. Here, we present the first integrated stoichiometric multiscale model of metabolism and macromolecular synthesis for Escherichia coli K12 MG1655, which describes the sequence-specific synthesis and function of almost 2000 gene products at molecular detail. We added linear constraints, which couple enzyme synthesis and catalysis reactions. Comparison with experimental data showed improvement of growth phenotype prediction with the multiscale model over E. coli's metabolic model alone. Many of the genes covered by this integrated model are well conserved across enterobacters and other, less related bacteria. We addressed the question of whether the bias in synonymous codon usage could affect the growth phenotype and environmental niches that an organism can occupy. We created two classes of in silico strains, one with more biased codon usage and one with more equilibrated codon usage than the wildtype. The reduced growth phenotype in biased strains was caused by tRNA supply shortage, indicating that expansion of tRNA gene content or tRNA codon recognition allow E. coli to respond to changes in codon usage bias. Our analysis suggests that in order to maximize growth and to adapt to new environmental niches, codon usage and tRNA content must co-evolve. These results provide further evidence for the mutation-selection-drift balance theory of codon usage bias. This integrated multiscale reconstruction successfully demonstrates that the constraint-based modeling approach is well suited to whole-cell modeling endeavors. PMID- 23029154 TI - Associations between interleukin-1 gene polymorphisms and coronary heart disease risk: a meta-analysis. AB - OBJECTIVE: A great number of studies regarding the associations between IL-1B 511, IL-1B+3954 and IL-1RN VNTR polymorphisms within the IL-1gene cluster and coronary heart disease (CHD) have been published. However, results have been inconsistent. In this study, a meta-analysis was performed to investigate the associations. METHODS: Published literature from PubMed and Embase databases were searched for eligible publications. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed- effect model. RESULTS: Thirteen studies (3,219 cases/2,445 controls) for IL-1B-511 polymorphism, nine studies (1,828 cases/1,818 controls) for IL-1B+3954 polymorphism and twelve studies (2,987 cases/ 2,208 controls) for IL-1RN VNTR polymorphism were included in this meta analysis. The results indicated that both IL-1B-511 and IL-1B+3954 polymorphisms were not associated with CHD risk (IL-1B-511 T vs. C: OR = 0.98, 95%CI 0.87-1.09; IL-1B+3954 T vs. C: OR = 1.06, 95%CI 0.95-1.19). Similarly, there was no association between IL-1RN VNTR polymorphism and CHD risk (*2 vs. L: OR = 1.00, 95%CI 0.85-1.17). CONCLUSIONS: This meta-analysis suggested that there were no associations between IL-1 gene cluster polymorphisms and CHD. PMID- 23029155 TI - Optimizing network connectivity for mobile health technologies in sub-Saharan Africa. AB - BACKGROUND: Mobile health (mHealth) technologies hold incredible promise to improve healthcare delivery in resource-limited settings. Network reliability across large catchment areas can be a major challenge. We performed an analysis of network failure frequency as part of a study of real-time adherence monitoring in rural Uganda. We hypothesized that the addition of short messaging service (SMS+GPRS) to the standard cellular network modality (GPRS) would reduce network disruptions and improve transmission of data. METHODS: Participants were enrolled in a study of real-time adherence monitoring in southwest Uganda. In June 2011, we began using Wisepill devices that transmit data each time the pill bottle is opened. We defined network failures as medication interruptions of >48 hours duration that were transmitted when network connectivity was re-established. During the course of the study, we upgraded devices from GPRS to GPRS+SMS compatibility. We compared network failure rates between GPRS and GPRS+SMS periods and created geospatial maps to graphically demonstrate patterns of connectivity. RESULTS: One hundred fifty-seven participants met inclusion criteria of seven days of SMS and seven days of SMS+GPRS observation time. Seventy-three percent were female, median age was 40 years (IQR 33-46), 39% reported >1-hour travel time to clinic and 17% had home electricity. One hundred one had GPS coordinates recorded and were included in the geospatial maps. The median number of network failures per person-month for the GPRS and GPRS+SMS modalities were 1.5 (IQR 1.0-2.2) and 0.3 (IQR 0-0.9) respectively, (mean difference 1.2, 95%CI 1.0-1.3, p-value<0.0001). Improvements in network connectivity were notable throughout the region. Study costs increased by approximately $1USD per person-month. CONCLUSIONS: Addition of SMS to standard GPRS cellular network connectivity can significantly reduce network connection failures for mobile health applications in remote areas. Projects depending on mobile health data in resource-limited settings should consider this upgrade to optimize mHealth applications. PMID- 23029156 TI - Choosing the best plant for the job: a cost-effective assay to prescreen ancient plant remains destined for shotgun sequencing. AB - DNA extracted from ancient plant remains almost always contains a mixture of endogenous (that is, derived from the plant) and exogenous (derived from other sources) DNA. The exogenous 'contaminant' DNA, chiefly derived from microorganisms, presents significant problems for shotgun sequencing. In some samples, more than 90% of the recovered sequences are exogenous, providing limited data relevant to the sample. However, other samples have far less contamination and subsequently yield much more useful data via shotgun sequencing. Given the investment required for high-throughput sequencing, whenever multiple samples are available, it is most economical to sequence the least contaminated sample. We present an assay based on quantitative real-time PCR which estimates the relative amounts of fungal and bacterial DNA in a sample in comparison to the endogenous plant DNA. Given a collection of contextually similar ancient plant samples, this low cost assay aids in selecting the best sample for shotgun sequencing. PMID- 23029157 TI - Clinical features of severe malaria associated with death: a 13-year observational study in the Gambia. AB - BACKGROUND: Severe malaria (SM) is a major cause of death in sub-Saharan Africa. Identification of both specific and sensitive clinical features to predict death is needed to improve clinical management. METHODS: A 13-year observational study was conducted from 1997 through 2009 of 2,901 children with SM enrolled at the Royal Victoria Teaching Hospital in The Gambia to identify sensitive and specific predictors of poor outcome in Gambian children with severe malaria between the ages 4 months to 14 years. We have measured the sensitivity and specificity of clinical features that predict death or development of neurological sequelae. FINDINGS: Impaired consciousness (odds ratio {OR} 4.4 [95% confidence interval {CI}, 2.7-7.3]), respiratory distress (OR 2.4 [95%CI, 1.7-3.2]), hypoglycemia (OR 1.7 [95%CI, 1.2-2.3]), jaundice (OR 1.9 [95%CI, 1.2-2.9]) and renal failure (OR 11.1 [95%CI, 3.3-36.5]) were independently associated with death in children with SM. The clinical features that showed the highest sensitivity and specificity to predict death were respiratory distress (area under the curve 0.63 [95%CI, 0.60 0.65]) and impaired consciousness (AUC 0.61[95%CI, 0.59-0.63]), which were comparable to the ability of hyperlactatemia (blood lactate>5 mM) to predict death (AUC 0.64 [95%CI, 0.55-0.72]). A Blantyre coma score (BCS) of 2 or less had a sensitivity of 74% and specificity of 67% to predict death (AUC 0.70 [95% C.I. 0.68-0.72]), and sensitivity and specificity of 74% and 69%, respectively to predict development of neurological sequelae (AUC 0.72 [95% CI, 0.67-0.76]).The specificity of this BCS threshold to identify children at risk of dying improved in children less than 3 years of age (AUC 0.74, [95% C.I 0.71-0.76]). CONCLUSION: The BCS is a quantitative predictor of death. A BCS of 2 or less is the most sensitive and specific clinical feature to predict death or development of neurological sequelae in children with SM. PMID- 23029158 TI - Plant kin recognition enhances abundance of symbiotic microbial partner. AB - BACKGROUND: The stability of cooperative interactions among different species can be compromised by cheating. In the plant-mycorrhizal fungi symbiosis, a single mycorrhizal network may interact with many plants, providing the opportunity for individual plants to cheat by obtaining nutrients from the fungi without donating carbon. Here we determine whether kin selection may favour plant investment in the mycorrhizal network, reducing the incentive to cheat when relatives interact with a single network. METHODOLOGY/PRINCIPAL FINDINGS: We show that mycorrhizal network size and root colonization were greater when Ambrosia artemisiifolia L. was grown with siblings compared to strangers. Soil fungal abundance was positively correlated with group leaf nitrogen, and increased root colonization was associated with a reduced number of pathogen-induced root lesions, indicating greater benefit to plants grown with siblings. CONCLUSIONS/SIGNIFICANCE: Plants can benefit their relatives through investment in mycorrhizal fungi, and kin selection in plants could promote the persistence of the mycorrhizal symbiosis. PMID- 23029159 TI - Drosophila Zpr1 (Zinc finger protein 1) is required downstream of both EGFR and FGFR signaling in tracheal subcellular lumen formation. AB - The cellular and molecular cues involved in creating branched tubular networks that transport liquids or gases throughout an organism are not well understood. To identify factors required in branching and lumen formation of Drosophila tracheal terminal cells, a model for branched tubular networks, we performed a forward genetic-mosaic screen to isolate mutations affecting these processes. From this screen, we have identified the first Drosophila mutation in the gene Zpr1 (Zinc finger protein 1) by the inability of Zpr1-mutant terminal cells to form functional, gas-filled lumens. We show that Zpr1 defective cells initiate lumen formation, but are blocked from completing the maturation required for gas filling. Zpr1 is an evolutionarily conserved protein first identified in mammalian cells as a factor that binds the intracellular domain of the unactivated epidermal growth factor receptor (EGFR). We show that down-regulation of EGFR in terminal cells phenocopies Zpr1 mutations and that Zpr1 is epistatic to ectopic lumen formation driven by EGFR overexpression. However, while Zpr1 mutants are fully penetrant, defects observed when reducing EGFR activity are only partially penetrant. These results suggest that a distinct pathway operating in parallel to the EGFR pathway contributes to lumen formation, and this pathway is also dependent on Zpr1. We provide evidence that this alternative pathway may involve fibroblast growth factor receptor (FGFR) signaling. We suggest a model in which Zpr1 mediates both EGFR and FGFR signal transduction cascades required for lumen formation in terminal cells. To our knowledge, this is the first genetic evidence placing Zpr1 downstream of EGFR signaling, and the first time Zpr1 has been implicated in FGFR signaling. Finally, we show that down-regulation of Smn, a protein known to interact with Zpr1 in mammalian cells, shows defects similar to Zpr1 mutants. PMID- 23029160 TI - Action of vitamin D and the receptor, VDRa, in calcium handling in zebrafish (Danio rerio). AB - The purpose of the present study was to use zebrafish as a model to investigate how vitamin D and its receptors interact to control Ca(2+) uptake function. Low Ca(2+) fresh water stimulated Ca(2+) influx and expressions of epithelial calcium channel (ecac), vitamin D-25-hydroxylase (cyp2r1), vitamin D receptor a (vdra), and vdrb in zebrafish. Exogenous vitamin D increased Ca(2+) influx and expressions of ecac and 25-hydroxyvitamin D(3)-24-hydroxylase (cyp24a1), but downregulated 1alpha-OHase (cyp27b1) with no effects on other Ca(2+) transporters. Morpholino oligonucleotide knockdown of VDRa, but not VDRb, was found as a consequence of calcium uptake inhibition by knockdown of ecac, and ossification of vertebrae is impaired. Taken together, vitamin D-VDRa signaling may stimulate Ca(2+) uptake by upregulating ECaC in zebrafish, thereby clarifying the Ca(2+)-handling function of only a VDR in teleosts. Zebrafish may be useful as a model to explore the function of vitamin D-VDR signaling in Ca(2+) homeostasis and the related physiological processes in vertebrates. PMID- 23029161 TI - Activation biosensor for G protein-coupled receptors: a FRET-based m1 muscarinic activation sensor that regulates G(q). AB - We describe the design, construction and validation of a fluorescence sensor to measure activation by agonist of the m1 muscarinic cholinergic receptor, a prototypical class I G(q)-coupled receptor. The sensor uses an established general design in which Forster resonance energy transfer (FRET) from a circularly permuted CFP mutant to FlAsH, a selectively reactive fluorescein, is decreased 15-20% upon binding of a full agonist. Notably, the sensor displays essentially wild-type capacity to catalyze activation of Galpha(q), and the purified and reconstituted sensor displays appropriate regulation of affinity for agonists by G(q). We describe the strategies used to increase the agonist-driven change in FRET while simultaneously maintaining regulatory interactions with Galpha(q), in the context of the known structures of Class I G protein-coupled receptors. The approach should be generally applicable to other Class I receptors which include numerous important drug targets. PMID- 23029162 TI - Serum microRNA-122 predicts survival in patients with liver cirrhosis. AB - BACKGROUND: Liver cirrhosis is associated with high morbidity and mortality. MicroRNAs (miRs) circulating in the blood are an emerging new class of biomarkers. In particular, the serum level of the liver-specific miR-122 might be a clinically useful new parameter in patients with acute or chronic liver disease. AIM: Here we investigated if the serum level of miR-122 might be a prognostic parameter in patients with liver cirrhosis. METHODS: 107 patients with liver cirrhosis in the test cohort and 143 patients in the validation cohort were prospectively enrolled into the present study. RNA was extracted from the sera obtained at the time of study enrollment and the level of miR-122 was assessed. Serum miR-122 levels were assessed by quantitative reverse-transcription PCR (RT PCR) and were compared to overall survival time and to different complications of liver cirrhosis. RESULTS: Serum miR-122 levels were reduced in patients with hepatic decompensation in comparison to patients with compensated liver disease. Patients with ascites, spontaneous bacterial peritonitis and hepatorenal syndrome had significantly lower miR-122 levels than patients without these complications. Multivariate Cox regression analysis revealed that the miR-122 serum levels were associated with survival independently from the MELD score, sex and age. CONCLUSIONS: Serum miR-122 is a new independent marker for prediction of survival of patients with liver cirrhosis. PMID- 23029164 TI - A multiplex assay to measure RNA transcripts of prostate cancer in urine. AB - The serum prostate-specific antigen (PSA) test has a high false positive rate. As a single marker, PSA provides limited diagnostic information. A multi-marker test capable of detecting not only tumors but also the potentially lethal ones provides an unmet clinical need. Using the nanoString nCounter gene expression system, a 20-gene multiplex test was developed based on digital gene counting of RNA transcripts in urine as a means to detect prostate cancer. In this test, voided urine is centrifuged to pellet cells and the purified RNA is amplified for hybridization to preselected probesets. Amplification of test cell line RNA appeared not to introduce significant bias, and the counts matched well with gene abundance levels as measured by DNA microarrays. For data analysis, the individual counts were compared to that of beta2 microglobulin, a housekeeping gene. Urine samples of 5 pre-operative cases and 2 non-cancer were analyzed. Pathology information was then retrieved. Signals for a majority of the genes were low for non-cancer and low Gleason scores, and 6/6 known prostate cancer markers were positive in the cases. One case of Gleason 4+5 showed, in contrast, strong signals for all cancer-associated markers, including CD24. One non-cancer also showed signals for all 6 cancer markers, and this man might harbor an undiagnosed cancer. This multiplex test assaying a natural waste product can potentially be used for screening, early cancer detection and patient stratification. Diagnostic information is gained from the RNA signatures that are associated with cell types of prostate tumors. PMID- 23029163 TI - The unique cysteine knot regulates the pleotropic hormone leptin. AB - Leptin plays a key role in regulating energy intake/expenditure, metabolism and hypertension. It folds into a four-helix bundle that binds to the extracellular receptor to initiate signaling. Our work on leptin revealed a hidden complexity in the formation of a previously un-described, cysteine-knotted topology in leptin. We hypothesized that this unique topology could offer new mechanisms in regulating the protein activity. A combination of in silico simulation and in vitro experiments was used to probe the role of the knotted topology introduced by the disulphide-bridge on leptin folding and function. Our results surprisingly show that the free energy landscape is conserved between knotted and unknotted protein, however the additional complexity added by the knot formation is structurally important. Native state analyses led to the discovery that the disulphide-bond plays an important role in receptor binding and thus mediate biological activity by local motions on distal receptor-binding sites, far removed from the disulphide-bridge. Thus, the disulphide-bridge appears to function as a point of tension that allows dissipation of stress at a distance in leptin. PMID- 23029165 TI - Serum acylated ghrelin is negatively correlated with the insulin resistance in the CODING study. AB - OBJECTIVE: Ghrelin is a 28-amino acid orexigenic peptide synthesized mainly in the stomach. Acute administration of ghrelin has been found to decrease insulin secretion. However, little data is available regarding whether ghrelin contributes to the long-term regulation of insulin resistance at the population level. The aim of this study is to investigate the association between circulating ghrelin and insulin resistance in a large population based study. DESIGN: A total of 2082 CODING study (Complex Diseases in the Newfoundland population: Environment and Genetics) subjects were assessed. Subjects were of at least third generation Newfoundland descent, between the ages of 20 and 79 years, and had no serious metabolic, cardiovascular, or endocrine diseases. Ghrelin was measured with an Enzyme Immunoassay method. Insulin and fasting glucose were measured by Immulite 2500 autoanalyzer and Lx20 clinical chemistry analyzer, respectively. Homeostatic Model Assessment of beta cell function (HOMA-beta) and Insulin Resistance (HOMA-IR) and Quantitative Insulin-sensitivity Check Index (QUICKI) were used for measurement of insulin resistance. RESULTS: Partial correlation analyses showed a significant negative correlation between circulating ghrelin and insulin level and insulin resistance in the entire cohort and also in men and women separately. The aforementioned correlation was independent of age, percentage of trunk fat and HDL-cholesterol. According to menopausal status, only pre-menopausal women revealed negative correlations. CONCLUSION: Our results suggest that except for postmenopausal women, high circulating ghrelin level is associated with lower insulin resistance in the general population. PMID- 23029166 TI - The density of knobs on Plasmodium falciparum-infected erythrocytes depends on developmental age and varies among isolates. AB - BACKGROUND: The virulence of Plasmodium falciparum malaria is related to the parasite's ability to evade host immunity through clonal antigenic variation and tissue-specific adhesion of infected erythrocytes (IEs). The P. falciparum erythrocyte membrane protein 1 (PfEMP1) family expressed on dome-shaped protrusions called knobs on the IE surface is central to both. Differences in receptor specificity and affinity of expressed PfEMP1 are important for IE adhesiveness, but it is not known whether differences in the number and size of the knobs on which the PfEMP1 proteins are expressed also play a role. Therefore, the aim of this study was to provide detailed information on isolate- and time dependent differences in knob size and density. METHODOLOGY/PRINCIPAL FINDINGS: We used atomic force microscopy to characterize knobs on the surface of P. falciparum-infected erythrocytes. Fourteen ex vivo isolates from Ghanaian children with malaria and 10 P. falciparum isolates selected in vitro for expression of a particular PfEMP1 protein (VAR2CSA) were examined. Knob density increased from ~20 h to ~35 h post-invasion, with significant variation among isolates. The knob density ex vivo, which was about five-fold higher than following long-term in vitro culture, started to decline within a few months of culture. Although knob diameter and height varied among isolates, we did not observe significant time-dependent variation in these dimensions. CONCLUSIONS/SIGNIFICANCE: The density of knobs on the P. falciparum-IE surface depends on time since invasion, but is also determined by the infecting isolate in a time-independent manner. This is the first study to quantitatively evaluate knob densities and dimensions on different P. falciparum isolates, to examine ex vivo isolates from humans, and to compare ex vivo and long-term in vitro-cultured isolates. Our findings contribute to the understanding of the interaction between P. falciparum parasites and the infected host. PMID- 23029168 TI - Treatment with activated protein C (aPC) is protective during the development of myocardial fibrosis: an angiotensin II infusion model in mice. AB - AIMS: Myocardial fibrosis contributes to the development of heart failure. Activated Protein C (aPC) is a circulating anticoagulant with anti-inflammatory and cytoprotective properties. Using a model of myocardial fibrosis second to Angiotensin II (AngII) infusion, we investigated the novel therapeutic function aPC in the development of fibrosis. METHODS AND RESULTS: C57Bl/6 and Tie2-EPCR mice were infused with AngII (2.0 ug/kg/min), AngII and aPC (0.4 ug/kg/min) or saline for 3d. Hearts were harvested and processed for analysis or used for cellular isolation. Basic histology and collagen deposition were assessed using histologic stains. Transcript levels of molecular mediators were analyzed by quantitative RT-PCR. Mice infused with AngII exhibited multifocal areas of myocardial cellular infiltration associated with significant collagen deposition compared to saline control animals (p<0.01). AngII-aPC infusion inhibited this cellular infiltration and the corresponding collagen deposition. AngII-aPC infusion also inhibited significant expression of the pro-fibrotic cytokines TGF beta1, CTGF and PDGF found in AngII only infused animals (p<0.05). aPC signals through its receptor, EPCR. Using Tie2-EPCR animals, where endothelial cells over express EPCR and exhibit enhanced aPC-EPCR signaling, no significant reduction in cellular infiltration or fibrosis was evident with AngII infusion suggesting aPC mediate protection is endothelial cell independent. Isolated infiltrating cells expressed significant EPCR transcripts suggesting a direct effect on infiltrating cells. CONCLUSIONS: This data indicates that aPC treatment abrogates the fibrogenic response to AngII. aPC does not appear to confer protection by stimulating the endothelium but by acting directly on the infiltrating cells, potentially inhibiting migration or activation. PMID- 23029167 TI - Functional characterization of newly-discovered mutations in human SR-BI. AB - In rodents, SR-BI has been firmly established as a physiologically relevant HDL receptor that mediates removal of HDL-cholesteryl esters (CE). However, its role in human lipoprotein metabolism is less defined. Recently, two unique point mutations in human SR-BI - S112F or T175A - were identified in subjects with high HDL-cholesterol (HDL-C) levels. We hypothesized that mutation of these conserved residues would compromise the cholesterol-transport functions of SR-BI. To test this hypothesis, S112F- and T175A-SR-BI were generated by site-directed mutagenesis. Cell surface expression was confirmed for both mutant receptors in COS-7 cells upon transient transfection, albeit at lower levels for T175A-SR-BI. Both mutant receptors displayed defective HDL binding, selective uptake of HDL-CE and release of free cholesterol (FC) from cells to HDL. Mutant receptors were also unable to re-organize plasma membrane pools of FC. While these impaired functions were independent of receptor oligomerization, inability of T175A-SR-BI to mediate cholesterol-transport functions could be related to altered N-linked glycosylation status. In conclusion, high HDL-C levels observed in carriers of S112F- or T175A-SR-BI mutant receptors are consistent with the inability of these SR-BI receptors to mediate efficient selective uptake of HDL-CE, and suggest that increased plasma HDL concentrations in these settings may not be associated with lower risk of cardiovascular disease. PMID- 23029169 TI - Distance and character-based evaluation of the V4 region of the 18S rRNA gene for the identification of diatoms (Bacillariophyceae). AB - DNA barcoding is a molecular tool that exploits a unique DNA sequence of a standardized gene or non-coding region for the species identification of unknown individuals. The investigation into a suitable barcode for diatoms is ongoing and there are several promising candidates including mitochondrial, plastidial and nuclear markers. We analyzed 272 sequences from 76 diatoms species in the orders Thalassiosirales, Lithodesmiales and Cymatosirales, using distance and character based approaches, to assess the applicability of a DNA barcode based on the hypervariable V4 region of the nuclear 18S rRNA gene. We show that the proposed V4 barcode separated ca. 97% of all centric diatom taxa tested using a threshold p-distance of 0.02 and that many problem pairs were further separated using a character based approach. The reliability of amplification, extensive reference library and variability seen in the V4 region make it the most promising candidate to date for a barcode marker for diatoms particularly when combined with DNA character analysis. PMID- 23029171 TI - Monitoring and identification of sepsis development through a composite measure of heart rate variability. AB - Tracking the physiological conditions of a patient developing infection is of utmost importance to provide optimal care at an early stage. This work presents a procedure to integrate multiple measures of heart rate variability into a unique measure for the tracking of sepsis development. An early warning system is used to illustrate its potential clinical value. The study involved 17 adults (age median 51 (interquartile range 46-62)) who experienced a period of neutropenia following chemoradiotherapy and bone marrow transplant; 14 developed sepsis, and 3 did not. A comprehensive panel (N = 92) of variability measures was calculated for 5 min-windows throughout the period of monitoring (12 +/- 4 days). Variability measures underwent filtering and two steps of data reduction with the objective of enhancing the information related to the greatest degree of change. The proposed composite measure was capable of tracking the development of sepsis in 12 out of 14 patients. Simulating a real-time monitoring setting, the sum of the energy over the very low frequency range of the composite measure was used to classify the probability of developing sepsis. The composite revealed information about the onset of sepsis about 60 hours (median value) before of sepsis diagnosis. In a real monitoring setting this quicker detection time would be associated to increased efficacy in the treatment of sepsis, therefore highlighting the potential clinical utility of a composite measure of variability. PMID- 23029170 TI - Functional studies of ssDNA binding ability of MarR family protein TcaR from Staphylococcus epidermidis. AB - The negative transcription regulator of the ica locus, TcaR, regulates proteins involved in the biosynthesis of poly-N-acetylglucosamine (PNAG). Absence of TcaR increases PNAG production and promotes biofilm formation in Staphylococci. Previously, the 3D structure of TcaR in its apo form and its complex structure with several antibiotics have been analyzed. However, the detailed mechanism of multiple antibiotic resistance regulator (MarR) family proteins such as TcaR is unclear and only restricted on the binding ability of double-strand DNA (dsDNA). Here we show by electrophoretic mobility shift assay (EMSA), electron microscopy (EM), circular dichroism (CD), and Biacore analysis that TcaR can interact strongly with single-stranded DNA (ssDNA), thereby identifying a new role in MarR family proteins. Moreover, we show that TcaR preferentially binds 33-mer ssDNA over double-stranded DNA and inhibits viral ssDNA replication. In contrast, such ssDNA binding properties were not observed for other MarR family protein and TetR family protein, suggesting that the results from our studies are not an artifact due to simple charge interactions between TcaR and ssDNA. Overall, these results suggest a novel role for TcaR in regulation of DNA replication. We anticipate that the results of this work will extend our understanding of MarR family protein and broaden the development of new therapeutic strategies for Staphylococci. PMID- 23029172 TI - Iron supplementation decreases severity of allergic inflammation in murine lung. AB - The incidence and severity of allergic asthma have increased over the last century, particularly in the United States and other developed countries. This time frame was characterized by marked environmental changes, including enhanced hygiene, decreased pathogen exposure, increased exposure to inhaled pollutants, and changes in diet. Although iron is well-known to participate in critical biologic processes such as oxygen transport, energy generation, and host defense, iron deficiency remains common in the United States and world-wide. The purpose of these studies was to determine how dietary iron supplementation affected the severity of allergic inflammation in the lungs, using a classic model of IgE mediated allergy in mice. Results showed that mice fed an iron-supplemented diet had markedly decreased allergen-induced airway hyperreactivity, eosinophil infiltration, and production of pro-inflammatory cytokines, compared with control mice on an unsupplemented diet that generated mild iron deficiency but not anemia. In vitro, iron supplementation decreased mast cell granule content, IgE triggered degranulation, and production of pro-inflammatory cytokines post degranulation. Taken together, these studies show that iron supplementation can decrease the severity of allergic inflammation in the lung, potentially via multiple mechanisms that affect mast cell activity. Further studies are indicated to determine the potential of iron supplementation to modulate the clinical severity of allergic diseases in humans. PMID- 23029173 TI - Modeling impacts of alternative practices on net global warming potential and greenhouse gas intensity from rice-wheat annual rotation in China. AB - BACKGROUND: Evaluating the net exchange of greenhouse gas (GHG) emissions in conjunction with soil carbon sequestration may give a comprehensive insight on the role of agricultural production in global warming. MATERIALS AND METHODS: Measured data of methane (CH(4)) and nitrous oxide (N(2)O) were utilized to test the applicability of the Denitrification and Decomposition (DNDC) model to a winter wheat - single rice rotation system in southern China. Six alternative scenarios were simulated against the baseline scenario to evaluate their long term (45-year) impacts on net global warming potential (GWP) and greenhouse gas intensity (GHGI). PRINCIPAL RESULTS: The simulated cumulative CH(4) emissions fell within the statistical deviation ranges of the field data, with the exception of N(2)O emissions during rice-growing season and both gases from the control treatment. Sensitivity tests showed that both CH(4) and N(2)O emissions were significantly affected by changes in both environmental factors and management practices. Compared with the baseline scenario, the long-term simulation had the following results: (1) high straw return and manure amendment scenarios greatly increased CH(4) emissions, while other scenarios had similar CH(4) emissions, (2) high inorganic N fertilizer increased N(2)O emissions while manure amendment and reduced inorganic N fertilizer scenarios decreased N(2)O emissions, (3) the mean annual soil organic carbon sequestration rates (SOCSR) under manure amendment, high straw return, and no-tillage scenarios averaged 0.20 t C ha(-1) yr(-1), being greater than other scenarios, and (4) the reduced inorganic N fertilizer scenario produced the least N loss from the system, while all the scenarios produced comparable grain yields. CONCLUSIONS: In terms of net GWP and GHGI for the comprehensive assessment of climate change and crop production, reduced inorganic N fertilizer scenario followed by no-tillage scenario would be advocated for this specified cropping system. PMID- 23029174 TI - Low ERK phosphorylation in cancer-associated fibroblasts is associated with tamoxifen resistance in pre-menopausal breast cancer. AB - PURPOSE: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. PATIENTS AND METHODS: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMAalpha) in cancer-associated fibroblasts (CAFs) and links to clinico pathological data and treatment-predictive values were delineated. RESULTS: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ERalpha-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis). In both clinical materials we further show a significant association between pERK and SMAalpha, a characteristic marker for activated fibroblasts. SMAalpha expression however was not linked to treatment-predictive information but instead had prognostic qualities. CONCLUSION: The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer. PMID- 23029175 TI - Pre-saccadic shifts of visual attention. AB - The locations of visual objects to which we attend are initially mapped in a retinotopic frame of reference. Because each saccade results in a shift of images on the retina, however, the retinotopic mapping of spatial attention must be updated around the time of each eye movement. Mathot and Theeuwes [1] recently demonstrated that a visual cue draws attention not only to the cue's current retinotopic location, but also to a location shifted in the direction of the saccade, the "future-field". Here we asked whether retinotopic and future-field locations have special status, or whether cue-related attention benefits exist between these locations. We measured responses to targets that appeared either at the retinotopic or future-field location of a brief, non-predictive visual cue, or at various intermediate locations between them. Attentional cues facilitated performance at both the retinotopic and future-field locations for cued relative to uncued targets, as expected. Critically, this cueing effect also occurred at intermediate locations. Our results, and those reported previously [1], imply a systematic bias of attention in the direction of the saccade, independent of any predictive remapping of attention that compensates for retinal displacements of objects across saccades [2]. PMID- 23029176 TI - Different degree in proteasome malfunction has various effects on root growth possibly through preventing cell division and promoting autophagic vacuolization. AB - The ubiquitin/proteasome pathway plays a vital role in plant development. But the effects of proteasome malfunction on root growth, and the mechanism underlying this involvement remains unclear. In the present study, the effects of proteasome inhibitors on Arabidopsis root growth were studied through the analysis of the root length, and meristem size and cell length in maturation zone using FM4-64, and cell-division potential using GFP fusion cyclin B, and accumulation of ubiquitinated proteins using immunofluorescence labeling, and autophagy activity using LysoTracker and MDC. The results indicated that lower concentration of proteasome inhibitors promoted root growth, whereas higher concentration of inhibitors had the opposite effects. The accumulation of cyclin B was linked to MG132-induced decline in meristem size, indicating that proteasome malfunction prevented cell division. Besides, MG132-induced accumulation of the ubiquitinated proteins was associated with the increasing fluorescence signal of LysoTracker and MDC in the elongation zone, revealing a link between the activation of autophagy and proteasome malfunction. These results suggest that weak proteasome malfunction activates moderate autophagy and promotes cell elongation, which compensates the inhibitor-induced reduction of cell division, resulting in long roots. Whereas strong proteasome malfunction induces severe autophagy and disturbs cell elongation, resulting in short roots. PMID- 23029177 TI - NaCl potentiates human fibrocyte differentiation. AB - Excessive NaCl intake is associated with a variety of fibrosing diseases such as renal and cardiac fibrosis. This association has been attributed to increased blood pressure as the result of high NaCl intake. However, studies in patients with high NaCl intake and fibrosis reveal a connection between NaCl intake and fibrosis that is independent of blood pressure. We find that increasing the extracellular concentration of NaCl to levels that may occur in human blood after high-salt intake can potentiate, in serum-free culture conditions, the differentiation of freshly-isolated human monocytes into fibroblast-like cells called fibrocytes. NaCl affects the monocytes directly during their adhesion. Potassium chloride and sodium nitrate also potentiate fibrocyte differentiation. The plasma protein Serum Amyloid P (SAP) inhibits fibrocyte differentiation. High levels of extracellular NaCl change the SAP Hill coefficient from 1.7 to 0.8, and cause a four-fold increase in the concentration of SAP needed to inhibit fibrocyte differentiation by 95%. Together, our data suggest that NaCl potentiates fibrocyte differentiation. NaCl-increased fibrocyte differentiation may thus contribute to NaCl-increased renal and cardiac fibrosis. PMID- 23029178 TI - The different immunoregulatory functions of mesenchymal stem cells in patients with low-risk or high-risk myelodysplastic syndromes. AB - Myelodysplastic syndrome (MDS) are a group of progressive, clonal, neoplastic bone marrow disorders characterized by hematopoietic stem cell dysregulation and abnormalities in the immune system. Mesenchymal stem cells (MSC) have gained further interests after the demonstration of an immunoregulatory role. Nevertheless, the immunoregulatory function of MDS bone marrow derived MSC (MDS MSC) remains poorly defined. In addition, it is not clear whether there are differences in the regulatory functions between low-risk and high-risk MDS-MSC. In this study, we obtain and expand MSC from bone marrow of patients with MDS. Our results show that there are significant differences in the immunoregulatory functions between low-risk and high-risk MDS-MSC. Compare to low-risk MDS-MSC, high-risk MDS-MSC is associated with the presence of increased TGF-beta1, higher apoptosis, higher immunosuppressive rate and a poor ability of hematopoietic support. In addition, our results find that there are great differences in the CD4+CD25+Foxp3+Tregs inducible rate between high-risk MDS-MSC and low-risk MDS MSC. Compared to high-risk MDS-MSC, the inducible rate of CD4+CD25+Foxp3+Tregs of low-risk MDS-MSC is lower. At last, we find that MDS-MSC derived TGF-beta1 is largely responsible for the increase in CD4+CD25+Foxp3+Tregs based on knockdown studies. These results elucidate the different immunoregulatory role of MSC in low-risk and high-risk MDS, which may be important for understand the pathogenesis of MDS and the development of novel immunomodulatory strategies for the treatment of MDS. PMID- 23029179 TI - Audio-visual detection benefits in the rat. AB - Human psychophysical studies have described multisensory perceptual benefits such as enhanced detection rates and faster reaction times in great detail. However, the neural circuits and mechanism underlying multisensory integration remain difficult to study in the primate brain. While rodents offer the advantage of a range of experimental methodologies to study the neural basis of multisensory processing, rodent studies are still limited due to the small number of available multisensory protocols. We here demonstrate the feasibility of an audio-visual stimulus detection task for rats, in which the animals detect lateralized uni- and multi-sensory stimuli in a two-response forced choice paradigm. We show that animals reliably learn and perform this task. Reaction times were significantly faster and behavioral performance levels higher in multisensory compared to unisensory conditions. This benefit was strongest for dim visual targets, in agreement with classical patterns of multisensory integration, and was specific to task-informative sounds, while uninformative sounds speeded reaction times with little costs for detection performance. Importantly, multisensory benefits for stimulus detection and reaction times appeared at different levels of task proficiency and training experience, suggesting distinct mechanisms inducing these two multisensory benefits. Our results demonstrate behavioral multisensory enhancement in rats in analogy to behavioral patterns known from other species, such as humans. In addition, our paradigm enriches the set of behavioral tasks on which future studies can rely, for example to combine behavioral measurements with imaging or pharmacological studies in the behaving animal or to study changes of integration properties in disease models. PMID- 23029180 TI - Cwc24p is a general Saccharomyces cerevisiae splicing factor required for the stable U2 snRNP binding to primary transcripts. AB - Splicing of primary transcripts is an essential process for the control of gene expression. Specific conserved sequences in premature transcripts are important to recruit the spliceosome machinery. The Saccharomyces cerevisiae catalytic spliceosome is composed of about 60 proteins and 5 snRNAs (U1, U2, U4/U6 and U5). Among these proteins, there are core components and regulatory factors, which might stabilize or facilitate splicing of specific substrates. Assembly of a catalytic complex depends on the dynamics of interactions between these proteins and RNAs. Cwc24p is an essential S. cerevisiae protein, originally identified as a component of the NTC complex, and later shown to affect splicing in vivo. In this work, we show that Cwc24p also affects splicing in vitro. We show that Cwc24p is important for the U2 snRNP binding to primary transcripts, co-migrates with spliceosomes, and that it interacts with Brr2p. Additionally, we show that Cwc24p is important for the stable binding of Prp19p to the spliceosome. We propose a model in which Cwc24p is required for stabilizing the U2 association with primary transcripts, and therefore, especially important for splicing of RNAs containing non-consensus branchpoint sequences. PMID- 23029181 TI - Comparative proteome analysis of Milnesium tardigradum in early embryonic state versus adults in active and anhydrobiotic state. AB - Tardigrades have fascinated researchers for more than 300 years because of their extraordinary capability to undergo cryptobiosis and survive extreme environmental conditions. However, the survival mechanisms of tardigrades are still poorly understood mainly due to the absence of detailed knowledge about the proteome and genome of these organisms. Our study was intended to provide a basis for the functional characterization of expressed proteins in different states of tardigrades. High-throughput, high-accuracy proteomics in combination with a newly developed tardigrade specific protein database resulted in the identification of more than 3000 proteins in three different states: early embryonic state and adult animals in active and anhydrobiotic state. This comprehensive proteome resource includes protein families such as chaperones, antioxidants, ribosomal proteins, cytoskeletal proteins, transporters, protein channels, nutrient reservoirs, and developmental proteins. A comparative analysis of protein families in the different states was performed by calculating the exponentially modified protein abundance index which classifies proteins in major and minor components. This is the first step to analyzing the proteins involved in early embryonic development, and furthermore proteins which might play an important role in the transition into the anhydrobiotic state. PMID- 23029182 TI - Effect of combined nitrogen dioxide and carbon nanoparticle exposure on lung function during ovalbumin sensitization in Brown Norway rat. AB - The interaction of particulate and gaseous pollutants in their effects on the severity of allergic inflammation and airway responsiveness are not well understood. We assessed the effect of exposure to NO(2) in the presence or absence of repetitive treatment with carbon nanoparticle (CNP) during allergen sensitization and challenges in Brown-Norway (BN) rat, in order to assess their interactions on lung function and airway responses (AR) to allergen and methacholine (MCH), end-expiratory lung volume (EELV), bronchoalveolar lavage fluid (BALF) cellular content, serum and BALF cytokine levels and histological changes. Animals were divided into the following groups (n = 6): Control; CNP (Degussa-FW2): 13 nm, 0.5 mg/kg instilled intratracheally *3 at 7-day intervals; OVA: ovalbumin-sensitised; OVA+CNP: both sensitized and exposed to CNP. Rats were divided into equal groups exposed either to air or to NO(2), 10 ppm, 6 h/d, 5d/wk for 4 weeks. Exposure to NO(2), significantly enhanced lung inflammation and airway reactivity, with a significantly larger effect in animals sensitized to allergen, which was related to a higher expression of TH1 and TH2-type cytokines. Conversely, exposure to NO(2) in animals undergoing repeated tracheal instillation of CNP alone, increased BALF neutrophilia and enhanced the expression of TH1 cytokines: TNF-alpha and IFN-gamma, but did not show an additive effect on airway reactivity in comparison to NO(2) alone. The exposure to NO(2) combined with CNP treatment and allergen sensitization however, unexpectedly resulted in a significant decrease in both airway reactivity to allergen and to methacholine, and a reduction in TH2-type cytokines compared to allergen sensitization alone. EELV was significantly reduced with sensitization, CNP treatment or both. These data suggest an immunomodulatory effect of repeated tracheal instillation of CNP on the proinflammatory effects of NO(2) exposure in sensitized BN rat. Furthermore, our findings suggest that NO(2), CNP and OVA sensitization may significantly slow overall lung growth in parenchymally mature animals. PMID- 23029183 TI - Heart-type fatty acid binding protein is associated with proteinuria in obesity. AB - RATIONALE: Lipid metabolism contributes to the formation of obesity-related glomerulopathy (ORG). Heart-type fatty acid binding protein (H-FABP or FABP3) is involved in lipid metabolism and was predicted to relate to renal lesions in obesity. METHODS: A total of 28 patients with ORG were investigated, and renal tissue from 7 kidney donors served as controls. Db/db mice with albuminuria were treated with Simvastatin for 12 weeks. RESULTS: Immunohistochemistry demonstrated the H-FABP staining in glomerular and tubular areas of patients with ORG, and the percentage of H-FABP in the glomerular area was significantly higher than in controls (15.8+/-1.62 versus 4.51+/-0.56%, P<0.001). Moreover, H-FABP expression correlated with proteinuria, high-density lipoprotein (HDL) cholesterol, waist circumference and the homeostatic model assessment - insulin resistance (HOMA-IR) among patients with ORG. Enhanced expression of H-FABP was also detected in the db/db mice, and expression increased from 8 to 20 weeks of age and was weakly related to increased albuminuria (r = 0.433; P = 0.020). Furthermore, H-FABP was co-localized with synaptopodin and demonstrated a podocyte pattern distribution. After Simvastation treatment, the urine albumin levels decreased with lipid levels and H-FABP expression in the glomeruli. The expression of H-FABP was related to Simvastatin treatment, albuminuria and triglycerides, while it was only linked with triglycerides and albuminuria (r = 0.643, P = 0.036). CONCLUSIONS: This study confirmed an association of H-FABP with the pathogenesis of clinical and experimental ORG, and suggests that such a process might be related to podocytes and lipid dysmetabolism. PMID- 23029184 TI - Advances in the conceptualization and measurement of Health Care Empowerment: development and validation of the Health Care Empowerment inventory. AB - The Health Care Empowerment Model offers direction for the investigation of patient-controlled engagement and involvement in health care. At the core of the model is the construct of Health Care Empowerment (HCE), for which there exist no validated measures. A set of 27 candidate self-report survey items was constructed to capture five hypothesized inter-related facets of HCE (informed, engaged, committed, collaborative, and tolerant of uncertainty). The full item set was administered to 644 HIV-infected persons enrolled in three ongoing research studies. Exploratory and confirmatory factor analyses resulted in a two factor solution comprising four items each on two subscales: (1) HCE: Informed, Committed, Collaborative, and Engaged HCE ICCE) and (2) HCE Tolerance of Uncertainty (HCE TU). Subscale scores were evaluated for relationships with relevant constructs measured in the three studies, including depression, provider relationships, medication adherence, and HIV-1 viral load. Findings suggest the utility of this 8-item Health Care Empowerment Inventory (HCEI) in efforts to measure, understand, and track changes in the ways in which individuals engage in health care. PMID- 23029185 TI - Relationships between inflammation, adiponectin, and oxidative stress in metabolic syndrome. AB - Metabolic syndrome (MS) represents a cluster of physiological and anthropometric abnormalities. The purpose of this study was to investigate the relationships between the levels of inflammation, adiponectin, and oxidative stress in subjects with MS. The inclusion criteria for MS, according to the Taiwan Bureau of Health Promotion, Department of Health, were applied to the case group (n = 72). The control group (n = 105) comprised healthy individuals with normal blood biochemical values. The levels of inflammatory markers [high sensitivity C reactive protein (hs-CRP) and interleukin-6 (IL-6), adiponectin, an oxidative stress marker (malondialdehyde), and antioxidant enzymes activities [catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)] were measured. Subjects with MS had significantly higher concentrations of inflammatory markers and lower adiponectin level, and lower antioxidant enzymes activities than the control subjects. The levels of inflammatory markers and adiponectin were significantly correlated with the components of MS. The level of hs-CRP was significantly correlated with the oxidative stress marker. The IL-6 level was significantly correlated with the SOD and GPx activities, and the adiponectin level was significantly correlated with the GPx activity. A higher level of hs-CRP (>=1.00 mg/L), or IL-6 (>=1.50 pg/mL) or a lower level of adiponectin (<7.90 ug/mL) were associated with a significantly greater risk of MS. In conclusion, subjects suffering from MS may have a higher inflammation status and a higher level of oxidative stress. A higher inflammation status was significantly correlated with decreases in the levels of antioxidant enzymes and adiponectin and an increase in the risk of MS. PMID- 23029186 TI - Role of vegetation-associated protease activity in valve destruction in human infective endocarditis. AB - AIMS: Infective endocarditis (IE) is characterized by septic thrombi (vegetations) attached on heart valves, consisting of microbial colonization of the valvular endocardium, that may eventually lead to congestive heart failure or stroke subsequent to systemic embolism. We hypothesized that host defense activation may be directly involved in tissue proteolytic aggression, in addition to pathogenic effects of bacterial colonization. METHODS AND RESULTS: IE valve samples collected during surgery (n = 39) were dissected macroscopically by separating vegetations (VG) and the surrounding damaged part of the valve from the adjacent, apparently normal (N) valvular tissue. Corresponding conditioned media were prepared separately by incubation in culture medium. Histological analysis showed an accumulation of platelets and polymorphonuclear neutrophils (PMNs) at the interface between the VG and the underlying tissue. Apoptotic cells (PMNs and valvular cells) were abundantly detected in this area. Plasminogen activators (PA), including urokinase (uPA) and tissue (tPA) types were also associated with the VG. Secreted matrix metalloproteinase (MMP) 9 was also increased in VG, as was leukocyte elastase and myeloperoxidase (MPO). The presence of neutrophil extracellular traps (NETs) associating MPO and externalized nucleosomes, was shown by immunostaining in the VG. Both MPO and cell-free DNA were released in larger amounts by VG than N samples, suggesting bacterial activation of PMNs within the vegetation. Finally, evidence of proteolytic tissue damage was obtained by the release of fragments of extracellular matrix components such as fibrinogen and fibronectin, as well as protease-sensitive receptors such as the uPA receptor. CONCLUSION: Our data obtained using human IE valves suggest that septic vegetations represent an important source of proteases originating from massive leukocyte recruitment and activation of the host plasminergic system. The latter forms a potential therapeutic target to minimize valvular tissue degradation independently from that induced by bacterial proteases. PMID- 23029187 TI - Impaired transcriptional activity of Nrf2 in age-related myocardial oxidative stress is reversible by moderate exercise training. AB - Aging promotes accumulation of reactive oxygen/nitrogen species (ROS/RNS) in cardiomyocytes, which leads to contractile dysfunction and cardiac abnormalities. These changes may contribute to increased cardiovascular disease in the elderly. Inducible antioxidant pathways are regulated by nuclear erythroid 2 p45-related factor 2 (Nrf2) through antioxidant response cis-elements (AREs) and are impaired in the aging heart. Whereas acute exercise stress (AES) activates Nrf2 signaling and promotes myocardial antioxidant function in young mice (~2 months), aging mouse (>23 months) hearts exhibit significant oxidative stress as compared to those of the young. The purpose of this study was to investigate age-dependent regulation of Nrf2-antioxidant mechanisms and redox homeostasis in mouse hearts and the impact of exercise. Old mice were highly susceptible to oxidative stress following high endurance exercise stress (EES), but demonstrated increased adaptive redox homeostasis after moderate exercise training (MET; 10m/min, for 45 min/day) for ~6 weeks. Following EES, transcription and protein levels for most of the ARE-antioxidants were increased in young mice but their induction was blunted in aging mice. In contrast, 6-weeks of chronic MET promoted nuclear levels of Nrf2 along with its target antioxidants in the aging heart to near normal levels as seen in young mice. These observations suggest that enhancing Nrf2 function and endogenous cytoprotective mechanisms by MET, may combat age induced ROS/RNS and protect the myocardium from oxidative stress diseases. PMID- 23029188 TI - Test of IL28B polymorphisms in chronic hepatitis C patients treated with PegIFN and ribavirin depends on HCV genotypes: results from a meta-analysis. AB - BACKGROUND: Many studies have been published on the association between single nucleotide polymorphisms (SNP) near the IL28B gene and response to the combined treatments of pegylated-interferon (PegIFN) and ribavirin (RBV) in chronic HCV infected patients, but without identical conclusions. The aim of this study was to assess impact of the IL28B polymorphisms on the effect of HCV standard treatment using meta-analysis based method. METHODS: Association studies between polymorphisms of rs12979860 or rs8099917 and response to PegIFN/RBV treatment in chronic HCV patients were retrieved from PubMed. Data of qualified studies on sustained virological response (SVR) in different genotypes were extracted and analyzed using meta-analysis method in Stata 10 software. RESULTS: Thirty-four papers, containing 46 independent studies, were included in the analysis. In the HCV G1/4 patients without treatment history, individuals carrying rs12979860 CC genotype were more likely to achieve SVR (OR 3.97, 95%CI 3.29-4.80) compared to those carrying CT/TT genotypes. Similar results were observed in the HCV G1/4 patients with unsuccessful or unknown treatment history (OR 3.76, 95%CI 2.67 5.28) or in the patients co-infected with human immunodeficiency virus (OR 5.20, 95%CI 3.04-8.90). However, associations could not be observed in HCV G2/3 patients. For rs8099917, similar results were obtained for genotype TT compared to genotypes TG/GG, indicating that TT genotype was significantly associated with better treatment response in patients infected with genotype 1 or 4 HCV, but not genotype 2 or 3 HCV. CONCLUSION: Polymorphisms of rs12979860 and rs8099917 near IL28B only associate with the treatment response to PegIFN/RBV in patients infected with HCV genotype 1 or 4 but not with genotype 2 or 3, irrespective of the previous treatment history or HIV co-infected status. Therefore, identification of IL28B genotypes is necessary only in patients infected with relatively difficult-to-treat genotype 1 or 4 HCV. PMID- 23029189 TI - Combined effect of AMPK/PPAR agonists and exercise training in mdx mice functional performance. AB - The present investigation was undertaken to test whether exercise training (ET) associated with AMPK/PPAR agonists (EM) would improve skeletal muscle function in mdx mice. These drugs have the potential to improve oxidative metabolism. This is of particular interest because oxidative muscle fibers are less affected in the course of the disease than glycolitic counterparts. Therefore, a cohort of 34 male congenic C57Bl/10J mdx mice included in this study was randomly assigned into four groups: vehicle solution (V), EM [AICAR (AMPK agonist, 50 mg/Kg-1.day 1, ip) and GW 1516 (PPARdelta agonist, 2.5 mg/Kg-1.day-1, gavage)], ET (voluntary running on activity wheel) and EM+ET. Functional performance (grip meter and rotarod), aerobic capacity (running test), muscle histopathology, serum creatine kinase (CK), levels of ubiquitined proteins, oxidative metabolism protein expression (AMPK, PPAR, myoglobin and SCD) and intracellular calcium handling (DHPR, SERCA and NCX) protein expression were analyzed. Treatments started when the animals were two months old and were maintained for one month. A significant functional improvement (p<0.05) was observed in animals submitted to the combination of ET and EM. CK levels were decreased and the expression of proteins related to oxidative metabolism was increased in this group. There were no differences among the groups in the intracellular calcium handling protein expression. To our knowledge, this is the first study that tested the association of ET with EM in an experimental model of muscular dystrophy. Our results suggest that the association of ET and EM should be further tested as a potential therapeutic approach in muscular dystrophies. PMID- 23029191 TI - Bone turnover and metabolism in patients with early multiple sclerosis and prevalent bone mass deficit: a population-based case-control study. AB - BACKGROUND: Low bone mass is prevalent in ambulatory multiple sclerosis (MS) patients even shortly after clinical onset. The mechanism is not known, but could involve shared etiological risk factors between MS and low bone mass such as hypovitaminosis D operating before disease onset, or increased bone loss after disease onset. The aim of this study was to explore the mechanism of the low bone mass in early-stage MS patients. METHODOLOGY/PRINCIPAL FINDINGS: We performed a population-based case-control study comparing bone turnover (cross-linked N terminal telopeptide of type 1 collagen; NTX, bone alkaline phosphatase; bALP), metabolism (25-hydroxy- and 1, 25-dihydroxyvitamin D, calcium, phosphate, and parathyroid hormone), and relevant lifestyle factors in 99 patients newly diagnosed with clinically isolated syndrome (CIS) or MS, and in 159 age, sex, and ethnicity matched controls. After adjustment for possible confounders, there were no significant differences in NTX (mean 3.3; 95% CI -6.9, 13.5; p = 0.519), bALP (mean 1.6; 95% CI -0.2, 3.5; p = 0.081), or in any of the parameters related to bone metabolism in patients compared to controls. The markers of bone turnover and metabolism were not significantly correlated with bone mass density, or associated with the presence of osteoporosis or osteopenia within or between the patient and control groups. Intake of vitamin D and calcium, reported UV exposure, and physical activity did not differ significantly. CONCLUSIONS/SIGNIFICANCE: Bone turnover and metabolism did not differ significantly in CIS and MS patients with prevalent low bone mass compared to controls. These findings indicate that the bone deficit in patients newly diagnosed with MS and CIS is not caused by recent acceleration of bone loss, and are compatible with shared etiological factors between MS and low bone mass. PMID- 23029190 TI - Mycobacterium tuberculosis infection and tissue factor expression in macrophages. AB - A number of earlier studies reported the occurrence of thrombotic complications, particularly disseminated intravascular coagulation and deep vein thrombosis, in tuberculosis (TB) patients. The aberrant expression of tissue factor (TF), the primary activator of coagulation cascade, is known to be responsible for thrombotic disorders in many diseases including bacterial infections. Further, expression of TF by cells of the monocyte/macrophage lineage is also shown to contribute to the development and progression of local and systemic inflammatory reactions. In the present study, we have investigated whether Mycobacterium tuberculosis (Mtb) infection induces TF expression in macrophages, and various host and pathogenic factors responsible for TF expression. We have tested the effect of live virulent Mtb H37Rv, gamma-irradiated Mtb H37Rv (gamma-Mtb) and various components derived from Mtb H37Rv on TF expression in macrophages. The data presented in the manuscript show that both live virulent Mtb and gamma-Mtb treatments markedly increased TF activity in macrophages, predominantly in the CD14(+) macrophages. Detailed studies using gamma-Mtb showed that the increased TF activity in macrophages following Mtb treatment is the result of TF transcriptional activation. The signaling pathways of TF induction by Mtb appears to be distinct from that of LPS-induced TF expression. Mtb-mediated TF expression is dependent on cooperation of CD14/TLR2/TLR4 and probably yet another unknown receptor/cofactor. Mtb cell wall core components, mycolyl arabinogalactan peptidoglycan (mAGP), phosphatidylinositol mannoside-6 (PIM6) and lipomannan (LM) were identified as factors responsible for induction of TF in the order of mAGP>PIM6>LM. A direct contact between bacteria and macrophage and not Mtb released soluble factors is critical for TF induction by Mtb. In summary, our data show that Mtb induces TF expression in macrophages and Mtb signaling pathways that elicit TF induction require cooperation of multiple receptors, co receptors/co-factors including Toll-like receptors. The importance of TF in granuloma formation and containment of Mtb is discussed. PMID- 23029192 TI - A polymeric protein induces specific cytotoxicity in a TLR4 dependent manner in the absence of adjuvants. AB - Lumazine synthase from Brucella spp. (BLS) is a highly immunogenic decameric protein. It is possible to insert foreign peptides or proteins at its ten-amino acid termini. These chimeras elicit systemic and oral immunity without adjuvants, which are commonly needed in the formulation of subunit-based vaccines. Here, we show that BLS induces the cross presentation of a covalently attached peptide OVA(257-264) and a specific cytotoxic response to this peptide in the absence of adjuvants. Unlike other subunit-based vaccines, this chimera induces rapid activation of CTLs and a specific cytotoxic response, making this polymeric protein an ideal antigen carrier for vaccine development. Adoptive transfer of transgenic OT-I T cells revealed efficient cross presentation of BLS-OVA(257 264)in vivo. BLS-OVA(257-264) immunization induced the proliferation of OVA(257 264)-specific CD8+ lymphocytes and also increased the percentage of OVA(257-264) specific CD8+ cells expressing the early activation marker CD69; after 5 days, the percentage of OVA(257-264)-specific CD8+ cells expressing high levels of CD44 increased. This cell subpopulation showed decreased expression of IL-7Ralpha, indicating that BLS-OVA(257-264) induced the generation of CD8+ effector cells. BLS-OVA(257-264) was cross presented in vitro independently of the presence of a functional TLR4 in the DCs. Finally, we show that immunization of wild type mice with the chimera BLS-OVA(257-264) without adjuvants induced a strong OVA(257-264) specific effector cytotoxic response. This cytotoxicity is dependent on TLR4 as is not induced in mice lacking a functional receptor. These data show that TLR4 signaling is necessary for the induction of a cytotoxic response but not for antigen cross presentation. PMID- 23029194 TI - Prevalence and correlates of stability and change in maternal depression: evidence from the Fragile Families And Child Wellbeing Study. AB - Children of depressed mothers have impaired cognitive, behavioral, and health outcomes from infancy through adulthood, and are especially at risk when maternal depression persists over multiple years. But there are several important limitations to our current descriptive knowledge about maternal depression, especially depression among unmarried mothers. Data from the Fragile Families and Child Wellbeing Study, a recent cohort of children born in urban areas to mostly unmarried parents (N = 4,366), was used to examine the prevalence and correlates of maternal depression when children were about 1, 3, 5, and 9 years old. Results show that, at any given survey wave, between 16% and 21% of mothers reported depression. Nearly two-fifths (38%) of mothers reported depression at least once during the eight-year period, and 7% reported persistent depression (depression at three or four of the four survey waves). Employment status, relationship status, and fathers' depression were among the sociodemographic characteristics most robustly associated with both stability and change in maternal depression. Given the important social consequences of maternal depression, not least of which is impaired wellbeing among children of depressed mothers, prevention and treatment of maternal depression should be an imperative for researchers, clinicians, and policymakers alike. PMID- 23029193 TI - Cooperativity of stress-responsive transcription factors in core hypoxia inducible factor binding regions. AB - The transcriptional response driven by Hypoxia-inducible factor (HIF) is central to the adaptation to oxygen restriction. Despite recent characterization of genome-wide HIF DNA binding locations and hypoxia-regulated transcripts in different cell types, the molecular bases of HIF target selection remain unresolved. Herein, we combined multi-level experimental data and computational predictions to identify sequence motifs that may contribute to HIF target selectivity. We obtained a core set of bona fide HIF binding regions by integrating multiple HIF1 DNA binding and hypoxia expression profiling datasets. This core set exhibits evolutionarily conserved binding regions and is enriched in functional responses to hypoxia. Computational prediction of enriched transcription factor binding sites identified sequence motifs corresponding to several stress-responsive transcription factors, such as activator protein 1 (AP1), cAMP response element-binding (CREB), or CCAAT-enhancer binding protein (CEBP). Experimental validations on HIF-regulated promoters suggest a functional role of the identified motifs in modulating HIF-mediated transcription. Accordingly, transcriptional targets of these factors are over-represented in a sorted list of hypoxia-regulated genes. Altogether, our results implicate cooperativity among stress-responsive transcription factors in fine-tuning the HIF transcriptional response. PMID- 23029196 TI - Noninvasive evaluation of nuclear morphometry in breast lesions using multispectral diffuse optical tomography. AB - Breast cancer is the most prevalent cancer and the main cause of cancer-related death in women worldwide. There are limitations associated with the existing clinical tools for breast cancer detection and alternative modalities for early detection and classification of breast cancer are urgently needed. Here we describe an optical imaging technique, called multispectral diffuse optical tomography (DOT), and demonstrate its ability of non-invasively evaluating nuclear morphometry for differentiating benign from malignant lesions. Photon densities along the surface of the breast were measured to allow for the extraction of three statistical parameters including the size, elongation and density of nuclei inside the breast tissue. The results from 14 patients (4 malignant and 10 benign lesions) show that there exist significant contrasts between the diseased and surrounding normal nuclei and that the recovered nuclear morphological parameters agree well the pathological findings. We found that the nuclei of cancer cells were less-spherical compared with those of surrounding normal cells, while the nuclear density or volume fraction provided the highest contrast among the three statistical parameters recovered. This pilot study demonstrates the potential of multispectral DOT as a cellular imaging method for accurate determination of breast cancer. PMID- 23029195 TI - Degradation of PsbO by the Deg protease HhoA Is thioredoxin dependent. AB - The widely distributed members of the Deg/HtrA protease family play an important role in the proteolysis of misfolded and damaged proteins. Here we show that the Deg protease rHhoA is able to degrade PsbO, the extrinsic protein of the Photosystem II (PSII) oxygen-evolving complex in Synechocystis sp. PCC 6803 and in spinach. PsbO is known to be stable in its oxidized form, but after reduction by thioredoxin it became a substrate for recombinant HhoA (rHhoA). rHhoA cleaved reduced eukaryotic (specifically, spinach) PsbO at defined sites and created distinct PsbO fragments that were not further degraded. As for the corresponding prokaryotic substrate (reduced PsbO of Synechocystis sp. PCC 6803), no PsbO fragments were observed. Assembly to PSII protected PsbO from degradation. For Synechocystis sp. PCC 6803, our results show that HhoA, HhoB, and HtrA are localized in the periplasma and/or at the thylakoid membrane. In agreement with the idea that PsbO could be a physiological substrate for Deg proteases, part of the cellular fraction of the three Deg proteases of Synechocystis sp. PCC 6803 (HhoA, HhoB, and HtrA) was detected in the PSII-enriched membrane fraction. PMID- 23029197 TI - Worsening endothelial function with efavirenz compared to protease inhibitors: a 12-month prospective study. AB - OBJECTIVE: Changes in endothelial function, measured as flow-mediated dilation (FMD) of the brachial artery, has not been systematically assessed beyond 6 months of initiation of antiretroviral therapy (ART) when drug-related effects might offset initial improvements with virologic control. DESIGN: We assessed 6 and 12 month changes in FMD [presented as median (quartile 1, quartile 3)] and circulating HIV and cardiovascular biomarkers in 23 subjects initiating ART. RESULTS: There were no significant changes in FMD at 6 or 12 months overall despite significant increases in CD4 cell count and HDL-C and reductions in HIV RNA level, MCP-1, IP-10, sVCAM-1, sTNFR2, and sCD14. However, there were significant differences (P = 0.04) in the changes in FMD between those receiving efavirenz [N = 12; -3.50% (-4.90%, 0.68%)] vs. protease inhibitors at 12 months [N = 11; 1.50% (-0.86%, 4.56%)]. The differences in changes in FMD between those receiving and not receiving emtricitabine/tenofovir/efavirenz were more pronounced and were significantly different at both 6 and 12 months (P<0.02 for both). Additional studies showed no significant differences in changes in 25-(OH) vitamin D, PTH, FGF-23, of F2-isoprostane levels between efavirenz and PI use or between those receiving and not receiving emtricitabine/tenofovir/efavirenz. CONCLUSION: Efavirenz use was associated with reduced FMD at 12 months compared to PI-based regimens while emtricitabine/tenofovir/efavirenz was associated with reduced FMD at both 6 and 12 months compared to those not receiving this combination. Long-term effects of antiretrovirals on endothelial function may play an important role in the risk of cardiovascular disease in HIV-infected patients. PMID- 23029198 TI - Optogenetic stimulation of the corticothalamic pathway affects relay cells and GABAergic neurons differently in the mouse visual thalamus. AB - The dorsal lateral geniculate nucleus (dLGN) serves as the primary conduit of retinal information to visual cortex. In addition to retinal input, dLGN receives a large feedback projection from layer VI of visual cortex. Such input modulates thalamic signal transmission in different ways that range from gain control to synchronizing network activity in a stimulus-specific manner. However, the mechanisms underlying such modulation have been difficult to study, in part because of the complex circuitry and diverse cell types this pathway innervates. To address this and overcome some of the technical limitations inherent in studying the corticothalamic (CT) pathway, we adopted a slice preparation in which we were able to stimulate CT terminal arbors in the visual thalamus of the mouse with blue light by using an adeno-associated virus to express the light gated ion channel, ChIEF, in layer VI neurons. To examine the postsynaptic responses evoked by repetitive CT stimulation, we recorded from identified relay cells in dLGN, as well as GFP expressing GABAergic neurons in the thalamic reticular nucleus (TRN) and intrinsic interneurons of dLGN. Relay neurons exhibited large glutamatergic responses that continued to increase in amplitude with each successive stimulus pulse. While excitatory responses were apparent at postnatal day 10, the strong facilitation noted in adult was not observed until postnatal day 21. GABAergic neurons in TRN exhibited large initial excitatory responses that quickly plateaued during repetitive stimulation, indicating that the degree of facilitation was much larger for relay cells than for TRN neurons. The responses of intrinsic interneurons were smaller and took the form of a slow depolarization. These differences in the pattern of excitation for different thalamic cell types should help provide a framework for understanding how CT feedback alters the activity of visual thalamic circuitry during sensory processing as well as different behavioral or pathophysiological states. PMID- 23029199 TI - Muscarinic receptors in amygdala control trace fear conditioning. AB - Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF) is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs) and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA). The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine) or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning. PMID- 23029200 TI - Glutamyl phosphate is an activated intermediate in actin crosslinking by actin crosslinking domain (ACD) toxin. AB - Actin Crosslinking Domain (ACD) is produced by several life-threatening Gram negative pathogenic bacteria as part of larger toxins and delivered into the cytoplasm of eukaryotic host cells via Type I or Type VI secretion systems. Upon delivery, ACD disrupts the actin cytoskeleton by catalyzing intermolecular amide bond formation between E270 and K50 residues of actin, leading to the formation of polymerization-deficient actin oligomers. Ultimately, accumulation of the crosslinked oligomers results in structural and functional failure of the actin cytoskeleton in affected cells. In the present work, we advanced in our understanding of the ACD catalytic mechanism by discovering that the enzyme transfers the gamma-phosphoryl group of ATP to the E270 actin residue, resulting in the formation of an activated acyl phosphate intermediate. This intermediate is further hydrolyzed and the energy of hydrolysis is utilized for the formation of the amide bond between actin subunits. We also determined the pH optimum for the reaction and the kinetic parameters of ACD catalysis for its substrates, ATP and actin. ACD showed sigmoidal, non-Michaelis-Menten kinetics for actin (K(0.5) = 30 uM) reflecting involvement of two actin molecules in a single crosslinking event. We established that ACD can also utilize Mg(2+)-GTP to support crosslinking, but the kinetic parameters (K(M) = 8 uM and 50 uM for ATP and GTP, respectively) suggest that ATP is the primary substrate of ACD in vivo. The optimal pH for ACD activity was in the range of 7.0-9.0. The elucidated kinetic mechanism of ACD toxicity adds to understanding of complex network of host pathogen interactions. PMID- 23029202 TI - Specifying the probability characteristics of funnel plot control limits: an investigation of three approaches. AB - BACKGROUND: Emphasis is increasingly being placed on the monitoring and comparison of clinical outcomes between healthcare providers. Funnel plots have become a standard graphical methodology to identify outliers and comprise plotting an outcome summary statistic from each provider against a specified 'target' together with upper and lower control limits. With discrete probability distributions it is not possible to specify the exact probability that an observation from an 'in-control' provider will fall outside the control limits. However, general probability characteristics can be set and specified using interpolation methods. Guidelines recommend that providers falling outside such control limits should be investigated, potentially with significant consequences, so it is important that the properties of the limits are understood. METHODS: Control limits for funnel plots for the Standardised Mortality Ratio (SMR) based on the Poisson distribution were calculated using three proposed interpolation methods and the probability calculated of an 'in-control' provider falling outside of the limits. Examples using published data were shown to demonstrate the potential differences in the identification of outliers. RESULTS: The first interpolation method ensured that the probability of an observation of an 'in control' provider falling outside either limit was always less than a specified nominal probability (p). The second method resulted in such an observation falling outside either limit with a probability that could be either greater or less than p, depending on the expected number of events. The third method led to a probability that was always greater than, or equal to, p. CONCLUSION: The use of different interpolation methods can lead to differences in the identification of outliers. This is particularly important when the expected number of events is small. We recommend that users of these methods be aware of the differences, and specify which interpolation method is to be used prior to any analysis. PMID- 23029201 TI - IP-FCM measures physiologic protein-protein interactions modulated by signal transduction and small-molecule drug inhibition. AB - Protein-protein interactions (PPI) mediate the formation of intermolecular networks that control biological signaling. For this reason, PPIs are of outstanding interest in pharmacology, as they display high specificity and may represent a vast pool of potentially druggable targets. However, the study of physiologic PPIs can be limited by conventional assays that often have large sample requirements and relatively low sensitivity. Here, we build on a novel method, immunoprecipitation detected by flow cytometry (IP-FCM), to assess PPI modulation during either signal transduction or pharmacologic inhibition by two different classes of small-molecule compounds. First, we showed that IP-FCM can detect statistically significant differences in samples possessing a defined PPI change as low as 10%. This sensitivity allowed IP-FCM to detect a PPI that increases transiently during T cell signaling, the antigen-inducible interaction between ZAP70 and the T cell antigen receptor (TCR)/CD3 complex. In contrast, IP FCM detected no ZAP70 recruitment when T cells were stimulated with antigen in the presence of the src-family kinase inhibitor, PP2. Further, we tested whether IP-FCM possessed sufficient sensitivity to detect the effect of a second, rare class of compounds called SMIPPI (small-molecule inhibitor of PPI). We found that the first-generation non-optimized SMIPPI, Ro-26-4550, inhibited the IL-2:CD25 interaction detected by IP-FCM. This inhibition was detectable using either a recombinant CD25-Fc chimera or physiologic full-length CD25 captured from T cell lysates. Thus, we demonstrate that IP-FCM is a sensitive tool for measuring physiologic PPIs that are modulated by signal transduction and pharmacologic inhibition. PMID- 23029203 TI - Quantitative live imaging of endogenous DNA replication in mammalian cells. AB - Historically, the analysis of DNA replication in mammalian tissue culture cells has been limited to static time points, and the use of nucleoside analogues to pulse-label replicating DNA. Here we characterize for the first time a novel Chromobody cell line that specifically labels endogenous PCNA. By combining this with high-resolution confocal time-lapse microscopy, and with a simplified analysis workflow, we were able to produce highly detailed, reproducible, quantitative 4D data on endogenous DNA replication. The increased resolution allowed accurate classification and segregation of S phase into early-, mid-, and late-stages based on the unique subcellular localization of endogenous PCNA. Surprisingly, this localization was slightly but significantly different from previous studies, which utilized over-expressed GFP tagged forms of PCNA. Finally, low dose exposure to Hydroxyurea caused the loss of mid- and late-S phase localization patterns of endogenous PCNA, despite cells eventually completing S phase. Taken together, these results indicate that this simplified method can be used to accurately identify and quantify DNA replication under multiple and various experimental conditions. PMID- 23029204 TI - Overexpression of miR-30b in the developing mouse mammary gland causes a lactation defect and delays involution. AB - BACKGROUND: MicroRNA (miRNA) are negative regulators of gene expression, capable of exerting pronounced influences upon the translation and stability of mRNA. They are potential regulators of normal mammary gland development and of the maintenance of mammary epithelial progenitor cells. This study was undertaken to determine the role of miR-30b on the establishment of a functional mouse mammary gland. miR-30b is a member of the miR-30 family, composed of 6 miRNA that are highly conserved in vertebrates. It has been suggested to play a role in the differentiation of several cell types. METHODOLOGY/PRINCIPAL FINDINGS: The expression of miR-30b was found to be regulated during mammary gland development. Transgenic mice overexpressing miR-30b in mammary epithelial cells were used to investigate its role. During lactation, mammary histological analysis of the transgenic mice showed a reduction in the size of alveolar lumen, a defect of the lipid droplets and a growth defect of pups fed by transgenic females. Moreover some mammary epithelial differentiated structures persisted during involution, suggesting a delay in the process. The genes whose expression was affected by the overexpression of miR-30b were characterized by microarray analysis. CONCLUSION/SIGNIFICANCE: Our data suggests that miR-30b is important for the biology of the mammary gland and demonstrates that the deregulation of only one miRNA could affect lactation and involution. PMID- 23029205 TI - Age-related disease association of endogenous gamma-H2AX foci in mononuclear cells derived from leukapheresis. AB - The phosphorylated form of histone H2AX (gamma-H2AX) forms immunohistochemically detectable foci at DNA double strand breaks. In peripheral blood mononuclear cells (PBMCs) derived from leukapheresis from patients enrolled in the Baltimore Longitudinal Study of Aging, gamma-H2AX foci increased in a linear fashion with regards to age, peaking at ~57 years. The relationship between the frequency of gamma-H2AX foci and age-related pathologies was assessed. We found a statistically significant (p = 0.023) 50% increase in foci in PBMCs derived from patients with a known history of vitamin D deficiency. In addition, there were trends toward increased gamma-H2AX foci in patients with cataracts (34% increase, p<0.10) and in sleep apnea patients (44%, p<0.10). Among patients >=57 y/o, we found a significant (p = 0.037) 36% increase in the number of gamma-H2AX foci/cell for patients with hypertension compared to non-hypertensive patients. Our results support a role for increased DNA damage in the morbidity of age related diseases. gamma -H2AX may be a biomarker for human morbidity in age related diseases. PMID- 23029206 TI - The movement ecology of the straw-colored fruit bat, Eidolon helvum, in sub Saharan Africa assessed by stable isotope ratios. AB - Flying foxes (Pteropodidae) are key seed dispersers on the African continent, yet their migratory behavior is largely unknown. Here, we studied the movement ecology of the straw-colored fruit bat, Eidolon helvum, and other fruit bats by analyzing stable isotope ratios in fur collected from museum specimens. In a triple-isotope approach based on samples of two ecologically similar non migratory pteropodids, we first confirmed that a stable isotope approach is capable of delineating between geographically distinct locations in Sub-Saharan Africa. A discriminant function analysis assigned 84% of individuals correctly to their capture site. Further, we assessed how well hydrogen stable isotope ratios (delta(2)H) of fur keratin collected from non-migratory species (n = 191 individuals) records variation in delta(2)H of precipitation water in sub-Saharan Africa. Overall, we found positive, negative and no correlations within the six studied species. We then developed a reduced major axis regression equation based on individual data of non-migratory species to predict where potentially migratory E. helvum (n = 88) would come from based on their keratin delta(2)H. Across non-migratory species, delta(2)H of keratin and local water correlated positively. Based on the isoscape origin model, 22% of E. helvum were migratory, i.e. individuals had migrated over at least 250 km prior to their capture. Migratory individuals came from locations at a median distance of about 860 km from the collection site, four even from distances of at least 2,000 km. Ground truthing of our isoscape origin model based on keratin delta(2)H of extant E. helvum (n = 76) supported a high predictive power of assigning the provenance of African flying foxes. Our study highlights that stable isotope ratios can be used to explain the migratory behavior of flying foxes, even on the isotopically relatively homogenous African continent, and with material collected by museums many decades or more than a century ago. PMID- 23029207 TI - Functional analysis of Rift Valley fever virus NSs encoding a partial truncation. AB - Rift Valley fever virus (RVFV), belongs to genus Phlebovirus of the family Bunyaviridae, causes high rates of abortion and fetal malformation in infected ruminants as well as causing neurological disorders, blindness, or lethal hemorrhagic fever in humans. RVFV is classified as a category A priority pathogen and a select agent in the U.S., and currently there are no therapeutics available for RVF patients. NSs protein, a major virulence factor of RVFV, inhibits host transcription including interferon (IFN)-beta mRNA synthesis and promotes degradation of dsRNA-dependent protein kinase (PKR). NSs self-associates at the C terminus 17 aa., while NSs at aa.210-230 binds to Sin3A-associated protein (SAP30) to inhibit the activation of IFN-beta promoter. Thus, we hypothesize that NSs function(s) can be abolished by truncation of specific domains, and co expression of nonfunctional NSs with intact NSs will result in the attenuation of NSs function by dominant-negative effect. Unexpectedly, we found that RVFV NSs truncated at aa. 6-30, 31-55, 56-80, 81-105, 106-130, 131-155, 156-180, 181-205, 206-230, 231-248 or 249-265 lack functions of IFN-beta mRNA synthesis inhibition and degradation of PKR. Truncated NSs were less stable in infected cells, while nuclear localization was inhibited in NSs lacking either of aa.81-105, 106-130, 131-155, 156-180, 181-205, 206-230 or 231-248. Furthermore, none of truncated NSs had exhibited significant dominant-negative functions for NSs-mediated IFN-beta suppression or PKR degradation upon co-expression in cells infected with RVFV. We also found that any of truncated NSs except for intact NSs does not interact with RVFV NSs even in the presence of intact C-terminus self-association domain. Our results suggest that conformational integrity of NSs is important for the stability, cellular localization and biological functions of RVFV NSs, and the co expression of truncated NSs does not exhibit dominant-negative phenotype. PMID- 23029208 TI - Development and function of the voltage-gated sodium current in immature mammalian cochlear inner hair cells. AB - Inner hair cells (IHCs), the primary sensory receptors of the mammalian cochlea, fire spontaneous Ca(2+) action potentials before the onset of hearing. Although this firing activity is mainly sustained by a depolarizing L-type (Ca(V)1.3) Ca(2+) current (I(Ca)), IHCs also transiently express a large Na(+) current (I(Na)). We aimed to investigate the specific contribution of I(Na) to the action potentials, the nature of the channels carrying the current and whether the biophysical properties of I(Na) differ between low- and high-frequency IHCs. We show that I(Na) is highly temperature-dependent and activates at around -60 mV, close to the action potential threshold. Its size was larger in apical than in basal IHCs and between 5% and 20% should be available at around the resting membrane potential (-55 mV/-60 mV). However, in vivo the availability of I(Na) could potentially increase to >60% during inhibitory postsynaptic potential activity, which transiently hyperpolarize IHCs down to as far as -70 mV. When IHCs were held at -60 mV and I(Na) elicited using a simulated action potential as a voltage command, we found that I(Na) contributed to the subthreshold depolarization and upstroke of an action potential. We also found that I(Na) is likely to be carried by the TTX-sensitive channel subunits Na(V)1.1 and Na(V)1.6 in both apical and basal IHCs. The results provide insight into how the biophysical properties of I(Na) in mammalian cochlear IHCs could contribute to the spontaneous physiological activity during cochlear maturation in vivo. PMID- 23029210 TI - An extract of Crataegus pinnatifida fruit attenuates airway inflammation by modulation of matrix metalloproteinase-9 in ovalbumin induced asthma. AB - BACKGROUND: Crataegus pinnatifida (Chinese hawthorn) has long been used as a herbal medicine in Asia and Europe. It has been used for the treatment of various cardiovascular diseases such as myocardial weakness, tachycardia, hypertension and arteriosclerosis. In this study, we investigated the anti-inflammatory effects of Crataegus pinnatifida ethanolic extracts (CPEE) on Th2-type cytokines, eosinophil infiltration, expression of matrix metalloproteinase (MMP)-9, and other factors, using an ovalbumin (OVA)-induced murine asthma model. METHODS/PRINCIPAL FINDING: Airways of OVA-sensitized mice exposed to OVA challenge developed eosinophilia, mucus hypersecretion and increased cytokine levels. CPEE was applied 1 h prior to OVA challenge. Mice were administered CPEE orally at doses of 100 and 200 mg/kg once daily on days 18-23. Bronchoalveolar lavage fluid (BALF) was collected 48 h after the final OVA challenge. Levels of interleukin (IL)-4 and IL-5 in BALF were measured using enzyme-linked immunosorbent (ELISA) assays. Lung tissue sections 4 um in thickness were stained with Mayer's hematoxylin and eosin for assessment of cell infiltration and mucus production with PAS staining, in conjunction with ELISA, and Western blot analyses for the expression of MMP-9, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 protein expression. CPEE significantly decreased the Th2 cytokines including IL-4 and IL-5 levels, reduced the number of inflammatory cells in BALF and airway hyperresponsiveness, suppressed the infiltration of eosinophil-rich inflammatory cells and mucus hypersecretion and reduced the expression of ICAM-1, VCAM-1 and MMP-9 and the activity of MMP-9 in lung tissue of OVA-challenged mice. CONCLUSIONS: These results showed that CPEE can protect against allergic airway inflammation and can act as an MMP-9 modulator to induce a reduction in ICAM-1 and VCAM-1 expression. In conclusion, we strongly suggest the feasibility of CPEE as a therapeutic drug for allergic asthma. PMID- 23029209 TI - Age-related expansion of Tim-3 expressing T cells in vertically HIV-1 infected children. AB - As perinatally HIV-1-infected children grow into adolescents and young adults, they are increasingly burdened with the long-term consequences of chronic HIV-1 infection, with long-term morbidity due to inadequate immunity. In progressive HIV-1 infection in horizontally infected adults, inflammation, T cell activation, and perturbed T cell differentiation lead to an "immune exhaustion", with decline in T cell effector functions. T effector cells develop an increased expression of CD57 and loss of CD28, with an increase in co-inhibitory receptors such as PD-1 and Tim-3. Very little is known about HIV-1 induced T cell dysfunction in vertical infection. In two perinatally antiretroviral drug treated HIV-1-infected groups with median ages of 11.2 yr and 18.5 yr, matched for viral load, we found no difference in the proportion of senescent CD28(-)CD57(+)CD8(+) T cells between the groups. However, the frequency of Tim-3(+)CD8(+) and Tim-3(+)CD4(+) exhausted T cells, but not PD-1(+) T cells, was significantly increased in the adolescents with longer duration of infection compared to the children with shorter duration of HIV-1 infection. PD-1(+)CD8(+) T cells were directly associated with T cell immune activation in children. The frequency of Tim-3(+)CD8(+) T cells positively correlated with HIV-1 plasma viral load in the adolescents but not in the children. These data suggest that Tim-3 upregulation was driven by both HIV-1 viral replication and increased age, whereas PD-1 expression is associated with immune activation. These findings also suggest that the Tim-3 immune exhaustion phenotype rather than PD-1 or senescent cells plays an important role in age related T cell dysfunction in perinatal HIV-1 infection. Targeting Tim-3 may serve as a novel therapeutic approach to improve immune control of virus replication and mitigate age related T cell exhaustion. PMID- 23029211 TI - Irregular bedtime and nocturnal cellular phone usage as risk factors for being involved in bullying: a cross-sectional survey of Japanese adolescents. AB - PURPOSE: A number of studies have tried to identify risk factors for being involved in bullying in order to help developing preventive measures; however, to our knowledge, no study has investigated the effect of nocturnal lifestyle behavior such as sleep pattern or cellular phone usage. In the present study, we aimed to investigate the relationship between school bullying and sleep pattern or nocturnal cellular phone usage in adolescents. The effect of school size on school bullying was also examined. METHODS: Data from the cross-sectional survey of psychopathologies conducted for 19,436 Japanese students from 45 public junior high schools (7(th)-9(th) grade) and 28 senior high schools (10(th)-12(th) grade) were analyzed. RESULTS: Bullying status was significantly associated with irregular bedtime (OR = 1.23 and 1.41 for pure bullies and bully-victims, respectively) and e-mail exchange or calling after lights-out (OR = 1.53 and 1.31 for pure bullies and bully-victims, respectively) after controlling domestic violence and substance usage. In addition, school size was significantly associated with the increased risk of bullying in junior high school students (OR = 1.13 for bully-victims). CONCLUSIONS: The present results suggested that sleep pattern and nocturnal cellular phone usage might be risk factors for being involved in school bullying in adolescents. Although further accumulation of data is needed, progressive trend towards nocturnal lifestyle and increasing usage of cellular phone might impair the well-being of adolescents. School-based interventions for lifestyle including sleep pattern and cellular phone usage may be encouraged to reduce school bullying. PMID- 23029212 TI - Ex vivo and in silico feasibility study of monitoring electric field distribution in tissue during electroporation based treatments. AB - Magnetic resonance electrical impedance tomography (MREIT) was recently proposed for determining electric field distribution during electroporation in which cell membrane permeability is temporary increased by application of an external high electric field. The method was already successfully applied for reconstruction of electric field distribution in agar phantoms. Before the next step towards in vivo experiments is taken, monitoring of electric field distribution during electroporation of ex vivo tissue ex vivo and feasibility for its use in electroporation based treatments needed to be evaluated. Sequences of high voltage pulses were applied to chicken liver tissue in order to expose it to electric field which was measured by means of MREIT. MREIT was also evaluated for its use in electroporation based treatments by calculating electric field distribution for two regions, the tumor and the tumor-liver region, in a numerical model based on data obtained from clinical study on electrochemotherapy treatment of deep-seated tumors. Electric field distribution inside tissue was successfully measured ex vivo using MREIT and significant changes of tissue electrical conductivity were observed in the region of the highest electric field. A good agreement was obtained between the electric field distribution obtained by MREIT and the actual electric field distribution in evaluated regions of a numerical model, suggesting that implementation of MREIT could thus enable efficient detection of areas with insufficient electric field coverage during electroporation based treatments, thus assuring the effectiveness of the treatment. PMID- 23029213 TI - Cardiopulmonary bypass during cardiac surgery modulates systemic inflammation by affecting different steps of the leukocyte recruitment cascade. AB - BACKGROUND: It is known that the use of a cardiopulmonary bypass (CPB) during cardiac surgery leads to leukocyte activation and may, among other causes, induce organ dysfunction due to increased leukocyte recruitment into different organs. Leukocyte extravasation occurs in a cascade-like fashion, including capturing, rolling, adhesion, and transmigration. However, the molecular mechanisms of increased leukocyte recruitment caused by CPB are not known. This clinical study was undertaken in order to investigate which steps of the leukocyte recruitment cascade are affected by the systemic inflammation during CPB. METHODS: We investigated the effects of CPB on the different steps of the leukocyte recruitment cascade in whole blood from healthy volunteers (n = 9) and patients undergoing cardiac surgery with the use of cardiopulmonary bypass (n = 7) or in off-pump coronary artery bypass-technique (OPCAB, n = 9) by using flow chamber experiments, transmigration assays, and biochemical analysis. RESULTS: CPB abrogated selectin-induced slow leukocyte rolling on E-selectin/ICAM-1 and P selectin/ICAM-1. In contrast, chemokine-induced arrest and transmigration was significantly increased by CPB. Mechanistically, the abolishment of slow leukocyte rolling was due to disturbances in intracellular signaling with reduced phosphorylation of phospholipase C (PLC) gamma2, Akt, and p38 MAP kinase. Furthermore, CPB induced an elevated transmigration which was caused by upregulation of Mac-1 on neutrophils. CONCLUSION: These data suggest that CPB abrogates selectin-mediated slow leukocyte rolling by disturbing intracellular signaling, but that the clinically observed increased leukocyte recruitment caused by CPB is due to increased chemokine-induced arrest and transmigration. A better understanding of the underlying molecular mechanisms causing systemic inflammation after CPB may aid in the development of new therapeutic approaches. PMID- 23029214 TI - A high density consensus genetic map of tetraploid cotton that integrates multiple component maps through molecular marker redundancy check. AB - A consensus genetic map of tetraploid cotton was constructed using six high density maps and after the integration of a sequence-based marker redundancy check. Public cotton SSR libraries (17,343 markers) were curated for sequence redundancy using 90% as a similarity cutoff. As a result, 20% of the markers (3,410) could be considered as redundant with some other markers. The marker redundancy information had been a crucial part of the map integration process, in which the six most informative interspecific Gossypium hirsutum*G. barbadense genetic maps were used for assembling a high density consensus (HDC) map for tetraploid cotton. With redundant markers being removed, the HDC map could be constructed thanks to the sufficient number of collinear non-redundant markers in common between the component maps. The HDC map consists of 8,254 loci, originating from 6,669 markers, and spans 4,070 cM, with an average of 2 loci per cM. The HDC map presents a high rate of locus duplications, as 1,292 markers among the 6,669 were mapped in more than one locus. Two thirds of the duplications are bridging homoeologous A(T) and D(T) chromosomes constitutive of allopolyploid cotton genome, with an average of 64 duplications per A(T)/D(T) chromosome pair. Sequences of 4,744 mapped markers were used for a mutual blast alignment (BBMH) with the 13 major scaffolds of the recently released Gossypium raimondii genome indicating high level of homology between the diploid D genome and the tetraploid cotton genetic map, with only a few minor possible structural rearrangements. Overall, the HDC map will serve as a valuable resource for trait QTL comparative mapping, map-based cloning of important genes, and better understanding of the genome structure and evolution of tetraploid cotton. PMID- 23029215 TI - Interaction between Medicago truncatula and Pseudomonas fluorescens: evaluation of costs and benefits across an elevated atmospheric CO(2). AB - Soil microorganisms play a key role in both plants nutrition and health. Their relation with plant varies from mutualism to parasitism, according to the balance of costs and benefits for the two partners of the interaction. These interactions involved the liberation of plant organic compounds via rhizodeposition. Modification of atmospheric CO(2) concentration may affect rhizodeposition and as a consequence trophic interactions that bind plants and microorganisms. Positive effect of elevated CO(2) on plants are rather well known but consequences for micoorganisms and their interactions with plants are still poorly understood. A gnotobiotic system has been developed to study the interaction between Medicago truncatula Jemalong J5 and the mutualistic bacteria Pseudomonas fluorescens strain C7R12 under two atmospheric CO(2) concentrations: ambient (365 ppm) versus enriched (750 ppm). Costs and benefits for each partner have been determined over time by measuring plant development and growth, the C and N contents of the various plant parts and the density of the bacteria in rhizosphere compartments. Following the increase in CO(2), there was a beneficial effect of P. fluorescens C7R12 on development, vegetative growth, and C/N content of M. truncatula. Concerning plant reproduction, an early seed production was noticed in presence of the bacterial strain combined with increased atmospheric CO(2) conditions. Paradoxically, this transient increase in seed production was correlated with a decrease in bacterial density in the rhizosphere soil, revealing a cost of increased CO(2) for the bacterial strain. This shift of costs-benefits ratio disappeared later during the plant growth. In conclusion, the increase in CO(2) concentration modifies transiently the cost-benefit balance in favor of the plant. These results may be explained either by a competition between the two partners or a change in bacterial physiology. The ecosystem functioning depends on the stability of many plant-microbe associations that abiotic factors can disrupt. PMID- 23029216 TI - Rhomboids of Mycobacteria: characterization using an aarA mutant of Providencia stuartii and gene deletion in Mycobacterium smegmatis. AB - BACKGROUND: Rhomboids are ubiquitous proteins with unknown roles in mycobacteria. However, bioinformatics suggested putative roles in DNA replication pathways and metabolite transport. Here, mycobacterial rhomboid-encoding genes were characterized; first, using the Providencia stuartii null-rhomboid mutant and then deleted from Mycobacterium smegmatis for additional insight in mycobacteria. METHODOLOGY/PRINCIPAL FINDINGS: Using in silico analysis we identified in M. tuberculosis genome the genes encoding two putative rhomboid proteins; Rv0110 (referred to as "rhomboid protease 1") and Rv1337 ("rhomboid protease 2"). Genes encoding orthologs of these proteins are widely represented in all mycobacterial species. When transformed into P. stuartii null-rhomboid mutant (DeltaaarA), genes encoding mycobacterial orthologs of "rhomboid protease 2" fully restored AarA activity (AarA is the rhomboid protein of P. stuartii). However, most genes encoding mycobacterial "rhomboid protease 1" orthologs did not. Furthermore, upon gene deletion in M. smegmatis, the DeltaMSMEG_4904 single mutant (which lost the gene encoding MSMEG_4904, orthologous to Rv1337, "rhomboid protease 2") formed the least biofilms and was also more susceptible to ciprofloxacin and novobiocin, antimicrobials that inhibit DNA gyrase. However, the DeltaMSMEG_5036 single mutant (which lost the gene encoding MSMEG_5036, orthologous to Rv0110, "rhomboid protease 1") was not as susceptible. Surprisingly, the double rhomboid mutant DeltaMSMEG_4904-DeltaMSMEG_5036 (which lost genes encoding both homologs) was also not as susceptible suggesting compensatory effects following deletion of both rhomboid-encoding genes. Indeed, transforming the double mutant with a plasmid encoding MSMEG_5036 produced phenotypes of the DeltaMSMEG_4904 single mutant (i.e. susceptibility to ciprofloxacin and novobiocin). CONCLUSIONS/SIGNIFICANCE: Mycobacterial rhomboid-encoding genes exhibit differences in complementing aarA whereby it's only genes encoding "rhomboid protease 2" orthologs that fully restore AarA activity. Additionally, gene deletion data suggests inhibition of DNA gyrase by MSMEG_4904; however, the ameliorated effect in the double mutant suggests occurrence of compensatory mechanisms following deletion of genes encoding both rhomboids. PMID- 23029217 TI - Correlation of humoral immune response in southern bluefin tuna, T. maccoyii, with infection stage of the blood fluke, Cardicola forsteri. AB - The blood fluke, Cardicola forsteri, is a prevalent infection in ranched southern bluefin tuna. This project aimed to define the timing and intensity of the various developmental stages of C. forsteri within southern bluefin tuna as well as to relate infection to host pathology and immune response. Archival samples from several cohorts of T. maccoyii sampled from 2008 to 2010 were used in this study. The prevalence and intensity of C. forsteri infection was described using heart flushes and histological examination. Humoral immune response, i.e. C. forsteri specific antibody, lysozyme activity, and alternative complement activity, was also described. Based on the validated and detailed C. forsteri infection timeline, relationships between infection events, physiological response, and diagnosis were proposed. Immune response developed concurrently with C. forsteri infection, with the majority of physiological response coinciding with commencing egg production. Further research is needed to confirm the origin of C. forsteri antigen which is responsible for immune response development and how T. maccoyii immune response works against infection. To aide this research, further diagnostic methods for confirmation of infection need to be developed. PMID- 23029218 TI - Transcriptome analysis of responses to rhodomyrtone in methicillin-resistant Staphylococcus aureus. AB - Rhodomyrtone, purified from Rhodomyrtus tomentosa (Aiton) Hassk, exhibits a high degree of potency against methicillin-resistant Staphylococcus aureus (MRSA). We recently demonstrated that exposure of MRSA to a subinhibitory concentration (0.174 ug/ml) of rhodomyrtone resulted in the alteration of expression of several functional classes of bacterial proteins. To provide further insight into the antibacterial mode of action of this compound, we determined the impact of exposure to rhodomyrtone on the gene transcriptional profile of MRSA using microarray analysis. Exposure of MRSA to subinhibitory concentrations (0.5MIC; 0.5 ug/ml) of rhodomyrtone revealed significant modulation of gene expression, with induction of 64 genes and repression of 35 genes. Prominent changes in response to exposure to rhodomyrtone involved genes encoding proteins essential to metabolic pathways and processes such as amino acid metabolism, membrane function, ATP-binding cassette (ABC) transportation and lipoprotein and nucleotide metabolism. Genes involved in the synthesis of the aspartate family of amino acids, in particular proteins encoded by the dap operon were prominent. The diaminopimelate (DAP) biosynthetic pathway is the precursor of lysine synthesis and is essential for peptidoglycan biosynthesis. However, phenotypic analysis of the peptidoglycan amino acid content of rhodomyrtone-treated MRSA did not differ significantly from that extracted from control cells. Genes involved in the biosynthesis of amino acids and peptidoglycan, and a high affinity ATP-driven K ((+)) transport system, were investigated by quantitative reverse transcription PCR (qRT-PCR) using EMRSA-16 1, 4, or 18 h after exposure to rhodomyrtone and in general the data concurred with that obtained by microarray, highlighting the relevance of the DAP biosynthetic pathway to the mode of action of rhodomyrtone. PMID- 23029220 TI - Household food insecurity is not associated with BMI for age or weight for height among Brazilian children aged 0-60 months. AB - We examined the association between Household Food Insecurity (HFI), weight for height z-score (WHZ) and Body Mass Index for age z-score (BMI-Z) in a representative sample of children 0-60 months of age (n = 3,433) in five Brazilian geographical regions. Data were derived from the 2006-07 Brazilian Demographic and Health Survey. HFI was measured with the Brazilian Food Insecurity Scale. Associations were estimated using multiple linear regression models (beta coefficients and 95% CI) taking into account the complex sampling design. Interaction terms between HFI and geographical region and HFI and child sex and child age were assessed. The weighted prevalence of any level of HFI was 48.6%. Severe food insecurity was more prevalent among children from the North region (16.8%), born from mothers with <4 years of schooling (15.9%) and those from families with >=3 children (18.8%). The interaction between HFI and geographical region was non-significant for BMI-Z (P = 0.119) and WHZ (P = 0.198). Unadjusted results indicated that HFI was negatively associated with BMI Z (moderate to severe HFI: beta = -0.19, 95% CI: -0.35 - -0.03, P = 0.047), and WHZ (moderate to severe HFI: beta = -0.26, 95% CI: -0.42 - -0.09, P = 0.009). Estimates lost significance after adjustments for key confounders such as mothers' skin color, mothers' years of schooling, place of household, household income quartiles, mothers' smoking habit, mothers' marital status, number of children 0-60 months in the household, and birth order. HFI is unrelated to weight outcomes among Brazilian children 0-60 months. PMID- 23029219 TI - Illuminating the off-pathway nature of the molten globule folding intermediate of an alpha-beta parallel protein. AB - Partially folded protein species transiently form during folding of most proteins. Often, these species are molten globules, which may be on- or off pathway to the native state. Molten globules are ensembles of interconverting protein conformers that have a substantial amount of secondary structure, but lack virtually all tertiary side-chain packing characteristics of natively folded proteins. Due to solvent-exposed hydrophobic groups, molten globules are prone to aggregation, which can have detrimental effects on organisms. The molten globule observed during folding of the 179-residue apoflavodoxin from Azotobacter vinelandii is off-pathway, as it has to unfold before native protein can form. Here, we study folding of apoflavodoxin and characterize its molten globule using fluorescence spectroscopy and Forster Resonance Energy Transfer (FRET). Apoflavodoxin is site-specifically labeled with fluorescent donor and acceptor dyes, utilizing dye-inaccessibility of Cys69 in cofactor-bound protein. Donor (i.e., Alexa Fluor 488) is covalently attached to Cys69 in all apoflavodoxin variants used. Acceptor (i.e., Alexa Fluor 568) is coupled to Cys1, Cys131 and Cys178, respectively. Our FRET data show that apoflavodoxin's molten globule forms in a non-cooperative manner and that its N-terminal 69 residues fold last. In addition, striking conformational differences between molten globule and native protein are revealed, because the inter-label distances sampled in the 111 residue C-terminal segment of the molten globule are shorter than observed for native apoflavodoxin. Thus, FRET sheds light on the off-pathway nature of the molten globule during folding of an alpha-beta parallel protein. PMID- 23029221 TI - Serum acylated ghrelin concentrations in response to short-term overfeeding in normal weight, overweight, and obese men. AB - BACKGROUND: Ghrelin, an orexigenic gut hormone secreted primarily from the stomach, is involved in energy homeostasis. However, little data is available regarding its response to energy surplus and the development of human obesity. OBJECTIVE: The present study investigated the response of circulating acylated ghrelin to a 7-day positive energy challenge. DESIGN: A total of 68 healthy young men were overfed 70% more calories than required, for 1-week. Subjects were classified based on percent body fat (measured by dual-energy X-ray absorptiometry) as normal weight, overweight, and obese. Serum acylated ghrelin concentration was measured before and after the positive energy challenge. Additionally, the relationship between acylated ghrelin and obesity-related phenotypes including weight, body mass index, percent body fat, cholesterol, HDL c, LDL-c, glucose, insulin and homeostasis model assessment of insulin resistance and beta-cell function at baseline and change due to overfeeding, were assessed. RESULTS: Contrary to our expectations, serum acylated ghrelin was significantly increased in response to overfeeding and the increase was independent of obesity status. There was no significant difference in fasting acylated ghrelin between normal weight, overweight, and obese men at baseline. Acylated ghrelin was negatively correlated with weight and BMI for normal weight and with BMI in overweight men. Also ghrelin was correlated with change in weight and BMI in overweight (negative relationship) and obese (positive relationship) groups. CONCLUSION: Our results showed that circulating acylated ghrelin was increased after a 7-day positive energy challenge regardless of adiposity status. However, acylated ghrelin was correlated with change in weight and BMI in opposing directions, in overweight and obese subjects respectively, thus dependent on obesity status. PMID- 23029222 TI - Herpes simplex virus 1 ICP22 inhibits the transcription of viral gene promoters by binding to and blocking the recruitment of P-TEFb. AB - ICP22 is a multifunctional herpes simplex virus 1 (HSV-1) immediate early protein that functions as a general repressor of a subset of cellular and viral promoters in transient expression systems. Although the exact mechanism of repression remains unclear, this protein induces a decrease in RNA polymerase II Serine 2 (RNAPII Ser-2) phosphorylation, which is critical for transcription elongation. To characterize the mechanism of transcriptional repression by ICP22, we established an in vivo transient expression reporter system. We found that ICP22 inhibits transcription of the HSV-1 alpha, beta and gamma gene promoters. The viral tegument protein VP16, which plays vital roles in initiation of viral gene expression and viral proliferation, can overcome the inhibitory effect of ICP22 on alpha-gene transcription. Further immunoprecipitation studies indicated that both ICP22 and VP16 bind to positive transcription elongation factor b (P-TEFb) and form a complex with it in vivo. We extended this to show that P-TEFb regulates transcription of the viral alpha-gene promoters and affects transcriptional regulation of ICP22 and VP16 on the alpha-genes. Additionally, ChIP assays demonstrated that ICP22 blocks the recruitment of P-TEFb to the viral promoters, while VP16 reverses this blocking effect by recruiting P-TEFb to the viral alpha-gene promoters through recognition of the TAATGARAT motif. Taken together, our results suggest that ICP22 interacts with and blocks the recruitment of P-TEFb to viral promoter regions, which inhibits transcription of the viral gene promoters. The transactivator VP16 binds to and induces the recruitment of P-TEFb to viral alpha-gene promoters, which counteracts the transcriptional repression of ICP22 on alpha-genes by recruiting p-TEFb to the promoter region. PMID- 23029223 TI - Comparative analysis of FLC homologues in Brassicaceae provides insight into their role in the evolution of oilseed rape. AB - We identified nine FLOWERING LOCUS C homologues (BnFLC) in Brassica napus and found that the coding sequences of all BnFLCs were relatively conserved but the intronic and promoter regions were more divergent. The BnFLC homologues were mapped to six of 19 chromosomes. All of the BnFLC homologues were located in the collinear region of FLC in the Arabidopsis genome except BnFLC.A3b and BnFLC.C3b, which were mapped to noncollinear regions of chromosome A3 and C3, respectively. Four of the homologues were associated significantly with quantitative trait loci for flowering time in two mapping populations. The BnFLC homologues showed distinct expression patterns in vegetative and reproductive organs, and at different developmental stages. BnFLC.A3b was differentially expressed between the winter-type and semi-winter-type cultivars. Microsynteny analysis indicated that BnFLC.A3b might have been translocated to the present segment in a cluster with other flowering-time regulators, such as a homologue of FRIGIDA in Arabidopsis. This cluster of flowering-time genes might have conferred a selective advantage to Brassica species in terms of increased adaptability to diverse environments during their evolution and domestication process. PMID- 23029224 TI - ROC generated thresholds for field-assessed aerobic fitness related to body size and cardiometabolic risk in schoolchildren. AB - OBJECTIVES: 1. to investigate whether 20 m multi-stage shuttle run performance (20mSRT), an indirect measure of aerobic fitness, could discriminate between healthy and overweight status in 9-10.9 yr old schoolchildren using Receiver Operating Characteristic (ROC) analysis; 2. Investigate if cardiometabolic risk differed by aerobic fitness group by applying the ROC cut point to a second, cross-sectional cohort. DESIGN: Analysis of cross-sectional data. PARTICIPANTS: 16,619 9-10.9 year old participants from SportsLinx project and 300 11-13.9 year old participants from the Welsh Schools Health and Fitness Study. OUTCOME MEASURES: SportsLinx; 20mSRT, body mass index (BMI), waist circumference, subscapular and superilliac skinfold thicknesses. Welsh Schools Health and Fitness Study; 20mSRT performance, waist circumference, and clustered cardiometabolic risk. ANALYSES: Three ROC curve analyses were completed, each using 20mSRT performance with ROC curve 1 related to BMI, curve 2 was related to waist circumference and 3 was related to skinfolds (estimated % body fat). These were repeated for both girls and boys. The mean of the three aerobic fitness thresholds was retained for analysis. The thresholds were subsequently applied to clustered cardiometabolic risk data from the Welsh Schools study to assess whether risk differed by aerobic fitness group. RESULTS: The diagnostic accuracy of the ROC generated thresholds was higher than would be expected by chance (all models AUC >0.7). The mean thresholds were 33 and 25 shuttles for boys and girls respectively. Participants classified as 'fit' had significantly lower cardiometabolic risk scores in comparison to those classed as unfit (p<0.001). CONCLUSION: The use of the ROC generated cut points by health professionals, teachers and coaches may provide the opportunity to apply population level 'risk identification and stratification' processes and plan for "at-risk" children to be referred onto intervention services. PMID- 23029225 TI - Identification of prostate-specific G-protein coupled receptor as a tumor antigen recognized by CD8(+) T cells for cancer immunotherapy. AB - BACKGROUND: Prostate cancer is the most common cancer among elderly men in the US, and immunotherapy has been shown to be a promising strategy to treat patients with metastatic castration-resistant prostate cancer. Efforts to identify novel prostate specific tumor antigens will facilitate the development of effective cancer vaccines against prostate cancer. Prostate-specific G-protein coupled receptor (PSGR) is a novel antigen that has been shown to be specifically over expressed in human prostate cancer tissues. In this study, we describe the identification of PSGR-derived peptide epitopes recognized by CD8(+) T cells in an HLA-A2 dependent manner. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-one PSGR derived peptides were predicted by an immuno-informatics approach based on the HLA-A2 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs) obtained from either HLA-A2(+) healthy donors or HLA-A2(+) prostate cancer patients. The recognition of HLA-A2 positive and PSGR expressing LNCaP cells was also tested. Among the 21 PSGR-derived peptides, three peptides, PSGR3, PSGR4 and PSGR14 frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and prostate cancer patients. Importantly, these peptide-specific T cells recognized and killed LNCaP prostate cancer cells in an HLA class I restricted manner. CONCLUSIONS/SIGNIFICANCE: We have identified three novel HLA A2-restricted PSGR-derived peptides recognized by CD8(+) T cells, which, in turn, recognize HLA-A2(+) and PSGR(+) tumor cells. The PSGR-derived peptides identified may be used as diagnostic markers as well as immune targets for development of anticancer vaccines. PMID- 23029226 TI - Identifying more epidemic clones during a hospital outbreak of multidrug resistant Acinetobacter baumannii. AB - Infections caused by multidrug-resistant bacteria are a major concern in hospitals. Current infection-control practices legitimately focus on hygiene and appropriate use of antibiotics. However, little is known about the intrinsic abilities of some bacterial strains to cause outbreaks. They can be measured at a population level by the pathogen's transmission rate, i.e. the rate at which the pathogen is transmitted from colonized hosts to susceptible hosts, or its reproduction number, counting the number of secondary cases per infected/colonized host. We collected data covering a 20-month surveillance period for carriage of multidrug-resistant Acinetobacter baumannii (MDRAB) in a surgery ward. All isolates were subjected to molecular fingerprinting, and a cluster analysis of profiles was performed to identify clonal groups. We then applied stochastic transmission models to infer transmission rates of MDRAB and each MDRAB clone. Molecular fingerprinting indicated that 3 clonal complexes spread in the ward. A first model, not accounting for different clones, quantified the level of in-ward cross-transmission, with an estimated transmission rate of 0.03/day (95% credible interval [0.012-0.049]) and a single admission reproduction number of 0.61 [0.30-1.02]. The second model, accounting for different clones, suggested an enhanced transmissibility of clone 3 (transmission rate 0.047/day [0.018-0.091], with a single-admission reproduction number of 0.81 [0.30-1.56]). Clones 1 and 2 had comparable transmission rates (respectively, 0.016 [0.001-0.045], 0.014 [0.001-0.045]). The method used is broadly applicable to other nosocomial pathogens, as long as surveillance data and genotyping information are available. Building on these results, more epidemic clones could be identified, and could lead to follow-up studies dissecting the functional basis for variation in transmissibility of MDRAB lineages. PMID- 23029227 TI - U2AF1 mutations in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. AB - Somatic mutations of U2AF1 gene have recently been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we analyzed the frequency and clinical impact of U2AF1 mutations in a cohort of 452 Chinese patients with myeloid neoplasms. Mutations in U2AF1 were found in 2.5% (7/275) of AML and 6.3% (6/96) of MDS patients, but in none of 81 CML. All mutations were heterozygous missense mutations affecting codon S34 or Q157. There was no significant association of U2AF1 mutation with blood parameters, FAB subtypes, karyotypes and other gene mutations in AML. The overall survival (OS) of AML patients with U2AF1 mutation (median 3 months) was shorter than those without mutation (median 7 months) (P = 0.035). No difference in the OS was observed between MDS patients with and without U2AF1 mutations. Our data show that U2AF1 mutation is a recurrent event at a low frequency in AML and MDS. PMID- 23029228 TI - The miR-17 family links p63 protein to MAPK signaling to promote the onset of human keratinocyte differentiation. AB - The p63 protein plays a key role in regulating human keratinocyte proliferation and differentiation. Although some p63-regulating microRNAs (miRNAs) have been identified in the control of epidermal homeostasis, little is known about miRNAs acting downstream of p63. In this paper, we characterized multiple p63-regulated miRNAs (miR-17, miR-20b, miR-30a, miR-106a, miR-143 and miR-455-3p) and elucidated their roles in the onset of keratinocyte differentiation. We identified RB, p21 and multiple MAPKs as targets of these p63-controlled miRNAs. Upon inhibition of most of these miRNAs, we observed defects in commitment to differentiation that could be reversed by siRNA-mediated silencing of their targets. Furthermore, knockdown of MAPK8 and MAPK9 efficiently restored expression of the early differentiation markers keratin 1 and keratin 10 in p63 silenced primary human keratinocytes. These results highlight new mechanistic roles of multiple miRNAs, particularly the miR-17 family (miR-17, miR-20b and miR 106a), as regulatory intermediates for coordinating p63 with MAPK signaling in the commitment of human mature keratinocytes to early differentiation. PMID- 23029229 TI - Non-structured amino-acid impact on GH11 differs from GH10 xylanase. AB - The Aspergillus niger xylanase (Xyn) was used as a model to investigate impacts of un-structured residues on GH11 family enzyme, because the beta-jelly roll structure has five residues (Ser1Ala2Gly3Ile4Asn5) at N-terminus and two residues (Ser183Ser184) at C-terminus that do not form to helix or strand. The N- or/and C terminal residues were respectively deleted to construct three mutants. The optimal temperatures of XynDeltaN, XynDeltaC, and XynDeltaNC were 46, 50, and 46 degrees C, and the thermostabilities were 15.7, 73.9, 15.5 min at 50 degrees C, respectively, compared to 48 degrees C and 33.9 min for the Xyn. After kinetic analysis, the substrate-binding affinities for birch-wood xylan decreased in the order XynDeltaC>Xyn>XynDeltaNC>XynDeltaN, while the K(cat) values increased in the order XynDeltaC=0.77) obtained from all measurements. The correlation coefficient between the Young's moduli of the tissue-mimicking materials obtained using a mechanical method and ultrasound elastography was 0.996, which was equivalent to values previously obtained using magnetic resonance elastography. The Young's moduli of the medial gastrocnemius muscle obtained using ultrasound elastography were within the range of values previously obtained using magnetic resonance elastography. The reliability and validity of the quantitative method for measuring absolute muscle hardness using ultrasound elastography were thus verified. PMID- 23029230 TI - Salidroside improves behavioral and histological outcomes and reduces apoptosis via PI3K/Akt signaling after experimental traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) induces a complex sequence of apopototic cascades that contribute to secondary tissue damage. The aim of this study was to investigate the effects of salidroside, a phenolic glycoside with potent anti apoptotic properties, on behavioral and histological outcomes, brain edema, and apoptosis following experimental TBI and the possible involvement of the phosphoinositide 3-kinase/protein kinase B (PI3K)/Akt signaling pathway. METHODOLOGY/PRINCIPAL FINDINGS: Mice subjected to controlled cortical impact injury received intraperitoneal salidroside (20, or 50 mg/kg) or vehicle injection 10 min after injury. Behavioral studies, histology analysis and brain water content assessment were performed. Levels of PI3K/Akt signaling-related molecules, apoptosis-related proteins, cytochrome C (CytoC), and Smac/DIABLO were also analyzed. LY294002, a PI3K inhibitor, was administered to examine the mechanism of protection. The protective effect of salidroside was also investigated in primary cultured neurons subjected to stretch injury. Treatment with 20 mg/kg salidroside significantly improved functional recovery and reduced brain tissue damage up to post-injury day 28. Salidroside also significantly reduced neuronal death, apoptosis, and brain edema at day 1. These changes were associated with significant decreases in cleaved caspase-3, CytoC, and Smac/DIABLO at days 1 and 3. Salidroside increased phosphorylation of Akt on Ser473 and the mitochondrial Bcl-2/Bax ratio at day 1, and enhanced phosphorylation of Akt on Thr308 at day 3. This beneficial effect was abolished by pre-injection of LY294002. Moreover, delayed administration of salidroside at 3 or 6 h post-injury reduced neuronal damage at day 1. Salidroside treatment also decreased neuronal vulnerability to stretch-induced injury in vitro. CONCLUSIONS/SIGNIFICANCE: Post-injury salidroside improved long-term behavioral and histological outcomes and reduced brain edema and apoptosis following TBI, at least partially via the PI3K/Akt signaling pathway. PMID- 23029232 TI - Immunization with M2e-displaying T7 bacteriophage nanoparticles protects against influenza A virus challenge. AB - Considering the emergence of highly pathogenic influenza viruses and threat of worldwide pandemics, there is an urgent need to develop broadly-protective influenza vaccines. In this study, we demonstrate the potential of T7 bacteriophage-based nanoparticles with genetically fused ectodomain of influenza A virus M2 protein (T7-M2e) as a candidate universal flu vaccine. Immunization of mice with non-adjuvanted T7-M2e elicited M2e-specific serum antibody responses that were similar in magnitude to those elicited by M2e peptide administered in Freund's adjuvant. Comparable IgG responses directed against T7 phage capsomers were induced following vaccination with wild type T7 or T7-M2e. T7-M2e immunization induced balanced amounts of IgG(1) and IgG(2a) antibodies and these antibodies specifically recognized native M2 on the surface of influenza A virus infected mammalian cells. The frequency of IFN-gamma-secreting T cells induced by T7-M2e nanoparticles was comparable to those elicited by M2e peptide emulsified in Freund's adjuvant. Emulsification of T7-M2e nanoparticles in Freund's adjuvant, however, induced a significantly stronger T cell response. Furthermore, T7-M2e-immunized mice were protected against lethal challenge with an H1N1 or an H3N2 virus, implying the induction of hetero-subtypic immunity in our mouse model. T7-M2e-immunized mice displayed considerable weight loss and had significantly reduced viral load in their lungs compared to controls. We conclude that display of M2e on the surface of T7 phage nanoparticles offers an efficient and economical opportunity to induce cross-protective M2e-based immunity against influenza A. PMID- 23029233 TI - Application of a novel strategy of engineering conditional alleles to a single exon gene, Sox2. AB - BACKGROUND: The Conditional by Inversion (COIN) method for engineering conditional alleles relies on an invertible optimized gene trap-like element, the COIN module, for imparting conditionality. The COIN module contains an optimized 3' splice site-polyadenylation signal pair, but is inserted antisense to the target gene and therefore does not alter transcription, until it is inverted by Cre recombinase. In order to make COIN applicable to all protein-coding genes, the COIN module has been engineered within an artificial intron, enabling insertion into an exon. METHODOLOGY/PRINCIPAL FINDINGS: Therefore, theoretically, the COIN method should be applicable to single exon genes, and to test this idea we engineered a COIN allele of Sox2. This single exon gene presents additional design challenges, in that its proximal promoter and coding region are entirely contained within a CpG island, and are also spanned by an overlapping transcript, Sox2Ot, which contains mmu-miR1897. Here, we show that despite disruption of the CpG island by the COIN module intron, the COIN allele of Sox2 (Sox2(COIN)) is phenotypically wild type, and also does not interfere with expression of Sox2Ot and miR1897. Furthermore, the inverted COIN allele of Sox2, Sox2(INV) is functionally null, as homozygotes recapitulate the phenotype of Sox2(betageo/betageo) mice, a well-characterized Sox2 null. Lastly, the benefit of the eGFP marker embedded in the COIN allele is demonstrated as it mirrors the expression pattern of Sox2. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate the applicability of the COIN technology as a method of choice for targeting single exon genes. PMID- 23029234 TI - Longevity in bovids is promoted by sociality, but reduced by sexual selection. AB - Selection on intrinsic lifespan depends on both external factors affecting mortality and inherent tradeoffs in resource allocation between viability traits and other fitness-related traits. Longevity is therefore likely to vary between species in a sex-specific manner due to interspecific and intersexual differences in behavioural ecology. Here I focus on the bovid family to test two central hypotheses on longevity selection using the comparative method: firstly, that a reduction of extrinsic mortality in social species strengthens selection on intrinsic lifespan, and secondly, that mortality costs associated with intense sexual selection lead to shorter intrinsic lifespan. The results show that longevity (i) increases with sociality in both sexes and (ii) decreases with male biased sexual size-dimorphism, but in males only. These discoveries suggest that sociality, a key ungulate strategy to reduce predation-related mortality, selects for inherently longer-lived organisms, and that strong sexual selection, which is known to compromise survival rates in the wild, can constrain also intrinsic lifespan. The contrasting results for males and females indicate that selection on longevity in the two sexes is partly uncoupled. PMID- 23029235 TI - Revealing topological organization of human brain functional networks with resting-state functional near infrared spectroscopy. AB - BACKGROUND: The human brain is a highly complex system that can be represented as a structurally interconnected and functionally synchronized network, which assures both the segregation and integration of information processing. Recent studies have demonstrated that a variety of neuroimaging and neurophysiological techniques such as functional magnetic resonance imaging (MRI), diffusion MRI and electroencephalography/magnetoencephalography can be employed to explore the topological organization of human brain networks. However, little is known about whether functional near infrared spectroscopy (fNIRS), a relatively new optical imaging technology, can be used to map functional connectome of the human brain and reveal meaningful and reproducible topological characteristics. RESULTS: We utilized resting-state fNIRS (R-fNIRS) to investigate the topological organization of human brain functional networks in 15 healthy adults. Brain networks were constructed by thresholding the temporal correlation matrices of 46 channels and analyzed using graph-theory approaches. We found that the functional brain network derived from R-fNIRS data had efficient small-world properties, significant hierarchical modular structure and highly connected hubs. These results were highly reproducible both across participants and over time and were consistent with previous findings based on other functional imaging techniques. CONCLUSIONS: Our results confirmed the feasibility and validity of using graph theory approaches in conjunction with optical imaging techniques to explore the topological organization of human brain networks. These results may expand a methodological framework for utilizing fNIRS to study functional network changes that occur in association with development, aging and neurological and psychiatric disorders. PMID- 23029237 TI - Improved learning in U.S. history and decision competence with decision-focused curriculum. AB - Decision making is rarely taught in high school, even though improved decision skills could benefit young people facing life-shaping decisions. While decision competence has been shown to correlate with better life outcomes, few interventions designed to improve decision skills have been evaluated with rigorous quantitative measures. A randomized study showed that integrating decision making into U.S. history instruction improved students' history knowledge and decision-making competence, compared to traditional history instruction. Thus, integrating decision training enhanced academic performance and improved an important, general life skill associated with improved life outcomes. PMID- 23029236 TI - Trichodysplasia spinulosa-associated polyomavirus (TSV) and Merkel cell polyomavirus: correlation between humoral and cellular immunity stronger with TSV. AB - Merkel Cell Polyomavirus (MCV) is a common infectious agent likely to be involved in the pathogenesis of most Merkel cell carcinomas (MCC). Trichodysplasia spinulosa-associated polyomavirus (TSV), which exhibit high seroprevalence in general population, has been detected in trichodysplasia spinulosa (TS) skin lesions suggesting an etiological role for this disease. Previous studies have shown strong MCV-specific T-cell responses, while no data exist on T-cell immunity against TSV. In order to characterize Th-cell immunity against TSV, and to allow comparisons with the MCV-specific Th-cell immunity, we studied TSV specific proliferation, IFN-gamma, IL-10 and IL-13, and MCV-specific IFN-gamma and IL-10 responses in 51 healthy volunteers, and in one MCC patient. Recombinant TSV and MCV VP1 virus-like particles (VLPs) were used as antigens. A significant correlation was found between virus-specific Th-cell and antibody responses with TSV; with MCV it proved weaker. Despite significant homology in amino acid sequences, Th-cell crossreactivity was not evident between these viruses. Some subjects seronegative to both TSV and MCV exhibited Th-cell responses to both viruses. The agent initially priming these Th-cells remains an enigma. As CD8(+) cells specific to MCV T-Ag oncoprotein clearly provide an important defense against established MCC, the MCV VP1-specific Th-cells may, by suppressing MCV replication with antiviral cytokines such as IFN-gamma, significantly contribute to preventing the full process of oncogenesis. PMID- 23029238 TI - Impairment of retrograde neuronal transport in oxaliplatin-induced neuropathy demonstrated by molecular imaging. AB - BACKGROUND AND PURPOSE: The purpose of our study was to utilize a molecular imaging technology based on the retrograde axonal transport mechanism (neurography), to determine if oxaliplatin-induced neurotoxicity affects retrograde axonal transport in an animal model. MATERIALS AND METHODS: Mice (n = 8/group) were injected with a cumulative dose of 30 mg/kg oxaliplatin (sufficient to induce neurotoxicity) or dextrose control injections. Intramuscular injections of Tetanus Toxin C-fragment (TTc) labeled with Alexa 790 fluorescent dye were done (15 ug/20 uL) in the left calf muscles, and in vivo fluorescent imaging performed (0-60 min) at baseline, and then weekly for 5 weeks, followed by 2 weekly imaging out to 9 weeks. Tissues were harvested for immunohistochemical analysis. RESULTS: With sham treatment, TTc transport causes fluorescent signal intensity over the thoracic spine to increase from 0 to 60 minutes after injection. On average, fluorescence signal increased 722%+/-117% (Mean+/-SD) from 0 to 60 minutes. Oxaliplatin treated animals had comparable transport at baseline (787%+/-140%), but transport rapidly decreased through the course of the study, falling to 363%+/-88%, 269%+/-96%, 191%+/-58%, 121%+/-39%, 75%+/-21% with each successive week and stabilizing around 57% (+/-15%) at 7 weeks. Statistically significant divergence occurred at approximately 3 weeks (p<=0.05, linear mixed effects regression model). Quantitative immuno-fluorescence histology with a constant cutoff threshold showed reduced TTc in the spinal cord at 7 weeks for treated animals versus controls (5.2 Arbitrary Units +/-0.52 vs 7.1 AU +/-1.38, p<0.0004, T-test). There was no significant difference in neural cell mass between the two groups as shown with NeuN staining (10.2+/-1.21 vs 10.5 AU +/ 1.53, p>0.56, T-test). CONCLUSION: We show-for the first time to our knowledge that neurographic in vivo molecular imaging can demonstrate imaging changes in a model of oxaliplatin-induced neuropathy. Impaired retrograde neural transport is suggested to be an important part of the pathophysiology of oxaliplatin-induced neuropathy. PMID- 23029239 TI - Reverting antibiotic tolerance of Pseudomonas aeruginosa PAO1 persister cells by (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one. AB - BACKGROUND: Bacteria are well known to form dormant persister cells that are tolerant to most antibiotics. Such intrinsic tolerance also facilitates the development of multidrug resistance through acquired mechanisms. Thus persister cells are a promising target for developing more effective methods to control chronic infections and help prevent the development of multidrug-resistant bacteria. However, control of persister cells is still an unmet challenge. METHODOLOGY/PRINCIPAL FINDINGS: We show in this report that (Z)-4-bromo-5 (bromomethylene)-3-methylfuran-2(5H)-one (BF8) can restore the antibiotic susceptibility of Pseudomonas aeruginosa PAO1 persister cells at growth non inhibitory concentrations. Persister control by BF8 was found to be effective against both planktonic and biofilm cells of P. aeruginosa PAO1. Interestingly, although BF8 is an inhibitor of quorum sensing (QS) in Gram-negative bacteria, the data in this study suggest that the activities of BF8 to revert antibiotic tolerance of P. aeruginosa PAO1 persister cells is not through QS inhibition and may involve other targets. CONCLUSION: BF8 can sensitize P. aeruginosa persister cells to antibiotics. PMID- 23029240 TI - Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring. AB - The ability of ultrasonically-induced oscillations of circulating microbubbles to permeabilize vascular barriers such as the blood-brain barrier (BBB) holds great promise for noninvasive targeted drug delivery. A major issue has been a lack of control over the procedure to ensure both safe and effective treatment. Here, we evaluated the use of passively-recorded acoustic emissions as a means to achieve this control. An acoustic emissions monitoring system was constructed and integrated into a clinical transcranial MRI-guided focused ultrasound system. Recordings were analyzed using a spectroscopic method that isolates the acoustic emissions caused by the microbubbles during sonication. This analysis characterized and quantified harmonic oscillations that occur when the BBB is disrupted, and broadband emissions that occur when tissue damage occurs. After validating the system's performance in pilot studies that explored a wide range of exposure levels, the measurements were used to control the ultrasound exposure level during transcranial sonications at 104 volumes over 22 weekly sessions in four macaques. We found that increasing the exposure level until a large harmonic emissions signal was observed was an effective means to ensure BBB disruption without broadband emissions. We had a success rate of 96% in inducing BBB disruption as measured by in contrast-enhanced MRI, and we detected broadband emissions in less than 0.2% of the applied bursts. The magnitude of the harmonic emissions signals was significantly (P<0.001) larger for sonications where BBB disruption was detected, and it correlated with BBB permeabilization as indicated by the magnitude of the MRI signal enhancement after MRI contrast administration (R(2) = 0.78). Overall, the results indicate that harmonic emissions can be a used to control focused ultrasound-induced BBB disruption. These results are promising for clinical translation of this technology. PMID- 23029242 TI - Modelling stream-fish functional traits in reference conditions: regional and local environmental correlates. AB - Identifying the environmental gradients that control the functional structure of biological assemblages in reference conditions is fundamental to help river management and predict the consequences of anthropogenic stressors. Fish metrics (density of ecological guilds, and species richness) from 117 least disturbed stream reaches in several western Iberia river basins were modelled with generalized linear models in order to investigate the importance of regional- and local-scale abiotic gradients to variation in functional structure of fish assemblages. Functional patterns were primarily associated with regional features, such as catchment elevation and slope, rainfall, and drainage area. Spatial variations of fish guilds were thus associated with broad geographic gradients, showing (1) pronounced latitudinal patterns, affected mainly by climatic factors and topography, or (2) at the basin level, strong upstream downstream patterns related to stream position in the longitudinal gradient. Maximum native species richness was observed in midsize streams in accordance with the river continuum concept. The findings of our study emphasized the need to use a multi-scale approach in order to fully assess the factors that govern the functional organization of biotic assemblages in 'natural' streams, as well as to improve biomonitoring and restoration of fluvial ecosystems. PMID- 23029241 TI - IL-36alpha exerts pro-inflammatory effects in the lungs of mice. AB - Interleukin (IL-) 36 cytokines (previously designated as novel IL-1 family member cytokines; IL-1F5- IL-1F10) constitute a novel cluster of cytokines structurally and functionally similar to members of the IL-1 cytokine cluster. The effects of IL-36 cytokines in inflammatory lung disorders remains poorly understood. The current study sought to investigate the effects of IL-36alpha (IL-1F6) and test the hypothesis that IL-36alpha acts as a pro-inflammatory cytokine in the lung in vivo. Intratracheal instillation of recombinant mouse IL-36alpha induced neutrophil influx in the lungs of wild-type C57BL/6 mice and IL-1alphabeta(-/-) mice in vivo. IL-36alpha induced neutrophil influx was also associated with increased mRNA expression of neutrophil-specific chemokines CXCL1 and CXCL2 in the lungs of C57BL/6 and IL-1alphabeta(-/-) mice in vivo. In addition, intratracheal instillation of IL-36alpha enhanced mRNA expression of its receptor IL-36R in the lungs of C57BL/6 as well as IL-1alphabeta(-/-) mice in vivo. Furthermore, in vitro incubation of CD11c(+) cells with IL-36alpha resulted in the generation of neutrophil-specific chemokines CXCL1, CXCL2 as well as TNFalpha. IL-36alpha increased the expression of the co-stimulatory molecule CD40 and enhanced the ability of CD11c(+) cells to induce CD4(+) T cell proliferation in vitro. Furthermore, stimulation with IL-36alpha activated NF-kappaB in a mouse macrophage cell line. These results demonstrate that IL-36alpha acts as a pro inflammatory cytokine in the lung without the contribution of IL-1alpha and IL 1beta. The current study describes the pro-inflammatory effects of IL-36alpha in the lung, demonstrates the functional redundancy of IL-36alpha with other agonist cytokines in the IL-1 and IL-36 cytokine cluster, and suggests that therapeutic targeting of IL-36 cytokines could be beneficial in inflammatory lung diseases. PMID- 23029243 TI - Plasticity of peripheral auditory frequency sensitivity in Emei music frog. AB - In anurans reproductive behavior is strongly seasonal. During the spring, frogs emerge from hibernation and males vocalize for mating or advertising territories. Female frogs have the ability to evaluate the quality of the males' resources on the basis of these vocalizations. Although studies revealed that central single torus semicircularis neurons in frogs exhibit season plasticity, the plasticity of peripheral auditory sensitivity in frog is unknown. In this study the seasonally plasticity of peripheral auditory sensitivity was test in the Emei music frog Babina daunchina, by comparing thresholds and latencies of auditory brainstem responses (ABRs) evoked by tone pips and clicks in the reproductive and non-reproductive seasons. The results show that both ABR thresholds and latency differ significantly between the reproductive and non-reproductive seasons. The thresholds of tone pip evoked ABRs in the non-reproductive season increased significantly about 10 dB than those in the reproductive season for frequencies from 1 KHz to 6 KHz. ABR latencies to waveform valley values for tone pips for the same frequencies using appropriate threshold stimulus levels are longer than those in the reproductive season for frequencies from 1.5 to 6 KHz range, although from 0.2 to 1.5 KHz range it is shorter in the non-reproductive season. These results demonstrated that peripheral auditory frequency sensitivity exhibits seasonal plasticity changes which may be adaptive to seasonal reproductive behavior in frogs. PMID- 23029244 TI - Identification of Bacillus strains for biological control of catfish pathogens. AB - Bacillus strains isolated from soil or channel catfish intestine were screened for their antagonism against Edwardsiella ictaluri and Aeromonas hydrophila, the causative agents of enteric septicemia of catfish (ESC) and motile aeromonad septicaemia (MAS), respectively. Twenty one strains were selected and their antagonistic activity against other aquatic pathogens was also tested. Each of the top 21 strains expressed antagonistic activity against multiple aquatic bacterial pathogens including Edwardsiella tarda, Streptococcus iniae, Yersinia ruckeri, Flavobacterium columnare, and/or the oomycete Saprolegnia ferax. Survival of the 21 Bacillus strains in the intestine of catfish was determined as Bacillus CFU/g of intestinal tissue of catfish after feeding Bacillus spore supplemented feed for seven days followed by normal feed for three days. Five Bacillus strains that showed good antimicrobial activity and intestinal survival were incorporated into feed in spore form at a dose of 8*10(7) CFU/g and fed to channel catfish for 14 days before they were challenged by E. ictaluri in replicate. Two Bacillus subtilis strains conferred significant benefit in reducing catfish mortality (P<0.05). A similar challenge experiment conducted in Vietnam with four of the five Bacillus strains also showed protective effects against E. ictaluri in striped catfish. Safety of the four strains exhibiting the strongest biological control in vivo was also investigated in terms of whether the strains contain plasmids or express resistance to clinically important antibiotics. The Bacillus strains identified from this study have good potential to mediate disease control as probiotic feed additives for catfish aquaculture. PMID- 23029245 TI - The effect of deltamethrin-treated net fencing around cattle enclosures on outdoor-biting mosquitoes in Kumasi, Ghana. AB - Classic vector control strategies target mosquitoes indoors as the main transmitters of malaria are indoor-biting and -resting mosquitoes. However, the intensive use of insecticide-treated bed-nets (ITNs) and indoor residual spraying have put selective pressure on mosquitoes to adapt in order to obtain human blood meals. Thus, early-evening and outdoor vector activity is becoming an increasing concern. This study assessed the effect of a deltamethrin-treated net (100 mg/m(2)) attached to a one-meter high fence around outdoor cattle enclosures on the number of mosquitoes landing on humans. Mosquitoes were collected from four cattle enclosures: Pen A - with cattle and no net; B - with cattle and protected by an untreated net; C - with cattle and protected by a deltamethrin-treated net; D - no cattle and no net. A total of 3217 culicines and 1017 anophelines were collected, of which 388 were Anopheles gambiae and 629 An. ziemanni. In the absence of cattle nearly 3 times more An. gambiae (p<0.0001) landed on humans. The deltamethrin-treated net significantly reduced (nearly three-fold, p<0.0001) culicine landings inside enclosures. The sporozoite rate of the zoophilic An. ziemanni, known to be a secondary malaria vector, was as high as that of the most competent vector An. gambiae; raising the potential of zoophilic species as secondary malaria vectors. After deployment of the ITNs a deltamethrin persistence of 9 months was observed despite exposure to African weather conditions. The outdoor use of ITNs resulted in a significant reduction of host seeking culicines inside enclosures. Further studies investigating the effectiveness and spatial repellence of ITNs around other outdoor sites, such as bars and cooking areas, as well as their direct effect on vector-borne disease transmission are needed to evaluate its potential as an appropriate outdoor vector control tool for rural Africa. PMID- 23029246 TI - The overlooked biodiversity of flower-visiting invertebrates. AB - Estimates suggest that perhaps 40% of all invertebrate species are found in tropical rainforest canopies. Extrapolations of total diversity and food web analyses have been based almost exclusively on species inhabiting the foliage, under the assumption that foliage samples are representative of the entire canopy. We examined the validity of this assumption by comparing the density of invertebrates and the species richness of beetles across three canopy microhabitats (mature leaves, new leaves and flowers) on a one hectare plot in an Australian tropical rainforest. Specifically, we tested two hypotheses: 1) canopy invertebrate density and species richness are directly proportional to the amount of resource available; and 2) canopy microhabitats represent discrete resources that are utilised by their own specialised invertebrate communities. We show that flowers in the canopy support invertebrate densities that are ten to ten thousand times greater than on the nearby foliage when expressed on a per-unit resource biomass basis. Furthermore, species-level analyses of the beetle fauna revealed that flowers support a unique and remarkably rich fauna compared to foliage, with very little species overlap between microhabitats. We reject the hypothesis that the insect fauna on mature foliage is representative of the greater canopy community even though mature foliage comprises a very large proportion of canopy plant biomass. Although the significance of the evolutionary relationship between flowers and insects is well known with respect to plant reproduction, less is known about the importance of flowers as resources for tropical insects. Consequently, we suggest that this constitutes a more important piece of the 'diversity jigsaw puzzle' than has been previously recognised and could alter our understanding of the evolution of plant-herbivore interactions and food web dynamics, and provide a better foundation for accurately estimating global species richness. PMID- 23029247 TI - Improving indel detection specificity of the Ion Torrent PGM benchtop sequencer. AB - The emergence of benchtop sequencers has made clinical genetic testing using next generation sequencing more feasible. Ion Torrent's PGMTM is one such benchtop sequencer that shows clinical promise in detecting single nucleotide variations (SNVs) and microindel variations (indels). However, the large number of false positive indels caused by the high frequency of homopolymer sequencing errors has impeded PGMTM's usage for clinical genetic testing. An extensive analysis of PGMTM data from the sequencing reads of the well-characterized genome of the Escherichia coli DH10B strain and sequences of the BRCA1 and BRCA2 genes from six germline samples was done. Three commonly used variant detection tools, SAMtools, Dindel, and GATK's Unified Genotyper, all had substantial false positive rates for indels. By incorporating filters on two major measures we could dramatically improve false positive rates without sacrificing sensitivity. The two measures were: B-Allele Frequency (BAF) and VARiation of the Width of gaps and inserts (VARW) per indel position. A BAF threshold applied to indels detected by UnifiedGenotyper removed ~99% of the indel errors detected in both the DH10B and BRCA sequences. The optimum BAF threshold for BRCA sequences was determined by requiring 100% detection sensitivity and minimum false discovery rate, using variants detected from Sanger sequencing as reference. This resulted in 15 indel errors remaining, of which 7 indel errors were removed by selecting a VARW threshold of zero. VARW specific errors increased in frequency with higher read depth in the BRCA datasets, suggesting that homopolymer-associated indel errors cannot be reduced by increasing the depth of coverage. Thus, using a VARW threshold is likely to be important in reducing indel errors from data with higher coverage. In conclusion, BAF and VARW thresholds provide simple and effective filtering criteria that can improve the specificity of indel detection in PGMTM data without compromising sensitivity. PMID- 23029248 TI - Pitstop 2 is a potent inhibitor of clathrin-independent endocytosis. AB - Clathrin independent endocytosis (CIE) is a form of endocytosis present in all cells that mediates the entry of nutrients, macromolecules and membrane proteins into cells. When compared to clathrin-dependent endocytosis (CDE), however, much less is known about the machinery involved in forming CIE endosomes. One way to distinguish CIE from CDE has been to deplete cells of coat proteins involved in CDE such as clathrin or the dynamin GTPase, leading to a block of CDE but not CIE. A drawback of such genetic manipulations is that depletion of proteins important for mediating CDE over a period of days can have complex indirect effects on cellular function. The identification of chemical compounds that specifically and rapidly block CDE or CIE would facilitate the determination of whether a process involved CDE or CIE. To date, all of those compounds have targeted CDE. Dynasore and the dynoles specifically target and block dynamin activity thus inhibiting CDE but not most forms of CIE. Recently, a new compound called pitstop 2 was identified as an inhibitor of the interaction of amphiphysin with the amino terminal domain of clathrin, and shown to inhibit CDE in cells. Here we show that pitstop 2 is also a potent inhibitor of CIE. The effects of pitstop 2 are not restricted to inhibition of clathrin since knockdown of clathrin fails to rescue the inhibition of endocytosis of CIE proteins by the drug. Thus pitstop 2 has additional cellular targets besides the amino terminal domain of clathrin and thus cannot be used to distinguish CIE from CDE. PMID- 23029249 TI - West Nile virus (WNV) replication is independent of autophagy in mammalian cells. AB - Autophagy is a homeostatic process responsible for recycling cytosolic proteins and organelles. Moreover, this pathway contributes to the cell's intrinsic innate defenses. While many viruses have evolved mechanisms to antagonize the antiviral effects of the autophagy pathway, others subvert autophagy to facilitate replication. Here, we have investigated the role of autophagy in West Nile virus (WNV) replication. Experiments in cell lines derived from a variety of sources, including the kidney, liver, skin, and brain, indicated that WNV replication does not upregulate the autophagy pathway. Furthermore, WNV infection did not inhibit rapamycin-induced autophagy, suggesting that WNV does not disrupt the authophagy signaling cascade. Perturbation of the autophagy pathway by depletion of the major autophagy factors Atg5 or Atg7 had no effect on WNV infectious particle production, indicating that WNV does not require a functional autophagy pathway for replication. Taken together, the results of our study provide evidence that WNV, unlike several other viruses of the family Flaviviridae, does not significantly interact with the conventional autophagy pathway in mammalian cells. PMID- 23029250 TI - Interleukin 27 induces the expression of complement factor H (CFH) in the retina. AB - Complement factor H (CFH) is a central regulator of the complement system and has been implicated in the etiology of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. In view of previous studies showing that reduced expression of CFH in the retina is a risk factor for developing AMD, there is significant interest in understanding how CFH expression is regulated in the retina. In this study, we have shown that the anti-inflammatory cytokine, IL 27, induced CFH expression in mouse retinal cells and human retinal pigmented epithelial cells (RPE) through STAT1-mediated up-regulation of Interferon Regulatory Factor-1 (IRF-1) and IRF-8. We further show that cells in the ganglion and inner-nuclear layers of the retina constitutively express IRF-1 and IRF-8 and enhanced CFH expression in the retina during ocular inflammation correlated with significant increase in the expression of IRF-1, IRF-8 and IL-27 (IL-27p28 and Ebi3). Our data thus reveal a novel role of IL-27 in regulating complement activation through up-regulation of CFH and suggest that defects in IL-27 signaling or expression may contribute to the reduction of CFH expression in the retina of patients with AMD. PMID- 23029251 TI - Tackling heterogeneity: a leaf disc-based assay for the high-throughput screening of transient gene expression in tobacco. AB - Transient Agrobacterium-mediated gene expression assays for Nicotiana tabacum (N. tabacum) are frequently used because they facilitate the comparison of multiple expression constructs regarding their capacity for maximum recombinant protein production. However, for three model proteins, we found that recombinant protein accumulation (rpa) was significantly influenced by leaf age and leaf position effects. The ratio between the highest and lowest amount of protein accumulation (max/min ratio) was found to be as high as 11. Therefore, construct-based impacts on the rpa level that are less than 11-fold will be masked by background noise. To address this problem, we developed a leaf disc-based screening assay and infiltration device that allows the rpa level in a whole tobacco plant to be reliably and reproducibly determined. The prototype of the leaf disc infiltration device allows 14 Agrobacterium-mediated infiltration events to be conducted in parallel. As shown for three model proteins, the average max/min rpa ratio was reduced to 1.4 using this method, which allows for a sensitive comparison of different genetic elements affecting recombinant protein expression. PMID- 23029252 TI - Chemokines CCL3/MIP1alpha, CCL5/RANTES and CCL18/PARC are independent risk predictors of short-term mortality in patients with acute coronary syndromes. AB - Cytokines play an important role in ischemic injury and repair. However, little is known about their prognostic value in cardiovascular disease. The aim of this study was to investigate the prognostic importance of chemokines CCL3/MIP-1alpha, CCL5/RANTES and CCL18/PARC for the risk of future cardiovascular events in patients with acute coronary syndromes (ACS). Baseline levels of CCL3/MIP-1alpha, CCL5/RANTES and CCL18/PARC were determined in ACS patients from the Bad Nauheim ACS II registry (n = 609). During the following 200 days, patients were monitored for the occurrence of fatal and non-fatal cardiovascular events. Patients with CCL3/MIP1alpha, CCL5/RANTES and CCL18/PARC concentrations in the highest tertile were associated with an increased risk of a fatal event during follow-up (HR: 2.19, 95%CI: 1.04-4.61 for CCL3/MIP1alpha, HR: 3.45, 95%CI: 1.54-7.72 for CCL5/RANTES and HR: 3.14, 95%CI: 1.33-7.46 for CCL18/PARC). This risk was highest for patients with all three biomarkers concentrations in the upper tertile (HR: 2.52, 95%CI: 1.11-5.65). Together with known risk predictors of cardiovascular events, CCL3/MIP-1alpha, CCL5/RANTES and CCL18/PARC combined improved the c statistics from 0.74 to 0.81 (p = 0.007). In conclusion, CCL3/MIP-1alpha, CCL5/RANTES and CCL18/PARC are independently associated with the risk of short term mortality in ACS patients. Combining all three biomarkers further increased their prognostic value. PMID- 23029253 TI - Influenza A/H1N1 2009 pandemic and respiratory virus infections, Beijing, 2009 2010. AB - To determine the role of the pandemic influenza A/H1N1 2009 (A/H1N1 2009pdm) in acute respiratory tract infections (ARTIs) and its impact on the epidemic of seasonal influenza viruses and other common respiratory viruses, nasal and throat swabs taken from 7,776 patients with suspected viral ARTIs from 2006 through 2010 in Beijing, China were screened by real-time PCR for influenza virus typing and subtyping and by multiplex or single PCR tests for other common respiratory viruses. We observed a distinctive dual peak pattern of influenza epidemic during the A/H1N1 2009pdm in Beijing, China, which was formed by the A/H1N1 2009pdm, and a subsequent influenza B epidemic in year 2009/2010. Our analysis also shows a small peak formed by a seasonal H3N2 epidemic prior to the A/H1N1 2009pdm peak. Parallel detection of multiple respiratory viruses shows that the epidemic of common respiratory viruses, except human rhinovirus, was delayed during the pandemic of the A/H1N1 2009pdm. The H1N1 2009pdm mainly caused upper respiratory tract infections in the sampled patients; patients infected with H1N1 2009pdm had a higher percentage of cough than those infected with seasonal influenza or other respiratory viruses. Our findings indicate that A/H1N1 2009pdm and other respiratory viruses except human rhinovirus could interfere with each other during their transmission between human beings. Understanding the mechanisms and effects of such interference is needed for effective control of future influenza epidemics. PMID- 23029254 TI - Does the axillary lymph node ratio have any added prognostic value over pN staging for South East Asian breast cancer patients? AB - INTRODUCTION: Lymph node ratio (LNR, i.e. the ratio of the number of positive nodes to the total number of nodes excised) is reported to be superior to the absolute number of nodes involved (pN stage) in classifying patients at high versus low risk of death following breast cancer. The added prognostic value of LNR over pN in addition to other prognostic factors has never been assessed. METHODS: All patients diagnosed with lymph node positive, non-metastatic invasive breast cancer at the National University Hospital (Singapore) and University of Malaya Medical Center (Kuala Lumpur) between 1990-2007 were included (n = 1589). Overall survival of the patients was estimated by the Kaplan Meier method for LNR [categorized as low (>0 and <0.2), intermediate (0.2-0.65) and high (>0.65-1)] and pN staging [pN1, pN2 and pN3]. Adjusted overall relative mortality risks associated with LNR and pN were calculated by Cox regression. The added prognostic value of LNR over pN was evaluated by comparing the discriminating capacity (as indicated by the c statistic) of two multivariate models, one including pN and one including LNR. RESULTS: LNR was superior to pN in categorizing mortality risks for women >=60 years, those with ER negative or grade 3 tumors. In combination with other factors (i.e. age, treatment, grade, tumor size and receptor status), substituting pN by LNR did not result in better discrimination of women at high versus low risk of death, neither for the entire cohort (c statistic 0.72 [0.70-0.75] and 0.73 [0.71-0.76] respectively for pN versus LNR), nor for the subgroups mentioned above. CONCLUSION: In combination with other prognosticators, substitution of pN by LNR did not provide any added prognostic value for South East Asian breast cancer patients. PMID- 23029255 TI - Genes encoding Cher-TPR fusion proteins are predominantly found in gene clusters encoding chemosensory pathways with alternative cellular functions. AB - Chemosensory pathways correspond to major signal transduction mechanisms and can be classified into the functional families flagellum-mediated taxis, type four pili-mediated taxis or pathways with alternative cellular functions (ACF). CheR methyltransferases are core enzymes in all of these families. CheR proteins fused to tetratricopeptide repeat (TPR) domains have been reported and we present an analysis of this uncharacterized family. We show that CheR-TPRs are widely distributed in GRAM-negative but almost absent from GRAM-positive bacteria. Most strains contain a single CheR-TPR and its abundance does not correlate with the number of chemoreceptors. The TPR domain fused to CheR is comparatively short and frequently composed of 2 repeats. The majority of CheR-TPR genes were found in gene clusters that harbor multidomain response regulators in which the REC domain is fused to different output domains like HK, GGDEF, EAL, HPT, AAA, PAS, GAF, additional REC, HTH, phosphatase or combinations thereof. The response regulator architectures coincide with those reported for the ACF family of pathways. Since the presence of multidomain response regulators is a distinctive feature of this pathway family, we conclude that CheR-TPR proteins form part of ACF type pathways. The diversity of response regulator output domains suggests that the ACF pathways form a superfamily which regroups many different regulatory mechanisms, in which all CheR-TPR proteins appear to participate. In the second part we characterize WspC of Pseudomonas putida, a representative example of CheR TPR. The affinities of WspC-Pp for S-adenosylmethionine and S adenosylhomocysteine were comparable to those of prototypal CheR, indicating that WspC-Pp activity is in analogy to prototypal CheRs controlled by product feed back inhibition. The removal of the TPR domain did not impact significantly on the binding constants and consequently not on the product feed-back inhibition. WspC-Pp was found to be monomeric, which rules out a role of the TPR domain in self-association. PMID- 23029256 TI - Environmental stress affects DNA methylation of a CpG rich promoter region of serotonin transporter gene in a nurse cohort. AB - BACKGROUND: Shift-working nurses are exposed to a stressful work environment, which puts them at an increased risk for burnout and depression. We explored the effect of environmental stress on serotonin transporter gene (SLC6A4) promoter methylation among nurses from high and low work stress environments. METHODOLOGY: Using bisulfite sequencing, we investigated the methylation status of five CpG residues of a CpG-rich region in the promoter of SLC6A4 by comparing female shift working nurses from a high work stress environment (n = 24) to low work stress environment (n = 25). We also analyzed the association of 5-HTTLPR polymorphism at 5' end of SLC6A4. Work stress was assessed by the Karasek's Model and possible signs of burnout or depression were measured by the Maslach Burnout Index General Survey and Beck Depression Index. Methylation levels were assessed by bisulfite sequencing of DNA extracted from peripheral blood leucocytes. Restriction enzyme treatment followed by standard PCR was used to identify 5-HTTLPR genotypes. PRINCIPAL FINDINGS: We found that nurses in the high stress environment had significantly lower promoter methylation levels at all five CpG residues compared to nurses in the low stress environment (p<0.01). There was no significant interaction of 5-HTTLPR genotype and work stress with methylation (p = 0.58). In unadjusted (bivariate) analysis, burnout was not significantly associated to methylation levels. However, when mutually adjusted for both, burnout and work stress were significant contributors (p = 0.038 and p<0.0001 respectively) to methylation levels. CONCLUSIONS: Our findings show that environmental stress is concurrent with decreased methylation of the SLC6A4 promoter. This may lead to increased transcriptional activity of the gene, increased reuptake of serotonin from synaptic clefts, and termination of the activity of serotonin. This could present a possible coping mechanism for environmental stress in humans that could eventually increase risk for disturbed functional capability and experience of depressed mood in long-term stress. PMID- 23029257 TI - Urban stormwater runoff: a new class of environmental flow problem. AB - Environmental flow assessment frameworks have begun to consider changes to flow regimes resulting from land-use change. Urban stormwater runoff, which degrades streams through altered volume, pattern and quality of flow, presents a problem that challenges dominant approaches to stormwater and water resource management, and to environmental flow assessment. We used evidence of ecological response to different stormwater drainage systems to develop methods for input to environmental flow assessment. We identified the nature of hydrologic change resulting from conventional urban stormwater runoff, and the mechanisms by which such hydrologic change is prevented in streams where ecological condition has been protected. We also quantified the increase in total volume resulting from urban stormwater runoff, by comparing annual streamflow volumes from undeveloped catchments with the volumes that would run off impervious surfaces under the same rainfall regimes. In catchments with as little as 5-10% total imperviousness, conventional stormwater drainage, associated with poor in-stream ecological condition, reduces contributions to baseflows and increases the frequency and magnitude of storm flows, but in similarly impervious catchments in which streams retain good ecological condition, informal drainage to forested hillslopes, without a direct piped discharge to the stream, results in little such hydrologic change. In urbanized catchments, dispersed urban stormwater retention measures can potentially protect urban stream ecosystems by mimicking the hydrologic effects of informal drainage, if sufficient water is harvested and kept out of the stream, and if discharged water is treated to a suitable quality. Urban stormwater is a new class of environmental flow problem: one that requires reduction of a large excess volume of water to maintain riverine ecological integrity. It is the best type of problem, because solving it provides an opportunity to solve other problems such as the provision of water for human use. PMID- 23029258 TI - Cigarette smoking increases abdominal and visceral obesity but not overall fatness: an observational study. AB - BACKGROUND: Cigarette smoking and obesity are leading public health concerns. Both increase the risk for cardiovascular disease, cancer, and metabolic abnormalities. This study was conducted to assess the association between cigarette smoking and different types of obesity. METHODOLOGY/PRINCIPAL FINDINGS: Two hundred eighty-three visitors to university hospitals located in four main provinces of South Korea were participated. All participants were classified as either current/past or never smokers and were divided into quartiles according to the total pack-years. Body mass index, waist circumference, total body fat percentage, and area of visceral and abdominal subcutaneous fat were measured. These results of each groups were compared. Waist circumference, and visceral fat area showed a J- or U-shaped association with total smoking amount during a lifetime. After restricting the analyses to past/current smokers, we found significant dose-dependent associations of smoking pack-years with abdominal and visceral obesity. Overall obesity measured by body mass index and total body fat percentage did not show such associations. Although current smokers clearly showed significant associations, we could not demonstrate these in past smokers, possibly because of the limited sample size. CONCLUSIONS/SIGNIFICANCE: Although smokers did not show significant difference in mean body mass index than those who never smoked, they showed more metabolically adverse fat distributions with increasing smoking amounts. This finding suggests that smoking is not beneficial for weight control. Therefore, smoking cessation and avoidance of smoking commencement should be addressed as important public health issues in preventing obesity and related complications. PMID- 23029259 TI - GAGE cancer-germline antigens are recruited to the nuclear envelope by germ cell less (GCL). AB - GAGE proteins are highly similar, primate-specific molecules with unique primary structure and undefined cellular roles. They are restricted to cells of the germ line in adult healthy individuals, but are broadly expressed in a wide range of cancers. In a yeast two-hybrid screen we identified the metazoan transcriptional regulator, Germ cell-less (GCL), as an interaction partner of GAGE12I. GCL directly binds LEM-domain proteins (LAP2beta, emerin, MAN1) at the nuclear envelope, and we found that GAGE proteins were recruited to the nuclear envelope inner membrane by GCL. Based on yeast two-hybrid analysis and pull-down experiments of GCL polypeptides, GCL residues 209-320 (which includes the BACK domain) were deduced sufficient for association with GAGE proteins. GAGE mRNAs and GCL mRNA were demonstrated in human testis and most types of cancers, and at the protein level GAGE members and GCL were co-expressed in cancer cell lines. Structural studies of GAGE proteins revealed no distinct secondary or tertiary structure, suggesting they are intrinsically disordered. Interestingly GAGE proteins formed stable complexes with dsDNA in vitro at physiological concentrations, and GAGE12I bound several different dsDNA fragments, suggesting sequence-nonspecific binding. Dual association of GAGE family members with GCL at the nuclear envelope inner membrane in cells, and with dsDNA in vitro, implicate GAGE proteins in chromatin regulation in germ cells and cancer cells. PMID- 23029260 TI - p53 codon 72 polymorphism and hematological cancer risk: an update meta-analysis. AB - BACKGROUND: Previous studies on the association of p53 codon 72 (Arg72Pro) polymorphism with hematological malignancies risk have produced conflicting results. The purpose of this meta-analysis is to define the effect of p53 Arg72Pro polymorphism on hematological malignancies risk. METHODOLOGY/PRINCIPAL FINDINGS: Through searching PubMed databases (or hand searching) up to April 2012 using the following MeSH terms and keywords: "p53", "codon 72" "polymorphism" and "leukemia", or "lymphoma", or "myeloma", thirteen were identified as eligible articles in this meta-analysis for p53 Arg72Pro polymorphism (2,731 cases and 7, 356 controls), including nine studies on leukemia (1,266 cases and 4, 474 controls), three studies on lymphoma (1,359 cases and 2,652 controls), and one study on myeloma. The overall results suggested that p53 Arg72Pro polymorphism was not associated with hematological malignancies risk. In stratified analyses, significantly increased non-Hodgkin lymphomas risk was found in p53 Arg72Pro polymorphism heterozygote model (Arg/Pro vs. Arg/Arg: OR = 1.18, 95%CI: 1.02 1.35) and dominant model (Arg/Pro+Pro/Pro vs. Arg/Arg: OR = 1.18, 95%CI: 1.03 1.34), but no significant association was found between leukemia risk and p53 Arg72Pro polymorphism. Further studies showed no association between leukemia risk and p53 Arg72Pro polymorphism when stratified in subtypes of leukemias, ethnicities and sources of controls. CONCLUSIONS/SIGNIFICANCE: This meta-analysis indicates that the p53 Arg72Pro polymorphism may contribute to susceptibility to non-Hodgkin lymphomas. PMID- 23029261 TI - Engagement of Siglec-7 receptor induces a pro-inflammatory response selectively in monocytes. AB - Sialic acid binding immunoglobulin-like lectin-7 (Siglec-7) is a trans-membrane receptor carrying immunoreceptor tyrosine based inhibitory motifs (ITIMs) and delivering inhibitory signals upon ligation with sialylated glycans. This inhibitory function can be also targeted by several pathogens that have evolved to express sialic acids on their surface to escape host immune responses. Here, we demonstrate that cross-linking of Siglec-7 by a specific monoclonal antibody (mAb) induces a remarkably high production of IL-6, IL-1alpha, CCL4/MIP-1beta, IL 8 and TNF-alpha. Among the three immune cell subsets known to constitutively express Siglec-7, the production of these pro-inflammatory cytokines and chemokines selectively occurs in monocytes and not in Natural Killer or T lymphocytes. This Siglec-7-mediated activating function is associated with the phosphorylation of the extracellular signal-regulated kinase (ERK) pathway. The present study also shows that sialic acid-free Zymosan yeast particles are able to bind Siglec-7 on monocytes and that this interaction mimics the ability of the anti Siglec-7 mAb to induce the production of pro-inflammatory mediators. Indeed, blocking or silencing Siglec-7 in primary monocytes greatly reduced the production of inflammatory cytokines and chemokines in response to Zymosan, thus confirming that Siglec-7 participates in generating a monocyte-mediated inflammatory outcome following pathogen recognition. The presence of an activating form of Siglec-7 in monocytes provides the host with a new and alternative mechanism to encounter pathogens not expressing sialylated glycans. PMID- 23029262 TI - The whereabouts of flower visitors: contrasting land-use preferences revealed by a country-wide survey based on citizen science. AB - BACKGROUND: In the past decade, accumulating evidence of pollinator decline has raised concerns regarding the functioning of terrestrial ecosystems and the sustainability of crop production. Although land-use changes have been advanced as the major causes, the affinities of most wild pollinators with the main land use types remain unknown. Filling this gap in our knowledge is a prerequisite to improving conservation and management programmes. METHODOLOGY/PRINCIPAL FINDINGS: We estimated the affinity of flower visitors with urban, agricultural and natural land-uses using data from a country-wide scale monitoring scheme based on citizen science (Spipoll). We tested whether the affinities differed among insect orders and according to insect frequency (frequent or infrequent). Our results indicate that the affinities with the three land-use types differed among insect orders. Apart from Hymenopterans, which appeared tolerant to the different land-uses, all flower visitors presented a negative affinity with urban areas and a positive affinity with agricultural and natural areas. Additionally, infrequent taxa displayed a lower affinity with urban areas and a higher affinity with natural areas than did frequent taxa. Within frequent taxa, Hymenoptera and Coleoptera included specialists of the three land-use types whereas Diptera and Lepidoptera contained specialists of all but urban areas. CONCLUSIONS/SIGNIFICANCE: Our approach allowed the first standardised evaluation of the affinity of flower visitors with the main land-use types across a broad taxonomical range and a wide geographic scope. Our results suggest that the most detrimental land-use change for flower visitor communities is urbanisation. Moreover, our findings highlight the fact that agricultural areas have the potential to host highly diverse pollinator communities. We suggest that policy makers should, therefore, focus on the implementation of pollinator-friendly practices in agricultural lands. This may be a win-win strategy, as both biodiversity and crop production may benefit from healthier communities of flower visitors in these areas. PMID- 23029263 TI - Expression of the human glucokinase gene: important roles of the 5' flanking and intron 1 sequences. AB - BACKGROUND: Glucokinase plays important tissue-specific roles in human physiology, where it acts as a sensor of blood glucose levels in the pancreas, and a few other cells of the gut and brain, and as the rate-limiting step in glucose metabolism in the liver. Liver-specific expression is driven by one of the two tissue-specific promoters, and has an absolute requirement for insulin. The sequences that mediate regulation by insulin are incompletely understood. METHODOLOGY/PRINCIPAL FINDINGS: To better understand the liver-specific expression of the human glucokinase gene we compared the structures of this gene from diverse mammals. Much of the sequence located between the 5' pancreatic beta cell-specific and downstream liver-specific promoters of the glucokinase genes is composed of repetitive DNA elements that were inserted in parallel on different mammalian lineages. The transcriptional activity of the liver-specific promoter 5' flanking sequences were tested with and without downstream intronic sequences in two human liver cells lines, HepG2 and L-02. While glucokinase liver-specific 5' flanking sequences support expression in liver cell lines, a sequence located about 2000 bases 3' to the liver-specific mRNA start site represses gene expression. Enhanced reporter gene expression was observed in both cell lines when cells were treated with fetal calf serum, but only in the L-02 cells was expression enhanced by insulin. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the normal liver L-02 cell line may be a better model to understand the regulation of the liver-specific expression of the human glucokinase gene. Our results also suggest that sequences downstream of the liver-specific mRNA start site have important roles in the regulation of liver-specific glucokinase gene expression. PMID- 23029264 TI - Upregulation of MircoRNA-370 induces proliferation in human prostate cancer cells by downregulating the transcription factor FOXO1. AB - Forkhead box protein O1 (FOXO1), a key member of the FOXO family of transcription factors, acts as a tumor suppressor and has been associated with various key cellular functions, including cell growth, differentiation, apoptosis and angiogenesis. Therefore, it is puzzling why FOXO protein expression is downregulated in cancer cells. MicroRNAs, non-coding 20~22 nucleotide single stranded RNAs, result in translational repression or degradation and gene silencing of their target genes, and significantly contribute to the regulation of gene expression. In the current study, we report that miR-370 expression was significantly upregulated in five prostate cancer cell lines, compared to normal prostatic epithelial (PrEC) cells. Ectopic expression of miR-370 induced proliferation and increased the anchorage-independent growth and colony formation ability of DU145 and LNCaP prostate cancer cells, while inhibition of miR-370 reduced proliferation, anchorage-independent growth and colony formation ability. Furthermore, upregulation of miR-370 promoted the entry of DU145 and LNCaP prostate cancer cells into the G1/S cell cycle transition, which was associated with downregulation of the cyclin-dependent kinase (CDK) inhibitors, p27(Kip1) and p21(Cip1), and upregulation of the cell-cycle regulator cyclin D1 mRNA. Additionally, we demonstrated that miR-370 can downregulate expression of FOXO1 by directly targeting the FOXO1 3'-untranslated region. Taken together, our results suggest that miR-370 plays an important role in the proliferation of human prostate cancer cells, by directly suppressing the tumor suppressor FOXO1. PMID- 23029265 TI - Mitochondrial fusion is essential for steroid biosynthesis. AB - Although the contribution of mitochondrial dynamics (a balance in fusion/fission events and changes in mitochondria subcellular distribution) to key biological process has been reported, the contribution of changes in mitochondrial fusion to achieve efficient steroid production has never been explored. The mitochondria are central during steroid synthesis and different enzymes are localized between the mitochondria and the endoplasmic reticulum to produce the final steroid hormone, thus suggesting that mitochondrial fusion might be relevant for this process. In the present study, we showed that the hormonal stimulation triggers mitochondrial fusion into tubular-shaped structures and we demonstrated that mitochondrial fusion does not only correlate-with but also is an essential step of steroid production, being both events depend on PKA activity. We also demonstrated that the hormone-stimulated relocalization of ERK1/2 in the mitochondrion, a critical step during steroidogenesis, depends on mitochondrial fusion. Additionally, we showed that the SHP2 phosphatase, which is required for full steroidogenesis, simultaneously modulates mitochondrial fusion and ERK1/2 localization in the mitochondrion. Strikingly, we found that mitofusin 2 (Mfn2) expression, a central protein for mitochondrial fusion, is upregulated immediately after hormone stimulation. Moreover, Mfn2 knockdown is sufficient to impair steroid biosynthesis. Together, our findings unveil an essential role for mitochondrial fusion during steroidogenesis. These discoveries highlight the importance of organelles' reorganization in specialized cells, prompting the exploration of the impact that organelle dynamics has on biological processes that include, but are not limited to, steroid synthesis. PMID- 23029266 TI - Human pentraxin 3 (PTX3) as a novel biomarker for the diagnosis of pulmonary arterial hypertension. AB - BACKGROUND: Although inflammation is an important feature of pulmonary arterial hypertension (PAH), the usefulness of local inflammatory markers as biomarkers for PAH is unknown. In this study, we tested whether plasma concentrations of human pentraxin 3 (PTX3), a local inflammatory marker, would be a useful biomarker for detecting PAH. METHODS: Plasma PTX3 concentrations were evaluated in 50 PAH patients (27 with idiopathic PAH, 17 with PAH associated with connective tissue disease (CTD-PAH), and six with congenital heart disease), 100 age and sex-matched healthy controls, and 34 disease-matched CTD patients without PAH. Plasma concentrations of B-type natriuretic peptide (BNP) and C-reactive protein (CRP) were also determined. RESULTS: Mean PTX3 levels were significantly higher in all PAH patients than in the healthy controls (4.40+/-0.37 vs. 1.94+/ 0.09 ng/mL, respectively; P<0.001). Using a threshold level of 2.84 ng/mL, PTX3 yielded a sensitivity of 74.0% and a specificity of 84.0% for the detection of PAH. In CTD-PAH patients, mean PTX3 concentrations were significantly higher than in CTD patients without PAH (5.02+/-0.69 vs. 2.40+/-0.14 ng/mL, respectively; P<0.001). There was no significant correlation between plasma levels of PTX3 and BNP or CRP. Receiver operating characteristic (ROC) curves for screening PAH in patients with CTD revealed that PTX3 (area under the ROC curve 0.866) is superior to BNP. Using a PTX3 threshold of 2.85 ng/mL maximized true-positive and false negative results (sensitivity 94.1%, specificity 73.5%). CONCLUSION: Plasma concentrations of PTX3 may be a better biomarker of PAH than BNP, especially in patients with CTD. PMID- 23029267 TI - In vivo FRET imaging revealed a regulatory role of RanGTP in kinetochore microtubule attachments via Aurora B kinase. AB - Under the fluctuating circumstances provided by the innate dynamics of microtubules and opposing tensions resulted from microtubule-associated motors, it is vital to ensure stable kinetochore-microtubule attachments for accurate segregation. However, a comprehensive understanding of how this regulation is mechanistically achieved remains elusive. Using our newly designed live cell FRET time-lapse imaging, we found that post-metaphase RanGTP is crucial in the maintenance of stable kinetochore-microtubule attachments by regulating Aurora B kinase via the NES-bearing Mst1. More importantly, our study demonstrates that by ensuring stable alignment of metaphase chromosomes prior to segregation, RanGTP is indispensible in governing the genomic integrity and the fidelity of cell cycle progression. Our findings suggest an additional role of RanGTP beyond its known function in mitotic spindle assembly during the prometaphase-metaphase transition. PMID- 23029268 TI - Genome-wide expression profiling identifies type 1 interferon response pathways in active tuberculosis. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infected with M.tb worldwide, thus being at risk of developing TB reactivation disease later in life. The underlying mechanisms and pathways of protection against TB in humans, as well as the dynamics of the host response to M.tb infection, are incompletely understood. We carried out whole genome expression profiling on a cohort of TB patients longitudinally sampled along 3 time-points: during active infection, during treatment, and after completion of curative treatment. We identified molecular signatures involving the upregulation of type-1 interferon (alpha/beta) mediated signaling and chronic inflammation during active TB disease in an Indonesian population, in line with results from two recent studies in ethnically and epidemiologically different populations in Europe and South Africa. Expression profiles were captured in neutrophil-depleted blood samples, indicating a major contribution of lymphocytes and myeloid cells. Expression of type-1 interferon (alpha/beta) genes mediated was also upregulated in the lungs of M.tb infected mice and in infected human macrophages. In patients, the regulated gene expression-signature normalized during treatment, including the type-1 interferon mediated signaling and a concurrent opposite regulation of interferon-gamma. Further analysis revealed IL15RA, UBE2L6 and GBP4 as molecules involved in the type-I interferon response in all three experimental models. Our data is highly suggestive that the innate immune type-I interferon signaling cascade could be used as a quantitative tool for monitoring active TB disease, and provide evidence that components of the patient's blood gene expression signature bear similarities to the pulmonary and macrophage response to mycobacterial infection. PMID- 23029269 TI - Lack of innate interferon responses during SARS coronavirus infection in a vaccination and reinfection ferret model. AB - In terms of its highly pathogenic nature, there remains a significant need to further define the immune pathology of SARS-coronavirus (SARS-CoV) infection, as well as identify correlates of immunity to help develop vaccines for severe coronaviral infections. Here we use a SARS-CoV infection-reinfection ferret model and a functional genomics approach to gain insight into SARS immunopathogenesis and to identify correlates of immune protection during SARS-CoV-challenge in ferrets previously infected with SARS-CoV or immunized with a SARS virus vaccine. We identified gene expression signatures in the lungs of ferrets associated with primary immune responses to SARS-CoV infection and in ferrets that received an identical second inoculum. Acute SARS-CoV infection prompted coordinated innate immune responses that were dominated by antiviral IFN response gene (IRG) expression. Reinfected ferrets, however, lacked the integrated expression of IRGs that was prevalent during acute infection. The expression of specific IRGs was also absent upon challenge in ferrets immunized with an inactivated, Al(OH)(3) adjuvanted whole virus SARS vaccine candidate that protected them against SARS CoV infection in the lungs. Lack of IFN-mediated immune enhancement in infected ferrets that were previously inoculated with, or vaccinated against, SARS-CoV revealed 9 IRG correlates of protective immunity. This data provides insight into the molecular pathogenesis of SARS-CoV and SARS-like-CoV infections and is an important resource for the development of CoV antiviral therapeutics and vaccines. PMID- 23029270 TI - Specific silencing of the REST target genes in insulin-secreting cells uncovers their participation in beta cell survival. AB - The absence of the transcriptional repressor RE-1 Silencing Transcription Factor (REST) in insulin-secreting beta cells is a major cue for the specific expression of a large number of genes. These REST target genes were largely ascribed to a function of neurotransmission in a neuronal context, whereas their role in pancreatic beta cells has been poorly explored. To identify their functional significance, we have generated transgenic mice expressing REST in beta cells (RIP-REST mice), and previously discovered that REST target genes are essential to insulin exocytosis. Herein we characterized a novel line of RIP-REST mice featuring diabetes. In diabetic RIP-REST mice, high levels of REST were associated with postnatal beta cell apoptosis, which resulted in gradual beta cell loss and sustained hyperglycemia in adults. Moreover, adenoviral REST transduction in INS-1E cells led to increased cell death under control conditions, and sensitized cells to death induced by cytokines. Screening for REST target genes identified several anti-apoptotic genes bearing the binding motif RE-1 that were downregulated upon REST expression in INS-1E cells, including Gjd2, Mapk8ip1, Irs2, Ptprn, and Cdk5r2. Decreased levels of Cdk5r2 in beta cells of RIP-REST mice further confirmed that it is controlled by REST, in vivo. Using siRNA-mediated knock-down in INS-1E cells, we showed that Cdk5r2 protects beta cells against cytokines and palmitate-induced apoptosis. Together, these data document that a set of REST target genes, including Cdk5r2, is important for beta cell survival. PMID- 23029271 TI - Compound C prevents the unfolded protein response during glucose deprivation through a mechanism independent of AMPK and BMP signaling. AB - Inhibiting the unfolded protein response (UPR) can be a therapeutic approach, especially for targeting the tumor microenvironment. Here, we show that compound C (also known as dorsomorphin), a small-molecule inhibitor of AMP-activated protein kinase (AMPK) and bone morphogenetic protein (BMP) signaling, inhibit the UPR-induced transcription program depending on the glucose deprivation conditions. We found that compound C prevented UPR marker glucose-regulated protein 78 (GRP78) accumulation and exerted enhanced cytotoxicity during glucose deprivation. Gene expression profiling, together with biochemical analysis, revealed that compound C had a unique mode of action to suppress the transcriptional activation of UPR-targeted genes, as compared with the classic UPR inhibitors versipelostatin and biguanides. Surprisingly, the UPR-inhibiting activity of compound C was not associated with either AMPK or BMP signaling inhibition. We further found that combination treatments of compound C and the classic UPR inhibitors resulted in synergistic cell death with UPR suppression during glucose deprivation. Our findings demonstrate that compound C could be a unique tool for developing a UPR-targeted antitumor therapy. PMID- 23029272 TI - A survey to assess family physicians' motivation to teach undergraduates in their practices. AB - BACKGROUND: In Germany, family physicians (FPs) are increasingly needed to participate in undergraduate medical education. Knowledge of FPs' motivation to teach medical students in their practices is lacking. PURPOSE: To describe a novel questionnaire that assesses the motivation of FPs to teach undergraduates in their practices and to show the results of a subsequent survey using this instrument. METHODS: The questionnaire was developed based on a review of the literature. Previously used empirical instruments assessing occupational values and motivation were included. A preliminary version was pretested in a pilot study. The resulting 68-item questionnaire was sent to 691 FPs involved in undergraduate medical education. Reliability was assessed and subgroups were analyzed with regard to differences in motivation. RESULTS: A total of 523 physicians in n = 458 teaching practices participated (response rate 75.7%). 'Helping others' and 'interest' were revealed as the predominant motives. Responses showed a predominantly intrinsic motivation of the participating FPs. Their main incentives were an ambition to work as a medical preceptor, to generally improve undergraduate education and to share knowledge. Material compensation was of minor importance. Time restraints were indicated as a barrier by some FPs, but were not a general concern. CONCLUSION: German FPs involved in medical education have altruistic attitudes towards teaching medical students in their practices. Motivational features give an important insight for the recruitment of FP preceptors as well as for their training in instructional methods. PMID- 23029274 TI - Green sturgeon distribution in the Pacific Ocean estimated from modeled oceanographic features and migration behavior. AB - The green sturgeon (Acipenser medirostris), which is found in the eastern Pacific Ocean from Baja California to the Bering Sea, tends to be highly migratory, moving long distances among estuaries, spawning rivers, and distant coastal regions. Factors that determine the oceanic distribution of green sturgeon are unclear, but broad-scale physical conditions interacting with migration behavior may play an important role. We estimated the distribution of green sturgeon by modeling species-environment relationships using oceanographic and migration behavior covariates with maximum entropy modeling (MaxEnt) of species geographic distributions. The primary concentration of green sturgeon was estimated from approximately 41-51.5 degrees N latitude in the coastal waters of Washington, Oregon, and Vancouver Island and in the vicinity of San Francisco and Monterey Bays from 36-37 degrees N latitude. Unsuitably cold water temperatures in the far north and energetic efficiencies associated with prevailing water currents may provide the best explanation for the range-wide marine distribution of green sturgeon. Independent trawl records, fisheries observer records, and tagging studies corroborated our findings. However, our model also delineated patchily distributed habitat south of Monterey Bay, though there are few records of green sturgeon from this region. Green sturgeon are likely influenced by countervailing pressures governing their dispersal. They are behaviorally directed to revisit natal freshwater spawning rivers and persistent overwintering grounds in coastal marine habitats, yet they are likely physiologically bounded by abiotic and biotic environmental features. Impacts of human activities on green sturgeon or their habitat in coastal waters, such as bottom-disturbing trawl fisheries, may be minimized through marine spatial planning that makes use of high-quality species distribution information. PMID- 23029273 TI - Probing protein sequences as sources for encrypted antimicrobial peptides. AB - Starting from the premise that a wealth of potentially biologically active peptides may lurk within proteins, we describe here a methodology to identify putative antimicrobial peptides encrypted in protein sequences. Candidate peptides were identified using a new screening procedure based on physicochemical criteria to reveal matching peptides within protein databases. Fifteen such peptides, along with a range of natural antimicrobial peptides, were examined using DSC and CD to characterize their interaction with phospholipid membranes. Principal component analysis of DSC data shows that the investigated peptides group according to their effects on the main phase transition of phospholipid vesicles, and that these effects correlate both to antimicrobial activity and to the changes in peptide secondary structure. Consequently, we have been able to identify novel antimicrobial peptides from larger proteins not hitherto associated with such activity, mimicking endogenous and/or exogenous microorganism enzymatic processing of parent proteins to smaller bioactive molecules. A biotechnological application for this methodology is explored. Soybean (Glycine max) plants, transformed to include a putative antimicrobial protein fragment encoded in its own genome were tested for tolerance against Phakopsora pachyrhizi, the causative agent of the Asian soybean rust. This procedure may represent an inventive alternative to the transgenic technology, since the genetic material to be used belongs to the host organism and not to exogenous sources. PMID- 23029275 TI - Hypoxia enhances the proliferative response of macrophages to CSF-1 and their pro survival response to TNF. AB - In chronic inflammatory lesions there are increased numbers of macrophages with a possible contribution of enhanced survival/proliferation due, for example, to cytokine action; such lesions are often hypoxic. Prior studies have found that culture in low oxygen can promote monocyte/macrophage survival. We show here, using pharmacologic inhibitors, that the hypoxia-induced pro-survival response of macrophages exhibits a dependence on PI3-kinase and mTOR activities but surprisingly is suppressed by Akt and p38 MAPK activities. It was also found that in hypoxia at CSF-1 concentrations, which under normoxic conditions are suboptimal for macrophage proliferation, macrophages can proliferate more strongly with no evidence for alteration in CSF-1 receptor degradation kinetics. TNF promoted macrophage survival in normoxic conditions with an additive effect in hypoxia. The enhanced hypoxia-dependent survival and/or proliferation of macrophages in the presence of CSF-1 or TNF may contribute to their elevated numbers at a site of chronic inflammation. PMID- 23029276 TI - Prediction of protein cleavage site with feature selection by random forest. AB - Proteinases play critical roles in both intra and extracellular processes by binding and cleaving their protein substrates. The cleavage can either be non specific as part of degradation during protein catabolism or highly specific as part of proteolytic cascades and signal transduction events. Identification of these targets is extremely challenging. Current computational approaches for predicting cleavage sites are very limited since they mainly represent the amino acid sequences as patterns or frequency matrices. In this work, we developed a novel predictor based on Random Forest algorithm (RF) using maximum relevance minimum redundancy (mRMR) method followed by incremental feature selection (IFS). The features of physicochemical/biochemical properties, sequence conservation, residual disorder, amino acid occurrence frequency, secondary structure and solvent accessibility were utilized to represent the peptides concerned. Here, we compared existing prediction tools which are available for predicting possible cleavage sites in candidate substrates with ours. It is shown that our method makes much more reliable predictions in terms of the overall prediction accuracy. In addition, this predictor allows the use of a wide range of proteinases. PMID- 23029277 TI - Gene flow among populations of two rare co-occurring fern species differing in ploidy level. AB - Differences in ploidy levels among different fern species have a vast influence on their mating system, their colonization ability and on the gene flow among populations. Differences in the colonization abilities of species with different ploidy levels are well known: tetraploids, in contrast to diploids, are able to undergo intra-gametophytic selfing. Because fertilization is a post-dispersal process in ferns, selfing results in better colonization abilities in tetraploids because of single spore colonization. Considerably less is known about the gene flow among populations of different ploidy levels. The present study examines two rare fern species that differ in ploidy. While it has already been confirmed that tetraploid species are better at colonizing, the present study focuses on the gene flow among existing populations. We analyzed the genetic structure of a set of populations in a 10*10 km study region using isoenzymes. Genetic variation in tetraploid species is distributed mainly among populations; the genetic distance between populations is correlated with the geographical distance, and larger populations host more genetic diversity than smaller populations. In the diploid species, most variability is partitioned within populations; the genetic distance is not related to geographic distance, and the genetic diversity of populations is not related to the population size. This suggests that in tetraploid species, which undergo selfing, gene flow is limited. In contrast, in the diploid species, which experience outcrossing, gene flow is extensive and the whole system behaves as one large population. Our results suggest that in ferns, the ability to colonize new habitats and the gene flow among existing populations are affected by the mating system. PMID- 23029278 TI - Sleepiness, long distance commuting and night work as predictors of driving performance. AB - Few studies have examined the effect of working night shift and long distance commuting. We examined the association between several sleep related and demographic variables, commuting distance, night work and use of mobile phones on driving performance. We used a prospective design to recruit participants and conducted a telephone survey (n = 649). The survey collected demographic and journey details, work and sleep history and driving performance concerning the day the participant was recruited. Participants also completed the Karolinska Sleepiness Scale and the Epworth Sleepiness Scale. Night workers reported significantly more sleepiness, shorter sleep duration and commuting longer distances. Seven variables were significant predictors of lane crossing. The strongest predictor was acute sleepiness (OR = 5.25, CI, 1.42-19.49, p<0.01) followed by driving >=150 kms (OR = 3.61, CI, 1.66-7.81, p<0.001), obtaining less than 10 hours sleep in the previous 48 hours (OR = 2.58, CI, 1.03-6.46, p<0.05), driving after night shift (OR = 2.19, CI, 1.24-3.88, p<0.001), being <43 years old (OR = 1.95, CI, 1.11-3.41, p<0.05) and using mobile phones during the journey (OR = 1.90, CI, 1.10-3.27, p<0.05). Sleep related variables, long-distance commuting and night work have a major impact on lane crossing. Several interventions should be considered to reduce the level of sleepiness in night workers. PMID- 23029279 TI - Changes of hand switching costs during bimanual sequential learning. AB - Many tasks in our daily life demand not only the use of different fingers of one hand in a serial fashion, but also to alternate from one hand to the other. Here, we investigated performance in a bimanual serial reaction time task (SRTT) with particular emphasis on learning-related changes in reaction time (RT) for consecutive button presses for homologous index- and middle fingers. The bimanual SRTT consisted of sequential button presses either with the left or right index- and middle-finger to a series of visual letters displayed on a computer screen. Each letter was assigned a specific button press with one of four fingers. Two outcome measures were investigated: (a) global sequence learning as defined by the time needed to complete a 15-letter SRTT sequence and (b) changes in hand switch costs across learning. We found that bimanual SRTT resulted in a global decrease in RT during the time course of learning that persisted for at least two weeks. Furthermore, RT to a button press showed an increase when the previous button press was associated with another hand as opposed to the same hand. This increase in RT was defined as switch costs. Hand switch costs significantly decreased during the time course of learning, and remained stable over a time of approximately two weeks. This study provides evidence for modulations of switch costs during bimanual sequence learning, a finding that might have important implications for theories of bimanual coordination and learning. PMID- 23029280 TI - Arhgef15 promotes retinal angiogenesis by mediating VEGF-induced Cdc42 activation and potentiating RhoJ inactivation in endothelial cells. AB - BACKGROUND: Drugs inhibiting vascular endothelial growth factor (VEGF) signaling are globally administered to suppress deregulated angiogenesis in a variety of eye diseases. However, anti-VEGF therapy potentially affects the normal functions of retinal neurons and glias which constitutively express VEGF receptor 2. Thus, it is desirable to identify novel drug targets which are exclusively expressed in endothelial cells (ECs). Here we attempted to identify an EC-specific Rho guanine nucleotide exchange factor (GEF) and evaluate its role in retinal angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: By exploiting fluorescence-activated cell sorting and microarray analyses in conjunction with in silico bioinformatics analyses, we comprehensively identified endothelial genes in angiogenic retinal vessels of postnatal mice. Of 9 RhoGEFs which were highly expressed in retinal ECs, we show that Arhgef15 acted as an EC-specific GEF to mediate VEGF-induced Cdc42 activation and potentiated RhoJ inactivation, thereby promoting actin polymerization and cell motility. Disruption of the Arhgef15 gene led to delayed extension of vascular networks and subsequent reduction of total vessel areas in postnatal mouse retinas. CONCLUSIONS/SIGNIFICANCE: Our study provides information useful to the development of new means of selectively manipulating angiogenesis without affecting homeostasis in un-targeted tissues; not only in eyes but also in various disease settings such as cancer. PMID- 23029281 TI - Treatment of autoimmune inflammation by a TLR7 ligand regulating the innate immune system. AB - The Toll-like receptors (TLR) have been advocated as attractive therapeutic targets because TLR signaling plays dual roles in initiating adaptive immune responses and perpetuating inflammation. Paradoxically, repeated stimulation of bone marrow mononuclear cells with a synthetic TLR7 ligand 9-benzyl-8-hydroxy-2 (2-methoxyethoxy) adenine (called 1V136) leads to subsequent TLR hyporesponsiveness. Further studies on the mechanism of action of this pharmacologic agent demonstrated that the TLR7 ligand treatment depressed dendritic cell activation, but did not directly affect T cell function. To verify this mechanism, we utilized experimental allergic encephalitis (EAE) as an in vivo T cell dependent autoimmune model. Drug treated SJL/J mice immunized with proteolipid protein (PLP)(139-151) peptide had attenuated disease severity, reduced accumulation of mononuclear cells in the central nervous system (CNS), and limited demyelination, without any apparent systemic toxicity. Splenic T cells from treated mice produced less cytokines upon antigenic rechallenge. In the spinal cords of 1V136-treated EAE mice, the expression of chemoattractants was also reduced, suggesting innate immune cell hyposensitization in the CNS. Indeed, systemic 1V136 did penetrate the CNS. These experiments indicated that repeated doses of a TLR7 ligand may desensitize dendritic cells in lymphoid organs, leading to diminished T cell responses. This treatment strategy might be a new modality to treat T cell mediated autoimmune diseases. PMID- 23029282 TI - Strain-specific protective effect of the immunity induced by live malarial sporozoites under chloroquine cover. AB - The efficacy of a whole-sporozoite malaria vaccine would partly be determined by the strain-specificity of the protective responses against malarial sporozoites and liver-stage parasites. Evidence from previous reports were inconsistent, where some studies have shown that the protective immunity induced by irradiated or live sporozoites in rodents or humans were cross-protective and in others strain-specific. In the present work, we have studied the strain-specificity of live sporozoite-induced immunity using two genetically and immunologically different strains of Plasmodium cynomolgi, Pc746 and PcCeylon, in toque monkeys. Two groups of monkeys were immunized against live sporozoites of either the Pc746 (n = 5), or the PcCeylon (n = 4) strain, by the bites of 2-4 sporozoite-infected Anopheles tessellates mosquitoes per monkey under concurrent treatments with chloroquine and primaquine to abrogate detectable blood infections. Subsequently, a group of non-immunized monkeys (n = 4), and the two groups of immunized monkeys were challenged with a mixture of sporozoites of the two strains by the bites of 2-5 infective mosquitoes from each strain per monkey. In order to determine the strain-specificity of the protective immunity, the proportions of parasites of the two strains in the challenge infections were quantified using an allele quantification assay, PyrosequencingTM, based on a single nucleotide polymorphism (SNP) in the parasites' circumsporozoite protein gene. The PyrosequencingTM data showed that a significant reduction of parasites of the immunizing strain in each group of strain-specifically immunized monkeys had occurred, indicating a stronger killing effect on parasites of the immunizing strain. Thus, the protective immunity developed following a single, live sporozoite/chloroquine immunization, acted specifically against the immunizing strain and was, therefore, strain-specific. As our experiment does not allow us to determine the parasite stage at which the strain-specific protective immunity is directed, it is possible that the target of this immunity could be either the pre-erythrocytic stage, or the blood-stage, or both. PMID- 23029283 TI - Lysophosphatidic acid increases the electrophysiological instability of adult rabbit ventricular myocardium by augmenting L-type calcium current. AB - Lysophosphatidic acid (LPA) has diverse actions on the cardiovascular system and is widely reported to modulate multiple ion currents in some cell types. However, little is known about its electrophysiological effects on cardiac myocytes. This study investigated whether LPA has electrophysiological effects on isolated rabbit myocardial preparations. The results indicate that LPA prolongs action potential duration at 90% repolarization (APD(90)) in a concentration- and frequency-dependent manner in isolated rabbit ventricular myocytes. The application of extracellular LPA significantly increases the coefficient of APD(90) variability. LPA increased L-type calcium current (I(Ca,L)) density without altering its activation or deactivation properties. In contrast, LPA has no effect on two other ventricular repolarizing currents, the transient outward potassium current (I(to)) and the delayed rectifier potassium current (I(K)). In arterially perfused rabbit left ventricular wedge preparations, the monophasic action potential duration, QT interval, and Tpeak-end are prolonged by LPA. LPA treatment also significantly increases the incidence of ventricular tachycardia induced by S(1)S(2) stimulation. Notably, the effects of LPA on action potentials and I(Ca,L) are PTX-sensitive, suggesting LPA action requires a G(i)-type G protein. In conclusion, LPA prolongs APD and increases electrophysiological instability in isolated rabbit myocardial preparations by increasing I(Ca,L) in a G(i) protein-dependent manner. PMID- 23029285 TI - Systematic review and meta-analysis of artemisinin based therapies for the treatment and prevention of schistosomiasis. AB - BACKGROUND: Chemotherapy based on repeated doses of praziquantel is still the most effective control strategy against Schistosomiasis, however artemisinin derivatives emerged as a family of compounds with schistomicide activity. The aim of the present work is to compare the efficacy of artemisinin-based therapies in the treatment and prophylaxis of human schistosomiasis. The design of this work involved a quantitative systematic review and meta-analysis. METHODOLOGY/PRINCIPAL FINDINGS: Retrieval of published studies was carried out through an electronic search of the PubMed (MEDLINE), EMBASE, Cochrane Library and CINAHL databases. This included reports comparing the therapeutic efficacy of artesunate alone, artesunate plus sulfadoxine-pyrimethamine and a combination of artemisinin derivatives plus praziquantel against praziquantel alone on different types of schistosomiasis. Moreover, studies on artesunate and artemether used as preventive drugs were also analyzed against placebo. The primary outcome measure for schistosomiasis treatment was "parasitological cure", whereas for the prophylaxis the outcome evaluated was "infection rate". Our results show that patients treated with artesunate alone have significantly lower cure rates than those treated with praziquantel (OR = 0.27 (95% C.I. 0.13-0.53; p<0.001)) and that the combined therapy of artesunate plus sulfadoxine-pyrimethamine is also significantly less effective than praziquantel treatment (OR = 0.14 (95% C.I. 0.02-0.92; p = 0.04)). However, the combination of an artemisinin derivatives plus praziquantel showed a higher cure rate than praziquantel monotherapy with OR = 2.07 (95% C.I. 1.27-3.36; p = 0.003). Finally, chemoprophylaxis with either artesunate (RR = 0.11 (95% C.I. 0.06-0.22; p<0.001)) or artemether (RR = 0.25 (95% C.I. 0.16-0.40; p<0.001)) was significantly better than a placebo in both cases. CONCLUSIONS/SIGNIFICANCE: This meta-analysis confirms that artemisinin derivatives used in combination with praziquantel have the potential to increase the cure rates in schistosomiasis treatment, but not artesunate alone. It is also confirmed that repeated doses of artemisinin derivatives play a prophylactic role, significantly reducing the incidence of Schistosoma japonicum infections compared with placebo. PMID- 23029284 TI - Comprehensive exploration of the effects of miRNA SNPs on monocyte gene expression. AB - We aimed to assess whether pri-miRNA SNPs (miSNPs) could influence monocyte gene expression, either through marginal association or by interacting with polymorphisms located in 3'UTR regions (3utrSNPs). We then conducted a genome wide search for marginal miSNPs effects and pairwise miSNPs * 3utrSNPs interactions in a sample of 1,467 individuals for which genome-wide monocyte expression and genotype data were available. Statistical associations that survived multiple testing correction were tested for replication in an independent sample of 758 individuals with both monocyte gene expression and genotype data. In both studies, the hsa-mir-1279 rs1463335 was found to modulate in cis the expression of LYZ and in trans the expression of CNTN6, CTRC, COPZ2, KRT9, LRRFIP1, NOD1, PCDHA6, ST5 and TRAF3IP2 genes, supporting the role of hsa mir-1279 as a regulator of several genes in monocytes. In addition, we identified two robust miSNPs * 3utrSNPs interactions, one involving HLA-DPB1 rs1042448 and hsa-mir-219-1 rs107822, the second the H1F0 rs1894644 and hsa-mir-659 rs5750504, modulating the expression of the associated genes.As some of the aforementioned genes have previously been reported to reside at disease-associated loci, our findings provide novel arguments supporting the hypothesis that the genetic variability of miRNAs could also contribute to the susceptibility to human diseases. PMID- 23029286 TI - Identification of a novel splicing form of amelogenin gene in a reptile, Ctenosaura similis. AB - Amelogenin, the major enamel matrix protein in tooth development, has been demonstrated to play a significant role in tooth enamel formation. Previous studies have identified the alternative splicing of amelogenin in many mammalian vertebrates as one mechanism for amelogenin heterogeneous expression in teeth. While amelogenin and its splicing forms in mammalian vertebrates have been cloned and sequenced, the amelogenin gene, especially its splicing forms in non mammalian species, remains largely unknown. To better understand the mechanism underlying amelogenin evolution, we previously cloned and characterized an amelogenin gene sequence from a squamate, the green iguana. In this study, we employed RT-PCR to amplify the amelogenin gene from the black spiny-tailed iguana Ctenosaura similis teeth, and discovered a novel splicing form of the amelogenin gene. The transcript of the newly identified iguana amelogenin gene (named C. Similis-T2L) is 873 nucleotides long encoding an expected polypeptide of 206 amino acids. The C. Similis-T2L contains a unique exon denominated exon X, which is located between exon 5 and exon 6. The C. Similis-T2L contains 7 exons including exon 1, 2, 3, 5, X, 6, and 7. Analysis of the secondary and tertiary structures of T2L amelogenin protein demonstrated that exon X has a dramatic effect on the amelogenin structures. This is the first report to provide definitive evidence for the amelogenin alternative splicing in non-mammalian vertebrates, revealing a unique exon X and the splicing form of the amelogenin gene transcript in Ctenosaura similis. PMID- 23029287 TI - Mixed organic solvents induce renal injury in rats. AB - To investigate the injury effects of organic solvents on kidney, an animal model of Sprague-Dawley (SD) rats treated with mixed organic solvents via inhalation was generated and characterized. The mixed organic solvents consisted of gasoline, dimethylbenzene and formaldehyde (GDF) in the ratio of 2:2:1, and were used at 12,000 PPM to treat the rats twice a day, each for 3 hours. Proteinuria appeared in the rats after exposure for 5-6 weeks. The incidences of proteinuria in male and female rats after exposure for 12 weeks were 43.8% (7/16) and 25% (4/16), respectively. Urinary N-Acetyl-beta-(D)-Glucosaminidase (NAG) activity was increased significantly after exposure for 4 weeks. Histological examination revealed remarkable injuries in the proximal renal tubules, including tubular epithelial cell detachment, cloud swelling and vacuole formation in the proximal tubular cells, as well as proliferation of parietal epithelium and tubular reflux in glomeruli. Ultrastructural examination found that brush border and cytoplasm of tubular epithelial cell were dropped, that tubular epithelial cells were partially disintegrated, and that the mitochondria of tubular epithelial cells were degenerated and lost. In addition to tubular lesions, glomerular damages were also observed, including segmental foot process fusion and loss of foot process covering on glomerular basement membrane (GBM). Immunofluorescence staining indicated that the expression of nephrin and podocin were both decreased after exposure of GDF. In contrast, increased expression of desmin, a marker of podocyte injury, was found in some areas of a glomerulus. TUNEL staining showed that GDF induced apoptosis in tubular cells and glomerular cells. These studies demonstrate that GDF can induce both severe proximal tubular damage and podocyte injury in rats, and the tubular lesions appear earlier than that of glomeruli. PMID- 23029288 TI - Species richness-environment relationships of European arthropods at two spatial grains: habitats and countries. AB - We study how species richness of arthropods relates to theories concerning net primary productivity, ambient energy, water-energy dynamics and spatial environmental heterogeneity. We use two datasets of arthropod richness with similar spatial extents (Scandinavia to Mediterranean), but contrasting spatial grain (local habitat and country). Samples of ground-dwelling spiders, beetles, bugs and ants were collected from 32 paired habitats at 16 locations across Europe. Species richness of these taxonomic groups was also determined for 25 European countries based on the Fauna Europaea database. We tested effects of net primary productivity (NPP), annual mean temperature (T), annual rainfall (R) and potential evapotranspiration of the coldest month (PET(min)) on species richness and turnover. Spatial environmental heterogeneity within countries was considered by including the ranges of NPP, T, R and PET(min). At the local habitat grain, relationships between species richness and environmental variables differed strongly between taxa and trophic groups. However, species turnover across locations was strongly correlated with differences in T. At the country grain, species richness was significantly correlated with environmental variables from all four theories. In particular, species richness within countries increased strongly with spatial heterogeneity in T. The importance of spatial heterogeneity in T for both species turnover across locations and for species richness within countries suggests that the temperature niche is an important determinant of arthropod diversity. We suggest that, unless climatic heterogeneity is constant across sampling units, coarse-grained studies should always account for environmental heterogeneity as a predictor of arthropod species richness, just as studies with variable area of sampling units routinely consider area. PMID- 23029289 TI - Response of retinal blood flow to systemic hyperoxia as measured with dual-beam bidirectional Doppler Fourier-domain optical coherence tomography. AB - PURPOSE: There is a long-standing interest in the study of retinal blood flow in humans. In the recent years techniques have been established to measure retinal perfusion based on optical coherence tomography (OCT). In the present study we used a technique called dual-beam bidirectional Doppler Fourier-domain optical coherence tomography (FD-OCT) to characterize the effects of 100% oxygen breathing on retinal blood flow. These data were compared to data obtained with a laser Doppler velocimeter (LDV). METHODS: 10 healthy subjects were studied on 2 study days. On one study day the effect of 100% oxygen breathing on retinal blood velocities was studied using dual-beam bidirectional Doppler FD-OCT. On the second study day the effect of 100% oxygen breathing on retinal blood velocities was assessed by laser Doppler velocimetry (LDV). Retinal vessel diameters were measured on both study days using a commercially available Dynamic Vessel Analyzer. Retinal blood flow was calculated based on retinal vessel diameters and red blood cell velocity. RESULTS: As expected, breathing of pure oxygen induced a pronounced reduction in retinal vessel diameters, retinal blood velocities and retinal blood flow on both study days (p<0.001). Blood velocity data correlated well between the two methods applied under both baseline as well as under hyperoxic conditions (r = 0.98 and r = 0.75, respectively). Data as obtained with OCT were, however, slightly higher. CONCLUSION: A good correlation was found between red blood cell velocity as measured with dual-beam bidirectional Doppler FD-OCT and red blood cell velocity assessed by the laser Doppler method. Dual beam bidirectional Doppler FD-OCT is a promising approach for studying retinal blood velocities in vivo. PMID- 23029290 TI - Fibroblast growth factor receptor 1 activation in mammary tumor cells promotes macrophage recruitment in a CX3CL1-dependent manner. AB - Tumor formation is an extensive process requiring complex interactions that involve both tumor cell-intrinsic pathways and soluble mediators within the microenvironment. Tumor cells exploit the intrinsic functions of many soluble molecules, including chemokines and their receptors, to regulate pro-tumorigenic phenotypes that are required for growth and progression of the primary tumor. Previous studies have shown that activation of inducible FGFR1 (iFGFR1) in mammary epithelial cells resulted in increased proliferation, migration, and invasion in vitro and tumor formation in vivo. These studies also demonstrated that iFGFR1 activation stimulated recruitment of macrophages to the epithelium where macrophages contributed to iFGFR1-mediated epithelial cell proliferation and angiogenesis. The studies presented here further utilize this model to identify the mechanisms that regulate FGFR1-induced macrophage recruitment. Results from this study elucidate a novel role for the inflammatory chemokine CX3CL1 in FGFR1-induced macrophage migration. Specifically, we illustrate that activation of both the inducible FGFR1 construct in mouse mammary epithelial cells and endogenous FGFR in the triple negative breast cancer cell line, HS578T, leads to expression of the chemokine CX3CL1. Furthermore, we demonstrate that FGFR-induced CX3CL1 is sufficient to recruit CX3CR1-expressing macrophages in vitro. Finally, blocking CX3CR1 in vivo leads to decreased iFGFR1-induced macrophage recruitment, which correlates with decreased angiogenesis. While CX3CL1 is a known target of FGF signaling in the wound healing environment, these studies demonstrate that FGFR activation also leads to induction of CX3CL1 in a tumor setting. Furthermore, these results define a novel role for CX3CL1 in promoting macrophage recruitment during mammary tumor formation, suggesting that the CX3CL1/CX3CR1 axis may represent a potential therapeutic approach for targeting breast cancers associated with high levels of tumor-associated macrophages. PMID- 23029291 TI - ThioFinder: a web-based tool for the identification of thiopeptide gene clusters in DNA sequences. AB - Thiopeptides are a growing class of sulfur-rich, highly modified heterocyclic peptides that are mainly active against Gram-positive bacteria including various drug-resistant pathogens. Recent studies also reveal that many thiopeptides inhibit the proliferation of human cancer cells, further expanding their application potentials for clinical use. Thiopeptide biosynthesis shares a common paradigm, featuring a ribosomally synthesized precursor peptide and conserved posttranslational modifications, to afford a characteristic core system, but differs in tailoring to furnish individual members. Identification of new thiopeptide gene clusters, by taking advantage of increasing information of DNA sequences from bacteria, may facilitate new thiopeptide discovery and enrichment of the unique biosynthetic elements to produce novel drug leads by applying the principle of combinatorial biosynthesis. In this study, we have developed a web based tool ThioFinder to rapidly identify thiopeptide biosynthetic gene cluster from DNA sequence using a profile Hidden Markov Model approach. Fifty-four new putative thiopeptide biosynthetic gene clusters were found in the sequenced bacterial genomes of previously unknown producing microorganisms. ThioFinder is fully supported by an open-access database ThioBase, which contains the sufficient information of the 99 known thiopeptides regarding the chemical structure, biological activity, producing organism, and biosynthetic gene (cluster) along with the associated genome if available. The ThioFinder website offers researchers a unique resource and great flexibility for sequence analysis of thiopeptide biosynthetic gene clusters. ThioFinder is freely available at http://db-mml.sjtu.edu.cn/ThioFinder/. PMID- 23029292 TI - Analyzing gene expression from whole tissue vs. different cell types reveals the central role of neurons in predicting severity of Alzheimer's disease. AB - Alterations in gene expression resulting from Alzheimer's disease have received considerable attention in recent years. Although expression has been investigated separately in whole brain tissue, in astrocytes and in neurons, a rigorous comparative study quantifying the relative utility of these sources in predicting the progression of Alzheimer's disease has been lacking. Here we analyze gene expression from neurons, astrocytes and whole tissues across different brain regions, and compare their ability to predict Alzheimer's disease progression by building pertaining classification models based on gene expression sets annotated to different biological processes. Remarkably, we find that predictions based on neuronal gene expression are significantly more accurate than those based on astrocyte or whole tissue expression. The findings explicate the central role of neurons, particularly as compared to glial cells, in the pathogenesis of Alzheimer's disease, and emphasize the importance of measuring gene expression in the most relevant (pathogenically 'proximal') single cell types. PMID- 23029293 TI - Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits. AB - Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer's disease (AD). It can occur before significant Abeta deposition and appears to "spread" into anatomically connected brain regions. To determine whether this early-stage pathology is sufficient to cause disease progression and cognitive decline in experimental models, we overexpressed mutant human tau (hTauP301L) predominantly in layer II/III neurons of the mouse EC. Cognitive functions remained normal in mice at 4, 8, 12 and 16 months of age, despite early and extensive tau accumulation in the EC. Perforant path (PP) axon terminals within the dentate gyrus (DG) contained abnormal conformations of tau even in young EC-hTau mice, and phosphorylated tau increased with age in both the EC and PP. In old mice, ultrastructural alterations in presynaptic terminals were observed at PP-to granule cell synapses. Phosphorylated tau was more abundant in presynaptic than postsynaptic elements. Human and pathological tau was also detected within hippocampal neurons of this mouse model. Thus, hTauP301L accumulation predominantly in the EC and related presynaptic pathology in hippocampal circuits was not sufficient to cause robust cognitive deficits within the age range analyzed here. PMID- 23029294 TI - Meta-analysis of the relationship between common type 2 diabetes risk gene variants with gestational diabetes mellitus. AB - BACKGROUND: A number of case-control studies were conducted to investigate the association of common type 2 diabetes (T2D) risk gene polymorphisms with gestational diabetes mellitus (GDM). However, these studies have yielded contradictory results. We therefore performed a meta-analysis to derive a more precise estimation of the association between these polymorphisms and GDM, hence achieve a better understanding to the relationship between T2D and GDM. METHODS: PubMed, EMBASE, ISI web of science and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between 9 polymorphisms from 8 genes and susceptibility to GDM. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity among articles and their publication bias were also tested. RESULTS: We identified 22 eligible studies including a total of 10,336 GDM cases and 17,445 controls. We found 8 genetic polymorphisms were significantly associated with GDM in a random-effects meta-analysis. These polymorphisms were in or near the following genes: TCF7L2 (rs7903146), MTNR1B (rs10830963), IGF2BP2 (rs4402960), KCNJ11 (rs5219), CDKAL1 (rs7754840), KCNQ1 (rs2237892 and rs2237895) and GCK (rs4607517); while no association was found for PPARG with GDM risk. Similar results were also observed under dominant genetic model for these polymorphisms. CONCLUSIONS: This meta-analysis found 8 genetic variants associated with GDM. The relative contribution and relevance of the identified genes in the pathogenesis of GDM should be the focus of future studies. PMID- 23029295 TI - Involvement of cytochrome P450 in pentachlorophenol transformation in a white rot fungus Phanerochaete chrysosporium. AB - The occurrence of cytochrome P450 and P450-mediated pentachlorophenol oxidation in a white rot fungus Phanerochaete chrysosporium was demonstrated in this study. The carbon monoxide difference spectra indicated induction of P450 (103+/-13 pmol P450 per mg protein in the microsomal fraction) by pentachlorophenol. The pentachlorophenol oxidation by the microsomal P450 was NADPH-dependent at a rate of 19.0+/-1.2 pmol min(-1) (mg protein)(-1), which led to formation of tetrachlorohydroquinone and was significantly inhibited by piperonyl butoxide (a P450 inhibitor). Tetrachlorohydroquinone was also found in the cultures, while the extracellular ligninases which were reported to be involved in tetrachlorohydroquinone formation were undetectable. The formation of tetrachlorohydroquinone was not detectable in the cultures added with either piperonyl butoxide or cycloheximide (an inhibitor of de novo protein synthesis). These results revealed the pentachlorophenol oxidation by induced P450 in the fungus, and it should be the first time that P450-mediated pentachlorophenol oxidation was demonstrated in a microorganism. Furthermore, the addition of the P450 inhibitor to the cultures led to obvious increase of pentachlorophenol, suggesting that the relationship between P450 and pentachlorophenol methylation is worthy of further research. PMID- 23029296 TI - An automatic refolding apparatus for preparative-scale protein production. AB - Protein refolding is an important process to recover active recombinant proteins from inclusion bodies. Refolding by simple dilution, dialysis and on-column refolding methods are the most common techniques reported in the literature. However, the refolding process is time-consuming and laborious due to the variability of the behavior of each protein and requires a great deal of trial and-error to achieve success. Hence, there is a need for automation to make the whole process as convenient as possible. In this study, we invented an automatic apparatus that integrated three refolding techniques: varying dilution, dialysis and on-column refolding. We demonstrated the effectiveness of this technology by varying the flow rates of the dilution buffer into the denatured protein and testing different refolding methods. We carried out different refolding methods on this apparatus: a combination of dilution and dialysis for human stromal cell derived factor 1 (SDF-1/CXCL12) and thioredoxin fused-human artemin protein (Trx ARTN); dilution refolding for thioredoxin fused-human insulin-like growth factor I protein (Trx-IGF1) and enhanced fluorescent protein (EGFP); and on-column refolding for bovine serum albumin (BSA). The protein refolding processes of these five proteins were preliminarily optimized using the slowly descending denaturants (or additives) method. Using this strategy of decreasing denaturants concentration, the efficiency of protein refolding was found to produce higher quantities of native protein. The standard refolding apparatus configuration can support different operations for different applications; it is not limited to simple dilution, dialysis and on-column refolding techniques. Refolding by slowly decreasing denaturants concentration, followed by concentration or purification on-column, may be a useful strategy for rapid and efficient recovery of active proteins from inclusion bodies. An automatic refolding apparatus employing this flexible strategy may provide a powerful tool for preparative scale protein production. PMID- 23029297 TI - Cutting a drop of water pinned by wire loops using a superhydrophobic surface and knife. AB - A water drop on a superhydrophobic surface that is pinned by wire loops can be reproducibly cut without formation of satellite droplets. Drops placed on low density polyethylene surfaces and Teflon-coated glass slides were cut with superhydrophobic knives of low-density polyethylene and treated copper or zinc sheets, respectively. Distortion of drop shape by the superhydrophobic knife enables a clean break. The driving force for droplet formation arises from the lower surface free energy for two separate drops, and it is modeled as a 2-D system. An estimate of the free energy change serves to guide when droplets will form based on the variation of drop volume, loop spacing and knife depth. Combining the cutting process with an electrofocusing driving force could enable a reproducible biomolecular separation without troubling satellite drop formation. PMID- 23029298 TI - Identification of common prognostic gene expression signatures with biological meanings from microarray gene expression datasets. AB - Numerous prognostic gene expression signatures for breast cancer were generated previously with few overlap and limited insight into the biology of the disease. Here we introduce a novel algorithm named SCoR (Survival analysis using Cox proportional hazard regression and Random resampling) to apply random resampling and clustering methods in identifying gene features correlated with time to event data. This is shown to reduce overfitting noises involved in microarray data analysis and discover functional gene sets linked to patient survival. SCoR independently identified a common poor prognostic signature composed of cell proliferation genes from six out of eight breast cancer datasets. Furthermore, a sequential SCoR analysis on highly proliferative breast cancers repeatedly identified T/B cell markers as favorable prognosis factors. In glioblastoma, SCoR identified a common good prognostic signature of chromosome 10 genes from two gene expression datasets (TCGA and REMBRANDT), recapitulating the fact that loss of one copy of chromosome 10 (which harbors the tumor suppressor PTEN) is linked to poor survival in glioblastoma patients. SCoR also identified prognostic genes on sex chromosomes in lung adenocarcinomas, suggesting patient gender might be used to predict outcome in this disease. These results demonstrate the power of SCoR to identify common and biologically meaningful prognostic gene expression signatures. PMID- 23029299 TI - Associations between the expression of epigenetically regulated genes and the expression of DNMTs and MBDs in systemic lupus erythematosus. AB - OBJECTIVES: We determined the expression of ITGAL, PRF1, KIR2DL4, CD70, and CD40LG in patients with SLE and performed correlations with the global DNA methylation status and the levels of three DNA methylation enzymes and two methyl CpG-binding domain (MBD) proteins. PATIENTS AND METHODS: CD4(+) T cells were isolated from 35 SLE patients and 30 healthy controls. DNA deoxymethylcytosine content was measured by an enzyme-linked immunosorbent assay (ELISA). Transcript levels of ITGAL, PRF1, KIR2DL4, CD70, CD40LG, DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 were quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: SLE patients had significantly elevated transcript levels of ITGAL (18.61+/-22.17 vs. 7.33+/-9.17, p = 0.042), PRF1 (21.67+/-26.34 vs. 10.67+/ 11.65, p = 0.039), and CD70 (1.45+/-1.63 vs. 0.67+/-0.28, p = 0.011). A positive correlation was observed between transcript levels of CD40LG and ITGAL (r = 0.477, p = 0.004) as well as between CD40LG and PRF1 (r = 0.557, p = 0.001). Transcript levels of KIR2DL4 were higher than controls' but it did not reach statistical significance (1.36+/-3.52 vs. 0.22+/-0.79, p = 0.560). A tight relationship with global DNA hypomethylation as well as with the expression of most of the DNA methylation-related genes was observed, especially for ITGAL, PRF1, and CD40LG. CONCLUSIONS: ITGAL, PRF1, and CD70 are overexpressed in SLE CD4(+) T cells. The tight association of CD40LG with ITGAL and PRF1 leads us to infer that it probably contributes to the pathogenesis of the disease. The apparent simultaneous regulation between their expression and the global DNA hypomethylation as well as with the transcription of many DNA methylation-related enzymes, reinforces the idea that epigenetic mechanisms are responsible for the deregulation of ITGAL, PRF1, and CD40LG. PMID- 23029300 TI - Epidemiological and virological characteristics of pandemic influenza A (H1N1) school outbreaks in China in 2009. AB - BACKGROUND: During the 2009 pandemic influenza H1N1 (2009) virus (pH1N1) outbreak, school students were at an increased risk of infection by the pH1N1 virus. However, the estimation of the attack rate showed significant variability. METHODS: Two school outbreaks were investigated in this study. A questionnaire was designed to collect information by interview. Throat samples were collected from all the subjects in this study 6 times and sero samples 3 times to confirm the infection and to determine viral shedding. Data analysis was performed using the software STATA 9.0. FINDINGS: The attack rate of the pH1N1 outbreak was 58.3% for the primary school, and 52.9% for the middle school. The asymptomatic infection rates of the two schools were 35.8% and 37.6% respectively. Peak virus shedding occurred on the day of ARI symptoms onset, followed by a steady decrease over subsequent days (p = 0.026). No difference was found either in viral shedding or HI titer between the symptomatic and the asymptomatic infectious groups. CONCLUSIONS: School children were found to be at a high risk of infection by the novel virus. This may be because of a heightened risk of transmission owing to increased mixing at boarding school, or a lack of immunity owing to socio-economic status. We conclude that asymptomatically infectious cases may play an important role in transmission of the pH1N1 virus. PMID- 23029302 TI - Geographic variation in the diet of opaleye (Girella nigricans) with respect to temperature and habitat. AB - We studied diet variation in an omnivorous fish across its range, which allowed us to test predictions about the effect of ocean temperature and habitat on herbivory. Throughout most of its geographic range, from Southern California to central Baja California, the opaleye (Girella nigricans) fed primarily on red and green algae, but there was significant variation in the amount of algal material in the diet among sites. The proportion of algal material in the diet was related to habitat, with algae making up a larger proportion of a fish's diet in algal dominated habitats than in urchin barrens. Independent of habitat, the proportion of algal material in the diet increased with environmental temperature. Analyses of stable isotopes revealed similar changes in trophic position and confirmed that these associations with diet persisted over relatively long time scales. The shift to a more herbivorous diet at warmer temperatures is in agreement with past laboratory studies on this species that show a diet-dependent change in performance with temperature and can indicate a diet shift across the species' geographic range to meet its physiological demands. A possible plastic response to herbivory was a longer gut relative to body size. The results of this study are consistent with past findings that associate temperature with increases in the relative diversity of herbivorous fishes in tropical parts of the ocean. PMID- 23029301 TI - Eicosapentaenoic acid and oxypurinol in the treatment of muscle wasting in a mouse model of cancer cachexia. AB - Cancer cachexia is a wasting condition, driven by systemic inflammation and oxidative stress. This study investigated eicosapentaenoic acid (EPA) in combination with oxypurinol as a treatment in a mouse model of cancer cachexia. Mice with cancer cachexia were randomized into 4 treatment groups (EPA (0.4 g/kg/day), oxypurinol (1 mmol/L ad-lib), combination, or control), and euthanized after 29 days. Analysis of oxidative damage to DNA, mRNA analysis of pro-oxidant, antioxidant and proteolytic pathway components, along with enzyme activity of pro and antioxidants were completed on gastrocnemius muscle. The control group displayed earlier onset of tumor compared to EPA and oxypurinol groups (P<0.001). The EPA group maintained body weight for an extended duration (20 days) compared to the oxypurinol (5 days) and combination (8 days) groups (P<0.05). EPA (18.2+/ 3.2 pg/ml) and combination (18.4+/-3.7 pg/ml) groups had significantly higher 8 OH-dG levels than the control group (12.9+/-1.4 pg/ml, P<=0.05) indicating increased oxidative damage to DNA. mRNA levels of GPx1, MURF1 and MAFbx were higher following EPA treatment compared to control (P<=0.05). Whereas oxypurinol was associated with higher GPx1, MnSOD, CAT, XDH, MURF1, MAFbx and UbB mRNA compared to control (P<=0.05). Activity of total SOD was higher in the oxypurinol group (32.2+/-1.5 U/ml) compared to control (27.0+/-1.3 U/ml, P<0.01), GPx activity was lower in the EPA group (8.76+/-2.0 U/ml) compared to control (14.0+/ 1.9 U/ml, P<0.05), and catalase activity was lower in the combination group (14.4+/-2.8 U/ml) compared to control (20.9+/-2.0 U/ml, P<0.01). There was no change in XO activity. The increased rate of weight decline in mice treated with oxypurinol indicates that XO may play a protective role during the progression of cancer cachexia, and its inhibition is detrimental to outcomes. In combination with EPA, there was little significant improvement from control, indicating oxypurinol is unlikely to be a viable treatment compound in cancer cachexia. PMID- 23029303 TI - Different water use strategies of juvenile and adult Caragana intermedia plantations in the Gonghe Basin, Tibet Plateau. AB - BACKGROUND: In a semi-arid ecosystem, water is one of the most important factors that affect vegetation dynamics, such as shrub plantation. A water use strategy, including the main water source that a plant species utilizes and water use efficiency (WUE), plays an important role in plant survival and growth. The water use strategy of a shrub is one of the key factors in the evaluation of stability and sustainability of a plantation. METHODOLOGY/PRINCIPAL FINDINGS: Caragana intermedia is a dominant shrub of sand-binding plantations on sand dunes in the Gonghe Basin in northeastern Tibet Plateau. Understanding the water use strategy of a shrub plantation can be used to evaluate its sustainability and long-term stability. We hypothesized that C. intermedia uses mainly deep soil water and its WUE increases with plantation age. Stable isotopes of hydrogen and oxygen were used to determine the main water source and leaf carbon isotope discrimination was used to estimate long-term WUE. The root system was investigated to determine the depth of the main distribution. The results showed that a 5-year-old C. intermedia plantation used soil water mainly at a depth of 0-30 cm, which was coincident with the distribution of its fine roots. However, 9- or 25-year-old C. intermedia plantations used mainly 0-50 cm soil depth water and the fine root system was distributed primarily at soil depths of 0-50 cm and 0-60 cm, respectively. These sources of soil water are recharged directly by rainfall. Moreover, the long-term WUE of adult plantations was greater than that of juvenile plantations. CONCLUSIONS: The C. intermedia plantation can change its water use strategy over time as an adaptation to a semi-arid environment, including increasing the depth of soil water used for root growth, and increasing long-term WUE. PMID- 23029304 TI - Wls is expressed in the epidermis and regulates embryonic hair follicle induction in mice. AB - Wnt proteins are secreted molecules that play multiple roles during hair follicle development and postnatal hair cycling. Wntless (Wls) is a cargo protein required for the secretion of various Wnt ligands. However, its role during hair follicle development and hair cycling remains unclear. Here, we examined the expression of Wls during hair follicle induction and postnatal hair cycling. We also conditionally deleted Wls with K14-cre to investigate its role in hair follicle induction. K14-cre;Wls(c/c) mice exhibited abnormal hair follicle development, which is possibly caused by impaired canonical Wnt signaling. Meanwhile, Wnt5a is also expressed in embryonic epidermis, but Wnt5a null mice showed no significant defect in embryonic hair follicle morphogenesis. Therefore, Wls may regulate hair follicle induction by mediating the Wnt/beta-catenin pathway. PMID- 23029305 TI - Human beta casein fragment (54-59) modulates M. bovis BCG survival and basic transcription factor 3 (BTF3) expression in THP-1 cell line. AB - Immunostimulatory peptides potentiate the immune system of the host and are being used as a viable adjunct to established therapeutic modalities in treatment of cancer and microbial infections. Several peptides derived from milk protein have been reported to induce immunostimulatory activity. Human beta -casein fragment (54-59), natural sequence peptide (NS) carrying the Val-Glu-Pro-Ile-Pro-Tyr amino acid residues, was reported to activate the macrophages and impart potent immunostimulatory activity. In present study, we found that this peptide increases the clearance of M. bovis BCG from THP-1 cell line in vitro. The key biomolecules, involved in the clearance of BCG from macrophage like, nitric oxide, pro-inflammatory cytokines and chemokines, were not found to be significantly altered after peptide treatment in comparison to the untreated control. Using proteomic approach we found that BTF3a, an isoform of the Basic Transcription Factor, BTF3, was down regulated in THP-1 cell line after peptide treatment. This was reconfirmed by real time RT-PCR and western blotting. We report the BTF3a as a novel target of this hexapeptide. Based on the earlier findings and the results from the present studies, we suggest that the down regulation of BTF3a following the peptide treatment may augment the M. bovis BCG mediated apoptosis resulting in enhanced clearance of M. bovis BCG from THP-1 cell line. PMID- 23029306 TI - Implication of glutathione in the in vitro antiplasmodial mechanism of action of ellagic acid. AB - The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to current drugs. Ellagic acid (EA) is a polyphenol, recently found in various plant products, that has effective antimalarial activity in vitro and in vivo without toxicity. To further understand the antimalarial mechanism of action of EA in vitro, we evaluated the effects of EA, ascorbic acid and N-acetyl-L-cysteine (NAC), alone and/or in combination on the production of reactive oxygen species (ROS) during the trophozoite and schizonte stages of the erythrocytic cycle of P. falciparum. The parasitized erythrocytes were pre-labelled with DCFDA (dichlorofluorescein diacetate). We showed that NAC had no effect on ROS production, contrary to ascorbic acid and EA, which considerably reduced ROS production. Surprisingly, EA reduced the production of the ROS with concentrations (6.6*10(-9) - 6.6*10(-6) M) ten-fold lower than ascorbic acid (113*10(-6) M). Additionally, the in vitro drug sensitivity of EA with antioxidants showed that antiplasmodial activity is independent of the ROS production inside parasites, which was confirmed by the additive activity of EA and desferrioxamine. Finally, EA could act by reducing the glutathione content inside the Plasmodium parasite. This was consolidated by the decrease in the antiplasmodial efficacy of EA in the murine model Plasmodium yoelii- high GSH strain, known for its high glutathione content. Given its low toxicity and now known mechanism of action, EA appears as a promising antiplasmodial compound. PMID- 23029307 TI - Relationship between inflammatory cytokines and uric acid levels with adverse cardiovascular outcomes in patients with stable coronary heart disease. AB - BACKGROUND: So far it is unclear whether the association between serum uric acid (SUA), inflammatory cytokines and risk of atherosclerosis is causal or an epiphenomenon. The aim of the project is to investigate the independent prognostic relationship of inflammatory markers and SUA levels with adverse cardiovascular outcomes in a patient population with stable coronary heart disease (CHD). METHODS: SUA, C-reactive protein (CRP) and interleukin (IL)-6 were measured at baseline in a cohort of 1,056 patients aged 30-70 years with CHD. Cox proportional hazards model was used to determine the prognostic value of these markers on a combined CVD endpoint during eight year follow-up after adjustment for covariates. RESULTS: For 1,056 patients with stable coronary heart disease aged 30-70 years (mean age 58.9 years, SD 8.0) follow-up information and serum measurements were complete and n = 151 patients (incidence 21.1 per 1000 patients years) experienced a fatal or non-fatal CVD event during follow-up (p-value = 0.05 for quartiles of SUA, p = 0.002 for quartiles of CRP, p = 0.13 for quartiles of IL-6 in Kaplan-Meier analysis). After adjustment for age, gender and hospital site the hazard ratio (HR) for SUA increased from 1.37 to 1.65 and 2.27 in the second, third, and top quartile, when compared to the bottom one (p for trend <0.0005). The HR for CRP increased from 0.85 to 0.98 and 1.64 in the respective quartiles (p for trend 0.02). After further adjustment for covariates SUA still showed a clear statistically significant relationship with the outcome (p for trend 0.045), whereas CRP did not (p for trend 0.10). CONCLUSION: The data suggest that compared to inflammatory markers such as CRP and IL-6 serum uric acid levels may predict future CVD risk in patients with stable CHD with a risk increase even at levels considered normal. PMID- 23029308 TI - Inhibition of glioma cell lysosome exocytosis inhibits glioma invasion. AB - Cancer cells invade by secreting enzymes that degrade the extracellular matrix and these are sequestered in lysosomal vesicles. In this study, the effects of the selective lysosome lysing drug GPN and the lysosome exocytosis inhibitor vacuolin-1 on lysosome exocytosis were studied to determine their effect on glioma cell migration and invasion. Both GPN and vacuolin-1 evidently inhibited migration and invasion in transwell experiments and scratch experiments. There are more lysosomes located on the cell membrane of glioma cells than of astrocytes. GPN decreased the lysosome number on the cell membrane. We found that rab27A was expressed in glioma cells, and colocalized with cathepsin D in lysosome. RNAi-Rab27A inhibited lysosome cathepsin D exocytosis and glioma cell invasion in an in vitro assay. Inhibition of cathepsin D inhibited glioma cell migration. The data suggest that the inhibition of lysosome exocytosis from glioma cells plays an important modulatory role in their migration and invasion. PMID- 23029309 TI - Reduced cellular susceptibility to in vitro HIV infection is associated with CD4+ T cell quiescence. AB - BACKGROUND: HIV preferentially establishes productive infection in activated CD4+ T cells. Since proportions of activated CD4+ T cells vary between individuals, this study aimed to determine if individuals with a greater proportion of activated CD4+ T cells would be more susceptible to in vitro HIV infection. METHODOLOGY/PRINCIPAL FINDINGS: Unstimulated peripheral blood mononuclear cells (PBMC) from various donors were inoculated with HIV(ML1956)in vitro. HIV replication was evaluated by HIV p24 ELISA of culture supernatants and intracellular staining for HIV p24, which was detected by flow cytometry. Baseline T cell phenotypes and infected cell phenotypes were also evaluated by flow cytometry. Ex vivo phenotyping at the time of blood draw showed that elevated T cell activation and reduced Tregs were associated with increased cellular susceptibility to in vitro infection. Furthermore, the infected CD4+ T cell population was enriched for activated cells. CONCLUSION/SIGNIFICANCE: These data suggest that CD4+ T cell quiescence provides an environment less conducive to the establishment of HIV infection by limiting the pool of activated target cells. PMID- 23029310 TI - Point-of-care urine tests for smoking status and isoniazid treatment monitoring in adult patients. AB - BACKGROUND: Poor adherence to isoniazid (INH) preventive therapy (IPT) is an impediment to effective control of latent tuberculosis (TB) infection. TB patients who smoke are at higher risk of latent TB infection, active disease, and TB mortality, and may have lower adherence to their TB medications. The objective of our study was to validate IsoScreen and SmokeScreen (GFC Diagnostics, UK), two point-of-care tests for monitoring INH intake and determining smoking status. The tests could be used together in the same individual to help identify patients with a high-risk profile and provide a tailored treatment plan that includes medication management, adherence interventions, and smoking cessation programs. METHODOLOGY/PRINCIPAL FINDINGS: 200 adult outpatients attending the TB and/or the smoking cessation clinic were recruited at the Montreal Chest Institute. Sensitivity and specificity were measured for each test against the corresponding composite reference standard. Test reliability was measured using kappa statistic for intra-rater and inter-rater agreement. Univariate and multivariate logistic regression models were used to explore possible covariates that might be related to false-positive and false-negative test results. IsoScreen had a sensitivity of 93.2% (95% confidence interval [CI] 80.3, 98.2) and specificity of 98.7% (94.8, 99.8). IsoScreen had intra-rater agreement (kappa) of 0.75 (0.48, 0.94) and inter rater agreement of 0.61 (0.27, 0.90). SmokeScreen had a sensitivity of 69.2% (56.4, 79.8), specificity of 81.6% (73.0, 88.0), intra-rater agreement of 0.77 (0.56, 0.94), and inter-rater agreement of 0.66 (0.42, 0.88). False-positive SmokeScreen tests were strongly associated with INH treatment. CONCLUSIONS: IsoScreen had high validity and reliability, whereas SmokeScreen had modest validity and reliability. SmokeScreen tests did not perform well in a population receiving INH due to the association between INH treatment and false-positive SmokeScreen test results. Development of the next generation SmokeScreen assay should account for this potential interference. PMID- 23029311 TI - GATA-4 and FOG-2 expression in pediatric ovarian sex cord-stromal tumors replicates embryonal gonadal phenotype: results from the TREP project. AB - AIM: GATA proteins are a family of zinc finger transcription factors regulating gene expression, differentiation and proliferation in various tissues. The expression of GATA-4 and FOG-2, one of its modulators, was studied in pediatric Sex Cord-Stromal tumors of the ovary, in order to evaluate their potential role as diagnostic markers and prognostic factors. MATERIALS AND METHODS: Clinical and histological data of 15 patients, enrolled into the TREP Project since 2000 were evaluated. When available, immunostaines for FOG-2, GATA-4, alpha-Inhibin, Vimentin and Pancytokeratin were also analyzed. RESULTS: In our series there were 6 Juvenile Granulosa Cell Tumors (JGCT), 6 Sertoli-Leydig Cell Tumors (SLCT), 1 Cellular Fibroma, 1 Theca Cell Tumor and 1 Stromal Sclerosing Tumor (SST). Thirteen patients obtained a complete remission (CR), 1 reached a second CR after the removal of a metachronous tumor and 1 died of disease. Inhibin was detectable in 11/15, Vimentin in 13/15, Pancytokeratin in 6/15, GATA-4 in 5/13 and FOG-2 in 11/15. FOG-2 was highly expressed in 5/6 JGCT, while GATA-4 was weakly detectable only in 1 of the cases. SLCT expressed diffusely FOG-2 (4/6) and GATA-4 (3/5). GATA-4 and FOG-2 were detected in fibroma and thecoma but not in the SST. CONCLUSIONS: Pediatric granulosa tumors appear to express a FOG-2/GATA-4 phenotype in keeping with primordial ovarian follicles. High expression of GATA-4 does not correlate with aggressive behaviour as seen in adults, but it is probably involved in cell proliferation its absence can be associated with the better outcome of JGCT. SLCTs replicate the phenotype of Sertoli cells during embryogenesis in normal testis. In this group, the lack of expression of FOG-2 in tumors in advanced stages might reveal a hypothetical role in inhibiting GATA-4 cell proliferation pathway. In fibroma/thecoma group GATA-4 and FOG-2 point out the abnormal activation of GATA pathway and might be involved in the onset of these tumors. PMID- 23029312 TI - Intra-population genetic variation in the temporal pattern of egg maturation in a parasitoid wasp. AB - Parasitoid wasps are taxonomically and biologically extremely diverse. A conceptual framework has recently been developed for understanding life-history evolution and diversification in these animals, and it has confirmed that each of two linked life-history traits - the mode of larval development and the temporal pattern of egg maturation - acts as an organiser of life-history. The framework has been predicated on the assumption that there exists sufficient genetic variation in the latter trait to allow it to be shaped by natural selection. Focusing on the parasitoid wasp Trichogramma brassicae, our aim was to test the validity of that assumption, using established quantitative genetic methods. We demonstrate the existence of a statistically significant degree of intra population polygenic variation in the temporal pattern of egg production within the wasp population we studied. Furthermore, our results, together with published data on clinal variation in the egg maturation pattern of another species, suggest that intra-specific evolutionary shifts in the temporal pattern of egg maturation of parasitoid wasps can result from a change in allocation to egg production either before, or very shortly after adult emergence, without there being an accompanying change in lifetime fecundity. As well as opening new avenues of research into the reproductive strategies, behaviour, community organisation and biological control potential of parasitoid wasps, this discovery also has implications for studies of life-history evolution and diversification in insects generally. PMID- 23029313 TI - IL-4 attenuates pulmonary epithelial cell-mediated suppression of T cell priming. AB - We have previously shown that Th2-polarized airway inflammation facilitates sensitization towards new, protein antigens. In this context, we could demonstrate that IL-4 needs to act on cells of the hematopoetic and the structural compartment in order to facilitate sensitization towards new antigens. We thus aimed to elucidate possible mechanisms of action of IL-4 on structural cells choosing to analyze pulmonary epithelial cells as an important part of the lung's structural system. We used a co-culture system of DC- or APC-dependent in vitro priming of T cells, co-cultivated on a layer of cells of a murine pulmonary epithelial cell line (LA-4) pretreated with or without IL-4. Effects on T cell priming were analyzed via CFSE-dilution and flow cytometric assessment of activation status. Pulmonary epithelial cells suppressed T cell proliferation in vitro but this effect was attenuated by pre-treatment of the epithelial cells with IL-4. Transwell experiments suggest that epithelial-mediated suppression of T cell activation is mostly cell-contact dependent and leads to attenuation in an early naive T cell phenotype. Secretion of soluble factors like TARC, TSLP, GM CSF and CCL20 by epithelial cells did not change after IL-4 treatment. However, analysis of co-stimulatory expression on pulmonary epithelial cells revealed that pre-treatment of epithelial cells with IL-4 changed expression GITR-L, suggesting a possible mechanism for the effects observed. Our studies provide new insight into the role of IL-4 during the early phases of pulmonary sensitization: The inhibitory activity of pulmonary epithelial cells in homeostasis is reversed in the presence of IL-4, which is secreted in the context of Th2-dominated allergic airway inflammation. This mechanism might serve to explain facilitated sensitization in the clinical context of polysensitization where due to a pre existing sensitization increased levels of IL-4 in the airways might facilitate T cell priming towards new antigens. PMID- 23029314 TI - Spatiotemporal correlations between cytosolic and mitochondrial Ca(2+) signals using a novel red-shifted mitochondrial targeted cameleon. AB - The transfer of Ca(2+) from the cytosol into the lumen of mitochondria is a crucial process that impacts cell signaling in multiple ways. Cytosolic Ca(2+) ([Ca(2+)](cyto)) can be excellently quantified with the ratiometric Ca(2+) probe fura-2, while genetically encoded Forster resonance energy transfer (FRET)-based fluorescent Ca(2+) sensors, the cameleons, are efficiently used to specifically measure Ca(2+) within organelles. However, because of a significant overlap of the fura-2 emission with the spectra of the cyan and yellow fluorescent protein of most of the existing cameleons, the measurement of fura-2 and cameleons within one given cell is a complex task. In this study, we introduce a novel approach to simultaneously assess [Ca(2+)](cyto) and mitochondrial Ca(2+) ([Ca(2+)](mito)) signals at the single cell level. In order to eliminate the spectral overlap we developed a novel red-shifted cameleon, D1GO-Cam, in which the green and orange fluorescent proteins were used as the FRET pair. This ratiometric Ca(2+) probe could be successfully targeted to mitochondria and was suitable to be used simultaneously with fura-2 to correlate [Ca(2+)](cyto) and [Ca(2+)](mito) within same individual cells. Our data indicate that depending on the kinetics of [Ca(2+)](cyto) rises there is a significant lag between onset of [Ca(2+)](cyto) and [Ca(2+)](mito) signals, pointing to a certain threshold of [Ca(2+)](cyto) necessary to activate mitochondrial Ca(2+) uptake. The temporal correlation between [Ca(2+)](mito) and [Ca(2+)](cyto) as well as the efficiency of the transfer of Ca(2+) from the cytosol into mitochondria varies between different cell types. Moreover, slow mitochondrial Ca(2+) extrusion and a desensitization of mitochondrial Ca(2+) uptake cause a clear difference in patterns of mitochondrial and cytosolic Ca(2+) oscillations of pancreatic beta-cells in response to D-glucose. PMID- 23029315 TI - Lamin A/C mutants disturb sumo1 localization and sumoylation in vitro and in vivo. AB - A-type lamins A and C are nuclear intermediate filament proteins in which mutations have been implicated in multiple disease phenotypes commonly known as laminopathies. A few studies have implicated sumoylation in the regulation of A type lamins. Sumoylation is a post-translational protein modification that regulates a wide range of cellular processes through the attachment of small ubiquitin-related modifier (sumo) to various substrates. Here we showed that laminopathy mutants result in the mislocalization of sumo1 both in vitro (C2C12 cells overexpressing mutant lamins A and C) and in vivo (primary myoblasts and myopathic muscle tissue from the Lmna(H222P/H222P) mouse model). In C2C12 cells, we showed that the trapping of sumo1 in p.Asp192Gly, p.Gln353Lys, and p.Arg386Lys aggregates of lamin A/C correlated with an increased steady-state level of sumoylation. However, lamin A and C did not appear to be modified by sumo1. Our results suggest that mutant lamin A/C alters the dynamics of sumo1 and thus misregulation of sumoylation may be contributing to disease progression in laminopathies. PMID- 23029316 TI - Regional frontal gray matter volume associated with executive function capacity as a risk factor for vehicle crashes in normal aging adults. AB - Although low executive functioning is a risk factor for vehicle crashes among elderly drivers, the neural basis of individual differences in this cognitive ability remains largely unknown. Here we aimed to examine regional frontal gray matter volume associated with executive functioning in normal aging individuals, using voxel-based morphometry (VBM). To this end, 39 community-dwelling elderly volunteers who drove a car on a daily basis participated in structural magnetic resonance imaging, and completed two questionnaires concerning executive functioning and risky driving tendencies in daily living. Consequently, we found that participants with low executive function capacity were prone to risky driving. Furthermore, VBM analysis revealed that lower executive function capacity was associated with smaller gray matter volume in the supplementary motor area (SMA). Thus, the current data suggest that SMA volume is a reliable predictor of individual differences in executive function capacity as a risk factor for vehicle crashes among elderly persons. The implication of our results is that regional frontal gray matter volume might underlie the variation in driving tendencies among elderly drivers. Therefore, detailed driving behavior assessments might be able to detect early neurodegenerative changes in the frontal lobe in normal aging adults. PMID- 23029317 TI - Patterns of information-seeking for cancer on the internet: an analysis of real world data. AB - Although traditionally the primary information sources for cancer patients have been the treating medical team, patients and their relatives increasingly turn to the Internet, though this source may be misleading and confusing. We assess Internet searching patterns to understand the information needs of cancer patients and their acquaintances, as well as to discern their underlying psychological states. We screened 232,681 anonymous users who initiated cancer specific queries on the Yahoo Web search engine over three months, and selected for study users with high levels of interest in this topic. Searches were partitioned by expected survival for the disease being searched. We compared the search patterns of anonymous users and their contacts. Users seeking information on aggressive malignancies exhibited shorter search periods, focusing on disease- and treatment-related information. Users seeking knowledge regarding more indolent tumors searched for longer periods, alternated between different subjects, and demonstrated a high interest in topics such as support groups. Acquaintances searched for longer periods than the proband user when seeking information on aggressive (compared to indolent) cancers. Information needs can be modeled as transitioning between five discrete states, each with a unique signature representing the type of information of interest to the user. Thus, early phases of information-seeking for cancer follow a specific dynamic pattern. Areas of interest are disease dependent and vary between probands and their contacts. These patterns can be used by physicians and medical Web site authors to tailor information to the needs of patients and family members. PMID- 23029318 TI - High mannose-binding antiviral lectin PFL from Pseudomonas fluorescens Pf0-1 promotes cell death of gastric cancer cell MKN28 via interaction with alpha2 integrin. AB - Novel anti-HIV lectin family which shows a strict binding specificity for high mannose glycans has been found in lower organisms. The bacterial orthologue has been identified in the genome of Pseudomonas fluorescens Pf0-1 and the gene coding a putative lectin was cloned, expressed in Escherichia coli and purified by one step gel filtration. Glycan array screening of the recombinant lectin, termed PFL, has revealed that PFL preferentially recognizes high mannose glycans with alpha1-3 Man that was highly exposed at the D2 position. In contrast, masking of this alpha1-3 Man with alpha1-2 Man dramatically impaired lectin carbohydrate interactions. Reducing terminal disaccharide, GlcNAc-GlcNAc of high mannose glycans was also essential for PFL-binding. PFL showed a potent anti influenza virus activity by inhibiting the virus entry into cells at doses of low nanomolar concentration. At micromolar concentration or higher, PFL showed a cytotoxicity accompanying loss of the cell adhesion against human gastric cancer MKN28 cells. The cell surface molecule to which PFL bound was co-precipitated with biotin-labeled PFL and identified as integrin alpha2 by peptide mass fingerprinting using MALDI-TOF mass spectrometry. Intriguingly, upon treatment with exogenous PFL, integrin alpha2 on the cell surface underwent rapid internalization to the cytoplasm and accumulated to perinuclear region, together with the bound PFL. The resulting loss of cell adherence would trigger a signaling pathway that induced anoikis-like cell death. These events were effectively inhibited by pretreatment of PFL with mannnan, indicating the involvement of high mannose glycans on PFL-induced cell death that was triggered by PFL-integrin alpha2 interactions. PMID- 23029319 TI - Nemaline myopathy-related skeletal muscle alpha-actin (ACTA1) mutation, Asp286Gly, prevents proper strong myosin binding and triggers muscle weakness. AB - Many mutations in the skeletal muscle alpha-actin gene (ACTA1) lead to muscle weakness and nemaline myopathy. Despite increasing clinical and scientific interest, the molecular and cellular pathogenesis of weakness remains unclear. Therefore, in the present study, we aimed at unraveling these mechanisms using muscles from a transgenic mouse model of nemaline myopathy expressing the ACTA1 Asp286Gly mutation. We recorded and analyzed the mechanics of membrane permeabilized single muscle fibers. We also performed molecular energy state computations in the presence or absence of Asp286Gly. Results demonstrated that during contraction, the Asp286Gly acts as a "poison-protein" and according to the computational analysis it modifies the actin-actin interface. This phenomenon is likely to prevent proper myosin cross-bridge binding, limiting the fraction of actomyosin interactions in the strong binding state. At the cell level, this decreases the force-generating capacity, and, overall, induces muscle weakness. To counterbalance such negative events, future potential therapeutic strategies may focus on the inappropriate actin-actin interface or myosin binding. PMID- 23029321 TI - Birds of a feather: Neanderthal exploitation of raptors and corvids. AB - The hypothesis that Neanderthals exploited birds for the use of their feathers or claws as personal ornaments in symbolic behaviour is revolutionary as it assigns unprecedented cognitive abilities to these hominins. This inference, however, is based on modest faunal samples and thus may not represent a regular or systematic behaviour. Here we address this issue by looking for evidence of such behaviour across a large temporal and geographical framework. Our analyses try to answer four main questions: 1) does a Neanderthal to raptor-corvid connection exist at a large scale, thus avoiding associations that might be regarded as local in space or time?; 2) did Middle (associated with Neanderthals) and Upper Palaeolithic (associated with modern humans) sites contain a greater range of these species than Late Pleistocene paleontological sites?; 3) is there a taphonomic association between Neanderthals and corvids-raptors at Middle Palaeolithic sites on Gibraltar, specifically Gorham's, Vanguard and Ibex Caves? and; 4) was the extraction of wing feathers a local phenomenon exclusive to the Neanderthals at these sites or was it a geographically wider phenomenon?. We compiled a database of 1699 Pleistocene Palearctic sites based on fossil bird sites. We also compiled a taphonomical database from the Middle Palaeolithic assemblages of Gibraltar. We establish a clear, previously unknown and widespread, association between Neanderthals, raptors and corvids. We show that the association involved the direct intervention of Neanderthals on the bones of these birds, which we interpret as evidence of extraction of large flight feathers. The large number of bones, the variety of species processed and the different temporal periods when the behaviour is observed, indicate that this was a systematic, geographically and temporally broad, activity that the Neanderthals undertook. Our results, providing clear evidence that Neanderthal cognitive capacities were comparable to those of Modern Humans, constitute a major advance in the study of human evolution. PMID- 23029320 TI - Comparative mitogenomic analysis of damsel bugs representing three tribes in the family Nabidae (Insecta: Hemiptera). AB - BACKGROUND: Nabidae, a family of predatory heteropterans, includes two subfamilies and five tribes. We previously reported the complete mitogenome of Alloeorhynchus bakeri, a representative of the tribe Prostemmatini in the subfamily Prostemmatinae. To gain a better understanding of architecture and evolution of mitogenome in Nabidae, mitogenomes of five species representing two tribes (Gorpini and Nabini) in the subfamily Nabinae were sequenced, and a comparative mitogenomic analysis of three nabid tribes in two subfamilies was carried out. METHODOLOGY/PRINCIPAL FINDINGS: Nabid mitogenomes share a similar nucleotide composition and base bias, except for the control region, where differences are observed at the subfamily level. In addition, the pattern of codon usage is influenced by the GC content and consistent with the standard invertebrate mitochondrial genetic code and the preference for A+T-rich codons. The comparison among orthologous protein-coding genes shows that different genes have been subject to different rates of molecular evolution correlated with the GC content. The stems and anticodon loops of tRNAs are extremely conserved, and the nucleotide substitutions are largely restricted to TpsiC and DHU loops and extra arms, with insertion-deletion polymorphisms. Comparative analysis shows similar rates of substitution between the two rRNAs. Long non-coding regions are observed in most Gorpini and Nabini mtDNAs in-between trnI-trnQ and/or trnS2 nad1. The lone exception, Nabis apicalis, however, has lost three tRNAs. Overall, phylogenetic analysis using mitogenomic data is consistent with phylogenies constructed mainly form morphological traits. CONCLUSIONS/SIGNIFICANCE: This comparative mitogenomic analysis sheds light on the architecture and evolution of mitogenomes in the family Nabidae. Nucleotide diversity and mitogenomic traits are phylogenetically informative at subfamily level. Furthermore, inclusion of a broader range of samples representing various taxonomic levels is critical for the understanding of mitogenomic evolution in damsel bugs. PMID- 23029322 TI - Ignored faces produce figural face aftereffects. AB - Following adaptation to faces with contracted (or expanded) internal features, faces previously perceived as normal appear distorted in the opposite direction. This figural face aftereffect suggests face-coding mechanisms adapt to changes in the spatial relations of features and/or the global structure of faces. Here, we investigated whether the figural aftereffect requires spatial attention. Participants ignored a distorted adapting face and performed a highly demanding letter-count task. Before and after adaptation, participants rated the normality of morphed distorted faces ranging from 50% contracted through undistorted to 50% expanded. A robust aftereffect was observed. These results suggest that the figural face aftereffect can occur in the absence of spatial attention, even when the attentional demands of the relevant task are high. PMID- 23029323 TI - The fungal pathogen Moniliophthora perniciosa has genes similar to plant PR-1 that are highly expressed during its interaction with cacao. AB - The widespread SCP/TAPS superfamily (SCP/Tpx-1/Ag5/PR-1/Sc7) has multiple biological functions, including roles in the immune response of plants and animals, development of male reproductive tract in mammals, venom activity in insects and reptiles and host invasion by parasitic worms. Plant Pathogenesis Related 1 (PR-1) proteins belong to this superfamily and have been characterized as markers of induced defense against pathogens. This work presents the characterization of eleven genes homologous to plant PR-1 genes, designated as MpPR-1, which were identified in the genome of Moniliophthora perniciosa, a basidiomycete fungus responsible for causing the devastating witches' broom disease in cacao. We describe gene structure, protein alignment and modeling analyses of the MpPR-1 family. Additionally, the expression profiles of MpPR-1 genes were assessed by qPCR in different stages throughout the fungal life cycle. A specific expression pattern was verified for each member of the MpPR-1 family in the conditions analyzed. Interestingly, some of them were highly and specifically expressed during the interaction of the fungus with cacao, suggesting a role for the MpPR-1 proteins in the infective process of this pathogen. Hypothetical functions assigned to members of the MpPR-1 family include neutralization of plant defenses, antimicrobial activity to avoid competitors and fruiting body physiology. This study provides strong evidence on the importance of PR-1-like genes for fungal virulence on plants. PMID- 23029324 TI - Early postnatal B cell ontogeny and antibody repertoire maturation in the opossum, Monodelphis domestica. AB - Marsupials are a lineage of mammals noted for giving birth to highly altricial young, which complete much of their "fetal" development externally attached to a teat. Postnatal B cell ontogeny and diversity was investigated in a model marsupial species, the gray short-tailed opossum, Monodelphis domestica. The results support the initiation of B cell development late in gestation and progressing into the first two weeks of postnatal life. Transcription of CD79a and CD79b was detected in embryonic tissue prior to birth, while immunoglobulin heavy chain locus transcription was not detected until the first postnatal 24 hours. Transcription of the Ig light chains was not detected until postnatal day 7 at the earliest. The predicted timing of the earliest appearance of mature B cells and completion of gene rearrangements is consistent with previous analyses on the timing of endogenous antibody responses in newborn marsupials. The diversity of early B cell IgH chains is limited, as has been seen in fetal humans and mice, but lacks bias in the gene segments used to encode the variable domains. Newborn light chain diversity is, from the start, comparable to that of the adult, consistent with an earlier hypothesis that light chains contribute extensively to antibody diversity in this species. PMID- 23029325 TI - APC/C(Cdh1) targets brain-specific kinase 2 (BRSK2) for degradation via the ubiquitin-proteasome pathway. AB - Studies of brain-specific kinase 2 (BRSK2), an AMP-activated protein kinase (AMPK)-related kinase, and its homologs suggest that they are multifunctional regulators of cell-cycle progression. BRSK2, which contains a ubiquitin associated (UBA) domain, is polyubiquitinated in cells. However, the regulatory mechanisms and exact biological function of BRSK2 remain unclear. Herein, we show that BRSK2 co-localizes with the centrosomes during mitosis. We also demonstrate that BRSK2 protein levels fluctuate during the cell cycle, peaking during mitosis and declining in G1 phase. Furthermore, Cdh1, rather than Cdc20, promotes the degradation of BRSK2 in vivo. Consistent with this finding, knock-down of endogenous Cdh1 blocks BRSK2 degradation during the G1 phase. The conserved KEN box of BRSK2 is required for anaphase-promoting complex/cyclosome-Cdh1 (APC/C(Cdh1))-dependent degradation. Additionally, overexpression of either BRSK2(WT) or BRSK2(DeltaKEN) increases the percentage of cells in G2/M. Thus, our results provide the first evidence that BRSK2 regulates cell-cycle progression controlled by APC/C(Cdh1) through the ubiquitin-proteasome pathway. PMID- 23029326 TI - Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. AB - We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3Kalpha, PI3Kbeta, PI3Kdelta, and PI3Kgamma), and (iii) transgenic mice lacking functional PI3K isoforms (p110delta(KO)gamma(KO) or p110gamma(KO)). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect. Likewise, isolated blood neutrophils derived from double knockout PI3K p110delta(KO)gamma(KO) mice underwent normal time-dependent constitutive apoptosis and displayed identical GM-CSF mediated survival to wild type cells, but were sensitized to pharmacological inhibition of the remaining PI3K isoforms. Surprisingly, the pro-survival neutrophil phenotype observed in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) was resilient to inactivation of the PI3K pathway. PMID- 23029327 TI - Flare, persistently active disease, and serologically active clinically quiescent disease in systemic lupus erythematosus: a 2-year follow-up study. AB - OBJECTIVE: Several indices have been proposed to assess disease activity in patients with Systemic Lupus Erythematosus (SLE). Recent studies have showed a prevalence of flare between 28-35.3%, persistently active disease (PAD) between 46%-52% and serologically active clinically quiescent (SACQ) disease ranging from 6 to 15%. Our goal was to evaluate the flare, PAD and SACQ rate incidence in a cohort of SLE patients over a 2-year follow-up. METHODS: We evaluated 394 SLE patients. Flare was defined as an increase in SLEDAI-2K score of >=4 from the previous visit; PAD was defined as a SLEDAI-2K score of >=4, on >2 consecutive visits; SACQ was defined as at least a 2-year period without clinical activity and with persistent serologic activity. RESULTS: Among the 95 patients eligible for the analysis in 2009, 7 (7.3%) had >=1 flare episode, whereas 9 (9.4%) had PAD. Similarly, among the 118 patients selected for the analysis in 2010, 6 (5%) had >=1 flare episode, whereas 16 (13.5%) had PAD. Only 1/45 patient (2.2%) showed SACQ during the follow-up. CONCLUSION: We showed a low incidence of flare, PAD and SACQ in Italian SLE patients compared with previous studies which could be partly explained by ethnic differences. PMID- 23029328 TI - The introgression of RNAi silencing of gamma-gliadins into commercial lines of bread wheat changes the mixing and technological properties of the dough. AB - In the present work the effects on dough quality by the down-regulation of gamma gliadins in different genetic backgrounds of bread wheat were investigated. RNAi mediated silencing of gamma-gliadins was introgressed by conventional crossing into three commercial bread wheat lines (namely 'Gazul', 'Podenco' and 'Arpain'), and along with the transgenic line A1152 (cv. Bobwhite) compared with their respective wild types. The protein fractions were quantified by RP-HPLC, whereas the technological and mixing properties were assessed by SDSS test and by the Mixograph instrument. Principal component analysis (PCA) was carried out for both the wild types and the transgenic lines, showing differences in the factors affecting the technological and mixing properties of the dough as a consequence of the reduction of the gamma-gliadins. In transgenic lines, the alpha- and omega gliadins, and total gliadins negatively affected the dough strength and tolerance to over-mixing, whereas the L/H ratio showed the opposite effect, positively influencing the dough quality. The increase of the SDSS volume in the transgenic lines of 'Gazul', 'Podenco' and 'Arpain' indicates increased gluten strength and quality respect to the wild types. SDSS volume was found to be positively influenced by the amount of glutenins, which were also increased in the transgenic lines. In addition, a positive effect was observed in the MT, PR1 and RBD in some of the transgenic lines of 'Podenco' and 'Arpain'. In conclusion, the down-regulation of gamma-gliadins resulted in stronger doughs and a better tolerance to over-mixing in some transgenic lines. Although the reduction of gamma-gliadins seems not to have a direct effect on the mixing and bread-making properties, the compensatory effect on the synthesis of the other prolamins may result in stronger doughs with improved over-mixing resistance. PMID- 23029329 TI - Altered brain activity during reward anticipation in pathological gambling and obsessive-compulsive disorder. AB - BACKGROUND: Pathological gambling (PG) and obsessive-compulsive disorder (OCD) are conceptualized as a behavioral addiction, with a dependency on repetitive gambling behavior and rewarding effects following compulsive behavior, respectively. However, no neuroimaging studies to date have examined reward circuitry during the anticipation phase of reward in PG compared with in OCD while considering repetitive gambling and compulsion as addictive behaviors. METHODS/PRINCIPAL FINDINGS: To elucidate the neural activities specific to the anticipation phase of reward, we performed event-related functional magnetic resonance imaging (fMRI) in young adults with PG and compared them with those in patients with OCD and healthy controls. Fifteen male patients with PG, 13 patients with OCD, and 15 healthy controls, group-matched for age, gender, and IQ, participated in a monetary incentive delay task during fMRI scanning. Neural activation in the ventromedial caudate nucleus during anticipation of both gain and loss decreased in patients with PG compared with that in patients with OCD and healthy controls. Additionally, reduced activation in the anterior insula during anticipation of loss was observed in patients with PG compared with that in patients with OCD which was intermediate between that in OCD and healthy controls (healthy controls < PG < OCD), and a significant positive correlation between activity in the anterior insula and South Oaks Gambling Screen score was found in patients with PG. CONCLUSIONS: Decreased neural activity in the ventromedial caudate nucleus during anticipation may be a specific neurobiological feature for the pathophysiology of PG, distinguishing it from OCD and healthy controls. Correlation of anterior insular activity during loss anticipation with PG symptoms suggests that patients with PG fit the features of OCD associated with harm avoidance as PG symptoms deteriorate. Our findings have identified functional disparities and similarities between patients with PG and OCD related to the neural responses associated with reward anticipation. PMID- 23029331 TI - Conversion of solid organic wastes into oil via Boettcherisca peregrine (Diptera: Sarcophagidae) larvae and optimization of parameters for biodiesel production. AB - The feedstocks for biodiesel production are predominantly from edible oils and the high cost of the feedstocks prevents its large scale application. In this study, we evaluated the oil extracted from Boettcherisca peregrine larvae (BPL) grown on solid organic wastes for biodiesel production. The oil contents detected in the BPL converted from swine manure, fermentation residue and the degreased food waste, were 21.7%, 19.5% and 31.1%, respectively. The acid value of the oil is 19.02 mg KOH/g requiring a two-step transesterification process. The optimized process of 12?1 methanol/oil (mol/mol) with 1.5% H(2)SO(4) reacted at 70 degrees C for 120 min resulted in a 90.8% conversion rate of free fatty acid (FFA) by esterification, and a 92.3% conversion rate of triglycerides into esters by alkaline transesterification. Properties of the BPL oil-based biodiesel are within the specifications of ASTM D6751, suggesting that the solid organic waste grown BPL could be a feasible non-food feedstock for biodiesel production. PMID- 23029330 TI - Soil-transmitted helminth infections and correlated risk factors in preschool and school-aged children in rural Southwest China. AB - We conducted a survey of 1707 children in 141 impoverished rural areas of Guizhou and Sichuan Provinces in Southwest China. Kato-Katz smear testing of stool samples elucidated the prevalence of ascariasis, trichuriasis and hookworm infections in pre-school and school aged children. Demographic, hygiene, household and anthropometric data were collected to better understand risks for infection in this population. 21.2 percent of pre-school children and 22.9 percent of school aged children were infected with at least one of the three types of STH. In Guizhou, 33.9 percent of pre-school children were infected, as were 40.1 percent of school aged children. In Sichuan, these numbers were 9.7 percent and 6.6 percent, respectively. Number of siblings, maternal education, consumption of uncooked meat, consumption of unboiled water, and livestock ownership all correlated significantly with STH infection. Through decomposition analysis, we determined that these correlates made up 26.7 percent of the difference in STH infection between the two provinces. Multivariate analysis showed that STH infection is associated with significantly lower weight-for-age and height-for-age z-scores; moreover, older children infected with STHs lag further behind on the international growth scales than younger children. PMID- 23029332 TI - TNFAIP3 facilitates degradation of microbial antigen SEB in enterocytes. AB - BACKGROUND AND AIMS: The enterocytes have the potential to absorb noxious substances, such as microbial products, from the gut lumen. How the enterocytes process the substances to harmless materials is not fully understood. This study aims to elucidate the role of ubiquitin E3 ligase TNFAIP3 (TNFAIP3) in facilitating the degradation of endocytic microbial products in enterocytes. METHODS: Human intestinal epithelial cell line, HT-29 cells, was cultured to monolayers using as an in vitro model to observe the endocytosis and degradation of microbial products, Staphylococcal enterotoxin B (SEB) in epithelial cells. The RNA interference was employed to knock down the TNFAIP3 gene in HT-29 cells to observe the role of TNFAIP3 in the degradation of endocytic SEB. The role of TNFAIP3 in facilitating the endosome/lysosome fusion was observed by immunocytochemistry. RESULTS: Upon the absorption of SEB, the expression of TNFAIP3 was increased in HT-29 cells. Silencing the TNFAIP3 gene in HT-29 cells resulted in a large quantity of SEB to be transported across the HT-29 monolayers to the transwell basal chambers; the transportation was via the intracellular pathway. TNFAIP3 was required in the fusion of SEB-carrying endosomes and lysosomes. CONCLUSIONS: TNFAIP3 plays a critical role in the degradation of endocytic SEB in enterocytes. PMID- 23029333 TI - Automated high-throughput RNAi screening in human cells combined with reporter mRNA transfection to identify novel regulators of translation. AB - Proteins that promote angiogenesis, such as vascular endothelial growth factor (VEGF), are major targets for cancer therapy. Accordingly, proteins that specifically activate expression of factors like VEGF are potential alternative therapeutic targets and may help to combat evasive resistance to angiogenesis inhibitors. VEGF mRNA contains two internal ribosome entry sites (IRESs) that enable selective activation of VEGF protein synthesis under hypoxic conditions that trigger angiogenesis. To identify novel regulators of VEGF IRES-driven translation in human cells, we have developed a high-throughput screening approach that combines siRNA treatment with transfection of a VEGF-IRES reporter mRNA. We identified the kinase MAPK3 as a novel positive regulator of VEGF IRES driven translation and have validated its regulatory effect on endogenous VEGF. Our automated method is scalable and readily adapted for use with other mRNA regulatory elements. Consequently, it should be a generally useful approach for high-throughput identification of novel regulators of mRNA translation. PMID- 23029334 TI - Predicting metabolic pathways of small molecules and enzymes based on interaction information of chemicals and proteins. AB - Metabolic pathway analysis, one of the most important fields in biochemistry, is pivotal to understanding the maintenance and modulation of the functions of an organism. Good comprehension of metabolic pathways is critical to understanding the mechanisms of some fundamental biological processes. Given a small molecule or an enzyme, how may one identify the metabolic pathways in which it may participate? Answering such a question is a first important step in understanding a metabolic pathway system. By utilizing the information provided by chemical chemical interactions, chemical-protein interactions, and protein-protein interactions, a novel method was proposed by which to allocate small molecules and enzymes to 11 major classes of metabolic pathways. A benchmark dataset consisting of 3,348 small molecules and 654 enzymes of yeast was constructed to test the method. It was observed that the first order prediction accuracy evaluated by the jackknife test was 79.56% in identifying the small molecules and enzymes in a benchmark dataset. Our method may become a useful vehicle in predicting the metabolic pathways of small molecules and enzymes, providing a basis for some further analysis of the pathway systems. PMID- 23029335 TI - Amino acids transitioning of 2009 H1N1pdm in Taiwan from 2009 to 2011. AB - A swine-origin influenza A was detected in April 2009 and soon became the 2009 H1N1 pandemic strain (H1N1pdm). The current study revealed the genetic diversity of H1N1pdm, based on 77 and 70 isolates which we collected, respectively, during the 2009/2010 and 2010/2011 influenza seasons in Taiwan. We focused on tracking the amino acid transitioning of hemagglutinin (HA) and neuraminidase (NA) genes in the early diversification of the virus and compared them with H1N1pdm strains reported worldwide. We identified newly emerged mutation markers based on A/California/04/2009, described how these markers shifted from the first H1N1pdm season to the one that immediately followed, and discussed how these observations may relate to antigenicity, receptor-binding, and drug susceptibility. It was found that the amino acid mutation rates of H1N1pdm were elevated, from 9.29*10( 3) substitutions per site in the first season to 1.46*10(-2) in the second season in HA, and from 5.23*10(-3) to 1.10*10(-2) in NA. Many mutation markers were newly detected in the second season, including 11 in HA and 8 in NA, and some were found having statistical correlation to disease severity. There were five noticeable HA mutations made to antigenic sites. No significant titer changes, however, were detected based on hemagglutination inhibition tests. Only one isolate with H275Y mutation known to reduce susceptibility to NA inhibitors was detected. As limited Taiwanese H1N1pdm viruses were isolated after our sampling period, we gathered 8,876 HA and 6,017 NA H1N1pdm sequences up to April 2012 from NCBI to follow up the dynamics of mentioned HA mutations. While some mutations described in this study seemed to either settle in or die out in the 2011-2012 season, a number of them still showed signs of transitioning, prompting the importance of continuous monitoring of this virus for more seasons to come. PMID- 23029336 TI - Validation of drug-like inhibitors against Mycobacterium tuberculosis L-aspartate alpha-decarboxylase using nuclear magnetic resonance (1H NMR). AB - The catalytic activity of L-aspartate alpha-decarboxylase (ADC) is essential for the growth of several micro-organisms, including Mycobacterium tuberculosis (Mtb), and has triggered efforts for the development of pharmaceutically active compounds against tuberculosis. The present study is a continuation of our recent chemoinformatics-based design approach for identifying potential drug-like inhibitors against MtbADC. We report an NMR-based protocol that allows label-free and direct monitoring of enzymatic conversion, which we have combined with a systematic testing of reported and newly identified potential inhibitors against MtbADC. Quantification of enzymatic conversion in the absence and presence of inhibitors allowed for a relative measure of the inhibitory effect (k(rel)). Among the newly identified compounds, D-tartrate, L-tartrate, and 2,4 dihydroxypyrimidine-5-carboxylate were found to inhibit the enzyme with k(rel) values of 0.36, 0.38, and 0.54, respectively. In addition to the identification of potential building blocks for the development of therapeutic agents, the current study highlights the importance of electrostatic interactions governing enzyme-inhibitor binding. PMID- 23029337 TI - Induction of the staphylococcal proteolytic cascade by antimicrobial fatty acids in community acquired methicillin resistant Staphylococcus aureus. AB - Community acquired methicillin resistant Staphylococcus aureus (CA-MRSA), and the USA300 strain of CA-MRSA in particular, are known for their rapid community transmission, and propensity to cause aggressive skin and soft tissue infections. To assess factors that contribute to these hallmark traits of CA-MRSA, we evaluated how growth of USA300 and production of secreted virulence factors was influenced on exposure to physiologic levels of unsaturated free fatty acids that would be encountered on the skin or anterior nares, which represent the first sites of contact with healthy human hosts. There was a sharp threshold between sub-inhibitory and inhibitory concentrations, such that 100 uM sapienic acid (C16?1) and linoleic acid (C18?1) were sufficient to prevent growth after 24 h incubation, while 25 uM allowed unrestricted growth, and 50 uM caused an approximate 10-12 h lag, followed by unimpeded exponential growth. Conversely, saturated palmitic or stearic acids did not affect growth at 100 uM. Although growth was not affected by 25 uM sapienic or linoleic acid, these and other unsaturated C16 and C18 fatty acids, but not their saturated counterparts, promoted robust production of secreted proteases comprising the Staphylococcal proteolytic cascade. This trait was also manifested to varying degrees in other CA-MRSA, and in genetically diverse methicillin susceptible S. aureus strains. Therefore, induction of the Staphylococcal proteolytic cascade by unsaturated fatty acids is another feature that should now be evaluated as a potential contributing factor in the aggressive nature of skin and soft tissue infections caused by USA300, and as a general virulence mechanism of S. aureus. PMID- 23029338 TI - De novo foliar transcriptome of Chenopodium amaranticolor and analysis of its gene expression during virus-induced hypersensitive response. AB - BACKGROUND: The hypersensitive response (HR) system of Chenopodium spp. confers broad-spectrum virus resistance. However, little knowledge exists at the genomic level for Chenopodium, thus impeding the advanced molecular research of this attractive feature. Hence, we took advantage of RNA-seq to survey the foliar transcriptome of C. amaranticolor, a Chenopodium species widely used as laboratory indicator for pathogenic viruses, in order to facilitate the characterization of the HR-type of virus resistance. METHODOLOGY AND PRINCIPAL FINDINGS: Using Illumina HiSeqTM 2000 platform, we obtained 39,868,984 reads with 3,588,208,560 bp, which were assembled into 112,452 unigenes (3,847 clusters and 108,605 singletons). BlastX search against the NCBI NR database identified 61,698 sequences with a cut-off E-value above 10(-5). Assembled sequences were annotated with gene descriptions, GO, COG and KEGG terms, respectively. A total number of 738 resistance gene analogs (RGAs) and homology sequences of 6 key signaling proteins within the R proteins-directed signaling pathway were identified. Based on this transcriptome data, we investigated the gene expression profiles over the stage of HR induced by Tobacco mosaic virus and Cucumber mosaic virus by using digital gene expression analysis. Numerous candidate genes specifically or commonly regulated by these two distinct viruses at early and late stages of the HR were identified, and the dynamic changes of the differently expressed genes enriched in the pathway of plant-pathogen interaction were particularly emphasized. CONCLUSIONS: To our knowledge, this study is the first description of the genetic makeup of C. amaranticolor, providing deep insight into the comprehensive gene expression information at transcriptional level in this species. The 738 RGAs as well as the differentially regulated genes, particularly the common genes regulated by both TMV and CMV, are suitable candidates which merit further functional characterization to dissect the molecular mechanisms and regulatory pathways of the HR-type of virus resistance in Chenopodium. PMID- 23029340 TI - Detection and early phase assessment of radiation-induced lung injury in mice using micro-CT. AB - Radiation therapy is an important therapeutic modality for thoracic malignancies. However, radiation-induced pulmonary injuries such as radiation pneumonitis and fibrosis are major dose-limiting factors. Previous research shows that micro computed tomography (micro-CT) can detect radiation-induced lung injuries a few months following irradiation, but studies to assess the early response of lung tissue are lacking. The aim of this study was to determine if micro-CT could be used to detect and assess early-phase radiation-induced lung injury in mice. Twenty-one animals were divided into three groups: normal (n = 7), one day after x-ray exposure (n = 7), and at four days after x-ray exposure (n = 7). The x-ray exposed groups received a single dose of 20 Gy, to the whole lung. Histology showed enlargements of the air space (Lm: mean chord length) following irradiation. 40.5 +/- 3.8 um and 60.0 +/- 6.9 um were observed after one and four days, respectively, compared to 26.5 +/- 3.1 um in normal mice. Three-dimensional micro-CT images were constructed and histograms of radiodensity - Hounsfield Units (HU) - were used to assess changes in mouse lungs. Radiation-induced lung injury was observed in irradiated mice, by the use of two parameters which were defined as shifts in peak HU between -200 to -800 HU (Peak(HU)) and increase in the number of pixels at -1000 HU (Number(-1000)). These parameters were correlated with histological changes. The results demonstrate that micro-CT can be used for the early detection and assessment of structural and histopathological changes resulting from radiation-induced lung injury in mice. Micro-CT has the advantage, over traditional histological techniques, of allowing longitudinal studies of lung disease progression and assessment of the entire lung, while reducing the number of animals required for such studies. PMID- 23029339 TI - Role of Abca7 in mouse behaviours relevant to neurodegenerative diseases. AB - ATP-binding cassette transporters of the subfamily A (ABCA) are responsible for the translocation of lipids including cholesterol, which is crucial for neurological function. Recent studies suggest that the ABC transporter ABCA7 may play a role in the development of brain disorders such as schizophrenia and Alzheimer's disease. However, Abca7's role in cognition and other behaviours has not been investigated. Therefore, we characterised homozygous Abca7 knockout mice in a battery of tests for baseline behaviours (i.e. physical exam, baseline locomotion and anxiety) and behaviours relevant to schizophrenia (i.e. prepulse inhibition and locomotor response to psychotropic drugs) and Alzheimer's disease (i.e. cognitive domains). Knockout mice had normal motor functions and sensory abilities and performed the same as wild type-like animals in anxiety tasks. Short-term spatial memory and fear-associated learning was also intact in Abca7 knockout mice. However, male knockout mice exhibited significantly impaired novel object recognition memory. Task acquisition was unaffected in the cheeseboard task. Female mice exhibited impaired spatial reference memory. This phenomenon was more pronounced in female Abca7 null mice. Acoustic startle response, sensorimotor gating and baseline locomotion was unaltered in Abca7 knockout mice. Female knockouts showed a moderately increased motor response to MK-801 than control mice. In conclusion, Abca7 appears to play only a minor role in behavioural domains with a subtle sex-specific impact on particular cognitive domains. PMID- 23029341 TI - What eye movements can tell about theory of mind in a strategic game. AB - This study investigates strategies in reasoning about mental states of others, a process that requires theory of mind. It is a first step in studying the cognitive basis of such reasoning, as strategies affect tradeoffs between cognitive resources. Participants were presented with a two-player game that required reasoning about the mental states of the opponent. Game theory literature discerns two candidate strategies that participants could use in this game: either forward reasoning or backward reasoning. Forward reasoning proceeds from the first decision point to the last, whereas backward reasoning proceeds in the opposite direction. Backward reasoning is the only optimal strategy, because the optimal outcome is known at each decision point. Nevertheless, we argue that participants prefer forward reasoning because it is similar to causal reasoning. Causal reasoning, in turn, is prevalent in human reasoning. Eye movements were measured to discern between forward and backward progressions of fixations. The observed fixation sequences corresponded best with forward reasoning. Early in games, the probability of observing a forward progression of fixations is higher than the probability of observing a backward progression. Later in games, the probabilities of forward and backward progressions are similar, which seems to imply that participants were either applying backward reasoning or jumping back to previous decision points while applying forward reasoning. Thus, the game theoretical favorite strategy, backward reasoning, does seem to exist in human reasoning. However, participants preferred the more familiar, practiced, and prevalent strategy: forward reasoning. PMID- 23029342 TI - Human pluripotent stem cell-derived cardiomyocytes: response to TTX and lidocain reveals strong cell to cell variability. AB - Stem cell derived cardiomyocytes generated either from human embryonic stem cells (hESC-CMs) or human induced pluripotent stem cells (hiPSC-CMs) hold great promise for the investigation of early developmental processes in human cardiomyogenesis and future cell replacement strategies. We have analyzed electrophysiological properties of hESC-CMs (HES2) and hiPSC-CMs, derived from reprogrammed adult foreskin fibroblasts that have previously been found to be highly similar in terms of gene expression. In contrast to the similarity found in the expression profile we found substantial differences in action potentials (APs) and sodium currents at late stage (day 60) of in vitro differentiation with higher sodium currents in hiPSC-CMs. Sensitivity to lidocain was considerably reduced in hESC CMs as compared to hiPSC-CMs, and the effect could not be explained by differences in beating frequency. In contrast, sensitivity to tetrodotoxin (TTX) was higher in hESC-CMs suggesting different contributions of TTX-sensitive and TTX-resistant sodium channels to AP generation. These data point to physiological differences that are not necessarily detected by genomics. We conclude that novel pharmacological screening-assays using hiPSC-CMs need to be applied with some caution. PMID- 23029343 TI - mRNA decay proteins are targeted to poly(A)+ RNA and dsRNA-containing cytoplasmic foci that resemble P-bodies in Entamoeba histolytica. AB - In higher eukaryotes, mRNA degradation and RNA-based gene silencing occur in cytoplasmic foci referred to as processing bodies (P-bodies). In protozoan parasites, the presence of P-bodies and their putative role in mRNA decay have yet to be comprehensively addressed. Identification of P-bodies might provide information on how mRNA degradation machineries evolved in lower eukaryotes. Here, we used immunofluorescence and confocal microscopy assays to investigate the cellular localization of mRNA degradation proteins in the human intestinal parasite Entamoeba histolytica and found evidence of the existence of P-bodies. Two mRNA decay factors, namely the EhXRN2 exoribonuclease and the EhDCP2 decapping enzyme, were localized in cytoplasmic foci in a pattern resembling P body organization. Given that amoebic foci appear to be smaller and less rounded than those described in higher eukaryotes, we have named them "P-body-like structures". These foci contain additional mRNA degradation factors, including the EhCAF1 deadenylase and the EhAGO2-2 protein involved in RNA interference. Biochemical analysis revealed that EhCAF1 co-immunoprecipitated with EhXRN2 but not with EhDCP2 or EhAGO2-2, thus linking deadenylation to 5'-to-3' mRNA decay. The number of EhCAF1-containing foci significantly decreased after inhibition of transcription and translation with actinomycin D and cycloheximide, respectively. Furthermore, results of RNA-FISH assays showed that (i) EhCAF1 colocalized with poly(A)(+) RNA and (ii) during silencing of the Ehpc4 gene by RNA interference, EhAGO2-2 colocalized with small interfering RNAs in cytoplasmic foci. Our observation of decapping, deadenylation and RNA interference proteins within P body-like foci suggests that these structures have been conserved after originating in the early evolution of eukaryotic lineages. To the best of our knowledge, this is the first study to report on the localization of mRNA decay proteins within P-body-like structures in E. histolytica. Our findings should open up opportunities for deciphering the mechanisms of mRNA degradation and RNA based gene silencing in this deep-branching eukaryote. PMID- 23029344 TI - Beclin-1 expression is a significant predictor of survival in patients with lymph node-positive gastric cancer. AB - BACKGROUND: Beclin 1 is a main actor of autophagy. The expression of Beclin 1 and its prognostic role in gastric cancer is largely unexplored. The purpose of the present study is to investigate the expression of beclin 1 in gastric cancer cells, tissues and its relationship with prognosis. METHODS: The expression of Beclin 1 was detected in 271 specimens of lymph-node positive gastric cancer patients by immunohistochemistry. The correlation of Beclin 1 expression to clinicopathologic features and survival of gastric cancer was studied. Beclin-1 expression in gastric cancer cell lines and clinical specimens is also detected using reverse transcription-PCR and Western blotting. RESULTS: Beclin 1 is up regulated at both mRNA and protein levels in six gastric cancer cell lines compared with those in normal gastric mucosa cell line (GES-1). The expression of Beclin-1 in gastric clinical specimens is also higher than those in the adjacent noncancerous tissues. Of the 271 patients, 229 (84.5%) were Beclin 1 high expression tumors by immunohistochemistry. Beclin 1 expression is closely associated with intravascular embolus. Kaplan-Meier analysis showed high beclin 1 expression was associated with longer overall survival. Both univariate analysis and multivariate analysis revealed that Beclin 1 expression were independent prognostic factors in the patients with node-positive gastric cancer. CONCLUSIONS: Our findings strongly suggest that Beclin 1 has a potential role in tumorigenesis of gastric cancer and could be a promising biomarker for predicting the prognosis of patients with lymph node-positive gastric cancer. It might also serve as a novel therapeutic target for gastric cancer treatment. PMID- 23029345 TI - Adenoviral delivery of the EMX2 gene suppresses growth in human gastric cancer. AB - BACKGROUND: EMX2 is a human orthologue of the Drosophila empty spiracles homeobox gene that has been implicated in embryogenesis. Recent studies suggest possible involvement of EMX2 in human cancers; however, the role of EMX2 in carcinogenesis needs further exploration. RESULTS: In this study, we reported that down regulation of EMX2 expression was significantly correlated with EMX2 promoter hypermethylation in gastric cancer. Restoring EMX2 expression using an adenovirus delivery system in gastric cancer cell lines lacking endogenous EMX2 expression led to inhibition of cell proliferation and Wnt signaling pathway both in vitro and in a gastric cancer xenograft model in vivo. In addition, we observed that animals treated with the adenoviral EMX2 expression vector had significantly better survival than those treated with empty adenoviral vector. CONCLUSION: Our study suggests that EMX2 is a putative tumor suppressor in human gastric cancer. The adenoviral-EMX2 may have potential as a novel gene therapy for the treatment of patients with gastric cancer. PMID- 23029346 TI - Extracellular vesicles from parasitic helminths contain specific excretory/secretory proteins and are internalized in intestinal host cells. AB - The study of host-parasite interactions has increased considerably in the last decades, with many studies focusing on the identification of parasite molecules (i.e. surface or excretory/secretory proteins (ESP)) as potential targets for new specific treatments and/or diagnostic tools. In parallel, in the last few years there have been significant advances in the field of extracellular vesicles research. Among these vesicles, exosomes of endocytic origin, with a characteristic size ranging from 30-100 nm, carry several atypical secreted proteins in different organisms, including parasitic protozoa. Here, we present experimental evidence for the existence of exosome-like vesicles in parasitic helminths, specifically the trematodes Echinostoma caproni and Fasciola hepatica. These microvesicles are actively released by the parasites and are taken up by host cells. Trematode extracellular vesicles contain most of the proteins previously identified as components of ESP, as confirmed by proteomic, immunogold labeling and electron microscopy studies. In addition to parasitic proteins, we also identify host proteins in these structures. The existence of extracellular vesicles explains the secretion of atypical proteins in trematodes, and the demonstration of their uptake by host cells suggests an important role for these structures in host-parasite communication, as described for other infectious agents. PMID- 23029348 TI - Transcellular targeting of fiber- and hexon-modified adenovirus vectors across the brain microvascular endothelial cells in vitro. AB - In central nervous system (CNS)-directed gene therapy, efficient targeting of brain parenchyma through the vascular route is prevented by the endothelium and the epithelium of the blood-brain and the blood-cerebrospinal fluid barriers, respectively. In this study, we evaluated the feasibility of the combined genetic and chemical adenovirus capsid modification technology to enable transcellular delivery of targeted adenovirus (Ad) vectors across the blood-brain barrier (BBB) in vitro models. As a proof-of-principle ligand, maleimide-activated full-length human transferrin (hTf) was covalently attached to cysteine-modified Ad serotype 5 vectors either to its fiber or hexon protein. In transcytosis experiments, hTf coupled vectors were shown to be redirected across the BBB models, the transcytosis activity of the vectors being dependent on the location of the capsid modification and the in vitro model used. The transduction efficiency of hTf-targeted vectors decreased significantly in confluent, polarized cells, indicating that the intracellular route of the vectors differed between unpolarized and polarized cells. After transcellular delivery the majority of the hTf-modified vectors remained intact and partly capable of gene transfer. Altogether, our results demonstrate that i) covalent attachment of a ligand to Ad capsid can mediate transcellular targeting across the cerebral endothelium in vitro, ii) the attachment site of the ligand influences its transcytosis efficiency and iii) combined genetic/chemical modification of Ad vector can be used as a versatile platform for the development of Ad vectors for transcellular targeting. PMID- 23029347 TI - Aquaporin-1 translocation and degradation mediates the water transportation mechanism of acetazolamide. AB - BACKGROUND: Diuretic agents are widely used on the treatment of water retention related diseases, among which acetazolamide (AZA) acts originally as a carbonic anhydrase (CA) inhibitor. Aquaporin-1 (AQP1) being located in renal proximal tubules is required for urine concentration. Previously our lab has reported AZA putatively modulated AQP1. Aim of this study is to testify our hypothesis that regulating AQP1 may mediate diuretic effect of AZA. METHODOLOGY/PRINCIPAL FINDINGS: For in vivo study, we utilized Sprague Dawley rats, as well as AQP1 knock-out (AQP1(-/-)) mice to examine urine volume, and human kidney-2 (HK-2) cell line was used for in vitro mechanism study. In our present study we found that AZA decreased CAs activity initially but the activity gradually recovered. Contrarily, diuretic effect was consistently significant. AQP1 protein expression was significantly decreased on day 7 and 14. By utilizing AQP1(-/-) mice, we found diuretic effect of AZA was cancelled on day 14, while urine volume continuously increased in wild-type mice. Surface plasmon resonance (SPR) results indicated AQP1 was physiologically bound by myosin heavy chain (MHC), immunoprecipitation and immunofluorescence results confirmed this protein interaction. In vitro study results proved AZA facilitated AQP1 translocation onto cell membrane by promoting interaction with MHC, dependent on ERK/ myosin light chain kinase (MLCK) pathway activation. MHC inhibitor BDM and ERK inhibitor U0126 both abolished above effect of AZA. Eventually AZA induced AQP1 ubiquitination, while proteasome inhibitor MG132 reversed AZA's down-regulating effect upon AQP1. CONCLUSIONS/SIGNIFICANCE: Our results identified AZA exerted diuretic effect through an innovative mechanism by regulating AQP1 and verified its inhibitory mechanism was via promoting MHC-dependent translocation onto cell membrane and then ubiquitin mediated degradation, implicating a novel mechanism and target for diuretic agent discovering. PMID- 23029349 TI - Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. AB - BACKGROUND: Measurement of serum cobalamin levels is routinely used to diagnose cobalamin deficiency. Surprisingly, approximately 15% of patients have high cobalamin levels and no consensus exists regarding the clinical implications. METHODS: Hospital-treated patients above 18 years of age referred for serum cobalamin measurement were included in groups of patients [percentage cobalamin supplemented] with low (<200 pmol/L, n = 200 [6%]), normal (200-600, n = 202 [6%]) high (601-1000, n = 217 [27%]) and very high (>1000, n = 199 [53%]) cobalamin levels. Total and cobalamin-saturated (holo) transcobalamin, total haptocorrin, soluble TC receptor, sCD320, and methylmalonic acid were analyzed. Data on diagnoses and medical prescriptions was obtained through medical files and the Aarhus University Prescription Database. RESULTS: Among patients not cobalamin supplemented median total haptocorrin and holo transcobalamin levels were markedly higher in the groups with high/very high cobalamin levels compared to groups with low/normal cobalamin levels. Median total transcobalamin and sCD320 levels were similar across the groups. A number of diagnoses were significantly associated to very high Cbl levels (odds ratio (95% confidence interval)): alcoholism (5.74 (2.76-11.96)), liver disease (8.53 (3.59-20.23)), and cancer (5.48 (2.85-10.55)). Elevated haptocorrin levels were seen in patients with alcoholism, cancer, liver-, renal-, autoimmune-, and bronchopulmonary disease. No clinical associations to sCD320 and total and holo transcobalamin levels were found. CONCLUSION: In non-supplemented patients, high cobalamin levels were associated to high haptocorrin levels, and several diagnoses, including alcoholism, liver disease and cancer. Our study emphasizes that clinicians should take high serum cobalamin levels into consideration in the diagnostic process. PMID- 23029350 TI - "Because somebody cared about me. That's how it changed things": homeless, chronically ill patients' perspectives on case management. AB - BACKGROUND: Case management programs for chronically ill, homeless people improve health and resource utilization by linking patients with case managers focused on improving management of medical and psychosocial problems. Little is known about participants' perspectives on case management interventions. METHODS: This qualitative study used in-depth, one-on-one interviews to understand the impact of a case management program from the perspective of participants. A standardized interview guide with open-ended questions explored experiences with the case management program and feelings about readiness to leave the program. RESULTS: FOUR RECURRENT THEMES EMERGED: (1) Participants described profound social isolation prior to case management program enrollment; (2) Participants perceived that caring personal relationships with case managers were key to the program; (3) Participants valued assistance with navigating medical and social systems; and (4) Participants perceived that their health improved through both the interpersonal and the practical aspects of case management. CONCLUSIONS: Chronically ill, homeless people enrolled in a case management program perceived that social support from case managers resulted in improved health. Programs for this population should consider explicitly including comprehensive social support interventions. Further research on case management should explore the impact of different types of social support on outcomes for homeless chronically ill patients. PMID- 23029351 TI - Biochemical and molecular dynamic simulation analysis of a weak coiled coil association between kinesin-II stalks. AB - DEFINITION: Kinesin-2 refers to the family of motor proteins represented by conserved, heterotrimeric kinesin-II and homodimeric Osm3/Kif17 class of motors. BACKGROUND: Kinesin-II, a microtubule-based anterograde motor, is composed of three different conserved subunits, named KLP64D, KLP68D and DmKAP in Drosophila. Although previous reports indicated that coiled coil interaction between the middle segments of two dissimilar motor subunits established the heterodimer, the molecular basis of the association is still unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here, we present a detailed heterodimeric association model of the KLP64D/68D stalk supported by extensive experimental analysis and molecular dynamic simulations. We find that KLP64D stalk is unstable, but forms a weak coiled coil heteroduplex with the KLP68D stalk when coexpressed in bacteria. Local instabilities, relative affinities between the C-terminal stalk segments, and dynamic long-range interactions along the stalks specify the heterodimerization. Thermal unfolding studies and independent simulations further suggest that interactions between the C-terminal stalk fragments are comparatively stable, whereas the N-terminal stalk reversibly unfolds at ambient temperature. CONCLUSIONS/SIGNIFICANCE: Results obtained in this study suggest that coiled coil interaction between the C-terminal stalks of kinesin-II motor subunits is held together through a few hydrophobic and charged interactions. The N-terminal stalk segments are flexible and could uncoil reversibly during a motor walk. This supports the requirement for a flexible coiled coil association between the motor subunits, and its role in motor function needs to be elucidated. PMID- 23029352 TI - Effects of partial and acute total sleep deprivation on performance across cognitive domains, individuals and circadian phase. AB - BACKGROUND: Cognitive performance deteriorates during extended wakefulness and circadian phase misalignment, and some individuals are more affected than others. Whether performance is affected similarly across cognitive domains, or whether cognitive processes involving Executive Functions are more sensitive to sleep and circadian misalignment than Alertness and Sustained Attention, is a matter of debate. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a 2 * 12-day laboratory protocol to characterize the interaction of repeated partial and acute total sleep deprivation and circadian phase on performance across seven cognitive domains in 36 individuals (18 males; mean +/- SD of age = 27.6 +/- 4.0 years). The sample was stratified for the rs57875989 polymorphism in PER3, which confers cognitive susceptibility to total sleep deprivation. We observed a deterioration of performance during both repeated partial and acute total sleep deprivation. Furthermore, prior partial sleep deprivation led to poorer cognitive performance in a subsequent total sleep deprivation period, but its effect was modulated by circadian phase such that it was virtually absent in the evening wake maintenance zone, and most prominent during early morning hours. A significant effect of PER3 genotype was observed for Subjective Alertness during partial sleep deprivation and on n-back tasks with a high executive load when assessed in the morning hours during total sleep deprivation after partial sleep loss. Overall, however, Subjective Alertness and Sustained Attention were more affected by both partial and total sleep deprivation than other cognitive domains and tasks including n back tasks of Working Memory, even when implemented with a high executive load. CONCLUSIONS/SIGNIFICANCE: Sleep loss has a primary effect on Sleepiness and Sustained Attention with much smaller effects on challenging Working Memory tasks. These findings have implications for understanding how sleep debt and circadian rhythmicity interact to determine waking performance across cognitive domains and individuals. PMID- 23029353 TI - Chloroplast NADPH-dependent thioredoxin reductase from Chlorella vulgaris alleviates environmental stresses in yeast together with 2-Cys peroxiredoxin. AB - Chloroplast NADPH-dependent thioredoxin reductase (NTRC) catalyzes the reduction of 2-Cys peroxiredoxin (2-Cys Prx) and, thus, probably functions as an antioxidant system. The functions of the enzyme in oxidative and salt stresses have been reported previously. We have previously identified and characterized NTRC in Chlorella vulgaris. In the present study, we isolated a full-length cDNA clone encoding 2-Cys Prx from C. vulgaris and investigated the involvement of Chlorella NTRC/2-Cys Prx system in several environmental stress tolerances by using yeast as a eukaryotic model. Deduced Chlorella 2-Cys Prx was homologous to those of chloroplast 2-Cys Prxs from plants, and two conserved cysteine residues were found in the deduced sequence. Enzyme assay showed that recombinant mature C. vulgaris NTRC (mCvNTRC) transferred electrons from NADPH to recombinant mature C. vulgaris 2-Cys Prx (mCvPrx), and mCvPrx decomposed hydrogen peroxide, tert butyl hydroperoxide, and peroxynitrite by cooperating with mCvNTRC. Based on the results, the mCvNTRC/mCvPrx antioxidant system was identified in Chlorella. The antioxidant system genes were expressed in yeast separately or coordinately. Stress tolerances of yeast against freezing, heat, and menadione-induced oxidative stresses were significantly improved by expression of mCvNTRC, and the elevated tolerances were more significant when both mCvNTRC and mCvPrx were co expressed. Our results reveal a novel feature of NTRC: it functions as an antioxidant system with 2-Cys Prx in freezing and heat stress tolerances. PMID- 23029354 TI - Anthropogenic influences on conservation values of white rhinoceros. AB - White rhinoceros (rhinos) is a keystone conservation species and also provides revenue for protection agencies. Restoring or mimicking the outcomes of impeded ecological processes allows reconciliation of biodiversity and financial objectives. We evaluate the consequences of white rhino management removal, and in recent times, poaching, on population persistence, regional conservation outcomes and opportunities for revenue generation. In Kruger National Park, white rhinos increased from 1998 to 2008. Since then the population may vary non directionally. In 2010, we estimated 10,621 (95% CI: 8,767-12,682) white rhinos using three different population estimation methods. The desired management effect of a varying population was detectable after 2008. Age and sex structures in sink areas (focal rhino capture areas) were different from elsewhere. This comes from relatively more sub-adults being removed by managers than what the standing age distribution defined. Poachers in turn focused on more adults in 2011. Although the effect of poaching was not detectable at the population level given the confidence intervals of estimates, managers accommodated expected poaching annually and adapted management removals. The present poaching trend predicts that 432 white rhinos may be poached in Kruger during 2012. The white rhino management model mimicking outcomes of impeded ecological processes predicts 397 rhino management removals are required. At present poachers may be doing "management removals," but conservationists have no opportunity left to contribute to regional rhino conservation strategies or generate revenue through white rhino sales. In addition, continued trends in poaching predict detectable white rhino declines in Kruger National Park by 2016. Our results suggest that conservationists need innovative approaches that reduce financial incentives to curb the threats that poaching poses to several conservation values of natural resources such as white rhinos. PMID- 23029356 TI - Individual differences in foraging strategies of parasitic sabre-tooth blennies. AB - Originally, evolutionary game theory typically predicted that optimal behaviour in a given situation is uniform or bimodal. However, the growing evidence that animals behave more variably while individuals may differ consistently in their behaviour, has led to the development of models that predict a distribution of strategies. Here we support the importance of such models in a study on a coral reef fish host-parasite system. Parasitic blennies (Plagiotremus sp.) regularly attack other fishes to bite off scales and mucus. Individuals of some victim species react to being bitten with punishing the parasite through aggressive chasing. Our field observations and laboratory experiments show that individual blennies differ markedly in how they incorporate being punished into their foraging decisions. We discuss how these differences may affect the payoff structure and hence the net effect of punishment on punishers and on the appearance of a public good for look-alikes. PMID- 23029355 TI - Differential regulation of breast cancer-associated genes by progesterone receptor isoforms PRA and PRB in a new bi-inducible breast cancer cell line. AB - Progesterone receptor isoforms (PRA and PRB) are expressed at equal levels in normal mammary cells. However, alteration in PRA/PRB expression is often observed in aggressive breast cancer suggesting differential contribution of PR isoforms in carcinogenesis. The mechanisms underlying such processes remain to be established mainly due to paucity of appropriate cellular models. To investigate the role of PR isoforms and the impact of imbalanced PRA/PRB ratio in transcriptional regulation, we have generated an original human breast cancer cell line conditionally expressing PRA and/or PRB in dose-dependence of non steroid inducers. We first focused on PR-dependent transcriptional regulation of the paracrine growth factor gene amphiregulin (AREG) playing important role in cancer. Interestingly, unliganded PRA increases AREG expression, independently of estrogen receptor, yet inhibitable by antiprogestins. We show that functional outcome of epidermal growth factor (EGF) on such regulation is highly dependent on PRA/PRB ratio. Using this valuable model, genome-wide transcriptomic studies allowed us to determine the differential effects of PRA and PRB as a function of hormonal status. We identified a large number of novel PR-regulated genes notably implicated in breast cancer and metastasis and demonstrated that imbalanced PRA/PRB ratio strongly impact their expression predicting poor outcome in breast cancer. In sum, our unique cell-based system strongly suggests that PRA/PRB ratio is a critical determinant of PR target gene selectivity and responses to hormonal/growth factor stimuli. These findings provide molecular support for the aggressive phenotype of breast cancers with impaired expression of PRA or PRB. PMID- 23029357 TI - Immature CD4+CD8+ thymocytes are preferentially infected by measles virus in human thymic organ cultures. AB - Cells of the human immune system are important target cells for measles virus (MeV) infection and infection of these cells may contribute to the immunologic abnormalities and immune suppression that characterize measles. The thymus is the site for production of naive T lymphocytes and is infected during measles. To determine which populations of thymocytes are susceptible to MeV infection and whether strains of MeV differ in their ability to infect thymocytes, we used ex vivo human thymus organ cultures to assess the relative susceptibility of different subpopulations of thymocytes to infection with wild type and vaccine strains of MeV. Thymocytes were susceptible to MeV infection with the most replication in immature CD4(+)CD8(+) double positive cells. Susceptibility correlated with the level of expression of the MeV receptor CD150. Wild type strains of MeV infected thymocytes more efficiently than the Edmonston vaccine strain. Thymus cultures from children >=3 years of age were less susceptible to MeV infection than cultures from children 5 to 15 months of age. Resistance in one 7 year-old child was associated with production of interferon-gamma suggesting that vaccination may result in MeV-specific memory T cells in the thymus. We conclude that immature thymocytes are susceptible to MeV infection and thymocyte infection may contribute to the immunologic abnormalities associated with measles. PMID- 23029358 TI - MAML1 acts cooperatively with EGR1 to activate EGR1-regulated promoters: implications for nephrogenesis and the development of renal cancer. AB - Mastermind-like 1 (MAML1) is a transcriptional coregulator of activators in various signaling pathways, such as Notch, p53, myocyte enhancer factor 2C (MEF2C) and beta-catenin. In earlier studies, we demonstrated that MAML1 enhanced p300 acetyltransferase activity, which increased the acetylation of Notch by p300. In this study, we show that MAML1 strongly induced acetylation of the transcription factor early growth response-1 (EGR1) by p300, and increased EGR1 protein expression in embryonic kidney cells. EGR1 mRNA transcripts were also upregulated in the presence of MAML1. We show that MAML1 physically interacted with, and acted cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters, which both contain EGR1 binding sites. Bioinformatics assessment revealed a correlation between p300, EGR1 and MAML1 copy number and mRNA alterations in renal clear cell carcinoma and p300, EGR1 and MAML1 gene alterations were associated with increased overall survival. Our findings suggest MAML1 may be a component of the transcriptional networks which regulate EGR1 target genes during nephrogenesis and could also have implications for the development of renal cell carcinoma. PMID- 23029360 TI - Evaluation of a polymerase chain reaction assay for pathogen detection in septic patients under routine condition: an observational study. AB - BACKGROUND: Treatment of septic shock relies on appropriate antimicrobial therapy. Current culture based methods deliver final results after days, which may delay potentially lifesaving adjustments in antimicrobial therapy. This study was undertaken to compare PCR with blood culture results under routine conditions regarding 1. impact on antimicrobial therapy, and 2. time to result, in patients with presumed sepsis. METHODOLOGY/PRINCIPAL FINDINGS: This was an observational study in a 50 beds ICU of a university hospital. In 245 patients with suspected sepsis, 311 concomitant blood cultures and blood for multiplex PCR (VYOO((r))) were obtained. 45 of 311 blood cultures (14.5%) and 94 of 311 PCRs (30.1%) were positive. However, blood culture or microbiological sampling from the presumed site of infection rarely confirmed PCR results and vice versa. Median time to positivity and interquartile range were 24.2 (18.0, 27.5) hours for the PCR and 68 (52.2, 88.5) hours for BC (p<0.01). PCR median time to result was dependent on technician availability (53.5 hours on Saturdays, 7.2 hours under optimal logistic conditions). PCR results showed good correlation with procalcitonin (p<0.001). In 34% of patients with positive PCRs antimicrobial therapy was considered inadequate according to assessment of clinical arbitrators including 5 patients with vancomycin-resistant enterococci (VRE), 3 cases with multiresistant staphylococci, and 4 patients with fungi. CONCLUSIONS: The results of this observational study support the hypothesis that PCR results are available faster, are more frequently positive, and may result in earlier adjustment of antimicrobial therapy. However, shorter time to result can only be fully exploited when the laboratory is adequately staffed for a 24 hour/7 day service, or when point of care/automated assay systems become available. PMID- 23029359 TI - Irrelevance of microsatellite instability in the epidemiology of sporadic pancreatic ductal adenocarcinoma. AB - BACKGROUND AND AIMS: Pancreatic cancer risk is increased in Lynch syndrome (LS) patients with mismatch repair gene defects predisposing to colonic and extracolonic cancers with microsatellite instability (MSI). However, the frequency of MSI pancreatic cancers has never been ascertained in consecutive, unselected clinical series, and their contribution to the sporadic and inherited burden of pancreatic cancer remains to be established. Aims of the study were to determine the prevalence of MSI in surgically resected pancreatic cancers in a multicentric, retrospective study, and to assess the occurrence of pancreatic cancer in LS. METHODS: MS-status was screened by a panel of 5 mononucleotide repeats (Bat26, Bat25, NR-21, NR-24 and NR-27) in 338 consecutive pancreatic ductal adenocarcinoma (PDAC), resected at two Italian and one German referral centres. The personal history of pancreatic cancer was assessed in an independent set of 58 probands with LS and in 138 first degree relatives who had cancers. RESULTS: Only one PDAC (0.3%) showed MSI. This was a medullary type cancer, with hMLH1-deficiency, and no identified germ-line mutation but methylation of hMLH1. Pancreatic cancer occurred in 5 (2.5%) LS patients. Histological sampling was available for 2 cases, revealing PDAC in one case and an ampullary cancer in the other one. CONCLUSIONS: MSI prevalence is negligible in sporadic, resected PDAC. Differently, the prevalence of pancreatic cancer is 2.5% in LS patients, and cancers other than PDAC may be encountered in this setting. Surveillance for pancreatic cancer should be advised in LS mutation carriers at referral centers. PMID- 23029361 TI - Relationship of Epstein-Barr virus and interleukin 10 promoter polymorphisms with the risk and clinical outcome of childhood Burkitt lymphoma. AB - Epstein-Barr virus (EBV) is an important environmental factor associated to the development of Burkitt lymphoma (BL) in endemic and intermediate risk regions. However, little is known about the contribution of genetic constitution to the development and clinical response of the disease. The aim of this work was to investigate the role of EBV and Interleukin 10 (IL10) single nucleotide polymorphisms (-1082A/G, -819C/T, -592C/A) and microsatellites (IL10.R and IL10.G) in susceptibility and clinical outcome in pediatric BL patients, in a region with intermediate EBV association frequency. The frequencies of IL10 promoter Single nucleotide polymorphisms -1082A/G, -819C/T, -592C/A, and IL10.R and IL10.G microsatellites were compared in 62 pediatric patients and 216 healthy donors. IL10 -1082GG and GCC/GCC genotypes were more frequent in patients than in controls, and associated to a higher risk of BL development (GG genotype OR 2.62, 95% CI, 1.25-5.51; P = 0.008; Pc = 0.024). EBV was detected in tumor samples by EBER-ISH in 54.1% of cases. EBV+ patients exhibited a better event free survival (EFS) (P = 0.019) than EBV- patients. Carriers of IL10 R3-GCC had worse EFS (P = 0.028). Our results suggest a risk effect and an independent prognostic value of IL10 polymorphisms and EBV in childhood BL patients. PMID- 23029362 TI - Increased tau phosphorylation and impaired presynaptic function in hypertriglyceridemic ApoB-100 transgenic mice. AB - AIMS: ApoB-100 is the major protein component of cholesterol- and triglyceride rich LDL and VLDL lipoproteins in the serum. Previously, we generated and partially described transgenic mice overexpressing the human ApoB-100 protein. Here, we further characterize this transgenic strain in order to reveal a possible link between hypeprlipidemia and neurodegeneration. METHODS AND RESULTS: We analyzed the serum and cerebral lipid profiles, tau phosphorylation patterns, amyloid plaque-formation, neuronal apoptosis and synaptic plasticity of young (3 month old), adult (6 month old) and aging (10-11 month old) transgenic mice. We show that ApoB-100 transgenic animals present i) elevated serum and cerebral levels of triglycerides and ApoB-100, ii) increased cerebral tau phosphorylation at phosphosites Ser(199), Ser(199/202), Ser(396) and Ser(404). Furthermore, we demonstrate, that tau hyperphosphorylation is accompanied by impaired presynaptic function, long-term potentiation and widespread hippocampal neuronal apoptosis. CONCLUSIONS: The results presented here indicate that elevated ApoB-100 level and the consequent chronic hypertriglyceridemia may lead to impaired neuronal function and neurodegeneration, possibly via hyperphosphorylation of tau protein. On account of their specific phenotype, ApoB-100 transgenic mice may be considered a versatile model of hyperlipidemia-induced age-related neurodegeneration. PMID- 23029363 TI - Gradual loss of ACTH due to a novel mutation in LHX4: comprehensive mutation screening in Japanese patients with congenital hypopituitarism. AB - Mutations in transcription factors genes, which are well regulated spatially and temporally in the pituitary gland, result in congenital hypopituitarism (CH) in humans. The prevalence of CH attributable to transcription factor mutations appears to be rare and varies among populations.This study aimed to define the prevalence of CH in terms of nine CH-associated genes among Japanese patients. We enrolled 91 Japanese CH patients for DNA sequencing of POU1F1, PROP1, HESX1, LHX3, LHX4, SOX2, SOX3, OTX2, and GLI2. Additionally, gene copy numbers for POU1F1, PROP1, HESX1, LHX3, and LHX4 were examined by multiplex ligation dependent probe amplification. The gene regulatory properties of mutant LHX4 proteins were characterized in vitro. We identified two novel heterozygous LHX4 mutations, namely c.249-1G>A, p.V75I, and one common POU1F1 mutation, p.R271W. The patient harboring the c.249-1G>A mutation exhibited isolated growth hormone deficiency at diagnosis and a gradual loss of ACTH, whereas the patient with the p.V75I mutation exhibited multiple pituitary hormone deficiency. In vitro experiments showed that both LHX4 mutations were associated with an impairment of the transactivation capacities of POU1F1 andalphaGSU, without any dominant negative effects. The total mutation prevalence in Japanese CH patients was 3.3%. This study is the first to describe, a gradual loss of ACTH in a patient carrying an LHX4 mutation. Careful monitoring of hypothalamic-pituitary -adrenal function is recommended for CH patients with LHX4 mutations. PMID- 23029364 TI - MicroRNA-330 is an oncogenic factor in glioblastoma cells by regulating SH3GL2 gene. AB - MicroRNAs have recently emerged as key regulators of cancers. This study was therefore conducted to investigate the role of miR-330 in biological behaviors of human glioblastoma U87 and U251 cell lines and its molecular mechanism. SH3GL2 gene was identified as the target of miR-330. MiR-330 overexpression was established by transfecting miR-330 precursor into U87 and U251 cells, and its effects on proliferation, migration, invasion, cell cycle and apoptosis were studied. Overexpression of miR-330 can enhance cellular proliferation, promote migration and invasion, activate cell cycle and also inhibit apoptosis in U87 and U251 cells. Collectively, these above-mentioned results suggest that miRNA-330 plays an oncogenic role in human glioblastoma by regulating SH3GL2 gene and might be a new therapeutic target of human glioblastoma. PMID- 23029365 TI - Voltage-driven translocation of DNA through a high throughput conical solid-state nanopore. AB - Nanopores have become an important tool for molecule detection at single molecular level. With the development of fabrication technology, synthesized solid-state membranes are promising candidate substrates in respect of their exceptional robustness and controllable size and shape. Here, a 30-60 (tip-base) nm conical nanopore fabricated in 100 nm thick silicon nitride (Si(3)N(4)) membrane by focused ion beam (FIB) has been employed for the analysis of lambda DNA translocations at different voltage biases from 200 to 450 mV. The distributions of translocation time and current blockage, as well as the events frequencies as a function of voltage are investigated. Similar to previously published work, the presence and configurations of lambda-DNA molecules are characterized, also, we find that greater applied voltages markedly increase the events rate, and stretch the coiled lambda-DNA molecules into linear form. However, compared to 6-30 nm ultrathin solid-state nanopores, a threshold voltage of 181 mV is found to be necessary to drive DNA molecules through the nanopore due to conical shape and length of the pore. The speed is slowed down ~5 times, while the capture radius is ~2 fold larger. The results show that the large nanopore in thick membrane with an improved stability and throughput also has the ability to detect the molecules at a single molecular level, as well as slows down the velocity of molecules passing through the pore. This work will provide more motivations for the development of nanopores as a Multi-functional sensor for a wide range of biopolymers and nano materials. PMID- 23029366 TI - Components of implicit stigma against mental illness among Chinese students. AB - Although some research has examined negative automatic aspects of attitudes toward mental illness via relatively indirect measures among Western samples, it is unclear whether negative attitudes can be automatically activated in individuals from non-Western countries. This study attempted to validate results from Western samples with Chinese college students. We first examined the three component model of implicit stigma (negative cognition, negative affect, and discriminatory tendencies) toward mental illness with the Single Category Implicit Association Test (SC-IAT). We also explored the relationship between explicit and implicit stigma among 56 Chinese university college students. In the three separate SC-IATs and the combined SC-IAT, automatic associations between mental illness and negative descriptors were stronger relative to those with positive descriptors and the implicit effect of cognitive and affective SC-IATs were significant. Explicit and implicit measures of stigma toward mental illness were unrelated. In our sample, women's overall attitudes toward mental illness were more negative than men's were, but no gender differences were found for explicit measures. These findings suggested that implicit stigma toward mental illness exists in Chinese students, and provide some support for the three component model of implicit stigma toward mental illness. Future studies that focus on automatic components of stigmatization and stigma-reduction in China are warranted. PMID- 23029367 TI - Mitochondria-dependent apoptosis of con A-activated T lymphocytes induced by asiatic acid for preventing murine fulminant hepatitis. AB - Selectively facilitating apoptosis of activated T cells is essential for the clearance of pathogenic injurious cells and subsequent efficient resolution of inflammation. However, few chemicals have been reported to trigger apoptosis of activated T cells for the treatment of hepatitis without affecting quiescent T cells. In the present study, we found that asiatic acid, a natural triterpenoid, selectively triggered apoptosis of concanavalin A (Con A)-activated T cells in a mitochondria-dependent manner indicated by the disruption of the mitochondrial transmembrane potential, release of cytochrome c from mitochondria to cytosol, caspases activation, and cleavage of PARP. In addition, asiatic acid also induced the cleavage of caspase 8 and Bid and augmented Fas expression in Con A-activated T cells. However, following activation of T cells from MRL(lpr/lpr) mice with mutation of Fas demonstrated a similar susceptibility to asiatic acid-induced apoptosis compared with normal T cells, suggesting that Fas-mediated death receptor apoptotic pathway does not mainly contribute to asiatic acid-induced cell death. Furthermore, asiatic acid significantly alleviated Con A-induced T cell-dependent fulminant hepatitis in mice, as assessed by reduced serum transaminases, pro-inflammatory cytokines, and pathologic parameters. Consistent with the in vitro results, asiatic acid also induced apoptosis of activated CD4(+) T cells in vivo. Taken together, our results demonstrated that the ability of asiatic acid to induce apoptosis of activated T cells and its potential use in the treatment of T-cell-mediated inflammatory diseases. PMID- 23029368 TI - Molecular characterization of invasive meningococcal isolates from countries in the African meningitis belt before introduction of a serogroup A conjugate vaccine. AB - BACKGROUND: The serogroup A conjugate meningococcal vaccine, MenAfriVac, was introduced in mass vaccination campaigns in December 2010 in Burkina Faso, Mali and Niger. In the coming years, vaccination will be extended to other African countries at risk of epidemics. To document the molecular characteristics of disease-causing meningococcal strains circulating in the meningitis belt of Africa before vaccine introduction, the World Health Organization Collaborating Centers on Meningococci in Europe and United States established a common strain collection of 773 isolates from cases of invasive meningococcal disease collected between 2004 and 2010 from 13 sub-Saharan countries. METHODOLOGY: All isolates were characterized by multilocus sequence typing, and 487 (62%) were also analyzed for genetic variation in the surface antigens PorA and FetA. Antibiotic susceptibility was tested for part of the collection. PRINCIPAL FINDINGS: Only 19 sequence types (STs) belonging to 6 clonal complexes were revealed. ST-5 clonal complex dominated with 578 (74.8%) isolates. All ST-5 complex isolates were remarkably homogeneous in their PorA (P1.20,9) and FetA (F3-1) and characterized the serogroup A strains which have been responsible for most epidemics during this time period. Sixty-eight (8.8%) of the 773 isolates belonged to the ST-11 clonal complex which was mainly represented by serogroup W135, while an additional 38 (4.9%) W135 isolates belonged to the ST-175 complex. Forty-eight (6.2%) serogroup X isolates from West Africa belonged to the ST-181 complex, while serogroup X cases in Kenya and Uganda were caused by an unrelated clone, ST 5403. Serogroup X, ST-181, emerged in Burkina Faso before vaccine introduction. CONCLUSIONS: In the seven years preceding introduction of a new serogroup A conjugate vaccine, serogroup A of the ST-5 clonal complex was identified as the predominant disease-causing strain. PMID- 23029369 TI - A candidate-gene association study for berry colour and anthocyanin content in Vitis vinifera L. AB - Anthocyanin content is a trait of major interest in Vitis vinifera L. These compounds affect grape and wine quality, and have beneficial effects on human health. A candidate-gene approach was used to identify genetic variants associated with anthocyanin content in grape berries. A total of 445 polymorphisms were identified in 5 genes encoding transcription factors and 10 genes involved in either the biosynthetic pathway or transport of anthocyanins. A total of 124 SNPs were selected to examine association with a wide range of phenotypes based on RP-HPLC analysis and visual characterization. The phenotypes were total skin anthocyanin (TSA) concentration but also specific types of anthocyanins and relative abundance. The visual assessment was based on OIV (Organisation Internationale de la Vigne et du Vin) descriptors for berry and skin colour. The genes encoding the transcription factors MYB11, MYBCC and MYC(B) were significantly associated with TSA concentration. UFGT and MRP were associated with several different types of anthocyanins. Skin and pulp colour were associated with nine genes (MYB11, MYBCC, MYC(B), UFGT, MRP, DFR, LDOX, CHI and GST). Pulp colour was associated with a similar group of 11 genes (MYB11, MYBCC, MYC(B), MYC(A), UFGT, MRP, GST, DFR, LDOX, CHI and CHS(A)). Statistical interactions were observed between SNPs within the transcription factors MYB11, MYBCC and MYC(B). SNPs within LDOX interacted with MYB11 and MYC(B), while SNPs within CHI interacted with MYB11 only. Together, these findings suggest the involvement of these genes in anthocyanin content and on the regulation of anthocyanin biosynthesis. This work forms a benchmark for replication and functional studies. PMID- 23029370 TI - Sequence features contributing to chromosomal rearrangements in Neisseria gonorrhoeae. AB - Through whole genome sequence alignments, breakpoints in chromosomal synteny can be identified and the sequence features associated with these determined. Alignments of the genome sequences of Neisseria gonorrhoeae strain FA1090, N.gonorrhoeae strain NCCP11945, and N. gonorrhoeae strain TCDC-NG08107 reveal chromosomal rearrangements that have occurred. Based on these alignments and dot plot pair-wise comparisons, the overall chromosomal arrangement of strain NCCP11945 and TCDC-NG08107 are very similar, with no large inversions or translocations. The insertion of the Gonococcal Genetic Island in strain NCCP11945 is the most prominent distinguishing feature differentiating these strains. When strain NCCP11945 is compared to strain FA1090, however, 14 breakpoints in chromosomal synteny are identified between these gonococcal strains. The majority of these, 11 of 14, are associated with a prophage, IS elements, or IS-like repeat enclosed elements which appear to have played a role in the rearrangements observed. Additional rearrangements of small regions of the genome are associated with pilin genes. Evidence presented here suggests that the rearrangements of blocks of sequence are mediated by activation of prophage and associated IS elements and reintegration elsewhere in the genome or by homologous recombination between IS-like elements that have generated inversions. PMID- 23029371 TI - Growth pattern responses to photoperiod across latitudes in a northern damselfly. AB - BACKGROUND: Latitudinal clines in temperature and seasonality impose strong seasonal constraints on ectotherms. Studies of population differentiation in phenotypic plasticity of life history traits along latitudinal gradients are important for understanding how organisms have adapted to seasonal environments and predict how they respond to climate changes. Such studies have been scarce for species with a northern distribution. METHODOLOGY/PRINCIPLE FINDING: Larvae of the northern damselfly Coenagrion johanssoni originating from semivoltine central, partivoltine northern, and partivoltine northernmost Swedish populations were reared in the laboratory. To investigate whether larvae use photoperiodic cues to induce compensatory growth along this latitudinal gradient, larvae were reared under two different photoperiods corresponding to a northern and southern latitude. In addition, field adult size was assessed to test the strength of possible compensatory growth mechanisms under natural conditions and hatchling size was measured to test for maternal effects. We hypothesized that populations originating from lower latitudes would be more time constrained than high latitude populations because they have a shorter life cycle. The results showed that low-latitude populations had higher growth rates in summer/fall. In general northern photoperiods induced higher growth rates, but this plastic response to photoperiod was strongest in the southernmost populations and negligible in the northernmost population. During spring, central populations grew faster under the southern rather than the northern photoperiod. On the other hand, northern and northernmost populations did not differ between each other and grew faster in the northern rather than in the southern photoperiod. Field sampled adults did not differ in size across the studied regions. CONCLUSION/SIGNIFICANCE: We found a significant differentiation in growth rate across latitudes and latitudinal difference in growth rate response to photoperiod. Importantly, growth responses measured at a single larval developmental stage in one season may not always generalize to other developmental stages or seasons. PMID- 23029372 TI - Effect of fish oil supplementation on fasting vascular endothelial function in humans: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Effect of fish oil supplementation on flow-mediated dilation, an index of endothelial function in humans, remains controversial. We performed a meta-analysis to determine whether fish oil supplementation could improve endothelial function. METHODS: Human intervention studies were identified by systematic searches of Medline, Embase, Cochrane's library and references of related reviews and studies. A random-effect model was applied to estimate the pooled results. Meta-regression and subgroup analyses were performed to evaluate the impact of study characteristics on the effect of fish oil supplementation on flow-mediated dilation. RESULTS: A total of sixteen records with 1,385 subjects were reviewed. The results of the pooled analysis showed that fish oil supplementation significantly improved flow-mediated dilation (weighed mean difference: 1.49%, 95% confidence interval 0.48% to 2.50%, p = 0.004). Meta regression and subgroup analysis suggested that the quality of included studies were inversely related to the overall effect (regression coefficient = -1.60, p = 0.04), and the significance of the effect was mainly driven by the studies with relatively poor quality. Sensitivity analysis including only double-blind, placebo-controlled studies indicated fish oil supplementation has no significant effect on endothelial function (weighed mean difference: 0.54%, 95% confidence interval -0.25% to 1.33%, p = 0.18). Besides, normoglycemic subjects or participants with lower diastolic blood pressure seemed to be associated with remarkable improvement of endothelial function after fish oil supplementation. CONCLUSIONS: Although current evidence suggested a possible role of fish oil in improving endothelial function, large-scale and high-quality clinical trials are needed to evaluate these effects before we can come to a definite conclusion. PMID- 23029373 TI - Sodium bicarbonate treatment during transient or sustained lactic acidemia in normoxic and normotensive rats. AB - INTRODUCTION: Lactic acidosis is a frequent cause of poor outcome in the intensive care settings. We set up an experimental model of lactic acid infusion in normoxic and normotensive rats to investigate the systemic effects of lactic acidemia per se without the confounding factor of an underlying organic cause of acidosis. METHODOLOGY: Sprague Dawley rats underwent a primed endovenous infusion of L(+) lactic acid during general anesthesia. Normoxic and normotensive animals were then randomized to the following study groups (n = 8 per group): S) sustained infusion of lactic acid, S+B) sustained infusion+sodium bicarbonate, T) transient infusion, T+B transient infusion+sodium bicarbonate. Hemodynamic, respiratory and acid-base parameters were measured over time. Lactate pharmacokinetics and muscle phosphofructokinase enzyme's activity were also measured. PRINCIPAL FINDINGS: Following lactic acid infusion blood lactate rose (P<0.05), pH (P<0.05) and strong ion difference (P<0.05) drop. Some rats developed hemodynamic instability during the primed infusion of lactic acid. In the normoxic and normotensive animals bicarbonate treatment normalized pH during sustained infusion of lactic acid (from 7.22 +/- 0.02 to 7.36 +/- 0.04, P<0.05) while overshoot to alkalemic values when the infusion was transient (from 7.24 +/ 0.01 to 7.53 +/- 0.03, P<0.05). When acid load was interrupted bicarbonate infusion affected lactate wash-out kinetics (P<0.05) so that blood lactate was higher (2.9 +/- 1 mmol/l vs. 1.0 +/- 0.2, P<0.05, group T vs. T+B respectively). The activity of phosphofructokinase enzyme was correlated with blood pH (R2 = 0.475, P<0.05). CONCLUSIONS: pH decreased with acid infusion and rose with bicarbonate administration but the effects of bicarbonate infusion on pH differed under a persistent or transient acid load. Alkalization affected the rate of lactate disposal during the transient acid load. PMID- 23029374 TI - Implication of DNA demethylation and bivalent histone modification for selective gene regulation in mouse primordial germ cells. AB - Primordial germ cells (PGCs) sequentially induce specific genes required for their development. We focused on epigenetic changes that regulate PGC-specific gene expression. mil-1, Blimp1, and Stella are preferentially expressed in PGCs, and their expression is upregulated during PGC differentiation. Here, we first determined DNA methylation status of mil-1, Blimp1, and Stella regulatory regions in epiblast and in PGCs, and found that they were hypomethylated in differentiating PGCs after E9.0, in which those genes were highly expressed. We used siRNA to inhibit a maintenance DNA methyltransferase, Dnmt1, in embryonic stem (ES) cells and found that the flanking regions of all three genes became hypomethylated and that expression of each gene increased 1.5- to 3-fold. In addition, we also found 1.5- to 5-fold increase of the PGC genes in the PGCLCs (PGC-like cells) induced form ES cells by knockdown of Dnmt1. We also obtained evidence showing that methylation of the regulatory region of mil-1 resulted in 2.5-fold decrease in expression in a reporter assay. Together, these results suggested that DNA demethylation does not play a major role on initial activation of the PGC genes in the nascent PGCs but contributed to enhancement of their expression in PGCs after E9.0. However, we also found that repression of representative somatic genes, Hoxa1 and Hoxb1, and a tissue-specific gene, Gfap, in PGCs was not dependent on DNA methylation; their flanking regions were hypomethylated, but their expression was not observed in PGCs at E13.5. Their promoter regions showed the bivalent histone modification in PGCs, that may be involved in repression of their expression. Our results indicated that epigenetic status of PGC genes and of somatic genes in PGCs were distinct, and suggested contribution of epigenetic mechanisms in regulation of the expression of a specific gene set in PGCs. PMID- 23029376 TI - Increased expression of the dsRNA-activated protein kinase PKR in breast cancer promotes sensitivity to doxorubicin. AB - It has been reported that the expression and activity of the interferon inducible, dsRNA-dependent protein kinase, PKR, is increased in mammary carcinoma cell lines and primary tumor samples. To extend these findings and determine how PKR signaling may affect breast cancer cell sensitivity to chemotherapy, we measured PKR expression by immunohistochemical staining of 538 cases of primary breast cancer and normal tissues. Significantly, PKR expression was elevated in ductal, lobular and squamous cell carcinomas or lymph node metastases but not in either benign tumor specimens or cases of inflammation compared to normal tissues. Furthermore, PKR expression was increased in precancerous stages of mammary cell hyperplasia and dysplasia compared to normal tissues, indicating that PKR expression may be upregulated by the process of tumorigenesis. To test the function of PKR in breast cancer, we generated MCF7, T-47D and MDA-MB-231 breast cancer cell lines with significantly reduced PKR expression by siRNA knockdown. Importantly, while knockdown of PKR expression had no effect on cell proliferation under normal growth conditions, MCF7, T-47D or MDA-MB-231 cells with reduced PKR expression or treated with a small molecule PKR inhibitor were significantly less sensitive to doxorubicin or H(2)O(2)-induced toxicity compared to control cells. In addition, the rate of eIF2alpha phosphorylation following treatment with doxorubicin was delayed in breast cancer cell lines with decreased PKR expression. Significantly, treatment of breast cancer lines with reduced PKR expression with either interferon-alpha, which increases PKR expression, or salubrinal, which increases eIF2alpha phosphorylation, restored doxorubicin sensitivity to normal levels. Taken together these results indicate that increased PKR expression in primary breast cancer tissues may serve as a biomarker for response to doxorubicin-containing chemotherapy and that future therapeutic approaches to promote PKR expression/activation and eIF2alpha phosphorylation may be beneficial for the treatment of breast cancer. PMID- 23029375 TI - Conditional mesenchymal disruption of pkd1 results in osteopenia and polycystic kidney disease. AB - Conditional deletion of Pkd1 in osteoblasts using either Osteocalcin(Oc)-Cre or Dmp1-Cre results in defective osteoblast-mediated postnatal bone formation and osteopenia. Pkd1 is also expressed in undifferentiated mesenchyme that gives rise to the osteoblast lineage. To examine the effects of Pkd1 on prenatal osteoblast development, we crossed Pkd1(flox/flox) and Col1a1(3.6)-Cre mice, which has been used to achieve selective inactivation of Pkd1 earlier in the osteoblast lineage. Control Pkd1(flox/flox) and Pkd1(flox/+), heterozygous Col1a1(3.6) Cre;Pkd1(flox/+) and Pkd1(flox/null), and homozygous Col1a1(3.6) Cre;Pkd1(flox/flox) and Col1a1(3.6)-Cre;Pkd1(flox/null) mice were analyzed at ages ranging from E14.5 to 8-weeks-old. Newborn Col1a1(3.6)-Cre;Pkd1(flox/null) mice exhibited defective skeletogenesis in association with a greater reduction in Pkd1 expression in bone. Conditional Col1a1(3.6)-Cre;Pkd1(flox/+) and Col1a1(3.6)-Cre;Pkd1(flox/flox) mice displayed a gene dose-dependent decrease in bone formation and increase in marrow fat at 6 weeks of age. Bone marrow stromal cell and primary osteoblast cultures from homozygous Col1a1(3.6) Cre;Pkd1(flox/flox) mice showed increased proliferation, impaired osteoblast development and enhanced adipogenesis ex vivo. Unexpectedly, we found evidence for Col1a1(3.6)-Cre mediated deletion of Pkd1 in extraskeletal tissues in Col1a1(3.6)-Cre;Pkd1(flox/flox) mice. Deletion of Pkd1 in mesenchymal precursors resulted in pancreatic and renal, but not hepatic, cyst formation. The non lethality of Col1a1(3.6)-Cre;Pkd1(flox/flox) mice establishes a new model to study abnormalities in bone development and cyst formation in pancreas and kidney caused by Pkd1 gene inactivation. PMID- 23029377 TI - Potential role of M. tuberculosis specific IFN-gamma and IL-2 ELISPOT assays in discriminating children with active or latent tuberculosis. AB - BACKGROUND: Although currently available IGRA have been reported to be promising markers for TB infection, they cannot distinguish active tuberculosis (TB) from latent infection (LTBI). OBJECTIVE: Children with LTBI, active TB disease or uninfected were prospectively evaluated by an in-house ELISPOT assay in order to investigate possible immunological markers for a differential diagnosis between LTBI and active TB. METHODS: Children at risk for TB infection prospectively enrolled in our infectious disease unit were evaluated by in-house IFN-gamma and IL-2 based ELISPOT assays using a panel of Mycobacterium tuberculosis antigens. RESULTS: Twenty-nine children were classified as uninfected, 21 as LTBI and 25 as active TB cases (including 5 definite and 20 probable cases). Significantly higher IFN-gamma ELISPOT responses were observed in infected vs. uninfected children for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p = 0.003), and AlaDH (p = 0.001), while differences were not significant considering Ag85B (p = 0.063), PstS1 (p = 0.512), and HspX (16 kDa) (p = 0.139). IL-2 ELISPOT assay responses were different for ESAT-6 (p<0.0001), CFP-10 (p<0.0001), TB 10.3 (p<0.0001), HspX (16 kDa) (p<0.0001), PstS1 (p<0.0001) and AlaDH (p = 0.001); but not for Ag85B (p = 0.063). Comparing results between children with LTBI and those with TB disease differences were significant for IFN-gamma ELISPOT only for AlaDH antigen (p = 0.021) and for IL-2 ELISPOT assay for AlaDH (p<0.0001) and TB 10.3 antigen (p = 0.043). ROC analyses demonstrated sensitivity of 100% and specificity of 81% of AlaDH-IL-2 ELISPOT assay in discriminating between latent and active TB using a cut off of 12.5 SCF per million PBMCs. CONCLUSION: Our data suggest that IL-2 based ELISPOT with AlaDH antigen may be of help in discriminating children with active from those with latent TB. PMID- 23029378 TI - Comparative analysis of the immunogenicity and protective effects of inactivated EV71 vaccines in mice. AB - BACKGROUND: Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD). Three inactivated EV71 whole-virus vaccines of different strains developed by different manufacturers in mainland China have recently entered clinical trials. Although several studies on these vaccines have been published, a study directly comparing the immunogenicity and protective effects among them has not been carried out, which makes evaluating their relative effectiveness difficult. Thus, properly comparing newly developed vaccines has become a priority, especially in China. METHODS AND FINDINGS: This comparative immunogenicity study was carried out on vaccine strains (both live and inactivated), final container products (FCPs) without adjuvant, and corresponding FCPs containing adjuvant (FCP-As) produced by three manufacturers. These vaccines were evaluated by neutralizing antibody (NAb) responses induced by the same or different dosages at one or multiple time points post-immunization. The protective efficacy of the three vaccines was also determined in one-day-old ICR mice born to immunized female mice. Survival rates were observed in these suckling mice after challenge with 20 LD(50) of EV71/048M3C2. Three FCP-As, in a dose of 200 U, generated nearly 100% NAb positivity rates and similar geometric mean titers (GMTs), especially at 14-21 days post-inoculation. However, the dynamic NAb responses were different among three vaccine strains or three FCPs. The FCP-As at the lowest dose used in clinical trials (162 U) showed good protective effects in suckling mice against lethal challenge (90-100% survival), while the ED(50) of NAb responses and protective effects varied among three FCP As. CONCLUSIONS: These studies establish a standard method for measuring the immunogenicity of EV71 vaccines in mice. The data generated from our mouse model study indicated a clear dose-response relationship, which is important for vaccine quality control and assessment, especially for predicting protective efficacy in humans when combined with future clinical trial results. PMID- 23029379 TI - Impact of corticosterone treatment on spontaneous seizure frequency and epileptiform activity in mice with chronic epilepsy. AB - Stress is the most commonly reported precipitating factor for seizures in patients with epilepsy. Despite compelling anecdotal evidence for stress-induced seizures, animal models of the phenomena are sparse and possible mechanisms are unclear. Here, we tested the hypothesis that increased levels of the stress associated hormone corticosterone (CORT) would increase epileptiform activity and spontaneous seizure frequency in mice rendered epileptic following pilocarpine induced status epilepticus. We monitored video-EEG activity in pilocarpine treated mice 24/7 for a period of four or more weeks, during which animals were serially treated with CORT or vehicle. CORT increased the frequency and duration of epileptiform events within the first 24 hours of treatment, and this effect persisted for up to two weeks following termination of CORT injections. Interestingly, vehicle injection produced a transient spike in CORT levels - presumably due to the stress of injection - and a modest but significant increase in epileptiform activity. Neither CORT nor vehicle treatment significantly altered seizure frequency; although a small subset of animals did appear responsive. Taken together, our findings indicate that treatment of epileptic animals with exogenous CORT designed to mimic chronic stress can induce a persistent increase in interictal epileptiform activity. PMID- 23029380 TI - MicroRNA expression profiles of whole blood in lung adenocarcinoma. AB - The association of lung cancer with changes in microRNAs in plasma shown in multiple studies suggests a utility for circulating microRNA biomarkers in non invasive detection of the disease. We examined if presence of lung cancer is reflected in whole blood microRNA expression as well, possibly because of a systemic response. Locked nucleic acid microarrays were used to quantify the global expression of microRNAs in whole blood of 22 patients with lung adenocarcinoma and 23 controls, ten of whom had a radiographically detected non cancerous lung nodule and the other 13 were at high risk for developing lung cancer because of a smoking history of >20 pack-years. Cases and controls differed significantly for age with a mean difference of 10.7 years, but not for gender, race, smoking history, blood hemoglobin, platelet count, or white blood cell count. Of 1282 quantified human microRNAs, 395 (31%) were identified as expressed in the study's subjects, with 96 (24%) differentially expressed between cases and controls. Classification analyses of microRNA expression data were performed using linear kernel support vector machines (SVM) and top-scoring pairs (TSP) methods, and classifiers to identify presence of lung adenocarcinoma were internally cross-validated. In leave-one-out cross-validation, the TSP classifiers had sensitivity and specificity of 91% and 100%, respectively. The values with SVM were both 91%. In a Monte Carlo cross-validation, average sensitivity and specificity values were 86% and 97%, respectively, with TSP, and 88% and 89%, respectively, with SVM. MicroRNAs miR-190b, miR-630, miR-942, and miR-1284 were the most frequent constituents of the classifiers generated during the analyses. These results suggest that whole blood microRNA expression profiles can be used to distinguish lung cancer cases from clinically relevant controls. Further studies are needed to validate this observation, including in non adenocarcinomatous lung cancers, and to clarify upon the confounding effect of age. PMID- 23029381 TI - Chromosome segregation analysis in human embryos obtained from couples involving male carriers of reciprocal or Robertsonian translocation. AB - The objective of this study was to investigate the frequency and type of chromosome segregation patterns in cleavage stage embryos obtained from male carriers of Robertsonian (ROB) and reciprocal (REC) translocations undergoing preimplantation genetic diagnosis (PGD) at our reproductive center. We used FISH to analyze chromosome segregation in 308 day 3 cleavage stage embryos obtained from 26 patients. The percentage of embryos consistent with normal or balanced segregation (55.1% vs. 27.1%) and clinical pregnancy (62.5% vs. 19.2%) rates were higher in ROB than the REC translocation carriers. Involvement of non-acrocentric chromosome(s) or terminal breakpoint(s) in reciprocal translocations was associated with an increase in the percent of embryos consistent with adjacent 1 but with a decrease in 3?1 segregation. Similar results were obtained in the analysis of nontransferred embryos donated for research. 3?1 segregation was the most frequent segregation type in both day 3 (31%) and spare (35%) embryos obtained from carriers of t(11;22)(q23;q11), the only non-random REC with the same breakpoint reported in a large number of unrelated families mainly identified by the birth of a child with derivative chromosome 22. These results suggest that chromosome segregation patterns in day 3 and nontransferred embryos obtained from male translocation carriers vary with the type of translocation and involvement of acrocentric chromosome(s) or terminal breakpoint(s). These results should be helpful in estimating reproductive success in translocation carriers undergoing PGD. PMID- 23029382 TI - Genome sequencing and phylogenetic analysis of 39 human parainfluenza virus type 1 strains isolated from 1997-2010. AB - Thirty-nine human parainfluenza type 1 (HPIV-1) genomes were sequenced from samples collected in Milwaukee, Wisconsin from 1997-2010. Following sequencing, phylogenetic analyses of these sequences plus any publicly available HPIV-1 sequences (from GenBank) were performed. Phylogenetic analysis of the whole genomes, as well as individual genes, revealed that the current HPIV-1 viruses group into three different clades. Previous evolutionary studies of HPIV-1 in Milwaukee revealed that there were two genotypes of HPIV-1 co-circulating in 1991 (previously described as HPIV-1 genotypes C and D). The current study reveals that there are still two different HPIV-1 viruses co-circulating in Milwaukee; however, both groups of HPIV-1 viruses are derived from genotype C indicating that genotype D may no longer be in circulation in Milwaukee. Analyses of genetic diversity indicate that while most of the genome is under purifying selection some regions of the genome are more tolerant of mutation. In the 40 HPIV-1 genomes sequenced in this study, the nucleotide sequence of the L gene is the most conserved while the sequence of the P gene is the most variable. Over the entire protein coding region of the genome, 81 variable amino acid residues were observed and as with nucleotide diversity, the P protein seemed to be the most tolerant of mutation (and contains the greatest proportion of non-synonymous to synonymous substitutions) while the M protein appears to be the least tolerant of amino acid substitution. PMID- 23029383 TI - Investigating avian influenza infection hotspots in old-world shorebirds. AB - Heterogeneity in the transmission rates of pathogens across hosts or environments may produce disease hotspots, which are defined as specific sites, times or species associations in which the infection rate is consistently elevated. Hotspots for avian influenza virus (AIV) in wild birds are largely unstudied and poorly understood. A striking feature is the existence of a unique but consistent AIV hotspot in shorebirds (Charadriiformes) associated with a single species at a specific location and time (ruddy turnstone Arenaria interpres at Delaware Bay, USA, in May). This unique case, though a valuable reference, limits our capacity to explore and understand the general properties of AIV hotspots in shorebirds. Unfortunately, relatively few shorebirds have been sampled outside Delaware Bay and they belong to only a few shorebird families; there also has been a lack of consistent oropharyngeal sampling as a complement to cloacal sampling. In this study we looked for AIV hotspots associated with other shorebird species and/or with some of the larger congregation sites of shorebirds in the old world. We assembled and analysed a regionally extensive dataset of AIV prevalence from 69 shorebird species sampled in 25 countries across Africa and Western Eurasia. Despite this diverse and extensive coverage we did not detect any new shorebird AIV hotspots. Neither large shorebird congregation sites nor the ruddy turnstone were consistently associated with AIV hotspots. We did, however, find a low but widespread circulation of AIV in shorebirds that contrast with the absence of AIV previously reported in shorebirds in Europe. A very high AIV antibody prevalence coupled to a low infection rate was found in both first-year and adult birds of two migratory sandpiper species, suggesting the potential existence of an AIV hotspot along their migratory flyway that is yet to be discovered. PMID- 23029384 TI - Uptake of biotin by Chlamydia Spp. through the use of a bacterial transporter (BioY) and a host-cell transporter (SMVT). AB - Chlamydia spp. are obligate intracellular Gram-negative bacterial pathogens that cause disease in humans and animals. Minor variations in metabolic capacity between species have been causally linked to host and tissue tropisms. Analysis of the highly conserved genomes of Chlamydia spp. reveals divergence in the metabolism of the essential vitamin biotin with genes for either synthesis (bioF_2ADB) and/or transport (bioY). Streptavidin blotting confirmed the presence of a single biotinylated protein in Chlamydia. As a first step in unraveling the need for divergent biotin acquisition strategies, we examined BioY (CTL0613) from C. trachomatis 434/Bu which is annotated as an S component of the type II energy coupling-factor transporters (ECF). Type II ECFs are typically composed of a transport specific component (S) and a chromosomally unlinked energy module (AT). Intriguingly, Chlamydia lack recognizable AT modules. Using (3)H-biotin and recombinant E. coli expressing CTL0613, we demonstrated that biotin was transported with high affinity (a property of Type II ECFs previously shown to require an AT module) and capacity (apparent K(m) of 3.35 nM and V(max) of 55.1 pmol*min(-1)*mg(-1)). Since Chlamydia reside in a host derived membrane vacuole, termed an inclusion, we also sought a mechanism for transport of biotin from the cell cytoplasm into the inclusion vacuole. Immunofluorescence microscopy revealed that the mammalian sodium multivitamin transporter (SMVT), which transports lipoic acid, biotin, and pantothenic acid into cells, localizes to the inclusion. Since Chlamydia also are auxotrophic for lipoic and pantothenic acids, SMVT may be subverted by Chlamydia to move multiple essential compounds into the inclusion where BioY and another transporter(s) would be present to facilitate transport into the bacterium. Collectively, our data validates the first BioY from a pathogenic organism and describes a two-step mechanism by which Chlamydia transport biotin from the host cell into the bacterial cytoplasm. PMID- 23029385 TI - Slug, twist, and E-cadherin as immunohistochemical biomarkers in meningeal tumors. AB - The overexpression of Twist and Slug and subsequent down-regulation of E-cadherin facilitate the acquirement of invasive growth properties in cancer cells. It is unclear which of these molecules are expressed in mesenchymal tumors in the central nervous system. Here, we investigated 10 cases each of hemangiopericytoma, solitary fibrous tumor, meningothelial, fibrous, angiomatous, and atypical meningiomas, and 5 cases of anaplastic meningioma for Slug, Twist, E cadherin, and N-cadherin immunoexpression. Nuclear Slug expression was observed in 9/10 (90%) hemangiopericytomas and 5/10 (50%) solitary fibrous tumors, but not in any meningiomas, except for 1 case. Similarly, nuclear Twist expression was more extensive in hemangiopericytomas and solitary fibrous tumors than meningiomas. In contrast to Slug and Twist, the positive expression of E-cadherin was observed in 39/45 (87%) meningiomas, but not in any hemangiopericytomas or solitary fibrous tumors (P<0.0001). The fraction of tumor cells expressing E cadherin in meningeal tumors was negatively correlated to those of Twist (P = 0.004) and Slug (P<0.0001). The overexpression of Slug and Twist with down regulation of E-cadherin was characteristic findings in hemangiopericytomas and solitary fibrous tumors, but not in meningiomas. The immunohistochemical profiles of the two tumor groups may be useful as diagnostic markers in cases that present a differential diagnosis challenge. PMID- 23029386 TI - Peer review of grant applications: criteria used and qualitative study of reviewer practices. AB - BACKGROUND: Peer review of grant applications has been criticized as lacking reliability. Studies showing poor agreement among reviewers supported this possibility but usually focused on reviewers' scores and failed to investigate reasons for disagreement. Here, our goal was to determine how reviewers rate applications, by investigating reviewer practices and grant assessment criteria. METHODS AND FINDINGS: We first collected and analyzed a convenience sample of French and international calls for proposals and assessment guidelines, from which we created an overall typology of assessment criteria comprising nine domains relevance to the call for proposals, usefulness, originality, innovativeness, methodology, feasibility, funding, ethical aspects, and writing of the grant application. We then performed a qualitative study of reviewer practices, particularly regarding the use of assessment criteria, among reviewers of the French Academic Hospital Research Grant Agencies (Programmes Hospitaliers de Recherche Clinique, PHRCs). Semi-structured interviews and observation sessions were conducted. Both the time spent assessing each grant application and the assessment methods varied across reviewers. The assessment criteria recommended by the PHRCs were listed by all reviewers as frequently evaluated and useful. However, use of the PHRC criteria was subjective and varied across reviewers. Some reviewers gave the same weight to each assessment criterion, whereas others considered originality to be the most important criterion (12/34), followed by methodology (10/34) and feasibility (4/34). Conceivably, this variability might adversely affect the reliability of the review process, and studies evaluating this hypothesis would be of interest. CONCLUSIONS: Variability across reviewers may result in mistrust among grant applicants about the review process. Consequently, ensuring transparency is of the utmost importance. Consistency in the review process could also be improved by providing common definitions for each assessment criterion and uniform requirements for grant application submissions. Further research is needed to assess the feasibility and acceptability of these measures. PMID- 23029387 TI - Lovastatin induces multiple stress pathways including LKB1/AMPK activation that regulate its cytotoxic effects in squamous cell carcinoma cells. AB - BACKGROUND: Cellular stress responses trigger signaling cascades that inhibit proliferation and protein translation to help alleviate the stress or if the stress cannot be overcome induce apoptosis. In recent studies, we demonstrated the ability of lovastatin, an inhibitor of mevalonate synthesis, to induce the Integrated Stress Response as well as inhibiting epidermal growth factor receptor (EGFR) activation. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluated the effects of lovastatin on the activity of the LKB1/AMPK pathway that is activated upon cellular energy shortage and can interact with the above pathways. In the squamous cell carcinoma (SCC) cell lines SCC9 and SCC25, lovastatin treatment (1-25 uM, 24 hrs) induced LKB1 and AMPK activation similar to metformin (1-10 mM, 24 hrs), a known inducer of this pathway. Lovastatin treatment impaired mitochondrial function and also decreased cellular ADP/ATP ratios, common triggers of LKB1/AMPK activation. The cytotoxic effects of lovastatin were attenuated in LKB1 null MEFs indicating a role for this pathway in regulating lovastatin-induced cytotoxicity. Of clinical relevance, lovastatin induces synergistic cytotoxicity in combination with the EGFR inhibitor gefitinib. In LKB1 deficient (A549, HeLa) and expressing (SCC9, SCC25) cell lines, metformin enhanced gefitinib cytotoxicity only in LKB1 expressing cell lines while both groups showed synergistic cytotoxic effects with lovastatin treatments. Furthermore, the combination of lovastatin with gefitinib induced a potent apoptotic response without significant induction of autophagy that is often induced during metabolic stress inhibiting cell death. CONCLUSION/SIGNIFICANCE: Thus, targeting multiple metabolic stress pathways including the LKB1/AMPK pathway enhances lovastatin's ability to synergize with gefitinib in SCC cells. PMID- 23029388 TI - Interaction between lysophosphatidic acid, prostaglandins and the endocannabinoid system during the window of implantation in the rat uterus. AB - Bioactive lipid molecules as lysophosphatidic acid (LPA), prostaglandins (PG) and endocannabinoids are important mediators of embryo implantation. Based on previous published data we became interested in studying the interaction between these three groups of lipid derivatives in the rat uterus during the window of implantation. Thus, we adopted a pharmacological approach in vitro using LPA, DGPP (a selective antagonist of LPA3, an LPA receptor), endocannabinoids' receptor selective antagonists (AM251 and AM630) and non selective (indomethacin) and selective (NS-398) inhibitors of cyclooxygenase-1 and 2 enzymes. Cyclooxygenase isoforms participate in prostaglandins' synthesis. The incubation of the uterus from rats pregnant on day 5 of gestation (implantation window) with LPA augmented the activity and the expression of fatty acid amide hydrolase, the main enzyme involved in the degradation of endocannabinoids in the rodent uteri, suggesting that LPA decreased endocannabinoids' levels during embryo implantation. It has been reported that high endocannabinoids are deleterious for implantation. Also, LPA increased PGE2 production and cyclooxygenase-2 expression. The incubation of LPA with indomethacin or NS-398 reversed the increment in PGE2 production, suggesting that cyclooxygenase-2 was the isoform involved in LPA effect. PGs are important mediators of decidualization and vascularization at the implantation sites. All these effects were mediated by LPA3, as the incubation with DGPP completely reversed LPA stimulatory actions. Besides, we also observed that endocannabinoids mediated the stimulatory effect of LPA on cyclooxygenase-2 derived PGE2 production, as the incubation of LPA with AM251 or AM630 completely reversed LPA effect. Also, LPA augmented via LPA3 decidualization and vascularization markers. Overall, the results presented here demonstrate the participation of LPA3 in the process of implantation through the interaction with other groups of lipid molecules, prostaglandins and endocannabinoids, which prepare the uterine milieu for embryo invasion during the window of implantation. PMID- 23029389 TI - Mild cognitive impairment predicts institutionalization among older men: a population-based cohort study. AB - BACKGROUND: There is a lack of evidence on the contribution of mild cognitive impairment (MCI) to institutionalization in older adults. This study aimed to evaluate a range of risk factors including MCI of institutionalization in older men. METHODS: Men aged >=70 years (n = 1705), participating in the Concord Health and Ageing in Men Project, Sydney, Australia were studied. Participants completed self-reported questionnaires and underwent comprehensive clinical assessments during 2005-2007. Institutionalization was defined as entry into a nursing home facility or hostel at any time over an average of 5 years of follow-up. Cox regression analysis was conducted to generate hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: A total of 125 (7.3%) participants were institutionalized. Piecewise Cox proportional models were generated and divided at 3.4 years (1250 days) of follow-up due to violation of the proportional hazards assumption for the association between MCI and institutionalization (chi(2) = 6.44, p = 0.01). Dementia, disability in Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL), poor grip strength, few social interactions, being a Non-English speaking immigrant and age were predictive of institutionalization during both time periods, whereas MCI (HR = 4.39, 95%CI 2.17-8.87) only predicted institutionalization in the period beyond 3.4 years of follow-up. Being married (HR = 0.42, 95%CI: 0.24-0.72) was protective only during the period after 3.4 years of follow-up. DISCUSSION: In this study, the strongest predictors of institutionalization were dementia, MCI, ADL and IADL disability. MCI was not a predictor of early institutionalization but became a significant predictor beyond 3.4 years of follow-up. PMID- 23029390 TI - 11,12-EET stimulates the association of BK channel alpha and beta(1) subunits in mitochondria to induce pulmonary vasoconstriction. AB - In the systemic circulation, 11,12-epoxyeicosatrienoic acid (11,12-EET) elicits nitric oxide (NO)- and prostacyclin-independent vascular relaxation, partially through the activation of large conductance Ca(2+)-activated potassium (BK) channels. However, in the lung 11,12-EET contributes to hypoxia-induced pulmonary vasoconstriction. Since pulmonary artery smooth muscle cells also express BK channels, we assessed the consequences of BKbeta(1) subunit deletion on pulmonary responsiveness to 11,12-EET as well as to acute hypoxia. In buffer-perfused mouse lungs, hypoxia increased pulmonary artery pressure and this was significantly enhanced in the presence of NO synthase (NOS) and cyclooxygenase (COX) inhibitors. Under these conditions the elevation of tissue EET levels using an inhibitor of the soluble epoxide hydrolase (sEH-I), further increased the hypoxic contraction. Direct administration of 11,12-EET also increased pulmonary artery pressure, and both the sEH-I and 11,12-EET effects were prevented by iberiotoxin and absent in BKbeta(1)(-/-) mice. In pulmonary artery smooth muscle cells treated with NOS and COX inhibitors and loaded with the potentiometric dye, di-8 ANEPPS, 11,12-EET induced depolarization while the BK channel opener NS1619 elicited hyperpolarization indicating there was no effect of the EET on classical plasma membrane BK channels. In pulmonary artery smooth muscle cells a subpopulation of BK channels is localized in mitochondria. In these cells, 11,12 EET elicited an iberiotoxin-sensitive loss of mitochondrial membrane potential (JC-1 fluorescence) leading to plasma membrane depolarization, an effect not observed in BKbeta(1)(-/-) cells. Mechanistically, stimulation with 11,12-EET time-dependently induced the association of the BK alpha and beta(1) subunits. Our data indicate that in the absence of NO and prostacyclin 11,12-EET contributes to pulmonary vasoconstriction by stimulating the association of the alpha and beta(1) subunits of mitochondrial BK channels. The 11,12-EET-induced activation of BK channels results in loss of the mitochondrial membrane potential and depolarization of the pulmonary artery smooth muscle cells. PMID- 23029391 TI - Differential expression of anthocyanin biosynthetic genes and transcription factor PcMYB10 in pears (Pyrus communis L.). AB - Anthocyanin biosynthesis in various plants is affected by environmental conditions and controlled by the transcription level of the corresponding genes. In pears (Pyrus communis cv. 'Wujiuxiang'), anthocyanin biosynthesis is significantly induced during low temperature storage compared with that at room temperature. We further examined the transcriptional levels of anthocyanin biosynthetic genes in 'Wujiuxiang' pears during developmental ripening and temperature-induced storage. The expression of genes that encode flavanone 3 hydroxylase, dihydroflavonol 4-reductase, anthocyanidin synthase, UDP-glucose: flavonoid 3-O-glucosyltransferase, and R2R3 MYB transcription factor (PcMYB10) was strongly positively correlated with anthocyanin accumulation in 'Wujiuxiang' pears in response to both developmental and cold-temperature induction. Hierarchical clustering analysis revealed the expression patterns of the set of target genes, of which PcMYB10 and most anthocyanin biosynthetic genes were related to the same cluster. The present work may help explore the molecular mechanism that regulates anthocyanin biosynthesis and its response to abiotic stress at the transcriptional level in plants. PMID- 23029392 TI - Estrogen and progesterone regulate p27kip1 levels via the ubiquitin-proteasome system: pathogenic and therapeutic implications for endometrial cancer. AB - The levels of proteins that control the cell cycle are regulated by ubiquitin mediated degradation via the ubiquitin-proteasome system (UPS) by substrate specific E3 ubiquitin ligases. The cyclin-dependent kinase inhibitor, p27kip1 (p27), that blocks the cell cycle in G1, is ubiquitylated by the E3 ligase SCF Skp2/Cks1 for degradation by the UPS. In turn, Skp2 and Cks1 are ubiquitylated by the E3 ligase complex APC/Cdh1 for destruction thereby maintaining abundant levels of nuclear p27. We previously showed that perpetual proteasomal degradation of p27 is an early event in Type I endometrial carcinogenesis (ECA), an estrogen (E2)-induced cancer. The present studies demonstrate that E2 stimulates growth of ECA cell lines and normal primary endometrial epithelial cells (EECs) and induces MAPK-ERK1/2-dependent phosphorylation of p27 on Thr187, a prerequisite for p27 ubiquitylation by nuclear SCF-Skp2/Cks1 and subsequent degradation. In addition, E2 decreases the E3 ligase [APC]Cdh1 leaving Skp2 and Cks1 intact to cause p27 degradation. Furthermore, knocking-down Skp2 prevents E2 induced p27 degradation and growth stimulation suggesting that the pathogenesis of E2-induced ECA is dependent on Skp2-mediated degradation of p27. Conversely, progesterone (Pg) as an inhibitor of endometrial proliferation increases nuclear p27 and Cdh1 in primary EECs and ECA cells. Pg, also increases Cdh1 binding to APC to form the active E3ligase. Knocking-down Cdh1 obviates Pg-induced stabilization of p27 and growth inhibition. Notably, neither E2 nor Pg affected transcription of Cdh1, Skp2, Cks1 nor p27. These studies provide new insights into hormone regulation of cell proliferation through the UPS. The data implicates that preventing nuclear p27 degradation by blocking Skp2/Cks1-mediated degradation of p27 or increasing Cdh1 to mediate degradation of Skp2-Cks1 are potential strategies for the prevention and treatment of ECA. PMID- 23029393 TI - T-cell phenotypes, apoptosis and inflammation in HIV+ patients on virologically effective cART with early atherosclerosis. AB - OBJECTIVE: We investigated the potential relationship between T-cell phenotype, inflammation, endotoxemia, and atherosclerosis evaluated by carotid intima-media thickness (IMT) in a cohort of HIV-positive patients undergoing long-term virologically suppressive combination antiretroviral therapy (cART). DESIGN: We studied 163 patients receiving virologically suppressive cART. METHODS: We measured IMT (carotid ultrasound); CD4+/CD8+ T-cell activation (CD38, CD45R0), differentiation (CD127), apoptosis (CD95), and senescence (CD28, CD57) (flow cytometry); plasma sCD14, IL-6, TNF- alpha, sVCAM-1, hs-CRP, anti-CMV IgG (ELISA); LPS (LAL). The results were compared by Mann-Whitney, Kruskal-Wallis or Chi-square tests, and factors associated with IMT were evaluated by multivariable logistic regression. RESULTS: Of 163 patients, 112 demonstrated normal IMT (nIMT), whereas 51 (31.3%) had pathological IMT (pIMT: >=1 mm). Of the patients with pIMT, 22 demonstrated an increased IMT (iIMT), and 29 were shown to have plaques. These patient groups had comparable nadir and current CD4+, VLs and total length of time on cART. Despite similar proportions of CD38-expressing CD8+ cells (p = .95), pIMT patients exhibited higher activated memory CD8+CD38+CD45R0+ cells (p = .038) and apoptotic CD4+CD95+ (p = .01) and CD8+CD95+ cells (p = .003). In comparison to nIMT patients, iIMT patients tended to have lower numbers of early differentiated CD28+CD57- memory CD4+ (p = .048) and CD28-CD57-CD8+ cells (p = .006), both of which are associated with a higher proliferative potential. Despite no differences in plasma LPS levels, pIMT patients showed significantly higher circulating levels of sCD14 than did nIMT patients (p = .046). No differences in anti-CMV IgG was shown. Although circulating levels of sCD14 seemed to be associated with a risk of ATS in an unadjusted analysis, this effect was lost after adjusting for classical cardiovascular predictors. CONCLUSIONS: Despite the provision of full viral suppression by cART, a hyperactivated, pro-apoptotic T-cell profile characterizes HIV-infected patients with early vascular damage, for whom the potential contribution of subclinical endotoxemia and anti-CMV immunity should be investigated further. PMID- 23029394 TI - Spatial distribution and interspecific associations of tree species in a tropical seasonal rain forest of China. AB - Studying the spatial pattern and interspecific associations of plant species may provide valuable insights into processes and mechanisms that maintain species coexistence. Point pattern analysis was used to analyze the spatial distribution patterns of twenty dominant tree species, their interspecific spatial associations and changes across life stages in a 20-ha permanent plot of seasonal tropical rainforest in Xishuangbanna, China, to test mechanisms maintaining species coexistence. Torus-translation tests were used to quantify positive or negative associations of the species to topographic habitats. The results showed: (1) fourteen of the twenty tree species were negatively (or positively) associated with one or two of the topographic variables, which evidences that the niche contributes to the spatial pattern of these species. (2) Most saplings of the study species showed a significantly clumped distribution at small scales (0 10 m) which was lost at larger scales (10-30 m). (3) The degree of spatial clumping deceases from saplings, to poles, to adults indicates that density dependent mortality of the offspring is ubiquitous in species. (4) It is notable that a high number of positive small-scale interactions were found among the twenty species. For saplings, 42.6% of all combinations of species pairs showed positive associations at neighborhood scales up to five meters, but only 38.4% were negative. For poles and adults, positive associations at these distances still made up 45.5% and 29.5%, respectively. In conclusion, there is considerable evidence for the presence of positive interactions among the tree species, which suggests that species herd protection may occur in our plot. In addition, niche assembly and limited dispersal (likely) contribute to the spatial patterns of tree species in the tropical seasonal rain forest in Xishuangbanna, China. PMID- 23029395 TI - The five-point test: reliability, validity and normative data for children and adults. AB - The present study provides normative data from a sample of 257 healthy children and 608 adults on a modified version of the Five-Point Test (5PT). The 5PT is a structured and standardized test measuring figural fluency functions. Interrater reliability, test-retest-reliability and construct validity of this measure were analyzed. The sensitivity of the task for cognitive disturbances of patients with neurological diseases was proven by analyzing the test performance in the 5PT of patients with Parkinson's disease. Finally, normative data stratified by age and corrected for education level is provided. The results of the present study confirm the value of the 5PT in the measurement of figural fluency functions in clinical examination and neuropsychological research. PMID- 23029396 TI - Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal. AB - Dysregulation of the sonic hedgehog (Shh) signaling pathway has been associated with cancer stem cells (CSC) and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN), an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4) as well as PDGFRalpha and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway. Thus Sulforaphane potentially represents an inexpensive, safe and effective alternative for the management of pancreatic cancer. PMID- 23029397 TI - Amplified and homozygously deleted genes in glioblastoma: impact on gene expression levels. AB - BACKGROUND: Glioblastoma multiforme (GBM) displays multiple amplicons and homozygous deletions that involve relevant pathogenic genes and other genes whose role remains unknown. METHODOLOGY: Single-nucleotide polymorphism (SNP)-arrays were used to determine the frequency of recurrent amplicons and homozygous deletions in GBM (n = 46), and to evaluate the impact of copy number alterations (CNA) on mRNA levels of the genes involved. PRINCIPAL FINDINGS: Recurrent amplicons were detected for chromosomes 7 (50%), 12 (22%), 1 (11%), 4 (9%), 11 (4%), and 17 (4%), whereas homozygous deletions involved chromosomes 9p21 (52%) and 10q (22%). Most genes that displayed a high correlation between DNA CNA and mRNA levels were coded in the amplified chromosomes. For some amplicons the impact of DNA CNA on mRNA expression was restricted to a single gene (e.g., EGFR at 7p11.2), while for others it involved multiple genes (e.g., 11 and 5 genes at 12q14.1-q15 and 4q12, respectively). Despite homozygous del(9p21) and del(10q23.31) included multiple genes, association between these DNA CNA and RNA expression was restricted to the MTAP gene. CONCLUSIONS: Overall, our results showed a high frequency of amplicons and homozygous deletions in GBM with variable impact on the expression of the genes involved, and they contributed to the identification of other potentially relevant genes. PMID- 23029398 TI - Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats. AB - BACKGROUND: Ischemic postconditioning (IPOC), or relief of ischemia in a stuttered manner, has emerged as an innovative treatment strategy to reduce programmed cell death, attenuate ischemic injuries, and improve neurological outcomes. However, the mechanisms involved have not been completely elucidated. Recent studies indicate that autophagy is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. This study aims to determine the role of autophagy in IPOC-induced neuroprotection against focal cerebral ischemia in rats. METHODOLOGY/PRINCIPAL FINDINGS: A focal cerebral ischemic model with permanent middle cerebral artery (MCA) occlusion plus transient common carotid artery (CCA) occlusion was established. The autophagosomes and the expressions of LC3/Beclin 1/p62 were evaluated for their contribution to the activation of autophagy. We found that autophagy was markedly induced with the upregulation of LC3/Beclin 1 and downregulation of p62 in the penumbra at various time intervals following ischemia. IPOC, performed at the onset of reperfusion, reduced infarct size, mitigated brain edema, inhibited the induction of LC3/Beclin 1 and reversed the reduction of p62 simultaneously. Rapamycin, an inducer of autophagy, partially reversed all the aforementioned effects induced by IPOC. Conversely, autophagy inhibitor 3-methyladenine (3-MA) attenuated the ischemic insults, inhibited the activation of autophagy, and elevated the expression of anti-apoptotic protein Bcl-2, to an extent comparable to IPOC. CONCLUSIONS/SIGNIFICANCE: The present study suggests that inhibition of the autophagic pathway plays a key role in IPOC induced neuroprotection against focal cerebral ischemia. Thus, pharmacological inhibition of autophagy may provide a novel therapeutic strategy for the treatment of stroke. PMID- 23029399 TI - Pno1 tissue-specific expression and its functions related to the immune responses and proteasome activities. AB - Pno1 is a protein that plays a role in proteasome and ribosome neogenesis in yeast. So far, its functions in mammalian cells have not been investigated. To understand its function in mammals, we performed in situ hybridization analysis of Pno1 expression in different development stages and generated Pno1 gene knockout (KO) and transgenic (Tg) mice lineages. The results showed early lethality of homozygous Pno1 KO lineage caused, as demonstrated in parallel by ex vivo experiments, by arrest of embryo development before compaction stage. Though, heterozygous (HET) mice with 50% of normal Pno1 mRNA concentration were fertile and showed no obvious anomalies. The lymphoid organs of HET mice were normal in size, weight and cellularity, with normal T and B cell subpopulations. TCR-triggered activation and proliferation of HET T cells were normal. Proteasome activities in HET organs were uncompromised. Tg mice with actin promoter-driven Pno1 expression were also fertile, with no apparent anomalies, although they expressed 2-5-fold higher Pno1 mRNA levels. The lymphoid organs of Tg mice were of normal size, weight and cellularity with normal T and B cell sub-populations. TCR-triggered activation and proliferation of Tg T cells were normal. Tg organs and tissues presented normal proteasome activity as did their wild type counterparts. Tagged Pno1 over-expression in L cells and density gradient fractionation established that Pno1 existed in large complexes with sedimentation rates between 20S and 26S, bigger than mature 26S proteasomes. Pno1 in fractions did not coincide with 40S or 60S ribosome subunits. Our study indicates that Pno1 is essential for cellular functions, but only a small percentage of its normal level is sufficient, and excessive amounts are neither harmful nor useful. The nature of the large complexes it associates with remains to be identified, but it is certain that they are not mature proteasomes or ribosomes. PMID- 23029400 TI - Discovery and characterization of human exonic transcriptional regulatory elements. AB - We sought exonic transcriptional regulatory elements by shotgun cloning human cDNA fragments into luciferase reporter vectors and measuring the resulting expression levels in liver cells. We uncovered seven regulatory elements within coding regions and three within 3' untranslated regions (UTRs). Two of the putative regulatory elements were enhancers and eight were silencers. The regulatory elements were generally but not consistently evolutionarily conserved and also showed a trend toward decreased population diversity. Furthermore, the exonic regulatory elements were enriched in known transcription factor binding sites (TFBSs) and were associated with several histone modifications and transcriptionally relevant chromatin. Evidence was obtained for bidirectional cis regulation of a coding region element within a tubulin gene, TUBA1B, by the transcription factors PPARA and RORA. We estimate that hundreds of exonic transcriptional regulatory elements exist, an unexpected finding that highlights a surprising multi-functionality of sequences in the human genome. PMID- 23029401 TI - Alterations in bone and erythropoiesis in hemolytic anemia: comparative study in bled, phenylhydrazine-treated and Plasmodium-infected mice. AB - Sustained erythropoiesis and concurrent bone marrow hyperplasia are proposed to be responsible for low bone mass density (BMD) in chronic hemolytic pathologies. As impaired erythropoiesis is also frequent in these conditions, we hypothesized that free heme may alter marrow and bone physiology in these disorders. Bone status and bone marrow erythropoiesis were studied in mice with hemolytic anemia (HA) induced by phenylhydrazine (PHZ) or Plasmodium infection and in bled mice. All treatments resulted in lower hemoglobin concentrations, enhanced erythropoiesis in the spleen and reticulocytosis. The anemia was severe in mice with acute hemolysis, which also had elevated levels of free heme and ROS. No major changes in cellularity and erythroid cell numbers occurred in the bone marrow of bled mice, which generated higher numbers of erythroid blast forming units (BFU-E) in response to erythropoietin. In contrast, low numbers of bone marrow erythroid precursors and BFU-E and low concentrations of bone remodelling markers were measured in mice with HA, which also had blunted osteoclastogenesis, in opposition to its enhancement in bled mice. The alterations in bone metabolism were accompanied by reduced trabecular bone volume, enhanced trabecular spacing and lower trabecular numbers in mice with HA. Taken together our data suggests that hemolysis exerts distinct effects to bleeding in the marrow and bone and may contribute to osteoporosis through a mechanism independent of the erythropoietic stress. PMID- 23029402 TI - The effect of combined exposure of 900 MHz radiofrequency fields and doxorubicin in HL-60 cells. AB - Human promyelocytic leukemia HL-60 cells were pre-exposed to non-ionizing 900 MHz radiofrequency fields (RF) at 12 uW/cm(2) power density for 1 hour/day for 3 days and then treated with a chemotherapeutic drug, doxorubicin (DOX, 0.125 mg/L). Several end-points related to toxicity, viz., viability, apoptosis, mitochondrial membrane potential (MMP), intracellular free calcium (Ca(2+)) and Ca(2+)-Mg(2+) ATPase activity were measured. The results obtained in un-exposed and sham exposed control cells were compared with those exposed to RF alone, DOX alone and RF+DOX. The results indicated no significant differences between un-exposed, sham exposed control cells and those exposed to RF alone while treatment with DOX alone showed a significant decrease in viability, increased apoptosis, decreased MMP, increased Ca(2+) and decreased Ca(2+)-Mg(2+-)ATPase activity. When the latter results were compared with cells exposed RF+DOX, the data showed increased cell proliferation, decreased apoptosis, increased MMP, decreased Ca(2+) and increased Ca(2+)-Mg(2+)-ATPase activity. Thus, RF pre-exposure appear to protect the HL-60 cells from the toxic effects of subsequent treatment with DOX. These observations were similar to our earlier data which suggested that pre-exposure of mice to 900 MHz RF at 120 uW/cm(2) power density for 1 hours/day for 14 days had a protective effect in hematopoietic tissue damage induced by subsequent gamma-irradiation. PMID- 23029403 TI - Comparison of optical and power Doppler ultrasound imaging for non-invasive evaluation of arsenic trioxide as a vascular disrupting agent in tumors. AB - Small animal imaging provides diverse methods for evaluating tumor growth and acute response to therapy. This study compared the utility of non-invasive optical and ultrasound imaging to monitor growth of three diverse human tumor xenografts (brain U87-luc-mCherry, mammary MCF7-luc-mCherry, and prostate PC3 luc) growing in nude mice. Bioluminescence imaging (BLI), fluorescence imaging (FLI), and Power Doppler ultrasound (PD US) were then applied to examine acute vascular disruption following administration of arsenic trioxide (ATO).During initial tumor growth, strong correlations were found between manual caliper measured tumor volume and FLI intensity, BLI intensity following luciferin injection, and traditional B-mode US. Administration of ATO to established U87 tumors caused significant vascular shutdown within 2 hrs at all doses in the range 5 to 10 mg/kg in a dose dependant manner, as revealed by depressed bioluminescent light emission. At lower doses substantial recovery was seen within 4 hrs. At 8 mg/kg there was >85% reduction in tumor vascular perfusion, which remained depressed after 6 hrs, but showed some recovery after 24 hrs. Similar response was observed in MCF7 and PC3 tumors. Dynamic BLI and PD US each showed similar duration and percent reductions in tumor blood flow, but FLI showed no significant changes during the first 24 hrs.The results provide further evidence for comparable utility of optical and ultrasound imaging for monitoring tumor growth, More specifically, they confirm the utility of BLI and ultrasound imaging as facile assays of the vascular disruption in solid tumors based on ATO as a model agent. PMID- 23029404 TI - Sex-dependent alterations in social behaviour and cortical synaptic activity coincide at different ages in a model of Alzheimer's disease. AB - Besides memory deficits, Alzheimer's disease (AD) patients suffer from neuropsychiatric symptoms, including alterations in social interactions, which are subject of a growing number of investigations in transgenic models of AD. Yet the biological mechanisms underlying these behavioural alterations are poorly understood. Here, a social interaction paradigm was used to assess social dysfunction in the triple-transgenic mouse model of AD (3xTg-AD). We observed that transgenic mice displayed dimorphic behavioural abnormalities at different ages. Social disinhibition was observed in 18 months old 3xTg-AD males compared to age and sex-matched control mice. In 3xTg-AD females, social disinhibition was present at 12 months followed by reduced social interactions at 18 months. These dimorphic behavioural alterations were not associated with alterations in AD neuropathological markers such as Abeta or tau levels in the frontal cortex. However, patch-clamp recordings revealed that enhanced social interactions coincided temporally with an increase in both excitatory and inhibitory basal synaptic inputs to layer 2-3 pyramidal neurons in the prefrontal cortex. These findings uncover a novel pattern of occurrence of psychiatric-like symptoms between sexes in an AD model. Our results also reveal that functional alterations in synapse activity appear as a potentially significant substrate underlying behavioural correlates of AD. PMID- 23029405 TI - Genetic variation in the TNF gene is associated with susceptibility to severe sepsis, but not with mortality. AB - BACKGROUND: Tumor necrosis factor (TNF) and TNF receptor superfamily (TNFR) mediated immune response play an essential role in the pathogenesis of severe sepsis. Studies examining associations of TNF and lymphotoxin-alpha (LTA) single nucleotide polymorphisms (SNPs) with severe sepsis have produced conflicting results. The objective of this study was to investigate whether genetic variation in TNF, LTA, TNFRSF1A and TNFRSF1B was associated with susceptibility to or death from severe sepsis in Chinese Han population. METHODOLOGY/PRINCIPAL FINDINGS: Ten SNPs in TNF, LTA, TNFRSF1A and TNFRSF1B were genotyped in samples of patients with severe sepsis (n = 432), sepsis (n = 384) and healthy controls (n = 624). Our results showed that rs1800629, a SNP in the promoter region of TNF, was significantly associated with risk for severe sepsis. The minor allele frequency of rs1800629 was significantly higher in severe sepsis patients than that in both healthy controls (P(adj) = 0.00046, odds ratio (OR)(adj) = 1.92) and sepsis patients (P(adj) = 0.002, OR(adj) = 1.56). Further, we investigated the correlation between rs1800629 genotypes and TNF-alpha concentrations in peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to lipopolysaccharides (LPS) ex vivo, and the association between rs1800629 and TNF alpha serum levels in severe sepsis patients. After exposure to LPS, the TNF alpha concentration in culture supernatants of PBMCs was significantly higher in the subjects with AA+AG genotypes than that with GG genotype (P = 0.007). Moreover, in patients with severe sepsis, individuals with AA+AG genotypes had significantly higher TNF-alpha serum concentrations than those with GG genotype (P(adj) = 0.02). However, there were no significant associations between SNPs in the four candidate genes and 30 day mortality for patients with severe sepsis. CONCLUSIONS/SIGNIFICANCE: Our findings suggested that the functional TNF gene SNP rs1800629 was strongly associated with susceptibility to severe sepsis, but not with lethality in Chinese Han population. PMID- 23029406 TI - Waking and sleeping following water deprivation in the rat. AB - Wake-sleep (W-S) states are affected by thermoregulation. In particular, REM sleep (REMS) is reduced in homeotherms under a thermal load, due to an impairment of hypothalamic regulation of body temperature. The aim of this work was to assess whether osmoregulation, which is regulated at a hypothalamic level, but, unlike thermoregulation, is maintained across the different W-S states, could influence W-S occurrence. Sprague-Dawley rats, kept at an ambient temperature of 24 degrees C and under a 12 h?12 h light-dark cycle, were exposed to a prolonged osmotic challenge of three days of water deprivation (WD) and two days of recovery in which free access to water was restored. Two sets of parameters were determined in order to assess: i) the maintenance of osmotic homeostasis (water and food consumption; changes in body weight and fluid composition); ii) the effects of the osmotic challenge on behavioral states (hypothalamic temperature (Thy), motor activity, and W-S states). The first set of parameters changed in WD as expected and control levels were restored on the second day of recovery, with the exception of urinary Ca(++) that almost disappeared in WD, and increased to a high level in recovery. As far as the second set is concerned, WD was characterized by the maintenance of the daily oscillation of Thy and by a decrease in activity during the dark periods. Changes in W-S states were small and mainly confined to the dark period: i) REMS slightly decreased at the end of WD and increased in recovery; ii) non-REM sleep (NREMS) increased in both WD and recovery, but EEG delta power, a sign of NREMS intensity, decreased in WD and increased in recovery. Our data suggest that osmoregulation interferes with the regulation of W-S states to a much lesser extent than thermoregulation. PMID- 23029407 TI - Cytotoxicity analysis of three Bacillus thuringiensis subsp. israelensis delta endotoxins towards insect and mammalian cells. AB - Three members of the delta-endotoxin group of toxins expressed by Bacillus thuringiensis subsp. israelensis, Cyt2Ba, Cry4Aa and Cry11A, were individually expressed in recombinant acrystalliferous B. thuringiensis strains for in vitro evaluation of their toxic activities against insect and mammalian cell lines. Both Cry4Aa and Cry11A toxins, activated with either trypsin or Spodoptera frugiperda gastric juice (GJ), resulted in different cleavage patterns for the activated toxins as seen by SDS-PAGE. The GJ-processed proteins were not cytotoxic to insect cell cultures. On the other hand, the combination of the trypsin-activated Cry4Aa and Cry11A toxins yielded the highest levels of cytotoxicity to all insect cells tested. The combination of activated Cyt2Ba and Cry11A also showed higher toxic activity than that of toxins activated individually. When activated Cry4Aa, Cry11A and Cyt2Ba were used simultaneously in the same assay a decrease in toxic activity was observed in all insect cells tested. No toxic effect was observed for the trypsin-activated Cry toxins in mammalian cells, but activated Cyt2Ba was toxic to human breast cancer cells (MCF 7) when tested at 20 ug/mL. PMID- 23029408 TI - Randomized, single blind, controlled trial to evaluate the prime-boost strategy for pneumococcal vaccination in renal transplant recipients. AB - Renal transplant recipients are at increased risk of developing invasive pneumococcal diseases but may have poor response to the 23-valent pneumococcal polysaccharide vaccine (PPV). It may be possible to enhance immunogenicity by priming with 7-valent pneumococcal conjugate vaccine (7vPnC) and boosting with PPV 1 year later. In a randomized single-blind, controlled study, adult recipients of renal transplants received either 7nPVC or PPV followed by PPV 1 year later. The vaccine response was defined as 2-fold increase in antibody concentration from baseline and an absolute post-vaccination values >=1 ug/ml. The primary endpoint was vaccine response of the primed group (7vPnC/PPV) compared with single PPV vaccination. Antibody concentrations for 10 serotypes were measured at baseline, 8 weeks after first vaccination, before second vaccination, and 8 weeks after second vaccination. Of 320 screened patients, 80 patients were randomized and 62 completed the study. Revaccination with PPV achieved no significant increase of immune response in the 7vPnC/PPV group compared with the single PPV recipients A response to at least 1 serotype was seen in 77.1% of patients who received 7vPnC and 93.1% of patients who received PPV (P = 0.046). After second vaccination response to at least 1 serotype was seen in 87.5% patients of 7vPnC/PPV group and 87.1% patients of PPV group (non significant p). The median number of serotypes eliciting a response was 3.5 (95% CI 2.5-4.5) in the 7vPnC/PPV group versus 5 (95% CI 3.9-6.1) in the PPV group (non-significant p). Immunogenicity of pneumococcal vaccination was not enhanced by the prime-boost strategy compared with vaccination with PPV alone. Administration of a single dose of PPV should continue to be the standard of care for adult recipients of renal transplants. TRIAL REGISTRATION: EudraCT 2007 004590-25. PMID- 23029410 TI - The resilience and resistance of an ecosystem to a collapse of diversity. AB - Diversity is expected to increase the resilience of ecosystems. Nevertheless, highly diverse ecosystems have collapsed, as did Lake Victoria's ecosystem of cichlids or Caribbean coral reefs. We try to gain insight to this paradox, by analyzing a simple model of a diverse community where each competing species inflicts a small mortality pressure on an introduced predator. High diversity strengthens this feedback and prevents invasion of the introduced predator. After a gradual loss of native species, the introduced predator can escape control and the system collapses into a contrasting, invaded, low-diversity state. Importantly, we find that a diverse system that has high complementarity gains in resilience, whereas a diverse system with high functional redundancy gains in resistance. Loss of resilience can display early-warning signals of a collapse, but loss of resistance not. Our results emphasize the need for multiple approaches to studying the functioning of ecosystems, as managing an ecosystem requires understanding not only the threats it is vulnerable to but also pressures it appears resistant to. PMID- 23029409 TI - The Relationship between fenestrations, sieve plates and rafts in liver sinusoidal endothelial cells. AB - Fenestrations are transcellular pores in endothelial cells that facilitate transfer of substrates between blood and the extravascular compartment. In order to understand the regulation and formation of fenestrations, the relationship between membrane rafts and fenestrations was investigated in liver sinusoidal endothelial cells where fenestrations are grouped into sieve plates. Three dimensional structured illumination microscopy, scanning electron microscopy, internal reflectance fluorescence microscopy and two-photon fluorescence microscopy were used to study liver sinusoidal endothelial cells isolated from mice. There was an inverse distribution between sieve plates and membrane rafts visualized by structured illumination microscopy and the fluorescent raft stain, Bodipy FL C5 ganglioside GM1. 7-ketocholesterol and/or cytochalasin D increased both fenestrations and lipid-disordered membrane, while Triton X-100 decreased both fenestrations and lipid-disordered membrane. The effects of cytochalasin D on fenestrations were abrogated by co-administration of Triton X-100, suggesting that actin disruption increases fenestrations by its effects on membrane rafts. Vascular endothelial growth factor (VEGF) depleted lipid-ordered membrane and increased fenestrations. The results are consistent with a sieve-raft interaction, where fenestrations form in non-raft lipid-disordered regions of endothelial cells once the membrane-stabilizing effects of actin cytoskeleton and membrane rafts are diminished. PMID- 23029411 TI - Profiling the anaerobic response of C. elegans using GC-MS. AB - The nematode Caenorhabditis elegans is a model organism that has seen extensive use over the last four decades in multiple areas of investigation. In this study we explore the response of the nematode Caenorhabditis elegans to acute anoxia using gas-chromatography mass-spectrometry (GC-MS). We focus on the readily accessible worm exometabolome to show that C. elegans are mixed acid fermenters that utilize several metabolic pathways in unconventional ways to remove reducing equivalents - including partial reversal of branched-chain amino acid catabolism and a potentially novel use of the glyoxylate pathway. In doing so, we provide detailed methods for the collection and analysis of excreted metabolites that, with minimal adjustment, should be applicable to many other species. We also describe a procedure for collecting highly volatile compounds from C. elegans. We are distributing our mass spectral library in an effort to facilitate wider use of metabolomics. PMID- 23029412 TI - Particulate organic matter distribution along the lower Amazon River: addressing aquatic ecology concepts using fatty acids. AB - One of the greatest challenges in understanding the Amazon basin functioning is to ascertain the role played by floodplains in the organic matter (OM) cycle, crucial for a large spectrum of ecological mechanisms. Fatty acids (FAs) were combined with environmental descriptors and analyzed through multivariate and spatial tools (asymmetric eigenvector maps, AEM and principal coordinates of neighbor matrices, PCNM). This challenge allowed investigating the distribution of suspended particulate organic matter (SPOM), in order to trace its seasonal origin and quality, along a 800 km section of the Amazon river-floodplain system. Statistical analysis confirmed that large amounts of saturated FAs (15:0, 18:0, 24:0, 25:0 and 26:0), an indication of refractory OM, were concomitantly recorded with high pCO(2) in rivers, during the high water season (HW). Contrastingly, FAs marker which may be attributed in this ecosystem to aquatic plants (18:2omega6 and 18:3omega3) and cyanobacteria (16:1omega7), were correlated with higher O(2), chlorophyll a and pheopigments in floodplains, due to a high primary production during low waters (LW). Decreasing concentrations of unsaturated FAs, that characterize labile OM, were recorded during HW, from upstream to downstream. Furthermore, using PCNM and AEM spatial methods, FAs compositions of SPOM displayed an upstream-downstream gradient during HW, which was attributed to OM retention and the extent of flooded forest in floodplains. Discrimination of OM quality between the Amazon River and floodplains corroborate higher autotrophic production in the latter and transfer of OM to rivers at LW season. Together, these gradients demonstrate the validity of FAs as predictors of spatial and temporal changes in OM quality. These spatial and temporal trends are explained by 1) downstream change in landscape morphology as predicted by the River Continuum Concept; 2) enhanced primary production during LW when the water level decreased and its residence time increased as predicted by the Flood Pulse Concept. PMID- 23029413 TI - Burnt sugarcane harvesting - cardiovascular effects on a group of healthy workers, Brazil. AB - BACKGROUND: Brazil is the world's largest producer of sugarcane. Harvest is predominantly manual, exposing workers to health risks: intense physical exertion, heat, pollutants from sugarcane burning. DESIGN: Panel study to evaluate the effects of burnt sugarcane harvesting on blood markers and on cardiovascular system. METHODS: Twenty-eight healthy male workers, living in the countryside of Brazil were submitted to blood markers, blood pressure, heart rate variability, cardiopulmonary exercise testing, sympathetic nerve activity evaluation and forearm blood flow measures (venous occlusion plethysmography) during burnt sugarcane harvesting and four months later while they performed other activities in sugar cane culture. RESULTS: Mean participant age was 31 +/- 6.3 years, and had worked for 9.8 +/- 8.4 years on sugarcane work. Work during the harvest period was associated with higher serum levels of Creatine Kinase - 136.5 U/L (IQR: 108.5-216.0) vs. 104.5 U/L (IQR: 77.5-170.5), (p = 0.001); plasma Malondialdehyde-7.5 +/- 1.4 uM/dl vs. 6.9 +/- 1.0 uM/dl, (p = 0.058); Glutathione Peroxidase - 55.1 +/- 11.8 Ug/Hb vs. 39.5 +/- 9.5 Ug/Hb, (p<0.001); Glutathione Transferase- 3.4+/-1.3 Ug/Hb vs. 3.0 +/- 1.3 Ug/Hb, (p = 0.001); and 24-hour systolic blood pressure - 120.1 +/- 10.3 mmHg vs. 117.0 +/- 10.0 mmHg, (p = 0.034). In cardiopulmonary exercise testing, rest-to-peak diastolic blood pressure increased by 11.12 mmHg and 5.13 mmHg in the harvest and non-harvest period, respectively. A 10 miliseconds reduction in rMSSD and a 10 burst/min increase in sympathetic nerve activity were associated to 2.2 and 1.8 mmHg rises in systolic arterial pressure, respectively. CONCLUSION: Work in burnt sugarcane harvesting was associated with changes in blood markers and higher blood pressure, which may be related to autonomic imbalance. PMID- 23029415 TI - Assessment of algorithms for inferring positional weight matrix motifs of transcription factor binding sites using protein binding microarray data. AB - The new technology of protein binding microarrays (PBMs) allows simultaneous measurement of the binding intensities of a transcription factor to tens of thousands of synthetic double-stranded DNA probes, covering all possible 10-mers. A key computational challenge is inferring the binding motif from these data. We present a systematic comparison of four methods developed specifically for reconstructing a binding site motif represented as a positional weight matrix from PBM data. The reconstructed motifs were evaluated in terms of three criteria: concordance with reference motifs from the literature and ability to predict in vivo and in vitro bindings. The evaluation encompassed over 200 transcription factors and some 300 assays. The results show a tradeoff between how the methods perform according to the different criteria, and a dichotomy of method types. Algorithms that construct motifs with low information content predict PBM probe ranking more faithfully, while methods that produce highly informative motifs match reference motifs better. Interestingly, in predicting high-affinity binding, all methods give far poorer results for in vivo assays compared to in vitro assays. PMID- 23029414 TI - Association between chronic obstructive pulmonary disease and lung cancer: a case control study in Southern Chinese and a meta-analysis. AB - BACKGROUND: Lung cancer and chronic obstructive pulmonary disease (COPD) share a common risk factor in cigarette smoking and a large portion of patients with lung cancer suffer from COPD synchronously. We therefore hypothesized that COPD is an independent risk factor for lung cancer. Our aim was to investigate the intrinsic linkage of COPD (or emphysema, chronic bronchitis and asthma) and lung cancer. METHODS: The present hospital-based case-control study included 1,069 patients with newly diagnosed lung cancer and 1,132 age frequency matched cancer-free controls. The odds ratios (ORs) for the associations between each previous pulmonary disease and lung cancer were estimated with logistic regression models, adjusting for age, sex, family history of cancer, BMI and pack year smoking. In meta-analysis, the pooled effects of previous pulmonary diseases were analyzed with random effects models; and stratification analyses were conducted on smoking status and ethnicity. RESULTS: In the case-control study, previous COPD was associated with the odds for increased risk of lung cancer (OR = 1.29, 95% confidence interval [CI] = 1.00~1.68); so were emphysema (OR = 1.55, 95%CI = 1.03~2.32) and chronic bronchitis (OR = 1.22, 95%CI = 0.99~1.67); while asthma was associated with odds for decreased risk of lung cancer (OR = 0.29, 95%CI = 0.16~0.53). These associations were more pronounced in smokers (P<.05 for all strata), but not in non-smokers. In meta-analysis, 35 studies (22,010 cases and 44,438 controls) were identified. COPD was significantly associated with the odds for increased risk of lung cancer (pooled OR = 2.76; 95% CI = 1.85-4.11), so were emphysema (OR = 3.02; 95% CI = 2.41-3.79) and chronic bronchitis (OR = 1.88; 95% CI = 1.49-2.36); and these associations were more pronounced in smokers than in non-smokers (P<.001 respectively). No significant association was observed for asthma. CONCLUSION: Previous COPD could increase the risk of lung cancer, especially in smokers. PMID- 23029416 TI - Decreased Mdm2 expression inhibits tumor development and extends survival independent of Arf and dependent on p53. AB - Inactivation of the Arf-Mdm2-p53 tumor suppressor pathway is a necessary event for tumorigenesis. Arf controls Mdm2, which in turn regulates p53, but Arf and Mdm2 also have p53-independent functions that affect tumor development. Moreover, inhibition of oncogene-induced tumorigenesis relies on Arf and p53, but the requirements of Arf and p53 in tumor development initiated in the absence of overt oncogene overexpression and the role of Mdm2 in this process remain unclear. In a series of genetic experiments in mice with defined deficiencies in Arf, Mdm2 and/or p53, we show Mdm2 haploinsufficiency significantly delayed tumorigenesis in mice deficient in Arf and p53. Mdm2 heterozygosity significantly inhibited tumor development in the absence of Arf, and in contrast to Myc oncogene-driven cancer, this delay in tumorigenesis could not be rescued with the presence of one allele of Arf. Notably, Mdm2 haploinsufficieny blocked the accelerated tumor development in Arf deficient mice caused by p53 heterozygosity. However, tumorigenesis was not inhibited in Mdm2 heterozygous mice lacking both alleles of p53 regardless of Arf status. Surprisingly, loss of Arf accelerated tumor development in p53-null mice. Tumor spectrum was largely dictated by Arf and p53 status with Mdm2 haploinsufficiency only modestly altering the tumor type in some of the genotypes and not the number of primary tumors that arose. Therefore, the significant effects of Mdm2 haploinsufficiency on tumor latency were independent of Arf and required at least one allele of p53, and an Mdm2 deficiency had minor effects on the types of tumors that developed. These data also demonstrate that decreased levels of Mdm2 are protective in the presence of multiple genetic events in Arf and p53 genes that normally accelerate tumorigenesis. PMID- 23029418 TI - Amino acid repeats cause extraordinary coding sequence variation in the social amoeba Dictyostelium discoideum. AB - Protein sequences are normally the most conserved elements of genomes owing to purifying selection to maintain their functions. We document an extraordinary amount of within-species protein sequence variation in the model eukaryote Dictyostelium discoideum stemming from triplet DNA repeats coding for long strings of single amino acids. D. discoideum has a very large number of such strings, many of which are polyglutamine repeats, the same sequence that causes various human neurological disorders in humans, like Huntington's disease. We show here that D. discoideum coding repeat loci are highly variable among individuals, making D. discoideum a candidate for the most variable proteome. The coding repeat loci are not significantly less variable than similar non-coding triplet repeats. This pattern is consistent with these amino-acid repeats being largely non-functional sequences evolving primarily by mutation and drift. PMID- 23029417 TI - Silibinin attenuates sulfur mustard analog-induced skin injury by targeting multiple pathways connecting oxidative stress and inflammation. AB - Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD induced skin injuries, efficacy studies were carried out employing HD analog 2 chloroethyl ethyl sulfide (CEES)-induced injury biomarkers in skin cells and SKH 1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 uM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p<0.05) reversal in CEES-induced decrease in cell viability, apoptotic and necrotic cell death, DNA damage, and an increase in oxidative stress. Silibinin (1 mg) applied topically to mouse skin 30 min post-CEES exposure (2 mg), was effective in reversing CEES-induced increases in skin bi-fold (62%) and epidermal thickness (85%), apoptotic cell death (70%), myeloperoxidase activity (complete reversal), induction of iNOS, COX-2, and MMP-9 protein levels (>90%), and activation of transcription factors NF-kappaB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5 dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8 oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants. PMID- 23029419 TI - Long span DNA paired-end-tag (DNA-PET) sequencing strategy for the interrogation of genomic structural mutations and fusion-point-guided reconstruction of amplicons. AB - Structural variations (SVs) contribute significantly to the variability of the human genome and extensive genomic rearrangements are a hallmark of cancer. While genomic DNA paired-end-tag (DNA-PET) sequencing is an attractive approach to identify genomic SVs, the current application of PET sequencing with short insert size DNA can be insufficient for the comprehensive mapping of SVs in low complexity and repeat-rich genomic regions. We employed a recently developed procedure to generate PET sequencing data using large DNA inserts of 10-20 kb and compared their characteristics with short insert (1 kb) libraries for their ability to identify SVs. Our results suggest that although short insert libraries bear an advantage in identifying small deletions, they do not provide significantly better breakpoint resolution. In contrast, large inserts are superior to short inserts in providing higher physical genome coverage for the same sequencing cost and achieve greater sensitivity, in practice, for the identification of several classes of SVs, such as copy number neutral and complex events. Furthermore, our results confirm that large insert libraries allow for the identification of SVs within repetitive sequences, which cannot be spanned by short inserts. This provides a key advantage in studying rearrangements in cancer, and we show how it can be used in a fusion-point-guided-concatenation algorithm to study focally amplified regions in cancer. PMID- 23029420 TI - Proteins with altered levels in plasma from glioblastoma patients as revealed by iTRAQ-based quantitative proteomic analysis. AB - Glioblastomas (GBMs) are the most common and lethal primary tumors of the central nervous system with high level of recurrence despite aggressive therapy. Tumor associated proteins/peptides may appear in the plasma of these patients as a result of disruption of the blood-brain barrier in them, raising the scope for development of plasma-based tests for diagnosis and monitoring the disease. With this objective, we analyzed the levels of proteins present in the plasma from GBM patients using an iTRAQ based LC-MS/MS approach. Analysis with pooled plasma specimens from the patient and healthy control samples revealed high confidence identification of 296 proteins, of which 61 exhibited a fold-change >=1.5 in the patient group. Forty-eight of them contained signal sequence. A majority have been reported in the differentially expressed transcript or protein profile of GBM tissues; 6 have been previously studied as plasma biomarkers for GBM and 16 for other types of cancers. Altered levels of three representative proteins ferritin light chain (FTL), S100A9, and carnosinase 1 (CNDP1)-were verified by ELISA in a test set of ten individual plasma specimens. FTL is an inflammation marker also implicated in cancer, S100A9 is an important member of the Ca(2+) signaling cascade reported to be altered in GBM tissue, and CNDP1 has been reported for its role in the regulation of the levels of carnosine, implicated as a potential drug for GBM. These and other proteins in the dataset may form useful starting points for further clinical investigations for the development of plasma based biomarker panels for GBM. PMID- 23029421 TI - Combining epidemiological and genetic networks signifies the importance of early treatment in HIV-1 transmission. AB - Inferring disease transmission networks is important in epidemiology in order to understand and prevent the spread of infectious diseases. Reconstruction of the infection transmission networks requires insight into viral genome data as well as social interactions. For the HIV-1 epidemic, current research either uses genetic information of patients' virus to infer the past infection events or uses statistics of sexual interactions to model the network structure of viral spreading. Methods for a reliable reconstruction of HIV-1 transmission dynamics, taking into account both molecular and societal data are still lacking. The aim of this study is to combine information from both genetic and epidemiological scales to characterize and analyse a transmission network of the HIV-1 epidemic in central Italy.We introduce a novel filter-reduction method to build a network of HIV infected patients based on their social and treatment information. The network is then combined with a genetic network, to infer a hypothetical infection transmission network. We apply this method to a cohort study of HIV-1 infected patients in central Italy and find that patients who are highly connected in the network have longer untreated infection periods. We also find that the network structures for homosexual males and heterosexual populations are heterogeneous, consisting of a majority of 'peripheral nodes' that have only a few sexual interactions and a minority of 'hub nodes' that have many sexual interactions. Inferring HIV-1 transmission networks using this novel combined approach reveals remarkable correlations between high out-degree individuals and longer untreated infection periods. These findings signify the importance of early treatment and support the potential benefit of wide population screening, management of early diagnoses and anticipated antiretroviral treatment to prevent viral transmission and spread. The approach presented here for reconstructing HIV 1 transmission networks can have important repercussions in the design of intervention strategies for disease control. PMID- 23029422 TI - Suicide gene reveals the myocardial neovascularization role of mesenchymal stem cells overexpressing CXCR4 (MSC(CXCR4)). AB - BACKGROUND: Our previous studies indicated that MSC(CXCR4) improved cardiac function after myocardial infarction (MI). This study was aimed to investigate the specific role of MSC(CXCR4) in neovascularization of infarcted myocardium using a suicide gene approach. METHODS: MSCs were transduced with either lentivirus-null vector/GFP (MSC(Null) as control) or vector encoding for overexpressing CXCR4/GFP. The MSC derived-endothelial cell (EC) differentiation was assessed by a tube formation assay, Dil-ac-LDL uptake, EC marker expression, and VE-cadherin promoter activity assay. Gene expression was analyzed by quantitative RT-PCR or Western blot. The suicide gene approach was under the control of VE-cadherin promoter. In vivo studies: Cell patches containing MSC(Null) or MSC(CXCR4) were transduced with suicide gene and implanted into the myocardium of MI rat. Rats received either ganciclovir (GCV) or vehicle after cell implantation. After one month, the cardiac functional changes and neovascularization were assessed by echocardiography, histological analysis, and micro-CT imaging. RESULTS: The expression of VEGF-A and HIF-1alpha was significantly higher in MSC(CXCR4) as compared to MSC(Null) under hypoxia. Additionally, MSC(CXCR4) enhanced new vessel formation and EC differentiation, as well as STAT3 phosphorylation under hypoxia. STAT3 participated in the transcription of VE-cadherin in MSC(CXCR4) under hypoxia, which was inhibited by WP1066 (a STAT3 inhibitor). In addition, GCV specifically induced death of ECs with suicide gene activation. In vivo studies: MSC(CXCR4) implantation promoted cardiac functional restoration, reduced infarct size, improved cardiac remodeling, and enhanced neovascularization in ischemic heart tissue. New vessels derived from MSC(CXCR4) were observed at the injured heart margins and communicated with native coronary arteries. However, the derived vessel networks were reduced by GCV, reversing improvement of cardiac function. CONCLUSION: The transplanted MSC(CXCR4) enhanced neovascularization after MI by boosting release of angiogenic factors and increasing the potential of endothelial differentiation. PMID- 23029423 TI - Tidal flushing restores the physiological condition of fish residing in degraded salt marshes. AB - Roads, bridges, and dikes constructed across salt marshes can restrict tidal flow, degrade habitat quality for nekton, and facilitate invasion by non-native plants including Phragmites australis. Introduced P. australis contributes to marsh accretion and eliminates marsh surface pools thereby adversely affecting fish by reducing access to intertidal habitats essential for feeding, reproduction, and refuge. Our study assessed the condition of resident fish populations (Fundulus heteroclitus) at four tidally restricted and four tidally restored marshes in New England invaded by P. australis relative to adjacent reference salt marshes. We used physiological and morphological indicators of fish condition, including proximate body composition (% lipid, % lean dry, % water), recent daily growth rate, age class distributions, parasite prevalence, female gravidity status, length-weight regressions, and a common morphological indicator (Fulton's K) to assess impacts to fish health. We detected a significant increase in the quantity of parasites infecting fish in tidally restricted marshes but not in those where tidal flow was restored to reduce P. australis cover. Using fish length as a covariate, we found that unparasitized, non-gravid F. heteroclitus in tidally restricted marshes had significantly reduced lipid reserves and increased lean dry (structural) mass relative to fish residing in reference marshes. Fish in tidally restored marshes were equivalent across all metrics relative to those in reference marshes indicating that habitat quality was restored via increased tidal flushing. Reference marshes adjacent to tidally restored sites contained the highest abundance of young fish (ages 0-1) while tidally restricted marshes contained the lowest. Results indicate that F. heteroclitus residing in physically and hydrologically altered marshes are at a disadvantage relative to fish in reference marshes but the effects can be reversed through ecological restoration. PMID- 23029424 TI - Immigration, local dispersal limitation, and the repeatability of community composition under neutral and niche dynamics. AB - Repeatability of community composition has been a critical aspect for community structure, which is closely associated with community stability, predictability, conservation biology and ecological restoration. It has been shown that both immigration and local dispersal limitation can affect the community composition in both neutral and niche model. Hence, we use a spatially explicit individual based model to investigate the potential influence of immigration rate and strength of local dispersal limitation on repeatability in both neutral and niche models. Similarity measures are used to quantify repeatability. We examine the repeatability of community composition among replicate communities (which means the same community repeats many times), and between niche and neutral replicate communities. We find the correlation between repeatability and immigration rate is positive in the neutral model and an inverted unimodal in the niche model. The correlation between repeatability and local dispersal distance is positive in the niche model and negative in the neutral model. High repeatability between niche communities and neutral communities is observed with high immigration rates or when high local dispersal distance appears in the niche model or low local dispersal distance in the neutral model. Our results show that repeatability of community composition is not only dependent on the types of community models (niche vs. neutrality) but also strongly determined by immigration rates and local dispersal limitation. PMID- 23029425 TI - Multiple distinct forms of CD8+ T cell cross-reactivity and specificities revealed after 2009 H1N1 influenza A virus infection in mice. AB - Influenza primed mice are protected against lethal infection with H1N1 A/CA/04/E3/09 virus, and T depletion and serum transfer studies suggest a T dependent mechanism. We therefore set out to investigate the quality of the cross reactive T cell response to CA/E3/09 in mice primed with H3N2 influenza A/Hong Kong/X31 virus. Sequences of the immunodominant nucleoprotein (NP) NP366-374 and acid polymerase (PA) PA224-233 CD8 epitopes from X31 each differ from the CA/E3/09 virus by one amino acid: an M371V substitution at position 6 of the NP peptide, and an S224P substitution at position 1 of the PA peptide, raising questions about the role of these epitopes in protection. PA224-233 peptides from either virus could elicit IFN-gamma spot forming cells from mice infected with X31, indicating cross-reactivity of these two peptides. However, no T cell responses to either PA224-233 peptide were detectable after primary CA/E3/09 infection, suggesting it is cryptic in this virus. In contrast, primary responses to the NP366 peptides were detectable after infection with either virus, but did not cross-react in vitro. Similarly, H2-D(b) tetramers of each NP epitope stained CD8+ T cells from each respective virus infection, but did not obviously cross react. Early after lethal CA/E3/09 challenge, X31 primed mice had enhanced IFN gamma responses toward both NP366 peptides, as well as recall responses to a set of subdominant NP and PA peptides not detectable after primary X31 infection alone. Furthermore, dual-tetramer staining revealed an expanded population of CD8 T cells reactive to both NP366 variant peptides also not seen after the priming infection alone. These observations demonstrate unusual CD8+ T cell cross reactivity and specificity are elicited after primary and secondary CA/E3/09 influenza virus infections. PMID- 23029426 TI - Detection of appearing and disappearing objects in complex acoustic scenes. AB - The ability to detect sudden changes in the environment is critical for survival. Hearing is hypothesized to play a major role in this process by serving as an "early warning device," rapidly directing attention to new events. Here, we investigate listeners' sensitivity to changes in complex acoustic scenes-what makes certain events "pop-out" and grab attention while others remain unnoticed? We use artificial "scenes" populated by multiple pure-tone components, each with a unique frequency and amplitude modulation rate. Importantly, these scenes lack semantic attributes, which may have confounded previous studies, thus allowing us to probe low-level processes involved in auditory change perception. Our results reveal a striking difference between "appear" and "disappear" events. Listeners are remarkably tuned to object appearance: change detection and identification performance are at ceiling; response times are short, with little effect of scene size, suggesting a pop-out process. In contrast, listeners have difficulty detecting disappearing objects, even in small scenes: performance rapidly deteriorates with growing scene-size; response times are slow, and even when change is detected, the changed component is rarely successfully identified. We also measured change detection performance when a noise or silent gap was inserted at the time of change or when the scene was interrupted by a distractor that occurred at the time of change but did not mask any scene elements. Gaps adversely affected the processing of item appearance but not disappearance. However, distractors reduced both appearance and disappearance detection. Together, our results suggest a role for neural adaptation and sensitivity to transients in the process of auditory change detection, similar to what has been demonstrated for visual change detection. Importantly, listeners consistently performed better for item addition (relative to deletion) across all scene interruptions used, suggesting a robust perceptual representation of item appearance. PMID- 23029427 TI - Twelve-month-olds' understanding of intention transfer through communication. AB - Do infants understand that intention can be transferred through communication? We answered this question by examining 12-month-olds' looking times in a violation of-expectation paradigm with two human agents. In familiarization, the non-acting agent spoke, clapped her hands, read aloud a book, or remained silent before the acting agent grasped one (the target) of two objects. During test only the non actor remained, grasping either the target or distractor. The infants looked longer in the distractor than target condition, suggesting violation of expectation, only if the non-actor had spoken or clapped in familiarization. Because the non-actor never had grasped any of the objects in familiarization, the infants' expectation on her behavior could have developed from the understanding that her intention was transferred to the actor, who executed it by grasping the target in familiarization, via speaking and clapping as acts of communication (but not reading aloud and remaining silent). PMID- 23029428 TI - Hit-to-lead development of the chamigrane endoperoxide merulin A for the treatment of African sleeping sickness. AB - BACKGROUND: Human African trypanosomiasis (HAT) is an infectious disease with a large global health burden occurring primarily in Central and Eastern Africa. Most current treatments have poor blood brain barrier (BBB) penetration, which prevent them from targeting the most lethal stage of the infection. In addition, current therapeutics suffer from a variety of limitations ranging from serious side effects to difficulties with treatment administration. Therefore it is of crucial importance to find new treatments that are safe, affordable, and effective against both sub-species of Trypanosoma brucei. METHODS: Semi-synthetic derivatization of the fungally-derived natural product merulin A (1) has led to the discovery of new development candidates for the protozoan parasite T. brucei, the causative agent of HAT. Creation of an initial SAR library based around the merulin scaffold revealed several key features required for activity, including the endoperoxide bridge, as well as one position suitable for further derivatization. Subsequent synthesis of a 20-membered analogue library, guided by the addition of acyl groups that improve the drug-like properties of the merulin A core, resulted in the development of compound 12 with an IC(50) of 60 nM against T. brucei, and a selectivity index greater than 300-fold against HeLa and immortalized glial cells. SIGNIFICANCE: We report the semi-synthetic optimization of the merulin class of endoperoxide natural products as development candidates against T. brucei. We have identified compounds with low nM antiparasitic activities and high selectivity indices against HeLa cells. These compounds can be produced economically in large quantities via a one step derivatization from the microbial fermentation broth isolate, making them encouraging lead candidates for further development. PMID- 23029429 TI - In vitro phosphorylation and acetylation of the murine pocket protein Rb2/p130. AB - The retinoblastoma protein (pRb) and the related proteins Rb2/p130 and 107 represent the "pocket protein" family of cell cycle regulators. A key function of these proteins is the cell cycle dependent modulation of E2F-regulated genes. The biological activity of these proteins is controlled by acetylation and phosphorylation in a cell cycle dependent manner. In this study we attempted to investigate the interdependence of acetylation and phosphorylation of Rb2/p130 in vitro. After having identified the acetyltransferase p300 among several acetyltransferases to be associated with Rb2/p130 during S-phase in NIH3T3 cells in vivo, we used this enzyme and the CDK4 protein kinase for in vitro modification of a variety of full length Rb2/p130 and truncated versions with mutations in the acetylatable lysine residues 1079, 128 and 130. Mutation of these residues results in the complete loss of Rb2/p130 acetylation. Replacement of lysines by arginines strongly inhibits phosphorylation of Rb2/p130 by CDK4; the inhibitory effect of replacement by glutamines is less pronounced. Preacetylation of Rb2/p130 strongly enhances CDK4-catalyzed phosphorylation, whereas deacetylation completely abolishes in vitro phosphorylation. In contrast, phosphorylation completely inhibits acetylation of Rb2/p130 by p300. These results suggest a mutual interdependence of modifications in a way that acetylation primes Rb2/p130 for phosphorylation and only dephosphorylated Rb2/p130 can be subject to acetylation. Human papillomavirus 16-E7 protein, which increases acetylation of Rb2/p130 by p300 strongly reduces phosphorylation of this protein by CDK4. This suggests that the balance between phosphorylation and acetylation of Rb2/p130 is essential for its biological function in cell cycle control. PMID- 23029430 TI - Prognostic role of host cyclooxygenase and cytokine genotypes in a Caucasian cohort of patients with gastric adenocarcinoma. AB - BACKGROUND: Genetic factors influencing the prognosis of gastric adenocarcinoma (GAC) are not well known. Given the relevance of cytokines and other pro inflammatory mediators in cancer progression and invasiveness, we aimed to assess the prognostic role of several functional cytokine and cyclooxygenase gene polymorphisms in patients with GAC. METHODOLOGY: Genomic DNA from 380 Spanish Caucasian patients with primary GAC was genotyped for 23 polymorphisms in pro inflammatory (IL1B, TNFA, LTA, IL6, IL12p40), anti-inflammatory (IL4, IL1RN, IL10, TGFB1) cytokine, and cyclooxygenase (PTGS1 and PTGS2) genes by PCR, RFLP and TaqMan assays. Clinical and histological information was collected prospectively. Survival curves were estimated by the Kaplan-Meier method and compared using the log rank test. Outcome was determined by analysis of Cox proportional hazards, adjusting for confounding factors. RESULTS: The median follow-up period and median overall survival (OS) time were 9.9 months (range 0.4 120.3) and 10.9 months (95% CI: 8.9-14.1), respectively. Multivariate analysis identified tumor stages III (HR, 3.23; 95% CI:2-5.22) and IV (HR, 5.5; 95% CI: 3.51-8.63) as independent factors associated with a significantly reduced OS, whereas surgical treatment (HR: 0.44; 95%CI: 0.3-0.6) was related to a better prognosis of the disease. Concerning genetic factors, none of the 23 polymorphisms evaluated in the current study did influence survival. Moreover, no gene-environment interactions on GAC prognosis were observed. CONCLUSIONS: Our results show that, in our population, the panel of selected pro- and anti inflammatory cytokine, and cyclooxygenase gene polymorphisms are not relevant in determining the prognosis of gastric adenocarcinoma. PMID- 23029431 TI - Human cells display reduced apoptotic function relative to chimpanzee cells. AB - Previously published gene expression analyses suggested that apoptotic function may be reduced in humans relative to chimpanzees and led to the hypothesis that this difference may contribute to the relatively larger size of the human brain and the increased propensity of humans to develop cancer. In this study, we sought to further test the hypothesis that humans maintain a reduced apoptotic function relative to chimpanzees by conducting a series of apoptotic function assays on human, chimpanzee and macaque primary fibroblastic cells. Human cells consistently displayed significantly reduced apoptotic function relative to the chimpanzee and macaque cells. These results are consistent with earlier findings indicating that apoptotic function is reduced in humans relative to chimpanzees. PMID- 23029432 TI - Increased response to beta2-adrenoreceptor stimulation augments inhibition of IKr in heart failure ventricular myocytes. AB - BACKGROUND: Increasing evidence indicates that the rapid component of delayed rectifier potassium current (I(Kr)) is modulated by alpha- and beta-adrenergic stimulation. However, the role and mechanism regulating I(Kr) through beta(2) adrenoreceptor (beta-AR) stimulation in heart failure (HF) are unclear. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we investigated the effects of fenoterol, a highly selective beta(2)-AR agonist, on I(Kr) in left ventricular myocytes obtained from control and guinea pigs with HF induced by descending aortic banding. I(Kr) was measured by using whole cell patch clamp technique. In control myocytes, superfusion of fenoterol (10 uM) caused a 17% decrease in I(Kr). In HF myocytes, the same concentration of fenoterol produced a significantly greater decrease (33%) in I(Kr). These effects were not modified by the incubation of myocytes with CGP-20712A, a beta(1)-AR antagonist, but were abolished by pretreatment of myocytes with ICI-118551, a beta(2)-AR antagonist. An inhibitory cAMP analog, Rp-cAMPS and PKA inhibitor significantly attenuated fenoterol-induced inhibition of I(Kr) in HF myocytes. Moreover, fenoterol markedly prolonged action potential durations at 90% (APD(90)) repolarization in HF ventricular myocytes. CONCLUSIONS: The results indicate that inhibition of I(Kr) induced by beta(2)-AR stimulation is increased in HF. The inhibitory effect is likely to be mediated through a cAMP/PKA pathway in HF ventricular myocytes. PMID- 23029433 TI - Changing malaria epidemiology and diagnostic criteria for Plasmodium falciparum clinical malaria. AB - BACKGROUND: In tropical Africa, where malaria is highly endemic, low grade infections are asymptomatic and the diagnosis of clinical malaria is usually based on parasite density. Here we investigate how changes in malaria control and endemicity modify diagnostic criteria of Plasmodium falciparum attacks. METHODS AND FINDINGS: Parasitological and clinical data from the population of Dielmo, Senegal, monitored during 20 years, are analyzed in a random-effect logistic regression model to investigate the relationship between the level of parasitemia and risk of fever. Between 1990 and 2010, P. falciparum prevalence in asymptomatic persons declined from 85% to 1% in children 0-3 years and from 34% to 2% in adults >=50 years. Thresholds levels of parasitemia for attributing fever episodes to malaria decreased by steps in relation to control policies. Using baseline threshold during following periods underestimated P. falciparum attacks by 9.8-20.2% in children and 18.9-40.2% in adults. Considering all fever episodes associated with malaria parasites as clinical attacks overestimated P. falciparum attacks by 42.2-68.5% in children and 45.9-211.7% in adults. CONCLUSIONS: Malaria control modifies in all age-groups the threshold levels of parasitemia to be used for the assessment of malaria morbidity and to guide therapeutic decisions. Even under declining levels of malaria endemicity, the parasite density method must remain the reference method for distinguishing malaria from other causes of fever and assessing trends in the burden of malaria. PMID- 23029434 TI - Netrin-1 protects against L-Arginine-induced acute pancreatitis in mice. AB - Acute pancreatitis (AP) is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with infiltration of leukocytes. The neuronal guidance protein, netrin-1, has been shown to control leukocyte trafficking and modulate inflammatory responses in several inflammation based diseases. The present study was aimed toward investigating the effects of netrin-1 in an in vivo model of AP in mice. AP was induced in C57BL/6 mice by administration of two intraperitoneal injections of L-Arginine (4 g/kg). Mice were treated with recombinant mouse netrin-1 at a dose of 1 ug/mouse or vehicle (0.1% BSA) intravenously through the tail vein immediately after the second injection of L-Arginine, and every 24 h thereafter. Mice were sacrificed at several time intervals from 0 to 96 h after the induction of pancreatitis. Blood and tissue samples of pancreas and lung were collected and processed to determine the severity of pancreatitis biochemically and histologically. Immunohistochemical staining demonstrated that netrin-1 was mainly expressed in the islet cells of the normal pancreas and the AP model pancreas, and the pancreatic expression of netrin-1 was down-regulated at both the mRNA and protein levels during the course of AP. Exogenous netrin-1 administration significantly reduced plasma amylase levels, myeloperoxidase activity, pro-inflammatory cytokine production, and pancreas and lung tissue damages. Furthermore, netrin-1 administration did not cause significant inhibition of nuclear factor-kappa B activation in the pancreas of L-Arginine-induced AP. In conclusion, our novel data suggest that netrin-1 is capable of improving damage of pancreas and lung, and exerting anti-inflammatory effects in mice with severe acute pancreatitis. Thus, our results indicate that netrin-1 may constitute a novel target in the management of AP. PMID- 23029435 TI - Mediating role of activity level in the depressive realism effect. AB - Several classic studies have concluded that the accuracy of identifying uncontrollable situations depends heavily on depressive mood. Nondepressed participants tend to exhibit an optimistic illusion of control, whereas depressed participants tend to better detect a lack of control. Recently, we suggested that the different activity levels (measured as the probability of responding during a contingency learning task) exhibited by depressed and nondepressed individuals is partly responsible for this effect. The two studies presented in this paper provide further support for this mediational hypothesis, in which mood is the distal cause of the illusion of control operating through activity level, the proximal cause. In Study 1, the probability of responding, P(R), was found to be a mediator variable between the depressive symptoms and the judgments of control. In Study 2, we intervened directly on the mediator variable: The P(R) for both depressed and nondepressed participants was manipulated through instructions. Our results confirm that P(R) manipulation produced differences in the participants' perceptions of uncontrollability. Importantly, the intervention on the mediator variable cancelled the effect of the distal cause; the participants' judgments of control were no longer mood dependent when the P(R) was manipulated. This result supports the hypothesis that the so-called depressive realism effect is actually mediated by the probability of responding. PMID- 23029436 TI - Photosystem II function and dynamics in three widely used Arabidopsis thaliana accessions. AB - Columbia-0 (Col-0), Wassilewskija-4 (Ws-4), and Landsberg erecta-0 (Ler-0) are used as background lines for many public Arabidopsis mutant collections, and for investigation in laboratory conditions of plant processes, including photosynthesis and response to high-intensity light (HL). The photosystem II (PSII) complex is sensitive to HL and requires repair to sustain its function. PSII repair is a multistep process controlled by numerous factors, including protein phosphorylation and thylakoid membrane stacking. Here we have characterized the function and dynamics of PSII complex under growth-light and HL conditions. Ws-4 displayed 30% more thylakoid lipids per chlorophyll and 40% less chlorophyll per carotenoid than Col-0 and Ler-0. There were no large differences in thylakoid stacking, photoprotection and relative levels of photosynthetic complexes among the three accessions. An increased efficiency of PSII closure was found in Ws-4 following illumination with saturation flashes or continuous light. Phosphorylation of the PSII D1/D2 proteins was reduced by 50% in Ws-4 as compared to Col-0 and Ler-0. An increase in abundance of the responsible STN8 kinase in response to HL treatment was found in all three accessions, but Ws-4 displayed 50% lower levels than Col-0 and Ler-0. Despite this, the HL treatment caused in Ws-4 the lagest extent of PSII inactivation, disassembly, D1 protein degradation, and the largest decrease in the size of stacked thylakoids. The dilution of chlorophyll-protein complexes with additional lipids and carotenoids in Ws-4 may represent a mechanism to facilitate lateral protein traffic in the membrane, thus compensating for the lack of a full complement of STN8 kinase. Nevertheless, additional PSII damage occurs in Ws-4, which exceeds the D1 protein synthesis capacity, thus leading to enhanced photoinhibition. Our findings are valuable for selection of appropriate background line for PSII characterization in Arabidopsis mutants, and also provide the first insights into natural variation of PSII protein phosphorylation. PMID- 23029437 TI - Effects of aging on cerebral oxygenation during working-memory performance: a functional near-infrared spectroscopy study. AB - Working memory is sensitive to aging-related decline. Evidence exists that aging is accompanied by a reorganization of the working-memory circuitry, but the underlying neurocognitive mechanisms are unclear. In this study, we examined aging-related changes in prefrontal activation during working-memory performance using functional Near-Infrared Spectroscopy (fNIRS), a noninvasive neuroimaging technique. Seventeen healthy young (21-32 years) and 17 healthy older adults (64 81 years) performed a verbal working-memory task (n-back). Oxygenated and deoxygenated hemoglobin concentration changes were registered by two fNIRS channels located over the left and right prefrontal cortex. Increased working memory load resulted in worse performance compared to the control condition in older adults, but not in young participants. In both young and older adults, prefrontal activation increased with rising working-memory load. Young adults showed slight right-hemispheric dominance at low levels of working-memory load, while no hemispheric differences were apparent in older adults. Analysis of the time-activation curve during the high working-memory load condition revealed a continuous increase of the hemodynamic response in the young. In contrast to that, a quadratic pattern of activation was found in the older participants. Based on these results it could be hypothesized that young adults were better able to keep the prefrontal cortex recruited over a prolonged period of time. To conclude, already at low levels of working-memory load do older adults recruit both hemispheres, possibly in an attempt to compensate for the observed aging related decline in performance. Also, our study shows that aging effects on the time course of the hemodynamic response must be taken into account in the interpretation of the results of neuroimaging studies that rely on blood oxygen levels, such as fMRI. PMID- 23029438 TI - Paired-end sequencing of long-range DNA fragments for de novo assembly of large, complex Mammalian genomes by direct intra-molecule ligation. AB - BACKGROUND: The relatively short read lengths from next generation sequencing (NGS) technologies still pose a challenge for de novo assembly of complex mammal genomes. One important solution is to use paired-end (PE) sequence information experimentally obtained from long-range DNA fragments (>1 kb). Here, we characterize and extend a long-range PE library construction method based on direct intra-molecule ligation (or molecular linker-free circularization) for NGS. RESULTS: We found that the method performs stably for PE sequencing of 2- to 5- kb DNA fragments, and can be extended to 10-20 kb (and even in extremes, up to ~35 kb). We also characterized the impact of low quality input DNA on the method, and develop a whole-genome amplification (WGA) based protocol using limited input DNA (<1 ug). Using this PE dataset, we accurately assembled the YanHuang (YH) genome, the first sequenced Asian genome, into a scaffold N50 size of >2 Mb, which is over 100-times greater than the initial size produced with only small insert PE reads(17 kb). In addition, we mapped two 7- to 8- kb insertions in the YH genome using the larger insert sizes of the long-range PE data. CONCLUSIONS: In conclusion, we demonstrate here the effectiveness of this long-range PE sequencing method and its use for the de novo assembly of a large, complex genome using NGS short reads. PMID- 23029439 TI - Molecular characterisation of endogenous Vangl2/Vangl1 heteromeric protein complexes. AB - BACKGROUND: Mutations in the Planar Cell Polarity (PCP) core gene Vangl2 cause the most severe neural tube defects (NTD) in mice and humans. Genetic studies show that the Vangl2 gene genetically interacts with a close homologue Vangl1. How precisely Vangl2 and Vangl1 proteins interact and crosstalk has remained a difficult issue to address, with the main obstacle being the accurate discrimination of the two proteins, which share close sequence homology. Experimental evidence previously presented has been sparse and addressed with ectopically expressed proteins or with antibodies unable to biochemically discriminate Vangl1 from Vangl2, therefore giving rise to unclear results. METHODOLOGY AND MAIN FINDINGS: A highly specific monoclonal anti-Vangl2 antibody was generated and rigorously tested on both recombinant and extracted Vangl2 using surface plasmon resonance (SPR) analysis, western blot, and immunoprecipitation experiments. This antibody efficiently affinity-purified Vangl2 from cell lysates and allowed the unambiguous identification of endogenous Vangl2 by proteomic analysis. Vangl1 was also present in Vangl2 immunoprecipitates, establishing the first biochemical evidence for the existence of Vangl2/Vangl1 heterodimers at an endogenous level. Epitope-tagged Vangl2 and Vangl1 confirmed that both proteins interact and colocalize at the plasma membrane. The Vangl2 antibody is able to acutely assess differential expression levels of Vangl2 protein in culture cell lines, as corroborated with gene expression analysis. We characterised Vangl2 expression in the cochlea of homozygous and heterozygous Lp mutant mice bearing a point mutation within the C terminal Vangl2 region that leads to profound PCP defects. Our antibody could detect much lower levels of Vangl2(Lp) protein in mutant mice compared to the wild type mice. CONCLUSION: Our results provide an in-depth biochemical characterisation of the interaction observed between Vangl paralogues. PMID- 23029441 TI - The use of intravenous antibiotics at the onset of neutropenia in patients receiving outpatient-based hematopoietic stem cell transplants. AB - Empirical antibiotics at the onset of febrile neutropenia are one of several strategies for management of bacterial infections in patients undergoing Hematopoietic Stem Cell Transplant (HSCT) (empiric strategy). Our HSCT program aims to perform HSCT in an outpatient setting, where an empiric antibiotic strategy was employed. HSCT recipients began receiving intravenous antibiotics at the onset of neutropenia in the absence of fever as part of our institutional policy from 01 Jan 2009; intravenous Prophylactic strategy. A prospective study was conducted to compare two consecutive cohorts [Year 2008 (Empiric strategy) vs. Year 2009 (Prophylactic strategy)] of patients receiving HSCT. There were 238 HSCTs performed between 01 Jan 2008 and 31 Dec 2009 with 127 and 111 in the earlier and later cohorts respectively. Infection-related mortality pre- engraftment was similar with a prophylactic compared to an empiric strategy (3.6% vs. 7.1%; p = 0.24), but reduced among recipients of autologous HSCT (0% vs. 6.8%; p = 0.03). Microbiologically documented, blood stream infections and clinically documented infections pre-engraftment were reduced in those receiving a prophylactic compared to an empiric strategy, (11.7% vs. 28.3%; p = 0.001), (9.9% vs. 24.4%; p = 0.003) and (18.2% vs. 33.9% p = 0.007) respectively. The prophylactic use of intravenous once-daily ceftriaxone in patients receiving outpatient based HSCT is safe and may be particularly effective in patients receiving autologous HSCT. Further studies are warranted to study the impact of this Prophylactic strategy in an outpatient based HSCT program. PMID- 23029440 TI - Comparative metagenomic analysis of soil microbial communities across three hexachlorocyclohexane contamination levels. AB - This paper presents the characterization of the microbial community responsible for the in-situ bioremediation of hexachlorocyclohexane (HCH). Microbial community structure and function was analyzed using 16S rRNA amplicon and shotgun metagenomic sequencing methods for three sets of soil samples. The three samples were collected from a HCH-dumpsite (450 mg HCH/g soil) and comprised of a HCH/soil ratio of 0.45, 0.0007, and 0.00003, respectively. Certain bacterial; (Chromohalobacter, Marinimicrobium, Idiomarina, Salinosphaera, Halomonas, Sphingopyxis, Novosphingobium, Sphingomonas and Pseudomonas), archaeal; (Halobacterium, Haloarcula and Halorhabdus) and fungal (Fusarium) genera were found to be more abundant in the soil sample from the HCH-dumpsite. Consistent with the phylogenetic shift, the dumpsite also exhibited a relatively higher abundance of genes coding for chemotaxis/motility, chloroaromatic and HCH degradation (lin genes). Reassembly of a draft pangenome of Chromohalobacter salaxigenes sp. (~8X coverage) and 3 plasmids (pISP3, pISP4 and pLB1; 13X coverage) containing lin genes/clusters also provides an evidence for the horizontal transfer of HCH catabolism genes. PMID- 23029442 TI - The ppm operon is essential for acylation and glycosylation of lipoproteins in Corynebacterium glutamicum. AB - BACKGROUND: Due to their contribution to bacterial virulence, lipoproteins and members of the lipoprotein biogenesis pathway represent potent drug targets. Following translocation across the inner membrane, lipoprotein precursors are acylated by lipoprotein diacylglycerol transferase (Lgt), cleaved off their signal peptides by lipoprotein signal peptidase (Lsp) and, in Gram-negative bacteria, further triacylated by lipoprotein N-acyl transferase (Lnt). The existence of an active apolipoprotein N-acyltransferase (Ms-Ppm2) involved in the N-acylation of LppX was recently reported in M. smegmatis. Ms-Ppm2 is part of the ppm operon in which Ppm1, a polyprenol-monophosphomannose synthase, has been shown to be essential in lipoglycans synthesis but whose function in lipoprotein biosynthesis is completely unknown. RESULTS: In order to clarify the role of the ppm operon in lipoprotein biosynthesis, we investigated the post-translational modifications of two model lipoproteins (AmyE and LppX) in C. glutamicum Deltappm1 and Deltappm2 mutants. Our results show that both proteins are anchored into the membrane and that their N-termini are N-acylated by Cg-Ppm2. The acylated N-terminal peptide of LppX was also found to be modified by hexose moieties. This O-glycosylation is localized in the N-terminal peptide of LppX and disappeared in the Deltappm1 mutant. While compromised in the absence of Cg-Ppm2, LppX O-glycosylation could be restored when Cg-Ppm1, Cg-Ppm2 or the homologous Mt Ppm1 of M. tuberculosis was overexpressed. CONCLUSION: Together, these results show for the first time that Cg-Ppm1 (Ppm synthase) and Cg-Ppm2 (Lnt) operate in a common biosynthetic pathway in which lipoprotein N-acylation and glycosylation are tightly coupled. PMID- 23029443 TI - Threat diversity will erode mammalian phylogenetic diversity in the near future. AB - To reduce the accelerating rate of phylogenetic diversity loss, many studies have searched for mechanisms that could explain why certain species are at risk, whereas others are not. In particular, it has been demonstrated that species might be affected by both extrinsic threat factors as well as intrinsic biological traits that could render a species more sensitive to extinction; here, we focus on extrinsic factors. Recently, the International Union for Conservation of Nature developed a new classification of threat types, including climate change, urbanization, pollution, agriculture and aquaculture, and harvesting/hunting. We have used this new classification to analyze two main factors that could explain the expected future loss of mammalian phylogenetic diversity: 1. differences in the type of threats that affect mammals and 2. differences in the number of major threats that accumulate for a single species. Our results showed that Cetartiodactyla, Diprotodontia, Monotremata, Perissodactyla, Primates, and Proboscidea could lose a high proportion of their current phylogenetic diversity in the coming decades. In contrast, Chiroptera, Didelphimorphia, and Rodentia could lose less phylogenetic diversity than expected if extinctions were random. Some mammalian clades, including Marsupiala, Chiroptera, and a subclade of Primates, are affected by particular threat types, most likely due solely to their geographic locations and associations with particular habitats. However, regardless of the geography, habitat, and taxon considered, it is not the threat type, but the threat diversity that determines the extinction risk for species and clades. Thus, some mammals might be randomly located in areas subjected to a large diversity of threats; they might also accumulate detrimental traits that render them sensitive to different threats, which is a characteristic that could be associated with large body size. Any action reducing threat diversity is expected to have a significant impact on future mammalian phylogeny. PMID- 23029444 TI - Elevational gradients in fish diversity in the Himalaya: water discharge is the key driver of distribution patterns. AB - BACKGROUND: Studying diversity and distribution patterns of species along elevational gradients and understanding drivers behind these patterns is central to macroecology and conservation biology. A number of studies on biogeographic gradients are available for terrestrial ecosystems, but freshwater ecosystems remain largely neglected. In particular, we know very little about the species richness gradients and their drivers in the Himalaya, a global biodiversity hotspot. METHODOLOGY/PRINCIPAL FINDINGS: We collated taxonomic and distribution data of fish species from 16 freshwater Himalayan rivers and carried out empirical studies on environmental drivers and fish diversity and distribution in the Teesta river (Eastern Himalaya). We examined patterns of fish species richness along the Himalayan elevational gradients (50-3800 m) and sought to understand the drivers behind the emerging patterns. We used generalized linear models (GLM) and generalized additive models (GAM) to examine the richness patterns; GLM was used to investigate relationship between fish species richness and various environmental variables. Regression modelling involved stepwise procedures, including elimination of collinear variables, best model selection, based on the least Akaike's information criterion (AIC) and the highest percentage of deviance explained (D(2)). This maiden study on the Himalayan fishes revealed that total and non-endemic fish species richness monotonously decrease with increasing elevation, while endemics peaked around mid elevations (700-1500 m). The best explanatory model (synthetic model) indicated that water discharge is the best predictor of fish species richness patterns in the Himalayan rivers. CONCLUSIONS/SIGNIFICANCE: This study, carried out along one of the longest bioclimatic elevation gradients of the world, lends support to Rapoport's elevational rule as opposed to mid domain effect hypothesis. We propose a species-discharge model and contradict species-area model in predicting fish species richness. We suggest that drivers of richness gradients in terrestrial and aquatic ecosystems are likely to be different. These studies are crucial in context of the impacts of unprecedented on-going river regulation on fish diversity and distribution in the Himalaya. PMID- 23029445 TI - Population diversity of rice stripe virus-derived siRNAs in three different hosts and RNAi-based antiviral immunity in Laodelphgax striatellus. AB - BACKGROUND: Small RNA-mediated gene silencing plays evolutionarily conserved roles in gene regulation and defense against invasive nucleic acids. Virus derived small interfering RNAs (vsiRNAs) are one of the key elements involved in RNA silencing-based antiviral activities in plant and insect. vsiRNAs produced after viruses infecting hosts from a single kingdom (i.e., plant or animal) are well described. In contrast, vsiRNAs derived from viruses capable of infecting both plants and their insect vectors have not been characterized. METHODOLOGY/PRINCIPAL FINDINGS: We examined Rice stripe virus (RSV)-derived small interfering RNAs in three different hosts, Oryza sativa, Nicotiana benthamiana and a natural RSV transmitting vector Laodelphgax striatellus, through deep sequencing. Our results show that large amounts of vsiRNAs generated in these hosts after RSV infection. The vsiRNAs from N. benthamiana and L. striatellus mapped equally to the genomic- and antigenomic-strand of RSV RNAs. They showed, however, a significant bias in those from O. sativa. Furthermore, our results demonstrate that the number and size distributions of vsiRNAs in the three hosts were very different. In O. sativa and N. benthamiana, most vsiRNAs were mapped to the discrete regions in the RSV genome sequence, and most of the vsiRNAs from these two hosts were generated from RSV genomic RNAs 3 and 4. In contrast, the vsiRNAs identified in L. striatellus distributed uniformly along the whole genome of RSV. We have also shown that silencing Agronaute 2 in L. striatellus enhanced RSV accumulation in this host. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that the core RNA-induced gene silencing (RNAi) machinery is present in L. striatellus. We also provide evidence that the RNAi-mediated immunity against RSV is present in L. striatellus. We propose that a common small RNA-mediated virus defense mechanism exists in both helipterum insects and plants, but the vsiRNAs are generated differentially in different hosts. PMID- 23029446 TI - Ferrous citrate up-regulates the NOS2 through nuclear translocation of NFkappaB induced by free radicals generation in mouse cerebral endothelial cells. AB - Previous studies indicate that the inducible nitric oxide synthase 2 (NOS2) of the brain vascular tissue in experimental subarachnoid hemorrhage (SAH) rats is a critical factor for inducing cerebral vasospasm. However, the underlying molecular mechanisms remain to be elucidated. Here, we applied ferrous citrate (FC) complexes to the primary cultured mouse cerebral endothelial cell (CEC) to mimic the SAH conditions and to address the issue how SAH-induced NOS2 up regulation. Using immunocytochemical staining technique, we demonstrated that NOS2 was expressed in the cultured CEC. Treatment of the CEC with FC induced increases of the intracellular level of ROS, nuclear factor kappa-light-chain enhancer of activated B cells (NFkappaB) nuclear translocation as well as NFkappaB binding onto the NOS promoter, and the levels of NOS2 mRNA and protein. These effects were abolished by pre-treatment of the cell with N-Acetyl-Cysteine (NAC), a reactive oxygen species (ROS) scavenger. In the present study, two previously predicted NFkappaB binding sites were confirmed in the NOS2 promoter within the range of -1529 bp to -1516 bp and -1224 bp to -1210 bp. Interestingly, both NFkappaB binding sites are involved in the FC-activated NOS2 transcriptional activity; the binding site located at -1529 bp to -1516 bp played a greater role than the other binding site located at -1224 bp to -1210 bp in the mouse CEC. These findings highlight the molecular mechanism underlying FC-induced up regulation of NOS2 in the mouse CEC. PMID- 23029447 TI - Differential effects of IL-12 on Tregs and non-Treg T cells: roles of IFN-gamma, IL-2 and IL-2R. AB - Complex interactions between effector T cells and Foxp3(+) regulatory T cells (Treg) contribute to clinical outcomes in cancer, and autoimmune and infectious diseases. Previous work showed that IL-12 reversed Treg-mediated suppression of CD4(+)Foxp3(-) T cell (Tconv) proliferation. We and others have also shown that Tregs express T-bet and IFN-gamma at sites of Th1 inflammation and that IL-12 induces IFN-gamma production by Tregs in vitro. To investigate whether loss of immunosuppression occurs when IFN-gamma is expressed by Tregs we treated mouse lymphocyte cultures with IL-12. IFN-gamma expression did not decrease the ability of Tregs to suppress Tconv proliferation. Rather, IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs. We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells, diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells. Together, these IL-12 mediated changes favored the outgrowth of non-Tregs. Additionally, we showed that treatment with a second cytokine, IL-27, decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation. Notably, IL-27 only slightly modified levels of IL-2R on non-Treg T cells. Together, these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-gamma expression in IL-12-mediated reversal of Treg immunosuppression. PMID- 23029448 TI - Transcriptional profiling of a yeast colony provides new insight into the heterogeneity of multicellular fungal communities. AB - Understanding multicellular fungal structures is important for designing better strategies against human fungal pathogens. For example, the ability to form multicellular biofilms is a key virulence property of the yeast Candida albicans. C. albicans biofilms form on indwelling medical devices and are drug resistant, causing serious infections in hospital settings. Multicellular fungal communities are heterogeneous, consisting of cells experiencing different environments. Heterogeneity is likely important for the phenotypic characteristics of communities, yet it is poorly understood. Here we used colonies of the yeast Saccharomyces cerevisiae as a model fungal multicellular structure. We fractionated the outside colony layers from the cells in the center by FACS, using a Cit1-GFP marker expressed exclusively on the outside. Transcriptomics analysis of the two subpopulations revealed that the outside colony layers are actively growing by fermentative metabolism, while the cells residing on the inside are in a resting state and experience changes to mitochondrial activity. Our data shows several parallels with C. albicans biofilms providing insight into the contributions of heterogeneity to biofilm phenotypes. Hallmarks of C. albicans biofilms - the expression of ribosome and translation functions and activation of glycolysis and ergosterol biosynthesis occur on the outside of colonies, while expression of genes associates with sulfur assimilation is observed in the colony center. Cell wall restructuring occurs in biofilms, and cell wall functions are enriched in both fractions: the outside cells display enrichment of cell wall biosynthesis enzymes and cell wall proteins, while the inside cells express cell wall degrading enzymes. Our study also suggests that noncoding transcription and posttranscriptional mRNA regulation play important roles during growth of yeast in colonies, setting the scene for investigating these pathways in the development of multicellular fungal communities. PMID- 23029449 TI - Transcriptomic responses to salinity stress in the Pacific oyster Crassostrea gigas. AB - BACKGROUND: Low salinity is one of the main factors limiting the distribution and survival of marine species. As a euryhaline species, the Pacific oyster Crassostrea gigas is considered to be tolerant to relative low salinity. The genes that regulate C. gigas responses to osmotic stress were monitored using the next-generation sequencing of whole transcriptome with samples taken from gills. By RNAseq technology, transcript catalogs of up- and down-regulated genes were generated from the oysters exposed to low and optimal salinity seawater. METHODOLOGY/PRINCIPAL FINDINGS: Through Illumina sequencing, we reported 1665 up regulated transcripts and 1815 down-regulated transcripts. A total of 45771 protein-coding contigs were identified from two groups based on sequence similarities with known proteins. As determined by GO annotation and KEGG pathway mapping, functional annotation of the genes recovered diverse biological functions and processes. The genes that changed expression significantly were highly represented in cellular process and regulation of biological process, intracellular and cell, binding and protein binding according to GO annotation. The results highlighted genes related to osmoregulation, signaling and interactions of osmotic stress response, anti-apoptotic reactions as well as immune response, cell adhesion and communication, cytoskeleton and cell cycle. CONCLUSIONS/SIGNIFICANCE: Through more than 1.5 million sequence reads and the expression data of the two libraries, the study provided some useful insights into signal transduction pathways in oysters and offered a number of candidate genes as potential markers of tolerance to hypoosmotic stress for oysters. In addition, the characterization of C. gigas transcriptome will not only provide a better understanding of the molecular mechanisms about the response to osmotic stress of the oysters, but also facilitate research into biological processes to find underlying physiological adaptations to hypoosmotic shock for marine invertebrates. PMID- 23029450 TI - Nrac, a novel nutritionally-regulated adipose and cardiac-enriched gene. AB - Obesity increases the risk of multiple diseases, such as type 2 diabetes and coronary heart diseases, and therefore the current obesity epidemic poses a major public health issue. Therapeutic approaches are urgently needed to treat obesity as well as its complications. Plasma-membrane proteins with restricted tissue distributions are attractive drug targets, because of their accessibility to various drug delivery mechanisms and potentially alleviated side effects. To identify genes involved in metabolism, we performed RNA-Seq on fat in mice treated with a high-fat diet or fasting. Here we show that the gene A530016L24Rik (human ortholog C14orf180), named Nrac, is a novel nutritionally-regulated adipose and cardiac-enriched gene. Nrac is expressed specifically and abundantly in fat and the heart. Both fasting and obesity reduced Nrac expression in white adipose tissue, and fasting reduced its expression in brown fat. Nrac is localized to the plasma membrane, and highly induced during adipocyte differentiation. Nrac is therefore a novel adipocyte marker and has potential functions in metabolism. PMID- 23029451 TI - Near infrared imaging of EGFR of oral squamous cell carcinoma in mice administered arsenic trioxide. AB - BACKGROUND: The effectiveness of near-infrared imaging (NIR) interrogation of epidermal growth factor receptor (EGFR) expression as a sensitive biomarker of oral squamous cell carcinoma (OSCC) response to arsenic trioxide therapy was studied in mice. MATERIAL AND METHODS: A431 OSCC in vitro were exposed to 0 uM, 0.5 uM, 2.5 uM, or 5 uM of As(2)O(3) for 0 h, 24 h, 48 h and 72 h. Confocal microscopy and flow cytometry confirmed EGFR expression and demonstrated a sensitivity dose-related signal decline with As(2)O(3) treatment. Next, mice with pharynx-implanted A431 cells received As(2)O(3) i.p. every 48 h at 0.0, 0.5, 2.5, or 5 mg/kg/day (n = 6/group) from day 0 to 10. An intravenous NIR probe, EGF Cy5.5, was injected at baseline and on days 4, 8, and 12 for dynamic NIR imaging. Tumor volume and body weights were measured three times weekly. RESULTS: In vitro, A431 EGFR expression was well appreciated in the controls and decreased (p<0.05) with increasing As(2)O(3) dose and treatment duration. In vivo EGFR NIR tumor signal intensity decreased (p<0.05) in As(2)O(3) treated groups versus controls from days 4 to 12, consistent with increasing dosage. Tumor volume diminished in a dose-related manner while body weight was unaffected. Immunohistochemical staining of excised tumors confirmed that EGFR expression was reduced by As(2)O(3) treatment in a dose responsive pattern. CONCLUSION: This study demonstrates for the first time that OSCC can be interrogated in vivo by NIR molecular imaging of the EGFR and that this biomarker is effective for the longitudinal assessment of OSCC response to As(2)O(3) treatment. PMID- 23029452 TI - Severe loss of suitable climatic conditions for marsupial species in Brazil: challenges and opportunities for conservation. AB - A wide range of evidences indicate climate change as one the greatest threats to biodiversity in the 21st century. The impacts of these changes, which may have already resulted in several recent species extinction, are species-specific and produce shifts in species phenology, ecological interactions, and geographical distributions. Here we used cutting-edge methods of species distribution models combining thousands of model projections to generate a complete and comprehensive ensemble of forecasts that shows the likely impacts of climate change in the distribution of all 55 marsupial species that occur in Brazil. Consensus projections forecasted range shifts that culminate with high species richness in the southeast of Brazil, both for the current time and for 2050. Most species had a significant range contraction and lost climate space. Turnover rates were relatively high, but vary across the country. We also mapped sites retaining climatic suitability. They can be found in all Brazilian biomes, especially in the pampas region, in the southern part of the Brazilian Atlantic Forest, in the north of the Cerrado and Caatinga, and in the northwest of the Amazon. Our results provide a general overview on the likely effects of global climate change on the distribution of marsupials in the country as well as in the patterns of species richness and turnover found in regional marsupial assemblages. PMID- 23029453 TI - Does the mode of plastid inheritance influence plastid genome architecture? AB - Plastid genomes show an impressive array of sizes and compactnesses, but the forces responsible for this variation are unknown. It has been argued that species with small effective genetic population sizes are less efficient at purging excess DNA from their genomes than those with large effective population sizes. If true, one may expect the primary mode of plastid inheritance to influence plastid DNA (ptDNA) architecture. All else being equal, biparentally inherited ptDNAs should have a two-fold greater effective population size than those that are uniparentally inherited, and thus should also be more compact. Here, we explore the relationship between plastid inheritance pattern and ptDNA architecture, and consider the role of phylogeny in shaping our observations. Contrary to our expectations, we found no significant difference in plastid genome size or compactness between ptDNAs that are biparentally inherited relative to those that are uniparentally inherited. However, we also found that there was significant phylogenetic signal for the trait of mode of plastid inheritance. We also found that paternally inherited ptDNAs are significantly smaller (n = 19, p = 0.000001) than those that are maternally, uniparentally (when isogamous), or biparentally inherited. Potential explanations for this observation are discussed. PMID- 23029454 TI - A single nucleotide polymorphism within DUSP9 is associated with susceptibility to type 2 diabetes in a Japanese population. AB - AIMS: The DUSP9 locus on chromosome X was identified as a susceptibility locus for type 2 diabetes in a meta-analysis of European genome-wide association studies (GWAS), and GWAS in South Asian populations identified 6 additional single nucleotide polymorphism (SNP) loci for type 2 diabetes. However, the association of these loci with type 2 diabetes have not been examined in the Japanese. We performed a replication study to investigate the association of these 7 susceptibility loci with type 2 diabetes in the Japanese population. METHODS: We genotyped 11,319 Japanese participants (8,318 with type 2 diabetes and 3,001 controls) for each of the 7 SNPs-rs5945326 near DUSP9, rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, rs2028299 near AP3S2, and rs4812829 in HNF4A-and examined the association of each of these 7 SNPs with type 2 diabetes by using logistic regression analysis. RESULTS: All SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. One SNP, rs5945326 near DUSP9, was significantly associated with type 2 diabetes at a genome-wide significance level (p = 2.21*10(-8); OR 1.39, 95% confidence interval [CI]: 1.24-1.56). The 6 SNPs derived from South Asian GWAS were not significantly associated with type 2 diabetes in the Japanese population by themselves (p>=0.007). However, a genetic risk score constructed from 6 South Asian GWAS derived SNPs was significantly associated with Japanese type 2 diabetes (p = 8.69*10(-4), OR = 1.06. 95% CI; 1.03-1.10). CONCLUSIONS/INTERPRETATION: These results indicate that the DUSP9 locus is a common susceptibility locus for type 2 diabetes across different ethnicities, and 6 loci identified in South Asian GWAS also have significant effect on susceptibility to Japanese type 2 diabetes. PMID- 23029455 TI - Dispersal patterns, active behaviour, and flow environment during early life history of coastal cold water fishes. AB - During the pelagic larval phase, fish dispersal may be influenced passively by surface currents or actively determined by swimming behaviour. In situ observations of larval swimming are few given the constraints of field sampling. Active behaviour is therefore often inferred from spatial patterns in the field, laboratory studies, or hydrodynamic theory, but rarely are these approaches considered in concert. Ichthyoplankton survey data collected during 2004 and 2006 from coastal Newfoundland show that changes in spatial heterogeneity for multiple species do not conform to predictions based on passive transport. We evaluated the interaction of individual larvae with their environment by calculating Reynolds number as a function of ontogeny. Typically, larvae hatch into a viscous environment in which swimming is inefficient, and later grow into more efficient intermediate and inertial swimming environments. Swimming is therefore closely related to length, not only because of swimming capacity but also in how larvae experience viscosity. Six of eight species sampled demonstrated consistent changes in spatial patchiness and concomitant increases in spatial heterogeneity as they transitioned into more favourable hydrodynamic swimming environments, suggesting an active behavioural element to dispersal. We propose the tandem assessment of spatial heterogeneity and hydrodynamic environment as a potential approach to understand and predict the onset of ecologically significant swimming behaviour of larval fishes in the field. PMID- 23029456 TI - Destabilizing domains mediate reversible transgene expression in the brain. AB - Regulating transgene expression in vivo by delivering oral drugs has been a long time goal for the gene therapy field. A novel gene regulating system based on targeted proteasomal degradation has been recently developed. The system is based on a destabilizing domain (DD) of the Escherichia coli dihydrofolate reductase (DHFR) that directs fused proteins to proteasomal destruction. Creating YFP proteins fused to destabilizing domains enabled TMP based induction of YFP expression in the brain, whereas omission of TMP resulted in loss of YFP expression. Moreover, induction of YFP expression was dose dependent and at higher TMP dosages, induced YFP reached levels comparable to expression of unregulated transgene., Transgene expression could be reversibly regulated using the DD system. Importantly, no adverse effects of TMP treatment or expression of DD-fusion proteins in the brain were observed. To show proof of concept that destabilizing domains derived from DHFR could be used with a biologically active molecule, DD were fused to GDNF, which is a potent neurotrophic factor of dopamine neurons. N-terminal placement of the DD resulted in TMP-regulated release of biologically active GDNF. Our findings suggest that TMP-regulated destabilizing domains can afford transgene regulation in the brain. The fact that GDNF could be regulated is very promising for developing future gene therapies (e.g. for Parkinson's disease) and should be further investigated. PMID- 23029457 TI - The transcriptional targets of mutant FOXL2 in granulosa cell tumours. AB - BACKGROUND: Despite their distinct biology, granulosa cell tumours (GCTs) are treated the same as other ovarian tumours. Intriguingly, a recurring somatic mutation in the transcription factor Forkhead Box L2 (FOXL2) 402C>G has been found in nearly all GCTs examined. This investigation aims to identify the pathogenicity of mutant FOXL2 by studying its altered transcriptional targets. METHODS: The expression of mutant FOXL2 was reduced in the GCT cell line KGN, and wildtype and mutant FOXL2 were overexpressed in the GCT cell line COV434. Total RNA was hybridised to Affymetrix U133 Plus 2 microarrays. Comparisons were made between the transcriptomes of control cells and cells altered by FOXL2 knockdown and overexpression, to detect potential transcriptional targets of mutant FOXL2. RESULTS: The overexpression of wildtype and mutant FOXL2 in COV434, and the silencing of mutant FOXL2 expression in KGN, has shown that mutant FOXL2 is able to differentially regulate the expression of many genes, including two well known FOXL2 targets, StAR and CYP19A. We have shown that many of the genes regulated by mutant FOXL2 are clustered into functional annotations of cell death, proliferation, and tumourigenesis. Furthermore, TGF-beta signalling was found to be enriched when using the gene annotation tools GATHER and GeneSetDB. This enrichment was still significant after performing a robust permutation analysis. CONCLUSION: Given that many of the transcriptional targets of mutant FOXL2 are known TGF-beta signalling genes, we suggest that deregulation of this key antiproliferative pathway is one way mutant FOXL2 contributes to the pathogenesis of adult-type GCTs. We believe this pathway should be a target for future therapeutic interventions, if outcomes for women with GCTs are to improve. PMID- 23029458 TI - Methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to cervical cancer and cervical intraepithelial neoplasia: a meta-analysis. AB - BACKGROUND: A number of studies have explored the association between methyl enetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to cervical cancer and cervical intraepithelial neoplasia (CIN). However, results remained controversial. To address this gap, we decided to conduct a meta analysis of all available published studies. METHODS: Electronic literature searches of the PubMed, EmBase and Medline databases were performed up to April 30, 2012. Fixed-effects or random-effects model was used to calculate the pooled ORs for different genetic models. RESULTS: A total of 12 case-control studies were ultimately identified. No statistical correlation was found between C677T variants and cervical cancer for the overall population. However, subgroup analyses on the White women pointed to a significant protective effect for individuals heterozygous or homozygous for the T-allele (for CT vs. CC: OR = 0.72, 95% CI 0.59-0.88; for TT vs. CC: OR = 0.69, 95% CI = 0.49-0.97; for CT+TT vs. CC: OR = 0.71, 95% CI 0.59-0.86). C677T variants were associated with neither combined nor stratified CIN among the overall population. CONCLUSIONS: This meta analysis suggests that White women with mutant C677T genotypes might have a lower risk of cervical cancer, yet lacking enough statistical robustness. Further investigations are needed to get more insight into the role of this polymorphism in cervical carcinogenesis. PMID- 23029459 TI - Crosstalk of Escherichia coli FadR with global regulators in expression of fatty acid transport genes. AB - Escherichia coli FadR plays two regulatory roles in fatty acid metabolism. FadR represses the fatty acid degradation (fad) system and activates the unsaturated fatty acid synthetic pathway. Cross-talk between E. coli FadR and the ArcA-ArcB oxygen-responsive two-component system was observed that resulted in diverse regulation of certain fad regulon beta-oxidation genes. We have extended such analyses to the fadL and fadD genes, the protein products of which are required for long chain fatty acid transport and have also studied the role of a third global regulator, the CRP-cAMP complex. The promoters of both the fadL and fadD genes contain two experimentally validated FadR-binding sites plus binding sites for ArcA and CRP-cAMP. Despite the presence of dual binding sites FadR only modestly regulates expression of these genes, indicating that the number of binding sites does not determine regulatory strength. We report complementary in vitro and in vivo studies indicating that the CRP-cAMP complex directly activates expression of fadL and fadD as well as the beta-oxidation gene, fadH. The physiological relevance of the fadL and fadD transcription data was validated by direct assays of long chain fatty acid transport. PMID- 23029460 TI - A new slow releasing, H2S generating compound, GYY4137 relaxes spontaneous and oxytocin-stimulated contractions of human and rat pregnant myometrium. AB - Better tocolytics are required to help prevent preterm labour. The gaseotransmitter Hydrogen sulphide (H(2)S) has been shown to reduce myometrial contractility and thus is of potential interest. However previous studies used NaHS, which is toxic and releases H(2)S as a non-physiological bolus and thus alternative H(2)S donors are sought. GYY4137 has been developed to slowly release H(2)S and hence better reflect endogenous physiological release. We have examined its effects on spontaneous and oxytocin-stimulated contractility and compared them to NaHS, in human and rat myometrium, throughout gestation. The effects on contractility in response to GYY4137 (1 nM-1 mM) and NaHS (1 mM) were examined on myometrial strips from, biopsies of women undergoing elective caesarean section or hysterectomy, and from non-pregnant, 14, 18, 22 day (term) gestation or labouring rats. In pregnant rat and human myometrium dose-dependent and significant decreases in spontaneous contractions were seen with increasing concentrations of GYY4137, which also reduced underlying Ca transients. GYY4137 and NaHS significantly reduced oxytocin-stimulated and high-K depolarised contractions as well as spontaneous activity. Their inhibitory effects increased as gestation advanced, but were abruptly reversed in labour. Glibenclamide, an inhibitor of ATP-sensitive potassium (K(ATP)) channels, abolished the inhibitory effect of GYY4137. These data suggest (i) H(2)S contributes to uterine quiescence from mid-gestation until labor, (ii) that H(2)S affects L-type calcium channels and K(ATP) channels reducing Ca entry and thereby myometrial contractions, (iii) add to the evidence that H(2)S plays a physiological role in relaxing myometrium, and thus (iv) H(2)S is an attractive target for therapeutic manipulation of human myometrial contractility. PMID- 23029461 TI - Comparative molecular modeling study of Arabidopsis NADPH-dependent thioredoxin reductase and its hybrid protein. AB - 2-Cys peroxiredoxins (Prxs) play important roles in the protection of chloroplast proteins from oxidative damage. Arabidopsis NADPH-dependent thioredoxin reductase isotype C (AtNTRC) was identified as efficient electron donor for chloroplastic 2 Cys Prx-A. There are three isotypes (A, B, and C) of thioredoxin reductase (TrxR) in Arabidopsis. AtNTRA contains only TrxR domain, but AtNTRC consists of N terminal TrxR and C-terminal thioredoxin (Trx) domains. AtNTRC has various oligomer structures, and Trx domain is important for chaperone activity. Our previous experimental study has reported that the hybrid protein (AtNTRA-(Trx D)), which was a fusion of AtNTRA and Trx domain from AtNTRC, has formed variety of structures and shown strong chaperone activity. But, electron transfer mechanism was not detected at all. To find out the reason of this problem with structural basis, we performed two different molecular dynamics (MD) simulations on AtNTRC and AtNTRA-(Trx-D) proteins with same cofactors such as NADPH and flavin adenine dinucleotide (FAD) for 50 ns. Structural difference has found from superimposition of two structures that were taken relatively close to average structure. The main reason that AtNTRA-(Trx-D) cannot transfer the electron from TrxR domain to Trx domain is due to the difference of key catalytic residues in active site. The long distance between TrxR C153 and disulfide bond of Trx C387 C390 has been observed in AtNTRA-(Trx-D) because of following reasons: i) unstable and unfavorable interaction of the linker region, ii) shifted Trx domain, and iii) different or weak interface interaction of Trx domains. This study is one of the good examples for understanding the relationship between structure formation and reaction activity in hybrid protein. In addition, this study would be helpful for further study on the mechanism of electron transfer reaction in NADPH-dependent thioredoxin reductase proteins. PMID- 23029462 TI - Temperature-dependent growth of Geomyces destructans, the fungus that causes bat white-nose syndrome. AB - White-nose syndrome (WNS) is an emergent disease estimated to have killed over five million North American bats. Caused by the psychrophilic fungus Geomyces destructans, WNS specifically affects bats during hibernation. We describe temperature-dependent growth performance and morphology for six independent isolates of G. destructans from North America and Europe. Thermal performance curves for all isolates displayed an intermediate peak with rapid decline in performance above the peak. Optimal temperatures for growth were between 12.5 and 15.8 degrees C, and the upper critical temperature for growth was between 19.0 and 19.8 degrees C. Growth rates varied across isolates, irrespective of geographic origin, and above 12 degrees C all isolates displayed atypical morphology that may have implications for proliferation of the fungus. This study demonstrates that small variations in temperature, consistent with those inherent of bat hibernacula, affect growth performance and physiology of G. destructans, which may influence temperature-dependent progression and severity of WNS in wild bats. PMID- 23029463 TI - Effects of late-cenozoic glaciation on habitat availability in Antarctic benthic shrimps (Crustacea: Decapoda: Caridea). AB - Marine invertebrates inhabiting the high Antarctic continental shelves are challenged by disturbance of the seafloor by grounded ice, low but stable water temperatures and variable food availability in response to seasonal sea-ice cover. Though a high diversity of life has successfully adapted to such conditions, it is generally agreed that during the Last Glacial Maximum (LGM) the large-scale cover of the Southern Ocean by multi-annual sea ice and the advance of the continental ice sheets across the shelf faced life with conditions, exceeding those seen today by an order of magnitude. Conditions prevailing at the LGM may have therefore acted as a bottleneck event to both the ecology as well as genetic diversity of today's fauna. Here, we use for the first time specific Species Distribution Models (SDMs) for marine arthropods of the Southern Ocean to assess effects of habitat contraction during the LGM on the three most common benthic caridean shrimp species that exhibit a strong depth zonation on the Antarctic continental shelf. While the shallow-water species Chorismus antarcticus and Notocrangon antarcticus were limited to a drastically reduced habitat during the LGM, the deep-water shrimp Nematocarcinus lanceopes found refuge in the Southern Ocean deep sea. The modeling results are in accordance with genetic diversity patterns available for C. antarcticus and N. lanceopes and support the hypothesis that habitat contraction at the LGM resulted in a loss of genetic diversity in shallow water benthos. PMID- 23029464 TI - Toxicity assessment of iron oxide nanoparticles in zebrafish (Danio rerio) early life stages. AB - Iron oxide nanoparticles have been explored recently for their beneficial applications in many biomedical areas, in environmental remediation, and in various industrial applications. However, potential risks have also been identified with the release of nanoparticles into the environment. To study the ecological effects of iron oxide nanoparticles on aquatic organisms, we used early life stages of the zebrafish (Danio rerio) to examine such effects on embryonic development in this species. The results showed that >=10 mg/L of iron oxide nanoparticles instigated developmental toxicity in these embryos, causing mortality, hatching delay, and malformation. Moreover, an early life stage test using zebrafish embryos/larvae is also discussed and recommended in this study as an effective protocol for assessing the potential toxicity of nanoparticles. This study is one of the first on developmental toxicity in fish caused by iron oxide nanoparticles in aquatic environments. The results will contribute to the current understanding of the potential ecotoxicological effects of nanoparticles and support the sustainable development of nanotechnology. PMID- 23029466 TI - Mitofusin-2 independent juxtaposition of endoplasmic reticulum and mitochondria: an ultrastructural study. AB - Besides its role in controlling the morphology of mitochondria, mitofusin-2 has been proposed to tether mitochondria to the endoplasmic reticulum (ER), based largely on light microscopic analysis. In this study we have examined by electron microscopy the organization of ER and mitochondria in cells expressing or not mitofusin-2. Contrary to previous studies, we observed that loss of mitofusin-2 increased ER-mitochondria juxtaposition. These results suggest that mitofusin-2 does not play a critical role in the juxtapostion of ER and mitochondria, and highlight the essential role of ultrastructural analysis to visualize and measure contact between two intracellular compartments. PMID- 23029465 TI - Sigma factor N, liaison to an ntrC and rpoS dependent regulatory pathway controlling acid resistance and the LEE in enterohemorrhagic Escherichia coli. AB - Enterohemorrhagic Escherichia coli (EHEC) is dependent on acid resistance for gastric passage and low oral infectious dose, and the locus of enterocyte effacement (LEE) for intestinal colonization. Mutation of rpoN, encoding sigma factor N (sigma(N)), dramatically alters the growth-phase dependent regulation of both acid resistance and the LEE. This study reports on the determinants of sigma(N)-directed acid resistance and LEE expression, and the underlying mechanism attributable to this phenotype. Glutamate-dependent acid resistance (GDAR) in TW14359DeltarpoN correlated with increased expression of the gadX-gadW regulatory circuit during exponential growth, whereas upregulation of arginine dependent acid resistance (ADAR) genes adiA and adiC in TW14359DeltarpoN did not confer acid resistance by the ADAR mechanism. LEE regulatory (ler), structural (espA and cesT) and effector (tir) genes were downregulated in TW14359DeltarpoN, and mutation of rpoS encoding sigma factor 38 (sigma(S)) in TW14359DeltarpoN restored acid resistance and LEE genes to WT levels. Stability, but not the absolute level, of sigma(S) was increased in TW14359DeltarpoN; however, increased stability was not solely attributable to the GDAR and LEE expression phenotype. Complementation of TW14359DeltarpoN with a sigma(N) allele that binds RNA polymerase (RNAP) but not DNA, did not restore WT levels of sigma(S) stability, gadE, ler or GDAR, indicating a dependence on transcription from a sigma(N) promoter(s) and not RNAP competition for the phenotype. Among a library of sigma(N) enhancer binding protein mutants, only TW14359DeltantrC, inactivated for nitrogen regulatory protein NtrC, phenocopied TW14359DeltarpoN for sigma(S) stability, GDAR and ler expression. The results of this study suggest that during exponential growth, NtrC-sigma(N) regulate GDAR and LEE expression through downregulation of sigma(S) at the post-translational level; likely by altering sigma(S) stability or activity. The regulatory interplay between NtrC, other EBPs, and sigma(N)-sigma(S), represents a mechanism by which EHEC can coordinate GDAR, LEE expression and other cellular functions, with nitrogen availability and physiologic stimuli. PMID- 23029467 TI - New functions of arthropod bursicon: inducing deposition and thickening of new cuticle and hemocyte granulation in the blue crab, Callinectes sapidus. AB - Arthropod growth requires molt-associated changes in softness and stiffness of the cuticle that protects from desiccation, infection and injury. Cuticle hardening in insects depends on the blood-borne hormone, bursicon (Burs), although it has never been determined in hemolymph. Whilst also having Burs, decapod crustaceans reiterate molting many more times during their longer life span and are encased in a calcified exoskeleton, which after molting undergoes similar initial cuticle hardening processes as in insects. We investigated the role of homologous crustacean Burs in cuticular changes and growth in the blue crab, Callinectes sapidus. We found dramatic increases in size and number of Burs cells during development in paired thoracic ganglion complex (TGC) neurons with pericardial organs (POs) as neurohemal release sites. A skewed expression of Burs beta/Burs alpha mRNA in TGC corresponds to protein contents of identified Burs beta homodimer and Burs heterodimer in POs. In hemolymph, Burs is consistently present at ~21 pM throughout the molt cycle, showing a peak of ~89 pM at ecdysis. Since initial cuticle hardness determines the degree of molt-associated somatic increment (MSI), we applied recombinant Burs in vitro to cuticle explants of late premolt or early ecdysis. Burs stimulates cuticle thickening and granulation of hemocytes. These findings demonstrate novel cuticle-associated functions of Burs during molting, while the unambiguous and constant presence of Burs in cells and hemolymph throughout the molt cycle and life stages may implicate further functions of its homo- and heterodimer hormone isoforms in immunoprotective defense systems of arthropods. PMID- 23029468 TI - H(2)S-releasing aspirin protects against aspirin-induced gastric injury via reducing oxidative stress. AB - The aim of this study was to examine the effect of ACS14, a hydrogen sulfide (H(2)S)-releasing derivative of aspirin (Asp), on Asp-induced gastric injury. Gastric hemorrhagic lesions were induced by intragastric administration of Asp (200 mg/kg, suspended in 0.5% carboxymethyl cellulose solutions) in a volume of 1 ml/100 g body weight. ACS14 (1, 5 or 10 mg/kg) was given 30 min before the Asp administration. The total area of gastric erosions, H(2)S concentration and oxidative stress in gastric tissues were measured three hours after administration of Asp. Treatment with Asp (200 mg/kg), but not ACS14 (430 mg/kg, at equimolar doses to 200 mg/kg Asp), for 3 h significantly increased gastric mucosal injury. The damage caused by Asp was reversed by ACS14 at 1-10 mg/kg in a concentration-dependent manner. ACS14 abrogated Asp-induced upregulation of COX-2 expression, but had no effect on the reduced PGE(2) level. ACS14 reversed the decreased H(2)S concentrations and blood flow in the gastric tissue in Asp treated rats. Moreover, ACS14 attenuated Asp-suppressed superoxide dismutase-1 (SOD-1) expression and GSH activity, suggesting that ACS14 may stimulate antioxidants in the gastric tissue. ACS14 also obviously inhibited Asp-induced upregulation of protein expression of oxidases including XOD, p47(phox) and p67(phox). In conclusion, ACS14 protects Asp induced gastric mucosal injury by inhibiting oxidative stress in the gastric tissue. PMID- 23029469 TI - Endothelin-1 augments Na+/H+ exchange activity in murine pulmonary arterial smooth muscle cells via Rho kinase. AB - Excessive production of endothelin-1 (ET-1), a potent vasoconstrictor, occurs with several forms of pulmonary hypertension. In addition to modulating vasomotor tone, ET-1 can potentiate pulmonary arterial smooth muscle cell (PASMC) growth and migration, both of which contribute to the vascular remodeling that occurs during the development of pulmonary hypertension. It is well established that changes in cell proliferation and migration in PASMCs are associated with alkalinization of intracellular pH (pH(i)), typically due to activation of Na(+)/H(+) exchange (NHE). In the systemic vasculature, ET-1 increases pH(i), Na(+)/H(+) exchange activity and stimulates cell growth via a mechanism dependent on protein kinase C (PKC). These results, coupled with data describing elevated levels of ET-1 in hypertensive animals/humans, suggest that ET-1 may play an important role in modulating pH(i) and smooth muscle growth in the lung; however, the effect of ET-1 on basal pH(i) and NHE activity has yet to be examined in PASMCs. Thus, we used fluorescent microscopy in transiently (3-5 days) cultured rat PASMCs and the pH-sensitive dye, BCECF-AM, to measure changes in basal pH(i) and NHE activity induced by increasing concentrations of ET-1 (10(-10) to 10(-8) M). We found that application of exogenous ET-1 increased pH(i) and NHE activity in PASMCs and that the ET-1-induced augmentation of NHE was prevented in PASMCs pretreated with an inhibitor of Rho kinase, but not inhibitors of PKC. Moreover, direct activation of PKC had no effect on pH(i) or NHE activity in PASMCs. Our results indicate that ET-1 can modulate pH homeostasis in PASMCs via a signaling pathway that includes Rho kinase and that, in contrast to systemic vascular smooth muscle, activation of PKC does not appear to be an important regulator of PASMC pH(i). PMID- 23029470 TI - Heteromerization of ciliary G protein-coupled receptors in the mouse brain. AB - Nearly every cell type in the mammalian body projects from its cell surface a primary cilium that provides important sensory and signaling functions. Defects in the formation or function of primary cilia have been implicated in the pathogenesis of many human developmental disorders and diseases, collectively termed ciliopathies. Most neurons in the brain possess cilia that are enriched for signaling proteins such as G protein-coupled receptors and adenylyl cyclase type 3, suggesting neuronal cilia sense neuromodulators in the brain and contribute to non-synaptic signaling. Indeed, disruption of neuronal cilia or loss of neuronal ciliary signaling proteins is associated with obesity and learning and memory deficits. As the functions of primary cilia are defined by the signaling proteins that localize to the ciliary compartment, identifying the complement of signaling proteins in cilia can provide important insights into their physiological roles. Here we report for the first time that different GPCRs can colocalize within the same cilium. Specifically, we found the ciliary GPCRs, melanin-concentrating hormone receptor 1 (Mchr1) and somatostatin receptor 3 (Sstr3) colocalizing within cilia in multiple mouse brain regions. In addition, we have evidence suggesting Mchr1 and Sstr3 form heteromers. As GPCR heteromerization can affect ligand binding properties as well as downstream signaling, our findings add an additional layer of complexity to neuronal ciliary signaling. PMID- 23029471 TI - Outer segment formation of transplanted photoreceptor precursor cells. AB - Transplantation of photoreceptor precursor cells (PPCs) into the retina represents a promising treatment for cell replacement in blinding diseases characterized by photoreceptor loss. In preclinical studies, we and others demonstrated that grafted PPCs integrate into the host outer nuclear layer (ONL) and develop into mature photoreceptors. However, a key feature of light detecting photoreceptors, the outer segment (OS) with natively aligned disc membrane staples, has not been studied in detail following transplantation. Therefore, we used as donor cells PPCs isolated from neonatal double transgenic reporter mice in which OSs are selectively labeled by green fluorescent protein while cell bodies are highlighted by red fluorescent protein. PPCs were enriched using CD73 based magnetic associated cell sorting and subsequently transplanted into either adult wild-type or a model of autosomal-dominant retinal degeneration mice. Three weeks post-transplantation, donor photoreceptors were identified based on fluorescent-reporter expression and OS formation was monitored at light and electron microscopy levels. Donor cells that properly integrated into the host wild-type retina developed OSs with the formation of a connecting cilium and well aligned disc membrane staples similar to the surrounding native cells of the host. Surprisingly, the majority of not-integrated PPCs that remained in the sub retinal space also generated native-like OSs in wild-type mice and those affected by retinal degeneration. Moreover, they showed an improved photoreceptor maturation and OS formation by comparison to donor cells located on the vitreous side suggesting that environmental cues influence the PPC differentiation and maturation. We conclude that transplanted PPCs, whether integrated or not into the host ONL, are able to generate the cellular structure for effective light detection, a phenomenon observed in wild-type as well as in degenerated retinas. Given that patients suffering from retinitis pigmentosa lose almost all photoreceptors, our findings are of utmost importance for the development of cell based therapies. PMID- 23029472 TI - Repulsive guidance molecule (RGM) family proteins exhibit differential binding kinetics for bone morphogenetic proteins (BMPs). AB - Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta superfamily that exert their effects via type I and type II serine threonine kinase receptors and the SMAD intracellular signaling pathway to regulate diverse biologic processes. Recently, we discovered that the repulsive guidance molecule (RGM) family, including RGMA, RGMB, and RGMC/hemojuvelin (HJV), function as co receptors that enhance cellular responses to BMP ligands. Here, we use surface plasmon resonance to quantitate the binding kinetics of RGM proteins for BMP ligands. We show that among the RGMs, HJV exhibits the highest affinity for BMP6, BMP5, and BMP7 with K(D) 8.1, 17, and 20 nM respectively, versus 28, 33, and 166 nM for RGMB, and 55, 83, and 63 nM for RGMA. Conversely, RGMB exhibits preferential binding to BMP4 and BMP2 with K(D) 2.6 and 5.5 nM respectively, versus 4.5 and 9.4 nM for HJV, and 14 and 22 nM for RGMA, while RGMA exhibits the lowest binding affinity for most BMPs tested. Among the BMP ligands, RGMs exhibit the highest relative affinity for BMP4 and the lowest relative affinity for BMP7, while none of the RGMs bind to BMP9. Thus, RGMs exhibit preferential binding for distinct subsets of BMP ligands. The preferential binding of HJV for BMP6 is consistent with the functional role of HJV and BMP6 in regulating systemic iron homeostasis. Our data may help explain the mechanism by which BMPs exert cell context specific effects via a limited number of type I and type II receptors. PMID- 23029474 TI - Performance comparison among the major healthcare financing systems in six cities of the Pearl River Delta region, mainland China. AB - BACKGROUND: The healthcare system of mainland China is undergoing drastic reform and the optimal models for healthcare financing for provision of primary care will need to be identified. This study compared the performance indicators of the community health centres (CHCs) under different healthcare financing systems in the six cities of the Pearl River Delta region. METHODS: Approximately 300 hypertensive patients were randomly recruited from the computerized chronic disease management records provided by one CHC in each of the six cities in 2011 using a multi-stage cluster random sampling method. The major outcome measures included the treatment rate of hypertension, defined as prescription of >= one antihypertensive agent; and the control rate of hypertension, defined as systolic blood pressure levels <140 mmHg and diastolic blood pressure levels <90 mmHg in patients without diabetes mellitus, or <130/80 mmHg among patients with concomitant diabetes. Binary logistic regression analyses were conducted with these two measures as outcome variables, respectively, controlling for patients' socio-demographic variables. The financing system (Hospital- vs. Government- vs. private-funded) was the independent variable tested for association with the outcomes. RESULTS: From 1,830 patients with an average age of 65.9 years (SD 12.8), the overall treatment and control rates were 75.4% and 20.2%, respectively. When compared with hospital-funded CHCs, patients seen in the Government-funded (adjusted odds ratio [AOR] 0.462, 95% C.I. 0.325-0.656) and private-funded CHCs (AOR 0.031, 95% C.I. 0.019-0.052) were significantly less likely to be prescribed antihypertensive medication. However, the Government funded CHC was more likely to have optimal BP control (AOR 1.628, 95% C.I. 1.157 2.291) whilst the privately-funded CHC was less likely to achieve BP control (AOR 0.146, 95% C.I. 0.069-0.310), irrespective of whether antihypertensive drugs were prescribed. CONCLUSIONS: Privately-funded CHCs had the lowest rates of BP treatment and control due to a variety of potential factors as discussed. PMID- 23029473 TI - The homozygote VCP(R155H/R155H) mouse model exhibits accelerated human VCP associated disease pathology. AB - Valosin containing protein (VCP) mutations are the cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia (IBMPFD). VCP gene mutations have also been linked to 2% of isolated familial amyotrophic lateral sclerosis (ALS). VCP is at the intersection of disrupted ubiquitin proteasome and autophagy pathways, mechanisms responsible for the intracellular protein degradation and abnormal pathology seen in muscle, brain and spinal cord. We have developed the homozygous knock-in VCP mouse (VCP(R155H/R155H)) model carrying the common R155H mutations, which develops many clinical features typical of the VCP-associated human diseases. Homozygote VCP(R155H/R155H) mice typically survive less than 21 days, exhibit weakness and myopathic changes on EMG. MicroCT imaging of the bones reveal non-symmetrical radiolucencies of the proximal tibiae and bone, highly suggestive of PDB. The VCP(R155H/R155H) mice manifest prominent muscle, heart, brain and spinal cord pathology, including striking mitochondrial abnormalities, in addition to disrupted autophagy and ubiquitin pathologies. The VCP(R155H/R155H) homozygous mouse thus represents an accelerated model of VCP disease and can be utilized to elucidate the intricate molecular mechanisms involved in the pathogenesis of VCP-associated neurodegenerative diseases and for the development of novel therapeutic strategies. PMID- 23029475 TI - Arteriolar and venular remodeling are differentially regulated by bone marrow derived cell-specific CX3CR1 and CCR2 expression. AB - The chemokine receptors CCR2 and CX3CR1 are critical for the recruitment of "inflammatory" and "resident" monocytes, respectively, subpopulations that differentially affect vascular remodeling in atherosclerosis. Here, we tested the hypothesis that bone marrow-derived cell (BMC)-specific CCR2 and CX3CR1 differentially control venular and arteriolar remodeling. Venular and arteriolar lumenal remodeling were observed by intravital microscopy in mice with either CCR2 or CX3CR1 deficient BMCs after implantation of a dorsal skinfold window chamber, a model in which arterioles and venules lumenally enlarge in wild-type (WT) mice. Arteriolar remodeling was abolished in mice with either CCR2 or CX3CR1 deficient BMCs. In contrast, the loss of CX3CR1 from BMCs, but not CCR2, significantly reduced small venule remodeling compared to WT controls. We conclude that microvascular remodeling is differentially regulated by BMC expressed chemokine receptors. Both CCR2 and CX3CR1 regulate arteriole growth; however, only BMC-expressed CX3CR1 impacts small venule growth. These findings may provide a basis for additional investigations aimed at determining how patterns of monocyte subpopulation recruitment spatially influence microvascular remodeling. PMID- 23029476 TI - Copy number variation in subjects with major depressive disorder who attempted suicide. AB - BACKGROUND: Suicide is one of the top ten leading causes of death in North America and represents a major public health burden, particularly for people with Major Depressive disorder (MD). Many studies have suggested that suicidal behavior runs in families, however, identification of genomic loci that drive this efffect remain to be identified. METHODOLOGY/PRINCIPAL FINDINGS: Using subjects collected as part of STAR D, we genotyped 189 subjects with MD with history of a suicide attempt and 1073 subjects with Major Depressive disorder that had never attempted suicide. Copy Number Variants (CNVs) were called in Birdsuite and analyzed in PLINK. We found a set of CNVs present in the suicide attempter group that were not present in in the non-attempter group including in SNTG2 and MACROD2 - two brain expressed genes previously linked to psychopathology; however, these results failed to reach genome-wide signifigance. CONCLUSIONS: These data suggest potential CNVs to be investigated further in relation to suicide attempts in MD using large sample sizes. PMID- 23029477 TI - ZNF385B and VEGFA are strongly differentially expressed in serous ovarian carcinomas and correlate with survival. AB - BACKGROUND: The oncogenesis of ovarian cancer is poorly understood. The aim of this study was to identify mRNAs differentially expressed between moderately and poorly differentiated (MD/PD) serous ovarian carcinomas (SC), serous ovarian borderline tumours (SBOT) and superficial scrapings from normal ovaries (SNO), and to correlate these mRNAs with clinical parameters including survival. METHODS: Differences in mRNA expression between MD/PD SC, SBOT and SNO were analyzed by global gene expression profiling (n = 23), validated by RT-qPCR (n = 41) and correlated with clinical parameters. RESULTS: Thirty mRNAs differentially expressed between MD/PD SC, SBOT and SNO were selected from the global gene expression analyses, and 21 were verified (p<0.01) by RT-qPCR. Of these, 13 mRNAs were differentially expressed in MD/PD SC compared with SNO (p<0.01) and were correlated with clinical parameters. ZNF385B was downregulated (FC = -130.5, p = 1.2*10(-7)) and correlated with overall survival (p = 0.03). VEGFA was upregulated (FC = 6.1, p = 6.0*10(-6)) and correlated with progression-free survival (p = 0.037). Increased levels of TPX2 and FOXM1 mRNAs (FC = 28.5, p = 2.7*10(-10) and FC = 46.2, p = 5.6*10(-4), respectively) correlated with normalization of CA125 (p = 0.03 and p = 0.044, respectively). Furthermore, we present a molecular pathway for MD/PD SC, including VEGFA, FOXM1, TPX2, BIRC5 and TOP2A, all significantly upregulated and directly interacting with TP53. CONCLUSIONS: We have identified 21 mRNAs differentially expressed (p<0.01) between MD/PD SC, SBOT and SNO. Thirteen were differentially expressed in MD/PD SC, including ZNF385B and VEGFA correlating with survival, and FOXM1 and TPX2 with normalization of CA125. We also present a molecular pathway for MD/PD SC. PMID- 23029478 TI - Up-regulation of TIMP-1 by genipin inhibits MMP-2 activities and suppresses the metastatic potential of human hepatocellular carcinoma. AB - AIM OF THE STUDY: Hepatocellular carcinoma is one of the most malignant human cancers with high metastatic potential. The aim of this study is to investigate the anti-metastatic effect of genipin and its underlying mechanism. EXPERIMENTAL APPROACH: The anti-metastatic potential of genipin was evaluated by both cell and animal model. Wound healing and invasion chamber assays were introduced to examine the anti-migration and anti-invasion action of genipin in human hepatocellular carcinoma cell HepG2 and MHCC97L; orthotopical implantation model was used for in vivo evaluation. Gelatin Zymography, Immunoblotting, quantitative real-time polymerase chain reaction and ELISA assays were used to study the mechanisms underlying genipin's anti-metastatic effect. KEY RESULTS: Genipin suppresses the motility and invasiveness of HepG2 and MHCC97L at non-toxic doses, which may be correlated to the inhibition of genipin on MMP-2 activities in the cells. No significant reduced expression of MMP-2 was observed either at mRNA or at protein level. Furthermore, genipin could specifically up-regulate the expression of TIMP-1, the endogenous inhibitor of MMP-2 activities. Silencing of TIMP-1 by RNA interference abolishes genipin's anti-metastaic effect. Activation of p38 MAPK signaling was observed in genipin-treated cells, which is responsible for the TIMP-1 overexpression and MMP-2 inhibition. Presence of SB202190, the p38 MAPK inhibitor, attenuates the anti-metastatic potential of genipin in hepatocellular carcinoma. Orthotopical implantation model showed that genipin could suppress the intrahepatic metastatic as well as tumor expansion in liver without exhibiting potent toxicity. CONCLUSION: Our findings demonstrated the potential of genipin in suppressing hepatocellular carcinoma metastasis, and p38/TIMP-1/MMP-2 pathway may be involved as the key mechanism of its anti metastasis effect. PMID- 23029479 TI - Genome-wide and locus specific alterations in CDC73/HRPT2-mutated parathyroid tumors. AB - Mutations in the hyperparathyroidism type 2 (HRPT2/CDC73) gene and alterations in the parafibromin protein have been established in the majority of parathyroid carcinomas and in subsets of parathyroid adenomas. While it is known that CDC73 mutated parathyroid tumors display specific gene expression changes compared to CDC73 wild-type cases, the molecular cytogenetic profile in CDC73-mutated cases compared to unselected adenomas (with an expected very low frequency of CDC73 mutations) remains unknown. For this purpose, nine parathyroid tumors with established CDC73 gene inactivating mutations (three carcinomas, one atypical adenoma and five adenomas) were analyzed for copy number alterations and loss of heterozygosity using array-comparative genomic hybridization (a-CGH) and single nucleotide polymorphism (SNP) microarrays, respectively. Furthermore, CDC73 gene promoter methylation levels were assessed using bisulfite Pyrosequencing. The panel included seven tumors with single mutation and three with double mutations of the CDC73 gene. The carcinomas displayed copy number alterations in agreement with previous studies, whereas the CDC73-mutated adenomas did not display the same pattern of alterations at loci frequently deleted in unselected parathyroid tumors. Furthermore, gross losses of chromosomal material at 1p and 13 were significantly (p = 0.012) associated with parathyroid carcinomas as opposed to adenomas. Quantitative PCR-based copy number loss regarding CDC73 was observed in three adenomas, while all the carcinomas were diploid or showed copy number gain for CDC73 gene. Hypermethylation of the CDC73 gene promoter was not observed. Our data could suggest that CDC73-mutated parathyroid adenomas exhibit a partly unique cytogenetic profile in addition to that of carcinomas and unselected adenomas. Furthermore, CDC73-mutated carcinomas displayed losses at 1p and 13 which are not seen in CDC73-mutated adenomas, making these regions of interest for further studies regarding malignant properties in tumors from CDC73-mutated cases. However, due to the small sample size, validation of the results in a larger cohort is warranted. PMID- 23029480 TI - Protein folding modulates the swapped dimerization mechanism of methyl-accepting chemotaxis heme sensors. AB - The periplasmic sensor domains GSU0582 and GSU0935 are part of methyl accepting chemotaxis proteins in the bacterium Geobacter sulfurreducens. Both contain one c type heme group and their crystal structures revealed that these domains form swapped dimers with a PAS fold formed from the two protein chains. The swapped dimerization of these sensors is related to the mechanism of signal transduction and the formation of the swapped dimer involves significant folding changes and conformational rearrangements within each monomeric component. However, the structural changes occurring during this process are poorly understood and lack a mechanistic framework. To address this issue, we have studied the folding and stability properties of two distinct heme-sensor PAS domains, using biophysical spectroscopies. We observed substantial differences in the thermodynamic stability (DeltaG = 14.6 kJ.mol(-1) for GSU0935 and DeltaG = 26.3 kJ.mol(-1) for GSU0582), and demonstrated that the heme moiety undergoes conformational changes that match those occurring at the global protein structure. This indicates that sensing by the heme cofactor induces conformational changes that rapidly propagate to the protein structure, an effect which is directly linked to the signal transduction mechanism. Interestingly, the two analyzed proteins have distinct levels of intrinsic disorder (25% for GSU0935 and 13% for GSU0582), which correlate with conformational stability differences. This provides evidence that the sensing threshold and intensity of the propagated allosteric effect is linked to the stability of the PAS-fold, as this property modulates domain swapping and dimerization. Analysis of the PAS-domain shows that disorder segments are found either at the hinge region that controls helix motions or in connecting segments of the beta-sheet interface. The latter is known to be widely involved in both intra- and intermolecular interactions, supporting the view that it's folding and stability are at the basis of the specificity and regulation of many types of PAS-containing signaling proteins. PMID- 23029481 TI - Molecular evidence for gender differences in the migratory behaviour of a small seabird. AB - Molecular sexing revealed an unexpectedly strong female bias in the sex ratio of pre-breeding European Storm Petrels (Hydrobates pelagicus), attracted to playback of conspecific calls during their northwards migration past SW Europe. This bias was consistent across seven years, ranging from 80.8% to 89.7% female (mean annual sex ratio +/- SD = 85.5% female +/-4.1%). The sex ratio did not differ significantly from unity (i.e., 50% female) among (i) Storm Petrel chicks at a breeding colony in NW France, (ii) adults found dead on beaches in Southern Portugal, (iii) breeding birds attending nest burrows in the UK, captured by hand, and (iv) adults captured near a breeding colony in the UK using copies of the same sound recordings as used in Southern Europe, indicating that females are not inherently more strongly attracted to playback calls than males. A morphological discriminant function analysis failed to provide a good separation of the sexes, showing the importance of molecular sexing for this species. We found no sex difference in the seasonal or nocturnal timing of migration past Southern Europe, but there was a significant tendency for birds to be caught in sex-specific aggregations. The preponderance of females captured in Southern Europe suggests that the sexes may differ in migration route or in their colony prospecting behaviour during migration, at sites far away from their natal colonies. Such differences in migration behaviour between males and females are poorly understood but have implications for the vulnerability of seabirds to pollution and environmental change at sea during the non-breeding season. PMID- 23029482 TI - A genotypic test for HIV-1 tropism combining Sanger sequencing with ultradeep sequencing predicts virologic response in treatment-experienced patients. AB - A tropism test is required prior to initiation of CCR5 antagonist therapy in HIV 1 infected individuals, as these agents are not effective in patients harboring CXCR4 (X4) coreceptor-using viral variants. We developed a clinical laboratory based genotypic tropism test for detection of CCR5-using (R5) or X4 variants that utilizes triplicate population sequencing (TPS) followed by ultradeep sequencing (UDS) for samples classified as R5. Tropism was inferred using the bioinformatic algorithms geno2pheno([coreceptor]) and PSSM(x4r5). Virologic response as a function of tropism readout was retrospectively assessed using blinded samples from treatment-experienced subjects who received maraviroc (N = 327) in the MOTIVATE and A4001029 clinical trials. MOTIVATE patients were classified as R5 and A4001029 patients were classified as non-R5 by the original Trofile test. Virologic response was compared between the R5 and non-R5 groups determined by TPS, UDS alone, the reflex strategy and the Trofile Enhanced Sensitivity (TF-ES) test. UDS had greater sensitivity than TPS to detect minority non-R5 variants. The median log(10) viral load change at week 8 was -2.4 for R5 subjects, regardless of the method used for classification; for subjects with non-R5 virus, median changes were -1.2 for TF-ES or the Reflex Test and -1.0 for UDS. The differences between R5 and non-R5 groups were highly significant in all 3 cases (p<0.0001). At week 8, the positive predictive value was 66% for TF-ES and 65% for both the Reflex test and UDS. Negative predictive values were 59% for TF-ES, 58% for the Reflex Test and 61% for UDS. In conclusion, genotypic tropism testing using UDS alone or a reflex strategy separated maraviroc responders and non responders as well as a sensitive phenotypic test, and both assays showed improved performance compared to TPS alone. Genotypic tropism tests may provide an alternative to phenotypic testing with similar discriminating ability. PMID- 23029483 TI - Temporal sequence of visuo-auditory interaction in multiple areas of the guinea pig visual cortex. AB - Recent studies in humans and monkeys have reported that acoustic stimulation influences visual responses in the primary visual cortex (V1). Such influences can be generated in V1, either by direct auditory projections or by feedback projections from extrastriate cortices. To test these hypotheses, cortical activities were recorded using optical imaging at a high spatiotemporal resolution from multiple areas of the guinea pig visual cortex, to visual and/or acoustic stimulations. Visuo-auditory interactions were evaluated according to differences between responses evoked by combined auditory and visual stimulation, and the sum of responses evoked by separate visual and auditory stimulations. Simultaneous presentation of visual and acoustic stimulations resulted in significant interactions in V1, which occurred earlier than in other visual areas. When acoustic stimulation preceded visual stimulation, significant visuo auditory interactions were detected only in V1. These results suggest that V1 is a cortical origin of visuo-auditory interaction. PMID- 23029484 TI - Iceberg scour and shell damage in the Antarctic bivalve Laternula elliptica. AB - We document differences in shell damage and shell thickness in a bivalve mollusc (Laternula elliptica) from seven sites around Antarctica with differing exposures to ice movement. These range from 60% of the sea bed impacted by ice per year (Hangar Cove, Antarctic Peninsula) to those protected by virtually permanent sea ice cover (McMurdo Sound). Patterns of shell damage consistent with blunt force trauma were observed in populations where ice scour frequently occurs; damage repair frequencies and the thickness of shells correlated positively with the frequency of iceberg scour at the different sites with the highest repair rates and thicker shells at Hangar Cove (74.2% of animals damaged) compared to the other less impacted sites (less than 10% at McMurdo Sound). Genetic analysis of population structure using Amplified Fragment Length Polymorphisms (AFLPs) revealed no genetic differences between the two sites showing the greatest difference in shell morphology and repair rates. Taken together, our results suggest that L. elliptica exhibits considerable phenotypic plasticity in response to geographic variation in physical disturbance. PMID- 23029485 TI - Regulation of COX2 expression in mouse mammary tumor cells controls bone metastasis and PGE2-induction of regulatory T cell migration. AB - BACKGROUND: The targeting of the immune system through immunotherapies to prevent tumor tolerance and immune suppression are at the front lines of breast cancer treatment and research. Human and laboratory studies have attributed breast cancer progression and metastasis to secondary organs such as the bone, to a number of factors, including elevated levels of prostaglandin E2 (PGE2) and the enzyme responsible for its production, cyclooxygenase 2 (COX2). Due to the strong connection of COX2 with immune function, we focused on understanding how variance in COX2 expression manipulates the immune profile in a syngeneic, and immune competent, mouse model of breast cancer. Though there have been correlative findings linking elevated levels of COX2 and Tregs in other cancer models, we sought to elucidate the mechanisms by which these immuno-suppressive cells are recruited to breast tumor and the means by which they promote tumor tolerance. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the mechanisms by which exacerbated COX2 expression potentiates metastasis we genetically manipulated non-metastatic mammary tumor cells (TM40D) to over-express COX2 (TM40D-COX2). Over-expression of COX2 in this mouse breast cancer model resulted in an increase in bone metastasis (an observation that was ablated following suppression of COX2 expression) in addition to an exacerbated Treg recruitment in the primary tumor. Interestingly, other immune-suppressive leukocytes, such as myeloid derived suppressor cells, were not altered in the primary tumor or the circulation. Elevated levels of PGE2 by tumor cells can directly recruit CD4+CD25+ cells through interactions with their EP2 and/or EP4 receptors, an effect that was blocked using anti-PGE2 antibody. Furthermore, increased Treg recruitment to the primary tumor contributed to the greater levels of apoptotic CD8+ T cells in the TM40D-COX2 tumors. CONCLUSION/SIGNIFICANCE: Due to the systemic effects of COX2 inhibitors, we propose targeting specific EP receptors as therapeutic interventions to breast cancer progression. PMID- 23029486 TI - The oropharyngeal morphology in the semiaquatic giant Asian pond turtle, Heosemys grandis, and its evolutionary implications. AB - The oropharynx as a functional entity plays a fundamental role in feeding. Transitions from aquatic to terrestrial lifestyles in vertebrates demanded major changes of the oropharynx for the required adaptations to a different feeding environment. Extant turtles evolved terrestrial feeding modes in three families (testudinids, emydids, geoemydids)-independently from other amniotes-and are therefore important model organisms to reconstruct morpho-functional changes behind aquatic-terrestrial transitions. In this study we hypothesized that the oropharyngeal morphology in semiaquatic turtles of the geoemydid family shows parallels to testudinids, the only purely terrestrial extant lineage. We provide an in-depth description of the oropharynx in the semiaquatic geoemydid Heosemys grandis by using a combination of micro computed tomography (micro-CT) and subsequent digital in situ 3-D reconstruction, scanning electron microscopy (SEM), and histology. We show that H. grandis has a large tongue with rough papillose surface and well-developed lingual muscles. The attachment sites of the lingual muscles on the hyolingual skeleton and their courses within the tongue are nearly identical with testudinids. The hyolingual skeleton itself is mainly cartilaginous and shows distinct-but compared to testudinids rather small anterior extensions of the hyoid body and hypoglossum. Oral glands are well developed in H. grandis but are smaller and simpler than in testudinids. Similarly, oropharyngeal keratinization was minimal and found only in the anterior palate, regions close to the beak, and tongue tip. We conclude that H. grandis shows distinct oropharyngeal morpho-functional adaptations for a terrestrial lifestyle but still retains characters typical for aquatic forms. This makes this species an important example showing the oropharyngeal adaptations behind aquatic-terrestrial transitions in turtles. PMID- 23029488 TI - Large-scale age-dependent skewed sex ratio in a sexually dimorphic avian scavenger. AB - Age-dependent skewed sex ratios have been observed in bird populations, with adult males generally outnumbering females. This trend is mainly driven by higher female mortality, sometimes associated with anthropogenic factors. Despite the large amount of work on bird sex ratios, research examining the spatial stability of adult sex ratios is extremely scarce. The Andean condor (Vultur gryphus) is the only bird of prey with strong sexual dimorphism favouring males (males are 30% heavier than females). By examining data from most of its South-American range, we show that while the juvenile sex ratio is balanced, or even female skewed, the sex ratio becomes increasing male-skewed with age, with adult males outnumbering females by >20%, and, in some cases by four times more. This result is consistent across regions and independent of the nature of field data. Reasons for this are unknown but it can be hypothesized that the progressive disappearance of females may be associated with mortality caused by anthropogenic factors. This idea is supported by the asymmetric habitat use by the two sexes, with females scavenging in more humanized areas. Whatever the cause, male-skewed adult sex ratios imply that populations of this endangered scavenger face higher risks of extinction than previously believed. PMID- 23029487 TI - Genotyping and molecular characterization of hepatitis B virus from human immunodeficiency virus-infected individuals in southern Africa. AB - Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) are hyperendemic in sub-Saharan Africa. The HBV genotypes prevailing in HIV-infected Africans are unknown. Our aim was to determine the HBV genotypes in HIV-infected participants and to identify clinically significant HBV mutations. From 71 HBV DNA(+ve) HIV infected participants, 49 basic core promoter/precore (BCP/PC) and 29 complete S regions were successfully sequenced. Following phylogenetic analysis of 29 specimens in the complete S region, 28 belonged to subgenotype A1 and one to D3. Mutations affecting HBeAg expression at the transcriptional (1762T1764A), translational (Kozak 1809-1812, initiation 1814-1816, G1896A with C1858T), or post translational levels (G1862T), were responsible for the high HBeAg negativity observed. The G1862T mutation occurred only in subgenotype A1 isolates, which were found in one third (7/21) of HBsAg(-ve) participants, but in none of the 18 HBsAg(+ve) participants (p<0.05). Pre-S deletion mutants were detected in four HBsAg(+ve) and one HBsAg(-ve) participant/s. The following mutations occurred significantly more frequently in HBV isolated in this study than in strains of the same cluster of the phylogenetic tree: ps1F25L, ps1V88L/A; ps2Q10R, ps2 R48K/T, ps2A53V and sQ129R/H, sQ164A/V/G/D, sV168A and sS174N (p<0.05). ps1I48V/T occurred more frequently in females than males (p<0.05). Isolates with sV168A occurred more frequently in participants with viral loads >200 IU per ml (p<0.05) and only sS174N occurred more frequently in HBsAg(-ve) than in HBsAg(+ve) individuals (p<0.05). Prior to initiation of ART, ten percent, 3 of 29 isolates sequenced, had drug resistance mutations rtV173L, rtL180M+rtM204V and rtV214A, respectively. This study has provided important information on the molecular characteristics of HBV in HIV-infected southern Africans prior to ART initiation, which has important clinical relevance in the management of HBV/HIV co-infection in our unique setting. PMID- 23029489 TI - Denatured G-protein coupled receptors as immunogens to generate highly specific antibodies. AB - G-protein coupled receptors (GPCRs) play a major role in a number of physiological and pathological processes. Thus, GPCRs have become the most frequent targets for development of new therapeutic drugs. In this context, the availability of highly specific antibodies may be decisive to obtain reliable findings on localization, function and medical relevance of GPCRs. However, the rapid and easy generation of highly selective anti-GPCR antibodies is still a challenge. Herein, we report that highly specific antibodies suitable for detection of GPCRs in native and unfolded forms can be elicited by immunizing animals against purified full length denatured recombinant GPCRs. Contrasting with the currently admitted postulate, our study shows that an active and well folded GPCR is not required for the production of specific anti-GPCR antibodies. This new immunizing strategy validated with three different human GPCR (MU opioid, kappa-opioid, neuropeptide FF2 receptors) might be generalized to other members of the GPCR family. PMID- 23029490 TI - Limited transfer of newly acquired movement patterns across walking and running in humans. AB - The two major modes of locomotion in humans, walking and running, may be regarded as a function of different speed (walking as slower and running as faster). Recent results using motor learning tasks in humans, as well as more direct evidence from animal models, advocate for independence in the neural control mechanisms underlying different locomotion tasks. In the current study, we investigated the possible independence of the neural mechanisms underlying human walking and running. Subjects were tested on a split-belt treadmill and adapted to walking or running on an asymmetrically driven treadmill surface. Despite the acquisition of asymmetrical movement patterns in the respective modes, the emergence of asymmetrical movement patterns in the subsequent trials was evident only within the same modes (walking after learning to walk and running after learning to run) and only partial in the opposite modes (walking after learning to run and running after learning to walk) (thus transferred only limitedly across the modes). Further, the storage of the acquired movement pattern in each mode was maintained independently of the opposite mode. Combined, these results provide indirect evidence for independence in the neural control mechanisms underlying the two locomotive modes. PMID- 23029491 TI - Limited phenotypic effects of selectively augmenting the SMN protein in the neurons of a mouse model of severe spinal muscular atrophy. AB - The selective vulnerability of motor neurons to paucity of Survival Motor Neuron (SMN) protein is a defining feature of human spinal muscular atrophy (SMA) and indicative of a unique requirement for adequate levels of the protein in these cells. However, the relative contribution of SMN-depleted motor neurons to the disease process is uncertain and it is possible that their characteristic loss and the overall SMA phenotype is a consequence of low protein in multiple cell types including neighboring spinal neurons and non-neuronal tissue. To explore the tissue-specific requirements for SMN and, especially, the salutary effects of restoring normal levels of the protein to neuronal tissue of affected individuals, we have selectively expressed the protein in neurons of mice that model severe SMA. Expressing SMN pan-neuronally in mutant mice mitigated specific aspects of the disease phenotype. Motor performance of the mice improved and the loss of spinal motor neurons that characterizes the disease was arrested. Proprioceptive synapses on the motor neurons were restored and defects of the neuromuscular junctions mitigated. The improvements at the cellular level were reflected in a four-fold increase in survival. Nevertheless, mutants expressing neuronal SMN did not live beyond three weeks of birth, a relatively poor outcome compared to the effects of ubiquitously restoring SMN. This suggests that although neurons and, in particular, spinal motor neurons constitute critical cellular sites of action of the SMN protein, a truly effective treatment of severe SMA will require restoring the protein to multiple cell types including non-neuronal tissue. PMID- 23029492 TI - Neural substrates for semantic memory of familiar songs: is there an interface between lyrics and melodies? AB - Findings on song perception and song production have increasingly suggested that common but partially distinct neural networks exist for processing lyrics and melody. However, the neural substrates of song recognition remain to be investigated. The purpose of this study was to examine the neural substrates involved in the accessing "song lexicon" as corresponding to a representational system that might provide links between the musical and phonological lexicons using positron emission tomography (PET). We exposed participants to auditory stimuli consisting of familiar and unfamiliar songs presented in three ways: sung lyrics (song), sung lyrics on a single pitch (lyrics), and the sung syllable 'la' on original pitches (melody). The auditory stimuli were designed to have equivalent familiarity to participants, and they were recorded at exactly the same tempo. Eleven right-handed nonmusicians participated in four conditions: three familiarity decision tasks using song, lyrics, and melody and a sound type decision task (control) that was designed to engage perceptual and prelexical processing but not lexical processing. The contrasts (familiarity decision tasks versus control) showed no common areas of activation between lyrics and melody. This result indicates that essentially separate neural networks exist in semantic memory for the verbal and melodic processing of familiar songs. Verbal lexical processing recruited the left fusiform gyrus and the left inferior occipital gyrus, whereas melodic lexical processing engaged the right middle temporal sulcus and the bilateral temporo-occipital cortices. Moreover, we found that song specifically activated the left posterior inferior temporal cortex, which may serve as an interface between verbal and musical representations in order to facilitate song recognition. PMID- 23029493 TI - Regeneration of stereocilia of hair cells by forced Atoh1 expression in the adult mammalian cochlea. AB - The hallmark of mechanosensory hair cells is the stereocilia, where mechanical stimuli are converted into electrical signals. These delicate stereocilia are susceptible to acoustic trauma and ototoxic drugs. While hair cells in lower vertebrates and the mammalian vestibular system can spontaneously regenerate lost stereocilia, mammalian cochlear hair cells no longer retain this capability. We explored the possibility of regenerating stereocilia in the noise-deafened guinea pig cochlea by cochlear inoculation of a viral vector carrying Atoh1, a gene critical for hair cell differentiation. Exposure to simulated gunfire resulted in a 60-70 dB hearing loss and extensive damage and loss of stereocilia bundles of both inner and outer hair cells along the entire cochlear length. However, most injured hair cells remained in the organ of Corti for up to 10 days after the trauma. A viral vector carrying an EGFP-labeled Atoh1 gene was inoculated into the cochlea through the round window on the seventh day after noise exposure. Auditory brainstem response measured one month after inoculation showed that hearing thresholds were substantially improved. Scanning electron microscopy revealed that the damaged/lost stereocilia bundles were repaired or regenerated after Atoh1 treatment, suggesting that Atoh1 was able to induce repair/regeneration of the damaged or lost stereocilia. Therefore, our studies revealed a new role of Atoh1 as a gene critical for promoting repair/regeneration of stereocilia and maintaining injured hair cells in the adult mammal cochlea. Atoh1-based gene therapy, therefore, has the potential to treat noise-induced hearing loss if the treatment is carried out before hair cells die. PMID- 23029494 TI - Drosophila Tel2 is expressed as a translational fusion with EpsinR and is a regulator of wingless signaling. AB - Tel2, a protein conserved from yeast to vertebrates, is an essential regulator of diverse cellular processes including telomere maintenance, DNA damage checkpoints, DNA repair, biological clocks, and cell signaling. The Drosophila Tel2 protein is produced as a translational fusion with EpsinR, a Clathrin adapter that facilitates vesicle trafficking between the Golgi and endosomes. EpsinR and Tel2 are encoded by a Drosophila gene called lqfR. lqfR is required for viability, and its specific roles include cell growth, proliferation, and planar cell polarity. We find that all of these functions of lqfR are attributed entirely to Tel2, not EpsinR. In addition, we find that Drosophila LqfR/Tel2 is a component of one or more protein complexes that contain E-cadherin and Armadillo. Moreover, Tel2 modulates E-cadherin and Armadillo cellular dynamics. We propose that at least one of the functions of Drosophila Tel2 is regulation of Wingless signaling. PMID- 23029495 TI - Properties of the nucleo-olivary pathway: an in vivo whole-cell patch clamp study. AB - The inferior olivary nucleus (IO) forms the gateway to the cerebellar cortex and receives feedback information from the cerebellar nuclei (CN), thereby occupying a central position in the olivo-cerebellar loop. Here, we investigated the feedback input from the CN to the IO in vivo in mice using the whole-cell patch clamp technique. This approach allows us to study how the CN-feedback input is integrated with the activity of olivary neurons, while the olivo-cerebellar system and its connections are intact. Our results show how IO neurons respond to CN stimulation sequentially with: i) a short depolarization (EPSP), ii) a hyperpolarization (IPSP) and iii) a rebound depolarization. The latter two phenomena can also be evoked without the EPSPs. The IPSP is sensitive to a GABA(A) receptor blocker. The IPSP suppresses suprathreshold and subthreshold activity and is generated mainly by activation of the GABA(A) receptors. The rebound depolarization re-initiates and temporarily phase locks the subthreshold oscillations. Lack of electrotonical coupling does not affect the IPSP of individual olivary neurons, nor the sensitivity of its GABA(A) receptors to blockers. The GABAergic feedback input from the CN does not only temporarily block the transmission of signals through the IO, it also isolates neurons from the network by shunting the junction current and re-initiates the temporal pattern after a fixed time point. These data suggest that the IO not only functions as a cerebellar controlled gating device, but also operates as a pattern generator for controlling motor timing and/or learning. PMID- 23029496 TI - SIRT1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of NF-kappaB activity. AB - Chronic inflammation is a major contributing factor in the pathogenesis of many age-associated diseases. One central protein that regulates inflammation is NF kappaB, the activity of which is modulated by post-translational modifications as well as by association with co-activator and co-repressor proteins. SIRT1, an NAD(+)-dependent protein deacetylase, has been shown to suppress NF-kappaB signaling through deacetylation of the p65 subunit of NF-kappaB resulting in the reduction of the inflammatory responses mediated by this transcription factor. The role of SIRT1 in the regulation of NF-kappaB provides the necessary validation for the development of pharmacological strategies for activating SIRT1 as an approach for the development of a new class of anti-inflammatory therapeutics. We report herein the development of a quantitative assay to assess compound effects on acetylated p65 protein in the cell. We demonstrate that small molecule activators of SIRT1 (STACs) enhance deacetylation of cellular p65 protein, which results in the suppression of TNFalpha-induced NF-kappaB transcriptional activation and reduction of LPS-stimulated TNFalpha secretion in a SIRT1-dependent manner. In an acute mouse model of LPS-induced inflammation, the STAC SRTCX1003 decreased the production of the proinflammatory cytokines TNFalpha and IL-12. Our studies indicate that increasing SIRT1-mediated NF-kappaB deacetylation using small molecule activating compounds is a novel approach to the development of a new class of therapeutic anti-inflammatory agents. PMID- 23029497 TI - Ethnic differences in the prevalence of metabolic syndrome: results from a multi ethnic population-based survey in Malaysia. AB - INTRODUCTION: The prevalence of metabolic syndrome is increasing disproportionately among the different ethnicities in Asia compared to the rest of the world. This study aims to determine the differences in the prevalence of metabolic syndrome across ethnicities in Malaysia, a multi-ethnic country. METHODS: In 2004, we conducted a national cross-sectional population-based study using a stratified two-stage cluster sampling design (N = 17,211). Metabolic syndrome was defined according to the International Diabetes Federation/National Heart, Lung and Blood Institute/American Heart Association (IDF/NHLBI/AHA-2009) criteria. Multivariate models were used to study the independent association between ethnicity and the prevalence of the metabolic syndrome. RESULTS: The overall mean age was 36.9 years, and 50.0% participants were female. The ethnic distribution was 57.0% Malay, 28.5% Chinese, 8.9% Indian and 5.0% Indigenous Sarawakians. The overall prevalence of the metabolic syndrome was 27.5%, with a prevalence of central obesity, raised triglycerides, low high density lipoprotein cholesterol, raised blood pressure and raised fasting glucose of 36.9%, 29.3%, 37.2%, 38.0% and 29.1%, respectively. Among those <40 years, the adjusted prevalence ratios for metabolic syndrome for ethnic Chinese, Indians, and Indigenous Sarawakians compared to ethnic Malay were 0.81 (95% CI 0.67 to 0.96), 1.42 (95% CI 1.19 to 1.69) and 1.37 (95% CI 1.08 to 1.73), respectively. Among those aged >=40 years, the corresponding prevalence ratios were 0.86 (95% CI 0.79 to 0.92), 1.25 (95% CI 1.15 to 1.36), and 0.94 (95% CI 0.80, 1.11). The P-value for the interaction of ethnicity by age was 0.001. CONCLUSIONS: The overall prevalence of metabolic syndrome in Malaysia was high, with marked differences across ethnicities. Ethnic Chinese had the lowest prevalence of metabolic syndrome, while ethnic Indians had the highest. Indigenous Sarawakians showed a marked increase in metabolic syndrome at young ages. PMID- 23029498 TI - Subdominant antigens in bacterial vaccines: AM779 is subdominant in the Anaplasma marginale outer membrane vaccine but does not associate with protective immunity. AB - Identification of specific antigens responsible for the ability of complex immunogens to induce protection is a major goal in development of bacterial vaccines. Much of the investigation has focused on highly abundant and highly immunodominant outer membrane proteins. Recently however, genomic and proteomic approaches have facilitated identification of minor components of the bacterial outer membrane that have previously been missed or ignored in immunological analyses. Immunization with Anaplasma marginale outer membranes or a cross-linked surface complex induces protection against bacteremia, however the components responsible for protection within these complex immunogens are unknown. Using outer membrane protein AM779 as a model, we demonstrated that this highly conserved but minor component of the A. marginale surface was immunologically sub dominant in the context of the outer membrane or surface complex vaccines. Immunologic sub-dominance could be overcome by targeted vaccination with AM779 for T lymphocyte responses but not for antibody responses, suggesting that both abundance and intrinsic immunogenicity determine relative dominance. Importantly, immunization with AM779 supports that once priming is achieved by specific targeting, recall upon infectious challenge is achieved. While immunization with AM779 alone was not sufficient to induce protection, the ability of targeted immunization to prime the immune response to highly conserved but low abundance proteins supports continued investigation into the role of sub-dominant antigens, individually and collectively, in vaccine development for A. marginale and related bacterial pathogens. PMID- 23029499 TI - Affective dimensions of intergroup humiliation. AB - Despite the wealth of theoretical claims about the emotion of humiliation and its effect on human relations, there has been a lack of empirical research investigating what it means to experience humiliation. We studied the affective characteristics of humiliation, comparing the emotional experience of intergroup humiliation to two other emotions humiliation is often confused with: anger and shame. The defining characteristics of humiliation were low levels of guilt and high levels of other-directed outrage (like anger and unlike shame), and high levels of powerlessness (like shame and unlike anger). Reasons for the similarities and differences of humiliation with anger and shame are discussed in terms of perceptions of undeserved treatment and injustice. Implications for understanding the behavioral consequences of humiliation and future work investigating the role of humiliation in social life are discussed. PMID- 23029500 TI - The structure of mindful brain. AB - Mindfulness is currently attracting a great deal of attention as a psychotherapy technique. It is defined as bringing one's complete attention to the experiences occurring in the present moment in a nonjudgmental or accepting way. The Five Facet Mindfulness Questionnaire (FFMQ) was developed to assess individual differences in mindfulness states. The FFMQ is composed of five facets representing elements of mindfulness: non-reactivity to inner experience, non judging, acting with awareness, describing, and observing. In the present study, we applied voxel-based morphometry to investigate the relationship between the brain structure and each facet as measured by the FFMQ. The results showed a positive association between the describing facet of mindfulness on the FFMQ and gray matter volume in the right anterior insula and the right amygdala. In conclusion, mindfulness was related with development in parts of the somatic marker circuit of the brain. PMID- 23029501 TI - Partial and full PCR-based reverse genetics strategy for influenza viruses. AB - Since 1999, plasmid-based reverse genetics (RG) systems have revolutionized the way influenza viruses are studied. However, it is not unusual to encounter cloning difficulties for one or more influenza genes while attempting to recover virus de novo. To overcome some of these shortcomings we sought to develop partial or full plasmid-free RG systems. The influenza gene of choice is assembled into a RG competent unit by virtue of overlapping PCR reactions containing a cDNA copy of the viral gene segment under the control of RNA polymerase I promoter (pol1) and termination (t1) signals - herein referred to as Flu PCR amplicons. Transfection of tissue culture cells with either HA or NA Flu PCR amplicons and 7 plasmids encoding the remaining influenza RG units, resulted in efficient virus rescue. Likewise, transfections including both HA and NA Flu PCR amplicons and 6 RG plasmids also resulted in efficient virus rescue. In addition, influenza viruses were recovered from a full set of Flu PCR amplicons without the use of plasmids. PMID- 23029502 TI - Cellular localization of aquaporin-1 in the human and mouse trigeminal systems. AB - Previous studies reported that a subpopulation of mouse and rat trigeminal neurons express water channel aquaporin-1 (AQP1). In this study we make a comparative investigation of AQP1 localization in the human and mouse trigeminal systems. Immunohistochemistry and immunofluorescence results showed that AQP1 was localized to the cytoplasm and cell membrane of some medium and small-sized trigeminal neurons. Additionally, AQP1 was found in numerous peripheral trigeminal axons of humans and mice. In the central trigeminal root and brain stem, AQP1 was specifically expressed in astrocytes of humans, but was restricted to nerve fibers within the central trigeminal root and spinal trigeminal tract and nucleus in mice. Furthermore, AQP1 positive nerve fibers were present in the mucosal and submucosal layers of human and mouse oral tissues, but not in the muscular and subcutaneous layers. Fluorogold retrograde tracing demonstrated that AQP1 positive trigeminal neurons innervate the mucosa but not skin of cheek. These results reveal there are similarities and differences in the cellular localization of AQP1 between the human and mouse trigeminal systems. Selective expression of AQP1 in the trigeminal neurons innervating the oral mucosa indicates an involvement of AQP1 in oral sensory transduction. PMID- 23029503 TI - EGF-induced expansion of migratory cells in the rostral migratory stream. AB - The presence of neural stem cells in the adult brain is currently widely accepted and efforts are made to harness the regenerative potential of these cells. The dentate gyrus of the hippocampal formation, and the subventricular zone (SVZ) of the anterior lateral ventricles, are considered the main loci of adult neurogenesis. The rostral migratory stream (RMS) is the structure funneling SVZ progenitor cells through the forebrain to their final destination in the olfactory bulb. Moreover, extensive proliferation occurs in the RMS. Some evidence suggest the presence of stem cells in the RMS, but these cells are few and possibly of limited differentiation potential. We have recently demonstrated the specific expression of the cytoskeleton linker protein radixin in neuroblasts in the RMS and in oligodendrocyte progenitors throughout the brain. These cell populations are greatly altered after intracerebroventricular infusion of epidermal growth factor (EGF). In the current study we investigate the effect of EGF infusion on the rat RMS. We describe a specific increase of radixin(+)/Olig2(+) cells in the RMS. Negative for NG2 and CNPase, these radixin(+)/Olig2(+) cells are distinct from typical oligodendrocyte progenitors. The expanded Olig2(+) population responds rapidly to EGF and proliferates after only 24 hours along the entire RMS, suggesting local activation by EGF throughout the RMS rather than migration from the SVZ. In addition, the radixin(+)/Olig2(+) progenitors assemble in chains in vivo and migrate in chains in explant cultures, suggesting that they possess migratory properties within the RMS. In summary, these results provide insight into the adaptive capacity of the RMS and point to an additional stem cell source for future brain repair strategies. PMID- 23029504 TI - Both lexical and non-lexical characters are processed during saccadic eye movements. AB - On average our eyes make 3-5 saccadic movements per second when we read, although their neural mechanism is still unclear. It is generally thought that saccades help redirect the retinal fovea to specific characters and words but that actual discrimination of information only occurs during periods of fixation. Indeed, it has been proposed that there is active and selective suppression of information processing during saccades to avoid experience of blurring due to the high-speed movement. Here, using a paradigm where a string of either lexical (Chinese) or non-lexical (alphabetic) characters are triggered by saccadic eye movements, we show that subjects can discriminate both while making saccadic eye movement. Moreover, discrimination accuracy is significantly better for characters scanned during the saccadic movement to a fixation point than those not scanned beyond it. Our results showed that character information can be processed during the saccade, therefore saccades during reading not only function to redirect the fovea to fixate the next character or word but allow pre-processing of information from the ones adjacent to the fixation locations to help target the next most salient one. In this way saccades can not only promote continuity in reading words but also actively facilitate reading comprehension. PMID- 23029505 TI - Presence of hydrogen peroxide, a source of hydroxyl radicals, in acid electrolyzed water. AB - BACKGROUND: Acid electrolyzed water (AEW), which is produced through the electrolysis of dilute sodium chloride (NaCl) or potassium chloride solution, is used as a disinfectant in various fields because of its potent antimicrobial activity. The hydroxyl radical, an oxygen radical species, is often suggested as a putative active ingredient for AEW antimicrobial activity. METHODOLOGY/PRINCIPAL FINDINGS: The aim of the present study is to detect hydroxyl radicals in AEW. The hydroxyl radicals in AEW prepared under different conditions were determined using an electron spin resonance (ESR) technique. A signal from 5,5-dimethyl-1-pyrroline N-oxide (DMPO)-OH, an adduct of DMPO and the hydroxyl radical, was detected in AEW prepared by double or triple electrolyses of 1% NaCl but not of 0.1% NaCl solution. Then the presence of hydrogen peroxide as a proposed source of hydroxyl radicals was examined using a combination of ESR and a Fenton reaction. The DMPO-OH signal was clearly detected, even in AEW prepared by single electrolysis of 0.1% NaCl solution, when ferrous sulfate was added to induce a Fenton reaction, indicating the presence of hydrogen peroxide in the AEW. Since sodium formate, a hydroxyl radical scavenger, did not affect the bactericidal activity of AEW, it is concluded that the radical is unlikely to contribute to the antimicrobial activity of AEW, although a small amount of the radical is produced from hydrogen peroxide. Dimethyl sulfoxide, the other hydroxyl radical scavenger used in the present study, canceled the bactericidal activity of AEW, accompanied by complete depletion of free available chlorine, suggesting that hypochlorous acid is probably a major contributor to the antimicrobial activity. CONCLUSIONS: It is strongly suggested that although hydrogen peroxide is present in AEW as a source of hydroxyl radicals, the antimicrobial activity of AEW does not depend on these radicals. PMID- 23029506 TI - Identification, characterization and application of a G-quadruplex structured DNA aptamer against cancer biomarker protein anterior gradient homolog 2. AB - BACKGROUND: Anterior gradient homolog 2 (AGR2) is a functional protein with critical roles in a diverse range of biological systems, including vertebrate tissue development, inflammatory tissue injury responses, and cancer progression. Clinical studies have shown that the AGR2 protein is overexpressed in a wide range of human cancers, including carcinomas of the esophagus, pancreas, breast, prostate, and lung, making the protein as a potential cancer biomarker. However, the general biochemical functions of AGR2 in human cells remain undefined, and the signaling mechanisms that drive AGR2 to inhibit p53 are still not clearly illustrated. Therefore, it is of great interest to develop molecular probes specifically recognizing AGR2 for its detection and for the elucidation of AGR2 associated molecular mechanism. METHODOLOGY/PRINCIPAL FINDINGS: Through a bead based and flow cytometry monitored SELEX technology, we have identified a group of DNA aptamers that can specifically bind to AGR2 with K(d) values in the nanomolar range after 14 rounds of selections. Aptamer C14B was chosen to further study, due to its high binding affinity and specificity. The optimized and shortened C14B1 has special G-rich characteristics, and the G-rich region of this binding motif was further characterized to reveal an intramolecular parallel G quadruplex by CD spectroscopy and UV spectroscopy. Our experiments confirmed that the stability of the G-quadruplex structure was strongly dependent on the nature of the monovalent ions and the formation of G-quadruplex structure was also important for the binding capacity of C14B1 to the target. Furthermore, we have designed a kind of allosteric molecule beacon (aMB) probe for selective and sensitive detection of AGR2. CONCLUSION/SIGNIFICANCE: In this work, we have developed new aptamer probes for specific recognition of the AGR2. Structural study have identified that the binding motif of aptamer is an intramolecular parallel G-quadruplex structure and its structure and binding affinity are strongly dependent on the nature of the monovalent ion. Furthermore, with our design of AGR2-aMB, AGR2 could be sensitively and selectively detected. This aptamer probe has great potential to serve as a useful tool for early diagnosis and prognosis of cancer and for fundamental research to elucidate the biochemical functions of AGR2. PMID- 23029507 TI - Emotional modulation of the attentional blink is awareness-dependent. AB - It is well known that emotion can modulate attentional processes. Previous studies have shown that even under restricted awareness, emotional facial expressions (especially threat-related) can guide the direction of spatial attention. However, it remains unclear whether emotional facial expressions under restricted awareness can affect temporal attention. To address this issue, we used a modified attentional blink (AB) paradigm in which masked (Experiment 1) or unmasked (Experiment 2) emotional faces (fearful or neutral) were presented before the AB sequence. We found that, in comparison with neutral faces, masked fearful faces significantly decreased the AB magnitude (Experiment 1), whereas unmasked fearful faces significantly increased the AB magnitude (Experiment 2). These results indicate that effects of emotional expression on the AB are modulated by the level of awareness. PMID- 23029508 TI - Terahertz electromagnetic fields (0.106 THz) do not induce manifest genomic damage in vitro. AB - Terahertz electromagnetic fields are non-ionizing electromagnetic fields in the frequency range from 0.1 to 10 THz. Potential applications of these electromagnetic fields include the whole body scanners, which currently apply millimeter waves just below the terahertz range, but future scanners will use higher frequencies in the terahertz range. These and other applications will bring along human exposure to these fields. Up to now, only a limited number of investigations on biological effects of terahertz electromagnetic fields have been performed. Therefore, research is strongly needed to enable reliable risk assessment.Cells were exposed for 2 h, 8 h, and 24 h with different power intensities ranging from 0.04 mW/cm(2) to 2 mW/cm(2), representing levels below, at, and above current safety limits. Genomic damage on the chromosomal level was measured as micronucleus formation. DNA strand breaks and alkali-labile sites were quantified with the comet assay. No DNA strand breaks or alkali-labile sites were observed as a consequence of exposure to terahertz electromagnetic fields in the comet assay. The fields did not cause chromosomal damage in the form of micronucleus induction. PMID- 23029509 TI - Lactobacillus reuteri maintains a functional mucosal barrier during DSS treatment despite mucus layer dysfunction. AB - Treatment with the probiotic bacterium Lactobacillus reuteri has been shown to prevent dextran sodium sulfate (DSS)-induced colitis in rats. This is partly due to reduced P-selectin-dependent leukocyte- and platelet-endothelial cell interactions, however, the mechanism behind this protective effect is still unknown. In the present study a combination of culture dependent and molecular based T-RFLP profiling was used to investigate the influence of L. reuteri on the colonic mucosal barrier of DSS treated rats. It was first demonstrated that the two colonic mucus layers of control animals had different bacterial community composition and that fewer bacteria resided in the firmly adherent layer. During DSS induced colitis, the number of bacteria in the inner firmly adherent mucus layer increased and bacterial composition of the two layers no longer differed. In addition, induction of colitis dramatically altered the microbial composition in both firmly and loosely adherent mucus layers. Despite protecting against colitis, treatment with L. reuteri did not improve the integrity of the mucus layer or prevent distortion of the mucus microbiota caused by DSS. However, L. reuteri decreased the bacterial translocation from the intestine to mesenteric lymph nodes during DSS treatment, which might be an important part of the mechanisms by which L. reuteri ameliorates DSS induced colitis. PMID- 23029510 TI - Enhanced adhesion of Campylobacter jejuni to abiotic surfaces is mediated by membrane proteins in oxygen-enriched conditions. AB - Campylobacter jejuni is responsible for the major foodborne bacterial enteritis in humans. In contradiction with its fastidious growth requirements, this microaerobic pathogen can survive in aerobic food environments, suggesting that it must employ a variety of protection mechanisms to resist oxidative stress. For the first time, C. jejuni 81-176 inner and outer membrane subproteomes were analyzed separately using two-dimensional protein electrophoresis (2-DE) of oxygen-acclimated cells and microaerobically grown cells. LC-MS/MS analyses successfully identified 42 and 25 spots which exhibited a significantly altered abundance in the IMP-enriched fraction and in the OMP-enriched fraction, respectively, in response to oxidative conditions. These spots corresponded to 38 membrane proteins that could be grouped into different functional classes: (i) transporters, (ii) chaperones, (iii) fatty acid metabolism, (iv) adhesion/virulence and (v) other metabolisms. Some of these proteins were up regulated at the transcriptional level in oxygen-acclimated cells as confirmed by qRT-PCR. Downstream analyses revealed that adhesion of C. jejuni to inert surfaces and swarming motility were enhanced in oxygen-acclimated cells or paraquat-stressed cells, which could be explained by the higher abundance of membrane proteins involved in adhesion and biofilm formation. The virulence factor CadF, over-expressed in the outer membrane of oxygen-acclimated cells, contributes to the complex process of C. jejuni adhesion to inert surfaces as revealed by a reduction in the capability of C. jejuni 81-176 DeltaCadF cells compared to the isogenic strain.Taken together, these data demonstrate that oxygen-enriched conditions promote the over-expression of membrane proteins involved in both the biofilm initiation and virulence of C. jejuni. PMID- 23029511 TI - Synaptic activity in serotonergic neurons is required for air-puff stimulated flight in Drosophila melanogaster. AB - BACKGROUND: Flight is an integral component of many complex behavioral patterns in insects. The giant fiber circuit has been well studied in several insects including Drosophila. However, components of the insect flight circuit that respond to an air-puff stimulus and comprise the flight central pattern generator are poorly defined. Aminergic neurons have been implicated in locust, moth and Drosophila flight. Here we have investigated the requirement of neuronal activity in serotonergic neurons, during development and in adults, on air-puff induced flight in Drosophila. METHODOLOGY/PRINCIPAL FINDINGS: To target serotonergic neurons specifically, a Drosophila strain that contains regulatory regions from the TRH (Tryptophan Hydroxylase) gene linked to the yeast transcription factor GAL4 was used. By blocking synaptic transmission from serotonergic neurons with a tetanus toxin transgene or by hyperpolarisation with Kir2.1, close to 50% adults became flightless. Temporal expression of a temperature sensitive Dynamin mutant transgene (Shi(ts)) suggests that synaptic function in serotonergic neurons is required both during development and in adults. Depletion of IP(3)R in serotonergic neurons via RNAi did not affect flight. Interestingly, at all stages a partial requirement for synaptic activity in serotonergic neurons was observed. The status of serotonergic neurons was investigated in the central nervous system of larvae and adults expressing tetanus toxin. A small but significant reduction was observed in serotonergic cell number in adult second thoracic segments from flightless tetanus toxin expressing animals. CONCLUSIONS: These studies show that loss of synaptic activity in serotonergic neurons causes a flight deficit. The temporal focus of the flight deficit is during pupal development and in adults. The cause of the flight deficit is likely to be loss of neurons and reduced synaptic function. Based on the partial phenotypes, serotonergic neurons appear to be modulatory, rather than an intrinsic part of the flight circuit. PMID- 23029512 TI - Physiological and biochemical performances of menthol-induced aposymbiotic corals. AB - The unique mutualism between corals and their photosynthetic zooxanthellae (Symbiodinium spp.) is the driving force behind functional assemblages of coral reefs. However, the respective roles of hosts and Symbiodinium in this endosymbiotic association, particularly in response to environmental challenges (e.g., high sea surface temperatures), remain unsettled. One of the key obstacles is to produce and maintain aposymbiotic coral hosts for experimental purposes. In this study, a simple and gentle protocol to generate aposymbiotic coral hosts (Isopora palifera and Stylophora pistillata) was developed using repeated incubation in menthol/artificial seawater (ASW) medium under light and in ASW in darkness, which depleted more than 99% of Symbiodinium from the host within 4~8 days. As indicated by the respiration rate, energy metabolism (by malate dehydrogenase activity), and nitrogen metabolism (by glutamate dehydrogenase activity and profiles of free amino acids), the physiological and biochemical performances of the menthol-induced aposymbiotic corals were comparable to their symbiotic counterparts without nutrient supplementation (e.g., for Stylophora) or with a nutrient supplement containing glycerol, vitamins, and a host mimic of free amino acid mixture (e.g., for Isopora). Differences in biochemical responses to menthol-induced bleaching between Stylophora and Isopora were attributed to the former digesting Symbiodinium rather than expelling the algae live as found in the latter species. Our studies showed that menthol could successfully bleach corals and provided aposymbiotic corals for further exploration of coral-alga symbioses. PMID- 23029513 TI - Small mutations in Bordetella pertussis are associated with selective sweeps. AB - Bordetella pertussis is the causative agent of pertussis, a highly contagious disease of the human respiratory tract. Despite high vaccination coverage, pertussis has resurged and has become one of the most prevalent vaccine preventable diseases in developed countries. We have proposed that both waning immunity and pathogen adaptation have contributed to the persistence and resurgence of pertussis. Allelic variation has been found in virulence-associated genes coding for the pertussis toxin A subunit (ptxA), pertactin (prn), serotype 2 fimbriae (fim2), serotype 3 fimbriae (fim3) and the promoter for pertussis toxin (ptxP). In this study, we investigated how more than 60 years of vaccination has affected the Dutch B. pertussis population by combining data from phylogeny, genomics and temporal trends in strain frequencies. Our main focus was on the ptxA, prn, fim3 and ptxP genes. However, we also compared the genomes of 11 Dutch strains belonging to successful lineages. Our results showed that, between 1949 and 2010, the Dutch B. pertussis population has undergone as least four selective sweeps that were associated with small mutations in ptxA, prn, fim3 and ptxP. Phylogenetic analysis revealed a stepwise adaptation in which mutations accumulated clonally. Genomic analysis revealed a number of additional mutations which may have a contributed to the selective sweeps. Five large deletions were identified which were fixed in the pathogen population. However, only one was linked to a selective sweep. No evidence was found for a role of gene acquisition in pathogen adaptation. Our results suggest that the B. pertussis gene repertoire is already well adapted to its current niche and required only fine tuning to persist in the face of vaccination. Further, this work shows that small mutations, even single SNPs, can drive large changes in the populations of bacterial pathogens within a time span of six to 19 years. PMID- 23029514 TI - Doxycycline does not influence established abdominal aortic aneurysms in angiotensin II-infused mice. AB - BACKGROUND: There is no proven medical approach to attenuating expansion and rupture of abdominal aortic aneurysms (AAAs). One approach that is currently being investigated is the use of doxycycline. Despite being primarily used as an antimicrobial drug, doxycycline has been proposed to function in reducing AAA expansion. Doxycycline is effective in reducing the formation in the most commonly used mouse models of AAAs when administered prior to the initiation of the disease. The purpose of the current study was to determine the effects of doxycycline on established AAAs when it was administered at a dose that produces therapeutic serum concentrations. METHODS AND RESULTS: LDL receptor -/- male mice fed a saturated-fat supplemented diet were infused with AngII (1,000 ng/kg/min) via mini-osmotic pumps for 28 days. Upon verification of AAA formation by noninvasive high frequency ultrasonography, mice were stratified based on aortic lumen diameters, and continuously infused with AngII while also administered either vehicle or doxycycline (100 mg/kg/day) in drinking water for 56 days. Administration of doxycycline led to serum drug concentrations of 2.3 +/- 0.6 ug/ml. Doxycycline administration had no effect on serum cholesterol concentrations and systolic blood pressures. Doxycycline administration did not prevent progressive aortic dilation as determined by temporal measurements of lumen dimensions using high frequency ultrasound. This lack of effect on AAA regression and progression was confirmed at the termination of the study by ex vivo measurements of maximal width of suprarenal aortas and AAA volumes. Also, doxycycline did not reduce AAA rupture. Medial and adventitial remodeling was not overtly changed by doxycycline as determined by immunostaining and histological staining. CONCLUSIONS: Doxycycline administration did not influence AngII-induced AAA progression and aortic rupture when administered to mice with established AAAs. PMID- 23029516 TI - Do private conservation activities match science-based conservation priorities? AB - BACKGROUND: Private land conservation is an essential strategy for biodiversity protection in the USA, where half of the federally listed species have at least 80% of their habitat on private lands. We investigated the alignment between private land protection conducted by the world's largest land trust (The Nature Conservancy) and the science driven identification of priority areas for conservation. This represents the first quantitative assessment of the influence of defining priority areas on the land acquisitions of a conservation non governmental organization (NGO). METHODOLOGY/PRINCIPAL FINDINGS: The lands acquired by The Nature Conservancy (TNC) were analyzed using GIS to determine to what extent they were in areas defined as priorities for conservation. The spatial analysis of TNC lands was broken up into land known to be acquired in the last five years, five to ten years ago, prior to ten years ago, and anytime during the last sixty years (including previous sets of data plus acquisitions lacking a date). For the entire history of TNC the proportion of TNC lands within the priority areas was 74%. Prior to 10 years ago it was 80%, 5-10 years ago it was 76%, and in the last five years it was 81%. Conservation easements were found to have lower alignment with priority areas (64%) than outright fee simple acquisitions (86%). CONCLUSIONS/SIGNIFICANCE: Overall the location of lands acquired was found to be well aligned with the priority areas. Since there was comparable alignment in lands acquired before and after formalized conservation planning had been implemented as a standard operating procedure, this analysis did not find evidence that defining priority areas has influenced land acquisition decisions. PMID- 23029515 TI - Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk? AB - The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD) is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions from the NHGRI genome-wide association study (GWAS) catalog, in an attempt to replicate the established notion of shared pathophysiology and risk. We used pathway-based analyses to detect subsets of pleiotropic genes involved in similar biological processes. We identified 107 eligible GWAS studies related to CVD and its established comorbidities and risk factors and assigned genes that correspond to the associated signals based on their position. We found 44 positional genes shared across at least two CVD related phenotypes that independently recreated the established relationship between the six phenotypes, but only if studies representing non-European populations were included. Seven genes revealed pleiotropy across three or more phenotypes, mostly related to lipid transport and metabolism. Yet, many genes had no relationship to each other or to genes with established functional connection. Whilst we successfully reproduced established relationships between CVD risk factors using GWAS findings, interpretation of biological pathways involved in the observed pleiotropy was limited. Further studies linking genetic variation to gene expression, as well as describing novel biological pathways will be needed to take full advantage of GWAS results. PMID- 23029517 TI - Survival and population dynamics of the marabou stork in an isolated population, Swaziland. AB - Investigating the ecology of long lived birds is particularly challenging owing to the time scales involved. Here an analysis is presented of a long term study of the survival and population dynamics of the marabou stork (Leptoptilos crumeniferus), a wide ranging scavenging bird from Sub-Saharan Africa. Using resightings data of tagged nestlings and free flying birds we show that the stork population can be divided into three general life stages with unique survival probabilities and fecundities. Fecundity of the storks is inversely related to rainfall during their breeding season. Corroborative evidence for a metapopulation structure is discussed highlighting the impact of the Swaziland birds on the ecology of the species in the broader region. The importance of tag loss or illegibility over time is highlighted. Clearly, any attempt at conserving a species will require a detailed understanding of its population structure, of the sort examined here. PMID- 23029518 TI - Predator-induced fleeing behaviors in phytoplankton: a new mechanism for harmful algal bloom formation? AB - In the plankton, heterotrophic microbes encounter and ingest phytoplankton prey, which effectively removes >50% of daily phytoplankton production in the ocean and influences global primary production and biochemical cycling rates. Factors such as size, shape, nutritional value, and presence of chemical deterrents are known to affect predation pressure. Effects of movement behaviors of either predator or prey on predation pressure, and particularly fleeing behaviors in phytoplankton are thus far unknown. Here, we quantified individual 3D movements, population distributions, and survival rates of the toxic phytoplankton species, Heterosigma akashiwo in response to a ciliate predator and predator-derived cues. We observed predator-induced defense behaviors previously unknown for phytoplankton. Modulation of individual phytoplankton movements during and after predator exposure resulted in an effective separation of predator and prey species. The strongest avoidance behaviors were observed when H. akashiwo co-occurred with an actively grazing predator. Predator-induced changes in phytoplankton movements resulted in a reduction in encounter rate and a 3-fold increase in net algal population growth rate. A spatially explicit population model predicted rapid phytoplankton bloom formation only when fleeing behaviors were incorporated. These model predictions reflected field observations of rapid H. akashiwo harmful algal bloom (HAB) formation in the coastal ocean. Our results document a novel behavior in phytoplankton that can significantly reduce predation pressure and suggests a new mechanism for HAB formation. Phytoplankton behaviors that minimize predatory losses, maximize resource acquisition, and alter community composition and distribution patterns could have major implications for our understanding and predictive capacity of marine primary production and biochemical cycling rates. PMID- 23029519 TI - Gene expression profiles in paired gingival biopsies from periodontitis-affected and healthy tissues revealed by massively parallel sequencing. AB - Periodontitis is a chronic inflammatory disease affecting the soft tissue and bone that surrounds the teeth. Despite extensive research, distinctive genes responsible for the disease have not been identified. The objective of this study was to elucidate transcriptome changes in periodontitis, by investigating gene expression profiles in gingival tissue obtained from periodontitis-affected and healthy gingiva from the same patient, using RNA-sequencing. Gingival biopsies were obtained from a disease-affected and a healthy site from each of 10 individuals diagnosed with periodontitis. Enrichment analysis performed among uniquely expressed genes for the periodontitis-affected and healthy tissues revealed several regulated pathways indicative of inflammation for the periodontitis-affected condition. Hierarchical clustering of the sequenced biopsies demonstrated clustering according to the degree of inflammation, as observed histologically in the biopsies, rather than clustering at the individual level. Among the top 50 upregulated genes in periodontitis-affected tissues, we investigated two genes which have not previously been demonstrated to be involved in periodontitis. These included interferon regulatory factor 4 and chemokine (C C motif) ligand 18, which were also expressed at the protein level in gingival biopsies from patients with periodontitis. In conclusion, this study provides a first step towards a quantitative comprehensive insight into the transcriptome changes in periodontitis. We demonstrate for the first time site-specific local variation in gene expression profiles of periodontitis-affected and healthy tissues obtained from patients with periodontitis, using RNA-seq. Further, we have identified novel genes expressed in periodontitis tissues, which may constitute potential therapeutic targets for future treatment strategies of periodontitis. PMID- 23029520 TI - The destructive citrus pathogen, 'Candidatus Liberibacter asiaticus' encodes a functional flagellin characteristic of a pathogen-associated molecular pattern. AB - Huanglongbing (HLB) is presently the most devastating citrus disease worldwide. As an intracellular plant pathogen and insect symbiont, the HLB bacterium, 'Candidatus Liberibacter asiaticus' (Las), retains the entire flagellum-encoding gene cluster in its significantly reduced genome. Las encodes a flagellin and hook-associated protein (Fla) of 452 amino acids that contains a conserved 22 amino acid domain (flg22) at positions 29 to 50 in the N-terminus. The phenotypic alteration in motility of a Sinorhizobium meliloti mutant lacking the fla genes was partially restored by constitutive expression of Fla(Las). Agrobacterium mediated transient expression in planta revealed that Fla(Las) induced cell death and callose deposition in Nicotiana benthamiana, and that the transcription of BAK1 and SGT1, which are associated with plant innate immunity, was upregulated. Amino acid substitution experiments revealed that residues 38 (serine) and 39 (aspartate) of Fla(Las) were essential for callose induction. The synthetic flg22(Las) peptide could not induce plant cell death but retained the ability to induce callose deposition at a concentration of 20 uM or above. This demonstrated that the pathogen-associated molecular pattern (PAMP) activity of flg22 in Las was weaker than those in other well-studied plant pathogenic bacteria. These results indicate that Fla(Las) acts as a PAMP and may play an important role in triggering host plant resistance to the HLB bacteria. PMID- 23029521 TI - Validation of reference genes for gene expression studies in virus-infected Nicotiana benthamiana using quantitative real-time PCR. AB - Nicotiana benthamiana is the most widely-used experimental host in plant virology. The recent release of the draft genome sequence for N. benthamiana consolidates its role as a model for plant-pathogen interactions. Quantitative real-time PCR (qPCR) is commonly employed for quantitative gene expression analysis. For valid qPCR analysis, accurate normalisation of gene expression against an appropriate internal control is required. Yet there has been little systematic investigation of reference gene stability in N. benthamiana under conditions of viral infections. In this study, the expression profiles of 16 commonly used housekeeping genes (GAPDH, 18S, EF1alpha, SAMD, L23, UK, PP2A, APR, UBI3, SAND, ACT, TUB, GBP, F-BOX, PPR and TIP41) were determined in N. benthamiana and those with acceptable expression levels were further selected for transcript stability analysis by qPCR of complementary DNA prepared from N. benthamiana leaf tissue infected with one of five RNA plant viruses (Tobacco necrosis virus A, Beet black scorch virus, Beet necrotic yellow vein virus, Barley stripe mosaic virus and Potato virus X). Gene stability was analysed in parallel by three commonly-used dedicated algorithms: geNorm, NormFinder and BestKeeper. Statistical analysis revealed that the PP2A, F-BOX and L23 genes were the most stable overall, and that the combination of these three genes was sufficient for accurate normalisation. In addition, the suitability of PP2A, F BOX and L23 as reference genes was illustrated by expression-level analysis of AGO2 and RdR6 in virus-infected N. benthamiana leaves. This is the first study to systematically examine and evaluate the stability of different reference genes in N. benthamiana. Our results not only provide researchers studying these viruses a shortlist of potential housekeeping genes to use as normalisers for qPCR experiments, but should also guide the selection of appropriate reference genes for gene expression studies of N. benthamiana under other biotic and abiotic stress conditions. PMID- 23029522 TI - The directed differentiation of human iPS cells into kidney podocytes. AB - The loss of glomerular podocytes is a key event in the progression of chronic kidney disease resulting in proteinuria and declining function. Podocytes are slow cycling cells that are considered terminally differentiated. Here we provide the first report of the directed differentiation of induced pluripotent stem (iPS) cells to generate kidney cells with podocyte features. The iPS-derived podocytes share a morphological phenotype analogous with cultured human podocytes. Following 10 days of directed differentiation, iPS podocytes had an up regulated expression of mRNA and protein localization for podocyte markers including synaptopodin, nephrin and Wilm's tumour protein (WT1), combined with a down-regulation of the stem cell marker OCT3/4. In contrast to human podocytes that become quiescent in culture, iPS-derived cells maintain a proliferative capacity suggestive of a more immature phenotype. The transduction of iPS podocytes with fluorescent labeled-talin that were immunostained with podocin showed a cytoplasmic contractile response to angiotensin II (AII). A permeability assay provided functional evidence of albumin uptake in the cytoplasm of iPS podocytes comparable to human podocytes. Moreover, labeled iPS-derived podocytes were found to integrate into reaggregated metanephric kidney explants where they incorporated into developing glomeruli and co-expressed WT1. This study establishes the differentiation of iPS cells to kidney podocytes that will be useful for screening new treatments, understanding podocyte pathogenesis, and offering possibilities for regenerative medicine. PMID- 23029523 TI - Essential roles and regulation of the Legionella pneumophila collagen-like adhesin during biofilm formation. AB - Legionellosis is mostly caused by Legionella pneumophila (Lp) and is defined by a severe respiratory illness with a case fatality rate ranging from 5 to 80%. In a previous study, we showed that a glycosaminoglycan (GAG)-binding adhesin of Lp, named Lcl, is produced during legionellosis and is unique to the L. pneumophila species. Importantly, a mutant depleted in Lcl (Deltalpg2644) is impaired in adhesion to GAGs and epithelial cells and in biofilm formation. Here, we examine the molecular function(s) of Lcl and the transcriptional regulation of its encoding gene during different stages of the biofilm development. We show that the collagen repeats and the C-terminal domains of Lcl are crucial for the production of biofilm. We present evidence that Lcl is involved in the early step of surface attachment but also in intercellular interactions. Furthermore, we address the relationship between Lcl gene regulation during biofilm formation and quorum sensing (QS). In a static biofilm assay, we show that Lcl is differentially regulated during growth phases and biofilm formation. Moreover, we show that the transcriptional regulation of lpg2644, mediated by a prototype of QS signaling homoserine lactone (3OC12-HSL), may play a role during the biofilm development. Thus, transcriptional down-regulation of lpg2644 may facilitate the dispersion of Lp to reinitiate biofilm colonization on a distal surface. PMID- 23029524 TI - Bmi1 is required for hepatic progenitor cell expansion and liver tumor development. AB - Bmi1 is a polycomb group transcriptional repressor and it has been implicated in regulating self-renewal and proliferation of many types of stem or progenitor cells. In addition, Bmi1 has been shown to function as an oncogene in multiple tumor types. In this study, we investigated the functional significance of Bmi1 in regulating hepatic oval cells, the major type of bipotential progenitor cells in adult liver, as well as the role of Bmi1 during hepatocarcinogenesis using Bmi1 knockout mice. We found that loss of Bmi1 significantly restricted chemically induced oval cell expansion in the mouse liver. Concomitant deletion of Ink4a/Arf in Bmi1 deficient mice completely rescued the oval cell expansion phenotype. Furthermore, ablation of Bmi1 delayed hepatocarcinogenesis induced by AKT and Ras co-expression. This antineoplastic effect was accompanied by the loss of hepatic oval cell marker expression in the liver tumor samples. In summary, our data demonstrated that Bmi1 is required for hepatic oval cell expansion via deregulating the Ink4a/Arf locus in mice. Our study also provides the evidence, for the first time, that Bmi1 expression is required for liver cancer development in vivo, thus representing a promising target for innovative treatments against human liver cancer. PMID- 23029525 TI - Maternal transmission effect of a PDGF-C SNP on nonsyndromic cleft lip with or without palate from a Chinese population. AB - Cleft lip with or without palate (CL/P) is a common congenital anomaly with a high birth prevalence in China. Based on a previous linkage signal of nonsyndromic CL/P (NSCL/P) on the chromosomal region 4q31-q32 from the Chinese populations, we screened the 4q31-q32 region for susceptibility genes in 214 trios of Han Chinese. PDGF-C, an important developmental factor, resides in the region and has been implicated in NSCL/P. However, in our family-based association test (transmission disequilibrium test; TDT), we could not conclude an association between PDGF-C and NSCL/P as previously suggested. Instead, we found strong evidence for parent-of-origin effect at a PDGF-C SNP, rs17035464, by a likelihood ratio test (unadjusted p-value = 0.0018; I(m) = 2.46). The location of rs17035464 is 13 kb downstream of a previously reported, NSCL/P-associated SNP, rs28999109. Furthermore, a patient from our sample trios was observed with a maternal segmental uniparental isodisomy (UPD) in a region containing rs17035464. Our findings support the involvement of PDGF-C in the development of oral clefts; moreover, the UPD case report contributes to the collective knowledge of rare variants in the human genome. PMID- 23029526 TI - Postconditioning with inhaled carbon monoxide counteracts apoptosis and neuroinflammation in the ischemic rat retina. AB - PURPOSE: Ischemia and reperfusion injury (I/R) of neuronal structures and organs is associated with increased morbidity and mortality due to neuronal cell death. We hypothesized that inhalation of carbon monoxide (CO) after I/R injury ('postconditioning') would protect retinal ganglion cells (RGC). METHODS: Retinal I/R injury was performed in Sprague-Dawley rats (n = 8) by increasing ocular pressure (120 mmHg, 1 h). Rats inhaled room air or CO (250 ppm) for 1 h immediately following ischemia or with 1.5 and 3 h latency. Retinal tissue was harvested to analyze Bcl-2, Bax, Caspase-3, HO-1 expression and phosphorylation of the nuclear transcription factor (NF)-kappaB, p38 and ERK-1/2 MAPK. NF-kappaB activation was determined and inhibition of ERK-1/2 was performed using PD98059 (2 mg/kg). Densities of fluorogold prelabeled RGC were analyzed 7 days after injury. Microglia, macrophage and Muller cell activation and proliferation were evaluated by Iba-1, GFAP and Ki-67 staining. RESULTS: Inhalation of CO after I/R inhibited Bax and Caspase-3 expression (Bax: 1.9 +/- 0.3 vs. 1.4 +/- 0.2, p = 0.028; caspase-3: 2.0 +/- 0.2 vs. 1.5 +/- 0.1, p = 0.007; mean +/- S.D., fold induction at 12 h), while expression of Bcl-2 was induced (1.2 +/- 0.2 vs. 1.6 +/ 0.2, p = 0.001; mean +/- S.D., fold induction at 12 h). CO postconditioning suppressed retinal p38 phosphorylation (p = 0.023 at 24 h) and induced the phosphorylation of ERK-1/2 (p<0.001 at 24 h). CO postconditioning inhibited the expression of HO-1. The activation of NF-kappaB, microglia and Muller cells was potently inhibited by CO as well as immigration of proliferative microglia and macrophages into the retina. CO protected I/R-injured RGC with a therapeutic window at least up to 3 h (n = 8; RGC/mm(2); mean +/- S.D.: 1255 +/- 327 I/R only vs. 1956 +/- 157 immediate CO treatment, vs. 1830 +/- 109 1.5 h time lag and vs. 1626 +/- 122 3 h time lag; p<0.001). Inhibition of ERK-1/2 did not counteract the CO effects (RGC/mm(2): 1956 +/- 157 vs. 1931 +/- 124, mean +/- S.D., p = 0.799). CONCLUSION: Inhaled CO, administered after retinal ischemic injury, protects RGC through its strong anti-apoptotic and anti-inflammatory effects. PMID- 23029527 TI - Checkpoint kinase ATR phosphorylates Cdt2, a substrate receptor of CRL4 ubiquitin ligase, and promotes the degradation of Cdt1 following UV irradiation. AB - The DNA replication-licensing factor Cdt1 is present during the G1 phase of the cell cycle. When cells initiate S phase or are UV-irradiated, Cdt1 is recruited to chromatin-bound PCNA and ubiquitinated by CRL4(Cdt2) for degradation. In both situations, the substrate-recognizing subunit Cdt2 is detected as a highly phosphorylated form. Here, we show that both caffeine-sensitive kinase and MAP kinases are responsible for Cdt2 phosphorylation following UV irradiation. We found that Cdt1 degradation was attenuated in the presence of caffeine. This attenuation was also observed in cells depleted of ATR, but not ATM. Following UV irradiation, Cdt2 was phosphorylated at the S/TQ sites. ATR phosphorylated Cdt2 in vitro, mostly in the C-terminal region. Cdt1 degradation was also induced by DNA damaging chemicals such as methyl methanesulfonate (MMS) or zeocin, depending on PCNA and CRL4-Cdt2, though it was less caffeine-sensitive. These findings suggest that ATR, activated after DNA damage, phosphorylates Cdt2 and promotes the rapid degradation of Cdt1 after UV irradiation in the G1 phase of the cell cycle. PMID- 23029528 TI - Hypoxia promotes osteogenesis but suppresses adipogenesis of human mesenchymal stromal cells in a hypoxia-inducible factor-1 dependent manner. AB - BACKGROUND: Bone fracture initiates a series of cellular and molecular events including the expression of hypoxia-inducible factor (HIF)-1. HIF-1 is known to facilitate recruitment and differentiation of multipotent human mesenchymal stromal cells (hMSC). Therefore, we analyzed the impact of hypoxia and HIF-1 on the competitive differentiation potential of hMSCs towards adipogenic and osteogenic lineages. METHODOLOGY/PRINCIPAL FINDINGS: Bone marrow derived primary hMSCs cultured for 2 weeks either under normoxic (app. 18% O(2)) or hypoxic (less than 2% O(2)) conditions were analyzed for the expression of MSC surface markers and for expression of the genes HIF1A, VEGFA, LDHA, PGK1, and GLUT1. Using conditioned medium, adipogenic or osteogenic differentiation as verified by Oil Red-O or von-Kossa staining was induced in hMSCs under either normoxic or hypoxic conditions. The expression of HIF1A and VEGFA was measured by qPCR. A knockdown of HIF-1alpha by lentiviral transduction was performed, and the ability of the transduced hMSCs to differentiate into adipogenic and osteogenic lineages was analyzed. Hypoxia induced HIF-1alpha and HIF-1 target gene expression, but did not alter MSC phenotype or surface marker expression. Hypoxia (i) suppressed adipogenesis and associated HIF1A and PPARG gene expression in hMSCs and (ii) enhanced osteogenesis and associated HIF1A and RUNX2 gene expression. shRNA mediated knockdown of HIF-1alpha enhanced adipogenesis under both normoxia and hypoxia, and suppressed hypoxia-induced osteogenesis. CONCLUSIONS/SIGNIFICANCE: Hypoxia promotes osteogenesis but suppresses adipogenesis of human MSCs in a competitive and HIF-1-dependent manner. We therefore conclude that the effects of hypoxia are crucial for effective bone healing, which may potentially lead to the development of novel therapeutic approaches. PMID- 23029529 TI - Inhibition of fatty acid metabolism reduces human myeloma cells proliferation. AB - Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of beta-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited beta-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40-70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma. PMID- 23029530 TI - Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is mediated by CUL7 E3 ligase. AB - Expression of the hominoid-specific TBC1D3 oncoprotein enhances growth factor receptor signaling and subsequently promotes cellular proliferation and survival. Here we report that TBC1D3 is degraded in response to growth factor signaling, suggesting that TBC1D3 expression is regulated by a growth factor-driven negative feedback loop. To gain a better understanding of how TBC1D3 is regulated, we studied the effects of growth factor receptor signaling on TBC1D3 post translational processing and turnover. Using a yeast two-hybrid screen, we identified CUL7, the scaffolding subunit of the CUL7 E3 ligase complex, as a TBC1D3-interacting protein. We show that CUL7 E3 ligase ubiquitinates TBC1D3 in response to serum stimulation. Moreover, TBC1D3 recruits F-box 8 (Fbw8), the substrate recognition domain of CUL7 E3 ligase, in pull-down experiments and in an in vitro assay. Importantly, alkaline phosphatase treatment of TBC1D3 suppresses its ability to recruit Fbw8, indicating that TBC1D3 phosphorylation is critical for its ubiquitination and degradation. We conclude that serum- and growth factor-stimulated TBC1D3 ubiquitination and degradation are regulated by its interaction with CUL7-Fbw8. PMID- 23029531 TI - The polyoma virus large T binding protein p150 is a transcriptional repressor of c-MYC. AB - p150, product of the SALL2 gene, is a binding partner of the polyoma virus large T antigen and a putative tumor suppressor. p150 binds to the nuclease hypersensitive element of the c-MYC promoter and represses c-MYC transcription. Overexpression of p150 in human ovarian surface epithelial cells leads to decreased expression, and downregulation to increased expression, of c-MYC. c-MYC is repressed upon restoration of p150 to ovarian carcinoma cells. Induction of apoptosis by etoposide results in recruitment of p150 to the c-MYC promoter and to repression of c-MYC. Analysis of data in The Cancer Genome Atlas shows negative correlations between SALL2 and c-MYC expression in four common solid tumor types. PMID- 23029532 TI - Evaluation of candidate reference genes for normalization of quantitative RT-PCR in soybean tissues under various abiotic stress conditions. AB - Quantitative RT-PCR can be a very sensitive and powerful technique for measuring differential gene expression. Changes in gene expression induced by abiotic stresses are complex and multifaceted, which make determining stably expressed genes for data normalization difficult. To identify the most suitable reference genes for abiotic stress studies in soybean, 13 candidate genes collected from literature were evaluated for stability of expression under dehydration, high salinity, cold and ABA (abscisic acid) treatments using delta CT and geNorm approaches. Validation of reference genes indicated that the best reference genes are tissue- and stress-dependent. With respect to dehydration treatment, the Fbox/ABC, Fbox/60s gene pairs were found to have the highest expression stability in the root and shoot tissues of soybean seedlings, respectively. Fbox and 60s genes are the most suitable reference genes across dehydrated root and shoot tissues. Under salt stress the ELF1b/IDE and Fbox/ELF1b are the most stably expressed gene pairs in roots and shoots, respectively, while 60s/Fbox is the best gene pair in both tissues. For studying cold stress in roots or shoots, IDE/60s and Fbox/Act27 are good reference gene pairs, respectively. With regard to gene expression analysis under ABA treatment in either roots, shoots or across these tissues, 60s/ELF1b, ELF1b/Fbox and 60s/ELF1b are the most suitable reference genes, respectively. The expression of ELF1b/60s, 60s/Fbox and 60s/Fbox genes was most stable in roots, shoots and both tissues, respectively, under various stresses studied. Among the genes tested, 60s was found to be the best reference gene in different tissues and under various stress conditions. The highly ranked reference genes identified from this study were proved to be capable of detecting subtle differences in expression rates that otherwise would be missed if a less stable reference gene was used. PMID- 23029533 TI - Effects of dopamine D2 receptor partial agonist antipsychotic aripiprazole on dopamine synthesis in human brain measured by PET with L-[beta-11C]DOPA. AB - Dopamine D(2) receptor partial agonist antipsychotic drugs can modulate dopaminergic neurotransmission as functional agonists or functional antagonists. The effects of antipsychotics on presynaptic dopaminergic functions, such as dopamine synthesis capacity, might also be related to their therapeutic efficacy. Positron emission tomography (PET) was used to examine the effects of the partial agonist antipsychotic drug aripiprazole on presynaptic dopamine synthesis in relation to dopamine D(2) receptor occupancy and the resulting changes in dopamine synthesis capacity in healthy men. On separate days, PET studies with [(11)C]raclopride and L-[beta-(11)C]DOPA were performed under resting condition and with single doses of aripiprazole given orally. Occupancy of dopamine D(2) receptors corresponded to the doses of aripiprazole, but the changes in dopamine synthesis capacity were not significant, nor was the relation between dopamine D(2) receptor occupancy and these changes. A significant negative correlation was observed between baseline dopamine synthesis capacity and changes in dopamine synthesis capacity by aripiprazole, indicating that this antipsychotic appears to stabilize dopamine synthesis capacity. The therapeutic effects of aripiprazole in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity. PMID- 23029534 TI - Pair-rule gene orthologues have unexpected maternal roles in the honeybee (Apis mellifera). AB - Pair-rule genes are a class of segmentation genes first identified in Drosophila melanogaster. In Drosophila, these genes act to translate non-periodic information produced by the overlapping patterns of gap gene expression into patterns of gene expression in every other segment. While pair-rule genes are, for the most part, conserved in metazoans, their function in pair-rule patterning is not. Many of these genes do, however, regulate segmentation in arthropods and do so with dual-segment periodicity. Here we examine the expression and function of honeybee orthologues of Drosophila pair-rule genes. Knockdown of the expression of these genes leads to extensive patterning defects, implying that they act in early patterning, as well as segmentation in honeybee embryos. We show that these pair-rule gene orthologues indeed regulate the expression of honeybee maternal and gap genes implying roles in maternal patterning of the honeybee embryo. PMID- 23029535 TI - Downregulation of genes involved in metabolism and oxidative stress in the peripheral leukocytes of Huntington's disease patients. AB - BACKGROUND: Huntington's disease (HD) is caused by expanded CAG repeats encoding a polyglutamine tract in the huntingtin (HTT) protein. A number of differentially expressed protein molecules have been identified in striatum of HD animal models. Here we examined if the expression changes could be visualized in the peripheral leukocytes of HD patients and pre-symptomatic HD (PreHD) carriers. METHODS AND FINDINGS: The expression levels of 17 candidate genes that differentially expressed in striatum between transgenic HD and wild-type mice in literature were measured in the peripheral leukocytes of 4 PreHD carriers, 16 HD patients and 20 healthy controls. Four genes majorly involved in metabolism and oxidative stress response, including AHCY1, ACO2, OXCT1 and CAP1, demonstrated consistent downregulation in peripheral leukocytes of both PreHD carriers and HD patients, while UCP2 was only down-regulated in HD patients. CONCLUSION: These results provide potential peripheral biomarkers to indicate disease onset in preclinical stage, and to monitor the efficacy of early treatment. Further studies of a large series of preHD carriers and symptomatic HD patients will be warranted to verify the findings and examine if these markers correlate with clinical features. PMID- 23029536 TI - MmPPOX inhibits Mycobacterium tuberculosis lipolytic enzymes belonging to the hormone-sensitive lipase family and alters mycobacterial growth. AB - Lipid metabolism plays an important role during the lifetime of Mycobacterium tuberculosis, the causative agent of tuberculosis. Although M. tuberculosis possesses numerous lipolytic enzymes, very few have been characterized yet at a biochemical/pharmacological level. This study was devoted to the M. tuberculosis lipolytic enzymes belonging to the Hormone-Sensitive Lipase (HSL) family, which encompasses twelve serine hydrolases closely related to the human HSL. Among them, nine were expressed, purified and biochemically characterized using a broad range of substrates. In vitro enzymatic inhibition studies using the recombinant HSL proteins, combined with mass spectrometry analyses, revealed the potent inhibitory activity of an oxadiazolone compound, named MmPPOX. In addition, we provide evidence that MmPPOX alters mycobacterial growth. Overall, these findings suggest that the M. tuberculosis HSL family displays important metabolic functions, thus opening the way to further investigations linking the involvement of these enzymes in mycobacterial growth. PMID- 23029537 TI - The relationship between associative learning, transfer generalization, and homocysteine levels in mild cognitive impairment. AB - Previous studies have shown that high total homocysteine levels are associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI). In this study, we test the relationship between cognitive function and total homocysteine levels in healthy subjects (Global Dementia Rating, CDR = 0) and individuals with MCI (CDR = 0.5). We have used a cognitive task that tests learning and generalization of rules, processes that have been previously shown to rely on the integrity of the striatal and hippocampal regions, respectively. We found that total homocysteine levels are higher in MCI individuals than in healthy controls. Unlike what we expected, we found no difference between MCI subjects and healthy controls in learning and generalization. We conducted further analysis after diving MCI subjects in two groups, depending on their Global Deterioration Scale (GDS) scores: individuals with very mild cognitive decline (vMCD, GDS = 2) and mild cognitive decline (MCD, GDS = 3). There was no difference among the two MCI and healthy control groups in learning performance. However, we found that individuals with MCD make more generalization errors than healthy controls and individuals with vMCD. We found no difference in the number of generalization errors between healthy controls and MCI individuals with vMCD. In addition, interestingly, we found that total homocysteine levels correlate positively with generalization errors, but not with learning errors. Our results are in agreement with prior results showing a link between hippocampal function, generalization performance, and total homocysteine levels. Importantly, our study is perhaps among the first to test the relationship between learning (and generalization) of rules and homocysteine levels in healthy controls and individuals with MCI. PMID- 23029538 TI - Rich club organization of macaque cerebral cortex and its role in network communication. AB - Graph-theoretical analysis of brain connectivity data has revealed significant features of brain network organization across a range of species. Consistently, large-scale anatomical networks exhibit highly nonrandom attributes including an efficient small world modular architecture, with distinct network communities that are interlinked by hub regions. The functional importance of hubs motivates a closer examination of their mutual interconnections, specifically to examine the hypothesis that hub regions are more densely linked than expected based on their degree alone, i.e. forming a central rich club. Extending recent findings of rich club topology in the cat and human brain, this report presents evidence for the existence of rich club organization in the cerebral cortex of a non-human primate, the macaque monkey, based on a connectivity data set representing a collation of numerous tract tracing studies. Rich club regions comprise portions of prefrontal, parietal, temporal and insular cortex and are widely distributed across network communities. An analysis of network motifs reveals that rich club regions tend to form star-like configurations, indicative of their central embedding within sets of nodes. In addition, rich club nodes and edges participate in a large number of short paths across the network, and thus contribute disproportionately to global communication. As rich club regions tend to attract and disperse communication paths, many of the paths follow a characteristic pattern of first increasing and then decreasing node degree. Finally, the existence of non-reciprocal projections imposes a net directional flow of paths into and out of the rich club, with some regions preferentially attracting and others dispersing signals. Overall, the demonstration of rich club organization in a non-human primate contributes to our understanding of the network principles underlying neural connectivity in the mammalian brain, and further supports the hypothesis that rich club regions and connections have a central role in global brain communication. PMID- 23029539 TI - Reperfusion promotes mitochondrial dysfunction following focal cerebral ischemia in rats. AB - BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been implicated in the cell death observed after cerebral ischemia, and several mechanisms for this dysfunction have been proposed. Reperfusion after transient cerebral ischemia may cause continued and even more severe damage to the brain. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. The purpose of this study was to observe the features of mitochondrial dysfunction in isolated mitochondria during the reperfusion period following focal cerebral ischemia. METHODS: Male Wistar rats were subjected to focal cerebral ischemia. Mitochondria were isolated using Percoll density gradient centrifugation. The isolated mitochondria were fixed for electron microscopic examination; calcium-induced mitochondrial swelling was quantified using spectrophotometry. Cyclophilin D was detected by Western blotting. Fluorescent probes were used to selectively stain mitochondria to measure their membrane potential and to measure reactive oxidative species production using flow cytometric analysis. RESULTS: Signs of damage were observed in the mitochondrial morphology after exposure to reperfusion. The mitochondrial swelling induced by Ca(2+) increased gradually with the increasing calcium concentration, and this tendency was exacerbated as the reperfusion time was extended. Cyclophilin D protein expression peaked after 24 hours of reperfusion. The mitochondrial membrane potential was decreased significantly during the reperfusion period, with the greatest decrease observed after 24 hours of reperfusion. The surge in mitochondrial reactive oxidative species occurred after 2 hours of reperfusion and was maintained at a high level during the reperfusion period. CONCLUSIONS: Reperfusion following focal cerebral ischemia induced significant mitochondrial morphological damage and Ca(2+)-induced mitochondrial swelling. The mechanism of this swelling may be mediated by the upregulation of the Cyclophilin D protein, the destruction of the mitochondrial membrane potential and the generation of excessive reactive oxidative species. PMID- 23029540 TI - A common origin for the bacterial toxin-antitoxin systems parD and ccd, suggested by analyses of toxin/target and toxin/antitoxin interactions. AB - Bacterial toxin-antitoxin (TA) systems encode two proteins, a potent inhibitor of cell proliferation (toxin) and its specific antidote (antitoxin). Structural data has revealed striking similarities between the two model TA toxins CcdB, a DNA gyrase inhibitor encoded by the ccd system of plasmid F, and Kid, a site-specific endoribonuclease encoded by the parD system of plasmid R1. While a common structural fold seemed at odds with the two clearly different modes of action of these toxins, the possibility of functional crosstalk between the parD and ccd systems, which would further point to their common evolutionary origin, has not been documented. Here, we show that the cleavage of RNA and the inhibition of protein synthesis by the Kid toxin, two activities that are specifically counteracted by its cognate Kis antitoxin, are altered, but not inhibited, by the CcdA antitoxin. In addition, Kis was able to inhibit the stimulation of DNA gyrase-mediated cleavage of DNA by CcdB, albeit less efficiently than CcdA. We further show that physical interactions between the toxins and antitoxins of the different systems do occur and define the stoichiometry of the complexes formed. We found that CcdB did not degrade RNA nor did Kid have any reproducible effect on the tested DNA gyrase activities, suggesting that these toxins evolved to reach different, rather than common, cellular targets. PMID- 23029541 TI - Renoprotective effect of human umbilical cord-derived mesenchymal stem cells in immunodeficient mice suffering from acute kidney injury. AB - It is unknown whether human umbilical cord-derived mesenchymal stem cells (hUC MSCs) can improve the renal function of patients suffering from acute kidney injury. Moreover, before beginning clinical trials, it is necessary to investigate this renoprotective effect of hUC-MSCs in a xenogeneic model of acute kidney injury. However, no previous studies have examined the application of hUC MSCs to immunodeficient mice suffering from acute kidney injury. The objectives of this study were to examine whether hUC-MSCs could improve renal function in nonobese diabetic-severe combined immune deficiency (NOD-SCID) mice suffering from acute kidney injury, and to investigate the mechanism(s) for hUC-MSCs to improve renal function in this xenogeneic model. Early (3 hr) and late (12 hr) administrations of hUC-MSCs (10(6) cells) were performed via the external jugular vein into NOD-SCID mice suffering from either folic acid (FA) (250 mg/kg body weight) or vehicle. The results showed that early administration of hUC-MSCs improved the renal function of NOD-SCID mice suffering from FA-induced acute kidney injury, as evidenced by decreased serum urea nitrogen and serum creatinine levels, as well as a reduced tubular injury score. The beneficial effects of hUC MSCs were through reducing apoptosis and promoting proliferation of renal tubular cells. These benefits were independent of inflammatory cytokine effects and transdifferentiation. Furthermore, this study is the first one to show that the reduced apoptosis of renal tubular cells by hUC-MSCs in this xenogeneic model is mediated through the mitochondrial pathway, and through the increase of Akt phosphorylation. PMID- 23029542 TI - A20 (TNFAIP3) alleviates CVB3-induced myocarditis via inhibiting NF-kappaB signaling. AB - BACKGROUND: Viral myocarditis, which is most prevalently caused by Coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. However, efficient therapies targeting inflammation are still lacking and much needed. A20, also known as tumor necrosis factor alpha induced protein 3 (TNFAIP3) is a key negative regulator of inflammation. But whether A20 may affect cardiac inflammation during acute viral myocarditis remains to be elucidated. The aim of this study was to investigate the potential protective effect of A20 on CVB3-induced myocarditis. METHODOLOGY/PRINCIPAL FINDINGS: Mice were intraperitoneally inoculated with CVB3 to establish acute viral myocarditis model. We found that the expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6 and monocyte chemotactic protein-1 (MCP-1) were markedly and persistently increased during the progression of CVB3-induced myocarditis, and positively correlated with the disease severity. Notably, intravenous injection in vivo with adenovirus expressed A20 (Ad-A20) remarkably reduced CVB3-induced pro-inflammatory cytokines production and alleviated the severity of myocarditis. Further, we observed that nuclear factor-kappaB (NF-kappaB) signaling which mediates inflammatory response was significantly inhibited in CVB3-infected mice with Ad-A20 treatment. Finally, we revealed that A20 was required to inhibit CVB3-induced NF-kappaB signaling by restricting TNF receptor associated factor 6 (TRAF6) ubiquitylation. CONCLUSION/SIGNIFICANCE: This study demonstrates the protective role of A20 against CVB3-induced myocarditis, which may provide a new therapeutic strategy for the treatment of viral myocarditis. PMID- 23029543 TI - New indices for predicting glycaemic variability. AB - Blood glucose variability is known to be associated with increased risk of long term complications. Reliable indices for predicting hyperglycaemic and hypoglycaemic fluctuations are therefore needed. Glycaemic standard deviation (SD) obtained by continuous glucose monitoring correlates closely with nine previously described glycaemic variability formulas. Here, new indices predictive of glycaemic variability were developed, which can be calculated from laboratory measures based on a single blood draw. The indices included the glycated albumin (GA) to HbA1c ratio (GA/A1c ratio) and the fasting C-peptide immunoreactivity (FCPR) to fasting plasma glucose (FPG) ratio (FCPR index). Predictive values of these indices were assessed in 100 adults with diabetes. GA/A1c ratio and FCPR index showed close associations with glycaemic SD in addition to the nine existing glucose variability formulas. Subjects with a GA/A1c ratio >= 2.8 and FCPR index <3.0 showed the greatest SD and longest durations of hypoglycaemia, while those with a GA/A1c ratio <2.8 and FCPR index >= 3.0 had smaller SDs and little sign of hypoglycaemia. In adults with diabetes, a high GA/A1c ratio and low FCPR index value reflect higher glycaemic excursions, irrespective of diabetes type. Simultaneous measurements of GA, HbA1c, FPG and FCPR may help to identify a group of patients who warrant closer monitoring in relation to glycaemic variability and hypoglycaemia. PMID- 23029544 TI - Modulators of sensitivity and resistance to inhibition of PI3K identified in a pharmacogenomic screen of the NCI-60 human tumor cell line collection. AB - The phosphoinositide 3-kinase (PI3K) signaling pathway is significantly altered in a wide variety of human cancers, driving cancer cell growth and survival. Consequently, a large number of PI3K inhibitors are now in clinical development. To begin to improve the selection of patients for treatment with PI3K inhibitors and to identify de novo determinants of patient response, we sought to identify and characterize candidate genomic and phosphoproteomic biomarkers predictive of response to the selective PI3K inhibitor, GDC-0941, using the NCI-60 human tumor cell line collection. In this study, sixty diverse tumor cell lines were exposed to GDC-0941 and classified by GI(50) value as sensitive or resistant. The most sensitive and resistant cell lines were analyzed for their baseline levels of gene expression and phosphorylation of key signaling nodes. Phosphorylation or activation status of both the PI3K-Akt signaling axis and PARP were correlated with in vitro response to GDC-0941. A gene expression signature associated with in vitro sensitivity to GDC-0941 was also identified. Furthermore, in vitro siRNA mediated silencing of two genes in this signature, OGT and DDN, validated their role in modulating sensitivity to GDC-0941 in numerous cell lines and begins to provide biological insights into their role as chemosensitizers. These candidate biomarkers will offer useful tools to begin a more thorough understanding of determinants of patient response to PI3K inhibitors and merit exploration in human cancer patients treated with PI3K inhibitors. PMID- 23029545 TI - Several different lactase persistence associated alleles and high diversity of the lactase gene in the admixed Brazilian population. AB - Adult-type hypolactasia is a common phenotype caused by the lactase enzyme deficiency. The -13910 C>T polymorphism, located 14 Kb upstream of the lactase gene (LCT) in the MCM6 gene was associated with lactase persistence (LP) in Europeans. This polymorphism is rare in Africa but several other variants associated with lactase persistence were observed in Africans. The aims of this study were to identify polymorphisms in the MCM6 region associated with the lactase persistence phenotype and to determine the distribution of LCT gene haplotypes in 981 individuals from North, Northeast and South Brazil. These polymorphisms were genotyped by PCR based methods and sequencing. The -13779*C, 13910*T, -13937*A, -14010*C, -14011*T LP alleles previously described in the MCM6 gene region that acts as an enhancer for the LCT gene were identified in Brazilians. The most common LP allele was -13910*T. Its frequency was highly correlated with European ancestry in the Brazilian populations investigated. The 13910*T was higher (0.295) in southern Brazilians of European ancestry and lower (0.175) in the Northern admixed population. LCT haplotypes were derived from the 10 LCT SNPs genotyped. Overall twenty six haplotypes previously described were identified in the four Brazilian populations studied. The Multidimensional Scaling analysis showed that Belem, in the north, was closer to Amerindians. Northeastern and southern Afro-descendants were more related with Bantu-speaking South Africans whereas the Southern population with European ancestry grouped with Southern and Northern Europeans. This study shows a high variability considering the number of LCT haplotypes observed. Due to the highly admixed nature of the Brazilian populations, the diagnosis of hypolactasia in Brazil, based only in the investigation of the -13910*T allele is an oversimplification. PMID- 23029546 TI - Human amnion epithelial cells induced to express functional cystic fibrosis transmembrane conductance regulator. AB - Cystic fibrosis, an autosomal recessive disorder caused by a mutation in a gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), remains a leading cause of childhood respiratory morbidity and mortality. The respiratory consequences of cystic fibrosis include the generation of thick, tenacious mucus that impairs lung clearance, predisposing the individual to repeated and persistent infections, progressive lung damage and shortened lifespan. Currently there is no cure for cystic fibrosis. With this in mind, we investigated the ability of human amnion epithelial cells (hAECs) to express functional CFTR. We found that hAECs formed 3-dimensional structures and expressed the CFTR gene and protein after culture in Small Airway Growth Medium (SAGM). We also observed a polarized CFTR distribution on the membrane of hAECs cultured in SAGM, similar to that observed in polarized airway cells in vivo. Further, hAECs induced to express CFTR possessed functional iodide/chloride (I(-/)Cl(-)) ion channels that were inhibited by the CFTR-inhibitor CFTR-172, indicating the presence of functional CFTR ion channels. These data suggest that hAECs may be a promising source for the development of a cellular therapy for cystic fibrosis. PMID- 23029547 TI - Hypoxic conditions induce a cancer-like phenotype in human breast epithelial cells. AB - INTRODUCTION: Solid tumors are less oxygenated than their tissue of origin. Low intra-tumor oxygen levels are associated with worse outcome, increased metastatic potential and immature phenotype in breast cancer. We have reported that tumor hypoxia correlates to low differentiation status in breast cancer. Less is known about effects of hypoxia on non-malignant cells. Here we address whether hypoxia influences the differentiation stage of non-malignant breast epithelial cells and potentially have bearing on early stages of tumorigenesis. METHODS: Normal human primary breast epithelial cells and immortalized non-malignant mammary epithelial MCF-10A cells were grown in a three-dimensional overlay culture on laminin-rich extracellular matrix for up to 21 days at normoxic or hypoxic conditions. Acinar morphogenesis and expression of markers of epithelial differentiation and cell polarization were analyzed by immunofluorescence, immunohistochemistry, qPCR and immunoblot. RESULTS: In large ductal carcinoma in situ patient-specimens, we find that epithelial cells with high HIF-1alpha levels and multiple cell layers away from the vasculature are immature compared to well-oxygenated cells. We show that hypoxic conditions impaired acinar morphogenesis of primary and immortalized breast epithelial cells grown ex vivo on laminin-rich matrix. Normoxic cultures formed polarized acini-like spheres with the anticipated distribution of marker proteins associated with mammary epithelial polarization e.g. alpha6-integrin, laminin 5 and Human Milk Fat Globule/MUC1. At hypoxia, cells were not polarized and the sub-cellular distribution pattern of the marker proteins rather resembled that reported in vivo in breast cancer. The hypoxic cells remained in a mitotic state, whereas proliferation ceased with acinar morphogenesis at normoxia. We found induced expression of the differentiation repressor ID1 in the undifferentiated hypoxic MCF-10A cell structures. Acinar morphogenesis was associated with global histone deacetylation whereas the hypoxic breast epithelial cells showed sustained global histone acetylation, which is generally associated with active transcription and an undifferentiated proliferative state. PMID- 23029548 TI - The CTX-M-15-producing Escherichia coli clone O25b: H4-ST131 has high intestine colonization and urinary tract infection abilities. AB - Increasing numbers of pyelonephritis-associated uropathogenic Escherichia coli (UPEC) are exhibiting high resistance to antibiotic therapy. They include a particular clonal group, the CTX-M-15-producing O25b:H4-ST131 clone, which has been shown to have a high dissemination potential. Here we show that a representative isolate of this E. coli clone, referred to as TN03, has enhanced metabolic capacities, acts as a potent intestine- colonizing strain, and displays the typical features of UPEC strains. In a modified streptomycin-treated mouse model of intestinal colonization where streptomycin was stopped 5 days before inoculation, we show that TN03 outcompetes the commensal E. coli strains K-12 MG1655, IAI1, and ED1a at days 1 and 7. Using an experimental model of ascending UTI in C3H/HeN mice, we then show that TN03 colonized the urinary tract. One week after the transurethral inoculation of the TN03 isolates, the bacterial loads in the bladder and kidneys were significantly greater than those of two other UPEC strains (CFT073 and HT7) belonging to the same B2 phylogenetic group. The differences in bacterial loads did not seem to be directly linked to differences in the inflammatory response, since the intrarenal expression of chemokines and cytokines and the number of polymorphonuclear neutrophils attracted to the site of inflammation was the same in kidneys colonized by TN03, CFT073, or HT7. Lastly, we show that in vitro TN03 has a high maximum growth rate in both complex (Luria-Bertani and human urine) and minimum media. In conclusion, our findings indicate that TN03 is a potent UPEC strain that colonizes the intestinal tract and may persist in the kidneys of infected hosts. PMID- 23029549 TI - Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. AB - Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury. We investigated whether deleterious effects of AR are due to its actions specifically in cardiomyocytes. We created mice with cardiac specific expression of human AR (hAR) using the alpha-myosin heavy chain (MHC) promoter and studied these animals during aging and with reduced fatty acid (FA) oxidation. hAR transgenic expression did not alter cardiac function or glucose and FA oxidation gene expression in young mice. However, cardiac overexpression of hAR caused cardiac dysfunction in older mice. We then assessed whether hAR altered heart function during ischemia reperfusion. hAR transgenic mice had greater infarct area and reduced functional recovery than non-transgenic littermates. When the hAR transgene was crossed onto the PPAR alpha knockout background, another example of greater heart glucose oxidation, hAR expressing mice had increased heart fructose content, cardiac fibrosis, ROS, and apoptosis. In conclusion, overexpression of hAR in cardiomyocytes leads to cardiac dysfunction with aging and in the setting of reduced FA and increased glucose metabolism. These results suggest that pharmacological inhibition of AR will be beneficial during ischemia and in some forms of heart failure. PMID- 23029550 TI - Associations between variation in CHRNA5-CHRNA3-CHRNB4, body mass index and blood pressure in the Northern Finland Birth Cohort 1966. AB - BACKGROUND: The CHRNA5-CHRNA3-CHRNB4 gene cluster on 15q25 has consistently been associated with smoking quantity, nicotine dependence and lung cancer. Recent research also points towards its involvement in cardiovascular homeostasis, but studies in large human samples are lacking, especially on the role of the gene cluster in blood pressure regulation. METHODOLOGY/PRINCIPAL FINDINGS: We studied the associations between 18 single nucleotide polymorphisms (SNPs) in CHRNA5 CHRNA3-CHRNB4 and systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) in 5402 young adults from the Northern Finland Birth Cohort 1966. We observed some evidence for associations between two SNPs and SBP and between six SNPs and BMI; the evidence for associations with DBP was weaker. The associations with the three phenotypes were driven by different loci with low linkage disequilibrium with each other. The associations appeared more pronounced in smokers, such that the smoking-increasing alleles would predict lower SBP and BMI. Each additional copy of the rs1948 G-allele and the rs950776 A-allele reduced SBP on average by -1.21 (95% CI -2.01, -0.40) mmHg in smokers. The variants associated with BMI included rs2036534, rs6495309, rs1996371, rs6495314, rs4887077 and rs11638372 and had an average effect size of -0.38 (-0.68, -0.08) kg/m(2) per an additional copy of the risk allele in smokers. Formal assessments of interactions provided weaker support for these findings, especially after adjustment for multiple testing. CONCLUSIONS: Variation at 15q25 appears to interact with smoking status in influencing SBP and BMI. The genetic loci associated with SBP were in low linkage disequilibrium with those associated with BMI suggesting that the gene cluster might regulate SBP through biological mechanisms that partly differ from those regulating BMI. Further studies in larger samples are needed for more precise evaluation of the possible interactions, and to understand the mechanisms behind. PMID- 23029551 TI - Protective effects of polydatin from Polygonum cuspidatum against carbon tetrachloride-induced liver injury in mice. AB - Polydatin is one of main compounds in Polygonum cuspidatum, a plant with both medicinal and nutritional value. The possible hepatoprotective effects of polydatin on acute liver injury mice induced by carbon tetrachloride (CCl(4)) and the mechanisms involved were investigated. Intraperitoneal injection of CCl(4) (50 ul/kg) resulted in a significant increase in the levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and hepatic malondialdehyde (MDA), also a marked enhancement in the expression of hepatic tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclearfactor-kappa B (NF-kappaB). On the other hand, decreased glutathione (GSH) content and activities of glutathione transferase (GST), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were observed following CCl(4) exposure. Nevertheless, all of these phenotypes were evidently reversed by preadministration of polydatin for 5 continuous days. The mRNA and protein expression levels of hepatic growth factor-beta1 (TGF-beta(1)) were enhanced further by polydatin. These results suggest that polydatin protects mice against CCl(4)-induced liver injury through antioxidant stress and antiinflammatory effects. Polydatin may be an effective hepatoprotective agent and a promising candidate for the treatment of oxidative stress- and inflammation-related diseases. PMID- 23029552 TI - Gene expression in uninvolved oral mucosa of OSCC patients facilitates identification of markers predictive of OSCC outcomes. AB - Oral and oropharyngeal squamous cell carcinomas (OSCC) are among the most common cancers worldwide, with approximately 60% 5-yr survival rate. To identify potential markers for disease progression, we used Affymetrix U133 plus 2.0 arrays to examine the gene expression profiles of 167 primary tumor samples from OSCC patients, 58 uninvolved oral mucosae from OSCC patients and 45 normal oral mucosae from patients without oral cancer, all enrolled at one of the three University of Washington-affiliated medical centers between 2003 to 2008. We found 2,596 probe sets differentially expressed between 167 tumor samples and 45 normal samples. Among 2,596 probe sets, 71 were significantly and consistently up or down-regulated in the comparison between normal samples and uninvolved oral samples and between uninvolved oral samples and tumor samples. Cox regression analyses showed that 20 of the 71 probe sets were significantly associated with progression-free survival. The risk score for each patient was calculated from coefficients of a Cox model incorporating these 20 probe sets. The hazard ratio (HR) associated with each unit change in the risk score adjusting for age, gender, tumor stage, and high-risk HPV status was 2.7 (95% CI: 2.0-3.8, p = 8.8E 10). The risk scores in an independent dataset of 74 OSCC patients from the MD Anderson Cancer Center was also significantly associated with progression-free survival independent of age, gender, and tumor stage (HR 1.6, 95% CI: 1.1-2.2, p = 0.008). Gene Set Enrichment Analysis showed that the most prominent biological pathway represented by the 71 probe sets was the Integrin cell surface interactions pathway. In conclusion, we identified 71 probe sets in which dysregulation occurred in both uninvolved oral mucosal and cancer samples. Dysregulation of 20 of the 71 probe sets was associated with progression-free survival and was validated in an independent dataset. PMID- 23029553 TI - Microbial regulation of glucose metabolism and cell-cycle progression in mammalian colonocytes. AB - A prodigious number of microbes inhabit the human body, especially in the lumen of the gastrointestinal (GI) tract, yet our knowledge of how they regulate metabolic pathways within our cells is rather limited. To investigate the role of microbiota in host energy metabolism, we analyzed ATP levels and AMPK phosphorylation in tissues isolated from germfree and conventionally-raised C57BL/6 mice. These experiments demonstrated that microbiota are required for energy homeostasis in the proximal colon to a greater extent than other segments of the GI tract that also harbor high densities of bacteria. This tissue-specific effect is consistent with colonocytes utilizing bacterially-produced butyrate as their primary energy source, whereas most other cell types utilize glucose. However, it was surprising that glucose did not compensate for butyrate deficiency. We measured a 3.5-fold increase in glucose uptake in germfree colonocytes. However, (13)C-glucose metabolic-flux experiments and biochemical assays demonstrated that they shifted their glucose metabolism away from mitochondrial oxidation/CO(2) production and toward increased glycolysis/lactate production, which does not yield enough ATPs to compensate. The mechanism responsible for this metabolic shift is diminished pyruvate dehydrogenase (PDH) levels and activity. Consistent with perturbed PDH function, the addition of butyrate, but not glucose, to germfree colonocytes ex vivo stimulated oxidative metabolism. As a result of this energetic defect, germfree colonocytes exhibited a partial block in the G(1)-to-S-phase transition that was rescued by a butyrate fortified diet. These data reveal a mechanism by which microbiota regulate glucose utilization to influence energy homeostasis and cell-cycle progression of mammalian host cells. PMID- 23029554 TI - The epithelial sodium channel (ENaC) establishes a trafficking vesicle pool responsible for its regulation. AB - The epithelial sodium channel (ENaC) is the rate-limiting step for sodium reabsorption across tight epithelia. Cyclic-AMP (cAMP) stimulation promotes ENaC trafficking to the apical surface to increase channel number and transcellular Na(+) transport. Removal of corticosteroid supplementation in a cultured cortical collecting duct cell line reduced ENaC expression. Concurrently, the number of vesicles trafficked in response to cAMP stimulation, as measured by a change in membrane capacitance, also decreased. Stimulation with aldosterone restored both the basal and cAMP-stimulated ENaC activity and increased the number of exocytosed vesicles. Knocking down ENaC directly decreased both the cAMP stimulated short-circuit current and capacitance response in the presence of aldosterone. However, constitutive apical recycling of the Immunoglobulin A receptor was unaffected by alterations in ENaC expression or trafficking. Fischer Rat Thyroid cells, transfected with alpha,beta,gamma-mENaC had a significantly greater membrane capacitance response to cAMP stimulation compared to non-ENaC controls. Finally, immunofluorescent labeling and quantitation revealed a smaller number of vesicles in cells where ENaC expression was reduced. These findings indicate that ENaC is not a passive passenger in regulated epithelial vesicle trafficking, but plays a role in establishing and maintaining the pool of vesicles that respond to cAMP stimulation. PMID- 23029555 TI - Npas4: a neuronal transcription factor with a key role in social and cognitive functions relevant to developmental disorders. AB - Npas4 is a transcription factor, which is highly expressed in the brain and regulates the formation and maintenance of inhibitory synapses in response to excitatory synaptic activity. A deregulation of the inhibitory-excitatory balance has been associated with a variety of human developmental disorders such as schizophrenia and autism. However, not much is known about the role played by inhibitory synapses and inhibitory pathways in the development of nervous system disorders. We hypothesized that alterations in the inhibitory pathways induced by the absence of Npas4 play a major role in the expression of the symptoms observed in psychiatric disorders. To test this hypothesis we tested mice lacking the transcription factor (Npas4 knock-out mice (Npas4-KO)) in a battery of behavioral assays focusing on general activity, social behaviors, and cognitive functions. Npas4-KO mice are hyperactive in a novel environment, spend less time exploring an unfamiliar ovariectomized female, spend more time avoiding an unfamiliar male during a first encounter, show higher social dominance than their WT littermates, and display pre-pulse inhibition, working memory, long-term memory, and cognitive flexibility deficits. These behavioral deficits may replicate schizophrenia related symptomatology such as social anxiety, hyperactivity, and cognitive and sensorimotor gating deficits. Immunohistochemistry analyses revealed that Npas4 expression is induced in the hippocampus after a social encounter and that Npas4 regulates the expression of c-Fos in the CA1 and CA3 regions of the hippocampus after a cognitive task. Our results suggest that Npas4 may play a major role in the regulation of cognitive and social functions in the brain with possible implications for developmental disorders such as schizophrenia and autism. PMID- 23029556 TI - Cortical neurovascular coupling driven by stimulation of channelrhodopsin-2. AB - While functional imaging is widely used in studies of the brain, how well the hemodynamic signal represents the underlying neural activity is still unclear. And there is a debate on whether hemodynamic signal is more tightly related to synaptic activity or action potentials. This study intends to address these questions by examining neurovascular coupling driven by pyramidal cells in the motor cortex of rats. Pyramidal cells in the motor cortex of rats were selectively transduced with the light sensitive cation channel channelrhodopsin-2 (ChR2). Electrophysiological recordings and optical intrinsic signal imaging were performed simultaneously and synchronously to capture the neural activity and hemodynamics induced by optical stimulation of ChR2-expressing pyramidal cells. Our results indicate that both synaptic activity (local field potential, LFP) and action potentials (multi-unit activity, MUA) are tightly related to hemodynamic signals. While LFPs in gamma band are better in predicting hemodynamic signals elicited by short stimuli, MUA has better predictions to hemodynamic signals elicited by long stimuli. Our results also indicate that strong nonlinearity exists in neurovascular coupling. PMID- 23029557 TI - LXR-mediated inhibition of CD4+ T helper cells. AB - T(H)17 cells, which require the expression of both retinoic acid receptor-related orphan receptors alpha and gammat (RORalphaand RORgammat) for full differentiation and function, have been implicated as major effectors in the pathogenesis of inflammatory and autoimmune diseases. We recently demonstrated that the Liver X Receptor (LXR) agonist, T0901317 (T09), also displays high affinity RORalpha and RORgamma inverse activity, potentially explaining its effectiveness in various T(H)17-mediated autoimmune disease models. However, recent studies suggest that in conjunction with the RORs, LXR mediates a negative regulatory effect on T(H)17 cell differentiation. Since T09 acts on both LXRs and RORs, it presents as a valuable tool to understand how compounds with mixed pharmacology affect potential pathological cell types. Therefore, using T09, we investigated the mechanism by which the LXRs and RORs affect T(H)17 cell differentiation and function. Here we demonstrate that T09 activity at RORalpha and gamma, not LXR, is facilitating the inhibition of T(H)17 cell differentiation and function. We also demonstrate that LXR activity inhibits the differentiation and function of T(H)1, T(H)2 and iT(reg) cells. Finally, T09 inhibited T cell proliferation and induced cell death. These data help explain much of the efficacy of T09 in inflammatory models and suggest that the generation of synthetic ligands with graded, combined LXR and ROR activity may hold utility in the treatment of inflammatory and autoimmune diseases where targeting both T(H)17 and T(H)1 cells is required. PMID- 23029558 TI - Myocilin polymorphisms and primary open-angle glaucoma: a systematic review and meta-analysis. AB - BACKGROUND: Glaucoma is the leading cause of irreversible blindness in the world. Recent evidence indicates a role for genetic susceptibility to primary open-angle glaucoma (POAG). The relation between myocilin polymorphisms and POAG susceptibility has been studied in different populations. METHODS: A meta analysis of 32 published genetic association case-control studies, which examined the relation between POAG and the R46X, R76K, Y347Y, T353I, and Q368X polymorphisms of the myocilin gene, was carried out. RESULTS: In meta-analysis, significant associations were observed between POAG risk and two myocilin polymorphisms with summarized odds ratio of 4.68 (95%CI, 2.02-10.85) for Q368X and 2.17 (95% CI, 1.32-3.57) for T353I. Both Q368X and T353I were significantly associated with high-tension glaucoma, with summarized odds ratio of 4.26 (1.69, 10.73) and 2.26 (1.37-3.72). In Westerners, significant association was observed for Q368X mutation (odds ratio, 5.17; 95% CI, 2.16-12.40). However, in Asians it was for T353I (odds ratio, 2.17; 95% CI, 1.32-3.57). CONCLUSIONS: There is strong evidence that myocilin polymorphisms are associated with POAG susceptibility, and the prevalence of myocilin mutations might be ethnicity-dependent in Caucasians for Q368X and in Asians for T353I. PMID- 23029559 TI - Using amino acid physicochemical distance transformation for fast protein remote homology detection. AB - Protein remote homology detection is one of the most important problems in bioinformatics. Discriminative methods such as support vector machines (SVM) have shown superior performance. However, the performance of SVM-based methods depends on the vector representations of the protein sequences. Prior works have demonstrated that sequence-order effects are relevant for discrimination, but little work has explored how to incorporate the sequence-order information along with the amino acid physicochemical properties into the prediction. In order to incorporate the sequence-order effects into the protein remote homology detection, the physicochemical distance transformation (PDT) method is proposed. Each protein sequence is converted into a series of numbers by using the physicochemical property scores in the amino acid index (AAIndex), and then the sequence is converted into a fixed length vector by PDT. The sequence-order information can be efficiently included into the feature vector with little computational cost by this approach. Finally, the feature vectors are input into a support vector machine classifier to detect the protein remote homologies. Our experiments on a well-known benchmark show the proposed method SVM-PDT achieves superior or comparable performance with current state-of-the-art methods and its computational cost is considerably superior to those of other methods. When the evolutionary information extracted from the frequency profiles is combined with the PDT method, the profile-based PDT approach can improve the performance by 3.4% and 11.4% in terms of ROC score and ROC50 score respectively. The local sequence-order information of the protein can be efficiently captured by the proposed PDT and the physicochemical properties extracted from the amino acid index are incorporated into the prediction. The physicochemical distance transformation provides a general framework, which would be a valuable tool for protein-level study. PMID- 23029560 TI - Interaction of nuclease colicins with membranes: insertion depth correlates with bilayer perturbation. AB - BACKGROUND: Protein transport across cellular membranes is an important aspect of toxin biology. Escherichia coli cell killing by nuclease colicins occurs through DNA (DNases) or RNA (RNases) hydrolysis and to this end their cytotoxic domains require transportation across two sets of membranes. In order to begin to unravel the molecular mechanisms underlying the membrane translocation of colicin nuclease domains, we have analysed the membrane association of four DNase domains (E9, a charge reduction E9 mutant, E8, and E7) and one ribosomal RNase domain (E3) using a biomembrane model system. PRINCIPAL RESULTS: We demonstrate, through the use of large unilamellar vesicles composed of synthetic and E. coli lipids and a membrane surface potential sensor, that the colicin nuclease domains bind anionic membranes only, with micromolar affinity and via a cooperative binding mechanism. The evaluation of the nuclease bilayer insertion depth, through a fluorescence quenching analysis using brominated lipids, indicates that the nucleases locate to differential regions in the bilayer. Colicin DNases target the interfacial region of the lipid bilayer, with the DNase E7 showing the deepest insertion, whereas the ribosomal RNase E3 penetrates into the hydrophobic core region of the bilayer. Furthermore, the membrane association of the DNase E7 and the ribosomal RNase E3 induces vesicle aggregation, lipid mixing and content leakage to a much larger extent than that of the other DNases analysed. CONCLUSIONS/SIGNIFICANCE: Our results show, for the first time, that after the initial electrostatically driven membrane association, the pleiotropic membrane effects induced by colicin nuclease domains relate to their bilayer insertion depth and may be linked to their in vivo membrane translocation. PMID- 23029561 TI - Medium-throughput processing of whole mount in situ hybridisation experiments into gene expression domains. AB - Understanding the function and evolution of developmental regulatory networks requires the characterisation and quantification of spatio-temporal gene expression patterns across a range of systems and species. However, most high throughput methods to measure the dynamics of gene expression do not preserve the detailed spatial information needed in this context. For this reason, quantification methods based on image bioinformatics have become increasingly important over the past few years. Most available approaches in this field either focus on the detailed and accurate quantification of a small set of gene expression patterns, or attempt high-throughput analysis of spatial expression through binary pattern extraction and large-scale analysis of the resulting datasets. Here we present a robust, "medium-throughput" pipeline to process in situ hybridisation patterns from embryos of different species of flies. It bridges the gap between high-resolution, and high-throughput image processing methods, enabling us to quantify graded expression patterns along the antero posterior axis of the embryo in an efficient and straightforward manner. Our method is based on a robust enzymatic (colorimetric) in situ hybridisation protocol and rapid data acquisition through wide-field microscopy. Data processing consists of image segmentation, profile extraction, and determination of expression domain boundary positions using a spline approximation. It results in sets of measured boundaries sorted by gene and developmental time point, which are analysed in terms of expression variability or spatio-temporal dynamics. Our method yields integrated time series of spatial gene expression, which can be used to reverse-engineer developmental gene regulatory networks across species. It is easily adaptable to other processes and species, enabling the in silico reconstitution of gene regulatory networks in a wide range of developmental contexts. PMID- 23029562 TI - ERK-mediated activation of Fas apoptotic inhibitory molecule 2 (Faim2) prevents apoptosis of 661W cells in a model of detachment-induced photoreceptor cell death. AB - In this study, we examined the role of Fas apoptotic inhibitory molecule 2 (Faim2), an inhibitor of the Fas signaling pathway, and its regulation by stress kinase signaling during Fas-mediated apoptosis of 661W cells, an immortalized photoreceptor-like cell line Treatment of 661W cells with a Fas-activating antibody led to increased levels of Faim2. Both ERK and JNK stress kinase pathways were activated in Fas-treated 661W cells, but only the inhibition of the ERK pathway reduced the levels of Faim2. Blocking the ERK pathway using a pharmacological inhibitor increased the susceptibility of 661W cells to Fas induced caspase activation and apoptosis. When the levels of Faim2 were reduced in 661W cells by siRNA knockdown, Fas activating antibody treatment resulted in earlier and more robust caspase activation, and increased cell death. These results demonstrate that Faim2 acts as a neuroprotectant during Fas-mediated apoptosis of 661W cells. The expression of Faim2 is triggered, at least in part, by Fas-receptor activation and subsequent ERK signaling. Our findings identify a novel protective pathway that auto-regulates Fas-induced photoreceptor apoptosis in vitro. Modulation of this pathway to increase Faim2 expression may be a potential therapeutic option to prevent photoreceptor death. PMID- 23029564 TI - Corresponding mitochondrial DNA and niche divergence for crested newt candidate species. AB - Genetic divergence of mitochondrial DNA does not necessarily correspond to reproductive isolation. However, if mitochondrial DNA lineages occupy separate segments of environmental space, this supports the notion of their evolutionary independence. We explore niche differentiation among three candidate species of crested newt (characterized by distinct mitochondrial DNA lineages) and interpret the results in the light of differences observed for recognized crested newt species. We quantify niche differences among all crested newt (candidate) species and test hypotheses regarding niche evolution, employing two ordination techniques (PCA-env and ENFA). Niche equivalency is rejected: all (candidate) species are found to occupy significantly different segments of environmental space. Furthermore, niche overlap values for the three candidate species are not significantly higher than those for the recognized species. As the three candidate crested newt species are, not only in terms of mitochondrial DNA genetic divergence, but also ecologically speaking, as diverged as the recognized crested newt species, our findings are in line with the hypothesis that they represent cryptic species. We address potential pitfalls of our methodology. PMID- 23029563 TI - Down-regulation of CDH1 is associated with expression of SNAI1 in colorectal adenomas. AB - INTRODUCTION: Down-regulation of E-cadherin (CDH1) and epithelial-mesenchymal transition (EMT) are considered critical events for invasion and metastasis of colorectal carcinoma. Here we tested whether the important regulators of E cadherin expression SNAI1 and TWIST1 are already detectable in human colorectal adenomas. METHODS: RNA was extracted from a set of randomly selected formalin fixed and paraffin-embedded (FFPE) colorectal adenomas (n = 41) and normal colon mucosa (n = 10). Subsequently mRNA expression of CDH1, CDH2, SNAI1 and TWIST1 was analysed by quantitative RT-PCR analysis. CDH1 as well as SNAI1 protein expression were assessed by immunohistochemistry (IHC). RESULTS: SNAI1 mRNA was expressed in 78% (n = 32/41), TWIST1 mRNA in 41% (n = 17/41) and CDH2 mRNA in 41% (n = 17/41) of the colorectal adenoma tissue, while normal colon mucosa was negative for these transcription factors. We found a significant correlation between reduced CDH1 and the presence of SNAI1 mRNA expression and for combined SNAI1 and TWIST1 mRNA expression, respectively. A correlation between CDH2 mRNA expression and reduced CDH1 expression was not observed. We confirmed the relationship between SNAI1 expression and reduced E-cadherin expression on the protein level via IHC. CONCLUSION: Our data show that SNAI1 and Twist1 are already expressed in benign precursor lesions of colorectal cancer and that SNAI1 expression was significantly correlated with lower expression of CDH1. Whether these findings reflect true EMT and/or are a sign of a more aggressive biology need to be investigated in further studies. PMID- 23029566 TI - Evidence in Australia for a case of airport dengue. PMID- 23029565 TI - Chip-based comparison of the osteogenesis of human bone marrow- and adipose tissue-derived mesenchymal stem cells under mechanical stimulation. AB - Adipose tissue-derived stem cells (ASCs) are considered as an attractive stem cell source for tissue engineering and regenerative medicine. We compared human bone marrow-derived mesenchymal stem cells (hMSCs) and hASCs under dynamic hydraulic compression to evaluate and compare osteogenic abilities. A novel micro cell chip integrated with microvalves and microscale cell culture chambers separated from an air-pressure chamber was developed using microfabrication technology. The microscale chip enables the culture of two types of stem cells concurrently, where each is loaded into cell culture chambers and dynamic compressive stimulation is applied to the cells uniformly. Dynamic hydraulic compression (1 Hz, 1 psi) increased the production of osteogenic matrix components (bone sialoprotein, oateopontin, type I collagen) and integrin (CD11b and CD31) expression from both stem cell sources. Alkaline phosphatase and Alrizarin red staining were evident in the stimulated hMSCs, while the stimulated hASCs did not show significant increases in staining under the same stimulation conditions. Upon application of mechanical stimulus to the two types of stem cells, integrin (beta1) and osteogenic gene markers were upregulated from both cell types. In conclusion, stimulated hMSCs and hASCs showed increased osteogenic gene expression compared to non-stimulated groups. The hMSCs were more sensitive to mechanical stimulation and more effective towards osteogenic differentiation than the hASCs under these modes of mechanical stimulation. PMID- 23029567 TI - Therapeutics for dengue: recommendations for design and conduct of early-phase clinical trials. PMID- 23029568 TI - Corticosteroid use for paradoxical reactions during antibiotic treatment for Mycobacterium ulcerans. PMID- 23029569 TI - Disability measurement for lymphatic filariasis: a review of generic tools used within morbidity management programs. AB - Lymphatic filariasis (LF)-related disability affects 40 million people globally, making LF the leading cause of physical disability in the world. Despite this, there is limited research into how the impacts of LF-related disability are best measured. This article identifies the tools currently being used to measure LF related disability and reviews their applicability against the known impacts of LF. The findings from the review show that the generic disability tools currently used by LF programs fail to measure the majority of known impacts of LF-related disability. The findings from the review support the development of an LF specific disability measurement tool and raise doubt about the suitability of generic disability tools to assess disability related to neglected tropical diseases (NTDs) globally. PMID- 23029570 TI - Determining treatment needs at different spatial scales using geostatistical model-based risk estimates of schistosomiasis. AB - BACKGROUND: After many years of neglect, schistosomiasis control is going to scale. The strategy of choice is preventive chemotherapy, that is the repeated large-scale administration of praziquantel (a safe and highly efficacious drug) to at-risk populations. The frequency of praziquantel administration is based on endemicity, which usually is defined by prevalence data summarized at an arbitrarily chosen administrative level. METHODOLOGY: For an ensemble of 29 West and East African countries, we determined the annualized praziquantel treatment needs for the school-aged population, adhering to World Health Organization guidelines. Different administrative levels of prevalence aggregation were considered; country, province, district, and pixel level. Previously published results on spatially explicit schistosomiasis risk in the selected countries were employed to classify each area into distinct endemicity classes that govern the frequency of praziquantel administration. PRINCIPAL FINDINGS: Estimates of infection prevalence adjusted for the school-aged population in 2010 revealed that most countries are classified as moderately endemic for schistosomiasis (prevalence 10-50%), while four countries (i.e., Ghana, Liberia, Mozambique, and Sierra Leone) are highly endemic (>50%). Overall, 72.7 million annualized praziquantel treatments (50% confidence interval (CI): 68.8-100.7 million) are required for the school-aged population if country-level schistosomiasis prevalence estimates are considered, and 81.5 million treatments (50% CI: 67.3 107.5 million) if estimation is based on a more refined spatial scale at the provincial level. CONCLUSIONS/SIGNIFICANCE: Praziquantel treatment needs may be over- or underestimated depending on the level of spatial aggregation. The distribution of schistosomiasis in Ethiopia, Liberia, Mauritania, Uganda, and Zambia is rather uniform, and hence country-level risk estimates are sufficient to calculate treatment needs. On the other hand, countries like Burkina Faso, Mali, Mozambique, Sudan, and Tanzania show large spatial heterogeneity in schistosomiasis risk, which should be taken into account for calculating treatment requirements. PMID- 23029571 TI - High prevalence of Schistosoma japonicum infection in Carabao from Samar Province, the Philippines: implications for transmission and control. AB - Schistosoma japonicum is endemic in the Philippines, China and Indonesia, and infects more than 40 mammalian host species, all of which can act as reservoirs of infection. In China, water buffaloes have been shown to be major reservoirs of human infection. However, in the Philippines, carabao have not been considered important reservoir hosts for S. japonicum due to the low prevalence and infection intensities reported, the only exception being a qPCR-based study indicating 51% of carabao were S. japonicum-positive. However, the low prevalence found for the same animals when using conventional copro-parasitological techniques means that there is still confusion about the role of carabao in the transmission of schistosomiasis japonicum. To address this inconsistency, and to shed light on the potential role of carabao in the transmission of S. japonicum in the Philippines, we undertook a pilot survey, collecting fecal samples from animals in Western Samar Province and we used a combination of molecular and copro-parasitological techniques to determine the prevalence and intensity of S. japonicum. We found a high prevalence of S. japonicum in the carabao using a validated real-time PCR (qPCR) and a copro-parasitological tool, the formalin ethyl acetate sedimentation (FEA-SD) technique. A much lower prevalence of S. japonicum was recorded for the same fecal samples using conventional PCR, the Kato-Katz technique and miracidial hatching. These results suggest that, due to their low diagnostic sensitivity, traditional copro-parasitological techniques underestimate infection in carabao. The use of FEA-SD and qPCR provides a more accurate diagnosis. Based on these findings, the role of bovines in the transmission of S. japonicum appears to be more important in the Philippines than previously recognized, and this may have significant implications for the future control of schistosomiasis there, particularly as, in contrast with previous surveys, we found an unprecedented high prevalence of S. japonicum in humans. PMID- 23029572 TI - Re-visiting Trichuris trichiura intensity thresholds based on anemia during pregnancy. AB - BACKGROUND: The intensity categories, or thresholds, currently used for Trichuris trichiura (ie. epg intensities of 1-999 (light); 1,000-9,999 epg (moderate), and >= 10,000 epg (heavy)) were developed in the 1980s, when there were little epidemiological data available on dose-response relationships. This study was undertaken to determine a threshold for T. trichiura-associated anemia in pregnant women and to describe the implications of this threshold in terms of the need for primary prevention and chemotherapeutic interventions. METHODOLOGY/PRINCIPAL FINDINGS: In Iquitos, Peru, 935 pregnant women were tested for T. trichiura infection in their second trimester of pregnancy; were given daily iron supplements throughout their pregnancy; and had their blood hemoglobin levels measured in their third trimester of pregnancy. Women in the highest two T. trichiura intensity quintiles (601-1632 epg and >= 1633 epg) had significantly lower mean hemoglobin concentrations than the lowest quintile (0-24 epg). They also had a statistically significantly higher risk of anemia, with adjusted odds ratios of 1.67 (95% CI: 1.02, 2.62) and 1.73 (95% CI: 1.09, 2.74), respectively. CONCLUSIONS/SIGNIFICANCE: This analysis provides support for categorizing a T. trichiura infection >= 1,000 epg as 'moderate', as currently defined by the World Health Organization. Because this 'moderate' level of T. trichiura infection was found to be a significant risk factor for anemia in pregnant women, the intensity of Trichuris infection deemed to cause or aggravate anemia should no longer be restricted to the 'heavy' intensity category. It should now include both 'heavy' and 'moderate' intensities of Trichuris infection. Evidence-based deworming strategies targeting pregnant women or populations where anemia is of concern should be updated accordingly. PMID- 23029573 TI - Simple clinical and laboratory predictors of Chikungunya versus dengue infections in adults. AB - BACKGROUND: Dengue and chikungunya are co-circulating vector-borne diseases with substantial overlap in clinical presentations. It is important to differentiate between them during first presentation as their management, especially for dengue hemorrhagic fever (DHF), is different. This study compares their clinical presentation in Singapore adults to derive predictors to assist doctors in diagnostic decision-making. METHODS: We compared 117 patients with chikungunya infection diagnosed with reverse transcription-polymerase chain reaction (RT-PCR) with 917 dengue RT-PCR-positive adult patients (including 55 with DHF). We compared dengue fever (DF), DHF, and chikungunya infections by evaluating clinical characteristics of dengue and chikungunya; developing classification tools via multivariate logistic regression models and classification trees of disease etiology using clinical and laboratory factors; and assessing the time course of several clinical variables. FINDINGS: At first presentation to hospital, significantly more chikungunya patients had myalgia or arthralgia, and fewer had a sore throat, cough (for DF), nausea, vomiting, diarrhea, abdominal pain, anorexia or tachycardia than DF or DHF patients. From the decision trees, platelets <118 * 10(9)/L was the only distinguishing feature for DF versus chikungunya with an overall correct classification of 89%. For DHF versus chikungunya using platelets <100 * 10(9)/L and the presence of bleeding, the overall correct classification was 98%. The time course analysis supported platelet count as the key distinguishing variable. INTERPRETATION: There is substantial overlap in clinical presentation between dengue and chikungunya infections, but simple clinical and laboratory variables can predict these infections at presentation for appropriate management. PMID- 23029574 TI - Epidemiology of tick-borne borreliosis in Morocco. AB - BACKGROUND: The presence in Morocco of Argasid ticks of the Ornithodoros erraticus complex, the vector of tick-borne relapsing fever (TBRF) in North Africa, has been known since 1919, but the disease is rarely diagnosed and few epidemiological data are available. METHODOLOGY/PRINCIPAL FINDINGS: Between 2006 and 2011, we investigated the presence of Ornithodoros ticks in rodent burrows in 34 sites distributed across Morocco. We also collected small mammals in 10 sites and we investigated TBRF in febrile patients in Kenitra district. The prevalence of Borrelia infections was assessed by nested PCR amplification in ticks and the brain tissue of small mammals, and by evaluation of thick blood films in patients. A high proportion of burrows were infested with ticks of the O. erraticus complex in all regions of Morocco, with a mean of 39.5% for the whole country. Borrelia infections were found in 39/382 (10.2%) of the ticks and 12/140 (8.6%) of the rodents and insectivores studied by PCR amplification, and 102 patients tested positive by thick blood film. Five small mammalian species were found infected: Dipodillus campestris, Meriones shawi, Gerbillus hoogstrali, Gerbillus occiduus and Atelerix algirus. Three Borrelia species were identified in ticks and/or rodents: B. hispanica, B. crocidurae and B. merionesi. CONCLUSIONS/SIGNIFICANCE: Tick populations belonging to O. erraticus complex are widely distributed in Morocco and a high proportion of ticks and small mammals are infected by Borrelia species. Although rarely diagnosed, TBRF may be a common cause of morbidity in all regions of Morocco. PMID- 23029575 TI - Field evaluation of a coproantigen detection test for fascioliasis diagnosis and surveillance in human hyperendemic areas of Andean countries. AB - BACKGROUND: Emergence of human fascioliasis prompted a worldwide control initiative including a pilot study in a few countries. Two hyperendemic areas were chosen: Huacullani, Northern Altiplano, Bolivia, representing the Altiplanic transmission pattern with high prevalences and intensities; Cajamarca valley, Peru, representing the valley pattern with high prevalences but low intensities. Coprological sample collection, transport and study procedures were analyzed to improve individual diagnosis and subsequent treatments and surveillance activities. Therefore, a coproantigen-detection technique (MM3-COPRO ELISA) was evaluated, using classical techniques for egg detection for comparison. METHODOLOGY AND FINDINGS: A total of 436 and 362 stool samples from schoolchildren of Huacullani and Cajamarca, respectively, were used. Positive samples from Huacullani were 24.77% using the MM3-COPRO technique, and 21.56% using Kato-Katz. Positive samples from Cajamarca were 11.05% using MM3-COPRO, and 5.24% using rapid sedimentation and Kato-Katz. In Huacullani, using Kato-Katz as gold standard, sensitivity and specificity were 94.68% and 98.48%, respectively, and using Kato-Katz and COPRO-ELISA test together, they were 95.68% and 100%. In Cajamarca, using rapid sedimentation and Kato-Katz together, results were 94.73% and 93.58%, and using rapid sedimentation, Kato-Katz and copro-ELISA together, they were 97.56% and 100%, respectively. There was no correlation between coproantigen detection by optical density (OD) and infection intensity by eggs per gram of feces (epg) in Cajamarca low burden cases (<400 epg), nor in Huacullani high burden cases (>= 400 epg), although there was in Huacullani low burden cases (<400 epg). Six cases of egg emission appeared negative by MM3 COPRO, including one with a high egg count (1248 epg). CONCLUSIONS: The coproantigen-detection test allows for high sensitivity and specificity, fast large mass screening capacity, detection in the chronic phase, early detection of treatment failure or reinfection in post-treated subjects, and usefulness in surveillance programs. However, this technique falls short when evaluating the fluke burden on its own. PMID- 23029576 TI - Factors associated with Leishmania asymptomatic infection: results from a cross sectional survey in highland northern Ethiopia. AB - BACKGROUND: In northern Ethiopia the prevalence of visceral leishmaniasis is steadily rising posing an increasing public health concern. In order to develop effective control strategies on the transmission of the disease it is important to generate knowledge on the epidemiological determinants of the infection. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional survey on children 4-15 years of age using a multi staged stratified cluster sampling on high incidence sub-districts of Amhara regional state, Ethiopia. The survey included a socio-demographic, health and dietary questionnaire, and anthropometric measurements. We performed rK39-ICT and DAT serological tests in order to detect anti-Leishmania antibodies and carried out Leishmanin Skin Test (LST) using L.major antigen. Logistic regression models were used. Of the 565 children surveyed 56 children were positive to infection (9.9%). The individual variables that showed a positive association with infection were increasing age, being male and sleeping outside [adjusted odds ratios (95% CI): 1.15 (1.03, 1.29), 2.56 (1.19, 5.48) and 2.21 (1.03, 4.71) respectively] and in relation to the household: past history of VL in the family, living in a straw roofed house and if the family owned sheep [adjusted OR (95% CI): 2.92 (1.25, 6.81), 2.71 (1.21, 6.07) and 4.16 (1.41, 12.31) respectively]. CONCLUSIONS/SIGNIFICANCE: A behavioural pattern like sleeping outside is determinant in the transmission of the infection in this area. Protective measures should be implemented against this identified risk activity. Results also suggest a geographical clustering and a household focalization of the infection. The behaviour of the vector in the area needs to be clarified in order to establish the role of domestic animals and house materials in the transmission of the infection. PMID- 23029577 TI - Comparison of Schistosoma mansoni soluble cercarial antigens and soluble egg antigens for serodiagnosing schistosome infections. AB - A Schistosoma mansoni cercarial antigen preparation (cercarial transformation fluid--SmCTF) was evaluated for detection of anti-schistosome antibodies in human sera in 4 collaborating laboratories. The performance of SmCTF was compared with that of S. mansoni egg antigens (SmSEA) in an indirect enzyme-immunoassay (ELISA) antigen assay, the latter being used routinely in 3 of the 4 participating laboratories to diagnose S. mansoni and S. haematobium infections. In the fourth laboratory the performance of SmCTF was compared with that of S. japonicum egg antigens (SjSEA) in ELISA for detection of anti-S. japonicum antibodies. In all 4 laboratories the results given by SmCTF in ELISA were very similar to those given by the antigen preparation routinely used in the respective laboratory to detect anti-schistosome antibodies in human infection sera. In so far as the ELISA results from SmCTF are thus so little different from those given by schistosome egg antigens and also cheaper to produce, the former is a potentially useful new diagnostic aid for schistosomiasis. PMID- 23029578 TI - Transcriptome patterns from primary cutaneous Leishmania braziliensis infections associate with eventual development of mucosal disease in humans. AB - INTRODUCTION: Localized Cutaneous Leishmaniasis (LCL) and Mucosal Leishmaniasis (ML) are two extreme clinical forms of American Tegumentary Leishmaniasis that usually begin as solitary primary cutaneous lesions. Host and parasite factors that influence the progression of LCL to ML are not completely understood. In this manuscript, we compare the gene expression profiles of primary cutaneous lesions from patients who eventually developed ML to those that did not. METHODS: Using RNA-seq, we analyzed both the human and Leishmania transcriptomes in primary cutaneous lesions. RESULTS: Limited number of reads mapping to Leishmania transcripts were obtained. For human transcripts, compared to ML patients, lesions from LCL patients displayed a general multi-polarization of the adaptive immune response and showed up-regulation of genes involved in chemoattraction of innate immune cells and in antigen presentation. We also identified a potential transcriptional signature in the primary lesions that may predict long-term disease outcome. CONCLUSIONS: We were able to simultaneously sequence both human and Leishmania mRNA transcripts in primary cutaneous leishmaniasis lesions. Our results suggest an intrinsic difference in the immune capacity of LCL and ML patients. The findings correlate the complete cure of L. braziliensis infection with a controlled inflammatory response and a balanced activation of innate and adaptive immunity. PMID- 23029580 TI - Cost-effectiveness analysis of three leprosy case detection methods in Northern Nigeria. AB - BACKGROUND: Despite several leprosy control measures in Nigeria, child proportion and disability grade 2 cases remain high while new cases have not significantly reduced, suggesting continuous spread of the disease. Hence, there is the need to review detection methods to enhance identification of early cases for effective control and prevention of permanent disability. This study evaluated the cost effectiveness of three leprosy case detection methods in Northern Nigeria to identify the most cost-effective approach for detection of leprosy. METHODS: A cross-sectional study was carried out to evaluate the additional benefits of using several case detection methods in addition to routine practice in two north eastern states of Nigeria. Primary and secondary data were collected from routine practice records and the Nigerian Tuberculosis and Leprosy Control Programme of 2009. The methods evaluated were Rapid Village Survey (RVS), Household Contact Examination (HCE) and Traditional Healers incentive method (TH). Effectiveness was measured as number of new leprosy cases detected and cost-effectiveness was expressed as cost per case detected. Costs were measured from both providers' and patients' perspectives. Additional costs and effects of each method were estimated by comparing each method against routine practise and expressed as incremental cost-effectiveness ratio (ICER). All costs were converted to the U.S. dollar at the 2010 exchange rate. Univariate sensitivity analysis was used to evaluate uncertainties around the ICER. RESULTS: The ICER for HCE was $142 per additional case detected at all contact levels and it was the most cost-effective method. At ICER of $194 per additional case detected, THs method detected more cases at a lower cost than the RVS, which was not cost-effective at $313 per additional case detected. Sensitivity analysis showed that varying the proportion of shared costs and subsistent wage for valuing unpaid time did not significantly change the results. CONCLUSION: Complementing routine practice with household contact examination is the most cost-effective approach to identify new leprosy cases and we recommend that, depending on acceptability and feasibility, this intervention is introduced for improved case detection in Northern Nigeria. PMID- 23029579 TI - Generation of Leishmania hybrids by whole genomic DNA transformation. AB - Genetic exchange is a powerful tool to study gene function in microorganisms. Here, we tested the feasibility of generating Leishmania hybrids by electroporating genomic DNA of donor cells into recipient Leishmania parasites. The donor DNA was marked with a drug resistance marker facilitating the selection of DNA transfer into the recipient cells. The transferred DNA was integrated exclusively at homologous locus and was as large as 45 kb. The independent generation of L. infantum hybrids with L. major sequences was possible for several chromosomal regions. Interfering with the mismatch repair machinery by inactivating the MSH2 gene enabled an increased efficiency of recombination between divergent sequences, hence favouring the selection of hybrids between species. Hybrids were shown to acquire the phenotype derived from the donor cells, as demonstrated for the transfer of drug resistance genes from L. major into L. infantum. The described method is a first step allowing the generation of in vitro hybrids for testing gene functions in a natural genomic context in the parasite Leishmania. PMID- 23029581 TI - G protein-coupled receptor kinase 2 promotes flaviviridae entry and replication. AB - Flaviviruses cause a wide range of severe diseases ranging from encephalitis to hemorrhagic fever. Discovery of host factors that regulate the fate of flaviviruses in infected cells could provide insight into the molecular mechanisms of infection and therefore facilitate the development of anti flaviviral drugs. We performed genome-scale siRNA screens to discover human host factors required for yellow fever virus (YFV) propagation. Using a 2 * 2 siRNA pool screening format and a duplicate of the screen, we identified a high confidence list of YFV host factors. To find commonalities between flaviviruses, these candidates were compared to host factors previously identified for West Nile virus (WNV) and dengue virus (DENV). This comparison highlighted a potential requirement for the G protein-coupled receptor kinase family, GRKs, for flaviviral infection. The YFV host candidate GRK2 (also known as ADRBK1) was validated both in siRNA-mediated knockdown HuH-7 cells and in GRK(-/-) mouse embryonic fibroblasts. Additionally, we showed that GRK2 was required for efficient propagation of DENV and Hepatitis C virus (HCV) indicating that GRK2 requirement is conserved throughout the Flaviviridae. Finally, we found that GRK2 participates in multiple distinct steps of the flavivirus life cycle by promoting both entry and RNA synthesis. Together, our findings identified GRK2 as a novel regulator of flavivirus infection and suggest that inhibition of GRK2 function may constitute a new approach for treatment of flavivirus associated diseases. PMID- 23029582 TI - Spatial and temporal patterns of dengue transmission along a Red Sea coastline: a longitudinal entomological and serological survey in Port Sudan city. AB - BACKGROUND: Dengue is an emerging health problem in several coastlines along the Red Sea. The objective of the present work is to elucidate spatial and temporal patterns of dengue transmission in Port Sudan. METHODS/FINDINGS: A longitudinal study with three cross-sectional surveys was carried out in upper, middle and lower class neighborhoods, from November 2008 to October 2009. Monthly, entomological surveys were followed by serological surveys in dengue vector positive houses. Meteorological records were obtained from two weather stations in the city during the same time. Overall, 2825 houses were inspected. Aedes aegypti represented 65% (35,714/54,944) and 68% (2526/3715) of the collected larvae and pupae, respectively. Out of 4640 drinking water containers, 2297 were positive for Ae. aegypti. Clay-pots "Zeirr" followed by plastic barrels were key productive containers for pupae of dengue vector, 63% (n = 3959) and 26% (n = 1651), respectively. A total of 791 blood samples were tested using PanBio Capture/Indirect IgM ELISA. Overall, the sero-prevalence rate of dengue ranged between 3%-8% (41/791), compared to an incidence of 29-40 new cases per 10,000 (193/54886) in the same examined population. Lower and middle class neighborhoods had higher entomological indices compared with upper class ones (p<0.001). Although, dengue incidence rate was significantly lower in the middle and lower class neighborhoods (F = 73.97, d.f. = 2, p<0.001), no difference in IgM prevalence was shown. The city is subject to two transmission peaks in the winter (i.e. November-January), and summer (i.e. June-August). The serological peaks of dengue are preceded by entomological peaks that occur before the onset of winter (November) and summer (March) respectively. CONCLUSION: Dengue incidence is heterogeneously distributed across the neighborhoods of Port Sudan and exhibits a bi-cyclic intra-annual pattern. Hence, it should be feasible to carry out timely vector control measures to prevent or reduce dengue transmission. PMID- 23029583 TI - Post-control surveillance of Triatoma infestans and Triatoma sordida with chemically-baited sticky traps. AB - BACKGROUND: Chagas disease prevention critically depends on keeping houses free of triatomine vectors. Insecticide spraying is very effective, but re-infestation of treated dwellings is commonplace. Early detection-elimination of re infestation foci is key to long-term control; however, all available vector detection methods have low sensitivity. Chemically-baited traps are widely used in vector and pest control-surveillance systems; here, we test this approach for Triatoma spp. detection under field conditions in the Gran Chaco. METHODOLOGY/PRINCIPAL FINDINGS: Using a repeated-sampling approach and logistic models that explicitly take detection failures into account, we simultaneously estimate vector occurrence and detection probabilities. We then model detection probabilities (conditioned on vector occurrence) as a function of trapping system to measure the effect of chemical baits. We find a positive effect of baits after three (odds ratio [OR] 5.10; 95% confidence interval [CI(95)] 2.59-10.04) and six months (OR 2.20, CI(95) 1.04-4.65). Detection probabilities are estimated at p ~ 0.40-0.50 for baited and at just p ~ 0.15 for control traps. Bait effect is very strong on T. infestans (three-month assessment: OR 12.30, CI(95) 4.44-34.10; p ~ 0.64), whereas T. sordida is captured with similar frequency in baited and unbaited traps. CONCLUSIONS/SIGNIFICANCE: Chemically-baited traps hold promise for T. infestans surveillance; the sensitivity of the system at detecting small re-infestation foci rises from 12.5% to 63.6% when traps are baited with semiochemicals. Accounting for imperfect detection, infestation is estimated at 26% (CI(95) 16-40) after three and 20% (CI(95) 11-34) after six months. In the same assessments, traps detected infestation in 14% and 8.5% of dwellings, whereas timed manual searches (the standard approach) did so in just 1.4% of dwellings only in the first survey. Since infestation rates are the main indicator used for decision-making in control programs, the approach we present may help improve T. infestans surveillance and control program management. PMID- 23029584 TI - Role of Bunyamwera Orthobunyavirus NSs protein in infection of mosquito cells. AB - BACKGROUND: Bunyamwera orthobunyavirus is both the prototype and study model of the Bunyaviridae family. The viral NSs protein seems to contribute to the different outcomes of infection in mammalian and mosquito cell lines. However, only limited information is available on the growth of Bunyamwera virus in cultured mosquito cells other than the Aedes albopictus C6/36 line. METHODOLOGY AND PRINCIPAL FINDINGS: To determine potential functions of the NSs protein in mosquito cells, replication of wild-type virus and a recombinant NSs deletion mutant was compared in Ae. albopictus C6/36, C7-10 and U4.4 cells, and in Ae. aegypti Ae cells by monitoring N protein production and virus yields at various times post infection. Both viruses established persistent infections, with the exception of NSs deletion mutant in U4.4 cells. The NSs protein was nonessential for growth in C6/36 and C7-10 cells, but was important for productive replication in U4.4 and Ae cells. Fluorescence microscopy studies using recombinant viruses expressing green fluorescent protein allowed observation of three stages of infection, early, acute and late, during which infected cells underwent morphological changes. In the absence of NSs, these changes were less pronounced. An RNAi response efficiently reduced virus replication in U4.4 cells transfected with virus specific dsRNA, but not in C6/36 or C7/10 cells. Lastly, Ae. aegypti mosquitoes were exposed to blood-meal containing either wild-type or NSs deletion virus, and at various times post-feeding, infection and disseminated infection rates were measured. Compared to wild-type virus, infection rates by the mutant virus were lower and more variable. If the NSs deletion virus was able to establish infection, it was detected in salivary glands at 6 days post-infection, 3 days later than wild-type virus. CONCLUSIONS/SIGNIFICANCE: Bunyamwera virus NSs is required for efficient replication in certain mosquito cell lines and in Ae. aegypti mosquitoes. PMID- 23029585 TI - Age-related patterns in human myeloid dendritic cell populations in people exposed to Schistosoma haematobium infection. AB - BACKGROUND: Urogenital schistosomiasis is caused by the helminth parasite Schistosoma haematobium. In high transmission areas, children acquire schistosome infection early in life with infection levels peaking in early childhood and subsequently declining in late childhood. This age-related infection profile is thought to result from the gradual development of protective acquired immunity. Age-related differences in schistosome-specific humoral and cellular responses have been reported from several field studies. However there has not yet been a systematic study of the age-related changes in human dendritic cells, the drivers of T cell polarisation. METHODS: Peripheral blood mononuclear cells were obtained from a cohort of 61 Zimbabwean aged 5-45 years with a S. haematobium prevalence of 47.5%. Two subsets of dendritic cells, myeloid and plasmacytoid dendritic cells (mDCs and pDCs), were analyzed by flow cytometry. FINDINGS: In this population, schistosome infection levels peaked in the youngest age group (5-9 years), and declined in late childhood and adulthood (10+ years). The proportions of both mDCs and pDCs varied with age. However, for mDCs the age profile depended on host infection status. In the youngest age group infected people had enhanced proportions of mDCs as well as lower levels of HLA-DR on mDCs than un-infected people. In the older age groups (10-13 and 14-45 years) infected people had lower proportions of mDCs compared to un-infected individuals, but no infection status related differences were observed in their levels of HLA-DR. Moreover mDC proportions correlated with levels of schistosome-specific IgG, which can be associated with protective immunity. In contrast proportions of pDCs varied with host age, but not with infection status. CONCLUSIONS: Our results show that dendritic cell proportions and activation in a human population living in schistosome-endemic areas vary with host age reflecting differences in cumulative history of exposure to schistosome infection. PMID- 23029586 TI - Proof-of-principle of onchocerciasis elimination with ivermectin treatment in endemic foci in Africa: final results of a study in Mali and Senegal. AB - BACKGROUND: Mass treatment with ivermectin controls onchocerciasis as a public health problem, but it was not known if it could also interrupt transmission and eliminate the parasite in endemic foci in Africa where vectors are highly efficient. A longitudinal study was undertaken in three hyperendemic foci in Mali and Senegal with 15 to 17 years of annual or six-monthly ivermectin treatment in order to assess residual levels of infection and transmission, and test whether treatment could be safely stopped. This article reports the results of the final evaluations up to 5 years after the last treatment. METHODOLOGY/PRINCIPAL FINDINGS: Skin snip surveys were undertaken in 131 villages where 29,753 people were examined and 492,600 blackflies were analyzed for the presence of Onchocerca volvulus larva using a specific DNA probe. There was a declining trend in infection and transmission levels after the last treatment. In two sites the prevalence of microfilaria and vector infectivity rate were zero 3 to 4 years after the last treatment. In the third site, where infection levels were comparatively high before stopping treatment, there was also a consistent decline in infection and transmission to very low levels 3 to 5 years after stopping treatment. All infection and transmission indicators were below postulated thresholds for elimination. CONCLUSION/SIGNIFICANCE: The study has established the proof of principle that onchocerciasis elimination with ivermectin treatment is feasible in at least some endemic foci in Africa. The study results have been instrumental for the current evolution from onchocerciasis control to elimination in Africa. PMID- 23029587 TI - Genetic characterizations of Giardia duodenalis in sheep and goats in Heilongjiang Province, China and possibility of zoonotic transmission. AB - BACKGROUND: Giardia duodenalis is a widespread intestinal protozoan of both humans and mammals. To date, few epidemiological studies have assessed the potential and importance of zoonotic transmission; and the human giardiasis burden attributable to G. duodenalis of animal origin is unclear. No information about occurrence and genotyping data of sheep and goat giardiasis is available in China. The aim of the present study was to determine prevalence and distribution of G. duodenalis in sheep and goats in Heilongjiang Province, China, and to characterize G. duodenalis isolates and assess the possibility of zoonotic transmission. METHODOLOGY/PRINCIPAL FINDINGS: A total of 678 fecal specimens were collected from sheep and goats on six farms ranging in age from one month to four years in Heilongjiang Province, China. The average prevalence of G. duodenalis infection was 5.0% (34/678) by microscopy after Lugol's iodine staining, with 5.6% (30/539) for the sheep versus 2.9% (4/139) for the goats. Molecular analysis was conducted on 34 G. duodenalis isolates based on the triosephosphate isomerase (tpi) gene. 29 tpi gene sequences were successfully obtained and identified as assemblages A (n = 4), B (n = 2) and E (n = 23). High heterogeneity was observed within assemblage E at the tpi locus, with five novel subtypes found out of seven subtypes. Two subtypes of assemblage A were detected, including subtype AI (n = 3) and a novel subtype (designated as subtype AIV) (n = 1). Two assemblage B isolates were identical to each other in the tpi gene sequences. CONCLUSIONS/SIGNIFICANCE: This is the first report of G. duodenalis infections in sheep and goats in China. The present data revealed the unique endemicity on prevalence, distribution and genetic characterization of G. duodenalis in sheep and goats in Heilongjiang Province. The findings of assemblages A and B in sheep and goats implied the potential of zoonotic transmission. PMID- 23029588 TI - Open source drug discovery in practice: a case study. AB - BACKGROUND: Open source drug discovery offers potential for developing new and inexpensive drugs to combat diseases that disproportionally affect the poor. The concept borrows two principle aspects from open source computing (i.e., collaboration and open access) and applies them to pharmaceutical innovation. By opening a project to external contributors, its research capacity may increase significantly. To date there are only a handful of open source R&D projects focusing on neglected diseases. We wanted to learn from these first movers, their successes and failures, in order to generate a better understanding of how a much discussed theoretical concept works in practice and may be implemented. METHODOLOGY/PRINCIPAL FINDINGS: A descriptive case study was performed, evaluating two specific R&D projects focused on neglected diseases. CSIR Team India Consortium's Open Source Drug Discovery project (CSIR OSDD) and The Synaptic Leap's Schistosomiasis project (TSLS). Data were gathered from four sources: interviews of participating members (n = 14), a survey of potential members (n = 61), an analysis of the websites and a literature review. Both cases have made significant achievements; however, they have done so in very different ways. CSIR OSDD encourages international collaboration, but its process facilitates contributions from mostly Indian researchers and students. Its processes are formal with each task being reviewed by a mentor (almost always offline) before a result is made public. TSLS, on the other hand, has attracted contributors internationally, albeit significantly fewer than CSIR OSDD. Both have obtained funding used to pay for access to facilities, physical resources and, at times, labor costs. TSLS releases its results into the public domain, whereas CSIR OSDD asserts ownership over its results. CONCLUSIONS/SIGNIFICANCE: Technically TSLS is an open source project, whereas CSIR OSDD is a crowdsourced project. However, both have enabled high quality research at low cost. The critical success factors appear to be clearly defined entry points, transparency and funding to cover core material costs. PMID- 23029589 TI - Bladder morbidity and hepatic fibrosis in mixed Schistosoma haematobium and S. mansoni Infections: a population-wide study in Northern Senegal. AB - BACKGROUND: The global distribution map of schistosomiasis shows a large overlap of Schistosoma haematobium- and S. mansoni-endemic areas in Africa. Yet, little is known about the consequences of mixed Schistosoma infections for the human host. A recent study in two neighboring co-endemic communities in Senegal indicated that infection intensities of both species were higher in mixed than in single infections. Here, we investigated the relationship between mixed Schistosoma infections and morbidity in the same population. So far, this has only been studied in children. METHODS: Schistosoma infection was assessed by microscopy. Schistosoma-specific morbidity was assessed by ultrasound according to WHO guidelines. Multivariable logistic regression models were used to identify independent risk factors for morbidity. PRINCIPAL FINDINGS: Complete parasitological and morbidity data were obtained from 403 individuals. Schistosoma haematobium-specific bladder morbidity was observed in 83% and S. mansoni-specific hepatic fibrosis in 27% of the participants. Bladder morbidity was positively associated with S. haematobium infection intensity (OR = 1.9 (95% CI 1.3-2.9) for a 10-fold increase in intensity). Moreover, people with mixed infections tended to have less bladder morbidity than those with single S. haematobium infections (OR = 0.3 (95% CI 0.1-1.1)). This effect appeared to be related to ectopic S. mansoni egg elimination in urine. Hepatic fibrosis on the other hand was not related to S. mansoni infection intensity (OR = 0.9 (95% CI 0.6-1.3)), nor to mixed infections (OR = 1.0 (95% CI 0.7-1.7)). CONCLUSIONS/SIGNIFICANCE: This is the first population-wide study on the relationship between mixed Schistosoma infections and morbidity. Mixed infections did not increase the risk of S. mansoni-associated morbidity. They even tended to reduce the risk of S. haematobium-associated morbidity, suggesting a protective effect of S. mansoni infection on bladder morbidity. These unexpected results may have important consequences for schistosomiasis control in co-endemic areas and warrant further investigation. PMID- 23029590 TI - Dramatic increase in glycerol biosynthesis upon oxidative stress in the anaerobic protozoan parasite Entamoeba histolytica. AB - Entamoeba histolytica, a microaerophilic enteric protozoan parasite, causes amebic colitis and extra intestinal abscesses in millions of inhabitants of endemic areas. Trophozoites of E. histolytica are exposed to a variety of reactive oxygen and nitrogen species during infection. Since E. histolytica lacks key components of canonical eukaryotic anti-oxidative defense systems, such as catalase and glutathione system, alternative not-yet-identified anti-oxidative defense strategies have been postulated to be operating in E. histolytica. In the present study, we investigated global metabolic responses in E. histolytica in response to H(2)O(2)- and paraquat-mediated oxidative stress by measuring charged metabolites on capillary electrophoresis and time-of-flight mass spectrometry. We found that oxidative stress caused drastic modulation of metabolites involved in glycolysis, chitin biosynthesis, and nucleotide and amino acid metabolism. Oxidative stress resulted in the inhibition of glycolysis as a result of inactivation of several key enzymes, leading to the redirection of metabolic flux towards glycerol production, chitin biosynthesis, and the non-oxidative branch of the pentose phosphate pathway. As a result of the repression of glycolysis as evidenced by the accumulation of glycolytic intermediates upstream of pyruvate, and reduced ethanol production, the levels of nucleoside triphosphates were decreased. We also showed for the first time the presence of functional glycerol biosynthetic pathway in E. histolytica as demonstrated by the increased production of glycerol 3-phosphate and glycerol upon oxidative stress. We proposed the significance of the glycerol biosynthetic pathway as a metabolic anti-oxidative defense system in E. histolytica. PMID- 23029591 TI - Whole genome sequence of Treponema pallidum ssp. pallidum, strain Mexico A, suggests recombination between yaws and syphilis strains. AB - BACKGROUND: Treponema pallidum ssp. pallidum (TPA), the causative agent of syphilis, and Treponema pallidum ssp. pertenue (TPE), the causative agent of yaws, are closely related spirochetes causing diseases with distinct clinical manifestations. The TPA Mexico A strain was isolated in 1953 from male, with primary syphilis, living in Mexico. Attempts to cultivate TPA Mexico A strain under in vitro conditions have revealed lower growth potential compared to other tested TPA strains. METHODOLOGY/PRINCIPAL FINDINGS: The complete genome sequence of the TPA Mexico A strain was determined using the Illumina sequencing technique. The genome sequence assembly was verified using the whole genome fingerprinting technique and the final sequence was annotated. The genome size of the Mexico A strain was determined to be 1,140,038 bp with 1,035 predicted ORFs. The Mexico A genome sequence was compared to the whole genome sequences of three TPA (Nichols, SS14 and Chicago) and three TPE (CDC-2, Samoa D and Gauthier) strains. No large rearrangements in the Mexico A genome were found and the identified nucleotide changes occurred most frequently in genes encoding putative virulence factors. Nevertheless, the genome of the Mexico A strain, revealed two genes (TPAMA_0326 (tp92) and TPAMA_0488 (mcp2-1)) which combine TPA- and TPE- specific nucleotide sequences. Both genes were found to be under positive selection within TPA strains and also between TPA and TPE strains. CONCLUSIONS/SIGNIFICANCE: The observed mosaic character of the TPAMA_0326 and TPAMA_0488 loci is likely a result of inter-strain recombination between TPA and TPE strains during simultaneous infection of a single host suggesting horizontal gene transfer between treponemal subspecies. PMID- 23029592 TI - Partially neutralizing potency against emerging genotype I virus among children received formalin-inactivated Japanese encephalitis virus vaccine. AB - BACKGROUND: Genotype I (GI) Japanese encephalitis virus (JEV) that replaced GIII virus has become the dominant circulating virus in Asia. Currently, all registered live and inactivated JEV vaccines are derived from genotype III viruses. In Taiwan, the compulsory JEV vaccination policy recommends that children receives four doses of formalin-inactivated Nakayama (GIII) JEV vaccine. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the influence of genotype replacement on the post-vaccination viral neutralizing ability by GIII and GI viruses, the small panel of vaccinated-children serum specimens was assembled, and the reciprocal 50% plaque-reduction neutralizing antibody titers (PRNT(50)) were measured against Nakayama vaccine strain, CJN GIII human brain isolate and TC2009 1 GI mosquito isolate. The seropositivity rate (PRNT(50) >= 1:10) and geometric mean titers (GMT) against the TC2009-1 virus were the lowest among the three viruses. The protective threshold against the CJN and TC2009-1 viruses could only be achieved when the GMT against Nakayama virus was >= 1:20 or >= 1:80, respectively. Using undiluted vaccinees' sera, the enhancement of JEV infection in K562 cells was observed in some low or non-neutralizing serum specimens. CONCLUSIONS/SIGNIFICANCE: Our preliminary study has shown that neutralizing antibodies, elicited by the mouse brain-derived and formalin-inactivated JEV Nakayama vaccine among a limited number of vaccinees, have reduced neutralizing capacity against circulating GI virus, but more detailed studies are needed to address the potential impact on the future vaccine policy. PMID- 23029593 TI - A new threat looming over the Mediterranean basin: emergence of viral diseases transmitted by Aedes albopictus mosquitoes. PMID- 23029594 TI - Molecular diagnostics for lassa fever at Irrua specialist teaching hospital, Nigeria: lessons learnt from two years of laboratory operation. AB - BACKGROUND: Lassa fever is a viral hemorrhagic fever endemic in West Africa. However, none of the hospitals in the endemic areas of Nigeria has the capacity to perform Lassa virus diagnostics. Case identification and management solely relies on non-specific clinical criteria. The Irrua Specialist Teaching Hospital (ISTH) in the central senatorial district of Edo State struggled with this challenge for many years. METHODOLOGY/PRINCIPAL FINDINGS: A laboratory for molecular diagnosis of Lassa fever, complying with basic standards of diagnostic PCR facilities, was established at ISTH in 2008. During 2009 through 2010, samples of 1,650 suspected cases were processed, of which 198 (12%) tested positive by Lassa virus RT-PCR. No remarkable demographic differences were observed between PCR-positive and negative patients. The case fatality rate for Lassa fever was 31%. Nearly two thirds of confirmed cases attended the emergency departments of ISTH. The time window for therapeutic intervention was extremely short, as 50% of the fatal cases died within 2 days of hospitalization--often before ribavirin treatment could be commenced. Fatal Lassa fever cases were older (p = 0.005), had lower body temperature (p<0.0001), and had higher creatinine (p<0.0001) and blood urea levels (p<0.0001) than survivors. Lassa fever incidence in the hospital followed a seasonal pattern with a peak between November and March. Lassa virus sequences obtained from the patients originating from Edo State formed--within lineage II--a separate clade that could be further subdivided into three clusters. CONCLUSIONS/SIGNIFICANCE: Lassa fever case management was improved at a tertiary health institution in Nigeria through establishment of a laboratory for routine diagnostics of Lassa virus. Data collected in two years of operation demonstrate that Lassa fever is a serious public health problem in Edo State and reveal new insights into the disease in hospitalized patients. PMID- 23029595 TI - Death adder envenoming causes neurotoxicity not reversed by antivenom--Australian Snakebite Project (ASP-16). AB - BACKGROUND: Death adders (Acanthophis spp) are found in Australia, Papua New Guinea and parts of eastern Indonesia. This study aimed to investigate the clinical syndrome of death adder envenoming and response to antivenom treatment. METHODOLOGY/PRINCIPAL FINDINGS: Definite death adder bites were recruited from the Australian Snakebite Project (ASP) as defined by expert identification or detection of death adder venom in blood. Clinical effects and laboratory results were collected prospectively, including the time course of neurotoxicity and response to treatment. Enzyme immunoassay was used to measure venom concentrations. Twenty nine patients had definite death adder bites; median age 45 yr (5-74 yr); 25 were male. Envenoming occurred in 14 patients. Two further patients had allergic reactions without envenoming, both snake handlers with previous death adder bites. Of 14 envenomed patients, 12 developed neurotoxicity characterised by ptosis (12), diplopia (9), bulbar weakness (7), intercostal muscle weakness (2) and limb weakness (2). Intubation and mechanical ventilation were required for two patients for 17 and 83 hours. The median time to onset of neurotoxicity was 4 hours (0.5-15.5 hr). One patient bitten by a northern death adder developed myotoxicity and one patient only developed systemic symptoms without neurotoxicity. No patient developed venom induced consumption coagulopathy. Antivenom was administered to 13 patients, all receiving one vial initially. The median time for resolution of neurotoxicity post-antivenom was 21 hours (5-168). The median peak venom concentration in 13 envenomed patients with blood samples was 22 ng/mL (4.4-245 ng/mL). In eight patients where post antivenom bloods were available, no venom was detected after one vial of antivenom. CONCLUSIONS/SIGNIFICANCE: Death adder envenoming is characterised by neurotoxicity, which is mild in most cases. One vial of death adder antivenom was sufficient to bind all circulating venom. The persistent neurological effects despite antivenom, suggests that neurotoxicity is not reversed by antivenom. PMID- 23029596 TI - Mucosal adjuvanticity of fibronectin-binding peptide (FBP) fused with Echinococcus multilocularis tetraspanin 3: systemic and local antibody responses. AB - BACKGROUND: Studies have shown that a bacterial fibronectin attachment protein (FAP) is able to stimulate strong systemic and mucosal antibody responses when it is used alone or co-administrated with other antigens (Ags). Thus, it has been suggested to be a promising adjuvant candidate for the development of efficient vaccines. However, the co-administered Ags and FAP were cloned, expressed and purified individually to date. In a recent study, we first evaluated the adjuvanticity of a fibronectin-binding peptide (FBP, 24 amino acids) of Mycobacterium avium FAP fused with Echinococcus multilocularis tetraspanin 3 (Em TSP3) by detecting systemic and local antibody responses in intranasally (i.n.) immunized BALB/c mice. METHODOLOGY/PRINCIPAL FINDINGS: Em-TSP3 and FBP fragments were linked with a GSGGSG linker and expressed as a single fusion protein (Em TSP3-FBP) using the pBAD/Thio-TOPO expression vector. BALB/c mice were immunized i.n. with recombinant Em-TSP3-FBP (rEm-TSP3-FBP) and rEm-TSP3+CpG and the systemic and local antibody responses were detected by ELISA. The results showed that both rEm-TSP3-FBP and rEm-TSP3+CpG evoked strong serum IgG (p<0.001) and IgG1 responses (p<0.001), whereas only the latter induced a high level IgG2alpha production (p<0.001), compared to that of rEm-TSP3 alone without any adjuvant. There were no significant differences in IgG and IgG1 production between the groups. Low level of serum IgA and IgM were detected in both groups. The tendency of Th1 and Th2 cell immune responses were assessed via detecting the IgG1/IgG2alpha ratio after the second and third immunizations. The results indicated that i.n. immunization with rEm-TSP3-FBP resulted in an increased IgG1/IgG2alpha ratio (a Th2 tendency), while rEm-TSP3+CpG caused a rapid Th1 response that later shifted to a Th2 response. Immunization with rEm-TSP3-FBP provoked significantly stronger IgA antibody responses in intestine (p<0.05), lung (p<0.001) and spleen (p<0.001) compared to those by rEm-TSP3+CpG. Significantly high level IgA antibodies were detected in nasal cavity (p<0.05) and liver (p<0.05) samples from both groups when compared to rEm-TSP3 alone without any adjuvant, with no significant difference between them. CONCLUSIONS: I.n. administration of rEm-TSP3-FBP can induce strong systemic and mucosal antibody responses in immunized BALB/c mice, suggesting that fusion of Em-TSP3 with FBP is a novel, prospective strategy for developing safe and efficient human mucosal vaccines against alveolar echinococcosis (AE). PMID- 23029597 TI - Candidatus Bartonella merieuxii, a potential new zoonotic Bartonella species in canids from Iraq. AB - Bartonellae are emerging vector-borne pathogens infecting erythrocytes and endothelial cells of various domestic and wild mammals. Blood samples were collected from domestic and wild canids in Iraq under the United States Army zoonotic disease surveillance program. Serology was performed using an indirect immunofluorescent antibody test for B. henselae, B. clarridgeiae, B. vinsonii subsp. berkhoffii and B. bovis. Overall seroprevalence was 47.4% in dogs (n = 97), 40.4% in jackals (n = 57) and 12.8% in red foxes (n = 39). Bartonella species DNA was amplified from whole blood and representative strains were sequenced. DNA of a new Bartonella species similar to but distinct from B. bovis, was amplified from 37.1% of the dogs and 12.3% of the jackals. B. vinsonii subsp. berkhoffii was also amplified from one jackal and no Bartonella DNA was amplified from foxes. Adjusting for age, the odds of dogs being Bartonella PCR positive were 11.94 times higher than for wild canids (95% CI: 4.55-31.35), suggesting their role as reservoir for this new Bartonella species. This study reports on the prevalence of Bartonella species in domestic and wild canids of Iraq and provides the first detection of Bartonella in jackals. We propose Candidatus Bartonella merieuxii for this new Bartonella species. Most of the Bartonella species identified in sick dogs are also pathogenic for humans. Therefore, seroprevalence in Iraqi dog owners and bacteremia in Iraqi people with unexplained fever or culture negative endocarditis requires further investigation as well as in United States military personnel who were stationed in Iraq. Finally, it will also be essential to test any dog brought back from Iraq to the USA for presence of Bartonella bacteremia to prevent any accidental introduction of a new Bartonella species to the New World. PMID- 23029598 TI - Risk of potentially rabid animal exposure among foreign travelers in Southeast Asia. AB - BACKGROUND: Each year millions of travelers visit Southeast Asia where rabies is still prevalent. This study aimed to assess the risk of rabies exposure, i.e., by being bitten or licked by an animal, among travelers in Southeast Asia. The secondary objective was to assess their attitudes and practices related to rabies. METHODOLOGY/PRINCIPAL FINDINGS: Foreign travelers departing to the destination outside Southeast Asia were invited to fill out the study questionnaire in the departure hall of Bangkok International Airport. They were asked about their demographic profile, travel characteristics, pre-travel health preparations, their possible exposure and their practices related to rabies during this trip. From June 2010 to February 2011, 7,681 completed questionnaires were collected. Sixty-two percent of the travelers were male, and the median age was 32 years. 34.0% of the participants were from Western/Central Europe, while 32.1% were from East Asia. Up to 59.3% had sought health information before this trip. Travel clinics were the source of information for 23.6% of travelers. Overall, only 11.6% of the participants had completed their rabies pre-exposure prophylaxis, and 15.3% had received only 1-2 shots, while 73.1% had not been vaccinated at all. In this study, the risk of being bitten was 1.11 per 100 travelers per month and the risk of being licked was 3.12 per 100 travelers per month. Among those who were bitten, only 37.1% went to the hospital to get post exposure treatment. Travelers with East Asian nationalities and longer duration of stay were significantly related to higher risk of animal exposure. Reason for travel was not related to the risk of animal exposure. CONCLUSIONS: Travelers were at risk of being exposed to potentially rabid animals while traveling in Southeast Asia. Many were inadequately informed and unprepared for this life threatening risk. Rabies prevention advice should be included in every pre-travel visit. PMID- 23029599 TI - Is physical activity able to modify oxidative damage in cardiovascular aging? AB - Aging is a multifactorial process resulting in damage of molecules, cells, and tissues. It has been demonstrated that the expression and activity of antioxidant systems (SOD, HSPs) are modified in aging, with reduced cell ability to counteract the oxidant molecules, and consequent weak resistance to ROS accumulation. An important mechanism involved is represented by sirtuins, the activity of which is reduced by aging. Physical activity increases the expression and the activity of antioxidant enzymes, with consequent reduction of ROS. Positive effects of physical exercise in terms of antioxidant activity could be ascribable to a greater expression and activity of SOD enzymes, HSPs and SIRT1 activity. The antioxidant effects could increase, decrease, or not change in relation to the exercise protocol. Therefore, some authors by using a new approach based on the in vivo/vitro technique demonstrated that the highest survival and proliferation and the lowest senescence were obtained by performing an aerobic training. Therefore, the in vivo/vitro technique described could represent a good tool to better understand how the exercise training mediates its effects on aging-related diseases, as elderly with heart failure that represents a special population in which the exercise plays an important role in the improvement of cardiovascular function, quality of life, and survival. PMID- 23029600 TI - Mitochondrial hormesis in pancreatic beta cells: does uncoupling protein 2 play a role? AB - In pancreatic beta cells, mitochondrial metabolism translates glucose sensing into signals regulating insulin secretion. Chronic exposure of beta cells to excessive nutrients, namely, glucolipotoxicity, impairs beta-cell function. This is associated with elevated ROS production from overstimulated mitochondria. Mitochondria are not only the major source of cellular ROS, they are also the primary target of ROS attacks. The mitochondrial uncoupling protein UCP2, even though its uncoupling properties are debated, has been associated with protective functions against ROS toxicity. Hormesis, an adaptive response to cellular stresses, might contribute to the protection against beta-cell death, possibly limiting the development of type 2 diabetes. Mitochondrial hormesis, or mitohormesis, is a defense mechanism observed in ROS-induced stress-responses by mitochondria. In beta cells, mitochondrial damages induced by sublethal exogenous H(2)O(2) can induce secondary repair and defense mechanisms. In this context, UCP2 is a marker of mitohormesis, being upregulated following stress conditions. When overexpressed in nonstressed naive cells, UCP2 confers resistance to oxidative stress. Whether treatment with mitohormetic inducers is sufficient to restore or ameliorate secretory function of beta cells remains to be determined. PMID- 23029601 TI - Design, Synthesis, and Testing of a Molecular Truck for Colonic Delivery of 5 Aminosalicylic Acid. AB - A molecular scaffold bearing eight terminal alkyne groups was synthesized from sucrose. Eight copies of an azide-terminated, azo-linked precursor to 5 aminosalicylic acid were attached to the scaffold via copper(I)-catalyzed azide alkyne cycloaddition. The resulting compound was evaluated in a DSS model of colitis in BALB/c mice against sulfasalazine as a control. Two independent studies verified that the novel pro-drug, administered in a dose calculated to result in an equimolar 5-ASA yield, outperformed sulfasalazine in terms of protection from mucosal inflammation and T cell activation. A separate study established that 5-ASA appeared in feces produced 24-48 hours following administration of the pro-drug. Thus, a new, orally administered pro-drug form of 5-aminosalicylic acid has been developed and successfully demonstrated. PMID- 23029603 TI - Inhibition of HIV Replication by Cyclic and Hairpin PNAs Targeting the HIV-1 TAR RNA Loop. AB - Human immunodeficiency virus-1 (HIV-1) replication and gene expression entails specific interaction of the viral protein Tat with its transactivation responsive element (TAR), to form a highly stable stem-bulge-loop structure. Previously, we described triphenylphosphonium (TPP) cation-based vectors that efficiently deliver nucleotide analogs (PNAs) into the cytoplasm of cells. In particular, we showed that the TPP conjugate of a linear 16-mer PNA targeting the apical stem loop region of TAR impedes Tat-mediated transactivation of the HIV-1 LTR in vitro and also in cell culture systems. In this communication, we conjugated TPP to cyclic and hairpin PNAs targeting the loop region of HIV-1 TAR and evaluated their antiviral efficacy in a cell culture system. We found that TPP-cyclic PNAs containing only 8 residues, showed higher antiviral potency compared to hairpin PNAs of 12 or 16 residues. We further noted that the TPP-conjugates of the 8-mer cyclic PNA as well as the 16-mer linear PNA displayed similar antiviral efficacy. However, cyclic PNAs were shown to be highly specific to their target sequences. This communication emphasizes on the importance of small constrained cyclic PNAs over both linear and hairpin structures for targeting biologically relevant RNA hairpins. PMID- 23029604 TI - Bioelectrical impedance and dual-energy x-ray absorptiometry assessments of changes in body composition following exercise in patients with type 2 diabetes mellitus. AB - We aimed to compare the level of agreement between leg-to-leg bioelectrical impedance analysis (LBIA) and dual-energy X-ray absorptiometry (DXA) for assessing changes in body composition following exercise intervention among individuals with Type 2 diabetes mellitus (T2DM). Forty-four adults with T2DM, age 53.2 +/- 9.1 years; BMI 30.8 +/- 5.9 kg/m(2) participated in a 6-month exercise program with pre and post intervention assessments of body composition. Fat free mass (FFM), % body fat (%FM) and fat mass (FM) were measured by LBIA (TBF-300A) and DXA. LBIA assessments of changes in %FM and FM post intervention showed good relative agreements with DXA variables (P < 0.001). However, Bland Altman plot(s) indicated that there were systematic errors in the assessment of the changes in body composition using LBIA compared to DXA such that, the greater the changes in participant body composition, the greater the disparity in body composition data obtained via LBIA versus DXA data (FFM, P = 0.013; %FM, P < 0.001; FM, P < 0.001). In conclusion, assessment of pre and post intervention body composition implies that LBIA is a good tool for assessment qualitative change in body composition (gain or loss) among people with T2DM but is not sufficiently sensitive to track quantitative changes in an individual's body composition. PMID- 23029602 TI - Soluble forms of tau are toxic in Alzheimer's disease. AB - Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer Disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer's disease and other tauopathies. PMID- 23029605 TI - Prevalence of Overweight and Obesity among Adolescents in Seven Arab Countries: A Cross-Cultural Study. AB - Objective. The aim of this study was to find out the prevalence of overweight and obesity among adolescents in seven Arab countries using similar reference standard. Methods. A school-based cross-sectional study was carried out in seven cities in Arab countries, namely, Algeria, Jordan, Kuwait, Libya, Palestine, Syria, and United Arab Emirates. A multistage stratified random sampling technique was used. The total sample included was 4698 adolescents aged from 15 to 18 years (2240 males, 2458 females). The International Obesity Task Force (IOTF) reference standard was used to classify the adolescents as nonobese, overweight, and obese. Results. Among males, overweight was highest among Kuwaiti adolescents (25.6%), followed by Jordanian (21.6%), and Syrian (19.7%) adolescents. Among females, the highest prevalence of overweight was reported in Libyan adolescents (26.6%), followed by Kuwaiti (20.8%), and Syrian (19.7%) adolescents. As for obesity, Kuwaiti adolescents showed the highest prevalence of obesity for both males (34.8%) and females (20.6%). Conclusion. There is an urgent need to establish a plan of action to combat obesity in schoolchildren in these countries. PMID- 23029607 TI - Religious and spiritual factors in depression. PMID- 23029606 TI - Associations of C-Reactive Protein to Indices of Vascular Health and the Influence of Serum 25(OH)D Status in Healthy Adults. AB - Elevated serum high-sensitivity C-reactive protein (hs-CRP) and low serum 25 hydroxyvitamin D [25(OH)D] are associated with increased cardiovascular disease (CVD) risk. Ethnic differences in serum hs-CRP and 25(OH)D concentrations and CVD are known. OBJECTIVES: to investigate the ethnic differences in hs-CRP concentrations, to assess the influence of 25(OH)D on these ethnic differences and to examine the influence of 25(OH)D on association between hs-CRP and cardiovascular health indices. SUBJECTS: 62 healthy adults [26 African Americans (AA), 26 European Americans (EA), and 10 Hispanic Americans (HA)], ages 18-55 years. Serum hs-CRP and 25(OH)D as well as pulse wave velocity (PWV), augmentation index (AIx), and flow-mediated dilatation (FMD) were measured. hs CRP was inversely associated with 25(OH)D (r = -0.25, P = 0.049), and hs-CRP was positively associated with PWV (r = 0.29, P = 0.04). The association of hs-CRP with PWV attenuated after adjustment for 25(OH)D (P = 0.15). hs-CRP was higher in AA compared to EA (P = 0.05); this differences was reduced by 32% after adjusting for serum 25(OH)D. CONCLUSION: eventhough the inverse association between serum 25(OH)D and CRP does not infer causality, lower serum 25(OH)D may increase risk for inflammation and endothelial dysfunction. The lower 25(OH)D in AA may predispose to greater inflammation and associated vascular dysfunction. PMID- 23029608 TI - Pelvic surgery. PMID- 23029609 TI - County Differences in Mortality among Foreign-Born Compared to Native Swedes 1970 1999. AB - Background. Regional variations in mortality and morbidity have been shown in Europe and USA. Longitudinal studies have found increased mortality, dissimilarities in mortality pattern, and differences in utilization of healthcare between foreign- and native-born Swedes. No study has been found comparing mortality among foreign-born and native-born Swedes in relation to catchment areas/counties. Methods. The aim was to describe and compare mortality among foreign-born persons and native Swedes during 1970-1999 in 24 counties in Sweden. Data from the Statistics Sweden and the National Board of Health and Welfare was used, and the database consisted of 723,948 persons, 361,974 foreign born living in Sweden in 1970 and aged 16 years and above and 361,974 matched Swedish controls. Results. Latest county of residence independently explained higher mortality among foreign-born persons in all but four counties; OR varied from 1.01 to 1.29. Counties with a more rural structure showed the highest differences between foreign-born persons and native controls. Foreign-born persons had a lower mean age (1.0-4.3 years) at time of death. Conclusion. County of residence influences mortality; higher mortality is indicated among migrants than native Swedes in counties with a more rural structure. Further studies are needed to explore possible explanations. PMID- 23029610 TI - The Initial Learning Curve for Robot-Assisted Sleeve Gastrectomy: A Surgeon's Experience While Introducing the Robotic Technology in a Bariatric Surgery Department. AB - Objective. Robot-assisted sleeve gastrectomy has the potential to treat patients with obesity and its comorbidities. To evaluate the learning curve for this procedure before undergoing Roux en-Y gastric bypass is the objective of this paper. Materials and Methods. Robot-assisted sleeve gastrectomy was attempted in 32 consecutive patients. A survey was performed in order to identify performance variables during completion of the learning curve. Total operative time (OT), docking time (DT), complications, and length of hospital stay were compared among patients divided into two cohorts according to the surgical experience. Scattergrams and continuous curves were plotted to develop a robotic sleeve gastrectomy learning curve. Results. Overall OT time decreased from 89.8 minutes in cohort 1 to 70.1 minutes in cohort 2, with less than 5% change in OT after case 19. Time from incision to docking decreased from 9.5 minutes in cohort 1 to 7.6 minutes in cohort 2. The time required to dock the robotic system also decreased. The complication rate was the same in the two cohorts. Conclusion. Our survey indicates that technique and outcomes for robot-assisted sleeve gastrectomy gradually improve with experience. We found that the learning curve for performing a sleeve gastrectomy using the da Vinci system is completed after about 20 cases. PMID- 23029611 TI - Thromboembolic prophylaxis in total joint arthroplasty. AB - Approximately 775,000 hip and knee arthroplasties are performed yearly in the United States, with a dramatic increase expected. Patients having hip and knee arthroplasties are at high risk of developing a venous thromboembolism. The American College of Chest Physicians (ACCP) and the American Academy of Orthopedic Surgeons (AAOS) have updated guidelines, which outline new prophylactic strategies. Factor Xa inhibitor rivaroxaban has a new recommendation by ACCP and is gradually being adopted by the joint arthroplasty community as an effective oral agent. Other more well-known agents including warfarin, low molecular-weight heparin, aspirin, and fondaparinux continue to be options for prophylaxis. While the goal of prophylaxis continues to be the prevention of venous thromboemboli and pulmonary emboli, it is important to consider the increased bleeding risk associated with their use. The most recent ACCP and AAOS guidelines give clinicians a greater autonomy in choosing a prophylactic agent with greater emphasis placed on dialogue between the surgeon and patient as to the choice of prophylaxis. PMID- 23029612 TI - Clinical Evaluation of COBAS TaqMan PCR for the Detection of Mycobacterium tuberculosis and M. avium Complex. AB - A retrospective observational study was performed to determine the sensitivity and limitation of PCR test for the detection of Mycobacterium tuberculosis and M. avium complex. We obtained clinical specimens collected from the respiratory tract, cultured M. tuberculosis or M. avium complex, and performed PCR analysis. A total of 299 samples (M. tuberculosis, 177; M. avium, 35; M. intracellulare, 87) were analyzed by COBAS TaqMan PCR from April 2007 to March 2011. The PCR positivity rates were 50-55%, 70-100%, 88-98%, and 100% in smear-negative, smear 1+, 2+, and 3+ groups, respectively. The PCR positivity of tuberculosis in smear 1+ was 80.6%, which was statistically significantly (P < 0.001) lower than that of smear 2+ (97.3%). From January 2005 to March 2007, we collected an additional 138 samples (M. tuberculosis, 74; M. avium, 21; M. intracellulare, 43), which were analyzed by COBAS Amplicor PCR. The PCR positivity rates obtained using COBAS TaqMan PCR and COBAS Amplicor PCR were not significantly different. The sensitivity of PCR test for mycobacteria is not sufficient in case of smear 1+. Careful consideration must be given to the interpretation of negative PCR test results in smear 1+, because smear-positive tuberculosis is the criterion for isolation. PMID- 23029613 TI - D-Serine Production, Degradation, and Transport in ALS: Critical Role of Methodology. AB - In mammalian systems, D-serine is perhaps the most biologically active D-amino acid described to date. D-serine is a coagonist at the NMDA-receptor, and receptor activation is dependent on D-serine binding. Because D-serine binding dramatically increases receptor affinity for glutamate, it can produce excitotoxicity without any change in glutamate per se. D-serine is twofold higher in the spinal cords of mSOD1 (G93A) ALS mice, and the deletion of serine racemase (SR), the enzyme that produces D-serine, results in an earlier onset of symptoms, but with a much slower rate of disease progression. Localization studies within the brain suggest that mSOD1 and subsequent glial activation could contribute to the alterations in SR and D-serine seen in ALS. By also degrading both D-serine and L-serine, SR appears to be a prime bidirectional regulator of free serine levels in vivo. Therefore, accurate and reproducible measurements of D-serine are critical to understanding its regulation by SR. Several methods for measuring D serine have been employed, and significant issues related to validation and standardization remain unresolved. Further insights into the intracellular transport and tissue-specific compartmentalization of D-serine within the CNS will aid in the understanding of the role of D-serine in the pathogenesis of ALS. PMID- 23029614 TI - Physical activity and blood lipids and lipoproteins in dialysis patients. AB - The relationship between physical activity and blood lipids and lipoproteins in dialysis patients is reviewed in the context of the potentially confounding factors such as nutritional intake, cigarette smoking, obesity, alcohol intake, and physical activity levels in the general population and additional confounding factors such as mode of dialysis and diabetes in dialysis patients. The known associations in the general population of physical activity with high-density lipoprotein cholesterol subfractions and apolipoprotein A-I are more pronounced in hemodialysis patients than in peritoneal dialysis patients even after adjusting for these confounding factors. Examining studies on the effects of physical activity on blood lipids and lipoproteins, the most consistent observation is the noted decrease in triglycerides and increase in high-density lipoprotein cholesterol and insulin sensitivity in hemodialysis patients. The changes in lipids and lipoproteins in hemodialysis patients could be caused by changes in activity levels of lipoprotein lipase, insulin sensitivity, and/or glucose metabolism. Future research investigating the relationship between physical activity and blood lipids and lipoproteins in dialysis patients should direct research towards the underlying mechanisms for changes in blood lipids and lipoproteins. PMID- 23029615 TI - Dynamic associations of change in physical activity and change in cognitive function: coordinated analyses of four longitudinal studies. AB - The present study used a coordinated analyses approach to examine the association of physical activity and cognitive change in four longitudinal studies. A series of multilevel growth models with physical activity included both as a fixed (between-person) and time-varying (within-person) predictor of four domains of cognitive function (reasoning, memory, fluency, and semantic knowledge) was used. Baseline physical activity predicted fluency, reasoning and memory in two studies. However, there was a consistent pattern of positive relationships between time-specific changes in physical activity and time-specific changes in cognition, controlling for expected linear trajectories over time, across all four studies. This pattern was most evident for the domains of reasoning and fluency. PMID- 23029617 TI - Barriers and facilitators to community mobility for assistive technology users. AB - Mobility is frequently described in terms of individual body function and structures however contemporary views of disability also recognise the role of environment in creating disability. Aim. To identify consumer perspectives regarding barriers and facilitators to optimal mobility for a heterogeneous population of impaired Victorians who use assistive technology in their daily lives. Method. An accessible survey investigated the impact of supports or facilitators upon actual and desired life outcomes and health-related quality of life, from 100 AT users in Victoria, Australia. This paper reports upon data pertaining to community mobility. Results. A range of barriers and enablers to community mobility were identified including access to AT devices, environmental interventions, public transport, and inclusive community environs. Substantial levels of unmet need result in limited personal mobility and community participation. Outcomes fall short of many principles enshrined in current policy and human rights frameworks. Conclusion. AT devices as well as accessible and inclusive home and community environs are essential to maximizing mobility for many. Given the impact of the environment upon the capacity of individuals to realise community mobility, this raises the question as to whether rehabilitation practitioners, as well as prescribing AT devices, should work to build accessible communities via systemic advocacy. PMID- 23029616 TI - The fetal origins of the metabolic syndrome: can we intervene? AB - Epidemiological studies have suggested that metabolic programming begins during fetal life and adverse events in utero are a critical factor in the etiology of chronic diseases and overall health. While the underlying molecular mechanisms linking impaired fetal development to these adult diseases are being elucidated, little is known about how we can intervene early in life to diminish the incidence and severity of these long-term diseases. This paper highlights the latest clinical and pharmaceutical studies addressing how dietary intervention in fetal and neonatal life may be able to prevent aspects of the metabolic syndrome associated with IUGR pregnancies. PMID- 23029618 TI - Two different protocols for knee joint motion analyses in the stance phase of gait: correlation of the rigid marker set and the point cluster technique. AB - Objective. There are no reports comparing the protocols provided by rigid marker set (RMS) and point cluster technique (PCT), which are similar in terms of estimating anatomical landmarks based on markers attached to a segment. The purpose of this study was to clarify the correlation of the two different protocols, which are protocols for knee motion in gait, and identify whether measurement errors arose at particular periods during the stance phase. Methods. The study subjects were 10 healthy adults. All estimated anatomical landmarks were which their positions, calculated by each protocol of the PCT and RMS, were compared using Pearson's product correlation coefficients. To examine the reliability of the angle changes of the knee joint measured by RMS and the PCT, the coefficient of multiple correlations (CMCs) was used. Results. Although the estimates of the anatomical landmarks showed high correlations of >0.90 (P < 0.01) for the Y- and Z-coordinates, the correlations were low for the X coordinates at all anatomical landmarks. The CMC was 0.94 for flexion/extension, 0.74 for abduction/adduction, and 0.71 for external/internal rotation. Conclusion. Flexion/extension and abduction/adduction of the knee by two different protocols had comparatively little error and good reliability after 30% of the stance phase. PMID- 23029619 TI - Implications of the Use of Eukaryotic Translation Initiation Factor 5A (eIF5A) for Prognosis and Treatment of Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is a primary liver malignancy and accounts for most of the total liver cancer cases. Lack of treatment options and late diagnosis contribute to high mortality rate of HCC. In eukaryotes, translation of messenger RNA (mRNA) to protein is a key process in protein biosynthesis in which initiation of translation involves interaction of different eukaryotic translation initiation factors (eIFs), ribosome subunits and mRNAs. Eukaryotic translation initiation factor 5A (eIF5A) is one of the eIFs involved in translation initiation and eIF5A2, one of its isoforms, is upregulated in various cancers including HCC as a result of chromosomal instability, where it resides. In HCC, eIF5A2 expression is associated with adverse prognosis such as presence of tumor metastasis and venous infiltration. Based on eIF5A2 functional studies, suppressing eIF5A2 expression by short interfering RNA alleviates the tumorigenic properties of HCC cells in vitro while ectopic expression of eIF5A2 enhances the aggressiveness of HCC cells in vivo and in vitro by inducing epithelial mesenchymal transition. In conclusion, eIF5A2 is a potential prognostic marker as well as a therapeutic target for HCC. PMID- 23029620 TI - Common Perceptions of Periodontal Health and Illness among Adults: A Qualitative Study. AB - Objective. Our aim was to explore perceptions of periodontal health and illness and to examine attitudes and beliefs regarding prevention of gum diseases among Iranian adults. Methods. Our qualitative approach included focus-group discussions among adults aged 18 and above based on convenient and purposive sampling in Tehran. Transcripts of the four focus-group discussions were analyzed by two independent reviewers using a content analysis method. Results. Two major themes in the analyses emerged: the common perception of periodontal health and illness and the attitude towards prevention. The study demonstrated the subjects' good understanding of prevention of periodontal disease, but their lack of knowledge of the aetiology of the diseases, and an inability to differentiate aetiology, symptoms, and prevention of dental caries and periodontal disease. Conclusion. This study revealed a need for oral health education among Iranian adults to improve their knowledge and change their attitudes to achieve deeper understanding of the aetiology and prevention of periodontal disease. Health promotion programs should address misconceptions about prevention of gum disease. PMID- 23029622 TI - Bioequivalence study of modified-release gliclazide tablets in healthy volunteers. AB - This study was aimed to investigate bioequivalence of modified-release 30 mg gliclazide tablets in 18 healthy Thai volunteers. A test product, Glycon MR (Siam Bheasach, TH), was compared with a reference product, Diamicron MR (Servier, France). The study was performed under a single-dose, two-treatment, two-period, and two-sequence crossover design in fasted and fed conditions with a washout period of 2 weeks. Blood samples were collected for 72 h after drug administration. Drug plasma concentrations were determined by HPLC with a UV detector. Analysis of pharmacokinetic characteristics was based on a non compartmental model. The logarithmically transformed data of C(max) and AUCs were analyzed for 90% confidence intervals using ANOVA. The test product gave slightly higher C(max) in both conditions and shorter T(max) in the fed condition. However, there is no significant difference in pharmacokinetic characteristics between both products under fasted and fed conditions. Effect of food was not significantly observed. The 90% confidence intervals were within the acceptance criteria of 0.80-1.25 regardless of the food effect, indicating bioequivalence between the two products on the rate and extent of gliclazide MR absorption without regard to meals. PMID- 23029621 TI - Improving hepatitis B vaccine efficacy in end-stage renal diseases patients and role of adjuvants. AB - Hepatitis B virus (HBV) infection is a serious global health problem.The prevalence of viral hepatitis is higher in dialysis patients than in the general population because of the opportunity for exposure during the dialysis procedure. Immunization is the most effective way to prevent transmission of hepatitis B virus (HBV) and hence the development of acute or chronic hepatitis B. It is well established that patients with end-stage renal disease including dialysis dependent patients, have an impaired immune response to hepatitis B vaccine. End stage renal diseases (ESRD) patients have lower seroconversion rates compared with the subjects with intact renal function. Moreover, even after the completion of vaccination schedule anti-hepatitis B (anti-HBs) titers of responder dialysis, patients are low and decline logarithmically with time. The impaired efficacy of HBV vaccine in patients with ESRD has been attributed to numerous factors such as immune compromise because of uremia and some other factors. One approach to improve the immunogenicity of existing HBV vaccines is adjuvantation, and it's very important to find more effective adjutants for improving HBV vaccine efficacy. In this paper we have a brief review on recently known new ways for improving HBV vaccine efficacy. PMID- 23029623 TI - UBR5 Gene Mutation Is Associated with Familial Adult Myoclonic Epilepsy in a Japanese Family. AB - The causal gene(s) for familial adult myoclonic epilepsy (FAME) remains undetermined. To identify it, an exome analysis was performed for the proband in a Japanese FAME family. Of the 383 missense/nonsense variants examined, only c.5720G>A mutation (p.Arg1907His) in the UBR5 gene was found in all of the affected individuals in the family, but not in the nonaffected members. Such mutation was not found in any of the 85 healthy individuals in the same community nor in any of the 24 individuals of various ethnicities. The present study demonstrated an FAME-associated mutation in the UBR5 gene, which is located close to the reported locus linked to Japanese FAME families. PMID- 23029624 TI - Hemostatic Agents in Hepatobiliary and Pancreas Surgery: A Review of the Literature and Critical Evaluation of a Novel Carrier-Bound Fibrin Sealant (TachoSil). AB - Background. Despite progress in surgical techniques applied during hepatobiliary and pancreas (HPB) surgery, bleeding and bile leak remain significant contributors to postoperative mortality and morbidity. Topical hemostatics have been developed and utilized across surgical specialties, but data regarding effectiveness remains inconsistent and sparse in HPB surgery. Methods. A comprehensive search for studies and reviews on hemostatics in HPB surgery was performed via an October 2011 query of Medline, EMBASE, and Cochrane Library. In depth evaluation of a novel carrier-bound fibrin sealant (TachoSil) was also performed. Results. The literature review illustrates multiple attempts have been made at developing different topical hemostatics and sealants to aid in surgical procedures. In HPB surgery, efforts have been directed at decreasing bleeding, biliary leakage, and pancreatic fistula. Conflicting scientific evidence exists regarding the effectiveness of these agents. Critical evaluation of the literature demonstrates TachoSil is a valuable tool in achieving hemostasis, and possibly biliostasis and pancreatic fistula prevention. Conclusion. While progress has been made in topical hemostatics for HPB surgery, an ideal agent has not yet been identified. TachoSil is promising, but larger randomized, controlled clinical trials are required to more fully evaluate its efficacy in reducing bleeding, biliary leakage, and pancreatic fistulas in HPB surgery. PMID- 23029626 TI - Fever following an Epidural Blood Patch in a Child. AB - There is increasing evidence that children suffer from the consequences of spontaneous or iatrogenic intracranial hypotension. Pediatric epidural blood patch is gaining popularity because of its ability to alter cerebrospinal fluid dynamics and to alleviate headaches attributed to low cerebrospinal fluid pressure. There is, however, still not enough data to document the safety profile of an epidural blood patch. Here we describe a case of a fever in a child temporally related to the administration of an epidural blood patch. This case depicts the dilemmas in making the diagnosis and instituting treatment for complications of this procedure in the pediatric population. PMID- 23029625 TI - Neural correlates of changes in a visual search task due to cognitive training in seniors. AB - This study aimed to elucidate the underlying neural sources of near transfer after a multidomain cognitive training in older participants in a visual search task. Participants were randomly assigned to a social control, a no-contact control and a training group, receiving a 4-month paper-pencil and PC-based trainer guided cognitive intervention. All participants were tested in a before and after session with a conjunction visual search task. Performance and event related potentials (ERPs) suggest that the cognitive training improved feature processing of the stimuli which was expressed in an increased rate of target detection compared to the control groups. This was paralleled by enhanced amplitudes of the frontal P2 in the ERP and by higher activation in lingual and parahippocampal brain areas which are discussed to support visual feature processing. Enhanced N1 and N2 potentials in the ERP for nontarget stimuli after cognitive training additionally suggest improved attention and subsequent processing of arrays which were not immediately recognized as targets. Possible test repetition effects were confined to processes of stimulus categorisation as suggested by the P3b potential. The results show neurocognitive plasticity in aging after a broad cognitive training and allow pinpointing the functional loci of effects induced by cognitive training. PMID- 23029627 TI - Malignant transformation of a mature cystic ovarian teratoma into thyroid carcinoma, mucinous adenocarcinoma, and strumal carcinoid: a case report and literature review. AB - Malignant transformation of a mature cystic teratoma (MCT) is an infrequent, often asymptomatic event. We report the first example of a struma ovarii with a focus of follicular variant of papillary thyroid carcinoma (a), mucinous adenocarcinoma (b), and strumal carcinoid tumor (c)-all three arising in one mature cystic teratoma of the ovary. From our reviews, we found limited data to guide management when these malignant foci occur within an MCT. Consideration should be given to thyroidectomy followed by total-body scanning and serum studies for foci of thyroid carcinoma and adjuvant therapy with thyroidectomy and radioablation if residual disease is identified (a). Additionally, extrapolating from data for mucinous adenocarcinomas, consideration could be given to adjuvant chemotherapy after appropriate staging (b). Strumal carcinoid tumors should be treated as tumors of low malignant potential. Observation is appropriate if after complete staging, no invasive implants are noted (c). PMID- 23029628 TI - Salvage therapy for refractory AIDS-related primary central nervous system lymphoma. AB - A 27-year-old male patient presented with speech disorders and multiple brain masses on MRI evaluation. He tested positive for HIV. A sterotactic biopsy diagnosed primary central nervous system lymphoma (diffuse large B-cell lymphoma). After two cycles of high-dose metotrexate (HD-MTX-)-based chemotherapy, the tumor progressed. He underwent whole brain radiotherapy achieving complete response. Six cycles of consolidating immunochemotherapy with rituximab-temozolomide were administered after radiation. Forty-three months after remission, he has not recurred and his neurological status is optimal. Younger HIV patients with refractory PCNSL and preserved immune function can face salvage therapy successfully achieving long term remissions with no remarkable neurotoxicity. PMID- 23029629 TI - Animal models of Parkinson's disease 2012. PMID- 23029631 TI - Morphological aspects and immunophenotypic profiles of mammary carcinomas in benign-mixed tumors of female dogs. AB - Carcinoma in benign-mixed tumor (CBMT) is common in the female canine mammary gland and comprises malignant epithelial between benign mesenchymal elements. This study investigated the morphological aspects of 29 CBMT and their immunophenotypical profiles, by using an immunohistochemistry panel based on five molecular markers-estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5 (CK5), and human epidermal growth factor receptor 1 (EGFR). From these, CBMT was classified into four subtypes: luminal A, luminal B, HER2-like, basal-like, and normal. "In situ" and invasive carcinomatous components were analyzed and compared. Histological grade I carcinoma was observed in 16 cases (55.2%) of the tumors analyzed, grade II in 10 cases (34.5%), and grade III in three cases (10.3%). The invasive carcinomatous component has shown, more frequently, luminal A (12/29 cases, 41.4%), followed by basal-like phenotype (8/29 cases, 27.6%). There was high concordance between immunophenotypical profiles of the in situ and invasive carcinomatous components (kappa coefficient = 0.816, P < 0.001). We concluded that CBMT predominantly has features of low-grade neoplasms of malignancy. The various immunophenotypic profiles suggest the origin of these lesions in more than one cell type (luminal and myoepithelial). PMID- 23029632 TI - Tension Gastrothorax Complicating Third Trimester of Pregnancy: Suspicion is the Key. AB - Gastrothorax is characterized by herniation of the stomach and other abdominal contents into the thoracic cavity either through the oesophageal hiatus or ruptured diaphragm. When gastrothorax causes pulmonary and hemodynamic compromise, due to compression of lungs and mediastinal structures, it is named as tension gastrothorax. Diagnosis of tension gastrothorax is often complicated during late pregnancy, because of unusual presentation, altered physiology, absence of trauma, hesitation about radiation exposure, and rarity of the condition. We report a case of a patient, in her 32nd week of pregnancy, who presented with left tension gastrothorax. Lower segment caesarean section was planned after steroid therapy, with all the preparations for thoracotomy. Intra operatively, stomach, spleen, and colon were found herniated in the left hemithorax, through a ruptured left hemidiaphragm. Thoracotomy was done immediately after caesarean section, with reduction of herniated contents and repair of the defect in the diaphragm. The patient and her baby were discharged in stable condition 2 weeks after thoracotomy. PMID- 23029633 TI - Use of CBCT in the Successful Management of Endodontic Cases. AB - The purpose of this article is to emphasize the use of Cone Beam Computed Tomography (CBCT) for root canal treatment. Two case reports are presented where CBCT has been used to locate and eventually treat extra canals in maxillary first molars. Dental clinicians should be aware of the anatomical variations in maxillary molars. CBCT should be an essential part of the diagnosis prior to initiating root canal treatment. PMID- 23029634 TI - Conservative Management of Type III Dens in Dente Using Cone Beam Computed Tomography. AB - Dens in dente, also known as dens invaginatus, dilated composite odontoma, or deep foramen caecum, is a developmental malformation that usually affects maxillary incisor teeth, particularly lateral incisors. It may occur in teeth anywhere within the jaws, other locations are comparatively rare. It can occur within both the crown and the root, although crown invaginations are more common. The use of cone beam computed tomography (CBCT) is very helpful in endodontic diagnosis of complex anatomic variations. In this case we demonstrate the use of CBCT in the evaluation and endodontic management of a Type III dens in dente (Oehler's Type III). PMID- 23029635 TI - Imaging in the diagnosis of cemento-ossifying fibroma: a case series. AB - Cemento-ossifying fibroma is a benign fibro-osseous lesion belonging to the same category as fibrous dysplasia and cementifying dysplasia. These are slow-growing lesions that are seen in the third and fourth decades of life. Both the ossifying fibroma and cemento-ossifying fibroma represent two extremes of the same disease process since histologically both contain bone and cementum. However, the term cemento-ossifying fibroma is justified on the basis of clinical and radiological correlation. Radiographs have become an essential tool in the diagnosis of lesions in the jaw, where the anatomy is complex. Nowadays, CT provides information for diagnosis as well as treatment planning. In this case series, we report three cases of cemento-ossifying fibroma that were histologically confirmed and discuss the imaging findings. PMID- 23029636 TI - Breast Hemangioma: MR Appearance with Histopathological Correlation. AB - Breast hemangioma is a rare tumor and when small, it may be difficult to diagnose using conventional imaging techniques. In this report the MR appearance is described with histopathological correlation. PMID- 23029637 TI - Portal vein aneurysm presenting with obstructive jaundice. AB - To the best of our knowledge, a portal vein aneurysm presenting with obstructive jaundice has not been reported in the literature. The preferred treatment for these aneurysms is surgical and a shunting procedure should be considered in cases with portal hypertension to preserve portal vein flow when portal hypertension is present or is secondary to the aneurysm itself. In our case, due to patient's advanced age and co-morbidities, an endoscopic biliary stent was placed which led to successful resolution of symptoms of obstructive jaundice. PMID- 23029638 TI - Large Multilocular Thymic Cyst: A Rare Finding in an HIV Positive Adult Female. AB - Multilocular thymic cysts with follicular hyperplasia are uncommon masses that occur in Human Immunodeficiency Virus (HIV) positive individuals. These cysts mostly present in HIV positive children. Here we report a rare case of multilocular thymic cyst in an HIV positive adult female. In this case report, the radiologic findings of multilocular thymic cyst, management and prognosis are discussed. PMID- 23029639 TI - Guest editor's introduction: Special section on the ACM SIGGRAPH/Eurographics Symposium on Computer Animation (SCA). PMID- 23029640 TI - Structural models of the human copper P-type ATPases ATP7A and ATP7B. AB - The human copper exporters ATP7A and ATP7B contain domains common to all P-type ATPases as well as class-specific features such as six sequential heavy-metal binding domains (HMBD1-HMBD6) and a type-specific constellation of transmembrane helices. Despite the medical significance of ATP7A and ATP7B related to Menkes and Wilson diseases, respectively, structural information has only been available for isolated, soluble domains. Here we present homology models based on the existing structures of soluble domains and the recently determined structure of the homologous LpCopA from the bacterium Legionella pneumophila. The models and sequence analyses show that the domains and residues involved in the catalytic phosphorylation events and copper transfer are highly conserved. In addition, there are only minor differences in the core structures of the two human proteins and the bacterial template, allowing protein-specific properties to be addressed. Furthermore, the mapping of known disease-causing missense mutations indicates that among the heavy-metal binding domains, HMBD5 and HMBD6 are the most crucial for function, thus mimicking the single or dual HMBDs found in most copper specific P-type ATPases. We propose a structural arrangement of the HMBDs and how they may interact with the core of the proteins to achieve autoinhibition. PMID- 23029643 TI - The proteasome: molecular machinery and pathophysiological roles. AB - The 26S proteasome, in collaboration with ubiquitin, operates the energy dependent regulated proteolysis process in eukaryotic cells. Over the past 30 years, several studies have comprehensively characterized the structure and molecular/physiological functions of the 26S proteasome. It is a sophisticated 2.5-MDa protein degradation machine comprising a proteolytic core particle (CP) and one or two terminal regulatory particle(s) (RP). The CP consists of two outer alpha rings and two inner beta rings, which are made up of seven structurally similar alpha and beta subunits, respectively. The CP contains catalytic threonine residues (beta1, beta2, and beta5; caspase-like, trypsin-like, and chymotrypsin-like activities, respectively) on the inner surface of the chamber formed by two abutting beta rings. Intriguingly, the immunotype proteasomes, named 'immunoproteasome' and 'thymoproteasome', whose catalytic subunits are replaced by the related counterparts, were discovered lately. Both unique isoenzymes essentially contribute to the acquisition of adaptive immunity in vertebrates. The RP, which serves to recognize polyubiquitylated substrate proteins and plays a role in their deubiquitylating, unfolding, and translocation into the interior of the CP for destruction, forms two subcomplexes: the base and the lid. On another front, the PA28 and PA200, alternative CP activator proteins discovered biochemically, both play independent roles in proteolysis of the 26S proteasome. Several studies have highlighted the importance of the proteasome in various intractable diseases that have been increasing in the aged society of the 21st century. PMID- 23029645 TI - At the cutting edge: applications and perspectives of laser nanosurgery in cell biology. AB - Laser-mediated nanosurgery has become popular in the last decade because of the previously unexplored possibility of ablating biological material inside living cells with sub-micrometer precision. A number of publications have shown the potential applications of this technique, ranging from the dissection of sub cellular structures to surgical ablations of whole cells or tissues in model systems such as Drosophila melanogaster or Danio rerio . In parallel, the recent development of micropatterning techniques has given cell biologists the possibility to shape cells and reproducibly organize the intracellular space. The integration of these two techniques has only recently started yet their combination has proven to be very interesting. The aim of this review is to present recent applications of laser nanosurgery in cell biology and to discuss the possible developments of this approach, particularly in combination with micropattern-mediated endomembrane organization. PMID- 23029648 TI - N-glycoproteomics: mass spectrometry-based glycosylation site annotation. AB - Glycosylations are ubiquitous and, in many cases, essential protein modifications. Yet comprehensive and detailed analysis of glycosylations on a proteome-wide scale is a daunting and still unsolved challenge. However, a common workflow has emerged over the last decade for large-scale N-glycosylation site annotation by application of proteomic methodology. Thereby, the qualitative and quantitative assessment of hundreds or thousands of modification sites is enabled. This review presents a short overview about common enrichment techniques and glycosylation site detection for N-glycopeptides, including benefits and challenges of analysis. PMID- 23029651 TI - Disorder-function relationships for the cell cycle regulatory proteins p21 and p27. AB - The classic structure-function paradigm has been challenged by a recently identified class of proteins: intrinsically disordered proteins (IDPs). Despite their lack of stable secondary or tertiary structure, IDPs are prevalent in all forms of life and perform myriad cellular functions, including signaling and regulation. Importantly, disruption of IDP homeostasis is associated with numerous human diseases, including cancer and neurodegeneration. Despite wide recognition of IDPs, the molecular mechanisms underlying their functions are not fully understood. Here we review the structural features and disorder-function relationships for p21 and p27, two cyclin-dependent kinase (Cdk) regulators involved in controlling cell division and fate. Studies of p21 bound to Cdk2/cyclin A revealed that a helix stretching mechanism mediates binding promiscuity. Further, investigations of Tyr88-phosphorylated p27 identified a signaling conduit that controls cell division and is disrupted in certain cancers. These mechanisms rely upon a balance between nascent structure in the free state, induced folding upon binding, and persistent flexibility within functional complexes. Although these disorder-function relationships are likely to be recapitulated in other IDPs, it is also likely that the vocabulary of their mechanisms is much more extensive than is currently understood. Further study of the physical properties of IDPs and elucidation of their links with function are needed to fully understand the mechanistic language of IDPs. PMID- 23029655 TI - Regional susceptibilities to mitochondrial dysfunctions in the CNS. AB - Mitochondrial dysfunctions are very common features of age-related neurological diseases such as Parkinson's, Alzheimer's and Huntington's disease. Several studies have shown that bioenergetic impairments have a major role in the degeneration of the central nervous system (CNS) in these patients. Accordingly, one of the main symptoms in many mitochondrial diseases is severe encephalopathy. The heterogeneity of the brain in terms of anatomic structures, cell composition, regional functions and biochemical properties makes the analysis on this organ very complex and difficult to interpret. Humans, in addition to animal models, exposed to toxins that affect mitochondrial function, in particular oxidative phosphorylation, exhibit degeneration of specific regions within the brain. Moreover, mutations in ubiquitously expressed genes that are involved in mitochondrial function also induce regional-specific cell death in the CNS. In this review, we will discuss some current hypotheses to explain the regional susceptibilities to mitochondrial dysfunctions in the CNS. PMID- 23029659 TI - Engaging students in gerontological research. AB - There is a critical need to prepare undergraduate and graduate nursing students to take active roles in gerontological nursing research. Nursing educators are faced with multiple challenges such as the demands of the tripartite role (teaching, scholarship, and service), and managing large numbers of students. These issues make it difficult to actively engage nursing research. Students Advancing Reminiscence Research (STARR) is and example of an innovative program that fosters student engagement in research using available resources while enhancing the faculty advisor's program of reminiscence research. The impetus for creating the STARR program is described in this article, and implications and recommendations for nursing education, practice, and policy are presented. PMID- 23029660 TI - Brain tumours among interventional cardiologists: a call for alarm? PMID- 23029661 TI - Change of heart for New Zealand's cardiology scene. PMID- 23029662 TI - The UK National Institute for Health Research. PMID- 23029663 TI - Patients wish for complementary medicine. PMID- 23029664 TI - Combating antimicrobial resistance and healthcare-associated infections: the role of the Specialist Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infections (ARHAI), 2007-2011. Preface. PMID- 23029665 TI - US presidential candidates outline health policies. PMID- 23029666 TI - Vaster, hotter, grainier. PMID- 23029667 TI - German doctors call for reform after organ scandal. PMID- 23029668 TI - Profile: KCMHR--dispelling myths about military health. PMID- 23029669 TI - The psychiatrist who wanted to believe. PMID- 23029670 TI - Advertisements in medical and health-related journals. PMID- 23029672 TI - "Bad" LDL cholesterol still trumps "good" HDL cholesterol. Results may explain why raising HDL doesn't protect against heart attack. PMID- 23029673 TI - Breakthrough in breast cancer treatment. "Smart bullet" T-DM1 delivers a payload to cancer cells and avoids healthy ones. PMID- 23029674 TI - Vitamin D revisited: benefits beyond bone health. There is increasing research on the nonskeletal health benefits of vitamin D, but more studies are needed. PMID- 23029671 TI - The Arabidopsis szl1 mutant reveals a critical role of beta-carotene in photosystem I photoprotection. AB - Carotenes and their oxygenated derivatives, the xanthophylls, are structural determinants in both photosystems (PS) I and II. They bind and stabilize photosynthetic complexes, increase the light-harvesting capacity of chlorophyll binding proteins, and have a major role in chloroplast photoprotection. Localization of carotenoid species within each PS is highly conserved: Core complexes bind carotenes, whereas peripheral light-harvesting systems bind xanthophylls. The specific functional role of each xanthophyll species has been recently described by genetic dissection, however the in vivo role of carotenes has not been similarly defined. Here, we have analyzed the function of carotenes in photosynthesis and photoprotection, distinct from that of xanthophylls, by characterizing the suppressor of zeaxanthin-less (szl) mutant of Arabidopsis (Arabidopsis thaliana) which, due to the decreased activity of the lycopene-beta cyclase, shows a lower carotene content than wild-type plants. When grown at room temperature, mutant plants showed a lower content in PSI light-harvesting complex I complex than the wild type, and a reduced capacity for chlorophyll fluorescence quenching, the rapidly reversible component of nonphotochemical quenching. When exposed to high light at chilling temperature, szl1 plants showed stronger photoxidation than wild-type plants. Both PSI and PSII from szl1 were similarly depleted in carotenes and yet PSI activity was more sensitive to light stress than PSII as shown by the stronger photoinhibition of PSI and increased rate of singlet oxygen release from isolated PSI light-harvesting complex I complexes of szl1 compared with the wild type. We conclude that carotene depletion in the core complexes impairs photoprotection of both PS under high light at chilling temperature, with PSI being far more affected than PSII. PMID- 23029676 TI - I've been under a great deal of stress lately, and a friend recommended I learn a relaxation technique. Do these really work? And can you suggest a particular technique? PMID- 23029675 TI - One step closer to defining Alzheimer's causes. ApoE4 gene identified as possible target for drug therapy in Alzheimer's treatment. PMID- 23029677 TI - There's been controversy about certain plastics in baby bottles, in ordinary juice and water bottles, and in canned goods. Can you clarify this? Also, are there any symbols on plastic goods that I should be aware of? PMID- 23029678 TI - My blood pressure is slightly elevated and I wake up a few times a night. Will poor sleep make it harder to manage my blood pressure. PMID- 23029679 TI - I've been hearing a lot about taurine lately. What is it, and why is it good for you? PMID- 23029680 TI - Treatment. Pre-existing mutation may cause HIV drug resistance. PMID- 23029681 TI - Research. Lifestyle changes from parenting may lower HIV risk in gay couples. PMID- 23029682 TI - Report suggests strategies to improve access to HIV drugs. PMID- 23029683 TI - Young men with HIV more susceptible to low bone mass. PMID- 23029684 TI - Prisons. Transferred inmate did not have right to refuse HIV testing. PMID- 23029685 TI - Insurance. Homeowner's policy did not cover transmission of HIV. PMID- 23029686 TI - SSI. Record did not support woman's disability claims from HIV. PMID- 23029687 TI - Prisons. Court dismissed HIV-positive inmate's right to privacy case. PMID- 23029689 TI - Ankle replacement tops ankle fusion as new gold standard. The procedure has evolved into come-in, have-surgery, go-home-the-next-day. PMID- 23029688 TI - Drug combination reduced infant HIV. PMID- 23029690 TI - High-salt diet may cause hypertension. Study suggests excessive salt use may damage blood vessels. PMID- 23029691 TI - Brain insulin resistance may exacerbate Alzheimer's progression. Researchers call it "Type III" diabetes. PMID- 23029692 TI - Weight loss: once it's off, the trick is keeping it off. Low-glycemic tops two other diets; and, stepped-care versus a standard behavioral approach to dieting. PMID- 23029693 TI - Early, aggressive treatment is effective in treating diabetes. Risk of long-term complications reduced significantly. PMID- 23029694 TI - What is "neuroplasticity"? And, is it attainable by older adults? PMID- 23029695 TI - One of my doctors recommends spinal surgery to correct a chronic back pain problem. Are there other options? PMID- 23029696 TI - I've heard a gluten-free diet can mitigate symptoms of celiac disease. What's the best approach to implementing this diet? PMID- 23029697 TI - Why is Tylenol in the news so much lately? PMID- 23029698 TI - [Health service research (23). SWOT, an analytical tool for health service providing plans and complete application of Gunn]. PMID- 23029699 TI - Fighting the resistance: rejuvenating anticancer platinum-based drugs. PMID- 23029701 TI - Slowing down to reflect on our work and the future of health care. PMID- 23029700 TI - US Senator calls for bill to increase access to HIV/AIDS medication. PMID- 23029702 TI - Retraction. Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behavior modification and oxidative damage in mice by Anil Kumar, Anant Singh and Puneet Kumar published in the Indian Journal of Experimental Biology, Vol. 49, March 2011, pp.211-218. PMID- 23029703 TI - [Progress in the treatment of C-type hepatitis and future prospect. Discussion]. PMID- 23029704 TI - [Q & A. Hepatic nodules complicated with alcoholic liver cirrhosis and presenting low signals in Gd-EOB-DTPA-contrasted MRI hepatocyte phase]. PMID- 23029705 TI - [Prediction of survival of the postoperative patients based on selected severity of-illness scoring systems]. AB - PURPOSE OF THE STUDY: To compare and evaluate preoperative assessment in ASA scale to predicted death rate (PDR) numbers, computed in commonly used severity of-illness and prognostic scoring systems (Portsmouth-POSSUM, SAPS 2, MPM 2, MPM for cancer patients, LODS, ODIN i TRIOS) on the first and on the third postoperative days. Evaluation of the mean PDR calculated from the scales. MATERIAL AND METHODS: There were analyzed 187 cases of non-survivors and 100 cases of survivors of 187 patients treated in surgical intensive care unit at University Hospital in Krakow. In each case PDR was calculated in seven severity of illness and prognostic scoring systems on the first and on the third postoperative day and compared to the ASA group and mean PDR computed from seven PDR numbers. Discrimination and calibration characteristics of the scoring systems was analyzed as area under receiver operating characteristic curves (AUROC) and predictive values. RESULTS: Length of hospital stay was shorter in survivors (16.6 days) as compared to nonsurvivors (25.3 days); similarly the time period between the hospital admittance and surgery was shorter in survivors (1.6 days vs 7.4 days). There were almost twice more frequent repeated surgical procedures in nonsurvivors (45.4% vs 26%). The mean ASA scale in non-survivors was 3.74 and 3.20 in survivors (p < 0.001). The mean PDR computed from seven scoring systems on the first postoperative day was 55.2 in non-survivors vs 21.2 in survivors (p < 0.001) and on the third postoperative day was 64.1 vs 32.3 (p < 0.001). The best discriminative properties, calculated as AUROC, showed: mean PDR computed from the used scoring systems on the first postoperative day (0.859), then ODIN (0.847), MPM2 (0.833), Portsmouth-POSSUM (0.83) and mean PDR computed on the third postoperative day (0827). CONCLUSIONS: There is none severity-of illness nor prognostic scoring system that could be commonly used in intensive care unit patients. There are discrepancies in predicted death rate (PDR) cal. culated in each of available risk models in population of intensive care unit patients. The mean PDR value computed from available scales could be a reasonable descriptive and prognostic alternative. PMID- 23029706 TI - Controversy about reversibility of cysts in cystic cystitis in children. AB - Most cystic cystitis cases in children exhibit cysts for an extended period, even after successful treatment of the underlying infection. Not much is known about the dynamics of cyst appearance and disappearance. In long-term follow-up some clinicians suggest complete eradication of the cysts. Contrary, histological studies describe the cystic cystitis as an irreversible process in von Brunn's nests. The endoscopic differentiation from reversible follicular cystitis is hard and uncertain. A group of 21 children with cystic cystitis was diagnosed and staged in a 10-year period. All of them clinically presented with recurrent uroinfections. We examined cystoscopic changes of cystic cystitis before and during the treatment of urinary infection to find objective signs of improvement in endoscopic findings after prolonged antibiotic therapy. Control cystoscopy was performed after a period of six infection-free months. In the average period of 20 months after the beginning of treatment there were no changes in cystic cystitis stage. The examined period seems to be too short for the changes of cystic cystitis to disappear. It is unclear if prolonged antibacterial treatment bears any influence on the number of cysts. PMID- 23029707 TI - [Brittle bone disease type III in neonates--own experience]. AB - Fractures of long bone and ribs in the neonatal period may be expression of genetic disturbances of collagen type I production. The aim of the study was to present clinical symptoms, results of radiological, biochemical and densitometric examinations in 11 newborns with osteogenesis imperfecta type III. METHODS: In all children accurate medical history, clinical examination and radiograph were performed. We measured concentration of 25-hydroxyvitamin D (25OHD) and osteocalcin (bone formation marker) in serum. Urinary excretion of bone resorption marker type I collagen N-telopeptide related to creatinine were made. In 5/11 children densitometric examination in Infant programme by DXA method (dual-X-ray absorptiometry) were done. RESULTS: In all family osteogenesis imperfecta occurred by the first. In clinical examination deformities in body proportion, shortness of the extremities, sabre shanks, flabbily of skull bones and reduction of activity were diagnosed. 8/11 newborns had blue sclera. In all X ray (baby-gram) bone fractures occurring in utero as well as after birth were founded. In biochemical indices a small numbers of abnormality were described. In 5/11 newborns with results of densitometric examination normal bone mineral density adequate to body mass were demonstrated, in 3/5 bone mineral content (BMC) were decreased. CONCLUSION: 1.Osteogens esis imperfecta is the one of reasons of bone fractures in neonates and its diagnosis is based on family history, clinical manifestation and X-ray examination. 2. In newborns with bone fractures dual X-ray absorptiometry are recomendated. PMID- 23029708 TI - [The comparison of 4th, 5th and 6th year medical students knowledge of rules and practical skills in the interpretation of electrocardiograms at Jagiellonian University]. AB - INTRODUCTION: The electrocardiogram (ECG) examination is one of the most frequent administered diagnostic tests. It is commonly ordered by General Practitioners, and it has became a routinely administered examination during admission to the hospital. During their studies, medical students has numerous opportunities to review and interpret the results of these tests. AIM OF THE STUDY: The aim of our research was to statistically compare and contrast the knowledge of the rules and practical skills in the interpretation of ECGs in 4th, 5th and 6th year medical students at Jagiellonian University. We wanted to better define in which year the students acquire the most of their clinical skills and determine if 6th year students have sufficient knowledge and skills to adequately perform in their future career. We additionally wanted to understand from which source students draw their knowledge of the ECG. MATERIAL AND METHODS: The population of 249- 4th, 5th and 6th year medical students of Jagiellonian University were asked to reply to an anonymous questionnaire. The questionnaire was comprised of three parts. The fist part contains four simple ECGs (STEMI, RBBB, PVC, normogram- sinus rhythm). The second part contained six questions regarding their theoretical knowledge. The third part contained seven questions which evaluated the students' background and approach to the problem. Students filled the questionnaire without prior preparation to avoid the short-term "examination knowledge". RESULTS: The question that was most frequent answered correctly was question regarding the proper time (in milliseconds) of QRS complex (24.1%). Differences in the percentage of correct answers to questionnaire amongst 4th and 5th year students were statistically uncharacteristic. The percentage of correct answers of 6th year students increased by about 16% (p < 0.0001). The comparison of answers between 6th year students - who in prior semester completed a cardiology course (group A 6th year) and 6th year students who did not yet complete cardiology course (group B 6th year) showed significant improvement in group A in the percentage of correct answers for all questions about ECG. The percentage of correct answers in group A was an average 62% and in group B 45.5% (p < 0.00025). In case of 4th and 5th year students, the picture was uncharacteristic. Self study of ECG had a significant, positive influence in the percentage of correct answers amongst respondents, especially in the 6th year student population. Improvement was also seen in 4th and 5th students, but to a lesser degree. Among the 6th year students who benefited from self study, their percentage of correct answers was nearly two times then that of their fellow of 6th year students who did not self study (p < 0.0001). Only 3 of questioned students stated that they felt that their present knowledge of ECG is sufficient. CONCLUSIONS: 4th and 5th year students have comparable knowledge of ECG. 6th year students showed a significantly improved ability to interpret the ECG, especially those who had already completed cardiology course in present term. The increase in skills of interpretation of ECG is gained primarily by self study. PMID- 23029709 TI - [Lipodystrophy: a new insight into an old disease]. AB - Adipose tissue is now recognized as a highly active metabolic and endocrine organ secreting a range of bioactive peptides with both local and distant action, known as adipokines. Some of these factors are specific fat-related hormones that are involved in regulating energy homeostasis, carbohydrate and lipid metabolism. Adipose tissue disorders may have potential repercussions in the pathophysiology of obesity, insulin resistance, and dyslipidemia. Lipodystrophies are characterized by a selective loss of body fat although the extent of fat loss is different. They may be either inherited or acquired, as well as either generalized or limited to some parts of the body. Females are affected more often than men. If the fat loss is marked, patients develop insulin resistance and its complications, such as diabetes, atherogenic dyslipidemia, hepatic steatosis, and indices of hyperandrogenism. The aim of this article is to discuss the aetiology, clinical manifestations, diagnosis and treatment of different lipodystrophy syndromes with a special emphasis on the most recent literature. PMID- 23029710 TI - [Carbohydrate sweeteners and obesity]. AB - The U.S. prevalence of obesity increases since the mid-70s of the 20th century. Around that time high-fructose corn syrup (HFCS)--mixture of fructose and glucose was introduced as a sweetener replacing sucrose in the food production. HFCS containing 55% fructose and 42-45% glucose (HFCS55) has dominated the American soft drink industry and HFCS has recently become commonly used in Poland. The coincidence of HFCS introduction and obesity epidemic raised widely publicized suspicions of a causal relationship between the two. As a possible mechanism, a higher content of fructose in the HFCS55, as compared with sucrose was suggested fructose is known to increase serum uric acid level, induce hepatic lipogenesis and not stimulate postprandial hyperinsulinemia, a main activator of leptin release. Few comparative studies of HFCS and sucrose have largely failed to reveal any different impacts on the metabolic parameters, yet they were mainly short-term. It has been recently shown that obesity is linked with changes in the intenstinal flora. Among the causes of allegedly different effects of sucrose and HFCS on metabolism, their influence on the gut microbiome has not been examined. Some bacterial types do not hydrolyze sucrose which may determine different compositions of gut flora with the use of both sweeteners. Studies involving quantitative analysis of bacterial DNA in the stool, both in animals and in humans, shall shed light on the issue that has recently so much absorbed the U.S. public opinion. PMID- 23029711 TI - [The past of Druskininkai (part I)]. AB - The development of hydrotherapy in the first half of the XIX century is presented in short. The geographical, climatic and epidemiological situation of Druskininkai, a health resort founded in 1837 has been mentioned. The natural substances: salt springs and therapeutic muds are described sufficiently. The development of the health resort in the XIX and the first half of XX century has been recounted. The physicians Ksawery Wolfgang (?-1864), Ludwik Zembrzycki, Izydor Nahumowicz (1800-1842), Anicety Renier (1804-1877), Kazimierz Choiski (1814-1882), Jan Pilecki (1821-1878), Jozef Markiewicz (1834-1923), Walery Bujakowski (1857-1919) and the others and local rich gentry played an important role in the development of Druskieniki. The physician was undoubtedly the most esteemed person-age of this health resort. Russification of this health resort on the turn of the XIX century is also presented. The role of Marshal J6zef Pitsudski in this development is pointed out. The comparison of the medical indications and contraindications in Druskininkai in the middle of the XIX century and in the thirties of the XX century are presented in more detail. The scale of medical indications was wide. Druskieniki was an important health resort in pre-war Poland. PMID- 23029712 TI - [The past of Druskininikai (part II)]. PMID- 23029713 TI - Antimicrobial resistance in the ICU: a gathering storm. PMID- 23029714 TI - Prevalence of rheumatic fever and rheumatic heart disease in rural population of Himachal--a population based study. AB - PURPOSE OF STUDY: Rheumatic heart disease is still the commonest valvular heart disease in India. There is no population based study regarding the prevalence of rheumatic fever/rheumatic heart disease (RF/RHD) from Himachal and hence the purpose of study. METHODS AND RESULTS: A community based survey for prevalence of RF/RHD was done in four villages of different districts of Himachal. The subjects suspected to have RF/RHD on clinical ground were subjected to echocardiography to confirm the diagnosis. Total 1882 subjects were screened. 909 were male and 973 were female. 11 of these were found to have RF/RHD (5.8/1000). Mean age of these patients was 30.35 +/- 14.17 years. 10 of these were female and one was male. Mitral valve was the commonest to be involved. Seven were known to have RF/ RHD and five were on penicillin prophylaxis. CONCLUSION: RF/RHD is still common in rural population of Himachal. Mitral valve is commonest to be involved and prevalence is much more in female than in male. PMID- 23029715 TI - Study of clinical profile in patients with H1N1 influenza in Surat district, June 2009-March 2010. AB - BACKGROUND: During spring of 2009, pandemic of Influenza A (H1N1) virus emerged and spread globally. We describe the clinical profile of patients who were found H1N1 Positive in Surat district from 27th June 2009 to march 2010. METHODS: Retrospective data of 824 patients from surat districts who were suspected with influenza like illness was collected They were subjected to throat swab testing for H1N1. Out of them 154 were positive for 2009 H1N1 virus with use of real time reverse transcriptase polymerase chain reaction assay. (TAQ MAN real time PCR CDC protocol). Clinical parameters of these 154 patients were analyzed. RESULTS: Out of 824 suspected H1N1, 154 (18.68%) patients were confirmed (positive) for 2009 HIN1. Maximum (70.77%) patients are in age group 14-50 years. Male [86 (55.84%)] were affected more than Females [68 (44.15%)]. 58 (37.66%) had underlying Co Morbid condition. Fever (98.70%) and cough (94.15%) were the most common presenting symptom. Total 41 (26.62 %) patients were put on mechanical ventilator, out of them 17 (41.46%) survived. Total 24 (58.53%) patients were initially put on noninvasive (Bipap) ventilator followed by invasive Mechanical ventilator, while 9 (21.95%) patients were put on only noninvasive (Bipap) ventilator and total 8 patients were put directly on invasive Mechanical ventilator. 154 H1N1 positive patients, who underwent chest x-ray on admission 112 (72%) had findings consistent with pneumonia/ARDS. Most common site is lower zone and simultaneous involvement of both lungs is more common than single lung involvement. Out of the 154 patients, those patients who received oseltamivir within 48 hour of onset of illness all were cured. Patients who expired had received oseltamivir after 48 hrs. Our data suggests that the use of oseltamivir was beneficial in hospitalized patients even up to 72 hrs of onset of symptoms. We observed no significant side effect of oseltamivir 150 mg twice day dose for 5 7 days. We observed two peaks of H1N1 during this period, second peak was less severe than first one. CONCLUSIONS: During evaluation period, 2009 H1N1 influenza caused severe illness requiring hospitalization, including pneumonia and respiratory distress and co-morbid condition. Maximum patients were between age group of 14-50 year. Fever and cough were most common presenting symptoms. Nearly 36.36% patients had one or more underlying medical conditions. Mechanical ventilatory support had role in reduction in mortality. Patients seemed to be benefited from antiviral therapy if started within 72 hour of onset of symptom. There were no significant side effects of Oseltamivir observed in this study. Development of ARDS, requirement of Mechanical ventilation and having co-morbid condition were poor prognostic factors. We observed two peaks of H1N1 during this period second peak was less severe than first one. It may be due to development of immunity, Disease awareness, early diagnosis and treatment and health education. PMID- 23029716 TI - Pentoxifylline in severe alcoholic hepatitis: a prospective, randomised trial. AB - BACKGROUND: Role of corticosteroids in treatment of severe alcoholic hepatitis (SAH) is controversial. Pentoxifylline (PTX), an inhibitor of TNF, has also been shown to decrease short term mortality in SAH. Aim of this study was to evaluate the effect of PTX on short term mortality, renal and hepatic functions in patients with SAH. METHODS: Fifty patients with SAH {Maddrey's Discriminant Function (DF) > or = 32} were prospectively enrolled. Twenty five patients received PTX (400 mg orally, three times a day), and 25 received placebo for 4 weeks. Serum tumor necrosis factor (TNF) was measured in both groups. RESULTS: Baseline characteristics of the two groups were similar. At 4 weeks, mortality in PTX group was lower than that in controls {20% (5/25) versus 40% (10/25) respectively; p = 0.216; RR 0.5; 95% CI 0.19-1.25}. Renal failure was the cause of mortality in 20% (1/5) patients in PTX group, and 70% (7/10) in controls (p = 0.11). Significant reduction in urea, creatinine, DF and TNF was noted in PTX group. Reduction in TNF did not correlate with reduction in creatinine or DF. CONCLUSIONS: In patients with SAH, PTX leads to a significant improvement in renal and hepatic functions, and a trend towards decreased short term mortality. PMID- 23029717 TI - Echocardiographic evaluation of diastolic dysfunction in asymptomatic type 2 diabetes mellitus. AB - INTRODUCTION: Diabetes mellitus is one of the most common diseases in the world and is acquiring epidemic proportions. Its prevalence is growing in both developed and developing countries. Indians are genetically more susceptible to diabetes compared to other races cardiovascular complications are known to be the main cause of morbidity and death in diabetic patients. There is an increased rate of ischemic heart disease and cardiomyopathy which may lead to heart failure (Diastolic heart failure). Left ventricular diastolic dysfunction represents an early stage of heart failure, without any clinical manifestations. In the view of these above facts the present study was done to assess the diastolic dysfunction in diabetic patients. METHODS: A cross-sectional hospital-based study was done which included 50 asymptomatic patients with type 2 diabetes mellitus without evidence of cardiovascular involvement and blood pressure less than 130/80 mmHg were studied. LVDD was evaluated by Doppler echocardiography, which included E/A ratio; left atrial size was assessed in relation with age/sex, duration of diabetes and HbAlc level. RESULTS: Results showed that diastolic dysfunction was present in 32 (64%) of the patients. Diastolic dysfunction was more common among female sex (68.18%) compared to male (60.17%). Diastolic dysfunction was significantly associated with uncontrolled diabetes as assessed by HbA1c levels. Diastolic dysfunction was more common in patients who were on treatment with both oral hypoglycemic agents and insulin. The prevalence of diastolic dysfunction increased with longer duration of diabetes. There was a linear progression of diastolic dysfunction with the increase age group. CONCLUSION: The findings in our study indicate that myocardial damage in patients with diabetes affects diastolic dysfunction before systolic function. E/A ratio and Left atrial size are significantly altered in diabetic patients with diastolic dysfunction. Diastolic dysfunction is significantly associated with duration of disease, glycemic levels and the type of treatments. Doppler Echocardiography is a simple non invasive valuable tool in diagnosing diastolic dysfunction. In diabetics before they develop cardiac symptoms it has to be done routinely on every diabetic patients to assess the cardiac function. PMID- 23029718 TI - Changing antimicrobial resistance pattern of isolates from an ICU over a 2 year period. AB - OBJECTIVE: To study the changing patterns of antimicrobial resistance in gram negative bacilli esp. E. coli, Klebsiella Pneumoniae, Pseudomonas and Staphylococcus aureus isolates from a 37 bedded ICU of a private hospital. METHODS: All isolates obtained from a wide range of clinical samples (e.g.: urine, pus, blood, sputum, BAL, tracheal secretions) from ICU patients were evaluated for sensitivity patterns by Kirby-Bauer disc diffusion method. RESULTS: In the 2 year study period the rise in the number of gram negative isolates was proportionally high along with increase in their resistance pattern. Dramatic rise in ESBL's has led to multidrug resistant E. coli and Klebsiella pneumoniae. Also organisms like Acinetobacter spp. and Pseudomonas aeruginosa are multiresistant making optimal therapy selection difficult. The incidence of ESBL's has increased from 30-75% of the total isolates. The sensitivity of Pseudomonas aeruginosa to Meropenem has decreased from 90% to 60%.The antibiotic that remained most active against all gram negative organisms for 2 years was Imepenem, Piperacillin-Tazobactum and Amikacin. The positive result from this study was decrease in the number of S. aureus isolates from 25% in 2008 to 12% in 2009. The reason for this achievement was implementation of good and strict infection control practices. CONCLUSION: 1) Antibiotic resistance continues to rise among hospital acquired gram negative pathogens and complicates empirical selection of antibiotics in the ICU. 2) Klebsiella pneumoniae and Pseudomonas are still the dominant organisms in the ICU. 3) Imepenem, Piperacillin-Tazobactum and Amikacin are still highly active against Enterobacteriacea. 4) Local data and strict infection control practices can only control the spread of virulent and resistant organisms. PMID- 23029719 TI - Study of 63 cases of methyl alcohol poisoning (hooch tragedy in Ahmedabad). AB - BACKGROUND: Many outbreaks of methyl alcohol poisoning have been reported from India. Early and aggressive management with bicarbonate, ethanol and hemodialysis in patients having significant toxicity will decrease mortality and improve patient's outcome. Our experience of retro bulbar steroid injection indicates that it may improve visual outcome. MATERIALS AND METHODS: Hospital based study of patients admitted to V.S. Hospital during the outbreak of methanol poisoning in Ahmedabad. Patients were identified by history supplemented by ophthalmic examination and biochemistry. A stepwise treatment was undertaken i.e. aggressive treatment with bicarbonate, ethanol and institution of hemodialysis in patients who had refractory high anion gap metabolic acidosis, visual signs and symptoms, deteriorating vital signs and serum methanol level > 50 mg/dL. Patients who were having optic neuritis were given retrobulbar steroids. RESULTS: Total 63 males were admitted between 18 to 60 years. 17 patients were terminally ill with hypotension, could not be subjected for hemodialysis and expired. Of remaining 46 patients, 20 responded to conservative management whereas 26 underwent hemodialysis of which only 3 died. CONCLUSION: Patients undergoing hemodialysis showed immediate improvement in their clinical and biochemical parameters with rapid reductions of methyl alcohol levels below the toxic range with subsequent reduction in morbidity and mortality. All the patients given retrobulbar corticosteroid injection showed improvement in fundoscopic examination and perimetric charting with maximal improvement in visual acuity in hemodialysed patients. PMID- 23029720 TI - Advances in small bowel imaging--capsule endoscopy. AB - The small bowel has been a difficult area to examine due to its anatomy, location and relative tortuosity. Capsule technology has revolutionized the imaging of small bowel. Capsule endoscopy has been recommended as the 3rd diagnostic test for patients with obscure bleeding after a normal endoscopic evaluation of the upper and lower gastrointestinal tract. Many studies have established its role in other clinical situations, such as detection of small bowel lesions in Crohn's disease, non steroidal anti-inflammatory drug enteropathies, celiac disease, small bowel polyposis syndromes and small bowel tumors. Capsule endoscopy of the oesophagus is recommended as an alternative to oesophagogastroduodenoscopy for screening Barrett's oesophagus, esophageal varices and of the colon for colorectal cancer. PMID- 23029721 TI - Can India be the wing commander in the global fight against antimicrobial resistance? PMID- 23029722 TI - The adventure of two dentures. PMID- 23029723 TI - INH induced lichenoid eruptions. PMID- 23029724 TI - Methotrexate-induced liver cirrhosis in a patient of psoriasis. AB - Methotrexate has been used for many years to treat refractory psoriasis. A case of methotrexate induced cirrhosis is being presented to emphasize the importance of strict adherence to published criteria for patient selection, monitoring of cumulative drug dosages, and the performance of serial liver biopsies. PMID- 23029725 TI - Hashimoto's encephalopathy. AB - Hashimoto's encephalopathy (HE) is a completely treatable but relapsing neuroendocrine disorder associated with Hashimoto's thyroiditis (HT). Though numerous neurological manifestations are often associated with thyroid disorder, this entity is less documented. We are reporting a case of HE in a 65 year old female presenting with sudden onset deep coma following an attack of mild fever and vomiting for two days. Patient was a known diabetic. Hypoglycemic coma, diabetic ketacidosis and hyperosmolar coma were excluded by laboratory investigations. High blood sugar was corrected with insulin. She had hyponatremia and hypokalemia which were corrected with electrolyte replacement. Liver function tests were normal, but serum ammonia was mildly raised. CSF study was normal. Despite correction of her metabolic derangements patient failed to regain her consciousness. CT scan of brain was normal. MRI of brain revealed diffuse brain atrophy. Patient's thyroid function tests were normal but anti-thyroid peroxidase (anti-TPO) antibody was highly raised. EEG showed diffuse slow wave pattern. Intravenous dexamethasone (24 mg/d) was started. Patient regained consciousness slowly over a period of one month. To reduce the toxicity of steroid, oral azathiprine 50 mg/day was added later with tapering of steroid dose. HE must be kept in mind in comatose patients when other metabolic, infective and structural neurological causes have been excluded. Proper and timely treatment can salvage the patient. PMID- 23029726 TI - Pulmonary lymphangioleiomyomatosis--a silent killer? AB - Pulmonary lymphangioleiomyomatosis (LAM) is a rare disorder presenting with remarkable features like recurrent pneumothorax or chylothorax, usually in young women. We report a case of sporadic LAM who presented with nothing but recent onset exertional dyspnoea and it was this unobtrusive presentation that led to delay in diagnosis. PMID- 23029727 TI - Wernicke's encephalopathy with visual loss in a patient with hyperemesis gravidarum. AB - OBJECTIVE: We describe a case of Wernicke's encephalopathy associated with visual loss that was caused by hyperemesis gravidarum. METHODS: A 25 year old lady in her 20th week of her pregnancy consulted us. She had history of nausea and vomiting for 3 months with resultant weight loss. She now presented with sub acute onset of visual loss in both her eyes, and gait disturbance with unsteadiness. Upon ophthalmologic examination she was found to have a visual acuity of 6/60 in both eyes; abduction restriction, nystagmus and retinal hemorrhages and macular oedema in both eyes. She also had truncal, stance and gait ataxia. RESULTS: She was treated with parenteral thiamine and her visual loss reversed and her ataxia improved dramatically. Magnetic resonance imaging (MRI) brain with diffusion weighted imaging showed findings consistent with Wernicke's Encephalopathy. CONCLUSION: Wernicke's Encephalopathy can occur in many hitherto under-recognised clinical scenarios associated with inadequate oral intake like hyperemesis gravidarum, after gastric bypass surgeries and those on total parenteral nutrition. Visual loss is increasingly being recognized as the additional, reversible feature of Wernicke's Encephalopathy. The changes that occur on MRI brain, especially on the diffusion weighted images, are characteristic and considered diagnostic of Wernicke's Encephalopathy. PMID- 23029728 TI - Isolated non-compacted right ventricular myocardium. AB - Ventricular non-compaction or spongy myocardium is a rare type of cardiomyopathy resulting from arrested myocardial development during embryogenesis. This rare entity is characterized by excessive prominent trabeculations and deep inter trabecular recesses in the ventricular wall. The clinical manifestations include heart failure, arrhythmias and cardioembolic events. The usual site of involvement is the left ventricle. Rarely the right ventricle (RV) is affected. Here we report a case of 40 year old male patient presenting with isolated RV non compaction. PMID- 23029729 TI - Primary cryptococcal prostatitis--rare occurrence. AB - Cryptococcosis is a well recognized infection in immunocompromised patients. Cryptococcal infection primarily involves the lung and is hematogeneously spread to other organs. Sometimes it might affect the genitourinary tract. The prostate gland is a rare site of primary infection due to cryptococcus neoformans. We report a case of granulomatous inflammation in the prostate as a result of crypyococcus neoformans infection in a 70 year old immunocompetent patient, a non diabetic, which was diagnosed by transrectal ultrasound guided biopsy. PMID- 23029730 TI - CARASIL. AB - We herewith report a case of 46 year old male with clinical features suggestive of CARASIL (Cerebral Autosomal Recessive Arteriopathy with Sub cortical Infarcts and Leucoencephalopathy). He had recurrent strokes in early age before reaching 35 years. He was normotensive and had severe degenerative changes in lumbar spine and knee joint on radiographs and had diffuse alopecia. Neuroimaging revealed diffuse hyperintense lesions in cerebral white matter and basal ganglia on MR images. PMID- 23029731 TI - Carlos Juan Finlay (1833-1915). PMID- 23029732 TI - Reversible atrioventricular block in thyroid storm. PMID- 23029733 TI - Hypomagnesemia--an under recognized metabolic disorder. PMID- 23029734 TI - Antibiotic resistance: need for rationale use. PMID- 23029735 TI - Hospital accreditation: a certificate of proficiency for healthcare institutions. PMID- 23029736 TI - Antibiotic use in the intensive care unit. AB - On a background of a number of antibiotics in hand and no governing laws for their rational use, we have attempted to get a snapshot of the current trends of use of antibiotics in critically ill patients with infection as a primary cause, in our hospital. This was a prospective observational study carried over a period of 1 year. Critical cases arising from Infection as a primary cause were selected. Demographic data, parameters to mark severity and corresponding list of Empiric, response related and culture driven changed antibiotics were noted. Data of 50 patients, with a mean age of 62.2 years were analyzed. In the 64% community and 34% hospital-acquired infections, Lung was the major source of infection. Mean APACHE score of the group was 18. There were 37 survivals and 13 deaths in the group. There is a trend of using Piperacillin Tazobactum and Third Generation Cephalosporins as Empiric antimicrobials. Fluoroquinolones are also found to be used frequently. The frequency of third generation cephalosporins drops in the response related changes and the dependence on Carbapenems significantly rises. The major finding here is that colistin sensitivity is frequently being indicated in Culture reports. This has resulted in significant increase in its use post culture reports The total cost incurred on antimicrobial agents in the entire group was Rs 14,55,160/-Thus the approximate amount of expenditure on microbials alone to save one life in our Intensive Care Unit was (1455160/37) Rs 39328/ Further study conducted for a longer time with a larger data size needs to be done to perform a multivariate analysis of Severity of Illness, Generation of Antimicrobial as empiric therapy and Outcome A significant variation in the costs of the various brands of the same molecule is noted. A vigilant approach to reduce unnecessary costs while treating critical patients is necessary. PMID- 23029737 TI - Study of prescribing pattern of antimicrobial agents in medicine intensive care unit of a teaching hospital in Central India. AB - OBJECTIVES: Intensive care unit (ICU) is a setting where large numbers of drugs are administered to patients and where the cost of hospitalization and drug treatment are high. The primary objective was to evaluate the current usage of anti-microbial agents in the Medical Intensive Care Unit (MICU) of a teaching hospital in central India. METHODS: The study was a prospective study for a period of six months from May 2010 - December 2010. Prescription and patient records are reviewed and analyzed. Rationality of drug usage was also evaluated by analyzing the drug prescriptions. RESULTS: In intensive care unit cefotaxime was the most commonly used AMA by 32 % patients, followed by metronidazole 24% patients and ampicillin by 17.29% patients. 77% patients were given 1-3 AMAs, 23% patients were given 4 - 8 AMAs. Most common indication for the antimicrobial therapy was infection. According to evaluation use of antimicrobial therapy was rational in only 30% patients. Average numbers of drugs per patients were 7.5 drugs. CONCLUSION: interventional programme should focus on infection control with rational antibiotic prescription aimed at minimizing unnecessary cost, adverse drug reaction and emergence of bacterial resistance. PMID- 23029738 TI - Right ventricular function in isolated occlusion of left anterior descending coronary artery. AB - BACKGROUND: Previous studies in this field have not excluded right coronary artery disease by coronary angiography and have included patients with co-morbid conditions that have independent impact on right ventricular function. METHODS: 14 patients with left ventricular (LV) anterior myocardial infarction (MI) due to isolated occlusion of left anterior descending coronary artery (LAD) on coronary angiography were studied. 14 normal persons matched for age, body mass index (BMI), pulse rate, systolic and diastolic blood pressure (SBP and DBP) were evaluated as controls. All conditions that could independently affect right ventricular (RV) function were strictly excluded. Detailed 2-Dimensional (2-D), M mode, pulse wave Doppler and tissue Doppler evaluation (DTI) of LV and RV was performed. RESULTS: Patients of LV anterior MI due to isolated occlusion of LAD had impairment of diastolic DTI parameters in all segments of RV. Impairment of systolic DTI parameters was seen only along Tricuspid annulus, lateral and anterior wall of RV. There was significant linear correlation between systolic and diastolic function parameters of the two ventricles. CONCLUSION: Presence of common myocardial fibers encircling the two ventricles (Myofibril interaction) can explain these observations. More research is needed to find exact explanation of observed findings. PMID- 23029739 TI - Secondary prevention therapies for coronary heart disease in patients with type 2 diabetes: an audit. AB - BACKGROUND: Use of evidence based pharmacotherapy reduces risk of secondary events in patients with established coronary heart disease (CHD). To determine frequency of their use in diabetic CHD we performed prescription audits. METHODS: Frequency of prescriptions of aspirin, beta-blockers, angiotensin converting enzymes inhibitors (ACEI) or angiotensin receptor blockers (ARB), lipid-lowering medicines, and other drugs in CHD patients at primary, secondary and tertiary levels of care in out-patients' departments in Rajasthan was determined. Patients' and physicians' demographic details and prescribing patterns were obtained. Descriptive statistics are reported. RESULTS: We audited prescriptions of 2290 CHD patients aged 60.9 +/- 8.7 years. There were 1033 patients of CHD with diabetes (45.1%, age 61.9 +/- 8.6) and 1257 without (54.9%, age 59.9 +/- 8.9). In CHD patients with diabetes vs. without, use of beta blockers was lower (59.4 vs 69.2%) while ACEI/ARB (86.5 vs 82.1%) and statins (67.1 vs 59.7%) greater. Use of other drugs such as aspirin (88.7 vs 88.3%), fibrates (11.9 vs 11.1%), non-dihydropyridine CCB (16.0 vs 17.9%) and nitrates (38.8 vs 14.5%) was similar. Use of beta blockers was lowest among diabetologists (37.6%) as compared to other physicians (64.4%) and cardiologists (59.4%) and was the lowest in primary care. CONCLUSIONS: Low use of beta-blockers is observed in diabetic CHD patients. PMID- 23029740 TI - Status of thyroid function in Indian adults: two decades after universal salt iodization. AB - OBJECTIVES: The aim was to find impact of two decades of universal salt iodization on the prevalence of goiter, thyroid autoimmunity and thyroid dysfunction in Indian adults. METHODS: This was a cross sectional study from Delhi, India. The subject population included 4409 adult members of resident welfare associations of 5 residential colonies, from 18-90 years of age, who participated in general health check-up camps. The subjects underwent a detailed evaluation including history, anthropometry, goiter grading, USG thyroid, thyroid auto-antibodies and thyroid function tests. All these subjects were regularly consuming iodized salt. RESULTS: Overall, 9.6% of subjects had clinical goiter (13.3% women and 3.3% in men). Prevalence of nodules on palpation was found to be in 1.6% which was lower in men. The nodule prevalence increased to 4.6% in men and 5.6% in women on ultrasonography. Thyroid hypoechogenicity was seen in 30.6% of subjects with severe hypoechogenicity higher in women (5.7% men and 15.5% women). TPO antibody was positive in 13.3% adults and it showed a positive correlation with age, female sex and hypothyroidism. Subclinical hypothyroidism was the commonest abnormality encountered and affected 19.3% subjects (15.9% men; 21.4% women). Thyroid dysfunction showed a rising trend with age in both genders. CONCLUSIONS: Normal UIE and low goiter prevalence, especially in males, suggest success of the universal salt iodization program in the region under review. High prevalence of subclinical hypothyroidism was not correlated with either thyroid autoimmunity or iodine intake, as reflected in urinary iodine excretion. PMID- 23029741 TI - Corticosteroids in rheumatology: use, misuse or plain abuse? PMID- 23029742 TI - Allergic bronchopulmonary aspergillosis--a clinical review. AB - Allergic Bronchopulmonary Aspergillosis (ABPA) was first described by Hinson and colleagues in 1952. ABPA is a hypersensitivity disorder induced by a fungus Aspergillus and affects non-immunocompromised patients. The diagnosis is based on the presence of a combination of clinical, biological and radiological criteria. The treatment is based on oral corticosteroids for 6-8 weeks at acute phase or exacerbation and Itraconazole is now recommended and validated at a dose of 200 mg/day for 16 weeks. PMID- 23029743 TI - Compensation guidelines for research related injury in India. PMID- 23029744 TI - Carcinoma of bronchus presenting as hydropneumothorax. PMID- 23029745 TI - Kartagener's syndrome with right bundle branch block and polydactyly. PMID- 23029746 TI - Evan's syndrome revisited. AB - A female aged 43 years presented with acute per vaginal bleeding since six days, severe thrombocytopenia and anaemia, she responded partially to platelets and blood transfusion initially. Four days later she started bleeding from nose, intravenous access sites, developed right sided hemiparesis and subsequently died. Her investigations were suggestive of Idiopathic Thrombocytopenia Purpura (ITP) and Autoimmune Haemolytic Anaemia (AIHA). So a diagnosis of Evan's syndrome was made. PMID- 23029747 TI - Case of Cronkhite Canada syndrome shows improvement with enteral supplements. AB - Cronkhite-Canada syndrome (CCS) is a rare nonfamilial syndrome characterized by marked epithelial disturbances in the GI tract and epidermis. Cronkhite and Canada described the first 2 cases in 1955. Since then only about 450 cases have been reported worldwide. Here we report a 33 year old Indian male admitted with history of loose stools and abdominal pain, loose stools associated with weight loss, generalized weakness, significant amount of hair loss as well as hyperpigmentation of his palms and soles. On subsequent days of the stay in the hospital he developed hypogeusia and showed onychodystrophy. Endoscopy of Upper GI and Lower GI tract revealed severe gastroduodenitis with polyp in duodenum and multiple polyps whole throughout the colon respectively. Biopsy report showed eosinophilic gastritis and hamartomatous polyps in colon as well as in duodenum. He was started on high protein supplement, proton pump inhibitors and zinc vitamin supplement and he showed a complete recovery in symptoms within 5 months of initiation of treatment. Hence, early diagnosis and initiation of appropriate treatment helped the patient to improve in symptoms from such a rare disease. PMID- 23029748 TI - Remitting seronegative symmetrical synovitis with pitting edema (RS3PE); a rare association with phyllodes tumour of breast. AB - Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare entity mainly found in elderly males. It is characterized by pitting edema mainly of dorsum of both hands giving a "boxing glove hand" appearance; rarely involving feet also, acute in onset, negative rheumatoid factor and a good response to low dose corticosteroid therapy. Clinically it almost resembles a case of polymyalgia rheumatica, late onset rheumatoid arthritis or other seronegative spondyloarthropathy.Though there are multiple underlying factors causing this rare entity but it has very close associations with many malignancies.So far its association with solid tumours and hematological malignancies has been reported. Phyllodes tumour of breast shows wide spectrum of activity from a benign condition to a locally aggressive and sometimes metastatic tumour.One fourth of the cases recur after definitive treatment.Our case represent an unusual association with recurrent phyllodes tumour of breast with RS3PE. PMID- 23029749 TI - Actinomycosis and nocardiosis co-infection in chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is an inherited disease of the phagocyte NADPH oxidase system that causes defective production of toxic oxygen metabolites, leading to impaired bacterial and fungal killing, and recurrent life threatening infections; mostly by catalase producing organisms. Nocardiosis in CGD is well described, however actinomycosis is rare. We describe a patient of CGD with actinomycosis and nocardiosis coinfection. A 43-year-old male with history of recurrent discharging sinuses presented with fever, dyspnea and cough. He had multiple discharging sinuses over neck and anterior chest wall. There was only partial response to intravenous penicillin. Needle aspirate from chest wall showed co-infection with actinomyces and nocardia. His nitroblue tetrazolium (NBT) reduction test was negative. He was treated with penicillin, amikacin and trimethoprim-sulfamethoxazole and had good clinical and radiological response. PMID- 23029751 TI - Type 2 lepra reaction as a cause of pyrexia of unknown origin. AB - Leprosy, a commonly encountered disease, can rarely present as a reactional state de novo with fever as the main presenting feature. Here we describe an uncommon presentation of leprosy [with type 2 lepra reaction] as pyrexia of unknown origin with prominent rheumatologic manifestations [acute polyarthritis], renal involvement and generalized lymphadenopathy with rare presentation of type 2 lepra reaction without the classic skin lesions of erythema nodosum leprosum, occurring in a treatment naive patient without prior history of leprosy. PMID- 23029750 TI - Post chikungunya brain stem encephalitis. AB - Chikungunya is an arthropod born acute febrile arbo viral illness characterized by acute severe polyarthralgia. During last few years there has been scattered out breaks with associated neurological complications in India. Here we report a case of post chikungunya reversible demyelinating encephalitis who presented with vertigo, dysarthria and ataxia. There was complete clinical as well as radiological improvement with steroids. PMID- 23029752 TI - Peripartum cardiomyopathy in an elderly patient with in-vitro fertilization pregnancy. AB - Peripartum cardiomyopathy as a diagnosis needs to be considered in antenatal and immediate postpartum women with clinical features of cardiac failure. As more and more women at increasing age go for assisted reproduction, screening for risk factors needs to be done. Treatment involves coordination between cardiologist and obstetrician as both the patient's cardiac status and well being of the baby needs to be considered. In this case report we present an elderly Primigravida, conceived with in-vitro fertilization (donor oocytes) who developed unexplained cardiac failure post LSCS. PMID- 23029753 TI - Pantothenate - kinase associated neurodegeneration. AB - Neurodegeneration with brain iron accumulation is a group of disorders, the commonest of which is PKAN (Pantothenate kinase associated neurodegeneration). We present here, a case of 18 year old boy with progressive dementia, pyramidal and extrapyramidal involvement, dysarthria, seizures and myoclonus. The patient was diagnosed as PKAN (formerly Hallervorden Spatz disease) after "eye of tiger" appearance on neuro-imaging. PMID- 23029754 TI - Primary clear cell carcinoma of lung presented with generalized lymphadenopathy mimicking lymphoma. AB - Primary Clear cell carcinoma of lung with distant metastasis is a rare tumour. Here is a case of 45 year old male presented with gradual onset dyspnoea, low grade fever and weight loss. Radiologically patient had hilar and parahilar lesion at posterior mediastinum with mild changes of chronic obstructive pulmonary disease with right supraclavicular, peripancreatic and celiac axis lymph nodes enlargement. Fine needle aspiration from lymph node followed by excision biopsy was done. For further localization Fibre optic Bronchoscopy was done which is followed by bronchial wash cytology and transbronchial needle aspiration and bronchial biopsy. Correlating all above diagnostic modalities diagnosis of metastatic clear cell adenocarcinoma of lung was made which is further supported by Immunohistochemistry. PMID- 23029755 TI - Medical philately: Selman Waksman and streptomycin. PMID- 23029756 TI - Growth hormone therapy in Turner's syndrome: what is the gain? PMID- 23029757 TI - The levels of oxidants and antioxidants status in chronic obstructive pulmonary diseases (COPD) with relation to oral vitamin E supplementation. PMID- 23029758 TI - Teaching with technology: a clinical instructor's journey. PMID- 23029760 TI - Health literacy. PMID- 23029759 TI - Put your money where your scores are HCAHPS and VBP. PMID- 23029761 TI - Interesting times: leave it to Leah to pose a different perspective. PMID- 23029762 TI - Mastery learning in nursing education. PMID- 23029763 TI - The Kit: Identifying and reducing the problem of MRSA. PMID- 23029764 TI - Have you ever had a terminal degree? AB - In closing, I thought I had a terminal degree when I proudly wrote MS after my name. Soon this APN will write DNP after her name! I will have my terminal degree. On second thought, in nursing, do we ever stop learning whether or not we earn more initials to write after our names? PMID- 23029765 TI - Preventing medication errors: acronyms as strategies. PMID- 23029767 TI - All children to receive flu vaccination. PMID- 23029766 TI - Courage and commitment: a mantra for the new school year. PMID- 23029768 TI - Research will give insight into child abuse fatalities and lead to greater child protection. PMID- 23029769 TI - Local health visitors campaign against nappy sack danger. PMID- 23029770 TI - "It takes a lot of courage". Children and young people's experiences of complaints procedures. PMID- 23029771 TI - Both seen and heard. PMID- 23029772 TI - Health visiting celebrating 150 years of public health. PMID- 23029773 TI - Embedding an electronic health record within a health visiting service. AB - County Durham and Darlington's implementation of an electronic health record across community health services provided an ideal opportunity for health visitors to take the lead in enhancing the system to reflect their paper clinical record. Practitioners' concerns, fears and anxieties in relation to confidentiality and professional accountability resulted in the project being further developed to include the employment of three full-time clinical IT facilitators. These were experienced health visitors and 'IT champions' with a sound knowledge of information governance with a specific remit to provide clinical support and supervision to health visitors in electronic clinical record keeping. These practitioners were instrumental in developing the system and proved the key to the project's success and ensuring that the electronic record was embedded into health visiting practice to improve the quality of patient care. PMID- 23029774 TI - Returning to health visiting practice: completing the circle. AB - One strategic health authority, NHS London, initiated a pilot return to health visiting/nursing practice scheme in London in 2010. This paper reports on the experiences of the first three cohorts of returnees on the City University London programme, one of the London programmes, and the adaptations that have been made to the programme to help provide returnees with the theory base and practice experience to equip them to work in today's health visiting. Written evaluation forms were completed by the returnees and information gathered from their application forms. This information was supplemented for Cohort 1 with some interviews with practice teachers and lecturers and a mid-stage questionnaire to the returnees. Of the 54 students in the three cohorts over half were still on one or both Nursing and Midwifery Council registers, which had not been anticipated at the start of the programme and led to modifications to the programme after Cohort 1 with an increase in the health visiting specific content. The returnees had a wide range of experience to bring back to health visiting reflecting the fact that a large number had been out of health visiting for more than 11 years. The evaluation shows that providing support by the university to the practice placement areas; ensuring that the taught element is current and useful to health visiting practice and having a relevant but not too onerous assessment process are critical. PMID- 23029775 TI - Breastfeeding knowledge and education needs of early childhood centre staff. AB - This survey investigated the breastfeeding knowledge, attitudes beliefs and education needs of supervisors and staff at 32 early childhood centres in New Zealand. This study explored numbers of mothers who breastfed at or supplied expressed breastmilk to the centres, and how breastfeeding education might enhance an increase in breastfeeding rates and child nutrition. Statistical analysis and open-ended questions revealed a positive attitude towards breastfeeding among staff. All centres recognised a need for breastfeeding education sessions and greater support for breastfeeding mothers. With increasing numbers of children attending early childhood centres, understanding the importance of and implementing support for mothers to continue to breastfeed is crucial. PMID- 23029777 TI - FNP in the USA. PMID- 23029776 TI - Building community by supporting mothers: new approaches to perinatal care. PMID- 23029778 TI - Focus on National Eczema Week 2012: recognising and managing childhood eczema. PMID- 23029779 TI - Independent Pay Review Body be next year.... PMID- 23029780 TI - Alert from family and friends--you are not alone! PMID- 23029781 TI - Mini dental implants: a retrospective analysis of 5640 implants placed over a 12 year period. AB - Mini dental implants are becoming increasingly popular in dental care today. Because of their smaller size they are often used in cases of limited bone anatomy. Mini dental implants have diameters ranging from 1.8 mm to 3 mm and are suitable for long-term use. This article describes a retrospective analysis of 5640 mini dental implants placed into 1260 patients over a 12-year period. The mean length of follow-up was 3.5 years. The implants placed supported removable (2319) and fixed prostheses (3321), with placement in the maxilla (3134) and mandible (2506). The overall implant survival was 92.1%. Failures of implants (445) were attributed to mobility of the implant; the mean time to failure for these implants was 14.4 months. The small size of these implants has led to the development of techniques that enable placement and use in a short amount of time for both the doctor and patient. The high rates of success show that mini dental implants are suitable for use in supporting fixed and removable prosthetics. PMID- 23029782 TI - Nursing practice in New Zealand. PMID- 23029783 TI - Preparing registered nurses depends on "us and us and all of us". AB - The primary goal of undergraduate nursing education is the preparation of graduates able to function as competent beginning clinicians. Avariety of academic-service partnerships are being used to support the clinical preparation of undergraduate nurses but, in today's demanding and fiscally challenged health and education environments, debate continues about how bestto provide students with quality learning in the clinical setting. This article reports the qualitative findings of a collaborative study undertaken to monitor implementation of a new model of clinical education for undergraduate nursing students. Three partners: a District Health Board (DHB) and two universities have developed, and are refining, a clinical education model based on the inclusion of student nurses in team nursing. In response to the question "How well is the student integration model working?" the qualitative findings, from a DHB and university staff perspective, suggest that students are better integrated within the nursing team. Registered nurses from academic and clinical backgrounds are sharing reponsibility for students' learning but there is a clear need to further develop relationships, skills and processes in order to maximise the student development. The survey results, which include the student perspective, have and are being reported separately. PMID- 23029784 TI - Perceptions of policy and political leadership in nursing in New Zealand. AB - This qualitative study was focused on the landscape of nursing policy and political leadership in New Zealand. A volunteer sample (N = 18) of nurse leaders (Fellows of the College of Nurses Aotearoa (NZ) Inc) drawn from across the country was interviewed with respect to issues that affect their interest in participating in political action and policy work. The framework of stages of nursing's political development published by Cohen and colleagues (1996) was used as an interview guide. Respondents were asked to describe their own stage of political development, their perception of the political development of New Zealand nurses and nursing organisations at large, and also their thoughts on what could be done to better position nursing in healthcare policy development. In general, respondents agreed that the major nursing organisations in New Zealand (the College of Nurses-- Aotearoa and New Zealand Nurses Organisation [NZNO]) were moving toward increasing policy sophistication. Qualitative content analysis suggested five themes which, taken together, describe nursing's policy/political development in New Zealand: languaging; succession/legacy planning; Tall Poppies and Queen Bees; "it's a small country"; and speaking with one voice. Although limited by sample size, the information collected provides a beginning focus for discussion that can steer New Zealand nursing activities toward the wider involvement of nurse leaders in healthcare policy work on behalf of the discipline. PMID- 23029785 TI - The impact of postgraduate education on registered nurses working in acute care. AB - Since 2007, Health Workforce New Zealand has provided District Health Boards (DHBs) with funding to support nurses undertaking postgraduate education. As a result, a significant number of nurses, many working in general medical and surgical wards, have now completed a postgraduate qualification. Anecdotal evidence for one DHB indicated that there were mixed views with respect to how the increase in the number of nurses with postgraduate education had impacted on patient outcomes. Following a review of relevant literature the researchers aimed to ascertain from registered nurses working in acute medical and surgical wards their perception of the impact that further study had on their practice. A quantitative descriptive study was undertaken to answer the question of what impact postgraduate study had on the practice of those nurses working in medical and surgical wards of a District Health Board hospital? An anonymous postal survey was sent to registered nurses (N = 57), and senior nurses (N=25) working in acute medical and surgical areas of practice. The latter group consisted of 16 nurse managers and 9 nurse educators. The results showed that registered nurses, nurse managers and nurse educators all perceived the clinical practice of registered nurses as having improved in some degree as a consequence of postgraduate education. There is also a need for further research to be undertaken in other District Health Boards, especially in non-hospital based areas such as primary health care; and also to investigate ways of linking post graduate education with career pathways, as well as identifying and minimising potential barriers likely to prevent application of post graduate learning in the workplace. PMID- 23029786 TI - Celebrating our differences to make nursing stronger. PMID- 23029787 TI - Advocating for the silent. PMID- 23029788 TI - ENs are highly valued. PMID- 23029789 TI - Patient falls all too common. PMID- 23029790 TI - TPPA is good for NZ--yeah, right! PMID- 23029791 TI - Women most at risk of violence from their male partner. PMID- 23029792 TI - Health sector attitudes to lesbian families. PMID- 23029793 TI - Midwife brings her whole-of-life experience to give the best care. PMID- 23029794 TI - The PhD research journey is not for the faint-hearted. PMID- 23029795 TI - Metabolism and excretion: eliminating drugs from the body. PMID- 23029796 TI - Paracetamol use in children--highlighting the risks. PMID- 23029797 TI - Setting up a nurse-run pessary clinic. PMID- 23029798 TI - Surveying the needs of older nurses. PMID- 23029799 TI - Reaching accord on student issues. PMID- 23029800 TI - Improving screening rates. PMID- 23029801 TI - Nurse colposcopy standards. PMID- 23029802 TI - New women's health nurse practitioner. PMID- 23029803 TI - Have you had your Tdap? PMID- 23029804 TI - Emailing X-rays: is it legal? PMID- 23029805 TI - ADA Board discusses 2013 budget, ADA Governance. PMID- 23029806 TI - How to answer an illegal interview question. PMID- 23029807 TI - Refusing a patient's phone calls. PMID- 23029809 TI - Management, leadership and teamwork: three suggestions. PMID- 23029810 TI - The two greatest threats to dentistry. PMID- 23029808 TI - Navigating medical plan coverage for dental services. PMID- 23029811 TI - Grass roots advocacy: how lobbying really gets done. PMID- 23029812 TI - A day in the life of a lobbyist. PMID- 23029813 TI - What happened at the Capitol during 2011-2012. PMID- 23029814 TI - Healthy kids dental expansion is coming: are you ready? PMID- 23029815 TI - Here's how successful legislative advocacy happens! PMID- 23029816 TI - Health care reform--revisited. PMID- 23029817 TI - Amlodipine- induced gingival overgrowth: a case report. AB - Drug-induced gingival overgrowth occurs in genetically susceptibIe individuals as a side effect of various drugs. There is a gross disfiguring enlargement of gingiva mostly in the anterior region leading to difficulty in mastication, speech and maintenance of oral hygiene. In this case report, amlodipine-induced gingival enlargement and its management are discussed. Drug substituion, appropriate non-surgical and surgical treatment along with excellent plaque control lead to the regression and prevention of recurrence of drug-induced gingival overgrowth. PMID- 23029818 TI - Reducing barriers for migratory agricultural workers to receive oral health care services. AB - Between one and two million migratory agricultural workers leave their homes each year to plant, cultivate, harvest and pack fruits, vegetables and nuts in the United States. While in the United States, most lack dental insurance and have no regular dentist. The primary purpose of this study was to describe issues associated with barriers to access and receiving oral health care from the perspective of migratory agricultural workers rather than the perspective of providers. Views and experiences regarding their use of oral health care services were collected from focus groups. Information from focus groups was used to design a questionnaire. Among the 157 respondents the most significant barriers hampering access to oral health care services were crop demands, travel distance, and transportation. Cost and the lack of an interpreter were ranked as the top two barriers to receiving oral health care. The most convenient times for respondents to visit a dentist were between 1 and 6 p.m. The most convenient day was Monday, followed by Sunday and Saturday. PMID- 23029819 TI - UDM school of dentistry: a year of success in a national presence. PMID- 23029820 TI - U-M School of Dentistry: synergy in action. PMID- 23029821 TI - Palliative care: an unmet need in the Indian scenario. PMID- 23029822 TI - Adverse events following immunisation with SA 14-14-2 Japanese encephalitis vaccine in children of Kolar in Karnataka. AB - Around 30 million children of 1 to 15 years have received the live attenuated SA 14-14-2 Japanese encephalitis (JE) vaccine in the campaign against JE in India from 2006 to 2007. This study aims to assess the short-term adverse events following JE vaccination as there is limited data on it in Indian children. A longitudinal study of children vaccinated in the campaign against JE in Kolar, in 2007 was undertaken. In July to August 2007, following the JE vaccination campaign in Kolar, 1640 children of 10 to 15 years were followed for four weeks. Events such as fever, pain at the injection site, cough, headache and nausea or vomiting were recorded. Surveillance was maintained on the referral hospitals for hospitalisation due to encephalitis and anaphylaxis following vaccination. The incidence of adverse events is summarised as frequencies and percentages with 95% confidence interval (CI). The analysis was performed using statistical package for social sciences (SPSS) 15.0 for Windows. The incidence of minor adverse events was 11.3% (95% CI 9.8-12.9%) for fever, 17% (15.2-18.8%) for pain at the injection site, 12.6% (11-14.2%) for cough, 2.6% (1.8-3.3%) for headache and 1.1% (0.6-1.6%) for nausea and/or vomiting. Severe adverse events were not observed. Mild adverse events following immunisation are common with SA14-14-2 JE vaccine. Hence the health personnel involved in JE control campaign should be aware of these adverse events. PMID- 23029823 TI - Management of large amoebic liver abscess--a comparative study of needle aspiration and catheter drainage. AB - Amoebiasis in endemic in the tropical countries with amoebic liver abscesses being a common complication. Different modalities of treatment of amoebic liver abscess are conservative (medical management), percutaneous needle aspiration, percutaneous catheter drainage, surgical drainage and endoscopic drainage. This study was carried out to compare the efficacy, safety and outcome of needle aspiration comparing with percutaneous catheter drainage of large (> or = 5cm diameter) amoebic liver abscesses. This was a prospective study carried over a period of two years (2006-2008) at the general surgery department of Calcutta National Medical College and Hospital, Kolkata. A total of 45 patients were included in this study. All of them had amoebic liver abscess with diameter of abscess cavity > or = 5cm. They were divided into two groups. Group A included 22 patients and they were treated with needle aspiration. Group B included 23 patients and they were treated by catheter drainage. Improvement in clinical features, liver function tests, ultrasonic evidence of decrease in the size of abscess cavity was considered as criteria for successful treatment. The sex ratio and the age incidence in the two groups were similar. In about 80% patients the right lobe was affected, in about 18% the left lobe was affected and in rest the abscess involved both lobes. Needle aspiration was successful in 15 (68.2%) and catheter drainage was successful in 23 patients (100%). The mean hospital stay of patients treated with needle aspiration was more than those treated with catheter drainage. The mean time in days taken for 50% decrease in the size of abscess cavity was significantly greater in group treated with needle aspiration than in those treated with catheter drainage (9 days versus 4 days). It is concluded that percutaneous catheter drainage is more effective in management of large amoebic liver abscess than needle aspiration. PMID- 23029825 TI - Is knowledge of medicolegal issues concordant with heightened risk among doctors? AB - Spurred by the wave of consumerism, patients do not hesitate to drag the doctor to the court. It has now become essential for doctors to educate themselves on the laws relevant to medical practice. This study addresses some of the issues. Doctors in private practice, belonging to different specialities, were given a self administered questionnaire which was then analysed by the percentage of responses to each question. Only 3% of the respondents faced medicolegal problems at the time of the study. All of them were fighting charges of negligence from their patients. Most (97%) did not keep records of patients seen in outpatient services, 63% used consent forms written in English only and 78% took blanket consent forms for procedures; 97% were not aware of any laws protecting them in their practice. This study highlights the gross ignorance of medicolegal issues among doctors and the need for compulsory certificate courses for them and changes in the curriculum for the postgraduates with respect to this important aspect of medical profession. PMID- 23029824 TI - Adenosine deaminase--the non-invasive marker of tuberculosis. AB - Pulmonary tuberculosis is the India's biggest health problem especially in rural areas. A quick and dependable investigation is absolutely essential. Adenosine deaminase was estimated from the biological fluids (ascitic/pleural/CSF) with the help of the kit obtained from Tulip India Pvt Ltd. The method is based on the principle of Galati & Giusti colorimetric method. The method is simple, inexpensive and results are also reproducible. Elevation of adenosine deaminase has shown high specificity in all biological fluids. As the estimation principle is based on synthesis of ammonia so there is limitation of the procedure when the site is kidney. Similarly if the site is skin, as fluid cannot be collected from the site, adenosine deaminase estimation is also not possible. PMID- 23029826 TI - Clinical predictors of influenza A(H1N1) in Kanpur, India. AB - Influenza A (H1N1) commonly known as swine flu, has covered a large part of the globe rapidly since the outbreak started in Mexico on 18th March, 2009. Given the rapid worldwide spread of the virus, it is important to identify the symptoms that require screening for influenza A(H1N1). Therefore, this study was planned to determine the clinical predictors of influenza A(H1N1) in the population of Kanpur city. Study sample comprised all cases with flu-like symptoms suspected of having influenza A(H1N1) whose nasopharyngeal samples had been sent for laboratory examination. Of the 119 samples sent to the laboratory, 34 were found to be positive for influenza A(H1N1). Best predictors found were fever with shortness of breath (positive predictive value=87.5%) followed by fever with cough without other cold like features (positive predictive value=68.6%). None of the clinical signs had all the attributes of a good predictor of influenza A(H1N1). Fever with cough was the most sensitive (70.6%) and fever with shortness of breath was the most specific indicator (98.8%). Therefore, it was concluded that symptoms like fever with cough without other cold like features and fever with shortness of breath should not be ignored and require expert medical attention for screening of influenza A(H1N1). PMID- 23029827 TI - Chronic pelvic pain evaluation and initial management--a study from rural, western Uttar Pradesh. AB - Chronic pelvic pain is an increasingly common complaint among women, particularly in the reproductive age group. Multiple factors contribute to causation and aggravation of such pain. It affects the social life of the female. The study evaluated demographic and historic variables in women with chronic pelvic pain, differentiated organic from functional causes by non-invasive available measures and evaluated the effectiveness of commonly used treatment options in treatment of chronic pelvic pain. The study was conducted on 160 cases of chronic pelvic pain, attending gynaecology OPD of UP RIMS&R, Etawah. They were evaluated with respect to age, parity, socio-economic status, pattern of pain, associated symptoms, pelvic examination and subsequent management outcome. Specific management was done for organic cause, while analgesics and tranquilisers were prescribed for functional pain. It was found most commonly in 31-35 years age group women, in which 62% were multipara and 74% belonged to the lower socio economic status (classes IV and V). Specific pathological diagnosis was done only in 56.25% cases. Chronic constant lower abdominal pain was the most common (64%) presentation. Only 65% of patients showed improvement with the medical treatment. Chronic pelvic pain is quite common complaint in rural western Uttar Pradesh. It requires more specific diagnostic aids and treatment protocols for functional pain. Therapeutic success can be achieved by regular supportive doctor-patient interaction. PMID- 23029828 TI - Sodium bicarbonate versus sodium hyaluronidase in ocular regional anaesthesia--a comparative study. AB - It has been reported that alkalinisation of an anaesthetic medication enhances the rate of onset of regional anaesthesia. The purpose of this study therefore was to find out whether alkalinisation really hastened peribulbar anaesthesia as given prior to routine cataract surgery. Two hundred and forty otherwise healthy patients with bilateral cataracts were selected for this study irrespective of their demographic attributes. The first eye (group FE) received a routine peribulbar block with a standard solution of 6 ml of 2% lignocaine mixed with 15 IU/l units of sodium hyaluronidase at a pH of 4.6. The second eye (group SE) was taken up for surgery after one week and received a peribulbar block with 6 ml lignocaine 2% mixed with 7.5% sodium bicarbonate at a pH 7.4. The time taken for onset of akinesia in both the situations was measured to the last minute with the aid of a stop watch by an independent observer. Thirty-five per cent of patients in group FE had complete akinesia at the end of 5 minutes, another 60% at the end of 7 minutes and remaining 6% at 10 minutes. Sixty-eight per cent of patients in group SE had complete akinesia at the end of 5 minutes and 100% at the end of 7 minutes. No anaesthesia related ocular or systemic complications were seen in any group. Sodium bicarbonate buffered peribulbar block is faster than routine hyaluronidase augmented block with a reduced time of onset of akinesia. PMID- 23029829 TI - Role of the family physician in controlling the epidemic of chronic kidney disease. AB - The term chronic kidney disease (CKD) signifies permanent reduction in renal function. It consists of 5 stages of increasing severity. CKD replaces the multiple terms like chronic renal failure in vogue earlier. The prevalence of CKD is rapidly increasing in the community and causing a huge burden on the community. Since the current marker of renal function-serum creatinine is not sensitive enough, measurement of estimated glomerular filtration rate (eGFR) has been proposed to quantify the renal function better. The family physician has a vital role to play in preventing the onset and progression of CKD. Prevention starts with maintaining a healthy lifestyle. The groups at risk for developing CKD like diabetics and hypertensives should be effectively treated. Yearly estimation of albuminuria (or microalbuminuria) and estimated GFR should be done. Optimal use of renoprotective drugs can delay the inevitable progression of CKD to end-stage renal disease (ESRD). The family physician is the key person, who can implement these measures at the primary care level. Referral to a nephrologist can be made once initially when the serum creatinine >2 mg% to establish the primary diagnosis; and subsequently the patient can be managed in consultation with the nephrologist. Only such an Integrated approach with the active participation of the family physician can successfully stem the upsurge in the tide of CKD. PMID- 23029830 TI - Utility of continuous glucose monitoring system in clinical practice--a report of two cases. AB - Continuous blood glucose monitoring by continuous glucose monitoring system is a recent tool available to clinicians which can give us an idea about trends of blood glucose during 24-hour period and helps formulate appropriate management. Two cases are reported of use of continuous glucose monitoring system in this institute which illustrate its usefulness in clinical practice. PMID- 23029831 TI - A rare case of Kikuchi's disease of the cervical lymph node. AB - Kikuchi's disease, or histiocytic necrotising lymphadenitis, is an uncommon and unique form of self-limiting lymphadenitis and typically affects the head and neck regions. The most common clinical manifestation is cervical lymphadenopathy, with or without systemic signs and symptoms. Clinically and histologically, the disease can be mistaken for lymphoma or systemic lupus erythematosus. Pathologically, presence of karyorrhexis, paracortical areas of necrosis and the absence of neutrophils, eosinophils and plasma cells were consistent with Kikuchi's disease. CT scan showed enlarged lymph nodes with hypodense centres and peripheral ring enhancement. As Kikuchi's disease can be cured by steroid, its diagnosis can prevent unnecessary surgery. PMID- 23029832 TI - Dengue fever with unusual thalamic involvement. AB - Dengue is the most important mosquito-borne viral disease in the world and is caused by four distinct viruses (type 1 to 4) that are closely related antigenically. Infection by dengue virus may be asymptomatic or may lead to undifferentiated fever, dengue fever or dengue haemorrhagic fever. Recent observations indicate that the clinical profile of dengue is changing and the neurological complications are being reported more frequently. The neurological features includeheadache, seizures, neck stiffness, depressed sensorium, behavioural disorders, delirium, paralysis and cranial nerve palsies. Such neurological symptoms in dengue fever wereattributed to cerebral oedema, haemorrhage, haemoconcentration due to increasing vascular permeability, coagulopathy and release of toxic substances. Cerebral oedema, encephalitis-like changes (oedema and scattered focal lesions), intracranial haemorrhages as well as selective involvement of bilateral hippocampus in dengue infection have been reported previously on selective neuro-imaging but thalamic involvement is rare. We here report a case of a typical presentation of encephalopathy with left sided complete hemiplegia due to thalamic involvement in dengue infection. PMID- 23029833 TI - Rare persistent kerato-acanthoma of left lower eyelid: a case report. AB - A 45-year-old man presented with a mass in left lower eyelid. On examination, the mass was diagnosed as kerato-acanthoma. The mass was excised and excision biopsy confirmed the diagnosis. Kerato-acanthoma almost always regress spontaneously within six months. So persistence of the lesion for more than one year is a rare presentation. PMID- 23029834 TI - Small bowel obstruction due to inflammatory fibroid polyp. AB - Inflammatory fibroid polyp is a benign and non-neoplastic condition of the intestinal tract, commonly affecting the gastric antrum, though it can affect any part of the gastro-intestinal tract. It is a submucosal, sessile, poypoid mass composed of myofibroblast like mesenchymal cells, numerous small blood vessels and marked inflammatory cell infiltrate mainly eosinophils. It commonly presents as intestinal obstruction or intussusception. A case of recurrent partial small intestinal obstruction due to intermittent intussusception associated with inflammatory fibroid polyp of jejunum is being reported. PMID- 23029835 TI - A fatal case of Kikuchi-Fujimoto disease. AB - Kikuchi-Fujimoto disease is an extremely rare, benign, auto-immune, clinicopathological condition presenting with fever and lymphadenopathy. It has higher prevalance among Japanese and other Asiatic individuals. It is usually self-limiting with extremely rare mortality. A case of an adolescent girl who presented with fever and cervical lymphadenopathy, found to have Kikuchi's disease on histopathology of cervical lymph node is being reported. She eventually succumbed to the disease. PMID- 23029836 TI - Venous thrombosis in ophthalmology. PMID- 23029837 TI - To evaluate efficacy and safety of fixed dose combination of aceclofenac + paracetamol + thiocolchicoside (acenac-MR) in the treatment of acute low back pain. AB - Low back pain is very common complaint in all age groups. Paracetamol, non steroidal anti-inflammatory drugs and muscle relaxants are commonly prescribed in combination for the treatment of back pain. The aim of the study was to evaluate efficacy and safety of fixed dose combination of aceclofenac + paracetamol + thiocolchicoside (acenac-MR) in the treatment of acute low back pain. Thirty-five patients, age being 18 to 76 years suffering from acute low back pain were enrolled in the study. Study drug acenac-MR tablet, (Medley pharmaceutical, Mumbai) containing aceclofenac 100 mg + thiocolchicoside 4 mg + paracetamol 500 mg was prescribed twice daily for a duration of 7 days. Intensity of pain was evaluated at the start of the therapy and on day 3 and day 7 with the help of visual analogue scale. Mobility assessment in low back patients was evaluated at the start of the therapy and on day 3 and day 7. A simple graduated bar (0 value at floor) evaluated hand-to-floor distance. Tolerability and efficacy was evaluated based on the global assessment by the investigator based on a 3-point scale marked as excellent/good/poor. There were 20 males and 10 females who were included for final analysis, 5 patients lost to follow-up. Intensity of pain at rest (p< or =0.0014 at day 3, p< or =0.0001 at day 7), during movement (p< or =0.0001 at day 3, p< or =0.0001 at day 7) and at night (p< or =0.0001 at day 3, p< or =0.0001 at day 7) was significantly reduced by acenac-MR compared to baseline. The mobility assessment revealed a statistically significant improvement in hand-to-floor distance on the 3rd (< or =0.0001) and 7th day (< or =0.0001) as compared to baseline with acenac-MR. As per investigators' assessment about efficacy of trial drug, 70% of patients reported excellent, 26.66 % good and 3.33 % reported poor efficacy. As per investigators' assessment about tolerability, 60 % of patients reported excellent, 36.66 % good and 3.33 % reported poor tolerability. None of the patients discontinued the therapy due to side-effects. Result of this study showed that aceclofenac + thiocolchicoside + paracetamol significantly reduced intensity of pain and improve the mobility of the patients. PMID- 23029838 TI - Predictive factors in oncology. PMID- 23029839 TI - Evaluation of airway blocks versus general anaesthesia for diagnostic direct laryngoscopy and biopsy for carcinoma larynx. AB - A prospective randomised study of 100 patients divided into two groups was done to compare the effects of regional airway nerve blocks versus general anaesthesia to evaluate intra-operative haemodynamic changes and compare the level of postoperative analgesia and sedation in both the groups. In group I whole airway block including bilateral superior laryngeal nerve block with bilateral glossopharyngeal block and recurrent laryngeal nerve block was given and in group II general anaesthesia was given. The mean duration was 27 +/- 5 minutes in all cases, all patients were of ASA grade 3 or 4. Baseline and pre-operative values of pulse and blood pressure were noted and were recorded at 0, 5, 7, 9, 10 and 15 minutes. Postoperative sedation and VAS scores were recorded at 0, 5, 15 and 30 minutes initially and then hourly. The present study showed significant haemodyanamic changes in group II with significant rise in mean arterial pressure and pulse rate during peri-operative period. Whereas in group I there was a stability in mean arterial pressure and pulse rate peri-operatively. The postoperative analgesia was significantly higher in group I and lasted longer as compared to group II and patients were less agitated and calm as assessed by the sedation score, in group II most of the patients required postoperative nebulisation as compared to group I where no patient needed nebulisation. In conclusion we suggest that regional airway block for anaesthesia in the short procedures of upper airways and also in cases of predicting difficult airway cases for securing the safe airway can be very useful alternate to general anaesthesia. PMID- 23029840 TI - Incidence of anaemia among the female tea garden workers in a tea plantation in upper Assam, India. AB - Nutritional anaemia is the most common type and cause of anaemia. Tea garden workers constitute approximately 1/5th of population in the state of Assam. Reports indicate higher prevalence of undernutrition in this population. The present study was designed to focus on the incidence of anaemia among the female tea garden workers and to examine the effect of iron with vitamin B12 and folic acid supplementation in them. Two hundred and forty-four female tea garden workers who could be persuaded to participate in the study were sampled for haemoglobin typing by agarose gel electrophoresis (pH 8.9). Their haematological parameters were measured on automated cell counter to read Hb, RBC, MCV, MCH and MCHC. BMI was calculated from weight/height in metre2. The study revealed 182 anaemic (<11.0 g/dl) subjects which included 32 cases of hereditary anaemia and 150 cases of nutritional anaemia. Iron supplementation for duration of 3 months was given to 150 workers out of total 182 subjects who had haemoglobin <11.0 g/dl. Thirteen subjects with haemoglobin >11.0 g/dl were studied as controls. Level of haemoglobin was rechecked after 3 months by Sahli's method. Based on the size of red blood cells it was observed that the workers suffered from all three forms of anaemia viz, microcytic, normocytic and macrocytic. There was a significant rise in haemoglobin concentration when the anaemic individuals took iron with vitamin B12 and folic acid supplement for three consecutive months supported by two doses of anthelminthic drug. The present study showed that nutritional anaemia is a major problem in the female tea garden workers and arrangement of supplementation therapy is utmost necessary to improve their general condition and work efficiency. PMID- 23029841 TI - Multiple percutaneous K-wire fixation for fracture distal radius: a projected technique. AB - A combination technique was performed in treating 34 adult patients with non comminuted variably displaced fractures of distal radius in either sex and in different age groups by popular multiple percutaneous K-wire fixation combined with a short period of dorsal plaster slab support, achieving an encouragable and highly satisfactory results without having known complications like persistent deformity, persistent pain due to collapse, due to alteration in ulnar variance and acute reflex sympathetic dystrophy, within 6 months follow-up. This recommendable operative technique is presented of fixing the manipulated and reduced fragments by 3 K-wires placed in different angles followed by a short period of dorsal plaster slab immobilisation with the periodical clinical and radiological follow-up assessment result in details with a brief discussion on the subject including the mechanism of action. PMID- 23029842 TI - Mortality predictors in severe hyponatraemia in emergency inpatients. AB - Hyponatraemia, one of the most common electrolyte abnormality when severe (<120 meq/l), has poor prognosis and fatal outcome. Published data on identification of mortality predictors in severe hyponatraemia is however insufficient. The aim of the study was to determine the characteristics, causes and outcome of severe hyponatraemia (<120 meq/l) in hospitalised patients and to identify the mortality predictors. A retrospective case note review of patients (n=175) admitted in emergency ward of a tertiary care hospital during a period of 12 months having severely hyponatraemic (<120 meq/l) were undertaken. Both at the time of admission and those developing during their stay were included. Severe hyponatraemia was found to be common in elderly males. Aetiology was predominantly multifactorial (60.5%), and single aetiologies were mainly, congestive cardiac failure (9.7%), alcoholic liver disease (8.6%) and obstructive airway disease (7.4%). Overall mortality in study group was 25.7%. The mortality was found to be higher (30.8%) in patients developing severe hyponatraemia during hospitalisation as compared to that on admission (24.2%). Mortality was also found to be significantly (p<0.05) higher in patients whose sodium levels were not normalised after treatment. A strong relation between lowest sodium levels rather than admission sodium levels was seen. Severe hyponatraemia (<120meq/l) is a commonly encountered clinical problem, associated with a poor prognosis. The data suggest that outlook in severe hyponatraemia is governed by aetiology and by the serum sodium levels. Identification of mortality predictors should not be overlooked, as correct diagnosis of the aetiology and early recognition of risk factors is critical both to determine correct management and for better prognosis. PMID- 23029843 TI - ECG manifestations in acute organophosphorus poisoning. AB - A cross-sectional study was conducted to evaluate the electrocardiographic changes in 107 patients of acute organophosphorus poisoning admitted at casuality ward of MGM Medical College, Kisanganj from June 2007 to June 2010. Electrocardiographic changes were recorded before the administration of atropine. Prolonged Q-Tc interval was the commonest ECG abnormality, found in 67 patients (62.6%), followed by sinus tachycardia in 36 patients (33.6%). Sinus bradycardia was found in 33 patients (30.8%). Elevation of ST segment was seen in 27 patients (25.2%). T wave inversion was seen in 21 patients (19.6%). First-degree heart block (P-R interval >0.20 seconds) occurred in 9 cases (8.4%). Atrial fibrillation was seen in 5 patients (4.6%). Ventricular tachycardia was seen in 6 cases (5.6%) and ventricular premature complexes in 3 patients (2.8%). Of these 6 cases of ventricular tachycardia 1 responded to intravenous lignocaine, and the other 5 developed ventricular fibrillation leading to death despite other resuscitative measures. All the electrocardiographical abnormalities returned to normal before the patients were discharged. Seventeen patients died. The cause of death was ventricular fibrillation in 5 patients and non-cardiogenic pulmonary oedema in others. In conclusion it can be said that ECG should be carefully recorded and analysed in all patients of acute organophosphorus poisoning, and depending upon these changes and other clinical and biochemical parameters, the patients should immediately be shifted to well equipped ICU for better care which will reduce the mortality rate caused by these highly lethal poisons. PMID- 23029844 TI - Evaluation of respiratory manifestations in systemic lupus erythematosus with special reference to pulmonary interstitial involvement. AB - Different respiratory manifestations in systemic lupus erythematosus (SLE) are not uncommon. We lack sufficient Indian data in this regard. Forty diagnosed cases of SLE were evaluated, to find out the prevalence of respiratory manifestations in SLE, as also to correlate the findings as observed by different diagnostic methods. It was a single centre cross-sectional observational study conducted at rheumatology clinic, IPGME&R, Kolkata. Patients suffering from chronic airways obstruction, upper airway diseases, left ventricular failure and lung cancer were all excluded from the study. After clinical evaluation and routine testing of organ specific parameters, patients underwent spirometry and chest x-ray in all cases and pleural fluid study, pleural biopsy and high resolution CT scan of thorax selectively as required. Mean age at presentation was 26.8 years and female to male ratio was 39:1. Commonest respiratory symptom was dyspnoea and commonest respiratory manifestation was pleural effusion. Pleural effusion was bilateral in 80% of cases. Interstitial lung disease (ILD) was found in 10% of cases presented either subacutely or chronically. High resonance CT was found to be more sensitive to diagnose ILD, as in 50% of ILDs diagnosed by scan, chest x-rays were normal. Pleuropulmonary infections (7.5%) were next most common manifestation and tuberculosis was found to be the commonest cause. Lupus pneumonitis was found in one only (2.5%). Screening lung function test as done by spirometry, could pick up some abnormality in 50% cases and restrictive change was the major abnormality (47%). None showed evidence of bronchial hyper-responsiveness. No case was detected to have neuromuscular disease, acute respiratory distress syndrome or pulmonary thrombo-embolism. All the respiratory manifestations as noted appeared in variable period after the onset of SLE. PMID- 23029845 TI - Tuberculosis infection control practices in healthcare settings. AB - The multiple tuberculosis outbreaks in 1980s and early 1990s found lapses in administrative, environmental and respiratory control measures. Guidelines and regulations were formulated for safe TB control measures. The guidelines were designed to provide up-to-date information about methods of reducing the risk of air-borne infections in healthcare facilities. A useful concept in these guidelines is three levels of control measures ordered according to their importance and priority for implementation ie, administrative controls, environmental controls and personal respiratory protection for healthcare workers who are exposed to TB in patient care. Standard precautions are there combining major features of universal precautions, body substance isolation and air-borne precautions. In this article, the precautions as envisaged are narrated. PMID- 23029846 TI - Huge malignant melanoma of caruncle with extensive involvement of conjunctiva. AB - The caruncle is nodular structure lying at internal canthus medial to plica semilunaris. It is composed of elements of conjunctiva, cutaneous and lacrimal tissue. In spite of its diverse histopathology, lesions of caruncle are rare and malignant melanoma is further rarer. This tumour is potentially lethal, even after prompt and proper treatment, especially after delayed onset of therapy. Clinical metastases usually occur first to the lymph nodes in approximately 45% to 60% of patients with regional metastases. Eventually systemic dissemination may occur to lung, brain, liver, skin, bone and the gastrointestinal tract, although this often arises without prior clinical evidence of regional lymph node involvement. Here a rare case of huge malignant melanoma of caruncle with extensive involvement of plica semilunaris, fornix and palpebral conjuctiva in a 58-years old male is reported who was treated with local excision combined with cryotherapy and topical 0.02% mitomycin-C eye drops. PMID- 23029847 TI - Filariasis of the breast--an unusual presentaion. AB - Filariasis of the breast presenting as a breast lump and clinically simulating as breast tumour is an unusual presentation. The present case is of a 30 years old female complaining of breast lump and on fine needle aspiration revealed microfilaria. PMID- 23029848 TI - Hypopituitarism following poisonous viperbite. AB - A 28 years old male had the history of viperbite 3 years back. He has treated in a nearby rural hospital with snake venom antiserum along with other supportive therapy. He responded and discharged from hospital within a week. Three years later he had history of fever, drowsiness which progressed to unconsciousness. On examination he was found to have scanty body hairs, smooth, shiny skin with superficial oral ulcers. Serum hormone estimation confirmed the deficiency of gonadotrophins, thyrotrophin and corticotrophin while growth hormone failed to rise >3ng/ml after insulin intolerance test. MRI brain revealed loss of pituitary mass with positive infundibular sign and filling of sella with cerebrospinal fluid. He was managed with hormone replacement therapy and recovered gradually. PMID- 23029849 TI - Fat embolism syndrome managed by non-invasive ventilation--a case report. AB - A 31-year-old male was struck by a motor cycle and diagnosed to have closed injury to the thigh involving right sided femur shaft fracture. Patient was operated on the next day by the orthopaedic surgeon. The patient did not have any signs of fat embolism syndrome before and after surgery. But the rare ECG change of S1Q3T3 (pulmonary embolism) was present before and after surgery. The presence of oedematous retina and cherry red spots in the macula was also present in the young patient. Patient developed all the classical signs of fat embolism syndrome 18 hours after surgery. The case had classic presentations of fat embolism syndrome managed by non-invasive ventilation. The role of steroids and albumin is also discussed as it was always a controversy in the management of fat embolism syndrome. PMID- 23029850 TI - Blast lung: experience at CIMS. AB - Blast lung is a clinical condition which is characterised by respiratory difficulty and hypoxia without obvious external injury to the chest in bomb blast cases. Two patients of the bomb blast episode were brought at emergency department at Chhattisgarh Institute of Medical Sciences, Bilaspur in a state of shock. After proper wound care, resuscitation and investigation both the cases proved to be that of blast lung. In bomb blast cases although there might not be any external injury over chest wall, it will be sensible to rule out blast lung in all cases with the help of computerised tomography. PMID- 23029851 TI - Born in travail, survival under a cloud: the birth, improbable survival and notable success of the Uniformed Services University of the Health Sciences (1972 2012). PMID- 23029852 TI - 40 years of military medical education: an overview of the Long-Term Career Outcome Study (LTCOS). AB - In 2005, the Long-Term Career Outcome Study (LTCOS) was established by the Dean, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences (USU). The original charge to the LTCOS team was to establish an electronic database of current and past students at USU. Since its inception, however, the LTCOS team has broadened its mission and started collecting and analyzing data on a continuous basis for the purposes of program evaluation and, in some cases, research. The purpose of this commentary is to review the history of the LTCOS, including details about USU, a brief review of prior LTCOS work, and progress made since our last essay on LTCOS efforts. This commentary also provides an introduction to the special issue, which is arranged as a series of articles that span the medical education continuum (i.e., before, during, and after medical school). The relative balance of articles in each phase of training represents the LTCOS team's efforts to address the entire continuum of medical education. PMID- 23029853 TI - Alternate list matriculants: outcome data from those medical students admitted from the alternate list. AB - BACKGROUND: Medical schools are increasing class size to meet future health care needs for our nation. This may lead to more students being accepted from an alternate list (vs. primary acceptances). Given these trends, performance outcomes were compared for alternate list matriculants and primary acceptances. Our hypothesis was that those students accepted from an alternate list would perform equally to the primary acceptances on these outcomes. METHOD: We compared medical school performance of students who received a primary recommendation of "accept" and compared them to those who received a recommendation of "alternate" over a 10-year period. Given the small sample size of this alternate list group (N = 23), descriptive statistics are reported. RESULTS: No consistent differences between alternate and primary acceptance matriculants in terms of cumulative medical school grade point average, United States Medical Licensing Examination (USMLE) Step 1 scores and USMLE Step 2 Clinical Knowledge scores were found. Only three alternates (13.0%) were presented to student promotion committee compared to 17.2% for matriculants who were primary acceptances. Three alternates were required to repeat a year (average percentage of 8.7%) compared to 5.6% of matriculants who were primary acceptances. CONCLUSIONS: This observational study provides some reassurance that as long as the qualifications of the applicant pool remain adequate, admissions policies that provide for alternate list acceptances may not produce poorer performing students, at least by our current outcome measures. PMID- 23029854 TI - Exploring the relationship between self-reported research experience and performance in medical school and internship. AB - PURPOSE: To investigate the relationship between self-reported research experience and medical students' performance in medical school and internship. METHODS: We collected data from seven year-groups (1993-1999; N = 1,112) and examined 7 performance outcomes: medical school preclinical grade point average (GPA), medical school clinical GPA, cumulative medical school GPA, U.S. Medical Licensing Examination Step 1 and 2 scores, and scores on a previously validated program director's survey of intern professionalism and expertise. We then conducted a series of multiple linear regressions to determine the relations between self-reported research experience and our seven outcomes. RESULTS: When compared to those who reported no prior research experience, students who reported research experience performed significantly better on U.S. Medical Licensing Examination Step 1 and had a higher medical school preclinical GPA. However, these same students scored significantly lower on intern professionalism and expertise ratings. Self-reported research experience did not show statistically significant correlations with the other outcome variables. CONCLUSIONS: The results from our large, multiyear, cohort study suggest that prior research experience may account for some variance in outcomes in the early stages of medical school education, but that variance explained diminishes considerably as trainees progress into the more senior phases of education. On the other hand, prior research experience may be negatively related to students' performance in internship. In all cases, however, effect sizes are small. PMID- 23029855 TI - Identifying themes within a medical school admission committee's reviews of applicants. AB - BACKGROUND: Admissions committees attempt to select the most qualified applicants based on many cognitive and "noncognitive" factors. PURPOSE: Identify common themes cited in the admissions committee member summaries of medical school matriculants and determine the relative frequency and importance of these themes. METHODS: After reviewing a convenience sample of 150 reviewer comments, 14 qualitative themes were identified. Utterances (thematic word strings) from each of the three reviewer comments for each matriculant for 7 academic years (1989 1996) were then categorized and coded as being positive, negative, or neutral. Intra-rater and inter-rater reliabilities were calculated. RESULTS: Utterances (n = 9299) about 981 matriculants were categorized by theme and sorted as being positive, neutral, or negative. Intra-rater reliabilities were excellent (mean K = 0.98, range 0.90-1.00). Similarly, inter-rater reliabilities were also excellent (mean K = 0.94, range 0.55-1.00 and mean K = 0.90, range 0.08-1.00). Four themes (overall summarizing comments, academic, test scores, and motivation) accounted for more than half (56%) of the utterances. CONCLUSIONS: We were able to qualitatively identify themes and provide information about how one committee weighs both cognitive and "noncognitive" factors. Admission committees should consider reexamining their process and potentially expanding, eliminating, or modifying application components. PMID- 23029856 TI - Relationship between admissions committee review and student performance in medical school and internship. AB - PURPOSE: To investigate the association between tertiary reviewer (admissions committee member) comments and medical students' performance during medical school and into internship. METHODS: We collected data from seven year-groups (1993-1999) and coded tertiary reviewer comments into 14 themes. We then conducted an exploratory factor analysis to reduce the dimensions of the themes (excluding the Overall impression theme). Subsequently, we performed Pearson correlation analyses and multiple linear regression analysis to examine the relationship between the factors and seven outcome measures: medical school preclinical grade point average (GPA), medical school clinical GPA, cumulative medical school GPA, U.S. Medical Licensing Examination Step 1 and 2 scores, and scores on a program director's evaluation measuring intern professionalism and expertise. RESULTS: We extracted seven factors from the 13 themes and found small to-moderate, significant correlations between the factors, the Overall impression theme, and the outcome measures. In particular, positive comments on Test and Maturity were associated with higher U.S. Medical Licensing Examination Step 1 and 2 scores. Negative comments on Interview and Recommendations were associated with lower ratings of professionalism during internship. Comments on Overall impression were significantly associated with all the outcome measures. CONCLUSIONS: Tertiary reviewer comments were weakly associated with performance in medical school and internship. Compared with positive comments, negative comments had stronger associations with medical school and internship performance measures. PMID- 23029857 TI - Writing, self-reflection, and medical school performance: the Human Context of Health Care. AB - INTRODUCTION: Finding ways to improve communication and self-reflection skills is an important element of medical education and continuing professional development. This study examines the relationship between self-reflection and educational outcomes. METHODS: We correlate performance in a preclinical course that focuses on self-reflection as it relates to contextual elements of patient care (Human Context of Health Care), with educational measures such as overall grade point average, clinical clerkship scores, and Medical College Admission Test (MCAT) scores. RESULTS: Student performance in Human Context of Health Care correlated with MCAT-Verbal scores, MCAT-writing sample scores, clerkship grades, and overall medical school grade point average (R = 0.3; p < 0.001). CONCLUSION: Writing and self-reflection skills are often neglected in undergraduate medical curricula. Our findings suggest that these skills are important and correlate with recognized long-term educational outcomes. PMID- 23029858 TI - Development and initial validation of a survey to assess students' self-efficacy in medical school. AB - Self-efficacy is a personal belief in one's capability to successfully execute the behaviors necessary to attain designated types of performances. Sometimes described as task-specific self-confidence, self-efficacy is a key component in many contemporary theories of motivation and learning. The purpose of this study was to develop a survey for measuring students' medical skills self-efficacy and to collect reliability and validity evidence for the instrument. A secondary purpose was to explore differences in students' self-efficacy from year 1 of medical school to year 4. We created 19 survey items based on the 6 core competencies of the Accreditation Council for Graduate Medical Education, and we collected data from 304 medical students. Results from an exploratory factor analysis suggested three interpretable factors: patient care self-efficacy (eight items, Cronbach's alpha = 0.92), interpersonal skills self-efficacy (three items, Cronbach's alpha = 0.76), and evidence-based medicine self-efficacy (three items, Cronbach's alpha = 0.79). We then compared students' self-efficacy at different stages of training using a one-way multivariate analysis of variance. Consistent with our expectations, we found several statistically significant differences, suggesting students' self-efficacy increased considerably from year 1 of medical school to year 4, F(9, 725) = 30.58, p < 0.001, Wilks' lambda = 0.46. Using this survey, medical educators and researchers have a psychometrically sound tool for measuring students' medical skills self-efficacy during undergraduate medical education. Practical implications and future directions are discussed. PMID- 23029859 TI - Instructional authenticity and clinical reasoning in undergraduate medical education: a 2-year, prospective, randomized trial. AB - OBJECTIVE: The purpose of the study was to investigate the relationship between authenticity (how close to actual practice) of preclerkship instructional formats and preclerkship and clerkship outcome measures. A secondary purpose was to investigate the effect of student's small-group assignment during preclerkship period on instructional formats and preclerkship and clerkship outcome measurements. METHODS: A prospective, randomized, crossover study was carried out with preclerkship students taking a clinical reasoning course. Students were randomized to small groups and exposed to three formats of differing instructional authenticity across three subject areas. Three student cohorts were taught using one instructional format per subject area with each cohort receiving a different instructional format for each of the three areas. Outcome measures at the end of the preclerkship year and the clerkship year were selected to determine the effect of each instructional format. Hierarchical linear modeling was performed to assess impact of format on outcomes and to assess potential group effect on outcomes. RESULTS: Increasingly authentic instructional formats did not significantly improve clinical reasoning performance. Small-group assignment did not significantly contribute to the outcomes providing evidence that teacher training was successful. CONCLUSIONS: Increasing authenticity of instructional formats does not appear to significantly improve clinical reasoning performance. Faculty can be successfully trained to teach consistently in a clinical reasoning course. Medical educators should balance increasing authenticity with factors such as cognitive load and learner experience as well as engaging in frame-of-reference training to minimize group effects with designing new instructional formats. PMID- 23029860 TI - Relationship between OSCE scores and other typical medical school performance indicators: a 5-year cohort study. AB - BACKGROUND: Objective Structured Clinical Examinations (OSCEs) are used at the majority of U.S. medical schools. Given the high resource demands with constructing and administering OSCEs, understanding how OSCEs relate to typical performance measures in medical school could help educators more effectively design curricula and evaluation to optimize student instruction and assessment. PURPOSE: To investigate the correlation between second-year and third-year OSCE scores, as well as the associations between OSCE scores and several other typical measures of students' medical school performance. METHODS: We tracked the performance of a 5-year cohort (classes of 2007-2011). We studied the univariate correlations among OSCE scores, U.S. Medical Licensing Examination (USMLE) scores, and medical school grade point average. We also examined whether OSCE scores explained additional variance in the USMLE Step 2 Clinical Knowledge score beyond that explained by the Step 1 score. RESULTS: The second- and third-year OSCE scores were weakly correlated. Neither second- nor third-year OSCE score was strongly correlated with USMLE scores or medical school grade point average. CONCLUSION: Our findings suggest that OSCEs capture a viewpoint that is different from typical assessment measures that largely reflect multiple choice questions; these results also support tenets of situated cognition theory. PMID- 23029861 TI - The association between specialty match and third-year clerkship performance. AB - PURPOSE: The United States is experiencing an accelerating physician shortage, especially within primary care. Medical educators are actively seeking ways to predict student specialty match and workforce requirements. Previous studies investigating specialty match have focused on factors known at the time of matriculation. This study examined whether third-year clerkship performance could be used to predict specialty match later in medical school. METHOD: The authors evaluated the clerkship performance of 802 students graduating from the Uniformed Services University between 2007 and 2011. They examined the relationship of students' clerkship grades and National Board of Medical Examiners' clinical subject examination scores to specialty match. In addition, the authors combined student performance in family medicine, internal medicine, and pediatrics to create composite variables and assessed their associations with the match. RESULTS: Among 802 students, 339 (42.4%) students matched to primary care specialties. There was a positive association between higher family medicine (Odds ratio [OR] 1.65, 95% confidence interval [CI] 1.05, 2.59), general surgery (OR 1.91, 95% CI 1.22, 2.99), internal medicine (OR 2.17, 95% CI 1.35, 3.49), and pediatrics (OR 2.59, 95% CI 1.52, 4.43) clerkship grades and students matching into family medicine, general surgery, internal medicine, and pediatrics, respectively. Only family medicine showed a weak correlation between higher National Board of Medical Examiners' scores and specialty match. CONCLUSIONS: Higher clerkship performance in four of six Uniformed Services University third year clerkships is associated with matching into the corresponding specialty. Clerkship performance provides a potential tool for educators in counseling students and predicting future specialty match. PMID- 23029862 TI - Reflections on LTCOS projects during medical school. PMID- 23029863 TI - Postinterview communication between military residency applicants and training programs. AB - PURPOSE: Each year military medical students participate in a separate, military match culminating with the Joint Services Graduate Medical Education Selection Board (JSGMESB). Prior studies have explored postinterview communication that occurs during the National Resident Matching Program (NRMP), but not during the JSGMESB. We examined the frequency and nature of communication during the JSGMESB and compared it with the NRMP. METHODS: Cross-sectional survey study of senior students conducted at Uniformed Services University of the Health Sciences (USU) and seven civilian U.S. medical schools during March to May 2010. Respondents answered questions regarding communication with residency programs during the match. RESULTS: Significantly fewer USU respondents communicated with programs compared with the civilian cohort (54.1% vs. 86.4%, p < 0.01). Specific inquiries regarding rank order were more commonly experienced by USU respondents compared with civilians (17.5% vs. 4.8%, p = 0.02). USU respondents found postinterview communication both helpful (41.3%) and stressful (41.3%). 11.1% of USU respondents indicated that they moved a program higher on their final rank lists because of further communication with these programs. CONCLUSIONS: Postinterview communication during the JSGMESB process is less common and less stressful than that reported in the NRMP. USU respondents are more likely to be asked directly about their rank list and occasionally do change their lists. Uniform guidance mirroring the NRMP's dealing with direct inquiries about rank lists could potentially improve the process. PMID- 23029864 TI - Leadership success and the Uniformed Services University: perspectives of flag officer alumni. AB - The Uniformed Services University of the Health Sciences (USU) houses the nation's only federal medical school, the F. Edward Hebert School of Medicine. A key aspect of the curriculum at USU is leadership education as graduates go on to serve the Department of Defense through a variety of senior positions in the military. We surveyed a specific group of USU graduates who have achieved the rank of General or Admiral ("flag officers") to enhance our understanding of successful leadership for military physicians and to gain an understanding of how USU might shape its curriculum in the future. METHODS: We sent an Internet-based survey to 13 flag officer graduates. The first section of the survey contained items from the multifactor leadership questionnaire-6S, a questionnaire with evidence of reliability and validity for evaluating leadership styles. The second section of the survey contained open-ended questions addressing key characteristics of an effective leader in the Military Health System, experiences that prepared them for leadership, USU's role in leadership positions, and advice for USU for better educating future leaders. The second section of the survey was coded using the constant comparative method. RESULTS: Eight flag officers (63%) responded to the survey. They all scored highly on transformational leadership style. Qualitative themes reached saturation for each open-ended question. The flag officers identified characteristics consistent with published literature from other fields regarding effective leadership. They endorsed USU's role in achieving their leadership positions and suggested areas for improvement. CONCLUSIONS: Characteristics of effective leadership (transformational leadership style) identified by the flag officers surveyed in this study are consistent with the literature from other fields. These finding have important implications for leadership education at USU and potentially other institutions. The results also provide additional data to support the notion that USU is meeting its societal obligation to educate future leaders in military medicine. PMID- 23029865 TI - Where are they now? USU School of Medicine graduates after their military obligation is complete. AB - The Uniformed Services University's (USU) F. Edward Hebert School of Medicine was chartered in 1972, with the goal of providing high-quality physicians for the Uniformed Services. In exchange for their education, USU graduates incur an active duty service obligation, after which they may choose to stay on active duty or transition to civilian practice. The purpose of this study is to describe the practice characteristics of USU graduates after this obligation has been completed in order to determine the societal benefits during this phase of their careers. To accomplish this purpose, we performed a retrospective cohort study of the first 20 years of USU graduates (1980-1999). We used the American Medical Association Physician Masterfile to determine the graduates' current practice location and characteristics, as well as their board certification status. Of these 2,760 graduates, nearly all (91%) were involved in active clinical practice in over 100 self-declared specialties, the vast majority (89%) practiced in locations other than the immediate vicinity of the medical school (i.e., Maryland and the District of Columbia), and most still worked for the federal government (71%). Finally, USU graduates in full-time clinical practice had a board certification rate of 93%, which was better than the average of all other graduates of U.S. Medical Schools (88%) in the same time period. Thus, it seems USU is attaining its goal of producing high-quality physicians who continue to benefit the nation after their service obligation has been completed, with many still in federal service. PMID- 23029866 TI - Using functional neuroimaging combined with a think-aloud protocol to explore clinical reasoning expertise in internal medicine. AB - BACKGROUND: Clinical reasoning is essential to medical practice, but because it entails internal mental processes, it is difficult to assess. Functional magnetic resonance imaging (fMRI) and think-aloud protocols may improve understanding of clinical reasoning as these methods can more directly assess these processes. The objective of our study was to use a combination of fMRI and think-aloud procedures to examine fMRI correlates of a leading theoretical model in clinical reasoning based on experimental findings to date: analytic (i.e., actively comparing and contrasting diagnostic entities) and nonanalytic (i.e., pattern recognition) reasoning. We hypothesized that there would be functional neuroimaging differences between analytic and nonanalytic reasoning theory. METHODS: 17 board-certified experts in internal medicine answered and reflected on validated U.S. Medical Licensing Exam and American Board of Internal Medicine multiple-choice questions (easy and difficult) during an fMRI scan. This procedure was followed by completion of a formal think-aloud procedure. RESULTS: fMRI findings provide some support for the presence of analytic and nonanalytic reasoning systems. Statistically significant activation of prefrontal cortex distinguished answering incorrectly versus correctly (p < 0.01), whereas activation of precuneus and midtemporal gyrus distinguished not guessing from guessing (p < 0.01). CONCLUSIONS: We found limited fMRI evidence to support analytic and nonanalytic reasoning theory, as our results indicate functional differences with correct vs. incorrect answers and guessing vs. not guessing. However, our findings did not suggest one consistent fMRI activation pattern of internal medicine expertise. This model of employing fMRI correlates offers opportunities to enhance our understanding of theory, as well as improve our teaching and assessment of clinical reasoning, a key outcome of medical education. PMID- 23029867 TI - Secrets of success in medical training. PMID- 23029868 TI - The Long-Term Career Outcome Study (LTCOS): what have we learned from 40 years of military medical education and where should we go? AB - The work of the Long-Term Career Outcome Study (LTCOS), F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences (USU) has been a multidisciplinary effort spanning more than 5 years. Borrowing from the established program evaluation and quality assurance literature, the LTCOS team has organized its evaluation and research efforts into three phases: before medical school, during medical school, and after medical school. The purpose of this commentary is to summarize the research articles presented in this special issue and to answer two fundamental questions: (1) what has been learned from LTCOS research conducted to date, and (2) where should the LTCOS team take its evaluation and research efforts in the future? Answers to these questions are relevant to USU, and they also can inform other medical education institutions and policy makers. What is more, answers to these questions will help to ensure USU meets its societal obligation to provide the highest quality health care to military members, their families, and society at large. PMID- 23029869 TI - Pregnancy and neonatal respiratory outcome. AB - Preterm labor is the final common pathway of different complications of pregnancy and despite substantial progress in antenatal care, preterm birth remains a major health issue across the globe. Preterm deliveries in the larger group of spontaneous preterm labor or preterm prelabor rupture of membranes (PPROM) are often associated with intrauterine chorioamnionitis. Current evidence underlines the role of "inflammatory" and "placental dysfunction" disorders in pregnancy on prematurity-associated morbidity, particularly respiratory outcome. (www.actabiomedica.it). PMID- 23029870 TI - Genetic susceptibility to neonatal lung diseases. AB - Advances in molecular genetics have enabled improvement of knowledge in pathogenesis and diagnosis of either monogenic or multifactorial neonatal lung diseases. Variants in genes regulating surfactant function and metabolism are implicated in some rare and common respiratory diseases. Congenital surfactant deficiencies are rare diseases due to mutations in genes encoding surfactant proteins and cause significant and often lethal respiratory failure in newborns and interstitial lung disease in older children. Diagnosis is made by molecular analysis and eventually confirmed by histological analysis of lung tissue. A multifactorial contribution, resulting from interaction between multiple genes and environmental factors, has been supposed for respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). Several potential candidate genes, especially regarding surfactant proteins and cytokines, have been shown in association with these diseases. Genetic variants predisposing to RDS or BPD are usually polymorphisms which are not causative, but can increase susceptibility to the disease. Identification of infants at risk of disease can be useful to provide them individualized therapies. (www.actabiomedica.it). PMID- 23029871 TI - Surfactant replacement in preterm infants with respiratory distress syndrome. AB - Surfactant treatment has been demonstrated to decrease pneumothorax and mortality in preterm infants (with RDS). In many neonatal intensive care units NCPAP is used immediately after birth, while surfactant is given as early rescue in infants who develop RDS. This approach has been found safe and effective in several studies and a recent meta-analysis demonstrated a decreased risk of bronchopulmonary dysplasia or death in infants following this strategy. (www.actabiomedica.it). PMID- 23029872 TI - Surfactant and mechanical ventilation. AB - Even if non invasive respiratory support is widespread used in the management of respiratory failure, nevertheless mechanical ventilation and surfactant replacement are standard care for many preterm infants with respiratory distress syndrome (RDS). The interaction between exogenous surfactant and different modalities of ventilatory support are very important and can influence respiratory outcome. The optimization of surfactant replacement during respiratory support is crucial for the successful of this therapy. In course of mechanical ventilation lung recruitment manoeuvres before and after tracheal instillation of surfactant seem to facilitate its distribution and allow to obtain a more homogeneous lung volume. (www.actabiomedica.it). PMID- 23029873 TI - Surfactant and non invasive ventilation for preterm infants. AB - Mechanical ventilation, although life-saving, predisposes preterm infants to BPD. NCPAP emerged as an alternative to invasive ventilation, but it fails in about 30% of infants even when coupled with surfactant therapy. Alternative modes of non invasive ventilation are currently used in neonatology in order to prevent mechanical ventilation. Among these, Synchronized Nasal Intermittent Positive Ventilation (SNIPPV) seems to ensure better results. (www.actabiomedica.it). PMID- 23029874 TI - Exogenous surfactant replacement: how to deliver it? AB - Exogenous surfactant is a therapeutic option for newborns, children and adults with acute respiratory distress disorders. Although tracheal instillation is still reputed as the classical method of surfactant delivery, alternative techniques have been investigated. Surfactant administration by using thin intra tracheal catheters, bronchoscopy, laryngeal mask airway, or nebulisation, although variably effective, appear to be less invasive when compared to tracheal intubation. However, further research is still needed to better clarify this matter. (www.actabiomedica.it). PMID- 23029876 TI - Solve the Nobel Prize dilemma. Now that teams, not individuals, drive high-impact science, the Nobel Foundation should change how it awards its prize. PMID- 23029875 TI - Effectiveness of treatment with surfactant in premature infants with respiratory failure and pulmonary infection. AB - INTRODUCTION: Surfactant inactivation is present in neonatal pneumonia. MATERIALS AND METHODS: One hundred thirty-nine preterm babies with Birth Weight (BW) < or = 1250 grams were studied and subdivided in two groups: RDS Group, with a diagnosis of "simple" RDS (N 80) and RDS with Pneumonia Group, consisting of babies with a diagnosis of RDS and a positive BALF culture in the first 24-48 h of life (N 59). OUTCOMES: Surfactant administration seems less effective in the latter group, because a significantly higher number of infants needed a second dose of surfactant, compared to the patients suffering from RDS alone. (www.actabiomedica.it). PMID- 23029877 TI - Target the super-spreaders. Inoculating kids is the best way to protect everyone from flu. Why don't we do it? PMID- 23029878 TI - The exposure cure. A major study moves food-allergy treatments a step closer to reality. PMID- 23029879 TI - Snap judgment. An ultrafast camera may help detect cancer before it spreads. PMID- 23029880 TI - The art of fishing. Ancient mosaics help scientists track grouper populations. PMID- 23029881 TI - Coding her way to the top. Interview by Anna Kuchment. PMID- 23029882 TI - Stuff that designs itself. Self-assembling nanoparticles may be key to new materials. PMID- 23029883 TI - Drug detectives. Physicians struggle to curb the growing number of lethal overdoses. PMID- 23029885 TI - A measure of the creativity of a nation is how well it works with those beyond its borders. PMID- 23029884 TI - Rent out your hot button. PMID- 23029886 TI - Why Germany still makes things. PMID- 23029887 TI - Can China keep rising? PMID- 23029888 TI - Citizen science U. PMID- 23029889 TI - The other 1 percent. PMID- 23029890 TI - Culture of creativity. Interview by Fred Guterl. PMID- 23029891 TI - The language of the brain. PMID- 23029892 TI - Ecosystems on the brink. PMID- 23029893 TI - The Higgs at last. PMID- 23029894 TI - Kinetic kite. PMID- 23029895 TI - The wisdom of psychopaths. PMID- 23029896 TI - Journey to the genetic interior. Interview by Stephen S Hall. PMID- 23029897 TI - Politically irrational. Subliminal influences guide our voting preferences. PMID- 23029898 TI - Fatter, drunker nation. And yet Americans are smoking less and exercising more. PMID- 23029899 TI - Use of Salmonella/microsome reversion bioassay for monitoring industrial wastewater treatment plants in Rajasthan, India. AB - Salmonella/microsome reversion assay was used as a biological parameter for monitoring the toxicity of common effluent treatment plant (CETP), Mandia road industrial area, Pali catering to textile industrial areas in Pali, Rajasthan. The influent and effluent water of CETP, surface water (Bandi river) and underground water were tested using Ames bioassay. The results showed presence of mutagens in surface water of Bandi river and the underground water in Pali. Further, comparison of mutagenicity of CETP influent and effluent water revealed that the treatment method employed at this plant has failed to remove mutagenic substances present in Pali textile wastewater. The study also showed that Ames assay is an important tool in genotoxic studies because of its simplicity, sensitivity to genetic damage, speed, low cost of experimentation and small amount of sample required. Further Ames assay, as seen from the results of this study, can be used as a monitoring tool for not only CETPs but also for other water resources. The outcomes of the Ames assay demonstrated its performance as a sensitive, cost-effective and relatively rapid screening tool to assess the genotoxic potential of complex environmental samples. PMID- 23029900 TI - Molecular typing of mealybug Phenacoccus solenopsis populations from different hosts and locations in Punjab, India. AB - True identity and existence of genetic variability in mealy bug from different regions holds immense significance for adopting appropriate control measures along with predicting the development of any biotypes. Mealy bug, Phenacoccus solenopsis adults were collected from four host plants i.e., Gossypium hirsutum- cotton (C), Abelmoschus esculentus--okra (O), Pennisetum glaucum--Napier Bajra (B) and a weed--Parthenium hysterophorus (P) in five cotton growing districts i.e., Abohar, Bathinda, Mansa, Muktsar and Faridkot of Punjab state. Variability among different populations was investigated through comparative analysis of four different RAPD markers. The genetic similarity dendrogram established that irrespective of the host plant and the collection site, 20 mealybug populations were distinguishable into two major clades that were related to each other by 68%. Clade 1 included populations from Abohar district; it also included a single population each from Muktsar and Bathinda districts. The populations from all the other districts were grouped under Clade 2 with genetic similarity of 78% Even under Clade 2, individual populations appeared to exist in location specific sub clades. Thus, there is great possibility of development of biotypes which may differ in resistance to insecticides and host plant specificity. PMID- 23029901 TI - Studies on the identification and control of pathogen Saprolegnia in selected Indian major carp fingerlings at mid hill altitude. AB - The Indian major carp cultured in ponds in the North Eastern hilly states of India frequently suffer from fungal disease during winter months resulting in mass mortality. This study examined the pathogenic fungi isolated from farmed raised Indian major carp fingerlings and identified as Saprolegnia. For treatment, the diseased fish were exposed to 4g salt per litre of water for 2 min followed by dip treatment with 5ppm KMnO4 for 10 min, thrice every week for a period of 6 weeks. The treatment resulted in recovery from the disease after 6 weeks from the beginning of treatment. Soon after recovery, the pond management practices such as removal of pond bottom soil, application of lime and replenishment with freshwater were followed in the infected ponds. Our study concluded that rapid decrease in pond water temperature from 22 to 8 degrees C that remains low for months together coupled with increased water pH (9) and decreas dissolved oxygen (4ppm) causes saprolegniasis to the fingerlings of Indian major carps. PMID- 23029902 TI - Colonization of probiotic bacteria and its impact on ornamental fish Puntius conchonius. AB - The present study was conducted to assess the establishment and effect of probiotic bacteria such as Bacillus coagulans, Bacillus mesentericus, and Bifidobacterium infantis in the gut of freshwater ornamental fish Puntius conchonius. Postlarvae of 60 days old Puntius conchonius divided in four experimental groups each with three replicates. T1, T2 and T3 groups were fed with Bacillus coagulans, Bacillus mesentericus and Bifidobacterium infantis enriched copepod Thermocyclops decipiens respectively. T0 was the control group (without probiotic treated T. decipiens). The experiment was conducted for 45 days. The initial gut analysis of fish showed significant level of pathogenic bacteria in the gut of fish (p < 0.05). Total plate count of initial gut analysis of fish larvae were enumerated as 1.2 x 10(4)CFU ml(-1). The bacteriological study indicated thatfinal gut microflora of post-larvae have decreased level of pathogens. Total plate count of T1, T2 T3 and T0 were reported to be as 1.0 8 x 10(4), 1.06 x 10(4), 1.27 x 10(4) and 2.1 x 10(5) CFU ml(-1), respectively. Three experimental groups (T1, T2 and T3) were significantly different from control group (T0) (p < 0.05). At the end of the experiment, establishment of probiotics were examined. One week after probiotics administration, gut analysis of fish larvae showed, poor spore formation of Bacillus coagulans (2.3 x 10(3) CFU mL( 1)), when compared to B. mesentericus (3.2 +/- 0.03 x10(3) CFU ml(-1)) and Bifidobacterium infantis(3.1 x 10(3) CFU ml(-1)). The results from the study suggest that the probiotic bacteria significantly established in gut of P. conchonius and significant effects on the pathogenic gut inhabitants of the fish. PMID- 23029903 TI - Studies on phyto-genotoxic assessment of tannery effluent and chromium on Allium cepa. AB - Tannery effluent contributes significantly to pollution of the environment. In this study, phytotoxic and genotoxic effects of tannery effluent and chromium (Cr) were investigated in Allium cepa. Forthis purpose, tannery effluent was collected from "Up flow Anaerobic Sludge Blanket" (U.A.S.B) Jajmau, Kanpur. A. cepa were exposed to various concentrations of tannery effluent (0.0, 3.125, 6.25, 12.50, 25.0%) and Cr (0.0, 1.0, 2.0, 4.0, 8.0 mgl(-1)) for 48 and 168 hr. The perusal of data revealed that the physico-chemical characteristics of tannery effluent viz. pH (8.5), EC (11.94 dSm(-1)), BOD (499 mgl(-1)), COD (1382 mgl(-1)) and Cr content (2.32 mgI(-1)) were much higher than the prescribed permissible limit for industrial effluent discharged into inland waters. These substances provoked phytotoxic and genotoxic effects in A. cepa. Total chlorophyll and protein content in leaves of tannery effluent and Cr treated plants decreased significantly in dose-duration dependent manner. A maximum decrease of 86.29 and 84.26% in total chlorophyll and 81.27 and 76.16% in protein content was observed after 168 hr of exposure while carotenoid content increased up to 6.25% effluent and 2.0 mgl(-1) Cr treatment and decreased further. In all treated plants, a significant (p > or = 0.05) reduction in root length, mitotic index (MI) and induction in chromosomal (CA)/mitotic (MA) aberration and micronuclei (MNC) were observed as compared to unstressed plants. A maximum reduction of 81.15 and 79.71% in MI, and induction of 6.8 and 4.8% in CA, 29.24 and 26.66% in MA and 0.52 and 0.43% in MNC were found at 12.50% effluent and 4 mgl(-1) Cr treated plants as compared to unstressed plants, however at highest effluent and Cr concentration both the plants showed pyknosis condition after 168 hr. PMID- 23029904 TI - The wild flora biodiversity in pesticide free bufferzones along old hedgerows. AB - The natural field margin ecotone from the field border and into a cropped field hosts a diversity of plant species. In conventional cropped fields, biodiversity suffers from fertilizer and pesticide application. In our study at Danish conventional spring-barley fields, we laid out bufferzones with no pesticide application spraying after sowing, with the widths: 24, 12, 6 and 4 m (and control) to the field edge hedgerow. Through one season: plant species number, biodiversity and evenness for each bufferzone at the distances: 18, 9, 5, 2 and 0 m from the hedgerow were significantly affected by distance to the hedge and by width of bufferzone. The bufferzones affected: species number (total of 92 weed species), species diversity (1.27 to 0.44) and species evenness index (0.63 to 0.87), and revealed that the bufferzone of 24 m gave the largest improvementof the field margin for plants. Decreasing the bufferzone widths provided smaller biodiversity and larger evenness of plants at distances larger than the buffer width: the distance at which diversity (Shannons) was reduced by half the difference between hedge- and field diversity was 1.2, 3.1, 6.7, 10.8 and 10.9 m in bufferwidth treatments of 0, 4, 6, 12 and 24 m; likewise, the half-way distance for Smiths and Wilsons evenness index was 1.2, 1.7, 5.4, 14.0 and 30.2 m in the bufferwidth treatments of 0, 4, 6,12 and 24 m. Based on modelled diversity and evenness indexes a positive effect of buffer was evident from 6 m bufferzone. The average diversity over the distances from 0 to 18 m was 0.66, 0.75, 0.98, 1.14 and 1.11 in bufferwidth treatments of 0, 4, 6, 12 and 24 m and the average evenness over the distances from 0 to 18 m was 0.82, 0.80, 0.74, 0.66 and 0.63, in bufferwidth treatments of 0, 4, 6, 12 and 24 m. Furthermore, the accumulated number of species revealed that a bufferzone width of at least 6 m was needed to significantly increase the species richness at all distances between 2 and 18 m. At 18 m distance, the accumulated number of species was 37.1, 39.7, 41.2, 42.4 and 42.7 in bufferwidth treatments of 0, 4, 6, 12 and 24 m. PMID- 23029905 TI - Adsorption, desorption and mobility of metsulfuron-methyl in soils of the oil palm agroecosystem in Malaysia. AB - Laboratory experiments were conducted to evaluate adsorption, desorption and mobility of metsulfuron-methyl in soils of the oil palm agroecosystem consisting of the Bernam, Selangor, Rengam and Bongor soil series. The lowest adsorption of metsulfuron-methyl occurred in the Bongor soil (0.366 ml g(-1)), and the highest in the Bemam soil (2.837 ml g(-1). The K(fads) (Freundlich) values of metsulfuron methyl were 0.366, 0.560, 1.570 and 2.837 ml g(-1) in Bongor, Rengam, Selangor and Bemam soil, respectively. The highest K(fdes) value of metsulfuron-methyl, observed in the Bemam soil, was 2.563 indicating low desorption 0.280 (relatively strong retention). In contrast, the lowest K(fdes) value of 0.564 was observed for the Bongor soil, which had the lowest organic matter (1.43%) and clay content (13.2%). Soil organic matter and clay content were the main factors affecting the adsorption of metsulfuron-methyl. The results of the soil column leaching studies suggested that metsulfuron-methyl has a moderate potential for mobility in the Bernam and Bongor soil series with 19.3% and 39%, respectively for rainfall at 200 mm. However, since metsulfuron-methyl is applied at a very low rate (the maximum field application rate used was 30 g ha(-1)) and is susceptible to biodegradation, the potential forground water contamination is low. PMID- 23029906 TI - Comparative study on growth, yield and carbon content in Pongamia pinnata under water stress and urea supplementation. AB - The growth, yield, and carbon content of eight-month old seedlings of Pongamia pinnata were compared under water and urea supplementation. One set of plants were subjected to water stress condition (WS), whereas the other supplied with 2 g of urea (WS+U) under WS. Both the experimental set ups were exposed to varying treatment levels which include full irrigation (100%, control) followed by 75% (T1), 50% (T2), 25% (T3) and 12.5% (T4). The growth, leaf area and relative water content were maximum under WS when compared to WS+U (p < 0.001). The maximum biomass was produced in the seedlings under WS in control (1.68 g) followed by T1 (1.38 g), T2 (1.53 g), T3 (0.93 g) and T4 (0.73 g). A significant (p < 0.001) reduction in biomass production was observed in WS+U in control (1.28 g), T1 (0.66 g), T2 (1.13 g) and T3 (0.44 g). T4 of WS+U showed similar biomass (0.73 g) as that of T4 of WS. Under WS, the highest biomass allocation was recorded in shoots followed by leaves and roots. Similar trend was observed in WS+U. However, the percentage of allocation was more in the roots of WS+U (27.2%) when compared to WS (22.24 %). The highest amount of carbon content was observed in control plants treated under WS (9.59 g) followed by control plants of WS+U (7.31 g) (p < 0.001). The results of the preliminary study clearly indicated that P. pinnata seedlings were able to cope-up with water stress conditions without urea application and can perform well in 50% water availability and is best suited for the plantation programs in the semi-arid ecosystems. PMID- 23029907 TI - Studies on phytoplankton characteristics in Ayyampattinam coast, India. AB - Physico-chemical variables in the marine environment are subjected to wide spatio temporal variations. The various physico-chemical parameters viz: temperature, salinity, pH, dissolved oxygen and nutrients of the environment are the factors which mainly influence the production and successful propagation of planktonic life in the coastal biotopes. The ranges of values of surface water temperature (0 degrees C), salinity (per thousand), pH and dissolved oxygen (ml l(-1)) were: 25.5 - 33.4; 23 - 35; 7.8 - 8.2; 3.6 - 5.2, respectively. The values (microg l( 1)) of nutrients were: nitrate 3.21 - 6.34, nitrite 0.74 - 0.896, phosphate 0.22 and 1.16, silicate 24.85 - 61.92 and ammonia 0.05 - 0.32. The recorded values of primary productivity (mgcm(-3)hr(1)) ranged between 16 - 116 and the chlorophyll "a" varied from 3.74 - 8.52. A total number of 51 species of phytoplankton representing different classes viz: Bacillariophyceae (40); Dinophyceae (8); Chlorophyceae (1) and Cyanophyceae (2) was recorded. Among the four classes, Bacillariophyceae appeared to be the dominant group in respect of total species and cell numbers. The population density of phytoplankton was high during summer season and quite low during monsoon season. PMID- 23029909 TI - Population dynamics of free living, nitrogen fixing bacteria Azospirillum in Manakkudi mangrove ecosystem, India. AB - Seasonal variations of population dynamics of free living nitrogen fixing bacteria, Azospirillum in relation to chemical parameters in Manakkudi mangrove ecosystem was assessed in root and rhizosphere soil samples of mangroves and mangrove associated plants. In rhizosphere soil and root samples, the counts of Azospirillum were recorded maximum in Acrostichum aureum as 8.63 +/- 0.92 x 10(4) and 115.48 +/- 17.36 x 10(4) CFU g(-1), respectively. The counts of Azospirillum in non-rhizosphere soil varied from 0.01 +/- 0.001 x 10(4) to 5.77 +/- 0.92 x 10(4) CFU g(-1) and found maximum in February and minimum in March and September. Azospirillum counts in water samples were found maximum (2.24 x 10(4) CFU l(-1)) in February. During seasonal variations maximum counts of Azospirillum were recorded during southwest monsoon season in Avicennia officinalis (1.40 x 10(4) CFU g(-1)) followed by Rhizophora mucronata (1.07 x 10(4) CFU g(-1)). The average maximum population density of Azospirillum counts was found during non monsoon season (9.73 x 10(4) CFU g(-1)) and the average maximum population density of Azospirillum counts was found with the mangrove associated root samples (13.73 x 10(4) CFU g(-1)). Of the selected isolates Azospirillum lipoferum (60%) was found to be predominant followed by Azospirillum brasilense (25%), Azospirillum irakense (5%), Azospirillum halopraeferens (5%) and Azospirillum amazonense (5%). Of the isolated species, A. halopraeferens exhibited better growth at 35 g l(-1) NaCl. The level of Fe, Cu, Zn and Mn were varied from 0.91 to 15.93 ppm. The level of Mn (12.13 ppm) was found maximum during non-monsoon of rhizosphere soil sample. Highest rainfall (192.80 mm) and atmospheric temperature (25.10 degrees C) were recorded during south west monsoon and non monsoon seasons. The increased population density was greatly influenced by the pH (r = +0.686). The present finding provides enough information on the nitrogen flow through biological process in Manakkudi mangrove ecosystem which can be useful for the effective implementation of mangrove management plan. PMID- 23029908 TI - Protective effects of amlodipine on mitochondrial injury in ischemic reperfused rat heart. AB - The most significant finding of the present study was the release of nitric oxide (NO). The effect of amlodipine on NO production associated with ischemic reperfused (IR) injury was investigated in rat heart model. Cardiac tissues from animal groups were processed for biochemical, histopathological and electron microscopic studies. There was a significant increase in myocardial catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) enzymes in amlodipine treated group (1.37, 10.27, 6.39) when compared to IR injured group (0.81, 6.87, 4.53). Histopathology studies showed amlodipine reduce cardiocyte damage in cardiac injury during the cardiac IR. Transmission electron microscopic (TEM) study confirmed the cardioprotective role of amlodipine against IR induced cardiac injury. On the basis of findings, it is hypothesized that a portion of the beneficial actions of amlodipine may involve the release or action of NO and probably by its antioxidant properties. PMID- 23029910 TI - Reproductive activities of Heliotropium indicum isolate against Helopeltis theivora and toxicity evaluation in mice. AB - A new compound E was isolated from the methanolic extract of the leaves of Heliotropium indicum by chromatographic fractionation. In the present study, the effect of the compound E on reproduction of Helopeltis theivora has been evaluated. The acute toxicity study (LD50) and sub-acute toxicity studies (haematological, biochemical and histopathological parameters) in albino Swiss mice were carried out to evaluate the safety aspect of the compound E. The compound showed significant inhibitory effect on the reproductive life of H. theivora. The oviposition period, fecundity and hatching percentage of H. theivora were found to be 15.67 days, 39.33 and 28.00% respectively after treatment with 2% compound E, whereas the control value were found to be 20.33 days, 77.67 and 77.33% respectively. The LD50 of the compound was found to be 780 mg kg(-1) in Swiss albino female mice. The compound did not show any toxicity in mice at sub-lethal dose treatment (78 mg kg(-1) b. wt., once daily) for 21 days as evident from different haematological, biochemical and histopathological parameters in compound E treated group when compared with control. PMID- 23029911 TI - Effect of environmental impact to molecular expression of heat-shock protein (HSP70) in oyster Crassostrea gigas from Gamak bay, Korea. AB - The cDNA of Crassostrea gigas HSP70 was cloned and rapid amplification of cDNA (RACE) techniques were used. The full length of HSP70 cDNA was 2045 bp, consisting of a 5' terminal untranslated region (UTR) of 80 bp, a 3' terminal UTR 146 bp, and an open reading frame (ORF) of 1829 bp encoding deduced 620 amino acids. The HSP70 cDNA contained HSP70 family signatures, ATP-GTP binding site motif, tetrapeptide (GGMP) and conserved carboxyl terminal region (EEVD) at C terminal of deduced amino acid sequence. BLAST analysis revealed that the HSP70 gene has an extreme similarity of 98.9% with C. gigas (AF144646). Northern blotting was used to examine the expression of HSP70 mRNA in the gill tissue of the oyster obtained from surface, middle and bottom layers. The HSP70 mRNA observed the samples taken from middle and bottom layers in September and February, but samples from the surface layer did not find a signal intensity of HSP70 mRNA transcript. Consequently, it seems that the oyster occurring middle and bottom layer have been stressed during the period of summer and winter, which is associated with the massive mortality in Gamak bay. PMID- 23029912 TI - Laboratory observations on the larvicidal efficacy of three plant species against mosquito vectors of malaria, dengue/dengue hemorrhagic fever (DF/DHF) and lymphatic filariasis in the semi-arid desert. AB - Comparative larvicidal efficacy of aqueous and organic solvent extracts from seeds, leaves and flowers of three desert plants viz. Calotropis procera (Aiton), Tephrosia purpurea (L.) Pers. and Prosopis juliflora (Sw.) DC. was evaluated against Anopheles stephensi (Liston), Aedes aegypti (Linnaeus) and Culex quinquefasciatus (Say). For this purpose larvae of all the three mosquito species were reared in the laboratory and studies carried out on late 3rd or early 4th instars using standard WHO technique. Based on concentration mortality data 24 and 48 hr LC50and LC90 values along with their 95% fiducial limits, regression equation, chi-square (chi2)/ heterogeneity of the response were determined by log probit regression analysis. Experiments were carried out with different solvent extracts of seeds of C. procera which revealed that methanol (24 hr LC50: 127.2, 194.8, 361.0) and acetone (229.9, 368.1,193.0 mg l(-1)) extracts were more effective with the three mosquito species, respectively. Petroleum ether extract was effective only on An. stephensi while aqueous extracts were not effective at all with any of the mosquito species (mortality < 10-30%). Tests carried out with methanol extracts of fresh leaves (24 hr LC50: 89.2, 171.2, 369.7) and flowers (24 hr LC50: 94.7,617.3, 1384.0 mg l-(-1)) of Calotropis showed that preparations from fresh parts were 2-3 times more effective as compared to the stored plant parts. Efficacy was less than 10-30% with both An. aegypti and Cx. quinquefasciatus while An. stephensi was still susceptible to extracts from both leaves and flowers even after two years of storage. The 24 hr LC50 values as observed for methanol extracts of seeds of T. purpurea and leaves of P. juliflora were 74.9, 63.2 and 47.0 and 96.2,128.1 and 118.8 mg l(-1) for the above three mosquito species, respectively. Experiments carried out up to 500 mg l-(1) with leaves (T. purpurea) and seeds (P. juliflora) extracts show only up to 10-30% mortality indicating that active larvicidal principle may be present only in the seeds of Tephrosia and leaves of Prosopis. In general, anophelines were found more susceptible than the culicines to the plant derived derivatives. More studies are being carried outon some other desert plants found in this arid region. The study would be of great importance while formulating vector control strategy based on alternative plant based insecticides in this semi-arid region. PMID- 23029913 TI - Hatchery production of the clownfish Amphiprion nigripes at Agatti Island, Lakshadweep, India. AB - Healthy individuals of matured clownfish, Amphiprion nigripes and sea anemone, Heteractis magnifica were collected from the Agatti island lagoon by snorkeling. During 'conditioning' for 3 months, pair formation occurred and the same were transferred to rectangular fiber glass spawning tanks of 10001 capacity. Suitable water quality parameters were maintained. The fishes were fed with tuna eggs, boiled clam meat, squid, octopus and trash fish thrice in a day. Reproductive behaviour and embryonic development were documented. Spawning took place in between 0900 - 1100 hr and hatched-out occurs, after sunset following an incubation period of 8-9 days. Size of the newly laid egg was 2.0-2.2 mm in length and 1.0-1.2 mm in width. The larval rearing tanks were maintained with UV treated water and followed the optimal physico-chemical parameters as in the parent tanks. The different light regimes and diets were used for the successful larval rearing. The maximum larval survival (61%) was achieved at the photoperiod of 24 L/0D. Within 15-17 days, the larvae metamorphosed and took up parent colouration and comparatively high growth rate was observed when fed on algae enriched rotifer than those with poly unsaturated fatty acid (PUFA). PMID- 23029914 TI - Chemical characterization of rain water in a seasonally dry tropical region (Varanasi), India. AB - Rain water samples, covering 44 rain events of 2008 and 52 rain events of 2009, were collected at urban and suburban locations of Varanasi and analyzed for pH, conductivity and for metal and nutrient ions. The pH of rainwater varied between 6.3 and 7.9, with over 70% of samples having alkaline range. Volume weighed mean concentration of ions indicated Ca2+ (11.62- 41.60 microeq l(-1)) to be the most dominant species followed by SO4(2-) (4.7-25.2 microeq I(-1)), Na+ (1.60-10.25 microeq l(-1)), Mg2+ (0.22-7.21 microeq I(-1)), (NO3(-) (0.73-4.02 microeq l( 1)), K+(0.50-3.70 microeq l(-1)) and PO4(3-) (0.02-0.97 microeq l(-1)) respectively. Among the heavy metals, Cr (12.60 to 44.60 microg l(-1)), Zn (4.25 to 34.55 microg l(-1)) and Mn (10.62 to 28.40 microg l(-1)) were found to be the dominant component of rain water. The varimax rotation of PCA results extracted four major factors namely urban-industrial emission, crustal aerosols, wind transport and biomass burning accounting for 80% of the total variance. The study has relevance in establishing cause-effect relationships for terrestrial as well as for aquatic ecosystems. PMID- 23029915 TI - Assessment of air pollution tolerance levels of selected plants around cement industry, Coimbatore, India. AB - Being the second largest manufacturing industry in India, cement industry is one of the major contributors of suspended particulate matter (SPM). Since plants are sensitive to air pollution, introducing suitable plant species as part of the greenbelt around cement industry was the objective of the present study. Suitable plant species were selected based on the Air pollution tolerance index (APTI) calculated by analyzing ascorbic acid (AA), pH, relative water content (RWC) and total chlorophyll (TChl) of the plants occuring in the locality. Plants were selected within a 6 km radius from the industry and were graded as per their tolerance levels by analyzing the biochemical parameters. From the statistical analysis at 0.05 level of significance a difference in the APTI values among the 27 plant species was observed, but they showed homogenous results when analysed zone wise using one-way analyses of variance. Analyses of individual parameters showed variation in the different zones surrounding the cement industry, whereas the APTI value (which is a combination of the parameter viz. AA, RWC, TChl, pH) showed more or less same gradation. Significant variation in individual parameters and APTI was seen with in the species. All the plants surrounding the cement industry are indicative of high pollution exposure comparable to the results obtain for control plants. Based on the APTI value, it was observed that about 37% of the plant species were tolerant. Among them Mangifera indica, Bougainvillea species, Psidum quajava showed high APTI values. 33% of the species were highly susceptible to the adverse effects of SPM, among which Thevetia neriifolia, Saraca indica, Phyllanthus emblica and Cercocarpus ledifolius showed low APTI values. 15% each of the species were at the intermediary and moderate tolerance levels. PMID- 23029916 TI - Seasonal variations and biodiversity of phytoplankton in Harsool-Savangi dam, Aurangabad, India. AB - The present study concerns seasonal variations, correlation coefficient and biodiversity indices of phytoplankton during January to December, 2008 in the Harsool-Savangi dam, Aurangabad, India. A total of 35 genera were recorded out of which 15 were Chlorophyceae, 7 Bacillariophyceae, 7 Cyanophyceae and 6 Euglenophyceae. Present study revealed maximum percentage wise compositions of Chlorophyceae at north site 41.91%, Bacillariophyceae at west site 32.70%, Cyanophyceae at south site 19.50% and Euglenophyceae at west site 11.47%. Minimum percentage wise compositions Chlorophyceae at south site 37.80%, Bacillariophyceae at east site 28.15%, Cyanophyceae at west site 17.47% and Euglenophyceae at north site 10.57%. Margalef's index (R1) and Menhinick index (R2) values (4.12 and 0.56) were found to be highest at south site and lowest values (3.77 and 0.38) were found at north site. Simpson's index (I) values (0.30) were found to be the highest at north site and lowest values (0.29) were found at south, east, and west sites. Shannon-Weiner index (H') values (1.26) were found to be the highest at south, east, and west sites and lowest values (1.24) were found at north site. Maximum species evenness was recorded at south site; minimum at north site. Maximum population density of Chlorophyceae, Bacillariophyceae, Cyanophyceae and Euglenophyceae (1923, 1173, 889 and 541 organisms I(-1)) were recorded at north site in summer and minimum (108,195, 67 and 24 organisms l(-1)) were recorded at south site in monsoon, respectively. PMID- 23029917 TI - Assessment and analysis of noise levels in and around Ib river coalfield, Orissa, India. AB - Heavy earth moving machineries, different capacities of dumpers and loaders, blasting and drilling make the mining environment noisy. A study was carried out to assess the noise level in different opencast projects in and around Belpahar and Brajarajnagar areas of Ib river coalfield. Noise assessment was carried out in various residential, commercial and industrial places. The noise levels, especially L(eq) values of different wheel loaders, dumpers, shovel and crusher units were also assessed and were more than permissible limit (90dB) in some of their operating conditions. Sound ressure level measurements while drilling into coal and overburden at Lakhanpur opencast project yielded noise levels (L(eq)) of 81.33 to 96.2 dB. Thus, these L(eq) values of drilling machines in most of the operating conditions were above permissible limit. The average noise intensities (6 a.m.-10 p.m.: 51.6-60.875dB and 10 p.m.-6 a.m.: 42.6-49.8dB) and L(eq) values (6 a.m.-10 p.m.: 50.9-67.0dB and 10 p.m.-6 a.m.: 40.8-53.3dB) during both day and night time of the residential areas around the Ib river coalfield were in close proximity or beyond the permissible limit. The L(eq) values at some of the commercial and industrial places were beyond (6 a.m.-10 p.m.: 61.6-88.3 dB and 10 p.m.-6 a.m.: 55.4-64.8dB) permissible limit. However, in most of the cases, the L(max) noise values were more (6 a.m.-10 p.m.: 68.5-91.4 dB and 10 p.m.-6 a.m.: 69.3-76.4dB) than the permissible limit. Analysis of variance was also computed for heavy earth moving machineries in different operating conditions and also for different residential, commercial and industrial places to infer the level of significance. The difference of noise intensity produced by different wheel loaders at Lakhanpur and Lilari opencast projects, drilling machines at Lakhanpur opencast project, 50 tons capacity dumpers at various conditions of Ib river coalfield within the same operating condition was significant at both 5% and 1% levels of significance. Similarly, the variance of estimated noise level in residential places during day time and commercial and industrial places during day and night time was significant at both 5% and 1% levels of significance. Moreover, a preliminary survey adopting questionnaire method amongst the mine workers and local inhabitants was also carried out to evaluate their perception about the mining related noise. PMID- 23029918 TI - Hydrogen peroxide-scavenging enzymes impart tolerance to high temperature induced oxidative stress in sugarcane. AB - Seventy-one genotypes of sugarcane from diverse agro-climatic zones of India viz. peninsular, northwest, north-central and eastern zones, were screened for their tolerance to high temperature stress based on the damage to leaf biomass i.e. necrosis of leaf-tips and margins, and rolling of leaves. Nine selected genotypes showing variable response to heat injury were tested for activity pattern of isoforms of two H2O2-scavenging enzymes; ascorbate peroxidase (APX) and catalase (CAT), under high temperature induced oxidative stress. Changes in the activity of APX and CAT isozymes in leaves corresponded to the level of tolerance of genotypes towards heat injury which was substantiated by the highly negative correlation coefficients of heat injury levels of leaves vs. integrated density of APX and CAT isozyme bands. This indicated that the criteria of higher expression of CATs' andAPXs', the two major reactive oxygen species scavenging proteins in leaves may be used to screen large seedling populations and germplasm for high temperature tolerance. PMID- 23029919 TI - Cytogenetic evaluation of cadmium chloride on Channa punctatus. AB - The aim of present study was to evaluate the genotoxic effect of heavy metal in Channa punctatus through the micronucleus test, chromosomal aberrations and sister chromatid exchange. The fish were kept separately in 0.5, 1.0, 2.0 and 5.0 ppm cadmium chloride for 3 days. For micronucleus test blood was collected from caudal vein and smeared on clean slides fixed in methanol and stained with 2% Giemsa. Mean frequency of micronuclei observed was 0.10, 0.15, 0.24, 0.34 and 0.39 in control, 0.5, 1.0, 2.0 and 5.0 ppm CdCl2 respectively. In vivo chromosome preparation from kidney tissues was carried out. The mean frequency of cells with aberrations observed was 0.13, 0.20, 0.34, 0.60 and 0.95 in control, 0.5,1.0, 2.0 and 5.0 ppm CdCl2 respectively. Likewise the mean frequency of SCE observed was 0.05, 0.16, 0.36, 0.44 and 0.52 in control, 0.5, 1.0, 2.0 and 5.0 ppm CdCl2 respectively. It has been revealed from the results of this study that cadmium produced genotoxic effects in fish. PMID- 23029920 TI - Biological decolorization of textile dyes from isolated microfungi. AB - In this study, biological decolorization of two textile dyestuff (Benazol black ZN and Cibacron black W-NN) was comparatively studied using 22 microfungi strains isolated from polluted industrial soil areas. The initial dye concentrations in the medium were 250 and 500 mg l(-1). Benazol black ZN was the best decolorized by Haematonectria haematococca (HH1) (36.0%) and Cibacron black W-NN was the best decolorized by Aspergillus niger (AN1) (33.0%) at 250 mg l(-1) dye concentration. At 500 mg l(-1) dye concentration for two different dyes all microfungi strains used showed weak decolorization rates, maximum 13.0% for Benazol black ZN and 6.0% for Cibacron Black W-NN. PMID- 23029921 TI - A convenient first aid kit for chemical and biological agents and for radiation exposure. AB - The chemical and biological warfare agents are extremely toxic in nature. They act rapidly even in very small quantities and death may occur in minutes. Hence, physical and medical protection must be provided immediately to save life or avoid serious injury. A first aid kit has thus been developed for providing immediate relief from chemical and biological warfare agents (FAKCBW) with the objective of easy detection, personal decontamination, antidote for chemical warfare agents (like nerve agents, sulphur mustard, phosgene, cyanide, radiation exposure and bacterial agents), along with basic medication aid for pain, fever and inflammation. The kit box also includes a user friendly handbook with a simple standard operating procedure. In addition, the kit is rugged to withstand normal jerks, vibration and is water-proof. PMID- 23029922 TI - Anaerobic stabilization and conversion of transformed intermediates of antibiotic pharmaceutical effluent in a fluidized bed reactor. AB - The formulation and implementation of regulatory standards for the ultimate disposal and reuse of transformed products of antibiotic drugs and solvents have been a pending issue in the waste management of pharmaceutical industries especially in the developing countries like India. A case study has been identified and the current issues in one of the major pharmaceutical industry (manufacturing cephalosporin drugs) located in Chennai, India, has been discussed for the possible implementation of anaerobically transformed intermediates of antibiotic pharmaceutical waste sludge. The objective of the study was to determine the effect of bioaugmentation on the convertibility of anaerobically transformed intermediates of antibiotic pharmaceutical waste sludge into residuals and biocompost. Cephalosporin is a common name refers to cephradine (C16H19N3O4S) and cephalexin (C16H17N3O4S.H2O). Based on the critical examination of results, the industry is looking for the alternatives of either direct disposal of 7-amino-3-deacetoxycephalosporanic acid (7-ADCA) and phenyl acetic acid or for further degradation and disposal, which will essentially require additional cost and maintenance. The present regulatory standard implemented in India does not envisage such disposal alternatives and hence this would invite suggestions and recommendations of the expertise for the possible implementation on the pending issue in the antibiotic based pharmaceutical industries. The presence of cephalosporin increases total strength (Chemical Oxygen Demand) of the effluent and indirectly increases the cost of the treatment. Hence the biotransformation of cephalosporin either alone or in combination with other energetic compounds, offers the potential for an economical and environment friendly disposal alternative for the anaerobically transformed intermediates of antibiotic pharmaceutical waste sludge. PMID- 23029923 TI - Artificial neural network and multiple regression model for nickel(II) adsorption on powdered activated carbons. AB - Nickel removal efficiency of powered activated carbons of coconut oilcake, neem oilcake and commercial carbon was investigated by using artificial neural network. The effective parameters for the removal of nickel (%R) by adsorption process, which included the pH, contact time (T), distinctiveness of activated carbon (Cn), amount of activated carbon (Cw) and initial concentration of nickel (Co) were investigated. Levenberg-Marquardt (LM) Back-propagation algorithm is used to train the network. The network topology was optimized by varying number of hidden layer and number of neurons in hidden layer. The model was developed in terms of training; validation and testing of experimental data, the test subsets that each of them contains 60%, 20% and 20% of total experimental data, respectively. Multiple regression equation was developed for nickel adsorption system and the output was compared with both simulated and experimental outputs. Standard deviation (SD) with respect to experimental output was quite higher in the case of regression model when compared with ANN model. The obtained experimental data best fitted with the artificial neural network. PMID- 23029924 TI - Pollutant intrusion modeling in water distribution networks using artificial neural networks. AB - The development and implementation of water quality models for water distribution systems have been growing interest for both environment and hydraulic researchers. It is imperative that the system is able to distribute disinfectants and/or chemicals efficiently for specified quality standards and recover the actual quality of water in case of intrusion of a pollutant into the distribution network. The present work presents hydraulic and quality analysis in a typical water distribution system to obtain the concentration at the sources (pumping station or tanks) affected by typical pollutants utilizing water quality at monitoring points as inputs to artificial neural network (ANN) model. The universal function approximation property of the ANN architecture is being employed for inverse mapping to predict the water quality at the source using the water quality at arbitrary monitoring locations in the distribution system. The optimal monitoring points are identified by water age analysis. The performance evaluation results are encouraging and demonstrate the potential applicability of the methodology. PMID- 23029925 TI - Removal of nickel ion from aqueous solution using Rambai stem (Baccaurea motleyana) adsorbent. AB - The presence of heavy metals in the environment results in a number of environmental problems. In this study, the potential of Rambai stem (Baccaurea motleyana) of Malaysia in removing nickel ion from aqueous solution has been evaluated. The raw material used in this study was obtained from local orchard. The collected material passed through physical preparation and treatment process. The adsorbent was thoroughly characterized by SEM, EDX and FTIR studies. The effect of initial nickel concentration, dosage of adsorbent and pH on the adsorption process were investigated. The highest adsorption capacity obtained at weak acidic conditions (pH 4-5) when dosage and initial concentrations are 0.1 and 30 ppm respectively. The percentage of removal of nickel from the solution was found to be 51%. The experimental data fitted well in Freundlich isotherms indicating the adsorption of nickel on Rambai stem (Baccaurea motleyana) followed heterogenous surface phenomena. PMID- 23029926 TI - Ozone pretreatment for effective biodegradation of monoethylene glycol. AB - Monoethylene glycol (MEG) undergoes various stages during metabolic degradation pathways from acetaldehydes to acetic acid before converting to carbon dioxide and water in a degradation process. Sequential degradation of MEG through biological route obsesses higher retention time. Ozone is considered as an effective oxidant for MEG degradation but involves higher operating cost. When used as pretreatment chemical, ozone is effective in improving the COD: BOD ratio, hence coupling chemical and biological process exhibit a viable option. An attempt was made to enhance the biodegradation by ozone pretreatment. MEG degradation was investigated by ozone pretreatment followed by a continuous bench scale reactor based on activated sludge bio-process. The influence of process variables such as pH, ozone concentration, and hydraulic retention time was studied during the pretreatment studies. The results indicate that pH plays an important role in effective treatment by ozone and would require around pH 10.5. An optimum concentration of 50 mg/L of ozone is required to improve the downstream biodegradation process. Improvement in biodegradation was measured by BOD: COD ratio and formation of intermediates. The intermediates were identified as acetaldehyde and acetic acid. The rate of MEG biodegradation was reduced to 4 hrs compared to reported values of 10 hrs after ozone pretreatment. The reaction time was found 2 hrs during ozone pretreatment. The overall COD reduction was achieved 93% after the biological process. PMID- 23029927 TI - Application of H2O and UV/H2O2 processes for enhancing the biodegradability of reactive black 5 dye. AB - Leather processing is a traditional activity in India during which many organic and inorganic chemicals are added while part of it is absorbed by the leather, the remaining chemicals are discharged along with the effluent. The effluent contains both easily biodegradable and not easily biodegradable synthetic organics like dyes, syntans. Easily biodegradable organics are removed in the existing biological treatment units whereas synthetic organics present in the wastewater are mostly adsorbed over the microbes. As the tannery effluent contains complex chemicals, it is difficult to ascertain the degradation of specific pollutants. To determine the increase in the biodegradability, one of the complex and synthetic organic chemical like dye used in the tanning operation was selected for Advanced Oxidation Process (AOPs) treatment for cleaving complex organics and its subsequent treatment in aerobic process. In the present study, Reactive Black 5 Dye used in the tanning operation was selected for Hydrogen Peroxide (H2O2) and UV/H2O2 pre-treatment for different operating conditions like pH, contact time and different volume of H2O2. A comparison was made between the untreated, Hydrogen Peroxide (H2O2) and UV/H2O2 treated effluent in order to ascertain the influence of AOP on the improvement of biodegradability of effluent. An increase in the BOD5/COD ratio from 0.21 to 0.435 was achieved in the UV/H2O2 pre-treatment process. This pre-treated effluent was further subjected to aerobic process. Biochemical Oxygen Demand (BOD5) and Chemical Oxygen Demand (COD) removal efficiency of the UV/H2O2 pre-treated dye solution in the aerobic process was found to be 86.39% and 77.82% when compared to 52.43% of BOD5 and 51.55% of COD removal efficiency without any pre-treatment. Hence from these results, to increase the biodegradability of Reactive Black 5 dye pre treatment methods like H2O2 and UV/H2O2 can be used prior to biological treatment process. PMID- 23029928 TI - Simultaneous degradation of cyanide and phenol in upflow anaerobic sludge blanket reactor. AB - Coal coking, precious metals mining and nitrile polymer industries generate over several billion liters of cyanide-containing waste annually. Economic and environmental considerations make biological technologies attractive for treatment of wastes containing high organic content, in which the microbial cultures can remove concentrations of organics and cyanide simultaneously. For cyanide and phenol bearing waste treatment, an upflow anaerobic sludge blanket reactor has been developed, which successfully removed free cyanide 98% (with feed concentration of 20 mg 1(-1)) in presence of phenol. The effect of cyanide on phenol degradation was studied with varying concentrations of phenol as well as cyanide under anaerobic conditions. This study revealed that the methanogenic degradation of phenol can occur in the presence of cyanide concentration 30-38 mg 1(-1). Higher cyanide concentration inhibited the phenol degradation rate. The inhibition constant Ki was found to be 38 mg 1(-1) with phenol removal rate of 9.09 mg 1(-1.) x h. PMID- 23029929 TI - Application of patent bio-rack wetland system using Phragmites sp. for domestic wastewater treatment in the presence of high total dissolved solids (TDS) and heavy metal salts. AB - The quality of water recourses is degrading due to improper wastewater management. The aim of this study is to examine the potential of bio-rack system for treatment of domestic wastewater in the presence of high total dissolved solids (TDS) and heavy metal salts. The bio-rack is a modified wetland system incorporated with the advantages of phytoremediation and attached growth microbial process. The bio-rack is void of the soil strata based root zone system and in lieu a support matrix is provided to enrich the micro flora. The studies indicate that, Phragmites sp. can tolerate TDS up to 9000 mg/L in the bio-rack. The heavy metal removal is a function of phytoaccumulation or phytoextraction, which can lead to morphological deformity if heavy metals exceed the saturation limit of 786 and 5760 mg/kg Cd, 854 and 9280 mg/kg Cu, 639 and 4720 mg/kg Ni, 1187 and 7516 mg/kg Zn, in shoots and roots respectively. The reduction in TDS is marginal (14%) at the highest tolerable limit whereas the heavy metal reduction is 68%, 69%, 67%, 71% for Cd, Cu, Ni and Zn respectively at the outlet of the treatment system. The sewage treatment performance of the bio-rack system for all other parameters is estimated as 75 % Chemical Oxygen Demand (COD), 86 % Biological Oxygen Demand (BOD5), 27% Total Dissolved Solids (TDS), 73% Total Suspended Solids (TSS), 9% chlorides, 70% ammonia nitrogen (NH3-N), 32% phosphate (PO4-P), 92% most probable number (MPN) and 93% total viable count (TVC) reduction. PMID- 23029931 TI - Carbon sequestration rate and aboveground biomass carbon potential of three young species in lower Gangetic plain. AB - Carbon is sequestered by the plant photosynthesis and stored as biomass in different parts of the tree. Carbon sequestration rate has been measured for young species (6 years age) of Shorea robusta at Chadra forest in Paschim Medinipur district, Albizzia lebbek in Indian Botanic Garden in Howrah district and Artocarpus integrifolia at Banobitan within Kolkata in the lower Gangetic plain of West Bengal in India by Automated Vaisala Made Instrument GMP343 and aboveground biomass carbon has been analyzed by CHN analyzer. The specific objective of this paper is to measure carbon sequestration rate and aboveground biomass carbon potential of three young species of Shorea robusta, Albizzia lebbek and Artocarpus integrifolia. The carbon sequestration rate (mean) from the ambient air during winter season as obtained by Shorea robusta, Albizzia lebbek and Artocarpus integrifolia were 11.13 g/h, 14.86 g/h and 4.22g/h, respectively. The annual carbon sequestration rate from ambient air were estimated at 8.97 t C ha(-1) by Shorea robusta, 11.97 t C ha(-1) by Albizzia lebbek and 3.33 t C ha(-1) by Artocarpus integrifolia. The percentage of carbon content (except root) in the aboveground biomass of Shorea robusta, Albizzia lebbek and Artocarpus integrifolia were 47.45, 47.12 and 43.33, respectively. The total aboveground biomass carbon stock per hectare as estimated for Shorea robusta, Albizzia lebbek and Artocarpus integrifolia were 5.22 t C ha(-1) , 6.26 t C ha(-1) and 7.28 t C ha(-1), respectively in these forest stands. PMID- 23029930 TI - Effect of flaring of natural gas in oil fields of Assam on rice cultivation. AB - Assam (India) is endowed with natural resources like oil, coal and natural gas. The crude oil, one of the most precious natural resources, is found in the districts of upper Assam. During the process of extraction of crude oil, low pressure natural gas is burnt in the air. Most of the oil wells in upper Assam are located near rice fields and therefore, rice crop grown near the oil wells is exposed to light uninterruptedly causing grain sterility resulting significant loss in grain yield. To identify promising varieties for these areas, we studied the effect of flare on rice varieties with different photoperiod sensitivity. The high light intensity and increased light hours were the factors responsible for substantial loss in grain yield near the flare resulting from delay in flower initiation, reduction of panicle length, having less number of grains per panicle and more grain sterility. To prevent significant loss in yield, photoperiod sensitive traditional and improved rice varieties should not be grown up to the distance of 80 and 100 m, respectively from the boundary wall of the flare pit. Modern weakly-photoperiod sensitive varieties like Ranjti and Mahsuri can be grown 40 m away from the wall while modern photoperiod insensitive variety like Jaya, can be cultivated 20 m away from the wall without significant loss in yield. PMID- 23029932 TI - Detection and analysis of forest cover changes of Indian Sundarbans using satellite data. AB - This study shows the forest cover estimation of Sundarban delta with the help of remote sensing together with Geographical Information System (GIS) and K-means clustering technique. GIS mainly deals with gathering repetitive coverage by satellites and aircrafts of real time forestry information that, finally enables to compile gross forest vegetation resource data of the area under investigation in a single format and monitor the changes. The main study area is the salinity prone south-western part of Sundarbans among Lothian, South-Surendranagar and Dhanchi Islands. Conservation of forestry and the mangroves of these Islands have been studied by the periodic remote-sensed data analysis. This paper also highlights the problems associated with the forest conservation and provides suggestions and schemes for protection and conservation of mangrove forest in Sundarban region. PMID- 23029933 TI - Effect of three carbamate pesticides on population dynamics of soil microorganisms. AB - The response of soil microflora to increasing concentration (300 and 500 mg kg( 1) of soil) of three carbamate pesticides, viz. Oxamyl (I); S-ethyl N(methylcarbamoyl) oxythioacetamidate (II) and N-Phenyl-4-ethylcarbamoyl propyl carbamate (III) was determined under fields conditions over a period of 91 days. After 0,7,14,21,28,35,42,49,56,63,70,77,84,91 days of application the number of bacteria, fungi, actinomycetes and protozoa population was estimated in soil. All the studied pesticides at both the rates of application initially (35-49 days after treatment, DAT) significantly decrease the population of fungi and actinomycetes and thereafter an enhancement of population occurs. Whereas bacteria population at lower dose of application initially (35-49 DAT) increased and thereafter decreased while at higher dose of pesticides population of bacteria continuously decreased. The protozoa population at both the studied concentration for all the studied pesticides decreased with time. The increase in bacteria population and decrease in population of fungi and actinomycetes up to 35-49 days may be due to stimulation of the mineralization rate of organic carbon and ability of bacteria to breakdown the pesticide and utilization of carbon source for their activity. The results also denote that activity of all the studied pesticides is almost same. PMID- 23029934 TI - Environmental impact of mine tailings in Redi mines, Sindhudurg District, Maharashtra (India). AB - Redi mine contains Fe, Mn as major elements, Al, Si as minor elements and also contains traces of Cr, Zn, Pb, Ni, Cu and P. The toxic trace elements present in the ore have also contributed to the contamination of the environment. Various operations of mining, the machinery used, transportation, the metallurgy and kind of waste management practices used are the significant factors of contributing to the nature of tailings of mine. The studies of tailings have revealed that, in addition to elemental contaminations, the operations create acidic environment around the area (pH-6.2 to 6.3 ), as water samples around showed acidic to slightly basic (pH 5.1 to 7.3) nature while soil samples were found acidic to the slightly basic (pH 6.1 to 7.4). In the samples of ore, tailings and soil, the most abundant elements found are Fe, Mn, Si and Al. In water samples, in addition to presence of Fe, Mn, Si, Al, P, significant quantities of Ni, Zn are also found. Ore, tailings and soil samples were analysed by X-Ray Diffraction technique and have shown the presence of goethite, gibbsite, kaolinite, quartz and mica alongwith haematite in the overall composition of ore. PMID- 23029935 TI - Effects of pH on copper accumulation and toxicity in the common carp, Cyprinus carpio. AB - Static, short-term acute toxicity tests were performed over a period of 96h, using different concentrations of copper on common carp (Cyprinus carpio) fingerlings (3.2 +/- 1.1 cm and 0.42 g +/- 0.2 g) at pH 6.5, pH 7.5 and pH 8.5. The effect of copper on carp was significantly high (determined as LC50) at pH 6.5 followed by pH 7.5 and pH 8.5. The lethal toxic effect of copper on common carp was directly proportional to pH. Exposure to sub-lethal doses of 0.25, 0.3, 0.35, 0.45 ppm for 15 days indicated that metal concentration and exposure time are determining factors in the copper accumulation processes. Nonetheless the BAF (Bioaccumulation factor) was found to be inversely proportional to cumulative dosage and duration. PMID- 23029937 TI - Decolourisation of azo dye, Acid Red-18 by Phanerochaete chrysosporium. AB - The ability of wood rotting fungus, Phanerochaete chrysosporium to decolourise azo dye, Acid Red -18 was investigated. The optimal parameters (pH and cell load) required for effective decolourisation were determined. The strain was capable of decolourising dye over a pH range of 4-6 and decolourisation was rather fast, more than 90% in all cases. The optimal pH 5 and cell load of 2.4 x 10(6) spores/mL is required for complete decolourisation of 100 micromol of azo dye Acid Red-18 at a temperature of 37 degrees C. The fungus proved to be capable of both biodegradation and biosorption, and biosorption was found to be the major dye removal mechanism. PMID- 23029936 TI - Assessment of groundwater quality in Ghataprabha command area, Karnataka, India. AB - The studies related to assessment of groundwater quality of Gokak, Mudhol Biligi and Bagalkot taluks of Ghataprabha command area, Belgaum District, Karnataka (India) were carried out during the pre-monsoon and post-monsoon seasons to evaluate its suitability for domestic and irrigation purpose. The samples were collected from 42 locations (including 25 open wells) during pre-monsoon (May, 2007) and post-monsoon (November, 2007) seasons. The samples were analyzed for pH, EC, TDS, carbonates, bicarbonates, alkalinity, chlorides, sulphates, hardness, calcium, magnesium, sodium, potassium, phosphates, nitrates, iron, manganese and fluorides. Based on the concentration of TDS, about 47 % of the samples were found within the permissible limits both for drinking and irrigation, 43% of the samples were useful only for irrigation and 10% of the samples were unfit for drinking and irrigation. Similarly during post-monsoon about 61% of the samples were within the permissible limits both for drinking and irrigation, 31% of the samples were useful only for irrigation and 8 % of the samples unfit for drinking and irrigation. Based on the irrigation water classification, it is understood that, the area falls under low to very high salinity zone for both seasons. The values of sodium absorption ratio indicate that all the samples fall under the category of low, medium and high sodium hazards. The Piper trilinear diagram shows that 60% fall under Na(2+)--K(2+)- HCO3- and Na(2+)-- K(2+)--Cl(-)--SO4(2-) types and rest 40% of the samples fall under Ca(2+)--Mg(2+)--HCO(3-) and Ca(2+)--Mg(2+)--Cl(-)--SO4(2) types. According to U.S.Salinity Laboratory Classification, water belongs to medium salinity to very high salinity and low sodium to high sodium water. PMID- 23029938 TI - Ecotechnological approach for consolidation of uranium tailings. AB - Present study has been undertaken to consolidate radioactivity in uranium mill tailings at Jaduguda, Jharkhand, India.Tailings that remain after processing of ore are released in tailing ponds specially designed for the purpose. The degraded tailing ponds have been capped with 30 cm. thick soil cover. For cosolidation of radioactivity in the tailings firstly the selected plant species should not have any socioeconomic relevance in that area and secondly, uptake of uranium by selected plants has to be low to avoid its dissemination in any form in environment. Seven native plant species of forestry origin were used for experimental trials. Above ground growth has been measured for two years under ex situ and in- situ conditions. Distribution and concentration of uranium have been evaluated in tailing pond soil as well as tailings. Uranium uptake by plants has been evaluated and discussed in this paper. The highest concentration of uranium has been found in the order as: in tailings > soil cover on tailings > roots of selected plant species > shoots of all the selected species. These results show that among seven species tried Jatropha gossypifolia and Furcraea foetida have lowest uptake (below detectable limit), while Saccharum spontaneum and Pogostemon benghalense have comparatively higher uptake among the studied species. PMID- 23029939 TI - Environmental impact assessment of cottage industries of Kashmir, India. AB - Our objective was to carry out environmental impact assessment of small scale industries in Kashmir (India). A prepared questionnaire was circulated among the workers, owners and residents to assess the pros and cons of the small scale industries in Kashmir. The study revealed that most of the small scale industries in Kashmir valley have an impact on the quality of the environment and may cause discomfort to the people living very close to these industries. It has been observed that small scale industries lack efficient waste management system. However, the generated wastes from these units may be used effectively, as a raw material in various ways when managed properly and may minimize the impact on the quality of the environment and may also contribute in improving the economy of the State. The proliferation of small scale industries has caused an irreversible damage to the agricultural land of the area studied. PMID- 23029941 TI - Giant African snail (Achatina fulica Bowdich). AB - The occurrence of great African snail, Achatina fulica, in Nagpur (India) in recent times and its eco-biology, pestiferous nature, uses and control methods are described in this paper. PMID- 23029940 TI - Processing of different types of organic wastes through vermicomposting. AB - In the present study, an effort has been made to utilize different types of organic wastes, i.e. kitchen waste, agro residue, institutional waste and cow dung through the process of vermicomposting. These organic wastes were collected separately, air dried, grinded and mixed in 4:1 ratio with cow dung (w/w). During the period of vermicomposting (75 days), different physico-chemical parameters were analyzed separately. During this process, pH, organic carbon, organic matter and C:N ratio of different organic waste mixtures showed a declining trend, however, total nitrogen, available phosphorus and exchangeable potassium contents showed increasing trend with the advancement of vermicomposting period. Besides, physico-chemical investigations of these wastes, estimation of earthworm population, biomass and number of cocoon produced during vermicomposting were also analyzed separately. It was found that earthworm population, biomass and cocoon production increased significantly as the duration of vermicomposting process increased upto 75 days. PMID- 23029942 TI - Women's health: the harbinger of a healthy society. PMID- 23029943 TI - Is immediate postoperative CA15.3 assay a predictive marker of early postoperative recurrence of carcinoma breast? AB - Breast cancer is still an enigma. Systemic metastasis is an important prognostic factor. Tumour marker can predict occult systemic metastasis. To evaluate the immediate postoperative CA15.3 as predictor of early recurrence, a study was carried out in 48 patients of carcinoma breast in whom immediate postoperative marker level was done. In follow-up, recurrence was noted and relation with tumour size and stage done. Null hypothesis and 't' test were used for analysis. Relation of tumour size with marker is weak but strong relation exists between tumour stage with marker and recurrence with marker. CA15.3 predicts tumour load, can also predict occult residual/occult metastatic disease better than other prognostic markers which only predict tumour behaviour. PMID- 23029944 TI - Level of accessibility of radiological diagnostic tools of high technology and its effect on human health: study of ultrasonography, CT scan and MRI in different perspective. AB - The study was conducted at JNMC, Aligarh, India, to discern the obstacles/hurdles that stood in the way of the patients and the high technology diagnostic tool. For this purpose several parameters were taken eg, education/literacy, occupation and income group, etc. From the study 97% chose to undergo USG and only 3% were defaulters; 86% chose to undergo CT scan and only 14% were defaulters; 79% chose to undergo MRI and 21% were defaulters. Low cost investigations ie, USG and CT scan were more prescribed to IVth social class but MRI was mostly prescribed to IInd. Most of the defaulters were from IVth social class and showed financial problem for getting investigation. Taking into consideration the cost and sensitivity of procedure, it was found in this study that mainly cost determines the outcome. Sensitivity did not matter in patient's perspective. This was the reason that maximum defaulters were found in MRI, followed by CT scan and least in USG. Financial constraint was primary reason declared by defaulters followed by distance. Additional parameters like literacy, occupation and social standing were also found significant in the study in the sense of prescription of investigation and being defaulter. PMID- 23029945 TI - Perinatal outcome in pregnancies with intra-uterine growth restriction by using umbilical and middle cerebral artery colour Doppler. AB - There are various biophysical methods used for diagnosing and monitoring foetal well being using in intra-uterine growth restriction foetus, out of which Doppler velocimetry proved to possess the predictive capacity in diagnosing and management of intra-uterine growth restriction foetuses. The objectives were to study Doppler velocimetry of foetal umbilical artery and middle cerebral artery in diagnosing intra-uterine growth restriction and to correlate Doppler finding with perinatal outcome. Random 50 patients with singleton pregnancies admitted in RG Kar Medical College and Hospital were studied in a duration of 1 year. Umbilical artery and middle cerebral artery were studied during foetal inactivity and apnoea. Percentage of normal and abnormal Doppler velocimetry of umbilical artery and middle cerebral artery was observed and its relation with perinatal outcome analysed. Out of 50 patients, 30% had normal and 70% had abnormal umbilical artery Doppler velocimetry. Neonatal intensive care unit admission was 20% in normal and 71.42% in abnormal umbilical artery Doppler, 46.4% in normal and 68.1% in abnormal middle cerebral artery Doppler and 9.09% in normal and 69.23% in abnormal cerebroplacental index. Neonatal mortality was 0% in normal and 14.3% in abnormal umbilical artery Doppler velocimetry. Oligohydramnios was 26% in normal and 71% in abnormal umbilical artery Doppler. The study revealed that overall perinatal outcome was poor in abnormal Doppler velocimetry group in comparison to normal group. Doppler investigation of the foetal circulation not only plays an important role in monitoring of the growth restricted foetuses but also helps in detecting foetal compromises early in intra-uterine growth restriction foetuses and thereby helps to determine the optimal time for delivery. PMID- 23029946 TI - Efficacy and safety of flupirtine maleate and tramadol hydrochloride in postoperative pain management--a prospective randomised double blinded study. AB - The study was conducted to evaluate the efficacy and safety of flupirtine maleate 100 mg thrice daily compared to tramadol hydrochloride 50 mg thrice daily as postoperative pain management for 5 days. A total of 113 postoperative patients were recruited for the study. Those who met the inclusion criteria (n = 104) were randomised into two treatment groups. One of the groups received flupirtine maleate and the other tramadol hydrochloride both orally. The pain intensity was assessed by visual analogue scale. Patients were informed to report any adverse effect encountered during the study period. The overall effect of the drug (global assessment of the study medication) on pain and side-effects was assessed by the patients at the end of the trial on a categorical scale. There was significant reduction in pain score (p < 0.001) in the flupirtine group with almost equal efficacy to that of tramadol group but the incidence of adverse effects were much less (7.4%) and didn't need discontinuation of the study. All drugs were assessed as good. Therefore it can be concluded that oral flupirtine can deliver the same analgesic efficacy as oral tramadol for postoperative pain relief, which might be beneficial for avoiding the adverse effects ofopioids and non-steroidal anti-inflammatory drug therapy. PMID- 23029947 TI - Achieving good glycaemic control-effective use of self monitoring of blood glucose (SMBG). AB - There is a sustained rise in the prevalence of diabetes and its complications over past decade worldwide. Self monitoring of blood glucose (SMBG) forms an integral part of the management plan for glycaemic control in diabetes which is directly related to the risk of diabetic complications. There have been significant advances in glucose monitoring techniques over years in order to improve and make diabetes management easier and more precise. Optimal use of SMBG requires correct monitoring technique, calibration of device and proper interpretation of data and adjustment of diet, exercise and drug therapy to achieve glycaemic goals. This review aims to highlight importance of SMBG in glycaemic control with emphasis on indication of monitoring, frequency and tools for effective use of SMBG for achieving glycaemic control. PMID- 23029948 TI - Frequency of auto-immune thyroiditis in Burdwan Medical College and Hospital. AB - To study the efficacy of fine needle aspiration cytology as a diagnostic tool and also to find out the incidence of auto-immune thyroiditis in Burdwan a prospective study was undertaken among 131 patients with thyroid swelling presented to the department of ENT, Burdwan Medical College and Hospital, Burdwan, a rural based medical college. All patients underwent fine needle aspiration cytology. Out of them satisfactory aspirates were obtained in 130 cases. There were 31 cases (23.84%) of auto-immune thyroiditis among 130 cases. Auto-immune thyroiditis is the archetype for organ-specific auto-immune disorders. Incidence of auto-immune thyroiditis is increasing day by day. Their accurate diagnosis and management needs a team approach. The incidence of auto immune thyroiditis patients is high in Burdwan Medical College and Hospital. PMID- 23029949 TI - Prevention of voice prosthesis biofilms: current scenario and future trends in prolonging prosthesis lifetime. AB - Voice rehabilitation after a total laryngectomy is an important requisite for patients' rehabilitation. Oesophageal speech using tracheo-oesophageal-valved prostheses is now considered the state-of-art in postlaryngectomy voice rehabilitation. One of the major drawbacks of voice prostheses is their limited device lifetime. This is due to the deterioration of the silicone rubber material by different bacterial and yeast species, which are organised in the form of a biofilm resulting in internal leakage, increased airflow resistance, impeding speech, respiration and swallowing. The use of antimicrobials though easily applicable is associated with development of resistance if used on long-term basis. Other techniques in the form of modification of physicochemical properties of the silicon surface or covalent binding of antimicrobial agents to the silicon surface have been employed. This article reviews the different strategies investigated until now and the future trends in preventing biofilm formation for prolonging the lifetime of the silicon voice prostheses. Data was collected by conducting a computer aided search of the MED-LINE and PUBMED databases, supplemented by hand searches of key journals. Over 35 articles in the last two decades on the topic have been reviewed out of which 27 were found to be of relevant value for this article. PMID- 23029950 TI - Medical practice and related insurance. AB - The liability of a doctor as regards medical negligence is now a well accepted eventuality. However still many doctors and hospitals are unaware of their liability on account of negligence on the part of their junior doctors and hospital staff. Indemnity insurance specifically protects you against your liability to pay compensation including legal costs, fees or expenses. If court orders to pay compensation for negligence of patient and you have a valid insurance cover, the insurance company is supposed to pay the money. In the present text we are highlighting the medical practice related insurance such as personal indemnity insurance, error and omission policy for hospital and nursing homes and insurance policy related to damage to hospital building, damage to electrical and electronics appliances and also insurance for doctor's kit, signboard, burglary, fidelity guarantee and loss of money in transit. All this medical practice related insurance is explained with its present charges, terms and conditions and its importance in today's practice. PMID- 23029951 TI - Diagnostic enigma in retroperitoneal paraganglioma--a case report. AB - Paragangliomas and pleomorphic undifferentiated sarcoma/malignant fibrous histiocytomas are examples of uncommon tumours in retroperitoneum. Where malignant fibrous histiocytoma is to be treated aggressively to save the life, long-term follow-up after surgery is the basic management for paraganglioma. Hence an inappropriate diagnosis of malignant fibrous histiocytoma in place of a paraganglioma which in most cases behave as benign tumour, can lead to a significant complication related to postoperative therapy. Here in this case a patient of retroperitoneal tumour having discrepancies between pre-operative cytological and postoperative histopathological diagnosis is reported. After careful review of clinical, radiological and histopathological features, the appropriate diagnosis of paraganglioma was rendered and the patient was kept for long-term close follow-up instead of aggressive therapy. The appropriate clinicopathologic correlation of the case by a group of experienced oncologists and pathologists revealed the diagnostic enigma and offered the appropriate management which may otherwise lead to iatrogenic complications. PMID- 23029952 TI - Primary tuberculosis of stomach. AB - Gastric tuberculosis is mostly secondary to pulmonary tuberculosis. Primary and isolated gastric tuberculosis is very rare. A case of primary gastric tuberculosis of stomach in a 45-year-old female, known diabetic and hypertensive who presented to the hospital with epigastric pain and vomiting is being reported. Endoscopy showed a gastric ulcerated nodular lesion and biopsy showed tuberculous granuloma. Repeat endoscopy after a course of antituberculosis treatment showed minimal gastritis and complete resolution of the ulcerated nodular lesion. PMID- 23029953 TI - Primary carcinoma of jejunum--a case report. AB - A 73 years old male presented with features of acute intestinal obstruction. At exploratory laparotomy, a mass was felt in jejunum. The growth with adequate margin and mesenteric lymph nodes were removed. The jejunal growth was diagnosed as adenocarcinoma on histopathology, which is a rare tumour of small intestine. He was planned adjuvant chemotherapy. He is in complete remission 6 months after follow-up. PMID- 23029954 TI - Atypical case of hypertrophic osteo-arthropathy. PMID- 23029955 TI - The abdominal cocoon. PMID- 23029957 TI - Immunology and Nobel Prize: a love story. PMID- 23029956 TI - Evaluation of efficacy and tolerability of fixed dose combination of ofloxacin with ornidazole infusion (infusion O2) in the management of diarrhoea and dysentery. AB - Acute diarrhoea in adults is one of the most commonly encountered medical emergency in general practice and is responsible for considerable morbidity around the world. To evaluate the efficacy and tolerability of fixed dose combination of ofloxacin with ornidazole infusion (infusion O2) in the management of diarrhoea and dysentery, a study was carried out among 290 patients, age group from 18 to 65 years suffering from diarrhoea, dysentery, gastro-enteritis. Study drug infusion O2, (Medley Pharmaceutical, Mumbai) containing ofloxacin 200 mg + ornidazole 500 mg was administrated twice daily for a duration of 5 days. Number of soft or watery stool, body temperature, nausea, abdominal pain, gas and flatulence were recorded at baseline and at the end of the study. Tolerability and efficacy was evaluated based on the global assessment by the investigator based on a 3-point scale marked as excellent/good/poor. Two hundred and fifty-six patients (160 male and 96 female) were included for final analysis, 34 patients lost to follow-up. Mean number of watery stool per day was reduced from 9.273 +/- 0.4537 to 1.375 +/- 0.07001 (p < 0.0001) by infusion O2. Body temperature was significantly reduced from 38.055 +/- 0.045 degrees C to 36.778 +/- 0.016 degrees C (p < 0.0001) at the end of the study. Pretreatment symptom nausea was significantly reduced in 90.34% of patients. Improvement in vomiting symptoms was reported in 72.35% of patients after administration of anti-emetic drug; 96.84% and 77.25% of patients reported improvement in abdominal pain and gas/flatulence respectively at the end of the trial by infusion O2. As per investigators' assessment about efficacy of trial drug, 98.43% of patients reported good to excellent and 1.56% reported poor efficacy. As per investigators' assessment about tolerability 98.43% of patients reported good to excellent and 1.17% reported poor tolerability. Minor incidences of nausea, gastritis, metallic taste were reported in 7.42%, 7.14%, and 5.85% of patients respectively. No serious adverse events were reported which led to withdrawal of patient from the study. Result of this study shows that, combination of ofloxacin with ornidazole infusion (infusion O2) significantly reduces number of watery stool and associated symptoms like nausea, abdominal pain, flatulence/gas with excellent tolerability. PMID- 23029958 TI - Moderate regular exercises reduce inflammatory response for physical stress. AB - Exercises induce pro-inflammatory cytokines. We assessed the effect of different grades of exercises on inflammatory cytokine response. Twenty healthy volunteers performed a single bout of moderate exercise, a single bout of strenuous exercise and one month regular moderate exercise using standardized 10m Shuttle Walk Test. Interleukin-6 (IL-6) and Tumour Necrosis Factor Alpha (TNF-alpha) were estimated by Sandwich ELISA method after each exercise regime. Statistics were run using SPSS software version 11.0, Systat software. Repeated measures ANOVA has been used for analysis of IL-6 values and Friedman test has been used for analyzing TNF-alpha and IL-6 values. Twenty healthy volunteers (18 to 30 years) were chosen for this study. The mean and SEM of plasma levels (pg/ml) of IL-6 before exercise was 10.70 +/- 1.11 pg/ml, whereas, after acute moderate exercise and acute strenuous exercise it was 12.00 +/- 1.09 pg/ml and 13.35 +/- 0.89 pg/ml respectively. interestingly, after one month of moderate exercise the values decreased to; 8.80 +/- 0.65 pg/ml. Mean and SEM of TNF-alpha before exercise was 121.78 +/- 29.06 pg/ml. With acute moderate exercise and after acute strenuous exercise the values were 132.90 +/- 35.75 pg/ml and 112.05 +/- 29.89 pg/ml respectively. After one month moderate exercise the levels decreased to 94.95 +/- 27.29 pg/ml. The observed changes in both IL-6 and TNF-alpha levels before and after both moderate and strenuous exercise were statistically significant. Although there was a slight decrease in the value of both the cytokines after one month of regular moderate exercise compared to baseline value, the difference in the values was not statistically significant. However, both IL-6 and TNF-alpha levels showed overall statistically significant difference among the different grades of exercise. Plasma IL-6 and TNF-alpha increase with acute moderate exercise and IL-6 increases further with acute strenuous exercise. Their levels tend to fall below baseline with one month of regular moderate exercise indicating that regular moderate exercise has beneficial effects. PMID- 23029959 TI - Effect of short duration aerobic exercise training on reflection index, stiffness index and pulse wave velocity. AB - The study was aimed to establish the effect of aerobic exercise on reflection index (RI), stiffness index (SI) and brachial finger pulse wave velocity (BFPWV) in healthy subjects of Bangalore, India. Students of 18 to 25 years (males) were recruited according to the inclusion criteria. The subjects were trained on treadmill for a period of 8 weeks, and the above parameters were measured using BIOPAC software and doppler machine. ANOVA of repeated measures was done to see the effect of training on RI, SI and BFPWV with bonferroni correction. There was a significant decrease in above parameters (P<0.0001) compared to basal levels. There was significant correlation between BFPWV and SI (P<0.001). 8 weeks of training showed beneficial effect by reducing BFPWV, SI, and RI and it returned towards baseline after subsequent 4 weeks of detraining. We conclude that changes are because of the effect of aerobic exercise and are reversible. PMID- 23029960 TI - Ejection fraction at the first attack of myocardial infarction and postinfarction survival in South Indian population. AB - Ischemic heart disease is estimated to be the most important cause of mortality by the end of 2020 world wide despite sufficient improvement in health care. It has several modifiable and few non modifiable prognostic variables. Therefore, we analyzed the data of all patients admitted for the first time for acute myocardial infarction (MI) and evaluated the long term modifiable prognostic variables retrospectively. We did not find any difference in the age, blood pressure, hematological and several biochemical parameters between patients who survived and those who expired in 4 years of follow up. Our study revealed that in the expired group patients, the mean admission heart rate, ejection fraction, serum urea and creatinine levels were higher and bicarbonate level was lower compared to survived group patients at the first attack of MI. Also, despite the less incidence of myocardial infarction in females, the percentage of cardiac death was higher in female MI patients. We suggest from our retrospective analysis that MI patients with higher heart rate, altered renal function and metabolic acidosis should be rigorously followed up and special counseling should be provided to old age female patients for better prognosis and survival. PMID- 23029961 TI - A study on quality of life in patients following myocardial infarction. AB - Subjective well being has been widely researched in the past few decades and in practical terms it is a term that encompasses the various ways people evaluate their lives including concepts such as life satisfaction, work and health etc. Since, it is well known, that psychological factors including stress, anxiety, poor sleeping habits etc are known to be important causes of life style disorders like myocardial infraction, we started with the hypothesis that subjective well being of post acute MI patients must be poorer compared to normal subjects in the same age group. A comparative study between normal subjects and post acute myocardial infarction patients was undertaken to compare their subjective well being and current mental health status, at Safdarjung Hospital, New Delhi using standardized questionnaires. The results showed significantly higher negative affect like inadequate mental mastery over immediate environment, perceived ill health including disturbed sleep, deficiency in social contacts, and a general ill being about life in the MI group (P<0.05). Regarding the positive emotions, the normal subjects showed a higher general well being positive affect, higher transcedence and higher perception of social support. (P<0.05). The GHQ also yielded significantly better sleeping habits, less anxiety, better perception of health and more satisfaction with life in the normal subjects compared to post acute MI patients. (P<0.05). PMID- 23029962 TI - Assessment of cardiovascular response to treadmill exercise in normal healthy Indian adolescents. AB - The study aims to assess the cardiovascular response to treadmill exercise test in healthy Indian adolescents. A group of 50 healthy adolescents took part in the study. Cardiovascular response was assessed by using treadmill exercise test as per Bruce protocol. Pulse rate, blood pressure and ECG were recorded before, during and after undertaking the treadmill test. Mean age and body mass index (BMI) were 18.7 +/- 0.51 yrs. and 21.4 +/- 3.44 kg/m2 respectively. Karl Pearson Correlation analysis showed highly significant negative correlation between BMI and exercise time (r = -0.598, P<0.001) and between resting DBP and Exercise Time (r = -0.424, P<0.002). While BMI and DBP showed highly significant positive correlation (r = 0.463, P<0.001). During exercise pulse and SBP rose and DBP fell. SBP rose from mean 122 to 175 (rise by 53 mm of Hg) and DBP fell from mean 78 to 65 (fall by 13 mm of Hg). One min recovery pulse was 156 indicating 22% fall from target heart rate. All the parameters returned to near resting value at 6 min recovery. In 30% students DBP showed exaggerated response i.e. rise during exercise. These students had more BMI and higher resting DBP as compared to other students, which could be the reason for exaggerated response in these participants. In ECG there were no significant ST/T changes during exercise or recovery period. This study provides normal data for small sample of healthy Indian adolescents when subjected to treadmill exercise test. PMID- 23029963 TI - Physiological taste threshold in type 1 diabetes mellitus. AB - The sense of taste is one of the important oral chemical senses that play a critical role in human life. The taste threshold increases by number of factors such as age, local and systemic disease like diabetes, consumption of alcohol, smoking. The aim of the present study was to assess the relationship between taste threshold in type 1 diabetics and non diabetics for four basic taste modalities (i.e. sweet, salt, sour and bitter). We studied 70 cases of type 1 diabetic and 70 non diabetics. The taste threshold was evaluated using 7 different serially half diluted concentrations of glucose (2.00 M-0.031 M), Nacl (1.00 M-0.0156 M), citric acid (0.05 M-0.0007 M) and quinine sulphate (0.001 M 0.000015 M). A significant increase in taste threshold for sweet (P<0.0001), salt, sour and bitter (P<0.001) in type 1 diabetic was observed. We concluded that taste sensation was reduced in type 1 diabetics. PMID- 23029964 TI - Effect of examination stress on mood, performance and cortisol levels in medical students. AB - Stress produces definable mental and physiological reactions in the body. Mild stress is beneficial in cognitive tasks and performance but persistently high stress may lead to neuropsychiatric illnesses like anxiety and depression. Examinations act as stressor and activate hypothalamic-pituitary adrenal axis causing an increase in cortisol level, which is reflected in saliva. Present study was done on 35 medical students. Their mood parameters were assessed, using Depression Anxiety Stress Scale (DASS) scoring, and salivary cortisol levels using quantitative ELISA. Subjects were evaluated for mood parameters two times, one during relaxed state (with no examinations in preceding 2 weeks and in coming 2 weeks) and another during stressed state (on the day of viva voce examination). The levels of mood parameters and salivary cortisol were significantly raised during examination stress. The changes in stress level significantly correlated with change in levels of anxiety and salivary cortisol though there was no significant effect on the performance. Males and females showed similar changes in mood parameters. This study suggests that as examinations act as unavoidable stressors, the medical educators as well as students should be made aware of the negative consequences of stress faced during medical training. Efficient relaxation program as well as counseling services should be provided to stressed students so that they are able to cope better with examination stress. PMID- 23029965 TI - An innovative device for creating tissue plane cleavage by hydro-dissection based on lever and ergonomic principle. AB - In the Third world countries, the occupational health of a Reconstructive Surgeon attracts due attention from the applied physiology fraternity, where the massive amount of surgical workload causes chronic fatigue and repeated stress and injury. The knowledge of human physiology and the science of ergonomics analyze these challenges and formulate guidelines for creating a work environment that is safe and comfortable for its operators. Presented here is an innovative, cost effective, sterilizable, manually controlled hydrodissection instrument for surgery. This easy to make Syringe Pressure Gun (SPG), has revolutionized the face of cleft palate surgery reducing the surgical time to 50% and the palatal fistula rate from 3% to Zero percent. The effects were studied on patients and the operating surgeon both. The experimental group comprising of 1500 cleft palate patients in whom the gun was used during surgery as compared to 500 controls showed statistically highly significant results in terms of reduction in average bleeding in millilitres (P<0.05), average operating time in minutes (P<0.001), palatal fistula formation (P<0.005) and reduction in surgical complications like flap necrosis. The results in the operating surgeon (self control) on using the instrument, showed highly statistically significant fall in the muscle strain induced by tedious surgical manoeuvres, as studied by EMG (P<0.005), subjective hand grip pain and tiredness on a scale of 0-10, high convenience in flap dissection and therefore work performance improved in spite of the high volume of surgery. This ergonomic innovation will provide clues for future inventions based on physiological principles for improving the occupational health of the doctors and outcome of the patients. PMID- 23029966 TI - Effect of yoga practices on pulmonary function tests including transfer factor of lung for carbon monoxide (TLCO) in asthma patients. AB - Prana is the energy, when the self-energizing force embraces the body with extension and expansion and control, it is pranayama. It may affect the milieu at the bronchioles and the alveoli particularly at the alveolo-capillary membrane to facilitate diffusion and transport of gases. It may also increase oxygenation at tissue level. Aim of our study is to compare pulmonary functions and diffusion capacity in patients of bronchial asthma before and after yogic intervention of 2 months. Sixty stable asthmatic-patients were randomized into two groups i.e group 1 (Yoga training group) and group 2 (control group). Each group included thirty patients. Lung functions were recorded on all patients at baseline, and then after two months. Group 1 subjects showed a statistically significant improvement (P<0.001) in Transfer factor of the lung for carbon monoxide (TLCO), forced vital capacity (FVC), forced expiratory volume in 1st sec (FEV1), peak expiratory flow rate (PEFR), maximum voluntary ventilation (MVV) and slow vital capacity (SVC) after yoga practice. Quality of life also increased significantly. It was concluded that pranayama & yoga breathing and stretching postures are used to increase respiratory stamina, relax the chest muscles, expand the lungs, raise energy levels, and calm the body. PMID- 23029967 TI - Assessment of knowledge, attitude and practices of traffic policemen regarding the auditory effects of noise. AB - The objectives of the present study were to (i) estimate noise levels at major traffic junctions in Bengaluru City, and (ii) assess the knowledge, attitude and practices of traffic policemen deputed at those junctions towards the auditory effects caused by noise pollution. The present questionnaire based study was carried among 60 traffic policemen. Road traffic noise was measured at different places in Bengaluru city using Sound level meter and it ranged from 71.2 to 91 dB. The questionnaire included the questions regarding the self assessment of the policemen about their hearing ability, past and present exposure to loud sound and the use of personal protective devices such as ear plugs and ear muffs. The questionnaire was filled by the subjects and the data was analyzed. The mean age was 42.2 +/- 7.4 years and the mean year of exposure was 10.82 +/- 8.53 yrs. Only 3.33% of the subjects felt that their hearing ability was below average. Thirteen subjects reported that they usually missed some conversation over phone while 25% reported similar condition while talking to someone in crowd. 16.66% had work related tinnitus (> once a day) and experienced it more during working hours. None of them used ear plugs/ear muffs and the reason for non-usage was nonavailability (100%). The self assessment of hearing by traffic policemen suggests that most of the traffic policemen have normal hearing. However, a systematic study with Audiometry of these subjects is recommended. PMID- 23029968 TI - A study of autonomic nervous system status in children of asthmatic parents. AB - Asthmatic patients are known to have autonomic abnormalities. This study evaluated the status of autonomic nervous system in children of asthmatic parents for any occurrences of autonomic abnormalities that are known to occur in asthma. In this study autonomic function tests were conducted in children (5 to 10 years of age) divided into two groups: Group A had children from non-asthmatic parents as Control Group and Group B had children from asthmatic parents as Test Group. Both the groups had healthy children showing no clinical signs and symptoms of asthma, allergy or any illness known to affect autonomic nervous system. In response to various parasympathetic function tests (S/L ratio, 30:15 ratio, valsalva ratio and tachycardia ratio) and sympathetic function tests (handgrip test and cold pressor test) done, the two groups did not show any statistically significant dissimilarity for any of the parameters. The results of our study showed that there were no autonomic abnormalities found in the children of asthmatic parents. Thus this study indicates that the autonomic defects seen in asthmatics could be secondary to asthma and not because of autonomic aberrations inheritance in asthmatics as shown by earlier few studies supporting the possible role of inherited automatic reactivity in the pathogenesis and progression of asthma. PMID- 23029970 TI - Effect of body mass index on parameters of nerve conduction study in Indian population. AB - As the adipose tissue in epineurium is related to some extent to amount of body fat, it is possible that the amount of such fat may affect the nerve conduction. In this study, we have analyzed effect of Body Mass Index (BMI) on various parameters of nerve conduction study in one hundred seventy five healthy volunteers between ages of 18 and 66 years. BMI was determined and nerve conduction studies were performed prospectively in all the subjects using standardized techniques. Prolongation of distal motor latency (DML) was observed with increasing BMI except in motor Peroneal nerve. (In Median Nerve, P<005). F Wave minimum latency was also found to be significantly prolonged in (P<0.05) in motor Tibial nerve. Higher BMI was found to be non-significantly associated with lower amplitude (both sensory and motor) except for peroneal nerve. Motor as well as sensory conduction velocity showed non-significant slowing along increasing BMI except sural and motor-sensory ulnar nerve in younger age group. This study demonstrated that various parameters of nerve conduction study can be affected by BMI. So, this biological factor has to be taken into consideration while interpreting nerve conduction studies. PMID- 23029969 TI - Influence of deep breathing exercise on spontaneous respiratory rate and heart rate variability: a randomised controlled trial in healthy subjects. AB - Studies show that yogic type of breathing exercises reduces the spontaneous respiratory rate. However, there are no conclusive studies on the effects of breathing exercise on heart rate variability. We investigated the effects of non yogic breathing exercise on respiratory rate and heart rate variability. Healthy subjects (21-33 years, both genders) were randomized into the intervention group (n=18), which performed daily deep breathing exercise at 6 breaths/min (0.1 Hz) for one month, and a control group (n=18) which did not perform any breathing exercise. Baseline respiratory rate and short-term heart rate variability indices were assessed in both groups. Reassessment was done after one month and the change in the parameters from baseline was computed for each group. Comparison of the absolute changes [median (inter-quartile ranges)] of the parameters between the intervention and control group showed a significant difference in the spontaneous respiratory rate [intervention group -2.50 (-4.00, -1.00), control group 0.00 (-1.00, 1.00), cycles/min, P<0.001], mean arterial pressure [intervention group -0.67 (-6.67, 1.33), control group 0.67 (0.00, 6.67), mmHg, (P<0.05)], high frequency power [intervention group 278.50 (17.00, 496.00), control group -1.00 (-341.00, 196.00), ms2 P<0.05] and sum of low and high frequency powers [intervention group 512.00 (-73.00, 999.00), control group 51.00 (-449.00, 324.00), ms2, P<0.05]. Neither the mean of the RR intervals nor the parameters reflecting sympatho-vagal balance were significantly different across the groups. In conclusion, the changes produced by simple deep slow breathing exercise in the respiratory rate and cardiac autonomic modulation of the intervention group were significant, when compared to the changes in the control group. Thus practice of deep slow breathing exercise improves heart rate variability in healthy subjects, without altering their cardiac autonomic balance. These findings have implications in the use of deep breathing exercises to improve cardiac autonomic control in subjects known to have reduced heart rate variability. PMID- 23029971 TI - Effect of age, gender and body mass index on visual and auditory reaction times in Indian population. AB - The effect of Age. Gender and Body Mass Index (BMI) on the Visual (VRT) and Auditory reaction time (ART) was studied in 30 males and 30 females in the age group of 18-20 years along with 30 males and 30 females in the age group of 65-75 years. Statistical analysis of the data by one-way ANOVA and post-hoc by Tukey HSD test showed that BMI, VRT and ART were significantly higher in old than young individuals. Females had higher BMI and longer reaction times than males. There was significant positive correlation between BMI and reaction times (VRT and ART) in both males and females by Pearson correlation analysis. Older individuals should be more careful and vigilant about the injuries and falls due to increased reaction time. Longer reaction times and higher BMI in females could be attributed to fluid and salt retention due to female sex hormones affecting sensorimotor co-ordination. PMID- 23029972 TI - Comparative study of lung functions in swimmers and runners. AB - In the present study pulmonary function tests of two different groups of athletes, swimmers and runners were studied and compared. Thirty swimmers who used to swim a distance of two to three kilometers per day regularly were compared with age, sex, height, and weight matched thirty middle distance runners. Runners and swimmers selected for this study were undergoing training since last three years. Tidal Volume (TV), forced Vital Capacity (FVC). Forced expiratory volume in one second (FEV1) and maximum voluntary ventilation (MVV) were higher in swimmers than runners. Swimming exercise affects lung volume measurements as respiratory muscles including diaphragm of swimmers are required to develop greater pressure as a consequence of immersion in water during respiratory cycle, thus may lead to functional improvement in these muscles and also alterations in elasticity of lung and chest wall or of ventilatory muscles, leading to an improvement in forced vital capacity and other lung functions of swimmers than runners. PMID- 23029973 TI - Why we should keep the social security retirement age. PMID- 23029974 TI - Reframing diabetes in American Indian communities: a social determinants of health perspective. AB - American Indians and Alaska Natives (AI/ANs) experience some of the greatest health inequities of any group within the United States. AI/ANs are diagnosed with diabetes more than twice as often as non-Hispanic white Americans. Diabetes is a chronic preventable disease often associated with individual risk factors and behaviors that indicate what interventions are needed to prevent or manage the disease. Individual ameliorative strategies in diabetes prevention and management do not fully address the fundamental causes and complexity of diabetes in American Indian communities. Through the application of a social determinants of health paradigm, social work has the opportunity to reframe diabetes and begin to understand it as a product of and a response to unjust conditions and environments, rather than as a disease rooted solely in individual pathology and responsibility. PMID- 23029975 TI - Intention to work with individuals with dual diagnosis: testing the theory of planned behavior among students from various professions. AB - Providing holistic care to individuals with the dual diagnosis (DD) of intellectual disability and mental illness is a challenging task that requires the work of various health care specialists. The aim of the current study was to examine the intentions of students from various fields to work with individuals with DD. A questionnaire was completed by 512 social work, occupational therapy, speech and language therapy, special education, and nursing students in Israel to measure students' attitudes toward working with individuals with DD, as well as their perceptions of subjective norms, controllability, and self-efficacy. Structural equation modeling showed that the students' intentions to work with individuals with DD were predicted by their attitudes and perceptions of subjective norms. Controllability was found to negatively affect their behavioral intentions. Furthermore, social work and nursing students were found to have the lowest behavioral intentions. Given the lack of education in the field of DD and the prevailing stigmatic attitudes toward this population, university programs should focus on increasing knowledge, promoting positive contact, and reducing the fear attached to working with people with DD. PMID- 23029976 TI - Riding third: social work in ambulance work. AB - This research explored the possible role of social work alongside emergency ambulance services. An ethnographic study included semistructured interviews and direct observations collected over 300 hours while riding in ambulances in an urban setting. The data suggest that social work could play a role by providing needed psychosocial care during ambulance calls. Emergency personnel were often consumed by the medical crises and further constrained by the perceived narrow parameters of their work roles. Consequently, social work's role, informed by a broader biopsychosocial perspective, is envisioned as responding to the observed gaps in service. PMID- 23029977 TI - Motivational interviewing may improve exercise experience for people with multiple sclerosis: A small randomized trial. AB - People with multiple sclerosis (MS) are likely to benefit from regular exercise, but physical inactivity is more common among people with MS than among the general population. This small randomized study evaluated whether motivational interviewing (MI) affects adherence to and personal experience in an exercise program. Inactive people with MS participating in an eight-week exercise program were randomized to either three brief MI (n = 7) or three health coaching (n = 6) sessions. Session attendance for both conditions was high, and MI fidelity was rigorously and reliably measured using the Motivational Interviewing Treatment Integrity Scales. The feasibility of using this approach was demonstrated with a small sample. Large effects favoring the MI condition were found for physical exertion, affect during exercise, and fatigue, but no effects were found for adherence to the exercise program. Treatment integrity measures of MI were correlated with outcomes in expected directions. Although this study demonstrated the feasibility of this MI approach, the large effect sizes found should be viewed with substantial skepticism and replicated in sufficiently powered studies using objective measures of exercise adherence. PMID- 23029978 TI - Attachment styles and changes among women members of overeaters anonymous who have recovered from binge-eating disorder. AB - In Overeaters Anonymous (OA), the 12-step self-help program for compulsive overeaters, binge eating is regarded as a physical, spiritual, and emotional disorder. Consequently, the program proposes recovery through the adoption of a lifestyle that leads to physical, spiritual, and emotional well-being. A qualitative phenomenological study that focused on the emotional recovery of OA members was conducted. Personal narratives were obtained through semistructured in-depth interviews. It was found that the tools used for spiritual and emotional work at OA are essential to recovery. Furthermore, the experience of secure attachment is likely to occur within OA when safe ground is provided and positive attachment figures are accessible. These safe ground and positive attachment figures facilitate a corrective emotional experience that compensates for a childhood recollected in terms of rejection and time spent with a caregiver who lacked the emotional availability required for the creation of a secure attachment. Theoretical, clinical, and future research implications are discussed. PMID- 23029979 TI - Community collaborations between the medical examiner's office and gerontological service providers: implementation of an older adult death review team. PMID- 23029980 TI - [Arterial Hypertension: turning a new leaf!]. PMID- 23029981 TI - [Team-based care involving pharmacists and nurses to improve the management of hypertension]. AB - Only half of hypertensive patients has controlled blood pressure. Chronic kidney disease (CKD) is also associated with low blood pressure control, 25-30% of CKD patients achieving adequate blood pressure. The Community Preventive Services Task Force has recently recommended team-based care to improve blood pressure control. Team-based care of hypertension involves facilitating coordination of care among physician, pharmacist and nurse and requires sharing clinical data, laboratory results, and medications, e.g., electronically or by fax. Based on recent studies, development and evaluation of team-based care of hypertensive patients should be done in the Swiss healthcare system. PMID- 23029982 TI - [Are all diuretics equal for the treatment of hypertensive patients?]. AB - Thiazide (hydrochlorothiazide,...) and thiazide-like (chlortalidone, indapamide,...) diuretics are widely used to treat hypertensive patients. There is growing evidence that these diuretics are not interchangeable and that it might be preferable to choose a thiazide-like diuretic whenever the use of a diuretic is considered. This is in order to prevent optimally the development of cardiovascular complications and the occurrence of metabolic side effects, in particular diabetes. PMID- 23029984 TI - [Arterial blood pressure circadian rhythm: significance and clinical implications]. AB - Arterial blood pressure circadian rhythm: significance and clinical implications Arterial blood pressure exhibits a circadian rhythm characterized by a decrease during the sleep period and a steep increase in the early morning hours that can be characterized by 24 h ambulatory blood pressure monitoring (ABPM). The absence of a nocturnal dipping or an excessive morning surge, commonly observed in hypertensive patients, is associated with an increased cardiovascular and renal risk. Numerous studies show that a better control of nocturnal blood pressure can be obtained by the administration of anti-hypertensive medication at the evening time, improving microalbuminuria, left heart hypertrophy, or arterial intima media thickness, but only one study has so far demonstrated a decrease of major cardiovascular events. In this context, the decision on restoring or not the nocturnal dipping should be left to the judgement of the clinician, and applied in an individual manner to each patient. PMID- 23029983 TI - [Is ABPM an extension of a well done physical examination?]. AB - Hypertension is a key risk factor for developing cardiovascular and renal diseases and one of the most important causes of morbidity and mortality worldwide. Iterative measurement of the clinical blood pressure is the method proposed by international and national organizations to establish the diagnosis of hypertension. However, current data suggest that neither in-hospital nor self home blood pressure measurement is sensitive and specific enough for one to recommend them as the sole diagnostic test. More accurate diagnosis of hypertension would allow a significant cost saving by reducing both cardiovascular and renal complication burden, and costs induced by erroneously diagnosing normal subjects as hypertensives. Therefore, 24h ABPM is increasingly becoming the gold standard for diagnosing hypertension. PMID- 23029985 TI - [Fetal programming of cardiovascular disease: new causes and underlying mechanisms]. AB - There exists an association between pathologic events occurring during early life and the development of cardiovascular disease in adulthood. For example, transient perinatal hypoxemia predisposes to exaggerated hypoxic pulmonary hypertension and preeclampsia predisposes the offspring to pulmonary and systemic endothelial dysfunction later in life. The latter finding offers a scientific basis for observations demonstrating an increased risk for premature cardiovascular morbidity in this population. Very recently, we showed that offspring of assisted reproductive technologies also display generalized vascular dysfunction and early arteriosclerosis. Studies in animal models have provided evidence that oxidative stress and/or epigenetic alterations play an important pathophysiological role in the fetal programming of cardiovascular disease. PMID- 23029987 TI - [Dyspnea in adults]. PMID- 23029986 TI - [Management of arterial hypertension in Tunisia: the challenge of a developing country]. AB - Tunisia is a north-African country where epidemiological and socio-economical transition lead cardio-metabolic diseases at the forefront of health concerns. Cardiovascular disease becomes the leading cause of death. Epidemiological studies noted that 30,6% of adults are hypertensive. Only 38,8% from those diagnosed with hypertension were aware about their disease. From those, 84% take antihypertensive treatment. Tunisian health authorities developed in 1993 a national program for diabetes and hypertension care. Hypertension benefits from a full support by the social security fund for policyholders and the state for the poor. Thus, hypertension followed by public health centers is controlled in 42.9% of cases. PMID- 23029988 TI - [Value and challenges in forced ambulatory care]. PMID- 23029989 TI - [Arrythmia in a healthy heart]. PMID- 23029990 TI - [Tuberculosis: antibiotic resistances, more than ever a menace]. PMID- 23029991 TI - [Anne, my sister, can't you see...]. PMID- 23029992 TI - [Thalidomide: this "mea culpa" which isn't one]. PMID- 23029993 TI - [Leprosy according to Saint Yersin (1)]. PMID- 23029994 TI - [Vanity of doping]. PMID- 23029995 TI - The upcoming field of theranostic nanomedicine: an overview. AB - Nanocarriers have drastically changed the face of health care by making a mark in diverse arenas of diagnosis, drug delivery, and gene delivery to name a few. The recent feat in nanotechnology has been the birth of nanotheranostics which aims at blending both therapeutic and diagnostic functions within a single nanoscaffold. The field of theranostic nanomedicine is a result of fruitful advances in fields of material science, imaging modalities, formulation development, and molecular biology. Theranostic nanomedicine that was at first developed for enhancing the quality of treatment meted out to cancer patients has now been explored even in atherosclerosis and infections, albeit to a lower extent. The review summarizes various types of nanocarriers that have been explored with one or sometimes multiple imaging modalities for an array of applications ranging from drug delivery and gene delivery to photosensitizing agent delivery for photodynamic therapy. The article also highlights the few but significant developments made in the field of theranostic nanomedicine for atherosclerosis and infections. In conclusion, theranostic nanomedicine is a rapidly growing field. However, there are a few problems that need to be addressed before theranostic nanocarriers carve a niche for themselves in the clinic. PMID- 23029996 TI - Local field enhanced Au/CuS nanocomposites as efficient photothermal transducer agents for cancer treatment. AB - Photothermal therapy (PTT) for cancer treatment is the use of heat between 41 degrees C and 45 degrees C to damage cancer cells. As a new type of transducer agent for PPT of cancer, CuS nanoparticles have several advantages over gold nanostructures. The most favorable features are the low cost, simple and easy preparation, and small size for targeting. However, the CuS nanoparticle PTT efficacy needs to be improved for practical applications. In this study, the CuS nano-PTT efficiency was enhanced via the local field enhancement from Au nanoparticle surface plasmon coupling. The results show that absorbance of CuS nanoparticles in Au/CuS nanocomposites is enhanced about 2.2 times by Au nanoparticle surface plasmon coupling. Consequently, the PTT efficacy is enhanced and a power of 0.2 W/cm2 with a 980 nm laser was sufficient for Au/CuS nano-PTT activation. We have demonstrated for the first time that surface plasmon coupling can be used to enhance CuS nanoparticle PTT for cancer treatment. PMID- 23029997 TI - Synthesis and biological evaluation of chitin hydrogel/nano ZnO composite bandage as antibacterial wound dressing. AB - We developed chitin hydrogel/nano ZnO composite bandages using chitin hydrogel and ZnO nanoparticles (nZnO). The homogenized mixture of chitin hydrogel and nZnO was freeze-dried to obtain micro-porous composite bandages. The prepared nanocomposite bandages were characterized using FT-IR, XRD and SEM. In addition, blood clotting, antibacterial, swelling, cytocompatibility and cell attachment capability of the prepared nanocomposite bandages were evaluated. The nanocomposite bandages showed enhanced swelling, blood clotting and antibacterial activity. The incorporation of nZnO helped to attain antibacterial activity. Cytocompatibility studies were carried out using human dermal fibroblast (HDF) cells proved the non-toxic nature of the composite bandages. HDF cell attachment and infiltration analysis showed that the cells were attached and penetrated into the interior (250 microm) of the nanocomposite bandages. These studies revealed that, this nanocomposite can be used for burn, diabetic and chronic wound defects. PMID- 23029998 TI - Green synthesis of biocompatible gold nanocrystals with tunable surface plasmon resonance using garlic phytochemicals. AB - Synthesis of biocompatible gold nanoparticles having tunable optical absorbance finds immense use in biomedical applications such as cancer diagnosis and photothermal therapy. Hence, it is imperative to develop environment and bio friendly green chemical processes that aid in preparing gold nanoparticles with tunable optical properties. In the present work, phytochemicals present in the medicinal herb, viz., garlic, were used to provide the dual effects of reduction of gold salts to gold nanoparticles as well as stabilization, in a single step process. The optical tunability of nanogold with respect to concentration of precursor and volume of garlic extract, processing conditions of garlic, its differing molecular weight fractions, reaction time and temperature has been demonstrated. The presence of a range of anisotropic nanogold including nanotriangles, nanorods and nanospheres as evident from TEM endows the colloid with a tunable optical absorption, specifically into the near infrared region. In vitro stability studies of the colloidal suspension in various media including saline, BSA, histidine and PBS showed that gold nanoparticles did not aggregate with time or differing pH conditions. The role of the garlic phytochemicals in providing stability against agglomeration was also substantiated by FTIR studies. Cytotoxicity studies performed using spherical and anisotropic gold nanoparticles on MCF-7 and L929 cell lines proved the biocompatibility of the material up to high doses of 500 microg/ml. The present work highlights the role of garlic phytochemicals in preparing biocompatible metallic gold nanoparticles with tunable optical properties and good in vitro stability, suggesting its potential use for molecular imaging or therapeutic nanomedicines. PMID- 23029999 TI - Suitability of polyelectrolyte shells modified with fullerene derivate for immunoisolation of cells. Experimental study. AB - The polymeric permiselective membranes application for immunoisolation of cells separating the transplanted cells from the host immunological system may eliminate immunosuppressive therapy during transplantation. The suitability of polyelectrolyte modified nanocoatings for immunoisolation of cells was assessed. The polymeric shells modified with incorporated fullerene derivate were applied for encapsulation of human T-lymphocyte cell line Jurkat or rat pancreatic islets of Langerhans using layer-by-layer technique. Hydroxylated fullerene was incorporated to the polyelectrolyte shell for hydrophility increase as well as for layer stability improvement. Evaluation with AFM, FTIR, fluorescence microscopy confirmed the nanocoating presence on the encapsulated cells. It was observed that polylysine-polyethyleneimine membrane with incorporated fullerenol allowed for encapsulated cells functioning in vitro. Membrane conformation applied for encapsulation of pancreatic rat islets allowed for glucose level decline during xenotransplantation into mice. The elaborated nanocoating may be recommended as the possible alternative to the space consuming microencapsulation for biomedical purposes. PMID- 23030000 TI - Comparative receptor based brain delivery of tramadol-loaded poly(lactic-co glycolic acid) nanoparticles. AB - Receptor mediated endocytosis or transcytosis has been reported for drug delivery across Blood-brain barrier (BBB) and hence, the aim of the present investigations was to prepare and compare brain targeting efficiency of tramadol-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface modified with transferrin (Tf) and lactoferrin (Lf). Nanoparticles of tramadol were prepared using nanoprecipitation technique and surface conjugated with Tf and Lf using epoxy linker. Prepared nanoparticles were characterized for their size, surface charge, drug entrapment, transmission electron microscopy and in vitro drug release. The surface density of Tf and Lf was estimated by protein estimation. The drug distribution in blood, brain and other tissues was studied in mice after intravenous administration. Tf and Lf anchored nanoparticles exhibit enhanced uptake with 2.38 and 3.85 folds higher targeting respectively in the brain when compared with unconjugated nanoparticles. The brain targeting observed for Lf anchored PLGA nanoparticles (Lf-TMD-PLGA-NP) was 1.62 folds that of Tf anchored PLGA nanoparticles (Tf-TMD-PLGA-NP). Hence, the study revealed Tf and specially Lf as promising ligand for enhanced brain deposition of tramadol. PMID- 23030002 TI - Development of a total temperature micro-volume blended incubating and hybridizing apparatus for DNA hybridization on nanoparticles. AB - With the wide application of nanomaterials in biomedical detection in recent years, hybridization methods which use nanoparticles as solid phase hybridization carriers have emerged. However, commercial equipments, such as conventional thermal cyclers and hybridization ovens are usually not appropriate for DNA hybridization on the surface of nanoparticles. We designed and improved a total temperature micro-volume blended incubating and hybridizing apparatus (TTMHA), which can be used for blending and suspending of nanoparticles in a small volume and liquid phase environment. This device highlights the mechanical rotation structure which can not only provide a uniform temperature field, but also makes the liquid flow fully in the reaction system and improves DNA hybridization efficiency significantly. A complex PID control algorithm, including Bang-Bang control and Fuzzy-PID control algorithm, was applied in this research project to improve the control accuracy and stability. Furthermore, a model detection experiment using ssDNA (single strand DNA) sequence was conducted in thermal cyclers and TTMHA respectively to verify the optimal hybridization efficiency of the TTMHA. PMID- 23030001 TI - Synthesis of cytarabine lipid drug conjugate for treatment of meningeal leukemia: development, characterization and in vitro cell line studies. AB - Cytarabine (Cyt) used in the treatment of meningeal leukemia is associated with drawbacks like non selectivity to tumor cells, very short half-life and inability to cross blood brain barrier (BBB) due to its hydrophilic nature. Therefore, stable lipid drug conjugate (LDC) of Cyt with stearic acid was prepared. LDC was characterized by NMR, FTIR, DSC and XRD studies. Polysorbate 80 stabilized nanoparticles of this LDC (LDC-NP) were prepared using solvent injection method and characterized for size, zeta potential and loading efficiency. The LDC-NPs were loaded with appreciable amount (considering hydrophilic nature of drug, prior to conjugation) of drug conjugate (58.39 +/- 4.69%). The prepared LDC-NPs had smooth surface, particle size of 136.80 +/- 3.24 nm, were non-aggregated and had almost spherical and uniform shapes. In vitro release pattern showed initial fast release (14.89 +/- 0.056% in 1 h) followed by sustained release up to 72 h (76.26 +/- 0.156%). The blank stearic acid nanoparticles showed no significant cytotoxic effect on leukemic EL-4 cells and LDC-NPs were more cytotoxic than Cyt solution at 48 h. The lyophilized LDC-NPs were found to be physically stable with respect to size and zeta potential at refrigerated condition for 90 days. These results suggest that Polysorbate 80 stabilized LDC-NPs can be explored for treatment of meningeal leukemia owing to their ability of providing sustained drug release, stability and improved cytotoxicity in leukemic EL-4 cell line. PMID- 23030003 TI - Development and evaluation of tocopherol-rich argan oil-based nanoemulsions as vehicles possessing anticancer activity. AB - In recent years, diverse nanoemulsion vehicles (NEs) have been developed with vast potential for improving therapeutic index of clinically approved and experimental drugs. Using oils rich in omega-3 and omega-6 polyunsaturated fatty acids (PUFA), several promising nanoemulsion formulations have been developed recently for oral and systemic administration. The aim of our present work is to successfully develop and characterize optimized nanoemulsion platform, using the PUFA-rich argan oil that contain several important anti-inflammatory and antimitotic natural components. Using various emulsifying mixtures of polyethoxylated solutol HS-15 and polyethyleneglucol Vitamin E succinyl ester (TPGS), to form different NEs showing extended shelf-life stability. The physicochemical properties of prototype argan NEs were analyzed and utilizing a 32 full factorial design, followed by biocompatibility screen, using normal vascular myocytes and areolar fibroblasts. While 90-180 day stability of NEs correlated with TPGS:solutol surfactant blend ratios, adverse effects on integrity of test cultures were only noted at high TPGS content in the emulsifier system, exceeding 80%. Finally, the anti-proliferative efficacy of selected stable and acceptably biocompatible nanoscale TPGS-emulsified argan oil formulations was investigated using murine breast and colon carcinoma cells. The IC50 values of the combination of argan oil and TPGS (40-80% wt of emulsifiers) were 5-9 folds lower compared to TPGS-free and argan-oil free control NEs. Argan oil NE, stabilized with Vitamin E TPGS and solutol HS mixtures, demonstrated significant pro-apoptotic effect on both test cancer cell lines, indicating built in anticancer properties for such NE platform, potentially enhancing overall antineoplastic effects of incorporated candidate chemotherapeutic agents. PMID- 23030004 TI - Zinc oxide nanoparticles impair the integrity of human umbilical vein endothelial cell monolayer in vitro. AB - Disruption of the intercellular interactions between endothelial cells leads to endothelial dysfunction. The role of nanoparticles in plasma membrane stability, actin cytoskeleton organization and intercellular junctions is unclear. Human umbilical vein endothelial cells were treated with zinc oxide NPs in vitro. Cell shape, adhesiveness and plasma membrane integrity were analyzed by means of optical fluorescence microscopy, scanning electron microscopy and flow cytometry methods. Additionally, lactate dehydrogenase activity assay and annexin V staining were performed. The scanning electron microscopy analysis showed changes in morphology and surface topography. The F-actin organization was typical for migrating cells. Cell membrane damage (significant increase in lactate dehydrogenase release and annexin V staining) was observed in the concentration of ZnO nanoparticles above 30 microg/ml. The relationship between ZnO nanoparticles and endothelial dysfunction was clearly established and the importance of cytoskeleton reorganization and loosening of the continuous endothelial monolayer after nanoparticles exposure has been documented. PMID- 23030005 TI - The effects of silver nanoparticles and doxorubicin combination on DNA structure and its antiproliferative effect against T47D and MCF7 cell lines. AB - The structural changes in DNA caused by the combined effects of silver nanoparticles (Ag NPs) and doxorubicin (DOX) was investigated along with their corresponding inhibitory roles in the growth of T47D and MCF7 cells. The UV visible titration studies showed that DOX + AgNPs could form a novel complex with DNA and this interaction is in the interface between the value induced by electrostatic and intercalative binding. The values of binding constants revealed that DOX + AgNPs interact more strongly with DNA as compared to Ag NPs or DOX alone. Our CD data revealed that although Ag NPs and DOX alone could alter DNA structure, this combination leads to transition of DNA conformation to an ordered and compact molecular form so called psi-type, considering that DNA is relatively thermally stable in the condition used. Thus, we observed that DOX + AgNPs induces conformational change on DNA. The anticancer property of DOX + AgNPs by MTT assay, DAPI stain and flow cytometry analyses demonstrated that this combination can tremendously diminish proliferation of T47D and MCF7 cells compared to DOX or Ag NPs alone. Furthermore, this combination was comparatively non-toxic towards the human endometrial stem cells proliferation. Collectively, these results reveal that DOX + AgNPs could proffer a novel strategy for the development of promising and efficient chemotherapy agents. PMID- 23030006 TI - Temperature-sensitive polymer-coated magnetic nanoparticles as a potential drug delivery system for targeted therapy of thyroid cancer. AB - The objective of this work was to develop and investigate temperature-sensitive poly(N-isopropylacrylamide-acrylamide-allylamine)-coated iron oxide magnetic nanoparticles (TPMNPs) as possible targeted drug carriers for treatments of advanced thyroid cancer (ATC). These nanoparticles were prepared by free radical polymerization of monomers on the surface of silane-coupled iron oxide nanoparticles. In vitro studies demonstrated that TPMNPs were cytocompatible and effectively taken up by cancer cells in a dose-dependent manner. An external magnetic field significantly increased nanoparticle uptake, especially when cells were exposed to physiological flow conditions. Drug loading and release studies using doxorubicin confirmed the temperature-responsive release of drugs from nanoparticles. In addition, doxorubicin-loaded nanoparticles significantly killed ATC cells when compared to free doxorubicin. The in vitro results indicate that TPMNPs have potential as targeted and controlled drug carriers for thyroid cancer treatment. PMID- 23030007 TI - Engineered multifunctional RGD-gold nanoparticles for the detection of tumour specific alpha(v)beta(3) expression: chemical characterisation and ecotoxicological risk assessment. AB - Radiolabelled nanoparticles conjugated to peptides that target specific molecules can be used as agents for diagnosis. For example, technetium-99m-labelled gold nanoparticles conjugated to the cyclic [Arg-Gly-Asp-Phe-Lys(Cys)] (c[RGDfK(C)]) peptide are used for the molecular imaging of tumour-specific alpha(epsilon)beta(3) expression. Gold nanoparticles (AuNPs, 18-20 nm) are assumed to be safe at the concentrations used in diagnostic studies, and several studies of human toxicology and health implications have been discussed in a wide number of reports. However, no data are available on the potential ecotoxicity of radio-AuNPs conjugated to thiol-peptides after complete radionuclide decay. The aim of this study was to determine the ecotoxicological risk, measured by oxidative stress (OS) induction in Hyalella azteca, of a well-characterised multifunctional RGD-AuNP system (Tc-HYNIC-GGC-AuNP-c[RGDfK(C)]). TEM, UV-Vis, Raman, XPS, FT-IR and Far-IR spectroscopy techniques demonstrated that AuNPs were functionalised with the conjugated peptides. An acute toxicity test predicted an LC50 (72 h) of 1.83 cm2 per millilitre of medium. There were no statistically significant increases in OS and antioxidant defences after sub-acute exposure to a surface area concentration of 1/10 of the LC50. Tc-HYNIC-GGC-AuNP-c[RGDfK(C)] (20 nm) was demonstrated to be a chemically stable and nontoxic system in biological media after complete radionuclide decay because it does not promote the expression of OS and antioxidant defence enzymes, such as catalase, glutathione peroxidase and superoxide dismutase in Hyalella azteca. PMID- 23030008 TI - Preparation and characterization of monodisperse core-shell Fe3O4@SiO2 microspheres and its application for magnetic separation of nucleic acids from E. coli BL21. AB - In this article, we present an easy route to prepare monodisperse core-shell Fe3O4@SiO2 microspheres with uniform size and shape. Their structures and properties were studied by transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared spectrometry (FT-IR), and vibrating sample magnetometer (VSM), respectively. The results showed that spherical Fe3O4 microspheres with well dispersion have a rough surface and an average diameter (about 500 nm). After the modification with silica, the particles have a well-defined core-shell structure and a much smoother surface and larger particle diameter (about 600 nm). Furthermore, VSM measurements indicated that the as-prepared Fe3O4 and Fe3O4@SiO2 microspheres were superparamagnetic at room temperature and the saturation magnetization (M(s)) were 58.110 emu/g and 33.479 emu/g, respectively. And then, the prepared monodisperse core-shell Fe3O4@SiO2 microspheres were subsequently applied to separate nucleic acids from the bacteria (E. coli BL21) and verified the great application prospects for bioseparation technology of the biomoleculars. PMID- 23030009 TI - Electrochemical detection of E. coli O157:H7 using porous pseudo-carbon paste electrode modified with carboxylic multi-walled carbon nanotubes, glutaraldehyde and 3-aminopropyltriethoxysilane. AB - Fabrication of three different electrodes based on functional porous pseudo carbon paste electrodes (PPCPEs) was described. PPCPEs were modified with carboxylic multi-walled carbon nanotubes (PPCPE-COOH), glutaraldehyde (PPCPE-CHO) and 3-aminopropyltriethoxysilane (PPCPE-NH2). The modified electrodes were applied in detection of E. coli O157:H7, it was showed that the electrochemical signal of PPCPE-CHO was the strongest among those three kinds of electrodes. A linear relationship between the anodic stripping peak current and the concentration of E. coli O157:H7 from 1.0 x 10(3) to 1.0 x 10(7) cells/mL and a limit of detection as low as 8.0 x 10(2) cells/mL were obtained when PPCPE-CHO was used. PMID- 23030011 TI - Abstracts of the 14th Congress of the International Society for Peritoneal Dialysis. Kuala Lumpur, Malaysia. September 9-12, 2012. PMID- 23030010 TI - Nanocoating of titanium implant surfaces with organic molecules. Polysaccharides including glycosaminoglycans. AB - Long-term stability of titanium implants are dependent on a variety of factors. Nanocoating with organic molecules is one of the method used to improve osseointegration. Nanoscale modification of titanium implants affects surface properties, such as hydrophilicity, biochemical bonding capacity and roughness. This influences cell behaviour on the surface such as adhesion, proliferation and differentiation of cells as well as the mineralization of the extracellular matrix at the implant surfaces. The aim of the present systematic review was to describe organic molecules used for surface nanocoating with focus on polysaccharides including glycosaminoglycans, and how these molecules change surface properties, cell reactions and affect on osseointegartion. The included in vitro studies demonstrated increased cell adhesion, proliferation and mineralization of a number of the tested polysaccharide nanocoatings. The included in vivo studies, showed improvement of bone interface reactions measured as increased Bone-to-Implant Contact length and Bone Mineral Density adjacent to the polysaccharide coated surfaces. Based on existing literature, surface modification with polysaccharide and glycosaminoglycans appears to be an effective way to stimulate bone regeneration on bone-implant interface. PMID- 23030012 TI - The loss of a giant in peritoneal dialysis. PMID- 23030013 TI - Image of the month: A prolapsing antral polyp causing gastric outlet obstruction. PMID- 23030016 TI - Abstracts of the IOF Regionals, 2nd Middle East & Africa Osteoporosis Meeting, 6th Pan Arab Osteoporosis Congress PAOC'6. September 27-October 1, 2012. Dead Sea, Jordan. PMID- 23030014 TI - Lymphoma-associated hemophagocytic lymphohistiocytosis. PMID- 23030017 TI - Abstracts of ESMRMB (European Society for Magnetic Resonance in Medicine and Biology) 2012, the 29th Annual Scientific Meeting. Lisbon, Portugal. October 4-6, 2012. PMID- 23030018 TI - Abstracts of the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. October 10-13, 2012. Lyon, France. PMID- 23030021 TI - Abstracts of the Eurobiotech 2012 Agriculture Symposium. April 12-14, 2012. Kayseri, Turkey. PMID- 23030020 TI - Location but not amount of stimulus occlusion influences the stability of visuomotor coordination. AB - The current study examined whether the amount and location of available movement information influenced the stability of visuomotor coordination. Participants coordinated a handheld pendulum with an oscillating visual stimulus in an inphase and antiphase manner. The effects of occluding different amounts of phase at different phase locations were examined. Occluding the 0 degrees /180 degrees phase locations (end-points) significantly increased the variability of the visuomotor coordination. The amount of occlusion had little or no affect on the stability of the coordination. We concluded that the end-points of a visual rhythm are privileged and provide access to movement information that ensures stable coordination. The results are discussed with respect to the proposal of Bingham (Ecol Psychol 16:45-43, 2004) and Wilson et al. (Exp Brain Res 165:351 361, 2005) that the relevant information for rhythmic visual coordination is relative direction information. PMID- 23030031 TI - Incomplete urethral duplication in an adult male. AB - INTRODUCTION: Urethral duplication is a rare congenital anomaly with less than 200 cases reported. It predominantly occurs in males and is nearly always diagnosed in childhood or adolescence. It is defined as a complete second passage from the bladder to the dorsum of the penis or as an accessory pathway that ends blindly on the dorsal or ventral surface. METHODS: We present the case of a 54 year-old patient with incomplete urethral duplication. DISCUSSION: Urethral duplication commonly occurs in the sagittal plane with one urethral channel lying dorsal to the other. Symptoms vary from completely asymptomatic to urinary incontinence which can lead to a mucopurulent discharge from a low grade urinary tract infection. Other symptoms include double stream (most common complaint) and intermittent urinary discharge. PMID- 23030032 TI - Retraction. Lipid metabolism disturbances and AMPK activation in prolonged propofol-sedated rabbits under mechanical ventilation. PMID- 23030033 TI - Estes NAM III, Halperin JL, Calkins H, et al. ACC/AHA/Physician Consortium 2008 clinical performance measures for adults with nonvalvular atrial fibrillation or atrial flutter. J Am Coll Cardiol 2008;51:865-84. PMID- 23030034 TI - Mesoporous carbon incorporated metal oxide nanomaterials as supercapacitor electrodes. AB - Supercapacitors have attracted huge attention in recent years as they have the potential to satisfy the demand of both huge energy and power density in many advanced technologies. However, poor conductivity and cycling stability remains to be the major challenge for its widespread application. Various strategies have been developed for meeting the ever-increasing energy and power demands in supercapacitors. This Research News article aims to review recent progress in the development of mesoporous carbon incorporated metal oxide nanomaterials, especially metal oxide nanoparticles confined in ordered mesoporous carbon and 1D metal oxides coated with a layer of mesoporous carbon for high-performance supercapacitor applications. In addition, a recent trend in supercapacitor development - hierarchical porous graphitic carbons (HPGC) combining macroporous cores, mesoporous walls, and micropores as an excellent support for metal oxides is also discussed. PMID- 23030035 TI - Graphene-based materials for energy conversion. AB - With the depletion of conventional energy sources, the demand for renewable energy and energy-efficient devices continues to grow. As a novel 2D nanomaterial, graphene attracts considerable research interest due to its unique properties and is a promising material for applications in energy conversion and storage devices. Recently, the fabrication of fuel cells and solar cells using graphene for various functional parts has been studied extensively. This research news summarizes and compares the advancements that have been made and are in progress in the utilization of graphene-based materials for energy conversion. PMID- 23030036 TI - Development of nanomaterials for SALDI-MS analysis in forensics. AB - Within the last decade, the escalation of research output in the field of nanotechnology has spurred the development of new nanomaterials for use as assisting agents in surface assisted laser desorption ionization mass spectrometry (SALDI-MS). Specifically modified nanomaterials, coupled with mass spectrometry, have improved the detection sensitivity, specificity, flexibility and reproducibility of SALDI-MS analysis. The technological advancement of LDI-MS has in turn, propelled the use of the analytical technique in the field of forensics. In this report, the various roles and applications of metal-, silicon- and carbon-based nanostructured materials as SALDI matrices in the analysis of forensic samples are described. The advantages of SALDI-MS as an analytical tool for forensic sample analysis are also discussed. PMID- 23030037 TI - Comparing clean intermittent catheterisation and transurethral indwelling catheterisation for incomplete voiding after vaginal prolapse surgery. PMID- 23030038 TI - Neonates with an antenatal diagnosis of isolated gastroschisis. PMID- 23030039 TI - Member support centre roll out. PMID- 23030040 TI - Undimmed passion for women's health. PMID- 23030041 TI - Pioneering organiser takes her leave. PMID- 23030043 TI - Medicinal significance of benzothiazole scaffold: an insight view. AB - Heterocycles bearing nitrogen, sulphur and thiazole moieties constitute the core structure of a number of biologically interesting compounds. Benzothiazole, a group of xenobiotic compounds containing a benzene ring fused with a thiazole ring, are used worldwide for a variety of therapeutic applications. Benzothiazole and their heterocyclic derivatives represent an important class of compounds possessing a wide spectrum of biological activities. The myriad spectrum of medicinal properties associated with benzothiazole related drugs has encouraged the medicinal chemists to synthesize a large number of novel therapeutic agents. Several analogues containing benzothiazole ring system exhibit significant antitumour, antimicrobial, antidiabetic, anti-inflammatory, anticonvulsant, antiviral, antioxidant, antitubercular, antimalarial, antiasthmatic, anthelmintic, photosensitizing, diuretic, analgesic and other activities. This article is an attempt to present the research work reported in recent scientific literature on different pharmacological activities of benzothiazole compounds. PMID- 23030044 TI - Molecular dynamics simulations to examine structure, energetics, and evaporation/condensation dynamics in small charged clusters of water or methanol containing a single monatomic ion. AB - We study small clusters of water or methanol containing a single Ca(2+), Na(+), or Cl(-) ion with classical molecular dynamics simulations, using models that incorporate polarizability via the Drude oscillator framework. Evaporation and condensation of solvent from these clusters is examined in two systems, (1) for isolated clusters initially prepared at different temperatures and (2) those with a surrounding inert (Ar) gas of varying temperature. We examine these clusters over a range of sizes, from almost bare ions up to 40 solvent molecules. We report data on the evaporation and condensation of solvent from the clusters and argue that the observed temperature dependence of evaporation in the smallest clusters demonstrates that the presence of heated gas alone cannot, in most cases, solely account for bare ion production in electrospray ionization (ESI), neglecting the key contribution of the electric field. We also present our findings on the structure and energetics of the clusters as a function of size. Our data agree well with the abundant literature on hydrated ion clusters and offer some novel insight into the structure of methanol and ion clusters, especially those with a Cl(-) anion, where we observe the presence of chain-like structures of methanol molecules. Finally, we provide some data on the reparameterizations necessary to simulate ions in methanol using the separately developed Drude oscillator models for methanol and for ions in water. PMID- 23030042 TI - Structural basis for isoform-selective inhibition in nitric oxide synthase. AB - Nitric oxide synthase (NOS) converts l-arginine into l-citrulline and releases the important signaling molecule nitric oxide (NO). In the cardiovascular system, NO produced by endothelial NOS (eNOS) relaxes smooth muscle which controls vascular tone and blood pressure. Neuronal NOS (nNOS) produces NO in the brain, where it influences a variety of neural functions such as neural transmitter release. NO can also support the immune system, serving as a cytotoxic agent during infections. Even with all of these important functions, NO is a free radical and, when overproduced, it can cause tissue damage. This mechanism can operate in many neurodegenerative diseases, and as a result the development of drugs targeting nNOS is a desirable therapeutic goal. However, the active sites of all three human isoforms are very similar, and designing inhibitors specific for nNOS is a challenging problem. It is critically important, for example, not to inhibit eNOS owing to its central role in controlling blood pressure. In this Account, we summarize our efforts in collaboration with Rick Silverman at Northwestern University to develop drug candidates that specifically target NOS using crystallography, computational chemistry, and organic synthesis. As a result, we have developed aminopyridine compounds that are 3800-fold more selective for nNOS than eNOS, some of which show excellent neuroprotective effects in animal models. Our group has solved approximately 130 NOS-inhibitor crystal structures which have provided the structural basis for our design efforts. Initial crystal structures of nNOS and eNOS bound to selective dipeptide inhibitors showed that a single amino acid difference (Asp in nNOS and Asn in eNOS) results in much tighter binding to nNOS. The NOS active site is open and rigid, which produces few large structural changes when inhibitors bind. However, we have found that relatively small changes in the active site and inhibitor chirality can account for large differences in isoform-selectivity. For example, we expected that the aminopyridine group on our inhibitors would form a hydrogen bond with a conserved Glu inside the NOS active site. Instead, in one group of inhibitors, the aminopyridine group extends outside of the active site where it interacts with a heme propionate. For this orientation to occur, a conserved Tyr side chain must swing out of the way. This unanticipated observation taught us about the importance of inhibitor chirality and active site dynamics. We also successfully used computational methods to gain insights into the contribution of the state of protonation of the inhibitors to their selectivity. Employing the lessons learned from the aminopyridine inhibitors, the Silverman lab designed and synthesized symmetric double-headed inhibitors with an aminopyridine at each end, taking advantage of their ability to make contacts both inside and outside of the active site. Crystal structures provided yet another unexpected surprise. Two of the double-headed inhibitor molecules bound to each enzyme subunit, and one molecule participated in the generation of a novel Zn(2+) site that required some side chains to adopt alternate conformations. Therefore, in addition to achieving our specific goal, the development of nNOS selective compounds, we have learned how subtle differences in dynamics and structure can control protein-ligand interactions and often in unexpected ways. PMID- 23030045 TI - Ischemia/reperfusion-induced renal failure in rats as a model for evaluating cell therapies. AB - Chronic renal failure is a devastating disease that leads to a multitude of complications. Cell therapy has emerged as a potential treatment modality for renal failure. However, efficacy testing on systemic renal function has been challenging due to the limited availability of reliable models that are fully characterized. In this study, we investigated the possibility of using renal ischemia/reperfusion (I/R) injury as a viable model for testing cell therapies. We examined functional and pathological changes in rat kidneys that were exposed to different ischemia times. Male Lewis rats were divided into five groups. Renal failure was induced by clamping both renal pedicles for combinations of 60, 75, and 90 min, followed by reperfusion. Age-matched healthy rats served as controls. Blood was collected at regular intervals for serum chemistry, and kidneys were harvested at the same intervals for histomorphological assessment. Serum creatinine levels of the animals with I/R injury increased significantly after 3 days and returned to normal levels at 4 weeks. Histologically, kidney tissue showed progressive glomerular and tubular deterioration with varying degrees of fibrosis. Animals exposed to 75- and 90-min ischemia combination times consistently generated more severe injury than the 60-min ischemia period. However, these groups resulted in a high mortality rate. A model in which one kidney is exposed to a shorter ischemia time (60 or 90 min) resulted in sustained renal damage with a lower mortality rate. This study shows that kidneys exposed to I/R result in renal tissue damage as well as decreased renal function. This model can be used to study both the short-term and longer-term effects of kidney disease by varying the length of the ischemic time. In particular, the use of longer ischemic times (75 and 90 min) could be used to study new therapies for acute renal disease, whereas shorter ischemic times (60 min) could be used to study therapies for chronic renal insufficiency. PMID- 23030046 TI - Bacterial community composition associated with freshwater algae: species specificity vs. dependency on environmental conditions and source community. AB - We studied bacterial associations with the green alga Desmodesmus armatus and the diatom Stephanodiscus minutulus under changing environmental conditions and bacterial source communities, to evaluate whether bacteria-algae associations are species-specific or more generalized and determined by external factors. Axenic and xenic algae were incubated in situ with and without allelopathically active macrophytes, and in the laboratory with sterile and nonsterile lake water and an allelochemical, tannic acid (TA). Bacterial community composition (BCC) of algae associated bacteria was analyzed by denaturing gradient gel electrophoresis (DGGE), nonmetric multidimensional scaling, cluster analyses, and sequencing of DGGE bands. BCC of xenic algal cultures of both species were not significantly affected by changes in their environment or bacterial source community, except in the case of TA additions. Species-specific interactions therefore appear to overrule the effects of environmental conditions and source communities. The BCC of xenic and axenic D. armatus cultures subjected to in situ bacterial colonization, however, had lower similarities (ca. 55%), indicating that bacterial precolonization is a strong factor for bacteria-algae associations irrespective of environmental conditions and source community. Our findings emphasize the ecological importance of species-specific bacteria-algae associations with important repercussions for other processes, such as the remineralization of nutrients, and organic matter dynamics. PMID- 23030047 TI - Rapid identification of Staphylococcus aureus directly from positive blood culture media using quantum dots as fluorescence probes. AB - The subcultivation of positive blood cultures for organism identification is a time-consuming process. We explored the use of fluorescent quantum dots (QDs) as probes for the improved detection and identification of Staphylococcus aureus directly from positive blood culture media. Immunofluorescence probes were synthesized by linking biotin-conjugated QDs to streptavidin-conjugated IgG molecules. This QDs-IgG complex is capable of binding anti-SPA antibodies which specifically bind to a cell surface protein of S. aureus. The specificity of the method was confirmed using reference strains. Among 372 positive blood cultures, 73 containing gram-positive cocci in clusters were investigated. Relative to the standard culture method, the immunofluorescence assay showed 90.5% (19/21) sensitivity and 100% (52/52) specificity for S. aureus. These results suggest that this immunofluorescence assay allows the rapid identification of S. aureus directly from specimens. PMID- 23030048 TI - Collection of lanthanides and actinides from natural waters with conventional and nanoporous sorbents. AB - Effective collection of trace-level lanthanides and actinides is advantageous for recovery and recycling of valuable resources, environmental remediation, chemical separations, and in situ monitoring. Using isotopic tracers, we have evaluated a number of conventional and nanoporous sorbent materials for their ability to capture and remove selected lanthanides (Ce and Eu) and actinides (Th, Pa, U, and Np) from fresh and salt water systems. In general, the nanostructured materials demonstrated a higher level of performance and consistency. Nanoporous silica surface modified with 3,4-hydroxypyridinone provided excellent collection and consistency in both river water and seawater. The MnO(2) materials, in particular the high surface area small particle material, also demonstrated good performance. Other conventional sorbents typically performed at levels below the nanostructured sorbents and demonstrate a larger variability and matrix dependency. PMID- 23030049 TI - Prostitution push and pull: male and female perspectives. AB - Smith, Grov, Seal, and McCall's (2012) analysis, focusing on how young men become, and stay, involved in male escorting, is a welcome contribution to the still relatively thin male sex worker literature. For this study group, notably supportive working surroundings, effective coping strategies, and a growing sense of "self-efficacy" eventually turn sex work into an increasingly comfortable experience and viable moneymaking option. In this commentary, I add some reflections from a broader perspective to these insights. I also consider some evidence on the numbers of men and women in sex work and make some observations on male versus female positions related to push and pull factors, stigma, and the experience of sex work. PMID- 23030050 TI - Syntheses and spectroscopic, structural, electrochemical, spectroelectrochemical, and theoretical studies of osmium(II) mono- and bis-alkynyl complexes. AB - The syntheses of trans-[Os(C=C-4-C(6)H(4)X)Cl(dppe)(2)] [X = Br (3), I (4)], trans-[Os(C=C-4-C(6)H(4)X)(NH(3))(dppe)(2)](PF(6)) [X = H (5(PF(6))), I (6(PF(6)))], and trans-[Os(C=C-4-C(6)H(4)X)(C=C-4-C(6)H(4)Y)(dppe)(2)] [X = Y = H (7), X = I, Y = C=CSiPr(i)(3) (8)] are reported, together with improved syntheses of cis-[OsCl(2)(dppe)(2)] (cis-1), trans-[Os(C=CPh)Cl(dppe)(2)] (2), and trans [Ru(C=C-4-C(6)H(4)I)(NH(3))(dppe)(2)](PF(6)) (9(PF(6))) (the last-mentioned direct from trans-[Ru(C=C-4-C(6)H(4)I)Cl(dppe)(2)]), and single-crystal X-ray structural studies of 2-4, 5(PF(6)), 6(PF(6)), and 7. Ammine complexes 5(PF(6))/6(PF(6)) are shown to afford a facile route to both symmetrical (7) and unsymmetrical (8) osmium bis(alkynyl) complexes. A combination of cyclic voltammetry, UV-vis-NIR spectroelectrochemistry, and time-dependent density functional theory (TD-DFT) has permitted identification and assignment of the intense transitions in both the resting state and the oxidized forms of these complexes. Cyclic voltammetric data show fully reversible oxidation processes at 0.32-0.42 V (3, 4, 7, 8) (with respect to ferrocene/ferrocenium 0.56 V), assigned to the (formal) Os(II/III) couple. The osmium(III) complex (di)cations 5(2+) and 7(+) were obtained by in situ oxidation of 5(+) and 7 using an optically transparent thin-layer electrochemical (OTTLE) cell. The UV-vis-NIR optical spectra of 5(2+) and 7(+) reveal low-energy bands in the near IR region, in contrast to 5(+) and 7 which are optically transparent at frequencies below 22,000 cm(-1). TD-DFT calculations on trans-1, 2, 5(+), and 7 and their oxidized forms suggest that the lowest-energy transitions are chloro-to-metal charge transfer (trans-1), chloro-to-phenylethynyl charge transfer (2), and metal-to phenylethynyl charge transfer (5(+), 7) in the resting state and chloro-to-metal charge transfer (trans-1(+)), phosphorus-to-metal charge transfer (5(2+)), alkynyl-to-metal charge transfer (7(+)), or phenylalkynyl-centered pi -> pi* (2(+)) following oxidation. The presence of intense CT bands in the resting states and oxidized states and their significantly different nature across the two states, coupled to their strong charge displacement suggest that these species have considerable potential as electrochemically switchable nonlinear optical materials, while the facile unsymmetrical bis(alkynyl)osmium(II) construction suggests potential in construction of multistate heterometallic modular assemblies. PMID- 23030051 TI - High expression of EphA1 in esophageal squamous cell carcinoma is associated with lymph node metastasis and advanced disease. AB - Eph receptors play important roles in the development of cancer. The present study aimed to investigate the expression of EphA1 and its clinicopathologic significance in esophageal squamous cell carcinoma (ESCC). The expression levels of the EphA1 transcript and protein were compared between ESCC and matched normal mucosa in the same patient. High expression levels of the EphA1 transcript and protein were detected in 25.6% (21/82) and 23.2% (19/82) of tumors compared with matched normal mucosa. The up-regulation of EphA1 transcript in tumors was positively associated with differentiation (p = 0.002), disease stage (p = 0.034), and lymph node metastasis (p = 0.042). Increased expression of EphA1 protein in tumors was more often observed in patients with well-differentiated tumors (p = 0.004), lymph node metastasis (p = 0.028), and advanced tumor stage (p = 0.008). EphA1 protein expression was detected in intraepithelial neoplasias as well. Decreased expression of EphA1 protein was detected in 65.2% (15/23) of samples with low-grade neoplasia and in 85.3% (8/15) of samples with high-grade intraepithelial neoplasia. Increased staining of EphA1 protein was not detected in low-grade intraepithelial neoplasia samples, but was detected in 21.3% (2/15) of high-grade intraepithelial neoplasia samples. Taken together, our results show that EphA1 appears to be a differentiation marker for esophageal squamous cells, and its increased expression is positively associated with lymph node metastasis and advanced disease stage. PMID- 23030052 TI - Damage to the dorsomedial thalamic nucleus, central lateral intralaminar thalamic nucleus, and midline thalamic nuclei on the right-side impair executive function and attention under conditions of high demand but not low demand. AB - This study reports a patient, OG, with a unilateral right-sided thalamic lesion. High resolution 3T magnetic resonance imaging revealed damage to the parvicellular and magnocellular subdivisions of the dorsomedial thalamus (DMT), the central lateral intralaminar nucleus (also known as the paralamellar DMT), the paraventricular and the central medial midline thalamic nuclei. According to the neuropsychological literature, the DMT, the midline and intralaminar thalamic nuclei influence a wide array of cognitive functions by virtue of their modulatory influences on executive function and attention, and this is particularly indicated under conditions of low arousal or high cognitive demand. We explored this prediction in OG, and compared his performance on a range of low and high demand versions of tests that tapped executive function and attention to a group of 6 age- and IQ-matched controls. OG, without exception, significantly under performed on the high-demand attention and executive function tasks, but performed normally on the low-demand versions. These findings extend and refine current understanding of the effects of thalamic lesion on attention and executive function. PMID- 23030054 TI - WiiTM-habilitation of upper extremity function in children with cerebral palsy. An explorative study. AB - OBJECTIVE: Commercially available virtual reality systems can possibly support rehabilitation objectives in training upper arm function in children with Cerebral Palsy (CP). The present study explored the effect of the Nintendo WiiTM training on upper extremity function in children with CP. METHODS: During six weeks, all children received twice a week training with the WiiTM, with their most affected arm. The Melbourne Assessment of Upper Limb Function and ABILHAND Kids were assessed pre- and post- training. In addition, user satisfaction of both children and health professionals was assessed after training. Enjoyment in gaming was scored on a visual analogue scale scale after each session by the children. RESULTS: Fifteen children with CP participated in the study. The quality of upper extremity movements did not change (-2.1, p > 0.05), while a significant increase of convenience in using hands/arms during performance of daily activities was found (0.6, p < 0.05). CONCLUSION: Daily activities seem to be easier performed after WiiTM training for most of the included children with CP. PMID- 23030053 TI - Enalapril reduces proliferation and hyaluronic acid release in orbital fibroblasts. AB - BACKGROUND: Orbital fibroblast proliferation and hyaluronic acid (HA) release are responsible for some of the clinical features of Graves' ophthalmopathy (GO). Thus, inhibition of these processes may be a possible therapeutic approach to this syndrome. Enalapril, a widely used antihypertensive drug, was found to have some inhibitory actions on fibroblast proliferation in cheloid scars in vivo, based on which we investigated its effects in primary cultures of orbital fibroblasts from GO patients and control subjects. METHODS: Primary cultures of GO and control fibroblasts were treated with enalapril or with a control compound (lisinopril). Cell proliferation assays, lactate dehydrogenase release assays (as a measure of cell necrosis), apoptosis assays, and measurement of HA in the cell media were performed. RESULTS: Enalapril significantly reduced cell proliferation in both GO and control fibroblasts. Because enalapril did not affect cell necrosis and apoptosis, we concluded that its effects on proliferation reflected an inhibition of cell growth and/or a delay in cell cycle. Enalapril significantly reduced HA concentrations in the media from both GO and control fibroblasts. CONCLUSIONS: Enalapril has antiproliferative and HA suppressing actions in both GO and control fibroblasts. Clinical studies are needed to investigate whether enalapril has any effects in vivo in patients with GO. PMID- 23030055 TI - Effect of nanoroughness on highly hydrophobic and superhydrophobic coatings. AB - The effect of nanoroughness on contact angles and pinning is investigated experimentally and numerically for low-energy surfaces. Nanoroughness is introduced by chemical vapor deposition of tetraethoxysilane and was quantified by scanning force microscopy. Addition of a root-mean-square roughness of 2 nm on a flat surface can increase the contact angle after fluorination by a semifluorinated silane by up to 30 degrees . On the other hand, nanoroughness can improve or impair the liquid repellency of superhydrophobic surfaces that were made from assembled raspberry particles. Molecular dynamics simulations are performed in order to gain a microscopic understanding on how the length and the surface coating density of semifluorinated silanes influence the hydrophobicity. Solid-liquid surface free energy computations reveal that the wetting behavior strongly depends on the density and alignment of the semifluorinated silane. At coating densities in the range of experimental values, some water molecules can penetrate between the semifluorinated chains, thus increasing the surface energy. Combining the experimental and numerical data exhibits that a roughness-induced increase of the contact angle competes with increased pinning caused by penetration of liquid into nanopores or between neighboring semifluorinated molecules. PMID- 23030056 TI - Editorial: Sports and concussion. PMID- 23030057 TI - Spectrum of acute clinical characteristics of diagnosed concussions in college athletes wearing instrumented helmets: clinical article. AB - OBJECT: Concussive head injuries have received much attention in the medical and public arenas, as concerns have been raised about the potential short- and long term consequences of injuries sustained in sports and other activities. While many student athletes have required evaluation after concussion, the exact definition of concussion has varied among disciplines and over time. The authors used data gathered as part of a multiinstitutional longitudinal study of the biomechanics of head impacts in helmeted collegiate athletes to characterize what signs, symptoms, and clinical histories were used to designate players as having sustained concussions. METHODS: Players on 3 college football teams and 4 ice hockey teams (male and female) wore helmets instrumented with Head Impact Telemetry (HIT) technology during practices and games over 2-4 seasons of play. Preseason clinical screening batteries assessed baseline cognition and reported symptoms. If a concussion was diagnosed by the team medical staff, basic descriptive information was collected at presentation, and concussed players were reevaluated serially. The specific symptoms or findings associated with the diagnosis of acute concussion, relation to specific impact events, timing of symptom onset and diagnosis, and recorded biomechanical parameters were analyzed. RESULTS: Data were collected from 450 athletes with 486,594 recorded head impacts. Forty-eight separate concussions were diagnosed in 44 individual players. Mental clouding, headache, and dizziness were the most common presenting symptoms. Thirty-one diagnosed cases were associated with an identified impact event; in 17 cases no specific impact event was identified. Onset of symptoms was immediate in 24 players, delayed in 11, and unspecified in 13. In 8 cases the diagnosis was made immediately after a head impact, but in most cases the diagnosis was delayed (median 17 hours). One diagnosed concussion involved a 30 second loss of consciousness; all other players retained alertness. Most diagnoses were based on self-reported symptoms. The mean peak angular and rotational acceleration values for those cases associated with a specific identified impact were 86.1 +/- 42.6g (range 16.5-177.9 g) and 3620 +/- 2166 rad/sec( 2 ) (range 183-7589 rad/sec( 2 )), respectively. CONCLUSIONS: Approximately two-thirds of diagnosed concussions were associated with a specific contact event. Half of all players diagnosed with concussions had delayed or unclear timing of onset of symptoms. Most had no externally observed findings. Diagnosis was usually based on a range of self-reported symptoms after a variable delay. Accelerations clustered in the higher percentiles for all impact events, but encompassed a wide range. These data highlight the heterogeneity of criteria for concussion diagnosis, and in this sports context, its heavy reliance on self reported symptoms. More specific and standardized definitions of clinical and objective correlates of a "concussion spectrum" may be needed in future research efforts, as well as in the clinical diagnostic arena. PMID- 23030058 TI - Occurrence of class 1 integrons in uropathogenic fluoroquinolone-resistant clinical Escherichia coli isolates from Jamaica. AB - Quinolone resistance is generally caused by chromosomal mutations, but has been more recently found associated with the plasmid-mediated qnr genes. The objective of this study was to screen and analyse polymorphisms of integrons in clinical isolates of Escherichia coli in Jamaica. Previous studies in Jamaica identified fluoroquinolone resistance in predominantly uropathogenic E. coli clinical isolates: 45% harbouring qnrA, qnrB and/or qnrS, and 17% were (Extended-spectrum beta-lactamase) ESBL-producers. These isolates were analysed for the presence and variation of class 1 and 2 integrase genes, 5'- and 3'- conserved segments and the Orf513 recombinase gene by primer-specific polymerase chain reaction (PCR) and restriction fragment-length polymorphism (RFLP). Results indicated integron encoded integrases in 93% of isolates primarily harbouring class 1 integrase genes; four of 58 isolates carried both classes. The Orf513 and 5'- and 3' conserved segment (CS) regions were identified in 83% and 55% of the isolates respectively. RFLP evaluation of the 5'- and 3'-CS regions in int1-positive strains yielded two main types. The reduced diversity, but wide dispersion of class 1 integrons harbouring qnr genes may give rise to the conservation of the mobile genetic elements in which they are carried. PMID- 23030059 TI - Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. AB - Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, is proposed to be death of a cell in any pathological format, when mediated by an intracellular program. These three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis and programmed necrosis invariably contribute to cell death, whereas autophagy can play either pro survival or pro-death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledge facilitating better understanding of cancer initiation and progression with the three distinctive types of cell death. To be able to decipher PCD signalling pathways may aid development of new targeted anti-cancer therapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy and programmed necrosis pathways and apoptosis-related microRNA regulation, in cancer. Taken together, understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosis may ultimately allow scientists and clinicians to harness the three types of PCD for discovery of further novel drug targets, in the future cancer treatment. PMID- 23030060 TI - Simultaneous multiple target detection in real-time loop-mediated isothermal amplification. AB - Loop-mediated isothermal amplification (LAMP) is a rapid and reliable sequence specific isothermal nucleic acid amplification technique. To date, all reported real-time detection methods for LAMP have been restricted to single targets, limiting the utility of this technique. Here, we adapted standard LAMP primers to contain a quencher-fluorophore duplex region that upon strand separation results in a gain of fluorescent signal. This approach permitted the real-time detection of 1-4 target sequences in a single LAMP reaction tube utilizing a standard real time fluorimeter. The methodology was highly reproducible and sensitive, detecting below 100 copies of human genomic DNA. It was also robust, with a 7 order of magnitude dynamic range of detectable targets. Furthermore, using a new strand-displacing DNA polymerase or its warm-start version, Bst 2.0 or Bst 2.0 WarmStart DNA polymerases, resulted in 50% faster amplification signals than wild type Bst DNA polymerase, large fragment in this new multiplex LAMP procedure. The coupling of this new multiplex technique with next generation isothermal DNA polymerases should increase the utility of the LAMP method for molecular diagnostics. PMID- 23030061 TI - Identification of artifactual microarray probe signals constantly present in multiple sample types. AB - The detection, identification, and quantitation of transcripts have evolved from simple Northern analysis, cDNA cloning, and sequencing to RT-PCR, microarrays, and now digital gene expression using ultra-high-throughput RNA sequencing (RNA Seq). During the course of our studies we observed that some microarray probes show very high signal intensity values yet are discordant when compared with RNA Seq. A total of 99 probes from approximately 30,000 were identified as consistently discordant in four human tissues or cell lines. Interestingly, this set of discordant probes appears array-dependent. Among the 99 probes identified, 70 constantly exhibited a high signal in all 713 available samples surveyed using the Illumina HumanHT-12v4 platform. Some were discordant with additional probes that annotated the same genes. Absence of a number of these transcripts was confirmed by quantitative RT-PCR (qRT-PCR). Our findings suggest that one must be cautious, as some array probes do not capture the level of the target. PMID- 23030062 TI - Continuous enzyme-coupled assay of phosphate- or pyrophosphate-releasing enzymes. AB - A coupled enzyme assay able to monitor the kinetics of reactions catalyzed by phosphate- or pyrophosphate-releasing enzymes is presented here. The assay is based on the concerted action of inorganic pyrophosphatase (PPase), purine nucleoside phosphorylase (PNPase), and xanthine oxidase (XOD). In the presence of phosphate, PNPase catalyzes the phosphorolysis of inosine, generating hypoxanthine, which is oxidized to uric acid by XOD. The uric acid accordingly formed can be spectrophotometrically monitored at 293 nm, taking advantage of a molar extinction coefficient which is independent of pH between 6 and 9. The coupled assay was tested using DNA polymerases as a model system. The activity of Klenow enzyme was quantitatively determined, and it was found in agreement with the corresponding activity determined by traditional methods. Moreover, the continuous coupled assay was used to determine Km and Vmax of Klenow enzyme, yielding values in good agreement with previous observations. Finally, the coupled assay was also used to determine the activity of partially purified DNA polymerases, revealing its potential use to monitor purification of phosphate- or pyrophosphate-releasing enzymes. PMID- 23030063 TI - Kinetically limited differential centrifugation as an inexpensive and readily available alternative to centrifugal elutriation. AB - When separating two species with similar densities but differing sedimentation velocities (because of differences in size), centrifugal elutriation is generally the method of choice. However, a major drawback to this approach is the requirement for specialized equipment. Here, we present a new method that achieves similar separations using standard benchtop centrifuges by loading the seperands as a layer on top of a dense buffer of a specified length, and running the benchtop centrifugation process for a calculated amount of time, thereby ensuring that all faster moving species are collected at the bottom, while all slower moving species remain in the buffer. We demonstrate the use of our procedure to isolate bacteria from blood culture broth (a mixture of bacterial growth media, blood, and bacteria). PMID- 23030064 TI - A 2,6-diformylnaphthalene-1,8:4,5-bis(dicarboximide): synthesis and Knoevenagel condensation with malononitrile. AB - Ozonolysis of the 2,6-divinyl derivative of a naphthalene diimide (NDI) affords a 2,6-diformyl-NDI, which can be used in Knoevenagel condensation reactions, as demonstrated by the synthesis of a 2,6-bis(2,2-dicyanovinyl)-NDI. UV-vis absorption and electrochemical data are compared to those of the parent NDI. PMID- 23030065 TI - Taking the F out of FLP: simple Lewis acid-base pairs for mild reductions with neutral boranes via borenium ion catalysis. AB - Discrete three-coordinate borenium salts 1c and 1d are accessed by cooperative Lewis acid-base pair-mediated heterolytic splitting of the B-H bond in pinacolborane by B(C(6)F(5))(3).DABCO and Ph(3)C(+)/DABCO, respectively. The resulting salts are competent catalysts in the reduction of a broad range of imines and can be generated in situ. Moreover, a mechanistic framework for borenium catalysis based on experimental evidence is proposed. The reaction is suggested to proceed by borenium activation of the imine substrate followed by counterintuitive hydride delivery from HBPin (with the assistance of DABCO) rather than from the HB(C(6)F(5))(3)(-) anion, contrary to typical mechanisms of reduction in FLP systems. PMID- 23030066 TI - Characterization of the cell-nanopillar interface by transmission electron microscopy. AB - Vertically aligned nanopillars can serve as excellent electrical, optical and mechanical platforms for biological studies. However, revealing the nature of the interface between the cell and the nanopillar is very challenging. In particular, a matter of debate is whether the cell membrane remains intact around the nanopillar. Here we present a detailed characterization of the cell-nanopillar interface by transmission electron microscopy. We examined cortical neurons growing on nanopillars with diameter 50-500 nm and heights 0.5-2 MUm. We found that on nanopillars less than 300 nm in diameter, the cell membrane wraps around the entirety of the nanopillar without the nanopillar penetrating into the interior of the cell. On the other hand, the cell sits on top of arrays of larger, closely spaced nanopillars. We also observed that the membrane-surface gap of both cell bodies and neurites is smaller for nanopillars than for a flat substrate. These results support a tight interaction between the cell membrane and the nanopillars and previous findings of excellent sealing in electrophysiology recordings using nanopillar electrodes. PMID- 23030069 TI - Reduced equations of motion for quantum systems driven by diffusive Markov processes. AB - The expansion of a stochastic Liouville equation for the coupled evolution of a quantum system and an Ornstein-Uhlenbeck process into a hierarchy of coupled differential equations is a useful technique that simplifies the simulation of stochastically driven quantum systems. We expand the applicability of this technique by completely characterizing the class of diffusive Markov processes for which a useful hierarchy of equations can be derived. The expansion of this technique enables the examination of quantum systems driven by non-Gaussian stochastic processes with bounded range. We present an application of this extended technique by simulating Stark-tuned Forster resonance transfer in Rydberg atoms with nonperturbative position fluctuations. PMID- 23030068 TI - Cytotoxicity of (-)-vitisin B in human leukemia cells. AB - Vitis thunbergii var. taiwaniana (VTT) is an indigenous Taiwanese wild grape and is used as a folk medicine in Taiwan. VTT is rich in polyphenols, especially quercetin and resveratrol derivatives, which were demonstrated to exhibit inhibitory activities against carcinogenesis and prevent some neurodegenerative diseases. (-)-Vitisin B is one of the resveratrol tetramers extracted from VTT. In this study, we investigated the mechanisms of (-)-vitisin B on the induction of apoptosis in human HL-60 promyelocytic leukemia cells. First, (-)-vitisin B significantly inhibited cell proliferation through inducing cell apoptosis. This effect appeared to occur in a time- and dose-dependent manner. Cell-cycle distribution was also examined, and we found that (-)-vitisin B significantly induced a sub-G1 population in a dose-dependent manner. In addition, (-)-vitisin B exhibited stronger inhibitory effects on cell proliferation than resveratrol. Second, (-)-vitisin B dose dependently induced apoptosis-related protein expressions, such as the cleavage form of caspase-3, caspase-8, caspase-9, poly(ADP ribose) polymerase, and the proapoptotic Bax protein. Third, (-)-vitisin B treatment also resulted in increases in c-Jun N-terminal kinase (JNK) phosphorylation and Fas ligand (FasL) expression. Moreover, the (-)-vitisin B induced FasL expression and caspase-3 activation could be reversed by a JNK inhibitor. These results suggest that (-)-vitisin B-induced apoptosis of leukemia cells might be mediated through activation of JNK and Fas death-signal transduction. PMID- 23030067 TI - The combined effect of persistent organic pollutants in the serum POP mixture in Greenlandic Inuit: xenoestrogenic, xenoandrogenic and dioxin-like transactivities. AB - Greenlandic Inuit have high body burden of persistent organic pollutants (POPs). We analyzed the combined effect of the actual lipophilic serum POP mixture on estrogen-, androgen- and aryl hydrocarbon-receptor functions as effect biomarkers, and the associations between the effect biomarkers and serum POPs, and lifestyle characteristics. The serum POPs were extracted from 232 Inuit from Ittoqqortoormiit, Narsaq and Qeqertarsuaq. The POP-related receptor transactivities correlated negatively to the POP levels and were associated to the lifestyle characteristics. The POP-related receptor transactivities can be used as effect biomarkers. The serum POPs have hormone disruptive potentials. PMID- 23030070 TI - Majorana modes in driven-dissipative atomic superfluids with a zero Chern number. AB - We investigate dissipation-induced p-wave paired states of fermions in two dimensions and show the existence of spatially separated Majorana zero modes in a phase with vanishing Chern number. We construct an explicit and natural model of a dissipative vortex that traps a single of these modes, and establish its topological origin by mapping the problem to a chiral one-dimensional wire where we observe a nonequilibrium topological phase transition characterized by an abrupt change of a topological invariant (winding number). We show that the existence of a single Majorana zero mode in the vortex core is intimately tied to the dissipative nature of our model. Engineered dissipation opens up possibilities for experimentally realizing such states with no Hamiltonian counterpart. PMID- 23030071 TI - Two-dimensional Fermi liquid with attractive interactions. AB - We realize and study an attractively interacting two-dimensional Fermi liquid. Using momentum-resolved photoemission spectroscopy, we measure the self-energy, determine the contact parameter of the short-range interaction potential, and find their dependence on the interaction strength. We successfully compare the measurements to a theoretical analysis, properly taking into account the finite temperature, harmonic trap, and the averaging over several two-dimensional gases with different peak densities. PMID- 23030072 TI - Experimental demonstration of adaptive quantum state estimation. AB - The first experimental demonstration of an adaptive quantum state estimation (AQSE) is reported. The strong consistency and asymptotic efficiency of AQSE have been mathematically proven [A. Fujiwara, J. Phys. A 39, 12489 (2006)]. In this Letter, the angle of linear polarization of single photons, the phase parameter between the right and the left circularly polarization, is estimated using AQSE, and the strong consistency and asymptotic efficiency are experimentally verified. AQSE will provide a general useful method in both quantum information processing and metrology. PMID- 23030073 TI - Unconditionally secure bit commitment by transmitting measurement outcomes. AB - We propose a new unconditionally secure bit commitment scheme based on Minkowski causality and the properties of quantum information. The receiving party sends a number of randomly chosen Bennett-Brassard 1984 (BB84) qubits to the committer at a given point in space-time. The committer carries out measurements in one of the two BB84 bases, depending on the committed bit value, and transmits the outcomes securely at (or near) light speed in opposite directions to remote agents. These agents unveil the bit by returning the outcomes to adjacent agents of the receiver. The protocol's security relies only on simple properties of quantum information and the impossibility of superluminal signalling. PMID- 23030074 TI - Entanglement negativity in quantum field theory. AB - We develop a systematic method to extract the negativity in the ground state of a 1+1 dimensional relativistic quantum field theory, using a path integral formalism to construct the partial transpose rho(A)(T(2) of the reduced density matrix of a subsystem [formula: see text], and introducing a replica approach to obtain its trace norm which gives the logarithmic negativity E=ln//rho(A)(T(2))//. This is shown to reproduce standard results for a pure state. We then apply this method to conformal field theories, deriving the result E~(c/4)ln[l(1)l(2)/(l(1)+l(2))] for the case of two adjacent intervals of lengths l(1), l(2) in an infinite system, where c is the central charge. For two disjoint intervals it depends only on the harmonic ratio of the four end points and so is manifestly scale invariant. We check our findings against exact numerical results in the harmonic chain. PMID- 23030075 TI - Reversible optical-to-microwave quantum interface. AB - We describe a reversible quantum interface between an optical and a microwave field using a hybrid device based on their common interaction with a micromechanical resonator in a superconducting circuit. We show that, by employing state-of-the-art optoelectromechanical devices, one can realize an effective source of (bright) two-mode squeezing with an optical idler (signal) and a microwave signal, which can be used for high-fidelity transfer of quantum states between optical and microwave fields by means of continuous variable teleportation. PMID- 23030076 TI - Interface phase transition induced by a driven line in two dimensions. AB - The effect of a localized drive on the steady state of an interface separating two phases in coexistence is studied. This is done using a spin-conserving kinetic Ising model on a two-dimensional lattice with cylindrical boundary conditions, where a drive is applied along a single ring on which the interface separating the two phases is centered. The drive is found to induce an interface spontaneous symmetry breaking whereby the magnetization of the driven ring becomes nonzero. The width of the interface becomes finite and its fluctuations around the driven ring are nonsymmetric. The dynamical origin of these properties is analyzed in an adiabatic limit, which allows the evaluation of the large deviation function of the magnetization of the driven ring. PMID- 23030077 TI - Entrainment and unit velocity: surprises in an accelerated exclusion process. AB - We introduce a class of distance-dependent interactions in an accelerated exclusion process inspired by the observation of transcribing RNA polymerase speeding up when "pushed" by a trailing one. On a ring, the accelerated exclusion process steady state displays a discontinuous transition, from being homogeneous (with augmented currents) to phase segregated. In the latter state, the holes appear loosely bound and move together, much like a train. Surprisingly, the current-density relation is simply J=1-rho, signifying that the "hole train" travels with unit velocity. PMID- 23030078 TI - Testing MOND over a wide acceleration range in x-ray ellipticals. AB - The gravitational fields of two isolated ellipticals, NGC 720 and NGC 1521, have been recently measured to very large galactic radii (~100 and ~200 kpc), assuming hydrostatic balance of the hot gas enshrouding them. They afford, for the first time to my knowledge, testing modified Newtonian dynamics (MOND) in ellipticals with force and quality that, arguably, approach those of rotation-curve tests in disk galaxies. In the context of MOND, it is noteworthy that the measured accelerations span a wide range, from more than 10a(0) to about 0.1a(0), unprecedented in individual ellipticals. I find that MOND predicts correctly the measured dynamical mass runs (apart from a possible minor tension in the inner few kpc of NGC 720, which might be due to departure from hydrostatic equilibrium): The predicted mass discrepancy increases outward from none near the center, to ~10 at the outermost radii. The implications for the MOND-versus-dark matter controversy go far beyond the simple fact of two more galaxies conforming to MOND. PMID- 23030079 TI - Black-hole bombs and photon-mass bounds. AB - Generic extensions of the standard model predict the existence of ultralight bosonic degrees of freedom. Several ongoing experiments are aimed at detecting these particles or constraining their mass range. Here we show that massive vector fields around rotating black holes can give rise to a strong superradiant instability, which extracts angular momentum from the hole. The observation of supermassive spinning black holes imposes limits on this mechanism. We show that current supermassive black-hole spin estimates provide the tightest upper limits on the mass of the photon (m(v) is < or approximately equal to 4*10(-20) eV according to our most conservative estimate), and that spin measurements for the largest known supermassive black holes could further lower this bound to m(v) < or approximately equal to 10(-22) eV. Our analysis relies on a novel framework to study perturbations of rotating Kerr black holes in the slow-rotation regime, that we developed up to second order in rotation, and that can be extended to other spacetime metrics and other theories. PMID- 23030080 TI - Three-point functions of aging dynamics and the AdS-CFT correspondence. AB - Aging can be realized as a subalgebra of Schrodinger algebra by discarding the time-translation generator. While the two-point functions of the age algebra have been known for some time, little else was known about the higher n-point correlators. In this Letter, we present novel three-point correlators of scalar primary operators. We find that the aging correlators are distinct from the Schrodinger correlators by more than certain dressings with time-dependent factors, as was the case with two-point functions. In the existing literature, the holographic geometry of aging is obtained by performing certain general coordinate transformations on the holographic dual of the Schrodinger theory. Consequently, the aging two-point functions derived from holography look as the Schrodinger two-point functions dressed by time-dependent factors. However, since the three-point functions obtained in this Letter are not merely dressed Schrodinger correlators and instead, depend on an additional time-translation breaking variable, we conclude that the most general holographic realization of aging is yet to be found. We also comment on various extensions of the Schrodinger and aging algebras. PMID- 23030082 TI - Magnetically amplified tunneling of the third kind as a probe of minicharged particles. AB - We show that magnetic fields significantly enhance a new tunneling mechanism in quantum field theories with photons coupling to fermionic minicharged particles (MCPs). We propose a dedicated laboratory experiment of the light-shining-through walls type that can explore a parameter regime comparable to and even beyond the best model-independent cosmological bounds. With present-day technology, such an experiment is particularly sensitive to MCPs with masses in and below the meV regime as suggested by new-physics extensions of the standard model. PMID- 23030083 TI - Percent-level-precision physics at the Tevatron: next-to-next-to-leading order QCD corrections to qq-->tt-+X. AB - We compute the next-to-next-to-leading order QCD corrections to the partonic reaction that dominates top-pair production at the Tevatron. This is the first ever next-to-next-to-leading order calculation of an observable with more than two colored partons and/or massive fermions at hadron colliders. Augmenting our fixed order calculation with soft-gluon resummation through next-to-next-to leading logarithmic accuracy, we observe that the predicted total inclusive cross section exhibits a very small perturbative uncertainty, estimated at +/-2.7%. We expect that once all subdominant partonic reactions are accounted for, and work in this direction is ongoing, the perturbative theoretical uncertainty for this observable could drop below +/-2%. Our calculation demonstrates the power of our computational approach and proves it can be successfully applied to all processes at hadron colliders for which high-precision analyses are needed. PMID- 23030085 TI - Enhancing the intense field control of molecular fragmentation. AB - We describe a pump-probe scheme with which the spatial asymmetry of dissociating molecular fragments-as controlled by the carrier-envelope phase of an intense few cycle laser pulse-can be enhanced by an order of magnitude or more. We illustrate the scheme using extensive, full-dimensional calculations for dissociation of H(2)(+) and include the averaging necessary for comparison with experiment. PMID- 23030084 TI - Search for the Theta+ pentaquark via the pi(-)p->K(-)X reaction at 1.92 GeV/c. AB - The Theta(+) pentaquark baryon was searched for via the pi(-)p->K(-)X reaction with a missing mass resolution of 1.4 MeV/c(2) (FWHM) at the Japan Proton Accelerator Research Complex (J-PARC). pi(-) meson beams were incident on the liquid hydrogen target with a beam momentum of 1.92 GeV/c. No peak structure corresponding to the Theta(+) mass was observed. The upper limit of the production cross section averaged over the scattering angle of 2 degrees to 15 degrees in the laboratory frame is obtained to be 0.26 MUb/sr in the mass region of 1.51-1.55 GeV/c(2). The upper limit of the Theta(+) decay width is obtained to be 0.72 and 3.1 MeV for J(Theta)(P)=1/2(+) and J(Theta)(P)=1/2(-), respectively, using the effective Lagrangian approach. PMID- 23030086 TI - Dynamics of the S(1D2)+HD(j=0) reaction at collision energies approaching the cold regime: a stringent test for theory. AB - We report integral cross sections for the S(1D2)+HD(j=0)->DS+H and HS+D reaction channels obtained through crossed-beam experiments reaching collision energies as low as 0.46 meV and from adiabatic time-independent quantum-mechanical calculations. While good overall agreement with experiment at energies above 10 meV is observed, neither the product channel branching ratio nor the low-energy resonancelike features in the HS+D channel can be theoretically reproduced. A nonadiabatic treatment employing highly accurate singlet and triplet potential energy surfaces is clearly needed to resolve the complex nature of the reaction dynamics. PMID- 23030087 TI - Imaging of isolated molecules with ultrafast electron pulses. AB - Imaging isolated molecules in three dimensions with atomic resolution is important for elucidating complex molecular structures and intermediate states in molecular dynamics. This goal has so far remained elusive due to the random orientation of molecules in the gas phase. We show that three-dimensional structural information can be retrieved from multiple electron diffraction patterns of aligned molecules. The molecules are aligned impulsively with a femtosecond laser pulse and probed with a femtosecond electron pulse two picoseconds later, when the degree of alignment reaches a maximum. PMID- 23030088 TI - High-capacity spatial multimode quantum memories based on atomic ensembles. AB - We study spatial multimode quantum memories based on light storage in extended ensembles of Lambda-type atoms. We show that such quantum light-matter interfaces allow for highly efficient storage of many spatial modes. In particular, forward operating memories possess excellent scaling with the important physical parameters: quadratic scaling with the Fresnel number and even cubic with the optical depth of the atomic ensemble. Thus, the simultaneous use of both the longitudinal and transverse shape of the stored spin wave modes constitutes a valuable and so far overlooked resource for multimode quantum memories. PMID- 23030089 TI - Emergence of spatial spin-wave correlations in a cold atomic gas. AB - Rydberg spin-waves are optically excited in a quasi-one-dimensional atomic sample of Rb atoms. Pairwise spin-wave correlations are observed by a spatially selective transfer of the quantum state onto a light field and photoelectric correlation measurements of the light. The correlations are interpreted in terms of the dephasing of multiply excited spin-waves by long-range Rydberg interactions. PMID- 23030090 TI - Collective state measurement of mesoscopic ensembles with single-atom resolution. AB - We demonstrate single-atom resolution, as well as detection sensitivity more than 20 dB below the quantum projection noise limit, for hyperfine-state-selective measurements on mesoscopic ensembles containing 100 or more atoms. The measurement detects the atom-induced shift of the resonance frequency of an optical cavity containing the ensemble. While spatially varying coupling of atoms to the cavity prevents the direct observation of a quantized signal, the demonstrated measurement resolution provides the readout capability necessary for atomic interferometry substantially below the standard quantum limit and down to the Heisenberg limit. PMID- 23030091 TI - Slack dynamics on an unfurling string. AB - An arch will grow on a rapidly deployed thin string in contact with a rigid plane. We present a qualitative model for the growing structure involving the amplification, rectification, and advection of slack in the presence of a steady stress field, validate our assumptions with numerical experiments, and pose new questions about the spatially developing motions of thin objects. PMID- 23030092 TI - Delayed buckling and guided folding of inhomogeneous capsules. AB - Colloidal capsules can sustain an external osmotic pressure; however, for a sufficiently large pressure, they will ultimately buckle. This process can be strongly influenced by structural inhomogeneities in the capsule shells. We explore how the time delay before the onset of buckling decreases as the shells are made more inhomogeneous; this behavior can be quantitatively understood by coupling shell theory with Darcy's law. In addition, we show that the shell inhomogeneity can dramatically change the folding pathway taken by a capsule after it buckles. PMID- 23030093 TI - Rotation rate of rods in turbulent fluid flow. AB - The rotational dynamics of anisotropic particles advected in a turbulent fluid flow are important in many industrial and natural settings. Particle rotations are controlled by small scale properties of turbulence that are nearly universal, and so provide a rich system where experiments can be directly compared with theory and simulations. Here we report the first three-dimensional experimental measurements of the orientation dynamics of rodlike particles as they are advected in a turbulent fluid flow. We also present numerical simulations that show good agreement with the experiments and allow extension to a wide range of particle shapes. Anisotropic tracer particles preferentially sample the flow since their orientations become correlated with the velocity gradient tensor. The rotation rate is heavily influenced by this preferential alignment, and the alignment depends strongly on particle shape. PMID- 23030094 TI - Ion-wake-mediated particle interaction in a magnetized-plasma flow. AB - The interaction forces between dust grains in a flowing plasma are strongly modified by the formation of ion wakes. Here, we study the interparticle forces mediated by ion wakes in the presence of a strong magnetic field parallel to the ion flow. For increasing magnetic flux densities a continuous decay of the interaction force is observed. This transition occurs at parameters, where the ion cyclotron frequency starts to exceed the ion plasma frequency, which is in agreement with theoretical predictions. The modification of the interparticle forces is important for the understanding of the structure and dynamics of magnetized dusty plasmas. PMID- 23030095 TI - Modification of turbulent transport with continuous variation of flow shear in the large plasma device. AB - Continuous control over azimuthal flow and shear in the edge of the Large Plasma Device (LAPD) has been achieved using a biasable limiter which has allowed a careful study of the effect of flow shear on pressure-gradient-driven turbulence and transport in the LAPD. The LAPD rotates spontaneously in the ion diamagnetic direction; positive limiter bias first reduces, then minimizes (producing a near zero shear state), and finally reverses the flow into the electron diamagnetic direction. Degradation of particle confinement is observed in the minimum shearing state and a reduction in the turbulent particle flux is observed with increasing shearing in both flow directions. Near-complete suppression of the turbulent particle flux is observed for shearing rates comparable to the turbulent autocorrelation rate measured in the minimum shear state. Turbulent flux suppression is dominated by amplitude reduction in low-frequency (<10 kHz) density fluctuations. An increase in fluctuations for the highest shearing states is observed with the emergence of a coherent mode which does not lead to net particle transport. The variations of density fluctuations are fit well with power laws and compare favorably to simple models of shear suppression of transport. PMID- 23030096 TI - Vanishing neoclassical viscosity and physics of the shear layer in stellarators. AB - The drift kinetic equation is solved for low density TJ-II plasmas employing slowly varying, time-dependent profiles. This allows us to simulate density ramp up experiments and describe from first principles the formation and physics of the radial electric field shear layer. The main features of the transition are perfectly captured by the calculation, and good quantitative agreement is also found. The results presented here, that should be valid for other nonquasisymmetric stellarators, provide a fundamental explanation for a wealth of experimental observations connected to the shear layer emergence in TJ-II. The key quantity is the neoclassical viscosity, which is shown to go smoothly to zero when the critical density is approached from below. This makes it possible for turbulence-related phenomena, and particularly zonal flows, to arise in the neighborhood of the transition. PMID- 23030097 TI - Penetrating radiography of imploding and stagnating beryllium liners on the Z accelerator. AB - The implosions of initially solid beryllium liners (tubes) have been imaged with penetrating radiography through to stagnation. These novel radiographic data reveal a high degree of azimuthal correlation in the evolving magneto-Rayleigh Taylor structure at times just prior to (and during) stagnation, providing stringent constraints on the simulation tools used by the broader high energy density physics and inertial confinement fusion communities. To emphasize this point, comparisons to 2D and 3D radiation magnetohydrodynamics simulations are also presented. Both agreement and substantial disagreement have been found, depending on how the liner's initial outer surface finish was modeled. The various models tested, and the physical implications of these models are discussed. These comparisons exemplify the importance of the experimental data obtained. PMID- 23030098 TI - Ambipolar transport via trapped-electron whistler instability along open magnetic field lines. AB - An open field line plasma is bounded by a chamber wall which intercepts the magnetic field. Steady state requires an upstream plasma source balancing the particle loss to the boundary. In cases where the electrons have a long mean free path, ambipolarity in parallel transport critically depends on collisionless detrapping of the electrons via wave-particle interaction. The trapped-electron whistler instability, whose nonlinear saturation produces a spectrum of whistler waves that is responsible for the electron detrapping flux, is shown to be an unusually robust kinetic instability, which is essential to the universality of the ambipolar constraint in plasma transport. PMID- 23030099 TI - Apparent low-energy scale invariance in two-dimensional Fermi gases. AB - Recent experiments on a 2D Fermi gas find an undamped breathing mode at twice the trap frequency over a wide range of parameters. To understand this seemingly scale-invariant behavior in a system with a scale, we derive two exact results valid across the entire Bardeen-Cooper-Schrieffer-Bose-Einstein condensation (BCS BEC) crossover at all temperatures. First, we relate the shift of the mode frequency from its scale-invariant value to gamma(d)=(1+2/d)P-rho(?P/?rho)(s) in d dimensions. Next, we relate gamma(d) to dissipation via a new low-energy bulk viscosity sum rule. We argue that 2D is special, with its logarithmic dependence of the interaction on density, and thus gamma(2) is small in both the BCS-BEC regimes, even though P-2epsilon/d, sensitive to the dimer binding energy that breaks scale invariance, is not. PMID- 23030100 TI - First-order phase transitions in optical lattices with tunable three-body onsite interaction. AB - We study the two-dimensional Bose-Hubbard model in the presence of a three-body interaction term, both at a mean-field level and via quantum Monte Carlo simulations. The three-body term is tuned by coupling the triply occupied states to a trapped universal trimer. We find that, for a sufficiently attractive three body interaction, the n=2 Mott lobe disappears and the system displays first order phase transitions separating the n=1 from the n=3 lobes and the n=1 and n=3 Mott insulator from the superfluid. We also analyze the effect of finite temperature and find that transitions are still of first order at temperatures T~J, where J is the hopping matrix element. PMID- 23030081 TI - Observation of B0->D-(0)K(+)K(-) and evidence for B(s)(0)->D-(0)K(+)K(-). AB - The first observation of the decay B0->D-(0)K(+)K(-) is reported from an analysis of 0.62 fb(-1) of pp collision data collected with the LHCb detector. Its branching fraction is measured relative to that of the topologically similar decay B(0)->D -(0)pi(+)pi(-) to be (B(B(0)->D-(0)K(+)K(-))/B(B(0)->D-(0)pi(+)pi( ))=0.056+/-0.011+/-0.007,where the first uncertainty is statistical and the second is systematic. The significance of the signal is 5.8sigma. Evidence, with 3.8sigma significance, for B(s)(0)->D-(0)K(+)K(-) decays is also presented. The relative branching fraction is measured to be B(B(s)(0)->D-(0)K(+)K(-))/B(B(0)->D (0)K(+)K(-))=0.90+/-0.27+/-0.20. These channels are of interest to study the mechanisms behind hadronic B decays, and open new possibilities for CP violation analyses with larger data sets. PMID- 23030101 TI - Formation and stability of cellular carbon foam structures: an ab initio study. AB - We use ab initio density functional calculations to study the formation and structural as well as thermal stability of cellular foamlike carbon nanostructures. These systems with a mixed sp(2)/sp(3) bonding character may be viewed as bundles of carbon nanotubes fused to a rigid contiguous 3D honeycomb structure that can be compressed more easily by reducing the symmetry of the honeycombs. The foam may accommodate the same type of defects as graphene, and its surface may be stabilized by terminating caps. We postulate that the foam may form under nonequilibrium conditions near grain boundaries of a carbon-saturated metal surface. PMID- 23030102 TI - Anisotropic strain enhanced hydrogen solubility in bcc metals: the independence on the sign of strain. AB - When an impurity is doped in a solid, it inevitably induces a local stress, tending to expand or contract the lattice. Consequently, strain can be applied to change the solubility of impurity in a solid. Generally, the solubility responds to strain "monotonically," increasing (decreasing) with the tensile (compressive) strain if the impurity induces a compressive stress or vice versa. Using first principles calculations, however, we discovered that the H solubility can be enhanced by anisotropic strain in some bcc metals, almost independent of the sign of strain. This anomalous behavior is found to be caused by a continuous change of H location induced by anisotropic strain. Our finding suggests a cascading effect of H bubble formation in bcc metals: the H solution leads to H bubble formation that induces anisotropic strain that in turn enhances H solubility to further facilitate bubble growth. PMID- 23030103 TI - Onset mechanism of strain-rate-induced flow stress upturn. AB - The strain-rate response of flow stress in a plastically deforming crystal is formulated through a stress-sensitive dislocation mobility model that can be evaluated by atomistic simulation. For the flow stress of a model crystal of bcc Fe containing a 1/2[111] screw dislocation, this approach describes naturally a non-Arrhenius upturn at high strain rate, an experimentally established transitional behavior for which the underlying mechanism has not been clarified. Implications of our findings regarding the previous explanations of strain-rate effects on flow stress are discussed. PMID- 23030104 TI - Metallic phase of the quantum Hall effect in four-dimensional space. AB - We study the phase diagram of the quantum Hall effect in four-dimensional (4D) space. Unlike in 2D, in 4D there exists a metallic as well as an insulating phase, depending on the disorder strength. The critical exponent nu~1.2 of the diverging localization length at the quantum Hall insulator-to-metal transition differs from the semiclassical value nu=1 of 4D Anderson transitions in the presence of time-reversal symmetry. Our numerical analysis is based on a mapping of the 4D Hamiltonian onto a 1D dynamical system, providing a route towards the experimental realization of the 4D quantum Hall effect. PMID- 23030105 TI - Triggering a phase transition by a spatially localized laser pulse: role of strain. AB - We report here the optical microscopic imaging of a first-order phase transition induced by a nanosecond laser pulse (532 nm) in a single crystal of the molecular spin-crossover complex [Fe(bapbpy)(NCS)(2)]. The transition starts with the formation of a high spin domain in the region irradiated by the focused laser beam, followed by the subsequent growth or contraction of the initial domain. Remarkably, in otherwise identical experimental conditions one can observe either the irreversible transition of the whole crystal or merely the formation of a transient domain-depending on which region of the crystal is excited. This observation as well as the rather slow dynamics suggest that the main control parameter is the inhomogeneous accommodation strain, which destabilizes the photoinduced domain. PMID- 23030106 TI - Hyperbolic interfaces. AB - Fluid interfaces, such as soap films, liquid droplets, or lipid membranes, are known to give rise to several special geometries, whose complexity and beauty continue to fascinate us, as observers of the natural world, and challenge us as scientists. Here I show that a special class of surfaces of constant negative Gaussian curvature can be obtained in fluid interfaces equipped with an orientational ordered phase. These arise in various soft and biological materials, such as nematic liquid crystals, cytoskeletal assemblies, or hexatic colloidal suspensions. The purely hyperbolic morphology originates from the competition between surface tension, that reduces the area of the interface at the expense of increasing its Gaussian curvature, and the orientational elasticity of the ordered phase, that in turn suffers for the distortion induced by the underlying curvature. PMID- 23030107 TI - Segmental relaxations have macroscopic consequences in glassy polymer films. AB - We have investigated the consequences of physical aging in thin spin-coated glassy polystyrene films through detailed dewetting studies. A simultaneous and equally fast exponential decay of dewetting velocity, width, and height of the rim with aging time was observed, which is related to a reduction of residual stresses within such films. The temperature dependence of these decay times followed an Arrhenius behavior, yielding an activation energy of 70+/-6 kJ/mol, on the same order of magnitude as values for the beta-relaxation of polystyrene and for relaxations of surface topographical features. Our results suggest that rearrangements at the level of chain segments are sufficient to partially relax frozen-in out-of-equilibrium local chain conformations, i.e., the cause of residual stresses, and they might also be responsible for macroscopic relaxations at polymer surfaces. PMID- 23030108 TI - (Sub)surface mobility of oxygen vacancies at the TiO2 anatase (101) surface. AB - Anatase is a metastable polymorph of TiO2. In contrast to the more widely studied TiO2 rutile, O vacancies (V(O)'s) are not stable at the anatase (101) surface. Low-temperature STM shows that surface V(O)'s, created by electron bombardment at 105 K, start migrating to subsurface sites at temperatures >=200 K. After an initial decrease of the V(O) density, a temperature-dependent dynamic equilibrium is established where V(O)'s move to subsurface sites and back again, as seen in time-lapse STM images. We estimate that activation energies for subsurface migration lie between 0.6 and 1.2 eV; in comparison, density functional theory calculations predict a barrier of ca. 0.75 eV. The wide scatter of the experimental values might be attributed to inhomogeneously distributed subsurface defects in the reduced sample. PMID- 23030109 TI - Can lattice models predict the density of states of amorphous organic semiconductors? AB - We extend existing lattice models of small-molecule amorphous semiconductors by accounting for changes in molecular polarizability upon charging or excitation. A compact expression of this contribution to the density of states is provided. Although the lattice model and the description based on a microscopic morphology both qualitatively predict an additional broadening, shift, and an exponential tail (traps) of the density of states, a quantitative agreement between the two cannot be achieved. PMID- 23030110 TI - Variation of charge dynamics in the course of metal-insulator transition for pyrochlore-type Nd2Ir2O7. AB - We have spectroscopically investigated the thermally and doping-induced metal insulator transitions for pyrochlore-type Nd2Ir2O7 as well as its Rh-doped analogs Nd2(Ir(1-x)Rh(x))(2)O(7), where the spin-orbit interaction as well as the electron correlation is effectively tuned by the doping level (x). The charge dynamics dramatically changes on an energy scale of 1 eV in the course of thermally and doping-induced metal-insulator transitions, while the insulating ground state shows a small but well-defined charge gap of 45 meV. Anomalous doping variation of the low-energy (<0.3 eV) optical-conductivity spectra at the ground state can be interpreted in terms of the phase changes among the narrow gap Mott insulator, Weyl semimetal, and correlated metal. PMID- 23030111 TI - Self-consistent vertex correction analysis for iron-based superconductors: mechanism of Coulomb interaction-driven orbital fluctuations. AB - We study the mechanism of orbital or spin fluctuations due to multiorbital Coulomb interaction in iron-based superconductors, going beyond the random-phase approximation. For this purpose, we develop a self-consistent vertex correction (VC) method, and find that multiple orbital fluctuations in addition to spin fluctuations are mutually emphasized by the "multimode interference effect" described by the VC. Then, both antiferro-orbital and ferro-orbital (=nematic) fluctuations simultaneously develop for J/U~0.1, both of which contribute to the s-wave superconductivity. Especially, the ferro-orbital fluctuations give the orthorhombic structure transition as well as the softening of shear modulus C(66). PMID- 23030112 TI - Microwave characterization of Josephson junction arrays: implementing a low loss superinductance. AB - We have measured the plasma resonances of an array of Josephson junctions in the regime E(J)>>E(C), up to the ninth harmonic by incorporating it as part of a resonator capacitively coupled to a coplanar waveguide. From the characteristics of the resonances, we infer the successful implementation of a superinductance, an electrical element with a nondissipative impedance greater than the resistance quantum [R(Q)=h/(2e)(2) is approximately equal to 6.5 kOmega] at microwave frequencies. Such an element is crucial for preserving the quantum coherence in circuits exploiting large fluctuations of the superconducting phase. Our results show internal losses less than 20 ppm, self-resonant frequencies greater than 10 GHz, and phase-slip rates less than 1 mHz, enabling direct application of such arrays for quantum information and metrology. Arrays with a loop geometry also demonstrate a new manifestation of flux quantization in a dispersive analog of the Little-Parks effect. PMID- 23030113 TI - Quantum superinductor with tunable nonlinearity. AB - We report on the realization of a superinductor, a dissipationless element whose microwave impedance greatly exceeds the resistance quantum R(Q). The design of the superinductor, implemented as a ladder of nanoscale Josephson junctions, enables tuning of the inductance and its nonlinearity by a weak magnetic field. The Rabi decay time of the superinductor-based qubit exceeds 1 MUs. The high kinetic inductance and strong nonlinearity offer new types of functionality, including the development of qubits protected from both flux and charge noises, fault tolerant quantum computing, and high-impedance isolation for electrical current standards based on Bloch oscillations. PMID- 23030114 TI - Suppression of superconductivity by twin boundaries in FeSe. AB - Low-temperature scanning tunneling microscopy and spectroscopy are employed to investigate twin boundaries in stoichiometric FeSe films grown by molecular beam epitaxy. Twin boundaries can be unambiguously identified by imaging the 90 degrees change in the orientation of local electronic dimers from Fe site impurities on either side. Twin boundaries run at approximately 45 degrees to the Fe-Fe bond directions, and noticeably suppress the superconducting gap, in contrast with the recent experimental and theoretical findings in other iron pnictides. Furthermore, vortices appear to accumulate on twin boundaries, consistent with the degraded superconductivity there. The variation in superconductivity is likely caused by the increased Se height in the vicinity of twin boundaries, providing the first local evidence for the importance of this height to the mechanism of superconductivity. PMID- 23030115 TI - Measurement of magnetic exchange in ferromagnet-superconductor La2/3Ca1/3MnO3/YBa2Cu3O7 bilayers. AB - The existence of coherent magnetic correlations in the normal phase of cuprate high-temperature superconductors has proven difficult to measure directly. Here we report on a study of ferromagnetic-superconductor bilayers of La2/3Ca1/3MnO3/YBa2Cu3O7 (LCMO/YBCO) with varying YBCO layer thicknesses. Using x ray magnetic circular dichroism, we demonstrate that the ferromagnetic layer induces a Cu magnetic moment in the adjacent high-temperature superconductor. For thin samples, this moment exists at all temperatures below the Curie temperature of the LCMO layer. However, for a YBCO layer thicker than 12 unit cells, the Cu moment is suppressed for temperatures above the superconducting transition, suggesting this to be a direct measurement of magnetic coherence in the normal state of a superconducting oxide. PMID- 23030116 TI - Room-temperature perpendicular exchange coupling and tunneling anisotropic magnetoresistance in an antiferromagnet-based tunnel junction. AB - We investigate the exchange coupling between perpendicular anisotropy (PMA) Co/Pt and IrMn in-plane antiferromagnets (AFMs), as well as tunneling anisotropic magnetoresistance (TAMR) in [Pt/Co]/IrMn/AlO_{x}/Pt tunnel junctions, where Co/Pt magnetization drives rotation of AFM moments with the formation of exchange spring twisting. When coupled with a PMA ferromagnet, the AFM moments partially rotate with out-of-plane magnetic fields, in contrast with being pinned along the easy direction of IrMn for in-plane fields. Because of the superior thermal tolerance of perpendicular exchange coupling and the stability of moments in ~6 nm-thick IrMn, TAMR gets significantly enhanced up to room temperature. Their use would advance the process towards practical AFM spintronics. PMID- 23030117 TI - Forbidden band gaps in the spin-wave spectrum of a two-dimensional bicomponent magnonic crystal. AB - The spin-wave band structure of a two-dimensional bicomponent magnonic crystal, consisting of Co nanodisks partially embedded in a Permalloy thin film, is experimentally investigated along a high-symmetry direction by Brillouin light scattering. The eigenfrequencies and scattering cross sections are interpreted using plane wave method calculations and micromagnetic simulations. At the boundary of both the first and the second Brillouin zones, we measure a forbidden frequency gap whose width depends on the magnetic contrast between the constituent materials. The modes above and below the gap exhibit resonant spin precession amplitudes in the complementary regions of periodically varying magnetic parameters. Our findings are key to advance both the physics and the technology of band gap engineering in magnonics. PMID- 23030118 TI - Sensing distant nuclear spins with a single electron spin. AB - We experimentally demonstrate the use of a single electronic spin to measure the quantum dynamics of distant individual nuclear spins from within a surrounding spin bath. Our technique exploits coherent control of the electron spin, allowing us to isolate and monitor nuclear spins weakly coupled to the electron spin. Specifically, we detect the evolution of distant individual 13C nuclear spins coupled to single nitrogen vacancy centers in a diamond lattice with hyperfine couplings down to a factor of 8 below the electronic spin bare dephasing rate. Potential applications to nanoscale magnetic resonance imaging and quantum information processing are discussed. PMID- 23030119 TI - Detection and control of individual nuclear spins using a weakly coupled electron spin. AB - We experimentally isolate, characterize, and coherently control up to six individual nuclear spins that are weakly coupled to an electron spin in diamond. Our method employs multipulse sequences on the electron spin that resonantly amplify the interaction with a selected nuclear spin and at the same time dynamically suppress decoherence caused by the rest of the spin bath. We are able to address nuclear spins with interaction strengths that are an order of magnitude smaller than the electron spin dephasing rate. Our results provide a route towards tomography with single-nuclear-spin sensitivity and greatly extend the number of available quantum bits for quantum information processing in diamond. PMID- 23030120 TI - Length and time scales of structural heterogeneities in deeply supercooled propylene carbonate. AB - Deactivation of excited phenanthrene by molecular oxygen is utilized to probe the structural heterogeneity of supercooled propylene carbonate. The diffusion rate of oxygen molecules in different regions varies over two orders of magnitude. The size of the regions of different oxygen mobility was determined to be 1.5 nm. Values from 0.2 to 30 s have been obtained for the lifetime of these regions over a temperature range from T(g)-1 to T(g)+4 K (T(g)=158 K). The heterogeneity lifetime is in close agreement with the alpha-relaxation time determined by dielectric spectroscopy. The obtained results argue in favor of the statement that the heterogeneous cooperative dynamics of host molecules (so-called dynamical heterogeneity) is of structural origin. PMID- 23030121 TI - Critical Casimir forces in cellular membranes. AB - Recent experiments suggest that membranes of living cells are tuned close to a miscibility critical point in the two-dimensional Ising universality class. We propose that one role for this proximity to criticality in live cells is to provide a conduit for relatively long-range critical Casimir forces. Using techniques from conformal field theory we calculate potentials of mean force between membrane bound inclusions mediated by their local interactions with the composition order parameter. We verify these calculations using Monte Carlo simulations where we also compare critical and off-critical results. Our findings suggest that membrane bound proteins experience weak yet long-range forces mediated by critical composition fluctuations in the plasma membranes of living cells. PMID- 23030122 TI - Flagellar synchronization independent of hydrodynamic interactions. AB - Inspired by the coordinated beating of the flagellar pair of the green algae Chlamydomonas, we study theoretically a simple, mirror-symmetric swimmer, which propels itself at low Reynolds number by a revolving motion of a pair of spheres. We show that perfect synchronization between these two driven spheres can occur due to the motion of the swimmer and local hydrodynamic friction forces. Hydrodynamic interactions, though crucial for net propulsion, contribute little to synchronization for this free-moving swimmer. PMID- 23030123 TI - Collective dynamics in sparse networks. AB - The microscopic and macroscopic dynamics of random networks is investigated in the strong-dilution limit (i.e., for sparse networks). By simulating chaotic maps, Stuart-Landau oscillators, and leaky integrate-and-fire neurons, we show that a finite connectivity (of the order of a few tens) is able to sustain a nontrivial collective dynamics even in the thermodynamic limit. Although the network structure implies a nonadditive dynamics, the microscopic evolution is extensive (i.e., the number of active degrees of freedom is proportional to the number of network elements). PMID- 23030124 TI - Minimizing the population extinction risk by migration. AB - Many populations in nature are fragmented: they consist of local populations occupying separate patches. A local population is prone to extinction due to the shot noise of birth and death processes. A migrating population from another patch can dramatically delay the extinction. What is the optimal migration rate that minimizes the extinction risk of the whole population? Here, we answer this question for a connected network of model habitat patches with different carrying capacities. PMID- 23030125 TI - Transfer entropy as a log-likelihood ratio. AB - Transfer entropy, an information-theoretic measure of time-directed information transfer between joint processes, has steadily gained popularity in the analysis of complex stochastic dynamics in diverse fields, including the neurosciences, ecology, climatology, and econometrics. We show that for a broad class of predictive models, the log-likelihood ratio test statistic for the null hypothesis of zero transfer entropy is a consistent estimator for the transfer entropy itself. For finite Markov chains, furthermore, no explicit model is required. In the general case, an asymptotic chi2 distribution is established for the transfer entropy estimator. The result generalizes the equivalence in the Gaussian case of transfer entropy and Granger causality, a statistical notion of causal influence based on prediction via vector autoregression, and establishes a fundamental connection between directed information transfer and causality in the Wiener-Granger sense. PMID- 23030126 TI - Controlled nanoparticle formation by diffusion limited coalescence. AB - Polymeric nanoparticles (NPs) have great application potential in science and technology. Their functionality strongly depends on their size. We present a theory for the size of NPs formed by precipitation of polymers into a bad solvent in the presence of a stabilizing surfactant. The analytical theory is based upon diffusion-limited coalescence kinetics of the polymers. Two relevant time scales, a mixing and a coalescence time, are identified and their ratio is shown to determine the final NP diameter. The size is found to scale in a universal manner and is predominantly sensitive to the mixing time and the polymer concentration if the surfactant concentration is sufficiently high. The model predictions are in good agreement with experimental data. Hence the theory provides a solid framework for tailoring NPs with a priori determined size. PMID- 23030127 TI - Near-field electromagnetic theory for thin solar cells. AB - Current methods for evaluating solar cell efficiencies cannot be applied to low dimensional structures where phenomena from the realm of near-field optics prevail. We present a theoretical approach to analyze solar cell performance by allowing rigorous electromagnetic calculations of the emission rate using the fluctuation-dissipation theorem. Our approach shows the direct quantification of the voltage, current, and efficiency of low-dimensional solar cells. This approach is demonstrated by calculating the voltage and the efficiency of a GaAs slab solar cell for thicknesses from several microns down to a few nanometers. This example highlights the ability of the proposed approach to capture the role of optical near-field effects in solar cell performance. PMID- 23030128 TI - Age-related changes in the reliability of antioxidant enzyme defense in monkeys with different types of adaptive behavior. AB - We have investigated age-related changes in the reliability of glutathione related antioxidant enzyme defense in monkeys that differ in adaptive behavior. Activities of gluthatione reductase (GR), glutathione peroxidase (GSH-Px), and gluthatione-S-transferase (GST) and also lipid peroxidation products (TBARS) under basal conditions and under acute psycho-emotional stress were evaluated in erythrocytes of young (6-8 years) and old (20-27 years) female rhesus monkeys with depression-like and standard (control) behavior. We have found that young animals with depression-like behavior, in comparison with young monkeys of standard behavior, demonstrated higher activity of GR in basal conditions and no significant changes in response to acute immobilization stress. With aging the activity of GR increased in monkeys with standard behavior in basal conditions but retained the ability to increase under acute stress. At the same time during aging in monkeys with depression-like behavior GR activity did not undergo significant changes in basal conditions and did not change in response to acute stress. Moreover, old animals with depression-like behavior demonstrated reduced activity of GSH-Px. More pronounced disturbances in GR and GSH-Px activities in animals with depression-like behavior evidence a more marked decrease in the reliability of antioxidant enzyme defense of cells and lead to activation of lipid peroxidation that may be considered as an important factor of aging. Thus, age-related dysfunctions of the antioxidant enzyme system correlate with the type of adaptive behavior characteristic of animals. PMID- 23030129 TI - Melatonin decreases levels of S100beta and NFKappaB, increases levels of synaptophysin in a rat model of Alzheimer's disease. AB - The effect of treatment with melatonin was investigated in a rat model of Alzheimer's disease (AD) involving a single intra-hippocampal injection of amyloid peptide Abeta1-42. Thirty days after this injection immunohistochemical analysis revealed significant increases of both S-100beta and NFkappaB in cortex and hippocampus of treated animals. Levels of synaptophysin were depressed following treatment and this was confirmed by Western blotting. Histopathological studies revealed a diminution of neuronal cell number in the CA3 area of the hippocampus. Behaviorally, the rate of learning escape from electroshock using a maze box was diminished in Abeta-treated mice. Another group of A treated also received an oral gavage of 0.5 mg/kg melatonin on each of the 30 days between Abeta treatment and sacrifice. The effect of this repeated melatonin exposure was to reverse Abeta-induced changes in CA3 cell number and S-100 levels. The increased cerebral content of NF-kappaB and the behavioral changes caused by A treatment were partially reversed by melatonin. However, melatonin administration had no effect on the reduced level of synaptophysin in Abeta-treated mice. Overall, these findings suggest that melatonin may exert a potentially beneficial effect upon the progression of AD. PMID- 23030130 TI - Mediterranean diet and dementia of the Alzheimer type. AB - Dementia of the Alzheimer type is the most common form of dementia affecting mostly the elderly population. It is a progressive and fatal neurodegenerative disorder with characteristic neuropathology and clinical symptomology. In the coming years, the number of individuals with Alzheimer's disease (AD) will increase as the elderly population worldwide is expected to grow significantly thus putting an added strain on national health care systems as well as caregivers who will inevitably carry most of the care burden. Thus it has been suggested that early intervention strategies which delay or halt the disease progression will have a strong impact on clinical outcomes. Changes in lifestyle habits such as diet modification or supplementation have been indicated as probable protective factors for a number of chronic conditions including AD. Particular attention has recently been devoted to the Mediterranean diet which is rich in the antioxidants Vitamins C and E, polyunsaturated fatty acids and polyphenolic compounds. Several in vitro, animal and population-based studies reported a positive effect between adherence to a Mediterranean diet and AD prevention, although contrasting views remain. This review will focus on the latest developments and findings in the ongoing research investigating the relationship between Mediterranean diet and its major constituents in AD onset and progression. PMID- 23030131 TI - Universal bound states of two particles in mixed dimensions or near a mirror. AB - Some novel two-body effects analogous to the well-known three-body Efimov effect are predicted. In the systems considered, particle A is constrained on a truncated or bent one-dimensional line or two-dimensional plane, or on one side of a flat mirror in three dimensions (3D). The constraining potential is fine tuned such that particle A's ground state wave function is a constant in the region in which it is constrained. Particle B moves in 3D and interacts with particle A, resonantly. An infinite sequence of giant two-body bound states are found in each case. PMID- 23030132 TI - Experimental bound on the maximum predictive power of physical theories. AB - The question of whether the probabilistic nature of quantum mechanical predictions can be alleviated by supplementing the wave function with additional information has received a lot of attention during the past century. A few specific models have been suggested and subsequently falsified. Here we give a more general answer to this question: We provide experimental data that, as well as falsifying these models, cannot be explained within any alternative theory that could predict the outcomes of measurements on maximally entangled particles with significantly higher probability than quantum theory. Our conclusion is based on the assumptions that all measurement settings have been chosen freely (within a causal structure compatible with relativity theory), and that the presence of the detection loophole did not affect the measurement outcomes. PMID- 23030133 TI - Facilitated spin models of dissipative quantum glasses. AB - We introduce a class of dissipative quantum spin models with local interactions and without quenched disorder that show glassy behavior. These models are the quantum analogs of the classical facilitated spin models. Just like their classical counterparts, quantum facilitated models display complex glassy dynamics despite the fact that their stationary state is essentially trivial. In these systems, dynamical arrest is a consequence of kinetic constraints and not of static ordering. These models display a quantum version of dynamic heterogeneity: the dynamics toward relaxation is spatially correlated despite the absence of static correlations. Associated dynamical fluctuation phenomena such as decoupling of time scales is also observed. Moreover, we find that close to the classical limit, quantum fluctuations can enhance glassiness, as recently reported for quantum liquids. PMID- 23030134 TI - Entropic test of quantum contextuality. AB - We study the contextuality of a three-level quantum system using classical conditional entropy of measurement outcomes. First, we analytically construct the minimal configuration of measurements required to reveal contextuality. Next, an entropic contextual inequality is formulated, analogous to the entropic Bell inequalities derived by Braunstein and Caves [Phys. Rev. Lett. 61, 662 (1988)], that must be satisfied by all noncontextual theories. We find optimal measurements for violation of this inequality. The approach is easily extendable to higher dimensional quantum systems and more measurements. Our theoretical findings can be verified in the laboratory with current technology. PMID- 23030135 TI - Macroscopic Zeno effect and stationary flows in nonlinear waveguides with localized dissipation. AB - We theoretically demonstrate the possibility of observing the macroscopic Zeno effect for nonlinear waveguides with localized dissipation. We show the existence of stable stationary flows, which are balanced by losses in the dissipative domain. The macroscopic Zeno effect manifests itself in the nonmonotonic dependence of the stationary flow on the strength of the dissipation. In particular, we highlight the importance of the dissipation parameters in observing the phenomenon. Our results are applicable to a large variety of systems, including the condensates of atoms or quasiparticles and optical waveguides. PMID- 23030136 TI - Shear viscosity of a unitary Fermi gas. AB - We present an ab initio determination of the shear viscosity eta of the unitary Fermi gas, based on finite temperature quantum Monte Carlo calculations and the Kubo linear-response formalism. We determine the temperature dependence of the shear viscosity-to-entropy density ratio eta/s. The minimum of eta/s appears to be located above the critical temperature for the superfluid-to-normal phase transition with the most probable value being (eta/s)min~0.2h/k(B), which is close the Kovtun-Son-Starinets universal value h/(4pik(B)). PMID- 23030137 TI - Spin waves and collisional frequency shifts of a trapped-atom clock. AB - We excite spin waves with spatially inhomogeneous Ramsey pulses and study the resulting frequency shifts of a chip-scale atomic clock of trapped 87Rb. The density-dependent frequency shifts of the hyperfine transition simulate the s wave collisional frequency shifts of fermions, including those of optical lattice clocks. As the spin polarizations oscillate in the trap, the frequency shift reverses and it depends on the area of the second Ramsey pulse, exhibiting a predicted beyond mean-field frequency shift. Numerical and analytic models illustrate these observed behaviors. PMID- 23030138 TI - How weak values emerge in joint measurements on cloned quantum systems. AB - A statistical analysis of optimal universal cloning shows that it is possible to identify an ideal (but nonpositive) copying process that faithfully maps all properties of the original Hilbert space onto two separate quantum systems, resulting in perfect correlations for all observables. The joint probabilities for noncommuting measurements on separate clones then correspond to the real parts of the complex joint probabilities observed in weak measurements on a single system, where the measurements on the two clones replace the corresponding sequence of weak measurement and postselection. The imaginary parts of weak measurement statics can be obtained by replacing the cloning process with a partial swap operation. A controlled-swap operation combines both processes, making the complete weak measurement statistics accessible as a well-defined contribution to the joint probabilities of fully resolved projective measurements on the two output systems. PMID- 23030139 TI - High-order noise filtering in nontrivial quantum logic gates. AB - Treating the effects of a time-dependent classical dephasing environment during quantum logic operations poses a theoretical challenge, as the application of noncommuting control operations gives rise to both dephasing and depolarization errors that must be accounted for in order to understand total average error rates. We develop a treatment based on effective Hamiltonian theory that allows us to efficiently model the effect of classical noise on nontrivial single-bit quantum logic operations composed of arbitrary control sequences. We present a general method to calculate the ensemble-averaged entanglement fidelity to arbitrary order in terms of noise filter functions, and provide explicit expressions to fourth order in the noise strength. In the weak noise limit we derive explicit filter functions for a broad class of piecewise-constant control sequences, and use them to study the performance of dynamically corrected gates, yielding good agreement with brute-force numerics. PMID- 23030140 TI - Measurement of the entanglement between photonic spatial modes in optical fibers. AB - We experimentally demonstrate the entanglement of spatial modes between two photons propagating through separate few-mode optical fibers. Quantum states over the two lowest-order spatial modes are measured with highly efficient spatial mode analyzers based on acousto-optics. Quantum state tomography verifies the entanglement of the spatial-domain Bell state. PMID- 23030141 TI - Coherent error suppression in multiqubit entangling gates. AB - We demonstrate a simple pulse shaping technique designed to improve the fidelity of spin-dependent force operations commonly used to implement entangling gates in trapped ion systems. This extension of the Molmer-Sorensen gate can theoretically suppress the effects of certain frequency and timing errors to any desired order and is demonstrated through Walsh modulation of a two qubit entangling gate on trapped atomic ions. The technique is applicable to any system of qubits coupled through collective harmonic oscillator modes. PMID- 23030142 TI - Measuring entanglement entropy of a generic many-body system with a quantum switch. AB - Entanglement entropy has become an important theoretical concept in condensed matter physics because it provides a unique tool for characterizing quantum mechanical many-body phases and new kinds of quantum order. However, the experimental measurement of entanglement entropy in a many-body system is widely believed to be unfeasible, owing to the nonlocal character of this quantity. Here, we propose a general method to measure the entanglement entropy. The method is based on a quantum switch (a two-level system) coupled to a composite system consisting of several copies of the original many-body system. The state of the switch controls how different parts of the composite system connect to each other. We show that, by studying the dynamics of the quantum switch only, the Renyi entanglement entropy of the many-body system can be extracted. We propose a possible design of the quantum switch, which can be realized in cold atomic systems. Our work provides a route towards testing the scaling of entanglement in critical systems as well as a method for a direct experimental detection of topological order. PMID- 23030143 TI - Measuring entanglement growth in quench dynamics of bosons in an optical lattice. AB - We discuss a scheme to measure the many-body entanglement growth during quench dynamics with bosonic atoms in optical lattices. By making use of a 1D or 2D setup in which two copies of the same state are prepared, we show how arbitrary order Renyi entropies can be extracted by using tunnel coupling between the copies and measurement of the parity of on-site occupation numbers, as has been performed in recent experiments. We illustrate these ideas for a superfluid-Mott insulator quench in the Bose-Hubbard model, and also for hard-core bosons, and show that the scheme is robust against imperfections in the measurements. PMID- 23030144 TI - Four locally indistinguishable ququad-ququad orthogonal maximally entangled states. AB - We explicitly exhibit a set of four ququad-ququad orthogonal maximally entangled states that cannot be perfectly distinguished by means of local operations and classical communication. Before our work, it was unknown whether there is a set of d locally indistinguishable d?d orthogonal maximally entangled states for some positive integer d. We further show that a 2?2 maximally entangled state can be used to locally distinguish this set of states without being consumed, thus demonstrate a novel phenomenon of entanglement discrimination catalysis. Based on this set of states, we construct a new set K consisting of four locally indistinguishable states such that K(?m) (with 4(m) members) is locally distinguishable for some m greater than one. As an immediate application, we construct a noisy quantum channel with one sender and two receivers whose local zero-error classical capacity can achieve the full dimension of the input space but only with a multi-shot protocol. PMID- 23030145 TI - Path finding on high-dimensional free energy landscapes. AB - We present a method for determining the average transition path and the free energy along this path in the space of selected collective variables. The formalism is based upon a history-dependent bias along a flexible path variable within the metadynamics framework but with a trivial scaling of the cost with the number of collective variables. Controlling the sampling of the orthogonal modes recovers the average path and the minimum free energy path as the limiting cases. The method is applied to resolve the path and the free energy of a conformational transition in alanine dipeptide. PMID- 23030146 TI - Phase transition and interpore correlations of water in nanopore membranes. AB - Using computer simulations, we study a membrane of parallel narrow pores filled with one-dimensional wires of hydrogen-bonded water molecules. We show that such a membrane is equivalent to a system of effective charges located at opposite sides of the membrane offering a computationally efficient way to model correlation effects in water-filled nanopore membranes. Based on our simulations we predict that membranes with square pore lattices undergo a continuous order disorder transition to an antiferroelectric low-temperature phase in which water wires in adjacent pores are oriented in opposite directions. Strong antiferroelectric correlations exist also in the disordered phase far above the critical temperature or in membranes with geometric frustration, leading to a dielectric constant that is reduced considerably with respect to the case of uncoupled water wires. These correlations are also expected to hinder proton translocation through the membrane. PMID- 23030147 TI - Asymmetric inclusion process as a showcase of complexity. AB - The asymmetric inclusion process is a lattice-gas model which replaces the "fermionic" exclusion interactions of the asymmetric exclusion process by "bosonic" inclusion interactions. Combining together probabilistic and Monte Carlo analyses, we showcase the model's rich statistical complexity-which ranges from "mild" to "wild" displays of randomness: gaussian load and draining, Rayleigh outflow with linear aging, inverse-gaussian coalescence, intrinsic power law scalings and power-law fluctuations and condensation. PMID- 23030148 TI - Multigrid algorithms for tensor network states. AB - The widely used density matrix renormalization group (DRMG) method often fails to converge in systems with multiple length scales, such as lattice discretizations of continuum models and dilute or weakly doped lattice models. The local optimization employed by DMRG to optimize the wave function is ineffective in updating large-scale features. Here we present a multigrid algorithm that solves these convergence problems by optimizing the wave function at different spatial resolutions. We demonstrate its effectiveness by simulating bosons in continuous space and study nonadiabaticity when ramping up the amplitude of an optical lattice. The algorithm can be generalized to tensor network methods and combined with the contractor renormalization group method to study dilute and weakly doped lattice models. PMID- 23030149 TI - New insights on the matter-gravity coupling paradigm. AB - The coupling between matter and gravity in general relativity is given by a proportionality relation between the stress tensor and the geometry. This is an oriented assumption driven by the fact that both the stress tensor and the Einstein tensor are divergenceless. However, general relativity is in essence a nonlinear theory, so there is no obvious reason why the coupling to matter should be linear. On another hand, modified theories of gravity usually affect the vacuum dynamics, yet keep the coupling to matter linear. In this Letter, we address the implications of consistent nonlinear gravity-matter coupling. The Eddington-inspired Born-Infeld theory recently introduced by Banados and Ferreira provides an enlightening realization of such coupling modifications. We find that this theory coupled to a perfect fluid reduces to general relativity coupled to a nonlinearly modified perfect fluid, leading to an ambiguity between modified coupling and modified equation of state. We discuss observational consequences of this degeneracy and argue that such a completion of general relativity is viable from both an experimental and theoretical point of view through energy conditions, consistency, and singularity-avoidance perspectives. We use these results to discuss the impact of changing the coupling paradigm. PMID- 23030150 TI - Lithium synthesis in microquasar accretion. AB - We study the synthesis of lithium isotopes in the hot tori formed around stellar mass black holes by accretion of the companion star. We find that sizable amounts of both stable isotopes 6Li and 7Li can be produced, the exact figures varying with the characteristics of the torus and reaching as much as 10(-2) M? for each isotope. This mass output is enough to contaminate the entire Galaxy at a level comparable with the original, pregalactic amount of lithium and to overcome other sources such as cosmic-ray spallation or stellar nucleosynthesis. PMID- 23030151 TI - First direct detection limits on sub-GeV dark matter from XENON10. AB - The first direct detection limits on dark matter in the MeV to GeV mass range are presented, using XENON10 data. Such light dark matter can scatter with electrons, causing ionization of atoms in a detector target material and leading to single- or few-electron events. We use 15 kg day of data acquired in 2006 to set limits on the dark-matter-electron scattering cross section. The strongest bound is obtained at 100 MeV where sigma(e)<3*10(-38) cm2 at 90% C.L., while dark-matter masses between 20 MeV and 1 GeV are bounded by sigma(e)<10(-37) cm2 at 90% C.L. This analysis provides a first proof of principle that direct detection experiments can be sensitive to dark-matter candidates with masses well below the GeV scale. PMID- 23030152 TI - New window on primordial non-gaussianity. AB - We know very little about primordial curvature perturbations on scales smaller than about a Mpc. Measurements of the MU distortion of the cosmic microwave background spectrum provide the unique opportunity to probe these scales over the unexplored range from 50 to 10(4) Mpc(-1). This is a very clean probe, in that it relies only on well understood linear evolution. Also, just the information about the low multipoles (l~100) of MU is necessary. We point out that correlations between MU distortion and temperature anisotropies can be used to test gaussianity at these very small scales. In particular the MUT two-point correlation is proportional to the very squeezed limit of the primordial bispectrum and hence measures f(NL)(loc), while MUMU is proportional to the primordial trispectrum and measures tau(NL). We present a Fisher matrix forecast of the observational constraints on f(NL)(loc) and stress that a cosmic variance limited experiment could in principle reach Deltaf(NL)(loc)~O(10(-3)). PMID- 23030153 TI - Evidence for CP violation in the decay D+ -> K(S)(0)pi+. AB - We observe evidence for CP violation in the decay D+ -> K(S)(0)pi+ using a data sample with an integrated luminosity of 977 fb(-1) collected by the Belle detector at the KEKB e+ e- asymmetric-energy collider. The CP asymmetry in the decay is measured to be (-0.363+/-0.094+/-0.067)%, which is 3.2 standard deviations away from zero, and is consistent with the expected CP violation due to the neutral kaon in the final state. PMID- 23030158 TI - Optomechanical superpositions via nested interferometry. AB - We present a scheme for achieving macroscopic quantum superpositions in optomechanical systems by using single photon postselection and detecting them with nested interferometers. This method relieves many of the challenges associated with previous optical schemes for measuring macroscopic superpositions and only requires the devices to be in the weak coupling regime. It requires only small improvements on currently achievable device parameters and allows the observation of decoherence on a time scale unconstrained by the system's optical decay time. Prospects for observing novel decoherence mechanisms are discussed. PMID- 23030156 TI - Dependence of Rydberg-atom optical lattices on the angular wave function. AB - We investigate the dependence of optical-lattice trapping potentials for Rydberg atoms on the angular portion of the atomic wave function. While ground-state atoms are pointlike in relation to an optical-lattice field, Rydberg-atom wave functions extend over a substantial fraction of the lattice period, which leads to a dependence of the lattice trapping potential on the angular portion of the spatial wave function. The angular dependence of the potential is measured using various (j, m(j)) levels of 85Rb Rydberg nD states (50<=n<=65) prepared in a one dimensional optical lattice (wavelength 1064 nm) and a transverse dc electric field. The measured optical-lattice depths are found to be in agreement with theoretical results. PMID- 23030157 TI - Appearance of low energy resonances in CO-para-H2 inelastic collisions. AB - We report on crossed-beam experiments and quantum-mechanical calculations performed on the CO(j=0) + H2(j=0) -> CO(j=1) + H2(j=0) system. The experimental cross sections determined in the threshold region of the CO(j=0 -> j=1) transition at 3.85 cm(-1) show resonance structures in good qualitative agreement with the theoretical ones. These results suggest that the potential energy surface which describes the CO-H2 van der Waals interaction should be reinvestigated for good quantitative agreement. PMID- 23030155 TI - N = 16 spherical shell closure in 24O. AB - The unbound excited states of the neutron drip-line isotope 24O have been investigated via the 24O(p,p')23O + n reaction in inverse kinematics at a beam energy of 62 MeV/nucleon. The decay energy spectrum of 24O* was reconstructed from the momenta of 23O and the neutron. The spin parity of the first excited state, observed at E(x) = 4.65+/-0.14 MeV, was determined to be J(pi) = 2+ from the angular distribution of the cross section. Higher-lying states were also observed. The quadrupole transition parameter beta2 of the 2(1)+ state was deduced, for the first time, to be 0.15+/-0.04. The relatively high excitation energy and small beta2 value are indicative of the N = 16 shell closure in 24O. PMID- 23030159 TI - Optical analogues for massless dirac particles and conical diffraction in one dimension. AB - We demonstrate that light propagating in an appropriately designed lattice can exhibit dynamics akin to that expected from massless relativistic particles as governed by the one-dimensional Dirac equation. This is accomplished by employing a waveguide array with alternating positive and negative effective coupling coefficients, having a band structure with two intersecting minibands. Through this approach optical analogues of massless particle-antiparticle pairs are experimentally realized. One-dimensional conical diffraction is also observed for the first time in this work. PMID- 23030160 TI - Diffraction regimes of single holes. AB - We investigate both experimentally and theoretically the far-field diffraction patterns of single circular apertures as a function of their diameters d and at a given illumination wavelength lambda. We observe the transition between the well known pseudoscalar regime of large holes (d?lambda) and the less-known vectorial regime of subwavelength ones (d?lambda). Four different diffraction regimes are identified for different d/lambda regions, each one with its polarization dependence. A thorough comparison with a theoretical model, which takes into account both finite hole size and the dielectric properties of the metal, allows us to explain and understand the physical processes leading to this behavior. Our results reveal the subtle interplay between two competing factors, one related to polarization symmetries associated with surface-plasmon excitations and the other originating in the coupling of the field to the waveguide mode of the aperture. PMID- 23030161 TI - Material-independent and size-independent tractor beams for dipole objects. AB - A Bessel beam without an axial gradient can exert a pulling force on an object [A. Novitsky, C. W. Qiu, and H. Wang, Phys. Rev. Lett. 107, 203601 (2011)]. However, it cannot be called a "tractor beam" per se, as long as the light pulling effect is ultrasensitive to the object's material and size, a perturbation of which will make the optical traction go away. In this Letter, we investigate and report on the universality for a Bessel beam to be either a material-independent or size-independent optical tractor beam within the dipolar regime. Moreover, a general condition for a nonparaxial laser to be simultaneously a material- and size-independent tractor beam is proposed. These universal pulling effects and conditions are discussed in association with insight on modified far-field scattering, scattering resonances, and induced polarizabilities. Interestingly, we find that the acoustic pulling force exhibits only size independence, owing to the acoustic scattering theory in contrast to the light scattering counterpart. The findings pave the way for the realistic engineering and application of universal tractor beams pulling a wide variety of objects. PMID- 23030162 TI - Inference of time-evolving coupled dynamical systems in the presence of noise. AB - A new method is introduced for analysis of interactions between time-dependent coupled oscillators, based on the signals they generate. It distinguishes unsynchronized dynamics from noise-induced phase slips and enables the evolution of the coupling functions and other parameters to be followed. It is based on phase dynamics, with Bayesian inference of the time-evolving parameters achieved by shaping the prior densities to incorporate knowledge of previous samples. The method is tested numerically and applied to reveal and quantify the time-varying nature of cardiorespiratory interactions. PMID- 23030163 TI - Controlling high-frequency collective electron dynamics via single-particle complexity. AB - We demonstrate, through experiment and theory, enhanced high-frequency current oscillations due to magnetically-induced conduction resonances in superlattices. Strong increase in the ac power originates from complex single-electron dynamics, characterized by abrupt resonant transitions between unbound and localized trajectories, which trigger and shape propagating charge domains. Our data demonstrate that external fields can tune the collective behavior of quantum particles by imprinting configurable patterns in the single-particle classical phase space. PMID- 23030164 TI - Thermal fluctuations in nanofluidic transport. AB - We explore the impact of thermal fluctuations on nanofluidic transport. We develop a generic description of the stochastic motion of a fluid confined in a nanopore, on the basis of the fluctuating hydrodynamics framework. The center of mass of the confined fluid is shown to perform a non-markovian random walk, whose diffusion coefficient depends on the nanopore geometrical characteristics and boundary slip at its surface. We discuss the implications of this brownian-like motion of hydrodynamic degrees of freedom in two different contexts. First, we show that hydrodynamic fluctuations can lead to a strongly enhanced diffusion of particles confined in a nanopore. Second, we extend our results to account for the hydrodynamic contribution to electrical noise in charged nanopores. PMID- 23030165 TI - Reconfigurable optothermal microparticle trap in air-filled hollow-core photonic crystal fiber. AB - We report a novel optothermal trapping mechanism that occurs in air-filled hollow core photonic crystal fiber. In the confined environment of the core, the motion of a laser-guided particle is strongly influenced by the thermal-gradient-driven flow of air along the core surface. Known as "thermal creep flow," this can be induced either statically by local heating, or dynamically by the absorption (at a black mark placed on the fiber surface) of light scattered by the moving particle. The optothermal force on the particle, which can be accurately measured in hollow-core fiber by balancing it against the radiation forces, turns out to exceed the conventional thermophoretic force by 2 orders of magnitude. The system makes it possible to measure pN-scale forces accurately and to explore thermally driven flow in micron-scale structures. PMID- 23030166 TI - Kinematic alpha tensors and dynamo mechanisms in a von Karman swirling flow. AB - We provide experimental and numerical evidence of in-blades vortices in the von Karman swirling flow. We estimate the associated kinematic alpha-effect tensor and show that it is compatible with recent models of the von Karman sodium (VKS) dynamo. We further show that depending on the relative frequency of the two impellers, the dominant dynamo mechanism may switch from alpha2 to alpha - Omega dynamo. We discuss some implications of these results for VKS experiments. PMID- 23030167 TI - From sticky to slippery droplets: dynamics of contact line depinning on superhydrophobic surfaces. AB - This study explores how surface morphology affects the dynamics of contact line depinning of an evaporating sessile droplet on micropillared superhydrophobic surfaces. The result shows that neither a liquid-solid contact area nor an apparent contact line is a critical physical parameter to determine the depinning force. The configuration of a contact line on a superhydrophobic surface is multimodal, composed of both two phases (liquid and air) and three phases (liquid, solid, and air). The multimodal state is dynamically altered when a droplet recedes. The maximal three-phase contact line attainable along the actual droplet boundary is found to be a direct and linear parameter that decides the depinning force on the superhydrophobic surface. PMID- 23030168 TI - Nonlinear frequency oscillation of Alfven eigenmodes in fusion plasmas. AB - A nonlinear oscillation of frequency and amplitude is found by massively parallel gyrokinetic simulations of Alfven eigenmodes excited by energetic particles in toroidal plasmas. The fast and repetitive frequency chirping is induced by the evolution of coherent structures in the phase space. The dynamics of the coherent structures is controlled by the competition between the phase-space island formation due to the nonlinear particle trapping and the island destruction due to the free streaming. The chirping dynamics provides a conceptual framework for understanding nonlinear wave-particle interactions underlying the transport process in collisionless plasmas. PMID- 23030169 TI - Formation of streamer discharges from an isolated ionization column at subbreakdown conditions. AB - This Letter reports a modeling study on the formation of streamer discharges from an isolated ionization column under subbreakdown condition. Numerical simulations show that positive streamers are able to form from the tip of an ionization column in a uniform applied electric field well below the breakdown threshold field. However, even when the applied field approaches the breakdown threshold field, negative streamers fail to originate from the other tip of the ionization column after the positive streamer has propagated a certain distance. The results reported explain some puzzling observations on streamer discharges in nature such as the predominant initiation of sprites by downward propagating positive streamers and help advance the initiation theories of sprites and lightning. PMID- 23030170 TI - Measurements of the T(t,2n)4He neutron spectrum at low reactant energies from inertial confinement implosions. AB - Measurements of the neutron spectrum from the T(t,2n)4He (tt) reaction have been conducted using inertial confinement fusion implosions at the OMEGA laser facility. In these experiments, deuterium-tritium (DT) gas-filled capsules were imploded to study the tt reaction in thermonuclear plasmas at low reactant center of-mass (c.m.) energies. In contrast to accelerator experiments at higher c.m. energies (above 100 keV), these results indicate a negligible n + 5He reaction channel at a c.m. energy of 23 keV. PMID- 23030171 TI - Transition from weak to strong cascade in MHD turbulence. AB - The transition from weak to strong turbulence when passing from large to small scales in magnetohydrodynamic (MHD) turbulence with guide field is a cornerstone of anisotropic turbulence theory. We present the first check of this transition, using the Shell-RMHD, which combines a shell model of perpendicular nonlinear coupling and linear propagation along the guide field. This model allows us to reach Reynolds numbers around 10(6). We obtain surprisingly good agreement with the theoretical predictions, with a reduced perpendicular energy spectrum scaling as k(?)(-2) at large scales and as k(?)(-5/3) at small scales, where critical balance between nonlinear and propagation time is reached. However, even in the strong regime, a high level of excitation is found in the weak coupling region of Fourier space, which is due to the rich frequency spectrum of large eddies. A corollary is that the reduced parallel spectral slope is not a definite test of the spectral anisotropy, contrary to standard belief. PMID- 23030172 TI - Determination of the ion temperature in a stainless steel slab exposed to intense ultrashort laser pulses. AB - We present an effective approach to determine the amount of energy absorbed by solid samples exposed to ultrashort laser pulses, thus, retrieving the maximum temperature attained by the ion lattice in the picosecond time scale. The method is based on the pyrometric detection of a slow temperature fluctuation on the rear side of a sample slab associated with absorption of the laser pulse on the front side. This approach, successfully corroborated by theoretical calculations, can provide a robust and practical diagnostic tool for characterization of laser generated warm dense matter. PMID- 23030173 TI - Stability of ultracold atomic Bose condensates with Rashba spin-orbit coupling against quantum and thermal fluctuations. AB - We study the stability of Bose condensates with Rashba-Dresselhaus spin-orbit coupling in three dimensions against quantum and thermal fluctuations. The ground state depletion of the plane-wave condensate due to quantum fluctuations is, as we show, finite, and therefore the condensate is stable. We also calculate the corresponding shift of the ground state energy. Although the system cannot condense in the absence of interparticle interactions, by estimating the number of excited particles we show that interactions stabilize the condensate even at nonzero temperature. Unlike in the usual Bose gas, the normal phase is not kinematically forbidden at any temperature; calculating the free energy of the normal phase at finite temperature, and comparing with the free energy of the condensed state, we infer that generally the system is condensed at zero temperature, and undergoes a transition to normal at nonzero temperature. PMID- 23030174 TI - Role of Bose statistics in crystallization and quantum jamming. AB - The indistinguishability of particles is a crucial factor destabilizing crystalline order in Bose systems. We describe this effect in terms of damped quasiparticle modes and in the dual language of Feynman paths, and illustrate it by first-principles simulations of dipolar bosons and bulk condensed 4He. The first major implication is that, contrary to conventional wisdom, zero-point motion alone cannot prevent 4He crystallization at near zero pressure. Second, Bose statistics leads to quantum jamming at finite temperature, dramatically enhancing the metastability of superfluid glasses. Only studies of indistinguishable particles can reliably address these issues. PMID- 23030175 TI - Anomalous behavior of spin systems with dipolar interactions. AB - We study the properties of spin systems realized by cold polar molecules interacting via dipole-dipole interactions in two dimensions. Using a spin wave theory, that allows for the full treatment of the characteristic long-distance tail of the dipolar interaction, we find several anomalous features in the ground state correlations and the spin wave excitation spectrum, which are absent in their counterparts with short-range interaction. The most striking consequence is the existence of true long-range order at finite temperature for a two dimensional phase with a broken U(1) symmetry. PMID- 23030176 TI - Order-disorder transition of aragonite nanoparticles in nacre. AB - Understanding nacre's bottom-up biomineralization mechanism, particularly, how individual aragonite platelets are formed, has long remained elusive due to its crystallographic peculiarity and structural complexity. Here we report that crystallographic order-disorder transition can be triggered within individual aragonite platelets in pristine nacre by means of heat treatment and/or inelastic deformation, offering a unique opportunity to discriminate mysterious aragonite nanoparticles in transmission electron microscopy. Our findings unambiguously uncover why aragonite nanoparticles in pristine nacre have long been inaccessible under TEM observation, which is attributed to the monocrystal-polycrystal duality of the aragonite platelet. The underlying physical mechanism for why an individual aragonite platelet adopts a highly oriented attachment of aragonite nanoparticles as its crystallization pathway is, for the first time, explained in terms of the thermodynamics. The finding of an order-disorder transition in nacre provides a new perspective for understanding the formation for other biominerals. PMID- 23030177 TI - "Compressed graphite" formed during C60 to diamond transformation as revealed by scattering computed tomography. AB - The collapsing of C60 into polycrystalline diamond has been studied after nonhydrostatic pressurization at ambient temperature using x-ray scattering computed tomography. Using this selective structural probe we provide evidence of concentric coexistence of "compressed graphite" (d(00l)~3.09-3.11 A), sp2 graphitelike phase (d(00l)~3.35-3.42 A), and sp3-like amorphous carbon surrounding polycrystalline diamond (a~3.56-3.59 A). The so-called "compressed graphite" exhibits a collapsed c axis and is textured with disordered layers. This latter phase is better described as a short interlayered carbon phase with buckled sp2-sp3 layers with possible interlayer bonding. Additionally, our 3D maps of phase distribution and of the residual stress retained in the polycrystalline diamond phase support the importance of stressed synthesis conditions for diamond formation. PMID- 23030178 TI - Strong coupling between mechanical modes in a nanotube resonator. AB - We report on the nonlinear coupling between the mechanical modes of a nanotube resonator. The coupling is revealed in a pump-probe experiment where a mode driven by a pump force is shown to modify the motion of a second mode measured with a probe force. In a second series of experiments, we actuate the resonator with only one oscillating force. Mechanical resonances feature exotic line shapes with reproducible dips, peaks, and jumps when the measured mode is commensurate with another mode with a frequency ratio of either 2 or 3. Conventional line shapes are recovered by detuning the frequency ratio using the voltage on a nearby gate electrode. The exotic line shapes are attributed to strong coupling between the mechanical modes. The possibility to control the strength of the coupling with the gate voltage holds promise for various experiments, such as quantum manipulation, mechanical signal processing, and the study of the quantum to-classical transition. PMID- 23030179 TI - Nanoscale bending of multilayered boron nitride and graphene ribbons: experiment and objective molecular dynamics calculations. AB - By combining experiments performed on nanoribbons in situ within a high resolution TEM with objective molecular dynamics simulations, we reveal common mechanisms in the bending response of few-layer-thick hexagonal boron nitride and graphene nanoribbons. Both materials are observed forming localized kinks in the fully reversible bending experiments. Microscopic simulations and theoretical analysis indicate platelike bending behavior prior to kinking, in spite of the possibility of interlayer sliding, and give the critical curvature for the kinking onset. This behavior is distinct from the rippling and kinking of multi- and single-wall nanotubes under bending. Our findings have implications for future study of nanoscale layered materials, including nanomechanical device design. PMID- 23030180 TI - One-dimensional to three-dimensional ripple-to-dome transition for SiGe on vicinal Si (1 1 10). AB - SiGe heteroepitaxy on vicinal Si (1 1 10) is studied as a model system for one dimensional (1D) to three-dimensional growth mode transitions. By in situ scanning tunneling microscopy it is shown that the 1D-3D transition proceeds smoothly from perfectly facetted 1D nanoripples to coarsened superripples, tadpoles, asymmetric domes, and barns without involving coalescence or agglomeration. By extension of the studies to a wide range of SiGe compositions, a 1D-3D growth phase diagram is obtained. Total energy calculations reveal that the observed critical transition volumes are fully consistent with thermodynamic driven strain relaxation. PMID- 23030181 TI - Scale and nature of sulcification patterns. AB - Sulci are surface folds commonly seen in strained soft elastomers and form via a strongly subcritical, yet scale-free, instability. Treating the threshold for nonlinear instability as a nonlinear critical point, we explain the nature of sulcus patterns in terms of the scale and translation symmetries which are broken by the formation of an isolated, small sulcus. Our perturbative theory and simulations show that sulcus formation in a thick, compressed slab can arise either as a supercritical or as a weakly subcritical bifurcation relative to this nonlinear critical point, depending on the boundary conditions. An infinite number of competing, equilibrium patterns simultaneously emerge at this critical point, but the one selected has the lowest energy. We give a simple, physical explanation for the formation of these sulcification patterns using an analogy to a solid-solid phase transition with a finite energy of transformation. PMID- 23030182 TI - Formation and structure of graphene waves on Fe(110). AB - A very rich Fe-C phase diagram makes the formation of graphene on iron surfaces a challenging task. Here we demonstrate that the growth of graphene on epitaxial iron films can be realized by chemical vapor deposition at relatively low temperatures, and that the formation of carbides can be avoided in excess of the carbon-containing precursors. The resulting graphene monolayer creates a novel periodically corrugated pattern on Fe(110). Using low-energy electron microscopy and scanning tunneling microscopy, we show that it is modulated in one dimension forming long waves with a period of ~4 nm parallel to the [001] direction of the substrate, with an additional height modulation along the wave crests. The observed topography of the graphene/Fe superstructure is well reproduced by density functional theory calculations, and found to result from a unique combination of the lattice mismatch and strong interfacial interaction, as probed by core-level photoemission and x-ray absorption spectroscopy. PMID- 23030183 TI - Induction of a photostationary ring-opening-ring-closing state of spiropyran monolayers on the semimetallic Bi(110) surface. AB - Molecular switches on metal surfaces typically show very little photoreactivity. Using scanning tunneling microscopy, we show that the ring-opening-ring-closing switch nitrospiropyran thermally and optically isomerizes to the open merocyanine form on a Bi(110) surface. Irradiation by blue light of a monolayer of spiropyran molecules leads to mixed domains of the two isomers. At large illumination intensities a photostationary state is established, indicating the bidirectional ring-opening and ring-closing reaction of these molecules on the bismuth surface. The enhanced photoactivity contrasts with the case of adsorption on other metal surfaces, probably due to the low density of states at the Fermi level of the semimetallic Bi(110) surface. PMID- 23030184 TI - High island densities and long range repulsive interactions: Fe on epitaxial graphene. AB - The understanding of metal nucleation on graphene is essential for promising future applications, especially of magnetic metals which can be used in spintronics or computer storage media. A common method to study the grown morphology is to measure the nucleated island density n as a function of growth parameters. Surprisingly, the growth of Fe on graphene is found to be unusual because it does not follow classical nucleation: n is unexpectedtly high, it increases continuously with the deposited amount theta and shows no temperature dependence. These unusual results indicate the presence of long range repulsive interactions. Kinetic Monte Carlo simulations and density functional theory calculations support this conclusion. In addition to answering an outstanding question in epitaxial growth, i.e., to find systems where long range interactions are present, the high density of magnetic islands, tunable with theta, is of interest for nanomagnetism applications. PMID- 23030185 TI - "Gray" BCS condensate of excitons and internal Josephson effect. AB - It has been recently suggested that the Bose-Einstein condensate formed by excitons in the dilute limit must be dark, i.e., not coupled to photons. Here, we show that, under a density increase, the dark exciton condensate must acquire a bright component due to carrier exchange in which dark excitons turn bright. This, however, requires a density larger than a threshold which seems to fall in the forbidden region of the phase separation between a dilute exciton gas and a dense electron-hole plasma. The BCS-like condensation which is likely to take place on the dense side, must then have a dark and a bright component--which makes it "gray." It should be possible to induce an internal Josephson effect between these two coherent components, with oscillations of the photoluminescence as a strong proof of the existence for this "gray" BCS-like exciton condensate. PMID- 23030186 TI - Phase transition of interacting disordered bosons in one dimension. AB - Interacting bosons generically form a superfluid state. In the presence of disorder it can get converted into a compressible Bose glass state. Here we study such a transition in one dimension at moderate interaction using bosonization and renormalization group techniques. We derive the two-loop scaling equations and discuss the phase diagram. We find that the correlation functions at the transition are characterized by universal exponents in a finite region around the fixed point. PMID- 23030188 TI - Quantum disordered phase near the Mott transition in the staggered-flux Hubbard model on a square lattice. AB - We investigate ground state properties of the half-filled staggered-flux Hubbard model on a square lattice. Energy gaps to charge and spin excitations and magnetic as well as dimer orders are calculated as a function of interaction strength U/t by means of a constrained-path quantum Monte Carlo method. It is found that the system is a semimetal at U/t?5.6 and a Mott insulator, with long range antiferromagnetic order, at U/t?6.6. In the range 5.6?U/t?6.6, the ground state is a correlated insulator where both magnetic and dimer orders are absent. Furthermore, spin excitation in the intermediate phase appears to be gapless, and the measured spin-spin correlation function exhibits power-law decaying behavior. The data suggest that the nonmagnetic ground state is a possible candidate for the putative algebraic spin liquid. PMID- 23030187 TI - Reentrant valence transition in EuO at high pressures: beyond the bond-valence model. AB - The pressure-dependent relation between Eu valence and lattice structure in model compound EuO is studied with synchrotron-based x-ray spectroscopic and diffraction techniques. Contrary to expectation, a 7% volume collapse at ~45 GPa is accompanied by a reentrant Eu valence transition into a lower valence state. In addition to highlighting the need for probing both structure and electronic states directly when valence information is sought in mixed-valent systems, the results also show that widely used bond-valence methods fail to quantitatively describe the complex electronic valence behavior of EuO under pressure. PMID- 23030189 TI - Extrinsic spin Nernst effect from first principles. AB - We present an ab initio description of the thermal transport phenomenon called the spin Nernst effect. It refers to generation of a spin accumulation or a pure spin current transverse to an applied temperature gradient. This is similar to the intensively studied spin Hall effect described by intrinsic and extrinsic mechanisms due to an applied electric field. Analogously, several contributions are present for the spin Nernst effect. Here we investigate the extrinsic skew scattering mechanism which is dominant in the limit of dilute alloys. Our calculations are based on a fully relativistic Korringa-Kohn-Rostoker method and a solution of the linearized Boltzmann equation. As a first application, we consider a Cu host with Au, Ti, and Bi impurities. PMID- 23030190 TI - Spin pumping driven by bistable exchange spin waves. AB - Spin pumping driven by bistable exchange spin waves is demonstrated in a Pt/Y3Fe5O12 film under parametric excitation. In the Pt/Y3Fe5O12 film, the spin pumping driven by parametric excitation selectively enhances the relaxation of short-wavelength exchange spin waves, indicating strong coupling between the exchange spin waves and spin currents at the interface through efficient spin transfer. The parametric spin pumping, furthermore, allows direct access to nonlinear spin wave dynamics in combination with the inverse spin Hall effect, revealing unconventional bistability of the exchange spin waves. PMID- 23030191 TI - Hidden reservoir of photoactive electrons in LiNbO3 crystals. AB - We show that a continuous-wave (cw) pump beam at a wavelength of 532 nm produces substantial light-induced (LI) absorption in the visible range in initially transparent undoped LiNbO3 crystals. The LI absorption coefficient stays linear in the pump intensity I(p) up to I(p)(max)=48 kW/cm2. Together with other features including long-term stretched-exponential relaxation of the LI absorption, it indicates that the present concept of LI electron processes in this important optical material must be revised: the amount of photoactive electrons increases already within the cw intensity range. A quantitative model is proposed that explains the experimental data and employs two-step excitations from filled localized states near the valence band via intermediate deep centers into the conduction band. The introduced localized states serve as a hidden reservoir of electrons. PMID- 23030192 TI - Noise-induced current switching in semiconductor superlattices: observation of nonexponential kinetics in a high-dimensional system. AB - We report on measurements of first-passage-time distributions associated with current switching in weakly coupled GaAs/AlAs superlattices driven by shot noise, a system that is both far from equilibrium and high dimensional. Static current voltage (I-V) characteristics exhibit multiple current branches and bistability; precision, high-bandwidth current switching data are collected in response to steps in the applied voltage to final voltages V1 near the end of a current branch. For a range of V1 values, the measured switching times vary stochastically. At short times (?10 MUs), the switching time distributions decay exponentially, while at longer times the distributions develop nonexponential tails that follow an approximate power law over several decades. The power law decay behavior is attributed to the presence of multiple switching pathways, which may arise from small spatial variations in the superlattice growth parameters. PMID- 23030193 TI - Controlling the topology of Fermi surfaces in metal nanofilms. AB - The properties of metal crystals are governed by the electrons of the highest occupied states at the Fermi level and determined by Fermi surfaces, the Fermi energy contours in momentum space. Topological regulation of the Fermi surface has been an important issue in synthesizing functional materials, which we found to be realized at room temperature in nanometer-thick films. Reducing the thickness of a metal thin film down to its electron wavelength scale induces the quantum size effect and the electronic system changes from three to two dimensional, transforming the Fermi surface topology. Such an ultrathin film further changes its topology through one-dimensional (1D) structural deformation of the film when it is grown on a 1D substrate. In particular, when the interface has 1D metallic bands, the system is additionally stabilized by forming an electron energy gap by hybridization between 1D states of the film and substrate. PMID- 23030194 TI - Chargeless heat transport in the fractional quantum Hall regime. AB - We demonstrate a direct approach to investigate heat transport in the fractional quantum Hall regime. At a filling factor of nu=4/3, we inject power at quantum point contacts and detect the related heating from the activated current through a quantum dot. The experiment reveals a chargeless heat transport from a significant heating that occurs upstream of the power injection point, in the absence of a concomitant electrical current. By tuning in situ the edge path, we show that the chargeless heat transport does not follow the reverse direction of the electrical current path along the edge. This unexpected heat conduction, whose mechanism remains to be elucidated, may play an important role in the physics of the fractional quantum Hall regime. PMID- 23030195 TI - Prediction of polaronlike vortices and a dissociation depinning transition in magnetic superconductors: the example of ErNi2B2C. AB - In borocarbide ErNi2B2C, the phase transition to the commensurate spin density wave at 2.3 K leaves 1/20 part of Ising-like Er spins practically free. Vortices polarize these spins nonuniformly and repolarize them when moving. At a low spin relaxation rate and at low bias currents, vortices carrying magnetic polarization clouds become polaronlike and their velocities are determined by the effective drag coefficient, which is significantly bigger than the Bardeen-Stephen (BS) one. As current increases, at a critical current J(c) vortices release polarization clouds and the velocity as well as the voltage in the I-V characteristics jump to values corresponding to the BS drag coefficient. The nonuniform components of the magnetic field and magnetization drop as velocity increases, resulting in weaker polarization and discontinuous dynamic dissociation depinning transition. As current decreases, on the way back, vortices are retrapped by polarization clouds at the current J(r)TE transformation of the polarization of terahertz electromagnetic waves reflected from a strongly anisotropic boundary of a layered superconductor. We consider the case when the wave is incident on the superconductor from a dielectric prism separated from the sample by a thin vacuum gap. The physical origin of the predicted phenomenon is similar to the Wood anomalies known in optics and is related to the resonance excitation of the oblique surface waves. We also discuss the dispersion relation for these waves, propagating along the boundary of the superconductor at some angle with respect to the anisotropy axis, as well as their excitation by the attenuated-total reflection method. PMID- 23030200 TI - Infrared measurement of the pseudogap of P-doped and Co-doped high-temperature BaFe2As2 superconductors. AB - We report on infrared studies of charge dynamics in a prototypical pnictide system: the BaFe2As2 family. Our experiments have identified hallmarks of the pseudogap state in the BaFe2As2 system that mirror the spectroscopic manifestations of the pseudogap in the cuprates. The magnitude of the infrared pseudogap is in accord with that of the spin-density-wave gap of the parent compound. By monitoring the superconducting gap of both P- and Co-doped compounds, we find that the infrared pseudogap is unrelated to superconductivity. The appearance of the pseudogap is found to correlate with the evolution of the antiferromagnetic fluctuations associated with the spin-density-wave instability. The strong-coupling analysis of infrared data further reveals the interdependence between the magnetism and the pseudogap in the iron pnictides. PMID- 23030201 TI - Dual antiferromagnetic coupling at La0.67Sr0.33MnO3/SrRuO3 interfaces. AB - We have studied the magnetic hysteresis cycle of La0.67Sr0.33MnO3/SrRuO3 antiferromagnetically coupled bilayers, by magnetometry and polarized neutron reflectometry. A positive exchange bias as well as an unusual asymmetry are observed on the magnetic reversal process of the La0.67Sr0.33MnO3 layer. Through an extended Stoner-Wohlfarth model comprising the magnetic anisotropy of both layers, we give experimental evidence that this asymmetry originates from two different but well-defined antiferromagnetic coupling strengths at the interface between the two magnetic oxides. The possible origin of this dual coupling is discussed in view of our experimental results. PMID- 23030202 TI - Casimir force and in situ surface potential measurements on nanomembranes. AB - We present Casimir force measurements in a sphere-plate configuration that consists of a high quality nanomembrane resonator and a millimeter sized gold coated sphere. The nanomembrane is fabricated from stoichiometric silicon nitride metallized with gold. A Kelvin probe method is used in situ to image the surface potentials to minimize the distance-dependent residual force. Resonance-enhanced frequency-domain measurements of the nanomembrane motion allow for very high resolution measurements of the Casimir force gradient (down to a force gradient sensitivity of 3 MUN/m). Using this technique, the Casimir force in the range of 100 nm to 2 MUm is accurately measured. Experimental data thus obtained indicate that the device system in the measured range is best described with the Drude model. PMID- 23030203 TI - Evidence of a bond-nematic phase in LiCuVO4. AB - Polarized and unpolarized neutron scattering experiments on the frustrated ferromagnetic spin-1/2 chain LiCuVO4 show that the phase transition at H(Q) of 8 T is driven by quadrupolar fluctuations and that dipolar correlations are short range with moments parallel to the applied magnetic field in the high-field phase. Heat-capacity measurements evidence a phase transition into this high field phase, with an anomaly clearly different from that at low magnetic fields. Our experimental data are consistent with a picture where the ground state above H(Q) has a next-nearest neighbor bond-nematic order along the chains with a fluidlike coherence between weakly coupled chains. PMID- 23030204 TI - Pressure tuning of the spin-orbit coupled ground state in Sr2IrO4. AB - X-ray absorption spectroscopy studies of the magnetic-insulating ground state of Sr2IrO4 at ambient pressure show a clear deviation from a strong spin-orbit (SO) limit J(eff)=1/2 state, a result of local exchange interactions and a nonzero tetragonal crystal field mixing SO split J(eff)=1/2, 3/2 states. X-ray magnetic circular dichroism measurements in a diamond anvil cell show a magnetic transition at a pressure of ~17 GPa, where the "weak" ferromagnetic moment is quenched despite transport measurements showing insulating behavior to at least 40 GPa. The magnetic transition has implications for the origin of the insulating gap and the nature of exchange interactions in this SO coupled system. The expectation value of the angular part of the SO interaction, , extrapolates to zero at ~80-90 GPa where an increased bandwidth strongly mixes J(eff)=1/2, 3/2 states and SO interactions no longer dominate the electronic ground state of Sr2IrO4. PMID- 23030205 TI - Hybrid states and charge transfer at a phthalocyanine heterojunction: MnPc(delta+)/F16CoPc(delta-). AB - Using photoelectron spectroscopy we demonstrate charge transfer at an interface between two well-known transition metal phthalocyanines, MnPc and F16CoPc, resulting in charged MnPc(delta+) and F16CoPc(delta-) species. Moreover, the transferred charge is substantially confined to the two transition metal centers. Density functional theory calculations reveal that a hybrid state is formed between the two types of phthalocyanines, which causes this charge transfer. For the hybrid state the Mn 3d(xz) interacts with the Co 3d(z2) orbital leading to a two-level system. As only the lower of the two hybrid states is occupied, the charge is directly transferred to the Co 3d(z2) orbital. PMID- 23030206 TI - Mixing times in evolutionary game dynamics. AB - Without mutation and migration, evolutionary dynamics ultimately leads to the extinction of all but one species. Such fixation processes are well understood and can be characterized analytically with methods from statistical physics. However, many biological arguments focus on stationary distributions in a mutation-selection equilibrium. Here, we address the mixing time required to reach stationarity in the presence of mutation. We show that mixing times in evolutionary games have the opposite behavior from fixation times when the intensity of selection increases: in coordination games with bistabilities, the fixation time decreases, but the mixing time increases. In coexistence games with metastable states, the fixation time increases, but the mixing time decreases. Our results are based on simulations and the Wentzel-Kramers-Brillouin approximation of the master equation. PMID- 23030207 TI - Determining biomembrane bending rigidities from simulations of modest size. AB - Thermal fluctuations of lipid orientation are analyzed to infer the bending rigidity of lipid bilayers directly from molecular simulations. Compared to the traditional analysis of thermal membrane undulations, the proposed method is reliable down to shorter wavelengths and allows for determination of the bending rigidity using smaller simulation boxes. The requisite theoretical arguments behind this analysis are presented and verified by simulations spanning a diverse range of lipid models from the literature. PMID- 23030208 TI - Colloids in active fluids: anomalous microrheology and negative drag. AB - We simulate an experiment in which a colloidal probe is pulled through an active nematic fluid. We find that the drag on the particle is non-stokesian (not proportional to its radius). Strikingly, a large enough particle in contractile fluid (such as an actomyosin gel) can show negative viscous drag in steady state: the particle moves in the opposite direction to the externally applied force. We explain this, and the qualitative trends seen in our simulations, in terms of the disruption of orientational order around the probe particle and the resulting modifications to the active stress. PMID- 23030209 TI - Coupling of active motion and advection shapes intracellular cargo transport. AB - Intracellular cargo transport can arise from passive diffusion, active motor driven transport along cytoskeletal filament networks, and passive advection by fluid flows entrained by such cargo-motor motion. Active and advective transport are thus intrinsically coupled as related, yet different representations of the same underlying network structure. A reaction-advection-diffusion system is used here to show that this coupling affects the transport and localization of a passive tracer in a confined geometry. For sufficiently low diffusion, cargo localization to a target zone is optimized either by low reaction kinetics and decoupling of bound and unbound states, or by a mostly disordered cytoskeletal network with only weak directional bias. These generic results may help to rationalize subtle features of cytoskeletal networks, for example as observed for microtubules in fly oocytes. PMID- 23030210 TI - Confinement-induced solidification of colloid-polymer depletion mixtures. AB - Using a model colloid-polymer suspension, we show that confinement induces solidification in attractive colloidal suspensions via a fundamentally different route from that active in hard sphere colloidal suspensions. For a range of polymer concentrations, the suspensions undergo a phase transition from a colloidal fluid of clusters to a colloidal gel as confinement increases while polymer and particle concentration are held constant. In both fluid- and solidlike attractive suspensions, effects of confinement on the structure and dynamics appear at much larger thicknesses than for hard-sphere suspensions. The solidification does not originate from structuring of the colloids by the walls. Instead, by analyzing cluster size distributions in the fluid phase and particle dynamics in the gel phase as a function of confinement, we find that the strength of the effective interparticle attraction increases as the samples are confined. We show that the increase in the effective attraction can be understood as a consequence of the increasing importance of excluded volume due to the walls to the free energy of the polymer as confinement is increased. PMID- 23030211 TI - Comment on "Finite size corrections to the radiation reaction force in classical electrodynamics". PMID- 23030213 TI - Prevalence and incidence of severe mental illness in the United States: an historical overview. AB - The nineteenth century witnessed growing alarm among professionals and the public in the United States and Europe that the number of people in mental hospitals was rapidly rising. Whether this growth was caused by an increase in the incidence or prevalence of mental illness or by other factors has been debated for over 150 years. Those who believe that mental illness did increase attribute the change mainly to a rise in alcoholism, functional psychoses, syphilis, and disorders related to senescence. The hypothesis that functional psychoses increased has generated the most debate and is the focus of the present article. Those who believe that mental illness did not increase attribute the growth in mental hospital populations to various other factors that influence hospitalization. This article presents an historical overview of this long and complex debate. It is a balanced presentation of the arguments for and against a rise in mental illness. Original data from U.S. censuses and national reporting of mental hospital statistics are incorporated. PMID- 23030214 TI - Teaching supportive psychotherapy in the twenty-first century. AB - Although supportive psychotherapy has had a long history in our field, relatively little attention has been paid to defining a body of material that residents should be taught in order to fulfill our current educational mandate. Teaching the evidence base for the efficacy of supportive psychotherapy is reviewed. The article then discusses three different conceptualizations of supportive psychotherapy--as comprising the fundamental elements of all psychotherapies, as one end of a spectrum of dynamic therapies, and as a distinct set of directly helpful therapeutic interventions. The importance of each of these perspectives to an integrated model of supportive therapy is discussed in the context of the teaching and training needs of psychiatric residents. PMID- 23030216 TI - Videotaping and writing about patients: lessons from the "Gloria films". PMID- 23030215 TI - Panic-focused psychodynamic psychotherapy in a woman with panic disorder and generalized anxiety disorder. PMID- 23030217 TI - Advanced stage diagnosis of cancer: who is at greater risk? PMID- 23030218 TI - Progress in pancreatic cancer: moving beyond gemcitabine? PMID- 23030220 TI - Primary systemic therapy in HER2-amplified breast cancer: a clinical review. AB - Primary systemic therapy (PST) in early breast cancer is utilized in locally advanced breast tumors and when breast-conserving surgery is desirable. In addition, the PST setting provides an opportunity to monitor response including histopathological and biomarker examination of the tumor and host tissues before and after systemic therapy. Trastuzumab is a monoclonal antibody targeting the hEGF receptor that is overexpressed in 15-20% of breast tumors. Trastuzumab is effective in prolonging survival when used to treat women with hEGF receptor overexpressed tumors, both in adjuvant and metastatic disease settings. Trastuzumab has also shown promising activity in PST/neoadjuvant studies by achieving high rates of complete pathologic response. This is a review of clinical studies that incorporated trastuzumab in PST and/or neoadjuvant chemotherapy, including the results of recently reported studies using trastuzumab in combination with other novel therapies such as lapatinib or pertuzumab. PMID- 23030221 TI - Bladder conservation for muscle-invasive bladder cancer. AB - In the UK alone, approximately 10,000 patients are diagnosed with bladder cancer each year. Of these, muscle-invasive bladder cancer stage T2 or T3 accounts for 10-15%, with the remainder being non-muscle-invasive tumors, dealt with by local intravesical treatment. This group of patients are often older, the median age at presentation being 65-70 years and since this is a smoking-associated cancer there are often significant comorbidities. Transitional cell carcinoma is the most common histological type and comprises >90% of bladder cancers. Other cell types include squamous cell carcinoma, adenocarcinoma, small-cell carcinoma, sarcoma, carcinosarcoma, lymphoma and melanoma. In bladder cancer, the most important prognostic factors are stage and grade. Cystectomy, radiotherapy and chemotherapy all have a role in the management of bladder cancer. In many centers across the world, the standard management of muscle-invasive bladder cancer, stage T2 and T3, is radical cystectomy and pelvic lymphadenectomy. There is now increasing evidence that modern nonsurgical approaches using chemoradiation achieve results at least as good as those with surgery and enable bladder preservation in the majority of patients. Optimal chemoradiation schedules and the role of radiosensitizers remain important areas of research to optimize the bladder-preserving approach. Ultimately, a prospective randomized trial is needed to compare modern state-of-the-art surgery with chemoradiation to provide high level evidence on which informed patient choices can be made. PMID- 23030222 TI - Breast cancer intratumor genetic heterogeneity: causes and implications. AB - There is burgeoning evidence to suggest that tumor evolution follows the laws of Darwinian evolution, whereby individual tumor cell clones harbor private genetic aberrations in addition to the founder mutations, and that these distinct populations of cancer cells interact in competitive and mutualistic manners. The combined effect of genetic and epigenetic instability, and differential selective pressures according to the microenvironment and therapeutic interventions, create many different evolutionary routes such that intratumor heterogeneity is inevitable. Numerous cytogenetic, comparative genomic hybridization and, more recently, massively parallel sequencing studies have generated indisputable evidence of this phenomenon. The impact of intratumor heterogeneity on response and resistance to therapy is beginning to be understood; this information may prove crucial for the potentials of personalized medicine to be realized. In this review, the evidence of intratumor heterogeneity in breast cancer, its potential causes and implications for the clinical management of breast cancer patients are discussed. PMID- 23030223 TI - Decision-making tools to assist prognosis and treatment choices in early breast cancer: a review. AB - Breast cancer remains the most common type of cancer affecting women worldwide with an estimated lifetime risk of 1:8. With developments in adjuvant treatment and the identification of breast cancer subtypes, rising expectation of 'personalized' and 'targeted' therapy, decisions on systemic therapy have become increasingly more difficult. In a bid to assist clinicians in correctly selecting patients in whom systemic adjuvant therapy would be of most benefit, a number of decision-making tools have been developed. In this article, the authors will review some of these tools, explore how they were developed and assess the impact they have had on daily clinical practice. PMID- 23030224 TI - Sarcomas of the breast. AB - Sarcomas of the breast are a rare group of heterogeneous mesenchymal tumors accounting for less than 1% of all breast malignancies. Owing to the rarity of the disease, current knowledge is mostly based on numerous case reports and relatively small retrospective series; unlike epithelial breast cancer, there is no high level evidence to support a standard of care for primary and/or adjuvant therapy. To overcome this relative shortage of data, most therapeutic strategies for breast sarcoma are extrapolated from current treatment for soft tissue sarcoma in other locations, mainly of the extremities and thoracic wall. In general, the therapeutic approach to sarcoma of the breast should be based on a multidisciplinary strategy including surgery, radiation to improve local control and systemic chemotherapy in selected patients. This review discusses the results of the key larger retrospective studies including data on incidence, etiology, presentation, diagnosis, management and prognosis of this challenging rare disease entity. PMID- 23030225 TI - The role of surgery in the multidisciplinary management of patients with localized gastrointestinal stromal tumors. AB - Surgical resection of localized gastrointestinal stromal tumors (GISTs) is associated with recurrence rates of approximately 50% at 5 years of follow-up. The introduction of tyrosine kinase inhibitors, such as imatinib, improved overall survival rates in advanced disease, while in the adjuvant setting, improved recurrence-free survival following resection of high-risk GIST. The demonstration of the clinical benefit of tyrosine kinase inhibitors in both the metastatic and adjuvant settings generated interest in neoadjuvant approaches for patients with operable locally advanced disease, particularly in difficult anatomic locations. The potential impact of tumor downsizing in areas such as the gastroesophageal junction, the duodenum or the rectum, on the extent of surgical resection and morbidity is real. The ongoing research regarding neoadjuvant therapy, the duration of adjuvant therapy and the optimal means by which to risk stratify patients with GIST continues to keep the treatment of this disease at the forefront of personalized cancer care. PMID- 23030226 TI - Surgery in soft tissue sarcoma: more conservative in extremities, more extended in the retroperitoneum. AB - Extremity soft-tissue sarcomas (ESTS) account for approximately 50% and retroperitoneal soft-tissue sarcomas (RSTS) for approximately 15% of all soft tissue sarcomas. Surgery remains the main treatment modality for all soft-tissue sarcomas. Neoadjuvant and/or adjuvant chemo-and radiation-therapy are also often used to improve the treatment outcomes. In ESTS, surgery had originally been mutilating. The introduction of principles of surgical adequacy and of complementary treatments, especially radiotherapy, led to a reduction in the amputation rate in favor of conservative treatments. The implementation of plastic, vascular and nerve reconstructions allowed for further increase in conservative procedures, with better functional and cosmetic results. Moreover, recent reports have demonstrated how preoperative treatments can offset the negative prognostic impact of marginal resection on local outcome and survival, extending the limit of limb and function preservation. In RSTS, surgery had consisted of simple excision, while the resection of surrounding organs/viscera had been considered only in cases of direct involvement/infiltration. This strategy was associated with a high rate of local recurrence, which in many cases it was the driving cause of death. In order to improve local control and subsequent overall survival, some authors have recently advocated a policy of extended surgery including surrounding organs/viscera en bloc with the tumor. In this review, the authors discuss the standard world wide accepted surgical treatment for ESTS and the new surgical approach for RSTS. PMID- 23030227 TI - Optimizing further treatment choices in short- and long-term responders to first line therapy for patients with advanced renal cell carcinoma. AB - Sequencing decisions in advanced renal cell carcinoma are likely to become more difficult when new targeted agents are approved for first and subsequent lines of therapy. Approximately 70% of patients benefit from targeted therapy before progression, of which 20% can be described as short-term responders (progression free survival: <6 months) and 50% as long-term responders (progression-free survival: >6 months). The remaining 30% show either no response (20%) or are intolerant to treatment (10%). The challenge is to establish the optimal second line agent for over 70% of patients who progress following initial response to a first-line tyrosine kinase inhibitor. As it is impossible to define the optimal second-line therapy for every patient, it is suggested that age and comorbidities of the patient, the sites of disease and the side effects of previous therapies be taken into account in order to optimize the use of different agents sequentially. PMID- 23030228 TI - Current strategies in the treatment of non-muscle-invasive bladder cancer. AB - This review is based on a data search up to the end of January 2012 on strategies in the treatment of non-muscle-invasive bladder cancer. One of the authors was chairman of the guidelines writing committee of the European Association of Urology, and these guidelines served as a backbone. They are updated and adapted according to the most recent data. It is astonishing how much important data were published in the last 2 years. Many data have a high level of evidence and allow well-supported recommendations. However, recommendations are not given but the discussion for reflection on it is given in this article. PMID- 23030230 TI - Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. AB - Mesenchymal stem cells (MSCs) from bone marrow (BM) are widely used for bone and less for cartilage tissue regeneration due to their self-renewal and differentiating properties into osteogenic or chondrogenic lineages. This review considers the last decade of clinical trials involving a two-step procedure, by expanding in vitro MSCs from BM, or the so called "one-step" procedure, using BM in toto or BM concentrate, for the regeneration of cartilage and osteochondral tissue defects. The following conclusions were drawn: (1) Cartilage defects that can be repaired by the two-step technique are about twice the size as those where the one-step method is used; (2) the two-step procedure is especially used for the treatment of osteoarthritic lesions, whereas the one-step procedure is used for osteochondral defects; (3) the number of transplanted cells ranges between 3.8*10(6) and 11.2*10(6) cells/mL, and the period of cell culture expansion of implanted MSCs varies widely with regard to the two-step procedure; (4) hyaluronic or collagenic scaffolds are used in all the clinical studies analyzed for both techniques; (5) the follow-up of the two-step procedure is longer than that of the one-step method, despite having a lower number of patients; and, finally, (6) the mean age of the patients (about 39 years old) is similar in both procedures. Clinical results underline the safety and good and encouraging outcomes for the use of MSCs in clinics. Although more standardized procedures are required, the length of follow-up and the number of patients observed should be augmented, and the design of trials should be implemented to achieve evidence based results. PMID- 23030231 TI - The ketogenic diet for type II bipolar disorder. AB - Successful mood stabilizing treatments reduce intracellular sodium in an activity dependent manner. This can also be achieved with acidification of the blood, as is the case with the ketogenic diet. Two women with type II bipolar disorder were able to maintain ketosis for prolonged periods of time (2 and 3 years, respectively). Both experienced mood stabilization that exceeded that achieved with medication; experienced a significant subjective improvement that was distinctly related to ketosis; and tolerated the diet well. There were no significant adverse effects in either case. These cases demonstrate that the ketogenic diet is a potentially sustainable option for mood stabilization in type II bipolar illness. They also support the hypothesis that acidic plasma may stabilize mood, perhaps by reducing intracellular sodium and calcium. PMID- 23030232 TI - Automatic single-trial classification of prefrontal hemodynamic activity in an individual with Duchenne muscular dystrophy. AB - Brain-computer interfaces (BCIs) allow users to control external devices via brain activity alone, circumventing the somatic nervous system and the need for overt movement. Essential to BCI development is the ability to accurately detect and classify patterns of activation associated with different mental tasks. Here, we investigate the ability to automatically distinguish a mental arithmetic (MA) task from a natural baseline state in an individual with Duchenne muscular dystrophy (DMD) using signals acquired via multichannel near-infrared spectroscopy (NIRS). Using dual-wavelength NIRS, we interrogated nine sites around the frontopolar locations while the individual performed MA to answer multiple-choice questions within a system-paced paradigm. An encouraging overall classification accuracy of 71.1% was obtained, which is comparable to the average accuracy we previously reported for healthy individuals performing the same task. This result demonstrates the potential of NIRS-BCI based on task-induced prefrontal activity for use by individuals with DMD. PMID- 23030235 TI - Evaluation of lipid damage related to pathological and physiological conditions. AB - Several diseases and xenobiotics are known to generate reactive species that may trigger oxidative stress when not properly scavenged by the antioxidant defenses and result in tissue damage. We investigated lipid peroxidation (LPO) as a possible mechanism for tissue damage in some pathologies, in the normal aging process, and in subjects exposed to organic solvents. Plasmatic malondialdehyde (MDA) was quantified by high-performance liquid chromatography with visible wavelength detection in 239 subjects and divided into the following: acute myocardium infarction (AMI), diabetes without complications (D) and hemodialysis (HD) patients; into healthy children, adults, and elderly, all nonexposed to xenobiotics; and into painters occupationally exposed to organic solvents (P). Troponin, glycated hemoglobin, and transminases [aspartate aminotransferase (AST) and alanine aminotransferase] were analyzed. An increase in LPO was observed in AMI, D, HD, and P groups, when compared to healthy adults. No correlation between MDA and age was found. Further, we found positive correlations between MDA versus troponin (r = 0.47), MDA versus HbA1c (r = 0.56), and MDA versus AST (r = 0.41) in AMI, diabetics, and painters, respectively. This work has demonstrated increased lipid and protein damages in myocardium and blood, along with an alteration of hepatic transaminase activities and induction of LPO, suggesting that MDA levels are important to evaluate the extent of tissue alterations and development of acute and chronic conditions. PMID- 23030234 TI - Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions. AB - Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user's genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT(2A) or alpha-beta adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients. PMID- 23030233 TI - Safety and proof-of-concept efficacy of inhaled drug loaded nano- and immunonanoparticles in a c-Raf transgenic lung cancer model. AB - Pulmonary delivery of drug-loaded nanoparticles is a novel approach for lung cancer treatment and the conjugation of nanoparticles to a targeting ligand further promotes specificity of the carrier cargo to cancer cells. Notably, the epithelial cell adhesion molecule (EpCAM, CD326) is over expressed in lung cancer. Here, we report the safety and proof-of-concept efficacy of drug-loaded nanoparticles and EpCAM immunonanoparticles in a c-Raf transgenic lung cancer model. PEG-PLA nanoparticles and immunonanoparticles were prepared whereby paclitaxel palmitate (Pcpl) was incorporated as a medication for its common use in lung cancer treatment. Four doses of aerosolized nanoparticle formulations or vehicle were endotracheally administered to mice by consecutive or alternate regimes. Pulmonary delivery of drug loaded nano- and/or immunonanoparticle formulations elicited mild inflammation as evidenced by the slightly increased neutrophil and activated macrophage counts in bronchoalveolar lavage. No evidence for pulmonary toxicity following treatment with either blank or drug-loaded nano- and/or immunonanoparticles was observed. Proof-of-concept efficacy was determined by serial CT scanning and histopathology. Animals treated with either EpCAM antibody or Pcpl solution or drug loaded nano- or immunonanoparticles inhibited disease progression. Conversely, disease progression was noted with vehicle treated animals with nearly 30% loss of their aerated lung volume. Importantly, treatment of mice with either Pcpl or EpCAM antibody solution caused 80% mortality and/or haemorrhage, respectively, thus causing unacceptable toxicity. In contrast, the survival of animals treated with either nano- or immunonanoparticles was 60 and 70%, respectively. Taken collectively, pulmonary delivered drug-loaded nano- and EpCAM immunonanoparticles were well tolerated and can be considered a promising strategy for improving lung cancer treatment. PMID- 23030236 TI - Short- and long-term changes in blood miRNA levels after nanogold injection in rats--potential biomarkers of nanoparticle exposure. AB - CONTEXT: Increased use of engineered nanoparticles may result in exposure of workers and consumers, making them a health concern. OBJECTIVE: To identify potential blood miRNA biomarkers after intravenous gold nanoparticle (AuNP) exposure. MATERIALS AND METHODS: miRNA microarray analysis was carried out on blood of rats at 1 week and 2 months after injection. RESULTS: Many up- and downregulated miRNAs were detected. Of these, rno-miR-298 was confirmed to be increased at 1 week postinjection by reverse transcription-PCR (RT-PCR). DISCUSSION AND CONCLUSION: Blood miRNAs could be useful as biomarkers for exposure to nanoparticles. miR-298 regulates beta-amyloid (Abeta) precursor protein-converting enzyme-1 (BACE1) in Alzheimer's disease. PMID- 23030237 TI - Vestibuloplasty: porcine collagen matrix versus free gingival graft: a clinical and histologic study. AB - BACKGROUND: A free gingival graft (FGG) is currently the gold standard for augmenting small areas of keratinized mucosa. The porcine collagen matrix (CM) represents an alternative to autologous tissue harvesting. This study aims to compare the CM versus FGGs for augmenting keratinized peri-implant mucosa based on clinical and histologic evaluations. METHODS: The study included 14 patients who underwent a vestibuloplasty with either a FGG from the palate (n = 7) or the CM (n = 7). An implant-fixed vestibular retention splint was inserted for 30 days. Follow-up examinations were performed at 4, 10, 30, and 90 days after surgery. Width of keratinized mucosa was measured in the region of each implant (days 10, 30, and 90). After 90 days, a biopsy was harvested for histologic and immunohistologic analyses. To characterize newly formed soft tissue, the authors stained for tissue-and differentiation-specific markers, cytokeratin (CK) 5/6, 13, and 14, to detect presence or absence of keratinization. RESULTS: The groups showed similar healing, with increased peri-implant keratinized mucosa. The CM group had overall significantly shorter operation times than the FGG group. Both groups showed similar overall shrinkage (32.98% CM versus 28.35% FGG). All biopsies showed a multilayered, keratinized, squamous epithelium. CKs 5/6 and 14 were detected in the basal and suprabasal layers, and spots of CK 13 were detected in the suprabasal layer. CONCLUSIONS: During the whole observation period, both groups showed comparable clinical and histologic outcomes. Within the limitations of the present study, CM seems to be a promising alternative for the regeneration of keratinized mucosa without tissue harvesting. Comparative long-term studies are needed to investigate changes over time. PMID- 23030238 TI - Beneficial effects of hormone replacement therapy on periodontitis are vitamin D associated. AB - BACKGROUND: Possible synergism between female sex hormones and vitamin D on periodontitis pathology has not been assessed. Here, the authors investigate effects of estrogen, progesterone, and vitamin D on periodontitis in a population based sample and use cell studies to explore mechanistic explanations of the population-based findings. METHODS: The epidemiologic analysis uses cross sectional data from the continuous National Health and Nutrition Examination Survey 2001 to 2004. The cross sections include 1,230 women aged 40 to 85 years who received a periodontal examination, responded to questions regarding hormone replacement therapy (HRT), and provided a blood sample for serum vitamin D assessments. For mechanistic cell culture studies, human monocytes were cultured with or without lipopolysaccharide (LPS), estradiol, progesterone, and/or 1,25 dihydroxyvitamin D3; and transcriptional activity of interleukin (IL)-6, IL 1beta, B lymphocyte chemoattractant (BLC), and regulated on activation normal T cell expressed and secreted (RANTES) was assessed. RESULTS: HRT use (versus none) was associated with higher attachment levels and more teeth only among participants who were vitamin D sufficient (>20 ng/mL). The odds ratio for having moderate/severe periodontitis among users of HRT versus participants who did not use HRT was 0.69 among participants who were vitamin D sufficient and 1.19 in participants who were vitamin D deficient. LPS-induced IL-6, IL-1beta, and BLC expression was attenuated in human monocytes treated with estrogen and progesterone. Downregulation of IL-6 expression by estrogen and progesterone was potentiated when vitamin D was included. LPS-induced IL-6 and RANTES expression was decreased, and BLC expression was totally reversed, by vitamin D treatment. CONCLUSIONS: The association between HRT and clinical periodontal measures was strongest among women with high vitamin D levels. This association is plausibly mediated via an anti-inflammatory transcriptional mechanism. PMID- 23030239 TI - Protective potential of non-dialyzable material fraction of cranberry juice on the virulence of P. gingivalis and F. nucleatum mixed infection. AB - BACKGROUND: Periodontitis is a polymicrobial infectious disease. A novel potential chemical treatment modality may lie in bacterial anti-adhesive materials, such as cranberry juice fractions. The aim of this study is to explore the effect of high molecular weight cranberry constituent (non-dialyzable material [NDM]) on the virulence of a mixed infection with Porphyromonas gingivalis and Fusobacterium nucleatum in mice. METHODS: In vitro, the anti adhesive property of NDM was validated on epithelial cell culture, and inhibition of coaggregation was tested using a coaggregation assay. The in vivo effect was tested on the outcome of experimental periodontitis induced by a P. gingivalis and F. nucleatum mixed infection, and also on the local host response using the subcutaneous chamber model of infection. Phagocytosis was also tested on RAW macrophages by the use of fluorescent-labeled bacteria. RESULTS: NDM was found to inhibit the adhesion of both species of bacteria onto epithelial cells and to inhibit coaggregation in a dose-dependent manner. NDM consumption by mice attenuated the severity of experimental periodontitis compared with a mixed infection without NDM treatment. In infected subcutaneous chambers, NDM alone reduced tumor necrosis factor-alpha (TNF-alpha) levels induced by the mixed infection. In vitro, NDM eliminated TNF-alpha expression by macrophages that were exposed to P. gingivalis and F. nucleatum, without impairing their viability. Furthermore, NDM increased the phagocytosis of P. gingivalis. CONCLUSIONS: The results indicate that the use of NDM may hold potential protective and/or preventive modalities in periodontal disease. Underlying mechanisms for this trait may perhaps be the anti-adhesive properties of NDM or its potential effect on inflammation. PMID- 23030240 TI - Treatment of supra-alveolar-type defects by a simplified papilla preservation technique for access flap surgery with or without enamel matrix proteins. AB - BACKGROUND: In this study, we compare the effectiveness of enamel matrix derivative (EMD) associated with a simplified papilla preservation flap (SPPF) technique to SPPF alone when surgically treating supra-alveolar-type defects. METHODS: Fifty patients, from 54 initially selected, presenting horizontal bone loss around >=4 adjacent teeth, were treated by an SPPF technique; 25 participants also received EMD (test group) and 25 patients underwent flap surgery alone (control group). A complete clinical and radiographic examination was performed at baseline and 12 months after treatment. Pre- and post-therapy probing depth (PD), clinical attachment level (CAL), gingival recession (GR), and radiographic bone level (BL) were compared between treatments. RESULTS: After 12 months, PD, CAL, and GR in both groups showed significant differences from baseline (P <0.001). No differences in BL scores were observed within the groups at the 12-month examination. After 1 year, the test group showed significantly (P <0.001) greater PD reduction (3.4 +/- 0.7 mm) and CAL gain (2.8 +/- 0.8 mm) and a smaller GR increase (0.6 +/- 0.4 mm) compared to the control group (PD, 2.2 +/- 0.8 mm; CAL, 1.0 +/- 0.6 mm; GR, 1.2 +/- 0.7 mm.) BL changes did not significantly differ between the experimental groups. CONCLUSION: The results of this study suggest that combining EMD and SPPF in the treatment of suprabony defects may lead to a greater clinical improvement compared to SPPF alone. PMID- 23030241 TI - Clinical efficacy of subgingivally delivered 1.2% atorvastatin in chronic periodontitis: a randomized controlled clinical trial. AB - BACKGROUND: Atorvastatin (ATV) is a specific competitive inhibitor of 3-hydroxy-2 methyl-glutaryl coenzyme A reductase. Recently, statins have shown pleiotropic effects such as anti-inflammation and bone stimulation. The aim of the present study is to investigate the effectiveness of 1.2% ATV as an adjunct to scaling and root planing (SRP) in the treatment of intrabony defects (IBDs). METHODS: Sixty individuals were randomized into two treatment groups: SRP plus 1.2% ATV and SRP plus placebo gel. At baseline and 3, 6, and 9 months, clinical parameters, which included modified sulcus bleeding index, plaque index, probing depth (PD), and clinical attachment level (CAL), were recorded at baseline. Radiologic assessment of IBD fill was done using computer-aided software at baseline and 6 and 9 months. RESULTS: Mean PD reduction and mean CAL gain were greater in the ATV group than the placebo group at 3, 6, and 9 months. A significantly greater mean percentage of radiographic bone fill was found in the ATV group (35.49% +/- 5.50%) compared to the placebo group (1.82% +/- 1.32%) after 9 months. CONCLUSION: ATV as an adjunct to SRP can provide a new direction in the management of IBDs. PMID- 23030242 TI - The sociodemographic characteristics, periodontal health status, and subgingival microbiota of patients with chronic periodontitis and type 2 diabetes mellitus: a case-control study in a Chinese population. AB - BACKGROUND: In China, chronic periodontitis (CP) is common in patients with type 2 diabetes mellitus (T2DM). The purpose of this study is to identify the sociodemographic characteristics associated with such patients and to assess the periodontal health status and subgingival microbiota of patients with CP and T2DM (T2DMCP) in the Chinese population. METHODS: A total of 150 patients with T2DMCP and 306 patients with CP without any systemic disease completed questionnaires, underwent clinical periodontal examinations and participated in diabetes-related parameter examinations. Subgingival plaques were obtained to determine the prevalence and amounts of selected oral bacterial species using polymerase chain reaction (PCR) and real-time PCR, respectively. RESULTS: The income level and mean body mass index (BMI) of the patients with T2DMCP were significantly higher than those of the patients with CP. Additionally, the patients with T2DMCP were more likely to be urban residents, and they had significantly more severe periodontitis than did the patients with CP. In the patients with T2DMCP, the prevalence and amounts of Treponema denticola and Tannerella forsythia were significantly higher than those in the patients with CP. Finally, compared with the patients with CP, the patients with T2DMCP had a significantly lower prevalence and amount of Prevotella intermedia. CONCLUSIONS: Compared with the patients with CP, the patients with T2DMCP were more likely to be urban residents and generally had higher incomes, higher mean BMI, and poorer periodontal health status. Higher levels of T. denticola and T. forsythia and lower levels of P. intermedia were identified in the subgingival plaque of the patients with T2DMCP. PMID- 23030243 TI - Adenovirus-mediated bone morphogenetic protein-2 gene transfection of bone marrow mesenchymal stem cells combined with nano-hydroxyapatite to construct bone graft material in vitro. AB - To study the adhesion, proliferation and expression of bone marrow mesenchymal stem cells (BMSCs) on nano-hydroxyapatite (Nano-HA) bone graft material after transfection of adenovirus-mediated human bone morphogenetic protein-2 expression vector (Ad-BMP-2). BMSCs were transfected using Ad-BMP-2. Immunohistochemistry and Western blot were used to detect BMP-2 expression in transfected cells. After transfection, BMP-2 protein was highly expressed in BMSCs; MTT test assay showed that the Nano-HA bone graft material could not inhibit in vitro proliferation of BMSCs. Ad-BMP-2-transfected BMSCs are well biocompatible with Nano-HA bone graft material, the transfected cells in material can secrete BMP-2 stably for a long time. PMID- 23030244 TI - Functionalization of graphene for efficient energy conversion and storage. AB - As global energy consumption accelerates at an alarming rate, the development of clean and renewable energy conversion and storage systems has become more important than ever. Although the efficiency of energy conversion and storage devices depends on a variety of factors, their overall performance strongly relies on the structure and properties of the component materials. Nanotechnology has opened up new frontiers in materials science and engineering to meet this challenge by creating new materials, particularly carbon nanomaterials, for efficient energy conversion and storage. As a building block for carbon materials of all other dimensionalities (such as 0D buckyball, 1D nanotube, 3D graphite), the two-dimensional (2D) single atomic carbon sheet of graphene has emerged as an attractive candidate for energy applications due to its unique structure and properties. Like other materials, however, a graphene-based material that possesses desirable bulk properties rarely features the surface characteristics required for certain specific applications. Therefore, surface functionalization is essential, and researchers have devised various covalent and noncovalent chemistries for making graphene materials with the bulk and surface properties needed for efficient energy conversion and storage. In this Account, I summarize some of our new ideas and strategies for the controlled functionalization of graphene for the development of efficient energy conversion and storage devices, such as solar cells, fuel cells, supercapacitors, and batteries. The dangling bonds at the edge of graphene can be used for the covalent attachment of various chemical moieties while the graphene basal plane can be modified via either covalent or noncovalent functionalization. The asymmetric functionalization of the two opposite surfaces of individual graphene sheets with different moieties can lead to the self-assembly of graphene sheets into hierarchically structured materials. Judicious application of these site-selective reactions to graphene sheets has opened up a rich field of graphene-based energy materials with enhanced performance in energy conversion and storage. These results reveal the versatility of surface functionalization for making sophisticated graphene materials for energy applications. Even though many covalent and noncovalent functionalization methods have already been reported, vast opportunities remain for developing novel graphene materials for highly efficient energy conversion and storage systems. PMID- 23030245 TI - Thermal fluctuations and infrared spectra of the formamide-formamidine complex. AB - Combined effects of hydrogen bonding and thermal fluctuations on the structure and infrared spectra of the formamide-formamidine dimer, FM...FI, are studied using ab initio molecular dynamics simulations. The equilibrium structure of the dimer is stabilized by two hydrogen bonds that form a pattern reminiscent of that found in the adenine-thymine base pair. The structure of the hydrogen bonds at 300 K is subject to large fluctuations, with the hydrogen atom being tightly bound to the donor in the covalent bonding scenario. The hydrogen bond acceptor has a tendency to detach farther away from the D-H pair, approaching the dimer dissociation limit. Moreover, the N-H...O hydrogen bond breaks occasionally, thus giving rise to an "open" structure of the dimer, while the N-H...N bond stays largely intact at this temperature. Thermal fluctuations result in the minor red shifts of the monomer vibrational frequencies indicative of the anharmonicity of the potential energy surface. In contrast, the IR frequencies of the two symmetric NH(2) vibrational modes of the FM and FI monomers are shifted substantially toward the red upon hydrogen bond formation in the FM...FI dimer. Dynamical effects studied here are relevant, in particular, to the hydrogen bonding of nucleic acids at finite temperatures. PMID- 23030246 TI - Tuning hemoglobin-poly(acrylic acid) interactions by controlled chemical modification with triethylenetetramine. AB - Protein-polymer interactions play a very important role in a number of applications, but details of these interactions are not fully understood. Chemical modification was introduced here to tune protein-polymer interactions in a systematic manner, where methemoglobin (Hb) and poly(acrylic acid) (PAA) served as a model system. Under similar conditions of pH and ionic strength, the influence of protein charge on Hb/PAA interaction was studied using chemically modified Hb by isothermal titration calorimetry (ITC). A small fraction of COOH groups of Hb were amidated with triethylenetetramine (TETA) or ammonium chloride to produce the corresponding charge ladders of Hb-TETA and Hb-ammonia derivatives, respectively. All the Hb/PAA complexes produced here are bioactive, entirely soluble in water, and indicated the retention of Hb structure to a significant extent. Binding of Hb to PAA was exothermic (DeltaH < 0). The binding of Hb-TETA charge ladder to PAA indicated decrease of DeltaH from -8 +/- 0.2 to 89 +/- 4 kcal/mol, at a rate of -3.8 kcal/mol per unit charge introduced via modification. The Hb-ammonia charge ladder, in contrast, showed a decrease of DeltaH from -8 +/- 0.2 to -17 +/- 1.5 kcal/mol, at much slower rate of -1.0 kcal/mol per unit charge. Thus, the amine used for the modification played a strong role in tuning Hb/PAA interactions, even after correcting for the charge, synergistically. Charge clustering may be responsible for this synergy, and this interesting observation may be exploited to construct protein/polymer platforms for advanced biomacromolecular applications. PMID- 23030247 TI - Nicotine alters MicroRNA expression and hinders human adult stem cell regenerative potential. AB - Adult stem cells are critical for the healing process in regenerative medicine. However, cigarette smoking inhibits stem cell recruitment to tissues and delays the wound-healing process. This study investigated the effect of nicotine, a major constituent in the cigarette smoke, on the regenerative potentials of human mesenchymal stem cells (MSC) and periodontal ligament-derived stem cells (PDLSC). The cell proliferation of 1.0 MUM nicotine-treated MSC and PDLSC was significantly reduced when compared to the untreated control. Moreover, nicotine also retarded the locomotion of these adult stem cells. Furthermore, their osteogenic differentiation capabilities were reduced in the presence of nicotine as evidenced by gene expression (RUNX2, ALPL, BGLAP, COL1A1, and COL1A2), calcium deposition, and alkaline phosphatase activity analyses. In addition, the microRNA (miRNA) profile of nicotine-treated PDLSC was altered; suggesting miRNAs might play an important role in the nicotine effects on stem cells. This study provided the possible mechanistic explanations on stem cell-associated healing delay in cigarette smoking. PMID- 23030248 TI - Superaerophobicity: repellence of air bubbles from submerged, surface-engineered silicon substrates. AB - Captive bubble experiments on surface-engineered silicon substrates with precisely tuned roughness and surface chemistry are reported. In these experiments, the substrates were submerged into water, and air bubbles were dispensed from below. Our measurements revealed a bubble-repellent behavior, with bubbles freely moving around on the submerged surfaces. Drawing an analogy to drops on superhydrophobic surfaces, this behavior is termed "superaerophobic", and the observed effects are explained with the formation of a composite wetting contact between bubble and substrate. The thermodynamics of the "superaerophobic" wetting state are analyzed, and an equation for the equilibrium contact angle is given. PMID- 23030249 TI - Synthesis and characterization of amine-bridged bis(phenolate)lanthanide alkoxides and their application in the controlled polymerization of rac-lactide and rac-beta-butyrolactone. AB - A series of neutral lanthanide alkoxides supported by an amine-bridged bis(phenolate) ligand were synthesized, and their catalytic behaviors for the polymerization of rac-lactide (LA) and rac-beta-butyrolactone (BBL) were explored. The reactions of (C(5)H(5))(3)Ln(THF) with amine-bridged bis(phenol) LH(2) [L = Me(2)NCH(2)CH(2)N{CH(2)-(2-OC(6)H(2)Bu(t)(2)-3,5)}(2)] in a 1:1 molar ratio in THF for 1 h and then with 1 equiv each of 2,2,2-trifluoroethanol, benzyl alcohol, and 2-propanol gave the neutral lanthanide alkoxides LLn(OCH(2)CF(3))(THF) [Ln = Y (1), Yb (2), Er (3), Sm (4)], LY(OCH(2)Ph)(THF) (5), and LY(OPr(i))(THF) (6), respectively. These lanthanide alkoxides are sensitive to moisture, and the yttrium complex [(LY)(2)(MU-OPr(i))(MU-OH)] (7) was also isolated as a byproduct during the synthesis of complex 6. Complexes 1-6 were well characterized by elemental analyses and IR and NMR spectroscopy in the cases of complexes 1 and 4-6. The definitive molecular structures of all of these complexes were determined by single-crystal X-ray analysis. It was found that complexes 1-6 can initiate efficiently the ring-opening polymerization of rac-LA and rac-BBL in a controlled manner. For rac-LA, polymerization gave polymers with very narrow molecular weight distributions (PDI <= 1.12) and very high heterotacticity (P(r) up to 0.99). The observed activity-increasing order is in agreement with the order of the ionic radii, whereas the order for stereoselectivity is in the reverse order. For rac-BBL polymerization, the resultant polymers have narrow molecular distributions (PDI <= 1.26) and high syndiotacticity (P(r) up to 0.83). It is worth noting that the activity decreasing order Yb > Er > Y >> Sm is observed for rac-BBL polymerization, which is opposite to the order of ionic radii and to the order of activity for rac-LA polymerization. The ionic radii of lanthanide metals have no obvious effect on the stereoselectivity for rac-BBL polymerization, which is quite different from that for rac-LA polymerization. End-group analysis of the oligomer of rac-BBL suggested that elimination side reactions occurred slowly in these systems, which led to chain cleavage and the formation of crotonate (and carboxy) end groups. PMID- 23030250 TI - High critical-current superconductor-InAs nanowire-superconductor junctions. AB - We report on the fabrication of InAs nanowires coupled to superconducting leads with high critical current and widely tunable conductance. We implemented a double lift-off nanofabrication method to get very short nanowire devices with Ohmic contacts. We observe very high critical currents of up to 800 nA in a wire with a diameter of 80 nm. The current-voltage characteristics of longer and suspended nanowires display either Coulomb blockade or supercurrent depending on a local gate voltage, combining different regimes of transport in a single device. PMID- 23030251 TI - Secondary structure of short beta-peptides as the chiral expression of monomeric building units: a rational and predictive model. AB - Chirality of the monomeric residues controls and determines the prevalent folding of small oligopeptides (from di- to tetramers) composed of 2-aminocyclobutane-1 carboxylic acid (ACBA) derivatives with the same or different absolute and relative configuration. The cis-form of the monomeric ACBA gives rise to two conformers, namely, Z6 and Z8, while the trans-form manifests uniquely as an H8 structure. By combining these subunits in oligo- and polypeptides, their local structural preference remains, thus allowing the rational design of new short foldamers. A lego-type molecular architecture evolves; the overall look depends only on the conformational properties of the structural building units. A versatile and efficient method to predict the backbone folds of designed cyclobutane beta-peptides is based on QM calculations. Predictions are corroborated by high-resolution NMR studies on selected stereoisomers, most of them being new foldamers that have been synthesized and characterized for the first time. Thus, the chiral expression of monomeric building units results in the defined secondary structures of small oligomers. As a result of this study, a new set of chirality controlled foldamers is provided to probe as biocompatible biopolymers. PMID- 23030154 TI - Azimuthal anisotropy of charged particles at high transverse momenta in Pb-Pb collisions at sqrt[s(NN)] = 2.76 TeV. AB - The azimuthal anisotropy of charged particles in Pb-Pb collisions at sqrt[s(NN)]=2.76 TeV is measured with the CMS detector at the LHC over an extended transverse momentum (p(T)) range up to approximately 60 GeV/c. The data cover both the low-p(T) region associated with hydrodynamic flow phenomena and the high-p(T) region where the anisotropies may reflect the path-length dependence of parton energy loss in the created medium. The anisotropy parameter (v2) of the particles is extracted by correlating charged tracks with respect to the event-plane reconstructed by using the energy deposited in forward-angle calorimeters. For the six bins of collision centrality studied, spanning the range of 0-60% most-central events, the observed v2 values are found to first increase with p(T), reaching a maximum around p(T)=3 GeV/c, and then to gradually decrease to almost zero, with the decline persisting up to at least pp(T)=40 GeV/c over the full centrality range measured. PMID- 23030252 TI - Effect of pilocarpine on substance P and calcitonin gene-related peptide releases correlate with salivary secretion in human saliva and plasma. AB - WHAT IS KNOWN AND OBJECTIVE: Pilocarpine, a muscarinic receptor agonist, has been used for the treatment of dry mouth. Salivary glands are supplied with nerve fibres that contain neuropeptides, such as substance P, calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP), which are important modulators of salivation. It is known that measurement of salivary and plasma levels of neuropeptides is useful for assessing the dose-pharmacological effect relationship of drugs. The relationship between the action of pilocarpine and neuropeptides in humans has not been studied. Moreover, studies evaluate the usefulness of drug salivary levels in the pharmacological evaluation of drugs are scarce. The aim of this study was to examine the effects of pilocarpine on the levels of substance P-, CGRP- and VIP-like immunoreactive substances (IS) in saliva and plasma taken in healthy humans. METHODS: Five healthy male subjects participated in this study. Pilocarpine tablet (10 mg) or placebo tablet was orally administered with 100 mL of water. Each subject was administered placebo and drug with an interval of 4 weeks in between. Saliva was sampled before and at 20, 40, 60, 90, 120, 180 and 240 min after administration of the test substances. Venous blood samples (10 mL) were also taken from a forearm vein at each time interval. The samples were then enzyme immunoassayed using a highly sensitive system for substance P-, CGRP- and VIP-IS. The amount of saliva was measured by the Saxon test. RESULTS: A single oral administration of pilocarpine increased the release of salivary substance P-IS (the area under the concentration-time curve: AUC(0->240 min)) compared with the placebo. Pilocarpine also significantly increased the release of salivary CGRP-IS (AUC(0->240 min)). Pilocarpine significantly increased the release of plasma CGRP-IS. The salivary volume correlated with the salivary level of substance P and CGRP-IS (r = 0.84, P < 0.05 and r = 0.59, P < 0.05, respectively). AUC(0->240 min) for substance P-IS in saliva correlated with that for plasma (r = 0.78, P < 0.05). WHAT IS NEW AND CONCLUSION: Pilocarpine increases the release of salivary substance P and CGRP IS. This suggests that one mechanism by which pilocarpine improves dry mouth is by local stimulation of neuropeptidergic nerves. Moreover, saliva levels of substance P showed good correlation with the plasma levels. The substance P levels in saliva and plasma may be good indicators of the effects of drugs used in dry mouth/xerostomic patients. PMID- 23030253 TI - Moving to the clinic with gene therapy through our new journal expansion, human gene therapy clinical development. PMID- 23030256 TI - Epstein-Barr virus frequency in primary central nervous system lymphomas in Turkey. AB - Primary central nervous system (CNS) lymphomas are rare neoplasms which are usually not associated with Epstein-Barr virus (EBV) in immunocompetent patients. The aim of this study was to investigate the incidence of EBV in primary CNS lymphomas in the Turkish population. Thirty-two primary CNS lymphomas diagnosed according to the WHO 2008 criteria were included in this study. The presence of EBV small ribonucleic acids was investigated by in situ hybridization using EBV encoded small RNA oligonucleotides. The expression of CD10, Bcl-6, MUM-1/IRF-4, Bcl-2, and Ki-67 were evaluated using immunohistochemistry. The patient cohort included 20 male patients and 12 female patients with a median age of 53.5 years (range 13-75). Seven (22%) of cases were classified as germinal center (GC) and 25 (78%) cases as non-GC phenotype according to the Hans criteria. Twenty-six (81%) of the cases showed strong Bcl-2 expression and the median Ki-67 index was 78%. EBV expression was observed in four primary CNS lymphoma cases (12.5%). Most primary CNS lymphomas show non-GC phenotype with high Bcl-2 expression and high proliferative rate. The incidence of EBV in primary CNS lymphomas from Turkey appears to be higher than that observed in the Western countries. PMID- 23030257 TI - Supporting deployed operations: are military nurses gaining the relevant experience from MDHUs to be competent in deployed operations? AB - AIMS AND OBJECTIVES: To explore how peacetime employment of military nurses in the UK National Health Service Medical Defence Hospital Units prepares them to be competent to practise in their role on deployment. BACKGROUND: Military secondary care nurses are employed within UK National Health Service Trusts to gain clinical experience that will be relevant to their military nursing role. DESIGN: A two-stage grounded theory study using mixed methods: postal questionnaire survey and in-depth interviews. METHODS: In stage one a postal questionnaire was distributed to all serving military nurses. Stage two involved 12 semi-structured interviews. The data from both parts of the study were analysed using grounded theory. RESULTS: Four categories and one core category were identified, which suggested that participants did not feel fully prepared for deployment. Their feelings of preparedness increased with deployment experience and decreased when the nature of injuries seen on deployment changed. Respondents argued that even when unprepared, they did not feel incompetent. The findings suggest that the peacetime clinical experience gained in the National Health Service did not always develop the necessary competencies to carry out roles as military nurses on deployment. This study highlights the unique role of military nurses. We discuss these findings in the light of the literature on competency and expertise. CONCLUSION: The military nurses in this study did not feel fully prepared for deployed operations. We propose a new model for how military nurses could gain relevant experience from their National Health Service placements. RELEVANCE TO CLINICAL PRACTICE: National Health Service clinical placements need to be reassessed regularly to ensure that they are meeting military nurses' clinical requirements. Experiences of nurses returning from deployment could be shared and used as a basis for reflection and learning within National Health Service Trusts and also inform decisions regarding the appropriateness of clinical placements for qualified military nurses. PMID- 23030254 TI - Photoinduced multistep charge separation in a heteroleptic Cu(I) bis(phenanthroline)-based donor-chromophore-acceptor triad. AB - A molecular triad assembly consisting of an electron donor, a bis(phenanthroline)copper(I) chromophore, and an electron acceptor has been prepared. Under visible-light excitation, this assembly undergoes efficient (ca. 50%) photoinduced, multistep formation of a diradical cation charge-separated state that has a lifetime of >100 ns and stores >1.0 eV of energy. This system constitutes an earth-abundant functional analogue of related Ru(bpy)(3) triad systems. PMID- 23030255 TI - The prognostic significance of growth factors and growth factor receptors in gastric adenocarcinoma. AB - We evaluated growth factors/receptors expression in gastric adenocarcinoma. Immunohistochemistry was used to evaluate epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), VEGF-D, VEGF receptor (VEGFR) 2, VEGFR-3, transforming growth factor (TGF)-alpha, TGF-beta1, and TGF-beta-RII in tissue microarrays of adenocarcinoma, dysplasia, metaplasia, and gastritis. In adenocarcinoma, the expression rates of EGFR, VEGF, VEGF-D, VEGFR-2, VEGFR-3, TGF alpha, TGF-beta1, and TGF-beta-RII were 2.0%, 0%, 10.7%, 4.4%, 11.2%, 26.3%, 9.4%, and 19.5%, respectively. VEGF-D, TGF-alpha, TGF-beta1, and TGF-beta-RII expression rate were higher in adenocarcinoma than in other groups. TGF-beta-RII expression was correlated with VEGFR-3, VEGF-D, and TGF-alpha expression in adenocarcinomas. Tumor location, histologic type, stage, lymphatic invasion, perineural invasion, angioinvasion, VEGF-D, and VEGFR-2 expressions were associated with patient survival in a log rank test and advanced stage and positive expression of VEGF-D were poor prognostic factors using Cox analysis. VEGF-D expression may be of prognostic value in gastric adenocarcinoma, whereas EGFR and TGF family expression may only have a minor influence. PMID- 23030258 TI - Oropharyngeal Candida colonization in human immunodeficiency virus infected patients. AB - Oropharyngeal candidiasis (OPC) is a very common oral symptom for HIV infected patients. OPC is often caused by overgrowth of commensal Candida strains which asymptomatically colonize oral cavity of HIV+ patients. HIV infection can not only weaken the systemic and local mucosal immunity but also interact with Candida species colonizing in oral cavity. These changes in host immunity and Candida species may facilitate Candida colonization in oral cavity of HIV infected patients. This review will discuss oral Candida colonization (including asymptomatic Candida carriage and OPC) prevalence, colonization spectrum, colonization intensity, relationship between oropharyngeal Candida colonization and peripheral blood CD4+ T cell counts, association of plasma levels of HIV RNA and Candida colonization, and other factors related with Candida colonization in HIV+ patients. PMID- 23030259 TI - Externalizing and tantrum behaviours in children with ASD and ADHD compared to children with ADHD. AB - OBJECTIVE: Compare rates of externalizing in children with autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) symptoms to children with ADHD. METHOD: Parents/caregivers of 85 children with ASD and/or ADHD were surveyed about their children's behaviours using the Autism Spectrum Disorders-Comorbidity for Children and the Autism Spectrum Disorders-Behaviour Problem for Children. RESULTS: Specific main effects analyses were then conducted. Children with ASD exhibited a higher number of externalizing (F(1, 83) = 83.34, p < 0.001) and tantrum behaviours (F(1,83) = 781.86, p < 0.001) than children without ASD. CONCLUSIONS: ASD exacerbates the externalizing symptoms of ADHD during childhood. This study adds to the literature on the importance of assessing for a wide-range of possible behaviour problems in children presenting with ADHD symptomatology. The implications of these findings are discussed in the context of other research. PMID- 23030260 TI - An educational intervention to improve resident comfort with communication at the end of life. AB - BACKGROUND: Approximately 20% of deaths in the United States occur in the intensive care unit (ICU). Physician trainees lack the practical communication skills required for end-of-life care, including establishing patient preferences, participating in shared decision making, discussing prognosis, and delivering bad news. Utilizing facilitated, case-based, peer interactions, we sought to assess the feasibility and impact of a novel resident curriculum in end-of-life education. METHODS: The study took place at each of the three University of California, San Francisco (UCSF) teaching hospitals, and involved all internal medicine residents at UCSF. The curriculum consisted of two one-hour lunch conference sessions and six one-hour morning reports. A pre- and post intervention electronic survey was administered. RESULTS AND DISCUSSION: The teaching sessions offered in this study were well-attended and well-received by residents. Our curriculum impacted resident reports of comfort with specific topics in end-of-life care, including discussions of code status and comfort care. Furthermore, we found that this curriculum, although brief, demonstrated a small impact on resident reports of self-efficacy for communication. Our findings demonstrate the feasibility of incorporating end-of-life communication skills training into an existing internal medicine resident curriculum. PMID- 23030261 TI - The NIH/NINDS Anticonvulsant Screening Program (ASP): recommendations from the working group's 2012 review of the Program. PMID- 23030262 TI - The response of NINDS to recommendations from the working group's 2012 review of the Program. PMID- 23030263 TI - Addressing the need for new therapies for epilepsy. PMID- 23030264 TI - Seizing the moment for the future: the U.S. Anticonvulsant Screening Project. PMID- 23030265 TI - The value of blind screening in the Anticonvulsant Screening Program. PMID- 23030266 TI - Commentary on Anticonvulsant Screening Program update: children are not little adults. PMID- 23030267 TI - Comments on the working group's 2012 review of the Program. PMID- 23030268 TI - A possible role of cyclooxygenase-2 in the relationship between sleep and sudden unexpected death in epilepsy. PMID- 23030269 TI - Asymmetric dimethylarginine may contribute to vascular risk factors in patients receiving antiepileptic drug treatment. PMID- 23030270 TI - To evaluate the change in release from solid dispersion using sodium lauryl sulfate and model drug sulfathiazole. AB - The solubility of drugs remains one of the most challenging aspects of formulation development. There are numerous ways to improve the solubility of drugs amongst which the most promising strategy is solid dispersion. Different ratios of sulfathiazole: PVP-K29/32: sodium lauryl sulfate (SLS) were prepared (1:1:0.1, 1:1:0.5, 1:1:1) and various methods were employed to characterize the prepared solid dispersions, namely modulated differential scanning calorimeter, X ray powder diffraction, Fourier Transformed Infrared Spectroscopy and dissolution studies. Lack of crystallinity was observed in internal and external systems suggesting a loss of crystallinity, whereas the physical mixtures showed a characteristic peak of sulfathiazole. In vitro dissolution results clearly showed that the incorporation of a relatively small amount of surfactants (5, 20 or 33% w/w) into a solid dispersion can improve its dissolution rates compared to binary solid dispersion (SD) alone and pure sulfathiazole. In all ratios solid dispersion internal shows a higher dissolution rate compared to a physical mixture and solid dispersion external which suggests that the way that the surfactant is incorporated into the solid dispersion plays an important role in changing the solubility of a drug. The solubilization mechanism is mainly responsible for this higher dissolution rate when we incorporate the SLS in SD. PMID- 23030271 TI - NGR peptide ligands for targeting CD13/APN identified through peptide array screening resemble fibronectin sequences. AB - Peptides containing the Asn-Gly-Arg (NGR) motif are known to bind CD13 isoforms expressed in tumor vessels and have been widely used for tumor targeting. Residues flanking the NGR sequence play an important role in modulating the binding affinity and specificity of NGR for the CD13 receptor. Herein, we have used a rapid, easy, and reliable peptide array-whole cell binding assay for screening a library of NGR peptides with different flanking residues. A peptide array consisting of forty-five NGR containing peptides was synthesized on a cellulose membrane, followed by screening against CD13 positive (HUVEC and HT 1080) and CD13 negative cell lines (MDA-MB-435 and MDA-MB-231). The library screening led to the identification of five cyclic and acyclic NGR peptides that display higher binding (up to 5-fold) to CD13 positive cells with negligible binding to CD13 negative cell lines when compared to the lead sequence cyclic CVLNGRMEC. Peptides with high binding affinity for the CD13 positive cells also showed improved in vitro cellular uptake and specificity using flow cytometry and fluorescence microscopy. Interestingly, the identified peptides resemble the NGR sequences present in the human fibronectin protein. These NGR peptides are promising new ligands for developing tumor vasculature targeted drugs, delivery systems and imaging agents with reduced systemic toxicity. PMID- 23030273 TI - Detection of superoxide radicals in tomato plants exposed to salinity, drought, cold and heavy metal stress using CMC-G-SOD biosensor. AB - A novel highly sensitive electrochemical carboxymethylcellulose-gelatin superoxide dismutase biosensor was used for the determination of superoxide radicals enhancement in tomato plants exposed to salinity, drought, cold and heavy metal stress. The variations in superoxide radicals depending on abiotic stress was determined using biosensor. The superoxide radical production with regard to control rapidly was increased in tomato plants exposed to salinity, drought, cold and heavy metal stress. The superoxide radical enhancement in tomato plants exposed to salinity, drought, cold and heavy metal stress was successfully determined using carboxymethylcellulose-gelatin-superoxide dismutase biosensor. PMID- 23030272 TI - Development of enantioselective synthetic routes to (-)-kinamycin F and (-) lomaiviticin aglycon. AB - The development of enantioselective synthetic routes to (-)-kinamycin F (9) and ( )-lomaiviticin aglycon (6) are described. The diazotetrahydrobenzo[b]fluorene (diazofluorene) functional group of the targets was prepared by fluoride-mediated coupling of a beta-trimethylsilylmethyl-alpha,beta-unsaturated ketone (38) with an oxidized naphthoquinone (19), palladium-catalyzed cyclization (39->37), and diazo transfer (37->53). The D-ring precursors 60 and 68 were prepared from m cresol and 3-ethylphenol, respectively. Coupling of the beta-trimethylsilylmethyl alpha,beta-unsaturated ketone 60 with the juglone derivative 61, cyclization, and diazo transfer provided the advanced diazofluorene 63, which was elaborated to ( )-kinamycin F (9) in three steps. The diazofluorene 87 was converted to the C(2) symmetric lomaiviticin aglycon precursor 91 by enoxysilane formation and oxidative dimerization with manganese tris(hexafluoroacetylacetonate) (94, 26%). The stereochemical outcome in the coupling is attributed to the steric bias engendered by the mesityl acetal of 87 and contact ion pairing of the intermediates. The coupling product 91 was deprotected (tert-butylhydrogen peroxide, trifluoroacetic acid-dichloromethane) to form mixtures of the chain isomer of lomaiviticin aglycon 98 and the ring isomer 6. These mixtures converged on purification or standing to the ring isomer 6 (39-41% overall). The scope of the fluoride-mediated coupling process is delineated (nine products, average yield = 72%); a related enoxysilane quinonylation reaction is also described (10 products, average yield = 77%). We establish that dimeric diazofluorenes undergo hydrodediazotization 2-fold faster than related monomeric diazofluorenes. This enhanced reactivity may underlie the cytotoxic effects of (-)-lomaiviticin A (1). The simple diazofluorene 103 is a potent inhibitor of ovarian cancer stem cells (IC(50) = 500 nM). PMID- 23030275 TI - Mechanism and kinetics for ammonium dinitramide (ADN) sublimation: a first principles study. AB - The mechanism for sublimation of NH(4)N(NO(2))(2) (ADN) has been investigated quantum-mechanically with generalized gradient approximation plane-wave density functional theory calculations; the solid surface is represented by a slab model and the periodic boundary conditions are applied. The calculated lattice constants for the bulk ADN, which were found to consist of NH(4)(+)[ON(O)NNO(2)]( ) units, instead of NH(4)(+)[N(NO(2))(2)](-), agree quite well with experimental values. Results show that three steps are involved in the sublimation/decomposition of ADN. The first step is the relaxation of the surface layer with 1.6 kcal/mol energy per NH(4)ON(O)NNO(2) unit; the second step is the sublimation of the surface layer to form a molecular [NH(3)]-[HON(O)NNO(2)] complex with a 29.4 kcal/mol sublimation energy, consistent with the experimental observation of Korobeinichev et al. (10) The last step is the dissociation of the [H(3)N]-[HON(O)NNO(2)] complex to give NH(3) and HON(O)NNO(2) with the dissociation energy of 13.9 kcal/mol. Direct formation of NO(2) (g) from solid ADN costs a much higher energy, 58.3 kcal/mol. Our calculated total sublimation enthalpy for ADN(s) -> NH(3)(g) + HON(O)NNO(2)) (g), 44.9 kcal/mol via three steps, is in good agreement with the value, 42.1 kcal/mol predicted for the one step sublimation process in this work and the value 44.0 kcal/mol computed by Politzer et al. (11) using experimental thermochemical data. The sublimation rate constant for the rate-controlling step 2 can be represented as k(sub) = 2.18 * 10(12) exp (-30.5 kcal/mol/RT) s(-1), which agrees well with available experimental data within the temperature range studied. The high pressure limit decomposition rate constant for the molecular complex H(3)N...HON(O)NNO(2) can be expressed by k(dec) = 3.18 * 10(13) exp (-15.09 kcal/mol/RT) s(-1). In addition, water molecules were found to increase the sublimation enthalpy of ADN, contrary to that found in the ammonium perchlorate system, in which water molecules were shown to reduce pronouncedly the enthalpy of sublimation. PMID- 23030274 TI - Association of plasma osteoprotegerin levels with stroke severity and functional outcome in acute ischaemic stroke patients. AB - Osteoprotegerin (OPG) is known to regulate processes involved in vascular injury and inflammation. We investigated the relationship between plasma OPG levels and stroke subtype, stroke severity at admission and functional outcome at 3 months in 172 patients with acute ischaemic stroke. Patients with large artery atherosclerosis and those with multiple causes had higher plasma OPG levels than patients with lacune. Increased plasma OPG levels were independently associated with more severe stroke and poor functional outcome. These results suggest pleiotropic roles of OPG in mediating atherosclerosis and ischaemic brain injury. OPG is a potential biomarker for predicting neurologic outcome in stroke. PMID- 23030276 TI - ANN-QSAR model for virtual screening of androstenedione C-skeleton containing phytomolecules and analogues for cytotoxic activity against human breast cancer cell line MCF-7. AB - The present study deals with the development of an artificial neural network based quantitative structure activity relationship (QSAR) model for virtual screening of active compounds which contain androstenedione carbonskeleton or their similar skeleton at the core. An empirical data modeling (with fitted data mapping) has been performed on the basis of bioassay record for human breast cancer cell line MCF7. The whole experimental data set was considered as test set. Standard feed-forward back-propagation neural network technique was applied to build the model. Leave-One- Out (LOO) cross-validation was performed to evaluate the performance of the model. The mapped model became the basis for selection best mapped compounds followed by development of Pharmacophore specific secondary QSAR model. In the present study, two best mapped molecules '4beta hydroxy Withanolide-E' and '7, 8-Dehydrocalotropin' were used for development of the secondary QSAR model. These secondary-QSAR models were resulted with R2 LOOCV value 0.9845 and 0.9666 respectively. Docking studies, in silico phamacokinetic and toxicity analysis was also done for selected compounds. The screened compounds CID_73621, CID_16757497, CID_301751, CID_390666 and CID_46830222 were found with promising binding affinity value with aromatase with reference to the co-crystallized control compound androstenedione. Due to excellent extent of variance coverage in ANN based QSAR map model, it can be used as a robust non linear QSAR model for androstenedione carbon-skeleton containing molecules and the protocol can be used to derive secondary QSAR models for other compounds set. PMID- 23030277 TI - Controlling morphology and chain aggregation in semiconducting conjugated polymers: the role of solvent on optical gain in MEH-PPV. AB - We report the results of a detailed investigation that addresses the influence of polymer morphology and chain aggregation, as controlled by the chemical nature of the solvent, on the optical gain properties of the conjugated polymer poly[2 methoxy-5-(2'-ethylhexyloxy)-p-phenylene vinylene] (MEH-PPV). Using the variable stripe length technique in the picosecond regime, we have extensively studied the optical gain performance of asymmetric planar waveguides formed with thin MEH-PPV films spin-cast from concentrated chlorobenzene (CB) and tetrahydrofuran (THF) solutions onto thermally oxidized silicon substrates. CB and THF solvents were chosen based on their known ability to promote and effectively limit aggregate formation, respectively. Very large net gain coefficients are demonstrated, reaching values of 330 and 365 cm(-1), respectively, when optically pumping the waveguides with a maximum energy density of 85 MUJ/cm(2). Our results clearly demonstrate that polymer morphology, and hence, the chain conformation dependence of the degree of aggregation in the films as controlled by the solvent, has minimal impact on the net gain. Moreover, the waveguides exhibit low loss coefficients of 10-20 cm(-1) at the ASE wavelength. These results question the importance of polymer morphology and aggregate formation in polymer-based optical devices operating at high excitation densities in the stimulated emission regime as would be characteristic of lasers and optical amplifiers. PMID- 23030278 TI - Correlation of polarity and crystal structure with optoelectronic and transport properties of GaN/AlN/GaN nanowire sensors. AB - GaN nanowires (NWs) with an AlN insertion were studied by correlated optoelectronic and aberration-corrected scanning transmission electron microscopy (STEM) characterization on the same single NW. Using aberration-corrected annular bright field and high angle annular dark field STEM, we identify the NW growth axis to be the N-polar [000-1] direction. The electrical transport characteristics of the NWs are explained by the polarization-induced asymmetric potential profile and by the presence of an AlN/GaN shell around the GaN base of the wire. The AlN insertion blocks the electron flow through the GaN core, confining the current to the radial GaN outer shell, close to the NW sidewalls, which increases the sensitivity of the photocurrent to the environment and in particular to the presence of oxygen. The desorption of oxygen adatoms in vacuum leads to a reduction of the nonradiative surface trap density, increasing both dark current and photocurrent. PMID- 23030279 TI - Isomer-directed structural diversity and its effect on the nanosheet exfoliation and magnetic properties of 2,3-dimethylsuccinate hybrid frameworks. AB - The structures of seven new transition metal frameworks featuring Mn, Co, or Zn and either the meso or chiral D and L isomers of the 2,3-dimethylsuccinate ligand are reported. Frameworks that exhibit two-dimensional covalently bonded layers with weak interlayer interactions can be made with all three cations by incorporation of the chiral isomers of the 2,3-dimethylsuccinate ligand. The formation of such structures, suitable for the creation of nanosheets via exfoliation, is, however, not as ubiquitous as is the case with the 2,2 dimethylsuccinate frameworks since frameworks that incorporate the meso-2,3 dimethylsuccinate ligand form three-dimensional structures. This clear distinction between the formation of structures with covalent connectivity in two and three dimensions, depending on the choice of 2,3-dimethylsuccinate isomer, is due to the different conformations adopted by the backbone of the ligand. The chiral isomer prefers to adopt an arrangement with its methyl and carboxylate groups gauche to the neighboring functional groups of the same type, while the meso-ligand prefers to adopt trans geometry. A gauche-arrangement of the methyl groups places them on the same side of the ligand, making this geometry ideal for the formation of layered structures; a trans-relationship leads to the methyl groups being further apart, reducing their steric hindrance and making it easier to accommodate them within a three-dimensional structure. The ease of exfoliation of the layered frameworks is examined and compared to those of known transition metal 2,2-dimethylsuccinate frameworks by means of UV-vis spectroscopy. It is suggested that layered frameworks with more corrugated surfaces exfoliate more rapidly. The size, structure, and morphology of the exfoliated nanosheets are also characterized. The magnetic properties of the paramagnetic frameworks reveal that only the three dimensionally covalently bonded phases containing meso-2,3 DMS in trans-arrangements order magnetically. These frameworks are antiferromagnets at low temperatures, although the Co compound undergoes an unusual antiferromagnetic to ferromagnetic transition with increasing applied magnetic field. PMID- 23030280 TI - Future challenges for patient-specific induced pluripotent stem cells in cardiovascular medicine. PMID- 23030281 TI - Bilateral cardiac sympathetic denervation: why, who and when? PMID- 23030283 TI - Safety of inhibition of cholesteryl ester transfer protein with anacetrapib: the DEFINE study. AB - Inhibition of cholesteryl ester transfer protein is a strategy under investigation for raising HDL cholesterol levels and addressing residual cardiovascular risk after effective reduction of LDL cholesterol. In the Phase III DEFINE trial conducted in patients with or at high risk for coronary heart disease, anacetrapib reduced LDL cholesterol levels by 39.8% after 24 weeks compared with placebo and demonstrated an acceptable safety profile through 76 weeks of treatment (the primary end points). Anacetrapib caused a placebo adjusted 138.1% increase in HDL cholesterol levels, with no alterations in blood pressure, aldosterone or electrolytes. The trial also provided reassurance that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with a previous cholesteryl ester transfer protein inhibitor. Sustained effects on lipids were observed 12 weeks following cessation of anacetrapib treatment. Anacetrapib is being evaluated in an ongoing cardiovascular outcomes trial. PMID- 23030284 TI - Rivaroxaban for stroke prevention in atrial fibrillation: a critical review of the ROCKET AF trial. AB - Oral anticoagulation is the mainstay of therapy for stroke prevention in patients with atrial fibrillation (AF). Vitamin K antagonists such as warfarin have many drawbacks that reduce their uptake, safety and effectiveness. The ROCKET AF trial compared rivaroxaban (20 mg/day; 15 mg/day in patients with creatinine clearance 30-49 ml/min) with dose-adjusted warfarin (international normalized ratio 2-3) in 14,264 patients with AF and a prior history of stroke or at least two other additional risk factors for stroke. The ROCKET AF trial demonstrated the noninferiority of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism, with a similar rate of major bleeding and a substantial reduction in intracranial hemorrhage. These results, in conjunction with its convenient once-daily dosing regimen, make rivaroxaban an attractive alternative to warfarin for stroke prevention in AF. PMID- 23030285 TI - Long-term clinical experience with zofenopril. AB - Angiotensin-converting enzyme inhibitors are extensively used to improve clinical outcome of patients with several cardiovascular diseases. Zofenopril proved to be very effective in patients with coronary artery disease and myocardial infarction, thanks to its unique effective mechanism of action for improving blood pressure control, left ventricular function and myocardial ischemia burden, as well as angiotensin-converting enzyme inhibition. The SMILE project involved more than 3500 patients with coronary artery disease and demonstrated that zofenopril treatment may reduce mortality and morbidity in patients with myocardial infarction, also when combined with acetyl salicylic acid and to a greater extent than lisinopril and ramipril. In addition, the results of the SMILE-ISCHEMIA study have demonstrated an interesting anti-ischemic effect of zofenopril, and these properties largely contribute to the overall clinical benefit of the drug. The effects of zofenopril on blood pressure control and cardiovascular protection clearly support its primary role for prevention and treatment of cardiovascular diseases. PMID- 23030286 TI - Innovation in the diagnosis and treatment of cardiac arrhythmias. AB - The 11th International Dead Sea Symposium on Cardiac Arrhythmias and Device Therapy - the 20th Anniversary of the meeting - was held in Jerusalem, Israel on the 26-29 February 2012. The global meeting was conducted with the goal of providing a venue for a multidisciplinary approach to exchange knowledge in all areas related to arrhythmia care. In addition to presentations of original research and keynote lectures, special educational sessions were offered that included hands-on anatomy training and interesting case presentations. A series of innovations sessions included presentations by start-up companies and inventors, leveraging the venue's entrepreneurial environment. PMID- 23030287 TI - Circulating endothelial cells, plaque rupture and acute coronary syndromes. AB - Acute coronary syndromes are the most common cause of death in the Western world. Plaque rupture is most commonly associated with acute coronary events, although they primarily involve a complex interplay of numerous initiating and perpetuating factors. The identification of coronary atherosclerotic plaques that are prone to rupture and can lead to acute coronary events is being intensely studied. Circulating endothelial cells (CECs) have been detected in association with endothelial injury and may reflect damage to the vascular tree. In this article, the authors evaluate a recent publication investigating CECs using an automated and clinically feasible CEC three-channel fluorescence microscopy assay. PMID- 23030288 TI - Cardiovascular biomarkers and surrogate end points: key initiatives and clinical trial challenges. AB - Biomarkers have proven to be critical tools in both cardiovascular clinical practice and clinical research. In clinical practice, biomarkers are used to identify patients at risk for disease, stratify disease severity, guide intervention decisions and monitor patient response to therapy. Biomarkers are also used extensively to improve the design of cardiovascular clinical trials, identify 'at-risk' populations, allow for preliminary screening for response, identify appropriate dose ranges, study subgroup differences and identify early safety concerns. The purpose of this paper is to describe current key cardiovascular biomarker initiatives and to outline some of the important considerations in applying these biomarkers in a clinical trial setting, utilizing the examples of HDL cholesterol, HDL-targeted therapies and imaging tools used to assess HDL-targeted therapies as a case study. PMID- 23030289 TI - Pulmonary vein isolation with a novel endoscopic ablation system using laser energy. AB - Pulmonary vein isolation (PVI) is the basis of all ablation techniques for paroxysmal atrial fibrillation. Performing conventional radiofrequency ablation for PVI is time consuming and sometimes challenging when using point-by-point applications to create continuous lesions. Small electrically conducting gaps evolving in the ablation lines may cause recurrences of atrial fibrillation or regular atrial re-entry tachycardias. Development of novel anatomically designed ablation catheters for PVI aim to facilitate the ablation procedure, to produce continuous and durable lesions with a limited number of ablation impulses and to reduce the complication rate. The endoscopic laser balloon ablation system (HeartLight(r) EAS, Cardiofocus Inc.) is the first system that allows direct visual guidance of energy delivery at the antral level of each pulmonary vein and uses a completely new energy source for ablation. PMID- 23030290 TI - Genetic influences of angiotensin-converting enzyme inhibitor response: an opportunity for personalizing therapy? AB - The angiotensin-converting enzyme (ACE) inhibitors are a cornerstone drug therapy in the current treatment of patients with hypertension, stable coronary artery disease and heart failure. Individualizing therapy of ACE inhibitors with clinical risk factors in low-risk patients with stable coronary artery disease is not feasible. The concept of pharmacogenetics, by studying patient factors more individually, offers a first glimpse in the quest for the 'holy grail' of personalized medicine. As such, genetic targets in the direct pharmacodynamic pathway of ACE inhibitors, the renin-angiotensin-aldosterone system, is a plausible candidate for such an approach. In the past few decades, results of pharmacogenetic studies were scarce and inconsistent. However, recently the first reports of larger pharmacogenetic studies are now confirming that the 'pharmacogenetic approach' might be feasible in the future. The current review focuses on the recent developments in pharmacogenetic research in response to ACE inhibitors in patients with stable coronary artery disease. PMID- 23030291 TI - Role of genotype-based personalized antiplatelet therapy in the era of potent P2Y12 receptor inhibitors. AB - Therapy with clopidogrel and aspirin, commonly known as dual antiplatelet therapy, is a widely adapted secondary prevention strategy among coronary artery disease patients treated with percutaneous coronary intervention. However, in addition to response variability and high on-treatment platelet reactivity and their relation to increased adverse events during clopidogrel therapy, candidate gene studies and genome-wide association studies have highlighted the significance of single nucleotide polymorphisms of genes associated with clopidogrel metabolism in coronary artery disease patients. Genotyping may have an emerging role in personalized antiplatelet therapy, particularly with the advent of new P2Y12 receptor blockers that have more rapid and potent pharmacodynamic properties than clopidogrel. The current review discusses the role of genotyping in personalizing P2Y12 receptor-blocker therapy. PMID- 23030292 TI - New cell therapies in cardiology. AB - Even today, cardiovascular disease remains the leading cause of death globally. Cardiological conditions such as myocardial infarction, ischemic injury and chronic cardiomyopathy result in permanent cardiac tissue damage followed by heart failure. Current therapies primarily aim to trigger the pathological remodeling that occurs after cardiac injury and also to reduce risk factors involved in cardiovascular diseases. Animal model studies over the last decade indicate that the systematic administration of autologous and allogeneic stem cells possesses therapeutic potential to improve overall cardiac functions. This evidence robustly indicates that cardiac tissue has the potential to undergo a systematic repair process. The past few years have also witnessed a splurge in clinical research that particularly aims to explore the regenerative properties of the naive stem cells to restore cardiac functions. The mechanisms involved in stem cell therapy remain unclear. The magnitude of benefit demonstrated in animal models is yet to be completely translated into humans. The future of cardiac research will require tangible synchrony between clinicians and basic scientists to unravel the precise mechanism of stem cell therapy. It is also pivotal to define an ideal cell type and a suitable cell delivery technique that provide maximum benefit, while eliminating the grey areas in translational cardiology research. In this article, the authors review the properties and therapeutic potential of the stem cell plethora reported for cardiac repair and regeneration, recent stem cell therapies, mode of action, their delivery techniques, recent clinical developments and the future for these stem cell therapies in cardiology. PMID- 23030294 TI - Coronary heart disease in type 2 diabetes: mechanisms and comprehensive prevention strategies. AB - Individuals with type 2 diabetes mellitus suffer from a higher incidence of coronary heart disease (CHD) compared with those without diabetes. The mechanisms for the increased CHD in diabetic patients are multifactorial, including endothelial dysfunction, vessel wall modification, hyperglycemic toxicity, oxidative stress and inflammation, and insulin resistance. Moreover, multifactorial intervention, other than glycemic control alone, is recognized as the promising strategy for diabetic patients with CHD. In this review, the roles of the major contributors to the development of CHD and the comprehensive management strategies dealing with diabetes mellitus are focused upon. PMID- 23030293 TI - Biomaterial applications in cardiovascular tissue repair and regeneration. AB - Cardiovascular disease physically damages the heart, resulting in loss of cardiac function. Medications can help alleviate symptoms, but it is more beneficial to treat the root cause by repairing injured tissues, which gives patients better outcomes. Besides heart transplants, cardiac surgeons use a variety of methods for repairing different areas of the heart such as the ventricular septal wall and valves. A multitude of biomaterials are used in the repair and replacement of impaired heart tissues. These biomaterials fall into two main categories: synthetic and natural. Synthetic materials used in cardiovascular applications include polymers and metals. Natural materials are derived from biological sources such as human donor or harvested animal tissues. A new class of composite materials has emerged to take advantage of the benefits of the strengths and minimize the weaknesses of both synthetic and natural materials. This article reviews the current and prospective applications of biomaterials in cardiovascular therapies. PMID- 23030295 TI - Preventing cardiovascular events with angiotensin II receptor blockers: a closer look at telmisartan and valsartan. AB - Angiotensin II receptor blockers (ARBs) inhibit the renin-angiotensin system. As a result, these agents provide beneficial effects in terms of cardiovascular (CV) and renal protection, independent of their blood pressure-lowering effects. Telmisartan and valsartan are the most intensively studied ARBs for the effects on CV outcomes. Randomized clinical trials assessing morbidity and mortality end points have included a range of patient types, including those with hypertension, hypertension with Type 2 diabetes, high CV risk without hypertension, ischemic heart disease, stroke and heart failure. Few head-to-head comparisons between telmisartan and valsartan have been performed. However, some blood pressure independent properties of these two ARBs can be scrutinized from separate studies in the available literature. PMID- 23030296 TI - Expression of NOX5 in human teratozoospermia compared to normozoospermia. AB - Spermatozoa are capable of producing small amounts of reactive oxygen species (ROS), and sperm in teratozoospermia generate more ROS than sperm in normozoospermia. The source of ROS production in ejaculated human sperm has not been fully clarified. Recently, NADPH oxidase 5 (NOX5) was detected in human sperm, and ROS generation by this enzyme was reported. We investigated the magnitude of NOX5 expression in normozoospermic (n = 12) and teratozoospermic (n = 13) semen samples with different percentages of abnormal sperm. The existence of NOX5 enzymes in sperm was analysed by immunocytochemistry and flow cytometry and correlated with morphological abnormalities. Immunofluorescent studies identified NOX5 in acrosomal, equatorial, post-acrosomal regions, the body and the tail of both normal and abnormal sperm. Teratozoospermic semen samples had higher percentages of NOX5-positive sperm and expressed more NOX5 (based on higher mean fluorescent intensity) than normal semen samples. Positive correlations were observed between abnormal sperm morphology and both the percentage of NOX5-positive sperm and the magnitude of NOX5 expression. Based on these findings, we can assume that there is a positive correlation between ROS generation in teratozoospermia and that in NOX5 expression. PMID- 23030297 TI - Characterizing size and porosity of hollow nanoparticles: SAXS, SANS, TEM, DLS, and adsorption isotherms compared. AB - A combination of experimental methods, including transmission and grazing incidence small-angle X-ray scattering (SAXS and GISAXS), small-angle neutron scattering (SANS), transmission electron microscopy (TEM), dynamic light scattering (DLS), and N(2) adsorption-desorption isotherms, was used to characterize SiO(2)/TiO(2) hollow nanoparticles (HNPs) of sizes between 25 and 100 nm. In the analysis of SAXS, SANS, and GISAXS data, the decoupling approximation and the Percus-Yevick structure factor approximation were used. Brunauer-Emmett-Teller, t-plot, and a spherical pore model based on Kelvin equation were applied in the treatment of N(2) isotherms. Extracted parameters from the scattering and TEM methods are the average outer and inner diameters and polydispersity. Good agreement was achieved between different methods for these extracted parameters. Merits, advantages, and disadvantages of the different methods are discussed. Furthermore, the combination of these methods provided us with information on the porosity of the shells of HNPs and the size of intrawall pores, which are critical to the applications of HNPs as drug delivery vehicles and catalyst supports. PMID- 23030299 TI - Is tissue CA125 expression in epithelial ovarian adenocarcinoma heterogenic? AB - To evaluate if heterogeneity of tissue cancer antigen 125 (CA125) expression is present in epithelial serous adenocarcinomas. Furthermore, to investigate whether there is a correlation between levels of CA125 tissue expression, serum level of CA125, stage, and grade. A total of 10 patients diagnosed with serous ovarian adenocarcinomas were included. Preoperative blood samples were collected to determine serum CA125 levels. Tumor tissue from primary surgery was collected and processed for immunohistochemical analyses. CA125 was expressed in varying degrees in tumor tissues from all patients. Mean tissue CA125 expression for each patient ranged from 36% to 98%. Intrapatient variations in tissue expression ranged from 10% to 90% point. No significant correlations between levels of CA125 tissue expression, serum level of CA125, stage, and grade were found. We found that the tissue expression of CA125 is heterogenic. Although most patients had a high mean expression, it covers a large intrapatient variation in expression. This suggests that if using CA125 as a tissue marker and anti-CA125 (oregovomab) as immunotherapy treatment in future studies, it will be necessary to take heterogeneity into consideration and examine a larger number of biopsies. Therefore, the study demonstrates the need for heterogeneity studies in future translational research. PMID- 23030300 TI - The basis for carbapenem hydrolysis by class A beta-lactamases: a combined investigation using crystallography and simulations. AB - Carbapenems are the most potent beta-lactam antibiotics and key drugs for treating infections by Gram-negative bacteria. In such organisms, beta-lactam resistance arises principally from beta-lactamase production. Although carbapenems escape the activity of most beta-lactamases, due in the class A enzymes to slow deacylation of the covalent acylenzyme intermediate, carbapenem hydrolyzing class A beta-lactamases are now disseminating in clinically relevant bacteria. The reasons why carbapenems are substrates for these enzymes, but inhibit other class A beta-lactamases, remain to be fully established. Here, we present crystal structures of the class A carbapenemase SFC-1 from Serratia fonticola and of complexes of its Ser70 Ala (Michaelis) and Glu166 Ala (acylenzyme) mutants with the carbapenem meropenem. These are the first crystal structures of carbapenem complexes of a class A carbapenemase. Our data reveal that, in the SFC-1 acylenzyme complex, the meropenem 6alpha-1R-hydroxyethyl group interacts with Asn132, but not with the deacylating water molecule. Molecular dynamics simulations indicate that this mode of binding occurs in both the Michaelis and acylenzyme complexes of wild-type SFC-1. In carbapenem-inhibited class A beta-lactamases, it is proposed that the deacylating water molecule is deactivated by interaction with the carbapenem 6alpha-1R-hydroxyethyl substituent. Structural comparisons with such enzymes suggest that in SFC-1 subtle repositioning of key residues (Ser70, Ser130, Asn132 and Asn170) enlarges the active site, permitting rotation of the carbapenem 6alpha-1R-hydroxyethyl group and abolishing this contact. Our data show that SFC-1, and by implication other such carbapenem-hydrolyzing enzymes, uses Asn132 to orient bound carbapenems for efficient deacylation and prevent their interaction with the deacylating water molecule. PMID- 23030302 TI - Quality doctoral programmes: views from the East Asian Forum of Nursing Scholars. PMID- 23030301 TI - Yes/no versus forced-choice recognition memory in mild cognitive impairment and Alzheimer's disease: patterns of impairment and associations with dementia severity. AB - Memory tests are sensitive to early identification of Alzheimer's disease (AD) but less useful as the disease advances. However, assessing particular types of recognition memory may better characterize dementia severity in later stages of AD. We sought to examine patterns of recognition memory deficits in individuals with AD and mild cognitive impairment (MCI). Memory performance and global cognition data were collected from participants with AD (n = 37), MCI (n = 37), and cognitively intact older adults (normal controls, NC; n = 35). One-way analyses of variance (ANOVAs) examined differences between groups on yes/no and forced-choice recognition measures. Individuals with amnestic MCI performed worse than NC and nonamnestic MCI participants on yes/no recognition, but were comparable on forced-choice recognition. AD patients were more impaired across yes/no and forced-choice recognition tasks. Individuals with mild AD (>=120 Dementia Rating Scale, DRS) performed better than those with moderate-to-severe AD (<120 DRS) on forced-choice recognition, but were equally impaired on yes/no recognition. There were differences in the relationships between learning, recall, and recognition performance across groups. Although yes/no recognition testing may be sensitive to MCI, forced-choice procedures may provide utility in assessing severity of anterograde amnesia in later stages of AD. Implications for assessment of insufficient effort and malingering are also discussed. PMID- 23030303 TI - Rehabilitation issues in Landau-Kleffner syndrome. PMID- 23030304 TI - An international comparison of patterns of participation in leisure activities for children with and without disabilities in Sweden, Norway and the Netherlands. AB - PURPOSE: To investigate whether there are differences in participation in leisure activities between children with and without disabilities in Sweden, Norway and the Netherlands and how much personal and environmental factors explain leisure performance. METHODS: In a cross-sectional analytic design, the Children's Assessment of Participation and Enjoyment, CAPE, was performed with 278 children with disabilities and 599 children without disabilities aged 6-17 years. A one way between-groups ANOVA explored the differences in participation between the countries. Hierarchical multiple regression analysis assessed if age, gender, educational level, living area and country of residence explained the variance in participation. RESULTS: Scandinavian children with disabilities participated in more activities with higher frequency compared to Dutch children. The strongest predictor was country of residence. For children without disabilities, differences existed in informal activities, the strongest predictor was gender. CONCLUSION: Differences in school- and support systems between the countries seem to influence patterns of participation, affecting children with disabilities most. PMID- 23030305 TI - Expression of apoptosis associated proteins Survivin, Livin and Thrombospondin-1 in Burkitt lymphoma. AB - Burkitt lymphoma (BL) accounts for 80% of Non-Hodgkin lymphoma in Uganda. The tumour is fast growing with a very short doubling time. Inhibition of apoptosis, achieved through the apoptosis inhibitor family of proteins enhances survival of cancer cells. The aim of this study was to explore the expression of apoptosis related proteins Survivin, Livin and Thrombospondin-1 (TSP-1) in BL and comparing it with the expression in reactive follicular hyperplasia. Among the BL cases, survivin was positive in 37 (75%) and negative in 12 (25%). Livin staining was positive in 23 (48%) and negative in 25 (52%) of the BL cases. TSP-1 was positive in 40 (87%) and negative in 6 (13%) of the BL cases. All the 10 reactive lymphoid hyperplasia (RLH) were positive for survivin, livin expression was found in 4 (40%), whereas TSP-1 was positive in 7 (70%) of the RLH cases. Among the BL, there was no statistically significant association between survivin and livin expression (p = 0.6), livin and TSP-1 (p = 1.0) or survivin and TSP-1 (p = 0.6). Likewise no statistical association was found between the expressions of the proteins in RLH. There was no statistically significant difference between the expression frequency of the apoptosis associated proteins examined in BL and RLH. In conclusion, we have demonstrated the expression of inhibitor of apoptosis proteins, survivin and Livin and the pro-apoptotic protein TSP-1 in endemic BL. No significant difference was found between BL and RLH. PMID- 23030306 TI - Profit status and delivery of hospice care for infants: the mediating role of pediatric knowledge. AB - BACKGROUND: Infant mortality is a persistent problem in the United States, and yet, hospice care is rarely provided for infants at the end of life. OBJECTIVE: To examine the influence of profit status on delivery of hospice care for infants, and to explore the mediating role of pediatric knowledge (pediatric program and pediatric knowledge) on the relationship between profit status and the delivery of infant care. METHODS: Our study was a cross-sectional secondary analysis, using data from the 2008 California State Utilization Data File of Home Health Agencies and Hospice Facilities survey. RESULTS: Of the hospices in the sample, 13% delivered care for infants. Nonprofit hospices were more likely to delivery care for infants (B=0.67, p<0.05), have a specialized pediatric program (B=0.85, p<0.05) and have more experience caring for pediatric patients (B=1.49, p<0.05). Regarding the mediator variables, hospices with a pediatric program were no more likely to deliver care to infants than hospices without a pediatric program (B=0.82, p>0.05). Experience with greater numbers of any pediatric patients facilitated the delivery of hospice infant care in nonprofits (B=0.86, p<0.05). CONCLUSION: Hospices may need to explore ways to direct resources toward assisting hospice staff members in gaining pediatric experience. PMID- 23030307 TI - Integrons, beta-lactamase and qnr genes in multidrug resistant clinical isolates of Proteus mirabilis and P. vulgaris. AB - Thirty-three isolates of Proteus mirabilis and two P. vulgaris were examined for their antimicrobial resistance, the presence of integrons with regard to gene cassette content, and genetic determinants of beta-lactam and low-level quinolone resistance. Integrons were detected in 23 (69.7%) P. mirabilis isolates; six (18.2%) of them had class 1 integrons, 11 (33.3%) possessed class 2 integrons and six (18.2%) carried integrons of both classes. One P. vulgaris strain possessed class 1 and class 2 integrons. The presence of integrons was associated with increased frequency of resistance to gentamicin, ciprofloxacin, sulfamethoxazole and co-trimoxazole. Moreover, integron presence was associated with increased resistance range in terms of both the number of antimicrobials and the number of classes of antimicrobials to which a strain was resistant. Class 1 integrons contained aadA1, aadB-aadA1, dfrA1-aadA1, bla(PSE-1) -aadA1 and aacA4-orfA-orfB aadA1 gene cassette arrays, whereas all class 2 integrons had a dfrA1-sat2-aada1 array. beta-lactamase genes not associated with integrons comprised bla(TEM-2) , bla(DHA-1) and bla(CMY-15) . Plasmid-mediated fluoroquinolone resistance was determined by qnrD and qnrS1 genes. This is the first report of P. vulgaris strains harbouring qnrD genes in Europe. PMID- 23030308 TI - In vivo imaging of glia activation using 1H-magnetic resonance spectroscopy to detect putative biomarkers of tissue epileptogenicity. AB - PURPOSE: Long-lasting activation of glia occurs in brain during epileptogenesis, which develops after various central nervous system (CNS) injuries. Glia is the cell source of the biosynthesis and release of molecules that play a role in seizure recurrence and may contribute to epileptogenesis, thus representing a putative biomarker of epilepsy development and severity. In this study, we set up an in vivo longitudinal study using (1) H-magnetic resonance spectroscopy (MRS) to measure metabolite content in the rat hippocampus that could reflect the extent and the duration of glia activation. Our aim was to explore if glia activation during epileptogenesis, or in the chronic epileptic phase, can be used as a biomarker of tissue epileptogenicity (i.e., a measure of epilepsy severity). METHODS: (1) H-MRS measurements were done in the adult rat hippocampus every 24 h for 7 days after status epilepticus (SE) and in chronic epileptic rats, using a 7 T Bruker Biospec MRI (magnetic resonance imaging)/MRS scanner. We studied changes in metabolite levels that reflect astrocytes (myo inositol, mIns; glutathione, GSH), microglia/macrophage activation and the associated neuronal cell injury/dysfunction (lactate, Lac; N-acetyl-aspartate, NAA). (1) H-MRS results were validated by post hoc immunohistochemistry using cell-specific markers. Data analysis was done to determine whether correlations exist between the metabolite changes and spontaneous seizure frequency or the extent of neuronal cell loss. KEY FINDINGS: The analysis of (1) H-MRS spectra showed a progressive increase in mIns and GSH levels after SE, which was maintained in epileptic rats. Lac signal transiently increased during epileptogenesis being undetectable in chronic epileptic tissue. NAA levels were chronically reduced from day 2 post-SE. Immunohistochemistry confirmed the activation of microglia and astrocytes and the progressive neuronal cell loss. GSH levels during epileptogenesis showed a negative correlation with the frequency of spontaneous seizures, whereas S100beta levels in epileptic tissue were positively correlated with this outcome measure. A negative correlation was also found between GSH or mIns levels during epileptogenesis and the extent of neurodegeneration in hippocampus of epileptic rats. SIGNIFICANCE: (1) H-MRS is a valuable in vivo technique for determining the extent and temporal profile of glia activation after an epileptogenic injury. S100beta levels measured in the epileptic tissue may represent a biomarker of seizure frequency, whereas GSH levels during epileptogenesis could serve as a predictive marker of seizure frequency. Both mIns and GSH levels measured before the onset of spontaneous seizures predict the extent of neuronal cell loss in epileptic tissue. These findings highlight the potential of serial (1) H-MRS analysis for searching epilepsy biomarkers for prognostic, diagnostic, or therapeutic purposes. PMID- 23030311 TI - Application of alpha-N-acetylgalactosaminidase and alpha-galactosidase in AB to O red blood cells conversion. AB - BACKGROUND: Enzymatical conversion of A or B RBCs into group O RBCs (ECORBCs) was achieved by using alpha-N-acetylgalactosaminidase and alpha-galactosidase, respectively. Now, we initiated AB to O-RBC conversion by using these two enzymes together. But alpha-N-acetylgalactosaminidase and alpha-galactosidase's preserving and their reaction buffer were quite different. The aim of this study is to confirm an available system for converting AB to O RBCs, especially to study the maximal permission amount of PCS which was brought to the system accompanied enzyme addition. METHOD: Enzyme activity was detected by using GalNAc pNp or Gal-pNp as substrates. The efficiency of the conversion of A or B antigen was evaluated by routine method and measured by fluorescence-activated cell sorting analysis. The optimal buffer component and the doses of alpha-N acetylgalactosaminidase and alpha-galactosidase were confirmed according to A and B antigen epitope removal efficiency. RESULTS: The activity of alpha-N acetylgalactosaminidase and alpha-galactosidase was not decreased drastically when they were kept in PCS Buffer in 4 degrees C. The optimal reaction buffer composed of glycine 250 mM and NaCl 3 mM, pH 6.8 and PCS less than 10%(v/v). For converting A(1)B to O RBCs completely, the doses of alpha-N acetylgalactosaminidase and alpha-galactosidase were confirmed as 0.015 mg/ml packed RBCs(pRBCs) for A(1) antigen epitopes and 0.005 mg/ml pRBCs for B epitopes. Approximately 0.004 mg alpha-N-acetylgalactosaminidase and 0.005 mg alpha-galactosidase were required to convert 1 ml pRBCs. CONCLUSION: Our studies indicated that alpha-N-acetylgalactosaminidase and alpha-galactosidase were stable in PCS buffer and a modified protocol which was propitious to converting AB to O RBCs was provided. PMID- 23030309 TI - Pharmacokinetic properties and bioequivalence of candesartan cilexetil in Korean healthy volunteers. AB - Candesartan is a long-acting and selective nonpeptide AT1 subtype angiotensin II receptor antagonist. The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two candesartan cilexetil 16 mg formulations. Forty healthy volunteers were randomly assigned into two groups. After a single dose of 16 mg candesartan cilexetil oral administration, blood samples were collected at specific time intervals from 0-36 h. The plasma concentrations of candesartan cilexetil were determined by LC-MS/MS. The pharmacokinetic parameters such as AUC(last), AUC(inf) and C(max) were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data. The mean for AUC(last) in the reference and the test drug were 1530.1 +/- 434.6 and 1315.7 +/- 368.6 ng.h/mL. The mean for AUC(inf) in the reference and the test drug were 1670.0 +/- 454.5 and 1441.2 +/- 397.8 ng.h/mL. The mean value for C(max) in the reference and the test drug was 142.6 +/- 41.0 and 134.9 +/- 41.4 ng/mL. The 90% confidence intervals for the AUC(last), AUC(inf) and C(max) were in the range of log 0.81-log 0.91, log 0.81-log 0.91 and log 0.88-log1.01, respectively. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these health volunteers. Both formulations were safe and well tolerated in 16 mg of candesartan cilexetil hydrochloride. PMID- 23030312 TI - Automated determination of axonal orientation in the deep white matter of the human brain. AB - The wide-spread utilization of diffusion-weighted imaging in the clinical neurosciences to assess white-matter (WM) integrity and architecture calls for robust validation strategies applied to the data that are acquired with noninvasive imaging. However, the pathology and detailed fiber architecture of WM tissue can only be observed postmortem. With these considerations in mind, we designed an automated method for the determination of axonal orientation in high resolution microscope images. The algorithm was tested on tissue that was stained using a silver impregnation technique that was optimized to resolve axonal fibers against very low levels of background. The orientation of individual nerve fibers was detected using spatial filtering and a template-matching algorithm, and the results are displayed as color-coded overlays. Quantitative models of WM fiber architecture at the microscopic level can lead to improved interpretation of low resolution neuroimaging data and to more accurate mapping of fiber pathways in the human brain. PMID- 23030313 TI - Revisiting zinc coordination in human carbonic anhydrase II. AB - Carbonic anhydrase (CA, general abbreviation for human carbonic anhydrase II) is a well-studied, zinc-dependent metalloenzyme that catalyzes hydrolysis of carbon dioxide to the bicarbonate ion. The apo-form of CA (apoCA, CA where Zn(2+) ion has been removed) is relatively easy to generate, and reconstitution of the human erythrocyte CA has been initially investigated. In the past, these studies have continually relied on equilibrium dialysis measurements to ascertain an extremely strong association constant (K(a) ~ 1.2 * 10(12)) for Zn(2+). However, new reactivity data and isothermal titration calorimetry (ITC) data reported herein call that number into question. As shown in the ITC experiments, the catalytic site binds a stoichiometric quantity of Zn(2+) with a strong equilibrium constant (K(a) ~ 2 * 10(9)) that is 3 orders of magnitude lower than the previously established value. Thermodynamic parameters associated with Zn(2+) binding to apoCA are unraveled from a series of complex equilibria associated with the in vitro metal binding event. This in-depth analysis adds clarity to the complex ion chemistry associated with zinc binding to carbonic anhydrase and validates thermochemical methods that accurately measure association constants and thermodynamic parameters for complex-ion and coordination chemistry observed in vitro. Additionally, the zinc sites in both the as-isolated and the reconstituted ZnCA (active CA containing a mononuclear Zn(2+) center) were probed using X-ray absorption spectroscopy. Both X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) analyses indicate the zinc center in the reconstituted carbonic anhydrase is nearly identical to that of the as-isolated protein and confirm the notion that the metal binding data reported herein is the reconstitution of the zinc active site of human CA II. PMID- 23030314 TI - Dilational properties of novel amphiphilic dendrimers at water-air and water heptane interfaces. AB - In this work, a series of novel amphiphilic dendrimers taking polyamidoamine dendrimer as the core with different hydrophobic tails QPAMC(m) were synthesized and the dilational properties were studied as monolayers by dilational rheological measurements at the water-air and water-n-heptane interfaces to explore the nature of adsorption behaviors. The results showed that the maximum values of the dilational modulus seemed to have no obvious variation in a wide change of hydrophobic chain length at the surface. However, there was considerable variability in the tendency of the influence of bulk concentration on the dilational modulus at the two different interfaces. It was interestingly found that the diffusion-exchange process slowed down with the increase of alkyl chain length leading to more elastic nature of adsorption film, which was contrary to the tendencies of conventional single chain and gemini surfactants. It is reasonable to consider that, in the case of the molecule having short chain length such as QPAMC(8), the alkyl chains are too short to overlap across the headgroup, enable the intermolecular hydrophobic interaction to be predominant with increasing of surface concentration, which enhances the elasticity and shows the slowest diffusion-exchange process. Whereas, when the chain length increases to 12 or 16, the alkyl chains are long enough to act intramolecularly to form intracohesion conformation, which results in enhancing the diffusion-exchange process. In conclusion, the interfacial behaviors are dictated by the size ratio between the tail and headgroup. A reasonable model with respect to the molecular interaction was proposed on the basis of experimental data. The results of interfacial tension relaxation and dynamic light scattering (DLS) experiments, in accord with the proposed mechanism, also present the unusual tendency comparing to the traditional single or gemini surfactants. PMID- 23030315 TI - Angiotensin-(1-7) treatment ameliorates angiotensin II-induced apoptosis of human umbilical vein endothelial cells. AB - Angiotensin (Ang)-(1-7), a metabolite of AngI and AngII, is a counter-regulatory mediator of AngII. In the present study, we investigated the effects of Ang-(1-7) on AngII-induced apoptosis in human umbilical vein endothelial cells (HUVEC). To this end, HUVEC were pretreated with 10(-9), 10(-8), 10(-7) or 10(-6) mol/L Ang (1-7) at for 30 min before being stimulated with 10(-6) mol/L Ang-II for another 24 h. Acridine orange/ethidium bromide and propidium iodide staining were used to analyse the effects of Ang-(1-7) on AngII-induced apoptosis. Alone, 10(-6) mol/L Ang-(1-7) had no effect on the apoptosis of HUVEC following exposure of cells for 30 min, whereas AngII (10(-6) mol/L, 24 h) significantly enhanced the number of apoptotic cells (P < 0.01). The AngII-induced apoptosis of HUVEC was suppressed by 10(-9)-10(-6) mol/L Ang-(1-7). The anti-apoptotic effects of Ang-(1-7) were almost completely abolished by A-779 (10(-6) mol/L, 30 min), a specific Mas receptor antagonist. In addition, Ang-(1-7) inhibited AngII-induced accumulation of cleaved caspase 3 and enhanced the expression of the anti-apoptotic factor Bcl 2 at both the mRNA and protein levels. Angiotensin II upregulated the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which is involved in endothelial apoptosis, at both the mRNA and protein levels. This effect was blocked by Ang-(1-7) in a concentration-dependent manner, although A 779 almost completely reversed Ang-(1-7)-mediated inhibition of AngII-induced upregulation of LOX-1. Silencing of LOX-1 using short interference RNA enhanced the protective effects of Ang-(1-7) against AngII-induced apoptosis in HUVEC. Together, the results suggest that Ang-(1-7) ameliorates AngII-induced apoptosis of HUVEC at least in part by suppressing LOX-1 expression. PMID- 23030316 TI - Does rational selection of training and test sets improve the outcome of QSAR modeling? AB - Prior to using a quantitative structure activity relationship (QSAR) model for external predictions, its predictive power should be established and validated. In the absence of a true external data set, the best way to validate the predictive ability of a model is to perform its statistical external validation. In statistical external validation, the overall data set is divided into training and test sets. Commonly, this splitting is performed using random division. Rational splitting methods can divide data sets into training and test sets in an intelligent fashion. The purpose of this study was to determine whether rational division methods lead to more predictive models compared to random division. A special data splitting procedure was used to facilitate the comparison between random and rational division methods. For each toxicity end point, the overall data set was divided into a modeling set (80% of the overall set) and an external evaluation set (20% of the overall set) using random division. The modeling set was then subdivided into a training set (80% of the modeling set) and a test set (20% of the modeling set) using rational division methods and by using random division. The Kennard-Stone, minimal test set dissimilarity, and sphere exclusion algorithms were used as the rational division methods. The hierarchical clustering, random forest, and k-nearest neighbor (kNN) methods were used to develop QSAR models based on the training sets. For kNN QSAR, multiple training and test sets were generated, and multiple QSAR models were built. The results of this study indicate that models based on rational division methods generate better statistical results for the test sets than models based on random division, but the predictive power of both types of models are comparable. PMID- 23030317 TI - A survey of the awareness, use and attitudes of women towards Down syndrome screening. AB - AIMS AND OBJECTIVES: To determine awareness, use and attitudes of Turkish women towards prenatal screening tests (PST) for Down syndrome (DS). BACKGROUND: The technology of screening and diagnosing congenital diseases and abnormalities of foetuses has rapidly developed in the past few decades and prenatal screening for DS in early pregnancy is a valued component representing a cost-effective public health intervention in modern developed countries. DESIGN: Cross-sectional and descriptive study. METHODS: The study was carried out in 518 women in the early postpartum period at the Maternity and Children's Hospital between 1 September 2010 and 1 March 2011 using a questionnaire developed by the researchers. RESULTS: Awareness about the first- and second-trimester PST [nuchal translucency (NT), triple test] was 21.6 and 59.7%, whereas use of them was 13.7 and 44.8%, respectively. Women who had lower education, were unemployed, had a patriarchal family type, had a low income status, were unmarried, had consanguineous marriage and did not have a private doctor were less aware and had less use of NT and/or triple test. Women who did not have a genetic disease in their family, were multiparous, had an unplanned pregnancy and did not receive antenatal care were less aware and had less use of the triple test. In case, the foetus was diagnosed as DS, women made the following decisions: continuing the pregnancy, terminating the pregnancy, leaving the decision to the doctor and being not sure 34.9, 12.0, 29.9 and 23.2%, respectively. CONCLUSION: Women's knowledge about and attitudes towards PST are important. This study shows that Turkish women have limited knowledge about and use of PST. Therefore, health professionals play a significant role in improving patients' information about PST. They should dedicate more time to discussions with women, provide appropriate and understandable information tailored to women's socio-economical level and should emphasise the indications, purposes and limitations of PST. RELEVANCE TO CLINICAL PRACTICE: Discovering women's opinions and knowledge about PST will help healthcare providers determine their information needs. PMID- 23030318 TI - Tackling multidrug-resistant gonorrhea: how should we prepare for the untreatable? PMID- 23030319 TI - Decades down the line: the viability of praziquantel for future schistosomiasis treatment. PMID- 23030320 TI - Visceral leishmaniasis treatment in the Indian subcontinent: how to reach the most vulnerable. PMID- 23030322 TI - Telavancin for the treatment of hospital-acquired pneumonia: findings from the ATTAIN studies. AB - Treatment options for hospital-acquired pneumonia caused by Gram-positive organisms are far from ideal. The increase in vancomycin MICs among methicillin resistant Staphylococcus aureus (MRSA) isolates, and the slow bactericidal action and poor lung penetration of vancomycin have driven the search for an alternative agent. Telavancin, a once-daily lipoglycopeptide, displays strong bactericidal activity against S. aureus. Two large Phase III randomized trials have recently compared intravenous telavancin (10 mg/kg every 24 h) with vancomycin (1 g intravenously every 12 h) for 7-21 days for the treatment of hospital-acquired pneumonia caused by Gram positives. No significant differences were observed in the cure rates in the all-treated (n = 1503), the clinically evaluable (n = 654) and the microbiologically evaluable (n =480) populations. Telavancin performed better than vancomycin in patients with monomicrobial S. aureus pneumonia (84.2 vs 74.3%; 95% CI: 0.7-19.1), with MRSA (81.8 vs 74.1%; 95% CI: -3.5 to 19.3), and with strains having vancomycin MICs >=1 ug/ml (87.1 vs 74.3; 95% CI: 0.5-23). The rate of adverse events, including serious adverse events, was similar in both groups, with a slightly higher rate of serum creatinine increase in the telavancin-treated group. Based on these results, telavancin (already approved for this indication by the EMA) could certainly be added to the current treatment options, particularly in patients with MRSA pneumonia. PMID- 23030323 TI - Viral latency and potential eradication of HIV-1. AB - Although HAART can suppress plasma viral loads to undetectable levels, individuals infected with HIV-1 harbor latent reservoirs of integrated proviruses that re-emerge upon the cessation of drug treatment. The 2012 Keystone Symposium on Frontiers in HIV Pathogenesis, Therapy and Eradication highlighted the current understanding of latent infection and new methods to activate and target these reservoirs for eradication. This report focuses on a select few aspects of the discussion, including the extent that ongoing replication might contribute to the persistent viral reservoir, recent advances in activating the expression of latent proviruses, progress in developing effective animal models and potential avenues to eradicate the cells that constitute the latent reservoir. PMID- 23030324 TI - What is next in sepsis: current trials in sepsis. AB - International experts reviewed and updated the most recent and relevant scientific advances on severe sepsis during the 17th International Symposium on Infections in the Critically Ill Patients in Barcelona (Spain) in February 2012. All new pharmacological therapeutic strategies have failed to demonstrate a survival benefit. Despite the large variability among countries and hospitals, the improvement of standard care according to the Surviving Sepsis campaign recommendations reduced the 28-day mortality to 24%. These results may have implications for future clinical trials in which much larger samples sizes of patients at high risk of death will be necessary. The identification of novel proinflammatory endogeneous signals and pathways may lead to the discovery of new drugs to reduce inflammatory reactions and end-organ dysfunction in critically ill patients with sepsis. Extracorporeal blood purification stem or progenitor cells have received increasing interest for the treatment of inflammation and organ injury. A better understanding of how these therapies work is essential and its benefit should be confirmed in future prospective randomized studies. PMID- 23030325 TI - Managing tuberculosis in patients with diabetes mellitus: why we care and what we know. AB - As the global prevalence of diabetes mellitus (DM) increases, especially in low to-middle income countries where tuberculosis (TB) remains endemic, we will encounter a growing number of TB patients with DM. This is a major concern for TB control programs, clinicians and patients alike because DM patients are at an increased risk of TB and are more likely to face poor TB treatment outcomes, including treatment failure, relapse and even death. Priority should be placed on early detection of both diseases through active screening, monitoring of adherence to medications for both diseases, and integration of TB and DM management strategies that would facilitate the provision of more comprehensive services that TB patients with DM require. PMID- 23030326 TI - Why and how thioridazine in combination with antibiotics to which the infective strain is resistant will cure totally drug-resistant tuberculosis. AB - Over a period of 14 years, the authors have studied thioridazine, an old neuroleptic, that has been shown to have in vitro activity against intracellular Mycobacterium tuberculosis, regardless of its antibiotic resistance status, thioridazine cures infected mice of antibiotic-susceptible and multidrug resistant tuberculosis (TB) infections and, when used in combination with antibiotics used for therapy of TB, renders the organism significantly more susceptible. This article will describe the authors' further work and the mechanisms by which thioridazine alone and in combination with antibiotics cures an extensively drug-resistant infection and why it is expected to cure totally drug-resistant TB infections as well. The concepts presented are entirely new and because they focus on the activation of killing by nonkilling macrophages where M. tuberculosis normally resides during infection, and coupled to the inhibition of efflux pumps which contribute to the antibiotic-resistant status, effective therapy of any antibiotic-resistant TB infection is possible. PMID- 23030327 TI - Urinary tract analgesics for the treatment of patients with acute cystitis: where is the clinical evidence? AB - Acute cystitis is one of the most common health-related problems in the female population. Over the last few decades, a number of drugs labeled as 'urinary tract analgesics' were released; these are available over the counter and are gaining widespread resonance among the North American population. The main representatives of this class of drugs are phenazopyridine and methenamine hippurate. Methenamine's efficacy and side effects have been well studied in a recent systematic review. On the other hand, in contrast to its widespread use, the published clinical evidence regarding phenazopyridine's effectiveness and safety is scarce. In addition, consumers (potentially patients) appear to ignore the limitations of this kind of treatment. In this article, concerns regarding the use of over-the-counter uroanalgesics, with a focus on the relevant clinical evidence, are discussed. PMID- 23030328 TI - Infections associated with chronic granulomatous disease: linking genetics to phenotypic expression. AB - Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by the absence or malfunction of the NADPH oxidase in phagocytic cells. As a result, there is an impaired ability to generate superoxide anions and the subsequent reactive oxygen intermediates. Consequently, CGD patients suffer from two clinical manifestations: recurrent, life-threatening bacterial and fungal infections and excessive inflammatory reactions leading to granulomatous lesions. Although the genotype of CGD was linked to the phenotypic expression of the disease, this connection is still controversial and poorly understood. Certain correlations were reported, but the clinical expression of the disease is usually unpredictable, regardless of the pattern of inheritance. CGD mainly affects the lungs, lymph nodes, skin, GI tract and liver. Patients are particularly susceptible to catalase-positive microorganisms, including Staphyloccocus aureus, Nocardia spp. and Gram-negative bacteria, such as Serratia marcescens, Burkholderia cepacea and Salmonella spp. Unusually, catalase-negative microorganisms were reported as well. New antibacterial and antimycotic agents considerably improved the prognosis of CGD. Therapy with IFN-gamma is still controversial. Bone marrow stem cell transplantation is currently the only curative treatment and gene therapy needs further development. In this article, the authors discuss the genetic, functional and molecular aspects of CGD and their impact on the clinical expression, infectious complications and the hyperinflammatory state. PMID- 23030329 TI - Diagnosis of dengue: an update. AB - Early diagnosis of dengue, the most common mosquito-borne disease globally, remains challenging. Dengue presents initially as undifferentiated fever, with symptoms becoming more pathognomonic in the later stages of illness. This limits the timeliness in the delivery of appropriate supportive interventions. Laboratory tests are useful for diagnosis although the short-lived viremia and the presence of secondary infection with one of the four heterologous viral serotypes collectively complicate the choice and interpretation of laboratory tests. In this article, the authors review the various approaches for diagnosis of dengue and discuss the appropriate tests to use, including when a dengue vaccine, which is in the late stages of development, is licensed for use. The ensuing reduced dengue prevalence could make diagnosis for vaccine efficacy and escape-mutant monitoring even more challenging. PMID- 23030330 TI - Pulmonary bacterial coinfection in infants and children with viral respiratory infection. AB - The true incidence of pulmonary bacterial coinfection in infants and children hospitalized with a viral respiratory infection is difficult to ascertain but can vary widely from under 1 to 44%. For the same patient group admitted to pediatric intensive care units and/or requiring ventilatory support, the evidence is more convincing, with reported incidences of 17-39%. Studies covering influenza and respiratory syncytial virus infection dominate the recent literature. Whether treatment (or 'cover') with antibiotics is indicated/justified lies in the balance of risk of pulmonary bacterial coinfection (or risk of not diagnosing it), severity of disease and the patient setting. The balance between the overprescription of antibiotics and the possible sequelae associated with bacterial coinfection in infants and children continues to fuel debate. PMID- 23030331 TI - Colistin: an update on the antibiotic of the 21st century. AB - The emergence of multidrug-resistant Gram-negative bacteria that cause nosocomial infections is a growing problem worldwide. Colistin was first introduced in 1952 and was used until the early 1980s for the treatment of infections caused by Gram negative bacilli. In vitro, colistin has demonstrated excellent activity against various Gram-negative rod-shaped bacteria, including multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Recent clinical findings regarding colistin activity, pharmacokinetic properties, clinical uses, emerging resistance, toxicities and combination therapy have been reviewed. Recent approaches to the use of colistin in combination with other antibiotics hold promise for increased antibacterial efficacy. It is probable that colistin will be the 'last-line' therapeutic drug against multidrug resistant Gram-negative pathogens in the 21st century. PMID- 23030333 TI - Treatment of candidiasis: insights from host genetics. AB - Candida species are major causes of mucosal and invasive infections, leading to substantial morbidity and mortality. Despite the development of new classes of antifungal drugs, mortality in patients with systemic candidiasis remains high. Host-Candida interaction plays an important role in effective elimination of the pathogen. Genetic studies have rendered important insights into antifungal host defense and have identified potential targets for adjunctive therapy. In this article, the authors review the genetic variations in the host defense to Candida and their implications for the treatment of mucosal and systemic candidiasis. PMID- 23030332 TI - Candida parapsilosis and the neonate: epidemiology, virulence and host defense in a unique patient setting. AB - Invasive candidiasis is a common problem in premature infants that leads to high morbidity and mortality. Although Candida albicans has historically been the most prominent species involved in these infections and has therefore been the subject of the most study, Candida parapsilosis is increasing in frequency, and neonates are disproportionately affected. This article reviews unique aspects of the epidemiology of this organism as well as strategies for prophylaxis against invasive candidiasis in general. Additionally, important differences between C. parapsilosis and C. albicans are coming to light related to virulence determinants and interactions with components of host immunity. These developments are reviewed while highlighting the significant gaps in our understanding that remain to be elucidated. PMID- 23030335 TI - Exciton dynamics in disordered poly(p-phenylenevinylene). 2. Exciton diffusion. AB - We present a first principles theory of exciton diffusion in conformationally disordered conjugated polymers. Central to our theory is that exciton transfer occurs from vibrationally relaxed states (VRSs) to local exciton ground states (LEGSs). LEGSs are determined by the diagonal and off-diagonal disorder induced by static density and torsional fluctuations, and VRSs are further localized by exciton-phonon coupling. The theory is implemented using the Frenkel-Holstein model to calculate the wave functions and energies of the LEGSs and VRSs. The coupling of VRSs and LEGSs via long-range dipole-dipole interactions leads to the familiar line-dipole approximation for the exciton transfer integral. The exciton transfer rates are derived from the Fermi Golden rule. The theory is applied to an ensemble of conformationally disordered poly(p-phenylenevinylene) chains using a kinetic Monte Carlo algorithm. The following are shown: (i) Torsional disorder and trans-cis defects reduce the exciton diffusion length. (ii) Radiative recombination occurs from VRSs in the tail of their density of states. (iii) Torsional disorder increases the band gap, the line width of the density of states, and the Stokes shift. As a consequence, it causes a blue shift in the vertical absorption, but a red shift in the emission. (iv) The energy of the radiated photon decreases as -log t, with a gradient that increases with torsional disorder. The predicted exciton diffusion lengths of ~8-11 nm are in good agreement with experimental values. PMID- 23030336 TI - Evolutionary and developmental aspects of avian-specific traits in limb skeletal pattern. AB - The two sets of paired appendages, called limbs, are locomotory organs in tetrapods that are used for various functions (e.g., walking, running, crawling, digging, climbing, diving, swimming, and flying). Unlike such organs as the eye, which contain specialized tissues such as the lens and photoreceptor, the limb does not have any specialized cells or tissues, but consists of common tissues, such as bone, cartilage, muscle, blood vessels, and dermis. However, limb morphology is highly specialized and varies to provide species-specific modes of locomotion. As do the vertebrae and skull, the limb skeleton varies in morphology among species. The diversity of limb skeletal morphology provides examples of material for studies on morphogenesis. Avian forelimbs have evolved into wings for flight. The skeletal pattern in the avian limb has many traits that are unique among extant species of vertebrates; some of such traits are avian specific, others are shared with more basal members of Theropoda, to which Aves belongs. Since such avian traits generally form during ontogenic development, determining when and how they appear in the developing embryonic limbs or limb buds provides important insights into the mechanisms underlying the generation of vertebrate morphological diversity. Here, we present an overview of several features of the skeletal pattern in the avian limb and discuss the developmental mechanisms responsible for their unique and lineage-specific traits. PMID- 23030337 TI - Song complexity and auditory feedback in birds: a comparison between two strains of Bengalese finches with different degrees of song complexity. AB - In adult songbirds, the degree of dependency on audition for maintenance of stable song structure varies from species to species. To date, studies suggest that song deterioration after deafening may be related to the song complexity of the species. Bengalese finches sing songs that are composed of complex note-to note transitions, and their songs are critically dependent on auditory feedback. Song deterioration occurs within five days of auditory deprivation surgery, much faster than in other species. In contrast, white-rumped munias, a wild strain of Bengalese finches, sing simple songs. To test the hypothesis that the degree of dependency on auditory feedback for the maintenance of song structure is related to song complexity, we deafened two adult white-rumped munias by cochlear removal. Songs of white-rumped munias changed in syntax within five days of surgery, a similar trend observed in Bengalese finches. We suggest that real-time auditory feedback is important in white-rumped munias, despite the simplicity of their song structure. The time course of song alteration by deafened adult birds not determined solely by song complexity. PMID- 23030338 TI - A new mutation of mouse ruby-eye 2, ru2(d)/Hps5(ru2-d) inhibits eumelanin synthesis but stimulates pheomelanin synthesis in melanocytes. AB - We previously demonstrated that a novel mutation, characterized by light-colored coats and ruby eyes, which occurred spontaneously in mice in our laboratory, exhibited deletion in the Hps5 gene (ru2(d)/Hps5(ru2-d)). To clarify the mechanism of this hypopigmentation, the characteristics of the neonatal development of ru2(d)/ru2(d) melanocytes were investigated in detail with special reference to those of +/+ melanocytes. In ru2(d)/ru2(d) mice, there were fewer epidermal melanocytes than in +/+ mice, whereas there was no difference in numbers of epidermal melanoblasts in +/+ and ru2(d)/ru2(d)mice, both in dorsal and ventral skin. Epidermal melanocytes with increased dopa-melanin deposition and dendritogenesis were greatly increased by injecting L-Tyr subcutaneously into newborn ru2(d)/ru2(d) mice. The eumelanin content in the epidermis and dermis in postnatal ru2(d)/ru2(d) mice was much lower than in +/+ mice, whereas similar pheomelanin content was observed 5.5 or 7.5 days after birth both in dorsal and ventral skins. Moreover, the eumelanin content in the dorsal and ventral hairs in 5-week-old ru2(d)/ru2(d) mice was much lower than in +/+ mice, whereas pheomelanin content was two to four times greater than in +/+ mice. These results suggest that the ru2(d) allele suppresses the differentiation of melanocytes through the inhibition of eumelanin synthesis, but stimulates pheomelanin synthesis in melanocytes. PMID- 23030340 TI - The complete mitochondrial genome of Dugesia japonica (Platyhelminthes; order Tricladida). AB - We used two sequencing methods, namely long polymerase chain reaction (PCR) and primer walking, to determine the complete mitochondrial DNA (mtDNA) sequence of Dugesia japonica and most of the mtDNA sequence of Dugesia ryukyuensis. The genome of D. japonica contained 36 genes including 12 of the 13 protein-coding genes characteristic of metazoan mitochondrial genomes, two ribosomal RNA genes, and 22 transfer RNA genes. The genome of D. ryukyuensis contained 33 genes, including 12 protein-coding genes, two ribosomal RNA genes, and 19 transfer RNA genes. The gene order of the mitochondrial genome from the Dugesia species showed no clear homology with either the Neodermata or other free-living Rhabditophora. This indicates that the platyhelminths exhibit great variability in mitochondrial gene order. This is the first complete sequence analysis of the mitochondrial genome of a free-living member of Rhabditophora, which will facilitate further studies on the population genetics and genomic evolution of the Platyhelminthes. PMID- 23030339 TI - Highly complex mitochondrial DNA genealogy in an endemic Japanese subterranean breeding brown frog Rana tagoi (Amphibia, Anura, Ranidae). AB - The endemic Japanese frog Rana tagoi is unique among Holarctic brown frogs in that it breeds in small subterranean streams. Using mitochondrial 16S ribosomal RNA and NADH dehydrogenase subunit 1 genes, we investigated genealogical relationships among geographic samples of this species together with its relative R. sakuraii, which is also a unique stream breeder. These two species together form a monophyletic group, within which both are reciprocally paraphyletic. Rana tagoi is divided into two major clades (Clade A and B) that are composed of 14 genetic groups. Rana sakuraii is included in Clade A and split into two genetic groups, one of which forms a clade (Subclade A-2) with sympatric R. tagoi. This species-level paraphyly appears to be caused by incomplete taxonomy, in addition to introgressive hybridization and/or incomplete lineage sorting. Rana tagoi strongly differs from other Japanese anurans in its geographic pattern of genetic differentiation, most probably in relation to its unique reproductive habits. Taxonomically, R. tagoi surely includes many cryptic species. PMID- 23030341 TI - Distribution of two distinctive mitochondrial DNA lineages of the Japanese robin Luscinia akahige across its breeding range around the Japanese islands. AB - The genetic structure of the Japanese robin Luscinia akahige across its breeding range was investigated based on mitochondrial cytochrome b and a control region sequence to reveal the phylogeographic history of this species, which is endemic to the islands around Japan. We obtained the 2,230-bp combined sequences of 77 robins from eight locations and identified 33 haplotypes. Of these, two phylogenetic clades, Ak and Tn, were evident in both maximum-likelihood and Bayesian analyses. Clade Ak was found throughout the range, whereas clade Tn was endemic to the Izu Islands, resulting in the mixture of both clades at this location. These two mtDNA lineages were inferred to have originated in different refugia during the mid-Pleistocene glacial period, probably one in southwestern Japan and the other in the Izu Islands. The population in the Izu Islands has been described as an independent subspecies, tanensis, and is known to be distinguished phenotypically from the nominotypical akahige. Therefore, the distribution pattern of the two mtDNA lineages may be better explained by past introgression of mitochondrial DNA rather than by assuming continuous hybridization with immigrants from the mainland. Future nuclear DNA analysis is needed to evaluate the effect of this introgression event on the genetic bases of the current Izu Islands population. Within clade Ak, the haplotype distribution pattern was inferred to be primarily a result of contiguous range expansion, reflecting the history of both range and population expansion after the last glacial period, with some effects of allopatric fragmentation in its southwestern range. PMID- 23030342 TI - Molecular cloning and expression profile of sex-specific genes, Figla and Dmrt1, in the protogynous hermaphroditic fish, Halichoeres poecilopterus. AB - The genes folliculogenesis specific basic helix-loop-helix (facor in the germline alpha, Figla) and doublesex and mab-3 related transcription factor 1 (Dmrt1) are female- and male-specific genes that play key roles in sex differentiation. To obtain a better understanding of the molecular mechanisms underlying female-to male sex change, we cloned the cDNAs of these genes from an ovary and a testis of the protogynus wrasse, Halichoeres poecilopterus. This fish has two isoforms of Dmrt1, Dmrt1a and Dmrt1b, caused by an alternative splicing. The Dmrt1b has an insertion of three nucleotides (CAG) in the open reading frame. Figla and Dmrt1 displayed gonadal-specific expression and abundant in the ovaries and in the testes, respectively. In particular, levels of Figla expression in the ovaries were higher in the spawning season than in the non-spawning season. Once sex change began, Figla mRNA decreased and Dmrt1 mRNA increased with progression of oocyte degeneration and spermatogenesis. These expression levels were maintained until the completion of the sex change. Low Figla and high Dmrt1 were also observed in testes of primary males, which functioned as a gonochoristic male throughout its life span in this wrasse. The results of this study suggest that these genes may regulate the gonadal transition from ovary to testis by the same mechanism as that of formation and maintenance of the primary testis in H. poecilopterus. PMID- 23030343 TI - High degree of mitochondrial haplotype diversity in the Japanease common toad Bufo japonicus in urban Tokyo. AB - The Japanese common toad Bufo japonicus is widely distributed across mainland Japan and is classified into two subspecies, B. japonicus japonicus and B. japonicus formosus, in the western and eastern regions, respectively. To investigate the genetic diversity of B. japonicus at the breeding pond (local population) level, we sequenced 831 base pairs of mitochondrial DNA (mtDNA) cytochrome b (Cyt b) from 75 individuals collected from nine ponds in urban Tokyo and the surrounding area. Phylogenetic and population genetic analyses revealed high mtDNA haplotype diversity (Hd, 0.716 (mean) +/- 0.230 (SD)) within local populations (breeding ponds). Most local populations had multiple haplotypes of the mitochondrial Cyt b gene, and seven of the 18 haplotypes were identified in two or more local populations. These results indicate that mitochondrial gene flow had occurred across different breeding sites. We also identified five haplotypes that belonged to the western clade and correspond to B. japonicus japonicus. Our results provide genetic evidence that B. japonicus japonicus was introduced artificially from Western Japan to Tokyo, where it occupied the natural habitat of B. japonicus formosus. The urban Tokyo area was found to represent an admixed population consisting of both native and non-native B. japonicus subspecies. PMID- 23030344 TI - Molecular cytogenetic identification and characterization of Robertsonian chromosomes in the large Japanese field mouse (Apodemus speciosus) using FISH. AB - Robertsonian (Rb) karyotypic polymorphism in Apodemus speciosus has interested many researchers with particular referece to the genetic divergence between Rb and non-Rb populations. Failure to find morphologic, biochemical, or genetic differences in previous studies reveals the necessity of focusing on loci on Rb chromosomes, which can be characterized by FISH mapping with DNA probes. In an Rb heterozygote, DNA probes from laboratory mouse chromosomes (MMUs) 1 and 10 were simultaneously hybridized to the long arm of a metacentric and a medium-sized acrocentric chromosome and to the short arm of the metacentric and a small acrocentric chromosome, respectively. Four additional probes derived from each of MMUs 1 and 10 were mapped to the long and short arms, respectively, of the Rb chromosome identified by the above markers. Homologies between the long arm of the Rb chromosome and MMU 1 and between the short arm and MMU 10 were supported by all ten markers, which were dispersed along nearly the entire lengths of the Rb chromosomes. These results indicate that the long and short arms of the Rb chromosomes are homologous to Apodemus speciosus chromosomes 12 and 19 (defined in a previous study), respectively. This ten-marker series can be useful for detecting chromosome-specific divergence between the two karyotypic populations at the gene level. PMID- 23030345 TI - The DNA barcoding and the caveats with respect to its application to some species of Palaemonidae (Crustacea, Decapoda). AB - DNA-barcoding has recently attracted considerable attention due to its potential utility in aiding in species identification and discovery through the use of a short standardized sequence of mitochondrial DNA. Nevertheless, despite the fact that this technology has been proven a useful tool in several animal taxa, it also demonstrated limitations that may hinder correct application. Thus, its validity needs to be empirically evaluated in each taxonomic category before forward implementation. As the use of DNA barcoding within Palaemonidae may be of special interest, given its great interspecific morphological conservatism associated with considerable intraspecific morphological variation, we analyze here the potential of this technology in distinguishing and recovering some taxonomic boundaries within this family. We asked whether two GenBank-retrieved sets of COI sequences encompassing the conventional Barcode and Jerry-Pat regions possess the desired properties of reciprocal monophyly among species, and existence of a barcoding gap between intra- and interspecific variations, after performing a careful analysis of numt (nuclear mitochondrial DNA) contamination. These analyses revealed nine non-monophyletic species, with some cases of divergent intraspecific sequences, contrasted with interspecific similarity attained in others. Moreover, we were unable to identify any barcoding gap between intraspecific and interspecific divergences within Palaemonidae, although a threshold of 0.18 substitutions per site would differentiate intraspecific and congeneric divergences in 95% of the cases for the barcoding region. A fraction of the overlap could be certainly attributed to artifacts related to poor taxonomy, but even from this perspective DNA barcoding studies may help to uncover previously disregarded taxonomic and evolutionary issues. PMID- 23030346 TI - Direct measurement of coherency limits for strain relaxation in heteroepitaxial core/shell nanowires. AB - The growth of heteroepitaxially strained semiconductors at the nanoscale enables tailoring of material properties for enhanced device performance. For core/shell nanowires (NWs), theoretical predictions of the coherency limits and the implications they carry remain uncertain without proper identification of the mechanisms by which strains relax. We present here for the Ge/Si core/shell NW system the first experimental measurement of critical shell thickness for strain relaxation in a semiconductor NW heterostructure and the identification of the relaxation mechanisms. Axial and tangential strain relief is initiated by the formation of periodic a/2 <110> perfect dislocations via nucleation and glide on {111} slip-planes. Glide of dislocation segments is directly confirmed by real time in situ transmission electron microscope observations and by dislocation dynamics simulations. Further shell growth leads to roughening and grain formation which provides additional strain relief. As a consequence of core/shell strain sharing in NWs, a 16 nm radius Ge NW with a 3 nm Si shell is shown to accommodate 3% coherent strain at equilibrium, a factor of 3 increase over the 1 nm equilibrium critical thickness for planar Si/Ge heteroepitaxial growth. PMID- 23030347 TI - Association of SOD1 and SOD2 single nucleotide polymorphisms with susceptibility to gastric cancer in a Korean population. AB - Oxidative stress is accepted as one of the main factors involved in the development and progression of cancer. Superoxide dismutases (SODs) are important in avoiding oxidative stress by eliminating reactive oxygen species (ROS). To determine whether single nucleotide polymorphisms at G7958A within SOD1 and at T5482C within SOD2 are associated with an increased susceptibility to gastric cancer, we investigated the genotype and allele frequencies of the genes from 294 gastric cancer patients and 300 healthy individuals. A polymerase chain reaction single strand conformation polymorphism assay was used to identify the SOD1 G7958A and the SOD2 T5482C genotypes. Statistically significant differences in the genotype and allele frequencies of SOD2 T5482C were found between the healthy controls and gastric cancer patients (p = 0.0001 and p < 0.0001, respectively). When the data were stratified according to gastric cancer histological subtypes, the risk of both diffuse- and intestinal-type gastric cancer was statistically higher for carriers of the C allele compared with carriers of the T allele. However, there were no statistically significant differences in genotype distribution (p = 0.5069) and allele frequencies (p = 0.3714) of SOD1 G7958A between gastric cancer patients and controls. Our findings suggest that polymorphism of the SOD2 T5482C may be closely associated with an increased susceptibility to the development and differentiation of gastric cancer in the Korean population. PMID- 23030348 TI - Response to acute concussive injury in soccer players: is gender a modifying factor? AB - OBJECT: Several studies have suggested a gender difference in response to sports related concussion (SRC). The Concussion in Sport group did not include gender as a modifying factor in SRC, concluding that the evidence at that point was equivocal. In the present study the authors endeavored to assess acute neurocognitive and symptom responses to an SRC in equivalent cohorts of male and female soccer players. The authors hypothesized that female athletes would experience greater levels of acute symptoms and neurocognitive impairment than males. METHODS: Baseline symptom and neurocognitive scores were determined in 40 male and 40 female soccer players by using the Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) scale prior to any SRC. After sustaining an SRC, each athlete completed postconcussion ImPACT tests and was carefully matched on a wide array of biopsychosocial variables. Baseline symptom and neurocognitive test scores were compared, and their acute symptoms and neurocognitive responses to concussive injury were assessed. RESULTS: Specific a priori hypotheses about differences between males and females at baseline and at postconcussion measurements of verbal and visual memory ImPACT scores were evaluated according to simple main effects of the gender variable and according to baseline-to-postconcussion main effect and interaction of 2 * 2 split-plot ANOVA. Neither the interaction nor the main effects nor the simple main effects for either ImPACT variable were found to be statistically significant. Exploratory ANOVAs applied to the remaining ImPACT variables of visualmotor speed, reaction time, impulse control, and symptom total scores revealed only a single statistically significant baseline-to-postconcussion main effect for the symptom total. CONCLUSIONS: The results failed to replicate prior findings of gender-specific baseline neurocognitive differences in verbal and visual memory. The findings also indicated no differential gender-based acute response to concussion (symptoms or neurocognitive scores) among high school soccer players. The implications of these findings for the inclusion of gender as a modifying factor in this tightly matched cohort are addressed. Potential explanations for the null findings are discussed. PMID- 23030349 TI - Comparison of diagnostic values of thyroid aspiration samples using liquid-based preparation and conventional smear: one-year experience in a single institution. AB - Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. Fine needle aspiration (FNA) is the most useful tool in the diagnosis of thyroid nodules. Liquid-based preparation (LBP) in FNA of thyroid nodules is now widely used and is replacing the conventional smear (CS). We compared the diagnostic value of the LBP method with that of CS in thyroid lesions. A total of 1767 CS FNA samples and 2523 LBP FNA samples were included in this comparison of diagnostic values. We also assessed the differences in cytomorphologic features in 41 randomly selected cases of PTC. The measured sensitivities of CS and LBP were 78.9% and 76.3%, respectively, and the specificities were 64.2% and 54.9%, respectively, whereas the positive predictive values were 92.3% and 94.3%, respectively, and the negative predictive values were 89.5% and 81.8%, respectively. The cytomorphological features of LBP showed better-preserved nuclear details, cleaner background and fewer large papillae than were evident in CS. The results indicate that LBP reduces the diagnosis of non-diagnostic or unsatisfactory/atypia of undetermined significance or follicular lesion of undetermined significance, although the diagnostic values for CS and LBP are not appreciably different. PMID- 23030350 TI - Concentration dependence on the shape and size of sol-gel-derived yttria stabilized zirconia ceramic features by soft lithographic patterning. AB - Typical surface areas of 5 * 5 mm(2) were patterned with high-aspect-ratio micrometer- and submicrometer-sized structures of yttria-stabilized zirconia using a combination of micromolding in capillaries and sol-gel chemistry. The influence of precursor solution concentration and mold geometry on the final shape and dimensions of the patterned structures was investigated. At a precursor concentration of [Zr] = 0.724 mol/dm(3), isolated objects-due to the controlled cracking of patterned films-such as crosses (height 1.4 MUm, width 6.0 MUm) and "dog bones" (height 800-900 nm, width 900 nm) or patterned films (height 450 nm) were obtained, depending on the mold geometry. Lower precursor concentrations led to differently sized and shaped structures, with changes in dimensions of more than an order of magnitude. Employing a precursor concentration of [Zr] = 0.036 mol/dm(3) yielded isolated rings (height 100-150 nm, line width 20 nm) and squares (height 40 nm, line width 40 nm). A better understanding of the relationship between the precursor concentration, mold geometry, and observed coherent crack patterns in as-dried sol-gel structures may lead to new techniques in patterning isolated features. PMID- 23030351 TI - Ability of Lactobacillus rhamnosus GAF01 to remove AFM1 in vitro and to counteract AFM1 immunotoxicity in vivo. AB - Aflatoxin M1 (AFM1) has been detected in many parts of the world both in raw milk and many dairy products, causing great economic losses and human disease. Unfortunately, there are few studies dealing with AFM1 immunotoxicity/interactions with lactic acid bacteria for potential application as a natural preventive agent. The aim of this study was to isolate (from dairy products) food-grade probiotic bacteria able to degrade/bind AFM1 in vitro and evaluate whether the same organism(s) could impart a protective role against AFM1 induced immunotoxicity in exposed Balb/c mice. Bacteria (Lactobacillus plantarum MON03 and L. rhamnosus GAF01) were isolated from Tunisian artisanal butter and then tested for abilities to eliminate AFM1 from phosphate-buffered saline (PBS) and reconstituted milk (containing 0.05, 0.10, and 0.20 ug AFM1/ml) after 0, 6, and 24 h at 37 degrees C. Results showed that the selected bacteria could 'remove' AFM1 both in PBS and skimmed milk. The binding abilities of AFM1 by L. plantarum MON03 and L. rhamnosus GAF01 strains (at 10(8) CFU/ml) in PBS and reconstituted milk ranged, respectively, from 16.1-78.6% and 15.3-95.1%; overall, L. rhamnosus showed a better potential for removal than L. plantarum. 'Removal' appeared to be by simple binding; the bacteria/AFM1 complex was stable and only a very small proportion of mycotoxin was released back into the solution. L. rhamnosus GAF01 had the highest binding capacity and was selected for use in the in vivo study. Those results indicated that use of the organism prevented AFM1 induced effects on total white and red blood cells, and lymphocyte subtypes, after 15 days of host treatment. These studies clearly indicated that L. rhamnosus GAF01 was able to bind AFM1 in vitro and-by mechanisms that might also be related to a binding effect-counteract AFM1-induced immunotoxicity. Moreover, by itself, this bacterium was not toxic and could potentially be used as an additive in dairy products and in biotechnology for mycotoxin detoxification. PMID- 23030353 TI - Epidemiology of Behcet disease. AB - Behcet disease (BD) is a multisystem inflammatory disorder that is an important cause of morbidity worldwide. BD is most common along the ancient "Silk Road" route in the Far East and Mediterranean basin. The eye is the most commonly involved organ in BD patients.The prototypical form of involvement is a relapsing remitting panuveitis and retinal vasculitis. Less commonly, BD may present in the form of conjunctivitis, conjunctival ulcers, keratitis, episcleritis, scleritis, and extraocular muscle paralysis. Uveitis in BD carries significant implications for the patient, because it is a chronic recurrent disease characterized by explosive attacks of severe inflammation that may cause significant, cumulative damage to the intraocular structures. This review summarizes the epidemiology of systemic and ocular clinical features of BD with particular focus on risk factors, clinical characteristics, complications, and prognosis of BD-associated uveitis. PMID- 23030354 TI - Topical use of rapamycin in herpetic stromal keratitis. AB - PURPOSE: To evaluate and compare the efficacy of rapamycin used topically in a mouse model of herpetic stromal keratitis. METHODS: The corneas were infected with herpes simplex virus type-1 strain KOS. Animals were divided into: control (CG), rapamycin (RAPA), cyclosporine (CsA), and dexamethasone (DEXA). The evolution of the disease was assessed clinically and histologically. RESULTS: On day 10 postinfection (pi), the RAPA group showed only a significantly lower angiogenic development than the CG. On day 14 pi, the treated groups had significantly lower scores for angiogenesis and necrosis than the CG. Also, on day 14 pi, the RAPA and DEXA groups showed significantly lower histopathological scores compared to the CG. CONCLUSIONS: The topical application of 0.05% rapamycin showed greater efficacy than 0.5% cyclosporine and similar efficacy to 0.1% dexamethasone to minimize the immuno-inflammatory process. Also, rapamycin showed early inhibition of the formation of new vessels. PMID- 23030352 TI - Substance of abuse and movement disorders: complex interactions and comorbidities. AB - The relationship between movement disorders and substance abuse, which we previously reviewed, is updated. We examine these relationships bidirectionally with focus on drugs of abuse that are known to cause movement disorders, as well as primary movement disorders that are associated with use and abuse of alcohol and dopaminergic medications. First, we review the movement disorders that may develop from the acute use or withdrawal of frequent drugs of abuse, including alcohol, cocaine, heroin, amphetamine and methcathinone. We then comment on the interaction between alcoholism and alcohol-responsive movement disorders, such as essential tremor and myoclonus-dystonia. Lastly, we discuss the potential for abuse of antiparkinsonian dopaminergic agents in patients with Parkinson's disease (PD). PMID- 23030355 TI - Changes in the intraocular cytokine levels after intravitreal bevacizumab in uveitic macular edema. AB - PURPOSE: To evaluate the changes in intraocular cytokine after intravitreal bevacizumab (IVB) for uveitic cystoid macular edema (CME). METHODS: The authors evaluated 9 eyes of 8 patients who underwent IVB for uveitic CME. The aqueous humor-levels of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL 8, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF) beta(2)were measured using suspension array technology at baseline and 1 month after IVB. RESULTS: The VEGF level was decreased to insignificant level (p = .008). TGF-beta(2) and TNF-alpha levels increased significantly (p = .008 and .021, respectively). IL-6 and IL-8 showed no significant change (p = .051 and.110, respectively). CONCLUSION: IVB resulted in a significant decrease of VEGF levels, which was associated with anatomical improvement of CME at 1 month. Compensatory elevations of proinflammatory cytokines (IL-6 and IL-8) after selective VEGF inhibition were not observed. Marked elevation of TGF-beta(2) after IVB seems to play an immunosuppressive role. PMID- 23030356 TI - IgG4-positive sclerosing orbital inflammation involving the conjunctiva: a case report. AB - PURPOSE: To describe IgG4-positive sclerosing orbital inflammation with prominent conjunctival and scleral involvement. DESIGN: Case report. METHODS: Clinical, radiologic, and pathologic correlation. RESULTS: A 66-year-old man presented with right eye redness and irritation. Examination revealed unilateral scleritis and nongranulomatous anterior uveitis with elevated p-ANCA and CRP. Orbital CT scan showed inferotemporal scleral thickening. Biopsy revealed sclerosis and IgG4 positive plasma cells in the conjunctiva and inferior rectus. CONCLUSIONS: IgG4 mediated sclerosing inflammation is well-recognized in the orbit and adnexa, particularly the lacrimal gland. Scleritis with anterior uveitis should be recognized as a possible presentation for this entity, which has important systemic associations. PMID- 23030357 TI - Comparison of the effects of a new 32-gauge * 4-mm pen needle and a 32-gauge * 6 mm pen needle on glycemic control, safety, and patient ratings in Japanese adults with diabetes. AB - BACKGROUND: This study was designed to evaluate two pen needles (PNs) with the same diameter but different lengths (4 mm and 6 mm) and different needle tip shapes (straight and tapered) to compare their effects on glycemic control, perceived pain, safety, patients' ease of use and preferences, and visual impression. SUBJECTS AND METHODS: In this prospective, open-label, controlled crossover study, 41 insulin-treated patients with type 1 or type 2 diabetes were randomized into either Group 1 (the 32-gauge * 4-mm PN was used during Study Period 1, then the 32-gauge * 6-mm PN was used during Study Period 2) or Group 2 (the order for using the PNs was reversed). RESULTS: The 32-gauge * 4-mm PN provided an equivalent glycemic control in diabetes patients as the 32-gauge * 6 mm PN, with an equivalent occurrence rate of adverse events. The 32-gauge * 4-mm PN was perceived as significantly less painful and rated as significantly more favorable than the 32-gauge * 6-mm PN according to the survey results on patients' ease of use and preferences and on their visual impressions. CONCLUSIONS: The 32-gauge * 4-mm PN was not only as safe and efficacious as the 32-gauge * 6-mm PN, but also was perceived as less painful, easier to use, and more favorable to Japanese adult patients with diabetes. PMID- 23030358 TI - Extending the biotic ligand model to account for positive and negative feedback interactions between cadmium and zinc in a freshwater alga. AB - Low concentrations of essential trace metals such as zinc (Zn) were recently shown to strongly modulate cadmium (Cd) uptake in the freshwater alga Chlamydomonas reinhardtii. Here we studied the mechanisms of Cd and Zn acquisition by this alga, using metal uptake kinetics experiments. Cadmium uptake rates fitted a three transport site model characterized by the affinity constants K(Cd-1)(Cd) = 10(5.0), K(Cd-2)(Cd) = 10(7.6), and K(Cd-3)(Cd) = 10(8.8). Similar uptake kinetics were obtained for Zn with K(Zn-1)(Zn) = 10(5.0), K(Zn-2)(Zn) = 10(7.4), and K(Zn-3)(Zn) > 10(9). Competitive binding experiments suggest that Zn and Cd share the same three transport systems. The capacities of the transport systems were modulated by as much as 10-fold following preacclimation to high or low Zn(2+) and Cd(2+) concentrations. We conclude that the strong protective effect of Zn on Cd accumulation is mainly due to the reduction of the maximal uptake rate of the high-affinity Zn-2 (or Cd-2) transport system. A biotic ligand model was developed to incorporate the effects of both chemical speciation and physiological regulation of Cd transport systems. The model successfully predicts the experimentally measured steady-state Cd content of C. reinhardtii in the presence of low or high [Zn(2+)]. PMID- 23030359 TI - Spontaneous thermoreversible formation of cationic vesicles in a protic ionic liquid. AB - The search for stable vesicular structures is a long-standing topic of research because of the usefulness of these structures and the scarcity of surfactant systems that spontaneously form vesicles in true thermodynamic equilibrium. We report the first experimental evidence of spontaneous formation of vesicles for a pure cationic double tail surfactant (didodecyldimethylammonium bromide, DDAB) in a protic ionic liquid (ethylammonium nitrate, EAN). Using small and ultra-small angle neutron scattering, rheology and bright field microscopy, we identify the coexistence of two vesicle containing phases in compositions ranging from 2 to 68 wt %. A low density highly viscous solution containing giant vesicles (D ~ 30 MUm) and a sponge (L(3)) phase coexists with a dilute high density phase containing large vesicles (D ~ 2.5 MUm). Vesicles form spontaneously via different thermodynamic routes, with the same size distribution, which strongly supports that they exist in a true thermodynamic equilibrium. The formation of equilibrium vesicles and the L(3) phase is facilitated by ion exchange between the cationic surfactant and the ionic liquid, as well as the strength of the solvophobic effect in the protic ionic liquid. PMID- 23030360 TI - The cellular cancer resistance of the SR/CR mouse. AB - The SR/CR mouse phenotype, first described in 1999 in BALB/c and later bred into C57BL/6 mice, is resistant to cancer formation following high doses of cancer cells administered intraperitoneally. The tumor cell targeting and destruction mechanisms have not been identified. By fluorescence-activated cell sorting analysis, the immune response of SR/CR mice after intraperitoneal injection of cancer cells was investigated and compared with parent strain mice. A massive influx of leukocytes into the peritoneal cavity was found. A large fraction of these leukocytes were polymorphonuclear granulocytes, macrophages and natural killer cells. A relative decrease in influx of B-cells compared with controls was demonstrated. Increased proportions of leukocytes belonging to the innate immune system were also demonstrated in splenocytes of SR/CR mice. Cytospins of peritoneal fluid from SR/CR mice after cancer cell injection showed formations of immune cells morphologically resembling polymorphonuclear granulocytes and macrophages adjoining the cancer cells. The results point to the potential involvement of innate immune cells in cancer immunology. Our data support migration of polymorphonuclear granulocytes, macrophages and NK cells into the peritoneum of the SR/CR mouse in response to intraperitoneal injection of S180 cancer cells. The cell composition of spleens of SR/CR mice reflected the differential regulation of the innate immune cells in peritoneal exudates. Both peritoneal exudates and the spleens of SR/CR mice contained decreased proportions of B-cells compared with BALB/c and C57BL/6 mice. We reproduce important aspects of previous published data and further extend them by showing differentially regulated populations of splenocytes including B-lymphocytes in SR/CR mice compared with parent strain controls. Importantly, this differentially regulated immune response of SR/CR mice could not be found in response to challenge with the lymphoma cell line EL-4. PMID- 23030361 TI - Interictal PET and ictal subtraction SPECT: sensitivity in the detection of seizure foci in patients with medically intractable epilepsy. AB - PURPOSE: Interictal positron emission tomography (PET) and ictal subtraction single photon emission computed tomography (SPECT) of the brain have been shown to be valuable tests in the presurgical evaluation of epilepsy. To determine the relative utility of these methods in the localization of seizure foci, we compared interictal PET and ictal subtraction SPECT to subdural and depth electrode recordings in patients with medically intractable epilepsy. METHODS: Between 2003 and 2009, clinical information on all patients at our institution undergoing intracranial electroencephalography (EEG) monitoring was charted in a prospectively recorded database. Patients who underwent preoperative interictal PET and ictal subtraction SPECT were selected from this database. Patient characteristics and the findings on preoperative interictal PET and ictal subtraction SPECT were analyzed. Sensitivity of detection of seizure foci for each modality, as compared to intracranial EEG monitoring, was calculated. KEY FINDINGS: Fifty-three patients underwent intracranial EEG monitoring with preoperative interictal PET and ictal subtraction SPECT scans. The average patient age was 32.7 years (median 32 years, range 1-60 years). Twenty-seven patients had findings of reduced metabolism on interictal PET scan, whereas all 53 patients studied demonstrated a region of relative hyperperfusion on ictal subtraction SPECT suggestive of an epileptogenic zone. Intracranial EEG monitoring identified a single seizure focus in 45 patients, with 39 eventually undergoing resective surgery. Of the 45 patients in whom a seizure focus was localized, PET scan identified the same region in 25 cases (56% sensitivity) and SPECT in 39 cases (87% sensitivity). Intracranial EEG was concordant with at least one study in 41 cases (91%) and both studies in 23 cases (51%). In 16 (80%) of 20 cases where PET did not correlate with intracranial EEG, the SPECT study was concordant. Conversely, PET and intracranial EEG were concordant in two (33%) of the six cases where the SPECT did not demonstrate the seizure focus outlined by intracranial EEG. Thirty-three patients had surgical resection and >2 years of follow-up, and 21 of these (64%) had Engel class 1 outcome. No significant effect of imaging concordance on seizure outcome was seen. SIGNIFICANCE: Interictal PET and ictal subtraction SPECT studies can provide important information in the preoperative evaluation of medically intractable epilepsy. Of the two studies, ictal subtraction SPECT appears to be the more sensitive. When both studies are used together, however, they can provide complementary information. PMID- 23030363 TI - Accommodation of a central arginine in a transmembrane peptide by changing the placement of anchor residues. AB - Both Trp and Arg in transmembrane protein domains make important interactions with lipids at the membrane/water interface, but at different depths. Derivatives of the designed peptide GWALP23, acetyl-GGALW(5)LALALALALALALW(19)LAGA-amide, with single Trp anchors, have proven useful for characterizing such interactions. Indeed, previous work revealed quite different effects emanating from Arg substitutions at positions 12 and 14 within GWALP23, with the R12 peptide exhibiting multiple positions and orientations with respect to DOPC bilayer membranes (Vostrikov et al. J. Am. Chem. Soc. 2010, 132, 5803-5811). To gain further understanding of the multistate behavior, we moved the Trp "anchor" residues to more outer positions 3 and 21 in GWALP23 itself, and in the R12 and R14 derivatives. The locations and orientations of the peptides with respect to lipid bilayer membranes of differing thickness were investigated by means of solid-state (2)H NMR spectroscopy, using labeled alanines, and coarse-grained molecular dynamics simulations. Interestingly, relatively intense and narrow (2)H resonances from selected backbone C(alpha) deuterons were observed over quite narrow ranges of frequency and sample orientation. The backbone resonances reflect dynamic complexities and at the same time provide important contributions for the analysis of peptide transmembrane orientation. With the Trp(3,21) anchors relatively far from the peptide and bilayer center, the results indicate significantly large apparent tilt angles, for example, close to 30 degrees for the new R12 and R14 peptides with respect to the bilayer normal of DLPC membranes. The R12 side chain indeed is "rescued" to a stable position, where it is accommodated within the transmembrane helix, when the Trp anchors are moved outward and to another face of the helix. At the same time, the R14 side chain of transmembrane GW(3,21)ALP23 also retains a stable favored position. PMID- 23030364 TI - Role of intra-operative neurophysiologic monitoring during decompression and neurolysis after peripheral nerve injury: case report. AB - This paper reports the case of a patient presenting motor and sensitive deficits of the left forearm and hand after a traumatic injury of the median, ulnar, and radial nerves. Decompression and neurolysis of the three nerves was performed. Spontaneous electromyographic activity and the amplitude of compound muscle action potentials (CMAPs) were monitored. Surgery led to an increased amplitude of the aforesaid parameters and a long-term clinical improvement. PMID- 23030365 TI - Benchmarking parameter-free AMaLGaM on functions with and without noise. AB - We describe a parameter-free estimation-of-distribution algorithm (EDA) called the adapted maximum-likelihood Gaussian model iterated density-estimation evolutionary algorithm (AMaLGaM-ID[Formula: see text]A, or AMaLGaM for short) for numerical optimization. AMaLGaM is benchmarked within the 2009 black box optimization benchmarking (BBOB) framework and compared to a variant with incremental model building (iAMaLGaM). We study the implications of factorizing the covariance matrix in the Gaussian distribution, to use only a few or no covariances. Further, AMaLGaM and iAMaLGaM are also evaluated on the noisy BBOB problems and we assess how well multiple evaluations per solution can average out noise. Experimental evidence suggests that parameter-free AMaLGaM can solve a wide range of problems efficiently with perceived polynomial scalability, including multimodal problems, obtaining the best or near-best results among all algorithms tested in 2009 on functions such as the step-ellipsoid and Katsuuras, but failing to locate the optimum within the time limit on skew Rastrigin-Bueche separable and Lunacek bi-Rastrigin in higher dimensions. AMaLGaM is found to be more robust to noise than iAMaLGaM due to the larger required population size. Using few or no covariances hinders the EDA from dealing with rotations of the search space. Finally, the use of noise averaging is found to be less efficient than the direct application of the EDA unless the noise is uniformly distributed. AMaLGaM was among the best performing algorithms submitted to the BBOB workshop in 2009. PMID- 23030366 TI - Synthesis of binucleating macrocycles and their nickel(II) hydroxo- and cyano bridged complexes with divalent ions: anatomical variation of ligand features. AB - The planar NNN-pincer complexes [M(II)(pyN(2)(Me2))(OH)](1-) (M(II) = Ni, Cu) fix CO(2) in eta(1)-OCO(2)H complexes; results for the copper system are described. Mn(II), Fe(II), Co(II), and Zn(II) behave differently, forming [M(II)(pyN(2)(Me2))(2)](2-) with N(4)O(2) coordination. Incorporation of the Ni(II) pincer into binucleating macrocycle 2 containing a triamino M(II) locus connected by two 1,3-biphenylene groups affords proximal Ni(II) and M(II) sites for investigation of the synthesis, structure, and reactivity of Ni-X-M bridge units. This ligand structure is taken as a reference for variations in M(II) atoms and binding sites and bridges X = OH(-) and CN(-) to produce additional members of the macrocyclic family with improved properties. Macrocycle 2 with a 22-membered ring is shown to bind M(II) = Mn, Fe, and Cu with hydroxo bridges. Introduction of the 4-Bu(i)O group (macrocycle 3) improves the solubility of neutral complexes such as those with Ni(II)-OH-Cu(II) and Ni(II)-CN-Fe(II) bridges. Syntheses of macrocycle 5 with a 7-Me-[12]aneSN(3) and macrocycle 6 with a 1,8-Me(2)-[14]aneN(4) M(II) binding site are described together with hydoxo bridged Ni/Cu and cyano-bridged Ni/Fe complexes. This work was motivated by the presence of a Ni...(HO)-Fe bridge grouping in a reactive state of carbon monoxide dehydrogenase. Attempted decrease in Ni-(OH)-M distances (3.70-3.87 A) to smaller values observed in the enzyme by use of macrocycle 4 having 1,2-biphenylene connectors led to a mononuclear octahedral Ni(II) complex. Bridge structural units are summarized, and the structures of 14 macrocyclic complexes including 8 with bridges are described. PMID- 23030368 TI - Introduction. Appropriate use criteria for Mohs surgery. PMID- 23030369 TI - Commentary: perceptions of expertise in cutaneous surgery and cosmetic procedures: what primary care physicians think. PMID- 23030370 TI - Commentary: A prospective comparison between neutralizing the pH of 1% lidocaine with epinephrine (buffering) and pre-operative skin cooling in reducing the pain of infiltration of local anesthetic. PMID- 23030371 TI - Commentary: beneficial effects of early pulsed dye laser therapy in patients with infantile hemangiomas. PMID- 23030372 TI - Commentary: a new way of treating silicone granulomas? PMID- 23030373 TI - Negative-pressure suction therapy for epidermal cysts. PMID- 23030374 TI - Radiosurgery excision of rhinophyma. PMID- 23030375 TI - "Red dot" basal cell carcinoma: an early and distinct clinical presentation. PMID- 23030376 TI - Regarding assisting second-intention healing by guiding tissue movement. PMID- 23030377 TI - Poorly differentiated synovial sarcoma showing Homer-Wright rosette structures: a potential diagnostic pitfall. PMID- 23030378 TI - Spectroscopic evidence for self-organization of N-iodoacetylamphotericin B in crystalline and amorphous phases. AB - In this paper, we propose a new way of thinking about molecular self-organization of the antibiotic amphotericin B (AmB) by examination of its N-iodoacetyl derivative (AmB-I). This choice was dictated by the simplicity of AmB-I crystallization as compared to pure AmB. The studies focus on spectroscopic investigations of the monocrystal and the amorphous state of AmB-I. The results of vibrational, FTIR, and Raman spectroscopy show differences between the crystalline and amorphous forms, in particular for bands attributed to C?O (1700 1730 cm(-1)) and C-C-H groups, as well as C?C-C (ca. 1010 cm(-1)) stretching vibrations. The process of crystallization is identified by strong differences in the intensities and locations of these characteristic bands. For the AmB-I crystals, the carbonyl band is shifted toward lower frequencies as a result of intensified hydrogen bonding in the crystalline form. Detailed analysis indicates that bands in the region characteristic for the C?C-C bending distortion in the chromophore are particularly intense for AmB-I in the crystalline form as compared to the intensity of this band in the amorphous state. These findings are corroborated by the results of fluorescence spectroscopy. We observe a much faster decay of the emission for the AmB-I monocrystal as compared to the DMSO solution of AmB-I. Interestingly, the fluorescence decay in the amorphous form requires three decay times for simulating the observed behavior; two of these decay constants are sufficient for estimating the decay measured for the AmB-I crystals. The proof of the molecular organization of AmB-I molecules is obtained from polarization-resolved fluorescence spectroscopy on a single AmB-I crystal. Strong anisotropy of the emission intensity correlates with the axes of the crystal, providing insight into actual alignment of the molecules in the AmB-I crystals. These findings related to molecular organization in AmB-I crystals are crucial for understanding toxicity mechanisms of the clinically used drug, amphotericin B. PMID- 23030379 TI - In silico prediction of chemical Ames mutagenicity. AB - Mutagenicity is one of the most important end points of toxicity. Due to high cost and laboriousness in experimental tests, it is necessary to develop robust in silico methods to predict chemical mutagenicity. In this paper, a comprehensive database containing 7617 diverse compounds, including 4252 mutagens and 3365 nonmutagens, was constructed. On the basis of this data set, high predictive models were then built using five machine learning methods, namely support vector machine (SVM), C4.5 decision tree (C4.5 DT), artificial neural network (ANN), k-nearest neighbors (kNN), and naive Bayes (NB), along with five fingerprints, namely CDK fingerprint (FP), Estate fingerprint (Estate), MACCS keys (MACCS), PubChem fingerprint (PubChem), and Substructure fingerprint (SubFP). Performances were measured by cross validation and an external test set containing 831 diverse chemicals. Information gain and substructure analysis were used to interpret the models. The accuracies of fivefold cross validation were from 0.808 to 0.841 for top five models. The range of accuracy for the external validation set was from 0.904 to 0.980, which outperformed that of Toxtree. Three models (PubChem-kNN, MACCS-kNN, and PubChem-SVM) showed high and reliable predictive accuracy for the mutagens and nonmutagens and, hence, could be used in prediction of chemical Ames mutagenicity. PMID- 23030380 TI - Molecular beam epitaxy growth of GaAs/InAs core-shell nanowires and fabrication of InAs nanotubes. AB - We present results about the growth of GaAs/InAs core-shell nanowires (NWs) using molecular beam epitaxy. The core is grown via the Ga droplet-assisted growth mechanism. For a homogeneous growth of the InAs shell, the As(4) flux and substrate temperature are critical. The shell growth starts with InAs islands along the NW core, which increase in time and merge giving finally a continuous and smooth layer. At the top of the NWs, a small part of the core is free of InAs indicating a crystal phase selective growth. This allows a precise measurement of the shell thickness and the fabrication of InAs nanotubes by selective etching. The strain relaxation in the shell occurs mainly via the formation of misfit dislocations and saturates at ~80%. Additionally, other types of defects are observed, namely stacking faults transferred from the core or formed in the shell, and threading dislocations. PMID- 23030382 TI - Performance analysis of the protective effects of bicycle helmets during impact and crush tests in pediatric skull models. AB - OBJECT: Bicycle accidents are a very important cause of clinically important traumatic brain injury (TBI) in children. One factor that has been shown to mitigate the severity of lesions associated with TBI in such scenarios is the proper use of a helmet. The object of this study was to test and evaluate the protection afforded by a children's bicycle helmet to human cadaver skulls with a child's anthropometry in both "impact" and "crushing" situations. METHODS: The authors tested human skulls with and without bicycle helmets in drop tests in a monorail-guided free-fall impact apparatus from heights of 6 to 48 in onto a flat steel anvil. Unhelmeted skulls were dropped at 6 in, with progressive height increases until failure (fracture). The maximum resultant acceleration rates experienced by helmeted and unhelmeted skulls on impact were recorded by an accelerometer attached to the skulls. In addition, compressive forces were applied to both helmeted and unhelmeted skulls in progressive amounts. The tolerance in each circumstance was recorded and compared between the two groups. RESULTS: Helmets conferred up to an 87% reduction in so-called mean maximum resultant acceleration over unhelmeted skulls. In compression testing, helmeted skulls were unable to be crushed in the compression fixture up to 470 pound-force (approximately 230 kgf), whereas both skull and helmet alone failed in testing. CONCLUSIONS: Children's bicycle helmets provide measurable protection in terms of attenuating the acceleration experienced by a skull on the introduction of an impact force. Moreover, such helmets have the durability to mitigate the effects of a more rare but catastrophic direct compressive force. Therefore, the use of bicycle helmets is an important preventive tool to reduce the incidence of severe associated TBI in children as well as to minimize the morbidity of its neurological consequences. PMID- 23030383 TI - Mapping of depositional and non-depositional areas in Salinas, California streams with concurrent pyrethroid and benthic macroinvertebrate assessments. AB - This study used sediment mapping to determine the spatial extent of depositional and non-depositional areas in the wetted stream bed of four urban streams in Salinas, California. After the stream mapping was completed, 8 pyrethroids were analytically measured from randomly selected sites in 12 depositional and 12 non depositional areas in the four Salinas streams. Benthic macroinvertebrate samples were collected and identified from depositional and non-depositional areas where pyrethroids were measured. In addition, physical habitat was also evaluated at each site where benthic communities were collected. Based on a random sampling design, 24 % of the 96 sediment sampling sites in the Salinas streams were classified as predominately depositional areas. Mean total pyrethroid concentrations were approximately 2* to 61* times higher in depositional areas of the Salinas streams when compared to non-depositional areas. Physical habitat scores from the 12 depositional and 12 non-depositional areas in the Salinas stream sites were extremely low compared with other California streams thus demonstrating that impaired physical habitat is a critical stressor in these streams. Approximately 6,300 individual macroinvertebrates were picked and identified from 70 taxa from the 24 Salinas stream sites. The most dominant taxa collected were all considered tolerant of environmental stressors and dominant taxa from both depositional and non-deposition areas were similar. Ten different benthic metrics for the Salinas streams were similar for the depositional areas, where pyrethroid concentrations consistently exceeded laboratory based toxicity thresholds, and non-depositional areas where pyrethroid concentrations were much lower. These results suggest that factors other than pyrethroids are responsible for impacting resident benthic communities in these urban Salinas streams. PMID- 23030384 TI - A GIS-based multi-source and multi-box modeling approach (GMSMB) for air pollution assessment--a North American case study. AB - This article presents a GIS-based multi-source and multi-box modeling approach (GMSMB) to predict the spatial concentration distributions of airborne pollutant on local and regional scales. In this method, an extended multi-box model combined with a multi-source and multi-grid Gaussian model are developed within the GIS framework to examine the contributions from both point- and area-source emissions. By using GIS, a large amount of data including emission sources, air quality monitoring, meteorological data, and spatial location information required for air quality modeling are brought into an integrated modeling environment. It helps more details of spatial variation in source distribution and meteorological condition to be quantitatively analyzed. The developed modeling approach has been examined to predict the spatial concentration distribution of four air pollutants (CO, NO(2), SO(2) and PM(2.5)) for the State of California. The modeling results are compared with the monitoring data. Good agreement is acquired which demonstrated that the developed modeling approach could deliver an effective air pollution assessment on both regional and local scales to support air pollution control and management planning. PMID- 23030381 TI - Acid-labile mPEG-vinyl ether-1,2-dioleylglycerol lipids with tunable pH sensitivity: synthesis and structural effects on hydrolysis rates, DOPE liposome release performance, and pharmacokinetics. AB - A family of 3-methoxypoly(ethylene glycol)-vinyl ether-1,2-dioleylglycerol (mPEG VE-DOG) lipopolymer conjugates, designed on the basis of DFT calculations to possess a wide range of proton affinities, was synthesized and tested for their hydrolysis kinetics in neutral and acidic buffers. Extruded ~100 nm liposomes containing these constructs in >=90 mol % 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine (DOPE) produced dispersions that retained their calcein cargo for more than 2 days at pH 7.5, but released the encapsulated contents over a wide range of time scales as a function of the electronic properties of the vinyl ether linkage, the solution pH, and the mPEG-VE-DOG composition in the membrane. The in vivo performance of two different 90:10 DOPE:mPEG-VE-DOG compositions was also evaluated for blood circulation time and biodistribution in mice, using (125)I-tyraminylinulin as a label. The pharmacokinetic profiles gave a t(1/2) of 7 and 3 h for 90:10 DOPE:ST302 and 90:10 DOPE:ST502, respectively, with the liposomes being cleared predominantly by liver and spleen uptake. The behavior of these DOPE:mPEG-VE-DOG formulations is consistent with their relative rates of vinyl ether hydrolysis, i.e., the more acid-sensitive mPEG-VE-DOG derivatives produced faster leakage rates from DOPE:mPEG-VE-DOG liposomes, but decreased the blood circulation times in mice. These findings suggest that the vinyl ether based PEG-lipid derivatives are promising agents for stabilizing acid-sensitive DOPE liposomes to produce formulations with a priori control over their pH responsiveness in vitro. Our data also suggest, however, that the same factors that contribute to enhanced acid sensitivity of the DOPE:mPEG-VE-DOG dispersions are also likely responsible for their reduced pharmacokinetic profiles. PMID- 23030385 TI - Biodegradation of specified risk material and fate of scrapie prions in compost. AB - Composting may be a viable alternative to rendering and land filling for the disposal of specified risk material (SRM) provided that infectious prion proteins (PrP(TSE)) are inactivated. This study investigated the degradation of SRM and the fate of scrapie prions (PrP(Sc)) over 28 days in laboratory-scale composters, with and without feathers in the compost matrices. Compost was mixed at day 14 to generate a second heating cycle, with temperatures exceeding 65 degrees C in the first cycle and 50 degrees C in the second cycle. Approximately 63% and 77% of SRM was degraded after the first and second cycles, respectively. Inclusion of feathers in the compost matrices did not alter compost properties during composting other than increasing (P < 0.05) total nitrogen and reducing (P < 0.05) the C/N ratio. However, addition of feathers enhanced (P < 0.05) SRM degradation by 10% upon completion of experiment. Scrapie brain homogenates were spiked into manure at the start of composting and extracted using sodium dodecyl sulphate followed by detection using Western blotting (WB). Prior to composting, PrP(Sc) was detectable in manure with 1-2 log(10) sensitivity, but was not observable after 14 or 28 days of composting. This may have been due to either biological degradation of PrP(Sc) or the formation of complexes with compost components that precluded its detection. PMID- 23030386 TI - Application of radio-immunoassays to assess the fate of estrogen EDCs in full scale wastewater treatment plants. AB - Wastewater effluents have been documented as major contributors of hormone endocrine disrupting compounds (EDCs) in to the aquatic ecosystem. The need for rapid, simple and cost effective methods to detect these EDCs has increased. The use of Radio-immunoassays (RIA) were assessed to determine the fate of estradiol in a laboratory batch test and the three natural estrogens (estrone (E1), estradiol (E2) and estriol (E3)) in wastewater treatment plants (WWTPs) with different types of configurations. Precision of the RIAs were done using intra assay and inter-assay validations. The E2 intra-assay variation was <8% and inter assay variation was <11% for standards 1 to 6. E1 RIA showed less than 8% for both the intra-assay and inter-assay variations. E3 RIA showed extremely good variations with both the intra and inter-assay variations being below <8% for all standards. The lab scale investigation showed a 94% reduction in E2 after 5 h and after 10 h both E2 and E1 were no longer detected. The simple activated sludge process, the biological nutrient removal (BNR) activated sludge process and the oxidation pond had final effluent concentrations of 10.75, 5.96 and 25.48 pg E2/mL respectively; 20.80, 9.30 and 46.55 pg E1/mL, respectively, and 0.12, 0.07 and 0.17 ng E3/mL, respectively. Thus far findings indicated that the RIA can be employed as a rapid technique for detection of natural estrogens in water. Results indicate that these potential problematic hormone EDCs are still present in final wastewater effluents that are discharged in to South African aquatic sources. PMID- 23030387 TI - Passivation of bimetallic catalysts used in water treatment: prevention and reactivation. AB - With respect to degradation rates and the range in contaminants treated, bimetals such as Ni-Fe or Pd-Fe generally outperform unamended granular iron. However, the catalytic enhancement is generally short-lived, lasting from a few days to months. To take advantage of the significant benefits of bimetals, this study aims at developing an effective method for the rejuvenation of passivated bimetals and alternatively, the prevention of rapid reactivity loss of bimetals. Because the most likely cause of Ni-Fe and Pd-Fe passivation is the deposition of iron oxide films over the catalyst sites, it is hypothesized that removal of the iron oxide films will restore the lost reactivity or avoiding the deposition of iron oxide films will prevent passivation. Two organic ligands (ethylenediaminetetraacetic acid (EDTA), and [s,s]-ethylenediaminedisuccinate acid ([s,s]-EDDS)) and two acids (citric acid and sulphuric acid) were tested as possible chemical reagents for both passivation rejuvenation and prevention. Trichloroethene (TCE) and Ni-Fe were chosen as probes for chlorinated solvents and bimetals respectively. The test was carried out using small glass columns packed with Ni-Fe. TCE solution containing a single reagent at various concentrations was pumped through the Ni-Fe columns with a residence time in the Ni-Fe of about 6.6 min. TCE concentrations in the influent and effluent were measured to evaluate the performance of each chemical reagent. The results show that (i) for passivated Ni-Fe, flushing with a low concentration of acid or ligand solution without mechanical mixing can fully restore the lost reactivity; and (ii) for passivation prevention, adding a small amount of a ligand or an acid to the feed solution can successfully prevent or at least substantially reduce Ni Fe passivation. All four chemicals tested are effective in both rejuvenation and prevention, but sulphuric acid and citric acid are considered to be the most practical reagents due to their relatively low costs and environmentally friendly nature. This study suggests that the use of bimetals in above-groundwater treatment applications could become practical with appropriate engineering design. PMID- 23030388 TI - Assessment of toxicity in waters due to heavy metals derived from atmospheric deposition using Vibrio fischeri. AB - Water toxicity originating from the atmospheric deposition of six heavy metals (Cd, Cr, Cu, Ni, Pb, Zn) was investigated on Vibrio fischeri activity in Izmir, Turkey. A LUMIStox(r) test was applied to dry and wet deposition samples and metal solutions. The inhibition levels and effective toxicity concentrations of these samples and solutions were determined. Interactive toxicity effects among the metals were investigated. When the impacts of the synthetic single heavy metal solutions were compared with each other, a toxicity ranking of Cr>Cd>Pb>Cu>Zn>Ni was obtained in order of decreasing severity. The total effective concentrations of these six metals were in the ranges of 0.074-0.221 mg/L and 0.071-0.225 mg/L for receiving aqueous solutions of dry and wet atmospheric depositions, respectively. The toxicity data showed that the wet deposition samples were 15% more toxic than the dry deposition samples. The interactive toxicity effects of the heavy metals in both dry and wet deposition samples were classified as antagonistic. High levels of heavy metals deposited in dissolved form may constitute an important input in the biochemical cycle and may have significant impacts. PMID- 23030389 TI - Investigation onto feasibility of an adsorbent for chromium abatement with its extended application for real mine drainage water. AB - The feasibilities of the adsorbents ferrous modified calcined bauxite (FEMCB) and ferric modified calcined bauxite (FRMCB) in the abatement of Cr(VI) was investigated in the present study. The adsorbents were characterized by scanning electron micrographs (SEM), electro diffraction spectra (EDS), X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectra. Parameter optimization of both adsorbents was done and performance efficiencies in the removal of Cr(VI) were compared. Although pH and temperature seemed to have no significant role in the removal efficiency of FEMCB, sorption by FRMCB was found to be depending on both. The optimum pH and temperature was found to be 5 +/- 0.2, and 30 degrees C, respectively. At optimum conditions, both adsorbents demonstrated removal efficiencies of >99% for a concentration of 5 mg L(-1). Sorption of Cr(VI) by FEMCB followed Freundlich isotherm model, while that of FRMCB fitted well with Langmuir isotherm model. The isotherm parameters were optimized by minimizing the error functions. The kinetics of sorption by FEMCB followed a pseudo-second-order model confirming chemisorptive mechanism, while FRMCB followed pseudo-first order. Thermodynamic study revealed that sorption process was spontaneous and that the rate limiting step was governed by film diffusion. Both the adsorbents showed removal efficiencies of >99% in removing Cr(VI) from real sample of mine drainage water of concentration 1.86 mg L(-1) at optimum conditions. PMID- 23030390 TI - Enzymatically mediated bioprecipitation of heavy metals from industrial wastes and single ion solutions by mammalian alkaline phosphatase. AB - The study was aimed at investigating the potential use of calf intestinal alkaline phosphatase (CIAP) enzyme in the removal of heavy metals (Cd(2+), Ni(2+), Co(2+) and Cr(3+/6+)) from single ion solutions as well as tannery and electroplating effluents. CIAP mediated bioremediation (white biotechnology) is a novel technique that is eco-friendly and cost effective unlike the conventional chemical technologies. Typical reactions containing the enzyme (CIAP) and p nitrophenyl phosphate (pNPP) as substrate in Tris-HCl buffer (pH 8 and 11) and either single ion metal solutions (250 ppm and 1000 ppm) or effluents from tannery or electroplating industry were incubated at 37 degrees C for 30 min, 60 min and 120 min. The inorganic phosphate (P(i)) generated due to catalytic breakdown of pNPP complexes free metal ions as metal-phosphate and the amount of metal precipitated was derived by estimating the reduction in the free metal ion present in the supernatant of reactions employing atomic absorption spectrophotometer (AAS). Better precipitation of metal was obtained at pH 11 than at pH 8 and between the two concentrations of different metals tested, an initial metal concentration of 250 ppm in the reaction gave more precipitation than with 1000 ppm. Experimental data showed that at pH 11, the percentage of removal of metal ions (for an initial concentration of 250 ppm) was in the following order: Cd(2+) (80.99%) > Ni(2+) (64.78%) > Cr(3+) > (46.15%) > Co(2+) (36.47%) > Cr(6+) (32.33%). The overall removal of Cr(3+) and Cr(6+) from tannery effluent was 32.77% and 37.39% respectively in 120 min at pH 11. Likewise, the overall removal of Cd(2+), Co(2+) and Ni(2+) from electroplating effluent was 50.42%, 13.93% and 38.64% respectively in 120 min at pH 11. The study demonstrates that bioprecipitation by CIAP may be a viable and environmental friendly method for clean-up of heavy metals from tannery and electroplating effluents. PMID- 23030391 TI - Treatment of NO and NO2 with a Mg-Al oxide slurry. AB - A selective catalytic reduction process is generally used to treat NO(x); however, this approach results in the leakage of ammonia and requires expensive catalysts. In light of these issues, the specific objective of this study was to develop a new treatment method for a NO(x) gas stream with a Mg-Al oxide slurry. In this study, we examined the ability of a Mg-Al oxide slurry to treat NO and NO(2) gas streams. The Mg-Al oxide slurry only partially removed the NO and NO(2). The ability of Mg-Al oxide to remove NO is based on the adsorption of NO molecules onto the surface of the Mg-Al oxide rather than the formation of an Mg Al layered double hydroxide (Mg-Al LDH) intercalated with NO(-)(2). NO(2) removal was greater than NO removal because of the higher solubility of NO(2). For NO(2) removal, the Mg-Al oxide adsorbed NO(-)(2) and NO(-)(3) onto the surface and formed Mg-Al LDH intercalated with NO(-)(2) and NO(-)(3). Based on these results, we conclude that the Mg-Al oxide slurry is an effective treatment for NO(x). PMID- 23030392 TI - Dechlorination of polychlorinated biphenyls in transformer oil using UV and visible light. AB - A study on dechlorination of PCB138 in transformer oil (TO) and 2-propanol (IPA) using 254 nm ultraviolet (UV) light as well as dye sensitized visible light has been conducted. Studies on dechlorination of polychlorinated biphenyls (PCBs) in TO using visible light in the presence of methylene blue (MB) and triethylamine (TEA) (providing a 'photocatalytic' cycle) in both deaerated and aerated conditions have been conducted to determine effects of TO, MB and TEA on reaction rates. The results show that photolytic methods are effective in treating PCBs in TO, and that the oil plays a limited adverse role. Under UV irradiation, PCB 138 can be >99% dechlorinated in the presence 0.06% (w/w) TO in IPA within 1 h with a rate constant of 0.0853 min(-1), while 47% of PCB138 can be dechlorinated in 92.1% (w/w) TO in IPA within 2 h with a rate constant of 0.0051 min(-1). In the 'photocatalytic' system, 94% reduction of PCB 138 was achieved within 30 min with a rate constant of 0.0968 min(-1) when the solvent was 60.70% (w/w) TO in IPA, while 71% dechlorination of PCB138 was achieved within 30 min with a rate constant of 0.0382 min(-1) when 81.62% (w/w) TO was present. In treatment of 30 73 ppm PCBs in TO, the optimal concentration of MB and TEA were found to be 0.5 g/L and 58.08 g/L respectively. Because of quenching by oxygen, deaeration of the solution is necessary for an efficient reaction. The photocatalytic system is especially adapted for treating lower concentration of PCBs in TO. PMID- 23030393 TI - Characterization of PM10 samples from Vanderbijlpark in South Africa. AB - In this study, mass concentrations and physico-chemical characteristics of suspended particulates of aerodynamic size 10 MUm (PM10) were evaluated. A dual E Sampler which combines the light scatter and the gravimetric filter methods was used. Sampling occurred between August and December 2009. Scanning Electron Microscope - Energy Dispersive Spectrometry (SEM-EDS) and Inductively Coupled Plasma 6000 were used for elemental and physical characterization. The highest daily average mass concentration measured was 0.03543 mg/m(3) and was below the international and national daily limit of 0.150 mg/m(3), as well as the strict Vaal Triangle regional standard of 0.075 MUg/m(3). Relatively high daily average mass concentrations were obtained during the winter period. Concentrations of evaluated heavy metals decreased in the following order: iron (Fe) > manganese (Mn) > zinc (Zn) > copper (Cu) > vanadium (V) > titanium (Ti) > nickel (Ni) > lead (Pb). Positive correlations were established between Zn and Pb (r = 0.916); Zn and Mn (r = 0.883); Zn and V (0.984); Zn and Ni (r = 0.877); Zn and Fe (r = 0.914), which suggests common sources. However, Zn and Ti (r = 0.522); Zn and Cu (0.781) were poorly correlated. PMID- 23030394 TI - Influence of nutrient mixtures on p-nitrophenol degradation by Stenotrophomonas sp. isolated from groundwater. AB - We isolated strain CERAR5, a Stenotrophomonas sp., from an aquifer contaminated with chlorinated hydrocarbons that utilizes up to 1.0 mM PNP within 62 h in M9 medium as a source of carbon and nitrogen. To assess the potential of this strain for use in bioremediation, we investigated the influence of external sources of carbon and nitrogen on bacterial degradation of PNP following a full factorial design analysis. Glucose, sodium acetate, phenol, sodium nitrate and ammonium chloride were the factors chosen, while per cent removal of PNP, growth of the bacterial strain, and change in pH of the medium were the responses measured. Glucose and acetate had significant positive influence on the removal PNP. In particular, acetate exhibited a significant positive effect on all the three responses measured, clearly suggesting that the addition of acetate greatly contributes to an efficient bioremediation of habitats contaminated with PNP by Stenotrophomonas sp. CERAR5. PMID- 23030395 TI - Modeling the photodegradation of emerging contaminants in waters by UV radiation and UV/H2O2 system. AB - Five emerging contaminants (1-H-Benzotriazole, N,N-diethyl-m-toluamide or DEET, Chlorophene, 3-Methylindole, and Nortriptyline HCl), frequently found in surface waters and wastewaters, were selected to be photooxidized in several water matrices. Previous degradation experiments of these compounds individually dissolved in ultra pure water were performed by using UV radiation at 254 nm and the Fenton's reagent. These oxidation systems allowed the determination of the quantum yields and the rate constants for the radical reaction between each compound and hydroxyl radicals. Later, the simultaneous photodegradation of mixtures of the selected ECs in several types of water (ultrapure water, reservoir water, and two effluents from WWTPs) was carried out and a kinetic study was conducted. A model is proposed for the ECs elimination, and the theoretically calculated concentrations with this model agreed well with the experimental results obtained, which confirmed that it constitutes an excellent tool to predict the elimination of these compounds in waters. PMID- 23030396 TI - Usefulness of Ki-67 (MIB-1) immunostaining in the diagnosis of pulmonary sclerosing hemangiomas. AB - Pulmonary sclerosing hemangioma (PSH) is an uncommon lung neoplasm with a clinical outcome that is generally benign. However, differentiating PSH from pulmonary carcinoma is sometimes difficult as both lesions share similar histopathologic and immunohistochemical features. In this study, we investigated the usefulness of Ki-67 (MIB-1) immunostaining in the diagnosis of PSH. We compared the staining pattern for Ki-67 (MIB-1) in 29 cases of typical PSH and 79 cases of pulmonary non-small cell carcinoma (NSCLC) using an immunohistochemical method on formalin-fixed paraffin-embedded tissues. In all studied PSH cases, we noted cell membrane and cytoplasmic staining for Ki-67 (MIB-1), but this was not observed in any of the NSCLC cases. The Ki-67 proliferation index was lower in PSH than in the NSCLC cases (mean, 1.1% vs mean, 5.5%; p < 0.001). These findings suggest that cell membrane and cytoplasmic staining for Ki-67 (MIB-1), as well as the Ki-67 proliferation index, may be useful for distinguishing PSH from pulmonary carcinoma. PMID- 23030397 TI - Synthesis of (R)-(+)-4-methylcyclohex-2-ene-1-one. AB - A three-step synthesis of (R)-(+)-4-methylcyclohex-2-ene-1-one (1) from (R)-(+) pulegone (3), proceeding in 44% overall yield, is described. The sequence comprises vinyl triflate formation, site-selective ozonolysis, and reduction. The route requires only one chromatographic purification and provides a convenient method to access multigram quantities of (R)-(+)-4-methylcyclohex-2-ene-1-one (1). PMID- 23030398 TI - Immunotoxic effects of cyclophosphamide and cyclosporine in the dog. AB - Limited non-clinical immunotoxicity data are available in the dog, although this is a major non-rodent species in regulatory safety studies. The present study aimed to test whether widely accepted immunotoxicity endpoints including lymphocyte subset immunophenotyping, the anti-KLH TDAR assay, and histological examination of the main lymphoid organs were reliable to detect immunosuppression induced by cyclosporine and cyclophosphamide in dogs and could, therefore, be used for non-clinical immunotoxicity evaluation in this species. Male and female Beagle dogs were treated orally from Day 1 for 4 weeks with 25 mg/kg cyclosporine daily, or with 2 mg/kg cyclophosphamide on 4 consecutive days each week, or the same volume of drinking water daily. Blood samples were withdrawn pre-test and on Days 11, 18, and 23 to measure standard hematology parameters and analyze lymphocyte subsets. All animals received an intramuscular injection of 5 mg KLH on Day 11. Sandwich ELISA assays were used to quantify anti-KLH IgM and anti-KLH IgG levels in blood samples taken pre-test, on Days 18 and 23, and pre-test, on Days 23 and 28, respectively. At the end of the treatment period, all animals were submitted to histological examination of lymphoid organs, liver, and kidneys. No signs of marked toxicity were observed. No changes in lymphocyte subsets, but markedly decreased primary anti-KLH IgM and IgG responses, and a slightly-to-markedly increased cortex/medulla ratio in the thymus were observed in cyclosporine-treated dogs. Lower total WBC counts correlating with lower total and B-lymphocyte subset and decreased germinal center development in mesenteric lymph nodes, but no changes in primary anti-KLH IgM and IgG responses were observed in cyclophosphamide-treated dogs. These results demonstrate that widely accepted immunotoxicity endpoints can adequately detect the effects of known immunosuppressive drugs in the dog and support the conclusion that it is a relevant animal species for immunotoxicity evaluation. PMID- 23030399 TI - Synthesis of palladium nanoparticles supported on mesoporous N-doped carbon and their catalytic ability for biofuel upgrade. AB - We report a catalyst made of Pd nanoparticles (NPs) supported on mesoporous N doped carbon, Pd@CN(0132), which was shown to be highly active in promoting biomass refining. The use of a task-specific ionic liquid (3-methyl-1 butylpyridine dicyanamide) as a precursor and silica NPs as a hard template afforded a high-nitrogen-content (12 wt %) mesoporous carbon material that showed high activity in stabilizing Pd NPs. The resulting Pd@CN(0.132) catalyst showed very high catalytic activity in hydrodeoxygenation of vanillin (a typical model compound of lignin) at low H(2) pressure under mild conditions in aqueous media. Excellent catalytic results (100% conversion of vanillin and 100% selectivity for 2-methoxy-4-methylphenol) were achieved, and no loss of catalytic activity was observed after six recycles. PMID- 23030400 TI - Evidence of interspecies O antigen gene cluster transfer between Shigella boydii 15 and Escherichia fergusonii. AB - An environmental bacterial isolate, Iso10, previously found to show serological cross-reactivity with type-specific Shigella boydii 15 antisera was subjected to further molecular and serological analyses that revealed interspecies transfer of the O antigen gene cluster. Western blot analysis of Iso10 cell surface extracts and purified lipopolysaccharides demonstrated strong cross-reactivity with S. boydii 15-specific monovalent antisera and a lipopolysaccharide gel banding profile similar to that of S. boydii 15. Biochemical and phylogenetic analyses identified the Iso10 isolate as Escherichia fergusonii. O antigen gene cluster analyses of Iso10, carried out by restriction fragment length analysis of the amplified ~10-kb O antigen-encoding gene cluster, revealed a profile highly similar to that of S. boydii 15, confirming the presence of the S. boydii 15 somatic antigen in Iso10. To the best of our knowledge, this is the first report of interspecies transfer of O antigen-encoding genes between S. boydii and E. fergusonii, and it has implications for our understanding of the role of lateral gene transfer in the emergence of novel Shigella serotypes. PMID- 23030401 TI - Persistence of Escherichia coli O157:H7 in major leafy green producing soils. AB - Persistence of Escherichia coli O157:H7 in 32 (16 organically managed and 16 conventionally managed) soils from California (CA) and Arizona (AZ) was investigated. Results showed that the longest survival (ttd, time needed to reach detection limit, 100 CFU g(-1) dry soil) of E. coli O157:H7 was observed in the soils from Salinas Valley, CA and in organically managed soils from AZ. Detrended correspondence analysis revealed that the survival profiles in organically managed soils in Yuma, AZ were different from the ones in conventionally managed soils from the same site. Principal component analysis and stepwise regression analysis showed that E. coli O157:H7 survival in soils was negatively correlated with salinity (EC) (P < 0.001), while positively correlated with assimilable organic carbon (AOC) and total nitrogen (TN) (P < 0.01). Pearson correlation analysis revealed that a greater ttd was associated with a larger delta (time needed for first decimal reduction in E. coli population). EC was negatively correlated and TN was positively correlated (P < 0.05) with delta, suggesting that EC and TN likely have a direct impact on ttd. On the other hand, AOC showed a close correlation with p (the shape parameter) that was not directly related to ttd, indicating that AOC might have an indirect effect in the overall survival of E. coli O157:H7 in soils. Our data showed that AOC and EC significantly affected the survival of E. coli O157:H7 in leafy green producing soils and the development of good agricultural practices (manure/composting/irrigation water source management) in the preharvest environment must be followed to minimize foodborne bacterial contamination on fresh produce. PMID- 23030402 TI - Is it possible to predict low-volume and insignificant prostate cancer by core needle biopsies? AB - In an attempt to minimize overtreatment of localized prostate cancer (PCa) active surveillance (AS) and minor invasive procedures have received increased attention. We investigated the accuracy of pre-operative findings in defining insignificant disease and distinguishing between unilateral/unifocal and bilateral/multifocal PCa. One-hundred and sixty patients undergoing radical prostatectomy were included. Histology reports from the biopsies and matching prostatectomies were compared. Three definitions of insignificant cancer were used: InsigE: tumour volume <=0.5 mL; InsigW: tumour volume <=1.3 mL; InsigM: tumour <=5% of total prostate volume and prostate-specific antigen (PSA) <=10 ng/mL. In all definitions, Gleason score (GS) was <=6 and the tumour was organ confined. Biopsies alone performed poorly as a predictor of unifocal and unilateral cancer in the prostatectomy specimens with positive predictive values of 17.8% and 18.9% respectively. Inclusion of other clinical and biochemical parameters did not significantly increase the predictive value. However, the combination of GS <= 6, PSA <= 10 ng/mL and unifocal or unilateral cancer in biopsy cores resulted in a positive predictive value of 61.1%, 38.9% and 12.0%, respectively, for identifying InsigM, InsigW and InsigE in the prostate specimen. Conclusively, routine prostate biopsies cannot predict unifocal and unilateral PCa, and must be regarded insufficient to select patients for focal therapy. Although candidates for AS may be identified using standard biopsies, a considerable fraction of patients will be understaged. There is a need for more precise diagnostic tools to assess intraprostatic tumour growth. PMID- 23030403 TI - Sudden unexpected death in epilepsy in lamotrigine randomized-controlled trials. AB - PURPOSE: Nonrandomized studies of the relationship of antiepileptic drugs (AEDs) with sudden unexpected death in epilepsy (SUDEP) may be susceptible to confounding by tonic-clonic seizure frequency, polypharmacy, and other potential risk factors for SUDEP. We evaluated the risk of SUDEP with lamotrigine (LTG) compared to active comparators and placebo in randomized controlled clinical trials conducted by GlaxoSmithKline (GSK) between 1984 and 2009. METHODS: Among 7,774 subjects in 42 randomized clinical trials, there were 39 all-cause deaths. Ten deaths occurred >2 weeks after discontinuation of study medication and were excluded. Narrative summaries of deaths were independently reviewed by three clinical experts (TT, LH, DF), who were blinded to randomized treatment arm. The risk of definite or probable SUDEP was compared between treatment arms for each trial type (placebo-controlled, active-comparator, crossover), using exact statistical methods. KEY FINDINGS: Of 29 on-treatment deaths, eight were definite/probable SUDEP, four were possible SUDEP, and 17 were non-SUDEP. The overall, unadjusted rate of definite/probable SUDEP for LTG was 2.2 events per 1,000-patient years (95% confidence interval [95% CI] 0.70-5.4). The odds ratios (OR) for on-treatment, definite/probable SUDEP in LTG arms relative to comparator arms, adjusted for length of exposure and trial, were the following: placebo controlled, OR 0.22 (95% CI 0.00-3.14; p = 0.26); active-comparator, OR 2.18 (95% CI 0.17-117; p = 0.89); and placebo-controlled cross-over, OR 1.08 (95% CI 0.00 42.2; p = 1.0). SIGNIFICANCE: There was no statistically significant difference in rate of SUDEP between LTG and comparator groups. However, the CIs were wide and a clinically important effect cannot be excluded. PMID- 23030404 TI - The effect of advance information about the sequence of a to-be-signaled motor response on corticospinal excitability during the foreperiod. AB - We investigated the effect of advance information about the sequence of a to-be signaled motor response on corticospinal excitability during the foreperiod in healthy humans. Advance information about the sequence of a to-be-signaled motor response was provided by a precue signal 600 ms before a response signal during a warned choice reaction task. The precue signal indicated the sequence of one of three to-be-signaled motor responses: simple, repetitive, or sequential motor responses. The amplitude of the motor-evoked potential (MEP) decreased significantly 100 ms before the response signal in both the first dorsal interosseous (FDI) and abductor pollicis brevis (APB) muscles, but a significant decrease was present only in the APB muscle 300 ms before the response signal. The decrease in the MEP amplitude 100 ms before the response signal induced by the precue signal indicating the repetitive motor response was significantly smaller than that induced by the precue signal indicating the simple or sequential motor response in the FDI muscle, and was significantly smaller than that induced by the precue signal indicating the sequential motor response in the APB muscle. The decrease in corticospinal excitability in the middle foreperiod is larger when the advance information about a to-be-signaled motor response is unrelated to the muscle tested, and the decrease in the late foreperiod is affected by advance information about the sequence of a to-be-signaled motor response. PMID- 23030405 TI - Native and beta-cyclodextrin-enclosed curcumin: entrapment within liposomes and their in vitro cytotoxicity in lung and colon cancer. AB - With a view to improving the solubility and delivery characteristics of poorly water-soluble drugs, we prepared beta-cyclodextrin-curcumin (betaCD-C) inclusion complexes (hydrophilic curcumin) and entrapped both native curcumin (hydrophobic) and the complexes separately into liposomes; these were then assessed for in vitro cytotoxicity in lung and colon cancer cell lines. Optimization of curcumin entrapment within betaCD was achieved, with the resultant betaCD-C complexes prepared by methanol reflux. Inclusion complexes were confirmed using UV spectroscopy, Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction. The water solubility of betaCD-C complexes improved markedly (c.f. native curcumin) and successful entrapment of complexes into liposomes, prepared using a thin-film hydration approach, was also achieved. All the liposomal formulations were characterized for curcumin and betaCD-C complex entrapment efficiency, particle size, polydispersity and stability at 2-8 degrees C. Curcumin, betaCD-C complex and their optimized liposomal formulations were evaluated for anticancer activity in lung (A-459) and colon (SW-620) cancer cell lines. All curcumin-containing formulations tested were effective in inhibiting cell proliferation, as determined via an MTT assay. The median effective dose (EC(50)) for all curcumin formulations was found to be in the low uM range for both lung and colon cancer cell lines tested. Our results confirm that betaCD inclusion complexes of poorly water soluble drugs, such as curcumin can be entrapped within biocompatible vesicles such as liposomes, and this does not preclude their anticancer activity. PMID- 23030407 TI - Recurrent lacrimal sac rhinosporidiosis involving the periocular subcutaneous tissues, nasolacrimal duct and nasopharynx. AB - Rhinosporidiosis is a chronic infection caused by the organism Rhinosporidium seeberi. It is endemic in parts of southern India and Sri Lanka, but rarely seen outside these areas. The infection predominantly affects the nasal mucosa; however, it can also affect the ocular surface and adnexa. We present a case of rhinosporidiosis initially involving the lacrimal sac, with recurrence in the periocular subcutaneous tissues, nasolacrimal duct and nasopharynx. PMID- 23030406 TI - Methotrexate as an alternative treatment for orbital angiolymphoid hyperplasia with eosinophilia. AB - Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon, benign disorder that presents as solitary or multiple nodules in the dermis or subcutaneous tissue. Orbital ALHE has been reported on occasion. We report a case of orbital ALHE which was refractory to systemic steroids but effectively treated with low-dose subcutaneous methotrexate. To our knowledge, this is the first reported case of methotrexate as a successful treatment for refractory ALHE. PMID- 23030408 TI - Gamma-delta T-cell lymphoma with CNS involvement presenting with proptosis: a case study workup, treatment and prognosis. AB - INTRODUCTION: Ocular adnexal lymphomas are rare and T cell variants are a minor subset of these lymphomas. We aim to describe a case report which underlines the diagnostic and treatment challenge of this rare pathology. CASE: A 34-year-old gentleman has been shown to have exophthalmos and dysfunction of cranial nerve V andVII unilaterally. Imaging including CT and MRI brain and orbits do not show a CNS component to the disease. It was later identified as an ocular adnexal lymphoma with a central nervous system (CNS) component diagnosed via lumbar puncture. DISCUSSION: We highlight the importance of excluding ocular adnexal lymphoma and difficulty of management of the disease where it presents as a masquerade syndrome for orbital cellulitis. PMID- 23030409 TI - Understanding the effectiveness of the entertainment-education strategy: an investigation of how audience involvement, message processing, and message design influence health information recall. AB - A growing body of evidence suggests that entertainment-education (EE) is a promising health communication strategy. The purpose of this study was to identify some of the factors that facilitate and hinder audience involvement with EE messages. Using confirmatory factor analysis, the authors introduce a construct they call experiential involvement, which describes the experience of being cognitively and emotionally involved with EE messages and is a product of transportation into an EE text and identification with EE characters. Using an experimental design, the authors also investigated how reports of experiential involvement and health information recall varied depending on the degree to which the educational content was well integrated with the narrative content in EE messages. Findings indicated that integration significantly influenced health information recall. Results indicated that experiential involvement and the perception that the health topic in EE messages was personally relevant predicted participants' systematic processing of the information in EE messages. Contrary to expectation, personal relevance did not predict experiential involvement, and systematic message processing was negatively related to health information recall. Implications for the construction of EE messages and the study of the EE strategy are discussed. PMID- 23030410 TI - Copper-catalyzed amination of silyl ketene acetals with N-chloroamines. AB - A copper(I)/2,2'-bipyridyl complex catalyzes an amination reaction of silyl ketene acetals with N-chloroamines, presenting a new preparative method of alpha amino esters. PMID- 23030411 TI - Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion. AB - The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations >=3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a threshold value for SR(M) was evident, regardless of formulation composition and drug solubilization reduced markedly above SR(M) > 2.5. The threshold SR(M) may prove to be an effective tool in discriminating between LBFs based on performance. PMID- 23030412 TI - Selenium and cardiovascular surgery: an overview. AB - Selenium is an essential nutritional element to mammalians necessary for the active function of different oxidant enzymes, as glutathione peroxidase (GPx), thioredoxin reductases (TrxR), and iodothyronine deiodinases (IDD). The anti oxidative effect of selenium is pivotal for the human physiology. Oxidative stress is associated with various diseases, such as cardiovascular disease, diabetes mellitus or cancer, and is also associated with the majority of surgical procedures. Particularly, the use of cardiopulmonary bypass for open cardiac surgery with aortic clamping is always related to oxidative stress due to ischemia and reperfusion. Whereas myocardial protection with different temperatures and cardioplegic solutions has become more efficient, reperfusion is often followed by the activation of an injurious oxidative cascade. The pathogenesis of ischemia/reperfusion injury depends on many factors, among them, reactive nitrogen species (RNS) and reactive oxygen species (ROS) are considered as initiators of the injury. ROS formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks. ROS production is physiologically controlled by free radical scavengers such as GPx and TrxR, and superoxide dismutase systems. GPx and TrxR are seleno cysteine dependent enzymes, and their activity is known to be related to selenium availability. Furthermore, selenium has been reported to regulate gene expression of these selenoproteins as a cofactor and there is some evidence that selenium supplementation can attenuate the oxidative stress and decrease the complications after cardiac surgery. However, other clinical studies failed to demonstrate an association between selenium deficiency and cardiovascular outcomes. The aim of our review is to summarize the experimental and clinical evidence of preoperative selenium supplementation and therapy after cardiac surgery, focusing on the pathophysiology of oxidative stress and the clinical usage of selenium. PMID- 23030413 TI - Preparation and characterization of microemulsion formulations of nicotinic acid and its prodrugs for transdermal delivery. AB - At pharmacological doses, nicotinic acid has a lipid-regulating effect and is in use clinically for that purpose. However, despite of all features, its utility is strongly limited by several disadvantages such as, extensive hepatic metabolism and flushing. Transdermal delivery of nicotinic acid may, therefore, be the solution to reducing side effects associated with oral administration, and to maintaining constant therapeutic blood levels for longer duration. The aim of this investigation was to develop a suitable formulation or select a suitable vehicle for the transdermal delivery of highly lipophilic prodrugs of nicotinic acid (dodecyl and myristyl nicotinate) designed to deliver nicotinic acid through skin without causing vasodilatation and flushing and optimizing its delivery to the blood stream. A microemulsion system and penetration enhancers have been attempted in this study. The microemulsion system was composed of isopropyl myristate (IPM), water and a 4:1 (w/w) mixture of Labrasol and Peceol where a pseudoternary phase diagram was constructed. Furthermore, the microemulsion formulations with different component ratios were characterized by determination of conductivity, pH, particle size, viscosity and refractive index. According to the particle size analysis, conductivity and viscosity measurements, the microemulsion formulations that formed were of oil-in-water type. The transdermal permeability of nicotinic acid and its prodrugs was evaluated in vitro using Franz diffusion cells fitted with mice skin and nicotinic acid concentration was analyzed by high performance liquid chromatography. A theoretical design of percutaneous penetration optimization in which prodrugs derivation and enhancer application are combined based on the skin diffusion model was experimentally verified. The selected formulations seemed promising for developing a transdermal drug delivery system of nicotinic acid from dodecyl nicotinate that would offer advantages like possible controlled drug release, reduced flushing, increased drug stability and ease of large-scale production. PMID- 23030414 TI - Long-term follow-up of early mycosis fungoides patients treated with narrowband ultraviolet B phototherapy. AB - BACKGROUND: Narrowband ultraviolet B (UVB) provides complete response (CR) in 54 91% of early mycosis fungoides (MF) patients. Data concerning relapse rate and relapse-free interval after discontinuation of therapy need clarification. The purpose of this study was to evaluate the relapse rate and the relapse-free intervals of early MF patients after achieving complete response with narrowband UVB phototherapy. METHODS: Retrospective evaluation of data, which belong to early MF patients treated with narrowband UVB phototherapy between May 2000 and July 2010, and followed-up until May 2012 in a single institution, for the occurrence of relapse and the time to relapse. RESULTS: Of 31 patients, who were followed-up for a mean of 56.5 +/- 30.2 months (median 55 months, range 20-120 months), relapse was observed in 11 (35.5%) patients, within a mean of 28.8 +/- 18.2 months (median 33 months, range 4-59 months), whereas 20 (64.5%) patients stayed relapse-free for a mean of 54.2 +/- 28.8 months (median 55.5 months, range 20-119 months). Patients received maintenance phototherapy with a median duration of 12 months (range 1-30 months) after achieving complete response. CONCLUSION: Results indicate that narrowband UVB phototherapy may induce low relapse rates and long relapse-free intervals for early MF. PMID- 23030415 TI - B22- and B23-: all-boron analogues of anthracene and phenanthrene. AB - Clusters of boron atoms exhibit intriguing size-dependent structures and chemical bonding that are different from bulk boron and may lead to new boron-based nanostructures. We report a combined photoelectron spectroscopic and ab initio study of the 22- and 23-atom boron clusters. The joint experimental and theoretical investigation shows that B(22)(-) and B(23)(-) possess quasi-planar and planar structures, respectively. The quasi-planar B(22)(-) consists of fourteen peripheral atoms and eight interior atoms in a slightly buckled triangular lattice. Chemical bonding analyses of the closed-shell B(22)(2-) species reveal seven delocalized pi orbitals, which are similar to those in anthracene. B(23)(-) is a perfectly planar and heart-shaped cluster with a pentagonal cavity and a pi-bonding pattern similar to that in phenanthrene. Thus, B(22)(-) and B(23)(-), the largest negatively charged boron clusters that have been characterized experimentally to date, can be viewed as all-boron analogues of anthracene and phenanthrene, respectively. The current work shows not only that boron clusters are planar at very large sizes but also that they continue to yield surprises and novel chemical bonding analogous to specific polycyclic aromatic hydrocarbons. PMID- 23030416 TI - Atonal homolog 1 expression in lung cancer correlates with inhibitors of the Wnt pathway as well as the differentiation and primary tumor stage. AB - Atonal homolog 1 (Atoh1) is crucial to the differentiation of many cell types and participates in tumorigenesis and progression. This study investigated the role of Atoh1 in lung cancer development and its correlation with key members of the Wnt pathway. We used immunohistochemistry to examine the expressions of Atoh1, beta-catenin, Axin, chibby, and Disabled-2 (Dab2) in 118 samples of lung cancer. We also detected the cytoplasmic and nuclear expression of Atoh1 in lung cancer tissues using western blot. Atoh1 nuclear expression was negatively correlated with differentiation level (p = 0.004) and primary tumor stage (p = 0.044) of lung cancer. Nuclear Atoh1 expression was positively correlated with nuclear expression of chibby (p < 0.001) and Dab2 (p < 0.001). Cytoplasmic Atoh1 expression was positively correlated with the cytoplasmic expression of Axin (p = 0.028), chibby (p < 0.001), and Dab2 (p < 0.001). We conclude that the nuclear expression of Atoh1 was inversely correlated with the differentiation and primary tumor stage of lung cancers. The expression and localization of Atoh1 correlated with Axin, chibby, or Dab2. Atoh1 may be a potential therapeutic target for the inhibition of growth and progression of lung cancers. PMID- 23030417 TI - How does Pin1 catalyze the cis-trans prolyl peptide bond isomerization? A QM/MM and mean reaction force study. AB - Pin1 represents an enzyme that specifically catalyzes the isomerization of peptide bonds between phosphorylated threonine or serine residues and proline. Despite its relevance as molecular timer in a number of biological processes related to cancer and Alzheimer disease, a detailed understanding of the factors contributing to the catalysis is still missing. In this study, we employ extensive QM/MM molecular dynamics simulations in combination with the mean reaction force (MRF) to discern the influence of the enzyme on the reaction mechanism and the origin of the catalysis. As a recently introduced method, the MRF separates the activation free energy barrier to reach the transition state into structural and electronic contributions providing a more detailed description of the enzyme's function. As a reference, we first study the isomerization starting from the cis form in solution and obtain a free energy barrier and a reaction free energy, which are in agreement with previous studies and experiment. With the new mean reaction force method, intramolecular hydrogen bonds in the peptide were identified that stabilize the transition state and reduce the electronic contribution to the free energy barrier. To elucidate the mechanism of catalysis of Pin1, the reaction in solution and in the catalytic cavity of the enzyme were compared. Both yield the same free energy barrier for the isomerization of the cis form, but with different decomposition in structural and electronic contributions by the mean reaction force. The enzyme reduces the energy required for structural rearrangements to reach the transition state, pointing to a destabilization of the reactant, but increases the electronic contribution to the barrier through specific enzyme-peptide hydrogen bonds. In the reverse reaction, the isomerization of the trans form, the enzyme alters the energetics and the mechanism of the reaction considerably. Unfavorable enzyme peptide interactions in the catalytic cavity during the isomerization change the reaction coordinate, resulting in two minima with small energy differences to the transition state. These small free energy barriers should in principle make the reaction feasible at room temperature once the conformer is bound in the right conformation. PMID- 23030418 TI - Pseudomonas infection in chronic obstructive pulmonary disease. PMID- 23030419 TI - Host detection of pathogen-induced translational inhibition: a new pathogen specific branch of the innate immune system? PMID- 23030421 TI - Latest trends in fungal epidemiology inform treatment choices and stewardship initiatives. AB - Twelve months after the WHO launched its global campaign to safeguard current antimicrobial medicines for future generations, antifungal stewardship initiatives were a major focus for the 2012 European Congress of Clinical Microbiology and Infectious Diseases, in London, UK. Speakers from Europe, North and South America and Asia reported significant variations in fungal epidemiology and resistance, and demonstrated the value of multidisciplinary infectious disease advisory teams in monitoring local trends and making recommendations about the most appropriate antifungal treatment. PMID- 23030423 TI - Detecting risk and predicting patient mortality in patients with extended spectrum beta-lactamase-producing Enterobacteriaceae bloodstream infections. AB - Extended-spectrum beta-lactamases (ESBLs) have been increasingly described worldwide, especially among Enterobacteriaceae isolates, and recently not only in the nosocomial, but also in the community setting. Bloodstream infections (BSIs) caused by ESBL-producing Enterobacteriaceae have been associated with increased rates of treatment failure, mortality and hospital costs. Any delay in the initiation of adequate antibiotic therapy is potentially lethal for patients with BSIs caused by ESBL-producing Enterobacteriaceae. The awareness of changes in bacterial resistance patterns, the careful knowledge of risk factors for ESBL infection and of factors facilitating adverse outcome, giving attention to local epidemiology, can improve the efficacy of empirical treatment protocols. The aim of this review is to focus on the main characteristics of BSIs caused by ESBL producing Enterobacteriaceae, with particular emphasis on risk factors for these infections and factors related to mortality. PMID- 23030424 TI - Instigation of Notch signaling in the pathogenesis of Kaposi's sarcoma-associated herpesvirus and other human tumor viruses. AB - The Notch pathway is a highly conserved signaling circuit with a critical role in cell-fate determination and tumor initiation. Notch is reported to regulate various key events in tumor progression, such as angiogenesis, maintenance of cancer stem cells, resistance to therapeutic agents and metastasis. This review describes the intimate interplay of human tumor viruses with the Notch signaling pathway. Special attention is paid to Kaposi's sarcoma-associated herpesvirus, the etiological agent of Kaposi's sarcoma and rare lymphoproliferative disorders. The past decade of active research has led to significant advances in understanding how Kaposi's sarcoma-associated herpesvirus exploits the Notch pathway to regulate its replication phase and to modulate the host cellular microenvironment to make it more favorable for viral persistence and spreading. PMID- 23030425 TI - Manipulating intestinal immunity and microflora: an alternative solution to viral myocarditis? AB - Viral myocarditis (VMC) is an important cause of heart failure and dilated cardiomyopathy with no effective clinical diagnosis and treatment, and has been commonly associated with Coxsackievirus B3 (CVB3) infection. Current evidence from CVB3 myocarditis in mice indicates that acute myocarditis is mainly mediated by the host immune responses, including Th1, Th17 and type I macrophages. Recently, innate immunity triggered by TLR3, TLR4, TLR8 and MDA5 has also been demonstrated to participate in the induction of inflammatory cytokines in response to CVB3. Apart from the heart tissue, the intestine, which is the assumed initial infection and important replication site for CVB3, needs to be investigated, where induction of innate immunity and interactions with microflora may shape the immune response involved in the pathogenesis of VMC. This review presents recent advances in research into innate and adaptive immunity to CVB3, and provides insights into developing new strategies for the future treatment for VMC. PMID- 23030422 TI - Bacteriophage endolysins as novel antimicrobials. AB - Endolysins are enzymes used by bacteriophages at the end of their replication cycle to degrade the peptidoglycan of the bacterial host from within, resulting in cell lysis and release of progeny virions. Due to the absence of an outer membrane in the Gram-positive bacterial cell wall, endolysins can access the peptidoglycan and destroy these organisms when applied externally, making them interesting antimicrobial candidates, particularly in light of increasing bacterial drug resistance. This article reviews the modular structure of these enzymes, in which cell wall binding and catalytic functions are separated, as well as their mechanism of action, lytic activity and potential as antimicrobials. It particularly focuses on molecular engineering as a means of optimizing endolysins for specific applications, highlights new developments that may render these proteins active against Gram-negative and intracellular pathogens and summarizes the most recent applications of endolysins in the fields of medicine, food safety, agriculture and biotechnology. PMID- 23030426 TI - Atherosclerosis and infection: is the jury still not in? AB - Atherosclerosis is a chronic inflammatory process accounting for increased cardiovascular and cerebrovascular morbidity and mortality. A wealth of recent data has implicated several infectious agents, mainly Chlamydophila pneumoniae, Helicobacter pylori, CMV and periodontal pathogens, in atherosclerosis. Thus, we sought to comprehensively review the available data on the topic, exploring in particular the pathogenetic mechanisms, and discuss anticipated future directions. PMID- 23030429 TI - Scientific validation of the antidiabetic effects of Syzygium jambolanum DC (black plum), a traditional medicinal plant of India. AB - BACKGROUND: In spite of the tremendous progress achieved in medical sciences in the last century, the management of diabetes mellitus, a disease as old as mankind, is poor. Diabetes is currently the world's largest endocrine disorder, and estimates are that it affects almost 5% of the population. Ayurveda, the Indian traditional system of medicine, is one of the world's oldest systems to have documented the diagnosis and treatment of diabetes. METHODS: Experimental studies performed in accordance with the modern medicine principles have shown that some of the medicinal plants and polyherbal preparations made using the plants used in Ayurveda are effective in preventing both hyperglycemia and its complications. Syzygium jambolanum (Syn Syzygium cumini, Eugenia cumini, Eugenia jambolana), commonly known as black plum and originally indigenous to India, is one of the important antidiabetic plants. RESULTS: Jamun has been used in various complementary and alternative systems of medicine and, before the discovery of insulin, was a frontline antidiabetic medication even in Europe. The brew prepared by boiling the Jamun seeds in boiling water has been used in the various traditional systems of medicine in India. CONCLUSIONS: This review includes the validated antidiabetic effects of Jamun and some of its compounds. Emphasis is also placed on addressing the various mechanisms of action contributing to the pharmacological effects and the aspects that need future investigations for Jamun to be of clinical use. PMID- 23030430 TI - Recourse to alternative medicine during pregnancy: motivations of women and impact of research findings. AB - OBJECTIVES: The aims of this study were to gain a better understanding of the motivations of pregnant women utilizing moxibustion for breech presentation and to measure the impact of research results on these patients' treatment decisions regarding this alternative medicine technique. DESIGN: The study involved a statistical analysis of two self-administered questionnaires to 212 women who had previously participated in a randomized clinical trial on the efficacy of moxibustion; in addition, a qualitative thematic content analysis for open-ended questions was also performed. RESULTS: Most women (69%) reported treating themselves at least once with complementary and alternative medicine (CAM). Higher use of CAM was associated with higher education and Caucasian origin. Pregnancy was associated with a significant reduction in utilization of CAMs. After reading the results of a previous randomized clinical trial, which did not demonstrate efficacy of moxibustion, 60% of the women questioned expressed the intention of resorting to this technique in case of a subsequent pregnancy with a fetus in the breech position. The principal motivation was their desire to try anything that may possibly turn such fetuses to increase the chances of delivering them vaginally. CONCLUSIONS: It is important to consider the regard that pregnant women attribute to CAMs for self-care strategies. Despite a lack of scientific evidence supporting the use of moxibustion to address breech presentation, pregnant women consider CAMs, in general, to be safe and effective. Studies investigating the physical and psychologic effects of CAMs will enable clinicians to advise patients better about treatment options. PMID- 23030431 TI - Regulation of tristetraprolin expression by mitogen-activated protein kinase phosphatase-1. AB - Tristetraprolin (TTP) is an acute phase protein, and its expression is rapidly up regulated by inflammatory signals, such as lipopolysaccharide (LPS) and cytokines. TTP regulates gene expression by governing the mRNA stability of its target genes, which include cytokines and growth factors. MAP kinase phosphatase 1 (MKP-1) is a nuclear phosphatase that inhibits p38 mitogen-activated protein kinase (MAPK) signaling. This study investigated the role of MKP-1 in TTP expression in A549 human lung epithelial cells, THP-1 human macrophages, J774 mouse macrophages, and primary mouse macrophages. TTP and MKP-1 expression was increased by cytokines or LPS. Silencing of MKP-1 by siRNA enhanced TTP expression in response to LPS, and LPS-induced TTP expression was increased in macrophages from MKP-1 (-/-) mice as compared with that in macrophages from wild type animals. The inhibition of p38 MAPK by SB202190 reduced TTP expression. In conclusion, MKP-1 suppressed TTP expression by inhibiting p38 MAPK pathway. PMID- 23030432 TI - On-cell MAS NMR: physiological clues from living cells. AB - While structural information on biomolecules is mainly obtained from purified in vitro samples, NMR can also be applied in the context of entire cells or organisms. The present study describes maturation processes in living Salmonella enterica serovar Typhimurium, a prevalent cause for human gastroenteritis. In our physiological study, we follow the composition of the O-antigen on the outer bacterial membrane with high-resolution MAS NMR spectroscopy. We detect and characterize an evolution of the O-antigen composition, in particular of the O acetylation state of the O-antigen, a factor that can play an important role in vaccine development. PMID- 23030433 TI - Abstracts of the 13th World Congress of the International Society for Diseases of the Esophagus. October 15-17, 2012. PMID- 23030434 TI - A direct competitive enzyme-linked immunosorbent assay for rapid detection of anilofos residues in agricultural products and environmental samples. AB - A direct competitive enzyme-linked immunosorbent assay (dc-ELISA) was developed to measure anilofos levels in agricultural and environmental samples. The ELISA was developed using rabbit polyclonal antibodies against a hapten-protein conjugate of anilofos-bovine serum albumin. The limit of detection was 0.1 MUg L( 1), and there was no cross-reactivity with other related pesticides or structurally similar compounds. The matrix effects of rice (aromatic rice, white rice, brown rice), corn, barley, wheat and soil were measured and removed by extraction and dilution with phosphate buffered saline with 0.05% Tween-20. For water samples (tap water and river water), the matrix effects were also removed by dilution with phosphate buffered saline with Tween-20. The detection limits for anilofos in authentic samples (aromatic rice, white rice, brown rice, corn, barley, wheat, soil, tap water and river water) were 2, 2, 2, 3, 2, 2, and 2 MUg kg(-1), and 0.5 and 1 MUg L(-1), respectively . The anilofos recovery ranged from 81.0-116.0% with a coefficient of variation of 1.7-9.0%. The method was validated using GC, and the results showed good correlation with the dc-ELISA data (r(2) = 0.9795). Forty-two cereal samples were randomly collected from different supermarkets and analyzed using the developed dc-ELISA. No anilofos was found in these products. The developed immunoassay is suitable for rapid quantitation of anilofos residues. PMID- 23030435 TI - Synthesis of hapten and production of a monoclonal antibody against a derivative of L-hydroxyproline, a special amino acid in hydrolyzed animal protein. AB - China's government has prohibited the addition of simply hydrolyzed animal protein from solid leather waste into milk. The objective of this study was to produce a monoclonal antibody against L-hydroxyproline, a special amino acid in hydrolyzed animal protein. L-hydroxyproline was derivatized with N acetylsulfanilyl chloride and 5-chlorovaleric acid to synthesize the haptens HP1 and HP2. Then, two immunogens from the two haptens were prepared to produce the antibodies. Results showed that only HP1 was able to stimulate the animal immune system and generate the specific antibody to L-hydroxyproline (as the formation of HP1). The obtained monoclonal antibody from HP1 and the heterologous coating hapten HP2 were incorporated into a competitive indirect enzyme linked immunosorbent assay (ELISA) to determine the antibody's specificity and sensitivity. The IC(50) and the limit of detection for HP1 were 0.16 MUg/mL and 0.05 MUg/mL respectively. The antibody showed low crossreactivity to parental L hydroxyproline and showed negligible crossreactivity to D-hydroxyproline and other amino acids. The monoclonal antibody was therefore suitable for the development of an immunoassay to monitor the simply hydrolyzed animal protein from solid leather waste in foodstuffs with L-hydroxyproline as the target analyte. PMID- 23030436 TI - Nematicidal activity of terpenoids. AB - Thirty four phytoterpenoids were evaluated for their nematicidal effect using the model nematode Caenorhabditis elegans. Nematicidal activities of the tested compounds at concentrations of 50 MUg/mL showed wide variation in their effects ranging from no effect, weak, moderate and strong effects. Terpenoids exerting 50% or higher mortality at 50 MUg/mL were further tested at five different concentrations to calculate the concentration that will kill 50% of the nematode population (LC(50)). Among the most effective terpenoids were carvacrol, thymol, nerolidol, alpha-terpinene, geraniol, citronellol, farnesol, limonene, pseudoionone and eugenol in a descending order. These compounds exhibited a dose dependent effect. The results suggest that the selected monoterpenoids and essential oils with a high concentration of these compounds mayprovide potential natural nematicides and merit further study as botanical nematicides for the control of both plant and animal parasitic nematodes. In general, oxygenated terpenoids and phenolic terpenoids exhibited higher nematicidal activity than hydrocarbons terpenoids. PMID- 23030437 TI - Residue levels of organochlorine pesticides in cattle meat and organs slaughtered in selected towns in West Shoa Zone, Ethiopia. AB - Residue levels of organochlorine pesticides (OCP) in a total of 90 cattle samples comprising meat, liver and kidney collected from carcasses slaughtered in six towns in West Shoa Zone, Ethiopia, (Ambo, Guder, Ginchi, Gedo, Holeta and Tikur Inchini), have been determined. The pesticides were extracted by solid phase extraction (SPE) and quantification was carried out using gas chromatography-mass spectrometry (GC-MS). A good linearity (r(2) > 0.998) was found in the range 0.001-7.00 mg/kg for the samples studied. Most of the pesticides had recoveries in the range 81-99% and values of relative standard deviation (RSD) <7.2% for repeatability and reproducibility, showing good accuracy and precision of the method. The concentration level of the studied organochlorines followed the order: p, p' dichloro-diphenyl-trichloroethane (DDT) > endosulfan>o,p'-DDT >lindane>dieldrin>endrin>aldrin>chlorothanolin while the order of contamination in the analyzed organs was liver > kidney > meat. Heat treatment of the meat, kidney and liver samples (boiling for 90 min.) produced an overall reduction of 62.2%, 44.5%, 37.7%, 29%, 31%, 34.3% and 30.8% in lindane, o, p'-DDT, endosulfan, p, p'-DDT, chlorothanolin, aldrin, dieldrin, and endrin, respectively. Although the residual contents of the organochlorines detected in all the contaminated samples analyzed from the six cities were below the respective maximal permissible levels set by international organizations, samples from Holeta town were more contaminated and may necessitate effective monitoring as bioaccumulation of these residues may pose health problems in human beings. PMID- 23030438 TI - Immunotoxic damage in floriculturists exposed to pesticide mixtures. AB - The aim of the present work was to determine if the use of pesticide mixtures produced alterations in immunotoxicity biomarkers. The study was undertaken in three groups: the first group consisted of 38 floriculturists, the second comprised 38 vendors of the local market, and the last comprised 33 non-exposed persons from another locality. The determinations included haematocrit, mean cellular volume, hemoglobin, number of erythrocytes and leukocytes, immunoglobulins (IgA, IgG, IgM, and IgE), percentage of T-lymphocytes, and mitotic index from lymphocyte cultures with and without phytohaemagglutinin (PHA). The obtained results indicated the following: (i) in the level of the studied immunoglobulins, the results were within the reference values; (ii) there was a reduction in the amount of T-lymphocytes in the floriculturists in comparison with the determined in the other two groups; (iii) there was a decrease in the mitotic index of PHA-stimulated lymphocyte cultures of floriculturists and vendors in relation to the value of the control group; (iv) there was an increase in the mitotic index of unstimulated lymphocytes of floriculturists compared with the lymphocytes of the other two groups; and (v) there was no correlation between the results and the personal characteristics of the studied individuals. Our results established an immunotoxic effect in the floriculturists exposed to pesticides. PMID- 23030439 TI - Effects of carbon amendment on in situ atrazine degradation and total microbial biomass. AB - This study elucidates the effects of carbon amendment on metabolic degradation of atrazine (6-chloro-N(2)-ethyl-N(4)-isopropyl-1,3,5-triazine-2,4-diamine) and total microbial biomass in soil. Degradation of (14)C-ring-labelled atrazine was monitored in laboratory incubations of soils supplemented with 0, 10, 100 and 1000 MUg g(-1) sucrose concentrations. An experiment to determine the effect of carbon amendment on total microbial biomass and soil respiration was carried out with different concentrations of sucrose and non-labelled atrazine. The soils were incubated at a constant temperature and constant soil moisture at water potential of -15 kPa and a soil density of 1.3 g cm(-3). Mineralization of (14)C ring-labelled atrazine was monitored continuously over a period of 59 d in the first experiment. The CO(2) production was monitored for 62 d in the second experiment and microbial biomass determined at the end of the incubation period. The addition of 1000 MUg g(-1) sucrose reduced atrazine mineralization to 43.5% compared to 51.7% of the applied amount for the treatment without sucrose. The addition of 1000 MUg g(-1) sucrose modified the transformation products to 1.08 MUg g(-1) deisopropylatrazine (DIA), 0.32 MUg g(-1) desethylatrazine (DEA) and 0.18 MUg g(-1) deisopropyl-2-hydroxyatrazine (OH-DIA). Treatment without sucrose resulted in formation of 0.64 MUg g(-1) hydroxyatrazine (HA), 0.28 MUg g(-1) DIA and 0.20 MUg g(-1) OH-DIA. Atrazine dealkylation was enhanced in treatments with 100 and 1000 MUg g(-1) of sucrose added. HA metabolite was formed in the control (no sucrose) and in the presence of 10 MUg g(-1) of sucrose, whereas DEA was only detected in treatment with 1000 MUg g(-1) sucrose. Results indicate that total microbial biomass increased significantly (P < 0.001) with the addition of 1000 MUg g(-1) sucrose. PMID- 23030440 TI - Phylogenetic changes in soil microbial and diazotrophic diversity with application of butachlor. AB - We investigated changes in population and taxonomic distribution of cultivable bacteria and diazotrophs with butachlor application in rice paddy soils. Population changes were measured by the traditional plate-count method, and taxonomic distribution was studied by 16S rDNA sequencing, then maximum parsimony phylogenic analysis with bootstrapping (1,000 replications). The bacterial population was higher after 39 than 7 days of rice cultivation, which indicated the augmentation of soil microbes by rice root exudates. The application of butachlor increased the diazotrophic population in both upper (0-3 cm) and lower (3-15 cm) layers of soils. Especially at day 39, the population of diazotrophs was 1.8 and 1.6 times that of the control in upper and lower layer soils, respectively. We found several bacterial strains only with butachlor application; examples are strains closest to Bacillus arsenicus, B. marisflavi, B. luciferensis, B. pumilus, and Pseudomonas alvei. Among diazotrophs, three strains closely related to Streptomyces sp. or Rhrizobium sp. were found only with butachlor application. The population of cultivable bacteria and the species composition were both changed with butachlor application, which explains in part the contribution of butachlor to augmenting soil nitrogen-fixing ability. PMID- 23030441 TI - Sensitivity of different aquatic bioassays in the assessment of a new natural formicide. AB - Agrochemicals have the potential to cause deleterious effects on living organisms and therefore they must be subjected to various (eco)toxicological studies and monitoring programs in order to protect human health and the environment. The aim of this study was to assess the ecotoxicity of a new natural formicide with a battery of three classical and three ecotox-kit tests. The former tests were performed with Aliivibrio fischeri bacteria (Lumistox test), the cladoceran Daphnia magna and Pseudokirchneriella subcapitata algae, and the latter with Thamnotoxkit F(TM) (Thamnocephalus platyurus), Ostracodtoxkit F(r) (Heterocypris incongruens) and LuminoTox (photosynthetic enzyme complexes). In the range of formicide concentrations tested (from 0.06 to 2.0 g L(-1)), the measurement endpoint values varied from 0.79 g L(-1) for the algal test to > 2 g L(-1) for the LuminoTox and Ostracodtoxkit F(r) tests. Hierarchical sensitivity ranking based on the no-observed effect concentration (NOEC) values established to assess the formicide ecotoxicity was as follows: algal growth inhibition test ~ daphnid immobilization test ~ bacterial luminescence inhibition test > Thamnotoxkit FTM > LuminoTox > Ostracodtoxkit F(r). Overall, results from the battery of bioassays showed that this formicide preparation presents low ecotoxicity as compared to the aquatic ecotoxicity of presently commercialized formicides. In conclusion, classical aquatic bioassays are more sensitive than ecotox-kit tests in the assessment and monitoring of the new natural formicide. PMID- 23030442 TI - Antimicrobial properties of three lactic acid bacterial cultures and their cell free supernatants against Listeria monocytogenes. AB - Control of Listeria monocytogenes in ready-to-eat (RTE) food products is a significant challenge and improved means for control are needed. In this study, the anti-listerial effects of three lactic acid bacteria (LAB) were investigated. Spot-on-lawn assays demonstrated the largest zones of inhibition against L. monocytogenes were produced by the Pediococcus acidilactici strain, with zone diameters ranging from 13 to 18 mm. Minimum inhibitory concentration (MIC) experiments using cell free supernatant (CFS) from the LAB revealed that while two of the strains were effective at inhibiting L. monocytogenes growth only up to a 1:4 dilution, P. acidilactici was able to inhibit growth up to a 1:256 dilution. Survival assays performed at 7 degrees C determined that the P. acidilactici strain was capable of producing a 4.5 log reduction in L. monocytogenes counts and maintaining the reduction for 21 days. The effectiveness of P. acidilactici was reduced under log phase growth, autoclaving for longer than 15 min (121 degrees C and 15 psi), and treatment with proteinase K (25 mg/mL). PMID- 23030443 TI - Accumulation of elements by edible mushroom species: part I. Problem of trace element toxicity in mushrooms. AB - The aim of this study was to evaluate Cd, Co, Cu, Hg, Ni, Pb, Sr and Zn accumulation in six edible mushroom species and to assess their risk and benefits to human consumers. Mushrooms (Leccinium aurantiacum, Xerocomus badius, Lactarius deliciosus, Boletus edulis, Cantharellus cibarius and Suillus luteus) were collected from selected regions of Poland during 1990-2010. The highest diversity between studied mushroom species was observed in terms of Cu and Zn accumulation. Significant differences in the accumulation efficiency were found among the six mushroom species examined. The most efficient were Boletus edulis (Cd and Hg), Suillus luteus (Cu and Sr), and Lactarius deliciosus (Pb and Zn). In the case of Co and Ni, the most effective were Xerocomus badius and Leccinium aurantiacum, respectively. The calculated bioconcentration factor (BCF) values of Cd, Cu, Hg, Sr and Zn were > 1 for all species in this study while Co, Ni and Pb usually were bioexcluded (BCF < 1). Additionally, based on the calculated daily intake rates of trace elements determined it can be concluded that occasional consumption of fruiting bodies of L. aurantiacum, X. badius, L. deliciosus, B. edulis, C. cibarius and S. luteus collected in Poland is safe and this finding largely agrees with results from recent studies by other authors. PMID- 23030444 TI - Roles of SM22alpha in cellular plasticity and vascular diseases. AB - SM22alpha is a shape change and transformation sensitive 22 kDa actin-binding protein of the calponin family. It is ubiquitous to vascular and visceral smooth muscle, and is an early marker of smooth muscle differentiation. It is also present in fibroblasts, and some epithelium. SM22alpha may be involved in calcium independent smooth muscle contraction. Recent evidence suggests that disruption of SM22alpha induces vascular inflammation and is involved in osteochondrogenesis in arterial diseases. This is consistent with activation of NF-kappaB signaling, where NF-kappaB activity is upregulated in vascular injury. High expression of SM22alpha inhibits cell proliferation in VSMCs and in injured arteries. SM22alpha acts as a tumor suppressor. Loss of its expression is an early event in cell transformation and the development of some tumors, coinciding with cellular plasticity. PMID- 23030445 TI - Platelets in thrombosis and hemostasis: old topic with new mechanisms. AB - Platelets are small anucleate cells generated from megakaryocytes in the bone marrow. After being released into the circulation, platelets play key roles in the surveillance of vascular injury, and can quickly adhere and aggregate at the site of injury, which are critical events for vascular repair and hemostasis. However, the same biological processes of platelet adhesion and aggregation may also cause thrombotic disorders. The formation of a platelet plug at sites of atherosclerotic lesion rupture is the most common mechanism leading to myocardial or cerebral infarction. Platelet-related deep vein thrombosis is also one of the leading causes of mortality worldwide. The contribution of several platelet receptors and their ligands has been highlighted in these processes. In platelet adhesion, particularly at high shear stress, GPIbalpha-von Willebrand factor (VWF) interaction may initiate this event, which is followed by GPVI signalling and firm platelet adhesion mediated by members of the integrin family, such as beta3 (alphaIIbbeta3) and beta1 (alpha2beta1, alpha5beta1) integrins. In platelet aggregation, although GPIbalpha-VWF, P selectin-sulfatides, and other molecules, may be involved, the process is mainly mediated by beta3 (alphaIIbbeta3) integrin and its ligands, such as fibrinogen and VWF. It is intriguing that platelet adhesion and aggregation still occur in mice lacking both fibrinogen and VWF, suggesting that other unforeseen molecule(s) may also be important in these processes. Identification and characterization of these molecules will enrich our knowledge in the basic science of hemostasis and thrombosis, and may lead to the development of new therapies against bleeding disorders and thrombotic diseases. PMID- 23030446 TI - Regulation of intestinal chylomicron production by glucagon-like peptides. AB - Apolipoprotein B48 (apoB48)-containing triglyceride-rich lipoproteins are atherogenic and therefore it is important to understand factors that regulate their metabolism in the intestine. Insulin resistant states are associated with increased intestinal output of apo B48, but the mechanistic studies explaining this overproduction have relied heavily on models of diet-induced insulin resistance. There is evidence that glucagon-like peptide (GLP) secretion is diminished in insulin resistant and diabetic states, which may have implications for postprandial lipid secretion. This review presents a survey of studies on GLPs and intestinal lipoprotein metabolism, along with some insights into the net physiological significance of GLP action in postprandial lipoprotein metabolism. Studies with GLP-1 receptor agonists and dipeptidyl peptidase-IV inhibitors have indicated that GLP-1 in pharmacological and physiological doses can inhibit intestinal TRL production. On the other hand, GLP-2 has an acute stimulatory effect on intestinal apoB48 secretion. Modulating GLP action may serve as a strategy to improve postprandial dyslipidemia in insulin resistant states. PMID- 23030447 TI - Citrus flavonoids and the prevention of atherosclerosis. AB - Epidemiological studies have demonstrated that diets rich in fruits and vegetables can prevent or delay the onset of many chronic diseases including cardiovascular disease (CVD). While more current research has begun to focus on the effects of specific polyphenol compounds found in fruits and vegetables, mechanistic insights have been hampered by the multiple simultaneous effects these compounds may have on the disease process. In this article, we review the basic research studies that have evaluated the effects of citrus flavonoids to: improve dyslipidemia, normalize glucose homeostasis, prevent oxidative stress, and attenuate inflammation, which collectively have the ability to enhance metabolic health and improve CVD risk. PMID- 23030448 TI - A review of obesity and body fat distribution and its relationship to cardio metabolic risk in men and women of Chinese origin. AB - Obesity is increasing in people of Chinese background whether in China or in other countries. The purpose of this review is to discuss the associations of obesity in men and women of Chinese background with cardio-metabolic risk with specific attention to body fat distribution. Evidence suggests that current BMI and WC targets may actually underestimate the cardio-metabolic risk in Chinese compared to European populations from which they were derived. Through a number of investigations, we and others have identified that Chinese men and women tend to have higher cardio-metabolic risk factors at a given body size than people of European background (from which guidelines are generally derived). Our additional investigations have indicated that Chinese men and women have greater amounts of VAT, but similar amounts of DSAT at a given body fat than Europeans and it may be the higher VAT in Chinese people that is, in part, responsible for the greater cardio-metabolic risk in the Chinese. Further investigation of this topic should prove fruitful in shedding light onto the determinants of body fat accumulation and distribution that may help to inform obesity prevention and treatment strategies. PMID- 23030449 TI - Mitochondrial dysfunction, oxidative stress and diabetic cardiovascular disorders. AB - The prevalence of diabetes has been rapidly increasing in world-wide countries. The dominant cause of mortality in diabetic patients is cardiovascular complications. Mechanism for the susceptibility of diabetic patients to cardiovascular disorders remains unclear. Elevated oxidative stress was detected in diabetic patients or in animal models. Mitochondria are one of major sources of reactive oxygen species (ROS) in cells. Mitochondrial dysfunction and DNA mutations have been detected in diabetic patients. Diabetes-associated metabolic disorders, including hyperglycemia, hypertriglyceridemia, hypercholesterolemia, hypoalphalipoproteinemia, and increased levels of advanced glycation end products, glycated and oxidized lipoproteins, are associated with oxidative stress. Glycated or oxidized low density lipoproteins (LDL) impair the activities of mitochondrial respiratory chain complex enzymes in vascular endothelial cells (EC). Dysfunction in mitochondrial respiration may increase the formation of ROS in mitochondria. NADPH oxidase (NOX) generates ROS in cytosol. Increased NOX activity was detected in diabetic patients. Glycated and oxidized LDL increase the expression of NOX and ROS production in EC. Diabetes-associated metabolic disorders may lead to mitochondrial dysfunction, NOX activation and excess ROS production, which results in oxidative stress and promotes cardiovascular disorders in diabetic patients. Statins, metformin and anthocyanidins may help to attenuate oxidative stress in vasculature induced by diabetes-associated metabolic disorders. PMID- 23030450 TI - Regulatory role of Brg1 and Brm in the vasculature: from organogenesis to stress induced cardiovascular disease. AB - ATPase-dependent chromatin remodeling complex encompasses a group of evolutionarily conserved proteins that utilize energy derived from ATP hydrolysis to drive nucleosome movement contributing to transcriptional regulation. Brahma related gene 1 (Brg1) and Brahma (Brm) are the core components of the mammalian remodeling complex. The past decade has witnessed a great expansion in our knowledge regarding the role of Brg1 and Brm in modulating the function of the cardiovascular system (CVS) under both physiological conditions and disease states owing much to the availability of tissue-specific Brg1/Brm-null animals. This review summarizes the current proceedings on how Brg1 and Brm contribute to the morphogenesis within the CVS and importantly, how Brg1 and Brm maintain the homeostasis of adult organisms, the disruption of which bears clear implications in the pathogenesis of such cardiovascular diseases as atherosclerosis and cardiac hypertrophy. PMID- 23030451 TI - Human apolipoprotein C-III - a new intrahepatic protein factor promoting assembly and secretion of very low density lipoproteins. AB - Apolipoprotein (apo) C-III is a small protein (79 amino acids) and a component of triacylglycerol (TAG)-rich very low density lipoproteins (VLDL) and high density lipoproteins. We have unraveled a new intracellular role of apoCIII in promoting hepatic VLDL(1) (Sf > 100) assembly/secretion under lipid-rich conditions. Feeding apoc3-null mice with a high fat diet for two weeks or palm oil gavage failed to stimulate VLDL(1) production in vivo. Reconstitution of apoC-III expression using adenovirus encoding human apoC-III resulted in robust production of VLDL(1) containing apoB-100 or apoB-48. The stimulatory effect of human apoC III on the assembly and secretion of VLDL(1) was recapitulated ex vivo in McA RH7777 cells cultured in lipid-rich media. Metabolic labeling experiments showed that apoC-III plays a central role in (i) the formation of lumenal lipid droplets (LLD) rich in TAG, and (ii) promoting bulk TAG incorporation during VLDL(1) assembly. Structure-function analysis of naturally occurring apoC-III variants (Ala23Thr and Lys58Glu) defined two functional domains that play respective roles in LLD formation and VLDL(1) assembly. Unraveling the intracellular role of apoC III in the atherogenic TAG-rich VLDL(1) production provides new insights into the strong influence of the APOA5-A4-C3-A1 gene locus on plasma TAG concentrations and premature atherosclerosis. PMID- 23030452 TI - Cyclooxygenase-2 expression, prostacyclin production and endothelial protection of high-density lipoprotein. AB - Atherosclerosis is a multi-factorial inflammatory disease with accumulation of lipids and recruitment of leukocytes into the subendothelial space. Due to the consistent inflammation in vessels, a subset of atherosclerotic plaques is even prone to physical disruption or producing thrombosis that triggers acute coronary syndromes (ACS). Cyclooxygenase (COX) and the downstream diverse prostanoids are involved in numerous physiological activities and inflammatory processes. Remarkably, prostanoids are a group of bioactive lipid mediators, and play a series of complicated and even contradictory roles during the progression of atherogenesis. Some, mainly prostacyclin (PGI2) have cardioprotective effects to inhibit the aggravation of atherosclerosis, however, others including prostaglandin E2 (PGE2) and thromboxane A2 (TXA2), increase the risk of cardiovascular thromboembolic events. Therefore, the controversial effects bring about a debate on the use of cyclooxygenase-2 (COX-2) specific and non-specific inhibitors in the prevention from cardiovascular diseases. In addition to reverse cholesterol transport (RCT), high-density lipoprotein (HDL) exerts several beneficial effects on endothelial protection. Moreover, HDL could also regulate the expression of COX-2 and the production of PGI2 in endothelial cells. While as a diverse complex of heterogeneous particle composed of various apolipoproteins, enzymes and lipids, the individual components of HDL, such as apolipoprotein A-I (apoA-I) and sphingosine-1-phosphate (S1P), have distinct effects on COX-2 expression and PGI2 production in endothelial cells. In the present review, we summarize the roles of COX-2 as well as PGI2 in atherosclerosis and atherothrombosis, the controversial vascular effects on prostanoid inhibition by COX-2 inhibitors, and the effects of HDL on the endothelial protection by the upregulation of COX-2 and the release of PGI2 during the progression of atherosclerosis. PMID- 23030454 TI - Molecular dynamics simulation to investigate the impact of disulfide bond formation on conformational stability of chicken cystatin I66Q mutant. AB - Chicken cystatin (cC) mutant I66Q is located in the hydrophobic core of the protein and increases the propensity for amyloid formation. Here, we demonstrate that under physiological conditions, the replacement of Ile with the Gln in the I66Q mutant increases the susceptibility for the disulfide bond Cys71-Cys81 to be reduced when compared to the wild type (WT) cC. Molecular dynamics (MD) simulations under conditions favoring cC amyloid fibril formation are in agreement with the experimental results. MD simulations were also performed to investigate the impact of disrupting the Cys71-Cys81 disulfide bond on the conformational stability of cC at the atomic level, and highlighted major disruption to the cC appendant structure. Domain swapping and extensive unfolding has been proposed as one of the possible mechanisms initiating amyloid fibril formation by cystatin. Our in silico studies suggest that disulfide bond formation between residues Cys95 and Cys115 is necessary to maintain conformational stability of the I66Q mutant following breakage of the Cys71-Cys81 disulfide bridge. Subsequent breakage of disulfide bond Cys95-Cys115 resulted in large structural destabilization of the I66Q mutant, which increased the alpha beta interface distance and expanded the hydrophobic core. These experimental and computational studies provide molecular-level insight into the relationship between disulfide bond formation and progressive unfolding of amyloidogenic cC mutant I66Q. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:23. PMID- 23030453 TI - Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression. AB - Bcl-2 and Bcl-xL antiapoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3 carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with K(i) < 1 nM and has low nanomolar IC(50) values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete, and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose schedule. PMID- 23030455 TI - Characteristics of children with positive coeliac serology and normal villous morphology: potential coeliac disease. AB - Positive coeliac serology with normal villous morphology (NVM) indicates potential coeliac disease (CD). Few studies have compared characteristics of NVM vs villous atrophy in patients with positive serology. Our aim was to determine the independent clinical predictors of NVM in children with positive CD serology. We performed a structured medical record review of patients aged 1-19 years who presented for an initial CD evaluation between 2000 and 2010 at a large teaching hospital. Data collection included demographics, medical history, prior history of gluten avoidance, CD-specific serology, oesophagogastroduodenoscopy and histopathology. Predictors of NVM (vs Marsh III) were determined using multivariable logistic regression. Among 320 patients with positive serology, we identified 62 patients (19%, 95% CI 15-24) with NVM (i.e. potential CD). Younger children may have been more likely to exhibit NVM (p = 0.06). Three significant predictors of NVM were prior gluten avoidance (OR 4.17, 95% CI 1.02-17.13), positive tissue transglutaminase antibody but <100 U/mL (OR 14.75, 95% CI 3.33 65.30), and absence of gross duodenal abnormalities (OR 3.48, 95% CI 1.51-8.03). Among children with positive CD serology, prior gluten avoidance predicts NVM. Future studies are warranted on the impact of gluten intake and CD testing in children without prior established CD diagnosis. PMID- 23030456 TI - North American transmission of hemosporidian parasites in the Swainson's thrush (Catharus ustulatus), a migratory songbird. AB - The geographic structuring of parasite communities across the range of a single host species can illuminate patterns of host-population connectivity. To determine the location of parasite transmission in a Neotropical migrant bird species, we sampled adult and hatch-year (HY) birds across the breeding and wintering range of the Swainson's thrush (SWTH), an abundant passerine with a migratory divide. We examined the phylogenetic relationships among cytochrome b lineages of the avian blood parasite genera Haemoproteus, Plasmodium, and Leucocytozoon and determined the transmission location of unique lineages. We found that Haemoproteus and Plasmodium lineages are transmitted on California breeding grounds, whereas Leucocytozoon transmission occurs on Alaskan breeding grounds. The presence of hemosporidians on wintering grounds and shared lineages between the SWTH and resident species suggests that transmission of some of these lineages occurs on both breeding and wintering grounds. We emphasize that the sampling of HY birds and local resident heterospecifics will supplement vector studies to determine the key players in hemosporidian host switching and range expansion events. PMID- 23030457 TI - Comparative stroke risk of antiepileptic drugs in patients with epilepsy. AB - PURPOSE: Patients with epilepsy have higher stroke-related morbidity and mortality, leading to the suspicion that the increased stroke events may be associated with antiepileptic drug (AED) exposure. We evaluated the comparative risk of stroke in adult patients with epilepsy receiving phenytoin (PHT), valproic acid (VPA), or carbamazepine (CBZ) to help determine the stroke risk for Asian patients with specific AED exposure. METHODS: We conducted a population based, retrospective cohort study using the Taiwan National Health Insurance Research Database (NHIRD). The cohort consists of adult patients with epilepsy who were new to PHT, CBZ, or VPA monotherapy and without prior stroke history. Patients were followed for 5 years. The event of interest was a hospitalization or emergency visit due to stroke. Cox proportional hazard models were used to estimate the comparative risk of AEDs. Subanalyses included an evaluation of different subtypes of stroke, the propensity score matched technique, the intention-to-treat approach, and stratification analyses. KEY FINDINGS: Patients receiving PHT had a significantly higher stroke risk (adjusted hazard ratio [HR] 1.72; 95% confidence interval [CI] 1.20-2.47), followed by VPA (adjusted HR 1.27; 95% CI 0.78-2.07), when compared with CBZ. The results of all subanalyses showed a consistent trend of higher stroke risk with PHT use. In addition, there appeared to be a dose-response relationship between stroke risk and PHT prescriptions. SIGNIFICANCE: The stroke risk was higher in PHT but not significantly different in VPA as compared to CBZ. Physicians should reconsider using PHT for patients with epilepsy who already have a higher risk of stroke. PMID- 23030459 TI - Facile "modular assembly" for fast construction of a highly oriented crystalline MOF nanofilm. AB - The preparation of crystalline, ordered thin films of metal-organic frameworks (MOFs) will be a critical process for MOF-based nanodevices in the future. MOF thin films with perfect orientation and excellent crystallinity were formed with novel nanosheet-structured components, Cu-TCPP [TCPP = 5,10,15,20-tetrakis(4 carboxyphenyl)porphyrin], by a new "modular assembly" strategy. The modular assembly process involves two steps: a "modularization" step is used to synthesize highly crystalline "modules" with a nanosized structure that can be conveniently assembled into a thin film in the following "assembly" step. With this method, MOF thin films can easily be set up on different substrates at very high speed with controllable thickness. This new approach also enabled us to prepare highly oriented crystalline thin films of MOFs that cannot be prepared in thin-film form by traditional techniques. PMID- 23030458 TI - Long-circulating PEG-PE micelles co-loaded with paclitaxel and elacridar (GG918) overcome multidrug resistance. AB - Overexpression of drug efflux pump P-gp is one of the major reasons to cause multidrug resistance (MDR). To overcome P-gp mediated MDR, modulators, so called P-gp inhibitors, can be used to block efflux pump activity. Elacridar is one of the most potent P-gp inhibitors, which can cause irreversible and total P-gp blockage. Elacridar, among with other P-gp inhibitors, can be used in combination with anticancer drugs to enhance the effectiveness of chemotherapy against resistant tumor cells. On the other hand, P-gp is presented in normal tissues, thus non-selective blockage of P-gp can cause undesired side effects. Therefore, it is important to deliver P-gp inhibitor only to the tumor cells (along with anticancer drug) and limit its distribution in the body. In this study, we have developed PEG-PE-based long-circulating ca. 15 nm micelles co-loaded with elacridar and paclitaxel, and investigated their ability to overcome paclitaxel resistance in two cancer cell lines. Vitamin E, a common solubility enhancer for PEG-PE micelles, was found to have a negative effect on both particle size and encapsulation efficiencies. The human MDR1 gene-transfected and thus paclitaxel resistant MDCKII-MDR1 P-gp overexpressing cells were used for cytotoxicity evaluation. Even though PEG-PE based micelles itself have a potential to enhance the cytotoxicity of paclitaxel, elacridar/paclitaxel-co-loaded micelles demonstrated the highest cytotoxicity compared to both free and micellar paclitaxel. The obtained results suggest that co-loading of paclitaxel and elacridar into micellar drug carriers results in promising preparations capable of overcoming paclitaxel resistance. PMID- 23030460 TI - N-Heterocyclic carbene dichotomy in Pd-catalyzed acylation of aryl chlorides via C-H bond functionalization. AB - The first Pd-catalyzed intramolecular acylation of aryl chlorides via C-H bond functionalization is presented. The method allows for the synthesis of a variety of elusive benzocyclobutenones with a wide range of functional groups and substitution patterns. We demonstrate that a change in the ligand backbone dictates the selectivity pattern. PMID- 23030461 TI - Increased frequency of Attention Deficit Hyperactivity Disorder (ADHD) in acne versus dermatologic controls: analysis of an epidemiologic database from the US. AB - INTRODUCTION: Acne can be associated with psychiatric morbidity and suicide, which have sometimes been considered an adverse reaction to some acne therapies such as isotretinoin. A recent population-based study reports that suicide in acne is related to the psychosocial burden of substantial acne, rather than medication effects. As suicidality is not always directly related to acne severity, factors other than acne's direct psychosocial burden also likely contribute to the suicide risk. Attention Deficit Hyperactivity Disorder (ADHD) is a disorder of childhood and adolescence that is associated with increased suicidality. We examined the frequency of ADHD in acne versus all other dermatology-related patient visits, after controlling for age and other factors. METHODS: Retrospective cross-sectional study of epidemiologic databases (NAMCS and NHAMCS) representing 55 825 dermatology outpatient visits from 1995 to 2009. RESULTS: In comparison to other dermatologic disorders, acne was over two times more likely to be associated with ADHD (odds ratio = 2.34, 95%CI 1.06-5.14) after controlling for the possible confounding effects of age, sex, stimulant medications, comorbid anxiety or depressive disorders, and atopic dermatitis, a condition previously associated with ADHD. DISCUSSION: Our preliminary findings suggest a significant association of acne with ADHD, which could contribute to the increased psychological morbidity and suicidality in some acne patients. PMID- 23030462 TI - Inactivation of bacteriophage MS2 with potassium ferrate(VI). AB - Ferrate [Fe(VI); FeO(4)(2-)] is an emerging oxidizing agent capable of controlling chemical and microbial water contaminants. Here, inactivation of MS2 coliphage by Fe(VI) was examined. The inactivation kinetics observed in individual batch experiments was well described by a Chick-Watson model with first-order dependences on disinfectant and infective phage concentrations. The inactivation rate constant k(i) at a Fe(VI) dose of 1.23 mgFe/L (pH 7.0, 25 degrees C) was 2.27(+/-0.05) L/(mgFe * min), corresponding to 99.99% inactivation at a Ct of ~4 (mgFe * min)/L. Measured k(i) values were found to increase with increasing applied Fe(VI) dose (0.56-2.24 mgFe/L), increasing temperature (5-30 degrees C), and decreasing pH conditions (pH 6-11). The Fe(VI) dose effect suggested that an unidentified Fe byproduct also contributed to inactivation. Temperature dependence was characterized by an activation energy of 39(+/-6) kJ mol(-1), and k(i) increased >50-fold when pH decreased from 11 to 6. The pH effect was quantitatively described by parallel reactions with HFeO(4)(-) and FeO(4)(2-). Mass spectrometry and qRT-PCR analyses demonstrated that both capsid protein and genome damage increased with the extent of inactivation, suggesting that both may contribute to phage inactivation. Capsid protein damage, localized in the two regions containing oxidant-sensitive cysteine residues, and protein cleavage in one of the two regions may facilitate genome damage by increasing Fe(VI) access to the interior of the virion. PMID- 23030463 TI - Improved Candida methylica formate dehydrogenase fermentation through statistical optimization of low-cost culture media. AB - NAD+-dependent formate dehydrogenase (FDH, EC 1.2.1.2) is of use in the regeneration of NAD(P)H coenzymes, and therefore has strong potential for practical application in chemical and medical industries. A low-cost production of recombinant Escherichia coli (E. coli) containing FDH from Candida methylica (cmFDH) was optimized in molasses-based medium by using response surface methodology (RSM) based on central composite design (CCD). The beet molasses as a sole carbon source, (NH4)2HPO4 as a nitrogen and phosphorus source, KH2PO4 as a buffer agent, and Mg2SO4 . 7H2O as a magnesium and sulfur source were used as variables in the medium. The optimum medium composition was found to be 34.694 g L-1 of reducing sugar (equivalent to molasses solution), 8.536 g L-1 of (NH4)2HPO4, 3.073 g L-1 of KH2PO4, and 1.707 g L-1 of Mg2SO4 . 7H2O. Molasses based culture medium increased the yield of cmFDH about three times compared to LB medium. The currently developed media has the potential to be used in industrial bioprocesses with low-cost production. PMID- 23030464 TI - Synthesis of a precursor tripeptide Z-Asp-Val-Tyr-OH of thymopentin by chemo enzymatic method. AB - The precursor tripeptide of thymopentin was synthesized by a combination of chemical and enzymatic methods. First, Val-Tyr-OH dipeptide was synthesized by a novel chemical method in two steps involving preparation of NCA-Val. Second, the linkage of the third amino acid Z-Asp-OMe to Val-Tyr-OH was completed by an enzymatic method under kinetic control. An industrial alkaline protease alcalase was used in water-organic cosolvent systems. The synthesis reaction conditions were optimized by examining the effects of several factors including organic solvents, water content, temperature, pH, and reaction time on the yield of Z-Asp Val-Tyr-OH. The optimum condition is of pH 10.0, 35 degrees C, acetonitrile/Na2CO3-NaHCO3 buffer system (85:15, v/v), and reaction time of 2.5 hr, which achieves tripeptide yield of more than 70%. PMID- 23030465 TI - Statistical optimization of green fluorescent protein production from Escherichia coli BL21(DE3). AB - An optimized cultivation condition is needed to maximize the functional green fluorescent protein (GFP) production. Six process variables (agitation rate, temperature, initial medium pH, concentration of inducer, time of induction, and inoculum density) were screened using the fractional factorial design. Three variables (agitation rate, temperature, and time of induction) exerted significant effects on functional GFP production in E. coli shake flask cultivation and were optimized subsequently using the Box-Behnken design. An agitation rate of 206 rpm at 31 degrees C and induction of the protein expression when the cell density (OD(600nm)) reaches 1.04 could enhance the yield of functional GFP production from 0.025 g/L to 0.241 g/L, which is about ninefold higher than the unoptimized conditions. Unoptimized cultivation conditions resulted in protein aggregation and hence reduced the quantity of functional GFP. The model and regression equation based on the shake flask cultivation could be applied to a 2-L bioreactor for maximum functional GFP production. PMID- 23030466 TI - Synthesis of folate receptor-targeted and Doxorubicin-coupled chemotherapeutic nanoconjugate and research into its medical applications. AB - Folate-targeted drug delivery has become an alternative therapy for the treatment of various cancers. Folate receptors are known to be responsible for cellular accumulation of folate and folate analogs with high binding affinity. The anthracycline antibiotic doxorubicin has a broad spectrum of antineoplastic action and a correspondingly widespread degree of clinical use. In this work, we aimed to prepare a folate receptor-targeted doxorubicin delivery system to achieve minimal effect of doxorubicin on healthy cells and more cytotoxicity of it on tumor cells. Folate-poly(ethylene glycol)-doxorubicin (FOL-PEG-DOX) nanoconjugate was synthesized through this aim and characterized with nuclear magnetic resonance (NMR), zetasizer, and atomic force microscopy (AFM). Doxorubicin release studies were also performed in vitro. The size of FOL-PEG-DOX was 78.84 nm. The results indicated that doxorubicin release rate from the conjugate was faster at pH 5.0 than pH 7.4 and the amide bond between DOX and PEG was more stable at pH 7.4 than pH 5.0. As a consequence, FOL-PEG-DOX nanoconjugate could be a potentially useful delivery system for folate receptor positive cancer cells. PMID- 23030467 TI - The effect of temperature on L-lactic acid production and metabolite distribution of Lactobacillus casei. AB - The effect of temperature on the growth and L-lactic acid production of Lactobacillus casei G-03 was investigated in a 7-L bioreactor. It was found that the maximum specific growth rate (0.27 hr-1) and L-lactic acid concentration (160.2 g L-1) were obtained at a temperature of 41 degrees C. Meanwhile, the maximum L-lactic acid yield, productivity, and dry cell weight were up to 94.1%, 4.44 g L-1 hr-1, and 4.30 g L-1, respectively. At lower or higher temperature, the Lactobacillus casei G-03 showed lower acid production and biomass. Moreover, the main metabolite distribution of strain G-03 response to variations in temperatures was studied. The results suggested that temperature has a remarkable effect on metabolite distribution, and the maximum carbon flux toward lactic acid at the pyruvate node was obtained at 41 degrees C, which had the minimum carbon flux toward acetic acid. PMID- 23030468 TI - Kinetic studies of L-asparaginase from Penicillium digitatum. AB - L-Asparaginase is an enzyme used in the treatment of acute lymphoblastic leukemia and other related malignancies. Its further use includes reduction of asparagine concentration in food products, which may lead to formation of acrylamide. Currently bacterial asparaginase is produced at industrial scale, but the enzyme isolated from bacterial origin is often associated with adverse reactions. These side effects require development of asparaginase from alternative sources. In the present study, Penicillium digitatum was explored for the production of extracellular L-asparaginase using modified Czapek-Dox media. The enzyme was purified about 60.95-fold and then kinetic study showed that the Km value of the enzyme was 1 * 10-5 M. The optimum pH and temperature for the enzyme were 7.0 and 30 degrees C, respectively. The optimum incubation period for L-asparaginase was 15 min. This work concludes that this enzyme can be a suitable candidate due to its strong kinetic properties, and further research can usher into development of asparaginase formulation from fungal origin with less adverse effects. PMID- 23030469 TI - Production of ligninolytic enzymes by solid-state fermentation using Pleurotus eryngii. AB - Pleurotus eryngii (DC.) Gillet (MCC58) was investigated for its ability to produce various ligninolytic enzymes such as laccase (Lac), manganese peroxidase (MnP), aryl alcohol oxidase (AAO), and lignin peroxidase (LiP) by solid-state fermentation (SSF), which was carried out using a support substrate from the fruit juice industry. The chemical content of grape waste from this industry was studied. Also, the production patterns of these extracellular enzymes were researched during the growth of the organism for a period of 20 days and the protein, reducing sugar, and nitrogen levels were monitored during the stationary cultivation. The highest Lac activity was obtained as 2247.62 +/- 75 U/L on day 10 in the presence of 750 uM Mn2+, while the highest MnP activity was attained as 2198.44 +/- 65 U/L on day 15 in the presence of 500 uM Mn2+. Decolorization of methyl orange and reactive red 2 azo dyes was also achieved with ligninolytic enzymes, produced in SSF of P. eryngii. PMID- 23030470 TI - IgG purification using affinity filtration with sulfamethazine-affinity carriers. AB - Immunoglobulin G (IgG) antibodies are used extensively for analytical, diagnostic, and therapeutic applications. However, there are some disadvantages to purify IgG antibodies by protein A and G affinity chromatography. Therefore, it is necessary to find an effective alternative and nonchromatographic method to purify IgG. Dextran microparticles were activated and coupled with sulfamethazine to form sulfamethazine-affinity carriers. Then the carriers were used to purify IgG by affinity filtration. Quantitative and qualitative determination proved that sulfamethazine would successfully bond to the surface of dextran microparticles with a density of 85.5 MUmol/g (wet). Affinity carriers were proved to withstand high shear force and reveal rare sulfamethazine leakage under filtration conditions between pH 3 to 11. The maximum IgG-binding capacity of affinity carriers was 8.03 mg IgG/g (wet). The affinity filtration process obtained a recovery yield above 80% and purity above 90%. Thus, this work involved in both the advantages of membrane filtration and affinity purification. The results, for the first time, proved that it is possible to use the small ligand sulfamethazine for affinity filtration of IgG. It is an attractive alternative to conventional protein A or G affinity chromatography. PMID- 23030472 TI - MnO-labeled cells: positive contrast enhancement in MRI. AB - Manganese oxide (MnO) nanoparticles have been suggested as a promising "positive" MRI contrast agent for cellular and molecular studies. Mn-based contrast agents could enable T(1)-weighted quantitative cell tracking procedures in vivo based on signal enhancement. In this study, ultrasmall MnO particles were synthesized and coated with thiolated molecules (DMSA) and polyethylene glycol (PEG) to allow enhanced cell labeling properties and colloidal stability. This coating allowed the fabrication of individual ultrasmall nanoparticles of MnO (USPMnO) as well as of nanoaggregates of the same material (SPMnO). Particle size was measured by TEM and DLS. Physico-chemical properties were characterized by XPS and FTIR. The relaxometric properties of these aqueous suspensions were measured at various magnetic fields. The suspensions provided strong positive contrast enhancement in T(1)-weighted imaging due to high longitudinal relaxivities (r(1)) and low r(2)/r(1) ratios (USPMnO: r(1) = 3.4 +/- 0.1 mM(-1)s(-1), r(2)/r(1) = 3.2; SPMnO: r(1) = 17.0 +/- 0.5 mM(-1)s(-1), r(2)/r(1) = 4.0, at 1.41T). HT-1080 cancer cells incubated with the contrast agents were clearly visualized in MRI for Mn contents >1.1 pg Mn/cell. The viability of cells was not affected, contrarily to cells labeled with an equivalent concentration of Mn(2+) ions. A higher signal per cell was found for SPMnO-labeled compared with USPMnO-labeled cells, due to the higher relaxometric properties of the agglomerates. As a result, the "positive" signal enhancement effect is not significantly affected upon agglomeration of MnO particles in endosomes. This is a major requirement in the development of reliable cell tracking procedures using T(1)-weighted imaging sequences. This study confirms the potential of SPMnO and USPMnO to establish more quantitative cell tracking procedures with MRI. PMID- 23030473 TI - Microfluidic device for automated synchronization of bacterial cells. AB - We report the development of an automated microfluidic "baby machine" to synchronize the bacterium Caulobacter crescentus on-chip and to move the synchronized populations downstream for analysis. The microfluidic device is fabricated from three layers of poly(dimethylsiloxane) and has integrated pumps and valves to control the movement of cells and media. This synchronization method decreases incubation time and media consumption and improves synchrony quality compared to the conventional plate-release technique. Synchronized populations are collected from the device at intervals as short as 10 min and at any time over four days. Flow cytometry and fluorescence cell tracking are used to determine synchrony quality, and cell populations synchronized in minimal growth medium with 0.2% glucose (M2G) and peptone yeast extract (PYE) medium contain >70% and >80% swarmer cells, respectively. Our on-chip method overcomes limitations with conventional physical separation methods that consume large volumes of media, require manual manipulations, have lengthy incubation times, are limited to one collection, and lack precise temporal control of collection times. PMID- 23030474 TI - Iron deficiency in infants and toddlers in the United States. AB - Iron deficiency anemia (IDA) continues to be overwhelmingly the leading cause of anemia in early childhood and a global public health challenge. Although there has been a significant decrease in the frequency of IDA and iron deficiency (ID) in infants and toddlers in recent years in the United States, ID and IDA persist and the adverse effects of ID are long-lasting if not permanent. Moreover, ID can result in lead toxicity, and this toxic exposure, even with low levels, can impair neurocognitive function as well. This review describes the major steps that have taken place to decrease the frequency of ID and IDA. PMID- 23030476 TI - Outcomes of patients with chronic heart failure and iron deficiency treated with intravenous iron: a meta-analysis. AB - BACKGROUND: Trials studying iron repletion in patients with chronic heart failure (CHF) and iron deficiency are underpowered to find consistent hard endpoint (mortality and hospitalization) reductions. We conducted a meta-analysis of controlled trials to examine the effects of iron repletion on these parameters. METHODS AND RESULTS: Pubmed, CENTRAL, EMBASE and NIH Clinical Trials databases were searched for controlled trials utilizing intravenous iron, with or without erythropoietin, in patients with CHF with NYHA class >= II, iron deficiency, and left ventricular dysfunction. Data regarding hospitalizations, mortality, adverse events, NYHA class, and ejection fraction were extracted, analyzed for heterogeneity, and pooled using the DerSimonian and Laird random effects model. We identified 5 controlled trials (n = 631 patients). Patients treated with intravenous iron had significant reductions in hospitalizations (OR 0.26, 95% CI 0.08-0.80), adverse events (OR 0.35, 95% CI 0.21-0.60), NYHA class (mean improvement 1.2 classes, 95% CI 0.69-1.78, and LVEF (mean improvement 5.0%, 95% CI 0.13-9.80) but no relationship was found on mortality (OR 0.66, 95% CI 0.30 1.44). CONCLUSION: Treatment of iron deficiency in patients with CHF reduces the risk of hospitalizations without increased adverse events, suggesting its role as a potential therapeutic target in this group of patients. PMID- 23030477 TI - The effect of lead exposure on selected blood inflammatory biomarkers in guinea pigs. AB - This study was aimed to examine the effect of lead acetate on inflammatory biomarkers in blood of guinea pigs in comparison with sensitized animals. Thirty guinea pigs were randomly allocated into control (group C), sensitized (group S), and three Pb-exposed (groups 0.1M Pb, 0.2M Pb and 0.4M Pb). Animal sensitized after aerosolized-ovalbumin (OA) challenge. Pb-exposed groups inhaled 0.1M, 0.2M and 0.4M lead acetate for 1 h, three times a week for two weeks. Total and differential WBC counts, PLA2 activity and total protein levels were evaluated in blood of all animal groups. Serum PLA2 activity, total protein and total WBC number in sensitized and animal exposed to lead were significantly higher as compared to control group (p <0.05). When compared to control group, the percentages of eosinophil, nuetrophil and basophiles were also increased in sensitized guinea pigs (p <0.01). The percentage of eosinophil and basophile in animals exposed to high level of lead and that of basophile in animals exposed to middle lead concentration versus to control group significantly increased (p <0.05). In addition, the significant difference between the lymphocyte percentages of Pb-exposed groups and control group were decreased in concentration dependent manner. The findings of the present study indicated that exposure to inhaled lead acetate may lead to asthma-like disease. PMID- 23030475 TI - Correlates of concurrent energy drink and alcohol use among socially active adults. AB - BACKGROUND: Research indicates that energy drink consumption and the combined use of energy drinks and alcohol are popular among young adults, although this research has typically focused on college students. Because of the potential for harms associated with this combination, it is critical to understand use among adults in nightlife scenes who may be most at risk for harms associated with combined energy drink and alcohol consumption. OBJECTIVES: By focusing our sample on individuals in a range of nightlife scenes, we aim to gain a deeper understanding of the demographic factors associated with energy drink use and combined energy drink and alcohol consumption to benefit the targeting of intervention and prevention efforts beyond college campuses. METHODS: Using a field-based survey in New York City to survey adults active in various nightlife scenes, this study reports on the survey results of 1476 venue patrons at venues in five nightlife scenes in addition to college bar scenes. RESULTS: Men, younger individuals, Latinos, and sexual minority individuals reported higher prevalence of recent energy drink consumption. Younger individuals, men, and those recruited in gay venues reported higher prevalence of combining alcohol and energy drinks. CONCLUSION: These findings provide information useful to target education and prevention efforts. They also suggest the need for additional research to understand differences in motivations for use and in the behavioral and alcohol related outcomes associated with consuming energy drinks and combining them with alcohol. PMID- 23030479 TI - Cancer and infection: friends or foes? PMID- 23030478 TI - The expression and significance of WWOX and beta-catenin in hepatocellular carcinoma. AB - WW domain-containing oxidoreductase (WWOX) is a novel tumor suppressor gene, and its expression is reduced in various cancers, including hepatocellular carcinoma (HCC). WWOX has been reported to be downregulated in HCC cell lines as well as in primary HCC tissues. It has been suggested that WWOX is implicated in Wnt/beta catenin pathway, which is frequently affected in HCC. The aim of this study was to evaluate the expression of WWOX, beta-catenin and T-cell factor 4 (TCF4) in HCC. Our result showed that downregulation of WWOX in HCC was correlated with cytoplasmic accumulation of beta-catenin. In addition, strong nuclear TCF4 expression was associated with tumor grade and stage in HCC. In conclusion, our result implied that downregulation of WWOX might lead to accumulation of cytoplasmic beta-catenin and the subsequent activation of Wnt/beta-catenin signaling pathway in HCC. PMID- 23030480 TI - Targeting tumoral hypoxia: finding opportunity in complexity. PMID- 23030482 TI - The role of enzalutamide in the treatment of castration-resistant prostate cancer. AB - Prostate cancer is the most common solid organ cancer affecting the male population. Men with metastatic prostate cancer treated with androgen ablation therapy often respond rapidly, with improvement in bone pain and decreases in serum prostate-specific antigen. However, almost all patients progress to the castration-resistant state and abiraterone acetate was the last treatment available with proven survival benefit. Enzalutamide (formerly MDV3100) is an androgen receptor signaling inhibitor that has been shown to improve survival in men with metastatic castration-resistant prostate cancer previously treated with chemotherapy. In this article we discuss the characteristics of enzalutamide and provide a review of its clinical development. PMID- 23030483 TI - Brivanib: a review of development. AB - The development of new agents in oncology has focused on disrupting key pathways in oncogenesis. Both malignant angiogenesis and peptide growth factor signaling have been studied extensively and have been validated for cancer treatment. While antibody-directed therapeutics offer increased specificity, small-molecule tyrosine kinase inhibitors often have the ability to hit multiple targets. Brivanib alaninate (BMS582664) is an oral, potent selective inhibitor of both the FGF and VEGF family of receptors. It is a first-in-class FGF/VEGF inhibitor now in late-phase clinical trials. Besides its antiangiogenic activity from blocking VEGF receptor 1-3, its ability to disrupt FGF receptors 1-3 has been suggested to add additional antiangiogenic activity, overcome resistance from VEGF blockade, and block FGF-dependent tumor proliferation. In this review, we will discuss the preclinical science driving brivanib's development and the clinical data generated to date. PMID- 23030484 TI - Significance of clustered tumor suppressor genes in cancer. AB - The two-hit model is a well-known mechanism for the inactivation of tumor suppressor genes in cancer and it has been assumed that chromosomal deletions are the second inactivating event. Large deletions are frequently found in cancer and can lead to the haploinsufficiency of the loci mapped to the deleted region. The study by Xue et al. demonstrated that hemizygous 8p deletions can attenuate the activity of multiple genes that control growth and promote tumorigenesis, and showed that the effect of large 8p deletions on tumor phenotype goes beyond the effects of the individual genes as the characteristics of a tumor are also influenced by the additive and/or combined effect of the haploinsufficiency of multiple genes. These convincing findings, demonstrating that the hemizygosity of a cluster of genes negatively regulates proliferation and promotes tumor growth, have opened up new study perspectives aimed at characterizing the genomic organization of this new class of tumor suppressor genes and their role in tumorigenesis. PMID- 23030486 TI - PTEN and melanomagenesis. AB - The PI3K-PTEN-AKT signaling pathway is involved in various cellular activities, including proliferation, migration, cell growth, cell survival and differentiation during adult homeostasis as well as in tumorigenesis. It has been suggested that the constitutive activation of PI3K/AKT signaling with concurrent loss of function of the tumor suppressor molecule PTEN contributes to cancer formation. Members of the PI3K-PTEN-AKT pathway, including these proteins and mTOR, are altered in melanoma tumors and cell lines. A hallmark of activation of the pathway is the loss of function of PTEN. Indeed, loss of heterozygosity of PTEN has been observed in approximately 30% of human melanomas, implicating this signaling pathway in this cancer. PI3K signaling activation, via loss of PTEN function, can inhibit proapoptotic genes such as the FoxO family of transcription factors, while inducing cell growth- and cell survival-related elements such as p70S6K and AKT. Determining how the PI3K-PTEN-AKT signaling pathway, alone or in cooperation with other pathways, orchestrates the induction of target genes involved in a diverse range of activities is a major challenge in research into melanoma initiation and progression. Moreover, the acquisition of basic knowledge will help patient management with appropriate therapies that are already, or will shortly be, on the market. PMID- 23030485 TI - LOXL2 in epithelial cell plasticity and tumor progression. AB - Several members of the lysyl oxidase family have recently emerged as important regulators of tumor progression. Among them, LOXL2 has been shown to be involved in tumor progression and metastasis of several tumor types, including breast carcinomas. Secreted LOXL2 participates in the remodeling of the extracellular matrix of the tumor microenvironment, in a similar fashion to prototypical lysyl oxidase. In addition, new intracellular functions of LOXL2 have been described, such as its involvement in the regulation of the epithelial-to-mesenchymal transition, epithelial cell polarity and differentiation mediated by transcriptional repression mechanisms. Importantly, intracellular (perinuclear) expression of LOXL2 is associated with poor prognosis and distant metastasis of specific tumor types, such as larynx squamous cell carcinoma and basal breast carcinomas. These recent findings open new avenues for the therapeutic utility of LOXL2. PMID- 23030487 TI - Sequence and structural basis for chromosomal fragility during translocations in cancer. AB - Chromosomal aberration is considered to be one of the major characteristic features in many cancers. Chromosomal translocation, one type of genomic abnormality, can lead to deregulation of critical genes involved in regulating important physiological functions such as cell proliferation and DNA repair. Although chromosomal translocations were thought to be random events, recent findings suggest that certain regions in the human genome are more susceptible to breakage than others. The possibility of deviation from the usual B-DNA conformation in such fragile regions has been an active area of investigation. This review summarizes the factors that contribute towards the fragility of these regions in the chromosomes, such as DNA sequences and the role of different forms of DNA structures. Proteins responsible for chromosomal fragility, and their mechanism of action are also discussed. The effect of positioning of chromosomes within the nucleus favoring chromosomal translocations and the role of repair mechanisms are also addressed. PMID- 23030488 TI - The changing landscape of therapeutic strategies for recurrent ovarian cancer. AB - Advanced epithelial ovarian cancer, cancer of the fallopian tube and primary peritoneal cancer have a poor prognosis and a high rate of disease recurrence following primary therapy. Recurrent ovarian cancer is currently classified according to sensitivity to platinum-based chemotherapy. Data on targeted therapy provide evidence of improvement with systemic treatment in addition to chemotherapy. Other strategies, although not proven in randomized trials, offer interesting options for future research and therapeutic development. In this review, the covered treatment modalities include surgery, chemotherapy and targeted therapy, immunological approaches and irradiation. PMID- 23030489 TI - The future of glioma treatment: stem cells, nanotechnology and personalized medicine. AB - The development of novel therapies, imaging techniques and insights into the processes that drive growth of CNS tumors have allowed growing enthusiasm for the treatment of CNS malignancies. Despite this energized effort to investigate and treat brain cancer, clinical outcomes for most patients continue to be dismal. Recognition of diverse tumor subtypes, behaviors and outcomes has led to an interest in personalized medicine for the treatment of brain tumors. This new paradigm requires evaluation of the tumor phenotype at the time of diagnosis so that therapy can be specifically tailored to each individual patient. Investigating novel therapies involving stem cells, nanotechnology and molecular medicine will allow diversity of therapeutic options for patients with brain cancer. These exciting new therapeutic strategies for brain tumors are reviewed in this article. PMID- 23030490 TI - Detection of smell print differences between nonmalignant and malignant prostate cells with an electronic nose. AB - AIM: To determine whether an electronic nose can differentiate cultured nonmalignant and malignant prostatic cells from each other and whether the smell print is secreted to the surrounding medium. MATERIALS & METHODS: Prostatic nonmalignant (EP-156T and controls) and malignant (LNCaP) cell lines, as well as conditioned and unconditioned media, were collected. The smell prints of the samples were analyzed by a ChemPro((r)) 100 electronic nose device. The data were normalized and dimension reduction was conducted. The samples were classified and misclassification rates were calculated. RESULTS: The electronic nose differentiated the nonmalignant and malignant cell lines from each other, achieving misclassification rates of 2.9-3.6%. Cells did not differ from the conditioned medium but differed from the unconditioned medium (misclassification rates: 0.0-25.6%). CONCLUSION: Malignant and nonmalignant prostatic cell lines have distinct smell prints. Prostatic cancer cells seem to modify the smell print of their medium. PMID- 23030491 TI - Nanoscale radiotherapy with hafnium oxide nanoparticles. AB - AIM: There is considerable interest in approaches that could improve the therapeutic window of radiotherapy. In this study, hafnium oxide nanoparticles were designed that concentrate in tumor cells to achieve intracellular high energy dose deposit. MATERIALS & METHODS: Conventional methods were used, implemented in different ways, to explore interactions of these high-atomic number nanoparticles and ionizing radiation with biological systems. RESULTS: Using the Monte Carlo simulation, these nanoparticles, when exposed to high energy photons, were shown to demonstrate an approximately ninefold radiation dose enhancement compared with water. Importantly, the nanoparticles show satisfactory dispersion and persistence within the tumor and they form clusters in the cytoplasm of cancer cells. Marked antitumor activity is demonstrated in human cancer models. Safety is similar in treated and control animals as demonstrated by a broad program of toxicology evaluation. CONCLUSION: These findings, supported by good tolerance, provide the basis for developing this new type of nanoparticle as a promising anticancer approach in human patients. PMID- 23030492 TI - Psychosocial and spiritual problems of terminally ill patients in Kerala, India. AB - AIM: To investigate psychosocial and spiritual problems of terminally ill patients in Kerala, India. MATERIALS & METHODS: Semi-structured qualitative interviews of terminally ill patients were carried out at the Trivandrum Institute of Palliative Sciences Palliative Care Clinic in Trivandrum, Kerala, India and in patients' homes in the surrounding area. RESULTS: Interviews with 37 terminally ill patients in Kerala showed several problems regarding their emotional state, faith, knowledge about the disease, family life and the major impact of financial issues. CONCLUSION: This study shows that more effort should be focused on the reduction of the problems terminally ill patients have to face. While many of these problems are a result of financial troubles and could be eliminated if sufficient funds were available, others are a consequence of tradition and culture. Solutions for the improvement of patients' situations in accord with tradition and culture have to be found. PMID- 23030493 TI - Bevacizumab plus chemotherapy in metastatic colorectal cancer patients treated in clinical practice. AB - AIM: The effect of KRAS status on response to bevacizumab plus chemotherapy in metastatic colorectal cancer is still unclear. We aimed to evaluate the overall clinical response to such a therapy in clinical practice and assess the role of KRAS status on therapy response. PATIENTS & METHODS: This was a retrospective study enrolling 108 metastatic colorectal cancer patients. KRAS mutation analysis was performed by PCR. RESULTS: Overall, 41.7% of patients had stable disease, 39.8% a partial response, 3.7% a complete response and 14.8% disease progression. Both clinical benefit and objective response rate tended to be higher in patients with only hepatic metastases than those with extrahepatic or multiple metastases. Response to therapy would appear to be independent of KRAS status, but larger studies are needed. CONCLUSION: Bevacizumab plus chemotherapy provides clinical benefit and objective response rate in patients with metastatic colorectal cancer independently of KRAS expression, especially in those patients with only liver metastases. PMID- 23030494 TI - Advanced vulvar apocrine carcinoma expressing estrogen receptors that responds to tamoxifen therapy. AB - Primary vulvar carcinoma is rare and thought to arise from either anogenital mammary-like glands or native apocrine sweat glands. The diagnosis is predominantly based on tumor morphology with supportive evidence from immunohistochemical staining and exclusion of a primary breast carcinoma. The primary modality of treatment is surgery, while optimal managment of advanced disease is unclear. We present the case of a lady who had metastatic recurrent apocrine carcinoma expressing estrogen receptors, who had a complete response assessed by PET-CT scanning after 7 months of tamoxifen therapy. The report includes a discussion of the histological diagnosis and assessment of response to treatment by PET-CT scanning. PMID- 23030496 TI - Asymmetric noncovalent synthesis of self-assembled one-dimensional stacks by a chiral supramolecular auxiliary approach. AB - Stereoselective noncovalent synthesis of one-dimensional helical self-assembled stacks of achiral oligo(p-phenylenevinylene) ureidotriazine (AOPV3) monomers is obtained by a chiral supramolecular auxiliary approach. The racemic mixture of helical stacks of achiral AOPV3 molecules is converted into homochiral helical stacks, as shown by both spectroscopic measurements and molecular modeling simulations. The conversion is promoted by an orthogonal two-point ion-pair interaction with the chiral auxiliary dibenzoyl tartaric acid (D- or L-TA) molecules, which biases the angle population distribution and thereby the stack helicity. The induced preferred helicity is maintained by the OPV stacks even after the removal of the chiral auxiliary by extraction with ethylenediamine (EDA), due to the kinetic stability of the OPV stacks at room temperature. Spectroscopic probing of the helical self-assembly and the racemization process of these pi-conjugated OPV chromophores shed further light into the mechanistic pathways of this chiral asymmetric noncovalent synthesis and the kinetic stability of the stacks produced. The racemization of the stacks follows first order kinetics and no switch in mechanism is observed as a result of a temperature change; therefore, a racemization via disassembly assembly is proposed. Remarkably, the preferred helicity of the stacks of achiral AOPV3 can be retained almost completely after a heating-cooling cycle where the stacks first partially depolymerize and then polymerize again with the still existing stacks being the seeds for self-assembly of achiral AOPV3. Only after a fully dissociated state is obtained at high temperatures, the optical activity of the supramolecular stack self-assembled at room temperature is lost. PMID- 23030498 TI - Phosphorylation-dependent protein-protein interaction modules as potential molecular targets for cancer therapy. AB - Protein phosphorylation is a key event in signal transduction pathways. When upstream signals are stimulated, protein kinases are activated and phosphorylate their substrates, modulating their localization, conformation, and activity. In some cases, phosphorylated substrates become recognizable to other proteins-such interactions transduce and propel the signal onward. Certain domains specifically recognize phosphorylated residues of proteins, regulating cell growth and differentiation. Because the proteins that contain these domains also mediate diseases that are caused by dysregulated signal transduction, small molecules that inhibit such motifs are attractive candidates for the treatment of diseases, such as cancer. In this review, we summarize the domains that recognize phosphorylated proteins, particularly serine- and threonine-phosphorylated sequences in target proteins. In addition, we introduce a high-throughput screen that we developed to identify small-molecule inhibitors of phosphorylation dependent protein-protein interactions. An example is presented, and the potential uses of this system are discussed. PMID- 23030497 TI - Suppressed blinking and auger recombination in near-infrared type-II InP/CdS nanocrystal quantum dots. AB - Nonblinking excitonic emission from near-infrared and type-II nanocrystal quantum dots (NQDs) is reported for the first time. To realize this unusual degree of stability at the single-dot level, novel InP/CdS core/shell NQDs were synthesized for a range of shell thicknesses (~1-11 monolayers of CdS). Ensemble spectroscopy measurements (photoluminescence peak position and radiative lifetimes) and electronic structure calculations established the transition from type-I to type II band alignment in these heterostructured NQDs. More significantly, single-NQD studies revealed clear evidence for blinking suppression that was not strongly shell-thickness dependent, while photobleaching and biexciton lifetimes trended explicitly with extent of shelling. Specifically, very long biexciton lifetimes up to >7 ns-were obtained for the thickest-shell structures, indicating dramatic suppression of nonradiative Auger recombination. This new system demonstrates that electronic structure and shell thickness can be employed together to effect control over key single-dot and ensemble NQD photophysical properties. PMID- 23030499 TI - Trimethylaluminum-triflimide complexes for the catalysis of highly hindered Diels Alder reactions. AB - Two catalysts, Me(2)AlNTf(2) and MeAl(NTf(2))(2), derived from the mixing of trimethylaluminum with triflimide, proved to be highly effective catalysts in hindered Diels-Alder reactions, generating the desired Diels-Alder cycloadducts from both hindered 2-silyloxydienes and hindered dienophiles. Thus reaction of 1 with 2 afforded the hindered cycloadduct 4 in excellent yield in 0.5-1.5 h at -40 degrees C. PMID- 23030500 TI - Involvement of viral glycoprotein gC-1 in expression of the selectin ligand sialyl-Lewis X induced after infection with herpes simplex virus type 1. AB - Several herpesviruses induce expression of the selectin receptor sialyl-Lewis X (sLe(x) ) by activating transcription of one or more of silent host FUT genes, each one encoding a fucosyltransferase that catalyses the rate-limiting step of sLe(x) synthesis. The aim here was to identify the identity of the glycoconjugate associated with sLe(x) glycoepitope in herpes simplex virus type 1 (HSV-1) infected human diploid fibroblasts, using immunofluorescence confocal microscopy. Cells infected with all tested HSV-1 strains analysed demonstrated bright sLe(x) fluorescence, except for two mutant viruses that were unable to induce proper expression of viral glycoprotein gC-1: One gC-1 null mutant and another mutant expressing gC-1 devoid of its major O-glycan-containing region (aa 33-116). The sLe(x) reactivity of HSV-1 infected cells was abolished by mild alkali treatment. Altogether the results indicated that the detectable sLe(x) was associated with O linked glycans, situated in the mucin region of gC-1. No evidence for sLe(x) (i) in other HSV-1 glycoproteins with mucin domains such as gI-1 or (ii) in host cell glycoproteins/glycolipids was found. Thus, the mucin domain of HSV-1 gC-1 may support expression of selectin ligands such as sLe(x) and other larger O-linked glycans in cell types lacking endogenous mucin domain-containing glycoproteins, optimized for O-glycan expression, provided that the adequate host glycosyltransferase genes are activated. PMID- 23030501 TI - Enhanced activity of carvacrol against biofilm of Staphylococcus aureus and Staphylococcus epidermidis in an acidic environment. AB - Carvacrol is an antimicrobial monoterpenic phenol which occurs in many plant essential oils. The aim of this study was to investigate its activity at acidic pH on staphylococcal forming and yet established biofilms, with particular focus to improve its effectiveness on Staphylococcus epidermidis biofilm. The results showed that the subinhibitory doses (1/2, 1/4 and 1/8 MIC) of carvacrol determined a higher reduction of S. epidermidis biofilm formation than that observed at neutral pH. A potentiated inhibitory effect was also observed on established biofilm, carvacrol caused either a strong reduction of biomass (>50%) and bacteria attached to polystyrene (>7 log units). The images of scanning electron microscopy and the gas-chromatographic analysis support these results. The development of acidic formulations containing carvacrol could be an important tool to control the staphylococcal biofilm in the medical and food environment. PMID- 23030502 TI - Acyl guanidine inhibitors of beta-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis. AB - This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-pi interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single digit nanomolar activity in cells afforded good plasma exposures and a dose dependent reduction in plasma Abeta levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Abeta levels were not obtained. PMID- 23030503 TI - High-resolution colonic manometry accurately predicts colonic neuromuscular pathological phenotype in pediatric slow transit constipation. AB - BACKGROUND: Severe pediatric slow transit constipation (STC) is commonly due to intrinsic colonic neuromuscular disease. We sought to correlate neuromuscular histological phenotypes in pediatric STC with colonic manometric phenotypes using high-resolution manometry (HRM). We tested the hypothesis that failure of motor quiescence (FQ) between bisacodyl-induced high amplitude propagating sequences (HAPSs) might predict neuromuscular pathology. METHODS: Eighteen children (10 males, median age: 7.5 years) with refractory STC underwent stationary colonic HRM before segmental colonic resection. Six age-matched constipated children with normal colonic transit served as controls. Colonic resection specimens underwent histopathological analysis. Conventional manometric parameters and area under the curve (AUC) during a 1-min period following bisacodyl-induced HAPSs [PBAUC(1) ], as measure of FQ, were calculated. KEY RESULTS: Numbers of postbisacodyl HAPSs in descending and sigmoid segments were lower in patients than controls (P < 0.01, respectively). Low amplitude propagating sequences (LAPSs) were common prebisacodyl in controls and rare in STC (P < 0.001), whereas postbisacodyl LAPS were more common in STC (P < 0.001). Postbisacodyl, both retrograde propagating contractions and bursts of contractions were present in STC patients only (P < 0.001 and P < 0.01). Postbisacodyl simultaneous pressurization was seen only in STC (P < 0.05 and P < 0.001, in descending and rectosigmoid segments). Histological abnormalities were present in 17/18. Fourteen were neurogenic, one neuro-myogenic, and two myogenic. In segments with HAPS, PBAUC(1) was predictive of colonic neuropathy using a cutoff of 205 mmHg.s(-1) (Sensitivity 100%, specificity 86%, PPV92%, NPV100%). CONCLUSIONS & INFERENCES: PBAUC(1) is increased in multiple colonic segments in neuropathic pediatric STC and constitutes a sensitive and specific biomarker of neuropathy. PMID- 23030504 TI - Participant perceptions of a novel physiotherapy approach ("Blue Prescription") for increasing levels of physical activity in people with multiple sclerosis: a qualitative study following intervention. AB - PURPOSE: The aim of this study was to investigate experiences of participating in a feasibility trial of a novel physiotherapy intervention (Blue Prescription). The trial was designed to increase participation in physical activity for people with multiple sclerosis living in the community. METHODS: We individually interviewed 27 volunteers from two New Zealand metropolitan areas at the conclusion of their participation in Blue Prescription. We asked volunteers about what participation in Blue Prescription had meant to them; how participants intended to continue with their physical activity; how the approach differed from previous experiences of physiotherapy encounters; and how Blue Prescription could be improved. Interviews were semi-structured, audio-recorded, transcribed verbatim, and analysed using a General Inductive Approach. RESULTS: 'Support' was identified as a key theme with three sub-themes: 'The therapeutic relationship'; 'The Blue Prescription approach'; and 'Supporting themselves'. We identified two additional themes 'Motivation to participate' and 'Improving the Blue Prescription approach'. CONCLUSION: A novel approach (Blue Prescription) which facilitates engagement in higher levels of desirable physical activity was perceived by participants to be supportive, motivating and enabling. This approach might be particularly useful for people with multiple sclerosis ready to adopt new health-related behaviours. For future studies, this approach requires further refinement, particularly with regards to methods of communication and evaluation. PMID- 23030505 TI - Anti-endothelial cell antibodies in patients with cerebral small vessel disease. AB - The pathogenesis of cerebral small vessel disease (CSVD) in the elderly is poorly understood. Endothelial cell activation and dysfunction may play a causal role in the pathogenesis of CSVD. It was reported that anti-endothelial cell antibodies (AECAs) are associated with endothelial cell dysfunction and inflammation. We hypothesized that AECAs may be associated with the pathogenesis of CSVD. We examined AECAs in sera from 12 elderly subjects with CSVD, 12 elderly subjects without CSVD, and 18 healthy volunteers by 2-dimensional immunoblotting using primary cultured human brain microvascular endothelial cells as the antigen source. We identified 4 AECAs that were detected in sera from more than one-half of the elderly subjects with CSVD. Subsequently, we analyzed the target antigens of these 4 antibodies by liquid chromatography-tandem mass spectrometry. The target antigens of these 4 antibodies were tropomyosin alpha-4 chain (TPM4), vimentin, alpha-enolase, and annexin A2. Among these 4 antibodies, the anti-TPM4 antibody was significantly more frequently detected in sera from the elderly subjects with CSVD than the other subjects. We determined the anti-TPM4 antibody level in sera from 21 elderly subjects with CSVD and 25 subjects without CSVD by enzyme-linked immunosorbent assay. The anti-TPM4 antibody level was significantly higher in the subjects with than without CSVD. Therefore, an autoimmune, inflammatory process with high levels of anti-TPM4 antibody may contribute to the development of CSVD in the elderly. PMID- 23030506 TI - Single nucleotide polymorphism and serum levels of VEGFR2 are associated with age related macular degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of blindness and is the third leading cause of blindness. Genetic factors are known to influence an individual's risk for developing AMD. Linkage has earlier been shown to the vascular endothelial growth factor 2 (VEGF2) gene and AMD. To examine the role of VEGFR2 in north Indian population, we conducted a case control study. Total 176 subjects were enrolled in a case-control genetic study. Real-Time PCR was used to analyze the SNPs (rs1531289 and rs2305948) of VEGFR-2 gene. ELISA was conducted to determine the levels of VEGFR2. A non-parametric Mann-Whitney-U test was applied for comparison of the ELISA levels and pearson's Chi-square test was applied to study the association of polymorphism between various groups. The single SNP (rs1531289) AG genotype was significantly associated with AMD (OR= 2.13, 95%CI= 1.011-4.489, P=0.047). VEGFR2 levels were found to be increased significantly in AMD patients as compared to normal controls. We also found significant increase in the levels of wet AMD as compared to dry AMD. This study demonstrates higher levels of VEGFR2 and frequency of AG (rs1531289) genotype in AMD patient population, suggesting the role of VEGFR-2 in pathogenesis of AMD. PMID- 23030507 TI - Construction and assessment of reaction models between F1F0-synthase and organotin compounds: molecular docking and quantum calculations. AB - Organotin compounds are the active components of some fungicides, which are potential inhibitors of the F1F0-ATP synthase. The studies about the reaction mechanism might indicate a pathway to understand how these compounds work in biological systems, however, has not been clarified so far. In this line, molecular modeling studies and density functional theory calculations were performed in order to understand the molecular behavior of those compounds when they interact with the active site of the enzyme. Our findings indicate that a strong interaction with His132 can favor a chemical reaction with organotin compounds due to pi-pi stacking interactions with aromatic rings of organotin compounds. Furthermore, dependence on molecule size is related to possibility of reaction with the amino acid residue His132. Thus, it can also be noticed, for organotin compounds, that substituents with four carbons work by blocking the subunit a, in view of the high energy transition found characterized by steric hindrance. PMID- 23030508 TI - Experimental early-life febrile seizures induce changes in GABA(A) R-mediated neurotransmission in the dentate gyrus. AB - PURPOSE: Febrile seizures (FS), the most frequent seizure type during childhood, have been linked to temporal lobe epilepsy (TLE) in adulthood. Yet, underlying mechanisms are still largely unknown. Altered gamma-aminobutyric acid (GABA)ergic neurotransmission in the dentate gyrus (DG) circuit has been hypothesized to be involved. This study aims at analyzing whether experimental FS change inhibitory synaptic input and postsynaptic GABA(A) R function in dentate granule cells. METHODS: We applied an immature rat model of hyperthermia (HT) induced FS. GABA(A) R-mediated neurotransmission was studied using whole-cell patch-clamp recordings from dentate granule neurons in hippocampal slices within 6-9 days post-HT. KEY FINDINGS: Frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs) were reduced in HT rats that had experienced seizures, whereas sIPSC amplitudes were enhanced. Whole-cell GABA responses revealed a doubled GABA(A) R sensitivity in dentate granule cells from HT animals, compared to that of normothermic (NT) controls. Analysis of sIPSCs and whole-cell GABA responses showed similar kinetics in postsynaptic GABA(A) Rs of HT and NT rats. quantitative real-time polymerase chain reaction (qPCR) experiments indicated changes in DG GABA(A) R subunit expression, which was most pronounced for the alpha3 subunit. SIGNIFICANCE: The data support the hypothesis that FS persistently alter neuronal excitability. PMID- 23030510 TI - Optimization of arsenic removal water treatment system through characterization of terminal electron accepting processes. AB - Terminal electron accepting process (TEAP) zones developed when a simulated groundwater containing dissolved oxygen (DO), nitrate, arsenate, and sulfate was treated in a fixed-bed bioreactor system consisting of two reactors (reactors A and B) in series. When the reactors were operated with an empty bed contact time (EBCT) of 20 min each, DO-, nitrate-, sulfate-, and arsenate-reducing TEAP zones were located within reactor A. As a consequence, sulfate reduction and subsequent arsenic removal through arsenic sulfide precipitation and/or arsenic adsorption on or coprecipitation with iron sulfides occurred in reactor A. This resulted in the removal of arsenic-laden solids during backwashing of reactor A. To minimize this by shifting the sulfate-reducing zone to reactor B, the EBCT of reactor A was sequentially lowered from 20 min to 15, 10, and 7 min. While 50 mg/L (0.81 mM) nitrate was completely removed at all EBCTs, more than 90% of 300 MUg/L (4 MUM) arsenic was removed with the total EBCT as low as 27 min. Sulfate- and arsenate-reducing bacteria were identified throughout the system through clone libraries and quantitative PCR targeting the 16S rRNA, dissimilatory (bi)sulfite reductase (dsrAB), and dissimilatory arsenate reductase (arrA) genes. Results of reverse transcriptase (RT) qPCR of partial dsrAB (i.e., dsrA) and arrA transcripts corresponded with system performance. The RT qPCR results indicated colocation of sulfate- and arsenate-reducing activities, in the presence of iron(II), suggesting their importance in arsenic removal. PMID- 23030509 TI - COMT influences on prefrontal and striatal blood oxygenation level-dependent responses during working memory among individuals with schizophrenia, their siblings, and healthy controls. AB - INTRODUCTION: Recent theories have suggested that corticostriatal interactions may play an important part in mediating working memory demands and may impact clinical symptomology of schizophrenia. These effects are thought to occur through changes in dopamine signalling from the midbrain and via feedback from the frontal cortex. The catechol-O-methyltransferase (COMT) Val158Met polymorphism may prove useful for studying these effects in vivo. METHODS: In this study, patients with schizophrenia, their well siblings, and healthy controls were genotyped and scanned using functional magnetic resonance imaging (fMRI) while they performed a working memory task. RESULTS: We found that patients and their siblings, but not controls, who were Val homozygotes displayed greater activity of the DLPFC, striatum, and the cerebellum during the task than respective Met carriers. We also found a relationship between striatal activity and negative symptoms for the Val homozygote group. CONCLUSIONS: Our findings support and extend previous studies of COMT effects on cognition and neural activity, and suggest that changes in dopamine availability may differentially impact corticostriatal functioning of individuals at risk for schizophrenia from those who are not. We also found some evidence supporting the proposed role of striatal dopamine signalling and clinical symptoms associated with anhedonia and apathy. PMID- 23030511 TI - Long-pulsed Nd:YAG laser on periorbital wrinkles in Asian patients: randomized split face study. AB - BACKGROUND AND OBJECTIVE: This study evaluated clinical usefulness of long-pulsed Nd:YAG laser (LPNY) for periorbital wrinkles in Asian patients. METHODS: Twenty seven Korean patients were treated with several passes of LPNY (5 mm spot size, fluence: 54.7-61.8 J/cm(2), pulse duration: 56.5 microseconds). Three treatment sessions were conducted every 2 weeks on the half side of face that was randomly assigned. Outcome assessments included photography, global evaluation by two blinded independent dermatologists (using Fitzpatrick Wrinkle Classification System), and objective measurements of skin elasticity. Adverse events were documented. Patients reported their degree of satisfaction on a 6-point {0-5) visual analog scale (VAS). RESULTS: All patients showed modest improvement. The mean wrinkle score on the treated side decreased by 34.9% (p < 0.05), while it did not change significantly on the control site. Skin elasticity (R2) increased significantly on the treated site. The average VAS score was 2.85 at 2 months but it dropped down to 1.05 at 6 months follow-up. No adverse effects were noted except 2 weeks lasting erythema in one patient. CONCLUSION: LPNY may be considered as a safe treatment option for periorbital wrinkles in Asian patients. However, three treatment sessions are not enough for maintaining optimal clinical outcome. PMID- 23030512 TI - Full disclosure: the practical side of nanoscale total synthesis. AB - Colloidal hybrid nanoparticles merge multiple distinct materials into single particles, producing nanostructures that often exhibit synergistic properties and multifunctionality. As the complexity of such nanostructures continues to expand and the design criteria become increasingly stringent, the synthetic pathways required to access such materials are growing in sophistication. Multistep pathways are typically needed to generate complex hybrid nanoparticles, and these synthetic protocols have important conceptual analogies to the total synthesis framework used by chemists to construct complex organic molecules. This issue of ACS Nano includes a new nanoscale total synthesis: a five-step route to Co(x)O(y) Pt-(CdSe@CdS)-Pt-Co(x)O(y) nanorods, a material which consists of CdSe@CdS nanorods that have Pt and cobalt oxide (Co(x)O(y)) at the tips. In addition to the conceptual analogies between molecular and nanoparticle total syntheses, there are practical analogies, as well, which are important for ensuring the reproducible and high-yield production of multicomponent nanostructured products with the highest possible purities. This Perspective highlights some of the practical considerations that are important for all nanoparticle syntheses but that become magnified significantly when multiple sequential reactions are required to generate a target product. These considerations include detailed reporting of reaction setups, experimental and workup procedures, hazards, yields of all intermediates and final products, complete data analysis, and separation techniques for ensuring high purity. PMID- 23030513 TI - Clinical epidemiology of ALS in Liguria, Italy. AB - Our objective was to assess the incidence and trends of amyotrophic lateral sclerosis (ALS) in Liguria, a north-west region of Italy, utilizing a prospective design. Liguria (1,615,064 residents in 2010) is the site of a multicentre multisource prospective population based registry called LIGALS (Liguria Amyotrophic Lateral Sclerosis Registry). All incident ALS cases during the period 2009-2010 were enrolled and followed up. Cases were identified using several concurrent sources. ALS diagnosis was based on the revised El Escorial criteria. One hundred and four cases were enrolled, generating an annual crude incidence of 3.22/100,000 (95% CI 2.66-3.90), with a male/female ratio of 1.34. The annual standardized incidence, age and gender adjusted to the 2001 Italian population, was 2.51. At last observation on 1 March 2012, 45% of patients registered in the LIGALS had died, with a median survival of 45 months from symptoms onset. According to capture-recapture estimation, three patients were unobserved. For both genders, demographic and clinical features were collected. In conclusion, comparing these data to those of epidemiological studies with a similar prospective design, the occurrence of ALS is similar. The observed crude incidence was higher compared to other Italian studies, due in part to a very careful case ascertainment and in part to a high percentage of the elderly in Liguria. PMID- 23030515 TI - Dropped head syndrome in amyotrophic lateral sclerosis. PMID- 23030516 TI - Characterization of a saturated and flexible aliphatic polyol anion receptor. AB - Nature employs flexible molecules to bind anions in a variety of physiologically important processes whereas supramolecular chemists have been designing rigid substrates that minimize or eliminate intramolecular hydrogen bond interactions to carry out anion recognition. Herein, the association of a flexible polyhydroxy alkane with chloride ion is described and the bound receptor is characterized by infrared and photoelectron spectroscopy in the gas phase, computations, and its binding constant as a function of temperature in acetonitrile. PMID- 23030514 TI - ALSUntangled no. 18: apoaequorin (Prevagen). PMID- 23030517 TI - Effects of niobium ions released from calcium phosphate invert glasses containing Nb2O5 on osteoblast-like cell functions. AB - The effects of niobium ions released from 60CaO-30P(2)O(5)-(10-x)Na(2)O xNb(2)O(5) (mol %, x = 0-10) glasses on MC3T3-E1 cell functions were evaluated by culture tests with two systems; cell culture on glass plates, or in culture media containing glass extracts. Alkaline phosphatase (ALP) activity in the cells cultured on the glass plates containing 3 and 5 mol % of Nb(2)O(5) was significantly higher than that on the Nb(2)O(5)-free glass, although proliferation was not enhanced on all glasses containing Nb(2)O(5). Cells cultured in the medium containing 3 * 10(-7) M niobium ions showed the highest ALP activity in comparison with other Nb-containing media or normal medium, regardless of the presence of osteogenic factors (ascorbic acid, beta glycerophosphate and dexamethasone) in the media. Calcium deposition by the cells cultured in the medium containing 3 * 10(-7) M niobium ions was twice as high as those cultured in medium containing no niobium ions. The effects of niobium ions were thought to depend on ion concentration, and to enhance differentiation and mineralization of osteogenic cells rather than their initial adhesion or proliferation. PMID- 23030518 TI - Communication competence, social support, and depression among college students: a model of facebook and face-to-face support network influence. AB - This study examined the influence of the social networking site Facebook and face to-face support networks on depression among (N = 361) college students. The authors used the Relational Health Communication Competence Model as a framework for examining the influence of communication competence on social support network satisfaction and depression. Moreover, they examined the influence of interpersonal and social integrative motives as exogenous variables. On the basis of previous work, the authors propose and test a theoretical model using structural equation modeling. The results indicated empirical support for the model, with interpersonal motives predicting increased face-to-face and computer mediated competence, increased social support satisfaction with face-to-face and Facebook support, and lower depression scores. The implications of the findings for theory, key limitations, and directions for future research are discussed. PMID- 23030519 TI - Endovenous laser ablation of incompetent perforating veins with 1470 nm, 400 MUm radial fiber. AB - OBJECTIVE: To evaluate the efficacy of endovenous laser ablation (EVLA) of incompetent perforating veins (IPVs) with 1470 nm laser with 400 MUm radial fiber. BACKGROUND DATA: EVLA for perforating veins can be performed with insignificant postprocedural morbidity. This allows treatment to be offered to elderly patients with comorbidities that would preclude anesthesia for surgical treatment or subfascial endoscopic perforator surgery (SEPS). METHODS: A total of 24 perforating veins in 16 limbs of 13 patients were treated between July 2010 and December 2011 in our clinic. Follow-up duplex scans were performed at 1 week and 1, 3, 6, and 12 months after the procedure, to determine the treatment outcome. RESULTS: Of the 23 treated IPVs, 20 (86.9%) were occluded on the duplex examination at 12 months. The average energy administrated per perforating vein treated was 174 J (range 105-236 J). Four of five ulcers had healed after 8 weeks in clinical-etiology-anatomy-pathophysiology (CEAP) C6 group. Two patients reported localized paresthesia, which subsided spontaneously, but no deep venous thrombosis or skin burn was observed. All components of the Venous Clinical Severity Score (VCSS) demonstrated significant improvements at each postprocedural visit (p<0.001 for all), except for pigmentation and compression, which exhibited variation throughout the follow-up period. CONCLUSIONS: Especially in the case of liposclerotic or ulcerated skin in the affected region, EVLA of IPVs with 1470 nm diode laser is highly effective and safe, and appears to be feasible. Additionally, repeat treatment can easily be performed should recurrence of IPVs arise. PMID- 23030520 TI - Salvia x jamensis J. Compton: Trichomes, essential oil constituents and cytotoxic apoptotic activity. AB - Salvia x jamensis J. Compton is a hybrid between Salvia greggii A. Gray and Salvia microphylla Kunt. In this study, we describe three hair types identified by Scanning Electron Microscopy. In the essential oil of the aerial parts of S. jamensis 56 different compounds were identified. The two main constituents were beta-caryophyllene (14.8%) and beta-pinene (6.8%). Cytotoxic-apoptotic activity of S. x jamensis essential oil has been investigated by using U937 cell line. The essential oil EC50 for cell number and for cell apoptosis have been shown to be 360 and 320 ug mL(-1), respectively. Among the constituents of the oil examined, only beta-caryophyllene, beta-pinene and alpha-pinene displayed cytotoxic and apoptotic activities. For the first time, it has been demonstrated that some of the pure constituents identified within S. x jamensis essential oil are responsible for its cytotoxic-apoptotic activity when properly combined. PMID- 23030521 TI - A multiresistant clone of Pseudomonas aeruginosa sequence type 773 spreading in a burn unit in Orumieh, Iran. AB - Herein, we describe the phenotypic and genotypic characterization of a multiresistant clone of Pseudomonas aeruginosa disseminating in a burn unit in Orumieh, Iran. A total of 58 isolates of P. aeruginosa were collected during August 2007 and June 2008. Minimum inhibitory concentrations (MICs) of P. aeruginosa isolates were determined against 11 antimicrobial agents by E test. Serotyping, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were used for studying the clonal relationship among the isolates. Antibiotic susceptibility testing revealed that most of the isolates were multidrug resistant and colistin was the antibiotic with the highest activity. Pseudomonas aeruginosa isolates fell into nine different serotypes, and O10 and O11 were the most common. PFGE analyses showed 12 different genotypes and 68.1% of isolates showed more than 80% similarity, indicating possible clonal relatedness. These isolates were found to belong to the same sequence type, ST773. This sequence type has earlier been reported from China, and a double locus variant of this ST has been found earlier in France in a PER-1 extended spectrum beta-lactamase-producing P. aeruginosa. PMID- 23030522 TI - Increased Rab25 expression is not correlated with peritoneal metastasis of ovarian cancers. AB - Ovarian cancer is the leading cause of death in gynecological cancer. Studies suggested Rab25 is involved in the pathogenesis of ovarian cancers. We here investigated the expression of Rab25 is in all ovarian cancers and whether the expression of Rab25 is associated with peritoneal metastasis. Fifty-nine ovarian cancer patients were included and the levels of Rab25 measured by immunohistochemistry. Our data showed Rab25 was highly expressed in all subtypes of epithelial ovarian cancers, and two subtypes of germ cell tumors, but not in sex cord stromal tumors. Furthermore, the Rab25 expression was not correlated with peritoneal metastasis of ovarian cancer. PMID- 23030523 TI - Generation of toxic degradation products by sonication of Pluronic(r) dispersants: implications for nanotoxicity testing. AB - Poloxamers (known by the trade name Pluronic(r)) are triblock copolymer surfactants that contain two polyethylene glycol blocks and one polypropylene glycol block of various sizes. Poloxamers are widely used as nanoparticle dispersants for nanotoxicity studies wherein nanoparticles are sonicated with a dispersant to prepare suspensions. It is known that poloxamers can be degraded during sonication and that reactive oxygen species contribute to the degradation process. However, the possibility that poloxamer degradation products are toxic to mammalian cells has not been well studied. We report here that aqueous solutions of poloxamer 188 (Pluronic(r) F-68) and poloxamer 407 (Pluronic(r) F 127) sonicated in the presence or absence of multi-walled carbon nanotubes (MWNTs) can became highly toxic to cultured cells. Moreover, toxicity correlated with the sonolytic degradation of the polymers. These findings suggest that caution should be used in interpreting the results of nanotoxicity studies where the potential sonolytic degradation of dispersants was not controlled. PMID- 23030524 TI - Assessing HER2 amplification by IHC, FISH, and real-time polymerase chain reaction analysis (real-time PCR) following LCM in formalin-fixed paraffin embedded tissue from 40 women with ovarian cancer. AB - We compare HER2 receptor amplification analysis by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and real-time polymerase chain reaction (real-time PCR) DNA copy-number assay following laser capture microdissection (LCM) in formalin-fixed paraffin embedded tissue from 40 women with verified ovarian cancer. We speculate that LCM should result in a more accurate assessment of HER2 amplification in our real-time PCR assay compared with IHC and FISH. HER2 overexpression measured by IHC, FISH, or real-time PCR was found in 5.0%, 5.0%, and 22.5%, respectively. HER2 negative results measured by IHC, FISH, or real-time PCR were found in 95%, 92.5%, and 60.0%, respectively. Analysis failed for IHC, FISH, or real-time PCR in 0%, 2.5%, or 17.5% of cases. Concordance between IHC and FISH, IHC and real-time PCR, or FISH and real-time PCR were 89.7%, 72.7%, or 78.1%, respectively. Only few ovarian cancer patients were HER2 overexpressed measured by IHC or FISH and thus could be eligible for antibody-based therapy with trastuzumab (Herceptin). Interestingly, we find an increased number of HER2 positive patients by real-time PCR analysis on microdissected cancer cells, suggesting a number of HER2 positive patients not detected by current methods. Thus, the concept of quantitative measurement of HER2 on microdissected cancer cells should be explored further. PMID- 23030525 TI - Fundamental questions before recording or measuring functioning and disability. AB - PURPOSE: This paper seeks to contribute to thoughtful description, recording and measurement of functioning, by discussing some fundamental questions to consider before starting, framed as: why, what, how and who. METHOD: Generic literature on measurement methods and the more specialised literature on application of the ICF over the last decade inform the consideration of these questions. The context of recording or measurement is examined, including the moral and legal framework of the UN Convention on the Rights of Persons with Disabilities (UNCRPD) and the technical framework of the International Classification of Functioning, Disability and Health (ICF). RESULTS: Whatever the setting in which describing, recording or measuring is being undertaken - in policy development, service planning and management, clinical management or population health monitoring - determining the purpose is the key starting point. Purpose (why) frames the consideration of content (what), method (how) and source (who). Many generic measurement methods can be applied in the disability field, but there are challenges particular to the field. The perspectives of people with disabilities and "patients" require consideration, especially with the trend to person-centred care and the social justice principles emanating from the UNCRPD. CONCLUSIONS: Considering these basic questions is a pre-requisite to meaningful recording and measurement of functioning and disability. Future challenges include: incorporating environmental factors into measurement; setting thresholds on the disability spectrum; and combining the views of the person concerned with those of various professionals. PMID- 23030526 TI - Enhancement of immune response induced by DNA vaccine cocktail expressing complete LACK and TSA genes against Leishmania major. AB - Leishmaniasis is an important disease in humans. Leishmania homologue of receptor for Activated C Kinase (LACK) and thiol specific antioxidant (TSA) as immuno dominant antigens of Leishmania major are considered the most promising molecules for a DNA vaccine. We constructed a DNA cocktail, containing plasmids encoding LACK and TSA genes of Leishmania major and evaluated the immune response and survival rate in BALB/c mice. IgG and Interferon gamma values were noticeably increased in the immunized group with DNA cocktail vaccine, which were significantly higher than those in the single-gene vaccinated and control groups (p < 0.05) following the immunization and after challenging with Leishmania major. Interleukin 4 values were decreased in all immunized groups, but only in DNA vaccine cocktail and single-gene vaccination with pc-LACK there were statistical differences with control groups (p > 0.05). The immunized mice with the cocktail DNA vaccine presented a considerable reduction in diameter of lesion compared to other groups and a significant difference was observed (p < 0.05) in this regard. The survival time of the immunized mice with the cocktail DNA vaccine was significantly higher than that in the other groups (p < 0.05) after their being challenged with Leishmania major. The findings of this study indicated that the cocktail DNA vaccine increased the cellular response and survival rate and induced protection against infection with Leishmania in the mice. PMID- 23030527 TI - Synthesis of bacillithiol and the catalytic selectivity of FosB-type fosfomycin resistance proteins. AB - Bacillithiol (BSH) has been prepared on the gram scale from the inexpensive starting material, D-glucosamine hydrochloride, in 11 steps and 8-9% overall yield. The BSH was used to survey the substrate and metal-ion selectivity of FosB enzymes from four Gram-positive microorganisms associated with the deactivation of the antibiotic fosfomycin. The in vitro results indicate that the preferred thiol substrate and metal ion for the FosB from Staphylococcus aureus are BSH and Ni(II), respectively. However, the metal-ion selectivity is less distinct with FosB from Bacillus subtilis, Bacillus anthracis, or Bacillus cereus. PMID- 23030528 TI - Suspected collagen disorders in the bleeding disorder clinic: a case-control study. AB - Disorders of collagen are associated with a mild bleeding tendency because of the potential abnormal interaction of collagen, von Willebrand factor (VWF) and platelets required during primary haemostasis and due to generalized soft tissue fragility. Abnormal collagen may contribute to bleeding in existing mucocutaneous bleeding disorders, but the prevalence in this setting is unknown. Generalized symptomatic joint hypermobility (SJH) is common in collagen disorders and may be objectively measured. To assess the association between symptomatic joint hypermobility and mucocutaneous bleeding disorders, we performed a case-control study in which case subjects were 55 consecutive individuals who had visited our bleeding disorder clinic with a diagnosis of von Willebrand disease, low von Willebrand factor levels, mild platelet function disorder or undefined bleeding disorder. Controls were 50 subjects without a bleeding disorder, and were age and gender matched to the cases. All subjects were assessed with: (i) Beighton score for joint hypermobility, (ii) revised Brighton criteria, (iii) Condensed MCMDM1 VWD bleeding questionnaire, and (iv) haemostasis laboratory studies. The prevalence of SJH/suspected collagen disorder in the bleeding disorder clinic was 24% (13/55) compared with 2% (1/50) in the control population (OR 15, 95% CI 2 121). Seventy-seven per cent of bleeding disorder clinic SJH subjects (10/13) had a prior personal or family history of Ehlers-Danlos, Benign Joint Hypermobility Syndrome or Osteogenesis Imperfecta (OI). Symptomatic joint hypermobility was associated with increased odds of an underlying mucocutaneous bleeding disorder. These findings suggest that a collagen disorder is common and often unrecognized in the bleeding disorder clinic as a potential contributor to the bleeding symptoms. PMID- 23030530 TI - Crystal structures of Acetobacter aceti succinyl-coenzyme A (CoA):acetate CoA transferase reveal specificity determinants and illustrate the mechanism used by class I CoA-transferases. AB - Coenzyme A (CoA)-transferases catalyze transthioesterification reactions involving acyl-CoA substrates, using an active-site carboxylate to form covalent acyl anhydride and CoA thioester adducts. Mechanistic studies of class I CoA transferases suggested that acyl-CoA binding energy is used to accelerate rate limiting acyl transfers by compressing the substrate thioester tightly against the catalytic glutamate [White, H., and Jencks, W. P. (1976) J. Biol. Chem. 251, 1688-1699]. The class I CoA-transferase succinyl-CoA:acetate CoA-transferase is an acetic acid resistance factor (AarC) with a role in a variant citric acid cycle in Acetobacter aceti. In an effort to identify residues involved in substrate recognition, X-ray crystal structures of a C-terminally His(6)-tagged form (AarCH6) were determined for several wild-type and mutant complexes, including freeze-trapped acetylglutamyl anhydride and glutamyl-CoA thioester adducts. The latter shows the acetate product bound to an auxiliary site that is required for efficient carboxylate substrate recognition. A mutant in which the catalytic glutamate was changed to an alanine crystallized in a closed complex containing dethiaacetyl-CoA, which adopts an unusual curled conformation. A model of the acetyl-CoA Michaelis complex demonstrates the compression anticipated four decades ago by Jencks and reveals that the nucleophilic glutamate is held at a near-ideal angle for attack as the thioester oxygen is forced into an oxyanion hole composed of Gly388 NH and CoA N2". CoA is nearly immobile along its entire length during all stages of the enzyme reaction. Spatial and sequence conservation of key residues indicates that this mechanism is general among class I CoA-transferases. PMID- 23030531 TI - Introduction: HCNE Stowe meeting 2012. PMID- 23030532 TI - Dangerous and thunderclap headaches. AB - The International Classification of Headache Disorders-II considers dangerous and thunderclap headaches as secondary headaches--in other words due to an underlying cause. Many, but not all of the underlying etiologies, are vascular disorders, and many are potentially life threatening. An especially comprehensive clinical approach is necessary when seeing patients with these potential disorders. PMID- 23030533 TI - Acute treatment of migraine: established and emerging therapies. AB - Migraine is a chronic, episodic, often disabling, neurological condition that affects more than 12% of the US population, 3 times more in women than men. It has widespread effects on cerebral function and appears to be inherited. There are many types of therapy including behavioral, complementary, acute pharmacologic care, preventive pharmacologic care, and physical techniques. General treatment principles include lifestyle changes and using rapidly acting acute care medications alone or in combination early in the migraine attack. Migraine-specific medications such as triptans and non steroidal anti inflammatory drugs should be used when possible. There are several promising medications and devices in the migraine pipeline. PMID- 23030534 TI - Preventive treatment of migraine. AB - Migraine is a prevalent and disabling episodic brain state with protean symptoms dominated by headache. When migraine attacks are frequent or severe over a sustained period, use of daily preventive medications are indicated to significantly reduce disability and improve quality of life. Recently issued evidence-based guidelines outline an array of pharmaceutical and complementary treatment choices with data establishing them as effective or probably effective for prevention of episodic or menstrually associated migraine. OnabotulinutoxinA is the only Food and Drug Administration-approved medication for the prevention of chronic migraine. PMID- 23030535 TI - Mind/Body and behavioral treatments: the evidence and approach. AB - Nonpharmacological treatments may help many patients with headaches. This review addresses the most common questions about nondrug treatment options from the perspective of patients by (1) defining behavioral and mind/body treatments, (2) discussing the research evidence supporting their use, and (3) describing their role in the management of headaches. Research suggests that mind/body and behavioral treatments may decrease the frequency of migraine or tension-type headaches by 35-50%, an effect size comparable with those observed in medication trials but with fewer side effects than drugs. Most benefit seems to occur in those who combine medications with nonpharmacological treatments. Despite the fact that research evidence for behavioral treatment of headaches is stronger than that for specific mind/body treatments, research shows that adults with headache in the general population are more likely to use mind/body treatments. Nondrug treatments may have a longer time to onset of benefits than drugs, but their effect may be broader and more durable because they may improve stress, coping, and self-efficacy. Additional research is needed to address other questions that patients and their physicians may have about these interventions. PMID- 23030536 TI - Herbal treatment of headache. AB - Herbal (botanical) therapy has been used as treatment for headache disorders for millennia. Botanical therapy can be divided into 3 categories: oral, topical, and "aromatherapy." In this article, the options in these categories and the evidence supporting their use are discussed. Unfortunately, evidence is sparse for most herbal treatments, in large part due to a paucity of funding for the type of studies needed to assess their efficacy. Butterbur and feverfew are the 2 herbal oral preparations best studied, and they seem to have real potential to help many patients with migraine and perhaps other headache types. Patients most appropriate for trials of herbal therapy include those who have been refractory to pharmaceutical and other modes of therapy, patients who have had intolerable side effects from pharmaceutical medications, and patients willing to participate in controlled comparative studies. As for mechanisms behind botanical treatments, the lack of funding for studying these agents will continue to retard progress in this area as well, but hopefully the future will bring more concentrated efforts in this field. PMID- 23030537 TI - CoEnzyme Q10 and riboflavin: the mitochondrial connection. AB - OBJECTIVE: We conducted a short review of relevant literature which contends that migraine is associated with a wide-spread metabolic abnormality of mitochondrial oxidative metabolism, leading to the use of riboflavin and coenzyme Q10 as prophylactic therapy for migraine. BACKGROUND: Riboflavin and coenzyme Q10 supplementation has been recommended widely as safe and effective prophylactic therapy for migraine. The background neurophysiological studies that led to the development of this therapy, which are extremely complex, deserve wider distribution. METHODS: A brief review of the relevant literature was conducted and summarized. RESULTS: Brain energy metabolism in migraine has been found to be abnormal in all types of migraine, making the migrainous brain hyper-responsive to many stimuli. The metabolic abnormalities are more severe in the more-severe types of migraine, such as hemiplegic migraine and migrainous stroke, but they are present both during and between attacks. The metabolic abnormality in migraine extends beyond the brain to platelets and muscles, as proven by techniques of biochemistry, muscle morphology, and nuclear magnetic spectroscopy. There are strong similarities between migraine and certain inborn errors of metabolism, the metabolic encephalomyopathies, in which patients suffer genetic abnormalities in mitochondrial energy production to produce lactic acidosis, stroke, and migraine headaches. The theory of migraine as a mitochondrial disorder seems to have abundant evidence. However, aside from the genetic abnormalities discovered for the familial hemiplegic migraines, molecular genetic studies in migraine have been negative until recently, when whole genome sequencing has now reported positive results. CONCLUSION: Arising from these extensive neurophysiological studies, the treatment of metabolic encephalomyopathies with pharmacological doses of riboflavin and coenzyme Q10 has shown positive benefits. The same treatment has now been applied to migraine, adding clinical support to the theory that migraine is a mitochondrial disorder. PMID- 23030538 TI - Risk stratification with opioid therapy. AB - The use of chronic opioid therapy for persistent headache remains controversial because of limited supporting data and potential risks. In addition to possible individual risks for the patient, society risks associated with diversion and substance abuse are well documented. Few studies directly address risk stratification for opioid therapy where a diagnosis of headache is present, making it necessary to extrapolate from other pain research when developing recommendations for screening and patient management. Considering the historical framework of opioid prescribing, relevant studies assessing risk stratification of chronic opioid therapy are reviewed. Specific risk factors that may lead to a problematic course with chronic opioid therapy are outlined. Both clinical experience and the limited empirical research underscore the need for multiple assessment tools and ongoing patient monitoring in the evaluation of these risk factors. PMID- 23030539 TI - Hallucinogens and cannabinoids for headache. AB - Most hallucinogens and cannabinoids fall into Federal Controlled Substances schedule 1, meaning they cannot be prescribed by practitioners, allegedly have no accepted medical use, and have a high abuse potential. The legal and regulatory status has inhibited clinical research on these substances such that there are no blinded studies from which to assess true efficacy. Despite such classification, hallucinogens and cannabinoids are used by patients with headache on occasion. Cannabinoids in particular have a long history of use for headache and migraine before prohibition and are still used by patients as a migraine abortive. Hallucinogens are being increasing used by cluster headache patients outside of physician recommendation mainly to abort a cluster period and to maintain quiescence for which there is considerable anecdotal success. PMID- 23030540 TI - Pain, emotion, headache. AB - Pain has been considered as part of a defensive strategy whose specific role is to signal an immediate active danger to the organism. This definition fits well for acute pain. It does not work well, however, for chronic pain that is maintained even in absence of an ongoing, active threat. Currently, acute and chronic pain are considered to be separate conditions. What follows is a review of the different theories about pain and its history. Different hypotheses regarding pain mechanisms are illustrated. New data emerging from scientific research on chronic pain (migraine in particular) involving innovative imaging techniques are reported and discussed. PMID- 23030542 TI - Identification of novel genes involved in migraine. AB - BACKGROUND: Migraine is a common form of headache affecting about 12% of the population. Genetic studies in the rare form of familial hemiplegic migraine have identified mutations in 3 genes (CACNA1A, ATP1A2, and SCN1A) encoding proteins involved in ion homeostasis and suggesting that other such genes may be involved in the more common forms of migraine. OBJECTIVES: To test this proposition, the coding regions of 150 brain-expressed genes involved in ion homeostasis (ion channels, transporters, exchangers, and accessory subunits) were systematically screened to identify DNA variants in a group of 110 migraine probands and 250 control samples. METHODS: DNA variants were analyzed using a number of complementary in silico approaches. RESULTS: Several genes encoding potassium channels, including KCNK18, KCNG4, and KCNAB3, were identified as potentially linked to migraine. In situ hybridization studies of the mouse Kcnk18 ortholog show that it is developmentally expressed in the trigeminal and dorsal root ganglia, further supporting the involvement of this gene in migraine pathogenesis. CONCLUSIONS: Our study is the first to link variations in these K(+) channel genes to migraine, thus expanding on the view of migraine as a channelopathy and providing potential molecular targets for further study and therapeutic applications. PMID- 23030543 TI - The clinical overlap of multiple sclerosis and headache. AB - Multiple sclerosis (MS) and migraine headache coexist in many young female patients. Whether this is coincidental or causally linked remains unclear. The presenting symptoms and signs of MS relapse and migraine aura can be similar and should be differentiated by careful history and examination to ensure proper diagnosis and treatment. White matter lesions on magnetic resonance imaging have specific patterns for each entity and also need to be interpreted carefully. Although a clear link has not been established between migraine and MS, numerous studies have been reported assessing risks, prevalence, and causation. Complicating these assessments are the disease-modifying therapies used to treat MS which have been known to be implicated in causing headache. The recent development of novel treatment options for MS requires practitioners to be aware of polypharmacy and potential drug interactions. PMID- 23030541 TI - Migraine: maladaptive brain responses to stress. AB - Migraine offers a unique model to understand the consequences of repeated stressors on the brain. Repeated stressors can alter the normal response of physiological systems, and this concept has been termed "allostatic load." In the case of the brain, the effects of repeated stress may lead to alteration in brain networks both functionally and structurally. As a result, the brain responds abnormally to environmental conditions (psychological or physiological). Here, we present an alternative perspective on migraine disease and propose that changes in brain states may occur as a result of repeated migraine attacks through maladaptive coping mechanisms. The cascade of these effects can lead to further deterioration of adaptation and thus lead to transformation or chronification of the disease. PMID- 23030544 TI - Bioaugmentation of sewage sludge with Trametes versicolor in solid-phase biopiles produces degradation of pharmaceuticals and affects microbial communities. AB - The use of sludge (biosolids) in land application may contribute to the spread of organic micropollutants as wastewater treatments do not completely remove these compounds. Therefore, the development of alternative strategies for sludge treatment is a matter of recent concern. The elimination of pharmaceuticals at pre-existent concentrations from sewage sludge was assessed, for the first time, in nonsterile biopiles by means of fungal bioaugmentation with Trametes versicolor (BTV-systems) and compared with the effect of autochthonous microbiota (NB-systems). The competition between the autochthonous fungal/bacterial communities and T. versicolor was studied using denaturing gradient gel electrophoresis (DGGE) and the cloning/sequencing approach. An inhibitory effect exerted by T. versicolor over bacterial populations was suggested. However, after 21 days, T. versicolor was no longer the main taxon in the fungal communities. The elimination profiles revealed an enhanced removal of atorvastatin-diclofenac hydrochlorothiazide (during the whole treatment) and ranitidine-fenofibrate (at short periods) in the BTV biopiles in respect to NB biopiles, coincident with the presence of the fungus. For ibuprofen-clarithromycin-furosemide, the elimination profiles were similar irrespective of the system, and with carbamazepine no significant degradation was obtained. The results suggest that a fungal treatment with T. versicolor could be a promising process for the remediation of some pharmaceuticals in complex matrices such as biosolids. PMID- 23030546 TI - Umbilical cord knots and cord blood gases, erythropoietin and nucleated red blood cell levels: a study of possible chronic fetal hypoxia. PMID- 23030547 TI - Catalytic functionalization of unactivated sp3 C-H bonds via exo-directing groups: synthesis of chemically differentiated 1,2-diols. AB - We describe a Pd-catalyzed site-selective functionalization of unactivated aliphatic C-H bonds, providing chemically differentiated 1,2-diols from monoalcohol derivatives. The oxime was employed as both a directing group (DG) and an alcohol surrogate for this transformation. As demonstrated in a range of substrates, the C-H bonds beta to the oxime group are selectively oxidized. Besides activation of the methyl groups, methylene groups (CH(2)) in cyclic substrates and methine groups (CH) at bridge-head positions can also be functionalized. In addition, an intriguing oxidative skeleton rearrangement was observed using the menthol-derived substrate. The use of exo-directing groups in C-H activation, as illustrated in this work, would potentially open doors for the discovery of new transformations and new cleavable DGs. PMID- 23030548 TI - Spectroscopic imaging of photopotentials and photoinduced potential fluctuations in a bulk heterojunction solar cell film. AB - We present spatially resolved photovoltage spectra of a bulk heterojunction solar cell film composed of phase-separated poly(9,9'-dioctylfluorene-co benzothiadiazole) (F8BT) and poly(9,9'-dioctylfluorene-co-bis-N,N'-(4 butylphenyl)-bis-N,N'-phenyl-1,4-phenylenediamine) (PFB) polymers prepared on ITO/PEDOT:PSS and aluminum substrates. Over both PFB- and F8BT-rich domains, the photopotential spectra were found to be proportional to a linear combination of the polymers' absorption spectra. Charge trapping in the film was studied using photopotential fluctuation spectroscopy, in which low-frequency photoinduced electrostatic potential fluctuations were measured by observing noise in the oscillation frequency of a nearby charged atomic force microscope cantilever. Over both F8BT- and PFB-rich regions, the magnitude, distance dependence, frequency dependence, and illumination wavelength dependence of the observed cantilever frequency noise are consistent with photopotential fluctuations arising from stochastic light-driven trapping and detrapping of charges in F8BT. Taken together, our findings suggest a microscopic mechanism by which intermixing of phases leads to charge trapping and thereby to suppressed open-circuit voltage and decreased efficiency in this prototypical bulk heterojunction solar cell film. PMID- 23030549 TI - Insights into the drug resistance induced by the BaDHPS mutations: molecular dynamic simulations and MM/GBSA studies. AB - Dihydropteroate synthase (DHPS) is essential for the folic acid biosynthetic pathway in prokaryotes; the mutation forms for DHPS are found to be relative to the urgent drug resistance problems. In our study, the Bacillus anthracis DHPS (BaDHPS) was selected for molecular dynamics and binding free energy studies to investigate the biochemistry behaviors of the wild-type and mutation form BaDHPS proteins (D184N and K220Q). It is found that the conformational change of the ligand dihydropteroate sulfathiazole binding site in mutation D184N and K220Q systems is mainly attributed from the Loop 1, Loop 2, and Loop 7 regions, and the binding free energy of these mutation systems is lower than that of the wild-type system. Additionally, some important hydrogen bonds of the mutation systems are disrupted during the simulations. But the shortening of the distance between residue Thr67 and the ligand would cause significant change of the binding pose in the K220Q system. These studies of DHPS family will be helpful for further drug resistance investigations. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:24. PMID- 23030550 TI - Improved electrochemical capacity of precursor-derived Si(B)CN-carbon nanotube composite as Li-ion battery anode. AB - We study the electrochemical behavior of precursor-derived siliconboron carbonitride (Si(B)CN) ceramic and Si(B)CN coated-multiwalled carbon nanotube (CNT) composite as a lithium-ion battery anode. Reversible capacity of Si(B)CN was observed to be 138 mA h/g after 30 cycles, which is four times that of SiCN (~25 mA h/g) processed under similar conditions, while the Si(B)CN-CNT composite showed further enhancement demonstrating 412 mA h/g after 30 cycles. Improved performance of Si(B)CN is attributed to the presence of boron that is known to modify SiCN's nanodomain structure resulting in improved chemical stability and electronic conductivity. Post-cycling microscopy and chemical analysis of the anode revealed formation of a stable passivating layer, which resulted in stable cycling. PMID- 23030552 TI - Incisor inclination changes produced by two compliance-free Class II correction protocols for the treatment of mild to moderate Class II malocclusions. AB - OBJECTIVE: To compare the changes in incisor inclination between two compliance free Class II correction protocols for the treatment of mild to moderate Class II malocclusions. MATERIALS AND METHODS: Among Class II malocclusion patients a total of 38 consecutive patients treated with the Xbow appliance and later with full brackets (XB) were compared to 36 consecutive patients treated with Forsus connected to the archwire while on full brackets (FO). Evaluated cephalometric variables were overjet, overbite, skeletal Class II, lower incisor inclination, and upper incisor inclination. Factors that were analyzed were gender, treatment type, age at start of treatment (T1), and treatment length. Independent t-tests, chi(2), multiple analysis of variance, and Pearson correlations were applied. RESULTS: No differences in incisor inclination between both treatment protocols were identified. At T1 no statistical difference for any cephalometric variable was demonstrated with regard to gender and treatment type. Gender was also not associated with a different treatment time or age at T1. The mean treatment time was 24.2 months for XB and 30.2 months for the FO group (P = .037). XB patients averaged 10 fewer months of fixed edgewise appliances compared to FO patients. Neither gender nor treatment type had any influence on the changes of the evaluated dependent variables between T1 and the end of treatment. Lower incisors proclined more the longer the treatment (P = .005). Both overjet and upper incisor inclination were affected by age at T1 (P = .001 and P = .014, respectively). CONCLUSIONS: Both compliance-free Class II correction protocols for the treatment of mild to moderate Class II malocclusions appear to generate the same amount of incisor inclination. Large variability was identified. PMID- 23030553 TI - In vivo microcomputed tomography evaluation of rat alveolar bone and root resorption during orthodontic tooth movement. AB - OBJECTIVE: To observe the real-time microarchitecture changes of the alveolar bone and root resorption during orthodontic treatment. MATERIALS AND METHODS: A 10 g force was delivered to move the maxillary left first molars mesially in twenty 10-week-old rats for 14 days. The first molar and adjacent alveolar bone were scanned using in vivo microcomputed tomography at the following time points: days 0, 3, 7, and 14. Microarchitecture parameters, including bone volume fraction, structure model index, trabecular thickness, trabecular number, and trabecular separation of alveolar bone, were measured on the compression and tension side. The total root volume was measured, and the resorption crater volume at each time point was calculated. Univariate repeated measures analysis of variance with Bonferroni corrections were performed to compare the differences in each parameter between time points with significance level at P < .05. RESULTS: From day 3 to day 7, bone volume fraction, structure model index, trabecular thickness, and trabecular separation decreased significantly on the compression side, but the same parameters increased significantly on the tension side from day 7 to day 14. Root resorption volume of the mesial root increased significantly on day 7 of orthodontic loading. CONCLUSIONS: Real-time root and bone resorption during orthodontic movement can be observed in 3 dimensions using in vivo micro-CT. Alveolar bone resorption and root resorption were observed mostly in the apical third on day 7 on the compression side; bone formation was observed on day 14 on the tension side during orthodontic tooth movement. PMID- 23030554 TI - The challenges for drug development: cytokines, genes, and stem cells. PMID- 23030556 TI - Advancing health literacy research. PMID- 23030557 TI - Health literacy and the disenfranchised: the importance of collaboration between limited English proficiency and health literacy researchers. AB - Inadequate health literacy and limited English proficiency are associated with poor health care access and outcomes. Despite what appears to be an interaction phenomenon--whereby the rate of inadequate health literacy is particularly high among limited English proficiency populations--researchers in health literacy and limited English proficiency rarely collaborate. As a result, few health literacy instruments and interventions have been developed or validated for smaller linguistic populations. Interventions to improve health outcomes for people with low health literacy and limited English proficiency show great potential to alleviate many of the health disparities currently experienced by some of the most disenfranchised individuals in our health care system, those from smaller linguistic minority groups, including Deaf American Sign Language users. It is critical for health literacy and limited English proficiency researchers to work together to understand how culture, language, literacy, education, and disabilities influence health disparities and health outcomes. It is important to ensure that research is collaborative and inclusive in order to broaden the reach of future interventions to smaller linguistic minority populations. PMID- 23030558 TI - What do health literacy and cultural competence have in common? Calling for a collaborative health professional pedagogy. AB - Limited health literacy is recognized as contributing to racial/ethnic and other health disparities through mechanisms of poor understanding and adherence, as well as to limited access to health care. Recent studies have focused on interventions to address literacy gaps between patients and health care providers, focusing on communication techniques and redefining the responsibility for closing gaps. Cultural differences between patient and provider, if left unaddressed, have been shown to contribute to poor health outcomes through misunderstanding, value conflicts, and disparate concepts of health and illness. The dual challenges of limited health literacy and cultural differences are likely to increase with an expanding, increasingly diverse, and older population. There is evidence that training providers to attend to both issues can reduce medical errors, improve adherence, patient-provider-family communication, and outcomes of care at both individual and population levels. The two fields continue to have separate trajectories, vocabularies, and research agendas, competing for limited curricular resources. This article presents a conceptual framework for health professions education that attends simultaneously to limited health literacy and cultural differences as a coherent way forward in training culturally competent providers with a common skill-set to deliver patient centered care that focuses on health disparities reduction. PMID- 23030559 TI - The role of information technology in health literacy research. AB - Without concerted effort, the current explosion in health information technology will further widen the digital health divide for individuals with inadequate health literacy. However, with focused investment of time and energy, technology has the potential for reducing disparities through intelligent, usable, and accessible systems that tailor information, advice, counseling, and behavioral support to an individual's need at a given time and place. PMID- 23030560 TI - The health literacy skills framework. AB - Although there are a variety of models and frameworks that describe factors that are associated with health literacy skills, few illustrate the full pathway from development and moderators of health literacy skills, their application, and the outcomes that result all in one framework or model. This article introduces the Health Literacy Skills conceptual framework that does encompass this full continuum. To develop the framework, the authors reviewed and built upon existing health literacy frameworks. The Health Literacy Skills framework hypothesizes the relations between health literacy and health-related outcomes and depicts how health literacy functions at the level of the individual. The framework also reflects how factors external to the individual (e.g., family, setting, community, culture, and media) influence the constructs and relations represented in the framework. The framework is organized into 4 primary components: (a) factors that influence the development and use of health literacy skills; (b) health-related stimuli; (c) health literacy skills needed to comprehend the stimulus and perform the task; and (d) mediators between health literacy and health outcomes. Previous theoretical frameworks lend support to the proposed causal pathways it illustrates. The authors hope this conceptual framework can serve as a springboard for further discussion and advancement in operationalizing this complex construct. The Health Literacy Skills framework could also be used to guide the development of interventions to improve health literacy. Future research should be conducted to fully test the relations in the framework. PMID- 23030561 TI - Advancing organizational health literacy in health care organizations serving high-needs populations: a case study. AB - Health care organizations, well positioned to address health literacy, are beginning to shift their systems and policies to support health literacy efforts. Organizations can identify barriers, emphasize and leverage their strengths, and initiate activities that promote health literacy-related practices. The current project employed an open-ended approach to conduct a needs assessment of rural federally qualified health center clinics. Using customized assessment tools, the collaborators were then able to determine priorities for changing organizational structures and policies in order to support continued health literacy efforts. Six domains of organizational health literacy were measured with three methods: environmental assessments, patient interviews, and key informant interviews with staff and providers. Subsequent strategic planning was conducted by collaborators from the academic and clinic teams and resulted in a focused, context-appropriate action plan. The needs assessment revealed several gaps in organizational health literacy practices, such as low awareness of health literacy within the organization and variation in perceived values of protocols, interstaff communication, and patient communication. Facilitators included high employee morale and patient satisfaction. The resulting targeted action plan considered the organization's culture as revealed in the interviews, informing a collaborative process well suited to improving organizational structures and systems to support health literacy best practices. The customized needs assessment contributed to an ongoing collaborative process to implement organizational changes that aided in addressing health literacy needs. PMID- 23030562 TI - Chronic disease self-management and health literacy in four ethnic groups. AB - Research from several fields has explored health literacy as a multidimensional construct. The authors' multimethod study, "The Impact of Cultural Differences on Health Literacy and Chronic Disease Outcomes," assessed health literacy and chronic disease self-management among 296 patients from four ethnic groups (Vietnamese, African American, White, Latino) at a Massachusetts community health center between 2006 and 2010. Health literacy was assessed using the short form of the Test of Functional Health Literacy in Adults (S-TOFHLA), the Rapid Estimate of Adult Literacy in Medicine (REALM), and the Short Assessment of Health Literacy for Spanish-speaking Adults (SAHLSA) measures. Qualitative research methods, including in-depth interviews (n = 34), home visits (n = 12), chronic disease diaries (n = 15), and focus groups (n = 47), were completed with a subset of participants. Qualitative interviews indicated a wide range of interpretations of S-TOFHLA questions in which participants substituted their own illness or health care experiences for the abstract examples offered in the instrument, at times leading to incorrect responses. Situating these responses in a broader social and cultural context, this article describes examples of the wide range of chronic disease self-management abilities among participants with limited education and/or low health literacy. It also discusses the culturally variable health beliefs identified among participants interviewed that may play important roles in their chronic disease self-management practices. PMID- 23030563 TI - Low health literacy, limited English proficiency, and health status in Asians, Latinos, and other racial/ethnic groups in California. AB - This study estimated health status by low health literacy and limited English proficiency alone and in combination for Latino, Chinese, Korean, Vietnamese, and White respondents in a population-based sample: 48,427 adults from the 2007 California Health Interview Survey, including 3,715 with limited English proficiency. Multivariate logistic models examined self-reported health by health literacy and English proficiency in the full sample and in racial/ethnic subgroups. Overall, 44.9% with limited English proficiency reported low health literacy, versus 13.8% of English speakers. Among the limited English proficient, Chinese respondents had the highest prevalence of low health literacy (68.3%), followed by Latinos (45.3%), Koreans (35.6%), Vietnamese (29.7%), and Whites (18.8%). In the full sample, respondents with both limited English proficiency/low health literacy reported the highest prevalence of poor health (45.1%), followed by limited English proficiency-only (41.1%), low health literacy-only (22.2%), and neither (13.8%), a hierarchy that remained significant in multivariate models. However, subanalyses revealed that limited English proficient Latinos, Vietnamese, and Whites had equal or greater odds of poor health compared with low health literate/limited English proficient respondents. Individuals with both limited English proficiency and low health literacy are at high risk for poor health. Limited English proficiency may carry greater health risk than low health literacy, though important racial/ethnic variations exist. PMID- 23030564 TI - Prevalence of limited health literacy among Irish adults. AB - The authors conducted 2 health literacy investigations in Cork, Ireland. Study 1 was undertaken in 5 community pharmacies and the outpatient department of 2 urban hospitals and assessed patients' health literacy skills using the Rapid Estimate of Adult Literacy in Medicine (REALM) and the Newest Vital Sign (NVS). Study 2 took place in 1 outpatient department and evaluated health literacy using the REALM and the short form of the Test of Functional Health Literacy.in Adults (S TOFHLA). The authors collected data relating to age, gender, ethnicity, and educational level achieved. All subjects were asked items relating to their ability to use health-specific materials. A total of 1,759 people (61.2% female) completed either Study 1 (n = 1,339) or Study 2 (n = 420). Limited health literacy ranged from 18.4% (REALM) and 57.2% (NVS) in Study 1, and 21.9% (REALM) and 14.1% (S-TOFHLA) in Study 2 and was associated with increased age and lower educational attainment across all three tools (p < .001). Patients with limited health literacy were significantly more likely to report problems with using health materials received from a doctor or pharmacist. At minimum, 1 in 7 Irish adults were found to have limited health literacy, which may affect their ability to promote, protect, and manage health. As in the United States and in the United Kingdom, improving health literacy should be a public health objective for Ireland. PMID- 23030565 TI - Do patient preferences for health information vary by health literacy or numeracy? A qualitative assessment. AB - Seeking health information can be a complicated process for a patient. Patients must know the topic of interest, where to look or ask, how to assess and comprehend, and how to evaluate the credibility and trustworthiness of the sources. In this study, the authors describe preferences of patients with multiple risk factors for cardiovascular disease with varying health literacy and numeracy abilities for receiving health information. Participants were recruited from 2 health care systems. Health literacy and numeracy were assessed and participants completed an orally administered survey consisting of open-ended questions about obtaining health information and preferences for health information. In-depth interviews were conducted with a subset of participants. A diverse sample of 150 individuals (11.3% Latino, 37.3% African American, 44.7% with income less than $15,000/year) participated. Most participants had adequate functional health literacy, while 65% had low numeracy skills. Regardless of health literacy or numeracy ability, participants overwhelmingly preferred to receive health information during a face-to-face conversation with their health care provider. While individuals with adequate functional health literacy identified a variety of health information sources, actions are needed to ensure multiple modalities are available and are in plain, clear language that reinforces patients' understanding and application of information to health behavior. PMID- 23030566 TI - Using health literacy and learning style preferences to optimize the delivery of health information. AB - Limited patient understanding of hypertension contributes to poor health outcomes. In 2 sequential randomized studies, the authors determined the impact of administering information tailored to health literacy level alone or in combination with preferred learning style on patients' understanding of hypertension. Patients with high blood pressure were recruited in an academic emergency department. In Experiment 1 (N = 85), the control group received only the routine discharge instructions; the intervention group received discharge instructions combined with information consistent with their health literacy level as determined by the Short Test of Functional Health Literacy. In Experiment 2 (N = 87), the information provided to the intervention group was tailored to both health literacy and learning style, as indicated by the VARKTM Questionnaire. To measure learning, the authors compared scores on a hypertension assessment administered during the emergency department visit and 2 weeks after discharge. Participants who received materials tailored to both health literacy level and learning style preference showed greater gains in knowledge than did those receiving information customized for health literacy level only. This study demonstrates that personalizing health information to learning style preferences and literacy level improves patient understanding of hypertension. PMID- 23030567 TI - Measurement variation across health literacy assessments: implications for assessment selection in research and practice. AB - National priorities and recent federal initiatives have brought health literacy to the forefront in providing safe accessible care. Having valid and reliable health literacy measures is a critical factor in meeting patients' health literacy needs. In this study, the authors examined variation across three brief health literacy instruments in categorizing health literacy levels and identifying associated factors. The authors screened 378 veterans using the short form of the Test of Functional Health Literacy in Adults; the Rapid Estimate of Adult Literacy in Medicine; and a 4-Item Brief Health Literacy Screening Tool (known as the BRIEF). They analyzed data using prevalence estimates, Pearson product moment correlations, and logistic regression. When categorizing individuals' health literacy, agreement among instruments was present for 37% of the sample. There were consistencies; however, categorization and estimated risk factors varied by instrument. Depending on instrument, increased age, low education, minority status, and self-reported poor reading level were associated with low health literacy. Findings suggest that these instruments measure health literacy differently and are likely conceptually different. As the use of health literacy screening gains momentum, alignment between instrument and intended purpose is essential; in some cases, multiple instruments may be appropriate. When selecting an instrument, one should consider style of administration, purpose for measure, and availability of time and resources. PMID- 23030568 TI - Addressing the "other" health literacy competencies--knowledge, dispositions, and oral/aural communication: development of TALKDOC, an intervention assessment tool. AB - Most health literacy assessments evaluate literacy skills including reading, writing; numeracy and interpretation of tables, graphs, diagrams and charts. Some assess understanding of health systems, and the ability to adequately apply one's skills to specific health-related tasks or demands in health situations. However, to achieve functional health literacy, the ability to "obtain, process, and understand basic health information and services needed to make appropriate health decisions," other health literacy dimensions should be assessed: a person's knowledge and attitudes about a health issue affects his or her ability to and interest in participating in his or her own care. In patient care settings, the abilities to listen, ask questions and check one's understanding are crucial to making appropriate decisions and carrying out instructions. Although literacy is a skill associated with educational attainment and therefore difficult to change in a short time, health education interventions can address health literacy domains such as knowledge, attitudes and oral communication skills. For this reason, an instrument that can assess these constructs is a valuable part of a health educator's toolbox. The authors describe the development and process and outcomes of testing a novel instrument targeted to assess HPV and cervical cancer health literacy competencies, TALKDOC, including its validation with the Health Activities Literacy Scale. PMID- 23030569 TI - Listenability as a tool for advancing health literacy. AB - Health literacy research and practice has focused mainly on the readability of written documents. Yet oral communication plays at least as important a role in the interpersonal ecology in which people make real decisions about their health. Moreover, the single-minded quest for short sentences and simple vocabulary inherent in the readability paradigm can subvert the effort to engage in patient- or consumer-centered communication. Listenability is the quality of discourse that eases the cognitive burden that aural processing imposes. Listenability is a function of oral-based language plus "considerate" rhetorical structures. The Listenability Style Guide presented in this article offers evidence-based recommendations for producing listenable discourse. A study testing the applicability of the Listenability Style Guide to postsurgical discharge instructions was conducted. College students either heard or read discharge instructions composed in either high or moderate listenability. Comprehension was higher for this population in reading than in listening. Across modalities, the high listenability version was easiest to comprehend. Incorporating listenability concerns in research and practice is consistent with emerging, broad conceptions of health literacy and with the dictates of the National Action Plan to Improve Health Literacy. PMID- 23030570 TI - The Health Literacy Skills Instrument: a 10-item short form. AB - The 25-item Health Literacy Skills Instrument (HLSI) was designed to measure the ability to read and understand text and locate and interpret information in documents (print literacy), to use quantitative information (numeracy), to listen effectively (oral literacy), and to seek information through the Internet (navigation). It is a publically available measure that can be used in surveillance activities, to evaluate interventions, and in research examining the relation between health literacy and health outcomes. The authors developed a 10 item, short form (SF) version of the HLSI, the HLSI-SF, using data gathered for the development of the longer form. The authors selected 10 items for inclusion in the HLSI-SF and conducted a confirmatory factor analysis and item response theory analyses, then computed Cronbach's alpha. The HLSI-SF demonstrated acceptable internal consistency reliability (alpha = .70) for use in group-level comparisons. The HSLI-SF has many of the same advantages of the longer version with the additional benefit of taking only approximately 5 to 10 min to administer. The HLSI-SF offers researchers and practitioners a valid and reliable measure of health literacy skills. PMID- 23030571 TI - Health Literacy INDEX: development, reliability, and validity of a new tool for evaluating the health literacy demands of health information materials. AB - There is no consensus on how best to assess the health literacy demands of health information materials. Comprehensive, reliable, and valid assessment tools are needed. The authors report on the development, refinement, and testing of Health Literacy INDEX, a new tool reflecting empirical evidence and best practices. INDEX is comprised of 63 indicators organized into 10 criteria: plain language, clear purpose, supporting graphics, user involvement, skill-based learning, audience appropriateness, user instruction, development details, evaluation methods, and strength of evidence. In a sample of 100 materials, intercoder agreement was high: 90% or better for 52% of indicators, and above 80% for nearly all others. Overall scores generated by INDEX were highly correlated with average ratings from 12 health literacy experts (r = 0.89, p < .0001). Additional research is warranted to examine the association between evaluation ratings generated by INDEX and individual understanding, behaviors, and improved health. Health Literacy INDEX is a comprehensive tool with evidence for reliability and validity that can be used to evaluate the health literacy demands of health information materials. Although improvement in health information materials is just one aspect of mitigating the effects of limited health literacy on health outcomes, it is an essential step toward a more health literate public. PMID- 23030572 TI - Effects of text cohesion on comprehension and retention of colorectal cancer screening information: a preliminary study. AB - Increasing readability of written cancer prevention information is a fundamental step to increasing awareness and knowledge of cancer screening. Instead of readability formulas, the present study focused on text cohesion, which is the degree to which the text content ties together. The purpose of this study was to examine the effect of text cohesion on reading times, comprehension, and retention of colorectal cancer prevention information. English-speaking adults (50 years of age or older) were recruited from local communities. Participants were randomly assigned to read colorectal cancer prevention subtopics presented at 2 levels of text cohesion: from higher cohesion to lower cohesion, or vice versa. Reading times, word recognition, text comprehension, and recall were assessed after reading. Two weeks later, text comprehension and recall were reassessed. Forty-two adults completed the study, but five were lost to follow up. Higher text cohesion showed a significant effect on reading times and text comprehension but not on word recognition and recall. The effect of text cohesion was not found on text comprehension and recall after 2 weeks. Increasing text cohesion facilitates reading speed and comprehension of colorectal cancer prevention information. Further research on the effect of text cohesion is warranted. PMID- 23030573 TI - Association of health literacy with medication knowledge, adherence, and adverse drug events among elderly veterans. AB - Health literacy is an important priority in health care delivery, but its effect on clinical outcomes remains incompletely elucidated. This observational cohort study examined the association of health literacy with medication knowledge, adherence, and adverse drug events among cognitively intact veterans older than 65 years old who were taking 5 or more medications and who were enrolled in a Veterans Administration primary care clinic. Health literacy was determined by the Rapid Estimate of Adult Literacy in Medicine. Medication knowledge and adherence were assessed by clinical pharmacist interview and refill data. Adverse drug events were determined by interview and chart review at 3 and 12 months. The 310 subjects had a mean age of 74 years, 99% were White, and 97% were male. Percentage of medications known was 29% for the low health literacy group versus 49% (marginal) and 56% (adequate), p < .001. Known medication purposes were lower in the lower health literacy group (49% vs. 71% vs. 74%; p < .001). Health literacy was not associated with medication adherence: the low health literacy group took 84% of medications by label instructions compared with 80% (marginal) and 77% (adequate), p = .14; or with adverse drug events at 1 year (48% vs. 33% vs. 40%; p = .30). Patients with lower health literacy have poorer medication knowledge but not lower adherence or increased adverse drug events. PMID- 23030574 TI - Literacy barriers to colorectal cancer screening in community clinics. AB - This article examines the relationship between literacy and colorectal cancer (CRC) screening knowledge, beliefs, and experiences, with a focus on fecal occult blood tests (FOBTs). Participants were 975 patients in 8 Louisiana federally qualified health centers. Participants were 50 years of age or older and not up to date with CRC screening; approximately half (52%) had low literacy (less than a 9th-grade level). Participants with low literacy were less likely than were those with adequate literacy to be aware of advertisements promoting CRC screening (58.7% vs. 76.3%, p < .0001) or to believe it was very helpful to find CRC early (74.5% vs. 91.9%, p < .0001). The majority of participants had positive beliefs about the benefits of CRC screening using FOBTs. Participants with low literacy had more perceived barriers to FOBT completion and were more likely to strongly agree or agree that FOBTs would be confusing, embarrassing, or a lot of trouble; however, none of these remained significant in multivariate analyses controlling for relevant covariates. Confidence in being able to obtain an FOBT kit was high among those with low and adequate literacy (89.8% vs. 93.1%, respectively, p = .20); yet multivariate analyses revealed a significant difference in regard to literacy (p = .04) with low-literacy participants indicating less confidence. There was no significant difference by literacy in ever receiving a physician recommendation for CRC screening (38.4% low vs. 39.0% adequate, p = .79); however, multivariate analyses revealed significant differences in FOBT completion by literacy (p = .036). Overall, findings suggest that literacy is a factor in patients' CRC knowledge, beliefs, and confidence in obtaining a FOBT. PMID- 23030575 TI - Increasing awareness of gynecological cancer symptoms and reducing barriers to medical help seeking: does health literacy play a role? AB - Health literacy may influence the efficacy of print-based public health interventions. A key part of the U.K. cancer control strategy is to provide information to the public on earlier diagnoses with a view to improving the United Kingdom's relatively poor 1-year cancer survival statistics. This study examined the effect of health literacy on the efficacy of a gynecological cancer information leaflet. Participants (n = 451) were recruited from 17 Cancer Research UK events. Health literacy was assessed with the Newest Vital Sign test. Gynecological cancer symptom awareness and barriers to medical help seeking were assessed before and after participants read the leaflet. Symptom awareness improved, and barriers to medical help seeking were reduced (ps < .001). Symptom awareness was lower in individuals in lower health literacy groups, both at baseline and at follow-up (p < .05, p < .001, respectively), but there were no significant differences in barriers to medical help seeking at either time point (p > .05). As predicted, individuals with lower health literacy benefited less after exposure to the leaflet (ps < .01 for interactions). Despite careful consideration of information design principles in the development of the leaflet, more intensive efforts may be required to ensure that inequalities are not exacerbated by reliance on print-based public health interventions. PMID- 23030576 TI - The influence of symbols on the short-term recall of pharmacy-generated prescription medication information in a low health literate sample. AB - The effect of symbols on conveying health information has been studied in a variety of contexts and populations. This investigation assessed whether short term recall of prescription medication information could be enhanced in a low health literate population through the use of symbols. Participants recruited from various nonpharmacy educational service locations were randomly assigned to receive a prescription medication information leaflet in either a text-only, text with symbols, or symbols-only format and then administered the Rapid Estimate of Adult Literacy in Medicine (REALM). Only those with REALM scores indicative of a sixth grade or lower reading level were included in data analysis. An 8-item, interviewer-administered questionnaire was used to assess participants' recall of information contained in the leaflet. A fictitious medication was used to control for participants' past experiences with medications. Results of statistical testing revealed that the three groups did not differ with respect to their ability to recall the medication information, F(2, 157) = 0.943, p = .392. The symbols used in this investigation were not found to enhance the short-term recall of the medication information presented. These findings should not be considered a wholesale indictment of the use of symbols within health care and in pharmacies. Rather, they should serve as a caution to their widespread use without careful consideration. PMID- 23030577 TI - Who gets a teach-back? Patient-reported incidence of experiencing a teach-back. AB - To ensure comprehension, clinicians have been urged to use "teach-backs" explicitly asking patients to repeat back key points of instruction-with every patient receiving new care management instructions. Yet, it is not known whether certain patient groups are more likely to receive teach-backs than others. This study used results from the patient survey of the Communication Climate Assessment Toolkit to examine patient-reported incidence of teach-back by patient education level, age, language preference, race/ethnicity, and perception of sufficient time with doctors. In a multivariable model, patients had significantly greater odds of reporting a teach-back if they were of African American race/ethnicity, had non-English language preference, less education, increased age, or perceived that they had sufficient time with their doctor. This study concludes that some physicians seem to be directing teach-back efforts at certain patients, including those from demographic groups where lower literacy is more common, potentially leading patients who could benefit from teach-back to be overlooked. In addition, the strong correlation between reporting receiving a teach-back and reporting having enough time with a doctor merits further study. PMID- 23030578 TI - Successful enrollment in Text4Baby more likely with higher health literacy. AB - Adequate health literacy is vital for understanding and using health information. The authors assessed the health literacy of pregnant women and mothers of children under the age of 1 year and their success in self-enrolling in the Text4Baby health message program: 468 pregnant women and mothers of children under the age of 1 year completed an in-person baseline survey, including the Newest Vital Sign health literacy assessment, at 2 Metro-Atlanta Women, Infants, and Children clinics. They were asked to self-enroll in the Text4Baby message program and were later contacted by phone to see whether they had attempted to enroll in the program and whether they were successful. Of the 333 women contacted by phone to assess enrollment efforts, 21% had a high likelihood of limited literacy (a score of 0-1 on the Newest Vital Sign assessment), 48% had a chance of limited literacy (a score of 2-3), and 31% had adequate literacy (a score of 4-6). Attempting to self-enroll was not associated with health literacy (p = .70), but successful enrollment was more likely with higher literacy (p = .01). Results suggested a positive association between health literacy skills and successful self-enrollment in the Text4Baby program, which suggests the need for additional outreach efforts to assure enrollment by women with low health literacy skills. PMID- 23030579 TI - Improving care transitions: the patient perspective. AB - After hospital discharge, patients commonly suffer potentially avoidable adverse events and hospital readmissions. As hospitals implement interventions to improve discharge transitions, it is important to understand patients' perspectives on which intervention components are most beneficial. This study examined a sample of 125 patients randomized to the intervention arm of the Pharmacist Intervention for Low Literacy in Cardiovascular Disease study who completed a telephone survey about the helpfulness of different components of the intervention, which included medication reconciliation, inpatient counseling, simple adherence aids, and telephone follow-up. The majority of patients indicated that it was "very helpful" to speak with a pharmacist about their medications before discharge (72.8%), particularly about how to take the medications and how to prevent and manage side effects. Receiving an illustrated medication list (69.6%) and a follow-up phone call after discharge (68.0%) were also considered very helpful. Patients with limited health literacy indicated the greatest benefit. Patients also reported feeling more comfortable speaking with their outpatient providers about their medications after receiving the intervention. In conclusion, patients -particularly those with limited health literacy--found a hospital pharmacist based intervention to be very helpful and empowering. PMID- 23030580 TI - Health literacy and 30-day postdischarge hospital utilization. AB - Low health literacy is associated with higher mortality, higher rates of hospitalization, and poor self-management skills for chronic disease. Early, unplanned hospital reutilization after discharge is a common and costly occurrence in U.S. hospitals. Still, few studies have examined the relation between health literacy and 30-day hospital reutilization rates. The authors examined the association between health literacy and 30-day reutilization of hospital services (readmission or return to the emergency department) in an urban safety net hospital, and conducted a secondary analysis of data from the control arm subjects of the Project RED and the RED-LIT trials. Health literacy was measured using the REALM tool. The primary outcome was rate of 30-day reutilization. The authors used multivariate Poisson regression analysis to control for potential confounding. Of the 703 subjects, 20% had low health literacy, 29% had marginal health literacy, and 51% had adequate health literacy. Sixty-two percent of subjects had a 12th-grade education or less. Subjects with low health literacy were more likely to be insured by Medicaid (p < .001); Black non-Hispanic (p < .001); unemployed, disabled, or retired (p < .001); low income (p < .001); and less educated (high school education or less, p < .001). The fully adjusted incidence rate ratio for low health literacy compared with adequate health literacy was 1.46 (CI [1.04, 2.05]). Low health literacy is a significant, independent, and modifiable risk factor for 30-day hospital reutilization after discharge. Interventions designed to reduce early, unplanned, hospital utilization after discharge should include activities to mitigate the effect of patients' low health literacy. PMID- 23030581 TI - Electrokinetic analysis to reveal composition and structure of biohybrid hydrogels. AB - Biohybrid hydrogels combining electrically neutral synthetic polymers and highly anionic glycosaminoglycans (GAGs) offer exciting options for regenerative therapies as they allow for the electrostatic conjugation of various growth factors. Unraveling details of ionization and structure within such networks defines an important analytical challenge that requires the extension of current methodologies. Here, we present a mean-field approach to quantify the density of ionizable groups, GAG concentration, and cross-linking degree of such hydrogels based on experimental data from microslit electrokinetics and ellipsometry. An exemplary poly(ethylene glycol)-heparin system was analyzed to demonstrate how electrostatic fingerprints of hydrogels obtained by the introduced strategy can sensitively display composition and structure of the polymer networks. PMID- 23030582 TI - Performance of younger and older adults in lateralised right and left hemisphere asymmetry tasks supports the HAROLD model. AB - The population of industrialised societies has increased tremendously over the last century, raising the question of how an enhanced age affects cognition. The relevance of two models of healthy ageing are contrasted in the present study that both target the functioning of the two cerebral hemispheres. The right hemi ageing model (RHAM) assumes that functions of the right hemisphere decline before those of the left hemisphere. The Hemispheric Asymmetry Reduction in Older Adults (HAROLD) model suggests that the contralateral hemisphere supports the normally superior hemisphere in a given task resulting in a reduced hemispheric asymmetry overall. In a mixed design 20 younger and 20 older adults performed both a task assessing a left (lateralised lexical decisions) and a right (sex decisions on chimeric faces) hemisphere advantage. Results indicated that lateralised performance in both tasks was attenuated in older as compared to younger adults, in particular in men. These observations support the HAROLD model. Future studies should investigate whether this reduced functional hemispheric asymmetry in older age results from compensatory processes or from a process of de-differentiation. PMID- 23030583 TI - Immunohistological expression of HIF-1alpha, GLUT-1, Bcl-2 and Ki-67 in consecutive biopsies during chemoradiotherapy in patients with rectal cancer. AB - The aim of this study was to describe the dynamics of HIF-1alpha, GLUT-1, Bcl-2 and Ki-67 during chemoradiotherapy (CRT) of rectal cancer, and to investigate the fluctuation of these biomarkers in relation to pathological response to CRT. The study included 86 patients with rectal adenocarcinoma receiving preoperative CRT (>50.4 Gy and Uracil/Tegafur). Immunohistological expressions of HIF-1alpha, GLUT 1, Bcl-2 and Ki-67 were investigated in biopsies taken before treatment, after 2, 4 and 6 weeks of CRT and in specimens from the operation. Decreasing expressions of HIF-1alpha, Bcl-2 and Ki-67 were observed during CRT, whereas GLUT-1 overall was unchanged. No significant changes of the markers were observed in the interval between CRT and surgery. A significant association was observed between the presence of residual carcinoma after 6 weeks of treatment and pathological response to CRT, but no association was seen between the fluctuations of any of the markers and response to CRT. This unique material containing specimens before, after and during CRT for rectal cancer demonstrated biological dynamics in HIF-1alpha, Bcl-2 and Ki-67, but not GLUT-1, expression during CRT, and a significant association was seen between the presence of residual carcinoma after 6 weeks of treatment and pathological response to CRT. PMID- 23030584 TI - Adherence to a pulmonary rehabilitation program: start by understanding the patient. PMID- 23030585 TI - Pulmonary rehabilitation in chronic obstructive pulmonary disease: predictors of program completion and success. AB - Although participation in pulmonary rehabilitation (PR) improves the health outcomes in patients with Chronic Obstructive Pulmonary Disease (COPD), there are insufficient resources to provide PR to all patients with COPD. Thus, predicting which patients are at risk for drop-out and non-response to rehabilitation is necessary in order to optimize limited resources. This study examined which patient characteristics are predictive of PR drop-out and non-response. 814 patients with COPD took part in standard out-patient PR for 8 weeks. Demographic and standard clinical data were collected before the rehabilitation program had started. Data was analyzed retrospectively to determine if baseline patient characteristics could predict drop-out and non-response to rehabilitation. Drop out was defined as participation in less than 50% of the rehabilitation sessions. Non-response was defined as improvement less than 4% on the St. George's Respiratory Questionnaire (SGRQ). A discriminant function analysis identified age, smoking history, and health status as predictors of patient drop-out, p < .0001, with younger, current smokers and patients with lower health status being at risk for drop-out. No variables measured significantly predicted who those at risk would be for non-response to rehabilitation, p > .05. Pulmonary function data did not predict drop-out or non-response to PR. These findings indicate that perceived impairment (i.e., health status) is more likely to influence completion of rehabilitation than actual pulmonary impairment and that demographic and standard clinical data do not adequately predict patient drop-out and non response to rehabilitation. PMID- 23030586 TI - Effectiveness, attendance, and completion of an integrated, system-wide pulmonary rehabilitation service for COPD: prospective observational study. AB - Pulmonary rehabilitation (PR) is one of the most effective treatments for COPD but not widely available. Uptake is poor and completion rates are low. In this integrated PR service we report on effectiveness, attendance, and completion of twice weekly rolling recruitment and once weekly cohort recruitment programmes in two hospital and five community PR sites. The hospital and two of the community programmes were 'rolling' recruitment twice weekly for 8 weeks. Three community programmes ran in once weekly cohorts for 8 weeks. Predictors of attendance, completion and effectiveness were sought. 1114 eligible COPD patients were referred. 812 (73%) attended assessment, 656 (59%) started and 441 (40%) completed. Significant improvements were seen in incremental shuttle walk test (ISWT) (mean 68.3 m; 95%CI 59.3-77.4), Chronic Respiratory Questionnaire self report dyspnoea scale (CRQ-SR) (0.94; 0.80-1.07), Hospital Anxiety and Depression Scale anxiety (0.9; 0.5-1.2) and depression (1.1; 0.8-1.4) components, exceeding the minimum clinically important difference for ISWT and CRQ-SR. Twice weekly compared with once weekly programmes showed similar improvement. Patients were less likely to complete if they were deprived (4(th) quintile of deprivation 0.56; 0.33-0.94, 5(th) quintile 0.57; 0.34-0.85), reported MRC dyspnoea scale 4 (0.61; 0.37-0.97) or 5 (0.39; 0.16-0.93), or had been referred by their general practitioner (0.42; 0.24-0.74) (pseudo R(2) 0.103). PR is effective for COPD in real-world practice achieving results comparable to trials. Low rates of attendance and completion of PR were not explained by demographic characteristics, disease severity, psychological morbidity and source of referral despite the large number of participants. PMID- 23030587 TI - CC-16 as a biomarker in chronic obstructive pulmonary disease. PMID- 23030590 TI - Potent antibacterial antisense peptide-peptide nucleic acid conjugates against Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic pathogen causing severe infections in hospital settings, especially with immune compromised patients, and the increasing prevalence of multidrug resistant strains urges search for new drugs with novel mechanisms of action. In this study we introduce antisense peptide peptide nucleic acid (PNA) conjugates as antibacterial agents against P. aeruginosa. We have designed and optimized antisense peptide-PNA conjugates targeting the translation initiation region of the ftsZ gene (an essential bacterial gene involved in cell division) or the acpP gene (an essential bacterial gene involved in fatty acid synthesis) of P. aeruginosa (PA01) and characterized these compounds according to their antimicrobial activity and mode of action. Four antisense PNA oligomers conjugated to the H-(R-Ahx-R)(4)-Ahx betaala or the H-(R-Ahx)(6)-betaala peptide exhibited complete growth inhibition of P. aeruginosa strains PA01, PA14, and LESB58 at 1-2 MUM concentrations without any indication of bacterial membrane disruption (even at 20 MUM), and resulted in specific reduction of the targeted mRNA levels. One of the four compounds showed clear bactericidal activity while the other significantly reduced bacterial survival. These results open the possibility of development of antisense antibacterials for treatment of Pseudomonas infections. PMID- 23030591 TI - Antibacterial activity of selected metabolites from Chilean lichen species against methicillin-resistant staphylococci. AB - The in vitro antibacterial activities of eight compounds isolated from lichens, collected in several Southern regions of Chile (including Antarctica), were evaluated against methicillin-resistant clinical isolates strains of Staphylococcus aureus, Staphylococcus haemolyticus and Staphylococcus warneri. The minimum inhibitory concentrations, calculated in microdilution, were ranging from 8 ug mL(-1) for sphaerophorin to 1024 ug mL(-1) for fumarprotocetraric acid. These findings suggest, however, that the natural compounds from lichens are good candidates for the individuation of novel templates for the development of new antimicrobial agents or combinations of drugs for chemotherapy. PMID- 23030589 TI - Aptamer-mediated delivery of chemotherapy to pancreatic cancer cells. AB - Gemcitabine is a nucleoside analog that is currently the best available single agent chemotherapeutic drug for pancreatic cancer. However, efficacy is limited by our inability to deliver sufficient active metabolite into cancer cells without toxic effects on normal tissues. Targeted delivery of gemcitabine into cancer cells could maximize effectiveness and concurrently minimize toxic side effects by reducing uptake into normal cells. Most pancreatic cancers overexpress epidermal growth factor receptor (EGFR), a trans-membrane receptor tyrosine kinase. We utilized a nuclease resistant RNA aptamer that binds and is internalized by EGFR on pancreatic cancer cells to deliver gemcitabine-containing polymers into EGFR-expressing cells and inhibit cell proliferation in vitro. This approach to cell type-specific therapy can be adapted to other targets and to other types of therapeutic cargo. PMID- 23030592 TI - Loss of ARID1A expression is uncommon in gastric, colorectal, and prostate cancers. PMID- 23030594 TI - Active LifestyLe Rehabilitation interventions in aging spinal cord injury (ALLRISC): a multicentre research program. AB - BACKGROUND: With today's specialized medical care, life expectancy of persons with a spinal cord injury (SCI) has considerably improved. With increasing age and time since injury, many individuals with SCI, however, show a serious inactive lifestyle, associated with deconditioning and secondary health conditions (SHCs) (e.g. pressure sores, urinary and respiratory tract infections, osteoporosis, upper-extremity pain, obesity, diabetes, cardiovascular disease) and resulting in reduced participation and quality of life (QoL). Avoiding this downward spiral, is crucial. OBJECTIVES: To understand possible deconditioning and SHCs in persons aging with a SCI in the context of active lifestyle, fitness, participation and QoL and to examine interventions that enhance active lifestyle, fitness, participation and QoL and help prevent some of the SHCs. METHODS: A multicentre multidisciplinary research program (Active LifestyLe Rehabilitation Interventions in aging Spinal Cord injury, ALLRISC) in the setting of the long standing Dutch SCI-rehabilitation clinical research network. RESULTS: ALLRISC is a four-study research program addressing inactive lifestyle, deconditioning, and SHCs and their associations in people aging with SCI. The program consists of a cross-sectional study (n = 300) and three randomized clinical trials. All studies share a focus on fitness, active lifestyle, SHCs and deconditioning and outcome measures on these and other (participation, QoL) domains. It is hypothesized that a self-management program, low-intensity wheelchair exercise and hybrid functional electrical stimulation-supported leg and handcycling are effective interventions to enhance active life style and fitness, help to prevent some of the important SHCs in chronic SCI and improve participation and QoL. CONCLUSION: ALLRISC aims to provide evidence-based preventive components of a rehabilitation aftercare system that preserves functioning in aging persons with SCI. PMID- 23030593 TI - Relationships among neighborhood environment, racial discrimination, psychological distress, and preterm birth in African American women. AB - OBJECTIVES: To (a) examine the relationships among objective and perceived indicators of neighborhood environment, racial discrimination, psychological distress, and gestational age at birth; (b) determine if neighborhood environment and racial discrimination predicted psychological distress; (c) determine if neighborhood environment, racial discrimination, and psychological distress predicted preterm birth; and (d) determine if psychological distress mediated the effects of neighborhood environment and racial discrimination on preterm birth. DESIGN: Descriptive correlational comparative. SETTING: Postpartum unit of a medical center in Chicago. PARTICIPANTS: African American women (n(1) = 33 with preterm birth; n(2) = 39 with full-term birth). METHODS: Women completed the instruments 24 to 72 hours after birth. Objective measures of the neighborhood were derived using geographic information systems (GIS). RESULTS: Women who reported higher levels of perceived social and physical disorder and perceived crime also reported higher levels of psychological distress. Women who reported more experiences of racial discrimination also had higher levels of psychological distress. Objective social disorder and perceived crime predicted psychological distress. Objective physical disorder and psychological distress predicted preterm birth. Psychological distress mediated the effect of objective social disorder and perceived crime on preterm birth. CONCLUSION: Women's neighborhood environments and racial discrimination were related to psychological distress, and these factors may increase the risk for preterm birth. PMID- 23030595 TI - OK-432-stimulated chemokine secretion from human monocytes depends on MEK1/2, and involves p38 MAPK and NF-kappaB phosphorylation, in vitro. AB - Interaction between the immune system and cancer cells allows for the use of biological response modifiers, like OK-432, in cancer therapy. We have studied the involvement of monocytes (MOs) in the immune response to OK-432 by examining MCP-1, MIP-1alpha and MIP-1beta secretion, in vitro. OK-432-induced IL-6/TNF alpha secretion has previously been shown to depend on mitogen-activated protein kinases (MAPKs) ERK1/2 and p38, and we therefore investigated the role of these MAPKs in OK-432-induced chemokine secretion. Here we demonstrate that pharmacological MEK1/2 kinase inhibition generally impaired chemokine secretion from MOs, whereas p38 MAPK inhibition in particular reduced MIP-1alpha production. Furthermore, simultaneous inhibition of MEK1/2 and Syk kinase was seen to have an additive impact on reduced MCP-1, MIP-1alpha and MIP-1beta secretion. Based on single cell flow cytometry analyses, OK-432, lipoteichoic acid (LTA) and lipopolysaccharide (LPS) were seen to induce p38 MAPK and NF kappaB phosphorylation in MOs with different time kinetics. LTA and LPS have been shown to induce ERK1/2 phosphorylation, whereas the levels of phosphorylated ERK1/2 remained constant following OK-432 treatment at the time points tested. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, and we demonstrate increased TLR2 cell surface levels on the MO population, most profoundly following stimulation with LTA and OK-432. Together these results indicate that modulation of MEK1/2 and p38 MAPK signalling could affect the response to OK-432 treatment, having the potential to improve its therapeutic potential within cancer and lymphangioma treatment. PMID- 23030596 TI - Copper-catalyzed aminooxygenation of N-allylamidines with PhI(OAc)2. AB - A Cu-catalyzed aminoacetoxylation of N-alkenylamidines has been achieved using PhI(OAc)(2) as an oxygen source for synthesis of 4-acetoxymethyl-4,5 dihydroimidazoles, which could be further converted into 2,3-diaminopropanol derivatives using AlH(3) as a reductant. PMID- 23030597 TI - Agricultural irrigation mediates climatic effects and density dependence in population dynamics of Chinese striped hamster in North China Plain. AB - Several studies show that climatic (extrinsic) factors can interact with density dependent (intrinsic) factors to alter long-term population dynamics, yet there is a surprising lack of investigations of how anthropogenic disturbance modifies such dynamics. Such interactions could be especially important in agricultural systems subject to climate change. We investigated the effects of density dependence, climate, recurrent disturbance from flood irrigation and their interactions on the population dynamics of an important rodent pest, the Chinese striped hamster (Cricetulus barabensis), over 27 years in the croplands of the North China Plain. Strong density-dependent feedbacks occurred at both annual and seasonal scales. While warmer weather increased population sizes in nonbreeding seasons, this effect was counteracted by the negative effect of flood irrigation in breeding seasons. Precipitation showed significant positive effects in nonbreeding seasons, but negative effects in breeding seasons. There were important interactions between intrinsic dynamics, extrinsic dynamics and disturbance. Low temperature significantly increased the strength of density dependence in nonbreeding seasons, whereas intensification of flood irrigation area significantly increased the strength of density dependence but reduced the effect of summer precipitation in breeding seasons. Overall climate change is expected to increase population levels, but anthropogenic disturbance from flood irrigation will help prevent long-term population increases. The interactions between anthropogenic disturbance and both intrinsic and extrinsic (weather driven) population dynamics caution that we need to consider anthropogenic disturbance as an integral component of population responses to climate change. PMID- 23030598 TI - An ICF-based approach for cerebral palsy from a biopsychosocial perspective. AB - OBJECTIVES: To integrate instruments to operationalize an ICF-based approach for cerebral palsy (CP); to assess differences in activity and participation among children with hemiplegia, diplegia and quadriplegia CP; to verify the facilitators or barriers to functioning; and to investigate the explanatory factors (cognitive and motor) for the type of school attended by children with CP (regular or special). METHODS: Sixty children with CP were assessed using the Mini-Mental State Examination and an ICF-based instrument and their parents were interviewed. Data were analysed by Chi-Squared, Anova's and Kruskal-Wallis tests and multivariate logistic regression. RESULTS: Significant differences between CP sub-groups were found for chewing, urinary function, cognitive function and activities and participation. Twelve environmental factors were identified as barriers. Multivariate regression identified cognitive function as a significant explanatory variable for the type of school attended, whereas motor function was not significant. CONCLUSIONS: The ICF-based approach allows a comprehensive assessment, relevant for planning interventions. PMID- 23030599 TI - Docking interactions of hematopoietic tyrosine phosphatase with MAP kinases ERK2 and p38alpha. AB - Hematopoietic tyrosine phosphatase (HePTP) regulates orthogonal MAP kinase signaling cascades by dephosphorylating both extracellular signal-regulated kinase (ERK) and p38. HePTP recognizes a docking site (D-recruitment site, DRS) on its targets using a conserved N-terminal sequence motif (D-motif). Using solution nuclear magnetic resonance spectroscopy and isothermal titration calorimetry, we compare, for the first time, the docking interactions of HePTP with ERK2 and p38alpha. Our results demonstrate that ERK2-HePTP interactions primarily involve the D-motif, while a contiguous region called the kinase specificity motif also plays a key role in p38alpha-HePTP interactions. D-Motif DRS interactions for the two kinases, while similar overall, do show some specific differences. PMID- 23030600 TI - Per- and polyfluoroalkyl substances in landfill leachate: patterns, time trends, and sources. AB - Concentrations and isomer profiles for 24 per- and polyfluoroalkyl substances (PFASs) were monitored over 5 months (February-June, 2010) in municipal landfill leachate. These data were used to assess the role of perfluoroalkyl acid (PFAA) precursor degradation on changes in PFAA concentrations over time. The influence of total organic carbon, total suspended solids, pH, electrical conductivity (EC), leachate flow rates, and meteorological data (precipitation, air temperature) on leachate PFAS concentrations was also investigated. Perfluoropentanoate and perfluorohexanoate were typically the dominant PFASs in leachate, except for March-April, when concentrations of perfluorooctane sulfonate, perfluorooctanoate, and numerous PFAA-precursors (i.e., (N-alkyl) perfluorooctane sulfonamides and fluorotelomer carboxylic acids) increased by a factor of 2-10 (~4 MUg/L to ~36 MUg/L SigmaPFASs). During this time, isomer profiles of PFOA became increasingly dominated by the linear isomer, likely from transformation of linear, telomer-manufactured precursors. While SigmaPFAA precursors accounted for up to 71% of SigmaPFASs (molar basis) in leachate from this site, leachate from a second landfill displayed only low concentrations of precursors (<1% of SigmaPFASs). Overall, degradation of PFAA-precursors and changes in leachate pH, EC, and 24-h precipitation were important factors controlling PFAS occurrence in leachate. Finally, 8.5-25 kg/yr (mean 16 kg/yr) of SigmaPFASs was estimated to leave the landfill via leachate for subsequent treatment at a wastewater treatment plant. PMID- 23030601 TI - Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder. AB - OBJECTIVES: Kynurenic acid (KYNA), an end metabolite of tryptophan degradation, antagonizes glutamatergic and cholinergic receptors in the brain. Recently, we reported elevated levels of cerebrospinal fluid (CSF) KYNA in male patients with bipolar disorder. Here, we investigate the relationship between symptomatology and the concentration of CSF KYNA in patients with bipolar I disorder. METHODS: CSF KYNA levels from euthymic male {n = 21; mean age: 41 years [standard deviation (SD) = 14]} and female [n = 34; mean age: 37 years (SD = 14)] patients diagnosed with bipolar I disorder were analyzed using high-performance liquid chromatography (HPLC). RESULTS: Euthymic bipolar I disorder patients with a lifetime occurrence of psychotic features had higher CSF levels of KYNA {2.0 nm [standard error of the mean (SEM) = 0.2]; n = 43} compared to patients without any history of psychotic features [1.3 nm (SEM = 0.2); n = 12] (p = 0.01). Logistic regression, with age as covariate, similarly showed an association between a history of psychotic features and CSF KYNA levels [n = 55; odds ratio (OR) = 4.9, p = 0.03]. Further, having had a recent manic episode (within the previous year) was also associated with CSF KYNA adjusted for age (n = 34; OR = 4.4, p = 0.03), and the association remained significant when adjusting for a lifetime history of psychotic features (OR = 4.1, p = 0.05). CONCLUSIONS: Although the causality needs to be determined, the ability of KYNA to influence dopamine transmission and behavior, along with previous reports showing increased brain levels of the compound in patients with schizophrenia and bipolar disorder, may indicate a possible pathophysiological role of KYNA in the development of manic or psychotic symptoms. PMID- 23030603 TI - Treatment of melasma by low-fluence 1064 nm Q-switched Nd:YAG laser. AB - BACKGROUND: Low-fluence 1064 nm Q-switched Nd:YAG laser has recently been shown to be effective for the melasma treatment. OBJECTIVE: The purpose of this study is to evaluate the clinical efficacy and safety of low-fluence 1064 nm Q-switched Nd:YAG laser treatment of melasma in Asian patients. METHODS: Fifty patients with melasma underwent 15 weeks of weekly treatments, using a Q-switched Nd:YAG laser (RevLite(r); HOYA ConBio(r), Freemont, CA, USA) at 1064 nm with an 8-mm spot size, and a fluence of 2.8 J/cm(2). Patients and investigators subjectively evaluated the intensity of pigmentation after completion of 15 weekly treatments. The objective assessment was also performed with digital photographs and a pigment imaging tool (Janus(r), PSI Co., Ltd., KOREA). RESULTS: Both patients and investigators rated the treatment outcome as "good improvement" on average with improvement rate of 50-74%. The pigment imaging technology system also confirmed the improvement of the pigmentation level on all three locations of the face. None of the 50 patients showed any signs of severe side effects during the course of the treatment. CONCLUSION: Low-fluence 1064 nm Q-switched Nd:YAG laser is an effective method to treat melasma without serious side effects in Asian patients. PMID- 23030602 TI - Molecular insights into the biosynthesis of guadinomine: a type III secretion system inhibitor. AB - Guadinomines are a recently discovered family of anti-infective compounds produced by Streptomyces sp. K01-0509 with a novel mode of action. With an IC(50) of 14 nM, guadinomine B is the most potent known inhibitor of the type III secretion system (TTSS) of Gram-negative bacteria. TTSS activity is required for the virulence of many pathogenic Gram-negative bacteria including Escherichia coli , Salmonella spp., Yersinia spp., Chlamydia spp., Vibrio spp., and Pseudomonas spp. The guadinomine (gdn) biosynthetic gene cluster has been cloned and sequenced and includes 26 open reading frames spanning 51.2 kb. It encodes a chimeric multimodular polyketide synthase, a nonribosomal peptide synthetase, along with enzymes responsible for the biosynthesis of the unusual aminomalonyl acyl carrier protein extender unit and the signature carbamoylated cyclic guanidine. Its identity was established by targeted disruption of the gene cluster as well as by heterologous expression and analysis of key enzymes in the biosynthetic pathway. Identifying the guadinomine gene cluster provides critical insight into the biosynthesis of these scarce but potentially important natural products. PMID- 23030604 TI - Fabrication of large domain crack-free colloidal crystal heterostructures with superposition bandgaps using hydrophobic polystyrene spheres. AB - An improved convective self-assembly method was developed to fabricate crack-free colloidal crystal heterostructure over a relatively large area. A composite opaline heterostructure composed of polystyrene (PS) colloids was first fabricated. Subsequent calcination of the opaline heterostructure led to the formation of inverse opaline heterostructure composed of SiO(2) or TiO(2). Both opaline and inverse opaline heterostructures demonstrated long-range ordering in a relatively large domain (>100 * 100 MUm(2)). Optical reflection measurements of the inverse opaline heterostructures showed dual stop bands as a consequence of the superposition of the stop bands from the individual compositional colloidal crystals (CCs). In addition, the relative position of the two stop bands can be adjusted by varying the size of the colloidal spheres in the original CCs template. Both types of colloidal crystal heterostructures can be used for optical filters, high-efficiency back-reflectors or electrodes in solar cells, differential drug release, and protein patterning. PMID- 23030606 TI - Why are current efforts to eliminate female circumcision in Ethiopia misplaced? AB - This paper discusses the eradication challenges of female circumcision in Ethiopia. It argues that despite an overall decline in the practice nationally, eradication efforts have caused significant quandaries for girls and their families. The most common justification by far for its continuance is that circumcision confirms a girl's social place by proving her readiness for marriage and adulthood and thereby ensures her protection against material want. Hence, intervention has often resulted in the transformation, rather than the elimination, of the practice, the exchange of one type of risk for another, or even increased risk to girls. In discussing policy, the paper argues that there has been a misapplication of the risk concept in the promotion of change in Ethiopia. It calls for risk definitions and interventions that are more holistic, correspond more closely with children's social realities and take into account the phenomenological dimensions of experience. PMID- 23030605 TI - A pilot trial of integrated behavioral activation and sexual risk reduction counseling for HIV-uninfected men who have sex with men abusing crystal methamphetamine. AB - Crystal methamphetamine use is a major driver behind high-risk sexual behavior among men who have sex with men (MSM). Prior work suggests a cycle of continued crystal methamphetamine use and high-risk sex due to loss of the ability to enjoy other activities, which appears to be a side effect of this drug. Behavioral activation (BA) is a treatment for depression that involves learning to reengage in life's activities. We evaluated a novel intervention for crystal methamphetamine abuse and high-risk sex in MSM, incorporating 10 sessions of BA with integrated HIV risk reduction counseling (RR). Forty-four subjects were screened, of whom 21 met initial entry criteria. A total of 19 participants enrolled; 16 completed an open-phase study of the intervention. Behavioral assessments were conducted at baseline, 3 months postbaseline, and 6 months postbaseline. Linear mixed effects regression models were fit to assess change over time. Mean unprotected anal intercourse (UAI) episodes decreased significantly from baseline to acute postintervention (beta=-4.86; 95% confidence interval [CI]=-7.48, -2.24; p=0.0015) and from baseline to 6 months postbaseline (beta=-5.07; 95% CI=-7.85, -2.29; p=0.0017; test of fixed effects chi(2)=16.59; df=2,13; p=0.0002). On average, there was a significant decrease over time in the number of crystal methamphetamine episodes in the past 3 months (chi(2)=22.43; df=2,15; p<0.0001), and the number of days of crystal methamphetamine use in the past 30 days (chi(2)=9.21; df=2,15; p=0.010). Statistically significant reductions in depressive symptoms and poly-substance use were also maintained. Adding behavioral activation to risk reduction counseling for MSM with problematic crystal methamphetamine use may augment the potency of a risk reduction intervention for this population. Due to the small sample size and time intensive intervention, future testing in a randomized design is necessary to determine efficacy, with subsequent effectiveness testing. PMID- 23030607 TI - Evidence to practice commentary: Is more therapy better? PMID- 23030608 TI - Editorial: QSAR models for computer-aided drug design and molecular docking for disorders of the central nervous system and other diseases. PMID- 23030609 TI - QSAR and molecular docking techniques for the discovery of potent monoamine oxidase B inhibitors: computer-aided generation of new rasagiline bioisosteres. AB - The search for new therapies against neurodegenerative disorders (NDs) such as Alzheimer (AD) and Parkinson (PD) constitutes a very active area. Although the scientific community has realized great efforts for the study of AD and PD from the most diverse points of view, these diseases remain incurable. Consequently, the design of new and more potent compounds for proteins associated with AD and PD represents nowadays, an objective of major importance. In this sense, the protein known as monoamine oxidase B (MAO-B) constitutes one of the key targets for the search of new drug candidates which could be employed as neuroprotective agents in both anti-AD and anti-PD chemotherapies. The present work is focused on the role of the Quantitative-Structure Activity Relationship (QSAR) analysis and molecular docking (MDock) techniques which have been applied for the discovery of new and promising molecular entities with high inhibitory activity against MAO-B. We also give a brief overview about one of the most potent MAO-B inhibitor drugs: rasagiline. Finally, as contribution to the field, we constructed a QSAR model using artificial neural network (ANN) analysis for the virtual screening of potent MAO-B inhibitors. By realizing a careful inspection of the meaning of the variables in the QSAR-ANN model, new rasagiline bioisosteres were suggested as possible potent MAO-B inhibitors. PMID- 23030610 TI - Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme. AB - Thermolysin (TLN) and other thermolysin-like zinc metalloproteinases (TLPs),are important virulence factors for pathogenesis of bacterial infections by suppressing the innate immune system of the host. Therapeutic inhibition ofTLPs is believed to be a novel strategy inthe development of a new generation antibiotics.In the present study inhibition of TLN and angiotensin I-converting enzyme (ACE) by small peptides were studied by in vitro binding assays and theoretical calculations. The capacity of the peptides to inhibitTLN induced cleavage ofthe transcription factor nuclear factor kappa beta (NF-kappaB) was studied by electrophoretic mobility shift assays (EMSAs).Nine peptides inhibited ACE with IC50 values in the range 0.48 (IVY) to 1408 (HF) MUM, while seven inhibited TLN with IC50 values in the range 0.00034 (IY) to 95640 (FW) MUM. Calculations indicated that the peptides occupied the S1' and S2' subsites of ACE, and that IY, LW and IW occupiedthe S1' and S2' subsites, while FW, WL and WV occupiedthe S1 and S1' subsites of TLN. EMSA showed that peptides inhibited TLN induced cleavage of NF-kappaB. The studied peptides may form as a basis for the design of new compoundstargeting TLN with a potential in the treatment of bacterial infections. PMID- 23030611 TI - Identification of LOGP values and Electronegativities as structural insights to model inhibitory activity of HIV-1 capsid inhibitors - a SVM and MLR aided QSAR studies. AB - Linear and non-linear QSAR studies have been performed in present investigation with multiple linear regressions (MLR) analysis and Support vector machine (SVM) using different kernels. Three relevant descriptors out of fifteen descriptors calculated are identified as LOGP values, G3e and Rte+. Their relationship with biological activity IC50 have provided structural insights in interpretation and serializing the results into a pragmatic approachable technique. QSAR models obtained show statistical fitness and good predictability. SVM using Gaussian kernel function was found more efficient in prediction of IC50 of training set of thirty small molecules HIV-1 capsid inhibitors. Y-scrambling, PRESS and test set were used as validation parameters. SVM was found superior to training set prediction and internal validations and found inferior to external test set (11 molecules) predictions. Wherein MLR analysis it was vice-versa. Mechanistic interpretation of selected descriptors from both the models actuates further research. PMID- 23030613 TI - A parallel systematic-Monte Carlo algorithm for exploring conformational space. AB - Computational algorithms to explore the conformational space of small molecules are complex and computer demand field in chemoinformatics. In this paper a hybrid algorithm to explore the conformational space of organic molecules is presented. This hybrid algorithm is based in a systematic search approach combined with a Monte Carlo based method in order to obtain an ensemble of low-energy conformations simulating the flexibility of small chemical compounds. The Monte Carlo method uses the Metropolis criterion to accept or reject a conformation through an in-house implementation of the MMFF94s force field to calculate the conformational energy. The parallel design of this algorithm, based on the message passing interface (MPI) paradigm, was implemented. The results showed a performance increase in the terms of speed and efficiency. PMID- 23030612 TI - Structure-activity relationship and efficacy of pyridinium oximes in the treatment of poisoning with organophosphorus compounds: a review of recent data. AB - During more than five decades, pyridinium oximes have been developed as therapeutic agents used in the medical treatment of poisoning with organophosphorus compounds. Their mechanism of action is reactivation of acetylcholinesterase (AChE) inhibited by organophosphorus agents. Organophosphorus compounds (OPC) are used as pesticides and developed as warfare nerve agents such as tabun, soman, sarin, VX and others. Exposure to even small amounts of an OPC can be fatal and death is usually caused by respiratory failure resulting from paralysis of the diaphragm and intercostal muscles, depression of the brain respiratory center, bronchospasm, and excessive bronchial secretions. The mechanism of OPC poisoning involves phosphorylation of the serine hydroxyl group at the active site of AChE leading to the inactivation of this essential enzyme, which has an important role in neurotransmission. AChE inhibition results in the accumulation of acetylcholine at cholinergic receptor sites, producing continuous stimulation of cholinergic fibers throughout the central and peripheral nervous systems. Presently, a combination of an antimuscarinic agent, e.g. atropine, AChE reactivator such as one of the standard pyridinium oximes (pralidoxime, trimedoxime, obidoxime, HI-6) and diazepam are used for the treatment of organophosphate poisoning in humans. Despite of enormous efforts devoted to synthesis and development of new pyridinium oximes as potential antidotes against poisoning with OPC, only four compounds have found their application in human medicine so far. However, they differ in their activity in poisoning with warfare nerve agents and pesticides and there is still no universal broad-spectrum oxime capable of protecting against all known OPC. In this article the latest data on structure-activity relationship of pyridinium oximes including their efficacy in treatment of poisoning with organophosphorus compounds are reviewed. PMID- 23030614 TI - Manipulating kynurenic acid levels in the brain - on the edge between neuroprotection and cognitive dysfunction. AB - A number of neurodegenerative diseases have been associated with potentially neurotoxic alterations in the kynurenine pathway. Due to the potent inhibitory effect of kynurenic acid on glutamate receptor function, the potential use of the elevation of its concentrations in the brain in the protection against excitotoxic injury has earned an ever greater interest. The first strong preclinical achievements of protection in transgenic murine models of chronic neurodegenerative diseases by kynurenergic approaches have recently been published. Despite the remarkable neuroprotection provided by these molecules, the potential risk of interfering with cognitive functions when dealing with molecules capable of impairing glutamatergic and cholinergic transmission should always be considered. This issue is of particular interest in light of the high affinity of kynurenic acid towards the glycine site of NMDA receptors, the antagonism of which is known to recapitulate key behavioral features of schizophrenia. In the past decade, however, a number of other sites of action have been revealed, most of them being possible contributors of either the neuroprotective or the cognitive deteriorating effects of kynurenic acid. This paper reviews the current understanding about how kynurenic acid can influence cognitive functions in experimental animals, and discusses the possibility of exploiting the neuroprotective potential of kynurenic acid without impairing cognitive functions. PMID- 23030615 TI - Computational approaches to screen candidate ligands with anti- Parkinson's activity using R programming. AB - It is estimated that by 2050 over 100 million people will be affected by the Parkinson's disease (PD). We propose various computational approaches to screen suitable candidate ligand with anti-Parkinson's activity from phytochemicals. Five different types of dopamine receptors have been identified in the brain, D1 D5. Dopamine receptor D3 was selected as the target receptor. The D3 receptor exists in areas of the brain outside the basal ganglia, such as the limbic system, and thus may play a role in the cognitive and emotional changes noted in Parkinson's disease. A ligand library of 100 molecules with anti-Parkinson's activity was collected from literature survey. Nature is the best combinatorial chemist and possibly has answers to all diseases of mankind. Failure of some synthetic drugs and its side effects have prompted many researches to go back to ancient healing methods which use herbal medicines to give relief. Hence, the candidate ligands with anti-Parkinson's were selected from herbal sources through literature survey. Lipinski rules were applied to screen the suitable molecules for the study, the resulting 88 molecules were energy minimized, and subjected to docking using Autodock Vina. The top eleven molecules were screened according to the docking score generated by Autodock Vina Commercial drug Ropinirole was computed similarly and was compared with the 11 phytochemicals score, the screened molecules were subjected to toxicity analysis and to verify toxic property of phytochemicals. R Programming was applied to remove the bias from the top eleven molecules. Using cluster analysis and Confusion Matrix two phytochemicals were computationally selected namely Rosmarinic acid and Gingkolide A for further studies on the disease Parkinson's. PMID- 23030616 TI - Immunotoxicity, flow cytometry, and chemoinformatics: review, bibliometric analysis, and new QSAR model of drug effects over macrophages. AB - Bibliometric methods for analyzing and describing research output have been supported internationally by the establishment and operation of organizations such as the Institute for Scientific Information (ISI) or Scimago Ranking Institutions (SRI). This study provides an overview of the research performance of major World countries in the field cytokines, Citometric bead assays and QSAR, the most important journals in which they published their research articles, and the most important academic institutions publishing them. The analysis was based on Thomson Scientific's Web of Science (WoS), and Scimago group calculated bibliometric indicators of publication activity and actual citation impact. Studying the time period 2005-2010, and shows the visibility of Medicinal Chemistry Bioorganic in this thematic noting that the visibility of a journal must take into account not only the impact factor, but the prestige, popularity and representativeness of the theme that addresses the same making a comprehensive assessment of bibliometric indicators. PMID- 23030617 TI - Review on chemogenomics approach: interpreting antagonist activity of secreted frizzled-related protein 1 in glaucoma disease with in-silico docking. AB - Computer-aided drug discovery is a growing frontier in science. It covers different sub areas like chemoinformatics and chemogenomics. Chemogenomics is one of the emerging inter-disciplinary approaches in drug discovery, which combines conventional ligand based approach with biological information of drug targets. The main goal of this review is to check effective application of chemogenomics in understanding interactions between all possible ligands and their potential drug targets at molecular level. Recent studies revealed that increased expression of sFRP1an inhibitor of Wnt signalling pathway, seems to be responsible for Elevated Intracellular Pressure (IOP) in glaucoma patients. Glaucoma is a worldwide spread disease. Here, secreted frizzled-related protein-1 (sFRP1) has been used as a target protein. An important role of sFRP1, an antagonist of Wnt signalling pathway, has been found in regulating IOP. Wnt3a ligand protein and a natural compound from marine source Mycaperoxide H - have been used as ligands. In-silico docking of these ligands with sFRP family implies answers to many intricate queries in drug development field. Using above mentioned ligand-protein model in this study, application of chemogenomics has tried to explore the interaction of active site of proteins with the novel ligands. Henceforth, the present review will focus on predictive in-silico chemogenomic approaches with computer aided drug design could be used in drug design domain in identifying new targets in various diseases, in time and cost effective manner. PMID- 23030618 TI - 3D MI-DRAGON: new model for the reconstruction of US FDA drug- target network and theoretical-experimental studies of inhibitors of rasagiline derivatives for AChE. AB - The number of neurodegenerative diseases has been increasing in recent years. Many of the drug candidates to be used in the treatment of neurodegenerative diseases present specific 3D structural features. An important protein in this sense is the acetylcholinesterase (AChE), which is the target of many Alzheimer's dementia drugs. Consequently, the prediction of Drug-Protein Interactions (DPIs/nDPIs) between new drug candidates and specific 3D structure and targets is of major importance. To this end, we can use Quantitative Structure-Activity Relationships (QSAR) models to carry out a rational DPIs prediction. Unfortunately, many previous QSAR models developed to predict DPIs take into consideration only 2D structural information and codify the activity against only one target. To solve this problem we can develop some 3D multi-target QSAR (3D mt QSAR) models. In this study, using the 3D MI-DRAGON technique, we have introduced a new predictor for DPIs based on two different well-known software. We have used the MARCH-INSIDE (MI) and DRAGON software to calculate 3D structural parameters for drugs and targets respectively. Both classes of 3D parameters were used as input to train Artificial Neuronal Network (ANN) algorithms using as benchmark dataset the complex network (CN) made up of all DPIs between US FDA approved drugs and their targets. The entire dataset was downloaded from the DrugBank database. The best 3D mt-QSAR predictor found was an ANN of Multi-Layer Perceptron-type (MLP) with profile MLP 37:37-24-1:1. This MLP classifies correctly 274 out of 321 DPIs (Sensitivity = 85.35%) and 1041 out of 1190 nDPIs (Specificity = 87.48%), corresponding to training Accuracy = 87.03%. We have validated the model with external predicting series with Sensitivity = 84.16% (542/644 DPIs; Specificity = 87.51% (2039/2330 nDPIs) and Accuracy = 86.78%. The new CNs of DPIs reconstructed from US FDA can be used to explore large DPI databases in order to discover both new drugs and/or targets. We have carried out some theoretical-experimental studies to illustrate the practical use of 3D MI DRAGON. First, we have reported the prediction and pharmacological assay of 22 different rasagiline derivatives with possible AChE inhibitory activity. In this work, we have reviewed different computational studies on Drug- Protein models. First, we have reviewed 10 studies on DP computational models. Next, we have reviewed 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compounds to find Drug-Protein QSAR models. Last, we have developped a 3D multi-target QSAR (3D mt-QSAR) models for the prediction of the activity of new compounds against different targets or the discovery of new targets. PMID- 23030619 TI - Enhanced condensation on lubricant-impregnated nanotextured surfaces. AB - Nanotextured superhydrophobic surfaces have received significant attention due to their ability to easily shed liquid drops. However, water droplets have been shown to condense within the textures of superhydrophobic surfaces, impale the vapor pockets, and strongly pin to the surface. This results in poor droplet mobility and degrades condensation performance. In this paper, we show that pinning of condensate droplets can be drastically reduced by designing a hierarchical micro-nanoscale texture on a surface and impregnating it with an appropriate lubricant. The choice of lubricant must take into account the surface energies of all phases present. A lubricant will cloak the condensate and inhibit growth if the spreading coefficient is positive. If the lubricant does not fully wet the solid, we show how condensate-solid pinning can be reduced by proper implementation of nanotexture. On such a surface, condensate droplets as small as 100 MUm become highly mobile and move continuously at speeds that are several orders of magnitude higher than those on identically textured superhydrophobic surfaces. This remarkable mobility produces a continuous sweeping effect that clears the surface for fresh nucleation and results in enhanced condensation. PMID- 23030620 TI - Electrochemical immunosensing platform for DNA methyltransferase activity analysis and inhibitor screening. AB - In this paper, we developed a novel electrochemical method to quantify DNA methyltransferase (MTase) and analyze DNA MTase activity. After the double DNA helix structure was assembled on the surface of gold nanoparticle modified glassy carbon electrode, it was first methylated by M. SssI MTase and then digested by restriction endonuclease HpaII, which could not recognize the methylated CpG site. Successively, anti-5-methylcytosine antibody was specifically conjugated on the CpG methylation site and horseradish peroxidase labeled goat antimouse IgG (HRP-IgG) was conjugated on anti-5-methylcytosine antibody. In the detection buffer solution containing H(2)O(2) and hydroquinone, HRP-IgG can catalyze hydroquinone oxidation by H(2)O(2) to generate benzoquinone, resulting in a highly electrochemical reduction signal. Consequently, the activity of M. SssI MTase was assayed, and DNA methylation was detected using the signal change with and without methylation. Furthermore, the inhibition investigation demonstrated that, in the presence of 160 MUM S-adenosyl-L-methionine as methyl donor, 5-aza 2'-deoxycytidine, procaine, epicatechin, and caffeic acid could inhibit the M. SssI MTase activity with the IC(50) values of 45.77, 410.3, 129.03, and 124.2 MUM, respectively. Therefore, this study may provide a sensitive platform for screening DNA MTase inhibitors. PMID- 23030621 TI - A case of levetiracetam induced bullous pemphigoid. AB - Bullous pemphigoid is a chronic, acquired autoimmune skin disease. Certain drugs such as furosemide, penicillins, sulfonamides, ciprofloxacins, penicillamines, angiotensin converting enzyme inhibitors, chloroquine, and phenacetin were reported to cause bullous pemphigoid. This is a case report of a 70-year-old female, who presented with the formation of diffuse cutaneous blister in month after starting to use levetiracetam. Dermatological exam and histopathological findings were consistent with bullous pemphigoid. To the best of our knowledge this is the first case of bullous pemphigoid in the literature associated with levetiracetam use. PMID- 23030623 TI - Microheterogeneity of some imidazolium ionic liquids as revealed by fluorescence correlation spectroscopy and lifetime studies. AB - The microscopic structure and dynamics of the room temperature ionic liquids (RTILs) that are responsible for some of the peculiar properties of this class of solvents continue to intrigue the researchers and stimulate new investigations. Herein, we use the fluorescence correlation spectroscopy (FCS) technique to study the diffusion of some probe molecules in RTILs, the results of which, when combined with those obtained from fluorescence lifetime studies, provide insights into the microscopic structural details of this class of novel solvents. Experiments performed with three charged and neutral probe molecules in five carefully selected 1-alkyl-3-methylimidazolium ionic liquids reveal that unlike in conventional solvents these probes exhibit a bimodal diffusion behavior in RTILs thus indicating the presence of two distinct environments. It is found that the contribution of the slow component of the diffusion increases with increasing alkyl chain length of the cation. Not only are these results supported by the biexponential decay behavior of the fluorescence intensity of the systems, but the individual values of the lifetime components and their weight allow determination of the nature of the two major environments. In essence, the results point to the potential of the two combined techniques in unraveling some of the complex features of the ionic liquids. PMID- 23030624 TI - Imagined anatomy and other lessons from learner verification interviews with Mexican immigrant women. AB - OBJECTIVE: To identify clearer, learner-preferred, educational approaches for aspects of cervical cancer education found to be difficult to understand for low literacy, Mexican, immigrant women. SETTING: Kansas City, Kansas; Garden City, Kansas; San Antonio, Texas. PARTICIPANTS: Forty-five Mexican immigrant women in the United States for 5 years or less, ninth grade education or less, and predominantly Spanish speaking. METHODS: Interviews were conducted to evaluate preference and best comprehension among options for specific cervical cancer educational elements, including reproductive system terminology, the purpose of Pap tests and meaning of results, Human Papilloma Virus (HPV), and illustrations of anatomy and Pap procedure. RESULTS: We identified terminology, translation, content, and illustrations preferred by participants and areas of inadequate existing knowledge needed for comprehension of concepts being taught. Analogies, illustrations, and introduction of medical terms in conjunction with equivalent common Spanish terms were effective ways of building bridges from existing knowledge to new knowledge. Participants desired detailed information and shared new information with others CONCLUSION: We learned the importance of assessing patients' existing body knowledge. The detail desired by participants challenged common simplification approaches to teaching low-literacy learners. Participant willingness to share information challenged ideas of cultural taboo. Results provide evidence for more effective delivery of women's health education and call for further research on best approaches to teaching low-literacy learners. PMID- 23030625 TI - Two new dammarane-type saponins from leaves of Panax quinquefolium. AB - Two new saponins were isolated from the leaves of Panax quinquefolium and their structures were elucidated as 3beta, 6alpha, 20S-trihydroxy-12beta, 23R epoxydammar-24-ene 6-O-[alpha-L-rhamnosyl(1 -> 2)-beta-D-glucopyranosyl]-20-O beta-D-glucopyranoside (1) and 3beta, 20S-dihydroxy-12beta, 23R-epoxydammar-24 ene 3-O-[beta-D-glucopyranosyl(1 -> 2)-beta-D-glucopyranosyl]-20-O-beta-D glucopyranoside (2) on the basis of physicochemical evidence. PMID- 23030626 TI - Expression of snail, twist, and Zeb1 in malignant mesothelioma. AB - We examined 56 malignant mesotheliomas, 117 lung adenocarcinomas, and 34 metastatic lung adenocarcinomas with antibodies to transcription factors involved in epitheliomesenchymal transition. The tumors were stained immunohistochemically with antibodies zeb1, twist, and snail. Malignant mesotheliomas exhibited a stronger expression of zeb1 and twist than lung adenocarcinomas (p < 0.001 for both). Metastatic adenocarcinomas displayed a more frequent expression of zeb1 and twist (p < 0.001 for both) than lung adenocarcinomas. Patients with snail positive mesotheliomas experienced a better survival (p = 0.046), whereas in lung adenocarcinomas, this trait predicted worse survival (p = 0.024). Biphasic mesotheliomas had a more frequent expression of snail or zeb1 than epithelioid and sarcomatoid mesotheliomas as a group (p = 0.034 and p = 0.005, respectively). E-cadherin was more commonly present in epithelioid mesotheliomas (p = 0.002). Cases with snail positivity showed a significantly lower apoptotic index (p = 0.039). Malignant mesotheliomas display strong twist and zeb1 expression, which may be an indication of transdifferentiation between the epithelioid and sarcomatoid cell types with biphasic mesotheliomas representing tumors in active transition. Metastatic adenocarcinomas show a higher expression of zeb1 and twist than primary lung tumors, confirming our previous findings and highlighting their significance in the metastatic process. Snail expression is associated with poor prognosis in lung adenocarcinomas, but an opposite effect was seen in mesothelioma, a fact which may be related to the different cellular origin of epithelial and mesothelial cells. PMID- 23030627 TI - Ribotyping of Clostridium difficile strains associated with nosocomial transmission and relapses in a Swedish County. AB - Clostridium difficile is an emerging threat in hospital environments. To analyse possible transmission and to distinguish between relapse and reinfection a collection of C. difficile isolates, sampled from 162 consecutive episodes of C. difficile infection, were PCR ribotyped. Two ribotypes (001 and 012) were prone to cause nosocomial acquisition. Moreover, ribotype 001 had a tendency to cause relapses as almost one in two patients with this ribotype had one or more relapses. By using PCR ribotyping strains inclined to cause relapses and strains associated with hospital transmission might be detected. This enables optimized hygiene measures and may improve the choice of treatment regimen. PMID- 23030628 TI - A personal digital assistant for improving independent transitioning in adolescents with high-functioning autism spectrum disorder. AB - OBJECTIVE: This study evaluated the effectiveness of a personal digital assistant (PDA) on independent transitioning between activities in a day treatment centre for youth with high-functioning ASD. METHODS: Within a multiple baseline design across four participants, data were collected on participant's transitioning and staff's prompting behaviour. Intervention by staff consisted of one technical instruction session on use of the PDA and non-specific instruction following incorrect transitions while not using the PDA, in the natural setting. RESULTS: Analysis revealed a significant increase in percentage independent daily transitions, which resulted from the independent use of the PDA. The change in staff's prompt use during intervention was mainly the result of a significant decrease in the use of non-specific prompts in correcting participant's transition behaviour. CONCLUSION: A brief intervention was effective in improving independent transitioning using a PDA. Findings are evaluated in light of their clinical implications and suggestions for future research are discussed. PMID- 23030630 TI - Malignant transformation of adenomyoepithelioma of the breast by a monophasic population: a report of two cases and review of literature. AB - Two cases of adenomyoepithelioma of the breast with malignant transformation by monophasic population of cells are presented. The underlying benign adenomyoepithelioma with typical biphasic architectural pattern was identified and represented at least 30% of the tumor in each case. In both cases, malignant portion of tumor was composed of relatively uniform monophasic population of highly atypical cells. The malignant component in case 1 was positive for pan cytokeratin, myoepithelial markers, and basal-type cytokeratins and also focally positive for luminal-type of cytokeratins, but negative for hormone receptors (estrogen and progesterone) and HER-2/neu protein overexpression. The malignant component in case 2 was positive for spectrum of myoepithelial markers but negative for luminal cytokeratins, hormone receptors and HER-2/neu protein overexpression. The bilinear immunophenotype in the case 1 suggests that the malignant tumor may have developed from precursor multipotent cells that can differentiate into both luminal epithelial and myoepithelial cells, although malignant component in case 2 appears to be the of pure myoepithelial phenotype. PMID- 23030629 TI - Conformational changes in orotidine 5'-monophosphate decarboxylase: a structure based explanation for how the 5'-phosphate group activates the enzyme. AB - The binding of a ligand to orotidine 5'-monophosphate decarboxylase (OMPDC) is accompanied by a conformational change from an open, inactive conformation (E(o)) to a closed, active conformation (E(c)). As the substrate traverses the reaction coordinate to form the stabilized vinyl carbanion/carbene intermediate, interactions that destabilize the carboxylate group of the substrate and stabilize the intermediate (in the E(c).S(?) complex) are enforced. Focusing on the OMPDC from Methanothermobacter thermautotrophicus, we find the "remote" 5' phosphate group of the substrate activates the enzyme 2.4 * 10(8)-fold; the activation is equivalently described by an intrinsic binding energy (IBE) of 11.4 kcal/mol. We studied residues in the activation that (1) directly contact the 5' phosphate group, (2) participate in a hydrophobic cluster near the base of the active site loop that sequesters the bound substrate from the solvent, and (3) form hydrogen bonding interactions across the interface between the "mobile" and "fixed" half-barrel domains of the (beta/alpha)(8)-barrel structure. Our data support a model in which the IBE provided by the 5'-phosphate group is used to allow interactions both near the N-terminus of the active site loop and across the domain interface that stabilize both the E(c).S and E(c).S(?) complexes relative to the E(o).S complex. The conclusion that the IBE of the 5'-phosphate group provides stabilization to both the E(c).S and E(c).S(?) complexes, not just the E(c).S(?) complex, is central to understanding the structural origins of enzymatic catalysis as well as the requirements for the de novo design of enzymes that catalyze novel reactions. PMID- 23030631 TI - Sources of data about children's executive functioning: review and commentary. AB - Accurate measurement of a child's executive functioning (EF) is important for diagnosis, description of functional impairment, and treatment planning. EF assessment typically consists of administration of a battery of performance-based tests involving abilities such as attention, inhibition, reasoning, planning, and mental flexibility. In recent years, observer (e.g., parent) rating scales have been added to the typical EF battery. However, research has revealed that performance-based tests and parent rating scales are not highly correlated. In other words, level of impairment indicated by one source of data often does not match level of impairment indicated by the other source of data. This disagreement places the clinician in a difficult situation when attempting to interpret evaluation results. The profession of pediatric neuropsychology needs to provide guidance about handling this disagreement. Using the current assessment tools, specific EF subdomains may need to be examined systematically to identify precisely where the disagreements lie. Perhaps the relative validity of the two data sources can be determined, and decisions can be made about what to emphasize and what/when to interpret cautiously. Alternatively, perhaps the goal should be to develop and/or refine measurement tools to increase agreement in order to improve accuracy and validity of test interpretation. At this time, the results of performance-based tests and rating scales of EF are being used together but are not being integrated. Evidence-based practice requires that more work be done to enhance the use of these two sources of data. PMID- 23030632 TI - Injectable materials with magnetically controlled anisotropic porosity. AB - We propose a method to create aligned porosity in injectable materials by using magnetically responsive microrods as pore forming sacrificial templates. Rod alignment occurs through the application of an external magnetic field after injecting the material into the desired end location. Removal of the sacrificial templates through dissolution or resorption generates porosity in deliberately tuned orientations after injection, offering a powerful method to design the porous architecture of injectable materials. PMID- 23030633 TI - Conflict resolution techniques applied to interprofessional collaborative practice. PMID- 23030634 TI - The power of prepositions: a taxonomy for interprofessional education. AB - This is the second paper in a two-part series. The first paper presented a study that provided a more contextual description of the commonly applied definition of interprofessional education (IPE) offered in 2002 by the Centre for the Advancement of Interprofessional Education (CAIPE) in the UK. The study's results confirm and consolidate key characteristics of IPE by exploring the meaning of with, from and about. This second paper presents a proposed taxonomy for IPE that may serve to inform emerging applications for IPE in the context of education, service delivery and policy. This paper contributes to an emerging understanding of IPE that will support competency development and sound curriculum design, continuing professional development and evaluation of the impact of IPE and collaboration on health outcomes. PMID- 23030635 TI - Application of the team objective structured clinical encounter (TOSCE) for continuing professional development amongst postgraduate health professionals. AB - Educators in healthcare face significant challenges trying to improve interprofessional teamworking skills, with a lack of clarity on how to teach and evaluate such skills. Previously, the team objective structured clinical encounter (TOSCE) has been reported as a teaching and assessment tool, but it has been used primarily in homogenous groups of undergraduates. An interprofessional team of educators set out to evaluate the TOSCE as a teaching intervention amongst a large interprofessional group of postgraduate nurses and midwives. After the TOSCE, 83% of participants reported that they were more aware of potential weaknesses in teamworking and 60% felt more able to work in a team. Mean Likert scale ratings were 4/5 for usefulness, enjoyment and relevance. The TOSCE is a feasible tool for teamwork skill assessment in the demanding postgraduate interprofessional setting and requires further investigation to ascertain its potential for formative and summative assessment of skills. PMID- 23030637 TI - Environmental Microbiology: evolution of your premier journal. PMID- 23030636 TI - Characterization and analysis of migration patterns of dentospheres derived from periodontal tissue and the palate. AB - BACKGROUND AND OBJECTIVE: Stem cells derived from periodontal and palatal tissues may be useful for regenerative therapies of periodontal tissues. In addition to the use of single periodontium-derived stem cells (pdSCs) and palatal-derived stem cells (paldSCs), the application of pdSC and paldSC dentospheres, providing a pool of vital stem cells, may be a useful approach. As cell migration is a prerequisite for stem cells to regenerate a three-dimensional tissue environment, we characterized pdSCs and paldSCs and investigated the migratory activity of dentospheres within a three-dimensional environment. We also investigated the capacity of the dentospheres to grow on zirconium dioxide surfaces. MATERIAL AND METHODS: The capacity of pdSCs and paldSCs to differentiate into the neuronal and osteogenic lineages was proved by RT-PCR and immunohistochemistry through the detection of specific lineage markers, such as alkaline phosphatase, glutamate decarboxylase 1 (also known as GAD67, the 67-kDa isoform of glutamate decarboxylase), neurofilament-M and beta-III-tubulin. The expression profile of surface molecules on pdSCs and paldSCs was analyzed by flow cytometry. Adhesion and growth of pdSC/paldSC dentospheres on zirconium dioxide surfaces were determined using confocal laser-scanning microscopy. The migratory behavior of the cells was analyzed using a three-dimensional collagen matrix migration assay. RESULTS: Both pdSCs and paldSCs were positive for epidermal growth factor receptor, CC chemokine receptor 2 and CXC chemokine receptor 4 expression and were able to grow on zirconium dioxide surfaces. Cell-migration experiments revealed that both stem-cell populations responded similarly to epidermal growth factor (EGF), monocyte chemotactic protein 1 (MCP-1) and stromal cell-derived factor 1alpha (SDF-1alpha). Stimulation with EGF resulted in an increased migratory activity of both stem-cell types, whereas the locomotory behavior of the cells was impaired by both MCP-1 and SDF-1alpha. CONCLUSION: Dentospheres represent a pool of vital pdSCs/paldSCs. As a result of the migratory activity demonstrated, along with the capacity to grow on zirconium dioxide surfaces, dentospheres may be useful for regenerative purposes in periodontal tissues. PMID- 23030638 TI - Completely OH-selective FeCl3-catalyzed Prins cyclization: highly stereoselective synthesis of 4-OH-tetrahydropyrans. AB - The completely OH-selective Prins cyclization has been realized from the enantioselective ene reaction product. A variety of 4-hydroxyl-tetrahydropyrans were exclusively generated via FeCl(3)-catalyzed Prins reaction. Excellent stereoselectivities (up to >99:1 dr and >99.5:0.5 er) were obtained for a remarkably broad range of substrates under mild reaction conditions. The control experiments, including NOE effects and (18)O-labeling studies, as well as DFT calculations were conducted to provide fundamental insights into the mechanism of the reaction. A different [2 + 2] cycloaddition process was suggested to rationalize the observed OH-selectivity. PMID- 23030639 TI - Microbiological effectiveness of mineral pot filters in Cambodia. AB - Mineral pot filters (MPFs) are household water treatment (HWT) devices that are manufactured and distributed by the private sector, with millions of users in Southeast Asia. Their effectiveness in reducing waterborne microbes has not been previously investigated. We purchased three types of MPFs available on the Cambodian market for systematic evaluation of bacteria, virus, and protozoan surrogate microbial reduction in laboratory challenge experiments following WHO recommended performance testing protocols. Results over the total 1500 L testing period per filter indicate that the devices tested were highly effective in reducing Esherichia coli (99.99%+), moderately effective in reducing bacteriophage MS2 (99%+), and somewhat effective against Bacillus atrophaeus, a spore-forming bacterium we used as a surrogate for protozoa (88%+). Treatment mechanisms for all filters included porous ceramic and activated carbon filtration. Our results suggest that these commercially available filters may be at least as effective against waterborne pathogens as other, locally available treatment options such as ceramic pot filters or boiling. More research is needed on the role these devices may play as interim solutions to the problem of unsafe drinking water in Cambodia and globally. PMID- 23030640 TI - Inclusion of compliance and persistence in economic models: past, present and future. AB - Economic models are developed to provide decision makers with information related to the real-world effectiveness of therapeutics, screening and diagnostic regimens. Although compliance with these regimens often has a significant impact on real-world clinical outcomes and costs, compliance and persistence have historically been addressed in a relatively superficial fashion in economic models. In this review, we present a discussion of the current state of economic modelling as it relates to the consideration of compliance and persistence. We discuss the challenges associated with the inclusion of compliance and persistence in economic models and provide an in-depth review of recent modelling literature that considers compliance or persistence, including a brief summary of previous reviews on this topic and a survey of published models from 2005 to 2012. We review the recent literature in detail, providing a therapeutic-area specific discussion of the approaches and conclusions drawn from the inclusion of compliance or persistence in economic models. In virtually all publications, variation of model parameters related to compliance and persistence was shown to have a significant impact on predictions of economic outcomes. Growing recognition of the importance of compliance and persistence in the context of economic evaluations has led to an increasing number of economic models that consider these factors, as well as the use of more sophisticated modelling techniques such as individual simulations that provide an avenue for more rigorous consideration of compliance and persistence than is possible with more traditional methods. However, we note areas of continuing concern cited by previous reviews, including inconsistent definitions, documentation and tenuous assumptions required to estimate the effect of compliance and persistence. Finally, we discuss potential means to surmount these challenges via more focused efforts to collect compliance and persistence data. PMID- 23030641 TI - Quantum tunneling enabled self-assembly of hydrogen atoms on Cu(111). AB - Atomic and molecular self-assembly are key phenomena that underpin many important technologies. Typically, thermally enabled diffusion allows a system to sample many areas of configurational space, and ordered assemblies evolve that optimize interactions between species. Herein we describe a system in which the diffusion is quantum tunneling in nature and report the self-assembly of H atoms on a Cu(111) surface into complex arrays based on local clustering followed by larger scale islanding of these clusters. By scanning tunneling microscope tip-induced scrambling of H atom assemblies, we are able to watch the atomic scale details of H atom self-assembly in real time. The ordered arrangements we observe are complex and very different from those formed by H on other metals that occur in much simpler geometries. We contrast the diffusion and assembly of H with D, which has a much slower tunneling rate and is not able to form the large islands observed with H over equivalent time scales. Using density functional theory, we examine the interaction of H atoms on Cu(111) by calculating the differential binding energy as a function of H coverage. At the temperature of the experiments (5 K), H(D) diffusion by quantum tunneling dominates. The quantum-tunneling enabled H and D diffusion is studied using a semiclassically corrected transition state theory coupled with density functional theory. This system constitutes the first example of quantum-tunneling-enabled self-assembly, while simultaneously demonstrating the complex ordering of H on Cu(111), a catalytically relevant surface. PMID- 23030642 TI - Imageability and age of acquisition effects in disyllabic word recognition. AB - Imageability and age of acquisition (AoA) effects, as well as key interactions between these variables and frequency and consistency, were examined via multiple regression analyses for 1,936 disyllabic words, using reaction time and accuracy measures from the English Lexicon Project. Both imageability and AoA accounted for unique variance in lexical decision and naming reaction time performance. In addition, across both tasks, AoA and imageability effects were larger for low frequency words than high-frequency words, and imageability effects were larger for later acquired than earlier acquired words. In reading aloud, consistency effects in reaction time were larger for later acquired words than earlier acquired words, but consistency did not interact with imageability in the reaction time analysis. These results provide further evidence that multisyllabic word recognition is similar to monosyllabic word recognition and indicate that AoA and imageability are valid predictors of word recognition performance. In addition, the results indicate that meaning exerts a larger influence in the reading aloud of multisyllabic words than monosyllabic words. Finally, parallel distributed-processing approaches provide a useful theoretical framework to explain the main effects and interactions. PMID- 23030643 TI - Assessing the extent of bone degradation using glutamine deamidation in collagen. AB - Collagen peptides are analyzed using a low-cost, high-throughput method for assessing deamidation using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). For each chosen peptide, the theoretical distribution is calculated and the measured distribution for each sample compared with this to determine the extent of glutamine deamidation. The deamidation of glutamine (Q) to glutamic acid (E) results in a mass shift of +0.984 Da. Thus, from the resolution of our data, the second peak in the isotope distribution for a peptide containing one glutamine residue coincides with the first peak of the isotope distribution for the peptide in which the residue is deamidated. A genetic algorithm is used to determine the extent of deamidation that gives the best fit to the measured distribution. The method can be extended to peptides containing more than one glutamine residue. The extent of protein degradation assessed in this way could be used, for example, to assess the damage of collagen, and screen samples for radiocarbon dating and DNA analysis. PMID- 23030644 TI - An extended spectrum of target proteins and modification sites in the general O linked protein glycosylation system in Neisseria gonorrhoeae. AB - The bacterial human pathogen Neisseria gonorrhoeae expresses a general O-linked protein glycosylation (Pgl) system known to target at least 12 membrane associated proteins. To facilitate a better understanding of the mechanisms, significance and function of this glycosylation system, we sought to further delineate the target proteome of the Pgl system. To this end, we employed immunoaffinity enrichment of glycoproteins using a monoclonal antibody against the glycan moiety. Enzymatically generated peptides were subsequently analyzed by MS to identify glycopeptides and glycosylation sites. In this way, we increase the total number of known glycoproteins in N. gonorrhoeae to 19. These new glycoproteins are involved in a wide variety of extracytoplasmic functions. By employing collision fragmentation, we mapped nine new glycosylation sites, all of which were serine. No target sequon was readily apparent, although attachment sites were most often localized with regions of low sequence complexity. Moreover, we found that 5 of the proteins were modified with more than one glycan. This work thus confirms and extends earlier observations on the structural features of Neisseria glycoproteins. PMID- 23030645 TI - Role of new agents affecting NO/cGMP pathway on ovalbumin-sensitized guinea pig trachea. AB - Asthma is a chronic inflammatory disease in which cell components play important roles. We aimed to evaluate the effects of NO/cGMP cleavage at trachea preparations isolated from ovalbumin-sensitized guinea pigs in vitro. Trachea rings were exposed to 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC 12), (+/-)-(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexen-1-yl-nicotinamide (NOR-4), 2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2 yl) methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T-0156), and electrical field stimulation (EFS). cGMP levels in trachea tissues were also measured. The relaxation responses of NOC-12, NOR-4, T 0156, and EFS were significantly decreased at ovalbumin-sensitized group. Nitric oxide (NO) donors significantly decreased the relaxation responses in the presence of 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ). L-Nitro Arginine Methyl Ester (L-NAME) significantly decreased the EFS relaxation responses in both groups (experimental group and control group), but this effect was reversed by L-Arginine addition. In the experimental group, cGMP levels after EFS, carbachol, NOC-12, NOR-4, and T-0156 exposure were significantly lower than control group. In both groups, cGMP levels after NO donors' exposure were significantly lower in the presence of ODQ and the cGMP levels after EFS + L-NAME were significantly lower than EFS alone. These results may show the increased formation of NO because of the increased iNOS activity in airway sensitization leading to the inhibition of cNOS resulting in the decrease of endogen NO and decrease of activation of guanylyl cyclase. PMID- 23030647 TI - Phagocytosis and cytokine response to rough and smooth colony variants of Mycobacterium abscessus by human peripheral blood mononuclear cells. AB - Mycobacterium abscessus is a non-tuberculous mycobacteria able to cause opportunistic infections in selected patient groups. During the last decades it has emerged as a cause of chronic pulmonary infection in patients with cystic fibrosis (CF). M. abscessus strains exhibit either smooth or rough colony morphology. Strains exhibiting the rough phenotype more often cause pulmonary infections in CF patients than did the smooth ones. Here, we examined phagocytosis and production of cytokines by human peripheral blood mononuclear cells, in response to M. abscessus strains with smooth and rough colony phenotype. The rough isolates all formed multicellular cords, similar to what is observed in Mycobacterium tuberculosis. Monocytes were generally unable to internalize these rough cord isolates, in contrast with the smooth ones. Furthermore, the rough M. abscessus strains induced a distinct cytokine profile differing from that induced by the smooth ones. Rough isolates induced significantly less IL-10 and tumour necrosis factor compared to smooth strains, but more IL-1beta. Both varieties induced equal amounts of IFN-gamma, IL-17, IL 23, IL-6, IL-8 and equally little IL-12. The ability to withstand phagocytosis might be a virulence factor contributing to the capacity of rough M. abscessus strains to give persistent pulmonary infections. PMID- 23030646 TI - Phospholipase D participates in H(2)O(2)-induced A549 alveolar epithelial cell migration. AB - To investigate the effects of phospholipase D (PLD) on low-concentration hydrogen peroxide (H(2)O(2))-induced growth and migration in alveolar epithelial A549 cells, the cells were exposed to H(2)O(2) (3-100 MUM) for 12-48 hours, cell proliferation was determined by MTT assay and cell migration was tested by a modified epithelial wound healing assay. We found that one bolus of H(2)O(2) (10 100 MUM) did not affect proliferation, but significantly stimulated migration (143-161% of control) after a 12-hour exposure. Pretreatment with the antioxidants catalase (1000 U/ml), N-acetyl-cysteine (2 mM), or edaravone (10 MUM) abolished the migration induced by 30 MUM H(2)O(2); the PLD inhibitor 1 butanol (0.5%) also attenuated H(2)O(2)-induced migration to the control level; while exogenous phosphatidic acid (PA) (10(-7)-10(-4) M) mimicked the effects of PLD activation and induced migration in a dose-dependent manner. We suggest that the alveolar epithelial cell migration induced by exposure to low concentrations of H(2)O(2) benefits tissue repair during acute lung injury (ALI) and PLD is involved in the underlying mechanism. PMID- 23030648 TI - Possible association of the GSK3beta gene with the anxiety symptoms of major depressive disorder and P300 waveform. AB - Glycogen synthase kinase-3beta (GSK3beta) may play an important role in the brain of patients with major depressive disorder (MDD); therefore, we investigated whether the GSK3beta gene is involved in the etiology of MDD and whether it affects MDD endophenotypes. Three single-nucleotide polymorphisms (SNPs) (rs6438552, rs7633279, and rs334558) were genotyped in 559 MDD patients and 486 healthy controls. To explore quantitative traits of MDD, we analyzed the association of these SNPs with the factor scores of the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Hamilton Anxiety Rating Scale (HAMA). We also determined the effects of these SNPs on the measurement of the P300 wave. Although no significant association between GSK3beta SNPs and MDD was found, some genotypes and haplotypes were associated with anxiety symptoms in MDD. The three SNPs were associated with the HAMA total score and with the HAMD anxiety and somatization factor score (p<0.05). Three-locus haplotype analysis showed the C-T G carriers to have a strong association with the HAMA total score (p=0.032). Moreover, the P300 latency and amplitude were also associated with GSK3beta genotypes. The individuals with the T allele genotype, both in rs6438552 and rs7633279, have a longer P300 latency than those carrying the C/C (p=0.04) and A/A genotype (p=0.013). The individuals with the G/G genotype in rs334558 have a lower amplitude than those carrying the A allele genotype (p=0.007). Our findings show, for the first time, that GSK3beta polymorphisms may play an important role in MDD endophenotypes, especially in anxiety symptoms. PMID- 23030649 TI - Possible association of a novel missense mutation A6375G in the mitochondrial cytochrome C oxidase I gene with asthenospermia in the Tunisian population. AB - Cytochrome c oxidase encoded by multiple mitochondrial genes (COXI, COXII, and COXIII) and nuclear genes is an essential component of the mitochondrial respiratory chain that catalyzes the reduction of molecular oxygen by reduced cytochrome c. Subunits COXI and COXII of cytochrome c oxidase are known to play the most essential role in proton pumping and electron transfer. In this study we screened the somatic mitochondrial COXI gene of infertile men suffering from asthenospermia (n=34) in comparison to normozoospermic infertile men (n=32) and fertile men (n=100) from the Tunisian population. A novel homoplasmic missense mitochondrial mutation (m.6375A>G) was found in 5 asthenospermic patients (14%) but not in any of normozoospermic infertile men and fertile men. This mutation substituting the isoleucine at position 158 to valine in a highly conserved amino acid induces a reduction of the hydropathy index (from +1.920 to +0.239) and a decrease of the protein 3D structure number (from 50 to 26) as shown by PolyPhen bioinformatic program. PMID- 23030650 TI - Triplet-primed PCR is more sensitive than southern blotting-long PCR for the diagnosis of myotonic dystrophy type1. AB - Genetic testing of myotonic dystrophy type 1 (DM1) is very important because it enables the diagnosis and indicates the severity of the disease. Mutation analysis is based on the detection of the number of CTG triplets in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Sometimes it could be complicated by the presence of different patterns of repeat interruptions in the 5' and 3' ends of the expanded alleles recently described in about 3% to 5% of patients. To make molecular diagnosis easier and faster, the use of triplet-primed PCR (TP-PCR) for the detection of expansions in DM1 and other dynamic mutation diseases was proposed. Here we present the results of a retrospective study performed by TP-PCR on 100 subjects previously analyzed by Southern blotting-long PCR. PMID- 23030651 TI - Polyaromatic hydrocarbons of smoked cured muscle foods prepared by Canadian Tl'azt'en and Llheidli T'enneh First Nation communities. AB - Tl'azt'en and Lheidli T'enneh First Nation communities have traditionally used smoking, drying, and salting of fish and game as preservation methods to enhance food security. Our results showed that levels of 16 polycyclic aromatic hydrocarbons (PAH) were significantly higher in smoked salmon samples compared to moose meats, and further, that PAH contents were also dependent on the duration of smoke processing. Benzo[a]pyrene (BaP) was not detected in fresh or partially smoked foods, but was present in both fully smoked moose (1.4 MUg/kg) and fully smoked salmon (3.6 MUg/kg) meats, respectively. The total concentrations of PAH present in fully smoked meats using traditional smoke processing methods employed by Tl'azt'en and Lheidli T'enneh nations indicate that a risk assessment is required to determine the safety of these smoke-processed foods. PMID- 23030653 TI - Evaluation of the concentration of nonessential and essential elements in chicken, pork, and beef samples produced in Brazil. AB - Food safety is a global concern. Meat represents the most important protein source for humans. Thus, contamination of meat products by nonessential elements is a ready source of human exposure. In addition, knowledge of the concentration of essential elements is also relevant with respect to human nutrition. The aim of the present study was to determine the concentration of 17 elements in pork, beef, and chicken produced in Brazil. Meat samples were analyzed by inductively coupled plasma mass spectrometry. The estimated daily intake for nonessential elements including arsenic (As), cadmium (Cd), lead (Pb), mercury (Hg), and antimony (Sb) through meat consumption is below the toxicological reference values. However, high levels were detected for the nonessential element cesium (Cs), mainly in beef samples, an observation that deserves future studies to identify the source of contamination and potential adverse consequences. PMID- 23030652 TI - Evaluation of a prototype point-of-care instrument based on monochromatic x-ray fluorescence spectrometry: potential for monitoring trace element status of subjects with neurodegenerative disease. AB - Assessment of trace elements such as Cu, Zn, and Se in patients with neurodegenerative disease, such as Alzheimer's (AD) and Parkinson's disease (PD), may be useful in etiologic studies and in assessing the risk of developing these conditions. A prototype point-of-care (POC) instrument based on monochromatic x ray fluorescence (M-XRF) was assembled and evaluated for the determination of Cu, Zn, and Se in whole blood, plasma, and urine. The prototype instrument was validated using certified reference materials for Cu and Zn in serum/plasma, and the reported bias and relative imprecision were <10%. The M-XRF prototype performance was further assessed using human specimens collected from AD and PD subjects, and was found to be satisfactory (<20% bias) for monitoring Cu and Zn levels in plasma and whole blood. However, the prototype M-XRF sensitivity was not sufficient for quantifying Cu, Zn, or Se in urine. Nonetheless, while validating the prototype instrument, body fluids (whole blood, plasma, and urine) were collected from 19 AD patients, 23 PD patients, and 24 controls specifically for trace element analysis using well-validated methods based on inductively coupled plasma mass spectrometry (ICP-MS). This limited biomonitoring study provided robust data for up to 16 elements including Sb, As, Ba, Cd, Cs, Co, Cr, Cu, Hg, Pb, Mo, Se, Tl, Sn, Zn, and U in plasma, whole blood, and urine. The results did not indicate any significant differences in most trace elements studied between AD or PD patients compared to controls, although the sample size is limited. A statistically significant increase in plasma Se was identified for PD patients relative to AD patients, but this could be due to age differences. PMID- 23030654 TI - Screening-level risk assessment for styrene-acrylonitrile (SAN) trimer detected in soil and groundwater. AB - A screening-level risk assessment was conducted for styrene-acrylonitrile (SAN) Trimer detected at the Reich Farm Superfund site in Toms River, NJ. Consistent with a screening-level approach, on-site and off-site exposure scenarios were evaluated using assumptions that are expected to overestimate actual exposures and hazards at the site. Environmental sampling data collected for soil and groundwater were used to estimate exposure point concentrations. Several exposure scenarios were evaluated to assess potential on-site and off-site exposures, using parameter values for exposures to soil (oral, inhalation of particulates, and dermal contact) and groundwater (oral, dermal contact) to reflect central tendency exposure (CTE) and reasonable maximum exposure (RME) conditions. Three reference dose (RfD) values were derived for SAN Trimer for short-term, subchronic, and chronic exposures, based upon its effects on the liver in exposed rats. Benchmark (BMD) methods were used to assess the relationship between exposure and response, and to characterize appropriate points of departure (POD) for each RfD. An uncertainty factor of 300 was applied to each POD to yield RfD values of 0.1, 0.04, and 0.03 mg/kg-d for short-term, subchronic, and chronic exposures, respectively. Because a chronic cancer bioassay for SAN Trimer in rats (NTP 2011a) does not provide evidence of carcinogenicity, a cancer risk assessment is not appropriate for this chemical. Potential health hazards to human health were assessed using a hazard index (HI) approach, which considers the ratio of exposure dose (i.e., average daily dose, mg/kg-d) to toxicity dose (RfD, mg/kg-d) for each scenario. All CTE and RME HI values are well below 1 (where the average daily dose is equivalent to the RfD), indicating that there is no concern for potential noncancer effects in exposed populations even under the conservative assumptions of this screening-level assessment. PMID- 23030655 TI - Dietary contaminant exposure affects plasma testosterone, but not thyroid hormones, vitamin A, and vitamin E, in male juvenile arctic foxes (Vulpes lagopus). AB - Levels of persistent organic pollutants (POP), such as polychlorinated biphenyls (PCB), are high in many Arctic top predators, including the Arctic fox (Vulpes lagopus). The aim of this study was to examine possible endocrine-disruptive effects of dietary POP exposure in male juvenile Arctic foxes in a controlled exposure experiment. The study was conducted using domesticated farmed blue foxes (Vulpes lagopus) as a model species. Two groups of newly weaned male foxes received a diet supplemented with either minke whale (Baleneoptera acutorostrata) blubber that was naturally contaminated with POP (exposed group, n = 5 or 21), or pork (Sus scrofa) fat (control group, n = 5 or 21). When the foxes were 6 mo old and had received the 2 diets for approximately 4 mo (147 d), effects of the dietary exposure to POP on plasma concentrations of testosterone (T), thyroid hormones (TH), thyroid-stimulating hormone (TSH), retinol (vitamin A), and tocopherol (viramin E) were examined. At sampling, the total body concentrations of 104 PCB congeners were 0.1 +/- 0.03 MUg/g lipid weight (l.w.; n = 5 [mean +/- standard deviation]) and 1.5 +/- 0.17 MUg/g l.w. (n = 5) in the control and exposed groups, respectively. Plasma testosterone concentrations in the exposed male foxes were significantly lower than in the control males, being approximately 25% of that in the exposed foxes. There were no between-treatment differences for TH, TSH, retinol, or tocopherol. The results suggest that the high POP levels experienced by costal populations of Arctic foxes, such as in Svalbard and Iceland, may result in delayed masculine maturation during adolescence. Sex hormone disruption during puberty may thus have lifetime consequences on all aspects of reproductive function in adult male foxes. PMID- 23030656 TI - Is maximal lactate steady state during intermittent cycling different for active compared with passive recovery? AB - The purpose of this study was to analyze the effect of recovery type (passive vs. active) during prolonged intermittent exercises on the blood lactate concentration (MLSS) and work rate (MLSS(wint)) at maximal lactate steady state. Nineteen male trained cyclists were divided into 2 groups for the determination of MLSS(wint) using passive (maximal oxygen uptake = 58.1 +/- 3.5 mL.kg(-1).min( 1); N = 9) or active recovery (maximal oxygen uptake = 60.3 +/- 9.0 mL.kg( 1).min(-1); N = 10). They performed the following tests, on different days, on a cycle ergometer: (i) incremental test until exhaustion to determine maximal oxygen uptake; (ii) 2 to 3 continuous submaximal constant work rate tests (CWRT) for the determination of the work rate at continuous maximal lactate steady state (MLSS(wcont)); and (iii) 2 to 3 intermittent submaximal CWRT (7 * 4 min and 1 * 2 min, with 2-min recovery) with either passive or active recovery for the determination of MLSS(wint). MLSS(wint) was significantly higher when compared with MLSS(wcont) for both passive recovery (294.7 +/- 32.2 vs. 258.7 +/- 24.5 W, respectively) and active recovery groups (300.5 +/- 23.9 vs. 273.2 +/- 21.5 W, respectively). The percentage increments in MLSS(wint) were similar between conditions (passive = 13% vs. active = 10%). MLSS (mmol.L(-1)) was not significantly different between MLSS(wcont) and MLSS(wint) for either passive recovery (4.50 +/- 2.10 vs. 5.61 +/- 1.78, respectively) and active recovery (4.06 +/- 1.49 vs. 4.91 +/- 1.91, respectively) conditions. We can conclude that using a work/rest ratio of 2:1, MLSS(wint) was ~10%-13% higher than MLSS(wcont), irrespective of the recovery type performed during prolonged intermittent exercises. PMID- 23030657 TI - Implementation of the baby-friendly hospital initiative steps in Iowa hospitals. AB - OBJECTIVE: To determine the status of each of the Baby-Friendly Hospital Initiative (BFHI) Ten Steps and associated policies in Iowa hospitals. DESIGN: Exploratory, descriptive study using the World Health Organization BFHI self assessment survey. SETTING: Iowa hospitals with maternity services. PARTICIPANTS: Fifty-three Iowa hospital administrators. METHODS: Hospitals were classified by level of implementation of each of the Ten Steps and related criteria. RESULTS: The majority of the hospitals were implementing at least three of the Ten Steps. The most widely adopted policy, encouraging breastfeeding on demand, was implemented by 83% of the hospitals. None of the hospitals had implemented all six criteria included in Step One. Step One describes a written breastfeeding policy routinely communicated to all healthcare staff. CONCLUSION: Implementation of the steps varied by hospital locale; urban hospitals had higher implementation rates for Step 10 than rural hospitals. Areas identified as needing the greatest attention by hospitals were posting of breastfeeding policy, evaluation, and providing education to all mothers. PMID- 23030658 TI - Peptidomimetics as potent and selective PTP1B inhibitors. AB - A series of peptidomimetic containing bidentate pTyr mimetics (9a-w) are reported as potent and selective PTP1B inhibitors. Compounds (9p and 9q) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro), which confirms discovery of highly potent and selective PTP1B inhibitors. PMID- 23030659 TI - Visual impairment in children with spastic cerebral palsy measured by psychophysical and electrophysiological grating acuity tests. AB - BACKGROUND: This study measured grating visual acuity in 173 children between 6 48 months of age who had different types of spastic cerebral palsy (CP). METHOD: Behavioural acuity was measured with the Teller Acuity Cards (TAC) using a staircase psychophysical procedure. Electrophysiological visual acuity was estimated using the sweep VEP (sVEP). RESULTS: The percentage of children outside the superior tolerance limits was 44 of 63 (69%) and 50 of 55 (91%) of tetraplegic, 36 of 56 (64%) and 42 of 53 (79%) of diplegic, 10 of 48 (21%) and 12 of 40 (30%) of hemiplegic for sVEP and TAC, respectively. For the sVEP, the greater visual acuity deficit found in the tetraplegic group was significantly different from that of the hemiplegic group (p<0.001). In the TAC procedure the mean visual acuity deficits of the tetraplegic and diplegic groups were significantly different from that of hemiplegic group (p<0.001). The differences between sVEP and TAC means of visual acuity difference were statistically significant for the tetraplegic (p<0.001), diplegic (p<0.001), and hemiplegic group (p=0.004). DISCUSSION: Better visual acuities were obtained in both procedures for hemiplegic children compared to diplegic or tetraplegic. Tetraplegic and diplegic children showed greater discrepancies between the TAC and sVEP results. Inter-ocular acuity difference was more frequent in sVEP measurements. CONCLUSIONS: Electrophysiologically measured visual acuity is better than behavioural visual acuity in children with CP. PMID- 23030660 TI - RimabotulinumtoxinB vs. onabotulinumtoxinA for the treatment of forehead lines: an evaluator-blind, randomized, pilot study. AB - BACKGROUND: Optimum dose ratios of rimabotulinumtoxinB (BTX-B) and onabotulinumtoxinA (BTX-A) have not been determined for forehead wrinkles. OBJECTIVE: To compare the efficacy and safety of BTX-B and BTX-A for the treatment of forehead lines. METHODS: Twenty-two women (mean age, 40 years) with symmetrical moderate to severe forehead lines were randomized to receive single intramuscular injections of BTX-A and BTX-B on either side of the forehead, at a potency ratio of 1 : 70 or 1 : 100. Subjects were followed-up for 16 weeks. Four physicians evaluated patients' photographs according to the 4-point Facial Wrinkling Grade (FWG). Clinical Improvement Scale (CIS) was calculated by subtracting FWG score at each visit from that at baseline. Patient satisfaction scores and adverse events were also recorded. RESULTS: Both BTX-A and BTX-B were effective for the treatment of forehead lines. At both potency ratios, BTX-A had a longer duration of action than BTX-B, while BTX-B led to faster improvement than BTX-A. There was no significant difference in CIS between 700 U and 1000 U BTX-B treatments. Adverse effects were mild and transient. CONCLUSION: Both BTX-A and BTX-B were effective and well tolerated for the treatment of forehead wrinkles at potency ratios of 1 : 70 and 1 : 100. PMID- 23030661 TI - p53-Pathway activity and apoptosis in hydrogen sulfide-exposed stem cells separated from human gingival epithelium. AB - BACKGROUND AND OBJECTIVE: Hydrogen sulfide ( H2S ) is a volatile sulfur compound responsible for physiological halitosis. H2S was also reported as having periodontal pathologic activities. Gingival crevicular epithelium is the first barrier against periodontal pathogens and their products; oral keratinocyte stem cells OKSCs play key roles in maintaining this barrier. The p53 pathway is responsible for regulating key biological events. Increased apoptosis and cell cycle arrest of DNA repair can affect keratinocyte stem cells, having a direct impact on the architecture of the oral epithelial tissue. However, the link between H2S , p53 activity and OKSCs has not yet been fully explored. The main objective of the present study was to explore the implications of the p53 pathway in OKSCs following exposure to H2S. MATERIAL AND METHODS: OKSCs were isolated from human gingival epithelium and incubated with physiological levels of H2S for 24 and 48 h. Apoptosis and the mitochondrial membrane potential were detected using flow cytometry. Cytochrome c, total p53, phosphorylated p53 and caspase activity were assessed using specific ELISAs. p53 Pathway gene activity was assayed using quantitative RT-PCR. RESULTS: The levels of apoptosis were significantly increased following incubation in the presence of H2S, especially after 48 h (36.95 +/- 1.91% vs. 4.77 +/- 0.74%). Caspases 9 and 3 were activated, whereas caspase-8 activity remained low. Total p53 activity and particularly phosphorylated p53 at serine 46, were significantly enhanced compared with controls (47.11 +/- 9.84 units/mL vs. 1.5 +/- 0 units/mL and 32.22 +/- 10.23 units/mL vs. 0.15 +/- 0 units/mL, respectively, at 48 h). Among p53 pathway genes, apoptosis-related genes [i.e. phosphatase and tensin homolog ( PTEN ), B cell CLL/lymphoma 2 ( BCL2), sirtuin 3 ( SIRT3) and caspases]) were dramatically increased when compared with controls. Moreover, cell-cycle progression genes [i.e. E2F transcription factor (E2F) family and histone deacetylase ( HDAC )] and DNA-repair genes [i.e. growth arrest and DNA-damage-inducible, gamma ( GADD45G ) family and serine/threonine-protein kinase Chk2 ( CHEK2)] were also increased. CONCLUSION: Following incubation with H2 S , OKSCs express multiple p53 associated genes, including programmed cell death, cell-cycle control and DNA repair genes. PMID- 23030664 TI - Prospective memory and ageing paradox with event-based tasks: a study of young, young-old, and old-old participants. AB - Research on ageing and prospective memory--remembering to do something in the future--has resulted in paradoxical findings, whereby older adults are often impaired in the laboratory but perform significantly better than younger adults in naturalistic settings. Nevertheless, there are very few studies that have examined prospective memory both in and outside the laboratory using the same sample of young and old participants. Moreover, most naturalistic studies have used time-based tasks, and it is unclear whether the prospective memory and ageing paradox extends to event-based tasks. In this study, 72 young (18-30 years), 79 young-old (61-70 years), and 72 old-old (71-80 years) participants completed several event-based tasks in and outside the laboratory. Results showed that the ageing paradox does exist for event-based tasks but manifests itself differently from that in time-based tasks. Thus, younger adults outperformed old old participants in two laboratory event-based tasks, but there were no age effects for a naturalistic task completed at home (remembering to write the date and time in the upper left corner of a questionnaire). The young and old-old also did not differ in remembering to retrieve a wristwatch from a pocket at the end of the laboratory session. This indicates that the paradox may be due to differences in ongoing task demands in the lab and everyday life, rather than the location per se. The findings call for a concentrated effort towards a theory of cognitive ageing that identifies the variables that do, or do not, account for this paradox. PMID- 23030663 TI - Assembly of asperlicin peptidyl alkaloids from anthranilate and tryptophan: a two enzyme pathway generates heptacyclic scaffold complexity in asperlicin E. AB - Members of the asperlicin family of fungal metabolites produced by Aspergillus alliaceus are known potent CCK(A) antagonists. Herein, we report the identification of the gene cluster responsible for directing their biosynthesis. We validate and probe the pathway by genetic manipulation, and provide the first biochemical characterization of the oxidative cyclization en route to the heptacyclic asperlicin E by reconstituting the activity of the FAD depend monooxygenase AspB. This report provides the first genetic characterization of a NRPS assembly line that efficiently activates two anthranilate building blocks and illustrates the remarkably efficient biosynthesis of the complex heptacyclic asperlicin E. PMID- 23030665 TI - Transrectal specimen extraction after laparoscopic left colectomy: a case-matched study. AB - AIM: Avoiding 'mini-laparotomy' to extract a colectomy specimen may decrease wound complications and further improve recovery after laparoscopic surgery. The aim of this study was to develop a new technique for transrectal specimen extraction (TRSE) and to compare it with conventional laparoscopy (CL) for left sided colectomy. METHOD: Eleven patients with benign disease requiring either sigmoid or left colon resection underwent TRSE. The unfired circular stapler was inserted transanally and used as a guide to suture-close the recto-sigmoid junction laparoscopically and as a handle to pull the sutured sigmoid through the opened rectum inside a laparoscopic camera bag. The anvil was inserted into the lumen of the intussuscepted sigmoid and pushed to the level of the anastomosis. The anastomosis was fashioned end-to-end in the first patients and side-to-end in the following patients to improve safety. Intra-operative and postoperative outcomes of patients undergoing TRSE were compared with those of a group of 20 patients undergoing CL, who were matched for type of resection, body mass index and age. RESULTS: The procedure was successful in all but the first patient who was converted to conventional laparoscopic colectomy without any additional morbidity. Two patients in the end-to-end anastomosis group, but none in the side to-end group, developed peri-anastomotic sepsis. Compared with CL, patients undergoing TRSE did not show any significant differences in operative time, recovery or morbidity. CONCLUSION: Transrectal specimen extraction after left colectomy using the circular stapler technique is feasible. A side-to-end anastomosis appears safer than an end-to-end anastomosis. Further studies are needed to explore the potential advantages of this procedure over CL. PMID- 23030666 TI - Fabrication of a novel and simple microcystin-LR photoelectrochemical sensor with high sensitivity and selectivity. AB - Microcystin-LR (MC-LR), an inert electrochemical species, is difficult to be detected by a simple and direct electrochemical method. In the present work, a novel photoelectrochemical sensor is developed on highly ordered and vertically aligned TiO(2) nanotubes (TiO(2) NTs) with convenient surface modification of molecularly imprinted polymer (MIP) (denoted as MIP@TiO(2) NTs) for highly sensitive and selective determination of MC-LR in solutions. Molecularly imprinted polypyrrole (PPy) of MC-LR is chosen as the recognition element. The designed MIP@TiO(2) NTs photoelectrochemical sensor presents excellent applicability in MC-LR determination, with linear range from 0.5 to 100 MUg L(-1) and limit of detection of 0.1 MUg L(-1). Moreover, the sensor exhibits outstanding selectivity while used in coexisting systems containing 2,4 dichorophenoxyacetic acid, atrazine, paraquat, or monosultap with high concentration, 100 times that of MC-LR. The sensor presents good photoelectric conversion efficiency and detection sensitivity, as well as broad linear detection range, mainly because of the high specific surface area and photoelectric activity of TiO(2) NTs and the pi bond delocalized electron system of PPy that promotes the separation of electron-holes. The prominent selectivity is from the MIP by forming multiple hydrogen bonds between PPy and MC-LR. Mechanisms for photoelectrochemical analysis and selective recognition are also discussed. PMID- 23030667 TI - Electrical property heterogeneity at transparent conductive oxide/organic semiconductor interfaces: mapping contact ohmicity using conducting-tip atomic force microscopy. AB - We demonstrate mapping of electrical properties of heterojunctions of a molecular semiconductor (copper phthalocyanine, CuPc) and a transparent conducting oxide (indium-tin oxide, ITO), on 20-500 nm length scales, using a conductive-probe atomic force microscopy technique, scanning current spectroscopy (SCS). SCS maps are generated for CuPc/ITO heterojunctions as a function of ITO activation procedures and modification with variable chain length alkyl-phosphonic acids (PAs). We correlate differences in small length scale electrical properties with the performance of organic photovoltaic cells (OPVs) based on CuPc/C(60) heterojunctions, built on these same ITO substrates. SCS maps the "ohmicity" of ITO/CuPc heterojunctions, creating arrays of spatially resolved current-voltage (J-V) curves. Each J-V curve is fit with modified Mott-Gurney expressions, mapping a fitted exponent (gamma), where deviations from gamma = 2.0 suggest nonohmic behavior. ITO/CuPc/C(60)/BCP/Al OPVs built on nonactivated ITO show mainly nonohmic SCS maps and dark J-V curves with increased series resistance (R(S)), lowered fill-factors (FF), and diminished device performance, especially near the open-circuit voltage. Nearly optimal behavior is seen for OPVs built on oxygen-plasma-treated ITO contacts, which showed SCS maps comparable to heterojunctions of CuPc on clean Au. For ITO electrodes modified with PAs there is a strong correlation between PA chain length and the degree of ohmicity and uniformity of electrical response in ITO/CuPc heterojunctions. ITO electrodes modified with 6-8 carbon alkyl-PAs show uniform and nearly ohmic SCS maps, coupled with acceptable CuPc/C(60)OPV performance. ITO modified with C14 and C18 alkyl-PAs shows dramatic decreases in FF, increases in R(S), and greatly enhanced recombination losses. PMID- 23030668 TI - IL-17/IFN-gamma interactions regulate intestinal inflammation in TNBS-induced acute colitis. AB - Colonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced acute colitis in mice and elicited a Th1 immune response. Th17 cells are believed to play a major role in TNBS-induced colitis. The aim of this study is to investigate the roles of interleukin (IL)-17 and interferon (IFN)-gamma in the pathogenesis of TNBS-induced acute colitis. We assessed the inflammation scores of TNBS-induced acute colitis in wild-type (WT), IL-17 knockout (KO), and IFN gamma KO mice and measured the levels of inflammatory cytokines using real-time PCR and ELISAs. Histology data showed that IL-17 KO mice with TNBS-induced colitis had significantly lower neutrophil infiltration and inflammatory macroscopic scores compared to the IFN-gamma KO mice and WT mice. Intraperitoneal injection of anti-IL-17 monoclonal antibody confirmed a specific role for IL-17 in TNBS-induced acute colitis in the 3 strains of mice. The severity of colitis was higher in IFN-gamma KO mice and lower in IL-17 KO mice compared to WT mice. Our data suggested that IL-17 signaling plays a critical role in the local inflammation of TNBS-induced colitis, while IFN-gamma was not an important mediator of the local inflammation response. IL-17 may represent a target for therapeutic intervention in inflammatory bowel disease patients. PMID- 23030669 TI - Interleukin 28B rs12979860 (CT/TT) genotype is associated with milder hepatic damage in the natural evolution of HCV/HIV coinfection. AB - Hepatitis C virus (HCV)/human immunodefficiency virus (HIV) coinfection is a major health problem, affecting mostly to individuals with exposure to blood products, as hemophiliacs or intravenous drug users, or those exposed to high risk sexual practices. Genotyping of interleukin 28B (IL-28B) rs12979860 polymorphism is a useful tool for guiding therapeutic decisions in this disease. On the contrary, there is not enough information on the pathogenic role of this polymorphism in the natural history of the disease. The objective of this study is to describe the relationships between the CT/TT genotype of this polymorphism with viral loads and also with a number of biomarkers of liver function in coinfected patients naive for treatment for HCV. Seventy-five HCV/HIV coinfected patients were retrospectively recruited in our Hospital from 2010 to 2011. Logistic regression analysis adjusting by [Age], [Sex], [HCV viral genotype], [HCV viral load], [HIV viral load], and [CD4 T cells levels] revealed the IL-28B rs12979860 (CT/TT) genotype as a protective factor against alanine aminotransferase (ALT) levels (>100 IU/L), aspartate aminotransferase (AST) levels (>75 IU/L), and AST-to-platelet ratio index (APRI) score for liver fibrosis (>1.5) [OR, (95% CI), p]: ALT [0.026 (0.001-0.576) 0.021]; AST [0.001 (0.000-0.297) 0.019]; APRI [0.031 (0.002-0.41) 0.008]. Stepwise regression analysis considering the same adjusting variables showed the same results. In consequence, the IL-28B rs12979860 (CT/TT) genotype, which is a marker of poor response to HCV treatment, could be mediating on the contrary a certain protective effect against the hepatic damage caused by this virus in patients coinfected by HIV. PMID- 23030670 TI - Lactobacillus casei and Lactobacillus acidophilus regulate inflammatory pathway and improve antioxidant status in collagen-induced arthritic rats. AB - In view of well-established immunomodulatory properties of Lactobacillus, present investigation was carried out to evaluate antioxidant and anti-inflammatory potential of Lactobacillus casei and Lactobacillus acidophilus, against inflammatory pathway and oxidative stress developed in an experimental model of arthritis. Collagen-induced arthritis (CIA) model was used. Oral administration of L. casei, L. acidophilus, standard antiarthritic drug indomethacin, and vehicle were started after induced arthritis and continued up to day 28. Interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, IL-1beta, IL-17, IL-4, and IL-10 levels were estimated in serum. In parallel, oxidative stress parameters were also measured from synovial effsuate. All rats were graded for arthritis score at the end of each week. L. casei, L. acidophilus, and indomethacin treatment significantly downregulated proinflammatory and upregulated anti inflammatory cytokines at P<0.0001. They have significantly decreased oxidative stress in synovial effsuate (P<0.0001) and also arthritis score (P<0.05). Protection provided by L. casei and L. acidophilus was more pronounced than that of indomethacin. These lines of evidence suggest that L. casei and L. acidophilus exert potent protective effect against CIA. It further establishes effective anti inflammatory and antioxidant properties of Lactobacillus. However, additional clinical investigations are needed to prove the efficacy of Lactobacillus in treatment/management of rheumatoid arthritis. PMID- 23030671 TI - Treatment with ligands for toll-like receptors 2 and 5 induces a mixed T-helper 1 and 2-like response in chicken splenocytes. AB - Toll-like receptors (TLRs) play an important role in the induction of host responses to pathogens. Interactions between TLRs and their ligands result in the production of cytokines that modulate the adaptive immune response through polarizing CD4+ T cells into either T-helper (T(H))1 or T(H)2 phenotypes. In this regard, TLR2 and TLR5 ligands have been shown to induce responses in mammals that are biased toward T(H)1 or T(H)2 phenotypes. However, whether a similar phenomenon occurs in chickens remains to be elucidated. To this end, chicken splenocytes were stimulated with the TLR2 ligand Pam3CSK4 and the TLR5 ligand flagellin, and the relative expression of several cytokines and transcription factors was quantified at 1, 3, 8, and 18 h poststimulation. The results suggest that both TLR ligands induce a mixed T(H)1- and T(H)2-like response, as characterized by the upregulation of both the T(H)1-associated cytokine interferon-gamma and the T(H)1-inducing cytokine interleukin (IL)-12, in addition to the T(H)2-associated cytokine IL-4, and in the case of flagellin, IL-13 as well. Future studies may be aimed at assessing the adjuvant potential of these ligands. PMID- 23030672 TI - Observation of 1D behavior in Si nanowires: toward high-performance TFETs. AB - This article provides experimental evidence of one-dimensional behavior of silicon (Si) nanowires (NWs) at low-temperature through both transfer (I(d)-V(G)) and capacitance-voltage characteristics. For the first time, operation of Si NWs in the quantum capacitance limit (QCL) is experimentally demonstrated and quantitatively analyzed. This is of relevance since working in the QCL may allow, e.g., tunneling field-effect transistors (TFETs) to achieve higher on-state currents (I(on)) and larger on-/off-state current ratios (I(on)/I(off)), thus addressing one of the most severe limitations of TFETs. Comparison of the experimental data with simulations finds excellent agreement using a simple capacitor model. PMID- 23030673 TI - Cardiovascular and autonomic effects of water ingestion during postexercise circulatory occlusion. AB - As with water ingestion, the activation of the muscle metaboreflex leads to heightened muscle sympathetic nerve activity. Thus, we hypothesized that water ingestion might enhance the pressor effect of the muscle metaboreflex activation. We examined the effect of water ingestion (50 vs. 500 mL) on the cardiovascular and autonomic responses to static handgrip followed by postexercise circulatory occlusion (PECO) in 19 healthy participants (29.2 +/- 8.6 years). Beat-to-beat blood pressure, baroreflex sensitivity (BRS), and R-R intervals were recorded in both conditions (pre- and postingestion). Changes in stroke volume and cardiac output were assessed using Modelflow. Cardiac autonomic regulation was investigated by spectral heart rate variability (HRV); baroreflex control of heart rate was assessed by the sequence method. Water ingestion did not increase the pressor effect induced by PECO. Even though 500 mL of water elicited an overall bradycardia, paired by an increase in the high-frequency HRV, there were no differences between conditions for the decrease in BRS or the resetting of the baroreflex to operate at higher blood pressure. Nevertheless, after the ingestion of 500 mL of water, there were no significant correlations between the percent change in cardiac output and that of BRS, from rest to PECO. This contrasts with that seen in the 50 mL condition (r = -0.68, p < 0.05). Contrasting with our hypothesis, 500 mL of water did not increase the pressor effect induced by PECO. Nevertheless, we found that water ingestion may influence the mechanisms by which the muscle metaboreflex elicits an increased cardiac output during PECO. PMID- 23030674 TI - Expression of suppressor of cytokine signalling 3 (SOCS3) in human bladder epithelial cells infected with uropathogenic Escherichia coli. AB - Suppressor of cytokine signalling (SOCS) proteins inhibit pro-inflammatory signalling mediated by Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathways. To evade the immune response some pathogens appear to modify the host SOCS proteins. Uropathogenic Escherichia coli (UPEC) are able to subvert the host response evoked by bladder epithelial cells, but the mechanisms are not fully understood. The objective of this study was to investigate whether UPEC can modify the host SOCS and STAT3 response. Real time RT-PCR studies demonstrated an increased SOCS1 and SOCS3 expression in the isolated human bladder epithelial cell lines (RT-4 and 5637) in response to cytokines. UPEC strain IA2 increased SOCS3, but not SOCS1, mRNA levels with a peak at 6 h after infection. The increase of SOCS3 was confirmed at the protein level by Western blotting. The UPEC strain IA2 caused a time-dependent decrease in the phosphorylation of STAT3. This study demonstrates that UPEC are able to affect SOCS3 and STAT3 signalling in human uroepithelial cells. The finding that UPEC are able to induce mediators involved in suppression of host cytokine signalling may help to elucidate how UPEC may circumvent the host response during urinary tract infection. PMID- 23030675 TI - A national study on craniosynostosis surgical repair. AB - Objective : Our study aimed to use national data to assess the perioperative outcomes of craniosynostosis surgical repair. Design : Data were obtained from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project Kids Inpatient Database from 1997, 2000, 2003, and 2006. Setting : Community hospitals in the United States. Patients : The cohort was identified using the ICD-9-CM procedure codes for craniosynostosis surgical repair (2.01, 2.03, 2.04, 2.06). Main Outcome Measures(s) : We determined patient and hospital characteristics. We clustered patients by age group (<7 months, 7 to 12 months, 1 to 3 years) and assessed mortality, comorbidities, mean length of stay (LOS), and total charge. We performed logistic regression with our dependent variable being longer average hospital stay: LOS > 4.2 days. Results : We found 3426 patients. Average age at the time of surgery was 181 days (SD 84). Average length of stay was 4.2 days. The majority of the patients were boys (66%), white (71%), and insured (93%). Nearly all patients underwent surgery in a teaching hospital (98%) in urban centers (99%). Approximately 10% of patients experienced an acute complication, most commonly hemorrhages or hematomas and airway or respiratory failure. Patients ages 1 to 3 years had the highest rates of comorbidities and a longer LOS. Mortality rate was <1%. Conclusions : Craniosynostosis surgery is safe with low rates of mortality and acute complications. LOS >4.2 appears to be associated more with comorbidities than with complications. Higher rates of comorbidities and LOS >4.2 days for patients age 1 to 3 years warrant addition research to assess potential barriers to care. PMID- 23030676 TI - Causal attributions of cleft lip and palate across cultures. AB - Objective : To describe and compare the causal beliefs associated with cleft lips and/or palates across several different countries. Design : Cross-sectional survey. Setting : Operation Smile surgery screenings in six developing countries. Participants : Two hundred seventy-nine adult patients and parents of children with cleft lips and/or palates in Kenya, Russia, Cambodia, India, Egypt, and Peru. Interventions : In person interviews were conducted with interpreters. Main Outcome Measure : As part of a larger study, a semistructured questionnaire was created to explore cleft perceptions, belief systems that affect these perceptions, and social reactions to individuals with clefts. Results : Causal attributions were grouped by category (environment, self-blame, supernatural, chance, unknown, or other) and type of locus of control (external, internal, or unknown). Results indicate significant difference by country for both causal attribution category (P < .001) and type (P < .001). This difference was maintained in multivariate analyses, which controlled for differences by demographic variables between countries. Conclusions : This study provides evidence that causal attributions for clefts are influenced by culture. As harmful beliefs about cause may continue to impact affected individuals and their families even after a repair, it is insufficient to provide surgical care alone. Care of the entire person must include attempts to change misinformed cultural beliefs through educating the broader community. PMID- 23030677 TI - The US approach to biosimilars: the long-awaited FDA approval pathway. AB - In the US, the Biologics Price Competition and Innovation Act (BPCI Act, 2009) provided the pathway to create an abbreviated licensure procedure for biologic products that are demonstrated to be biosimilar to or interchangeable with a Food and Drug Administration (FDA) licensed biologic product. In February 2012, the FDA issued three guidelines that list the requirements for biosimilar registration. The topics covered include scientific and quality considerations to demonstrate biosimilarity to a reference product and a guidance that clarifies the BPCI Act implementation. The sponsor application for the biosimilar approval must contain biosimilarity information based on data derived from analytical, animal, and clinical studies. Clinical studies should include an assessment of immunogenicity, pharmacokinetics, pharmacodynamics, and address one or more indications licensed for the reference product. To demonstrate biosimilarity the applicant is allowed to use comparative animal or clinical data with a non-US licensed product. According to these guidelines, the FDA will consider different aspects when evaluating biosimilarity, such as product formulation, complexity, and stability which will have a risk-based approach and will depend on the degree of knowledge of the product characteristics, as well as clinical experience with the reference one. The FDA intends to use a risk-based and facts-focused approach for review of applications of biosimilars, although it faces several challenges. Once a biologic medicine has been demonstrated to be biosimilar to the reference product, an abridged development program for the biosimilar medicine can be carried out in a similar way to that established by the European Medicines Agency (EMA). In addition, FDA legislation goes a step further than the EMA, offering the possibility to adopt full interchangeability for biosimilars. PMID- 23030679 TI - GOFAST: an integrated approach for efficient and comprehensive membrane proteome analysis. AB - Membrane proteomics, the large-scale analysis of membrane proteins, is often constrained by the difficulties of achieving fully resolvable separation and resistance to proteolysis, both of which could lead to low recovery and low identification rates of membrane proteins. Here, we introduce a novel integrated approach, GELFrEE Optimized FASP Technology (GOFAST) for large-scale and comprehensive membrane proteins analysis. Using an array of sample preparation techniques including gel-eluted liquid fraction entrapment electrophoresis (GELFrEE), filter-aided sample preparation (FASP), and microwave-assisted on filter enzymatic digestion, we identified 2 090 proteins from the membrane fraction of a leukemia cell line (K562). Of these, 37% are annotated as membrane proteins according to gene ontology analysis, resulting in the largest membrane proteome of leukemia cells reported to date. Our approach combines the advantages of GELFrEE high-loading capacity, gel-free separation, efficient depletion of detergents, and microwave-assisted on-filter digestion, minimizing sample losses and maximizing MS-detectable sequence coverage of individual proteins. In addition, this approach also shows great potential for the identification of alternative splicing products. PMID- 23030678 TI - Factors associated with differences in Canadian perinatal nurses' attitudes toward birth practices. AB - OBJECTIVE: To test whether demographic characteristics predict registered nurses' attitudes toward birth practices. DESIGN: A secondary analysis of a cross sectional survey, the National Maternity Care Attitudes Survey. SETTING: A national survey conducted with health care providers providing maternity care in Canada. PARTICIPANTS: A convenience sample of 545 registered nurses. METHODS: Hierarchical regression analysis was used to examine three hypotheses about nurses' demographic differences in relationship to their attitudes toward birth practices. Attitude scales included acceptability of doulas, effects of routine electronic fetal monitoring, factors decreasing cesarean birth rates, the importance of vaginal birth for women, safety of birth, episiotomy, and epidural analgesia. RESULTS: Tertiary hospital-level of employment was associated with more positive attitudes toward epidural analgesia and less positive attitudes toward the importance of vaginal birth. Nurses working at a tertiary hospital were more likely to select an obstetrician for their own maternity care. Those who worked at a community hospital were more likely to select a family physician. Nurses' selection of an obstetrician was associated with less positive attitudes toward the safety of birth and importance of vaginal birth and more positive attitudes toward electronic fetal monitoring, episiotomy, and epidural analgesia. CONCLUSION: Nurses' attitudes may be influenced by exposure in their workplaces to predominant care providers' birth practices. Research examining the relationships between nurses' workplace exposures, attitudes, and practice behaviors is needed to develop understanding about how nurses contribute to rates of intervention in maternity care. PMID- 23030680 TI - In vitro metabolism of the 5-hydroxytryptamine1B receptor antagonist elzasonan. AB - The metabolism of elzasonan has been examined in vitro using hepatic microsomes from human and recombinant heterologously expressed P450 enzymes (rCYP). Metabolism occurs primarily via oxidative N-demethylation to form M4 and oxidation reactions to form elzasonan N-oxide (M5) and 5-hydroxyelzasonan metabolite (M3). Additionally, elzasonan was shown to be metabolized to the novel cyclized indole metabolite (M6) which undergoes subsequent oxidation to form the iminium ion metabolite (M3a). The rCYP data was normalized relative to the levels of each CYP form in native human liver microsomes to better assess the contribution of each rCYP in the metabolism of elzasonan. Results demonstrated the involvement of CYP3A4 in the pathways leading to M3a, M3, M5 and M6 and CYP2C8 in the formation of M4. Kinetic constants for the formation of M3 were determined and correlation and inhibition studies suggested that CYP3A4 is primarily responsible for the formation of M3 and CYP2C19 plays a very minor role in its formation. Cytochrome b5 has shown to be an essential component in P450 3A4 catalyzed 5-hydroxyelzasonan formation and provides insights on the disconnect between human liver microsomes data and that of rCYP. Furthermore, rCYP3A4 containing b5 are useful models for predicting the rates for liver microsomes P450-dependent drug oxidations and should be utilized routinely. PMID- 23030681 TI - Effects of video modeling on communicative social skills of college students with Asperger syndrome. AB - INTRODUCTION: Empirical support regarding effective interventions for individuals with autism spectrum disorder (ASD) within a postsecondary community is limited. Video modeling, an empirically supported intervention for children and adolescents with ASD, may prove effective in addressing the needs of individuals with ASD in higher education. OBJECTIVE: This study evaluated the effects of video modeling without additional treatment components to improve social communicative skills, specifically, eye contact, facial expression, and conversational turntaking in college students with ASD. METHOD: This study utilized a multiple baseline single-case design across behaviors for two post secondary students with ASD to evaluate the effects of the video modeling intervention. RESULTS: Large effect sizes and statistically significant change across all targeted skills for one participant and eye contact and turntaking for the other participant were obtained. CONCLUSION: The use of video modeling without additional intervention may increase the social skills of post-secondary students with ASD. Implications for future research are discussed. PMID- 23030682 TI - Phosphoproteomic analysis of Rhodopseudomonas palustris reveals the role of pyruvate phosphate dikinase phosphorylation in lipid production. AB - Rhodopseudomonas palustris (R. palustris) is a purple nonsulfur anoxygenic phototrophic bacterium with metabolic versatility and is able to grow under photoheterotrophic and chemoheterotrophic states. It has uses in carbon management, carbon recycling, hydrogen generation, and lipid production; therefore, it has the potential for bioenergy production and biodegradation. This study is the first to identify the phosphoproteome of R. palustris including 100 phosphopeptides from 54 phosphoproteins and 74 phosphopeptides from 42 phosphoproteins in chemoheterotrophic and photoheterotrophic growth conditions, respectively. In the identified phosphoproteome, phosphorylation at the threonine residue, Thr487, of pyruvate phosphate dikinase (PPDK, RPA1051) was found to participate in the regulation of carbon metabolism. Here, we show that PPDK enzyme activity is higher in photoheterotrophic growth, with Thr487 phosphorylation as a possible mediator. Under the same photoheterotrophic conditions, R. palustris with overexpressed wild-type PPDK showed an enhanced accumulation of total lipids than those with mutant PPDK (T487V) form. This study reveals the role of the PPDK in the production of biodiesel material, lipid content, with threonyl-phosphorylation as one of the possible regulatory events during photoheterotrophic growth in R. palustris. PMID- 23030683 TI - A study on genetic test of lactase persistence in relation to milk consumption in regional groups of India. AB - BACKGROUND: Lactase nonpersistence (LNP) is characterized by the decrease in lactase expression in the small intestine. Studies have shown that -13910 C>T and -22018 G>A single-nucleotide polymorphisms (SNPs) located upstream of the lactase gene are associated with an LNP/lactase persistence (LP) trait. OBJECTIVE: The current study evaluated the LP allelic frequency in 227 healthy Indian subjects consisting of North Indians, Maharashtrians, Gujaratis, Parsis, and South Indians, and for the first time assessed its relation with milk consumption pattern in Indian subjects. METHODS: The two SNPs were genotyped using the polymerase chain reaction and restriction fragment length polymorphism methods. The milk consumption pattern for the studied subjects was noted by questionnaire. RESULTS: The two SNPs were present in a strong linkage disequilibrium. LP prevalence varied in these Indian regional groups. The LP frequency was highest for North Indians and lowest for Parsis (p=0.03 CC vs. CT+TT, p=0.008 GG vs. GA+AA). South Indians had a lower LP frequency compared to North Indians (p=0.07 for each SNP). The milk consumption pattern varied in these Indian subgroups, with the Gujaratis exhibiting the highest milk intake and Parsis the lowest (p=0.04). CONCLUSION: Our study indicates that the milk intake in Indians might be influenced by their dietary habits in addition to their ancestral history. An overall correlation, however, between milk consumption and LP genotypes was not observed. PMID- 23030684 TI - Immunohistochemical characterization of molecular subtypes of invasive breast cancer: a study from North India. AB - In recent years breast cancer has been classified on the basis of its molecular characteristics by gene expression profiling. A similar classification using immunohistochemistry has been identified so that it has a wider application. This study was designed to define the precise prevalence of molecular subtypes of invasive breast carcinoma using immunohistochemistry in patients from north India and to correlate it with known clinical and histological prognostic factors. Based on ER/PR/Her2/neu expression, 100 cases of invasive breast cancer were categorized into: ER+ and / or PR+ and Her2/neu- (47%), ER+ and/or PR+ and Her2/neu+ (15%), ER- and / or PR- and Her2/neu+ (Her2/neu overexpressing, 21%), ER-, PR- and Her2/neu- (Triple negative, 17%). All cases demonstrated positivity for the luminal Cytokeratins 8/18. In addition, 10% of these tumours showed expression of the basal markers (CK4/14, CK5/6). Among the 17 triple negative cases, eight cases were positive for one of the basal markers and two cases with basal marker expression were Her2/neu overexpressing. The basal markers showed significant correlations only with histological grade and ER negative status. On the basis of hormone receptor, Her-2/neu and cytokeratin expressions, distinct subclasses of breast cancer have been identified which show significant differences in relation to histological grade and ER status. Expression of basal markers is needed to define basal-like breast cancer. PMID- 23030685 TI - Depression and the risk of psoriasis in US women. AB - BACKGROUND: Depression is a common mental health condition that has been associated with psoriasis. In the absence of prospective data, it remains unclear whether depression precedes psoriasis as a risk factor. OBJECTIVES: To examine the association between depression and the risk of new-onset psoriasis. METHODS: A prospective cohort of 86 880 US female nurses, The Nurses' Health Study II, was followed up from 1993 to 2005. Participants reported anti-depressant use and completed the Mental Health Index (MHI), a subscale of the Short-Form 36 in 1993. The MHI assessed for depression and scores was categorized into four strata: 0 52, 53-75, 76-85 and 86-100, with lower scores associated with increasing depressive symptoms. We excluded participants with a history of psoriasis prior to 1993. A self-report of incident physician-diagnosed psoriasis constituted the main outcome measure. For a sensitivity analysis, we had a subset of confirmed psoriasis cases. RESULTS: Depression was associated with an increased risk of incident psoriasis. Compared to women in the non-depressed group (MHI 86-100), women who reported either having high depressive symptomatology (MHI scores < 52) or who were on anti-depressants had a multivariate relative risk (RR) of 1.59 for developing subsequent psoriasis (95% confidence interval [CI], 1.21-2.08). These associations became stronger among confirmed psoriasis cases. CONCLUSIONS: We found that depression was independently associated with an increased risk of psoriasis in this population of US women. PMID- 23030686 TI - Three-dimensional poly(epsilon-caprolactone) bioactive scaffolds with controlled structural and surface properties. AB - The requirement of a multifunctional scaffold for tissue engineering capable to offer at the same time tunable structural properties and bioactive interface is still unpaired. Here we present three-dimensional (3D) biodegradable polymeric (PCL) scaffolds with controlled morphology, macro-, micro-, and nano-mechanical performances endowed with bioactive moieties (RGD peptides) at the surface. Such result was obtained by a combination of rapid prototyping (e.g., 3D fiber deposition) and surface treatment approach (aminolysis followed by peptide coupling). By properly designing process conditions, a control over the mechanical and biological performances of the structure was achieved with a capability to tune the value of compressive modulus (in the range of 60-90 MPa, depending on the specific lay-down pattern). The macromechanical behavior of the proposed scaffolds was not affected by surface treatment preserving bulk properties, while a reduction of hardness from 0.50-0.27 GPa to 0.1-0.03 GPa was obtained. The penetration depth of the chemical treatment was determined by nanoindentation measurements and confocal microscopy. The efficacy of both functionalization and the following bioactivation was monitored by analytically quantifying functional groups and/or peptides at the interface. NIH3T3 fibroblast adhesion studies evidenced that cell attachment was improved, suggesting a correct presentation of the peptide. Accordingly, the present work mainly focuses on the effect of the surface modification on the mechanical and functional performances of the scaffolds, also showing a morphological and analytical approach to study the functionalization/bioactivation treatment, the distribution of immobilized ligands, and the biological features. PMID- 23030687 TI - Phytotoxic effect, uptake, and transformation of biochanin A in selected weed species. AB - Certain isoflavones are plant growth inhibitors, and biochanin A is a major isoflavone in clover species used for weed management. The effect of biochanin A on the monocot weed species Echinochloa crus-galli L. and Lolium perenne L. and dicot species Silene noctiflora L., Geranium molle L., and Amaranthus caudatus L. was evaluated in agar medium bioassays. S. noctiflora and G. molle root growth was progressively inhibited with increasing concentrations of biochanin A, whereas the monocot species were unaffected. With regard to the dicot species, S. noctiflora (EC(50) = 35.80 MUM and EC(25) = 5.20 MUM) was more susceptible than G. molle (EC(50), EC(25) > 400 MUM). S. noctiflora, G. molle, and E. crus-galli root and shoot samples, representing a susceptible, a less susceptible, and a nonsusceptible species, respectively, were analyzed by LC-MS to quantify biochanin A and its transformation products. Biochanin A and its known transformation products genistein, dihydrobiochanin A, pratensein, and p coumaric acid were quantified. Sissotrin was identified and quantified while assigning unknown peaks. The treated root samples contained more biochanin A, genistein, pratensein, and dihydrobiochanin A than shoot samples. PMID- 23030688 TI - Ectocranial suture fusion in primates: as related to cranial volume and dental eruption. AB - BACKGROUND: Timing of calvarial suture fusion is important in primate ontogeny. Ages at death are difficult to assess especially for museum collections. METHODS: 1550 skulls of Hominoid, Hylobatidae, Macaca and Papio were observed for fusion. Calvarial expansion (early) and dental eruption (late) were utilized as indicators of ontogeny. Homogeneity of slopes and ANOVA were used to determine differences in timing of fusion. RESULTS: For calvarial growth the great apes all showed small levels of calvarial suture remodeling prior to full calvarial expansion. For dental eruption, Homo and Macaca share a common pattern of fusion in late adulthood. The other species show early remodeling. Papio was observed to have distinct patterns for suture fusion progression. CONCLUSIONS: Thus, suture fusion progression although influenced by evolutionary changes in the robusticity of the craniofacial skeleton can be modeled by the phylogeny among this group. Overall, Homo appears to have a distinct pattern of delayed suture fusion progression. PMID- 23030689 TI - Irbesartan promotes erection recovery after nerve-sparing radical retropubic prostatectomy: a retrospective long-term analysis. AB - Study Type--Therapy (retrospective cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Erectile dysfunction following radical prostatectomy (RP) is among the most common and dreaded adverse effects of the surgery. Multiple studies confirm the potential benefit of various drug classes to accelerate the return of erectile function (EF) after RP. There is pre clinical evidence supporting the use of angiotensin-receptor blockers (ARBs) for this purpose, although this has not been studied in humans. The present study shows that there may be a benefit in the recovery of EF post-RRP in patients taking a daily dose of irbesartan, an ARB, following RRP. In addition, the use of irbesartan may curb the loss of stretched penile length which occurs postoperatively. Further study in the form of prospective, randomized, placebo controlled clinical trials are necessary to confirm these findings. OBJECTIVE: * To evaluate retrospectively the potential benefit of administering irbesartan, an angiotensin-receptor blocker, to improve erectile function (EF) recovery after nerve-sparing radical retropubic prostatectomy (RRP). PATIENTS AND METHODS: * Before surgery potent patients who underwent nerve-sparing RRP between April and December 2009 elected to start daily oral irbesartan 300 mg on postoperative day 1 (n= 17). A contemporaneously clinically matched cohort consisting of patients who declined irbesartan use served as the control group (n= 12). * Postoperative 'on demand' use of erectile aids (phosphodiesterase type 5 [PDE5] inhibitors and intracavernous injections) was adopted. * Potency was monitored by the administration of International Index of Erectile Function-5 (IIEF-5) questionnaires before surgery and at early (3 months) and long-term (12 and 24 months) postoperative intervals. * Stretched penile length (SPL) was measured both immediately and 3 months after surgery. RESULTS: * EF status was no different between groups at baseline (P > 0.05). * While the IIEF-5 scores at 24 months after surgery were statistically similar between the two groups (control = 15.2 +/- 2.0, irbesartan = 14.1 +/- 3.1, P = 0.77), at 12 months the IIEF-5 scores of the irbesartan group were significantly higher than those of the control group (14 +/- 2.6 vs. 7.2 +/- 1.6, P < 0.05). * The proportional loss of SPL after RRP was less in the irbesartan than in the control group at 3 months ( 0.9 +/- 1.5% vs -5.6 +/- 1.5, P < 0.05). CONCLUSION: * Regular irbesartan use after nerve-sparing RRP in patients with normal preoperative erectile function could improve EF recovery after surgery and mitigate early loss of SPL. PMID- 23030690 TI - Synthesis, structures, and solid state self-assemblies of formyl and acetyl substituted triptycenes and their derivatives. AB - Starting from triptycene, 2-, (2,6- or 2,7-)di-, and (2,6,14- or 2,7,14 )triformyl or acetyl substituted triptycenes were selectively synthesized. The derivatization of the formyl or acetyl substituted triptycenes was then investigated. Consequently, it was found that the formyl-substituted triptycenes could be transformed into cyano substituted triptycene derivatives by the aldoxime formation and dehydration. Acetoxyl- and acetamino-substituted triptycenes were synthesized by Baeyer-Villiger oxidation of acetyl-substituted triptycenes and Beckmann rearrangement of acetyl-oxime triptycenes, respectively. Deacetylation of triacetaminotriptycene provided an alternative way to the synthesis of triaminotriptycene. In addition, 2-ethynyltriptycene could be conveniently synthesized by Corey-Fuchs reaction of 2-formyltriptycene, and 1,3,5 tritriptycenebenzene was obtained in high yield by the dehydration cyclotrimerization of 2-acetyltriptycene. The different functionalized triptycene derivatives and their regioisomers were well characterized by the FT-IR, (1)H NMR, (13)C NMR, MS spectra, and single crystal X-ray analyses. Moreover, it was also found that 2,6,14-triacetaminotriptycene with the three amide groups paralleled to their connected aromatic rings could self-assemble into a 2D layer with porous structure, and further 3D microporous architecture by the hydrogen bond network in the solid state. PMID- 23030691 TI - Selective molecular transport through intrinsic defects in a single layer of CVD graphene. AB - We report graphene composite membranes with nominal areas more than 25 mm(2) fabricated by transfer of a single layer of CVD graphene onto a porous polycarbonate substrate. A combination of pressure-driven and diffusive transport measurements provides evidence of size-selective transport of molecules through the membrane, which is attributed to the low-frequency occurrence of intrinsic 1 15 nm diameter pores in the CVD graphene. Our results present the first step toward the realization of practical membranes that use graphene as the selective material. PMID- 23030692 TI - Catalytic, enantioselective N-acylation of lactams and thiolactams using amidine based catalysts. AB - In contrast to alcohols and amines, racemic lactams and thiolactams cannot be resolved directly via enzymatic acylation or classical resolution. Asymmetric N acylation promoted by amidine-based catalysts, particularly Cl-PIQ 2 and BTM 3, provides a convenient method for the kinetic resolution of these valuable compounds and often achieves excellent levels of enantioselectivity in this process. Density functional theory calculations indicate that the reaction occurs via N-acylation of the lactim tautomer and that cation-pi interactions play a key role in the chiral recognition of lactam substrates. PMID- 23030693 TI - Does frequency trajectory influence word identification? A cross-task comparison. AB - In a series of six experiments, the influence of frequency trajectory in visual word recognition was investigated. In Experiment 1, frequency trajectory was found to exert a strong and reliable influence on age of acquisition (AoA) ratings. In word reading (experiment 2), lexical decision (experiments 3 and 6), proper name decision (experiment 4), progressive demasking (experiment 5), and a multiple regression analysis of lexical decision times taken from the French Lexicon Project, the effect of frequency trajectory was not reliable. In contrast, in all the experiments and in the multiple regression analysis, cumulative frequency had a strong and reliable influence on word recognition times. The findings firmly establish that in alphabetic languages such as French, age-limited learning effects do not surface readily in word recognition. In contrast, the total exposure to words across the lifetime is a strong determinant of word recognition speed. The implications of the findings are discussed. PMID- 23030694 TI - Autism characteristics in children with fetal alcohol spectrum disorders. AB - BACKGROUND: Children with fetal alcohol spectrum disorders (FASD) exhibit difficulties in many cognitive and behavioral domains and also have high comorbidity with other disorders such as attention deficit/hyperactivity disorder (ADHD) and conduct disorder as well as autism. Although the FASD profile is shown to be distinct from ADHD and conduct disorder, far less is known about the commonalities with autism. The current study used a parent-rated questionnaire containing an autism subscale to explore the autistic-like features that children with FASD exhibit. METHODS: Studied were 25 children with FASD (age: M = 10.3 years) and 17 normal controls (NCs; age: M = 10.2 years). As part of a larger study, all parents/caregivers completed the Social Skills Improvement System (SSIS; Gresham & Elliot, 2008), which in addition to evaluating social skills and behavior problems globally, includes an Autism subscale. RESULTS: Between-group comparisons showed the FASD group not only scored significantly lower in social skills and significantly higher in behavior problems than the NC group but children with FASD also scored significantly higher on the Autism subscale. Item analysis revealed they showed the most difficulty in terms of social and communicative functioning and the least in repetitive and restrictive behaviors. CONCLUSION: Current findings signify that FASD and autism share similarities with regard to social and communicative functioning. These findings, which further our knowledge of the FASD phenotype, may be useful in specifying the particular interventions these children need. PMID- 23030695 TI - Validation of companion diagnostic for detection of mutations in codons 12 and 13 of the KRAS gene in patients with metastatic colorectal cancer: analysis of the NCIC CTG CO.17 trial. AB - CONTEXT: The therascreen KRAS RGQ polymerase chain reaction kit is being developed as a companion diagnostic to aid clinicians, through detection of KRAS mutations, in the identification of patients with metastatic colorectal cancer (mCRC) who are more likely to benefit from cetuximab. OBJECTIVES: To assess whether KRAS mutation status, determined by using the therascreen KRAS kit, is a predictive marker of cetuximab efficacy. DESIGN: Tissue samples were obtained from patients with mCRC treated on the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) CO.17 phase 3 study of cetuximab plus best supportive care (BSC) versus BSC alone. Tumor DNA samples were assessed for the presence of KRAS mutations by using the therascreen KRAS kit. Efficacy and safety were assessed to determine whether mutation status was predictive of outcomes. Results.-Evaluable samples were available from 453 patients (79.2%) enrolled in the NCIC CTG CO.17 trial. The KRAS wild-type subset represented 54.1% (245 of 453) of the evaluated population. Median overall survival of patients with KRAS wild-type tumors was 8.6 months among those who received cetuximab plus BSC and 5.0 months among patients who received BSC alone (hazard ratio [HR], 0.63; P = .002). Among patients with KRAS mutant mCRC, no meaningful difference in overall survival was observed between arms (HR, 0.91; P = .55). These results are consistent with a previous report that analyzed patient tumor samples by using bidirectional sequencing. CONCLUSIONS: These data support the utility of the therascreen KRAS kit as a means of selecting patients who may benefit from cetuximab therapy. PMID- 23030696 TI - Treatment fidelity instrument to measure a brief opportunistic intervention for prenatal substance use. AB - OBJECTIVE: To develop and psychometrically evaluate an instrument designed to measure the treatment fidelity associated with implementation of the I Am Concerned (IAC) brief opportunistic intervention by frontline, prenatal, primary care staff. DESIGN: A methodologic approach framed development of the IAC Treatment Fidelity Instrument in a six-phase protocol. SETTING: A simulated prenatal clinic with standardized patients portraying substance-using pregnant women. PARTICIPANTS: Prenatal, primary care, frontline staff (N = 6), experienced in IAC implementation. METHODS: Following development of the IAC treatment fidelity instrument, independent raters used the instrument to evaluate audio recordings (N = 49) of frontline staff implementing the IAC brief opportunistic intervention with standardized patients representing substance-using pregnant women. RESULTS: Psychometric analysis provided evidence of content validity. Intraclass correlation coefficients calculated for inter-rater reliability were satisfactory for subscales (0.64) and (0.62) and ranged from -0.07 to 0.81 for individual items. Internal consistency alpha coefficients were satisfactory for the total scale (0.72) and lower than acceptable for adherence (0.54) and competence (0.56) subscales. Overall high rater percentage agreement and negatively skewed ratings distribution indicated reliability results were paradoxically low due to the base rate problem. CONCLUSION: Results support revision and ongoing testing of the IAC treatment fidelity instrument. The impact on reliability statistics exerted by this study's skewed data distribution has implications for nursing research as low variance can be anticipated when measuring care provided to homogenous patient populations. It is important to recognize the resulting influence on inter-rater agreement to avoid making inaccurate interpretations about the reliability of an instrument's measurements. PMID- 23030697 TI - The perspectives of children and young people living with cleft lip and palate: a review of qualitative literature. AB - Objective : To explore the experiences of children and young people with cleft lip and/or palate (CL/P) in relation to being treated for and living with this condition. Design : A systematic review of qualitative research. Electronic databases and hand-searching were employed to identify relevant studies. The review centered on studies examining the views or experiences of young patients first-hand. Any study using a qualitative/mixed method design was eligible for inclusion. Results : From 184 potential references, 38 papers were read in full, from which only two studies of young people met all the review's inclusion criteria. Common reasons for exclusion were not being a qualitative study, not focusing on CL/P, or data coming from parents only. A further two papers provided a retrospective account of childhood with CL/P from interviews with adults. Their suitability for the review's aims was limited, but they were discussed. Conclusions : This review demonstrates that there is a paucity of evidence about the experiences of young people living with CL/P. No studies of children and only two studies of young people met all inclusion criteria. Identified papers implied that more attention is needed within families and services to help young people manage everyday difficulties such as bullying and self-consciousness due to facial difference. PMID- 23030698 TI - Nanowire antenna emission. AB - We experimentally demonstrate the directional emission of polarized light from single semiconductor nanowires. The directionality of this emission has been directly determined with Fourier microphotoluminescence measurements of vertically oriented InP nanowires. Nanowires behave as efficient optical nanoantennas, with emission characteristics that are not only given by the material but also by their geometry and dimensions. By means of finite element simulations, we show that the radiated power can be enhanced for frequencies and diameters at which leaky modes in the structure are present. These leaky modes can be associated to Mie resonances in the cylindrical structure. The radiated power can be also inhibited at other frequencies or when the coupling of the emission to the resonances is not favored. We anticipate the relevance of these results for the development of nanowire photon sources with optimized efficiency and/or controlled emission by the geometry. PMID- 23030699 TI - Synthesis, topoisomerase I inhibitory and cytotoxic activities of chromone derivatives. AB - A series of chromone derivatives were designed as potential topoisomerase I (Top I) inhibitors based on the docking simulation study. Sixteen synthesized compounds were evaluated for Top I inhibitory activity and some compounds were further tested for in vitro cytotoxic activity. The most potent inhibitor, chromone 11b showed greater inhibitory activity (IC50 = 1.46 MUM) than the known Top I inhibitors, i.e., camptothecin, fisetin and morin, but inactive against breast cancer cell (MCF-7), oral cavity cancer cell (KB) and small cell lung cancer (NCI-H187). Chromone 11c, another potent inhibitor (IC50 = 6.16 MUM), exhibited cytotoxic activity against KB (IC50 = 73.32 MUM) and NCI-H187 (IC50 = 36.79 MUM). PMID- 23030700 TI - The correlation of cortactin and fascin-1 expression with clinicopathological parameters in pancreatic and ampulla of Vater adenocarcinoma. AB - Cortactin and fascin-1 are important factors affecting progression and metastasis of carcinomas. We tested the hypothesis that cortactin and fascin expression has significant correlation with clinicopathological parameters in pancreatic and ampulla of Vater adenocarcinomas. Immunohistochemical analysis of cortactin and fascin-1 was performed in 50 pancreatic and 40 ampulla of Vater adenocarcinomas. The specimens were from 29 R0, 8 R1, and 13 palliative resections of pancreatic adenocarcinomas and 18 R0, 14 R1, and 8 palliative resections of ampulla of Vater adenocarcinomas. 'R0' resection is defined by complete removal of the tumor and histologically negative surgical margins and 'R1' resection indicates the presence of microscopically residual disease at the surgical margins. The level of expression was assessed by scoring the intensity of cytoplasmic or membranous immunostaining on a 4-point scale. Higher immunostaining scores of cortactin and fascin-1 were both significantly correlated with histological grade, American Joint Committee on Cancer (AJCC) stage, and survival rate in all patients. In conclusion, overexpression of cortactin and fascin-1 implies poorer tumor differentiation, advanced AJCC stage, and shorter survival rate in pancreatic and ampulla of Vater adenocarcinomas. PMID- 23030702 TI - Mild traumatic brain injury: a description of how children and youths between 16 and 18 years of age perform leisure activities after 1 year. AB - OBJECTIVE: The aim is to describe how children and youths perform leisure activities, 1 year after a mild traumatic brain injury (MTBI). METHODS: Basis is to compile previously collected material; patients were extracted from a prospective randomized controlled trial of MTBI. A retrospective analysis was conducted among 73 children and youths between 16 and 18 years of age. The entire group administrated the Interest Checklist at baseline and at 1-year follow-up. RESULTS: Statistical significant difference was found in 31 of 50 different activities. The result showed that children and youths did not return to perform leisure activities. Fewer returned in the intervention group than in the control group. CONCLUSION: An occupational therapist can help children and youths to have balance in their life and continue a functional life after a MTBI. Continued research is needed, how to prevent MTBI and how to support children and youths to continue with leisure activities. PMID- 23030703 TI - Microenvironment-dependent homeostasis and differentiation of epidermal basal undifferentiated keratinocytes and their clinical applications in skin repair. AB - Skin homeostasis is maintained by controlling the balance between proliferation and differentiation of epidermal stem cells. The microenvironment, including extrinsic stresses, growth factors, soluble molecules, cell-ECM and cell-cell communications, plays an important role in cell fate determination in vivo and in vitro. In response to external signals, keratinocytes cooperate with other cell types to modulate and facilitate the wound microenvironment during wound healing; however, the aberrant signals or conjunctions in the environment will lead to pathologic abnormalities. In addition, despite some drawbacks, the epidermal stem cellbased bioengineered skin substitutes have greatly improved the quality of cutaneous repair. Thus, exploring the characteristics and regulation mechanisms of microenvironment-dependent homeostasis and differentiation of epidermal basal undifferentiated keratinocytes is necessary to understand skin development and wound repair and to design novel therapeutic strategies for skin wound healing. PMID- 23030704 TI - Triacylglycerol profile as a chemical fingerprint of mushroom species: evaluation by principal component and linear discriminant analyses. AB - Mushrooms are becoming relevant foods due to their nutritional, gastronomic, and pharmacological properties, namely, antioxidant, antitumor, and antimicrobial properties. However, although several mushroom species have been chemically characterized, the evaluation of the triacylglycerol (TAG) profile remains nearly unknown. Because TAG was formerly used to assess the authentication of highly valued commercial oils, and the distribution of fatty acids on the glycerol molecule is genetically controlled, the potential of the TAG profile to act as a taxonomical marker was evaluated in 30 wild mushroom species. Principal component analysis and linear discriminant analysis were used to verify the taxonomical rank (order, family, genus, or species) more related with the detected TAG profile. The results pointed out that the ability of the TAG profile to discriminate mushroom samples increased for the lower taxonomical ranks, reaching a maximal performance for species discrimination. Because there is a high resemblance among mushroom species belonging to the same genus and considering that conservation techniques applied to mushrooms often change their physical properties, this might be considered as a valuable outcome with important practical applications. PMID- 23030705 TI - Preparation and characterization of carbon powder paste ultramicroelectrodes as tips for scanning electrochemical microscopy applications. AB - We report a simple method of preparation of carbon paste ultramicroelectrodes (UMEs) for use as probe tips in scanning electrochemical microscopy (SECM). Carbon paste UMEs were prepared by packing the carbon paste into a chemically etched tip of a Pt-UME or a pulled glass capillary. Carbon-based UMEs are attractive in micrometer to nanometer gap experiments and in electrodeposition of single metal nanoparticles for electrocatalytic studies because of their high overpotential in proton and oxygen reduction. We have demonstrated the preparation of conically shaped carbon paste UMEs, appropriate for SECM measurements and micrometer to nanometer gap experiments. PMID- 23030706 TI - Use of precision-cut renal cortical slices in nephrotoxicity studies. AB - 1.Unlike cell lines and primary cells in culture, precision-cut tissue slices remain metabolically differentiated for at least 24-48 h and allow to study the effect of xenobiotics during short-term and long-term incubations. 2.In this article, we illustrate the use of such an experimental model to study the nephrotoxic effects of (i) chloroacetaldehyde, a metabolite of the anticancer drug ifosfamide, (ii) of cobalt chloride, a potential leakage product of the cobalt-containing nanoparticles, and (iii) of valproate, a widely used antiepileptic drug. 3.Since all the latter test compounds, like many toxic compounds, negatively interact with cellular metabolic pathways, we also illustrate our biochemical toxicology approach in which we used not only enzymatic but also carbon 13 NMR measurements and mathematical modelling of metabolic pathways. 4.This original approach, which can be applied to any tissue, allows to predict the nephrotoxic effects of milligram amounts of test compounds very early during the research and development processes of drugs and chemicals. This approach, combined with the use of cells that retain their in vivo metabolic properties and, therefore, are predictive, reduces the risk, the time and cost of such processes. PMID- 23030707 TI - A Holstein cow-calf model for the transfer of ciprofloxacin through milk after a long-term intravenous infusion. AB - This study is part of an ongoing effort to develop animal models that provide milk and sufficient infant (offspring) plasma samples to fully describe a drug's pharmacokinetics to quantitate the risk to the nursing infant. Ciprofloxacin was administered to six healthy Holstein cows as a constant rate intravenous infusion (flow rate was weight adjusted) to achieve a steady-state concentration of approximately 300 ng/mL for 7 days. Plasma and milk samples were collected from the cow at regular intervals over the course of the 7 days. The plasma and milk samples were analyzed for ciprofloxacin by high-performance liquid chromatography. The milk was fed to calves, and calf plasma samples were analyzed to study the lactational transfer of ciprofloxacin from dam to nursing neonate. Remarkably, concentrations of ciprofloxacin in milk were 45 times higher than plasma drug concentrations in the dam. Approximately 6% of the administered dose was transferred to the milk, resulting in an average oral dose of 0.5 mg/kg to the calves with every feeding. The drug did not accumulate in the calves, and plasma concentrations were between one-tenth and one-fifth the plasma concentrations of the dam. PMID- 23030708 TI - Gene variability and degree of expression of vaccine candidate factor H binding protein in clinical isolates of Neisseria meningitidis. AB - The factor H binding protein (fHbp) is currently being evaluated in clinical trials as a vaccine candidate for a meningococcal group B vaccine. We have previously described the prevalence and sequence variation of fHbp (Jacobsson et al., 2009) and here we investigate the expression of the antigen. The present study includes isolates from carriers (n = 62) and patients with invasive Neisseria meningitidis infections (n = 146), of which 62 had a fatal outcome. Among the invasive isolates from patients with fatal and non-fatal infections fHbp allele 1 was most common (42% and 29% respectively), but it was only identified in 3% of the carrier isolates, where allele 16 was most frequent (13%). The Fluorescence-activated cell sorting analysis identified fHbp expression in all except seven isolates and further analysis by Western blot showed that five of these seven samples were indeed negative using a polyclonal anti-fHbp serum. The negative isolates belonged to serogroup B fHbp allele 24, Y allele 104, and W-135 allele 16 (all invasive). Two were non-serogroupable carrier isolates (allele 21 and 101). An interesting finding is that isolates from invasive infections with fatal outcome had lower expression of fHbp or lower affinity for the fHbp antibody compared to isolates from non-fatal invasive infections and carriers. PMID- 23030709 TI - Construction of a 4 zeptoliters switchable 3D DNA box origami. AB - The DNA origami technique is a recently developed self-assembly method that allows construction of 3D objects at the nanoscale for various applications. In the current study we report the production of a 18 * 18 * 24 nm(3) hollow DNA box origami structure with a switchable lid. The structure was efficiently produced and characterized by atomic force microscopy, transmission electron microscopy, and Forster resonance energy transfer spectroscopy. The DNA box has a unique reclosing mechanism, which enables it to repeatedly open and close in response to a unique set of DNA keys. This DNA device can potentially be used for a broad range of applications such as controlling the function of single molecules, controlled drug delivery, and molecular computing. PMID- 23030710 TI - Massive respiratory dysfunction as sign of fulminant peripartum cardiomyopathy (PPCM). AB - OBJECTIVE: Case report of a 35-year-old gravida 3, para 2, at 40 + 6 weeks with massive respiratory dysfunction with need of oxygenation, requiring cesarean section. CASE REPORT: Postpartum investigations revealed pathological cardiomegaly with left ventricular failure (NYHAIV). Cardiac biopsy diagnosed postpartum dilatative cardiomyopathy. Despite medication with bromocriptine and levosimendan, cardiac function continued to decrease, requiring surgical intervention and implantation of an intracorporal, left ventricular assist device. Following surgery, cardiac function progressively improved and stabilized. OBJECTIVE: Peripartum cardiomyopathy (PPCM) is a rare, pregnancy induced disease and requires an interdisciplinary approach for diagnostics and therapeutical treatment. PMID- 23030711 TI - Severe myocardial impairment and chamber dysfunction in preterm preeclampsia. AB - OBJECTIVE: The long-term cardiovascular risk of preeclampsia is known to be significantly higher in women requiring preterm delivery before 37 weeks compared with those delivered at term. The aim of this study is to assess and compare maternal cardiac function and geometry in acute preterm and term preeclampsia. METHODS: This is a prospective case-control study of 27 preterm and 50 term preeclampsia and 104 matched controls assessed by conventional echocardiography and tissue Doppler imaging. RESULTS: Preeclampsia is associated with biventricular diastolic dysfunction, altered geometry, and widespread myocardial impairment. However, only preterm but not term preeclampsia is characterized by biventricular systolic dysfunction (26% vs. 4%; p < 0.05) and severe left ventricular hypertrophy (19% vs. 2%; p < 0.05). CONCLUSIONS: Women with preterm preeclampsia have a more severe cardiac impairment than those with term preeclampsia. This finding may explain the increased long-term cardiovascular risk associated with preterm preeclampsia. The cardiac assessment of women with preterm preeclampsia may be of relevance in identifying women at higher risk of developing cardiovascular morbidity and mortality in later life. PMID- 23030712 TI - TEFDDOLs (alpha,alpha,alpha',alpha'-tetrakis(perfluoroaryl/alkyl)-2,2'-dimethyl 1,3-dioxolane-4,5-dimethanols): highly fluorinated chiral H-bond donors and Bronsted acids with distinct H-bonding patterns and supramolecular architectures. AB - The synthesis of six enantiopure alpha,alpha,alpha',alpha' tetrakis(perfluoroalkyl/aryl)-2,2'-dimethyl-1,3-dioxolane-4,5-dimethanols (TEFDDOLs), by addition of perfluorinated organolithium reagents or Ruppert's reagent (TMS-CF(3)) to isopropylidene tartaric dichloride, is reported. X-ray crystal structures of the TEFDDOLs alone or in complexes with H-bond acceptors such as water and DABCO revealed that this new class of highly fluorinated chiral 1,4-diols forms distinct intra- and intermolecular H-bond patterns. Intramolecular OH-OH bonding accounts for the relatively high acidity of the perfluoroalkyl TEFDDOLs (pK(a) in DMSO: tetrakis-CF(3), 5.7; tetrakis-C(2)F(5), 2.4). For the tetrakis(perfluorophenyl) TEFDDOL, a quite unusual "pseudo-anti" conformation of the diol, with no intramolecular (and no intermolecular) OH-OH bonds, was found both in the crystal and in solution (DOSY and NOESY NMR). The latter conformation results from a total of four intramolecular OH-F(aryl) hydrogen bonds overriding OH-OH bonding. Due to their H-bonding properties, the TEFDDOLs are promising new building blocks for supramolecular and potentially catalytic applications. PMID- 23030713 TI - Syllabic pseudohomophone priming in tip-of-the-tongue states resolution: the role of syllabic position and number of syllables. AB - The tip-of-the-tongue (TOT) state is a common experience, usually coupled with a frustrating feeling caused by the incapability of retrieving a familiar word. It is thought that TOTs occur when the semantic and syntactic information of the word is retrieved but not its phonology. This study aims to further understand the role of phonology in TOT resolution. Specifically, using a syllabic pseudohomophone priming paradigm, we aim to analyse the role of the phonological syllabic position (first vs. last) and the number of syllables in TOT states resolution. TOT was elicited by a picture naming task, after which a lexical decision task was presented. Here, first, last, or none of the phonological syllables of the target word were embedded in pseudohomophone primes. Results showed a significant syllabic pseudohomophone priming effect facilitating TOT resolution. The effect was stronger for four-syllable words, especially when the last syllable was used as prime. These results seem to reinforce the importance of phonology in TOT states resolution, particularly the role of the syllable as an important sublexical unit in speech processing. PMID- 23030714 TI - Palladium-catalyzed diastereo- and enantioselective formal [3 + 2]-cycloadditions of substituted vinylcyclopropanes. AB - We describe a palladium-catalyzed diastereo- and enantioselective formal [3 + 2] cycloaddition between substituted vinylcyclopropanes and electron-deficient olefins in the form of azlactone- and Meldrum's acid alkylidenes to give highly substituted cyclopentane products. By modulation of the electronic properties of the vinylcyclopropane and the electron-deficient olefin, high levels of stereoselectivity were obtained. The remote stereoinduction afforded by the catalyst, distal from the chiral pocket generated by the ligand, is proposed to be the result of a new mechanism invoking the Curtin-Hammett principle. PMID- 23030715 TI - Frameshift mutations of a chromatin-remodeling gene SMARCC2 in gastric and colorectal cancers with microsatellite instability. PMID- 23030716 TI - Transurethral resection of prostate and the role of pharmacological treatment with dutasteride in decreasing surgical blood loss. AB - PURPOSE: Transurethral resection of prostate (TURP) still represents the gold standard in the surgical treatment of symptomatic benign prostatic hyperplasia (BPH). The most frequent complication is represented by intra- and perioperative bleeding. Preoperative use of 5-alpha-reductase inhibitors (finasteride or dutasteride) to reduce surgical bleeding is still a topic of debate in literature. Previous studies provided favorable data on blood loss reduction by preoperative administration of finasteride or dutasteride. The aim of this study was to evaluate whether pretreatment with dutasteride for six weeks before surgery can reduce surgical blood loss. METHODS: A total of 142 patients with BPH who were to undergo TURP-were enrolled and randomized into two groups. The dutasteride group comprising of 71 patients, was treated with dutasteride (0.5 mg/day) for 6 weeks before surgery and the control group, comprising of other 71 patients, did not receive dutasteride. Blood loss was evaluated in terms of a reduction in the serum hemoglobin level (DeltaHb and DeltaHCT), and was estimated by measuring the Hb and hematocrit levels before and 24 hours after surgery. RESULTS: None of the patients treated with dutasteride reported any side effects. A significantly lower mean blood loss was observed in the dutasteride group compared to the control group (DeltaHb=-1.29 +/- 0.81 v -1.83 +/- 1.25, respectively, p<0.0027; DeltaHCT=-5.67 +/- 2.58 v -6.50 +/- 2.40, respectively, p<0.0491). CONCLUSIONS: Our results showed that pretreatment with dutasteride for 6 weeks before TURP reduces the surgical bleeding considerably. This treatment schedule can be used routinely to decrease TURP surgical bleeding. PMID- 23030717 TI - Neuropeptides and epitheliopeptides: structural and functional diversity in an ancestral metazoan Hydra. AB - Peptides are known to play important developmental and physiological roles in signaling. The rich diversity of peptides, with functions as diverse as intercellular communication, neurotransmission and signaling that spatially and temporally controls axis formation and cell differentiation, hints at the wealth of information passed between interacting cells. Little is known about peptides that control developmental processes such as cell differentiation and pattern formation in metazoans. The cnidarian Hydra is one of the most basic metazoans and is a key model system for study of the peptides involved in these processes. We developed a novel peptidomic approach for the isolation and identification of functional peptide signaling molecules from Hydra (the Hydra Peptide Project). Over the course of this project, a wide variety of novel neuropeptides were identified. Most of these peptides act directly on muscle cells and their functions include induction of contraction and relaxation. Some peptides are involved in cell differentiation and morphogenesis. Moreover, epitheliopeptides that are produced by epithelial cells were originally identified in Hydra. Some of these epitheliopeptides exhibit morphogen-like activities, whereas others are involved in regulating neuron differentiation, possibly through neuron-epithelial cell interactions. We also describe below our high-throughput reverse-phase nano flow LCMALDI- TOF-MS/MS approach, which has proved a powerful tool for the discovery of novel peptide signaling molecules in Hydra. PMID- 23030718 TI - Soluble diamagnetic model for malaria pigment: coordination chemistry of gallium(III)protoporphyrin-IX. AB - The facile axial ligand exchange properties of gallium(III) protoporphyrin IX in methanol solution were utilized to explore self-association interactions by NMR techniques. Structural changes were observed, as well as competitive behavior with the ligands acetate and fluoride, which differed from that seen with the synthetic analogue gallium(III) octaethylporphyrin which lacks acid groups in its side-chains and has less solution heterogeneity as indicated by absorption and MCD spectroscopies. The propionic acid side chains of protoporphyrin IX are implicated in all such interactions of PPIX, and both dynamic metal-propionic interactions and the formation of propionate-bridged dimers are observed. Fluoride coordination provides an unusual example of slow ligand exchange, and this allows for the identification of a fluoride bridged dimer in solution. An improved synthesis of the chloride and hydroxide complexes of gallium(III) protoporphyrin IX is reported. An insoluble gallium analogue of hematin anhydride is described. In general, the interactions between solvent and the metal are found to confer very high solubility, making [Ga(PPIX)](+) a useful model for ferric heme species. PMID- 23030719 TI - Sugar-binding proteins from fish: selection of high affinity "lambodies" that recognize biomedically relevant glycans. AB - Glycan-binding proteins are important for a wide variety of basic research and clinical applications, but proteins with high affinity and selectivity for carbohydrates are difficult to obtain. Here we describe a facile and cost effective strategy to generate monoclonal lamprey antibodies, called lambodies, that target glycan determinants. We screened a library of yeast surface-displayed (YSD) lamprey variable lymphocyte receptors (VLR) for clones that can selectively bind various biomedically important glycotopes. These glycoconjugates included tumor-associated carbohydrate antigens (Tn and TFalpha), Lewis antigens (LeA and LeX), N-glycolylneuraminic acid, targets of broadly neutralizing HIV antibodies (poly-Man9 and the HIV gp120), and the glycoproteins asialo-ovine submaxillary mucin (aOSM) and asialo-human glycophorin A (aGPA). We isolated clones that bind each of these targets in a glycan-dependent manner and with very strong binding constants, for example, 6.2 nM for Man9 and 44.7 nM for gp120, determined by surface plasmon resonance (SPR). One particular lambody, VLRB.aGPA.23, was shown by glycan array analysis to be selective for the blood group H type 3 trisaccharide (BG-H3, Fucalpha1-2Galbeta1-3GalNAcalpha), aGPA, and TFalpha (Galbeta1-3GalNAcalpha), with affinity constants of 0.2, 1, and 8 nM, respectively. In human tissue microarrays this lambody selectively detected cancer-associated carbohydrate antigens in 14 different types of cancers. It stained 27% of non-small cell lung cancer (NSCLC) samples in a pattern that correlated with poor patient survival. Lambodies with exquisite affinity and selectivity for glycans may find myriad uses in glycobiology and biomedical research. PMID- 23030721 TI - Probing quantum confinement within single core-multishell nanowires. AB - Theoretically core-multishell nanowires under a cross-section of hexagonal geometry should exhibit peculiar confinement effects. Using a hard X-ray nanobeam, here we show experimental evidence for carrier localization phenomena at the hexagon corners by combining synchrotron excited optical luminescence with simultaneous X-ray fluorescence spectroscopy. Applied to single coaxial n GaN/InGaN multiquantum-well/p-GaN nanowires, our experiment narrows the gap between optical microscopy and high-resolution X-ray imaging and calls for further studies on the underlying mechanisms of optoelectronic nanodevices. PMID- 23030720 TI - 10-Hydroxy-2-decenoic acid prevents ultraviolet A-induced damage and matrix metalloproteinases expression in human dermal fibroblasts. AB - BACKGROUND: 10-Hydroxy-2-decenoic acid (10-HDA) is a major fatty acid component of royal jelly, which has been reported to have a variety of beneficial pharmacological characteristics. However, the effects of 10-HDA on skin photoageing and its potential mechanism of action are unclear. OBJECTIVE: We investigated the protective effects of 10-HDA on ultraviolet (UV) A-induced damage in human dermal fibroblasts (HDFs). We then explored the inhibitory effects of 10-HDA on UVA-induced matrix metalloproteinases (MMPs) expression and elucidated the signalling pathways controlling MMPs inhibition. METHODS: Primary human dermal fibroblasts were exposed to UVA. Cell proliferation, cellular senescent state and collagen content were analysed using CCK-8, senescence associated beta-galactosidase staining and Sircol collagen assay, respectively. Fluorometric assays were performed to detect the formation of reactive oxygen species (ROS) in the cells. The mRNA levels of MMP-1, MMP-3 and type I (alpha1) collagen were determined by quantitative real-time PCR. Western blot was applied to detect the expression of MMP-1, MMP-3, JNK and p38 MAPK. RESULTS: HDFs treated with 10-HDA were significantly protected from UVA-induced cytotoxicity, ROS, cellular senescence and stimulated collagen production. Moreover, 10-HDA suppressed the UVA-induced expression of MMP-1 and MMP-3 at both the transcriptional and protein levels. Treatment with 10-HDA also reduced the UVA induced activation of the JNK and p38 MAPK pathways. CONCLUSION: The data obtained in this study provide evidence that 10-HDA could prevent UVA-induced damage and inhibit MMP-1 and MMP-3 expressions. Therefore, 10-HDA may be a potential agent for the prevention and treatment of skin photoageing. PMID- 23030722 TI - More challenges since Wikipedia: the effects of exposure to internet information about the Rorschach on selected comprehensive system variables. AB - To determine the effects of reading the Wikipedia article on the Rorschach on Comprehensive System variables, participants in this study (recruited from parent teacher associations, online message boards, and graduate schools; N = 50) were provided with either a copy of the Wikipedia article on the Rorschach (from April 2010) or an irrelevant article, then administered the Rorschach and instructed to "fake good." Monetary incentives were used to increase motivation to dissimulate. Initial results indicated that participants given the Wikipedia article produced a lower number of responses (R) and had higher scores on Populars, X+%, XA%, and WDA% as compared to controls. However, post-hoc analyses revealed that when the influence of Populars was controlled, significant differences for X+%, XA%, and WDA% disappeared. No significant differences were found for Form%, Zf, Blends, or PER, although post-hoc analyses controlling for differences in R revealed a significant difference between groups on Zf%. Limitations of the study and implications for clinical and forensic practice are discussed. PMID- 23030723 TI - Low sorption and fast dissipation of the herbicide saflufenacil in surface soils and subsoils of an eroded prairie landscape. AB - Saflufenacil partitioning and dissipation were evaluated in soils from an eroded prairie landscape to provide information on its expected environmental fate. Saflufenacil K(d) values followed trends in soil organic carbon content. In surface soils, K(d) values ranged from 0.05 to 0.2 L kg(-1) in the depositional lower slope and from 0.02 to 0.06 L kg(-1) in the eroded upper slope. In subsurface soils, K(d) values were an order of magnitude higher in the lower slope (mean 0.1 L kg(-1)) than in the upper slope (mean 0.01 L kg(-1)). Sorption was slightly higher in samples aged 1-8 weeks compared to freshly spiked soils. Mean dissipation half-lives (DT(50)) were 13 d in surface soils and 32 d in subsurface soils. The observed low sorption and relatively rapid dissipation of saflufenacil suggest that this herbicide will be readily available for degradation or plant uptake in the root zone. PMID- 23030724 TI - Expression of the carcinoma markers: the sialylated Lewis A and X carbohydrate antigens in normal laryngeal surface epithelium and submucosal glands from old humans. AB - Aberrant surface expression of the carbohydrate ABH and Lewis antigens are often used as markers for the diagnosis of cancer, but while the distribution of these histo-blood group antigens is relatively well-described in tissues and organs from young and middle-aged humans little is known of their expression in old age. The objective for this study was to estimate if the Lewis A and X antigens together with their sialylated modifications, are expressed in sections of normal laryngeal tissue from old humans. Antibodies directed against the tumor markers Sialyl Lewis A and Sialyl Lewis X showed positive reaction in the surface epithelia from normal larynx autopsies obtained from people aged 77-90 years. The sialylated and non-sialylated Lewis A antigens were more frequently expressed in the pseudostratified epithelium than in squamous surface epithelium. Both the sialylated and the non-sialylated carbohydrates were stained in the submucosal glands in all the autopsies. In conclusion, visualization of Lewis tumor markers in the larynx should be interpreted with great care, as they may be present in normal laryngeal epithelial cells from old humans. PMID- 23030725 TI - The reality of the paperless office. PMID- 23030726 TI - Confronting the global NCD epidemic through healthy smiles. PMID- 23030727 TI - Developing a digital dental team. PMID- 23030728 TI - Intraoral digital radiography: elements of effective imaging. AB - Intraoral digital imaging has evolved from an experimental and sometimes disparaged technique in the mid 1980s to a reliable and ubiquitously used technology today. There are many advantages for use of digital radiographic techniques in dentistry, one of the chief ones being patient dose reduction. However, as important as dose reduction is for safe and effective radiography, practicing dentists would also like to understand the fundamental differences between digital system configurations so they may be able to make an informed choice as to which system best fits their needs. In addition, there has been considerable debate on the following topics: sensor technology; factors associated with image display; optimum techniques for image manipulation; and image storage, retrieval, and archiving. This article provides insight into these and other elements of effective imaging in intraoral digital imaging. PMID- 23030729 TI - Using digital technology to enhance restorative dentistry. AB - While there are many benefits for dental practices that incorporate digital systems into their workflow, the dental team must first master the learning curve involved in order to maximize their advantages for creating well-fitting restorations. This article describes the current systems-both digital impression systems and chairside CAD/CAM systems-including software and digital cameras and scanners. The author emphasizes that to consistently capture accurate impressions with this technology, the dental team must continue to rely on traditional skills such as achieving optimal soft-tissue retraction and maintaining moisture control and isolation. PMID- 23030730 TI - Using computer-guided surgery for partial guidance of zygoma implants. AB - Patients with advanced atrophy of the maxilla benefit greatly from the use of dental implants. In the past, protocols recommended highly invasive bone grafting, which required months of maturation before implant placement. Over the past decade, zygoma implants have been used as an alternative procedure. While computer-guided surgery provides a great benefit, its use for complete placement of zygoma implants is not yet predictable. The following protocol provides a way to facilitate the placement of zygoma implants into the best position surgically and prosthetically using partially computer-guided surgery. PMID- 23030731 TI - Digital impressioning on its way to becoming mainstream. PMID- 23030733 TI - Caries detection tools keep making progress. PMID- 23030735 TI - Passion for dentistry front and center in Hong Kong. PMID- 23030734 TI - Cellular and salivary diagnostics: linking oral and systemic health. PMID- 23030737 TI - Highly enantioselective fluorination of unprotected 3-substituted oxindoles: one step synthesis of BMS 204352 (MaxiPost). AB - The catalytic enantioselective fluorination of N-H-free 3-substituted oxindoles was accomplished by a Sc(III)/N,N'-dioxide complex. Under mild reaction conditions, a series of 3-aryl- and 3-alkyl-3-fluoro-2-oxindoles were obtained in excellent yields (up to 98%) and enantioselectivities (up to 99% ee) by using N fluorobisbenzenesulfonimide (NFSI) as the fluorination agent. MaxiPost was synthesized efficiently in 81% yield with 96% ee. PMID- 23030738 TI - Examination and validation of a measure of anxiety specific to children with autism spectrum disorders. AB - OBJECTIVE: Investigated the use of a combined scale (Worry/Depressed and Avoidant scales) from the Autism Spectrum Disorders-Comorbidity for Children (ASD-CC) as a measure of anxiety. Alternative methods of measuring anxiety were examined using the ASD-CC in an ASD population. METHODS: Participants included 147 children, age 2-16 years, evincing a mixture of behavior problems. Comparisons between scores on the ASD-CC and Behavior Assessment System for Children, Second Edition (BASC 2) were examined to determine the most efficacious method of measuring anxiety and to establish convergent and discriminant validity. RESULTS: The worry/depressed subscale was the most effective subscale of the ASD-CC to measure anxiety with proven incremental validity over the combined scale. CONCLUSION: The worry/depressed subscale is the best measure of anxiety utilizing the ASD-CC in children with an ASD. Additionally, convergent and discriminant validity was demonstrated by comparing the scale with similar and dissimilar scales of the BASC-2. PMID- 23030736 TI - Promiscuous 8-alkoxyadenosines in the guide strand of an siRNA: modulation of silencing efficacy and off-pathway protein binding. AB - 8-Alkoxyadenosines have the potential to exist in anti or syn conformations around the glycosidic bond when paired opposite to U or G in the complementary strands, thereby placing the sterically demanding 8-alkoxy groups in the major or minor groove, respectively, of duplex RNA. These modified bases were used as "base switches" in the guide strands of an siRNA to prevent off-pathway protein binding during delivery via placement of the alkoxy group in the minor groove, while maintaining significant RNAi efficacy by orienting the alkoxy group in the major groove. 8-Alkoxyadenosine phosphoramidites were synthesized and incorporated into the guide strand of caspase 2 siRNA at four different positions: two in the seed region, one at the cleavage junction, and another nearer to the 3'-end of the guide strand. Thermal stabilities of the corresponding siRNA duplexes showed that U is preferred over G as the base pairing partner in the complementary strand. When compared to the unmodified positive control siRNAs, singly modified siRNAs knocked down the target mRNA efficiently and with little or no loss of efficacy. Doubly modified siRNAs were found to be less effective and lose their efficacy at low nanomolar concentrations. SiRNAs singly modified at positions 6 and 10 of the guide strand were found to be effective in blocking binding to the RNA-dependent protein kinase PKR, a cytoplasmic dsRNA-binding protein implicated in sequence independent off-target effects. PMID- 23030739 TI - A community-based participatory research approach to understanding pap testing adherence among Vietnamese American immigrants. AB - OBJECTIVE: To explore factors potentially influencing Pap testing practices among Vietnamese American immigrant women (VIW, foreign-born) and describe their awareness of cervical cancer screening resources in their community. DESIGN: Descriptive study guided by the ecological model and community-based participatory research principles. SETTING: Portland, Oregon, metropolitan area. PARTICIPANTS: Vietnamese American immigrant women (211) who were age 21 and older. METHODS: We used descriptive statistics and logistic regression analyses to analyze a self-administered questionnaire that was pretested and translated using a team approach. RESULTS: Approximately 74% of VIW who completed the survey reported at least one Pap test, and 69% reported Pap testing history adherent to national guidelines. The factor most strongly associated with Pap testing receipt was suggestion from a friend, followed by longer residency in the United States, lower perceived common barriers, and lower perceived cultural barriers, for example, lack of family support and use of Eastern/Asian medicine. The factor most strongly associated with guideline adherence was having health insurance, followed by a recommendation from a physician or nurse practitioner. Only 11% of VIW knew where to obtain a free or low-cost Pap tests. CONCLUSION: Nurses can influence rates of Pap testing among VIW by providing health education through outreach programs targeted at lay health workers and their social networks, identifying at-risk patients such as recently immigrated women, reducing perceived common and cultural barriers to Pap testing, and helping women seek alternative payment options if they lack health insurance. Primary health care providers should be reminded of their essential role in increasing Pap testing adherence. PMID- 23030740 TI - Investigation of Acinetobacter baumannii resistance to carbapenems in Marseille hospitals, south of France: a transition from an epidemic to an endemic situation. AB - Carbapenem-resistant Acinetobacter baumannii infections are a worldwide endemic nosocomial threat. Between December 2010 and April 2011, an increase of carbapenem-resistant A. baumannii infections occurred in several Marseille University Hospitals. The aim of this study was to investigate the increase of carbapenem-resistant A. baumannii infections and to characterize the mechanisms of carbapenem resistance. The increase was detected by a homemade computer surveillance program, known as EPIMIC, that monitors antibiotic resistance profiles on a weekly basis. During this period, positive samples of carbapenem resistant A. baumannii were retrieved from patients hospitalized in different units. Genotyping of the isolates was performed using pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST), and carbapenemase gene analyses were performed to detect the presence of carbapenemases and to determine the relationships of the isolates. Carbapenem-resistant A. baumannii were isolated in a total of 11 patients who were hospitalized in different hospitals units. We identified the presence of the bla(OXA23-like) carbapenemase encoding gene in all of the isolates and found four major PFGE groups and different MLST groups. These results demonstrate a current evolution in the A. baumannii epidemiology in Marseille with a switch from an epidemic situation to an endemic situation and with several circulating clones. PMID- 23030741 TI - Identification of the metabolites of lesogaberan using linear trap quadrupole orbitrap mass spectrometry and hydrophilic interaction liquid chromatography. AB - 1. In this study, hydrophilic interaction liquid chromatography (HILIC), radiochemical activity monitoring and linear trap quadrupole orbitrap mass spectrometry (MS) and tandem mass spectrometry (MS/MS) were used to identify the metabolites of a highly polar novel gamma-aminobutyric acid type-B receptor agonist, lesogaberan, in rats. 2. Urine was collected from three male Wistar rats for 24 h after dosing with (14)C-labelled lesogaberan (170 mg/kg, 10 MBq/kg); plasma samples were taken 2 and 24 h after dosing. Pooled samples were separated by HILIC and eluents were analysed by radiochemical activity monitoring, MS and MS/MS. 3. Only the parent compound was detected in plasma, but six metabolites (M1-M6) were detected in urine. Analysis of MS and MS/MS data and comparison with synthetic reference standards enabled the identification of the structure of each metabolite. M1 was identified as the N-acetylated species [(2R)-3-acetamido-2 fluoropropyl]-phosphinic acid, and M6 as [(2R)-3-amino-2-fluoropropyl]-phosphonic acid. Metabolites M2 and M5 were the alcohol and carboxylic acid species 3 hydroxypropyl-phosphinic acid and 3-hydroxyphosphonoyl-propanoic acid, respectively, both of which had lost the fluorine atom present in the parent compound. M3 was the corresponding carboxylic acid species retaining the fluorine atom, (2R)-2-fluoro-3-hydroxyphosphonoyl-propanoic acid. Finally M4 was identified as [(2R)-2-fluoro-3-guanidino-propyl]-phosphinic acid. PMID- 23030742 TI - Inkjet injection of DNA droplets for microchannel array electrophoresis. AB - We demonstrated DNA droplets could be injected with an inkjet injector for microchannel array electrophoresis and attained high throughput analysis of biomolecules. This injection method greatly reduced both analysis time and sample amount, compared with a conventional microchip electrophoresis method, and allowed high parallelization of a microchannel array on a small substrate. Since we do not need to use complicated electric programs or microchannel design, our injection method should facilitate omics analyses and contribute to high performance clinical assays. PMID- 23030743 TI - Attention to the media and worry over becoming infected: the case of the Swine Flu (H1N1) Epidemic of 2009. AB - This paper examines the relationship between attention to the mass media and concern about becoming infected with H1N1 in two nationwide random samples interviewed during the flu epidemic of 2009. The first sample (N = 1004) was taken at the end of the first wave of the outbreak in the US and the second sample (N = 1006) was taken as the second wave was accelerating. The data were gathered by the Pew Research Center for the People & the Press. Over the period studied, the percentage worried about becoming infected increased in almost all social categories of respondents. With social category controlled, both those who followed the H1N1 outbreak closely and those who were more interested in reports about it were more likely to be worried about becoming infected. As time went on, interest in media reports declined, but worry over infection continued to increase. Our findings imply that despite the decrease in the percentage of the population expressing interest and following the news, media exposure was the most important factor as it explained the likelihood of being concerned about the possibility of infection. PMID- 23030744 TI - ACE gene I/D polymorphism and risk of sarcoidosis development in Turkish patients. AB - INTRODUCTION: Etiology of sarcoidosis is unknown but the prevalence of disease in different ethnic groups and identical twins, family characteristics indicate that genetic predisposition is a possible factor. The angiotensin-converting enzyme (ACE) has been implicated in the pahophysiology of sarcoidosis. The aim of this study is to investigate the influence of a polymorphism in I/D (Insertion/Deletion) of the ACE gene on the susceptibility to sarcoidosis. PATIENTS AND METHODS: Our study included 70 Turkish patients who had histopathological diagnosis of sarcoidosis and 69 healthy age and sex matched control subjects. Polymerase chain reaction was used for analysing an I/D polymorphism in the gene coding for ACE. Genotyping was done according to bands that were formed on the agarose gel electrophoresis. Chi-square test was used for statistical analysis and p< 0.05 was accepted as significance. RESULTS: Although the D allele was more frequent in the sarcoidosis patients group, the frequency of the D allele was 67% and 54% respectively in the sarcoidosis and the control group. No significant difference in allele frequencies of I/I, I/D, D/D polymorphisms was observed between the sarcoidosis and control group (p> 0.05). Similarly allele frequencies of I/I, I/D, D/D polymorphisms was not different between sarcoidosis patients with extrapulmonary involvement and sarcoidosis patients without extrapulmonary involvement (p> 0.05). CONCLUSION: Our findings have showed that contribution of ACE gene polymorphisms to susceptibility of disease development in Turkish sarcoidosis patients is not different from the healthy control subjects. PMID- 23030745 TI - [Prognostic factors in non-small cell lung cancer patients and prognostic importance of PET/CT SUV max value]. AB - INTRODUCTION: This study planned to investigate the maximum standard uptake values (SUV max) at fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) whether associated with survival or not and the effect of demographic, clinical and laboratory data on survival in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: This study was created by examining retrospectively the records of 101 patients with NSCLC that received a definitive diagnosis and FDG-PET/CT used for staging in our center between May 2006-March 2011. Especially FDG-PET/CT, SUV max and the other clinical, histopathologic, laboratory and treatment parameters that effects prognosis were recorded and statistical analysis was performed. RESULTS: Eighty eight (87.1%) of the patients were men and 13 (12.9%) were women. The average survival period was 10.6 +/- 8.5 (1-49 months) months. The demographic, clinical, laboratory and radiological parameters were divided into two groups with the median value of SUV max (12.0). There was not a significant difference in survival between the two groups (p= 0.807). The study showed that advanced stage, presence of metastasis, high lactate dehydrogenase (LDH) levels, high white blood cell levels, inoperability, low albumin levels and low performance effect negative on survival. CONCLUSION: It was considered that SUV max does not play an important role in the survival period of NSCLC patients. Knowledge of performance condition, serum LDH, leukocyte and albumin values may provide a better prognostic evaluation. PMID- 23030746 TI - [Inverse relation between atopic status and tuberculin response in adult asthmatics]. AB - INTRODUCTION: We aimed to examine the relation between tuberculosis infection and both atopic and nonatopic asthma. MATERIALS AND METHODS: Eighty six patients with asthma were included. These patients were divided into two groups according to atopic status. Seventy one patients with positive prick tests to at least one aeroallergen together with history of allergy were named as atopic asthma group, and the other 15 patients with negative prick tests, who do not have any history of allergy were named as nonatopic asthma group. Two different control groups similar in terms of age and gender were taken for each group. Tuberculin skin test was done. RESULTS: As a different from most of the previous studies, we included nonatopic asthmatics besides atopic asthma group. PPD value in atopic asthma group was significantly lower (p< 0.001) than the control group. In nonatopic asthmatics, PPD value was also lower than the control group, but it wasn't statistically significant. When we take all patients and controls, negative correlation was seen between mean PPD value and total IgE levels. CONCLUSION: PPD reactivity has been detected as remarkably suppressed in atopic asthma group while mildly suppressed in nonatopic asthmatics. The results may be affected by the fact that mycobacterium infection or BCG vaccination may have suppressive effect on atopic asthma development which comes out in early ages, but they don't have the same effect on nonatopic asthma development which comes out in elder ages. PMID- 23030747 TI - [Prevalence of silicosis among employees in feldspat and quartz mills and associated factors with silicosis]. AB - INTRODUCTION: Problems in legal definition and diagnosis of occupational diseases in Turkey makes the diagnosis of these diseases and informing the parties important. For this purpose, this study was planned to elicit the frequency of silicosis in quartz mill workers in Cine which is one of the largest quartz and feldspat areas, and to detect the working conditions, to inform the workers to improve the working conditions. The aim was to evaluate 592 workers in 10 quartz mill and mines around Cine in 2004. MATERIALS AND METHODS: A structured questionnaire including personal information and work-related questions was applied. Standards chest X-rays taken in the last six months were evaluated according to International Labour Organization (ILO) 1980 standards. Dust concentration and respirable dust concentration in the work place were measured in enterprises. RESULTS: The mean age of the workers was 31.8 +/- 8.26 years and 71.7% was smoker. Duration of working was <= 5 years in 80.5% and >= 10 years in only 4.2%. According to the results of dust measurements, threshold value was found to be exceeded in chopping, packaging and bagging parts of three workplaces. Frequency of silicosis was calculated to be 23.7%. CONCLUSION: Frequency of pneumoconiosis was found to be high like previous studies carried out in similar workplaces in this study. Although it was impossible to put forward the cumulative effect of dust exposure because of frequent altering in workplace, the high frequency of working in similar workplaces among the cases supported the significant risk of silicosis in these enterprises. The workplaces were observed after the workers and persons responsible from occupational health and safety. PMID- 23030748 TI - Systemic inflammation and metabolic syndrome in stable COPD patients. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) has extrapulmonary effects that seems to be related with systemic inflammation. The relationship between metabolic syndrome which is an important determinant of systemic inflammation in general population and COPD is still not clear. The aim of the current study was to investigate the frequency of metabolic syndrome and C reactive protein (CRP) levels, as a marker of systemic inflammation in stable COPD patients with different severity levels and in age and sex matched control group. PATIENTS AND METHODS: Ninety-one stable COPD patients and 42 control subjects were included in the study. The severity level in patients with COPD were determined according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. ATP III (The National Cholesterol Education Program's Adult Treatment Panel III) was used in diagnosis of metabolic syndrome. Hs-CRP levels were measured in venous samples of patients and control subjects. RESULTS: The frequency of metabolic syndrome was found higher in patient group than control subjects, especially in GOLD stages I, II (p= 0.004). Abdominal obesity, hypertension, hyperglycemia components of metabolic syndrome were significantly more prevalent in patient group (p< 0.0001). Increased CRP levels were higher in control and patient groups in all GOLD stages, with metabolic syndrome than without metabolic syndrome (p= 0.047, p= 0.217, p< 0.001, p= 0.05, p= 0.467). CONCLUSION: The study showed that frequency of metabolic syndrome was higher in stable COPD patients than control subjects and general Turkish population. Abdominal obesity, hypertension and hyperglycemia were significantly more prevalent in patient group. Systemic inflammation was more intense in COPD patients with metabolic syndrome than without metabolic syndrome. PMID- 23030749 TI - [Evaluation of carotis intima media thickness in chronic obstructive pulmonary disease patients]. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) and atherosclerosis may occur due to similar risk factors and have a significant cause of morbidity and mortality. In this study to assess the relationship between COPD and atherosclerosis; carotid intima media thickness (CIMT) of COPD patients and adult healthy individuals with normal body mass index and metabolic parameters compared. MATERIALS AND METHODS: 2298 participants aged between 18-92; 46 patients diagnosed with COPD according to clinical features and pulmonary function tests the study, 47 healthy controls who do not have exclusion criteria were evaluated. Doppler ultrasound was performed for the assessment of CIMT to all participants. p values < 0.05 were considered to be significant. RESULTS: Mean CIMT in COPD group and control group were 0.79 +/- 0.16 mm and 0.616 +/- 0.1 mm, respectively (p< 0.001). In multiple linear regression analysis that made to determine the atherosclerotic risk parameters affecting CIMT; it was found that CIMT was related to age with direct proportion (p= 0.002) and to FEV(1)% with inversely proportion (p= 0.04). In multivariate logistic regression analysis that made to determine the parameters affecting atherosclerosis; we found that any parameters were related with atherosclerosis. CONCLUSION: Persistent low-grade systemic inflammation in COPD and atherosclerotic disease may possibly have been reported a factor in both pathologies. Early atherosclerosis and cardiovascular risks in adults with COPD increase independent of risk factors. CIMT which shows direct proportion with age and inverse proportion with FEV(1)% is a non-invasive, easily applicable and cheap method that can be used in determining the risk of atherosclerosis. PMID- 23030750 TI - Primary pulmonary non-Hodgkin's lymphoma: ten cases with a review of the literature. AB - INTRODUCTION: Primary pulmonary non-Hodgkin's lymphoma (PPNHL) of the lung occurs very rarely. To clarify clinical features, treatment alternatives and outcomes, we evaluated our surgically diagnosed PPNHL cases. MATERIALS AND METHODS: A retrospective review of PPNHL cases from January 2004 to December 2009 was performed. Demographic and clinical data are presented as means or medians. Overall survival was estimated using the Kaplan-Meier method. Survival rates were compared using the log-rank test. A p value < 0.05 was considered significant. RESULTS: Patients were eight males and two females with a median age of 50 years (range, 29-76 years). In 40% of the patients, antigenic stimulation, immune suppression or auto-immune disease could not been found. All patients were symptomatic at presentation. Surgical procedures were needed to obtain a diagnosis (nine wedge resections and one pneumonectomy). Eight patients had an extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), and two had diffuse large B-cell lymphomas. The patients were treated with observation (pneumonectomy case), chemotherapy (n= 7), and chemotherapy and radiotherapy (n= 1). Five-year survival was 76%. Difference in survival rates of patients with bilateral vs. unilateral disease were not statistically different. CONCLUSIONS: On contrary of the literature, PPNHL can occur with absence of antigenic stimulation, and patients generally have some symptoms. Chemotherapy or surgery can be used to treat PPNHL. Patient survival is good. PMID- 23030751 TI - Right pulmonary venous atresia: a case report and review of literature. AB - Isolated pulmonary vein atresia without associated congenital malformation is a very rare condition in adults. It is associated with significant mortality and morbidity. Recurrent pulmonary infections, dyspnea on exertion and hemoptysis may be the presenting complaints. Owing to the limited number of patients with this condition there may be some difficulties in it's diagnosis and therapy. We report an adult case with this rare congenital malformation and discuss it's diagnosis and management options. PMID- 23030752 TI - [Spontaneous tension haemopneumothorax]. AB - Spontaneous tension haemopneumothorax is a very rare condition. Forty two-year- old male patient who applied with sudden onset of dyspnea, chest pain was tachypneic, tachycardic, cyanotic and hypotensive. This is the second case of spontaneous tension haemopneumothorax in English literature, according to our knowledge. We present this case because of being a rare condition. PMID- 23030753 TI - Multidrug resistant tuberculosis with multiple organ involvement. AB - Multidrug resistant tuberculosis has been a challenging situation in the clinical practice with respect to appropriate clinical treatment and management of the disease. The likelihood of resistance development is known to be lower in lesions with lesser percentages of the bacterial population. The present paper was designed to present a rare case of pulmonary multidrug resistant tuberculosis with extrapulmonary involvement to emphasize the consideration of genital tuberculosis with possible infertility in patients admitting with a scrotal mass. PMID- 23030754 TI - [A case of pulmonary sequestration presenting as solitary pulmonary nodule]. AB - Pulmonary sequestration is a rare, usually a cystic mass which is composed of nonfunctioning pulmonary tissue that does not communicate with the tracheobronchial tree. In computed tomography pulmonary sequestration is seen as usually a discrete mass lesion, with or without cystic changes, associated with local emphysematous areas located in lower lobes. We present a case of pulmonary sequestration located in apicoposterior segment of left upper lobe and presented as a solitary pulmonary nodule having smooth margins different from the classical radiological appearance of pulmonary sequestration. PMID- 23030755 TI - [False positive 18F-FDG PET/CT findings mimicking malignant disease in patients with pneumoconiosis (due to three case reports)]. AB - Besides the risk of developing pneumoconiosis and chronic obstructive pulmonary disease, potential lung cancer risk may also increase due to exposure to silica and other carcinogens. Patients with hemoptysis symptom referred to our clinic depending on different forms of mass images in their thorax computerize tomography (CT) scan with the suspicion of coal-worker pneumoconiosis and lung cancer were hospitalized for investigation and treatment. The results of routine tests, sputum acid-fast bacilli and sputum cytology were evaluated as normal. PET/CT was ordered from patients for identifying malignancy. In PET/CTs of the patients, a pathological level of 18F fluorodeoxyglucose uptake was identified in different forms of mass images observed previously in thorax CTs. All the pathological specimens obtained by fiberoptic bronchoscopic biopsy and/or by mediastinoscopy were reported as benign. We aimed to present three pneumoconiosis patients with false positive PET/CT findings in the light of relevant literature. As a result, we thought that pneumoconiosis must be in mind also when considering about false positive results of PET/CT. PMID- 23030756 TI - A case with multisystemic involved of Tuberculosis. AB - Cases of tuberculosis with multisystemic involvement are rarely reported and these are often children and patients with AIDS whose and immune system is suppressed. Tuberculosis can mimic and present with various disorders. A 18-year old Georgian male patient was admitted to the hospital with double vision, swelling and wound on the 3rd digit of the right hand. We defined the multisystemic tuberculous disease including orbital bone with soft tissue tuberculosis, tuberculosis spondylitis, tuberculosis dactylitis, scrofuloderma and pulmonary tuberculosis in these patient. PMID- 23030757 TI - [Current approach to respiratory problems in neuromuscular diseases]. AB - Neuromuscular diseases lead to respiratory failure as they cause progressive weakness of the muscle of respiration. Studies show that noninvasive mechanical ventilation improves symptoms, gas exchange, quality of life, and survival in these patients. Noninvasive mechanical ventilation should be use at the onset of nocturnal hypoventilation. Airway clearance therapy is very important in these patients. The combination of noninvasive mechanical ventilation with cough-assist techniques decreases pulmonary morbidity and hospital admissions. Invasive mechanical ventilation is indicated for patients who require continuous mechanical ventilation for longer than a few days, or those who have contraindications to noninvasive mechanical ventilation. Diaphragmatic pacemakers may be a treatment option in patients with high spinal cord injuries. Episodes of acute respiratory failure in neuromuscular diseases are precipitated by respiratory infections. Management of episodes of acute respiratory failure may require endotracheal intubation. PMID- 23030758 TI - The importance of associations in the struggle against tuberculosis in Turkey. AB - Tuberculosis is a disease as old as human history and has affected every area of human life. The struggle against tuberculosis had been started by non governmental organizations and achieved success after second world war. In Anatolia as well as all over the world fight against tuberculosis, with the leading names in medicine, started during the Ottoman Empire. In the following years of struggle within the executive team will host association (Istanbul Anti tuberculosis Association) was founded in 1918. Due to political developments that occurred shortly after standing association studies, in 1923, the Republic of Turkey in Izmir during the re-started. In the 1925 and 1927 a national medical congress, tuberculosis as the main election issue, was organized, and then in 1928 in Istanbul Tuberculosis Association again take action in the fight against decisive role in association studies have begun to undertake. In the years 1953 1973, UNICEF, Ministry of Health and later efforts Turkish National Anti tuberculosis Association jointly significant results were obtained in the fight against tuberculosis. These positive statements given the lethargy environment, economic and political crises in the last 10 years, in parallel with the increase of tuberculosis around the world experiencing, there was an increase in Turkey. In 1986, the National Anti-Tuberculosis Federation was founded by Anti Tuberculosis Associations. The Anti-Tuberculosis Federation has put in practice DOTS programme in 2005 in Turkey. In conclusion, we evaluate that the Anti Tuberculosis Associations in Turkey have played a major role in struggle against tuberculosis in Turkey since the last century. PMID- 23030759 TI - Massive hemoptysis, the etiology is aorto-bronchial fistula. PMID- 23030760 TI - A rare benign tumor mimicking malignancy. PMID- 23030761 TI - Scoring systems of cleft-related facial deformities: a review of literature. AB - Objective : There is a need for an internationally agreed objective method of assessing cleft-related deformities in order to compare the results of individual surgeons and different surgical techniques or to determine the optimal timing for primary lip closure. To assess the current methods, an overview of the recent developments in postoperative scoring systems of cleft-related deformities was made. Methods : A Medline search from June 2003 through July 2011 was conducted, and references in the selected articles were checked. This search yielded 428 articles, and after application of the inclusion and exclusion criteria, 40 articles were included in this review. Results : Twenty-five studies used two dimensional (2D) photographs for the assessment of cleft-related deformities. Fourteen of these studies used a subjective method for the assessment and 11 performed anthropometric measurements. Good reliability has been found for subjective assessments and measurements from 2D photographs. Fifteen studies assessed three-dimensional (3D) imaging. Conclusions : Although there is a wide variety in study design, 3D imaging seems most reliable in assessing cleft related facial deformities. However, scoring on 2D photographs is easier to perform and more applicable in daily practice because all cleft patients are photographed through the course of their treatment. PMID- 23030762 TI - Optimization of a natural product-based class of gamma-secretase modulators. AB - A series of triterpene-based gamma-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compounds with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochemical properties of the analogues. This strategy gave compounds with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compounds, 100 and 120, were tested for a pharmacodynamic effect in the strain and lowered brain Abeta42 levels. PMID- 23030763 TI - Synthesis, structural characterization, and ab initio study of Cu(5+delta)In(2+x)Sb(2-x): a new B8-related structure type. AB - A new ternary orthorhombic compound with the formula Cu(5+delta)In(2+x)Sb(2-x), crystallizing in the space group Cmc2(1) with 36 atoms per unit cell [a = 10.1813(4) A, b = 8.4562(4) A, c = 7.3774(2) A, Z = 4], has been synthesized by conventional high-temperature methods. The structure is based on the B8 archetype (NiAs/Ni(2)In) and features In/Sb ordering as well as ordering of interstitial copper. Details of the experimental study and the structural parameters of this compound are reported in the first part of the work. In the second part, ab initio calculations based on the density functional theory and the projector augmented-wave method are used to characterize the structural, thermodynamic, and phase-stability properties of the new ternary phase. The present calculations include the lattice parameters, molar volume, bulk modulus and its pressure derivative, the energy of formation from the elements, and the electronic density of states. Moreover, the present ab initio method is used to investigate the thermodynamic properties of the anti-structure Cu(5)Sb(2)In(2) compound obtained by exchanging the In and Sb Wyckoff symmetric positions. PMID- 23030764 TI - Evaluation of a new 240-MUm single-use holmium:YAG optical fiber for flexible ureteroscopy. AB - BACKGROUND AND PURPOSE: Numerous holmium:yttrium-aluminum-garnet laser fibers are available for flexible ureteroscopy. Performance and durability of fibers can vary widely among different manufacturers and their product lines with differences within a single product line have been reported. We sought to evaluate a newly developed nontapered, single-use 240-MUm fiber, FlexivaTM 200 (Boston Scientific, Natick, MA), during clinical use and in a bench-testing model. MATERIALS AND METHODS: A total of 100 new fibers were tested after their use in 100 consecutive flexible ureteroscopic lithotripsy procedures by a single surgeon (B.K.). Prospectively recorded clinical parameters were laser pulse energy and frequency settings, total energy delivered and fibers failure. Subsequently, each fiber was bench-tested using an established protocol. Parameters evaluated for were fibers true diameter, flexibility, tip degradation, energy transmission in straight and 180 degrees bend configuration and fibers failure threshold with stress testing. RESULTS: The mean total energy delivered was 2.20 kJ (range 0-18.24 kJ) and most common laser settings used were 0.8 J at 8 Hz, 0.2 J at 50 Hz, and 1.0 J at 10 Hz, respectively. No fiber fractured during clinical procedures. The true fiber diameter was 450 MUm. Fiber tips burnt back an average of 1.664 mm, but were highly variable. With laser setting of 400 mJ at 5 Hz, the mean energy transmitted was 451 and 441 mJ in straight and 180 degrees bend configuration, respectively. Thirteen percent of fibers fractured at the bend radius of 0.5 cm with a positive correlation to the total energy transmitted during clinical use identified. CONCLUSION: Fiber performance was consistent in terms of energy transmission and resistance to fracture when activated in bent configuration. Fiber failure during stress testing showed significant correlation with the total energy delivered during the clinical procedure. The lack of fiber fracture during clinical use may reduce the risk of flexible endoscope damage due to fiber failure. PMID- 23030765 TI - Short-term and long-term sequelae in intrauterine growth retardation (IUGR). AB - Intrauterine Growth Retardation (IUGR) is defined as a rate of growth of a fetus that is less than normal for the growth potential of the fetus (for that particular gestational age). Small for Gestational Age (SGA) is defined infant born following IUGR, with a weight at birth below the 10th percentile.Suboptimal fetal growth occurring in IUGR fetuses is an important cause of perinatal mortality and morbidity. The acute neonatal consequences of IUGR include metabolic and hematological disturbances, and disrupted thermoregulation; in addition, respiratory distress (RDS), necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP) may contribute to perinatal morbidity. Metabolic disturbances are related to glucose and fatty acid metabolism. It is well-known that individuals who display poor growth in utero are at significantly increased risk for type 2 diabetes mellitus (T2DM), obesity, hypertension, dyslipidemia, and insulin resistance (the so-called metabolic syndrome, MS). MS ultimately leads to the premature development of cardiovascular diseases. In addition, short stature in children and adults, premature adrenarche, and the polycystic ovarian syndrome (PCOS) are endocrinological sequelae of IUGR. (8) Early onset growth delay and prematurity significantly increase the risk for neurological sequelae and motor and cognitive delay.Future prospective studies need to investigate risk factors for infants who are SGA. If reliable prediction can be achieved, there is potential to reduce future perinatal morbidity and mortality, and long term consequences among SGA babies. PMID- 23030766 TI - Effective phagocytosis of low Her2 tumor cell lines with engineered, aglycosylated IgG displaying high FcgammaRIIa affinity and selectivity. AB - Glycans anchored to residue N297 of the antibody IgG Fc domain are critical in mediating binding toward FcgammaRs to direct both adaptive and innate immune responses. However, using a full length bacterial IgG display system, we have isolated aglycosylated Fc domains with mutations that confer up to a 160-fold increase in the affinity toward the low affinity FcgammaRIIa-R131 allele as well as high selectivity against binding to the remarkably homologous human inhibitory receptor, FcgammaRIIb. The mutant Fc domain (AglycoT-Fc1004) contained a total of 5 amino acid substitutions that conferred an activating to inhibitory ratio of 25 (A/I ratio; FcyRIIa-R131:FcgammaRIIb). Incorporation of this engineered Fc into trastuzumab, an anti-Her2 antibody, resulted in a 75% increase in tumor cell phagocytosis by macrophages compared to that of the parental glycosylated trastuzumab with both medium and low Her2-expressing cancer cells. A mathematical model has been developed to help explain how receptor affinity and the A/I ratio relate to improved antibody dependent cell-mediated phagocytosis. Our model provides guidelines for the future engineering of Fc domains with enhanced effector function. PMID- 23030767 TI - Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison study. AB - BACKGROUND: Apremilast, a small molecule specific inhibitor of phosphodiesterase 4, works intracellularly to modulate pro-inflammatory and anti-inflammatory mediator production. OBJECTIVE: Assess apremilast efficacy and safety in moderate to severe plaque psoriasis. METHODS: Phase II, 12-week, multicenter, double blind, placebo-controlled, parallel-group, dose-comparison study of 259 subjects randomized 1 : 1 : 1 to placebo, apremilast 20 mg QD or apremilast 20 mg BID. RESULTS: More subjects receiving apremilast 20 mg BID achieved >= 75% reduction in Psoriasis Area and Severity Index (PASI-75) vs. placebo (24.4% vs. 10.3%; P = 0.023). A similar proportion of subjects receiving apremilast 20 mg QD and placebo achieved PASI-75 at week 12 [9/87 (10.3%, each group)]. Mean per cent reduction in PASI from baseline was 17.4% for placebo, 30.3% for apremilast 20 mg QD (P = 0.021 vs. placebo) and 52.1% for apremilast 20 mg BID (P < 0.001). Apremilast 20 mg BID significantly decreased mean body surface area involvement vs. placebo (30.8% vs. 3.2%; P < 0.001). The most common adverse events were headache, nasopharyngitis, diarrhoea and nausea. Most events (> 90%) were mild to moderate and did not lead to study discontinuation. Serious adverse events occurred in four placebo subjects (panic attack, hospitalization for rehabilitation, hospitalization for alcoholism, worsening psoriasis), one receiving apremilast 20 mg QD (knee surgery) and in one receiving apremilast 20 mg BID (worsening psoriasis). The panic attack was considered treatment-related; both cases of worsening psoriasis occurred after medication discontinuation. No deaths or opportunistic infections were reported. CONCLUSION: Apremilast 20 mg BID for 12 weeks was effective and well tolerated in subjects with moderate to severe plaque psoriasis. PMID- 23030768 TI - Defect-free <110> zinc-blende structured InAs nanowires catalyzed by palladium. AB - We report the epitaxial growth of defect-free zinc-blende structured InAs nanowires on GaAs{111}(B) substrates using palladium catalysts in a metal-organic chemical vapor deposition reactor. Through detailed morphological, structural, and chemical characterizations using electron microscopy, it is found that these defect-free InAs nanowires grew along the <1[combining overline]1[combining overline]0> directions with four low-energy {111} faceted side walls and {1[combining overline]1[combining overline]3[combining overline]} nanowire/catalyst interfaces. It is anticipated that these defect-free <1[combining overline]1[combining overline]0> nanowires benefit from the fact that the nanowire/catalyst interfaces does not contain the {111} planes, and the nanowire growth direction is not along the <111> directions. This study provides an effective approach to control the crystal structure and quality of epitaxial III-V nanowires. PMID- 23030769 TI - Examining faking on personality inventories using unfolding item response theory models. AB - A concern about personality inventories in diagnostic and decision-making contexts is that individuals will fake. Although there is extensive research on faking, little research has focused on how perceptions of personality items change when individuals are faking or responding honestly. This research demonstrates how the delta parameter from the generalized graded unfolding item response theory model can be used to examine how individuals' perceptions about personality items might change when responding honestly or when faking. The results indicate that perceptions changed from honest to faking conditions for several neuroticism items. The direction of the change varied, indicating that faking can operate to increase or decrease scores within a personality factor. PMID- 23030770 TI - Toxicity and metabolism of exogenous alpha,beta-unsaturated carbonyls in potato (Solanum tuberosum L.) tubers. AB - A group of aliphatic alpha,beta-unsaturated carbonyl compounds was evaluated for their utility as inhibitors of sprout growth in stored potato tubers (Solanum tuberosum L.). Nondormant tubers were treated with vapors of six 8-10-carbon compounds of this chemistry. Subsequent sprout growth at 16 degrees C (95% relative humidity) over ca. 3 months in storage was suppressed by all compounds in a concentration-dependent manner. The volatile metabolites produced by sprout and associated tuber tissues following treatment with 3-octen-2-one, 3-nonen-2 one, and 3-decen-2-one were the corresponding alkyl ketones and alkyl secondary alcohols. In contrast, (E)-2-octenal, (E)-2-nonenal, and (E)-2-decenal were metabolized by two pathways: (1) parent compound to the corresponding alkyl aldehyde and then to the alkyl primary alcohol and (2) parent compound to the alkenyl primary alcohol. Residues of 3-nonen-2-one and (E)-2-nonenal and their metabolites were analyzed in whole tubers over a 28 day post-treatment period. The concentrations of the parent ketone and aldehyde declined rapidly following application, and the most persistent metabolites were 2-nonanol and (E)-2-nonen-1 ol, respectively. The sequence of reactions leading from the alpha,beta unsaturated carbonyls to the alcohols was determined by application of each of the 9-carbon compounds individually to tubers. In long-term efficacy studies, a single application of (E)-2-nonenal and 3-nonen-2-one to nondormant tubers terminated sprout growth and prevented regrowth for 2-3 months. A second application suppressed sprouting for at least 4-5 additional months. This efficacy, combined with rapid metabolism and low residue levels, makes the 8-10 carbon alpha,beta-unsaturated ketones and aldehydes worth consideration for use as sprout inhibitors. PMID- 23030771 TI - Further observations on conformational and substituent effects in acid-catalyzed "3 + 1" cyclizations of tripyrranes with aromatic dialdehydes. AB - Tripyrranes with tert-butyl and phenyl substituents have been prepared and used to synthesize oxybenziporphyrins, oxypyriporphyrins, benzocarbaporphyrins, and azuliporphyrins with phenyl and tert-butyl substituents via a "3 + 1" methodology. The proton NMR spectra for the tripyrrane dibenzyl esters indicate that these tripyrrolic systems take on a helical conformation that favors macrocycle formation, and the NMR data can be a useful predictor on the efficiency of the "3 + 1" synthesis. Nevertheless, a tetraphenyltripyrrane proved to be susceptible to acidolytic cleavage under the usual reaction conditions and gave poor yields of porphyrinoid products. This problem could be overcome to a certain extent by carrying out the reactions in neat TFA. The presence of these substituents led to significant changes in the spectroscopic properties and diatropic character of the new porphyrinoid structures. PMID- 23030772 TI - Secrecy as embodied practice: beyond the confessional imperative. AB - This introduction to this special issue of Culture, Health & Sexuality aims to intervene critically in debates in public health about sexual rights and ways of de-stigmatising HIV/AIDS, in which silence and secrets are seen to undermine well being and perpetuate stigma. It presents key insights from collaborative studies on HIV/AIDS and youth sexual health, arguing that advocates of disclosure and sexual rights need to think more contextually and tactically in promoting truth telling. The authors aim to enhance current thinking on secrecy, which examines it primarily as a social practice, by emphasising the centrality of the body and the experience of embodiment in the making and unmaking of secrets. To understand secrecy as embodied practice requires understanding how it simultaneously involves the body as subject - as the basis from which we experience the world - and the body as object - that can be actively manipulated, silenced and 'done'. The authors show how tensions emerge when bodies reveal reproductive mishaps and describe how the dissonances are resolved through a variety of silencing practices. The paper ends by discussing the implications of these insights for sexual-health programmes. PMID- 23030773 TI - Injuries due to firearms and air guns among U.S. military members not participating in overseas combat operations, 2002-2011. AB - During 2002-2011, active component U.S. service members sustained 4,657 firearm related injuries in circumstances other than deployment to the wars in Iraq/Afghanistan; 35 percent of the injuries were fatal. The highest firearm related injury rates reflected service members in law enforcement/security and combat occupations. Of fatal injuries, 28 percent and 24 percent were suicides and homicides, respectively; among service members 30 and older, 84 percent of noncombat firearm-related deaths were suicides and 14 percent were homicides. In circumstances other than war, rates of both fatal and nonfatal firearm- related injuries are much lower among military members than civilian males aged 18-44. During the period, rates of nonfatal firearm-related injuries among non-deployed military members increased sharply, peaking in 2008. The trend reflects that among U.S. civilian males aged 18-44. However, firearm-related fatality rates were stable among civilians but increased among military members. The increase in rates of firearm-related fatalities among non-deployed military members reflects the increase in rates of suicides by firearms. Rates of injuries due to BB, pellet or paintball guns also increased during the period. PMID- 23030774 TI - Health care encounters for injuries associated with a gun mechanism or component, U.S. Armed Forces. PMID- 23030775 TI - Images in health surveillance: West Nile virus vectors and prevention. PMID- 23030776 TI - Coccidioidomycosis, active component, U.S. Armed Forces, January 2000-June 2012. PMID- 23030777 TI - Update: pneumonia-influenza and severe acute respiratory illnesses, active component, U.S. Armed Forces, July 2000-June 2012. AB - Pneumonias are among the leading causes of hospitalizations of U.S. service members. During July 2000-June 2012, there were 13,291 incident hospitalizations for pneumonia and influenza. The most cases during any "respiratory illness year" (July-June) were in 2002-2003 (n=1,359); the fewest cases were in 2010-2011 (n=937). During 28 of the 31 months from December 2009 through June 2012, there were fewer pneumonia and influenza-related hospitalizations than expected (relative to the means for the respective months overall). The relatively few hospitalizations for pneumonia-influenza in recent years reflect, at least in part, the effectiveness of influenza vaccines against the predominant circulating strains of influenza viruses. During the period, on average, there were approximately three hospitalizations for "severe acute respiratory illnesses" (SARI) (e.g., acute respiratory failure or distress) per month; however, numbers of SARI-related hospitalizations generally increased during the period. The cause(s) of this increase are not clear. PMID- 23030778 TI - Pneumonia and influenza among military members and other beneficiaries of the U.S. military health system, 2007-2012. PMID- 23030779 TI - Lightning-related medical encounters, active and reserve components, U.S. Armed Forces, January 2009-August 2012. PMID- 23030780 TI - Ultrasensitive liquid chromatography-tandem mass spectrometric methodologies for quantification of five HIV-1 integrase inhibitors in plasma for a microdose clinical trial. AB - HIV-1 integrase strand transfer inhibitors are an important class of compounds targeted for the treatment of HIV-1 infection. Microdosing has emerged as an attractive tool to assist in drug candidate screening for clinical development, but necessitates extremely sensitive bioanalytical assays, typically in the pg/mL concentration range. Currently, accelerator mass spectrometry is the predominant tool for microdosing support, which requires a specialized facility and synthesis of radiolabeled compounds. There have been few studies attempted to comprehensively assess a liquid chromatography-tandem mass spectrometry (LC MS/MS) approach in the context of microdosing applications. Herein, we describe the development of automated LC-MS/MS methods to quantify five integrase inhibitors in plasma with the limits of quantification at 1 pg/mL for raltegravir and 2 pg/mL for four proprietary compounds. The assays involved double extractions followed by UPLC coupled with negative ion electrospray MS/MS analysis. All methods were fully validated to the rigor of regulated bioanalysis requirements, with intraday precision between 1.20 and 14.1% and accuracy between 93.8 and 107% at the standard curve concentration range. These methods were successfully applied to a human microdose study and demonstrated to be accurate, reproducible, and cost-effective. Results of the study indicate that raltegravir displayed linear pharmacokinetics between a microdose and a pharmacologically active dose. PMID- 23030781 TI - The liberated domain I of urokinase plasminogen activator receptor--a new tumour marker in small cell lung cancer. AB - The prognosis of small cell lung cancer (SCLC) remains poor with a 5-year survival rate of 4-6%. In non-small cell lung cancer (NSCLC), high levels of intact and cleaved forms of the receptor for urokinase plasminogen activator (uPAR) are significantly associated with short overall survival. Our aim was therefore to determine the prognostic value of the different uPAR forms in blood from SCLC patients. Serum samples from 92 treatment naive SCLC patients were analysed. Intact uPAR, uPAR(I-III), intact and cleaved uPAR, uPAR(I-III) + uPAR(II-III) and the liberated domain I, uPAR(I) were measured using time resolved fluorescence immunoassays (TR-FIA 1-3). Assessment of association of the uPAR forms to overall survival (OS) was done using Cox regression analysis adjusted for clinical covariates [age, gender, stage, lactate dehydrogenase (LDH), WHO performance status (PS)]. Multivariate survival analysis demonstrated that high levels of uPAR(I) were significantly (p = 0.009) associated with short overall survival (OS). Patients with uPAR(I) levels above the second tertile had a hazard ratio (HR) of 1.9 (95% confidence interval (CI): 1.1-3.3), compared to patients with levels below the first tertile. High serum uPAR(I) levels are associated with short OS in SCLC patient, independent of LDH and PS. PMID- 23030782 TI - Frequency of transferrin receptor positive reticulocytes (TF-Ret) in blood as an indicator of total-body radiation exposure: a pilot study in nuclear medicine patients. AB - Approximately 3-20% of all reticulocytes in blood of healthy persons are immature and transferrin receptor positive (Tf-Ret). Tf-Ret were measured by flow cytometry in 27 patients treated with three different radiopharmaceuticals labeled with (131)I and in 25 healthy controls. Patients were chronically exposed within 6 days to blood doses from 0.18-1.89 Gy (D6). Typically, two-thirds of D6 was administered within the first day (D1). The study had to be confined to intra subject investigations due to high biological variability of Tf-Ret counts. A significant radiation-induced decline was found in patients D1 doses that were >=0.5 Gy. Tf-Ret frequency declined during the first 4 to 5 days of nuclear therapy to about 30-60% of its initial value, and increased in the following 3 days without reaching the initial value. At the time of nadir, the relative frequency of Tf-Ret was more depressed than that of reticulocytes and lymphocytes. The relative Tf-Ret frequency at nadir could be fitted to the equation: %-Tf-Ret=exp-(D1/D(o)). D(o) was found to be 1.0 +/- 0.4 Gy (Mean +/- SEM). The study shows that Tf-Ret frequency in blood might be a good parameter for estimation of the radiation dose to red marrow. PMID- 23030783 TI - Distribution and levels of alpha-1-antitrypsin in the lung and plasma in smokers and chronic obstructive pulmonary disease. AB - Our recent non-biased proteomic screening study revealed elevated SerpinA1 i.e. alpha-1-antitrypsin (AAT) levels in induced sputum of smokers with Chronic obstructive pulmonary disease (COPD). This study was designed to further investigate the role of AAT in smokers and subjects with COPD. The expression/distribution of AAT was studied by immunohistochemistry/digital image morphometry in the lung, by Western blot in the lung and sputum, and by ELISA in the plasma at baseline (n = 349) and after a 2-year follow-up (n = 58). AAT was localized mainly in airway and alveolar epithelium and endothelium, especially in smokers and in those with COPD. AAT was elevated in smokers and in subjects with COPD in the lung endothelial cells. Total lung AAT immunoreactivity was elevated in subjects with moderate COPD compared with smokers and with non-smokers. AAT showed elevated tendency in sputum of smokers with COPD compared with 'healthy' smokers. Plasma AAT levels were elevated in smokers with/without COPD compared with non-smokers. In the follow-up, plasma AAT concentrations decreased significantly after quitting smoking. Chronic smoking/COPD leads to AAT elevation especially in the endothelium of the lung periphery; these changes reflect only modestly to the AAT in sputum, while plasma AAT significantly reflects smoking related systemic manifestations, and decreases after smoking cessation. PMID- 23030784 TI - Increased risk of pertussis in adult patients with mannose-binding lectin deficiency. AB - Mannose-binding lectin (MBL) is an important molecule of the innate immunity. The low level of MBL in the serum is associated with increased susceptibility to respiratory infections. In this study, MBL concentrations were determined from the sera of 125 Finnish pertussis patients and from 430 control subjects. Severe MBL deficiency (<50 ng/mL) was found more often in the patients than in the controls (11.2% vs 5.8%, p = 0.038). Moreover, the deficiency was detected more frequently in the adult patients than in the controls [20.4% vs 8.6%, p = 0.021; odds ratio 2.7 (95% confidence interval 1.1-6.5)]. Our findings suggest, for the first time, that MBL deficiency predisposes to pertussis infection, at least in adults. PMID- 23030785 TI - Staff training effective in increasing learning opportunities for school-aged children with autism spectrum disorders. AB - OBJECTIVE: This study examined the effectiveness of instruction and video feedback on staff's ABA skills during one-to-one play situations and initiations of children with autism spectrum disorder (ASD). METHODS: Data were collected within a multiple baseline design across 5 dyads. A continuous 20 s interval recording system was used to record motivation, creating opportunities, prompting and reinforcement of staff and child initiations. Training included instruction, consisting of instructions, video examples and role-plays. After this, a 4-h delayed video feedback condition started. RESULTS: Three staff members created significantly more learning opportunities during post-instruction and a significant increase occurred during video feedback for one staff member. Initiatives increased significantly in two children during post-instruction. During follow-up, three children showed unprompted initiatives. The mean percentage of spontaneous initiations increased during follow-up. CONCLUSION: The findings provide support for training staff in a clinical setting to create learning opportunities, which also may result in concomittant improvement in child initiations. PMID- 23030786 TI - Learning to doctor: tinkering with visibility in residency training. AB - Medical doctors in teaching hospitals aim to serve the two central goals of patient care and medical training. Whereas patient care asks for experience, expertise and close supervision, medical training requires space to practise and the 'invisibility' of medical residents. Yet current reforms in postgraduate medical training point to an increasing emphasis on the measurable visibility of residents. Drawing on an ethnographic study of gynaecology training in The Netherlands, this article demonstrates that in daily clinical routines multiple practices of residents' visibility (visibilities) coexist. The article lists four visibilities: staging residents, negotiating supervision, playing the invisibility game and filming surgical operations. The article shows how attending physicians and medical residents tinker with these visibilities in daily clinical work to provide good care while enacting learning space, highlighting the increasing importance of visualising technologies in clinical work. Moreover, the article contributes to traditional sociological accounts on medical education, shifting the focus from medical education as a social institution to the practices of medical training itself. Such a focus on practice helps to gain an understanding of how the current reform challenges clinicians' educational activities. PMID- 23030787 TI - Seeing citrulline: development of a phenylglyoxal-based probe to visualize protein citrullination. AB - Protein arginine deiminases (PADs) catalyze the hydrolysis of peptidyl arginine to form peptidyl citrulline. Abnormally high PAD activity is observed in a host of human diseases, but the exact role of protein citrullination in these diseases and the identities of specific citrullinated disease biomarkers remain unknown, largely because of the lack of readily available chemical probes to detect protein citrullination. For this reason, we developed a citrulline-specific chemical probe, rhodamine-phenylglyoxal (Rh-PG), which we show can be used to investigate protein citrullination. This methodology is superior to existing techniques because it possesses higher throughput and excellent sensitivity. Additionally, we demonstrate that this probe can be used to determine the kinetic parameters for a number of protein substrates, monitor drug efficacy, and identify disease biomarkers in an animal model of ulcerative colitis that displays aberrantly increased PAD activity. PMID- 23030789 TI - Mechanistic investigation of the nickel-catalyzed Suzuki reaction of N,O-acetals: evidence for boronic acid assisted oxidative addition and an iminium activation pathway. AB - The mechanism of a recently reported Suzuki coupling reaction of quinoline derived allylic N,O-acetals has been studied using a combination of structural, stereochemical, and kinetic isotope effect experiments. The data indicate that C O activation is facilitated by Lewis acid assistance from the boronic acid coupling partner and an ionic S(N)1-like mechanism accounts for oxidative addition. In this context, we demonstrate the first direct observation of oxidative addition to a quinolinium salt. Notably, this mechanism is distinct from the more commonly described S(N)2(')-type oxidative addition of low-valent transition metals to most allylic electrophiles. PMID- 23030790 TI - Evaluation of an auditory assessment protocol for Chinese infants with nonsyndromic cleft lip and/or palate. AB - OBJECTIVE: To objectively investigate the auditory status of mainland Chinese infants with nonsyndromic cleft lip and/or palate and to evaluate an auditory assessment protocol for this group. DESIGN: Prospective cohort case review. PATIENTS OR OTHER PARTICIPANTS: A total of 42 Chinese infants with nonsyndromic cleft lip and/or palate aged 6 to 24 months. INTERVENTION: The hearing profiles of participants were acquired using otoscopy, tympanometry, transient-evoked otoacoustic emissions, and auditory brainstem response estimated hearing threshold. The efficiency of the current audiological test battery was analyzed also. RESULTS: Sixty-four (64.2) percent of infants with nonsyndromic cleft lip and/or palate (55.9% of ears) were suspected to have middle ear disorder, and 85.7% of all subjects (83.3% of ears) were found to have hearing loss. Of those with confirmed loss, the overall mean auditory brainstem response estimated air conduction hearing threshold was 53.5 +/- 13.6 decibel normal hearing level [db nHL]. Using auditory brainstem response thresholds as a reference standard, the diagnostic agreement with the other assessment tools for normal/abnormal results was otoscopy, 69% (kappa = .57); tympanometry, 66.7% (kappa = .53); and transient-evoked otoacoustic emissions, 80% (kappa = .64). CONCLUSION: The high prevalence of middle ear disease and hearing loss in mainland Chinese infants with nonsyndromic cleft lip and/or palate in this study was in contrast to previous studies of older age groups of Chinese children conducted in Hong Kong and Singapore. The audiological assessment protocol used in our study could provide useful information; although, modifications may be necessary to ensure a complete diagnostic overview for children with craniofacial clefts. PMID- 23030792 TI - Metabolic inflexibility and protein lysine acetylation in heart mitochondria of a chronic model of type 1 diabetes. AB - Diabetic cardiomyopathy refers to the changes in contractility that occur to the diabetic heart that can arise in the absence of vascular disease. Mitochondrial bioenergetic deficits and increased free radical production are pathological hallmarks of diabetic cardiomyopathy, but the mechanisms and causal relationships between mitochondrial deficits and the progression of disease are not understood. We evaluated cardiac mitochondrial function in a rodent model of chronic Type 1 diabetes (OVE26 mice) before the onset of contractility deficits. We found that the most pronounced change in OVE26 heart mitochondria is severe metabolic inflexibility. This inflexibility is characterized by large deficits in mitochondrial respiration measured in the presence of non-fatty acid substrates. Metabolic inflexibility occurred concomitantly with decreased activities of PDH (pyruvate dehydrogenase) and complex II. Hyper-acetylation of protein lysine was also observed. Treatment of control heart mitochondria with acetic anhydride (Ac2O), an acetylating agent, preferentially inhibited respiration by non-fatty acid substrates and increased superoxide production. We have concluded that metabolic inflexibility, induced by discrete enzymatic and molecular changes, including hyper-acetylation of protein lysine residues, precedes mitochondrial defects in a chronic rodent model of Type 1 diabetes. PMID- 23030793 TI - Precision cut lung slices as an efficient tool for in vitro lung physio pharmacotoxicology studies. AB - 1.We review the specific approaches for lung tissue slices preparation and incubation systems and the research application fields in which lung slices proved to be a very efficient alternative to animal experimentation for biomechanical, physiological, pharmacological and toxicological approaches. 2.Focus is made on air-liquid interface dynamic organ culture systems that allow direct tissue exposure to complex aerosol and that best mimic in vivo lung tissue physiology. 3.A compilation of research applications in the fields of vascular and airway reactivity, mucociliary transport, polyamine transport, xenobiotic biotransformation, chemicals toxicology and complex aerosols supports the concept that precision cut lung slices are a very efficient tool maintaining highly differentiated functions similar to in vivo lung organ when kept under dynamic organ culture. They also have been successfully used for lung gene transfer efficiency assessment, for lung viral infection efficiency assessment, for studies of tissue preservation media and tissue post-conditioning to optimize lung tissue viability before grafting. 4.Taken all together, the reviewed studies point to a great interest for precision cut lung slices as an efficient and valuable alternative to in vivo lung organ experimentation. PMID- 23030794 TI - Scoring and modeling psychological measures in the presence of multidimensionality. AB - Confirmatory factor analytic studies of psychological measures showing item responses to be multidimensional do not provide sufficient guidance for applied work. Demonstrating that item response data are multifactorial in this way does not necessarily (a) mean that a total scale score is an inadequate indicator of the intended construct, (b) demand creating and scoring subscales, or (c) require specifying a multidimensional measurement model in research using structural equation modeling (SEM). To better inform these important decisions, more fine grained psychometric analyses are necessary. We describe 3 established, but seldom used, psychometric approaches that address 4 distinct questions: (a) To what degree do total scale scores reflect reliable variation on a single construct? (b) Is the scoring and reporting of subscale scores justified? (c) If justified, how much reliable variance do subscale scores provide after controlling for a general factor? and (d) Can multidimensional item response data be represented by a unidimensional measurement model in SEM, or are multidimensional measurement models (e.g., second-order, bifactor) necessary to achieve unbiased structural coefficients? In the discussion, we provide guidance for applied researchers on how best to interpret the results from applying these methods and review their limitations. PMID- 23030795 TI - An ecological compass for planetary engineering. AB - Proposals to address present-day global warming through the large-scale application of technology to the climate system, known as geoengineering, raise questions of environmental ethics relevant to the broader issue of planetary engineering. These questions have also arisen in the scientific literature as discussions of how to terraform a planet such as Mars or Venus in order to make it more Earth-like and habitable. Here we draw on insights from terraforming and environmental ethics to develop a two-axis comparative tool for ethical frameworks that considers the intrinsic or instrumental value placed upon organisms, environments, planetary systems, or space. We apply this analysis to the realm of planetary engineering, such as terraforming on Mars or geoengineering on present-day Earth, as well as to questions of planetary protection and space exploration. PMID- 23030796 TI - The Holy Grail of outer space: pluralism, Druidry, and the religion of cinema in The Sky Ship. AB - The Danish silent movie Himmelskibet (in English, A Trip to Mars or The Sky Ship) premiered in 1918, and a novelization of the movie appeared in 1921. The film is about a trip to Mars and portrays a Martian civilization that embraces a life of peace, vegetarianism, and non-alcoholism. Both movie and novel, though especially the novel, provide insight into the plurality-of-worlds debate in Denmark in the early 20(th) century, forming as it did a part of a general debate about the relationship between science and religion. Yet The Sky Ship did not only form part of this debate but also displayed strong religious currents itself. Most notably, a romantic, Neo-Platonically inspired Christian version of Druidry informed the portrayal of the Martians and their society. Finally, the medium itself played a role in the story. By transcending language barriers, silent movies were imagined by some to be a kind of "Esperanto of the eye" that would usher in a new golden age for mankind, even contributing to ending the horrors of World War I. Thus, The Sky Ship offers insight into an intriguing conglomeration of pluralism, religion, and technology that should be of interest to historians of astrobiology. PMID- 23030798 TI - Predictors of immediate continence following robot-assisted radical prostatectomy. AB - INTRODUCTION: Few studies have examined the patient characteristics that lead to early continence after robot-assisted radical prostatectomy (RARP), and to date, there has been no investigation into the predictors of immediate continence. In the current study, we examine a large multisurgeon population of patients undergoing RARP to assess for predictors of this outcome. PATIENTS AND METHODS: Between January 2008 and December 2010, 1270 patients who underwent RARP at our institution, with complete preoperative and follow-up data, were assessed for urinary function prospectively. Univariable and multivariable logistic regressions were used to assess for predictors of zero pad usage after RARP. Patient and operative characteristics examined include age, body-mass index, prostate-specific antigen, adjusted Charlson comorbidity index (CCI), Gleason sum, international prostate symptom score, clinical stage, nerve sparing, bladder neck reconstruction, posterior anastomotic reconstruction, surgeon volume, and percutaneous suprapubic tube (PST) bladder drainage. RESULTS: Overall, 17.3% of patients (n=219) never required a pad after catheter removal. Characteristics associated with never requiring a pad are age, preoperative Gleason sum, CCI, nerve sparing, prostate weight, surgeon volume, and PST bladder drainage. Independent predictors of never requiring a pad after catheter removal included nerve-sparing (B/L standard as referent) wide dissection [OR: 0.96 (95% CI: 0.49, 1.88)], unilateral inter-/intrafascial [OR: 1.20 (0.70, 2.06)], bilateral inter /intrafascial [OR: 1.97 (1.36, 2.86)], and PST drainage [OR: 2.53 (1.56, 4.11)]. CONCLUSION: In a study reflective of broad RARP practice at our institution, 17.3% of patients were entirely pad free after RARP. The type of nerve sparing performed and placement of a PST for bladder drainage postoperatively were found to be independently predictive of never requiring a pad after RARP. PMID- 23030797 TI - Trojan-horse nanotube on-command intracellular drug delivery. AB - A major challenge to nanomaterial-based medicine is the ability to release drugs on-command. Here, we describe an innovative drug delivery system based on carbon nanotubes (CNTs), in which compounds can be released inside cells from within the nanotube "on-command" by inductive heating with an external alternating current or pulsed magnetic field. Without inductive heating the drug remains safely inside the CNTs, showing no toxicity in cell viability tests. Similar to the "Trojan-Horse" in function, we demonstrate the delivery of a combination of chemotherapeutic agents with low aqueous solubility, paclitaxel (Taxol), and C6 ceramide, to multidrug resistant pancreatic cancer cells. Nanotube encapsulation permitted the drugs to be used at a 100-fold lower concentration compared to exogenous treatment yet achieve a comparable ~70% cancer kill rate. PMID- 23030799 TI - Indole-derived psammaplin A analogues as epigenetic modulators with multiple inhibitory activities. AB - A SAR study has been carried out around a modified scaffold of the natural product psammaplin A obtained by replacing the o-bromophenol unit by an indole ring. A series of indole psammaplin A constructs were generated in a short synthetic sequence that starts with the functionalization of the C3 indole position with in situ generated nitrosoacrylate, and this is followed by protection of the beta-indole-alpha-oximinoesters, saponification, condensation with symmetrical diamines, and deprotection. Biochemical and cellular characterization using U937 and MCF-7 cells confirmed that many of these analogues displayed more potent actitivies than the parent natural product. Moreover, in addition to the reported HDAC and DNMT dual epigenetic inhibitory profile of the parent compound, some analogues, notably 4a (UVI5008), also inhibited the NAD(+)-dependent SIRT deacetylase enzymes. The SAR study provides structural insights into the mechanism of action of these multiple epigenetic ligands and paves the way for additional structural exploration to optimize their pharmacological profiles. Because of their multi(epi)target features and their action in ex vivo samples, the indole-based psammaplin A derivatives are attractive molecules for the modulation of epigenetic disorders. PMID- 23030801 TI - Controlled growth and applications of complex metal oxide ZnSn(OH)6 polyhedra. AB - We successfully controlled the crystallographic surface of ZnSn(OH)(6) crystals and systematically obtained ZnSn(OH)(6) crystals in different shapes including cubes, truncated cubes, cuboctahedrons, truncated octahedrons, and octahedrons using a simple solvothermal method in a methylcellulose (MC) ethanol/water solution. By simply adjusting the amount of the NaOH solution added to the reaction system, we observed the shape evolution of ZnSn(OH)(6) particles from cube to octahedron, with the sizes gradually increasing from about 200 nm to 1-2 MUm. These results not only provide ZnSn(OH)(6) polyhedra bound by different lattice planes, but also make it possible to investigate the morphology-property relationship of ZnSn(OH)(6) particles with different morphologies obtained under similar conditions. The antibacterial activities of the as-prepared ZnSn(OH)(6) polyhedral particles were studied. It was found that the antibacterial activities of ZnSn(OH)(6) particles against Escherichia coli depend on the shape of the ZnSn(OH)(6) particles, demonstrating that the surface structure of nanocrystals affects the antibacterial activity. Additionally, the obtained ZnSn(OH)(6) polyhedra can be applied as precursors for Zn(2)SnO(4)/SnO(2) composites with different morphologies by calcining at 600 degrees C. PMID- 23030800 TI - Atomic covalent functionalization of graphene. AB - Although graphene's physical structure is a single atom thick, two-dimensional, hexagonal crystal of sp(2) bonded carbon, this simple description belies the myriad interesting and complex physical properties attributed to this fascinating material. Because of its unusual electronic structure and superlative properties, graphene serves as a leading candidate for many next generation technologies including high frequency electronics, broadband photodetectors, biological and gas sensors, and transparent conductive coatings. Despite this promise, researchers could apply graphene more routinely in real-world technologies if they could chemically adjust graphene's electronic properties. For example, the covalent modification of graphene to create a band gap comparable to silicon (~1 eV) would enable its use in digital electronics, and larger band gaps would provide new opportunities for graphene-based photonics. Toward this end, researchers have focused considerable effort on the chemical functionalization of graphene. Due to its high thermodynamic stability and chemical inertness, new methods and techniques are required to create covalent bonds without promoting undesirable side reactions or irreversible damage to the underlying carbon lattice. In this Account, we review and discuss recent theoretical and experimental work studying covalent modifications to graphene using gas phase atomic radicals. Atomic radicals have sufficient energy to overcome the kinetic and thermodynamic barriers associated with covalent reactions on the basal plane of graphene but lack the energy required to break the C-C sigma bonds that would destroy the carbon lattice. Furthermore, because they are atomic species, radicals substantially reduce the likelihood of unwanted side reactions that confound other covalent chemistries. Overall, these methods based on atomic radicals show promise for the homogeneous functionalization of graphene and the production of new classes of two-dimensional materials with fundamentally different electronic and physical properties. Specifically, we focus on recent studies of the addition of atomic hydrogen, fluorine, and oxygen to the basal plane of graphene. In each of these reactions, a high energy, activating step initiates the process, breaking the local pi structure and distorting the surrounding lattice. Scanning tunneling microscopy experiments reveal that substrate mediated interactions often dominate when the initial binding event occurs. We then compare these substrate effects with the results of theoretical studies that typically assume a vacuum environment. As the surface coverage increases, clusters often form around the initial distortion, and the stoichiometric composition of the saturated end product depends strongly on both the substrate and reactant species. In addition to these chemical and structural observations, we review how covalent modification can extend the range of physical properties that are achievable in two-dimensional materials. PMID- 23030803 TI - Cerebellar gene expression following human traumatic brain injury. AB - Gene expression of specific brain biomarkers offers the possibility of shedding light on the difficult molecular pathways of traumatic brain injury (TBI) and may be useful to estimate the age of trauma. Gene expression rates of cerebellar injuries are not yet sufficiently established. In 12 cases (mean age 42 years) of TBI including a pathological change in cerebellum (with known survival times ranging from immediate death to 96 h), brain tissue samples from different brain regions were analyzed with real-time polymerase chain reaction (PCR) for expression of caspase-3, tyrosine kinase receptor B (TrkB), S100B, and glial fibrillary acidic protein (GFAP) mRNA. The pH was measured to gain information about a possible correlation to RNA degradation. For comparison, corresponding brain regions were arranged from control samples of subjects that died from sudden death. We found a correlation between pH and the degradation of RNA in samples from the contralateral site, where the samples with degraded RNA have a lower pH (p<0.05). For short survival times, the expression changes of caspase-3 (p<0.05) and the expression changes of TrkB (p<0.1) in the cerebellum show a significant increase compared to the controls. The cerebellar gene expression changes seem to occur much faster and stronger compared to the other investigated regions, in particular the cerebral trauma site. These findings could make the cerebellum an important target area to study the expression changes after TBI. PMID- 23030804 TI - A ratiometric fluorescent on-off Zn2+ chemosensor based on a tripropargylamine pyrene azide click adduct. AB - A new, easy-to-prepare and highly selective pyrene-linked tris-triazole amine fluorescent chemosensor has been designed from tripropargylamine and pyrene azide using Cu(I)-catalyzed click chemistry. The fluorescence on-off sensor 1 is highly selective for Zn(2+) displaying a ratiometric change in emission. The relative intensity ratio of monomer to excimer fluorescence (M(376)/E(465)) of the sensor increases 80-fold upon the addition of 10 equiv of Zn(2+) ions (with a detection limit of 0.2 MUM). PMID- 23030805 TI - Does JC virus have a role in the etiology and prognosis of Egyptian colorectal carcinoma? AB - John Cunningham virus (JCV) encodes an oncogenic T-antigen, which is capable of interacting with key growth regulatory pathways. JCV definite role as causal agent of human cancer, still awaits final confirmation. The present study was conducted to assess the possible role of JCV in Egyptian colorectal carcinoma (CRC) and correlate the expression with the clinicopathological features and survival. JCV in situ hybridization (ISH) signals and large T antigen immunoreactivity were examined in 87 colonic specimens. Positive glandular JCV ISH signals were detected in 20%, 25% and 40% of normal, adenoma and CRC cases respectively. Stromal JCV ISH signals were identified in 26% of CRC cases and 5% of adenoma however, normal mucosa did not show stromal positivity with significant difference (p = 0.03). Glandular JCV expression was significantly associated with high grade (p = 0.03), high mitotic index (p=0.02) and low apoptotic index (p = 0.00). Positive stromal signals were significantly associated with low apoptosis (p = 0.00). No positive nuclear immunostaining of JCV large T antigen was detected in all specimens. JCV stromal expression was the 2nd most powerful indicator of short survival and bad prognosis (p = 0.03) in CRC patients. JCV might play an etiological role in CRC tumorogenesis and short survival in Egyptian CRC patients. PMID- 23030806 TI - Metabolic profiling of lignans and other secondary metabolites from rapeseed ( Brassica napus L.). AB - A metabolic profiling study was carried out on rapeseed ( Brassica napus L.). Eleven glucosinolates were identified by high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD) and mass spectrometry (MS). Additionally, 18 phenolic compounds were profiled from an ethanol extract of rapeseed. Besides two major phenols, sinapine and methyl sinapate, 16 minor phenolic compounds were isolated and identified. Seven of them are new lignans including three (+/-)-thomasidioic acid derivatives and four (E,E)-dienolignan derivatives. The structures of novel phenolic compounds were elucidated by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and MS. The analytical data of secondary metabolites in rapeseed winter cultivar "Emerald" and information about purification on a microscale are useful for upcoming studies on tissue-specific localization of these compounds. PMID- 23030807 TI - Self-regulated music stimulation for persons with Alzheimer's disease: impact assessment and social validation. AB - OBJECTIVE: To assess the impact and the social rating of an active music condition (in which 10 patients with Alzheimer's disease regulated their music input) vs. a passive music condition. METHOD: In the active condition, the patients used a simple hand response and a microswitch to activate music stimulation periods. In the passive condition, music stimulation was prearranged and continued through the sessions. The active and passive stimulation sessions were preceded and followed by control (non-stimulation) sessions. RESULTS: The active condition sessions showed an increase in the patients' indices of positive participation (e.g., singing or music-related movements, and smiles) similar to that observed in the passive condition sessions. Social raters (140 psychology students) favored the active condition on a six-item questionnaire dealing, among others, with conditions' suitability, respect of patients' dignity and independence, and practicality. CONCLUSION: An active music stimulation condition can be viable, effective, and socially preferable. PMID- 23030808 TI - Survey on hospital-acquired urinary tract infection in neurological intensive care unit. AB - This study aimed to explore the causes, incidence, and risk factors of urinary tract infection patients in neurological intensive care unit (ICU). Patients (n = 916) admitted to the neurological ICU from January 2005 to December 2010 were retrospectively surveyed for urinary tract infections. There were 246 patients in neurological ICU who were diagnosed with hospital-acquired urinary tract infection during that period of time (26.9%). Forty-three cases were upper urinary tract infection, and 203 cases were lower urinary tract infection. The top three strains were Escherichia coli, Enterococcus faecalis, and Klebsiella pneumoniae. Older age (UTI rate, 22.6%), female patients (21.7%), hospital stay for more than 7 days (16.7%), diabetes (11.7%), and catheterization (21.1%) were the risk factors for hospital-acquired urinary tract infection. There is a high incidence of nosocomial urinary tract infection in the neurological intensive care unit. Active prevention program and surveillance need to be carried out in neurological ICU, especially in those with risk factors. PMID- 23030810 TI - A cohort study reporting clinical risk factors and individual risk perceptions of prostate cancer: implications for PSA testing. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Prostate cancer has three known clinical risk factors: age, ethnicity and family history. Men's knowledge of prostate cancer is low. This study demonstrates that men rely on family and friends to learn about prostate cancer and help them interpret their risk. The findings suggest the need for tailored prostate cancer education, through social networks, to encourage risk-stratified PSA testing, which will lead to earlier diagnosis for those most at risk. OBJECTIVES: To determine men's perceptions of their risk of developing prostate cancer. To consider the implications for PSA testing based on individual risk perceptions. PATIENTS AND METHODS: The research adopted an embedded mixed-method design, using clinical records and a retrospective postal survey. Patients (N = 474) diagnosed with prostate cancer in a two-year period (2008-2009) in Greater Glasgow were identified from pathology records. In all, 458 men received a postal survey (16 deceased patients were excluded); 320 men responded (70%). RESULTS: Analysis indicates that there is no association between known clinical risk factors and men's perceptions of their own risk. Older men did not display increased perceived risk. Men with a family history of prostate cancer (11%) had no increase in their own perception of risk. PSA tests are not requested by those who are at greater risk. The subsample of patients who had requested a test were no more likely to have a family history of prostate cancer. They were more likely, however, to perceive themselves to be at high risk, to have friends with prostate cancer, to be affluent and to have a low grade tumour. CONCLUSIONS: GPs need to balance men's risk perceptions in discussions about known clinical risk factors. Men's knowledge of prostate cancer stems largely from interpersonal sources (such as friends/family). Social networks may consequently offer an additional opportunity to increase awareness of risk-stratified testing. PMID- 23030811 TI - The effects of low-dose irradiation on inflammatory response proteins in a 3D reconstituted human skin tissue model. AB - Skin responses to moderate and high doses of ionizing radiation include the induction of DNA repair, apoptosis and stress response pathways. Additionally, numerous studies indicate that radiation exposure leads to inflammatory responses in skin cells and tissue. However, the inflammatory response of skin tissue to low-dose radiation (<=10 cGy) is poorly understood. To address this, we have utilized a reconstituted human skin tissue model (MatTek EpiDermFTTM) and assessed changes in 23 cytokines, 24 and 48 h after treatment of skin with either 3 or 10 cGy low dose of radiation. Three cytokines, IFN-gamma, IL-2, MIP-1alpha, were significantly altered in response to low-dose radiation. In contrast, seven cytokines were significantly altered in response to a high radiation dose of 200 cGy (IL-2, IL-10, IL-13, IFN-gamma, MIP-1alpha, TNFalpha and VEGF) or the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (G-CSF, GM-CSF, IL-1alpha, IL-8, MIP-1alpha, MIP-1beta and RANTES). Additionally, radiation induced inflammation appears to have a distinct cytokine response relative to the nonradiation induced stressor, TPA. Overall, these results indicate that there are subtle changes in the inflammatory protein levels after exposure to low-dose radiation and this response is a subset of what is seen after a high dose in a human skin tissue model. PMID- 23030812 TI - Preparation and culture of precision-cut organ slices from human and animal. AB - 1.Human and animal precision-cut organ slices are being widely used to obtain drug metabolism and toxicity profiles in vitro. These data are then used to predict what might be seen in human patients. The accuracy of this prediction and extrapolation of the findings based on human or animal in vitro systems to the findings that occur in vivo is dependent on both the quality of the tissue itself and the quality of the in vitro system. 2.The quality of human organs used in research is dependent on procurement methods, warm ischaemia time, preservation solutions, cold ischaemia time, and donor-specific factors. It is important to confirm that the organs being used are highly viable and fully functional before using them in scientific studies. 3.The optimal preparation and incubation of organ slices is also essential in maintaining slice viability and function. It is important to prepare the slices in a cold preservation solution, to prepare the slices at a correct thickness, and to incubate the slices in a system where the slice rotates in out of the oxygen atmosphere and medium. 4.Meeting the criteria outlined here will lead to successful organ slice cultures for investigating drug induced mechanisms and organ-specific toxicity. PMID- 23030813 TI - Paramagnetic relaxation enhancement reveals oligomerization interface of a membrane protein. AB - Protein-protein interactions play critical roles in cellular function and oligomerization of membrane proteins is a commonly observed phenomenon. Determining the oligomerization state and defining the intermolecular interface in the bilayer is generally a difficult task. Here, we use site-specific spin labeling to demonstrate that relaxation enhancements induced by covalently attached paramagnetic tag can provide distance restraints defining the intermonomer interface in oligomers formed by a seven-helical transmembrane protein Anabaena Sensory Rhodopsin (ASR). We combine these measurements with visible CD spectroscopy and cross-linking experiments to demonstrate that ASR forms tight trimers in both detergents and lipids. PMID- 23030814 TI - Development of chitosan oligosaccharide-modified gold nanorods for in vivo targeted delivery and noninvasive imaging by NIR irradiation. AB - In the present study, we demonstrate the synthesis and applications of multifunctional gold nanorod-based probes for specific targeting and noninvasive imaging based on localized heating generated by gold nanorods after NIR irradiation. The structural design of the probe consists of MUA (11 mercaptoundecanoic acid)-capped gold nanorods covalently linked with low molecular-weight chitosan oligosaccharide (M(w) ~5000) via carbodiimide (EDC) coupling agent. This surface modification is performed for complete replacement of toxic CTAB (hexadecyltrimethyl-ammonium chloride) and acid-responsive delivery of gold nanorods in acidic environment as known to be present at tumor surrounding areas. The resulting chitosan oligosaccharide-modified gold nanorods (CO-GNRs) were further conjugated with tumor targeting monoclonal antibody against EGFR (epidermal growth factor receptor) to provide localized targeting functionality owing to the overexpression of EGFR in human oral adenosquamous carcinoma cell line CAL 27. Initial in vitro and in vivo toxicity assessments indicated that CO-GNRs did not induce any significant toxicity and are thus suitable for biological applications. Furthermore, selective targeting and accumulation of CO-GNRs were observed in vitro via two-photon luminescence imaging studies in CAL 27, which was also observed through in vivo targeting studies performed via NIR (near-infrared) laser irradiation in CAL 27 xenografts of BALB/c nude mice. Hence, the CO-GNRs that we have developed are biocompatible and nontoxic and can be a potential candidate for in vivo targeted delivery, noninvasive imaging based on localized hyperthermia, and photothermal-related therapies. PMID- 23030815 TI - Why the French did not choose to panic: a dynamic analysis of the public response to the influenza pandemic. AB - To understand the French public's response to the 2009 pandemic A/H1N1 influenza health threat a sequence analysis framework has been employed mobilising different theoretical strands such as innovations diffusion theory, surprise theory and social representation theory. These tend to suggest that disease episodes, public health policy and the public's response should be considered within a larger socio-cognitive frame incorporating representations anchored by prior disease episodes and campaigns. It is suggested in this article that the public's response was greatly influenced by the pervasive anchoring of the social representations of the pandemic threat to the 1918 Spanish flu in the lay and scientific media. These representations were eventually seen not to match the reality of the disease and consequently the French public did not panic during the 2009 pandemic. This hypothesis has been tested empirically by examining retrospective media, bibliographical data and an analysis of risk perception carried out through three cross-sectional studies prior to and during the pandemic episode and one month after the launch of the vaccination campaign. These findings suggest that alarmist framings of health threats may be counterproductive since they may reduce the capacity of public health organisations to mobilise the public in the case of more serious emerging disease. PMID- 23030816 TI - The relative importance of Staphylococcus saprophyticus as a urinary tract pathogen: distribution of bacteria among urinary samples analysed during 1 year at a major Swedish laboratory. AB - To determine the distribution of urinary tract pathogens with focus on Staphylococcus saprophyticus and analyse the seasonality, antibiotic susceptibility, and gender and age distributions in a large Swedish cohort. S. saprophyticus is considered an important causative agent of urinary tract infection (UTI) in young women, and some earlier studies have reported up to approximately 40% of UTIs in this patient group being caused by S. saprophyticus. We hypothesized that this may be true only in very specific outpatient settings. During the year 2010, 113,720 urine samples were sent for culture to the Karolinska University Hospital, from both clinics in the hospital and from primary care units. Patient age, gender and month of sampling were analysed for S. saprophyticus, Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis. Species data were obtained for 42,633 (37%) of the urine samples. The most common pathogens were E. coli (57.0%), Enterococcus faecalis (6.5%), K. pneumoniae (5.9%), group B streptococci (5.7%), P. mirabilis (3.0%) and S. saprophyticus (1.8%). The majority of subjects with S. saprophyticus were women 15-29 years of age (63.8%). In this age group, S. saprophyticus constituted 12.5% of all urinary tract pathogens. S. saprophyticus is a common urinary tract pathogen in young women, but its relative importance is low compared with E. coli even in this patient group. For women in other ages and for men, growth of S. saprophyticus is a quite uncommon finding. PMID- 23030817 TI - College men, unplanned pregnancy, and marriage: what do they expect? AB - We conducted a qualitative content analysis of written responses from 148 college men to questions about pregnancy resolution and marriage in the event of an unplanned pregnancy. We used Marsiglio's ( 1991 ) concepts of procreative consciousness and responsibility as a source of theoretical sensitivity during data analysis. Men's written comments were analyzed using a modified version of the grounded theory method of open, axial, and selective coding. Three distinct groups emerged: "I expect to raise my child" (86.5%); "I don't expect to raise the child" (10.1%); and "I expect to let my partner decide" (3.4%). Several subgroups also emerged among men who intended to raise the unplanned child: Yes, I expect to get married; "No, I don't expect to get married"; "I don't know if we'd marry"; and "My partner and I would coparent." Across subgroups, conditional variations and reasons underlying expectations were noted. Much variability was observed in men's descriptions of their procreative responsibility. A majority expressed high expectations for personal obligation and responsibility if involved in an unplanned pregnancy. Future research on men's sexual and reproductive health and procreative consciousness and responsibility are discussed. PMID- 23030819 TI - The constant multiplier assumption misestimates long-term sex offender recidivism rates. AB - Many clinical psychologists have claimed that long-term sexual recidivism rates are a fixed multiple of short-term rates and have estimated that the true value of this constant falls somewhere between 1.5 and 3.0. They have also proposed that it is "mathematically sound" for evaluators to estimate the long-term rate for any actuarial score in sexually violent predator civil commitment cases by multiplying its short-term rate by this constant. The present paper questions the "constant multiplier assumption" and summarizes disconfirming data collected by its proponents and others showing that the fixed ratios for groups with low short term rates are actually greater than the ratios for groups with high short-term rates. These results rule out the use of the constant multiplier assumption by risk evaluators. It is concerning that this assumption has not been previously tested. The authors call on the developers of risk assessment systems to collect and report data that clearly validate the assumptions that underpin their actuarial tables before they are disseminated or administered. The American Psychological Association ethical standards also require forensic evaluators to acknowledge the limitations of their risk assessments when they testify, a practice that is invaluable to the trier of fact. PMID- 23030818 TI - "That never happened": adults' discernment of children's true and false memory reports. AB - Adults' evaluations of children's reports can determine whether legal proceedings are undertaken and whether they ultimately lead to justice. The current study involved 92 undergraduates and 35 laypersons who viewed and evaluated videotaped interviews of 3- and 5-year-olds providing true or false memory reports. The children's reports fell into the following categories based on a 2 (event type: true vs. false) * 2 (child report: assent vs. denial) factorial design: accurate reports, false reports, accurate denials, and false denials. Results revealed that adults were generally better able to correctly judge accurate reports, accurate denials, and false reports compared with false denials: For false denials, adults were, on average, "confident" that the event had not occurred, even though the event had in fact been experienced. Participant age predicted performance. These findings underscore the greater difficulty adults have in evaluating young children's false denials compared with other types of reports. Implications for law-related situations in which adults are called upon to evaluate children's statements are discussed. PMID- 23030820 TI - Assessing nonchoosers' eyewitness identification accuracy from photographic showups by using confidence and response times. AB - While recent research has shown that the accuracy of positive identification decisions can be assessed via confidence and decision times, gauging lineup rejections has been less successful. The current study focused on 2 different aspects which are inherent in lineup rejections. First, we hypothesized that decision times and confidence ratings should be postdictive of identification rejections if they refer to a single lineup member only. Second, we hypothesized that dividing nonchoosers according to the reasons they provided for their decisions can serve as a useful postdictor for nonchoosers' accuracy. To test these assumptions, we used (1) 1-person lineups (showups) in order to obtain confidence and response time measures referring to a single lineup member, and (2) asked nonchoosers about their reasons for making a rejection. Three hundred and eighty-four participants were asked to identify 2 different persons after watching 1 of 2 stimulus films. The results supported our hypotheses. Nonchoosers' postdecision confidence ratings were well-calibrated. Likewise, we successfully established optimum time and confidence boundaries for nonchoosers. Finally, combinations of postdictors increased the number of accurate classifications compared with individual postdictors. PMID- 23030821 TI - Psychopathy and crime: testing the incremental validity of PCL-R-measured psychopathy as a predictor of general and violent recidivism. AB - It has been argued that psychopathy plays a vital role in the criminal justice system. To test this assumption, the incremental validity of the psychopathy construct was examined in 198 male Canadian prison inmates serving time for nonsexual offenses and 122 male U. S. inmates undergoing forensic evaluations. When these two samples--which had been used previously to test the incremental validity of the four Psychopathy Checklist-Revised (PCL-R: Hare, 2003) facet scores (Walters, Wilson, & Glover, 2011)--were treated as a single group, second order confirmatory factor analysis and item response theory principles indicated that a three-factor hierarchical model of the PCL-R facets (interpersonal, affective, lifestyle) fit the data better than a four-factor hierarchical model (interpersonal, affective, lifestyle, antisocial). When the two samples were examined separately, a composite of the first three PCL-R facets (interpersonal, affective, lifestyle) failed to predict general and violent recidivism above and beyond the contributions of age and criminal history. These results bring into question the utility of the psychopathy construct, as measured by Facets 1, 2, and 3 of the PCL-R, to predict important criminal justice outcomes like recidivism. Additional research using alternative measures of psychopathy and a wider array of outcome measures is required to determine the extent to which the psychopathy construct contributes to our understanding of criminal behavior. PMID- 23030822 TI - How can lymphocele development be prevented after laparoscopic radical prostatectomy? AB - OBJECTIVES: Lymphocele development is the most frequently reported postoperative complication of pelvic lymph node dissection (PLND) performed with laparoscopic radical prostatectomy (LRP). This study evaluated the efficacy of a vessel sealing device (VSD) for the prevention of lymphocele development. METHODS: A total of 120 patients who underwent LRP with PLND were prospectively enrolled. The patients were randomly assigned to one of the two groups: PLND using a conventional technique (group 1), and PLND performed with VSD (group 2). All patients underwent computed tomography (CT) scanning 1 month postoperatively to evaluate the maximum sectional area of the lymphoceles. RESULTS: Lymphoceles developed in 63 cases (52.5%). One case (0.8%) was symptomatic with infection, and drainage tube placement was required. In the other 62 patients, the lymphoceles developed asymptomatically and were detected by CT scanning. There was no significant difference in the lymphocele development ratio between the two groups. However, when we defined a lymphocele over 1500 mm(2) as being a significant size, lymphoceles were present in 16 of 60 patients in group 1 and 4 of 60 patients in group 2. The incidence of significant lymphoceles over 1500 mm(2) in the group using VSD was much lower than that of the group without VSD (p<0.01). Multivariate analysis demonstrated that VSD was the only independent factor that had an effect on preventing the development of lymphoceles over 1500 mm(2) (p<0.01, odds ratio=4.96). CONCLUSION: The results indicate that the development of large lymphoceles can be prevented by using VSD in LRP with PLND. PMID- 23030823 TI - Akt is efficiently activated by PIF-pocket- and PtdIns(3,4,5)P3-dependent mechanisms leading to resistance to PDK1 inhibitors. AB - Mutations leading to inappropriate activation of Akt isoforms contribute to proliferation and survival of a significant proportion of human cancers. Akt is activated by phosphorylation of its T-loop residue (Thr(308)) by PDK1 (3 phosphoinositide-dependent kinase-1) and its C-terminal hydrophobic motif (Ser(473)) by mTORC2 [mTOR (mammalian target of rapamycin) complex 2]. Potent PDK1 inhibitors such as GSK2334470 have recently been elaborated as potential anti-cancer agents. However, these compounds were surprisingly ineffective at suppressing Akt activation. In the present study we demonstrate that resistance to PDK1 inhibitors results from Akt being efficiently recruited to PDK1 via two alternative mechanisms. The first involves ability of Akt and PDK1 to mutually interact with the PI3K (phosphoinositide 3-kinase) second messenger PtdIns(3,4,5)P3. The second entails recruitment of PDK1 to Akt after its phosphorylation at Ser(473) by mTORC2, via a substrate-docking motif termed the PIF-pocket. We find that disruption of either the PtdIns(3,4,5)P3 or the Ser(473) phosphorylation/PIF-pocket mechanism only moderately impacts on Akt activation, but induces marked sensitization to PDK1 inhibitors. These findings suggest that suppression of Ser(473) phosphorylation by using mTOR inhibitors would disrupt the PIF-pocket mechanism and thereby sensitize Akt to PDK1 inhibitors. Consistent with this, we find combing PDK1 and mTOR inhibitors reduced Akt activation to below basal levels and markedly inhibited proliferation of all of the cell lines tested. Our results suggest further work is warranted to explore the utility of combining PDK1 and mTOR inhibitors as a therapeutic strategy for treatment of cancers that harbour mutations elevating Akt activity. PMID- 23030824 TI - Moving beyond mass: the unmet need to consider dose metrics in environmental nanotoxicology studies. PMID- 23030825 TI - Carbon nanotube-nanocup hybrid structures for high power supercapacitor applications. AB - Here, we design and develop high-power electric double-layer capacitors (EDLCs) using carbon-based three dimensional (3-D) hybrid nanostructured electrodes. 3-D hybrid nanostructured electrodes consisting of vertically aligned carbon nanotubes (CNTs) on highly porous carbon nanocups (CNCs) were synthesized by a combination of anodization and chemical vapor deposition techniques. A 3-D electrode-based supercapacitor showed enhanced areal capacitance by accommodating more charges in a given footprint area than that of a conventional CNC-based device. PMID- 23030826 TI - Bi-, tri-, and polycyclic acylphloroglucinols from Hypericum empetrifolium. AB - The 1H NMR-guided fractionation of a petroleum ether extract of Hypericum empetrifolium led to the isolation of four new bicyclic (1-4), four known bicyclic (5-8), three new tricyclic (9-11), and three new polycyclic acylphloroglucinols (12/13 and 14) possessing a monoterpenoid citran moiety. Compounds 12/13 were isolated as a mixture of two inseparable structural isomers. The compounds showed in vitro antiproliferative activity against human microvascular endothelial cells (HMEC-1) with IC50 values in the range 9.2 +/- 2.0 to 29.6 +/- 3.5 MUM. PMID- 23030827 TI - Palladium-catalyzed synthesis of benzimidazoles and quinazolinones from common precursors. AB - N-(o-Halophenyl)imidoyl chlorides and the corresponding imidates are easily prepared and can be utilized as complementary precursors for the synthesis of important heterocycles. The synthesis of N-substituted benzimidazoles was possible from the palladium-catalyzed reaction of both classes of substrate with a variety of N-nucleophiles. The use of the imidate precursor for the synthesis of N-substituted quinazolinones by incorporation of a palladium-catalyzed aminocarbonylation reaction has also been demonstrated. Both processes tolerate a wide range of functional groups. PMID- 23030828 TI - Electron attachment to C7F14, thermal detachment from C7F14(-), the electron affinity of C7F14, and neutralization of C7F14(-) by Ar+. AB - Rate coefficients and branching fractions have been measured for electron attachment to perfluoromethylcyclohexane, C(7)F(14), along with thermal detachment rate coefficients for C(7)F(14)(-), from 300 to 630 K, using a flowing afterglow Langmuir-probe apparatus. The attachment rate coefficient at room temperature is 4.5 +/- 1.2 * 10(-8) cm(3) s(-1) and increases with temperature at a rate described by an activation energy of 50 +/- 25 meV. Thermal electron detachment is negligible at room temperature, but measurable at 600 K and above, reaching 2300 +/- 1300 s(-1) at 630 K. Analysis of the attachment-detachment equilibrium yields EA(C(7)F(14)) = 1.02 +/- 0.06 eV, in agreement with the literature value while more than halving the uncertainty. Implications of the measurement for the electron affinity of SF(6) are discussed. The dominant product of electron attachment is the parent anion, but C(6)F(11)(-) and C(7)F(13)(-) are also observed at very low levels (<0.1%) at room temperature and increase in importance as the temperature is increased, reaching ~10% each at 630 K. In the course of this work we have also measured rate coefficients for the neutralization of C(7)F(14)(-) by Ar(+) at 300, 400, and 500 K: 4.8, 3.5, and 3.1 * 10(-8) cm(3) s(-1), respectively, with uncertainties of +/-5 * 10(-9) cm(3) s( 1). PMID- 23030829 TI - Molecularly imprinted Ru complex catalysts integrated on oxide surfaces. AB - Selective catalysis is critical for the development of green chemical processes, and natural enzymes that possess specialized three-dimensional reaction pockets with catalytically active sites represent the most sophisticated systems for selective catalysis. A reaction space in an enzyme consists of an active metal center, functional groups for molecular recognition (such as amino acids), and a surrounding protein matrix to prepare the reaction pocket. The artificial design of such an integrated catalytic unit in a non-enzymatic system remains challenging. Molecular imprinting of a supported metal complex provides a promising approach for shape-selective catalysis. In this process, an imprinted cavity with a shape matched to a template molecule is created in a polymer matrix with a catalytically active metal site. In this Account, we review our studies on molecularly imprinted metal complex catalysts, focusing on Ru complexes, on oxide surfaces for shape-selective catalysis. Oxide surface-attached transition metal complex catalysts not only improve thermal stability and catalyst dispersion but also provide unique catalytic performance not observed in homogeneous precursors. We designed molecularly imprinted Ru complexes by using surface-attached Ru complexes with template ligands and inorganic/organic surface matrix overlayers to control the chemical environment around the active metal complex catalysts on oxide surfaces. We prepared the designed, molecularly imprinted Ru complexes on SiO(2) surfaces in a step-by-step manner and characterized them with solid-state (SS) NMR, diffuse-reflectance (DR) UV-vis, X ray photoelectron spectroscopy (XPS), Brunauer-Emmett-Teller isotherm (BET), X ray fluorescence (XRF), and Ru K-edge extended X-ray absorption fine structure (EXAFS). The catalytic performances of these Ru complexes suggest that this process of molecular imprinting facilitates the artificial integration of catalytic functions at surfaces. Further advances such as the imprinting of a transition state structure or the addition of multiple binding sites could lead to systems that can achieve 100% selective catalysis. PMID- 23030830 TI - Incorporation of neptunium(VI) into a uranyl selenite. AB - The incorporation of neptunium(VI) into the layered uranyl selenite Cs[(UO(2))(HSeO(3))(SeO(3))] has yielded the highest level of neptunium uptake in a uranyl compound to date with an average of 12(+/-3)% substitution of Np(VI) for U(VI). Furthermore, this is the first case in nearly 2 decades of dedicated incorporation studies in which the oxidation state of neptunium has been determined spectroscopically in a doped uranyl compound and also the first time in which neptunium incorporation has resulted in a structural transformation. PMID- 23030831 TI - Gram-positive anaerobic cocci--commensals and opportunistic pathogens. AB - Among the Gram-positive anaerobic bacteria associated with clinical infections, the Gram-positive anaerobic cocci (GPAC) are the most prominent and account for approximately 25-30% of all isolated anaerobic bacteria from clinical specimens. Still, routine culture and identification of these slowly growing anaerobes to the species level has been limited in the diagnostic laboratory, mainly due to the requirement of prolonged incubation times and time-consuming phenotypic identification. In addition, GPAC are mostly isolated from polymicrobial infections with known pathogens and therefore their relevance has often been overlooked. However, through improvements in diagnostic and in particular molecular techniques, the isolation and identification of individual genera and species of GPAC associated with specific infections have been enhanced. Furthermore, the taxonomy of GPAC has undergone considerable changes over the years, mainly due to the development of molecular identification methods. Existing species have been renamed and novel species have been added, resulting in changes of the nomenclature. As the abundance and significance of GPAC in clinical infections grow, knowledge of virulence factors and antibiotic resistance patterns of different species becomes more important. The present review describes recent advances of GPAC and what is known of the biology and pathogenic effects of Anaerococcus, Finegoldia, Parvimonas, Peptoniphilus and Peptostreptococcus, the most important GPAC genera isolated from human infections. PMID- 23030832 TI - Detection of human papillomavirus in esophageal papillomas: systematic review and meta-analysis. AB - Since first suggested (in 1982), etiological role for human papillomavirus (HPV) in esophageal papillomas has aroused increasing interest. The objective of this study was to perform systematic review and formal meta-analysis of the literature reporting on HPV detection in esophageal squamous cell papillomas (ESCP). Literature was searched through May 2012. The effect size was calculated as event rates (95% CI), with homogeneity testing using Cochran's Q and I(2) statistics. Meta-regression was used to test the impact of study-level covariates (HPV detection method, geographic origin) on effect size, and potential publication bias was estimated using funnel plot symmetry. Thirty nine studies were eligible, covering 427 ESCPs from different geographic regions. Altogether, 132 (30.9%) cases tested HPV positive; effect size 0.375 (95% CI 0.319-0.434) using the fixed effects (FE) model and 0.412 (95% CI 0.295-0.540) using the random-effects model. In meta-analysis stratified by (i) HPV detection technique and (ii) geographic study origin, the between-study heterogeneity was not significant (p = 0.071 and p = 0.105, respectively). In meta-regression, HPV detection method (p = 0.260) and geographic origin (p = 0.436) were not significant study-level covariates accounting for the heterogeneity in HPV prevalence. Some evidence for publication bias was found only for PCR-based studies, with a marginal impact on summary effect size estimates. In sensitivity analysis, all meta-analytic results were robust to all one-by-one study removals. In stratified meta-analysis and formal meta-regression, the variability in HPV detection rates in ESCPs is not explained by the HPV detection method or geographic origin of the study. PMID- 23030833 TI - Shiga toxin-encoding genes (stx genes) in human faecal samples. AB - The aim of the two studies reported here was to investigate the distribution of stx genes in human faecal samples from volunteers and in faecal samples submitted to a regional microbiology hospital laboratory, and to isolate and characterize STEC from stx-positive samples. In total, faecal samples from 13.9% of 165 volunteers and 36.1% of 416 swabs from the regional microbiology hospital laboratory were positive for stx genes after screening by PCR. Isolation of STEC and of E. coli O157 from stx-positive faecal samples was performed by a filter hybridization protocol and by automated immunomagnetic separation, respectively, and isolates were further characterized by serotyping, virulence typing by PCR and toxin production by the Vero cell assay. STEC were isolated from two samples only, an O146:H21 isolate from one of the volunteers and an O157:H7 isolate from a human case of diarrhoea. To conclude; the results show that it is not unusual to detect stx genes in faecal samples from humans in Norway, both from asymptomatic people and from people with gastrointestinal illness. This finding emphasizes the importance of correct diagnostic criteria for interpretation of the finding of an occasional stx-positive sample or an STEC isolate when searching for an aetiological agent of human cases of diarrhoea. PMID- 23030834 TI - Cord blood S100B levels in low-risk term pregnancies with meconium-stained amniotic fluid. AB - OBJECTIVE: The aim of this study was to compare cord blood S100B levels and cord blood gas parameters of term infants with meconium-stained amniotic fluid (MSAF) to those infants with clear amniotic fluid. METHODS: Term pregnant women at an active phase of labor and having MSAF were defined as the study group (n = 35) and pregnant women with clear amniotic fluid, and matched for age, parity, and gestational age were defined as the control group (n = 35). Cord blood S100B levels and gas parameters were measured. RESULTS: LogS100B values of study and control groups were 2.40 +/- 0.21 and 2.43 +/- 0.29 pg/ml, respectively. The difference was not statistically significant (p = 0.675). LogS100B levels slightly increased as meconium thickened. (2.32 +/- 0.16, 2.41 +/- 0.17, and 2.44 +/- 0.28 pg/ml, respectively). However, no difference was found between groups (p = 0.438). Moreover, the study group had a statistically lower HCO(3) level (21.80 vs 23.60 mmol/l) and a higher rate of base deficit (4.85 vs 3.25 mmol/l) than the control group. However, median HCO(3) and base deficit values were within normal limits in both groups. CONCLUSION: The present study showed that cord blood S100B levels of infants born through MSAF were not different from those with clear amniotic fluid. This finding suggests that MSAF, regardless of its thickness, may not be related to brain damage in low risk term pregnancies. PMID- 23030835 TI - Isolation and identification of Flavobacterium columnare and Streptococcus iniae antibacterial compounds from the terrestrial plant Atraphaxis laetevirens. AB - Columnaris disease, enteric septicemia of catfish, and streptococcosis are common bacterial diseases of certain freshwater fish and are caused by Flavobacterium columnare , Edwardsiella ictaluri , and Streptococcus iniae , respectively. During the process of evaluating several species of plants to isolate and identify compounds with toxicity against these bacteria, a promising extract from the aerial parts of the terrestrial plant Atraphaxis laetevirens (Ledeb.) Jaub. et Spach (Polygonaceae Juss.) was selected for bioassay-guided fractionation using a rapid microplate bioassay. The active dichloromethane extract was subjected to liquid-liquid partitioning, and active fractions were further separated by normal-phase column chromatography and normal-phase high-performance liquid chromatography (HPLC). Nepodin (3) and emodin (4) were isolated from two fractions with strong toxicities against S. iniae . A chloroform fraction was further separated by normal-phase column chromatography to yield two active fractions against F. columnare , and these fractions contained chrysophanol (1), physcion (2), and nepodin (3). Compound 1 had strong activity, and compound 3 had moderate activity against F. columnare , while compounds 2 and 4 were not toxic at the concentrations tested. PMID- 23030836 TI - The effect of the Nintendo Wii Fit on balance control and gross motor function of children with spastic hemiplegic cerebral palsy. AB - OBJECTIVE: To study the impact of training using the Nintendo Wii Fit in 14 children with spastic hemiplegic cerebral palsy. METHODS: A single-subject single blinded design with multiple subjects and baselines was utilised. Interactive video gaming (IVG) in lieu of regular physiotherapy was given for 3 weeks. Outcome measures included modified balance and running speed and agility (RSA) scales of the Bruininks-Oserestky test of Motor Performance 2 and the timed up and down stairs (TUDS). RESULTS: Balances score improved significantly (F(2, 26) = 9.8286, p = 0.001). Changes over time in the RSA (F(2, 26) = 0.86198, p = 0.434) and the TUDS (F(2, 26) = 1.3862, p = 0.268) were not significant. Ten children preferred the intervention to conventional physiotherapy. CONCLUSION: Most children preferred the IVG but as the effect did not carry over into function, IVG should not be used in place of conventional therapy and further research is needed into its use as an adjunct to therapy. PMID- 23030837 TI - Bithiopheneimide-dithienosilole/dithienogermole copolymers for efficient solar cells: information from structure-property-device performance correlations and comparison to thieno[3,4-c]pyrrole-4,6-dione analogues. AB - Rational creation of polymeric semiconductors from novel building blocks is critical to polymer solar cell (PSC) development. We report a new series of bithiopheneimide-based donor-acceptor copolymers for bulk-heterojunction (BHJ) PSCs. The bithiopheneimide electron-deficiency compresses polymer bandgaps and lowers the HOMOs--essential to maximize power conversion efficiency (PCE). While the dithiophene bridge progression R(2)Si->R(2)Ge minimally impacts bandgaps, it substantially alters the HOMO energies. Furthermore, imide N-substituent variation has negligible impact on polymer opto-electrical properties, but greatly affects solubility and microstructure. Grazing incidence wide-angle X-ray scattering (GIWAXS) indicates that branched N-alkyl substituents increased polymer pi-pi spacings vs linear N-alkyl substituents, and the dithienosilole based PBTISi series exhibits more ordered packing than the dithienogermole-based PBTIGe analogues. Further insights into structure-property-device performance correlations are provided by a thieno[3,4-c]pyrrole-4,6-dione (TPD) dithienosilole copolymer PTPDSi. DFT computation and optical spectroscopy show that the TPD-based polymers achieve greater subunit-subunit coplanarity via intramolecular (thienyl)S...O(carbonyl) interactions, and GIWAXS indicates that PBTISi-C8 has lower lamellar ordering, but closer pi-pi spacing than does the TPD based analogue. Inverted BHJ solar cells using bithiopheneimide-based polymer as donor and PC(71)BM as acceptor exhibit promising device performance with PCEs up to 6.41% and V(oc) > 0.80 V. In analogous cells, the TPD analogue exhibits 0.08 V higher V(oc) with an enhanced PCE of 6.83%, mainly attributable to the lower lying HOMO induced by the higher imide group density. These results demonstrate the potential of BTI-based polymers for high-performance solar cells, and provide generalizable insights into structure-property relationships in TPD, BTI, and related polymer semiconductors. PMID- 23030838 TI - Relationship between focal cortical dysplasia and epilepsy-associated low-grade tumors: an immunohistochemical study. AB - We retrospectively analyzed 29 seizure-associated temporal lobe low-grade tumors to evaluate the utility of CD34 and bcl-2 expression in clarifying the relationship of these tumors with different classes of focal cortical dysplasia (FCD). CD34 immunostained 75% of gangliogliomas (GG) and 60% of pleomorphic xanthoastrocytomas. FCD type IIIb [i.e. abnormal cortical layering associated with a glioneuronal tumor, according to the new International League Against Epilepsy (ILAE) classification] presented CD34-immunopositive cells in 2/9 (22.2%) cases, whereas FCD type II in 6/7 (85.7%) cases, a difference statistically significant (p = 0.0117). Bcl-2 immunostained 9/12 (75%) gangliogliomas and 2/3 (66.6%) gangliocytomas. The cases of FCD type IIIb resulted negative for Bcl-2, whereas 4/7 cases (57.1%) of FCD type II showed immunopositive cells. These differences in Bcl-2 expression between FCD type IIIb and FCD type II resulted statistically significant (p = 0.0088). Abnormal cortical layering, overall, represents the kind of FCD more commonly associated with seizure-related low-grade tumors, whereas FCD type II is more frequently associated with GG. The profile of CD34 and Bcl-2 expression exhibited by GG is more similar to that observed in FCD type II. Such immunoprofile suggests the existence of a common pathogenesis linking glioneuronal tumors and FCD type II. PMID- 23030839 TI - Use of a patient-specific CAD/CAM surgical jig in extremity bone tumor resection and custom prosthetic reconstruction. AB - Computer navigation has recently been introduced for bone tumor surgery in the orthopedic field, with the aim of achieving increased accuracy and precision in tumor resection and in custom prosthetic reconstruction. However, the technique requires bulky navigation facilities, the presence of a system operator in the operating room, and surgeons with prior experience in navigated surgery. We describe a new and simple method of using a patient-specific computer-aided design/computer-aided modeling (CAD/CAM) surgical jig to realize the preoperative planning in the surgical field. The accuracy of the proposed method was first tested in a cadaver trial. It took one minute to set the location of the jig prior to the bone resection and three minutes to perform the bone resections via the cutting slits of the jig. The dimensional difference between the achieved and planned bone resection was <1 mm on validation with the help of a junctional plate and a navigation system. The technique was then applied successfully to a patient with a low-grade osteosarcoma of the femur. An intercalated tumor resection was performed using a patient-specific surgical jig, and a custom CAD prosthesis reconstruction matched accurately to the skeletal defect. Further assessment in a larger population is necessary to determine the clinical efficacy of the technique. PMID- 23030840 TI - Stabilization of Aspergillus parasiticus cytosine deaminase by immobilization on calcium alginate beads improved enzyme operational stability. AB - Cytosine deaminase (CD) from Aspergillus parasiticus, which has half-life of 1.10 h at 37 degrees C, was stabilized by immobilization on calcium alginate beads. The immobilized CD had pH and temperature optimum of 5 and 50 degrees C respectively. The immobilized enzyme also stoichiometrically deaminated Cytosine and 5-fluorocytosine (5-FC) with the apparent K(M) values of 0.60 mM and 0.65 mM respectively, displaying activation energy of 10.72 KJ/mol. The immobilization of native CD on calcium alginate beads gave the highest yield of apparent enzymatic activity of 51.60% of the original activity and the enzymatic activity was lost exponentially at 37 degrees C over 12 h with a half-life of 5.80 h. Hence, the operational stability of native CD can be improved by immobilization on calcium alginate beads. PMID- 23030841 TI - Evidence-based medicine and the governance of pandemic influenza. AB - The conventional response of governments to protect their populations against the threat of influenza has been to ensure adequate vaccine production and/or access to supplies of vaccines and antiviral medications. This focus has, in turn, shaped the global governance structures around pandemic influenza, with collective efforts centred on facilitating virus sharing, maintaining and increasing vaccine production, and ensuring access to pharmaceuticals - responses that remain unattainable for many low- and middle-income countries (LMICs) in the short to medium term. This paper argues that this emphasis on pharmacological responses reflects a particular view of biomedicine that pays inadequate attention to the weak capacity of many health systems. In more recent years, this dynamic has been further exacerbated by the influence of evidence-based medicine (EBM) that preferences certain types of biomedical knowledge and practice. This paper explores the role that EBM has played in shaping the global governance of pandemic influenza, and how it has served to reinforce and reify the authority of particular groups of actors, including policy-makers, elected officials and the medical community. The paper concludes that only by unpacking these structures and revealing the political authority in play can alternative policy responses more appropriate to LMICs be considered. PMID- 23030842 TI - Soluble fms-like tyrosine kinase-1 (sFLT-1) predicts post-percutaneous coronary intervention (PCI) myocardial infarction (MI type 4a). AB - CONTEXT: Acute myocardial infarction (AMI) related to percutaneous coronary intervention (PCI) (MI type 4a) occurs in up to 26% of elective patients. OBJECTIVE: To evaluate if sFLT-1 helps to predict MI type 4a in troponin negative patients with elective PCI. MATERIALS AND METHODS: We enrolled 135 patients, 106 had a PCI. sFLT-1 levels were assessed at five time points before and after PCI. RESULTS: MI type 4a occurred in 22.1% of patients. sFLT-1 levels at admission above 251 pg/mL indicated a significant relative risk for MI type 4a of 2.83. CONCLUSION AND DISCUSSION: Increased sFLT-1 levels at baseline might indicate unstable atherosclerosis and risk for microembolization and thus be predictive of MI type 4a. PMID- 23030843 TI - Ethnic differences in predictors of HPV vaccination: comparisons of predictors for Latina and non-Latina White women. AB - The purpose of this study was to examine how social and behavioral factors such as age of first intercourse, mother-daughter communication, and perceived norms are associated with human papillomavirus (HPV) vaccination behaviors, and whether ethnicity moderates those associations (non-Latina White versus Latina participants). From June through December 2009, we surveyed a community sample of 309 White and Latina women, ages 15 to 30. We recruited participants from local health care clinics in Des Moines, Iowa. Vaccination status was not significantly different for Whites versus Latinas. The effects of age at first intercourse, mother-daughter communication about values related to sex, and descriptive norms of HPV vaccine uptake were all significantly moderated by ethnicity. The current findings reveal that sociocultural and behavioral factors that affect HPV vaccine uptake do not affect White and Latina women in the same fashion. In the future, public health campaigns about HPV and the HPV vaccine may be more effective if their messages are sensitive to these differences. PMID- 23030845 TI - Characterization of zebrafish polymerase III promoters for the expression of short-hairpin RNA interference molecules. AB - RNA interference (RNAi) is a powerful, sequence specific, and long-lasting method of gene knockdown, and can be elicited by the expression of short-hairpin RNA (shRNA) molecules driven via polymerase III type 3 promoters from a DNA vector or transgene. To further develop RNAi as a tool in zebrafish, we have characterized the zebrafish U6 and H1 snRNA promoters and compared the efficiency of each of the promoters to express an shRNA and silence a reporter gene, relative to previously characterized U6 promoters from pufferfish, chicken, and mouse. Our results show that the zebrafish polymerase III promoters were capable of effective gene silencing in the zebrafish ZF4 cell line, but were ineffective in mammalian Vero cells. In contrast, mouse and chicken promoters were active in Vero but not ZF4 cells, highlighting the importance of homologous promoters to achieve effective silencing. PMID- 23030844 TI - Role of Met(58) in the regulation of electron/proton transfer in trihaem cytochrome PpcA from Geobacter sulfurreducens. AB - The bacterium Gs (Geobacter sulfurreducens) is capable of oxidizing a large variety of compounds relaying electrons out of the cytoplasm and across the membranes in a process designated as extracellular electron transfer. The trihaem cytochrome PpcA is highly abundant in Gs and is most probably the reservoir of electrons destined for the outer surface. In addition to its role in electron transfer pathways, we have previously shown that this protein could perform e( )/H(+) energy transduction. This mechanism is achieved by selecting the specific redox states that the protein can access during the redox cycle and might be related to the formation of proton electrochemical potential gradient across the periplasmic membrane. The regulatory role of haem III in the functional mechanism of PpcA was probed by replacing Met(58), a residue that controls the solvent accessibility of haem III, with serine, aspartic acid, asparagine or lysine. The data obtained from the mutants showed that the preferred e(-)/H(+) transfer pathway observed for PpcA is strongly dependent on the reduction potential of haem III. It is striking to note that one residue can fine tune the redox states that can be accessed by the trihaem cytochrome enough to alter the functional pathways. PMID- 23030846 TI - Seed concentration control of metal nanowire diameter. AB - Gold/silver nanowires (NWs) of controlled diameters were synthesized from catalytic metal seed particles at the substrate/solution interface. Small seed nanoparticles of three different sizes: ~1 nm (11 gold atoms), ~1.4 nm (~55 gold atoms), and homemade nanoparticles of ~2 nm were used. By varying a single type of seed particle concentration in the growth solution, the NW diameters and morphology could be controlled, between bundles of ultrathin NWs of ~2-3 nm diameter to thicker isolated single NWs with a mean diameter of ~16 nm. In addition, the catalytic reduction rate leading to NW growth was found to be seed size dependent at small seed sizes (<2 nm). The two types of metallic NW films were tested for their performance as transparent electrodes after additional metal deposition for their stabilization and conductivity enhancement. The thin NW bundles exhibit superior transparent conductor properties. PMID- 23030847 TI - Analysis of perfluoroalkyl carboxylic acids in composite dietary samples by gas chromatography/mass spectrometry with electron capture negative ionization. AB - A gas chromatography-mass spectrometry and electron-capture negative ionization (ECNI) method was developed to quantify perfluorinated carboxylic acids (PFCAs) in composite dietary samples. Benzyl esterification was used for pretreatment before PFCAs analysis. This stabilized the benzyl radical leaving group preferentially, and gave carboxylic anions of the PFCAs with ECNI. The method had a low detection limit (0.3-10 pg g(-1)) and good recoveries (98-90%) for PFCAs with 8-14 carbon atoms (C8 to C14). The method was applied to 24-h dietary samples from subjects in Japan (Hokkaido, Kyoto, and Okinawa; 1992 to 2007, and 2009), Korea (Seoul; 1994 and 2007), and China (Beijing; 1993 and 2009). The levels of the PFCAs were between 39 and 169 ng day(-1) in Korea, 58 and 71 ng day(-1) in China, and 56 and 67 ng day(-1) in Japan. Between the two sampling years, the total levels of PFCAs (C8 to C14) increased significantly (p < 0.05). The interaction between the sampling location in Korea and year was significant (p < 0.05). PMID- 23030848 TI - Antimicrobial rubrolides from a South African species of Synoicum tunicate. AB - The CH2Cl2-MeOH extract of a South African tunicate described as the new Synoicum globosum Parker-Nance sp. nov. (Ascidiacea, Aplousobranchia) was subjected to 1H NMR-guided fractionation. This resulted in the identification of new 3" bromorubrolide F (1), 3'-bromorubrolide E (2), 3'-bromorubrolide F (3), and 3',3" dibromorubrolide E (4) and reisolation of known rubrolides E (5) and F (6), based on NMR spectroscopic and mass spectrometric data. Biological testing of both new and known members of this reported antimicrobial family of halogenated, aryl substituted furanones indicated moderate antibacterial properties for 3' bromorubrolide E (2), 3',3"-dibromorubrolide E (4), and rubrolide F (6) against methicillin-resistant Staphylococcus aureus (MRSA) and S. epidermidis. PMID- 23030849 TI - Kinetic study of the gas phase reactions of a series of alcohols with the NO3 radical. AB - The rate coefficients for the reaction of NO(3) radical with 2-butanol, 3-methyl 2-butanol, and 2,3-dimethyl-2-butanol were determined using relative rate technique in a 50 L glass pyrex photoreactor using in situ FT-IR spectroscopy at room temperature and a pressure of 350-670 Torr. The rate coefficient for the reaction of 2-methyl-2-butanol with NO(3) radical was also determined using, in this case, GC/MS. The rate coefficients calculated (in units of cm(3) molecule( 1) s(-1)) were (2.51 +/- 0.42) * 10(-15), (3.06 +/- 0.52) * 10(-15), (2.67 +/- 0.3) * 10(-15), and (1.57 +/- 0.16) * 10(-15), respectively. Results indicate that the reaction occurs by an initial H-abstraction of the alcohols by the NO(3) radical and that NO(3) is more reactive toward a H atom attached to a tertiary carbon than that attached to a secondary or primary carbon. Results are also discussed as related to their homologous structural alkanes and in comparison with the reactivity of other atmospheric oxidants. Atmospheric relevance of the considered reactions is evaluated, concluding that they are potential ozone generators, they have no significant influence on global warming, and the dominant atmospheric loss process for these alcohols is their daytime reaction with OH radicals. PMID- 23030850 TI - Differential strain-related tissue immune response to sublethal systemic Aspergillus fumigatus infection in mice. AB - Using a nonlethal systemic Aspergillus fumigatus infection, we have recently shown that similarly efficient elimination of fungus from spleens of prototypic Th1 (C57BL/6) and prototypic Th2 (BALB/c) mice is associated with differential immune responses. In light of these data and given the disseminated character of infection, the aim of the present study is to explore whether there are also strain-dependent differences in antifungal responses in peripheral tissues of infected mice. Although similar efficiency of conidia removal was noted in liver and kidneys of both strains, BALB/c mice seemed more prone to tissue injury. Compared with other nonlymphoid organs, lungs proved immunologically the most responsive in systemic aspergillosis. Lower numbers of neutrophils and macrophages in the lungs of infected BALB/c mice, delayed and lower (compared with C57BL/6 mice) expression of their oxidative activity, along with late IFN gamma and upregulated IL-4 production by lung cells might be responsible for slower elimination of A. fumigatus from the lungs of this mouse strain. The data obtained imply that lungs should be viewed as mandatory organ in evaluation of immune-mediated antifungal potential of drugs in models of systemic/disseminated infection and that strain differences noted in tissue responses should be taken into account in these settings. PMID- 23030851 TI - Closed-loop liquid-vapor equilibrium in a one-component system. AB - We report Monte Carlo simulations that show a closed-loop liquid-vapor equilibrium in a pure substance. This finding has been achieved on a two dimensional lattice model for patchy particles that can form network fluids. We have considered related models with a slightly different patch distribution in order to understand the features of the distribution of patches on the surface of the particles that make possible the presence of the closed-loop liquid-vapor equilibrium, and its relation to the phase diagram containing so-called empty liquids. Finally we discuss the likelihood of finding the closed-loop liquid vapor equilibria on related models for three-dimensional models of patchy particles in the continuum, and speculate on the possible relationship between the mechanism behind the closed-loop liquid-vapor equilibrium of our simple lattice model and the salt-induced reentrant condensation found in complex systems. PMID- 23030852 TI - Criticality governed by the stable renormalization fixed point of the Ising model in the hierarchical small-world network. AB - We study the Ising model in a hierarchical small-world network by renormalization group analysis and find a phase transition between an ordered phase and a critical phase, which is driven by the coupling strength of the shortcut edges. Unlike ordinary phase transitions, which are related to unstable renormalization fixed points (FPs), the singularity in the ordered phase of the present model is governed by the FP that coincides with the stable FP of the ordered phase. The weak stability of the FP yields peculiar criticalities, including logarithmic behavior. On the other hand, the critical phase is related to a nontrivial FP, which depends on the coupling strength and is continuously connected to the ordered FP at the transition point. We show that this continuity indicates the existence of a finite correlation-length-like quantity inside the critical phase, which diverges upon approaching the transition point. PMID- 23030853 TI - Universality classes of transport in time-dependent random potentials. AB - The growth of the average kinetic energy of classical particles is studied for potentials that are random both in space and time. Such potentials are relevant for recent experiments in optics and in atom optics. It is found that for small velocities uniform acceleration takes place, and at a later stage fluctuations of the potential are encountered, resulting in a regime of anomalous diffusion. This regime was studied in the framework of the Fokker-Planck approximation. The diffusion coefficient in velocity was expressed in terms of the average power spectral density, which is the Fourier transform of the potential correlation function. This enabled to establish a scaling form for the Fokker-Planck equation and to compute the large and small velocity limits of the diffusion coefficient. A classification of the random potentials into universality classes, characterized by the form of the diffusion coefficient in the limit of large and small velocity, was performed. It was shown that one-dimensional systems exhibit a large variety of universality classes, contrary to systems in higher dimensions, where only one universality class is possible. The relation to Chirikov resonances, which are central in the theory of chaos, was demonstrated. The general theory was applied and numerically tested for specific physically relevant examples. PMID- 23030854 TI - Noninvasive measurement of dissipation in colloidal systems. AB - According to Harada and Sasa [Phys. Rev. Lett. 95, 130602 (2005)], heat production generated in a nonequilibrium steady state can be inferred from measuring response and correlation functions. In many colloidal systems, however, it is a nontrivial task to determine response functions, whereas details about spatial steady state trajectories are easily accessible. Using a simple conditional averaging procedure, we show how this fact can be exploited to reliably evaluate average heat production. We test this method using Brownian dynamics simulations, and apply it to experimental data of an interacting driven colloidal system. PMID- 23030855 TI - Dynamic scaling for anomalous transport in supercooled liquids. AB - The anomalous mesoscopic transport in supercooled liquids was investigated using three-dimensional molecular dynamics simulation. We show that the dynamic correlation length, xi, can be identified as a crossover length between the microscopic and macroscopic transports. We also find that in highly supercooled states, where a clear stress plateau is observed in the stress autocorrelation, cooperative transport, in both the (longitudinal) density diffusion and the (transverse) viscous relaxation, can be characterized by the single length scale, xi. The present identification of the dynamic correlation length has an advantage over other characterization methods in that it directly interprets the anomalous hydrodynamic transport in terms of the growing length scale. In the context of the present study, we provide a simple explanation for the long-standing problem of the breakdown of the Stokes-Einstein relation. PMID- 23030856 TI - Cooperative heterogeneous facilitation: multiple glassy states and glass-glass transition. AB - The formal structure of glass singularities in the mode-coupling theory (MCT) of supercooled liquids dynamics is closely related to that appearing in the analysis of heterogeneous bootstrap percolation on Bethe lattices, random graphs, and complex networks. Starting from this observation one can build up microscopic on lattice realizations of schematic MCT based on cooperative facilitated spin mixtures. I discuss a microscopic implementation of the F(13) schematic model including multiple glassy states and the glass-glass transition. Results suggest that our approach is flexible enough to bridge alternative theoretical descriptions of glassy matter based on the notions of quenched disorder and dynamic facilitation. PMID- 23030857 TI - +/-1/2 wedge disclinations stabilized by a sinusoidal boundary in a thin hybrid nematic liquid-crystal film. AB - As an interesting example of how geometry affects the formation of defects, we study the defect structures of a hybrid nematic liquid-crystal film in a wedge shaped cell made up of sinusoidal microwrinkles and an elastomer sheet. When the cell thickness is larger than a threshold value h(c), +1/2 and -1/2 disclinations are simultaneously stabilized along concave grooves and convex crests, respectively. A simple theoretical analysis gives a good estimate of h(c). The disclinations also show alternating optical rotations resulting from the curved boundary and liquid-crystal elastic anisotropy. PMID- 23030858 TI - Defect coalescence in spherical nematic shells. AB - We study coalescence of topological defects in nematic liquid crystals confined to spherical shells using both experiments and computer simulations. We observe that the four s=+1/2 defects that are present due to topological constraints imposed by the spherical geometry coalesce by pairs after changing the molecular orientation at the outer surface from tangential to perpendicular; the result is the formation of two single s=+1 defects. It is noteworthy that the speed of the coalescence process is peaked when the defects are at opposite points on the equator of the shell; this maximum results from the thickness inhomogeneity of the shells. PMID- 23030859 TI - Nucleation-induced transition to collective motion in active systems. AB - While the existence of polar ordered states in active systems is well established, the dynamics of the self-assembly processes are still elusive. We study a lattice gas model of self-propelled elongated particles interacting through excluded volume and alignment interactions, which shows a phase transition from an isotropic to a polar ordered state. By analyzing the ordering process we find that the transition is driven by the formation of a critical nucleation cluster and a subsequent coarsening process. Moreover, the time to establish a polar ordered state shows a power-law divergence. PMID- 23030860 TI - Convergence to equilibrium under a random Hamiltonian. AB - We analyze equilibration times of subsystems of a larger system under a random total Hamiltonian, in which the basis of the Hamiltonian is drawn from the Haar measure. We obtain that the time of equilibration is of the order of the inverse of the arithmetic average of the Bohr frequencies. To compute the average over a random basis, we compute the inverse of a matrix of overlaps of operators which permute four systems. We first obtain results on such a matrix for a representation of an arbitrary finite group and then apply it to the particular representation of the permutation group under consideration. PMID- 23030861 TI - Two-step condensation of the charged Bose gas. AB - The condensation of the spinless ideal charged Bose gas in the presence of a magnetic field is revisited. The conventional approach is extended to include the macroscopic occupation of excited kinetic states lying in the lowest Landau level, which plays an essential role in the case of large magnetic fields. In that limit, signatures of two diffuse phase transitions (crossovers) appear in the specific heat. In particular, at temperatures lower than the cyclotron frequency, the system behaves as an effectively one-dimensional free boson system, with the specific heat equal to 1/2Nk(B) and a gradual condensation at lower temperatures. PMID- 23030862 TI - Geometric theory for Weibull's distribution. AB - Weibull's distribution is the principal phenomenological law of relaxation in the physical sciences and spans three different relaxation regimes: subexponential ("stretched exponential"), exponential, and superexponential. The probabilistic theory of extreme-value statistics asserts that the linear scaling limits of minima of ensembles of positive-valued random variables, which are independent and identically distributed, are universally governed by Weibull's distribution. However, this probabilistic theory does not take into account spatial geometry, which often plays a key role in the physical sciences. In this paper we present a general and versatile model of random reactions in random environments and establish a geometry-based theory for the universal emergence of Weibull's distribution. PMID- 23030864 TI - Narrow-escape-time problem: the imperfect trapping case. AB - We present a master equation approach to the narrow escape time (NET) problem, i.e., the time needed for a particle contained in a confining domain with a single narrow opening to exit the domain for the first time. We introduce a finite transition probability, nu, at the narrow escape window, allowing the study of the imperfect trapping case. Ranging from 0 to infinity, nu allowed the study of both extremes of the trapping process: that of a highly deficient capture and situations where escape is certain ("perfect trapping" case). We have obtained analytic results for the basic quantity studied in the NET problem, the mean escape time, and we have studied its dependence in terms of the transition (desorption) probability over (from) the surface boundary, the confining domain dimensions, and the finite transition probability at the escape window. Particularly we show that the existence of a global minimum in the NET depends on the "imperfection" of the trapping process. In addition to our analytical approach, we have implemented Monte Carlo simulations, finding excellent agreement between the theoretical results and simulations. PMID- 23030863 TI - Stochastic noise in atomic force microscopy. AB - Having reached the quantum and thermodynamic limits of detection, atomic force microscopy (AFM) experiments are routinely being performed at the fundamental limit of signal to noise. A critical understanding of the statistical properties of noise leads to more accurate interpretation of data, optimization of experimental protocols, advancements in instrumentation, and new measurement techniques. Furthermore, accurate simulation of cantilever dynamics requires knowledge of stochastic behavior of the system, as stochastic noise may exceed the deterministic signals of interest, and even dominate the outcome of an experiment. In this article, the power spectral density (PSD), used to quantify stationary stochastic processes, is introduced in the context of a thorough noise analysis of the light source used to detect cantilever deflections. The statistical properties of PSDs are then outlined for various stationary, nonstationary, and deterministic noise sources in the context of AFM experiments. Following these developments, a method for integrating PSDs to provide an accurate standard deviation of linear measurements is described. Lastly, a method for simulating stochastic Gaussian noise from any arbitrary power spectral density is presented. The result demonstrates that mechanical vibrations of the AFM can cause a logarithmic velocity dependence of friction and induce multiple slip events in the atomic stick-slip process, as well as predicts an artifactual temperature dependence of friction measured by AFM. PMID- 23030865 TI - Fluctuations of current in nonstationary diffusive lattice gases. AB - We employ the macroscopic fluctuation theory to study fluctuations of integrated current in one-dimensional lattice gases with a steplike initial density profile. We analytically determine the variance of the current fluctuations for a class of diffusive processes with a density-independent diffusion coefficient. Our calculations rely on a perturbation theory around the noiseless hydrodynamic solution. We consider both quenched and annealed types of averaging (the initial condition is allowed to fluctuate in the latter situation). The general results for the variance are specialized to a few interesting models including the symmetric exclusion process and the Kipnis-Marchioro-Presutti model [Kipnis, Marchioro, and Presutti, J. Stat. Phys. 27, 65 (1982)]. We also probe large deviations of the current for the symmetric exclusion process. This is done by numerically solving the governing equations of the macroscopic fluctuation theory using an efficient iteration algorithm. PMID- 23030866 TI - Thermal conduction and interface effects in nanoscale Fermi-Pasta-Ulam conductors. AB - We perform classical nonequilibrium molecular dynamics simulations to calculate heat flow through a microscopic junction connecting two larger reservoirs. In contrast to earlier papers, we also include the reservoirs in the simulated region to study the effect of the bulk-nanostructure interfaces and the bulk conductance. The scalar Fermi-Pasta-Ulam (FPU) model is used to describe the effects of anharmonic interactions in a simple manner. The temperature profile close to the junction in the low-temperature limit is shown to exhibit strong directional features that fade out when temperature increases. Simulating both the FPU chain and the two bulk regions is also shown to eliminate the nonmonotonous temperature variations found for simpler geometries and models. We show that, with sufficiently large reservoirs, the temperature profile in the chain does not depend on the details of thermalization used at the boundaries. PMID- 23030867 TI - Generalized Hurst exponent and multifractal function of original and translated texts mapped into frequency and length time series. AB - A nonlinear dynamics approach can be used in order to quantify complexity in written texts. As a first step, a one-dimensional system is examined: two written texts by one author (Lewis Carroll) are considered, together with one translation into an artificial language (i.e., Esperanto) are mapped into time series. Their corresponding shuffled versions are used for obtaining a baseline. Two different one-dimensional time series are used here: one based on word lengths (LTS), the other on word frequencies (FTS). It is shown that the generalized Hurst exponent h(q) and the derived f(alpha) curves of the original and translated texts show marked differences. The original texts are far from giving a parabolic f(alpha) function, in contrast to the shuffled texts. Moreover, the Esperanto text has more extreme values. This suggests cascade model-like, with multiscale time asymmetric features as finally written texts. A discussion of the difference and complementarity of mapping into a LTS or FTS is presented. The FTS f(alpha) curves are more opened than the LTS ones. PMID- 23030868 TI - Paramagnetic and glass transitions in sudoku. AB - We study the statistical mechanics of a model glassy system based on sudoku, a familiar and popular mathematical puzzle. Sudoku puzzles provide a very rare example of a class of frustrated systems with a unique ground state without symmetry. Here, the puzzle is recast as a thermodynamic system where the number of violated rules defines the energy. We use Monte Carlo simulation to show that the "sudoku Hamiltonian" exhibits two transitions as a function of temperature, a paramagnetic, and a glass transition. Of these, the intermediate condensed phase is the only one that visits the ground state (i.e., it solves the puzzle, though this is not the purpose of the study). Both transitions are associated with an entropy change, paramagnetism measured from the dynamics of the Monte Carlo run, showing a peak in specific heat, while the residual glass entropy is determined by finding multiple instances of the glass by repeated annealing. There are relatively few such simple models for frustrated or glassy systems that exhibit both ordering and glass transitions; sudoku puzzles are unique for the ease with which they can be obtained, with the proof of the existence of a unique ground state via the satisfiability of all constraints. Simulations suggest that in the glass phase there is an increase in information entropy with lowering temperature. In fact, we have shown that sudoku puzzles have the type of rugged energy landscape with multiple minima that typifies glasses in many physical systems. This puzzling result is a manifestation of the paradox of the residual glass entropy. These readily available puzzles can now be used as solvable model Hamiltonian systems for studying the glass transition. PMID- 23030869 TI - Decay of unstable states driven by colored noise in an electromagnetic field. AB - The statistics of the first passage time in connection with the quasideterministic (QD) approach is used to characterize the non-Markovian decay process of the unstable state of an electrically charged Brownian particle under the influence of an electromagnetic field. We consider a constant magnetic field and a fluctuating electric field, which satisfies the properties of a Gaussian exponentially correlated noise. It is shown that at the beginning of the decay process, the magnetic field is strongly coupled to the noise correlation time and thus the requirements of the QD approach are not satisfied. Only in the approximation of a weak coupling between both parameters can the time characterization of the decay process be successfully achieved. Our theoretical approach relies on a Langevin equation for the charged particle in an arbitrary two-dimensional unstable potential and applies to a bistable potential as a particular case. PMID- 23030870 TI - Diffusion in a soft confining environment: dynamic effects of thermal fluctuations. AB - A dynamical model of a soft, thermally fluctuating two-dimensional tube is used to study the effect of thermal fluctuations of a confining environment on diffusive transport. The tube fluctuations in both space and time are driven by Brownian motion and suppressed by surface tension and the rigidity of the surrounding environment. The dynamical fluctuations modify the concentration profile boundary condition at the tube surface. They decrease the diffusive transport rate through the tube for two important cases: uniform tube fluctuations (wave vector, q=0 mode) for finite tube lengths and fluctuations of any wave vector for infinitely long tubes. PMID- 23030871 TI - Driving kinetically constrained models into nonequilibrium steady states: Structural and slow transport properties. AB - Complex fluids in shear flow and biased dynamics in crowded environments exhibit counterintuitive features which are difficult to address both at a theoretical level and by molecular dynamic simulations. To understand some of these features we study a schematic model of a highly viscous liquid, the two-dimensional Kob Andersen kinetically constrained model, driven into nonequilibrium steady states by a uniform non-Hamiltonian force. We present a detailed numerical analysis of the microscopic behavior of the model, including transversal and longitudinal spatial correlations and dynamic heterogeneities. In particular, we show that at high particle density the transition from positive to negative resistance regimes in the current vs field relation can be explained via the emergence of nontrivial structures that intermittently trap the particles and slow down the dynamics. We relate such spatial structures to the current vs field relation in the different transport regimes. PMID- 23030872 TI - Percolation transitions with nonlocal constraint. AB - We investigate percolation transitions in a nonlocal network model numerically. In this model, each node has an exclusive partner and a link is forbidden between two nodes whose r-neighbors share any exclusive pair. The r-neighbor of a node x is defined as a set of at most N(r) neighbors of x, where N is the total number of nodes. The parameter r controls the strength of a nonlocal effect. The system is found to undergo a percolation transition belonging to the mean-field universality class for r<1/2. On the other hand, for r>1/2, the system undergoes a peculiar phase transition from a nonpercolating phase to a quasicritical phase where the largest cluster size G scales as G~N(alpha) with alpha=0.74(1). In the marginal case with r=1/2, the model displays a percolation transition that does not belong to the mean-field universality class. PMID- 23030873 TI - 1/m expansion in spin glasses and the de Almeida-Thouless line. AB - It is shown by means of a 1/m expansion about the large-m limit of the m-vector spin glass that the value of the intercept of the de Almeida-Thouless line on the zero temperature axis h(AT) is proportional to T(c)(d), the zero-field transition temperature of the large-m model in d dimensions. Since numerical studies indicate that T(c)(d)=0 for d<=6, it follows that there should be no Almeida Thouless line for d<=6. PMID- 23030874 TI - Weighted correlation approach: an extended version with applications to the hard sphere fluid. AB - The purpose of this study is to extend the weighted correlation approach (WCA) for inhomogeneous fluids. It now introduces a generic expression to evaluate the single-particle direct correlation function in terms of a series of pair direct correlation functions weighted by different correlation-weight functions and adjustable weight factors. When applied for practical use, however, approximations of the pair direct correlation functions have to be made, together with appropriate definitions of the weighted densities and the choices of the correlation-weight functions. The WCA approach would, then, not only help us to connect and compare different strategies and their underlying assumptions in the density functional approaches, but also enable us to propose and apply density functional theory methods to predict the density profile of, e.g., the hard sphere fluid confined between a pair of parallel planar hard walls. Numerical results of the extended WCA approach, against the Monte Carlo (MC) simulations in a range of surface separations and bulk densities, suggest that it is capable of representing the fine features of the hard-sphere density distributions. The WCA results also agree well with the calculations from the fundamental measure theory. In addition, the thermodynamic self-consistency of the WCA approach is confirmed by its fairly good agreement with the MC fitted data for the surface tension of a hard-sphere fluid at a planar hard wall. All these tests show that a pure WCA approach can be constructed to investigate the states of ionic hard sphere fluids. PMID- 23030875 TI - Boolean decision problems with competing interactions on scale-free networks: critical thermodynamics. AB - We study the critical behavior of Boolean variables on scale-free networks with competing interactions (Ising spin glasses). Our analytical results for the disorder-network-decay-exponent phase diagram are verified using Monte Carlo simulations. When the probability of positive (ferromagnetic) and negative (antiferromagnetic) interactions is the same, the system undergoes a finite temperature spin-glass transition if the exponent that describes the decay of the interaction degree in the scale-free graph is strictly larger than 3. However, when the exponent is equal to or less than 3, a spin-glass phase is stable for all temperatures. The robustness of both the ferromagnetic and spin-glass phases suggests that Boolean decision problems on scale-free networks are quite stable to local perturbations. Finally, we show that for a given decay exponent spin glasses on scale-free networks seem to obey universality. Furthermore, when the decay exponent of the interaction degree is larger than 4 in the spin-glass sector, the universality class is the same as for the mean-field Sherrington Kirkpatrick Ising spin glass. PMID- 23030876 TI - Nonadiabatic entropy production for non-Markov dynamics. AB - We extend the definition of nonadiabatic entropy production given for Markovian systems by Esposito and Van den Broeck [Phys. Rev. Lett. 104, 090601 (2010)], to arbitrary non-Markov ergodic dynamics. We also introduce a notion of stability characterizing non-Markovianity. For stable non-Markovian systems, the nonadiabatic entropy production satisfies an integral fluctuation theorem, leading to the second law of thermodynamics for transitions between nonequilibrium steady states. This quantity can also be written as a sum of products of generalized fluxes and forces, thus being suitable for thermodynamics. On the other hand, the generalized fluctuation-dissipation relation also holds, clarifying that the conditions for it to be satisfied are ergodicity and stability instead of Markovianity. We show that in spite of being counterintuitive, the stability criterion introduced in this work may be violated in non-Markovian systems even if they are ergodic, leading to a violation of the fluctuation theorem and the generalized fluctuation-dissipation relation. Stability represents then a necessary condition for the above properties to hold and explains why the generalized fluctuation-dissipation relation has remained elusive in the study of non-Markov systems exhibiting nonequilibrium steady states. PMID- 23030877 TI - Structure of trajectories of complex-matrix eigenvalues in the Hermitian-non Hermitian transition. AB - The statistical properties of trajectories of eigenvalues of Gaussian complex matrices whose Hermitian condition is progressively broken are investigated. It is shown how the ordering on the real axis of the real eigenvalues is reflected in the structure of the trajectories and also in the final distribution of the eigenvalues in the complex plane. PMID- 23030878 TI - von Neummann's and related scaling laws in rock-paper-scissors-type games. AB - We introduce a family of rock-paper-scissors-type models with Z(N) symmetry (N is the number of species), and we show that it has a very rich structure with many completely different phases. We study realizations that lead to the formation of domains, where individuals of one or more species coexist, separated by interfaces whose (average) dynamics is curvature driven. This type of behavior, which might be relevant for the development of biological complexity, leads to an interface network evolution and pattern formation similar to the ones of several other nonlinear systems in condensed matter and cosmology. PMID- 23030879 TI - Impact of structured heterogeneities on reactive two-phase porous flow. AB - Two-phase flow through heterogeneous media leads to scale-free distributions of irregularly shaped pockets of one fluid trapped within the other. Although reactions within these fluids are often modeled at the homogeneous continuum scale, there exists no current framework for upscaling from the pore scale that accounts for the complex and scale-free geometry of the bubbles. In this paper, we apply a linear-kinetics reaction-diffusion model to characterize the steady state chemical environment inside the irregular pockets. Using a combination of theory and invasion-percolation simulations, we derive scaling laws describing the distribution of diffusion times within bubbles. We show that chemical concentrations within the bubbles are determined by the Laplace transform of the entire distribution of diffusion times from each location. This serves as a means to compute average concentrations of reactant within a bubble of unique geometry and size. Furthermore, the overall system size imposes upper bounds on the distribution of bubble sizes, thereby imposing a system-size dependence on the statistics and average concentrations. These conclusions have profound implications for continuum models of porous reactive flow, where kinetic and equilibrium parameters are often chosen from laboratory measurements made at centimeter scales. PMID- 23030880 TI - Dynamical heterogeneities as fingerprints of a backbone structure in Potts models. AB - We investigate slow nonequilibrium dynamical processes in a two-dimensional q state Potts model with both ferromagnetic and +/-J couplings. Dynamical properties are characterized by means of the mean-flipping time distribution. This quantity is known for clearly unveiling dynamical heterogeneities. Using a two-times protocol we characterize the different time scales observed and relate them to growth processes occurring in the system. In particular we target the possible relation between the different time scales and the spatial heterogeneities originated in the ground-state topology, which are associated to the presence of a backbone structure. We perform numerical simulations using an approach based on graphis processing units (GPUs) which permits us to reach large system sizes. We present evidence supporting both the idea of a growing process in the preasymptotic regime of the glassy phases and the existence of a backbone structure behind this process. PMID- 23030881 TI - Matrix-valued Boltzmann equation for the Hubbard chain. AB - We study, both analytically and numerically, the Boltzmann transport equation for the Hubbard chain with nearest-neighbor hopping and spatially homogeneous initial condition. The time-dependent Wigner function is matrix-valued because of spin. The H theorem holds. The nearest-neighbor chain is integrable, which, on the kinetic level, is reflected by infinitely many additional conservation laws and linked to the fact that there are also nonthermal stationary states. We characterize all stationary solutions. Numerically, we observe an exponentially fast convergence to stationarity and investigate the convergence rate in dependence on the initial conditions. PMID- 23030882 TI - Single-file diffusion in periodic energy landscapes: the role of hydrodynamic interactions. AB - We report on the dynamical properties of interacting colloids confined to one dimension and subjected to external periodic energy landscapes. We particularly focus on the influence of hydrodynamic interactions on the mean-square displacement. Using Brownian dynamics simulations, we study colloidal systems with two types of repulsive interparticle interactions, namely, Yukawa and superparamagnetic potentials. We find that in the homogeneous case, hydrodynamic interactions lead to an enhancement of the particle mobility and the mean-square displacement at long times scales as t(alpha), with alpha=1/2+epsilon and epsilon being a small correction. This correction, however, becomes much more important in the presence of an external field, which breaks the homogeneity of the particle distribution along the line and, therefore, promotes a richer dynamical scenario due to the hydrodynamical coupling among particles. We provide here the complete dynamical scenario in terms of the external potential parameters: amplitude and commensurability. PMID- 23030883 TI - Two-dimensional lattice liquid models. AB - A family of models of liquid on a two-dimensional lattice (2D lattice liquid models) have been proposed as primitive models of soft-material membrane. As a first step, we have formulated them as single-component, single-layered, classical particle systems on a two-dimensional surface with no explicit viscosity. Among the family of the models, we have shown and constructed two stochastic models, a vicious walk model and a flow model, on an isotropic regular lattice and on some honeycomb lattices of various sizes. In both cases, the dynamics is governed by the nature of the frustration of the particle movements. By simulations, we have found the approximate functional form of the frustration probability and peculiar anomalous diffusions in their time-averaged mean-square displacements in the flow model. The relations to other existing statistical models and possible extensions of the models are also discussed. PMID- 23030884 TI - Scattering lengths and universality in superdiffusive Levy materials. AB - We study the effects of scattering lengths on Levy walks in quenched, one dimensional random and fractal quasilattices, with scatterers spaced according to a long-tailed distribution. By analyzing the scaling properties of the random walk probability distribution, we show that the effect of the varying scattering length can be reabsorbed in the multiplicative coefficient of the scaling length. This leads to a superscaling behavior, where the dy-namical exponents and also the scaling functions do not depend on the value of the scattering length. Within the scaling framework, we obtain an exact expression for the multiplicative coefficient as a function of the scattering length both in the annealed and in the quenched random and fractal cases. Our analytic results are compared with numerical simulations, with excellent agreement, and are supposed to hold also in higher dimensions. PMID- 23030885 TI - Stochastic analysis of complex reaction networks using binomial moment equations. AB - The stochastic analysis of complex reaction networks is a difficult problem because the number of microscopic states in such systems increases exponentially with the number of reactive species. Direct integration of the master equation is thus infeasible and is most often replaced by Monte Carlo simulations. While Monte Carlo simulations are a highly effective tool, equation-based formulations are more amenable to analytical treatment and may provide deeper insight into the dynamics of the network. Here, we present a highly efficient equation-based method for the analysis of stochastic reaction networks. The method is based on the recently introduced binomial moment equations [Barzel and Biham, Phys. Rev. Lett. 106, 150602 (2011)]. The binomial moments are linear combinations of the ordinary moments of the probability distribution function of the population sizes of the interacting species. They capture the essential combinatorics of the reaction processes reflecting their stoichiometric structure. This leads to a simple and transparent form of the equations, and allows a highly efficient and surprisingly simple truncation scheme. Unlike ordinary moment equations, in which the inclusion of high order moments is prohibitively complicated, the binomial moment equations can be easily constructed up to any desired order. The result is a set of equations that enables the stochastic analysis of complex reaction networks under a broad range of conditions. The number of equations is dramatically reduced from the exponential proliferation of the master equation to a polynomial (and often quadratic) dependence on the number of reactive species in the binomial moment equations. The aim of this paper is twofold: to present a complete derivation of the binomial moment equations; to demonstrate the applicability of the moment equations for a representative set of example networks, in which stochastic effects play an important role. PMID- 23030886 TI - Demonstration of Jarzynski's equality in open quantum systems using a stepwise pulling protocol. AB - We present a generalization of Jarzynski's equality, applicable to quantum systems, that is related to discretized mechanical work and free-energy changes. The theory is based on a stepwise pulling protocol. We find that work distribution functions can be constructed from fluctuations of a reaction coordinate along a reaction pathway in the stepwise pulling protocol. We also propose two sets of equations to determine the two possible optimal pathways that provide the most significant contributions to free-energy changes. We find that the transitions along these most optimal pathways, satisfying both sets of equations, follow the principle of detailed balance. We then test the theory by explicitly computing the free-energy changes for a one-dimensional quantum harmonic oscillator. This approach suggests a feasible way of measuring the fluctuations to experimentally test Jarzynski's equality in many-body systems, such as Bose-Einstein condensates. PMID- 23030887 TI - Diffusive and subdiffusive dynamics of indoor microclimate: a time series modeling. AB - The indoor microclimate is an issue in modern society, where people spend about 90% of their time indoors. Temperature and relative humidity are commonly used for its evaluation. In this context, the two parameters are usually considered as behaving in the same manner, just inversely correlated. This opinion comes from observation of the deterministic components of temperature and humidity time series. We focus on the dynamics and the dependency structure of the time series of these parameters, without deterministic components. Here we apply the mean square displacement, the autoregressive integrated moving average (ARIMA), and the methodology for studying anomalous diffusion. The analyzed data originated from five monitoring locations inside a modern office building, covering a period of nearly one week. It was found that the temperature data exhibited a transition between diffusive and subdiffusive behavior, when the building occupancy pattern changed from the weekday to the weekend pattern. At the same time the relative humidity consistently showed diffusive character. Also the structures of the dependencies of the temperature and humidity data sets were different, as shown by the different structures of the ARIMA models which were found appropriate. In the space domain, the dynamics and dependency structure of the particular parameter were preserved. This work proposes an approach to describe the very complex conditions of indoor air and it contributes to the improvement of the representative character of microclimate monitoring. PMID- 23030888 TI - Depinning phase transition in the two-dimensional clock model with quenched randomness. AB - With Monte Carlo simulations, we systematically investigate the depinning phase transition in the two-dimensional driven random-field clock model. Based on the short-time dynamic approach, we determine the transition field and critical exponents. The results show that the critical exponents vary with the form of the random-field distribution and the strength of the random fields, and the roughening dynamics of the domain interface belongs to the new subclass with zeta?zeta(loc)?zeta(s) and zeta(loc)?1. More importantly, we find that the transition field and critical exponents change with the initial orientations of the magnetization of the two ordered domains. PMID- 23030889 TI - Ab initio simulation of transport phenomena in rarefied gases. AB - Ab initio potentials are implemented into the direct simulation Monte Carlo (DSMC) method. Such an implementation allows us to model transport phenomena in rarefied gases without any fitting parameter of intermolecular collisions usually extracted from experimental data. Applying the method proposed by Sharipov and Strapasson [Phys. Fluids 24, 011703 (2012)], the use of ab initio potentials in the DSMC requires the same computational efforts as the widely used potentials such as hard spheres, variable hard sphere, variable soft spheres, etc. At the same time, the ab initio potentials provide more reliable results than any other one. As an example, the transport coefficients of a binary mixture He-Ar, viz., viscosity, thermal conductivity, and thermal diffusion factor, have been calculated for several values of the mole fraction. PMID- 23030890 TI - Effect of external fields in Axelrod's model of social dynamics. AB - The study of the effects of spatially uniform fields on the steady-state properties of Axelrod's model has yielded plenty of counterintuitive results. Here, we reexamine the impact of this type of field for a selection of parameters such that the field-free steady state of the model is heterogeneous or multicultural. Analyses of both one- and two-dimensional versions of Axelrod's model indicate that the steady state remains heterogeneous regardless of the value of the field strength. Turning on the field leads to a discontinuous decrease on the number of cultural domains, which we argue is due to the instability of zero-field heterogeneous absorbing configurations. We find, however, that spatially nonuniform fields that implement a consensus rule among the neighborhood of the agents enforce homogenization. Although the overall effects of the fields are essentially the same irrespective of the dimensionality of the model, we argue that the dimensionality has a significant impact on the stability of the field-free homogeneous steady state. PMID- 23030891 TI - Role of the on-site pinning potential in establishing quasi-steady-state conditions of heat transport in finite quantum systems. AB - We study the transport of energy in a finite linear harmonic chain by solving the Heisenberg equation of motion, as well as by using nonequilibrium Green's functions to verify our results. The initial state of the system consists of two separate and finite linear chains that are in their respective equilibriums at different temperatures. The chains are then abruptly attached to form a composite chain. The time evolution of the current from just after switch-on to the transient regime and then to later times is determined numerically. We expect the current to approach a steady-state value at later times. Surprisingly, this is possible only if a nonzero quadratic on-site pinning potential is applied to each particle in the chain. If there is no on-site potential a recurrent phenomenon appears when the time scale is longer than the traveling time of sound to make a round trip from the midpoint to a chain edge and then back. Analytic expressions for the transient and steady-state currents are derived to further elucidate the role of the on-site potential. PMID- 23030892 TI - Conditions under which a superdiffusive random-search strategy is necessary. AB - Intuitively, lower target densities and lower detection capabilities should demand more sophisticated search strategies for a random search reasonable outcome. In contrast, when targets are easily found, a simple Brownian random walk strategy is enough. But where is the threshold between these two scenarios and when is optimization really necessary? We address this considering the interplay between two essential scales in random search, the average distance between neighbor targets l(0) and the detection capability r(v). In the limit cases the ratio beta=r(v)/l(0) suffices to characterize the problem. For low (high) beta a superdiffusive behavior is (is not) crucial for the process optimization. However, there is a crossover range, which is a nontrivial function of r(v) and l(0), separating the two regimes. We analyze this intermediate region, common in nature, and discuss the often overlooked important trade between resources availability and the searcher location power. Our results highlight contexts where efficient random search is a key factor for survival, such as in animal foraging. PMID- 23030893 TI - Nonlinear driven diffusive systems with dissipation: fluctuating hydrodynamics. AB - We consider a general class of nonlinear diffusive models with bulk dissipation and boundary driving and derive its hydrodynamic description in the large size limit. Both the average macroscopic behavior and the fluctuating properties of the hydrodynamic fields are obtained from the microscopic dynamics. This analysis yields a fluctuating balance equation for the local energy density at the mesoscopic level, characterized by two terms: (i) a diffusive term, with a current that fluctuates around its average behavior given by nonlinear Fourier's law, and (ii) a dissipation term which is a general function of the local energy density. The quasielasticity of microscopic dynamics, required in order to have a nontrivial competition between diffusion and dissipation in the macroscopic limit, implies a noiseless dissipation term in the balance equation, so dissipation fluctuations are enslaved to those of the density field. The microscopic complexity is thus condensed in just three transport coefficients-the diffusivity, the mobility, and a new dissipation coefficient-which are explicitly calculated within a local equilibrium approximation. Interestingly, the diffusivity and mobility coefficients obey an Einstein relation despite the fully nonequilibrium character of the problem. The general theory here presented is applied to a particular albeit broad family of systems, the simplest nonlinear dissipative variant of the so-called KMP model for heat transport. The theoretical predictions are compared to extensive numerical simulations, and an excellent agreement is found. PMID- 23030894 TI - High-activity perturbation expansion for the hard square lattice gas. AB - We study a system of particles with nearest- and next-nearest-neighbor exclusion on the square lattice (hard squares). This system undergoes a transition from a fluid phase at low density to a columnar-ordered phase at high density. We develop a systematic high-activity perturbation expansion for the free energy per site about a state with perfect columnar order. We show that the different terms of the series can be regrouped to get a Mayer-like series for a polydisperse system of interacting vertical rods in which the nth term is of order z( (n+1)/2), where z is the fugacity associated with each particle. We sum this series to get the exact expansion to order 1/z(3/2). PMID- 23030895 TI - Moments of action provide insight into critical times for advection-diffusion reaction processes. AB - Berezhkovskii and co-workers introduced the concept of local accumulation time as a finite measure of the time required for the transient solution of a reaction diffusion equation to effectively reach steady state [Biophys J. 99, L59 (2010); Phys. Rev. E 83, 051906 (2011)]. Berezhkovskii's approach is a particular application of the concept of mean action time (MAT) that was introduced previously by McNabb [IMA J. Appl. Math. 47, 193 (1991)]. Here, we generalize these previous results by presenting a framework to calculate the MAT, as well as the higher moments, which we call the moments of action. The second moment is the variance of action time, the third moment is related to the skew of action time, and so on. We consider a general transition from some initial condition to an associated steady state for a one-dimensional linear advection-diffusion-reaction partial differential equation (PDE). Our results indicate that it is possible to solve for the moments of action exactly without requiring the transient solution of the PDE. We present specific examples that highlight potential weaknesses of previous studies that have considered the MAT alone without considering higher moments. Finally, we also provide a meaningful interpretation of the moments of action by presenting simulation results from a discrete random-walk model together with some analysis of the particle lifetime distribution. This work shows that the moments of action are identical to the moments of the particle lifetime distribution for certain transitions. PMID- 23030896 TI - Information geometry and quantum phase transitions in the Dicke model. AB - We study information geometry of the Dicke model, in the thermodynamic limit. The scalar curvature R of the Riemannian metric tensor induced on the parameter space of the model is calculated. We analyze this both with and without the rotating wave approximation, and show that the parameter manifold is smooth even at the phase transition, and that the scalar curvature is continuous across the phase boundary. PMID- 23030897 TI - Heat conduction in systems with Kolmogorov-Arnold-Moser phase space structure. AB - We study heat conduction in a billiard channel formed by two sinusoidal walls and the diffusion of particles in the corresponding channel of infinite length; the latter system has an infinite horizon, i.e., a particle can travel an arbitrary distance without colliding with the rippled walls. For small ripple amplitudes, the dynamics of the heat carriers is regular and analytical results for the temperature profile and heat flux are obtained using an effective potential. The study also proposes a formula for the temperature profile that is valid for any ripple amplitude. When the dynamics is regular, ballistic conductance and ballistic diffusion are present. The Poincare plots of the associated dynamical system (the infinitely long channel) exhibit the generic transition to chaos as ripple amplitude is increased. When no Kolmogorov-Arnold-Moser (KAM) curves are present to forbid the connection of all chaotic regions, the mean square displacement grows asymptotically with time t as tln(t). PMID- 23030898 TI - Unusual shock wave in two-species driven systems with an umbilic point. AB - Using dynamical Monte Carlo simulations we observe the occurrence of an unexpected shock wave in driven diffusive systems with two conserved species of particles. This U shock is microscopically sharp, but does not satisfy the usual criteria for the stability of shocks. Exact analysis of the large-scale hydrodynamic equations of motion reveals the presence of an umbilical point which we show to be responsible for this phenomenon. We prove that such an umbilical point is a general feature of multispecies driven diffusive systems with reflection symmetry of the bulk dynamics. We argue that a U shock will occur whenever there are strong interactions between species such that the current density relation develops a double well and the umbilical point becomes isolated. PMID- 23030899 TI - Social climber attachment in forming networks produces a phase transition in a measure of connectivity. AB - The formation and fragmentation of networks are typically studied using percolation theory, but most previous research has been restricted to studying a phase transition in cluster size, examining the emergence of a giant component. This approach does not study the effects of evolving network structure on dynamics that occur at the nodes, such as the synchronization of oscillators and the spread of information, epidemics, and neuronal excitations. We introduce and analyze an alternative link-formation rule, called social climber (SC) attachment, that may be combined with arbitrary percolation models to produce a phase transition using the largest eigenvalue of the network adjacency matrix as the order parameter. This eigenvalue is significant in the analyses of many network-coupled dynamical systems in which it measures the quality of global coupling and is hence a natural measure of connectivity. We highlight the important self-organized properties of SC attachment and discuss implications for controlling dynamics on networks. PMID- 23030900 TI - Referring to the social performance promotes cooperation in spatial prisoner's dilemma games. AB - We propose a new pairwise Fermi updating rule by considering a social average payoff when an agent copies a neighbor's strategy. In the update rule, a focal agent compares her payoff with the social average payoff of the same strategy that her pairwise opponent has. This concept might be justified by the fact that people reference global and, somehow, statistical information, not local information when imitating social behaviors. We presume several possible ways for the social average. Simulation results prove that the social average of some limited agents realizes more significant cooperation than that of the entire population. PMID- 23030901 TI - Fast fixation with a generic network structure. AB - We investigate the dynamics of a broad class of stochastic copying processes on a network that includes examples from population genetics (spatially structured Wright-Fisher models), ecology (Hubbell-type models), linguistics (the utterance selection model), and opinion dynamics (the voter model) as special cases. These models all have absorbing states of fixation where all the nodes are in the same state. Earlier studies of these models showed that the mean time when this occurs can be made to grow as different powers of the network size by varying the degree distribution of the network. Here we demonstrate that this effect can also arise if one varies the asymmetry of the copying dynamics while holding the degree distribution constant. In particular, we show that the mean time to fixation can be accelerated even on homogeneous networks when certain nodes are very much more likely to be copied from than copied to. We further show that there is a complex interplay between degree distribution and asymmetry when they may covary, and that the results are robust to correlations in the network or the initial condition. PMID- 23030902 TI - First passages in bounded domains: when is the mean first passage time meaningful? AB - We study the first passage statistics to adsorbing boundaries of a Brownian motion in bounded two-dimensional domains of different shapes and configurations of the adsorbing and reflecting boundaries. From extensive numerical analysis we obtain the probability P(omega) distribution of the random variable omega=tau(1)/(tau(1)+tau(2)), which is a measure for how similar the first passage times tau(1) and tau(2) are of two independent realizations of a Brownian walk starting at the same location. We construct a chart for each domain, determining whether P(omega) represents a unimodal, bell-shaped form, or a bimodal, M-shaped behavior. While in the former case the mean first passage time (MFPT) is a valid characteristic of the first passage behavior, in the latter case it is an insufficient measure for the process. Strikingly we find a distinct turnover between the two modes of P(omega), characteristic for the domain shape and the respective location of absorbing and reflective boundaries. Our results demonstrate that large fluctuations of the first passage times may occur frequently in two-dimensional domains, rendering quite vague the general use of the MFPT as a robust measure of the actual behavior even in bounded domains, in which all moments of the first passage distribution exist. PMID- 23030903 TI - Finite-temperature and finite-time scaling of the directed polymer free energy with respect to its geometrical fluctuations. AB - We study the fluctuations of the directed polymer in 1+1 dimensions in a Gaussian random environment with a finite correlation length xi and at finite temperature. We address the correspondence between the geometrical transverse fluctuations of the directed polymer, described by its roughness, and the fluctuations of its free energy, characterized by its two-point correlator. Analytical arguments are provided in favor of a generic scaling law between those quantities, at finite time, nonvanishing xi, and explicit temperature dependence. Numerical results are in good agreement both for simulations on the discrete directed polymer and on a continuous directed polymer (with short-range correlated disorder). Applications to recent experiments on liquid crystals are discussed. PMID- 23030904 TI - Large rare fluctuations in systems with delayed dissipation. AB - We study the probability distribution and the escape rate in systems with delayed dissipation that comes from the coupling to a thermal bath. To logarithmic accuracy in the fluctuation intensity, the problem is reduced to a variational problem. It describes the most probable fluctuational paths, which are given by acausal equations due to the delay. In thermal equilibrium, the most probable path passing through a remote state has time-reversal symmetry, even though one cannot uniquely define a path that starts from a state with given system coordinate and momentum. The corrections to the distribution and the escape activation energy for small delay and small noise correlation time are obtained in explicit form. PMID- 23030905 TI - Balance between absorbing and positive fixed points in resource consumption models. AB - The effect of resource usage on economic growth has been studied in multiple models. However, the generic effect of improving resource usage efficacy through improved technical skills has not been studied in detail. We here analyze a model incorporating resource usage by capital and the parallel production of technical skill in order to study the effect of improving the efficacy of resources usage with advanced technologies. We show that a practically inevitable result of such a model is that improving the resource usage efficacy leads to a lower steady state level of resources. A surprising conclusion from ordinary differential equations realization of the model is an extreme sensitivity to parameters, where a small parameter change can lead to an irreversible state through a hysteresis mechanism between a scenario of a collapse of the economy and a scenario of sustainable economy. This sensitivity is lost when spatial stochastic simulations are performed. In the stochastic regime the two scenarios coexist, with different fractions of the lattice residing in each state. Changing parameters smoothly changes the fraction of lattice sites in each state. The transition between the collapsed economy and the sustainable one is not symmetrical. Escape from the collapsed situation can only occur through diffusion from neighboring sustained lattice sites. On the other hand, the collapse can occur even in the absence of diffusion. This difference leads to diffusion dependent capital growth, where an optimal capital is obtained for middiffusion values. Such a transition may actually be generic phenomena in ecological and economic systems. PMID- 23030906 TI - Flow-induced shear instabilities of cohesive granulates. AB - In this work we use a multiscale framework to calculate the fluidization threshold of three-dimensional cohesive granulates under shear forces exerted by a creeping flow. A continuum model of flow through porous media provides an analytical expression for the average drag force on a single grain. The balance equation for the forces and a force propagation model are then used to investigate the effects of porosity and packing structure on the stability of the pile. We obtain a closed-form expression for the instability threshold of a regular packing of monodisperse frictionless cohesive spherical grains in a planar fracture. Our result quantifies the compound effect of structural (packing orientation and porosity) and dynamical properties of the system on its stability. PMID- 23030907 TI - Maximally dense packings of two-dimensional convex and concave noncircular particles. AB - Dense packings of hard particles have important applications in many fields, including condensed matter physics, discrete geometry, and cell biology. In this paper, we employ a stochastic search implementation of the Torquato-Jiao adaptive shrinking-cell (ASC) optimization scheme [Nature (London) 460, 876 (2009)] to find maximally dense particle packings in d-dimensional Euclidean space R(d). While the original implementation was designed to study spheres and convex polyhedra in d>=3, our implementation focuses on d=2 and extends the algorithm to include both concave polygons and certain complex convex or concave nonpolygonal particle shapes. We verify the robustness of this packing protocol by successfully reproducing the known putative optimal packings of congruent copies of regular pentagons and octagons, then employ it to suggest dense packing arrangements of congruent copies of certain families of concave crosses, convex and concave curved triangles (incorporating shapes resembling the Mercedes-Benz logo), and "moonlike" shapes. Analytical constructions are determined subsequently to obtain the densest known packings of these particle shapes. For the examples considered, we find that the densest packings of both convex and concave particles with central symmetry are achieved by their corresponding optimal Bravais lattice packings; for particles lacking central symmetry, the densest packings obtained are nonlattice periodic packings, which are consistent with recently-proposed general organizing principles for hard particles. Moreover, we find that the densest known packings of certain curved triangles are periodic with a four-particle basis, and we find that the densest known periodic packings of certain moonlike shapes possess no inherent symmetries. Our work adds to the growing evidence that particle shape can be used as a tuning parameter to achieve a diversity of packing structures. PMID- 23030908 TI - Discrete simulation of dense flows of polyhedral grains down a rough inclined plane. AB - The influence of grain angularity on the properties of dense flows down a rough inclined plane are investigated. Three-dimensional numerical simulations using the nonsmooth contact dynamics method are carried out with both spherical (rounded) and polyhedral (angular) grain assemblies. Both sphere and polyhedra assemblies abide by the flow start and stop laws, although much higher tilt angle values are required to trigger polyhedral grain flow. In the dense permanent flow regime, both systems show similarities in the bulk of the material (away from the top free surface and the substrate), such as uniform values of the solid fraction, inertial number and coordination number, or linear dependency of the solid fraction and effective friction coefficient with the inertial number. However, discrepancies are also observed between spherical and polyhedral particle flows. A dead (or nearly arrested) zone appears in polyhedral grain flows close to the rough bottom surface, reflected by locally concave velocity profiles, locally larger coordination number and solid fraction values, smaller inertial number values. This dead zone disappears for smooth bottom surfaces. In addition, unlike sphere assemblies, polyhedral grain assemblies exhibit significant normal stress differences, which increase close to the substrate. PMID- 23030909 TI - Internal energy fluctuations of a granular gas under steady uniform shear flow. AB - The stochastic properties of the total internal energy of a dilute granular gas in the steady uniform shear flow state are investigated. A recent theory formulated for fluctuations about the homogeneous cooling state is extended by analogy with molecular systems. The theoretical predictions are compared with molecular dynamics simulation results. Good agreement is found in the limit of weak inelasticity, while systematic and relevant discrepancies are observed when the inelasticity increases. The origin of this behavior is discussed. PMID- 23030910 TI - Effects of weak disorder on stress-wave anisotropy in centered square nonlinear granular crystals. AB - The present study describes wave propagation characteristics in a weakly disordered two-dimensional granular media composed of a square array of spheres accommodating interstitial cylindrical intruders. Previous investigations, performed experimentally as well as numerically, emphasized that wave-front shapes in similar systems are tunable via choice of material combinations. Here, we investigate the effects of statistical variation in the particle diameters and compare the effects of the resulting disorder in experiments and numerical simulations, finding good agreement. PMID- 23030911 TI - Flow and clogging in a silo with an obstacle above the orifice. AB - In a recent paper [Zuriguel et al., Phys. Rev. Lett. 107, 278001 (2011)] it has been shown that the presence of an obstacle above the outlet can significatively reduce the clogging probability of granular matter pouring from a silo. The amount of this reduction strongly depends on the obstacle position. In this work, we present new measurements to analyze different outlet sizes, extending foregoing results and revealing that the effect of the obstacle is enhanced as the outlet size is increased. In addition, the effect of the obstacle position on the flow rate properties and in the geometrical features of arches is studied. These results reinforce previous evidence of the pressure reduction induced by the obstacle. In addition, it is shown how the mean avalanche size and the average flow rate are not necessarily linked. On the other hand, a close relationship is suggested between the mean avalanche size and the flow rate fluctuations. PMID- 23030912 TI - Shape effects on the random-packing density of tetrahedral particles. AB - Regular tetrahedra have been demonstrated recently giving high packing density in random configurations. However, it is unknown whether the random-packing density of tetrahedral particles with other shapes can reach an even higher value. A numerical investigation on the random packing of regular and irregular tetrahedral particles is carried out. Shape effects of rounded corner, eccentricity, and height on the packing density of tetrahedral particles are studied. Results show that altering the shape of tetrahedral particles by rounding corners and edges, by altering the height of one vertex, or by lateral displacement of one vertex above its opposite face, all individually have the effect of reducing the random-packing density. In general, the random-packing densities of irregular tetrahedral particles are lower than that of regular tetrahedra. The ideal regular tetrahedron should be the shape which has the highest random-packing density in the family of tetrahedra, or even among convex bodies. An empirical formula is proposed to describe the rounded corner effect on the packing density, and well explains the density deviation of tetrahedral particles with different roundness ratios. The particles in the simulations are verified to be randomly packed by studying the pair correlation functions, which are consistent with previous results. The spherotetrahedral particle model with the relaxation algorithm is effectively applied in the simulations. PMID- 23030913 TI - Stability, deformation, and variability of granular fills composed of polyhedral particles. AB - By means of extensive contact dynamics simulations, we investigate the mechanical equilibrium and deformation of a granular material composed of irregular polyhedral particles confined between two horizontal frictional planes. We show that, as a consequence of mobilized wall-particle friction forces at the top and bottom boundaries, the transient deformation induced by a constant vertical load is controlled by the aspect ratio (thickness over width) of the packing as well as the stress ratio. The transient deformation declines considerably for increasingly smaller aspect ratios and grows with the stress ratio. From the simulation data for a large number of independent configurations, we find that sample-to-sample fluctuations of the deformation have a broad distribution and they scale with the average deformation. We also analyze the evolution of particle connectivity during settlement and with the applied force. The face-face and edge-face contacts between polyhedral particles concentrate strong force chains with a growing proportion as a function of the applied force. PMID- 23030914 TI - Dynamical configurations and bistability of helical nanostructures under external torque. AB - We study the motion of a ferromagnetic helical nanostructure under the action of a rotating magnetic field. A variety of dynamical configurations were observed that depended strongly on the direction of magnetization and the geometrical parameters, which were also confirmed by a theoretical model, based on the dynamics of a rigid body under Stokes flow. Although motion at low Reynolds numbers is typically deterministic, under certain experimental conditions the nanostructures showed a surprising bistable behavior, such that the dynamics switched randomly between two configurations, possibly induced by thermal fluctuations. The experimental observations and the theoretical results presented in this paper are general enough to be applicable to any system of ellipsoidal symmetry under external force or torque. PMID- 23030915 TI - Amorphous to amorphous transition in particle rafts. AB - Space-filling assemblies of athermal hydrophobic particles floating at an air water interface, called particle rafts, are shown to undergo an unusual phase transition between two amorphous states, i.e., a low density "less-rigid" state and a high density "more-rigid" state, as a function of particulate number density (Phi). The former is shown to be a capillary bridged solid and the latter is shown to be a frictionally coupled one. Simultaneous studies involving direct imaging as well as measuring its mechanical response to longitudinal and shear stresses show that the transition is marked by a subtle structural anomaly and a weakening of the shear response. The structural anomaly is identified from the variation of the mean coordination number, mean area of the Voronoi cells, and spatial profile of the displacement field with Phi. The weakened shear response is related to local plastic instabilities caused by the depinning of the contact line of the underlying fluid on the rough surfaces of the particles. PMID- 23030916 TI - Structural responses of quasi-two-dimensional colloidal fluids to excitations elicited by nonequilibrium perturbations. AB - We investigate the response of a dense monodisperse quasi-two-dimensional colloid suspension when a particle is dragged by a constant velocity optical trap. Consistent with microrheological studies of other geometries, the perturbation induces a leading density wave and trailing wake. We also use a hybrid version of Stokesian dynamics simulations to parse direct colloid-colloid and hydrodynamic interactions. We go on to analyze the underlying individual particle-particle collisions in the experimental images. The displacements of particles occur in chains reminiscent of stress propagation in sheared granular materials. From these data, we can reconstruct steady-state dipolar-like flow patterns that were predicted for dilute suspensions and previously observed in granular analogs to our system. The decay of this field differs, however, from point Stokeslet calculations, indicating that the nonzero size of the colloids is important. Moreover, there is a pronounced angular dependence that corresponds to the surrounding colloid structure, which develops in response to the perturbation. Put together, our results show that the response of the complex fluid is highly anisotropic owing to the fact that the effects of the perturbation propagate through the structured medium via chains of colloid-colloid collisions. PMID- 23030917 TI - Scaling of volumetric data in model systems based on the Lennard-Jones potential. AB - The crucial problem for better understanding the nature of glass transition and related relaxation phenomena is to find proper interrelations between the molecular dynamics and thermodynamics of viscous systems. To make progress towards this goal the recently observed density scaling of viscous liquid dynamics has been very intensively and successfully studied in the past few years. However, previous attempts at related scaling of volumetric data yielded results inconsistent with those found from the density scaling of molecular dynamics. In this paper, we show that volumetric data obtained from simulations in simple molecular models based on the Lennard-Jones (LJ) potential, such as the Kob-Andersen binary LJ liquid, its repulsive inverse power-law version, and the Lewis-Wahnstrom o-terphenyl model, can be scaled by using the same value of the exponent, which scales dynamic quantities and is directly related to the exponent of the repulsive inverse power law that underlies short-range approximations of the LJ potential. PMID- 23030918 TI - Finite-size effects in the dynamics of glass-forming liquids. AB - We present a comprehensive theoretical study of finite-size effects in the relaxation dynamics of glass-forming liquids. Our analysis is motivated by recent theoretical progress regarding the understanding of relevant correlation length scales in liquids approaching the glass transition. We obtain predictions both from general theoretical arguments and from a variety of specific perspectives: mode-coupling theory, kinetically constrained and defect models, and random first order transition theory. In the last approach, we predict in particular a nonmonotonic evolution of finite-size effects across the mode-coupling crossover due to the competition between mode-coupling and activated relaxation. We study the role of competing relaxation mechanisms in giving rise to nonmonotonic finite size effects by devising a kinetically constrained model where the proximity to the mode-coupling singularity can be continuously tuned by changing the lattice topology. We use our theoretical findings to interpret the results of extensive molecular dynamics studies of four model liquids with distinct structures and kinetic fragilities. While the less fragile model only displays modest finite size effects, we find a more significant size dependence evolving with temperature for more fragile models, such as Lennard-Jones particles and soft spheres. Finally, for a binary mixture of harmonic spheres we observe the predicted nonmonotonic temperature evolution of finite-size effects near the fitted mode-coupling singularity, suggesting that the crossover from mode coupling to activated dynamics is more pronounced for this model. Finally, we discuss the close connection between our results and the recent report of a nonmonotonic temperature evolution of a dynamic length scale near the mode coupling crossover in harmonic spheres. PMID- 23030919 TI - Hydration and anomalous solubility of the Bell-Lavis model as solvent. AB - We address the investigation of the solvation properties of the minimal orientational model for water originally proposed by [Bell and Lavis, J. Phys. A 3, 568 (1970)]. The model presents two liquid phases separated by a critical line. The difference between the two phases is the presence of structure in the liquid of lower density, described through the orientational order of particles. We have considered the effect of a small concentration of inert solute on the solvent thermodynamic phases. Solute stabilizes the structure of solvent by the organization of solvent particles around solute particles at low temperatures. Thus, even at very high densities, the solution presents clusters of structured water particles surrounding solute inert particles, in a region in which pure solvent would be free of structure. Solute intercalates with solvent, a feature which has been suggested by experimental and atomistic simulation data. Examination of solute solubility has yielded a minimum in that property, which may be associated with the minimum found for noble gases. We have obtained a line of minimum solubility (TmS) across the phase diagram, accompanying the line of maximum density. This coincidence is easily explained for noninteracting solute and it is in agreement with earlier results in the literature. We give a simple argument which suggests that interacting solute would dislocate TmS to higher temperatures. PMID- 23030920 TI - Spatial inhomogeneities in ionic liquids, charged proteins, and charge stabilized colloids from collective variables theory. AB - Effects of size and charge asymmetry between oppositely charged ions or particles on spatial inhomogeneities are studied for a large range of charge and size ratios. We perform a stability analysis of the primitive model of ionic systems with respect to periodic ordering using the collective variables-based theory. We extend previous studies [Ciach et al., Phys. Rev. E 75, 051505 (2007)] in several ways. First, we employ a nonlocal approximation for the reference hard-sphere fluid which leads to the Percus-Yevick pair direct correlation functions for the uniform case. Second, we use the Weeks-Chandler-Anderson regularization scheme for the Coulomb potential inside the hard core. We determine the relevant order parameter connected with the periodic ordering and analyze the character of the dominant fluctuations along the lambda lines. We show that the above-mentioned modifications produce large quantitative and partly qualitative changes in the phase diagrams obtained previously. We discuss possible scenarios of the periodic ordering for the whole range of size and charge ratios of the two ionic species, covering electrolytes, ionic liquids, charged globular proteins or nanoparticles in aqueous solutions, and charge-stabilized colloids. PMID- 23030921 TI - Critical scaling of a jammed system after a quench of temperature. AB - Critical behavior of soft repulsive particles after quench of temperature near the jamming transition is numerically investigated. It is found that the plateau of the mean-square displacement of tracer particles and the pressure satisfy critical scaling laws. The critical density for the jamming transition depends on the protocol to prepare the system, while the values of the critical exponents which are consistent with the prediction of a phenomenology are independent of the protocol. PMID- 23030922 TI - Impact of water on molecular dynamics of amorphous alpha-, beta-, and gamma cyclodextrins studied by dielectric spectroscopy. AB - Dielectric, calorimetric, and x-ray diffraction measurements were carried out on alpha-, beta-, and gamma-cyclodextrins, which are cyclic saccharides built by, respectively, six, seven, and eight glucose units connected via glycosidic linkage. Differential scanning calorimetry measurements indicated that each carbohydrate has a melting temperature located much above the temperature at which thermal decomposition begins. Moreover, calorimetric data revealed that it is possible to completely dehydrate each cyclodextrin by annealing them above 413 K. Unfortunately, it is impossible to obtain amorphous forms of cyclodextrin by simple cooling of the melt. Thus, a solid state amorphization method has been applied. X-ray diffraction studies demonstrated that by ball milling at room temperature we are able to obtain completely amorphous cyclodextrins. Finally, dielectric measurements were carried out to probe molecular dynamics in the amorphous state of cyclodextrins. It was found that there is only one relaxation process in amorphous hydrated cyclodextrins, while in dried samples two secondary relaxations are present. Moreover, we have shown that water has an enormous effect on the dynamics of both relaxation modes, i.e., with increasing content of water, the activation energy of the slow mode decreases, while that evaluated for the fast mode increases. We were not able to follow the dynamics of the structural relaxation process, because glass transition temperatures of amorphous cyclodextrins were found to lie above thermal degradation points. PMID- 23030923 TI - Phase behavior and structure of a fluid confined between competing (solvophobic and solvophilic) walls. AB - We consider a model fluid with long-range r(-6) (dispersion) interparticle potentials confined between competing parallel walls. One wall is solvophilic and would be completely wet at bulk liquid-gas coexistence MU(co)(-), whereas the other is solvophobic and would be completely dry at MU=MU(co)(+). When the wall separation L is large and the system is below the bulk critical temperature T(C) and close to bulk liquid-gas coexistence, a delocalized interface or soft-mode phase forms with a liquid-gas interface near the center of the slit; this interacts with the walls via the power-law tails of the interparticle potentials. We use a coarse-grained effective Hamiltonian approach to derive explicit scaling expressions for the Gibbs adsorption Gamma, the surface tension gamma, the solvation force f(s), and the total susceptibility chi. These quantities depend on the dimensionless scaling variable (L/sigma)(3)betadeltaMU, where beta=(k(B)T)(-1), sigma is the diameter of the fluid particles and deltaMU=MU MU(co) is the chemical potential deviation from bulk coexistence. Using a nonlocal density functional theory, we calculate density profiles for the asymmetrically confined fluid at different chemical potentials and for sufficiently large L confirm the scaling predictions for the four thermodynamic quantities. Since the upper critical dimension for complete wetting with power law potentials is less than 3, we argue that our (mean-field) scaling predictions should remain valid in treatments that incorporate the effects of interfacial fluctuations. As the wall separation L is decreased at MU(co), we predict a capillary evaporation transition from the delocalized interface phase to a dilute gas state with just a thin adsorbed film of liquidlike density next to the solvophilic wall. This transition is closely connected to the first-order prewetting transition that occurs at the solvophilic wall in the semi-infinite system. We compare the phase diagram for the competing walls system with the phase diagrams for the fluid confined between identical solvophilic and identical solvophobic walls. Comparisons are also made with earlier studies of asymmetric confinement for systems with short-range forces. PMID- 23030924 TI - Perturbation theory of solid-liquid interfacial free energies of bcc metals. AB - A perturbation theory is used to calculate bcc solid-liquid interfacial free energies of metallic systems with embedded-atom model potentials. As a reference system for bcc crystals we used a single-occupancy cell, hard-sphere bcc system. Good agreements between the perturbation theory results and the corresponding results from simulations are found. The strategy to extract hard-sphere bcc solid liquid interfacial free energies may have broader applications for other crystal lattices. PMID- 23030925 TI - Solidification fronts in supercooled liquids: how rapid fronts can lead to disordered glassy solids. AB - We determine the speed of a crystallization (or, more generally, a solidification) front as it advances into the uniform liquid phase after the system has been quenched into the crystalline region of the phase diagram. We calculate the front speed by assuming a dynamical density functional theory (DDFT) model for the system and applying a marginal stability criterion. Our results also apply to phase field crystal (PFC) models of solidification. As the solidification front advances into the unstable liquid phase, the density profile behind the advancing front develops density modulations and the wavelength of these modulations is a dynamically chosen quantity. For shallow quenches, the selected wavelength is precisely that of the crystalline phase and so well ordered crystalline states are formed. However, when the system is deeply quenched, we find that this wavelength can be quite different from that of the crystal, so the solidification front naturally generates disorder in the system. Significant rearrangement and aging must subsequently occur for the system to form the regular well-ordered crystal that corresponds to the free energy minimum. Additional disorder is introduced whenever a front develops from random initial conditions. We illustrate these findings with simulation results obtained using the PFC model. PMID- 23030926 TI - Spontaneous wrinkle branching by gradient stiffness. AB - The concept of coherency loss is proposed to understand wrinkle branching as a pathway toward hierarchical wrinkling pattern formation in a compressed film substrate system with gradient stiffness of the film or substrate. A simple model indicates that the wrinkle branching arises when the characteristic length of the stiffness inhomogeneity zone is larger than the coherency persistent length, which depends on the amplitude of the stiffness inhomogeneity. Numerical simulations of nonlinear wrinkles based on the model of the Foppl-von Karman plate on compliant substrates show how regulating the size and amplitude of the stiffness inhomogeneities results in branched wrinkles in striking agreement with the existing observations. The paper reveals the origin of such kinds of branched wrinkles and may provide a guideline for controllable hierarchical wrinkles by patterning the stiffness gradient. PMID- 23030927 TI - Influence of an external field on the surface tension of free-standing smectic films. AB - We have carried out a theoretical study of the effect of the electric field E on the thermodynamical properties and surface tension gamma of free-standing smectic films. Calculations, based upon the extended McMillan approach with anisotropic forces, show a stepwise reduction and increase of the values of the Helmholtz free energy f and gamma, respectively, per partially fluorinated 5-n-alkyl-2-[4-n (perfluoroalkyl-metheleneoxy)phenyl] (H10F5MOPP) molecule, as the temperature is raised above that for the bulk smectic-A-isotropic transition. Calculations show that E may not only affect the layer-thinning transition sequence, but also change the first multilayer jump in the thickness and increase the value of gamma per H10F5MOPP molecule. Reasonable agreement between the theoretically predicted and the experimentally obtained data on gamma of the partially fluorinated H10F5MOPP film has been obtained. PMID- 23030928 TI - Propagation of electromagnetic waves in stochastic helical media. AB - We have developed a model for studying the axial propagation of elliptically polarized electromagnetic waves in a spatially random helical media. We start by writing Maxwell equations for a structurally chiral medium whose dielectric permittivities, polar, and helical angles contain both a stochastic contribution and a deterministic one. We write the electromagnetic equations into a Marcuvitz Schwigner representation to transform them afterward in a simpler expression by using the Oseen transformation. We exhibit that in the Oseen frame the Marcuvitz Schwigner equations turns out to be a linear vector stochastic system of differential equations with multiplicative noise. Applying to the resulting equation a formalism for treating stochastic differential equations, we find the governing equations for the first moments of the electromagnetic field amplitudes for a general autocorrelation function for the system diffractive indexes, and calculate their corresponding band structure for a particular spectral noise density. We have shown that the average resulting electromagnetic fields exhibit a decaying exponential dependence which stems from by dissipation and the presence of qualitative modifications in the band structure including a considerable widening of the band gap and the existence of new local maxima for the modes without a band gap. PMID- 23030929 TI - Relativistic Lagrangian model of a nematic liquid crystal interacting with an electromagnetic field. AB - We develop a relativistic variational model for a nematic liquid crystal interacting with an electromagnetic field. The constitutive relation for a general anisotropic uniaxial diamagnetic and dielectric medium is analyzed. We discuss light wave propagation in this moving uniaxial medium, for which the corresponding optical metrics are identified explicitly. A Lagrangian for the coupled system of a nematic liquid crystal and the electromagnetic field is constructed, from which a complete set of equations of motion for the system is derived. The canonical energy-momentum and spin tensors are systematically obtained. We compare our results with those within the nonrelativistic models. As an application of our general formalism, we discuss the so-called Abraham Minkowski controversy on the momentum of light in a medium. PMID- 23030930 TI - Anisotropic self-diffusion in nematic, smectic-A, and reentrant nematic phases. AB - The nature of the reentrant nematic phase has been actively investigated both experimentally and theoretically during the past few decades. Most studies concluded that, as concerning molecular dynamics, a reentrant nematic phase is essentially analogous to a conventional nematic one. Recent computer simulations [Mazza et al., Phys. Rev. Lett. 105, 227802 (2010)], however, predicted molecular translational self-diffusion along the phase director that was dominated by a collective transport mode and was, relative to that observed in a conventional nematic phase, enhanced by an order of magnitude. In the present work, the principal components of the diffusion tensor in a reentrant nematic phase are determined experimentally and compared to those in conventional nematic and smectic-A phases. We find that the temperature dependence of the translational diffusion in the two nematic phases, within experimental error, follows a uniform trend and can be adequately described in terms of available diffusion models in nematics. Hence, we find no evidence for enhanced diffusion but confirm instead the similarity of conventional and reentrant nematic phases with respect to molecular translational dynamics. PMID- 23030931 TI - Piezoelectric and flexoelectric effects in ferroelectric liquid crystals. AB - Flexoelectric and piezoelectric effects in ferroelectric liquid crystals (FLCs) have been studied. It is shown that nonlinear electromechanical coupling is determined by a local flexoelectric effect. Dependence of the parameters of nonlinearity of the flexoelectric effect on the parameter of phase transition from a paraelectric phase to a polar phase has been studied. Dependencies of flexoelectric and piezoelectric coefficients on the frequency of the mechanical vibrations have been studied. PMID- 23030932 TI - Analytic theory of the interactions between nanocolloids mediated by reversibly adsorbed polymers. AB - We develop an analytic theory of the polymer mediated interactions between nanocolloids reversibly adsorbing the excluded volume polymers. This theory describes the limit of the weak adsorption where the correlation length xi of the polymer system is much smaller than the characteristic adsorption length (colloid absorbance) alpha. By making use of the developed theory, we calculate the colloid immersion energy and the potential of the polymer mediated interactions as functions of the colloid radius R, the absorbance alpha, and the polymer volume fraction phi(P). PMID- 23030933 TI - Concentration dependence of rheological properties of telechelic associative polymer solutions. AB - We consider concentration dependence of rheological properties of associative telechelic polymer solutions. Experimental results for model telechelic polymer solutions show rather strong concentration dependence of rheological properties. For solutions with relatively high concentrations, linear viscoelasticity deviates from the single Maxwell behavior. The concentration dependence of characteristic relaxation time and moduli is different in high- and low concentration cases. These results suggest that there are two different concentration regimes. We expect that densely connected (well percolated) networks are formed in high-concentration solutions, whereas sparsely connected (weakly percolated) networks are formed in low-concentration solutions. We propose single chain type transient network models to explain experimental results. Our models incorporate the spatial correlation effect of micellar cores and average number of elastically active chains per micellar core (the network functionality). Our models can reproduce nonsingle Maxwellian relaxation and nonlinear rheological behavior such as the shear thickening and thinning. They are qualitatively consistent with experimental results. In our models, the linear rheological behavior is mainly attributable to the difference of network structures (functionalities). The nonlinear rheological behavior is attributable to the nonlinear flow rate dependence of the spatial correlation of micellar core positions. PMID- 23030934 TI - Chain conformation of ring polymers under a cylindrical nanochannel confinement. AB - We investigate the chain conformation of ring polymers confined to a cylindrical nanochannel using both theoretical analysis and three-dimensional Langevin dynamics simulations. We predict that the longitudinal size of a ring polymer scales with the chain length and the diameter of the channel in the same manner as that for linear chains based on scaling analysis and Flory-type theory. Moreover, Flory-type theory also gives the ratio of the longitudinal sizes for a ring polymer and a linear chain with identical chain length. These theoretical predictions are confirmed by numerical simulations. Finally, our simulation results show that this ratio first decreases and then saturates with increasing the chain stiffness, which explains the discrepancy in experiments. Our results have biological significance. PMID- 23030935 TI - Directional motion of forced polymer chains with hydrodynamic interaction. AB - We study the propulsion of a one-dimensional (1D) polymer chain under sinusoidal external forces in the overdamped (low Reynolds number) regime. We show that, when hydrodynamical interactions are included, the polymer presents directional motion which depends on the phase differences of the external force applied along the chain. Moreover, the velocity shows a maximum as a function of the frequency. We discuss the relevance of all these results in light of recent nanotechnology experiments. PMID- 23030936 TI - Universal properties of knotted polymer rings. AB - By performing Monte Carlo sampling of N-steps self-avoiding polygons embedded on different Bravais lattices we explore the robustness of universality in the entropic, metric, and geometrical properties of knotted polymer rings. In particular, by simulating polygons with N up to 10(5) we furnish a sharp estimate of the asymptotic values of the knot probability ratios and show their independence on the lattice type. This universal feature was previously suggested, although with different estimates of the asymptotic values. In addition, we show that the scaling behavior of the mean-squared radius of gyration of polygons depends on their knot type only through its correction to scaling. Finally, as a measure of the geometrical self-entanglement of the self avoiding polygons we consider the standard deviation of the writhe distribution and estimate its power-law behavior in the large N limit. The estimates of the power exponent do depend neither on the lattice nor on the knot type, strongly supporting an extension of the universality property to some features of the geometrical entanglement. PMID- 23030937 TI - Morphological control of grafted polymer films via attraction to small nanoparticle inclusions. AB - Control of the morphologies of polymer films and layers by addition of nanosize particles is a novel technique for design of nanomaterials and is also at the core of some important biological processes. In order to facilitate the analysis of experimental data and enable predictive engineering of such systems, solid theoretical understanding is necessary. We study theoretically and computationally the behavior of plane-grafted polymer layers (brushes) in athermal solvent, decorated with small nanoparticle inclusions, using mean field theory and coarse-grained simulations. We show that the morphology of such layers is very sensitive to the interaction between the polymers and the nanoparticles and to the nanoparticle density. In particular, the mean field model shows that for a certain range of parameters, the nanoparticles induce a sharp transition in the layer height, accompanied by a sharp increase in the number of adsorbed nanoparticles. At other parameter values, the layer height depends smoothly on the nanoparticle concentration. Predictions of the theoretical model are verified by Langevin dynamics simulations. The results of the paper are in qualitative agreement with experiments on in vitro models of biological transport and suggest strategies for morphological control of nanocomposite materials. PMID- 23030938 TI - Free-energy calculations along a high-dimensional fragmented path with constrained dynamics. AB - Free-energy calculations for high-dimensional systems, such as peptides or proteins, always suffer from a serious sampling problem in a huge conformational space. For such systems, path-based free-energy methods, such as thermodynamic integration or free-energy perturbation, are good choices. However, both of them need sufficient sampling along a predefined transition path, which can only be controlled using restrained or constrained dynamics. Constrained simulations produce more reasonable free-energy profiles than restrained simulations. But calculations of standard constrained dynamics require an explicit expression of reaction coordinates as a function of Cartesian coordinates of all related atoms, which may be difficult to find for the complex transition of biomolecules. In this paper, we propose a practical solution: (1) We use restrained dynamics to define an optimized transition path, divide it into small fragments, and define a virtual reaction coordinate to denote a position along the path. (2) We use constrained dynamics to perform a formal free-energy calculation for each fragment and collect the values together to provide the entire free-energy profile. This method avoids the requirement to explicitly define reaction coordinates in Cartesian coordinates and provides a novel strategy to perform free-energy calculations for biomolecules along any complex transition path. PMID- 23030939 TI - Effect of hydrogen bond interaction on protein phase transition. AB - We derive the grand partition function of protein chain by restricting dihedral angles to exist only in five distinct states and assume that the dominant noncovalent potential is the hydrogen bond interaction. We investigate the phase transition of protein secondary structures and the order of the transition through analyzing its heat capacity. Our theory demonstrates the presence of alpha-beta-coil structural phase transition in the protein polyalanine. PMID- 23030940 TI - Macroscopic limits of individual-based models for motile cell populations with volume exclusion. AB - Partial differential equation models are ubiquitous in studies of motile cell populations, giving a phenomenological description of events which can be analyzed and simulated using a wide range of existing tools. However, these models are seldom derived from individual cell behaviors and so it is difficult to accurately include biological hypotheses on this spatial scale. Moreover, studies which do attempt to link individual- and population-level behavior generally employ lattice-based frameworks in which the artifacts of lattice choice at the population level are unclear. In this work we derive limiting population-level descriptions of a motile cell population from an off-lattice, individual-based model (IBM) and investigate the effects of volume exclusion on the population-level dynamics. While motility with excluded volume in on-lattice IBMs can be accurately described by Fickian diffusion, we demonstrate that this is not the case off lattice. We show that the balance between two key parameters in the IBM (the distance moved in one step and the radius of an individual) determines whether volume exclusion results in enhanced or slowed diffusion. The magnitude of this effect is shown to increase with the number of cells and the rate of their movement. The method we describe is extendable to higher dimensional and more complex systems and thereby provides a framework for deriving biologically realistic, continuum descriptions of motile populations. PMID- 23030941 TI - Surface traction and the dynamics of elastic rods at low Reynolds number. AB - Molecular and cell biological processes often use proteins and structures that are significantly longer in one dimension than they are in the other two, for example, DNA, actin, and bacterial flagella. The dynamics of these structures are the consequence of the balance between the elastic forces from the structure itself and viscous forces from the surrounding fluid. Typically, the motion of these filamentary objects is described using variations of the Kirchhoff rod equations with resistive forces from the fluid treated as body forces acting on the centerline. In reality, though, these forces are applied to the surface of the filament; however, the standard derivation of the Kirchhoff equations ignores surface traction stresses. Here, we rederive the Kirchhoff rod equations in the presence of resistive traction stresses and determine the conditions under which treating the drag forces as body forces is reasonable. We show that in most biologically relevant cases the standard implementation of resistive forces into the Kirchhoff rod equations is applicable; however, we note one particular biological system where the Kirchhoff rod formalism may not apply. PMID- 23030942 TI - Limit-cycle oscillations and stable patterns in repressor lattices. AB - As a model for cell-to-cell communication in biological tissues, we construct repressor lattices by repeating a regulatory three-node motif on a hexagonal structure. Local interactions can be unidirectional, where a node either represses or activates a neighbor that does not communicate backwards. Alternatively, they can be bidirectional where two neighboring nodes communicate with each other. In the unidirectional case, we perform stability analyses for the transitions from stationary to oscillating states in lattices with different regulatory units. In the bidirectional case, we investigate transitions from oscillating states to ordered patterns generated by local switches. Finally, we show how such stable patterns in two-dimensional lattices can be generalized to three-dimensional systems. PMID- 23030943 TI - Membrane-mediated interactions between rigid inclusions: an effective field theory. AB - An approach based on effective field theory (EFT) is discussed and applied to the problem of surface-mediated interactions between rigid inclusions of circular footprint on a membrane. Instead of explicitly constraining the surface fluctuations in accord with the boundary conditions around the inclusions, the EFT formalism rewrites the theory; the Hamiltonian of a freely fluctuating surface is augmented by pointwise localized terms that capture the same constraints. This allows one to compute the interaction free energy as an asymptotic expansion in inverse separations in a systematic, efficient, and transparent way. Both entropic (fluctuation-induced, Casimir-like) and curvature elastic (ground-state) forces are considered. Our findings include higher-order corrections to known asymptotic results, on both the pair and the multibody levels. We also show that the few previous attempts in the literature at predicting subleading orders missed some terms due to an uncontrolled point particle approximation. PMID- 23030944 TI - Distributions of lifetime and maximum size of abortive clathrin-coated pits. AB - Clathrin-mediated endocytosis is a complex process through which eukaryotic cells internalize nutrients, antigens, growth factors, pathogens, etc. The process occurs via the formation of invaginations on the cell membrane, called clathrin coated pits (CCPs). Over the years, much has been learned about the mechanism of CCP assembly, but a complete understanding of the assembly process still remains elusive. In recent years, using fluorescence microscopy, studies have been done to determine the statistical properties of CCP formation. In this paper, using a recently proposed coarse-grained, stochastic model of CCP assembly [Banerjee, Berezhkovskii, and Nossal, Biophys. J. 102, 2725 (2012)], we suggest new ways of analyzing such experimental data. To be more specific, we derive analytical expressions for the distribution of maximum size of abortive CCPs, and the probability density of their lifetimes. Our results show how these functions depend on the kinetic and energetic parameters characterizing the assembly process, and therefore could be useful in extracting information about the mechanism of CCP assembly from experimental data. We find excellent agreement between our analytical results and those obtained from kinetic Monte Carlo simulations of the assembly process. PMID- 23030945 TI - Stick-slip motion and elastic coupling in crawling cells. AB - Crawling cells exhibit a variety of cell shape dynamics, ranging from complex ruffling and bubbling to oscillatory protrusion and retraction. Periodic shape changes during cell migration are recorded in fast-moving fish epithelial keratocytes where sticking and slipping at opposite sides of the cell's broad trailing edge generate bipedal locomotion. Barnhart et al. [Biophys. J. 98, 933 (2010)] recently proposed a mechanical spring model specifically designed to capture bipedal locomotion in these cells. We extend their model by benchmarking the dynamics of four mechanical configurations against those of crawling keratocytes. Our analysis shows that elastic coupling to the cell nucleus is necessary to generate its lateral motion. We select one configuration to study the effects of cell elasticity, size, and aspect ratio on crawling dynamics. This configuration predicts that shape dynamics are highly dependent on the lamellipodial elasticity but less sensitive to elasticity at the trailing edge. The model predicts a wide range of dynamics seen in actual crawling keratocytes, including coherent bipedal, coherent nonbipedal, and decoherent motions. This work highlights how the dynamical behavior of crawling cells can be derived from mechanical properties through which biochemical factors may operate to regulate cellular locomotion. PMID- 23030946 TI - Finding multiple minimum-energy conformations of the hydrophobic-polar protein model via multidomain sampling. AB - We demonstrate the efficiency of the multidomain sampler (MDS) in finding multiple distinct global minima and low-energy local minima in the hydrophobic polar (HP) lattice protein model. Extending the idea of partitioning energy space in the Wang-Landau algorithm, our approach introduces an additional partitioning scheme to divide the protein conformation space into local basins of attraction. This double-partitioning design is very powerful in guiding the sampler to visit the basins of unexplored local minima. An H-residue subchain distance is used to merge the basins of similar local minima into one domain, which increases the diversity among identified minimum-energy conformations. Moreover, a visit enhancement factor is introduced for long protein chains to facilitate jumps between basins. Results on three benchmark protein sequences reveal that our approach is capable of finding multiple global minima and hundreds of low-energy local minima of great diversity. PMID- 23030947 TI - First-passage-probability analysis of active transport in live cells. AB - The first-passage-probability can be used as an unbiased method for determining the phases of motion of individual organelles within live cells. Using high speed microscopy, we observe individual lipid droplet tracks and analyze the motor protein driven motion. At short passage lengths (<10(-2)MUm), a log-normal distribution in the first-passage-probability as a function of time is observed, which switches to a Gaussian distribution at longer passages due to the running motion of the motor proteins. The mean first-passage times () as a function of the passage length (L), averaged over a number of runs for a single lipid droplet, follow a power law distribution ~L(alpha), alpha>2, at short times due to a passive subdiffusive process. This changes to another power law at long times where 1~t(beta), where 0theta(MA). Expansion of the model to include discrimination between the combined effects of alignment disorder and collagen fiber volume fraction on the diffusion tensor is discussed. PMID- 23030953 TI - Mathematical modeling of genome replication. AB - Eukaryotic DNA replication is initiated from multiple sites on the chromosome, but little is known about the global and local regulation of replication. We present a mathematical model for the spatial dynamics of DNA replication, which offers insight into the kinetics of replication in different types of organisms. Most biological experiments involve average quantities over large cell populations (typically >10(7) cells) and therefore can mask the cell-to-cell variability present in the system. Although the model is formulated in terms of a population of cells, using mathematical analysis we show that one can obtain signatures of stochasticity in individual cells from averaged quantities. This work generalizes the result by Retkute et al. [Phys. Rev. Lett. 107, 068103 (2011)] to a broader set of parameter regimes. PMID- 23030955 TI - Reanalysis of the hydrodynamic theory of fluid, polar-ordered flocks. AB - I reanalyze the hydrodynamic theory of fluid, polar-ordered flocks. I find new linear terms in the hydrodynamic equations which slightly modify the anisotropy, but not the scaling, of the damping of sound modes. I also find that the nonlinearities allowed in equilibrium do not stabilize long-ranged order in spatial dimensions d=2, in accord with the Mermin-Wagner theorem. Nonequilibrium nonlinearities do stabilize long-ranged order in d=2, as argued by earlier work. Some of these were missed by earlier work; it is unclear whether or not they change the scaling exponents in d=2. PMID- 23030956 TI - Relation between the change in DNA elasticity on ligand binding and the binding energetics. AB - The widespread use of tweezers for measurement of ligand-DNA binding parameters is based on the McGhee-von Hippel treatment of the DNA contour and persistence length as a function of concentration. The McGhee-von Hippel approach contains the basic assumption that the binding constant K is independent of the number of already bound ligands. However, the change in elasticity of DNA on binding affects the entropic part of the Gibbs free energy and, hence, the K value in a concentration-dependent manner, making the whole approach inconsistent. In the present work we show that the energetic effect of DNA stiffening on noncovalent binding of small ligands is negligible with respect to the net energy of reaction, whereas the DNA stiffening on binding of large ligands must always be considered in each particular case. PMID- 23030957 TI - Biological evolution in a multidimensional fitness landscape. AB - We considered a multiblock molecular model of biological evolution, in which fitness is a function of the mean types of alleles located at different parts (blocks) of the genome. We formulated an infinite population model with selection and mutation, and calculated the mean fitness. For the case of recombination, we formulated a model with a multidimensional fitness landscape (the dimension of the space is equal to the number of blocks) and derived a theorem about the dynamics of initially narrow distribution. We also considered the case of lethal mutations. We also formulated the finite population version of the model in the case of lethal mutations. Our models, derived for the virus evolution, are interesting also for the statistical mechanics and the Hamilton-Jacobi equation as well. PMID- 23030958 TI - Experimental determination of Philodendron melinonii and Arabidopsis thaliana tissue microstructure and geometric modeling via finite-edge centroidal Voronoi tessellation. AB - Plant petioles and stems are hierarchical cellular structures, displaying structural features defined at multiple length scales. One or more of the intermediate hierarchical levels consists of tissues, in which the cellular distribution is quasirandom. The current work focuses on the realistic modeling of plant tissue microstructures. The finite-edge centroidal Voronoi tessellation (FECVT) is here introduced to overcome the drawbacks of the semi-infinite edges of a typical Voronoi model. FECVT can generate a realistic model of a tissue microstructure, which might have finite edges at its border, be defined by a boundary contour of any shape, and include complex heterogeneity and cellular gradients. The centroid-based Voronoi tessellation is applied to model the microstructure of the Philodendron melinonii petiole and the Arabidopsis thaliana stem, which both display intense cellular gradients. FECVT coupled with a digital image processing algorithm is implemented to capture the nonperiodic microstructures of plant tissues. The results obtained via this method satisfactorily obey the geometric, statistical, and topological laws of naturally evolved cellular solids. The predicted models are also validated by experimental data. PMID- 23030959 TI - Effects of quantum coherence in metalloprotein electron transfer. AB - Many intramolecular electron transfer (ET) reactions in biology are mediated by metal centers in proteins. This process is commonly described by a model of diffusive hopping according to the semiclassical theories of Marcus and Hopfield. However, recent studies have raised the possibility that nontrivial quantum mechanical effects play a functioning role in certain biomolecular processes. Here, we investigate the potential effects of quantum coherence in biological ET by extending the semiclassical model to allow for the possibility of quantum coherent phenomena using a quantum master equation based on the Holstein Hamiltonian. We test the model on the structurally defined chain of seven iron sulfur clusters in nicotinamide adenine dinucleotide plus hydrogen:ubiquinone oxidoreductase (complex I), a crucial respiratory enzyme and one of the longest chains of metal centers in biology. Using experimental parameters where possible, we find that, in limited circumstances, a small quantum mechanical contribution can provide a marked increase in the ET rate above the semiclassical diffusive hopping rate. Under typical biological conditions, our model reduces to well known diffusive behavior. PMID- 23030960 TI - Random pinning limits the size of membrane adhesion domains. AB - Theoretical models describing specific adhesion of membranes predict (for certain parameters) a macroscopic phase separation of bonds into adhesion domains. We show that this behavior is fundamentally altered if the membrane is pinned randomly due to, e.g., proteins that anchor the membrane to the cytoskeleton. Perturbations which locally restrict membrane height fluctuations induce quenched disorder of the random-field type. This rigorously prevents the formation of macroscopic adhesion domains following the Imry-Ma argument [Imry and Ma, Phys. Rev. Lett. 35, 1399 (1975)]. Our prediction of random-field disorder follows from analytical calculations and is strikingly confirmed in large-scale Monte Carlo simulations. These simulations are based on an efficient composite Monte Carlo move, whereby membrane height and bond degrees of freedom are updated simultaneously in a single move. The application of this move should prove rewarding for other systems also. PMID- 23030961 TI - Group-size distribution of skeins of wild geese. AB - In appropriate situations, large populations of geese exhibit dynamical rearrangements by repeated mergers and splits among the groups. We describe the grouping process in terms of a mean-field model based on the Smoluchowski equation of coagulation with fragmentation and observationally plausible kernels. To verify our model, we conducted field observations on skeins of airborne geese, noting both the group-size distribution and the group-forming processes. We found that the group-size distribution we obtained in our field measurements could be represented by a fractional power function with an exponential cutoff. This function matches the asymptotic form of the steady-state solution of our model. Furthermore, we estimated the effective number of individuals involved in interactions by comparison of the model to our field data. PMID- 23030962 TI - Superdiffusive comb: application to experimental observation of anomalous diffusion in one dimension. AB - A possible mechanism of superdiffusion of ultracold atoms in a one-dimensional polarization optical lattice, observed experimentally in Phys. Rev. Lett. 108, 093002 (2012), is suggested. The analysis is based on a consideration of anomalous diffusion in a fractal comb [Phys. Rev. E 83, 052106 (2011)]. It is shown that the transport exponent is determined by the fractal geometry of the comb due to recoil distributions resulting in Levy flights of atoms. PMID- 23030963 TI - Motion-dependent levels of order in a relativistic universe. AB - Consider a generally closed system of continuous three-space coordinates x with a differentiable amplitude function psi(x). What is its level of order R? Define R by the property that it decreases (or stays constant) after the system is coarse grained. Then R turns out to obey R=8(-1)L(2)I,where quantity I=4?dx[nabla]psi(*).[nabla]psi is the classical Fisher information in the system and L is the longest chord that can connect two points on the system surface. In general, order R is (i) unitless, and (ii) invariant to uniform stretch or compression of the system. On this basis, the order R in the Universe was previously found to be invariant in time despite its Hubble expansion, and with value R=26.0*10(60) for flat space. By comparison, here we model the Universe as a string-based "holostar," with amplitude function psi(x)[proportionality]1/r over radial interval r=(r(0),r(H)). Here r(0) is of order the Planck length and r(H) is the radial extension of the holostar, estimated as the known value of the Hubble radius. Curvature of space and relative motion of the observer must now be taken into account. It results that a stationary observer observes a level of order R=(8/9)(r(H)/r(0))(3/2)=0.42*10(90); while for a free-falling observer R=2( 1)(r(H)/r(0))(2)=0.85*10(120). Both order values greatly exceed the above flat space value. Interestingly, they are purely geometric measures, depending solely upon ratio r(H)/r(0). Remarkably, the free-fall value ~10(120) of R approximates the negentropy of a universe modeled as discrete. This might mean that the Universe contains about equal amounts of continuous and discrete structure. PMID- 23030964 TI - Cluster-size heterogeneity in the two-dimensional Ising model. AB - We numerically investigate the heterogeneity in cluster sizes in the two dimensional Ising model and verify its scaling form recently proposed in the context of percolation problems [Phys. Rev. E 84, 010101(R) (2011)]. The scaling exponents obtained via the finite-size scaling analysis are shown to be consistent with theoretical values of the fractal dimension d(f) and the Fisher exponent tau for the cluster distribution. We also point out that strong finite size effects exist due to the geometric nature of the cluster-size heterogeneity. PMID- 23030965 TI - First-passage time: lattice versus continuum. AB - The well known approach, based on Schrodinger's integral equation, to the problem of calculating the first-passage probability density in time for classical diffusion on a continuum is revisited for the case of diffusion by hopping on a discrete lattice. It turns out that a certain boundary condition central to solving the integral equation, invoked first by Schrodinger and then by others on the basis of a physical argument, needs to be modified for the discrete case. In fact, the required boundary condition turns out to be determined entirely by the normalization condition for the first-passage probability density. An explicit analytical expression is derived for the first-passage density for a three-site problem modeling escape over a barrier. The related quantum first-passage problem is also commented upon briefly. PMID- 23030966 TI - Thermal-insulating effect in a quantum harmonic chain with alternating masses. AB - We present an analytical study of the heat conduction in a quantum harmonic chain of oscillators with alternate particle masses. We find that a thermal-insulating effect already observed in some classical models consisting of chains with alternate masses also holds in the quantum version of the one-dimensional harmonic model with thermal reservoirs at the boundaries. Namely, we show that if the heat conduction is to be avoided, then alternating small and large masses in a wire is more effective than having all of the masses equally large. The presence of a similar effect in different models indicates that the phenomenon may be rather general, with possible applications in the heat-flow control. PMID- 23030967 TI - Efficiency, power, and period at two optimum operations of a thermoelectric single-level quantum dot. AB - We take a single-level quantum dot embedded between two metallic leads at different temperatures and chemical potentials which works as a heat engine. Two optimization criteria were used and their corresponding optimized efficiencies, powers, and periods evaluated. A comparison between similar quantities of the two optimization criteria reveals mixed advantages and disadvantages. We quantify the engine's overall performance by suggesting a figure of merit that takes into account the contribution of each of the three quantities. Based on the proposed figure of merit, one of the optimization criterion presents a clear advantage. This same criterion is found to be invariably advantageous when applied to three other representative models. PMID- 23030968 TI - Symmetric and asymmetric instability of buried polymer interfaces. AB - We demonstrate using neutron reflectometry that the internal interfaces in a trilayer system of two identical thick polystyrene layers sandwiching a much thinner (deuterated) poly(methyl methacrylate) layer 15 nm thick (viscosity matched with the polystyrene layers) increase in roughness at the same rate. When the lower polystyrene layer is replaced with a layer of the same polymer of much greater molecular mass, two different growths of the interfaces are observed. From the growth of the interface for this asymmetric case in the solid regime using the theoretical prediction of the spinodal instability including slippage at the interface, a value of the Hamaker constant of the system has been extracted in agreement with the calculated value. For the symmetric case the rise time of the instability is much faster. PMID- 23030969 TI - Estimating the value of containment strategies in delaying the arrival time of an influenza pandemic: a case study of travel restriction and patient isolation. AB - With a simple phenomenological metapopulation model, which characterizes the invasion process of an influenza pandemic from a source to a subpopulation at risk, we compare the efficiency of inter- and intrapopulation interventions in delaying the arrival of an influenza pandemic. We take travel restriction and patient isolation as examples, since in reality they are typical control measures implemented at the inter- and intrapopulation levels, respectively. We find that the intrapopulation interventions, e.g., patient isolation, perform better than the interpopulation strategies such as travel restriction if the response time is small. However, intrapopulation strategies are sensitive to the increase of the response time, which might be inevitable due to socioeconomic reasons in practice and will largely discount the efficiency. PMID- 23030970 TI - Dynamical model for the full stretching curve of DNA. AB - We present a phenomenological dynamical model able to describe the stretching features of the curve of DNA length vs applied force. As concerns the chain, the model is based on the discrete wormlike chain model with elastic modifications, which properly describes the elongation features at low and intermediate forces. The dynamics is developed under a double-well potential with a linear term, which, at high forces, accounts for the narrow transition present in the DNA elongation (overstretching). A quite good agreement between simulation and experiment is obtained. PMID- 23030971 TI - Clustering of finite-size particles in turbulence. AB - We investigate experimentally the spatial distributions of heavy and neutrally buoyant particles of finite size in a fully turbulent flow. Because their Stokes number (i.e., the ratio of the particle viscous relaxation time to a typical flow time scale) is close to unity, one may expect both classes of particles to aggregate in specific flow regions. This is not observed. Using a Voronoi analysis we show that neutrally buoyant particles sample turbulence homogeneously, whereas heavy particles do cluster. These results show that several dimensionless numbers are needed in the modeling (and understanding) of the behavior of particles entrained by turbulent motions. PMID- 23030972 TI - Reflectional symmetry breaking of the separated flow over three-dimensional bluff bodies. AB - Experimental observation of a permanent reflectional symmetry breaking (RSB) is reported for a laminar three-dimensional wake. Based on flow visualizations, a first bifurcation from the trivial steady symmetric state to a steady RSB state is characterized at Re=340. The RSB state becomes unsteady after a second bifurcation at Re=410. It is found that this RSB regime is persistent at large Reynolds numbers and is responsible for a bistable turbulent wake. PMID- 23030973 TI - Contact between representative rough surfaces. AB - A numerical analysis of mechanical frictionless contact between rough self-affine elastic manifolds was carried out. It is shown that the lower cutoff wave number in surface spectra is a key parameter controlling the representativity of the numerical model. Using this notion we demonstrate that for representative surfaces the evolution of the real contact area with load is universal and independent of the Hurst roughness exponent. By introducing a universal law containing three constants, we extend the study of this evolution beyond the limit of infinitesimal area fractions. PMID- 23030974 TI - Risk-driven migration and the collective-risk social dilemma. AB - A collective-risk social dilemma implies that personal endowments will be lost if contributions to the common pool within a group are too small. Failure to reach the collective target thus has dire consequences for all group members, independently of their strategies. Wanting to move away from unfavorable locations is therefore anything but surprising. Inspired by these observations, we here propose and study a collective-risk social dilemma where players are allowed to move if the collective failure becomes too probable. More precisely, this so-called risk-driven migration is launched depending on the difference between the actual contributions and the declared target. Mobility therefore becomes an inherent property that is utilized in an entirely self-organizing manner. We show that under these assumptions cooperation is promoted much more effectively than under the action of manually determined migration rates. For the latter, we in fact identify parameter regions where the evolution of cooperation is greatly inhibited. Moreover, we find unexpected spatial patterns where cooperators that do not form compact clusters outperform those that do, and where defectors are able to utilize strikingly different ways of invasion. The presented results support the recently revealed importance of percolation for the successful evolution of public cooperation, while at the same time revealing surprisingly simple methods of self-organization towards socially desirable states. PMID- 23030975 TI - Microscale simulation and numerical upscaling of a reactive flow in a plane channel. AB - A bimolecular homogeneous irreversible reaction of the kind A+B->C is simulated in a plane channel as a base example of reactive transport processes taking place at the microscale within porous and/or fractured media. The numerical study explores the way microscale processes embedded in dimensionless quantities such as Peclet (Pe) and Damkohler (Da) numbers propagate to upscaled coefficients describing effective system dynamics. The microscale evolution of the reactant concentrations is obtained through a particle-based numerical method which has been specifically tailored to the considered problem. Key results include a complete documentation of the process evolution for a wide range of Pe and Da, in terms of the global reaction rate, space-time distribution of reactants, and local mixing features leading to characterization of effective reaction and dispersion coefficients governing a section-averaged upscaled model of the system. The robustness of previously presented theoretical analyses concerning closures of volume-averaged (upscaled) formulations is assessed. The work elucidates the dependence of the effective dispersion and reactive parameters on the microscale mixing and reactive species evolution. Our results identify the role played by Da and Pe on the occurrence of incomplete mixing of reactants, which affects the features of the reactive transport scenario. PMID- 23030976 TI - Analysis of complex contagions in random multiplex networks. AB - We study the diffusion of influence in random multiplex networks where links can be of r different types, and, for a given content (e.g., rumor, product, or political view), each link type is associated with a content-dependent parameter ci in [0,infinity] that measures the relative bias type i links have in spreading this content. In this setting, we propose a linear threshold model of contagion where nodes switch state if their "perceived" proportion of active neighbors exceeds a threshold tau. Namely a node connected to mi active neighbors and ki-mi inactive neighbors via type i links will turn active if ?cimi/?ciki exceeds its threshold tau. Under this model, we obtain the condition, probability and expected size of global spreading events. Our results extend the existing work on complex contagions in several directions by (i) providing solutions for coupled random networks whose vertices are neither identical nor disjoint, (ii) highlighting the effect of content on the dynamics of complex contagions, and (iii) showing that content-dependent propagation over a multiplex network leads to a subtle relation between the giant vulnerable component of the graph and the global cascade condition that is not seen in the existing models in the literature. PMID- 23030977 TI - Taxonomies of networks from community structure. AB - The study of networks has become a substantial interdisciplinary endeavor that encompasses myriad disciplines in the natural, social, and information sciences. Here we introduce a framework for constructing taxonomies of networks based on their structural similarities. These networks can arise from any of numerous sources: They can be empirical or synthetic, they can arise from multiple realizations of a single process (either empirical or synthetic), they can represent entirely different systems in different disciplines, etc. Because mesoscopic properties of networks are hypothesized to be important for network function, we base our comparisons on summaries of network community structures. Although we use a specific method for uncovering network communities, much of the introduced framework is independent of that choice. After introducing the framework, we apply it to construct a taxonomy for 746 networks and demonstrate that our approach usefully identifies similar networks. We also construct taxonomies within individual categories of networks, and we thereby expose nontrivial structure. For example, we create taxonomies for similarity networks constructed from both political voting data and financial data. We also construct network taxonomies to compare the social structures of 100 Facebook networks and the growth structures produced by different types of fungi. PMID- 23030978 TI - Collective decision dynamics in the presence of external drivers. AB - We develop a sequence of models describing information transmission and decision dynamics for a network of individual agents subject to multiple sources of influence. Our general framework is set in the context of an impending natural disaster, where individuals, represented by nodes on the network, must decide whether or not to evacuate. Sources of influence include a one-to-many externally driven global broadcast as well as pairwise interactions, across links in the network, in which agents transmit either continuous opinions or binary actions. We consider both uniform and variable threshold rules on the individual opinion as baseline models for decision making. Our results indicate that (1) social networks lead to clustering and cohesive action among individuals, (2) binary information introduces high temporal variability and stagnation, and (3) information transmission over the network can either facilitate or hinder action adoption, depending on the influence of the global broadcast relative to the social network. Our framework highlights the essential role of local interactions between agents in predicting collective behavior of the population as a whole. PMID- 23030979 TI - Correlations in complex networks under attack. AB - For any initially correlated network after any kind of attack where either nodes or edges are removed, we obtain general expressions for the degree-degree probability matrix and degree distribution. We show that the proposed analytical approach predicts the correct topological changes after the attack by comparing the evolution of the assortativity coefficient for different attack strategies and intensities in theory and simulations. We find that it is possible to turn an initially assortative network into a disassortative one, and vice versa, by fine tuning removal of either nodes or edges. For an initially uncorrelated network, on the other hand, we discover that only a targeted edge-removal attack can induce such correlations. PMID- 23030980 TI - Metabolic network modularity arising from simple growth processes. AB - Metabolic networks consist of linked functional components, or modules. The mechanism underlying metabolic network modularity is of great interest not only to researchers of basic science but also to those in fields of engineering. Previous studies have suggested a theoretical model, which proposes that a change in the evolutionary goal (system-specific purpose) increases network modularity, and this hypothesis was supported by statistical data analysis. Nevertheless, further investigation has uncovered additional possibilities that might explain the origin of network modularity. In this work we propose an evolving network model without tuning parameters to describe metabolic networks. We demonstrate, quantitatively, that metabolic network modularity can arise from simple growth processes, independent of the change in the evolutionary goal. Our model is applicable to a wide range of organisms and appears to suggest that metabolic network modularity can be more simply determined than previously thought. Nonetheless, our proposition does not serve to contradict the previous model; it strives to provide an insight from a different angle in the ongoing efforts to understand metabolic evolution, with the hope of eventually achieving the synthetic engineering of metabolic networks. PMID- 23030981 TI - Spreading of multiple epidemics with cross immunization. AB - Pathogen-host relationships are the result of an ongoing coevolutionary race where the immune system of the host attempts to eliminate the pathogen, while the successful pathogen mutates to become invisible for the host's immune system. We here propose a minimal pathogen-host evolution model that takes into account cross immunization and allows for evolution of a spatially heterogeneous immune status of a population of hosts. With only the mutation rate as a determining parameter, the model allows us to produce an evolutionary tree of diseases which is highly branched, but hardly ever splits into separate long-lived trunks. Side branches remain short lived and seldom diverge to the extent of losing all cross immunizations. PMID- 23030982 TI - Exploring complex networks via topological embedding on surfaces. AB - We demonstrate that graphs embedded on surfaces are a powerful and practical tool to generate, to characterize, and to simulate networks with a broad range of properties. Any network can be embedded on a surface with sufficiently high genus and therefore the study of topologically embedded graphs is non-restrictive. We show that the local properties of the network are affected by the surface genus which determines the average degree, which influences the degree distribution, and which controls the clustering coefficient. The global properties of the graph are also strongly affected by the surface genus which is constraining the degree of interwovenness, changing the scaling properties of the network from large world kind (small genus) to small- and ultrasmall-world kind (large genus). Two elementary moves allow the exploration of all networks embeddable on a given surface and naturally introduce a tool to develop a statistical mechanics description for these networks. Within such a framework, we study the properties of topologically embedded graphs which dynamically tend to lower their energy towards a ground state with a given reference degree distribution. We show that the cooling dynamics between high and low "temperatures" is strongly affected by the surface genus with the manifestation of a glass-like transition occurring when the distance from the reference distribution is low. We prove, with examples, that topologically embedded graphs can be built in a way to contain arbitrary complex networks as subgraphs. This method opens a new avenue to build geometrically embedded networks on hyperbolic manifolds. PMID- 23030983 TI - Opinion formation in time-varying social networks: The case of the naming game. AB - We study the dynamics of the naming game as an opinion formation model on time varying social networks. This agent-based model captures the essential features of the agreement dynamics by means of a memory-based negotiation process. Our study focuses on the impact of time-varying properties of the social network of the agents on the naming game dynamics. In particular, we perform a computational exploration of this model using simulations on top of real networks. We investigate the outcomes of the dynamics on two different types of time-varying data: (1) the networks vary on a day-to-day basis and (2) the networks vary within very short intervals of time (20 sec). In the first case, we find that networks with strong community structure hinder the system from reaching global agreement; the evolution of the naming game in these networks maintains clusters of coexisting opinions indefinitely leading to metastability. In the second case, we investigate the evolution of the naming game in perfect synchronization with the time evolution of the underlying social network shedding new light on the traditional emergent properties of the game that differ largely from what has been reported in the existing literature. PMID- 23030984 TI - Bouchaud-Mezard model on a random network. AB - We studied the Bouchaud-Mezard (BM) model, which was introduced to explain Pareto's law in a real economy, on a random network. Using "adiabatic and independent" assumptions, we analytically obtained the stationary probability distribution function of wealth. The results show that wealth condensation, indicated by the divergence of the variance of wealth, occurs at a larger J than that obtained by the mean-field theory, where J represents the strength of interaction between agents. We compared our results with numerical simulation results and found that they were in good agreement. PMID- 23030985 TI - Junctions and spiral patterns in generalized rock-paper-scissors models. AB - We investigate the population dynamics in generalized rock-paper-scissors models with an arbitrary number of species N. We show that spiral patterns with N arms may develop both for odd and even N, in particular in models where a bidirectional predation interaction of equal strength between all species is modified to include one N-cyclic predator-prey rule. While the former case gives rise to an interface network with Y-type junctions obeying the scaling law L?t1/2, where L is the characteristic length of the network and t is the time, the latter can lead to a population network with N-armed spiral patterns, having a roughly constant characteristic length scale. We explicitly demonstrate the connection between interface junctions and spiral patterns in these models and compute the corresponding scaling laws. This work significantly extends the results of previous studies of population dynamics and could have profound implications for the understanding of biological complexity in systems with a large number of species. PMID- 23030986 TI - Propagation speed of a starting wave in a queue of pedestrians. AB - The propagation speed of a starting wave, which is a wave of people's successive reactions in the relaxation process of a queue, has an essential role for pedestrians and vehicles to achieve smooth movement. For example, a queue of vehicles with appropriate headway (or density) alleviates traffic jams since the delay of reaction to start is minimized. In this paper, we have investigated the fundamental relation between the propagation speed of a starting wave and the initial density by both our mathematical model built on the stochastic cellular automata and experimental measurements. Analysis of our mathematical model implies that the relation is characterized by the power law alpharho-beta (beta?1), and the experimental results verify this feature. Moreover, when the starting wave is characterized by the power law (beta>1), we have revealed the existence of optimal density, where the required time, i.e., the sum of the waiting time until the starting wave reaches the last pedestrian in a queue and his/her travel time to pass the head position of the initial queue, is minimized. This optimal density inevitably plays a significant role in achieving a smooth movement of crowds and vehicles in a queue. PMID- 23030987 TI - Strategy to suppress epidemic explosion in heterogeneous metapopulation networks. AB - We propose an efficient strategy to suppress epidemic explosion in heterogeneous metapopulation networks, wherein each node represents a subpopulation with any number of individuals and is assigned a curing rate that is proportional to kalpha with the node degree k and an adjustable parameter alpha. We perform stochastic simulations of the dynamical reaction-diffusion processes associated with the susceptible-infected-susceptible model in scale-free networks. We find that the epidemic threshold reaches a maximum when alpha is tuned at alphaopt?1.3. This nontrivial phenomenon is robust to the change of the network size and the average degree. In addition, we carry out a mean field analysis to further validate our scheme, which also demonstrates that epidemic explosion follows different routes for alpha larger or less than alphaopt. Our work suggests that in order to efficiently suppress epidemic spreading on heterogeneous complex networks, subpopulations with higher degrees should be allocated more resources than just being linearly dependent on k. PMID- 23030988 TI - Stability of Boolean multilevel networks. AB - The study of the interplay between the structure and dynamics of complex multilevel systems is a pressing challenge nowadays. In this paper, we use a semiannealed approximation to study the stability properties of random Boolean networks in multiplex (multilayered) graphs. Our main finding is that the multilevel structure provides a mechanism for the stabilization of the dynamics of the whole system even when individual layers work on the chaotic regime, therefore identifying new ways of feedback between the structure and the dynamics of these systems. Our results point out the need for a conceptual transition from the physics of single-layered networks to the physics of multiplex networks. Finally, the fact that the coupling modifies the phase diagram and the critical conditions of the isolated layers suggests that interdependency can be used as a control mechanism. PMID- 23030989 TI - Exploring the low-energy landscape of large-scale signed social networks. AB - Analogously to a spin glass, a large-scale signed social network is characterized by the presence of disorder, expressed in this context (and in the social network literature) by the concept of structural balance. If, as we have recently shown, the signed social networks currently available have a limited amount of true disorder (or frustration), it is also interesting to investigate how this frustration is organized, by exploring the landscape of near-optimal structural balance. What we obtain in this paper is that while one of the networks analyzed shows a unique valley of minima, and a funneled landscape that gradually and smoothly worsens as we move away from the optimum, another network shows instead several distinct valleys of optimal or near-optimal structural balance, separated by energy barriers determined by internally balanced subcommunities of users, a phenomenon similar to the replica-symmetry breaking of spin glasses. Multiple, essentially isoenergetic, arrangements of these communities are possible. Passing from one valley to another requires one to destroy the internal arrangement of these balanced subcommunities and then to reform it again. It is essentially this process of breaking the internal balance of the subcommunities which gives rise to the energy barriers. PMID- 23030990 TI - Epidemic spreading with information-driven vaccination. AB - Epidemic spreading has been well studied in the past decade, where the main concentration is focused on the influence of network topology but little attention is paid to the individual's crisis awareness. We here study how the crisis awareness, i.e., personal self-protection, influences the epidemic spreading by presenting a susceptible-infected-recovered model with information driven vaccination. We introduce two parameters to quantitatively characterize the crisis awareness. One is the information creation rate lambda and the other is the information sensitivity eta. We find that the epidemic spreading can be significantly suppressed in both the homogeneous and heterogeneous networks when both lambda and eta are relatively large. More interesting is that the needed vaccine will be significantly reduced when the information is well spread, which is a good news for the poor countries and regions with limited resources. PMID- 23030991 TI - Effects of translational coupling on dissipative localized states. AB - Nonequilibrium localized states under the influence of translational coupling are studied experimentally and theoretically. We show that localized structures are deformed and advected in the direction of the coupling, thus undergoing different instabilities. Experimentally, localized structures are obtained in a light valve with optical feedback. By introducing a tilt of one mirror in the feedback loop, localized structures acquire a translational coupling. To understand the phenomenon in a universal framework we consider a prototypical model of localized states with translational coupling in one and two spatial dimensions. The model allows us to analytically characterize the propagation speed and the deformation exhibited by the localized state profiles as well as to figure out different mechanisms of destabilization of these dissipative structures. The results are in good qualitative agreement with the experimental and numerical observations. PMID- 23030992 TI - Local nature and scaling of chaos in weakly nonlinear disordered chains. AB - The dynamics of a disordered nonlinear chain can be either regular or chaotic with a certain probability. The chaotic behavior is often associated with the destruction of Anderson localization by the nonlinearity. In the present work it is argued that at weak nonlinearity chaos is nucleated locally on rare resonant segments of the chain. Based on this picture, the probability of chaos is evaluated analytically. The same probability is also evaluated by direct numerical sampling of disorder realizations and quantitative agreement between the two results is found. PMID- 23030993 TI - Stickiness in a bouncer model: A slowing mechanism for Fermi acceleration. AB - Some phase space transport properties for a conservative bouncer model are studied. The dynamics of the model is described by using a two-dimensional measure preserving mapping for the variables' velocity and time. The system is characterized by a control parameter epsilon and experiences a transition from integrable (epsilon=0) to nonintegrable (epsilon?0). For small values of epsilon, the phase space shows a mixed structure where periodic islands, chaotic seas, and invariant tori coexist. As the parameter epsilon increases and reaches a critical value epsilonc, all invariant tori are destroyed and the chaotic sea spreads over the phase space, leading the particle to diffuse in velocity and experience Fermi acceleration (unlimited energy growth). During the dynamics the particle can be temporarily trapped near periodic and stable regions. We use the finite time Lyapunov exponent to visualize this effect. The survival probability was used to obtain some of the transport properties in the phase space. For large epsilon, the survival probability decays exponentially when it turns into a slower decay as the control parameter epsilon is reduced. The slower decay is related to trapping dynamics, slowing the Fermi Acceleration, i.e., unbounded growth of the velocity. PMID- 23030994 TI - Noise-induced synchronization in small world networks of phase oscillators. AB - A small-world (SW) network of similar phase oscillators, interacting according to the Kuramoto model, is studied numerically. It is shown that deterministic Kuramoto dynamics on SW networks has various stable stationary states. This can be attributed to the so-called defect patterns in an SW network, which it inherits from deformation of helical patterns in its regular parent. Turning on an uncorrelated random force causes vanishing of the defect patterns, hence increasing the synchronization among oscillators for moderate noise intensities. This phenomenon, called stochastic synchronization, is generally observed in some natural networks such as the brain neural network. PMID- 23030995 TI - Scroll wave filaments self-wrap around unexcitable heterogeneities. AB - Scroll waves are three-dimensional excitation vortices rotating around one dimensional phase singularities called filaments. In experiments with a chemical reaction-diffusion system and in numerical simulations, we study the pinning of closed filament loops to inert cylindrical heterogeneities. We show that the filament wraps itself around the heterogeneity and thus avoids contraction and annihilation. This entwining steadily increases the total length of the pinned filament and reshapes the entire rotation backbone of the vortex. Self-pinning is fastest for thin cylinders with radii not much larger than the core of the unpinned rotor. The process ends when the filament is attached to the entire length of the cylinder. The possible importance of self-pinning in cardiac systems is discussed. PMID- 23030996 TI - Effective transport barriers in nontwist systems. AB - In fluids and plasmas with zonal flow reversed shear, a peculiar kind of transport barrier appears in the shearless region, one that is associated with a proper route of transition to chaos. These barriers have been identified in symplectic nontwist maps that model such zonal flows. We use the so-called standard nontwist map, a paradigmatic example of nontwist systems, to analyze the parameter dependence of the transport through a broken shearless barrier. On varying a proper control parameter, we identify the onset of structures with high stickiness that give rise to an effective barrier near the broken shearless curve. Moreover, we show how these stickiness structures, and the concomitant transport reduction in the shearless region, are determined by a homoclinic tangle of the remaining dominant twin island chains. We use the finite-time rotation number, a recently proposed diagnostic, to identify transport barriers that separate different regions of stickiness. The identified barriers are comparable to those obtained by using finite-time Lyapunov exponents. PMID- 23030997 TI - Linear stability analysis of first-order delayed car-following models on a ring. AB - The evolution of a line of vehicles on a ring is modeled by means of first-order car-following models. Three generic models describe the speed of a vehicle as a function of the spacing ahead and the speed of the predecessor. The first model is a basic one with no delay. The second is a delayed car-following model with a strictly positive parameter for the driver and vehicle reaction time. The last model includes a reaction time parameter with an anticipation process by which the delayed position of the predecessor is estimated. Explicit conditions for the linear stability of homogeneous configurations are calculated for each model. Two methods of calculus are compared: an exact one via Hopf bifurcations and an approximation by second-order models. The conditions describe stable areas for the parameters of the models that we interpret. The results notably show that the impact of the reaction time on the stability can be palliated by the anticipation process. PMID- 23030998 TI - Diffraction and tunneling in systems with mixed phase space. AB - The role of diffraction is investigated for two-dimensional area-preserving maps with sharply or almost sharply divided phase space, in relation to the issue of dynamical tunneling. The diffraction effect is known to appear in general when the system contains indifferentiable or discontinuous points. We find that it controls the quantum transition between regular and chaotic regions in mixed phase space in the case where the border between these regions is set to be sharp. However, its manifestation is rather subtle: it would be possible to identify the diffraction effect under suitable coordinates if the support of the wave function contains indifferentiable or discontinuous points, whereas it is mixed with the tunneling effect and the whole process becomes hybrid if the support does not contain the sources of diffraction. We make detailed analyses, including the semiclassical treatment of edge contributions of the one-step propagator, to clarify the nature of diffraction in mixed phase space. Our result implies that chaos does not play any roles in the regular-to-chaotic transition process when the phase space is sharply divided. PMID- 23030999 TI - Manifold learning approach for chaos in the dripping faucet. AB - Dripping water from a faucet is a typical example exhibiting rich nonlinear phenomena. For such a system, the time stamps at which water drops separate from the faucet can be directly observed in real experiments, and the time series of intervals taun between drop separations becomes a subject of analysis. Even if the mass mn of a drop at the onset of the nth separation, which is difficult to observe experimentally, exhibits perfectly deterministic dynamics, it may be difficult to obtain the same information about the underlying dynamics from the time series taun. This is because the return plot taun-1 vs. taun may become a multivalued relation (i.e., it doesn't represent a function describing deterministic dynamics). In this paper, we propose a method to construct a nonlinear coordinate which provides a "surrogate" of the internal state mn from the time series of taun. Here, a key of the proposed approach is to use isomap, which is a well-known method of manifold learning. We first apply it to the time series of taun generated from the numerical simulation of a phenomenological mass spring model for the dripping faucet system. It is shown that a clear one dimensional map is obtained by the proposed approach, whose characteristic quantities such as the Lyapunov exponent, the topological entropy, and the time correlation function coincide with the original dripping faucet system. Furthermore, we also analyze data obtained from real dripping faucet experiments, which also provide promising results. PMID- 23031001 TI - Motion of rotating pairs in a hexagonal superlattice pattern within dielectric barrier discharge. AB - Stochastic rotation of rotating pairs in a hexagonal superlattice pattern is observed in a dielectric barrier discharge system. It is found that the pairs rotate with orientation and diameter randomly changing by observing a series of frames recorded by a high speed video camera. Frames recorded by a high speed framing camera with an exposure time corresponding to current pulse phases in one half cycle of the applied voltage show that one rotating spot, six small spots, and another rotating spot in one cell discharge successively. Based on this discharging sequence, forces exerted on a rotating spot are analyzed at different discharging stages in a half voltage cycle. A resultant force on a rotating spot with both magnitude and direction varied leads to the stochastic rotation. PMID- 23031000 TI - Stabilizing oscillation death by multicomponent coupling with mismatched delays. AB - The dynamics of a symmetric network of oscillators that are mutually coupled via multiple dynamical components with mismatched delays is studied. We find that networked oscillators experience oscillation death (OD) over a much larger domain of parameters when their different dynamical components are linked with mismatched delays than with only one delay. In particular, if the delays are mismatched by retaining a certain bias, OD is proved to be linearly stable even for very large delays for an arbitrary symmetric network. Further, we show that the minimal value of the intrinsic frequency necessary to induce OD decreases as the degree of mismatch in the coupling delays increases. The stabilizing effect of multicomponent coupling with mismatched delays is shown to be valid in networked chaotic oscillators also. The proposed coupling strategy can possibly be applied in controlling several pathological activities in neuronal systems and in engineering applications. PMID- 23031002 TI - Random symmetry breaking and freezing in chaotic networks. AB - Parameter space of a driven damped oscillator in a double well potential presents either a chaotic trajectory with sign oscillating amplitude or a nonchaotic trajectory with a fixed sign amplitude. A network of such delay coupled damped oscillators is shown to present chaotic dynamics while the sign amplitude of each damped oscillator is randomly frozen. This phenomenon of random broken global symmetry of the network simultaneous with random freezing of each degree of freedom is accompanied by the existence of exponentially many randomly frozen chaotic attractors with the size of the network. Results are exemplified by a network of modified Duffing oscillators with infinite range pseudoinverse delayed interactions. PMID- 23031003 TI - Quantum versus classical dynamics in a driven barrier: The role of kinematic effects. AB - We study the dynamics of the classical and quantum mechanical scattering of a wave packet from an oscillating barrier. Our main focus is on the dependence of the transmission coefficient on the initial energy of the wave packet for a wide range of oscillation frequencies. The behavior of the quantum transmission coefficient is affected by tunneling phenomena, resonances, and kinematic effects emanating from the time dependence of the potential. We show that when kinematic effects dominate (mainly in intermediate frequencies), classical mechanics provides very good approximation of quantum results. In that frequency region, the classical and quantum transmission coefficients are in optimal agreement. Moreover, the transmission threshold (i.e., the energy above which the transmission coefficient becomes larger than a specific small threshold value) is found to exhibit a minimum. We also consider the form of the transmitted wave packet and we find that for low values of the frequency the incoming classical and quantum wave packet can be split into a train of well-separated coherent pulses, a phenomenon that admits purely classical kinematic interpretation. PMID- 23031004 TI - Estimation of noise parameters in dynamical system identification with Kalman filters. AB - A method is proposed for determining dynamical and observational noise parameters in state and parameter identification from time series using Kalman filters. The noise covariances are estimated in a secondary optimization by maximizing the predictive likelihood of the data. The approach is based on internal consistency; for the correct noise parameters, the uncertainty projected by the Kalman filter matches the actual predictive uncertainty. The method is able to disentangle dynamical and observational noise. The algorithm is demonstrated for the linear, extended, and unscented Kalman filters using an Ornstein-Uhlenbeck process, the noise-driven Lorenz system, and van der Pol oscillator as well as a paleoclimatic ice-core record as examples. The approach is also applicable to the ensemble Kalman filter and can be readily extended to non-Gaussian estimation frameworks such as Gaussian-sum filters and particle filters. PMID- 23031005 TI - Nonlinear diffusion effects on biological population spatial patterns. AB - Motivated by the observation that anomalous diffusion is a realistic feature in the dynamics of biological populations, we investigate its implications in a paradigmatic model for the evolution of a single species density u(x,t). The standard model includes growth and competition in a logistic expression, and spreading is modeled through normal diffusion. Moreover, the competition term is nonlocal, which has been shown to give rise to spatial patterns. We generalize the diffusion term through the nonlinear form ?tu(x,t)=D?xxu(x,t)nu (with D,nu>0), encompassing the cases where the state-dependent diffusion coefficient either increases (nu>1) or decreases (nu<1) with the density, yielding subdiffusion or superdiffusion, respectively. By means of numerical simulations and analytical considerations, we display how that nonlinearity alters the phase diagram. The type of diffusion imposes critical values of the model parameters for the onset of patterns and strongly influences their shape, inducing fragmentation in the subdiffusive case. The detection of the main persistent mode allows analytical prediction of the critical thresholds. PMID- 23031006 TI - Generalized synchronization in mutually coupled oscillators and complex networks. AB - We introduce a concept of generalized synchronization, able to encompass the setting of collective synchronized behavior for mutually coupled systems and networking systems featuring complex topologies in their connections. The onset of the synchronous regime is confirmed by the dependence of the system's Lyapunov exponents on the coupling parameter. The presence of a generalized synchronization regime is verified by means of the nearest neighbor method. PMID- 23031007 TI - Role of conductivity in the electrohydrodynamic patterning of air-liquid interfaces. AB - The effect of electrical conductivity on the wavelength of an electrohydrodynamic instability of a leaky dielectric-perfect dielectric (LD-PD) fluid interface is investigated. For instabilities induced by dc fields, two models, namely the PD PD model, which is independent of the conductivity, and the LD-PD model, which shows very weak dependence on the conductivity of the LD fluid, have been previously suggested. In the past, experiments have been compared with either of these two models. In the present work, experiments, analytical theory, and simulations are used to elucidate the dependence of the wavelength obtained under dc fields on the ratio of the instability time (taus=1/smax) and the charge relaxation time (tauc=epsilonepsilon0/sigma, where epsilon0 is the permittivity of vacuum, epsilon is the dielectric constant, and sigma is the electrical conductivity). Sensitive dependence of the wavelength on the nondimensional conductivity S2=sigma2MU2h0(2)/(epsilon0(2)phi0(2)delta2) (where sigma2 is the electrical conductivity, MU2 is the viscosity, h0 is the thickness of the thin liquid film, phi0 is the rms value of the applied field, and delta is a small parameter) is observed and the PD-PD and the LD-PD cases are observed only as limiting behaviors at very low and very high values of S2, respectively. Under an alternating field, the frequency of the applied voltage can be altered to realize several regimes of relative magnitudes of the three time scales inherent to the system, namely tauc, taus, and the time period of the applied field, tauf. The wavelength in the various regimes that result from a systematic variation of these three time scales is studied. It is observed that the linear Floquet theory is invalid in most of these regimes and nonlinear analysis is used to complement it. Systematic dependence of the wavelength of the instability on the frequency of the applied field is presented and it is demonstrated that nonlinear simulations are necessary to explain the experimental results. PMID- 23031008 TI - Anomalous scaling of a passive scalar field near two dimensions. AB - The anomalous scaling of the single-time structure functions of a passive scalar field advected by the velocity field governed by the stochastic Navier-Stokes equation is investigated by the field theoretic renormalization group and the operator-product expansion with inclusion of additional ultraviolet divergences related to the spatial dimension d=2. Some modification of the standard minimal subtraction scheme is used to calculate the turbulent Prandtl number and the anomalous exponents within the one-loop approximation of a perturbation theory. It is shown that the taking into account of these additional divergences is in full agreement with results obtained in the framework of the usual analytical expansion technique, which are valid for d>2. PMID- 23031009 TI - Jet impact on a soap film. AB - We experimentally investigate the impact of a liquid jet on a soap film. We observe that the jet never breaks the film and that two qualitatively different steady regimes may occur. The first one is a refractionlike behavior obtained at small incidence angles when the jet crosses the film and is deflected by the film jet interaction. For larger incidence angles, the jet is absorbed by the film, giving rise to a new class of flows in which the jet undulates along the film with a characteristic wavelength. Besides its fundamental interest, this paper presents a different way to guide a micrometric flow of liquid in the inertial regime and to probe foam stability submitted to violent perturbations at the soap film scale. PMID- 23031010 TI - Cavitation dynamics and directional microbubble ejection induced by intense femtosecond laser pulses in liquids. AB - We study cavitation dynamics when focusing ring-shaped femtosecond laser beams in water. This focusing geometry reduces detrimental nonlinear beam distortions and enhances energy deposition within the medium, localized at the focal spot. We observe remarkable postcollapse dynamics of elongated cavitation bubbles with high-speed ejection of microbubbles out of the laser focal region. Bubbles are ejected along the laser axis in both directions (away and towards the laser). The initial shape of the cavitation bubble is also seen to either enhance or completely suppress jet formation during collapse. In the absence of jetting, microbubble ejection occurs orthogonal to the laser propagation axis. PMID- 23031011 TI - Nonlinear shallow ocean-wave soliton interactions on flat beaches. AB - Ocean waves are complex and often turbulent. While most ocean-wave interactions are essentially linear, sometimes two or more waves interact in a nonlinear way. For example, two or more waves can interact and yield waves that are much taller than the sum of the original wave heights. Most of these shallow-water nonlinear interactions look like an X or a Y or two connected Ys; at other times, several lines appear on each side of the interaction region. It was thought that such nonlinear interactions are rare events: they are not. Here we report that such nonlinear interactions occur every day, close to low tide, on two flat beaches that are about 2000 km apart. These interactions are closely related to the analytic, soliton solutions of a widely studied multidimensional nonlinear wave equation. On a much larger scale, tsunami waves can merge in similar ways. PMID- 23031012 TI - Effects of forcing geometry on two-dimensional weak turbulence. AB - Using high-resolution particle tracking velocimetry, we study the effects of the forcing geometry on the statistics of an electromagnetically stirred thin-layer flow. We consider two forcing arrangements: one that produces a lattice of vortices as a base flow, and one that produces an array of shear bands. We find that the vortex flow drives stronger fluctuating kinetic energy while the shear band flow leads to more intense fluctuating velocity gradients. We explain our results by considering the spectral flow of energy in the system. Our results have implications for the design of two-dimensional flow experiments. PMID- 23031013 TI - Long-time properties of magnetohydrodynamic turbulence and the role of symmetries. AB - Using direct numerical simulations with grids of up to 512(3) points, we investigate long-time properties of three-dimensional magnetohydrodynamic turbulence in the absence of forcing and examine in particular the roles played by the quadratic invariants of the system and the symmetries of the initial configurations. We observe that when sufficient accuracy is used, initial conditions with a high degree of symmetries, as in the absence of helicity, do not travel through parameter space over time, whereas by perturbing these solutions either explicitly or implicitly using, for example, single precision for long times, the flows depart from their original behavior and can either become strongly helical or have a strong alignment between the velocity and the magnetic field. When the symmetries are broken, the flows evolve towards different end states, as already predicted by statistical arguments for nondissipative systems with the addition of an energy minimization principle. Increasing the Reynolds number by an order of magnitude when using grids of 64(3) 512(3) points does not alter these conclusions. Furthermore, the alignment properties of these flows, between velocity, vorticity, magnetic potential, induction, and current, correspond to the dominance of two main regimes, one helically dominated and one in quasiequipartition of kinetic and magnetic energies. We also contrast the scaling of the ratio of magnetic energy to kinetic energy as a function of wave number to the ratio of eddy turnover time to Alfven time as a function of wave number. We find that the former ratio is constant with an approximate equipartition for scales smaller than the largest scale of the flow, whereas the ratio of time scales increases with increasing wave number. PMID- 23031014 TI - Chaotic gas turbine subject to augmented Lorenz equations. AB - Inspired by the chaotic waterwheel invented by Malkus and Howard about 40 years ago, we have developed a gas turbine that randomly switches the sense of rotation between clockwise and counterclockwise. The nondimensionalized expressions for the equations of motion of our turbine are represented as a starlike network of many Lorenz subsystems sharing the angular velocity of the turbine rotor as the central node, referred to as augmented Lorenz equations. We show qualitative similarities between the statistical properties of the angular velocity of the turbine rotor and the velocity field of large-scale wind in turbulent Rayleigh Benard convection reported by Sreenivasan et al. [Phys. Rev. E 65, 056306 (2002)]. Our equations of motion achieve the random reversal of the turbine rotor through the stochastic resonance of the angular velocity in a double-well potential and the force applied by rapidly oscillating fields. These results suggest that the augmented Lorenz model is applicable as a dynamical model for the random reversal of turbulent large-scale wind through cessation. PMID- 23031015 TI - Jets and sprays arising from a spark-induced oscillating bubble near a plate with a hole. AB - An experimental study of jets and sprays formed by a spark-induced bubble collapsing near a plate with a hole is presented. A Perspex plate with a hole at its center is placed in a half-filled water tank with its top face near the air water interface. A bubble is created using a low-voltage electrical spark below the hole in the plate. The bubble expands against the hole, which pushes the liquid present within the hole and leads to an initial primary jet of water that emerges from the other end of the hole into air. The bubble subsequently collapses and leads to a second jet that is characterized by short bursts of liquid spray followed by a thicker continuous liquid column. The impact of the sprays onto the primary jet leads to perturbations in the jet and the breakup of the latter into fine droplets. The entire phenomenon is recorded using a high speed camera to visualize the mechanism both within and outside the hole. The results give a clearer indication of the mechanism behind a recently reported phenomenon on the formation of impacting jets caused by bubble expansion and collapse at the micrometer length scale. The variation of the jet characteristics with parameters such as the position of the water-air interface with respect to the plate and the hole geometry (i.e., the hole diameter and the plate thickness) is also presented. PMID- 23031016 TI - Electrohydrodynamics of a liquid drop in confined domains. AB - The steady-state electrohydrodynamics of a leaky dielectric drop in confined domains is investigated analytically. The governing electrohydrodynamic equations are solved for Newtonian and immiscible fluids in the framework of leaky dielectric theory and for the creeping flow regime. The domain confinement strengthens or weakens the electric field, depending on R>1 or R<1, respectively, where R=sigmai/sigmao is the ratio of electric conductivity of the drop to that of the surrounding fluid. Similarly, the flow intensity decreases for R<1, but it remains unchanged or increases for R>1, depending on the interplay of electric and hydrodynamic effects. An expression for the drop deformation for small distortion from the spherical shape is found using the domain perturbation technique. It is shown that below a threshold domain size the confinement effect will lead to the reversal of the tendency of the net normal hydrodynamic stress in deforming the drop to an oblate or a prolate shape, and that below a critical domain size the necessary condition for having an oblate drop will be opposite to the classical one for an unbounded domain. PMID- 23031017 TI - Macroscopic description of nonequilibrium effects in thermal transpiration flows in annular microchannels. AB - Thermal transpiration flow of rarefied gases in annular channels is considered where the driving force for the flow is a temperature gradient applied in the channel walls. The influence of gas rarefaction, aspect ratio of the annulus, and surface accommodation coefficient on mass and heat transfer in the process are investigated. An analytical approach to the problem is conducted based on linearized Navier-Stokes-Fourier (NSF) and regularized 13-moment (R13) equations, and a closed-form expression for Knudsen boundary layers is obtained. The results are compared to available solutions of the Boltzmann equation to highlight the advantages of the R13 over the NSF equations in describing nonequilibrium effects in this particular thermally driven flow. Through comparisons with kinetic data, it is shown that R13 equations are valid for moderate Knudsen numbers, i.e., Kn<0.5 where NSF equations fail to describe the flow fields properly. PMID- 23031018 TI - Subcritical transition to turbulence: What we can learn from the physics of glasses. AB - In this note, we discuss possible analogies between the subcritical transition to turbulence in shear flows and the glass transition in supercooled liquids. We briefly review recent experimental and numerical results, as well as theoretical proposals, and compare the difficulties arising in assessing the divergence of the turbulence lifetime in subcritical shear flow with that encountered for the relaxation time in the study of the glass transition. In order to go beyond the purely methodological similarities, we further elaborate on this analogy and propose a simple model for the transition to turbulence, inspired by the random energy model (a standard model for the glass transition), with the aim to possibly foster yet-unexplored directions of research in subcritical shear flows. PMID- 23031019 TI - Viscosity calculation of a nanoparticle suspension confined in nanochannels. AB - The kinetic properties of the pressure-driven Poiseuille flow in nanochannels with and without nanoparticles were studied with a nonequilibrium molecular dynamics simulation. To allow the fluid to dissipate heat, the boundary was kept at a constant temperature. Pure fluid simulations were taken as references and also used to study the fluid-wall interfacial interaction effects. The viscosity profiles of the fluid were calculated on the basis of velocity profiles and known applied shear stress. We present the relationship between the viscosity increase and particle loading. The role of channel wall-fluid wetting properties on the flow and viscosity was also investigated. PMID- 23031020 TI - ac electric fields drive steady flows in flames. AB - We show that time-oscillating electric fields applied to plasmas present in flames create steady flows of gas. Ions generated within the flame move in the field and migrate a distance delta before recombining; the net flow of ions away from the flame creates a time-averaged force that drives the steady flows observed experimentally. A quantitative model describes the response of the flame and reveals how delta decreases as the frequency of the applied field increases. Interestingly, above a critical frequency, ac fields can be used to manipulate flames at a distance without the need for proximal electrodes. PMID- 23031021 TI - Directional motion of impacting drops on dual-textured surfaces. AB - In this work, we analyze the directional movement of impacting liquid drops on dual-textured solid surfaces comprising two different surface morphologies: a textured surface and a smooth surface. The dynamics of liquid drops impacting onto the junction line between the two parts of the dual-textured surfaces is studied experimentally for varying drop impact velocity. The dual-textured surfaces used here featured a variation in their textures' geometrical parameters as well as their surface chemistry. Two types of liquid drop differing in their surface tension were used. The impact process develops a net horizontal drop velocity towards the higher-wettability surface portion and results in a bulk movement of the impacting drop liquid. The final distance moved by the impacting drop from the junction line decreases with increasing impacting drop Weber number We. A fully theoretical model, employing a balance of forces acting at the drop contact line as well as energy conservation, is formulated to determine the variation, with We, of net horizontal drop velocity and subsequent movement of the impacting drop on the dual-textured surfaces. PMID- 23031022 TI - Taylor dispersion with adsorption and desorption. AB - We use a stochastic approach to show how Taylor dispersion is affected by kinetic processes of adsorption and desorption onto surfaces. A general theory is developed, from which we derive explicitly the dispersion coefficients of canonical examples such as Poiseuille flows in planar and cylindrical geometries, in both constant and sinusoidal velocity fields. These results open the way for the measurement of adsorption and desorption rate constants using stationary flows and molecular sorting using the stochastic resonance of the adsorption and desorption processes with the oscillatory velocity field. PMID- 23031023 TI - Microfluidic breakups of confined droplets against a linear obstacle: The importance of the viscosity contrast. AB - Combining experiments and theory, we investigate the break-up dynamics of deformable objects, such as drops and bubbles, against a linear micro-obstacle. Our experiments bring the role of the viscosity contrast Deltaeta between dispersed and continuous phases to light: the evolution of the critical capillary number to break a drop as a function of its size is either nonmonotonic (Deltaeta>0) or monotonic (Deltaeta<=0). In the case of positive viscosity contrasts, experiments and modeling reveal the existence of an unexpected critical object size for which the critical capillary number for breakup is minimum. Using simple physical arguments, we derive a model that well describes observations, provides diagrams mapping the four hydrodynamic regimes identified experimentally, and demonstrates that the critical size originating from confinement solely depends on geometrical parameters of the obstacle. PMID- 23031024 TI - Predicting enhanced mass flow rates in gas microchannels using nonkinetic models. AB - Different nonkinetic approaches are adopted in this paper towards theoretically predicting the experimentally observed phenomenon of enhanced mass flow rates accompanying pressure-driven rarefied gas flows through microchannels. Our analysis utilizes a full set of mechanically consistent volume-diffusion hydrodynamic equations, allowing complete, closed-form, analytical solutions to this class of problems. As an integral part of the analysis, existing experimental data pertaining to the subatmospheric pressure dependence of viscosity were analyzed. The several nonkinetic approaches investigated were (1) pressure-dependent viscosity exponent model, (2) slip-velocity models, and (3) volume diffusion model. We explored the ability to predict the gas's mass flow rate over the full range of Knudsen numbers, including furnishing a physically sound interpretation of the well-known Knudsen minimum observed in the mass flow rate. Matching of a pressure-dependent viscosity model, one that follows the standard temperature-viscosity power law and its supporting single momentum diffusion mechanism, did not allow an accurate interpretation of the data. Rather, matching of this model with the flow rate was found to mismatch the experimental pressure dependence of the viscosity. An additional transport mechanism model, one based on volume diffusion, offered a comprehensive understanding of the Knudsen minimum, while also resulting in excellent agreement with experimental data well into the transition regime (up to a Knudsen number of 5). PMID- 23031025 TI - Anisotropy and nonuniversality in scaling laws of the large-scale energy spectrum in rotating turbulence. AB - Rapidly rotating turbulent flow is characterized by the emergence of columnar structures that are representative of quasi-two-dimensional behavior of the flow. It is known that when energy is injected into the fluid at an intermediate scale Lf, it cascades towards smaller as well as larger scales. In this paper we analyze the flow in the inverse cascade range at a small but fixed Rossby number, Rof~0.05. Several numerical simulations with helical and nonhelical forcing functions are considered in periodic boxes with unit aspect ratio. In order to resolve the inverse cascade range with reasonably large Reynolds number, the analysis is based on large eddy simulations which include the effect of helicity on eddy viscosity and eddy noise. Thus, we model the small scales and resolve explicitly the large scales. We show that the large-scale energy spectrum has at least two solutions: one that is consistent with Kolmogorov-Kraichnan-Batchelor Leith phenomenology for the inverse cascade of energy in two-dimensional (2D) turbulence with a ~k?-5/3 scaling, and the other that corresponds to a steeper ~k?-3 spectrum in which the three-dimensional (3D) modes release a substantial fraction of their energy per unit time to the 2D modes. The spectrum that emerges depends on the anisotropy of the forcing function, the former solution prevailing for forcings in which more energy is injected into the 2D modes while the latter prevails for isotropic forcing. In the case of anisotropic forcing, whence the energy goes from the 2D to the 3D modes at low wave numbers, large-scale shear is created, resulting in a time scale taush, associated with shear, thereby producing a ~k-1 spectrum for the total energy with the horizontal energy of the 2D modes still following a ~k?-5/3 scaling. PMID- 23031026 TI - Bubble dynamics and sonoluminescence from helium or xenon in mercury and water. AB - Numerical simulations of bubble pulsation and sonoluminescence (SL) have been performed for helium or xenon bubbles in mercury and water under the experimental conditions of Futakawa et al. [M. Futakawa, T. Naoe, and M. Kawai, in Nonlinear Acoustics-Fundamentals and Applications: 18th International Symposium on Nonlinear Acoustics (ISNA 18), AIP Conf. Proc. No. 1022, edited by B. O. Enflo, C. M. Hedberg, and L. Kari (AIP, New York, 2008), p. 197]. The results of the numerical simulations have revealed that the bubble expansion is much larger in water than in mercury mainly because the density of water is one order of magnitude smaller than that of mercury. The SL intensity is higher in water than that in mercury although the maximum bubble temperature is lower. This is caused by the much larger amount of vapor inside a bubble as the saturated vapor pressure of water is four orders of magnitude larger than that of mercury at room temperature. The SL intensity from xenon is much larger than that from helium due both to lower ionization potential and higher bubble temperature due to lower thermal conductivity. The instantaneous SL power may be as large as 200 W from xenon in water. The maximum temperature inside a xenon bubble in mercury may be as high as about 80 000 K. It is suggested that the maximum pressure in mercury due to shock waves emitted from bubbles increases as the SL intensity increases, although they are not simply correlated in water because the amount of water vapor trapped inside a bubble influences the SL intensity in a complex way. PMID- 23031027 TI - Clustering of inelastic soft spheres in homogeneous turbulence. AB - In this paper we numerically investigate the influence of dissipation during particle collisions in an homogeneous turbulent velocity field by coupling a discrete element method to a lattice-Boltzmann simulation with spectral forcing. We show that even at moderate particle volume fractions the influence of dissipative collisions is important. We also investigate the transition from a regime where the turbulent velocity field significantly influences the spatial distribution of particles to a regime where the distribution is mainly influenced by particle collisions. PMID- 23031028 TI - Modeling of radiation losses in ultrahigh power laser-matter interaction. AB - Radiation losses of electrons in ultraintense laser fields constitute a process that can be important for electron and ion acceleration and creation of secondary emissions. The importance of this effect for ion acceleration to high energies is studied as a function of the laser intensity and the target thickness and density. For instance, in the piston regime, radiation losses lead to a reduction of the piston velocity and to less-efficient ion acceleration. Radiation losses have been implemented in the relativistic particle-in-cell code by using a renormalized Lorentz-Abraham-Dirac model. PMID- 23031029 TI - Head-on collisions of electrostatic solitons in nonthermal plasmas. AB - In contrast to overtaking interactions, head-on collisions between two electrostatic solitons can be dealt with only by use of an approximate method, which limits the range of validity but offers valuable insights. Treatments in the plasma physics literature all use assumptions in the stretching of space and time and in the expansion of the dependent variables that are seldom, if ever, discussed. All models force a separability to lowest order, corresponding to two linear waves with opposite but equally large velocities. A systematic exposition of the underlying hypotheses is illustrated by considering a plasma composed of cold ions and nonthermal electrons. This is general enough to yield critical compositions that lead to modified rather than standard Korteweg-de Vries equations, an aspect not discussed so far. The nonlinear evolution equations for both solitons and their phase shifts due to the collision are established. A Korteweg-de Vries description is the generic conclusion, except when the plasma composition is critical, rendering the nonlinearity in the evolution equations cubic, with concomitant repercussions on the phase shifts. In the latter case, the solitons can have either polarity, so combinations of negative and positive solitons can occur, contrary to the generic case, where both solitons necessarily have the same polarity. PMID- 23031030 TI - Coupling of detailed configuration kinetics and hydrodynamics in materials submitted to x-ray free-electron-laser irradiation. AB - We describe a model for the study of the interaction of short x-ray free-electron laser (XFEL) pulses with matter. Hydrodynamics is solved in one-dimensional planar geometry together with XFEL energy deposition, transport by thermal conduction and electron-ion energy exchange. Along with XFEL energy deposition, a proper detailed configuration accounting atomic physics model has been implemented in line with the calculations. Simulations typical of current XFEL conditions of irradiation are presented and discussed. Finally, the corresponding spectral emission of this XFEL-heated matter is calculated with the unresolved transition array formalism. PMID- 23031031 TI - Coulomb clusters of dust particles in a cusp magnetic trap under microgravity conditions. AB - We have performed experimental and theoretical investigation of the formation and behavior of Coulomb clusters of charged diamagnetic particles in a cusp magnetic trap under microgravity conditions aboard the International Space Station. Graphite particles of 100-400 MUm in size were used in experiments due to the highest specific magnetic susceptibility. We have observed the formation of clusters in the shape of an oblate ellipsoid of revolution and their oscillations after dynamical action by changing the magnetic field. Observing the excitation and damping of oscillations we have made some estimations. Molecular dynamics simulations of the observed processes have been made. Their results are in reasonable agreement with experiments. Some differences are evidently due to some unaccounted-for reasons. PMID- 23031032 TI - Dynamics of plasma gratings in atomic and molecular gases. AB - The decay of the plasma grating formed at the intersection of two femtosecond filaments is measured in several molecular and atomic gases. The grating evolution is ruled by ambipolar diffusion in atomic gases and by a combination of ambipolar diffusion and collision-assisted free electron recombination in molecular gases. Electron diffusion and recombination coefficients are extracted for Ne, Ar, Kr, Xe, N2, O2, CO2, and air at 1 bar. PMID- 23031033 TI - Negative energy waves and quantum relativistic Buneman instabilities. AB - The quantum relativistic Buneman instability is investigated theoretically using a collective Klein-Gordon model for the electrons and a cold fluid model for the ions. The growth rate and unstable wave spectrum is investigated in different parameter regimes corresponding to various degrees of relativistic and quantum effects. The results may be important for streaming instabilities involving ion dynamics in very dense plasmas. PMID- 23031034 TI - Electron-ion and ion-ion potentials for modeling warm dense matter: Applications to laser-heated or shock-compressed Al and Si. AB - The pair interactions Uij(r) determine the thermodynamics and linear transport properties of matter via the pair-distribution functions (PDFs), i.e., gij(r). Great simplicity is achieved if Uij(r) could be directly used to predict material properties via classical simulations, avoiding many-body wave functions. Warm dense matter (WDM) is encountered in quasiequilibria where the electron temperature Te differs from the ion temperature Ti, as in laser-heated or in shock-compressed matter. The electron PDFs gee(r) as perturbed by the ions are used to evaluate fully nonlocal exchange-correlation corrections to the free energy, using hydrogen as an example. Electron-ion potentials for ions with a bound core are discussed with Al and Si as examples, for WDM with Te?Ti, and valid for times shorter than the electron-ion relaxation time. In some cases the potentials develop attractive regions and then become repulsive and "Yukawa-like" for higher Te. These results clarify the origin of initial phonon hardening and rapid release. Pair potentials for shock-heated WDM show that phonon hardening would not occur in most such systems. Defining meaningful quasiequilibrium static transport coefficients consistent with the dynamic values is addressed. There seems to be no meaningful "static conductivity" obtainable by extrapolating experimental or theoretical sigma(omega,Ti,Te) to omega->0, unless Ti->Te as well. Illustrative calculations of quasistatic resistivities R(Ti,Te) of laser heated as well as shock-heated aluminum and silicon are presented using our pseudopotentials, pair potentials, and classical integral equations. The quasistatic resistivities display clear differences in their temperature evolutions, but are not the strict omega->0 limits of the dynamic values. PMID- 23031035 TI - Amplitude modulation of hydromagnetic waves and associated rogue waves in magnetoplasmas. AB - It is shown that the dynamics of amplitude-modulated compressional dispersive Alfvenic (CDA) waves in a collisional megnetoplasma is governed by a complex Ginzburg-Landau (CGL) equation. The nonlinear dispersion relation for the modulational instability of the CDA waves is derived and investigated numerically. It is found that the growth rate of the modulational instability decreases (increases) with the increase of the normalized electron-ion collision frequency alpha (the plasma beta). The modulational instability criterion for the CGL equation is defined precisely and investigated numerically. The region of the modulational instability becomes narrower with the increase of alpha and beta, indicating that the system dissipates the wave energy by collisions, and a stable CDA wave envelope packet in the form of a hole will be a dominant localized pulse. For a collisionless plasma, i.e., alpha=0, the CGL equation reduces to the standard nonlinear Schrodinger (NLS) equation. The latter is used to investigate the modulational (in)stability region for the CDA waves in a collisionless magnetoplasma. It is shown that, within unstable regions, a random set of nonlinearly interacting CDA perturbations leads to the formation of CDA rogue waves. In order to demonstrate that the characteristics of the CDA rogue waves are influenced by the plasma beta, the relevant numerical analysis of the appropriate nonlinear solution of the NLS equation is presented. The application of our investigation to space and laboratory magnetoplasmas is discussed. PMID- 23031036 TI - Thomson scattering in the average-atom approximation. AB - The average-atom model is applied to study Thomson scattering of x-rays from warm dense matter with emphasis on scattering by bound electrons. Parameters needed to evaluate the dynamic structure function (chemical potential, average ionic charge, free electron density, bound and continuum wave functions, and occupation numbers) are obtained from the average-atom model. The resulting analysis provides a relatively simple diagnostic for use in connection with x-ray scattering measurements. Applications are given to dense hydrogen, beryllium, aluminum, and titanium plasmas. In the case of titanium, bound states are predicted to modify the spectrum significantly. PMID- 23031037 TI - Effect of two-particle correlations on x-ray coherent diffractive imaging studies performed with continuum models. AB - Coherent diffraction imaging (CDI) of single molecules at atomic resolution is a major goal for the x-ray free-electron lasers (XFELs). However, during an imaging pulse, the fast laser-induced ionization may strongly affect the recorded diffraction pattern of the irradiated sample. The radiation tolerance of the imaged molecule should then be investigated a priori with a dedicated simulation tool. The continuum approach is a powerful tool for modeling the evolution of irradiated large systems consisting of more than a few hundred thousand atoms. However, this method follows the evolution of average single-particle densities, and the experimentally recorded intensities reflect the spatial two-particle correlations. The information on these correlations is then inherently not accessible within the continuum approach. In this paper we analyze this limitation of continuum models and discuss the applicability of continuum models for imaging studies. We derive a formula to calculate scattered intensities (including both elastic and inelastic scattering) from the estimates obtained with a single-particle continuum model under conditions typical for CDI studies with XFELs. We demonstrate through numerical simulations that it describes the scattered signal with good accuracy. Two-particle correlation effects manifest themselves only in the region of low momentum transfers, together with the effects of the finite size of the sample. We also show that inelastic scattering on bound electrons can have a significant impact on the measured intensities: it contributes to the background that reduces the contrast of the recorded image. This effect is even more pronounced at larger momentum transfers. Therefore, whereas inelastic scattering can be neglected for nanocrystals, where Bragg scattering dominates, and in experiments imaging single objects at low resolution, it should be taken into account when planning atomic resolution imaging of nonperiodic samples. Finally, we show the effect of the electronic damage on the recorded total signal. Progressing damage does not change the positions of intensity peaks that correspond to the (fixed) positions of imaged ions. It only changes the contrast between intensity minima and maxima, which reduces the image contrast. Our results have implications for imaging-oriented studies of radiation damage performed with continuum models, as they define the limits of applicability of these models for CDI simulations. PMID- 23031038 TI - Propagation of a laser-driven relativistic electron beam inside a solid dielectric. AB - Laser probe diagnostics: shadowgraphy, interferometry, and polarimetry were used for a comprehensive characterization of ionization wave dynamics inside a glass target induced by a laser-driven, relativistic electron beam. Experiments were done using the 50-TW Leopard laser at the University of Nevada, Reno. We show that for a laser flux of ~2 * 10(18) W/cm2 a hemispherical ionization wave propagates at c/3 for 10 ps and has a smooth electron-density distribution. The maximum free-electron density inside the glass target is ~2 * 10(19) cm-3, which corresponds to an ionization level of ~0.1%. Magnetic fields and electric fields do not exceed ~15 kG and ~1 MV/cm, respectively. The electron temperature has a hot, ringlike structure with a maximum of ~0.7 eV. The topology of the interference phase shift shows the signature of the "fountain effect", a narrow electron beam that fans out from the propagation axis and heads back to the target surface. Two-dimensional particle-in-cell (PIC) computer simulations demonstrate radial spreading of fast electrons by self-consistent electrostatic fields driven by laser. The very low ionization observed after the laser heating pulse suggests a fast recombination on the sub-ps time scale. PMID- 23031039 TI - Matter rogue waves in an F=1 spinor Bose-Einstein condensate. AB - We report new types of matter rogue waves of a spinor (three-component) model of the Bose-Einstein condensate governed by a system of three nonlinearly coupled Gross-Pitaevskii equations. The exact first-order rational solutions containing one free parameter are obtained by means of a Darboux transformation for the integrable system where the mean-field interaction is attractive and the spin exchange interaction is ferromagnetic. For different choices of the parameter, there exists a variety of different shaped solutions including two peaks in bright rogue waves and four dips in dark rogue waves. Furthermore, by utilizing the relation between the three-component and the one-component versions of the nonlinear Schrodinger equation, we can devise higher-order rational solutions, in which three components have different shapes. In addition, it is noteworthy that dark rogue wave features disappear in the third-order rational solution. PMID- 23031040 TI - Deformation of an asymmetric thin film. AB - Experiments have investigated shape changes of polymer films induced by asymmetric swelling by a chemical vapor. Inspired by recent work on the shaping of elastic sheets by non-Euclidean metrics [Y. Klein, E. Efrati, and E. Sharon, Science 315, 1116 (2007)], we represent the effect of chemical vapors by a change in the target metric tensor. In this problem, unlike that earlier work, the target metric is asymmetric between the two sides of the film. Changing this metric induces a curvature of the film, which may curve into a partial cylinder or a partial sphere. We calculate the elastic energy for each of these shapes and show that the sphere is favored for films smaller than a critical size, which depends on the film thickness, while the cylinder is favored for larger films. PMID- 23031041 TI - Green's function of the time-dependent radiative transport equation in terms of rotated spherical harmonics. AB - The time-dependent radiative transport equation is solved for the three dimensional spatially uniform infinite medium which is illuminated by a point unidirectional source using a spherical harmonics transform under rotation. Apart from the numerical evaluation of a spherical Hankel transform which connects the spatial distance with the radial distance in Fourier space, the dependence on all variables is found analytically. For the special case of a harmonically modulated source, even the spherical Hankel transform can be carried out analytically. Additionally, a special solution for the isotropically scattering infinite medium is given. The Monte Carlo method is used for a successful verification of the derived solution. PMID- 23031042 TI - Rogue waves in the Davey-Stewartson I equation. AB - General rogue waves in the Davey-Stewartson-I equation are derived by the bilinear method. It is shown that the simplest (fundamental) rogue waves are line rogue waves which arise from the constant background with a line profile and then disappear into the constant background again. It is also shown that multirogue waves describe the interaction of several fundamental rogue waves. These multirogue waves also arise from the constant background and then decay back to it, but in the intermediate times, interesting curvy wave patterns appear. However, higher-order rogue waves exhibit different dynamics. Specifically, only part of the wave structure in the higher-order rogue waves rises from the constant background and then retreats back to it, and this transient wave possesses patterns such as parabolas. But the other part of the wave structure comes from the far distance as a localized lump, which decelerates to the near field and interacts with the transient rogue wave, and is then reflected back and accelerates to the large distance again. PMID- 23031043 TI - Undular bore theory for the Gardner equation. AB - We develop modulation theory for undular bores (dispersive shock waves) in the framework of the Gardner, or extended Korteweg-de Vries (KdV), equation, which is a generic mathematical model for weakly nonlinear and weakly dispersive wave propagation, when effects of higher order nonlinearity become important. Using a reduced version of the finite-gap integration method we derive the Gardner Whitham modulation system in a Riemann invariant form and show that it can be mapped onto the well-known modulation system for the Korteweg-de Vries equation. The transformation between the two counterpart modulation systems is, however, not invertible. As a result, the study of the resolution of an initial discontinuity for the Gardner equation reveals a rich phenomenology of solutions which, along with the KdV-type simple undular bores, include nonlinear trigonometric bores, solibores, rarefaction waves, and composite solutions representing various combinations of the above structures. We construct full parametric maps of such solutions for both signs of the cubic nonlinear term in the Gardner equation. Our classification is supported by numerical simulations. PMID- 23031044 TI - Binding energy of soliton molecules in time-dependent harmonic potential and nonlinear interaction. AB - We calculate the binding energy of soliton molecules of an integrable nonlinear Schro[over ]dinger equation with time-dependent harmonic potential and cubic nonlinearity. Through a scaling transformation, an exact formula for the binding energy can be derived from that of the free soliton molecules in a homogeneous background. In the special case of oscillatory time dependence, sharp resonances occur at some integer and fractional multiples of the natural frequency of the molecule. Enhanced binding is obtained at these resonances and over some finite continuous range of low frequencies. PMID- 23031045 TI - Bright solitons in defocusing media with spatial modulation of the quintic nonlinearity. AB - It has been recently demonstrated that self-defocusing (SDF) media with cubic nonlinearity, whose local coefficient grows from the center to the periphery fast enough, support stable bright solitons without the use of any linear potential. Our objective is to test the genericity of this mechanism for other nonlinearities, by applying it to one- and two-dimensional (1D and 2D) quintic SDF media. The models may be implemented in optics (in particular, in colloidal suspensions of nanoparticles), and the 1D model may be applied to the description of the Tonks-Girardeau gas of ultracold bosons. In 1D, the nonlinearity modulation function is taken as g0+sinh2(betax). This model admits a subfamily of exact solutions for fundamental solitons. Generic soliton solutions are constructed in a numerical form and also by means of the Thomas-Fermi and variational approximations (TFA and VA). In particular, a new ansatz for the VA is proposed, in the form of "raised sech," which provides for an essentially better accuracy than the usual Gaussian ansatz. The stability of all the fundamental (nodeless) 1D solitons is established through the computation of the corresponding eigenvalues for small perturbations and also verified by direct simulations. Higher-order 1D solitons with two nodes have a limited stability region, all the modes with more than two nodes being unstable. It is concluded that the recently proposed inverted Vakhitov-Kolokolov stability criterion for fundamental bright solitons in systems with SDF nonlinearities holds here too. Particular exact solutions for 2D solitons are produced as well. PMID- 23031046 TI - Pinned modes in lossy lattices with local gain and nonlinearity. AB - We introduce a discrete linear lossy system with an embedded "hot spot" (HS), i.e., a site carrying linear gain and complex cubic nonlinearity. The system can be used to model an array of optical or plasmonic waveguides, where selective excitation of particular cores is possible. Localized modes pinned to the HS are constructed in an implicit analytical form, and their stability is investigated numerically. Stability regions for the modes are obtained in the parameter space of the linear gain and cubic gain or loss. An essential result is that the interaction of the unsaturated cubic gain and self-defocusing nonlinearity can produce stable modes, although they may be destabilized by finite-amplitude perturbations. On the other hand, the interplay of the cubic loss and self defocusing gives rise to a bistability. PMID- 23031047 TI - Multicomponent interparticle-potential lattice Boltzmann model for fluids with large viscosity ratios. AB - This work focuses on an improved multicomponent interparticle-potential lattice Boltzmann model. The model results in viscosity-independent equilibrium densities and is capable of simulating kinematic viscosity ratios greater than 1000. External forces are incorporated into the discrete Boltzmann equation, rather than through an equilibrium velocity shift as in the original Shan and Chen (hereafter, SC) model. The model also requires the derivation of a momentum conserving effective velocity, which is substituted into the equilibrium distribution function and applies to both the single- and multiple-relaxation time formulations. Additionally, higher-order isotropy is used in the calculation of the fluid-fluid interaction forces to reduce the magnitude of spurious currents (i.e., numerical errors) in the vicinity of interfaces. First, we compare the model to the SC model for static bubble simulations. We demonstrate that the model results in viscosity-independent equilibrium bubble densities for a wide range of kinematic viscosities, which is not the case for the SC model. Furthermore, we show that the model is capable of simulating stable bubbles for kinematic viscosity ratios greater than 1000 (when higher-order isotropy is used), whereas the SC model is known to be limited to kinematic viscosity ratios on the order of 10. Next we verify the model for surface tension via Laplace's law and show that the model results in the same surface tension values for a range of kinematic viscosities and kinematic viscosity ratios of 10, 100, and 1000. The model is also verified for layered cocurrent flow though parallel plates. We show that the simulated velocity profiles preserve continuity at the interface for kinematic viscosity ratios ranging from 0.001 to 1000 and that the model accurately predicts nonwetting and wetting phase relative permeability for kinematic viscosity ratios of 0.01 to 100. PMID- 23031048 TI - Simulation of stochastic systems via polynomial chaos expansions and convex optimization. AB - Polynomial chaos expansions represent a powerful tool to simulate stochastic models of dynamical systems. Yet, deriving the expansion's coefficients for complex systems might require a significant and nontrivial manipulation of the model, or the computation of large numbers of simulation runs, rendering the approach too time consuming and impracticable for applications with more than a handful of random variables. We introduce a computationally tractable technique for computing the coefficients of polynomial chaos expansions. The approach exploits a regularization technique with a particular choice of weighting matrices, which allows to take into account the specific features of polynomial chaos expansions. The method, completely based on convex optimization, can be applied to problems with a large number of random variables and uses a modest number of Monte Carlo simulations, while avoiding model manipulations. Additional information on the stochastic process, when available, can be also incorporated in the approach by means of convex constraints. We show the effectiveness of the proposed technique in three applications in diverse fields, including the analysis of a nonlinear electric circuit, a chaotic model of organizational behavior, and finally a chemical oscillator. PMID- 23031049 TI - Framework for constructing generic Jastrow correlation factors. AB - We have developed a flexible framework for constructing Jastrow factors which allows for the introduction of terms involving arbitrary numbers of particles. The use of various three- and four-body Jastrow terms in quantum Monte Carlo calculations is investigated, including a four-body van der Waals-like term, and anisotropic terms. We have tested these Jastrow factors on one- and two dimensional homogeneous electron gases, the Be, B, and O atoms, and the BeH, H2O, N2, and H2 molecules. Our optimized Jastrow factors retrieve more than 90% of the fixed-node diffusion Monte Carlo correlation energy in variational Monte Carlo for each system studied. PMID- 23031050 TI - Molecular dynamics method to locally resolve Poisson's ratio: Mechanical description of the solid-soft-matter interphase. AB - A method based on "small-deformation mechanical response" has been developed to locally resolve the Poisson's ratio via molecular dynamics simulations. The approach can be used for simple and composite materials to characterize systems with two or more continuous phases in the framework of periodic boundary conditions. The proposed technique represents a simple method to obtain a local mechanical description of complex systems. A polystyrene bulk, a silica bulk, and a polystyrene-silica heterogeneous composite material have been characterized under imposed strain. The results show the effects of local material inhomogeneities which are present in the glassy material and in the composite system. The Poisson's ratio spatial profiles for silica, the polystyrene bulk, and in the interphase region between the soft polymer bulk and the hard surface have also been calculated. The obtained local mechanical description can be employed in micromechanical models developed to predict the overall mechanical properties of multicomponent materials. PMID- 23031051 TI - Kinetic Monte Carlo simulations for transient thermal fields: Computational methodology and application to the submicrosecond laser processes in implanted silicon. AB - Pulsed laser irradiation of damaged solids promotes ultrafast nonequilibrium kinetics, on the submicrosecond scale, leading to microscopic modifications of the material state. Reliable theoretical predictions of this evolution can be achieved only by simulating particle interactions in the presence of large and transient gradients of the thermal field. We propose a kinetic Monte Carlo (KMC) method for the simulation of damaged systems in the extremely far-from equilibrium conditions caused by the laser irradiation. The reference systems are nonideal crystals containing point defect excesses, an order of magnitude larger than the equilibrium density, due to a preirradiation ion implantation process. The thermal and, eventual, melting problem is solved within the phase-field methodology, and the numerical solutions for the space- and time-dependent thermal field were then dynamically coupled to the KMC code. The formalism, implementation, and related tests of our computational code are discussed in detail. As an application example we analyze the evolution of the defect system caused by P ion implantation in Si under nanosecond pulsed irradiation. The simulation results suggest a significant annihilation of the implantation damage which can be well controlled by the laser fluence. PMID- 23031052 TI - Nonlinear propagation of light in structured media: Generalized unidirectional pulse propagation equations. AB - Unidirectional pulse propagation equations [UPPE, Phys. Rev. E 70, 036604 (2004)] have provided a theoretical underpinning for computer-aided investigations into dynamics of high-power ultrashort laser pulses and have been successfully utilized for almost a decade. Unfortunately, they are restricted to applications in bulk media or, with additional approximations, to simple waveguide geometries in which only a few guided modes can approximate the propagating waveform. The purpose of this work is to generalize the directional pulse propagation equations to structures characterized by strong refractive index differences and material interfaces. We also outline a numerical solution framework that draws on the combination of the bulk-media UPPE method with single-frequency beam-propagation techniques. PMID- 23031053 TI - Calculating diffusion and permeability coefficients with the oscillating forward reverse method. AB - The forward-reverse or FR method is an efficient bidirectional work method for determining the potential of mean force w(z) and also supposedly gives in principle the position-dependent diffusion coefficient D(z). Results from a variation called the OFR (oscillating FR) method suggest inconsistencies in the D(z) values when calculated as prescribed by the FR method. A new steering protocol has thus been developed and applied to the OFR method for the accurate determination of D(z) and also provides greater convergence for w(z) in molecular dynamics simulations. The bulk diffusion coefficient for water was found to be (6.03+/-0.16)*10(-5) cm2/s at 350 K with system size dependence within the statistical error bars. Using this steering protocol, D(z) and w(z) for water permeating a dipalmitoylphosphatidylcholine (DPPC) bilayer were determined. The potential of mean force is shown to have a barrier of peak height, wmax/(kBT)=8.4, with a width of about 10 A on either side from the membrane center. The diffusion constant is shown to be highest in the core region of the membrane [peak value ~(8.0+/-0.8)*10(-5) cm2/s], lowest in the head-group region [minimum value ~(2.0+/-0.3)*10(-5) cm2/s], and to tend toward the bulk value as the water molecule leaves the membrane. The permeability coefficient P for H2O in DPPC was determined using the simulated D(z) and w(z) to give values of (0.129+/ 0.075) cm/s at 323 K and (0.141+/-0.043) cm/s at 350 K. The results show more spatial detail than results presented in previous work while reducing the computational and user effort. PMID- 23031054 TI - Degree correlations in random geometric graphs. AB - Spatially embedded networks are important in several disciplines. The prototypical spatial network we assume is the Random Geometric Graph, of which many properties are known. Here we present new results for the two-point degree correlation function in terms of the clustering coefficient of the graphs for two dimensional space in particular, with extensions to arbitrary finite dimensions. PMID- 23031055 TI - Stochastic resonance on the transverse displacement of swimmers in an oscillatory shear flow. AB - Self-propelled microorganisms, such as unicellular algae or bacteria, swim along their director relative to the fluid velocity. Under a steady shear flow the director rotates in close orbit, a periodic structure that is preserved under an oscillatory shear flow. If the shear flow is subjected to small fluctuations produced by small irregularities in the microchannel or by other swimmers nearby, the director dynamics becomes stochastic. Numerical integration of the swimmer motion shows that there is stochastic resonance: The displacement in the vorticity direction is maximized for a finite noise intensity. This transverse displacement resonance is observed when the displacement is coarse grained over several periods, although the director is preferentially oriented along the flow. The resonant noise intensity is proportional to the oscillation frequency and independent of the shear rate. The enhanced displacement can have effects on the transverse diffusion of swimmers and the rheology of the suspension. PMID- 23031056 TI - Localized pulses for the quintic derivative nonlinear Schrodinger equation on a continuous-wave background. AB - Quintic derivative nonlinear Schrodinger equations arise in various physical contexts, notably in the study of hydrodynamic wave packets and media with negative refractive index. A procedure to isolate propagating wave patterns in such nonlinear Schrodinger equations is proposed which is based on two integrals of motion. As an illustration of the method, a "gray" solitary pulse, a "dark" localized mode with nonzero minimum in intensity on a continuous-wave background is identified. PMID- 23031058 TI - On the reaction of lupulones, hops beta-acids, with 1-hydroxyethyl radical. AB - Lupulones, hops beta-acids, are one of the main constituents of the hops resin and have an important contribution to the overall bacteriostatic activity of hops during beer brewing. The use of lupulones as natural alternatives to antibiotics is increasing in the food industry and also in bioethanol production. However, lupulones are easy oxidizable and have been shown to be very reactive toward 1 hydroxyethyl radical with apparent bimolecular rate constants close to diffusion control k = 2.9 * 10(8) and 2.6 * 10(8) L mol(-1) s(-1) at 25.0 +/- 0.2 degrees C in ethanol-water solution (10% of ethanol (v/v)) as probed by EPR and ESI-IT MS/MS spin-trapping competitive kinetics, respectively. The free energy change for an electron-transfer mechanism is DeltaG degrees = 106 kJ/mol as calculated from the oxidation peak potential experimentally determined for lupulones (1.1 V vs NHE) by cyclic voltammetry and the reported reduction potential for 1 hydroxyethyl radical. The major reaction products identified by LC-ESI-IT-MS/MS and ultrahigh-resolution accurate mass spectrometry (orbitrap FT-MS) are hydroxylated lupulone derivatives and 1-hydroxyethyl radical adducts. The lack of pH dependence for the reaction rate constant, the calculated free energy change for electron transfer, and the main reaction products strongly suggest the prenyl side chains at the hops beta-acids as the reaction centers rather than the beta,beta'-triketone moiety. PMID- 23031057 TI - Divergent patterns of endogenous small RNA populations from seed and vegetative tissues of Glycine max. AB - BACKGROUND: Small non-coding RNAs (smRNAs) are known to have major roles in gene regulation in eukaryotes. In plants, knowledge of the biogenesis and mechanisms of action of smRNA classes including microRNAs (miRNAs), short interfering RNAs (siRNAs), and trans-acting siRNAs (tasiRNAs) has been gained mostly through studies with Arabidopsis. In recent years, high throughput sequencing of smRNA populations has enabled extension of knowledge from model systems to plants with larger, more complex genomes. Soybean (Glycine max) now has many genomics resources available including a complete genome sequence and predicted gene models. Relatively little is known, however, about the full complement of its endogenous smRNAs populations and the silenced genes. RESULTS: Using Illumina sequencing and computational analysis, we characterized eight smRNA populations from multiple tissues and organs of soybean including developing seed and vegetative tissues. A total of 41 million raw sequence reads collapsed into 135,055 unique reads were mapped to the soybean genome and its predicted cDNA gene models. Bioinformatic analyses were used to distinguish miRNAs and siRNAs and to determine their genomic origins and potential target genes. In addition, we identified two soybean TAS3 gene homologs, the miRNAs that putatively guide cleavage of their transcripts, and the derived tasiRNAs that could target soybean genes annotated as auxin response factors. Tissue-differential expression based on the flux of normalized miRNA and siRNA abundances in the eight smRNA libraries was evident, some of which was confirmed by smRNA blotting. Our global view of these smRNA populations also revealed that the size classes of smRNAs varied amongst different tissues, with the developing seed and seed coat having greater numbers of unique smRNAs of the 24-nt class compared to the vegetative tissues of germinating seedlings. The 24-nt class is known to be derived from repetitive elements including transposons. Detailed analysis of the size classes associated with ribosomal RNAs and transposable element families showed greater diversity of smRNAs in the 22- and 24-nt size classes. CONCLUSIONS: The flux of endogenous smRNAs within multiple stages and tissues of seed development was contrasted with vegetative tissues of soybean, one of the dominant sources of protein and oil in world markets. The smRNAs varied in size class, complexity of origins, and possible targets. Sequencing revealed tissue-preferential expression for certain smRNAs and expression differences among closely related miRNA family members. PMID- 23031059 TI - Differential effects of decoy receptor- and antibody-mediated tumour necrosis factor blockage on FoxP3 expression in responsive arthritis patients. AB - Our aim was to clarify if anti-tumour necrosis factor (TNF) drugs have effect on expression of three splice forms of FoxP3 mRNA in blood CD4+ T cells from rheumatoid arthritis (RA) patients compared with healthy controls. Forty-five rheumatoid arthritis patients treated with anti-TNF therapy were investigated in a 12-week prospective cohort study. FoxP3 isoforms, CD25 and CTLA-4 mRNA in blood CD4+ T cells were measured with quantitative real-time PCR. Patients benefitting from the treatment, based on changes in DAS28 scores, revealed a significant decrease in expression of full-length FoxP3 following 12 weeks treatment with TNF receptor 2 fusion protein (Etanercept), but not following treatment with anti-TNF antibodies (Adalimumab or Infliximab). A partial normalization of the CTLA 4/FoxP3fl ratio and a correlation between clinical improvement and change in FoxP3 mRNA expression were also seen in Etanercept responders. These changes were not observed in responsive patients treated with the antibody therapies. Our data suggest that TNF decoy receptor and anti-TNF antibodies differ in their effect on FoxP3 expression in responsive patients. As Etanercept binds both TNF-alpha and Lymphotoxin-alpha (LT-alpha), whereas the antibodies only target TNF-alpha, LT alpha may regulate FoxP3 expression in a subset of RA patients. Our findings support the view that anti-TNF treatment is mainly symptomatic. PMID- 23031060 TI - The effect of DSM-5 criteria on the developmental quotient in toddlers diagnosed with autism spectrum disorder. AB - OBJECTIVE: To determine the effect of the changing fifth edition of the Diagnostic and Statistical Manual (DSM-5) criteria on the developmental profiles of children diagnosed with an Autism spectrum disorder (ASD). METHODS: This study examines the effect of DSM-5 changes on impairment profiles of a population of 2054 at-risk toddlers aged 17-36 months using the Battelle Developmental Inventory, Second Edition. RESULTS: Toddlers diagnosed with an ASD according to the DSM-5 were found to represent a more impaired population compared to those who qualified for a diagnosis of an ASD based on the DSM-IV-TR, but not the DSM 5. The group diagnosed according to the DSM-IV-TR represented a population of toddlers who were more impaired than atypically developing peers. CONCLUSIONS: The proposed changes to the DSM will likely result in those diagnosed with an ASD according to the new criteria representing a more functionally impaired group. Implications of this proposed change are discussed. PMID- 23031061 TI - Using ballistocardiography to measure cardiac performance: a brief review of its history and future significance. AB - Ballistocardiography (BCG) is a non-invasive technology that has been used to record ultra-low-frequency vibrations of the heart allowing for the measurement of cardiac cycle events including timing and amplitudes of contraction. Recent developments in BCG have made this technology simple to use, as well as time- and cost-efficient in comparison with other more complicated and invasive techniques used to evaluate cardiac performance. Recent technological advances are considerably greater since the advent of microprocessors and laptop computers. Along with the history of BCG, this paper reviews the present and future potential benefits of using BCG to measure cardiac cycle events and its application to clinical and applied research. PMID- 23031062 TI - Hepatitis C virus infection and risk of coronary artery disease: a systematic review of the literature. AB - BACKGROUND: Several chronic infections have been associated with cardiovascular diseases, including Chlamydia pneumoniae, human immunodeficiency virus and viral hepatitis. This review evaluates the literature on the association between chronic hepatitis C virus (HCV) infection and the risk of coronary artery disease (CAD). METHODS: Studies were identified using several databases. Only studies on CAD in patients with HCV infection were included. A set of criteria for evaluating potential biases was made, based on known confounders and biases in observational research. Data were not synthesized because of the large heterogeneity in the included studies. RESULTS: Twelve eligible references were identified. Nine did not comply with our criteria of minimizing bias, and six studies were evaluated as potentially heavily biased. The studies of the highest quality showed a trend towards association of HCV with CAD. Five studies showed this association (three studies significantly), while one showed that HCV was a protective factor against CAD. CONCLUSION: Our findings suggest an increased risk of CAD in HCV-infected individuals. Further studies are needed to confirm this and to evaluate the magnitude of the association. Clinicians should be aware of this and strive to reduce CAD risk factors in patients with chronic HCV infection. PMID- 23031063 TI - Evaluation and optimization of administered activity, scanning parameters and hydration at (99m) Tc hydroxymethylene diphosphonate adult whole-body bone imaging. AB - PURPOSE: To find out the method of optimal activity administration and scanning parameters to fulfil guidelines and diagnostic reference levels and to reach a maximal contrast-to-noise ratio (CNR) in bone imaging. We also investigate the influence on CNR and bladder activity in well-hydrated patients. METHODS: A total of 225 patients were included. The first group of 101 patients was used to find out the optimal method to administer activity in terms of optimized CNR. The next two groups with 62 patients each were hydrated with 1500 ml water in two different time periods. CNR, bladder area and content were calculated. RESULTS: An administrated activity per metre body height gave the highest CNR (5.43). A standard activity had the lowest percentage (2%) of images with < 1.5 million counts. Early hydration decreased CNR from 5.41 to 4.85 (P = 0.06), with late hydration to 5.29 (NS). Studies with too few pulses were increased from 2 to 11% to a level of 15-26% and 11-21%, respectively. Early hydration reduced the bladder activity from 20.7 to 10.1 MBq (P< 0.01), late hydration to 14.8 MBq (P = 0.08). The bladder size was enlarged from the no hydrated group (1406 mm(2) ) to the early hydrated group (2406 mm(2) , P< 0.000) and between the early and late hydrated group (3183 mm(2) , P< 0.05). CONCLUSION: A standard activity in sufficient quantity is the most practical method, in addition to have the lowest percentage of images with too few pulses. A high fluid intake is not recommended because of problems with disturbing bladder content. PMID- 23031064 TI - Assessment of changes in cardiac autonomic tone resulting from inflammatory response to the influenza vaccination. AB - A total of 71 healthy volunteers opting to have a routine influenza vaccination were investigated for potential changes in cardiovascular autonomic tone resulting from the temporary inflammatory effects of an influenza vaccination. A number of temporal and frequency domain parameters of heart rate and breathing were assessed 2-5 days prior to vaccination and 1-4 days postvaccination. Three lead electrocardiograph (ECG), beat-to-beat finger blood pressure and chest plethysmography signals were measured. After an extended resting period, patients performed metronome-guided breathing at six breaths per min for a period of 2 min. Standard Ewing tests of autonomic function were also performed. All volunteers completed a vaccine symptom questionnaire. A subgroup of 15 volunteers who reported significant symptomatic reaction to the vaccination for at least 24 h following vaccination were identified based on the results of the questionnaire. A significant reduction in measures of heart rate variability (HRV) obtained during metronome-guided breathing was noted following vaccination in the subgroup of 15 symptomatic volunteers. No significant changes were observed in standard Ewing assessment, fractal dimension analysis, baroreflex sensitivity assessment or resting HRV. There was no evidence of significant reduction in autonomic tone following vaccination in the full sample of 71 volunteers. Results suggest a significant change in HRV response to a small inflammatory provocation and suggest further investigation of the inflammatory causes of dysautonomia is of value. PMID- 23031065 TI - Effects of exercise prescription on daily physical activity and maximal exercise capacity in coronary artery disease patients with and without type 2 diabetes. AB - BACKGROUND: Promotion of and adherence to increased physical activity (PA) is an important part of the prevention and treatment of coronary artery disease (CAD). We hypothesized that individually tailored home-based exercise prescriptions will increase long-term PA and maximal exercise capacity among CAD patients without and with type 2 diabetes (CAD+T2D). METHODS: Physical activity of patients with CAD (n = 44) and CAD+T2D (n = 39), matched by age, sex and ejection fraction, was measured over 5 days with an accelerometer pre- and postexercise prescription. PA was assessed as the average time per day of moderate (METs = 2-5) and high (METs > 5) intensities. Six-month exercise prescriptions were introduced based on individual maximal heart rate reserve. RESULTS: At the baseline, patients with CAD+T2D engaged in less moderate-intensity PA (2:40 +/- 1:23 versus 3:24 +/- 1:17 h, P = 0.014) and exhibited a non-significant trend to reduced high-intensity PA (2:08 +/- 2:57 versus 5:02 +/- 9:19 min, P = 0.091) compared with patients with CAD. High-intensity PA increased markedly in CAD (5:02 +/- 9:19 versus 9:59 +/- 15:03 min) and patients with CAD+T2D (2:08 +/- 2:57 versus 6:14 +/- 10:18 min) after exercise prescription (main effect for time P = 0.001). Also maximal exercise capacity increased in both groups (main effect for time P< 0.001). CONCLUSION: Patients with CAD with T2D are physically less active than CAD patients without diabetes in their daily life. Individually tailored home-based exercise prescriptions are an effective way to promote more active lifestyles and improve fitness in both patient groups. PMID- 23031066 TI - Normal stress databases in myocardial perfusion scintigraphy--how many subjects do you need? AB - BACKGROUND: Commercial normal stress databases in myocardial perfusion scintigraphy (MPS) commonly consist of 30-40 individuals. The aim of the study was to determine how many subjects are needed. METHODS: Four normal stress databases were developed using patients who underwent 99mTc MPS: non-corrected images (NC) for male, NC for female, attenuation-corrected images (AC) for male and AC for female subjects. 126 male and 205 female subjects were included. The normal database was created by alternatingly computing the mean of all normal subjects and normalizing the subjects with respect to this mean, until convergence. Coefficients of variation (CV) were created for increasing number of included patients in the four different normal stress databases. RESULTS: Normal stress databases with < 35 subjects had a high CV. Mean CV -2 standard deviations (SD) decreased with 28% between two and five included subjects, 71% between two and 35 subjects and 83% between two and 100 included subjects for NC man. CONCLUSIONS: We conclude that the commonly used 30-40 individuals for making a normal stress database might not be enough due to the high CV. We propose that normal stress databases should consist of more than 30-40 individuals, preferably more than 50 individuals, both for NC and AC studies. PMID- 23031067 TI - Thermal responses to whole-body cooling in air with special reference to arteriovenous anastomoses in fingers. AB - The arteriovenous anastomoses (AVAs) in the distal parts of the extremities play a significant role in the heat exchange with the environment. The aim of the study was to examine the thermal responses to whole-body cooling in air, and especially the behaviour of finger skin temperature (T(f) , rich in AVAs). Eight young men sat in minimal clothing at 32 degrees C air temperature (T(a) ), which was then lowered gradually to 13 degrees C in 100 min. In the beginning of cooling, T(f) was high and fluctuating, and then suddenly exhibited a rapid fall, while temperatures in other skin sites fell fairly linearly along decreasing T(a) to the end of cooling. During the period from start to the rapid fall in T(f) , rectal temperature decreased from 37.4 degrees C (SD 0.2) to 37.2 degrees C (0.2), mean skin temperature (T(sk) ) from 34.6 degrees C (0.5) to 31.2 degrees C (2.0) and whole-body thermal sensation from 'slightly warm/warm' to 'slightly cool/cold'. The start of the steep fall in T(f) varied considerably between individuals in terms of time (2-75 min), T(a) (16.7 - 32.0 degrees C) and T(sk) (28.8 - 34.7 degrees C). On the other hand, the range of T(f) at that point was narrower (32.1 - 35.8 degrees C). The findings stress the importance of taking into account the distal skin temperatures in thermoregulatory studies in addition to the ordinarily used more proximal and central skin sites. Also, it might be advisable to start such experiments with relatively high and fluctuating T(f) to guarantee that the thermal state of the subject is well defined. PMID- 23031068 TI - Real-time imaging required for optimal echocardiographic assessment of aortic valve calcification. AB - INTRODUCTION: Aortic valve calcification (AVC), even without haemodynamic significance, may be prognostically import as an expression of generalized atherosclerosis, but techniques for echocardiographic assessment are essentially unexplored. METHODS: Two-dimensional (2D) echocardiographic recordings (Philips IE33) of the aortic valve in short-axis and long-axis views were performed in 185 consecutive patients within 1 week before surgery for aortic stenosis (n = 109, AS), aortic regurgitation (n = 61, AR), their combination (n = 8) or dilation of the ascending aorta (n = 7). The grey scale mean (GSMn) of the aortic valve in an end-diastolic short-axis still frame was measured. The same frame was scored visually 1-5 as indicating that the aortic valve was normal, thick, or had mild, moderate or severe calcification. The visual echodensity of each leaflet was determined real time applying the same 5-grade scoring system for each leaflet, and the average for the whole valve was calculated. Finally, a similar calcification score for the whole valve based on inspection and palpation by the surgeon was noted. RESULTS: Visual assessment of real-time images using the proposed scoring system showed better correlation with the surgical evaluation of the degree of valve calcification (r = 0.83, P<0.001) compared to evaluation of stop frames by visual assessment (r = 0.66, P< 0.001) or the GSMn score (r = 0.64, P< 0.001). High inter- and intra-observer correlations were observed for real-time visual score (both intraclass correlation coefficient = 0.93). CONCLUSION: Real-time evaluation of the level of AVC is superior to using stop frames assessed either visually or by dedicated computer grey scale measurement software. PMID- 23031069 TI - Relationship between cardioventilatory coupling and pulmonary gas exchange. AB - Cardioventilatory coupling (CVC) is a temporal alignment between the heartbeat and inspiratory activity caused by pulsatile baroreceptor afferent activity. However, although first described over a century ago, the functional significance of CVC has yet to be established. One hypothesis is that baroreceptor triggering of inspiration positions heartbeats into phases of the respiratory cycle that may optimize pulmonary gas exchange efficiency. To test this hypothesis, we recruited ten patients with permanently implanted fixed-rate cardiac pacemakers and instructed them to pace breathe at heart rate-to-respiratory rate (HR/f) ratios of 3.8, 4.0 and 4.2. This breathing protocol enabled us to simulate heartbeat distributions similar to those seen in the presence (4.0) and complete absence (3.8, 4.2) of CVC. Results showed that heart rate, mean arterial pressure, end tidal carbon dioxide and tidal volume remained unchanged across the three conditions (P> 0.05). Pulmonary gas exchange efficiency, as determined by the ventilatory equivalents of carbon dioxide (V.E/V.CO2) and oxygen (V.E/V.O2) did not differ significantly by HR/f ratio (P = 0.29 and P = 0.70, respectively). These data suggest that CVC does not play a significant role in optimizing pulmonary gas exchange efficiency in humans. PMID- 23031070 TI - Subject-specific aortic wall shear stress estimations using semi-automatic segmentation. AB - Atherosclerosis development is strongly believed to be influenced by hemodynamic forces such as wall shear stress (WSS). To estimate such an entity in-vivo in humans, image-based computational fluid dynamics (CFD) is a useful tool. In this study, we use a combination of magnetic resonance imaging (MRI) and CFD to estimate WSS. In such method, a number of steps are included. One important step is the interpretation of images into 3D models, named segmentation. The choice of segmentation method can influence the resulting WSS distribution in the human aorta. This is studied by comparing WSS results gained from the use of two different segmentation approaches: manual and semi-automatic, where the manual approach is considered to be the reference method. The investigation is performed on a group of eight healthy male volunteers. The different segmentation methods give slightly different geometrical depictions of the human aorta (difference in the mean thoracic Aorta lumen diameter were 0.7% P< 0.86). However, there is a very good agreement between the resulting WSS distribution for the two segmentation approaches. The small differences in WSS between the methods increase in the late systole and early diastolic cardiac cycle time point indicating that the WSS is more sensitive to local geometric differences in these parts of the cardiac cycle (correlation coefficient is 0.96 at peak systole and 0.68 at early diastole). We can conclude that the results show that the semi automatic segmentation method can be used in future to estimate relevant aortic WSS. PMID- 23031071 TI - Exercise and nutrition for head and neck cancer patients: a patient oriented, clinic-supported randomized controlled trial. AB - BACKGROUND: Research on physical activity and nutrition interventions aimed at positively impacting symptom management, treatment-related recovery and quality of life has largely excluded head and neck (HN) cancer populations. This translates into a lack of clinical programming available for these patient populations. HN cancer patients deal with severe weight loss, with more than 70% attributed to lean muscle wasting, leading to extended recovery times, decreased quality of life (QoL), and impaired physical functioning. To date, interventions to address body composition issues have focused solely on diet, despite findings that nutritional therapy alone is insufficient to mitigate changes. A combined physical activity and nutrition intervention, that also incorporates important educational components known to positively impact behaviour change, is warranted for this population. Our pilot work suggests that there is large patient demand and clinic support from the health care professionals for a comprehensive program. METHODS/DESIGN: Therefore, the purpose of the present study is to examine the impact and timing of a 12-week PA and nutrition intervention (either during or following treatment) for HN cancer patients on body composition, recovery, serum inflammatory markers and quality of life. In addition, we will examine the impact of a 12-week maintenance program, delivered immediately following the intervention, on adherence, patient-reported outcomes (i.e., management of both physical and psychosocial treatment-related symptoms and side effects), as well as return to work. DISCUSSION: This research will facilitate advancements in patient wellness, survivorship, and autonomy, and carve the path for a physical-activity and wellness-education model that can be implemented in other cancer centers. TRIAL REGISTRATION: Current Controlled Trials NCT01681654. PMID- 23031073 TI - Looking back as we prepare to move forward: US presidential candidates' adoption of YouTube. AB - As the United States prepares for the 2012 Presidential Election, we reflect on how the 2008 candidates and the voting public adopted social computing technology with specific focus on YouTube. Using the Social Influence Model as a framework, this article sought to examine how candidates adopted YouTube to determine what types of messages were disseminated via YouTube and what kind of response from viewers videos received. We conducted a content analysis of candidate YouTube sites, focusing on video characteristics and content. Findings indicate that the candidates did not use YouTube to its fullest extent and that there were significant differences between the candidates in terms of the types of videos posted and the content posted and that constituents did adopt the medium as demonstrated in viewership numbers and responses. PMID- 23031072 TI - In Vitro efficacy of antimicrobial extracts against the atypical ruminant pathogen Mycoplasma mycoides subsp. capri. AB - BACKGROUND: Mycoplasmosis is a common infection in human and veterinary medicine, and is associated with chronic inflammation and high morbidity. Mycoplasma species are often intrinsically resistant to many conventional antimicrobial therapies, and the resistance patterns of pathogenic mycoplasmas to commonly used medicinal (antimicrobial) plant extracts are currently unknown. METHODS: Aqueous extracts, ethanol extracts, or oils of the targeted plant species and colloidal silver were prepared or purchased. Activity against the wall-less bacterial pathogen Mycoplasma mycoides subsp. capri was determined and compared to activities measured against Escherichia coli and Bacillus subtilis. Antimicrobial susceptibility testing was performed by broth microdilution assays. The lethal or inhibitory nature of each extract was determined by subculture into neat growth medium. RESULTS: Growth of M. mycoides capri, E. coli, and B. subtilis was inhibited by elderberry extract, oregano oil, ethanol extract of oregano leaves, and ethanol extract of goldenseal root. No inhibition was seen with aqueous extract of astragalus or calendula oil. Growth of M. mycoides capri and B. subtilis was inhibited by ethanol extract of astragalus, whereas growth of E. coli was not. Similarly, M. mycoides capri and E. coli were inhibited by aqueous extract of thyme, but B. subtilis was unaffected. Only B. subtilis was inhibited by colloidal silver. Measured MICs ranged from 0.0003 mg/mL to 3.8 mg/mL. Bacteriostatic and bactericidal effects differed by species and extract. CONCLUSIONS: The atypical pathogen M. mycoides capri was sensitive to extracts from many medicinal plants commonly used as antimicrobials in states of preparation and concentrations currently available for purchase in the United States and Europe. Variation in bacteriostatic and bactericidal activities between species and extracts indicates that multiple effecter compounds are present in these plant species. PMID- 23031074 TI - EBV+ cutaneous B-cell lymphoproliferation of the leg in an elderly patient with mycosis fungoides and methotrexate treatment. AB - A 77-year-old man with a 5-year history of mycosis fungoides (MF) who had received several lines of therapy, including intravenous courses of Methotrexate (MTX) for the past 2 years, went on to develop several ulcerated cutaneous nodules on the left leg. Biopsy revealed diffuse sheets of EBV-positive large B cells (CD20+ CD30 +/- IgM Lambda), with an angiocentric distribution and a monoclonal IGH gene rearrangement. Although the pathological features were diagnostic for an EBV-positive diffuse large B-cell lymphoma (DLBCL), several possibilities could be considered for assignment to a specific entity: EBV positive DLBCL of the elderly, methotrexate-induced lymphoproliferative disorder (LPD), lymphomatoid granulomatosis, or the more recently described EBV-positive mucocutaneous ulcer. The development of EBV+ lymphoproliferations has been reported in two other patients with MF under MTX, and occurred as skin lesions of the leg in one of these and in the current case, which may question the relatedness to primary cutaneous DLCBL, leg-type. PMID- 23031076 TI - Active gaming in Dutch adolescents: a descriptive study. AB - BACKGROUND: Adequate levels of physical activity are part of a healthy lifestyle and in this way linked to better health outcomes. For children and adolescents, the physical activity guideline recommends at least 60 minutes of moderate-to vigorous physical activity every day. However, many adolescents are not physically active enough and they spend a lot of their time on sedentary activities (such as video games). A new generation of video games that require body movements to play them, so-called "active games", could serve to increase physical activity in adolescents. The activity level while playing these games is comparable to light-to-moderate intensity physical activity. The current study aims to increase our understanding of 1) the demographic characteristics of adolescents who play active games regularly (>= 1 hour per week) and non regularly (< 1 hour per week), 2) time spent on active games, 3) the contribution of active games to daily physical activity and 4) the type and amount of activities being replaced by active gaming. METHODS: A cross-sectional survey was conducted in a Dutch internet panel, questioning adolescents in conjunction with one of their parents. A random sample of 320 households (with stratification on gender of the parent and the adolescent, the age of the adolescent and the region of the household) was selected that owned a console or application for active video games and that had a child aged 12 through 16 years. 201 child-parent couples (63% response) completed an internet survey with questions about demographics, physical activity and sedentary behaviour, and gaming behaviour. The questionnaire also contained questions designed to assess whether and how active gaming replaces other activities. Besides descriptive analyses, independent t-test, Pearson's chi-square and Mann-Whitney test (when data were not normally distributed) were used for comparisons between regular and non regular active gamers. RESULTS: Eleven percent of the adolescents with an active game in their household never used the game. There were no significant differences in gender, education level (of adolescent and parent), ethnicity and sedentary behaviour between regular (n = 65) and non-regular active gamers (n = 114). Adolescents' (regular and non-regular active gamers) meantime spent on active gaming was 80 (+/- 136) minutes a week; this potentially amounts to 11% of total physical activity. When time spent on active gaming was included in the calculation of the percentage of adolescents that met the physical activity guideline, the percentage increased significantly (p < 0.05) from 67 to 73%. According to the adolescents, active gaming mainly replaces sedentary screen time such as TV viewing, internet and non-active gaming. Parental opinions concurred with this appraisal. CONCLUSIONS: The results of this study confirm the idea that active gaming may contribute to an active lifestyle in adolescents, primarily because it potentially contributes substantially to time spent on physical activity. Secondly, active gamers indicate that they spent time on active games which they would have spent otherwise on less active activities. PMID- 23031075 TI - Fructose metabolism in humans - what isotopic tracer studies tell us. AB - Fructose consumption and its implications on public health are currently under study. This work reviewed the metabolic fate of dietary fructose based on isotope tracer studies in humans. The mean oxidation rate of dietary fructose was 45.0% +/- 10.7 (mean +/- SD) in non-exercising subjects within 3-6 hours and 45.8% +/- 7.3 in exercising subjects within 2-3 hours. When fructose was ingested together with glucose, the mean oxidation rate of the mixed sugars increased to 66.0% +/- 8.2 in exercising subjects. The mean conversion rate from fructose to glucose was 41% +/- 10.5 (mean +/- SD) in 3-6 hours after ingestion. The conversion amount from fructose to glycogen remains to be further clarified. A small percentage of ingested fructose (<1%) appears to be directly converted to plasma TG. However, hyperlipidemic effects of larger amounts of fructose consumption are observed in studies using infused labeled acetate to quantify longer term de novo lipogenesis. While the mechanisms for the hyperlipidemic effect remain controversial, energy source shifting and lipid sparing may play a role in the effect, in addition to de novo lipogenesis. Finally, approximately a quarter of ingested fructose can be converted into lactate within a few of hours. The reviewed data provides a profile of how dietary fructose is utilized in humans. PMID- 23031077 TI - Transgenic rice with inducible ethylene production exhibits broad-spectrum disease resistance to the fungal pathogens Magnaporthe oryzae and Rhizoctonia solani. AB - Rice blast (Magnaporthe oryzae) and sheath blight (Rhizoctonia solani) are the two most devastating diseases of rice (Oryza sativa), and have severe impacts on crop yield and grain quality. Recent evidence suggests that ethylene (ET) may play a more prominent role than salicylic acid and jasmonic acid in mediating rice disease resistance. In this study, we attempt to genetically manipulate endogenous ET levels in rice for enhancing resistance to rice blast and sheath blight diseases. Transgenic lines with inducible production of ET were generated by expressing the rice ACS2 (1-aminocyclopropane-1-carboxylic acid synthase, a key enzyme of ET biosynthesis) transgene under control of a strong pathogen inducible promoter. In comparison with the wild-type plant, the OsACS2 overexpression lines showed significantly increased levels of the OsACS2 transcripts, endogenous ET and defence gene expression, especially in response to pathogen infection. More importantly, the transgenic lines exhibited increased resistance to a field isolate of R. solani, as well as different races of M. oryzae. Assessment of the growth rate, generational time and seed production revealed little or no differences between wild type and transgenic lines. These results suggest that pathogen-inducible production of ET in transgenic rice can enhance resistance to necrotrophic and hemibiotrophic fungal pathogens without negatively impacting crop productivity. PMID- 23031078 TI - Meeting the need for regenerative therapies: translation-focused analysis of U.S. regenerative medicine opportunities in cardiovascular and peripheral vascular medicine using detailed incidence data. AB - Cardiac and vascular diseases represent one of the most substantial medical areas for the applications of regenerative medicine. Despite advances in endovascular repair, surgical intervention, and disease management, atherosclerosis and heart failure continue to be prominent health problems. This report analyzes the regenerative medicine treatment opportunities in both cardiovascular and peripheral vascular repair, examining the treatment opportunities for tissue engineered vascular grafts as well as cell-based therapies. U.S. hospital discharge data were used to generate a detailed estimate of the relative target populations for cardiac and vascular disease. Gap analyses were performed for vascular access, small caliber vascular grafts, and cell-based therapies for revascularization and heart failure. The analysis compared current alternatives, gaps in medical need, and what a tissue-engineered or regenerative alternative should achieve for optimum medical and commercial feasibility. Although the number of coronary bypass grafts vastly outnumbered peripheral grafts, a detailed consideration of re-grafts and the success of first grafts combined with gap analysis (GAP) leads us to conclude that peripheral vascular disease is the more commercially feasible and attractive target opportunity for engineered small caliber grafts for the foreseeable future. Cardiac bypass would need substantial long-term clinical experience, which could be a significant hurdle. Vascular access, often regarded as a first-in-man indication, is an excellent opportunity for an engineered graft as an alternative to arteriovenous fistula that could overcome complications associated with a prosthetic graft. The GAP also suggests that for heart failure, cellular therapies should link near-term changes in repair, such as improvement in cardiac output and reduced scarring with limiting progression of the disease, reducing the need for complex pharmacologic management, and reducing rates of hospitalization. Naturally, researchers must determine where their technology and know-how can be applied most effectively, but it is clear from our analysis that an astute strategy in the use of science and technology will be important to successful translation in this space. PMID- 23031079 TI - Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of bone and cartilage. Although its etiology is unknown, the hydroxyl radical has been suggested to be involved in the pathogenesis of RA. Recently, molecular hydrogen (H2) was demonstrated to be a selective scavenger for the hydroxyl radical. Also, the method to prepare water containing extremely high concentration of H2 has been developed. We hypothesized that H2 in the water could complement conventional therapy by reducing the oxidative stress in RA. METHODS: Twenty patients with rheumatoid arthritis (RA) drank 530 ml of water containing 4 to 5 ppm molecular hydrogen (high H2 water) every day for 4 weeks. After a 4-week wash-out period, the patients drank the high H2 water for another 4 weeks. Urinary 8-hydroxydeoxyguanine (8-OHdG) and disease activity (DAS28, using C-reactive protein [CRP] levels) was estimated at the end of each 4-week period. RESULTS: Drinking high H2 water seems to raise the concentration of H2 more than the H2 saturated (1.6 ppm) water in vivo. Urinary 8 OHdG was significantly reduced by 14.3% (p < 0.01) on average. DAS28 also decreased from 3.83 to 3.02 (p < 0.01) during the same period. After the wash-out period, both the urinary 8-OHdG and the mean DAS28 decreased, compared to the end of the drinking period. During the second drinking period, the mean DAS28 was reduced from 2.83 to 2.26 (p < 0.01). Urinary 8-OHdG was not further reduced but remained below the baseline value. All the 5 patients with early RA (duration < 12 months) who did not show antibodies against cyclic citrullinated peptides (ACPAs) achieved remission, and 4 of them became symptom-free at the end of the study. CONCLUSIONS: The results suggest that the hydroxyl radical scavenger H2 effectively reduces oxidative stress in patients with this condition. The symptoms of RA were significantly improved with high H2 water. PMID- 23031080 TI - High-energy focussed extracorporeal shockwave therapy reduces pain in plantar fibromatosis (Ledderhose's disease). AB - BACKGROUND: Plantar fibromatosis is a benign disease creating nodules on the medial plantar side of affected patients. While surgical removal is regarded as the therapeutic mainstay, recurrence rates and impairment of daily activities remains substantial. High-energy focussed extracorporeal shockwave therapy has been suggested to be potentially effective in plantar fibromatosis in terms of pain reduction. HYPOTHESIS: High-energy focussed extracorporeal shockwave therapy reduces pain in plantar fibromatosis. FINDINGS: A total number of six patients (5 males, 58+/-4 years) were included with plantar fibromatosis (Ledderhose's disease) associated with pain. Three patients were operated on previously, one had concomitant Dupuytren's contracture. High-energy focussed ESWT was applied using a Storz Duolith SD1 (2000 impulses, 3 Hz, 1.24 mJ/mm2) in two sessions with 7 days between. Pain was 6+/-2 at baseline, 2+/-1 after 14 days and 1+/-1 after 3 months. Softening of the nodules was noted by all patients. No adverse effects were noted. CONCLUSIONS: High-energy focussed extracorporeal shockwave energy reduces pain in painful plantar fibromatosis (Morbus Ledderhose). Further large scale prospective trials are warranted to elucidate the value of high-energy focussed extracorporeal shockwave therapy (ESWT) in plantar fibromatosis in terms of recurrence and efficacy. PMID- 23031081 TI - Approach to kidney transplant in sensitized potential transplant recipients. AB - More than one-third of patients on waiting lists for kidney transplant are sensitized. Most have previously formed donor-specific and non-donor-specific serum antibodies and/or positive crossmatch by complement-dependent cytotoxity and/or flow cytometry. Two categories of alloantibodies include antibodies against major histocompatibility complex human leukocyte antigen class 1 and class 2 and antibodies against minor histocompatibility complex. A current positive crossmatch is an absolute contraindication for transplant. Positive historical panel reactive antibody and/or donor-specific antibodies (human leukocyte antigen and minor histocompatibility complex), even in the absence of a historical positive crossmatch, are associated with an increased risk for allosensitization, antibodymediated rejection, and accelerated graft failure. Desensitization protocols are numerous, complex, and expensive. It is recommended to perform a systematic determination of historical and current panel reactive antibody, donor-specific antibodies (human leukocyte antigen and minor histocompatibility complex), and crossmatch by the most sensitive assays. The risk of sensitization may be estimated from the combined results of the crossmatch with the donor and those of the recipient's panel reactive antibody and donor-specific antibodies at baseline. The adoption of a scoring system for risk stratification may facilitate the task of organ allocation for sensitized patients. Recipients with an estimated sensitization risk >= high may be referred preferably to the national waiting priority list and informed about the financial and the medical risks that may incur with future transplant. Sensitized patients at high risk for antibody-mediated rejection may benefit from a structured monitoring process involving systematic and regular immunologic, histologic, and functional assessments of the graft after transplant. We recommend the adoption and regular updating of these approaches to ensure safe and appropriate therapeutic standards in these sensitized patients, in accordance with best clinical practice. PMID- 23031082 TI - Long-term graft function in a randomized clinical trial comparing laparoscopic versus open donor nephrectomy. AB - OBJECTIVES: To evaluate and compare the long-term graft and survival rates in kidney transplant recipients who had undergone laparoscopic donor nephrectomy versus those who underwent open donor nephrectomy. MATERIALS AND METHODS: Our study was done with 100 cases of laparoscopic donor nephrectomy and 100 cases of open donor nephrectomy, performed between July 2001 and September 2003. Mean follow-up of recipients in this study was 6.6 +/- 2.4 years (range, 1-9.3 y). This study has a longer follow-up than previous randomized clinical trials. We compared patient and graft survival in recipients of laparoscopic donor nephrectomy versus those who had open donor nephrectomy. RESULTS: Mean duration of kidney warm ischemia time was 8.7 +/- 2.7 minutes for laparoscopic donor nephrectomy and 1.8 +/- 0.92 minutes for open donor nephrectomy. There were no significant differences in 5-year graft survival between the laparoscopic donor nephrectomy and open donor nephrectomy groups (89.5% vs 84.3%; P = .96). There were no differences in delayed graft function between the laparoscopic donor nephrectomy and open donor nephrectomy groups (8 and 11 patients; P = .135). There was a significant difference in 5-year graft survival between recipients with a history of delayed graft function and those without delayed graft function (63.2% vs 89.7%; P = .04). Despite a longer warm ischemia time in laparoscopic donor nephrectomy group (8.69 vs 1.87 min; P = .0001), warm ischemia time had no effect on graft outcome in long-term follow-up. CONCLUSIONS: Although earlier experiences with laparoscopic donor nephrectomies were associated with concerns about long-term effects of laparoscopic donation on the graft function in the recipient, our long-term results confirm that laparoscopic donor nephrectomy provides similar graft outcome to open donor nephrectomy. PMID- 23031083 TI - Risk factors for steroid-resistant T-cell-mediated acute cellular rejection and their effect on kidney graft and patient outcome. AB - OBJECTIVES: Acute rejection in renal transplant is considered a risk factor for short-term and long-term allograft survival. The expected reversal rate for the first acute cellular rejection, by steroid pulse, ranges between 60% and 100%, and lack of improvement within 1 week of treatment is defined as steroid resistant rejection. This work sought to evaluate factors that lead to steroid resistant acute cellular rejection among patients with first live-donor renal allotransplant and its effect on graft and patient survival. MATERIALS AND METHODS: Patients with an improvement in serum creatinine levels were considered controls (group 1; n=100); while the others were considered an early steroid resistant group (group 2; n=99). Both groups were matched demographically. RESULTS: Patients with a target cyclosporine level below accepted therapeutic levels were significantly higher in group 2 (P = .02). We found no significant differences between the groups regarding posttransplant complications (P > .05). Mean hospital stay was longer in group 2 (P = .021). Living patients with functioning graft were more prevalent in group 1, while those alive on dialysis were more prevalent in group 2. The groups were comparable regarding long-term patient and graft survival despite significantly lower creatinine values in patients of group 1 at 6 months' follow-up (P <= .001). CONCLUSIONS: Prebiopsy low cyclosporine trough levels and associated chronic changes among patients who were maintained on calcineurin inhibitor-based regimens represented the most important risk factors for the early steroid-resistant group. Rescue therapies improve short-term graft outcome; however, they did not affect either patient or long-term graft survival after 5 years' follow-up. PMID- 23031084 TI - Resistive index of the remaining kidney in allograft kidney donors. AB - OBJECTIVES: Kidney transplant is the last resort in patients with end-stage renal disease. In living-kidney donors undergoing nephrectomy for transplant; however, morphologic and hemodynamic changes may occur in the remaining kidney with time. If there would be such a change, then it may alter the diagnostic utility of Doppler ultrasound in evaluating diseased conditions of the solitary kidney. Using Doppler ultrasound, this study sought to determine whether there are hemodynamic changes in the remaining kidney. MATERIALS AND METHODS: Forty-one patients (38 men, 3 women) for kidney donation were examined using a MyLab 50 color Doppler apparatus with a convex 3.5- to 5-MHz probe. Resistive index values of the main renal, interlobar, and interlobular arteries in the remaining kidney were assessed before, and at 7 and 90 days after nephrectomy. The size and parenchymal thickness of the remaining kidney also were measured before and after nephrectomy. RESULTS: At day 90, a statistically significant increase (P < .001) in resistive index was seen at all levels, compared with before and 7 days after nephrectomy. No significant changes, however, could be noticed on the day 7, when compared with before the nephrectomy. Renal size and parenchymal thickness remained constant over the time studied. CONCLUSIONS: Although a statistically significant increase in resistive index values of the remaining kidney was seen 90 days after the nephrectomy, these values have remained within the normal limits of renal resistive index. So, our findings indicate that resistive index measurement is useful in assessing the diseased condition of the remaining kidney after removing the contralateral kidney. PMID- 23031085 TI - Sex matching plays a role in outcome of kidney transplant. AB - OBJECTIVES: The effect of sex matching between donors and recipients was studied in 135 kidney transplant operations performed in our center between December 1998 and December 2007. MATERIALS AND METHODS: Patients were divided into 4 groups: group 1 (63 patients, male donor-male recipient), group 2 (25 patients, male donor-female recipient), group 3 (37 patients, female donor-male recipient), and group 4 (10 patients, female donor-female recipient). Except for donor age, recipient body mass index and donor-recipient HLA AB-DR matching, recipient, and donor demographics, and the immunosuppression were comparable in all groups. RESULTS: Acute rejection and the need for antithymocyte globulin Fresenius rescue therapy were comparable between the 4 donor-recipient combinations. Excellent 1 year actuarial patient and graft survival, comparable hospital stay, and incidence of delayed graft and slow graft function were comparable between the 4 groups. One death occurred, each, in groups 1 and 2; posttransplant complications being comparable. While 1-year graft survival (death censored and uncensored) were comparable, 1-year graft function (serum creatinine) showed that the worst graft function was seen in group 3 (female-to-male). Significant differences between the 4 patient groups also were seen in pretransplant and posttransplant hemoglobin levels as well as in posttransplant arterial hypertension and high density lipoprotein cholesterol blood levels. Other metabolic indices were generally comparable between the 4 patient groups. CONCLUSIONS: These results revealed that sex mismatching (group 2, male donor to female recipient) had the best 1-year graft function but the same 1-year patient and graft survival. PMID- 23031086 TI - Treatment of refractory cerebral aspergillosis in a liver transplant recipient with voriconazole: case report and review of the literature. AB - OBJECTIVES: Extension of invasive aspergillosis to the central nervous system is associated with high mortality, in part because of poor central nervous system penetration of antifungal drugs. Voriconazole yields fungicidal drug concentrations within the central nervous system, but use of this drug is limited in liver transplant recipients because of hepatotoxicity and drug interactions. MATERIALS AND METHODS: We reviewed medical records and antifungal treatment for all liver transplant recipients from 2007 to 2009 who had cerebral aspergillosis (Proven [2]; Probable [1]; Possible [1]) at week 3, 4, 6, and 12 after transplant. CASE REPORT: A 33-year-old white man underwent orthotopic liver transplant for acute liver failure that was caused by acetaminophen overdosage. Risk factors for fungal infection included major blood loss (8 L), prolonged surgery (9 h), and emergency revision transplant that was done because of nonfunctioning of the primary transplant at 48 hours. He developed postoperative aspergillus pneumonia and invasive aspergillosis of the kidneys, brain, and eye. Treatment with voriconazole and amphotericin B was successful, with moderate residual renal impairment. CONCLUSIONS: Voriconazole was effective and safe in the treatment of cerebral aspergillosis in this liver transplant recipient. PMID- 23031089 TI - Presence of arginine catabolic mobile element among community-acquired meticillin resistant Staphylococcus aureus is linked to a specific genetic background. AB - The prevalence of arginine catabolic mobile element (ACME) among diverse and heterogeneous community-associated methicillin-resistant Staphylococcus aureus community-associated Methicillin-resistant S. aureus (CA-MRSA) (n = 114) in a low endemic area, i.e. Sweden, was investigated. Among the CA-MRSA, represented by 47 different spa types, ACME was only found in 10 isolates with a common genetic background [t008, SCCmec type IV, Panton-Valentine leukocidin (PVL) positive, and indistinguishable or closely related pulsed-field gel electrophoresis (PFGE) patterns] corresponding to USA300. This strain does not seem to be established in our area as most of the patients contracted the CA-MRSA abroad. Presence of ACME does not seem to be associated with colonization, long-term carriership, or intra familiar transmission in a higher extent than CA-MRSA in general. PMID- 23031090 TI - Symmetry aspects of H2 splitting by five-coordinate d6 ruthenium amides, and calculations on acetophenone hydrogenation, ruthenium alkoxide formation, and subsequent hydrogenolysis in a model trans-Ru(H)2(diamine)(diphosphine) system. AB - The potential energy surface (PES) of H(2) addition to the Ru?N bond of a model five-coordinate ruthenium amide (Ru?N), leading to an octahedral trans Ru(H)(2)(diamine)(diphosphine) (HRu-NH) and subsequent acetophenone hydrogenation, is studied using M06 density functional theory methods. A qualitative molecular orbital analysis reveals that H(2) addition to the ground state of Ru?N (which has a distorted trigonal-bipyramidal geometry) fits the criterion of a symmetry-forbidden reaction. A transition state (TS) for H(2) heterolytic splitting by Ru?N corresponds to the reaction taking place on an excited state of the Ru?N having a square-pyramidal geometry and gives DeltaG degrees (?) = 19.5 kcal/mol. The reaction between HRu-NH and acetophenone proceeds by a localized hydride-transfer TS with DeltaG degrees (?) = 11.5 kcal/mol. This TS leads to an ion pair between a square-pyramidal d(6) ruthenium amino cation and the alkoxide and is uphill from the separated reactants by 3.5 kcal/mol. Subsequent abstraction of the amino proton by the alkoxide within the ion pair is barrierless, but it also lacks any thermodynamic driving force. In contrast, reorientation of the alkoxide within the ion pair to form an octahedral ruthenium alkoxide is calculated to be exoergic by 7.1 kcal/mol. These features of the PES suggest that the known rapid production of ruthenium alkoxides when stoichiometric amounts of acetophenone and HRu-NH are reacted at low temperatures proceeds by a simple direct route following hydride transfer. For the simplified model complex, ruthenium alkoxide is calculated to be the thermodynamic product of the hydrogenation reaction (exoergic by 3.6 kcal/mol). A TS for H(2) heterolytic splitting across the Ru-alkoxide bond is calculated to have DeltaG degrees (?) (16.0 kcal/mol), slightly smaller than that of H(2) addition to the five-coordinate Ru?N. PMID- 23031087 TI - Dual inhibition of gamma-oryzanol on cellular melanogenesis: inhibition of tyrosinase activity and reduction of melanogenic gene expression by a protein kinase A-dependent mechanism. AB - The in vitro effects on melanogenesis of gamma-oryzanol (1), a rice bran-derived phytosterol, were investigated. The melanin content in B16F1 cells was significantly and dose-dependently reduced (-13% and -28% at 3 and 30 MUM, respectively). Tyrosinase enzyme activity was inhibited by 1 both in a cell-free assay and when analyzed based on the measurement of cellular tyrosinase activity. Transcriptome analysis was performed to investigate the biological pathways altered by 1, and it was found that gene expression involving protein kinase A (PKA) signaling was markedly altered. Subsequent analyses revealed that 1 stimulation in B16 cells reduced cytosolic cAMP concentrations, PKA activity ( 13% for cAMP levels and -40% for PKA activity), and phosphorylation of the cAMP response element binding protein (-57%), which, in turn, downregulated the expression of microphthalmia-associated transcription factor (MITF; -59% for mRNA and -64% for protein), a key melanogenic gene transcription factor. Accordingly, tyrosinase-related protein 1 (TRP-1; -69% for mRNA and -82% for protein) and dopachrome tautomerase (-51% for mRNA and -92% for protein) in 1-stimulated B16F1 cells were also downregulated. These results suggest that 1 has dual inhibitory activities for cellular melanogenesis by inhibiting tyrosinase enzyme activity and reducing MITF and target genes in the PKA-dependent pathway. PMID- 23031091 TI - Higgs mode in a two-dimensional superfluid. AB - We present solid evidence for the existence of a well-defined Higgs amplitude mode in two-dimensional relativistic field theories based on analytically continued results from quantum Monte Carlo simulations of the Bose-Hubbard model in the vicinity of the superfluid-Mott insulator quantum critical point, featuring emergent particle-hole symmetry and Lorentz invariance. The Higgs boson, seen as a well-defined low-frequency resonance in the spectral density, is quickly pushed to high energies in the superfluid phase and disappears by merging with the broad secondary peak at the characteristic interaction scale. Simulations of a trapped system of ultracold (87)Rb atoms demonstrate that the low-frequency resonance is lost for typical experimental parameters, while the characteristic frequency for the onset of a strong response is preserved. PMID- 23031092 TI - Wess-Zumino consistency condition for entanglement entropy. AB - In this Letter, we consider the variation of the entanglement entropy of a region as the shape of the entangling surface is changed. We show that the variation satisfies a Wess-Zumino-like integrability condition in field theories which can be consistently coupled to gravity. In this case, the "anomaly" is localized on the entangling surface. The solution of the integrability condition should give all the nontrivial finite local terms which can appear in the variation of the entanglement entropy. The answers depend on the intrinsic and extrinsic geometry of the entangling surface, but the form does not depend on the details of the field theory. The coefficients, which multiply the purely geometric contributions, will depend on the particular details of the field theory. PMID- 23031093 TI - Spin Peierls quantum phase transitions in Coulomb crystals. AB - The spin Peierls instability describes a structural transition of a crystal due to strong magnetic interactions. Here, we demonstrate that cold Coulomb crystals of trapped ions provide an experimental test bed in which to study this complex many-body problem and to access extreme regimes where the instability is triggered by quantum fluctuations alone. We present a consistent analysis based on different analytical and numerical methods, and we provide a detailed discussion of its experimental feasibility. PMID- 23031094 TI - Dynamical decoupling and dephasing in interacting two-level systems. AB - We implement dynamical decoupling techniques to mitigate noise and enhance the lifetime of an entangled state that is formed in a superconducting flux qubit coupled to a microscopic two-level system. By rapidly changing the qubit's transition frequency relative to the two-level system, we realize a refocusing pulse that reduces dephasing due to fluctuations in the transition frequencies, thereby improving the coherence time of the entangled state. The coupling coherence is further enhanced when applying multiple refocusing pulses, in agreement with our 1/f noise model. The results are applicable to any two-qubit system with transverse coupling and they highlight the potential of decoupling techniques for improving two-qubit gate fidelities, an essential prerequisite for implementing fault-tolerant quantum computing. PMID- 23031095 TI - Quantized adiabatic transport in momentum space. AB - Though topological aspects of energy bands are known to play a key role in quantum transport in solid-state systems, the implications of Floquet band topology for transport in momentum space (i.e., acceleration) have not been explored so far. Using a ratchet accelerator model inspired by existing cold-atom experiments, here we characterize a class of extended Floquet bands of one dimensional driven quantum systems by Chern numbers, reveal topological phase transitions therein, and theoretically predict the quantization of adiabatic transport in momentum space. Numerical results confirm our theory and indicate the feasibility of experimental studies. PMID- 23031096 TI - Radiation from quantum weakly dynamical horizons in loop quantum gravity. AB - We provide a statistical mechanical analysis of quantum horizons near equilibrium in the grand canonical ensemble. By matching the description of the nonequilibrium phase in terms of weakly dynamical horizons with a local statistical framework, we implement loop quantum gravity dynamics near the boundary. The resulting radiation process provides a quantum gravity description of the horizon evaporation. For large black holes, the spectrum we derive presents a discrete structure which could be potentially observable. PMID- 23031097 TI - Constraints on cosmic superstrings from Kaluza-Klein emission. AB - Cosmic superstrings interact generically with a tower of light and/or strongly coupled Kaluza-Klein (KK) modes associated with the geometry of the internal space. We study the production of KK particles by cosmic superstring loops, and show that it is constrained by big bang nucleosynthesis. We study the resulting constraints in the parameter space of the underlying string theory model and highlight their complementarity with the regions that can be probed by current and upcoming gravitational wave experiments. PMID- 23031100 TI - Ultrafast dynamics in postcollision interaction after multiple auger decays in argon 1s photoionization. AB - Argon 1s photoionization followed by multiple Auger decays is investigated both experimentally, by means of photoelectron-ion coincidences, and theoretically. A strong influence of the different Auger decays on the photoelectron spectra is observed through postcollision interaction which shifts the maximum of the energy distribution and distorts the spectral shape. A good agreement between the calculated and measured spectra for selected Ar(n+) ions (n=1-5) allows one to estimate the widths (lifetimes) of the intermediate states for each specific decay pathway. PMID- 23031102 TI - Multielectron transitions induced by neutron impact on helium. AB - We explore excitation and ionization by neutron impact as a novel tool for the investigation of electron-electron correlations in helium. We present single- and double-ionization spectra calculated in accurate numerical ab initio simulations for incoming neutrons with kinetic energies of up to 150 keV. The resulting electron spectra are found to be fundamentally different from photoionization or charged particle impact due to the intrinsic many-body character of the interaction. In particular, doubly excited resonances that are strongly suppressed in electron or photon impact become prominent. The ratio of double to single ionization is found to differ significantly from those of photon and charged-particle impact. PMID- 23031101 TI - Scaling laws for photoelectron holography in the midinfrared wavelength regime. AB - Midinfrared strong-field laser ionization offers the promise of measuring holograms of atoms and molecules, which contain both spatial and temporal information of the ion and the photoelectron with subfemtosecond temporal and angstrom spatial resolution. We report on the scaling of photoelectron holographic interference patterns with the laser pulse duration, wavelength, and intensity. High-resolution holograms for the ionization of metastable xenon atoms by 7-16 MUm light from the FELICE free electron laser are presented and compared to semiclassical calculations that provide analytical insight. PMID- 23031103 TI - Optimal squeezing in resonance fluorescence via atomic-state purification. AB - Squeezing of atomic resonance fluorescence is shown to be optimized by a properly designed environment, which can be realized by a quasiresonant cavity. Optimal squeezing is achieved if the atomic coherence is maximized, corresponding to a pure atomic quantum state. The atomic-state purification is achieved by the backaction of the cavity field on the atom, which increases the atomic coherence and decreases the atomic excitation. For realistic cavities, the coupling of the atom to the cavity field yields a purity of the atomic state of more than 99%. The fragility of squeezing against dephasing is substantially reduced in this scenario, which may be important for various applications. PMID- 23031104 TI - X-ray parametric down-conversion in the Langevin regime. AB - We experimentally and theoretically study the coincidence count rate for down converted x-ray photons. Because of photoionization, parametric down-conversion at x-ray wavelengths generally involves loss and the theoretical description requires a Langevin approach. By working in a transmission geometry (Laue) rather than in the Bragg geometry of previous experiments, we obtain an improvement in the signal-to-noise ratio of 12.5, and find agreement between experiment and theory. PMID- 23031099 TI - Shell-structure and pairing interaction in superheavy nuclei: rotational properties of the z=104 nucleus (256)rf. AB - The rotational band structure of the Z=104 nucleus (256)Rf has been observed up to a tentative spin of 20h using state-of-the-art gamma-ray spectroscopic techniques. This represents the first such measurement in a superheavy nucleus whose stability is entirely derived from the shell-correction energy. The observed rotational properties are compared to those of neighboring nuclei and it is shown that the kinematic and dynamic moments of inertia are sensitive to the underlying single-particle shell structure and the specific location of high-j orbitals. The moments of inertia therefore provide a sensitive test of shell structure and pairing in superheavy nuclei which is essential to ensure the validity of contemporary nuclear models in this mass region. The data obtained show that there is no deformed shell gap at Z=104, which is predicted in a number of current self-consistent mean-field models. PMID- 23031105 TI - Optomechanical quantum information processing with photons and phonons. AB - We describe how strong resonant interactions in multimode optomechanical systems can be used to induce controlled nonlinear couplings between single photons and phonons. Combined with linear mapping schemes between photons and phonons, these techniques provide a universal building block for various classical and quantum information processing applications. Our approach is especially suited for nano optomechanical devices, where strong optomechanical interactions on a single photon level are within experimental reach. PMID- 23031106 TI - Weak measurements of light chirality with a plasmonic slit. AB - We examine, both experimentally and theoretically, an interaction of tightly focused polarized light with a slit on a metal surface supporting plasmon polariton modes. Remarkably, this simple system can be highly sensitive to the polarization of the incident light and offers a perfect quantum weak measurement tool with a built-in postselection in the plasmon-polariton mode. We observe the plasmonic spin Hall effect in both coordinate and momentum spaces which is interpreted as weak measurements of the helicity of light with real and imaginary weak values determined by the input polarization. Our experiment combines the advantages of (i) quantum weak measurements, (ii) near-field plasmonic systems, and (iii) high-numerical aperture microscopy in employing the spin-orbit interaction of light and probing light chirality. PMID- 23031107 TI - Large bubble rupture sparks fast liquid jet. AB - This Letter presents the novel experimental observation of long and narrow jets shooting out in disconnecting large elongated bubbles. We investigate this phenomenon by carrying out experiments with various viscosities, surface tensions, densities and nozzle radii. We propose a universal scaling law for the jet velocity, which unexpectedly involves the bubble height to the power 3/2. This anomalous exponent suggests an energy focusing phenomenon. We demonstrate experimentally that this focusing is purely gravity driven and independent of the pinch-off singularity. PMID- 23031108 TI - Clustering of salt fingers in double-diffusive convection leads to staircaselike stratification. AB - We report on high-resolution, three-dimensional, high Rayleigh number, and low density ratio numerical simulations of fingering convection. We observe a previously unreported phenomenon of self-organization of fingers that cluster together to form larger-scale coherent structures. The flow ultimately forms density staircases, alternating well-mixed regions with fingering convective zones. We give evidence that the mechanical mixing induced by the clusters forms the staircases with a mechanism analogous to staircase formation in a stably stratified, nonconvective, stirred fluid. PMID- 23031109 TI - Controlling fast-electron-beam divergence using two laser pulses. AB - This Letter describes the first experimental demonstration of the guiding of a relativistic electron beam in a solid target using two colinear, relativistically intense, picosecond laser pulses. The first pulse creates a magnetic field that guides the higher-current, fast-electron beam generated by the second pulse. The effects of intensity ratio, delay, total energy, and intrinsic prepulse are examined. Thermal and Kalpha imaging show reduced emission size, increased peak emission, and increased total emission at delays of 4-6 ps, an intensity ratio of 10?1 (second:first) and a total energy of 186 J. In comparison to a single, high contrast shot, the inferred fast-electron divergence is reduced by 2.7 times, while the fast-electron current density is increased by a factor of 1.8. The enhancements are reproduced with modeling and are shown to be due to the self generation of magnetic fields. Such a scheme could be of considerable benefit to fast-ignition inertial fusion. PMID- 23031110 TI - Stable Skyrmions in SU(2) gauged Bose-Einstein condensates. AB - We demonstrate that the three-dimensional Skyrmion, which has remained elusive so far, spontaneously appears as the ground state of SU(2) symmetric Bose-Einstein condensates coupled with a non-Abelian gauge field. The gauge field is a three dimensional analogue of the Rashba spin-orbit coupling. Upon squashing the SO(3) symmetric gauge field to one- or two-dimensional shapes, we find that the ground state continuously undergoes a change from a three-dimensional to a one- or two dimensional Skyrmion, which is identified by estimating winding numbers and helicity. All of the emerged Skyrmions are physically understandable with the concept of the helical modulation in a unified way. These topological objects might potentially be realizable in two-component Bose-Einstein condensates experimentally. PMID- 23031111 TI - Topological interface engineering and defect crossing in ultracold atomic gases. AB - We propose an experimentally feasible scheme for topological interface engineering and show how it can be used for studies of dynamics of topologically nontrivial interfaces and perforation of defects and textures across such interfaces. The method makes use of the internal spin structure of the atoms together with locally applied control of interaction strengths to create many particle states with highly complex topological properties. In particular, we consider a constructed coherent interface between topologically distinct phases of spinor Bose-Einstein condensates. PMID- 23031113 TI - Collective effects in second-harmonic generation from split-ring-resonator arrays. AB - Optical experiments on second-harmonic generation from split-ring-resonator square arrays show a nonmonotonic dependence of the conversion efficiency on the lattice constant. This finding is interpreted in terms of a competition between dilution effects and linewidth or near-field changes due to interactions among the individual elements in the array. PMID- 23031112 TI - Strain and structure driven complex magnetic ordering of a CoO overlayer on Ir(100). AB - We investigate the magnetic ordering in the ultrathin c(10*2) CoO(111) film supported on Ir(100) on the basis of ab initio calculations. We find a close relationship between the local structural properties of the oxide film and the induced magnetic order, leading to alternating ferromagnetically and antiferromagnetically ordered segments. While the local magnetic order is directly related to the geometric position of the Co atoms, the mismatch between the CoO film and the Ir substrate leads to a complex long-range order of the oxide. PMID- 23031114 TI - Nonequilibrium dynamic critical scaling of the quantum Ising chain. AB - We solve for the time-dependent finite-size scaling functions of the one dimensional transverse-field Ising chain during a linear-in-time ramp of the field through the quantum critical point. We then simulate Mott-insulating bosons in a tilted potential, an experimentally studied system in the same equilibrium universality class, and demonstrate that universality holds for the dynamics as well. We find qualitatively athermal features of the scaling functions, such as negative spin correlations, and we show that they should be robustly observable within present cold atom experiments. PMID- 23031115 TI - Fixed-energy sandpiles belong generically to directed percolation. AB - Fixed-energy sandpiles with stochastic update rules are known to exhibit a nonequilibrium phase transition from an active phase into infinitely many absorbing states. Examples include the conserved Manna model, the conserved lattice gas, and the conserved threshold transfer process. It is believed that the transitions in these models belong to an autonomous universality class of nonequilibrium phase transitions, the so-called Manna class. Contrarily, the present numerical study of selected (1+1)-dimensional models in this class suggests that their critical behavior converges to directed percolation after very long time, questioning the existence of an independent Manna class. PMID- 23031116 TI - Size fluctuations of near critical nuclei and Gibbs free energy for nucleation of BDA on Cu(001). AB - We present a low-energy electron microscopy study of nucleation and growth of BDA on Cu(001) at low supersaturation. At sufficiently high coverage, a dilute BDA phase coexists with c(8*8) crystallites. The real-time microscopic information allows a direct visualization of near-critical nuclei, determination of the supersaturation and the line tension of the crystallites, and, thus, derivation of the Gibbs free energy for nucleation. The resulting critical nucleus size nicely agrees with the measured value. Nuclei up to 4-6 times larger still decay with finite probability, urging reconsideration of the classic perception of a critical nucleus. PMID- 23031117 TI - Exactly solvable fermion chain describing a nu=1/3 fractional quantum Hall state. AB - We introduce an exactly solvable fermion chain that describes a nu=1/3 fractional quantum Hall (FQH) state beyond the thin-torus limit. The ground state of our model is shown to be unique for each center-of-mass sector, and it has a matrix product representation that enables us to exactly calculate order parameters, correlation functions, and entanglement spectra. The ground state of our model shows striking similarities with the BCS wave functions and quantum spin-1 chains. Using the variational method with matrix product ansatz, we analytically calculate excitation gaps and vanishing of the compressibility expected in the FQH state. We also show that the above results can be related to a nu=1/2 bosonic FQH state. PMID- 23031119 TI - Statistical transmutation in doped quantum dimer models. AB - We prove a "statistical transmutation" symmetry of doped quantum dimer models on the square, triangular, and kagome lattices: the energy spectrum is invariant under a simultaneous change of statistics (i.e., bosonic into fermionic or vice versa) of the holes and of the signs of all the dimer resonance loops. This exact transformation enables us to define the duality equivalence between doped quantum dimer Hamiltonians and provides the analytic framework to analyze dynamical statistical transmutations. We investigate numerically the doping of the triangular quantum dimer model with special focus on the topological Z(2) dimer liquid. Doping leads to four (instead of two for the square lattice) inequivalent families of Hamiltonians. Competition between phase separation, superfluidity, supersolidity, and fermionic phases is investigated in the four families. PMID- 23031118 TI - Frustrated quantum critical theory of putative spin-liquid phenomenology in 6H-B Ba(3)NiSb(2)O(9). AB - A recently discovered material, 6H-B-Ba(3)NiSb(2)O(9) was found to display unusual low-temperature phenomenology, interpreted as a quantum spin liquid with spin S=1 on a triangular lattice. We study a spin S=1 exchange model on an AB stacked triangular lattice near its quantum paramagnet-to-spiral transition, driven by easy-plane single-ion anisotropy. We demonstrate that the frustrated inter- and intralayer exchanges induce contour lines of low-energy excitations that lead to a broad crossover regime of linear-temperature dependence of the specific heat. Based on this and various other predictions, we argue that the observed phenomenology can be understood in terms of a conventional picture of a proximity to this frustrated critical point. PMID- 23031120 TI - Spontaneous symmetry breaking in a polariton and photon laser. AB - We report on the simultaneous observation of spontaneous symmetry breaking and long-range spatial coherence both in the strong- and the weak-coupling regime in a semiconductor microcavity. Under pulsed excitation, the formation of a stochastic order parameter is observed in polariton and photon lasing regimes. Single-shot measurements of the Stokes vector of the emission exhibit the buildup of stochastic polarization. Below threshold, the polarization noise does not exceed 10%, while above threshold we observe a total polarization of up to 50% after each excitation pulse, while the polarization averaged over the ensemble of pulses remains nearly zero. In both polariton and photon lasing regimes, the stochastic polarization buildup is accompanied by the buildup of spatial coherence. We find that the Landau criterion of spontaneous symmetry breaking and Penrose-Onsager criterion of long-range order for Bose-Einstein condensation are met in both polariton and photon lasing regimes. PMID- 23031121 TI - Dielectric properties of charge-ordered LuFe(2)O(4) revisited: the apparent influence of contacts. AB - We show results of broadband dielectric measurements on the charge ordered, proposed to be multiferroic material LuFe(2)O(4). The temperature and frequency dependence of the complex permittivity as investigated for temperatures above and below the charge-order transition near T(CO)~320 K and for frequencies up to 1 GHz can be well described by a standard equivalent-circuit model considering Maxwell-Wagner-type contacts and hopping induced ac conductivity. No pronounced contribution of intrinsic dipolar polarization could be found, and thus the ferroelectric character of the charge order in LuFe(2)O(4) has to be questioned. PMID- 23031122 TI - Unusual thermoelectric behavior indicating a hopping to bandlike transport transition in pentacene. AB - An unusual increase in the Seebeck coefficient with increasing charge carrier density is observed in pentacene thin film transistors. This behavior is interpreted as being due to a transition from hopping transport in static localized states to bandlike transport, occurring at temperatures below ~250 K. Such a transition can be expected for organic materials in which both static energetic disorder and dynamic positional disorder are important. While clearly visible in the temperature and density dependent Seebeck coefficient, the transition hardly shows up in the charge carrier mobility. PMID- 23031124 TI - Model of the electron-phonon interaction and optical conductivity of Ba(1 x)K(x)BiO(3) superconductors. AB - We investigate the physical properties of the Ba(1-x)K(x)BiO(3) compounds with a focus on the optical properties. Results from the simple Holstein model, describing a single band coupled to an oxygen breathing mode with parameters derived from first principles calculations, are in excellent agreement with a broad range of experimental information. It accounts for an insulating parent compound at x=0, with a direct (optical) and an indirect gap, and a metal insulator transition around x=0.38. Strong electron-phonon coupling leads to spectral weight redistribution over a frequency scale much larger than the characteristic phonon frequency and to strongly anharmonic phonons. We find that the metallic phase in the vicinity of phase boundary is close to the polaronic regime. PMID- 23031123 TI - Spatial and energy distribution of topological edge states in single Bi(111) bilayer. AB - By combining scanning tunneling microscopy and spectroscopy, angle-resolved photoemission spectroscopy, and density functional theory band calculations, we directly observe and resolve the one-dimensional edge states of single bilayer (BL) Bi(111) islands on clean Bi(2)Te(3) and Bi(111)-covered Bi(2)Te(3) substrates. The edge states are localized in the vicinity of step edges having an ~2 nm wide spatial distribution in real space and reside in the energy gap of the Bi(111) BL. Our results demonstrate the existence of nontrivial topological edge states of single Bi(111) bilayer as a two-dimensional topological insulator. PMID- 23031125 TI - Suppression of the Berezinskii-Kosterlitz-Thouless transition in 2D superconductors by macroscopic quantum tunneling. AB - The evolution with thickness of the properties of quench-deposited homogeneous amorphous bismuth (a-Bi) thin films with a 14.67 A amorphous antimony (a-Sb) underlayer has been studied. In contrast with the results of previous investigations on similar systems the transition between the insulating and superconducting regimes is not direct, but involves an intervening metallic regime over a range of thicknesses. For these metallic films the temperature dependencies of the resistances at temperatures above the metallic regime can be described by the Halperin-Nelson form suggesting the occurrence of a Berezinskii Kosterlitz-Thouless (BKT) transition at lower temperatures. However, this transition never occurs as curves of R(T) flatten out as temperature is reduced. We suggest that this phenomenon is evidence of a crossover between a classical regime of thermal vortex unbinding at high temperatures and a regime of macroscopic quantum tunneling at low temperatures. The latter prevents the BKT transition from occurring. PMID- 23031126 TI - Nanoscale layering of antiferromagnetic and superconducting phases in Rb(2)Fe(4)Se(5) single crystals. AB - We studied phase separation in the single-crystalline antiferromagnetic superconductor Rb(2)Fe(4)Se(5) (RFS) using a combination of scattering-type scanning near-field optical microscopy and low-energy muon spin rotation (LE MUSR). We demonstrate that the antiferromagnetic and superconducting phases segregate into nanometer-thick layers perpendicular to the iron-selenide planes, while the characteristic in-plane size of the metallic domains reaches 10 MUm. By means of LE-MUSR we further show that in a 40-nm thick surface layer the ordered antiferromagnetic moment is drastically reduced, while the volume fraction of the paramagnetic phase is significantly enhanced over its bulk value. Self-organization into a quasiregular heterostructure indicates an intimate connection between the modulated superconducting and antiferromagnetic phases. PMID- 23031127 TI - Power-law spin correlations in the pyrochlore antiferromagnet Tb(2)Ti(2)O(7). AB - We investigate the low-temperature state of the rare-earth pyrochlore Tb(2)Ti(2)O(7) using polarized neutron scattering. Tb(2)Ti(2)O(7) is often described as an antiferromagnetic spin liquid with spin correlations extending over lengths comparable to individual tetrahedra of the pyrochlore lattice. We confirm this picture at 20 K but find that at 0.05 K the data contain evidence of pinch-point scattering, suggesting that the low temperature state of Tb(2)Ti(2)O(7) has power-law spin correlations. PMID- 23031128 TI - Unbounded growth of entanglement in models of many-body localization. AB - An important and incompletely answered question is whether a closed quantum system of many interacting particles can be localized by disorder. The time evolution of simple (unentangled) initial states is studied numerically for a system of interacting spinless fermions in one dimension described by the random field XXZ Hamiltonian. Interactions induce a dramatic change in the propagation of entanglement and a smaller change in the propagation of particles. For even weak interactions, when the system is thought to be in a many-body localized phase, entanglement shows neither localized nor diffusive behavior but grows without limit in an infinite system: interactions act as a singular perturbation on the localized state with no interactions. The significance for proposed atomic experiments is that local measurements will show a large but nonthermal entropy in the many-body localized state. This entropy develops slowly (approximately logarithmically) over a diverging time scale as in glassy systems. PMID- 23031129 TI - Charge transfer from an aromatic adsorbate to a semiconductor TiO(2) surface probed on the femtosecond time scale with resonant inelastic x-ray scattering. AB - The excited state charge transfer dynamics of an aromatic adsorbate to a rutile TiO(2) surface is studied using a core-hole clock (CHC) implementation of resonant inelastic x-ray scattering (RIXS) on the low femtosecond time scale. Comparing the abundance of the elastic and inelastic radiative N 1s core-hole decay channels provides a method for probing ultrafast injection of electrons resonantly excited to unoccupied molecular orbitals that lie above the conduction band of the substrate on the time scale of the core-hole lifetime. The method is analogous to the CHC implementation of resonant photoemission, but in the case of RIXS it is the emitted soft x-ray photons that are measured rather than photoelectrons, leaving the probed molecules in a neutral rather than ionized final state. The results reveal a charge transfer time of 2.8+/-1.5 fs from the lowest unoccupied molecular orbital +1 state of adsorbed bi-isonicotinic acid to the conduction band of the TiO(2) substrate. PMID- 23031130 TI - Self-similar gold-nanoparticle antennas for a cascaded enhancement of the optical field. AB - We experimentally demonstrate cascaded field enhancement by means of gold nanoparticle dimer and trimer antennas. The local field enhancement is probed by single-molecule fluorescence using fluorophores with high intrinsic quantum efficiency (Q(0)>80%). Using a self-similar trimer antenna consisting of 80, 40, and 20 nm gold nanoparticles, we demonstrate a fluorescence enhancement of 40 and a spatial confinement of 15 nm. Compared with a single gold nanoparticle, the self-similar trimer antenna improves the enhancement-confinement ratio by more than an order of magnitude. Self-similar antennas hold promise for high resolution imaging and spectroscopy, ultrasensitive detection, and efficient single-photon sources. PMID- 23031131 TI - Pattern-stabilized decorated polar liquid-crystal fibers. AB - Geometric frustration gives rise to new fundamental phenomena and is known to yield the formation of exotic states of matter, such as incommensurate crystals, modulated liquid-crystalline phases, and phases stabilized by defects. In this Letter, we present a detailed study of polar structure of freely suspended fluid filaments in a polarization modulated liquid-crystal phase. We show that a periodic pattern of polarization-splay stripes separated by defect boundaries and decorating smectic layers can stabilize the structure of fluid fibers against the Rayleigh-Plateau instability. The instability is suppressed by the resistance of the defect structure to a radial compression of the cylindrical fibers. Our results provide direct experimental observation of a link between the stability of the liquid fibers, internal polar order, and geometrical constraints. They open a new perspective on a wide range of fluid polar fiber materials. PMID- 23031132 TI - Mechanical instabilities of biological tubes. AB - We study theoretically the morphologies of biological tubes affected by various pathologies. When epithelial cells grow, the negative tension produced by their division provokes a buckling instability. Several shapes are investigated: varicose, dilated, sinuous, or sausagelike. They are all found in pathologies of tracheal, renal tubes, or arteries. The final shape depends crucially on the mechanical parameters of the tissues: Young's modulus, wall-to-lumen ratio, homeostatic pressure. We argue that since tissues must be in quasistatic mechanical equilibrium, abnormal shapes convey information as to what causes the pathology. We calculate a phase diagram of tubular instabilities which could be a helpful guide for investigating the underlying genetic regulation. PMID- 23031133 TI - New alphabet-dependent morphological transition in random RNA alignment. AB - We study the fraction f of nucleotides involved in the formation of a cactuslike secondary structure of random heteropolymer RNA-like molecules. In the low temperature limit, we study this fraction as a function of the number c of different nucleotide species. We show, that with changing c, the secondary structures of random RNAs undergo a morphological transition: f(c)->1 for c<=c(cr) as the chain length n goes to infinity, signaling the formation of a virtually perfect gapless secondary structure; while f(c)<1 for c>c(cr), which means that a nonperfect structure with gaps is formed. The strict upper and lower bounds 2<=c(cr)<=4 are proven, and the numerical evidence for c(cr) is presented. The relevance of the transition from the evolutional point of view is discussed. PMID- 23031134 TI - Resolution of nested neuronal representations can be exponential in the number of neurons. AB - Collective computation is typically polynomial in the number of computational elements, such as transistors or neurons, whether one considers the storage capacity of a memory device or the number of floating-point operations per second of a CPU. However, we show here that the capacity of a computational network to resolve real-valued signals of arbitrary dimensions can be exponential in N, even if the individual elements are noisy and unreliable. Nested, modular codes that achieve such high resolutions mirror the properties of grid cells in vertebrates, which underlie spatial navigation. PMID- 23031135 TI - Unified study of glass and jamming rheology in soft particle systems. AB - We explore numerically the shear rheology of soft repulsive particles at large volume fraction. The interplay between viscous dissipation and thermal motion results in multiple rheological regimes encompassing Newtonian, shear-thinning, and yield stress regimes near the "colloidal" glass transition when thermal fluctuations are important, crossing over to qualitatively similar regimes near the "jamming" transition when dissipation dominates. In the crossover regime, glass and jamming sectors coexist and give complex flow curves. Although glass and jamming limits are characterized by similar macroscopic flow curves, we show that they occur over distinct time and stress scales and correspond to distinct microscopic dynamics. We propose a simple rheological model describing the glass to-jamming crossover in the flow curves, and discuss the experimental implications of our results. PMID- 23031136 TI - Computation by switching in complex networks of states. AB - Complex networks of dynamically connected saddle states persistently emerge in a broad range of high-dimensional systems and may reliably encode inputs as specific switching trajectories. Their computational capabilities, however, are far from being understood. Here, we analyze how symmetry-breaking inhomogeneities naturally induce predictable persistent switching dynamics across such networks. We show that such systems are capable of computing arbitrary logic operations by entering into switching sequences in a controlled way. This dynamics thus offers a highly flexible new kind of computation based on switching along complex networks of states. PMID- 23031137 TI - Heterogeneous connections induce oscillations in large-scale networks. AB - Realistic large-scale networks display a heterogeneous distribution of connectivity weights that might also randomly vary in time. We show that, depending on the level of heterogeneity in the connectivity coefficients, different qualitative macroscopic and microscopic regimes emerge. We evidence, in particular, generic transitions from stationary to perfectly periodic phase locked regimes as the disorder parameter is increased, both in a simple model treated analytically and in a biologically relevant network made of excitable cells. PMID- 23031138 TI - Cattle genomics and its implications for future nutritional strategies for dairy cattle. AB - The recently sequenced cattle (Bos taurus) genome unraveled the unique genomic features of the species and provided the molecular basis for applying a systemic approach to systematically link genomic information to metabolic traits. Comparative analysis has identified a variety of evolutionary adaptive features in the cattle genome, such as an expansion of the gene families related to the rumen function, large number of chromosomal rearrangements affecting regulation of genes for lactation, and chromosomal rearrangements that are associated with segmental duplications and copy number variations. Metabolic reconstruction of the cattle genome has revealed that core metabolic pathways are highly conserved among mammals although five metabolic genes are deleted or highly diverged and seven metabolic genes are present in duplicate in the cattle genome compared to their human counter parts. The evolutionary loss and gain of metabolic genes in the cattle genome may reflect metabolic adaptations of cattle. Metabolic reconstruction also provides a platform for better understanding of metabolic regulation in cattle and ruminants. A substantial body of transcriptomics data from dairy and beef cattle under different nutritional management and across different stages of growth and lactation are already available and will aid in linking the genome with metabolism and nutritional physiology of cattle. Application of cattle genomics has great potential for future development of nutritional strategies to improve efficiency and sustainability of beef and milk production. One of the biggest challenges is to integrate genomic and phenotypic data and interpret them in a biological and practical platform. Systems biology, a holistic and systemic approach, will be very useful in overcoming this challenge. PMID- 23031139 TI - Optimal barn characteristics for high-yielding Holstein cows as derived by a new heat-stress model. AB - Meticulous planning is required to minimize heat-stress conditions in barns. The objective of this study was to determine optimum barn characteristics for high yielding dairy cows under Israeli (Mediterranean) summer ambient conditions, by using a new stress model that takes ambient temperature, relative humidity and wind velocity into account. During the summers of 2004 and 2005, three meteorological stations were alternately installed in 39 barns: two stations inside the barn at the prevailing downwind direction, and a third station outside the upwind end of the barn. Ambient temperature, relative humidity, wind speed and direction were measured and recorded every 10 min for 3 to 5 consecutive days at each barn in turn. The data were collected at different geographical and climatic conditions. Therefore, the data collected by an outside station were used as covariates. A heat-stress model was used to determine the threshold temperature (THRT) at which a cow begins to increase its respiratory rate; THRT was the response variable in the statistical model. The THRT model takes in account assumed values of a cow's physiological characteristics: daily milk yield of 45 kg, containing 3.5% fat, and 3 mm fur depth. The independent variables were: orientation, barn type, roof slope, roof ridge, marginal height, roof type (fixed or sliding) and barn width. Results showed that the optimal barn for high yielding cows is the loose-housing type, oriented with its long axis perpendicular to the prevailing wind direction. Advantageous to the design would be an open ridge or pagoda with marginal height of over 4.7 m for north-south orientation and over 5 m for east-west orientation, roof slope over 11%, and barn width between 43 and 51 m for north-south orientation but lower than 42 m for east-west orientation. A sliding roof was also found to be an excellent solution when outside yards are banned by environmental regulations. PMID- 23031140 TI - Behavioural adaptations of sheep to repeated acidosis challenges and effect of yeast supplementation. AB - This study aims to determine whether sheep modify their feeding and general behaviour when they undergo acidosis challenge, whether these modifications are maintained when acidosis challenges are repeated and whether yeast supplementation affects these modifications. Twelve rumen-cannulated wethers fed concentrate (wheat) and forage (hay) were exposed to three 28-day periods consisting of a 23-day recovery phase (20% of wheat) followed by a 5-day acidosis challenge (60% of wheat). Both diets limited food intake to 90% of ad libitum intake. Six sheep received a daily supplementation of a live yeast product, six received a placebo. Ruminal pH was recorded continuously. Daily consumption of wheat, hay, water and weekly consumption of salt were monitored. Behavioural observations were performed twice in each period: once under the recovery phase and once under acidosis challenge. These observations included video recordings over 24 h (time budget), social tests (mixing with another sheep for 5 min) and nociception tests (CO2 hot laser). As expected, sheep spent more time with a ruminal pH below 5.6 during challenges than during recovery phases (12.5 v. 4.7 h/day). Sheep drank more water (3.87 v. 3.27 l/day) and ingested more salt (16 v. 11 g/day) during challenges. They also spent more time standing than during recovery phases, adopting more frequent alarm postures and reacting more slowly to the hot stimulus. More severe behavioural modifications were observed during the first challenge than the two other challenges. Significant concentrate refusals were observed during challenge 1: from days 3 to 5 of this challenge, sheep ate only half of the distributed concentrate. Sheep were also more active and more aggressive towards each other in challenge 1. These behavioural modifications disappeared as the challenges were repeated: no behavioural modifications were observed between challenges and recovery phases during periods 2 and 3, and furthermore, sheep rapidly ate all the concentrate distributed during the third challenge. Focusing on the effects of yeast, the only differences registered between the two groups concerned ruminal pH, that is, mean ruminal pH values in the supplemented group were lower during the first challenge (5.11 v. 5.60) but higher during the third challenge (5.84 v. 5.28). In conclusion, our experiment suggests sheep can adapt to acidosis challenges, especially with yeast supplementation. Otherwise, ruminal pH values remained low during challenges, indicating that the modifications of general and feeding behaviour in subacute ruminal acidosis situations are not due exclusively to low ruminal pH values. PMID- 23031141 TI - Psychosomatic research in hypertension: the lack of impact of decades of research and new directions to consider. PMID- 23031142 TI - Editorial commentary on dilemmas in treating hypertension in octogenarians. PMID- 23031143 TI - Adherence to blood pressure telemonitoring in a cluster-randomized clinical trial. AB - Hypertension is a leading cause of cardiovascular disease and death worldwide. Advances in technology have added telemedicine as a tool for managing hypertension. The effectiveness of telemedicine depends on patients' ability to adhere to schedules of home monitoring and case management. Participants with uncontrolled hypertension in the intervention arm of a randomized trial who completed 6 months of follow-up were included in this analysis. They were asked to measure their blood pressure (BP) a minimum of 6 times per week using a telemonitor that transmitted the readings to their pharmacist case manager. Hypertensive patients in this study had high adherence to telemonitoring (73% took at least 6 BP readings per week) and phone visits (88% of expected visits were attended). In a multivariate analysis, older age, male sex, and some college education predicted better telemonitoring adherence. White non-Hispanic race/ethnicity predicted better adherence to phone visits with pharmacist case managers. Telemonitoring adherence and phone adherence were highly correlated; participants who did not send readings on schedule were more likely to skip at least one phone visit with their pharmacist case manager. The findings from this analysis indicate that hypertensive patients in this study were able to achieve and maintain high adherence to both the telemonitoring and the phone case management visits. PMID- 23031145 TI - Diuretics for hypertension-reasons for a contradiction in primary care prescribing behavior: a qualitative study. AB - There has been a long international discussion on diuretics as first-line therapy for hypertension. In Germany, thiazide diuretics are very rarely prescribed in monotherapy and concurrently highly prescribed in fixed-combinations. The aim of this study was to approach the reasons for this inconsistency in primary care prescribing behavior. A qualitative study design consisting of single interviews with general practitioners (GPs) was chosen. Most GPs perceived diuretics as too weak to treat arterial hypertension effectively in monotherapy. In combination therapy, GPs expected to spare the dose and to offset certain side effects of other drugs. The convenient availability of diuretics in most fixed-dose combinations on the German drug market was seen as an important reason for their frequent prescription in combination therapy. Thus, the reasons given by the GPs differed from the main arguments of the academic debate. Dissemination strategies for guidelines should take the perceptions and opinions of practicing GPs into account. PMID- 23031144 TI - Hypertension and the risk of incident gout in a population-based study: the atherosclerosis risk in communities cohort. AB - The authors quantified the impact of hypertension on gout incidence in middle aged white and African American men and women. The Atherosclerosis Risk in Communities Study (ARIC) was a prospective population-based cohort that recruited patients between 1987 and 1989 from 4 US communities. Using a time-dependent Cox proportional hazards model, the authors estimated the adjusted hazard ratio (HR) of incident gout by time-varying hypertension and tested for mediation by serum urate level. There were 10,872 participants among whom 45% had hypertension during follow-up; 43% were men and 21% were African American. Over 9 years, 274 (2.5%) participants developed gout (1.8% of women and 3.5% of men). The unadjusted HR of incident gout was approximately 3 times (HR, 2.87; 95% confidence interval [CI], 2.24-3.78) greater for those with hypertension. Adjusting for confounders resulted in an attenuated but still significant association between hypertension and gout (HR, 2.00; 95% CI, 1.54-2.61). Adjustment for serum urate level further attenuated but did not abrogate the association (HR, 1.36, 95% CI, 1.04-1.79). There was no evidence of effect modification by sex (P=.35), race (P=.99), or obesity at baseline (P=.82). Hypertension was independently associated with increased gout risk in middle-aged African American and white adults. Serum urate level may be a partial intermediate on the pathway between hypertension and gout. PMID- 23031146 TI - Discrepancy between tonometric ambulatory and cuff-based office blood pressure measurements in patients with type 1 diabetes. AB - The aim of the current study was to compare ambulatory blood pressure (ABP) with office blood pressure (OBP) in diagnosing hypertension (HTN) in type 1 diabetes. The cross-sectional study included 569 type 1 diabetes patients, with a mean +/- standard deviation (SD) age of 55 +/- 13 years and diabetes duration of 33 +/- 16 years, and 315 (55%) men. Blood pressure >= 130/80 mm Hg defined HTN. ABP was measured by tonometry and OBP by sphygmomanometry. Elevated ABP with normal OBP defined masked uncontrolled HTN, and normal ABP with elevated OBP defined isolated uncontrolled clinic HTN. Mean +/- SD 24-hour ABP, daytime ABP, and OBP was 128 +/- 16/75 +/- 10 mm Hg, 133 +/- 16/77 +/- 11 mm Hg, and 136 +/- 14/76 +/- 8 mm Hg, respectively (P<.001). With 24-hour and daytime ABP, HTN was present in 256 (45%) and 304 (53%) patients; normal BP in 102 (18%) and 88 (15%) patients; isolated uncontrolled clinic HTN in 154 (27%) and 104 (%) patients; and masked uncontrolled HTN in 57 (10%) and 73 (13%) patients. Twenty-four-hour ABP and OBP showed disagreement in diagnosing HTN in 211 (37%) patients. Daytime ABP and OBP disagreed in 177 (31%) patients. HTN by 24-hour and daytime ABP was present in 313 (55%) and 377 (66%) patients. ABP measurements were well-tolerated and successful in 98%. A total of 92% would volunteer for repeat measurements and 83% preferred the tonometry to conventional cuff-based devices. In patients with type 1 diabetes, tonometric ABP measurements are feasible. ABP and OBP disagree in diagnosing HTN in 31% to 37% of patients. Furthermore, 55% to 66% of patients do not reach target BP of <130/80 mm Hg despite regular follow-up. PMID- 23031147 TI - Prevalence and correlates of low medication adherence in apparent treatment resistant hypertension. AB - Low medication adherence may explain part of the high prevalence of apparent treatment-resistant hypertension (aTRH). The authors assessed medication adherence and aTRH among 4026 participants taking >= 3 classes of antihypertensive medication in the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) trial using the 4-item Morisky Medication Adherence Scale (MMAS). Low adherence was defined as an MMAS score >= 2. Overall, 66% of participants taking >= 3 classes of antihypertensive medication had aTRH. Perfect adherence on the MMAS was reported by 67.8% and 70.9% of participants with and without aTRH, respectively. Low adherence was present among 8.1% of participants with aTRH and 5.0% of those without aTRH (P<.001). Among those with aTRH, female sex, residence outside the US stroke belt or stroke buckle, physical inactivity, elevated depressive symptoms, and a history of coronary heart disease were associated with low adherence. In the current study, a small percentage of participants with aTRH had low adherence. PMID- 23031148 TI - Observations on degenerative changes within the optic nerve in patients with primary open glaucoma and arterial hypertension: 6-month follow-up. AB - The authors aimed to determine the effect of the time of hypotensive drug administration on the progress of degenerative changes within the optic nerve in patients with hypertension and glaucoma. Two groups were included in the study: group A comprised patients-dippers taking drugs in the mornings, and group B comprised patients-nondippers taking drugs both in the mornings and in the evenings. After 6 months, group B showed significant drops in nocturnal diastolic blood pressure (BP) (month 1=73.27 mm Hg vs month 6=67.50 mm Hg), nocturnal mean BP (89.34 vs 84.65 mm Hg), and minimum diastolic BP (50.74 vs 44.03 mm Hg). Group B also showed significant reductions in nocturnal ocular perfusion pressure (43.0 vs 39.73), retinal nerve fiber layer thickness (131.31 vs 113.12 MUm), and flow in the eye vessels. Taking hypotensive drugs in the evening may significantly decrease blood flow in the eye arteries, cause degenerative changes within the optic nerves, and result in greater loss in the field of vision. PMID- 23031149 TI - Dilemmas in treating hypertension in octogenarians. AB - One quarter of Americans will be older than 80 by 2030, and hypertension in this group will be ubiquitous. Most studies of hypertension exclude octogenarians and are not able to be generalized because of differences in physiologic and social phenomena. This review evaluates the existing literature in an effort to identify unresolved issues and guide future areas of investigation. Hypertension has been well characterized in adults and the young elderly, and the focus is on optimizing treatment regimens. However, research specifically involving this rapidly growing minority is sparse. Most studies are still trying to characterize blood pressure goals, and only one major series has begun to evaluate treatment options. Based on available evidence, it appears that an appropriate blood pressure goal may be somewhat higher in octogenarians and that thiazide diuretics may be the initial treatment of choice. PMID- 23031150 TI - Role of single-pill combination therapy in optimizing blood pressure control in high-risk hypertension patients and management of treatment-related adverse events. AB - Renin-angiotensin-aldosterone system (RAAS) inhibitors in combination with other antihypertensive drugs (eg, calcium channel blockers [CCBs] and/or diuretics) are a preferred treatment option for managing uncontrolled hypertension in high-risk patients with chronic kidney disease (CKD), diabetes, or heart failure because RAAS inhibitors provide cardiorenal benefits in addition to lowering blood pressure (BP). However, when prescribing antihypertensive therapies to high-risk patients, physicians must be aware of the risks of treatment-related adverse events of hyperkalemia and peripheral edema associated with RAAS inhibitors and CCBs, respectively. This review discusses the use of single-pill combination antihypertensive therapy to optimize BP control in high-risk patients with CKD, diabetes, and/or heart failure and provides strategies for preventing and managing hyperkalemia and peripheral edema in this group. Single-pill combination therapy can utilize different classes of antihypertensive drugs to reduce BP while mitigating the risks of treatment-related adverse events, reducing pill burden, lowering medical cost, and improving patient compliance. PMID- 23031151 TI - The new anticoagulant drugs: are they really superior to warfarin? PMID- 23031152 TI - Liddle's-like syndrome in the elderly. PMID- 23031153 TI - Appropriateness of referral to a European society of hypertension center of excellence. PMID- 23031154 TI - Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for hypertension on clinical end points: a cohort study. PMID- 23031155 TI - Overlapping spironolactone dosing in primary aldosteronism and resistant essential hypertension. PMID- 23031156 TI - Influence of rearing system, diet and gender on performance, carcass traits and meat quality of Polish Landrace pigs. AB - Forty-eight Polish Landrace pigs (initially 32.43 +/- 0.70 kg live weight) were assigned to a 2 * 2 * 2 factorial arrangement in order to assess the effects of the rearing system (outdoor v. indoor), diet (with corn grain silage v. without corn grain silage) and gender (barrows v. gilts) on performance, carcass traits, meat quality and intramuscular collagen (IMC) characteristics. During the trial period of 14 weeks, each group was housed in a pen of 12 m2, and the outdoor reared animals had access to a paddock of 24 m2. Pigs were fed a diet computed according to standard requirements and supplied on a basis of 9% of metabolic weight (live weight0.75). Pigs were slaughtered at 110.69 +/- 0.85 kg. The rearing system did not significantly affect growth, hot and cold dressing, meat quality of m. longissimus lumborum or IMC. Outdoor pigs had less (P < 0.05) backfat thickness, slightly higher (P = 0.082) lean percent and a meat with lower pH and fat than the conventional system. In light of these results, alternative pig rearing systems with indoor space and free outdoor access could be an interesting production system for the pigs. Compared with the pigs fed diets with corn grain silage, those fed diets without corn had higher (P < 0.05) lean, ham percentage and IMC content, lower (P < 0.05) neck percentage but similar main tissue components of the ham and meat quality. Compared with the gilts, barrows were fatter and showed a meat with different physico-chemical traits, which was slightly more tender and had similar IMC properties. PMID- 23031157 TI - Mutational analysis of DNMT3A gene in acute leukemias and common solid cancers. AB - DNMT3A, a DNA methyltransferase that functions for de novo methylation, is important in development and many cellular processes related to tumorigenesis. Somatic mutations of DNMT3A gene, including recurrent mutations in its Arg-882, were recently reported in acute myelogenous leukemia (AML), strongly suggesting its role in development of AML. To see whether DNMT3A mutation occurs in other malignancies as well, we analyzed DNMT3A in 916 cancer tissues from 401 hematologic malignancies (AML, acute lymphoblastic leukemias (ALL), multiple myelomas and lymphomas) and 515 carcinomas (lung, breast, prostate, colorectal and gastric carcinomas) using a single-strand conformation polymorphism (SSCP) assay. We identified DNMT3A mutations, especially the Arg-882 mutations, in adulthood AML (9.4%). In addition, we found DNMT3A mutations in pre-B-ALL and three lung cancers at lower frequencies. Allelic loss of DNMT3A was frequently observed in most cancer types analyzed, including lymphomas (48.1%), gastric cancers (23.5%) and lung cancers (18.3%) irrespective of DNMT3A mutation. Also, loss of DNMT3A expression was common in lung cancers (46.4%), and was associated with the allelic loss. Our data indicate that DNMT3A gene is mutated mainly in AML, but it occurs in other cancers, such as ALL and lung cancer, despite the lower incidences. Also, the data suggest that DNMT3A is altered in many cancer types by various ways, including somatic mutations, allelic loss and loss of expression that might play roles in tumorigenesis. PMID- 23031158 TI - Tissue engineering of the tympanic membrane. AB - Tympanic membrane (TM) perforations are common, with current treatments for chronic perforations involving surgery, using various graft materials, from autologous cartilage or fascia through to paper patch. Recent research developments in this field have begun applying the principles of tissue engineering, with appropriate scaffolds, cells, and bioactive molecules (BMs). This has revolutionized the therapeutic approach due to the availability of a wide range of materials with appropriate compatibility and mechanical properties to regenerate the membrane acoustics and may also represent a paradigm shift in the management of TM perforations in an outpatient setting without surgery. However, many factors need to be considered in the fabrication of a bioengineered TM. This review discusses the issues associated with current treatment and examines TM wound healing relevant to the construction of a bioengineered TM. It also describes the tissue-engineering approach to TM regeneration by summarizing currently used scaffolds, BMs, and cells in TM wound healing. Finally, it considers the design of scaffolds, delivery of BMs, and cell engraftment toward potential clinical application. PMID- 23031159 TI - The presence of black vultures at the calving sites and its effects on cows' and calves' behaviour immediately following parturition. AB - Black vultures (Coragyps atratus) are often present near calving sites, and under this situation they may play a positive role by removing animal carcasses and afterbirth or a negative role by attacking neonate calves or disturbing cow-calf behaviours following parturition. Cow-calf behaviour was recorded over a 4-year study period from a total of 300 births involving 200 Nellore, 54 Guzerat, 20 Gyr and 26 Caracu cows. The calving site in relation to the location of the herd, considering cow-calf pairs within, close or distant to the herd, the presence of vultures and the behaviour of cows and calves were recorded instantaneously, at 5 min interval. On average, vultures were present at 80% of the calving sites. The frequency of vultures present at calving sites was dependent on the years for the Nellore herd, increasing from 1998 to 2003. When vultures were present, the time that the cow was in contact with its calf decreased, and the percentage of time that the cow was standing still increased. Vultures were observed pecking cows and their neonates during 34.1% of all recordings. However, in only two cases pecking injuries were actually observed on calves that were noted to be very weak. The preliminary results suggest that although black vultures cannot be characterized as a predator of neonate calves, they sometimes attack neonate calves and their presence near the calving sites alter the behaviours of cows and calves. PMID- 23031161 TI - Platelet-rich plasma enhances the dermal regeneration efficacy of human adipose derived stromal cells administered to skin wounds. AB - The administration of human adipose-derived stromal cells (hASCs) enhances skin wound healing. However, poor survival of hASCs that are administered to avascular wound regions may limit the therapeutic efficacy of the hASCs. The aim of this study was to determine whether the coadministration of platelet-rich plasma (PRP) and hASCs enhanced the skin wound-healing efficacy of hASCs. Skin regeneration was examined in skin wounds of athymic mice that were either untreated or treated with hASCs, PRP, or both hASCs and PRP. Coadministration of PRP and hASCs resulted in better skin regeneration than hASC administration alone in part by significantly improving the proliferation of administered hASCs by the angiogenic growth factor secretion of the hASCs and surrounding mouse host cells in the wound areas and by promoting neovascularization in the wound beds. PMID- 23031163 TI - Spinal cord injury. PMID- 23031160 TI - What serial hCG can tell you, and cannot tell you, about an early pregnancy. AB - The serial measurement of serum hCG concentrations is an important clinical tool used to differentiate normal from abnormal pregnancies. At hCG values below which ultrasonography can be diagnostic, the comparison of a patient's hCG dynamics to those of established expected curves of rise or fall can aid the clinician in determining when to follow expectantly and when to intervene. Still, this method has some limitations and should never supersede clinical judgment based on symptoms or signs. PMID- 23031164 TI - About Toronto rehab. PMID- 23031165 TI - Evidence-based and heuristic approaches for customization of care in cardiometabolic syndrome after spinal cord injury. AB - Component and coalesced health risks of the cardiometabolic syndrome (CMS) are commonly reported in persons with spinal cord injuries (SCIs). These CMS hazards are also co-morbid with physical deconditioning and elevated pro-atherogenic inflammatory cytokines, both of which are common after SCI and worsen the prognosis for all-cause cardiovascular disease. This article describes a systematic procedure for individualized CMS risk assessment after SCI, and emphasizes evidence-based and intuition-centered countermeasures to disease. A unified approach will propose therapeutic lifestyle intervention as a routine plan for aggressive primary prevention in this risk-susceptible population. Customization of dietary and exercise plans then follow, identifying shortfalls in diet and activity patterns, and ways in which these healthy lifestyles can be more substantially embraced by both stakeholders with SCI and their health care providers. In cases where lifestyle intervention utilizing diet and exercise is unsuccessful in countering risks, available pharmacotherapies and a preferred therapeutic agent are proposed according to authoritative standards. The over arching purpose of the monograph is to create an operational framework in which existing evidence-based approaches or heuristic modeling becomes best practice. In this way persons with SCI can lead more active and healthy lives. PMID- 23031166 TI - Training to achieve over ground walking after spinal cord injury: a review of who, what, when, and how. AB - OBJECTIVES: (1) To provide clinicians with the best evidence for effective retraining of walking after spinal cord injury (SCI) to achieve over ground walking. (2) To identify gaps in our knowledge to guide future research. METHODS: Articles that addressed the retraining of walking in adults with SCI and reported outcome measures of over ground walking ability were identified through a non-systematic search of the PubMed, Scopus, and CINAHL databases. No restriction was applied to the method of training. Selected articles were appraised using the Physiotherapy Evidence Database scale. Information was synthesized to answer who best responds to what type of treatment, how that treatment should be delivered, and at what stage after injury. RESULTS: Individuals with motor incomplete SCI (American Spinal Injury Association (ASIA) Impairment scale (AIS) C and D) are most likely to regain walking over ground. The effective methods of training all involved a substantial component of walking in the training, and if assistance was provided, partial assistance was more effective than total assistance. Walking training resulted in a change in over ground walking speed of 0.06-0.77 m/s, and 6 minute walk distance of 24-357 m. The effective training schedules ranged from 10 to 130 sessions, with a density of sessions ranging from 2 per week to 5 per week. Earlier training led to superior results both in the subacute (<6 months) and chronic phases (>6 months) after injury, but even individuals with chronic injuries of long duration can improve. CONCLUSIONS: Frequent, early treatment for individuals with motor incomplete SCI using walking as the active ingredient whether on the treadmill or over ground, generally leads to improved walking over ground. Much work remains for the future, including better quantification of treatment intensity, better outcome measures to quantify a broader range of walking skills, and better ways to retrain individuals with more severe lesions (AIS A and B). PMID- 23031167 TI - Profiling motor control in spinal cord injury: moving towards individualized therapy and evidence-based care progression. AB - This article, based on the keynote address at the 5th National Spinal Cord Injury Conference in Toronto, addresses methods to neurophysiologically characterize patients after spinal cord injury and proposes how those methods could be used to individualize therapeutic interventions and monitor their efficacy over the course of neurorehabilitation. PMID- 23031168 TI - Changes in hand muscle synergies in subjects with spinal cord injury: characterization and functional implications. AB - BACKGROUND/OBJECTIVES: In order to guide and improve rehabilitation interventions for grip function after spinal cord injury (SCI), it is important to have a detailed understanding of the motor control strategies that the central nervous system uses to control the hand. We examined whether changes in the motor control of the hand after SCI are manifested in the form of changes to muscle synergies. We further sought to determine a correlation between functional ability and the extent of muscle synergy disruption. METHODS: Surface electromyographic (EMG) data were recorded from 8 hand muscles in 10 able-bodied subjects and 6 subjects with SCI as they performed various functional tasks using grip types relevant to activities of daily living. Muscle synergies were extracted using non-negative matrix factorization. Functional performance in each task was quantified using a 5-point clinical scale. RESULTS: The synergies most commonly observed in able-bodied subjects were co-activation of extensor digitorum communis and extensor indicis proprius, as well as of flexor digitorum superficialis with flexor carpi ulnaris. The proportion of subjects in which particular synergies occurred was significantly different for subjects with SCI compared to able-bodied subjects (P < 0.001). Deviations from the average able bodied synergies in subject with SCI were found to be poorly correlated (r = 0.04) with functional ability. CONCLUSIONS: Results suggest that the disruptions and re-organizations of neural circuitry after SCI are reflected by the extracted muscle synergies, but the question of how muscle synergies can guide rehabilitation interventions remains open. PMID- 23031169 TI - SCI-U: e-learning for patient education in spinal cord injury rehabilitation. AB - BACKGROUND/OBJECTIVES: To develop an online patient education resource for use in spinal cord injury rehabilitation. PARTICIPANTS: The development process involved more than 100 subject-matter experts (SMEs) (rehabilitation professionals and consumers) from across Canada. Preliminary evaluation was conducted with 25 end users. METHODS: An iterative development process was coordinated by a project team; SMEs (including patients) developed the content in working groups using wiki-based tools. Multiple rounds of feedback based on early prototypes helped improve the courses during development. RESULTS: Five courses were created, each featuring more than 45 minutes of video content and hundreds of media assets. Preliminary evaluation results indicate that users were satisfied by the courses and perceived them to be effective. CONCLUSIONS: This is an effective process for developing multimedia patient education resources; the involvement of patients in all parts of the process was particularly helpful. Future work will focus on implementation, integration into clinical practice and other delivery formats (smart phones, tablets). PMID- 23031171 TI - Which trunk inclination directions best predict multidirectional-seated limits of stability among individuals with spinal cord injury? AB - OBJECTIVE: To determine which trunk inclination directions most accurately predict multidirectional-seated limits of stability among individuals with spinal cord injury (SCI). DESIGN: Predictive study using cross-sectional data. SETTING: Pathokinesiology Laboratory. PARTICIPANTS: Twenty-one individuals with complete or incomplete sensorimotor SCI affecting various vertebral levels participated in this study. INTERVENTIONS: Participants were instructed to lean their trunk as far as possible in eight directions, separated by 45 degrees intervals, while seated on an instrumented chair with their feet positioned on force plates. OUTCOMES MEASURES: Eight direction-specific stability indices (DSIs) were used to define an overall stability index (OSI) (limits of stability). RESULTS: All DSIs significantly correlated with the OSI (r = 0.816-0.925). A protocol that only tests the anterior, left postero-lateral, and right lateral trunk inclinations accurately predicts multidirectional-seated postural stability (r(2) = 0.98; P < 0.001). CONCLUSION: Multidirectional-seated postural stability can be predicted almost perfectly by evaluating trunk inclinations performed toward the anterior, left postero-lateral, and right lateral directions. PMID- 23031170 TI - Social networks and secondary health conditions: the critical secondary team for individuals with spinal cord injury. AB - OBJECTIVES: To describe the structure of informal networks for individuals with spinal cord injury (SCI) living in the community, to understand the quality of relationship of informal networks, and to understand the role of informal networks in the prevention and management of secondary health conditions (SHCs). DESIGN: Mixed-method descriptive study. SETTING: Ontario, Canada Participants: Community-dwelling adults with an SCI living in Ontario Interventions/methods: The Arizona Social Support Interview Survey was used to measure social networks. Participants were asked the following open-ended questions: (1) What have been your experiences with your health care in the community? (2) What have been your experiences with care related to prevention and/or management of SHCs?, (3)What has been the role of your informal social networks (friends/family) related to SHCs? RESULTS: Fourteen key informant interviews were conducted (6 men, 8 women). The overall median for available informal networks was 11.0 persons (range 3-19). The informal network engaged in the following roles: (1) advice/validating concerns; (2) knowledge brokers; (3) advocacy; (4) preventing SHCs; (5) assisting with finances; and (6) managing SHCs. Participants described their informal networks as a "secondary team"; a critical and essential force in dealing with SHCs. CONCLUSIONS: While networks are smaller for persons with SCI compared with the general population, these ties seems to be strong, which is essential when the roles involve a level of trust, certainty, tacit knowledge, and flexibility. These informal networks serve as essential key players in filling the gaps that exist within the formal health care system. PMID- 23031172 TI - A randomized trial of functional electrical stimulation for walking in incomplete spinal cord injury: effects on body composition. AB - OBJECTIVE: To evaluate the effects of functional electrical stimulation (FES) assisted walking on body composition, compared to a non-FES exercise program in individuals with a spinal cord injury (SCI). DESIGN: Parallel-group randomized controlled trial. METHODS: Individuals with chronic (>= 18 months) incomplete SCI (level C2 to T12, AIS C or D) were recruited and randomized to FES-assisted walking (intervention), or aerobic and resistance training (control) sessions thrice-weekly for 16 weeks. Whole body and leg lean mass and whole body fat mass, measured with dual-energy X-ray absorptiometry, and lower-limb muscle cross sectional area (CSA) and fat CSA, measured with peripheral computed tomography were assessed at baseline, 4 months, and 12 months. Intention-to-treat analyses using repeated measures general linear models were used to assess between-group differences. RESULTS: Thirty-four individuals were randomized (17 per group); 27 remained at 12 months. There were no significant main effects of FES-assisted walking on body composition variables in intention-to-treat analyses with group means. There was a significant group-by-time interaction for muscle area from baseline to 12 months (P = 0.04). Intention-to-treat analysis of muscle area change scores between baseline and 12 months revealed a significant difference between groups (mean (SD) muscle area change score 212 (517) mm(s) for FES, -136 (268) mm(s) for control, P = 0.026). There were 13 side effects or adverse events deemed related to study participation (7 intervention, 5 control); most were resolved with modifications to the protocol. One fainting episode resulted in a hospital visit and study withdrawal. CONCLUSIONS: Thrice-weekly FES-assisted walking exercise over 4 months did not result in a change in body composition in individuals with chronic, motor incomplete C2 to T12 SCI (AIS classification C and D). However, longer-term follow-up revealed that it might maintain muscle area. PMID- 23031173 TI - Impact of impairment and secondary health conditions on health preference among Canadians with chronic spinal cord injury. AB - CONTEXT/OBJECTIVES: To describe the relationships between secondary health conditions and health preference in a cohort of adults with chronic spinal cord injury (SCI). STUDY DESIGN: Cross-sectional telephone survey. SETTING: Community. PARTICIPANTS: Community-dwelling adult men and women (N = 357) with chronic traumatic and non-traumatic SCI (C1-L3 AIS A-D) who were at least 1 year post injury/onset. INTERVENTIONS: Not applicable. OUTCOME MEASURES: Health Utilities Index-Mark III (HUI-Mark III) and SCI Secondary Conditions Scale-Modified (SCS M). RESULTS: SCS-M responses for different secondary health conditions were used to create "low impact = absent/mild" and "high impact = moderate/significant" secondary health condition groups. Analysis of covariance was used to examine differences in HUI-Mark III scores for different secondary health conditions while controlling for impairment. The mean HUI-Mark III was 0.24 (0.27, range, 0.28 to 1.00). HUI-Mark III scores were lower (P < 0.001) in high impact groups for spasms, bladder and bowel dysfunction, urinary tract infections, autonomic dysreflexia, circulatory problems, respiratory problems, chronic pain, joint pain, psychological distress, and depression compared with the low impact groups. As well, HUI-Mark III scores were lower (P < 0.05) in high impact groups for pressure sores, unintentional injuries, contractures, heterotopic bone ossification, sexual dysfunction, postural hypotension, cardiac problems, and neurological deterioration than low-impact groups. CONCLUSION: High-impact secondary health conditions are negatively associated with health preference in persons with SCI. Although further work is required, the HUI-Mark III data may be a useful tool for calculating quality-adjusted life years, and advocating for additional resources where secondary health conditions have substantial adverse impact on health. PMID- 23031174 TI - Walking-related outcomes for individuals with traumatic and non-traumatic spinal cord injury inform physical therapy practice. AB - OBJECTIVES: To describe and compare patient demographics, inpatient lengths of stay (LOS), and walking-related functional outcomes of individuals with spinal cord injuries (SCIs) of traumatic (TSCI) and non-traumatic (NTSCI) etiologies. To contrast these features between individuals who walked from those who did not walk at discharge from inpatient rehabilitation. DESIGN: Prospective observational study; comparisons between TSCI and NTSCI, walkers and non-walkers. Information collected as a pilot project within a provincial SCI informatics strategy. SETTING: Rehabilitation hospital specialized for SCIs. PARTICIPANTS: Adults with NTSCI (n = 31) or TSCI (n = 59) admitted to inpatient rehabilitation, 2007-2009. OUTCOME MEASURES: Lower-extremity motor scores (LEMS), spinal cord independence measure version III (SCIM-III) total and mobility subscores, functional independence measure (FIM), Length of Stay (LOS) at inpatient facilities. RESULTS: Groups (NTSCI vs. TSCI) did not differ in the proportion of individuals that achieved "walker" status (SCIM-III mobility indoors (MI) score >= 3 at rehab discharge) (P = 0.41, 48.9% overall). Inpatient LOS at both acute care and rehabilitation facilities did not differ between groups; however, TSCI non-walkers had longer inpatient rehabilitation LOS than TSCI walkers. Among walkers, improvement was shown on all three mobility subscores of the SCIM-III between admission and discharge from rehabilitation; highest significance was shown on the SCIM-III MI. Walking status at discharge (SCIM-III MI) was most strongly correlated with LEMS at rehab admission (r = 0.71, P < 0.001). CONCLUSION: Walking outcomes are comparable among individuals with NTSCI vs. TSCI admitted for specialized SCI rehabilitation. Routine use of SCIM-III mobility items for assessment of walking outcome is recommended for inpatient rehabilitation. PMID- 23031175 TI - Real-time two-dimensional asynchronous control of a computer cursor with a single subdural electrode. AB - OBJECTIVE: To test the feasibility of controlling a computer cursor asynchronously in two dimensions using one subdural electrode. DESIGN: Proof of concept study. SETTING: Acute care hospital in Toronto, Canada. PARTICIPANT: A 68 year-old woman with a subdural electrode implanted for the treatment of essential tremor (ET) using direct brain stimulation of the primary motor cortex (MI). INTERVENTIONS: Power changes in the electrocorticography signals were used to implement a "brain switch". To activate the switch the subject had to decrease the power in the 7-13 Hz frequency range using motor imagery of the left hand. The brain switch was connected to a system for asynchronous control of movement in two dimensions. Each time the user reduced the amplitude in the 7-13 Hz frequency band below an experimentally defined threshold the direction of cursor changed randomly. The new direction was always different from those previously rejected ensuring the convergence of the system on the desired direction. OUTCOME MEASURES: Training time, time and number of switch activations required to reach specific targets, information transfer rate. RESULTS: The user was able to control the cursor to specific targets on the screen after only 15 minutes of training. Each target was reached in 51.7 +/- 40.2 seconds (mean +/- SD) and after 9.4 +/- 6.8 switch activations. Information transfer rate of the system was estimated to be 0.11 bit/second. CONCLUSION: A novel brain-machine interface for asynchronous two-dimensional control using one subdural electrode was developed. PMID- 23031176 TI - Using scoping review methods to describe current capacity and prescribe change in Canadian SCI rehabilitation service delivery. AB - OBJECTIVE: To describe the methodology used to conduct a scoping review of spinal cord injury (SCI) rehabilitation service delivery in Canada, and to explain the reporting process intended to advance future service delivery. EVIDENCE ACQUISITION: A SCI rehabilitation framework derived from the International Classification of Function, Disability and Health was developed to describe the goals and interprofessional processes of rehabilitation. An adapted Arksey and O'Malley (2005) methodological framework was used to conduct a scoping review of SCI rehabilitation services in Canada. Data were obtained from multiple relevant sources via survey (N = 3572 data fields) from 13 of 15 Canadian tertiary SCI rehabilitation sites, systematic reviews, white papers, literature reviews, clinical practice resources, and clinicians. Multidisciplinary teams of content experts (N = 17), assisted with data interpretation and validation by articulating practice trends, gaps, and priorities. EVIDENCE SYNTHESIS: The findings will be presented in an atlas, which includes aggregate national data regarding impairment and demographic characteristics, service utilization, available resources (staff and capital equipment), specialized services, local expertise, and current best practice indicators, outcome measures, and clinical guidelines. Data were collated and synthesized relative to specific rehabilitation goals. The current state of SCI rehabilitation service delivery (specific to each rehabilitation goal) is summarized in a report card within three domains, knowledge generation, clinical application, and policy change, and specifies key 2020 priorities. CONCLUSION: These findings should prompt critical evaluation of current Canadian SCI rehabilitation service delivery while specifying enhancements in knowledge generation, clinical application and policy change domains likely to assist with achievement of best practices by 2020. PMID- 23031178 TI - Crystal structure and location of gp131 in the bacteriophage phiKZ virion. AB - Pseudomonas phage phiKZ and its two close relatives phiPA3 and 201phi2-1 are very large bacteriophages that form a separate branch in phage classification because their genomes are very different from the rest of GenBank sequence data. The contractile tail of phiKZ is built from at least 32 different proteins, but a definitive structural function is assigned to only one of them-the tail sheath protein. Here, we report the crystal structure of the C-terminal domain of another phiKZ tail protein, gene product 131 (gp131C). We show that gp131 is located at the periphery of the baseplate and possibly associates with fibers that emanate from the baseplate. Gp131C is a seven-bladed beta-propeller that has a shape of a skewed toroid. A small but highly conserved and negatively charged patch on the surface of gp131C might be important for substrate binding or for interaction with a different tail protein. PMID- 23031179 TI - Extensive bilateral arteriovenous malformations of the mandible successfully controlled by combined endovascular and transcutaneous angio-embolization: case report and review of the literature. AB - We report a unique case of extensive bilateral arteriovenous malformation (AVMs) in a child's mandible, discuss treatment options and review literature. A healthy 8 year-old girl presented with bright blood of unknown source found on her pillow. Three large AVMs involving the symphyseal region and bilateral mandibular bodies were found on angiography. Due to the extent of surgical resection required, the patient underwent a series of endovascular and transcutaneous angio embolization. In cases of extensive intraosseous AVMs, serial embolization procedures can be successful in controlling episodes of hemorrhage and allow for bone remineralization. A multidisciplinary approach by otolaryngologists and neurointerventional radiologists can optimize the results. PMID- 23031177 TI - Test-retest reliability of pulse wave velocity in individuals with chronic spinal cord injury. AB - BACKGROUND: Pulse wave velocity (PWV), which reflects arterial stiffness, is an important predictor of future coronary artery disease. The test-retest reliability of PWV has not been investigated in people with spinal cord injury (SCI). PURPOSE: To report the test-retest (day-to-day) reliability of PWV measurements among people with SCI, and to determine the smallest real difference (SRD) of PWV values. PARTICIPANTS: Twenty men (n = 19) and a woman (n = 1) with SCI (C4-T10; AIS A-D; >= 1-year post-injury; 10 with paraplegia and 10 with tetraplegia; time post-injury: 11.8 +/- 8.7 years; age: 43.0 +/- 12.6 years). METHODS: On two occasions within a 2-week period, aortic PWV (between the common carotid and femoral artery), arm PWV (between the brachial and radial artery), and leg PWV (between femoral and posterior tibial artery) were assessed at the same time of day using Doppler flowmeters. RESULTS: No statistically significant differences were found between days 1 and 2 in aortic PWV (day 1: 941 +/- 185 cm/seconds, day 2: 917 +/- 160 cm/seconds, P = 0.257), leg PWV (day 1: 1088 +/- 141 cm/seconds, day 2: 1122 +/- 165 cm/seconds, P = 0.099) and arm PWV (day 1: 1283 +/- 185 cm/seconds, day 2: 1358 +/- 256 cm/seconds, P = 0.180). The aortic and leg PWVs had high test-retest reliability (intraclass correlation coefficient: ICC = 0.920 and 0.913, respectively; P < 0.001 for both) and arm PWV had moderate test-retest reliability (ICC = 0.598, P = 0.03). SRDs for each PWV were 104 cm/seconds (aortic PWV), 97 cm/seconds (leg PWV) and 143 cm/seconds (arm PWV). CONCLUSION: The test-retest reliability of PWV assessment is high among patients with chronic SCI. Changes in aortic PWV values above 104 cm/seconds with repeated testing like represent true changes in health status. PMID- 23031180 TI - Risk factors for upper respiratory infection in the first year of life in a birth cohort. AB - OBJECTIVES: Despite being one of the commonest causes of morbidity among infants, there are no reliable data on the incidence and risk factors of upper respiratory infection among Indian infants. Accordingly, we aimed to study the incidence and age related prevalence, socio-demographic risk factors and association between upper respiratory infection and nasopharyngeal colonization with Streptococcus pneumoniae in the first year of life among rural Indian infants. METHODS: A birth cohort of 210 babies was evaluated monthly with nasopharyngeal swabbing to note the frequency of upper respiratory infection and carriage rate with S. pneumoniae. Data on 11 potential risk factors were noted and subjected to statistical analysis. RESULTS: Upper respiratory infection episodes commenced within a few weeks of life and increased in frequency with age, peaking at 72% in the 9th month. There were 747 episodes of upper respiratory infection overall (6.1 episodes per child-year follow up). The prevalence was maximum in the winter months (65%). There were 3 significant risk factors for upper respiratory infection in the first year of life, i.e., winter season (OR=1.86; 95% CI=1.4 3.5), nasopharyngeal colonization with S. pneumoniae (OR=1.34; 95% CI=1.1-1.7) and parental occupation (OR=1.37; 95% CI=1.1-1.8). The OR were adjusted for other covariates like sex of the child, parents' education, type of house, birth weight, number of family members, passive smoking, use of firewood for cooking and water source. CONCLUSIONS: Seasonal predilection in winter, nasopharyngeal colonization with S. pneumoniae and parental occupation (poor socioeconomic status) are the most important risk factors for upper respiratory infection among rural Indian infants. PMID- 23031181 TI - Outbreak of tungiasis following a trip to Ethiopia. AB - Tungiasis is a skin disease caused by the ectoparasite sand flea Tunga penetrans. Although tungiasis is an important health problem in endemic areas, mainly South America and sub-Saharan Africa, it is reported uncommonly in travelers. We describe an outbreak of tungiasis in a group of travelers to Ethiopia. Following the diagnosis of tungiasis in a member of a group of 17 Israeli travelers to Ethiopia, other affected members were identified by photograph assisted self diagnosis. The characteristics, including relevant demographic and epidemiologic data were recorded using a telephone interview and computerized questionnaire, and analyzed subsequently. The attack rate of tungiasis in the travel group was 53% (9 patients). Most of the patients (89%) wore open sandals during prolonged periods of their journey, but the pattern of shoeware use was similar in unaffected group members. An insect bite was not felt by any patient. The median number of skin lesions was one, and most lesions were located on the foot (7 of 9 travelers), but the hands were also affected in 2 travelers. All skin lesions healed without a need for a major intervention and without major sequela within 5 weeks of their appearance. Tungiasis may be underdiagnosed in travelers. Medical personnel should include tungiasis in pre-travel recommendations, and post-travel assessment. PMID- 23031182 TI - Mixing sainfoin and lucerne to improve the feed value of legumes fed to sheep by the effect of condensed tannins. AB - The aim of this study was to investigate whether the use of sainfoin-based condensed tannins (CT) enhances feed value when given with tannin-free legumes (lucerne) to sheep. The experiments were conducted with fresh sainfoin and lucerne harvested at two stages (vegetative stage as compared with early flowering) in the first growth cycle. Fresh sainfoin and lucerne forages were combined in ratios of 100 : 0, 75 : 25, 25 : 75 and 0 : 100 (denoted S100, S75, S25 and S0, respectively). Voluntary intake, organic matter digestibility (OMD) and nitrogen (N) retention were measured in sheep fed the different sainfoin and lucerne mixtures. Loss of dry matter (DM) and N from polyester bags suspended in the rumen, abomasum and small intestine (SI) was also measured using rumen fistulated sheep and intestinally fistulated sheep. The CT content in sainfoin (S100) decreased with increasing percentage of lucerne in the mixture (mean value from 58 g/kg DM for S100 to 18 g/kg DM for S25) and with growth stage (S100: 64 to 52 g/kg DM). OMD did not differ between different sainfoin/lucerne mixture ratios. Sainfoin and lucerne had an associative effect (significant quadratic contrast) on voluntary intake, N intake, total-tract N digestibility, N in faeces and urine (g/g N intake) and N retained (g/g N intake). Compared with lucerne mixtures (S0 and S25), high-sainfoin-content mixtures (S100 and S75) increased the in situ estimates of forage N escaping from the rumen (from 0.162, 0.188 for S0 and S25 to 0.257, 0.287 for S75 and S100) but decreased forage N intestinal digestibility (from 0.496, 0.446 for S0 and S25 to 0.469, 0.335 for S75 and S100). The amount of forage N disappearing from the bags in the SI (per g forage N) was the highest for high-sainfoin mixtures (from 0.082, 0.108 for S100 and S75 to 0.056, 0.058 for S25 and S0, P < 0.001). Rumen juice total N (tN) and ammonia N (NH3-N) values were the lowest in the high-sainfoin diet (mean tN 0.166 mg/g in S100 as compared with 0.514 mg/g in S0; mean NH3-N 0.104 mg/g in S100 as compared with 0.333 mg/g in S0, P < 0.001). PMID- 23031183 TI - May viral (antigen) load be the real crucial tool leading to anergy in a "micro evolutionary" model of host/virus interaction? AB - HYPOTHESIS: The hypothesis in the present work is that in host/virus/tumor (antigens) interactions, leading to anergy of the immune system, the Viral (antigen) load plays a crucial and central role, which all interactions turn around. BACKGROUND: Notwithstanding apparent strong favorable evidences, the still prevailing concept of "active virus strategies to escape" may be misleading, since it might hide the cited pivotal role in a wide number of researches. This concept could be easily substituted by a microevolutionary model explaining many unresolved questions and allowing to emerge the role of antigen load conditioned reactions of the host's immune system as motivated choices. EVIDENCES: An anergy induced condition can be detected not only in HCV, but also in the course of persistent viral (e.g. HBV, HIV) and non viral parasitic infections (e.g. Leishmania and Helminths) which share the same host's reactions leading to anergy, independently on the infecting agents. The starting point of those reactions is always time elapsing from the primary infection after a short early (often undetected) period of high viral(antigen) load in the lack of clearance. This latter seems then the only conceivable link between such so different infections determining, as far as HBV and HCV are concerned, also Hepatocarcinoma under indirect facilitating conditions. In a wide majority of studies it seems clearly evident that viral load exerts a main role which contributes to determine host chosen reactions aimed at avoiding dangerous outcomes while controlling viral load. Strong clinical (i.e. both HIV infected patients treated with HAART, and helminths infected people with deworming drugs acting directly on viral and parasitic loads) and experimental studies (i.e. chimpanzees (the only animal model of HCV infection) infected with HBV inocula of different size) are here reported or cited to highlight the crucial role of antigen load also on HIV infection transmission, seroconversion, disease progression, treatment initiation and efficacy. CONCLUDING SUGGESTIONS: The new era for antiviral drugs like protease and polymerase inhibitors that seem to be more efficacious and less toxic than Ribavirin, may open the possibility to verify, when administered during the early phase of HCV infection (eventually helped by an immune-stimulant cytokine as IL-2), whether a precocious significant reduction of viral load (threshold) may allow the host to sustain his strong reactions and clear the virus within the due time, confirming the hypothesis about the crucial role of this tool which may be extended to all the cited infections. PMID- 23031184 TI - Genetic parameters for haemoglobin levels in pigs and iron content in pork. AB - Genetic parameters were obtained for iron content in m. longissimus dorsi (2255 records) and haemoglobin levels recorded at 5 (4974 records) and 21 (2405 records) weeks of age in two sire lines from September 2009 until January 2011. The measure of iron in pork was the mean of two replicates. Genetic associations of haematological traits with meat quality traits (2255 records), as well as growth rate and backfat (close to 60 000 records), were estimated. Analyses were based on an animal model using residual maximum likelihood procedures. Iron content in pork was moderately heritable (0.34 +/- 0.07) and genetic correlations with haemoglobin measures ranged from 0.39 +/- 0.24 to 0.58 +/- 0.13, indicating their potential use as selection criteria for increasing iron levels in pork. However, heritabilities for haemoglobin levels were low, ranging from 0.04 +/- 0.2 to 0.18 +/- 0.04. Procedures to measure haemoglobin on farm may require refinement. Redness of pork, quantified by a* value, had high genetic correlations with iron content (0.90 +/- 0.04 to 0.94 +/- 0.03) and moderate genetic correlations with haemoglobin levels (0.31 +/- 0.22 to 0.55 +/- 0.15). Iron content had significant genetic associations with L* measures (-0.61 +/- 0.14 to -0.54 +/- 0.23), b* value (0.60 +/- 0.14 for dorsal b* measure, 0.50 +/- 0.15 for average of dorsal and ventral b* measures) and pH at 45 min post mortem (-0.42 +/- 0.14). These high genetic correlations between colour measurements and iron content in pork provide further avenues for selection strategies to improve iron content in pork. Current selection practices are not expected to affect iron content in pork, as no significant genetic correlations between performance and haematological traits were found. PMID- 23031185 TI - Antioxidative activity and protective effect of probiotics against high-fat diet induced sperm damage in rats. AB - In this study, antioxidant capability and protective effect of probiotics on reproductive damage induced by diet oxidative stress were investigated. Thirty male Sprague-Dawley rats were randomly divided into three groups with 10 rats in each group. The control group consumed a normal standard diet (5% fat, w/w). The other two treatment groups were fed with a high-fat diet (20% fat, w/w), and a high-fat diet supplemented with 2% probiotics (w/w), respectively. At the end of the experimental period, that is, after 6 weeks, rats were killed. Activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), contents of nitric oxide (NO) free radical and malondialdehyde (MDA) in serum and sperm suspension were examined. Sperm parameters including sperm concentration, viability, motility and DNA integrity were analyzed. The results showed that high-fat diet could induce oxidative stress, shown as significant increases in lipid peroxidation, NO free radical, significant decrease in activities of SOD, GSH-Px, significant reduction in sperm concentration, viability and motility, and damage in sperm DNA (P < 0.05), compared with the control group. These alterations were significantly reversed in the probiotics-supplemented group and had no significant difference in antioxidant capability, lipid peroxidation and sperm parameters compared with the control group. The percentage of sperm with DNA damage was significantly lower than the high-fat diet group and still higher than the control group, which means that probiotics could attenuate sperm damage to some extent. The present results indicated that dietary probiotics had antioxidant activity and the protective effect against sperm damage induced by high-fat diet to some extent. PMID- 23031186 TI - Scar sarcoidosis on a finger mimicking a rapidly growing soft tissue tumour: a case report. AB - BACKGROUND: Scar sarcoidosis is a rare and uncommon but specific cutaneous manifestation of sarcoidosis. In general it arises in pre-existing scars deriving from mechanical traumas. As most surgeons dealing with scars might not be aware of cutaneous sarcoidosis and its different types of appearance the appropriate staging and treatment might be missed or at least delayed. To our knowledge this is the first case in literature of scar sarcoidosis on a finger. CASE PRESENTATION: We present a case of a 33-year-old carpenter who developed scar sarcoidosis on his right index finger 4 years after the tendon of the long digital flexor got accidentally cut by an angle grinder. He was referred due to a swelling of the finger suspected to be a malignant soft tissue tumour. The circumference of the affected finger had almost doubled, adding up to 94 mm. Incision biopsy revealed typical noncaseating granulomas. Further investigation showed a systemic extent of the disease with involvement of the lung. A systemic treatment with oral steroids led to an almost full regression of the swelling with restoration of function and resolution of lung infiltrates. CONCLUSION: In case of a suspicious and/or progressive swelling a definite diagnosis should be achieved by biopsy within a short time to enable a proper treatment. If scar sarcoidosis is proven further investigation is necessary to exclude a systemical involvement. A surgical treatment of the swelling is not indicated. PMID- 23031187 TI - Sustainable management for rangelands in a variable climate: evidence and insights from northern Australia. AB - Inter-annual rainfall variability is a major challenge to sustainable and productive grazing management on rangelands. In Australia, rainfall variability is particularly pronounced and failure to manage appropriately leads to major economic loss and environmental degradation. Recommended strategies to manage sustainably include stocking at long-term carrying capacity (LTCC) or varying stock numbers with forage availability. These strategies are conceptually simple but difficult to implement, given the scale and spatial heterogeneity of grazing properties and the uncertainty of the climate. This paper presents learnings and insights from northern Australia gained from research and modelling on managing for rainfall variability. A method to objectively estimate LTCC in large, heterogeneous paddocks is discussed, and guidelines and tools to tactically adjust stocking rates are presented. The possible use of seasonal climate forecasts (SCF) in management is also considered. Results from a 13-year grazing trial in Queensland show that constant stocking at LTCC was far more profitable and largely maintained land condition compared with heavy stocking (HSR). Variable stocking (VAR) with or without the use of SCF was marginally more profitable, but income variability was greater and land condition poorer than constant stocking at LTCC. Two commercial scale trials in the Northern Territory with breeder cows highlighted the practical difficulties of variable stocking and provided evidence that heavier pasture utilisation rates depress reproductive performance. Simulation modelling across a range of regions in northern Australia also showed a decline in resource condition and profitability under heavy stocking rates. Modelling further suggested that the relative value of variable v. constant stocking depends on stocking rate and land condition. Importantly, variable stocking may possibly allow slightly higher stocking rates without pasture degradation. Enterprise-level simulations run for breeder herds nevertheless show that poor economic performance can occur under constant stocking and even under variable stocking in some circumstances. Modelling and research results both suggest that a form of constrained flexible stocking should be applied to manage for climate variability. Active adaptive management and research will be required as future climate changes make managing for rainfall variability increasingly challenging. PMID- 23031188 TI - Examining the validity of the ActivPAL monitor in measuring posture and ambulatory movement in children. AB - BACKGROUND: Decreasing sedentary activities that involve prolonged sitting may be an important strategy to reduce obesity and other physical and psychosocial health problems in children. The first step to understanding the effect of sedentary activities on children's health is to objectively assess these activities with a valid measurement tool. PURPOSE: To examine the validity of the ActivPAL monitor in measuring sitting/lying, standing, and walking time, transition counts and step counts in children in a laboratory setting. METHODS: Twenty five healthy elementary school children (age 9.9 +/- 0.3 years; BMI 18.2 +/- 1.9; mean +/- SD) were randomly recruited across the Auckland region, New Zealand. Children were fitted with ActivPAL monitors and observed during simulated free-living activities involving sitting/lying, standing and walking, followed by treadmill and over-ground activities at various speeds (slow, normal, fast) against video observation (criterion measure). The ActivPAL sit-to-stand and stand-to-sit transition counts and steps were also compared with video data. The accuracy of step counts measured by the ActivPAL was also compared against the New Lifestyles NL-2000 and the Yamax Digi-Walker SW-200 pedometers. RESULTS: We observed a perfect correlation between the ActivPAL monitor in time spent sitting/lying, standing, and walking in simulated free-living activities with direct observation. Correlations between the ActivPAL and video observation in total numbers of sit-to-stand and stand-to-sit transitions were high (r = 0.99 +/ 0.01). Unlike pedometers, the ActivPAL did not misclassify fidgeting as steps taken. Strong correlations (r = 0.88-1.00) between ActivPAL step counts and video observation in both treadmill and over-ground slow and normal walking were also observed. During treadmill and over-ground fast walking and running, the correlations were low (r = 0.21-0.46). CONCLUSION: The ActivPAL monitor is a valid measurement tool for assessing time spent sitting/lying, standing, and walking, sit-to-stand and stand-to-sit transition counts and step counts in slow and normal walking. The device did not measure accurately steps taken during treadmill and over-ground fast walking and running in children. PMID- 23031189 TI - The effects of supplementing varying molecular weights of chitooligosaccharide on performance, selected microbial populations and nutrient digestibility in the weaned pig. AB - An experiment (complete randomised design) was conducted to investigate the effects of supplementing different molecular weights (MW) of chitooligosaccharide (COS) on pig performance, selected microbial populations and nutrient digestibility post-weaning. A total of 396 weaned piglets (24 days of age, 7.3 kg +/- (s.d.) 1.7 kg live weight) were assigned to one of six dietary treatments (22 replicates/treatment) for a 33-day experimental period. The dietary treatments were as follows (1) control diet (0 ppm COS), (2) control diet plus <1 kDa COS, (3) control diet plus 3 to 5 kDa COS, (4) control diet plus 5 to 10 kDa COS, (5) control diet plus 10 to 50 kDa COS and (6) control diet plus 50 to 100 kDa COS. The COS were included at 250 ppm in the diets. There was no significant effect of dietary treatment on piglet performance during the starter period (days 0 to 18; P > 0.05). However, there were quadratic responses in both daily gain (P < 0.05) and gain to feed ratio (P < 0.05) to the increased MW of COS inclusion during the weaner period (days 18 to 33) with all COS-supplemented treatments improving daily gain and gain to feed ratio compared with the control. There was a quadratic response in faecal scoring to the increased MW of COS inclusion from days 0 to 7 (P < 0.001), days 7 to 14 (P < 0.001) and during the overall experimental period (P < 0.01) with all the COS-supplemented treatments having an improved faecal score compared with the control. During the weaner period, there was a cubic response in lactic acid bacteria and Escherichia coli populations as the MW of COS increased (P < 0.05). The 5 to 10 kDa and 10 to 50 kDa COS increased lactic acid bacteria populations compared with the control, whereas lactic acid bacteria populations decreased at 50 to 100 kDa. The 5 to 10 kDa, 10 to 50 kDa and 50 to 100 kDa COS decreased E. coli populations compared with the control. There was a cubic response in the apparent total tract digestibility of dry matter (DM; P < 0.01), organic matter (OM; P < 0.01), ash (P < 0.01), nitrogen (N; P < 0.01) and gross energy (GE; P < 0.01) to the increased MW of COS inclusion during the weaner period. The 5 to 10 kDa COS had a higher apparent total tract digestibility of DM, OM, ash, N and GE in comparison to the control, whereas the apparent total tract nutrient digestibility of these nutrients decreased at 10 to 50 kDa. The current results indicate that the MW ranges of 5 to 10 kDa and 10 to 50 kDa COS decreased E. coli numbers while increasing nutrient digestibility of the diets. PMID- 23031191 TI - Meta-analysis of repetitive transcranial magnetic stimulation in the treatment of auditory verbal hallucinations: update and effects after one month. AB - OBJECTIVE: Several meta-analyses considering repetitive transcranial magnetic stimulation (rTMS) for auditory verbal hallucinations (AVH) have been performed with moderate to high mean weighted effect sizes. Since then several negative findings were reported in relatively large samples. The aim of this study was to provide an update of the literature on the efficacy of rTMS for AVH and to investigate the effect of rTMS one month after the end of treatment. DATA SOURCES: A literature search was performed from 1966 through August 2012 using Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Embase Psychiatry, Ovid Medline, PsycINFO and PubMed. Randomized, double blind, sham-controlled studies with severity of AVH or severity of psychosis as an outcome measure were included. STUDY SELECTION: Data were obtained from 17 randomized studies of rTMS for AVH. Five studies fulfilled the criteria for the meta-analysis on the effect of rTMS one month after the end of treatment. DATA EXTRACTION: Standardized mean weighted effect sizes of rTMS versus sham were computed on pre- and posttreatment comparisons. DATA SYNTHESIS: The mean weighted effect size of rTMS directed at the left temporoparietal area was 0.44 (95% CI 0.19-0.68). A separate meta analysis including studies directing rTMS at other brain regions revealed a mean weighted effect size of 0.33 (95% CI 0.17-0.50) in favor of real TMS. The effect of rTMS was no longer significant at one month of follow-up (mean weighted effect size=0.40, 95% CI -0.23-0.102). Side effects were mild and the number of dropouts in the real TMS group was not significantly higher than in the sham group. CONCLUSIONS: With the inclusion of studies with larger patient samples, the mean weighted effect size of rTMS directed at the left temporoparietal area for AVH has decreased, although the effect is still significant. The duration of the effect of rTMS may be less than one month. More research is needed in order to optimize parameters and further evaluate the clinical relevance of this intervention. PMID- 23031190 TI - Stable feature selection and classification algorithms for multiclass microarray data. AB - BACKGROUND: Recent studies suggest that gene expression profiles are a promising alternative for clinical cancer classification. One major problem in applying DNA microarrays for classification is the dimension of obtained data sets. In this paper we propose a multiclass gene selection method based on Partial Least Squares (PLS) for selecting genes for classification. The new idea is to solve multiclass selection problem with the PLS method and decomposition to a set of two-class sub-problems: one versus rest (OvR) and one versus one (OvO). We use OvR and OvO two-class decomposition for other recently published gene selection method. Ranked gene lists are highly unstable in the sense that a small change of the data set often leads to big changes in the obtained ordered lists. In this paper, we take a look at the assessment of stability of the proposed methods. We use the linear support vector machines (SVM) technique in different variants: one versus one, one versus rest, multiclass SVM (MSVM) and the linear discriminant analysis (LDA) as a classifier. We use balanced bootstrap to estimate the prediction error and to test the variability of the obtained ordered lists. RESULTS: This paper focuses on effective identification of informative genes. As a result, a new strategy to find a small subset of significant genes is designed. Our results on real multiclass cancer data show that our method has a very high accuracy rate for different combinations of classification methods, giving concurrently very stable feature rankings. CONCLUSIONS: This paper shows that the proposed strategies can improve the performance of selected gene sets substantially. OvR and OvO techniques applied to existing gene selection methods improve results as well. The presented method allows to obtain a more reliable classifier with less classifier error. In the same time the method generates more stable ordered feature lists in comparison with existing methods. PMID- 23031192 TI - Diabetes is associated with lower global cognitive function in schizophrenia. AB - BACKGROUND: Co-morbidity of schizophrenia (SZ) and metabolic problems such as diabetes mellitus (DM) has been suggested by many studies. Nonetheless, it is still debated whether DM affects cognitive dysfunction associated with SZ and how much treatment for DM is beneficial for cognitive functions in SZ. We addressed these questions by re-assessing the cognitive dataset from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study. METHODS: We identified 1289 SZ patients in which scores for several cognitive domains of verbal memory, vigilance, processing speed, reasoning, and working memory together with the composite score and metabolic characteristics (body mass index, dyslipidemia, hypertension, and DM) were available at baseline of the trial. We performed multiple linear regression analyses to assess the impact of DM on cognitive performance of SZ patients, controlling for a number of other confounding factors including obesity, hypertension, and dyslipidemia. We also conducted analyses of covariance to compare cognitive performance among SZ patients without DM and diabetic SZ sub-groups based on anti-diabetic drugs they were receiving at baseline of the trial. RESULTS: Co-morbid DM with SZ predicted worse overall cognitive performance and lower scores for three cognitive domains (vigilance, processing speed, and reasoning), but none of the other metabolic factors (i.e., obesity, hypertension and dyslipidemia) correlated with cognitive function in SZ. Furthermore, SZ patients with untreated DM showed poorer overall cognitive performance and a significantly lower score in the domain of vigilance compared with SZ patients without DM. CONCLUSION: Our data suggest that DM negatively affects the overall cognitive function of SZ patients. PMID- 23031193 TI - The safety of Homnawakod herbal formula containing Aristolochia tagala Cham. in Wistar rats. AB - BACKGROUND: A dried root of Aristolochia tagala Cham. (ATC) is often used in Thai traditional medicine as an antipyretic, anti-inflammatory agent, muscle relaxant, appetite-enhancing agent, and analeptic. Homnawakod, an important herbal recipe, originally contains ATC in its formula, however, some Aristolochia species have been reported to cause nephrotoxicity due to aristolochic acid (AA) and its derivatives, resulting in ATC removal from all formulae. Therefore, this study investigates the chemical profiles of ATC, the original (HNK+ATC) and the present Homnawakod Ayurved Siriraj Herbal FormularyTM (HNK), and investigates whether they could cause nephrotoxicity or aggravate LPS-induced organ injuries in vivo. METHODS: HPLC and LC/MS were used for chemical profile study. Male Wistar rats were randomly divided into groups in which the rats were intragastrically administered distilled water (2 groups), ATC (10 or 30 mg/kg), HNK+ATC (540 or 1,620 mg/kg), or HNK (1,590 mg/kg) for 21 days. A positive control group was administered with single dose 100 mg/kg standard AA-I intragastrically at day 1. Serum creatinine and urea were measured at baseline and at 7, 14 and 21 days of the treatment. On day 22, a model of lipopolysaccharide (LPS)-induced endotoxemia was used. One-way and two-way analyses of variance were performed and a P value of less than 0.05 was considered to be significant. RESULTS: The similarity of the HPLC chromatograms of HNK+ATC and HNK could suggest that the qualities of both formulae are nearly the same in terms of chemical profile. The amount of AA I found in ATC is 0.24%w/w. All experimental groups exhibited similar levels of serum urea at baseline and 7 and 14 days of the treatment. At 21 days, rats received AA exhibited a significant increase in serum urea, whereas the others did not exhibit such toxicity. On day 22, there were no significant changes in LPS-induced renal and liver dysfunction, or LPS-induced mean arterial pressure (MAP) reduction upon administration of ATC, HNK+ATC, HNK or AA-I. CONCLUSIONS: These results suggest that ATC, HNK+ATC or HNK, at the animal dose equivalent to that used in human, do not cause the acute nephrotoxicity in rats and do not aggravate LPS-induced organ injuries even further. PMID- 23031194 TI - Factors associated with health-related quality of life in adults with asthma. A cross-sectional study. AB - BACKGROUND: The measurement of health-related quality of life (HRQoL) is increasingly recognized as an important endpoint, as a reflection of the effects of the disease from a patient perspective. Our aim was to evaluate the factors determining the HRQoL in patients with asthma, according to the EQ-5D questionnaire. METHODS: Patients were included using multi-stage sampling, from Primary Care clinics from all the Autonomous Communities in Spain. The patients included were: over 18 years-old, with a confirmed diagnosis of asthma for at least one year, and had visited a Health Centre in the previous 2 years. The characteristics of the asthma disease, the adherence to treatment, the socio demographic variables, the smoking habits, and the asthma control were collected using a questionnaire. The influence of the different variables included in the study on the EQ-5D was evaluated using multivariate logistic regression analysis. RESULTS: A total of 2,125 patients were finally included (57.7% females, mean age 48 years). The response rate was 95.4%. Some factors showed a considerable detrimental effect on the HRQoL of asthmatics. Advanced age, lower educational level and poor control of asthma are significantly associated with a worse quality of life in all the dimensions assessed by the EQ-5D scale. The baseline severity of the asthma, and having been admitted to hospital are related to a worse quality of life in 5 of the 6 dimensions analyzed. CONCLUSION: In our study, we could identify some factors related to quality of life in asthma patients. The most important were advanced age, lower education level, and poor control of the asthma. PMID- 23031195 TI - Detection of Pseudomonas aeruginosa in sputum headspace through volatile organic compound analysis. AB - INTRODUCTION: Chronic pulmonary infection is the hallmark of cystic fibrosis lung disease. Searching for faster and easier screening may lead to faster diagnosis and treatment of Pseudomonas aeruginosa (P. aeruginosa). Our aim was to analyze and build a model to predict the presence of P. aeruginosa in sputa. METHODS: Sputa from 28 bronchiectatic patients were used for bacterial culturing and analysis of volatile compounds by gas chromatography-mass spectrometry. Data analysis and model building were done by Partial Least Squares Regression Discriminant analysis (PLS-DA). Two analysis were performed: one comparing P. aeruginosa positive with negative cultures at study visit (PA model) and one comparing chronic colonization according to the Leeds criteria with P. aeruginosa negative patients (PACC model). RESULTS: The PA model prediction of P. aeruginosa presence was rather poor, with a high number of false positives and false negatives. On the other hand, the PACC model was stable and explained chronic P. aeruginosa presence for 95% with 4 PLS-DA factors, with a sensitivity of 100%, a positive predictive value of 86% and a negative predictive value of 100%. CONCLUSION: Our study shows the potential for building a prediction model for the presence of chronic P. aeruginosa based on volatiles from sputum. PMID- 23031196 TI - Cost-effectiveness of a 21-gene recurrence score assay versus Canadian clinical practice in women with early-stage estrogen- or progesterone-receptor-positive, axillary lymph-node negative breast cancer. AB - BACKGROUND: A 21-gene recurrence score (RS) assay may inform adjuvant systematic treatment decisions in women with early stage breast cancer. We sought to investigate the cost effectiveness of using the RS-assay versus current clinical practice (CCP) in women with early-stage estrogen- or progesterone-receptor positive, axilliary lymph-node negative breast cancer (ER+/ PR + LN- ESBC) from the perspective of the Canadian public healthcare system. METHODS: We developed a Markov model to project the lifetime clinical and economic consequences of ESBC. We evaluated adjuvant therapy separately in post- and pre-menopausal women with ER+/ PR + LN- ESBC. We assumed that the RS-assay would reclassify pre- and post menopausal women among risk levels (low, intermediate and high) and guide adjuvant systematic treatment decisions. The model was parameterized using 7 year follow up data from the Manitoba Cancer Registry, cost data from Manitoba administrative databases, and secondary sources. Costs are presented in 2010 CAD. Future costs and benefits were discounted at 5%. RESULTS: The RS-assay compared to CCP generated cost-savings in pre-menopausal women and had an ICER of $60,000 per QALY gained in post-menopausal women. The cost effectiveness was most sensitive to the proportion of women classified as intermediate risk by the RS assay who receive adjuvant chemotherapy and the risk of relapse in the RS-assay model. CONCLUSIONS: The RS-assay is likely to be cost effective in the Canadian healthcare system and should be considered for adoption in women with ER+/ PR + LN- ESBC. However, ongoing assessment and validation of the assay in real-world clinical practice is warranted. PMID- 23031197 TI - Comparison of zotarolimus-eluting and sirolimus-eluting coronary stents: a study from the Western Denmark Heart Registry. AB - BACKGROUND: We evaluated the effectiveness and safety of a zotarolimus-eluting (ZES) versus a sirolimus-eluting (SES) coronary stent in a large cohort of patients treated with one of these stents in Western Denmark. METHODS: A total of 6,122 patients treated with ZES (n=2,282) or SES (n=3,840) were followed for up to 27 months. We ascertained clinical outcomes based on national medical databases. RESULTS: Incidence of target lesion revascularization (no. per 100 person-years) was 5.3 in the ZES group compared to 1.9 in the SES group (adjusted hazard ratio (HR)=2.19, 95% confidence intervals (CI): 1.39-3.47; p=0.001). All cause mortality was also higher in the ZES group (ZES: 6.3; SES: 3.3; adjusted HR=1.34, 95% CI: 1.05-1.72; p=0.02), while stent thrombosis (ZES: 1.2; SES: 0.5; adjusted HR=1.98, 95% CI: 0.75-5.23; p=0.14) did not differ significantly. CONCLUSIONS: In agreement with previously published randomised data, this observational study indicated that the ZES was associated with an increased risk of death and TLR in a large cohort of consecutive patients. PMID- 23031199 TI - Stem cell grafting improves both motor and cognitive impairments in a genetic model of Parkinson's disease, the aphakia (ak) mouse. AB - Stem cell-based cell replacement of lost midbrain dopamine (mDA) neurons is a potential therapy for Parkinson's disease (PD). Toward this goal, it is critical to optimize various aspects of cell transplantation and to assess functional recovery through behavioral tests in validated animal model(s) of PD. At present, cell transplantation studies are being done almost exclusively in neurotoxin based animal models, because few genetic models of PD exhibit robust mDA neuronal loss. Here we used a genetic model of PD, the aphakia mouse, which demonstrates selective degeneration of mDA neurons in the substantia nigra. We systematically investigated the functional effects of transplanting embryonic stem cell-derived cells at different stages of in vitro differentiation: embryoid body (EB), neural progenitor (NP), and neuronal differentiated (ND) stages. We found that transplantation of NP cells yielded the best outcomes for both survival and behavioral improvement, while transplantation of EB and ND cells resulted in high teratoma-like tumor formation and poor survival, respectively. In behavioral paradigms specific to basal ganglia, the NP cells group prominently improved motor behavioral defects 1 and 2 months posttransplantation. Furthermore, we found that NP cell transplantation also improved cognitive impairments of aphakia mice, as examined by the passive avoidance task. Importantly, these graft-induced functional improvements well correlated with survival of tyrosine hydroxylase positive DA neurons. Taken together, we propose that the aphakia mouse can serve as a novel and useful platform for cell transplantation studies to assess both neurological and cognitive improvements and that NP stage cells represent an optimal stage for transplantation. PMID- 23031200 TI - Residual effects of combat-related mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) has gained considerable notoriety during the past decade of conflict in Afghanistan and Iraq. However, the relationship between combat-related mTBI and residual mTBI symptoms, post-traumatic stress disorder (PTSD) symptoms, and neurocognitive deficits remains unclear. The purpose of the study was to compare residual mTBI and PTSD symptoms, and neurocognitive deficits among U.S. Army Special Operations Command (USASOC) personnel with diagnosed blunt, blast, and blast-blunt combination mTBIs. This study involved a retrospective medical records review of 27,169 USASOC personnel who completed a military version of the Immediate Post-Concussion Assessment Cognitive Test (ImPACT), Post-Concussion Symptom Scale (PCSS), and PTSD Checklist (PCL) between November 2009 and December 2011. Of the 22,203 personnel who met criteria for the study, 2,813 (12.7%) had a diagnosis of at least one mTBI. A total of 28% (n=410) of USASOC personnel with a history of diagnosed mTBI reported clinical levels of PTSD symptoms. Personnel with a history of diagnosed blunt (OR=3.58), blast (OR=4.23) or combination (OR=5.73) mTBI were at significantly (p=0.001) greater risk of reporting clinical levels of PTSD symptoms than those with no history of mTBI. A dose-response gradient for exposure to blast/combination mTBI on clinical levels of PTSD symptoms was also significant (p=0.001). Individuals with blast/combination mTBIs scored higher in residual mTBI (p=0.001) and PTSD symptoms (p=0.001), and performed worse on tests of visual memory (p=0.001), and reaction time (p=0.001) than those with blunt or no mTBI history. Individuals with combination mTBIs scored lower in verbal memory (p=0.02) than those with blunt mTBIs. Residual PTSD and mTBI symptoms appear to be more prevalent in personnel with blast mTBI. A dose-response gradient for blast mTBI and symptoms suggests that repeated exposures to these injuries may have lingering effects. PMID- 23031201 TI - Perceptual experience modulates cortical circuits involved in visual awareness. AB - Successful interactions with the environment entail interpreting ambiguous sensory information. To address this challenge it has been suggested that the brain optimizes performance through experience. Here we used functional magnetic resonance imaging (fMRI) to investigate whether perceptual experience modulates the cortical circuits involved in visual awareness. Using ambiguous visual stimuli (binocular rivalry or ambiguous structure-from-motion) we were able to disentangle the co-occurring influences of stimulus repetition and perceptual repetition. For both types of ambiguous stimuli we observed that the mere repetition of the stimulus evoked an entirely different pattern of activity modulations than the repetition of a particular perceptual interpretation of the stimulus. Regarding stimulus repetition, decreased fMRI responses were evident during binocular rivalry but weaker during 3-D motion rivalry. Perceptual repetition, on the other hand, entailed increased activity in stimulus-specific visual brain regions - for binocular rivalry in the early visual regions and for ambiguous structure-from-motion in both early as well as higher visual regions. This indicates that the repeated activation of a visual network mediating a particular percept facilitated its later reactivation. Perceptual repetition was also associated with a response change in the parietal cortex that was similar for the two types of ambiguous stimuli, possibly relating to the temporal integration of perceptual information. We suggest that perceptual repetition is associated with a facilitation of neural activity within and between percept specific visual networks and parietal networks involved in the temporal integration of perceptual information, thereby enhancing the stability of previously experienced percepts. PMID- 23031202 TI - Expression of leptin and its receptor genes in the ovarian follicles of cycling and early pregnant pigs. AB - Leptin is a polypeptide hormone produced primarily by adipocytes. It has been implicated in the regulation of satiety and energy homeostasis. Leptin has been suggested to play a role in reproduction based on its involvement in the regulation of the hypothalamic-pituitary-gonadal axis via endocrine, paracrine and/or autocrine pathways. The aim of the present study was to localize the cellular distribution of leptin and the long isoform of leptin receptor (OB-Rb) genes in porcine ovarian antral follicles and to compare the expression levels of leptin and OB-Rb mRNAs in porcine granulosa cells (GC), theca interna (TIC) and theca externa (TEC) cells during the luteal phase of the estrous cycle and in early pregnancy. The expression of leptin and OB-Rb genes was detected in GC, TIC and TEC. Significantly higher levels of leptin gene expression in GC were observed during the mid- and late-luteal phases of the cycle than on days 30 to 32 of pregnancy. On days 14 to 16 of pregnancy, leptin mRNA expression was higher than that on days 14 to 16 of the cycle. The expression of the OB-Rb gene in GC and TEC increased during pregnancy in comparison with the analyzed luteal phases of the cycle. Our results validate the hypothesis that locally produced leptin plays a role in the regulation of porcine reproduction at the ovarian level and exerts a direct effect on porcine follicles. The differences in OB-Rb gene expression in porcine GC and theca cells also suggest that their sensitivity to leptin varies in the ovaries of pregnant and cyclic pigs. PMID- 23031204 TI - Correlations of unfavorable movement characteristics in warmblood foals and mares with routinely assessed conformation and performance traits. AB - New movement traits reflecting unfavorable movement characteristics were defined on the basis of detailed movement evaluations (DME) of warmblood foals and mares performed in connection with regular breeding events of the Oldenburg horse breeding societies in 2009 and 2010. DME information was available for 3374 foals and 2844 mares and used for correlation analyses with conformation information on 1987 mares from studbook inspections (SBI) in 2009 and performance information on 2758 mares from mare performance tests (MPT) in 2000 to 2008. Analyses of variance revealed few significant differences between scores for SBI and MPT traits in mares without and with indications of imbalance (IMB) in general or specific findings like irregular tail tone or posture (TTP). SBI scores for general impression and development were significantly lower and MPT scores for trot under rider tended to be higher in IMB-positive mares. Genetic parameters were estimated in linear animal models with residual maximum likelihood. Additive genetic correlations and Pearson correlation coefficients between univariately predicted breeding values indicated unfavorable genetic correlations of IMB and TTP with dressage-related conformation and performance traits. For SBI and MPT traits, we found similarities between the correlation patterns for DME traits in foals and mares. The results implied that breeding of dressage horses may benefit from revision of current movement evaluation and consideration of specific movement characteristics. PMID- 23031203 TI - Indices of body fat distribution for assessment of lipodysthrophy in people living with HIV/AIDS. AB - BACKGROUND: Metabolic and morphological changes associated with excessive abdominal fat, after the introduction of Antiretroviral Therapy, increase the risk of cardiovascular disease in people living with HIV/AIDS(PLWHA). Accurate methods for body composition analysis are expensive and the use of anthropometric indices is an alternative. However the investigations about this subject in PLWHA are rare, making this research very important for clinical purpose and to advance scientific knowledge. The aim of this study is to correlate results of anthropometric indices of evaluation of body fat distribution with the results obtained by Dual-energy X-Ray Absorptiometry(DEXA), in people living with HIV/AIDS. METHODS: The sample was of 67 PLWHA(39 male and 28 female), aged 43.6+/ 7.9 years. Body mass index, conicity index, waist/hip ratio, waist/height ratio and waist/thigh were calculated. Separated by sex, each index/ratio was plotted in a scatter chart with linear regression fit and their respective Pearson correlation coefficients. Analyses were performed using Prism statistical program and significance was set at 5%. RESULTS: The waist/height ratio presented the highest correlation coefficient, for both male (r=0.80, p<0.001) and female (r=0.87, p <001), while the lowest were in the waist/thigh also for both: male group (r=0.58, p<0.001) and female group (r=0.03, p=0.86). The other indices also showed significant positive correlation with DEXA. CONCLUSION: Anthropometric indices, especially waist/height ratio may be a good alternative way to be used for evaluating the distribution of fat in the abdominal region of adults living with HIV/ADIS. PMID- 23031206 TI - Effects of duodenal infusion of free alpha-linolenic acid on the plasma and milk proteome of lactating dairy cows. AB - This study is an exploratory analysis for understanding the effect of a duodenal infusion of an alpha-linolenic acid (LNA) on the plasma and milk proteome of lactating dairy cows. Four primiparous Holstein cows were fitted with duodenal cannulas and received 0, 100, 200, 300 and 400 g/day of LNA in a two-treatment crossover design. Blood and milk were collected for determination of protein composition by two-dimensional gel electrophoresis. Alteration of protein spots was detected and identified using matrix-assisted laser desorption/ionization time-of-flight/time-of-flight tandem mass spectrometry (MALDI-TOF-TOF MS). Plasma haptoglobin levels, and milk beta-casein A2, alphas1-casein variant and albumin, did not differ in cows after infusion of 0, 100, 200 and 300 g/day of LNA, but were increased after the cows received duodenal infusion of 400 g/day of LNA. Western blot analysis of haptoglobin expression in plasma confirmed the alterations in protein expression seen using MS. This study demonstrated that infusion of high doses of LNA by duodenal cannula can result in metabolic stress within the bovine intestine and in changes in milk composition. PMID- 23031205 TI - Differences in lifestyle behaviors, dietary habits, and familial factors among normal-weight, overweight, and obese Chinese children and adolescents. AB - BACKGROUND: Pediatric obesity has become a global public health problem. Data on the lifestyle behaviors, dietary habits, and familial factors of overweight and obese children and adolescents are limited. The present study aims to compare health-related factors among normal-weight, overweight, and obese Chinese children and adolescents. METHODS: We conducted a cross-sectional study consisted of 4262 children and adolescents aged 5-18 years old from rural areas of the northeast China. Anthropometric measurements and self-reported information on health-related variables, such as physical activities, sleep duration, dietary habits, family income, and recognition of weight status from the views of both children and parents, were collected by trained personnel. RESULTS: The prevalence rates of overweight and obesity were 15.3 and 6.4%, respectively. Compared to girls, boys were more commonly overweight (17.5% vs. 12.9%) and obese (9.5% vs. 3.1%). Approximately half of the parents with an overweight or obese child reported that they failed to recognize their child's excess weight status, and 65% of patients with an overweight child reported that they would not take measures to decrease their child's body weight. Obese children and adolescents were more likely to be nonsnackers [odds ratio (OR): 1.348; 95% confidence interval (CI): 1.039-1.748] and to have a family income of 2000 CNY or more per month (OR: 1.442; 95% CI: 1.045-1.99) and less likely to sleep longer (>=7.5 h) (OR: 0.475; 95% CI: 0.31-0.728) than the normal-weight participants. CONCLUSIONS: Our study revealed a high prevalence of overweight and obesity in a large Chinese pediatric population. Differences in sleep duration, snacking, family income, and parental recognition of children's weight status among participants in different weight categories were observed, which should be considered when planning prevention and treatment programs for pediatric obesity. PMID- 23031207 TI - Novel transcripts and alternatively spliced genes are associated with early development in bovine embryos. AB - Infertility in cattle is a major concern of farmers worldwide and despite the enormous improvements in assisted reproduction technologies, the success rates of pregnancies are still low. Embryonic loss is considered one of the main factors of infertility in cattle. As such, the identification of genetic markers for embryo quality and development can help elucidate the molecular mechanisms involved in the formation of embryos with the highest developmental potential. In a previous study, using next-generation RNA sequencing, we identified novel transcripts and alternatively spliced genes that were associated with embryo quality. The objectives of this study were to characterize these transcripts and validate their expression in new biological replications of embryos using quantitative real-time PCR. Two types of embryos differing in morphological and developmental statuses (blastocysts and degenerate embryos) were produced using in vitro fertilization. Quantitative expression of eight novel transcripts revealed a range of 2.5- to 90-fold difference in expression between degenerate embryos and blastocysts. Some of these novel transcripts showed sequence similarity to human and cattle genes known to affect differentiation, growth and development. In addition, expression analysis of alternative splicing isoforms of five genes (MYL6, NOP10, RNF187, RPS24 and RPS28) revealed significant differential expression of these isoforms in the different embryo types. Thus, results of this study suggest that novel transcripts and alternatively spliced genes, found to be differentially expressed between blastocysts and degenerate embryos, can be used as markers for blastocyst formation and development. PMID- 23031208 TI - Mobile air quality studies (MAQS) in inner cities: particulate matter PM10 levels related to different vehicle driving modes and integration of data into a geographical information program. AB - BACKGROUND: Particulate matter (PM) is assumed to exert a major burden on public health. Most studies that address levels of PM use stationary measure systems. By contrast, only few studies measure PM concentrations under mobile conditions to analyze individual exposure situations. METHODS: By combining spatial-temporal analysis with a novel vehicle-mounted sensor system, the present Mobile Air Quality Study (MAQS) aimed to analyse effects of different driving conditions in a convertible vehicle. PM10 was continuously monitored in a convertible car, driven with roof open, roof closed, but windows open, or windows closed. RESULTS: PM10 values inside the car were nearly always higher with open roof than with roof and windows closed, whereas no difference was seen with open or closed windows. During the day PM10 values varied with high values before noon, and occasional high median values or standard deviation values due to individual factors. Vehicle speed in itself did not influence the mean value of PM10; however, at traffic speed (10 - 50 km/h) the standard deviation was large. No systematic difference was seen between PM10 values in stationary and mobile cars, nor was any PM10 difference observed between driving within or outside an environmental (low emission) zone. CONCLUSIONS: The present study has shown the feasibility of mobile PM analysis in vehicles. Individual exposure of the occupants varies depending on factors like time of day as well as ventilation of the car; other specific factors are clearly identifiably and may relate to specific PM10 sources. This system may be used to monitor individual exposure ranges and provide recommendations for preventive measurements. Although differences in PM10 levels were found under certain ventilation conditions, these differences are likely not of concern for the safety and health of passengers. PMID- 23031209 TI - Comparison of performance and welfare of single-caged and group-housed rabbit does. AB - Although rabbit does are generally single housed on rabbit farms worldwide, it has been suggested by some specialists and recommendation of organic rabbit production systems that group housing of does is more comfortable and similar to the living conditions of the European wild rabbits. The aim of this experiment was to compare production of single-caged (S) and group-housed does (G). The S does were housed in commercial rabbit cages (floor area 0.32 m(2) and 0.3 m high). In treatment G, four does and one buck were housed in four pens measuring 7.7 m(2) (half of the floor was deep litter and the other half was plastic slat), with four nest boxes in each pen (n = 16). In treatment S, approximately half of the does (n = 18) were inseminated 2 days after kindling (S-33), whereas in the remaining does (n = 16) AI was done 11 days after kindling (S-42). A single-batch system (all of the does in the group were inseminated on the same day) was used in both S treatments. Kindling rates were 77.6%, 85.2% and 45.6% in treatments S 33, S-42 and G, respectively (P < 0.05). During the experiment, the percentage of does that kindled 0, 1, 2, 3, 4 and 5 times were 17%, 25%, 17%, 25%, 17% and 0% (G); 0%, 0%, 0%, 8%, 69% and 23% (S-33); and 0%, 0%, 17%, 58% and 25% (S-42, in this treatment does had a maximum of four kindlings). There were no significant differences among treatments for litter size. In treatments S-33, S-42 and G, suckling mortality was 14.0%, 15.2% and 38.5%, respectively (P < 0.001); survival of does was 71%, 81% and 50% (P = 0.084); and faecal corticosterone concentrations were 61, 54 and 175 nmol/g (P < 0.001). The high mortality of kits was associated with stress and aggressive behaviour of does, including scratching, biting or killing the kits, which resulted in the high rates of mortality and culling, as well as shorter lifespan of does. Because of high stress, increased mortality and morbidity, and low productivity, group housing of rabbit does resulted in poorer animal welfare and increased production costs, and therefore is not recommended. PMID- 23031210 TI - Opportunities for telemetry techniques in studies on the nutritional ecology of free-ranging domesticated ruminants. AB - The principles of domestic herbivore nutrition are well understood and have been developed through detailed physiological studies, although methods to accurately measure field-based intake still challenge herbivore nutrition research. Nutritional ecology considers an animal's interaction with the environment based on its nutritional demands. Although there are a number of theoretical frameworks that can be used to explore nutritional ecology, optimal foraging provides a suitable starting point. Optimal foraging models have progressed from deterministic techniques to spatially explicit agent-based simulation methods. The development of optimal foraging modelling points towards opportunities for field-based research to explore behavioural preferences within studies that have an array of nutritional choices that vary both spatially and temporally. A number of techniques including weighing animals, weighing herbage, using markers (both natural and artificial) and sampling forage, using oesophageal-fistulated animals, have been used to determine intake in the field. These intake measurement techniques are generally most suited to studies that occur over a few days and with relatively small (often less than 10) groups of animals. Over the last 10 years, there have been a number of advances in automated behavioural monitoring technology (e.g. global positioning systems) to track animal movement. A number of recent studies have integrated detailed spatial assessments of vegetation using on-ground sampling and satellite remote sensing; these data have been linked to behavioural preferences of herbivores. Although the recent studies still do not address nutritional interactions over months or years, they do point to methods that could be used to address landscape scale nutritional interactions. Emerging telemetry techniques used to monitor herbivore behavioural preferences and also to determine detailed landscape vegetation mapping provide the opportunity for future herbivore nutritional ecology studies. PMID- 23031211 TI - Anti-inflammatory effect of ethanolic extract from Myagropsis myagroides on murine macrophages and mouse ear edema. AB - BACKGROUND: This study aims to investigate anti-inflammatory effect of ethanolic extract of Myagropsis myagroides (EMM) in the lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and the phorbol 12-myristate 13-acetate (PMA)-induced ear edema in mice, and to clarify its underlying molecular mechanisms. METHODS: The levels of nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines were measured by Griess assay and enzyme linked immunosorbent assay. The expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX 2), mitogen-activated protein kinases (MAPKs), and Akt were measured using Western blotting. Nuclear translocation and transcriptional activation of nuclear factor-kappaB (NF-kappaB) were determined by immunocytochemistry and reporter gene assay, respectively. PMA-induced mouse ear edema was used as the animal model of inflammation. Anti-inflammatory compounds in EMM were isolated using high-performance liquid chromatography and identified by nuclear magnetic resonance. RESULTS: EMM significantly inhibited the production of NO, PGE2, and pro-inflammatory cytokines in a dose-dependent manner and suppressed the expression of iNOS and COX-2 in LPS-stimulated RAW 264.7 cells. EMM strongly suppressed nuclear translocation of NF-kappaB by preventing degradation of inhibitor of kappaB-alpha as well as by inhibiting phosphorylation of Akt and MAPKs. EMM reduced ear edema in PMA-induced mice. One of the anti-inflammatory compounds in EMM was identified as 6,6'-bieckol. CONCLUSIONS: These results suggest that the anti-inflammatory properties of EMM are associated with the down regulation of iNOS, COX-2, and pro-inflammatory cytokines through the inhibition of NF-kappaB pathway in LPS-stimulated macrophages. PMID- 23031212 TI - Secretome analysis of chondroitin sulfate-treated chondrocytes reveals anti angiogenic, anti-inflammatory and anti-catabolic properties. AB - INTRODUCTION: Chondroitin sulfate (CS) is a symptomatic slow-acting drug for osteoarthritis (OA) widely used in the clinic. The aim of this work is to find proteins whose secretion from cartilage cells under proinflammatory stimuli (IL 1beta) is regulated by CS, employing a novel quantitative proteomic approach. METHODS: Human articular chondrocytes released from three normal cartilages were grown in SILAC medium. When complete incorporation of the heavy isotope was achieved, chondrocytes were stimulated with IL-1beta 5 ng/ml with or without CS pretreatment (200 ug/ml). Forty-eight hours later, chondrocyte secretomes were analyzed by nano-scale liquid chromatography-mass spectrometry. Real-time PCR, western blot and immunohistochemistry analyses were employed to confirm some of the results. RESULTS: We could identify 75 different proteins in the secretome of human articular chondrocytes. Eighteen of these were modulated by CS with statistical significance (six increased and 12 decreased). In normal chondrocytes stimulated with IL-1beta, CS reduces inflammation directly by decreasing the presence of several complement components (CFAB, C1S, CO3, and C1R) and also indirectly by increasing proteins such as TNFalpha-induced protein (TSG6). TSG6 overexpression correlates with a decrease in pro-matrix metalloproteinase activation (observed in MMP1 and MMP3 levels). Finally, we observed a strong CS dependent increase of an angiogenesis inhibitor, thrombospondin-1. CONCLUSION: We have generated a quantitative profile of chondrocyte extracellular protein changes driven by CS in the presence of IL-1beta. We have also provided novel evidences of its anti-angiogenic, anti-inflammatory, and anti-catabolic properties. Demonstration of the anti-angiogenic action of CS might provide a novel therapeutic approach for OA targeting. PMID- 23031213 TI - Lipoteichoic acid induces surfactant protein-A biosynthesis in human alveolar type II epithelial cells through activating the MEK1/2-ERK1/2-NF-kappaB pathway. AB - BACKGROUND: Lipoteichoic acid (LTA), a gram-positive bacterial outer membrane component, can cause septic shock. Our previous studies showed that the gram negative endotoxin, lipopolysaccharide (LPS), could induce surfactant protein-A (SP-A) production in human alveolar epithelial (A549) cells. OBJECTIVES: In this study, we further evaluated the effect of LTA on SP-A biosynthesis and its possible signal-transducing mechanisms. METHODS: A549 cells were exposed to LTA. Levels of SP-A, nuclear factor (NF)-kappaB, extracellular signal-regulated kinase 1/2 (ERK1/2), and mitogen-activated/extracellular signal-regulated kinase kinase (MEK)1 were determined. RESULTS: Exposure of A549 cells to 10, 30, and 50 MUg/ml LTA for 24 h did not affect cell viability. Meanwhile, when exposed to 30 MUg/ml LTA for 1, 6, and 24 h, the biosynthesis of SP-A mRNA and protein in A549 cells significantly increased. As to the mechanism, LTA enhanced cytosolic and nuclear NF-kappaB levels in time-dependent manners. Pretreatment with BAY 11-7082, an inhibitor of NF-kappaB activation, significantly inhibited LTA-induced SP-A mRNA expression. Sequentially, LTA time-dependently augmented phosphorylation of ERK1/2. In addition, levels of phosphorylated MEK1 were augmented following treatment with LTA. CONCLUSIONS: Therefore, this study showed that LTA can increase SP-A synthesis in human alveolar type II epithelial cells through sequentially activating the MEK1-ERK1/2-NF-kappaB-dependent pathway. PMID- 23031214 TI - Use of a chemically induced-colon carcinogenesis-prone Apc-mutant rat in a chemotherapeutic bioassay. AB - BACKGROUND: Chemotherapeutic bioassay for colorectal cancer (CRC) with a rat model bearing chemically-induced CRCs plays an important role in the development of new anti-tumor drugs and regimens. Although several protocols to induce CRCs have been developed, the incidence and number of CRCs are not much enough for the efficient bioassay. Recently, we established the very efficient system to induce CRCs with a chemically induced-colon carcinogenesis-prone Apc-mutant rat, Kyoto Apc Delta (KAD) rat. Here, we applied the KAD rat to the chemotherapeutic bioassay for CRC and showed the utility of the KAD rat. METHODS: The KAD rat has been developed by the ENU mutagenesis and carries a homozygous nonsense mutation in the Apc gene (S2523X). Male KAD rats were given a single subcutaneous injection of AOM (20 mg/kg body weight) at 5 weeks of age. Starting at 1 week after the AOM injection, they were given 2% DSS in drinking water for 7 days. Tumor-bearing KAD rats were divided into experimental and control groups on the basis of the number of tumors observed by endoscopy at week 8. The 5-fluorouracil (5-FU) was administrated intravenously a dose of 50 or 75 mg/kg weekly at week 9, 10, and 11. After one-week interval, the 5-FU was given again at week 13, 14, and 15. At week 16, animals were sacrificed and tumor number and volume were measured macroscopically and microscopically. RESULTS: In total 48 tumors were observed in 27 KAD rats with a 100% incidence at week 8. The maximum tolerated dose for the KAD rat was 50 mg/kg of 5-FU. Macroscopically, the number or volume of tumors in the 5-FU treated rats was not significantly different from the control. Microscopically, the number of adenocarcinoma in the 5-FU treated rats was not significantly different (p < 0.02) from that of the control. However, the volume of adenocarcinomas was significantly lower than in the control. Anticancer effect of the 5-FU could be obtained only after the 16 weeks of experimental period. CONCLUSION: The use of the AOM/DSS-treated tumor-bearing KAD rats could shorten the experimental period and reduce the number of animals examined in the chemotherapeutic bioassay. The efficient bioassay with the AOM/DSS-treated tumor bearing KAD rats would promote the development of new anti-tumor drugs and regimens. PMID- 23031215 TI - RHYTHM-AF: design of an international registry on cardioversion of atrial fibrillation and characteristics of participating centers. AB - BACKGROUND: Atrial fibrillation is a serious public health problem posing a considerable burden to not only patients, but the healthcare environment due to high rates of morbidity, mortality, and medical resource utilization. There are limited data on the variation in treatment practice patterns across different countries, healthcare settings and the associated health outcomes. METHODS/DESIGN: RHYTHM-AF was a prospective observational multinational study of management of recent onset atrial fibrillation patients considered for cardioversion designed to collect data on international treatment patterns and short term outcomes related to cardioversion. We present data collected in 10 countries between May 2010 and June 2011. Enrollment was ongoing in Italy and Brazil at the time of data analysis. Data were collected at the time of atrial fibrillation episode in all countries (Australia, Brazil, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom), and cumulative follow-up data were collected at day 60 (+/-10) in all but Spain. Information on center characteristics, enrollment data, patient demographics, detail of atrial fibrillation episode, medical history, diagnostic procedures, acute treatment of atrial fibrillation, discharge information and the follow-up data on major events and rehospitalizations up to day 60 were collected. DISCUSSION: A total of 3940 patients were enrolled from 175 acute care centers. 70.5% of the centers were either academic (44%) or teaching (26%) hospitals with an overall median capacity of 510 beds. The sites were mostly specialized with anticoagulation clinics (65.9%), heart failure (75.1%) and hypertension clinics (60.1%) available. The RHYTHM-AF registry will provide insight into regional variability of antiarrhythmic and antithrombotic treatment of atrial fibrillation, the appropriateness of such treatments with respect to outcomes, and their cost efficacy. Observations will help inform strategies to improve cardiovascular outcomes in patients with atrial fibrillation. TRIAL REGISTRATION: Clinical trials NCT01119716. PMID- 23031216 TI - Differentiation of human adipose tissue-derived stem cells into aggregates of insulin-producing cells through the overexpression of pancreatic and duodenal homeobox gene-1. AB - The pancreatic and duodenal homeobox gene 1 (Pdx-1) plays a key role in normal pancreas development and is required for maintaining the normal function of islets. In this study, we examined whether human adipose tissue-derived stem cells (hASCs) could differentiate into insulin-producing cells by exogenously expressed Pdx-1. hASCs were infected with recombinant adenovirus encoding the mouse Pdx-1 gene and differentiated under high-glucose conditions. Insulin transcript levels and the expression of key transcription factors required for pancreatic development including FoxA2, Nkx2.2, and NeuroD were significantly increased by exogenous Pdx-1 overexpression. The expression of Nkx6.1 was found only in Pdx-1-induced hASCs. In addition to transcripts for transcription factors involved in pancreatic development, transcripts for the GLP-1 receptor, glucokinase, and glucose transporter, which are required for maintaining the function of pancreatic beta-cells, were observed only in Pdx-1-induced hASCs. Pdx 1-induced hASCs exhibited insulin secretion in response to glucose challenge in vitro. When Pdx-1-induced hASCs were transplanted into streptozotocin (STZ) induced diabetic mice, they reduced blood glucose levels, although they did not restore normoglycemia. These results demonstrate that the expression of exogenous Pdx-1 is sufficient to induce pancreatic differentiation in vitro but does not induce the fully functional, mature insulin-producing cells that are required for restoring normoglycemia in vivo. PMID- 23031217 TI - The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury. AB - In this single-center, double-blind, randomized, sham-controlled, prospective trial at the U.S. Air Force School of Aerospace Medicine, the effects of 2.4 atmospheres absolute (ATA) hyperbaric oxygen (HBO2) on post-concussion symptoms in 50 military service members with at least one combat-related, mild traumatic brain injury were examined. Each subject received 30 sessions of either a sham compression (room air at 1.3 ATA) or HBO2 treatments at 2.4 ATA over an 8-week period. Individual and total symptoms scores on Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT(r)) and composite scores on Post traumatic Disorder Check List-Military Version (PCL-M) were measured just prior to intervention and 6 weeks after completion of intervention. Difference testing of post-intervention means between the sham-control and HBO2 group revealed no significant differences on the PCL-M composite score (t=-0.205, p=0.84) or on the ImPACT total score (t=-0.943, p=0.35), demonstrating no significant effect for HBO2 at 2.4 ATA. PCL-M composite scores and ImPACT total scores for sham-control and HBO(2) groups revealed significant improvement over the course of the study for both the sham-control group (t=3.76, p=0.001) and the HBO2 group (t=3.90, p=0.001), demonstrating no significant HBO2 effect. Paired t-test results revealed 10 ImPACT scale scores in the sham-control group improved from pre- to post-testing, whereas two scale scores significantly improved in the HBO2 group. One PCL-M measure improved from pre- to post-testing in both groups. This study showed that HBO2 at 2.4 ATA pressure had no effect on post-concussive symptoms after mild TBI. PMID- 23031219 TI - Potential role of sirtuins in livestock production. AB - Sirtuins are NAD(+)-dependent histone and protein deacetylases, which have been studied during the last decade with a focus on their role in lifespan extension and age-related diseases under normal and calorie-restricted or pathological conditions. However, sirtuins also have the ability to regulate energy homeostasis as they can sense the metabolic state of the cell through the NAD(+)/NADH ratio; hence, changes in the diet can modify the expression of these enzymes. Dietary manipulations are a common practice currently being used in livestock production with favorable results, probably due in part to the enhanced activity of sirtuins. Nevertheless, sirtuin expression in livestock species has not been a research target. For these reasons, the goal of this review is to awaken interest in these enzymes for future detailed characterization in livestock species by presenting a general introduction to what sirtuins are, how they work and what is known about their role in livestock. PMID- 23031218 TI - SUCROSE TRANSPORTER 5 supplies Arabidopsis embryos with biotin and affects triacylglycerol accumulation. AB - The Arabidopsis SUC5 protein represents a classical sucrose/H(+) symporter. Functional analyses previously revealed that SUC5 also transports biotin, an essential co-factor for fatty acid synthesis. However, evidence for a dual role in transport of the structurally unrelated compounds sucrose and biotin in plants was lacking. Here we show that SUC5 localizes to the plasma membrane, and that the SUC5 gene is expressed in developing embryos, confirming the role of the SUC5 protein as substrate carrier across apoplastic barriers in seeds. We show that transport of biotin but not of sucrose across these barriers is impaired in suc5 mutant embryos. In addition, we show that SUC5 is essential for the delivery of biotin into the embryo of biotin biosynthesis-defective mutants (bio1 and bio2). We compared embryo and seedling development as well as triacylglycerol accumulation and fatty acid composition in seeds of single mutants (suc5, bio1 or bio2), double mutants (suc5 bio1 and suc5 bio2) and wild-type plants. Although suc5 mutants were like the wild-type, bio1 and bio2 mutants showed developmental defects and reduced triacylglycerol contents. In suc5 bio1 and suc5 bio2 double mutants, developmental defects were severely increased and the triacylglycerol content was reduced to a greater extent in comparison to the single mutants. Supplementation with externally applied biotin helped to reduce symptoms in both single and double mutants, but the efficacy of supplementation was significantly lower in double than in single mutants, showing that transport of biotin into the embryo is lower in the absence of SUC5. PMID- 23031220 TI - The prevalence and features of thyroid pyramidal lobe, accessory thyroid, and ectopic thyroid as assessed by computed tomography: a multicenter study. AB - BACKGROUND AND PURPOSE: Understanding the computed tomography (CT) characteristics of the pyramidal lobe and other thyroid variations and detecting them accurately using preoperative neck CT will minimize unnecessary remnant thyroid tissue after total thyroidectomy in patients with thyroid cancer. The purpose of the present study was to assess the frequency, location, and size of the pyramidal lobe and other thyroid variations using a large-scaled, multicenter study. METHODS: Neck CT scans for 200 patients were selected from 11 institutions; a total of 2200 patients were included in the study. The patients underwent neck CT for the following reasons: trauma, known thyroid malignancy, cervical lymphadenopathy, palpable neck mass, oropharyngolaryngeal malignancy, vocal cord palsy, postchemotherapy CT follow-up, inflammatory or infectious neck lesion, parathyroid abnormality, and patient request. A single radiologist at each institution retrospectively analyzed 200 neck CT scans. Each radiologist investigated the presence, location, length, volume, and upper end of the pyramidal lobe and its separation or continuity with the main thyroid gland as well as the presence, location, length, and volume of the accessory or ectopic thyroid using a picture archiving and communication system. RESULTS: A pyramidal lobe was present in 44.6% (981/2200) of the patients. The prevalence for the pyramidal lobe at the participating institutions ranged from 28.0% to 55.0% (mean, 44.6%). Pyramidal lobes originating from the left side of the thyroid were most common, and the number of pyramidal lobes showing separation from the main thyroid gland was 90 (9.2%). The mean anteroposterior diameter, transverse diameter, and length of the pyramidal lobe were 2.3, 5.9, and 20.8 mm, respectively. Among both men and women, the most common level of the upper end of the pyramidal lobes was the thyroid cartilage, but there was a significant difference in the frequency of the pyramidal lobe between males and females (p<0.0001). The rate of the pyramidal lobe detection in the 2-mm-slice-thickness group was higher than those in the 2.5- and 3-mm groups (p=0.0003). CONCLUSION: Neck CT is useful for detecting the presence, size, configuration, and location of the pyramidal lobe and other thyroid variations. PMID- 23031221 TI - Quantitative trait locus mapping of genes that control body length and plasma insulin-like growth factor 1 level in mice. AB - BACKGROUND: The Ay allele at the agouti locus causes obesity and promotes linear growth in mice. The effect of the Ay allele on obesity has been extensively investigated, whereas its effect on body length is only poorly analyzed. To gain insight into the genetic control of body length, quantitative trait locus (QTL) analysis was performed in F2 female mice produced by crossing C57BL/6 J females and DDD.Cg-Ay males. A congenic DDD.Cg-Ay strain was established by introgressing the Ay allele from the B6.Cg-Ay strain by backcrossing for 12 generations. DDD.Cg Ay females were longer than B6.Cg-Ay females; therefore, QTLs that interact with the Ay allele may be identified for body length. In addition, QTL analysis was also performed for plasma insulin-like growth factor 1 (IGF1) levels because IGF1 is known to play essential roles in growth and development. If QTLs for IGF1 levels coincide with those for body length, we can gain endocrinological insight into the QTLs for body length. RESULTS: Correlations between body length and IGF1 levels were statistically significant in F2 populations. For body length, two significant QTLs were identified on chromosomes 15 and 17. For IGF1 levels, three significant QTLs were identified on chromosomes 10, 12, and 19. QTLs on chromosomes 12 and 19 appeared to be novel, and the latter interacted with the Ay allele. CONCLUSION: QTLs for body length and IGF1 levels contained candidate genes that were components of the growth hormone/insulin-like growth factor axis. However, there was no overlap between QTLs for these two traits. Contrary to our expectations, QTLs that interacted with the Ay allele were identified not for body length but for IGF1 levels. Body length and IGF1 levels were, thus, controlled by different sets of genes. PMID- 23031222 TI - Impact of general injection anaesthesia and analgesia on post-castration behaviour and teat order of piglets. AB - Injection anaesthesia with a combination of ketamine and azaperone (K/A) is discussed as a painless alternative to commonly used non-anaesthetized castration. To protect anaesthetized piglets from being crushed, they have to be separated from the sow for 3 h following castration. The aim of this study was to test if this separation and the different treatments would affect short-term behaviour after castration (3 to 6 h after castration) as well as weight gain. Piglets were 5 to 7 days old. Treatment Group 1 received a combination of anaesthesia and analgesia (n = 29, ketamine: 25 mg/kg BW; azaperone: 2 mg/kg BW; meloxicam: 0.4 mg/kg BW), Group 2 received only analgesia (n = 24) and Group 3 received no medication (n = 29). Behaviour and suckling order were compared for a 3 h period the day before castration and after castration. A significantly higher number of teats used by anaesthetized piglets (P = 0.004) suggests a decrease in suckling order stability. There were significant treatment effects between all three groups in the time spent at the sow's teat, with an increase in Group 2 (+69%), decrease in Group 1 (-28%), whereas the control Group 3 (+2%) almost remained unchanged. The anaesthetized piglets showed an increase in the time spent active away from the sow after castration of almost 200% (Groups 2 and 3: ~50%, P < 0.001). However, no significant treatment effect was seen for weight gain. The results suggest that analgesia has an effect on behaviour, perhaps due to less post-castration pain. This advantage is not apparent for animals receiving additional anaesthesia, probably because of impaired coordination. Although the behavioural changes did not affect weight gain significantly, a decrease in suckling order stability indicates a certain degree of stress due to fighting over teat positions as a consequence of separation. Thus, post castration behaviour must be taken into account when evaluating alternative castration methods. PMID- 23031223 TI - Comparison of growth performance and agonistic interaction in weaned piglets of different weight classes from farrowing systems with group or single housing. AB - The present study was designed to analyze the growth performance, behavioral patterns and intensity of injuries of weaned pigs (26 days) during a rearing period of 6 weeks. The farrowing system (group housing (GH) v. single housing (SH)) and the post-weaning regrouping weight class (light, medium, heavy) were considered as the main factors. A number of 120 GH-pigs and 120 SH-pigs were kept in three batches (20 pens, 12 pigs each). The GH- and SH-pigs were divided by weight into three groups: light (5 to ?7 kg), medium (>7 to ?9 kg) and heavy (>9 to ?12 kg), with two pigs of six different litters in each pen. The pigs were weighed individually at weaning (week 1) and during rearing (weeks 2, 3 and 7). The feed conversion ratio (FCR) was calculated between weeks 1 and 7. The duration and number of fights (NF) per pen and hour were determined by continuous sampling (40 h after weaning). Lesions of the integument were scored into four classes (none, minor, medium, severe) and recorded at weaning and 48 h afterwards. The farrowing system had no effect on the weights in week 1 (GH: 7.8 kg v. SH: 7.7 kg; week as linear, quadratic regression nested within housing systems) or in week 7 (GH: 29.4 kg v. SH: 28.6 kg). The body weights were influenced significantly by the weaning weight class (light: 11.7 kg (s.e.m.: 0.30), medium: 14.8 kg (s.e.m.: 0.22), heavy: 17.3 kg (s.e.m.: 0.26)). The FCR of the GH-pigs was 1.64 (s.e.m.: 0.03) and 1.58 (s.e.m.: 0.03) for SH-pigs. A reduced agonistic behavior of the GH-pigs was observed with 2.1 fights per pen and hour (s.e.m.: 0.07) v. the SH-pigs with 4.6 fights per pen and hour (s.e.m.: 0.05). The fight duration of the GH-pigs with 10.3 s per pen and hour (s.e.m.: 1.07) was significantly lower in comparison to the SH-pigs with 18.8 s per pen and hour (s.e.m.: 1.06). The SH-pigs had more new skin lesions at the shoulders than the GH-pigs 48 h after weaning (P < 0.05). In conclusion, early mixing of unacquainted litters during lactation had no influence on their growth performance during rearing but reduced agonistic behavior and lesion score difference during the first 2 days after weaning. No significant interaction between the farrowing system and weaning weight class was detected with regard to growth performance and NF. PMID- 23031224 TI - Leisure time physical activity in a 22-year follow-up among Finnish adults. AB - BACKGROUND: The aim of this study was to explore long-term predictors of leisure time physical activity in the general population. METHODS: This study comprised 718 men and women who participated in the national Mini-Finland Health Survey from 1978-1980 and were re-examined in 2001. Participants were aged 30-80 at baseline. Measurements included interviews, health examinations, and self administered questionnaires, with information on socioeconomic position, occupational and leisure time physical activity, physical fitness, body mass index, smoking, alcohol consumption, and physical functional capacity. Analyses included persons who were working and had no limitations in functional capacity at baseline. RESULTS: The strongest predictor of being physically active at the follow-up was participation in physical activity at baseline, with an OR 13.82 (95%CI 5.50-34.70) for 3 or more types of regular activity, OR 2.33 (95%CI 1.22 4.47) for 1-2 types of regular activity, and OR 3.26 (95%CI 2.07-5.15) for irregular activity, as compared to no activity. Other determinants for being physically active were moving upwards in occupational status, a high level of baseline occupational physical activity and remaining healthy weight during the follow-up. CONCLUSIONS: To prevent physical inactivity among older adults, it is important to promote physical activity already in young adulthood and in middle age and to emphasize the importance of participating in many types of physical activity. PMID- 23031225 TI - Nutritional impact on health and performance in intensively reared rabbits. AB - The present work summarizes research related to the definition of nutrient recommendations for feeds used in the intensive production of rabbit's meat. Fibre is the main chemical constituent of rabbit diets that typically contain 320 to 360 and 50 to 90 g/kg of insoluble and soluble fibre, respectively. Instead, the dietary contents of cereal grains (~120 to 160 g/kg), fat (15 to 25 g/kg) and protein concentrates (150 to 180 g/kg) are usually low with respect to other intensively reared monogastric animals. Cell wall constituents are not well digested in rabbits, but this effect is compensated by its stimulus of gut motility, which leads to an increasing rate of passage of digesta, and allows achieving an elevated dry matter intake. A high feed consumption and an adequate balance in essential nutrients are required to sustain the elevated needs of high productive rabbits measured either as reproductive yield, milk production or growth rate in the fattening period. Around weaning, pathologies occur in a context of incomplete development of the digestive physiology of young rabbits. The supply of balanced diets has also been related to the prevention of disorders by means of three mechanisms: (i) promoting a lower retention time of the digesta in the digestive tract through feeding fibre sources with optimal chemical and physical characteristics, (ii) restricting feed intake after weaning or (iii) causing a lower flow of easily available substrates into the fermentative area by modifying feed composition (e.g. by lowering protein and starch contents, increasing its digestibility or partially substituting insoluble with soluble fibre), or by delaying age at weaning. The alteration in the gut microbiota composition has been postulated as the possible primary cause of these pathologies. PMID- 23031226 TI - Long-term exposure to unpredictable and uncontrollable aversive events alters fearfulness in sheep. AB - Numerous studies have investigated the emotional effects of various acute, potentially alarming events in animals, but little is known about how an accumulation of emotional experiences affects fearfulness. Fearfulness is a temperament trait that characterizes the propensity of an individual to be frightened by a variety of alarming events. The aim of this study was to investigate a putative alteration of fearfulness in sheep repeatedly exposed to various aversive events. Forty-eight 5-month-old female lambs were used. Over a period of 6 weeks, 24 of them (treated group) were exposed daily to various unpredictable and uncontrollable aversive events related to predatory cues, social context and negative handling that can occur under farming conditions. The other 24 lambs (control group) were housed in standard farming conditions (predictable food distribution and group handling). Fearfulness (behavioural and physiological responses) was assessed before and after the treatment period by subjecting the lambs to three standardized tests: individual exposure to suddenness and then to novelty in a test arena, and group exposure to a motionless human in the home pen. As biomarkers of stress, leukocyte counts, heart rate and cortisol concentrations were measured in the lambs in their home pens. Before the treatment, the emotional responses of the groups did not differ. After the treatment, treated lambs approached the human less often, had less contact with the novel object and vocalized more than controls in individual tests, suggesting that long-term exposure to unpredictable and uncontrollable aversive events increases subsequent fearfulness in sheep. In addition, treated lambs had lower leukocyte counts, heart rate and cortisol levels, pointing to a chronic stress state. These findings suggest that increased fearfulness may be used as a sign of chronic stress in farm animals. PMID- 23031098 TI - Determination of the strange-quark density of the proton from ATLAS measurements of the W->lnu and Z->ll cross sections. AB - A QCD analysis is reported of ATLAS data on inclusive W(+/-) and Z boson production in pp collisions at the LHC, jointly with ep deep-inelastic scattering data from HERA. The ATLAS data exhibit sensitivity to the light quark sea composition and magnitude at Bjorken x~0.01. Specifically, the data support the hypothesis of a symmetric composition of the light quark sea at low x. The ratio of the strange-to-down sea quark distributions is determined to be 1.00( 0.28)(+0.25) at absolute four-momentum transfer squared Q(2)=1.9 GeV(2) and x=0.023. PMID- 23031228 TI - Survey of UK radiology trainees in the aftermath of 'Modernising Medical Careers'. AB - BACKGROUND: Following implementation of Modernising Medical Careers (MMC) in the UK, potential radiology trainees must decide on their career and apply sooner than ever before. We aimed to determine whether current trainees were sufficiently informed to make an earlier career decision by comparing the early radiology experiences of Traditional and Foundation Trainees. METHODS: 344 radiology trainees were appointed through MMC in 2007/08. This cohort was surveyed online. RESULTS: Response rate was 174/344 (51%). Traditional Trainees made their career decision 2.6 years after graduation compared with 1.2 years for Foundation Trainees (57/167, 34%). Nearly half of responders (79/169, 47%) experienced no formal radiology teaching as undergraduates. Most trainees regularly attended radiology meetings, spent time in a radiology department and/or performed radiology research. Many trainees received no career advice specific to radiology (69/163, 42%) at any point prior to entering the specialty; this includes both formal and informal advice. Junior doctor experiences were more frequently cited as influencing career choice (98/164, 60%). An earlier career decision was associated with; undergraduate radiology projects (-0.72 years, p = 0.018), career advice (-0.63 years, p = 0.009) and regular attendance at radiology meetings (-0.65 years, p = 0.014). CONCLUSION: Early experience of radiology enables trainees to make an earlier career decision, however current radiology trainees were not always afforded relevant experiences prior to entering training. Radiologists need to be more proactive in encouraging the next generation of trainees. PMID- 23031227 TI - CD20-positive NK/T-cell lymphoma with indolent clinical course: report of case and review of literature. AB - CD20-positive T-cell lymphoma is extremely rare and only two cases of CD20 positive NK/T-cell lymphoma with aggressive clinical courses have been described in the literature. We present a case of unusual NK/T-cell lymphoma with CD20 expression in nasal cavity occurring in an elder female patient. The patient had presented with left nasal cavity nodule for 10 years. CT scan revealed a mass was located at the left anterior nasal cavity and was observed to extend into the ethmoid sinus. There was no regional lymph node involvement. Biopsy was performed and microscopical inspection revealed the lesion was composed of small- to middle size atypical lymphoid cell, histiocytes, eosinophils, and neutrophils. The lymphoid cells were strongly immunoreactive to CD3, CD20, CD56, TIA-1 and granzyme-B. The Epstein-Barr virus genomes were also found in tumor cells by in situ hybridization. By genetic analysis, however, no clonal rearrangement of the T cell receptor-gamma genes (TCRG), or the immunoglobulin heavy chain (IgH) gene was found. A diagnosis of CD20-positive extranodal NK/T-cell lymphoma, nasal type was made. The patient refused chemotherapy, and had been only on regular follow up for 6 months. There was no sign of enlargement of tumor and extra-nasal dissemination by whole body positron emission tomography/computed tomography (PET/CT) study. The accurate diagnosis of NK/T-cell lymphoma with CD20 expression is important, but the indolent behavior of the present case is more unusual. A long-term follow-up is suggested to be performed to inspect the progression for this tumor. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1320848277788495. PMID- 23031233 TI - [Possibly fewer donors due to decreasing hospital mortality rates]. AB - Over the past ten years, the mortality rate at the Amphia Hospital in the Netherlands has decreased and the average age at death has increased significantly. This downward trend in hospital mortality rates is a national trend in the Netherlands. In addition, in recent years road traffic fatalities have steadily decreased. Both trends have had a significant impact on the availability of potential organ and tissue donors. Currently the main barriers to donation are the limited number of registrations in the donor registry and obtaining permission from relatives. To achieve the maximum number of donors, several initiatives must be undertaken. These include hospitals encouraging registration in the donor registry, training of professionals in communication skills concerning donation, increasing opportunities for organ donations in the emergency department and recruiting donors extramurally. If no measures are taken, a decreasing number of patients with end-stage organ failure will be able to profit from organ transplantation. PMID- 23031230 TI - Optimization of a direct spectrophotometric method to investigate the kinetics and inhibition of sialidases. AB - BACKGROUNDS: Streptococcus pneumoniae expresses three distinct sialidases, NanA, NanB, and NanC, that are believed to be key virulence factors and thus, potential important drug targets. We previously reported that the three enzymes release different products from sialosides, but could share a common catalytic mechanism before the final step of product formation. However, the kinetic investigations of the three sialidases have not been systematically done thus far, due to the lack of an easy and steady measurement of sialidase reaction rate. RESULTS: In this work, we present further kinetic characterization of pneumococcal sialidases by using a direct spectrophotometric method with the chromogenic substrate p nitrophenyl-N-acetylneuraminic acid (p-NP-Neu5Ac). Using our assay, the measured kinetic parameters of the three purified pneumococcal sialidase, NanA, NanB and NanC, were obtained and were in perfect agreement with the previously published data. The major advantage of this alternative method resides in the direct measurement of the released product, allowing to readily determine of initial reaction rates and record complete hydrolysis time courses. CONCLUSION: We developed an accurate, fast and sensitive spectrophotometric method to investigate the kinetics of sialidase-catalyzed reactions. This fast, sensitive, inexpensive and accurate method could benefit the study of the kinetics and inhibition of sialidases in general. PMID- 23031231 TI - [A woman with urinary tract infections and flank pain]. AB - A 52-year-old woman presented with recurrent urinary tract infections and flank pain. Both an abdominal CT-scan and a plain abdominal X-ray showed bilateral nephrocalcinosis and a kidney stone in the left ureter. These findings are suggestive of medullary sponge kidneys. PMID- 23031232 TI - [Pressure ulcer prevention with pressure-reducing seat cushions]. AB - OBJECTIVE: Analysis of the effectiveness of pressure-reducing seat cushions. DESIGN: Literature review. METHOD: Investigation of the literature yielded 8 relevant studies. These studies encompassed three clinical trials with a total of 296 patients, and five laboratory experiments with a total of 107 subjects, including patients. The publications were written at level A (RCT and meta analysis) and level B (other study forms) according to the principles of evidence based medicine. Both the pressure parameters of the pressure-reducing seat cushion and the development of pressure ulcers were used as measures for outcome. A 7.6 cm foam cushion was used as reference; it was not considered as one of the pressure-reducing systems. RESULTS: Two studies compared different types of air seat cushions with a foam/gel seat cushion. The best distribution of pressure was found for the air compartment seat cushion. This type of seat cushion provided the smallest contact surface with high pressures. Three studies compared the pressure-reducing systems with a 7.6 cm foam cushion. The methodologically most solid one of these three studies found a lower incidence of sitting-related pressure ulcers for users of a pressure-reducing system (0.9 vs. 6.7%; p = 0.04). The two other studies had too low a power to show significant differences. These two compared different types of foam/gel seat cushions and a low profile air seat cushion and found no significant differences in distribution of pressures. One study compared various foam cushions of differing thickness and found that foam cushions most optimally distributed pressure at a thickness of 8 centimetres. CONCLUSION: Pressure-reducing systems are effective in preventing pressure ulcers. Within the group of pressure-reducing systems, the air compartment seat cushion has the best pressure-distributing properties. PMID- 23031234 TI - [Vigilance in experimental treatment]. AB - When all standard care options are exhausted, it may be justifiable to carry out an experimental treatment. In the Netherlands, experimental treatment is distinguished from medical research; the latter primarily serves the public interest (obtaining medical knowledge), while the former does not. In experimental treatment, it is a doctor's duty to explain the treatment to the patient carefully and to obtain the patient's explicit consent. In addition, the doctor needs to list all relevant aspects of the treatment in the patient's medical record. A medical practitioner who abides by these rules has acted in accordance with the Dutch law. But, given the sometimes highly risky nature of experimental treatments, is this enough? We do not think so and therefore argue for two additional conditions which are focused on transparency. First, there is a need for a service to ensure that experimental treatments are registered. Second, the effects and side effects of each experimental treatment should be reported. We envision the further elaboration of these conditions to be not only a task for the medical profession but possibly also for government-appointed institutions. PMID- 23031229 TI - Aberrant cytokine pattern of the nasal mucosa in granulomatosis with polyangiitis. AB - INTRODUCTION: In granulomatosis with polyangiitis (GPA), a complex autoimmune small-vessel vasculitis frequently associated with chronic necrotizing inflammation of the nasal mucosa, elevated nasal Staphylococcus (S.) aureus carrier rates are a risk factor for relapse. As cytokines are primarily involved in the regulation of defense against potentially pathogenic microorganisms, the aim of this study was to compare healthy individuals and GPA patients with respect to their baseline cytokine expression of nasal epithelial cells (NEC), which form the first barrier against such triggers. The ability of S. aureus to influence the nasal microenvironment's cytokine secretion was assessed by exemplary stimulation experiments. METHODS: Baseline expression of 19 cytokines of primary NEC of GPA patients and normal controls (NC) was quantified by a multiplex cytokine assay. Stimulation experiments were performed with supernatants of S. aureus and expression of interleukin-8 was determined by ELISA. RESULTS: In GPA, an altered pattern of baseline cytokine expression with significantly up-regulated G-CSF and reduced interleukin (IL)-8 concentrations was observed. Both NEC of GPA patients and NC responded to stimulation with S. aureus, but GPA patients displayed a significantly lower IL-8 secretion and a diminished dynamic range of response towards the stimulus. CONCLUSIONS: The data presented underline the hypothesis of a disturbed epithelial nasal barrier function in GPA. The dysregulated baseline expression of G-CSF and IL-8 and the reduced response to microbial stimulation may facilitate changes in the composition of the nasal flora and favour an imbalanced inflammatory response, which might be relevant for the disease course. PMID- 23031235 TI - [Papanicolaou and the cervical smear]. AB - George N. Papanicolaou (1883-1962) was born in Kymi (on the island of Euboea, Greece). He studied medicine in Athens but chose not to join his father's practice in Kymi. Instead, he obtained his doctoral degree at the Zoological Institute in Munich (1910) and - after a brief return and marriage in Greece - went to work at the Oceanographic Institute in Monaco. Recalled in 1912 by the death of his mother and the Balkan Wars, he and his wife emigrated a year later to New York. After some difficulty, he found work as a research biologist at the Cornell University Department of Anatomy. Papanicolaou concentrated on vaginal cells right from the start, initially from guinea pigs. His real goal was to harvest egg cells for the study of sex differentiation; he succeeded in finding the right time by recording the cyclic changes in genital epithelium. These same changes appeared to occur during the human menstrual cycle. It was by chance that he encountered cancer cells in a human specimen in 1928. More than 10 years would pass before he took up the subject of cancer again, in collaboration with the gynaecologist Herbert F. Traut (1894-1963). After their first publication in 1941, Papanicolaou gradually fine-tuned the technique of cytological diagnostics in a variety of organs. In 1961, he moved to Miami Beach as head of a new cancer centre, but suddenly died a few months later. PMID- 23031237 TI - [New developments in the treatment and rehabilitation of head and neck cancer in the Netherlands]. AB - Head and neck cancer is relatively rare: in the Netherlands, some 2600 newly diagnosed cases are registered annually. Its treatment is centralised and is actually performed only in Dutch Head and Neck Society (DHNS) accredited medical centres. Although survival rates have improved only marginally, treatment regimens have changed over the past few years. Treatment has become increasingly focused on the preservation of organs and their functionalities. The effects of both a tumour and its treatment can have a serious impact on the functioning and quality of life of a patient. Therefore, sufficient attention to post-treatment rehabilitation is necessary. The Netherlands Cancer Institute has recently collaborated with the Amsterdam Rehabilitation Research Center Reade in developing a structured multidisciplinary rehabilitation programme. This programme has also been made available to other DHNS centres. PMID- 23031238 TI - [Detection of inappropriate medication use in the elderly; will the STOPP and START criteria become the new Dutch standards?]. AB - Many drugs that can be prescribed safely and effectively to younger patients are potentially inappropriate for the elderly as a result of physiological changes and increased comorbidity. A screening tool can be useful for detecting potentially inappropriate medication use in the elderly. When analysing medication use in the elderly, both overtreatment and undertreatment should be assessed. In Ireland, a screening method called the STOPP and START criteria has been developed; these provide 'handles' for the detection of potential overtreatment and undertreatment. The STOPP and START criteria, therefore, seem to be more fitting to the Dutch situation than the widely used Beers' criteria. In the new Dutch multidisciplinary guideline, 'Polypharmacy in the elderly' the use of the STOPP and START criteria is advised. In this article, we present a translation of the STOPP and START criteria which has been adapted for Dutch practice. PMID- 23031239 TI - [Progressive insight into treatment of appendicitis: antibiotic use appears to be a safe step forward]. AB - Since the late 19th century, standard treatment for acute appendicitis has been an appendectomy. Recently, two new developments have induced a new paradigm. More accurate diagnosis by imaging has since overruled the old adagium: 'When in doubt, take it out.' Secondly, new insights into the pathogenesis of appendicitis have negated the theory that simple appendicitis will inevitably progress into complicated appendicitis, with associated perforation and generalised peritonitis. Four randomised controlled trials in adults have demonstrated that antibiotic treatment in selected patients is safe and effective: in two-thirds of healthy and relatively young men, antibiotics cured the appendicitis. In 15%, an operation was indicated for failure to respond and 15% relapsed within one year. These promising results need to be confirmed in other populations such as children and women. Furthermore, the establishment of prognostic factors such as the presence of a faecolith is needed before the treatment of appendicitis can be removed from the surgeon's realm. PMID- 23031240 TI - [Probiotics have a limited role in the treatment of inflammatory bowel disease]. AB - Probiotics are frequently prescribed for the treatment of inflammatory bowel disease (IBD). However, supporting evidence for the use of probiotics in IBD is scarce. Most studies are limited by design or do not show that probiotic treatment is effective. Only a few randomised controlled trials have demonstrated any beneficial effect of probiotic use in IBD; namely, the use of VSL#3 in patients with pouchitis and ulcerative colitis. So far, the efficacy of probiotics in the treatment of Crohn's disease has not been clearly demonstrated. Furthermore, issues pertaining to their mechanisms of action, dosages and dosing intervals, safety, and health insurance coverage are currently unresolved. Given the limited body of evidence of their efficacy from controlled trials and the many unanswered questions on probiotic treatment, we recommend following the evidence obtained from well-designed randomised controlled trials and only prescribing probiotic treatment (e.g. VSL #3) for the prevention of pouchitis and the treatment of patients with mildly active ulcerative colitis. PMID- 23031241 TI - [Blunt trauma to the eye in children: more than a black eye]. AB - BACKGROUND: The consequences of orbital floor fractures are different in children than in adults. Children have more elastic bones and increased chance of a trapdoor fracture, a fracture in which muscle tissue may be trapped. CASE DESCRIPTION: A 12-year-old girl presented to the general practitioner after she had been hit in her left eye by a swing. The patient had a painful eye and double vision. She was sent home with the advice to wake her every hour during the night. The next morning she went back to the general practitioner because she had been vomiting through the night and this time she was sent to the hospital. She was diagnosed with an orbital floor fracture with an entrapment of the inferior rectus muscle and underwent immediate surgery. Unfortunately, the release of the muscle had been too late and resulted in an uncorrectable diplopia. CONCLUSION: Warning signs of entrapment of the inferior rectus muscle are a painful eye with a mobility disorder in combination with nausea and vomiting. Immediate surgical intervention offers the best outcome in terms of recovery of the eye motility. PMID- 23031242 TI - [Risk stratification at the emergency ward is a must]. AB - In light of the growing number of elderly patients visiting emergency rooms, a different approach is needed than that used toward the younger patient. Healthcare should be tailored to this specific elderly target group. Study results have recently been published on an instrument used to stratify risks in older patients who are acutely admitted to the hospital; this instrument is called 'Identification of Seniors at Risk-Hospitalized Patients' (ISAR-HP). The ISAR-HP score, however, is not predictive on an individual level. Disease-related risk scores are better for deriving prognoses for individual patients. The ISAR HP may be considered as a first step in streamlining elderly care; however, better and validated measurement tools are needed. PMID- 23031243 TI - [Pregnancy-associated breast cancer: current opinions on diagnosis and treatment]. AB - Because of the trend to postpone childbirth until later in life we will be increasingly confronted with pregnancy-associated breast cancer. We report on two patients with pregnancy-associated breast cancer. Complete treatment of this condition during pregnancy by means of surgery, radiotherapy and chemotherapy is possible without any known damage to the foetus, even if the breast cancer is diagnosed early in pregnancy. Treatment should be multidisciplinary and preferably centralized. Pregnancy does not seem to influence the prognosis of breast cancer. All patients with pregnancy-associated breast cancer should be registered in a registration study. PMID- 23031244 TI - [Vulvar basal cell carcinoma with destructive consequences]. AB - BACKGROUND: Basal cell carcinoma is the most common form of skin cancer. Generally, the prognosis is relatively good and curative surgical treatment is accomplished in the great majority of patients. CASE DESCRIPTION: Here we report a case that illustrates the natural course of a vulvar basal cell carcinoma. It concerns an 80-year-old woman who was diagnosed with a so-called 'giant' vulvar basal cell carcinoma causing severe destruction of the anogenital anatomy. At the time of diagnosis, haematogenous metastases were strongly suspected and curative therapy was not possible. CONCLUSION: This case description illustrates that a basal cell carcinoma can transform into a 'giant' basal cell carcinoma if it is left untreated for many years. 'Giant' basal cell carcinomas carry a significantly higher risk of metastases than basal cell tumours smaller than 5 cm. In addition, 'giant' basal cell carcinoma is associated with higher morbidity and mortality rates. PMID- 23031245 TI - [Experimental treatment versus scientific research: data collection is not fundamentally different]. AB - The authors of a recent article in the Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine) suggest that experimental treatment should only be performed if the effects and side effects are monitored and described systematically, and a report is published. I believe this may intuitively be the right thing to do, but that there are nevertheless many problems. It would become impossible to differentiate experimental treatment from scientific research, resulting in problems concerning the informed consent of the patient, for example. Their approach would imply that more assessments are necessary for studying the effects of an experimental treatment than there would be in a standard treatment context. These measurements can only be performed with the informed consent of the patient. But if the patient refuses to consent, he or she will not receive the experimental treatment. This situation seriously compromises the voluntary status of informed consent. Therefore, more discussion is needed before this proposal is adopted. PMID- 23031247 TI - Perimetric and retinal nerve fiber layer findings in patients with Parkinson's disease. AB - BACKGROUND: Visual dysfunction is common in Parkinson's disease (PD). It remains, however, unknown whether it is related to structural alterations of the retina. The aim of this study is to compare visual field (VF) findings and circumpapillary retinal nerve fiber layer (RNFL) thickness in a series of PD patients and normal controls, in order to assess possible retinal anatomical changes and/or functional damage associated with PD. METHODS: PD patients and controls were recruited and underwent VF testing with static automated perimetry and RNFL examination with optical coherence tomography (OCT). Cognitive performance using Mini Mental State Examination (MMSE), PD staging using modified Hoehn and Yahr (H-Y) scale and duration of the disease was recorded in PD patients. RESULTS: One randomly selected eye from each of 24 patients and 24 age matched controls was included. OCT RNFL thickness analysis revealed no difference in the inferior, superior, nasal or temporal sectors between the groups. The average peripapillary RNFL was also similar in the two groups. However, perimetric indices of generalized sensitivity loss (mean deviation) and localized scotomas (pattern standard deviation) were worse in patients with PD compared to controls (p < 0.01). 73% of eyes of PD patients had glaucomatous-like asymmetrical hemifield defects with abnormal Glaucoma Hemifield Test and various combinations of arcuate defects (n = 12), nasal steps (n = 11) and paracentral scotomas (n = 16). Bilateral defects were found in 14 patients (58%). No correlation was found between VF indices and MMSE or H-Y scores. CONCLUSION: PD patients may demonstrate glaucomatous-like perimetric defects even in the absence of decreased RNFL thickness. PMID- 23031246 TI - New perspectives on neuronal development via microfluidic environments. AB - Understanding the signals that guide neuronal development and direct formation of axons, dendrites, and synapses during wiring of the brain is a fundamental challenge in developmental neuroscience. Discovery of how local signals shape developing neurons has been impeded by the inability of conventional culture methods to interrogate microenvironments of complex neuronal cytoarchitectures, where different subdomains encounter distinct chemical, physical, and fluidic features. Microfabrication techniques are facilitating the creation of microenvironments tailored to neuronal structures and subdomains with unprecedented access and control. The design, fabrication, and properties of microfluidic devices offer significant advantages for addressing unresolved issues of neuronal development. These high-resolution approaches are poised to contribute new insights into mechanisms for restoring neuronal function and connectivity compromised by injury, stress, and neurodegeneration. PMID- 23031248 TI - Transformation of tetracycline during chloramination: kinetics, products and pathways. AB - To assess the potential adverse effects stemming from tetracycline (TC) in drinking water or disinfected wastewater, the kinetics of the chloramination of TC was investigated at room temperature, the transformation products and pathways of their generation were elucidated, and their growth inhibiting properties towards sludge bacteria were assessed. The chloramination of TC exhibited pseudo first-order kinetics with the rate constants (k(obs)) ranging from 0.0082 to 0.041 min(-1) at pH of 6-8. Chloramination of TC generated at least 13 discernible products, and the structures of 12 products, including five chlorinated compounds, were identified using LC-ESI-MS. Two main pathways for the generation of these products were proposed: (1) chlorine substitution reactions followed by dehydration; and (2) oxidization by chloramine. The chlorinated products were proposed to be further degraded to small molecules via the scission of benzene rings of TC, and two oxidization products (2,11a-dihydroxy-keto-TC and 6,11-epoxy-2,11a-dihydroxy-TC) were the final products obtained under the experimental conditions. The chlorinated solution, even without detection of TC, exhibited greater than 80% of TC inhibitory effects towards sludge bacteria, suggesting potential effects on microorganisms in aquatic environment. PMID- 23031249 TI - Esophageal stent fixation with endoscopic suturing device (with video). PMID- 23031250 TI - Functional neural correlates of emotional expression processing deficits in behavioural variant frontotemporal dementia. AB - BACKGROUND: Frontotemporal dementia (FTD) is a neurodegenerative disorder resulting in social-cognitive deficits partially attributed to abnormalities processing social cues, such as facial expressions. However, to our knowledge, the functional neuroanatomy of deficient social cue processing in individuals with FTD has not been examined. The objective of this study was to delineate the functional abnormalities under lying altered facial expression processing in individuals with FTD using functional magnetic resonance imaging (fMRI). METHODS: Patients meeting Neary criteria for behavioural variant FTD (bvFTD) with supportive neuroimaging and 18 age-matched healthy controls completed an implicit facial expression task during fMRI. We conducted volumetric brain morphometry to correct functional imaging data for volume differences. RESULTS: We included 20 patients with bvFTD and 18 controls in our study. The results demonstrate emotion specific functional abnormalities in frontal and limbic regions in patients with bvFTD. Patients also showed decreased activity in posterior ventral visual regions, specifically the fusiform cortex, possibly reflecting reduced afferent input from limbic regions. Finally, bvFTD was associated with increased activity in posterior regions, including the inferior parietal cortex. LIMITATIONS: Autopsy validation of frontotemporal dementia is not yet available for this cohort. CONCLUSION: Together, these findings suggest that fMRI combined with tasks targeting social-cognitive deficits is a powerful technique to objectively measure neural systems involved in emotion processing in individuals with bvFTD. As viewing emotional expressions is known to engage many of the same neural systems that are active when experiencing the emotion itself, fMRI during expression processing provides a novel window into the emotions of patients with FTD. PMID- 23031251 TI - Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice. AB - BACKGROUND: The brain levels of glutamate (Glu) and glutamine (Gln) are partially regulated through the Glu-Gln cycle. Astrocytes play a role in regulating the Glu Gln cycle, and loss of astrocytes has been associated with depressive disorders. We hypothesized that levels of Glu and Gln would be affected by astrocyte loss and dysregulation of the Glu-Gln cycle and that depressive-like behaviours would be closely related to the level of changes in Glu and Gln. METHODS: We used liquid chromatography to measure Glu and Gln concentrations in the prefrontal cortex of male mice infused with L-alpha aminoadipic acid (L-AAA), a specific astrocyte toxin, in the prelimbic cortex. Methionine sulfoximine, a Gln synthetase inhibitor, and alpha-methyl-amino-isobutyric acid, a blocker of neuronal Gln transporters, were used to disturb the Glu-Gln cycle. We assessed the behavioural change by drug infusion using the forced swim test (FST) and sucrose preference test. RESULTS: The Glu and Gln levels were decreased on the fifth day after L-AAA infusion, and the infused mice showed longer durations of immobility in the FST and lower sucrose preference, indicative of depressive-like behaviour. Mice in which Gln synthetase or Gln transport were inhibited also exhibited increased immobility in the FST. Direct infusion of L-Gln reversed the increased immobility induced by astrocyte ablation and Glu-Gln cycle impairments. LIMITATIONS: Genetically modified animal models and diverse behavioural assessments would have been helpful to solidify our conclusions. CONCLUSION: Neuronal Gln deficiency in the prefrontal cortex may cause depressive behaviours. PMID- 23031253 TI - Formation of regularly spaced wetting ridges at 1 MUm intervals on the surface of a liquid-crystalline polymer. AB - A liquid-crystalline (LC) polymer melt coating a glass support shows a remarkable wetting ridge pattern resulting from a "stick-and-break" phenomenon when submerged into water at a velocity of 20 cm/s. A series of parallel, regularly spaced wetting ridges of 0.2 MUm height are formed perpendicular to the advancing direction of the plate at 1 MUm intervals, and the pattern continues over a wide area (1 * 2 cm(2)). The ridges function as a narrow line diffraction grating, similar to a prism that separates white light into the spectrum of colors. This process provides new insight into the controlled nanofabrication of polymers that is low-cost and high-throughput. PMID- 23031252 TI - Protocadherin alpha (PCDHA) as a novel susceptibility gene for autism. AB - BACKGROUND: Synaptic dysfunction has been shown to be involved in the pathogenesis of autism. We hypothesized that the protocadherin alpha gene cluster (PCDHA), which is involved in synaptic specificity and in serotonergic innervation of the brain, could be a suitable candidate gene for autism. METHODS: We examined 14 PCDHA single nucleotide polymorphisms (SNPs) for genetic association with autism in DNA samples of 3211 individuals (841 families, including 574 multiplex families) obtained from the Autism Genetic Resource Exchange. RESULTS: Five SNPs (rs251379, rs1119032, rs17119271, rs155806 and rs17119346) showed significant associations with autism. The strongest association (p < 0.001) was observed for rs1119032 (z score of risk allele G = 3.415) in multiplex families; SNP associations withstand multiple testing correction in multiplex families (p = 0.041). Haplotypes involving rs1119032 showed very strong associations with autism, withstanding multiple testing corrections. In quantitative transmission disequilibrium testing of multiplex fam - ilies, the G allele of rs1119032 showed a significant association (p = 0.033) with scores on the Autism Diagnostic Interview-Revised (ADI-R)_D (early developmental abnormalities). We also found a significant difference in the distribution of ADI-R_A (social interaction) scores between the A/A, A/G and G/G genotypes of rs17119346 (p = 0.002). LIMITATIONS: Our results should be replicated in an independent population and/or in samples of different racial backgrounds. CONCLUSION: Our study provides strong genetic evidence of PCDHA as a potential candidate gene for autism. PMID- 23031254 TI - Cocaine-induced loss of white matter proteins in the adult mouse nucleus accumbens is attenuated by administration of a beta-lactam antibiotic during cocaine withdrawal. AB - We report significantly decreased white matter protein levels in the nucleus accumbens in an adult mouse model of chronic cocaine abuse. Previous studies from human cocaine abuse patients show disruption of white matter and myelin loss, thus supporting our observations. Understanding the neuropathological mechanisms for white matter disruption in cocaine abuse patients is complicated by polydrug use and other comorbid factors, hindering the development of effective therapeutic strategies to ameliorate damage or compliment rehabilitation programs. In this context, our data further demonstrate that cocaine-induced loss of white matter proteins is absent in mice treated with the beta-lactam antibiotic, ceftriaxone, during cocaine withdrawal. Other studies report that ceftriaxone, a glutamate transporter subtype-1 activator, is neuroprotective in murine models of multiple sclerosis, thereby demonstrating potential therapeutic properties for diseases with white matter loss. Cocaine-induced white matter abnormalities likely contribute to the cognitive, motor, and psychological deficits commonly afflicting cocaine abusers, yet the underlying mechanisms responsible for these changes remain unknown. Our observations describe an adult animal model for the study of cocaine-induced myelin loss for the first time, and highlight a potential pharmacological intervention to ameliorate cocaine-induced white matter loss. PMID- 23031255 TI - Lipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration. AB - Cancer cell migration is an early event in metastasis, the main cause of breast cancer-related deaths. Cholesterol-enriched membrane domains called lipid rafts influence the function of many molecules, including the raft-associated protein CD44. We describe a novel mechanism whereby rafts regulate interactions between CD44 and its binding partner ezrin in migrating breast cancer cells. Specifically, in nonmigrating cells, CD44 and ezrin localized to different membranous compartments: CD44 predominantly in rafts, and ezrin in nonraft compartments. After the induction of migration (either nonspecific or CD44 driven), CD44 affiliation with lipid rafts was decreased. This was accompanied by increased coprecipitation of CD44 and active (threonine-phosphorylated) ezrin radixin-moesin (ERM) proteins in nonraft compartments and increased colocalization of CD44 with the nonraft protein, transferrin receptor. Pharmacological raft disruption using methyl-beta-cyclodextrin also increased CD44-ezrin coprecipitation and colocalization, further suggesting that CD44 interacts with ezrin outside rafts during migration. Conversely, promoting CD44 retention inside lipid rafts by pharmacological inhibition of depalmitoylation virtually abolished CD44-ezrin interactions. However, transient single or double knockdown of flotillin-1 or caveolin-1 was not sufficient to increase cell migration over a short time course, suggesting complex crosstalk mechanisms. We propose a new model for CD44-dependent breast cancer cell migration, where CD44 must relocalize outside lipid rafts to drive cell migration. This could have implications for rafts as pharmacological targets to down-regulate cancer cell migration. PMID- 23031256 TI - Unfolded protein response causes a phenotypic shift of inflamed glomerular cells toward redifferentiation through dual blockade of Akt and Smad signaling pathways. AB - During recovery from acute glomerulonephritis, cell proliferation, matrix expansion, and expression of the dedifferentiation marker alpha-smooth muscle actin (alpha-SMA) subside spontaneously. However, the molecular mechanisms underlying this recovery process remain elusive. In mesangioproliferative glomerulonephritis, the unfolded protein response (UPR) is induced in activated, dedifferentiated mesangial cells. We investigated the role of the UPR in mesangial cell deactivation and redifferentiation and found that, during experimental glomerulonephritis in rats, reinforcement of the UPR significantly attenuated mesangial cell proliferation, matrix expansion, and expression of alpha-SMA. Consistent with this in vivo result, induction of the UPR suppressed cell proliferation and transcriptional expression of type IV collagen (ColIV) and alpha-SMA in activated mesangial cells. The UPR reduced phosphorylation of Akt in vitro and in vivo, and it was responsible for attenuation of cell proliferation. The UPR also preferentially depressed levels of total and phosphorylated Smads without affecting transcriptional levels, and it was responsible for suppression of ColIV and alpha-SMA. Translational suppression via the eIF2alpha pathway, but not proteasome-mediated protein degradation, was responsible for the down regulation of Smads. These results suggest the novel potential of the UPR to facilitate a phenotypic shift of activated glomerular cells toward deactivation and redifferentiation. The UPR may serve as endogenous machinery that supports recovery of glomeruli from acute inflammation. PMID- 23031257 TI - The hedgehog system machinery controls transforming growth factor-beta-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog (SHH) pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor (TGF)-beta1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-beta pathway in human lung fibroblasts. TGF-beta1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-beta1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI dependent transcription in the nucleus, was required for the TGF-beta1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis. PMID- 23031258 TI - DNA methylation plasticity of human adipose-derived stem cells in lineage commitment. AB - Adult stem cells have an enormous potential for clinical use in regenerative medicine that avoids many of the drawbacks characteristic of embryonic stem cells and induced pluripotent stem cells. In this context, easily obtainable human adipose-derived stem cells offer an interesting option for future strategies in regenerative medicine. However, little is known about their repertoire of differentiation capacities, how closely they resemble the target primary tissues, and the potential safety issues associated with their use. DNA methylation is one of the most widely recognized epigenetic factors involved in cellular identity, prompting us to consider how the analyses of 27,578 CpG sites in the genome of these cells under different conditions reflect their different natural history. We show that human adipose-derived stem cells generate myogenic and osteogenic lineages that share much of the DNA methylation landscape characteristic of primary myocytes and osteocytes. Most important, adult stem cells and in vitro generated myocytes and osteocytes display a significantly different DNA methylome from that observed in transformed cells from these tissue types, such as rhabdomyosarcoma and osteosarcoma. These results suggest that the plasticity of the DNA methylation patterns plays an important role in lineage commitment of adult stem cells and that it could be used for clinical purposes as a biomarker of efficient and safely differentiated cells. PMID- 23031260 TI - Human multipotent adult progenitor cells are nonimmunogenic and exert potent immunomodulatory effects on alloreactive T-cell responses. AB - Multipotent adult progenitor cells (MAPCs) are bone marrow-derived nonhematopoietic stem cells with a broad differentiation potential and extensive expansion capacity. A comparative study between human mesenchymal stem cells (hMSCs) and human MAPCs (hMAPCs) has shown that hMAPCs have clearly distinct phenotypical and functional characteristics from hMSCs. In particular, hMAPCs express lower levels of MHC class I than hMSCs and cannot only differentiate into typical mesenchymal cell types but can also differentiate in vitro and in vivo into functional endothelial cells. The use of hMSCs as cellular immunomodulatory stem cell products gained much interest since their immunomodulatory capacities in vitro became evident over the last decade. Currently, the clinical grade stem cell product of hMAPCs is already used in clinical trials to prevent graft-versus host disease (GVHD), as well as for the treatment of acute myocardial infarct, ischemic stroke, and Crohn's disease. Therefore, we studied the immune phenotype, immunogenicity, and immunosuppressive effect of hMAPCs in vitro. We demonstrated that hMAPCs are nonimmunogenic for T-cell proliferation and cytokine production. In addition, hMAPCs exert strong immunosuppressive effects on T-cell alloreactivity and on T-cell proliferation induced by mitogens and recall antigens. This immunomodulatory effect was not MHC restricted, which makes off the-shelf use promising. The immunosuppressive effect of hMAPCs is partially mediated via soluble factors and dependent on indoleamine 2,3-dioxygenase (IDO) activity. At last, we isolated hMAPCs, the clinical grade stem cell product of hMAPCs, named MultiStem, and hMSCs from one single donor and observed that both the immunogenicity and the immunosuppressive capacities of all three stem cell products are comparable in vitro. In conclusion, hMAPCs have potent immunomodulatory properties in vitro and can serve as a valuable cell source for the clinical use of immunomodulatory cellular stem cell product. PMID- 23031259 TI - Short-term akt activation in cardiac muscle cells improves contractile function in failing hearts. AB - Akt is a serine/threonine protein kinase that is activated by a variety of growth factors or cytokines in a phosphatidylinositol 3-kinase-dependent manner. By using a conditional transgenic system in which Akt signaling can be turned on or off in the adult heart, we previously showed that short-term Akt activation induces a physiological form of cardiac hypertrophy with enhanced coronary angiogenesis and maintained contractility. Here we tested the hypothesis that induction of physiological hypertrophy by short-term Akt activation might improve contractile function in failing hearts. When Akt signaling transiently was activated in murine hearts with impaired contractility, induced by pressure overload or doxorubicin treatment, contractile dysfunction was attenuated in both cases. Importantly, improvement of contractility was observed before the development of cardiac hypertrophy, indicating that Akt activation improves contractile function independently of its growth-promoting effects. To gain mechanistic insights into Akt-mediated positive inotropic effects, transcriptional profiles in the heart were determined in a pressure overload induced heart failure model. Biological network analysis of differentially expressed transcripts revealed significant alterations in the expression of genes associated with cell death, and these alterations were reversed by short-term Akt activation. Thus, short-term Akt activation improves contractile function in failing hearts. This beneficial effect of Akt on contractility is hypertrophy independent and may be mediated in part by inhibition of cell death associated with heart failure. PMID- 23031261 TI - Clostridium septicum growth from a total knee arthroplasty associated with intestinal malignancy: a case report. AB - BACKGROUND: Previous reports of infection with Clostridium septicum have identified an unexpected association with concurrent malignancy. The reported rate of associated malignancy has been found to be as high as 81 percent. The purpose of this case report was to present a case of a total knee arthroplasty infected with C. septicum and the subsequent finding of an occult colonic malignancy. CASE PRESENTATION: A 74 year-old man underwent uneventful bilateral total knee arthroplasties. Two weeks post-operatively, he presented with acute swelling, redness and pain of the left knee. Aspiration of the knee was sent for cell count and culture. The cell count demonstrated 39,000 white blood cells per cubic millimeter with 71% of white blood cells identified as neutrophils. Synovial fluid cultures identified the presence of C. septicum, Enterobacter and coagulase negative Staphylococcus. After urgent irrigation and debridement and polyethylene exchange of the affected knee, the patient was placed on intravenous Penicillin G for a period of six weeks. Two weeks into his course of antibiotics, the patient developed hematochezia and was found to have an obstructive colonic malignancy. The patient underwent hemi-colectomy and has since made a complete recovery of both his malignancy and total knee arthroplasty infection. CONCLUSION: Recognition of the association between C. septicum and malignancy is especially important considering the large predicted increase in total joint arthroplasty procedures over the coming decades. In addition to the standard treatment for infection after total joint arthroplasty, identification of Clostridium septicum should initiate a search for associated occult malignancy. PMID- 23031262 TI - The effect of protein kinase C activator and nitric oxide donor on oocyte activation and cortical granule exocytosis in porcine eggs. AB - Nitric oxide (NO) and protein kinase C (PKC) are involved in the activation of mammalian oocytes, although their role in the exit from the metaphase II stage and cortical granule (CG) exocytosis is still not fully understood. The aim of this study was to verify whether the NO-donor together with specific PKC activators induce the complete activation of porcine oocytes assessed as meiosis resumption and a cortical reaction. Pig maturated oocytes were treated with the NO-donor S-nitroso-N-acetylpenicillamine (SNAP, 2 mM) or PKC-activators such as phorbol-12-myristate-13-acetate (PMA, 100 nM), 1-oleoyl-2-acetyl-sn-glycerol (OAG, 400 MUM) and l-alpha-phosphatidylinositol-3,4,5-trisphosphate dipalmitoyl heptaammonium salt (DPAM, 2 MUM). To study the combined effect of NO-donor and PKC-activators, aliquots of oocytes were also incubated with SNAP (0.5 mM) together with PKC-activators at the same concentration as above (SNAP-DPAM, SNAP OAG and SNAP-PMA groups). After in vitro maturation, an aliquot of oocytes was placed in a fresh medium without NO-donor or PKC-activators (Control group). Another aliquot of oocytes was activated by calcium ionophore A23187 (25 MUM, 5 min). The results showed that 0% of the control oocytes reassumed meiosis. However, both the PKC-activators (DPAM 44.0 +/- 10.0%, OAG 63.3 +/- 1.0% and PMA 45.0 +/- 16.5%) as well as the NO-donor alone (48.7 +/- 21.0%) significantly induced exit from MII. Interestingly, the combination of PKC-activators and SNAP mainly restrained to the meiosis resumption (SNAP-OAG 0, SNAP-DPAM 17.4 +/- 2.5% and SNAP-PMA 38.4 +/- 8.5%). Control oocytes did not show a cortical reaction and the area occupied by CG reached 25.9 +/- 1.7%, whereas CGs were partially released after Ca2+ ionophore treatment (13.0 +/- 3.2%). Treatment with PKC activators induced a cortical reaction compared with the control group (8.6 +/- 2.5, 6.7 +/- 1.9 and 0.7 +/- 0.4%, respectively, for DPAM, OAG and PMA groups). However, treatment with the NO-donor alone (SNAP group 17.2 +/- 2.2%) or combined with any PKC-activator prevented cortical reaction (SNAP-DPAM 20.7 +/- 2.6%, SNAP OAG 16.7 +/- 2.9% or SNAP-PMA 20.0 +/- 2.4%). Besides, meiosis resumption was not always accompanied by a cortical reaction, indicating that these two activation events are independent. In conclusion, PKC-activators alone induce CG exocytosis to the same degree as calcium ionophore. However, an NO-donor alone or combined with PKC-activators is not able to induce a cortical reaction in pig oocytes. PMID- 23031263 TI - Perspective: Protein supplementation against sarcopenia and frailty: future perspectives from novel data. PMID- 23031264 TI - Falls related to accidental deactivation of deep brain stimulators in patients with Parkinson's disease living in long term care facilities. AB - This case series highlights three patients with Parkinson's disease residing at nursing home facilities whose deep brain stimulators were accidentally deactivated for varying lengths of time, which was associated with an increase in falls. In all three cases, neither the patients nor the caregivers were aware of the random deactivations/reactivations. We propose a specific care plan for these patients that includes further education of caregivers regarding deep brain stimulators and regular checks of the review device, especially when there is concern about a patient's mobility or balance that is out of character. PMID- 23031265 TI - Impact of the raising immunizations safely and effectively (RISE) program on healthcare worker influenza immunization rates in long term care settings. AB - INTRODUCTION AND RATIONALE: National influenza immunization rates for healthcare workers (HCW) in long-term care (LTC) remain unacceptably low. This poses a serious public health threat to residents. Prior work has suggested high staff turnover rates as a contributing factor to low immunization rates. There is a critical need to identify and deploy successful models of HCW influenza immunization programs to LTC facilities. This report describes one potential model that has been successfully initiated in a network of LTC facilities. METHODS: All facilities served by a single regional LTC pharmacy were invited to participate in a HCW influenza immunization program. This voluntary immunization program began in 2005 and continues to the present. As part of the program, the pharmacy promoted organizational change by assuming oversight and control of HCW immunization policies and processes for all facilities. Primary and secondary outcomes are the number of facilities reaching HCW influenza immunization rates of 60% and 80%. RESULTS: Fourteen of the 16 LTC facilities participated. Facilities were diverse and included both nursing and assisted living facilities; unionized and nonunionized facilities; and urban, suburban, and rural facilities. The pharmacy provided educational and communication materials, centralized data collection using a standardized definition for HCW immunization rates, and facility feedback. All 14 LTC facilities achieved the primary goal of 60% and nearly two thirds reached the secondary goal of 80%. Twenty percent reached the new Healthy People 2020 goal of 90%. CONCLUSION: It is possible for LTC facilities to improve HCW immunization rates using a pharmacy based, voluntary HCW influenza immunization approach. Such an approach may help attenuate the negative influence of staff turnover on HCW immunizations. Attainment of the new Health People 2020 goals still remains a challenge and may require mandatory programs. PMID- 23031266 TI - A study of antimicrobial activity, acute toxicity and cytoprotective effect of a polyherbal extract in a rat ethanol-HCl gastric ulcer model. AB - BACKGROUND: The decoction of the aerial parts of Rhynchosia recinosa (A.Rich.) Bak. [Fabaceae] is used in combination with the stem barks of Ozoroa insignis Del. (Anacardiaceae), Maytenus senegalensis (Lam.) Excell. [Celastraceae] Entada abyssinica Steud. ex A.Rich [Fabaceae] and Lannea schimperi (Hochst.)Engl. [Anacardiaceae] as a traditional remedy for managing peptic ulcers. However, the safety and efficacy of this polyherbal preparation has not been evaluated. This study reports on the phytochemical profile and some biological activities of the individual plant extracts and a combination of extracts of the five plants. METHODS: A mixture of 80% ethanol extracts of R. recinosa, O. insignis, M. senegalensis, E. abyssinica and L. schimperi at doses of 100, 200, 400 and 800 mg/kg body wt were evaluated for ability to protect Sprague Dawley rats from gastric ulceration by an ethanol-HCl mixture. Cytoprotective effect was assessed by comparison with a negative control group given 1% tween 80 in normal saline and a positive control group given 40 mg/kg body wt pantoprazole. The individual extracts and their combinations were also tested for antibacterial activity against four Gram negative bacteria; Escherichia coli (ATCC 25922), Salmonella typhi (NCTC 8385), Vibrio cholerae (clinical isolate), and Klebsiella pneumoniae (clinical isolate) using the microdilution method. In addition the extracts were evaluated for brine shrimp toxicity and acute toxicity in mice. Phytochemical tests were done using standard methods to determine the presence of tannins, saponins, steroids, cardiac glycosides, flavonoids, alkaloids and terpenoids in the individual plant extracts and in the mixed extract of the five plants. RESULTS: The combined ethanolic extracts of the 5 plants caused a dose-dependent protection against ethanol/HCl induced ulceration of rat gastric mucosa, reaching 81.7% mean protection as compared to 87.5% protection by 40 mg/kg body wt pantoprazole. Both the individual plant extracts and the mixed extracts of 5 plants exhibited weak to moderate antibacterial activity against four G-ve bacteria. Despite Ozoroa insignis being toxic to mice at doses above 1000 mg/kg body wt, the other plant extracts and the combined extract of the 5 plants were tolerated by mice up to 5000 mg/kg body wt. The brine shrimp test results showed the same pattern of toxicity with Ozoroa insignis being the most toxic (LC50 = 10.63 MUg/ml). Phytochemical tests showed that the combined extract of the five plants contained tannins, saponins, steroids, cardiac glycosides, flavonoids and terpenoids. Flavonoids, tannins and terpenoids are known to have antioxidant activity. CONCLUSION: The combined extract of the five plants exhibited a dose dependent protective activity in the rat ethanol-HCl gastric ulcer model. The extracts also exhibited weak antibacterial activity against four Gram negative bacteria and low acute toxicity in mice and brine shrimps. Although the results support claims by traditional healers who use a decoction of the five plants for treatment of peptic ulcers, more models of gastric ulceration and proper animal toxicity studies are needed to validate possible clinical use of the polyherbal extract. It is also evident that the doses of the crude extracts showing protection of the gastric mucosa are too large for realistic translation to direct clinical application, but further studies using bioassay guided fractionation are important to either identify more practical fractions or active compound/s. PMID- 23031267 TI - Evaluation of on-farm veal calves' responses to unfamiliar humans and potential influencing factors. AB - The human-animal relationship is an important component of the welfare of farm animals and for this reason animal responsiveness tests to humans are included in on-farm welfare assessment schemes that provide indicators for this. However, apart from the behaviour of stockpersons towards their animals, other factors may also influence animals' reactivity to humans as observed through behavioural tests, which can add a further layer of complexity to the interpretation of test results. Knowledge of these factors may help a better interpretation of differences from one farm to another in the outcome of human-animal relationship tests, and may provide clues for improving the relationship between animals and humans. The main objective of this study was to identify whether management or environmental factors could influence the outcome of human-animal relationship tests in veal calves. Two tests were performed when calves were aged 14.9 +/- 1.6 (SD) weeks in 148 veal farms: the voluntary approach of an unfamiliar human standing at the feeding fence and the reaction towards an unfamiliar human who entered the home pen and tried to touch each calf in a standardised way (Calf Escape Test (CET) - score 0 to 4). Questionnaires were filled in and interviews with the stockpersons were performed in order to obtain information on stockpersons, management, animal and building characteristics. The latency to touch an unfamiliar human at the feeding fence was significantly correlated with the CET scores. Total number of calves on the farm, space allowance, breed, environmental enrichment, stockperson's experience and season of observation influenced the percentage of calves that scored 0 in CET (i.e. calves that could not be approached). Type of milk distribution, type of breed and number of calves per stockperson influenced the percentage of calves that scored 4 in CET (i.e. calves could be touched). For both CET0 and CET4, the level of self-reported contacts by the stockperson (analysed only on the French subset of 36 farms) did not influence the results. This paper concludes that according to the tests conducted on veal calves on commercial farms, factors such as milk distribution method, breed of the calves or the level of experience of stockpersons with veal farming can have an impact on the results of tests focusing on human-animal relationships. PMID- 23031268 TI - Prediction of beef eating quality in France using the Meat Standards Australia system. AB - An experiment was set up for (i) comparing Australian and French consumer preferences to beef and to (ii) quantify how well the Meat Standards Australia (MSA) grading model could predict the eating quality of beef in France. Six muscles from 18 Australian and 18 French cattle were tested as paired samples. In France, steaks were grilled 'medium' or 'rare', whereas in Australia 'medium' cooking was used. In total, 360 French consumers took part in the 'medium' cooking test, with each eating half Australian beef and half French beef and 180 French consumers tested the 'rare' beef. Consumers scored steaks for tenderness (tn), juiciness (ju), flavour liking (fl) and overall liking (ov). They also assigned a quality rating to each sample: 'unsatisfactory', 'satisfactory everyday quality' (3*), 'better than everyday quality' (4*) or 'premium quality' (5*). The prediction of the final ratings (3*, 4*, 5*) by the French consumers using the MSA-weighted eating quality score (0.3 tn + 0.1 ju + 0.3 fl + 0.3 ov) was over 70%, which is at least similar to the Australian experience. The boundaries between 'unsatisfactory', 3*, 4* and 5* were found to be ca. 38, 61 and 80, respectively. The differences between extreme classes are therefore slightly more important in France than in Australia. On average, even though it does not have predictive equations for bull meat, the mean predicted scores calculated by the MSA model deviated from observed values by a maximum of 5 points on a 0 to 100 scale except for the Australian oyster blade and the French topside, rump and outside (deviating by <15). Overall, the data indicate that it would be possible to manage a grading system in France as there is high agreement and consistency across consumers. The 'rare' and 'medium' results are also very similar, indicating that a common set of weightings and cut-offs can be employed. PMID- 23031269 TI - Effects of feeding a single or sequence of beta-adrenergic agonists on cull cow meat quality. AB - Sixty cull cows were implanted and assigned to four treatments: C = concentrate ration only; RH = supplemented with ractopmaine-HCl (8.33 mg/kg of feed) for 25 d; ZH = supplemented with zilpaterol-HCl (ZH) (200mg head (-1)d(-1)) for the last 20 d; and RH + ZH = supplemented with RH for 25 d followed by ZH for 20 d. All cows were fed a concentrate ration for 74 d. Infraspinatus steaks from cows supplemented with RH and/or ZH had lower (P<0.05) shear force than steaks from C cows. Longissimus (LM) steaks from the 6-8th rib section of ZH and RH+ZH cows had decreased (P<0.0001) desmin degradation at 10 and 21 d postmortem compared to steaks from C and RH cows. Collagen solubility of the LM was increased (P<0.05) by ZH and RH+ZH compared to C. There were no treatment differences in 12th rib LM tenderness when enhanced with calcium lactate. Color and sensory traits of meat from RH+ZH cows were not different from C but flavor intensity was greater and off-flavor less than for C cows. PMID- 23031270 TI - Kinetics of nitrite evaluated in a meat product. AB - The evaluation of the efficiency with which the reactions involving nitrite proceed in mortadella and of the effect exercised on their kinetics by some variables (ingoing amount of sodium nitrite and temperature) is the purpose of this work. Kinetics parameters were calculated at each level of nitrite added (40, 70, 100 and 150 mg/kg) and at five temperature (55 degrees , 60 degrees , 65 degrees , 70 degrees and 72 degrees C). While the colour formation reaction is favoured by low activation energy, it becomes crucial to enable nitrite to proceed according to direct reduction thus preventing an increase in nitrate concentration as well as an excess of nitric oxide in the product. Kinetics data suggest that this scope is performed when the product achieves the temperature of 65 degrees C as fast as possible with an ingoing amount of sodium nitrite of 70 mg/kg. PMID- 23031271 TI - Rumen microbial (meta)genomics and its application to ruminant production. AB - Meat and milk produced by ruminants are important agricultural products and are major sources of protein for humans. Ruminant production is of considerable economic value and underpins food security in many regions of the world. However, the sector faces major challenges because of diminishing natural resources and ensuing increases in production costs, and also because of the increased awareness of the environmental impact of farming ruminants. The digestion of feed and the production of enteric methane are key functions that could be manipulated by having a thorough understanding of the rumen microbiome. Advances in DNA sequencing technologies and bioinformatics are transforming our understanding of complex microbial ecosystems, including the gastrointestinal tract of mammals. The application of these techniques to the rumen ecosystem has allowed the study of the microbial diversity under different dietary and production conditions. Furthermore, the sequencing of genomes from several cultured rumen bacterial and archaeal species is providing detailed information about their physiology. More recently, metagenomics, mainly aimed at understanding the enzymatic machinery involved in the degradation of plant structural polysaccharides, is starting to produce new insights by allowing access to the total community and sidestepping the limitations imposed by cultivation. These advances highlight the promise of these approaches for characterising the rumen microbial community structure and linking this with the functions of the rumen microbiota. Initial results using high-throughput culture-independent technologies have also shown that the rumen microbiome is far more complex and diverse than the human caecum. Therefore, cataloguing its genes will require a considerable sequencing and bioinformatic effort. Nevertheless, the construction of a rumen microbial gene catalogue through metagenomics and genomic sequencing of key populations is an attainable goal. A rumen microbial gene catalogue is necessary to understand the function of the microbiome and its interaction with the host animal and feeds, and it will provide a basis for integrative microbiome-host models and inform strategies promoting less-polluting, more robust and efficient ruminants. PMID- 23031272 TI - Tumor biobanks in translational medicine. AB - The concept of tissue banking as a "bio-repository" aimed to collection, storing and distribution of human biological material and clinical information, is emerging as a successful strategy to support clinical and translational research. In particular, Tumor Biobanks represent a key resource for diagnosis, research and experimental therapies, especially for those correlated to clinical application of a new type of medicine known as "intelligent drugs". Biobanks are not "spontaneous" collections, but they needs an institutional organization, basically a research unit, whose effectiveness and quality can be guaranteed only if it is carefully organized according to precise and shared rules. PMID- 23031273 TI - Functional analysis of GNG2 in human malignant melanoma cells. AB - BACKGROUND: Previous studies have revealed that heterotrimeric G protein is composed of a Galpha-subunit and a Gbetagamma-dimer and is correlated with c-Src and AKT activities. Our recent study showed reduced G protein gamma2 subunit (Gng2/GNG2) expression levels in malignant melanoma cells compared with those in benign melanocytic cells in both mice and humans. At present, however, there is no evidence showing an effect of Gng2/GNG2 alone on cancer biology. OBJECTIVE: The purpose of this study was to examine the biological significance of GNG2 in human malignant melanoma cells. METHODS: Levels of proliferation and activities of signal transduction molecules were examined in both GNG2-overexpressed and depleted human malignant melanoma cells. RESULTS: Proliferation of GNG2 overexpressed SK-Mel28 human malignant melanoma cells was suppressed with decreased c-SRC and AKT activities and increased p21(Cip/WAF1) expression level in vitro. In contrast, proliferation of GNG2-depleted A375P human malignant melanoma cells was enhanced with increased c-SRC and AKT activities and decreased p21(Cip/WAF1) expression level in vitro. In the in vivo experiment, the mean tumor size of GNG2-overexpressed SK-Mel28 cells was less than 1/45th of that of control SK-Mel28 cells in nude mice at 95 days after inoculation. CONCLUSION: We demonstrated for the first time that increased protein expression level of GNG2 alone inhibits proliferation of malignant melanoma cells in vitro and in vivo, suggesting that GNG2 could be a novel molecular target for malignant melanoma therapy. PMID- 23031274 TI - Wildlife uses and hunting patterns in rural communities of the Yucatan Peninsula, Mexico. AB - BACKGROUND: Subsistence hunting is a traditional practice providing food and many other goods for households in the Yucatan Peninsula, southeast Mexico. Economic, demographic, and cultural change in this region drive wildlife habitat loss and local extinctions. Improving our understanding about current practices of wildlife use may support better management strategies for conserving game species and their habitat. We aimed to evaluate if wildlife use remained relevant for the subsistence of rural residents of the Yucatan Peninsula, as well as if local hunting practices were related to environmental, geographical, and cultural factors. METHODS: Fieldwork was done between March 2010 and March 2011. Information was obtained through conversations, interviews, and participant observation. Record forms allowed recording animals hunted, biomass extracted, distance intervals to hunting sites, habitat types and seasonality of wildlife harvests. Data were analyzed using one-way Analysis of Variance, and Generalized Linear Models. RESULTS: Forty-six terrestrial vertebrate species were used for obtaining food, medicine, tools, adornments, pets, ritual objects, and for sale and mitigating damage. We recorded 968 animals taken in 664 successful hunting events. The Great Curassow, Ocellated Turkey, paca, white-tailed deer, and collared peccary were the top harvested species, providing 80.7% of biomass (10,190 kg). The numbers of animals hunted and biomass extracted declined as hunting distances increased from villages. Average per capita consumption was 4.65 +/- 2.7 kg/person/year. Hunting frequencies were similar in forested and agricultural areas. DISCUSSION: Wildlife use, hunting patterns, and technologies observed in our study sites were similar to those recorded in previous studies for rural Mayan and mestizo communities in the Yucatan Peninsula and other Neotropical sites. The most heavily hunted species were those providing more products and by-products for residents. Large birds such as the Great Curassow and the Ocellated Turkey were extremely important for local hunters, representing around 40% of total prey taken. FINAL CONSIDERATIONS: Our results suggest that hunting is frequent in our study areas. Low human densities allow low hunting pressure on most game species and favor conservation of the tropical forest. We suggest that co-management may help regulating hunting, prioritizing cultural practices of sustainable use and conservation for benefiting local users and animal populations. PMID- 23031275 TI - Physicians' perceptions on the usefulness of contextual information for prioritizing and presenting alerts in Computerized Physician Order Entry systems. AB - BACKGROUND: One possible approach towards avoiding alert overload and alert fatigue in Computerized Physician Order Entry (CPOE) systems is to tailor their drug safety alerts to the context of the clinical situation. Our objective was to identify the perceptions of physicians on the usefulness of clinical context information for prioritizing and presenting drug safety alerts. METHODS: We performed a questionnaire survey, inquiring CPOE-using physicians from four hospitals in four European countries to estimate the usefulness of 20 possible context factors. RESULTS: The 223 participants identified the 'severity of the effect' and the 'clinical status of the patient' as the most useful context factors. Further important factors are the 'complexity of the case' and the 'risk factors of the patient'. CONCLUSIONS: Our findings confirm the results of a prior, comparable survey inquiring CPOE researchers. Further research should focus on implementing these context factors in CPOE systems and on subsequently evaluating their impact. PMID- 23031276 TI - Intrauterine crowding impairs formation and growth of secondary myofibers in pigs. AB - There are indications that intrauterine crowding may cause intrauterine growth retardation with the possibility of an impaired myofiber hyperplasia. The aim of the study was to confirm this by generating large differences in uterine space using sows that were unilaterally hysterectomized-ovariectomized (HO; crowded) or unilaterally oviduct ligated (OL; non-crowded). In the study, seven HO and seven OL Swiss Large White third parity sows were used. At farrowing, litter size and litter birth weight were determined. Subsequently, within each litter two male and two female progenies each with the respectively lowest (L) and highest (H) birth weight were sacrificed. Internal organs and brain were weighed, and longissimus (LM) and semitendinosus muscle (SM) samples were collected. Histological analyses were performed in both muscles using mATPase staining after preincubation at pH 4.3 and 10.2. Myosin heavy chain (MyHC) polymorphism was determined in the LM by means of SDS-PAGE. The number of piglets born alive was similar in both sow groups, but litter size expressed per uterine horn was lower (P < 0.05) in OL than HO sows. Consequently, OL progeny were markedly heavier (P < 0.01). Regardless of gender, the organs, the brain and the SM were heavier (P < 0.001) in OL and H compared with HO and L offspring, respectively. Compared with HO pigs, the SM of OL offspring tended (P < 0.1) to have more myofibers, which were of larger (P < 0.05) size. However, myofiber density appeared to be lower (P < 0.1) in the SM of OL than HO pigs. The impact of birth weight on myofiber characteristics was limited to the lower (P < 0.05) myofiber density in the SM and the larger (P < 0.01) myofiber size in the light portion of the SM of H than L offspring, whereas myofiber hyperplasia did not differ between birth weight categories. The SM, but not the LM, of male offspring had a greater (P < 0.05) myofiber density. This did not affect total SM myofiber number. The relative abundance of fetal and type I MyHC in the LM was lower (P < 0.05) and that of type II MyHC was greater (P < 0.001) in OL than HO pigs. The current data suggest that regardless of birth weight and gender, in the LM and SM of individuals born from a crowded environment, not only hyperplasia but also hypertrophy of myofibers is impaired and their maturity seems delayed. PMID- 23031277 TI - VarioML framework for comprehensive variation data representation and exchange. AB - BACKGROUND: Sharing of data about variation and the associated phenotypes is a critical need, yet variant information can be arbitrarily complex, making a single standard vocabulary elusive and re-formatting difficult. Complex standards have proven too time-consuming to implement. RESULTS: The GEN2PHEN project addressed these difficulties by developing a comprehensive data model for capturing biomedical observations, Observ-OM, and building the VarioML format around it. VarioML pairs a simplified open specification for describing variants, with a toolkit for adapting the specification into one's own research workflow. Straightforward variant data can be captured, federated, and exchanged with no overhead; more complex data can be described, without loss of compatibility. The open specification enables push-button submission to gene variant databases (LSDBs) e.g., the Leiden Open Variation Database, using the Cafe Variome data publishing service, while VarioML bidirectionally transforms data between XML and web-application code formats, opening up new possibilities for open source web applications building on shared data. A Java implementation toolkit makes VarioML easily integrated into biomedical applications. VarioML is designed primarily for LSDB data submission and transfer scenarios, but can also be used as a standard variation data format for JSON and XML document databases and user interface components. CONCLUSIONS: VarioML is a set of tools and practices improving the availability, quality, and comprehensibility of human variation information. It enables researchers, diagnostic laboratories, and clinics to share that information with ease, clarity, and without ambiguity. PMID- 23031278 TI - Association of circulating levels of MMP-8 with mortality from respiratory disease in patients with rheumatoid arthritis. AB - INTRODUCTION: Matrix metalloproteinases (MMPs) are implicated in the destruction of the joint and have been shown to be strongly associated with inflammation in rheumatoid arthritis (RA). Circulating MMPs have also been associated with cardiovascular disease in the general population, and are predictive of cardiovascular mortality. The purpose of the present study was to determine whether circulating levels of MMPs are predictive of mortality in RA. METHODS: A multiplex suspension array system (Luminex(r)) was used to measure levels of MMPs (1, 2, 3, 8 and 9) in sera taken at recruitment of RA patients (n = 487) in a study of factors associated with mortality in RA. Patients were tracked on the National Health Service Central Register for notification of death, and the relationship between baseline MMP levels and mortality was analysed using Cox proportional hazards regression analysis. RESULTS: At the time of follow-up, 204/486 patients had died, of which 94 (46.1%) had died of circulatory diseases, 49 of malignancy (24.0%), and 42 (20.6%) of respiratory diseases. In a stepwise analysis which included all MMPs, only MMP-8 was significantly associated with all cause mortality (P = 0.0007, 0.6% hazard ratio increase per ng/ml). No association was found between MMP levels and mortality due to circulatory disease or malignancy. However MMP-8 levels were strongly associated with mortality due to respiratory disease (P < 0.0001, 1.3% hazard ratio increase per ng/ml). The association with respiratory disease related mortality remained highly significant in multivariate models which included smoking as well as markers of severity and disease activity such as rheumatoid factor, nodular disease, and C reactive protein (CRP). CONCLUSIONS: The serum level of MMP-8 is a strong predictor of mortality in RA, especially that due to respiratory disease. This finding is consistent with increased activation of neutrophils in RA and identifies serum MMP-8 as a useful marker for increased risk of premature death. PMID- 23031279 TI - Attitudes of UK psychiatrists to the diagnosis of MCI in clinical practice. AB - BACKGROUND: Mild cognitive impairment (MCI) may represent a transitional stage between normal functioning and dementia. Following the initial criteria developed by Petersen et al. in 1999, which focused on memory deficit in the context of otherwise normal cognition and general functioning, the concept has evolved with the introduction of subtypes of MCI and improved understanding of etiology. Our aim was to investigate current practice as well as familiarity with and attitudes toward the concept of MCI amongst UK old age psychiatrists. METHOD: We sent an anonymized postal survey to all clinicians on the Royal College of Psychiatrists Old Age Psychiatry register. Questions covered attitudes toward the concept of MCI in addition to diagnostic criteria and assessment tools used. RESULTS: The response rate was 39% (453 of 1,154 questionnaires returned completed). The majority of respondents were consultants (83%) and 91% diagnosed MCI. Only 4.4% of the respondents thought that the concept of MCI was not useful and 79% of them required a memory complaint from either the patient or an informant for a diagnosis, but the majority did not have a specific cut-off on cognitive testing. Eighty-two percent reported that they required no or minimal impairment in activities of daily living for a diagnosis of MCI. The two most frequently used tools for assessment were the Mini-Mental State Examination and the Addenbrooke's Cognitive Examination-Revised. CONCLUSIONS: Our survey shows that in the United Kingdom, the term MCI has become part of everyday clinical practice in psychiatry, suggesting that clinicians find it a useful term to conceptualize the transitional stage between normal aging and dementia. However, there is variability in diagnostic practice. PMID- 23031280 TI - Myocardial damages and left and right ventricular strains after an extreme mountain ultra-long duration exercise. PMID- 23031281 TI - Anemia, heart failure and exercise training. PMID- 23031282 TI - Prevalence and spectrum of GATA5 mutations associated with congenital heart disease. PMID- 23031283 TI - First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. AB - BACKGROUND: Sympathetic overactivation, is reduced by renal denervation in drug resistant hypertension. A similar role for renal denervation in heart failure remains unstudied, partly due to the concern about potential concomitant deleterious blood pressure reductions. This pilot study evaluated the safety of renal denervation for heart failure using an intensive follow-up protocol. METHOD: 7 patients (mean age 69 years) with chronic systolic heart failure (mean BP on referral 112/65 mmHg) on maximal tolerated heart failure therapy underwent bilateral renal denervation May-July 2011. Patients were admitted for pre procedure baseline assessments and in-patient observation for 5 days following denervation. Follow-up was weekly for 4 weeks, and then monthly for 6 months. RESULTS: No significant haemodynamic disturbances were noted during the acute phase post renal denervation. Over 6 months there was a non-significant trend to blood pressure reduction (Deltasystolic -7.1 +/- 6.9 mmHg, p=0.35; Deltadiastolic -0.6 +/- 4.0 mmHg, p=0.88). No hypotensive or syncopal episodes were reported. Renal function remained stable (Deltacreatinine -5.7 +/- 8.4 MUmol/l, p=0.52 and Deltaurea -1.0 +/- 1.0 mmol/l, p=0.33). All 7 patients described themselves as symptomatically improved. The six minute walk distance at six months was significantly increased (Delta=27.1 +/- 9.7 m, p=0.03), with each patient showing an increase. CONCLUSIONS: This study found no procedural or post procedural complications following renal denervation in patients with chronic systolic heart failure in 6 months of intensive follow-up. Results suggested improvements in both symptoms and exercise capacity, but further randomised, blinded sham controlled clinical trials are required to determine the impact of renal denervation on morbidity and mortality in systolic heart failure. These data suggest such trials will be safe. ClinicalTrial.gov NCT01584700 PMID- 23031284 TI - Optical coherence tomography (OCT) as an adjunct to percutaneous coronary intervention; a single centre experience. PMID- 23031285 TI - Left ventricular twist in clinically stable heart transplantation recipients: a speckle tracking echocardiography study. AB - BACKGROUND AND AIM: Cavity twist is an integral part of LV function and its pattern in transplanted hearts is not well known. This study aimed at exploring LV twist in clinically stable heart transplant (HT) recipients with no evidence for rejection. METHODS: We studied 32 HT patients (54 +/- 24 months after HT), 34 other cardiac surgery (CS) patients and compared them with 35 health controls using speckle tracking echocardiography, measuring peak twist angle, time-to-peak twist, and untwist rate. RESULTS: LV twist angle was smaller in the HT group (6.2 +/- 3.3 degrees ) in comparison with the CS group and controls (13.2 +/- 3.5 degrees and 13.1 +/- 4.5 degrees , respectively; p<0.0001 for all) and untwist rate was reduced (HT group: -74 +/- 30 degrees /s; CS group: -118 +/- 43 degrees /s; controls: -116 +/- 39 degrees /s; p<0.0001 for all). Time-to-peak twist was not different between groups. Time after HT was the main independent predictor of both LV twist angle and untwist rate (beta=0.8, p<0.0001). CONCLUSION: Though clinically stable, LV twist dynamics are significantly impaired in HT recipients, even in comparison with patients who underwent other cardiac surgery. PMID- 23031286 TI - Novel insights into the development of chagasic cardiomyopathy: role of PI3Kinase/NO axis. AB - BACKGROUND: Chagas' disease is one of the leading causes of heart failure in Latin American countries. Despite its great social impact, there is no direct evidence in the literature explaining the development of heart failure in Chagas' disease. Therefore, the main objective of the study was to investigate the development of the Chagas' disease towards its chronic phase and correlate with modifications in the cellular electrophysiological characteristics of the infected heart. METHODS AND RESULTS: Using a murine model of Chagas' disease, we confirmed and extended previous findings of altered electrocardiogram and echocardiogram in this cardiomyopathy. The observed changes in the electrocardiogram were correlated with the prolonged action potential and reduced transient outward potassium current density. Reduced heart function was associated with remodeling of intracellular calcium handling, altered extracellular matrix content, and to a set of proteins involved in the control of cellular contractility in ventricular myocytes. Furthermore, disruption of calcium homeostasis was partially due to activation of the PI3Kinase/nitric oxide signaling pathway. Finally, we propose a causal link between the inflammatory mediators and heart remodeling during chagasic cardiomyopathy. CONCLUSION: Altogether our results demonstrate that heart failure in Chagas' disease may occur due to electrical and mechanical remodeling of cardiac myocytes, and suggest that AKT/PI3K/NO axis could be an important pharmacological target to improve the disease outcome. PMID- 23031287 TI - Restored cardiac function after successful resynchronization by right anterior and anteroseptal accessory pathway ablation in Wolff-Parkinson-White syndrome associated dilated cardiomyopathy. PMID- 23031288 TI - Hypertension trends in Chinese children in the national surveys, 1993 to 2009. PMID- 23031289 TI - Eligibility of patients with atrial fibrillation for new oral anticoagulants. PMID- 23031290 TI - Statins and atrial fibrillation in patients with left ventricular dysfunction: insights from the AF-CHF trial. PMID- 23031291 TI - Integrated modelling and monitoring at different river basin scales under global change. PMID- 23031292 TI - Modelling native fish richness to evaluate the effects of hydromorphological changes and river restoration (Jucar River Basin, Spain). AB - The richness of native fish is considered to be an indicator of aquatic ecosystem health, and improving richness is a key goal in the management of river ecosystems. An artificial neural network (ANN) model based on field data from 90 sample sites distributed throughout the Jucar River Basin District was developed to predict the native fish species richness (NFSR). The Levenberg-Marquardt learning algorithm was used for model training. When constructing the model, we tried different numbers of neurons (hidden layers), compared different transfer functions, and tried different k values (from 3 to 10) in the k-fold cross validation method. This process and the final selection of key variables with relevant ecological meaning support the reliability and robustness of the final ANN model. The partial derivatives method was applied to determine the relative importance of input environmental variables. The final ANN model combined variables describing riparian quality, water quality, and physical habitat and helped identify the primary drivers of the NFSR patterns in Mediterranean rivers. In the second part of the study, the model was used to evaluate the effectiveness of two restoration actions in the Jucar River: the removal of two abandoned weirs and the progressive increase in the proportion of riffles. The model indicated that the combination of these actions produced a rise in NFSR, which ultimately reached the maximum values observed in the reference site of that river ecotype (sensu the European Water Framework Directive). The results demonstrate the importance of longitudinal connectivity and riffle proportion for improving NFSR and the power of ANNs to help decisions in the management and ecological restoration of Mediterranean rivers. Furthermore, this model at the basin scale is the first step for further research on the effects of water scarcity and global change on Mediterranean fish communities. PMID- 23031293 TI - Linking in-stream nutrient flux to land use and inter-annual hydrological variability at the watershed scale. AB - The significance of nutrient inputs at the watershed scale is best expressed in terms of in-stream processes, compared to evaluating simple field measurements of nutrient inputs. Modeling tools are necessary to consider the complexity of river networks in the determination of the sources and processes by which nutrients are transported at the watershed scale. Mediterranean rivers are potentially vulnerable to climate change (decrease in precipitation and increase of extreme events), and identifying and quantifying nutrient pollution sources and their spatial distribution can improve water resource management at the watershed scale. We apply a hybrid process-based and statistical model (SPARROW, spatially referenced regression on watershed attributes) to a largely disturbed Mediterranean watershed in NE Spain in order to estimate the annual nitrate and phosphate loads reaching the drainage network. The model emphasized the contribution of in-stream processes in nutrient transport and retention, and the inter-annual (7 years) effects of hydrological variability on the export of nutrients from the landscape to water bodies. Although forest and grassland land cover types predominate, agricultural activities and human agglomerations were significant sources of nutrient enrichment. Nutrient flux apportionment was also linked to inter-annual hydrological variability. Exported nutrient load increased in the downstream direction and coincided with decreased in-stream nutrient removal, probably worsened by the significant chemical and geomorphological impairment found in the lower parts of the watershed. PMID- 23031294 TI - Cognitive correlates of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression--a pilot study. AB - BACKGROUND: The aim of the current study was to investigate the cognitive correlates of repetitive transcranial magnetic stimulation (rTMS) in 10 treatment resistant depression patients. METHODS: Patients received forty 20-min sessions of fast-frequency (10 Hz) rTMS of the left dorsolateral prefrontal cortex (DLPFC) over 20 days. Concept-shift ability (accuracy and duration of performance) was assessed daily with a Modified Concept-Shifting Task (mCST) in patients and in eight healthy volunteers. General cognitive functioning test (Repeatable Battery for the Assessment of Neuropsychological Status; RBANS), Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HAM-D) were applied before the first and after the last rTMS. RESULTS: Compared to before rTMS on the first 10 days, the patients performed the mCST significantly more accurately after rTMS on the last 10 days (p < .001, partial eta squared=.78) while the same comparison in healthy volunteers was not statistically significant (p = .256, partial eta squared=.18). A significant improvement in immediate memory on RBANS and reduction in BDI and HAM-D scores were also observed after the last compared to before the first rTMS. CONCLUSION: The rTMS is associated with an improvement in selective cognitive functions that is not explained by practice effects on tasks administered repeatedly. TRIAL REGISTRATION: Name: "Repetitive Transcranial Magnetic Stimulation (rTMS) in the treatment of depression, assessed with HAM-D over a four week period."URL: www.actr.org.au REGISTRATION NUMBER: ACTRN012605000145606. PMID- 23031295 TI - [Deaths related to physical restraint of very agitated persons should be possible to avoid]. PMID- 23031296 TI - [Nationwide Survey of Patient Experiences--respecting patients]. PMID- 23031297 TI - [Sudden deaths by hobble restraint of severely hyperactive persons]. AB - Cardiac arrest may occur while persons are being kept in hobble restraint. It has been suggested that asphyxia caused by the restraint position, so-called restraint asphyxia, is the cause, but experimental evidence has not confirmed this theory. Some of the sudden deaths are associated with excited delirium syndrome (EDS), an acute condition characterized by a hyperactive, combative behaviour in individuals, who are influenced by psychoactive drugs or suffer from psychiatric illness. Autopsy findings fail to explain this type of deaths. The pathophysiology of EDS is complex and poorly understood. Sensibilisation of the heart by a hyperadrenergic autonomous dysfunction, metabolic acidosis and hyperthermia offer possible mechanisms. PMID- 23031298 TI - [The National Danish Survey of Patient Experiences has a small positive bias]. AB - The response rate in The National Danish Survey of Patient Experiences in 2009 was 54%. In order to evaluate bias due to non-responders, The Unit of Patient perceived Quality merged survey data and data on patient background from Statistics Denmark. The relationships between the responding patients' background and their answers to six questions in the survey questionnaire are estimated with logistic regression analysis and subsequently used for predicting the answers of the non-responders. Results indicate a small positive bias in four of the questions and no bias in the remaining two. PMID- 23031299 TI - [Chronic constipation in adults]. AB - Constipation is generally sufficiently treated with dietary modifications, lifestyle changes, and peroral laxatives. New pharmacological treatments are promising, but still need to prove their benefits. Anal physiology tests and colonic transit studies can further categorize the disease into three main groups: slow transit constipation, obstructed defaecation and normal transit constipation. More advanced treatment includes biofeedback, transanal irrigation, antegrade colonic irrigation and sacral nerve stimulation. Stoma surgery is only indicated very rarely. PMID- 23031300 TI - [Splenic marginal zone lymphoma]. AB - Splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes is a low-grade malignant lymphoma, which primarily involves the spleen, the bone marrow and the blood. Even though the prognosis of the disease is good and there is a long overall survival, about two thirds of the patients will require treatment and in 10% of the patients the lymphoma will transform into a high grade malignant lymphoma. The treatment of SMZL remains empirical, since there is lack of large, prospective studies. Without such studies, the best treatment modality cannot be established. PMID- 23031301 TI - [Lethal course following overlooked foreign body in the airway]. AB - A 52-year-old previously healthy woman suffered death from choking. Asphyxia after aspiration of a foreign body is a well-known, but frequently overlooked cause of sudden death. We describe a case in which a foreign body in the airway was initially overlooked. Early recognition and treatment might have altered the outcome. PMID- 23031302 TI - [Neurological symptoms following infusion of infliximab]. AB - Infliximab is indicated for treatment of plaque psoriasis when traditional systemic therapy is inadequate or inappropriate. The treatment is efficient but also carries a risk of serious adverse drug events. We describe a case of neurological symptoms following the first infusion of infliximab in a patient treated for plaque psoriasis. The patient fully recovered after sensation of the therapy. We believe the symptoms could be related to infliximab and stress the importance of thorough information of patients treated with tumour necrosis factor-alpha-inhibitors, also about the risk of serious adverse events. PMID- 23031303 TI - [Pyomyositis caused by Streptococcus pneumoniae in a previously healthy 20-year old man]. AB - Pyomyositis is a bacterial infection of the skeletal muscle usually caused by Staphylococcus aureus. This case report presents a 20-year-old man with pyomyositis caused by Streptococcus pneumoniae. Pyomyositis is a rare but potentially critical disease, and early diagnosis, drainage and use of appropriate antibiotic therapy are essential to reduce morbidity and mortality. However, early diagnosis of pyomyositis can be challenging as initial symptoms may be vague, but the condition should be suspected in patients with acute onset of severe, localised muscle pain and fever. PMID- 23031304 TI - [Primary hyperparathyroidism can be mistaken as pregnancy inconvenience]. AB - This case report describes a pregnant woman with severe primary hyperparathyroidism. The symptoms, mainly nausea and vomiting, were not recognized as symptoms of hypercalcaemia, but ascribed to the pregnancy. As she was diagnosed, parathyroidectomy was performed and the symptoms ceased. Primary hyperparathyroidism in pregnancy can among other things cause pregnancy loss, intrauterine growth retardation and neonatal tetanus caused by hypocalcaemia. The case demonstrates the need for measuring serum calcium in pregnant women with severe hyper emesis and a record of unexplained miscarriages. PMID- 23031305 TI - Qualitative dermatoglyphic traits in monozygotic and dizygotic twins of Albanian population in Kosovo. AB - Dermatoglyphs are polygenetically determined epidermal ridge configurations on the fingers, palms and soles. An analysis of the digito-palmar dermatoglyphics obtained from 69 pairs of same-sex twins (32 monozygotic and 37 dizygotic) was performed in the population of Kosovo. Qualitative traits on the fingers (whorls, arches, radial and ulnar loops) and palms (pattern frequencies in the thenar/I, II, III and IV interdigital areas and hypothenar, the frequencies of positions of axial triradius) of both hands were analysed. The homolateral and heterolateral concordance of dermatoglyphic patterns between twin pairs were calculated for the monozygotic and dizygotic twins separately. The estimates of heritability for qualitative dermatoglyphic traits and the impacts of twin's shared (c(2)) and non shared (individual) environments (e(2)) were presented. According to our results, the heritability patterns sharply distinguish highly heritable dermatoglyphic traits (patterns on the thenar and I interdigital area, II interdigital area and all the digits) and the traits with weak genetic component (patterns on the III and IV interdigital area, the hypothenar and the axial triradius position). In addition, the concordance and the heritability estimates in twins correspond to the embryonic growth of fingers (from the first to the fifth finger) and palm patterns (the II interdigital area). Based on findings presented here, we expect that the noxious environmental factors (possibly causing diseases later in life) would leave traces on the dermatoglyphs, which could be recognized as the increased dissimilarity of the twins (and other relatives) in the III and IV interdigital area, hypothenar, and in axial triradius position. PMID- 23031306 TI - The equine periodontium: the (re)model tissue. PMID- 23031307 TI - Proliferative enteropathy in foals: disease, diagnostics and transmission. PMID- 23031308 TI - Histopathological and immunohistochemical assessment of invasive micropapillary mammary carcinoma in dogs: a retrospective study. AB - Invasive micropapillary carcinoma (IMPC) of the mammary gland, despite its rare occurrence in humans and dogs, is an important neoplasm due to its aggressive behaviour. The aim of this study was to evaluate the clinicopathological and immunophenotypical characteristics of IMPC and to determine the overall survival of dogs with this tumour. Of the selected cases, the majority had >3 cm neoplasms (15/19, 78.95%) and lymph node metastases (16/16, 100%), but only two cases (2/9, 22.2%) had distant metastases. The IMPCs were classified as either pure (15/22, 68.18%) or mixed (7/22, 31.82%) types. There was a predominance of moderate histological grade tumours (16 grade II) and the average overall survival was 120 days. Positive immunohistochemical staining for epithelial membrane antigen and negative staining for CD-31, p63 and cytokeratin (CK) AE1AE3 in cystic formations confirmed the micropapillary nature of these neoplasms. A proportion of cases exhibited positive epithelial staining for p63 (4/20, 20%) and CK34betaE12 (20/22, 90.9%). Most cases were positive for oestrogen (19/20, 95%) and progesterone (19/20, 95%) receptors, but lacked HER-2 (16/22, 72.72%) and epidermal growth factor receptor (15/22, 68.18%) over-expression. The mean proliferation index was 14.8%. The findings demonstrate that, similar to humans, canine IMPCs behave aggressively with high rates of metastasis to regional lymph nodes and short overall survival times. PMID- 23031309 TI - Osteomyelitis pubis caused by Kingella kingae in an adult patient: report of the first case. AB - BACKGROUND: Kingella kingae is the second most common pathogen causing paediatric arthritis and is described to be the causative bacteria in some paediatric osteomyelitis. Its microbiological detection is particularly difficult due to its slow growing. To our best knowledge this is the first case description of osteomyelitis pubis caused by this microorganism. CASE PRESENTATION: We report the unusual case of pubic osteomyelitis with soft tissue abcess caused by Kingella kingae in an adult patient of 66 years with a history of end-stage renal disease and breast carcinoma. Diagnosis was based on imaging and the microorganism was isolated from Computed Tomography-guided aspiration of synovial fluid. The infection resolved completely after twelve weeks of treatment with oral amoxicillin. CONCLUSION: This case description highlights the importance in osteoarticular infections of systematic inoculation of synovial liquid in BACTEC vials to optimise the detection of causative organisms, which can necessitate specific treatments. PMID- 23031310 TI - Pyrethroids cypermethrin, deltamethrin and fenvalerate have different effects on in vitro maturation of pig oocytes at different stages of growth. AB - Pesticides can significantly harm reproduction in animals and people. Pyrethroids are often used as insecticides, and their toxicity for mammals is considered to be low. However, cypermethrin, deltamethrin and fenvalerate - as potent specific inhibitors of protein phosphatase calcineurin - can influence the meiosis of mammalian oocytes. The objective of this study was to evaluate the effects of these pyrethroids on the in vitro maturation of pig oocytes at different levels of meiotic competence. Under the tested concentrations, cypermethrin, deltamethrin and fenvalerate neither had a significant effect on the viability of oocytes nor did they induce significant degeneration of oocytes. However, these pyrethroids significantly affected meiotic maturation. The effects depended on the stage of meiotic competence of the oocytes. Maturation of growing pig oocytes with partial meiotic competence was induced. On the other hand, in fully grown pig oocytes with full meiotic competence, maturation in vitro was delayed. The specificity of these effects was further supported by the same effect of non pyrethroidal inhibitors of calcineurin - cyclosporin A or hymenistatin I - on the maturation of oocytes with different levels of meiotic competence. However, pyrethroids, which do not inhibit calcineurin - allethrin or permethrin - had no effect on pig oocyte maturation. We demonstrated a significant effect of pyrethroids on the maturation of mammalian oocytes under in vitro conditions. This indicates that exposure to these substances could affect the fertility of people or animals. PMID- 23031313 TI - Effect of forage particle length on rumen fermentation, sorting and chewing activity of late-lactation and non-lactating dairy cows. AB - The objective of this study was to determine the effects of varying forage particle length on chewing activity, sorting behavior, rumen pH and rumen fill in late lactation and dry dairy cattle, fed rations with similar physically effective NDF but different mean particle length. Treatments consisted of three diets differing only in geometric mean length of forage: hay (5.40, 8.96 and 77.90 mm, for short (S), medium (M) and long (L) diets, respectively) for Experiment 1 (E1), and straw (10.16, 24.68 and 80.37 mm) for S, M and L diets, respectively, for Experiment 2 (E2). Hay or straw comprised the sole source of forage (50% and 75% of ration dry matter (DM) for E1 and E2, respectively). Both experiments used three rumen cannulated Holstein dairy cows, in late lactation for E1 and dry in E2, with 3 * 3 Latin square designs with 14 day periods. In E1, DM intake (DMI; 18.3 +/- 2.1 kg/day; mean +/- s.e.), pH (6.4 +/- 0.1), time spent eating (280 +/- 22.5 min/day), time spent ruminating (487 +/- 17 min/day), and total time spent chewing (767 +/- 34 min/day) were not different, whereas eating minutes per kilogram of DMI and NDF intake (NDFI) tended to increase linearly as forage length increased. Rumen digesta volume (l; 113.3 S, 117.8 M and 114.4 L +/ 17.1) had a quadratic response, and rumen digesta weight tended to respond quadratically; however, differences were numerically small. In E2, DMI (8.3 +/- 1.3 kg/day), pH (6.7 +/- 0.1), time spent eating (236 +/- 23.5 min/day), time spent ruminating (468 +/- 45.2 min/day), total time spent chewing (704 +/- 67.7 min/day) and minutes per kilogram NDFI were not different, whereas minutes per kilogram of DMI had a trend for a quadratic effect. Rumen digesta volume (111 +/- 18.8 l) and weight (103 +/- 17.4 kg) were not different. In both experiments, cows sorted against longer particles as determined by a particle length selection index; this behavior increased linearly as particle length increased. Greater forage particle length increased sorting behavior, but had no effect on rumen fermentation or chewing behavior. PMID- 23031311 TI - Longitudinal course and impact of insomnia symptoms in adolescents with and without chronic pain. AB - This study aimed to 1) examine trajectories of insomnia symptoms in adolescents with chronic pain compared to their healthy peers; 2) evaluate psychological and behavioral risk factors for longitudinal insomnia symptoms; and 3) evaluate insomnia as a predictor of quality of life, activity limitations, and healthcare utilization over 12 months. Participants included 61 adolescents with chronic pain and 60 youths without chronic pain (12-18 years; 72% female). Questionnaires were completed at enrollment, 6 months, and 12 months and assessed pain intensity, insomnia symptoms, sleep hygiene, presleep arousal, depression, pubertal status, activity limitations, quality of life, and healthcare utilization. Insomnia symptoms persisted for both groups and remained higher at all time points for youths with chronic pain. Generalized estimating equations modeling identified 3 risk factors for longitudinal insomnia symptoms: having chronic pain, poorer sleep hygiene, and higher depressive symptoms. Insomnia symptoms also predicted poorer quality of life over time and were associated with more frequent healthcare utilization. Findings suggest that sleep problems are persistent and associated with negative impact for youths with chronic pain. Treatment of insomnia symptoms in youths with chronic pain may lead to improvements in quality of life and reductions in healthcare costs. PERSPECTIVE: Insomnia symptoms are persistent over a 12-month period and are associated with negative impact for youths with chronic pain. These findings suggest that treatment of insomnia symptoms in youths with chronic pain may lead to improvements in quality of life and reductions in healthcare costs. PMID- 23031312 TI - Identification of the transcript isoforms and expression characteristics for chicken Lpin1. AB - Lpin1 was a gene with important effects on controlling lipid/energy metabolism in humans and mice. However, little was known about chicken Lpin1 gene. In the present study, two transcript isoforms of chicken Lpin1 were identified. Lpin1 alpha was predicted encoding one 902 amino acid protein, whereas Lpin1-delta was predicted encoding one 918 amino acid protein with an insertion of 48-bp fragment from intron 12 of chicken Lpin1-alpha, and a conservative element was found to be located in intron 12 of chicken Lpin1-alpha genomic sequence. Ten variants were identified from chicken Lpin1-alpha coding sequence, and two missense mutations were predicted to affect the protein function of Lpin1. Reverse transcription PCR (RT-PCR) analysis revealed that chicken total Lpin1, Lpin1-alpha and Lpin1-delta were expressed in all analyzed tissues, and presented clear tissue expression differences. Real-time quantitative RT-PCR revealed that 30% energy restriction significantly elevated the total Lpin1 mRNA expression level in hepatic (P < 0.01) and adipose (P < 0.01) tissues of birds. Chicken total Lpin1 gene mRNA expression level presented a significantly inverse correlation with some traits including abdominal fat rate (P < 0.01), serum high-density lipoprotein (P < 0.05) and total cholesterol (P < 0.05), which would make a foundation for the further study on chicken Lpin1 gene function. PMID- 23031314 TI - Vanishing left ventricular thrombus in a woman with peripartum cardiomyopathy: a case report. AB - BACKGROUND: Peripartum cardiomyopathy (PPCM) is a rare cardiac disorder characterized by the development of heart failure in the last month of pregnancy or up to 5 months postpartum in women without other identifiable causes of cardiac failure. The combination of left ventricular (LV) systolic dysfunction and hypercoaguability can cause thromboembolic complications including intra cardiac thrombi. CASE PRESENTATION: A 25-year-old Caucasian female with PPCM demonstrated multiple thrombi in the LV on transthoracic echocardiography. Following anticoagulation with parenteral heparin, a cardiac MRI four days later demonstrated near resolution of the thrombi. CONCLUSION: We review the presentation, diagnosis and management of LV thrombi in the clinical setting of PPCM. PMID- 23031316 TI - [Duration of breastfeeding from 15 maternity wards of the perinatal network in the Pays de la Loire area]. AB - The "securite naissance - naitre ensemble" network in the Pays de la Loire region of France, with 24 maternity units, conducted a survey of nursing women to determine the duration of breastfeeding and to study the factors influencing this practice. Phone calls were made to mothers at 1 month, 2 months, 3 months, and 6 months or until weaning. The statistical methods used were the Kaplan-Meier survival curve method with the calculation of the median duration of breastfeeding (exclusive or partial) in weeks, and the Cox multivariate model. The hazard ratio or relative risk (RR) was used in univariate analysis, and the adjusted odds ratio (aOR) in multivariate analysis (>1 related to short duration, and<1 related to long duration). Fifteen maternity units participated, and 239 women were followed. The median duration of breastfeeding was 15 weeks (3.5 months) with 10% discontinuing the first month and 25% continuing breastfeeding at 6 months. The final model of risk of duration contains the following variables: maternal age less than 30 years (aOR=1.54; 1.08-2.19), the time the decision was made before pregnancy (aOR=0.56; 0.38-0.83), BMI greater or equal to 30 (aOR=2.12 (1.18-3.79), and for the first month, the administration of bottle feeding or complements (aOR=2.51; 1.62-3.89), the baby's need to be stimulated to feed (aOR=5.07; 3.24-7.90), breastfeeding on demand (aOR=0.56; 0.39-0.82), and problems breastfeeding (aOR=1.45; 1.005-2.09). This survey to determine the duration of breastfeeding in western France, a region with low initiation rates, duration appears to be relatively long compared to other studies. The factors influencing breastfeeding duration were for some non-modifiable (age, time of the decision, etc.), and for others assistance by a professional (supplements, need for stimulation, difficulty sucking, breastfeeding on demand, etc.). Criteria for identifying difficulties are presented. PMID- 23031317 TI - Effect of stage of maturity of grass at harvest on intake, chewing activity and distribution of particle size in faeces from pregnant ewes. AB - This study was conducted to investigate the effect of stage of maturity at harvest on the intake of grass silage, eating and ruminating activity and the distribution of faecal particle size in ewes during late pregnancy. A total of 18 Swedish Finull x Dorset 85 +/- 8 kg (mean 6 +/- s.d.) ewes bearing twins were randomly assigned to three dietary treatments 6 weeks before lambing. The treatments included ad libitum feeding with early harvested (EH), medium harvested (MH) or late harvested (LH) primary-growth grass silage with 45%, 58% and 63% NDF on a dry matter (DM) basis, respectively. Intake and chewing activity were recorded and faeces were sampled over 4 continuous days for each individual ewe. The faeces samples were washed in nylon bags, freeze dried and sieved with pore sizes from 2.4mm to 0.1 mm; particles less than 0.1mm in size were also collected. Subsamples of each sieving fraction were scanned and the dimensions of the individual particles in each sieving fraction were measured by image analysis. In addition, the number of particles longer than 7 mm was counted from the particles retained on a sieve with a pore size of 2.4mm using a simple wet sieving technique. The time spent eating and ruminating per kg of DM intake was affected by the stage of maturity at harvest; it was shorter in ewes fed EH compared with ewes fed MH and LH ( P < 0.05). In comparison with feeding LH, feeding EH resulted in the retention of a larger proportion of particles in the lower and upper sieve fractions (< 0.2mm and > 1 mm, respectively, P < 0.01), a smaller mean particle size ( P < 0.05) and a smaller mean particle width in faeces ( P < 0.01). The results from the simple wet sieving technique confirmed the results from dry sieving and image analysis, showing a higher number of large particles in faeces from ewes fed the EH compared with the ewes fed the MH and LH (P < 0.001). In conclusion, the distribution of faecal particle size might be considered as a footprint of the characteristics of forage fibre eaten by ewes. PMID- 23031315 TI - Atomistic simulations of the optical absorption of type-II CdSe/ZnTe superlattices. AB - We perform accurate tight binding simulations to design type-II short-period CdSe/ZnTe superlattices suited for photovoltaic applications. Absorption calculations demonstrate a very good agreement with optical results with threshold strongly depending on the chemical species near interfaces. PMID- 23031318 TI - Proteomic profiling of secreted proteins for the hematopoietic support of interleukin-stimulated human umbilical vein endothelial cells. AB - Human umbilical cord vein endothelial cells (HUVECs) secrete a number of factors that greatly impact the proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). These factors remain largely unknown. Here, we report on the most comprehensive proteomic profiling of the HUVEC secretome and identified 827 different secreted proteins. Two hundred and thirty-one proteins were found in all conditions, whereas 369 proteins were identified only under proinflammatory conditions following IL-1beta, IL-3, and IL-6 stimulation. Thirteen proteins including complement factor b (CFb) were identified only under IL-1beta and IL-3 conditions and may potentially represent HSPC proliferation factors. The combination of bioinformatics and gene ontology annotations indicates the role of the complement system and its activation. Furthermore, CFb was found to be transcriptionally strongly upregulated. Addition of complement component 5b-9 (C5b-9) monoclonal antibody to the stem cell expansion assay was capable of significantly reducing their proliferation. This study suggests a complement-mediated cross-talk between endothelial cells and HSPCs under proinflammatory conditions. PMID- 23031320 TI - Normalized N50 assembly metric using gap-restricted co-linear chaining. AB - BACKGROUND: For the development of genome assembly tools, some comprehensive and efficiently computable validation measures are required to assess the quality of the assembly. The mostly used N50 measure summarizes the assembly results by the length of the scaffold (or contig) overlapping the midpoint of the length-order concatenation of scaffolds (contigs). Especially for scaffold assemblies it is non-trivial to combine a correctness measure to the N50 values, and the current methods for doing this are rather involved. RESULTS: We propose a simple but rigorous normalized N50 assembly metric that combines N50 with such a correctness measure; assembly is split into as many parts as necessary to align each part to the reference. For scalability, we first compute maximal local approximate matches between scaffolds and reference in distributed manner, and then proceed with co-linear chaining to find a global alignment. Best alignment is removed from the scaffold and the process is iterated with the remaining scaffold content in order to split the scaffold into correctly aligning parts. The proposed normalized N50 metric is then the N50 value computed for the final correctly aligning parts. As a side result of independent interest, we show how to modify co-linear chaining to restrict gaps to produce a more sensible global alignment. CONCLUSIONS: We propose and implement a comprehensive and efficient approach to compute a metric that summarizes scaffold assembly correctness and length. Our implementation can be downloaded from http://www.cs.helsinki.fi/group/scaffold/normalizedN50/. PMID- 23031319 TI - Comparison of the efficacy of autogenous inactivated Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) vaccines with that of commercial vaccines against homologous and heterologous challenges. AB - BACKGROUND: The porcine reproductive and respiratory syndrome virus (PRRSV) is a rapidly evolving pathogen of swine. At present, there is a high demand for safe and more effective vaccines that can be adapted regularly to emerging virus variants. A recent study showed that, by the use of a controlled inactivation procedure, an experimental BEI-inactivated PRRSV vaccine can be developed that offers partial protection against homologous challenge with the prototype strain LV. At present, it is however not known if this vaccine can be adapted to currently circulating virus variants. In this study, two recent PRRSV field isolates (07 V063 and 08 V194) were used for BEI-inactivated vaccine production. The main objective of this study was to assess the efficacy of these experimental BEI-inactivated vaccines against homologous and heterologous challenge and to compare it with an experimental LV-based BEI-inactivated vaccine and commercial inactivated and attenuated vaccines. In addition, the induction of challenge virus-specific (neutralizing) antibodies by the different vaccines was assessed. RESULTS: In a first experiment (challenge with 07 V063), vaccination with the experimental homologous (07 V063) inactivated vaccine shortened the viremic phase upon challenge with approximately 2 weeks compared to the mock-vaccinated control group. Vaccination with the commercial attenuated vaccines reduced the duration of viremia with approximately one week compared to the mock-vaccinated control group. In contrast, the experimental heterologous (LV) inactivated vaccine and the commercial inactivated vaccine did not influence viremia. Interestingly, both the homologous and the heterologous experimental inactivated vaccine induced 07 V063-specific neutralizing antibodies upon vaccination, while the commercial inactivated and attenuated vaccines failed to do so.In the second experiment (challenge with 08 V194), use of the experimental homologous (08 V194) inactivated vaccine shortened viremia upon challenge with approximately 3 weeks compared to the mock-vaccinated control group. Similar results were obtained with the commercial attenuated vaccine. The experimental heterologous (07 V063 and LV) inactivated vaccines did not significantly alter viremia. In this experiment, 08 V194-specific neutralizing antibodies were induced by the experimental homologous and heterologous inactivated vaccines and a faster appearance post challenge was observed with the commercial attenuated vaccine. CONCLUSIONS: The experimental homologous inactivated vaccines significantly shortened viremia upon challenge. Despite the concerns regarding the efficacy of the commercial attenuated vaccines used on the farms where the field isolates were obtained, use of commercial attenuated vaccines clearly shortened the viremic phase upon challenge. In contrast, the experimental heterologous inactivated vaccines and the commercial inactivated vaccine had no or only a limited influence on viremia. The observation that homologous BEI-inactivated vaccines can provide a more or less standardized, predictable degree of protection against a specific virus variant suggests that such vaccines may prove useful in case virus variants emerge that escape the immunity induced by the attenuated vaccines. PMID- 23031321 TI - Sequential detection of influenza epidemics by the Kolmogorov-Smirnov test. AB - BACKGROUND: Influenza is a well known and common human respiratory infection, causing significant morbidity and mortality every year. Despite Influenza variability, fast and reliable outbreak detection is required for health resource planning. Clinical health records, as published by the Diagnosticat database in Catalonia, host useful data for probabilistic detection of influenza outbreaks. METHODS: This paper proposes a statistical method to detect influenza epidemic activity. Non-epidemic incidence rates are modeled against the exponential distribution, and the maximum likelihood estimate for the decaying factor lambda is calculated. The sequential detection algorithm updates the parameter as new data becomes available. Binary epidemic detection of weekly incidence rates is assessed by Kolmogorov-Smirnov test on the absolute difference between the empirical and the cumulative density function of the estimated exponential distribution with significance level 0 <= alpha <= 1. RESULTS: The main advantage with respect to other approaches is the adoption of a statistically meaningful test, which provides an indicator of epidemic activity with an associated probability. The detection algorithm was initiated with parameter lambda0 = 3.8617 estimated from the training sequence (corresponding to non-epidemic incidence rates of the 2008-2009 influenza season) and sequentially updated. Kolmogorov-Smirnov test detected the following weeks as epidemic for each influenza season: 50-10 (2008-2009 season), 38-50 (2009-2010 season), weeks 50-9 (2010-2011 season) and weeks 3 to 12 for the current 2011-2012 season. CONCLUSIONS: Real medical data was used to assess the validity of the approach, as well as to construct a realistic statistical model of weekly influenza incidence rates in non-epidemic periods. For the tested data, the results confirmed the ability of the algorithm to detect the start and the end of epidemic periods. In general, the proposed test could be applied to other data sets to quickly detect influenza outbreaks. The sequential structure of the test makes it suitable for implementation in many platforms at a low computational cost without requiring to store large data sets. PMID- 23031323 TI - Carcass and meat quality traits of rabbits under heat stress. AB - Rabbits are very sensitive to heat stress because they have difficulty eliminating excess body heat. The objective of the current study was to evaluate the effects of heat stress on slaughter weight, dressing percentage and carcass and meat quality traits of rabbits from two genetic groups. Ninety-six weaned rabbits were used: half were from the Botucatu genetic group and half were crossbreds between New Zealand White sires and Botucatu does. They were assigned to a completely randomized design in a 2 * 3 factorial arrangement (two genetic groups and three ambient temperatures: 18 degrees C, 25 degrees C and 30 degrees C) and kept under controlled conditions in three environmental chambers from 5 to 10 weeks of age. Slaughter took place at 10 weeks, on 2 consecutive days. Meat quality measurements were made in the longissimus muscle. Actual average ambient temperature and relative humidity in the three chambers were 18.4 degrees C and 63.9%, 24.4 degrees C and 80.2% and 29.6 degrees C and 75.9%, respectively. Purebred rabbits were heavier at slaughter and had heavier commercial and reference carcasses than crossbreds at 30 degrees C; however, no differences between genetic groups for these traits were found at lower temperatures. No genetic group * ambient temperature interaction was detected for any other carcass or meat quality traits. The percentages of distal parts of legs, skin and carcass forepart were higher in crossbred rabbits, indicating a lower degree of maturity at slaughter in this group. The percentage of thoracic viscera was higher in the purebreds. Lightness of the longissimus muscle was higher in the purebreds, whereas redness was higher in the crossbreds. Slaughter, commercial and reference carcass weights and the percentages of thoracic viscera, liver and kidneys were negatively related with ambient temperature. Commercial and reference carcass yields, and the percentage of distal parts of legs, on the other hand, had a positive linear relationship with ambient temperature. Meat redness and yellowness diminished as ambient temperature increased, whereas cooking loss was linearly elevated with ambient temperature. Meat color traits revealed paler meat in the purebreds, but no differences in instrumental texture properties and water-holding capacity between genetic groups. Purebred rabbits were less susceptible to heat stress than the crossbreds. Heat stress resulted in lower slaughter and carcass weights and proportional reductions of organ weights, which contributed to a higher carcass yield. Moreover, it exerted a small, but negative, effect on meat quality traits. PMID- 23031322 TI - Glycemic variability and glucose complexity in critically ill patients: a retrospective analysis of continuous glucose monitoring data. AB - INTRODUCTION: Glycemic variability as a marker of endogenous and exogenous factors, and glucose complexity as a marker of endogenous glucose regulation are independent predictors of mortality in critically ill patients. We evaluated the impact of real time continuous glucose monitoring (CGM) on glycemic variability in critically ill patients on intensive insulin therapy (IIT), and investigated glucose complexity--calculated using detrended fluctuation analysis (DFA)--in ICU survivors and non-survivors. METHODS: Retrospective analysis were conducted of two prospective, randomized, controlled trials in which 174 critically ill patients either received IIT according to a real-time CGM system (n = 63) or according to an algorithm (n = 111) guided by selective arterial blood glucose measurements with simultaneously blinded CGM for 72 hours. Standard deviation, glucose lability index and mean daily delta glucose as markers of glycemic variability, as well as glucose complexity and mean glucose were calculated. RESULTS: Glycemic variability measures were comparable between the real time CGM group (n = 63) and the controls (n = 111). Glucose complexity was significantly lower (higher DFA) in ICU non-survivors (n = 36) compared to survivors (n = 138) (DFA: 1.61 (1.46 to 1.68) versus 1.52 (1.44 to 1.58); P = 0.003). Diabetes mellitus was significantly associated with a loss of complexity (diabetic (n = 33) versus non-diabetic patients (n = 141) (DFA: 1.58 (1.48 to 1.65) versus 1.53 (1.44 to 1.59); P = 0.01). CONCLUSIONS: IIT guided by real time CGM did not result in significantly reduced glycemic variability. Loss of glucose complexity was significantly associated with mortality and with the presence of diabetes mellitus. PMID- 23031324 TI - Blood and tissue fatty acid compositions, lipoprotein levels, performance and meat flavor of broilers fed fish oil: changes in the pre- and post-withdrawal design. AB - Administration of fish oil (FO) in broiler diets can elevate alpha-linolenic acid (ALA), eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) levels, which are protective against cardiovascular disease. However, optimization based solely on n-3 polyunsaturated fatty acid (n-3 PUFA) enrichment in chicken meat could lead to lower meat quality, unless the withdrawal period (plan) is applied for 1 week. The present study investigated whether the incorporation of FO in the diet for 32 days followed by its withdrawal for 1 week affected blood lipid profiles, lipoprotein particles, performance and meat flavor in male broiler chickens. Two hundred and forty birds (1-day-old, Ross 308) were assigned to 1 of 4 dietary groups: 0%, 1%, 2% or 3% FO with four replicates. Broilers were fed for 49 days according to a 4-phase feeding program. The experimental phase comprised day 11 to 42, and FO was removed on day 42. Blood samples were collected during the pre- and post-withdrawal period after the recordings before slaughter. The FO groups demonstrated decreased low-density lipoprotein (LDL) and increased high-density lipoprotein levels on day 42 (P < 0.01); however, these values were not significant after design withdrawal. Diet supplementation with FO elevated the blood levels of palmitic acid (C16:0) and n-3 PUFAs, especially long-chain (LC) PUFAs (EPA, C20:5n-3 and DHA, C22:6n-3), and caused a decline in the level of arachidonic acid (AA, C20:4n-6; P < 0.05). Application of a one-week withdrawal period resulted in a decrease in (P < 0.05) linoleic acid (C18:2n-6) and an increase in the level of AA, unlike their amounts on day 42. Although blood and tissue LC n-3 PUFA levels on day 49 were significantly higher in the FO groups compared with the control, they demonstrated a substantial decrease on day 49 compared with day 42. The best results, mainly the lowest n-6/n-3 fatty acids (FAs) and feed conversion ratio (FCRs), were observed for 3% FO (group T4), even after institution of the withdrawal design. Degradation of total n-3 FAs deposited in tissues occurred after instituting the withdrawal plan diet, but deposited levels of EPA and DHA in tissues could ensure omega-3 enrichment of broiler meat in groups 3 and 4. On the basis of the dissatisfaction of the panelists toward group 4 meats (scored as near to acceptable) and their satisfaction with cooked samples of T3 (scored as good), group 3 meats were selected as good-quality n-3-enriched broiler meat. PMID- 23031325 TI - Implications for colistin use in patients with cystic fibrosis (CF): letter in response to "Prophylactic and metaphylactic antimicrobial use in Belgian fattening pig herds" by Callens et al. [Prev. Vet. Med. 106 (2012) 53-62]. PMID- 23031326 TI - Flock-level risk factors associated with leptospirosis in dairy goats in a semiarid region of Northeastern Brazil. AB - A cross-sectional study based on a planned sampling was carried out to determine flock-level risk factors associated to Leptospira spp. infection in dairy goat flocks in a semiarid region of Northeastern Brazil. Serum samples from 975 adult dairy goats from 110 flocks were examined for Leptospira spp. antibodies by MAT using 24 serovars. A structured questionnaire focusing on risk factors for leptospirosis was completed for each flock. Of the 110 flocks 48 (43.6%; 95% CI: 34.2-53.4%) presented at least one seropositive animal, and most frequent serovar was Autumnalis (10.9%). Ninety-eight (8.7%; 95% CI: 5.7-12.9%; design effect=4.23) of the 975 goats tested seropositive at MAT, and serovar Autumnalis was also the most frequent (1.74%). Presence of rodents (OR=2.78; P=0.015) was identified as a risk factor. There was also association between history of infertility (OR=14.74; P=0.015) and prevalence of positive flocks. We suggest that a program of rodent control should be included in the flock management practices aiming to reduce transmission of the agent and then to reduce prevalence of positive flocks and occurrence of reproductive disorders such as impaired fertility. PMID- 23031327 TI - Demography of Q fever seroprevalence in sheep and goats in The Netherlands in 2008. AB - At the end of 2007, the first year of what later turned out to be one of the largest Q fever outbreaks in the world with ultimately almost 3500 human patients notified in three years time, dairy goats were suspected to be the possible cause. However, current information on the Q fever prevalence in small ruminants in The Netherlands was lacking. A serological survey, using an indirect ELISA, was carried out in 15,186 sheep and goats in The Netherlands in 2008. In total, 2.4% (95% CI: 2.2-2.7) of the sheep and 7.8% (95% CI: 6.9-8.8) of the goats was seropositive for antibodies against Coxiella burnetii. In 14.5% (95% CI: 12.5 16.5) of the sheep flocks and 17.9% (95% CI: 14.2-21.5) of the goat herds at least one seropositive animal was found. In sheep flocks with at least one seropositive sheep, the within herd seroprevalence was 14.8% (95% CI: 12.6-17.0). In goat herds with at least one seropositive goat, the within herd seroprevalence was 29.0% (95% CI: 24.6-33.3). The seropositive sheep were equally distributed across the country. The seroprevalence in goats in the south-eastern part of The Netherlands, the area where most of the human Q fever cases were notified, was significantly higher than the seroprevalence in goats in the rest of The Netherlands. Dairy sheep and dairy goats had a significantly higher chance of being seropositive than non-dairy sheep and goats. During pregnancy and in the periparturient period, small ruminants tested significantly more often seropositive than in the early- or non-pregnant period. The seroprevalence as well as the true prevalence among small ruminants in The Netherlands were lower than prevalences reported elsewhere. The seroprevalence among sheep was also lower than reported in an earlier Dutch study in 1987. The Q fever seroprevalence was highest in pregnant and periparturient dairy goats in the south-eastern part of The Netherlands, which coincides with the region with the highest human incidence of Q fever. PMID- 23031328 TI - Falls prevention interventions for community-dwelling older persons with cognitive impairment: a systematic review. AB - BACKGROUND: Globally, falls in older people are a leading cause of injury-related mortality and morbidity. Cognitive impairment is a well-known risk factor for falls in this population group. While there is now a large body of evidence to support effective interventions for falls reduction across care settings, very little is known about interventions in the vulnerable, but increasing population of cognitively impaired community-dwelling older people. Therefore, the purpose of this systematic review is to investigate interventions designed to reduce falls in community-dwelling, cognitively impaired older adults. METHODS: A literature search of databases was conducted to identify original research published in English, which met predefined inclusion and exclusion criteria for effective (non-pharmacological) falls prevention interventions in cognitively impaired community-dwelling people over 65 years of age. Data from the selected papers were extracted into data extraction tables and analyzed according to study characteristics, measures, results, and quality. RESULTS: The review identified 11 studies providing data from 1,928 participants. Interventions included exercise, health assessment and management of risk, multi-component and cognitive behavioral programs, and hip protectors as falls risk reduction strategies. Seven of the selected studies showed an intervention effect in decreasing falls risk; however, only two of these showed a significant improvement in physical performance measures specifically in a cognitively impaired group. CONCLUSIONS: The diversity of interventions, study designs, populations, and quality of the studies, which met inclusion criteria, resulted in conflicting evidence and inconclusive results for falls prevention interventions in this highly complex population. PMID- 23031329 TI - Increased ADAMTS13 activity in patients with venous thromboembolism. AB - Increased levels of inflammatory markers and clotting factors have been related to the pathogenesis and prognosis of venous thromboembolism. In particular, the imbalance between VWF and ADAMTS13 has been described in patients with arterial thrombosis. In this study, 77 patients with previous VTE and 77 matched controls were selected for the evaluation of the inflammatory markers, FVW, ADAMTS 13 and D-dimer. The presences of post-thrombotic syndrome and residual vein obstruction were also assessed in patients. Serum levels of TNF-alpha and IL-6 were significantly increased in patients compared to controls (median=2.25 vs 1.59 pg/mL, P <= 0.001; 1.16 vs 0.98 pg/ml, P=0.013, respectively). Plasma levels and activity of VWF (median=150.25 vs 95.39 U/dL, P <= 0.001; 145.26% vs 92.39%, P <= 0.001) and ADAMTS 13 (median=1088.84 vs 950.80 ng/mL, P <= 0.001; 96.03 vs 83.64%, P <= 0.001) were also higher in patients. We further analysed the subgroups of patients with higher risk for VTE recurrence or VTE sequelae, defined as the presence of high D-dimer levels, RVO or PTS. All inflammatory markers were significantly higher in patients with increased D-dimer. The presence of PTS or RVO was not associated with higher inflammatory or coagulation parameters. The increased levels of inflammatory markers and VWF may suggest that there is a persistence of inflammatory activity in patients even at long periods after the VTE episode. In this context, it may be postulated that increased levels of ADAMTS13 could represent a compensatory mechanism against persistently increased levels of VWF. Moreover, increased inflammatory activity was associated with increased D-dimer levels, thus it is possible that this inflammatory activity may also be related to the risk of VTE recurrence. PMID- 23031330 TI - 'I am not a depressed person': how identity conflict affects help-seeking rates for major depressive disorder. AB - BACKGROUND: There is a significant treatment gap for patients with depression. A third of sufferers never seek help, and the vast majority of those who do only do so after considerable delay. Little is understood regarding poor help-seeking rates amongst people with depression, with existing research mainly focussed on the impact of barriers to treatment. The current study explored psychological factors affecting help-seeking behaviour in clinically depressed individuals. METHODS: Semi-structured interviews were conducted with 20 current or previously clinically depressed participants who either had or had not sought professional help. Thematic analysis was used to analyse results. RESULTS: The onset of depressive symptoms created conflict with participants' identity and personal goals. Delays in seeking help were primarily attributed to the desire to protect identity and goals from the threat of depressive symptoms. Participants used avoidance strategies to reduce the perceived threat of depressive symptoms on identity. These strategies interfered with help-seeking. Help-seeking was only undertaken once participants reached a point of acceptance and began to make concessions in their identity and goals, at which time they reduced their use of avoidance. CONCLUSIONS: Difficulties resolving conflict between identity and depressive symptoms may account for significant delays in seeking help for depression. The results have implications for predicting health behaviour and improving treatment uptake for depression, and may inform existing help-seeking models. PMID- 23031331 TI - Emergency obstetric hysterectomy at University Hospital, Yaounde, Cameroon. PMID- 23031332 TI - The perception and use of chaperones by Nigerian gynecologists. AB - OBJECTIVE: To determine how Nigerian gynecologists perceive and use chaperones during intimate gynecologic examinations. METHODS: A cross-sectional survey of Nigerian gynecologists was conducted with the aid of self-administered, semi structured questionnaires. Data were analyzed for descriptive and inferential statistics. RESULTS: In all, 97.6% of respondents considered the use of a chaperone necessary during intimate gynecologic examinations and recommended that the Society of Gynaecology and Obstetrics of Nigeria (SOGON) should endorse the routine offer of chaperones for such examinations. However, just 35.9% of male physicians always or often used chaperones, while 76.9% of female physicians used chaperones only under special circumstances. No female physician always or often used a chaperone during pelvic examination. The main obstacles to the use of chaperones were scarcity of personnel to serve in this capacity (87.6%) and patients' refusal to be examined in the presence of a third party (12.4%). CONCLUSION: Most Nigerian gynecologists use chaperones at least some of the time and also support a policy of routinely offering chaperones during intimate gynecologic examination while respecting patients' right to decline this offer. Scarcity of personnel to serve as chaperones is the greatest challenge to the implementation of this policy. PMID- 23031333 TI - Outcomes of women with postcoital bleeding. PMID- 23031334 TI - Aspergillus-PCR in bronchoalveolar lavage for detection of invasive pulmonary aspergillosis in immunocompromised patients. AB - BACKGROUND: Invasive fungal disease (IFD) is a frequent and serious infectious complication in immunocompromised patients. Culture and cytology in bronchoalveolar lavage (BAL) have a high specificity but low sensitivity for the diagnosis of IFD as assessed by histology. Molecular methods are expected to allow a rapid diagnosis of IFD with a high sensitivity. We evaluated the diagnostic accuracy of conventional nested PCR in the bronchoalveolar fluid to diagnose IFD in severely immunocompromised patients. METHODS: Consecutive immunosuppressed patients undergoing bronchoscopy for suspected pulmonary infection in a tertiary care hospital were included. Patients were classified as having "proven", "probable", "possible", and "no" IFD based on definitions of the European Organization for Research and Treatment of Cancer and National Institute of Allergy and Infectious Diseases (EORTC/NIAID) and on clinical grounds. Conventional nested PCR for aspergillus fumigatus, flavus, niger, glaucus, terreus and tomarrii were applied to 2.5 ml bronchoalveolar fluid. RESULTS: A total of 191 patients were included. Mean age was 51 y, 61% were male. There were 129 patients with hematological conditions, 26 solid organ transplant recipients, 24 auto-immune disorders, and 12 HIV. According to the EORTC/NIAID classification, there were 53 patients with potential IFD: 3 (2%) had proven, 8 (4%) probable, 42 (22%) possible and 138 (72%) no IFD. A total of 111 (58%) of the patients - 10 (90.9%) proven or probable IFD, 32 (76.2%) possible IFD and 69 (50%) "no" IFD) were on anti-fungal therapy at the time of bronchoscopy. Conventional nested PCR for Aspergillus was positive in 55 cases (28.8%). According to these results, sensitivity, specificity, PPV and NPV for "proven" IFD was 0%, 71%, 0%, 98%, respectively and "probable" IFD was 36%, 72%, 7%, 95%, respectively. In 53 (28%) cases there was a strong clinical suspicion of IFD in the chest-x-ray and/or chest-CT irrespective of the EORTC/NIAID classification. However, from those, only 15 (28%) had a positive conventional nested PCR. CONCLUSION: In our experience, conventional nested Aspergillus PCR in the BAL seems to be of limited usefulness for detection of invasive fungal disease in immunocompromised patients due to the limited sensitivity and specificity of the method. PMID- 23031335 TI - The insulin like growth factor system in cirrhosis. Relation to changes in body composition following adrenoreceptor blockade. AB - OBJECTIVE: Circulating levels of IGF-I and IGFBP-3 are low in cirrhosis and are related to liver dysfunction. Metabolic disturbances include malnutrition with altered body composition and osteopenia. Since the effects of IGF-I may be associated to changes in body composition and bone mineral content (BMC) in cirrhotic patients, we investigated the relations between changes in the IGF system and body composition and the effects of long-term alpha- and beta blockade. DESIGN: The study was designed as a combined cross-sectional and prospective randomised controlled study of 62 patients with cirrhosis. Twenty three of these patients were randomised to treatment with beta- or combined alpha/beta-blocker for 3 months. Haemodynamics, body composition, and systemic and hepatic IGF-I and IGFBP-3 levels were determined in all patients. In the subgroup changes in body composition and IGF-I/IGFBP-3 levels after 3 months of beta- or combined alpha/beta-blockade were additionally examined. RESULTS: Both the hepatic and the systemic IGF systems were suppressed and correlated with liver dysfunction and anthropometrics (p<0.05-0.001). Multivariate analyses revealed that changes in the IGF-system were determined by metabolic liver dysfunction as well as anthropometrics. In the follow-up study, hepatic venous IGF-I (p=0.05) and IGFBP-3 (p=0.02) increased after 3 months only in the group who received beta-blocker. In both groups, fat body mass increased significantly after 3 months (p=0.05-0.001). CONCLUSIONS: In cirrhosis, the IGF-system is associated with both anthropometrics and synthetic capacity of the liver. Changes in IGF-I relate to changes in anthropometrics and there seems to be a differential effect depending on the type of adrenoreceptor blockade. Future longitudinal studies are needed to unravel these mechanisms in cirrhosis. PMID- 23031336 TI - Bias in medicine: a survey of medical student attitudes towards HIV-positive and marginalized patients in Russia, 2010. AB - BACKGROUND: Russia has a substantial HIV epidemic which is poised to escalate in the coming years. The increases in prevalence of HIV will result in increased healthcare needs by a medical system with limited experience with HIV. A healthcare provider's attitude towards a patient plays a significant role in determining the patient's health-related behaviours and medical outcomes. Previous studies have identified negative attitudes of medical students towards people living with HIV. Studying the prevalence of such attitudes is of particular interest, as medical students represent the future workforce and also as the schooling years present a unique opportunity to nurture bias-free healthcare providers. The study measures prevalence of prejudicial attitudes towards HIV-positive and HIV-negative patients who belong to marginalized subgroups. METHODS: The cross-sectional survey was conducted among medical students of a Russian medical university. Of 500 students surveyed, 436 provided sufficient data to be included in the analysis. Prejudicial attitudes were defined as reluctance to provide medical care to a specified hypothetical patient. Nine hypothetical HIV-positive and HIV-negative patients were proposed: physicians, injecting drug users, commercial sex workers, men who have sex with men and a patient HIV-positive due to blood transfusion. A log-binomial regression solved using generalized estimating equations was utilized to identify factors associated with reluctance to treat. RESULTS: Prevalence of reluctance to provide medical care to HIV-positive patients in marginalized subgroups was high (ranging from 26.4% up to 71.9%), compared to a maximum of 7.5% if a patient was an HIV-negative physician. Students in their clinical years reported more negative attitudes than preclinical students. In general, female students were less willing to provide care than their male counterparts. CONCLUSIONS: Prejudicial attitudes about HIV-positive patients and those in marginalized subgroups of the population are prevalent among medical students in Russia. Given the increasing prevalence of HIV in the country, reasons for this hesitance to treat must be identified and addressed. Educational programs for healthcare providers are urgently needed to eliminate bias in the delivery of critically needed medical care. These targeted interventions should be coupled with other programs to eliminate structural barriers to care. PMID- 23031337 TI - Genome-wide associations for feed utilisation complex in primiparous Holstein Friesian dairy cows from experimental research herds in four European countries. AB - Genome-wide association studies for difficult-to-measure traits are generally limited by the sample size with accurate phenotypic data. The objective of this study was to utilise data on primiparous Holstein-Friesian cows from experimental farms in Ireland, the United Kingdom, the Netherlands and Sweden to identify genomic regions associated with the feed utilisation complex: fat and protein corrected milk yield (FPCM), dry matter intake (DMI), body condition score (BCS) and live-weight (LW). Phenotypic data and 37 590 single nucleotide polymorphisms (SNPs) were available on up to 1629 animals. Genetic parameters of the traits were estimated using a linear animal model with pedigree information, and univariate genome-wide association analyses were undertaken using Bayesian stochastic search variable selection performed using Gibbs sampling. The variation in the phenotypes explained by the SNPs on each chromosome was related to the size of the chromosome and was relatively consistent for each trait with the possible exceptions of BTA4 for BCS, BTA7, BTA13, BTA14, BTA18 for LW and BTA27 for DMI. For LW, BCS, DMI and FPCM, 266, 178, 206 and 254 SNPs had a Bayes factor .3, respectively. Olfactory genes and genes involved in the sensory smell process were overrepresented in a 500 kbp window around the significant SNPs. Potential candidate genes were involved with functions linked to insulin, epidermal growth factor and tryptophan. PMID- 23031338 TI - Highlights in clinical autonomic neurosciences: non-pharmacological therapy for vasovagal syncope. PMID- 23031339 TI - Effects of dietary fish meal and soybean meal on the ovine innate and acquired immune response during pregnancy and lactation. AB - In recent years, livestock producers have been supplementing animal diets with fish meal (FM) to produce value-added products for health conscious consumers. As components of FM have unique neuroendocrine-immunomodulatory properties, we hypothesize that livestock producers may be influencing the overall health of their animals by supplementing diets with FM. In this study, 40 pregnant ewes were supplemented with rumen protected (RP) soybean meal (SBM: control diet) or RP FM, commencing gestation day 100 (gd100), in order to evaluate the impact of FM supplementation on the innate and acquired immune response and neuroendocrine response of sheep during pregnancy and lactation. On gd135, half the ewes from each diet (n = 10 FM, n = 10 SBM) were challenged iv with lipopolysaccharide (LPS) to simulate a systemic bacterial infection and the febrile, respiratory and neuroendocrine responses were monitored over time; the other half (n = 10 FM, n = 10 SBM) of the ewes received a saline injection as control. On lactation day 20 (ld20), all ewes (n = 20 FM, n = 20 SBM) were sensitized with hen egg white lysozyme (HEWL) and the serum haptoglobin (Hp) response was measured over time. The cutaneous hypersensitivity response (CHR) to HEWL challenge was measured on ld30 (n = 20 FM, n = 20 SBM), and blood samples were collected over time to measure the primary and secondary immunoglobulin G (IgG) response to HEWL. There was an attenuated trend in the LPS-induced febrile response by the FM treatment when compared with the SBM treatment (P = 0.06), as was also true for the respiratory response (P = 0.07), but significant differences in neuroendocrine function (serum cortisol and plasma ACTH) were not observed between treatments. Basal Hp levels were significantly lower in the FM supplemented ewes when compared with the SBM supplemented ewes (P < 0.01), and the Hp response to HEWL sensitization differed significantly over time between treatments (P < 0.01). The CHR to HEWL was also significantly attenuated in the FM treatment compared with the SBM (P < 0.01); however, treatment differences in the primary and secondary IgG responses to HEWL were not observed. These results indicate that FM supplementation differentially affects the innate and acquired immune responses in pregnant and lactating sheep compared with a typical SBM diet of commercial flocks. The long-term implications of this immunomodulation warrant further investigation. PMID- 23031340 TI - Comparative study of Nosema ceranae (Microsporidia) isolates from two different geographic origins. AB - The intestinal honey bee parasite Nosema ceranae (Microsporidia) is at the root of colony losses in some regions while in others its presence causes no direct mortality. This is the case for Spain and France, respectively. It is hypothesized that differences in honey bee responses to N. ceranae infection could be due to the degree of virulence of N. ceranae strains from different geographic origins. To test this hypothesis, we first performed a study to compare the genetic variability of an rDNA fragment that could reveal differences between two N. ceranae isolates, one from Spain and one from France. Then we compared the infection capacity of both isolates in Apis mellifera iberiensis, based on the anatomopathological lesions due to N. ceranae development in the honey bee midgut, N. ceranae spore-load in the midgut and the honey bee survival rate. Our results suggest that there is no specific genetic background of the two N. ceranae isolates, from Spain or France, used in this study. These results agree with the infection development, honey bee survival and spore-loads that were similar between honey bees infected with both N. ceranae isolates. Probably, differences in honey bee response to infection are more related to the degree of tolerance of honey bee subspecies or local hybrids to N. ceranae, or experimental conditions in the case of laboratory trials, than to differences between N. ceranae isolates. Further studies should be done to estimate the contribution of each of these factors on the response of the honey bees to infection. PMID- 23031341 TI - Toxoid construction of AsaP1, a lethal toxic aspzincin metalloendopeptidase of Aeromonas salmonicida subsp. achromogenes, and studies of its activity and processing. AB - AsaP1 is a toxic aspzincin metalloendopeptidase secreted by the fish pathogen Aeromonas salmonicida subsp. achromogenes. The protease is highly immunogenic and antibodies against AsaP1 evoke a passive protection against infection with A. salmonicida subsp. achromogenes. The protease is expressed as 37 kDa pre-pro protein and processed to an active enzyme of 19kDa in A. salmonicida subsp. achromogenes. Recombinant expression of AsaP1(rec) in E. coli results in a protease of 22 kDa that is not secreted. AsaP1(rec) induces comparable pathological changes in Atlantic salmon (Salmo salar L.) to native AsaP1(wt). The aim of the study was to construct AsaP1 toxoids by exchanging catalytically important amino acids in the active site region of the protease. Four different AsaP1 mutants (AsaP1(E294A), AsaP1(E294Q), AsaP1(Y309A), and AsaP1(Y309F)) were successfully constructed by one step site directed mutagenesis, expressed in E. coli BL21 C43 as pre-pro-proteins and purified by His-tag affinity chromatography and gel filtration. Three of the resulting mutants (AsaP1(E294A), AsaP1(E294Q), and AsaP1(Y309A)) were not caseinolytic active and are detected as unprocessed pre-pro-proteins of 37 kDa. Caseinolytic active AsaP1(rec) and a mutant with reduced activity, AsaP1(Y309F), were processed to a size of 22 kDa. Furthermore, AsaP1(rec) is able to process the inactive mutants to the mature size of 22 kDa, allowing the conclusion that AsaP1 is autocatalytically processed. All four mutants AsaP1(E294A), AsaP1(E294Q), AsaP1(Y309A) and AsaP1(Y309F) are non-toxic in fish but induce a specific anti-AsaP1 antibody response in Arctic charr (Salvelinus alpinus L.) and are therefore true toxoids and possible vaccine additives. PMID- 23031342 TI - Evaluation of serum galactomannan detection for diagnosis of feline upper respiratory tract aspergillosis. AB - Measurement of serum galactomannan (GM), a polysaccharide fungal cell-wall component, is a non-invasive test for early diagnosis of invasive aspergillosis in humans. Feline upper respiratory tract (URT) aspergillosis is an emerging infectious disease in cats. Diagnosis requires biopsy for procurement of tissue specimens for cytological or histological detection of fungal hyphae and for fungal culture. The aim of this study was to evaluate serum GM measurement as a non-invasive diagnostic test for URT aspergillosis in cats. A one-stage, immunoenzymatic sandwich ELISA was used to detect serum GM in 4 groups of cats; Group 1 (URT aspergillosis) - confirmed URT aspergillosis (n=13, sinonasal aspergillosis (SNA) n=6 and sino-orbital aspergillosis (SOA) n=7), Group 2 (URT other) - other URT diseases (n=15), Group 3 (beta-lactam) - cats treated with beta-lactam antibiotics for non-respiratory tract disease (n=14), Group 4a - healthy young cats (<= 1 y of age, n=28), Group 4b - healthy adult cats (>1 y of age, n=16). One cat with SNA and two cats with SOA caused by an Aspergillus fumigatus-mimetic species, tested positive for serum GM. For a cut-off optical density index of 1.5, the overall sensitivity and specificity of the assay was 23% and 78% respectively. False positive results occurred in 29% of cats in Group 3 and 32% of cats in Group 4a. Specificity increased to 90% when Groups 3 and 4a were excluded from the analysis. Overall, serum GM measurement has a poor sensitivity but is a moderately specific, non-invasive screening test to rule out infection in patients with suspected feline upper respiratory tract aspergillosis. PMID- 23031343 TI - Exploratory study of Torque teno sus viruses in pulmonary inflammatory lesions in pigs. AB - The pathogenic role of Torque teno sus viruses 1 (TTSuV1) and 2 (TTSuV2), and their capacity to induce lesions are controversial. TTSuVs have been linked to porcine circovirus diseases (PCVDs) and described as cause of mild respiratory lesions in gnotobiotic pigs; moreover, an increased TTSuV prevalence has been found in porcine respiratory disease complex (PRDC) affected pigs. In the present study, TTSuV1 and TTSuV2 loads and their prevalence were evaluated in formalin fixed, paraffin-embedded (FFPE) lung samples displaying different types of inflammatory lesions. Such measurements were made by means of a real time quantitative PCR technique to detect these viruses. The technique was optimised for its use on FFPE tissues comparing results with frozen lung tissues. Selection criteria included negativity against porcine circovirus type 2 (PCV2), porcine reproductive and respiratory syndrome virus (PRRSV), Aujeszky's disease virus (ADV) and swine influenza virus (SIV). Results from the present study demonstrated that both TTSuVs were present in lung. However, TTSuV2 had higher viral load and prevalence in all the studied groups when compared to TTSuV1. TTSuV2 mean load was also higher in lungs with viral background (interstitial pneumonia and broncho-interstitial pneumonia) when compared to normal lungs or to those with bacterial background (catarrhal-purulent bronchopneumonia, fibrinous pleuritis and fibrinous-necrotizing pleuropneumonia). This result suggests a possible role of TTSuV2 in the pathogenic mechanism of inflammatory lesions of lungs compatible with viral infection. PMID- 23031344 TI - The development of Leishmania turanica in sand flies and competition with L. major. AB - BACKGROUND: In Central Asian foci of zoonotic cutaneous leishmaniases, mixed infections of Leishmania turanica and L. major have been found in a reservoir host (the great gerbil, Rhombomys opimus) as well as in the sand fly vector Phlebotomus papatasi, but hybrids between these two Leishmania species have never been reported. In addition, the role of sand fly species other than P. papatasi in L. turanica circulation is not clear. METHODS: In this work we compared the development of L. turanica in three sand fly species belonging to different subgenera. In addition, we studied experimental co-infections of sand flies by both Leishmania species using GFP transfected L. turanica (MRHO/MN/08/BZ18(GFP+)) and RFP transfected L. major (WHOM/IR/-/173-DsRED(RFP+)). The possibility of Leishmania genetic exchange during the vectorial part of the life cycle was studied using flow cytometry combined with immunofluorescent microscopy. RESULTS: Late-stage infections of L. turanica with frequent colonization of the stomodeal valve were observed in the specific vector P. (Phlebotomus) papatasi and in the permissive vector P. (Adlerius) arabicus. On the other hand, in P. sergenti (the specific vector of L. tropica), L. turanica promatigotes were present only until the defecation of bloodmeal remnants. In their natural vector P. papatasi, L. turanica and L. major developed similarly, and the spatiotemporal dynamics of localization in the sand fly gut was the same for both leishmania species. Fluorescence microscopy in combination with FACS analyses did not detect any L. major / L. turanica hybrids in the experimental co-infection of P. papatasi and P. duboscqi. CONCLUSION: Our data provide new insight into the development of different leishmania parasite species during a mixed infection in the sand fly gut. Despite the fact that both Leishmania species developed well in P. papatasi and P. duboscqi and did not outcompete each other, no genetic exchange was found. However, the ability of L. turanica to establish late-stage infections in these specific vectors of L. major suggests that the lipophosphoglycan of this species must be identical or similar to that of L. major. PMID- 23031345 TI - Association between age at first calving, year and season of first calving and milk production in Holstein cows. AB - The effects of first calving (FC) in Holstein heifers on their first lactation, second lactation and lifetime milk production were examined from an initial database of 459 743 animals that first calved between 1 January 1990 and 31 July 2010 in Wallonia, Belgium. The FC age class (18 to 22, 22 to 26, 26 to 30, 30 to 34, 34 to 38 and 38 to 42 months), the FC season and FC year class (1990 to 1994, 1995 to 1999, 2000 to 2004 and 2005 to 2010) were considered when analysing the first and second lactation data. Lifetime data were similarly analysed, but did not include animals that calved after 2005 because many of them were still lactating. Only 24% of animals had their FC before 26 months of age. Animals that first calved between 22 and 26 months of age had more lactations and productive days during their life. They also had higher first and second lactation milk production and lifetime milk production. Summer or autumn FC improved first lactation, second lactation and lifetime milk production, as well as production per day of lactation, compared with winter or spring FC. Compared with animals that calved for the first time in 1990 to 1994, animals with a FC in 2000 to 2004 had a longer calving interval (0.5 months), fewer lactations per animal (-0.6) and fewer days in their lifetime lactation (a reduction of 144 days). As a result, the animals' lifetime production did not increase between 1990 to 1994 and 2000 to 2004, although milk production per day of lactation (22.85 v. 20.49 l/day) and per day of life (11.49 v. 10.78 l/day) improved. Milk fat content was lower in 2000 to 2004 than in 1990 to 1994, but protein content remained relatively constant, probably because of the cows' higher production level and increased dietary concentrate supplementation. PMID- 23031346 TI - The precarious path to diagnostic accuracy: the Ontario hormone receptor guideline. PMID- 23031347 TI - Three-dimensional AlZnO/Al2O3/AlZnO nanocapacitor arrays on Si substrate for energy storage. AB - High density three-dimensional AZO/Al2O3/AZO nanocapacitor arrays have been fabricated for energy storage applications. Using atomic layer deposition technique, the stack of AZO/Al2O3/AZO has been grown in the porous anodic alumina template which is directly formed on the Si substrate. The fabricated capacitor shows a high capacitance density of 15.3 fF/MUm2 at 100 kHz, which is nearly 2.5 times over the planar capacitor under identical conditions in theory. Further, the charge-discharge characteristics of the capacitor are characterized, indicating that the resistance-capacitance time constants are equal to 300 ns for the charging and discharging processes, and have no dependence on the voltage supply. This reflects good power characteristics of the electrostatic capacitor. PMID- 23031348 TI - Quantifying the relative contribution of ante- and post-mortem factors to the variability in beef texture. AB - This study aims to investigate the relative contribution of ante- and post-mortem factors to the final quality of beef. In all, 112 steers (four breed-crosses) were arranged in a 2 * 2 * 2 factorial experimental including production system, growth implant and beta-adrenergic agonist strategies. Carcasses were suspended by the Achilles tendon or the aitch bone and meat was aged for 2/6/13/21/27 days (longissimus muscle) or 2/27 days (semimembranosus muscle). Meat quality traits related to beef texture were measured. Statistical analyses were developed including ante- and post-mortem factors and their relative contribution to the variability observed for each measured trait was calculated. The main factor responsible for the variability in sarcomere length was the suspension method (91.1%), which also influenced drip-loss (44.3%). Increasing the percentage of British breeds increased (P < 0.05) the intramuscular fat content in longissimus muscle, but only when implants were not used. Thus, the breed-cross, implant strategy and their interaction were responsible for >58% of the variability in this trait. The variability in instrumental and sensory tenderness was mainly affected by post-mortem factors (carcass suspension, ageing time and their interaction), explaining generally ~70% of the variability in these traits. Breed cross was the second most important effect (~15%) when carcass suspension was not considered in the model, but still ageing time was responsible for a much larger proportion of the variability in tenderness (>45%). In conclusion, post-mortem handling of the carcasses may be much more effective in controlling beef tenderness than pre-mortem strategies. PMID- 23031349 TI - Clinical value of total white blood cells and neutrophil counts in patients with suspected appendicitis: retrospective study. AB - INTRODUCTION: Acute appendicitis (AA) is common surgical problem associated with acute-phase reaction. Blood tests role in decision-making process is unclear. This retrospective study aimed to determine diagnostic value of preoperative evaluation of white blood cells (WBCs) and neutrophils and its value in predicting AA severity. METHODS: Medical records of 456 patients who underwent appendectomy during 4-years period were retrospectively reviewed. Patients were subdivided according to histological finding into: normal appendix (n = 29), uncomplicated inflamed appendix (n = 350), complicated appendicitis (n = 77). Diagnostic performances of WBCs and neutrophils were analyzed using receiver operating characteristic (ROC) curves. RESULTS: WBCs and neutrophils counts were higher in patients with inflamed and complicated appendix than normal appendix and in complicated than inflamed appendix. In patients, WBCs count 9.400 * 103/mL had sensitivity of 76.81%, specificity of 65.52%, positive predictive value (PPV) of 97.0%, negative predictive value (NPV) of 16.1%, positive likelihood ratio [LR(+)] of 2.23, negative LR(-) of 0.35. Neutrophil count 7.540 * 103/mL had sensitivity of 70.96%, specificity of 65.52%, PPV of 96.8%, NPV of 13.3%, LR(+) of 2.06, LR(-) of 0.44. Areas under ROC curve were 0.701, 0.680 for elevated WBCs and neutrophils count. CONCLUSIONS: Clinicians should not rely on either elevated WBCs or neutrophils count as appendicitis indicator as clinical data are superior in decision-making appendectomy. PMID- 23031350 TI - Phylogenetic estimation error can decrease the accuracy of species delimitation: a Bayesian implementation of the general mixed Yule-coalescent model. AB - BACKGROUND: Species are considered the fundamental unit in many ecological and evolutionary analyses, yet accurate, complete, accessible taxonomic frameworks with which to identify them are often unavailable to researchers. In such cases DNA sequence-based species delimitation has been proposed as a means of estimating species boundaries for further analysis. Several methods have been proposed to accomplish this. Here we present a Bayesian implementation of an evolutionary model-based method, the general mixed Yule-coalescent model (GMYC). Our implementation integrates over the parameters of the model and uncertainty in phylogenetic relationships using the output of widely available phylogenetic models and Markov-Chain Monte Carlo (MCMC) simulation in order to produce marginal probabilities of species identities. RESULTS: We conducted simulations testing the effects of species evolutionary history, levels of intraspecific sampling and number of nucleotides sequenced. We also re-analyze the dataset used to introduce the original GMYC model. We found that the model results are improved with addition of DNA sequence and increased sampling, although these improvements have limits. The most important factor in the success of the model is the underlying phylogenetic history of the species under consideration. Recent and rapid divergences result in higher amounts of uncertainty in the model and eventually cause the model to fail to accurately assess uncertainty in species limits. CONCLUSION: Our results suggest that the GMYC model can be useful under a wide variety of circumstances, particularly in cases where divergences are deeper, or taxon sampling is incomplete, as in many studies of ecological communities, but that, in accordance with expectations from coalescent theory, rapid, recent radiations may yield inaccurate results. Our implementation differs from existing ones in two ways: it allows for the accounting for important sources of uncertainty in the model (phylogenetic and in parameters specific to the model) and in the specification of informative prior distributions that can increase the precision of the model. We have incorporated this model into a user friendly R package available on the authors' websites. PMID- 23031352 TI - Neonatal ascending aortic thrombus: successful medical treatment. AB - Neonatal aortic thrombosis is a potentially life-threatening condition with significant morbidity and mortality if undiagnosed and untreated. The most common location of arterial thrombosis in neonates is in the abdominal aorta and is associated with umbilical artery catheterisation. There are only a few previous reports of thrombosis in the ascending aorta. We describe a case of ascending aortic thrombosis in a neonate who underwent successful thrombolytic therapy. PMID- 23031351 TI - Exposure to second-hand smoke and direct healthcare costs in children - results from two German birth cohorts, GINIplus and LISAplus. AB - BACKGROUND: Although the negative health consequences of the exposure to second hand tobacco smoke during childhood are already known, evidence on the economic consequences is still rare. The aim of this study was to estimate excess healthcare costs of exposure to tobacco smoke in German children. METHODS: The study is based on data from two birth cohort studies of 3,518 children aged 9-11 years with information on healthcare utilisation and tobacco smoke exposure: the GINIplus study (German Infant Study On The Influence Of Nutrition Intervention Plus Environmental And Genetic Influences On Allergy Development) and the LISAplus study (Influence of Life-Style Factors On The Development Of The Immune System And Allergies In East And West Germany Plus The Influence Of Traffic Emissions And Genetics). Direct medical costs were estimated using a bottom-up approach (base year 2007). We investigated the impact of tobacco smoke exposure in different environments on the main components of direct healthcare costs using descriptive analysis and a multivariate two-step regression analysis. RESULTS: Descriptive analysis showed that average annual medical costs (physician visits, physical therapy and hospital treatment) were considerably higher for children exposed to second-hand tobacco smoke at home (indoors or on patio/balcony) compared with those who were not exposed. Regression analysis confirmed these descriptive trends: the odds of positive costs and the amount of total costs are significantly elevated for children exposed to tobacco smoke at home after adjusting for confounding variables. Combining the two steps of the regression model shows smoking attributable total costs per child exposed at home of ?87 [10 165] (patio/balcony) and ?144 [6-305] (indoors) compared to those with no exposure. Children not exposed at home but in other places showed only a small, but not significant, difference in total costs compared to those with no exposure. CONCLUSIONS: This study shows adverse economic consequences of second hand smoke in children depending on proximity of exposure. Tobacco smoke exposure seems to affect healthcare utilisation in children who are not only exposed to smoke indoors but also if parents reported exclusively smoking on patio or balcony. Preventing children from exposure to second-hand tobacco smoke might thus be desirable not only from a health but also from an economic perspective. PMID- 23031353 TI - Evolution of the fatty acid profile of subcutaneous back-fat adipose tissue in growing Iberian and Landrace * Large White pigs. AB - The lipid content and fatty acid (FA) profile in pig tissues are strongly influenced by genotype and nutrient supply, with implications in meat quality. The de novo lipid synthesis and pattern of FA unsaturation could be an important cause of variation in the overall efficiency of energy utilization among breeds. To test the effects of pig genotype and CP supply on the evolution of back-fat tissue FA profile throughout the growing and finishing stages, 32 Iberian (IB) and Landrace * Large White (LR * LW) barrows were offered one of two diets differing in CP content (13% or 17% as fed). A pair-fed procedure (0.8 * ad libitum intake of IB pigs) was used. Subcutaneous fat samples were taken at the dorso-lumbar region at ~38, 50, 65, 90 and 115 kg BW. Higher proportions of total monounsaturated FA (MUFA; P < 0.01) and lower proportions of total saturated FA (SFA; P < 0.01 to 0.05) were found in the outer back-fat layer of pigs both at 50 and 115 kg BW. Pig genotype affected the FA composition of both subcutaneous back fat layers. The proportions of C18:0 and SFA in fat tissue were higher in IB than in LR * LW pigs from 38 to 65 kg BW, especially in the outer layer. In addition, MUFA contents were higher in IB pigs at 115 kg BW in both layers (+5% on average; P < 0.01). Increased proportions of C18:2 n-6 and polyunsaturated FA (PUFA) were found in LR * LW pigs, irrespective of the stage of growth and back-fat layer (P?0.02). At 50 kg BW, pigs receiving the high-protein diet presented the highest C18:2 n-6, C18:3 n-3, C20:5 n-3 and PUFA contents. A significant genotype * CP content interaction was observed for C18:3 n-3 because of the increased concentration of this FA in LR * LW pigs when offered the 17% CP diet (P < 0.05). Higher C16:0 and SFA contents (+5%; P = 0.03) were found in pigs offered the 13% CP diet and slaughtered at 115 kg BW. There was a genotype * CP interaction for MUFA concentration because of the higher MUFA content observed in IB pigs offered the highest protein content diet (P = 0.03). Our results suggest that genetic variation in de novo lipid synthesis and pattern of FA unsaturation might contribute to explain differences in back-fat FA profile of IB and LR * LW pigs under identical nutritional management. They could be also relevant to explain the low efficiency of nutrient and energy utilization in the IB pig. PMID- 23031355 TI - Probiotics for every body. PMID- 23031356 TI - Postnatal transplantation of interneuronal precursor cells decreases anxiety-like behavior in adult mice. AB - The GABAergic system is critically involved in the modulation of anxiety levels, and dysfunction of GABAergic neurotransmission appears to be involved in the development of generalized anxiety disorder. Precursor cells from the medial ganglionic eminence (MGE) have the ability to migrate and differentiate into inhibitory GABAergic interneurons after being transplanted into the mouse brain. Thus, transplantation of interneuronal precursor cells derived from the MGE into a postnatal brain could modify the neuronal circuitry, increasing GABAergic tone and decreasing anxiety-like behavior in animals. Our aim was to verify the in vivo effects of transplanted MGE cells by evaluating anxiety-like behavior in mice. MGE cells from 14-day green fluorescent protein (GFP) embryos were transplanted into newborn mice. At 15, 30, and 60 days posttransplant, the animals were tested for anxiety behavior with the elevated plus maze (EPM) test. Our results show that transplanted cells from MGE were able to migrate to different regions of the brain parenchyma and to differentiate into inhibitory interneurons. The neuronal precursor cell transplanted animals had decreased levels of anxiety, indicating a specific function of these cells in vivo. We suggested that transplantation of MGE-derived neuronal precursors into neonate brain could strengthen the inhibitory function of the GABAergic neuronal circuitry related to anxiety-like behavior in mice. PMID- 23031354 TI - Does a reduced glucose intake prevent hyperglycemia in children early after cardiac surgery? a randomized controlled crossover study. AB - INTRODUCTION: Hyperglycemia in children after cardiac surgery can be treated with intensive insulin therapy, but hypoglycemia is a potential serious side effect. The aim of this study was to investigate the effects of reducing glucose intake below standard intakes to prevent hyperglycemia, on blood glucose concentrations, glucose kinetics and protein catabolism in children after cardiac surgery with cardiopulmonary bypass (CPB). METHODS: Subjects received a 4-hour low glucose (LG; 2.5 mg/kg per minute) and a 4-hour standard glucose (SG; 5.0 mg/kg per minute) infusion in a randomized blinded crossover setting. Simultaneously, an 8 hour stable isotope tracer protocol was conducted to determine glucose and leucine kinetics. Data are presented as mean +/- SD or median (IQR); comparison was made by paired samples t test. RESULTS: Eleven subjects (age 5.1 (20.2) months) were studied 9.5 +/- 1.9 hours post-cardiac surgery. Blood glucose concentrations were lower during LG than SG (LG 7.3 +/- 0.7 vs. SG 9.3 +/- 1.8 mmol/L; P < 0.01), although the glycemic target (4.0-6.0 mmol/L) was not achieved. No hypoglycemic events occurred. Endogenous glucose production was higher during LG than SG (LG 2.9 +/- 0.8 vs. SG 1.5 +/- 1.1 mg/kg per minute; P = 0.02), due to increased glycogenolysis (LG 1.0 +/- 0.6 vs. SG 0.0 +/- 1.0 mg/kg per minute; P < 0.05). Leucine balance, indicating protein balance, was negative but not affected by glucose intake (LG -54.8 +/- 14.6 vs. SG -58.8 +/- 16.7 MUmol/kg per hour; P = 0.57). CONCLUSIONS: Currently recommended glucose intakes aggravated hyperglycemia in children early after cardiac surgery with CPB. Reduced glucose intake decreased blood glucose concentrations without causing hypoglycemia or affecting protein catabolism, but increased glycogenolysis. TRIAL REGISTRATION: Dutch trial register NTR2079. PMID- 23031357 TI - The effect of lactation length on greenhouse gas emissions from the national dairy herd. AB - Many governments have signed up to greenhouse gas emission (GHGE) reduction programmes under their national climate change obligations. Recently, it has been suggested that the use of extended lactations in dairy herds could result in reduced GHGE. Dairy GHGE were modelled on a national basis and the model was used to compare emissions from lactations of three different lengths (305, 370 and 440 days), and a current 'base' scenario on the basis of maintaining current milk production levels. In addition to comparing GHGE from the average 'National Herd' under these scenarios, results were used to investigate how accounting for lactations of different lengths might alter the estimation of emissions calculated from the National Inventory methodology currently recommended by Intergovernmental Panel on Climate Change. Data for the three lactation length scenarios were derived from nationally recorded dairy performance information and used in the GHGE model. Long lactations required fewer milking cows and replacements to maintain current milk yield levels than short ones, but GHGEs were found to rise from 1214 t of CO2 equivalent (CE)/farm per year for lactations of 305 days to 1371 t CE/farm per year for 440-day lactations. This apparent anomaly can be explained by the less efficient milk production (kg milk produced per kg cow weight) found in later lactation, a more pronounced effect in longer lactations. The sensitivity of the model to changes in replacement rate, persistency and level of milk yield was investigated. Changes in the replacement rate from 25% to 20% and in persistency by -10% to +20% resulted in very small changes in GHGE. Differences in GHGE due to the level of milk yield were much more dramatic with animals in the top 10% for yield, producing about 25% less GHGE/year than the average animal. National Inventory results were investigated using a more realistic spread of lactation lengths than recommended for such calculations using emissions calculated in the first part of the study. Current UK emission calculations based on the National Inventory were 329 Gg of methane per year from the dairy herd. Using the national distribution of lactation lengths, this was found to be an underestimate by about 10%. This work showed that the current rise in lactation length or a move towards calving every 18 months would increase GHGE by 7% to 14% compared with the current scenario, assuming the same milk yield in all models. Increased milk yield would have a much greater effect on reducing GHGE than changes to lactation length, replacement rate or persistency. National Inventory methodology appears to underestimate GHGE when the distribution of lactation lengths is considered and may need revising to provide more realistic figures. PMID- 23031358 TI - Expression of androgen receptors in triple negative breast carcinomas. AB - Triple negative breast cancer (TNBC) consists of a group of tumors with poor prognosis, owing to aggressive tumor biology and lack of targeted therapy. The aim of this study was to assess the immunostaining for androgen receptors (ARs) in the group of TNBC, in addition to basal-like (BL) immunophenotype, BL morphology and conventional clinicopathological factors and to demonstrate its prognostic relevance in this group of tumors. The study included 83 patients. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER2, CK5/6, CK14, EGFR, Ki-67 and AR. Of the 83 TNBC samples, 32.5% showed positive immunostaining for AR, 66.3% had BL immunophenotype, and 48.2% had BL morphology. Positive AR immunostaining was inversely correlated with higher clinical stage, higher mitotic score, higher histological grade and higher proliferation index measured by Ki-67. Significantly more AR negative tumors were observed among the tumors with BL immunophenotype and BL morphology. There was no significant association between positive AR immunostaining and disease free survival or overall survival. More than one third of TNBC were AR-positive, and this represents a potential opportunity for novel targeted treatment in the group of breast tumors for which therapeutic options are currently limited. PMID- 23031359 TI - The effect a of community-based social marketing campaign on recruitment and retention of low-income groups into physical activity programmes - a controlled before-and-after study. AB - BACKGROUND: The beneficial effect of physical activity for the prevention of a range of chronic diseases is widely acknowledged. These conditions are most prevalent in low-income groups where physical activity levels are consistently lower. Social marketing is the government's recommended approach to promoting physical activity but evidence of its effectiveness is limited. The purpose of this study was to examine the effect of a social marketing campaign on the monthly recruitment, attendance and retention levels at a community-based physical activity programme in a low income area. METHODS: A six-month social marketing campaign was designed and delivered in a highly-deprived suburban neighbourhood. Analysis of variance was used to assess effects on recruitment and attendance. chi2 tests of independence were used to compare dropouts and adherers and effectiveness of recruitment mechanisms. Percentages were used to compare adherence rates at intervention, pre-existing sessions in the intervention area and control area sessions. RESULTS: Attendance data were collected weekly and presented and analysed monthly to provide a view of changing participation over the six month intervention period, as compared to attendance at pre-existing sessions in the intervention area and in a control area. Recruitment into intervention sessions was significantly greater than into pre-existing and control area sessions in Month 1 (18.13v1.04 p = .007, 18.13v.30 p=.005), Month 5 (3.45v.84 p=.007, 3.45v.30 p<.001) and Month 6 (5.60v.65 p<.001, 5.60v.25 p<.001). Attendance at intervention sessions was significantly greater in all six months than at pre-existing and control area sessions; Month 1 (38.83v7.17 p<.001, 38.83v4.67, p<.001), Month 2 (21.45v6.20 p<.001, 21.45v4.00, p<.001), Month 3 (9.57v6.15 p<.001, 9.57v3.77, p<.001), Month 4 (17.35v7.31 p<.001, 17.35v4.75, p<.001), Month 5 (20.33v8.81 p=.007, 20.33v4.54 p<.001) and Month 6 (28.72v8.28 p<.001, 28.72v.4.00 p<.001). Drop-out rates in the intervention area were similar to the control area (66.2%v69.9%), and considerably lower than in pre-existing sessions (83%). In months one and two, traditional marketing techniques (posters/outdoor banners/flyers) had the greatest influence on recruitment compared to word of mouth communication (84.5%v15.5%). In months five and six word of mouth influenced 57.5% of new recruits. CONCLUSIONS: Direct comparisons with other programmes were difficult due to a lack of standard definitions of recruitment and adherence and limited reporting of findings. However when compared to pre-existing sessions and sessions delivered in a control area, monthly attendance patterns indicated that a reasonably well funded social marketing campaign increased recruitment into exercise sessions, maintained good levels of attendance and reasonable levels of adherence. Good attendance levels support on-going campaign success by offering evidence of peer and social support for the activity and increasing opportunities for social interaction. They also increase the capacity and reach of the word of mouth communication channels, the most effective form of promotion. Further study into methods of improving exercise adherence is required. PMID- 23031360 TI - Complement system and small HDL particles are associated with subclinical atherosclerosis in SLE patients. AB - BACKGROUND: The complement system is involved in the pathogenic course of SLE. These patients exhibit metabolic disturbances in lipoprotein metabolism characterized by a pro-inflammatory status and an accelerated atherosclerosis. The aim of this study is to investigate whether levels of the complement are associated to the presence of subclinical atherosclerosis, lipid and glucose metabolism and inflammatory markers in SLE patients. METHODS: Sixty-nine consecutive patients with SLE were recruited for the study. Fasting venous blood samples were collected on the same day as the measurements of cIMT were performed. Total plasma lipids and the distribution of subclasses of lipoproteins were analyzed by nuclear magnetic resonance spectroscopy. RESULTS: We found direct correlations between cIMT values and the levels of C3, C4 and CH50. In multivariate analyses, the mean cIMT from the three territories were predicted by age (beta = 0.005, 95% CI: 0.002-0.007, P < 0.001) and the functional hemolytic assay of the complement activity CH50 (beta = 0.003, 95% CI: 0.001-0.006, P < 0.0013). The complement components were associated with BMI, SBP and levels of glucose. Small, dense HDL particles also correlated with the three complement components C3, C4 and CH50 in bivariate analyses. In multivariate analyses small HDL particles predicted levels of C3: beta = 0.024, 95% CI: 0.013-0.035, P < 0.001; and C4: beta = 0.005, 95% CI: 0.002-0.008, P = 0.006. CONCLUSIONS: Activation of the complement system measured by functional assay CH50 is related to subclinical atherosclerosis in quiescent lupus patients and is activated by the small dense HDL particles. PMID- 23031361 TI - Hyperglycemia and arterial stiffness: the Atherosclerosis Risk in the Communities study. AB - OBJECTIVES: Hyperglycemia has been associated with an increased risk of cardiovascular morbidity and mortality. Although numerous studies have demonstrated that hyperglycemia is associated with the atherosis component of atherosclerosis, limited studies have addressed the independent role of hyperglycemia in the pathophysiology of sclerotic vascular disease. We hypothesized that hyperglycemia, as assessed by hemoglobin A1c (HbA1c), would be independently associated two common indices of arterial stiffness (pressure strain elastic modulus (Ep) and Young's elastic modulus (YEM)). METHODS: We examined the cross-sectional association between HbA1c and arterial stiffness using B-mode ultrasound examination of the carotid artery in 9050 participants from the community-based Atherosclerosis Risk in Communities (ARIC) study. We used multivariable linear and logistic regression models to characterize the association between HbA1c and increased Ep and YEM. RESULTS: Higher values of HbA1c were associated in a graded fashion with increased arterial stiffness (P trend < 0.001 for both EP and YEM). After adjusting for traditional risk factors, increasing HbA1c deciles were significantly associated with elevated EP (OR for the highest decile of HbA1c compared to the lowest, 2.01, 95% CI: 1.30, 3.11) and YEM (OR = 1.71, 95% CI: 1.15, 2.55). CONCLUSION: Elevated HbA1c is associated with measures of increased arterial stiffness, even after accounting for arterial wall thickness. This is consistent with the hypothesis that hyperglycemia contributes to arterial stiffness beyond its effects on atherosis and suggests that hyperglycemia is associated with altered material within the arterial wall. PMID- 23031362 TI - Arterial stiffness and ischemic stroke in subjects with and without metabolic syndrome. AB - We conducted a study to evaluate arterial stiffness markers in subjects with acute ischemic stroke and metabolic syndrome and in relation to TOAST subtype of stroke. We enrolled 130 patients with acute ischemic stroke and metabolic syndrome, 127 patients with acute ischemic stroke without metabolic syndrome and 120 control subjects without acute stroke. Applanation tonometry to record pulse wave velocity (PWV). Stroke patients with metabolic syndrome, compared control subjects without stroke showed higher PWV. In subjects with ischemic stroke and metabolic syndrome, PWV was more significantly and positively correlated with body mass index, systolic blood pressure, hypertension, diabetes, glucose blood levels, LDL cholesterol levels, total cholesterol levels, micro-albuminuria, carotid plaque, previous brain infarct at neuro-imaging. Our findings underline important role of both small vessel disease and atherosclerosis on arterial stiffness pathogenesis in the clinical setting of metabolic syndrome. PMID- 23031363 TI - Omega-3 fatty acids: benefits for cardio-cerebro-vascular diseases. AB - BACKGROUND AND PURPOSE: Intracranial artery stenosis (ICAS) is a narrowing of an intracranial artery, which is a common etiology for ischemic stroke. In this commentary, we review key aspects of the discrimination between non-stroke controls and ischemic stroke patients on the background of phospholipid omega3 fatty acid (DHA, EPA) composition. The discussion is embedded in the presentation of general effects of long-chain omega3 polyunsaturated fatty acids (PUFAs) in cardio-cerebro-vascular diseases (CCVDs) and Alzheimer dementia (AD). SUMMARY OF COMMENTARY: ICAS is a common stroke subtype and has emerged as a major factor in recurrent stroke and vascular mortality. DHA and EPA are important fatty acids to distinguish between NCAS (no cerebral arteriosclerotic stenosis) and ICAS in stroke. The risk of ICAS is inversely correlated with the DHA content in phospholipids. Furthermore, a mechanistic explanation has been proposed for the beneficial effects of PUFAs in CCVDs and AD. CONCLUSIONS: Whereas the beneficial effects of EPA/DHA for cardiovascular diseases and stroke seem to be beyond question, preventive effects in patients with very mild cognitive dysfunction and beginning Alzheimer's disease undoubtedly need confirmation by larger clinical trials. A collaborative international basic science approach is warranted considering cautiously designed studies in order to avoid ethical problems. PMID- 23031364 TI - Differential outcome of neurological HCMV infection in two hematopoietic stem cell transplant recipients. AB - BACKGROUND: Human cytomegalovirus (HCMV) infection of the central nervous system (CNS) is a rare but life threatening condition which may follow hematopoietic stem cell transplantation. Diagnosis, monitoring and treatment approaches rely on anecdotal reports. CASE PRESENTATIONS: The different outcomes of HCMV CNS disease in an adult and a pediatric T-cell depleted hematopoietic stem cell transplant (HSCT) recipient are reported. In the first case, HCMV encephalitis emerged in the context of simultaneous impairment of the T- and B-cell immunity. Antiviral treatment only reduced viral load in peripheral blood and the patient died. In the second case, an HCMV radiculopathy was observed and antiviral treatment was adjusted on the basis of intrathecal drug level. In addition, donor HCMV-specific cytotoxic T lymphocytes (CTLs) were infused. Viral load in the CNS decreased and the patient recovered from the acute event. In neither case were drug-resistant HCMV variants observed in blood or CNS samples. CONCLUSIONS: T-cell depleted HSCT appears a predisposing condition for CNS HCMV infection since never observed in other HSCT recipients at our center in the last 15 years. Intensive diagnostic approaches and timely aggressive combination treatments might improve clinical outcome in these patients. PMID- 23031365 TI - Guanidinoacetate methyltransferase deficiency: first steps to newborn screening for a treatable neurometabolic disease. AB - BACKGROUND: GAMT deficiency is an autosomal recessive disorder of creatine biosynthesis resulting in severe neurological complications in untreated patients. Currently available treatment is only successful to stop disease progression, but is not sufficient to reverse neurological complications occurring prior to diagnosis. Normal neurodevelopmental outcome in a patient, treated in the newborn period, highlights the importance of early diagnosis. METHODS: Targeted mutation analysis (c.59G>C and c.327G>A) in the GAMT gene by the QIAxcel system and GAA measurement by a novel two-tier method were performed in 3000 anonymized newborn blood dot spot cards. RESULTS: None of the targeted mutations were detected in any newborn. Two novel heterozygous variants (c.283_285dupGTC; p.Val95dup and c.278_283delinsCTCGATGCAC; p.Asp93AlafsX35) were identified by coincidence. Carrier frequency for these insertion/deletion types of GAMT mutations was 1/1475 in this small cohort of newborns. GAA levels were at or above the 99th percentile (3.12 MUmol/l) in 4 newborns. Second-tier testing showed normal results for 4 newborns revealing 0.1% false positive rate. No GAMT mutations were identified in 4 of the newborns with elevated GAA levels in the first tier testing. CONCLUSION: This is the first two-tier study to investigate carrier frequency of GAMT deficiency in the small cohort of newborn population to establish evidence base for the first steps toward newborn screening for this treatable neurometabolic disorder. PMID- 23031366 TI - Open-label extension study following the Late-Onset Treatment Study (LOTS) of alglucosidase alfa. AB - OBJECTIVE: Late-onset Pompe disease is a progressive, debilitating, and often fatal neuromuscular disorder resulting from the deficiency of a lysosomal enzyme, acid alpha-glucosidase. This extension study was conducted to determine the durability of the efficacy and safety of alglucosidase alfa observed over a period of 78 weeks in the Late-Onset Treatment Study (LOTS). METHODS: Patients who completed the LOTS study were eligible for this open-label extension study and received alglucosidase alfa 20mg/kg biweekly for an additional 26 weeks. The primary efficacy assessments were the distance walked during a 6-minute walk test and the percentage of predicted forced vital capacity in the upright position. Data are reported as change from patient's original LOTS baseline for each measure. RESULTS: The benefit of alglucosidase alfa treatment observed in LOTS at Week 78 was, in general, maintained at Week 104. The mean increase in distance walked measured 28.2 +/- 66.5m from LOTS baseline to Week 78 and 21.3 +/- 78.0m from LOTS baseline to Week 104. The mean change from baseline in percentage of predicted forced vital capacity was 1.3% +/- 5.7% from LOTS baseline to Week 78 and 0.8% +/- 6.7% from LOTS baseline to Week 104. Treatment-related adverse events were mainly infusion-associated reactions observed in 35% of patients. No deaths or anaphylactic reactions were observed during the extension study. CONCLUSIONS: The LOTS Extension study showed that patients treated with alglucosidase alfa for up to 104 weeks maintained the improved walking distance and stabilization in pulmonary function observed in the first 78 weeks of alglucosidase alfa therapy. PMID- 23031368 TI - Local reactions to imiquimod in the treatment of basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common form of skin cancer. The most commonly utilized surgical therapies for BCC are curettage and electrodesiccation (E and C) and surgical excision. Whereas surgical modalities have acceptable levels of morbidity and a high cure rate, effective non-invasive topical medical treatments of BCC are of great interest. Imiquimod is FDA approved for the treatment of superficial BCC (sBCC), actinic keratoses, and genital warts. There are several situations in which imiquimod is commonly utilized. Patients with multiple or large sBCCs may wish to avoid surgical approaches more likely to be complicated by scarring. We have also found imiquimod to be useful in elderly patients with marginal involvement of nodular BCC when the patient wishes to avoid additional surgery. Imiquimod is also useful when sBCC recurs following surgical treatments such as electrodessication and currettage and when sBCC occurs in areas that heal poorly after surgery. It is essential for physicians to explain to patients that an exuberant skin reaction is a positive indication of treatment success. Using clinical images to demonstrate the range of possible local reactions may be more effective than verbal descriptions. This minimizes the potential for premature discontinuation of therapy by patients. PMID- 23031367 TI - Intrafamilial variability for novel TAZ gene mutation: Barth syndrome with dilated cardiomyopathy and heart failure in an infant and left ventricular noncompaction in his great-uncle. AB - BACKGROUND: The tafazzin gene (TAZ) is located at Xq28 and encodes a protein involved in the transacylation of cardiolipin, an essential mitochondrial phospholipid. Mutations in TAZ are associated with Barth syndrome (BTHS), the X linked recessive condition with dilated cardiomyopathy, skeletal myopathy, growth retardation, neutropenia and organic aciduria. TAZ mutations also contribute to left ventricular noncompaction (LVNC), a cardiomyopathy characterized by loose, trabeculated myocardium. CASE REPORT: We report a family with a novel TAZ mutation and the clinical spectrum from severe BTHS in an infant to skeletal myopathy with LVNC in an adult, the oldest individual with BTHS reported. The proband is a 51-year-old male with muscle weakness since early childhood. He remained stable until the age of 43. His initial evaluations found LVNC and borderline neutropenia with no elevation of urine 3-methylglutaconic acid. The proband's great nephew is a 3-year-old who presented at birth with poor feeding, hypotonia, lactic acidosis and hypoglycemia. At three months he was admitted with failure to thrive, lethargy and respiratory distress due to heart failure. Cardiac studies revealed dilated cardiomyopathy with a spongiform trabeculated pattern of the left ventricle. Laboratory studies showed cyclic neutropenia and elevated urine 3-methylglutaconic and 3-methylglutaric acids. At age 11months the patient had a heart transplant. We conducted sequence analysis of the TAZ gene for two affected individuals, the proband first and then his great-nephew. A novel, hemizygous nonsense mutation in TAZ exon 7 (c.583G>T, p.Gly195X) was detected. CONCLUSION: At his current age of 51years-old, the proband is the oldest surviving individual reported with a confirmed molecular diagnosis and features of Barth syndrome. Further studies will be conducted to identify the genetic modifying factor(s) associated with the wide phenotypic range seen in this family. PMID- 23031369 TI - Clinico histopathological correlation in leprosy. AB - INTRODUCTION: Leprosy is a chronic infectious disease caused by M. leprae, which presents in different clinico-pathological forms, depending upon the immune status of the host. Clinical classification gives recognition only to gross appearances of the lesions, whereas the parameters used for the histopathological classification are well defined, precise, and also take into account the immunological features. RESULTS: Of the 182 suspected cases of leprosy which were biopsied, the clinical diagnosis was TT in 32 (17.5%), BT in 70 (38.4%), BB in 5(2.7%), BL in 24 (13.1%), LL in 23 (12.6%), and indeterminate in 28 (15.3%) cases. Of the 182 cases, which were biopsied, only 136 (74.7%) showed histological features consistent with any one type of leprosy. The overall clinicohistological correlation was 74.7 percent. A comparison of the histopathological pattern with that of clinical pattern revealed that the maximum correlation was seen with LL (84.2%), followed by BL (73.3%), BT (64.1%), TT (56%), BB, and IL (50%). CONCLUSION: Because there is some degree of overlap in different types of leprosy, especially the unstable forms, the correlation can be made more accurate by combining clinical and histopathological features. PMID- 23031370 TI - Metastatic atypical fibroxanthoma. AB - Atypical fibroxanthoma (AFX) is an undifferentiated pleomorphic sarcoma that typically has low-grade malignant potential. Although recurrences do occur, only approximately 25 cases of metastasizing AFX have been reported. Herein a patient with an AFX that metastasized and eventuated in death is described. Although AFX remains a diagnosis of exclusion, through this pedagogic case, the clinical, immunohistochemical, and genetic features that can assist in diagnosis are discussed. PMID- 23031371 TI - Extramammary Paget disease: Immunohistochemistry is critical to distinguish potential mimickers. AB - Extra-mammary Paget disease (EMPD) is a rare intra-epithelial carcinoma that is usually found on the apocrine-rich skin of the perineum. We report 2 cases in which EMPD was initially misdiagnosed on the initial punch biopsy as melanoma-in situ and Bowen disease respectively. Reasons for the misdiagnoses included a rare pigmented axillary variant of EMPD in the first case and atypical bowenoid features on H&E in the second. The cases are described with a critical review of the histopathological findings, along with a review of the current literature. This highlights the necessity of a comprehensive immunohistochemical panel for the assessment of intra-epithelial pagetoid atypical cells. PMID- 23031372 TI - Sebaceous nevus syndrome: a case report of a child with nevus sebaceus, mental retardation, seizures, and mucosal and ocular abnormalities. AB - A 12-year-old girl presented with extensive epidermal nevi, new onset seizures, mental retardation, and oral and ocular abnormalities. We briefly review the case and epidermal nevus syndrome (ENS), which is characterized by epidermal nevi occurring in conjunction with neurologic, ocular, skeletal, and/or other system involvement. PMID- 23031373 TI - Intracranial anaplastic meningioma presenting as a cutaneous lesion: a case report of a cutaneous meningioma. AB - Meningiomas are tumors of the central nervous system that rarely present as extracranial soft tissue masses. Meningioma of the skin is referred to as cutaneous meningioma. Cutaneous meningioma of the scalp is extremely rare and may cause diagnostic challenges. A 70-year-old female patient presented with a painless mass on her scalp. A punch biopsy was performed; histological examination of the specimen revealed an infiltration of spindle-shaped and epithelioid atypical cells arranged in whorls. Immunohistochemistry was positive for vimentin and epithelial membrane antigen. On magnetic resonance imaging, a large intracranial mass eroding through the skull was observed. A diagnosis of intracranial anaplastic meningioma was established and excision was performed in the Department of Neurosurgery. It is important to consider intracranial tumors in the differential diagnosis of nodules on scalp. PMID- 23031374 TI - Cutaneous leishmaniasis with histopathologic pattern of non-necrotizing granulomatous dermatitis in patients treated with adalimumab. AB - Human leishmaniasis produced by Leishmania infantum is endemic in Mediterranean countries. In the context of a leishmaniasis outbreak in the town of Fuenlabrada, Madrid, Spain, we had two patients with cutaneous leishmaniasis that developed non-necrotizing cutaneous granulomas. They had both been receiving anti-TNF treatment with adalimumab for rheumatic diseases. Neither of them developed visceral disease and did not require anti-TNF treatment withdrawal to control the cutaneous disease. It is well known that anti-TNF therapy is associated with opportunistic diseases, especially with those in which granuloma formation is an important part of the host defence, as in tuberculosis. We think that granuloma formation through activation of Toll-like receptor-9 and via induction of a Th17 response may be precipitated by the parasites in the dermis. PMID- 23031375 TI - Kikuchi-Fujimoto disease with cutaneous presentation in a patient with subacute cutaneous lupus erythematosus. AB - We report the case of a 45-year-old female patient previously diagnosed with subacute cutaneous lupus erythematosus who presented with a one-week history of fever, tender erythematous nodules on her limbs, and palpable lymphadenopathy. Two incisional biopsies showed histiocytic infiltrates with abundant nuclear debris in the dermis and at the dermosubcutaneous junction with absence of neutrophils, characteristic of Kikuchi-Fujimoto disease (KFD). The dermatologic and dermopathologic details of KFD are very heterogeneous and yet poorly described. We have reviewed the literature regarding KFD cases reported with cutaneous involvement trying to assess the skin features of the KFD or histiocytic necrotizing lymphadenitis. PMID- 23031376 TI - A case of zosteriform lichen planus developing after extracorporeal shockwave lithotripsy. AB - Lichen planus is a relatively common papulosquamous skin disease of unknown etiology. It is characterized by flat-topped, shiny pinkish-purple papules and plaques on the skin or mucous membranes. The zosteriform type is a rare variant of lichen planus with dermatomal or zonal distribution. A 29-year-old female patient was admitted to our clinic with a 2-month history of a pruritic eruption on the dermatomes on the left between T6-T10. Based on clinical and histological findings, the patient was diagnosed with zosteriform lichen planus. The patient had undergone extracorporeal shock wave lithotripsy (ESWL) for left kidney stones two weeks before the appearance of the lesions. There was no history of skin diseases with dermatomal distribution including herpes zoster in the lesion area. This condition was considered as an isomorphic response following ESWL. PMID- 23031377 TI - Fiddler's neck: Chin rest-associated irritant contact dermatitis and allergic contact dermatitis in a violin player. AB - Fiddler's neck refers to an irritant contact dermatitis on the submandibular neck of violin and viola players and an allergic contact dermatitis to nickel from the bracket attaching the violin to the chin rest on the violinist's supraclavicular neck. A 26-year-old woman developed submandibular and supraclavicular left neck lesions corresponding to the locations of the chin rest and bracket that was attached to her violin that held it against her neck when she played. Substitution of a composite chin rest, which did not contain nickel, and the short-term application of a low potency topical corticosteroid cream, resulted in complete resolution of the allergic contact dermatitis supraclavicular neck lesion. The irritant contact dermatitis submandibular neck lesion persisted. In conclusion, violin players are predisposed to developing irritant contact dermatitis or allergic contact dermatitis from the chin rest. We respectfully suggest that the submandibular neck lesions from contact with the chin rest be referred to as 'fiddler's neck - type 1,' whereas the supraclavicular neck lesions resulting from contact of the bracket holding the chin rest in place be called 'fiddler's neck - type 2.' A composite chin rest should be considered in patients with a preceding history of allergic contact dermatitis to nickel. PMID- 23031379 TI - Follicular unit extraction hair transplant automation: options in overcoming challenges of the latest technology in hair restoration with the goal of avoiding the line scar. AB - Follicular unit extraction (FUE) provides many advantages over the strip surgical method of harvesting hair grafts for hair restoration. However, FUE also has its shortcomings because it is a more time intensive approach that results in increased costs and is technically a more challenging technique of hair transplantation. In this manuscript, we seek to share approaches used at our center to help minimize and/or improve on some of the challenges of FUE. PMID- 23031378 TI - Sjogren-Larsson syndrome: importance of early diagnosis and aggressive physiotherapy. AB - Sjogren-Larsson syndrome (SLS) is a congenital ichthyotic disorder with spasticity. We describe a case of a 5-year-old boy with SLS diagnosed clinically based on congenital ichythosis, quadriplegia, and mental retardation. The child responded well to emollients and antihistamines. His quadriplegia was managed by aggressive physiotherapy and mental retardation by stimulation techniques. After a 3-year follow up, significant improvement was seen in his motor and mental disability. This case highlights the importance of clinical diagnosis and early intervention for such a disabling disorder. PMID- 23031380 TI - Erosive pustular dermatosis of the scalp after photodynamic therapy. AB - Erosive pustular dermatosis of the scalp is a rare condition that tends to occur mainly in elderly patients. Clinically it is characterized by the presence of pustules, chronic crusted erosions with progressive scarring alopecia, and skin atrophy. Although etiology remains unclear, it seems to be triggered by local trauma such as surgical procedures, skin graft, ultraviolet light exposure, cryotherapy, craniotomy, or radiotherapy. To our knowledge, erosive pustular dermatosis of the scalp after photodynamic therapy has been seldom reported. We described a 81-year-old woman presenting with erosive pustular dermatosis of the scalp after photodynamic therapy for actinic keratosis. PMID- 23031381 TI - Temporary alopecia after embolization of an arteriovenous malformation. AB - Alopecia after head and neck radiotherapy has been extensively reported in the literature. However, alopecia after endovascular procedures is seldom reported in the dermatological literature. Prolonged fluoroscopic imaging during these procedures may cause serious radiation injuries to the skin, such as dermatitis or alopecia. Radiation-induced temporary alopecia is a peculiar form of radiodermitis that occurs over the areas of the scalp that receive the highest doses of radiation. Although repopulation of alopecic patches occurs spontaneously without treatment, it is important to recognize this disorder to establish a correct diagnosis and inform patients about this transient side effect. We report a 44-year-old woman presenting with temporary alopecia after embolization of an arteriovenous malformation. PMID- 23031382 TI - Follicular acneiform eruption induced by bevacizumab. AB - Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). This antibody, in combination with other antineoplastic agents, is currently used to treat various neoplasms, including colorectal, lung, breast, kidney cancer, and glioblastoma. It is also being used as an off-label intravitreal agent in the treatment of proliferative (neovascular) eye diseases. We report the development of a skin rash with two different patterns in a patient with a hemangiopericytoma of the meninges, a rare aggressive sarcoma, who was treated with repeated intravenous injections of bevacizumab. PMID- 23031383 TI - The "fringe sign" for public education on traction alopecia. AB - The "fringe sign" introduced by Samrao and co-authors is a phenomenally descriptive catch phrase for translating study data for public education in the prevention of traction alopecia. PMID- 23031384 TI - Analysis of several factors of variation of gestation loss in breeding mares. AB - The files for ultrasound diagnosis of gestating mares belonging to the French equine herd recorded for 3 consecutive years were joined with the files for foal birth of these same mares, allowing the statistical analysis of factors of pregnancy loss. For 28 872 positive diagnoses of gestation, 2898 losses were recorded, that is, a global rate of gestation interruption of 9.12%. The etiology of these interruptions is mainly extrinsic: the year and month of insemination, as well as region for climatic reasons. The intrinsic causes that are implicated are breed of the father (heavy breeds except the hypermetric ones lose fewer pregnancies than warm-blooded breeds), age of the mother (losses are lower in mares of 7 to 10 years of age) and status (mares with foals have fewer pregnancy losses than mares not having foaled the previous year), as well as fetuses with consanguinity (when this increases, the pregnancy losses increase as well). However, the additive genetic effect is extremely low; it corresponds to heritability below 5% and few effects of the environment, common to the offspring of the same mare, were identified. This therefore gives little hope of being able to select against the 'gestation loss' trait. PMID- 23031385 TI - Optimised parent selection and minimum inbreeding mating in small aquaculture breeding schemes: a simulation study. AB - The effectiveness of low cost breeding scheme designs for small aquaculture breeding programmes were assessed for their ability to achieve genetic gain while managing inbreeding using stochastic simulation. Individuals with trait data were simulated over 15 generations with selection on a single trait. Combinations of selection methods, mating strategies and genetic evaluation options were evaluated with and without the presence of common environmental effects. An Optimal Parent Selection (OPS) method using semi-definite programming was compared with a truncation selection (TS) method. OPS constrains the rate of inbreeding while maximising genetic gain. For either selection method, mating pairs were assigned from the selected parents by either random mating (RM) or Minimum Inbreeding Mating (MIM), which used integer programming to determine mating pairs. Offspring were simulated for each mating pair with equal numbers of offspring per pair and these offspring were the candidates for selection of parents of the next generation. Inbreeding and genetic gain for each generation were averaged over 25 replicates. Combined OPS and MIM led to a similar level of genetic gain to TS and RM, but inbreeding levels were around 75% lower than TS and RM after 15 generations. Results demonstrate that it would be possible to manage inbreeding over 15 generations within small breeding programmes comprised of 30 to 40 males and 30 to 40 females with the use of OPS and MIM. Selection on breeding values computed using Best Linear Unbiased Prediction (BLUP) with all individuals genotyped to obtain pedigree information resulted in an 11% increase in genetic merit and a 90% increase in the average inbreeding coefficient of progeny after 15 generations compared with selection on raw phenotype. Genetic evaluation strategies using BLUP wherein elite individuals by raw phenotype are genotyped to obtain parentage along with a range of different samples of remaining individuals did not increase genetic progress in comparison to selection on raw phenotype. When common environmental effects on full-sib families were simulated, performance of small breeding scheme designs was little affected. This was because the majority of selection must anyway be applied within family due to inbreeding constraints. PMID- 23031386 TI - Effect of autoimmune diseases on incidence and survival in subsequent multiple myeloma. AB - BACKGROUND: Patients with many types of autoimmune diseases (AIDs) are at an increased risk of cancer, which may depend on underlying dysregulation of the immune system or treatment. We systematically analyzed myeloma risk and survival in patients diagnosed with 33 different AIDs. METHODS: Data on patients with AIDs were retrieved from the Swedish Hospital Discharge Register and were linked to myeloma diagnoses from the Cancer Registry. Standardized incidence ratios (SIR) and hazard ratios (HRs) were calculated for subsequent myeloma between 1964 and 2008. RESULTS: Among patients with the 33 AIDs analyzed, 457 cases of myeloma were diagnosed. The overall SIR for myeloma was 1.12 and the overall HR was 0.92 and non-significant. SIRs for myeloma were significantly increased after ankylosing spondylitis (2.02) and systemic sclerosis (2.63). Only the HR for myeloma after rheumatic fever (5.27) was significantly increased. The SIR for myeloma before age 60 years was 1.45; the SIR for myeloma was only increased in the period 1964-1990 (1.31) and not later (1.04). Only the SIR for myeloma after ankylosing spondylitis was increased in the period 1991-2008 (2.09); the HRs for myeloma were increased after polymyositis/dermatomyositis (6.44) and rheumatic fever (4.43) but there were only three deaths of myeloma after these AIDs. CONCLUSIONS: The present data showed an increase in myeloma SIR after two AIDs, ankylosing spondylitis and systemic sclerosis, and in HR after rheumatic fever. The overall myeloma risk after any AID was no longer increased in the latter follow-up period of 1991 through 2008. PMID- 23031387 TI - Managing severe infection in infancy in resource poor settings. AB - Reducing childhood mortality in resource-poor regions depends on effective interventions to decrease neonatal mortality from severe infection, which contributes up to a half of all neonatal deaths. There are key differences in resource-poor, compared to resource-rich, countries in terms of diagnosis, supportive care and treatment. In resource-poor settings, diagnosis is based on identifying clinical syndromes from international guidelines; microbiological investigations are restricted to a few research facilities. Low levels of staffing and equipment limit the provision of basic supportive care, and most facilities cannot provide respiratory support. Empiric antibiotic treatment guidelines are based on few aetiological and antimicrobial susceptibility data. Research on improving health care systems to provide effective supportive care, and implementation of simple pragmatic interventions, such as low-cost respiratory support, are essential, together with improved surveillance to monitor emerging drug resistance and treatment failures. Reductions in mortality will also be achieved through prevention of infection; including emerging vaccination and anti-sepsis strategies. PMID- 23031388 TI - Gene expression of regulatory enzymes involved in the intermediate metabolism of sheep subjected to feed restriction. AB - The effect of feed restriction on gene expression of regulatory enzymes of intermediary metabolism was studied in two sheep breeds (Australian Merino and Dorper) subjected to two nutritional treatments: feed restriction (85% of daily maintenance requirements) and control (ad libitum feeding), during 42 days. The experimental animals (ram lambs) were divided into four groups, n = 5 (Australian Merino control (MC), Australian Merino Restriction (MR), Dorper control (DC) and Dorper Restriction (DR)). After the trial, animals were sacrificed and samples were taken from liver tissue to quantify glucose levels and gene expression of relevant intermediary metabolism enzymes (phosphofructokinase (PFK), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, glucose-6-phosphatase, glycogen synthase (GS), fatty acid synthase (FAS), glutamate dehydrogenase (GDH) and carbamoyl phosphate synthase (CPS)) through real-time PCR. During the experimental period, the MR animals lost 12.6% in BW compared with 5.3% lost by the Dorper lambs. MC and DC rams gained, respectively, 8.8% and 14% during the same period. Within the Dorper breed, restricted feed animals revealed a significant decrease over controls in the transcription of PFK (1.95-fold) and PK (2.26-fold), both glycolytic enzymes. The gluconeogenesis showed no change in the feed restricted animals of both breeds. DR feed group presented a significant decrease over the homologous Merino sheep group on GS. In both experimental breeds, FAS mRNA expression was decreased in restricted feed groups. GDH expression was decreased only in the DR animals (1.84-fold) indicating a reduced catabolism of amino acids in these animals. Finally, CPS was significantly (P < 0.05) higher in the Dorper sheep, indicating a facilitated urea synthesis in this breed. These results indicate a better adaptation of metabolic intermediate regulatory enzymes and hepatic glucose production of Dorper sheep to feed restriction concurring with the BW results in the experimental groups. PMID- 23031389 TI - Growth changes of the mandibular body with eruption of mandibular third molars: analysis of anatomical morphometry and quantitative bone mineral content by using radiography. AB - This study aimed to analyze growth changes in mandibular body morphology and quantitative bone mineral content (QBMC) with eruption of mandibular third molars (M3s) and the relationship between those variables and posterior mandibular body length. Linear and angular measurements were conducted using standard lateral radiographs of 37 dried mandibles in Hellman's dental developmental stages IVA (14 specimens) to VA (23 specimens). Cortical and trabecular basal bone mineral contents (CBMC and TBMC) in the mandible were expressed in millimeter titanium equivalent values using a titanium step wedge. The largest significant change in the mandibular body morphology was an increase in the horizontal dimension (M2DP' Go': 7.59mm), followed by vertical dimension - total height of the mandibular body (THOMB: 4.96mm) and mandibular cortical width (MCW: 1.22mm). The gonial angle (GA) decreased significantly by 6.72 degrees between stages IVA and VA. The mandibular cortical index (MCI) was classified only as C1 or C2 in each stage. Among 4 types of line profile, types 1 and 2 were most commonly observed in both stages. Mean values for CBMC and TBMC increased significantly between stages IVA and VA. Posterior mandibular body length (MeF'-Go') correlated positively with M2DP'-Go', THOM, MCW, and CBMC (r=0.816, 0.698, 0.595, and 0.507), respectively and negatively with GA (r=-0.582). These results demonstrated that the morphological changes in the posterior mandibular body and the QBMC increased significantly with M3 eruption, while the GA became significantly smaller. The posterior mandibular body length had a linear correlation with these variables. PMID- 23031390 TI - Room temperature passive mode-locked laser based on InAs/GaAs quantum-dot superlattice. AB - Passive mode-locking is achieved in two sectional lasers with an active layer based on superlattice formed by ten layers of quantum dots. Tunnel coupling of ten layers changes the structural polarization properties: the ratio between the transverse electric and transverse magnetic polarization absorption coefficients is less by a factor of 1.8 in the entire electroluminescence spectrum range for the superlattice. PMID- 23031391 TI - Consumption of a high-salt diet by ewes during pregnancy alters nephrogenesis in 5-month-old offspring. AB - Maternal nutrition during pregnancy can affect kidney development in the foetus, which may lead to adverse consequences in the mature kidney. It was expected that high-salt intake by pregnant ewes would lead to a reduction in foetal glomerular number but that the ovine kidney would adapt to maintain homoeostasis, in part by increasing the size of each glomerulus. Merino ewes that were fed either a control (1.5% NaCl) or high-salt (10.5% NaCl) diet during pregnancy, as well as their 5-month-old offspring, were subjected to a dietary salt challenge, and glomerular number and size and sodium excretion were measured. The high-salt offspring had 20% fewer glomeruli compared with the control offspring (P < 0.001), but they also had larger glomerular radii compared with the control offspring (P < 0.001). Consequently, the cross-sectional area of glomeruli was 18% larger in the high-salt offspring than in the control offspring (P < 0.05). There was no difference in the daily urinary sodium excretion between the two offspring groups (P > 0.05), although the high-salt offspring produced urine with a higher concentration of sodium. Our results demonstrated that maternal high salt intake during pregnancy affected foetal nephrogenesis, altering glomerular number at birth. However, the ability to concentrate and excrete salt was not compromised, which indicates that the kidney was able to adapt to the reduction in the number of glomeruli. PMID- 23031392 TI - Chronic pain is more than a peripheral event. PMID- 23031393 TI - The etiology and symptomatology of spontaneous pain. PMID- 23031395 TI - Pain is associated with short leukocyte telomere length in women with fibromyalgia. AB - Telomere length, considered a measure of biological aging, is linked to morbidity and mortality. Psychosocial factors associated with shortened telomeres are also common in chronic pain; yet, little is known about telomere length in pain populations. Leukocyte telomere length was evaluated in 66 women with fibromyalgia and 22 healthy female controls. Participants completed questionnaires and a subgroup of fibromyalgia patients underwent quantitative sensory testing (QST; n = 12) and neuroimaging (n = 12). Telomere length was measured using the quantitative polymerase chain reaction method. Although patients had shorter telomere length than controls, the difference was not statistically significant. However, higher levels of pain within fibromyalgia were associated with shorter telomere length (P = .039). When pain and depression were combined, patients categorized as high-pain/high-depression had an age adjusted telomere length 265 base pairs shorter than those with low-pain/low depression (P = .043), a difference consistent with approximately 6 years of chronological aging. In the subset tested, telomere length was also related to pain threshold and pain sensitivity, as well as gray matter volume, such that patients with shorter telomeres were more sensitive to evoked pain and had less gray matter in brain regions associated with pain processing (eg, primary somatosensory cortex). These preliminary data support a relationship between pain and telomere length. PERSPECTIVE: Our findings support a link between premature cellular aging and chronic pain. These preliminary data imply that chronic pain is a more serious condition than has typically been recognized in terms of bodily aging. PMID- 23031396 TI - Psychometric properties of the Tampa Scale for Kinesiophobia-11 (TSK-11). AB - The aim of this study was to investigate the psychometric properties of an abbreviated version of the Tampa Scale for Kinesiophobia (TSK) in a clinical sample of patients with chronic pain. Chronic pain patients (n = 276) seeking treatment at an interdisciplinary treatment center completed self-report questionnaires including the TSK-13, and 2 tests of physical functioning. Four competing models of the TSK were tested using confirmatory factor analysis. Internal consistency was assessed, as were discriminant evidence of construct validity and concurrent criterion-related validity. Incremental validity was assessed with hierarchical multiple regressions controlling for pain severity. The analyses indicated that an 11-item, 2-factor structure best fit the data. The first factor, somatic focus, consisted of 5 items, while the second factor, activity avoidance, was comprised of 6 items. The TSK-11 scales demonstrated acceptable levels of internal consistency, as well as evidence of discriminant, concurrent criterion-related, and incremental validity. Somatic focus uniquely predicted perceived disability while activity avoidance uniquely predicted actual physical performance, controlling for pain severity. The 2-factor structure of the TSK-11 was found to be a brief, reliable, and valid measure of fear of movement/(re)injury for chronic pain patients. We recommend that the TSK-11 be used in future research and in clinical settings. PERSPECTIVE: In this study, confirmatory factor analysis identified the 2-factor TSK-11 as the best fitting model of TSK factor structure. The TSK-11 is a brief, reliable, and valid measure of fear of movement/(re)injury for chronic pain patients. PMID- 23031397 TI - Pain tolerance and pain perception in adolescents born extremely preterm. AB - Neonatal pain experiences have been associated with altered processing and perception of pain in later life, but findings tend to vary among studies. We have compared experimental pain tolerance and subjective health complaints in a population-based cohort of adolescents born extremely preterm to that of matched term controls. Subjects performed a standardized cold pressor task (hand in ice water) and completed validated questionnaires regarding current subjective health complaints, including pain issues. Thirty-one (89%) of 35 eligible preterm subjects (mean gestational age 26.8 weeks) and 28 (80%) term controls participated in this follow-up study at mean age 17.8 years. Ten (32%) subjects born preterm versus 17 (61%) born at term reached the ceiling time of 180 seconds immersion time in the ice water, a hazard ratio for early withdrawal of 2.05 (95% confidence interval, 1.72 to 2.44), with males explaining most of the difference. For subjects born preterm, the risk of early withdrawal decreased significantly with more days of mechanical ventilation, more pain events, and more doses of morphine during the newborn period. Subjective pain ratings during the cold pressor task as well as health-related complaints and pain issues reported in the questionnaires were similar in the preterm and term groups. PERSPECTIVE: Despite reduced tolerance to experimental pain, subjects born preterm scored their pain experiences similarly to those of term controls. Surprisingly, preterm subjects exposed to most painful and invasive neonatal experiences and also to most doses of morphine had a pain response at follow-up most closely resembling that of the control group. PMID- 23031398 TI - Geographic variation in opioid prescribing in the U.S. AB - Estimates of geographic variation among states and counties in the prevalence of opioid prescribing are developed using data from a large (135 million) representative national sample of opioid prescriptions dispensed during 2008 by 37,000 retail pharmacies. Statistical analyses are used to estimate the extent to which county variation is explained by characteristics of resident populations, their healthcare utilization, proxy measures of morbidity, availability of healthcare resources, and prescription monitoring laws. Geographic variation in prevalence of prescribed opioids is large, greater than the variation observed for other healthcare services. Counties having the highest prescribing rates for opioids were disproportionately located in Appalachia and in southern and western states. The number of available physicians was by far the strongest predictor of amounts prescribed, but only one-third of county variation is explained by the combination of all measured factors. Wide variation in prescribing opioids reflects weak consensus regarding the appropriate use of opioids for treating pain, especially chronic noncancer pain. Patients' demands for treatment have increased, more potent opioids have become available, an epidemic of abuse has emerged, and calls for increased government regulation are growing. Greater guidance, education, and training in opioid prescribing are needed for clinicians to support appropriate prescribing practices. PERSPECTIVE: Wide geographic variation that does not reflect differences in the prevalence of injuries, surgeries, or conditions requiring analgesics raises questions about opioid prescribing practices. Low prescription rates may indicate undertreatment, while high rates may indicate overprescribing and insufficient attention to risks of misuse. PMID- 23031400 TI - Activation of Src family kinases in spinal microglia contributes to formalin induced persistent pain state through p38 pathway. AB - Protein tyrosine phosphorylation has been implicated in normal and pathological functions such as cell proliferation, migration and differentiation. Recently, some studies have shown that Src family kinases (SFKs) were involved in neurological disorders and neuropathic pain states in which microglial activation plays a role. In the formalin test, we have reported that microglia undergo at least 2 distinct stages of activation on the basis of signaling events regarding p38 mitogen-activated protein kinases (MAPK). Here, we investigated the involvement of SFKs signaling in a formalin pain animal model and the association with p38 MAPK. Our results showed that SFKs were activated in the spinal microglia beginning 1 day after peripheral formalin injection lasting for 7 days. Pretreatment with SFK specific inhibitor PP2 could not inhibit formalin-induced spontaneous pain behaviors. However, PP2 inhibited formalin injury, induced persistent mechanical hyperalgesia, and reversed microglial phospho-p38 expression as well using immunohistostaining and Western blot at day 3 and 7 after injection. Our results suggested that the activation of the Src/p38MAPK signaling cascade in spinal microglia contributed to late stage persistent mechanical hyperalgesia evoked by formalin injection into the paw. PERSPECTIVE: This study presents unique properties of spinal microglial activation in a pain animal model. This finding could potentially help clinicians to further understand the contributions of spinal microglia to acute and persistent pain state. PMID- 23031399 TI - Preprotachykinin-A gene disruption attenuates nociceptive sensitivity after opioid administration and incision by peripheral and spinal mechanisms in mice. AB - The preprotachykinin A gene (ppt-A) codes for Substance P (SP), supports nociceptive sensitization, and modulates inflammatory responses after incision. Repeated opioid use produces paradoxical pain sensitization-termed opioid-induced hyperalgesia (OIH) -which can exacerbate pain after incision. Here the contribution of SP to peri-incisional nociceptive sensitization and nociceptive mediator production after opioid treatment was examined utilizing ppt-A knockout (-/-) mice and the neurokinin (NK1) receptor antagonist LY303870. Less mechanical allodynia was observed in ppt-A(-/-) mice compared to wild types (wt) after morphine treatment both before and after incision. Moreover, LY303870 administered with morphine reduced incisional hyperalgesia in wt mice. Incision after saline or escalating morphine treatment upregulated skin IL-1beta, IL-6, G CSF and MIP-1alpha levels in ppt-A(-/-) and wt mice similarly. However, chronic morphine treatment greatly exacerbated increases in skin nerve growth factor levels after incision, an effect entirely dependent upon intact SP signaling. Additionally, SP dependent upregulation of prodynorphin, NMDA1 and NK1 receptor expression in spinal cord was seen after morphine treatment and incision. A similar pattern was seen for 5-HT3 receptor expression in tissue from dorsal root ganglia. Therefore, SP may work at both central and peripheral sites to enhance nociceptive sensitization after morphine treatment and incision. PERSPECTIVE: These studies show that SP signaling modulates enhanced nerve growth factor production and changes in neuronal gene expression seen after incision in mice previously exposed to morphine. PMID- 23031401 TI - Relationship between temporomandibular disorders, widespread palpation tenderness, and multiple pain conditions: a case-control study. AB - The multiple bodily pain conditions in temporomandibular disorders (TMD) have been associated with generalized alterations in pain processing. The purpose of this study was to examine the relationship between the presence of widespread body palpation tenderness (WPT) and the likelihood of multiple comorbid pain conditions in TMD patients and controls. This case-control study was conducted in 76 TMD subjects with WPT, 83 TMD subjects without WPT, and 181 non-TMD matched control subjects. The study population was also characterized for clinical pain, experimental pain sensitivity, and related psychological phenotypes. Results showed that: 1) TMD subjects reported an average of 1.7 comorbid pain conditions compared to .3 reported by the control subjects (P < .001); 2) Compared to control subjects, the odds ratio (OR) for multiple comorbid pain conditions is higher for TMD subjects with WPT [OR 8.4 (95% CI 3.1-22.8) for TMD with WPT versus OR 3.3 (95% CI 1.3-8.4) for TMD without WPT]; 3) TMD subjects with WPT presented with reduced pressure pain thresholds (PPTs) in both cranial and extracranial regions compared to TMD subjects without WPT; and 4) TMD subjects with WPT reported increased somatic symptoms. These findings suggest that pain assessment outside of the orofacial region may prove valuable for the classification, diagnosis, and management of TMD patients. PERSPECTIVE: TMD subjects with WPT experience a greater level of multiple comorbid pain conditions, compared to TMD subjects without WPT and non-TMD controls. Integration of bodily pain assessments can be informative for evaluation, diagnosis, and management of TMD. PMID- 23031402 TI - Emerging new therapeutic options for paclitaxel-induced neuropathic pain. PMID- 23031403 TI - Extramedullary versus intramedullary tibial cutting guides in megaprosthetic total knee replacement. AB - BACKGROUND: In a standard total knee replacement, tibial component alignment is a key factor for the long term success of the surgery. The purpose of this study is to compare the accuracy of extramedullary and intramedullary tibial cutting guides used in indigenous and imported implants respectively, in positioning of the tibial components in megaprosthetic knee replacements. METHODS: A comparative study of the accuracy of extramedullary and intramedullary tibial cutting guides was carried out in 92 megaprosthetic knee replacements for distal femoral tumors. For the proximal tibia cut for tibial component placement, an extramedullary guide was used in 65 patients and an intramedullary guide was used in 27 patients. Tibial component alignment angles were measured in postoperative X-rays with the help of CAD software. RESULTS: There was more varus placement in coronal plane with extramedullary cutting guide (-1.18 +/- 2.4 degrees) than the intramedullary guide (-0.34 +/- 2.31 degrees) but this did not reach statistical significance. The goal of 90 +/- 2 degrees alignment of tibial component was achieved in 54% of patients in the extramedullary group versus 67% in the intramedullary group. In terms of sagittal plane alignment, extramedullary guide showed less accurate results (2.09 +/- 2.4 degrees) than intramedullary guide (0.50 +/- 3.80 degrees) for tibial component alignment, though 78% of patients were aligned within the goal of 0-5 degrees of tibial slope angle in extramedullary group versus 63% in intramedullary group. The mean error in the measurements due to rotation of the knee during taking the X-rays was less than 0.1 degrees and distribution of the X-rays with the rotation of knee was similar in both the groups. CONCLUSIONS: Overall, in megaprosthetic knee replacement intramedullary guides gave more accurate results in sagittal plane and exhibited similar variability as of extramedullary guides in coronal plane. PMID- 23031404 TI - Peripheral PDLIM5 expression in bipolar disorder and the effect of olanzapine administration. AB - BACKGROUND: One of the genes suggested to play an important role in the pathophysiology of bipolar disorder (BPD) is PDLIM5, which encodes LIM domain protein. Our main objective was to examine the effect of olanzapine treatment on PDLIM5 mRNA expression in the peripheral blood leukocytes of BPD patients. METHODS: We measured the expression of PDLIM5 mRNA from 16 patients with BPD Type I after 0, 4, and 8 weeks of treatment with olanzapine using quantitative real time PCR. The Young Mania Rating Scale was used to evaluate the severity of manic symptoms in BPD patients. We also compared PDLIM5 mRNA expression in treatment naive BPD patients with that in healthy control subjects. RESULTS: No significant difference was found in PDLIM5 mRNA expression between patients before olanzapine treatment and following 4 and 8 weeks of treatment (p>0.05). Although we observed a significant reduction in the severity of manic symptoms in all BPD patients (p<0.05), the effectiveness of the medication did not significantly correlate with the expression of PDLIM5 mRNA (p>0.05). Interestingly, PDLIM5 mRNA expression differed significantly between treatment-naive BPD patients and healthy control subjects (p=0.002). CONCLUSION: PDLIM5 mRNA expression did not appear to be a reflection of the efficacy of olanzapine in reducing the manic symptoms of BPD. The significant difference in expression of PDLIM5 mRNA in the peripheral blood leukocytes of treatment-naive BPD patients versus that of healthy control subjects, however, suggests that it may be a good biological marker for BPD. PMID- 23031405 TI - Evolution of major histocompatibility complex class I and class II genes in the brown bear. AB - BACKGROUND: Major histocompatibility complex (MHC) proteins constitute an essential component of the vertebrate immune response, and are coded by the most polymorphic of the vertebrate genes. Here, we investigated sequence variation and evolution of MHC class I and class II DRB, DQA and DQB genes in the brown bear Ursus arctos to characterise the level of polymorphism, estimate the strength of positive selection acting on them, and assess the extent of gene orthology and trans-species polymorphism in Ursidae. RESULTS: We found 37 MHC class I, 16 MHC class II DRB, four DQB and two DQA alleles. We confirmed the expression of several loci: three MHC class I, two DRB, two DQB and one DQA. MHC class I also contained two clusters of non-expressed sequences. MHC class I and DRB allele frequencies differed between northern and southern populations of the Scandinavian brown bear. The rate of nonsynonymous substitutions (dN) exceeded the rate of synonymous substitutions (dS) at putative antigen binding sites of DRB and DQB loci and, marginally significantly, at MHC class I loci. Models of codon evolution supported positive selection at DRB and MHC class I loci. Both MHC class I and MHC class II sequences showed orthology to gene clusters found in the giant panda Ailuropoda melanoleuca. CONCLUSIONS: Historical positive selection has acted on MHC class I, class II DRB and DQB, but not on the DQA locus. The signal of historical positive selection on the DRB locus was particularly strong, which may be a general feature of caniforms. The presence of MHC class I pseudogenes may indicate faster gene turnover in this class through the birth-and-death process. South-north population structure at MHC loci probably reflects origin of the populations from separate glacial refugia. PMID- 23031406 TI - Moving from rhetoric to reality: adapting Housing First for homeless individuals with mental illness from ethno-racial groups. AB - BACKGROUND: The literature on interventions addressing the intersection of homelessness, mental illness and race is scant. The At Home/Chez Soi research demonstration project is a pragmatic field trial investigating a Housing First intervention for homeless individuals with mental illness in five cities across Canada. A unique focus at the Toronto site has been the development and implementation of a Housing First Ethno-Racial Intensive Case Management (HF ER ICM) arm of the trial serving 100 homeless individuals with mental illness from ethno-racial groups. The HF ER-ICM program combines the Housing First approach with an anti-racism/anti-oppression framework of practice. This paper presents the findings of an early implementation and fidelity evaluation of the HF ER-ICM program, supplemented by participant narrative interviews to inform our understanding of the HF ER-ICM program theory. METHODS: Descriptive statistics are used to describe HF ER-ICM participant characteristics. Focus group interviews, key informant interviews and fidelity assessments were conducted between November 2010 and January 2011, as part of the program implementation evaluation. In-depth qualitative interviews with HF ER-ICM participants and control group members were conducted between March 2010 and June 2011. All qualitative data were analysed using grounded theory methodology. RESULTS: The target population had complex health and social service needs. The HF ER-ICM program enjoyed a high degree of fidelity to principles of both anti-racism/anti oppression practice and Housing First and comprehensively addressed the housing, health and sociocultural needs of participants. Program providers reported congruence of these philosophies of practice, and program participants valued the program and its components. CONCLUSIONS: Adapting Housing First with anti racism/anti-oppression principles offers a promising approach to serving the diverse needs of homeless people from ethno-racial groups and strengthening the service systems developed to support them. The use of fidelity and implementation evaluations can be helpful in supporting successful adaptations of programs and services. PMID- 23031407 TI - Effects of dietary grape seed extract on growth performance, amino acid digestibility and plasma lipids and mineral content in broiler chicks. AB - Polyphenols are chemically and biologically active compounds. Grape seed extracts (GSEs) have been widely used as a human food supplement for health promotion and disease prevention. However, there is little information regarding its application in animal feeds. An experiment was conducted to investigate the effect of inclusion of GSE at 0.025, 0.25, 2.5 and 5.0 g/kg in a wheat soya bean control diet on growth performance, protein and amino acid (AA) digestibility and plasma lipid and mineral concentrations in broiler chickens at 21 days of age. Performance was not affected by dietary treatment except in the case of birds fed the diet with the highest GSE concentration, which showed a worsening of weight gain and feed conversion. Apparent ileal digestibility (AID) of protein was significantly reduced in the birds fed the highest concentration of GSE, which also had a reduction on the AID of arginine, histidine, phenylalanine, cystine, glutamic acid and proline compared with those fed control diet. The inclusion of graded concentration of GSE in the chicken diets caused a significant linear decrease in the concentrations of plasma copper, iron and zinc. Plasma cholesterol, triglycerides and lipoproteins (high-density lipoprotein, low density lipoprotein and very-low-density lipoprotein) concentrations were not affected by dietary GSE. In conclusion, this study demonstrated that incorporation of GSE in chicken diets up to 2.5 g/kg had no adverse effect on growth performance or protein and AA digestibility. Feed conversion was reduced and growth rate was retarded, when chickens were fed 5 g/kg of GSE. This study also indicated that grape polyphenols reduce the free plasma minerals. PMID- 23031409 TI - Flood-related work disruption and poor health outcomes among university students. AB - INTRODUCTION: Globally, floods are the most common and among the most devastating of natural disasters. Natural disasters such as floods impact local businesses, increasing local unemployment by up to 8.2%. Previous research has linked individual losses from disasters with symptoms such as posttraumatic stress disorder. However, little is known about the impact of work disruption and job loss on post-disaster psychological symptoms. University students, who are often living far away from family support structures and have limited resources, may be particularly vulnerable. This study examines student psychological health following a large flood at a university. HYPOTHESIS: Students who experienced flood-related job loss or disruption had a higher proportion of psychological symptoms than those who did not experience job loss or disruption, controlling for individual loss such as injury, home loss or evacuation. METHODS: On June 8, 2008, a major flood affected seven US Midwestern states. A total of two dozen people were killed and 148 injured, although no deaths or serious injuries were reported in the population used for this study. At the study university, operations were closed for one week, and 20 buildings were severely damaged. A cross-sectional survey of all students enrolled during the semester of the flood was conducted. Students were sent an online survey six weeks after the flood. In addition to questions about damage to their homes, the survey asked students if their work was disrupted because of the floods. Symptoms of PTSD were measured through the modified Child PTSD Symptom Scale. RESULTS: Of the 1,231 responding students with complete surveys, 667 (54.2%) reported that their work was disrupted due to the floods. Controlling for gender, ethnicity, grade, and damage to the student's home, students reporting work disruption were more than four times more likely to report PTSD symptoms (95% CI, 2.5-8.2). Work disruption was independently associated with decreases in general mental and physical health following the floods, as well as with increases in alcohol use. CONCLUSION: Disaster research has focused on damage to individuals and homes, but there has been little focus on work losses. Individuals who lose their jobs may be a vulnerable population post-disaster. PMID- 23031408 TI - Effects of respiratory mechanics on the capnogram phases: importance of dynamic compliance of the respiratory system. AB - INTRODUCTION: The slope of phase III of the capnogram (SIII) relates to progressive emptying of the alveoli, a ventilation/perfusion mismatch, and ventilation inhomogeneity. S(III) depends not only on the airway geometry, but also on the dynamic respiratory compliance (Crs); this latter effect has not been evaluated. Accordingly, we established the value of SIII for monitoring airway resistance during mechanical ventilation. METHODS: Sidestream capnography was performed during mechanical ventilation in patients undergoing elective cardiac surgery (n = 144). The airway resistance (Raw), total respiratory resistance and Crs displayed by the ventilator, the partial pressure of arterial oxygen (PaO2) and S(III) were measured in time domain (S(T-III)) and in a smaller cohort (n = 68) by volumetry (S(V-III)) with and without normalization to the average CO2 phase III concentration. Measurements were performed at positive end-expiratory pressure (PEEP) levels of 3, 6 and 9 cmH2O in patients with healthy lungs (Group HL), and in patients with respiratory symptoms involving low (Group LC), medium (Group MC) or high Crs (Group HC). RESULTS: S(T-III) and S(V-III) exhibited similar PEEP dependencies and distribution between the protocol groups formed on the basis of Crs. A wide interindividual scatter was observed in the overall Raw S(T-III) relationship, which was primarily affected by Crs. Decreases in Raw with increasing PEEP were reflected in sharp falls in S(III) in Group HC, and in moderate decreases in S(III) in Group MC, whereas S(T-III) was insensitive to changes in airway caliber in Groups LC and HL. CONCLUSIONS: SIII assessed in the time domain and by volumetry provide meaningful information about alterations in airway caliber, but only within an individual patient. Although S(T-III) may be of value for bedside monitoring of the airway properties, its sensitivity depends on Crs. Thus, assessment of the capnogram shape should always be coupled with Crs when the airway resistance or oxygenation are evaluated. PMID- 23031410 TI - Two-port laparoscopic donor nephrectomy with simple retraction technique. AB - OBJECTIVE: To present our experience of 2-port laparoscopic donor nephrectomy (TPLDN) and to introduce a simple retraction suture technique. MATERIAL AND METHODS: From October 2010 to November 2010, 10 consecutive, left TPLDNs were performed. The SILS Port was inserted through the umbilicus and was used for 5-mm laparoscope and laparoscopic instruments. A 12-mm trocar, for another working channel, was inserted along the midclavicular line at the umbilicus level. No articulating or bent laparoscopic instruments were needed. Two retraction sutures were used; a 3-0 Prolene suture was passed through the pericolic fat and then brought out of the abdominal wall and secured to the skin. Another suture was passed around the lower pole fat of the kidney, which was then fixed on the abdominal wall with a clamp. RESULTS: TPLDN was performed successfully in all patients, with no conversions to a conventional laparoscopic procedure or additional trocar insertion needed. The mean operative time was 152 +/- 16.3 minutes, and the mean warm ischemia time was 2.9 +/- 0.9. The average estimated blood loss was 77.3 +/- 70 mL, and the postoperative hospital stay was 3.6 +/- 0.6 days. No perioperative or postoperative complications were observed. Cosmesis was excellent, with a mean incision length of 5.6 +/- 0.4 cm. All allografts functioned after transplantation. CONCLUSION: Our initial experience suggests that TPLDN appears safe and cosmetically effective and a feasible option for donor nephrectomy. The appropriate use of retraction sutures, during TPLDN, helps to overcome the technical problems associated with the inadequate retraction and exposure. PMID- 23031411 TI - Posterior nutcracker phenomenon in patient with renal arteriovenous malformation. AB - A 31-year-old woman was referred to our hospital because of gross hematuria. Radiologic examinations with computed tomography and magnetic resonance imaging revealed renal arteriovenous malformation in the right kidney and an entrapped retroaortic left renal vein. Because the patient was free of hematuria, she refused additional treatment for economic reasons. Renal arteriovenous malformation associated with the posterior nutcracker phenomenon is a very rare condition. PMID- 23031412 TI - Effectiveness of gestational diabetes treatment: a systematic review with quality of evidence assessment. AB - AIMS: To evaluate the effectiveness of gestational diabetes (GDM) treatment compared to usual antenatal care, in the prevention of adverse pregnancy outcomes. Additionally, to assess the quality of the evidence to support GDM treatment according to GRADE guidelines. METHODS: Fourteen electronic databases and reference lists of relevant literature were searched for articles published from inception to February, 2012. Controlled clinical trials comparing GDM treatment to usual antenatal care were included. Independent extraction of articles was done by two authors using predefined data fields. RESULTS: Seven trials involving 3157 women were included. We found high quality evidence that treatment of GDM reduces macrosomia (RR=0.47; 95% CI, 0.34-0.65; NNT=11.4) and large for gestational age birth (RR=0.57; 95% CI, 0.47-0.71; NNT=12.2); moderate quality evidence that treatment reduces preeclampsia (RR=0.61; 95% CI, 0.46-0.81; NNT=21.0) and hypertensive disorders in pregnancy (RR=0.64; 95% CI, 0.51-0.81; NNT=18.1); and low quality evidence that treatment reduces shoulder dystocia (RR=0.41; 95% CI, 0.22-0.76; NNT=48.8). No statistically significant reduction was seen for caesarean section. No increase in small for gestational age or preterm birth was found. CONCLUSIONS: Treatment of GDM is effective in reducing macrosomia (high quality evidence), preeclampsia and shoulder dystocia. PMID- 23031413 TI - Identification of phase II metabolites of thiol-conjugated [6]-shogaol in mouse urine using high-performance liquid chromatography tandem mass spectrometry. AB - Ginger is frequently consumed as a spice and has numerous medicinal properties. Extensive research has characterized the anti-inflammatory, antioxidant, and antitumor activities of ginger. Previously, we reported the mercapturic acid pathway as a major metabolic route of [6]-shogaol in mice and the thiol conjugates of [6]-shogaol existed in the glucuronidated and sulfated forms in mouse urine. However, their structures are still unknown. In the present study, we further investigated the phase II metabolism of thiol-conjugated [6]-shogaol in mouse urine, in which we identified sixteen phase II metabolites of thiol conjugated [6]-shogaol: 5-cysteinyl-[6]-shogaol glucuronide (9), 5-N acetylcysteinyl-[6]-shogaol glucuronide (10), 5-cysteinylglycinyl-[6]-shogaol glucuronide (11), 5-methylthio-[6]-shogaol glucuronide (12), 5-cysteinyl-M6 glucuronide (13 and 14), 5-cysteinyl-M6 sulfate (15 and 16), 5-N-acetylcysteinyl M6 glucuronide (17 and 18), 5-cysteinylglycinyl-M6 glucuronide (19 and 20), 5 cysteinylglycinyl-M6 sulfate (21 and 22), and 5-methylthio-M6 glucuronide (23 and 24) using liquid chromatography/electrospray ionization tandem mass spectrometry. The structures of these metabolites were confirmed by analyzing their MS(n) (n=1 4) spectra as well as comparing with the tandem mass spectra of authentic standards. To the best of our knowledge, this is the first report involving identification of phase II urinary metabolites of [6]-shogaol in mice. PMID- 23031415 TI - Low molecular weight dextran sulfate binds to human myoblasts and improves their survival after transplantation in mice. AB - Myoblast transplantation represents a promising therapeutic strategy in the treatment of several genetic muscular disorders including Duchenne muscular dystrophy. Nevertheless, such an approach is impaired by the rapid death, limited migration, and rejection of transplanted myoblasts by the host. Low molecular weight dextran sulfate (DXS), a sulfated polysaccharide, has been reported to act as a cytoprotectant for various cell types. Therefore, we investigated whether DXS could act as a "myoblastprotectant" either in vitro or in vivo after transplantation in immunodeficient mice. In vitro, DXS bound human myoblasts in a dose-dependent manner and significantly inhibited staurosporine-mediated apoptosis and necrosis. DXS pretreatment also protected human myoblasts from natural killer cell-mediated cytotoxicity. When human myoblasts engineered to express the renilla luciferase transgene were transplanted in immunodeficient mice, bioluminescence imaging analysis revealed that the proportion of surviving myoblasts 1 and 3 days after transplantation was two times higher when cells were preincubated with DXS compared to control (77.9 +/- 10.1% vs. 39.4 +/- 4.9%, p = 0.0009 and 38.1 +/- 8.5% vs. 15.1 +/- 3.4%, p = 0.01, respectively). Taken together, we provide evidence that DXS acts as a myoblast protectant in vitro and is able in vivo to prevent the early death of transplanted myoblasts. PMID- 23031414 TI - Survey of nasal carriage of Staphylococcus aureus and intestinal parasites among food handlers working at Gondar University, Northwest Ethiopia. AB - BACKGROUND: Food borne disease are major health problems in developing countries like Ethiopia. Food handlers with poor personal hygiene working in food establishments could be potential sources of disease due to pathogenic organisms. However; information on disease prevalence among food handlers working in University of Gondar cafeterias are very scarce. The aim of this study is to assess the prevalence of nasal carriage of Staphylococcus aureus, their drug resistance pattern and prevalence of intestinal parasites among food handlers working in University of Gondar student's cafeterias. METHOD: A cross sectional study was conducted among food handlers working in University of Gondar student's cafeterias. A pretested structured questionnaire was used for collecting data. Nasal swab and stool were investigated for S. aureus and intestinal parasites; respectively as per the standard of the laboratory methods. RESULTS: Among 200 food handlers, females comprised 171(85.5%). The majority (67.5%) of the food handlers were young adults aged 18-39 years. One hundred ninety four (97%) of the food handlers were not certified as a food handler. Forty one (20.5%) food handlers were positive for nasal carriage of S. aureus, of these 4(9.8%) was resistant for methicilin. Giardia lamblia was the most prevalent parasites 22 (11%), followed by Ascaris lumbricoides 13(6.5%), Entamoeba histolytica 12 (6%), Strongyloides stercolaris (0.5), Taenia species 1(0.5%) and Schistosoma mansoni 1(0.5%). CONCLUSION: The finding stressed that food handlers with different pathogenic micro organisms may pose significant risk on the consumers. Higher officials should implement food handler's training on food safety, periodic medical checkup and continuous monitoring of personal hygiene of food handlers. PMID- 23031416 TI - A non-invasive technique for estimating carpal tunnel pressure by measuring shear wave speed in tendon: a feasibility study. AB - Although a close relationship between carpal tunnel pressure and median nerve dysfunction has been found, the current methods for pressure measurements are invasive, using a catheter in the carpal canal to monitor the pressure. A noninvasive method for quantifying carpal tunnel pressure would be useful as an alternative to the catheter method. In this study, a simplified experimental model was developed to measure the shear wave speed in a canine Achilles tendon under different tunnel pressures. The results showed that the speed of waves through the inside-tunnel tendon had a linear relationship with the pressure in the tunnel (first measurement: r=0.966, P<0.001; second measurement: r=0.970, P<0.001). This indicates that the tendon could serve as a strain gauge to evaluate the tunnel pressure by detecting the changes of wave propagation speed. However, further validations in human cadavers and clinical subjects are necessary. PMID- 23031417 TI - The role of organic selenium in cadmium toxicity: effects on broiler performance and health status. AB - This work was part of a project designed to assess whether organic selenium (Se) can protect against the toxic effects of cadmium (Cd). A total of 300 1-day-old, as hatched, broilers were randomly distributed in four dietary treatments with five replicate pens per treatment. In T1 treatment, broilers were fed a diet with 0.3 mg/kg added Se, as Se-yeast, without added Cd; in T2, broilers were fed a diet with 0.3 mg/kg Se and 10 mg/kg Cd; in T3, broilers were fed a diet with 0.3 mg/kg Se and 100 mg/kg of Cd; and in T4 treatment broilers were fed a diet with 3 mg/kg Se and 100 mg/kg Cd. The Cd was added to diets T2, T3 and T4 as CdCl2. On the 4th and 6th week, two broilers per replicate pen were killed in order to obtain whole blood, liver, kidney and breast samples. Body mass, feed conversion ratio and mortality were assessed and haematological analyses were performed. Se and Cd levels in tissues were analysed by inductively coupled plasma mass spectrometry. Broilers supplemented with 0.3 mg/kg Se can tolerate low levels of Cd added to the diets, as there were no significant negative effects on the examined performance parameters, whereas addition of excess Cd led to an impairment of broilers' performance. Mortality of broilers did not differ between the four dietary treatments at any interval point or the whole period. The examined haematological parameters such as haematocrit, total blood protein concentration, and leukocytes types ranged within physiological values, revealing no negative health effects after simultaneous Cd and Se addition. The present study indicated that Se can help against the negative effects of Cd, but cannot counteract all of its negative effects. PMID- 23031418 TI - Factors associated with low bone mineral density in a Brazilian cohort of vertically HIV-infected adolescents. AB - OBJECTIVE: To assess the prevalence and factors associated with low bone mineral density (BMD) in HIV-infected adolescents. METHODS: This was a cross-sectional study of a Brazilian cohort of vertically HIV-infected adolescents. Body composition and lumbar spine (LS) and total body (TB) BMD were estimated by dual energy X-ray absorptiometry (DXA). Low BMD was considered for a Z-score <=-2 standard deviations. Pubertal development, anthropometric data, laboratory measurements, antiretroviral regimen, and time of immunological and virological recovery were evaluated as factors associated with a low BMD. RESULTS: Seventy four adolescents aged 17.3 +/- 1.8 years were studied. Low BMD was present in 32.4% of them. LS and TB BMD Z-scores were positively correlated with weight, body mass index (BMI), BMI Z-score, total body fat, and nutritional status. Patients on tenofovir had lower LS and TB BMD Z-scores. Time on tenofovir was indirectly correlated with LS and TB BMD Z-scores. No difference was found regarding levels of calcium, parathyroid hormone, or 25-hydroxyvitamin D according to BMD status. CONCLUSIONS: Control of the HIV infection, especially before the initiation of puberty, might have a positive influence on bone gain. Body composition and nutritional status had a positive influence on BMD that was more evident in females, suggesting that nutritional intervention may have a positive impact on BMD. PMID- 23031419 TI - Cytomegalovirus viremia in dried blood spots is associated with an increased risk of death in HIV-infected patients: a cohort study from rural Tanzania. AB - OBJECTIVES: The objectives of the study were to assess the utility of dried blood spots (DBS) for the detection of cytomegalovirus (CMV) antibody and viremia in a resource-poor setting, to study the prevalence of CMV antibody and viremia in HIV infected patients with access to antiretroviral therapy (ART) in Tanzania, and to relate CMV viremia to outcome. METHODS: DBS were prepared from 168 ART-naive patients at baseline. Demographic, clinical, and laboratory data were obtained from patient records. CMV antibody was analyzed by chemiluminescent microparticle immunoassay and viremia by quantitative PCR. RESULTS: All patients were CMV seropositive. At baseline 38 (22.6%) had detectable CMV viremia and 14 (8.3%) had a CMV viral load >= 200 copies/ml. In 135 patients available for follow-up, CMV >= 200 copies/ml was an independent risk factor for death with a hazard ratio of 5.0 (95% confidence interval 2.1-11.9) after adjusting for confounders. Symptoms compatible with CMV disease were common with viremia >= 200 copies/ml and CD4+ T cell counts <100 cells/mm(3), but confirmatory diagnostic procedures were unavailable. CONCLUSIONS: DBS are suitable for the detection of CMV antibody and viremia in HIV patients in resource-poor areas. CMV viremia was frequent and associated with an increased risk of death. Improved diagnosis and treatment of CMV may improve the prognosis for HIV-infected patients in developing countries and should be addressed in future studies. PMID- 23031420 TI - Measures to improve dairy cow foot health: consequences for farmer income and dairy cow welfare. AB - Dairy farming in western countries with cubicle housing is an efficient way of dairy farming. Though, a disadvantage is the high prevalence and incidence of foot disorders (clinical and subclinical), which cause high economic losses and also seriously impair the welfare of dairy cattle. To point out the importance of reducing the amount and severity of foot disorders, advice to farmers should include information about the scale of the problem and the consequences in terms of economics and animal welfare. To provide support in making decisions on implementing intervention measures, insight into costs and benefits of different measures should be available. The objective of this study, therefore, is to provide more insight into the costs and benefits, for farmer and cow, of different intervention measures to improve dairy cow foot health. Intervention measures were modeled when they were applicable on a dairy farm with cubicle housing and when sufficient information was available in literature. Net costs were calculated as the difference between the costs of the measure and the economic benefits resulting from the measure. Welfare benefits were calculated as well. Cost-effective measures are: improving lying surface (mattress and bedding, ?7 and ?1/cow per year, respectively), reducing stocking density (break even) and performing additional foot trimming (?1/cow per year). Simultaneously, these measures have a relative high welfare benefit. Labor costs play an important role in the cost-effectiveness of labor-intensive measures. More insight into cost effectiveness and welfare benefits of intervention measures can help to prioritize when choosing between intervention measures. PMID- 23031422 TI - Overwhelming response to Dabrafenib in a patient with double BRAF mutation (V600E; V600M) metastatic malignant melanoma. AB - The recent findings brought the necessity of testing the mutational status of a series of genes which had been already identified as responsible for melanomas development and progression, such as BRAF, CKIT and PTEN: the consequent results are, in fact, essential to guide the assessment of the novel treatment protocols based on tailored targeted therapies. We present here the case of a 66 year-old male patient, diagnosed with an advanced melanoma in June 2011, and treated with Dabrafenib for double mutant metastatic disease. The patient was referred to our attention for a large exophytic malignant melanoma on the left shoulder. After complete surgical excision and elective lymph node dissection for presence of metastatic sentinel lymph node, the patient has started high-dose interferon alfa 2b injections as adjuvant therapy for a complete negative staging. The treatment was interrupted in August 2011 due to the appearance of metastatic lymph nodes. Tumor burden was rapidly growing reaching in few months the size of a tennis ball for the tumor mass located in the shoulder. Mutational study of the tumor revealed a double BRAF mutation on V-600E and V600M. This finding incited us to enroll the patient in compassionate Dabrafenib clinical trial. The therapy was started on may 2012 at 150 mg bid dosage. Almost surprisingly for the rapidity of the effect, one week later the lesion on the shoulder has reduced its size by 60% and one month later it has completely disappeared from sight. CT scan of June 2012 documented the astonishing clinical response. PMID- 23031421 TI - Effects of escitalopram on menopause-specific quality of life and pain in healthy menopausal women with hot flashes: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effects of escitalopram 10-20 mg/day on menopause related quality of life and pain in healthy menopausal women with hot flashes. STUDY DESIGN: A double-blind, placebo-controlled randomized trial of escitalopram 10-20mg/day vs. identical placebo was conducted among 205 women ages 40-62 years with an average of >=4 daily hot flashes recruited at 4 clinical sites from July 2009 to June 2010. MAIN OUTCOME MEASURES: The primary trial outcomes, reported previously, were the frequency and severity of vasomotor symptoms at 8 weeks. Here, we report on the pre-specified secondary endpoints of total and domain scores from the Menopause-Specific Quality of Life Questionnaire (MENQOL) and the pain intensity and interference scale (PEG). RESULTS: Outcome data were collected on 97% of randomized women and 87% of women took at least 70% of their study medication. Treatment with escitalopram resulted in significantly greater improvement in total MENQOL scores (mean difference at 8 weeks of -0.41; 95% confidence interval (CI) -0.71 to -0.11; p<0.001), as well as Vasomotor, Psychosocial, and Physical domain scores with the largest difference seen in the Vasomotor domain (mean difference -0.75; 95% CI -1.28 to -0.22; p=0.02). There was no significant treatment group difference for the Sexual Function domain. Escitalopram treatment resulted in statistically significant improvements in PEG scores compared to placebo (mean treatment group difference at 8 weeks of -0.33; 95% CI -0.81 to 0.15; p=0.045). CONCLUSIONS: Treatment with escitalopram 10 20mg/day in healthy women with vasomotor symptoms significantly improved menopause-related quality of life and pain. PMID- 23031423 TI - Subwavelength Fabry-Perot resonator: a pair of quantum dots incorporated with gold nanorod. AB - The two apexes of an elongated gold nanorod (GNR) irradiated by a plane wave are shown to be the hotspots at the longitudinal plasmon modes. This phenomenon implies that a pair of quantum dots (QDs) located at these apexes might be excited simultaneously if the excitation band of QDs coincides with one of these modes. Consequently, a coherent emission of the two emitters could happen subsequently. In the following coherent emission, these two-level emitters are simulated as two oscillating dipoles (bi-dipole) with some possible phase differences. Our results show that the maximum radiative and nonradiative powers of the bi-dipole occur at the longitudinal plasmon dipole, quadrupole, sextupole, and octupole modes of GNR. Moreover, the strongest emissions are induced by the in-phase bi-dipole coupled to the odd modes and the 180 degrees out-of-phase one to the even modes, respectively. The excitation and emission behaviors of a pair of QDs incorporated with GNR demonstrate the possibility of using this structure as a subwavelength resonator of Fabry-Perot type. In addition, the correlation between these modes of the GNR and the dispersion relation of gold nanowire is also discussed. PMID- 23031424 TI - WITHDRAWN: Cyanobacterial bioactive molecules - Biosynthesis and genetic regulation. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23031425 TI - Delayed sternal closure after pediatric cardiac operations; single center experience: a retrospective study. AB - BACKGROUND: Delayed sternal closure (DSC) after cardiac surgery is a therapeutic option in the treatment of the severely impaired heart in pediatric cardiac surgery. The results with the technique of DSC over a 4-year period are examined with regard to mortality and morbidity. METHODS: We retrospectively reviewed records of 38 patients who had undergone DSC among 1100 congenital cardiac operations. Indication of DSC, time to sternal closure, pre and post closure cardiopulmonary and metabolic status, mortality, rate of wound and bloodstream infections were recorded. RESULTS: The mean sternal closure time was 2.9 days. The mortality rate was 34.2% (n = 13). Twenty (52.6%) patients required prolonged antibiotic use due to postoperative infection. There was gram negative microorganism predominance. There were 4 (10.5%) patients with postoperative mediastinitis. Postoperative infection rate statistically increased with cardiopulmonary bypass time (CPBT), sternal closure time (SCT) and intensive care unit (ICU) stay time (p = 0.039;p = 0.01;p = 0.012). On the other hand, the mortality rate significantly increased with increased cross clamp time (CCT), SCT, and extracorporeal membrane oxygenation (ECMO) use (p = 0.017; p = 0.026; p = 0.03). Single ventricular physiology was found to be risk factor for mortality in delayed sternal closure (p < 0.007). CONCLUSIONS: Elective DSC does not reduce the morbidity. The prolonged sternal closure time is associated with increased rate of postoperative infection rate; therefore early closure is strongly advocated. PMID- 23031426 TI - T(-786)->C polymorphism of the endothelial nitric oxide synthase gene is associated with insulin resistance in patients with ischemic or non ischemic cardiomyopathy. AB - BACKGROUND: Insulin resistance (IR) and endothelial dysfunction are frequently associated in cardiac disease. The T(-786)->C variant in the promoter region of the endothelial nitric oxide synthase (eNOS) gene has been associated with IR in both non-diabetic and diabetic subjects. Aim of the study was to assess the reciprocal relationships between T(-786)->C eNOS polymorphism and IR in ischemic and non-ischemic cardiomyopathy. METHOD: A group of 132 patients (108 males, median age 65 years) with global left ventricular (LV) dysfunction secondary to ischemic or non-ischemic heart disease was enrolled. Genotyping of T(-786)->C eNOS gene promoter, fasting glucose, insulin, and insulin resistance (defined as HOMA-IR index > 2.5) were determined in all patients. RESULTS: Genotyping analysis yielded 37 patients homozygous for the T allele (TT), 70 heterozygotes (TC) and 25 homozygous for C (CC). Patients with CC genotype had significantly higher systemic arterial pressure, blood glucose, plasma insulin and HOMA index levels than TT. At multivariate logistic analysis, the history of hypertension and the genotype were the only predictors of IR. In particular, CC genotype increased the risk of IR (CI% 1.4-15.0, p < 0.01) 4.5-fold. The only parameter independently associated with the extent of LV dysfunction and the presence of heart failure (HF) was the HOMA index (2.4 CI% 1.1-5.6, p < 0.04). CONCLUSIONS: T(-786)->C eNOS polymorphism was the major independent determinant of IR in a population of patients with ischemic and non-ischemic cardiomyopathy. The results suggest that a condition of primitive eNOS lower expression can predispose to an impairment of glucose homeostasis, which in turn is able to affect the severity of heart disease. PMID- 23031427 TI - A genome-wide association study using international breeding-evaluation data identifies major loci affecting production traits and stature in the Brown Swiss cattle breed. AB - BACKGROUND: The genome-wide association study (GWAS) is a useful approach to identify genes affecting economically important traits in dairy cattle. Here, we report the results from a GWAS based on high-density SNP genotype data and estimated breeding values for nine production, fertility, body conformation, udder health and workability traits in the Brown Swiss cattle population that is part of the international genomic evaluation program. RESULT: GWASs were performed using 50 k SNP chip data and deregressed estimated breeding values (DEBVs) for nine traits from between 2061 and 5043 bulls that were part of the international genomic evaluation program coordinated by Interbull Center. The nine traits were milk yield (MY), fat yield (FY), protein yield (PY), lactating cow's ability to recycle after calving (CRC), angularity (ANG), body depth (BDE), stature (STA), milk somatic cell score (SCS) and milk speed (MSP). Analyses were performed using a linear mixed model correcting for population confounding. A total of 74 SNPs were detected to be genome-wide significantly associated with one or several of the nine analyzed traits. The strongest signal was identified on chromosome 25 for milk production traits, stature and body depth. Other signals were on chromosome 11 for angularity, chromosome 24 for somatic cell score, and chromosome 6 for milking speed. Some signals overlapped with earlier reported QTL for similar traits in other cattle populations and were located close to interesting candidate genes worthy of further investigations. CONCLUSIONS: Our study shows that international genetic evaluation data is a useful resource for identifying genetic factors influencing complex traits in livestock. Several genome wide significant association signals could be identified in the Brown Swiss population, including a major signal on BTA25. Our findings report several associations and plausible candidate genes that deserve further exploration in other populations and molecular dissection to explore the potential economic impact and the genetic mechanisms underlying these production traits in cattle. PMID- 23031428 TI - Cost-effectiveness of compression technologies for evidence-informed leg ulcer care: results from the Canadian Bandaging Trial. AB - BACKGROUND: Venous leg ulcers, affecting approximately 1% of the population, are costly to manage due to poor healing and high recurrence rates. We evaluated an evidence-informed leg ulcer care protocol with two frequently used high compression systems: 'four-layer bandage' (4LB) and 'short-stretch bandage' (SSB). METHODS: We conducted a cost-effectiveness analysis using individual patient data from the Canadian Bandaging Trial, a publicly funded, pragmatic, randomized trial evaluating high compression therapy with 4LB (n = 215) and SSB (n = 209) for community care of venous leg ulcers. We estimated costs (in 2009 2010 Canadian dollars) from the societal perspective and used a time horizon corresponding to each trial participant's first year. RESULTS: Relative to SSB, 4LB was associated with an average 15 ulcer-free days gained, although the 95% confidence interval [-32, 21 days] crossed zero, indicating no treatment difference; an average health benefit of 0.009 QALYs gained [-0.019, 0.037] and overall, an average cost increase of $420 [$235, $739] (due to twice as many 4LB bandages used); or equivalently, a cost of $46,667 per QALY gained. If decision makers are willing to pay from $50,000 to $100,000 per QALY, the probability of 4LB being more cost effective increased from 51% to 63%. CONCLUSIONS: Our findings differ from the emerging clinical and economic evidence that supports high compression therapy with 4LB, and therefore suggest another perspective on high compression practice, namely when delivered by trained registered nurses using an evidence-informed protocol, both 4LB and SSB systems offer comparable effectiveness and value for money. PMID- 23031430 TI - Oxygen deficit and H2S in hemorrhagic shock in rats. AB - INTRODUCTION: Hemorrhagic shock induced O2 deficit triggers inflammation and multiple organ failure (MOF). Endogenous H2S has been proposed to be involved in MOF since plasma H2S concentration appears to increase in various types of shocks and to predict mortality. We tested the hypothesis that H2S increases during hemorrhagic shock associated with O2 deficit, and that enhancing H2S oxidation by hydroxocobalamin could reduce inflammation, O2 deficit or mortality. METHODS: We used a urethane anesthetized rat model, where 25 ml/kg of blood was withdrawn over 30 minutes. O2 deficit, lactic acid, tumor necrosis factor (TNF)-alpha and H2S plasma concentrations (Siegel method) were measured before and after the bleeding protocol in control animals and animals that received 140 mg/kg of hydroxocobalamin. The ability to oxidize exogenous H2S of the plasma and supernatants of the kidney and heart homogenates was determined in vitro. RESULTS: We found that withdrawing 25 ml/kg of blood led to an average oxygen deficit of 122 +/- 23 ml/kg. This O2 deficit was correlated with an increase in the blood lactic acid concentration and mortality. However, the low level of absorbance of the plasma at 670 nm (A670), after adding N, N-Dimethyl-p phenylenediamine, that is, the method used for H2S determination in previous studies, did not reflect the presence of H2S, but was a marker of plasma turbidity. There was no difference in plasmatic A670 before and after the bleeding protocol, despite the large oxygen deficit. The plasma sampled at the end of bleeding maintained a very large ability to oxidize exogenous H2S (high MUM), as did the homogenates of hearts and kidneys harvested just after death. Hydroxocobalamin concentrations increased in the blood in the MUM range in the vitamin B12 group, and enhanced the ability of plasma and kidneys to oxidize H2S. Yet, the survival rate, O2 deficit, H2S plasma concentration, blood lactic acid and TNF-alpha levels were not different from the control group. CONCLUSIONS: In the presence of a large O2 deficit, H2S did not increase in the blood in a rat model of untreated hemorrhagic shock. Hydroxocobalamin, while effective against H2S in vitro, did not affect the hemodynamic profile or outcome in our model. PMID- 23031431 TI - Managed competition in the Netherlands-a qualitative study. AB - BACKGROUND: In 2006, the Health Insurance Act changed Dutch health insurance by implementing managed competition, whereby the health insurance market is strongly regulated by the government. The aim of the study is to investigate key stakeholders' opinions about effects of recent changes in Dutch healthcare policy, focussing upon three important requirements for successful managed competition: risk-adjustment, consumer choice and instruments for managed care. METHOD: Expert interviews with 12 key stakeholders were performed (October/November 2009), transcribed and analyzed in a four-step qualitative process. RESULTS: The Dutch risk-adjustment scheme is very advanced but incentives for health insurers to select risks remain. The Health Insurance Act has given insurers new incentives to focus upon consumer needs and preferences, whereby large group contracts have replaced individual consumer choice with collective decision-making. Managed care concepts are slow in developing. Patient organizations and insurers report taking part in such efforts, but other stakeholders do not perceive that progress has been made. CONCLUSIONS: The pre requisites for successful managed competition in the Netherlands are not yet entirely in place: risk-adjustment schemes cannot yet counteract all incentives to select risks, consumer preferences are just beginning to influence insurer policies and managed care elements are currently in the development stage. PMID- 23031432 TI - Factors associated with the willingness of health care personnel to work during an influenza public health emergency: an integrative review. AB - INTRODUCTION: The first decade of the 21st century has witnessed three major influenza public health emergencies: (1) the severe acute respiratory syndrome of 2002-2003; (2) the avian flu of 2006; and (3) the 2009 H1N1 pandemic influenza. An effective public health response to an influenza public health emergency depends on the majority of uninfected health care personnel (HCP) continuing to report to work. The purposes of this study were to determine the state of the evidence concerning the willingness of HCP to work during an influenza public health emergency, to identify the gaps for future investigation, and to facilitate evidence-based influenza public health emergency planning. METHODS: A systemic literature review of relevant, peer-reviewed, quantitative, English language studies published from January 1, 2001 through June 30, 2010 was conducted. Search strategies included the Cochrane Library, PubMed, PubMed Central, EBSCO Psychological and Behavioral Sciences Collection, Google Scholar, ancestry searching of citations in relevant publications, and information from individuals with a known interest in the topic. RESULTS: Thirty-two studies met the inclusion criteria. Factors associated with a willingness to work during an influenza public health emergency include: being male, being a doctor or nurse, working in a clinical or emergency department, working full-time, prior influenza education and training, prior experience working during an influenza emergency, the perception of value in response, the belief in duty, the availability of personal protective equipment (PPE), and confidence in one's employer. Factors found to be associated with less willingness were: being female, being in a supportive staff position, working part-time, the peak phase of the influenza emergency, concern for family and loved ones, and personal obligations. Interventions that resulted in the greatest increase in the HCP's willingness to work were preferential access to Tamiflu for the HCP and his/her family, and the provision of a vaccine for the individual and his/her family. CONCLUSIONS: Understanding the factors that contribute to the willingness of HCP to report to work during an influenza public health emergency is critical to emergency planning and preparedness. Information from this review can guide emergency policy makers, planners, and implementers in both understanding and influencing the willingness of HCP to work during an influenza public health emergency. PMID- 23031429 TI - A genome-wide association study of monozygotic twin-pairs suggests a locus related to variability of serum high-density lipoprotein cholesterol. AB - Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors(P=3.98 x 10-8). We followed up the association in further genotyped monozygotic twins (N= 1,261),which showed a moderate association for the variant (P= 0.200, same direction of an effect). In addition,we report a new association on the level of apolipoprotein A-ll (P= 4.03 x 1 o-8). PMID- 23031433 TI - Glucagon-like peptide 1 and cardiac cell survival. AB - During myocardial infarction (MI), a variety of mechanisms contribute to activation of cell death processes in cardiomyocytes, which determines the final MI size, subsequent mortality, and post-MI remodeling. The deleterious mechanisms activated during the ischemia and reperfusion phases in MI include oxygen deprival, decreased availability of nutrients and survival factors, accumulation of waste products, generation of oxygen free radicals, calcium overload, neutrophil infiltration in the ischemic area, depletion of energy stores, and opening of the mitochondrial permeability transition pore, all of them contributing to activation of apoptosis and necrosis in cardiomyocytes. Glucagon like peptide-1 [GLP-1 (7-36) amide] has gained relevance in recent years for metabolic treatment of patients with type 2 diabetes mellitus. Cytoprotection of different cell types, including cardiomyocytes, is among the pleiotropic actions reported for GLP-1. This paper reviews the most relevant experimental studies that have contributed to a better understanding of the molecular mechanisms and intracellular pathways involved in cardioprotection induced by GLP-1 and analyzes in depth its potential role as a therapeutic target both in the ischemic and reperfused myocardium and in other conditions that are associated with myocardial remodeling and heart failure. PMID- 23031434 TI - Treatment holidays in patients with postmenopausal osteoporosis: whom and when? PMID- 23031435 TI - A case of systemic pseudohypoaldosteronism with a novel mutation in the SCNN1A gene. AB - We report a neonatal case of systemic pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene (homozygous c.1052+2dupT in intron 3) in which the patient presented with life-threatening hyperkalemia, hyponatremia and metabolic acidosis. It remains uncertain if there is genotype-phenotype correlation, due to the rarity of the disease. This mutation, which to our best knowledge has not been described before, was associated with a very severe phenotype requiring aggressive therapy. PMID- 23031436 TI - Glucagon-like peptide-2 (GLP-2) increases net amino acid utilization by the portal-drained viscera of ruminating calves. AB - Glucagon-like peptide-2 (GLP-2) increases small intestinal mass and blood flow in ruminant calves, but its impact on nutrient metabolism across the portal-drained viscera (PDV) and liver is unknown. Eight Holstein calves with catheters in the carotid artery, mesenteric vein, portal vein and hepatic vein were paired by age and randomly assigned to control (0.5% bovine serum albumin in saline; n = 4) or GLP-2 (100 MUg/kg BW per day bovine GLP-2 in bovine serum albumin; n = 4). Treatments were administered subcutaneously every 12 h for 10 days. Blood flow was measured on days 0 and 10 and included 3 periods: baseline (saline infusion), treatment (infusion of bovine serum albumin or 3.76 MUg/kg BW per h GLP-2) and recovery (saline infusion). Arterial concentrations and net PDV, hepatic and total splanchnic fluxes of glucose, lactate, glutamate, glutamine, beta hydroxybutyrate and urea-N were measured on days 0 and 10. Arterial concentrations and net fluxes of all amino acids and glucose metabolism using continuous intravenous infusion of [U13-C]glucose were measured on day 10 only. A 1-h infusion of GLP-2 increased blood flow in the portal and hepatic veins when administered to calves not previously exposed to exogenous GLP-2, but after a 10 day administration of GLP-2 the blood flow response to the 1-h GLP-2 infusion was substantially attenuated. The 1-h GLP-2 infusion also did not appreciably alter nutrient fluxes on either day 0 or 10. In contrast, long-term GLP-2 administration reduced arterial concentrations and net PDV flux of many essential and non-essential amino acids. Despite the significant alterations in amino acid metabolism, glucose irreversible loss and utilization by PDV and non-PDV tissues were not affected by GLP-2. Fluxes of amino acids across the PDV were generally reduced by GLP-2, potentially by increased small intestinal epithelial growth and thus energy and amino acid requirements of this tissue. Increased PDV extraction of glutamine and alterations in PDV metabolism of arginine, ornithine and citrulline support the concept that GLP-2 influences intestine-specific amino acid metabolism. Alterations in amino acid metabolism but unchanged glucose metabolism suggests that the growth effects induced by GLP-2 in ruminants increase reliance on amino acids preferentially over glucose. Thus, GLP-2 increases PDV utilization of amino acids, but not glucose, concurrent with stimulated growth of the small intestinal epithelium in post-absorptive ruminant calves. PMID- 23031437 TI - Adherence to the oral contraceptive pill: a cross-sectional survey of modifiable behavioural determinants. AB - BACKGROUND: Poor adherence to the oral contraceptive pill (OCP) is reported as one of the main causes of unintended pregnancy in women that rely on this form of contraception. This study aims to estimate the associations between a range of well-established modifiable psychological factors and adherence to OCP. METHOD: A cross-sectional survey of 130 female University students currently using OCP (Mean age: 20.46 SD: 3.01, range 17-36) was conducted. An OCP specific Medication Adherence Report Scale was used to assess non-adherence. Psychological predictor measures included necessity and concern beliefs about OCP, intentions, perceived behavioural control (pbc), anticipated regret and action and coping planning. Multiple linear regression was used to analyse the data. RESULTS: Fifty-two per cent of participants reported missing their OCP once or more per month and 14% twice or more per month. In bivariate analysis intentions (r = -0.25), perceived behavioural control (r= -0.66), anticipated regret (r=0.20), concerns about OCP (r =0.31), and action (r= -0.25) and coping (r= -0.28) planning were all significantly associated with adherence to OCP in the predicted direction. In a multivariate model almost half (48%) of the variation in OCP adherence could be explained. The strongest and only statistically significant predictors in this model were perceived behavioural control (beta=-0.62, p<0.01) and coping planning (beta =-0.23, p=0.03). A significant interaction between intentions and anticipated regret was also observed. CONCLUSION: The present data point to a number of key modifiable psychological determinants of OCP use. Future work will establish whether changing these variables results in better adherence to the OCP. PMID- 23031438 TI - Extraction and analysis of polycyclic aromatic hydrocarbons and benzo[a]pyrene metabolites in microalgae cultures by off-line/on-line methodology based on matrix solid-phase dispersion, solid-phase extraction and high-performance liquid chromatography. AB - This paper describes the development and validation of an analytical methodology to determine the presence of four PAHs: benzo[a]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene and benzo[a]pyrene in cultures of the green microalgae Selenastrum capricornutum. The metabolites of benzo[a]pyrene (BaP), 4,5 dihydrodiol benzo[a]pyrene, 9,10-dihydrodiol benzo[a]pyrene, 3-hydroxy benzo[a]pyrene and 9-hydroxy benzo[a]pyrene were also included. The methodology consisted of three parts: (1) separation of liquid media from biomass samples by centrifugation of pure cultures, (2) off-line extraction of analytes from biomass by a miniaturized matrix solid phase dispersion (MSPD) method and from liquid media by a solid phase extraction (SPE) method and (3) on-line SPE preconcentration and analysis of the MSPD and SPE extracts, separately, by high performance liquid chromatography with fluorescence detection (HPLC-FD). The off line/on-line (MSPD/SPE-HPLC-FD) method was validated over a concentration range of 20-200 pg mg(-1) obtaining good linearity (r(2)>0.9912) and precision values measured as relative standard deviation (RSD)<5%, recovery values were in the range of (40-66%) and the limits of detection (LODs) ranged from 2 to 6.5 pg mg( 1). The off-line/on-line (SPE/SPE-HPLC-FD) method was validated over a concentration range of 5-120 pg mL(-1); r(2)>0.9913 and RSD<7.36%, recovery values were in the range of 38-74% and LODs ranged from 0.8 to 2.3 pg mL(-1). This methodology was applied to samples from cultures exposed to BaP at 5 ng mL( 1) with different exposure times (0.75, 1.5, 3, 6, 24 and 48 h). The analytical methodology was suitable for measuring the very low amounts of residual BaP and metabolites produced in bioassays. Results showed that some of the metabolites favored by the microalgae are the dihydrodiols. The microalgae cultures were able to decrease the BaP level in the liquid medium below the United States Environmental Protection Agency (USEPA) limit (<0.2 ng mL(-1)). PMID- 23031439 TI - Partially hydrolyzed guar gum characterization and sensitive quantification in food matrices by high performance anion exchange chromatography with pulsed amperometric detection--validation using accuracy profile. AB - Interest concerning functional ingredients and especially dietary fibres has been growing in recent years. At the same time, the variety of ingredient accepted as dietary fibres and their mixing at low level in complex matrices have considerably complicated their quantitative analysis by approved AOAC methods. These reasons have led to the specific development of an innovative analytical method performed by high-performance anion-exchange chromatography (HPAEC) with pulsed amperometric detection (PAD) to detect and quantify partially hydrolyzed guar gum (PHGG) in fruit preparation and dairy matrices. The analytical methodology was divided in two steps which could be deployed separately or in conjunction. The first, consists in a complete characterization of PHGG by size exclusion chromatography (SEC) with multi-angle light scattering and refractive index detection and HPAEC-PAD to determine its physico-chemical properties and galactomannans content, and the second step is the development of a new HPAEC-PAD method for PHGG direct quantification in complex matrices (dairy product). Validation in terms of detection and quantification limits, linearity of the analytical range, average accuracy (recovery, trueness) and average uncertainty were statistically carried out with accuracy profile. Overall, this new chromatographic method has considerably improved the possibility to quantify without fractionation treatment, low level of dietary fibres emerging from specific galactomannans, in complex matrices and many foodstuffs. PMID- 23031440 TI - Effect of non-thermostated capillary inlet in affinity capillary electrophoresis: uranyl-selenate system at variable temperatures. AB - The influence of non-thermostated capillary inlet on accuracy of data obtained by affinity capillary electrophoresis is examined in the case of kinetically labile systems (with fast kinetics of equilibrium) at different temperatures. The system uranyl-selenate is studied in aqueous perchloric acid solutions (pH 2.5, ionic strength 0.05 mol l(-1)) in the temperature range from 15 degrees C to 55 degrees C. Moving of the sample through the non-thermostated inlet into the thermostated region of the capillary is used in order to avoid the influence of non efficiently thermostated short capillary inlet. The data on mobility values of uranyl and the values of stability constants obtained by this mode are compared with the data obtained in a traditionally used mode (injection in non thermostated inlet region). The uranyl mobility values obtained by the two methods are different at temperature higher than 35 degrees C. However, the difference between stability constants obtained by the two methods is not significant (ambient temperature is 20 degrees C). PMID- 23031441 TI - Use of recovered frying oils in chicken and rabbit feeds: effect on the fatty acid and tocol composition and on the oxidation levels of meat, liver and plasma. AB - The addition of some fat co- and by-products to feeds is usual nowadays; however, the regulations of their use are not always clear and vary between countries. For instance, the use of recycled cooking oils is not allowed in the European Union, but they are used in other countries. However, oils recovered from industrial frying processes could show satisfactory quality for this purpose. Here we studied the effects of including oils recovered from the frying industry in rabbit and chicken feeds (at 30 and 60 g/kg, respectively) on the fatty acid (FA) and tocol (tocopherol + tocotrienol) compositon of meat, liver and plasma, and on their oxidative stability. Three dietary treatments (replicated eight times) were compared: fresh non-used oil (LOX); oil discarded from the frying industry, having a high content of secondary oxidation compounds (HOX); and an intermediate level (MOX) obtained by mixing 50 : 50 of LOX and HOX. The FA composition of oil diets and tissues was assessed by GC, their tocol content by HPLC, the thiobarbituric acid value was used to assess tissue oxidation status, and the ferrous oxidation-xylenol orange method was used to assess the susceptibility of tissues to oxidation. Our results indicate that FA composition of rabbit and chicken meat, liver and plasma was scarcely altered by the addition of recovered frying oils to feed. Differences were encountered in the FA composition between species, which might be attributed mainly to differences in the FA digestion, absorption and metabolism between species, and to some physiological dietary factors (i.e. coprophagy in rabbits that involves fermentation with FA structure modification). The alpha-tocopherol (alphaT) content of tissues was reduced in response to the lower alphaT content in the recovered frying oil. Differences in the content of other tocols were encountered between chickens and rabbits, which might be attributable to the different tocol composition of their feeds, as well as to species differences in the digestion and metabolism of tocols. Tissue oxidation and susceptibility to oxidation were in general low and were not greatly affected by the degree of oxidation of the oil added to the feeds. The relative content of polyunsaturated fatty acids/alphaT in these types of samples would explain the differences observed between species in the susceptibility of each tissue to oxidation. According to our results, oils recovered from the frying industry could be useful for feed uses. PMID- 23031442 TI - Translational research and therapeutic applications of stem cell transplantation in periodontal regenerative medicine. AB - Stem cells have received a great deal of interest from the research community as potential therapeutic "tools" for a variety of chronic debilitating diseases that lack clinically effective therapies. Stem cells are also of interest for the regeneration of tooth-supporting tissues that have been lost to periodontal disease. Indeed, substantial data have demonstrated that the exogenous administration of stem cells or their derivatives in preclinical animal models of periodontal defects can restore damaged tissues to their original form and function. As we discuss here, however, considerable hurdles must be overcome before these findings can be responsibly translated to novel clinical therapies. Generally, the application of stem cells for periodontal therapy in clinics will not be realized until the best cell(s) to use, the optimal dose, and an effective mode of administration are identified. In particular, we need to better understand the mechanisms of action of stem cells after transplantation in the periodontium and to learn how to preciously control stem cell fates in the pathological environment around a tooth. From a translational perspective, we outline the challenges that may vary across preclinical models for the evaluation of stem cell therapy in situations that require periodontal reconstruction and the safety issues that are related to clinical applications of human stem cells. Although clinical trials that use autologous periodontal ligament stem cells have been approved and have already been initiated, proper consideration of the technical, safety, and regulatory concerns may facilitate, rather than inhibit, the clinical translation of new therapies. PMID- 23031444 TI - [A local hospital embarks on transfusion cares: lessons learnt from the medical unit of Pays de Retz's Intercommunal Hospital]. PMID- 23031443 TI - After GWAS: mice to the rescue? AB - The genetic basis of human autoimmune diseases remains incompletely understood, despite significant progress from genome-wide association studies (GWAS). In this review we outline how studies in mice may help filling these knowledge gaps. Forward genetic approaches including mutagenesis screens and quantitative trait locus (QTL) mapping studies can identify candidate genes for in depth analysis in human patient populations. Reverse genetic approaches utilize genetically engineered mice to analyze the function of disease-associated genes and their variants. Inbred strains are a distinctive feature of mouse genetics and we discuss their history, advantages and disadvantages. Three factors need to be considered when comparing experimental results from studies in mice and humans: In addition to species-specific differences, phenotypes are affected by the genetic background of the mouse strain being analyzed, and by microbial factors. Despite of these complexities, mice are essential discovery tools in the post GWAS era. PMID- 23031445 TI - Genetic diversity and natural selection of Duffy binding protein of Plasmodium vivax Korean isolates. AB - Plasmodium vivax Duffy binding protein (PvDBP) is a micronemal type I membrane protein that plays an essential role in erythrocyte invasion of merozoites. PvDBP is a prime blood stage vaccine candidate antigen against P. vivax, but its polymorphic nature represents a major obstacle to the successful design of a protective vaccine against vivax malaria. In this study, we analyzed the genetic polymorphism and natural selection at the N-terminal cysteine-rich region of PvDBP (PvDBPII) among 70 P. vivax isolates collected from Korean patients during 2005-2010. Seventeen single nucleotide polymorphisms (SNP), which resulted in 14 non-synonymous and 3 synonymous mutations, were found in PvDBPII among the Korean P. vivax isolates. Sequence analyses revealed that 13 different PvDBPII haplotypes, which were clustered into 3 distinct clades, were identified in Korean P. vivax isolates. The difference between the rates of nonsynomyous and synonymous mutations suggested that the region has evolved under natural selection. High selective pressure preferentially acted on regions identified or predicted to be B- and T-cell epitopes and MHC binding regions of PvDBPII. Recombination may also contribute to genetic diversity of PvDBPII. Our results suggest that PvDBPII of Korean P. vivax isolates display a limited genetic polymorphism and are under selective pressure. These results have significant implications for understanding the nature of the P. vivax population circulating in Korea and provide useful information for development of malaria vaccines based on this antigen. PMID- 23031446 TI - Improving neuro-oncological patients care: basic and practical concepts for nurse specialist in neuro-rehabilitation. AB - BACKGROUND: Neuro-oncological population well expresses the complexity of neurological disability due to the multiple neurological deficits that affect these patients. Moreover, due to the therapeutical opportunities survival times for patients with brain tumor have increased and more of these patients require rehabilitation care. The figure of nurse in the interdisciplinary specialty of neurorehabilitation is not clearly defined, even if their role in this setting is recognized as being critical and is expanding.The purpose of the study is to identify the standard competencies for neurorehabilitation nurses that could be taught by means of a specialization course. METHODS: A literature review was conducted with preference given to works published between January 2000 and December 2008 in English. The search strategy identified 523 non-duplicated references of which 271 titles were considered relevant. After reviewing the abstracts, 147 papers were selected and made available to a group of healthcare professionals who were requested to classify them in few conceptual main areas defining the relative topics. RESULTS: The following five main areas were identified: clinical aspects of nursing; nursing techniques; nursing methodology; relational and organisational models; legal aspects of nursing. The relative topics were included within each area. As educational method a structured course based on lectures and practical sessions was designed. Also multi-choices questions were developed in order to evaluate the participants' level of knowledge, while a semi-structured interview was prepared to investigate students' satisfaction. CONCLUSIONS: Literature shows that the development of rehabilitation depends on the improvement of scientific and practical knowledge of health care professionals. This structured training course could be incorporated into undergraduate nursing education programmes and also be inserted into continuing education programmes for graduate nurses. Developing expertise in neuro-rehabilitation for nurses, will be critical to improve overall care and care management of patients with highly complex disabilities as patients affected by brain tumors. The next step will be to start discussing, at the level of scientific societies linked to the field of neurorehabilitation and oncology, the development of a specialisation course in neurorehabilitation nursing. PMID- 23031448 TI - Daily grazing time as a risk factor for alterations at the hock joint integument in dairy cows. AB - Structural changes lead to increasing sizes of dairy herds and a reduction in grazing use. Thus, cows spend more time in the barn and become more exposed to the barn environment. The cubicle surface can result in damages of the cows' hock joint integument. Pasture is generally seen as a beneficial environment for cows. We hypothesized that a higher number of daily grazing hours reduce the probability of hock joint alterations in dairy cows from large herds. In total, 3148 lactating cows from 36 grazing and 20 zero-grazing dairy herds, with an average herd size of 173 cows, were assessed individually on one randomly selected body side for alterations in hock integument (score 0 for no alterations or hairless areas <2 cm, 1 for at least one hairless area of >=2 cm, 2 for lesion or swelling). The cows were further assessed for lameness and cleanliness. Information on breed, parity and days in milk per cow was extracted from a national database. Cubicle surface was evaluated for each herd. Daily grazing hours 30 days before herd visits were recorded by the stockmen and later categorized as follows: zero hours (zero-grazing), few hours (3 to 9) and many hours (>9 to 21). The effects of daily grazing hours and other potential cow and herd-level risk factors were evaluated for their impact on hock integument alterations using a logistic analysis with a multi-level model structure. The probability for hock integument alterations such as hair loss, lesions or swellings decreased with increasing amount of grazing hours (odds of 3 to 9 h 2.2 times and odds of >9 to 21 h 4.8 times lower than of zero-grazing). The probability for only lesions or swellings decreased with >9 to 21 grazing hours (odds 2.1 times) but not with 3 to 9 h (odds 1.0 times) compared with zero grazing. Lameness, hard cubicle surface and Danish Holstein v. other breeds showed an increasing effect on the probability for integument alterations. Increase in days in milk only showed an increasing effect on the probability for lesions and swellings. We concluded that a long daily stay on pasture is most beneficial for the hock joint integument of a dairy cow. PMID- 23031449 TI - Opto-structural studies of well-dispersed silicon nano-crystals grown by atom beam sputtering. AB - Synthesis and characterization of nano-crystalline silicon grown by atom beam sputtering technique are reported. Rapid thermal annealing of the deposited films is carried out in Ar + 5% H2 atmosphere for 5 min at different temperatures for precipitation of silicon nano-crystals. The samples are characterized for their optical and structural properties using various techniques. Structural studies are carried out by micro-Raman spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy (TEM), high resolution transmission electron microscopy, and selected area electron diffraction. The optical properties are studied by photoluminescence and UV-vis absorption spectroscopy, and bandgaps are evaluated. The bandgaps are found to decrease after rapid thermal treatment. The micro-Raman studies show the formation of nano crystalline silicon in as-deposited as well as annealed films. The shifting and broadening in Raman peak suggest formation of nano-phase in the samples. Results of micro-Raman, photoluminescence, and TEM studies suggest the presence of a bimodal crystallite size distribution for the films annealed at higher temperatures. The results show that atom beam sputtering is a suitable technique to synthesize nearly mono-dispersed silicon nano-crystals. The size of the nano crystals may be controlled by varying annealing parameters. PMID- 23031450 TI - Metachronous pulmonary metastasis after radical esophagectomy for esophageal cancer: prognosis and outcome. AB - BACKGROUND: Few reports discuss the outcome of pulmonary metastasis after radical esophagectomy for esophageal cancer. To clarify the data from such cases, we conducted a retrospective study on the clinical outcome of patients who developed pulmonary metastasis after undergoing radical esophagectomy. METHODS: We retrospectively reviewed the prognosis and clinical outcome of 25 patients who developed metachronous pulmonary metastasis after esophagectomy for esophageal cancer. RESULTS: The site of recurrence was pulmonary without extrapulmonary metastasis in 14 patients and extrapulmonary metastasis was observed in 11. Nineteen patients had multiple pulmonary metastasis and 6 had solitary pulmonary metastasis. Twenty-four of patients underwent systemic chemotherapy during initial treatment for metastatic lesions. Pulmonary metastasectomy was indicated in 5 patients with solitary metastasis. The actual 1-, 2- and 4-year survival rates were 60%, 36% and 27%, respectively. Gender, operative procedure, and postoperative morbidity were not significant prognostic factors. However, pathological staging of primary esophageal cancer was a significant prognostic factor. Survival was significantly worse in patients who did not undergo resection than in those who did. The number of pulmonary metastasis, complicated extrapulmonary metastasis and the time of recurrence were also significant prognostic factors. CONCLUSIONS: Multiple pulmonary metastases or complicated extrapulmonary metastasis were unfavorable prognostic factors for patients with pulmonary metastasis arising from esophageal cancer. Although, surgical intervention is not recommended in such cases, metastasectomy is an acceptable choice of treatment for solitary pulmonary metastasis. PMID- 23031451 TI - DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY - Registry (DESTINY-R): design and protocols. AB - BACKGROUND: Randomized controlled trials (RCT) on the treatment of severe space occupying infarction of the middle cerebral artery (malignant MCA infarction) showed that early decompressive hemicraniectomy (DHC) is life saving and improves outcome without promoting most severe disablity in patients aged 18-60 years. It is, however, unknown whether the results obtained in the randomized trials are reproducible in a broader population in and apart from an academical setting and whether hemicraniectomy has been implemented in clinical practice as recommended by national and international guidelines. In addition, they were not powered to answer further relevant questions, e.g. concerning the selection of patients eligible for and the timing of hemicraniectomy. Other important issues such as the acceptance of disability following hemicraniectomy, the existence of specific prognostic factors, the value of conservative therapeutic measures, and the overall complication rate related to hemicraniectomy have not been sufficiently studied yet. METHODS/DESIGN: DESTINY-R is a prospective, multicenter, open, controlled registry including a 12 months follow-up. The only inclusion criteria is unilateral ischemic MCA stroke affecting more than 50% of the MCA-territory. The primary study hypothesis is to confirm the results of the RCT (76% mRS <= 4 after 12 months) in the subgroup of patients additionally fulfilling the inclusion cirteria of the RCT in daily routine. Assuming a calculated proportion of 0.76 for successes and a sample size of 300 for this subgroup, the width of the 95% CI, calculated using Wilson's method, will be 0.096 with the lower bound 0.709 and the upper bound 0.805. DISCUSSION: The results of this study will provide information about the effectiveness of DHC in malignant MCA infarction in a broad population and a real-life situation in addition to and beyond RCT. Further prospectively obtained data will give crucial information on open questions and will be helpful in the plannig of upcomming treatment studies. TRIAL REGISTRATION: (ICTRP and DRKS): DRKS00000624. PMID- 23031452 TI - Transcriptome analyses of early cucumber fruit growth identifies distinct gene modules associated with phases of development. AB - ABBACKGROUND: Early stages of fruit development from initial set through exponential growth are critical determinants of size and yield, however, there has been little detailed analysis of this phase of development. In this study we combined morphological analysis with 454 pyrosequencing to study transcript level changes occurring in young cucumber fruit at five ages from anthesis through the end of exponential growth. RESULTS: The fruit samples produced 1.13 million ESTs which were assembled into 27,859 contigs with a mean length of 834 base pairs and a mean of 67 reads per contig. All contigs were mapped to the cucumber genome. Principal component analysis separated the fruit ages into three groups corresponding with cell division/pre-exponential growth (0 and 4 days post pollination (dpp)), peak exponential expansion (8dpp), and late/post-exponential expansion stages of growth (12 and 16 dpp). Transcripts predominantly expressed at 0 and 4 dpp included homologs of histones, cyclins, and plastid and photosynthesis related genes. The group of genes with peak transcript levels at 8dpp included cytoskeleton, cell wall, lipid metabolism and phloem related proteins. This group was also dominated by genes with unknown function or without known homologs outside of cucurbits. A second shift in transcript profile was observed at 12-16dpp, which was characterized by abiotic and biotic stress related genes and significant enrichment for transcription factor gene homologs, including many associated with stress response and development. CONCLUSIONS: The transcriptome data coupled with morphological analyses provide an informative picture of early fruit development. Progressive waves of transcript abundance were associated with cell division, development of photosynthetic capacity, cell expansion and fruit growth, phloem activity, protection of the fruit surface, and finally transition away from fruit growth toward a stage of enhanced stress responses. These results suggest that the interval between expansive growth and ripening includes further developmental differentiation with an emphasis on defense. The increased transcript levels of cucurbit-specific genes during the exponential growth stage may indicate unique factors contributing to rapid growth in cucurbits. PMID- 23031453 TI - Introduction: Coagulation disorders. PMID- 23031454 TI - New models of hemostasis. AB - Hemostasis is an essential protective mechanism that depends on a delicate balance of procoagulant and anticoagulant processes. The waterfall/cascade models of coagulation are useful for understanding several essential steps of coagulation in vitro. These have resulted in the creation of the plasma-based tests used commonly and the ability to identify deficiencies in the extrinsic, intrinsic, and common pathways of coagulation. The model was also essential in elucidating the role of several of the inhibitors of coagulation and is currently used to demonstrate coagulation as it occurs in plasma in a static environment that is devoid of endothelial interactions. The intrinsic pathway originally described by these models does not appear to be essential for in vivo hemostasis but may play a role in pathologic thrombosis. The waterfall/cascade models' lack of cellular elements sets the stage for the cell-based model of coagulation. The cell-based model of blood coagulation, which includes the varied, complicated network of factors necessary for appropriate in vivo coagulation to occur, was the next step in the evolution of our understanding of coagulation. Recently, researchers have focused on real-time, in vivo models of hemostasis and this research reveals unexpected phenomena. PMID- 23031456 TI - Inherited disorders of hemostasis in dogs and cats. AB - Inherited disorders of hemostasis encompass abnormalities in primary hemostasis, coagulation, and fibrinolysis resulting from genetic mutations. There is significant variation in the phenotype expressed ranging from life limiting to the absence of overt clinical signs. Von Willebrand disease is the most common primary hemostatic disorder in dogs, and hemophilia A is the most common coagulation factor disorder. The diagnosis of inherited bleeding disorders is made by functional and/or quantitative evaluation. Genetic testing has added to the knowledge base, allowing prevention through targeted breeding. Avoidance of trauma and injury is paramount in the prevention of bleeding in animals diagnosed with inherited hemostatic disorders. Current therapeutic options include platelet transfusions, broad replacement of coagulation factors (e.g., plasma), targeted factor replacement (e.g., cryoprecipitate), antifibrinolytic agents and specific factor replacement, and treatment of the symptoms (i.e., bleeding) with blood transfusions. PMID- 23031455 TI - The reciprocal relationship between inflammation and coagulation. AB - Inflammation and coagulation constitute two host defense systems with complementary roles in eliminating invading pathogens, limiting tissue damage, and restoring homeostasis. Extensive cross talk exists between these 2 systems, whereby inflammation leads to activation of coagulation, and coagulation considerably affects inflammatory activity. Infection leads to the production of proinflammatory cytokines that, in turn, stimulate the production of tissue factor. Activation of the coagulation system and ensuing thrombin generation are dependent on the expression of tissue factor. Conversely, activated coagulation proteases may affect specific receptors on inflammatory cells and endothelial cells and thereby modulate the inflammatory response. Activation of coagulation with the simultaneous down-regulation of endothelial-bound anticoagulant mechanisms and endogenous fibrinolysis characterizes the pathophysiology of sepsis. The mechanisms by which these highly complex and codependent defense strategies are linked together both in health and disease is the focus of this review. PMID- 23031457 TI - Diseases associated with thrombosis. AB - Coagulation abnormalities are commonly encountered in critical illness. Traditionally, clinically relevant coagulation disorders have consisted mostly of bleeding associated with advanced stages of disseminated intravascular coagulation or toxin ingestion. However, advances in critical care have highlighted hypercoagulability as a clinically relevant state that must be recognized and treated to optimize the chances of a positive outcome. Retrospective studies of dogs with confirmed thrombosis in varying locations have identified populations most likely to experience hypercoagulable states. Diseases most frequently complicated by thrombosis include immune-mediated disease, neoplasia, systemic inflammation and sepsis, cardiac disease, protein-losing states, and infectious diseases. In this report, the existing retrospective studies will be discussed along with a review of specific disease processes that predispose to a hypercoagulable state. Studies targeting those populations most at risk for thrombotic complications are necessary for better understanding the need for prophylactic anticoagulant therapy. PMID- 23031458 TI - Update on disseminated intravascular coagulation: when to consider it, when to expect it, when to treat it. AB - Disseminated intravascular coagulation (DIC) spans a continuum in which clinical signs can range from a prothrombotic to a hemorrhagic phenotype, with some patients suffering from both concurrently. DIC is always caused by an underlying condition, with most cases linked to systemic inflammation or infection. Numerous factors contribute to the development of DIC, including aberrations in endothelial function, and altered levels of endogenous procoagulant, anticoagulant, and fibrinolytic factors. Excessive thrombin generation, or failure to localize thrombin production, is the unifying theme throughout this broad condition. DIC can be described as overt or nonovert, each with varying degrees of severity. The ability to concisely define and diagnose such a broad condition has proven challenging, especially in veterinary medicine, where interspecies differences result in phenotypic variability. In most patients, DIC is recognized when a patient experiences noteworthy hematologic changes, such as a drop in circulating platelet count in concert with a 20% to 30% prolongation in the activated partial thromboplastin time. Similar to diagnosing, proven benefits of any particular therapy are difficult to identify. Despite these difficulties, therapy can be optimized with an understanding of the underlying pathology(ies). With appropriate care and a committed owner/veterinary team, patients with DIC can have a favorable outcome. PMID- 23031459 TI - Diagnostic approach to small animal bleeding disorders. AB - A well-designed and executed diagnostic approach to patients with bleeding disorders is critical to determine disease etiology and guide therapeutic measures. This systematic process begins with a comprehensive history and physical examination, followed by laboratory tests of primary hemostasis (platelet enumeration, platelet function testing, and von Willebrand factor assays), secondary hemostasis (prothrombin time, activated partial thromboplastin time, activated clotting time, and individual factor deficiencies), and fibrinolysis (fibrinogen activity, thrombin time, fibrin degradation products, D dimers), dependent on the clinical picture. Equally valuable are proper specimen collection, handling, and storage methods, which provide reliable and reproducible result interpretation. This review will emphasize the common diagnostic tools and blood sampling techniques important to the workup of hemostatic diseases as well as provide an overview of advanced clinical and research methods and equipment available to assist our bleeding veterinary patients, including thromboelastography/thromboelastometry, calibrated automated thrombogram, and the thrombin-antithrombin assay. PMID- 23031460 TI - Endogenous anticoagulants. AB - Blood coagulation is a complex and highly coordinated process that is constantly altered and impacted by procoagulant and anticoagulant "players." It is vital that these components work in concert to maintain a balance to keep coagulation in check. Several important endogenous anticoagulants will be discussed in this review including tissue factor pathway inhibitor, antithrombin, protein C, and protein S in origin, structure, mechanism of action, effects of deficiency, and current knowledge in veterinary medicine. PMID- 23031461 TI - Antithrombotic therapy. AB - Thrombosis or thromboembolism are significant concerns in companion animals and can be associated with cardiac, metabolic, neoplastic disease processes or can be one manifestation of inflammatory, infectious, and neoplastic disease conditions. Options for thromboprophylaxis available for clinical use in small animal patients are very limited, with heparin (primarily unfractionated, but more recently low-molecular-weight forms) and aspirin predominating. Controlled studies evaluating the use of these drugs are few, but there is some limited evidence for efficacy in prevention of formation of thrombi. Use of the vitamin K antagonist warfarin has been described, but the narrow therapeutic window has resulted in a high rate of serious adverse events. In human patients, the efficacy of aspirin, heparins, and vitamin K antagonists is well documented in a variety of thrombotic conditions, but there are significant limitations to each of these options. These limitations have prompted the search for new alternatives, some of which are now in wide clinical use in humans. Although the use of some of the drugs discussed here has not yet been described in veterinary patients at risk for thrombosis, many of these agents have been evaluated experimentally in dogs, cats, or both. These new thromboprophylactic agents may soon be beneficial in management of small animal patients at risk for thrombosis. PMID- 23031462 TI - Relationship between dairy cow genetic merit and profit on commercial spring calving dairy farms. AB - Because not all animal factors influencing profitability can be included in total merit breeding indices for profitability, the association between animal total merit index and true profitability, taking cognisance of all factors associated with costs and revenues, is generally not known. One method to estimate such associations is at the herd level, associating herd average genetic merit with herd profitability. The objective of this study was to primarily relate herd average genetic merit for a range of traits, including the Irish total merit index, with indicators of performance, including profitability, using correlation and multiple regression analyses. Physical, genetic and financial performance data from 1131 Irish seasonal calving pasture-based dairy farms were available following edits; data on some herds were available for more than 1 year of the 3 year study period (2007 to 2009). Herd average economic breeding index (EBI) was associated with reduced herd average phenotypic milk yield but with greater milk composition, resulting in higher milk prices. Moderate positive correlations (0.26 to 0.61) existed between genetic merit for an individual trait and average herd performance for that trait (e.g. genetic merit for milk yield and average per cow milk yield). Following adjustment for year, stocking rate, herd size and quantity of purchased feed in the multiple regression analysis, average herd EBI was positively and linearly associated with net margin per cow and per litre as well as gross revenue output per cow and per litre. The change in net margin per cow per unit change in the total merit index was ?1.94 (s.e. = 0.42), which was not different from the expectation of ?2. This study, based on a large data set of commercial herds with accurate information on profitability and genetic merit, confirms that, after accounting for confounding factors, the change in herd profitability per unit change in herd genetic merit for the total merit index is within expectations. PMID- 23031463 TI - Merging and characterising phenotypic data on conventional and rare traits from dairy cattle experimental resources in three countries. AB - This study set out to demonstrate the feasibility of merging data from different experimental resource dairy populations for joint genetic analyses. Data from four experimental herds located in three different countries (Scotland, Ireland and the Netherlands) were used for this purpose. Animals were first lactation Holstein cows that participated in ongoing or previously completed selection and feeding experiments. Data included a total of 60 058 weekly records from 1630 cows across the four herds; number of cows per herd ranged from 90 to 563. Weekly records were extracted from the individual herd databases and included seven traits: milk, fat and protein yield, milk somatic cell count, liveweight, dry matter intake and energy intake. Missing records were predicted with the use of random regression models, so that at the end there were 44 weekly records, corresponding to the typical 305-day lactation, for each cow. A total of 23 different lactation traits were derived from these records: total milk, fat and protein yield, average fat and protein percentage, average fat-to-protein ratio, total dry matter and energy intake and average dry matter intake-to-milk yield ratio in lactation weeks 1 to 44 and 1 to 15; average milk somatic cell count in lactation weeks 1 to 15 and 16 to 44; average liveweight in lactation weeks 1 to 44; and average energy balance in lactation weeks 1 to 44 and 1 to 15. Data were subsequently merged across the four herds into a single dataset, which was analysed with mixed linear models. Genetic variance and heritability estimates were greater (P < 0.05) than zero for all traits except for average milk somatic cell count in weeks 16 to 44. Proportion of total phenotypic variance due to genotype-by-environment (sire-by-herd) interaction was not different (P > 0.05) from zero. When estimable, the genetic correlation between herds ranged from 0.85 to 0.99. Results suggested that merging experimental herd data into a single dataset is both feasible and sensible, despite potential differences in management and recording of the animals in the four herds. Merging experimental data will increase power of detection in a genetic analysis and augment the potential reference population in genome-wide association studies, especially of difficult-to-record traits. PMID- 23031464 TI - Modulation of intestinal mucin composition and mucosal morphology by dietary phytogenic inclusion level in broilers. AB - The effect of a dietary phytogenic feed additive (PFA) inclusion level in mucin monosaccharide composition, mucosal morphometry and mucus histochemistry along the broiler intestinal tract was studied. Cobb male broilers (n = 525) were allocated into five experimental treatments that, depending on the type of addition in the basal diet (BD), were labeled as follows: C (BD based on maize soybean meal with no other additions), E1 (80 mg PFA/kg BD), E2 (125 mg PFA/kg BD), E3 (250 mg PFA/kg of BD) and A (2.5 mg avilamycin/kg BD). Samples from duodenum, ileum and cecum of 14- and 42-day-old broilers were collected and analyzed. In 14-day-old broilers, treatments E2 and E3 had higher (P < 0.01) duodenal mannose than treatments C, E1 and A. Ileal mannose was lower (P < 0.05) in treatment C compared with PFA treatments, and ileal galactose (Gal) was higher (P < 0.01) in treatments E2 and E3 compared with C and A. Polynomial contrast analysis with respect to PFA inclusion level showed that in 14-day-old broilers there was a linear increase (P = 0.001) in duodenal mannose and a quadratic effect (P = 0.038) in duodenal N-acetyl-galactosamine with increasing PFA level. Ileal Gal and mannose increased linearly (P = 0.002 and P = 0.012, respectively) with PFA inclusion level. There were no significant differences between treatments in mucin monosaccharide molar ratios of 42-day-old broilers. However, increasing PFA inclusion level resulted in a linear decrease of ileal fucose (P = 0.021) and cecal N-acetylgalactosamine (P = 0.036). Experimental treatments did not differ (P > 0.05) regarding duodenal villus height (Vh), crypt depth (Cd) and Vh/Cd ratio, irrespective of broiler age and the intestinal segment examined. However, increasing dietary PFA inclusion level showed a pattern of linear increase of duodenal Vh/Cd ratio in 14-day-old broilers and ileal Vh in 42-day old broilers (P = 0.039 and P = 0.039, respectively). Alcian Blue-Periodic Acid Schiff (pH 2.5) staining of neutral and acidic mucins showed that the staining intensity of mucus layer in villi was fragment (i.e. tip, midsection and base) dependent, whereas in crypts it was dependent both on intestinal segment (i.e. duodenum, ileum and cecum) and fragment. Finally, mucus layer thickness did not differ (P > 0.05) between treatments, yet a pattern of linear increase (P < 0.05) with PFA inclusion level was observed in the duodenum of 42-day-old broilers. In conclusion, the dietary inclusion level of PFA modulated broiler intestinal mucin composition and morphology. Further studies are required to elucidate the physiological implications of such changes in host-microflora interactions. PMID- 23031466 TI - Plasma glucose response and glycemic indices in pigs fed diets differing in in vitro hydrolysis indices. AB - Different dietary starch sources can have a great impact in determining starch digestion potential, thus influencing the postprandial blood glucose response. Our objectives were to define: (i) the incremental plasma glucose response in pigs fed diets containing various sources of starch differing in in vitro digestion patterns, (ii) the in vivo glycemic index (GI) values for the same diets, (iii) the possible relationship between in vitro and in vivo data. Diets, formulated with 70% of starch from five heterogeneous sources, were characterized in depth by using two distinct in vitro evaluations. The first one was based on the Englyst-assay for nutritional classification of starch fractions, whereas the second one was based on a time-course multi-enzymatic assay up to 180 min from which the hydrolysis indices (HIs) were calculated and used as a link between the physicochemical properties of starch from diets and the in vivo responses. For the in vivo study, five jugular-catheterized pigs (35.3 +/- 1.1 kg body weight) were fed one of the five diets for 6-day periods in a 5 * 5 Latin square design. On day 5, blood was collected for 8 h postprandially for evaluating glucose appearance. On day 6, blood was collected for 3 h postprandially for the estimation of the GI. Starchy diets differed for rapidly digestible starch (from 8.6% to 79.8% of total starch (TS)) and resistant starch contents (from 72.5% to 4.5% of TS). Wide between-diets variations were recorded for all the kinetic parameters and for the HI calculated from the in vitro digestion curves (P < 0.05). On the basis of the obtained HI, diets contained starch with a very low to a very high in vitro digestion potential (ranging from 26.7% to 100.0%; P < 0.05). The glucose response differed among diets (P < 0.05), with marked differences between 15 and 120 min postprandial. Overall, the ranking of incremental glucose appearance among diets agreed with their in vitro HI classification: high HI diets increased plasma glucose response more (P < 0.05) than low HI diets. Lastly, different in vivo GIs were measured (ranging from 30.9% to 100.0%; P < 0.05). The relationship between HI and GI showed a high coefficient of determination (R2 = 0.95; root mean square error (RMSE) = 15.8; P < 0.05). In conclusion, diets formulated with starches with a wide range in HI potential can strongly affect the postprandial glucose response in pigs. PMID- 23031465 TI - Impact of dietary betaine and conjugated linoleic acid on insulin sensitivity, protein and fat metabolism of obese pigs. AB - To determine possible mechanisms of action that might explain the nutrient partitioning effect of betaine and conjugated linoleic acid (CLA) in Iberian pigs and to address potential adverse effects, twenty gilts were restrictively fed from 20 to 50 kg BW Control, 0.5% betaine, 1% CLA or 0.5% betaine + 1% CLA diets. Serum hormones and metabolites profile were determined at 30 kg BW and an oral glucose test was performed before slaughter. Pigs were slaughtered at 50 kg BW and livers were obtained for chemical and histological analysis. Decreased serum urea in pigs fed betaine and betaine + CLA diets (11%; P = 0.0001) indicated a more efficient N utilization. The increase in serum triacylglycerol (58% and 28%, respectively; P = 0.0098) indicated that CLA and betaine + CLA could have reduced adipose tissue triacylglycerol synthesis from preformed fatty acids. Serum glucose, low-density lipoprotein (LDL) cholesterol and non-esterified fatty acids were unaffected. CLA and betaine + CLA altered serum lipids profile, although liver of pigs fed CLA diet presented no histopathological changes and triglyceride content was not different from Control pigs. Compared with controls, serum growth hormone decreased (20% to 23%; P = 0.0209) for all treatments. Although serum insulin increased in CLA, and especially in betaine + CLA pigs (28% and 83%; P = 0.0001), indices of insulin resistance were unaffected. In conclusion, CLA, and especially betaine + CLA, induced changes in biochemical parameters and hormones that may partially explain a nutrient partitioning effect in young pigs. Nevertheless, they exhibited weak, although detrimental, effects on blood lipids. Moreover, although livers were chemically and histologically normal, pigs fed CLA diet challenged with a glucose load had higher serum glucose than controls. PMID- 23031467 TI - Impact of chicory inclusion in a cereal-based diet on digestibility, organ size and faecal microbiota in growing pigs. AB - A total of 30 7-week-old pigs were used to evaluate the effects of chicory inclusion on digestibility, digestive organ size and faecal microbiota. Five diets were formulated: a cereal-based control diet and four diets with inclusion of 80 and 160 g/kg chicory forage (CF80 and CF160), 80 g/kg chicory root (CR80) and a mix of 80 g/kg forage and 80 g/kg chicory root (CFR). Generally, the pigs showed a high growth rate and feed intake, and no differences between the different diets were observed. The coefficients of total tract apparent digestibility (CTTAD) of energy, organic matter and CP did not differ between the control and CF80, whereas they were impaired in diet CF160. The CTTAD of non starch polysaccharides and especially the uronic acids were higher (P < 0.05) with chicory inclusion, with highest (P < 0.05) values for diet CF160. Coliform counts were lower and lactobacilli : coliform ratio was higher (P < 0.05) in diet CFR than in the control. Global microbial composition was investigated by terminal restriction fragment length polymorphism combined with cloning and sequencing. Analysis of gut microbiota pattern revealed two major clusters where diet CF160 differed from the control and CR80 diet. Chicory forage diets were correlated with an increased relative abundance of one species related to Prevotella and decreased abundance of two other species related to Prevotella. For diet CFR, the relative abundance of Lactobacillus johnsonii was higher than in the other diets. This study shows that both chicory forage and root can be used as fibre sources in pig nutrition and that they modulate the composition of the gut microbiota differently. PMID- 23031468 TI - Effects of feeding programme on the performance and energy balance of nulliparous rabbit does. AB - A total of 190 rabbit females were used to evaluate five feeding programmes from 9 weeks of age to the first parturition: CAL, fed ad libitum with a control diet (C: 11.0 MJ digestible energy (DE) and 114 g digestible protein (DP)/kg dry matter (DM)) until first parturition; CR, fed ad libitum with C diet until 12 weeks of age and then C diet restricted (140 g/day) until first parturition; F, fed ad libitum with a low-energy, high-fibre diet (F: 8.7 MJ DE and 88 g DP/kg DM) until first parturition; FC, fed with F diet ad libitum until 16 weeks of age, and C diet ad libitum until first parturition; FCF, fed with F diet ad libitum until 16 weeks of age, then C diet ad libitum until 20 weeks and then F diet ad libitum until first parturition. The rabbits were artificially inseminated at 18 weeks of age. CAL group had a higher mortality rate compared with the other groups between 9 and 12 weeks of age (34% v. 3%; P < 0.05) and during the last 3 weeks of first pregnancy (14% v. 3%; P < 0.05). The CAL and FC females presented higher BW and perirenal fat thickness (PFT) than CR females at 11 days of pregnancy (+0.41 kg and +0.6 mm; P < 0.05), with F females showing medium values. The type of feeding procedure did not affect the fertility rate of young females at first artificial insemination. Differences in BW disappeared at parturition, when only CAL females presented a greater PFT than CR and FC females (+0.3 mm; P < 0.05). In comparison with FCF, CAL females had smaller and thinner live born litters (-2.5 kits and -139 g, respectively; P < 0.05), with CR, F and FC females showing medium values. The low number of kits born alive for CAL females was because of their lesser total number of kits born (-1.7 kits; P < 0.05) and the greater mortality of their litters at birth (+13.9%; P < 0.05) compared with FCF females. Non-esterified fatty acid was higher in the blood of females fed C diet (CAL and CR) than in others at partum day (on average +0.15 mmol/l; P < 0.05). In conclusion, the ad libitum use of diets for lactating rabbit does throughout the rearing period could lead young rabbit females to present a higher risk of early death and smaller litter size at first parturition. Feed restriction or earlier use of suitably fibrous diets led females to achieve the critical BW and fat mass at first mating to ensure reproduction. PMID- 23031469 TI - The influence of casein and urea as nitrogen sources on in vitro equine caecal fermentation. AB - To access the fermentative response of equine caecal microbial population to nitrogen availability, an in vitro study was conducted using caecal contents provided with adequate energy sources and nitrogen as limiting nutrient. Two nitrogen (N) sources were provided, protein (casein) and non-protein (urea). Caecal fluid, taken from three cannulated horses receiving a hay-concentrate diet, was mixed with a N-free buffer-mineral solution. The influence of four N levels (3.7, 6.3, 12.5 or 25 mg of N in casein or urea) was studied using the gas production technique. Total volatile fatty acids (VFA), NH3-N and gas production were measured after a 24-h incubation period. Microbial biomass was estimated using adenine and guanine bases as internal markers, and ATP production was estimated stoichiometrically. Microbial growth efficiency (YATP) and gas efficiency (Egas) were estimated. Fermentation with casein as the sole N source was generally characterized by lower total VFA, NH3-N, total gas production and higher acetate : propionate (A : P) ratio and YATP than with urea. Results herein presented indicate that, under these in vitro conditions, caecal microbial population does in fact use urea N, but less efficiently than casein in terms of microbial growth. PMID- 23031470 TI - Partial replacement of barley grain and soybean meal by fleabane (Conyza bonariensis) in diets of growing Awassi lambs. AB - Effects of partial substitution of barley grain and soybean meal with fleabane (FB) Conyza bonariensis on growth performances and body compositions of 24 male local Awassi lambs were studied. All lambs were male with an average BW of 20.3 kg (s.d. = 2.0 kg) at the beginning of the experiment. Animals were randomly divided into four groups of six lambs each. Lambs in each group received individually their cereal-soybean-based total mixed rations with levels of FB: 0, 50, 100 and 150 g/kg dry matter (DM) diet, which replaced similar values of barley and soybean meal. All rations were isonitrogenous and isocaloric. The fattening experiment lasted 9 weeks, after which all lambs were slaughtered. The composition of nutrients in the C. bonariensis were 89.6%, 15.0%, 28.0%, 30.0% and 10% for organic matter, CP, NDF, ADF and lignin, respectively. At the end of the experiment, lambs fed 100 and 150 g FB/kg DM diets gained more weight (P < 0.05) than those fed the control and 50 g FB/kg DM diets. The DM intake was lower in lambs fed the highest level of FB compared with intakes of lambs in other treatments. Diet content of FB had significant effect (P < 0.05) on weights of empty body, carcass, gut and external (hide, head and feet) among all animals. However, FB had no effects on lambs' thoracic organs (lungs and heart) and liver. Muscle, bone, omental and mesenteric fat, subcutaneous, intermuscular, pelvic and kidney fat weights (g/kg empty BW) were not affected by FB feeding. Carcass fat was decreased (P < 0.05) by the increase of FB. Total body fat was the same in all animals of the experiment. PMID- 23031471 TI - Comparison of intake and digestibility of fresh Digitaria decumbens grass fed to sheep, indoors or at pasture, at two different stages of regrowth. AB - The effect of two feeding systems (indoors and at pasture) on intake and digestion of fresh grass was studied at two stages of regrowth (21 and 35 days of regrowth) in two parallel experiments. In Experiment 1, 10 adult Martinik rams weighing, on average, 50.5 (+/- 0.9) kg, including four fitted with rumen cannula, were randomly allocated to two groups according to a 2 * 2 Latin Square design. These rams consumed a 21-day regrowth of Digitaria decumbens grass diet during two successive 28-day periods, indoors (five rams) or at pasture (five tethered rams). In Experiment 2, 10 other Martinik rams weighing, on average, 45.5 (+/- 0.9) kg, including four fitted with rumen cannula, were randomly allocated to two groups according to a 2 * 2 Latin Square design. These rams consumed a 35-day regrowth of D. decumbens grass diet during two successive 28 day periods, either indoors (five rams) or at pasture (five tethered rams). For the indoors groups, in vivo organic matter digestibility (OMD) was measured by total collection of feces. In addition, OMD was estimated indoors and at pasture using the fecal CP (CPf) method (OMDCPf). Organic matter intake (OMI) was then estimated using OMDCPf and fecal organic matter output (OMICPf). Correlations of 0.49 and 0.77 were found between in vivo OMD and OMDCPf (P < 0.05) and between OMI and OMICPf (P < 0.001), respectively. OMDCPf was 1.8% (P < 0.05) and 2.7% (P < 0.01) lower indoors than at pasture at 21 and 35 days of regrowth, respectively, whereas OMICPf indoors was 1.1 and 1.16 times that registered at pasture at 21 and 35 days of regrowth, respectively. The higher OMDCPf at pasture was linked to the higher selective behavior of rams at pasture, whereas the differences in OMICPf between the two feeding systems were linked to differences in the total bulk density of the grass. These studies show that differences in OMDCPf and OMICPf exist between animals fed indoors and at pasture with the same forage and that these differences may vary according to the stage of regrowth of the grass offered. PMID- 23031472 TI - Pre-analytical factors affecting the results of laboratory blood analyses in farm animal veterinary diagnostics. AB - The quality of the laboratory diagnostic approach in farm animals can be severely affected by pre-analytical factors of variation. They induce increase/decrease of biochemical and hematological analyte concentrations and, as a consequence, they may cause unsuitable conclusions and decisions for animal health management and research projects. The pre-analytical period covers the preparation of sampling, the sampling procedure itself, as well as all specimen handling until the beginning of the specific laboratory analysis. Pre-analytical factors may have either an animal-related or a technique-related background. Animal-related factors cover daytime/season, meals/fasting, age, gender, altitude, drugs/anesthesia, physical exercise/stress or coinfection. Technique-related factors are the choice of the tube including serum v. plasma, effects of anticoagulants/gel separators, the anticoagulant/blood ratio, the blood collection procedure itself, specimen handling, contamination, labeling, storage and serum/plasma separation, transportation of the specimen, as well as sample preparation before analysis in the laboratory. It is essential to have proper knowledge about the importance and source of pre-analytical factors to alter the entire diagnostic process. Utmost efforts should be made to minimize controllable factors. Analytical results have to be evaluated with care considering that pre analytical factors of variation are possible causes of misinterpretation. PMID- 23031473 TI - Application of captive bolt to cattle stunning - a survey of stunner placement under practical conditions. AB - In two cattle head deboning plants, a total of 8879 cattle skulls were investigated for number and precision of shots. Deviation from the ideal position on the forehead and the direction of the shot were measured, results were then attributed to three classes of precision. In all, 64.7% of the skulls in plant 1 and 65.3% in plant 2 were shot from the ideal position and in the ideal direction. A medium precision was observed in 31.3% and 31.5% of cases, 4.0% and 3.1%, respectively, of the skulls indicated a poor precision. In both plants, skulls with more than one shot hole were observed. Shot holes may indicate the precision of a shot, and thus the risk of suffering during the sensitive time of stunning. In addition to observations at the time of stunning, the observation of shot holes on skulls at random or in total after a day's slaughter can reflect the shooting precision. PMID- 23031474 TI - How do sheep affect plant communities and arthropod populations in temperate grasslands? AB - Grasslands being used in sheep farming systems are managed under a variety of agricultural production, recreational and conservational objectives. Although sheep grazing is rarely considered the best method for delivering conservation objectives in seminatural temperate grasslands, the literature does not provide unequivocal evidence on the impact of sheep grazing on pasture biodiversity. Our aim was therefore to review evidence of the impacts of stocking rate, grazing period and soil fertility on plant communities and arthropod populations in both mesotrophic grasslands typical of agriculturally improved areas and in native plant communities. We therefore conducted a literature search of articles published up to the end of the year 2010 using 'sheep' and 'grazing' as keywords, together with variables describing grassland management, plant community structure or arthropod taxa. The filtering process led to the selection of 48 articles, with 42 included in the stocking rate dataset, 9 in the grazing period dataset and 10 in the soil fertility dataset. The meta-analysis did not reveal any significant trends for plant species richness or plant community evenness along a wide stocking rate gradient. However, we found frequent shifts in functional groups or plant species abundance that could be explained by the functional properties of the plants in the community. The meta-analysis confirmed that increasing soil fertility decreased plant species richness. Despite the very limited dataset, plant species richness was significantly greater in autumn grazed pastures than in ungrazed areas, which suggests that choosing an appropriate grazing period would be a promising option for preserving biodiversity in sheep farming systems. Qualitative review indicated that low grazing intensity had positive effects on Orthoptera, Hemiptera (especially phytophagous Auchenorrhyncha) and, despite a diverse range of feeding strategies, for the species richness of Coleoptera. Lepidoptera, which were favoured by more abundant flowering plants, also benefited from low grazing intensities. Spider abundance and species richness were higher in ungrazed than in grazed pastures. In contrast, there are insufficient published studies to draw any firm conclusions on the benefits of late grazing or stopping fertilization on insect diversity, and no grounds for including any of this information in decision support tools at this stage. PMID- 23031475 TI - Response of lamb plasma carotenoid concentration to a shift from a low to a high dietary carotenoid level. AB - This study was conducted to investigate the pattern of plasma carotenoid concentration (PCC) in lambs switching from a low to a high dietary carotenoid level. A total of 12 Romane lambs were individually penned indoors and fed a low dietary carotenoid level for 23 days (period 1) and then a high dietary carotenoid level for 15 days (period 2). At the beginning of period 2, the lambs were 15 weeks old and weighed 29.9 kg (s.d. 2.7) on average. Lambs were fed daily (dry matter) 0.558 kg alfalfa pellets, 0.181 kg straw and 0.181 kg barley. Plasma content of total carotenoids was measured daily in period 2 by spectrophotometry. PCC (MUg/l) varied with the animal (P < 0.001) and with time elapsed since the beginning of alfalfa distribution (P < 0.001). Mean PCC was 8 MUg/l (s.d. 3.3) at the beginning of period 2, then increased curvilinearly with the time elapsed since the beginning of alfalfa distribution. As early as 24 h on the alfalfa diet, PCC was already higher than before the switch (P < 0.001). Mean PCC continued to increase until day 6 on average and reached a plateau thereafter. We propose a monomolecular function to model this pattern, the equation obtained on the mean data being: PCC = 97 (s.e. 2.2) * (1-exp(-0.3378 (s.e. 0.0282)*d)), where r2 = 0.997, r.s.d. = 4.47, n = 15 and d = day. The percentage of variance explained by the model ranged between 95.9% and 99.2%, depending on the animal. The parameters of the monomolecular function varied among animals, confirming the interindividual variability in animal response. Plateau for PCC was reached slightly earlier for the six lambs with the lowest values of the asymptote than for the six lambs with the highest values of the asymptote. PMID- 23031476 TI - Influence of age, body weight and body condition score before mating start date on the pubertal rate of maiden Holstein-Friesian heifers and implications for subsequent cow performance and profitability. AB - The aim of this study was to assess the influence of age, body weight (BW) and body condition score (BCS) of maiden Holstein-Friesian heifers before mating start date (MSD) on the rate of puberty, subsequent production and longevity and their implications with regard to farm profitability. Data were available on 871 Holstein-Friesian heifers from 48 herds. BW was recorded electronically and BCS was recorded by a single operator on a scale of 1 to 5. Heifer age was calculated as the number of days from birth to the day of visit. All of the independent variables of interest were grouped into three or four categories. Three age categories (thirtiles), four BW categories (quartiles) and four BCS categories (<= 2.75, 3.00, 3.25 and >= 3.50) were formed. Heifers with an identifiable corpus lutuem (CL) in the presence or absence of large follicles and peri ovulatory signs and with a plasma progesterone (P4) concentration >= 1 ng/ml were classified as pubertal. In addition, heifers without an identifiable CL in the presence or absence of large follicles and peri-ovulatory signs but with a P4 concentration >= 1 ng/ml were also classified as pubertal. Age, BW and BCS at MSD were all found to be significantly associated with pubertal rate (P < 0.05). Age was shown to have no practical implications on subsequent cow performance. BW at MSD was favourably associated with subsequent calving date (P < 0.05), subsequent cow BW (P < 0.001) and potential (305 days) milk fat plus protein yield (P < 0.001). BCS at MSD was found to be favourably associated with milk fat plus protein yield potential (P < 0.05) and BCS (P < 0.001) during lactation. The economic analysis undertaken indicated that larger, well-grown heifers will be more profitable because of superior production potential, all else being equal. However, because of the finding of poorer reproductive efficiency in heifers grown to more than 343 kg at MSD, heifers at ~330 kg at MSD are deemed optimal. This will correspond to mature cow BW of ~550 kg. PMID- 23031477 TI - Structural vulnerability of the French swine industry trade network to the spread of infectious diseases. AB - The networks generated by live animal movements are the principal vector for the propagation of infectious agents between farms, and their topology strongly affects how fast a disease may spread. The structural characteristics of networks may thus provide indicators of network vulnerability to the spread of infectious disease. This study applied social network analysis methods to describe the French swine trade network. Initial analysis involved calculating several parameters to characterize networks and then identifying high-risk subgroups of holdings for different time scales. Holding-specific centrality measurements ('degree', 'betweenness' and 'ingoing infection chain'), which summarize the place and the role of holdings in the network, were compared according to the production type. In addition, network components and communities, areas where connectedness is particularly high and could influence the speed and the extent of a disease, were identified and analysed. Dealer holdings stood out because of their high centrality values suggesting that these holdings may control the flow of animals in part of the network. Herds with growing units had higher values for degree and betweenness centrality, representing central positions for both spreading and receiving disease, whereas herds with finishing units had higher values for in-degree and ingoing infection chain centrality values and appeared more vulnerable with many contacts through live animal movements and thus at potentially higher risk for introduction of contagious diseases. This reflects the dynamics of the swine trade with downward movements along the production chain. But, the significant heterogeneity of farms with several production units did not reveal any particular type of production for targeting disease surveillance or control. Besides, no giant strong connected component was observed, the network being rather organized according to communities of small or medium size (<20% of network size). Because of this fragmentation, the swine trade network appeared less structurally vulnerable than ruminant trade networks. This fragmentation is explained by the hierarchical structure, which thus limits the structural vulnerability of the global trade network. However, inside communities, the hierarchical structure of the swine production system would favour the spread of an infectious agent (especially if introduced in breeding herds). PMID- 23031478 TI - Melamine in eggs, plasma and tissues of hens fed contaminated diets. AB - A study was conducted to evaluate the excretion pattern of melamine from feed into eggs, plasma, kidney, liver and muscle of laying hens. In particular, 90 laying hens were randomly allocated to three dietary treatments and fed diets contaminated with melamine at a level of 2.5, 25 and 250 mg of melamine/kg of diet for T1, T2 and T3 groups, respectively. The diets were offered in six replicate boxes (five hens each) for 13 days. Eggs were collected from each group for melamine quantification on days 0, 1, 3, 6, 9 and 13. At the end of the experimental period, one hen per box was randomly selected and slaughtered to collect plasma, liver, kidney and muscle samples. During the experiment, feeding diets with increasing levels of melamine had no effect (P > 0.05) on weight gain, feed intake, egg production, egg weight and mortality of laying hens. The melamine in eggs increased from day 1 after melamine ingestion and reached a plateau between days 6 and 13 of melamine ingestion. At steady-state condition, the melamine egg concentrations increased (P < 0.01) with treatments, being 0.026, 0.352 and 4.631 mg/kg for T1, T2 and T3, respectively. Similarly, the carryover of melamine from feed to egg increased (P < 0.05) with the levels of melamine in the diets, varying from 0.50 to 0.70 and 0.84 for T1, T2 and T3, respectively. The melamine was detected in plasma of all tested groups, increasing (P < 0.01) with levels of melamine in the diets (0.030, 0.266 and 4.102 mg/l in T1, T2 and T3, respectively). Melamine was not detected in kidney, liver and muscle of hens fed T1. Except for kidney sampled in the T3, no melamine concentration higher than 2.5 mg/kg, representing the maximum allowable limit set by the US Food and Drug Administration and European Union for food and feeds, was measured. The melamine resulted higher in plasma and kidneys than in the liver and muscle both in T2 and T3. The results confirmed the presence of an excretion pattern of melamine from feed to eggs and tissues in laying hens. PMID- 23031479 TI - Real-time visual/near-infrared analysis of milk-clotting parameters for industrial applications. AB - The economical profitability of the dairy industry is based on the quality of the bulk milk collected in the farms, therefore it was based on the herd level rather than on the individual animals at real time. Udder infection and stage of lactation are directly related to the quality of milk produced on the herd level. However, improvement of milk quality requires testing each animal's milk separately and continuously. Recently, it was postulated that online equipment can estimate milk quality according to its clotting parameters, and thus result in better economical return for cheese making. This study further investigated the potential application of the AfiLabTM equipment to provide real-time analysis of milk-clotting parameters for cheese manufacture and cheese yield on quarter (1018) and individual cow (277) levels. Days in milk, lactose, log SCC and udder infection were found to have a significant effect on curd firmness and cheese properties and yield. The results clearly indicate that: (a) the parameter Afi-CF determined with the AfiLabTM is suitable for assessing milk quality for its clotting parameters, a value which is not provided by merely measuring fat and protein content on the gland and the cow levels; (b) bacterial type is the single major cause of reduced milk quality, with variations depending on the bacterial species; and (c) early and late lactation also had negative effects on milk clotting parameters. Cheese made from the various milk samples that were determined by the AfilabTM to be of higher quality for cheese making resulted in higher yield and better texture, which were related mainly to the bacterial species and stage of lactation. PMID- 23031480 TI - The effect of N-fertilisation rate or inclusion of red clover to timothy leys on fatty acid composition in milk of dairy cows fed a commercial silage: concentrate ratio. AB - The aim of this experiment was to, under typical Swedish production conditions, evaluate the effects of grass silages subjected to different N-fertilisation regimes fed to dairy cows on the fatty acid (FA) composition of their milk, and to compare the grass silages in this respect to red clover-dominated silage. Grass silages made from first year Phleum pratense L. leys subjected to three N fertilisation regimes (30, 90 and 120 kg N/ha, designated G-30, G-90 and G-120, respectively) and a mixed red clover-grass silage (Trifolium pratense L. and P. pratense L.; 60/40 on dry matter (DM) basis, designated RC-G) were produced. The experiment was conducted as a change-over design, including 24 primiparous and multiparous dairy cows of the Swedish Red breed, each of which was allocated to three of the four diets. The cows were offered 11 kg DM of silage and 7 kg concentrates. The silages had similar DM and energy concentrations. The CP concentration increased with increase in N-fertilisation level. There was a linear increase in DM intake of the different silages with increased N fertilisation. There were also differences in concentrations of both individual and total FAs amongst silages. The daily milk production (kg/day) did not significantly differ between treatments, but G-30 silage resulted in higher concentrations of 18:2n-6 in the milk compared with the other two grass silages. The highest concentrations of 18:3n-3 and cis-9, trans-11 18:2 were found in milk from cows offered the RC-G silage. The G-30 diet resulted in higher concentration of 18:2n-6 and the same concentration of 18:3n-3 in the milk as the other grass silages, despite lower intake levels of these FAs. The apparent recoveries of 18:3n-3 from feed to milk were 5.74%, 4.27%, 4.10% and 5.31% for G-30, G-90, G 120 and RC-G, respectively. A higher recovery when red clover is included in the diet confirms previous reports. The higher apparent recovery of 18:3n-3 on the G 30 treatment may be related to the lower silage DM intake, which led to a higher relative proportion of ingested FAs originating from concentrates compared with the G-90 and G-120 diets. With the rates and types of concentrates used in this study, the achieved differences in FA composition among the silages were not enough to influence the concentrations of unsaturated FAs in milk. PMID- 23031481 TI - Effect of low- and high-forage diets on meat quality and fatty acid composition of Alentejana and Barrosa beef breeds. AB - This study investigated the effects of genotype and diet on meat fat composition and palatability obtained from Alentejana (AL) and Barrosa (BA) breeds. Herein, 20 males from each breed allocated at 11 months of age were fed ad libitum a low forage diet or a high-forage diet and slaughtered at 18 months of age. Trained sensory panel analysis found that the longissimus lumborum (Ll) muscle from BA had higher tenderness, juiciness and overall acceptability scores than the AL breed. The highest scores for those attributes were observed in the BA breed fed the high-forage diet. Regarding the semitendinosus (St) muscle, breed was a source of variation of tenderness scores. In contrast to the Ll muscle, the highest tenderness scores for the St muscle were observed in the AL breed. The intramuscular fat (IMF) content was positively correlated with tenderness, juiciness and overall acceptability in Ll muscle and negatively correlated with flavour in the St muscle. The levels of 14:0 and 16:0, 16:1c9, 18:1c9 and 18:1c11 were positively correlated to juiciness, tenderness and overall acceptability in the Ll muscle. These correlations were not observed in the St muscle, which may be related to its low IMF content. Nonetheless, negative correlations were observed for the St muscle between flavour and 14:0, 16:0 and 18:0 FA contents.The IMF varied widely in the Ll but not in the St muscle. The latter had higher levels of 16:1c9 and trans fatty acids (?TFA) in the BA than in the AL breed. Regarding the Ll muscle, the BA had higher amounts of 14:0, 16:0, 16:1c9, 18:0, 18:1c9, 18:1c11, saturated fatty acids (?SFA), cis monounsaturated fatty acids (?cis MUFA), ?TFA and n-3 polyunsaturated fatty acids (?n-3 PUFA) than the AL breed. The diet exerted an influence on the IMF content and on the levels of 14:0, 16:0, 16:1c9, 18:0, 18:1c9, 18:1c11, ?SFA, ?cis MUFA and ?TFA in both Ll and St muscles. Moreover, the levels of ?n-3 PUFA in the Ll muscle and 18:2n-6, 20:4n-6, ?n-6 PUFA and ?PUFA in the St muscle were influenced by diet. The results obtained in this study, with two Portuguese breeds, confirm that genetic background plays a major role in the determination of meat eating quality. PMID- 23031482 TI - Patient satisfaction in pediatric outpatient settings from the parents' perspective - the Child ZAP: a psychometrically validated standardized questionnaire. AB - BACKGROUND: Patient surveys constitute a valuable source of information in patient-focused health care. The objective of this study was to develop and validate a standardized, patient centered, quantitative instrument to assess parent satisfaction in ambulatory pediatric care to be used in quality management and benchmarking activities, the Child-ZAP. METHODS: A preliminary version of the survey (38 items) was conducted in n = 19 pediatric practices. After psychometric testing a modified Child-ZAP was tested in a second survey (n = 20 new pediatric practices). Data from n = 979 patients were available for analysis. RESULTS: The final version of the Child-ZAP contains eight dimensions, three "Child-Scales" and five "Parent-Scales". Confirmatory factor analysis confirms the three hypothesized child dimensions as well as the five parent dimensions. The factorial structure is confirmed in subgroups of younger and older children. CONCLUSIONS: With satisfactory to good results for validity and reliability testing, the final Child-ZAP is applicable in pediatric ambulatory care for children of all age groups. PMID- 23031483 TI - Riboflavin as a dentin crosslinking agent: ultraviolet A versus blue light. AB - OBJECTIVES: To investigate the effect of photo-activation of riboflavin either by ultraviolet (UVA) or visible blue light (BL) on the biodegradation resistance, strength of demineralized dentin matrix, bond strength to dentin and resin/dentin interface morphology. METHODS: Dentin beams were demineralized, treated with 0.1% or 1% riboflavin solution for 5min and photo-activated with UVA or BL for 20s. The ultimate tensile strength (UTS) and hydroxyproline (HYP) release were assessed after 24h collagenase challenge. For micro-tensile bond strength (MUTBS) testing and resin/dentin interface morphology investigation, dentin was acid etched, crosslinked with riboflavin and bonded with an etch-and-rinse adhesive system. Riboflavin was photo-activated separately with UVA or BL followed by photo-polymerization of the bonding resin with BL (two-step) or both riboflavin photo-activation and bonding resin photo-polymerization were done in one-step using BL. RESULTS: Significant improvement in the UTS and biodegradation resistance against collagenase challenge was found when riboflavin was photo activated either with UVA or BL. However, UVA showed more significant improvement compared to BL. After 4months of water-storage, both UV and BL two-step photo activation methods significantly preserved higher values of the MUTBS compared to the non-crosslinked control group, where UVA showed significantly higher MUTBS than BL. SIGNIFICANCE: Although UVA most effectively activated riboflavin, visible blue light showed to be a promising substitute for UVA as it is clinically more applicable and acceptable, and still managed to increase the biodegradation resistance, enhance the mechanical properties of dentin collagen and improve and maintain the bond strength and interface integrity after short term water storage. PMID- 23031484 TI - Odontogenic responses of human dental pulp cells to collagen/nanobioactive glass nanocomposites. AB - OBJECTIVES: Collagen-based nanocomposite incorporating nanobioactive glass (Col/nBG) was developed as a scaffolding matrix for dentin-pulp regeneration. The effects of the novel matrix on the proliferation of human dental pulp cells (hDPCs) and their differentiation into odontoblastic lineage were investigated. METHODS: Nanocomposite scaffold was prepared by incorporating nBG within the Col solution and then reconstituting them into a membrane form. Cell growth by MTS assay, adhesion by scanning electron microscopy (SEM), and odontoblastic differentiation by alkaline phosphatase (ALP) activity, mineralization, and the mRNA expression of differentiation-related genes of DPCs on each scaffold were evaluated. RESULTS: The introduction of nBG significantly improved the bone mineral-like apatite formation in the simulated body fluid, suggesting excellent acellular bone-bioactivity. The hDPCs cultured on the Col/nBG nanocomposite have shown active growth behavior during culture for 14 days. The mRNA levels of major organic extracellular matrix of dentin, collagen type I and III were highly expressed in the Col/nBG matrix. Moreover, the alkaline phosphatase (ALP) activity and the mineralized nodule formation were increased in the Col/nBG nanocomposite compared to those in Col. Odontoblatic differentiation genes, including dentin sialophosphoprotein, dentin matrix protein I, ALP, osteopontin and osteocalcin were significantly stimulated in the Col containing nBG. Moreover, the key adhesion receptor integrin components alpha2 and beta1, specifically binding to collagen molecule sequence, were upregulated in Col/nBG compared to Col, suggesting that odontogenic stimulation was closely related to the integrin-mediated process. SIGNIFICANCE: In our study, the nanocomposite Col/nBG matrix induced the growth and odontogenic differentiation more effectively than Col alone, providing a promising scaffold condition for regeneration of dentin-pulp complex tissue. PMID- 23031485 TI - Nanomechanical properties of dental resin-composites. AB - OBJECTIVE: To determine by nanoindentation the hardness and elastic modulus of resin-composites, including a series with systematically varied filler loading, plus other representative materials that fall into the categories of flowable, bulk-fill and conventional nano-hybrid types. METHODS: Ten dental resin composites: three flowable, three bulk-fill and four conventional were investigated using nanoindentation. Disc specimens (15mm*2mm) were prepared from each material using a metallic mold. Specimens were irradiated in the mold at top and bottom surfaces in multiple overlapping points (40s each) with light curing unit at 650mW/cm(2). Specimens were then mounted in 3cm diameter phenolic ring forms and embedded in a self-curing polystyrene resin. After grinding and polishing, specimens were stored in distilled water at 37 degrees C for 7 days. Specimens were investigated using an Agilent Technologies XP nanoindenter equipped with a Berkovich diamond tip (100nm radius). Each specimen was loaded at one loading rate and three different unloading rates (at room temperature) with thirty indentations, per unloading rate. The maximum load applied by the nanoindenter to examine the specimens was 10mN. RESULTS: Dependent on the type of the resin-composite material, the mean values ranged from 0.73GPa to 1.60GPa for nanohardness and from 14.44GPa to 24.07GPa for elastic modulus. There was a significant positive non-linear correlation between elastic modulus and nanohardness (r(2)=0.88). Nonlinear regression revealed a significant positive correlation (r(2)=0.62) between elastic moduli and filler loading and a non significant correlation (r(2)=0.50) between nanohardness and filler loading of the studied materials. Varying the unloading rates showed no consistent effect on the elastic modulus and nanohardness of the studied materials. SIGNIFICANCE: For a specific resin matrix, both elastic moduli and nanohardness correlated positively with filler loading. For the resin-composites investigated, the group average elastic moduli and nanohardnesses for bulk-fill and flowable materials were lower than those for conventional nano-hybrid composites. PMID- 23031486 TI - Mass-gathering medicine: creation of an online event and patient registry. AB - INTRODUCTION/PROBLEM: A review of the mass-gathering medicine literature confirms that the research community currently lacks a standardized approach to data collection and reporting in relation to large-scale community events. This lack of consistency, particularly with regard to event characteristics, patient characteristics, acuity determination, and reporting of illness and injury rates makes comparisons between and across events difficult. In addition, a lack of access to good data across events makes planning medical support on-site, for transport, and at receiving hospitals, challenging. This report describes the development of an Internet-hosted, secure registry for event and patient data in relation to mass gatherings. METHODS: Descriptive; development and pilot testing of a Web-based event and patient registry. RESULTS: Several iterations of the registry have resulted in a cross-event platform for standardized data collection at a variety of events. Registry and reporting field descriptions, successes, and challenges are discussed based on pilot testing and early implementation over two years of event enrollment. CONCLUSION: The Mass-Gathering Medicine Event and Patient Registry provides an effective tool for recording and reporting both event and patient-related variables in the context of mass-gathering events. Standardizing data collection will serve researchers and policy makers well. The structure of the database permits numerous queries to be written to generate standardized reports of similar and dissimilar events, which supports hypothesis generation and the development of theoretical foundations in mass-gathering medicine. PMID- 23031487 TI - Estimation of the concordance correlation coefficient for repeated measures using SAS and R. AB - The concordance correlation coefficient is one of the most common approaches used to assess agreement among different observers or instruments when the outcome of interest is a continuous variable. A SAS macro and R package are provided here to estimate the concordance correlation coefficient (CCC) where the design of the data involves repeated measurements by subject and observer. The CCC is estimated using U-statistics (UST) and variance components (VC) approaches. Confidence intervals and standard errors are reported along with the point estimate of the CCC. In the case of the VC approach, the linear mixed model output and variance components estimates are also provided. The performance of each function is shown by means of some examples with real data sets. PMID- 23031488 TI - Automatically designed machine vision system for the localization of CCA transverse section in ultrasound images. AB - The common carotid artery (CCA) is a source of important information that doctors can use to evaluate the patients' health. The most often measured parameters are arterial stiffness, lumen diameter, wall thickness, and other parameters where variation with time is usually measured. Unfortunately, the manual measurement of dynamic parameters of the CCA is time consuming, and therefore, for practical reasons, the only alternative is automatic approach. The initial localization of artery is important and must precede the main measurement. This article describes a novel method for the localization of CCA in the transverse section of a B-mode ultrasound image. The novel method was designed automatically by using the grammar-guided genetic programming (GGGP). The GGGP searches for the best possible combination of simple image processing tasks (independent building blocks). The best possible solution is represented with the highest detection precision. The method is tested on a validation database of CCA images that was specially created for this purpose and released for use by other scientists. The resulting success of the proposed solution was 82.7%, which exceeded the current state of the art by 4% while the computation time requirements were acceptable. The paper also describes an automatic method that was used in designing the proposed solution. This automatic method provides a universal approach to designing complex solutions with the support of evolutionary algorithms. PMID- 23031489 TI - The impact of having natural teeth on the QoL of frail dentulous older people. A qualitative study. AB - BACKGROUND: In order to adapt oral care and treatment to the demands of the growing group of frail dentulous older people, it is important to understand how and to which extent having natural teeth contributes to the quality of life (QoL) of frail older people and how frailty influences their perspective. METHODS: A qualitative approach was used. Interviews with 38 Dutch frail older dentulous people were tape-recorded, transcribed, coded for content and analyzed. Additional information was collected which included age, gender, living situation, use of dental prostheses, self-reported oral health status, chronic disorders, and an index for frailty. RESULTS: Seven themes were identified in the relationship between natural teeth and the QoL of the participants: pride and achievement; intactness; sense of control; oral function; appearance; comfort; along with coping and adapting to disabilities. Having natural teeth generally had a positive effect on QoL. Positive effects through pride and achievement, intactness, and sense of control were most apparent for the most severely frail. They compared themselves with peers who are more often edentate, and valued the good state of their teeth against the background of their declining health, especially those with disabilities causing severe chronic pain or impaired fine motor skills. The effect of coping with and adaptation to tooth loss was also most apparent for the most severely frail. There was a gender effect in that the men generally cared less about having natural teeth than women, regardless of their level of frailty. CONCLUSIONS: QoL of frail older people is positively influenced by natural teeth, and this effect seems to increase with increasing frailty. Preservation of teeth contributes to a positive body image and self worth. Oral care for frail people should aim to preserve natural teeth if possible. PMID- 23031491 TI - Selective transport of long-chain fatty acids by FAT/CD36 in skeletal muscle of broilers. AB - Fatty acid translocase (FAT/CD36) is a membrane receptor that facilitates long chain fatty acid uptake. To investigate its role in the regulation of long-chain fatty acid composition in muscle tissue, we studied and compared FAT/CD36 gene expression in muscle tissues of commercial broiler chickens and Chinese local Silky fowls. The results from gas chromatography-mass spectrometry analysis of muscle samples demonstrated that Chinese local Silky fowls had significantly higher (P < 0.05) proportions of linoleic acid (LA) and palmitic acid, lower proportions (P < 0.05) of arachidonic acid (AA) and oleic acid than the commercial broiler chickens. The mRNA expression levels of fatty acid (FA) transporters (FA transport protein-1, membrane FA-binding protein, FAT/CD36 and caveolin-1) in the m. ipsilateral pectoralis and biceps femoris were analyzed by Q-PCR, and FAT/CD36 expression levels showed significant differences between these types of chickens (P < 0.01). Interestingly, the levels of FAT/CD36 expression are positively correlated with LA content (r = 0.567, P < 0.01) but negatively correlated with palmitic acid content (r = -0.568, P < 0.01). Further experiments in the stably transfected Chinese hamster oocytes cells with chicken FAT/CD36 cDNA demonstrated that overexpression of FAT/CD36 improves total FA uptake with a significant increase in the proportion of LA and AA, and a decreased proportion of palmitic acid. These results suggest that chicken FAT/CD36 may selectively transport LA and AA, which may lead to the higher LA deposition in muscle tissue. PMID- 23031492 TI - Nanostructured copper, chromium, and tin oxide multicomponent materials as catalysts for methanol decomposition: 11C-radiolabeling study. AB - Copper and chromium modified tin oxide nanocomposites were obtained via incipient wetness impregnation of high surface area nanosized SnO(2) with the corresponding metal acetylacetonates and their further decomposition in air. Powder X-ray diffraction (XRD), Nitrogen physisorption, UV-Vis, and Temperature-programmed reduction (TPR) with hydrogen were applied for the samples characterization. The catalytic activity of the obtained materials was tested in methanol conversion. A new approach based on the selective coverage of the surface with (11)C-methanol was used for the characterization of the catalytic sites. It was demonstrated that the products distribution could be controlled by the surface coverage with methanol and the role of different active sites was discussed. The modification of SnO(2) with copper oxide increased the activity in methanol decomposition to CO(2)via dioxymethylene intermediates, but the catalyst suffered considerable loss of activity due to the reduction transformations by the reaction medium and formation of an inactive intermetallic alloy. The modification with chromium changed the acid-basic properties of SnO(2) by the formation of Cr(2)O(3) nanoparticles as well as anchored to the support chromate species. The former particles facilitated the formation of dimethyl ether (DME), while the latter species converted methanol predominantly to hydrocarbons. The fraction of chromate species increased in Cu-Cr-Sn oxide multicomponent nanocomposites and promoted the formation of hydrocarbons over DME at low temperatures, while at higher temperatures, the activity of the copper species leading to CO(2) formation was more pronounced. PMID- 23031493 TI - An apparatus to measure electrical charge of bubble swarms. AB - An apparatus has been developed to characterize bubble charge by measuring the swarm potential of gas bubbles. The technique allows in-process measurement of all system variables associated with bubble surface electrical charge: swarm potential, solution conductivity, gas holdup, pH and bubble size distribution. The method was validated by comparing with literature iso-electric point (iep) values. Bubble swarm potential was measured as a function of concentration and pH for a series of non-ionic surfactant frothers, ionic surfactant collectors and multivalent metal ions. Results showed good agreement with established theory and prior experimental findings. The setup is a step towards measurement of charge on flotation size range of bubble swarms. PMID- 23031494 TI - Evolutionary screening and adsorption behavior of engineered M13 bacteriophage and derived dodecapeptide for selective decoration of gold interfaces. AB - There is a growing interest in identifying biomacromolecules such as proteins and peptides to functionalize metallic surfaces through noncovalent binding. One method for functionalizing materials without fundamentally changing their inherent structure is using biorecognition moieties. Here, we proved a general route to select a biomolecule adhesive motif for surface functionalization by comprehensively screening phage displayed peptides. In particular, we selected a genetically engineered M13 bacteriophage and a linear dodecapeptide derived from its pIII domain for recognizing gold surfaces in a specific and selective manner. In the phage context, we demonstrated the adhesive motif was capable to adsorb on gold in a preferential way with a morphological and viscoelastic signature of the adsorbed layer as evidenced by QCM-D and AFM investigations. Out of the phage context, the linear dodecapeptide is reproducibly found to adhere to the gold surface, and by quantitative SPR measurements, high affinity constants (K(eq)~10(6)M(-1), binding energy ~-8 kcal/mol) were determined. We proved that the interactions occurring at gold interface were mainly hydrophobic as a consequence of high frequency of hydrophobic residues in the peptide sequence. Moreover, by CD, molecular dynamics and steered molecular dynamics, we demonstrated that the molecular flexibility only played a minor role in the peptide adsorption. Such noncovalent but specific modification of inorganic surfaces through high affinity biomolecule adsorption represents a general strategy to modulate the functionality of multipurpose metallic surfaces. PMID- 23031495 TI - Mesoporous silica containing =Si(CH2)3NHC(S)NHC2H5 functional groups in the surface layer. AB - One-step synthesis technique of mesoporous SBA-15 type silica with thiourea =Si(CH(2))(3)NHC(S)NHC(2)H(5) groups in the surface layer was developed. According to elemental analysis, the content of surface groups is 1.25 mmol/g, which is consistent with TGA data. FT-IR spectra of the obtained sample contain characteristic absorption bands of thiourea groups (-NH-C(S)-NH-), as well as polysiloxane network (SiOSi). The synthesized sample was studied by XRD, TEM, SEM, and adsorption method. It was demonstrated that the sample features porous microspheres ~0.5 MUm with well-ordered internal spatial structure of the hexagonal lattice type due to the usage of template P123 during synthesis. According to XRD and TEM, the diameter of pores is 4.2-5 nm and the wall thickness between them is 2.6 nm. These data are consistent with the structural adsorption characteristics calculated from nitrogen adsorption-desorption isotherms: S(sp.)=510 m(2)/g, V(s)=0.47 cm(3)/g, and d=4.3 nm. Equilibrium is established within 60 min during sorption of silver(I) and mercury(II) ions from acidified aqueous solutions for this sample, and with the complexes are formed 1.1/1 for Ag(+) and 0.8/1 for Hg(2+) at metal/ligand ratio. PMID- 23031496 TI - Indacaterol therapy in patients with COPD not receiving other maintenance treatment. AB - BACKGROUND: Recent findings of rapid lung function decline in younger patients with moderate COPD severity suggest the need for effective early treatment. AIM: To evaluate the effectiveness of indacaterol as maintenance therapy in COPD patients not receiving other maintenance treatments. METHODS: Pooled data from three randomised, placebo-controlled studies provided a population of patients with moderate-to-severe COPD not receiving maintenance treatment at baseline and who received once-daily, double-blind treatment with indacaterol 150 MUg, indacaterol 300 MUg or placebo. Data from an open-label tiotropium treatment arm in one study were available for comparison. Efficacy evaluations included trough FEV1, dyspnoea (transition dyspnoea index, TDI) and health status (St George's Respiratory Questionnaire, SGRQ) at 6 months and risk of COPD exacerbations. RESULTS: The maintenance-naive population comprised 232 (indacaterol 150 MUg), 220 (indacaterol 300 MUg) and 325 (placebo) patients, plus 156 (tiotropium) (30% of overall study population). Patients treated with indacaterol 150 and 300 MUg had statistically significant improvements relative to placebo (p < 0.05) in trough FEV1 (170 and 180 mL), TDI total score (1.27 and 1.04 points), rescue use and SGRQ total score (-6.1 and -2.5 units) at 6 months. Patients receiving tiotropium had statistically significant improvements versus placebo (p < 0.05) in trough FEV1 (130 mL) and TDI total score (0.69 points). Exacerbations were rare and not significantly reduced by any treatment. Treatments were well tolerated. CONCLUSIONS: Indacaterol, given to patients with moderate-to-severe COPD not receiving other maintenance treatments, provided effective bronchodilation with significant, clinically relevant improvements in dyspnoea and health status compared with placebo. PMID- 23031497 TI - The role of interleukin-6 in gynaecological malignancies. AB - There are many parallels between gynaecological cancers in relation to cytokine networks within their respective tumour microenvironments and evidence to support interleukin-6 (IL-6) being an appropriate therapeutic target in these diseases. This article provides an overview on IL-6 biology including updates on novel discoveries in IL-6 signalling and then focuses on the role of IL-6 in processes such as cell proliferation, migration, angiogenesis, evasion of tumour immunity and chemoresistance and presents data relating to the abrogation of these processes with anti-IL-6 targeted therapy in preclinical and clinical studies. The overall aim will be to highlight the necessity for further translational studies concentrating on combinations of anti-IL-6/IL-6R therapies with other novel targets in an attempt to significantly improve overall survival in patients with gynaecological cancers. PMID- 23031498 TI - Immune interference in the setting of same-day administration of two similar inactivated alphavirus vaccines: eastern equine and western equine encephalitis. AB - We compared the effect on primary vaccination plaque-reduction neutralization 80% titers (PRNT80) responses of same-day administration (at different injection sites) of two similar investigational inactivated alphavirus vaccines, eastern equine encephalitis (EEE) vaccine (TSI-GSD 104) and western equine encephalitis (WEE) vaccine (TSI-GSD 210) to separate administration. Overall, primary response rate for EEE vaccine was 524/796 (66%) and overall primary response rate for WEE vaccine was 291/695 (42%). EEE vaccine same-day administration yielded a 59% response rate and a responder geometric mean titer (GMT)=89 while separate administration yielded a response rate of 69% and a responder GMT=119. WEE vaccine same-day administration yielded a 30% response rate and a responder GMT=53 while separate administration yielded a response rate of 54% and a responder GMT=79. EEE response rates for same-day administration (group A) vs. non-same-day administration (group B) were significantly affected by gender. A logistic regression model predicting response to EEE comparing group B to group A for females yielded an OR=4.10 (95% CL 1.97-8.55; p=.0002) and for males yielded an OR=1.25 (95% CL 0.76-2.07; p=.3768). WEE response rates for same-day administration vs. non-same-day administration were independent of gender. A logistic regression model predicting response to WEE comparing group B to group A yielded an OR=2.14 (95% CL 1.22-3.73; p=.0077). We report immune interference occurring with same-day administration of two completely separate formalin inactivated viral vaccines in humans. These findings combined with the findings of others regarding immune interference would argue for a renewed emphasis on studying the immunological mechanisms of induction of inactivated viral vaccine protection. PMID- 23031499 TI - Nucleosome assembly proteins and their interacting proteins in neuronal differentiation. AB - Neuronal differentiation from neural stem cells into mature neurons is guided by the concerted action of specific transcription factors that stepwise exercise their role in the context of defined chromatin states. Amongst the classes of proteins that influence chromatin compaction and modification are nucleosome assembly proteins (NAPs). Mammals possess several nucleosome assembly protein 1 like proteins (NAP1L) that show either ubiquitous or neuron-restricted expression. The latter group is presumably involved in the process of neuronal differentiation. Mammalian NAP1Ls can potentially form both homo- and hetero dimers and octamers, in theory allowing thousands of different combinations to be formed. Detailed studies have been performed on several of the NAP1Ls that point to a range of molecular roles, including transcriptional regulation, nuclear import, and control of cell division. This article aims at summarizing current knowledge of the mammalian NAP1L family and its interactions. PMID- 23031500 TI - Tumor-induced lymphangiogenesis in cervical lymph nodes in oral melanoma-bearing mice. AB - BACKGROUND: Metastasis via the lymphatic system is promoted by lymphangiogenesis. Alterations of the lymphatic channels during the progression of metastasis to regional lymph nodes (LNs) remain unexplored. To examine whether tumor-induced LN lymphangiogenesis controls metastasis to regional LNs, we investigated cervical LN metastasis in a mouse model of oral melanoma. METHODS: Injection of B16F10 melanoma cells into mouse tongues replicated spontaneous cervical LN metastasis. We performed histological, immunofluorescent, and histomorphometric analyses of tumor-reactive lymphadenopathy and lymphangiogenesis in tumor-associated LNs. We investigated the expression of vascular endothelial growth factor (VEGF)-C and its receptor, VEGF receptor-3 (VEGFR-3), in tumor cells and tissues, and LNs by reverse transcription polymerase chain reaction and immunofluorescence. RESULTS: Tumor-associated LNs comprised sentinel LNs (SLNs) before and after tumor cell invasion (tumor-bearing SLNs), and LNs adjacent or contralateral to tumor-bearing SLNs. Extensive lymphangiogenesis appeared in SLNs before evidence of metastasis. After metastasis was established in SLNs, both LNs adjacent and contralateral to tumor-bearing SLNs demonstrated lymphangiogenesis. Interaction between VEGF-C positive melanoma cells and VEGFR-3-positive lymphatic vessels was evident in tumor-associated LNs. CONCLUSIONS: LN lymphangiogenesis contributes a progression of tumor metastasis from SLNs to other regional LNs. PMID- 23031501 TI - Decision-theoretic analysis of forensic sampling criteria using bayesian decision networks. AB - Sampling issues represent a topic of ongoing interest to the forensic science community essentially because of their crucial role in laboratory planning and working protocols. For this purpose, forensic literature described thorough (bayesian) probabilistic sampling approaches. These are now widely implemented in practice. They allow, for instance, to obtain probability statements that parameters of interest (e.g., the proportion of a seizure of items that present particular features, such as an illegal substance) satisfy particular criteria (e.g., a threshold or an otherwise limiting value). Currently, there are many approaches that allow one to derive probability statements relating to a population proportion, but questions on how a forensic decision maker--typically a client of a forensic examination or a scientist acting on behalf of a client- ought actually to decide about a proportion or a sample size, remained largely unexplored to date. The research presented here intends to address methodology from decision theory that may help to cope usefully with the wide range of sampling issues typically encountered in forensic science applications. The procedures explored in this paper enable scientists to address a variety of concepts such as the (net) value of sample information, the (expected) value of sample information or the (expected) decision loss. All of these aspects directly relate to questions that are regularly encountered in casework. Besides probability theory and bayesian inference, the proposed approach requires some additional elements from decision theory that may increase the efforts needed for practical implementation. In view of this challenge, the present paper will emphasise the merits of graphical modelling concepts, such as decision trees and bayesian decision networks. These can support forensic scientists in applying the methodology in practice. How this may be achieved is illustrated with several examples. The graphical devices invoked here also serve the purpose of supporting the discussion of the similarities, differences and complementary aspects of existing bayesian probabilistic sampling criteria and the decision-theoretic approach proposed throughout this paper. PMID- 23031503 TI - Cambrian problematica and the diversification of deuterostomes. AB - Vetulicolians are an enigmatic group of Cambrian organisms that have been affiliated at various times with arthropods, lobopodians, kinorhynchs and deuterostomes. New evidence on the structure of the lateral pores of vetulicolians published in BMC Biology strengthens the view that they may be total group deuterostomes, but unfortunately sheds no new light on early deuterostome evolution. PMID- 23031502 TI - Macroporous three-dimensional PDMS scaffolds for extrahepatic islet transplantation. AB - Clinical islet transplantation has demonstrated success in treating type 1 diabetes. A current limitation is the intrahepatic portal vein transplant site, which is prone to mechanical stress and inflammation. Transplantation of pancreatic islets into alternative sites is preferable, but challenging, as it may require a three-dimensional vehicle to confer mechanical protection and to confine islets to a well-defined, retrievable space where islet neovascularization can occur. We have fabricated biostable, macroporous scaffolds from poly(dimethylsiloxane) (PDMS) and investigated islet retention and distribution, metabolic function, and glucose-dependent insulin secretion within these scaffolds. Islets from multiple sources, including rodents, nonhuman primates, and humans, were tested in vitro. We observed high islet retention and distribution within PDMS scaffolds, with retention of small islets (< 100 um) improved through the postloading addition of fibrin gel. Islets loaded within PDMS scaffolds exhibited viability and function comparable to standard culture conditions when incubated under normal oxygen tensions, but displayed improved viability compared to standard two-dimensional culture controls under low oxygen tensions. In vivo efficacy of scaffolds to support islet grafts was evaluated after transplantation in the omental pouch of chemically induced diabetic syngeneic rats, which promptly achieved normoglycemia. Collectively, these results are promising in that they indicate the potential for transplanting islets into a clinically relevant, extrahepatic site that provides spatial distribution of islets as well as intradevice vascularization. PMID- 23031504 TI - Genetic parameters for production, health, fertility and longevity traits in dairy cows. AB - Milk production, fertility, longevity and health records, were extracted from databases of two milk recording organisations in the United Kingdom for the first three lactations of the Holstein-Friesian breed. These included data related to health events (mastitis and lameness), voluntarily recorded on a proportion of farms. The data were analysed to calculate disease incidence levels and to estimate genetic parameters for health traits and their relationships with production and other functional traits. The resulting dataset consisted of 124,793 lactations from 75,137 animals of 1586 sires, recorded in 2434 herds. Incidence of health events increased with parity. The overall incidence of mastitis (MAS) and lameness (LAM), defined as binary traits, were 17% and 16%, respectively. Heritability estimates for MAS and LAM were 0.04 and 0.02, respectively, obtained from repeatability linear sire models. Heritability estimates of mastitis and lameness as count traits were slightly higher, 0.05 and 0.03, respectively. Genetic correlations were obtained by bivariate analyses of all pair-wise combinations between milk 305-day yield (MY), protein 305-day yield (PY), fat 305-day yield (FY), lactation average loge transformed lactation average somatic cell count (SCS), calving interval (CI), days to first service (DFS), non-return at 56 days (NR56), number of inseminations (NINS), mastitis (MAS), number of mastitis episodes (NMAS), lameness (LAM), number of lameness episodes (NLAM) and lifespan score (LS). As expected, MAS was correlated most strongly with SCS (0.69), which supports the use of SCS as an indicator trait for mastitis. Genetic correlations between MAS and yield and fertility traits were of similar magnitude ranging from 0.27 to 0.33. Genetic correlations between MAS with LAM and LS were 0.38 and -0.59, respectively. Not all genetic correlations between LAM and other traits were significant because of fewer numbers of lameness records. LAM had significant genetic correlations with MY (0.38), PY (0.28), CI (0.35), NINS (0.38) and LS (-0.53). The heritability estimates of mastitis and lameness were low; therefore, genetic gain through direct selection alone would be slow, yet still positive and cumulative. Direct selection against mastitis and lameness as additional traits should reduce incidence of both diseases, and simultaneously improve fertility and longevity. However, both health traits had antagonistic relationships with production traits, thus genetic gain in production would be slower. PMID- 23031505 TI - NLRP1 polymorphisms in patients with asbestos-associated mesothelioma. AB - BACKGROUND: An increasing incidence of malignant mesothelioma (MM) cases in patients with low levels of asbestos exposure suggests the interference of alternative cofactors. SV40 infection was detected, as co-morbidity factor, only in 22% of asbestos-MM patients from a North-Eastern Italy area. An additional mechanism of injury related to asbestos exposure in MM development has been recently associated to inflammatory responses, principally driven by interleukin (IL)-1 beta (beta) activated within the inflammasome complex.NLRP3 inflammosome has been described as the intracellular sensor for asbestos able to induce inflammasome activation and IL-1beta secretion while NLRP1 is expressed in lung epithelial cells and alveolar macrophages and contributes to the immune response and to survival/apoptosis balance. This study proposes to evaluate the impact of known NLRP3 and NLRP1 polymorphisms in the individual susceptibility to asbestos induced mesothelioma in subjects from a hyperendemic area for MM. METHODS: 134 Italian patients with diagnosis of mesothelioma due (MMAE, n=69) or not (MMAF, n=65) to asbestos, 256 healthy Italian blood donors and 101 Italian healthy subjects exposed to asbestos (HCAE) were genotyped for NLRP1 (rs2670660 and rs12150220) and NLRP3 (rs35829419 and rs10754558) polymorphisms. RESULTS: While NLRP3 SNPs were not associated to mesothelioma, the NLRP1 rs12150220 allele T was significantly more frequent in MMAE (0.55) than in HCAE (0.41) (p=0.011; OR=1.79) suggesting a predisponent effect of this allele on the development of mesothelioma. This effect was amplified when the NLRP1 rs2670660 allele was combined with the NLRP1 rs12150220 allele (p=0.004; OR=0.52). CONCLUSION: Although NLRP3 SNPs was not involved in mesothelioma predisposition, these data proposed NLRP1 as a novel factor possibly involved in the development of mesothelioma. PMID- 23031506 TI - Comparison of gait in progressive supranuclear palsy, Parkinson's disease and healthy older adults. AB - BACKGROUND: Progressive supranuclear palsy and Parkinson's disease have characteristic clinical and neuropathologic profiles, but also share overlapping clinical features. This study aimed to analyze the gait of people with progressive supranuclear palsy (n=19) and compare it with people with Parkinson's disease (n=20) and healthy older adults (n=20). METHODS: Gait was recorded at self-selected preferred, fast, very fast, slow and very slow speeds. Stride length was normalized to leg length. Linear regression analyses were carried out between cadence and stride length. Other gait variables were compared for each participant's 'walk' which had stride length closest to 1.4. RESULTS: All groups showed a strong linear relationship between stride length and cadence with no difference between groups (p>0.05). The intercept between cadence and stride length was lowest in the progressive supranuclear palsy group and highest for older adults (p<0.001). The progressive supranuclear palsy group had higher cadence than older adults (p>0.05), and greater step width and greater double support phase compared with the other two groups (p<0.05). CONCLUSIONS: The temporal-spatial gait characteristics of progressive supranuclear palsy and Parkinson's disease are largely similar, with similar disruption to scaling of stride length. The additional findings of increased step width and double support percentage suggest increased severity of gait abnormality compared to Parkinson's disease, despite similar disease duration. The findings are consistent with the clinical features of greater instability and more rapid disease progression in progressive supranuclear palsy compared to Parkinson's disease and implicates the early pathological involvement of brain regions involved in gait control. PMID- 23031507 TI - Comparison of transcriptome technologies in the pathogenic fungus Aspergillus fumigatus reveals novel insights into the genome and MpkA dependent gene expression. AB - BACKGROUND: The filamentous fungus Aspergillus fumigatus has become the most important airborne fungal pathogen causing life-threatening infections in immuno compromised patients. Recently developed high-throughput transcriptome and proteome technologies, such as microarrays, RNA deep-sequencing, and LC-MS/MS of peptide mixtures, are of enormous value for systematically investigating pathogenic organisms. In the field of infection biology, one of the priorities is to collect and standardise data, in order to generate datasets that can be used to investigate and compare pathways and gene responses involved in pathogenicity. The "omics" era provides a multitude of inputs that need to be integrated and assessed. We therefore evaluated the potential of paired-end mRNA-Seq for investigating the regulatory role of the central mitogen activated protein kinase (MpkA). This kinase is involved in the cell wall integrity signalling pathway of A. fumigatus and essential for maintaining an intact cell wall in response to stress. RESULTS: The comparison of the transcriptome and proteome of an A. fumigatus wild-type strain with an mpkA null mutant strain revealed that 70.4% of the genome was found to be expressed and that MpkA plays a significant role in the regulation of many genes involved in cell wall remodelling, oxidative stress and iron starvation response, and secondary metabolite biosynthesis. Moreover, absence of the mpkA gene also strongly affects the expression of genes involved in primary metabolism. The data were further processed to evaluate the potential of the mRNA-Seq technique. We comprehensively matched up our data to published transcriptome studies and were able to show an improved data comparability of mRNA-Seq experiments independently of the technique used. Analysis of transcriptome and proteome data revealed only a weak correlation between mRNA and protein abundance. CONCLUSIONS: High-throughput analysis of MpkA-dependent gene expression confirmed many previous findings that this kinase is important for regulating many genes involved in metabolic pathways. Our analysis showed more than 2000 differentially regulated genes. RNA deep-sequencing is less error-prone than established microarray-based technologies. It also provides additional information in A. fumigatus studies and as a result is more suitable for the creation of extensive datasets. PMID- 23031509 TI - Migrant workers' occupation and healthcare-seeking preferences for TB-suspicious symptoms and other health problems: a survey among immigrant workers in Songkhla province, southern Thailand. AB - BACKGROUND: Much of the unskilled and semi-skilled workforce in Thailand comprises migrant workers from neighbouring countries. While, in principle, healthcare facilities in the host country are open to those migrants registered with the Ministry of Labour, their actual healthcare-seeking preferences and practices, as well as those of unregistered migrants, are not well documented. This study aimed to describe the patterns of healthcare-seeking behaviours of immigrant workers in Thailand, emphasizing healthcare practices for TB-suspicious symptoms, and to identify the role of occupation and other factors influencing these behaviours. METHODS: A survey was conducted among 614 immigrant factory workers (FW), rubber tappers (RT) and construction workers (CW), in which information was sought on socio-demography, history of illness and related healthcare-seeking behaviour. Mixed effects logistic regression modeling was employed in data analysis. RESULTS: Among all three occupations, self-medication was the most common way of dealing with illnesses, including the development of TB-suspicious symptoms, for which inappropriate drugs were used. Only for GI symptoms and obstetric problems did migrant workers commonly seek healthcare at modern healthcare facilities. For GI illness, FW preferred to attend the in factory clinic and RT a private facility over government facilities owing to the quicker service and greater convenience. For RT, who were generally wealthier, the higher cost of private treatment was not a deterrent. CW preferentially chose a government healthcare facility for their GI problems. For obstetric problems, including delivery, government facilities were utilized by RT and CW, but most FW returned to their home country. After adjusting for confounding, having legal status in the country was associated with overall greater use of government facilities and being female and being married with use of both types of modern healthcare facility. One-year estimated period prevalence of TB-suspicious symptoms was around 6% among FW but around 27% and 30% in RT and CW respectively. However, CW were the least likely to visit a modern healthcare facility for these symptoms. CONCLUSIONS: Self medication is the predominant mode of healthcare seeking among these migrant workers. When accessing a modern healthcare facility the choice is influenced by occupation and its attendant lifestyle and socioeconomic conditions. Utilization of modern facilities could be improved by reducing the current barriers by more complete registration coverage and better provision of healthcare information, in which local vendors of the same ethnicity could play a useful role. Active surveillance for TB among migrant workers, especially CW, may lead to better TB control. PMID- 23031511 TI - Integration of genomic information into sport horse breeding programs for optimization of accuracy of selection. AB - Reliable selection criteria are required for young riding horses to increase genetic gain by increasing accuracy of selection and decreasing generation intervals. In this study, selection strategies incorporating genomic breeding values (GEBVs) were evaluated. Relevant stages of selection in sport horse breeding programs were analyzed by applying selection index theory. Results in terms of accuracies of indices (r(TI) ) and relative selection response indicated that information on single nucleotide polymorphism (SNP) genotypes considerably increases the accuracy of breeding values estimated for young horses without own or progeny performance. In a first scenario, the correlation between the breeding value estimated from the SNP genotype and the true breeding value (= accuracy of GEBV) was fixed to a relatively low value of r(mg) = 0.5. For a low heritability trait (h(2) = 0.15), and an index for a young horse based only on information from both parents, additional genomic information doubles r(TI) from 0.27 to 0.54. Including the conventional information source 'own performance' into the before mentioned index, additional SNP information increases r(TI) by 40%. Thus, particularly with regard to traits of low heritability, genomic information can provide a tool for well-founded selection decisions early in life. In a further approach, different sources of breeding values (e.g. GEBV and estimated breeding values (EBVs) from different countries) were combined into an overall index when altering accuracies of EBVs and correlations between traits. In summary, we showed that genomic selection strategies have the potential to contribute to a substantial reduction in generation intervals in horse breeding programs. PMID- 23031510 TI - Structural view on recycling of archaeal and eukaryotic ribosomes after canonical termination and ribosome rescue. AB - Ribosome recycling usually occurs after canonical termination triggered by a stop codon. Additionally, ribosomes that are stalled by aberrant mRNAs need to be recognized and subsequently recycled. In eukaryotes and archaea, the factors involved in canonical termination and ribosome rescue are structurally and functionally related. Both termination and ribosome rescue are mediated by class I release factors (eRF1/aRF1 in eukaryotic/archaeal termination) or their paralogs (Pelota/aPelota for ribosome rescue) and homologs of translational GTPases (eRF3/aEF1alpha in termination, Hbs1/aEF1alpha in ribosome rescue). These events are followed by recycling of the ribosome. Recently the ATPase ABCE1 was shown to be the main ribosome recycling factor. In concert with eRF1 or Pelota, ABCE1 dissociates the ribosome into subunits. During the past two years, several structures of ribosome rescue and ribosome recycling complexes have been solved by cryo-electron microscopy and crystallography. These structures along with recent functional data make it possible to propose a molecular model of these late translation events in termination and recycling. PMID- 23031513 TI - Feed intake limitation strategies for the growing rabbit: effect on feeding behaviour, welfare, performance, digestive physiology and health: a review. AB - This review aims to present the different effects produced by a post-weaning intake limitation strategy on the growing rabbit, now largely used by French professional rabbit breeders. Although a quantitative feed restriction leads to slower growth, feed conversion (FC) is improved, particularly when the rabbits are again fed freely, as compensatory growth occurs. This better FC or the healthy rabbit is because of better digestion resulting from slower passage through the intestine, whereas the digestive physiology is slightly modified (morphometry of the intestinal mucosa, fermentation pattern, microbiota). Meat quality and carcass characteristics are not greatly affected by feed restriction, except for a lower dressing-out percentage. One of the main advantages of limiting post-weaning intake of the rabbit is to reduce the mortality and morbidity rate due to digestive disorders (particularly epizootic rabbit enteropathy syndrome). The consequences for animal welfare are debatable, as feed restriction probably leads to hunger, but it reduces the incidence of digestive troubles after weaning. However, the growing rabbit adapts very well to an intake limitation strategy, without any aggressive behaviour for congener. In conclusion, restriction strategies could improve profitability of rabbit breeding, but they should be adapted to any specific breeding situation, according to the national market, feed prices, etc. PMID- 23031512 TI - Estimating variance components and predicting breeding values for eventing disciplines and grades in sport horses. AB - Eventing competitions in Great Britain (GB) comprise three disciplines, each split into four grades, yielding 12 discipline-grade traits. As there is a demand for tools to estimate (co)variance matrices with a large number of traits, the aim of this work was to investigate different methods to produce large (co)variance matrices using GB eventing data. Data from 1999 to 2008 were used and penalty points were converted to normal scores. A sire model was utilised to estimate fixed effects of gender, age and class, and random effects of sire, horse and rider. Three methods were used to estimate (co)variance matrices. Method 1 used a method based on Gibbs sampling and data augmentation and imputation. Methods 2a and 2b combined sub-matrices from bivariate analyses; one took samples from a multivariate Normal distribution defined by the covariance matrix from each bivariate analysis, then analysed these data in a 12-trait multivariate analysis; the other replaced negative eigenvalues in the matrix with positive values to obtain a positive definite (co)variance matrix. A formal comparison of models could not be conducted; however, estimates from all methods, particularly Methods 2a/2b, were in reasonable agreement. The computational requirements of Method 1 were much less compared with Methods 2a or 2b. Method 2a heritability estimates were as follows: for dressage 7.2% to 9.0%, for show jumping 8.9% to 16.2% and for cross-country 1.3% to 1.4%. Method 1 heritability estimates were higher for the advanced grades, particularly for dressage (17.1%) and show jumping (22.6%). Irrespective of the model, genetic correlations between grades, for dressage and show jumping, were positive, high and significant, ranging from 0.59 to 0.99 for Method 2a and 0.78 to 0.95 for Method 1. For cross country, using Method 2a, genetic correlations were only significant between novice and pre-novice (0.75); however, using Method 1 estimates were all significant and low to moderate (0.36 to 0.70). Between-discipline correlations were all low and of mixed sign. All methods produced positive definite 12 * 12 (co)variance matrices, suitable for the prediction of breeding values. Method 1 benefits from much reduced computational requirements, and by performing a true multivariate analysis. PMID- 23031514 TI - Effect of feed restriction on the performance and behaviour of pigs immunologically castrated with Improvac(r). AB - For centuries, entire male pigs have been castrated to reduce the risk of boar taint. However, physical castration of pig is increasingly being questioned with regard to animal welfare considerations. Immunization against gonadotrophin releasing hormone (GnRH) provides an alternative to physical castration. Using the currently available commercial product (Improvac(r); Pfizer Animal Health), a two-dose regimen of a GnRH vaccine is administered. After the second vaccination, a substantial increase in feed consumption has been reported, which may be associated with increased body fatness and decreased feed efficiency when compared with unvaccinated entire male pigs. The aim of the present study was to investigate the effect of a feed restriction on these traits and on the behaviour of 120 group-housed entire males (five pigs/pen) vaccinated against GnRH. The first vaccination was performed at 62 days of age and the second (V2) at 130 days of age. Pigs were slaughtered in two batches 4 to 5 weeks after V2. They were either offered feed ad libitum over the 22 to 114 kg BW range (AL treatment) or ad libitum up to a maximum of 2.50 (R2.50 treatment) or 2.75 kg/day per pig (R2.75 treatment). Behavioural observations and skin lesion scoring were conducted 1 week before V2, and 1 and 3 weeks after V2. At slaughter, the volumetric lean meat content was measured using an X-ray computed tomography scanner. Between V2 and slaughter, the average feed intakes for the R2.75 and R2.50 treatments were 15% and 22% lower than the average AL feed intake (3.20 kg/day), respectively. Feed restriction was associated with a reduced average daily gain after V2 (846, 932 and 1061 g/day in the R2.50, R2.75 and AL groups, P < 0.01) but had no effect on the feed conversion ratio (3.00 kg feed/kg BW gain on average, P = 0.62). No difference was observed in the lean meat content (71.8%, 70.7% and 70.4% in the R2.50, R2.75 and AL groups, P = 0.14), despite a reduced backfat thickness measured in restrictively fed pigs (12.0, 13.0 and 13.6 mm in the R2.50, R2.75 and AL groups, P < 0.01). Higher skin lesion scores were observed 3 weeks after V2 in R2.50 and R2.75 pigs than in the AL ones (scores 33.4, 27.7 and 25.5, respectively, P = 0.04). These results, combined with an unimproved feed efficiency and no marked change in carcass characteristics, suggest that immunologically castrated pigs should not be restrictively fed during the late finishing period. PMID- 23031515 TI - Reevaluation of vitamin E supplementation of dairy cows: bioavailability, animal health and milk quality. AB - Although vitamin E has been known as an essential nutrient for almost 80 years, we are far from a complete understanding of all the aspects related to bioavailability and its effects on health and milk quality in dairy cows. Vitamin E is a generic descriptor for two families of lipid-soluble compounds, the tocopherols and the tocotrienols, of which alpha-tocopherol has the highest biological activity. Commercially available alpha-tocopherol supplements for dairy cows contain either the natural RRR form or the synthetic (all-rac) form, which contains all the eight possible stereoisomers (four possessing the 2R and four possessing the 2S configuration) in equimolar amounts. Recent data clearly suggest that an almost complete discrimination against the 2S isomers occurs in dairy cows. Thus, 1 g of the all-rac form is essentially equivalent to 0.5 g of the RRR form. With respect to the effect of vitamin E supplementation of dairy cows on health and milk quality, the majority of published studies suggests that vitamin E supplementation at the level 1000 to 4000 IU/cow per day during the dry period reduces both the frequency of intramammary infection and that of clinical mastitis and improves milk quality, as shown by a reduction in the levels of somatic cell count (SCC)/ml in milk, decreased plasmin activity and increased oxidative stability of milk. However, a recent study from the Netherlands suggested that vitamin E supplementation at the 3000 IU/cow per day level during the dry period when combined with high levels of plasma vitamin E at dry-off (>14.5 MUmol/l) increases the incidence of mastitis. Data from previously unpublished survey studies and those from published vitamin E feeding trials, in which high levels of blood vitamin E were observed, were reanalyzed. All farms selected for the analysis implemented oral administration of vitamin E at the 3000 IU/cow per day level throughout or during the late dry period (4 weeks before the expected day of parturition). Dairy cows were divided into three groups, depending on blood alpha-tocopherol levels at dry-off: high (>6.25 MUg/ml), medium (between 6.25 and 4.25 MUg/ml) and low (<4.25 MUg/ml). Data indicate that there were no differences in the incidence of mastitis and in the level of SCC/ml of milk between the three groups. Thus, supplementation of 3000 IU vitamin E/cow per day in the late dry period remains recommended because it is generally associated with decreased risk of mastitis. Conditional or opposite effects have not been repeated and require further research before changing recommendations for vitamin E supplementation. PMID- 23031516 TI - Histochemistry evaluation of the oxidative stress and the antioxidant status in Cu-supplemented cattle. AB - The aim of this paper is to evaluate at a histopathological level the effect of the most commonly used copper (Cu) supplementation (15 mg/kg dry matter (DM)) in the liver of intensively reared beef cattle. This was done by a histochemistry evaluation of (i) the antioxidant capacity in the liver - by the determination of metallothioneins (MT) and superoxide dismutase (SOD) expression - as well as (ii) the possible induction of oxidative damage - by the determination of inducible nitric oxide synthase (iNOS), nitrotyrosine (NITT), malondialdehyde (MDA) and 8 oxoguanine (8-oxo) - that (iii) could increase apoptotic cell death - determined by cytochrome-c (cyto-c), caspase 1 (casp1) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Liver samples from Cu-supplemented (15 mg Cu sulphate/kg DM, n = 5) and non-supplemented calves (n = 5) that form part of other experiments to evaluate Cu status were collected at slaughter and processed for immunohistochemistry and TUNEL. MT expression was diffuse and SOD showed slight changes although without statistical significance. iNOS and NITT positive (+) cells significantly increased, mainly around the central veins in the animals from the Cu-supplemented group, whereas no differences were appreciated for the rest of the oxidative stress and apoptosis markers. Under the conditions of this study, which are the conditions of the cattle raised in intensive systems in NW Spain and also many European countries, routinely Cu supplementation increased the risk of the animals to undergo subclinical Cu toxicity, with no significant changes in the Cu storage capacity and the antioxidant defensive system evaluated by MT and SOD expression, but with a significant and important increase of oxidative damage measured by iNOS and NITT. The results of this study indicated that iNOS and NITT could be used as early markers of initial pathological changes in the liver caused by Cu supplementation in cattle, although more studies in cattle under different levels of Cu supplementation are needed. PMID- 23031517 TI - The effect of equol injection in ovo on lipid metabolism and hepatic lipogenic gene expression in broilers. AB - This study investigated the effects of in ovo administration of equol (Eq) on post-hatch growth and hepatic lipid metabolism in broiler chickens. Fertilized eggs (146 eggs/group) were injected with 0 MUg (control, Con), 20 MUg (low dose, L) and 100 MUg (high dose, H) Eq in the albumen on the 7th day of incubation. Except a trend increase in the weight of total fat (P = 0.09), Eq had no effect on growth or liver weight in broilers at 49 days of age. Males presented higher liver and BWs and lower total fat and relative liver weights than females (P < 0.01). However, there were no significant effects of Eq or Eq-gender interactions on growth performance or tissues weight (P > 0.05). With respect to lipid parameters in the serum, the results showed that female broilers presented higher triacyglycerol (TG) and low-density lipoprotein cholesterol concentrations than males, whereas there was no gender difference in serum total cholesterol (TC) or high-density lipoprotein cholesterol (HDLC) concentration (P > 0.05). Eq administration significantly decreased serum TG and TC but increased HDLC concentrations in serum of broilers at 49 days of age (P < 0.05), whereas there were no interactions between gender and Eq (P > 0.05). To elucidate the mechanism behind the significant changes of serum TG and TC levels, the expression of genes involved in lipid metabolism in the liver was investigated in female chickens using reverse transcription-PCR. Carnitine palmitoyl transferase I (CPTI) messenger RNA (mRNA) was significantly upregulated by 20 and 100 MUg Eq (P < 0.05). High-dose Eq significantly decreased fatty acid synthase (FAS) and enhanced cholesterol-7alpha-hydroxylase (CYP7A1) mRNA levels in the liver (P < 0.05). Eq had no significant effects on acetyl-CoA carboxylase, sterol regulatory element binding protein-1c, malic enzyme, low-density lipoprotein receptor or 3 hydroxy-3-methylglutaryl coenzyme A reductase mRNA in the liver (P > 0.05). These results in female broilers suggest that Eq decreased blood TG by upregulating CPTI and downregulating FAS mRNA expression in the liver, and that high serum cholesterol levels stimulated CYP7A1 gene transcription in the liver. PMID- 23031519 TI - Effects of ambient temperature and early open-field response on the behaviour, feed intake and growth of fast- and slow-growing broiler strains. AB - Increased activity improves broiler leg health, but also increases the heat production of the bird. This experiment investigated the effects of early open field activity and ambient temperature on the growth and feed intake of two strains of broiler chickens. On the basis of the level of activity in an open field test on day 3 after hatching, fast-growing Ross 208 and slow-growing i657 chickens were allocated on day 13 to one of the 48 groups. Each group included either six active or six passive birds from each strain and the groups were housed in floor-pens littered with wood chips and fitted with two heat lamps. Each group was fed ad libitum and subjected to one of the three temperature treatments: two (HH; 26 degrees C), one (HC; 16 degrees C to 26 degrees C) or no (CC; 16 degrees C) heat lamps turned on. Production and behavioural data were collected every 2 weeks until day 57. For both strains, early open-field activity had no significant effects on their subsequent behaviour or on any of the production parameters measured, and overall, the slow-growing strain was more active than the fast-growing strain. Ambient temperature had significant effects on production measures for i657 broilers, with CC chickens eating and weighing more, and with a less efficient feed conversion than HH chickens, with HC birds intermediate. A similar effect was found for Ross 208 only for feed intake from 27 to 41 days of age. Ross 208 chickens distributed themselves in the pen with a preference for cooler areas in the hottest ambient temperature treatments. In contrast, the behaviour of the slow-growing strain appeared to be relatively unaffected by the ambient temperature. In conclusion, fast-growing broilers use behavioural changes when trying to adapt to warm environments, whereas slow growing broilers use metabolic changes to adapt to cooler ambient temperatures. PMID- 23031518 TI - Lipopolysaccharide challenge of the mammary gland in cows induces nitrosative stress that impairs milk oxidative stability. AB - The aim of this work was to study the effects of mastitis induced by intramammary lipopolysaccharide (LPS) challenge on milk oxidative stability, as well as to understand the underlying biochemical processes that cause such changes. LPS challenge was associated with nitric oxide burst from the surrounding mammary epithelial cells and consequently induced nitrosative stress that was induced by the formation of NO2* from nitrite by lactoperoxidase. This response was associated with an ~3-fold increased formation of hazardous compounds: nitrotyrosines, carbonyls and lipid peroxides. We sustained the involvement of xanthine oxidase as a major source of hydrogen peroxide. In consistent with previous findings, catalase has been shown to play a major role in modulating the nitrosative stress by oxidizing nitrite to nitrate. The current hygienic quality criteria cannot detect mixing of low-quality milk, such as milk with high somatic cells, and nitrite with high-quality milk. Thus, development of an improved quality control methodology may be important for the production of high-quality milk. PMID- 23031520 TI - Effects of a local anaesthetic and NSAID in castration of piglets, on the acute pain responses, growth and mortality. AB - The present study addresses the questions whether on-farm use of local anaesthesia with lidocaine leads to a reduction in pain responses during castration, and whether the non-steroidal anti-inflammatory drug meloxicam improves technical performance after castration of piglets. Five treatments were included in the study: (1) castration without anaesthesia or analgesia (CAST), (2) castration after local anaesthesia with lidocaine (LIDO), (3) castration after administration of meloxicam (MELO), (4) castration after lidocaine and meloxicam (L + M) and (5) sham castration (SHAM). To reduce litter influences, each treatment was present in each of the 32 litters (n = 32 per treatment). During castration, vocalizations were recorded continuously. Blood samples were collected 15 min before and 20 min after castration for determination of plasma levels of total cortisol, glucose, lactate and creatine kinase (CK). Mortality was registered and piglets were weighed several times to calculate growth. Several aspects of vocalizations during castration showed consistent and significantly different levels in CAST compared with LIDO, L + M and SHAM. CAST piglets squealed longer, louder and higher. Vocalizations of MELO piglets most resembled those of CAST. An increase in cortisol was seen in all treatments. However, in SHAM piglets this increase was significantly lower than in the other treatments. LIDO piglets showed a significantly smaller increase in plasma cortisol levels compared with CAST and MELO. L + M piglets differed significantly only from the SHAM group. Lactate levels differed significantly between LIDO and MELO, the level in LIDO being decreased after castration. In the other treatments an increase was measured. No treatment effects were found in plasma glucose and CK levels, nor in growth and mortality of the piglets. In conclusion, on the basis of vocalizations and plasma cortisol, local anaesthesia with lidocaine reduces pain responses in piglets during castration. A positive effect of meloxicam on technical performance was not found. PMID- 23031521 TI - Meta-analytical study of productive and nutritional interactions of mycotoxins in growing pigs. AB - A meta-analysis was carried out in order to study the association of mycotoxins with performance and organ weights in growing pigs. A total of 85 articles published between 1968 and 2010 were used, totaling 1012 treatments and 13 196 animals. The meta-analysis followed three sequential analyses: graphical, correlation and variance-covariance. The presence of mycotoxins in diets was seen to reduce the feed intake by 18% and the weight gain in 21% compared with the control group. Deoxynivalenol and aflatoxins were the mycotoxins with the greatest impact on the feed intake and growth of pigs, reducing by 26% and 16% in the feed intake and by 26% and 22% in the weight gain. The mycotoxin concentration in diets and the animal age at challenge were the variables that more improved the coefficient of determination in equations for estimating the effect of mycotoxins on weight gain. The mycotoxin effect on growth proved to be greater in younger animals. In addition, the residual analysis showed that the greater part of the variation in weight gain was explained by the variation in feed intake (87%). The protein and methionine levels in diets could influence the feed intake and the weight gain in challenged animals. The weight gain in challenged pigs showed a positive correlation with the methionine level in diets (0.68). The mycotoxin effect on growth was greater in males compared with the effect on females. The reduction in weight gain was of 15% in the female group and 19% in the male group. Mycotoxin presence in pig diets has interfered in the relative weight of the liver, the kidneys and the heart. Mycotoxins have an influence on performance and organ weight in pigs. However, the magnitude of the effects varies with the type and concentration of mycotoxin, sex and the animal age, as well as nutritional factors. PMID- 23031522 TI - Effect of feeding method on intake and behaviour of individually reared beef heifers fed a concentrate diet from 115 to 185 kg of body weight. AB - A total of eight Simmental heifers (114 +/- 3.2 days old and weighing 118 +/- 3.8 kg BW) were used to study the effects of feeding method on intake and animal behaviour in a crossover design experiment. Treatments consisted of feeding concentrate and chopped barley straw as (1) choice (CH; concentrate and straw in separate feedbunks) or (2) total mixed ration (TMR; concentrate and straw in one feedbunk). Feeds were offered on an ad libitum basis, but always maintaining a concentrate to straw ratio of 90 to 10. The experiment was performed in two 21 day periods, and sampling was carried out in the last week of each period. At the end of each period, treatment was changed for heifers; hence, the final number of animals per treatment was eight. Intake was recorded over 7 consecutive days. BW was recorded at the beginning and the end of the experiment and on day 21 of each experimental period. Barley straw was coarsely chopped with a chopping machine. Once chopped, all the straw was handled for particle size separation using the 2 screen Penn State Particle Separator and only material of more than 8 mm was used to feed the heifers. Animal behaviour was video-recorded for 24 h on day 2 and day 6 of each experimental period. Concentrate intake and total dry matter intake of heifers fed with the CH feeding method were higher (P < 0.01 and P < 0.05) than when fed with TMR (5.1 and 5.3 v. 4.7 and 5.0 kg dry matter (DM)/day, respectively). Conversely, barley straw was consumed in higher amounts in heifers fed with the TMR feeding method (0.3 v. 0.2 kg DM/day, respectively; P = 0.001). The total NDF intake was similar in both treatments. In contrast, NDF intake from barley straw and physically effective NDF intake were higher in heifers fed with the TMR feeding method than when fed with CH. Feeding method used to feed heifers did not affect the consumption of the different kinds of barley straw particles and eating and drinking behaviours but affected ruminating behaviour. Heifers fed TMR spent more time ruminating than heifers fed concentrate and barley straw separately (376 v. 287 min/day, respectively; P < 0.01). TMR as the feeding method in intensive beef production systems could be a good approach to promote roughage intake. PMID- 23031523 TI - Behavioural and physiological measures following treadmill exercise as potential indicators to evaluate fatigue in sheep. AB - The welfare consequences of long-distance transportation of animals remain a controversial topic. Animals that stand for most of the long journey (especially if additional muscular activity is required to deal with postural instability) are at risk of developing fatigue. Previous observational studies of behaviour and physiology suggested either that sheep do not become markedly fatigued by long journeys or that previous methods did not adequately identify fatigue. A range of behavioural and physiological measures were made on eight pairs of sheep during and after treadmill exercise. Within each pair of sheep, a treatment sheep was walked on a treadmill at 0.5 m/s for up to 5 h or until the sheep voluntarily stopped exercising or showed other signs of reduced performance, and a control sheep was exercised for two 10-min periods on either side of the exercise period for the treatment sheep. With the exception of one sheep that only walked for 4.5 h, all treatment sheep walked for 5 h without apparent difficulty. After exercise, the plasma cortisol concentration of treatment sheep was significantly greater than that of control sheep. However, there were no significant treatment effects on plasma creatine kinase activity or blood lactate concentration. After 5 h of exercise, there was a proportionate decrease in the median frequency of the electromyogram recorded over the m. semitendinosus, and this was significantly different from control sheep. There was no evidence that treatment sheep lay down sooner or for longer after treadmill exercise than controls. In sheep tested in a maze to examine whether there was increased motivation to rest after exercise, there was no significant difference between the times taken by treatment and control sheep to obtain a food reward. Qualitative behavioural assessment of the sheep by a panel of observers identified two main dimensions of sheep demeanour, but among descriptors elicited from observers only one person used a term associated with fatigue. No significant difference was found between the scores of treatment and control sheep on these two demeanour dimensions. Thus, there was little evidence that prolonged gentle walking exercise fatigues sheep. Further development of methods to both repeatedly induce and to identify fatigue in sheep is required. PMID- 23031524 TI - Evaluation of organic, conventional and intensive beef farm systems: health, management and animal production. AB - The overall aim of the present study was to analyse and compare organic beef cattle farming in Spain with intensive and conventional systems. An on-farm study comparing farm management practices and animal health was carried out. The study also focussed on a slaughterhouse analysis by comparing impacts on the safety and quality of the cattle products. Twenty-four organic and 26 conventional farms were inspected, and farmers responded to a questionnaire that covered all basic data on their husbandry practices, farm management, veterinary treatments and reproductive performance during 2007. Furthermore, data on the hygiene and quality of 244, 2596 and 3021 carcasses of calves from organic, intensive and conventional farms, respectively, were retrieved from the official yearbook (2007) of a slaughterhouse. Differences found between organic and conventional farms across the farm analysis did not substantially reflect differences between both farm types in the predominant diseases that usually occur on beef cattle farms. However, calves reared organically presented fewer condemnations at slaughter compared with intensive and to a lesser extent with conventionally reared calves. Carcass performance also reflected differences between farm type and breed and was not necessarily better in organic farms. PMID- 23031525 TI - Evaluation of the effect of accounting method, IPCC v. LCA, on grass-based and confinement dairy systems' greenhouse gas emissions. AB - Life cycle assessment (LCA) and the Intergovernmental Panel on Climate Change (IPCC) guideline methodology, which are the principal greenhouse gas (GHG) quantification methods, were evaluated in this study using a dairy farm GHG model. The model was applied to estimate GHG emissions from two contrasting dairy systems: a seasonal calving pasture-based dairy farm and a total confinement dairy system. Data used to quantify emissions from these systems originated from a research study carried out over a 1-year period in Ireland. The genetic merit of cows modelled was similar for both systems. Total mixed ration was fed in the Confinement system, whereas grazed grass was mainly fed in the grass-based system. GHG emissions from these systems were quantified per unit of product and area. The results of both methods showed that the dairy system that emitted the lowest GHG emissions per unit area did not necessarily emit the lowest GHG emissions possible for a given level of product. Consequently, a recommendation from this study is that GHG emissions be evaluated per unit of product given the growing affluent human population and increasing demand for dairy products. The IPCC and LCA methods ranked dairy systems' GHG emissions differently. For instance, the IPCC method quantified that the Confinement system reduced GHG emissions per unit of product by 8% compared with the grass-based system, but the LCA approach calculated that the Confinement system increased emissions by 16% when off-farm emissions associated with primary dairy production were included. Thus, GHG emissions should be quantified using approaches that quantify the total GHG emissions associated with the production system, so as to determine whether the dairy system was causing emissions displacement. The IPCC and LCA methods were also used in this study to simulate, through a dairy farm GHG model, what effect management changes within both production systems have on GHG emissions. The findings suggest that single changes have a small mitigating effect on GHG emissions (<5%), except for strategies used to control emissions from manure storage in the Confinement system (14% to 24%). However, when several management strategies were combined, GHG emissions per unit of product could be reduced significantly (15% to 30%). The LCA method was identified as the preferred approach to assess the effect of management changes on GHG emissions, but the analysis indicated that further standardisation of the approach is needed given the sensitivity of the approach to allocation decisions regarding milk and meat. PMID- 23031526 TI - A global foresight on food crop needs for livestock. AB - Increasingly more studies are raising concerns about the increasing consumption of meat and the increasing amount of crops (cereals and oilseeds in particular) used to feed animals and that could be used to feed people. The evolution of this amount is very sensitive to human diets and to the productivity of feed. This article provides a 2050 foresight on the necessary increase in crop production for food and feed in three contrasting scenarios: diets with no animal products; current diets in each main region of the world; and the average diet of developed countries extended to the whole world. We develop empirical aggregate production models for seven world regions, using 43 years and 150 countries. These models realistically account for the contribution of feed from food plants (i.e. plants that would be edible for humans) and of grassland to animal products. We find that the amount of edible crops necessary to feed livestock in 2050 is between 8% and 117% of today's need. The latter figure is lower than that in comparable foresight studies because our models take into account empirical features occurring at an aggregate level, such as the increasing share of animal production from regions using less crop product per unit of animal product. In particular, the expected increase in animal production is estimated to occur mostly in Sub-Saharan Africa and Asia, where the amount of feed from food crops required per unit of animal product proves to be lower than that in other areas. This 117% increase indicates that crop production would have to double if the whole world adopted the present diet of developed countries. PMID- 23031527 TI - Association of halothane sensitivity with growth and meat quality in pigs. AB - Previous reports have indicated that a proportion of pigs, homozygous normal for the skeletal muscle ryanodine receptor gene (RYR1), was halothane sensitive, and this was associated with poor meat quality when pigs were handled aggressively. This study was conducted to evaluate halothane sensitivity in RYR1-normal pigs, managed under simulated commercial conditions, to ascertain the association of halothane sensitivity with growth rate and meat quality. A total of 363 pigs across four farrowing groups, from seven Landrace sires and 38 Yorkshire-Landrace F1 dams, were tested at 8 weeks of age for halothane sensitivity using a closed system that delivered 5% halothane at 2 l/min for 3 (group 1) or 2 (groups 2 to 4) min. After 1 min, limb rigidity, limb tremors and abdominal discoloration were evaluated on a binomial scale with 0 indicating no reaction and 1 indicating reaction. Testing was repeated 2 days later. At 10 weeks of age, pigs were moved to finishing pens and not moved again until marketing. Within farrowing group, pigs were harvested in one of two groups, and at marketing were moved a distance of 91 m, weighed, tattooed, loaded and transported a distance of 550 km to a commercial harvest plant. After overnight rest, pigs were harvested and the pH of the loin muscle was measured at 45 min (pH45) after stunning. After an 18-h chill, loin muscle pH (pHu), International Commission on Illumination (CIE) L*, a*, b*, color (1 to 6) and marbling (1 to 10) scores and fluid loss percent were collected. Generalized linear mixed models were used to estimate repeatabilities for response to halothane challenge. Repeatabilities for limb rigidity for the front right and left legs were 0.24 and 0.31, respectively, whereas rear right and left leg repeatabilities were 0.19 and 0.17, respectively. Repeatabilities for front right and left leg tremors were 0.16 and 0.20, respectively. Growth rate was not influenced by any measure of halothane sensitivity. Carcasses from pigs exhibiting limb rigidity tended to have lower pH45 (5.88 v. 5.97; P = 0.06), similar pHu (5.47 v. 5.49; P = 0.32), less pH decline from 45 min to 18 h (-0.40 v. -0.50; P = 0.04) and a tendency for greater fluid loss percent (5.01 v. 4.55; P = 0.08) than carcasses from pigs that did not exhibit limb rigidity during halothane challenge. A proportion of pigs normal for RYR1 did exhibit limb rigidity during halothane gas challenge, and subsequently tended to have lower 45 min pH and greater longissimus muscle fluid loss post harvest. PMID- 23031528 TI - The effect of granulated barley as single major ingredient in the growing or finishing diet on productive performance, carcass, meat and fat quality of heavy pigs. AB - A total of 48 Duroc * (Large White * Landrace) gilts of 46.8 kg BW (86 +/- 3 days of age) were used to investigate the effect of diet during the growing and finishing periods on growth performance and carcass, meat and fat quality. The control diet consisted of a commercial feedstuff and the granulated barley diet had that cereal as the single major ingredient. There were three treatments: (i) control diet provided from 45.6 to 127.8 kg BW (C group), (ii) control diet from 47.0 to 91.8 kg BW and granulated barley from 91.8 to 129.7 kg BW (C + GB group) and (iii) granulated barley from 47.9 to 93.1 kg BW and control diet from 93.1 to 135.1 kg BW (GB + C group). Each treatment was replicated eight times, with two pigs per replicate. The C group grew faster (P < 0.001) and had a better feed conversion ratio (P < 0.001) than the GB + C group, with C + GB being intermediate. Carcasses from C + GB gilts had higher backfat depth than those from C gilts, with GB + C being intermediate (P < 0.05). Also, the main joints (ham + shoulder + loin) had a higher (P < 0.01) yield in carcass in the GB + C group than in the C group, with C + GB being intermediate. The intramuscular fat (IMF) content was higher (P < 0.001) in loin from C + GB and GB + C gilts than in C gilts. The IMF of loin from C + GB gilts had higher (P < 0.05) C18:1n-9 and total monounsaturated fatty acid (FA) proportions than that from C gilts, whereas the C18:2n-6 and total polyunsaturated FA percentages were lower (P < 0.05) in C + GB gilts than in the remaining gilts. The total saturated FA percentage was lower (P < 0.05) in loin from GB + C than in that from C gilts. Hams from C + GB and GB + C gilts had higher (P < 0.05) C18:1n-9 and total monounsaturated FA proportions and lower C18:2n-6 and total polyunsaturated FA contents than those from C gilts. We can conclude that granulated barley provided during the growing or the finishing period improved some carcass and meat characteristics of heavy gilts desirable for dry-cured ham production. PMID- 23031529 TI - Influence of slaughter age and carcass suspension on meat quality in Angus heifers. AB - This study investigated the effects of pelvic suspension and slaughter age on longissimus thoracis et lumborum (LTL) from 40 heifers with at least 75% Angus breeding. A total of 20 heifers were slaughtered directly from pasture at 18 months of age, and carcass sides were hung either by the Achilles tendon or the pelvic bone. The other 20 heifers were assigned to an additional winter housing period and slaughtered at 22 months of age; carcass sides were hung only by Achilles suspension. All carcasses were electrically stimulated and assessed according to the EUROP carcass classification system. In addition, the LTL muscles were aged for 7 or 14 days before meat quality was evaluated for intramuscular fat (IMF), drip loss, colour, shear force, compression and sensory analysis. The 22-month-old heifers were heavier, fatter and had more IMF than 18 month-old heifers. Conformation scores (muscling) did not differ between the two slaughter groups. Pelvic suspension reduced both between- and within-animal variation for peak force, total energy and compression peak force. For the 18 month-old heifers, pelvic suspension also decreased peak force, total energy and compression variables for the LTL muscles from both ageing periods, whereas Achilles-suspended samples had lower shear force values only at day 14. Sensory analysis showed that pelvic-suspended sides had greater tenderness, lower bite resistance, less threadiness, higher juiciness and meat flavour and less visible marbling than meat from Achilles-suspended sides. Pelvic-suspended sides at 18 months of age were similar in peak force and total energy values to the 22-month old heifers. The importance of ageing the Achilles-suspended sides was more obvious for samples from 18-month-old heifers than from the 22-month-old animals. The correlations between the different instrumental measurements and sensory tenderness were considerably higher for carcasses suspended by the Achilles tendon (r = -0.55 to 0.20) than for those hung by the pelvic bone (r = -0.25 to 0.19). More correlations between sensory-evaluated tenderness and shear variables were significant after 7 days (n = 6) of ageing than after 14 days (n = 4) of ageing. This study clearly shows the benefits of pelvic suspension, which reduces the need for additional feeding after pasture. PMID- 23031530 TI - Dual-functional liposomes based on pH-responsive cell-penetrating peptide and hyaluronic acid for tumor-targeted anticancer drug delivery. AB - Dual-functional liposomes with pH-responsive cell-penetrating peptide (CPP) and active targeting hyaluronic acid (HA) were fabricated for tumor-targeted drug delivery. A series of synthetic tumor pH-triggered CPPs rich in arginines and histidines were screened by comparing tumor cellular uptake efficiency at pH 6.4 with at pH 7.4, and R6H4 (RRRRRRHHHH) was obtained with the optimal pH-response. To construct R6H4-modified liposomes (R6H4-L), stearyl R6H4 was anchored into liposomes due to hydrophobic interaction. HA was utilized to shield positive charge of R6H4-L to assemble HA-coated R6H4-L (HA-R6H4-L) by electrostatic effect for protecting the liposomes from the attack of plasma proteins. The rapid degradation of HA by hyaluronidase (HAase) was demonstrated by the viscosity and zeta potential detection, allowing the R6H4 exposure of HA-R6H4-L at HAase-rich tumor microenvironment as the protection by HA switches off and cell-penetrating ability of R6H4 turns on. After HAase treatment, paclitaxel-loaded HA-R6H4-L (PTX/HA-R6H4-L) presented a remarkably stronger cytotoxicity toward the hepatic cancer (HepG2) cells at pH 6.4 relative to at pH 7.4, and additionally coumarin 6 loaded HA-R6H4-L (C6/HA-R6H4-L) showed efficient intracellular trafficking including endosomal/lysosomal escape and cytoplasmic liberation by confocal laser scanning microscopy (CLSM). In vivo imaging suggested the reduced accumulation of near infrared dye 15 (NIRD15)-loaded HA-R6H4-L (NIRD/HA-R6H4-L) at the tumor site, when mice were pre-treated with an excess of free HA, indicating the active tumor targeting of HA. Indeed, PTX/HA-R6H4-L had the strongest antitumor efficacy against murine hepatic carcinoma (Heps) tumor xenograft models in vivo. These findings demonstrate the feasibility of using tumor pH-sensitive CPPs and active targeting HA to extend the applications of liposomal nanocarriers to efficient anticancer drug delivery. PMID- 23031531 TI - Human fibroblast-derived ECM as a scaffold for vascular tissue engineering. AB - The self-assembly approach is based on the capability of mesenchymal cells to secrete and organize their own extracellular matrix (ECM). This tissue engineering method allows for the fabrication of autologous living tissues, such as tissue-engineered blood vessels (TEBV) and skin. However, the secretion of ECM by smooth muscle cells (SMCs), required to produce the vascular media, may represent a long process in vitro. The aim of this work was to reduce the time required to produce a tissue-engineered vascular media (TEVM) and extend the production of TEVM with SMCs from all patients without compromising its mechanical and functional properties. Therefore, we developed a decellularized matrix scaffold (dMS) produced from dermal fibroblasts (DF) or saphenous vein fibroblasts (SVF), in which SMCs were seeded to produce a TEVM. Mechanical and contractile properties of these TEVM (referred to as nTEVM) were compared to standard self-assembled TEVM (sTEVM). This approach reduced the production time from 6 to 4 weeks. Moreover, nTEVM were more resistant to tensile load than sTEVM and their vascular reactivity was also improved. This new fabrication technique allows for the production of a vascular media using SMCs isolated from any patient, regardless of their capacity to synthesize ECM. Moreover, these scaffolds can be stored to be available when needed, in order to accelerate the production of the vascular substitute using autologous vascular cells. PMID- 23031532 TI - Embracing a culture in conducting research requires more than nurses' enthusiasm. AB - AIMS: This study explored the perceptions of clinical nurses about their research knowledge and experiences to highlight any gaps in nurse education in supporting research activities in healthcare organisations. BACKGROUND: Nurses' research activities have been encouraged by moving hospital-based nurse education into higher education institutions whereby there is a stronger emphasis on teaching and developing nursing research at both undergraduate and post graduate levels. They were further encouraged by the introduction of advanced nurse practitioner roles, in the hope to increase opportunities for research participation. Whilst nurses' research activities have been explored in many countries, nurses in Singapore where there is a strong emphasis on evidence-based practice have not been investigated. METHODS: A mixed-methods exploratory descriptive design, using a questionnaire based on open and closed questions was employed to obtain the views of clinical nurses about their capacity and organisational support in conducting research. The questionnaires were distributed to convenient samples who attended one of the 4 research seminars held on separate occasions between July and August 2011 in Singapore. RESULTS: A total of 146 nurses were recruited. Whilst nurses demonstrated strong enthusiasm in conducting research, this characteristic feature was not adequate for them to embrace a research culture in organisations. Active participation as co-investigators was not possible in healthcare organisations where skewed distribution of resources towards medical and nurse researchers was perceived. CONCLUSIONS: The results suggest a need for a significant shift in focus on educational training from imparting research contents to providing opportunities to experience the research process. Organisational support in terms of protected time and financial support ought to be in place for nursing research experience. The findings also demonstrated that in places where organisational support was available, awareness of research opportunities such as educational and organisational support needed to be strengthened. This in turn would enable more nurses particularly those who provide direct patient care to conduct research within the context of the competing nursing practice demands. PMID- 23031533 TI - Importance of public health nurses precepting students in clinical practice: a qualitative study. AB - BACKGROUND: Preceptors' working environment, support and competence affect how they perform the preceptor role, are therefore important for developing students and can influence students' roles as students and future professionals. Previous research has focused on precepting student nurses and not so much on public health nurses or other postgraduate students. Knowledge in this field is therefore lacking. OBJECTIVE: The article aims to present a grounded theory of the role of public health nurses as student preceptors in Norway. DESIGN: We conducted 20 interviews with public health nurses in addition to a focus group with four participants. We used classical grounded theory method to gather and analyze data. FINDINGS: The preceptors were strongly concerned about invisibility and lack of recognition of the preceptor role. This main concern was resolved by the strategy of being obligated and included three patterns: optimistic, ambivalent and reluctant performance, all with differing motivation for being obligated. All stakeholders involved in clinical practice seem to contribute to making the preceptors' role invisible and thereby contribute to the lack of recognition, support and reward, which again seem to self-reinforce invisibility. CONCLUSION: The study highlights the obligation of public health nurses in precepting students and increases the understanding of the challenges of this role. Ensuring education of a high academic standard requires paying more attention to developing effective support for the people involved. PMID- 23031534 TI - Prehospital trauma care systems: potential role toward reducing morbidities and mortalities from road traffic injuries in Nigeria. AB - INTRODUCTION: Road traffic injuries (RTIs) and attendant fatalities on Nigerian roads have been on an increasing trend over the past three decades. Mortality from RTIs in Nigeria is estimated to be 162 deaths/100,000 population. This study aims to compare and identify best prehospital trauma care practices in Nigeria and some other African countries where prehospital services operate. METHODS: A review of secondary data, grey literature, and pertinent published articles using a conceptual framework to assess: (1) policies; (2) structures; (3) first responders; (4) communication facilities; (5) transport and ambulance facilities, and (6) roadside emergency trauma units. RESULTS: There is no national prehospital trauma care system (PTCS) in Nigeria. The lack of a national emergency health policy is a factor in this absence. The Nigerian Federal Road Safety Corps (FRSC) mainly has been responsible for prehospital services. South Africa, Zambia, Kenya, and Ghana have improved prehospital services in Africa. CONCLUSIONS: Commercial drivers, laypersons, military, police, a centrally controlled communication network, and government ambulance services are feasible delivery models that can be incorporated into the Nigerian prehospital system. Prehospital trauma services have been useful in reducing morbidities and mortalities from traffic injuries, and appropriate implementation of this study's recommendations may reduce this burden in Nigeria. PMID- 23031535 TI - Comparison of diagnostic tools with multiplex polymerase chain reaction for pediatric lower respiratory tract infection: a single center study. AB - BACKGROUND/PURPOSE: Acute respiratory tract infections are a leading cause of morbidity and mortality in children worldwide. Most have a viral etiology, with pneumococcus as an important pathogen. This single-center study compared the use of conventional diagnostic tools and two multiplex polymerase chain reaction (PCR) examinations for determining pathogens in lower respiratory tract infections (LRTIs) among children aged <5 years. METHODS: From July to October 2010, 45 patients aged 2 months to 60 months and diagnosed as having LRTIs were enrolled. Their nasopharyngeal aspirates were evaluated through viral culture and two multiplex PCR examinations. The patients' clinical course, symptoms, signs, and laboratory findings were recorded and analyzed. RESULTS: Among the 45 patients, 38 (84.4%) had detectable pathogens. Conventional viral and blood cultures had 35.6% positive rate, which increased to 51.1% when the quick antigen tests (Influenza A+B test and respiratory syncytial virus) and urine pneumococcal antigen test were combined. The positive rate further increased to 84.4% when the two multiplex PCR methods were combined. Twelve patients had co-infection, including 10 detected by the multiplex PCR methods. The co-infection rate was 26.7% (12/45). CONCLUSION: Most LRTIs in children have a viral etiology. Multiplex PCR tests are rapid assays that can increase the diagnostic yield rate and detect slow-growing viruses and can detect more pathogens than conventional viral culture to enable, thereby helping clinicians to provide appropriate and timely treatment. PMID- 23031536 TI - Complexity of beta-lactamases among clinical Aeromonas isolates and its clinical implications. AB - Aeromonas species, aquatic Gram-negative bacilli, distributed globally and ubiquitously in the natural environment, may be implicated in a variety of human diseases. They can produce various beta-lactamases which confer resistance to a broad spectrum of beta-lactams, and therefore in vitro susceptibility testing must be used to guide antimicrobial therapy. However, conventional in vitro susceptibility tests may sometimes fail to detect these beta-lactamases, and hence raise a therapeutic challenge. In this review article, two chromosomally mediated beta-lactamases (i.e., AmpC beta-lactamases and metallo-beta-lactamases) and acquired extended-spectrum beta-lactamases in aeromonads are reviewed, and the clinical implications of the complexity of beta-lactamases are discussed. PMID- 23031537 TI - Bench experiments comparing simulated inspiratory effort when breathing helium oxygen mixtures to that during positive pressure support with air. AB - BACKGROUND: Inhalation of helium-oxygen (He/O2) mixtures has been explored as a means to lower the work of breathing of patients with obstructive lung disease. Non-invasive ventilation (NIV) with positive pressure support is also used for this purpose. The bench experiments presented herein were conducted in order to compare simulated patient inspiratory effort breathing He/O2 with that breathing medical air, with or without pressure support, across a range of adult, obstructive disease patterns. METHODS: Patient breathing was simulated using a dual-chamber mechanical test lung, with the breathing compartment connected to an ICU ventilator operated in NIV mode with medical air or He/O2 (78/22 or 65/35%). Parabolic or linear resistances were inserted at the inlet to the breathing chamber. Breathing chamber compliance was also varied. The inspiratory effort was assessed for the different gas mixtures, for three breathing patterns, with zero pressure support (simulating unassisted spontaneous breathing), and with varying levels of pressure support. RESULTS: Inspiratory effort increased with increasing resistance and decreasing compliance. At a fixed resistance and compliance, inspiratory effort increased with increasing minute ventilation, and decreased with increasing pressure support. For parabolic resistors, inspiratory effort was lower for He/O2 mixtures than for air, whereas little difference was measured for nominally linear resistance. Relatively small differences in inspiratory effort were measured between the two He/O2 mixtures. Used in combination, reductions in inspiratory effort provided by He/O2 and pressure support were additive. CONCLUSIONS: The reduction in inspiratory effort afforded by breathing He/O2 is strongly dependent on the severity and type of airway obstruction. Varying helium concentration between 78% and 65% has small impact on inspiratory effort, while combining He/O2 with pressure support provides an additive reduction in inspiratory effort. In addition, breathing He/O2 alone may provide an alternative to pressure support in circumstances where NIV is not available or poorly tolerated. PMID- 23031538 TI - Effects of protein sources on concentrations of hydrogen sulphide in the rumen headspace gas of dairy cows. AB - Two Latin square design experiments investigated the relationship between hydrogen sulphide concentration in the rumen headspace gas of dairy cows and the early stages of protein degradation in the rumen. In Expt 1, three protein sources differing in rumen N (nitrogen) degradability (maize gluten feed (MGF); sunflower meal (SFM); and soyabean meal (SBM)) were used, whereas in Expt 2 four different batches of the same feed (MGF) differing in colour (CIE L*, a*, b* (CIELAB) scale) were used. After allowing the concentration of hydrogen sulphide in rumen gas to decline close to zero, a fixed amount of protein sources was offered to cows and the concentrations of hydrogen sulphide were recorded in rumen headspace gas at 30-min intervals. In Expt 1, the concentration of hydrogen sulphide showed considerable variation between protein sources, with MGF having the highest concentration followed by SFM and SBM resulting in very low concentrations. The N wash losses (zero time measurements with nylon bags) ranked the feeds in the same way, from MGF (highest; 61%) to SBM (lowest; 26%). There were marked differences in the degradation of cystine and methionine between protein sources, although the degradation of cystine was always higher than for methionine. MGF (Expt 2) led to increased concentrations of hydrogen sulphide, with peak concentrations achieved between 1 and 2 h after feeding. The concentrations of hydrogen sulphide were higher for MGF1, intermediate for MGF2 and lower for MGF3 and MGF4, agreeing with colour scale. Differences in the early stages of dietary sulphur degradation corresponded with differences in hydrogen sulphide concentrations in rumen gas. The results suggest that hydrogen sulphide concentrations in the rumen headspace gas could be useful to evaluate nutritional parameters not measured by the in sacco technique, contributing to a better understanding of the response of dairy cows to different protein supplements. PMID- 23031539 TI - Identification of some unknown transcripts from SSH cDNA library of buffalo follicular oocytes. AB - A buffalo oocyte-specific subtracted cDNA library was constructed to identify exclusively or preferentially oocyte-expressed genes. The library represented an enriched population of transcripts obtained from oocytes of diverse ovarian follicular origin and at different stages of in vitro maturation. A total of 1173 high-quality sequences of oocyte-specific genes were clustered into 645 unique sequences, out of which 65.76% were represented as singlets and 34.26% as contig expressed sequence tags (ESTs; clusters). Analysis of sequences revealed that 498 of these sequences were identified as a known sequence in mammalian species including buffalo, 103 as uncharacterized ESTs and 44 unknown sequences including 1 novel EST, so far not reported in any species. Gene ontology annotation classified these sequences into functional categories of cellular events and biological processes associated with oocyte competence. Expression status of the isolated unknown ESTs confirmed that many of these are expressed in oocytes exclusively and in others preferentially, some in excess of 80-fold greater in comparison with a variety of somatic tissues. The isolated novel EST was detected to be expressed exclusively in oocytes and testicular cells only. To our knowledge, this is the first report giving a detailed transcriptome account of oocyte-expressed genes in buffalo. This study will provide important information on the physiological control of oocyte development, as well as many questions yet to be addressed on the reproductive process of buffalo. PMID- 23031541 TI - The computational and neural basis of voluntary motor control and planning. AB - Optimal feedback control (OFC) provides a powerful tool to interpret voluntary motor control, highlighting the importance of sensory feedback in the control and planning of movement. Recent studies in the context of OFC have increasingly used mechanical perturbations and visual shifts to probe voluntary control processes. These studies reveal the surprising sophistication of corrective responses, which are goal-directed and exhibit knowledge of the physical properties of the limb and the environment. These complex feedback processes appear to be generated through transcortical feedback pathways. The research reviewed here opens and enhances several lines of discovery, including testing whether feedback corrections share all of the attributes associated with voluntary control, identifying how prediction influences optimal state estimation, and importantly, how these voluntary control processes are generated by the highly distributed circuitry within the brain. PMID- 23031542 TI - 'Domino' systems biology and the 'A' of ATP. AB - We develop a strategic 'domino' approach that starts with one key feature of cell function and the main process providing for it, and then adds additional processes and components only as necessary to explain provoked experimental observations. The approach is here applied to the energy metabolism of yeast in a glucose limited chemostat, subjected to a sudden increase in glucose. The puzzles addressed include (i) the lack of increase in adenosine triphosphate (ATP) upon glucose addition, (ii) the lack of increase in adenosine diphosphate (ADP) when ATP is hydrolyzed, and (iii) the rapid disappearance of the 'A' (adenine) moiety of ATP. Neither the incorporation of nucleotides into new biomass, nor steady de novo synthesis of adenosine monophosphate (AMP) explains. Cycling of the 'A' moiety accelerates when the cell's energy state is endangered, another essential domino among the seven required for understanding of the experimental observations. This new domino analysis shows how strategic experimental design and observations in tandem with theory and modeling may identify and resolve important paradoxes. It also highlights the hitherto unexpected role of the 'A' component of ATP. PMID- 23031543 TI - A threshold value in Shear Wave elastography to rule out malignant thyroid nodules: a reality? AB - OBJECTIVES: To evaluate the ability of a threshold value in ShearWaveTM elastography to rule out malignant thyroid nodules while studying its pertinence in association with morphological signs. EQUIPMENT AND METHODS: 148 patients (110 women and 38 men; 52.5 y.o. 15.8) referred for surgery of thyroid nodules underwent standard ultrasound as well as elastography. Characteristics of the morphological signs and maximum elastographic index were calculated in relation to histology. Association of morphological signs alone and then of elastography was also evaluated. One hundred and fifty one nodules were studied on a double blind basis. RESULTS: 297 nodules were studied. Thirty-five cancers were detected (11.6%). Elastographic index was higher in malignant nodules (115 kPa 60.4) than in benign nodules (41 kPa 25.8) (p<0.001, Student's t-test). Cut off value of 66 kPa was the best to discriminate malignant nodules with a sensitivity of 80% (CI 95%, 62.5; 90.9) and a specificity of 90.5% (CI 95%, 86.1; 93.6) (p=0.0001). Association of elastography and morphological ultrasound signs presented a sensitivity of 97% (CI 95%, 83.3; 99.8) and a negative predictive value of 99.5% (CI 95%, 95.6; 99.9). Interobserver reproducibility proved to be excellent with an interclass correlation of 0.97 (CI 95%, 0.96; 0.98) (p<0.001). CONCLUSION: The 66 kPa threshold in Shear Wave elastography is the best ultrasound sign to rule out malignant thyroid nodules. The method is simple, quantitative, reproducible and usable in the study of nodules larger than 3 cm. Progress must still be made in the study of calcified nodules and follicular tumors. PMID- 23031544 TI - Early insulin resistance in severe trauma without head injury as outcome predictor? A prospective, monocentric pilot study. AB - BACKGROUND: Hyperglycemia following major trauma is a well know phenomenon related to stress-induced systemic reaction. Reports on glucose level management in patients with head trauma have been published, but the development of insulin resistance in trauma patients without head injury has not been extensively studied. The aim of this study was therefore to investigate the prognostic role of acute insulin-resistance, assessed by the HOMA model, in patients with severe trauma without head injury. METHODS: All patients consecutively admitted to the Intensive Care Unit (ICU) of a tertiary referral center (Careggi Teaching Hospital, Florence, IT) for major trauma without head injury (Jan-Dec 2010) were enrolled. Patients with a previous diagnosis of diabetes mellitus requiring insulin therapy or metabolism alteration were excluded from the analysis. Patients were divided into "insulin resistant" and "non-insulin resistant" based on the Homeostasis Model Assessment index (HOMA IR). Results are expressed as medians. RESULTS: Out of 175 trauma patients admitted to the ICU during the study period, a total of 54 patients without head trauma were considered for the study, 37 of whom met the inclusion criteria. In total, 23 patients (62.2%) resulted insulin resistant, whereas 14 patients (37.8%) were non-insulin resistant. Groups were comparable in demographic, clinical/laboratory characteristics, and severity of injury. Insulin resistant patients had a significantly higher BMI (P=0.0416), C-reactive protein (P=0.0265), and leukocytes count (0.0301), compared to non insulin resistant patients. Also ICU length of stay was longer in insulin resistant patients (P=0.0381). CONCLUSIONS: Our data suggest that admission insulin resistance might be used as an early outcome predictor. PMID- 23031545 TI - Evidence for gill slits and a pharynx in Cambrian vetulicolians: implications for the early evolution of deuterostomes. AB - BACKGROUND: Vetulicolians are a group of Cambrian metazoans whose distinctive bodyplan continues to present a major phylogenetic challenge. Thus, we see vetulicolians assigned to groups as disparate as deuterostomes and ecdysozoans. This divergence of opinions revolves around a strikingly arthropod-like body, but one that also bears complex lateral structures on its anterior section interpreted as pharyngeal openings. Establishing the homology of these structures is central to resolving where vetulicolians sit in metazoan phylogeny. RESULTS: New material from the Chengjiang Lagerstatte helps to resolve this issue. Here, we demonstrate that these controversial structures comprise grooves with a series of openings. The latter are oval in shape and associated with a complex anatomy consistent with control of their opening and closure. Remains of what we interpret to be a musculature, combined with the capacity for the grooves to contract, indicate vetulicolians possessed a pumping mechanism that could process considerable volumes of seawater. Our observations suggest that food captured in the anterior cavity was transported to dorsal and ventral gutters, which then channeled material to the intestine. This arrangement appears to find no counterpart in any known fossil or extant arthropod (or any other ecdysozoan). Anterior lateral perforations, however, are diagnostic of deuterostomes. CONCLUSIONS: If the evidence is against vetulicolians belonging to one or other group of ecdysozoan, then two phylogenetic options seem to remain. The first is that such features as vetulicolians possess are indicative of either a position among the bilaterians or deuterostomes but apart from the observation that they themselves form a distinctive and recognizable clade current evidence can permit no greater precision as to their phylogenetic placement. We argue that this is too pessimistic a view, and conclude that evidence points towards vetulicolians being members of the stem-group deuterostomes; a group best known as the chordates (amphioxus, tunicates, vertebrates), but also including the ambulacrarians (echinoderms, hemichordates), and xenoturbellids. If the latter, first they demonstrate that these members of the stem group show few similarities to the descendant crown group representatives. Second, of the key innovations that underpinned deuterostome success, the earliest and arguably most seminal was the evolution of openings that define the pharyngeal gill slits of hemichordates (and some extinct echinoderms) and chordates. PMID- 23031546 TI - Economic values of body weight, reproduction and parasite resistance traits for a Creole goat breeding goal. AB - A specific breeding goal definition was developed for Creole goats in Guadeloupe. This local breed is used for meat production. To ensure a balanced selection outcome, the breeding objective included two production traits, live weight (BW11) and dressing percentage (DP) at 11 months (the mating or selling age), one reproduction trait, fertility (FER), and two traits to assess animal response to parasite infection: packed cell volume (PCV), a resilience trait, and faecal worm eggs count (FEC), a resistance trait. A deterministic bio-economic model was developed to calculate the economic values based on the description of the profit of a Guadeloupean goat farm. The farm income came from the sale of animals for meat or as reproducers. The main costs were feeding and treatments against gastro intestinal parasites. The economic values were 7.69? per kg for BW11, 1.38? per % for FER, 3.53? per % for DP and 3 * 10(-4)? per % for PCV. The economic value for FEC was derived by comparing the expected profit and average FEC in a normal situation and in an extreme situation where parasites had developed resistance to anthelmintics. This method yielded a maximum weighting for FEC, which was -18.85? per log(eggs per gram). Alternative scenarios were tested to assess the robustness of the economic values to variations in the economic and environmental context. The economic values of PCV and DP were the most stable. Issues involved in paving the way for selective breeding on resistance or resilience to parasites are discussed. PMID- 23031547 TI - Risk factors for ischemic stroke; results from 9 years of follow-up in a population based cohort of Iran. AB - BACKGROUND: Data about the risk factors of stroke are sparse in the Middle East populations. We aimed to determine the potential risk factors and their population attributable fraction (PAF) for stroke in an Iranian population. METHODS: A cohort Study consisted of 1089 men and 1289 women, with mean (SD) ages of 61.1(7.6) and 59.0(6.7) years, respectively. Cox regression was implemented to estimate the hazard ratio (HR) of each risk factor for stroke events in a stepwise method. We calculated a multivariate adjusted population attributable fraction (PAF) for any risk factors remained in the model. RESULTS: During 9.3 years of follow-up, 69 events of stroke occurred with incidence rates of 4.5 (95% CI: 3.3-6.0) and 2.5 (1.7-3.6) in 1000 person-years for men and women respectively. Among potential risk factors, only age >= 65 years (HR: 2.03, CI: 1.24-3.31), male gender (HR: 2.00, CI: 1.16-3.43), hypertension (HR: 3.03, CI: 1.76-5.22), diabetes mellitus (HR: 2.18, CI: 1.34-3.56), and chronic kidney disease (CKD) (HR: 2.01, CI: 1.22-3.33), were independently associated with increased risk of stroke events in the total population. A paired homogeneity test showed that the hazard ratio of CKD did not differ from other independent risk factors. The PAFs were 29.7% and 25% for male gender and age >= 65 as non modifiable and 48.6%, 29.1% and 22.0% for hypertension, CKD and diabetes as modifiable risk factors respectively. CONCLUSION: Following this population based study of Iranians, we demonstrated that among modifiable risk factors, CKD as well as hypertension and diabetes are the strongest independent predictors of stroke. PMID- 23031548 TI - Primary glioblastoma of the cerebellum in a 19-year-old woman: a case report. AB - INTRODUCTION: Cerebellar glioblastoma is an uncommon adult lesion. The pathogeny and prognosis of cerebellar glioblastoma are still incompletely elucidated. CASE PRESENTATION: We report the case of a 19-year-old Moroccan woman. A neurologic examination revealed the presence of cerebellar signs. A diagnosis of cerebellar glioblastoma is rarely made before surgery. An encephalic computer tomography scan and magnetic resonance imaging increased the accuracy of defining the nature of the lesion. Magnetic resonance imaging showed a heterogeneously enhancing mass in the vermis and the right cerebellar hemisphere. After surgery, glioblastoma was histologically confirmed. Post-operative radiotherapy followed. The outcome of our patient was favorable after one year of follow-up. CONCLUSIONS: We report an unusual case of cerebellar gliobastoma. Cerebellar glioblastoma multiforme should be considered in the differential diagnosis of a cerebellar mass lesion. PMID- 23031549 TI - Development of the first oligonucleotide microarray for global gene expression profiling in guinea pigs: defining the transcription signature of infectious diseases. AB - BACKGROUND: The Guinea pig (Cavia porcellus) is one of the most extensively used animal models to study infectious diseases. However, despite its tremendous contribution towards understanding the establishment, progression and control of a number of diseases in general and tuberculosis in particular, the lack of fully annotated guinea pig genome sequence as well as appropriate molecular reagents has severely hampered detailed genetic and immunological analysis in this animal model. RESULTS: By employing the cross-species hybridization technique, we have developed an oligonucleotide microarray with 44,000 features assembled from different mammalian species, which to the best of our knowledge is the first attempt to employ microarray to study the global gene expression profile in guinea pigs. To validate and demonstrate the merit of this microarray, we have studied, as an example, the expression profile of guinea pig lungs during the advanced phase of M. tuberculosis infection. A significant upregulation of 1344 genes and a marked down regulation of 1856 genes in the lungs identified a disease signature of pulmonary tuberculosis infection. CONCLUSION: We report the development of first comprehensive microarray for studying the global gene expression profile in guinea pigs and validation of its usefulness with tuberculosis as a case study. An important gap in the area of infectious diseases has been addressed and a valuable molecular tool is provided to optimally harness the potential of guinea pig model to develop better vaccines and therapies against human diseases. PMID- 23031550 TI - Mesenchymal stem cells expressing vasoactive intestinal peptide ameliorate symptoms in a model of chronic multiple sclerosis. AB - Multiple sclerosis (MS) is a severe debilitating disorder characterized by progressive demyelination and axonal damage of the central nervous system (CNS). Current therapies for MS inhibit the immune response and demonstrate reasonable benefits if applied during the early phase of relapsing-remitting MS (RRMS) while there are no treatments for patients that progress neither to the chronic phase nor for the primary progressive form of the disease. In this manuscript, we have studied the therapeutic efficacy of a cell and gene therapy strategy for the treatment of a mouse model of chronic MS [myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE)]. We used allogenic mesenchymal stem cells (MSCs) asa therapeutic tool and also as vehicle to deliver fully processed 3.3-kDa vasoactive intestinal peptide (VIP) to the peripheral immune organs and to the inflamed CNS. Intraperitoneal administrations of MSCs expressing VIP stopped progression and reduced symptoms when administered at peak of disease. The improvement in clinical score correlated with diminished peripheral T-cell responses against MOG as well as lower inflammation,lower demyelination, and higher neuronal integrity in the CNS. Interestingly, neither lentiviral vectors expressing VIP nor unmodified MSCs were therapeutic when administer at the peak of disease. The increased therapeutic effect of MSCs expressing VIP over unmodified MSCs requires the immunoregulatory and neuroprotective roles of both VIP and MSCs and the ability of the MSCs to migrate to peripheral lymph organs and the inflamed CNS. PMID- 23031551 TI - Turning off the cameras: Red light running characteristics and rates after photo enforcement legislation expired. AB - In 2005 the Virginia legislature allowed the law permitting automated enforcement for red light running violations to expire. An opportunity presented itself to evaluate what would happen to red light running behavior at formerly enforced locations. Using intersections previously studied to document one city's deployment and use of photo enforcement (see Martinez and Porter, 2006), we mobilized multiple pre-expiration, immediate post-expiration, and one year post expiration observations at camera-enforced intersections as well as two control groups consisting of same-city and a different city's non-camera locations. More than 2700 direct observations were made in these time periods, documenting the near-immediate increase in red light running at previously camera-enforced intersections. These intersections had a rate that nearly tripled immediately after the law expired, and more than quadrupled one year later. Further, within a year of the law's expiration, the low red light running rates at the previous camera locations had recidivated to red light running rates of the control locations. Driver characteristics were not significant predictors of these rates once intersection group and traffic volume (and their interaction) were controlled, meaning red light running in this study was not linked to a particular driver type. Our results are important for scholars of intersection safety, as this is the first known peer-reviewed study documenting estimates of what could happen when automated enforcement is removed. PMID- 23031552 TI - Strong stimulation of recombinant protein production in Escherichia coli by combining stimulatory control elements in an expression cassette. AB - BACKGROUND: The XylS/Pm expression system has been used to produce recombinant proteins at industrial levels in Escherichia coli. Activation of transcription from the Pm promoter takes place in the presence of benzoic acid or derivatives of it. Previous mutagenesis studies resulted in identification of several variants of the expression control elements xylS (X), Pm (P) and the 5' untranslated region (U) that individually gave rise to strongly stimulated expression. The goal of this study was to test if combination of such stimulatory mutations in the same expression vectors would lead to further increase of expression levels. RESULTS: We combined X, P and U variants that were originally identified due to their ability to strongly stimulate expression of the reporter gene bla (resistance to penicillin). Combination of optimized elements stimulated bla expression up to 75-fold (X, P and U combined) relative to the wild-type system, while accumulated transcript levels increased about 50-fold. This is much more than for the elements individually. We also tested combination of the variant elements on two other and unrelated genes, celB (encoding phosphoglucomutase) and the human growth factor gene gm-csf. Protein production from these genes is much more efficient than from bla in the wild-type system, but expression was still significantly stimulated by the combination of X, P and U variants, although not to the same extent as for bla. We also integrated a single copy of the expression cassette with each gene into the E. coli chromosome and found that the expression level from this single copy was higher for bla than for the wild-type plasmid system, while it was lower for celB and gm-csf. CONCLUSION: Our results show that combination of stimulatory expression control elements can be used to further increase production of different proteins in E. coli. For one reporter gene (bla) this allowed for more protein production from a single gene copy integrated on the chromosome, compared to the wild-type plasmid system. The approach described here should in principle be applicable for improvement of any expression cassette. PMID- 23031553 TI - Melanoma of unknown primary origin: a population-based study in the Netherlands. AB - AIM: Few population-based studies have been published on melanoma of unknown primary origin (MUP). This study's aim is to describe characteristics and survival of MUP patients in the Netherlands, based on nationwide data from the Netherlands Cancer Registry (NCR). METHODS: Patient and tumour characteristics of MUP patients were retrieved from the NCR. Subgroups were made according to metastatic site: nodal or distant. Survival rates were calculated using the Kaplan-Meier method. To obtain a better insight in the composition and prognosis of the MUP group, the survival was compared to that of patients with melanoma of a known primary origin (MKP), tumour-node-metastasis (TNM) stage III and IV. RESULTS: Of all 33,181 melanoma patients diagnosed between 2003 and 2009, 2.6% (n=857) were diagnosed with MUP. MUP patients with nodal metastases had a similar survival as MKP stage III with macroscopic nodal involvement. After stratification according to the number of involved lymph nodes, the survival of patients with nodal metastases with one involved lymph node was not significantly different between MUP and MKP. The survival of MUP patients with two or more involved lymph nodes was slightly worse than that of MKP stage III patients with macroscopic nodal involvement with two or more involved lymph nodes. MUP patients with distant metastases had a similar survival as MKP stage IV. After stratification according to number of metastatic sites and metastatic site category, the survival in MKP stage IV patients with (sub)cutaneous metastases was slightly worse than MUP distant patients with (sub)cutaneous metastases. CONCLUSIONS: The results of this study imply that MUP patients form a heterogeneous group, and that MUP patients with nodal metastases could be classified as stage III melanoma with macroscopic nodal involvement, and MUP patients with distant metastases as stage IV melanoma. PMID- 23031554 TI - Clinical implications of human papillomavirus genotype in cervical adeno adenosquamous carcinoma. AB - BACKGROUND: Our aims were to evaluate the genotype distribution of human papillomavirus (HPV) and the correlation between HPV parameters and clinicopathological/treatment variables with prognosis in cervical adeno adenosquamous carcinoma (AD/ASC). PATIENTS AND METHODS: Consecutive patients who received primary treatment for cervical AD/ASC International Federation of Gynecology and Obstetrics (FIGO) stages I-IV between 1993 and 2008 were retrospectively reviewed. Prognostic models were constructed and followed by internal validation with bootstrap resampling. RESULTS: A total of 456 AD/ASC patients were eligible for HPV genotyping, while 452 were eligible for survival analysis. HPV18 was detected in 51.5% and HPV16 in 36.2% of the samples. Age >50 years old, FIGO stages III-IV and HPV16-negativity were significantly related to cancer relapse, and age >50, FIGO stages III-IV, HPV16-negativity and HPV58 positivity were significant predictors for cancer-specific survival (CSS) by multivariate analyses. HPV16-positivity was also significantly associated with good prognosis in those receiving primary radiotherapy or concurrent chemoradiation (RT/CCRT) (CSS: hazard ratio 0.41, 95% confidence interval 0.21 0.78). Patients with FIGO stages I-II and HPV16-negative AD/ASC treated with primary RH-PLND had significantly better CSS (p<0.0001) than those treated with RT/CCRT. CONCLUSIONS: Age >50 years old, FIGO stages III-IV and HPV16-negativity were significant poor prognostic factors in cervical AD/ASC. Patients with HPV16 negative tumour might better be treated with primary surgery (e.g. radical hysterectomy for stages I-II and pelvic exenteration for stage IVA). Those with unresectable HPV16-negative tumour (stage IIIB) should undergo CCRT in combination with novel drugs. The inferences of a single-institutional retrospective study require prospective studies to confirm. PMID- 23031555 TI - Therapy-related acute myeloid leukemia with favorable cytogenetics: still favorable? AB - Therapy-related acute myeloid leukemia (t-AML) is occasionally associated with favorable risk cytogenetics including core binding factor AML and acute promyelocytic leukemia (APL). It is unclear if these leukemias have the same favorable outcomes as their de novo counterparts. Interpretation of published data is difficult due to lack of data on the contribution of the original neoplasm as well as its treatment to overall mortality. Based on available evidence, we conclude that t-AML with favorable risk cytogenetics have superior outcomes among t-AMLs and should be treated similar to de novo AML in patients who are candidates for definitive therapy. Therapy-related APL has similar outcome as de novo APL. There is no evidence at the present time to support the routine use of allogeneic HSCT in first complete remission in t-AML with favorable cytogenetics. PMID- 23031556 TI - Can we safely discontinue imatinib? Searching for new endpoints in CML: a standardized definition of "cure". PMID- 23031557 TI - Influence of feeding sorghum on the growth, gizzard development and carcass traits of growing geese. AB - The aim of this trial was to study the influence of feed form on the performance, gizzard development and carcass traits of growing geese. Between 42 and 98 days of age, 360 geese (type Maxipalm((r))) were fed a diet containing 500 g sorghum/kg (nitrogen-corrected apparent metabolizable energy 12.6 MJ/kg, 15.1 g/kg CP). Birds were divided into three groups differing in feed form: complete pellets (Control group, n = 120); a coarse-ground meal (CG group, n = 120); or a mixture containing protein-rich pellets and sorghum whole grains (M group, n = 120). Feed intake per pen (40 birds/pen) was measured weekly between 42 and 98 days of age, and individual live weight (LW) was measured every 2 weeks. At 84 and 98 days of age, 12 birds were slaughtered in each group to measure the gizzard development and body traits. Irrespective of the goose sex, LW at 98 days was lower for the CG group than for the Control group (5555 v. 5888 g, P < 0.05 for males and 5039 v. 5215 g, P < 0.05 for females). The feed intake over the entire period was 5.5% higher in the M group (P < 0.05) than in the Control and CG groups but the feed conversion ratio (6.91, P > 0.05) was similar in the three groups. The gizzard development (as % of LW) was higher in birds of the CG group than those of the Control and M groups at 84 days of age (+13.98% and +13.51%, respectively; P < 0.05) but was similar in all three groups at 98 days of age (4.01%, P > 0.05). The relative liver development was lower in the birds of the CG group than those of the other two groups at 84 and 98 days of age (-20%, P < 0.001 and -10%, P < 0.05, respectively). The other body traits were similar in the three groups at both 84 and 98 days of age. The present results suggest that a simplified diet presented in the form of a mixture of sorghum whole grains and protein-rich pellets did not reduce the performance of growing geese. PMID- 23031558 TI - Meta-analysis of phosphorus utilization by growing pigs: effect of dietary phosphorus, calcium and exogenous phytase. AB - Optimizing phosphorus (P) utilization in pigs requires improving our capacity to predict the amount of P absorbed and retained, with the main modulating factors taken into account, as well as precisely determining the P requirements of the animals. Given the large amount of published data on P utilization in pigs, a meta-analysis was performed to quantify the impact of the different dietary P forms, calcium (Ca) and exogenous phytases on the digestive and metabolic utilization criteria for dietary P in growing pigs. Accordingly, the amount of phytate P (PP) leading to digestible P (g/kg) was estimated to be 21%, compared with 73% for non-phytate P (NPP) from plant ingredients and 80% for NPP from mineral and animal ingredients (P < 0.001). The increase in total digestible dietary P following the addition of microbial phytase (PhytM) from Aspergillus niger (P < 0.001) was curvilinear and about two times higher than the increase following the addition of plant phytase, which leads to a linear response (P < 0.001). The response of digestible P to PhytM also depends on the amount of substrate, PP (PhytM(2) * PP, P < 0.001). The digestibility of dietary P decreased with dietary Ca concentration (P < 0.01) independently of phytase but increased with body weight (BW, P < 0.05). Although total digestible dietary P increased linearly with total NPP concentration (P < 0.001), retained P (g/kg), average daily gain (ADG, g/day) and average daily feed intake (ADFI, g/day) increased curvilinearly (P < 0.001). Interestingly, whereas dietary Ca negatively affected P digestibility, the effect of dietary Ca on retained P, ADG and ADFI depended on total dietary NPP (NPP * Ca, P < 0.01, P < 0.05 and P < 0.01, respectively). Increasing dietary Ca reduced retained P, ADG and ADFI at low NPP levels, but at higher NPP concentrations it had no effect on ADG and ADFI despite a positive effect on retained P. Although the curvilinear effect of PhytM on digestible P increased with PP (P < 0.001), this effect was lessened by total NPP for ADG and ADFI (PhytM * NPP and PhytM(2) * NPP, P < 0.05) and depended on both total NPP and Ca for retained P (PhytM(2) * NPP * Ca, P < 0.01). This meta analysis improves our understanding of P utilization, with major modulating factors taken into account. The information generated will be useful for the development of robust models to formulate environmentally friendly diets for growing pigs. PMID- 23031559 TI - Meta-analysis of the response of growing pigs to the isoleucine concentration in the diet. AB - The efficiency of nitrogen utilization will be highest when the amino acid (AA) supply approaches the requirement of the animal. With the availability of different crystalline AA, it is theoretically possible to formulate low-protein diets for growing pigs in which seven AA are co-limiting for performance. In such a diet, the concentration of Lys, Met, Met + Cys, Thr, Trp and Val and a seventh AA would exactly match the requirement. To determine the extent to which low protein diets can be used, it is important to have reliable information about the requirements for these AA. Isoleucine is often considered the seventh-limiting AA in diets for growing pigs; however, information about the Ile requirement is limited and sometimes conflicting. The purpose of this study was to carry out a meta-analysis of the available literature information to determine the Ile requirement in growing pigs. A total of 46 Ile dose-response experiments were identified that used at least four concentrations of Ile in the diet. Because of differences in experimental design, both the Ile concentration and the response criteria were standardized. In 13 dose-response experiments, there was no indication of a response to an increasing Ile concentration. For the other 33 experiments, a response to the increasing Ile concentration was observed and the Ile requirement estimates ranged from 53% to 114% of that of the National Research Council (1998). An Ile concentration below the requirement resulted in important reductions in both feed intake and growth. A 10% reduction in the Ile concentration (below the requirement) resulted in a 15% reduction in feed intake and a 21% reduction in daily gain. The use of blood products in the diet was the main factor determining whether a response to the Ile concentration was observed or not. Blood meal and blood cells are protein sources with a very low Ile concentration, but with high or very high concentrations of Leu, Val, Phe and His. Some of these AA compete with Ile for catabolic pathways or transport across the blood-brain barrier, thereby potentially increasing the requirement for Ile. In diets without blood products, the Ile requirement appears to be lower than the currently recommended requirement. On the basis of the outcome of this study, we recommend a Ile : Lys requirement ratio of at least 50% on a standardized ileal digestible basis. PMID- 23031560 TI - Effect of feeding genetically modified Bt MON810 maize to ~40-day-old pigs for 110 days on growth and health indicators. AB - A total of 72 male weaned pigs were used in a 110-day study to investigate the effect of feeding genetically modified (GM) Bt MON810 maize on selected growth and health indicators. It was hypothesised that in pigs fed Bt maize, growth and health are not impacted compared with pigs fed isogenic maize-based diets. Following a 12-day basal period, pigs (10.7 +/- 1.9 kg body weight (BW); ~40 days old) were blocked by weight and ancestry and randomly assigned to treatments: (1) non-GM maize diet for 110 days (non-GM), (2) GM maize diet for 110 days (GM), (3) non-GM maize diet for 30 days followed by GM maize diet up to day 110 (non-GM/GM) and (4) GM maize diet for 30 days followed by non-GM maize diet up to day 110 (GM/non-GM). BW and daily feed intake were recorded on days 0, 30, 60 and 110 (n = 15). Body composition was determined by dual energy X-ray absorptiometry (n = 10) on day 80. Following slaughter on day 110, organs and intestines were weighed and sampled for histological analysis and urine was collected for biochemical analysis (n = 10). Serum biochemistry analysis was performed on days 0, 30, 60, 100 and 110. Growth performance and serum biochemistry were analysed as repeated measures with time and treatment as main factors. The slice option of SAS was used to determine treatment differences at individual time points. There was no effect of feeding GM maize on overall growth, body composition, organ and intestinal weight and histology or serum biochemistry on days 60 and 100 and on urine biochemistry on day 110. A treatment * time interaction was observed for serum urea (SU; P < 0.05), creatinine (SC; P < 0.05) and aspartate aminotransferase (AST; P < 0.05). On day 30, SU was lower for the non-GM/GM treatment compared with the non-GM, GM and GM/non-GM treatments (P < 0.05). On day 110, SC was higher for the non-GM/GM and GM/non-GM treatments compared with non-GM and GM treatments (P < 0.05). Overall, serum total protein was lower for the GM/non-GM treatment compared with the non-GM/GM treatment (P < 0.05). The magnitude of change observed in some serum biochemical parameters did not indicate organ dysfunction and the changes were not accompanied by histological lesions. Long-term feeding of GM maize to pigs did not adversely affect growth or the selected health indicators investigated. PMID- 23031561 TI - The effect of chitooligosaccharide supplementation on intestinal morphology, selected microbial populations, volatile fatty acid concentrations and immune gene expression in the weaned pig. AB - An experiment (complete randomised design) was conducted to investigate the effects of supplementing different molecular weights (MW) of chitooligosaccharide (COS) on intestinal morphology, selected microbial populations, volatile fatty acid (VFA) concentrations and the immune status of the weaned pig. A total of 28 piglets (24 days of age, 9.1 kg (+/- s.d. 0.80) live weight) were assigned to one of four dietary treatments for 8 days and then sacrificed. The treatments were (1) control diet (0 ppm COS), (2) control diet plus 5 to 10 kDa COS, (3) control diet plus 10 to 50 kDa COS and (4) control diet plus 50 to 100 kDa COS. The COS was included in dietary treatments at a rate of 250 mg/kg. Tissue samples were taken from the duodenum, jejunum and ileum for morphological measurements. Digesta samples were taken from the proximal colon to measure lactobacilli and Escherichia coli populations and digesta samples were taken from the caecum and proximal colon for VFA analysis. Gene expression levels for specific cytokines were investigated in colonic tissue of the pig. Supplementation of different MW of COS had no significant effect on pig performance during the post-weaning period (days 0 to 8; P > 0.05). The inclusion of COS at all MW in the diet significantly reduced faecal scores compared with the control treatment (P < 0.01). Pigs fed the 10 to 50 kDa COS had a higher villous height (P < 0.05) and villous height : crypt depth ratio (P < 0.05) in the duodenum and the jejunum compared with the control treatment. Pigs fed the 5 to 10 kDa COS had a lower lactobacilli population (P < 0.05) and E. coli population (P < 0.05) in the colon compared with the control group. Pigs offered the 5 to 10 kDa COS had significantly lower levels of acetic acid and valeric acid compared with the control group (P < 0.05). The inclusion of different MW of COS had no significant effect on the expression of the cytokines tumour necrosis factor-alpha, Interleukin (IL)-6, IL-8 and IL-10 in the gastro-intestinal tract of the weaned pig. The current results indicate that a lower MW of 5 to 10 kDa COS possessed an antibacterial activity, while the higher MW of 10 to 50 kDa was optimum for enhancing the intestinal structure. PMID- 23031562 TI - The effect of a non-starch polysaccharide-hydrolysing enzyme (Rovabio(r) Excel) on feed intake and body condition of sows during lactation and on progeny growth performance. AB - A total of 200 (Large White * Landrace) sows were used in a 39-day study to evaluate the effects of feeding a non-starch polysaccharide (NSP)-hydrolysing enzyme multicomplex (Rovabio((r)) Excel) in conjunction with a high- or reduced nutrient-density diet during lactation on sow body condition, feed intake and progeny performance. Eight sows were selected each week for 25 weeks, blocked by parity and BW into groups of four, and within the block randomly assigned to one of the four treatments (n = 50/treatment). Treatments were: (1) LND: low energy (13.14 MJ of DE/kg), low CP (15%) diet; (2) LND + RE: LND with 50 mg/kg NSP hydrolysing enzyme; (3) HND: high energy (14.5 MJ of DE/kg), high CP (16.5%) diet; and (4) HND + RE: HND with 50 mg/kg NSP-hydrolysing enzyme. Sows were fed treatment diets from day 109 of gestation until the day of subsequent service. Between weaning and re-service, Rovabio((r)) Excel addition to LND diets resulted in an increase in energy intake; however, a reduction was observed when supplemented to the HND diet (P < 0.05). The inclusion of Rovabio((r)) Excel increased feed and energy intake during week 3 (days 15 to 21) of lactation (P < 0.05). Sows fed diets supplemented with Rovabio((r)) Excel had greater back-fat depth at weaning and service (P < 0.05); however, the magnitude of change in back fat depth during lactation and from farrowing to service was not different between treatments. Feeding the HND diet increased energy intake before farrowing, throughout lactation and during the weaning to service interval (P < 0.01); however, overall, average daily feed intake tended to be reduced (P < 0.10). At service, sows fed the HND diet were heavier than sows fed the LND diet (P < 0.05); however, the magnitude of change in BW between treatments was not different. Feeding the HND diet to sows resulted in a tendency for heavier piglets at birth (P = 0.10) that tended to grow at a faster rate and be heavier at weaning than piglets from sows fed the LND diet (P = 0.06). These results indicate that NSP-degrading enzymes offer minimal benefit to sows and their progeny when fed before and during lactation; however, increasing energy intake of sows during lactation may beneficially affect progeny. PMID- 23031563 TI - Rumen digestion of rice straw structural polysaccharides: effect of ammonia treatment and lucerne extract supplementation in vitro. AB - The combined effects of lucerne (Medicago sativa L.) extract supplementation and ammonia treatment of rice straw (Oryza sativa, variety Thaibonnet) on the ruminal digestion of cell wall components were investigated in six continuous culture systems using a randomised complete block design. Data were fitted to second order polynomial models. Untreated rice straw had higher contents of ash-free cell wall residues (CWR; 763 v. 687 g/kg dry matter (DM)) and non-cellulosic sugars (191 v. 166 g/kg DM) than treated rice straw. Ammoniation preferentially removed xylose, which resulted in a lower xylose-to-arabinose ratio (5.1 v. 5.8). In absence of lucerne supplementation and ammoniation, degradability coefficients were 0.54, 0.46, 0.58, 0.54, 0.42 and 0.60 for cellulose-glucose, xylose, arabinose, galactose, mannose and uronic acids, respectively. Both factors had significant effects on the microbial degradation of structural polysaccharides. With lucerne extract at an optimal level, ammonia treatment increased ash-free cell wall degradation by more than 10%. The degradability coefficients were increased by ammoniation without any significant interaction with lucerne extract, except for glucose, whose degradability was mostly influenced by lucerne extract in a curvilinear way. The comparison of regression coefficients in cell wall and CWR models suggested that ammoniation improved the degradabilities of xylose, galactose and mannose by partly solubilising the corresponding hemicelluloses and by improving the susceptibility of the remaining fraction to microbial attack, whereas it increased the degradability of arabinose only by favouring microbial attack. PMID- 23031564 TI - Grazed grass herbage intake and performance of beef heifers with predetermined phenotypic residual feed intake classification. AB - Data were collected on 85 Simmental and Simmental * Holstein-Friesian heifers. During the indoor winter period, they were offered grass silage ad libitum and 2 kg of concentrate daily, and individual dry matter intake (DMI) and growth was recorded over 84 days. Individual grass herbage DMI was determined at pasture over a 6-day period, using the n-alkane technique. Body condition score, skeletal measurements, ultrasonic fat and muscle depth, visual muscularity score, total tract digestibility, blood hormones, metabolites and haematology variables and activity behaviour were measured for all heifers. Phenotypic residual feed intake (RFI) was calculated for each animal as the difference between actual DMI and expected DMI during the indoor winter period. Expected DMI was calculated for each animal by regressing average daily DMI on mid-test live weight (LW)(0.75) and average daily gain (ADG) over an 84-day period. Standard deviations above and below the mean were used to group animals into high (>0.5 s.d.), medium (+/-0.5 s.d.) and low (<0.5 s.d.) RFI. Overall mean (s.d.) values for DMI (kg/day), ADG (kg), feed conversion ratio (FCR) kg DMI/kg ADG and RFI (kg dry matter/day) were 5.82 (0.73), 0.53 (0.18), 12.24 (4.60), 0.00 (0.43), respectively, during the RFI measurement period. Mean DMI (kg/day) and ADG (kg) during the grazing season was 9.77 (1.77) and 0.77 (0.14), respectively. The RFI groups did not differ (P > 0.05) in LW, ADG or FCR at any stage of measurement. RFI was positively correlated (r = 0.59; P < 0.001) with DMI during the RFI measurement period but not with grazed grass herbage DMI (r = 0.06; P = 0.57). Low RFI heifers had 0.07 greater (P < 0.05) concentration of plasma creatinine than high RFI heifers and, during the grazed herbage intake period, spent less time standing and more time lying (P < 0.05) than high RFI heifers. However, low and high RFI groups did not differ (P > 0.05) in ultrasonic backfat thickness or muscle depth, visual muscle scores, skeletal size, total tract digestibility or blood hormone and haematology variables at any stage of the experiment. Despite a sizeable difference in intake of grass silage between low and high RFI heifers during the indoor winter period, there were no detectable differences between RFI groupings for any economically important performance traits measured when animals were offered ensiled or grazed grass herbage. PMID- 23031565 TI - Prediction of water intake and excretion flows in Holstein dairy cows under thermoneutral conditions. AB - The increase in the worldwide demand for dairy products, associated with global warming, will emphasize the issue of water use efficiency in dairy systems. The evaluation of environmental issues related to the management of animal dejections will also require precise biotechnical models that can predict effluent management in farms. In this study, equations were developed and evaluated for predicting the main water flows at the dairy cow level, based on parameters related to cow productive performance and diet under thermoneutral conditions. Two datasets were gathered. The first one comprised 342 individual measurements of water balance in dairy cows obtained during 18 trials at the experimental farm of Mejussaume (INRA, France). Predictive equations of water intake, urine and fecal water excretion were developed by multiple regression using a stepwise selection of regressors from a list of seven candidate parameters, which were milk yield, dry matter intake (DMI), body weight, diet dry matter content (DM), proportion of concentrate (CONC) and content of crude protein (CP) ingested with forage and concentrate (CPf and CPc, g/kg DM). The second dataset was used for external validation of the developed equations and comprised 196 water flow measurements on experimental lots obtained from 43 published papers related to water balance or digestibility measurements in dairy cows. Although DMI was the first predictor of the total water intake (TWI), with a partial r(2) of 0.51, DM was the first predictive parameter of free water intake (FWI), with a partial r(2) of 0.57, likely due to the large variability of DM in the first dataset (from 11.5 to 91.4 g/100 g). This confirmed the compensation between water drunk and ingested with diet when DM changes. The variability of urine volume was explained mainly by the CPf associated with DMI (r.s.d. 5.4 kg/day for an average flow of 24.0 kg/day) and that of fecal water was explained by the proportion of CONC in the diet and DMI. External validation showed that predictive equations excluding DMI as predictive parameters could be used for FWI, urine and fecal water predictions if cows were fed a well-known total mixed ration. It also appeared that TWI and FWI were underestimated when ambient temperature increased above 25 degrees C and possible means of including climatic parameters in future predictive equations were proposed. PMID- 23031566 TI - Potential use of milk mid-infrared spectra to predict individual methane emission of dairy cows. AB - This study investigates the feasibility to predict individual methane (CH(4)) emissions from dairy cows using milk mid-infrared (MIR) spectra. To have a large variability of milk composition, two experiments were conducted on 11 lactating Holstein cows (two primiparous and nine multiparous). The first experiment aimed to induce a large variation in CH(4) emission by feeding two different diets: the first one was mainly composed of fresh grass and sugar beet pulp and the second one of maize silage and hay. The second experiment consisted of grass and corn silage with cracked corn, soybean meal and dried pulp. For each milking period, the milk yields were recorded twice daily and a milk sample of 50 ml was collected from each cow and analyzed by MIR spectrometry. Individual CH(4) emissions were measured daily using the sulfur hexafluoride method during a 7-day period. CH(4) daily emissions ranged from 10.2 to 47.1 g CH(4)/kg of milk. The spectral data were transformed to represent an average daily milk spectrum (AMS), which was related to the recorded daily CH(4) data. By assuming a delay before the production of fermentation products in the rumen and their use to produce milk components, five different calculations were used: AMS at days 0, 0.5, 1, 1.5 and 2 compared with the CH(4) measurement. The equations were built using Partial Least Squares regression. From the calculated R(2)(cv), it appears that the accuracy of CH(4) prediction by MIR changed in function of the milking days. In our experimental conditions, the AMS at day 1.5 compared with the measure of CH(4) emissions gave the best results. The R(2) and s.e. of the cross-validation were equal to 0.79 and 5.14 g of CH(4)/kg of milk. The multiple correlation analysis performed in this study showed the existence of a close relationship between milk fatty acid (FA) profile and CH(4) emission at day 1.5. The lower R(2) (R(2) = 0.76) obtained between FA profile and CH(4) emission compared with the one corresponding to the obtained calibration (R(2)(c) = 0.87) shows the interest to apply directly the developed CH(4) equation instead of the use of correlations between FA and CH(4). In conclusion, our preliminary results suggest the feasibility of direct CH(4) prediction from milk MIR spectra. Additional research has the potential to improve the calibrations even further. This alternative method could be useful to predict the individual CH(4) emissions at farm level or at the regional scale and it also could be used to identify low CH(4)-emitting cows. PMID- 23031567 TI - Determinations of feed-milk-manure relationships on grazing-based dairy farms. AB - Feed conversion into milk, nutrient excretion in manure and subsequent environment impacts of manure management are highly influenced by the diets that farmers feed their lactating cows (Bos taurus). On confinement-based dairy farms, determinations of diet composition are relatively straightforward because the types, amounts and nutrients contained in stored feeds are often well known. However, on grazing-based dairy farms, diet composition is more difficult to determine because forage intake during grazing must be estimated. The objectives of this study were to determine relationships between (1) feed N intake (NI), milk production, milk urea N (MUN), feed N use efficiency (FNUE) and excreted manure N (ExN); and (2) between feed P intake (PI), dung P concentrations (g/kg dry matter (DM)) and excreted manure P (ExP) for grazing-based lactating cows having a very wide range of diets and milk production. An additional objective was to evaluate how well these relationships compare with similar relationships based on more direct measurement of feed-milk-manure on confinement-based dairy farms. Four dairy farms located in southeastern Australia were visited during autumn and spring, and data were collected on feed, milk and dung of 18 cows on each farm. Estimated dry matter intake (DMI) from pasture comprised 12% to 75% of total diet DMI, and the crude protein (CP) concentrations in the total diets ranged from 167 to 248 g/kg. During spring, as diet CP increased FNUE declined. Total diet DMI and NI provided the best predictors of ExN, and PI provided the most accurate prediction of ExP. These results indicated accuracy in the study's indirect estimates of pasture DMI. Likely due to high levels and great variability in dietary CP and P concentrations associated with use of diet supplements, MUN did not appear to be a good indicator of dietary CP, and P in dung was not a good indicator of dietary P. PMID- 23031568 TI - The relationship of breakfast skipping and type of breakfast consumed with overweight/obesity, abdominal obesity, other cardiometabolic risk factors and the metabolic syndrome in young adults. The National Health and Nutrition Examination Survey (NHANES): 1999-2006. AB - OBJECTIVE: To examine the association between breakfast skipping and type of breakfast consumed with overweight/obesity, abdominal obesity, other cardiometabolic risk factors and the metabolic syndrome (MetS). DESIGN: Cross sectional. Three breakfast groups were identified, breakfast skippers (BS), ready to-eat-cereal (RTEC) consumers and other breakfast (OB) consumers, using a 24 h dietary recall. Risk factors were compared between the breakfast groups using covariate-adjusted statistical procedures. SETTING: The 1999-2006 National Health and Nutrition Examination Survey, USA. SUBJECTS: Young adults (20-39 years of age). RESULTS: Among these young adults (n 5316), 23.8% were BS, 16.5% were RTEC consumers and 59.7% were OB consumers. Relative to the BS, the RTEC consumers were 31%, 39%, 37%, 28%, 23%, 40% and 42% less likely to be overweight/obese or have abdominal obesity, elevated blood pressure, elevated serum total cholesterol, elevated serum LDL-cholesterol, reduced serum HDL-cholesterol or elevated serum insulin, respectively. Relative to the OB consumers, the BS were 1.24, 1.26 and 1.44 times more likely to have elevated serum total cholesterol, elevated serum LDL-cholesterol or reduced serum HDL-cholesterol, respectively. Relative to the OB consumers, the RTEC consumers were 22%, 31% and 24% less likely to be overweight/ obese or have abdominal obesity or elevated blood pressure, respectively. No difference was seen in the prevalence of the MetS by breakfast skipping or type of breakfast consumed. CONCLUSIONS: Results suggest that consumption of breakfast, especially that included an RTEC, was associated with an improved cardiometabolic risk profile in U.S. young adults. Additional studies are needed to determine the nature of these relationships. PMID- 23031569 TI - Influence of oilseed supplement ranging in n-6/n-3 ratio on fatty acid composition and Delta5-, Delta6-desaturase protein expression in steer muscles. AB - This study investigated effects of roasted or extruded oilseed supplementation ranging in n-6/n-3 ratios from 0.3 to 5.0 on the fatty acid composition and expression of delta-5 desaturase (Delta5d) and Delta6-desaturase (Delta6d) protein in commercial steer cheek (m. masseter) and diaphragm (pars costalis diaphragmatis) muscles. In general, the n-6/n-3 ratio of the diet had a subsequent effect on the muscle n-6/n-3 ratio (P < 0.05), with muscle 18:2n-6 and 18:3n-3 content relating to proportion of dietary soya bean and linseed (P < 0.01). Compared with canola, pure linseed and soya bean diets reduced 14:1c-9 and 16:1c-9 (P < 0.05) but increased 18:1t-11 and c-9,t-11 conjugated linoleic acid (CLA) content (P < 0.01). Oilseed processing had a minor influence but extruded oilseeds increase 18:1t-11 and c-9,t-11 CLA compared with roasted (P < 0.05). Polar lipid 18:3n-3 and n-3 long-chain polyunsaturated fatty acid (LC, ?20 carbons PUFA) derivative content increased in relation to dietary linseed supplementation in the diaphragm (P < 0.01), whereas only 18:3n-3 was increased in the cheek (P < 0.01). Protein expression did not differ between diets; however, in each muscle the Delta5d protein expression had a stronger association with the desaturase products rather than the precursors. The relationship between Delta5d protein expression and the muscle LC n-6/n-3 ratio was negative in both muscles (P < 0.05). The relationship between Delta6d protein expression and the LC n-6/n-3 ratio was positive in the cheek (P < 0.001) and negative in the diaphragm (P < 0.05). In conclusion, diet n-6/n-3 ratio affected muscle 18:2n-6 and 18:3n-3 deposition, whereas the Delta5d and Delta6d protein expression had some influence on the polar lipid LC-PUFA profile. Results reaffirm that processed oilseeds can be used to increase the proportion of fatty acids potentially beneficial for human health, by influencing the formation of LC-PUFA and reducing the n-6/n-3 ratio. PMID- 23031571 TI - The use of crossbreeding with beef bulls in dairy herds: effects on calving difficulty and gestation length. AB - This study was designed to analyse the evolution in the use of beef bull semen for dairy cattle insemination and, mainly, to assess calving difficulty, gestation length and proportion of stillbirths after breeding pure Holsteins or crossbreeding. Data were collected during 2004 to 2011 for 552 571 Holstein calvings (457 070 Holstein * Holstein, 43 384 Holstein * Limousine, 32 174 Holstein * Belgian Blue and 19 943 Holstein * Galician Blonde). The highest calving difficulty, compared with pure Holsteins was for crosses with Belgian Blue followed by Limousine and Galician Blonde. The Holstein * Limousine and Holstein * Galician Blonde crossbred calves had significantly longer gestation lengths than Holstein * Holstein and Holstein * Belgian Blue calves. Between the latter two, pure Holstein had the shortest gestation length. Calving difficulty and gestation length decreased as the age of the dam advanced. The most difficult calvings were observed in twin calvings, followed by the calvings of male calves and female calves. The gestations leading to the birth of male calves were longer than those leading to female calves and twin calves. Stillbirths were not related to the breed used for mating. Through examining these parameters, sire breed should be considered when selecting a beef breed for the insemination of milk producing dams. PMID- 23031570 TI - The effect of continuous ultrasound on chronic non-specific low back pain: a single blind placebo-controlled randomized trial. AB - BACKGROUND: Non-specific chronic low back pain (NSCLBP) is one of the most common musculoskeletal disorders around the world including Iran. One of the most widely used modalities in the field of physiotherapy is therapeutic ultrasound (US). Despite its common use, there is still inconclusive evidence to support its effectiveness in patients with NSCLBP. The objective of this study was to evaluate the effect of continuous US compared with placebo US additional to exercise therapy for patients with NSCLBP. METHODS: In this single blind placebo controlled study, 50 patients with NSCLBP were randomized into two treatment groups: 1) continuous US (1 MHz &1.5 W/cm2) plus exercise 2) placebo US plus exercise. Patients received treatments for 4 weeks, 10 treatment sessions, 3 times per week, every other day. Treatment effects were assessed in terms of primary outcome measures: 1) functional disability, measured by Functional Rating Index, and 2) global pain, measured by a visual analog scale. Secondary outcome measures were lumbar flexion and extension range of motion (ROM), endurance time and rate of decline in median frequency of electromyography spectrum during a Biering Sorensen test. All outcome variables were measured before, after treatment, and after one-month follow-up. An intention to treat analysis was performed. Main effects of Time and Group as well as their interaction effect on outcome measures were investigated using repeated measure ANOVA. RESULTS: Analysis showed that both groups had improved regarding function (FRI) and global pain (VAS) (P < .001). Lumbar ROM as well as holding time during the Sorensen test and median frequency slope of all measured paravertebral muscles did not change significantly in either group (P > .05). Improvement in function and lumbar ROM as well as endurance time were significantly greater in the group receiving continuous US (P < .05). CONCLUSIONS: The study showed that adding continuous US to a semi supervised exercise program significantly improved function, lumbar ROM and endurance time. Further studies including a third group of only exercise and no US can establish the possible effects of placebo US. TRIAL REGISTRATION: NTR2251. PMID- 23031572 TI - Thermotropic and structural effects of poly(malic acid) on fully hydrated multilamellar DPPC-water systems. AB - The thermotropic and structural effects of low molecular weight poly(malic acid) (PMLA) on fully hydrated multilamellar dipalmitoylphosphatidylcholine (DPPC) water systems were investigated using differential scanning calorimetry (DSC), small-angle X-ray scattering (SAXS), and freeze-fracture transmission electron microscopy (FFTEM). Systems of 20wt% DPPC concentration and 1 and 5wt% PMLA to lipid ratios were studied. The PMLA derivatives changed the thermal behavior of DPPC significantly and caused a drastic loss in correlation between lamellae in the three characteristic thermotropic states (i.e., in the gel, rippled gel and liquid crystalline phases). In the presence of PBS or NaCl, the perturbation was more moderate. The structural behavior on the atomic level was revealed by FTIR spectroscopy. The molecular interactions between DPPC and PMLA were simulated via modeling its measured infrared spectra, and their peculiar spectral features were interpreted. Through this interpretation, the poly(malic acid) is inferred to attach to the headgroups of the phospholipids through hydrogen bonds between the free hydroxil groups of PMLA and the phosphodiester groups of DPPC. PMID- 23031573 TI - Effects of a polar amino acid substitution on helix formation and aggregate size along the detergent-induced peptide folding pathway. AB - Membrane proteins constitute a significant fraction of the proteome and are important drug targets. While the transmembrane (TM) segments of these proteins are primarily composed of hydrophobic residues, the inclusion of polar residues either naturally occurring or as a consequence of a disease-related mutation places a significant folding burden in this environment, potentially impacting bilayer insertion and/or association of neighboring TM helices. Here we investigate the role of an anionic detergent, sodium dodecylsulfate (SDS), and a zwitterionic detergent, dodecylphosphocholine (DPC), in the folding process, and the effects induced by a single polar substitution, on structure and topology of model alpha-helical TM segments. The peptides, represented by KK YAAAIAAIAWAXAAIAAAIAA-KKK-NH(2), where X is I or N, are designed with high aqueous solubilities, through poly-lysine tags. Circular dichroism (CD) and NMR were used to monitor peptide secondary structure and diffusional mobility of both peptide and the detergent hosts. For both peptides, SDS binding commenced at a concentration below its CMC, due to Coulombic attraction of anionic SDS to cationic Lys residues. Increasing SDS binding correlated with increasing peptide helicity. Pulsed field gradient (PFG) NMR diffusion measurements revealed that the Asn-containing peptide bound four fewer detergent molecules, corresponding to ca. 20% less SDS than bound by the Ile peptide. Conversely, zwitterionic DPC binding to either peptide was not observed until the DPC concentration approached its CMC. Our findings confirm quantitatively that a single polar residue within a TM segment may have a significant influence on its local membrane environment. PMID- 23031575 TI - Transcription factors on the move. AB - Mobile transcription factors play essential roles in plant development including the control of cell identity and tissue patterning, as well as organ initiation and the induction of major developmental switches. Within the past few years, the molecules and cellular structures that regulate the movement of these signals have emerged. Here we cover some of the major findings of the past two years as they relate to the intercellular movement of multiple different families of transcription factors. PMID- 23031574 TI - Insight into the modulation of Shaw2 Kv channels by general anesthetics: structural and functional studies of S4-S5 linker and S6 C-terminal peptides in micelles by NMR. AB - The modulation of the Drosophila Shaw2 Kv channel by 1-alkanols and inhaled anesthetics is correlated with the involvement of the S4-S5 linker and C-terminus of S6, and consistent with stabilization of the channel's closed state. Structural analysis of peptides from S4-S5 (L45) and S6 (S6c), by nuclear magnetic resonance and circular dichroism spectroscopy supports that an alpha helical conformation was adopted by L45, while S6c was only in an unstable/dynamic partially folded alpha-helix in dodecylphosphocholine micelles. Solvent accessibility and paramagnetic probing of L45 revealed that L45 lies parallel to the surface of micelles with charged and polar residues pointing towards the solution while hydrophobic residues are buried inside the micelles. Chemical shift perturbation introduced by 1-butanol on residues Gln320, Thr321, Phe322 and Arg323 of L45, as well as Thr423 and Gln424 of S6c indicates possible anesthetic binding sites on these two important components in the channel activation apparatus. Diffusion measurements confirmed the association of L45, S6c and 1-butanol with micelles which suggests the capability of 1-butanol to influence a possible interaction of L45 and S6c in the micelle environment. PMID- 23031576 TI - Recent developments in qualitative and quantitative analysis of phytochemical constituents and their metabolites using liquid chromatography-mass spectrometry. AB - Over the past few years, the applications of liquid chromatography coupled with mass spectrometry (LC-MS) in natural product analysis have been dramatically growing because of the increasingly improved separation and detection capabilities of LC-MS instruments. In particular, novel high-resolution hybrid instruments linked to ultra-high-performance LC and the hyphenations of LC-MS with other separation or analytical techniques greatly aid unequivocal identification and highly sensitive quantification of natural products at trace concentrations in complex matrices. With the aim of providing an up-to-date overview of LC-MS applications on the analysis of plant-derived compounds, papers published within the latest years (2007-2012) involving qualitative and quantitative analysis of phytochemical constituents and their metabolites are summarized in the present review. After briefly describing the general characteristics of natural products analysis, the most remarkable features of LC MS and sample preparation techniques, the present paper mainly focuses on screening and characterization of phenols (including flavonoids), alkaloids, terpenoids, steroids, coumarins, lignans, and miscellaneous compounds in respective herbs and biological samples, as well as traditional Chinese medicine (TCM) prescriptions using tandem mass spectrometer. Chemical fingerprinting analysis using LC-MS is also described. Meanwhile, instrumental peculiarities and methodological details are accentuated. PMID- 23031577 TI - Knee hemarthrosis after arthroscopic surgery in an athlete with low factor XIII activity. AB - We report a thirteen-year-old tennis player with knee hemarthrosis caused by low factor XIII activity. She visited our hospital because of medial peripatellar pain for two years. Although there was no abnormal sign in X-ray or MRI, diagnostic arthroscopy was performed. It revealed some cartilage debris, medial plica and complete septum of suprapatellar plica. Removing the debris by washing out and resecting the medial plica, she could return to play tennis without perioperative symptom. Two months after the first operation, her knee got swelling without any apparent cause. Since 20 ml blood was aspirated twice and MRI revealed suprapatellar mass, we performed arthroscopy again. Suprapatellar mass was old blood clot covered with complete suprapatellar plica. Resection of suprapatellar plica and washing out blood clot were performed, and severe postoperative hemarthrosis was progressively occurred. As factor XIII level was 54% preoperatively, we diagnosed that this condition was caused by low activity level of the factor and administered factor XIII concentrates. The level got improved to 129% and then hemarthrosis gradually relieved. She had no signs of recurrence. We should keep in mind of low factor XIII activity case in case of unexplained postoperative hemarthrosis after arthroscopy because consumption of the factor might promote this condition. PMID- 23031579 TI - The decrease in milk yield during once daily milking is due to regulation of synthetic activity rather than apoptosis of mammary epithelial cells in goats. AB - Once daily milking (ODM) is a management practice that can improve working conditions and reduce production costs in dairy farming compared with twice daily milking (TDM). However, ODM is associated with a decrease in milk yield. Previous research indicated that disruption of tight junctions in the mammary gland may be one of the regulatory factors involved in the milk yield decrease observed during ODM. The aim of this study was to investigate the involvement of mammary epithelium disruption in the regulation of the activity and dynamics of mammary epithelial cells (MEC) during 5 weeks of ODM in goats. Twelve alpine goats (producing 3.67 +/- 0.64 kg/day and 47 +/- 1.6 days in milk) were assigned to two groups that were milked once or twice a day during 5 weeks and then switched back to TDM. Mammary biopsies were collected before and on days 2 and 16 of both ODM and TDM switchback periods. Milk purified epithelial cells were collected before and on days 1, 7, 21 and 28 during ODM as well on days 1 and 7 of the TDM switchback period. The mRNA levels of genes involved in the regulation of synthetic activity and apoptosis were analysed by RT-PCR in milk MEC and mammary biopsies. ODM decreased yields of milk (-23%), lactose (-23%) and casein (-16%). Lactose synthesis was regulated at the transcriptional level by downregulation of alpha-lactalbumin mRNA levels in both biopsy samples (-30%) and milk MEC (-74%). TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling) staining of mammary gland biopsies did not show any increase in cell apoptosis after 2 and 16 days of ODM (0.8% and 1%, respectively) despite upregulation of Bax mRNA levels in milk MEC. This suggests that the decrease in milk yield observed during ODM is attributable to a decrease in synthetic activity rather than to induction of MEC cell death. ODM induced the disruption of tight junctions in the mammary gland only on the first day of the treatment as indicated by increased blood lactose concentration. This indicates that the decrease in MEC activity observed over the 5 weeks of ODM was not due to disruption of the mammary gland tight junctions. There was no carryover effect of 5 weeks of ODM on milk production. Therefore, it appears that the decrease in milk yield that occurs during ODM in goats is due to regulation of synthetic activity rather than to apoptosis of MEC. PMID- 23031578 TI - MESSA: MEta-Server for protein Sequence Analysis. AB - BACKGROUND: Computational sequence analysis, that is, prediction of local sequence properties, homologs, spatial structure and function from the sequence of a protein, offers an efficient way to obtain needed information about proteins under study. Since reliable prediction is usually based on the consensus of many computer programs, meta-severs have been developed to fit such needs. Most meta servers focus on one aspect of sequence analysis, while others incorporate more information, such as PredictProtein for local sequence feature predictions, SMART for domain architecture and sequence motif annotation, and GeneSilico for secondary and spatial structure prediction. However, as predictions of local sequence properties, three-dimensional structure and function are usually intertwined, it is beneficial to address them together. RESULTS: We developed a MEta-Server for protein Sequence Analysis (MESSA) to facilitate comprehensive protein sequence analysis and gather structural and functional predictions for a protein of interest. For an input sequence, the server exploits a number of select tools to predict local sequence properties, such as secondary structure, structurally disordered regions, coiled coils, signal peptides and transmembrane helices; detect homologous proteins and assign the query to a protein family; identify three-dimensional structure templates and generate structure models; and provide predictive statements about the protein's function, including functional annotations, Gene Ontology terms, enzyme classification and possible functionally associated proteins. We tested MESSA on the proteome of Candidatus Liberibacter asiaticus. Manual curation shows that three-dimensional structure models generated by MESSA covered around 75% of all the residues in this proteome and the function of 80% of all proteins could be predicted. AVAILABILITY: MESSA is free for non-commercial use at http://prodata.swmed.edu/MESSA/ PMID- 23031580 TI - Assessing protein availability of different bioethanol coproducts in dairy cattle. AB - Bioethanol production has led to the production of considerable quantities of different coproducts. Variation in nutrient profiles as well as nutrient availability among these coproducts may lead to an imbalance in the formulation of diets. The objectives of this study were to fractionate protein and carbohydrates by an in situ approach, to determine ruminal availability of nutrients for microbial protein synthesis and to determine protein availability to dairy cattle for three types of dried distiller's grains with solubles (DDGS; 100% wheat DDGS (WDDGS); DDGS blend1 (BDDGS1, corn to wheat ratio 30 : 70); DDGS blend2 (BDDGS2, corn to wheat ratio 50 : 50)) and for different batches within DDGS type using the 2010 DVE/OEB protein evaluation system. The results indicated that all DDGS types are quantitatively good sources of true protein digested and absorbed in the small intestine (DVE values; 177, 184 and 170 g/kg dry matter (DM) for WDDGS, BDDGS1 and BDDGS2, respectively). Rumen degraded protein balances (OEB) values were 159, 82, 65 g/kg DM in WDDGS, BDDGS1 and BDDGS2, respectively. Despite the differences in ruminal availability of nutrients among the different batches of DDGS, the DVE values only differed between the batches of BDDGS1 (194 v. 176 g/kg DM). In conclusion, when DDGS is included in the rations of dairy cattle, variation in its protein value due to factors such as DDGS batch should be taken into consideration. PMID- 23031581 TI - Post-partum, post-sterilization tubo-ovarian abscess caused by Fusobacterium necrophorum: a case report. AB - INTRODUCTION: Post-partum, post-sterilization tubo-ovarian abscess is a rare event. Fusobacterium necrophorum subspecies funduliforme, a normal flora found mainly in the oral cavity, appears to be the etiologic organism. CASE PRESENTATION: In this case report, a 25-year-old Thai woman had a post-partum, post-sterilization tubo-ovarian abscess caused by the strictly anaerobic bacterium, Fusobacterium necrophorum subspecies funduliforme. Progressively severe symptoms started 3 weeks after her third vaginal delivery with a tubal sterilization on the following day. On admission, she presented with peritonitis and impending shock. An exploratory laparotomy showed a ruptured left tubo ovarian abscess. A segment of her ileum had to be resected because of severe inflammation. CONCLUSIONS: Fusobacterium necrophorum subspecies funduliforme can be an etiologic organism of a ruptured tubo-ovarian abscess following tubal sterilization in a healthy host. PMID- 23031582 TI - Meiotic maps of sockeye salmon derived from massively parallel DNA sequencing. AB - BACKGROUND: Meiotic maps are a key tool for comparative genomics and association mapping studies. Next-generation sequencing and genotyping by sequencing are speeding the processes of SNP discovery and the development of new genetic tools, including meiotic maps for numerous species. Currently there are limited genetic resources for sockeye salmon, Oncorhynchus nerka. We develop the first dense meiotic map for sockeye salmon using a combination of novel SNPs found in restriction site associated DNA (RAD tags) and SNPs available from existing expressed sequence tag (EST) based assays. RESULTS: We discovered and genotyped putative SNPs in 3,430 RAD tags. We removed paralogous sequence variants leaving 1,672 SNPs; these were combined with 53 EST-based SNP genotypes for linkage mapping. The map contained 29 male and female linkage groups, consistent with the haploid chromosome number expected for sockeye salmon. The female map contains 1,057 loci spanning 4,896 cM, and the male map contains 1,118 loci spanning 4,220 cM. Regions of conservation with rainbow trout and synteny between the RAD based rainbow trout map and the sockeye salmon map were established. CONCLUSIONS: Using RAD sequencing and EST-based SNP assays we successfully generated the first high density linkage map for sockeye salmon. PMID- 23031583 TI - Short sleep duration, complaints of vital exhaustion and perceived stress are prevalent among pregnant women with mood and anxiety disorders. AB - BACKGROUND: Psychiatric disorders have been associated with sleep disorders in men and non-pregnant women, but little is known about sleep complaints and disorders among pregnant women with psychiatric disorders. METHODS: A cohort of 1,332 women was interviewed during early pregnancy. We ascertained psychiatric diagnosis status and collect information about sleep duration, daytime sleepiness, vital exhaustion and perceived stress. Logistic regression procedures were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Approximately 5.1% of the cohort (n=68) reported having a physician diagnosis of mood or anxiety disorder before interview. Compared with women without a psychiatric diagnosis, the multivariable-adjusted OR (95% CI) for short sleep duration in early pregnancy (<=6 hours) were 1.95 (1.03-3.69). The corresponding OR (95%CI) for long sleep duration (>=9 hours) during early pregnancy was 1.13 (0.63-2.03). Women with psychiatric disorders had an increased risk of vital exhaustion (OR=2.41; 95%CI 1.46-4.00) and elevated perceived stress (OR=3.33; 95%CI 1.89-5.88). Observed associations were more pronounced among overweight/obese women. CONCLUSIONS: Women with a psychiatric disorder were more likely to report short sleep durations, vital exhaustion and elevated perceived stress. Prospective studies are needed to more thoroughly explore factors that mediate the apparent mood/anxiety-sleep comorbidity among pregnant women. PMID- 23031584 TI - Comparative evaluation of flavone from Mucuna pruriens and coumarin from Ionidium suffruticosum for hypolipidemic activity in rats fed with high fat diet. AB - The objective of the study is a comparative evaluation of flavone isolated from Mucuna pruriens and coumarin isolated from Ionidium suffruticosum was assessed for the hypolipidemic activity in rats fed with high fat diet. The acute toxicity study was found that flavone (M.pruriens) and coumarin (I.suffruticosum) are safe up to 100 mg/kg, so one tenth of this dose (10 mg/kg) was consider as a evaluation dose. High fat diet group of rats showed significant (p<0.001) elevation in plasma total and LDL-cholesterol, triglycerides and phospholipids. Administration of flavone (M. pruriens) and coumarin isolated from (I.suffruticosum) at the dose of 10mg/kg b.wt/day along with high fat diet significantly (p<0.001) prevented the rise in the plasma total and LDL cholesterol, triglycerides and phospholipids than that of other extracts. However, treatment of coumarin isolated from (I.suffruticosum) had showed more cardio protective effect against hyperlipidemia than that of flavone (M.pruriens). PMID- 23031585 TI - Effects of MSC coadministration and route of delivery on cord blood hematopoietic stem cell engraftment. AB - Hematopoietic stem cell transplantation (HSCT) using umbilical cord blood (UCB) progenitors is increasingly being used. One of the problems that may arise after UCB transplantation is an impaired engraftment. Either intrabone (IB) injection of hematopoietic progenitors or mesenchymal stem cell (MSC) coadministration has been proposed among the strategies to improve engraftment. In the current study, we have assessed the effects of both approaches. Thus, NOD/SCID recipients were transplanted with human UCB CD34+ cells administered either intravenously (IV) or IB, receiving or not bone marrow (BM)-derived MSCs also IV or IB (in the right femur). Human HSC engraftment was measured 3 and 6 weeks after transplantation. Injected MSCs were tracked weekly by bioluminescence. Also, lodgment within the BM niche was assessed at the latter time point by immuno-fluorescence. Our study shows regarding HSC engraftment that the number of BM human CD45+ cells detected 3 weeks after transplantation was significantly higher in mice cotransplanted with human MSCs. Moreover, these mice had a higher myeloid (CD13+) engraftment and a faster B-cell (CD19+) chimerism. At the late time point evaluated (6 weeks), human engraftment was higher in the group in which both strategies were employed (IB injection of HSC and MSC coadministration). When assessing human MSC administration route, we were able to track MSCs only in the injected femurs, whereas they lost their signal in the contralateral bones. These human MSCs were mainly located around blood vessels in the subendosteal region. In summary, our study shows that MSC coadministration can enhance HSC engraftment in our xenogenic transplantation model, as well as IB administration of the CD34+ cells does. The combination of both strategies seems to be synergistic. Interestingly, MSCs were detected only where they were IB injected contributing to the vascular niche. PMID- 23031586 TI - Toxic effects of oil sand naphthenic acids on the biomass accumulation of 21 potential phytoplankton remediation candidates. AB - The oil sands of northern Alberta, Canada contain an estimated 170 billion barrels of crude oil. Extraction processes produce large amounts of liquid tailings known as oil sand process affected water (OSPW) that are toxic to aquatic organisms. Naphthenic acids (NAs), and their sodium salts, represent a significant contributor to the toxicity of these waters. Due to the recalcitrant nature of these compounds, an effective mode of remediation has yet to be established. This study investigates the suitability of the use of phytoplankton for remediation efforts based on two criteria: the ability of phytoplankton strains to withstand the toxic effects of NAs, and their rate of biomass accumulation. A total of 21 phytoplankton strains were isolated from waters containing NAs, cultured, and maintained under unialgal conditions. These strains were then exposed to NAs in concentrations ranging from 0mg L(-1) to 1000mg L(-1) over a 14 day period. Inhibition of growth was observed at 30mg L(-1) NA (one strain), 100mg L(-1) NA (one strain), 300mg L(-1) NA (six strains), and 1000mg L( 1) NA (six strains). Five strains failed to show any growth inhibition at any test concentration and two strains could not be analysed due to poor growth during the test period. Strains were then ranked based on their suitability for use in remediation efforts. PMID- 23031587 TI - Removal of 2,4-dichlorophenol in hydroponic solution by four Salix matsudana clones. AB - Using plants to treat polluted sites and groundwater is an approach called phytoremediation. The aim of the present study was to investigated the toxicity, uptake, accumulation, and removal of 2,4-dichlorophenol (2,4-DCP) in four Salix matsudana clones and to screen the feasibility of phytoremediation using S. matsudana clones. Willows were exposed to 2,4-DCP in hydroponic solution with the concentrations of 10, 20 and 30mg L(-1) for 96h. The biomass of shoots and roots were reduced. Chlorophyll content decreased significantly compared with the control. All root morphology values were different between clones and different concentrations. The 2,4-DCP endurance of four S. matsudana clones was gauged as follows: clone 18> clone 22> clone 8> clone 10. S. matsudana was found to promote 2,4-DCP removal relative to the contaminated solution without plants. From 52.2% to 73.7% of 2,4-DCP were removed by all treatments after 96h exposure. 2,4-DCP was mainly accumulated in roots than in shoots. Clone 22 was the most efficient for the accumulation of 2,4-DCP in plant tissues. The removal of 2,4-DCP from the media may result from its degradation or polymerized in the root zone by the plant enzymes. Phytoremediation of 2,4-DCP with S. matsudana clone 8, 18 and 22 seem to be a viable option, especially at lower concentrations. These clones could remove 2,4-DCP from aquatic environment rapidly and efficiently. In addition, the toxic effect on trees during the removal process is not lethal. PMID- 23031588 TI - Chemotherapy of leishmaniasis. Part IX: synthesis and bioevaluation of aryl substituted ketene dithioacetals as antileishmanial agents. AB - A new series of aryl substituted ketene dithioacetals 6a-h was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. Two compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC(50) values 3.56 and 5.12 MUM and were found promising as compared with reference drug, miltefosine. On the basis of good Selectivity Indices (S.I.), they were further tested for their in vivo response against L. donovani/hamster model and showed significant inhibition of parasite multiplication 78% and 83%, respectively. These compounds were better than the existing antileishmanials in respect to IC(50) and SI values, but were less active than miltefosine in vivo. PMID- 23031589 TI - First total synthesis of prasinic acid and its anticancer activity. AB - The first total synthesis of prasinic acid is being reported along with its biological evaluation. The ten step synthesis involved readily available and cheap starting materials and can easily be transposed to large scale manufacturing. The crucial steps of the synthesis included the formation of two different aromatic units (7 and 9) and their coupling reaction. The synthetic prasinic acid exhibited moderate antitumor activity (IC(50) 4.3-9.1 MUM) in different lines of cancer cells. PMID- 23031590 TI - Identification of a glutathione peroxidase inhibitor that reverses resistance to anticancer drugs in human B-cell lymphoma cell lines. AB - Cancer cells isolated from two patients with malignant non-Hodgkin B-cell lymphomas that became resistant to chemotherapy during clinical treatment were made >=fourfold resistant in culture to anticancer drugs, that is cisplatin, etoposide, methotrexate and bortezomib. Because most resistant lines showed significantly increased expression of the anti-oxidative enzyme glutathione peroxidase 1 (GPx1), GPx1 was investigated as a target for inhibitor development. Virtual screening of a library of diverse structures by docking them to the active site of the X-ray crystal structure of bovine GPx1 uncovered compounds that might block the enzyme. An enzyme assay confirmed an acylhydrazone heterocycle (3) with GPx inhibitory activity. Combinations of 3 with the anticancer drugs listed above led to reversal of resistance in the lymphoma cell lines. PMID- 23031591 TI - The discovery of CCR3/H1 dual antagonists with reduced hERG risk. AB - A series of dual CCR3/H(1) antagonists based on a bispiperidine scaffold were discovered. Introduction of an acidic group overcame hERG liability. Bioavailability was optimised by modulation of physico-chemical properties and physical form to deliver a compound suitable for clinical evaluation. PMID- 23031592 TI - Downregulation of mdr1 and abcg2 genes is a mechanism of inhibition of efflux pumps mediated by polymeric amphiphiles. AB - The ability of cells to acquire resistance to multiple pharmaceuticals, namely multidrug resistance (MDR), is often mediated by the over-expression of efflux transporters of the ATP-binding cassette (ABC) superfamily; for example P glycoprotein (P-gp or MDR1), breast cancer resistance protein (BCRP or ABCG2), and multidrug resistance-associated protein MRP1. ABCs pump drug molecules out of cells against a concentration gradient, reducing their intracellular concentration. The ability of polymeric amphiphiles to inhibit ABCs as well as the cellular pathways involved in the inhibition has been extensively investigated. This work investigated for the first time the effect of branched poly(ethylene oxide)-poly(propylene oxide) block copolymers (poloxamines) on the levels of mRNA encoding for MDR1, BCRP and MRP1, in a human hepatoma cell line (Huh7). Copolymers with a broad range of molecular weights and hydrophilic lipophilic balances were assayed. Results confirmed the down-regulation of mdr1 and abcg2 genes. Conversely, the mrp1 gene was not affected. These findings further support the versatility of these temperature- and pH-responsive copolymers to overcome drug resistance in cancer and infectious diseases. PMID- 23031593 TI - Design, synthesis, spectral and biological evaluation of novel 1-allyl substituted 2,6-diphenylpiperidin-4-ones and its derivatives of oximes/oxime ethers. AB - A series of 1-allyl-2,6-diphenylpiperidin-4-one oximes 17-24 and 1-allyl-2,6 diphenylpiperidin-4-one O-benzyloximes 25-32 were synthesized from respective 1 allyl-2,6-diphenylpiperidin-4-ones 9-16. The structure and the conformations have been investigated for all the synthesized compounds 9-32 by analytical and spectral techniques (IR, Mass, 1H, 13C, 2D NMR and X-ray Diffraction). Based on the proton NMR analysis, all the synthesized compounds 9-32, exposed chair conformation except compounds 22 and 30 (twist boat conformation). For all the synthesized compounds 9-32 antimicrobial activity has been carried out against a panel of selected bacterial and fungal strains using Streptomycin and Amphotericin B as standards. Antibacterial and antifungal activity of compounds 19, 21, 23 (allyl oximes) 25-29, 31, 32 (allyl oxime ethers) and 11, 13 (ketones) exerted moderate to excellent activity against Staphylococcus aureus, Bacillus subtilis, Salmonella typhi bacterial strains and Penicillium chrysogenum, Aspergillus niger, Fusarium oxysporum fungal strains. The MIC results of all the synthesized compounds revealed that most of the oxime ether compounds exhibit excellent activity against selected bacterial and fungal strains. PMID- 23031594 TI - Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: possible confounding effects on in vivo and in vitro studies. AB - SB-334867 has been an important ligand for the study of the orexin 1 (OX1) receptor due to its high OX1/OX2 selectivity and bioavailability. This ligand however, contains a 2-methylbenzoxazole ring system which is known to undergo hydrolysis, particularly under acidic or basic conditions. The possibility that SB-334867 would be susceptible to significant hydrolysis was evaluated in various formulations and in the solid state. SB-334867 was found to be unstable under conditions commonly employed to prepare stock solutions for in vitro and in vivo studies. In addition, and most alarmingly, the hydrochloride salt of SB-334867 was found to quantitatively decompose to an OX1-inactive product even in the solid state. These findings combine to suggest that studies using SB-334867 (and any other 2-methylbenzoxazole-containing compound) should be performed with great care to avoid the confounding effects of the rapid hydrolytic decomposition of this susceptible structure. PMID- 23031595 TI - Design, synthesis, and evaluation of potential prodrugs of DFMO for reductive activation. AB - A series of potential DFMO prodrugs was designed through the incorporation of 4 nitrobenzyl ester or carbamate groups for potential activation by trypanosomal nitroreductase. It was found that only modification of N(epsilon)-amino group of DFMO by 4-nitro-2-fluorobenzyloxycarbonyl resulted in significant trypanocidal activity and could serve as a lead for further investigation. PMID- 23031596 TI - Diarylheptanoid glycosides from Tacca plantaginea and their effects on NF-kappaB activation and PPAR transcriptional activity. AB - In the screening search for NF-kappaB inhibitory and PPAR transactivational agents from medicinal plants, a methanol extract of the whole plant of Tacca plantaginea and its aqueous fraction showed the significant activities. Bioassay guided fractionation combined with repeated chromatographic separation of the aqueous fraction of the methanol extract of T. plantaginea resulted in the isolation of two new diarylheptanoid glycosides, plantagineosides A (1) and B (2), an unusual new cyclic diarylheptanoid glycoside, plantagineoside C (3), and three known compounds (4-6). Their structures were determined by extensive spectroscopic and chemical methods. Compounds 3-6 significantly inhibited TNFalpha-induced NF-kappaB transcriptional activity in HepG2 cells in a dose dependent manner, with IC(50) values ranging from 0.9 to 9.4 MUM. Compounds 1-6 significantly activated the transcriptional activity of PPARs in a dose-dependent manner, with EC(50) values ranging from 0.30 to 10.4 MUM. In addition, the transactivational effects of compounds 1-6 were evaluated on three individual PPAR subtypes, including PPARalpha, gamma, and beta(delta). Compounds 1-6 significantly enhanced the transcriptional activity of PPARbeta(delta), with EC(50) values in a range of 11.0-30.1 MUM. These data provide the rationale for using T. plantaginea and its components for the prevention and treatment of inflammatory and metabolic diseases. PMID- 23031597 TI - Chemotherapy of leishmaniasis. Part XI: synthesis and bioevaluation of novel isoxazole containing heteroretinoid and its amide derivatives. AB - Novel isoxazole containing heteroretinoid (4) and its amide derivatives (5a-j) have been synthesized and evaluated for their in vivo antileishmanial activity against Leishmania donovani in hamsters. Compounds 3, 5a, 5d, 5k and 5l inhibited 70-76% parasite growth at 50 mg kg(-1) *5 days. The present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent. PMID- 23031598 TI - Synthesis and in vitro and in vivo anticancer activity of novel 3-methyl-5H isoxazolo[5',4':5,6]pyrido[2,3-b]indoles. AB - A series of novel isoxazolo[5',4':5,6]pyrido[2,3-b]indoles 7a-h were synthesized and tested for their in vitro and in vivo anticancer activities. The analogs 7d and 7g have shown potential anticancer activity as compared with the reference compound Cisplatin. PMID- 23031599 TI - Inheritance of duration of fertility in female common ducks (Anas platyrhynchos) inseminated in pure breeding or in inter-generic crossbreeding with Muscovy drakes (Cairina moschata). AB - Ducks (common, Muscovy and mule ducks) are the third most important bird species in animal production for human consumption worldwide. Our study aimed to improve the efficiency of mule duck breeding, thus contributing to the efficiency of food production in general. In the common duck, females can be bred either with males of the same species (i.e. in pure breeding (PB) subscript p) or in inter-generic crossbreeding (CB; subscript c) with Muscovy drakes to produce the hybrid mule duck. The aim of the present study was to estimate the genetic parameters of several indicators of duration of fertility, considered to be a trait of the female duck, within and between breeding schemes and, in particular, to estimate the purebred-crossbred genetic correlation (rg pc). These indicators were maximum duration of fertility (MD), that is, the time interval between insemination and the last fertilised egg, the number of fertile eggs (F) and of hatched ducklings (H) after a single artificial insemination (AI), and the fertility rate over days 2 to 12 after AI (F 2,12), taking three sub-periods (F 2,4, F 5,8, F 9,12) into account. A total of 494 females and 2655 inseminations were involved. PB resulted in longer duration of fertility (MD p = 8.1 v. MD c = 6.4 days). Heritability (h 2) was higher for MD p (estimate +/- s.e.: 0.27 +/- 0.04) than for MD c (0.15 +/- 0.04), but both traits were highly correlated with each other (rg pc = 0.85 +/- 0.07). F p and F c had similar heritability (h 2 around 0.24) and displayed a high genetic correlation (0.78 +/- 0.07). The same was true for H p and H c (h 2 around 0.17 and rg pc = 0.88 +/- 0.05). The heritability estimates were 0.24 +/- 0.03 for F 2,12p and 0.20 +/- 0.04 for F 2,12c, with a 0.80 +/- 0.07 genetic correlation between each other. Permanent environmental effects influenced MD p far less than MD c, F p less than F c, but H p and H c to the same extent. The high values for rg pc (>0.78) indicated that the same genes are involved in the duration of fertility for both PB and CB. Unlike CB, initial fertility for PB (F 2,4p) was not correlated to overall fertility rate and to duration of fertility and probably involves different genes, if any. In both breeding schemes, indirect selection on F would be better than direct selection on H to improve H, and easier to implement than selection on MD. Moreover, any gain in one breeding scheme will have its correlated counterpart in the other one, because of the high values of rg pc. PMID- 23031600 TI - Sanitary housing conditions modify the performance and behavioural response of weaned pigs to feed- and housing-related stressors. AB - Pigs are confronted with changes in farming practices that may affect performance and animal well-being. The sanitary conditions of the farm can have an impact on the ability of pigs to adapt to these changes. This study aimed to analyse how weaned pigs respond to common farming practices of changes in diet and housing in terms of performance, health and behaviour, and how these responses are affected by the sanitary housing conditions, qualified here as good or poor. At weaning at 4 weeks of age, 20 piglets were assigned to 10 blocks of two littermates and each pig within a litter was randomly assigned to one of two sanitary conditions. Pigs were housed individually and received a starter diet. A diet change occurred on day 12 post weaning (starter to weaner diets) and pigs were transferred to the grower unit on day 33 post weaning and continued to receive the weaner diet. From 43 days post weaning, pigs were offered a grower diet and were vaccinated against swine influenza on day 47 and 61 post weaning. On the basis of this design, three post-weaning phases were identified: phase I from day 1 to 11 (post weaning), phase II from day 12 to 32 (after the diet change) and phase III from day 33 to 42 (after the housing change). Individual BW was measured every 3 days, and feed refusals and faecal scores were recorded on a daily basis. Behavioural observations were performed during 28 days by using the instantaneous scan sampling method. Individual blood samples were collected at the end of each phase to analyse the plasma concentration of haptoglobin and on day 68 post weaning to analyse the anti-influenza immunoglobulins G (IgG). Poor sanitary conditions resulted in a decrease in daily gain, feed intake and gain to feed ratio of, respectively, 11%, 5% and 7% (P < 0.05). Pigs in poor sanitary conditions had higher faecal scores (P < 0.05), tended to have higher plasma haptoglobin concentration in phase II (P = 0.06) and had a higher anti-influenza IgG titre (P = 0.11). The diet change affected performance and behavioural responses of pigs in poor but not in good sanitary conditions. Housing change resulted in a 30% decrease in growth and an increase in behaviour oriented towards exploration and excitement. The results of this study show an effect of sanitary conditions on the responses of pigs to a diet change, whereas those to a housing change were little affected by the sanitary conditions. PMID- 23031601 TI - Microstructural analysis of Iberian expanded clay aggregates. AB - This article presents a detailed study of the microstructure of Iberian expanded clay lightweight aggregates (LWA). Other than more commonly used mercury porosimetry (MP) and water absorption methods, the experimental study involves optical microscopy, scanning electron microscopy (SEM), and microtomography (MU CT). Pore connectivity and how it is deployed are shown to some degree, and the pore size spectrum is estimated. LWA are in general characterized by a dense outer shell up to 200 MUm thick, encasing an inner cellular structure of 10-100 times bigger pore size. Aggregate pore sizes may span from some hundreds of nanometers up to over 1 mm, though the range of 1-25 MUm is more typical. A noteworthy fraction of these pores is closed, and they are mainly up to 1 MUm. It is also shown that macropore spatial arrangement is affected by the manufacturing process. A step forward is given to understanding how the outer shell and the inner pore network influence the mechanical and physical LWA properties, particularly the density and water absorption. The joint consideration of MU-CT and SEM seems to be the most appropriate methodology to study LWA microstructure. MP analysis is likely to distort LWA pore spectrum assessment. PMID- 23031602 TI - Effect of estradiol-17beta on follicle-stimulating hormone secretion and egg laying performance of Japanese quail. AB - The aim of this study was to measure the effect of estradiol-17beta (E2) injection on follicle-stimulating hormone (FSH) secretion and egg-laying performance of Japanese quail. Female Japanese quail were housed in cages and fed ad libitum. After a 7-day adaptation period, the birds were randomly assigned to three groups, that is, one control group and two test groups. The birds were weighed, before every injection. The control group was subcutaneously injected with 0.2 ml sesame oil-ethanol mixture, whereas test groups were injected, twice in a week, with 0.2 ml sesame oil-ethanol mixture containing 0.1 or 0.2 mg E2 along the study. One day after the first injection, egg number, egg weight, eggshell strength and food conception were daily recorded. On the last day of the experiment, the birds were injected and 3 h later seven birds from each group were randomly selected for bleeding. Blood samples (2 ml/bird) were collected from the jugular vein for the measurements of serum concentrations of E2, FSH, calcium (Ca) and phosphorus (P). E2 injection did not cause any significant changes in serum FSH concentrations, daily egg laid/bird, food conception/bird, serum concentrations of the Ca and the P. Egg weight was significantly increased in the 0.1 mg E2-injected group as compared with the control and 0.2 mg E2 injected groups. Eggshell strength in the 0.2 mg E2-injected group was significantly high as compared with the control, whereas the difference between the 0.1 mg E2- and 0.2 mg E2-injected groups was not statistically important. These results show that serum FSH concentration was not increased even when slightly suppressed by subcutaneous injection of 0.1 or 0.2 mg E2. Different doses of E2 have different functions. The increase in BWs in the 0.1 mg E2 injected group was a result of the dose effect, which probably increased growth hormone secretion from the pituitary or IGF-1 synthesis from the liver or both. The dose, 0.2 mg E2, was ineffective in increasing the BW, but it significantly increased eggshell strength probably via the increase in Ca and P utilizations. PMID- 23031603 TI - Genome-wide transcript profiling indicates induction of energy-generating pathways and an adaptive immune response in the liver of sows during lactation. AB - The present study aimed to explore the lactation-induced changes in hepatic gene expression in sows (Sus scrofa) during lactation. Using a porcine whole-genome microarray a total of 632 differentially expressed genes in the liver of lactating compared to non-lactating sows could be identified. Enrichment analysis revealed that the differentially expressed genes were mainly involved in fatty acid metabolism, pyruvate metabolism, glutathione metabolism, glycine, serine and threonine metabolism, citrate cycle, glycerophospholipid metabolism, PPAR signaling, and focal adhesion. The most striking observation with respect to intermediary metabolism was that genes involved in fatty acid catabolism, the catabolism of gluconeogenic amino acids, the citrate cycle and the respiratory chain were up-regulated in the liver of sows during lactation. With respect to immune response, it could be demonstrated that genes encoding acute phase proteins and genes involved in tissue repair were up-regulated and genes encoding adhesion molecules were down-regulated in the liver of sows during lactation. The results indicate that energy-generating pathways and pathways involved in the delivery of gluconeogenic substrates are induced in sow liver during lactation. The alterations of expression of genes encoding proteins involved in immune response suggest that lactation in sows may cause an adaptive immune response that possibly counteracts hepatic inflammation. PMID- 23031604 TI - Altruism and participation in longitudinal health research? Insights from the Whitehall II Study. AB - Research that follows people over a period of time (longitudinal or panel studies) is important in understanding the ageing process and changes over time in the lives of older people. Older people may choose to leave studies due to frailty, or illness and this may diminish the value of the study. However, people also drop out of studies for other reasons and understanding the motivation behind participation or drop out may prevent further loss of valuable longitudinal information and assist the continuation of longitudinal studies. This paper examines qualitative data from interviews and focus groups in 2003/2008 with participants of the Whitehall II Study (based at UCL), and investigates reasons participants give for participating in longitudinal health studies, and recommendations they give for encouraging continued participation as they grow older. A total of 28 participants and 14 staff were interviewed, and 17 participants took part in focus groups. Our findings are discussed in the light of the debate between of altruism and reciprocity. Rather than being wholly motivated by altruism, as research staff had assumed, participants were motivated by the benefits they perceived, particularly the information and care received during the medical examinations and the sense of loyalty and membership associated with being part of the study. Our findings support the view that far from being primarily motivated by altruism, research participation in studies such as this may also involve a degree of implicit and explicit reciprocity. However, participants disliked the obligation to complete the study questionnaires--which may have influenced the expectation of payment or reciprocation, as participation was not wholly pleasing. To try and maintain participation in longitudinal health studies this project recommended gathering information from exit interviews as a way of preventing further withdrawals and closer involvement of participants through a user panel. PMID- 23031605 TI - Parental employment and children's body weight: Mothers, others, and mechanisms. AB - A robust body of literature spanning several countries indicates a positive association between maternal employment and child body mass index (BMI). Fewer studies have examined the role of paternal employment. More importantly, little empirical work examines the mechanisms that might explain the relationships between parental employment and children's BMI. Our paper tests the relationship between the cumulative experience of maternal and spouse employment over a child's lifetime and that child's BMI, overweight, and obesity at age 13 or 14. We further examine several mechanisms that may explain these associations. We use data from the U.S. National Longitudinal Survey of Youth (NLSY79) merged mother child file on cohorts of children who were born during a period of dramatic increase in both childhood obesity and maternal employment. We find that the number of hours that highly-educated mothers work over her child's lifetime is positively and statistically significantly associated with her child's BMI and risk of overweight at ages 13 or 14. The work hours of mothers' spouses and partners, on the other hand, are not significantly associated with these outcomes. Results suggest that, for children of highly-educated mothers, the association between maternal work hours and child BMI is partially mediated by television viewing time. PMID- 23031606 TI - Repeated in vivo inguinal measurements to estimate a single optimal mesh size for inguinal herniorrhaphy. AB - BACKGROUND: Inguinal hernia is a common condition and its repair (herniorrhaphy) is one of the most commonly performed procedures in general surgery. The Lichtenstein herniorrhaphy technique is a widely used and effective surgery that uses mesh to reinforce the area of weakness. Although a wide range of mesh sizes are available for use in hernia repair, in low-resource health care settings the provision of multiple products may not be supportable and it may be necessary for the provision and use of a single mesh size. This study aimed to determine whether the recommended 7.0 cm x 15.0 cm size is an appropriate single mesh size. METHODS: In order to determine the optimal mesh size according to recommended surgical practices, in vivo measurements of key dimensions of the inguinal floor were taken in patients undergoing herniorrhaphy. RESULTS: Measurements were taken in 43 patients: 40 men and 3 women, mean age 43 years (SD 13.6); 39 with indirect hernias, 4 with direct. Allowing for recommended mesh overlaps, the optimal mesh size for provision to be appropriate for the majority of patients was determined to be 8.5 cm x 14.0 cm, 21% wider than the mesh size currently recommended for use in Lichtenstein herniorrhaphy. CONCLUSIONS: An appropriate size for routine provision in low-resource settings, or other settings where the provision of several mesh sizes is not supportable, may be 8.5 cm x 14.0 cm. PMID- 23031607 TI - Influence of sex and immunocastration on feed intake behavior, skatole and indole concentrations in adipose tissue of pigs. AB - Feed intake behavior was studied between 9 weeks of age and slaughter in a total of 36 gilts, 32 immunocastrates, 33 surgically castrated barrows and 33 boars from 36 litters. Consequences for the concentration of substances contributing to off odor of pork (skatole, indole) were evaluated. Animals were kept in groups of 12 pigs of the same sex and treatment and fed ad libitum (13.4 MJ ME, 17% CP, 1.1% lysine). Individual feed intake behavior was recorded continuously by an electronic feeder. Immunocastration was carried out with two injections of Improvac with at least 4 weeks between both injections (1st: 12 to 17 weeks of age, 2nd: 19 to 21 weeks of age). Feed intake/day increased from an average of 0.91 +/- 0.02 kg/day up to 3.15 +/- 0.04 kg/day before slaughter. This increase was associated with a 50% reduction in the number of meals/day (from 15.8 +/- 0.44 to 7.2 +/- 0.29 meals/day). The larger meal sizes resulted from an increase in both, the duration of feed intake/meal and the feed intake rate (g/min). In addition, sex and treatment differences were observed: Feed intake in boars was lower than in all other groups due to a reduction in the number of meals/day and in the time spent feeding/day. In females, time spent feeding/day was quite similar to boars, but resulted from a higher number of meals of shorter duration. Barrows had a significantly higher feed intake because of a higher number of meals/day resulting in more time spent feeding/day. The feed intake rate was similar in boars, gilts and barrows and showed an increasing trend during the study, starting from about 15 g/min up to four times the amount. Immunocastration affected feed intake behavior severely, especially the meal size increased dramatically because of higher feed intake rate, which exceeded that of all other groups by 25% at the end of the study. The number of meals/day was not influenced by immunocastration and was almost identical to that of boars. Highest skatole concentrations were measured in fat of boars, whereas indole concentrations were higher in immunocastrates than in all other groups. In gilts and barrows, skatole concentrations were related to growth rate. Additionally, the feeding rate was an important factor explaining the variability in skatole/indole concentrations in adipose tissue. The physiological mechanisms however need further clarification. PMID- 23031609 TI - Anterior cruciate ligament reconstruction in a patient with Athetoid cerebral palsy: a case report. AB - Recent years have seen ACL reconstruction performed in a broad range of patients, regardless of age, sex or occupation, thanks to great advances in surgical techniques, instrumentation and the basic research. Favorable results have been reported; however, we have not been able to locate any reports describing ACL reconstruction in patients with athetoid cerebral palsy.We present herein a previously unreported anterior cruciate ligament (ACL) reconstruction performed in a patient with athetoid cerebral palsy. The patient was a 25-year old woman with level II athetoid cerebral palsy according to the Gross Motor Function Classification System. She initially injured her right knee after falling off a bicycle. Two years later, she again experienced right-knee pain and a feeling of instability. A right-knee ACL tear and avulsion fracture was diagnosed upon physical examination and confirmed with magnetic resonance imaging (MRI) and X-ray examination at that time. An ACL reconstruction using an autologous hamstring double-bundle graft was performed for recurrent instability nine years after the initial injury. Cast immobilization was provided for 3 weeks following surgery and knee extension was restricted for 3 months with the functional ACL brace to prevent hyperextension due to involuntary movement. Partial weight-bearing was started 1 week postoperatively, with full weight bearing after 4 weeks. The anterior drawer stress radiography showed a 63% anterior displacement of the involved tibia on the femur six months following the surgery, while the contralateral knee demonstrated a 60% anterior displacement of the tibia. The functional ACL functional brace was then removed. A second-look arthroscopy was performed 13 months after the ACL reconstruction, and both the anteromedial and posterolateral bundles were in excellent position as per Kondo's criteria. The Lachman and pivot shift test performed under anesthesia were also negative. An anterior drawer stress radiography of the involved knee at 36 months following surgery showed a 61% anterior translation of the tibia. The preoperative symptoms of instability resolved and the patient expressed a high degree of satisfaction with the result of her surgery. PMID- 23031610 TI - Web-based self-management support training for health professionals: a pilot study. AB - OBJECTIVE: To evaluate a web-based self-management training for health professionals. Patients spend 99% of their time outside the healthcare system. Thus self-management support from health professionals is central to optimal care. Our objective was to teach health professionals the skills to provide this support. METHODS: Primary care residents and practicing providers enrolled in six groups. Each group received four web-based interactive training sessions derived from self-efficacy theory. Retrospective-pre/post assessed changes in self management beliefs and confidence. Wilcoxon signed-rank tests with Bonferroni correction compared responses. Focus groups solicited qualitative feedback. RESULTS: Fifty-seven residents and providers across the United States enrolled. Residents demonstrated positive changes on all belief questions (P 0.001-0.012). Practicing providers had a non-significant positive change on one and significant changes on the remainder (P 0.001-0.018). Both types of participants demonstrated significant increases on confidence questions regarding their ability to support self-management (P<0.01 for all). Participants described learned techniques as being useful, reducing burnout, and increasing acceptance of patient involvement in care planning. CONCLUSION: The web-based self-management support training for health professionals was feasible and changed beliefs and confidence. PRACTICE IMPLICATIONS: The program may maximize patient self-management by increasing provider self-efficacy and skill for self-management support. PMID- 23031611 TI - Integration of complementary and alternative medicine in primary care: what do patients want? AB - OBJECTIVE: To explore patients' perspectives towards integration of Complementary and Alternative Medicine (CAM) in primary care. METHODS: A mixed-methods approach was used. This included a survey on use, attitudes and disclosure of CAM, an e panel consultation and focus group among patients with joint diseases. RESULTS: A total of 416 patients responded to the survey who suffered from osteoarthritis (51%), rheumatoid arthritis (29%) or fibromyalgia (24%). Prevalence of CAM use was 86%, of which 71% visited a CAM practitioner. Manual therapies, acupuncture and homeopathy were most frequently used. A minority (30%) actively communicated CAM use with their General Practitioner (GP). The majority (92%) preferred a GP who informed about CAM, 70% a GP who referred to CAM, and 42% wanted GPs to collaborate with CAM practitioners. Similar attitudes were found in the focus group and upon e-panel consultation. CONCLUSIONS: Most patients in primary care want a GP who listens, inquires about CAM and if necessary refers to or collaborates with CAM practitioners. PRACTICE IMPLICATIONS: To meet needs of patients, primary care disease management would benefit from an active involvement of GPs concerning CAM communication/referral. This study presents a model addressing the role of patients and GPs within such an integrative approach. PMID- 23031613 TI - Dance therapy improves self-body image among obese patients. AB - OBJECTIVE: Obesity and disturbed eating behaviors are both associated with low self-esteem and distorted body images. The aim of this study was to assess the influence of a dance therapy program on the evolution of mental representations linked to body image among obese patients. Changes in body image were evaluated in terms of four parameters: physical, psychological, cognitive, and social. METHODS: In total, 18 obese patients were enrolled in a longitudinal dance therapy workshop (DTW) program lasting 36 weeks. Patients danced for 2h per week and were evaluated three times: at baseline, after 18 weeks, and at the end of the study (36 weeks). Evaluation was performed using questionnaires addressing health-related quality of life, sensorial-motor perception, and mental representations linked to body schema and self-body image. RESULTS: Obese patients enrolled in the DTW displayed a significant improvement in health related quality of life (p<0.03), body consciousness (p<0.001), and mental representations linked to self body image (p<0.001). CONCLUSION: DTW allowed obese patients to reset both their somatic and psychic consciousness of their body image. PRACTICE IMPLICATIONS: Patients are usually reluctant to practice physical activity. Dance therapy improves not only body image, but also psycho social aspects of their personality. PMID- 23031612 TI - A feasibility study to evaluate breast cancer patients' knowledge of their diagnosis and treatment. AB - OBJECTIVE: To evaluate the feasibility of an electronic survey to assess patients' knowledge of their breast cancer and treatment, and interest in receiving a medical summary. METHODS: Women undergoing breast cancer treatment completed an interviewer-administered electronic survey in person or by telephone. Medical records were abstracted to evaluate knowledge accuracy. RESULTS: Among 38 eligible patients approached for the study, 35 (92%) participated and 33 (94%) completed the survey. Participants' perceived knowledge tended to be greater than their actual knowledge. Reporting of clinicopathologic features was most accurate for stage (91%) and lymph node status (88%), and least accurate for tumor size (61%), type (61%), and grade (33%). Accurate reporting of tumor receptor over-expression varied from 76% (estrogen receptor) to 39% (progesterone receptor). Many patients correctly recalled general treatment modalities and details of surgery; fewer recalled details of radiation and chemotherapy. Importantly, nearly all (32/33) were interested in receiving a breast cancer medical summary. CONCLUSION: An electronic survey is feasible to assess breast cancer patients' knowledge. This data suggest that patients have gaps in knowledge and would like a personalized medical summary. PRACTICE IMPLICATIONS: Larger studies are needed to validate and characterize knowledge gaps, and test interventions to improve physician-patient information sharing. PMID- 23031614 TI - Commentary on the role of treatment-related HIV compensatory mutations on increasing virulence: new discoveries twenty years since the clinical testing of protease inhibitors to block HIV-1 replication. AB - Approximately 20 years has passed since the first human trial with HIV-1 protease inhibitors. Protease inhibitors set the stage for combination therapy in the mid 1990s but are now rarely used in first-line combination therapy and reserved for salvage therapy. Initially, resistance to protease inhibitors was deemed unlikely due to the small enzymatic target with limited genetic diversity, the extended drug binding site in protease, and the need to cleave multiple sites in the HIV-1 precursor proteins. However, a highly protease inhibitor-resistant virus can emerge during treatment and is found to harbor a collection of primary drug resistant mutations near the drug and/or substrate binding site as well as secondary mutations that compensate for fitness loss. For years, the research field has debated the impact of these secondary mutations on the emergence rates of high-level protease inhibitor resistance. A recent study poses a more pertinent question, related to disease progression in patients newly infected with a virus harboring secondary protease inhibitor-associated polymorphisms. The authors of that study show that increased rates of disease progression, inferred by increased viral loads and decreased CD4 cell counts, correlate with a fitness score of the infecting virus. The modeled fitness scores increased with an accumulation of these secondary protease inhibitors mutations, and not because of any one specific polymorphism. PMID- 23031615 TI - Effects of Bacillus subtilis natto on milk production, rumen fermentation and ruminal microbiome of dairy cows. AB - Two experiments were conducted to evaluate the effects of Bacillus subtilis natto, which was initially isolated from fermented soybeans on milk production, rumen fermentation and ruminal microbiome in dairy cows. In Experiment 1, 36 early lactation Chinese Holstein dairy cows (56 +/- 23 days in milk) were randomly assigned to three groups: Control, cows were fed total mixed ration (TMR); BSNLOW, TMR plus 0.5 * 1011 colony-forming units (cfu) of B. subtilis natto/cow per day; and BSNHIGH, TMR plus 1.0 * 1011 cfu of B. subtilis natto/cow per day. During the 70-day treatment period, daily milk production and daily milk composition were determined in individual cows. The results showed that supplementing dairy cows with 0.5 * 1011 and 1.0 * 1011 cfu of B. subtilis natto linearly increased (P < 0.01) milk production (25.2 and 26.4 kg/day v. 23.0 kg/day), 4% fat-corrected milk (27.3 and 28.1 kg/day v. 24.2 kg/day), energy corrected milk (27.3 and 28.2 kg/day v. 24.2 kg/day), as well as milk fat (1.01 and 1.03 kg/day v. 0.88 kg/day), protein (0.77 and 0.82 kg/day v. 0.69 kg/day) and lactose yield (1.16 and 1.22 kg/day v. 1.06 kg/day) but decreased milk somatic cell counts (SCC) by 3.4% to 5.5% (P < 0.01) in BSNLOW and BSNHIGH treatments compared with Control. In Experiment 2, four rumen-cannulated dairy cows were fed the basal diet from 1 to 7 days (pre-trial period) and rumen samples were collected on days 6 and 7; the same cows then were fed 1.0 * 1011 cfu/day B. subtilis natto from days 8 to 21 (trial period) and rumen samples were collected on days 20 and 21. B. subtilis natto was discontinued from days 22 to 28 (post-trial period) and rumen samples were collected on days 27 and 28. Compared with the pre- and post-periods, ruminal pH decreased by 2.7% to 3.0% during the trial period (P < 0.01), whereas ammonia nitrogen (NH3-N), total volatile fatty acids and molar proportion of propionate (P < 0.01) and valerate (P < 0.05) increased. Molar proportion of acetate decreased and the acetate to propionate ratio was lower (P < 0.01) during the trial period. However, no differences for 24-h in sacco dry matter digestibility were detected among different periods (treatments) though NDF digestibility was reduced in the trial and post-trial periods (P < 0.01). Compared with pre-trial period, total ruminal bacteria, proteolytic and amylolytic bacteria in rumen enumerated by culture methods increased by 15.0%, 16.2% and 11.7%, respectively (P < 0.01) but protozoa decreased to 5.35 log10 cfu/ml (P < 0.01) during the trial period. These results demonstrate that B. subtilis natto improves milk production and milk components yield, decreases SCC and promotes the growth of total ruminal bacteria, proteolytic and amylolytic bacteria, which indicate that B. subtilis natto has potential to be applied as a probiotic for dairy cows. PMID- 23031616 TI - Gitelman syndrome manifesting in early childhood and leading to delayed puberty: a case report. AB - INTRODUCTION: Gitelman syndrome is an inherited autosomal recessive renal salt wasting disorder. It presents with variable clinical symptoms including muscle weakness and fatigue, and the diagnosis is based on metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria. It is usually diagnosed incidentally in early adulthood. There are rare cases of Gitelman syndrome presenting in early childhood; however, to the best of our knowledge it has not previously been associated with delayed puberty. CASE PRESENTATION: A 17-year-old South Asian man with recurrent episodes of generalized muscle weakness, fatigue and cramps from the age of two years was admitted for further workup. Before the age of 12 years, the episodes had been mild, but they then got progressively worse. Other symptoms include polyuria, polydipsia, nocturia, paresthesia and occasional watery diarrhea. He also had a history of short stature, poor weight gain and delayed developmental landmarks. His family history was unremarkable except for the consanguineous marriage of his parents. An examination revealed a thin and lean man with blood pressure of 95/60mmHg. His height and weight were below the third percentile and his sexual development was at Tanner Stage II. Laboratory work revealed serum sodium of 124mmol/L, potassium 2.4mmol/L, calcium 6.5mmol/L and magnesium of 1.2mg/dL. His testosterone level was low (0.85ng/mL, normal for his age 2.67 to 10.12ng/mL) with normal levels of luteinizing hormone and follicle-stimulating hormone. The sex hormone findings were attributed to delayed puberty. A 24-hour urinary analysis revealed decreased excretion of calcium (25.9mg/24 hours). Based on the findings of hypokalemic metabolic alkalosis without hypertension, severe hypomagnesemia and hypocalciuria, a diagnosis of Gitelman syndrome was made. Treatment was started with oral supplementation of potassium, magnesium and calcium along with spironolactone and liberal salt intake. CONCLUSION: Diagnosis of Gitelman syndrome is usually made incidentally during adolescence or early adulthood based on clinical and biochemical findings. We report that Gitelman syndrome can present during the early childhood years. If undiagnosed and untreated, it can lead to growth retardation and delayed puberty. PMID- 23031617 TI - Development of a genome-wide multiple duplex-SSR protocol and its applications for the identification of selfed progeny in switchgrass. AB - BACKGROUND: Switchgrass (Panicum virgatum) is a herbaceous crop for the cellulosic biofuel feedstock development in the USA and Europe. As switchgrass is a naturally outcrossing species, accurate identification of selfed progeny is important to producing inbreds, which can be used in the production of heterotic hybrids. Development of a technically reliable, time-saving and easily used marker system is needed to quantify and characterize breeding origin of progeny plants of targeted parents. RESULTS: Genome-wide screening of 915 mapped microsatellite (simple sequence repeat, SSR) markers was conducted, and 842 (92.0%) produced clear and scorable bands on a pooled DNA sample of eight switchgrass varieties. A total of 166 primer pairs were selected on the basis of their relatively even distribution in switchgrass genome and PCR amplification quality on 16 tetraploid genotypes. Mean polymorphic information content value for the 166 markers was 0.810 ranging from 0.116 to 0.959. From them, a core set of 48 loci, which had been mapped on 17 linkage groups, was further tested and optimized to develop 24 sets of duplex markers. Most of (up to 87.5%) targeted, but non-allelic amplicons within each duplex were separated by more than 10-bp. Using the established duplex PCR protocol, selfing ratio (i.e., selfed/all progeny x100%) was identified as 0% for a randomly selected open-pollinated 'Kanlow' genotype grown in the field, 15.4% for 22 field-grown plants of bagged inflorescences, and 77.3% for a selected plant grown in a growth chamber. CONCLUSIONS: The study developed a duplex SSR-based PCR protocol consisting of 48 markers, providing ample choices of non-tightly-linked loci in switchgrass whole genome, and representing a powerful, time-saving and easily used method for the identification of selfed progeny in switchgrass. The protocol should be a valuable tool in switchgrass breeding efforts. PMID- 23031618 TI - [Cirugia Espanola receives its first impact factor]. PMID- 23031620 TI - Effect of harvest time and physical form of alfalfa silage on chewing time and particle size distribution in boli, rumen content and faeces. AB - The study examined the effects of physical form and harvest time of alfalfa silage on eating and ruminating activity and particle size distribution in feed boli, rumen content and faeces in dry cows. The alfalfa crop was harvested at two stages of growth (early: NDF 37%, late: NDF 44% in dry matter (DM)), and from each harvest, a chopped (theoretical cutting length: 19 mm) and an unchopped crop was ensiled in bales. The silages were fed restrictively to four rumen cannulated non-lactating Jersey cows (391 +/- 26 kg) in a 4 * 4 Latin square design. The cows were fed restrictively 80% of their ad libitum intake twice daily. Chewing activity was recorded for 96 h continuously. Swallowed boli, rumen content, rumen fluid and faeces samples were collected, washed in nylon bags (0.01 mm pore size) and freeze-dried before dry sieving through 4.750, 2.360, 1.000, 0.500 and 0.212 mm pore sizes into six fractions. The length (PL) and width (PW) of particles within each fraction was measured by the use of image analysis. The eating activity (min/kg dry matter intake (P < 0.01) and min/kg NDF (P < 0.05)) was affected by harvest time. The mean ruminating time (min/kg DM) was affected by harvest time (P < 0.01), physical form (P < 0.05) and NDF intake per kg BW (P < 0.01). The proportion of washed particle DM of total DM in boli, rumen content, rumen fluid and faeces was affected by harvest time (P < 0.01) and highest by feeding late-harvested alfalfa silage. Two peaks on the probability density distribution function (PDF) of PW and PL values of boli, rumen content and faeces were identified. Chopping of the silage decreased the mean PL and PW, the most frequent PL (mode) and 95% percentile PL and PW values in boli. In the rumen content, chopping increased the mean PW (P < 0.05). The dimension sizes of faeces particles were not significantly affected by chopping. The mode PW value was lower in rumen content and faeces than in boli (P < 0.001), and the mode PL value was higher in boli and lower in faeces compared with rumen contents (P < 0.001). In conclusion, the mean total chewing activity per kg NDF decreased due to chopping and early harvest time. The mean PL and PW in boli decreased due to chopping and late harvest. The two peak values on the PDF (PL) and PDF (PW) of boli, rumen content and faeces particles are most likely related to the leaf and the stem residues. PMID- 23031619 TI - Breast density as indicator for the use of mammography or MRI to screen women with familial risk for breast cancer (FaMRIsc): a multicentre randomized controlled trial. AB - BACKGROUND: To reduce mortality, women with a family history of breast cancer often start mammography screening at a younger age than the general population. Breast density is high in over 50% of women younger than 50 years. With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases. Therefore, mammography might not be the optimal method for breast cancer screening in young women. Adding MRI increases sensitivity, but also the risk of false-positive results. The limitation of all previous MRI screening studies is that they do not contain a comparison group; all participants received both MRI and mammography. Therefore, we cannot empirically assess in which stage tumours would have been detected by either test.The aim of the Familial MRI Screening Study (FaMRIsc) is to compare the efficacy of MRI screening to mammography for women with a familial risk. Furthermore, we will assess the influence of breast density. METHODS/DESIGN: This Dutch multicentre, randomized controlled trial, with balanced randomisation (1:1) has a parallel grouped design. Women with a cumulative lifetime risk for breast cancer due to their family history of >=20%, aged 30-55 years are eligible. Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded. Group 1 receives yearly mammography and clinical breast examination (n = 1000), and group 2 yearly MRI and clinical breast examination, and mammography biennially (n = 1000).Primary endpoints are the number and stage of the detected breast cancers in each arm. Secondary endpoints are the number of false-positive results in both screening arms. Furthermore, sensitivity and positive predictive value of both screening strategies will be assessed. Cost-effectiveness of both strategies will be assessed. Analyses will also be performed with mammographic density as stratification factor. DISCUSSION: Personalized breast cancer screening might optimize mortality reduction with less over diagnosis. Breast density may be a key discriminator for selecting the optimal screening strategy for women < 55 years with familial breast cancer risk; mammography or MRI. These issues are addressed in the FaMRIsc study including high risk women due to a familial predisposition. TRIAL REGISTRATION: Netherland Trial Register NTR2789. PMID- 23031621 TI - Impact of acute exercise on brachial artery flow-mediated dilatation in young healthy people. AB - BACKGROUND: Although chronic effects of exercise on endothelial function are established, the impact of acute exercise on flow-mediated dilatation (FMD) of brachial artery has not been elucidated yet. METHODS: Eighty-six young healthy volunteers were prospectively enrolled from January 2011 to December 2011. The subjects completed FMD tests at rest and immediately after treadmill exercise test. Primary outcome was the impact of acute exercise on FMD, measured by the difference of FMD before and after exercise. Secondary outcomes were the relationship of gender and exercise habit with FMD. RESULTS: Seventy-four subjects who met the eligibility criteria were included for analysis. Thirty-five (47.3%) were male, and the mean age was 22.7+/-2.7 years. FMD was reduced after exercise (8.98+/-4.69 to 7.51+/-4.03%; P=0.017) and the reduction was found in female group (10.36+/-5.26 to 7.62+/-3.71%; P=0.002) but not in male group. Post exercise FMD was significantly impaired in subjects who did not exercise regularly (6.92+/-3.13% versus 8.95+/-5.33%; P=0.003). The decrease of FMD after exercise was greater in female group (-2.75+/-5.28% versus 0.27+/-3.24%; P=0.003) and was associated with exercise habit (beta=2.532; P=0.027). CONCLUSIONS: In healthy young subjects, FMD was reduced after a bout of acute exercise. The impact of acute exercise showed significant differences according to gender and exercise habit. FMD impairment after acute exercise was observed in females and subjects without regular exercise. PMID- 23031622 TI - Dabigatran in clinical practice. AB - BACKGROUND: Stroke and systemic thromboembolism remain critical causes of mortality and morbidity in patients with paroxysmal or persistent atrial fibrillation. Dabigatran etexilate is a novel oral direct thrombin inhibitor, which provides stroke risk reduction for patients with nonvalvular atrial fibrillation. Randomized clinical data demonstrate dabigatran to be an alternative oral anticoagulant with an improved efficacy profile compared with oral warfarin dose adjusted to an INR (international normalized ratio) target of 2.0 to 3.0. OBJECTIVES: Our aim was to review the pharmacology, mechanism of action, drug metabolism, and clinical trial data supporting dabigatran use. METHODS: We reviewed all the major published clinical studies of dabigatran and analyzed data regarding practical applications in selected clinical scenarios. RESULTS: This review provides recommendations for clinicians regarding dosing during invasive surgical procedures, transitioning off alternative anticoagulants, and a discussion of storage and handling of the drug. CONCLUSIONS: Our effort should facilitate the safe and effective use of dabigatran in atrial fibrillation. PMID- 23031623 TI - Safety of exenatide once weekly in patients with type 2 diabetes mellitus treated with a thiazolidinedione alone or in combination with metformin for 2 years. AB - BACKGROUND: Patients with type 2 diabetes mellitus are routinely treated with combinations of glucose-lowering agents. The adverse event (AE) profile and effects on glycemic control have not been assessed for the glucagon-like peptide 1 receptor agonist exenatide once weekly in combination with a thiazolidinedione (TZD) with or without metformin. OBJECTIVE: This study was conducted to examine the long-term safety profile and changes in glycemic control and weight for exenatide once weekly with TZD with or without metformin in patients with type 2 diabetes mellitus over 2 years. METHODS: In this single-arm, open-label trial with treatment up to 104 or 117 weeks, patients received 2 mg exenatide once weekly while continuing treatment with a TZD with or without metformin. Patients were either exenatide-naive before this study or had previously received exenatide twice daily, which was discontinued on initiating exenatide once weekly. Patients were on a stable dosage of TZD (rosiglitazone or pioglitazone) and, if applicable, metformin. Treatment-emergent AEs were defined as those first occurring or worsening post baseline. Descriptive statistics were used for absolute and change-from-baseline data, and a one-sample t test for within-group change in glycosylated hemoglobin (HbA(1c)). RESULTS: Of 134 patients in the intent-to-treat population (baseline mean [SD] HbA(1c),7.2% [1.0%]), 44 were exenatide-naive (baseline HbA(1c), 7.8% [1.0%]) and 90 switched from exenatide twice daily (baseline HbA(1c), 7.0% [0.8%]). Of intent-to-treat patients, 106 (79%) completed the final treatment visit (week 104 or week 117). The most common AEs were nausea (17% of patients) and injection-site nodule (12% of patients). Serious AEs were reported in 14% of patients and 5% withdrew because of a treatment-emergent AE. No identifiable pattern of serious AEs was observed. There were 4 reports of edema and no reports of heart failure. No major hypoglycemia was reported; minor hypoglycemia was reported in 4% of patients. Exenatide-naive patients experienced mean (SE) HbA(1c) reductions of -0.7% (0.2%) and weight reductions of -2.7 (0.8) kg, whereas patients with prior exposure to exenatide twice daily experienced a reduction of -0.4% (0.1%) in HbA(1c) and no change in weight. CONCLUSIONS: Adverse events over 2 years were consistent with the reported safety profiles of exenatide once weekly and TZDs. Exenatide-naive patients experienced improvements in HbA(1c) and weight, while patients with the benefit of prior exenatide therapy experienced an additional reduction from baseline in HbA(1c) and no additional change in weight after 2 years. ClinicalTrials.gov identifier: NCT00753896. PMID- 23031624 TI - Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin associated periodic syndromes: results of a 72-week open-label extension study. AB - BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) are rare, inherited autoinflammatory disorders associated with considerable hardship to patients. The interleukin-1 inhibitor rilonacept has been shown to be well-tolerated and effective in preventing CAPS symptoms in 2 pivotal studies. OBJECTIVE: In this study, the long-term effects of rilonacept for improvement in CAPS symptoms and its safety and tolerability were evaluated during extended treatment. METHODS: Patients with CAPS entered a 72-week open-label extension (OLE) following 2 sequential placebo-controlled Phase III studies (n = 44), or entered directly into the OLE (n = 57). Adults received weekly subcutaneous rilonacept 160 mg, and pediatric patients received subcutaneous rilonacept 2.2 mg/kg, up to 160 mg/week. Safety was evaluated in all patients, and efficacy was evaluated using a validated composite key symptom score in 56 patients. RESULTS: After rilonacept treatment for 72 to 96 weeks mean key symptom score at OLE Week 72 was reduced from 2.6 to 0, and the mean number of multisymptom flare days was reduced from 7.3 (34.8% of days) at baseline to 0.6 (2.9% of days) at end point. Elevated levels of inflammatory markers (eg, high sensitivity-C reactive protein and serum amyloid A, were normalized. Adverse events were generally mild to moderate, the most common being injection site reactions and upper respiratory tract infections. The incidence of these events was similar to or lower than the rate reported in the pivotal studies. CONCLUSIONS: Long-term treatment with rilonacept of up to 96 weeks resulted in improvements in clinical signs and symptoms of CAPS and normalized biomarkers of inflammation. Rilonacept exhibited a generally favorable safety and tolerability profile in adult and pediatric patients with CAPS throughout the extended treatment period. ClinicalTrials.gov identifier: NCT 00288704. PMID- 23031625 TI - Trends in the utilization of, spending on, and prices for outpatient antifungal agents in US Medicaid programs: 1991-2009. AB - BACKGROUND: The incidence of invasive fungal infections (IFIs) has increased substantially in the recent past. Advances in medical technology, including broad spectrum antibiotics, may increase the risk for fungal infections. Moreover, immunocompromised patients with cancer, HIV/AIDS, and/or transplants are susceptible to IFIs. Meanwhile, superficial fungal infections (SFIs) are common and can be difficult to cure. OBJECTIVE: To provide a historical perspective on a dynamic market with expensive medications, this study describes trends in the utilization of, spending on, and average per-prescription spending on outpatient antifungal medications individually, in classes (for IFIs or SFIs), and overall, by the US Medicaid programs from 1991 to 2009. METHODS: The publicly available Medicaid State Drug Utilization Data, maintained by the Centers for Medicare & Medicaid Services, were used. Annual prescription counts and reimbursement amounts were calculated for each of the antifungals reimbursed by Medicaid. Average per-prescription spending as a proxy for drug price was calculated by dividing reimbursement by the number of prescriptions. RESULTS: Overall utilization for Medicaid beneficiaries remained steady, with 4.56 million prescriptions in 1991 and 4.51 million in 2009. Expenditures rose from $93.87 million to $143.76 million (in current-year US$) over the same time period. The drop in the utilization of first-generation azoles over the last 5 years of the study period can be explained in part by the movement of dual-eligibles from Medicaid to Medicare Part D and in part to a rise in fungal infections better treated with second-generation azoles or echinocandins. Whereas the average per prescription price for generic (oral) fluconazole was $8 in 2009, the price per prescription of branded (intravenous) voriconazole was $2178. CONCLUSIONS: Overall spending by Medicaid on outpatient antifungal medications increased more slowly than did the growth of the Medicaid programs from 1991 to 2009. However, the utilization of antifungal agents for IFIs increased almost 10-fold over this period, far outpacing the rise in the number of Medicaid beneficiaries. PMID- 23031626 TI - Adaptation of gait termination on a slippery surface in Parkinson's disease. AB - Parkinson's disease (PD) causes instability and difficulty adapting to changing environmental and task demands. We examined the effects of PD on the adaptation of gait termination (GT) on a slippery surface under unexpected and cued circumstances. An unexpected slip perturbation during GT was followed by a slip perturbation during GT under two conditions: planned over multiple steps and cued one step prior to GT. Feed forward and feedback-based responses to the perturbation were compared to determine (1) how PD affects the ability to integrate adaptive feed forward and feedback-based GT strategies on a slippery surface, (2) if adaptations can be implemented when GT is required within one step, and (3) if behaviour changes with repeated exposure. Similar to the control group (n=10), the PD group (n=8) adapted and integrated feed forward and feedback based components of GT under both stop conditions. Feed forward adaptations included a shorter, wider step, and appropriate stability margin modifications. Feedback-based adaptations included a longer, wider subsequent step. When cued to stop quickly, both groups maintained most of these adaptations: foot angle at contact increased in the first cued stop but adapted with practice. The group with PD differed in their ability to adapt GT with slower, wider steps and less stability. PMID- 23031627 TI - Mobile decontamination units-room for improvement? AB - INTRODUCTION: Mobile decontamination units are intended to be used at the accident site to decontaminate persons contaminated by toxic substances. A test program was carried out to evaluate the efficacy of mobile decontamination units. OBJECTIVE: The tests included functionality, methodology, inside environment, effects of wind direction, and decontamination efficacy. METHODS: Three different types of units were tested during summer and winter conditions. Up to 15 test persons per trial were contaminated with the imitation substances Purasolve ethyl lactate (PEL) and methyl salicylate (MES). Decontamination was carried out according to standardized procedures. During the decontamination trials, the concentrations of the substances inside the units were measured. After decontamination, substances evaporating from test-persons and blankets as well as remaining amounts in the units were measured. RESULTS: The air concentrations of PEL and MES inside the units during decontamination in some cases exceeded short term exposure limits for most toxic industrial chemicals. This was a problem, especially during harmful wind conditions, i.e., wind blowing in the same direction as persons moving through the decontamination units. Although decontamination removed a greater part of the substances from the skin, the concentrations evaporating from some test-persons occasionally were high and potentially harmful if the substances had been toxic. The study also showed that blankets placed in the units absorbed chemicals and that the units still were contaminated five hours after the end of operations. CONCLUSIONS: After decontamination, the imitation substances still were present and evaporating from the contaminated persons, blankets, and units. These results indicate a need for improvements in technical solutions, procedures, and training. PMID- 23031628 TI - Individualisation or standardisation: trends in National Health Service prescription durations in England 1998-2009. AB - AIM: This study aims to evaluate changes in the durations of English National Health Service prescriptions, as indicated by the volumes of unit doses supplied between 1998 and 2009, and consider relevant policy implications. BACKGROUND: Around the world, countries are seeking to manage the increase in medicines prescribing. In England, many primary care organisations, using limited supporting evidence of cost-effectiveness and clinical improvement, have sought to restrict the number of dosage units on a prescription to 28 days supply. This is based on a conviction that this reduces wastage costs. METHODS: Prescription Cost Analysis (PCA) statistics for England for the period January 1998 to December 2009 were used to analyse trends in the average number of unit doses (tablets or capsules) supplied per prescription for 11 drugs supplied in 34 different presentations. FINDINGS: The changes in prescription lengths observed between 1999 and 2009 ranged from +4.2% in the case of Amoxicillin 500 mg capsules to -41.3% in the case of Levothyroxine 50 MUg tablets. All but four of the medicines selected showed statistically significant negative correlations (r > 0.8, P < 0.001) between the year of prescribing and the prescription length. If prescription lengths had been the same in 2009 as they were in 1999, then 33 million fewer prescription items would have been written for the preparations in this analysis. This shift across a range of medications suggests a generalised change in prescribing behaviour. The full balance of benefits and costs associated with this trend, as expressed via drug wastage avoided, patient (in)convenience experienced, professional time costs incurred or saved and positive or negative health outcome impacts, is not known. Although this study does not provide a definitive answer favouring prescription duration individualisation as opposed to standardisation, the available evidence indicates that policies that rigidly favour 28-day standard periods may require review. PMID- 23031629 TI - Delayed intranasal delivery of hypoxic-preconditioned bone marrow mesenchymal stem cells enhanced cell homing and therapeutic benefits after ischemic stroke in mice. AB - Stem cell transplantation therapy has emerged as a potential treatment for ischemic stroke and other neurodegenerative diseases. Effective delivery of exogenous cells and homing of these cells to the lesion region, however, have been challenging issues that hinder the efficacy and efficiency of cell-based therapy. In the present investigation, we tested a delayed treatment of noninvasive and brain-targeted intranasal delivery of bone marrow mesenchymal stem cells (BMSCs) in a mouse focal cerebral ischemia model. The investigation tested the feasibility and effectiveness of intranasal delivery of BMSCs to the ischemic cortex. Hypoxia preconditioning (HP) of BMSCs was performed before transplantation in order to promote their survival, migration, and homing to the ischemic brain region after intranasal transplantation. Hoechst dye-labeled normoxic- or hypoxic-pretreated BMSCs (1 * 10(6) cells/animal) were delivered intranasally 24 h after stroke. Cells reached the ischemic cortex and deposited outside of vasculatures as early as 1.5 h after administration. HP-treated BMSCs (HP-BMSCs) showed a higher level of expression of proteins associated with migration, including CXC chemokine receptor type 4 (CXCR4), matrix metalloproteinase 2 (MMP-2), and MMP-9. HP-BMSCs exhibited enhanced migratory capacities in vitro and dramatically enhanced homing efficiency to the infarct cortex when compared with normoxic cultured BMSCs (N-BMSCs). Three days after transplantation and 4 days after stroke, both N-BMSCs and HP-BMSCs decreased cell death in the peri-infarct region; significant neuroprotection of reduced infarct volume was seen in mice that received HP-BMSCs. In adhesive removal test of sensorimotor functional assay performed 3 days after transplantation, HP-BMSC treated mice performed significantly better than N-BMSC- and vehicle-treated animals. These data suggest that delayed intranasal administration of stem cells is feasible in the treatment of stroke and hypoxic preconditioning of transplanted cells, significantly enhances cell's homing to the ischemic region, and optimizes the therapeutic efficacy. PMID- 23031630 TI - Bilateral deep inferior epigastric perforator flaps based on unilateral perforators. AB - This report highlights the case of an unusual bilateral breast reconstruction using bilateral Deep Inferior Epigastric Perforator flaps based solely upon unilateral perforators. The usual lower paramedian perforating vessels were absent on one side and subsequently the main abdominal flap was split obliquely (rather than midline) to base both individual flaps on perforators arising from the same side. The operation was a success with no flap complications post operatively. PMID- 23031631 TI - Use of a pre-expanded "propeller" deep inferior epigastric perforator (DIEP) flap for a large abdominal wall defect. AB - Large abdominal wall soft tissue defects are traditionally reconstructed using loco-regional flaps and/or tissue expanders. Pedicled perforator flaps offer similar tissue coverage with minimal donor site morbidity and do not require microsurgical skills. The deep inferior epigastric perforator (DIEP) flap has become increasingly popular for breast reconstruction and offers abundant soft tissue while permitting primary donor site closure. To minimize operative sessions, recovery time, donor site morbidity, and avoid microsurgery, we combined tissue expansion with a "propeller" flap design and report this first case of a pre-expanded pedicled perforator flap based on the DIEP to address a large abdominal wall defect due to a burn injury. PMID- 23031632 TI - The treatment of melasma by silymarin cream. AB - BACKGROUND: Melasma is an acquired increased pigmentation of the skin characterized by symmetrical and confluent grey-brown patches usually on the areas of the face exposed to the sun. Silymarin strongly prevents photocarcinogenesis, and significantly prevented melanin production. The objectives of this study were the assessment of safety and efficacy of topical Silymain (SM) cream in a double-blind placebo controlled study for treatment of melasma patients. METHODS: Experimentally on 24 Albino rabbits were randomly divided into 4 equal groups. [A] No treatment, [B] received placebo, [C] treated with SM cream (0.1), & [D] treated by SM (0.2), were applied topically before UV sun light exposure for 30 days, assessed clinically & tissue pathology. Clinically on 96 adults diagnosed with melasma randomized to three equal groups to receive one of the tested drugs applied twice daily for 4 weeks, evaluated by the response; lesion size, melasma area and severity index score, Physician global assessment, and subjective assessment. RESULTS: The Clinical and histopathology observations were reduced significantly in SM groups. Clinically; all patients showed significant excellent pigment improvement & lesion size reduction with SM treatments from the 1st week. All patients were fully satisfied 100%. No side effects were observed. CONCLUSIONS: Silymarin showed tremendous improvement of melasma in a dose-dependent manner, and was effective in prevention of skin damage caused by U.V. sunlight. It is a safe new candidate effective treatment for melasma. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN12612000602820. PMID- 23031633 TI - A blood test for acute rejection after renal transplantation? Commentary on "Osteopontin level correlates with acute cellular renal allograft rejection". PMID- 23031634 TI - Bioavailability of zinc sources and their interaction with phytates in broilers and piglets. AB - Zinc (Zn) is essential for swine and poultry and native Zn concentrations in feedstuffs are too low to meet their Zn requirement. Dietary Zn bioavailability is affected by phytate, phytase and Zn supplemented in organic form is considered as more bioavailable than inorganic sources. A meta-analysis using GLM procedures was processed using broiler and piglet databases to investigate, within the physiological response of Zn, (1) the bioavailability of inorganic and organic Zn sources (Analysis I); (2) the bioavailability of native and inorganic Zn dependent from dietary phytates, vegetal and supplemental phytase activity (Analysis II). Analysis I: the bioavailability of organic Zn relative to inorganic Zn sources ranged, depending on the variable, from 85 to 117 never different from 100 (P > 0.05). The coefficients of determination of the regressions were 0.91 in broilers and above 0.89 in piglets. Analysis II: in broilers, bone Zn was explained by supplemental Zn (linear and quadratic, P < 0.001) and by supplemental phytase (linear, P < 0.001). In piglets, the interaction between dietary Zn and phytates/phytases was investigated by means of a new variable combining dietary phytic phosphorus (PP) and phytase activity. This new variable represents the remaining dietary PP after its hydrolysis in the digestive tract, mainly due to phytase and is called non-hydrolyzed phytic phosphorus (PP(NH)). Bone Zn was increased with native Zn (P < 0.001), but to a lower extent in high PP or low phytase diets (ZN(N) * PP(NH), P < 0.001). In contrast, the increase in bone zinc in response to supplemental Zn (P < 0.001) was not modulated by PP(NH) (P > 0.05). The coefficients of determination of the regressions were 0.92 in broilers and above 0.92 in piglets. The results from the two meta-analyses suggest that (1) broilers and piglets use supplemented Zn, independent from Zn source; (2) broiler use native Zn and the use is slightly enhanced with supplemental phytase; (3) however, piglets are limited in the use of native Zn because of the antagonism of non-hydrolyzed dietary phytate. This explains the higher efficacy of phytase in improving Zn availability in this specie. PMID- 23031635 TI - Hip abduction weakness in elite junior footballers is common but easy to correct quickly: a prospective sports team cohort based study. AB - BACKGROUND: Hip abduction weakness has never been documented on a population basis as a common finding in a healthy group of athletes and would not normally be found in an elite adolescent athlete. This study aimed to show that hip abduction weakness not only occurs in this group but also is common and easy to correct with an unsupervised home based program. METHODS: A prospective sports team cohort based study was performed with thirty elite adolescent under-17 Australian Rules Footballers in the Australian Institute of Sport/Australian Football League Under-17 training academy. The players had their hip abduction performance assessed and were then instructed in a hip abduction muscle training exercise. This was performed on a daily basis for two months and then they were reassessed. RESULTS: The results showed 14 of 28 athletes who completed the protocol had marked weakness or a side-to-side difference of more than 25% at baseline.Two months later ten players recorded an improvement of >= 80% in their recorded scores. The mean muscle performance on the right side improved from 151 Newton (N) to 202 N (p<0.001) while on the left, the recorded results improved from 158 N to 223 N (p<0.001). CONCLUSIONS: The baseline values show widespread profound deficiencies in hip abduction performance not previously reported. Very large performance increases can be achieved, unsupervised, in a short period of time to potentially allow large clinically significant gains. This assessment should be an integral part of preparticipation screening and assessed in those with lower limb injuries. This particular exercise should be used clinically and more research is needed to determine its injury prevention and performance enhancement implications. PMID- 23031637 TI - Immunization with a peptide of Semliki Forest virus promotes remyelination in experimental autoimmune encephalomyelitis. AB - Remyelination is one of the elusive topics in treatment of multiple sclerosis (MS). Our previous studies have shown that Semliki Forest virus (SFV)-infected delta-knock-out (KO) mice did not exhibit the extensive remyelination, seen in wild type (WT) B6 mice, after viral clearance and demyelination. The Remyelination in SFV-infected WT mice started on day 15 and was completed by day 35 post-infection (pi), whereas the KO mice remained partially demyelinated through day 42 pi. Treatment with E2 peptide2 in incomplete Freund's adjuvant (IFA), resulted in higher antibody production and earlier remyelination in SFV infected KO (day 28 pi), than WT mice. This finding suggested that anti-E2 peptide2 antibody could play a part in remyelination. In the current study, the effect of E2 peptide2 treatment was evaluated in the experimental autoimmune encephalomyelitis (EAE) model. Mice with established EAE were treated with E2 peptide2 in IFA to develop antibody. Treated EAE mice made significantly higher anti-E2 peptide2 antibody than untreated EAE group. Average clinical disease scores were significantly lower in peptide treated compared to untreated EAE mice. Furthermore, histopathological and immunohistochemical studies demonstrated increased remyelinating areas and higher number of activated oligodendrocytes and astrocytes, in treated compared to untreated EAE groups. Moreover, the anti-E2 peptide2 antibody showed higher binding to the myelinated areas of treated than untreated EAE mice. We conclude that treatment with, or antibody to, SFV E2 peptide2 triggers some mechanism that promotes remyelination. PMID- 23031638 TI - Recent developments in altering the fatty acid composition of ruminant-derived foods. AB - There is increasing evidence to indicate that nutrition is an important factor involved in the onset and development of several chronic human diseases including cancer, cardiovascular disease (CVD), type II diabetes and obesity. Clinical studies implicate excessive consumption of medium-chain saturated fatty acids (SFA) and trans-fatty acids (TFA) as risk factors for CVD, and in the aetiology of other chronic conditions. Ruminant-derived foods are significant sources of medium-chain SFA and TFA in the human diet, but also provide high-quality protein, essential micronutrients and several bioactive lipids. Altering the fatty acid composition of ruminant-derived foods offers the opportunity to align the consumption of fatty acids in human populations with public health policies without the need for substantial changes in eating habits. Replacing conserved forages with fresh grass or dietary plant oil and oilseed supplements can be used to lower medium-chain and total SFA content and increase cis-9 18:1, total conjugated linoleic acid (CLA), n-3 and n-6 polyunsaturated fatty acids (PUFA) to a variable extent in ruminant milk. However, inclusion of fish oil or marine algae in the ruminant diet results in marginal enrichment of 20- or 22-carbon PUFA in milk. Studies in growing ruminants have confirmed that the same nutritional strategies improve the balance of n-6/n-3 PUFA, and increase CLA and long-chain n-3 PUFA in ruminant meat, but the potential to lower medium-chain and total SFA is limited. Attempts to alter meat and milk fatty acid composition through changes in the diet fed to ruminants are often accompanied by several fold increases in TFA concentrations. In extreme cases, the distribution of trans 18:1 and 18:2 isomers in ruminant foods may resemble that of partially hydrogenated plant oils. Changes in milk fat or muscle lipid composition in response to diet are now known to be accompanied by tissue-specific alterations in the expression of one or more lipogenic genes. Breed influences both milk and muscle fat content, although recent studies have confirmed the occurrence of genetic variability in transcript abundance and activity of enzymes involved in lipid synthesis and identified polymorphisms for several key lipogenic genes in lactating and growing cattle. Although nutrition is the major factor influencing the fatty acid composition of ruminant-derived foods, further progress can be expected through the use of genomic or marker-assisted selection to increase the frequency of favourable genotypes and the formulation of diets to exploit this genetic potential. PMID- 23031639 TI - Characterization and analytical application of Morin - bovine serum albumin system by spectroscopic approaches. AB - It is found that the fluorescence intensity of Morin can be strongly quenched by proteins. Based on this, a new fluorimetric method for the determination of protein was developed. Under optimum conditions, the quenchment of Morin fluorescence was in proportion to the concentration of proteins in the range 0.0001-0.1000 g.L(-1) for bovine serum albumin (BSA) and 0.0005-0.1000 g.L(-1) for human serum albumin (HSA). The reaction mechanism indicates that proteins can bind with Morin at the 3-hydroxyl and the 4-carbonyl and form a non-fluorescence complex 4:1 molar ratio of Morin/BSA, which results in the fluorescence of Morin and BSA are all quenched. PMID- 23031636 TI - Establishing causality for dopamine in neural function and behavior with optogenetics. AB - Dopamine (DA) is known to play essential roles in neural function and behavior. Accordingly, DA neurons have been the focus of intense experimental investigation that has led to many important advances in our understanding of how DA influences these processes. However, it is becoming increasingly appreciated that delineating the precise contributions of DA neurons to cellular, circuit, and systems-level phenomena will require more sophisticated control over their patterns of activity than conventional techniques can provide. Specifically, the roles played by DA neurons are likely to depend on their afferent and efferent connectivity, the timing and length of their neural activation, and the nature of the behavior under investigation. Recently developed optogenetic tools hold great promise for disentangling these complex issues. Here we discuss the use of light sensitive microbial opsins in the context of outstanding questions in DA research. A major technical advance offered by these proteins is the ability to bidirectionally modulate DA neuron activity in in vitro and in vivo preparations on a time scale that more closely approximates those of neural, perceptual and behavioral events. In addition, continued advances in rodent genetics and viral mediated gene delivery have contributed to the ability to selectively target DA neurons or their individual afferent and efferent connections. Further, these tools are suitable for use in experimental subjects engaged in complex behaviors. After reviewing the strengths and limitations of optogenetic methodologies, we conclude by describing early efforts in the application of this valuable new approach that demonstrate its potential to improve our understanding of the neural and behavioral functions of DA. This article is part of a Special Issue entitled Optogenetics (7th BRES). PMID- 23031640 TI - Spectroscopic and quantum chemical investigation on non-covalent interaction in chromophore appended fullerene complexes of calix[4]arene. AB - The present paper describes the spectroscopic and theoretical insights on non covalent interaction of a calix[4]arene molecule, namely, 4-iso-propyl calix[4]arene (1) with chromophore appended fullerenes, namely, tert-butyl-(1,2 methanofullerene)-61-carboxylate (2) and [6,6]-phenyl-C(71)- butyric acid methyl ester (3) in solvents having varying polarity, viz., toluene and benzonitrile. Absorption spectrophotometric studies reveal appreciable ground state interaction between fullerenes and 1. The most fascinating feature of the present study is that 1 binds very effectively with both 2 and 3 as obtained from binding constant (K) data of such complexes; i.e., K(2-1) and K(3-1) exhibit value of 4.53 * 10(5) dm(3) mol(-1) (7.95 * 10(5) dm(3) mol(-1)) and 13.35 * 10(5) dm(3) mol(-1) (27.62 * 10(5) dm(3) mol(-1)) in toluene (benzonitrile), respectively. The effect of solvent over the complexation between fullerenes and 1 is clearly observed from the trend in the K values. Estimation of solvent reorganization energy (R(S)) evokes that both 2-1 and 3-1 complexes are stabilized more in toluene compared to benzonitrile. Molecular mechanics force field (MMMF) calculations in vacuo evoke geometrical structures of the 2-1 and 3-1 complexes and reveal interesting feature regarding binding pattern of fullerenes toward 1 in terms of heat of formation value of the respective complexes. PMID- 23031641 TI - Comparison of spherical aberration and small-pupil profiles in improving depth of focus for presbyopic corrections. AB - PURPOSE: To compare the validity and effectiveness of 2 methods for expanding depth of focus to correct for presbyopia; that is, induction of spherical aberration and small-pupil apertures. SETTING: University of California, Berkeley, California, USA. DESIGN: Comparative case series. METHODS: A random 4 alternative forced-choice acuity task was performed on 13 subjects. Visual performance and depth of focus were compared using adaptive optics-corrected distance visual acuity (CDVA) values and mean visual acuity over a 3.0 diopter (D) range of defocus using the following 3 adaptive optics-corrected profiles: 2.0 mm pupil, 5.0 mm pupil, and 5.0 mm pupil with -0.274 MUm of spherical aberration. RESULTS: The 5.0 mm pupil profile had a CDVA of -0.218 logMAR and a mean visual acuity through focus of 0.156 logMAR. The 2.0 mm pupil profile had a worse CDVA (0.012 logMAR) but an improved mean visual acuity (0.061 logMAR). The 5.0 mm pupil profile with -0.274 MUm of spherical aberration measured a CDVA of 0.082 logMAR and a mean visual acuity of 0.103 logMAR. CONCLUSIONS: The spherical aberration and small-pupil profiles improved the mean visual acuity across a 3.0 D range of defocus but resulted in decreased CDVA at the plane of best focus in comparison to an adaptive optics-corrected 5.0 mm pupil. Small-pupil profiles are a better choice than spherical aberration profiles for presbyopic corrections due to expected accuracy, predictability, and patient satisfaction. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23031644 TI - Diffuse nesidioblastosis with hypoglycemia mimicking an insulinoma: a case report. AB - INTRODUCTION: We describe a case of diffuse nesidioblastosis in an adult patient who presented with exclusively fasting symptoms and a focal pancreatic 111In pentetreotide uptake mimicking an insulinoma. CASE PRESENTATION: A 23-year-old Caucasian man had severe daily fasting hypoglycemia with glucose levels below 2mmol/L. Besides rare neuroglycopenic symptoms (confusion, sleepiness), he was largely asymptomatic. His investigations revealed low venous plasma glucose levels, high insulin and C-peptide levels and a 72-hour fast test that were all highly suggestive for an insulinoma. Abdominal computed tomography and magnetic resonance imaging did not reveal any lesions. The sole imagery that was compatible with an insulinoma was a 111In-somatostatin receptor scintigraphy that showed a faint but definite focal tracer between the head and the body of the pancreas. However, this lesion could not be confirmed by endoscopic ultrasonography of the pancreas. Following duodenopancreatectomy, the histological findings were consistent with diffuse nesidioblastosis. Postoperatively, the patient continued to present with fasting hypoglycemia and was successfully treated with diazoxide. CONCLUSION: In the absence of gastrointestinal surgery, nesidioblastosis is very rare in adults. In addition, nesidioblastosis is usually characterized by post-prandial hypoglycemia, whereas this patient presented with fasting hypoglycemia. This case also illustrates the risk for a false positive result of 111In-pentetreotide scintigraphy in the case of nesidioblastosis. Selective arterial calcium stimulation and venous sampling is the most reliable procedure for the positive diagnosis of insulinoma or nesidioblastosis and should be used to confirm any suspicion based on imaging modalities. PMID- 23031642 TI - A connecter-like factor, CacA, links RssB/RpoS and the CpxR/CpxA two-component system in Salmonella. AB - BACKGROUND: Bacteria integrate numerous environmental stimuli when generating cellular responses. Increasing numbers of examples describe how one two-component system (TCS) responds to signals detected by the sensor of another TCS. However, the molecular mechanisms underlying this phenomenon remain poorly defined. RESULTS: Here, we report a connector-like factor that affects the activity of the CpxR/CpxA two-component system in Salmonella enterica serovar Typhimurium. We isolated a clone that induced the expression of a cpxP-lac gene fusion from a high-copy-number plasmid pool of random Salmonella genomic fragments. A 63-amino acid protein, CacA, was responsible for the CpxA/CpxR-dependent activation of the cpxP gene. The CpxR-activated genes cpxP and spy exhibited approximately 30% and 50% reductions in transcription, respectively, in a clean cacA deletion mutant strain in comparison to wild-type. From 33 response regulator (RR) deletion mutants, we identified that the RssB regulator represses cacA transcription. Substitution mutations in a conserved -10 region harboring the RNA polymerase recognition sequence, which is well conserved with a known RpoS -10 region consensus sequence, rendered the cacA promoter RpoS-independent. The CacA mediated induction of cpxP transcription was affected in a trxA deletion mutant, which encodes thioredoxin 1, suggesting a role for cysteine thiol-disulfide exchange(s) in CacA-dependent Cpx activation. CONCLUSIONS: We identified CacA as an activator of the CpxR/CpxA system in the plasmid clone. We propose that CacA may integrate the regulatory status of RssB/RpoS into the CpxR/CpxA system. Future investigations are necessary to thoroughly elucidate how CacA activates the CpxR/CpxA system. PMID- 23031643 TI - Expression of myeloid differentiation factor 88 in neurons is not requisite for the induction of sickness behavior by interleukin-1beta. AB - BACKGROUND: Animals respond to inflammation by suppressing normal high-energy activities, including feeding and locomotion, in favor of diverting resources to the immune response. The cytokine interleukin-1 beta (IL-1beta) inhibits normal feeding and locomotor activity (LMA) via its actions in the central nervous system (CNS). Behavioral changes in response to IL-1beta are mediated by myeloid differentiation factor 88 (MyD88) in non-hematopoietic cells. It is unknown whether IL-1beta acts directly on neurons or requires transduction by non neuronal cells. METHODS: The Nestin-cre mouse was crossed with MyD88lox mice to delete MyD88 from neurons and glia in the CNS (MyD88DeltaCNS). These mice were compared to total body MyD88KO and wild type (WT) mice. Mice had cannulae stereotactically placed in the lateral ventricle and telemetry transponders implanted into the peritoneum. Mice were treated with either intracerebroventricular (i.c.v.) IL-1beta (10 ng) or vehicle. Food intake, body weight and LMA were continuously monitored for 24 h after treatment. I.c.v. tumor necrosis factor (TNF), a MyD88-independent cytokine, was used to control for normal immune development. Peripheral inflammation was modeled using intraperitoneal lipopolysaccharide (LPS). Groups were compared using two-way ANOVA with Bonferroni post-test. Efficacy of recombination was evaluated using tdTomato reporter mice crossed with the Nestin-cre mouse. MyD88 deletion was confirmed by Western blot. RESULTS: I.c.v. IL-1beta treatment caused a significant reduction in feeding, body weight and LMA in WT mice. MyD88KO mice were protected from these changes in response to i.c.v. IL-1beta despite having intact behavioral responses to TNF. Cre-mediated recombination was observed in neurons and astrocytes, but not microglia or endothelial cells. In contrast to MyD88KO mice, the behavioral responses of MyD88DeltaCNS mice to i.c.v. IL-1beta or intraperitoneal (i.p.) LPS were indistinguishable from those of WT mice. CONCLUSION: Sickness behavior is mediated by MyD88 and is dependent on the activity of cytokines within the brain. Our results demonstrate that MyD88 is not required in neurons or astrocytes to induce this behavioral response to IL-1beta or LPS. This suggests that a non-Nestin expressing cell population responds to IL 1beta in the CNS and transduces the signal to neurons controlling feeding and activity. PMID- 23031645 TI - Effects of feeding finisher pigs with chicory or lupine feed for one week or two weeks before slaughter with respect to levels of Bifidobacteria and Campylobacter. AB - This study aimed to assess whether inclusion of chicory or lupine (prebiotics) in the diet of pre-slaughter pigs for just 1 or 2 weeks could change the composition of their intestinal microbiota, stimulate the growth of bifidobacteria and help to lower the amount of thermoplilic Campylobacter spp. (mainly Campylobacter jejuni and Campylobacter coli), which are a major cause of food-borne infections in humans. A total of 48 pigs that had an initial live weight of 90 kg were fed with either a lupine (organic concentrate with 25% blue lupine seeds), chicory (organic concentrate with 10% dried chicory roots) or control (100% organic concentrate) diet for 1 week (24 pigs) or 2 weeks (24 pigs) before slaughter. The Campylobacter spp. level in rectal faecal samples after 0, 1 and 2 weeks of feeding and in the luminal content from ileum, caecum and colon at slaughter was determined by direct plating on modified charcoal-cefoperazone-deoxycholate agar plates. DNA extracted from the luminal content of distal ileum and caecum was used for terminal restriction fragment length polymorphism (T-RFLP) analysis of the composition of intestinal microbiota and for measuring the amount of bifidobacterial and total bacterial DNA by quantitative real-time PCR (qPCR). Campylobacter spp. were excreted by all pigs and present in the luminal content from distal ileum to midway colon with particularly high numbers in the caecum, but the excretion was reduced by 10-fold in pigs fed lupines for 1 week as compared with control- and chicory-fed pigs (mean log(10) 2.9 v. 4.1 CFU/g; P < 0.05). The qPCR analysis showed that feeding with lupines resulted in higher levels of bifidobacteria in caecum as compared with the other diets (P < 0.05). T RFLP analysis showed that four of the most abundant bacteria with terminal restriction fragment values >5% relative to the intensity of total abundance differed between the feed treatments (P < 0.05). Therefore, this study showed that even a short-term alternative feeding strategy with prebiotics in the diet of pre-slaughter pigs elicited changes in the composition of the intestinal microbiota, where lupine increased the level of bifidobacteria in caecum and reduced the Campylobacter spp. excretion level after 1 week. PMID- 23031646 TI - Stress responses to comparative handling procedures in sheep. AB - The objective of this study was to compare some husbandry procedures on the base of physiological stress parameters and evaluate the welfare status in sheep. Forty ewes were used as the study material. Measurements were taken during several routine husbandry procedures such as milking, shearing, weighing, loading and hoof care. Data regarding time spent for each application, as well as heart and respiratory rates were recorded during the applications. Blood samples were taken 15 min before and after each application and malondialdehyde (MDA), glutathione-peroxidase (GSH-Px), cortisol T(3) and T(4) parameters were measured. In addition, changes in the same parameters between pre- and post-application periods were evaluated. According to the results, machine milking caused less stress than hand milking. No significant difference was seen between shearing methods for hand shearer or clipper; however, both applications caused stress in animals. The results for weighing methods of animals demonstrated significant differences in cortisol, T(3) and T(4) values in favor of traditional method. Cortisol, T(3) and T(4) levels were significantly higher in manual loading compared with loading by ramp. Regarding hoof care, all the examined parameters differed in favor of modern method. On the other hand, significant differences were determined between the stress parameters regarding pre- and post applications. All values differed for hand milking while no significant difference was observed in MDA and T(3) values in machine milking group. Parameters in weighing groups changed significantly. For loading process, GSH, cortisol, T(3) and T(4) values differed in both treatment groups. With regard to hoof care, parameters except T(4) in laying group differed significantly. An increase occurred in minute-based measurements of heart and respiratory rates parallel to physiological data. The number of the respiratory rates during the applications differed except for the shearing process. All the parameters displayed significant differences between groups in terms of heart rates. Time spent for each application also differed between groups. Time saved for milking, shearing, weighing, loading and hoof care was 3.23 min, 4.37 min, 1.71 min, 7.85 s and 1.55 min, respectively. These results appear to provide a tangible advantage of using new husbandry methods to the breeders. It was concluded that using new methods in sheep husbandry procedures provided advantages in terms of saving time and reducing labor, as well as improved conditions for welfare of animals. In addition, it facilitated the routine works and flock husbandry. PMID- 23031647 TI - Screening for distress, the 6th vital sign: common problems in cancer outpatients over one year in usual care: associations with marital status, sex, and age. AB - BACKGROUND: Very few studies examine the longitudinal prevalence of problems and the awareness or use of clinical programs by patients who report these problems. Of the studies that examine age, gender and marital status as predictors of a range of patient outcomes, none examines the interactions between these demographic variables. This study examined the typical trajectory of common practical and psychosocial problems endorsed over 12 months in a usual-care sample of cancer outpatients. Specifically, we examined whether marital status, sex, age, and their interactions predicted these trajectories. We did not actively triage or refer patients in this study in order to examine the natural course of problem reports. METHODS: Patients completed baseline screening (N = 1196 of 1707 approached) and the sample included more men (N = 696) than women (N = 498), average age 61.1 years. The most common diagnoses were gastrointestinal (27.1%), prostate (19.2%), skin (11.1%) and gynecological (9.2%). Among other measures, patients completed a Common Problem Checklist and Psychosocial Resources Use questions at baseline, 3, 6, and 12 months using paper and pencil surveys. RESULTS: Results indicated that patients reported psychosocial problems more often than practical and both decreased significantly over time. Younger single patients reported more practical problems than those in committed relationships. Younger patients and women of all ages reported more psychosocial problems. Among a number of interesting interactions, for practical problems, single older patients improved more; whereas among married people, younger patients improved more. For psychosocial problems we found that older female patients improved more than younger females, but among males, it was younger patients who improved more. Young single men and women reported the most past-and future-use of services. CONCLUSIONS: Younger women are particularly vulnerable to experiencing practical and psychosocial problems when diagnosed with cancer, but being married protects these younger women. Marriage appeared to buffer reports of both practical and psychosocial problems, and led to less awareness and use of services. Unexpectedly, young men reported the highest use of psychosocial services. This study informs clinical program development with information on these risk groups. PMID- 23031648 TI - Role of the side chain stereochemistry in the alpha-glucosidase inhibitory activity of kotalanol, a potent natural alpha-glucosidase inhibitor. Part 2. AB - To examine the role of the side chain of kotalanol (2), a potent natural alpha glucosidase inhibitor isolated from Salacia reticulata, on inhibitory activity, four diastereomers (11a-11d) with reversed configuration (S) at the C-4' position in the side chain were synthesized and evaluated. Two of the four (11b and 11d) significantly lost their inhibitory activity against both maltase and sucrase, while the other two (11a and 11c) sustained the inhibitory activity to a considerable extent, showing distinct activity in response to the change of stereochemistry of the hydroxyls at the 5'and 6' positions. Different activities were rationalized with reference to in silico docking studies on these inhibitors with hNtMGAM. Against isomaltase, all four analogs showed potent inhibitory activity as well as 2, and 11b and 11d exhibited enzyme selectivity. PMID- 23031649 TI - The therapeutic journey of benzimidazoles: a review. AB - Presence of benzimidazole nucleus in numerous categories of therapeutic agents such as antimicrobials, antivirals, antiparasites, anticancer, anti-inflammatory, antioxidants, proton pump inhibitors, antihypertensives, anticoagulants, immunomodulators, hormone modulators, CNS stimulants as well as depressants, lipid level modulators, antidiabetics, etc. has made it an indispensable anchor for development of new therapeutic agents. Varied substitutents around the benzimidazole nucleus have provided a wide spectrum of biological activities. Importance of this nucleus in some activities like, Angiotensin I (AT(1)) receptor antagonism and proton-pump inhibition is reviewed separately in literature. Even some very short reviews on biological importance of this nucleus are also known in literature. However, owing to fast development of new drugs possessing benzimidazole nucleus many research reports are generated in short span of time. So, there is a need to couple the latest information with the earlier information to understand the current status of benzimidazole nucleus in medicinal chemistry research. In the present review, various derivatives of benzimidazole with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole derived compounds for each activity. This discussion will further help in the development of novel benzimidazole compounds. PMID- 23031651 TI - Hypothetical constructs, hypothetical questions, and the expert witness. AB - Professor John Henry Wigmore in 1940 described the hypothetical question as an intolerable obstruction of truth. Since that time, the nature and application of the hypothetical question in the courtroom, as well as responses to this line of questioning during expert testimony, have been sources of controversy. Governed by legal philosophical foundations, the hypothetical construct addresses what there is, in a general sense, and what can or ought to be. Alexy (2004) has described the nature of legal philosophy as the epistemological question of what we can know. This article begins by examining the philosophical underpinnings, legal parameters, and teaching purposes of posing hypothetical queries. A social psychological backdrop for the use of hypothetical questions is then discussed followed by a broader discussion of the hypothetical question's role in court procedures. This paper identifies hypothetical questions used in court as devices to elicit information, or as predictions that potentially change underlying factual interpretations of evidence. In particular, on cross examination hypothetical questions seek to make opposing experts assume facts that are incongruent with their conclusions or opinions. Sometimes in these situations, experts are led to re-evaluate opinions based on alternative understandings of events and behaviors. Thus, this paper's final aim is to explore a foundational understanding of hypothetical questions asked of expert witnesses with special reference to mental health issues. Options for responding to hypothetical questions on the stand are considered along the dimensions of assertiveness passivity, compliance-resistance, and possible redefinitions of the hypothetical issues. PMID- 23031650 TI - Proteomic analysis reveals the diversity and complexity of membrane proteins in chickpea (Cicer arietinum L.). AB - BACKGROUND: Compartmentalization is a unique feature of eukaryotes that helps in maintaining cellular homeostasis not only in intra- and inter-organellar context, but also between the cells and the external environment. Plant cells are highly compartmentalized with a complex metabolic network governing various cellular events. The membranes are the most important constituents in such compartmentalization, and membrane-associated proteins play diverse roles in many cellular processes besides being part of integral component of many signaling cascades. RESULTS: To obtain valuable insight into the dynamic repertoire of membrane proteins, we have developed a proteome reference map of a grain legume, chickpea, using two-dimensional gel electrophoresis. MALDI-TOF/TOF and LC-ESI MS/MS analysis led to the identification of 91 proteins involved in a variety of cellular functions viz., bioenergy, stress-responsive and signal transduction, metabolism, protein synthesis and degradation, among others. Significantly, 70% of the identified proteins are putative integral membrane proteins, possessing transmembrane domains. CONCLUSIONS: The proteomic analysis revealed many resident integral membrane proteins as well as membrane-associated proteins including those not reported earlier. To our knowledge, this is the first report of membrane proteome from aerial tissues of a crop plant. The findings may provide a better understanding of the biochemical machinery of the plant membranes at the molecular level that might help in functional genomics studies of different developmental pathways and stress-responses. PMID- 23031652 TI - Challenges in the nutrition and management of herbivores in the temperate zone. AB - The expected higher global demand for animal proteins and the competition for starch and sugars between food, fuel and feed seem to favour herbivores that convert solar energy captured in fibrous plants into animal products. However, the required higher production level of herbivores questions the sustainability of this conversion. An increase in herbivore production can be achieved by increasing the number of animals associated with the increasing demand of plant biomass or by improving the efficiency with which plant biomass is converted into meat and milk. The potential to increase food production by cattle, the main food producing herbivore in the temperate zones outside China, was considered in three production systems: grassland-based, mixed rain-fed and mixed irrigated systems. The potential to increase plant biomass production in grassland-based systems seems limited, unless fertiliser is imported in large quantities and crop production is increased, sacrificing valuable, high-quality grasslands, which often conflicts with sustainable production methods. Also, in mixed systems with high inputs of fertiliser or water, improvements in plant biomass production seem marginal and the main challenges for these systems are in breeding high-quality plant biomass at lower levels of fertiliser and the use of new co-products from food processing and bio-based economies. Consequently, the main challenge in herbivore nutrition management is to improve the efficiency of plant biomass utilisation. Stocking rate management along with seasonal variation in the grazing capacity of grasslands and moderate use of fertiliser may increase meat production in grassland-based systems by 400%. Improving plant biomass utilisation in the more industrialised mixed rain-fed systems seems possible by better feed storage technologies and for dairy cattle by improving animal health and lifetime production level. Managing the transition period seems crucial to achieve more sustainable mixed rain-fed and mixed irrigated dairy production systems. Whether sustainable production methods will be implemented also depends on macro-economic conditions and awareness of regional and global environmental concerns. PMID- 23031653 TI - Reply to Dr. Yamamoto's letter. PMID- 23031654 TI - Structural and mechanistic investigations on Salmonella typhimurium acetate kinase (AckA): identification of a putative ligand binding pocket at the dimeric interface. AB - BACKGROUND: Bacteria such as Escherichia coli and Salmonella typhimurium can utilize acetate as the sole source of carbon and energy. Acetate kinase (AckA) and phosphotransacetylase (Pta), key enzymes of acetate utilization pathway, regulate flux of metabolites in glycolysis, gluconeogenesis, TCA cycle, glyoxylate bypass and fatty acid metabolism. RESULTS: Here we report kinetic characterization of S. typhimurium AckA (StAckA) and structures of its unliganded (Form-I, 2.70 A resolution) and citrate-bound (Form-II, 1.90 A resolution) forms. The enzyme showed broad substrate specificity with k(cat)/K(m) in the order of acetate > propionate > formate. Further, the Km for acetyl-phosphate was significantly lower than for acetate and the enzyme could catalyze the reverse reaction (i.e. ATP synthesis) more efficiently. ATP and Mg(2+) could be substituted by other nucleoside 5'-triphosphates (GTP, UTP and CTP) and divalent cations (Mn(2+) and Co(2+)), respectively. Form-I StAckA represents the first structural report of an unliganded AckA. StAckA protomer consists of two domains with characteristic betabetabetaalphabetaalphabetaalpha topology of ASKHA superfamily of proteins. These domains adopt an intermediate conformation compared to that of open and closed forms of ligand-bound Methanosarcina thermophila AckA (MtAckA). Spectroscopic and structural analyses of StAckA further suggested occurrence of inter-domain motion upon ligand-binding. Unexpectedly, Form-II StAckA structure showed a drastic change in the conformation of residues 230-300 compared to that of Form-I. Further investigation revealed electron density corresponding to a citrate molecule in a pocket located at the dimeric interface of Form-II StAckA. Interestingly, a similar dimeric interface pocket lined with largely conserved residues could be identified in Form-I StAckA as well as in other enzymes homologous to AckA suggesting that ligand binding at this pocket may influence the function of these enzymes. CONCLUSIONS: The biochemical and structural characterization of StAckA reported here provides insights into the biochemical specificity, overall fold, thermal stability, molecular basis of ligand binding and inter-domain motion in AckA family of enzymes. Dramatic conformational differences observed between unliganded and citrate-bound forms of StAckA led to identification of a putative ligand-binding pocket at the dimeric interface of StAckA with implications for enzymatic function. PMID- 23031656 TI - The safety of codeine in patients with non-steroidal anti-inflammatory drug hypersensitivity: a preliminary study. AB - BACKGROUND: Drug provocation testing should be performed before safely prescribing an analgesic for patients that are hypersensitive to non-steroidal anti-inflammatory drugs (NSAIDs). Whether or not the direct histamine releasing effect of codeine renders it useful in NSAID-hypersensitive patients is unknown. This study aimed to determine if codeine could be recommended as a safe treatment option for NSAID-hypersensitive patients without the need for oral drug provocation testing. METHODS: The study included NSAID-hypersensitive patients with and without concurrent asthma, rhinitis, and chronic urticaria that presented to the allergy clinic between 1 January 1991 and 31 December 2010. Patient data were collected from the allergy clinic computer database. Patients challenged with codeine were included in the codeine group. The non-codeine group included those patients that were tested with analgesics other than codeine. RESULTS: In total, data for 1071 patients, of whom 301 were in the codeine group, were analysed. The reaction rate to codeine was 7.3% and when compared in pairs, the rate was significantly lower than to meloxicam and nimesulide (odds ratios=0.26-0.31, respectively). The reaction rate to codeine did not differ from that to benzydamine, rofecoxib, and paracetamol. Symptomatic dermographism was associated (p=0.009) with test positivity to any drug. CONCLUSIONS: Although, codeine was among the safest alternative drugs and none of the patients had an anaphylactic reaction to it, thus a challenge with codeine may be considered especially in patients with dermographism. The results of this preliminary study should be confirmed in a prospective study including a control group. PMID- 23031655 TI - Knowledge and attitudes of primary care physicians regarding food allergy and anaphylaxis in Turkey. AB - BACKGROUND: Food allergy, which becomes an important public health problem, can lead to important morbidity and mortality. Patients with food allergies are more likely to first present to their primary care physicians. We aimed to determine the knowledge of primary care physicians with regard to management of food allergies and anaphylaxis. METHODS: Primary care physicians were surveyed via a questionnaire aimed to document their knowledge and attitudes about food allergy and anaphylaxis management. RESULTS: A total of 297 participants completed questionnaires, 55.6% of which were female. Participating physicians had a mean of 17.0 +/- 6.1 years of experience. Participants answered 47.2% of knowledge based items correctly. Overall, participants fared poorly with regard to their knowledge on the treatment of food allergies and anaphylaxis. For example while 60.7% knew that a child can die from the milk allergy reaction, only 37.5% were aware that a child with IgE mediated milk allergies cannot eat yoghourts/cheese with milk. Besides, 53.1% of them chose epinephrine as their first treatment of choice in case of anaphylaxis, yet only 16.6% gave the correct answer about its dosage. Nearly a third of participants (36.7%) felt they were knowledgeable enough regarding the management of patients with food allergies, while 98.2% extended their request for future periodic educational meetings on allergic disorders. CONCLUSION: Knowledge of food allergy and anaphylaxis among primary care physicians was unsatisfactory. Provision or periodic educational programmes should be aimed at improving the standard of practice as acknowledged by the participants. PMID- 23031657 TI - Efficacy and safety of once daily triamcinolone acetonide aqueous nasal spray in adults with non-allergic and allergic rhinitis. AB - BACKGROUND: The efficacy of corticosteroid has not been thoroughly studied in the treatment of non-allergic rhinitis. This study was designed to compare the efficacy of nasal corticosteroid in patients with allergic rhinitis (AR), and non allergic rhinitis (NAR). METHODS: The efficacy of triamcinolone acetonide nasal spray (TANS) on total nasal symptom scores (TNSS), and nasal peak inspiratory flow rate (nPIFR) was studied in a six-week parallel-group trial of NAR (n: 25), and AR (n: 16) patients. Health-related quality of life (HRQoL) and Epworth Sleepiness Scale (ESS) were also analysed. RESULTS: The TNSSs, and symptom scores of conjunctivitis, snoring, and postnasal drainage were significantly improved in both groups, after two and six weeks of treatment. In contrast to AR, patients with NAR had statistically significant improvement in nasal obstruction, and postnasal drainage beginning from two weeks of the treatment. nPIFR slightly increased in both groups. Scores of generic (SF-36), rhinitis specific (MiniRQLQ) and ESS questionnaires generally improved better in AR than NAR. TANS was well tolerated in AR and NAR groups with minor adverse events including headache, nasal burning, and bitter mouth taste. CONCLUSIONS: Our study disproved the idea of ineffectiveness of corticosteroid treatment in NAR, and showed that triamcinolone acetate may be an alternative drug in the treatment of NAR. PMID- 23031658 TI - Is age associated with the development of antibodies against botulinum toxin? PMID- 23031659 TI - Are drug provocation tests still necessary to test the safety of COX-2 inhibitors in patients with cross-reactive NSAID hypersensitivity? AB - BACKGROUND: COX-2 inhibitors are safe alternatives in patients with cross reactive non-steroidal anti-inflammatory drug (NSAID) hypersensitivity. These drugs are recommended to these patients after negative drug provocation tests (DPTs). However, cumulative data on encouraging results about the safety of COX-2 inhibitors in the majority of these patients bring the idea as to whether a DPT is always mandatory for introducing these drugs in all patients with cross reactive NSAID hypersensitivity. OBJECTIVE: To document the safety of COX-2 inhibitors currently available and to check whether or not any factor predicts a positive response. METHODS: This study included the retrospective analysis of cases with cross-reactive NSAID hypersensitivity who underwent DPTs with COX-2 inhibitors in order to find safe alternatives. DPTs were single-blinded and placebo controlled. RESULTS: The study group consisted of 309 patients. COX-2 inhibitors were well tolerated in the majority of the patients [nimesulide: 91.9%; meloxicam: 90.2%; rofecoxib: 94.9%; and celecoxib: 94.9%)]. Twenty-five patients (30 provocations) reacted to COX-2 inhibitors. None of the factors were found be associated with positive response. CONCLUSION: Our results suggest to follow the traditional DPT method to introduce COX-2 inhibitors for finding safe alternatives in all patients with cross-reactive NSAID hypersensitivity before prescription as uncertainty of any predictive factor for a positive response continues. However, these tests should be performed in hospital settings in which emergency equipment and experienced personnel are available. PMID- 23031660 TI - Administration of distillate thyme leaves into the diet of Segurena ewes: effect on lamb meat quality. AB - The effect of including thyme by-products from the distillation industry into the diet of pregnant ewes on the final quality of lamb meat was evaluated during meat storage in modified atmosphere. A total of 36 Segurena ewes were randomly assigned to three homogeneous groups. One group was fed a basal diet (BD) as control (C), whereas the diet of the other two groups was modified by substituting 10% (T 1) and 20% (T 2) of the BD with pellets made from 50% barley and 50% distilled thyme leaves (DTL). Meat spoilage (total viable, psychrotroph (PSY), moulds and yeasts, Enterobacteriaceae and lactic acid bacteria), thiobarbituric acid reactive substances (TBARS), colour (CIELab coordinates, metmyoglobin) and sensory characteristics of fresh lamb meat packed in modified atmosphere packaging (70% O2 : 30% CO2) were analysed after storage at 0, 7, 14 and 21 days. In general, the DTL-containing diet inhibited lipid and pigment oxidation in fresh lamb meat. Lower PSY counts and content of secondary oxidation product (TBARS) as a result of adding DTL to the ewe diet, whereas surface redness (a* values) was significantly higher on days 7 and 14. It can be concluded that thyme by-products from the distillation industry could be used as a source of natural antioxidant and antimicrobial in the feed for ewes. PMID- 23031661 TI - Histidine-tryptophan-ketoglutarate and University of Wisconsin solution demonstrate equal effectiveness in the preservation of human pancreata intended for islet isolation: a large-scale, single-center experience. AB - We previously reported a small-scale study on the efficacy of histidine tryptophan-ketoglutarate (HTK) solution versus University of Wisconsin (UW) solution on pancreas preservation for islet isolation. In this large-scale, retrospective analysis (n = 252), we extend our initial description of the impact of HTK on islet isolation outcomes and include pancreatic digestion efficacy, purification outcomes, and islet size distribution. Multivariable linear regression analysis, adjusted for donor age, sex, BMI, cold ischemia time, and enzyme, demonstrated similar results for the HTK group (n = 95) and the UW group (n = 157), including postpurification islet yields (HTK: 289,702 IEQ vs. UW: 283,036 IEQ; p = 0.76), percentage of digested pancreatic tissue (HTK: 66.9% vs. UW: 64.1%; p = 0.18), and islet loss from postdigestion to postpurification (HTK: 24,972 IEQ vs. UW: 39,551 IEQ; p = 0.38). Changes in islet size between the postdigestion and postpurification stages were comparable within each islet size category for HTK and UW (p = 0.14-0.99). Tissue volume distribution across purification fractions and islet purity in the top fractions were similar between the groups; however, the HTK group had significantly higher islet purity in the middle fractions (p = 0.003-0.008). Islet viability and stimulation indices were also similar between the HTK and the UW groups. In addition, we analyzed a small sample of patients transplanted either with HTK (n = 7) or UW (n = 8) preserved islets and found no significant differences in posttransplant HbA1c, beta-score, and frequency of insulin independence. This study demonstrates that HTK and UW solutions offer comparable pancreas preservation for islet transplantation. More in vivo islet outcome data are needed for a complete analysis of the effects of HTK on islet transplantation. PMID- 23031664 TI - mol2chemfig, a tool for rendering chemical structures from molfile or SMILES format to LATE X code. AB - : Displaying chemical structures in LATE X documents currently requires either hand-coding of the structures using one of several LATE X packages, or the inclusion of finished graphics files produced with an external drawing program. There is currently no software tool available to render the large number of structures available in molfile or SMILES format to LATE X source code. We here present mol2chemfig, a Python program that provides this capability. Its output is written in the syntax defined by the chemfig TE X package, which allows for the flexible and concise description of chemical structures and reaction mechanisms. The program is freely available both through a web interface and for local installation on the user's computer. The code and accompanying documentation can be found at http://chimpsky.uwaterloo.ca/mol2chemfig. PMID- 23031663 TI - Janus kinase (JAK) 2 V617F mutation in Asian Indians with cerebral venous thrombosis and without overt myeloproliferative disorders. AB - It is unclear whether the somatic JAK2V617F mutation, a marker for chronic myeloproliferative disorders (MPDs), is associated with cerebral venous thrombosis (CVT) in the absence of MPD. Our aim was to determine the prevalence and association of the JAK2V617F mutation among patients with CVT and without overt MPD. We investigated 372 CVT patients without features suggestive of MPD and 383 age- and gender-matched healthy controls, for the JAK2V617F mutation. Genotyping was done by polymerase chain reaction and restriction fragment length polymorphism. The heterozygous JAK2V617F mutation was present in 22 of 372 patients (5.9%) and 2 of 383 controls (0.5%). Logistic regression analysis showed this mutation to be an independent predictor of CVT after adjusting for the conventional risk factors (adjusted odds ratio: 5.47, 95% CI: 1.06-28.27, p=0.04). The mutation was more prevalent in men (p=0.005). Patients with JAK2V617F mutation were older (p=0.036), and had higher mean hemoglobin level (p<0.0001) than those without the mutation. Smokers with the mutation had 9.45 fold increased risk of CVT compared to non-smokers without the mutation (OR: 9.45, 95% CI: 1.17-76.02, p<0.0001). We conclude that the JAK2V617F mutation could contribute to increased risk of CVT in Indians. Larger studies in other ethnic populations are warranted before considering the inclusion of the JAK2V617F gene polymorphism into the routine diagnostic workup of CVT. PMID- 23031665 TI - Role of S100B protein in urine and serum as an early predictor of mortality after severe traumatic brain injury in adults. AB - S100B is a calcium-binding protein released into the blood from astroglial cells due to brain injury. Some authors have described a correlation between S100B serum concentration and severity of brain damage. There is not much information about the accuracy of urinary S100B for predicting outcome after severe traumatic brain injury (TBI). 55 patients with severe TBI were included in the study. Blood and urine samples were drawn to determine S100B levels on admission and on the subsequent 24, 48, 72 and 96 h. S100B concentrations (serum and urine) were significantly higher in patients who were dead a month after the accident compared to survivors. ROC-analysis showed that S100B at 24h post-severe TBI is a useful tool for predicting mortality (serum: AUC 0.958, urine: AUC 0.778). The best cut-offs for S100B were 0.461 MUg/L and 0.025 MUg/L (serum and urine respectively), with a sensitivity of 90% for both measurements and a specificity of 88.4% (serum) and 62.8% (urine). We can state that the determination of S100B levels both in urine and serum acts as a sensitive and an effective biomarker for the early prediction of mortality after severe TBI. PMID- 23031666 TI - FGF21 in ataxia patients with spinocerebellar atrophy and mitochondrial disease. AB - BACKGROUND: Serum fibroblast growth factor 21 (FGF21) was proven to be a useful biomarker for the presence of mitochondrial neuromuscular disease. METHODS: In the present study, we used the difference in the serum FGF21 level to differentiate between ataxia patients with hereditary spinocerebellar atrophy (SCA-ataxia) and those with mitochondrial syndrome (Mito-ataxia). Patients with SCA-ataxia (SCA2, SCA3) and Mito-ataxia (MELAS, MERRF, LHON, maternal inherited hearing impairment mtDNA A1555G mutation) were recruited in this study. All SCA ataxia patients revealed a consistent pattern of cerebellar atrophy. On the contrary, some of the Mito-ataxia patients exhibited a vascular lesion with cerebellar infarction. RESULTS: Extremely higher levels of serum FGF21 were found in the Mito-ataxia patients with MERRF and MELAS diseases, but not in patients with SCA-ataxia or LHON/mtDNA A1555G mutation. The positive trend between the mtDNA heteroplasmy and serum FGF21 was indicated in either MERRF (P=0.003, r=0.923) or MELAS (P=0.070, r=0.566) patients. CONCLUSION: Serum FGF21 can be applied as the first molecular screening among patients suspected to be victims of hereditary ataxia with neuromuscular degeneration prior to mass genetic screening. PMID- 23031667 TI - Effects of organic plant oils and role of oxidation on nutrient utilization in juvenile rainbow trout (Oncorhynchus mykiss). AB - Producing organic fish diets requires that the use of both fishmeal and fish oil (FO) be minimized and replaced by sustainable, organic sources. The purpose of the present study was to replace FO with organic oils and evaluate the effects on feed intake, feed conversion ratio (FCR), daily specific growth rate (SGR) and nutrient digestibility in diets in which fishmeal protein was partly substituted by organic plant protein concentrates. It is prohibited to add antioxidants to organic oils, and therefore the effects of force-oxidizing the oils (including FO) on feed intake and nutrient digestibility was furthermore examined. Four organic oils with either a relatively high or low content of polyunsaturated fatty acids were considered: linseed oil, rapeseed oil, sunflower oil and grapeseed oil. Substituting FO with organic oils did not affect feed intake (P > 0.05), FCR or SGR (P > 0.05) despite very different dietary fatty acid profiles. All organic plant oils had a positive effect on apparent lipid digestibility compared with the FO diet (P < 0.05), whereas there were no effects on the apparent digestibility of other macronutrients when compared with the FO diet (P > 0.05). Organic vegetable oils did not undergo auto-oxidation as opposed to the FO, and the FO diet consequently had a significantly negative effect on the apparent lipid digestibility. Feed intake was not affected by oxidation of any oils. In conclusion, the study demonstrated that it is possible to fully substitute FO with plant-based organic oils without negatively affecting nutrient digestibility and growth performance. Furthermore, plant-based organic oils are less likely to oxidize than FOs, prolonging the shelf life of such organic diets. PMID- 23031668 TI - Bilateral changes in foveal structure in individuals with amblyopia. AB - PURPOSE: To examine foveal structure in amblyopia using spectral-domain optical coherence tomography (SD-OCT). DESIGN: Prospective, cross-sectional study. PARTICIPANTS AND CONTROLS: Two subject groups were recruited to the study: 85 amblyopes (34 adults, 51 children) and 110 visually normal controls (44 adults, 66 children). METHODS: A detailed eye examination, including an SD-OCT scan, was performed in all participants. A total of 390 eyes of 195 subjects were imaged using a 3-dimensional (3D) macula scan covering a nominal 6 * 6-mm area with a resolution of 256 * 256 (65,536 axial scans). Data from the B-scans bisecting the fovea both horizontally and vertically were fitted with a mathematical model of the fovea to determine a range of foveal parameters. MAIN OUTCOME MEASURES: Foveal thickness, foveal pit depth, and foveal pit slope. RESULTS: Bilateral differences between the eyes of amblyopes compared with visually normal controls were found. The difference between foveal structure in amblyopic participants relative to structure in subjects with normal vision persisted even when variables such as age, ethnicity, axial length, and sex were taken into account. Amblyopes showed increased foveal thickness (+8.31 MUm; P = 0.006) and a reduction in pit depth in the horizontal meridian (-10.06 MUm; P = 0.005) but not in the vertical meridian (P = 0.082) when compared with subjects with normal vision. Foveal pit slopes were found to be approximately 1 degree flatter in the nasal (P = 0.033) and temporal (P = 0.014) meridians in amblyopes, but differences between amblyopes and controls in the superior (P = 0.061) and inferior (P = 0.087) meridians did not reach statistical significance. No statistically significant interocular differences were found in the foveal structure between amblyopic and fellow eyes. CONCLUSIONS: Differences were found in the foveal structure in both eyes of amblyopes compared with subjects with normal vision. These differences consisted of increased foveal thickness, reduced pit depth when measured along the horizontal meridian, and flattening of the nasal and temporal sides of the foveal pit. PMID- 23031662 TI - Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients. AB - BACKGROUND: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. RESULTS: Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. CONCLUSIONS: These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level. PMID- 23031669 TI - Comparison of clinical features between two different types of exotropia before 12 months of age based on stereopsis outcome. AB - PURPOSE: To compare the clinical outcomes and characteristics of 2 different types of early-onset exotropia on the basis of stereopsis outcome. DESIGN: Retrospective case series. PARTICIPANTS: A total of 24 patients with newly diagnosed exotropia before 12 months of age and at least 1 year of follow-up after surgery. METHODS: The clinical records of all patients were reviewed. Patients were divided into 2 groups according to stereopsis. The presumable early onset intermittent exotropia (EIE) group was composed of 6 patients (25%) who showed excellent stereopsis of >=60 arc seconds. The primary infantile exotropia (PIE) group was composed of 18 patients (75%) who showed stereopsis of <=100 arc seconds. We compared the preoperative and postoperative clinical features of the 2 groups. MAIN OUTCOME MEASURES: The age at onset and visit, age at surgery, constancy before surgery, preoperative and postoperative angles of deviation, distant suppression, reoperation rate, and presence of dissociative vertical deviation (DVD) and inferior oblique overaction (IOOA). RESULTS: The age at the stereopsis test was 6.8 years in the EIE group and 6.4 years in the PIE group (P=0.41). There was no statistical difference in the mean preoperative exodeviation (32.8 prism diopters [PD] in the EIE group vs. 34.7 PD in the PIE group, P=0.58) and postoperative deviation at the stereopsis test (1.0 PD in the EIE group vs. 2.0 PD in the PIE group, P=0.97). The reoperation rate was 33% in the EIE group and 27% in the PIE group (P=1.00). There was no statistical difference in constancy between the EIE and PIE groups (33% vs. 56%, respectively, P=0.64). However, DVD (61%) and IOOA (56%) were noted only in the PIE group (P=0.016, P=0.024, respectively), and distant suppression was noted only in the PIE group (61%, P=0.016). CONCLUSIONS: The results indicate that excellent sensory outcome was observed in only 25% of patients with exotropia before 12 months of age, but motor outcome and reoperation rate were not different between the 2 types of exotropia. We observed DVD, IOOA, and distant suppression only in the PIE group. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23031670 TI - Design and evaluation of a customized reading rehabilitation program for patients with age-related macular degeneration. AB - PURPOSE: To evaluate the efficacy of a reading rehabilitation program (RRP) specifically designed for patients with impaired central vision from age-related macular degeneration (AMD) and the impact of the program on the quality of life (QoL) and to determine any predictable reading performance improvements between visits. DESIGN: Prospective case series. PARTICIPANTS: Forty-one patients with AMD who attended to the Institute of Applied Ophthalmobiology Eye Institute. METHODS: An ad hoc-created RRP comprising 4 customized in-office training and in home training visits over 6 weeks was undertaken by AMD patients. The RRP was based on the principle of stepwise progressive goal achievement: the difficulty of training tasks increased depending on the success obtained when performing previous easier ones. Reading performance was evaluated during each in-office training visit, and the individual's perception of his or her QoL was assessed before and after the RRP. Reading performance parameters were assessed to evaluate RRP effectiveness. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), reading speed, reading duration, near visual acuity (VA), font size, and the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire scores. The effect sizes (mean differences and standard deviations) also were calculated. RESULTS: The mean distance BCVA was 0.81+/-0.29 logarithm of the minimum angle of resolution units. The mean near VA with the appropriate low-vision aid was 0.91+/ 0.18 (M notation) at baseline. The mean near magnification was 4.32+/-1.15 at the last in-office visit. The mean reading speed, reading duration, and font size improvement after the reading rehabilitation program were 48.31+/-22.06 words per minute (P<0.001), 35.46+/-15.68 minutes (P<0.001), and -4.08+/-2.19 font points (P<0.001), respectively. The effect sizes of reading speed, reading duration, and font size after the last visit were 2.19, 2.26, and -1.86, respectively. The final score of each WHOQOL-BREF domain improved significantly (P<=0.004) after the RRP. The increased ability to read a smaller font size was correlated with improvement in the physical health domain score of the WHOQOL-BREF (r=0.35; P=0.04). CONCLUSIONS: This customized RRP significantly enhanced reading performance and perceived QoL in patients with AMD. The improvement between visits seemed to be consistent. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23031671 TI - Vascular endothelial growth factor a in intraocular vascular disease. AB - The vascular beds supplying the retina may sustain injury as a result of underlying disease such as diabetes, and/or the interaction of genetic predisposition, environmental insults, and age. The vascular pathologic features observed in different intraocular vascular diseases can be categorized broadly as proliferation, exemplified by proliferative diabetic retinopathy, leakage such as macular edema secondary to retinal vein occlusion, or a combination of proliferation and leakage, as seen in neovascular age-related macular degeneration (AMD). The World Health Organization has identified diabetic retinopathy and AMD as priority eye diseases for the prevention of vision loss in developed countries. The pathologic transformations of the retinal vasculature seen in intraocular vascular disease are associated with increased expression of vascular endothelial growth factor A (VEGF), a potent endothelial-specific mitogen. Furthermore, in model systems, VEGF alone is sufficient to trigger intraocular neovascularization, and its inhibition is associated with functional and anatomic improvements in the affected eye. Therapeutic interventions with effect on VEGF include intraocular capture and neutralization by engineered antibodies or chimeric receptors, downregulation of its expression with steroids, or alleviation of retinal ischemia, a major stimulus for VEGF expression, with retinal ablation by laser treatment. Data from prospective randomized clinical trials indicate that VEGF inhibition is a potent therapeutic strategy for intraocular vascular disease. These findings are changing clinical practice and are stimuli for further study of the basic mechanisms controlling intraocular angiogenesis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23031672 TI - Rhinovirus genetic diversity among immunosuppressed and immunocompetent patients presenting with a severe respiratory infection. PMID- 23031673 TI - Downregulation of cyclophilin A by siRNA diminishes non-small cell lung cancer cell growth and metastasis via the regulation of matrix metallopeptidase 9. AB - BACKGROUND: Cyclophilin A (CypA) is a cytosolic protein possessing peptidyl prolyl isomerase activity that was recently reported to be overexpressed in several cancers. Here, we explored the biology and molecular mechanism of CypA in non-small cell lung cancer (NSCLC). METHODS: The expression of CypA in human NSCLC cell lines was detected by real-time reverse transcription PCR. The RNA interference-mediated knockdown of CypA was established in two NSCLC cell lines (95C and A549). 239836 CypA inhibitor was also used to suppress CypA activity. Tumorigenesis was assessed based on cellular proliferation, colony formation assays, and anchorage-independent growth assays; metastasis was assessed based on wound healing and transwell assays. RESULTS: Suppression of CypA expression inhibited the cell growth and colony formation of A549 and 95C cells. CypA knockdown resulted in the inhibition of cell motility and invasion. Significantly, we show for the first time that CypA increased NSCLC cell invasion by regulating the activity of secreted matrix metallopeptidase 9 (MMP9). Likewise, suppression of CypA with 239836 CypA inhibitor decreased cell proliferation and MMP9 activity. CONCLUSIONS: The suppression of CypA expression was correlated with decreased NSCLC cell tumorigenesis and metastasis. PMID- 23031675 TI - Developing tissue-engineered solutions for the treatment of extensive urethral strictures. PMID- 23031674 TI - Co-occurrence of resistance to different antibiotics among aquatic bacteria. AB - BACKGROUND: Antibiotic resistance is not confined to pathogens, but is also widespread in various natural environments. In nature the microbes producing antibiotic compounds have been around for millions of years. Heavy use of antibiotics in medicine and veterinary practice may lead to the accumulation of resistance genes in microbial populations, followed by a rise in multiresistant bacteria. RESULTS: To test the extent of resistance among aquatic bacteria, we have collected 760 isolates resistant to at least one antibiotic. The phylogeny of the isolates covers a wide range of Proteobacteria, Actinobacteria and Bacteroidetes. In order to determine the extent of multiresistance, the isolates were tested on six antibiotics. As the growth rate of the different bacteria was highly variable, the classical medical resistance tests could not be used, and an alternative method considering the full growth curve was developed. In general, the overall resistances to different antibiotics could be explained by random, independent distribution. An exception to this was the resistances against tetracycline and chloramphenicol, which tended to occur in pairs. CONCLUSIONS: We conclude that there is no massive spread of multiresistance determinants in the studied environment, although some specific cases can be found, awaiting for molecular characterization of the resistance mechanisms. PMID- 23031676 TI - Antibiotic prophylaxis in urology departments, 2005-2010. AB - BACKGROUND: Antibiotic prophylaxis (AP) is an important measure in preventing health care-associated urinary tract infections (HAUTIs). Despite regional variations in the bacterial spectrum and antibiotic susceptibility patterns, guideline recommendations are usually given on an international level. OBJECTIVE: To describe the use of AP in urology departments and relate this to relevant parameters such as country, type of hospital, and European Association of Urology guideline recommendations. DESIGN, SETTING, AND PARTICIPANTS: Data from the Global Prevalence Study on Infections in Urology for the period 2005-2010 were analysed to evaluate the use of antibiotics in general and AP for urologic procedures. Of the 13 723 patients enrolled, 8178 received antibiotics on the study days. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Study data were imported from the Web-based survey into Microsoft Access and exported into SPSS v.17.0. The data were then coded and analysed. The Pearson chi-Square test was used to compare categorical data and a probability level of 5% was considered significant. Multiple logistic regression analysis was used to define significantly different variables in multiple set categories. RESULTS AND LIMITATIONS: Questions on AP were answered on 8370 forms and 6306 (75.3%) investigators reported their routine application of AP. Routine AP was highest in Latin America (n=337; 84%), followed by Asia (n=1338; 86%), Africa (n=234; 85%), and Europe (n=4116; 67%). The antibiotics most frequently used for AP were second generation cephalosporins, ciprofloxacin, cefotaxime, and amoxicillin plus beta lactamase inhibitor. CONCLUSIONS: There were significant differences between countries/regions and types of hospitals, both in using AP for clean procedures and in the types of antibiotics used. AP was not always consistent with recommended guidelines. PMID- 23031677 TI - Temporal trends, practice patterns, and treatment outcomes for infected upper urinary tract stones in the United States. AB - BACKGROUND: The incidence of infected urolithiasis is unknown, and evidence describing the optimal management strategy for obstruction is equivocal. OBJECTIVE: To examine the trends of infected urolithiasis in the United States, the practice patterns of competing treatment modalities, and to compare adverse outcomes. DESIGN, SETTING, AND PARTICIPANTS: A weighted estimate of 396385 adult patients hospitalized with infected urolithiasis was extracted from the Nationwide Inpatient Sample, 1999-2009. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time trend analysis examined the incidence of infected urolithiasis and associated sepsis, as well as rates of retrograde ureteral catheterization and percutaneous nephrostomy (PCN) for urgent/emergent decompression. Propensity score matching compared the rates of adverse outcomes between approaches. RESULTS AND LIMITATIONS: Between 1999 and 2009, the incidence of infected urolithiasis in women increased from 15.5 (95% confidence interval [CI], 15.3-15.6) to 27.6 (27.4 27.8)/100 000); men increased from 7.8 (7.7-7.9) to 12.1 (12.0-12.3)/100000. Rates of associated sepsis increased from 6.9% to 8.5% (p=0.013), and severe sepsis increased from 1.7% to 3.2% (p<0.001); mortality rates remained stable at 0.25-0.20% (p=0.150). Among those undergoing immediate decompression, 113 459 (28.6%), PCN utilization decreased from 16.1% to 11.2% (p=0.001), with significant regional variability. In matched analysis, PCN showed higher rates of sepsis (odds ratio [OR]: 1.63; 95% CI, 1.52-1.74), severe sepsis (OR: 2.28; 95% CI, 2.06-2.52), prolonged length of stay (OR: 3.18; 95% CI, 3.01-3.34), elevated hospital charges (OR: 2.71; 95%CI, 2.57-2.85), and mortality (OR: 3.14; 95%CI, 13 4.63). However, observational data preclude the assessment of timing between outcome and intervention, and disease severity. CONCLUSIONS: Between 1999 and 2009, women were twice as likely to have infected urolithiasis. Rates of associated sepsis and severe sepsis increased, but mortality rates remained stable. Analysis of competing treatment strategies for immediate decompression demonstrates decreasing utilization of PCN, which showed higher rates of adverse outcomes. These findings should be viewed as preliminary and hypothesis generating, demonstrating the pressing need for further study. PMID- 23031678 TI - Tissue biomarkers as prognostic variables of cervical cancer. AB - The most important prognostic variables of cervical carcinoma are FIGO stage, lymph node status and clinical-pathological features of primary tumor. Recently, there has been increasing interest in the identification of biomarkers able to predict both response to treatment and survival. The aim of this review is to critically evaluate current published evidence on the ability of various tissue biomarkers to predict the clinical outcome of patients with cervical carcinoma. In particular, the paper takes into account DNA content, cell-cycle and apoptosis regulatory proteins, epidermal growth factor receptor [EGFR], vascular endothelial growth factor [VEGF], cyclooxygenase [COX]-2, signal transducer and activator of transcription [Stat]3, human papilloma virus [HPV] status, tumor hypoxia, tumor infiltrating lymphocytes [TIL], microarray technology and microRNA (miRNA). The presence of HPV-18 genotype and an elevated VEGF expression appear to be poor prognostic factors in women with early disease treated with primary surgery, whereas the expression of EGFR, VEGF, COX-2 and tumor hypoxia may have a major impact on the survival of patients treated with definitive radiotherapy or chemoradiation. The data supporting the reliability of DeltaNp73 and TAp73alpha as novel biomarkers of response to radiotherapy are interesting but still limited. DNA microarray technology could offer new laboratory tools for a rationale planning of treatment strategy, and miRNAs might represent new candidate targets to be investigated for both prognostic and therapeutic purposes. Moreover, the assessment of different types of TIL and their ligands in tumor biopsies could enable the identification of a subset of high-risk patients, paving the way to novel immune therapies aimed at blocking T-reg cell activity. PMID- 23031679 TI - HSQC spectral based similarity matching of compounds using nearest neighbours and a fast discrete genetic algorithm. AB - HSQC spectra are routinely acquired for chemical structure analysis based on hydrogen and carbon chemical environments. Two fast HSQC peak matching algorithms have been developed; a nearest neighbour approach and a probabilistic method based on an existing discrete genetic algorithm. Both of these techniques are intended to find HSQC spectra matches that supplement information generated by established molecular fingerprint methods. Our results are compared to those calculated using a specific implementation of molecular fingerprints. The nearest neighbour and genetic algorithm-based methods ranked highly particular structures missed by molecular fingerprints. Our analysis shows that by complementing molecular fingerprint matches with our findings, a comprehensive list of matches can be identified. The refined list of compounds could be used to improve the quality of compounds used in screening libraries in the pharmaceutical industry. PMID- 23031680 TI - Psychometric properties of the Chinese version of the Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) measuring health-related quality of life. AB - BACKGROUND: The Functional Assessment of Cancer Therapy (FACT) is one of the most commonly used self-report instruments for evaluation of health-related quality of life in oncology patients. However, cultural considerations necessitate testing of the subscales in different populations. We sought to qualitatively and quantitatively investigate the applicability and psychometric properties of the Chinese version of the FACT-Cervix (FACT-Cx) in Chinese women with cervical cancer. METHODS: Ten personal interviews were conducted in order to explore patients' opinions about the scale and its items in depth. In addition the questionnaire was administered to 400 women with cervical cancer to test its psychometric properties. Reliability was assessed using Cronbach's alpha coefficient and item-subscale correlation while validity was evaluated using factor analysis and known-group validity. RESULTS: Some items related to sex and the ability to give birth were questioned in the personal interviews, mostly regarding their significance and acceptance in the Chinese cultural context. The Cronbach's alphas of FACT-Cx and the subscales were greater than 0.7, except for the cervical-cancer-specific subscale which was 0.57. Factor analysis demonstrated that the FACT-G construct generally paralleled the original. There were significant differences in the FACT-Cx and some subscales between those receiving and not receiving treatment and among the patients with different performance status. CONCLUSIONS: In general, psychometric properties of the Chinese version supported its use with cervical cancer patients in Mainland China. Further work is needed to improve the psychometric adequacy of the cervical-cancer-specific subscale and adjust it to cultural considerations. PMID- 23031682 TI - Effects of caponization on growth performance, carcass composition and meat quality of males of a layer line. AB - The present experiment was conducted in order to evaluate the effects of caponization on growth, carcass composition and meat quality of males of a layer line reared until the 34th week of age. Two hundred and fifty males of a layer line were purchased and randomly divided in two equal groups: intact males and capons. Caponization was conducted at 45 days of age. Three slaughters were performed at the ages of 26, 30 and 34 weeks of age. Caponization did not affect feed intake and final live weight. Capons had a heavier breast and lighter leg than intact males. Lipid accumulation was enhanced by the caponization and fat was stored mainly at the fat pad and the skin of the commercial parts excluding the drumstick. The Pectoralis major muscle of capons had higher intramuscular fat content, lightness (L) and yellowness (b*) values and lower redness values (a*). In conclusion, caponization could be applied to a layer genotype in order to produce commercial chicken meat. PMID- 23031681 TI - Physical and rehabilitation medicine (PRM) care pathways: adults with severe traumatic brain injury. AB - This document is part of a series of guidelines documents designed by the French Physical and Rehabilitation Medicine Society (SOFMER) and the French Federation of PRM (FEDMER). These reference documents focus on a particular pathology (here patients with severe TBI). They describe for each given pathology patients' clinical and social needs, PRM care objectives and necessary human and material resources of the pathology-dedicated pathway. 'Care pathways in PRM' is therefore a short document designed to enable readers (physician, decision-maker, administrator, lawyer, finance manager) to have a global understanding of available therapeutic care structures, organization and economic needs for patients' optimal care and follow-up. After a severe traumatic brain injury, patients might be divided into three categories according to impairment's severity, to early outcomes in the intensive care unit and to functional prognosis. Each category is considered in line with six identical parameters used in the International Classification of Functioning, Disability and Health (World Health Organization), focusing thereafter on personal and environmental factors liable to affect the patients' needs. PMID- 23031683 TI - Advances in predicting nutrient partitioning in the dairy cow: recognizing the central role of genotype and its expression through time. AB - In recent years, it has become increasingly clear that understanding nutrient partitioning is central to a much broader range of issues than just being able to predict productive outputs. The extent to which nutrients are partitioned to other functions such as health and reproduction is clearly important, as are the efficiency consequences of nutrient partitioning. Further, with increasing environmental variability, there is a greater need to be able to predict the ability of an animal to respond to the nutritional limitations that arise from the environment in which it is placed. How the animal partitions its nutrients when resources are limited, or imbalanced, is a major component of its ability to cope, that is, its robustness. There is mounting evidence that reliance on body reserves is increased and that robustness of dairy cows is reduced by selection for increased milk production. A key element for predicting the partition of nutrients in this wider context is to incorporate the priorities of the animal, that is, an explicit recognition of the role of both the cow's genotype (genetic make-up), and the expression of this genotype through time on nutrient partitioning. Accordingly, there has been a growing recognition of the need to incorporate in nutritional models these innate driving forces that alter nutrient partitioning according to physiological state, the genetically driven trajectories. This paper summarizes some of the work carried out to extend nutritional models to incorporate these trajectories, the genetic effects on them, as well as how these factors affect the homeostatic capacity of the animal. At present, there are models capable of predicting the partition of nutrients throughout lactation for cows of differing milk production potentials. Information concerning genotype and stage of lactation effects on homeostatic capacity has not yet been explicitly included in metabolic models that predict nutrient partition, although recent results suggest that this is achievable. These developments have greatly extended the generality of nutrient partitioning models with respect to the type of animal and its physiological state. However, these models remain very largely focussed on predicting partition between productive outputs and body reserves and, for the most part, remain research models, although substantial progress has been made towards developing models that can be applied in the field. The challenge of linking prediction of nutrient partitioning to its consequences on health, reproduction and longevity, although widely recognized, is only now beginning to be addressed. This is an important perspective for future work on nutrient partitioning. PMID- 23031684 TI - Predicted accuracy of and response to genomic selection for new traits in dairy cattle. AB - Genomic selection relaxes the requirement of traditional selection tools to have phenotypic measurements on close relatives of all selection candidates. This opens up possibilities to select for traits that are difficult or expensive to measure. The objectives of this paper were to predict accuracy of and response to genomic selection for a new trait, considering that only a cow reference population of moderate size was available for the new trait, and that selection simultaneously targeted an index and this new trait. Accuracy for and response to selection were deterministically evaluated for three different breeding goals. Single trait selection for the new trait based only on a limited cow reference population of up to 10 000 cows, showed that maximum genetic responses of 0.20 and 0.28 genetic standard deviation (s.d.) per year can be achieved for traits with a heritability of 0.05 and 0.30, respectively. Adding information from the index based on a reference population of 5000 bulls, and assuming a genetic correlation of 0.5, increased genetic response for both heritability levels by up to 0.14 genetic s.d. per year. The scenario with simultaneous selection for the new trait and the index, yielded a substantially lower response for the new trait, especially when the genetic correlation with the index was negative. Despite the lower response for the index, whenever the new trait had considerable economic value, including the cow reference population considerably improved the genetic response for the new trait. For scenarios with a zero or negative genetic correlation with the index and equal economic value for the index and the new trait, a reference population of 2000 cows increased genetic response for the new trait with at least 0.10 and 0.20 genetic s.d. per year, for heritability levels of 0.05 and 0.30, respectively. We conclude that for new traits with a very small or positive genetic correlation with the index, and a high positive economic value, considerable genetic response can already be achieved based on a cow reference population with only 2000 records, even when the reliability of individual genomic breeding values is much lower than currently accepted in dairy cattle breeding programs. New traits may generally have a negative genetic correlation with the index and a small positive economic value. For such new traits, cow reference populations of at least 10 000 cows may be required to achieve acceptable levels of genetic response for the new trait and for the whole breeding goal. PMID- 23031687 TI - Nutrition, immune function and health of dairy cattle. AB - The large increase in milk yield and the structural changes in the dairy industry have caused major changes in the housing, feeding and management of the dairy cow. However, while large improvements have occurred in production and efficiency, the disease incidence, based on veterinary records, does not seem to be improved. Earlier reviews have covered critical periods such as the transition period in the cow and its influence on health and immune function, the interplay between the endocrine system and the immune system and nutrition and immune function. Knowledge on these topics is crucial for our understanding of disease risk and our effort to develop health and welfare improving strategies, including proactive management for preventing diseases and reducing the severity of diseases. To build onto this the main purpose of this review will therefore be on the effect of physiological imbalance (PI) on immune function, and to give perspectives for prevention of diseases in the dairy cow through nutrition. To a large extent, the health problems during the periparturient period relate to cows having difficulty in adapting to the nutrient needs for lactation. This may result in PI, a situation where the regulatory mechanisms are insufficient for the animals to function optimally leading to a high risk of a complex of digestive, metabolic and infectious problems. The risk of infectious diseases will be increased if the immune competence is reduced. Nutrition plays a pivotal role in the immune response and the effect of nutrition may be directly through nutrients or indirectly by metabolites, for example, in situations with PI. This review discusses the complex relationships between metabolic status and immune function and how these complex interactions increase the risk of disease during early lactation. A special focus will be placed on the major energetic fuels currently known to be used by immune cells (i.e. glucose, non-esterified fatty acids, beta-hydroxybutyrate and glutamine) and how certain metabolic states, such as degree of negative energy balance and risk of PI, contribute to immunosuppression during the periparturient period. Finally, we will address some issues on disease prevention through nutrition. PMID- 23031685 TI - Reduced ascending aorta distensibility relates to adverse ventricular mechanics in patients with hypoplastic left heart syndrome: noninvasive study using wave intensity analysis. AB - OBJECTIVE: To evaluate the aortic arch elastic properties and ventriculoarterial coupling efficiency in patients with single ventricle physiology, with and without a surgically reconstructed arch. METHODS: We studied 21 children with single ventricle physiology after bidirectional superior cavopulmonary surgery: 10 with hypoplastic left heart syndrome, who underwent surgical arch reconstruction, and 11 with other types of single ventricle physiology but without arch reconstruction. All children underwent pre-Fontan magnetic resonance imaging. No patient exhibited aortic recoarctation. Data on aortic wave speed, aortic distensibility and wave intensity profiles were all extracted from the magnetic resonance imaging studies using an in-house-written plug-in for the Digital Imaging and Communications in Medicine viewer OsiriX. RESULTS: Children with hypoplastic left heart syndrome had significantly greater wave speed (P = .002), and both stiffer (P = .004) and larger (P < .0001) ascending aortas than the patients with a nonreconstructed arch. Aortic distensibility was not influenced by ventricular stroke volume but depended on a combination of increased aortic diameter and abnormal wall mechanical properties. Those with hypoplastic left heart syndrome had a lower peak wave intensity and reduced energy carried by the forward compression and the forward expansion waves, even after correction for stroke volume, suggesting an abnormal systolic and diastolic function. Lower wave energy was associated with an increased aortic diameter. CONCLUSIONS: Using a novel, noninvasive technique based on image analysis, we have demonstrated that aortic arch reconstruction in children with hypoplastic left heart syndrome is associated with reduced aortic distensibility and unfavorable ventricular-vascular coupling compared with those with single ventricle physiology without aortic arch reconstruction. PMID- 23031688 TI - Trigeminal neuralgia post-styloidectomy in Eagle syndrome: a case report. AB - INTRODUCTION: Eagle syndrome is a condition characterized by an elongated (>3cm) styloid process with associated symptoms of recurrent facial or throat pain. In this report we present a case of Eagle syndrome exhibiting the typical findings of glossopharyngeal nerve involvement, as well as unusual involvement of the trigeminal nerve. Notably, this patient developed a classical trigeminal neuralgia post-styloidectomy. CASE PRESENTATION: A 68-year-old Caucasian woman presented with a 25-year history of dull pain along the right side of her throat, lateral neck, and jaw. Her symptoms were poorly controlled with medication until 15 years ago when she was diagnosed with Eagle syndrome, and underwent a manual fracture of her styloid process. This provided symptomatic relief until 5 years ago when the pain recurred and progressed. She underwent a styloidectomy via a lateral neck approach, which resolved the pain once again. However, 6 months ago a new onset of triggerable, electric shock-like facial pain began within the right V1 and V2 distributions. CONCLUSIONS: Eagle syndrome is distressing to patients and often difficult to diagnose due to its wide variability in symptoms. It is easily confused with dental pain or temporomandibular joint disorder, leading to missed diagnoses and unnecessary procedures. Pain along the jaw and temple is an unusual but possible consequence of Eagle syndrome. An elongated styloid process should be considered a possible etiology of dull facial pain in the trigeminal distributions, in particular V3. PMID- 23031689 TI - In silico identification and characterization of the ion transport specificity for P-type ATPases in the Mycobacterium tuberculosis complex. AB - BACKGROUND: P-type ATPases hydrolyze ATP and release energy that is used in the transport of ions against electrochemical gradients across plasma membranes, making these proteins essential for cell viability. Currently, the distribution and function of these ion transporters in mycobacteria are poorly understood. RESULTS: In this study, probabilistic profiles were constructed based on hidden Markov models to identify and classify P-type ATPases in the Mycobacterium tuberculosis complex (MTBC) according to the type of ion transported across the plasma membrane. Topology, hydrophobicity profiles and conserved motifs were analyzed to correlate amino acid sequences of P-type ATPases and ion transport specificity. Twelve candidate P-type ATPases annotated in the M. tuberculosis H37Rv proteome were identified in all members of the MTBC, and probabilistic profiles classified them into one of the following three groups: heavy metal cation transporters, alkaline and alkaline earth metal cation transporters, and the beta subunit of a prokaryotic potassium pump. Interestingly, counterparts of the non-catalytic beta subunits of Hydrogen/Potassium and Sodium/Potassium P-type ATPases were not found. CONCLUSIONS: The high content of heavy metal transporters found in the MTBC suggests that they could play an important role in the ability of M. tuberculosis to survive inside macrophages, where tubercle bacilli face high levels of toxic metals. Finally, the results obtained in this work provide a starting point for experimental studies that may elucidate the ion specificity of the MTBC P-type ATPases and their role in mycobacterial infections. PMID- 23031690 TI - An adjuvanted respiratory syncytial virus fusion protein induces protection in aged BALB/c mice. AB - BACKGROUND: Respiratory Syncytial Virus (RSV) causes significant disease in the elderly, in part, because immunosenescence impairs protective immune responses to infection in this population. Despite previous and current efforts, there is no RSV vaccine currently licensed in infants or elderly adults. Adjuvanted RSV subunit vaccines have the potential to boost waning immune responses and reduce the burden of RSV disease in the elderly population. RESULTS: We used an aged BALB/c mouse model to evaluate immune responses to RSV Fusion (F) protein in the absence and presence of an alum adjuvant. We demonstrate that aged BALB/c mice immunized with alum-adjuvanted RSV F protein had significantly reduced lung viral titers at day 4 following challenge with wild-type (wt) RSV. Serum neutralizing antibody titers measured on day 27 correlated with protection in both young and aged vaccinated mice, although the magnitude of antibody titers was lower in aged mice. Unlike young mice, in aged mice, alum-adjuvanted RSV F did not induce lung TH2-type cytokines or eosinophil infiltration compared to non-adjuvanted F protein following wt RSV challenge. CONCLUSION: Our studies demonstrate that neutralizing anti-RSV antibody titers correlate with protection in both young and aged BALB/c mice vaccinated with RSV F protein vaccines. The F + alum formulation mediated greater protection compared to the non-adjuvanted F protein in both young and aged mice. However, while alum can boost F-specific antibody responses in aged mice, it does not completely overcome the reduced ability of a senescent immune system to respond to the RSV F antigen. Thus, our data suggest that a stronger adjuvant may be required for the prevention of RSV disease in immunosenescent populations, to achieve the appropriate balance of protective neutralizing antibodies and effective TH1-type cytokine response along with minimal lung immunopathology. PMID- 23031691 TI - "Sprouting angiogenesis", a reappraisal. AB - Angiogenesis is defined as a new blood vessel sprouting from pre-existing vessels. This highly regulated process take place through two non-exclusive events, the so-called endothelial sprouting or non-sprouting (intussusceptive) microvascular growth. This review article will provide a brief overview of some relevant topics defining sprouting angiogenesis and including: (i) The concept of functional specialization of endothelial cells during different phases of this process, involving the specification of endothelial cells into tip cells, stalk cells, and phalanx cells bearing different morphologies and functional properties; (ii) The interplay between numerous signaling pathways, including Notch and Notch ligands, VEGF and VEGFRs, semaphorins, and netrins, in the regulation and modulation of the phenotypic characteristics of these cells; (iii) Some fundamental and consecutive morphological processes, including lumen formation and perfusion, network formation, remodeling, pruning, leading to the final vessel maturation and stabilization. PMID- 23031694 TI - Pathological biominerals: Raman and infrared studies of bioapatite deposits in human heart valves. AB - We studied pathological bioapatite from patients undergoing valvular replacement due to severe aortic and mitral stenosis. Three different types of mineralized human cardiac valves were analyzed. We used infrared and Raman spectroscopy to infer the presence of the carbonate group and evaluate the carbonate substitution in bioapatite structure. The Raman spectra showed that the pathological bioapatite is a B-type "carbonate-apatite" (CO(3)(2-) for PO(4)(3-)) similar to the major mineralized products derived from normal biomineralization processes occurring in the human body. Fourier transform infrared spectra (FT-IR) confirmed the B-type carbonate substitution (CO(3)(2-) for PO(4)(3-)) and showed evidence for the partial replacement of [OH] by [CO(3)] (A-type substitution). The carbonate content of the samples inferred by the spectroscopic measurements is in good agreement with the range of values estimated for biological apatite. On the contrary, the crystal size of the pathological apatite estimated using the percentage area of the component at 1059 cm(-1) of the infrared spectrum is in the nanometer range and it is significantly smaller than the crystal size of normal mineralized tissues. PMID- 23031695 TI - Automated model-based calibration of short-wavelength infrared (SWIR) imaging spectrographs. AB - Among the variety of available hyperspectral imaging systems, the line-scan technique stands out for its short acquisition time and good signal-to-noise ratio. However, due to imperfections in the camera lens and, in particular, optical components of the imaging spectrograph, the acquired images are spatially and spectrally distorted, which can significantly degrade the accuracy of the subsequent hyperspectral image analysis. In this work, we propose and evaluate an automated method for correction of spatial and spectral distortions introduced by a line-scan hyperspectral imaging system operating in the short wavelength infrared (SWIR) spectral range from 1000 nm to 2500 nm. The proposed method is based on non-rigid registration of the distorted and reference images corresponding to two passive calibration objects. The results of the validation show that the proposed method is accurate, efficient, and applicable for calibration of line-scan hyperspectral imaging systems. Moreover, the design of the method and of the calibration objects allows integration with systems operating in diffuse reflectance or transmittance modes. PMID- 23031693 TI - Infrared spectroscopic imaging: the next generation. AB - Infrared (IR) spectroscopic imaging seemingly matured as a technology in the mid 2000s, with commercially successful instrumentation and reports in numerous applications. Recent developments, however, have transformed our understanding of the recorded data, provided capability for new instrumentation, and greatly enhanced the ability to extract more useful information in less time. These developments are summarized here in three broad areas--data recording, interpretation of recorded data, and information extraction--and their critical review is employed to project emerging trends. Overall, the convergence of selected components from hardware, theory, algorithms, and applications is one trend. Instead of similar, general-purpose instrumentation, another trend is likely to be diverse and application-targeted designs of instrumentation driven by emerging component technologies. The recent renaissance in both fundamental science and instrumentation will likely spur investigations at the confluence of conventional spectroscopic analyses and optical physics for improved data interpretation. While chemometrics has dominated data processing, a trend will likely lie in the development of signal processing algorithms to optimally extract spectral and spatial information prior to conventional chemometric analyses. Finally, the sum of these recent advances is likely to provide unprecedented capability in measurement and scientific insight, which will present new opportunities for the applied spectroscopist. PMID- 23031696 TI - Metal stearate distributions in modern artists' oil paints: surface and cross sectional investigation of reference paint films using conventional and synchrotron infrared microspectroscopy. AB - Zinc oxide is a prevalent industrial-age pigment that readily reacts with fatty acids in oil-based paints to form zinc carboxylates. Zinc stearate aggregates are associated with deterioration in late nineteenth and twentieth century paintings. The current study uses both conventional and synchrotron Fourier transform infrared spectroscopy (FT-IR) to investigate metal carboxylate composition in a range of naturally aged artists' oil paints and reference paint film draw-downs. The paints contain zinc oxide alone or in combination with lead white, titanium white, and aluminum stearate and are prepared with linseed and safflower oils. Attenuated total reflectance (ATR)-FT-IR using the conventional source identifies marked differences in carboxylate profiles between exposed and protected surfaces in a large number of samples. Synchrotron FT-IR microspectroscopy of thin paint cross-sections maps metal carboxylate distributions at high spatial resolution and resolves broad concentration gradients and micrometer-scale phase separation of carboxylate species. Aluminum stearate, a common paint additive, is found to influence the distribution of zinc carboxylates more strongly than pigment composition or oil type. The presence of aluminum stearate results in higher concentrations and more pronounced separation of saturated C16 and C18 chain zinc carboxylates in the margin of paint nearest the polyester substrate. The presence of aluminum stearate in association with zinc oxide has a clear influence on zinc carboxylate formation and distribution, with potential implications for long term stability of vulnerable paintings. PMID- 23031697 TI - Water uptake of poly(2-N-alkyl-2-oxazoline)s: temperature-dependent Fourier transform infrared (FT-IR) spectroscopy and two-dimensional correlation analysis (2DCOS). AB - A library of poly(2-oxazoline)s with varying length of the alkyl side-chain has been investigated by variable-temperature Fourier transform infrared (FT-IR) spectroscopy. These polymers are suitable for studies of structure-property relationships as their cationic ring-opening polymerization and the relatively facile monomer synthesis enable a control of the molecular structure. In this contribution, the number of carbon atoms in the linear side-chain is systematically varied from a short methyl to a long nonyl group. Previous studies showed that the sample library can be split in two groups: poly(2-oxazoline)s with a short side-chain (methyl-, ethyl-, and isopropyl-) exhibit hygroscopic behavior, while those with longer side-groups (butyl- and longer) were found to be semi-crystalline. To gain further insight into the mechanisms of hydrogen bonding and crystallization, temperature-dependent infrared (IR) spectroscopy has been applied in the current study. The processes involved have been monitored by generalized two-dimensional correlation spectroscopy (2DCOS) and perturbation correlation moving-window two-dimensional correlation spectroscopy (PCMW2D) in the C=O stretching region around 1645 cm(-1). These advanced analysis techniques provided valuable additional information on the material behavior during heating. As water is removed from the samples in the course of the heating process, it was possible to clearly distinguish between "loosely associated" and hydrogen-bonded water. Furthermore, the melting process of the semi-crystalline samples could be depicted. For the poly(2-isopropyl-2-oxazoline) even a crystallization process could be monitored in the temperature range between glass transition and melting. PMID- 23031698 TI - Home-made N-channel fiber-optic spectrometer from a web camera. AB - This paper demonstrates the high potential of a web camera to be utilized as a low-cost multichannel fiber-optic spectrometer suitable for either educational or quality-control purposes in small and medium enterprises. The key idea is to arrange N input optical fibers in a line and position an external dispersive element to separate incoming optical beams into their associated spectral components in a two-dimensional (2D) space. With a commercial web camera, each set of the spectral components is imaged through a plastic lens onto the 2D image sensor of the web camera. For the demonstration, a five-channel webcam-based fiber-optic spectrometer is implemented where each channel is calibrated by selected reference light sources. The constructed spectrometer can perform wavelength analysis of the spectral irradiance in the range of 400 to 655 nm. Experimental results also show that peak operating wavelengths of five light emitting diodes and a laser pointer can be determined with a wavelength measurement error of less than 10.5 nm. The total cost of the webcam-based five channel fiber-optic spectrometer is only approximately US$92.50 and effectively performs to the desired results. PMID- 23031699 TI - Transmission resonance Raman spectroscopy: experimental results versus theoretical model calculations. AB - A laser spectroscopic technique is described that combines transmission and resonance-enhanced Raman inelastic scattering together with low laser power (< 30 mW) and good spatial resolution (< 200 MUm) as operational features. The monitoring of the transmitted inelastic scattering provides an increased signal to-noise ratio because the low fluorescence background and, on the other hand, the resonant character of the laser excitation, leads to enhanced analytical sensitivity. The spectroscopic technique was applied to investigate the carotenoid content (specifically the beta-carotene concentration) of distinct samples that included fruits, reaching a detection limit of the order of hundreds of picograms in solid samples, which is below the level needed for typical food control analysis. Additional features of the present development are direct sampling, noninvasive character, and fast analysis that is not time consuming. From a theoretical point of view, a model for the Raman signal dependence on the sample thickness is also presented. Essentially, the model considers the sample to be homogeneous and describes the underlying physics using only three parameters: the Raman cross-section, the laser-radiation attenuation cross section, and the Raman signal attenuation cross-section. The model was applied successfully to describe the sample-size dependence of the Raman signal in both beta-carotene standards and carrot roots. The present technique could be useful for direct, fast, and nondestructive investigations in food quality control and analytical or physiological studies of animal and human tissues. PMID- 23031700 TI - High-throughput screening system for creating and assessing surface-modified porous silicon. AB - A high-throughput screening system has been developed to rapidly produce, screen, and assess the usefulness of organically modified silane (ORMOSIL)-based xerogel films formed on the surface of porous silicon (pSi) surfaces. The ORMOSILs tested include methyltriethoxysilane, n-octyltriethoxysilane, n-hexyltriethoxysilane, n propyltriethoxysilane, 2-cyanoethyltriethoxysilane, phenyltriethoxysilane, benzyltriethoxysilane, vinyltriethoxysilane, tetraethoxysilane, and hexafluoroethyltriethoxysilane. Xerogel microarrays were pin-printed on the surface of O(3) oxidized pSi using a computer-controlled robotic pin-printer. The fragile pSi required careful pin-printing parameter optimization to simultaneously ensure sufficient sol application and limit pin-induced damage. These multi-functional xerogel-pSi microarrays were exposed to harsh conditions (0.1 mM NaOH, 15 min) to determine the extent to which the xerogel protected the pSi. Microarray assessment included multispectral photoluminescence and infrared imaging. Results demonstrate that the more hydrophobic/nonpolar xerogel films (n octyltriethoxysilane, n-hexyltriethoxysilane) protect the pSi surface the most and maintained the pSi photoluminescence. Also, unlike xerogel material doped with a reporter molecule, the uniformity of the printed feature plays a role in the protection of the pSi material underneath. Areas with thinner xerogel distributions allowed the permeation of NaOH whereas the thicker areas prohibit pSi exposure to NaOH. PMID- 23031701 TI - Looking inside catalyst extrudates with time-resolved surface-enhanced Raman spectroscopy (TR-SERS). AB - Raman spectroscopy is one of the major characterization methods employed over the last few decades as a nondestructive technique for the study of heterogeneous catalysts and related catalytic reactions. However, the promise of practical applicability on millimeter-sized catalyst bodies, such as extrudates, has not been fulfilled completely. Large fluorescence signals and the highly scattering nature of the extrudates often hamper its practical usage. Different approaches to overcome this problem were examined, including the use of time-resolved Raman spectroscopy (TRRS), spatially offset Raman spectroscopy (SORS), surface enhanced Raman spectroscopy (SERS), and combinations of these techniques. This paper demonstrates that especially TRRS can provide chemical information at depth within catalyst bodies, overcoming fluorescence background signals and allowing for visualization of analytes at different depths. It also examines the application of time-resolved SERS within catalyst bodies to gain insight into localized activity. With these options a wider applicability of Raman spectroscopy for industrial catalysis research becomes within reach. PMID- 23031702 TI - Multi-wavelength transmission spectroscopy revisited for micron and submicron particle characterization. AB - Multi-wavelength transmission (MWT) ultraviolet-visible-near-infrared (UV-Vis NIR) spectroscopy, a technique underappreciated for particle characterization, is systematically explored using a set of NIST traceable standards over the nominal size range of 20 to 20,000 nm. Experimental results demonstrate that the particle size distributions obtained from MWT spectral data are in excellent agreement with the values reported by the manufacturer. In addition, it is shown that quantitative information on the particle concentration can be obtained--which is not currently accessible from commercially available light scattering instrumentation. The results validate that MWT UV-Vis-NIR spectroscopy has a considerable dynamic range for particle size measurements and offers significant advantages over other particle characterization techniques. Among these are the simplicity of the instrumentation and the measurements and the wealth of quantitative information contained in the MWT spectra. Most importantly, with standardized measurement protocols and standardized spectrometer configurations, MWT measurements can be used to provide the user and the manufacturer of particles with traceable data (i.e., the spectra and the quantitative analysis) for quality assurance. PMID- 23031703 TI - Selective sampling and laser-induced breakdown spectroscopy (LIBS) analysis of organic explosive residues on polymer surfaces. AB - A method for selective sampling and analysis of explosive residues on solid surfaces based on laser-induced breakdown spectroscopy (LIBS) is presented. Organic explosives are difficult to analyze when present as residues on organic materials. Under these circumstances LIBS suffers from the limitations imposed by the limited spectroscopic information available for the analysis. Since ablation and subsequent plasma formation are sensitive to the beam focal conditions and the pulse energy deposited on the surface, the choice of an appropriate set of experimental conditions increases the surface sensitivity of the analysis and hence a selective inspection of the residue in the absence of spectral contribution from the organic support analyzed. 2-Mononitrotoluene (MNT), 2,6-dinitrotoluene (DNT), and 2,4,6-trinitrotoluene (TNT) are used as model residues, whereas nylon and Teflon are used as illustrative surfaces of daily life objects. The results demonstrate that selective sampling is successfully achieved in all cases when the plasma formation threshold of the residues and the object is substantially different. Plasma imaging demonstrates that the species distribution along the plume changes with beam focal conditions, which is exploited here to further increase the selectivity of the approach. PMID- 23031704 TI - Calibration of Raman spectroscopy in the stress measurement of air-plasma-sprayed yttria-stabilized zirconia. AB - Thermal barrier coatings (TBC) are used widely on a range of components that operate at high temperatures. We report measurement of the factor that is required to convert the Raman shift to stress for air plasma sprayed yttria (7 wt %) stabilized tetragonal zirconia (ZrO(2)) (YSZ) thermal barrier coatings. The factor is evaluated for the as-coated condition and also following a heat treatment at 1000 degrees C for 1050 h. Two Raman bands at 608 cm(-1) and 640 cm(-1) have been investigated in a diamond anvil cell under hydrostatic pressure up to ~24 GPa. In the range of zero to ~1.6 GPa, a linear behavior was observed in terms of the shifts of these two Raman bands with a gradient similar to dense bulk tetragonal ZrO(2). From these measurements the factors to convert wavenumber shift to stress have been derived. The application of these conversion factors to stress measurement in TBC coated test specimens and components is discussed. PMID- 23031705 TI - Simultaneous measurements of multiple parameters at elevated temperature using a frequency-division multiplexing scheme with tunable diode lasers. AB - A multiplexed diode-laser sensor system based on second harmonic detection of wavelength modulation spectroscopy (WMS) is developed for application at elevated temperatures with two near-infrared diode lasers multiplexed using a frequency division multiplexing scheme. One laser is tuned over a H(2)O line pair near 7079.176 and 7079.855 cm(-1), and another laser is tuned over a pair of CO(2) and CO lines near 6361.250 and 6361.344 cm(-1). Temperature and concentrations of H(2)O, CO(2), and CO could be measured simultaneously by this system. In order to remove the need for calibration and correct for transmission variation due to beam steering, mechanical misalignments, soot, and windows fouling, the WMS-1f normalized 2f method is used. Demonstration experiments are conducted in a heated static cell. The precision of temperature and the concentrations for H(2)O, CO(2), and CO are found to be 1.57%, 3.87%, 3.01%, and 3.58%, respectively. These results illustrate the potential of this sensor for applications at high temperatures. PMID- 23031706 TI - Chlorophyll a and NADPH fluorescence lifetimes in the microalgae Haematococcus pluvialis (Chlorophyceae) under normal and astaxanthin-accumulating conditions. AB - In vivo fluorescence lifetimes of chlorophyll-a (chl-a) and nicotinamide adenine dinucleotide phosphate (NADPH) were obtained from the green microalgae Haematococcus pluvialis under normal and nutrient-stressed conditions (green stage and red stage, respectively), using two-photon excitation provided by a laser generating pulses in the femtosecond range, and a Leica microscope setup. Analysis of the fluorescence lifetime decay curve revealed two separate lifetime components in all our measurements. A short-lifetime component for chl-a of ~250 ps was completely dominant, contributing more than 90% of overall intensity in both green-stage and red-stage cells. Green-stage cells inhibited by 3-(3,4 dichlorophenyl)-1,1-dimethyl-urea (DCMU) displayed a significant chl-a lifetime increase for the short component. However, this was not the case for red-stage cells, in which DCMU inhibition did not significantly affect the lifetime. For green-stage cells, we found a short NADPH (free) lifetime component at ~150 ps to be completely dominating, but for red-stage cells, a longer component (protein bound) at ~3 ns contributed as much as 35% of the total intensity. We hypothesize that the long lifetime component of NADPH is connected to photoprotection in the cells and coupled to production of astaxanthin. DCMU does not seem to affect the fluorescence lifetimes of NADPH. PMID- 23031707 TI - Characterizing diffusion and transport in microfluidics channels: a combined Raman microscopy and band-target entropy minimization study. AB - With the increasing use of microfluidics, there is a need for a rather general experimental approach in order to monitor and characterize transport effects. Indeed, micro-fabrication methods have allowed the inclusion of numerous new structures and devices within microfluidics channels, and such alterations in flow patterns should impact solute transport characteristics. In the present contribution, Raman microscopy is combined with band-target entropy minimization analysis (BTEM) in order to rapidly assess and map concentration profiles in various regions of a microfluidics device. Two isotopomers, CHCl(3) and CDCl(3), are contacted under laminar conditions. Special consideration is given to the point of contact between the two liquids, transport in straight sections, transport in curved sections, and wall effects. Break-through curves confirmed that stagnation of fluid at the wall is not occurring, despite substantial wall roughness. Since the methods used in the present study are quite general, they should be useful in rapidly accessing transport effects when fluids (also in conjunction with colloids, suspensions, and solids) are contacted in the presence of both simple as well as complex geometries. PMID- 23031708 TI - Photoluminescence properties of zinc oxide in paints: a study of the effect of self-absorption and passivation. AB - Zinc oxide has been widely used as a white artist pigment since the end of the eighteenth century. The luminescence properties of this compound have received great interest during the last decades for promising applications in different fields of material science, but their diagnostic implications in the cultural heritage context have been poorly exploited. This paper is intended to provide a clear picture of the luminescence behavior of zinc white in oil paintings. With this aim, three white pigments and three highly pure (analytical grade) zinc oxides were studied as powder substrates and as painting models by ultraviolet visible (UV-VIS) fluorescence and Fourier transform infrared (FT-IR) spectroscopy. The quenching of the luminescence intensity of the UV excitonic emission due to self-absorption and multiple scattering phenomena has been investigated, pointing out the possible difficulty of detecting this signal with negative consequences in the diagnostics of works of art. By contrast, the UV emission is notably enhanced by interaction with the binder, whereas the visible emission decreases. This phenomenon is probably due to the formation of covalent bonds between zinc atoms and carboxylates from the lipidic medium that are chemisorbed on zinc oxide surfaces. PMID- 23031709 TI - Ground-state features in the THz spectra of molecular clusters of beta-HMX. AB - We present calculations of absorption spectra arising from molecular vibrations at THz frequencies for molecular clusters of the explosive HMX using density functional theory (DFT). The features of these spectra can be shown to follow from the coupling of vibrational modes. In particular, the coupling among ground state vibrational modes provides a reasonable molecular-level interpretation of spectral features associated with the vibrational modes of molecular clusters. THz excitation from the ground state is associated with frequencies that characteristically perturb molecular electronic states, in contrast to frequencies, which are usually substantially above the mid-infrared (mid-IR) range, that can induce appreciable electronic-state transition. Owing to this characteristic of THz excitation, one is able to make a direct association between local oscillations about ground-state minima of molecules, either isolated or comprising a cluster, and THz absorption spectra. The DFT software program GAUSSIAN was used for the calculations of the absorption spectra presented here. PMID- 23031711 TI - DISCOV (DImensionless Shunting COlor Vision): a neural model for spatial data analysis. AB - The DISCOV (DImensionless Shunting COlor Vision) system models a cascade of primate color vision neurons: retinal ganglion, thalamic single opponent, and cortical double opponent. A unified model derived from psychophysical axioms produces transparent network dynamics and principled parameter settings. DISCOV fits an array of physiological data for each cell type, and makes testable experimental predictions. Binary DISCOV augments an earlier version of the model to achieve stable computations for spatial data analysis. The model is described in terms of RGB images, but inputs may consist of any number of spatially defined components. System dynamics are derived using algebraic computations, and robust parameter ranges that meet experimental data are fully specified. Assuming default values, the only free parameter for the user to specify is the spatial scale. Multi-scale analysis accommodates items of various sizes and perspective. Image inputs are first processed by complement coding, which produces an ON channel stream and an OFF channel stream for each component. Subsequent computations are on-center/off-surround, with the OFF channel replacing the off center/on-surround fields of other models. Together with an orientation filter, DISCOV provides feature input vectors for an integrated recognition system. The development of DISCOV models is being carried out in the context of a large-scale research program that is integrating cognitive and neural systems derived from analyses of vision and recognition to produce both biological models and technological applications. PMID- 23031710 TI - Sonic hedgehog (Shh)/Gli modulates the spatial organization of neuroepithelial cell proliferation in the developing chick optic tectum. AB - BACKGROUND: Sonic hedgehog (Shh)/Gli pathway plays an important regulatory role on the neuroepithelial cells (NEc) proliferation in the dorsal regions of the developing vertebrate Central Nervous System. The aim of this paper was to analyze the effect of the Shh/Gli signaling pathway activation on the proliferation dynamics and/or the spatial organization of the NEc proliferation activity during early stages of the developing chick optic tectum (OT). In ovo pharmacological gain and loss of hedgehog function approaches were complemented with in vivo electroporation experiments in order to create ectopic sources of either Shh or Gli activator (GliA) proteins in the OT. NEc proliferating activity was analyzed at ED 4/4.5 by recording the spatial co-ordinates of the entire population of mitotic NEc (mNEc) located along OT dorsal-ventral sections. Several space signals (numerical sequences) were derived from the mNEc spatial co ordinate records and analyzed by different standardized non-linear methods of signal analysis. RESULTS: In ovo pharmacologic treatment with cyclopamine resulted in dramatic failure in the OT expansion while the agonist purmorphamine produced the opposite result, a huge expansion of the OT vesicle. Besides, GliA and Shh misexpressions interfere with the formation of the intertectal fissure located along the dorsal midline. This morphogenetic alteration is accompanied by an increase in the mNEc density. There is a gradient in the response of NEcs to Shh and GliA: the increase in mNEc density is maximal near the dorsal regions and decrease towards the OT-tegmental boundary. Biomathematical analyses of the signals derived from the mNEc records show that both Shh and GliA electroporations change the proliferation dynamics and the spatial organization of the mNEc as revealed by the changes in the scaling index estimated by these methods. CONCLUSIONS: The present results show that the Shh/Gli signaling pathway plays a critical role in the OT expansion and modelling. This effect is probably mediated by a differential mitogenic effect that increases the NEc proliferation and modulates the spatial organization of the NEc proliferation activity. PMID- 23031712 TI - Autocrine TGF-beta induces epithelial to mesenchymal transition in human amniotic epithelial cells. AB - Human amniotic epithelial cells (hAECs) have been the object of intense research due to their potential therapeutic use. In this paper, we present molecular evidence of a bona fide epithelial to mesenchymal transition (EMT) undergone by hAECs. Amniotic membrane (AM)-derived hAECs showed the presence of typical epithelial markers such as E-cadherin and cytokeratins. hAECs in culture, however, underwent morphological changes acquiring a mesenchymal shape. Epithelial cell markers were lost and typical mesenchymal markers, such as vimentin and alpha-SMA, appeared. Several genes associated with EMT, such as SNAI1, MMP9, PAI1, or ACTA2, increased their expression. The expression of the transcription activators KLF4 or MTA3 was consistent with the downregulation of CDH1. We have shown that hAECs undergo EMT due to the autocrine production of TGF beta. Furthermore, the addition of the TGF-beta receptor I (ALK5) inhibitor SB 431542 or TGF-beta neutralizing antibody to hAECs prevented EMT and preserved the hAECs' epithelial phenotype. Altogether, these results suggest that cultured hAECs undergo EMT through the autocrine production of TGF-beta. PMID- 23031713 TI - Time trends of cancer mortality among elderly in Italy, 1970-2008: an observational study. AB - BACKGROUND: The aging of the Italian population will unavoidably lead to a growing number of persons diagnosed and living with cancer. A comprehensive description of the burden of cancer mortality among Italian elderly (65-84 years of age) in the last four decades has not been carried out yet. Cancer mortality rates were used to describe time trends between 1970-2008. METHODS: Mortality counts, provided by the Italian National Institute of Statistics, were grouped according to data availability: in quinquennia from 1970-74 through 1995-99, and in 2000-03 and 2006-08 groups. Age-standardized rates (world population) were computed by calendar periods while annual percent changes (APCs) were computed for elderly and middle aged (35-64 years) people for the period 1995-2008. RESULTS: The number of cancer deaths in elderly nearly doubled between 1970-74 (31,400 deaths/year in men, and 24,000 in women) and 2006-08 (63,000 deaths/year in men, and 42,000 in women). Overall cancer mortality rates peaked during the quinquennia 1985-89 and 1990-94 (about 1,500/100,000 in men and 680 in women) and declined thereafter. Throughout 1995-2008 cancer mortality rates decreased by 1.6%/year in men and -0.9%/year in women. These decreases were mainly driven by cancers of the stomach, bladder, prostate, and lung (APC = -3.3%, -2.7%, -2.5%, 2.2%, respectively) in men, and by cancers of the stomach, bladder, and breast (APC = -3.5%, -1.9%, -1.1%, respectively) in women. Conversely, increases in mortality rates between 1995 and 2008 were recorded for lung cancer (APC = +0.6%) in women, cutaneous melanoma (APC = +1.7%) in men, and pancreatic cancer (APC = +0.6% in men and +0.9% in women). CONCLUSIONS: Overall favorable trends in cancer mortality were observed among Italian elderly between 1995 and 2008. Early diagnosis, improved efficacy of anti-cancer treatments and management of comorbidities are the most likely explanations of these positive observations. However, enduring preventive interventions against the most common risk factor (e.g. cigarette smoking), early diagnosis, and access to care should be reconsidered and extended to match the reductions of cancer mortality recorded in the elderly with those in the middle aged. PMID- 23031714 TI - Isolation of inflammatory cells from rat brain tissue after stroke. AB - The pathophysiology of sterile inflammation following focal ischemic stroke is complex and not fully understood, but there is growing evidence that it offers several therapeutic options beyond the hitherto existing treatment strategies. The identification and quantification of infiltrating inflammatory cells in animal models of stroke is crucial both for understanding post-stroke inflammation and for drug target identification. Multicolor flow cytometry plays an important role in determining subtypes and quantity of leukocytes that infiltrate the brain tissue after stroke. Until now, most investigations have been performed in mice, most likely due to a significantly broader spectrum of disposable antibodies and available knockout models. Here, we introduce a specific and reproducible method to isolate leukocytes from rat brain specimen in the context of brain ischemia to ultimately allow multi-dimensional flow cytometric characterization and further downstream methods such as cell-subtype sorting and molecular biological approaches. PMID- 23031715 TI - EBNA1 and host factors in Epstein-Barr virus latent DNA replication. AB - Epstein-Barr virus episomes (EBV) replicate once per cell cycle during latent infection from the latent origin, oriP. This replication requires the viral EBNA1 protein, which specifically recognizes sequences in oriP and recruits cellular proteins to this origin. Replication from oriP requires the cellular origin recognition and MCM helicase complexes and also involves telomeric factors (including TRF2) that associate with repeated nonameric sequences at the origin. Replication from oriP occurs late in S-phase and this timing appears to be important for efficient replication. Replication from oriP has proven to be a valuable system for elucidating cellular proteins and mechanisms of origin activation. PMID- 23031716 TI - Nuclear BMI-1 expression in laryngeal carcinoma correlates with lymph node pathological status. AB - BACKGROUND: The main cause of treatment failure and death in laryngeal squamous cell carcinoma is metastasis to the regional lymph nodes. The current clinical staging criteria fail to differentiate patients with occult metastasis from patients without metastasis. Identifying molecular markers of the disease might improve our understanding of the molecular mechanisms underlying the pathogenesis and development of laryngeal carcinoma and may help improve clinical staging and treatment. METHODS: Sixty-four previously untreated patients who underwent surgical excision of laryngeal squamous cell carcinoma with neck dissection were included in this study. The expression of B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) was examined immunohistochemically on formalin fixed paraffin-embedded primary tissue specimens. RESULTS: Nuclear expression of BMI-1 (nBMI-1) was detected in 32 of the 64 tumors (50%), cytoplasmic expression of BMI-1 (cBMI-1) was detected in 22 (34.4%), and 10 tumors (15.6%) showed no BMI 1 immunoreactivity. High nBMI-1 expression levels (>= 10) were detected in 28 of the 32 (87.5%) nBMI-1-positive patients. Multivariate analysis including age at diagnosis, grade, tumor location, TNM status, and nBMI-1 expression showed that a high nBMI-1 expression level was an independent prognostic factor for lymph node metastasis. CONCLUSION: The expression of BMI-1 in patients with laryngeal carcinoma seems to correlate with lymph node metastasis. PMID- 23031717 TI - Effect of cull potatoes in the diet for finishing Belgian Blue double-muscled cows. AB - The use of culled potatoes was investigated in Belgian Blue double-muscled finishing cows, confined in tie stalls. The control diet (Treatment 1) consisted of concentrate and maize silage (50/50 on a dry matter (DM) basis). Potatoes either replaced 60% maize silage (Treatment 2) or 60% concentrate (Treatment 3). Diets were formulated to be isocaloric and isonitrogenous. They were fed ad libitum. Approximately 18 kg potatoes were fed daily in Treatments 2 and 3. Daily gain was not significantly altered; it decreased from 1.09 kg (Treatment 1) to 1.04 kg (Treatment 2) or increased to 1.20 kg (Treatment 3), although potatoes stimulated DM intake by 5% to 8% (P < 0.05). Feed conversion was unaffected in comparison with the control diet, when expressed in terms of DM, but energy efficiency (MJ/kg live weight gain) was substantially lower for Treatment 2 compared with Treatment 1 (89.9 v. 79.0; P = 0.046). Carcass weight, grading and composition were not affected by treatments, but potatoes increased dressing percentage (P = 0.009). Treatment had no significant effect on meat quality parameters. However, potatoes (Treatments 2 and 3) tended to decrease moisture content (P = 0.090) and tended to increase drip loss (P = 0.059) compared with Treatment 1. Because of a better animal performance and a lower feed cost, it is most appropriate to use potatoes as a replacement for concentrate. Feeding large amounts of potatoes besides concentrate may have an adverse effect on the fibrousness of the diet, resulting in a tendency (-5%) for a reduced daily gain and a lower energy efficiency (P < 0.05). PMID- 23031718 TI - Strategies to mitigate nitrous oxide emissions from herbivore production systems. AB - Herbivores are a significant source of nitrous oxide (N(2)O) emissions. They account for a large share of manure-related N(2)O emissions, as well as soil related N(2)O emissions through the use of grazing land, and land for feed and forage production. It is widely acknowledged that mitigation measures are necessary to avoid an increase in N(2)O emissions while meeting the growing global food demand. The production and emissions of N(2)O are closely linked to the efficiency of nitrogen (N) transfer between the major components of a livestock system, that is, animal, manure, soil and crop. Therefore, mitigation options in this paper have been structured along these N pathways. Mitigation technologies involving diet-based intervention include lowering the CP content or increasing the condensed tannin content of the diet. Animal-related mitigation options also include breeding for improved N conversion and high animal productivity. The main soil-based mitigation measures include efficient use of fertilizer and manure, including the use of nitrification inhibitors. In pasture based systems with animal housing facilities, reducing grazing time is an effective option to reduce N(2)O losses. Crop-based options comprise breeding efforts for increased N-use efficiency and the use of pastures with N(2)-fixing clover. It is important to recognize that all N(2)O mitigation options affect the N and carbon cycles of livestock systems. Therefore, care should be taken that reductions in N(2)O emissions are not offset by unwanted increases in ammonia, methane or carbon dioxide emissions. Despite the abundant availability of mitigation options, implementation in practice is still lagging. Actual implementation will only follow after increased awareness among farmers and greenhouse gases targeted policies. So far, reductions in N(2)O emissions that have been achieved are mostly a positive side effect of other N-targeted policies. PMID- 23031719 TI - Primary adenocarcinoma of the navel: an uncommon entity. PMID- 23031720 TI - Effect of grain and forage fractions of corn silage on milk production and composition in dairy cows. AB - Corn silage (CS) is associated with a reduction in milk fat content. The fact that CS is constituted of a grain and a forage fraction could explain this effect. This experiment evaluated the effect of grain fraction of CS on rumen fermentation, production performance and milk composition. Earless CS (ECS) was harvested after manually removing corn ears from the plant. Whole CS (WCS) was harvested from the same field on the same day. Eight (four ruminally fistulated) multiparous Holstein cows (84 days in milk) were utilized in a double 4 * 4 Latin square with 21-day periods. Treatments were (dry matter (DM) basis) (1) 23.0% WCS; (2) 12.4% ECS plus 10.6% high moisture corn (HMC) to obtain reconstituted CS (RCS); (3) 23.0% ECS; and (4) 23.0% timothy silage (TS). Diets were formulated to be isonitrogenous and were fed as total mixed ration once a day. DM intake (DMI), milk yield, 4.0% fat-corrected milk (FCM), as well as protein concentration and yield were higher for WCS than ECS. Compared with WCS, cows tended to eat less with RCS, and produced less milk and milk protein. However, yield of FCM was similar between WCS and RCS. Milk fat concentration and yield, as well as the specific ratio of t11 18:1 to t10 18:1 in milk fat did not differ among diets. Milk urea-N tended to be higher for ECS than WCS and TS, whereas ruminal NH3-N was higher with ECS than TS. Rumen pH decreased linearly with time after feeding but was not different between treatments. Higher acetate and lower propionate concentration resulted in greater acetate to propionate ratio with ECS compared with WCS. In conclusion, removing grain fraction from CS decreased milk production and modified rumen fermentation without affecting milk fat concentration and yield. Moreover, despite some differences in DMI and total ruminal volatile fatty acid concentration between WCS and RCS, the restoration of FCM yield, using HMC in RCS diets, to a level of production similar to WCS highlights the importance of energy and nutrients supplied by the grain fraction of CS to support milk yield. PMID- 23031721 TI - Validation of fatty acid predictions in milk using mid-infrared spectrometry across cattle breeds. AB - The aim of this study was to investigate the accuracy to predict detailed fatty acid (FA) composition of bovine milk by mid-infrared spectrometry, for a cattle population that partly differed in terms of country, breed and methodology used to measure actual FA composition compared with the calibration data set. Calibration equations for predicting FA composition using mid-infrared spectrometry were developed in the European project RobustMilk and based on 1236 milk samples from multiple cattle breeds from Ireland, Scotland and the Walloon Region of Belgium. The validation data set contained 190 milk samples from cows in the Netherlands across four breeds: Dutch Friesian, Meuse-Rhine-Yssel, Groningen White Headed (GWH) and Jersey (JER). The FA measurements were performed using gas-liquid partition chromatography (GC) as the gold standard. Some FAs and groups of FAs were not considered because of differences in definition, as the capillary column of the GC was not the same as used to develop the calibration equations. Differences in performance of the calibration equations between breeds were mainly found by evaluating the standard error of validation and the average prediction error. In general, for the GWH breed the smallest differences were found between predicted and reference GC values and least variation in prediction errors, whereas for JER the largest differences were found between predicted and reference GC values and most variation in prediction errors. For the individual FAs 4:0, 6:0, 8:0, 10:0, 12:0, 14:0 and 16:0 and the groups' saturated FAs, short chain FAs and medium-chain FAs, predictions assessed for all breeds together were highly accurate (validation R 2 > 0.80) with limited bias. For the individual FAs cis-14:1, cis-16:1 and 18:0, the calibration equations were moderately accurate (R 2 in the range of 0.60 to 0.80) and for the individual FA 17:0 predictions were less accurate (R 2 < 0.60) with considerable bias. FA concentrations in the validation data set of our study were generally higher than those in the calibration data. This difference in the range of FA concentrations, mainly due to breed differences in our study, can cause lower accuracy. In conclusion, the RobustMilk calibration equations can be used to predict most FAs in milk from the four breeds in the Netherlands with only a minor loss of accuracy. PMID- 23031722 TI - Awareness and utilization of modern contraceptives among street women in North West Ethiopia. AB - BACKGROUND: Contraception is a major component of reproductive health. Assessing the levels of contraceptive awareness and use helps to identify potential areas of intervention. Hence, this study was conducted to assess awareness, practice and associated factors of modern contraceptives among street women in North-West Ethiopia. METHODS: A cross-sectional study was conducted on 204 street women from Gondar and Bahir Dar cities. Participants were recruited from "cluster" sites such as main road sides, isolated slum areas, around Churches and/or Mosques (in the mornings of Sundays and other religious feast days) and streets where street women usually reside and/or sleep. Data were collected using a pre-tested and structured interview questionnaire in local language (Amharic) after informed verbal consent. Data were then entered into SPSS version 16.0 for analysis. Binary logistic regression models were fit to assess associations and control confounding. Associations were measured by the Odds ratio and its 95% confidence interval. RESULTS: The mean (+/- SD) age of participants was 30.9 (+/- 8.7) years. Majority (90.7%) had ever heard about modern contraceptives. Nearly half (47.1%) had ever used and a third (34.3%) were current users. Three quarter of the current users (74.3%) were using injectables while 10% were on long acting or permanent methods. Marital status (AOR=2.81), family size (AOR=2.67) and age of 25-34 years (AOR=3.45) were associated with modern contraceptive use. CONCLUSIONS: Current contraceptive use among street women is satisfactory considering their life styles and living conditions. However, further research is required to explain perceptions and hidden barriers. PMID- 23031723 TI - Transcranial direct current stimulation and cognitive-behavioral therapy: evidence of a synergistic effect in treatment-resistant depression. PMID- 23031724 TI - Sources of sire-specific genetic variance for birth and weaning weight in Bruna dels Pirineus beef calves. AB - This research investigated two sources of sire-specific genetic effects on the birth weight (BWT) and weaning weight (WWT) of Bruna dels Pirineus beef calves. More specifically, we focused on the influence of genes located in the non autosomal region of the Y chromosome and the contribution of paternal imprinting. Our analyses were performed on 8130 BWT and 1245 WWT records from 12 and 2 purebred herds, respectively, they being collected between years 1986 and 2010. All animals included in the study were registered in the Yield Recording Scheme of the Bruna dels Pirineus breed. Both BWT and WWT were analyzed using a univariate linear animal model, and the relevance of paternal imprinting and Y chromosome-linked effects were checked by the deviance information criterion (DIC). In addition to sire-specific and direct genetic effects, our model accounted for random permanent effects (dam and herd-year-season) and three systematic sources of variation, that is, sex of the calf (male or female), age of the dam at calving (six levels) and birth type (single or twin). Both weight traits evidenced remarkable effects from the Y chromosome, whereas paternal imprinting was only revealed in WWT. Note that differences in DIC between the preferred model and the remaining ones exceed 39 000 and 2 800 000 DIC units for BWT and WWT, respectively. It is important to highlight that Y chromosome accounted for ~2% and ~6% of the total phenotypic variance for BWT and WWT, respectively, and paternal imprinting accounted for ~13% of the phenotypic variance for WWT. These results revealed two relevant sources of sire-specific genetic variability with potential contributions to the current breeding scheme of the Bruna dels Pirineus beef cattle breed; moreover, these sire-specific effects could be included in other beef cattle breeding programs or, at least, they must be considered and appropriately analyzed. PMID- 23031725 TI - Subapical osteotomy to correct dental implant malpositioning and vertical ridge deficiency: a clinical report. AB - This clinical report describes a subapical osteotomy to correct vertical ridge deficiency and malpositioned maxillary anterior implants. A 37-year-old woman with a noncontributory medical history presented with the chief complaint of an unesthetic implant-supported prosthesis. The maxillary left central and lateral incisors were restored with metal ceramic restorations. Gingiva-colored porcelain was fabricated to compensate for severe vertical and horizontal soft tissue deficiency. The patient was dissatisfied with the esthetics associated with the restorations and soft tissues since she presented with a high smile line and gingival display. Under general anesthesia, a subapical osteotomy was performed. The implant and ridge segment was coronally repositioned to correct the ridge deficiency. The surgical procedure and postoperative healing were uneventful. The surgical outcome was stable for a follow-up period of 3 years. The subapical osteotomy provided a satisfactory clinical outcome in managing a severely deficient residual ridge and malpositioned maxillary anterior implants as an alternative treatment to other surgical approaches. PMID- 23031726 TI - Allergic contact stomatitis caused by a titanium nitride-coated implant abutment: a clinical report. AB - A patient developed contact mucositis after being treated with a titanium nitride implant abutment. Patch testing disclosed a positive reaction to titanium nitride. After removal of the titanium nitride-coated abutment and placement of an uncoated abutment, all signs and symptoms disappeared. This clinical report suggests that titanium nitride-coated abutments may be a potential allergen in some patients. PMID- 23031727 TI - Clinical efficacy of veneered zirconium dioxide-based posterior partial fixed dental prostheses: five-year results. AB - STATEMENT OF PROBLEM: In recent years, zirconium dioxide-based partial fixed dental prostheses (FDP) have been suggested as an alternative treatment to traditional metal ceramic FDPs. However, clinical studies evaluating their longevity and related complications are limited. PURPOSE: The purpose of this cohort clinical study was to assess the efficacy of zirconium dioxide-based posterior 3-unit FDPs. MATERIAL AND METHODS: Twenty 3-unit posterior FDPs (Lava) were placed in 16 participants missing a second premolar or a first molar. All participants met specific inclusion and exclusion criteria and provided informed consent. All teeth were prepared in a standardized manner: occlusal reduction of 1.5 to 2 mm; axial reduction of 1 to 1.5 mm; a 1.0 mm 360-degree rounded shoulder placed 0.5 mm subgingivally on the facial aspect and supragingivally on the lingual aspect on sound tooth structure; and rounded internal line angles. Definitive impressions were made with vinyl polysiloxane impression material. Frameworks were fabricated by using computer-aided design and computer-aided manufacturing (CAD/CAM) technology with a uniform retainer thickness of 0.6 mm and a minimal connector surface area of 9 mm(2). Restorations were luted with resin-modified glass ionomer cement (Rely-X Luting). Participants were recalled at 2 weeks, 6 months, and 12 months, and thereafter, annually for up to 60 months. Clinical fracture measurements, marginal discoloration, marginal adaptation, radiographic proximal recurrent caries, and periapical pathoses were assessed over time by using modified Ryge criteria. The probability distributions of these variables were calculated for the baseline data and for the recall data. An analysis of survival was made by using the Kaplan-Meier method. RESULTS: Eighteen FDPs were clinically evaluated at 5 years and 1 at 48 months. Fifteen were rated Alpha for fracture measurements, and 2 were rated Bravo (minor chipping of veneering porcelain and not requiring restoration replacement). Two were rated Charlie (major chipping of veneering porcelain and requiring restoration replacement). Eighteen FDPs were rated Alpha for marginal integrity, and 1 rated Bravo. All restorations were rated Alpha for marginal discoloration. One participant experienced root fracture after 60 months, while another was treated surgically for a periapical pathosis on an endodontically treated abutment. CONCLUSIONS: Zirconium dioxide-based posterior 3-unit FDPs performed well after 5 years of service. PMID- 23031728 TI - Accelerated aging characteristics of three yttria-stabilized tetragonal zirconia polycrystalline dental materials. AB - STATEMENT OF PROBLEM: Concerns have been expressed about the effect of aging on the mechanical properties of zirconia. PURPOSE: The purpose of this study was to assess the accelerated aging characteristics of 3 commercially available yttria stabilized tetragonal zirconia polycrystalline (Y-TZP) materials by exposing specimens to hydrothermal treatments at 134 degrees C, 0.2 MPa and 180 degrees C, 1.0 MPa in steam. MATERIAL AND METHODS: Thin bars of Y-TZP from 3 manufacturers, Lava, Zirkonzahn, and Zirprime, n=30 for each brand (22 * 3 * 0.2 mm), were cut and ground from blocks and sintered according to the manufacturer's specifications. Control specimens (n=10) for each brand were evaluated in the as received condition. Experimental specimens were artificially aged at standard autoclave sterilization conditions,134 degrees C at 0.2 MPa (n=5 per group at 50, 100, 150, and 200 hours) and standard industrial ceramic aging conditions, 180 degrees C at 1.0 MPa (n=5 per group at 8, 16, 24, 28, and 48 hours). Tetragonal to monoclinic transformation was measured by using X-ray diffraction (XRD) for all groups. Flexural strength was measured in 4-point bending (ASTM1161-B) for all groups. Fracture surfaces were examined by scanning electron microscopy (SEM). Data were analyzed as a function of aging time. The statistical comparisons were based on the log value and 2-way ANOVA with heteroscedasticity consistent standard errors used to compare mean strength among conditions (alpha=.05). RESULTS: After 200 hours at 134 degrees C and 0.2 MPa, flexural strength (SD) decreased significantly from 1156 (87.6) MPa to 829.5 (71) MPa for Lava; 1406 (243) MPa to 882.7 (91) MPa for Zirkonzahn; and 1126 (92.4) MPa to 976 (36.4) MPa for Zirprime with P<.001 for all 3 comparisons. After 200 hours at 134 degrees C and 0.2 MPa, some tetragonal crystals transformed to the monoclinic phase. The relative XRD peak intensity of the monoclinic to tetragonal crystal phases increased from 0.07 to 1.82 for Lava, from 0.06 to 2.43 for Zirkonzahn, and from 0.05 to 0.53 for Zirprime. After 28 hours at 180 degrees C and 1.0 MPa, all Lava and Zirkonzahn specimens spontaneously fractured during aging. The Noritake specimens were intact after 48 hours, and the flexural strength showed no significant change, 1156 (87.6) MPa to 1122 (108) MPa. The flexural strength decreased with an increase in the monoclinic phase. SEM micrographs revealed a transformed layer on the fracture surfaces. CONCLUSIONS: Hydrothermal aging of Y TZP can cause significant transformation from tetragonal to monoclinic crystal structure, which results in a statistically significant decrease in the flexural strength of thin bars. Although the strengths of all 3 Y-TZP materials are higher than other materials used for ceramic restorations, there are notable differences among them. PMID- 23031729 TI - Effects of different surface treatments on stainability of ceramics. AB - STATEMENT OF PROBLEM: Final adjustments may result in a loss of ceramic glaze, a situation which must be corrected by reglazing or polishing to obtain clinically successful restorations; such restorations may be susceptible to staining. PURPOSE: The purpose of this study was to determine the stainability of ceramics exposed to coffee after different surface treatments and to correlate the surface roughness with the color differences. MATERIAL AND METHODS: Sixty-six ceramic (IPS e.maxCeram) disks (15 * 2 mm) were fabricated and glazed according to the manufacturer's instructions, then assigned to 6 groups. Group Glaze (Group G), the control, was not subjected to any procedure. All the others were abraded with a diamond rotary cutting instrument. Group Reglaze (Group R) was reglazed; others were polished with different polishing materials; Group Shofu (Group S) was polished with abrasive stone (Dura-Green Stones), coarse silicon polisher (Ceramaster Coarse), silicon polisher (CeraMaster), and polishing paste (Ultra II) with polishing disks (Super-Snap Buff Disks); Group Ultradent (Group U) was polished with 1.0 and 0.5-MUm polishing pastes (Ultradent Diamond) with a goat hair brush (Jiffy) and Group Bredent (Group B) was polished with an abrasive stone (Diagen turbo grinder), a round polishing brush (Abraso-fix), and polishing paste (Diamond) with felt wheels. Group Diamond rotary cutting instrument (Group D) was not treated after abrasion with a diamond rotary cutting instrument. Surface roughness was evaluated by profilometer (n=10), and 1 specimen from each group was evaluated by scanning electron microscopy (SEM). Color difference was measured by a spectrophotometer before and after 12 days of immersion in a coffee solution. Data were analyzed by 1-way ANOVA, the Tukey HSD test, and the Pearson rank correlation tests (alpha=.05). RESULTS: The surface roughness (Ra) values were ordered from the highest to the lowest value, which were Group D, B, U, S, R, and G, respectively. Significant differences among groups (P<.01) were found, except for G and R. There were no significant differences between the color difference values of Groups G and R, both of which were significantly lower than the other groups (P<.01). Group D showed the highest DeltaE values (>2), which is considered clinically unacceptable (P<.01). No significant differences were found among the S, U, and B groups. There was an 83% positively significant relationship between Ra and DeltaE values (P<.01). Rough surfaces stained more after coffee immersion than did smooth surfaces. CONCLUSIONS: Surface treatments affected surface roughness and color stability. Smooth surfaces showed better color stability after discoloration. Ceramic staining may be related to surface texture changes after different surface treatments. PMID- 23031731 TI - Preparation time and surface roughness of core foundation resins and dentin. AB - STATEMENT OF PROBLEM: It is unclear if the preparation of core foundation resins is similar to that of dentin. PURPOSE: The purpose of this in vitro study was to compare the preparation time and resulting roughness of 5 core foundation resins and dentin. MATERIAL AND METHODS: Standardized preparations (10 mm length, 5 mm height) were made of 5 specimens of 5 core materials with a device-mounted dental handpiece (150 000 rpm, water-cooling) with weight-controlled contact pressure (50 g). To assess the cutting time of 100 MUm grit cylindrical diamond rotary cutting instruments, 2 mm and 4 mm depths were cut 3 times (n=15). Afterwards surface roughness Ra and Rz were measured. Blocks of dentin were used as a control. Both preparation time and surface roughness data were statistically analyzed (1-way ANOVA, Scheffe correction, alpha=.05). RESULTS: The average preparation times for dentin were 7 seconds for a 2 mm preparation depth and 22 seconds for a 4 mm depth with an average Ra of 5.4 MUm or Rz of 30 MUm. For a 4 mm depth, preparation times for Build-It, Rebilda LC, and Ti-Core ranged from 24 to 27 seconds. The preparation times of these 3 core foundation materials did not differ significantly from dentin for a 4 mm depth. The results of Core Paste and Luxacore were significantly lower (10 and 11 seconds, P<.001). For a 2 mm cutting depth, Core Paste and Luxacore showed similar preparation times compared to dentin (7 seconds, P>.05). Build-It (12 seconds) and Rebilda LC (10 seconds) showed greater preparation times compared to dentin, whereas Ti-Core preparation (5 seconds) was less. ANOVA revealed significantly lower Ra (5.0 MUm) and Rz values (23-26 MUm) after preparation of Core Paste, Luxacore, and Ti-Core than those of dentin (P<.05). CONCLUSIONS: The preparation times of only some core foundation materials were comparable to dentin. Regarding the cutting depths, different materials provided a dentin-like preparation ability. The surface roughness values of core resins were comparable with or significantly lower than those of dentin. PMID- 23031730 TI - The influence of implant placement depth and impression material on the stability of an open tray impression coping. AB - STATEMENT OF PROBLEM: Subgingival positioning of a single dental implant may result in a less stable impression coping in a polymerized impression material. PURPOSE: The purpose of this study was to evaluate the influence of a single dental implant placement depth and different impression materials on the stability of an open tray impression coping. MATERIAL AND METHODS: Six polyvinyl chloride-based plastic models with single embedded internal hexagon implant analogs were fabricated. The implant analogs were placed equally with their surface 0, 1, 2, 3, 4, or 5 mm below the simulated gingival margin. Open tray impression copings were connected to the embedded implant analogs, and impressions were made with different vinyl polysiloxane (VPS) impression materials, polyethers, and an addition silicone-based occlusal registration material. The laboratory analogs were connected to the impression copings and the plastic trays were placed in a locking device. A measuring device, consisting of a compression force gauge connected to a platform moving at a speed of 3.2 mm/s, was fabricated. The impression trays were fixed so that the pole of the force gauge would touch the surface of the implant analog in the same place and push it 1.0 mm. Measurements of each specimen were made 5 times. Statistical analysis was performed with a 1-way ANOVA, the Tukey test, and the Pearson correlation coefficient (alpha=.05). RESULTS: There was a significant negative correlation between the dental implant placement depth and the force needed to move the impression coping (P<.05). In all depth groups, the impression coping was significantly more stable when the impressions were made with the occlusal registration material (P<.05). CONCLUSIONS: As the dental implant placement depth increased, the force needed to move the impression coping decreased. The coping was significantly more stable when an occlusal registration material was used to make the impression. PMID- 23031732 TI - Effect of disinfection on irreversible hydrocolloid and alternative impression materials and the resultant gypsum casts. AB - STATEMENT OF PROBLEM: Many new products have been introduced and marketed as alternatives to traditional irreversible hydrocolloid materials. These alternative materials have the same structural formula as addition reaction silicone, also known as vinyl polysiloxane (VPS), impression materials. Currently, there is limited in vitro and in vivo research on these products, including on the effects of chemical disinfectants on the materials. PURPOSE: The purpose of this study was to compare the effects of a spray disinfecting technique on a traditional irreversible hydrocolloid and 3 new alternative impression materials in vitro. MATERIAL AND METHODS: The tests were performed in accordance with the American National Standards Institute/American Dental Association (ANSI/ADA) Specification Nos. 18 and 19. Under standardized conditions, 100 impressions were made of a ruled test block with an irreversible hydrocolloid and 3 alternative impression materials. Nondisinfected irreversible hydrocolloid was used as the control. The impressions were examined for surface detail reproduction before and after disinfection with a chloramine-T product. Type III and Type V dental stone casts were evaluated for linear dimensional change and gypsum compatibility. Comparisons of linear dimensional change were analyzed with 2-way ANOVA of mean ranks with the Scheffe post hoc comparisons (alpha=.05). Data for surface detail reproduction were analyzed with the Wilcoxon Signed-Rank procedure and gypsum compatibility with the Kruskal-Wallis Rank procedure (alpha=.05). RESULTS: The alternative impression materials demonstrated significantly better outcomes with all 3 parameters tested. Disinfection with chloroamine-T did not have any effect on the 3 alternative impression materials. The irreversible hydrocolloid groups produced the most variability in the measurements of linear dimensional change. All of the tested materials were within the ADA's acceptable limit of 1.0% for linear dimensional change, except for the disinfected irreversible hydrocolloid impression material. CONCLUSIONS: The alternative impression materials performed best for the parameters tested. Spray disinfection had no effect on the alternative impression materials. PMID- 23031733 TI - Esthetic considerations related to bone and soft tissue maintenance and development around dental implants: report of the Committee on Research in Fixed Prosthodontics of the American Academy of Fixed Prosthodontics. AB - In recent years the frequency of and esthetic demand for implant restorations in the esthetic zone has increased. Recent literature has revealed numerous consistent trends which may aid the clinician in achieving predictable esthetics. Maintaining generous facial bone by judicious placement as well as by using implants with diameters of less than 4 mm appears to be beneficial. Avoiding adjacent implants in the esthetic zone while maintaining an implant to tooth distance of between 2 mm and 4 mm seems to aid in bone and soft tissue maintenance. Abutment connections in which the abutment is narrower than the implant offer distinct advantages, most notably increased bone heights. Also, provisional restoration, especially early in treatment provides long-term esthetic benefits. PMID- 23031734 TI - Lead foil technique for partially edentulous radiographic guide. PMID- 23031735 TI - Evaluation of blood and milk oxidative status during early postpartum of dairy cows. AB - In dairy cows, the intensity of metabolic activity, associated with the negative energy balance (NEBAL), is responsible for an increased production of reactive oxygen species (ROS) and, subsequently, for the development of the condition of oxidative stress, which may overwhelm the antioxidant potential of the bovine maternal organism, making it prone to the development of many puerperal dysfunctions, as well as to an alteration of colostrum and milk quality. Given these premises, the aims of this study are to evaluate serum and milk concentrations of ROS and lipoperoxides, vitamins A and E, on the 10th, 12th, 14th and 16th day postpartum of dairy cows, a particularly critical period during which the NEBAL reaches its nadir, and to compare the trends of these parameters in two different bovine breeds. The study was performed in pluriparous Italian Friesian and Brown dairy cows. On the 10th day postpartum, all cows underwent a clinical examination to exclude the presence of alterations; furthermore, on the same day, a milk sample was collected from each cow, in order to perform the somatic cell count (SCC; (CE) N. 853/2004) and to establish which of them had an SCC <=400,000/ml or >400,000/ml. In this study, among the 110 cows that were initially selected, the evaluation of these parameters allowed the inclusion of 80 animals, which were divided into four groups of 20 subjects each: Group F and F1: Italian Friesian healthy cows, with SCC <=400,000/ml and >400,000/ml, respectively; Group B and B1: Italian Brown healthy cows, with SCC <=400,000/ml and >400,000/ml, respectively. On the 10th, 12th, 14th and 16th day postpartum, peripheral blood and milk samples were collected. The results obtained show that in group B1 there were higher concentrations of ROS and milk antioxidants compared with Friesian group cows. This datum let us suppose that even in the presence of higher ROS concentrations the antioxidant status found in group B1 seems to be able to counteract the oxidative damage, which is more likely to develop in these cows. PMID- 23031736 TI - Mortality and loss to programme before antiretroviral therapy among HIV-infected children eligible for treatment in The Gambia, West Africa. AB - BACKGROUND: HIV infection among children, particularly those under 24 months of age, is often rapidly progressive; as a result guidelines recommend earlier access to combination antiretroviral therapy (cART) for HIV infected children. Losses to follow-up (LTFU) and death in the interval between diagnosis and initiation of ART profoundly limit this strategy. This study explores correlates of LTFU and death prior to ART initiation among children. METHODS: The study is based on 337 HIV-infected children enrolled into care at an urban centre in The Gambia, including those alive and in care when antiretroviral therapy became available and those who enrolled later. Children were followed until they started ART, died, transferred to another facility, or were LTFU. Cox proportional hazards regression models were used to determine the hazard of death or LTFU according to the baseline characteristics of the children. RESULTS: Overall, 223 children were assessed as eligible for ART based on their clinical and/or immunological status among whom 73 (32.7%) started treatment, 15 (6.7%) requested transfer to another health facility, 105 (47.1%) and 30 (13.5%) were lost to follow-up and died respectively without starting ART. The median survival following eligibility for children who died without starting treatment was 2.8 months (IQR: 0.9 - 5.8) with over half (60%) of all deaths occurring at home. ART eligible children less than 2 years of age and those in WHO stage 3 or 4 were significantly more likely to be LTFU when compared with their respective comparison groups. The overall pre-treatment mortality rate was 25.7 per 100 child-years of follow-up (95% CI 19.9 - 36.8) and the loss to programme rate was 115.7 per 100 child-years of follow-up (95% CI 98.8 - 137). In the multivariable Cox proportional hazard model, significant independent predictors of loss to programme were being less than 2 years of age and WHO stage 3 or 4. The Adjusted Hazard Ratio (AHR) for loss to programme was 2.06 (95% CI 1.12 - 3.83) for being aged less than 2 years relative to being 5 years of age or older and 1.92 (95% CI 1.05 - 3.53) for being in WHO stage 3 or 4 relative to WHO stage 1 or 2. CONCLUSIONS: Earlier enrolment into HIV care is key to achieving better outcomes for HIV infected children in developing countries. Developing strategies to ensure early diagnosis, elimination of obstacles to prompt initiation of therapy and instituting measures to reduce losses to follow-up, will improve the overall outcomes of HIV-infected children. PMID- 23031737 TI - Dietary fatty acids and cardiovascular disease. AB - In 1991, the Committee on Medical Aspects of Food Policy produced a report on the dietary reference values for food energy and nutrients for groups of people in the United Kingdom. The resulting recommendations, which included specific limits for intakes of total, saturated, trans- and cis-polyunsaturated fatty acids (PUFA) have remained a cornerstone of public health policy ever since, and similar recommendations have been adopted by the World Health Organization. These recommendations were made largely on the basis of specific effects of these fatty acids on the risk of developing atherosclerotic cardiovascular disease (CVD). The intervening years have seen a plethora of human epidemiological and intervention trials to further elucidate the specific relationship between dietary fatty acid intake, plasma lipids and lipoproteins and cardiovascular morbidity and mortality. A number of recent meta-analyses and systematic reviews have revisited the role of specific dietary fatty acid classes and CVD risk. In general, these continue to support a link between saturated fatty acids (SFA) and CVD morbidity/mortality. They also highlight the potent adverse effects of trans fatty acids derived from partially hydrogenated vegetable oil. The most recent data suggest that replacing SFA with cis-PUFA (primarily linoleic acid) has the greatest impact on reducing CVD risk. Evidence of specific beneficial effects of n-3 PUFA is generally stronger for secondary, rather than primary, CVD risk, and it is restricted to very long chain fatty acids of marine origin as opposed to alpha-linolenic acid. Taken together, these data suggest that recent focus on dietary n-6-to-n-3 PUFA ratios may have been misguided, and that future strategies should focus on replacing dietary SFA with total PUFA, rather than concentrating on n-6 : n-3 PUFA ratio. PMID- 23031738 TI - Chronic hepatitis E virus infection in a patient with leukemia and elevated transaminases: a case report. AB - INTRODUCTION: Acute hepatitis E virus infection may cause mild, self-limiting hepatitis, either as epidemic outbreaks or sporadic cases, the latter of which have been reported in industrialized countries. Chronic infections are uncommon and have been reported in immunosuppressed patients, patients with human immunodeficiency virus infection, and patients with hematological malignancies. CASE PRESENTATION: A 46-year-old Caucasian man was admitted to the gastroenterology clinic with a history of increasing transaminases, persistent exhaustion, and occasional right-side abdominal pain over the course of a 6-month period. B-cell chronic lymphocytic leukemia had been diagnosed several years earlier, and the patient was treated with rituximab, pentostatin, and cyclophosphamide. A diagnostic workup ruled out autoimmune and metabolic liver disease, hepatitis A-C, and herpes virus infection. A physical examination revealed enlarged axillary lymph nodes. The results of an abdominal ultrasound examination were otherwise unremarkable. Hepatitis E virus infection was diagnosed by detection of hepatitis E virus-specific antibodies. Blood samples were positive for hepatitis E virus ribonucleic acid with high viral loads for at least 8 months, demonstrating a rare chronic hepatitis E virus infection. Sequencing and phylogenetic analysis revealed hepatitis E virus genotype 3c with homologies to other European isolates from humans and swine, indicating an autochthonous infection. CONCLUSIONS: Usually, hepatitis E virus infection appears as an acute infection; rare chronic infections have been reported for transplant patients, patients with human immunodeficiency virus, and patients with hematological malignancies. The chronic nature of hepatitis E infection in our patient was most likely induced by the immunosuppressive B-cell chronic lymphocytic leukemia treatment. The differential diagnosis in patients with unexplained hepatitis should include hepatitis E virus infection, and appropriate laboratory analyses should be considered. PMID- 23031739 TI - Calcification of vestibular schwannoma: a case report and literature review. AB - Calcification rarely occurs in vestibular schwannoma (VS), and only seven cases of calcified VS have been reported in the literature. Here, we report a 48-year old man with VS, who had a history of progressive left-sided hearing loss for 3 years. Neurological examination revealed that he had left-sided hearing loss and left cerebellar ataxia. Magnetic resonance imaging and computerized tomography angiography showed a mass with calcification in the left cerebellopontine angle (CPA). The tumor was successfully removed via suboccipital craniotomy, and postoperative histopathology showed that the tumor was a schwannoma. We reviewed seven cases of calcified VS that were previously reported in the literature, and we analyzed and summarized the characteristics of these tumors, including the calcification, texture, and blood supply. We conclude that calcification in VS is associated with its texture and blood supply, and these characteristics affect the surgical removal of the tumor. PMID- 23031740 TI - Li-Fraumeni syndrome with simultaneous osteosarcoma and liver cancer: increased expression of a CD44 variant isoform after chemotherapy. AB - BACKGROUND: Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome that is commonly associated with a germline mutation in the tumor suppressor gene p53. Loss of p53 results in increased expression of CD44, a cancer stem cell (CSC) marker, which is involved in the scavenging of reactive oxygen species (ROS). Here, we report a change in the expression of a CD44 variant isoform (CD44v8-10) in an 8-year-old female LFS patient with osteosarcoma and atypical liver cancer after chemotherapy. CASE PRESENTATION: The patient visited a clinic with a chief complaint of chronic pain in a bruise on her right knee. Magnetic resonance imaging (MRI) raised the possibility of a bone malignancy. Biochemical testing also revealed significantly elevated levels of AFP, which strongly suggested the existence of a primary malignancy in the liver. MRI imaging showed the simultaneous development of osteosarcoma and liver cancer, both of which were confirmed upon biopsy. Combined therapy with surgical resection after chemotherapy was successful in this patient. Regardless of the absence of a familial history of hereditary cancer, a germline mutation in p53 was identified (a missense mutation defined as c.722 C>T, p.Ser241Phe). To better understand the cancer progression and response to treatment, immunohistochemical (IHC) analysis of biopsy specimens obtained before and after chemotherapy was performed using a specific antibody against CD44v8-10. CONCLUSION: This case demonstrates the ectopic up-regulation of CD44v8-10 in a biopsy sample obtained after cytotoxic chemotherapy, which confers high levels of oxidative stress on cancer cells. Because the alternative splicing of CD44 is tightly regulated epigenetically, it is possible that micro-environmental stress resulting from chemotherapy caused the ectopic induction of CD44v8-10 in vivo. PMID- 23031741 TI - Trends in greenhouse gas emissions from consumption and production of animal food products - implications for long-term climate targets. AB - To analyse trends in greenhouse gas (GHG) emissions from production and consumption of animal products in Sweden, life cycle emissions were calculated for the average production of pork, chicken meat, beef, dairy and eggs in 1990 and 2005. The calculated average emissions were used together with food consumption statistics and literature data on imported products to estimate trends in per capita emissions from animal food consumption. Total life cycle emissions from the Swedish livestock production were around 8.5 Mt carbon dioxide equivalents (CO2e) in 1990 and emissions decreased to 7.3 Mt CO2e in 2005 (14% reduction). Around two-thirds of the emission cut was explained by more efficient production (less GHG emission per product unit) and one-third was due to a reduced animal production. The average GHG emissions per product unit until the farm-gate were reduced by 20% for dairy, 15% for pork and 23% for chicken meat, unchanged for eggs and increased by 10% for beef. A larger share of the average beef was produced from suckler cows in cow-calf systems in 2005 due to the decreasing dairy cow herd, which explains the increased emissions for the average beef in 2005. The overall emission cuts from the livestock sector were a result of several measures taken in farm production, for example increased milk yield per cow, lowered use of synthetic nitrogen fertilisers in grasslands, reduced losses of ammonia from manure and a switch to biofuels for heating in chicken houses. In contrast to production, total GHG emissions from the Swedish consumption of animal products increased by around 22% between 1990 and 2005. This was explained by strong growth in meat consumption based mainly on imports, where growth in beef consumption especially was responsible for most emission increase over the 15-year period. Swedish GHG emissions caused by consumption of animal products reached around 1.1 t CO2e per capita in 2005. The emission cuts necessary for meeting a global temperature-increase target of 2 degrees might imply a severe constraint on the long-term global consumption of animal food. Due to the relatively limited potential for reducing food-related emissions by higher productivity and technological means, structural changes in food consumption towards less emission-intensive food might be required for meeting the 2 degrees target. PMID- 23031742 TI - Leukocytosis in patients with neurologic deterioration after acute ischemic stroke is associated with poor outcomes. AB - BACKGROUND: Neurologic deterioration (ND) after acute ischemic stroke (AIS) has been shown to result in poor outcomes. ND is thought to arise from penumbral excitotoxic cell death caused in part by leukocytic infiltration. Elevated admission peripheral leukocyte levels are associated with poor outcomes in stroke patients who suffer ND, but little is known about the dynamic changes that occur in leukocyte counts around the time of ND. We sought to determine if peripheral leukocyte levels in the days surrounding ND are correlated with poor outcomes. METHODS: Patients with AIS who presented to our center within 48 hours of symptom onset between July 2008 and June 2010 were retrospectively identified by chart review and screened for ND (defined as an increase in National Institutes of Health Stroke Scale score >= 2 within a 24-hour period). Patients were excluded for steroid use during hospitalization or in the month before admission and infection within the 48 hours before or after ND. Demographics, daily leukocyte counts, and poor functional outcome (modified Rankin Scale score 3-6) were investigated. RESULTS: Ninety-six of the 292 (33%) patients screened had ND. The mean age was 69.5 years; 62.5% were male and 65.6% were black. Patients with a poor functional outcome had significantly higher leukocyte and neutrophil levels 1 day before ND (P = .048 and P = .026, respectively), and on the day of ND (P = .013 and P = .007, respectively), compared to patients with good functional outcome. CONCLUSIONS: Leukocytosis at the time of ND correlates with poor functional outcomes and may represent a marker of greater cerebral damage through increased parenchymal inflammation. PMID- 23031743 TI - Methods for extra-low voltage transcranial direct current stimulation: current and time dependent impedance decreases. AB - OBJECTIVE: Though tDCS is well tolerated, it is desirable to further limit the voltage applied for additional safety factors and optimized device design. We investigated the minimum voltage required for tDCS using 1.5 and 2.5mA. METHODS: Impedance data has been collected prior to, during and after 18 tDCS sessions, using 1.5mA and 2.5mA tDCS currents and three different test current magnitudes. Data was pooled and tested for differences using t-tests, corrected for multiple comparisons. Average impedance data was fitted into a RLC circuit model with additional double integrator. RESULTS: We report that the impedance drop during tDCS initiation significantly reduces the voltage compliance required to achieve the target current (14.5V for 1.5mA, 18.5V for 2.5mA). Data was well approximated by a 4th order linear impedance model. CONCLUSION: In addition to indicating the feasibility of reduced voltage tDCS, we propose an extra-low voltage "Limited Total Energy" approach where stimulation is continued at voltage compliance allowing time for impedance to decrease and target current to be reached. SIGNIFICANCE: Reduced-voltage and Limited Total Energy tDCS are viable approaches towards more protective and robust tDCS protocols. PMID- 23031744 TI - Source reconstruction based on subdural EEG recordings adds to the presurgical evaluation in refractory frontal lobe epilepsy. AB - OBJECTIVE: In presurgical investigations of refractory frontal lobe epilepsy, subdural EEG recordings offer extensive cortical coverage, but may overlook deep sources. Electrical Source Localization (ESL) from subdural recordings could overcome this sampling limitation. This study aims to assess the clinical relevance of this new method in refractory frontal lobe epilepsy associated with focal cortical dysplasia. METHODS: In 14 consecutive patients, we retrospectively compared: (i) the ESL of interictal spikes to the conventional irritative and seizure onset zones; (ii) the surgical outcome of cases with congruent ESL and resection volume to cases with incongruent ESL and resection volume. Each spike type was averaged to serve as a template for ESL by the MUSIC and sLORETA algorithms. Results were superimposed on the corresponding pre and post-surgical MRI. RESULTS: Both ESL methods were congruent and consistent with conventional electroclinical analysis in all patients. In 7 cases, ESL identified a common deep source for spikes of different 2D localizations. The inclusion of ESL in the resection volume correlated with seizure freedom. CONCLUSIONS: ESL from subdural recordings provided clinically relevant results in patients with refractory frontal lobe epilepsy. SIGNIFICANCE: ESL complements the conventional analysis of subdural recordings. Its potential in improving tailored resections and surgical outcomes should be prospectively assessed. PMID- 23031745 TI - The impact of probable anxiety and mood disorder on self-reported collisions: a population study. AB - BACKGROUND: Individuals diagnosed with psychiatric disorder are at significantly increased risk of death and serious injury, to which motor vehicle collisions may be important contributors. This study examined the association between probable anxiety or mood disorder (AMD) and self-reported collision risk in a large representative sample of the adult population in Ontario. METHODS: Based on data from a regionally stratified general-population telephone survey of adults conducted from 2002 through 2009 (N=12,830), a logistic regression analysis examined self-reported collision involvement in the previous 12 months by measures of demographic characteristics, driving exposure, impaired driving behaviour, and probable AMD. RESULTS: Controlling for demographic variables and potential confounders, probable AMD was associated with an increased risk of collision involvement (OR=1.78, 95% CI=1.37, 2.31). LIMITATIONS: The use of self report measures and the potential for bias created by groups excluded because they do not have access to landline telephones represent limitations to the current findings. Nevertheless, the benefits of a large sample derived from general population survey data far outweigh these limitations. CONCLUSIONS: The results suggest that the increased risk of injury and mortality associated with some psychiatric disorders is at least partially related to increased risk of collision involvement. The magnitude of the increase in risk associated with probable AMD is similar to that seen among individuals who drive after drinking or using cannabis. In view of these findings, more work to understand this risk among individuals experiencing probable AMD and how it can be avoided is necessary. PMID- 23031746 TI - Mural nodules in multiple cavernous haemangioma. PMID- 23031748 TI - Abducens nerve palsy as the unique sign of a trigeminal schwannoma. PMID- 23031747 TI - The functional anatomy of non-verbal (pitch memory) function in left and right anterior temporal lobectomy patients. AB - An fMRI pitch memory task was administered to left and right anterior temporal lobectomy (ATL) patients. The goal was to verify the neuroanatomical correlates of non-verbal memory, and to determine if pitch memory tasks can identify cognitive risk prior to ATL. The data showed that the bilateral posterior superior temporal lobes implement pitch memory in both ATL patients and NCs (normal controls), indicating that the task can be accomplished with either anterior temporal lobe resected. NCs activate the posterior temporal lobes more strongly than ATL patients during highly accurate performance. In contrast, both ATL groups activate the anterior cingulate in association with accuracy. While our data clarifies the functional neuroanatomy of pitch memory, it also indicates that such tasks do not serve well to lateralize and functionally map potentially "at risk" non-verbal memory skills prior to ATL. PMID- 23031749 TI - Cancer classification: Mutual information, target network and strategies of therapy. AB - BACKGROUND: Cancer therapy is a challenging research area because side effects often occur in chemo and radiation therapy. We intend to study a multi-targets and multi-components design that will provide synergistic results to improve efficiency of cancer therapy. METHODS: We have developed a general methodology, AMFES (Adaptive Multiple FEature Selection), for ranking and selecting important cancer biomarkers based on SVM (Support Vector Machine) classification. In particular, we exemplify this method by three datasets: a prostate cancer (three stages), a breast cancer (four subtypes), and another prostate cancer (normal vs. cancerous). Moreover, we have computed the target networks of these biomarkers as the signatures of the cancers with additional information (mutual information between biomarkers of the network). Then, we proposed a robust framework for synergistic therapy design approach which includes varies existing mechanisms. RESULTS: These methodologies were applied to three GEO datasets: GSE18655 (three prostate stages), GSE19536 (4 subtypes breast cancers) and GSE21036 (prostate cancer cells and normal cells) shown in. We selected 96 biomarkers for first prostate cancer dataset (three prostate stages), 72 for breast cancer (luminal A vs. luminal B), 68 for breast cancer (basal-like vs. normal-like), and 22 for another prostate cancer (cancerous vs. normal. In addition, we obtained statistically significant results of mutual information, which demonstrate that the dependencies among these biomarkers can be positive or negative. CONCLUSIONS: We proposed an efficient feature ranking and selection scheme, AMFES, to select an important subset from a large number of features for any cancer dataset. Thus, we obtained the signatures of these cancers by building their target networks. Finally, we proposed a robust framework of synergistic therapy for cancer patients. Our framework is not only supported by real GEO datasets but also aim to a multi-targets/multi-components drug design tool, which improves the traditional single target/single component analysis methods. This framework builds a computational foundation which can provide a clear classification of cancers and lead to an efficient cancer therapy. PMID- 23031750 TI - Congenital absence of the anterior arch of the atlas: a normal variant. AB - Congenital absence of the anterior arch of the atlas is incredibly rare with only two cases reported previously in the literature. We present a third case of a medically fit patient who suffered neck trauma with an abnormal odontoid peg x ray, which subsequently demonstrated a congenital non-fusion of the anterior vertebral arch of C1 on computed tomography. This case highlights the need to have an open diagnosis to include congenital anomaly when interpreting abnormal odontoid peg x-rays. PMID- 23031751 TI - Gastric perforation in an adult male following nasogastric intubation. AB - INTRODUCTION: Spontaneous gastric perforation is a well known surgical emergency which carries significant mortality and morbidity. Well documented causes in adults include peptic ulcer disease, drugs such as non-steroidal and gastric malignancy. Iatrogenic causes still remain relatively rare. We report an interesting case of an acutely unwell young man who developed gastric perforation secondary to nasogastric intubation. CASE REPORT: A 32 year old man initially treated for gastroenteritis underwent laparotomy for acute intra-abdominal bleeding. This was found to be secondary to a ruptured left hepatic artery aneurysm which was subsequently embolised. Patient had multiple laparotomies, a nasogastric tube inserted at the second laparotomy was later found to be the cause of gastric perforation. On further investigation the patient's multiple aneurysms were histologically confirmed to be secondary to fibromuscular dysplasia (FMD). CONCLUSION: We present here a case of gastric perforation from a nasogastric tube in an adult male and discussed its relevance to the diagnosis of FMD. This case highlights the importance of having a high index of suspicion for this complication when managing patients with severe abdominal sepsis. PMID- 23031752 TI - Ureteric stricture: an unusual presentation of metastatic prostate adenocarcinoma. AB - We describe an unusual case of a prostatic adenocarcinoma presenting with a ureteric stricture secondary to a discrete metastatic lesion. A 76-year-old man presented with a short history of right loin pain. Initial examination was unremarkable, digital rectal examination was normal and prostate specific antigen was within normal range. Computed tomography showed right hydronephrosis and a distal ureteric stricture. A distal ureteric transitional cell carcinoma was thought to be most likely. A nephroureterectomy was carried out and histology revealed a skipped lesion of a metastatic prostate adenocarcinoma. Metastatic lesions to the ureters due to prostate cancer are rare. It was believed to be secondary to a transitional cell carcinoma as there was no evidence initially to suggest prostatic disease as the cause. A prostatic adenocarcinoma should be considered in the differential diagnosis of any lesions in the ureter believed to have a malignant origin. PMID- 23031753 TI - Buruli ulcer in a nine-month-old boy. AB - The diagnosis of Buruli ulcer should be considered in all painless undermined ulcers in the tropics. The diagnosis and treatment are a challenge in rural settings despite the well established tuberculosis programmes. Immediate commencement on rifampicin and streptomycin is essential to halt the progression of disease and to, hopefully, reverse it. Surgery is indicated in those with complex ulcers or with complications. We report the case of a nine-month-old boy presenting to visiting British surgeons in a district hospital in Uganda with multiple ulcers to the right forearm. PMID- 23031754 TI - Ancient schwannoma of the parapharynx causing dysphagia: a rare entity. AB - A schwannoma is a benign, encapsulated tumour that is derived from neural sheath (Schwann) cells. Approximately 25-40% of schwannomas occur in the head and neck. The most common site is the parapharyngeal space of the neck; oropharyngeal occurrence is extremely rare. Among the various histological types of schwannomas reported to date, the ancient (degenerative) variant is the most rare. To our knowledge, this is the first report of an ancient schwannoma in the parapharynx with an extensive oropharyngeal component causing dysphagia. Dysphagia was the prominent symptom because of the location and volume of the lesion. The tumour was excised via a transcervical approach. PMID- 23031755 TI - Common bile duct stones: an unusual case of diarrhoea through a mucous fistula. AB - We present a very unusual case of diarrhoea in a 77-year-old man. He had a previously complicated surgical history, with a loop ileostomy and a colonic mucous fistula. He developed a sudden onset of diarrhoea from his mucous fistula. A contrast enema suggested a cholecystocolonic fistula and subsequent computed tomography demonstrated a common bile duct stone caused a degree of obstruction. The patient was treated successfully by endoscopic retrograde cholangiopancreatography and stone extraction. This case demonstrated the role that contrast enema may still play in unusual cases of diarrhoea. PMID- 23031756 TI - Mucinous ovarian tumour presenting as a ruptured incisional hernia. AB - We describe an ovarian borderline tumour that presented as an acute deterioration in an incisional hernia secondary to intraperitoneal mucin accumulation. The differential diagnosis associated with hernial sac contents and options for opportunistic diagnosis are discussed. This case raises awareness of potential serious diagnoses that may be overlooked during emergent hernia repair. PMID- 23031757 TI - Biliary and portal vein strictures following treatment of Hodgkin's lymphoma. AB - Treatment of abdominal lymphoma can be associated with bowel stricture or perforation. Rarely, the common bile duct or portal vein can be involved. This is the first case of stricture formation of both the portal vein and common bile duct in a patient following successful treatment of lymphoma. The development of extensive hilar varices rendered surgical management high risk. A staged approach to treatment was used. First, a percutaneous portal vein stent was placed, resulting in resolution of the hilar varices. This was followed by a surgical hepaticojejunostomy, performed without complication. Gastrointestinal complications are rare following treatment of lymphoma but may affect a variety of sites. The safe and effective treatment of this case highlights the benefit of a multidisciplinary approach to complex medical and surgical problems. PMID- 23031758 TI - Multiple large enteroliths associated with an incisional hernia: a rare case. AB - The surgeon frequently encounters renal and biliary stones but rarely may also encounter enteric stones or enteroliths. An enterolith is a stony foreign body that is formed in the gastrointestinal tract. We present a rare case of multiple, large enteroliths found associated with a longstanding incarcerated incisional hernia. PMID- 23031759 TI - A dermoid cyst fistulating with the transverse colon. AB - We present a rare case of fistulation of a dermoid cyst with the transverse colon. We illustrate how an infected dermoid cyst can be diagnosed as an appendix abscess although the management of these is quite different. The general surgeon should be aware of this as a differential diagnosis for an appendix abscess. PMID- 23031760 TI - New implants in orthopaedics--caveat emptor. PMID- 23031761 TI - Interactions in the aetiology, presentation and management of synchronous and metachronous adenocarcinoma of the prostate and rectum. AB - Adenocarcinoma of the prostate and rectum are common male pelvic cancers and may present synchronously or metachronously due to their anatomic proximity. The treatment of rectal or prostate cancer (in particular surgery and/or radiotherapy) may alter the presentation, incidence and management should a metachronous tumour develop. This review focuses on the interaction between prostatic and rectal cancer diagnosis and management. We have restricted the scope of this large topic to general considerations, management of rectal cancer after prostate cancer treatment and vice versa, management of synchronous disease and cancer follow-up issues. PMID- 23031762 TI - Graduated compression stockings in hip fractures. AB - INTRODUCTION: Hip fractures are the most common cause of acute admissions to orthopaedics units and in the UK approximately 70,000-75,000 hip fractures occur annually. Hip fractures carry a significant risk of developing a venous thromboembolism. The National Institute for Health and Clinical Excellence (NICE) estimated that the risk of developing a venous thromboembolism in patients with hip fractures who do not receive thromboprophylaxis is 43%. In their recent guidelines, NICE recommended that combined mechanical and pharmacological thromboprophylaxis should be offered to patients undergoing hip fracture surgery and mechanical prophylaxis should be commenced at admission. The aim of this review was to search for available evidence that could support using graduated compression stockings combined with low molecular weight heparin (LMWH) in hip fracture patients. METHODS: NICE guidelines and the reference list of the guidance were reviewed and a thorough literature search was performed on main electronic databases (MEDLINE((r)), EmbaseTM and the Cochrane Library). RESULTS: A literature search was unable to find sufficient evidence to support the use of graduated compression stockings combined with LMWH in hip fracture settings. The guidelines are critically reviewed and the available evidence is discussed. CONCLUSIONS: The evidence supporting these recommendations is very limited and there is considerable concern regarding the safety and efficacy of the mechanical devices used in thromboprophylaxis. Further studies are needed urgently before specific guidelines can be agreed confidently for patients with hip fractures. PMID- 23031763 TI - Hepaticocholecystoenterostomy as an alternative to hepaticojejunostomy for biliary bypass. AB - INTRODUCTION: Hepaticojejunostomy is the standard biliary bypass technique for periampullary cancer when trial dissection reveals unresectable disease or endoscopic stent placement is not possible. This anastomosis can be technically demanding and potentially difficult. The simpler technique of hepaticocholecystoenterostomy (HCE) has only previously been reported in very limited numbers and without outcome data. METHODS: All patients undergoing HCE for the management of periampullary cancer were identified from a prospectively maintained computerised database of a single surgeon and were reviewed retrospectively. The HCE technique achieves a biliary bypass by two anastomoses, using the gallbladder as a conduit. It involves an anastomosis of the infundibulum of the gallbladder to the common hepatic duct followed by a second anastomosis of the gallbladder fundus to the proximal small bowel. RESULTS: From 1996 to 2010, 30 patients with pancreatic adenocarcinoma required a biliary bypass after a failed trial of Whipple procedure (80%) or failed endoscopic stenting (20%). There were 19 men and 11 women with a mean age of 64.5 years. The mean operative time for HCE alone was 92 minutes. The mean length of hospital stay was nine days. There was a single grade 2 complication (readmission with gastric emptying delay) and a single grade 3 complication (bile leak requiring reoperation). Thirty-day mortality was zero and the mean survival was 12 months (with one patient still alive at the time of writing). There were no readmissions with recurrent biliary obstruction or cholangitis. One patient had developed an incisional hernia by the 24-month follow-up appointment. CONCLUSIONS: HCE in periampullary cancer is safe and effective in selected patients. It involves two simple anastomoses with good access rather than one more demanding anastomosis. Morbidity, patency and overall survival are comparable with contemporary published series of hepaticojejunostomy. PMID- 23031764 TI - An international survey of opinion regarding investigation of possible appendicitis and laparoscopic management of a macroscopically normal appendix. AB - INTRODUCTION: The use of imaging and laparoscopy in patients with right iliac fossa pain as tools to make or exclude a diagnosis of appendicitis is at the discretion of the clinician. We sought to establish a consensus of opinion on this matter by surveying professional bodies for laparoscopic surgery in France, Italy and the US. METHODS: A survey was sent to members of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), the French Society for Endoscopic Surgery (SFCE) and the Italian Society for Endoscopic Surgery (SICE). The survey asked about management of both male and female patients presenting with right iliac fossa pain and what operative strategy the respondents would pursue should they find a macroscopically normal appendix at laparoscopy. RESULTS: A total of 364 responses were returned from the three groups. The responses from SAGES showed computed tomography to be the preferred modality for investigating patients with right iliac fossa pain, irrespective of sex. Both SFCE and SICE preferred the use of diagnostic laparoscopy, especially in the female patient group. The majority of all respondents stated that they would remove a macroscopically normal appendix at laparoscopy. CONCLUSIONS: Laparoscopy remains a potent tool in the management of appendicitis. However, the dilemma of when to remove a macroscopically normal appendix remains. Our study shows that removal of the appendix in this instance would be supported by an international consensus. PMID- 23031765 TI - The incidence of post operative venous thromboembolism in patients undergoing varicose vein surgery recorded in Hospital Episode Statistics. AB - INTRODUCTION: The aim of this study was to establish the incidence of post operative venous thromboembolism (VTE) following varicose vein treatment. METHODS: Hospital Episode Statistics (HES) data were obtained for all patients undergoing varicose vein treatment between April 2006 and April 2007 to identify those reattending with either deep vein thrombosis or pulmonary embolism within 12 months. RESULTS: The incidence of VTE was 0.51%, which was comparable with the incidence for those undergoing open surgery (0.54%), sclerotherapy (0.19%) and endovenous laser therapy (EVLT) (0.47%). The incidence of VTE in those undergoing combined EVLT and phlebectomy was 1.26% (p=0.01). In contrast to unilateral treatment (all modalities), where bilateral treatment was performed an increase in the incidence of VTE was seen in those undergoing redo (1.62%) and short saphenous system (1.16%) treatments. Overall, 1.02% of cases were performed under local anaesthesia with zero incidence of VTE in this cohort. CONCLUSIONS: The overall incidence of VTE recorded in HES was 0.51% and appears to be highest in those undergoing bilateral redo or short saphenous system surgery as well as those undergoing a combination of EVLT and phlebectomy. The use of VTE prophylaxis, particularly in these groups, is recommended. PMID- 23031766 TI - Survey of UK practice for management of breast cancer metastases to the neck. AB - INTRODUCTION: Cervical metastases from breast carcinoma are rare and their management is controversial. Between 1987 and 2002 the American Joint Committee on Cancer (AJCC) staged patients with supraclavicular fossa nodal disease as M1 but the subsequent demonstration that patients with regional stage IV disease had better outcomes than visceral stage IV disease led to a reclassification of the former to stage IIIC in 2003. The literature remains inconsistent regarding the fate of these patients. Despite the attendant morbidity of treatment and lack of knowledge regarding long-term survival, we hypothesised that current practice varies in the UK and a unified approach does not exist. The aim of this study was therefore to determine current practice and opinion of both head and neck specialists and breast cancer clinicians in the UK. METHODS: Questionnaires were disseminated to 185 head and neck surgeons, breast surgeons and their oncology counterparts. These outlined a clinical scenario of a patient with a history of T3 primary breast cancer presenting with cervical and supraclavicular nodal metastases, with opinion being sought regarding the significance of this status and the individual's practical approach to the problem. The extent of any proposed neck dissection was also explored. RESULTS: Of the 117 respondents, a noticeable variation in opinion was evident. Contrary to the current AJCC staging, 61% of clinicians felt that both level V and III metastases represented stage IV disease. There was a tendency towards aggressive surgical treatment with a third recommending comprehensive neck dissection despite a lack of evidence base. A disparity was noted between adjuvant treatments offered and the final pN stage. CONCLUSIONS: This study suggests that at present there is widespread inconsistency in the management of breast carcinoma cervical metastases in the UK. There is a need to unify practice with an evidence base in order to improve informed multidisciplinary decision making and, ultimately, patient care. This study goes some way to supporting multicentre collaboration in order to achieve that aim. PMID- 23031767 TI - The clinical relevance of microbiology specimens in orofacial abscesses of dental origin. AB - INTRODUCTION: It is common surgical practice to take a specimen for microbial culture and susceptibility (MC&S) when draining an orofacial abscess. The aim of this study was to determine if routine MC&S has any therapeutic value in the care of these patients. METHODS: A retrospective study was undertaken of records of patients admitted for surgical management of orofacial abscesses between January 2010 and December 2011. Records were reviewed for bacteriology specimen and result, admission details, antimicrobial treatment and outcome. RESULTS: A total of 79 patients were included in the study and specimens sent from 62 patients (78.4%). Samples were positive in 86.2% of cases, of which Streptococcus viridans was the most commonly isolated organism (54.7%). Interim reports were published on average after 3.25 days, with 89.9% of patients having been discharged within 2 post-operative days. According to clinical records, no patients in the cohort required further intervention or alteration of prescribed antimicrobial treatments following discharge. CONCLUSIONS: Almost 90% of patients were discharged before bacteriology results were available, without complication. This study suggests bacteriology culture has no therapeutic value in these patients. Omission of this practice in the case of uncomplicated orofacial abscesses could improve efficiency in the National Health Service without affecting patient care. PMID- 23031768 TI - Correlating the deep inferior epigastric artery branching pattern with type of abdominal free flap performed in a series of 145 breast reconstruction patients. AB - INTRODUCTION: The deep inferior epigastric perforator (DIEP) flap is currently viewed as the gold standard in autologous breast reconstruction. We studied three dimensional computed tomography angiography (CTA) in 145 patients undergoing free abdominal flap breast reconstruction to try to correlate deep inferior epigastric artery (DIEA) branching pattern with the type of flap performed and patient outcome. Today, reconstructive breast surgeons have become more experienced in raising DIEP flaps and operative times are becoming more acceptable. However, there remains significant interest in finding ways to aid this challenging dissection. METHODS: We retrospectively evaluated consecutive patients between January 2007 and August 2008. CTAs were analysed using the Moon and Taylor (1988) classification of the DIEA branching pattern. Data gathered included pre-operative morbidity, type of abdominal wall free flap performed, length of operation, length of stay and complications. RESULTS: Some 150 breast reconstructions were performed in 145 patients. There were 67 DIEP flaps, 69 MS-2 transverse rectus abdominis myocutaneous (TRAM) flaps and 14 MS-1 TRAM flaps (where MS-1 spares the lateral muscle and MS-2 spares both lateral and medial segments). Proportionally more DIEP flaps were performed in patients with a type 2 branching pattern. There was one flap loss (0.67%). CONCLUSIONS: In this large CTA series, we found a type 1 (single artery) DIEA pattern most frequently, in contrast to the predominance of the type 2 bifurcating pattern observed previously. The higher proportion of DIEP flaps performed in the type 2 pattern patients is consistent with the documented shorter intramuscular course in this group. We have found CTA useful for faster selection of the best hemiabdomen for dissection and flap loss rates in our unit have reduced from 1.5% to 0.67%. PMID- 23031769 TI - Early results of a prospective study on the pyrolytic carbon (pyrocarbon) Amandys(r) for osteoarthritis of the wrist. AB - INTRODUCTION: The preliminary results of a pyrocarbon interpositional radiocarpal implant in a small cohort of patients were reviewed. As it is currently only a limited release product, we describe to potential users early complications and negative outcomes. METHODS: Patients were assessed using pain levels, ranges of motion, grip strength, type of and time to return to work as well as pre operative and post-operative DASH (Disabilities of the Arm, Shoulder and Hand) scores. Radiographs were taken and patient satisfaction was recorded. RESULTS: All six patients were contacted. One was not satisfied. Three had reduced motion. None experienced squeaking. There were no immediate or late post operative complications. There was one early volar displacement of an implant. CONCLUSIONS: Although our early results are somewhat encouraging, further and longer studies are warranted before supporting the use of this particular pyrocarbon implant as a primary procedure. PMID- 23031770 TI - Difficulties encountered removing locked plates. AB - INTRODUCTION: Locked plates are commonly used to obtain fixation in periarticular and comminuted fractures. Their use has also gained popularity in repairing fractures in osteoporotic bone. These plates provide stable fixation and promote biological healing. Over the last 3 years, we have used over 150 locked plates with varying success to fix periarticular fractures involving mainly the knee and ankle. In this study, we report our clinical experience and the difficulties encountered when removing locked plates in adult patients with a variety of indications including implant failure, infection, non-union and a palpable symptomatic implant. METHODS: A retrospective analysis was performed of patients enrolled prospectively into a database. Included in the study were 36 consecutive adult patients who each underwent the procedure of locked plate removal in a single inner city level 1 trauma centre. Data collected included primary indication for fixation, indication for implant removal, time of the implant in situ, grade of operating surgeon and difficulties encountered during the procedure. RESULTS: Implant removal was associated with a complication rate of 47%. The major problems encountered were difficulty in removing the locked screws and the implant itself. A total of ten cold welded screws were found in eight cases. Removal was facilitated by high speed metal cutting burrs and screw removal sets in all but one case, where a decision was made to leave the plate in situ. CONCLUSIONS: The majority of studies investigating implant removal and problems encountered in doing so report a relatively high complication rate. With the advent of locking plates and their growing popularity, difficulties are now being seen intraoperatively when removing them. There is a paucity of data, however, specifically directed at locking plate removal. We recommend that surgeons should be aware of the potential complications while removing locked plates. Fluoroscopic control and all available extra equipment (mainly metal cutting burrs and screw removal sets) should be available in theatre. PMID- 23031771 TI - Reliability of radiographic measurements of knee motion following knee arthroplasty for use in a virtual knee clinic. AB - INTRODUCTION: We sought to validate radiographic measurements of range of motion of the knee after arthroplasty as part of a new system of virtual clinics. METHODS: The range of motion of 52 knees in 45 patients was obtained by 2 clinicians using standardised techniques and goniometers. Inter-rater reliability and intraclass correlation coefficients (ICCs) were calculated. Radiographs of these patients' knees in full active flexion and extension were also used to calculate intra and inter-rater reliability compared with clinical measurements using four different methods for plotting angles on the radiographs. RESULTS: The ICC for inter-rater reliability using the goniometer was very high. The ICC was 0.91 in extension and 0.85 in flexion while repeatability was 8.49 degrees (-8.03-8.99 degrees ) in extension and 5.23 degrees (-4.54-5.74 degrees ) in flexion. The best ICC for radiographic measurement in extension was 0.86, indicating 'near perfect' agreement, and repeatability was 5.43 degrees (-4.04- 6.12 degrees ). The best ICC in flexion was 0.95 and repeatability was 5.82 degrees (-3.38-6.55 degrees ). The ICC for intrarater reliability was 0.98 for extension and 0.99 for flexion on radiographic measurements. CONCLUSIONS: Validating the use of radiographs to reliably measure range of motion following knee arthroplasty has allowed us to set up a 'virtual knee clinic'. Combining validated questionnaires and radiographic measurement of range of motion, we aim to maintain high quality patient surveillance following knee arthroplasty, reduce our ratio for new to follow-up patients in line with Department of Health guidelines and improve patient satisfaction through reduced travel to hospital outpatients. PMID- 23031772 TI - Buried or unburied K-wires for lateral condyle elbow fractures. AB - INTRODUCTION: Lateral humeral condyle fractures typically require a longer period of internal fixation than other distal humeral fractures due to the increased risk of non-union. K-wires can be buried and left in situ until union or they can be left unburied and require removal after four weeks, with plaster immobilisation until union. There is no consensus as to whether wire burial is preferable or not. The aim of this study was to determine whether K-wire burial is associated with more complications than non-buried wires in treating lateral condyle fractures of the elbow. METHODS: All patients with lateral humeral condyle fractures treated with K-wire fixation at our institution from May 2008 to August 2011 were included in the study. Fracture configuration, mode of reduction, wire burial and complications were assessed. RESULTS: Sixty-seven patients (19 girls and 48 boys, mean age: 6.5 years, range: 1-17 years) were included in the study. All had closed injuries and were treated with open reduction and K-wire fixation. K-wires were buried in 55 patients. Thirteen cases of buried wires eroded through skin and were removed on average 45 days (range: 30-58 days) post-operatively. Of the wire erosion cases, three developed microbiologically proven infections, one of which was a deep infection. There were a further three superficial wound infections in the absence of wire erosion through the skin. There were complications in 2 of the 12 cases in the unburied wires group: 1 microbiologically proven superficial wire site infection and 1 wire backed out after 11 days, requiring refixation. CONCLUSIONS: Wire erosion through the skin is the most common complication of K-wire burial. This may be due to the decrease in swelling after fracture fixation, making the wires more prominent under the skin. Skin integrity should be monitored closely if wires are buried. PMID- 23031773 TI - Management of recurrent stress urinary incontinence and urinary retention following midurethral sling insertion in women. AB - INTRODUCTION: Synthetic midurethral slings are the most common operations performed for women with stress urinary incontinence (SUI). However, there is only very scarce evidence regarding the management of complications from these operations. The aim of this survey was to canvass expert opinion regarding the management of recurrent SUI and urinary retention following insertion of these slings. METHODS: Expert urologists and urogynaecologists in the UK with an interest in SUI were identified. Three clinical scenarios on recurrent SUI and one on urinary retention following midurethral sling placements were emailed twice to the experts. RESULTS: The majority of the experts chose a repeat synthetic midurethral retropubic transvaginal tape (TVT) as the procedure of choice for recurrent SUI in patients who had had a previous TVT or midurethral transobturator tape inserted. In patients who continued to suffer SUI after a failed second TVT, there were mixed results with experts choosing fascial slings, colposuspension and bulking agents as their preferred method of treatment. In women who develop urinary retention following a TVT, tape pull-down within two weeks was the preferred method among the experts. However, division of the tape within two to six weeks following the procedure was also popular. CONCLUSIONS: Based on expert opinion, it is difficult to make a recommendation as to the best method of treating recurrent SUI or urinary retention following tape insertion. There is an urgent requirement for well conducted, multicentre, randomised clinical trials to look at the management of these complications and also the tools used to assess the patient before salvage surgical management. PMID- 23031774 TI - Recent medical technologies guidance relevant to surgeons. PMID- 23031776 TI - A novel technique for repairing anterior labral injuries of the shoulder. PMID- 23031777 TI - The Chase epicardial stabiliser as an adjunct tool for the management of penetrating cardiac injuries. PMID- 23031778 TI - Metacarpal Titanium Elastic Nail insertion. PMID- 23031779 TI - The poke test in lower limb fasciotomy: a potentially limb saving technical note. PMID- 23031780 TI - Use of Johan forceps as endoloop pushers for laparoscopic appendicectomy. PMID- 23031781 TI - A simple technique to avoid suturing in the drain during total knee arthroplasty. PMID- 23031782 TI - A simple way to allow continuous ventilation during tracheostomy. PMID- 23031783 TI - Localised bone grafting of acetabular cysts during total hip replacement. PMID- 23031785 TI - A genome-wide signature of glucocorticoid receptor binding in neuronal PC12 cells. AB - BACKGROUND: Glucocorticoids, secreted by the adrenals in response to stress, profoundly affect structure and plasticity of neurons. Glucocorticoid action in neurons is mediated by glucocorticoid receptors (GR) that operate as transcription factors in the regulation of gene expression and either bind directly to genomic glucocorticoid response elements (GREs) or indirectly to the genome via interactions with bound transcription factors. These two modes of action, respectively called transactivation and transrepression, result in the regulation of a wide variety of genes important for neuronal function. The objective of the present study was to identify genome-wide glucocorticoid receptor binding sites in neuronal PC12 cells using Chromatin ImmunoPrecipitation combined with next generation sequencing (ChIP-Seq). RESULTS: In total we identified 1183 genomic binding sites of GR, the majority of which were novel and not identified in other ChIP-Seq studies on GR binding. More than half (58%) of the binding sites contained a GRE. The remaining 42% of the GBS did not harbour a GRE and therefore likely bind GR via an intermediate transcription factor tethering GR to the DNA. While the GRE-containing binding sites were more often located nearby genes involved in general cell functions and processes such as apoptosis, cell motion, protein dimerization activity and vasculature development, the binding sites without a GRE were located nearby genes with a clear role in neuronal processes such as neuron projection morphogenesis, neuron projection regeneration, synaptic transmission and catecholamine biosynthetic process. A closer look at the sequence of the GR binding sites revealed the presence of several motifs for transcription factors that are highly divergent from those previously linked to GR-signaling, including Gabpa, Prrx2, Zfp281, Gata1 and Zbtb3. These transcription factors may represent novel crosstalk partners of GR in a neuronal context. CONCLUSIONS: Here we present the first genome-wide inventory of GR-binding sites in a neuronal context. These results provide an exciting first global view into neuronal GR targets and the neuron specific modes of GR action and potentially contributes to our understanding of glucocorticoid action in the brain. PMID- 23031786 TI - Significantly upregulated TACSTD2 and Cyclin D1 correlate with poor prognosis of invasive ductal breast cancer. AB - The tumor-associated calcium signal transducer 2 (TACSTD2) gene has been reported to be highly expressed in many types of human epithelial cancers, and is associated with tumor metastasis and poor prognosis. The aims of the present investigation were to analyze the TACSTD2 and Cyclin D1 expression at the mRNA and protein levels and to assess its prognostic significance in invasive ductal breast cancer (IDC). The expressions of TACSTD2 and Cyclin D1 in IDC tissues were consistently higher than those in the tumor-adjacent non-malignant tissues by a one-step real-time polymerase chain reaction and immunohistochemistry (P<0.001 and P=0.023, respectively). The statistical analysis of clinicopathologic characteristics and immunohistochemistry by the chi(2) test showed that the high expression of TACSTD2 in IDC was correlated to histological grade (P=0.023), P53 status (P=0.042), Cyclin D1 status (P<0.001), lymph node metastasis (P<0.001), distant metastasis (P=0.004) and TNM staging (P<0.001). Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of IDC. These analyses also showed that a high TACSTD2 expression (P=0.003), a high Cyclin D1 expression (P=0.041), and lymph node metastasis (P=0.006) were independent prognosis factors. Collectively, our studies demonstrated that the high expression of TACSTD2 correlates with a poor prognosis in IDC. PMID- 23031787 TI - Mammography-based screening program: preliminary results from a first 2-year round in a Brazilian region using mobile and fixed units. AB - BACKGROUND: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer deaths among women worldwide. The use of mobile mammography units to offer screening to women living in remote areas is a rational strategy to increase the number of women examined. This study aimed to evaluate results from the first 2 years of a government-organized mammography screening program implemented with a mobile unit (MU) and a fixed unit (FU) in a rural county in Brazil. The program offered breast cancer screening to women living in Barretos and the surrounding area. METHODS: Based on epidemiologic data, 54 238 women, aged 40 to 69 years, were eligible for breast cancer screening. The study included women examined from April 1, 2003 to March 31, 2005. The chi-square test and Bonferroni correction analyses were used to evaluate the frequencies of tumors and the importance of clinical parameters and tumor characteristics. Significance was set at p < 0.05. RESULTS: Overall, 17 964 women underwent mammography. This represented 33.1% of eligible women in the area. A mean of 18.6 and 26.3 women per day were examined in the FU and MU, respectively. Seventy six patients were diagnosed with breast cancer (41 (54%) in the MU). This represented 4.2 cases of breast cancer per 1000 examinations. The number of cancers detected was significantly higher in women aged 60 to 69 years than in those aged 50 to 59 years (p < 0.001) or 40 to 49 years (p < 0.001). No difference was observed between women aged 40 to 49 years and those aged 50 to 59 years (p = 0.164). The proportion of tumors in the early (EC 0 and EC I) and advanced (CS III and CS IV) stages of development were 43.4% and 15.8%, respectively. CONCLUSIONS: Preliminary results indicate that this mammography screening program is feasible for implementation in a rural Brazilian territory and favor program continuation. PMID- 23031788 TI - Activation of the mTOR pathway by the amino acid (L)-leucine in the 5q- syndrome and other ribosomopathies. AB - Patients with the 5q- syndrome and Diamond-Blackfan anemia (DBA) suffer from a severe macrocytic anemia. The 5q- syndrome and DBA are disorders of aberrant ribosome biogenesis (ribosomopathies) and haploinsufficiency of the ribosomal protein genes RPS14 and RPS19, respectively, underlies the anemia found in these disorders. Erythroblasts obtained from patients with the 5q- syndrome and DBA show impaired mRNA translation and this defect in translation may represent a potential therapeutic target in these ribosomopathies. There are some indications that the amino acid l-leucine, a translation enhancer, may have some efficacy in this group of disorders. Recent studies have shown that l-leucine treatment of zebrafish and murine models of the 5q- syndrome and DBA results in a marked improvement in the anemia. l-leucine treatment of RPS14-deficient and RPS19 deficient erythroblasts and erythroblasts from patients with the 5q- syndrome has been shown to result in an increase in cell proliferation, erythroid differentiation and mRNA translation in culture. l-leucine has been shown to improve hemoglobin levels and transfusion independence in a patient with DBA. l leucine activates the mTOR (mammalian target of rapamycin) signaling pathway that controls cell growth and mRNA translation. There is evidence to suggest that the promotion of translation via the mTOR pathway by l-leucine is the mechanism that underlies the enhanced erythroid progenitor cell growth and differentiation observed in animal and cellular models of the 5q- syndrome and DBA treated with this amino acid. These data support the rationale for clinical trials of l leucine as a therapeutic agent for the 5q- syndrome and DBA. PMID- 23031789 TI - Activation mechanisms of ASK1 in response to various stresses and its significance in intracellular signaling. AB - Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase family. ASK1 activates c-jun N-terminal kinase (JNK) and p38 in response to various stimuli such as oxidative stress, endoplasmic reticulum stress, infection and calcium influx. Under these stress conditions, ASK1 plays important roles in intracellular signaling pathways and biological functions. Diverse proteins are known to interact with ASK1 and regulate the activity of ASK1. However, activation mechanisms of ASK1 and ASK1-binding proteins which regulate the activity of ASK1 have not been completely understood. In this review, we focus on the recent findings on ASK1 and update the regulatory mechanisms of ASK1 activity. PMID- 23031790 TI - Effect of dietary iodine on thyroid hormones and energy blood metabolites in lactating goats. AB - Aim of this work was to evaluate if long-term dietary supplementation of potassium iodide (KI) to dairy goats can influence metabolic and hormonal parameters. Thirty Sarda crossbred dairy goats were divided into three groups, which were orally administered 0 (control group; CON), 0.45 (low iodine group; LI) or 0.90 (high iodine group; HI) mg of KI/day, respectively. The daily dose of KI (76.5% of iodine) was administered as salt dissolved in water for 8 weeks. Plasma contents of nonesterified fatty acids (NEFA), urea, glucose, insulin, free triiodothyronine (FT(3)) and thyroxine (FT(4)) were determined weekly. Iodine supplementation increased significantly the FT(3) hormone (P = 0.007) and FT(3)/FT(4) ratio (P = 0.001) and tended to influence the FT(4) hormone (P = 0.059). An iodine level * week of sampling interaction for NEFA (P = 0.013) evidenced a temporary concentration increase in supplemented groups. The 'Revised Quantitative Insulin Sensitivity Check Index' increased with KI supplementation (P <= 0.01). Blood urea nitrogen (BUN) and insulin were lowered (P <= 0.01) by iodine supplementation (groups LI and HI; P <= 0.01). The glucose concentration evidenced an iodine level * week of sampling interaction (P = 0.025) due to an unexpected and temporary increase of its concentration in the CON group. Glucose concentration was decreased by KI supplementation only in LI group (P < 0.05). In conclusion, the daily supplementation of low doses of KI can improve insulin sensitivity and decrease BUN in dairy goats. PMID- 23031792 TI - Managing variations in dairy cow nutrient supply under grazing. AB - Grazed pasture, which is the cheapest source of nutrients for dairy cows, should form the basis of profitable and low-input animal production systems. Management of high-producing dairy cows at pasture is thus a major challenge in most countries. The objective of the present paper is to review the factors that can affect nutrient supply for grazing dairy cows in order to point out areas with scope for improvement on managing variations in nutrient supply to achieve high animal performance while maintaining efficient pasture utilisation per hectare (ha). Reviewing the range in animal requirements, intake capacity and pasture nutritive values shows that high-producing cows cannot satisfy their energy requirements from grazing alone and favourable to unfavourable situations for grazing dairy cows may be classified according to pasture quality and availability. Predictive models also enable calculation of supplementation levels required to meet energy requirements in all situations. Solutions to maintain acceptable level of production per cow and high output per ha are discussed. Strategies of concentrate supplementation and increasing use of legumes in mixed swards are the most promising. It is concluded that although high-producing cow cannot express their potential milk production at grazing, there is scope to improve animal performance at grazing given recent developments in our understanding of factors influencing forage intake and digestion of grazed forages. PMID- 23031791 TI - Inhibition of HCV by the serpin antithrombin III. AB - BACKGROUND: Although there have been dramatic strides made recently in the treatment of chronic hepatitis C virus infection, interferon-alpha based therapy remains challenging for certain populations, including those with unfavorable IL28B genotypes, psychiatric co-morbidity, HIV co-infection, and decompensated liver disease. We have recently shown that ATIII, a serine protease inhibitor (serpin), has broad antiviral properties. RESULTS: We now show that ATIII is capable of inhibiting HCV in the OR6 replicon model at micromolar concentrations. At a mechanistic level using gene-expression arrays, we found that ATIII treatment down-regulated multiple host cell signal transduction factors involved in the pathogenesis of cirrhosis and hepatocellular carcinoma, including Jun, Myc and BMP2. Using a protein interactive network analysis we found that changes in gene-expression caused by ATIII were dependent on three nodes previously implicated in HCV disease progression or HCV replication: NFkappaB, P38 MAPK, and ERK1/2. CONCLUSIONS: Our findings suggest that ATIII stimulates a novel innate antiviral host cell defense different from current treatment options. PMID- 23031793 TI - Prevalence of hospital-acquired infections in the university medical center of Rabat, Morocco. AB - BACKGROUND: The aims of this study were to determine the hospital-acquired infections (HAI) prevalence in all institutions of Rabat University Medical Center, to ascertain risk factors, to describe the pathogens associated with HAI and their susceptibility profile to antibiotics. MATERIALS AND METHODS: Point prevalence survey in January 2010 concerning all patients who had been in the hospital for at least 48 hours. At bedside, 27 investigators filled a standardized questionnaire from medical records, temperature charts, radiographs, laboratory reports and by consultation with the ward's collaborating health professionals. Risk factors were determined using logistic regression. RESULTS: 1195 patients involved, occupancy rate was 51%. The prevalence of HAI was 10.3%. Intensive care units were the most affected wards (34.5%). Urinary tract infection was the most common infected site (35%). Microbiological documentation was available in 61% of HAI. Staphylococcus was the organism most commonly isolated (18.7%) and was methicillin-resistant in 50% of cases. In multivariate analysis, risk factors associated with HAI were advanced age, longer length of hospital stay, presence of comorbidity, invasive devices and use of antibiotic use. CONCLUSION: HAI prevalence was high in this study. Future prevention program should focus on patients with longer length of stay, invasive devices, and overprescribing antibiotics. PMID- 23031794 TI - Isolated Crohn's disease of the esophagus with esophago-mediastinal fistula formation. AB - Isolated Crohn's disease of the esophagus is rare, and accurate diagnosis and treatment in its early course are difficult. Most cases are often found very late, when severe strictures or other complications have occurred. We report the case of a male 60-year-old patient with complaints of progressive dysphagia for more than two months and the sudden appearance of heartburn for seven consecutive days. Clinical examination revealed severe esophageal stricture with a suspected fistula and mediastinitis. The patient received a successful esophagectomy. The resected specimen and pathological results confirmed a deep linear ulcer, chronic and noncaseating granulomatous inflammation, as well as a circular stricture of the esophagus with fistula into the mediastinum due to isolated esophageal Crohn's disease. PMID- 23031795 TI - Mechanisms involved in alternariol-induced cell cycle arrest. AB - Alternariol (AOH), a mycotoxin produced by Alternaria sp, is often found as a contaminant in fruit and cereal products. Here we employed the murine macrophage cell line RAW 264.7 to test the hypothesis that AOH causes toxicity as a response to DNA damage. AOH at concentrations of 15-30MUM almost completely blocked cell proliferation. Within 30min treatment, AOH (30MUM) significantly increased the level of reactive oxygen species (ROS). Furthermore, DNA base oxidations as well as DNA strand breaks and/or alkaline labile sites were detected by the comet assay after 2h exposure of AOH. Cell death (mostly necrosis) was observed after prolonged exposure to the highest concentration of AOH (60MUM for 24 and 48h) in our study. The DNA damage response involved phosphorylation (activation) of histone H2AX and check point kinase-1- and 2 (Chk-1/2). Moreover, AOH activated p53 and increased the expression of p21, Cyclin B, MDM2, and Sestrin 2; likewise the level of several miRNA was affected. AOH-induced Sestrin 2 expression was regulated by p53 and could at least partly be inhibited by antioxidants, suggesting a role of ROS in the response. Interestingly, the addition of antioxidants did not inhibit cell cycle arrest. Although the formation of ROS by itself was not directly linked cell proliferation, AOH-induced DNA damage and resulting transcriptional changes in p21, MDM2, and Cyclin B likely contribute to the reduced cell proliferation; while Sestrin 2 would contribute to the oxidant defense. PMID- 23031796 TI - Assessment of the mobile bag method for estimation of in vivo starch digestibility. AB - The objective was to assess the ability of the in situ mobile nylon bag method for predicting small intestinal and total tract starch digestibility. Starch disappearance was measured for 18 samples of different cereals and legumes subjected to different physical and chemical processing methods and compared with coherent in vivo digestibility. Starch disappearance was measured both with and without initial ruminal pre-incubation during 4 h. Bags were retrieved from either the ileal cannula or faeces. Two dry Danish Holstein cows fitted with rumen cannulas were used for rumen pre-incubations and two lactating Danish Holstein cows fitted with duodenal and ileal cannulas were used for intestinal incubations. Rumen pre-incubation had no significant effect on disappearance from bags recovered in faeces. The disappearance of legume starch was lower, both in the rumen and small intestine, compared with starch from barley, wheat, oats, ear maize and maize. Transit times of the mobile bags from duodenum to ileum were not significantly different between feeds. A weak positive correlation was found between in vivo small intestinal and total tract digestibility of starch and disappearance obtained using the mobile bag technique across a broad range of starch sources. Omitting two less conventional starch sources (NaOH wheat and xylose-treated barley) resulted in a high (0.87) correlation between total tract in vivo digestibility and mobile bag disappearance. The use of the mobile bag method for estimation of in vivo starch digestibility will therefore depend on the starch type. PMID- 23031798 TI - Autoimmune biomarkers in glaucoma patients. AB - There is growing evidence showing an autoimmune involvement in the pathogenesis of glaucoma, and that alterations in natural occurring autoantibody levels play a key role. The upregulation of autoantibodies can be associated with fatal conditions, but several studies demonstrate that natural autoantibodies entail also protective characteristics and influence the protein expression of neuroretinal cells. A disbalance of natural occurring autoantibodies may shift the physiological equilibrium of protective immunity leading to a predisposition for developing glaucoma. This article highlights recent advances in understanding of autoimmune mechanisms in the pathogenesis of glaucoma. PMID- 23031797 TI - Correlation between Slug transcription factor and miR-221 in MDA-MB-231 breast cancer cells. AB - BACKGROUND: Breast cancer and its metastatic progression is mainly directed by epithelial to mesenchymal transition (EMT), a phenomenon supported by specific transcription factors and miRNAs. METHODS: In order to investigate a possible correlation between Slug transcription factor and miR-221, we performed Slug gene silencing in MDA-MB-231 breast cancer cells and evaluated the expression of genes involved in supporting the breast cancer phenotype, using qRT-PCR and Western blot analysis. Chromatin immunoprecipitation and wound healing assays were employed to determine a functional link between these two molecules. RESULTS: We showed that Slug silencing significantly decreased the level of miR-221 and vimentin, reactivated Estrogen Receptor alpha and increased E-cadherin and TRPS1 expression. We demonstrated that miR-221 is a Slug target gene, and identified a specific region of miR-221 promoter that is transcriptionally active and binds the transcription factor Slug "in vivo". In addition, we showed that in Slug silenced cells, wich retained residual miR-221 (about 38%), cell migration was strongly inhibited. Cell migration was inhibited, but to a less degree, following complete knockdown of miR-221 expression by transfection with antagomiR-221. CONCLUSIONS: We report for the first time evidence of a correlation between Slug transcription factor and miR-221 in breast cancer cells. These studies suggest that miR-221 expression is, in part, dependent on Slug in breast cancer cells, and that Slug plays a more important role than miR-221 in cell migration and invasion. PMID- 23031799 TI - Life-history traits indicate local adaptation of the schistosome parasite, Schistosoma mansoni, to its snail host, Biomphalaria pfeifferi. AB - The digenean trematode Schistosoma mansoni causes schistosomiasis (Bilharziasis), a significant human disease especially in sub-Saharan Africa. We tested local adaptation of this parasite to its intermediate host, the freshwater snail Biomphalaria pfeifferi, by exposure of S. mansoni to B. pfeifferi from one sympatric and four allopatric populations and measurement of life-history traits of both species over time. The pre-patent period, infection rate, and cercarial production of the parasite were determined, and the shell diameter, fecundity, and survival of the snail host were determined. The results provide evidence for local adaptation of S. mansoni to its sympatric snail host: the pre-patent period was the shortest, the cercarial production was moderate and accompanied by a higher survival rate, the growth was greater during the pre-patent period, and the fecundity was greater during the pre-patent period. The greater growth and fecundity of sympatric B. pfeifferi suggests the presence of growth and fecundity compensation. These fitness traits are relevant to energy allocation of the snail host and to the transmission strategy of the schistosome parasite. PMID- 23031801 TI - Apoptotic-cell-derived membrane vesicles induce an alternative maturation of human dendritic cells which is disturbed in SLE. AB - The clearance of apoptotic cells occurs in a non-inflammatory context. Defects in this clearance process have been linked to the emergence of human autoimmune diseases like systemic lupus erythematosus (SLE). A characteristic of apoptotic cell death is the shedding of membrane coated vesicles from the cellular surfaces. Those vesicles have recently been recognized as mediators of intercellular communication or as adjuvant in the pathogenesis of autoimmune diseases. We analyzed the interactions between these apoptotic cell-derived membrane vesicles and professional antigen presenting cells. These vesicles were engulfed by monocyte-derived dendritic cells (mDC) and stimulated their maturation towards a phenotype comprising an upregulation of CD80, CD83, CD86, and a remarkable downregulation of MHC class II molecules. We observed only a minor release of proinflammatory cytokines from these mDC when compared to LPS stimulation. mDC stimulated by apoptotic vesicles did not cause significant T cell expansion. Interestingly, when compared to normal healthy donors SLE patients-derived dendritic cells showed a significantly different phenotype lacking the downregulation of MHC class II, which correlated to disease activity. PMID- 23031800 TI - Natural and emergent Trypanosoma cruzi I genotypes revealed by mitochondrial (Cytb) and nuclear (SSU rDNA) genetic markers. AB - Chagas disease is a tropical and systemic disease caused by the parasite Trypanosoma cruzi. This parasite has been divided into six Discrete Typing Units (DTU's) due to its high genetic diversity. T. cruzi I (TcI) is the most prevalent DTU in Colombia and recently associated to cardiomyopathies. The aim of this study was to unravel the genetic variability among a set of 70 cell-single TcI clones from different geographical regions and hosts using the sequences of Cytb and SSU rDNA. The results showed two genotypes associated to transmission cycles of Chagas disease in Colombia and supports the previous descriptions using SL-IR. Phylogenetic networks were developed detecting recombination events within TcI. We also tested the phylogenetic relationships beneath TcI clones and TcIII/TcIV sequences observing the high relatedness of TcI clones from sylvatic cycle with TcIII/TcIV. We corroborate the high genetic diversity displayed by TcI, the plausible recombination within this DTU supporting the previous model of genetic exchange proposed in T. cruzi populations. We conclude inquiring the need to pursue new studies to elucidate the genetic structure of TcI across Chagas disease endemic countries. PMID- 23031802 TI - Do SNPs of DRD4 gene predict adult persistence of ADHD in a Chinese sample? AB - The dopamine D4 receptor (DRD4) gene has been frequently studied in relation to attention deficit hyperactivity disorder (ADHD) but little is known about the contribution of single nucleotide polymorphisms (SNPs) of the DRD4 gene to the development and persistence of ADHD. In the present study, we examined the association between two SNPs in DRD4 (rs1800955, rs916455) and adult ADHD persistence in a Chinese sample. Subjects (n=193) were diagnosed with ADHD in childhood and reassessed in young adulthood at an affiliated clinic of Peking University Sixth Hospital. Kaplan-Meier survival analyses and Cox proportional hazard models were used to test the association between ADHD remission and alleles of the two SNPs. DRD4 rs916455 C allele carriers were more likely to have persistent ADHD symptoms in adulthood. No significant association was found between rs1800955 allele and the course of ADHD. These newly detected associations between DRD4 polymorphisms and ADHD prognosis in adulthood may help to predict the persistence of childhood ADHD into adulthood. PMID- 23031803 TI - The use of the theory of planned behavior to predict engagement in functional behaviors in schizophrenia. AB - In schizophrenia, low motivation may play a role in the initiation and frequency of functional behaviors. Several reviews support the efficacy of the Theory of Planned Behavior (TPB) to predict engagement in various behaviors, but little research has utilized the TPB to explain functional behavior in schizophrenia. This study tested the TPB for predicting prospective engagement in functional behaviors in a sample of 64 individuals with schizophrenia. Participants completed questionnaires assessing their attitudes toward, social norms regarding, perceived behavioral control over, and intention to engage in various functional behaviors during the upcoming week. Follow-up questionnaires assessed engagement in functional behaviors. Zero-order correlations indicated that positive attitudes, social norms, and perceived behavioral control were positively correlated with intentions to engage in functional behaviors. In turn, intentions were positively correlated with engagement in functional behaviors. Using path analysis, social norms and control were significantly related to intentions, which in turn predicted greater engagement in functional behaviors. Results suggest that patients with schizophrenia make reasoned decisions for or against engaging in functional behaviors. Skills training interventions that also target components of the TPB may be effective for increasing motivation to engage in learned behaviors. PMID- 23031804 TI - Psychometric properties of the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) in youth with OCD. AB - This study evaluated the psychometric properties of the treatment-emergent activation and suicidality assessment profile (TEASAP) in a clinical sample of 56 youth aged 7-17 with obsessive-compulsive disorder (OCD) who participated in a double-blind randomized controlled trial. The 38-item TEASAP demonstrated good internal consistency for its total score (alpha=0.93) and adequate to good performance for its five subscale scores (alpha=0.65-0.92). One-week test-retest stability (N=18) was adequate (Intraclass correlation coefficient [ICC]=0.68 0.80) except for Self-Injury (ICC=0.46). Construct validity was supported by total and subscale TEASAP score relationships with related constructs, including irritability, hyperactivity, externalizing behaviors, manic symptoms, and suicidal ideation, and the absence of relationships with unrelated constructs. Predictive validity was established for the Disinhibition subscale through significant associations with subsequent activation events. Furthermore, TEASAP sensitivity to change in activation scores over time was supported by longitudinal associations of TEASAP scores with clinician ratings of activation over the course of treatment. Findings indicate that the TEASAP has acceptable psychometric properties in a clinical sample of youth with OCD and merits further study in larger samples for additional refinement of its measurement approaches. PMID- 23031805 TI - Effect of Flabellaria paniculata Cav. extracts on gastric ulcer in rats. AB - BACKGROUND: The leaves and root of Flabellaria paniculata (Malpighiaceae) are frequently used in the treatment of wounds and ulcers in Nigerian folk medicine. The purpose of this study was to compare the effect of ethanolic extracts from the leaves (FPL) and root (FPR) of F. paniculata on gastric ulcers in rats. METHODS: The effect of FPL and FPR (100, 200 and 400 mg/kg) was evaluated in ethanol and indomethacin gastric ulcer models. Control groups for FPL and FPR were orally treated with 3% Tween 20 and distilled water respectively. FPL was further investigated in pylorus ligation model. Misoprostol and cimetidine were used as reference. RESULTS: FPL significantly (P < 0.05) reduced gastric lesions by 82.22% and 67.32% in ethanol and indomethacin induced ulcer models at 100 mg/kg respectively while FPR (100, 200 and 400 mg/kg) did not exert significant effect in the two models. In pylorus ligation model, FPL exerted a significant preventive antiulcer effect as indicated by reduction in gastric volume at 200 and 400 mg/kg doses. Only 400 mg/kg of the extract exerted a significant reduction in ulcer index when compared with the control group. The oral route LD50 of FPL was estimated to be 4570 mg/kg while that of FPR was 2754 mg/kg. The LD50 in intraperitoneal injection was estimated to be 1202.26 and 1380.38 mg/kg for FPL and FPR respectively. The phytochemical investigation showed that both extracts possess triterpenoids and saponin, while the presence of flavonoid was detected only in FPL. CONCLUSIONS: The results of this study indicated that FPL and not FPR is effective against experimentally induced gastric ulcers. The presence of varied phytochemical constituents probably influenced the pharmacological differences between the two extracts. PMID- 23031806 TI - miRNA-miRNA interaction implicates for potential mutual regulatory pattern. AB - BACKGROUND: Natural or endogenous sense/antisense miRNAs, located on sense and antisense strands in the same genomic region, respectively, are detected recently. However, little is known about these miRNA pairs, especially for their distributions in different animal species. We herein present systematic analysis of them in human, mouse and rat miRNAs, and their expression patterns based on deep sequencing datasets. METHODS AND RESULTS: The phenomenon of miRNA-miRNA interaction could be detected in different animal species. The common miRNAs pairs were found across species. These miRNA pairs could form miRNA:miRNA duplex with complete complementary structure, and were prone to be located on specific chromosomes. They might be homologous miRNA genes (especially in human), or clustered in a gene cluster (especially in rat), or simultaneously detected in different genomic regions due to multicopy pre-miRNAs. Remarkably, some miRNA pairs, located in different genomic regions, also showed complementarity as well as endogenous sense/antisense miRNAs. Based on published deep sequencing datasets, one member of miRNA pairs always was abundantly expressed, whereas another was quite rare. Rare common target mRNAs of these miRNA pairs were predicted. CONCLUSIONS: Interaction between miRNAs and significant expression divergence implied complex potential mutual regulatory pattern in the miRNA world. The study would enrich miRNA regulatory network. PMID- 23031807 TI - Prevalence of known mutations and a novel missense mutation (M694K) in the MEFV gene in a population from the Eastern Anatolia Region of Turkey. AB - Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever and serositis. Mutations in the Mediterranean fever gene (MEFV) localized on the short arm of chromosome 16 cause FMF. Over 90 MEFV missense/nonsense mutations have been identified so far in FMF patients, mostly in the 10th exon of the gene. In this study, the molecular test results of 891 patients identified as having FMF clinical symptoms referred to Molecular Genetics Laboratory of the Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University, Malatya/Turkey were retrospectively evaluated. Patients were referred by their physicians for MEFV mutation detection. The DNA fragments including hot spots within the coding sequences of the MEFV gene were amplified by PCR using genomic DNA and analyzed by pyrosequencing technique. Of the 891 patients investigated, 420 (47.13%) had at least one mutation. The most frequent mutation was E148Q, followed by M694V, M680I (G/C), P369S, V726A, R761H, A744S, M694I, K695R and F479L mutations. In addition, a novel missense mutation (M694K) was reported in seven members of a family in the course of mutation screening of patients. PMID- 23031808 TI - Association of peroxisome proliferator activated receptor-gamma gene with non alcoholic fatty liver disease in Asian Indians residing in north India. AB - BACKGROUND: Genetics of non-alcoholic fatty liver (NAFLD) in Asian Indians has been inadequately studied. We investigated the association of polymorphisms C161T and Pro12Ala of peroxisome proliferator-activated receptor gamma (PPARgamma) with clinical and biochemical parameters in Asian Indians with NAFLD. METHODS: In this case-control study, 162 NAFLD cases and 173 controls were recruited. Abdominal ultrasound, clinical and biochemical profiles, fasting insulin levels and value of homeostasis model assessment of insulin resistance were determined. Polymerase chain reaction-restriction fragment length polymorphisms of two polymorphisms were performed. The association of these polymorphisms with clinical and biochemical parameters was analysed. RESULTS: Higher frequency of Ala and T alleles of PPARgamma was obtained in cases. Ala/Ala genotype of PPARgamma (Pro12Ala) was associated with significantly higher serum triglycerides (TG), alkaline phosphatase (ALK) and waist-hip ratio in cases as compared to controls. In C161T polymorphism, TT genotype was significantly increased TG (p=0.04), total cholesterol (p=0.01), ALK (p=0.04) and gamma-glutamyl transpeptidase (p=0.007) in cases. The linkage disequilibrium for these two single-nucleotide polymorphisms of PPARgamma was differed in cases (D1=0.1; p=0.006) and controls (D1=0.07; p=0.1). Using a multivariate analysis after adjusting for age, sex and body mass index, the presence of NAFLD was linked to these two polymorphisms (odds ratio 1.64 (95% CI: 1.09-2.45, p=0.05)]. CONCLUSION: Asian Indians in north India carrying the alleles Ala and T of PPARgamma (Pro12Ala and C161T) polymorphisms are predisposed to develop NAFLD. PMID- 23031809 TI - cDNA cloning and characterization of LASP1 from silkworm, Bombyx mori, involved in cytoplasmic polyhedrosis virus infection. AB - Full-length cDNA of a LIM and SH3 contained protein 1 (named BmLASP1) was identified from the silkworm, Bombyx mori, for the first time by rapid amplification of cDNA ends. The full-length cDNA of BmLASP1 is 2094 bp, consisting of a 5'-terminal untranslated region (UTR) of 117 bp, and a 3'-UTR of 610 bp with two poly-adenylation signal sequence AATAAA and a poly (A) tail. The BmLASP1 cDNA encodes a polypeptide comprising 455 amino acids, including a LIM domain, two nebulin domains and an SH3 domain. The theoretical isoelectric point is 7.07 and the predicted molecular weight is 51.8 kDa. BmLASP1 has no signal peptide but three potential N-glycosylation sites. Sequence similarity and phylogenic analyses indicated that BmLASP1 belonged to the group of insect LASP1 with a longer linker region which is different from vertebrate LASP1. The LASP1 in silkworm contained eight exons in its coding regions, and the last exon-intron boundary was conserved the same as in mammalian and Ciona intestinalis LASP1 genes. By fluorescent quantitative real-time polymerase chain reaction, the mRNA transcripts of BmLASP1 were mainly detected in the gonad, head, and spiracle, and slightly in the silk gland, vasa mucosa, midgut, fat body, and hemocytes. After silkworm larvae were infected by B. mori cytoplasmic polyhedrosis virus (BmCPV), the relative expression level of BmLASP1 was down-regulated in the midgut. This result suggested that BmLASP1 may play an important role in the response of silkworm to BmCPV infection. PMID- 23031810 TI - Molecular cytogenetic characterization of the first reported case of an inv dup (4p)(p15.1-pter) with a concomitant 4q35.1-qter deletion and normal parents. AB - Inverted duplications associated with terminal deletions are complex anomalies described in an increasing of chromosome ends. We report on the cytogenetic characterization of the first de novo inv dup del(4) with partial 4p duplication and 4q deletion in a girl with clinical signs consistent with "recombinant 4 syndrome". This abnormality was suspected by banding, but high-resolution molecular cytogenetic investigations allowed us to define the breakpoints of the rearrangement. The terminal duplicated region extending from 4p15.1 to the telomere was estimated to be 29.27 Mb, while the size of the terminal deletion was 3.114 Mb in the 4q35.1 region. Until now, 10 patients with duplicated 4p14 p15 and deleted 4q35 chromosome 4 have been described. In all cases the abnormal chromosome 4 was derived from a pericentric inversion inherited from one of the parents. In conclusion, we have identified the first case of inv dup del(4) with normal parents suggesting that, often, terminal duplications or terminal deletions mask complex rearrangements. PMID- 23031811 TI - Exceptional complex chromosomal rearrangement and microdeletions at the 4q22.3q23 and 14q31.1q31.3 regions in a patient with azoospermia. AB - In this report we describe the first patient ever found to have azoospermia in association with both exceptional complex chromosomal rearrangements and microdeletions at two translocation breakpoints. A 36-year-old male who had been suffering from male factor infertility was admitted to our clinic. The patient also displayed mild dysmorphia. An analysis of the patient's semen revealed azoospermia. GTG banding revealed the presence of an exceptional complex chromosomal rearrangement involving chromosomes 1, 4, 10 and 14. Using subtelomeric FISH analysis, the patient's karyotype was designated as 46,XY,t(1;10)(q43q44;q21q26.1)(CEB108/T7+,D1S3738-;10PTEL006+,D10S2290+, D1S3738+), ins(14;4) (q31.3;q23q33)(D14S1420+; D4S3359+, D4S2930+). Array-CGH analysis revealed two microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions. We suggest that microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions associated with both an exceptional complex chromosomal rearrangement and the Homo sapiens chromosome 4 open reading frame 37 (C4orf37) gene located at the 4q22.3q23 region might be associated with male factor infertility. PMID- 23031812 TI - Partial monosomy 21 (q11.2->q21.3) combined with 3p25.3->pter monosomy due to an unbalanced translocation in a patient presenting dysmorphic features and developmental delay. AB - We describe a female patient of 1 year and 5 months-old, referred for genetic evaluation due to neuropsychomotor delay, hearing impairment and dysmorphic features. The patient presents a partial chromosome 21 monosomy (q11.2->q21.3) in combination with a chromosome 3p terminal monosomy (p25.3->pter) due to an unbalanced de novo translocation. The translocation was confirmed by fluorescence in situ hybridization (FISH) and the breakpoints were mapped with high resolution array. After the combined analyses with these techniques the final karyotype was defined as 45,XX,der(3)t(3;21)(p25.3;q21.3)dn,-21.ish der(3)t(3;21)(RP11-329A2 ,RP11-439F4-,RP11-95E11-,CTB-63H24+).arr 3p26.3p25.3(35,333 10,888,738))*1,21q11.2q21.3(13,354,643-27,357,765)*1. Analysis of microsatellite DNA markers pointed to a paternal origin for the chromosome rearrangement. This is the first case described with a partial proximal monosomy 21 combined with a 3p terminal monosomy due to a de novo unbalanced translocation. PMID- 23031813 TI - Investigation of secreted protein transcripts as early biomarkers for type 1 diabetes in the mouse model. AB - Type 1 diabetes (T1D) represents a serious health burden in the world, complicated by the fact that disease onset can be preceded by a long time period without evident clinical signs. It would be then of critical importance to detect the disease in its early stages. In this direction, we seek here to identify early preinflammatory markers for autoimmune diabetes, mining our previously reported transcriptome data relevant to distinct early sub-phenotypes in the NOD mouse, associated with early insulin autoantibodies (E-IAA). More specifically we focus on secreted or transmembrane protein transcripts, identifying in this category 71 differentially expressed transcripts which are regulated at the early preinflammatory stages of T1D in the pancreatic lymph nodes (PLN). Following the expression patterns of these 71 transcripts, correspondence analysis (a multivariate analysis method) reveals a clear-cut segregation of the individual samples according to the early subphenotype used. Thus the 71 transcripts coding for secreted proteins constitute a candidate-set of predictive biomarkers for the development of autoimmune damage of the beta cells of the pancreas. The majority of these genes have human orthologs and accordingly they represent potential candidate biomarkers for the human disease. In addition, for predictive purposes, the analysis reveals the possibility to reduce significantly the size of the candidate-set in practice, with various genes displaying identical expression profiles. PMID- 23031814 TI - [Idiopathic interstitial pneumonias]. AB - The idiopathic interstitial pneumonias are diffuse lung diseases characterized by interstitial inflammation and fibrosis. High resolution computed tomography (HRCT) is the best imaging technique for the study of interstitial disease. The general term "idiopathic interstitial pneumonia" includes usual interstitial pneumonia/idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, cryptogenic organizing pneumonia, acute interstitial pneumonia, and lymphocytic interstitial pneumonia. The radiologist's role consists of identifying the macroscopic morphological pattern and working together with clinicians and pathologists to generate an integrated clinical diagnosis. The objective of this article is to review the idiopathic interstitial pneumonias and to describe their different manifestations in HRCT. PMID- 23031815 TI - Bioprospecting for fast growing and biomass characterization of oleaginous microalgae from South-Eastern Buenos Aires, Argentina. AB - As part of pioneering efforts to assess the potential of native microalgae as biofuel feedstock in South-Eastern Buenos Aires, 34 monoalgal cultures (corresponding to the Phylum Chlorophyta) were established and 21 were selected for further growth and biomass composition characterization. Novel RNA sequences in the ITS1-5.8S-ITS2 region were identified. Some strains showed desirable traits as biodiesel feedstock such as (i) apparent maximal doubling times of 6h, (ii) lipids accumulation of up to 43% of their dry biomass, (iii) high ration of mono-unsaturated to poly-unsaturated fatty acids, (iv) high response to CO(2) supplementation, and (v) complete sedimentation in 4h. Data of the outdoors performance of some strains suggested they might represent valuable resources for future research towards the regional development of the technology for microalgae based biofuels. PMID- 23031816 TI - Development of VEGFR2-specific Nanobody Pseudomonas exotoxin A conjugated to provide efficient inhibition of tumor cell growth. AB - Angiogenesis targeting is an attractive approach for cancer treatment. Vascular endothelial growth factor receptor 2 (VEGFR2) is such an important target that is overexpressed in tumor vasculature compared to the endothelium cells of resting blood vessels and blocking of its signaling inhibits neovascularization and tumor metastasis. Immunotoxins represent a promising group of targeted therapeutics to combat tumors. They consist of an antibody linked to a toxin and are designed to kill specifically the tumor cells. In this study, we fused a VEGFR2-specific Nanobody, the antigen-binding single-domain fragment derived from functional Heavy-chain antibody of Camelidae, to the truncated form of Pseudomonas exotoxin A and evaluated its ability to bind the VEGFR2 molecule on the cell surface. We demonstrate that this immunotoxin inhibits the proliferation of VEGFR2-expressing cells in vitro. This finding is considered to be a significant achievement in tumor therapy and it forms a basis for further studies in animal models. PMID- 23031817 TI - Systematically characterizing and prioritizing chemosensitivity related gene based on Gene Ontology and protein interaction network. AB - BACKGROUND: The identification of genes that predict in vitro cellular chemosensitivity of cancer cells is of great importance. Chemosensitivity related genes (CRGs) have been widely utilized to guide clinical and cancer chemotherapy decisions. In addition, CRGs potentially share functional characteristics and network features in protein interaction networks (PPIN). METHODS: In this study, we proposed a method to identify CRGs based on Gene Ontology (GO) and PPIN. Firstly, we documented 150 pairs of drug-CCRG (curated chemosensitivity related gene) from 492 published papers. Secondly, we characterized CCRGs from the perspective of GO and PPIN. Thirdly, we prioritized CRGs based on CCRGs' GO and network characteristics. Lastly, we evaluated the performance of the proposed method. RESULTS: We found that CCRG enriched GO terms were most often related to chemosensitivity and exhibited higher similarity scores compared to randomly selected genes. Moreover, CCRGs played key roles in maintaining the connectivity and controlling the information flow of PPINs. We then prioritized CRGs using CCRG enriched GO terms and CCRG network characteristics in order to obtain a database of predicted drug-CRGs that included 53 CRGs, 32 of which have been reported to affect susceptibility to drugs. Our proposed method identifies a greater number of drug-CCRGs, and drug-CCRGs are much more significantly enriched in predicted drug-CRGs, compared to a method based on the correlation of gene expression and drug activity. The mean area under ROC curve (AUC) for our method is 65.2%, whereas that for the traditional method is 55.2%. CONCLUSIONS: Our method not only identifies CRGs with expression patterns strongly correlated with drug activity, but also identifies CRGs in which expression is weakly correlated with drug activity. This study provides the framework for the identification of signatures that predict in vitro cellular chemosensitivity and offers a valuable database for pharmacogenomics research. PMID- 23031818 TI - Administration of a negative vaccination induces hyporesponsiveness to islet allografts. AB - As a result of less than optimal outcomes the use of islet allografts as a standard insulin replacement therapy is limited to adults with a history of extreme glucose dysregulation and hypoglycemia unawareness. In this study, we examined the use of prophylactic immunotherapy to prevent islet allograft rejection in the absence of antirejection drugs. Our protocol to achieve allograft acceptance used a negative vaccination strategy that is comprised of apoptotic donor cells delivered in Incomplete Freund's Adjuvant (IFA) 1 week prior to islet transplantation. The goal of this new protocol is to elicit hyporesponsiveness to alloantigen prior to islet transplantation. First, we examined our protocol without islet allograft transplants and determined that the negative vaccination was not globally immunosuppressive or immunostimulatory. Islet allograft experiments using fully MHC-mismatched islet donors and recipients demonstrated that the negative vaccination strategy induced long-term islet allograft acceptance. Upon rechallenge with alloantigen, the negative vaccination protocol successfully achieved hyporesponsiveness. In addition, the microenvironment at the site of the tolerant allograft revealed a decrease in proinflammatory mediators (IFN-gamma, TNF-alpha) and an increase in the anti inflammatory mediator IL-10, as well as increased expression of the master regulator of T-regulatory cells, FOXP3. Our data suggest that pretreating allograft recipients with apoptotic donor alloantigen delivered in IFA induced long-term islet allograft acceptance and glycemic control by introducing alloantigen to the recipient immune system in a nonimmunostimulatory manner prior to transplant. PMID- 23031819 TI - Mechanism for the uncoupling of oxidative phosphorylation by juliprosopine on rat brain mitochondria. AB - Prosopis juliflora, popularly known as Algaroba, is a major problem because the lack of food during the driest times of the year and its high palatability and nutritional value make its fruits (pods) much appreciated by cattle, goats, sheep and other animals. However, the consumption of this plant for long periods can cause a disease called cara-torta (pie face), which is characterized by cranial nerve dysfunction, mainly due to the degeneration and disappearance of neurons in the trigeminal motor nucleus. Algaroba contains piperidine alkaloids that have been suggested as being responsible for its toxicity; one of these alkaloids is juliprosopine. This study was conducted to evaluate the mechanisms of action of juliprosopine in isolated rat brain mitochondria to evaluate the potential mechanisms that lead to neurotoxicity in animals intoxicated by algaroba. Juliprosopine stimulated state-4 respiration at concentrations of 10-25 MUM, affected the membrane potential at all concentrations studied (5-25 MUM) and affected ATP production only at higher concentrations (15 and 25 MUM). Juliprosopine cannot be classified as a member of the protonophoric class of uncouplers, such as 2,4-dinitrophenol or CCCP (m-chlorophenylhydrazone), due to its inability to promote mitochondrial swelling in the hyposmotic medium of potassium acetate. In addition, carboxyatractyloside, Mg(2+), cyclosporine A and dithiothreitol did not protect the uncoupling induced by juliprosopine. Because juliprosopine increased the fluorescence responses of mitochondria labeled with 1 aniline-8-naphthalene sulfonate (ANS) and DPH (1,6-diphenyl-1,3,5-hexatriene), we suggested that its uncoupling action must be attributed to a modification of the arrangement of the inner mitochondrial membrane. PMID- 23031820 TI - Secretion and maturation of conotoxins in the venom ducts of Conus textile. AB - The 700 or more species of cone snail attack prey by employing complex venom which can vary considerably both within species and from one species to another. Cone snail venom is remarkable for the high proportion of conotoxins with varied post-translational modifications (PTMs) and for the production of more diverse toxin scaffolds than any other known venomous animal. The venom gland, which is several times longer than its shell, is also unique in being tubular. These unusual characteristics both raise questions, and provide the opportunity for research, concerning the secretion and maturation of conotoxins along the venom duct, a process which is currently not fully understood. This research uses the two mass spectrometric techniques of isotope Coded Affinity Tagging (ICAT) and label-free quantification to study each of five portions of the venom duct of Conus textile snails from New Caledonia. Fifteen conotoxins, several with different post-translational modifications (PTMs) were identified and quantified. One hundred and forty three non-identified conotoxins were also quantified. Distinctive patterns emerged, with the largest group of conotoxins increasing, then peaking in the central-proximal part, before decreasing; whilst the second largest group peaked in the distal region, generally displaying nothing in the first parts. Conotoxins from different superfamilies were commonly found to have similar distributions. A new conotoxin, PCCSKLHDNSCCGL*, was sequenced. A comparison is made with other studies to see how the process varies in cone snails from different regions. PMID- 23031821 TI - In vivo body composition in autochthonous and conventional pig breeding groups by dual-energy X-ray absorptiometry and magnetic resonance imaging under special consideration of Cerdo Iberico. AB - The improvement of carcass quality is one of the main breeding goals in pig production. To select appropriate breeding animals, it is of major concern to exactly and reliably analyze the body composition in vivo. Therefore, the objective of the study was to examine whether the combination of dual-energy X ray absorptiometry (DXA) and magnetic resonance imaging (MRI) offers the opportunity to reliably analyze quantitative and qualitative body composition characteristics of different pig breeding groups in vivo. In this study, a total of 77 pigs were studied by DXA and MRI at an average age of 154 days. The pigs originated from different autochthonous or conventional breeds or crossbreeds and were grouped into six breed types: Cerdo Iberico (Ib); Duroc * Ib (Du_Ib); White Sow Lines (WSL, including German Landrace and German Large White); Hampshire/Pietrain (Pi_Ha, including Hampshire, Pietrain * Hampshire (PiHa) and Pietrain * PiHa); Pietrain/Duroc (Pi_Du, including Pietrain * Duroc (PiDu) and Pietrain * PiDu); crossbred WSL (PiDu_WSL, including Pietrain * WSL and PiDu * WSL). A whole-body scan was performed by DXA with a GE Lunar DPX-IQ in order to measure the amount and percentage of fat tissue (FM; %FM), lean tissue (LM; %LM) and bone mineral, whereas a Siemens Magnetom Open with a large body coil was used for MRI in the thorax region between 13th and 14th vertebrae in order to measure the area of the loin (LA) and the above back fat area (FA) of both body sides. A GLM procedure using SAS 9.2 was used to analyze the data. As expected, the native breed Ib followed by Du_Ib crossbreeds showed the highest %FM (27.2%, 25.0%) combined with the smallest LA (46.2 cm2, 73.6 cm2), whereas Ib had the lowest BW at an average age of 154 days. Pigs with Pi_Ha origin presented the least %FM (12.4%) and largest LA (99.5 cm2). The WSL and PiDu_WSL showed an intermediate body composition. Therefore, it could be concluded that DXA and MRI and especially their combination are very suitable methods to reliably identify differences in body composition and carcass traits among different pig lines in vivo. PMID- 23031823 TI - Oxidative stress in patients with epilepsy is independent of antiepileptic drugs. AB - PURPOSE: Oxidative stress has been implicated in many pathological processes. The brain is highly susceptible to oxidative stress because of its high lipid content. In this study, the oxidative parameters in patients with epilepsy and those of a control group were measured. The study's aim was to determine whether there are differences between the oxidative levels of treated and untreated patients and whether there are differences between individual antiepileptic drugs. METHODS: Oxidative parameters such as Malondialdehyde (MDA), Protein Carbonylation (PC) and Nitric Oxide (NO) levels were evaluated in 100 patients with epilepsy and compared to an equal number of age and sex matched healthy subjects. In the study group, the oxidative parameters of 25 untreated patients were compared to treated patients and the control group. The treated patients were divided into 2 groups based on their antiepileptic drugs (AEDs). Group 1 consisted of patients on a single AED, and group 2 was composed of patients taking more than one AED. A comparative study was performed on the oxidative parameters of medicated patients on single drug regimens and multidrug regimens. RESULTS: The MDA and PC levels were significantly higher in patients than in the control group (P<0.0001). However, there was no significant difference in the NO levels of patients and those of the control group. The 25 untreated patients had higher MDA and PC levels compared to both the control group (P<0.0001) and treated patients (P<0.0001). There was no difference in the oxidative levels between untreated patients and treated patients, group 1 and group 2, and individual AEDs. CONCLUSIONS: In this study, we demonstrated the presence of significantly increased levels of oxidative markers in patients with epilepsy as compared to the control group. AEDs did not influence the oxidative markers, suggesting the presence of seizure-induced oxidative stress. PMID- 23031822 TI - A population-based case-control study of extreme summer temperature and birth defects. AB - BACKGROUND: Although hyperthermia is a recognized animal teratogen and maternal fever has been associated with birth defects in humans, data on the relationship between high environmental temperatures and birth defects are limited. OBJECTIVE: To determine whether pregnancies are potentially vulnerable to the weather extremes anticipated with climate change, we evaluated the relationship between extreme summer temperature and the occurrence of birth defects. METHODS: We performed a population-based case-control study by linking the New York State Congenital Malformations Registry to birth certificates for the years 1992-2006. We selected nonmalformed infants from a 10% random sample of live births as controls. We assigned meteorologic data based on maternal residence at birth, summarized universal apparent temperature (UAT; degrees Fahrenheit) across the critical period of embryogenesis, and estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI) with multivariable logistic regression, controlling for confounders available on the birth certificate. RESULTS: Among 6,422 cases and 59,328 controls that shared at least 1 week of the critical period in summer, a 5-degree increase in mean daily minimum UAT was significantly associated with congenital cataracts (aOR = 1.51; 95% CI: 1.14, 1.99). Congenital cataracts were significantly associated with all ambient temperature indicators as well: heat wave, number of heat waves, and number of days above the 90th percentile. Inconsistent associations with a subset of temperature indicators were observed for renal agenesis/hypoplasia (positive) and anophthalmia/microphthalmia and gastroschisis (negative). CONCLUSIONS: We found positive and consistent associations between multiple heat indicators during the relevant developmental window and congenital cataracts which should be confirmed with other data sources. PMID- 23031824 TI - Gastric bands: what the general radiologist should know. AB - Obesity in the UK is increasing, it is estimated that in England 24% of men and 25% of women are obese.(1,2) In recent years bariatric surgery has become increasingly common and is effective in producing long-term weight loss.(4,5) The most popular form of bariatric surgery in Europe is laparoscopic adjustable gastric banding (LAGB).(6) Radiologists play a key role assessing the normal function of bands, adjusting their filling under fluoroscopic guidance, and in recognizing and managing complications. This review will describe the general principles of LAGB; how they are assessed, how to recognize the most common complications, an overview of the appearances of the bands used in the UK, and novel developments in their use and design. PMID- 23031825 TI - Embryonic-derived olfactory ensheathing cells remyelinate focal areas of spinal cord demyelination more efficiently than neonatal or adult-derived cells. AB - Transplanted olfactory ensheathing cells (OECs) contribute to functional recovery in a range of CNS injuries by several mechanisms, one of which is potentially their ability to form myelin sheaths. OECs sourced from donors of different ages have been shown to remyelinate in several in vitro and in vivo models. However, the optimal donor age for OEC associated remyelination is unclear. This project directly compared the remyelinating potential of p75 purified OEC transplants from three donor ages. OECs were sourced from the olfactory bulbs of embryonic, neonatal, and adult rats and purified by immunopanning, and their remyelinating potential was directly compared by transplantation into the same adult rat toxin induced model of spinal cord demyelination. Remyelination efficiency 3 weeks after transplantation was assessed morphologically and by immunostaining. Our results indicate that all donor ages remyelinate; however, this process is most efficiently achieved by embryonic-derived OECs. PMID- 23031826 TI - The histone variant macroH2A1.1 is recruited to DSBs through a mechanism involving PARP1. AB - The repair of DNA double-strand breaks (DSBs) requires remodeling of the local chromatin architecture to allow the repair machinery to access sites of damage. Here, we report that the histone variant macroH2A1.1 is recruited to DSBs. Cells lacking macroH2A1 have defective recruitment of 53BP1, defective activation of chk2 kinase and increased radiosensitivity. Importantly, macroH2A1.1 is not incorporated into nucleosomes at DSBs, but instead associates with the chromatin through a mechanism which requires PARP1 activity. These results reveal an unusual mechanism involving a direct association of macroH2A1.1 with PARylated chromatin which is critical for retaining 53BP1 at sites of damage. PMID- 23031827 TI - Changes in the plasma cytokine and growth factor profile are associated with impaired healing in pediatric patients treated with INTEGRA(r) for reconstructive procedures. AB - BACKGROUND: Large full thickness skin defects caused by trauma or surgery require skin grafting, often in conjunction with dermal scaffolds such as INTEGRA((r)). Due to the size and severity of these procedures, complications such as infection may occur. This can lead to poor healing outcomes. OBJECTIVE: To identify early biomarkers of complications during INTEGRA((r)) healing. METHODS: Levels of EGF, TGF-beta1, FGF-2, VEGF, IFN-alpha, GM-CSF, IL-4 and IL-8 were measured pre surgery and at days 1, 7 and 25 post-surgery in peripheral blood of 15 pediatric patients treated with INTEGRA((r)) for reconstructive procedures. The levels of these molecules were analysed with respect to the occurrence of complications. RESULTS: Complications (local infection) occurred in a group of 4 patients. This resulted in a reduced INTEGRA((r)) take rate comparing to the group without complications (71.5+/-5.4% vs. 98.1+/-0.7%). In cases with complications there were significantly higher plasma concentrations of IL-4 and FGF-2 on day 7 (p=0.037 and p=0.008 respectively). Other markers were not significantly different between groups or at very low level at all time-points. WCC and CRP remained within normal ranges at all time-points. CONCLUSIONS: This data suggests that elevated levels of IL-4 and FGF-2 at early time-points after surgery may predict the development of complications in patients with INTEGRA((r)). This may enable early interventions to prevent complications in procedures involving the use of INTEGRA((r)). PMID- 23031828 TI - The impact of laser Doppler imaging on the early decision-making process for surgical intervention in adults with indeterminate burns. AB - OBJECTIVE: We aimed to analyze whether laser Doppler imaging (LDI) can lead to earlier decision-making regarding the need for surgery in adults with indeterminate burns. METHODS: In a retrospective cohort study, we developed a prediction model for surgery in adults with indeterminate burns. Patient data (n=101) from January 2007 to December 2009 were used for model development, and those (n=40) from January 2010 to October 2010 for external validation. RESULTS: Between non-surgical and surgical groups, there were significant differences for mean age (p=0.009), % total body surface area burn (p=0.016), site of burn wound (p=0.033), and mean perfusion units (PU) (p<0.001). Multiple logistic regression showed that only the mean PU differed significantly between the groups. The area under the curve (AUC) of the equation derived from multiple logistic regression was 0.938, which did not differ from that of the mean PU alone (0.931; p=0.453). Using a cut-off point of 154.7PU, the sensitivity of LDI was 78.3% and the specificity was 92.7%. This cut-off point also yielded a sensitivity of 77.8% and specificity of 95.5% in the external validation dataset. CONCLUSION: LDI can help make a decision for surgery in the early stages of care for adults with indeterminate burns. PMID- 23031829 TI - Immune-mediated disease genetics: the shared basis of pathogenesis. AB - Recent genetic studies in multiple autoimmune and inflammatory diseases have identified hundreds of genomic loci harboring risk variants. These variants are shared between diseases at unexpectedly high rates, providing a molecular basis for the shared pathogenesis of immune-mediated disease. If properly used, these results could allow us to identify specific pathways underlying disease; explain disease heterogeneity by grouping patients by molecular causes rather than overall symptomatology; and develop more rational approaches to diagnosis and therapy targeting these molecular defects. Here we review the current state of play in the genetics of immune-mediated disease, evidence for this sharing and how this new knowledge can lead to medically actionable discoveries of pathobiology. PMID- 23031831 TI - Structure and stability of weakly chemisorbed ethene adsorbed on low-index Cu surfaces: performance of density functionals with van der Waals interactions. AB - We have investigated the performance of popular density functionals that include van der Waals interactions for the experimentally well-characterized problem of ethene (C(2)H(4)) adsorbed on the low-index surfaces of copper. This set of functionals does not only include three van der Waals density functionals-vdwDF PBE, vdwDF-revPBE and optB86b-vdwDF-and two dispersion-corrected functionals Grimme and TS-but also local and semi-local functionals such as LDA and PBE. The adsorption system of ethene on copper was chosen because it is a weakly chemisorbed system for which the vdW interactions are expected to give a significant contribution to the adsorption energy. Overall the density functionals that include vdW interactions increased substantially the adsorption energies compared to the PBE density functional but predicted the same adsorption sites and very similar C-C bonding distances except for two of the van der Waals functionals. The top adsorption site was predicted almost exclusively for all functionals on the (110), (100) and (111) surfaces, which is in agreement with experiment for the (110) surface but not for the (100) surface. On the (100) surface, all functionals except two van der Waals density functionals singled out the observed cross-hollow site from the calculated C-C bonding distances and adsorption heights. On the top sites on the (110) surface and the cross-hollow site on the Cu(100) surface, the ethene molecule was found to form a weak chemisorption bond. On the (111) surface, all functionals gave a C-C bonding distance and an adsorption height more typical for physisorption, in agreement with experiments. PMID- 23031830 TI - Advances in the development of cancer immunotherapies. AB - Manipulating the immune system in order to induce clinically relevant responses against cancer is a longstanding goal. Interventions to enhance tumor-specific immunity through vaccination, sustaining effector T cell activation, or increasing the numbers of tumor-specific T cells using ex vivo expansion, have all resulted in clinical successes. Here, we examine recent clinical advances and major ongoing studies in the field of cancer immunotherapy. Single agents have so far benefited a limited proportion of patients, and future studies combining different types of immunotherapies and other therapeutic modalities, such as drugs against specific signaling pathways driving cancer cell growth, are needed to pave the way for the development of effective anticancer treatments causing durable responses. PMID- 23031833 TI - Complement-dependent pathogenicity of brain-specific antibodies in cerebrospinal fluid. AB - The specificity and potential pathogenicity of autoantibodies vary between neurological diseases. It is often unclear whether their detection in cerebrospinal fluid (CSF) is a consequence or a cause of pathology. The goal was to test whether administration of brain-specific antibodies into CSF would be sufficient for pathology. Purified immunoglobulin G from a neuromyelitis optica patient was injected intrathecally with complement to naive mice. Histopathological analysis at 7 days revealed damage to the ependyma, disruption of the CSF parenchymal barrier and pathologic lesions, distant from the site of injection. In the absence of complement there was no pathology. Autoantibody and complement in CSF are thus sufficient to initiate a pathologic cascade. PMID- 23031832 TI - Inflammation and oxidative stress induced by cigarette smoke in Lewis rat brains. AB - Exposure to cigarette smoke has been associated with an increased risk of neurological diseases such as stroke, Alzheimer's disease and multiple sclerosis. In these studies, serum and brain sections from Lewis rats or those exposed to cigarette smoke and control rats were examined for evidence of increased inflammation and oxidative stress. Immunocytochemical staining of brain sections from CS-exposed rats showed increased expression of class II MHC and, in ELISA, levels of IFN-gamma and TNF-alpha were higher than for non-exposed rats. In polymerase chain reaction assays there was increased interferon-gamma, TNF-alpha, IL-1alpha, IL-1beta, IL-23, IL-6, IL-23, IL-17, IL-10, TGF-beta, T-bet and FoxP3 gene expression with CS exposure. There was also markedly elevated MIP 1alpha/CCL3, less prominent MCP-1/CCL2 and no elevation of SDF-1alpha gene expression. Analysis of samples from CS-exposed and control rats for anti-oxidant expression showed no significant difference in serum levels of glutathione and, in brain, similar levels of superoxide dismutase and decreased thioredoxin gene expression. In contrast, there was increased brain gene expression for the pro oxidants iNOS and the NADPH components NOX4, dual oxidase 1 and p22(phox). Nrf2 expression, which is typically triggered as a secondary response to oxidative stress, was also increased in brains from CS-exposed rats with nuclear translocation of this protein from cytoplasm demonstrated in astrocytes in association with increased expression of the aryl hydrocarbon receptor gene, an Nrf2 target. These studies, therefore, demonstrate that CS exposure in these animals can trigger multiple immune and oxidative responses that may have important roles in the pathogenesis of CNS inflammatory neurological diseases. PMID- 23031835 TI - A study on the thoron sensitivity of radon detectors available to Canadians. AB - Radon and its decay products have been identified as the second leading cause of lung cancer after tobacco smoking. Thoron is an isotope of radon. With increased awareness of radon, questions related to thoron are arising from the public. Currently, only radon detectors are commonly available to Canadian homeowners. A study on the thoron sensitivities of those radon detectors was undertaken. The average thoron sensitivity relative to radon varied from a factor of 0.012 to 0.74 for the five commonly available types of alpha track radon detectors. The potential impact of thoron sensitivity on radon test results is discussed. PMID- 23031836 TI - Caveolin-1 regulates neural differentiation of rat bone mesenchymal stem cells into neurons by modulating Notch signaling. AB - Bone marrow mesenchymal stem cells (MSCs) are known to differentiate into neurons in vitro. However, the mechanism underlying MSC differentiation remains controversial. A recent analysis has shown that Notch signaling is involved in regulating the differentiation of MSCs. This study examines the potential mechanism of the differentiation of MSCs into neurons, and it considers the role of caveolin-1 in this process. We investigated neuron differentiation and Notch signaling by detecting the expression levels of microtubule-associated protein 2 (MAP-2), Neuron-specific Enolase (NSE), Notch-1, Notch intracellular domain (NICD) and hairy enhancer of split 5 (Hes5). We found that by down-regulating caveolin-1 during induction, MSCs were prone to neural differentiation and expressed high levels of neuronal markers. Meanwhile, the expression levels of Notch-1, NICD and Hes5 decreased. Our results indicate that down-regulation of caveolin-1 promotes the neuronal differentiation of MSCs by modulating the Notch signaling pathway. PMID- 23031837 TI - Dimensions of socioeconomic status and clinical outcome after primary percutaneous coronary intervention. AB - BACKGROUND: The association between low socioeconomic status (SES) and high mortality from coronary heart disease is well-known. However, the role of SES in relation to the clinical outcome after primary percutaneous coronary intervention remains poorly understood. METHODS AND RESULTS: We studied 7385 patients treated with primary percutaneous coronary intervention. Participants were divided into high-SES and low-SES groups according to income, education, and employment status. The primary outcome was major adverse cardiac events (cardiac death, recurrent myocardial infarction, and target vessel revascularization) at maximum follow-up (mean, 3.7 years). Low-SES patients had more adverse baseline risk profiles than high-SES patients. The cumulative risk of major adverse cardiac events after maximum follow-up was higher among low-income patients and unemployed patients compared with their counterparts (income: hazard ratio, 1.68; 95% CI, 1.47-1.92; employment status: hazard ratio, 1.75; 95% CI, 1.46-2.10). After adjustment for patient characteristics, these differences were substantially attenuated (income: hazard ratio, 1.12; 95% CI, 0.93-1.33; employment status: hazard ratio, 1.27; 95% CI, 1.03-1.56). Further adjustment for admission findings, procedure-related data, and medical treatment during follow up did not significantly affect the associations. With education as the SES indicator, no between-group differences were observed in the risk of the composite end point. CONCLUSIONS: Even in a tax-financed healthcare system, low SES patients treated with primary percutaneous coronary intervention face a worse prognosis than high-SES patients. The poor outcome seems to be largely explained by differences in baseline patient characteristics. Employment status and income (but not education level) were associated with clinical outcomes. PMID- 23031838 TI - Carina shift versus plaque shift for aggravation of side branch ostial stenosis in bifurcation lesions: volumetric intravascular ultrasound analysis of both branches. AB - BACKGROUND: Although carina shift and plaque shift are suggested as mechanisms of side branch ostial (SBo) compromise after main vessel (MV) stenting in bifurcation lesions, there are few direct evidence. Our purpose was to confirm the mechanism of SBo compromise after MV stent implantation. METHODS AND RESULTS: Intravascular ultrasound images of both MV and SB before procedure and immediately after MV stenting were evaluated in 44 bifurcation lesions. Three 5 mm segments of interest were volumetrically analyzed: the proximal MV, distal MV, and SBo. SBo compromise was defined as a lumen volume decrease, carina shift as a vessel volume decrease, and plaque shift as a plaque volume increase in the SBo segment after MV stenting. The vessel volume increased, and the plaque volume decreased significantly in the proximal MV and distal MV. In contrast, in the SBo, the vessel volume decreased (53.0+/-17.5 mm(3) versus 50.4+/-16.2 mm(3); P<0.001), with the accompanying small increase in plaque volume (23.0+/-9.8 mm(3) versus 23.4+/-9.8 mm(3); P<0.001). The SBo compromise was significantly correlated with the carina shift (r=0.941; P<0.001), but not with the plaque shift (r=-0.019, P=0.90). Distal MV lumen volume increase was significantly correlated with SBo compromise (r=0.555; P<0.001) and carina shift (r=0.557; P<0.001), but not plaque shift (r=-0.228; P=0.14). CONCLUSIONS: Our study indicates that carina shift, not plaque shift, is the major mechanism of SBo compromise after MV stent implantation, and the carina shift is primarily influenced by distal MV lumen expansion. PMID- 23031839 TI - ADP-induced platelet aggregation after addition of tramadol in vitro in fed and fasted horses plasma. AB - Adenosine diphosphate (ADP)-induced platelet aggregation in fed and fasted horses after addition of tramadol hydrochloride was evaluated in vitro. On 10 horses citrated blood samples were collected 2h after feeding (fed animals) and 21 h after feeding (fasted animals). Final concentrations of ADP 1 and 0.5 MUM, and tramadol hydrochloride (1, 15, 30, 45 and 60 min after the addition of tramadol) were used to determine the maximum degree and initial velocity of platelet aggregation. Repeated measures multifactor analysis of variance (MANOVA) was used to evaluate the effect of feeding/fasting condition, ADP concentration and addition of tramadol. Findings showed statistical differences (P<=0.05) on studied parameters after addition of tramadol to different ADP concentrations in fed and fasted horses. The clinical relevance of these results is that tramadol provides many advantages as a therapeutic option; in fact, it is an inexpensive and a relatively new analgesic in equine veterinary medicine. Further investigations would be appropriate to compare the effects of different opioids but also using different concentrations of tramadol associated with other drugs in order to have substances which can regulate the functional activity of the platelets and to extend the knowledges on equine platelet aggregation. PMID- 23031840 TI - A structural perspective on RNA polymerase I and RNA polymerase III transcription machineries. AB - RNA polymerase I and III are responsible for the bulk of nuclear transcription in actively growing cells and their activity impacts the cellular biosynthetic capacity. As a consequence, RNA polymerase I and III deregulation has been directly linked to cancer development. The complexity of RNA polymerase I and III transcription apparatuses has hampered their structural characterization. However, in the last decade tremendous progresses have been made, providing insights into the molecular and functional architecture of these multi-subunit transcriptional machineries. Here we summarize the available structural data on RNA polymerase I and III, including specific transcription factors and global regulators. Despite the overall scarcity of detailed structural data, the recent advances in the structural biology of RNA polymerase I and III represent the first step towards a comprehensive understanding of the molecular mechanism underlying RNA polymerase I and III transcription. This article is part of a Special Issue entitled: Transcription by Odd Pols. PMID- 23031841 TI - Cholinergic neuron-like cells derived from bone marrow stromal cells induced by tricyclodecane-9-yl-xanthogenate promote functional recovery and neural protection after spinal cord injury. AB - The rate of neuronal differentiation of bone marrow stromal cells (BMSCs) in vivo is very low; therefore, it is necessary to elevate the number of BMSC-derived neurons to cure neurodegenerative diseases. We previously reported that tricyclodecane-9-yl-xanthogenate (D609), an inhibitor of phosphatidylcholine specific phospholipase C (PC-PLC), induced BMSCs to differentiate into neuron like cells in vitro. However, the neuronal type is not clear, and it is still unknown whether these neuron-like cells possess physiological properties of functional neurons and whether they can contribute to the recovery of neuron dysfunction. To answer these questions, we investigated their characteristics by detecting neuronal function-related neurotransmitters and calcium image. The results showed that these cells exhibited functional cholinergic neurons in vitro. Transplantation of these cholinergic neuron-like cells promoted the recovery of spinal cord-injured mice, and they were more effective than BMSCs. The number of cholinergic neurons was increased after injection with BMSC-derived cholinergic neuron-like cells, indicating their high differentiation rate in vivo. Moreover, the proportion of cholinergic neurons in host cells and secretion of acetylcholine were increased, and preservation of neurofilament was also observed in the lesion of mice implanted with BMSC-derived neurons, suggesting the neuronal protection of BMSC-derived neurons. Our findings provide both a simple method to induce the differentiation of BMSCs into cholinergic neuron-like cells and a putative strategy for the therapy of spinal cord injuries. PMID- 23031842 TI - An integrated fish-plankton aquaculture system in brackish water. AB - Integrated Multi-Trophic Aquaculture takes advantage of the mutualism between some detritivorous fish and phytoplankton. The fish recycle nutrients by consuming live (and dead) algae and provide the inorganic carbon to fuel the growth of live algae. In the meanwhile, algae purify the water and generate the oxygen required by fishes. Such mechanism stabilizes the functioning of an artificially recycling ecosystem, as exemplified by combining the euryhaline tilapia Sarotherodon melanotheron heudelotii and the unicellular alga Chlorella sp. Feed addition in this ecosystem results in faster fish growth but also in an increase in phytoplankton biomass, which must be limited. In the prototype described here, the algal population control is exerted by herbivorous zooplankton growing in a separate pond connected in parallel to the fish-algae ecosystem. The zooplankton production is then consumed by tilapia, particularly by the fry and juveniles, when water is returned to the main circuit. Chlorella sp. and Brachionus plicatilis are two planktonic species that have spontaneously colonized the brackish water of the prototype, which was set-up in Senegal along the Atlantic Ocean shoreline. In our system, water was entirely recycled and only evaporation was compensated (1.5% volume/day). Sediment, which accumulated in the zooplankton pond, was the only trophic cul-de-sac. The system was temporarily destabilized following an accidental rotifer invasion in the main circuit. This caused Chlorella disappearance and replacement by opportunist algae, not consumed by Brachionus. Following the entire consumption of the Brachionus population by tilapias, Chlorella predominated again. Our artificial ecosystem combining S. m. heudelotii, Chlorella and B. plicatilis thus appeared to be resilient. This farming system was operated over one year with a fish productivity of 1.85 kg/m2 per year during the cold season (January to April). PMID- 23031843 TI - Salt-sensitive and salt-tolerant barley varieties differ in the extent of potentiation of the ROS-induced K(+) efflux by polyamines. AB - Generation of high levels of polyamines and reactive oxygen species (ROS) is common under stress conditions. Our recent study on a salt-sensitive pea species revealed an interaction between natural polyamines and hydroxyl radicals in inducing non-selective conductance and stimulating Ca(2+)-ATPase pumps at the root plasma membrane (I. Zepeda-Jazo, A.M. Velarde-Buendia, R. Enriquez-Figueroa, B. Jayakumar, S. Shabala, J. Muniz, I. Pottosin, Polyamines interact with hydroxyl radicals in activating Ca2+ and K+ transport across the root epidermal plasma membranes, Plant Phys. 157 (2011) 1-14). In this work, we extended that study to see if interaction between polyamines and ROS may determine the extent of genotypic variation in salinity tolerance. This work was conducted using barley genotypes contrasting in salinity tolerance. Similar to our findings in pea, application of hydroxyl radicals-generating Cu(2+)/ascorbate mixture induced transient Ca(2+) and K(+) fluxes in barley roots. Putrescine and spermine alone induced only transient Ca(2+) efflux and negligible K(+) flux. However, both putrescine and spermine strongly potentiated hydroxyl radicals-induced K(+) efflux and respective non-selective current. This synergistic effect was much more pronounced in a salt-sensitive cultivar Franklin as compared to a salt tolerant TX9425. As retention of K(+) under salt stress is a key determinant of salinity tolerance in barley, we suggest that the alteration of cytosolic K(+) homeostasis, caused by interaction between polyamines and ROS, may have a substantial contribution to genetic variability in salt sensitivity in this species. PMID- 23031844 TI - Naringenin inhibits seed germination and seedling root growth through a salicylic acid-independent mechanism in Arabidopsis thaliana. AB - Flavonoids fulfill an enormous range of biological functions in plants. In seeds, these compounds play several roles; for instance proanthocyanidins protect them from moisture, pathogen attacks, mechanical stress, UV radiation, etc., and flavonols have been suggested to protect the embryo from oxidative stress. The present study aimed at determining the role of flavonoids in Arabidopsis thaliana (L.) seed germination, and the involvement of salicylic acid (SA) and auxin (indole-3-acetic acid), two phytohormones with the same biosynthetic origin as flavonoids, the shikimate pathway, in such a putative role. We show that naringenin, a flavanone, strongly inhibits the germination of A. thaliana seeds in a dose-dependent and SA-independent manner. Altered auxin levels do not affect seed germination in Arabidopsis, but impaired auxin transport does, although to a minor extent. Naringenin and N-1-naphthylphthalamic acid (NPA) impair auxin transport through the same mechanisms, so the inhibition of germination by naringenin might involve impaired auxin transport among other mechanisms. From the present study it is concluded that naringenin inhibits the germination of Arabidopsis seeds in a dose-dependent and SA-independent manner, and the results also suggest that such effects are exerted, at least to some extent, through impaired auxin transport, although additional mechanisms seem to operate as well. PMID- 23031845 TI - Effects of 24-epibrassinolide on nitrogen metabolism in cucumber seedlings under Ca(NO(3))(2) stress. AB - Ca(NO(3))(2) accumulation is a major factor that limits greenhouse production in China. The present investigation was carried out to study the effect of 24 epibrassinolide (EBL) on nitrogen metabolism (including contents of NO(3)(-), NH(4)(+) and amino acids and related enzymes activities) in cucumber seedlings (Cucumis sativus L. cv. Jinyou No. 4) under 80 mM Ca(NO(3))(2) stress. This study found that exogenous EBL significantly reduced the accumulation of NO(3)(-) and NH(4)(+) by Ca(NO(3))(2), and enhanced the inactivated enzymes activities involved in the nitrogen metabolism. In addition, EBL alleviated the inhibition of photosynthesis nitrogen-use efficiency by Ca(NO(3))(2). Increased total amino acids by EBL under stress increased the precursor of proteins biosynthesis, thus promoting the biosynthesis nitrogen containing compounds. The presence of Ca(NO(3))(2) increased polyamines level, which might result from the increased content of free putrescine that is harmful to plant growth. However, exogenous EBL induced a further increase in total polyamines. The increase is likely caused by the elevated contents of conjugated and bound forms of polyamines. In summary, exogenously EBL compensated for the damage/losses by Ca(NO(3))(2) stress to some extent through the regulation of nitrogen metabolism and metabolites. PMID- 23031846 TI - Relationship between endosperm cells redox homeostasis and glutenin polymers assembly in developing durum wheat grain. AB - Assembly of glutenin polymers was examined for two contrasted durum wheat cultivars in connection with changes in the redox status of the endosperm cells that accompanied grain development. The evolutions of the redox state of ascorbate and glutathione, as well as the activities of antioxidant enzymes were measured. Changes in the size distribution profile and redox state of storage proteins were evaluated, with particular emphasis on protein-bound glutathione (PSSG). At the beginning of grain filling phase, the size distribution profile of proteins included an extra peak shoulder at about 40,000 g mol(-1). The shoulder was assimilated to free glutenin subunits as it disappeared concomitantly with the upturn in glutenin polymers accumulation. Irrespective of cultivars, small SDS-soluble polymers accumulated first, followed by larger and insoluble ones, attesting for a progressive polymerization. During the grain filling phase, catalase (EC 1.11.1.6) activity dropped, reaching a very low level at physiological maturity. During the same period, superoxide dismutase (EC 1.15.1.1) and glutathione reductase (EC 1.6.4.2) activities increased steadily while the equilibrium constant between GSSG and PSSG shifted from 10(-2) to unity. These results demonstrated that grain filling was accompanied by a continuous decrease in cellular redox potential. In this context, formation of protein-bound glutathione would represent a protective mechanism against irreversible thiol oxidation. Storage protein S-glutathionylation instead of limiting glutenin polymer assembly as it has been proposed might be a required intermediate step for glutenin subunits pairing. PMID- 23031847 TI - Fish consumption and risk of stroke and its subtypes: accumulative evidence from a meta-analysis of prospective cohort studies. AB - BACKGROUND/OBJECTIVES: To provide a reliable assessment of the hypothesized association of fish consumption with stroke risk accumulatively, an updated meta analysis of published prospective cohort studies was conducted. SUBJECTS/METHODS: Prospective cohort studies through April 2012 in peer-reviewed journals indexed in MEDLINE and EMBASE were selected. Additional information was retrieved through Google or a search of the reference list in relevant articles. The main outcome measure was the weighted hazards ratio (HR) and corresponding 95% confidence interval (CI) for incident stroke according to fish consumption using a random effects model. RESULTS: A database was derived from 16 eligible studies (19 cohorts), including 402,127 individuals (10,568 incident cases) with an average 12.8 years of follow-up. Compared with those who never consumed fish or ate fish <1/month, the pooled adjusted HRs of total stroke risk were 0.97 (95% CI, 0.87 1.08), 0.86 (0.80-0.93), 0.91 (0.85-0.98) and 0.87 (0.79-0.96) for those who consumed fish 1-3/month, 1/week, 2-4/week and ~5/week, respectively (P(linear trend) = 0.09; P(nonlinear trend) = 0.02). Study location was a modifier. An inverse association between fish intake and stroke incidence was only found by studies conducted in North America. The modest inverse associations were more pronounced with ischemic stroke and were attenuated with hemorrhagic stroke. CONCLUSIONS: Accumulated evidence generated from this meta-analysis suggests that fish intake may have a protective effect against the risk of stroke, particularly ischemic stroke. PMID- 23031848 TI - Associations between flavored milk consumption and changes in weight and body composition over time: differences among normal and overweight children. AB - BACKGROUND/OBJECTIVES: Few studies have investigated the associations between flavored milk consumption and body composition in children. We aimed to examine the prospective relationships between flavored milk consumption and body fat. SUBJECTS/METHODS: Subjects included 2270 children from the Avon Longitudinal Study of Parents and Children. Flavored milk consumption at age 10 years was assessed using dietary records; consumption was dichotomized as consumers and non consumers. Percent body fat was measured using dual-energy X-ray absorptiometry at 11 and 13 years. Body weight at 11 and 13 years was included as a secondary outcome. Associations were also examined in a subset of plausible reporters to evaluate the influence of dietary reporting errors. There was an effect of interaction between flavored milk and baseline weight on body fat (P-interaction <0.02). RESULTS: In plausible reporters, overweight/obese children who consumed flavored milk had less favorable changes in body fat compared with non-consumers (adjusted means: -0.16%, 95% CI: -3.8, 3.5 vs -3.4%, 95% CI: -6.5, -0.42, P=0.02). Similar associations with body weight were observed. The adjusted mean percent body fat for overweight/obese girls who consumed flavored milk was greater at age 13 compared with 11 years (39.7%, 95% CI: 32, 47 vs 38.3%, 95% CI: 32, 44). The mean percent body fat for overweight/obese boys was similar between consumers and non-consumer is at 13 years (30.4%, 95% CI: 20, 41 vs 30.1%, 95% CI: 21, 40). CONCLUSIONS: Overweight/obese children who consumed flavored milk had less favorable changes in body composition over time. Although more research is needed, discouraging flavored milk consumption may be one beneficial strategy to address childhood obesity. PMID- 23031849 TI - Magnesium intake and risk of colorectal cancer: a meta-analysis of prospective studies. AB - Epidemiologic studies have suggested that magnesium intake may be associated with a decreased risk of colorectal cancer (CRC), but the findings have been inconsistent. We aimed to assess this association by conducting a meta-analysis of prospective studies. We performed a literature search on PubMed database through July 2012 to identify prospective studies of magnesium intake in relation to CRC risk. Reference lists of the retrieved articles were also reviewed. A random-effects model was used to compute the summary risk estimates. Eight prospective studies containing 338,979 participants and 8000 CRC cases met the inclusion criteria. The summary relative risk (RR) for the highest vs lowest category of magnesium intake for CRC was 0.89 (95% CI, 0.79-1.00), with little evidence of heterogeneity. Restricting the analysis to six studies that have adjusted for calcium intake yielded a similar result. For colon and rectal cancer, the pooled RR was 0.81 (95% CI, 0.70-0.93) and 0.94 (95% CI, 0.72-1.24), respectively. In the dose-response analyses, the summary RRs for an increment of magnesium intake of 50 mg/day for colorectal, colon and rectal cancer were, respectively, 0.95 (95% CI, 0.89-1.00), 0.93 (95% CI, 0.88-0.99) and 0.93 (95% CI, 0.83-1.04), and there was some evidence of heterogeneity; omitting one study that substantially contributed to the heterogeneity yielded generally similar results, but with low heterogeneity. We detected no indication of publication bias. On the basis of the findings of this meta-analysis, a higher magnesium intake seems to be associated with a modest reduction in the risk of CRC, in particular, colon cancer. PMID- 23031850 TI - Predictors of stunting, wasting and underweight among Tanzanian children born to HIV-infected women. AB - BACKGROUND/OBJECTIVES: Children born to human immunodeficiency virus (HIV) infected women are susceptible to undernutrition, but modifiable risk factors and the time course of the development of undernutrition have not been well characterized. The objective of this study was to identify maternal, socioeconomic and child characteristics that are associated with stunting, wasting and underweight among Tanzanian children born to HIV-infected mothers, followed from 6 weeks of age for 24 months. SUBJECTS/METHODS: Maternal and socioeconomic characteristics were recorded during pregnancy, data pertaining to the infant's birth were collected immediately after delivery, morbidity histories and anthropometric measurements were performed monthly. Multivariate Cox proportional hazards methods were used to assess the association between potential predictors and the time to first episode of stunting, wasting and underweight. RESULTS: A total of 2387 infants (54.0% male) were enrolled and followed for a median duration of 21.2 months. The respective prevalence of prematurity (<37 weeks) and low birth weight (<2500 g) was 15.2% and 7.0%; 11.3% of infants were HIV-positive at 6 weeks. Median time to first episode of stunting, wasting and underweight was 8.7, 7.2 and 7.0 months, respectively. Low maternal education, few household possessions, low infant birth weight, child HIV infection and male sex were all independent predictors of stunting, wasting and underweight. In addition, preterm infants were more likely to become wasted and underweight, whereas those with a low Apgar score at birth were more likely to become stunted. CONCLUSIONS: Interventions to improve maternal education and nutritional status, reduce mother-to-child transmission of HIV, and increase birth weight may lower the risk of undernutrition among children born to HIV infected women. PMID- 23031851 TI - Serum 25(OH)D and incident type 2 diabetes: a cohort study. AB - BACKGROUND/OBJECTIVES: Mild to moderate vitamin D insufficiency has been proposed as a risk factor for several common chronic diseases including type 2 diabetes. This study aimed to examine the association between serum 25-hydroxy vitamin D (25(OH)D) and incident diabetes. SUBJECTS/METHODS: The MONICA10 cohort consists of 2656 participants (men and women aged 41-71 years) who participated in a 10 year follow-up examination during 1993-1994 as part of the MONICA 1 population survey. A total of 2571 participants free of diabetes at baseline and with successful measurement of serum 25(OH)D were included in the current study. The Danish National Diabetes register enabled identification of 288 cases of incident diabetes during follow-up (median: 16.4 years). Data were analysed by Cox proportional hazard models and associations were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Serum 25(OH)D was inversely associated with incident diabetes adjusted for potential confounders (HR per 25 nmol/l=0.83; 95% CI: 0.72-0.95; P=0.009). A statistically significant interaction was observed between 25(OH)D and waist circumference (WC) (P(interaction)=0.042) suggesting an association in persons with a high WC (HR (95%CI) per 25 nmol/l=0.74 (0.63-0.88), 218 incident cases) and not in persons with a normal WC (HR (95%CI) per 25 nmol/l=0.98 (0.78-1.24), 70 incident cases). CONCLUSIONS: Low serum 25(OH)D was associated independently with incident diabetes. The inverse association was only found in overweight-obese and not in normal weight individuals, suggesting that obesity may modify the effect of vitamin D status on the risk of diabetes. PMID- 23031852 TI - Total and regional relationship between lean and fat mass with increasing adiposity--impact for the diagnosis of sarcopenic obesity. AB - BACKGROUND/OBJECTIVE: Besides the effect of age used to define sarcopenia, there is need to understand the impact of adiposity on the relationship between lean (fat-free mass, FFM) and fat mass (FM) in order to diagnose sarcopenic obese phenotypes. More importantly, the regional distribution of skeletal muscle (SM) to adipose tissue (AT) or the composition of FFM (that is, SM proportion of lean mass) may also depend on adiposity. SUBJECTS/METHODS: In a large database (n=1737) of healthy males and females (age 11-84 years, BMI 13.5-52.5 kg/m(2)) we investigated changes in the relationship between FFM and FM (normalized by height as fat-free mass index and fat mass index: FFMI and FMI, kg/m(2) assessed by densitometry) with increasing adiposity and age. In a subgroup (n=263) we analyzed the relationship between regional SM and (i) AT (by magnetic resonance imaging) or (ii) lean soft tissue (by dual X-ray absorptiometry) with increasing adiposity. RESULTS: The relationship between lean and FM was influenced by adiposity, age and gender. With increasing adiposity, SM/AT declined faster at the trunk in men and at the extremities in women. The contribution of appendicular SM to lean soft tissue of arms and legs tended to decrease at a higher adiposity in both genders (FMI >6.97 kg/m(2) in women; FMI>7.77 kg/m(2) in men). CONCLUSION: Besides age and gender, adiposity and body region should be considered when evaluating the normal relationship between lean and FM, SM/FFM and SM/AT. PMID- 23032061 TI - Pituitary disease from the past: a rare case of gigantism in skeletal remains from the Roman Imperial Age. PMID- 23032060 TI - Effects of type 2 diabetes and insulin on whole-body, splanchnic, and leg protein metabolism. AB - CONTEXT: Type 2 diabetes (T2D) is characterized by insulin resistance to glucose metabolism. Most studies suggest that protein metabolism is unaffected by T2D, but regional protein metabolism and response to multiple doses of insulin have not been examined. OBJECTIVE: Our objective was to determine whether insulin regulation of splanchnic and leg protein metabolism are affected by T2D during hyperglycemia and graded insulin levels. DESIGN AND SETTING: We conducted a cross sectional study at an academic medical center. PARTICIPANTS: T2D and non-T2D adults were matched for age (62 yr) and body mass index (30 kg/m(2)). INTERVENTIONS: Glucose was maintained at approximately 9 mmol/liter while insulin was infused at three progressively higher rates, achieving circulating concentrations of approximately 150, 350, and 700 pmol/liter, respectively. MAIN OUTCOME MEASURES: Protein kinetics were measured using labeled phenylalanine (Phe) and tyrosine (Tyr). RESULTS: Whole-body protein breakdown and synthesis rates were higher in T2D but declined with increasing insulin in both groups. Leg Phe and Tyr appearance and disappearance and estimates of protein breakdown and synthesis, respectively, were higher in T2D but did not decline significantly with insulin, resulting in similar net balance between groups. Splanchnic response to insulin was blunted in T2D, shown by a smaller reduction in rates of disappearance and net balance of Phe and Tyr as insulin increased. Splanchnic conversion of Phe to Tyr was lower in T2D and less sensitive to insulin, whereas nonsplanchnic Phe to Tyr tended to be higher in T2D. CONCLUSIONS: T2D results in higher whole-body, splanchnic, and leg protein turnover and blunts the insulin mediated suppression of splanchnic protein anabolism under hyperglycemic, hyperinsulinemic conditions. PMID- 23032062 TI - Circulating miRNA profiles in patients with metabolic syndrome. AB - CONTEXT: Coordinated interplay of dysregulated microRNAs in isolated metabolic disorder is implicated in the pathogenesis of metabolic syndrome. OBJECTIVE: The objective of the study was to characterize microRNA expression in the blood and exosomes of individuals with metabolic syndrome and compare them with those manifesting one of the metabolic vascular risk factors (type 2 diabetes, hypercholesterolemia, or hypertension). RESEARCH DESIGN/SETTING/PARTICIPANTS: A total of 265 participants were recruited in a health screening and characterized into distinct groups as follows: 1) healthy controls (n = 46); 2) metabolic syndrome (n = 50); 3) type 2 diabetes (n = 50); 4) hypercholesterolemia (n = 89); and 5) hypertension (n = 30). Total RNA was subjected to microRNA profiling, and a panel of significantly dysregulated microRNAs was validated using quantitative PCR. MAIN OUTCOME MEASURES: Analysis of profiling data characterized unique pools of miRNAs that could categorize the different risk factors of metabolic syndrome. RESULTS: We have identified miR-197, miR-23a, and miR-509-5p as potential contributors of dyslipidemia in metabolic syndrome (correlation with body mass index; P = 0.029, 0.021, and 0.042, respectively) and miR-130a and miR-195 as contributors of hypertension (correlation with blood pressure; P = 0.019 and 0.045, respectively). A plausible association of miR-27a and miR-320a with metabolic syndrome and type 2 diabetes patients has also been found because these miRNAs remained dysregulated in both cases (correlation with fasting glucose; P = 0.010 and 0.016, respectively). CONCLUSIONS: Significant dysregulation of seven candidate microRNAs has been found to be associated with risks involved in the manifestation of metabolic syndrome. PMID- 23032063 TI - Diagnosis of latent tuberculosis infection (LTBI) before anti-TNF-alpha treatment -the tuberculin skin test is useful. PMID- 23032064 TI - Downward causes and appropriate abstractions: Alternative argument for Noble's position. AB - In his article of this issue, Denis Noble argues that causation can occur at and between any scales - rather than levels - in nature. I agree with this conclusion, but do not find his reasoning fully persuasive. I offer an independent but related argument for his position, which focuses on the role of the process of abstraction in identifying and understanding a phenomenon. My aim is to give the reader another way to think about causal talk within the framework of Systems Biology. PMID- 23032065 TI - Similarity measure for quality control of dental CAD/CAM-applications. AB - There is no measure for morphometric quality control of dental CAD/CAM restorations as well as for evaluation of newly developed CAD/CAM-applications. The aim of this study was to (a) establish a 3D-measure for morphological comparisons, (b) to proof its metrical and subjective-visual validity and (c) to explore morphological features which have relevant impact on visual perception. 125 maxillary anterior teeth were chosen from a digital library of 3D data sets and compared by automatic superimposition with a best-fit method. The superimposition was analyzed by a newly defined 3-dimensional similarity measure, called shape similarity value (SSV). With this measure, similarity between symmetrical and non-symmetrical teeth was evaluated and the metrical validity was tested. Additionally, visual evaluation of tooth similarities were performed and analyzed by means of multivariate statistical procedures, to test the correspondence between metrical similarity measure and visual similarity perception. The measure clearly reproduced the similarity of contralateral teeth and the dissimilarity of teeth between different individuals. The coincidence between quantitative similarity measure and visual perception was moderate. In conclusion, the presented 3D-measure can be considered as a first substantial step towards a morphometric quality control of CAD/CAM-restorations of anterior teeth. PMID- 23032067 TI - Comparing peripheral blood stem cell collection using the COBE Spectra, Haemonetics MCS+, and Baxter Amicus. AB - Peripheral blood stem cells (PBSC) have become the most common source of hematopoietic cells for allogeneic or autologous blood and marrow transplantation (BMT). We performed an evaluation of PBSC collections using three different apheresis systems in two major transplantation centers in Singapore. Patients undergoing autologous BMT and donors collecting for allogeneic BMT were harvested using the COBE Spectra, Haemonetics MCS+, or Baxter Amicus. There were 99 Spectra collections (61 were autologous), 81 MCS+ collections (35 were autologous) and 38 Amicus collections (33 were autologous). Our data shows that the Amicus not only processed larger peripheral blood volumes but also yielded larger PBSC volume (P value<0.05). In terms of PBSC products, the Spectra produced more WBC, WBC/liter blood processed, and WBC/kg (P-value<0.05). The Spectra and MCS+ produced comparable amount of CD34+ cells. Amicus collected 50% less platelets compared to Spectra and MCS+. The total CD34+ cells in the PBSC products was linearly correlated to the circulating CD34+ cells using Spectra, MCS+, and Amicus. Our results suggest that, compared to MCS+ and Amicus, collecting PBSC using the COBE Spectra can produce more WBC with a similar number of CD34+ cells. With a linear correlation of circulating CD34+ cells to the total CD34+ cells in the products, the availability of an automated procedure, no rotating seal, and a small extracorporeal volume, the Spectra appears to be the preferred machine for PBSC collection. PMID- 23032068 TI - Tacrolimus (FK506) prevents early retinal neovascularization in streptozotocin induced diabetic mice. AB - Diabetic retinopathy is a complex disease that has potential involvement of inflammatory in its pathogenesis. We hypothesized that tacrolimus (FK506), one of the potent immunosuppressive agent, could be effective against diabetic retinopathy, which involves significant inflammation. The aim of the present study was to investigate the effects of FK506 in early retinal changes of streptozotocin-induced diabetic mice. The effect of FK506 treatment (10 MUg per eye for one week) was evaluated by TNF-a, VEGF, iNOS and COX-2 protein levels measurement, neovascularization, and the activation of NF-kB in the retina. Increased amounts of cytokines, neovascularization, inflammatory markers and activation of NF-kB were observed in retina from diabetic mice. FK506 treatment significantly lowered retinal TNF-a, VEGF, iNOS and COX-2. Further, treatment with FK506 significantly suppressed diabetes-related neovascularization, as well as the activation of NF-kB. These data demonstrated that FK506 attenuates the degree of retinal inflammation and preserving the neovascularization in early diabetic mice. PMID- 23032066 TI - Characterization and comparison of commercially available TNF receptor 2-Fc fusion protein products. AB - Because of rapidly increasing market demand and rising cost pressure, the innovator of etanercept (Enbrel(r)) will inevitably face competition from biosimilar versions of the product. In this study, to elucidate the differences between the reference etanercept and its biosimilars, we characterized and compared the quality attributes of two commercially available, biosimilar TNF receptor 2-Fc fusion protein products. Biosimilar 1 showed high similarity to Enbrel(r) in critical quality attributes including peptide mapping, intact mass, charge variant, purity, glycosylation and bioactivity. In contrast, the intact mass and MS/MS analysis of biosimilar 2 revealed a mass difference indicative of a two amino acid residue variance in the heavy chain (Fc) sequences. Comprehensive glycosylation profiling confirmed that biosimilar 2 has significantly low sialylated N-oligosaccharides. Biosimilar 2 also displayed significant differences in charge attributes compared with the reference product. Interestingly, biosimilar 2 exhibited similar affinity and bioactivity levels compared with the reference product despite the obvious difference in primary structure and partial physiochemical properties. For a biosimilar development program, comparative analytical data can influence decisions about the type and amount of animal and clinical data needed to demonstrate biosimilarity. Because of the limited clinical experience with biosimilars at the time of their approval, a thorough knowledge surrounding biosimilars and a case-by-case approach are needed to ensure the appropriate use of these products. PMID- 23032069 TI - ABCG2 protects kidney side population cells from hypoxia/reoxygenation injury through activation of the MEK/ERK pathway. AB - Breast cancer resistance protein 1 (BCRP1/ABCG2) is used to identify the side population (SP) within a population of cells, which is enriched for stem and progenitor cells in different tissues. Here, we investigated the role of extracellular signal-regulated kinase (ERK) 1/2 in the signaling mechanisms underlying ischemic/hypoxic conditions in kidney SP cells. Kidney SP cells were isolated using Hoechst 33342 dye-mediated fluorescein-activated cell sorting and then incubated under hypoxia/reoxygenation (H/R) with or without verapamil, a selective BCRP1/ABCG2 inhibitor. ABCG2 expression, ERK activity, cell viability, metabolic activity, and membrane damage were tested after H/R treatment. To evaluate the role of ERK 1/2 on the expression and function of ABCG2, the expression of mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), which preferentially activates ERK, was upregulated by transfection with the recombinant sense expression vector pcDNA3.1-MEK and downregulated by pretreatment with U0126, a specific MEK inhibitor. We found that hypoxia activated ERK activity in the kidney SP cells but not in non-SP cells both in vitro and in vivo. Overexpression of MEK mimicked hypoxia-induced ABCG2 expression. Contrarily, U0126 inhibited hypoxia- and MEK-upregulated ABCG2 expression. Furthermore, H/R induced significant increases in nuclear, metabolic, and membrane damage in both SP cells and non-SP cells; however, this H/R-induced cytotoxicity was much more severe in non-SP cells than in SP cells. Notably, the viability of kidney SP cells was enhanced by MEK overexpression and inhibited by U0126. Verapamil treatment reversed MEK-induced viability of kidney SP cells. When administered systemically into animals with renal ischemia/reperfusion injury, the SP cells significantly improved renal function, accelerated mitogenic response, and reduced cell apoptosis. However, this improved therapeutic potential of SP cells was significantly reduced by pretreatment with verapamil. Collectively, these findings provide evidence for a crucial role for the MEK/ERK ABCG2 pathway in protecting kidney SP cells from ischemic/hypoxic injury. PMID- 23032070 TI - Effects of levetiracetam as a monotherapy on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy. AB - PURPOSE: Antiepileptic drugs (AEDs) may have adverse effects on bone metabolism and bone mineral density (BMD). The aim of this study is to determine the changes of bone metabolism and BMD in epilepsy patients who are undergoing levetiracetam (LEV) monotherapy. METHODS: Drug-naive, sixty-one patients with recent onset epilepsy were recruited (24 female, 37 males; mean age: 31.0+/-13.1 years) in this study. We measured calcium, phosphate, bone alkaline phosphatase, parathyroid hormone, osteocalcin, insulin-like growth factor (IGF)-1, C telopeptide, vitamin D3 levels and bone density measurements with DEXA method before and after LEV administration of mean duration 14.16+/-3.36 months. RESULTS: T score in lumbar spine (L1-L4) was significantly increased with the correction of multiple T tests using Bonferroni's test across LEV monotherapy (p=0.0401). However, no significant change was observed in other parameters for BMD and T score. Repeated measures ANOVA with Bonferroni's correction of confounders such as sex, age, and treatment duration revealed significant increase in T score in lumbar spine (p=0.0164). The level of average LEV dosage itself did not reveal any significant association with BMD and bone metabolism. CONCLUSIONS: We suggest that LEV monotherapy may have no harmful effect on bone strength and metabolism for 1 year. PMID- 23032071 TI - Interacting effects of naltrexone and OPRM1 and DAT1 variation on the neural response to alcohol cues. AB - Variation at a single nucleotide polymorphism in the MU-opioid receptor gene (OPRM1), A118G (Asn40Asp), may moderate naltrexone (NTX) effects in alcohol dependence. Both NTX and A118G variation have also been reported to affect alcohol cue-elicited brain activation. This study investigated whether sub-acute NTX treatment and A118G genotype interacted in their effects on cue-elicited activation of the ventral striatum (VS), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Secondarily, variation at a variable number tandem repeat polymorphism in the dopamine transporter gene (DAT1/SLC6A3), which has been associated with increased reward-related activation in VS, was analyzed as a moderator of medication and A118G effects. Seventy-four non-treatment-seeking alcohol-dependent individuals, half preselected to carry at least one copy of the A118G G (Asp) allele, were randomized to NTX (50 mg) or placebo for 7 days, and performed an fMRI alcohol cue reactivity task on day 6. Region-of-interest analyses indicated no main effects of medication or A118G genotype. However, these factors interacted in their effects on OFC activation, such that, among NTX treated individuals, G-allele carriers had less activation than A-allele homozygotes. DAT1 variation also moderated medication/A118G effects. There was a three-way interaction between medication and A118G and DAT1 genotypes on VS activation, such that, among G-allele carriers who received NTX, DAT1 10-repeat allele (10R) homozygotes had less activation than 9-repeat-allele (9R) carriers. Further, 10R homozygotes who received NTX had less mPFC activation than 9R carriers. Polymorphic variation in OPRM1 and DAT1 should be considered in future studies of NTX, particularly regarding its effects on reward processing. PMID- 23032072 TI - Striatal adenosine signaling regulates EAAT2 and astrocytic AQP4 expression and alcohol drinking in mice. AB - Adenosine signaling is implicated in several neuropsychiatric disorders, including alcoholism. Among its diverse functions in the brain, adenosine regulates glutamate release and has an essential role in ethanol sensitivity and preference. However, the molecular mechanisms underlying adenosine-mediated glutamate signaling in neuroglial interaction remain elusive. We have previously shown that mice lacking the ethanol-sensitive adenosine transporter, type 1 equilibrative nucleoside transporter (ENT1), drink more ethanol compared with wild-type mice and have elevated striatal glutamate levels. In addition, ENT1 inhibition or knockdown reduces glutamate transporter expression in cultured astrocytes. Here, we examined how adenosine signaling in astrocytes contributes to ethanol drinking. Inhibition or deletion of ENT1 reduced the expression of type 2 excitatory amino-acid transporter (EAAT2) and the astrocyte-specific water channel, aquaporin 4 (AQP4). EAAT2 and AQP4 colocalization was also reduced in the striatum of ENT1 null mice. Ceftriaxone, an antibiotic compound known to increase EAAT2 expression and function, elevated not only EAAT2 but also AQP4 expression in the striatum. Furthermore, ceftriaxone reduced ethanol drinking, suggesting that ENT1-mediated downregulation of EAAT2 and AQP4 expression contributes to excessive ethanol consumption in our mouse model. Overall, our findings indicate that adenosine signaling regulates EAAT2 and astrocytic AQP4 expressions, which control ethanol drinking in mice. PMID- 23032073 TI - A randomized, double-blind, placebo-controlled phase 2 study of alpha4beta2 agonist ABT-894 in adults with ADHD. AB - Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel alpha4beta2 NNR agonist (ABT-894 (3 (5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners' Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT 894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of alpha4beta2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted. PMID- 23032075 TI - The goitrogenic efficiency of thioamides in a marine teleost, sea bream (Sparus auratus). AB - Studies on the role of thyroid hormones (THs) in teleost fish physiology have deployed the synthetic goitrogens, methimazol (MMI), propilthiouracil (PTU) and thiourea (TU) that are used to treat human hyperthyroidism. However, the action of the goitrogens, MMI, PTU and TU at different levels of the hypothalamic pituitary-thyroid (HPT) axis in teleosts is largely unknown. The central importance of the hypothalamus and pituitary in a number of endocrine regulated systems and the cross-talk that occurs between different endocrine axes makes it pertinent to characterize the effects of MMI, PTU and TU, on several endpoints of the thyroid system. The marine teleost, sea bream (Sparus auratus) was exposed to MMI, PTU and TU (1mg/kg wet weight per day), via the diet for 21days. Radioimmunoassays (RIA) of plasma THs and ELISA of the TH carrier transthyretin (TTR) revealed that MMI was the only chemical that significantly reduced plasma TH levels (p<0.05), although both MMI and PTU significantly (p<0.05) reduced plasma levels of circulating TTR (p<0.05). Histological analysis of the thyroid tissue revealed modifications in thyrocyte activity that explain the reduced circulating levels of THs. MMI also significantly (p<0.05) up-regulated transcript abundance of liver deiodinase 1 and 2 while significantly (p<0.05) decreasing TRbeta expression in the pituitary, all hallmarks of HPT axis action of goitrogens in vertebrates. The results indicate that in the sea bream MMI is the most effective goitrogen followed by PTU and that TU (1mg/kg wet weight for 21days) failed to have a goitrogenic effect. The study highlights the non-uniform effect of goitrogens on the thyroid axis of sea bream and provides the basis for future studies of thyroid disrupting pollutants. PMID- 23032074 TI - Activation and inhibition of neurons in the hippocampal ventral subiculum by norepinephrine and locus coeruleus stimulation. AB - The ventral subiculum (vSub) has been implicated in a wide range of neurocognitive functions, including responses to fear, stress, and anxiety. The vSub receives dense noradrenergic (NE) inputs from the locus coeruleus (LC), and the LC-NE system is heavily implicated in attention and is known to be activated by stressors. However, the way in which the neurons in the vSub respond to activation of the LC-NE is not well understood. In this study, the direct LC innervation of the vSub was investigated. The effect of norepinephrine (NE) on single vSub neurons was examined using microiontophoresis combined with electrophysiological recordings in anesthetized rats, and this response compared with the effect of electrical stimulation of the LC. Iontophoretic NE inhibited all vSub neurons tested, whereas LC stimulation inhibited 16% and activated 38% of neurons. Inhibition was mediated primarily by alpha-2 receptors, whereas activation was mediated by beta-adrenergic receptors. Furthermore, this effect was not mediated via the LC-basolateral amygdala (BLA) pathway, because BLA inactivation did not block LC stimulation-evoked activation of the vSub. These results indicate that the LC-NE system is a potent modulator of vSub activity. Based on these findings, stress-induced activation of the LC-NE system is expected to evoke inhibition and activation in the vSub, both of which may contribute to stress adaptation, whereas an imbalance of this system may lead to pathological stress responses in mental disorders. PMID- 23032076 TI - Regulation of the cell proliferation and migration as extra-pituitary functions of GnRH. AB - GnRH was originally identified as a hypothalamic factor which promotes gonadotropin release from the pituitary and was named gonadotropin-releasing hormone (GnRH). However, broad tissue distributions of GnRH and the GnRH receptor in various extrapituitary tissues and organs have been revealed and it has been suggested that GnRH has extrapituitary effects such as neuromodulation, immunomodulation, and regulation of follicular atresia and ovulation. Although a number of studies have been performed on these effects, little is known about the molecular mechanisms and physiological settings in which GnRH exerts its activities in extrapituitary organs or tissues. Our recent studies had demonstrated that GnRH is able to regulate both cell proliferation and cell migration at much lower concentration than that in the peripheral circulation by using human carcinoma cell lines. Moreover, stimulating activity of GnRH on the developing chick embryonic GnRH neurons was also demonstrated and strongly suggests possible involvement of GnRH in some of extrapituitary functions. This mini-review intends to provide solid evidence of GnRH activity in the regulation of cell proliferation and migration and its physiological relevance in extra pituitary functions. Recent other research, including that in various invertebrates, provides new insight into the evolutionary scenarios of GnRH signaling systems, and GnRH functions. Both proliferating and migrating activities are important fundamental cellular activities and could provide an important clue into understanding what the driving force behind the evolution of the GnRH signaling system was. PMID- 23032077 TI - Effects of early life stress on brain activity: implications from maternal separation model in rodents. AB - Adverse experiences in early life can affect the formation of neuronal circuits during postnatal development and exert long-lasting influences on neural function. Many studies have shown that daily repeated maternal separation (RMS), an animal model of early life stress, can modulate the hypothalamic-pituitary adrenal axis (HPA-axis) and can affect subsequent brain function and emotional behavior during adulthood. However, the molecular basis of the long-lasting effects of early life stress on brain function has not been completely elucidated. In this mini-review, we introduce various cases of maternal separation in rodents and illustrate the alterations in HPA-axis activity by focusing on corticosterone (CORT), an end-product of the HPA-axis in rodents. We then present the characterization of the brain regions affected by various patterns of MS, including RMS and single time maternal separation (SMS) at various stages before weaning, by investigating c-Fos expression, a biological marker of neuronal activity. These CORT and c-Fos studies suggest that repeated early life stress may affect neuronal function in region- and temporal-specific manners, indicating a critical period for habituation to early life stress. Furthermore, we introduce changes in behavioral aspects and gene expression in adult mice exposed to RMS. PMID- 23032078 TI - Are we van der Waals ready? AB - We apply a range of density-functional-theory-based methods capable of describing van der Waals interactions with weakly bonded layered solids in order to investigate their accuracy for extended systems. The methods under investigation are the local-density approximation, semi-empirical force fields, non-local van der Waals density functionals and the random-phase approximation. We investigate the equilibrium geometries, elastic constants and binding energies of a large and diverse set of compounds and arrive at conclusions about the reliability of the different methods. The study also points to some directions of further development for the non-local van der Waals density functionals. PMID- 23032079 TI - The GARD assay for assessment of chemical skin sensitizers. AB - Allergic contact dermatitis is a skin disease caused by an immunologic reaction to low molecular weight compounds, so called haptens. These substances are commonly present in products used by humans in daily life, such as in cosmetics and fragrances, as well as within chemical industry and in pharmaceuticals. The frequent usage of these compounds in different applications has led to increasing incidences of allergic contact dermatitis, which has become a substantial economic burden for society. As a consequence, chemicals are routinely tested for their ability to induce skin sensitization, using animal models such as the murine Local Lymph Node Assay. However, recent legislations regulate the use of animal models within chemical testing. Thus, there is an urgent need for in vitro alternatives to replace these assays for safety assessment of chemicals. Recently, we identified a signature of predictive genes, which are differentially regulated in the human myeloid cell-line MUTZ-3 when stimulated with sensitizing compounds compared to non-sensitizing compounds. Based on these findings, we have formulated a test strategy for assessment of sensitizing compounds, called Genomic Allergen Rapid Detection, GARD. In this paper, we present a detailed method description of how the assay should be performed. PMID- 23032080 TI - Developmental defects and genomic instability after x-irradiation of wild-type and genetically modified mouse pre-implantation and early post-implantation embryos. AB - Results obtained from the end of the 1950s suggested that ionizing radiation could induce foetal malformations in some mouse strains when administered during early pre-implantation stages. Starting in 1989, data obtained in Germany also showed that radiation exposure during that period could lead to a genomic instability in the surviving foetuses. Furthermore, the same group reported that both malformations and genomic instability could be transmitted to the next generation foetuses after exposure of zygotes to relatively high doses of radiation. As such results were of concern for radiation protection, we investigated this in more detail during recent years, using mice with varying genetic backgrounds including mice heterozygous for mutations involved in important cellular processes like DNA repair, cell cycle regulation or apoptosis. The main parameters which were investigated included morphological development, genomic instability and gene expression in the irradiated embryos or their own progeny. The aim of this review is to critically reassess the results obtained in that field in the different laboratories and to try to draw general conclusions on the risks of developmental defects and genomic instability from an exposure of early embryos to moderate doses of ionizing radiation. Altogether and in the range of doses normally used in diagnostic radiology, the risk of induction of embryonic death and of congenital malformation following the irradiation of a newly fertilised egg is certainly very low when compared to the 'spontaneous' risks for such effects. Similarly, the risk of radiation induction of a genomic instability under such circumstances seems to be very small. However, this is not a reason to not apply some precaution principles when possible. One way of doing this is to restrict the use of higher dose examinations on all potentially pregnant women to the first ten days of their menstrual cycle when conception is very unlikely to have occurred (the so-called ten-day rule), as already recommended by the Health Protection Agency. Such a precautionary attitude would also be supported by the uncertainties associated with later changes in gene expression which might result from irradiation or early embryos with moderate doses. PMID- 23032082 TI - Comparison of different solar reactors for household disinfection of drinking water in developing countries: evaluation of their efficacy in relation to the waterborne enteropathogen Cryptosporidium parvum. AB - Solar water disinfection (SODIS) is a type of treatment that can significantly improve the microbiological quality of drinking water at household level and therefore prevent waterborne diseases in developing countries. Cryptosporidium parvum is an obligate protozoan parasite responsible for the diarrhoeal disease cryptosporidiosis in humans and animals. Recently, this parasite has been selected by the WHO as a reference pathogen for protozoan parasites in the evaluation of household water treatment options. In this study, the field efficacy of different static solar reactors [1.5 l transparent plastic polyethylene terephthalate (PET) bottles as well as 2.5 l borosilicate glass and 25 l methacrylate reactors fitted with compound parabolic concentrators (CPC)] for solar disinfection of turbid waters experimentally contaminated with C. parvum oocysts was compared. Potential oocyst viability was determined by inclusion/exclusion of the fluorogenic vital dye propidium iodide. The results demonstrate that static solar reactors fitted with CPCs are an excellent alternative to the conventional SODIS method with PET bottles. These reactors improved the efficacy of the SODIS method by enabling larger volumes of water to be treated and, in some cases, the C. parvum oocysts were rendered totally unviable, minimising the negative effects of turbidity. PMID- 23032081 TI - Ribosomal multi-operon diversity: an original perspective on the genus Aeromonas. AB - 16S rRNA gene (rrs) is considered of low taxonomic interest in the genus Aeromonas. Here, 195 Aeromonas strains belonging to populations structured by multilocus phylogeny were studied using an original approach that considered Ribosomal Multi-Operon Diversity. This approach associated pulsed-field gel electrophoresis (PFGE) to assess rrn operon number and distribution across the chromosome and PCR-temporal temperature gel electrophoresis (TTGE) to assess rrs V3 region heterogeneity. Aeromonads harbored 8 to 11 rrn operons, 10 operons being observed in more than 92% of the strains. Intraspecific variability was low or nul except for A. salmonicida and A. aquariorum suggesting that large chromosomic rearrangements might occur in these two species while being extremely rarely encountered in the evolution of other taxa. rrn operon number at 8 as well as PFGE patterns were shown valuable for taxonomic purpose allowing resolution of species complexes. PCR-TTGE revealed a high rate of strains (41.5%) displaying intragenomic rrs heterogeneity. Strains isolated from human samples more frequently displayed intragenomic heterogeneity than strains recovered from non human and environmental specimens. Intraspecific variability ranged from 0 to 76.5% of the strains. The observation of species-specific TTGE bands, the recovery of identical V3 regions in different species and the variability of intragenomic heterogeneity (1-13 divergent nucleotides) supported the occurrence of mutations and horizontal transfer in aeromonad rrs evolution. Altogether, the presence of a high number of rrn operon, the high proportion of strains harboring divergent rrs V3 region and the previously demonstrated high level of genetic diversity argued in favor of highly adaptative capabilities of aeromonads. Outstanding features observed for A. caviae supported the ongoing process of adaptation to a specialized niche represented by the gut, previously hypothesized. 16S rRNA gene is an informative marker in the genus Aeromonas for both evolutionary and polyphasic taxonomic studies provided that multi-operon fingerprinting approaches are used. PMID- 23032083 TI - A prospective, multicenter, randomized study of the efficacy of eicosapentaenoic acid for cerebral vasospasm: the EVAS study. AB - OBJECTIVE: The sphingosylphosphorylcholine-Rho-kinase pathway plays an important role in Ca(2+) sensitization of vascular smooth muscle contraction. Eicosapentaenoic acid (EPA) inhibits sphingosylphosphorylcholine -Rho-kinase activated Ca(2+)-sensitization in vitro and in subarachnoid hemorrhage (SAH) models in vivo and has also been shown to inhibit the occurrence of cerebral vasospasm (CIV) after the onset of SAH in a prospective, nonrandomized study. The current prospective, multicenter, randomized study was performed to confirm the preventive effects of EPA on CIV in patients with SAH. METHODS: The trial population comprised 162 patients who underwent surgical clipping within 72 hours of the onset of SAH. Of these patients, 81 received 2700 mg/day EPA from the day after surgery until day 30 (EPA group), and 81 did not receive EPA (control group). The primary end point was the occurrence of symptomatic vasospasm (SV) or cerebral infarction caused by CIV. RESULTS: The occurrences of SV (15% vs. 30%; P = 0.022) and CIV (7% vs. 21%; P = 0.012) were lower in the EPA group. Multivariate analysis revealed an adjusted odds ratio of 0.39 (95% confidence interval, 0.17-0.89; P = 0.028) for SV inhibition by EPA and 0.27 (95% confidence interval, 0.09-0.72; P = 0.012) for CIV inhibition. CONCLUSIONS: These results indicate that oral EPA reduces the frequency of SV and CIV after the onset of aneurysmal SAH. PMID- 23032084 TI - 22-Oxacalcitriol prevents progression of peritoneal fibrosis in a mouse model. AB - OBJECTIVE: Vitamin D plays an important role in calcium homeostasis and is used to treat secondary hyperparathyroidism among dialysis patients. The biologic activity of vitamin D and its analogs is mediated by vitamin D receptor (VDR), which is distributed widely throughout the body. Recent papers have revealed that low vitamin D levels are correlated with severe fibrosis in chronic diseases, including cystic fibrosis and hepatitis. The aim of the present study was to evaluate the protective effects of vitamin D against the progression of peritoneal fibrosis. METHODS: Peritoneal fibrosis was induced by injection of chlorhexidine gluconate (CG) into the peritoneal cavity of mice every other day for 3 weeks. An analog of vitamin D, 22-oxacalcitriol (OCT), was administered subcutaneously daily from initiation of the CG injections. The peritoneal tissue was excised at 3 weeks. Changes in morphology were assessed by hematoxylin and eosin staining. Expression of VDR, alpha smooth muscle actin (as a marker of myofibroblasts), type III collagen, transforming growth factor beta(TGF-beta), phosphorylated Smad2/3, F4/80 (as a marker of macrophages), and monocyte chemoattractant protein-1 (MCP-1) was examined by immunohistochemistry. Southwestern histochemistry was used to detect activated nuclear factor kappaB (NF-kappaB). RESULTS: In the CG-injected mice, immunohistochemical analysis revealed expression of VDR in mesothelial cells, myofibroblasts, and macrophages in the thickened submesothelial zone. Treatment with OCT significantly prevented peritoneal fibrosis and reduced the accumulation of type III collagen in CG treated mice. Among the markers of fibrosis, the numbers of myofibroblasts, cells positive for TGF-beta, and cells positive for phosphorylated Smad2/3 were significantly decreased in the OCT-treated group compared with the vehicle treated group. Furthermore, OCT suppressed inflammatory mediators of fibrosis, as shown by the reduced numbers of activated NF-kappaB cells, macrophages, and MCP-1 expressing cells. CONCLUSIONS: Our results indicate that OCT attenuates peritoneal fibrosis, an effect accompanied by reduced numbers of myofibroblasts, infiltrating macrophages, and TGF-beta-positive cells, suggesting that vitamin D has potential as a novel therapeutic agent for preventing peritoneal sclerosis. PMID- 23032085 TI - Endogenous markers for estimation of renal function in peritoneal dialysis patients. AB - OBJECTIVE: This method comparison study, conducted at the peritoneal dialysis (PD) outpatient clinic of the Department of Renal Medicine, Aarhus University Hospital, Denmark, set out to evaluate the accuracy and reproducibility of methods for estimating glomerular filtration rate (GFR) based on endogenous markers in PD patients. PATIENTS: The 12 consecutive patients included in the study were examined twice while in a stable condition. All patients finished the study. Inclusion criteria were age 18 years or older, ability to collect 24-hour urine, and urine production greater than 300 mL in 24 hours. MAIN OUTCOME MEASURES: The methods for estimating GFR using endogenous markers included the average of urinary clearances of creatinine and urea [U-Cl(crea-urea)] and two equations using the serum concentration of cystatin C [eGFR(CysC)]. The resulting GFR estimates were compared with those obtained using urinary and corrected plasma clearances of (51)Cr-EDTA [U-Cl(EDTA) and cP-Cl(EDTA)], the corrected plasma clearance being plasma clearance minus dialysate clearance. RESULTS: Compared with the U-Cl(EDTA), the U-Cl(crea-urea) GFR estimate was 12% higher [95% confidence limits (CL): 3%, 21%]. Although significantly different (p = 0.01), the latter two methods showed the best agreement. The estimates obtained using the eGFR(CysC) methods were skewed from y = x compared with the estimates obtained using other methods, indicating strong bias, probably because of extrarenal elimination. The cP-Cl(EDTA) estimate was 34% (95% CL: 26%, 42%), higher than the U-Cl(EDTA) estimate (p < 0.001). The reproducibility (coefficients of variation) differed significantly between methods: cP-Cl(EDTA), 7%; U-Cl(EDTA), 14%; U-Cl(crea-urea), 18%; and both eGFR(CysC) methods, 3%. CONCLUSIONS: In PD patients, GFR may be estimated as U-Cl(crea-urea) when complete urine collection is performed, taking into account an overestimation of approximately 12%. The available equations for eGFR(CysC) seem to be inaccurate; further development and validation is desirable. Omitting the eGFR(CysC) methods, cP-Cl(EDTA) was the most reproducible method and might be useful in certain situations. PMID- 23032087 TI - Campylobacter peritonitis complicating peritoneal dialysis: a review of 12 consecutive cases. AB - BACKGROUND: Peritoneal dialysis-associated peritonitis secondary to Campylobacter organisms is uncommon. Few studies have assessed either treatment or clinical outcomes. METHODS: We reviewed all Campylobacter peritonitis episodes occurring in a single dialysis unit from 1994 to 2011. RESULTS: During the study period, 12 episodes of Campylobacter peritonitis (0.45% of all peritonitis episodes) were recorded. Diarrhea was uncommon (8.3%). The overall primary response rate was 91.7%; the complete cure rate was 75.0%. Among 6 patients who failed to respond to standard antibiotics by day 5, all improved after administration of an oral macrolide (erythromycin or clarithromycin). Of those 6 patients, 5 experienced a complete cure, and 1 patient experienced relapse of culture-negative peritonitis. No patient required Tenckhoff catheter removal or temporary hemodialysis support. The 30-day mortality was 0%. CONCLUSIONS: Campylobacter peritonitis might not respond to first-line conventional antibiotics, and an oral macrolide is recommended if Campylobacter is confirmed. The findings from our analysis do not support the use of fluoroquinolone, which is associated with a high resistance rate. PMID- 23032086 TI - Determinants of peritoneal dialysis technique failure in incident US patients. AB - OBJECTIVES: Switching from peritoneal dialysis (PD) to hemodialysis (HD) is undesirable, because of complications from temporary vascular access, disruption of daily routine, and higher costs. Little is known about the role that social factors play in technique failure. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: We followed for 3 years a nationally representative cohort of US patients who initiated PD in 1996 - 1997. Technique failure was defined as any switch from PD to HD for 30 days or more. We used Cox regression to examine associations between technique failure and demographic, medical, social, and pre-dialysis factors. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: We identified an inception cohort of 1587 patients undergoing PD. In multivariate analysis, female sex (HR: 0.78; 95% CI: 0.64 to 0.95) was associated with lower rates of technique failure, and black race [compared with white race (HR: 1.48; 95% CI: 1.20 to 1.82)] and receiving Medicaid (HR: 1.48; 95% CI: 1.17 to 1.86) were associated with higher rates. Compared with patients who worked full-time, those who were retired (HR: 1.49; 95% CI: 1.07 to 2.08) or disabled (HR: 1.38; 95% CI: 1.01 to 1.88) had higher rates of failure. Patients with a systolic blood pressure of 140 - 160 mmHg had a higher rate of failure than did those with a pressure of 120 - 140 mmHg (HR: 1.24; 95% CI: 1.00 to 1.52). Earlier referral to a nephrologist (>3 months before dialysis initiation) and the primary decision maker for the dialysis modality (physician vs patient vs shared) were not associated with technique failure. CONCLUSIONS: This study confirms that several socio-demographic factors are associated with technique failure, emphasizing the potential importance of social and financial support in maintaining PD. PMID- 23032088 TI - Atypical mycobacterial exit-site infection and peritonitis in peritoneal dialysis patients on prophylactic exit-site gentamicin cream. AB - We report 9 cases of exit-site infection and continuous ambulatory peritoneal dialysis peritonitis associated with atypical mycobacteria. All patients had been using topical gentamicin cream as prophylaxis for exit-site infection before the onset of these infections. Gentamicin cream is postulated to be a potential risk factor for atypical mycobacterial infection because of selective pressure on other micro-organisms. The microbiology of atypical mycobacteria and the treatment for atypical mycobacterial infections are discussed. PMID- 23032089 TI - Phenotypic plasticity of composite beef cattle performance using reaction norms model with unknown covariate. AB - The objective of the present study was to determine the presence of genotype by environment interaction (G * E) and to characterize the phenotypic plasticity of birth weight (BW), weaning weight (WW), postweaning weight gain (PWG) and yearling scrotal circumference (SC) in composite beef cattle using the reaction norms model with unknown covariate. The animals were born between 1995 and 2008 on 33 farms located throughout all Brazilian biomes between latitude -7 degrees and -31 degrees , longitude -40 degrees and -63 degrees . The contemporary group was chosen as the environmental descriptor, that is, the environmental covariate of the reaction norms. In general, higher estimates of direct heritability were observed in extreme favorable environments. The mean of direct heritability across the environmental gradient ranged from 0.05 to 0.51, 0.09 to 0.43, 0.01 to 0.43 and from 0.12 to 0.26 for BW, WW, PWG and SC, respectively. The variation in direct heritability observed indicates a different response to selection according to the environment in which the animals of the population are evaluated. The correlation between the level and slope of the reaction norm for BW and PWG was high, indicating that animals with higher average breeding values responded better to improvement in environmental conditions, a fact characterizing a scale of G * E. Low correlation between the intercept and slope was obtained for WW and SC, implying re-ranking of animals in different environments. Genetic variation exists in the sensitivity of animals to the environment, a fact that permits the selection of more plastic or robust genotypes in the population studied. Thus, the G * E is an important factor that should be considered in the genetic evaluation of the present population of composite beef cattle. PMID- 23032090 TI - Polymorphisms in an obesity-related gene (PCSK1) are associated with fat deposition and production traits in Italian heavy pigs. AB - The proprotein convertase subtilisin/kexin type 1 (PCSK1) gene encodes the prohormone convertase 1/3 enzyme that processes prohormones into functional hormones that, in turn, regulate central and peripheral energy metabolism. Mutations in the human PCSK1 gene cause severe monogenic obesity or confer risk of obesity. We herein investigated the porcine PCSK1 gene with the aim of identifying polymorphisms associated with fat deposition and production traits in Italian heavy pigs. By re-sequencing about 5.1 kb of this gene in 21 pigs of different breeds, we discovered 14 polymorphisms that were organized in nine haplotypes, clearly distributed in two clades of putative European and Asian origin. Then we re-mapped this gene on porcine chromosome 2 and analysed its expression in several tissues including gastric oxyntic mucosa of weanling pigs in which PCSK1 processes the pre-pro-ghrelin into ghrelin, which in turn is involved in the control of feed intake and energy metabolism. Association analyses between PCSK1 single-nucleotide polymorphisms (SNPs) and production, carcass and several other traits were conducted on five groups of pigs from three different experimental designs, for a total of 1221 animals. Results indicated that the analysed SNPs were associated (P < 0.01 or P < 0.05) with several traits including backfat thickness and visible intermuscular fat in Italian Duroc (ID) and growth performances in Italian Large White (ILW) and in ILW * Italian Landrace pigs. However, the effects estimated in the ILW were opposite to the effects reported in the ID pigs. Suggestive association (P < 0.10) was observed with muscle cathepsin B activity, opening, if confirmed, potential applications to reduce the excessive softness defect of the green hams that is of particular concern for the processing industry. The results obtained supported the need to further investigate the PCSK1 gene to fully exploit the value of its variability and apply this information in pig breeding programmes. PMID- 23032091 TI - Van der Waals interactions in advanced materials, in memory of David C Langreth. PMID- 23032093 TI - Vitamin D and the scientific calcium dogma: understanding the 'Panacea' of the sun. PMID- 23032096 TI - Correction of facial defects by autologous fat graft in local panatrophy. PMID- 23032094 TI - Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer. AB - OBJECTIVE: In light of the recent changes in the International Federation of Gynecology and Obstetrics (FIGO) staging system, the objective of this study was to determine the prognostic significance of positive peritoneal cytology (PPC) among patients with early stage endometrial cancer. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Only those patients with stage I/II endometrial cancer who had undergone a complete staging procedure (lymph-node removal) were included. Statistical analyses used Chi-square test, Kaplan-Meier log rank, and Cox proportional hazards models. RESULTS: A total of 14,704 patients were identified: 14,219 with negative peritoneal cytology (NPC) and 485 with positive peritoneal cytology. More patients with PPC compared to those with NPC were diagnosed with high-risk factors such grade III disease (40.2% vs. 23.8%, p<0.0001), and unfavorable histologic types such as clear cell/serous carcinoma (17.5% vs. 7.5%, p=<0.0001) and carcinosarcoma (9.3% vs. 5.6%, p<0.0001). When compared to patients with negative peritoneal cytology, survival was significantly worse among patients with positive peritoneal cytology (p<0.0001): 5-year disease specific survival 95.1% vs. 80.8% in endometrioid adenocarcinoma; 78.0% vs. 50.4% in clear cell/serous cancer; and 64.7% vs. 32.3% in carcinosarcoma. After adjusting for other contributing factors in the multivariable model, PPC remained an independent predictor of poor survival (p<0.0001) in all histologic types examined. CONCLUSION: PPC is an independent risk factor in patients with early stage endometrial cancer. Although, no longer a part of the current FIGO staging criteria, peritoneal cytology status should still be considered for accurate risk stratification of these patients. PMID- 23032097 TI - Site-specific functionalization of RNA molecules by an unnatural base pair transcription system via click chemistry. AB - Toward new biotechnology by genetic alphabet expansion, we developed an efficient site-specific labeling method for large RNA molecules. The combination of unnatural base pair transcription and post-transcriptional modification by click chemistry enables simple RNA labeling with a wide variety of functional groups at desired positions, in a one-pot reaction. PMID- 23032098 TI - The risk of failure after primary orchidopexy: an 18 year review. AB - OBJECTIVE: To review the primary orchidopexy failure rate and outcome of repeat orchidopexy in a tertiary paediatric surgical centre and identify risk factors. METHODS: A prospectively collected and validated audits system was used to identify all boys having a repeat orchidopexy from August 1990 to December 2008 (18 years). RESULTS: In total, 1538 boys underwent orchidopexy with 1886 testicles operated on. Of these 348 (22.6%) patients had bilateral cryptorchidism. A need for repeat orchidopexy was identified in 31 boys resulting in a primary failure rate of 1.6% over the 18 years. Unilateral orchidopexy as the primary operation had a 1.5% failure rate. The failure rate for bilateral cryptorchidism was 1.87% per testicle rising to 1.93% per testicle when the primary operation was synchronous bilateral orchidopexy. Orchidopexy failure occurred in 9 patients (1.97%) who were under 24 months, 15 (2.67%) who were between 24 and 72 months and 7 (0.8%) over 72 months at time of first operation. CONCLUSION: Possible risk factors for primary orchidopexy failure are bilateral operation and older age at time of operation. Failure in achieving a satisfactory scrotal position (and testicular loss) following orchidopexy has been postulated as a potential surgical standard for revalidation of paediatric surgeons. This study adds important contemporary data to inform that process. PMID- 23032100 TI - Myeloperoxidase-derived oxidants rapidly oxidize and disrupt zinc cysteine/histidine clusters in proteins. AB - Zinc is an abundant cellular transition metal ion, which binds avidly to protein cysteine (Cys) and histidine (His) residues to form zinc-Cys/His clusters; these play a key role in the function of many proteins (e.g., DNA binding and repair enzymes, transcription factors, nitric oxide synthase). Leukocyte-derived myeloperoxidase generates powerful oxidants including hypochlorous (HOCl), hypobromous (HOBr), and hypothiocyanous (HOSCN) acids from H(2)O(2) and (pseudo)halide ions. Excessive or misplaced formation of these species is associated with cellular dysfunction, apoptosis and necrosis, and multiple inflammatory diseases. HOCl and HOBr react rapidly with sulfur-containing compounds, and HOSCN reacts specifically with thiols. Consequently, we hypothesized that zinc-Cys/His clusters would be targets for these oxidants, and the activity of such enzymes would be perturbed. This hypothesis has been tested using yeast alcohol dehydrogenase (YADH), which contains a well-characterized Zn(1)Cys(2)His(1) cluster. Incubation of YADH with pathologically relevant concentrations of HOSCN, HOCl, and HOBr resulted in rapid oxidation of the protein (rate constants, determined by competition kinetics, for reaction of HOCl and HOSCN with YADH being (3.3+/-0.9)*10(8) and (2.9+/-0.4)*10(4) M(-1) s(-1) per YADH monomer, respectively), loss of enzyme activity, Zn(2+) release, changes in protein structure (particularly formation of disulfide cross-links), and oxidation of Cys residues. The loss of enzyme activity correlated with Zn(2+) release, loss of thiols, and changes in protein structure. We conclude that exposure of zinc-Cys/His clusters to inflammatory oxidants can result in impaired protein activity, thiol oxidation, and Zn(2+) release. These reactions may contribute to inflammation-induced tissue damage. PMID- 23032101 TI - Nonequilibrium thermodynamics of interacting tunneling transport: variational grand potential, density functional formulation and nature of steady-state forces. AB - The standard formulation of tunneling transport rests on an open-boundary modeling. There, conserving approximations to nonequilibrium Green function or quantum statistical mechanics provide consistent but computational costly approaches; alternatively, the use of density-dependent ballistic-transport calculations (e.g., Lang 1995 Phys. Rev. B 52 5335), here denoted 'DBT', provides computationally efficient (approximate) atomistic characterizations of the electron behavior but has until now lacked a formal justification. This paper presents an exact, variational nonequilibrium thermodynamic theory for fully interacting tunneling and provides a rigorous foundation for frozen-nuclei DBT calculations as a lowest-order approximation to an exact nonequilibrium thermodynamic density functional evaluation. The theory starts from the complete electron nonequilibrium quantum statistical mechanics and I identify the operator for the nonequilibrium Gibbs free energy which, generally, must be treated as an implicit solution of the fully interacting many-body dynamics. I demonstrate a minimal property of a functional for the nonequilibrium thermodynamic grand potential which thus uniquely identifies the solution as the exact nonequilibrium density matrix. I also show that the uniqueness-of-density proof from a closely related Lippmann-Schwinger collision density functional theory (Hyldgaard 2008 Phys. Rev. B 78 165109) makes it possible to express the variational nonequilibrium thermodynamic description as a single-particle formulation based on universal electron-density functionals; the full nonequilibrium single particle formulation improves the DBT method, for example, by a more refined account of Gibbs free energy effects. I illustrate a formal evaluation of the zero-temperature thermodynamic grand potential value which I find is closely related to the variation in the scattering phase shifts and hence to Friedel density oscillations. This paper also discusses the difference between the here presented exact thermodynamic forces and the often-used electrostatic forces. Finally the paper documents an inherent adiabatic nature of the thermodynamic forces and observes that these are suited for a nonequilibrium implementation of the Born-Oppenheimer approximation. PMID- 23032099 TI - Mitochondrial morphology-emerging role in bioenergetics. AB - Dynamic change in mitochondrial shape is a cellular process mediated mainly by fission and fusion of mitochondria. Studies have shown that mitochondrial fission and fusion are directly and indirectly associated with mitochondrial maintenance, bioenergetic demand, and cell death. Changes in mitochondrial morphology are frequently observed in response to changes in the surrounding cellular milieu, such as metabolic flux, that influence cellular bioenergetics. Connections between morphological regulation and the bioenergetic status of mitochondria are emerging as reciprocally responsive processes, though the nature of the signaling remains to be defined. Given the pivotal role mitochondria play in cellular fate, tight regulation of fission and fusion is therefore critical to preserving normal cellular physiology. Here we describe recent advancements in the understanding of the mechanisms governing mitochondrial morphology and their emerging role in mitochondrial bioenergetics. PMID- 23032102 TI - Human ex vivo studies on asexual Plasmodium vivax: the best way forward. AB - The lack of a continuous culture method for Plasmodium vivax has given the impression that investigations on this important species are severely curtailed. However, the use of new or improved ex vivo methods and tools to study fresh and thawed isolates from vivax malaria patients is currently providing useful data on P. vivax, such as sensitivity to antimalarial drugs, invasion mechanisms and pathobiology. This review discusses a practical framework for conducting ex vivo studies on the asexual erythrocytic stages of P. vivax and considers the synergies between ex vivo defined phenotypes, ex vivo derived 'omic' studies and in vivo clinical studies. PMID- 23032103 TI - Structural, electronic and ferroelectric properties of croconic acid crystal: a DFT study. AB - The recent discovery of high polarization at room temperature in croconic acid crystals as large as 21 MUC cm(-2) [Horiuchi et al., Nature, 2010, 463, 789] has lead to renewed interest in organic ferroelectrics, a promising class of materials for future electronic devices. We present here an extended ab initio study of this molecular crystal, using different approximations for the exchange correlation functionals, ranging from local and semi-local types to more sophisticated hybrid functionals and van der Waals corrected functionals. Furthermore, by using distortion mode analysis, we focus on the different contributions to the polarization and on their microscopic origins. PMID- 23032105 TI - Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice. AB - This study evaluated the role of osteocyte-derived insulin-like growth factor 1 (IGF-1) in developmental bone growth by assessing the bone phenotype of osteocyte Igf1 conditional knockout (KO) mice, generated by crossing the Dmp1-driven Cre expressing transgenic mice with Igf1 floxed mice containing loxP sites that flank exon 4 of the Igf1 gene. The periosteal diameter of femurs of homozygous conditional KO mutants was 8-12% smaller than wild-type (WT) littermates. The conditional mutants had 14-20%, 10-21%, and 15-31% reduction in total, trabecular, and cortical bone mineral contents, respectively. However, there were no differences in the total, trabecular, or cortical bone mineral densities, or in trabecular bone volume, thickness, number, and separation at secondary spongiosa between the mutants and WT littermates. The conditional KO mutants showed reduction in dynamic bone formation parameters at both periosteal and endosteal surfaces at the mid-diaphysis and in trabecular bone formation rate and resorption parameters at secondary spongiosa. The lower plasma levels of PINP and CTx in conditional KO mice support a regulatory role of osteocyte-derived IGF-1 in the bone turnover. The femur length of conditional KO mutants was 4-7% shorter due to significant reduction in the length of growth plate and hypertropic zone. The effect on periosteal expansion appeared to be bigger than that on longitudinal bone growth. The conditional KO mice had 14% thinner calvaria than WT littermates, suggesting that deficient osteocyte IGF-1 production also impairs developmental growth of intramembraneous bone. Conditional disruption of Igf1 in osteocytes did not alter plasma levels of IGF-1, calcium, or phosphorus. In summary, this study shows for the first time that osteocyte-derived IGF-1 plays an essential role in regulating bone turnover during developmental bone growth. PMID- 23032104 TI - Wnt/beta-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. AB - The BMP and Wnt/beta-catenin signaling pathways cooperatively regulate osteoblast differentiation and bone formation. Although BMP signaling regulates gene expression of the Wnt pathway, much less is known about whether Wnt signaling modulates BMP expression in osteoblasts. Given the presence of putative Tcf/Lef response elements that bind beta-catenin/TCF transcription complex in the BMP2 promoter, we hypothesized that the Wnt/beta-catenin pathway stimulates BMP2 expression in osteogenic cells. In this study, we showed that Wnt/beta-catenin signaling is active in various osteoblast or osteoblast precursor cell lines, including MC3T3-E1, 2T3, C2C12, and C3H10T1/2 cells. Furthermore, crosstalk between the BMP and Wnt pathways affected BMP signaling activity, osteoblast differentiation, and bone formation, suggesting Wnt signaling is an upstream regulator of BMP signaling. Activation of Wnt signaling by Wnt3a or overexpression of beta-catenin/TCF4 both stimulated BMP2 transcription at promoter and mRNA levels. In contrast, transcription of BMP2 in osteogenic cells was decreased by either blocking the Wnt pathway with DKK1 and sFRP4, or inhibiting beta-catenin/TCF4 activity with FWD1/beta-TrCP, ICAT, or DeltaTCF4. Using a site-directed mutagenesis approach, we confirmed that Wnt/beta-catenin transactivation of BMP2 transcription is directly mediated through the Tcf/Lef response elements in the BMP2 promoter. These results, which demonstrate that the Wnt/beta-catenin signaling pathway is an upstream activator of BMP2 expression in osteoblasts, provide novel insights into the nature of functional cross talk integrating the BMP and Wnt/beta-catenin pathways in osteoblastic differentiation and maintenance of skeletal homeostasis. PMID- 23032106 TI - Tuberculosis infection control in primary health clinics in eThekwini, KwaZulu Natal, South Africa. AB - SETTING: Primary health clinics in KwaZulu-Natal, South Africa. OBJECTIVE: To assess and describe current practices in infection control at local government primary health clinics. DESIGN: A descriptive study using a standardised tool to assess adherence to recommended infection control policies in 51 primary health clinics in 2009-2010. Administrative policies, engineering controls and personal respiratory protection were assessed by observations and interviews at the clinics. RESULTS: Of 51 clinics, 11 (22%) had infection control policies, 13 (26%) triaged coughing patients and 16 (31%) had a dedicated nurse and a dedicated consulting room for treating tuberculosis (TB) patients. Study clinics treated a median of 99 patients (range 3-331) daily and a median of 15 TB patients (range 2-73) monthly. Of the rooms in the clinics, all of which rely on natural ventilation, half (149/284) had <=12 air changes per hour. Eleven (22%) of 51 clinics had N95 masks available for staff use. CONCLUSION: Limited infection control practices exist in clinics in a high TB burden setting in KwaZulu-Natal, South Africa. These practices need to be implemented more widely to minimise the spread of TB to non-infected patients and health care workers in primary health clinics. PMID- 23032107 TI - Synthesis of silica protected photoluminescence QDs and their applications for transparent fluorescent films with enhanced photochemical stability. AB - In this paper, we have demonstrated a novel and simple way to prepare transparent composite fluorescent films by using poly (acrylic acid) co-polymer as a matrix and silica coated photoluminescence (PL) quantum dots (QDs) as light-emitting materials. The strategies include preparing aqueous amphiphilic oligomer (polymaleic acid n-hexadecanol ester, PMAH) modified QDs, encapsulating the aqueous QDs in silica with a modified Stober method and fabricating the QD-PMAH SiO(2)-polymer composite fluorescent films with a spin-coating method. The obtained light-emitting thin films were transparent under room light and showed bright red, green and deep-blue light under the irradiation of UV light. The PL intensity of the composite films increased incrementally with the number of layers and the concentration of QD-PMAH-SiO(2) within each film. A white light emitting film was also fabricated by combining the silica coated red, green and deep-blue QDs in a proper ratio. Moreover, the photochemical stability of the QD PMAH-SiO(2) in composite film was enhanced significantly compared with PMAH coated QDs, because of a thicker and compact passivating silica layer formed on the surfaces of the PL QDs. PMID- 23032108 TI - Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders. AB - Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders, including childhood autism, atypical autism, and Asperger syndrome, with an estimated prevalence of 1.0-2.5% in the general population. ASDs have a complex multifactorial etiology, with genetic causes being recognized in only 10 20% of cases. Recently, copy-number variants (CNVs) have been shown to contribute to over 10% of ASD cases. We have applied a custom-designed oligonucleotide array comparative genomic hybridization with an exonic coverage of over 1700 genes, including 221 genes known to cause autism and autism candidate genes, in a cohort of 145 patients with ASDs. The patients were classified according to ICD-10 standards and the Childhood Autism Rating Scale protocol into three groups consisting of 45 individuals with and 69 individuals without developmental delay/intellectual disability (DD/ID), and 31 patients, in whom DD/ID could not be excluded. In 12 patients, we have identified 16 copy-number changes, eight (5.5%) of which likely contribute to ASDs. In addition to known recurrent CNVs such as deletions 15q11.2 (BP1-BP2) and 3q13.31 (including DRD3 and ZBTB20), and duplications 15q13.3 and 16p13.11, our analysis revealed two novel genes clinically relevant for ASDs: ARHGAP24 (4q21.23q21.3) and SLC16A7 (12q14.1). Our results further confirm the diagnostic importance of array CGH in detection of CNVs in patients with ASDs and demonstrate that CNVs are an important cause of ASDs as a heterogeneous condition with a variety of contributory genes. PMID- 23032109 TI - Clinical utility gene card for: familial polycythaemia vera. PMID- 23032110 TI - Functional characterization of desmin mutant p.P419S. PMID- 23032112 TI - Genome-wide linkage analysis is a powerful prenatal diagnostic tool in families with unknown genetic defects. AB - Genome-wide linkage analysis is an established tool to map inherited diseases. To our knowledge it has not been used in prenatal diagnostics of any genetic disorder. We present a family with a severe recessive mental retardation syndrome, where the mother wished pregnancy termination to avoid delivering another affected child. By genome-wide scanning using the Affymetrix (Santa Clara, CA, USA) 10k chip we were able to establish the disease haplotype. Without knowing the exact genetic defect, we excluded the condition in the fetus. The woman finally gave birth to a healthy baby. We suggest that genome-wide linkage analysis--based on either SNP mapping or full-genome sequencing--is a very useful tool in prenatal diagnostics of diseases. PMID- 23032113 TI - Reply to Brodehl et al. PMID- 23032111 TI - Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A. AB - Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance. PMID- 23032114 TI - Frictional temperature rise in a sliding physisorbed monolayer of Kr/graphene. AB - A quartz crystal microbalance (QCM) with a graphene/Ni(111) electrode has been used to probe frictional heating effects in Kr monolayers sliding on the microbalance electrode in response to its oscillatory motion. The temperatures of the sliding Kr monolayers are observed to rise approximately 13 K higher than their static counterparts, but show surprisingly little dependence on oscillation amplitude. Although counterintuitive, the observation can be explained by noting that the Kr surface residence times are limited, which effectively caps how much the temperature can rise. PMID- 23032115 TI - Two-dimensional dendritic Ag3PO4 nanostructures and their photocatalytic properties. AB - Two-dimensional dendritic Ag(3)PO(4) nanostructures have been synthesized in high yield by reacting Ag nanowires with H(2)O(2) and NaH(2)PO(4) in aqueous solution at room temperature, which exhibit much higher photocatalytic activities than irregular Ag(3)PO(4) nanocrystals and N-doped TiO(2) catalyst for the degradation of organic contaminants under visible light irradiation. PMID- 23032116 TI - Whether generic model works for rapid ERP-based BCI calibration. AB - Event-related potential (ERP)-based brain-computer interfacing (BCI) is an effective method of basic communication. However, collecting calibration data, and classifier training, detracts from the amount of time allocated for online communication. Decreasing calibration time can reduce preparation time thereby allowing for additional online use, potentially lower fatigue, and improved performance. Previous studies, using generic online training models which avoid offline calibration, afford more time for online spelling. Such studies have not examined the direct effects of the model on individual performance, and the training sequence exceeded the time reported here. The first goal of this work is to survey whether one generic model works for all subjects and the second goal is to show the performance of a generic model using an online training strategy when participants could use the generic model. The generic model was derived from 10 participant's data. An additional 11 participants were recruited for the current study. Seven of the participants were able to use the generic model during online training. Moreover, the generic model performed as well as models obtained from participant specific offline data with a mean training time of less than 2 min. However, four of the participants could not use this generic model, which shows that one generic mode is not generic for all subjects. More research on ERPs of subjects with different characteristics should be done, which would be helpful to build generic models for subject groups. This result shows a potential valuable direction for improving the BCI system. PMID- 23032118 TI - Genetic diversity of Guernsey population using pedigree data and gene-dropping simulations. AB - The objectives of this study were to analyze the trend of within-breed genetic diversity and identify major causes leading to loss of genetic diversity in Guernsey breed in three countries. Pedigree files of Canadian (GCN), South African (GSA) and American (GUS) Guernsey populations containing 130 927, 18 593 and 1 851 624 records, respectively, were analyzed. Several parameters derived from the in-depth pedigree analyses were used to measure trends and current levels of genetic diversity. Pedigree completeness index of GCN, GSA and GUS populations, in the most recent year (2007), was 97%, 74% and 79%, respectively, considering four generations back in the analysis. The rate of inbreeding in each population was 0.19%, 0.16% and 0.17% between 2002 and 2007, respectively. For the same period, the estimated effective population size for GCN, GSA and GUS was 46, 57 and 46, respectively. The estimated percentage of genetic diversity lost within each population over the last four decades was 8%, 3% and 5%, respectively. The relative proportion of genetic diversity lost due to random genetic drift in the three populations was 93%, 91% and 86%, respectively. In conclusion, the results suggested that GCN and GUS have lost more genetic diversity than GSA over the past four decades, and this loss is gaining momentum due to increasing rates of inbreeding. Therefore, strategies such as optimum contribution selection and migration of genetic material are advised to increase effective population size, particularly in GCN and GUS. PMID- 23032117 TI - Adaptive prior probability and spatial temporal intensity change estimation for segmentation of the one-year-old human brain. AB - The degree of white matter (WM) myelination is rather inhomogeneous across the brain. White matter appears differently across the cortical lobes in MR images acquired during early postnatal development. Specifically at 1-year of age, the gray/white matter contrast of MR T1 and T2 weighted images in prefrontal and temporal lobes is reduced as compared to the rest of the brain, and thus, tissue segmentation results commonly show lower accuracy in these lobes. In this novel work, we propose the use of spatial intensity growth maps (IGM) for T1 and T2 weighted images to compensate for local appearance inhomogeneity. The IGM captures expected intensity changes from 1 to 2 years of age, as appearance homogeneity is greatly improved by the age of 24 months. The IGM was computed as the coefficient of a voxel-wise linear regression model between corresponding intensities at 1 and 2 years. The proposed IGM method revealed low regression values of 1-10% in GM and CSF regions, as well as in WM regions at maturation stage of myelination at 1 year. However, in the prefrontal and temporal lobes we observed regression values of 20-25%, indicating that the IGM appropriately captures the expected large intensity change in these lobes mainly due to myelination. The IGM is applied to cross-sectional MRI datasets of 1-year-old subjects via registration, correction and tissue segmentation of the IGM corrected dataset. We validated our approach in a small leave-one-out study of images with known, manual 'ground truth' segmentations. PMID- 23032119 TI - Agreement between children and parents when reporting anxiety and depressive symptoms in pediatric epilepsy. AB - The levels of agreement between self- and parent/proxy-reports of anxiety and depressive symptoms in pediatric epilepsy were evaluated. Data were drawn from 56 pairs of children with epilepsy and at least one parent. Anxiety symptoms were assessed using the Screen for Child Anxiety Related Emotional Disorders (SCARED), while depressive symptoms were assessed using the Mood and Feeling Questionnaire (MFQ). Moderate to substantial levels of agreement between raters when reporting various anxiety symptoms, such as panic/somatic disorder, generalized anxiety disorder, separation anxiety disorder, social phobia, and school phobia symptoms, were observed. Levels of agreement between raters were substantial when reporting depressive symptoms. However, levels of agreement differed if raw or criterion referenced questionnaires' scores were used. In case of using raw questionnaire scores, substantial agreements appeared when reporting overall anxiety and depressive symptoms. On the other hand, moderate agreements appeared when reporting particular anxiety symptoms with raw questionnaire scores or when using criterion-referenced scores that indicate the presence of certain symptoms in a clinical range. Therefore, it is advisable to include both raters when assessing anxiety and depressive symptoms in pediatric epilepsy. PMID- 23032120 TI - Long-term risks following first remission in childhood-onset epilepsy. A population-based study. AB - Although most patients with newly-treated epilepsy enter remission, the risks associated with first remission are not well-known. It is thus of great clinical interest to assess the long-term risks of poor seizure outcome and premature retirement for those in their very first remission and to determine predictive clinical features. We determined the likelihood of seizure relapse, remission following relapse, and premature retirement after entering first seizure remission of 5 years or more in a population-based cohort of 115 medically treated patients, who were followed up since their first seizure during childhood. At the end of the 42-year median follow-up from the onset of adequate medication before the age of 16 years, 115 (82%)/141 patients entered a first remission of at least 5 years. Although 69 (60%) of the 115 patients had no relapse, at least one seizure relapse was seen in 46 (40%) and 14 (12%) never re entered five-year remission. Among the 115 patients, 33 (30%) were prematurely retired. On multivariate analysis of clinical features, cognitive impairment predicted seizure relapse for those entering their first remission of 5 years or more. Relapse, symptomatic etiology, and early onset of epilepsy were significant predictors of premature retirement. Despite entering their first remission of 5 years or more, individuals with epilepsy face clinically important risks including relapse, failure to re-enter remission following relapse, and premature retirement. Cognitive impairment predicted seizure relapse, while relapse, symptomatic etiology, and early onset of epilepsy were significant predictors of premature retirement. PMID- 23032122 TI - Characteristics of patients with epilepsy who use a website providing healthcare information about epilepsy in South Korea. AB - We studied characteristics of epilepsy patients who use 'Epilia', a healthcare website for epilepsy patients, and the impact of 'Epilia' on patient satisfaction and attitude about epilepsy. A total of 153 epilepsy patients from 'Epilia' (online group) and 367 patients from epilepsy clinics (offline group) were recruited. A survey was done to investigate their socio-demographic, epilepsy related, and psychological characteristics, as well as attitude alterations after beginning to use 'Epilia'. Factors affecting attitude were also identified in the online group. Online group had more severe and more frequent seizures, more adverse effects, more anxiety and depression, and worse quality of life than offline group. Online group patients who are more satisfied, who take two or more antiepileptic drugs, who visit to 'Epilia' more and longer had a greater positive attitude change than those without these characteristics. A healthcare website can contribute to self-management by providing useful information and education for epilepsy patients. PMID- 23032121 TI - A comparison of epilepsy self-management needs: provider and patient perspectives. AB - A consistent and serious empirical issue in the epilepsy self-management literature involves dropout and attrition in intervention studies. One explanation for this issue revolves around "top-down" intervention designs (i.e., interventions generated by epilepsy clinicians and researchers) and the potential for disparity with patient interests, capabilities, and perceived needs. The purpose of this study was to extend the work of Fraser et al. (2011) [19] by comparing perceptions regarding self-management problems, topics, and program design, between two subgroups of adult patients with epilepsy (n=165) and epilepsy clinicians (n=20). Results indicate differences in problem severity ratings, program emphasis (i.e., goal-setting, coping, education), and program leadership between clinicians and each patient subgroup to varying degrees. These findings highlight some of the differences in opinion between patients and clinicians and emphasize the need for patient-involved planning with regard to self-management programs. Implications and explanations are offered as points for consideration in self-management program development. PMID- 23032123 TI - A patient who misidentified all surrounding persons as her family. AB - This report describes a patient who misidentified all surrounding persons as her family after a cerebral hemorrhage in the right temporal lobe. She had no difficulty with visual face recognition. Single-photon emission computed tomography revealed hyperperfusion in the right amygdala and hippocampus. Electroencephalography showed a bilateral fronto-temporal delta burst intermittently during the symptom. Carbamazepine suppressed the symptom completely. These results suggest that hyperexcitability in the right limbic system and bilateral fronto-temporal cortex might cause the alteration of familiarity. She felt a strong sense of familiarity to others. Perhaps because it lasted a long time, she regarded these other people as her family. PMID- 23032124 TI - ESPERA study: applicability of the new ILAE criteria for antiepileptic drug resistance of focal epilepsies in current clinical practice. AB - A European observational cross-sectional study, ESPERA, was conducted in France and Spain in 2010. A random sample of neurologists, including specialists in epilepsy, prospectively enrolled adult patients treated for focal epilepsy with at least two antiepileptic drugs (AEDs) in combination. Investigators were asked to classify AED responsiveness of each enrolled patient according to the new 2009 ILAE criteria. These classifications were then reviewed by three experts. Potential factors of misclassification were then analyzed in order to evaluate the applicability of the new ILAE criteria for antiepileptic drug resistance in current clinical practice. Because of their complexity, use of the new ILAE criteria needs to be supported by relevant information and training to be adequately applied by neurologists in everyday practice. PMID- 23032125 TI - Pregabalin intoxication-induced encephalopathy with triphasic waves. AB - This report documents the case of a 79-year-old woman presenting with encephalopathy and triphasic waves (TWs) due to pregabalin (PGB) intoxication. For the two years prior to admission, she had taken PGB to treat post-herpetic neuralgia. Brain MRI revealed mild leukoaraiosis and cortical atrophy. Electroencephalography showed continuous frontal-dominant TWs. These TWs were suppressed by intravenous lorazepam, but mental function was not improved. Laboratory tests revealed prerenal azotemia, which may elevate serum PGB and cause toxic encephalopathy with TWs. After fluid therapy and discontinuation of PGB, mental status recovered completely and TWs disappeared. I conclude that PGB intoxication due to deficient renal clearance can cause a reversible encephalopathy with TWs. PMID- 23032126 TI - Oxcarbazepine-related retrograde ejaculation. PMID- 23032127 TI - Safety considerations in the epilepsy monitoring unit for psychogenic nonepileptic seizures. AB - Injury occurs in epilepsy monitoring units (EMUs) to patients with epileptic seizures (ES); however, there are limited data regarding the safety concerns of patients with psychogenic nonepileptic seizures (PNES) being monitored in EMUs. We reviewed EMU records from 116 PNES and compared them to 170 ES. Three falls (2.6%) occurred in PNES without injury compared to 6 falls (3.5%) in ES with 1 injury, a facial hematoma. Of the 9 total falls, 8 patients were ambulatory during their events. Several adverse incidents occurred for both groups. Of the PNES without staff response, 30 of 39 were due to PNES being less than 60s in duration, and 16 of 39 involved lack of push-button activation to alert the staff. For the ES group, 57 of 101 were due to electrographic seizures without seizure detection software or push-button activation. Similar safety protocols should be administered while monitoring these patients regardless of seizure type. PMID- 23032128 TI - Concurrent administration of the MMPI-2 and PAI in a sample of patients with epileptic or non-epileptic seizures: implications for an inpatient epilepsy monitoring unit. AB - The Minnesota Multiphasic Personality Inventory-second edition (MMPI-2) and the Personality Assessment Inventory (PAI) are commonly used in the epilepsy monitoring unit (EMU) to evaluate personality characteristics and mood-related symptoms in those individuals being evaluated for epileptic seizures (ES) or psychogenic non-epileptic seizures (PNES). A direct comparison of these measures through concurrent administration to the same group has not been carried out. Both measures were administered to 40 patients (17 ES and 23 PNES). Logistic regression suggested the optimal predictive model for EMU discharge diagnosis included subscales from each measure, which outperformed either measure separately. Combining the conversion (SOM-C) and health concerns (SOM-H) subscales from the PAI and the hysteria subscale (Hy) from the MMPI-2 resulted in 85% overall classification accuracy, 86.7% sensitivity, and 82.4% specificity. Variability in the literature regarding the predictive utility of these measures may stem from the possibility that they measure different aspects of PNES. PMID- 23032129 TI - Developing a culture of safety in the epilepsy monitoring unit: a retrospective study of safety outcomes. AB - This study retrospectively reviewed 971 consecutive admissions to our epilepsy monitoring unit (EMU) from July 2007 to May 2011 to compare falls and missed seizures before and after implementing stricter safety processes in May 2009. New safety processes included enhanced staff education, a falls prevention signed contract with patient/family, observation of video-EEG monitors only by EEG technologists, hourly nurse rounding, standby assistance for hygiene needs, and immediate review of adverse events. Wilcoxon's two-sample tests were used for statistical analysis of the two groups. Reduced events between pre-intervention (492 patients) and post-intervention (479 patients) were significant for missed seizures (26 pre- vs 6 post-intervention, p=0.009) but not for falls (12 pre- vs 7 post-intervention, p=0.694). Intensive safety efforts in the EMU produced a 15% reduction in the fall rate per 1000 patient days and a 77% decrease in missed seizures. This study shows stricter safety processes help improve EMU patient safety. PMID- 23032130 TI - Suppressors of interictal discharges in idiopathic childhood occipital epilepsy of Gastaut. AB - Idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) is a rare form of epilepsy, characterized by visual hallucinations, periods of blindness, motor seizures, and migraine-like symptoms. A characteristic EEG feature is fixation off sensitivity: epileptiform discharges are suppressed by visual input. Here, we present an 11-year-old girl suffering from ICOE-G, who was studied to identify potential additional suppressors of the epileptiform discharges. PMID- 23032131 TI - A case of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) coexisting with pervasive developmental disorder harboring SCN1A mutation in addition to CHRNB2 mutation. AB - We report a case of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) with several characteristics distinct from previously reported cases, in which genetic studies identified mutations in two different genes. This case differed from typical ADNFLE with respect to the following: (1) slightly younger onset and refractory to antiepileptic drugs and (2) borderline intellectual functioning and coexistence of pervasive developmental disorder from infancy. Genetic testing revealed a novel mutation and a silent substitution in SCN1A (c.4285G>T, A1429S and c.4371G>C, silent) in addition to a known mutation in CHRNB2 (c.1200C>G, I312M). SCN1A is a gene that codes for the voltage-dependent sodium channel alpha1 subunit and has been implicated in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy in infancy. However, the relation between SCN1A and ADNFLE is unknown. We report the clinical course and symptomatic characteristics of this case although the relationship between ADNFLE mutation and SCN1A mutation remains to be elucidated. PMID- 23032132 TI - A comparison of antiepileptic drug therapy in patients with severe intellectual disability and patients with normal intellect. AB - We describe and compare the antiepileptic drug (AED) management in patients with severe intellectual disability (ID) and those with normal intellect (NI) and focal epilepsy at a tertiary epilepsy center. Fifty patients with ID were compared to a control group of 50 patients with NI; the majority of the patients in both groups had medically refractory epilepsy. Patients with ID were currently taking and had been previously exposed to a greater number of different AEDs. Despite the fact that both groups of patients had beene qually exposed to both old and newer AEDs, patients with ID were more likely to be taking at least one old AED and were more commonly treated with benzodiazepines (clobazam was the most commonly used drug in this group). This difference is likely related to greater seizure frequency and co-morbid behavioral disturbance in the ID group as no bias was identified against utilization of the newer AEDs in patients with ID. PMID- 23032133 TI - A five-year follow-up study of the general public awareness and perception of epilepsy in Croatia. AB - Public reception of epilepsy in Croatia was re-assessed in 2009, 5 years after an initial survey, by interviewing 1000 randomly selected adults. Ninety-two percent (-5.0%) of the respondents had heard about epilepsy, 47% (-7.9%) knew someone with epilepsy, and 38.6% (-6.0%) had witnessed a seizure. Interviewees were quite ready to accept a person with epilepsy. Almost 8% (+1.1%) would object if their child played with a child with epilepsy, and 77.8% (+1.8%) believed that a child with epilepsy could succeed as well as a child without epilepsy. Although 45.9% ( 6.6%) would approach a person having a seizure and help, 36.1% (+3.0%) would also call "911." Citizens of Croatia re-declared a high tolerance toward people with epilepsy and positive attitude toward children with epilepsy. Experiential factors remained strong predictors of more positive attitudes. A more prominent role of patients and implementation of social marketing in addressing a large persisting degree of prejudice and stigmatization worldwide are warranted. PMID- 23032134 TI - Predictors of quality of life in patients with refractory mesial temporal lobe epilepsy. AB - PURPOSE: The identification of variables associated with health-related quality of life (HRQoL) in patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) would improve surgical decision-making and post operatory follow-up in this group of patients. METHODS: We analyzed the independent association between the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) of 81 consecutive patients with refractory MTLE-HS. The clinical, demographic, radiological and electrophysiological variables were analyzed by multiple linear regression analysis. KEY FINDINGS: Approximately 36% (adjusted R(2)=0.36; R coefficient=0.66) of the QOLIE-31 overall score variance was explained by the history of initial precipitant injury, family history of epilepsy, disease duration, age of epilepsy onset, seizure frequency and presence of psychiatric axis-II diagnosis. The variance of QOLIE-31 sub-scales was: seizure worry=7%; overall QOL=11%; emotional well-being=32%; energy/fatigue=38%; cognitive function=13%; medication effects=7%; social function=13% (R coefficient between 0.30 and 0.65). SIGNIFICANCE: The pre-surgical variables studied had relatively low prediction capacity for the overall QOLIE-31 score and its sub scales in this set of Brazilian patients with refractory MTLE-HS. PMID- 23032135 TI - Mental health problems in Nigerian children with epilepsy: associations and risk factors. AB - Epilepsy is the most common neurological disorder affecting children, and the greatest burden of childhood epilepsy is found in the developing countries of the world. Behavioral problems are reported to occur more frequently in children with epilepsy, but there are limited studies on the pattern of behavioral problems in children living with epilepsy in sub-Saharan Africa. Eighty-four consecutive cases of epilepsy aged >=5 years seen at the pediatric neurology clinic of the University College Hospital, Ibadan, Nigeria over a period of 9 months were screened for behavioral problems using the Rutter A2 scale. Behavioral problems were found in 39 (46.6%) of 84 subjects and occurred more frequently in males. Presence of associated learning difficulties (OR 5.13, 95% CI 1.61-16.36) and being diagnosed with epilepsy within 6 months of the onset of the first epileptic seizure (OR 4.54, 95% CI 0.073-0.69) independently predicted psychopathology in the cases studied. Emotional and behavioral problems are common in Nigerian children with epilepsy. There is a need for effective mental health services for children with epilepsy in order to optimize outcomes. PMID- 23032136 TI - Long-term follow-up after comprehensive rehabilitation of persons with epilepsy, with emphasis on participation in employment or education. AB - The objective of this study was to describe the current situation of patients with epilepsy after rehabilitation with emphasis on employment and education and to investigate if clinical factors at admission were associated with increase in employment or education. All patients that participated in a comprehensive rehabilitation were eligible. Data were collected from medical records at admission, during rehabilitation, at discharge and from a structured telephone interview at follow-up 1-17 years after admission. In total, 124 patients participated in the follow-up. Participation in employment or education improved from admission to follow-up in 38 patients. In univariable analysis, active epilepsy with tonic-clonic seizures at admission was significantly associated with increased participation in employment or education at follow-up, so was decreased frequency of tonic-clonic seizures from admission to follow-up. The significance of the associations disappeared in adjusted multivariable analysis. Participation in employment or education was improved for many patients at follow up. PMID- 23032137 TI - Comparing standard medical care for nonepileptic seizures in Chile and the United States. AB - OBJECTIVE: We sought to compare the diagnostic and treatment practices for psychogenic nonepileptic seizures (PNES) in the United States (US) to Chile. METHODS: A survey on the diagnostic and treatment practices for PNES was administered to practicing clinicians in Chile. Results from 96 Chilean respondents were compared to results from 307 US clinicians. Type I error (alpha) was set to 0.005 for multiple comparisons. RESULTS: DIAGNOSIS: The diagnosis of PNES is made by inpatient video-EEG/LTM in 89% of the US respondents compared to 25% of the Chilean respondents (p<0.0001). The diagnosis of PNES is made by history and exam alone at twice the rate in Chile (38%) than in the US (16%; p<0.0001). TREATMENT: A higher proportion of the Chilean respondents (65%) endorsed psychopharmacotherapy as potentially beneficial compared to the US respondents (31%; p<0.0001). DISCUSSION: This cross-cultural multi-site survey reveals some differences in PNES evaluation and management between neurologists and other clinicians in the US and in Chile. Access to video EEG may improve PNES diagnosis and treatment. PMID- 23032138 TI - The effect of coffee consumption on blood pressure and the development of hypertension: a systematic review and meta-analysis. AB - CONTEXT: Coffee is one of the most widely consumed beverages worldwide and is known to acutely raise blood pressure (BP), but the effects of chronic consumption on BP is unclear. OBJECTIVES: To conduct a systematic review and meta analysis of available randomized controlled trials (RCTs) and cohort studies to assess the effect of chronic coffee consumption on BP and the development of hypertension. DATA SOURCES: Ovid, MEDLINE (from 1948), EMBASE (from 1988), and all of Web of Science and Scopus. STUDY SELECTION: RCTs and cohort studies of at least 1-week duration that assessed BP and/or the incidence of hypertension in coffee consumers compared with a control group that consumed less or no coffee. DATA EXTRACTION: Two authors independently reviewed abstracts and full-text articles for inclusion. Data were abstracted using standardized forms. Risk of bias in the RCTs was examined using the method described in the Cochrane Handbook for Systematic Reviews of Interventions. Quality of the cohort studies were assessed using the Newcastle-Ottawa quality assessment scale for cohort studies. DATA SYNTHESIS: Six hundred and ten articles were retrieved and a total of 15 (10 RCTs and five cohort studies) met inclusion criteria. Meta-analysis of RCTs demonstrated a pooled weighted difference in mean change in SBP of -0.55 mmHg [95% confidence interval (CI) -2.46 to 1.36) and DBP -0.45 mmHg (95% CI -1.52 to 0.61). Meta-analysis of the cohort studies demonstrated a pooled risk ratio for developing hypertension of 1.03 (95% CI 0.98-1.08). CONCLUSION: Low-quality evidence did not show any statistically significant effect of coffee consumption on BP or the risk of hypertension. Given the quality of the currently available evidence, no recommendation can be made for or against coffee consumption as it relates to BP and hypertension. PMID- 23032139 TI - Circulating anandamide and blood pressure in patients with obstructive sleep apnea. AB - OBJECTIVE: Obstructive sleep apnea chronically increases blood pressure through sympathetic nervous system activation. In animals, hypertension and sympathetic activity are restrained by cannabinoid receptor activation. Therefore, we hypothesized that increased blood pressure in patients with obstructive sleep apnea is associated with increased circulating endocannabinoid concentrations. METHODS: Arterial oxygen saturation and apnea/hypopnea episodes were recorded in 29 patients with normal glucose tolerance, 26 patients with type 2 diabetes mellitus, and 21 patients obese subjects without sleep apnea. We determined seated blood pressure, insulin, glucose, and high-sensitive C-reactive protein in the morning, and insulin sensitivity by euglycemic-hyperinsulinemic clamp the next day. Anandamide, the sum of 1-arachidonoylglycerol and 2 arachidonoylglycerol, and oleoylethanolamide were measured in plasma by liquid chromatography-tandem mass spectrometry. RESULTS: Endocannabinoid concentrations in sleep apnea patients were increased compared to obese individuals without disordered nocturnal breathing. Correction for variables of obesity and insulin resistance almost completely abrogated this difference in endocannabinoids. Anandamide strongly correlated with blood pressure in sleep apnea patients (r = 0.60 for SBP and r = 0.58 for DBP, P < 0.001). In multivariate regression analysis, anandamide was a stronger determinant of blood pressure than sleep apnea severity, obesity, insulin resistance, and inflammation. CONCLUSION: Obstructive sleep apnea patients show positive correlations between blood pressure and venous anandamide concentrations independent of confounding factors. Our data suggest a previously not recognized role of the endocannabinoid system for blood pressure regulation in patients with high risk for hypertension and cardiovascular disease. PMID- 23032140 TI - Determinants of blood pressure treatment and control in obese people: evidence from the general population. AB - OBJECTIVE: We assessed hypertension prevalence, blood pressure (BP)-lowering treatment and control in obese adults compared with lean/normal-weight individuals in France. METHODS: Multistage stratified random sample of 2075 adults from the French Nutrition and Health Survey (ENNS), a cross-sectional national survey carried out in 2006-2007. BP was measured three times on the left arm using an automatic device. Weight and height were assessed using standardized methods to compute body mass index (BMI, kg/m(2)). BP-lowering drugs were self reported. BP control was defined as SBP/DBP less than 140/90 among hypertensive individuals. RESULTS: As anticipated, mean SBP and DBP increased significantly across BMI categories (P for trend <0.0001). The age-adjusted and sex-adjusted prevalence of hypertension also increased across the same categories (15.7, 24.7 and 56.9%, respectively, P < 0.001). Among hypertensive individuals, obese participants were more likely to receive BP-lowering drugs compared with their lean/normal weight counterparts (P = 0.02). However, independently of age, smoking status and alcohol intake, obesity was associated with a 62% lower risk of BP control (OR: 0.38, 95% CI: 0.19-0.75) compared with the lean/normal-weight status. CONCLUSION: Although hypertension was much more prevalent in the obese compared with overweight and lean/normal-weight individuals, uncontrolled hypertension was also more frequent despite a higher rate of treatment. To some extent, this observation may probably be the consequence of obesity and its complex pathophysiology, more than to an inadequate therapeutic decision by clinicians. PMID- 23032141 TI - Prognostic value of the extent of left ventricular hypertrophy and its evolution in the hypertensive patient. AB - OBJECTIVE: Left ventricular hypertrophy (LVH) is a marker of cardiovascular risk. However, the progression of the risk as a function of the course of the LVH has only been the subject of few studies. METHODS: We report the consequences of the evolution of the left ventricular mass (LVM) in a cohort of hypertensive patients whose LVM was measured before any antihypertensive treatment. RESULTS: We followed up for an average of 12 years, 763 hypertensives with LVM measurement by echocardiography on inclusion. In this population, 117 cardiovascular complications occurred and the initial LVM appeared to be the most powerful marker of risk. A cutoff of 51 g/m(2.7) for the LVM index (LVMI) offered the best compromise of sensitivity and specificity in the prediction of complications. A second determination of LVM was carried out in 436 patients on average 5 years after inclusion. In this sub-group, 82 complications were recorded after an average interval of 13 years. The 51 g/m(2.7) value of LVMI over the follow-up offered the same sensitivity (74%) and specificity (52%) in the prediction of complications. The progression of the LVM was related to the occurrence of complications independently of the basal value and other risk factors. CONCLUSIONS: We confirm LVMI as a powerful risk factor in hypertension with a cutoff of 51 g/m(2.7), which offers the same sensitivity and specificity whether the LVM was determined before or during treatment. The progression of LVM, on average 5 years after the initial measurement had a prognostic value independent of the initial determination. PMID- 23032142 TI - Divergent localization of angiotensinogen mRNA and protein in proximal tubule segments of normal rat kidney. AB - OBJECTIVES: Angiotensinogen in the kidneys is formed primarily in the proximal tubule cells and is secreted into the tubular fluid. Structurally, proximal tubules can be divided into three segments. The first segment, segment 1 (S1) is mainly confined to the pars convoluta, the second segment, segment 2 (S2) comprises the end of pars convoluta, and the third segment, segment 3 (S3) includes the major part of the pars recta. There are some reports describing angiotensinogen localization in kidneys; however, it remains uncertain which proximal tubule segments express angiotensinogen. To determine the detailed localization of angiotensinogen in the three proximal tubule segments, we established multistaining methods using segment-specific protein markers. METHODS: Using kidneys from Wistar-Kyoto rats, we performed immunohistochemistry and double or triple staining by fluorescence in-situ hybridization and/or immunofluorescence. RESULTS: Our results show that angiotensinogen mRNA and protein are expressed in the cortex and outer medulla of the normal rat kidney. Angiotensinogen mRNA was hardly detected in S1, detected weakly in S2 and strongly in S3 segments. In contrast, angiotensinogen protein was detected in S1 at high levels and less in S2 and S3 segments. CONCLUSION: These data indicate divergence of angiotensinogen mRNA transcription and angiotensinogen protein synthesis and metabolism in different segments of the normal rat proximal tubules. PMID- 23032143 TI - Association of birthplace and self-reported hypertension by racial/ethnic groups among US adults--National Health Interview Survey, 2006-2010. AB - BACKGROUND: Over the past few decades, the proportion of US adults who were foreign-born has been increasing, as has the overall prevalence of hypertension. Here, we compared the prevalence of self-reported hypertension among native-born adults with that among foreign-born adults, classified by racial/ethnic group. METHODS: Using 2006-2010 data from the National Health Interview Survey (NHIS), we compared the age-adjusted prevalence of hypertension among native-born adults to foreign-born adults, specified by continent of birthplace and race/ethnicity. Results are expressed as unadjusted odds ratios (ORs) and three sets of adjusted odds ratios (AORs) adjusted for selected sociodemographic, behavioral and health related characteristics. All results accounted for NHIS sampling design variables. RESULTS: The analytic sample was 124,260 with 16.3% foreign-born adults. Among the foreign-born adults, 56% were from Central or South America, 22% from Asia, 13% from Europe, and 4% from Africa. Overall and after adjustment, hypertension prevalence was significantly higher among US-born adults than among foreign-born adults (AOR: 1.28, 95% CI: 1.21-1.36). By race/ethnicity, hypertension prevalence was higher among US-born non-Hispanic blacks than either foreign-born non-Hispanic blacks (AOR: 1.24, 95%CI: 1.02-1.50) or all Africa-born immigrants of any race/ethnicity [AOR: 1.45, 95% confidence interval (CI): 1.07 1.97]. Among foreign-born adults, duration of US residence was positively associated with the likelihood of hypertension. CONCLUSION: Hypertension prevalence was higher among US-born adults than among foreign-born adults and higher among US-born non-Hispanic blacks than in any other group. Among foreign born adults, hypertension risk increased with the number of years they had lived in the United States. PMID- 23032144 TI - Does cigarette smoking exacerbate the effect of blood pressure on the risk of cardiovascular and all-cause mortality among hypertensive patients? AB - OBJECTIVE: To examine the risk of cigarette smoking on cardiovascular disease (CVD) and all-cause mortality among hypertensive patients. METHODS: We conducted a prospective cohort study among 36,943 hypertensive patients aged at least 40 years. Data on smoking and other variables were obtained in 1991 and follow-up evaluation was conducted in 1999-2000. RESULTS: During a median follow-up of 8.2 years, we documented 7194 deaths among 36 943 hypertensive patients. Compared with never-smokers, the multivariate-adjusted relative risks (MRRs) [95% confidence intervals (CIs)] for CVD mortality were 1.19 (1.07, 1.31) and 1.33 (1.23, 1.45) for those who smoked 0.1-19 pack-years and at least 20 pack-years (P for linear trends <0.001 for all). A similar pattern was observed for all-cause mortality. A dose-response association between pack-years smoked and risk of CVD and all-cause mortality (all P <= 0.01) was found among the SBP groups (140-159, 160-179, and >= 180 mmHg), DBP groups (<90, 90-94, and 100-109 mmHg), and pulse pressure groups (50-59, 60-69, and >= 70 mmHg). In addition, compared to never smokers with stage 1 hypertension, MRRs of CVD and all-cause mortality for those who smoked at least 20 pack-years with stage 3 hypertension were remarkably increased to 3.06 (2.64, 3.54) and 2.51 (2.24, 2.80), respectively. CONCLUSIONS: Smoking not only significantly increased the risk of CVD and all-cause mortality among hypertensive groups, but the synergistic effect on the risk of CVD and all cause mortality existed between cigarette smoking and blood pressure category. Therefore, apart from hypertension management, smoking cessation should be an essential component for preventing deaths related to smoking. PMID- 23032145 TI - Detection and recognition of hypertension in anxious and depressed patients. AB - OBJECTIVE: Hypertension management requires detection (i.e. confirmation of persistently high blood pressure (BP) after an initial elevated measurement) and recognition of the condition (evidenced by a formal diagnosis and/or initiation of treatment). Our objective was to determine whether disparities exist in detection of elevated BP and recognition (i.e. diagnosis or treatment) of hypertension in patients with depression and anxiety. METHODS: Using data from the Cardiovascular Research Network Hypertension Registry, we assessed time-to detection of elevated BP and recognition of hypertension in patients with comorbid anxiety and depression compared with patients with neither disorder. We performed multivariable survival analysis of time to detection and recognition in patients who entered the registry in 2002-2006. We adjusted for primary care visit rate and other relevant clinical factors. RESULTS: In 168,630 incident hypertension patients, detection occurred earlier among patients with anxiety and depression compared with patients without these diagnoses [adjusted hazard ratio for anxiety and depression 1.30, 95% confidence interval (CI) 1.26-1.35]. Recognition of hypertension within 12 months of the second elevated BP was similar (adjusted hazard ratio for anxiety and depression 0.94, 95% CI 0.89-1.00) or delayed (adjusted hazard ratio for anxiety 0.93, 95% CI 0.88-0.99 and for depression 0.93, 95% CI 0.90-0.97). CONCLUSIONS: Detection of elevated BP occurred earlier in patients with anxiety and depression. Time from detection to diagnosis or treatment was similar or delayed in patients with and without these diagnoses. Our findings suggest that as-yet-unidentified factors contribute to disparities in hypertension detection and recognition. PMID- 23032146 TI - Assessment of the knowledge of diabetes mellitus among school teachers within the scope of the managing diabetes at school program. AB - OBJECTIVE: Training teachers and education professionals on diabetes is crucial for full-time monitoring of diabetic children in schools. The objective of this study was to assess the knowledge on diabetes in a group of school teachers in Turkey. METHODS: Between November 2010 and November 2011, 1054 teachers from three regions of Ankara were given a questionnaire to assess their knowledge on diabetes. The mean age of the group (27% males, 73% females) was 38.8+/-8 years. 61.7% of the participants were class teachers, 23.3% were school counselors, and the rest were physical education teachers and administrators. RESULTS: A fair percentage (47.6%) of the participants had a moderate knowledge level on diabetes and 32.4% expressed a lower level of knowledge. A large proportion (94%) gave an accurate definition of diabetes. Of the total group of 1054 teachers, 625 were aware that blood glucose level might decrease in diabetic children during follow up. Also, 75% believed that diabetic children were eligible for physical education classes. 52.8% of these teachers had no diabetic child in their classes and teachers with a diabetic patient in their family had better knowledge of diabetes compared to their counterparts. CONCLUSIONS: Our study results indicate that school teachers have limited knowledge on diabetes. We believe that their knowledge levels can be improved by widespread training programs. PMID- 23032147 TI - An infant born to a mother with gestational diabetes presenting with 49,XXXXY syndrome and renal agenesis-a case report. AB - 49,XXXXY is a rare sex chromosome polysomy with an incidence of 1 in 85 000 male births. It has a characteristic triad of mental retardation, skeletal malformation and hypogonadism. This is the first case report of a child with 49,XXXXY syndrome and renal agenesis. This child was referred for genetic testing at 14 years of age due to facial dysmorphism and hypergonadotropic hypogonadism. He had coarse facial features, cryptorchidism of the right testis, genu valgus deformities, and patent ductus arteriosus which are known associations of 49,XXXXY syndrome. He also had agenesis of the right kidney, hydronephrosis of the left kidney with hydroureter which is not a known association of 49,XXXXY syndrome. The patient was the offspring of a mother with gestational diabetes. There is a strong correlation between maternal diabetes and congenital anomalies, especially renal and cardiovascular anomalies. Additionally, it has been noted that gestational diabetes increases the incidence of chromosomal aneuploidies. The teratogenic effects of maternal diabetes during embryogenesis may be the causative factor for the final phenotype of 49,XXXXY syndrome and renal agenesis. PMID- 23032148 TI - Growth hormone deficiency and diabetes insipidus as a complication of endoscopic third ventriculostomy. AB - Endoscopic third ventriculostomy (ETV) has become the procedure of choice for the treatment of obstructive hydrocephalus in children and adults. Endocrinological complications of ETV in children are rare. Diabetes insipidus (DI) is the most common and accounts for only 0.5% of complications from ETV. The majority of documented cases are transient. To date, there are no documented cases of multiple pituitary hormone deficiencies. We present here a 6-year-old girl with growth hormone deficiency and permanent DI which developed as a complication of ETV. This patient is unique in both demonstrating multiple pituitary hormone deficiencies and the classical triphasic response of DI after ETV. We postulate that these complications were caused by compression of the pituitary stalk and hypothalamic injury during the procedure. We compare our case presentation to experimental studies conducted in rats. PMID- 23032150 TI - Water-capsule strategy in crystal engineering for water-solubility conversion from insoluble to soluble. AB - (H(2)O)(32)-shell structure constructed by two unique water molecules in high symmetry crystal leads to good water-solubility of the obtained compound 1. PMID- 23032149 TI - Hyperinsulinaemic hypoglycaemia:genetic mechanisms, diagnosis and management. AB - Hyperinsulinaemic hypoglycaemia (HH) is characterized by unregulated insulin secretion from pancreatic beta-cells. Untreated hypoglycaemia in infants can lead to seizures, developmental delay, and subsequent permanent brain injury. Early identification and meticulous managementof these patients is vital to prevent neurological insult. Mutations in eight different genes (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1, HNF4A and UCP2) have been identified to date in patients with congenital forms of hyperinsulinism (CHI). The most severe forms of CHI are due to mutations in ABCC8 and KCJN11, which encode the two components of pancreatic beta-cell ATP-sensitive potassium channel. Recent advancement in understanding the genetic aetiology, histological characterisation into focal and diffuse variety combined with improved imaging (such as fluorine 18 L-3, 4 dihydroxyphenylalanine positron emission tomography 18F-DOPA-PET scanning) and laparoscopic surgical techniques have greatly improved management. In adults, HH can be due to an insulinoma, pancreatogenous hypoglycaemic syndrome, post gastric bypass surgery for morbid obesity as well as to mutations in insulin receptor gene. This review provides an overview of the molecular basis of CHI and outlines the clinical presentation, diagnostic criteria, and management of these patients. PMID- 23032151 TI - Lysosomal enzymes are decreased in the kidney of diabetic rats. AB - The objective of the present study was to investigate the expression and activities of lysosomal enzymes that act upon proteins and sulfated polysaccharides in diabetic rat kidney. Cathepsins, glycosidases and sulfatases were studied on the 10th (DM-10) and on the 30th (DM-30) day of streptozotocin induced diabetes mellitus (DM). The activity of cathepsin B, the main kidney cysteine protease, was decreased both in DM-10 and DM-30. Gel filtration chromatography of urinary proteins has shown the prevalence of low molecular weight peptides in normal and DM-10 urine, in contrast to the prevalence of high molecular weight peptides and intact proteins in DM-30. These results show that the decrease in lysosomal proteases could explain, at least in part, the increased albuminuria detected by radial immunodiffusion (RID), due to the excretion of less degraded or intact albumin. Concerning sulfated polysaccharides, the activities of beta-glucuronidase, N-acetyl-beta-d glucosaminidase, and N-acetyl-beta-d-galactosaminidase were also decreased in DM 30, while aryl sulfatases did not vary. Increased toluidine blue metachromatic staining of the tissue suggests that the lower activities of glycosidases could lead to intracellular deposition of partially digested molecules, and this could explain the decreased urinary excretion and increased tissue buildup of these molecules. The main morphological changes observed in kidney were proximal convoluted tubules with thinner walls and thinner brush border. Immunohistochemistry revealed that most of cathepsin B was located in the brush border of proximal tubular cells, highlighting the involvement of proximal convoluted tubules in diabetic nephropathy. PMID- 23032153 TI - Malic acid or orthophosphoric acid-heat treatments for protecting sunflower (Helianthus annuus) meal proteins against ruminal degradation and increasing intestinal amino acid supply. AB - The protection of sunflower meal (SFM) proteins by treatments with solutions of malic acid (1 M) or orthophosphoric acid (0.67 M) and heat was studied in a 3 * 3 Latin-square design using three diets and three rumen and duodenum cannulated wethers. Acid solutions were applied to SFM at a rate of 400 ml/kg under continuous mixing. Subsequently, treated meals were dried in an oven at 150 degrees C for 6 h. Diets (ingested at 75 g/kg BW0.75) were isoproteic and included 40% Italian ryegrass hay and 60% concentrate. The ratio of untreated to treated SFM in the concentrate was 100 : 0 in the control diet and around 40 : 60 in diets including acid-treated meals. The use of acid-treated meals did not alter either ruminal fermentation or composition of rumen contents and led to moderate reductions of the rumen outflow rates of untreated SFM particles, whereas it did not affect their comminution and mixing rate. In situ effective estimates of by-pass (BP) and its intestinal effective digestibility (IED) of dry matter (DM), CP and amino acids (AAs) were obtained considering both rates and correcting the particle microbial contamination in the rumen using 15N infusion techniques. Estimates of BP and IED decreased applying microbial correction, but these variations were low in agreement with the small contamination level. Protective treatments increased on average the BP of DM (48.5%) and CP (267%), mainly decreasing both the soluble fraction and the degradation rate but also increasing the undegradable fraction, which was higher using orthophosphoric acid. Protective treatments increased the IED of DM (108%) and CP, but this increase was lower using orthophosphoric acid (11.8%) than malic acid (20.7%). Concentrations of AA were similar among all meals, except for a reduction in lysine concentrations using malic acid (16.3%) or orthophosphoric acid (20.5%). Protective treatments also increased on average the BP of all AA, as well as the IED of most of them. Evidence of higher increases for those AA showing a high resistance to degradation in the untreated meal were also observed. The total supply of metabolisable AA was increased by 3.87 times for sulphur-containing AA, whereas that of lysine was increased by 2.5 times, mainly because of lysine losses with heat treatments. These treatments and especially that with malic acid would be useful to increase the protein value of these meals but their combined use with lysine-rich protein concentrates would improve the metabolisable protein profile. PMID- 23032152 TI - Serotonin paracrine signaling in tissue fibrosis. AB - The molecule serotonin (5-hydroxytryptamine or 5-HT) is involved in numerous biological processes both inside and outside of the central nervous system. 5-HT signals through 5-HT receptors and it is the diversity of these receptors and their subtypes that give rise to the varied physiological responses. It is clear that platelet derived serotonin is critical for normal wound healing in multiple organs including, liver, lung heart and skin. 5-HT stimulates both vasoconstriction and vasodilation, influences inflammatory responses and promotes formation of a temporary scar which acts as a scaffold for normal tissue to be restored. However, in situations of chronic injury or damage 5-HT signaling can have deleterious effects and promote aberrant wound healing resulting in tissue fibrosis and impaired organ regeneration. This review highlights the diverse actions of serotonin signaling in the pathogenesis of fibrotic disease and explores how modulating the activity of specific 5-HT receptors, in particular the 5-HT2 subclass could have the potential to limit fibrosis and restore tissue regeneration. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. PMID- 23032154 TI - High energy resolution off-resonant spectroscopy at sub-second time resolution: (Pt(acac)2) decomposition. AB - We report on the decomposition of platinum acetylacetonate (Pt(acac)(2)) in hydrogen induced by flash heating. The changes in the local Pt structure were followed by high energy resolution off-resonant spectroscopy uniquely performed with sub-second time resolution. The decomposition consists of a two-step reduction process of the Pt(II) species. PMID- 23032155 TI - Electric field control of the skyrmion lattice in Cu2OSeO3. AB - Small-angle neutron scattering has been employed to study the influence of applied electric (E-)fields on the skyrmion lattice in the chiral lattice magnetoelectric Cu(2)OSeO(3). Using an experimental geometry with the E-field parallel to the [111] axis, and the magnetic field parallel to the [11(-)0] axis, we demonstrate that the effect of applying an E-field is to controllably rotate the skyrmion lattice around the magnetic field axis. Our results are an important first demonstration for a microscopic coupling between applied E-fields and the skyrmions in an insulator, and show that the general emergent properties of skyrmions may be tailored according to the properties of the host system. PMID- 23032158 TI - Gold nanoparticle research before and after the Brust-Schiffrin method. AB - In this viewpoint we discuss the early contribution from Brust et al., which is not only the most cited paper ever published in Chem. Commun., but also a landmark in gold nanoparticle research and in nanotechnology. We provide here an overview of its major contributions and how the field has evolved since its publication in 1994. PMID- 23032157 TI - Influence of dark phase restricted high fat feeding on myocardial adaptation in mice. AB - Prolonged high fat feeding is associated with myocardial contractile dysfunction in rodents. However, epidemiological data do not necessarily support the concept that fat-enriched diets adversely affect cardiac function in humans. When fed in an ad libitum manner, laboratory rodents consume chow throughout the day. In contrast, humans typically consume food only during the awake phase. Discrepancies between rodent and human feeding behaviors led us to hypothesize that the time of day at which dietary lipids are consumed significantly influences myocardial adaptation. In order to better mimic feeding behavior in humans, mice were fed (either a control or high fat diet) only during the 12-hour dark phase (i.e., no food was provided during the light phase). We report that compared to dark phase restricted control diet fed mice, mice fed a high fat diet during the dark phase exhibit: 1) essentially normal body weight gain and energy balance; 2) increased fatty acid oxidation at whole body, as well as skeletal and cardiac muscle (in the presence of insulin and/or at high workloads) levels; 3) induction of fatty acid responsive genes, including genes promoting triglyceride turnover in the heart; 4) no evidence of cardiac hypertrophy; and 5) persistence/improvement of myocardial contractile function, as assessed ex vivo. These data are consistent with the hypothesis that ingestion of dietary fat only during the more active/awake period allows adequate metabolic adaptation, thereby preserving myocardial contractile function. This article is part of a Special Issue entitled "Focus on cardiac metabolism". PMID- 23032159 TI - Randomized trial to assess the immunogenicity, safety and antibody persistence up to three years after a single dose of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in toddlers. AB - Effective vaccines offering broad protection to toddlers, who are at high risk for invasive meningococcal disease, are needed. Here, the immunogenicity, safety and antibody persistence of the tetravalent meningococcal ACWY tetanus toxoid conjugate vaccine (MenACWY-TT) were evaluated in toddlers. Healthy participants aged 12 to 23 mo (n = 304) were randomized (3:1) to receive one dose of MenACWY TT or a monovalent meningococcal serogroup C conjugate vaccine (MenC-CRM 197). Serum bactericidal activity was evaluated with assays using rabbit (rSBA) and human (hSBA) complement up to three years post-vaccination. MenACWY-TT was demonstrated to be non-inferior to MenC-CRM 197 in terms of immunogenicity to serogroup C, and the pre-specified immunogenicity criteria for serogroups A, W 135 and Y were met. Exploratory analyses suggested that rSBA geometric mean titers (GMTs), hSBA GMTs and proportions of toddlers with rSBA titers >= 1:128 and hSBA titers >= 1:4 and >= 1:8 were higher for all serogroups at one month post-vaccination with MenACWY-TT compared with MenC-CRM 197. At three years post vaccination, at least 90.8% and 73.6% of MenACWY-TT recipients retained rSBA titers >= 1:8 for all serogroups and hSBA titers >= 1:4 for serogroups C, W-135 and Y, respectively, but the percentages of toddlers with hSBA titers >= 1:4 for serogroup A decreased to 21.8%. In both groups, grade 3 adverse events were infrequently reported and no serious adverse events were considered causally related to vaccination. These results suggest that one single dose of MenACWY-TT induces a robust and persistent immune response and has an acceptable safety profile in toddlers. PMID- 23032160 TI - Immunogenicity and safety results from a randomized multicenter trial comparing a Tdap-IPV vaccine (REPEVAX(r)) and a tetanus monovalent vaccine in healthy adults: new considerations for the management of patients with tetanus-prone injuries. AB - In adults with a tetanus-prone injury, combined vaccines such as Tdap-IPV (REPEVAX(r)) can boost immunity against several diseases simultaneously. This Phase IIIb, parallel-group, open-label trial compared antibody responses to Tdap IPV and tetanus monovalent vaccine (TMV; Vaccin Tetanique Pasteur(r) or Tetavax(r)) against tetanus toxoid 10 and 28 d post-vaccination. Between July and December 2009, four centers in France and five in Germany recruited healthy adults who had received a tetanus-containing vaccine 5-10 y previously. Participants were randomized 1:1 to receive at the first visit a single dose (0.5 mL) of Tdap-IPV or TMV, with follow-up visits at Day 10 and Day 28. OUTCOMES: per protocol (PP) population immunogenicity at Day 10 (primary) and at Day 28 (secondary); safety throughout the study. Of 456 adults randomized, 223 received Tdap-IPV and 233 received TMV (PP population: 183 and 199 participants, respectively). All participants receiving Tdap-IPV and 99.0% receiving TMV had an anti-tetanus antibody concentration >= 0.1 IU/mL, confirming non-inferiority of Tdap-IPV to TMV (95% confidence interval of the difference: -1.2, 3.6). Number of adverse events reported was comparable in each group. Injection-site reactions were reported by 76.6% participants receiving Tdap-IPV and 74.6% receiving TMV. Systemic events (e.g., malaise, myalgia and headache) were reported in 47.7% and 39.7% of the Tdap-IPV and the TMV groups, respectively. Tdap-IPV is effective and well-tolerated for use in the management of tetanus-prone injuries in emergency settings in persons for whom a booster against diphtheria, pertussis and poliomyelitis is also needed. PMID- 23032161 TI - Does the relative importance of MMR vaccine concerns differ by degree of parental vaccine hesitancy?: An exploratory study. AB - BACKGROUND: There has been a rise in the number of vaccine-hesitant parents (VHPs) in the US, many of whom express reservations about administering the MMR vaccine to their children. We studied the relative importance of attitudinal barriers to MMR vaccination among VHPs with differing levels of MMR vaccine hesitancy. METHODS: We performed a cross-sectional exploratory analysis of a parental survey that assessed common vaccination barriers among MMR vaccine hesitant parents in Michigan. The outcome of interest was parental MMR vaccination intention, measured on an 11-point scale, with higher numbers corresponding to greater intent. The relative importance of identified barriers to MMR vaccination was assessed across levels of vaccine hesitancy. Exploratory factor analysis was performed to identify underlying attitudinal constructs and assess if these constructs' importance varied depending on the degree of parental vaccine hesitancy. RESULTS: Our study population included 79 Michigan parents who initially screened positive for MMR vaccine-hesitancy. Within this sample, 47% of parents were unsure about their vaccination intentions and 20% expressed negative intentions, while a third (33%) of parents had positive vaccination intentions when further questioned. After grouping the barriers in our study into four underlying factors, parents with negative vaccination intentions had statistically significant higher factor score for the factor "risks versus benefits" and a statistically significant lower mean score for "vaccine importance," compared with parents with unsure or positive intentions. CONCLUSIONS: In this exploratory study we found that vaccine-specific concerns have varying salience for parents based on their vaccination intention. Thus, future educational programs likely should tailor messages based on the degree of vaccine hesitancy expressed in their target populations in order to improve their overall effectiveness. PMID- 23032162 TI - Acceptance and rejection of influenza vaccination by pregnant women in southern Iran: physicians' role and barriers. AB - OBJECTIVE: Vaccination provides the most effective protection against maternal, fetal and neonatal complications of influenza infection. This study aimed to determine the uptake rate of influenza vaccination including 2009 pandemic H1N1 influenza and seasonal influenza vaccination and the reasons for acceptance or rejection among pregnant women. RESULT: Mean age of the 416 pregnant women enrolled in this study was 27.06 +/- 5.27 y. Only 25 (6%) of 397 women had history of vaccination. Of 383 (92.06%) pregnant women who had rejected vaccination, 116 (30.28%) declared that they lacked information about influenza vaccination and 44 (11.48%) felt that they did not need vaccination. Concerns about the safety of influenza vaccination were reported by only 2 women (0.52%). Of the 25 (6%) pregnant women who were vaccinated against influenza, 15 (60%) accepted because of advice they received from persons other than physicians, 5 (20%) believed that influenza vaccination is necessary for everyone, and 3 (12%) accepted because of a history of frequent influenza virus infections in previous years. METHOD: This questionnaire based study was conducted at obstetrics and maternity hospitals affiliated with Shiraz University of Medical Sciences, Shiraz, Iran. Pregnant women were interviewed individually and privately. SPSS was used for data analysis. CONCLUSION: Most of the unvaccinated and vaccinated pregnant women lacked sufficient knowledge about influenza. Education of pregnant women about influenza vaccination and encouragement from physicians may have a remarkable effect on turning poor compliance into high flu vaccination uptake among pregnant women. PMID- 23032163 TI - Maturation of morphology, phenotype and functions of murine bone marrow-derived dendritic cells (DCs) induced by polysaccharide Kureha (PSK). AB - The aim of this work was to evaluate the influence of protein-bound polysaccharide Kureha(PSK) on murine dendritic cells (DCs). These impacts of PSK on DCs from bone marrow derived DCs(BMDCs) were assessed with inverted phase contrast microscope, conventional scanning electron microscopy (SEM), transmission electron microscopy (TEM) for morphology, fluorescence activated cell sorting (FACS) analysis, cytochemistry assay for key surface molecules, FITC dextran for phagocytosis, bio-assay and enzyme linked immunosorbent assay (ELISA) for cytokine production. We found that under the influence of PSK, immature DCs changed into mature DCs with decrease of antigens up-taking, simultaneously high expression of key surface molecules of the MHC classII,CD40, CD80, CD86 and CD83 as well as more production of IL-12p70 and tumor necrosis factor alpha (TNF alpha). These data indicate that PSK could markedly promote maturation of DCs and this adjuvant-like activity may have potential therapeutic value in vaccine preparation. PMID- 23032164 TI - Does the Syrian population have to wait for the new generation of human papillomaviruses vaccine? AB - We recently conducted several studies regarding the presence of high-risk HPVs in human cervical, colorectal and breast cancers in the Syrian population. Herein, we report that high-risk HPVs type 16, 18, 33, 45, 51, 52 and 58 are frequently present in colorectal cancer in this population. Therefore and based on previous studies and present data, we conclude that the most frequent high-risk HPV types, in the Syrian population, are 16, 18, 33, 35, 45, 51, 52 and 58. Thus, our data suggest that it will be useful to use the new generation of HPV vaccine to protect the Syrian population from high-risk HPVs and their associated cancers. PMID- 23032165 TI - Review of 10 years of marketing experience with Chinese domestic inactivated hepatitis A vaccine Healive(r). AB - In 2002, the first Chinese domestic preservative-free inactivated hepatitis A vaccine, Healive(r), was introduced in China. It is highly immunogenic, and provides lasting protection in healthy individuals and generates protective levels of antibodies in other at-risk individuals. Over 10 years since its first licensure, postmarketing surveillance data have confirmed the outstanding safety profile of the vaccine. Comparative clinical trials indicated that Healive(r) induce equal or similar immunogenicity with other currently available inactivated hepatitis A vaccines and are interchangeable for the course of HAV immunization in Chinese children. The vaccine is effective in curbing outbreaks of hepatitis A due to rapid seroconversion and the long incubation period of the disease. Additional issues surrounding the use of the vaccine are also reviewed. PMID- 23032167 TI - Meningococcal serogroup Y emergence in Europe: update 2011. AB - Neisseria meningitidis is differentiated into 12 distinct serogroups, of which A, B, C, W-135, X, and Y are medically most important and represent an important health problem in different parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. Recent epidemiological surveillance has indicated an increase of serogroup Y invasive meningococcal disease in some parts of Europe as shown in the epidemiological data for 2010 from various European countries previously published in this journal. ( 1) Here, data is reported indicating that the emergence of serogroup Y continued in 2011 in various regions of Europe. The average age of persons affected by N. meningitidis serogroup Y seems to have decreased in some countries in comparison to the previous decade. PMID- 23032166 TI - A dengue DNA vaccine formulated with Vaxfectin(r) is well tolerated, and elicits strong neutralizing antibody responses to all four dengue serotypes in New Zealand white rabbits. AB - A tetravalent DNA vaccine formulated with Vaxfectin adjuvant was shown to elicit high levels of neutralizing antibody against all four dengue virus serotypes (Porter et al., ( 16) ), warranting further testing in humans. In preparation for a phase 1 clinical testing, the vaccine and the adjuvant were manufactured under current good manufacturing practice guidelines. The formulated vaccine and the adjuvant were tested for safety and/or immunogenicity in New Zealand white rabbits using a repeat dose toxicology study. The formulated vaccine and the adjuvant were found to be well tolerated by the animals. Animals injected with formulated vaccine produced strong neutralizing antibody response to all four dengue serotypes. PMID- 23032169 TI - Clarity: an open-source manager for laboratory automation. AB - Software to manage automated laboratories, when interfaced with hardware instruments, gives users a way to specify experimental protocols and schedule activities to avoid hardware conflicts. In addition to these basics, modern laboratories need software that can run multiple different protocols in parallel and that can be easily extended to interface with a constantly growing diversity of techniques and instruments. We present Clarity, a laboratory automation manager that is hardware agnostic, portable, extensible, and open source. Clarity provides critical features including remote monitoring, robust error reporting by phone or email, and full state recovery in the event of a system crash. We discuss the basic organization of Clarity, demonstrate an example of its implementation for the automated analysis of bacterial growth, and describe how the program can be extended to manage new hardware. Clarity is mature, well documented, actively developed, written in C# for the Common Language Infrastructure, and is free and open-source software. These advantages set Clarity apart from currently available laboratory automation programs. The source code and documentation for Clarity is available at http://code.google.com/p/osla/. PMID- 23032170 TI - Mathematical modeling of vesicle drug delivery systems 1: vesicle formation and stability along with drug loading and release. AB - Vesicles represent an important class of nanoscale drug delivery vehicles. To significantly reduce the time and resources that are required to optimize these drug carriers, this review article discusses the mathematical models that have been derived for understanding the formation of vesicles and their stability, as well as for predicting drug loading and their release. With regard to vesicle formation and stability, the packing parameter can be used to predict how the solution environment, surfactant composition, and surfactant molecular architecture can influence the supermolecular self-assembled structures that are formed from amphiphiles. In the context of drug delivery, this is useful for facilitating vesicle formation and stability during transit through the body. At the target site, this information can be used to help trigger a rapid release of the drug. With regard to drug loading, kinetic and equilibrium models provide guidelines for appropriate pH conditions and drug incubation times during loading. The diffusivity, partition coefficient, and bilayer thickness also play significant roles during loading and release of the drug. Our hope is that more researchers in this exciting field will complement their experimental approaches with these mathematical models to more efficiently develop vesicle-based drug carriers. PMID- 23032171 TI - Room-temperature solution synthesis of Ag nanoparticle functionalized molybdenum oxide nanowires and their catalytic applications. AB - A simple chemical solution route for the synthesis of large-scale high-quality Ag nanoparticle functionalized molybdenum oxide nanowire at room temperature has been developed. In the synthesis, the protonated amine was intercalated into the molybdenum bronze layers to reduce the electrostatic force of the lamellar structures, and then the Ag nanoparticle functionalized long nanowires could be easily induced by a redox reaction between a molybdenum oxide-amine intermediate and Ag(+) at room temperature. The intercalation lamellar structures improved the nucleation and growth of the Ag nanoparticles, with the result that uniform Ag nanoparticles occurred on the surface of the MoO(3) nanowire. In this way Ag nanoparticles with average sizes of around 6 nm, and high-purity nanowires with mean diameter of around 50 nm and with typical lengths of several tens to hundreds of micrometers were produced. The heteronanostructured nanowires were intricately and inseparably connected to each other with hydrogen bonds and/or bridge oxygen atoms and packed together, forming a paper-like porous network film. The Ag-MoO(3) nanowire film performs a promoted catalytic property for the epoxidation of cis-cyclooctene, and the heteronanostructured nanowire film sensor shows excellent sensing performance to hydrogen and oxygen at room temperature. PMID- 23032168 TI - A randomized study to assess the immunogenicity, antibody persistence and safety of a tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine in children aged 2-10 years. AB - Incidence of meningococcal diseases is high in children, and effective vaccines are needed for this age group. In this phase II, open, controlled study, 309 children aged 2-10 y from Finland were randomized (3:1) into two parallel groups to receive one dose of meningococcal ACWY-tetanus toxoid conjugate vaccine (ACWY TT group; n = 231) or a licensed meningococcal ACWY polysaccharide vaccine (Men PS group; n = 78). Serum bactericidal activity using rabbit complement (rSBA) was evaluated up to three years post-vaccination. Exploratory comparisons suggested that rSBA vaccine response rates and geometric mean titers (GMTs) for each serogroup at one month post-vaccination and rSBA GMTs for serogroups A, W-135 and Y up to three years post-vaccination were higher in the ACWY-TT compared with Men PS group, but did not detect any difference between groups in terms of rSBA-MenC GMTs at three years post-vaccination; this is explained by the higher proportion of children from the Men-PS group who were excluded because they were re vaccinated with a monovalent meningococcal serogroup C vaccine due to loss of protective antibody levels against this serogroup. Although there was a higher incidence of local reactogenicity in the ACWY-TT group, general and unsolicited symptoms reporting rates were comparable in both groups. This study showed that MenACWY-TT was immunogenic with a clinically acceptable safety profile in children aged 2-10 y. MenACWY-TT induced higher functional antibody titers for all serogroups, which persisted longer for serogroups A, W-135 and Y, than the MenACWY polysaccharide vaccine. PMID- 23032172 TI - Reproductive endocrinology: menopausal vasomotor symptoms and insulin resistance. PMID- 23032173 TI - Endocrine disorders in pregnancy: maternal obesity associated with neonatal death in Africa. PMID- 23032177 TI - Obesity: is weight gain after smoking cessation an important concern? PMID- 23032175 TI - Endocrine disorders in pregnancy: stress responses in children after maternal glucocorticoids. PMID- 23032178 TI - Surgery: remission of type 2 diabetes mellitus after bariatric surgery--is it durable? PMID- 23032179 TI - Diabetes: PTEN mutations increase insulin sensitivity and obesity. PMID- 23032180 TI - Metabolism: iron metabolism, adiponectin and T2DM--the link with adipocyte insulin resistance. PMID- 23032182 TI - Diabetes: exercise benefits in type 2 diabetes mellitus. PMID- 23032183 TI - How to modify the van der Waals and Casimir forces without change of the dielectric permittivity. AB - We propose a new experiment on the measurement of the Casimir force and its gradient between a Au-coated sphere and two different plates made of doped semiconductors. The concentrations of charge carriers in the plates are chosen slightly below and above the critical density at which the Mott-Anderson insulator-metal transition occurs. We calculate changes in the Casimir force and the Casimir pressure due to the insulator-metal transition using the standard Lifshitz theory and the phenomenological approach neglecting the contribution of free charge carriers in the dielectric permittivity of insulator materials (this approach was recently supported by the measurement data of several experiments). It is demonstrated that for the special selection of semiconductor materials (S- or Se-doped Si, B-doped diamond) the calculation results using the two theoretical approaches differ significantly and the predicted effects are easily detectable using the existing laboratory setups. In the case that the prediction of the phenomenological approach is confirmed, this would open opportunities to modify the van der Waals and Casimir forces with almost no change of room temperature dielectric permittivity. PMID- 23032184 TI - L-type calcium channel blockade alleviates molecular and reversal spatial learning and memory alterations induced by entorhinal amyloid pathology in rats. AB - The entorhinal cortex (EC) is one of the most vulnerable brain regions that is affected by beta amyloid (Abeta) in the early phases of Alzheimer's disease (AD). Calcium dyshomeostasis is one reason of Abeta pathology and the role of calcium channel blockers (CCBs) in this phenomenon has not fully understood. In this study, we investigated the possible neuroprotective effect of CCBs, nimodipine and isradipine against amyloid pathogenesis in EC. The Abeta 1-42 was injected bilaterally into the EC of male rats and spatial performance was assessed between 7 and 12 days after Abeta injection by Morris water maze test. Animals were daily treated by injection of various doses of nimodipine or isradipine (both at 3, 10, or 30 MUg/2 MUl) or their vehicles into the lateral ventricle until the start of behavioral test. Lesion in EC was assessed by measuring some proteinases involved in calcium dependent apoptotic pathway (calpain 2, caspase 12 and 3). Despite normal performance in probe test, Abeta treated rats showed delayed acquisition in a spatial reference memory task. Abeta treated rats revealed delayed acquisition in reversal memory and had deficit in probe test. The observed impairments were attenuated by isradipine (10 and 30 MUg but not 3 MUg) and nimodipine (30 MUg). Calpain 2, caspase 12 and 3 were increased in the Abeta treated animals which was partially antagonized by isradipine and nimodipine. It is concluded that CCBs might have beneficial therapeutic effects in AD especially in the early phases of this disease. PMID- 23032185 TI - VESSEL CENTERLINE TRACKING AND BOUNDARY SEGMENTATION IN CORONARY MRA WITH MINIMAL MANUAL INTERACTION. AB - Magnetic resonance angiography (MRA) provides a noninvasive means to detect the presence, location and severity of atherosclerosis throughout the vascular system. In such studies, and especially those in the coronary arteries, the vessel luminal area is typically measured at multiple cross-sectional locations along the course of the artery. The advent of fast volumetric imaging techniques covering proximal to mid segments of coronary arteries necessitates automatic analysis tools requiring minimal manual interactions to robustly measure cross sectional area along the three-dimensional track of the arteries in under-sampled and non-isotropic datasets. In this work, we present a modular approach based on level set methods to track the vessel centerline, segment the vessel boundaries, and measure transversal area using two user-selected endpoints in each coronary of interest. Arterial area and vessel length are measured using our method and compared to the standard Soap-Bubble reformatting and analysis tool in in-vivo non-contrast enhanced coronary MRA images. PMID- 23032186 TI - A20 inhibits LUBAC-mediated NF-kappaB activation by binding linear polyubiquitin chains via its zinc finger 7. AB - Linear polyubiquitination of proteins has recently been implicated in NF-kappaB signalling and is mediated by the linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP and Sharpin. However, the mechanisms that regulate linear ubiquitination are still unknown. Here, we show that A20 is rapidly recruited to NEMO and LUBAC upon TNF stimulation and that A20 inhibits LUBAC-induced NF-kappaB activation via its C-terminal zinc-finger 7 (ZF7) domain. Expression of a polypeptide corresponding to only ZF7 was sufficient to inhibit TNF-induced NF-kappaB activation. Both A20 and ZF7 can form a complex with NEMO and LUBAC, and are able to prevent the TNF-induced binding of NEMO to LUBAC. Finally, we show that ZF7 preferentially binds linear polyubiquitin chains in vitro, indicating A20-ZF7 as a novel linear ubiquitin-binding domain (LUBID). We thus propose a model in which A20 inhibits TNF- and LUBAC-induced NF-kappaB signalling by binding to linear polyubiquitin chains via its seventh zinc finger, which prevents the TNF-induced interaction between LUBAC and NEMO. PMID- 23032188 TI - In vivo SELEX reveals novel sequence and structural determinants of Nrd1-Nab3 Sen1-dependent transcription termination. AB - The Nrd1-Nab3-Sen1 (NNS) complex pathway is responsible for transcription termination of cryptic unstable transcripts and sn/snoRNAs. The NNS complex recognizes short motifs on the nascent RNA, but the presence of these sequences alone is not sufficient to define a functional terminator. We generated a homogeneous set of several hundreds of artificial, NNS-dependent terminators with an in vivo selection approach. Analysis of these terminators revealed novel and extended sequence determinants for transcription termination and NNS complex binding as well as supermotifs that are critical for termination. Biochemical and structural data revealed that affinity and specificity of RNA recognition by Nab3p relies on induced fit recognition implicating an alpha-helical extension of the RNA recognition motif. Interestingly, the same motifs can be recognized by the NNS or the mRNA termination complex depending on their position relative to the start of transcription, suggesting that they function as general transcriptional insulators to prevent interference between the non-coding and the coding yeast transcriptomes. PMID- 23032190 TI - Interactions of marine-derived gamma-pyrone natural products with phospholipid membranes. AB - The sacoglossan mollusc-derived metabolite, tridachiahydropyrone (3), and its proposed biosynthetic precursors (1 and 2) form part of a complex chemical defence system against predators and harmful UV light. Here, we provide supporting biophysical evidence that the metabolites become selectively localised at cell membranes and outline a binding scheme that accommodates the observed data. The possibility that localised lipid domains within the membrane have an effect on the localisation is also addressed. PMID- 23032191 TI - Femoral version of the general population: does "normal" vary by gender or ethnicity? AB - OBJECTIVE: The purpose of this study was to compare various gender and ethnic groups to characterize differences in baseline version and rates of retroversion. DESIGN: Retrospective. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Between 2000 and 2009, 417 consecutive patients with femur fractures were treated with an intramedullary nail at level I trauma and tertiary referral center. Of these, 328 with computed tomography scanogram of the normal, uninjured contralateral femur were included in this study. MAIN OUTCOME MEASUREMENTS: Femoral version. RESULTS: The mean alignment for the all patients was 8.84 +/- 9.66 degrees of anteversion. There were no statistically significant differences in mean version between African American, white, and Hispanic patients for males or females. Although there were also no significant differences in rates between ethnicities, retroversion was found to be common in white males (21.4%), African American males (15.1%), and all groups of females (>14.3%). Furthermore, nearly 6% of both African American males and females exhibited >10 degrees retroversion. CONCLUSIONS: Although there may not be a significant difference in average femoral version between ethnic and gender groups, retroversion is relatively common, and retroversion >10 degrees was observed in nearly 6% of the African American population. This may have important implications in proper alignment restoration and successful clinical outcomes after intramedullary nailing of femur fractures. PMID- 23032187 TI - Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-kappaB regulation. AB - LUBAC (linear ubiquitin chain assembly complex) activates the canonical NF-kappaB pathway through linear polyubiquitination of NEMO (NF-kappaB essential modulator, also known as IKKgamma) and RIP1. However, the regulatory mechanism of LUBAC mediated NF-kappaB activation remains elusive. Here, we show that A20 suppresses LUBAC-mediated NF-kappaB activation by binding linear polyubiquitin via the C terminal seventh zinc finger (ZF7), whereas CYLD suppresses it through deubiquitinase (DUB) activity. We determined the crystal structures of A20 ZF7 in complex with linear diubiquitin at 1.70-1.98 A resolutions. The crystal structures revealed that A20 ZF7 simultaneously recognizes the Met1-linked proximal and distal ubiquitins, and that genetic mutations associated with B cell lymphomas map to the ubiquitin-binding sites. Our functional analysis indicated that the binding of A20 ZF7 to linear polyubiquitin contributes to the recruitment of A20 into a TNF receptor (TNFR) signalling complex containing LUBAC and IkappaB kinase (IKK), which results in NF-kappaB suppression. These findings provide new insight into the regulation of immune and inflammatory responses. PMID- 23032192 TI - The neuromuscular junction: selective remodeling of synaptic regulators at the nerve/muscle interface. AB - The peripheral synapses between motoneurons and skeletal muscle fibers, the neuromuscular junctions, are ideal to investigate the general principles of synaptogenesis that depend on the interaction of activity-dependent and activity independent signals. Much has been learned from gene "knock out" mouse models that helped to identify major synaptic regulators. The "knock out" approach, however, may not distinguish between changes arising from the disruption of molecular signaling pathways and changes caused by the absence of synaptic transmission. To circumvent these problems, postsynaptic activity was modulated in mouse models by specifically targeting endplate receptors or the activity of synaptic regulators such as MuSK. Both regulators have multiple functions and acetylcholine receptors are not just signal transducers but regulate the localization and architecture of endplates. The results show that detailed analysis of mouse models will help to understand the complexity in mechanisms that regulate synaptic remodeling. PMID- 23032193 TI - Development of coherent neuronal activity patterns in mammalian cortical networks: common principles and local hetereogeneity. AB - Many mammals are born in a very immature state and develop their rich repertoire of behavioral and cognitive functions postnatally. This development goes in parallel with changes in the anatomical and functional organization of cortical structures which are involved in most complex activities. The emerging spatiotemporal activity patterns in multi-neuronal cortical networks may indeed form a direct neuronal correlate of systemic functions like perception, sensorimotor integration, decision making or memory formation. During recent years, several studies--mostly in rodents--have shed light on the ontogenesis of such highly organized patterns of network activity. While each local network has its own peculiar properties, some general rules can be derived. We therefore review and compare data from the developing hippocampus, neocortex and--as an intermediate region--entorhinal cortex. All cortices seem to follow a characteristic sequence starting with uncorrelated activity in uncoupled single neurons where transient activity seems to have mostly trophic effects. In rodents, before and shortly after birth, cortical networks develop weakly coordinated multineuronal discharges which have been termed synchronous plateau assemblies (SPAs). While these patterns rely mostly on electrical coupling by gap junctions, the subsequent increase in number and maturation of chemical synapses leads to the generation of large-scale coherent discharges. These patterns have been termed giant depolarizing potentials (GDPs) for predominantly GABA-induced events or early network oscillations (ENOs) for mostly glutamatergic bursts, respectively. During the third to fourth postnatal week, cortical areas reach their final activity patterns with distinct network oscillations and highly specific neuronal discharge sequences which support adult behavior. While some of the mechanisms underlying maturation of network activity have been elucidated much work remains to be done in order to fully understand the rules governing transition from immature to mature patterns of network activity. PMID- 23032195 TI - Nitrosobenzene as a hydrogen acceptor in rhodium catalysed dehydrogenation reactions of alcohols: synthesis of aldehydes and azoxybenzenes. AB - Acids, esters and amides have to date been the only isolated products from the dehydrogenation of primary alcohols with [Rh(trop(2)N)(L)] (trop = 5-H dibenzo[a,d]cyclohepten-5yl) type complexes. With the reported method the available product family is finally to aldehydes. Using nitrosobenzene as a hydrogen acceptor the aldehydes could be isolated in up to 96% yield with substrate to catalyst ratios of up to 1000. Nitrosobenzene was found to be reductively coupled to azoxybenzene under the reaction conditions. Several symmetrically substituted azoxybenzene derivatives could be isolated in generally high yields after 2 to 4 h reaction time using a low catalyst loading. PMID- 23032194 TI - Maternal pak4 expression is required for primitive myelopoiesis in zebrafish. AB - Transcripts of pak4, the zebrafish ortholog of p21-activated kinase 4 (PAK4), are most abundant in the egg and fall to low levels by the end of gastrulation, after which expression is essentially ubiquitous. Translation of maternal mRNA into pak4 protein is first detectable at high stage (3.3hpf). Splice-blocking morpholino oligonucleotides (MOs) were used to prevent zygotic pak4 expression. This had no discernable effect on development through larval stages. In contrast, a translation-blocking MO, alone or in combination with the splice MOs, resulted in a complex lethal phenotype. In addition to disrupted somite development and other morphogenetic abnormalities, the knockdown of maternal pak4 expression led to alterations in regulatory gene expression in the primitive hematopoietic domains, leading to deficiencies in granulocyte and leukocyte lineages. At least some of the effects of pak4 knockdown on gene expression could be mimicked by treatment with actin depolymerization agents, suggesting a mechanistic link between regulation of microfilament dynamics by pak4 and regulation of gene expression in primitive myeloid cell differentiation. PMID- 23032196 TI - Acute heart failure: perspectives from a randomized trial and a simultaneous registry. AB - BACKGROUND: Randomized controlled trials (RCT) are limited by their generalizability to the broader nontrial population. To provide a context for Acute Study of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, we designed a complementary registry to characterize clinical characteristics, practice patterns, and in-hospital outcomes of acute heart failure patients. METHODS AND RESULTS: Eligible patients for the registry included those with a principal diagnosis of acute heart failure (ICD-9-CM 402 and 428; ICD-10 I50.x, I11.0, I13.0, I13.2) from 8 sites participating in ASCEND-HF (n=697 patients, 2007-2010). Baseline characteristics, treatments, and hospital outcomes from the registy were compared with ASCEND-HF RCT patients from 31 Canadian sites (n=465, 2007-2010). Patients in the registry were older, more likely to be female, and have chronic respiratory disease, less likely to have diabetes mellitus: they had a similar incidence of ischemic HF, atrial fibrillation, and similar B-type natriuretic peptide levels. Registry patients had higher systolic blood pressure (registry: median 132 mm Hg [interquartile range 115-151 mm Hg]; RCT: median 120 mm Hg [interquartile range 110-135 mm Hg]) and ejection fraction (registry: median 40% [interquartile range 27-58%]; RCT: median 29% [interquartile range 20 40 mm Hg]) than RCT patients. Registry patients presented more often via ambulance and had a similar total length of stay as RCT patients. In-hospital mortality was significantly higher in the registry compared with the RCT patients (9.3% versus 1.3%,P<0.001), and this remained after multivariable adjustment (odds ratio 6.6, 95% CI 2.6-16.8, P<0.001). CONCLUSIONS: Patients enrolled in a large RCT of acute heart failure differed significantly based on clinical characteristics, treatments, and inpatient outcomes from contemporaneous patients participating in a registry. These results highlight the need for context of RCTs to evaluate generalizability of results and especially the need to improve clinical outcomes in acute heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852. PMID- 23032197 TI - N-terminal pro-B-type natriuretic peptide, left ventricular mass, and incident heart failure: Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with clinically overt heart failure (HF). However, whether it provides additive prognostic information for incident HF beyond traditional risk factors and left ventricular (LV) mass index among multi-ethnic asymptomatic individuals has not yet been determined. We studied the associations of plasma NT-proBNP and magnetic resonance imaging defined LV mass index with incident HF in an asymptomatic multi-ethnic population. METHODS AND RESULTS: A total of 5597 multi ethnic participants without clinically apparent cardiovascular disease underwent baseline measurement of NT-proBNP and were followed for 5.5+/-1.1 years. Among them, 4163 also underwent baseline cardiac magnetic resonance imaging. During follow-up, 111 participants experienced incident HF. Higher NT-proBNP was significantly associated with incident HF, independent of baseline age, sex, ethnicity, systolic blood pressure, diabetes mellitus, smoking, estimated glomerular filtration rate, medications (anti-hypertensive and statin), LV mass index, and interim myocardial infarction (hazard ratio: 1.95 per 1U log NT-proBNP increment, 95% CI 1.54-2.46, P<0.001). This relationship held among different ethnic groups, non-Hispanic whites, African-Americans, and Hispanics. Most importantly, NT-proBNP provided additive prognostic value beyond both traditional risk factors and LV mass index for predicting incident HF (integrated discrimination index=0.046, P<0.001; net reclassification index; 6-year risk probability categorized by <3%, 3-10%, >10% =0.175, P=0.019; category-less net reclassification index=0.561, P<0.001). CONCLUSIONS: Plasma NT-proBNP provides incremental prognostic information beyond traditional risk factors and the magnetic resonance imaging-determined LV mass index for incident symptomatic HF in an asymptomatic multi-ethnic population. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005487. PMID- 23032199 TI - Guidelines for periodontal care and follow-up during orthodontic treatment in adolescents and young adults. AB - Aggressive periodontitis is characterized by non-contributory medical history, rapid attachment loss and bone destruction and familial aggregation of cases. Aggressive periodontitis (both localized and generalized) is usually diagnosed in a young population. This is frequently the age that an orthodontic care is provided to this population. The aim of the present paper is to draw guidelines for periodontal evaluation and monitoring prior to and during active orthodontic treatment. Strict adherence to these guidelines as a routine protocol for periodontal examination prior, during and following orthodontic treatment may dramatically decrease the severity and improve the prognosis of patients with aggressive periodontitis in orthodontic clinics. PMID- 23032200 TI - Influence of root canal sealer on the radiographic appearance of filling voids in maxillary single-rooted teeth. AB - OBJECTIVE: This study compared the influence of three epoxy resin-based sealers with distinct radiopacities on the observers' ability to detect root canal filling voids during radiographic analysis. MATERIAL AND METHODS: The root canals of 48 extracted maxillary canines were prepared and divided into three groups. Each group was laterally condensed with one sealer (AH Plus(r), Acroseal(r) or a non-radiopaque sealer), and a longitudinal void was simulated in half of the specimens from each group (n=8). Buccolingual radiographs were obtained and randomly interpreted for voids by a radiologist and an endodontist in a blinded fashion. Teeth were cut and inspected under a microscope to confirm the position of void. Differences in sensitivity and specificity between groups and examiners were compared using the Fisher's Exact and McNemar tests, respectively (alpha=0.05). RESULTS: Significantly lower sensitivity levels (p<0.05) were observed in the coronal portion of fillings performed with both radiopaque sealers. Specificity values for Acroseal(r) were significantly higher (p<0.05) in the coronal and apical portions of fillings. CONCLUSIONS: The type of root canal sealer can affect the observers' ability to detect root canal filling voids during radiographic analysis of upper single-rooted teeth. PMID- 23032201 TI - Calcium glycerophosphate supplemented to soft drinks reduces bovine enamel erosion. AB - OBJECTIVE: This in vitro study evaluated the effect of calcium glycerophosphate (CaGP) supplemented to soft drinks on bovine enamel erosion. MATERIAL AND METHODS: Four pH-cycles were performed, alternating demineralization by the beverage and remineralization in artificial saliva. RESULTS: Mean wear (+/- SD, um) was 7.91 +/- 1.13, 7.39 +/- 1.01, 7.50 +/- 0.91 and 5.21 +/- 1.08 for Coca Cola(r) without CaGP or containing CaGP at 0.1, 1.0 or 2.0 mM, respectively, while no wear was detected for CaGP at 5.0 and 10.0 mM. Corresponding figures for Sprite Zero(r) without CaGP or containing CaGP at 0.1, 1.0, 2.0, 5.0 or 10.0 mM were 8.04 +/- 1.30, 7.84 +/- 0.71, 7.47 +/- 0.80, 4.96 +/- 0.81, 3.99 +/- 0.10 and 1.87 +/- 0.12, respectively. CONCLUSION: Supplementation of both beverages with CaGP seems to be an alternative to reduce their erosive potential. PMID- 23032202 TI - Evaluation of tissue reaction to Aroeira (Myracrodruon urundeuva) extracts: a histologic and edemogenic study. AB - OBJECTIVES: This study evaluated subcutaneous tissue response to Aroeira (Myracrodruon urundeuva) extract employing edemogenic and histological analyses. MATERIAL AND METHODS: Test groups consisted of aqueous and ethanolic Aroeira extracts and saline (control). For edema quantification, 18 rats received an intravenous injection of Evan's Blue. After 30 min, the extracts and saline were injected on the dorsum of the rats, which were then sacrificed after 3 and 6 h. Readings were performed in a spectrophotometer. For subcutaneous implantation, 30 rats received a polyethylene tube containing the extracts on their dorsum and then they were killed after 7 and 28 days. The samples were processed for histological analysis and evaluated with a light microscope. The inflammatory infiltrate was quantified. RESULTS: There were no statistically significant differences between aqueous extract and saline groups in relation to edema quantification in the different periods (p>0.05). Ethanolic solution resulted in more edema independently of the experimental period (p<0.05). Histological analysis showed similar results on the 7-day period for the 3 groups. There was a notable reduction on inflammatory cell number for saline and aqueous extract groups at 28 days. CONCLUSION: The aqueous extract showed biocompatible properties similar to those of saline. PMID- 23032203 TI - Biomechanical in vitro evaluation of three stable internal fixation techniques used in sagittal osteotomy of the mandibular ramus: a study in sheep mandibles. AB - Among the osteotomies performed in orthognathic surgery, the sagittal osteotomy of the mandibular ramus (SOMR) is the most common, allowing a great range of movements and stable internal fixation (SIF), therefore eliminating the need of maxillomandibular block in the postoperative period. OBJECTIVES: The purpose of this study was to evaluate the biomechanical resistance of three national systems used for SIF in SOMR in sheep mandibles. MATERIAL AND METHODS: The study was performed in 30 sheep hemi-mandibles randomly divided into 3 experimental groups, each containing 10 hemi-mandibles. The samples were measured to avoid discrepancies and then subjected to SOMR with 5-mm advancement. In group I, 2.0x12 mm screws were used for fixation, inserted in an inverted "L" pattern (inverted "L" group). In group II, fixation was performed with two 2.0x12 mm screws, positioned in a linear pattern and a 4-hole straight miniplate and four 2.0x6.0 mm monocortical screws (hybrid group). In group III, fixation was performed with two 4-hole straight miniplates and eight 2.0x6.0 mm monocortical screws (mini plate group). All materials used for SIF were supplied by Osteosin - SIN. The hemimandibles were subjected to vertical linear load test by Kratos K2000MP mechanical testing unit for loading registration and displacement. RESULTS: All groups showed similar resistance during mechanical test for loading and displacement, with no statistically significant differences between groups according to analysis of variance. CONCLUSION: These results indicate that the three techniques of fixation are equally effective for clinical fixation of SOMR. PMID- 23032204 TI - Finite element analysis and fracture resistance testing of a new intraradicular post. AB - OBJECTIVES: The objective of the present study was to evaluate a prefabricated intraradicular threaded pure titanium post, designed and developed at the Sao Jose dos Campos School of Dentistry - UNESP, Brazil. This new post was designed to minimize stresses observed with prefabricated post systems and to improve cost benefits. MATERIAL AND METHODS: Fracture resistance testing of the post/core/root complex, fracture analysis by microscopy and stress analysis by the finite element method were used for post evaluation. The following four prefabricated metal post systems were analyzed: group 1, experimental post; group 2, modification of the experimental post; group 3, Flexi Post, and group 4, Para Post. For the analysis of fracture resistance, 40 bovine teeth were randomly assigned to the four groups (n=10) and used for the fabrication of test specimens simulating the situation in the mouth. The test specimens were subjected to compressive strength testing until fracture in an EMIC universal testing machine. After fracture of the test specimens, their roots were sectioned and analyzed by microscopy. For the finite element method, specimens of the fracture resistance test were simulated by computer modeling to determine the stress distribution pattern in the post systems studied. RESULTS: The fracture test presented the following averages and standard deviation: G1 (45.63 +/- 8.77), G2 (49.98 +/- 7.08), G3 (43.84 +/- 5.52), G4 (47.61 +/- 7.23). Stress was homogenously distributed along the body of the intraradicular post in group 1, whereas high stress concentrations in certain regions were observed in the other groups. These stress concentrations in the body of the post induced the same stress concentration in root dentin. CONCLUSIONS: The experimental post (original and modified versions) presented similar fracture resistance and better results in the stress analysis when compared with the commercial post systems tested (08/2008-PA/CEP). PMID- 23032205 TI - Comparative clinical study of the effectiveness of different dental bleaching methods - two year follow-up. AB - This study evaluated color change, stability, and tooth sensitivity in patients submitted to different bleaching techniques. MATERIAL AND METHODS: In this study, 48 patients were divided into five groups. A half-mouth design was conducted to compare two in-office bleaching techniques (with and without light activation): G1: 35% hydrogen peroxide (HP) (Lase Peroxide - DMC Equipments, Sao Carlos, SP, Brazil) + hybrid light (HL) (LED/Diode Laser, Whitening Lase II DMC Equipments, Sao Carlos, SP, Brazil); G2: 35% HP; G3: 38% HP (X-traBoost - Ultradent, South Jordan UT, USA) + HL; G4: 38% HP; and G5: 15% carbamide peroxide (CP) (Opalescence PF - Ultradent, South Jordan UT, USA). For G1 and G3, HP was applied on the enamel surface for 3 consecutive applications activated by HL. Each application included 3x3' HL activations with 1' between each interval; for G2 and G4, HP was applied 3x15' with 15' between intervals; and for G5, 15% CP was applied for 120'/10 days at home. A spectrophotometer was used to measure color change before the treatment and after 24 h, 1 week, 1, 6, 12, 18 and 24 months. A VAS questionnaire was used to evaluate tooth sensitivity before the treatment, immediately following treatment, 24 h after and finally 1 week after. RESULTS: Statistical analysis did not reveal any significant differences between in-office bleaching with or without HL activation related to effectiveness; nevertheless the time required was less with HL. Statistical differences were observed between the results after 24 h, 1 week and 1, 6, 12, 18 and 24 months (intergroup). Immediately, in-office bleaching increased tooth sensitivity. The groups activated with HL required less application time with gel. CONCLUSION: All techniques and bleaching agents used were effective and demonstrated similar behaviors. PMID- 23032206 TI - Methylparaben concentration in commercial Brazilian local anesthetics solutions. AB - OBJECTIVE: To detect the presence and concentration of methylparaben in cartridges of commercial Brazilian local anesthetics. MATERIAL AND METHODS: Twelve commercial brands (4 in glass and 8 in plastic cartridges) of local anesthetic solutions for use in dentistry were purchased from the Brazilian market and analyzed. Different lots of the commercial brands were obtained in different Brazilian cities (Piracicaba, Campinas and Sao Paulo). Separation was performed using high performance liquid chromatography (HPLC) with UV-Vis detector. The mobile phase used was acetonitrile:water (75:25 - v/v), pH 4.5, adjusted with acetic acid at a flow rate of 1.0 ml.min-1. RESULTS: When detected in the solutions, the methylparaben concentration ranged from 0.01% (m/v) to 0.16% (m/v). One glass and all plastic cartridges presented methylparaben. CONCLUSION: 1. Methylparaben concentration varied among solutions from different manufacturers, and it was not indicated in the drug package inserts; 2. Since the presence of methylparaben in dental anesthetics is not regulated by the Brazilian National Health Surveillance Agency (ANVISA) and this substance could cause allergic reactions, it is important to alert dentists about its possible presence. PMID- 23032207 TI - Dentine microhardness after different methods for detection and removal of carious dentine tissue. AB - There are several methods for identifying carious dentinal tissue aiming to avoid removal of healthy dentinal tissue. OBJECTIVES: The purpose of this study was to test different methods for the detection of carious dentinal tissue regarding the amount of carious tissue removed and the remaining dentin microhardness after caries removal. MATERIAL AND METHODS: The dentin surfaces of 20 bovine teeth were exposed and half of the surface was protected with nail polish. Cariogenic challenge was performed by immersion in a demineralizing solution for 14 days. After transverse cross-section of the crown, the specimens were divided into four groups (n=10), according to the method used to identify and remove the carious tissue: "Papacarie", Caries-detector dye, DIAGNOdent and Tactile method. After caries removal, the cross-sectional surface was included in acrylic resin and polished. In a microhardness tester, the removed dentin thickness and the Vickers microhardness of the following regions were evaluated: remaining dentin after caries removal and superficial and deep healthy dentin. RESULTS: ANOVA and Tukey's test (alpha=0.05) were performed, except for DIAGNOdent, which did not detect the presence of caries. Results for removed dentin thickness were: "Papacarie" (424.7 +/- 105.0; a), Caries-detector dye (370.5 +/- 78.3; ab), Tactile method (322.8 +/- 51.5; bc). Results for the remaining dentin microhardness were: "Papacarie" (42.2 +/- 10.5; bc), Caries-detector dye (44.6 +/ 11.8; abc), Tactile method (24.3 +/- 9.0; d). CONCLUSIONS: DIAGNOdent did not detect the presence of carious tissue; Tactile method and "Papacarie" resulted in the least and the most dentinal thickness removal, respectively; Tactile method differed significantly from "Papacarie" and Caries-detector dye in terms of the remaining dentin microhardness, and Tactile method was the one which presented the lowest microhardness values. PMID- 23032208 TI - Physicochemical properties of endodontic sealers of different bases. AB - OBJECTIVE: To assess the setting time (ST), flow (FL), radiopacity (RD), solubility (SB) and dimensional change following setting (DC) of different sealers (AH Plus(r), Polifil, Apexit Plus(r), Sealapex(r), Endomethasone(r) and Endofill(r)) according to American National Standards Institute/American Dental Association (ANSI/ADA) Specification 57. MATERIAL AND METHODS: Five samples of each material were used for each test. For ST, cast rings were filled with sealers and tested with a Gilmore needle. For FL, the sealer was placed on a glass plate. After 180 s, another plate with 20 g and a load of 100 g were applied on the material, and the diameters of the discs formed were measured. In RD, circular molds were filled with the sealers, radiographed and analyzed using Digora software. For SB, circular molds were filled with the sealers, a nylon thread was placed inside the material and another glass plate was positioned on the set, pressed and stored at 37 degrees C. Samples were weighed, placed in water, dried and reweighed. The water used for SB was analyzed by atomic absorption spectrometry. For DC, circular molds were filled with the sealers, covered by glass plates and stored at 37 degrees C. Samples were measured and stored in water for 30 days. After this period, they were dryed and measured again. RESULTS: Regarding ST, AH Plus(r), Apexit(r) and Endofil(r) sealers are in accordance with ANSI/ADA standards. Endomethasone's manufacturer did not mention the ST; Polifil is an experimental sealer and Sealapex(r) did not set. Considering RD, SB and DC, all sealers were in accordance with ANSI/ADA. The spectrometric analysis showed that a significant amount of K+ and Zn2+ ions was released from Apexit Plus(r) and Endofill(r), respectively. CONCLUSION: Except for DC, all other physicochemical properties of the tested sealers conformed to ANSI/ADA requirements. PMID- 23032209 TI - Influence of exogenous pigmentation on the optical properties of orthodontic elastic ligatures. AB - OBJECTIVES: The aim of this study was to assess the optical properties of orthodontic elastic ligatures under the influence of exogenous pigments contained in the daily diet. MATERIAL AND METHODS: For the analysis, colorless (clear) elastic segments (ORTHO Organizers, lot 660625A10) were used as received from the manufacturer, and were divided into 8 groups of 3 segments each. Each group was immersed in 200 mL of a solution containing a determined substance, as follows: distilled water (control group), Coca-Cola(r), Pomarola brand tomato sauce (Cica(r)), acai, Jasmine(r) brand green tea, Royal Blend(r) black tea brand, Pilao(r) brand coffee and Palmares(r) wine brand. All test specimens were immersed in the solutions and kept in an appropriate receptacle for 7 days at 37 degrees C14. After the staining session, the test specimens were washed with distilled water in an ultrasonic vat for 5 min and dried with paper tissues6. The portable digital spectrophotometer Vita Easyshade Compact was used to assess if there was color variation of the test specimens. This variation was quantified and qualified at the initial time (T0) and after staining (T1). RESULTS: These results were analyzed statistically using the software SPSS version 18.0. The Shapiro-Wilk test of normality was applied followed by the one-way analysis of variance and the Tukey's post hoc test. The level of significance adopted was 5%. CONCLUSIONS: From the substances evaluated in this study, those with higher staining potential on esthetic elastic ligatures were black tea, coffee and wine, respectively. Knowing this information, the dentist may advise their patients to avoid certain foods because of elastic staining may occur thus decreasing the aesthetics of the material. PMID- 23032210 TI - Buccal cells DNA extraction to obtain high quality human genomic DNA suitable for polymorphism genotyping by PCR-RFLP and Real-Time PCR. AB - OBJECTIVE: The aim of this study was to evaluate, by PCR-RFLP and real-time PCR, the yield and quality of genomic DNA collected from buccal cells by mouthwash after different storage times at room temperature. MATERIAL AND METHODS: A group of volunteers was recruited to collect buccal cells using a mouthwash solution. The collected solution was divided into 3 tubes, one tube were used for immediate extraction and the remaining received ethanol and were kept at room temperature for 4 and 8 days followed by dna extraction. The concentration, purity and integrity of the dna were determined using spectrophotometry and electrophoresis. DNA quality differences among the three incubation times were also evaluated for genotyping EGF +61 a/g (rs 4444903) polymorphism by PCR-RFLP and for IRF6 polymorphism (rs 17015215) using real-time PCR. RESULTS: There was no significant difference of dna yield (p=0.75) and purity (p=0.86) among the three different incubation times. DNA obtained from different incubation times presented high molecular weight. The PCR-RFLP and real time pcr reactions were successfully performed for all DNA samples, even those extracted after 8 days of incubation. All samples genotyped by real-time pcr presented c allele for irf6 gene polymorphism (homozygous: cc; heterozygous: Ct) and the C allele was used as a reference for Ct values. The samples presented the same genotype for the different times in both techniques. CONCLUSION: We demonstrated that the method described herein is simple and low cost, and that DNA can be extracted and pcr amplified after storage in mouthwash solution at room temperature. PMID- 23032212 TI - Retrieval analysis of different orthodontic brackets: the applicability of electron microprobe techniques for determining material heterogeneities and corrosive potential. AB - OBJECTIVE: The objective of this study was to investigate the applicability of micro-analytical methods with high spatial resolution to the characterization of the composition and corrosion behavior of two bracket systems. MATERIAL AND METHODS: The surfaces of six nickel-free brackets and six nickel-containing brackets were examined for signs of corrosion and qualitative surface analysis using an electron probe microanalyzer (EPMA), prior to bonding to patient's tooth surfaces and four months after clinical use. The surfaces were characterized qualitatively by secondary electron (SE) images and back scattered electron (BSE) images in both compositional and topographical mode. Qualitative and quantitative wavelength-dispersive analyses were performed for different elements, and by utilizing qualitative analysis the relative concentration of selected elements was mapped two-dimensionally. The absolute concentration of the elements was determined in specially prepared brackets by quantitative analysis using pure element standards for calibration and calculating correction-factors (ZAF). RESULTS: Clear differences were observed between the different bracket types. The nickel-containing stainless steel brackets consist of two separate pieces joined by a brazing alloy. Compositional analysis revealed two different alloy compositions, and reaction zones on both sides of the brazing alloy. The nickel free bracket was a single piece with only slight variation in element concentration, but had a significantly rougher surface. After clinical use, no corrosive phenomena were detectable with the methods applied. Traces of intraoral wear at the contact areas between the bracket slot and the arch wire were verified. CONCLUSION: Electron probe microanalysis is a valuable tool for the characterization of element distribution and quantitative analysis for corrosion studies. PMID- 23032211 TI - Water sorption of CH3- and CF3-Bis-GMA based resins with additives. AB - OBJECTIVES: To evaluate the effect of additives on the water sorption characteristics of Bis-GMA based copolymers and composites containing TEGDMA, CH3Bis-GMA or CF3Bis-GMA. MATERIAL AND METHODS: Fifteen experimental copolymers and corresponding composites were prepared combining Bis-GMA and TEGDMA, CH3Bis GMA or CF3Bis-GMA, with aldehyde or diketone (24 and 32 mol%) totaling 30 groups. For composites, barium aluminosilicate glass and pyrogenic silica was added to comonomer mixtures. Photopolymerization was effected by 0.2 wt% each of camphorquinone and N,N-dimethyl-p-toluidine. Specimen densities in dry and water saturated conditions were obtained by Archimedes' method. Water sorption and desorption were evaluated in a desorption-sorption-desorption cycle. Water uptake (%WU), water desorption (%WD), equilibrium solubility (ES; ug/mm3), swelling (f) and volume increase (%V) were calculated using appropriate equations. RESULTS: All resins with additives had increased %WU and ES. TEGDMA-containing systems presented higher %WU, %WD, ES, f and %V values, followed by resins based on CH3Bis-GMA and CF3Bis-GMA. CONCLUSIONS: Aldehyde and diketone led to increases in the water sorption characteristics of experimental resins. PMID- 23032213 TI - Serial extraction: 20 years of follow-up. AB - This paper reports a case treated by a serial extraction program at the mixed dentition stage followed by a corrective orthodontic treatment, with a long-term follow-up period. Twenty years after the interceptive treatment, a harmonious face was observed along with treatment stability in the anterior posterior direction, deep overbite (which has been mentioned as a disadvantage of the serial extraction program), and a small relapse of anterior tooth crowding. All these conditions have been regarded as normal occurrences for most orthodontic treatments with a long-term follow-up period. This case report demonstrated that the establishment of a serial extraction protocol determined relevant esthetic changes that afforded an improvement of the patient's self-esteem, with a positive social impact. Furthermore, the low cost of this protocol permits the use of this therapy with underprivileged populations. It is important to emphasize that an early correction of tooth crowding by this protocol does not guarantee stability, but small relapses do not invalidate its accomplishment. PMID- 23032214 TI - The furan route to tropolones: probing the antiproliferative effects of beta thujaplicin analogs. AB - A direct route to analogs of the naturally occurring tropolone beta-thujaplicin has been developed in just four steps from furan. Using this method, a series of derivatives were synthesized and evaluated. Several of these compounds demonstrated very high levels of potency against bacterial and fungal pathogens with good selectivity over mammalian cells. PMID- 23032216 TI - Backscattering from width variations in quasi-one-dimensional strips of topological insulators. AB - Conductance modulations in wide-narrow-wide electron waveguides constructed from a two-dimensional topological insulator are investigated numerically. The conductance exhibits the Fabry-Perot oscillation at the opening of the helical edge states in the narrow segment when the potential offset imposed in the segment is varied. The quantum multiple reflections between the two ends of the narrow segment manifested by the oscillation demonstrate that the topological states are not protected from the scattering caused by an abrupt change in the channel width. The bulk states do not affect the vulnerability against the geometry scattering but they give rise to resonant transmission in an unconventional fashion. PMID- 23032215 TI - Linezolid-containing regimens for the treatment of drug-resistant tuberculosis in South African children. AB - BACKGROUND: Treatment options for drug-resistant tuberculosis (DR-TB) are limited. Linezolid has been successfully used to treat DR-TB in adults, but there are few case reports of its use in children for TB. The reported rate of adverse events in adults is high. METHODS: We conducted a retrospective review of children with DR-TB treated with linezolid-containing regimens from February 2007 to March 2012 at two South African hospitals. RESULTS: Seven children (three human immunodeficiency virus [HIV] infected) received a linezolid-containing regimen. All had culture-confirmed DR-TB; five had previously failed second-line anti-tuberculosis treatment. Four children were cured and three were still receiving anti-tuberculosis treatment, but had culture converted. None of the non HIV-infected children experienced adverse events while receiving linezolid. Three HIV-infected children had adverse events, one of which was life-threatening; linezolid was permanently discontinued in this case. Adverse events included lactic acidosis (n = 1), pancreatitis (n = 2), peripheral neuropathy (n = 1) and asymptomatic bone marrow hypoplasia (n = 1). CONCLUSION: Linezolid-containing regimens can be effective in treating children with DR-TB even after failing second-line treatment. Adverse events should be monitored, especially in combination with medications that have similar adverse effects. Linezolid remains costly, and a reduced dosage and duration may result in fewer adverse events and lower cost. PMID- 23032218 TI - Multiphase modelling of vascular tumour growth in two spatial dimensions. AB - In this paper we present a continuum mathematical model of vascular tumour growth which is based on a multiphase framework in which the tissue is decomposed into four distinct phases and the principles of conservation of mass and momentum are applied to the normal/healthy cells, tumour cells, blood vessels and extracellular material. The inclusion of a diffusible nutrient, supplied by the blood vessels, allows the vasculature to have a nonlocal influence on the other phases. Two-dimensional computational simulations are carried out on unstructured, triangular meshes to allow a natural treatment of irregular geometries, and the tumour boundary is captured as a diffuse interface on this mesh, thereby obviating the need to explicitly track the (potentially highly irregular and ill-defined) tumour boundary. A hybrid finite volume/finite element algorithm is used to discretise the continuum model: the application of a conservative, upwind, finite volume scheme to the hyperbolic mass balance equations and a finite element scheme with a stable element pair to the generalised Stokes equations derived from momentum balance, leads to a robust algorithm which does not use any form of artificial stabilisation. The use of a matrix-free Newton iteration with a finite element scheme for the nutrient reaction-diffusion equations allows full nonlinearity in the source terms of the mathematical model. Numerical simulations reveal that this four-phase model reproduces the characteristic pattern of tumour growth in which a necrotic core forms behind an expanding rim of well-vascularised proliferating tumour cells. The simulations consistently predict linear tumour growth rates. The dependence of both the speed with which the tumour grows and the irregularity of the invading tumour front on the model parameters is investigated. PMID- 23032219 TI - Fibrillar structure and elasticity of hydrating collagen: a quantitative multiscale approach. AB - It is well known that hydration of collagenous tissues leads to their swelling, as well as to softening of their elastic behavior. However, it is much less clear which microstructural and micromechanical "rules" are involved in this process. Here, we develop a theoretical approach cast in analytical mathematical formulations, which is experimentally validated by a wealth of independent tests on collagenous tissues, such as X-ray diffraction, vacuum drying, mass measurements, and Brillouin light scattering. The overall emerging picture is the following: air-drying leaves water only in the gap zones between the triple helical collagen molecules; upon re-hydration, the extrafibrillar space is established at volumes directly proportional to the hydration-induced swelling of the (micro) fibrils, until the maximum equatorial distance between the long collagen molecules is reached. Thereafter, the volume of the fibrils stays constant, and only the extrafibrillar volume continues to grow. At all these hydration stages, the elastic behavior is governed by the same, hydration invariant mechanical interaction pattern of only two, interpenetrating mechanical phases: transversely isotropic molecular collagen and isotropic water (or empty pores in the vacuum-dried case). PMID- 23032220 TI - Endodontic management of three-rooted maxillary first and second premolars: a case report. AB - A thorough knowledge of root canal anatomy is essential for successful root canal treatment, because the number of roots and root canals in any tooth can vary. Failing to detect an extra root or canal can cause root canal treatment to fail. It is essential that clinicians interpret radiographs correctly to detect any anatomic variations and treat them successfully. Anatomic variations occur frequently in the root canal system of maxillary premolars; however, the presence of three separate root canals with three independent roots is rare. This article presents an unusual case of three-rooted maxillary first and second premolars, each with three distinct root canals. PMID- 23032221 TI - High energy words. PMID- 23032222 TI - Implant-retained removable partial dentures. AB - Providing the patient with an implant-retained RPD is fully within the prosthetic capability of most dentists, giving them an opportunity to treat their patients economically and without referral to a specialist. It is the author's experience that patients respond favorably to treatment recommendations for this type of prosthesis and are able to function far better than they would with conventional RPDs. PMID- 23032223 TI - Revisiting impressions using dual-arch trays. AB - Making routine perfect impressions is the goal of any restorative dentist. Using dual-arch trays is an easy, repeatable way to accomplish that goal, as long as each step is done before the next and each step is performed perfectly. This column reviewed several articles that support the metal dual-arch concept and provided some clinical tips that might help restorative dentists. The dual-arch technique does have its limits and is meant for one or two teeth in a quadrant when there are other teeth to occlude with. Also, if the case involves anterior guidance, a full-arch impression maybe advisable. PMID- 23032224 TI - A comparison of bleeding with and without warfarin and aspirin during single tooth extractions in cardiovascular patients. PMID- 23032225 TI - The evolution of dental caries treatment. PMID- 23032226 TI - Applications of CBCT in dental practice: a review of the literature. AB - This article reviews the various clinical applications of cone-beam computed tomography (CBCT). A literature search was conducted via PubMed for publications related to dental applications of CBCT published between January 1998 and June 15, 2010. The search revealed a total of 540 articles, 129 of which were clinically relevant and analyzed in detail. A literature review demonstrated that CBCT has been utilized for oral and maxillofacial surgery, endodontics, implantology, orthodontics, temporomandibular joint dysfunction, periodontics, and restorative and forensic dentistry. This literature review showed that the different indications for CBCT are governed by the needs of the specific dental discipline and the type of procedure performed. PMID- 23032227 TI - Comprehensive management of an orthognathic surgery patient with aggressive central giant cell granuloma of the mandible. AB - This article presents a case involving a 16-year-old boy who came to the Tripler Army Medical Center Oral and Maxillofacial Surgery with a central giant cell granuloma (CGCG) on the anterior mandible. Initial management consisted of surgical curettage and intralesional injection of corticosteroids. Upon completion of steroid therapy, there was clinical and radiographic evidence of remission; however, radiographic evidence of lesion recurrence was seen at a six month follow-up visit. The CGCG was retreated with curettage and five months of systemic injections of calcitonin, both of which failed. The lesion was most likely an aggressive form of CGCG that progressed despite conservative therapy, with destruction of hard and soft tissues, root resorption, tooth displacement, and paraesthesia in the anterior mandible. The authors present a treatment algorithm with comprehensive management involving surgical resection, reconstruction, orthodontics, and orthognathic surgery with prosthodontic considerations. PMID- 23032228 TI - A simple radiographic approach to maxillary pathologies. AB - This article describes an intraoral radiographic technique for identifying lesions located on the buccal surfaces of the maxillary alveolar process. An intraoral film is placed behind the maxillary tuberosity and the X-ray beam exposes the film perpendicularly, running laterally to the buccal surface of the cortical bone. As a result, any external alteration can be seen clearly, with no superimposed maxillary teeth or osseous tissues. PMID- 23032229 TI - Oral pigmentation: case report and review of malignant melanoma with flow charts for diagnosis and treatment. AB - The color of the human oral mucosa is not uniform. Chromatic variations can occur, depending on the degree of keratinization, melanogenic activity, number of melanocytes, vascularization, and type of submucosal tissue. If a pathological pigmentation is suspected, its benign or malignant nature will guide the treatment plan. This article presents a rare case of malignant melanoma of the anterior maxilla with asymptomatic palatal pigmentation and regional lymph node metastasis. Flow charts for the diagnosis and treatment of pigmented lesions (with special emphasis on treatment of primary and metastatic melanoma) are included. PMID- 23032230 TI - Morphological variations of the hamular process as visualized on adult bitewing radiographs. AB - The hamular process is the hook-like projection arising from the inferior aspect of the medial pterygoid plate of the sphenoid bone. It is regarded as a dynamic ossified projection, changing in length, width, and shape as patients age. To extend the knowledge of this structure, several radiographic examples are provided and various associated pain disorders and relevant clinical findings are reviewed. PMID- 23032232 TI - Multifocal radiolucencies with radiopacities. Florid cemento-osseous dysplasia. PMID- 23032231 TI - What every dentist should know about bisphenol A. AB - Bisphenol A (BPA) is a common industrial chemical that has been associated with a variety of biological disorders. From the unborn to the elderly, BPA affects every demographic of the population; however, its potential long-term effects on prenatal and prepubescent development have led to concern about its use in the field of pediatrics. Because BPA is omnipresent in modern society, the use of BPA derivatives (such as Bis-GMA and Bis-DMA) in dental materials in general, and acrylic resins in particular, will be increasingly examined as research continues to implicate BPA in a number of biological disorders. PMID- 23032233 TI - Image-based evaluation of facial fractures in a child using computed tomography. AB - This article describes the case of a boy who had a fracture of the mandibular parasymphysis region associated with a fracture of the contralateral condyle. Panoramic and computed tomography images were used to monitor bone remodeling. PMID- 23032234 TI - Comparative evaluation of the efficacy of turmeric and curcumin as a local drug delivery system: a clinicomicrobiological study. AB - When host defense mechanisms fail to contain or eliminate pathogenic periodontal microflora, an exaggerated host response releases inflammatory mediators, which in turn destroy soft and hard tissue components of the periodontium. This in vitro and in vivo study comparatively evaluated the adjunctive efficacy of turmeric, curcumin, and traditional nonsurgical methods for treating periodontal pockets. Turmeric and curcumin chips were prepared and the in vitro release pattern was estimated using a Keshary-Chien diffusion reaction. At 24 hours, the in vitro release pattern showed that 70% of turmeric was released, compared to 78% for curcumin chips. At 72 hours, these levels had increased to 78% of turmeric and 80% of curcumin. By the end of 80 hours, 100% of drug release had taken place. Plaque index and gingival index scores showed significant improvement from baseline through the end of the study. PMID- 23032235 TI - Five-year retrospective study involving the laser-assisted periodontal therapy. AB - This article outlines a five-year retrospective study involving a diode dental laser used on periodontally infected teeth. The present study utilized a specific protocol: scaling and root planing, light ultrasonic scaling, and the use of a diode laser. In 80% of cases, pocket depth of 3 mm or less was maintained. PMID- 23032236 TI - Fracture resistance of fixed partial dentures supported by different abutment combinations: an ex vivo study. AB - This study sought to compare the fracture resistance of and categorize failure modes exhibited by fixed partial dentures (FPDs) supported by natural teeth, implants, or mixed tooth-implant abutments. Three groups utilized three different abutment combinations: all natural teeth, all implants, and a mixture of teeth and implants. The teeth were prepared and zero-angled titanium abutments were installed over the implants. Standardized conventional three-unit porcelain-fused to-metal FPDs were fabricated, following the conventional ceramic build-up technique. The inner surfaces of the bridges were air-abraded (50 MUm Aluminum Oxide at 80 psi), cleaned in an ultrasonic bath for 10 minutes, and cemented over abutments using glass ionomer cement. The FPDs were fixed in a universal testing machine and compressed to fracture using a three-unit metal block at a 5 mm/minute crosshead speed. Fracture loads ranged from 460 to 5,700 N. Bridges supported by either implant abutments only or mixed implant-tooth abutments showed higher fracture loads (2,940 and 3,390 N, respectively) than those supported entirely by natural teeth (1,386 N) (p < 0.05). However, fracture of the veneering porcelain was common among all types of abutments. PMID- 23032237 TI - Diagnosing, managing, and preventing cracked tooth syndrome. AB - Cracked tooth syndrome (CTS) can be a perplexing disorder to diagnose and manage. Many practitioners wonder whether the latest dental materials and adhesives can or should be used when restoring these teeth. The authors reviewed the literature and developed recommendations for how to diagnose and manage CTS and prevent it in susceptible teeth. As the population continues to age and people retain their teeth longer, it is anticipated that patients will present even more frequently with symptoms of CTS. PMID- 23032238 TI - Efficacy of calcium sodium phosphosilicate in managing dentinal hypersensitivity. AB - A large number of home use products have been tested and used for managing dentinal hypersensitivity. This eight-week clinical trial compared the temporal efficacy of a commercially available toothpaste containing calcium sodium phosphosilicate to that of a toothpaste containing potassium nitrate. For this study, 20 subjects (age 18 - 65) were screened using a visual analog scale (VAS) for sensitivity to a cold stimulus. Baseline VAS sensitivity scores to tactile stimulus were recorded for a minimum of two teeth per patient. Dentifrices were prescribed for all patients and sensitivity scores were re-evaluated at two, four, and eight weeks. Though both groups showed significant reductions in sensitivity scores, only at eight weeks was there a marginally significant difference (p = 0.0551) in sensitivity scores between the test group and the positive control group. PMID- 23032239 TI - The efficacy of acid etching for removing contamination in layered dental restorations. AB - Contamination between incremental layers of a composite resin restoration can occur during surgical procedures. The present study sought to evaluate how two decontamination treatments affected the shear bond strength between layers of a saliva-contaminated composite resin surface. Forty disks of a nanohybrid composite resin were prepared and divided into four groups (n = 10). The surfaces of all specimens (except for samples in Group 1, the positive control) were contaminated with human saliva. For the negative control samples (Group 2), no decontamination was performed. For Group 3 samples, acid etching was performed and adhesive was applied. For Group 4, surfaces were roughened with a diamond bur prior to acid etching and adhesive application. The specimens were submitted to a shear bond strength test, and the data were analyzed using one-way ANOVA and Tukey tests (alpha = 0.05). No significant differences were detected between the mean shear bond strengths of samples in Groups 1, 3, and 4 (p < 0.05). Shear bond strength was significantly reduced in Group 2 samples (p < 0.05). Acid etching and the application of adhesive improved shear bond strength, producing values similar to those in the positive control group. PMID- 23032240 TI - Effect of ceramic surface treatment on the shear bond strength of a resin cement to different ceramic systems. AB - This study evaluated three surface treatments and their effect on the shear bond strength between a resin cement and one of three ceramics. The ceramic surfaces were evaluated with scanning electron microscopy (SEM) as well. Specimens were treated with 50 MUm aluminum oxide airborne particles, 10% hydrofluoric acid etching, or a combination of the two. Using a matrix with a center hole (5.0 mm x 3.0 mm), the ceramic bonding areas were filled with resin cement following treatment. The specimens were submitted to thermal cycling (1,000 cycles) and the shear bond strength was tested (0.5 mm/minute). The failure mode and the effect of surface treatment were analyzed under SEM. Data were submitted to ANOVA and a Tukey test (alpha = 0.05). Duceram Plus and IPS Empress 2 composite specimens produced similar shear bond strength results (p > 0.05), regardless of the treatment method used. Hydrofluoric acid decreased the shear bond strength of In Ceram Alumina specimens. For all materials, surface treatments changed the morphological surface. All treatments influenced the shear bond strength and failure mode of the ceramic/resin cement composites. PMID- 23032241 TI - Color stability of repaired composite submitted to accelerated artificial aging. AB - The aim of this study was to evaluate the color stability (DeltaE) of nanoparticulate composite, with consideration for the type of surface treatment performed before repair. A Teflon matrix was used to fabricate 50 test specimens from composite. After initial color readout, the specimens were submitted to 100 hours of accelerated artificial aging (AAA). The samples were divided into five groups (n = 10), according to the surface treatment performed: sandblasting with aluminum oxide powder, phosphoric acid, and an adhesive system (Group 1); sandblasting with aluminum oxide powder, phosphoric acid, and a flowable composite (Group 2); abrasion with a diamond bur, phosphoric acid, and an adhesive system (Group 3); abrasion with a diamond bur, phosphoric acid, and a nanoparticulate composite (Group 4); and a control group (Group 5). After repair, a new color readout was taken, the test specimens were submitted to a new AAA cycle (300 hours), and the final color readout was taken. Comparison of the DeltaE means (one-way ANOVA and Tukey tests, p < 0.05) demonstrated no statistically significant differences among the groups (p > 0.05) after 100 hours of AAA. After repair, Group 1 (4.61 +/- 2.03) presented the highest color alteration with a statistically significant difference compared with the other groups (p < 0.05). After 300 hours, Group 4 specimens (13.84 +/- 0.71) presented the lowest color alteration in comparison with the other groups, with a statistically significant difference (p < 0.05). It was concluded that the repair performed in Group 4 provided greater esthetic recovery, made possible by the regression in the DeltaE values of the restorations after repair, and less color alteration of the restorations over the course of time. PMID- 23032242 TI - Tobacco use and health risks in two dental clinic populations: Implementation and evaluation of a brief targeted intervention. AB - The present study compared emergency dental clinic and hygiene clinic patients in terms of tobacco use and health risks, and began and evaluated an Ask/Advise/Refer intervention in the emergency clinic. Randomly selected records (N = 820) of patients from both clinics were reviewed and demographics, tobacco, and health data were recorded and analyzed. After a brief training period, student dentists delivered a five-week emergency clinic tobacco intervention and completed a post-intervention evaluation survey. Tobacco use was higher in the emergency clinic and was correlated with systemic and oral disease. Of the 327 emergency clinic patients seen during the pilot study, 50% were smokers, 46% of whom expressed an interested in quitting and 35% of whom obtained cessation referral. Thirty students (86%) completed the evaluation; perceptions of the intervention were neutral to favorable. The emergency clinic Ask/Advise/Refer intervention was well-received by patients and clinicians. PMID- 23032243 TI - Prevalence of taurodontism in primary mandibular first molars of ethnic Indian children. AB - The objective of this study was to determine the prevalence of taurodontism in primary mandibular first molars in ethnic Indian children using periapical radiographs. Periapical radiographs of 274 children obtained from December 2008 to August 2010 were retrospectively screened and examined. Radiographs of 196 patients (99 boys and 97 girls; ages 2.5-10.5) with bilateral primary mandibular first molars were randomly selected and evaluated. The gender, symmetry, and frequencies of occurrence of taurodont primary mandibular first molars were compared and the obtained data were statistically analyzed using the x2 test. Eight (4.08%) taurodont primary mandibular first molars were found with a bilateral incidence of a symmetrical distribution of 38% (3/8). The prevalence of taurodontism in primary mandibular first molars did not differ significantly between right and left sides or with gender (P >= 0.05). The results of the present study indicate that approximately 4% of Indian children had taurodontism in primary mandibular first molars. Clinicians should be aware of the prevalence of this anatomic variant in primary mandibular first molars among the Indian population for early identification of taurodonts and for rendering the best care during dental treatment. PMID- 23032244 TI - The rate of adverse events during IV conscious sedation. AB - Conscious sedation has become an integral part of dentistry; it is often used to reduce anxiety or fear in some patients during oral surgery, periodontal surgery, implant placement, and general dentistry procedures. The purpose of this study was to evaluate the frequency of adverse events during IV conscious sedation provided by credentialed general dentists and periodontists in the United States Air Force (USAF). Sedation clinical records (Air Force Form 1417) from calendar year 2009 were requested from all USAF bases. A total of 1,468 records were reviewed and 19 adverse events were noted in 17 patients. IV complication (infiltration) was the most common adverse event. The overall adverse event rate was 1.3 per 100 patients treated. The results of this study show that moderate sedation provided by general dentists and periodontists in the USAF has a low incidence of adverse events, and conscious sedation remains a viable option for providers for the reduction of anxiety in select patients. PMID- 23032245 TI - Simulation of 20-year deterioration of acrylic IOLs using severe accelerated deterioration tests. AB - PURPOSE: To investigate IOL deterioration by conducting severe accelerated deterioration testing of acrylic IOLs. SETTING: Department of Ophthalmology, Tokai University School of Medicine Methods: Severe accelerated deterioration tests performed on 7 types of acrylic IOLs simulated 20 years of deterioration. IOLs were placed in a screw tube bottle containing ultra-pure water and kept in an oven (100 degrees C) for 115 days. Deterioration was determined based the outer appearance of the IOL in water and under air-dried conditions using an optical microscope. For accelerated deterioration of polymeric material, the elapse of 115 days was considered to be equivalent to 20 years based on the Arrhenius equation. RESULTS: All of the IOLs in the hydrophobic acrylic group except for AU6 showed glistening-like opacity. The entire optical sections of MA60BM and SA60AT became yellowish white in color. Hydrophilic acrylic IOL HP60M showed no opacity at any of the time points examined. CONCLUSION: Our data based on accelerated testing showed differences in water content to play a major role in transparency. There were differences in opacity among manufacturers. The method we have used for determining the relative time of IOL deterioration might not represent the exact clinical setting, but the appearance of the materials would presumably be very similar to that seen in patients. PMID- 23032246 TI - Home monitoring using portable polygraphy for perioperative assessment of pediatric obstructive sleep apnea syndrome. AB - OBJECTIVE: To overcome very few facilities available for polysomnography, a portable device of polygraphy was introduced into home monitoring for the assessment of obstructive sleep apnea syndrome (OSAS) in children. METHODS: Forty eight children (aged 2-11) presenting with snoring and sleep apnea were subjected to home monitoring. SleeptesterTM (Fukuda Lifetech, Japan) was used for this purpose, which was equipped with 5 channels for oronasal airflow, thoracoabdominal effort, snoring, body position, and oximetry (SpO2). Sensors were placed by guardians, and they were requested to attend their children as long as possible during a night. Results were analyzed manually by sleep technologists. Adenotonsillectomy was performed in all 48 children, and the same monitoring was utilized postoperatively. RESULTS: The mean duration of monitoring was 460 +/- 172 min. (Mean +/- S.D.) in the preoperative test and 471 +/- 126 min. in the postoperative test. The mean apnea-hypopnea index (AHI) was 20.6 +/- 16.6 and 4.4 +/- 2.1, respectively. There was a statistically significant decrease (p < 0.001). The lowest SpO2 value was 76.7 +/- 17.1% preoperatively and 80.8 +/- 14.6% postoperatively, demonstrating no significant difference (p = 0.16) CONCLUSION: Attended home monitoring by guardians using a portable device can be useful in the perioperative assessment of pediatric OSAS. PMID- 23032247 TI - Out-of-hospital scaling to recognize central vertigo. AB - OBJECTIVE: To determine parameters that could assist emergency medical services (EMS) or triage personnel in identifying patients with central vertigo (cerebellar stroke). METHODS: The medical records at a university-based emergency department (ED) were retrospectively analyzed. The study patients comprised of 23 patients who were transported by EMS between April 2011 and March 2012 with a chief complaint of vertigo. We reviewed their medical records, including their symptoms, vital signs, review of systems, and past medical histories, to identify several parameters that could be used by paramedics to recognize central vertigo (cerebellar stroke). RESULTS: Of the 23 patients, 4 had central vertigo (2 had cerebellar infarction and 2 had cerebellar hemorrhage) and 19 had peripheral vertigo. High blood pressure and lack of horizontal component of nystagmus were found to be good predictors of central vertigo (cerebellar stroke) in these patients. Using a systolic blood pressure of more than 160 mmHg and lack of horizontal component of nystagmus as parameters, we can predict central vertigo (cerebellar stroke) with 100% sensitivity, 84% specificity, 57% positive predictive value and 100% negative predictive value (P = 0.0035). CONCLUSION: Using limited sample data, high blood pressure and lack of horizontal component of nystagmus were identified as good out-of-hospital parameters that could be used by paramedics to recognize central vertigo (cerebellar stroke). PMID- 23032248 TI - Random skin biopsy of intravascular large B-cell lymphoma: a case report. AB - A 72-year-old woman visited our clinic with fever of unknown origin above 38 degrees C and arthralgia from 7 months before. Her symptoms recurred as oral steroid was reduced. Random skin biopsy was carried out from five points. One of the five specimens taken from abdomen revealed large atypical lymphoid cells in the vascular space of subcutaneous fat. Immunohistochemical analysis showed that these cells were positive for CD20, CD79a, bcl-2, bcl-6 and MUM-1. From these findings, a diagnosis of intravascular large B cell lymphoma was made. PMID- 23032250 TI - Psoriasis affects patient's quality of life more seriously in female than in male in Japan. AB - OBJECTIVE: The aim of this study was to assess the quality of life (QOL) of patients with psoriasis in Japan using Dermatology Life Quality Index (DLQI). Furthermore, we had evaluated the correlation between DLQI and clinical severity of psoriasis. METHODS: The Japanese version of DLQI was used to assess the QOL of patients. Psoriasis area and severity index (PASI) and Itch visual analogue scale (VAS) were used to assess clinical severity of psoriasis. RESULTS: The subjects were 102 Japanese patients with mild to severe psoriasis (77 males, 25 females, mean age 55.2 +/- 14.2). There were no statistically significant differences in age, PASI, and itch VAS between male and female. The mean DLQI scores in total were 3.6 +/- 3.2 in male and 7.2 +/- 1.2 in female. The mean total DLQI scores in female were higher than that in male (p = 0.0016). Significant correlation was observed between DLQI scores and PASI score (p < 0.001) or itch VAS score (p < 0.001). CONCLUSIONS: The mean total DLQI scores in female were significantly higher than that in male. Also, we confirmed the correlation between DLQI and clinical severity of psoriasis. These findings suggest that QOL assessment plays a greater role in females than in the males, when assessing the severity of psoriasis. PMID- 23032249 TI - Evaluation of high-density lipoprotein cholesterol levels in Japanese women. AB - OBJECTIVE: The aim of the present study was to clarify the significance of high levels of high-density lipoprotein cholesterol (HDL-C) in Japanese women receiving an annual health check-up. METHODS: A total of 1879 women who were not taking medication for hypertension, diabetes or dyslipidemia, with no prior history of ischemic heart disease, cerebrovascular disease or chronic renal failure were analyzed. First, the association between HDL-C and homeostasis model assessment of insulin resistance (HOMA-IR) was studied. Next, the association between HDL-C and the number of metabolic syndrome (MetS) risk factors, including HOMA-IR, was determined. In addition, clinical parameters including HOMA-IR, number of MetS risk factors, smoking, exercise, and alcohol consumption habits were compared according to HDL-C level. RESULTS: HOMA-IR was lower in subjects with elevated HDL-C. Additionally, a lower body mass index (BMI), waist circumference (WC), fasting plasma glucose (FPG), and triglycerides (TG) were observed in subjects with higher HDL-C. Moreover, the proportion of subjects who were obese, or those who had high FPG, high TG, and a high number of MetS risk factors was lower in subjects with higher HDL-C. Both obesity and smoking were associated with reduced HDL-C levels. Increasing levels of alcohol consumption, from < 25 g/day, to 25 -< 50 g/day, to 50 -< 75 g/day, were associated with a progressive increase in HDL-C level, but a progressive reduction in HOMA-IR. However, this apparent benefit of alcohol intake on HDL-C and HOMA-IR disappeared in subjects who drank >= 75 g/day. CONCLUSIONS: Female subjects who were not obese, did not smoke, and drank < 75 g alcohol/day had elevated HDL-C levels, which were associated with improved insulin sensitivity. Drinking alcohol in excess of 75 g/day appeared to provide no advantages in terms of HDL-C or HOMA-IR levels. Thus, it might be important for females to keep their alcohol intake below 75 g/day. PMID- 23032251 TI - Early diagnosis of anti-N-methyl-D-aspartate receptor encephalitis in a young woman with psychiatric symptoms. AB - A previously healthy 21-year-old woman, transported to our medical emergency center for excluding organic brain disease, had undergone medical examination 9 days before for trembling in her left hand, which was caused by stress. The patient exhibited fever and strange behaviors, e.g., wandering around, babbling, and making smoking gestures; hence, psychiatric examination was performed. The patient's Glasgow Coma Scale score was 4-3-5, and involuntary movement was observed. Cerebrospinal fluid examination revealed increased cell count; hence, we suspected anti-N-methyl-d-aspartate (NMDA) receptor encephalitis. We conducted an abdominal CT scan, which revealed a neoplastic lesion with calcification in the right ovary. Early steroid pulse therapy was started. On hospital day 25, she tested positive for anti-NMDA receptor antibodies; hence, anti-NMDA receptor encephalitis and concomitant ovarian teratoma was diagnosid. She underwent right adnexectomy; subsequently, immunotherapy was performed. The patient recovered and was discharged on hospital day 105. Anti-NMDA receptor encephalitis is not uncommon; however, this disease must be considered for young encephalitis patients exhibiting psychiatric symptoms. If patients (aged <= 30 years) presents with encephalitis of uncertain etiology, psychiatric symptoms, seizures, movement disorders, or psychosis, clinicians should consider anti-NMDA encephalitis as a possible diagnosis. Clinical diagnosis should be waged early to ensure timely treatment. PMID- 23032252 TI - An aqueous non-heme Fe(IV)oxo complex with a basic group in the second coordination sphere. AB - The Fe(IV)oxo complex of a coordinatively flexible multidentate mono-carboxylato ligand is obtained by the one electron oxidation of a low spin Fe(III) precursor in water. PMID- 23032253 TI - Spectroscopic characterization of van der Waals interactions in a metal organic framework with unsaturated metal centers: MOF-74-Mg. AB - The adsorption energies of small molecules in nanoporous materials are often determined by isotherm measurements. The nature of the interaction and the response of the host material, however, can best be studied by spectroscopic methods. We show here that infrared absorption and Raman spectroscopy measurements together with density functional theory calculations, utilizing the novel van der Waals density functional vdW-DF, constitute a powerful approach to studying the weak van der Waals interactions associated with the incorporation of small molecules in these materials. In particular, we show how vdW-DF assists the interpretation of the vibrational spectroscopy data to uncover the binding sites and energies of these molecules, including the subtle dependence on loading of the IR asymmetric stretch mode of CO(2) when adsorbed in MOF-74-Mg. To gain a better understanding of the adsorption mechanism of CO(2) in MOF-74-Mg, the results are compared with CO within MOF-74-Mg. PMID- 23032254 TI - Bacterial evolution: Decoding fossil records. PMID- 23032255 TI - Genetic variation in metabolic phenotypes: study designs and applications. AB - Many complex disorders are linked to metabolic phenotypes. Revealing genetic influences on metabolic phenotypes is key to a systems-wide understanding of their interactions with environmental and lifestyle factors in their aetiology, and we can now explore the genetics of large panels of metabolic traits by coupling genome-wide association studies and metabolomics. These genome-wide association studies are beginning to unravel the genetic contribution to human metabolic individuality and to demonstrate its relevance for biomedical and pharmaceutical research. Adopting the most appropriate study designs and analytical tools is paramount to further refining the genotype-phenotype map and eventually identifying the part played by genetic influences on metabolic phenotypes. We discuss such design considerations and applications in this Review. PMID- 23032256 TI - Stem cells: Revealing the reprogramming program. PMID- 23032258 TI - New functions for ecotropic viral integration site 1 (EVI1), an oncogene causing aggressive malignant disease. PMID- 23032257 TI - DNA secondary structures: stability and function of G-quadruplex structures. AB - In addition to the canonical double helix, DNA can fold into various other inter- and intramolecular secondary structures. Although many such structures were long thought to be in vitro artefacts, bioinformatics demonstrates that DNA sequences capable of forming these structures are conserved throughout evolution, suggesting the existence of non-B-form DNA in vivo. In addition, genes whose products promote formation or resolution of these structures are found in diverse organisms, and a growing body of work suggests that the resolution of DNA secondary structures is critical for genome integrity. This Review focuses on emerging evidence relating to the characteristics of G-quadruplex structures and the possible influence of such structures on genomic stability and cellular processes, such as transcription. PMID- 23032259 TI - An expanded role of the tumor suppressor TSC1 in T cell tolerance. PMID- 23032260 TI - CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD. AB - Autosomal dominant polycystic kidney disease (ADPKD) and other forms of PKD are associated with dysregulated cell cycle and proliferation. Although no effective therapy for the treatment of PKD is currently available, possible mechanism-based approaches are beginning to emerge. A therapeutic intervention targeting aberrant cilia-cell cycle connection using CDK-inhibitor R-roscovitine showed effective arrest of PKD in jck and cpk models that are not orthologous to human ADPKD. To evaluate whether CDK inhibition approach will translate into efficacy in an orthologous model of ADPKD, we tested R-roscovitine and its derivative S-CR8 in a model with a conditionally inactivated Pkd1 gene (Pkd1 cKO). Similar to ADPKD, Pkd1 cKO mice developed renal and hepatic cysts. Treatment of Pkd1 cKO mice with R-roscovitine and its more potent and selective analog S-CR8 significantly reduced renal and hepatic cystogenesis and attenuated kidney function decline. Mechanism of action studies demonstrated effective blockade of cell cycle and proliferation and reduction of apoptosis. Together, these data validate CDK inhibition as a novel and effective approach for the treatment of ADPKD. PMID- 23032262 TI - ORCA is regulated by ubiquitin-mediated degradation to control Orc2 function. PMID- 23032261 TI - B-Myb promotes S-phase independently of its sequence-specific DNA binding activity and interacts with polymerase delta-interacting protein 1 (Pdip1). AB - B-Myb is a highly conserved member of the Myb transcription factor family, which plays an essential role in cell cycle progression by regulating the transcription of genes at the G 2/M-phase boundary. The role of B-Myb in other parts of the cell cycle is less well-understood. By employing siRNA-mediated silencing of B Myb expression, we found that B-Myb is required for efficient entry into S-phase. Surprisingly, a B-Myb mutant that lacks sequence-specific DNA-binding activity and is unable to activate transcription of B-Myb target genes is able to rescue the S-phase defect observed after B-Myb knockdown. Moreover, we have identified polymerase delta-interacting protein 1 (Pdip1), a BTB domain protein known to bind to the DNA replication and repair factor PCNA as a novel B-Myb interaction partner. We have shown that Pdip1 is able to interact with B-Myb and PCNA simultaneously. In addition, we found that a fraction of endogenous B-Myb can be co-precipitated via PCNA, suggesting that B-Myb might be involved in processes related to DNA replication or repair. Taken together, our work suggests a novel role for B-Myb in S-phase that appears to be independent of its sequence-specific DNA-binding activity and its ability to stimulate the expression of bona fide B Myb target genes. PMID- 23032263 TI - UnCHKed DNA replication: A stressful matter. PMID- 23032265 TI - Dynamic nature of heterochromatin highlighted by a HP1Swi6-dependent gene silencing mechanism. PMID- 23032264 TI - cIAP2 represses IKKalpha/beta-mediated activation of MDM2 to prevent p53 degradation. AB - Cellular inhibitor of apoptosis proteins (cIAP1 and cIAP2) function to prevent apoptosis and are often overexpressed in various cancers. However, mutations in cIAP1/2 can activate the alternative NFkappaB pathway through IkappaBalpha-kinase alpha (IKKalpha) and are associated with hematopoetic malignancies. In the current study, we found that knockdown of cIAP2 in human mammary epithelial cells resulted in activation of MDM2 through increased SUMOylation and profound reduction of the pool of MDM2 not phosphorylated at Ser166. cIAP2 siRNA markedly decreased p53 levels, which were rescued by addition of the MDM2 inhibitor, Nutlin3a. An IAP antagonist, which induces cIAP degradation, transiently increased MDM2 mRNA. Simultaneous transfection of siRNA for cIAP2 and IKKalpha reduced MDM2 protein, while expression of a kinase-dead IKKbeta strongly increased non-Ser166 P-MDM2. Inhibition of either IKKalpha or -beta partially rescued p53 levels, while concomitant IKKalpha/beta inhibition fully rescued p53 after cIAP2 knockdown. Surprisingly, IKKalpha knockdown alone increased SUMO MDM2, suggesting that in the absence of activation, IKKalpha can prevent MDM2 SUMOylation. cIAP2 knockdown disrupted the interaction between the MDM2 SUMO ligase, PIAS1 and IKKalpha. Partial knockdown of cIAP2 cooperated with (V12) H ras-transfected mammary epithelial cells to enhance colony formation. In summary, our data identify a novel role for cIAP2 in maintaining wild-type p53 levels by preventing both an NFkappaB-mediated increase and IKKalpha/-beta-dependent transcriptional and post-translational modifications of MDM2. Thus, mutations or reductions in cIAP2 could contribute to cancer promotion, in part, through downregulation of p53. PMID- 23032266 TI - Cyclin-dependent kinase 4/6 inhibition in cancer therapy. PMID- 23032267 TI - Addicted to PAR? A closer look at PARP inhibitor sensitivity. PMID- 23032268 TI - Human embryonic stem cells: living on the edge. PMID- 23032269 TI - "Remembering" tissue-specific transcription patterns through mitosis. PMID- 23032270 TI - Historical perspective on advanced drug delivery: how engineering design and mathematical modeling helped the field mature. AB - We review the early developments in drug delivery from 1960 to 1990 with emphasis on the fundamental aspects of the field and how they shaped the collaboration of pharmaceutical scientists, chemists, biologists, engineers and medical scientists towards the development of advanced drug delivery systems. Emphasis is given on the advances of biomaterials as drug delivery agents and on the use of design equations and mathematical modeling to achieve a wide range of successful systems. PMID- 23032271 TI - The reaction of Criegee intermediates with NO, RO2, and SO2, and their fate in the atmosphere. AB - The reaction of Criegee intermediates (CI) with NO and RO(2) radicals is studied for the first time by theoretical methodologies; additionally, the reaction of CI with SO(2) molecules is re-examined. The reaction of CI with NO was found to be slow, with a distinct energy barrier. Their reaction with RO(2) radicals proceeds by the formation of a pre-reactive complex followed by addition of the RO(2) radical on the CI carbon over a submerged barrier, leading to a larger peroxy radical and opening the possibility for oligomer formation in agreement with experiment. The impact of singlet biradicals on the reaction of CI with SO(2) is examined, finding a different reaction mechanism compared to earlier work. For larger CI, the reaction with SO(2) at atmospheric pressures mainly yields thermalized sulfur-bearing secondary ozonides. The fate of the CI in the atmosphere is examined in detail, based on observed concentration of a multitude of coreactants in the atmosphere, and estimated rate coefficients available from literature data. The impact of SCI on tropospheric chemistry is discussed. PMID- 23032272 TI - Social modulation of learned behavior by dopamine in the basal ganglia: insights from songbirds. AB - Dysfunction of the dopaminergic system leads to motor, cognitive, and motivational symptoms in brain disorders such as Parkinson's disease. The basal ganglia (BG) are involved in sensorimotor learning and receive a strong dopaminergic signal, shown to play an important role in social interactions. The function of the dopaminergic input to the BG in the integration of social cues during sensorimotor learning remains however largely unexplored. Songbirds use learned vocalizations to communicate during courtship and aggressive behaviors. Like language learning in humans, song learning strongly depends on social interactions. In songbirds, a specialized BG-thalamo-cortical loop devoted to song is particularly tractable for elucidating the signals carried by dopamine in the BG, and the function of dopamine signaling in mediating social cues during skill learning and execution. Here, I review experimental findings uncovering the physiological effects and function of the dopaminergic signal in the songbird BG, in light of our knowledge of the BG-dopamine interactions in mammals. Interestingly, the compact nature of the striato-pallidal circuits in birds led to new insight on the physiological effects of the dopaminergic input on the BG network as a whole. In singing birds, D1-like receptor agonist and antagonist can modulate the spectral variability of syllables bi-directionally, suggesting that social context-dependent changes in spectral variability are triggered by dopaminergic input through D1-like receptors. As variability is crucial for exploration during motor learning, but must be reduced after learning to optimize performance, I propose that, the dopaminergic input to the BG could be responsible for the social-dependent regulation of the exploration/exploitation balance in birdsong, and possibly in learned skills in other vertebrates. PMID- 23032273 TI - Assessment of the relative dose-response test as indicators of hepatic vitamin A stores in various stages of chronic liver disease. AB - Hepatic vitamin A stores should be the best early indicator of vitamin A status because more than 90% of total body vitamin A is stored in the liver. The objective of the present study was to evaluate the hepatic vitamin A stores in all stages of chronic liver disease (CLD), including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). One hundred forty-four patients (age 55.34 +/- 9.38 years) were evaluated in a cross-sectional study. Vitamin A nutrition status was analyzed by serum retinol levels and relative dose-response (RDR) method. Patients with cholestasis were excluded from the sample group. Biochemical, clinical, and anthropometric evaluations were performed. Vitamin A deficiency (VAD) was detected in 51.4% of all patients. Patients with adequate levels of serum retinol presented adequate liver vitamin A reserves; in contrast, nearly half the patients with low serum retinol levels presented adequate levels of retinol in the liver, although none of the patients with hepatitis had this condition. Therefore, the effectiveness of the RDR method for evaluating vitamin A nutrition status was limited in patients with cirrhosis and HCC, perhaps due to the advanced age of these patients, since those in the chronic hepatitis group, who were younger, responded adequately to the test. Thus, the RDR method should be modified when applied to later stages of CLD, considering the time and dose of retinyl palmitate supplementation, as VAD may be a risk factor for the progression of the disease. PMID- 23032274 TI - Mapping and modelling neglected tropical diseases and poverty in Latin America and the Caribbean. AB - The prospects and opportunities for application of risk mapping and modelling of the neglected tropical diseases (NTDs) in Latin America are examined with the aim to broaden the interest in geospatial research there. Special reference is made to the potential use of geospatial tools in health planning and implementation of national disease control programmes. PMID- 23032275 TI - Biomphalaria species distribution and its effect on human Schistosoma mansoni infection in an irrigated area used for rice cultivation in northeast Brazil. AB - The role of irrigated areas for the spread of schistosomiasis is of worldwide concern. The aim of the present study was to investigate the spatial distribution of the intermediate snail host Biomphalaria in an area highly endemic for schistosomiasis due to Schistosoma mansoni, evaluating the relationship between irrigation and types of natural water sources on one hand, and the influence of place and time of water exposure on the intensity of human infection on the other. A geographical information system (GIS) was used to map the distribution of the intermediate snail hosts in Ilha das Flores, Sergipe, Brazil, combined with a clinical/epidemiological survey. We observed a direct correlation between the intensity of human infection with S. mansoni and irrigation projects. Malacological studies to identify snail species and infection rates showed that B. glabrata is the main species responsible for human schistosomiasis in the municipality, but that B. straminea also plays a role. Our results provide evidence for a competitive selection between the two snail species in rice fields with a predominance of B. glabrata in irrigation systems and B. straminea in natural water sources. PMID- 23032276 TI - The neglected tropical diseases (NTD) initiative for Latin America and the Caribbean of the Inter-American Development Bank and the role of geospatial analysis in health programmes. PMID- 23032277 TI - Modelling the ecological niche of hookworm in Brazil based on climate. AB - The distribution of hookworm in schistosomiasis-endemic areas in Brazil was mapped based on climate suitability. Known biological requirements of hookworm were fitted to data in a monthly long-term normal climate grid (18 x 18 km) using geographical information systems. Hookworm risk models were produced using the growing degree day (GDD) water budget (WB) concept. A moisture-adjusted model (MA GDD) was developed based on accumulation of monthly temperatures above a base temperature of 15 degrees C (below which there is no lifecycle progression of Necator americanus) conditional on concurrent monthly values (rain/potential, evapotranspiration) of over 0.4. A second model, designated the gradient index, was calculated based on the monthly accumulation of the product of GDD and monthly WB values (GDD x WB). Both parameters had a significant positive correlation to hookworm prevalence. In the northeastern part of Brazil (the Caatinga), low hookworm prevalence was due to low soil moisture content, while the low prevalence in southern Brazil was related to low mean monthly temperatures. Both environmental temperature and soil moisture content were found to be important parameters for predicting the prevalence of N. americanus. PMID- 23032278 TI - Neurological disability in leprosy: incidence and gender association in Sergipe, Brazil. AB - The environmental impact assessment process is over 40 years old and has dramatically expanded. Topics, such as social, health and human rights impact are now included. The main body of an impact analysis is generally hundreds of pages long and supported by countless technical appendices. For large, oil/gas, mining and water resources projects both the volume and technical sophistication of the reports has far exceeded the processing ability of host communities. Instead of informing and empowering, the reports are abstruse and overwhelming. Reinvention is required. The development of a visual integrated impact assessment strategy that utilizes remote sensing and spatial analyses is described. PMID- 23032279 TI - Climate information for public health: the role of the IRI climate data library in an integrated knowledge system. AB - Public health professionals are increasingly concerned about the potential impact of climate variability and change on health outcomes. Protecting public health from the vagaries of climate requires new working relationships between the public health sector and the providers of climate data and information. The Climate Information for Public Health Action initiative at the International Research Institute for Climate and Society (IRI) is designed to increase the public health community's capacity to understand, use and demand appropriate climate data and climate information to mitigate the public health impacts of the climate. Significant challenges to building the capacity of health professionals to use climate information in research and decision-making include the difficulties experienced by many in accessing relevant and timely quality controlled data and information in formats that can be readily incorporated into specific analysis with other data sources. We present here the capacities of the IRI climate data library and show how we have used it to build an integrated knowledge system in the support of the use of climate and environmental information in climate-sensitive decision-making with respect to health. Initiated as an aid facilitating exploratory data analysis for climate scientists, the IRI climate data library has emerged as a powerful tool for interdisciplinary researchers focused on topics related to climate impacts on society, including health. PMID- 23032280 TI - SandflyMap: leveraging spatial data on sand fly vector distribution for disease risk assessments. AB - We feature SandflyMap (www.sandflymap.org), a new map service within VectorMap (www.vectormap.org) that allows free public online access to global sand fly, tick and mosquito collection records and habitat suitability models. Given the short home range of sand flies, combining remote sensing and collection point data give a powerful insight into the environmental determinants of sand fly distribution. SandflyMap is aimed at medical entomologists, vector disease control workers, public health officials and health planners. Data are checked for geographical and taxonomic errors, and are comprised of vouchered specimen information, and both published and unpublished observation data. SandflyMap uses Microsoft Silverlight and ESRI's ArcGIS Server 10 software platform to present disease vector data and relevant remote sensing layers in an online geographical information system format. Users can view the locations of past vector collections and the results of models that predict the geographic extent of individual species. Collection records are searchable and downloadable, and Excel collection forms with drop down lists, and Excel charts to country, are available for data contributors to map and quality control their data. SandflyMap makes accessible, and adds value to, the results of past sand fly collecting efforts. We detail the workflow for entering occurrence data from the literature to SandflyMap, using an example for sand flies from South America. We discuss the utility of SandflyMap as a focal point to increase collaboration and to explore the nexus between geography and vector-borne disease transmission. PMID- 23032281 TI - An operative dengue risk stratification system in Argentina based on geospatial technology. AB - Based on an agreement between the Ministry of Health and the National Space Activities Commission in Argentina, an integrated informatics platform for dengue risk using geospatial technology for the surveillance and prediction of risk areas for dengue fever has been designed. The task was focused on developing stratification based on environmental (historical and current), viral, social and entomological situation for >3,000 cities as part of a system. The platform, developed with open-source software with pattern design, following the European Space Agency standards for space informatics, delivers two products: a national risk map consisting of point vectors for each city/town/locality and an approximate 50 m resolution urban risk map modelling the risk inside selected high-risk cities. The operative system, architecture and tools used in the development are described, including a detailed list of end users' requirements. Additionally, an algorithm based on bibliography and landscape epidemiology concepts is presented and discussed. The system, in operation since September 2011, is capable of continuously improving the algorithms producing improved risk stratifications without a complete set of inputs. The platform was specifically developed for surveillance of dengue fever as this disease has reemerged in Argentina but the aim is to widen the scope to include also other relevant vector borne diseases such as chagas, malaria and leishmaniasis as well as other countries belonging to south region of Latin America. PMID- 23032282 TI - Estimating the geographical distribution of the prevalence of the metabolic syndrome in young Mexicans. AB - The geographical distribution of the metabolic syndrome (MetS) prevalence in young Mexicans (aged 17-24 years) was estimated stepwise starting from its prevalence based on the body mass index (BMI) in a study of 3,176 undergraduate students of this age group from Mexico City. To estimate the number of people with MetS by state, we multiplied its prevalence derived from the BMI range found in the Mexico City sample by the BMI proportions (range and state) obtained from the Mexico 2006 national survey on health and nutrition. Finally, to estimate the total number of young people with MetS in Mexico, its prevalence by state was multiplied by the share of young population in each state according to the National Population and Housing Census 2010. Based on these figures, we estimated the national prevalence of MetS at 15.8%, the average BMI at 24.1 (standard deviation = 4.2), and the prevalence of overweight people (BMI >=25) of that age group at 39.0%. These results imply that 2,588,414 young Mexicans suffered from MetS in 2010. The Yucatan peninsula in the south and the Sonora state in the north showed the highest rates of MetS prevalence. The calculation of the MetS prevalence by BMI range in a sample of the population, and extrapolating it using the BMI proportions by range of the total population, was found to be a useful approach. We conclude that the BMI is a valuable public health tool to estimate MetS prevalence in the whole country, including its geographical distribution. PMID- 23032283 TI - Analysis of the El Nino/La Nina-Southern Oscillation variability and malaria in the Estado Sucre, Venezuela. AB - The last decade has seen an unprecedented, worldwide acceleration of environmental and climate changes. These processes impact the dynamics of natural systems, which include components associated with human communities such as vector-borne diseases. The dynamics of environmental and climate variables, altered by global change as reported by the Intergovernmental Panel on Climate Change, affect the distribution of many tropical diseases. Complex systems, e.g. the El Nino/La Nina-Southern Oscillation (ENSO), in which environmental variables operate synergistically, can provoke the reemergence and emergence of vector borne diseases at new sites. This research investigated the influence of ENSO events on malaria incidence by determining the relationship between climate variations, expressed as warm, cold and neutral phases, and their relation to the number of malaria cases in some north-eastern municipalities of Venezuela (Estado Sucre) during the period 1990-2000. Significant differences in malaria incidence were found, particularly in the La Nina ENSO phases (cold) of moderate intensity. These findings should be taken into account for surveillance and control in the future as they shed light on important indicators that can lead to reduced vulnerability to malaria. PMID- 23032284 TI - Environmental and socio-economic risk modelling for Chagas disease in Bolivia. AB - Accurately defining disease distributions and calculating disease risk is an important step in the control and prevention of diseases. Geographical information systems (GIS) and remote sensing technologies, with maximum entropy (Maxent) ecological niche modelling computer software, were used to create predictive risk maps for Chagas disease in Bolivia. Prevalence rates were calculated from 2007 to 2009 household infection survey data for Bolivia, while environmental data were compiled from the Worldclim database and MODIS satellite imagery. Socio-economic data were obtained from the Bolivian National Institute of Statistics. Disease models identified altitudes at 500-3,500 m above the mean sea level (MSL), low annual precipitation (45-250 mm), and higher diurnal range of temperature (10-19 degrees C; peak 16 degrees C) as compatible with the biological requirements of the insect vectors. Socio-economic analyses demonstrated the importance of improved housing materials and water source. Home adobe wall materials and having to fetch drinking water from rivers or wells without pump were found to be highly related to distribution of the disease by the receiver operator characteristic (ROC) area under the curve (AUC) (0.69 AUC, 0.67 AUC and 0.62 AUC, respectively), while areas with hardwood floors demonstrated a direct negative relationship (-0.71 AUC). This study demonstrates that Maxent modelling can be used in disease prevalence and incidence studies to provide governmental agencies with an easily learned, understandable method to define areas as either high, moderate or low risk for the disease. This information may be used in resource planning, targeting and implementation. However, access to high-resolution, sub-municipality socio-economic data (e.g. census tracts) would facilitate elucidation of the relative influence of poverty related factors on regional disease dynamics. PMID- 23032285 TI - A One-Health integrated approach to control fascioliasis in the Cajamarca valley of Peru. AB - Fasciola hepatica infection is reported from many Latin American countries, with very high prevalence rates in both humans and livestock in the Andean countries. Due to its environmental characteristics, particularly suitable for liver fluke infection, the Cajamarca valley of Peru has often been chosen as a model to study the epidemiology of liver fluke infection in the Andes. In this paper we describe the profile of a project aimed at a multidisciplinary and integrated approach for the control of fascioliasis in animals and humans in this valley. The One-Health integrated approach applied here is based on accurate and sensitive diagnostics, namely the FLOTAC, and the use of geospatial tools for epidemiological scrutiny. PMID- 23032286 TI - Climate-based risk models for Fasciola hepatica in Colombia. AB - A predictive Fasciola hepatica model, based on the growing degree day-water budget (GDD-WB) concept and the known biological requirements of the parasite, was developed within a geographical information system (GIS) in Colombia. Climate based forecast index (CFI) values were calculated and represented in a national scale, climate grid (18 x 18 km) using ArcGIS 9.3. A mask overlay was used to exclude unsuitable areas where mean annual temperature exceeded 25 degrees C, the upper threshold for development and propagation of the F. hepatica life cycle. The model was then validated and further developed by studies limited to one department in northwest Colombia. F. hepatica prevalence data was obtained from a 2008-2010 survey in 10 municipalities of 6,016 dairy cattle at 673 herd study sites, for which global positioning system coordinates were recorded. The CFI map results were compared to F. hepatica environmental risk models for the survey data points that had over 5% prevalence (231 of the 673 sites) at the 1 km2 scale using two independent approaches: (i) a GIS map query based on satellite data parameters including elevation, enhanced vegetation index and land surface temperature day-night difference; and (ii) an ecological niche model (MaxEnt), for which geographic point coordinates of F. hepatica survey farms were used with BioClim data as environmental variables to develop a probability map. The predicted risk pattern of both approaches was similar to that seen in the forecast index grid. The temporal risk, evaluated by the monthly CFIs and a daily GDD-WB forecast software for 2007 and 2008, revealed a major July-August to January transmission period with considerable inter-annual differences. PMID- 23032287 TI - The Pan American Health Organization's role and perspectives on the mapping and modeling of the neglected tropical diseases in Latin America and the Caribbean: an overview. AB - The Pan American Health Organization (PAHO), which functions as the regional office for the Americas of the World Health Organization, is committed to provide technical cooperation to countries to update the epidemiological information available for mapping and modelling of the neglected tropical diseases (NTDs), a set of diseases mainly caused by parasites affecting people living in low socioeconomic and favourable environmental conditions. This communication discusses PAHO's role and perspectives in the use of mapping and modelling of these diseases with a view to promote its use in the development and implementation of integrated, inter-programmatic and inter-sectoral plans for the prevention, control or elimination of the NTDs and other infectious diseases related to poverty. PMID- 23032288 TI - Application of a geographical information system approach for risk analysis of fascioliasis in southern Espirito Santo state, Brazil. AB - A model based on geographical information systems for mapping the risk of fascioliasis was developed for the southern part of Espirito Santo state, Brazil. The determinants investigated were precipitation, temperature, elevation, slope, soil type and land use. Weightings and grades were assigned to determinants and their categories according to their relevance with respect to fascioliasis. Theme maps depicting the spatial distribution of risk areas indicate that over 50% of southern Espirito Santo is either at high or at very high risk for fascioliasis. These areas were found to be characterized by comparatively high temperature but relatively low slope, low precipitation and low elevation corresponding to periodically flooded grasslands or soils that promote water retention. PMID- 23032289 TI - Spatial distribution of Biomphalaria spp., the intermediate host snails of Schistosoma mansoni, in Brazil. AB - Schistosomiasis mansoni remains an important parasitic disease of man, endemic in large parts of sub-Saharan Africa, the Middle East, South America and the Caribbean. The aetiological agent is the trematode Schistosoma mansoni, whereas aquatic snails of the genus Biomphalaria act as intermediate hosts in the parasite life cycle. In Brazil, the distribution of Biomphalaria spp. is closely associated with the occurrence of schistosomiasis. The purpose of this study was to map and predict the spatial distribution of the intermediate host snails of S. mansoni across Brazil. We assembled snail "presenceonly" data and used a maximum entropy approach, along with climatic and environmental variables to produce predictive risk maps. We identified a series of risk factors that govern the distribution of Biomphalaria snails. We find that high-risk areas for B. glabrata are concentrated in the regions of Northeast and Southeast and the northern part of the South region. B. straminea are found in the Northeast and Southeast regions, and B. tenagophila are concentrated in the Southeast and South regions. Our findings confirm that the presence of the intermediate host snails is correlated with the occurrence of schistosomiasis mansoni. The generated risk maps of intermediate host snails might assist the national control programme for spatial targeting of control interventions and to ultimately move towards schistosomiasis elimination in Brazil. PMID- 23032291 TI - CKIP-1 couples Smurf1 ubiquitin ligase with Rpt6 subunit of proteasome to promote substrate degradation. AB - CKIP-1 is an activator of the Smurf1 ubiquitin ligase acting to promote the ubiquitylation of Smad5 and MEKK2. The mechanisms involved in the recognition and degradation of these substrates by the proteasome remain unclear. Here, we show that CKIP-1, through its leucine zipper, interacts directly with the Rpt6 ATPase of the 19S regulatory particle of the proteasome. CKIP-1 mediates the Smurf1-Rpt6 interaction and delivers the ubiquitylated substrates to the proteasome. Depletion of CKIP-1 reduces the degradation of Smurf1 and its substrates by Rpt6. These findings reveal an unexpected adaptor role of CKIP-1 in coupling the ubiquitin ligase and the proteasome. PMID- 23032292 TI - Chd1 chromatin remodelers maintain nucleosome organization and repress cryptic transcription. AB - Chromatin organization is essential for defining transcription units and maintaining genomic integrity in eukaryotes. In this study, we found that deletion of the Schizosaccharomyces pombe Chd1 chromatin remodelers, hrp1 and hrp3, causes strong, genome-wide accumulation of antisense transcripts. Nucleosome mapping revealed a specific role for Chd1 remodelers in the positioning of nucleosomes in gene coding regions. Other mutations associated with enhanced cryptic transcription activity, such as set2Delta, alp13Delta and FACT complex subunit pob3Delta, did not, or only mildly, affect nucleosome positioning. These data indicate several mechanisms in the repression of cryptic promoter activity in eukaryotic cells. PMID- 23032293 TI - Cardiopulmonary exercise testing in the early-phase of myocardial infarction. AB - OBJECTIVE: To evaluate and to compare the cardiorespiratory and metabolic variables at the ventilatory anaerobic threshold level (AT) and at submaximal cardiopulmonary exercise testing (CPET) in both, healthy volunteers and in patients in the early phase after acute myocardial infarction (AMI). METHOD: Twenty-six volunteers underwent a submaximal or symptom-limited cardiopulmonary exercise testing (CPET) on a cycle ergometer and were divided into AMI group (AMIG=12, 56.33+/-8.65 years) and healthy group (CG=14, 53.33+/-3.28 years). The primary outcome measures were the cardiorespiratory and metabolic variables obtained at the peak workload and at the AT of the CPET. Statistical test: independent Student's t-test, alpha=5%. RESULTS: The AMIG presented lower values at the AT and the peak workload of the CPET compered to the CG: power in watts (91.06+/-30.10 and 64.88+/-19.92; 154.93+/-34.65 and 120.40+/-29.60); VO2 mL.kg 1.min-1 (17.26+/-2.71 and 12.19+/-2.51; 25.39+/-5.73 and 19.41+/-5.63); VCO2 L/min-1 (1.43+/-0.31 and 0.93+/-0.23; 2.07+/-0.43 and 1.42+/-0.36), VO2 L/min-1 (1.33+/-0.32 and 1.00+/-0.23; 1.97+/-0.39 and 1.49+/-0.36); VE L/min-1 (42.13+/ 8.32 and 27.51+/-5.86; 63.07+/-20.83 and 40.82+/-11.96); HR (bpm) (122.96+/-14.02 and 103.46+/-13.38; 149.67+/-13.77 and 127.60+/-10.04), double product (DP) (bpm.mmHg.min-1) (21835.86+/-3245.93 and 17333.25+/-2716.51; 27302.33+/-3053.08 and 21864.00+/-2051.48), respectively. The variable oxygen uptake efficiency slope (OUES L/min) was lower in the AMIG (1.79+/-0.51) than the CG (2.26+/-0.37). The AMIG presented neither ECG alterations nor symptoms that limited the CPET. CONCLUSION: The results suggest that patients with AMI Killip class I presented lower functional capacity and DP compared to the CG without presenting ischemic alterations. Thus, the study suggests that submaximal CPET can be applied at an early stage to evaluate cardiorespiratory status since it is both safe and highly sensitive to detect changes. PMID- 23032294 TI - Clinimetric properties of the Brazilian-Portuguese version of the Quick Exposure Check (QEC). AB - BACKGROUND: Most of the available instruments aimed to assess risk exposure associated with work-related musculoskeletal disorders were originally developed in English, which makes their use difficult in countries such as Brazil. OBJECTIVE: To test the clinimetric properties of the Quick Exposure Check (QEC) instrument previously adapted into Brazilian-Portuguese. METHOD: The original version of the QEC was translated and cross-culturally adapted into Brazilian Portuguese and tested with 107 workers in two sectors of a textile factory. The internal consistency and construct validity were tested using only baseline values from the participants while reproducibility (reliability and agreement) was evaluated in a test-retest design with a seven-day interval. RESULTS: The adapted version presented appropriate levels of internal consistency (Cronbach's alpha=0.76); moderate intra-observer reliability (ICCs ranging from 0.41 to 0.60); moderate to substantial inter-observer reliability (ICCs ranging between 0.62 and 0.86). The standard error of the measurement (SEM) ranged from 8.3 to 11.2 points. Moderate levels of construct validity (Pearson's r=0.38) were observed. CONCLUSIONS: The Brazilian version of the QEC has appropriate clinimetric properties for measuring different levels of exposure to ergonomics risk factors and can now be used by Brazilian researchers and Occupational Health professionals. PMID- 23032295 TI - Effects of physical therapy in older women with urinary incontinence: a systematic review. AB - BACKGROUND: Urinary incontinence (UI) is one of the most common public health problems among older women. Despite conservative treatment being recommended as the first treatment option, the effects of physical therapy in older women with UI is unclear. OBJECTIVE: This study aimed to systematically review the evidence about the effects of physical therapy on urinary symptoms in older women with UI. METHOD: The literature search for studies evaluating conservative treatment for incontinent in elderly women was conducted on Pubmed/Medline, Lilacs, Scielo, ISI Web of Knowledge and PEDro. We selected clinical trials published in English and Portuguese after the year 2000. The methodological quality of the studies was assessed using the PEDro scale. The results were analyzed using a critical review method. RESULTS: Six studies were reviewed in full revealing that pelvic floor muscle training was the treatment option in most studies. Five of the six selected studies were classified as having high methodological quality. There was significant improvement in urinary symptoms after treatment in five of the six selected studies. CONCLUSIONS: It was concluded that physical therapy treatment seems to be effective to decrease urinary incontinence symptoms in older women. However, the small number of studies and the use of concurrent interventions limit the conclusions on this issue. PMID- 23032296 TI - Iridium(III) complexes with polypyridine ligands coordinated as N-heterocyclic carbenes. Synthesis, structure and photophysical properties. AB - Unsaturated [Tp(Me2)Ir(III)] fragments, readily generated from compounds [Tp(Me2)Ir(C(6)H(5))(2)(N(2))], (1a) and [Tp(Me2)Ir(eta(4) CH(2)=C(Me)C(Me)=CH(2)] (1b) (Tp(Me2) = hydrotris(3,5-dimethylpyrazolyl)borate), induce the isomerisation of the polypyridines, 2,2'-bipyridine, 1,10 phenanthroline and 2,2':6'2''-terpyridine, to form complexes that contain the carbene tautomer of these ligands. For terpy, a binuclear compound has also been isolated, in which this molecule bridges two Ir(III) centres, thanks to its coordination as a bidentate N-heterocyclic carbene. The new compounds have been structurally authenticated by X-ray crystallography and their photophysical properties have been investigated. PMID- 23032297 TI - Estimating the contributions of rare and common genetic variations and clinical measures to a model trait: adiponectin. AB - Common genetic variation frequently accounts for only a modest amount of interindividual variation in quantitative traits and complex disease susceptibility. Circulating adiponectin, an adipocytokine implicated in metabolic disease, is a model for assessing the contribution of genetic and clinical factors to quantitative trait variation. The adiponectin locus, ADIPOQ, is the primary source of genetically mediated variation in plasma adiponectin levels. This study sought to define the genetic architecture of ADIPOQ in the comprehensively phenotyped Hispanic (n = 1,151) and African American (n = 574) participants from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Through resequencing and bioinformatic analysis, rare/low frequency (<5% MAF) and common variants (>5% MAF) in ADIPOQ were identified. Genetic variants and clinical variables were assessed for association with adiponectin levels and contribution to adiponectin variance in the Hispanic and African American cohorts. Clinical traits accounted for the greatest proportion of variance (POV) at 31% (P = 1.16 * 10-(47)) and 47% (P = 5.82 * 10-(20)), respectively. Rare/low frequency variants contributed more than common variants to variance in Hispanics: POV = 18% (P = 6.40 * 10-(15)) and POV = 5% (P = 0.19), respectively. In African Americans, rare/low frequency and common variants both contributed approximately equally to variance: POV = 6% (P = 5.44 * 10-(12)) and POV = 9% (P = 1.44 * 10-(10)), respectively. Importantly, single low frequency alleles in each ethnic group were as important as, or more important than, common variants in explaining variation in adiponectin. Cumulatively, these clinical and ethnicity-specific genetic contributors explained half or more of the variance in Hispanic and African Americans and provide new insight into the sources of variation for this important adipocytokine. PMID- 23032298 TI - A theoretical study of the hydrogen-storage potential of (H2)4CH4 in metal organic framework materials and carbon nanotubes. AB - The hydrogen-methane compound (H(2))(4)CH(4)-or for short H4M-is one of the most promising hydrogen-storage materials. This van der Waals compound is extremely rich in molecular hydrogen: 33.3 mass%, not including the hydrogen bound in CH(4); including it, we reach even 50.2 mass%. Unfortunately, H4M is not stable under ambient pressure and temperature, requiring either low temperature or high pressure. In this paper, we investigate the properties and structure of the molecular and crystalline forms of H4M, using ab initio methods based on van der Waals DFT (vdW-DF). We further investigate the possibility of creating the pressures required to stabilize H4M through external agents such as metal organic framework (MOF) materials and carbon nanotubes, with very encouraging results. In particular, we find that certain MOFs can create considerable pressure for H4M in their cavities, but not enough to stabilize it at room temperature, and moderate cooling is still necessary. On the other hand, we find that all the investigated carbon nanotubes can create the high pressures required for H4M to be stable at room temperature, with direct implications for new and exciting hydrogen-storage applications. PMID- 23032299 TI - Electrofusion of B16-F1 and CHO cells: the comparison of the pulse first and contact first protocols. AB - High voltage electric pulses induce permeabilisation (i.e. electroporation) of cell membranes. Electric pulses also induce fusion of cells which are in contact. Contacts between cells can be established before electroporation, in so-called contact first or after electroporation in pulse first protocol. The lowest fusion yield was obtained by pulse first protocol (0.8%+/-0.3%) and it was only detected by phase contrast microscopy. Higher fusion yield detected by fluorescence microscopy was obtained by contact first protocol. The highest fusion yield (15%) was obtained by modified adherence method whereas fusion yield obtained by dielectrophoresis was lower (4%). The results are in agreement with current understanding of electrofusion process and with existing electrochemical models. Our data indicate that probability of stalk formation leading to fusion pores and cytoplasmic mixing is higher in contact first protocol where cells in contact are exposed to electric pulses. Another contribution of present study is the comparison of two detection methods. Although fusion yield can be more precisely determined with fluorescence microscopy we should note that by using this detection method single coloured fused cells cannot be detected. Therefore low fusion yields are more reliably detected by phase contrast microscopy. PMID- 23032301 TI - Time-resolved detection of fluorescent light during inflow of ICG to the brain-a methodological study. AB - It was reported that time-resolved reflectance measurements carried out during inflow and washout of an optical contrast agent may provide information on the blood supply to the brain cortex of human adults. It was also shown that a measurement of fluorescence excited in the dye circulating in the brain is feasible. Unfortunately, patterns of time-resolved fluorescence signals observed during in vivo measurements are difficult to interpret. The aim of this study was to analyze the influence of several factors on the fluorescence signals measured during in vivo experiments. A laboratory instrument for recording the distributions of arrival of fluorescence photons was constructed and optimized for measurements on humans. Monte Carlo simulations and laboratory measurements on liquid phantoms as well as in vivo measurements on healthy volunteers were carried out. An influence of source-detector separation, position of the source detector pair on the head, as well as a dose of the injected indocyanine green (ICG) on the fluorescence signals were studied in detail. It was shown that even for a small dose of ICG (0.025 mg kg(-1)) the time-resolved signals can be successfully detected on the surface of the head. Strong influence of the studied factors on the fluorescence signals was observed. It was also noted that the changes in moments of distributions of arrival times of fluorescence photons depend on the anatomical structure of the tissues located between the source and the detector. PMID- 23032302 TI - Charge transfer in spinel Co3O4 at high pressures. AB - Charge transfer in cobalt oxide Co(3)O(4) in the spinel structure is evidenced by experimental results using x-ray diffraction (XRD), x-ray absorption near edge structure (XANES) spectroscopy, and Raman scattering at high pressures up to 42.1, 24.6 and 35.1 GPa, respectively. While the cubic structure was found to persist under pressure up to 42.1 GPa based on the XRD and Raman results, the mode Gruneisen parameter was calculated according to our Raman measurements. Our structural data refinement revealed a structural transition from the normal spinel structure at low pressures to a partially inverse spinel structure at pressures above 17.7 GPa. This transition may be caused by the interaction of charges between tetrahedral and octahedral sites via a charge transfer process. Evidence for the charge transfer process is further supported by changes of the pre-edge features in the XANES data. PMID- 23032300 TI - Electronic symptom reporting between patient and provider for improved health care service quality: a systematic review of randomized controlled trials. part 1: state of the art. AB - BACKGROUND: Over the last two decades, the number of studies on electronic symptom reporting has increased greatly. However, the field is very heterogeneous: the choices of patient groups, health service innovations, and research targets seem to involve a broad range of foci. To move the field forward, it is necessary to build on work that has been done and direct further research to the areas holding most promise. Therefore, we conducted a comprehensive review of randomized controlled trials (RCTs) focusing on electronic communication between patient and provider to improve health care service quality, presented in two parts. Part 2 investigates the methodological quality and effects of the RCTs, and demonstrates some promising benefits of electronic symptom reporting. OBJECTIVE: To give a comprehensive overview of the most mature part of this emerging field regarding (1) patient groups, (2) health service innovations, and (3) research targets relevant to electronic symptom reporting. METHODS: We searched Medline, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, and IEEE Xplore for original studies presented in English-language articles published from 1990 to November 2011. Inclusion criteria were RCTs of interventions where patients or parents reported health information electronically to the health care system for health care purposes and were given feedback. RESULTS: Of 642 records identified, we included 32 articles representing 29 studies. The included articles were published from 2002, with 24 published during the last 5 years. The following five patient groups were represented: respiratory and lung diseases (12 studies), cancer (6), psychiatry (6), cardiovascular (3), and diabetes (1). In addition to these, 1 study had a mix of three groups. All included studies, except 1, focused on long-term conditions. We identified four categories of health service innovations: consultation support (7 studies), monitoring with clinician support (12), self management with clinician support (9), and therapy (1). Most of the research (21/29, 72%) was conducted within four combinations: consultation support innovation in the cancer group (5/29, 17%), monitoring innovation in the respiratory and lung diseases group (8/29, 28%), and self-management innovations in psychiatry (4/29, 14%) and in the respiratory and lung diseases group (4/29, 14%). Research targets in the consultation support studies focused on increased patient centeredness, while monitoring and self-management mainly aimed at documenting health benefits. All except 1 study aiming for reduced health care costs were in the monitoring group. CONCLUSION: RCT-based research on electronic symptom reporting has developed enormously since 2002. Research including additional patient groups or new combinations of patient groups with the four identified health service innovations can be expected in the near future. We suggest that developing a generic model (not diagnosis specific) for electronic patient symptom reporting for long-term conditions may benefit the field. PMID- 23032303 TI - Breakfast habits, beliefs and measures of health and wellbeing in a nationally representative UK sample. AB - The aim of this study was to report UK adult breakfasting habits, beliefs and the relationship of both with measures of personality, health and wellbeing including physical activity and body mass index (BMI). A nationally representative sample of 1068 adults completed a web-based survey, combining standardised scales and self-designed questionnaire statements. Sixty-four percent of respondents consumed breakfast daily whilst 6% never ate breakfast. Breakfasting frequency was found to correlate with conscientiousness, wellbeing and age and general health. The survey found that breakfast eaters strongly believe that breakfast helps weight control and weight loss. Breakfast eaters were more likely to partake in vigorous exercise, although there was no significant difference in BMI. Multi-variate analysis identified conscientiousness, cognitive restraint and age as making unique contributions to predicting breakfast frequency. This study provides further support for the view that breakfast eating is likely to be a proxy-variable for a healthy lifestyle. The role of breakfast and related beliefs should be taken into consideration in breakfast behaviour research, interventions and health and wellbeing campaigns. PMID- 23032304 TI - Mixed selection. Effects of body images, dietary restraint, and persuasive messages on females' orientations towards chocolate. AB - Many women experience ambivalent reactions to chocolate: craving it but also wary of its impact on weight and health. Chocolate advertisements often use thin ideal models and previous research indicates that this exacerbates ambivalence. This experiment compared attitudes to, and consumption of, chocolate following exposure to images containing thin or overweight models together with written messages that were either positive or negative about eating chocolate. Participants (all female) were categorised as either low- or high-restraint. Approach, avoidance and guilt motives towards chocolate were measured and the participants had an opportunity to consume chocolate. Exposure to thin ideal models led to higher approach motives and this effect was most marked among the high restraint participants. Avoidance and guilt scores did not vary as a function of model size or message, but there were clear differences between the restraint groups, with the high restraint participants scoring substantially higher than low restraint participants on both of these measures. When the participants were provided with an opportunity to eat some chocolate, those with high restraint who had been exposed to the thin models consumed the most. PMID- 23032306 TI - Presyndromic phase: proposal for a new term for an emerging concept. PMID- 23032305 TI - The TaqIA RFLP is associated with attenuated intervention-induced body weight loss and increased carbohydrate intake in post-menopausal obese women. AB - INTRODUCTION: Polymorphisms of the dopamine receptor D2 (DRD2) gene have been associated with obesity phenotypes. Our aim was to examine if the genotype of TaqIA Restriction Fragment Length Polymorphism (RFPL) was related to an attenuated weight loss response or to changes in energy expenditure (EE) and food preference before and after weight loss. methods: Obese post-menopausal women (age=57.1 +/- 4.6 yr, weight=85.4 +/- 15.4 kg and BMI=32.8 +/- 4.5 kg/m(2)) were genotyped for TaqIA (n=127) by using PCR-RFLP analysis and categorized as possessing at least one copy of the A1 allele (A1(+)) or no copy (A1(-)). Women were randomized into two groups, caloric restriction (CR) and caloric restriction+resistance training (CRRT) and in this study were further classified as follows: A1(+)CR, A1(+)CRRT, A1-(-)CR and (-)A1(-)CRRT. Body composition, total daily EE, physical activity EE, Resting EE (REE), and energy intake were obtained at baseline and post-intervention using DXA, doubly-labeled water, indirect calorimetry, and 3-day dietary records, respectively. RESULTS: Overall, all of the anthropometric variables and REE significantly decreased post intervention (p<0.001). Women in the CRRT group lost significantly more fat mass (FM) than the CR women (p<0.05). There were significant time by group by allele interactions for attenuated body weight (BW), BMI, and FM loss for A1(+) (vs. A1( )) in CRRT (p<0.05) and for increased % carbohydrate intake (p<0.01). CONCLUSION: TaqIA genotype was associated with body weight loss post-intervention; more specifically, carriers of the A1 allele lost significantly less BW and FM than the A1(-) and had increased carbohydrate intake in the CRRT group. PMID- 23032307 TI - Open access: a revolution in scientific publication? Or just a minor amendment of accessibility? PMID- 23032309 TI - Of dogs and cows: a quasi-artificial selection scenario. PMID- 23032310 TI - Transcranial direct current stimulation intensity and duration effects on tinnitus suppression. AB - BACKGROUND: Perception of sound in the absence of an external auditory source is called tinnitus, which may negatively affect quality of life. Anodal transcranial direct current stimulation (tDCS) of the left temporoparietal area (LTA) was explored for tinnitus relief. OBJECTIVE: This pilot study examined tDCS dose (current intensity and duration) and response effects for tinnitus suppression. METHODS: Twenty-five participants with chronic tinnitus and a mean age of 54 years took part. Anodal tDCS of LTA was carried out. Current intensity (1 mA and 2 mA) and duration (10 minutes, 15 minutes, and 20 minutes) were varied and their impact on tinnitus measured. RESULTS: tDCS was well tolerated. Fifty-six percent of participants (14) experienced transient suppression of tinnitus, and 44% of participants (11) experienced long-term improvement of symptoms (overnight-less annoyance, more relaxed, and better sleep). There was an interaction between duration and intensity of the stimulus on the change in rated loudness of tinnitus, F(2, 48) = 4.355, P = .018, and clinical global improvement score, F(2, 48) = 3.193, P = .050, after stimulation. CONCLUSIONS: Current intensity of 2 mA for 20 minutes was the more effective stimulus parameter for anodal tDCS of LTA. tDCS can be a potential clinical tool for reduction of tinnitus, although longer term trials are needed. PMID- 23032308 TI - Integrated signaling in developing lymphocytes: the role of DNA damage responses. AB - Lymphocyte development occurs in a stepwise progression through distinct developmental stages. This ordered maturation ensures that cells express a single, non-autoreactive antigen receptor, which is the cornerstone of a diverse adaptive immune response. Expression of a mature antigen receptor requires assembly of the antigen receptor genes by the process of V(D)J recombination, a reaction that joins distant gene segments through DNA double-strand break (DSB) intermediates. These physiologic DSBs are generated by the recombinase-activating gene (RAG) -1 and -2 proteins, and their generation is regulated by lymphocyte and developmental stage-specific signals from cytokine receptors and antigen receptor chains. Collectively, these signals ensure that V(D)J recombination of specific antigen receptor genes occurs at discrete developmental stages. Once generated, RAG-induced DSBs activate the ataxia-telangiectasia mutated (ATM) kinase to orchestrate a multifaceted DNA damage response that ensures proper DSB repair. In response to RAG DSBs, ATM also regulates a cell type-specific transcriptional response, and here we discuss how this genetic program integrates with other cellular cues to regulate lymphocyte development. PMID- 23032312 TI - New cationic nanovesicular systems containing lysine-based surfactants for topical administration: Toxicity assessment using representative skin cell lines. AB - Cationic nanovesicles have attracted considerable interest as effective carriers to improve the delivery of biologically active molecules into and through the skin. In this study, lipid-based nanovesicles containing three different cationic lysine-based surfactants were designed for topical administration. We used representative skin cell lines and in vitro assays to assess whether the cationic compounds modulate the toxic responses of these nanocarriers. The nanovesicles were characterized in both water and cell culture medium. In general, significant agglomeration occurred after 24h incubation under cell culture conditions. We found different cytotoxic responses among the formulations, which depended on the surfactant, cell line (3T3, HaCaT, and THP-1) and endpoint assayed (MTT, NRU, and LDH). Moreover, no potential phototoxicity was detected in fibroblast or keratinocyte cells, whereas only a slight inflammatory response was induced, as detected by IL-1alpha and IL-8 production in HaCaT and THP-1 cell lines, respectively. A key finding of our research was that the cationic charge position and the alkyl chain length of the surfactants determine the nanovesicles resulting toxicity. The charge on the alpha-amino group of lysine increased the depletion of cell metabolic activity, as determined by the MTT assay, while a higher hydrophobicity tends to enhance the toxic responses of the nanovesicles. The insights provided here using different cell lines and assays offer a comprehensive toxicological evaluation of this group of new nanomaterials. PMID- 23032313 TI - Omega-3 Fatty Acid Ingestion as a TBI Prophylactic. AB - Given the hazardous nature of combat operations and training exercises (e.g. airborne operations) conducted by the United States military, servicemembers are at high risk for sustaining a traumatic brain injury (TBI). Since the beginning of the Iraq and Afghanistan wars, almost a quarter of a million servicemembers have sustained a TBI.1 A large number of TBIs are a result of the concussive forces generated by improvised explosive devices (IED). A smaller number are a result of penetrating head wounds. Others may be caused by activities resulting in powerful acceleration, deceleration, or rotational forces. Therapies for treating TBI thus far have been limited. Much of the research conducted to date has focused on post-injury pharmacological interventions.2 Additionally, better protective equipment could help in preventing TBIs; however, these issues are outside the scope of this paper. A relatively new area of research is investigating prophylactic measures taken to lessen the effects of TBI. One such measure involves nutritional interventions and their effects on TBI severity. Therefore, the purpose of this paper is to elucidate the potential benefits of omega-3 fatty acid intake as it relates to TBI severity. PMID- 23032314 TI - Planning for success: desired characteristics of special operations surgeons, a pilot study. AB - BACKGROUND: Selection criteria for Special Operations Forces (SOF) physicians are often unclear to potential candidates without prior SOF experience. To date, no published career resource exists to guide the careers of physicians interested in becoming a SOF surgeon. Using a survey tool, desirable characteristics and personal attributes were identified that can be used to inform candidate career decisions and better prepare them for a future position in Special Operations. METHODS: A descriptive, cross-sectional survey instrument was developed and distributed to current Army SOF Command Surgeons for further distribution to subordinate surgeons. RESULTS were analyzed as a cohort and by subordinate command. RESULTS: Respondents consisted of current SOF Surgeons. Uniformly, the individual characteristics most strongly desired are professionalism, being a team player, and leadership. Possessing or obtaining Airborne and Flight Surgeon qualifications prior to consideration for a surgeon position was highly desired. Residency training within Family Medicine or Emergency Medicine constituted the vast majority of specialty preference. CONCLUSIONS: Understanding which characteristics and attributes are desirable to current surgeons and commanders can aid physicians interested in SOF surgeon positions. Using this study and future studies can guide career planning and foster the selection of ideally trained physicians who will operate at the tip of the spear. The views expressed are those of the author(s) and do not reflect the official policy of the Department of the Army, the Department of Defense or the U.S. Government. PMID- 23032315 TI - Missions, Training and Equipment: A Retrospective View from the 160th SOAR (A). AB - On 3 October 2001, the first chalk of Night Stalkers left Campbell Army Airfield enroute to Uzbekistan in support of what would become our nation?s longest war. The vast majority of Soldiers were untested in war and would quickly have the opportunity to meet with the enemies of our nation in close combat. The two Special Operations Task Forces (TF), TF Dagger to the north in Uzbekistan and TF Sword in the south (aboard the USS Kitty Hawk) were our nation?s first strike options against Al Qaeda and Taliban forces in Afghanistan. Due to the inherent nature of forced entry operations (restrictive terrain, lack of medical infrastructure, etc.) TF Dagger and TF Sword utilized 160th Special Operations Aviation Regiment (Airborne) [SOAR (A)] rotary wing aircraft solely for the Casualty Evacuation (CASEVAC) operations during the first months of Operation ENDURING FREEDOM. PMID- 23032316 TI - Detection of increased intracranial pressure by ultrasound. AB - Increases in intracranial pressure (ICP) may damage the brain by compression of its structures or restriction of its blood flow, and medical providers my encounter elevated ICP in conventional and non-conventional medical settings. Early identification of elevated ICP is critical to ensuring timely and appropriate management. However, few diagnostic methods are available for detecting increased ICP in an acutely ill patient, which can be performed quickly and noninvasively at the bedside. The optic nerve sheath is a continuation of the dura mater of the central nervous system and can be viewed by ocular ultrasound. Pressure changes within the intracranial cavity affect the diameter of the optic nerve sheath. Data acquired from multiple clinical settings suggest that millimetric increases in the optic nerve sheath diameter detected via ocular ultrasound correlate with increasing levels of ICP. In this review, we discuss the use of ocular ultrasound to evaluate for the presence of elevated ICP via assessment of optic nerve sheath diameter, and describe critical aspects of this valuable diagnostic procedure. Ultrasound is increasingly becoming a medical fixture in the modern battlefield where other diagnostic modalities can be unavailable or impractical to employ. As Special Forces and other austere medical providers become increasingly familiar with ultrasound, ocular ultrasound for the assessment of increased intracranial pressure may help optimize their ability to provide the most effective medical management for their patients. PMID- 23032317 TI - Special operations forces and incidence of post-traumatic stress disorder symptoms. AB - To determine the rates of Post-traumatic Stress Disorder (PTSD) positive symptom scores in Special Operations Forces (SOF) personnel, an anonymous survey of SOF was employed, incorporating the PTSD Checklist (PCL-M) with both demographic and deployment data. Results indicate that all SOF units studied scored above the accepted cut-offs for PTSD positive screening.1 When total symptom severity score exceeded established cutoff points and were combined with criteria for Diagnostic and Statistical Manual of Mental Disorders, Edition 4 (DSM-IV) diagnosis of PTSD,2 approximately 16?20% of respondents met scoring threshold for positive screening, almost double those of conventional Army units. Collectively, Special Forces (SF) Soldiers and SOF combat-arms Soldiers had significantly higher PLC-M scores than their non-combat-arms SOF counterparts. SOF Soldiers with three or more deployments to Afghanistan had significantly higher PCL-M scores. Considering the evidence suggesting that SOF Soldiers are hyper-resilient to stress, these results should drive further research schemata and challenge clinical assumptions of PTSD within Special Operations. PMID- 23032318 TI - Unforeseen risk: leptospirosis and the u.s. Special operations community. AB - Leptospirosis is a bacterial zoonosis with worldwide distribution and is potentially lethal to those infected if left untreated. Due to the global posture of the U.S. Special Operations community, there is a seemingly perfect overlap of the regions in which they deploy and areas with concurrent endemic leptospirosis infection. Furthermore, Special Operations Forces (SOF) personel are known for working by, with, and through the host nation defense force, who tend to be commonly affected and often serve as a reservoir for this infection. Other risk factors including the usage of infected military working dogs, contaminated training sites, and certain recreational activities associated with water increase the danger of exposure for this cohort. Due to this increased risk of leptospirosis by U.S. Special Operations service members, medical providers within this community must understand and utilize proper preventive medicine, prophylaxis, early detection, diagnosis, and treatment for this potentially lethal infection. PMID- 23032319 TI - Tactical physical preparation: the case for a movement-based approach. AB - Progressive injury prevention and physical preparation programs are needed in military special operations to optimize mission success and Operator quality of life and longevity. While physical risk is inherent in Special Operations, non traumatic injuries resulting from overuse, poor biomechanics, and arbitrary exercise selection can be alleviated with proper medical care and patient education. An integrated approach to physical readiness that recognizes the continuity between rehabilitation and performance training is advocated to ensure that physiological adaptations do not come at the expense of orthopedic health or movement proficiency. Movement quality should be regularly evaluated and enforced throughout the training process to minimize preventable injuries and avoid undermining previous rehabilitative care. While fitness and proper movement are not substitutes for Operator specific tasks, they are foundational to many tactically-relevant skills. In light of how much is at stake, sports medicine care in the military, especially special operations, should parallel that which is practiced in professional and collegiate athletics. PMID- 23032320 TI - Atypical chronic insomnia in a special forces soldier: a case review. PMID- 23032321 TI - Exertional rhabdomyolysis: attrition through exercise, a case series and review of the literature. AB - Rhabdomyolysis is a common syndrome that can range from asymptomatic to a severe life-threatening condition. It is the result of acute muscle fiber necrosis leading to cell lysis and subsequent transfer of those byproducts into the circulatory system.1-3 The most significant constituent of these byproducts is myoglobin, which has been known to cause renal failure in 10?50% of patients that develop rhabdomyolysis.4,5 In addition, the electrolytes contained within these cells are leached into the blood stream, which can lead to significant electrolyte abnormalities. The etiology of rhabdomyolysis is broad and includes inherited diseases, drugs, toxins, muscle compression or overexertion, infections, and more. This syndrome may carry a mortality rate ranging from 7?80%.3,6 We describe five patients assigned to various companies within 160th Special Operations Aviation Regiment (Airborne) that developed exertional rhabdomyolysis of the bilateral upper extremities between June 2011 and January 2012. In this case series we will describe the events leading up to the diagnosis, lack of risk factors or family history, diagnostic criteria, treatment, and future concerns related to the condition. PMID- 23032322 TI - Effect of hetastarch bolus in trauma patients requiring emergency surgery. AB - If blood products are not available, current military guidelines recommend a hetastarch bolus (HEX, Hextend 6% hetastarch in lactated electrolyte buffer, www. hospira.com) for initial treatment of hypovolemic shock in the field. We previously reported that a HEX bolus plus standard of care (SOC = crystalloid plus blood products) was safe during initial resuscitation in 1714 trauma patients. This study tests the hypothesis that HEX+SOC is more effective than SOC alone for volume expansion in trauma patients requiring urgent operation. METHODS: From July 2009 to August 2010, the records from all adults who required emergency surgery within 4 hours of admission were screened for a retrospective cohort observational study. Burns, and those with primary neurosurgical or orthopedic indications, were excluded. The study population was comprised of 281 patients with blunt (n = 72) or penetrating (n = 209) trauma; 141 received SOC and 140 received SOC+HEX in the emergency room only (ER, n = 81) or the ER and operating room (OR, n = 59). Each case was reviewed with waiver of consent. RESULTS: After penetrating injury, with SOC, the injury severity score was 17 and mortality was 12%; the corresponding values in the HEX(ER) and HEX(OR) groups were 19?21 and 8%, but these apparent differences did not reach significance. However, in patients receiving HEX, initial heart rate was higher, base deficit was lower, and hematocrit was lower (consistent with relative hypovolemia), even though blood product requirements were reduced, and urine output was greater (all p < 0.05). These effects were absent in patients with blunt trauma. Platelet consumption was higher with HEX after either penetrating (p = 0.004) or blunt trauma (p = 0.045), but coagulation tests were unchanged. CONCLUSION: HEX is safe for initial resuscitation in young patients who required urgent operation after penetrating trauma, but there was no apparent effect after blunt trauma. A bolus of HEX reduced transfusion requirements without inducing coagulopathy or causing renal dysfunction, but a randomized controlled trial is necessary to eliminate the possibility of selection bias. PMID- 23032323 TI - Lighting did not affect self-application of a stretch and wrap style tourniquet. AB - The objective was to determine the effects of darkness on self-application of a stretch and wrap style tourniquet. METHODS: Following training and practice, 15 volunteers self-applied the Stretch, Wrap, and Tuck-Tourniquet (SWAT-T) to their leg, thigh, dominant forearm, and dominate arm. Proper application in lighted conditions was followed by the same applications in darkness. Proper stretch was determined by alteration of shapes printed on the tourniquet. RESULTS: High rates of proper application and successful arterial occlusion (60 second Doppler signal elimination) occurred in darkness just as in lighted conditions (darkness: 56 proper and 60 successful of 60 applications, lighted: 57 proper and 53 successful of 60 applications). Lighting did not affect ease of application or discomfort. Males (8) and females (7) were similarly successful. Lower limb applications were predominantly rated easy (51 of 60). Upper limb applications had fewer easy ratings (15 easy, 32 challenging, 13 difficult ratings). Arterial occlusion took < 60 seconds in 112 of 113 successful applications; completion took < 60 seconds in 88 of all 120 applications. Upper limb applications took longer for completion. CONCLUSIONS: The SWAT-T stretch and wrap style tourniquet can be self applied properly even in darkness. When properly applied, it can stop limb arterial flow. PMID- 23032325 TI - Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: report of the international turner syndrome aortic dissection registry. AB - BACKGROUND: Girls and women with Turner syndrome are at risk for aortic dissection and rupture. However, the size of the aorta and the clinical characteristics among those with Turner syndrome and dissection have received little attention. METHODS AND RESULTS: We obtained medical records from 20 individuals who voluntarily participated in the International Turner Syndrome Aortic Dissection Registry. Type A dissections occurred in 17 of 20 (85%) cases, and type B occurred in 3 cases of which 1 occurred after coarctation stent placement. Of those with spontaneous aortic dissections, 18 of 19 (95%) had an associated cardiac malformation that included a bicuspid aortic valve. In 1 individual there was no predisposing finding other than the presence of Turner syndrome. Associated pregnancy was documented in 1 of 19 (5%). More than half (13/19, 68%) came to medical attention >24 hours after the onset of symptoms. For those with type A dissections, the mean ascending aortic size index was 2.7+/-0.6 cm/m(2) (n=9). CONCLUSIONS: Aortic dissection in Turner syndrome occurs in young individuals at smaller aortic diameters than in the general population or other forms of genetically triggered aortopathy. The absence of aortic valve or other cardiac malformations appears to markedly reduce the risk of aortic dissection However, aortic dissection can occur in Turner syndrome without cardiac malformations or hypertension. Individuals with Turner syndrome who are >18 years of age with an ascending aortic size index >2.5 cm/m(2) should be considered for an aortic operation to prevent aortic dissection. PMID- 23032324 TI - Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis. AB - BACKGROUND: Coagulation disorders and reperfusion of ischemic myocardium are major causes of morbidity and mortality. Lectin pathway initiation complexes are composed of multimolecular carbohydrate recognition subcomponents and 3 lectin pathway-specific serine proteases. We have recently shown that the lectin pathway specific carbohydrate recognition subcomponent mannose-binding lectin plays an essential role in the pathophysiology of thrombosis and ischemia/reperfusion injury. Thus, we hypothesized that the endogenous mannose-binding lectin (MBL)/ficolin-associated protein-1 (MAP-1) that inhibits complement activation in vitro also could be an in vivo regulator by attenuating myocardial schema/reperfusion injury and thrombogenesis when used at pharmacological doses in wild-type mice. METHODS AND RESULTS: In 2 mouse models, MAP-1 preserves cardiac function, decreases infarct size, decreases C3 deposition, inhibits MBL deposition, and prevents thrombogenesis. Furthermore, we demonstrate that MAP-1 displaces MBL/ficolin-associated serine protease (MASP)-1, MASP-2, and MASP-3 from the MBL complex. CONCLUSIONS: Our results suggest that the natural, endogenous inhibitor MAP-1 effectively inhibits lectin pathway activation in vivo. MAP-1 at pharmacological doses represents a novel therapeutic approach for human diseases involving the lectin pathway and its associated MASPs. PMID- 23032327 TI - A novel method for visualising and quantifying through-plane skin layer deformations. AB - Skin is a multilayer composite and exhibits highly non-linear, viscoelastic, anisotropic material properties. In many consumer product and medical applications (e.g. during shaving, needle insertion, patient re-positioning), large tissue displacements and deformations are involved; consequently large local strains in the skin tissue can occur. Here, we present a novel imaging based method to study skin deformations and the mechanics of interacting skin layers of full-thickness skin. Shear experiments and real-time video recording were combined with digital image correlation and strain field analysis to visualise and quantify skin layer deformations during dynamic mechanical testing. A global shear strain of 10% was applied to airbrush-patterned porcine skin (thickness: 1.2-1.6mm) using a rotational rheometer. The recordings were analysed with ARAMIS image correlation software, and local skin displacement, strain and stiffness profiles through the skin layers determined. The results of this pilot study revealed inhomogeneous skin deformation, characterised by a gradual transition from a low (2.0-5.0%; epidermis) to high (10-22%; dermis) shear strain regime. Shear moduli ranged from 20 to 130kPa. The herein presented method will be used for more extended studies on viable human skin, and is considered a valuable foundation for further development of constitutive models which can be used in advanced finite element analyses of skin. PMID- 23032326 TI - Trends in the incidence of atrial fibrillation in older patients initiating dialysis in the United States. AB - BACKGROUND: One sixth of US dialysis patients 65 years of age have been diagnosed with atrial fibrillation/flutter (AF). Little is known, however, about the incidence of AF in this population. METHODS AND RESULTS: We identified 258 605 older patients (>=67 years of age) with fee-for-service Medicare initiating dialysis in 1995 to 2007, who had not been diagnosed with AF within the previous 2 years. Patients were followed for newly diagnosed AF. Multivariable proportional hazard regression was used to examine temporal trends and associations of race and ethnicity with incident AF. We also studied temporal trends in the mortality and risk of ischemic stroke after new AF. Over 514 395 person-years of follow-up, 76 252 patients experienced incident AF for a crude AF incidence rate of 148/1000 person-years. Incidence of AF increased by 11% (95% confidence interval, 5-16) from 1995 to 2007. Compared with non-Hispanic whites, blacks (-30%), Asians (-19%), Native Americans (-42%), and Hispanics (-29%) all had lower rates of incident AF. Mortality after incident AF decreased by 22% from 1995 to 2008. Even more pronounced reductions were seen for incident ischemic stroke during these years. CONCLUSIONS: The incidence of AF is high in older patients initiating dialysis in the United States and has been increasing over the 13 years of study. Mortality declined during that time but remained >50% during the first year after newly diagnosed AF. Because data on warfarin use were not available, we were unable to study whether trends toward better outcomes could be explained by higher rates of oral anticoagulation. PMID- 23032328 TI - Expansion of courses/places for nursing graduation and the quality of nurse's education process. PMID- 23032329 TI - [Re(thinking) nursing carative projects through the light of population health needs]. AB - The concept of needs is central to the work of Nursing. The Basic Human Needs Theory, formulated by Wanda Horta, influenced several generations of Brazilian nurses and possibly still is the most widespread in education and nursing practice in Brazil. However, there are other conceptions of needs that can illuminate health work that is, in general, organized to meet health needs through standardized, vertical and prescriptive service offerings. Reframing health care, specially nursing carative projects, demands to adopt a concept of health and disease capable of linking individual and collective aspects. PMID- 23032330 TI - [Expansion of undergraduate nursing and the labor market: reproducing inequalities?]. AB - This study aimed to analyze the relationship between the increase in the number of degree courses in nursing and the nursing job market. It is a descriptive exploratory study with a quantitative approach, which used data on Undergraduate Nursing courses, supply of nurses, connection with health facilities, and formal jobs in nursing in the state of Minas Gerais. The evolution of Undergraduate Nursing courses reveals a supply and demand decline in recent years. Such context is determined by the nurse's labor market being influenced by the contradiction of a professional quantitative surplus, particularly in the state's less developed areas, as opposed to a low percentage of nurses to care for the population's health. These characteristics of the nursing labor market reproduce inequalities furthermore aspects such as the regulation of nursing education and the creation of new jobs need to be discussed further. PMID- 23032331 TI - [Health education in the job of nurses in Santarem of Para, Brazil]. AB - This qualitative study aimed to analyze the knowledge and educational practices of nurses in the Family Health Units, in Santarem-PA, North of Brazil, and their utilization of health education tools within the labour process. We conducted semi-structured interviews and observation of educational activities of 15 nurses. From the content analysis, the following themes emerged: conceptions of health education; educational practices within the work process; and a trend to the Popular Education theoretical framework. Despite most of the nurses were Family Health specialists, they mentioned a gap in their professional education in terms of theoretical knowledge about health education. The traditional models were predominant in the conceptions and practices. The labour process is strongly based on Ministry of Health's programs. It was possible to recognize a discrete trend to Popular Education, with attempts to a reorientation of their educational practices, establishing partnerships with other care providers and community leaderships. PMID- 23032332 TI - [Educational actions in a Community Healthcare Agents Program]. AB - This study aimed to identify and analyze the actions performed by an educational program of Community Health Agents of a city in the state of Sao Paulo, Brazil, considering the educational concepts, the team approach and aspects which influence in desired change by the program. It is a qualitative research using case study. Semi-structured interviews were conducted that were treated with content analysis, thematic modality. The study showed that the predominant pedagogical concept is the transmission of information aimed at disease prevention, although there are some actions near the participative pedagogy. The organization of work and the link with the population also influence the educational work. It is concluded that educational activities are still grounded in Preventive challenges for health promotion and lack of investment in training and organization of health care network. PMID- 23032333 TI - [Nakedness of the patient from the perspective of students of fundamental nursing]. AB - The study aimed to analyze the speech of students, their view of the denudation of the body to handle. It was a descriptive qualitative research, whose subjects were 21 students from three courses of 3 to 5 semesters. The information was produced by transcribing the twenty-one semi-structured interviews and analyzed on the basis of Foucault's thought.The themes were: Care of the naked body implies observance of bioethical principle of autonomy as the school's reproductive power relationship in the act of stripping, naked Coping with the other requires care, Care of the naked body "moves" with their sexuality; Power relations with the naked body. It was possible to understand the exercise of power by students at the time of stripping, as response to insecurity arising from inadequate school preparation. PMID- 23032335 TI - [Assistance for people with hypertension in the perspective of the health professional]. AB - The study aimed at learning about the care provided to people with hypertension in primary care from the perspective of health workers. The data was collected through focus groups in five cities in the northwest of the state of Parana. It was observed that, although the study was conducted with teams of different municipalities, the meanings and perceptions regarding the care provided and the difficulties experienced are similar in many aspects. In general, the Basic Health Units meet the most urgent needs of users, despite the adoption of strategies for treatment adherence, for various reasons, cannot reach the entire population, undermining the quality of care, even with the commitment of the team. PMID- 23032334 TI - [Health promotion in the Pankararu indigenous community]. AB - The objective of the study was to know how the Pankararu indigenous perceive their health situation and identify actions they prioritize as necessary to promote health in their community. Qualitative research, in which the declarations collected were subjected to the technique of analyzing the Collective Subject Discourse. It was identified that in the indigenous perception, as the health status of their community, there is a lack of general assistance, and a lack of professionals to assist them meeting their needs. In relation to actions that the Indigenous prioritize as necessary to promote the health of their community, it was highlighted provision of health unit with trained professionals and access to health education actions. It was, thus, proposed an overhaul of the organizations and establishments of the subsystems in promoting indigenous health. PMID- 23032336 TI - Health related quality of life of chronic patients with immune system diseases: a pilot study. AB - Health related quality of life (HRQL) and survival are two important outcome measures in chronic diseases. This study aimed to compared HRQL in patients with different chronic diseases of immune system and normative data from the general Portuguese Population. It was selected 103 out-patients, by convenience, to complete SF-36v2. The lowest scores were found among measures for general health (41.0), vitality (47.5), bodily pain (51.0), mental health (56.4); women, except for role-physical, and patients with auto-immune diseases have had the worse scores on all assessed dimension of subjective health, when compared with normative data. Highest scores were obtained in the following scales: physical functioning (69.1), social functioning (66.9), role-emotional (64.9). Living with chronic immune disease have impact on HRQL and it can be expected that the Portuguese version of SF-36v2 provide valid and reliable HRQL data. PMID- 23032337 TI - [Professional practice of nurses who care for cancer patients in general hospitals]. AB - The present article discusses a qualitative study which aimed to understand the typical of nurses' professional practice caring for patient with cancer in general hospitals. In order to find out the reasons that motivate nurse's action, and to put in evidence what is original, significant, specific and typical about this phenomenon, we have taken into consideration the premises of the philosopher Alfred Schutz, which provide us with subsidies to unveil them. The data collected through semi-structured interviews reported that nurses admit not having the required theoretical knowledge and experience or enough practice to take care of a cancer patient. Thus, they don't feel capable of developing actions which may positively influence care on patients and their family members. PMID- 23032338 TI - [Assessment of Wiki technology: a tool for accessing information on mechanical ventilation in intensive care]. AB - The development and application of information technology influence all areas of knowledge, enabling new ways of learning. The Wiki is a tool of information and communication technology provided by the Web 2.0 that can be exploited and used in teaching, learning, care and research in nursing education. Thus, this quantitative study is a descriptive and exploratory objective was to evaluate the nursing students with the criteria of Ergonomics and Usability of the tool Wiki as a technology to access information on nursing care in mechanical ventilation in the Intensive Care Unit. The tool was evaluated as "excellent" in the criteria for Ergonomics and Usability, and is considered a new emerging technology suitable for educational use. PMID- 23032339 TI - [Use of alteplase in the treatment of acute ischemic stroke: what nurses know?]. AB - The study aimed at analyzing the knowledge of nurses about the use of alteplase in the treatment of acute ischemic stroke. An exploratory descriptive study was conducted in a stroke unit of a public hospital in the city of Fortaleza, Brazil, in the month of October 2010. The study included ten nurses, with a mean age of 25 years. The benefits of medication were presented in juxtaposition with the limitations of use. Strategies to expand the use of alteplase were pointed out by nurses. The knowledge of the investigation may contribute to the construction of nursing knowledge and help nurses who provide direct care to patients who undergo this treatment. PMID- 23032340 TI - [Epidemiological, clinical and of functional independence profile of an institutionalized elderly population]. AB - Descriptive and sectional study to describe socio-demographic, clinical and functional independence profile of 97 institutionalized elderly in two nursing homes of Itauna-MG. A socio-demographic and clinical data and Independence Daily Living Activity of Katz instruments were used. It was found a predominance of elderly women (59%), mean age of 77, illiterate (55%), white (67%), single (63%), without children (68%) and 30% lived alone and had difficulty to perform daily living activities, which is the main reason for institutionalization. The majority of elderly people (72%) had cardiovascular disease; 80.4% used neuroleptics/ psychotropic drugs, only 2.1% did not use drugs and 23% were independent to perform daily living activities. These seniors require more skilled care, justified by addiction, diseases, risk of complications and medications used. PMID- 23032341 TI - [Environmental factors as supportive components in communication and care for hospitalized elderly]. AB - This exploratory work with a qualitative approach was performed with 117 health professionals and undergraduate students in Sao Paulo State countryside. The goal was to identify environmental factors that could play a role in health professionals' communication with elderly patients. The findings were organized and grouped in seven categories: sound and vibration factors, decorative and spatial factors, light factors, colors and textures, heat and ventilation factors, hygiene and personal safety factors, and visual signs. It was found that making use of environmental factors while providing care services to the elderly may lead to effective health care. These factors not only interfere with patients' welfare and recovery, but also play a role in the relationship between health professionals and elderly patients. PMID- 23032342 TI - [Nurses and clientele with anorexia and bulimia: a case study]. AB - The research aimed to identify the interaction of nurses and clients suffering from bulimia and anorexia. We use the case study as a resource in which we collect clinical data and did interviews with eight of fourteen nurses, who have been our subject-object. According to the nurses, clients are isolated from the world living in a world without hunger and mirrors reflecting a body always above the "ideal weight", they were lonely people, personnel who have lost their shine, sending signals that could extinguish their lives at any time. In the study, was possible to identify the manner in which nurses interacted and perceived customers and, as a result, we elucidate a peculiar practice in nursing. PMID- 23032343 TI - [Qualitative assessment of the relationship of social actors with madness in a substitutive mental health service]. AB - This study aims to evaluate qualitatively the relationship between social actors and the madness. It was based in experiences produced in a Psychosocial Care Center in the Southern Brazilian context. This is a clipping from an evaluative and qualitative study. Was utilized the Fourth Generation Evaluation as a theoretical-philosophical framework. The methodological device applied was a adapted version of the Hermeneutic-dialectic circle. The statements haunt deinstitutionalization as a paradigm of mental health care, highlighting the need to combat the vices born of crystallized and exclusionary conduct, the typical model asylum. However, we can still see in practice a mixture of models, responsible for enhanced and innovative practices, and other crystallized and exclusive. Hopefully he can discuss the daily life of them, opening the way for understanding best madness, crazy and their relationships. PMID- 23032344 TI - [Childcare in nursing: profile and main problems found in children less than one year]. AB - Descriptive exploratory study that aimed to describe the profile of a population less than one year old of age, assisted in the nursing appointment in Childcare at a Health Basic Unit, in Rio Grande-RS; and to evaluate the association between the nutritional situation and the presence of oral candidiasis, perineal candidiasis and irritative dermatitis due to the diapers. The sample was constituted by all the children's charts (96 overall) who were less than one year old and who were assisted in a nursing appointment in Childcare. Most of the children were girls and were found eutrophic; all the ones who needed a pediatric evaluation were sent to the proper evaluation; the irritative dermatitis of the diapers was the most frequent alteration, and it was associated to the unfavorable nutritional situation; breastfeeding took place, at most, up to the seventh month of the baby. The study indicates the need to sensitize the population to about the importance of childcare for the prevention of injuries and promotion of child health. PMID- 23032345 TI - [Nursing and the relationship with the mothers of newborns in the neonatal intensive care unit]. AB - The relationships with the nursing experience of premature birth of a child, influences the experience of women. The aim of this study is to delineate the relationship between nursing staff and mothers with babies admitted to the Neonatal Intensive Care Unit presented in articles published between 2005 and 2010. We used the databases CINAHL, MEDLINE and LILACS for studies published between 2005 and 2010 with the following keywords: Neonatal Nursing, Premature, Mothers and Nursing Care, a total of 21 articles organized into categories: Phases Faced by Parents during the stay in the Baby NICU; Relationship between Nurse and Mother; Support of Nursing; Careless on the Relationship Between Mother and Nurse Education and Action in Health Studies point to the need of mothers for support that includes emotional support, involvement in caring for the baby, ready to come and talk. PMID- 23032346 TI - [Knowledge production about nurse education: a bibliometric study]. AB - This study aims to identify the nursing theses and dissertation production catalogued in the Center for Study in Nursing Research - CEPEN, which treats nurse formation according to the National Curricular Directives on the SUS formation approach. This is a bibliometric and descriptive study performed on the theses and dissertations catalog of CEPEN, between 2003 and 2007. Twenty seven papers were selected, and quantitatively analyzed according to institution, year of publication, degree of research (dissertations or theses), type of research, and qualitatively analyzed according to themes, philosophical theory, and methodological reference. The results show 100% of the work performed in public institutions, with increased production in theses, there are few studies that deal with the profile of graduates, as well as training for SUS. PMID- 23032347 TI - [Brazilian scientific production based on Orem's nursing theory: integrative review]. AB - Integrative review, held in the databases LILACS, SciELO and BDENF from January 2005 to May 2009, aimed to summarize the Brazilian scientific production based on Orem's Nursing Theory. We obtained 23 articles, analyzed by simple descriptive statistics. It was found that 100% of the studies focused on adults. Of this total, 65,22% returned to the chronicle diseases. In 39,15% of the searches, the theory was used in full and in 34,80% one of the constructs. 91,30% of publications aimed to the construction and deployment of the structured and theoretically grounded practice of care. It was concluded that the theory has been used as theoretical and philosophical basis to justify the practice of nursing in a variety of situations in order to emphasize the role of the nurse in the care. PMID- 23032348 TI - [Limits and possibilities of the nursing auditory and its theoretical and practical aspects]. AB - This article aims to make a critical-reflexive analysis about the nursing auditory, observing its limits and possibilities as well as its theoretical and practical aspects. The nursing auditory, nowadays, is practiced and advertised in public and private institutions, aiming to minimize material, medication, equipment and human resources loss. It is important to mention the presence of the nursing group which was fundamental to the auditory process. The professional nurse in auditory is responsible for the quality of the assistance directed towards the patient. There are many challenges involving the development of the nursing auditory, such as the discovery of a professional identity and the integration with auditory nurses all over the country, among others. PMID- 23032349 TI - Effects of a PEG additive on the biomolecular interactions of self-assembled dendron nanostructures. AB - The ability of self-assembling multivalent DNA-binding dendrons to interact with biological targets is modified by co-assembly with two novel low-molecular-weight cholesterol-functionalised PEG units, one based on triethylene glycol (Chol-PEG 3) and one on an octaethylene glycol (Chol-PEG-8). The addition of either PEG lipid affected the co-assembled nanostructure surface charge and size in different ways depending on the structure of the self-assembling DNA-binding dendron. Co-assembly with Chol-PEG-8 enhanced DNA binding, while Chol-PEG-3 inhibited it. Insertion of Chol-PEG-8 into the aggregates modified their ability to cross a model mucus layer, the details of which can be understood in terms of a balance between the mucoadhesivity due to the surface charge of the nanoscale aggregates and that due to the PEG groups. This study demonstrates that the interaction of nanoscale assemblies with biological systems depends on a number of different factors in a sometimes unpredictable way. Given how simply multiple building blocks can be combined by self-assembly, we conclude that self-assembled multivalent systems have great potential for optimisation to maximise their biological and clinical activity. PMID- 23032350 TI - The influence of dispersion interactions on the hydrogen adsorption properties of expanded graphite. AB - We demonstrate the importance of London dispersion forces in defining the adsorption capacity within expanded graphite, a simple model of the more complex experimental geometries of activated carbon, using a combination of the non-local correlation functional of Dion et al paired with a recent exchange functional of Cooper (vdW-DF(C09x)) and a classical continuum model. Our results indicate that longer ranged interactions due to dispersion forces increase the volume over which molecules interact with a porous medium. This significantly enhances the adsorption density within a material, and explains recent experimental work showing that the densification of H(2) in carbon nanopores is sensitive to the pore size. Remarkably, our slit pore geometries give adsorption densities of up to 3 wt% at 298 K and 20 MPa which correlates well with experimental values for 9 A pores-a value that could not be predicted using local density approximation (LDA) calculations. In its entirety, this work presents a powerful approach for assessing molecular uptake in porous media and may have serious impacts on efforts to optimize the properties of these materials. PMID- 23032351 TI - Vagus nerve stimulator stability and interference on radiation oncology x-ray beams. AB - Five different models of Cyberonics, Inc. vagus nerve stimulation (VNS) therapy pulse generators were investigated for their stability under radiation and their ability to change the absorbed dose from incident radiation. X-ray beams of 6 MV and 18 MV were used to quantify these results up to clinical doses of 68-78 Gy delivered in a single fraction. In the first part, the effect on electronic stimulation signaling of each pulse generator was monitored during and immediately afterwards with computer interrogation. In the second part, the effects of having the pulse generators scatter or attenuate the x-ray beam was also characterized from dose calculations on a treatment planning system as well as from actual radiation measurements. Some device models were found to be susceptible to radiation interference when placed directly in the beam of high energy therapeutic x-ray radiation. While some models exhibited no effect at all, others showed an apparent loss of stimulation output immediately after radiation was experienced. Still, other models were observed to have a cumulative dose effect with a reduced output signal, followed by battery depletion above 49 Gy. Absorbed dose changes on computer underestimated attenuation by nearly half for both energies amongst all pulse generators, although the computer did depict the proper shape of the changed distribution of dose around the device. Measured attenuation ranged from 7.0% to 11.0% at 6 MV and 4.2% to 5.2% at 18 MV for x rays. Processes of back-scatter and side-scatter were deemed negligible although recorded. Identical results from 6 MV and 18 MV x-ray beams conclude no neutron effect was induced for the 18 MV beam. As there were documented effects identified in this research regarding pulse generation, it emphasizes the importance of caution when considering radiation therapy on patients with implanted VNS devices with observed malfunctions consequential. PMID- 23032352 TI - Subcellular characteristics of functional intracellular renin-angiotensin systems. AB - The renin-angiotensin system (RAS) is now regarded as an integral component in not only the development of hypertension, but also in physiologic and pathophysiologic mechanisms in multiple tissues and chronic disease states. While many of the endocrine (circulating), paracrine (cell-to-different cell) and autacrine (cell-to-same cell) effects of the RAS are believed to be mediated through the canonical extracellular RAS, a complete, independent and differentially regulated intracellular RAS (iRAS) has also been proposed. Angiotensinogen, the enzymes renin and angiotensin-converting enzyme (ACE) and the angiotensin peptides can all be synthesized and retained intracellularly. Angiotensin receptors (types I and 2) are also abundant intracellularly mainly at the nuclear and mitochondrial levels. The aim of this review is to focus on the most recent information concerning the subcellular localization, distribution and functions of the iRAS and to discuss the potential consequences of activation of the subcellular RAS on different organ systems. PMID- 23032353 TI - Ethnicity and long-term prognosis after myocardial infarction: a population-based cohort study. AB - BACKGROUND: Health disparities are systematic differences in health, favoring members of advantaged over disadvantaged groups in the society. This study examines the contribution of multiple socioeconomic status (SES) measures to ethnic differences in after myocardial infarction (MI) prognosis. METHODS: Patients aged 65 years and younger (n=1040) belonging to Ashkenazi and Mizrahi advantaged and disadvantaged ethnic groups discharged from 8 hospitals in central Israel after incident MI in 1992-1993, were followed up through 2005 for all cause mortality, recurrent MI, heart failure, and ischemic stroke. RESULTS: Advantaged Ashkenazi had higher education, income, employment, and neighborhood SES compared with disadvantaged Mizrahi. Cardiovascular risk factors varied among the different ethnic groups. Results showed that the association between ethnic group and all outcomes differed substantially between models that included a single SES measure and those that included multiple measures. For example, the hazard ratio for mortality in disadvantaged Mizrahi compared with advantaged Ashkenazi was 1.87 [95% confidence interval (CI), 1.40-2.48] in a model adjusting only for demographic variables; 1.58 (95% CI, 1.18-2.12) in a model adjusting also for income; and 1.03 (95% CI, 0.74-2.04) in a model adjusting for all measured SES indicators. Further adjustment for clinical variables did not appreciably change the results. CONCLUSIONS: Findings show that a wide array of modifiable social factors shaped by income, education, and neighborhood socioeconomic conditions can explain ethnic health differences and highlight the importance of using multivariable models of SES. PMID- 23032354 TI - Disparities in potentially avoidable emergency department (ED) care: ED visits for ambulatory care sensitive conditions. AB - INTRODUCTION: Hospital care for ambulatory care sensitive conditions (ACSC) is potentially avoidable and often viewed as an indicator of suboptimal primary care. However, potentially preventable encounters with the health care system also occur in emergency department (ED) settings. We examined ED visits to identify subpopulations with disproportionate use of EDs for ACSC care. METHODS: We analyzed data from the 2007-2009 National Hospital Ambulatory Medical Care Survey for 78,114 ED visits by adults aged 18 and older. Outcomes were ACSC visits determined from the primary ED diagnosis. We constructed analytic groups aligned with Agency for Healthcare Research and Quality's priority populations. Multivariate logistic regression was used to estimate the odds of all-cause, acute, and chronic ACSC visits. We used Stata SE survey techniques to account for the complex survey design. RESULTS: Overall, 8.4% of ED visits were for ACSC, representing over 8 million potentially avoidable ED visits annually. ACSC visits were more likely to result in hospitalization than non-ACSC visits (34.4% vs. 14.0%, P<0.001). Multivariate models revealed significant disparities in ACSC visits to the ED by race/ethnicity, insurance status, age group, and socioeconomic status, although patterns differed for acute and chronic ACSC. CONCLUSIONS: Disproportionately higher use of EDs for ACSC care exists for many priority populations and across a broader range of priority populations than previously documented. These differences constitute disparities in potentially avoidable ED visits for ACSC. To avoid exacerbating disparities, health policy efforts to minimize economic inefficiencies in health care delivery by limiting ED visits for ACSC should first address their determinants. PMID- 23032355 TI - National newspaper portrayal of nursing homes: tone of coverage and its correlates. AB - OBJECTIVES: The mass media can exert considerable influence over the relative saliency of different public policy concerns. Because emotional resonance can have a strong impact on how the general public and policy makers perceive specific issues, the purpose of this study is to characterize the tone of nursing home coverage in the national media. METHODS: Keyword searches of LexisNexis were used to identify 1562 articles published in 4 national newspapers from 1999 to 2008. The content of each article was analyzed and tone, themes, prominence, focal entity, and geographic focus assessed. Multinomial logit was used to examine the correlates of tone. RESULTS: Most articles were negative (49.2%) or neutral (40.3%); few were positive (10.5%). Both positive and negative articles were considerably more likely than neutral articles (>10 times) to be an opinion piece. Negative articles were three quarters more likely to be on the front page and two thirds more likely to focus on industry actors. Positive articles were 10 times more likely to be about community actors and two and three quarters more likely to be about local issues. Positive articles were considerably more likely to be about quality; negative articles about negligence/fraud and natural disasters. CONCLUSIONS: Findings suggest that negative reporting predominates and its impact on public perceptions and government decision making may be reinforced by its prominence and focus on industry interests/behavior. The adverse impact of media coverage on the industry's reputation has likely influenced consumer care choices, particularly in light of growing competition from the home-based and community-based and assisted living sectors. PMID- 23032356 TI - The quality of mental health care for veterans of Operation Enduring Freedom/Operation Iraqi Freedom. AB - BACKGROUND: Some Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans experience serious mental health (MH) problems. As OEF/OIF soldiers leave active military duty, their growing numbers pose a challenge to the Department of Veterans Affairs (VA) in delivering high-quality mental health/substance-use disorder (MH/SUD) care. OBJECTIVE: To determine whether the quality of MH/SUD care provided by the VA differs by OEF/OIF veteran status. METHODS: Veterans with selected MH/SUDs were identified from administrative records using diagnostic codes. OEF/OIF service was determined based on Defense Manpower Data Center separation files. Eleven processes of care and 7 utilization performance indicators were examined. Regression analyses were adjusted for veteran demographic and clinical characteristics to test for differences in care by OEF/OIF status. RESULTS: Of the 836,699 veterans with selected diagnoses who received MH/SUD treatment in FY2007, 52,870 (6.3%) were OEF/OIF veterans. In unadjusted analyses, OEF/OIF veterans were more likely to receive evidence-based care processes captured by 6 of the 11 dichotomous performance indicators examined; however, among those receiving psychotherapy encounters, OEF/OIF veterans received significantly fewer visits (6.9 vs. 9.7, P<0.0001). In adjusted analyses, only postdischarge follow-up remained meaningfully higher for OEF/OIF veterans. CONCLUSIONS: Efforts to maintain and/or increase OEF/OIF veteran participation in VA MH/SUD services should be informed by their characteristics, such as younger age and better physical health relative to other veterans. PMID- 23032357 TI - Impact of length of stay after coronary bypass surgery on short-term readmission rate: an instrumental variable analysis. AB - OBJECTIVE: : To determine the effect of postoperative length of stay (LOS) on 30 day readmission after coronary artery bypass surgery. DATA SOURCES/STUDY SETTING: : We analyzed a final database consisting of Medicare claims of a cohort (N=157,070) of all fee-for-service beneficiaries undergoing bypass surgery during 2007-2008, the American Hospital Association annual survey file, and the rural urban commuting area file. STUDY DESIGN: : We regressed the probability of 30-day readmission on postoperative LOS using (1) a (naive) logit model that controlled for observed patient and hospital covariates only; and (2) a residual inclusion instrumental variable (IV) logit model that further controlled for unobserved confounding. The IV was defined using a measure of the hospital's risk-adjusted LOS for patients admitted for gastrointestinal hemorrhage. PRINCIPAL FINDINGS: : The naive logit model predicted that a 1-day reduction in median postoperative LOS (ie, from a median of 6-5 d) lowered the 30-day readmission rate by 2 percentage points. The IV model predicted that a 1-day reduction in median postoperative LOS increased 30-day readmission rate by 3 percentage points. CONCLUSIONS: : The findings indicate that a reduction in postoperative LOS is associated with an increased risk for 30-day readmission among Medicare patients undergoing bypass surgery, after both observed and unobserved confounding effects are corrected. PMID- 23032358 TI - Examining the impact of the AHRQ Patient Safety Indicators (PSIs) on the Veterans Health Administration: the case of readmissions. AB - BACKGROUND: By focusing primarily on outcomes in the inpatient setting one may overlook serious adverse events that may occur after discharge (eg, readmissions, mortality) as well as opportunities for improving outpatient care. OBJECTIVE: Our overall objective was to examine whether experiencing an Agency for Healthcare Research and Quality Patient Safety Indicator (PSI) event in an index medical or surgical hospitalization increased the likelihood of readmission. METHODS: We applied the Agency for Healthcare Research and Quality PSI software (version 4.1.a) to 2003-2007 Veterans Health Administration inpatient discharge data to generate risk-adjusted PSI rates for 9 individual PSIs and 4 aggregate PSI measures: any PSI event and composite PSIs reflecting "Technical Care," "Continuity of Care," and both surgical and medical care (Mixed). We estimated separate logistic regression models to predict the likelihood of 30-day readmission for individual PSIs, any PSI event, and the 3 composites, adjusting for age, sex, comorbidities, and the occurrence of other PSI(s). RESULTS: The odds of readmission were 23% higher for index hospitalizations with any PSI event compared with those with no event [confidence interval (CI), 1.19-1.26], and ranged from 22% higher for Iatrogenic Pneumothorax (CI, 1.03-1.45) to 61% higher for Postoperative Wound Dehiscence (CI, 1.27-2.05). For the composites, the odds of readmission ranged from 15% higher for the Technical Care composite (CI, 1.08 1.22) to 37% higher for the Continuity of Care composite (CI, 1.26-1.50). CONCLUSIONS: Our results suggest that interventions that focus on minimizing preventable inpatient safety events as well as improving coordination of care between and across settings may decrease the likelihood of readmission. PMID- 23032359 TI - Cost-related nonadherence by medication type among Medicare Part D beneficiaries with diabetes. AB - BACKGROUND: Despite the rollout of Medicare Part D, cost-related nonadherence (CRN) among older adults remains a problem. OBJECTIVES: To examine the rate and correlates of self-reported CRN among a population of older persons with diabetes. RESEARCH DESIGN: Cross-sectional. SUBJECTS: A total of 1264 Part D patients with diabetes, who entered the coverage gap in 2006. MEASURES: Initial administrative medication lists were verified in computer-assisted telephone interviews, in which participants brought their medication bottles to the phone. Medications were classified into cardiometabolic (diabetes, hypertension, cholesterol-lowering), symptom relief, and "other." Participants were asked if they had any CRN during 2006, and if so to which medication/s. We used the person medication dyad as the unit of analysis, and tested a multivariate random effects logistic regression model to analyze the correlates of CRN. RESULTS: Approximately 16% of participants reported CRN. CRN was more frequent for cholesterol-lowering medications (relative risk, 1.54; 95% confidence interval, 1.01-2.32) compared with medications taken for symptom relief. CRN was reported less frequently with increasing age above 75 years, compared with patients between 65 and 69. In addition, compared with those with incomes of >=$40,000, CRN risk for those with incomes of <$25,000 was markedly higher (relative risk, 3.05; 95% confidence interval, 1.99-4.65). CONCLUSIONS: In summary, we found high rates of CRN among Medicare beneficiaries with diabetes, particularly those with lower incomes. We observed more frequent CRN for cholesterol-lowering medications as compared with medications for symptom relief. Efforts to ensure medication affordability for this population will be important in boosting adherence to key medications. PMID- 23032360 TI - Type 2 diabetes and risk of prostate cancer: a meta-analysis of observational studies. AB - BACKGROUND: Emerging evidence suggests that diabetes may increase the risk of cancers. However, available evidence on prostate cancer is conflicting. We therefore examined the association between Type 2 diabetes and risk of prostate cancer by conducting a detailed meta-analysis of all studies published regarding this subject. METHODS: PubMed database and bibliographies of retrieved articles were searched for epidemiological studies (published between 1970 and 2011), investigating the relationship between Type 2 diabetes and prostate cancer. Pooled risk ratio (RR) was calculated using random-effects model. Subgroup, sensitivity analysis and cumulative meta-analysis were also done. RESULTS: Forty five studies (29 cohort and 16 case-control studies) involving 8.1 million participants and 132 331 prostate cancer cases detected a significant inverse association between Type 2 diabetes and risk of prostate cancer (RR 0.86, 95% confidence interval (CI) 0.80-0.92). For cohort studies alone, the RR was 0.87 (95% CI 0.80-0.94), and for case-control studies alone, the RR was 0.85 (95% CI 0.74-0.96). Sensitivity analysis done by excluding one outlier further strengthened our negative association (RR 0.83, 95% CI 0.78-0.87). No evidence of publication bias was observed. CONCLUSIONS: This meta-analysis provides strongest evidence supporting that Type 2 diabetes is significantly inversely associated with risk of developing prostate cancer. PMID- 23032361 TI - African-American men with low-grade prostate cancer have higher tumor burdens: results from the Duke Prostate Center. AB - BACKGROUND: To investigate racial differences in tumor burden (cancer volume, cancer percentage and cancer to PSA ratios) in a large cohort of men undergoing radical prostatectomy (RP). METHODS: Demographic, clinical and pathological data of patients undergoing RP between 1993-2010 were reviewed and compared between African-American (AA) and non African-American (nAA) men. Further assessments of pathological tumor burden (estimated tumor volume, percent of cancer involvement, and estimated tumor volume/PSA ratios) were performed across Gleason score categories. RESULTS: Of 4157 patients in the analysis, 604 (14.5%) were AA. Overall, AA patients were younger, had higher Gleason scores, PSA levels and incidence of palpable disease (all P < 0.001). Despite comparable prostate weights (39.4 vs. 39.6 g), AA men had higher percent cancer involvement and estimated tumor volume (all P < 0.001) but similar estimated tumor volume/PSA ratios ( P> 0.05). When stratified by Gleason scores, prostate weights were comparable; however, estimated tumor volume, percent cancer involvement and estimated tumor volume/PSA ratios were higher in AA men with low grade (<= 6) prostate cancer (PCa), similar in intermediate grade (7-8) and lower in high grade (9-10) PCa compared to nAA men. CONCLUSIONS: In this large series, AA patients had higher disease burden (estimated tumor volume, percent cancer involvement, estimated tumor volume/PSA ratios) compared to nAA but this association was especially pronounced in low grade (Gleason <= 6) cancers. These data depict a complex picture of relations between race and tumor burden across the spectrum of PCa aggressiveness. Further investigation is warranted to understand the mechanisms of racial disparities in PCa. PMID- 23032362 TI - Effects of site disorder, off-stoichiometry and epitaxial strain on the optical properties of magnetoelectric gallium ferrite. AB - We present a combined experimental-theoretical study demonstrating the role of site disorder, off-stoichiometry and strain on the optical properties of magnetoelectric gallium ferrite. Optical properties (bandgap, refractive indices and dielectric constants) were experimentally obtained by performing ellipsometric studies over the energy range 0.8-4.2 eV on pulsed laser deposited epitaxial thin films of stoichiometric gallium ferrite with b-axis orientation and the data were compared with theoretical results. Calculations on the ground state structure show that the optical activity in GaFeO(3) arises primarily from O 2p-Fe 3d transitions. Further, inclusion of site disorder and epitaxial strain in the ground state structure significantly improves the agreement between the theory and the room temperature experimental data substantiating the presence of site disorder in the experimentally derived strained GaFeO(3) films at room temperature. We attribute the modification of the ground state optical behavior upon inclusion of site disorder to the corresponding changes in the electronic band structure, especially in Fe 3d states leading to a lowered bandgap of the material. PMID- 23032364 TI - Interaction of oxygen vacancies in yttrium germanates. AB - Forming a good Ge/dielectric interface is important to improve the electron mobility of a Ge metal oxide semiconductor field-effect transistor. A thin yttrium germanate capping layer can improve the properties of the Ge/GeO(2) system. We employ electronic structure calculations to investigate the effect of oxygen vacancies in yttrium-doped GeO(2) and the yttrium germanates Y(2)Ge(2)O(7) and Y(2)GeO(5). The calculated densities of states indicate that dangling bonds from oxygen vacancies introduce in-gap states, but the system remains insulating. However, yttrium-doped GeO(2) becomes metallic under oxygen deficiency. Y-doped GeO(2), Y(2)Ge(2)O(7) and Y(2)GeO(5) are calculated to be oxygen substoichiometric under low Fermi energy conditions. The use of yttrium germanates is proposed as a way to effectively passivate the Ge/dielectric interface. PMID- 23032363 TI - Electronic symptom reporting between patient and provider for improved health care service quality: a systematic review of randomized controlled trials. part 2: methodological quality and effects. AB - BACKGROUND: We conducted in two parts a systematic review of randomized controlled trials (RCTs) on electronic symptom reporting between patients and providers to improve health care service quality. Part 1 reviewed the typology of patient groups, health service innovations, and research targets. Four innovation categories were identified: consultation support, monitoring with clinician support, self-management with clinician support, and therapy. OBJECTIVE: To assess the methodological quality of the RCTs, and summarize effects and benefits from the methodologically best studies. METHODS: We searched Medline, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, and IEEE Xplore for original studies presented in English-language articles between 1990 and November 2011. Risk of bias and feasibility were judged according to the Cochrane recommendation, and theoretical evidence and preclinical testing were evaluated according to the Framework for Design and Evaluation of Complex Interventions to Improve Health. Three authors assessed the risk of bias and two authors extracted the effect data independently. Disagreement regarding bias assessment, extraction, and interpretation of results were resolved by consensus discussions. RESULTS: Of 642 records identified, we included 32 articles representing 29 studies. No articles fulfilled all quality requirements. All interventions were feasible to implement in a real-life setting, and theoretical evidence was provided for almost all studies. However, preclinical testing was reported in only a third of the articles. We judged three-quarters of the articles to have low risk for random sequence allocation and approximately half of the articles to have low risk for the following biases: allocation concealment, incomplete outcome data, and selective reporting. Slightly more than one fifth of the articles were judged as low risk for blinding of outcome assessment. Only 1 article had low risk of bias for blinding of participants and personnel. We excluded 12 articles showing high risk or unclear risk for both selective reporting and blinding of outcome assessment from the effect assessment. The authors' hypothesis was confirmed for 13 (65%) of the 20 remaining articles. Articles on self-management support were of higher quality, allowing us to assess effects in a larger proportion of studies. All except one self-management interventions were equally effective to or better than the control option. The self-management articles document substantial benefits for patients, and partly also for health professionals and the health care system. CONCLUSION: Electronic symptom reporting between patients and providers is an exciting area of development for health services. However, the research generally is of low quality. The field would benefit from increased focus on methods for conducting and reporting RCTs. It appears particularly important to improve blinding of outcome assessment and to precisely define primary outcomes to avoid selective reporting. Supporting self-management seems to be especially promising, but consultation support also shows encouraging results. PMID- 23032365 TI - Scheduling of anticancer drugs: timing may be everything. AB - Many cancer patients are treated with a combination of anticancer drugs. Here, we discuss the importance of drug scheduling and the need for studies that investigate the optimal timing of the various anticancer drugs. Positron emission tomography (PET) using radiolabeled anticancer drugs could be an important tool for those studies. PMID- 23032366 TI - PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. AB - The programmed cell death-1 (PD)-1 receptor (CD279) is a potent T cell inhibitor with a critical role in peripheral tolerance, but it can also compromise anti viral and antitumor T cell responses. The effects of PD-1 on the cell cycle leading to inhibition of T cell expansion are poorly understood. Recently, we examined the effects of PD-1 on the molecular control of the cell cycle machinery and on TCR-activated signaling pathways that regulate these downstream outcomes. Our studies showed that PD-1 blocks cell cycle progression in the G 1 phase. PD-1 did not alter the expression of G 1 phase cyclins or cyclin-dependent kinases (Cdks) but, instead, suppressed the transcription of SKP2, the substrate recognition component of the SCF (Skp2) ubiquitin ligase that leads p27 (kip1) to degradation and resulted in accumulation of p27 (kip1) . Subsequently, T cells receiving PD-1 signals displayed impaired Cdk2 activation and failed to phosphorylate two critical Cdk2 substrates, the retinoblastoma gene product (Rb) and the TGFbeta-specific transcription factor Smad3, leading to suppression of E2F target genes but enhanced Smad3 transactivation. These events resulted in upregulation of the Cdk4/6 inhibitor p15 (INK4B) and repression of the Cdk activating phosphatase Cdc25A. The suppressive effect of PD-1 on Skp2 expression was mediated by inhibition of both PI3K/Akt and Ras/MEK/Erk pathways and was only partially reversed by IL-2, which restored activation of MEK/Erk but not Akt. Thus, PD-1 targets Ras and PI3K/Akt signaling to inhibit transcription of Skp2 and to activate Smad3 as an integral component of a pathway that regulates blockade of cell cycle progression in T lymphocytes. Here, we discuss the detailed sequence of these signaling events and their implications in mediating cell-intrinsic and -extrinsic mechanisms that inhibit proliferation of T effector cells in response to PD-1-mediated signaling. PMID- 23032368 TI - T regulatory cells: regulating both term and preterm labor? PMID- 23032367 TI - Developmental pathways in colon cancer: crosstalk between WNT, BMP, Hedgehog and Notch. AB - A hallmark of cancer is reactivation/alteration of pathways that control cellular differentiation during developmental processes. Evidence indicates that WNT, Notch, BMP and Hedgehog pathways have a role in normal epithelial cell differentiation, and that alterations in these pathways accompany establishment of the tumorigenic state. Interestingly, there is recent evidence that these pathways are intertwined at the molecular level, and these nodes of intersection may provide opportunities for effective targeted therapies. This review will highlight the role of the WNT, Notch, BMP and Hedgehog pathways in colon cancer. PMID- 23032369 TI - Divergent lymphocyte signalling revealed by a powerful new tool for analysis of time-lapse microscopy. AB - We describe a new approach for interactive analysis of time-lapse microscopy, and apply this approach to elucidating whether polarity regulation is conserved between epithelial cells and lymphocytes. A key advantage of our analysis platform, 'TACTICS', is the capacity to visualize individual data points in the context of large data sets, similar to standard approaches in flow cytometry. Scatter plots representing microscopic parameters or their derivations such as polarity ratios are linked to the original data such that clicking on each dot enables a link to images and movies of the corresponding cell. Similar to flow cytometric analysis, subsets of the data can be gated and reanalyzed to explore the relationships between different parameters. TACTICS was used to dissect the regulation of polarization of the cell fate determinant, Numb, in migrating lymphocytes. We show here that residues of Numb that are phosphorylated by atypical protein kinase C (aPKC) to mediate apicobasal polarity in epithelial cells are not required for polarization of Numb in T cells, indicating that the role of aPKC is not conserved between lymphocytes and epithelia. PMID- 23032370 TI - Business as usual: the p35 isoform of human CD74 retains function in antigen presentation. PMID- 23032371 TI - Promising long-lasting phosphor material: a novel metal-organic framework showing intriguing luminescent performance. AB - A distinct way to target long-lasting phosphors (LLPs) is disclosed. This new material is a metal-organic framework featuring a 1D zig-zag chain and 3D hydrogen bonded PtS net with three-fold interpenetration. It exhibits persistent luminescence lasting about 1 s which can be traced by the naked eye. The green persistent luminescence is exclusively due to emission from multiple triplet excited states. In this way, LLP can be easily achieved by using a simple hydrothermal synthesis without any codopant that in nature is responsible for well-known inorganic LLPs. PMID- 23032372 TI - Imaging properties of small-pixel spectroscopic x-ray detectors based on cadmium telluride sensors. AB - Spectroscopic x-ray imaging by means of photon counting detectors has received growing interest during the past years. Critical to the image quality of such devices is their pixel pitch and the sensor material employed. This paper describes the imaging properties of Medipix2 MXR multi-chip assemblies bump bonded to 1 mm thick CdTe sensors. Two systems were investigated with pixel pitches of 110 and 165 MUm, which are in the order of the mean free path lengths of the characteristic x-rays produced in their sensors. Peak widths were found to be almost constant across the energy range of 10 to 60 keV, with values of 2.3 and 2.2 keV (FWHM) for the two pixel pitches. The average number of pixels responding to a single incoming photon are about 1.85 and 1.45 at 60 keV, amounting to detective quantum efficiencies of 0.77 and 0.84 at a spatial frequency of zero. Energy selective CT acquisitions are presented, and the two pixel pitches' abilities to discriminate between iodine and gadolinium contrast agents are examined. It is shown that the choice of the pixel pitch translates into a minimum contrast agent concentration for which material discrimination is still possible. We finally investigate saturation effects at high x-ray fluxes and conclude with the finding that higher maximum count rates come at the cost of a reduced energy resolution. PMID- 23032373 TI - Comparison of estrogenic responses in bone and uterus depending on the parity status in Lewis rats. AB - The reproductive transition of women through peri- to postmenopause is characterized by changes in steroid hormone levels due to the cessation of the ovarian function. Beside several complaints associated with these hormonal changes, the deterioration of the trabecular bone micro-architecture and the loss of skeletal mass can cause osteoporosis. At this life stage, women often have a reproductive history of one to several pregnancies. The ovariectomized skeletally mature rat (>10 months old) is one of the most commonly used animal models for postmenopausal osteoporosis research. Despite the fact that mammals can undergo up to several reproductive cycles (primi-/pluriparous), nulliparous animals are often used and the question whether changes in the hormonal milieu subsequently affect the skeleton and influence the outcome of intervention studies is often neglected in study designs. Therefore, the aim of the present study was to compare the estrogen responsiveness of nulliparous and pluriparous rats. For this purpose, one year old virgin or retired breeder Lewis rats were either sham operated or ovariectomized, whereas half of the ovariectomized animals received subcutaneous 17beta-estradiol pellets eight weeks after surgery. After another four weeks, the effects on the uterus were determined by expression analysis of estrogen-dependently regulated steroid receptor genes and well-established marker genes. Moreover, trabecular bone parameters in the tibia were analyzed by micro computed tomography (MUCT). Parity-dependency in estrogen responsiveness was observed with respect to the achieved serum E2 levels in response to similar E2 treatment. This led to differences both on the uterus wet weight and on the expression level of uterine target genes. In addition, a reversal of the ovariectomy-induced changes of the bone architecture after 17beta-estradiol substitution was only observed among the nulliparous. In conclusion, the observations of this study support parity-dependent differences in the responses to estrogenic compounds in the uterus and the bone of rats. These results indicate that the parity-status has an impact on the outcome of studies aiming at the investigation of estrogenic effects of compounds potentially used in hormone replacement and thus, this should be taken into consideration for further studies and particularly for the discussion of data obtained with the preclinical ovariectomized rat animal model. PMID- 23032374 TI - Effects of nuclear receptor transactivation on boar taint metabolism and gene expression in porcine hepatocytes. AB - The accumulation of the testicular steroid androstenone (AND) and tryptophan degradation product skatole (3MI) in fat results in boar taint, an off odor and flavor in boar meat. Increasing boar taint metabolism in the liver may help limit the deposition of AND and 3MI in fat, thereby improving meat quality. The effects of transactivation of the nuclear receptors constitutive androstane receptor (CAR), pregnane X receptor (PXR), and farnesoid X receptor (FXR) on the expression levels of several transcripts of interest and the metabolism of AND and 3MI in primary porcine hepatocytes were tested. Primary cells were isolated from mature boars, and transcript expression levels were assayed using real-time PCR. The transcripts of interest included porcine orthologs of common phase I and phase II metabolic enzymes and transcripts previously shown to be differentially expressed in boars with high boar taint levels. Transactivation of CAR, PXR, or FXR resulted in altered expression of several transcripts, including increased expression of cytochrome P450 (CYP) 2B22 by CAR, of CYP2A19, CYP2B22, CYP2C33, and CYP2C49 by PXR, of CYP2C33 and CYP2E1 by FXR, and of CYP19A2 by all three receptors. Only transactivation of PXR had a significant effect on AND metabolism, resulting in 7.5+/-1.5% of the initial level of AND remaining compared to 21.4+/-3.1% remaining with control dimethyl sulfoxide (DMSO) treatment. FXR had the greatest effect on 3MI metabolism, increasing the expression of CYP2E1 by 1.29-fold and increasing the production of the key metabolite 6-hydroxy-3-methylindole (6-OH-3MI), while decreasing 5-hydroxy-3 methylindole (5-OH-3MI) production. 3-Hydroxy-3-methyloxindole (HMOI) production was increased by CAR transactivation, while indol-3-carbinol (I3C) production was increased by PXR and FXR transactivation, and by treatment with 5beta dihydrotestosterone (5beta-DHT). From this, it can be concluded that selective transactivation of PXR and FXR may be a viable means of decreasing boar taint by increasing the hepatic metabolism of AND and 3MI. PMID- 23032375 TI - Novel splicing events and post-transcriptional regulation of human estrogen receptor alpha E isoforms. AB - Expression of the estrogen receptor alpha (ERalpha) gene is subject to complex regulation. To elucidate the mechanisms of this regulation, the genomic organization and the physiological role of the multiple 5'-untranslated regions (5'-UTRs) must be determined. Here, we investigated the expression and splicing patterns of the human ERalpha E isoforms. We identified two novel untranslated exons, N1 and N2, in the 5'-region of the human ERalpha gene and multiple E isoform mRNA variants generated by alternative usage of non-coding internal exons. Expression of the N1-containing variants was observed only in the human breast adenocarcinoma cell line, MCF7, while the N2-containing variants were expressed in the adult liver and MCF7 cells. We examined post-transcriptional regulation of the variant mRNAs using luciferase reporter assays and quantitative PCR. The insertion of untranslated internal exons into the 5'-UTRs of the E isoforms reduced their translation efficiency, but barely influenced mRNA turnover. Our results indicate that the genomic organization of the human ERalpha gene and the splicing profiles of the human ERalpha E isoforms are more complicated than previously reported. Furthermore, the 5'-UTRs of the E isoforms post-transcriptionally control human ERalpha expression mainly through translational repression. PMID- 23032376 TI - Sensitivity and specificity: DSM-IV versus DSM-5 criteria for autism spectrum disorder. PMID- 23032377 TI - Does concomitant use of NSAIDs reduce the effectiveness of antidepressants? PMID- 23032378 TI - Substance-specific symptoms and general liability to addiction. PMID- 23032379 TI - Brain development and schizophrenia. PMID- 23032380 TI - Presidential address. PMID- 23032381 TI - Response to the presidential address. PMID- 23032383 TI - The changing "weightscape" of bulimia nervosa. PMID- 23032384 TI - The Massachusetts Mental Health Center: going forward after 100 years. PMID- 23032385 TI - Application of DSM-5 criteria for autism spectrum disorder to three samples of children with DSM-IV diagnoses of pervasive developmental disorders. AB - OBJECTIVE: Substantial revisions to the DSM-IV criteria for autism spectrum disorders (ASDs) have been proposed in efforts to increase diagnostic sensitivity and specificity. This study evaluated the proposed DSM-5 criteria for the single diagnostic category of autism spectrum disorder in children with DSM-IV diagnoses of pervasive developmental disorders (PDDs) and non-PDD diagnoses. METHOD: Three data sets included 4,453 children with DSM-IV clinical PDD diagnoses and 690 with non-PDD diagnoses (e.g., language disorder). Items from a parent report measure of ASD symptoms (Autism Diagnostic Interview-Revised) and clinical observation instrument (Autism Diagnostic Observation Schedule) were matched to DSM-5 criteria and used to evaluate the sensitivity and specificity of the proposed DSM 5 criteria and current DSM-IV criteria when compared with clinical diagnoses. RESULTS: Based on just parent data, the proposed DSM-5 criteria identified 91% of children with clinical DSM-IV PDD diagnoses. Sensitivity remained high in specific subgroups, including girls and children under 4. The specificity of DSM 5 ASD was 0.53 overall, while the specificity of DSM-IV ranged from 0.24, for clinically diagnosed PDD not otherwise specified (PDD-NOS), to 0.53, for autistic disorder. When data were required from both parent and clinical observation, the specificity of the DSM-5 criteria increased to 0.63. CONCLUSIONS: These results suggest that most children with DSM-IV PDD diagnoses would remain eligible for an ASD diagnosis under the proposed DSM-5 criteria. Compared with the DSM-IV criteria for Asperger's disorder and PDD-NOS, the DSM-5 ASD criteria have greater specificity, particularly when abnormalities are evident from both parents and clinical observation. PMID- 23032386 TI - Antidepressant response in patients with major depression exposed to NSAIDs: a pharmacovigilance study. AB - OBJECTIVE It has been suggested that there is a mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with antidepressant response, and poorer outcomes among NSAID-treated patients were reported in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. To attempt to confirm this association in an independent population-based treatment cohort and explore potential confounding variables, the authors examined use of NSAIDs and related medications among 1,528 outpatients in a New England health care system. METHOD Treatment outcomes were classified using a validated machine learning tool applied to electronic medical records. Logistic regression was used to examine the association between medication exposure and treatment outcomes, adjusted for potential confounding variables. To further elucidate confounding and treatment specificity of the observed effects, data from the STAR*D study were reanalyzed. RESULTS NSAID exposure was associated with a greater likelihood of depression classified as treatment resistant compared with depression classified as responsive to selective serotonin reuptake inhibitors (odds ratio=1.55, 95% CI=1.21-2.00). This association was apparent in the NSAIDs-only group but not in those using other agents with NSAID-like mechanisms (cyclooxygenase-2 inhibitors and salicylates). Inclusion of age, sex, ethnicity, and measures of comorbidity and health care utilization in regression models indicated confounding; association with outcome was no longer significant in fully adjusted models. Reanalysis of STAR*D results likewise identified an association in NSAIDs but not NSAID-like drugs, with more modest effects persisting after adjustment for potential confounding variables. CONCLUSIONS These results support an association between NSAID use and poorer antidepressant outcomes in major depressive disorder but indicate that some of the observed effect may be a result of confounding. PMID- 23032387 TI - Thalamocortical dysconnectivity in schizophrenia. AB - OBJECTIVE: The thalamus and cerebral cortex are connected via topographically organized, reciprocal connections. Previous studies have revealed thalamic abnormalities in schizophrenia; however, it is not known whether thalamocortical networks are differentially affected in the disorder. To explore this possibility, the authors examined functional connectivity in intrinsic low frequency blood-oxygen-level-dependent (BOLD) signal fluctuations between major divisions of the cortex and thalamus using resting-state functional MRI (fMRI). METHOD: Seventy-seven healthy subjects and 62 patients with schizophrenia underwent resting-state fMRI. To identify functional subdivisions of the thalamus, the authors parceled the cortex into six regions of interest: the prefrontal cortex, motor cortex/supplementary motor area, somatosensory cortex, temporal lobe, posterior parietal cortex, and occipital lobe. Mean BOLD time series were extracted for each region of interest and entered into a seed-based functional connectivity analysis. RESULTS: Consistent with previous reports, activity in distinct cortical areas correlated with specific, largely nonoverlapping regions of the thalamus in both healthy comparison subjects and schizophrenia patients. Direct comparison between groups revealed reduced prefrontal-thalamic connectivity and increased motor/somatosensory-thalamic connectivity in schizophrenia. The changes in connectivity were unrelated to local gray matter content within the thalamus and to antipsychotic medication dosage. No differences were observed in temporal, posterior parietal, or occipital cortex connectivity with the thalamus. CONCLUSIONS: These findings establish differential abnormalities of thalamocortical networks in schizophrenia. The etiology of schizophrenia may disrupt the development of prefrontal-thalamic connectivity and refinement of somatomotor connectivity with the thalamus that occurs during brain maturation. PMID- 23032388 TI - Presupplementary motor area hyperactivity during response inhibition: a candidate endophenotype of obsessive-compulsive disorder. AB - OBJECTIVE: Endophenotype studies of obsessive-compulsive disorder (OCD) may uncover heritable traits that are related to genetic susceptibility to OCD. Deficient response inhibition is a promising endophenotype of OCD, although its functional neural correlates have not been extensively studied. The authors sought to determine the functional neural correlates of response inhibition in a large sample of medication-free OCD patients and their unaffected siblings. METHOD: Forty-one OCD patients, 17 of their siblings, and 37 matched healthy comparison subjects performed a stop-signal task during 3-T functional MRI. The stop-signal reaction time provided a behavioral measure of response inhibition. The neural correlates of response inhibition were assessed in a region-of interest analysis that included the presupplementary motor area, inferior frontal gyrus, subthalamic nucleus, and inferior parietal cortex. RESULTS: Patients with OCD had greater stop-signal reaction times relative to healthy comparison subjects. The numerical stop-signal reaction time difference between siblings and comparison subjects failed to reach significance. Both patients with OCD and their siblings showed greater activity in the left presupplementary motor area during successful inhibition relative to comparison subjects. Relative to both the comparison subjects and the siblings, patients with OCD showed decreased activity in the right inferior parietal cortex and inferior frontal gyrus. In patients and siblings, presupplementary motor area activity correlated negatively with stop-signal reaction time. CONCLUSIONS: These findings suggest that presupplementary motor area hyperactivity is a neurocognitive endophenotype of OCD that is possibly related to inefficient neural processing within the presupplementary motor area itself. Patients with OCD further showed a state dependent deficit in recruiting right inferior parietal cortex and inferior frontal gyrus, which may contribute to their inhibition deficit. PMID- 23032389 TI - Amygdala response to preattentive masked fear in children with conduct problems: the role of callous-unemotional traits. AB - OBJECTIVE: In children with conduct problems, high levels of callous-unemotional traits are associated with amygdala hypoactivity to consciously perceived fear, while low levels of callous-unemotional traits may be associated with amygdala hyperactivity. Behavioral data suggest that fear processing deficits in children with high callous-unemotional traits may extend to stimuli presented below conscious awareness (preattentively). The authors investigated the neural basis of this effect. Amygdala involvement was predicted on the basis of its role in preattentive affective processing in healthy adults and its dysfunction in previous studies of conduct problems. METHOD: Functional MRI was used to measure neural responses to fearful and calm faces presented preattentively (for 17 ms followed by backward masking) in boys with conduct problems and high callous unemotional traits (N=15), conduct problems and low callous-unemotional traits (N=15), and typically developing comparison boys (N=16). Amygdala response to fearful and calm faces was predicted to differentiate groups, with the greatest response in boys with conduct problems and low callous-unemotional traits and the lowest in boys with conduct problems and high callous-unemotional traits. RESULTS: In the right amygdala, a greater amygdala response was seen in boys with conduct problems and low callous-unemotional traits than in those with high callous-unemotional traits. The findings were not explained by symptom levels of conduct disorder, attention-deficit hyperactivity disorder, anxiety, or depression. CONCLUSIONS: These data demonstrate differential amygdala activity to preattentively presented fear in children with conduct problems grouped by callous-unemotional traits, with high levels associated with lower amygdala reactivity. The study's findings complement increasing evidence suggesting that callous-unemotional traits are an important specifier in the classification of children with conduct problems. PMID- 23032390 TI - Age at migration and risk of schizophrenia among immigrants in Denmark: a 25-year incidence study. PMID- 23032391 TI - Response to Kaufman and Harper letter. PMID- 23032392 TI - Deficiency of the odds ratio for common outcomes. PMID- 23032393 TI - Research on medical marijuana. PMID- 23032395 TI - Serum IgG antibodies against the NR1 subunit of the NMDA receptor not detected in schizophrenia. PMID- 23032398 TI - Testing genetic association with rare variants in admixed populations. AB - Recent studies suggest that rare variants play an important role in the etiology of many traits. Although a number of methods have been developed for genetic association analysis of rare variants, they all assume a relatively homogeneous population under study. Such an assumption may not be valid for samples collected from admixed populations such as African Americans and Hispanic Americans as there is a great extent of local variation in ancestry in these populations. To ensure valid and more powerful rare variant association tests performed in admixed populations, we have developed a local ancestry-based weighted dosage test, which is able to take into account local ancestry of rare alleles, uncertainties in rare variant imputation when imputed data are included, and the direction of effect that rare variants exert on phenotypic outcome. We used simulated sequence data to show that our proposed test has controlled type I error rates, whereas naive application of existing rare variants tests and tests that adjust for global ancestry lead to inflated type I error rates. We showed that our test has higher power than tests without proper adjustment of ancestry. We also applied the proposed method to a candidate gene study on low-density lipoprotein cholesterol. Our results suggest that it is important to appropriately control for potential population stratification induced by local ancestry difference in the analysis of rare variants in admixed populations. PMID- 23032399 TI - Facile synthesis of InGaZn mixed oxide nanorods for enhanced hydrogen production under visible light. AB - A series of visible light responsive nanorods of InGaZn mixed oxide photocatalyst are designed by varying the concentration of In(NO(3))(3)via a solid state reaction method without the need for a surfactant or template. The photocatalysts are characterized by XRD, diffuse reflectance UV-vis spectra, TEM, BET surface area analysis, PL, and photoelectrochemical measurement. Increasing the concentration of In(NO(3))(3) changes the morphology from agglomerated to nanorod shaped, and reduces surface defects which inhibits the recombination of charge carriers. From photocurrent measurements, the conduction band minimum and valance band maximum of InGaZn (3 : 1 : 1) are found to be -0.75 and 1.65 V at pH 5.9, respectively, which is suitable for oxidation and reduction processes. The photocatalysts are tested towards hydrogen generation under visible light irradiation. Among all the photocatalysts, InGaZn (3 : 1 : 1) gives the best result towards the production of hydrogen energy under visible light irradiation. PMID- 23032400 TI - Neuroprotective effects of 17beta-estradiol associate with KATP in rat brain. AB - Previous studies have indicated that estrogen protects the brain from ischemic damage and regulates K(ATP) channel activity; the present study was designed to address the involvement of K(ATP) channels in the neuroprotective effects of estrogen in focal cerebral ischemia: in experiment 1, K(ATP) mRNA and protein in the cortices of rats were compared among groups of ovariectomized rats (Ovx-1), Sham-operated rats (Sham-1), and ovariectomized rats administered 17beta estradiol (Estr-1). In experiment 2, neurobehavioral scores and infarct volume of rats were evaluated after middle cerebral artery occlusion in ovariectomized rats (Ovx-2), Sham-operated rats (Sham-2), ovariectomized female rats administered 17beta-estradiol (Estr-2), and ovariectomized rats administered both 17beta estradiol and stereotactic injections of glibenclamide (Estr+G). Our results showed that the Kir6.2 and SUR1 mRNA and protein levels in the brain cortices of female ovariectomized rats were lower than those in Sham rats. However, the expression levels of Kir6.2 and SUR1 in brain cortices of ovariectomized rats recovered after supplementation with 17beta-estradiol. The protective effects of 17beta-estradiol were abolished by glibenclamide, a K(ATP) channel blocker. This indicates that estradiol significantly upregulates the expression of K(ATP) channel subunits and channel activity in the brain cortices of ovariectomized rats. This regulation is associated with the neuroprotective effects of estradiol. PMID- 23032401 TI - Adenosine A2a receptor induces GDNF expression by the Stat3 signal in vitro. AB - Adenosine A2a receptor (A2aR) is believed to play a role in a number of physiological responses and pathological conditions. Our group has shown previously that A2aR-activated astrocytes occurred following oxygen-glucose deprivation. However, the relationship between A2aR and neurotrophins is poorly understood. Here, we investigate the effect of A2aR on glial cell line-derived neurotrophic factor (GDNF) expression in rat brain astrocyte-2 (RBA-2) cells by quantitative PCR and western blot. We established a stable A2aR-overexpressing cell line and found that A2aR induced GDNF expression both at mRNA and protein levels. A2aR-selective antagonist Sch58261 decreased GDNF expression in a dose dependent manner with increased activation of Stat3. The Stat3 inhibitor reversed the effect of Sch58261 on GDNF expression. Therefore, these data indicate that A2aR induces GDNF expression by the Stat3 pathway, which provides a new insight into the function of A2aR in cerebral ischemia and neuroprotection. PMID- 23032402 TI - Amplitude and latency of feedback-related negativity: aging and sex differences. AB - Feedback-related negativity (FRN) is an electrophysiological index associated with impulsivity. However, the age and sex effects on FRN are not well understood. Using the single-outcome gambling task, this study investigated age related and sex-related differences between the FRN in middle and late adolescents and adults. Forty healthy adolescents (15-17 years old) and 28 healthy adults (20-25 years old) were recruited in the event-related potentials study. The electrophysiological response to gains and losses of low and high magnitude were recorded during the single-outcome gambling task. The FRN significantly delayed in middle and late adolescents compared with adults (232.875 vs. 211.714 ms). Adults are more sensitive to the magnitude of feedback (larger amounts: 50 cents vs. small amounts: 10 cents) than valence (gain: +50/10 vs. loss: -50/10). However, middle and late adolescents are neither sensitive to magnitude nor to valence. Men showed significantly more negative FRN amplitude than women both in adolescents and adults. In addition, the hostility subscore of the Buss-Perry Aggression Questionnaire was negatively correlated with FRN amplitude. The results of this study suggested that the age-related differences did exist between the FRN in adolescents and those in adults. Men require more neural activity than women to achieve similar feedback both in adolescents and adults. PMID- 23032403 TI - In-vivo evidence for the disruption of Rab11 vesicle transport by loss of huntingtin. AB - The neuropathology of Huntington's disease includes nuclear and cytoplasmic inclusions, striatal neuronal loss, and gliosis. Previous work put forward a tantalizing proposal that disruption of axonal transport within long, narrow caliber axons caused accumulations that could elicit cell death, ultimately resulting in neuronal dysfunction. Although a role for the Huntington's disease protein huntingtin (HTT) has been reported in axonal transport, it is unclear whether HTT affects the transport of all vesicles or influences only a specific class of vesicles. As an interaction between HTT and Rab5 was previously shown to mediate transport on actin filaments, here we tested the hypothesis that a HTT Rab5 complex also exists for transport on microtubules during axonal transport. Surprisingly, we found that HTT influences Rab11 vesicles, not Rab5 vesicles. Reduction of HTT perturbed the transport of Rab11 vesicles. Reductions in kinesin and dynein motors also perturbed Rab11 vesicle transport indicating that these motors are required for bidirectional transport of Rab11. These results suggest that HTT plays a key role in the movement of Rab11 vesicles within axons. Thus, disruption of transport mediated by mutant HTT could contribute to early neuropathology observed in Huntington's diseases. PMID- 23032404 TI - Effects of lifestyle intervention in obese pregnant women on gestational weight gain and mental health: a randomized controlled trial. AB - OBJECTIVE: Lifestyle intervention could help obese pregnant women to limit their weight gain during pregnancy and improve their psychological comfort, but has not yet been evaluated in randomized controlled trials. We evaluated whether a targeted antenatal lifestyle intervention programme for obese pregnant women influences gestational weight gain (GWG) and levels of anxiety or depressed mood. DESIGN AND SUBJECTS: This study used a longitudinal interventional design. Of the 235 eligible obese pregnant women, 205 (mean age (years): 29+/-4.5; body mass index (BMI, kg m(-)(2)): 34.7+/-4.6) were randomized to a control group, a brochure group receiving written information on healthy lifestyle and an experimental group receiving an additional four antenatal lifestyle intervention sessions by a midwife trained in motivational lifestyle intervention. Anxiety (State and Trait Anxiety Inventory) and feelings of depression (Edinburgh Depression Scale) were measured during the first, second and third trimesters of pregnancy. Socio-demographical, behavioural, psychological and medical variables were used for controlling and correcting outcome variables. RESULTS: We found a significant reduction of GWG in the brochure (9.5 kg) and lifestyle intervention (10.6 kg) group compared with normal care group (13.5 kg) (P=0.007). Furthermore, levels of anxiety significantly decreased in the lifestyle intervention group and increased in the normal care group during pregnancy (P=0.02); no differences were demonstrated in the brochure group. Pre-pregnancy BMI was positively related to levels of anxiety. Obese pregnant women who stopped smoking recently showed a significant higher GWG (beta=3.04; P=0.01); those with concurrent gestational diabetes mellitus (GDM) (beta=3.54; P=0.03) and those who consumed alcohol on a regular base (beta=3.69; P=0.04) showed significant higher levels of state anxiety. No differences in depressed mood or obstetrical/neonatal outcomes were observed between the three groups. CONCLUSIONS: A targeted lifestyle intervention programme based on the principles of motivational interviewing reduces GWG and levels of anxiety in obese pregnant women. PMID- 23032405 TI - Impact of UCP1 and beta3AR gene polymorphisms on age-related changes in brown adipose tissue and adiposity in humans. AB - BACKGROUND: Brown adipose tissue (BAT) is involved in the regulation of whole body energy expenditure and adiposity. The activity and prevalence of BAT decrease with age in humans. OBJECTIVE: To examine the effects of single nucleotide polymorphisms of the genes for uncoupling protein 1 (UCP1) and beta3 adrenergic receptor (beta3AR), key molecules of BAT thermogenesis, on age-related decline of BAT activity and accumulation of body fat in humans. METHODS: One hundred ninety-nine healthy volunteers (20-72 years old (y.o.)) underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) after 2-h cold exposure to assess BAT activity. The visceral and subcutaneous fat areas at the abdominal level were estimated from the CT images. They were genotyped for -3826 A/G polymorphism of the UCP1 gene and 64 Trp/Arg mutation of the beta3AR gene. RESULTS: BAT was detected in 88 subjects out of 199 (44%), more in younger (?30 y.o., 55%) than older subjects (>40 y.o., 15%). BAT prevalence of older subjects tended to be lower in the UCP1 G/G group than the A allele group (A/A and A/G), and also in the beta3AR Arg allele group (Trp/Arg and Arg/Arg) than the Trp/Trp group. When compared subjects who had two or more base substitutions on the two genes (the 2-4 allele group) with those who had less than two base substitutions (the 0-1 allele group), BAT prevalence was comparable in younger subjects (62% vs 50%) but lower in older subjects (0% vs 24%, P<0.05). Visceral fat area of the 2-4 allele group was higher than that of the 0-1 allele group (P<0.05) in older subjects, but not in younger subjects. CONCLUSION: UCP1 3826 A/G and beta3AR 64 Trp/Arg substitutions accelerate age-related decrease in BAT activity, and thereby may associate with visceral fat accumulation with age. PMID- 23032406 TI - Longitudinal multicenter analysis on the course of glucose metabolism in obese children. AB - OBJECTIVE: Although there is evidence of increasing prevalence of impaired glucose metabolism in obese children from smaller single cohorts, data are lacking on the progression of glucose metabolism in this patient group.We aimed to assess the prevalence and the longitudinal course of impaired glucose metabolism assessed by oral glucose tolerance test (oGTT) in a large multi-center pediatric obesity registry. SUBJECTS: We performed an observational multicenter (n=84) cross-sectional (n=11 156) and longitudinal analysis (n=1008) on the course of glucose metabolism evaluated by oGTT in obese children documented in the Adiposity Patients Verlaufsbeobachtung (APV) registry. Patients were stratified with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and Type 2 diabetes (T2D), according to American Diabetes Association criteria. RESULTS: A total of 12.6% of the children presented with abnormal glucose metabolism (5.99% IFG, 5.51% IGT, 1.07% T2D). Body mass index (BMI) correlated modestly with 2-h blood glucose (r=0.04, P<0.001).In the 1008 patients with follow-up oGTT, metabolic parameters improved and the percentage of abnormal glucose metabolism decreased from 18.7 to 14.2%. Of the children with initial IGT, 70.6% converted to normal glucose tolerance. The improvement in oGTT results was associated with, but not dependent on, a reduction of BMI s.d. score. CONCLUSION: In summary, we provide evidence for significant improvement of oGTT parameters in obese children treated in specialized treatment centers, even though reduction in BMI was modest. PMID- 23032407 TI - Unilateral lesion of the nigrostriatal pathway decreases the response of GABA interneurons in the dorsal raphe nucleus to 5-HT(1A) receptor stimulation in the rat. AB - This study examined the firing rate and pattern of electrophysiologically and chemically identified GABA interneurons in the dorsal raphe nucleus (DRN), and role of 5-HT(1A) receptor agonist 8-OH-DPAT and the medial prefrontal cortex (mPFC) in the firing activity in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The interneurons in rats with lesions of the SNc showed a more burst-firing, while having no change in the firing rate; the mPFC and combined mPFC and SNc lesions in rats decreased the firing rate of the interneurons and firing pattern shifted towards a more burst-firing compared to rats with sham lesions of the SNc, respectively. In rats with sham lesions of the SNc, administration of 8-OH-DPAT (1-243 MUg/kg, i.v.) produced excitatory inhibitory, excitatory and inhibitory effects in the firing rate of individual interneurons. However, when these effects were averaged over the group, 8-OH-DPAT had no significant effect on firing rate. In rats with lesions of the SNc, mPFC and the paired lesions, 8-OH-DPAT, at the same doses, inhibited all interneurons tested, respectively. Cumulative doses producing inhibition in rats with the paired lesions were higher than that of rats with lesions of the mPFC. In contrast to rats with sham lesions of the SNc, SNc lesion reduced expression of 5 HT(1A) receptor on parvalbumin positive neurons in the DRN, a subpopulation of GABA interneurons. Our results indicate that the SNc and mPFC regulate the firing activity of GABA interneurons in the DRN. Furthermore, response of likely GABA interneurons to systemic administration of 8-OH-DPAT is altered by lesion of the SNc and mPFC. PMID- 23032408 TI - Preserving future therapeutic options: should we limit the lamivudine use in young HIV-1 infected children initiating first-line HAART? PMID- 23032409 TI - The safety of flucloxacillin in HIV-infected patients with positive HLA-B*5701 genotype. AB - Positive HLA-B*5701 genotype has recently been identified as the main genetic risk factor for flucloxacillin drug-induced liver injury (DILI). Testing for HLA B*5701 is routine in many HIV clinics to identify those at risk of hypersensitivity reaction (HSR) to abacavir. Considering the high prevalence of soft-tissue infections in HIV patients, we conducted a retrospective study to investigate whether flucloxacillin use was associated with adverse events in HIV patients known to be HLA-B*5701 positive. PMID- 23032411 TI - Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers. AB - HIV-1 elite controllers spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary computed tomography angiography (CTA) in elite controllers, nonelite controller, chronically HIV-1 infected, antiretroviral therapy (ART)-treated patients with undetectable viral load ('chronic HIV'), and HIV-negative controls. Prevalence of atherosclerosis (78 vs. 42%, P < 0.05) and markers of immune activation were increased in elite controllers compared with HIV-negative controls. sCD163, a monocyte activation marker, was increased in elite controllers compared with chronic HIV-1 (P < 0.05) and compared with HIV-negative controls (P < 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among elite controllers. PMID- 23032410 TI - Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV infected patients on LPV/r-monotherapy. AB - OBJECTIVE: To determine changes of cerebrospinal fluid (CSF) biomarkers of patients on monotherapy with lopinavir/ritonavir. DESIGN: The Monotherapy Switzerland/Thailand study (MOST) trial compared monotherapy with ritonavir boosted lopinavir with continued therapy. The trial was prematurely stopped due to virological failure in six patients on monotherapy. It, thus, offers a unique opportunity to assess brain markers in the early stage of HIV virological escape. METHODS: : Sixty-five CSF samples (34 on continued therapy and 31 on monotherapy) from 49 HIV-positive patients enrolled in MOST. Using enzyme-linked immunosorbent assay, we determined the CSF concentration of S100B (astrocytosis), neopterin (inflammation), total Tau (tTau), phosphorylated Tau (pTau), and amyloid-beta 1 42 (Abeta), the latter three indicating neuronal damage. Controls were CSF samples of 29 HIV-negative patients with Alzheimer dementia. RESULTS: In the CSF of monotherapy, concentrations of S100B and neopterin were significantly higher than in continued therapy (P = 0.006 and P = 0.013, respectively) and Alzheimer dementia patients (P < 0.0001 and P = 0.0005, respectively). In Alzheimer dementia, concentration of Abeta was lower than in monotherapy (P = 0.005) and continued therapy (P = 0.016) and concentrations of tTau were higher than in monotherapy (P = 0.019) and continued therapy (P = 0.001). There was no difference in pTau among the three groups. After removal of the 16 CSF with detectable viral load in the blood and/or CSF, only S100B remained significantly higher in monotherapy than in the two other groups. CONCLUSION: Despite full viral load-suppression in blood and CSF, antiretroviral monotherapy with lopinavir/ritonavir can raise CSF levels of S100B, suggesting astrocytic damage. PMID- 23032412 TI - Bone mineral density in children and adolescents with perinatal HIV infection. AB - OBJECTIVE: To estimate prevalence of low bone mineral density (BMD) in perinatally HIV-infected (HIV+) and HIV-exposed but uninfected (HEU) children, and to determine predictors of BMD in HIV+. DESIGN: Cross-sectional analysis within a 15-site United States and Puerto Rico cohort study. METHODS: Total body and lumbar spine BMD were measured using dual energy-X-ray absorptiometry. BMD Z scores accounted for bone age and sex. Multiple linear regression was used to evaluate differences in Z-scores by HIV status and for predictors of BMD in HIV+. RESULTS: 350 HIV+ and 160 HEU were enrolled. Mean age was 12.6 and 10.7 years for HIV+ and HEU, respectively. Most (87%) HIV+ were receiving HAART. More HIV+ than HEU had total body and lumbar spine Z-scores less than -2.0 (total body: 7 vs. 1%, P = 0.008; lumbar spine: 4 vs. 1%, P = 0.08). Average differences in Z-scores between HIV+ and HEU were attenuated after height and/or weight adjustment. Among HIV+, total body Z-scores were lower in those with higher CD4% and in those who ever used boosted protease inhibitors or lamivudine. Lumbar spine Z-scores were lower with higher peak viral load and CD4%, more years on HAART, and ever use of indinavir. CONCLUSION: Rates of low BMD in HIV+ children were greater than expected based on normal population distributions. These differences were partially explained by delays in growth. As most HIV+ children in this study had not entered their pubertal growth spurt, prepubertal factors associated with BMD, magnified or carried forward, may result in sub-optimal peak BMD in adulthood. PMID- 23032413 TI - Raltegravir central nervous system tolerability in clinical practice: results from a multicenter observational study. AB - Central nervous system (CNS) symptoms have been reported in clinical trials and case reports in patients receiving raltegravir. We investigated CNS symptoms in 453 HIV-infected patients. Of these 47 (10.4%) developed at least one drug related CNS symptom. Predictors of CNS symptoms were concomitant therapy with tenofovir or with proton pump inhibitors that can increase raltegravir concentration. Thus, our data suggest a possible correlation between high raltegravir plasma concentrations and CNS symptoms, and therefore their monitoring in clinical practice. PMID- 23032414 TI - Population dynamics of HIV-2 in rural West Africa: comparison with HIV-1 and ongoing transmission at the heart of the epidemic. AB - OBJECTIVES: To compare the population dynamics of HIV-2 and HIV-1, and to characterize ongoing HIV-2 transmission in rural Guinea-Bissau. DESIGN: Phylogenetic and phylodynamic analyses using HIV-2 gag and env, and HIV-1 env sequences, combined with epidemiological data from a community cohort. METHODS: Samples were obtained from surveys in 1989-1991, 1996-1997, 2003 and 2006-2007. Phylogenies were reconstructed using sequences from 103 HIV-2-infected and 56 HIV 1-infected patients using Bayesian Evolutionary Analysis by Sampling Trees (BEAST), a relaxed molecular clock and a Bayesian skyline coalescent model. RESULTS: Bayesian skyline plots showed a strong increase in the 1990s of the HIV 1 effective population size (Ne) in the same period that the Ne of HIV-2 came into a plateau phase. The population dynamics of both viruses were remarkably similar following initial introduction. Incident infections were found more often in HIV-2 transmission clusters, with 55-58% of all individuals contributing to ongoing transmission. Some phylogenetically linked sexual partners had discordant viral loads (undetectable vs. detectable), suggesting host factors dictate the risk of disease progression in HIV-2. Multiple HIV-2 introductions into the cohort are evident, but ongoing transmission has occurred predominantly within the community. CONCLUSION: Comparison of HIV-1 and HIV-2 phylodynamics in the same community suggests both viruses followed similar growth patterns following introduction, and is consistent with the hypothesis that HIV-1 may have played a role in the decline of HIV-2 via competitive exclusion. The source of ongoing HIV 2 transmission in the cohort appears to be new HIV-2 cases, rather than the pool of older infections established during the early growth of HIV-2. PMID- 23032415 TI - Associations of human leukocyte antigen-G with resistance and susceptibility to HIV-1 infection in the Pumwani sex worker cohort. AB - OBJECTIVE: To determine the association between human leukocyte antigens (HLA)-G genotypes and resistance or susceptibility to HIV-1. DESIGN: A group of sex workers in Pumwani, Kenya can be epidemiologically defined as resistant to HIV-1 infection despite frequent exposure and provide an example of natural protective immunity. HLA class I and II molecules have been shown to be associated with resistance/susceptibility to infection in this cohort. HLA-G is a nonclassical class I allele that is primarily involved in mucosal and inflammatory response, which is of interest in HIV-1 resistance. METHODS: In this study, we used a sequence-based typing method to genotype HLA-G for 667 women enrolled in this cohort and examined the influence of HLA-G genotypes on resistance or susceptibility to HIV-1 infection. RESULTS: The G*01 : 01:01 genotype was significantly enriched in the HIV-1-resistant women [P = 0.002, Odds ratio: 2.11, 95% confidence interval (CI): 0.259-0.976], whereas the G*01 : 04:04 genotype was significantly associated with susceptibility to HIV-1 infection (P = 0.039, OR:0.502, 95% CI:0.259-0.976). Kaplan-Meier survival analysis correlated with these results. G*01 : 01:01 genotype was associated with significantly lower rate of seroconversion (P = 0.001). Whereas, G*01 : 04:04 genotype was significantly associated with an increased rate of seroconversion (P = 0.013). The associations of these HLA-G alleles are independent of other HLA class I and II alleles identified in this population. CONCLUSION: Our study showed that specific HLA-G alleles are associated with resistance or susceptibility to HIV-1 acquisition in this high-risk population. Further studies are needed to understand its functional significance in HIV-1 transmission. PMID- 23032416 TI - Preserved CD4 T-cell telomere length during long-lasting HIV-2 infection. AB - HIV-2 infection features a much slower course than HIV-1 infection, often asymptomatic for over 20 years, without antiretroviral therapy (ART). Nevertheless, CD4 T cells progressively decline, in direct correlation with immune activation and cell cycling. We report, for the first time, preserved telomere length within naive and memory CD4 subsets in prolonged HIV-2 infection despite the increased CD4 turnover. PMID- 23032417 TI - Efficacy and immunogenicity of influenza vaccine in HIV-infected children: a randomized, double-blind, placebo controlled trial. AB - BACKGROUND: HIV-infected children are at heightened risk for severe influenza illness; however, there is no study on the efficacy or effectiveness of influenza vaccine in these children. We evaluated the safety, immunogenicity, and efficacy of nonadjuvanted, trivalent inactivated influenza vaccine (TIV) against confirmed seasonal influenza virus illness in HIV-infected children. METHODS: A double blind, placebo-controlled trial was undertaken in Johannesburg in 2009. Four hundred and ten children were randomized to two doses of TIV or placebo 1 month apart. Nasopharyngeal aspirates obtained at respiratory illness visits were tested by influenza-specific reverse transcriptase-PCR (RT-PCR). Vaccine immunogenicity was evaluated by hemagglutinin inhibition (HAI) assay. Influenza isolates were sequenced and evaluated in maximum likelihood phylogenetic analysis. RESULTS: Overall, the median age of participants was 23.8 months and their median CD4% was 33.5. Ninety-two percent of enrolees were on antiretroviral therapy. Among children receiving both doses of vaccine/placebo, confirmed seasonal influenza illness occurred in 13 (all H3N2) of 205 TIV recipients and 17 (15 H3N2 and two influenza B) of 200 placebo recipients with vaccine efficacy of 17.7% (95% confidence interval <0-62.4%). The proportion of TIV recipients who seroconverted after second dose against vaccine strains of H1N1, H3N2, and influenza B were 47.5, 50.0, and 40.0%, compared to 4.7, 11.6, and 0%, respectively among placebo recipients. There were no TIV-related serious adverse events. Sequence analysis of wild-type H3N2 strains indicated drift from the H3N2 vaccine strain. CONCLUSION: Poor immunogenicity of TIV, coupled with drift of circulating H3N2 wild-type compared to vaccine strain, may explain the lack of efficacy of TIV in young HIV-infected children. Alternate TIV vaccine schedules or formulations warrant evaluation for efficacy in HIV-infected children. PMID- 23032419 TI - Age-related differences in plasma and intracellular tenofovir concentrations in HIV-1-infected children, adolescents and adults. AB - INTRODUCTION: There is limited pediatric information on the complex relationships among the dose of tenofovir disoproxil fumarate (TDF), plasma concentrations of tenofovir (TFV), and intracellular TFV diphosphate (TFV-DP) concentrations. Our objectives were to describe TFV-DP pharmacokinetics in children and adolescents and investigate the effect of age on TFV and TFV-DP concentrations. METHODS: TFV DP pharmacokinetics were determined in 47 children and adolescents. TFV and TFV DP were quantified with validated liquid chromatography/tandem mass spectrometry methods. Data were pooled with other studies in HIV-infected adults (N = 55). Nonlinear mixed effects modeling was used to develop the population model and explore the influence of covariates on TFV. A two-compartment model, partitioned for slow and fast absorbers by age, with weight allometrically scaled for children and adolescents, best described TFV pharmacokinetics. An indirect stimulation of response model best described TFV-DP formation. RESULTS: Apparent oral TFV clearance was significantly faster in patients less than 25 versus 25 years or more. The most significant covariate on apparent TFV oral clearance and central distribution volume was creatinine clearance. The TFV plasma concentration producing 50% of maximal TFV-DP concentrations was almost two-fold lower in patients less than 25 versus 25 years or more. The estimated intracellular TFV-DP half-life for these groups was 70 and 87 h, respectively. CONCLUSION: These data demonstrate that children and adolescents receiving standard TDF dosing of 300 mg once daily achieve higher intracellular TFV-DP concentrations than adults, despite lower plasma TFV concentrations. This age related difference appears to arise from an increased sensitivity to formation of TFV-DP. PMID- 23032420 TI - Safety and efficacy of topical cidofovir to treat high-grade perianal and vulvar intraepithelial neoplasia in HIV-positive men and women. AB - OBJECTIVE: To evaluate the safety and efficacy of topical cidofovir for treatment of high-grade squamous perianal intraepithelial neoplasia (PAIN) and vulvar intraepithelial neoplasia (VIN) lesions in HIV-positive individuals. DESIGN: Phase IIa prospective multicenter trial conducted at eight clinical sites through the AIDS Malignancy Consortium. METHODS: : HIV-positive patients with biopsy proven high-grade PAIN that was at least 3 cm were enrolled. PAIN biopsy specimens were assessed for human papillomavirus (HPV) using PCR and type specific HPV probing. Participants applied 1% topical cidofovir to PAIN and VIN (if present) for six 2-week cycles. Results were designated as complete response (CR), partial response (PR) (>50% reduction in size), stable disease, or progressive disease (PD). RESULTS: Twenty-four men and nine women (eight with high-grade VIN as well) were enrolled. Mean age was 44 years and mean CD4 cell count was 412 cells/MUl. HPV DNA (most commonly HPV16) was detected in all pretreatment study specimens. Twenty six (79%) participants completed treatment per protocol: CR, five (15%); PR, 12 (36%), stable disease, seven (21%); PD, two (6%) (one with a superficially invasive cancer and one with new area of high grade PAIN). Treatment was well tolerated with most common adverse events being mild to moderate affecting lesional skin: pain/burning/irritation (25 patients) and ulceration (13 patients). CONCLUSION: Topical cidofovir had 51% efficacy in the short-term treatment of high-grade PAIN and VIN with acceptable toxicity in HIV-positive individuals. Randomized control studies with more prolonged treatment courses and longer follow-up to assess the durability of the response are needed. PMID- 23032418 TI - Characterization of HIV-HBV coinfection in a multinational HIV-infected cohort. AB - OBJECTIVE: To understand the HIV-hepatitis B virus (HBV) epidemic from a global perspective by clinically and virologically characterizing these viruses at the time of antiretroviral therapy (ART) initiation in a multinational cohort. METHODS AND DESIGN: HIV-infected patients enrolled in two international studies were classified as HIV-HBV coinfected or HIV monoinfected prior to ART. HIV-HBV coinfected patients were tested for HBV characteristics, hepatitis D virus (HDV), a novel noninvasive marker of liver disease, and drug-resistant HBV. Comparisons between discrete covariates used chi or Fisher's exact tests (and Jonchkheere Terpstra for trend tests), whereas continuous covariates were compared using Wilcoxon Rank-Sum Test. RESULTS: Of the 2105 HIV-infected patients from 11 countries, the median age was 34 years and 63% were black. The 115 HIV-HBV coinfected patients had significantly higher alanine aminotransferase and aspartate aminotransferase values, lower BMI, and lower CD4 T-cell counts than HIV monoinfected patients (median 159 and 137 cells/MUl, respectively, P = 0.04). In the coinfected patients, 49.6% had HBeAg-negative HBV, 60.2% had genotype A HBV, and 13% were HDV positive. Of the HBeAg-negative patients, 66% had HBV DNA 2000 IU/ml or less compared to 5.2% of the HBeAg-positive individuals. Drug resistant HBV was not detected. CONCLUSION: Screening for HBV in HIV-infected patients in resource-limited settings is important because it is associated with lower CD4 T-cell counts. In settings in which HBV DNA is not available, HBeAg may be useful to assess the need for HBV treatment. Screening for drug-resistant HBV is not needed prior to starting ART in settings in which this study was conducted. PMID- 23032422 TI - The influence of HLA supertype on thymidine analogue associated with low peripheral fat in HIV. AB - OBJECTIVES: To examine the relationship between human leukocyte antigen (HLA) genotype and body composition changes induced by thymidine analogue nucleoside reverse transcriptase inhibitor (NtRTI) use in HIV-positive individuals. DESIGN: Data collected during the Simplification with Tenofovir-Emtricitabine (TDF-FTC) or Abacavir-Lamivudine (ABC-3TC) (STEAL) study were analysed to examine the potential association of HLA genotypes with changes in body composition in treatment-experienced HIV-positive individuals. METHODS: Demographic, HIV related, body composition and HLA genotyping data from the STEAL study were used in this analysis. The mean percentage peripheral fat at study baseline was compared in participants with and without prior NtRTI use. Analyses were also carried out for each HLA supertype strata, for five HLA genes, within the thymidine-exposed group. These comparisons were made using Mann-Whitney rank-sum tests. RESULTS: Participants with prior NtRTI use had a significantly lower baseline mean peripheral fat percentage compared to those without NtRTI use (31.9 vs. 34.7%; P = 0.0045). However, participants carrying one or more of the three particular HLA supertype alleles, A01, B08 and DQ2, showed no significant difference in mean peripheral fat percentage at baseline by NtRTI use. Among participants with prior NtRTI exposure, there were significant differences in mean peripheral fat by HLA A01, B08 and DQ2 allele expression compared to those without expression of these alleles (A01: 34.91% vs. no A01: 30.3%; P = 0.0087; B08: 36.2% vs. no B08: 31.1%; P = 0.0317; DQ2: 35.16% vs. no DQ2: 30.06%; P = 0.0081). CONCLUSION: This analysis suggests that HIV-infected individuals carrying HLA A01, B08 or DQ2 supertype alleles may be resistant to NtRTI-induced peripheral fat loss. PMID- 23032423 TI - Implementation of phantom-less IMRT delivery verification using Varian DynaLog files and R/V output. AB - This study aims to evaluate the use of Varian radiotherapy dynamic treatment log (DynaLog) files to verify IMRT plan delivery as part of a routine quality assurance procedure. Delivery accuracy in terms of machine performance was quantified by multileaf collimator (MLC) position errors and fluence delivery accuracy for patients receiving intensity modulated radiation therapy (IMRT) treatment. The relationship between machine performance and plan complexity, quantified by the modulation complexity score (MCS) was also investigated. Actual MLC positions and delivered fraction of monitor units (MU), recorded every 50 ms during IMRT delivery, were extracted from the DynaLog files. The planned MLC positions and fractional MU were taken from the record and verify system MLC control file. Planned and delivered beam data were compared to determine leaf position errors with and without the overshoot effect. Analysis was also performed on planned and actual fluence maps reconstructed from the MLC control file and delivered treatment log files respectively. This analysis was performed for all treatment fractions for 5 prostate, 5 prostate and pelvic node (PPN) and 5 head and neck (H&N) IMRT plans, totalling 82 IMRT fields in ~5500 DynaLog files. The root mean square (RMS) leaf position errors without the overshoot effect were 0.09, 0.26, 0.19 mm for the prostate, PPN and H&N plans respectively, which increased to 0.30, 0.39 and 0.30 mm when the overshoot effect was considered. Average errors were not affected by the overshoot effect and were 0.05, 0.13 and 0.17 mm for prostate, PPN and H&N plans respectively. The percentage of pixels passing fluence map gamma analysis at 3%/3 mm was 99.94 +/- 0.25%, which reduced to 91.62 +/- 11.39% at 1%/1 mm criterion. Leaf position errors, but not gamma passing rate, were directly related to plan complexity as determined by the MCS. Site specific confidence intervals for average leaf position errors were set at -0.03-0.12 mm for prostate and -0.02-0.28 mm for more complex PPN and H&N plans. For all treatment sites confidence intervals for RMS errors with the overshoot was set at 0-0.50 mm and for the percentage of pixels passing a gamma analysis at 1%/1 mm a confidence interval of 68.83% was set also for all treatment sites. This work demonstrates the successful implementation of treatment log files to validate IMRT deliveries and how dynamic log files can diagnose delivery errors not possible with phantom based QC. Machine performance was found to be directly related to plan complexity but this is not the dominant determinant of delivery accuracy. PMID- 23032424 TI - Issues in mHealth: findings from key informant interviews. AB - BACKGROUND: mHealth is enjoying considerable interest and private investment in the United States. A small but growing body of evidence indicates some promise in supporting healthy behavior change and self-management of long-term conditions. The unique benefits mobile phones bring to health initiatives, such as direct access to health information regardless of time or location, may create specific issues for the implementation of such initiatives. Other issues may be shared with general health information technology developments. OBJECTIVE: To determine the important issues facing the implementation of mHealth from the perspective of those within the US health system and those working in mHealth in the United States. METHODS: Semistructured interviews were conducted with 27 key informants from across the health and mHealth sectors in the United States. Interviewees were approached directly following an environmental scan of mHealth in the United States or recommendation by those working in mHealth. RESULTS: The most common issues were privacy and data security, funding, a lack of good examples of the efficacy and cost effectiveness of mHealth in practice, and the need for more high-quality research. The issues are outlined and categorized according to the environment within which they predominantly occur: policy and regulatory environments; the wireless industry; the health system; existing mHealth practice; and research. CONCLUSIONS: Many of these issues could be addressed by making the most of the current US health reform environment, developing a strategic and coordinated approach, and seeking to improve mHealth practice. PMID- 23032425 TI - Diabetes and risk of Parkinson's disease. PMID- 23032426 TI - Superelasticity and compression behavior of porous TiNi alloys produced using Mg spacers. AB - In the scope of the present study, Ni-rich TiNi (Ti-50.6 at %Ni) foams with porosities in the range 38-59% were produced by space holder technique using spherical magnesium powders as space formers. Single phase porous TiNi alloys produced with spherical pores were subjected to loading-unloading cycles in compression up to 250 MPa stress levels at different temperatures in as-processed and aged conditions. It has been observed that strength, elastic modulus and critical stress for inducing martensite decrease with increasing porosity. Partial superelasticity was observed for all porosity levels at different test temperatures and conditions employed. Irrecoverable strain was found to decrease with pre-straining and with increasing test temperature. Unlike in bulk TiNi alloys a constant stress plateau has not been observed during the compression testing of porous TiNi alloys. Instead linear superelasticity with a quite steep slope allowing 5% applied strain to be recovered after pre-straining or aging was observed. Even at test temperatures higher than austenite finish temperature in as-sintered and aged condition, strain applied could not be recovered fully due to martensite stabilization resulting from heavy deformation of macro-pore walls and sintering necks. TiNi foams produced with porosities in the range of 38-51% meet the main requirements of biomaterials in terms of mechanical properties for use as bone implant. PMID- 23032427 TI - Bio-inspired interfacial strengthening strategy through geometrically interlocking designs. AB - Many biological materials, such as nacre and bone, are hybrid materials composed of stiff brittle ceramics and compliant organic materials. These natural organic/inorganic composites exhibit much enhanced strength and toughness in comparison to their constituents and inspires enormous biomimetic endeavors aiming to synthesize materials with superior mechanical properties. However, most current synthetic composites have not exhibited their full potential of property enhancement compared to the natural prototypes they are mimicking. One of the key issues is the weak junctions between stiff and compliant phases, which need to be optimized according to the intended functions of the composite material. Motivated by the geometrically interlocking designs of natural biomaterials, here we propose an interfacial strengthening strategy by introducing geometrical interlockers on the interfaces between compliant and stiff phases. Finite element analysis (FEA) shows that the strength of the composite depends strongly on the geometrical features of interlockers including shape, size, and structural hierarchy. Even for the most unfavorable scenario when neither adhesion nor friction is present between stiff and compliant phases, the tensile strength of the composites with proper interlocker design can reach up to 70% of the ideal value. The findings in this paper would provide guidelines to the improvement of the mechanical properties of current biomimetic composites. PMID- 23032428 TI - Fatigue life assessment of cardiovascular balloon-expandable stents: a two-scale plasticity-damage model approach. AB - Cardiovascular disease has become a major global health care problem in the present decade. To tackle this problem, the use of cardiovascular stents has been considered a promising and effective approach. Numerical simulations to evaluate the in vivo behavior of stents are becoming more and more important to assess potential failures. As the material failure of a stent device has been often associated with fatigue issues, as a result of the high number of cyclic loads these devices are subjected to in vivo, numerical approaches for fatigue life assessment of stents has gained special interest in the engineering community. Numerical fatigue predictions can be used to modify the design and prevent failure, without making and testing numerous physical devices, thus preventing from undesired fatigue failures. This work presents a fatigue life numerical method for the analysis of cardiovascular balloon-expandable stainless steel stents. The method is based on a two-scale continuum damage mechanics model in which both plasticity and damage mechanisms are assumed to take place at a scale smaller than the scale of the representative volume element. The fatigue failure criterion is based on the Soderberg relation. The method is applied to the fatigue life assessment of both PalmazShatz and Cypher stent designs. Validation of the method is performed through comparison of the obtained numerical results with some experimental results available for the PalmazShatz stent design. The present study gives also possible directions for future research developments in the framework of the numerical fatigue life assessment of real balloon-expandable stents. PMID- 23032429 TI - Modeling and experimental validation of trabecular bone damage, softening and densification under large compressive strains. AB - Vertebral fractures represent a major health problem and involve the progressive collapse of trabecular bone over large compressive strains. This collapse is driven by local failure and interaction of the trabecular rod and plate elements, which translates into stress softening and densification at the material level. Current constitutive models for trabecular bone are essentially limited to infinitesimal strains. Accordingly, the aim of this work was to extend our current phenomenological model of trabecular bone (Garcia et al., 2009) for the simulation of large compressive strains by including post-yield softening and densification. A constitutive model of trabecular bone based on both volume fraction and trabecular orientation was formulated in a proper theoretical framework, implemented in commercial FE software and validated with human vertebral sections subjected to large compressive strains. As it is for infinitesimal strains, the evolution of plastic strains and damage is described by local internal variables. An isotropic softening rule was controlled by the cumulated plastic strain and a non-linear elastic spring was added to account for densification of the porous material in moderate-to-large compressive strains beyond a given threshold. To avoid convergence problems occurring as a result of softening, a consistent visco-plastic regularization approach was adopted. The experimental results for 37 vertebral sections from previous work (Dall'Ara et al., 2010) were used to validate the constitutive model for compressive loading up to 45% of the average axial deformation. This validation study showed that the model provides both qualitative predictions of damage localization on the cortex and quantitative predictions of dissipated energy (rho(C)=0.912) of vertebral body behavior under large compressive strains. Since the evolution of the internal variables was considered in local manner, a mesh sensitivity analysis of the finite element model was conducted via two different mesh sizes and revealed that strain localization was dominated by trabecular bone heterogeneity. To our knowledge, this model is the first to simulate collapse of trabecular bone and may help improve the biomechanical understanding of several musculoskeletal conditions such as vertebral fractures or orthopedic implant migration. PMID- 23032430 TI - Tribology and hydrophobicity of a biocompatible GPTMS/PFPE coating on Ti6Al4V surfaces. AB - Tribological properties of perfluoropolyether (PFPE) coated 3 glycidoxypropyltrimethoxy silane (GPTMS) SAMs (self-assembled monolayers) onto Ti6Al4V alloy substrate were studied using ball-on-disk experiments. GPTMS SAMs deposition onto a Ti6Al4V alloy surface was carried out using solution phase method. Ultra-thin layer of PFPE was dip-coated onto SAMs modified specimens. Tribological tests were carried out at 0.2 N normal load and rotational speed of 200 rpm using track radius of 2 mm. Wear track and counterface surface conditions were investigated using optical microscopy. PFPE modified specimens were baked at 150 degrees C for 1h to investigate the effect of thermal treatment on tribological properties. Surface characterization tests such as contact angle measurement, AFM morphology and X-ray photoelectron spectroscopy were carried out for differently modified specimens. PFPE overcoat meets the requirements of cytotoxicity test using the ISO 10993-5 elution method. PFPE top layer lowered the coefficient of friction and increased wear durability for different specimens (with and without GPTMS intermediate layer). PFPE overcoat onto GPTMS showed significant increase in the wear resistance compared with overcoat onto bare Ti6Al4V specimens. The observed improvement in the tribological properties can be attributed to the change in the interaction of PFPE molecules with the substrate surface due to the GPTMS intermediate layer. PMID- 23032432 TI - Effect of property gradients on enamel fracture in human molar teeth. AB - A model for the fracture of tooth enamel with graded elastic modulus and toughness is constructed using an extended finite element modeling (XFEM) package. The property gradients are taken from literature data on human molars, with maximum in modulus at the outer enamel surface and in toughness at the inner surface. The tooth is modeled as a brittle shell (enamel) and a compliant interior (dentin), with occlusal loading from a hard, flat contact at the cusp. Longitudinal radial (R) and margin (M) cracks are allowed to extend piecewise along the enamel walls under the action of an incrementally increasing applied load. A simple stratagem is deployed in which fictitious temperature profiles generate the requisite property gradients. The resulting XFEM simulations demonstrate that the crack fronts become more segmented as the property gradients become more pronounced, with enhanced propagation at the outer surface and inhibited propagation at the inner. Whereas the growth history of the cracks is profoundly influenced by the gradients, the ultimate critical loads required to attain full fractures are relatively unaffected. Some implications concerning dentistry are considered. PMID- 23032431 TI - Evaluation of the micro-mechanical strength of resin bonded-dentin interfaces submitted to short-term degradation strategies. AB - The aim of this study was to evaluate the microtensile bond strength (MUTBS) and confocal micropermeability of resin bonded-dentin specimens created using two representative two-step/self-etch adhesives submitted to short-term period degradation strategies such as simulated pulpal pressure, thermo- or mechanical cycling challenges. Clearfil SE Bond (CSE) and Silorane adhesive (SIL) were bonded to flat deep dentin from seventy extracted human molars and light-cured for 10 s. Composite build-ups were constructed using with Filtek Z350 XT and Filtek P90 respectively. The specimens of each adhesive group were subjected to three different accelerated aging methods: (1) thermo-cycling challenge (5000 cycles); (2) mechanical-cycling load (200,000 cycles); (3) experiment and (4) conventional method for simulated pulpal pressure (20 cm H2O). Control resin bonded specimens were stored in distilled water for 24 h. MUTBS and confocal microscopy (CLSM) micropermeability evaluation were performed and the results were analyzed using Two-way ANOVA and Tukey's tests (alpha=0.05). The CLSM evaluation revealed micro-cracks within the Silorane-bonded dentin subsequent to mechanical-cycling load, whereas, the simulated pulpal pressure induced evident micropermeability in both bonding agents. Mechanical loading provides discernible bonding degradation in a short-term period in resin-bonded dentin created using two-step/self-etch adhesives. However, simulated pulpal pressure may reduce the sealing ability of self-etch adhesives causing greater water uptake within the resin-dentin interface. PMID- 23032433 TI - Hyper-elastic properties of the human sternocleidomastoideus muscle in tension. AB - Numerical models of the human body require realistic mechanical properties of the muscles as input, but, generally, such data are available only for animals' muscles. As a consequence, the aim of this study was to identify the hyper elastic behavior of the human sternocleidomastoideus muscle in tension using different constitutive laws. Ten sternocleidomastoideus muscles were tested in vitro. The hyper-elastic behavior was modeled with an exponential law and a hyper elastic constitutive law studied analytically. The latter was also studied with an inverse approach using a subject-specific, finite-element model of each muscle. The three approaches were compared statistically. From these laws and methods, the shear modulus MU (4 to 98 kPa) and the curvature parameter alpha (17 to 52) were identified. Both the analytical and finite-element approaches gave parameters of the same order of magnitude. The parameters of the exponential and hyper-elastic laws were linked thanks to simple linear equations. Our results evidence that the hyper-elastic tension behavior of human sternocleidomastoideus muscle can be described using a simple model (exponential) considering basic geometric features (initial length and cross-sectional area). PMID- 23032434 TI - Mechanical properties of luffa sponge. AB - The paper presents the first scientific study of the stiffness, strength and energy absorption characteristics of the luffa sponge with a view to using it as an alternative sustainable engineering material for various practical applications. A series of compression tests on luffa sponge columns have been carried out. The stress-strain curves show a near constant plateau stress over a long strain range, which is ideal for energy absorption applications. It is found that the luffa sponge material exhibits remarkable stiffness, strength and energy absorption capacities that are comparable to those of some metallic cellular materials in a similar density range. Empirical formulae have been developed for stiffness, strength, densification strain and specific energy absorption at the macroscopic level. A comparative study shows that the luffa sponge material outperforms a variety of traditional engineering materials. PMID- 23032435 TI - Failure behavior of plasma-sprayed HAp coating on commercially pure titanium substrate in simulated body fluid (SBF) under bending load. AB - Four point bending tests with acoustic emission (AE) monitoring were conducted for evaluating failure behavior of the plasma-sprayed hydroxyapatite (HAp) top coat on commercially pure titanium (cp-Ti) plate with and without mixed HAp/Ti bond coat. Effect of immersion in simulated body fluid (SBF) on failure behavior of the coated specimen was also investigated by immersing the specimen in SBF. The AE patterns obtained from the bending test of the HAp coating specimens after a week immersion in SBF clearly showed the earlier stage of delamination and spallation of the coating layer compared to those without immersion in SBF. It was also found that the bond coating improved failure resistance of the HAp coating specimen compared to that without the bond coat. Four point bend fatigue tests under ambient and SBF environments were also conducted with AE monitoring during the entire fatigue test for investigating the influence of SBF environment on fatigue failure behavior of the HAp coating specimen with the mixed HAp/Ti bond coat. The specimens tested at a stress amplitude of 120 MPa under both ambient and SBF environments could survive up to 107 cycles without spallation of HAp coating layer. The specimens tested under SBF environment and those tested under ambient environment after immersion in SBF showed shorter fatigue life compared to those tested under ambient environment without SBF immersion. Micro cracks nucleated in the coating layer in the early stage of fatigue life and then propagated into the cp-Ti substrate in the intermediate stage, which unstably propagated to failure in the final stage. It was found from the XRD analysis that the dissolution of the co-existing phases and the precipitation of the HAp phase were taken place during immersion in SBF. During this process, the co-existing phases disappeared from the coating layer and the HAp phase fully occupied the coating layer. The degradation of bending strength and fatigue life of the HAp coating specimens tested under SBF environment would be induced by dissolution of the co-existing phases from the coating layer during immersion in SBF. PMID- 23032436 TI - Simulated bone remodeling around two types of osseointegrated implants for direct fixation of upper-leg prostheses. AB - Direct attachment of an upper leg prosthesis to the skeletal system by a percutaneous implant is an alternative solution to the traditional socket fixation. In this study, we investigated long-term periprosthetic bone changes around two types of fixation implants using two different initial conditions, namely immediate post-amputation implantation and the conventional implantation after considerable time of socket prosthesis use. We questioned the difference in bone modeling response the implants provoked and if it could lead to premature bone fracture. Generic CT-based finite element models of an intact femoral bone and amputated bone implanted with models of two existing direct-fixation implants, the OPRA system (Integrum AB) and the ISP Endo/Exo prosthesis (ESKA Implants AG) were created for this study. Adaptive bone-remodeling simulations used the heel-strike and toe-off loads from a normal walking cycle. The bone loss caused by prolonged use of socket prosthesis had more severe effects on the ultimate bone quality than adaptation induced by the direct-fixation implants. Both implants showed considerable bone remodeling; the titanium screw implant (OPRA system) provoked more bone loss than the porous coated CoCrMo stem (ISP implant). The chance of the peri-prosthetic bone fracture remained higher for the post-socket case as compared to the direct amputation cases. In conclusion, both direct-fixation implants lead to considerable bone loss and bone loss is more severe after a prolonged period of post-socket use. Hence, from a biomechanical perspective it is better to limit the post-socket time and to re-design direct fixation devices to reduce bone loss and the probability of peri-prosthetic bone fractures. PMID- 23032437 TI - Genipin crosslinking elevates the strength of electrochemically aligned collagen to the level of tendons. AB - Collagen-based tissue mimics are important in clinical research because collagen is the main structural element in tendons. The current study aimed to improve the mechanical strength of Electronically Aligned Collagen (ELAC) threads by optimizing several crosslinking parameters. The results indicated that elevating the concentration of genipin to 2% and the solvent to 90% ethanol significantly enhanced the wet ultimate tensile stress of ELAC threads to 109 MPa with a crosslinking degree of 65%. Furthermore, significantly higher adhesion and proliferation of hMSCs was observed in ELAC threads crosslinked with 2% genipin in 90% ethanol compared to 0.625% genipin in 1X PBS. In conclusion, ELAC threads with mechanical strength on par with native tendon have significant potential to be used as scaffolds in tendon tissue engineering applications. PMID- 23032438 TI - Will stringent total nitrogen wastewater treatment plant discharge regulations achieve stream water quality goals? AB - The Colorado Department of Public Health and Environment (CDPHE) proposed the in stream numeric nutrient criteria as 2 mg TN per L and 0.16 mg TP per L for warm surface waters and 0.40 mg TN per L and 0.11 mg TP per L for cold surface waters. Consequently the department presented the nutrient limits for the municipal wastewater treatment plants (WWTPs) as annual averages of 0.7 mg TP per L and 5.7 mg TIN per L and quarterly averages of 1.0 mg TP per L and 9.0 mg TIN per L. Implementing stringent nutrient reduction at point sources is unlikely to result in improvements to the environment without non-point source controls. In this study, total nitrogen (TN) load inputs from known point source, WWTPs, and other non-point sources at six sub-basins of the Cache La Poudre (CLP) River Basin were estimated and compared under various hydrologic conditions. Significant loading exceedance from the proposed limits was observed during lower flow conditions and other sources dominated during events when the exceedance was observed except for one point. The point receives direct TN inputs from a WWTP which has the highest TN concentration in its effluent among all WWTPs in the study area; however, TN loads entered the point from other sources were significant during higher flow conditions. TN loads in the CLP River were simulated to determine whether the loads meet the proposed in-stream limits in a case in which all WWTPs comply with the proposed regulations for WWTPs. From this study, it was observed that reducing TN concentrations only at WWTPs merely impacts total TN loads in the river. PMID- 23032439 TI - Functional analysis of the promoter of the heat shock cognate 70 gene of the Pacific white shrimp, Litopenaeus vannamei. AB - Current knowledge on cis-regulatory elements of immune genes of the Pacific white shrimp (Litopenaeus vannamei) is poor. In this study, we identified the promoter of the heat shock cognate protein 70 (HSC70) gene of L. vannamei (lvhsc70). The promoter activity of lvhsc70 promoter was analyzed in insect sf9 cell lines. First, the putative promoter sequence was proved to be able to drive the expression of reporter EGFP gene successfully. Then serial deletion experiments were conducted to investigate functional transcription elements in the promoter region. The results revealed that both positive and negative transcription elements existed in this region. These results are quite different from the previous report on the promoter of HSC70 gene in Penaeus monodon (pmhsc70), where only positive transcription elements were indicated. The sequences that are not conserved between the promoters of lvhsc70 and pmhsc70 might contribute to the differences. Finally, we tested the effect of a putative "NF-kappab binding site" in the promoter and, surprisingly, found that deletion of this site would result in a significantly enhancement of the expression of reporter genes, while the underlying mechanisms remain unrevealed. Our results would provide supports for future studies to identify the functional transcription elements in the lvhsc70 promoter and to expand our knowledge on regulation of innate immune genes in penaeid shrimp. PMID- 23032440 TI - Molecular cloning, characterization and mRNA expression of copper-binding protein hemocyanin subunit in Chinese mitten crab, Eriocheir sinensis. AB - Hemocyanin is a copper-binding protein and plays a crucial role in the physiological processes in crustacean. In this study, the cDNA encoding hemocyanin subunit from Chinese mitten crab Eriocheir sinensis (EsHc) was cloned by using EST analysis and rapid amplification of cDNA ends (RACE) approach. The full-length cDNA of EsHc was 2573 bp, consisting of a 5' untranslated region of 51 bp, a 3' untranslated region of 458 bp, and an open reading frame of 2064 bp. The deduced protein had 688 amino acid residues with molecular mass of 77,997.31 Da. Quantitative real-time RT-PCR analysis showed that the EsHc gene was expressed in haemocytes, hepatopancreas, muscles, gills, and intestines with the highest level of expression in the hepatopancreas and the lowest in the muscles. After Aeromonas hydrophila challenge, the relative expression level of EsHc in hemolymph was up-regulated at 3 h post-injection of bacteria followed by a gradual recovery from 12 to 24 h. In the second set of transcriptional studies, the mRNA expression patterns of EsHc in haemocytes and hepatopancreas were measured by quantitative real-time RT-PCR after the Chinese mitten crab were fed six diets containing different levels of copper (0, 10, 20, 40, 80 and 400 mg kg( 1)) for 8 weeks, respectively. The feeding trial showed that the expression levels of EsHc mRNA significantly increased at the copper levels of 20-40 mg kg( 1). This study implies that the expression levels of EsHc could be affected by dietary copper in the hepatopancreas and haemocytes, and hemocyanin may be potentially involved in the immune responses of the Chinese mitten crab. PMID- 23032441 TI - Flow cytometry assay for intracellular detection of Infectious Pancreatic Necrosis virus (IPNV) in Atlantic salmon (Salmo salar L.) leucocytes. AB - Infectious Pancreatic Necrosis virus (IPNV) is traditionally detected in adherent leucocytes using immunofluorescence labelled specific antibodies, PCR or by further cultivation of infected cell material in cell lines. We present a flow cytometry (FCM) assay for detection of intracellular IPNV in salmon leucocytes, where each single cell is analysed for presence of virus. The method is established using in vitro challenge of salmon leucocytes and CHSE-214 cells. For detection of intracellular virus antigen the Cytofix/Cytoperm kit from BD is optimal compared with paraformaldehyde or acetone/methanol for cell permeabilisation. This is combined with labelling procedures allowing both internal virus antigen labelling and external antibody labelling of cell markers to identify B-cells and neutrophils. The secondary antibodies were Alexa Fluor 647 for the internal labelling and RPE for the external labelling of bound cell subtype specific antibodies. The presences of virus within cells are also demonstrated by confocal and light microscopy of infected cells. IPNV is successfully detected in blood and head kidney leucocyte samples. IPNV is found both in B-cells and neutrophils as well as in other types of leucocytes that could not be identified due to lack of cell-specific antibodies. Serial samples from cultivation of in vitro infected leucocytes and CHSE-214 cells analysed by flow cytometry showed that number of infected cells increased with increasing number of days. The flow cytometry protocol for detection of intracellular IPNV is verified using CHSE-214 cells persistently infected with IPNV. These analyses are compared with virus titre and virus infected naive CHSE-214 cells. The detection of IPNV in persistently infected cells indicates that carrier fish can be analysed, as such cells are considered to have virus titres similar to carriers. PMID- 23032443 TI - Direct electrochemistry and electrocatalysis of a glucose oxidase-functionalized bioconjugate as a trace label for ultrasensitive detection of thrombin. AB - For the first time, a glucose oxidase-functionalized bioconjugate was prepared and served as a new trace label through its direct electrochemistry and electrocatalysis in a sandwich-type electrochemical aptasensor for ultrasensitive detection of thrombin. PMID- 23032444 TI - Heparin-induced thrombocytopenia in the ICU: a transatlantic perspective. PMID- 23032445 TI - F2-isoprostanes: an emerging pulmonary arterial hypertension biomarker and potential link to the metabolic theory of pulmonary arterial hypertension? PMID- 23032446 TI - Exploring the adipose tissue-lung interaction in COPD. PMID- 23032447 TI - Sleep-disordered breathing, heart failure, and phrenic nerve stimulation. PMID- 23032448 TI - Normal exercise capacity in chronic mountain sickness: how high can the hematocrit go without consequence? PMID- 23032450 TI - Acute pulmonary exacerbations of sarcoidosis. AB - Exacerbations of sarcoidosis are common. In particular, exacerbations of pulmonary sarcoidosis are reported in more than one-third of patients. Despite their frequent occurrence, there is little medical evidence concerning the definition, diagnosis, and treatment of pulmonary exacerbations of sarcoidosis. In this article, we propose a definition of acute pulmonary exacerbations of sarcoidosis (APES). We review the meager medical literature concerning the risk factors, diagnosis, and treatment of this condition. Given the limited information concerning APES, we acknowledge that this article is not a definitive resource but, rather, a position paper that will encourage greater consideration of the pathogenesis, diagnostic challenges, and treatment approaches to this condition. We believe that further focus on APES will improve the quality of care of patients with pulmonary sarcoidosis. PMID- 23032452 TI - Documentation tips for pulmonary medicine: implications for the inpatient setting. AB - Clinical documentation improvement is an important aspect to achieve top performance. Clinical documentation in a patient's record includes any and all documentation that relates to the care of the patient during the patient's stay or encounter at the hospital. Documentation is key to accurate clinical coding, validating length of stay, resource utilization, physician profiling, case management, severity of illness, risk of mortality, quality management, risk management, clinical outcomes, critical pathways, regulatory compliance, Joint Commission accreditation, managed care, and reimbursement. Good documentation minimizes coding errors, reduces claim denials, and optimizes reimbursement. Implementing quality improvement strategies that make documentation and coding an organizational priority can positively influence operations, services, and revenue. Other external and internal coding audits show that the cause of improper coding is due to lack of proper physician documentation to support reimbursement at the appropriate level. The purpose of this article is to provide tips for documenting pulmonary diagnoses that not only would ensure appropriate reimbursement but also would accurately represent the severity of a patient's condition. PMID- 23032451 TI - The expanding role of biomarkers in the assessment of smoking-related parenchymal lung diseases. AB - Recent advances in the field of clinical biomarkers suggest that quantification of serum proteins could play an important role in the diagnosis, classification, prognosis, and treatment response of smoking-related parenchymal lung diseases. COPD and idiopathic pulmonary fibrosis (IPF), two common chronic progressive parenchymal lung diseases, share cigarette smoke exposure as a common dominant risk factor for their development. We have recently shown that COPD and interstitial lung disease may represent distinct outcomes of chronic tobacco use, whereas others have demonstrated that both diseases coexist in some individuals. In this perspective, we examine the potential role of peripheral blood biomarkers in predicting which individuals will develop COPD or IPF, as well as their usefulness in tracking disease progression and exacerbations. Additionally, given the current lack of sensitive and effective metrics to determine an individual's response to treatment, we evaluate the potential role of biomarkers as surrogate markers of clinical outcomes. Finally, we examine the possibility that changes in levels of select protein biomarkers can provide mechanistic insight into the common origins and unique individual susceptibilities that lead to the development of smoking-related parenchymal lung diseases. This discussion is framed by a consideration of the properties of ideal biomarkers for different clinical and research purposes and the best uses for those biomarkers that have already been proposed and investigated. PMID- 23032453 TI - A case of variant scimitar syndrome. AB - Scimitar syndrome is one of the large congenital pulmonary venolobar syndromes and is defined as hypogenetic lung associated with partial anomalous pulmonary venous return. We report the case of a 25-year-old man with complex and exceptional variant scimitar syndrome. A chest CT scan with three-dimensional (3 D) reconstruction led us to identify hypoplastic right lung with homolateral hemidiaphragm agenesis and hypogenetic right pulmonary artery. There was a large and sinuous systemic arterial supply and anomalous venous return directed into the left atrium (venous return being usually directed into the right atrium or inferior vena cava in scimitar syndrome). Hyperoxia test showed no shunt. This variant scimitar syndrome has been previously reported and anomalous venous return called "meandering" pulmonary vein. Diagnosis and management of these patients with complex congenital anomalies are difficult because of their exceptional condition. Chest CT scan with 3-D reconstruction offers an accurate noninvasive diagnosis. PMID- 23032454 TI - Shock: ultrasound to guide diagnosis and therapy. AB - The availability of portable ultrasound devices is changing the approach to the diagnosis and management of shock by offering timely diagnosis and acting to guide therapy. Goal-directed echocardiography (GDE) can be performed well by noncardiologists and consists of a limited number of standard cardiac views: parasternal long axis, parasternal short axis, apical four chamber, subcostal long axis, and inferior vena cava long axis. GDE allows the intensivist to assess left and right ventricular pump function, pericardial effusion, septal dynamics, valvular morphology, major valve failure, and fluid responsiveness. Here, we review the questions involved in a systematic approach to the patient in shock, employing GDE: (1) Is there an imminently life-threatening cause for the shock? (2) Is the shock state likely to be fluid responsive? (3) Is there evidence of pump failure? (4) Is there more than one cause for the shock state? (5) Is the cause of the shock state other than cardiac in origin? In contrast to formal echocardiography, GDE is qualitative, can be performed in a few minutes, is interpreted immediately, can be repeated as often as needed, and is always integrated with other elements of the intensivist's assessment to arrive at an understanding of the basis for the shock and a rational treatment plan. An important part of using GDE is recognizing its limitations and judging when to proceed to a comprehensive echocardiography examination. Competence in GDE has become an essential skill for the practicing intensivist. PMID- 23032455 TI - Treatment of complex sleep apnea syndrome. AB - Complex sleep apnea syndrome (CompSAS) describes the coexistence or appearance and persistence of central apneas or hypopneas in patients with obstructive sleep apnea upon successful restoration of airway patency. We review data on treatment of CompSAS with CPAP, bilevel positive airway pressure, and adaptive servoventilation and discuss evidence for the addition of medications (analgesics, hypnotics, acetazolamide) and gases (oxygen, CO2) to positive airway pressure therapy. Future research should focus on defining outcomes in patients with CompSAS and allow for more accurate tailoring of therapy to the pathophysiology present in the individual patient. PMID- 23032456 TI - A 33-year-old man with chest pain, left upper lobe mass, pulmonary nodules, and bilateral bullae. PMID- 23032457 TI - A 75-year-old woman admitted to the ICU with respiratory failure. PMID- 23032463 TI - Complications of removal of indwelling pleural catheters. PMID- 23032465 TI - Spirometry in bronchial asthma: role of TB. PMID- 23032467 TI - Pulmonary embolism: weekend effect or Monday effect? PMID- 23032469 TI - Clarification of once-daily low-molecular-weight heparin dosing in pulmonary embolism. PMID- 23032471 TI - Decreased renal function and the prevalence of obstructive sleep apnea: more data are needed. PMID- 23032473 TI - Radiation dose for pediatric patients with cystic fibrosis: a continuous adjustment process and remaining concern. PMID- 23032479 TI - Cognitive change checklist: psychometric characteristics in community-dwelling older adults. AB - OBJECTIVE: To extend the psychometric study of the Cognitive Change Checklist (3CL) by examining the reliability, factor structure, and external correlates of 3CL informant and self-report ratings in community-dwelling adults. We also conducted receiver operating characteristic analyses examining rating scores from this normative sample with those of clinical samples. DESIGN: Scale reliability and validity study. SETTING: Community sites. PARTICIPANTS: Six hundred seventy nine older adults. RESULTS: The pattern of scale relationships within and across versions, and the failure to find associations with age and education, were consistent with findings in clinic samples reported previously. Factor analysis replicated the four-factor structure of the informant ratings. All informant version scales significantly discriminated amnestic mild cognitive impairment cases and patients with mild dementia from normals. CONCLUSION: These findings provide support for the use of the checklist as a clinical tool to facilitate identification of cases of mild cognitive impairment and early dementia. PMID- 23032480 TI - A DFT-D study of structural and energetic properties of TiO2 modifications. AB - The structures and relative energies of the three naturally occurring modifications of titanium dioxide (rutile, brookite and anatase) were investigated. For an accurate description, atom-pairwise dispersion-corrected density functional theory (DFT-D) was applied. The DFT-D3 scheme was extended non empirically to improve the description of Ti atoms in bulk systems. New dispersion coefficients were derived from TDDFT calculations for electrostatically embedded TiO(2) clusters. The dispersion coefficient [Formula: see text] is reduced by a factor of 18 compared to the free atom. The three TiO(2) modifications were optimized in periodic plane-wave calculations with dispersion-corrected GGA (PBE, revPBE) and hybrid density functionals (PBE0, revPBE0). The calculated lattice parameters are in good agreement with experimental data, in particular the dispersion-corrected PBE0 and revPBE0 hybrid functionals. Although the observed relative stabilities could not be reproduced in all cases, dispersion corrections improve the results. For an accurate description of bulk metal oxides, London dispersion is a prominent force that should not be neglected when energies and structures are computed with DFT. Additionally, the influence of dispersion interactions on the relaxation of the TiO(2)(110) surface is investigated. PMID- 23032478 TI - Cognitive outcomes after sertaline treatment in patients with depression of Alzheimer disease. AB - OBJECTIVES: Although many depressed patients with Alzheimer disease (AD) are treated with antidepressants, the effect of such treatment on cognitive performance in these patients is not known. The authors report cognitive outcomes in patients with depression of AD (dAD) after a 24-week trial of sertraline or placebo. DESIGN: Placebo-controlled, randomized, double-blind trial. SETTING: Outpatient memory clinics at five academic medical centers in the United States. PARTICIPANTS: A total of 131 patients with dAD (60 men) and Mini-Mental State Examination scores of 10-26. INTERVENTION: Sertraline (n = 67), target dose of 100 mg daily or matching placebo (n = 64). Caregivers received standardized psychosocial intervention throughout the trial. MEASUREMENTS: Mini-Mental State Examination, cognitive subscale of the Alzheimer's Disease Assessment Scale, letter fluency, backward digit span, Symbol Digit Modalities Test, and Finger Tapping Test, administered at baseline, and 8, 16, and 24 weeks following baseline. RESULTS: A series of linear models indicated no effect of treatment or of depression remission on cognitive test performance at 24 weeks. Regardless of treatment condition, very little change in cognitive test performance was noted in general. CONCLUSIONS: Treatment with sertraline in patients with dAD is not associated with greater improvement in cognition at week 24 than treatment with placebo. PMID- 23032481 TI - Simple pyrazoline and pyrazole "turn on" fluorescent sensors selective for Cd2+ and Zn2+ in MeCN. AB - An efficient two-step synthesis of pyrazoline ligand is described which is an effective "turn on" fluorescent sensor for Cd(2+) in MeCN. Oxidation to the corresponding pyrazole ligand creates a "turn on" fluorescent sensor now selective for Zn(2+) and able to distinguish it from Cd(2+). PMID- 23032482 TI - The evolution of the electronic structure at the Bi/Ag(111) interface studied using photoemission spectroscopy. AB - The growth of Bi on Ag(111) induces different surface structures, including (?3 * ?3)R30 degrees surface alloy, Bi-(p * ?3) overlayer and Bi(110) thin film, as a function of increasing Bi coverage. Here we report the study of electronic states of these structures using core level and valence band photoemission spectroscopy at room temperature. The sp-derived Shockley surface state on Ag(111) is rapidly quenched upon deposition of Bi, due to the strong variation of the in-plane surface potential in the Ag(2)Bi surface alloy. The Bi 4f core levels of the (?3 * ?3)R30 degrees alloy and Bi(110) thin film are shifted to lower binding energy by ~0.6 eV and ~0.3 eV compared with the Bi bulk value, respectively. Mechanisms inducing the core level shifts are discussed as due to a complex superposition of several factors. As Bi coverage increases and a Bi(110) overlayer forms on Ag(111), a new state is observed at ~0.9 ML arising from electronic states localized at the Ag-Bi interface. Finally the change of work function as a function of coverage is discussed on the basis of a charge transfer model. PMID- 23032483 TI - Prevention of JNK phosphorylation as a mechanism for rosiglitazone in neuroprotection after transient cerebral ischemia: activation of dual specificity phosphatase. AB - Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, prevents cell death after cerebral ischemia in animal models, but the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone protects neurons against ischemia. Mice treated with rosiglitazone were subjected to 60 minutes of focal ischemia followed by reperfusion. Rosiglitazone reduced infarct volume after ischemia and reperfusion. We show that this neuroprotective effect was reversed with a PPARgamma antagonist. Western blot analysis showed a significant increase in expression of phosphorylated stress-activated protein kinases (c-Jun N-terminal kinase (JNK) and p38) in ischemic brain tissue. Rosiglitazone blocked this increase. Furthermore, we observed that rosiglitazone increased expression of the dual specificity phosphatase 8 (DUSP8) protein and messenger RNA in ischemic brain tissue. Dual-specificity phosphatase 8 is a mitogen-activated protein kinase phosphatase that can dephosphorylate JNK and p38. Another key finding of the present study was that knockdown of DUSP8 in primary cultured cortical neurons that were subjected to oxygen-glucose deprivation diminished rosiglitazone's effect on downregulation of JNK phosphorylation. Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation. PMID- 23032485 TI - Neurovascular coupling varies with level of global cerebral ischemia in a rat model. AB - In this study, cerebral blood flow, oxygenation, metabolic, and electrical functional responses to forepaw stimulation were monitored in rats at different levels of global cerebral ischemia from mild to severe. Laser speckle contrast imaging and optical imaging of intrinsic signals were used to measure changes in blood flow and oxygenation, respectively, along with a compartmental model to calculate changes in oxygen metabolism from these measured changes. To characterize the electrical response to functional stimulation, we measured somatosensory evoked potentials (SEPs). Global graded ischemia was induced through unilateral carotid artery occlusion, bilateral carotid artery occlusion, bilateral carotid and right subclavian artery (SCA) occlusion, or carotid and SCA occlusion with negative lower body pressure. We found that the amplitude of the functional metabolic response remained tightly coupled to the amplitude of the SEP at all levels of ischemia observed. However, as the level of ischemia became more severe, the flow response was more strongly attenuated than the electrical response, suggesting that global ischemia was associated with an uncoupling between the functional flow and electrical responses. PMID- 23032484 TI - Sex differences in stroke. AB - Sex differences in stroke are observed across epidemiologic studies, pathophysiology, treatments, and outcomes. These sex differences have profound implications for effective prevention and treatment and are the focus of this review. Epidemiologic studies reveal a clear age-by-sex interaction in stroke prevalence, incidence, and mortality. While premenopausal women experience fewer strokes than men of comparable age, stroke rates increase among postmenopausal women compared with age-matched men. This postmenopausal phenomenon, in combination with living longer, are reasons for women being older at stroke onset and suffering more severe strokes. Thus, a primary focus of stroke prevention has been based on sex steroid hormone-dependent mechanisms. Sex hormones affect different (patho)physiologic functions of the cerebral circulation. Clarifying the impact of sex hormones on cerebral vasculature using suitable animal models is essential to elucidate male-female differences in stroke pathophysiology and development of sex-specific treatments. Much remains to be learned about sex differences in stroke as anatomic and genetic factors may also contribute, revealing its multifactorial nature. In addition, the aftermath of stroke appears to be more adverse in women than in men, again based on older age at stroke onset, longer prehospital delays, and potentially, differences in treatment. PMID- 23032486 TI - Genetic association test for multiple traits at gene level. AB - Genome-wide association studies (GWASs) at the gene level are commonly used to understand biological mechanisms underlying complex diseases. In general, one response or outcome is used to present a disease of interest in such studies. In this study, we consider a multiple traits association test from the gene level. We propose and examine a class of test statistics that summarizes the association information between single nucleotide polymorphisms (SNPs) and each of the traits. Our simulation studies demonstrate the advantage of gene-based multiple traits association tests when multiple traits share common genes. Using our proposed tests, we reanalyze the dataset from the Study of Addiction: Genetics and Environment (SAGE). Our result validates previous findings while presenting stronger evidence for consideration of multiple traits. PMID- 23032487 TI - Vision holds a greater share in visuo-haptic object recognition than touch. AB - The integration of visual and haptic input can facilitate object recognition. Yet, vision might dominate visuo-haptic interactions as it is more effective than haptics in processing several object features in parallel and recognizing objects outside of reaching space. The maximum likelihood approach of multisensory integration would predict that haptics as the less efficient sense for object recognition gains more from integrating additional visual information than vice versa. To test for asymmetries between vision and touch in visuo-haptic interactions, we measured regional changes in brain activity using functional magnetic resonance imaging while healthy individuals performed a delayed-match-to sample task. We manipulated identity matching of sample and target objects: We hypothesized that only coherent visual and haptic object features would activate unified object representations. The bilateral object-specific lateral occipital cortex, fusiform gyrus, and intraparietal sulcus showed increased activation to crossmodal compared to unimodal matching but only for congruent object pairs. Critically, the visuo-haptic interaction effects in these regions depended on the sensory modality which processed the target object, being more pronounced for haptic than visual targets. This preferential response of visuo-haptic regions indicates a modality-specific asymmetry in crossmodal matching of visual and haptic object features, suggesting a functional primacy of vision over touch in visuo-haptic object recognition. PMID- 23032489 TI - Neural basis of multisensory looming signals. AB - Approaching or looming signals are often related to extremely relevant environmental events (e.g. threats or collisions) making these signals critical for survival. However, the neural network underlying multisensory looming processing is not yet fully understood. Using functional magnetic resonance imaging (fMRI) we identified the neural correlates of audiovisual looming processing in humans: audiovisual looming (vs. receding) signals enhance fMRI responses in low-level visual and auditory areas plus multisensory cortex (superior temporal sulcus; plus parietal and frontal structures). When characterizing the fMRI-response profiles for multisensory looming stimuli, we found significant enhancements relative to the mean and maximum of unisensory responses in looming-sensitive visual and auditory cortex plus STS. Superadditive enhancements were observed in visual cortex. Subject-specific region-of-interest analyses further revealed superadditive response profiles within all sensory specific looming-sensitive structures plus bilateral STS for audiovisual looming vs. summed unisensory looming conditions. Finally, we observed enhanced connectivity of bilateral STS with low-level visual areas in the context of looming processing. This enhanced coupling of STS with unisensory regions might potentially serve to enhance the salience of unisensory stimulus features and is accompanied by superadditive fMRI-responses. We suggest that this preference in neural signaling for looming stimuli effectively informs animals to avoid potential threats or collisions. PMID- 23032488 TI - Characteristic profiles of high gamma activity and blood oxygenation level dependent responses in various language areas. AB - High gamma activity (HGA) has been shown to be positively correlated with blood oxygenation level-dependent (BOLD) responses in the primary cortices with simple tasks. It is, however, an open question whether the correlation is simply applied to the association areas related to higher cognitive functions. The aim of this study is to investigate quantitative correlation between HGA and BOLD and their spatial and temporal profiles during semantic processing. Thirteen patients with intractable epilepsy underwent fMRI and electrocorticography (ECoG) with a word interpretation task to evoke language-related responses. Percent signal change of BOLD was calculated at each site of ECoG electrode, which has power amplification of high gamma band (60-120 Hz) activity. We transformed locations of individual electrodes and brains to a universal coordination using SPM8 and made the quantitative comparisons on a template brain. HGAs were increased in several language-related areas such as the inferior frontal and middle temporal gyri and were positively correlated with BOLD responses. The most striking finding was different temporal dynamics of HGAs in the different brain regions. Whereas the frontal lobe showed longer-lasting HGA, the HGA-intensity on the temporal lobe quickly declined. The different temporal dynamics of HGA might explain why routine language-fMRI hardly detected BOLD in the temporal lobe. This study clarified different neural oscillation and BOLD response in various brain regions during semantic processing and will facilitate practical utilization of fMRI for evaluating higher-order cognitive functions not only in basic neuroscience, but also in clinical practice. PMID- 23032490 TI - Two brakes are better than one: the neural bases of inhibitory control of motor memory traces. AB - Inhibitory control of actions is one important aspect in daily life to warrant adequate context related behavior. Alpha activity (oscillatory brain activity around 10Hz) has been suggested to play a major role for the implementation of inhibitory control. In the present study electrophysiological correlates of voluntary suppression of acquired, memorized motor actions have been compared to the suppression of novel motor actions. Multichannel EEG analyses of alpha power and alpha phase coherence were used. Healthy subjects were asked to inhibit the execution of either well-trained, memorized or untrained, novel sequential finger movements depending on the respective context. An increase of focal upper alpha activity at bilateral sensorimotor cortices was found during suppression of movements independent of whether these were memorized or novel. This represents a memory unspecific mechanism of motor cortical inhibition. In contrast, interregional phase synchronization between frontal and (left) central recording sites showed a differential effect with decoupling during suppression of memorized movements which was not the case with novel ones. Increase of fronto central coupling at upper alpha frequency during retrieval of the memory trace and decrease during suppression of retrieval were obtained. This further supports the view of the functional relevance of upper alpha oscillations as a mechanism of context-dependent sustained inhibition of memory contents. PMID- 23032491 TI - Microstructural integrity of the cingulum is related to verbal memory performance in elderly with cerebral small vessel disease: the RUN DMC study. AB - BACKGROUND: Cerebral small vessel disease (SVD) is related to verbal memory failures. It is suggested that early white matter damage, is located, among others, in the (posterior) cingulum at an early stage in neurodegeneration. Changes in the microstructural integrity of the cingulum assessed with diffusion tensor imaging (DTI), beyond detection with conventional MRI, may precede macrostructural changes and be related to verbal memory failures. OBJECTIVE: To investigate the relation between cingular microstructural integrity and verbal memory performance in 503 non-demented elderly with cerebral SVD. METHODS: The RUN DMC study is a prospective cohort study in elderly (50-85 years) with cerebral SVD. All participants underwent T1 MPRAGE, FLAIR and DTI scanning and the Rey Auditory Verbal Learning Test. Mean diffusivity (MD) and fractional anisotropy (FA) were assessed in six different cingular regions of interests (ROIs). Linear regression analysis was used to assess the relation between verbal memory performance and cingular DTI parameters, with appropriate adjustments. Furthermore a TBSS analysis of the whole brain was performed to investigate the specificity of our findings. RESULTS: Both our ROI-based and TBSS analysis showed that FA was positively related to immediate memory, delayed recall, delayed recognition and overall verbal memory performance of the cingulum, independent of confounders. A similar distribution was seen for the inverse association with MD and verbal memory performance with TBSS analysis. No significant relations were found with psychomotor speed, visuospatial memory and MMSE. When stratified on hippocampal integrity, the MD and FA values of the cingular ROIs differed significantly between participants with a good and poor hippocampal integrity. CONCLUSION: Microstructural integrity of the cingulum, assessed by DTI, is specifically related to verbal memory performance, in elderly with SVD. Furthermore we found that when the integrity of the hippocampus is disrupted, the cingulum integrity is impaired as well. PMID- 23032492 TI - Quantifying temporal correlations: a test-retest evaluation of functional connectivity in resting-state fMRI. AB - There have been many interpretations of functional connectivity and proposed measures of temporal correlations between BOLD signals across different brain areas. These interpretations yield from many studies on functional connectivity using resting-state fMRI data that have emerged in recent years. However, not all of these studies used the same metrics for quantifying the temporal correlations between brain regions. In this paper, we use a public-domain test-retest resting state fMRI data set to perform a systematic investigation of the stability of the metrics that are often used in resting-state functional connectivity (FC) studies. The fMRI data set was collected across three different sessions. The second session took place approximately eleven months after the first session, and the third session was an hour after the second session. The FC metrics composed of cross-correlation, partial cross-correlation, cross-coherence, and parameters based on an autoregressive model. We discussed the strengths and weaknesses of each metric. We performed ROI-level and full-brain seed-based voxelwise test-retest analyses using each FC metric to assess its stability. For both ROI-level and voxel-level analyses, we found that cross-correlation yielded more stable measurements than the other metrics. We discussed the consequences of this result on the utility of the FC metrics. We observed that for negatively correlated ROIs, their partial cross-correlation is shrunk towards zero, thus affecting the stability of their FC. For the present data set, we found greater stability in FC between the second and third sessions (one hour between sessions) compared to the first and second sessions (approximately 11months between sessions). Finally, we report that some of the metrics showed a positive association between strength and stability. In summary, the results presented in this paper suggest important implications when choosing metrics for quantifying and assessing various types of functional connectivity for resting-state fMRI studies. PMID- 23032493 TI - [Second opinion in evaluating work capacity]. PMID- 23032495 TI - [Will foam sclerotherapy and endovenous thermal ablation replace varicose vein stripping?]. AB - Minimally invasive treatments of varicosis are increasingly establishing. Short and intermediate-term outcomes of endovenous treatments are satisfying: success rates are comparable with conventional surgery, whereas recovery is faster and complication rates are lower. Success rates are highest for endovenous laser ablation (EVLA). However, endovenous radiofrequency ablation (RFA) has advanced. Its short term outcomes are now comparable to EVLA, but with less side-effects. Ultrasound guided foam sclerotherapy (UGFS) replaced other forms of liquid sclerotherapy. In principle, this treatment can be combined with every other treatment for varicosis, but it loses its position as a monotherapy, due to poorer intermediate-term outcomes compared with EVLA and RFA. More prospective randomized controlled trials are needed in order to state an evidence based hierarchy of treatments for varicosis. With the minimally invasive treatments it is possible to treat patients on an outpatient basis. It will have to be assessed whether this will lead to higher cost-effectiveness. PMID- 23032496 TI - [Cardiovascular risk of non-steroidal anti-inflammatory drugs]. AB - Classical non-steroidal anti-inflammatory drugs (NSAID) and new selective inhibitors of cyclooxygenase-2(Cox-2 inhibitors) have been successfully used for several decades in the treatment of patients with chronic pain. In addition of their well known adverse gastrointestinal effects, these drugs have been recognized during recent years to increase cardiovascular risk. This risk exists with all drugs belonging to these two therapeutic classes and can be explained by a blood pressure increasing effect and the development of endothelial dysfunction. It there therefore necessary to check blood pressure and the renal function before and during administration of a NSAID or a Cox-2 inhibitor, as well as hemoglobinemia in patients exhibiting an increased gastrointestinal risk. International recommendations propose to avoid the use of these drugs in patients at high cardiovascular risk. If not possible naproxen, co-administered or not with a proton pump inhibitor, should be used preferentially, since this drug is the safest with regard to cardiovascular risk. PMID- 23032497 TI - [Diabetic neuropathies: clinical sub-types, early detection, and asking help from neurologist]. AB - In diabetes mellitus, it is expected to see a common, mainly sensitive, distal symmetrical polyneuropathy (DPN) involving a large proportion of diabetic patients according to known risk factors. Several other diabetic peripheral neuropathies are recognized, such as dysautonomia and multifocal neuropathies including lumbosacral radiculoplexus and oculomotor palsies. In this review, general aspects of DPN and other diabetic neuropathies are examined, and it is discussed why and how the general practitioner has to perform a yearly examination. At the present time, some consensus emerge to ask help from neurologist when faced to other forms of peripheral neuropathies than distal symmetrical DPN. PMID- 23032498 TI - [Late-onset-Typ-1-diabetes]. PMID- 23032499 TI - [Should we treat thalassemia-induced osteoporosis: two case reports]. AB - We report two cases of beta-thalassemia-induced osteoporosis. A man and a woman presented an osteoporosis at the densitometry and were treated with bisphoshonate iv. All the studies analysed the efficacity of bisphosphonate, in particular zoledronate seems to be effective. Concerning the pathogenesis, the RANK-RANK Ligand and OPG play a major role in bone-resorption and seem to be the principal implicated mechanism for the development of osteoporosis in BTM. At the moment there is no study evaluating the efficacity of denosumab in the BTM. PMID- 23032500 TI - [Aspirin reduces the risk of recurrent thromboembolism]. PMID- 23032501 TI - [Probiotics reduce the incidence of antibiotic-associated diarrhea]. PMID- 23032503 TI - [CME clinical laboratory values 27. Highly sensitive troponins]. PMID- 23032507 TI - Getting personal: understanding how genetic variation affects clinical outcomes in patients with tetralogy of Fallot. AB - The work by Jeewa et al. is an important step toward "personalizing" or individualizing our approach to care of patients with tetralogy of Fallot. Although future studies will need to confirm the potential role of HIF1A-mediated signaling in right ventricular remodeling, it raises the possibility that modulation of the HIF1A signaling pathway or its downstream effectors such as TGF beta may allow better preservation of ventricular function in patients with TOF. Furthermore, directed genotyping for HIF1A and other genetic variants may help identify patients at risk for adverse outcomes. This study demonstrates the potential for genetics-of- outcomes studies to evaluate novel therapeutic targets and to identify at-risk populations that may require specific therapeutic considerations. PMID- 23032508 TI - A reliable prognosis for congenital central hypoventilation syndrome should reflect a patient's genetic profile and management history. PMID- 23032510 TI - American Pediatric Society 2012 Presidential Address: mind the gap. PMID- 23032511 TI - Rheumatoid arthritis: new treatments, better outcomes. AB - There have been numerous changes regarding evidence-based care of patients with rheumatoid arthritis, a costly, chronic, autoimmune disease. This article provides an update on the factors that affect the safe use of biologic medications in this patient population. PMID- 23032512 TI - When tension headaches become chronic. AB - This article provides background, diagnostic, treatment, and management information about the most common form of headache: tension-type headache (TTH). Using a typical patient case scenario, it illustrates evidence-based therapies that NPs can offer patients whose TTH has become chronic due to medication overuse. PMID- 23032513 TI - Data analysis in emission tomography using emission-count posteriors. AB - A novel approach to the analysis of emission tomography data using the posterior probability of the number of emissions per voxel (emission count) conditioned on acquired tomographic data is explored. The posterior is derived from the prior and the Poisson likelihood of the emission-count data by marginalizing voxel activities. Based on emission-count posteriors, examples of Bayesian analysis including estimation and classification tasks in emission tomography are provided. The application of the method to computer simulations of 2D tomography is demonstrated. In particular, the minimum-mean-square-error point estimator of the emission count is demonstrated. The process of finding this estimator can be considered as a tomographic image reconstruction technique since the estimates of the number of emissions per voxel divided by voxel sensitivities and acquisition time are the estimates of the voxel activities. As an example of a classification task, a hypothesis stating that some region of interest (ROI) emitted at least or at most r-times the number of events in some other ROI is tested. The ROIs are specified by the user. The analysis described in this work provides new quantitative statistical measures that can be used in decision making in diagnostic imaging using emission tomography. PMID- 23032515 TI - 8-Hydroxycalamenene isolated from the rhizomes of Reynoutria elliptica exerts neuroprotective effects both in vitro and in vivo. AB - Retinal ganglion cells (RGCs) death caused by oxidative stress is a common risk factor for glaucoma. In the present study, 8-hydroxycalamenene was isolated from the hexane fraction of Reynoutria elliptica. We showed that 8-hydroxycalamenene attenuated the cell death of transformed RGC-5 cells. This compound also produced a dose-dependent decrease in the expression of apoptotic proteins (cleaved PARP and caspase-3) induced by l-buthionine-(S,R)-sulfoximine (BSO) plus glutamate and stimulated glutathione and glutathione S-transferase activity. Moreover, the addition of 8-hydroxycalamenene to cell cultures restored the reduced mitochondrial membrane potential resulting from glutamate/BSO treatment. The presence of N-methyl-d-aspartate in the retina of rats affected the thickness of the inner plexiform layer (IPL) and increased the number of TUNEL-positive RGCs. However, 8-hydroxycalamenene protected against thinning of the IPL and reduced TUNEL-positive cells in the ganglion cell layer. Thus, 8-hydroxycalamenene isolated from R. elliptica exerts neuroprotective effects both in vitro and in vivo. PMID- 23032516 TI - Solution-processed organic photovoltaic cells based on a squaraine dye. AB - In this work, 2,4-bis[4-(N,N-diisobutylamino)-2,6-dihydroxyphenyl] squaraine (SQ) was systematically studied as an electron donor in solution processed photovoltaic cells, showing power conversion efficiency of >4.0% under AM1.5G 1 sun illumination at room temperature. Low mobilities were found to limit charge transport in the bulk heterojunctions. Efficiency was thus improved to 5.1% at 80 degrees C mainly due to improvement of photocurrent extraction. We also demonstrated that the SQ compound synthesized via a simple method has high purity, and thus can be used in photovoltaic cells without further purification. Our results suggest the huge potential of SQ and its analogs in organic photovoltaic applications. PMID- 23032517 TI - Chiroptical, linear, and second-order nonlinear optical properties of binaphthol derivatives. AB - We have investigated the chiroptical, linear, and second-order nonlinear optical (NLO) properties of seven binaphthol derivatives and elucidated structure property relationships from the micromechanism for the first time. The excitation energies, oscillator strengths, and rotational strengths of the 150 lowest energy electron excitations for the most stable conformers have been calculated at TDB3LYP/cc-pVDZ level of theory. The experimental UV-vis absorption energies were reproduced well by our calculations. The simulated circular dichroism (CD) spectra and calculated optical rotation (OR) values are in reasonable agreement with experimental ones. These results demonstrate that TDDFT calculations can not only describe the electron transition property but also can be used to assign the absolute configurations (ACs) of binaphthol derivatives with high confidence. Whereas OR values are more sensitive to the molecular structures than CD spectra. The electron transition property and chiroptical origin have been assigned and analyzed. These derivatives possess remarkably large molecular first hyperpolarizabilities, especially compound 7 which has a value of 241.65 * 10( 30) esu. This value is about 60 times as large as that of highly pi-delocalized phenyliminomethyl ferrocene complex. Moreover, compound 6 exhibits pronounced different second-order NLO response values from neutral state to the two cationic states (6(2+) and 6(4+)), which indicates that this compound could act as a potential NLO switch material. The cooperativity of intramolecular charge transfer of the studied compounds was also discussed. PMID- 23032518 TI - Antitumor effects and preliminary systemic toxicity of ANISpm in vivo and in vitro. AB - Polyamines as a vector to ferry toxic agents have attracted attention, and naphthalimide-polyamine conjugates show potent activity and tumor cell selectivity. The present study was carried out to evaluate the antitumor effects and preliminary systemic toxicity of ANISpm, a novel 3-amino-naphthalimide spermine conjugate. The polyamine transport system recognition of ANISpm, supported by alpha-difluoromethylornithine (DFMO)/spermidine (Spd) experiments, is in accordance with its potent cell selectivity between human hepatoma HepG2 cells and normal QSG7701 hepatocyte. The antiproliferative effect is because of ANISpm-induced cell apoptosis, a common characteristic of both naphthalimide and polyamine analogs. Various apoptotic assessment assays have shown that ANISpm can induce apoptosis through the PI3K/Akt signal pathway. The apoptotic signaling cascade involves Akt inactivation, which results in a series of cellular events. The downstream pathway includes Bad dephosphorylation, dissociation of 14-3-3 and Bad, and binding to Bcl-xL, which triggers the disruption of the mitochondrial membrane, release of cytochrome c, and caspases' cascade activation. Furthermore, the Akt/mTOR signal pathway is also involved in ANISpm-mediated cell-cycle arrest. Additive DFMO or Spd, which only enhances or attenuates ANISpm-mediated cell apoptosis, respectively, does not alter the signal pathway. In addition, preliminary toxicology evaluation showed that ANISpm had no obvious system toxicity at a dose of 2.5 mg/kg, which exerted potent antitumor activity in vivo, especially hematotoxicity. Thus, ANISpm merits further investigation as a potential chemotherapeutic agent against hepatocellular carcinoma. PMID- 23032519 TI - Fluorescent stilbazolium dyes as probes of the norepinephrine transporter: structural insights into substrate binding. AB - We report the synthesis, binding kinetics, optical spectroscopy and predicted binding modes of a series of sterically demanding, fluorescent norepinephrine transporter (NET) ligands. A series of bulky stilbazolium dyes, including six newly synthesized compounds, were evaluated to determine the effect of extending the molecular probes' 'heads' or 'tails'. Taking advantage of the dyes' characteristic 'turn-on' emission, the kinetic binding parameters, k(on) and k(off) were determined revealing that extension of the molecules' tails is well tolerated while expansion of the head is not. Additionally, a 'headfirst' orientation appears to be preferred over a 'tail-first' binding pose. Further details of the possible binding modes were obtained from the emission spectra of the bound probes. A small range of interplanar twist angles, approximately 35 degrees to 60 degrees , is predicted to produce the observed emission. Docking experiments and molecular modelling support the kinetic and spectroscopic data providing structural insights into substrate binding. PMID- 23032522 TI - The cover. Castle of Chillon, evening. PMID- 23032526 TI - Clinicians remain reluctant to allow negative findings to influence practice. PMID- 23032527 TI - Blood type linked to heart disease risk, but clinical significance unlikely. PMID- 23032528 TI - IDSA: Avoid antibiotics for most throat infections. PMID- 23032534 TI - Bleeding risk with ischemic stroke therapy. PMID- 23032535 TI - Bleeding risk with ischemic stroke therapy. PMID- 23032537 TI - Computed tomographic screening for lung cancer. PMID- 23032539 TI - Definition of acute respiratory distress syndrome. PMID- 23032540 TI - Definition of acute respiratory distress syndrome. PMID- 23032542 TI - Influence of smoking on treatment with clopidogrel. PMID- 23032546 TI - Challenges at the intersection of team-based and patient-centered health care: insights from an IOM working group. PMID- 23032547 TI - A new model for medical education: celebrating restraint. PMID- 23032548 TI - A piece of my mind. Lack of data. PMID- 23032549 TI - Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. AB - CONTEXT: Observational studies have reported an inverse association between serum 25-hydroxyvitamin D (25-OHD) levels and incidence of upper respiratory tract infections (URTIs). However, results of clinical trials of vitamin D supplementation have been inconclusive. OBJECTIVE: To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial conducted among 322 healthy adults between February 2010 and November 2011 in Christchurch, New Zealand. INTERVENTION: Participants were randomly assigned to receive an initial dose of 200,000 IU oral vitamin D3, then 200,000 IU 1 month later, then 100,000 IU monthly (n = 161), or placebo administered in an identical dosing regimen (n = 161), for a total of 18 months. MAIN OUTCOME MEASURES: The primary end point was number of URTI episodes. Secondary end points were duration of URTI episodes, severity of URTI episodes, and number of days of missed work due to URTI episodes. RESULTS: The mean baseline 25-OHD level of participants was 29 (SD, 9) ng/mL. Vitamin D supplementation resulted in an increase in serum 25 OHD levels that was maintained at greater than 48 ng/mL throughout the study. There were 593 URTI episodes in the vitamin D group and 611 in the placebo group, with no statistically significant differences in the number of URTIs per participant (mean, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group; risk ratio, 0.97; 95% CI, 0.85-1.11), number of days of missed work as a result of URTIs (mean, 0.76 days in each group; risk ratio, 1.03; 95% CI, 0.81-1.30), duration of symptoms per episode (mean, 12 days in each group; risk ratio, 0.96; 95% CI, 0.73-1.25), or severity of URTI episodes. These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels. CONCLUSION: In this trial, monthly administration of 100,000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12609000486224. PMID- 23032550 TI - beta-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. AB - CONTEXT: beta-Blockers remain the standard of care after a myocardial infarction (MI). However, the benefit of beta-blocker use in patients with coronary artery disease (CAD) but no history of MI, those with a remote history of MI, and those with only risk factors for CAD is unclear. OBJECTIVE: To assess the association of beta-blocker use with cardiovascular events in stable patients with a prior history of MI, in those with CAD but no history of MI, and in those with only risk factors for CAD. DESIGN, SETTING, AND PATIENTS: Longitudinal, observational study of patients in the Reduction of Atherothrombosis for Continued Health (REACH) registry who were divided into 3 cohorts: known prior MI (n = 14,043), known CAD without MI (n = 12,012), or those with CAD risk factors only (n = 18,653). Propensity score matching was used for the primary analyses. The last follow-up data collection was April 2009. MAIN OUTCOME MEASURES: The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. The secondary outcome was the primary outcome plus hospitalization for atherothrombotic events or a revascularization procedure. RESULTS: Among the 44,708 patients, 21,860 were included in the propensity score-matched analysis. With a median follow-up of 44 months (interquartile range, 35-45 months), event rates were not significantly different in patients with beta-blocker use compared with those without beta-blocker use for any of the outcomes tested, even in the prior MI cohort (489 [16.93%] vs 532 [18.60%], respectively; hazard ratio [HR], 0.90 [95% CI, 0.79-1.03]; P = .14). In the CAD without MI cohort, the associated event rates were not significantly different in those with beta-blocker use for the primary outcome (391 [12.94%]) vs without beta-blocker use (405 [13.55%]) (HR, 0.92 [95% CI, 0.79-1.08]; P = .31), with higher rates for the secondary outcome (1101 [30.59%] vs 1002 [27.84%]; odds ratio [OR], 1.14 [95% CI, 1.03 1.27]; P = .01) and for the tertiary outcome of hospitalization (870 [24.17%] vs 773 [21.48%]; OR, 1.17 [95% CI, 1.04-1.30]; P = .01). In the cohort with CAD risk factors only, the event rates were higher for the primary outcome with beta blocker use (467 [14.22%]) vs without beta-blocker use (403 [12.11%]) (HR, 1.18 [95% CI, 1.02-1.36]; P = .02), for the secondary outcome (870 [22.01%] vs 797 [20.17%]; OR, 1.12 [95% CI, 1.00-1.24]; P = .04) but not for the tertiary outcomes of MI (89 [2.82%] vs 68 [2.00%]; HR, 1.36 [95% CI, 0.97-1.90]; P = .08) and stroke (210 [6.55%] vs 168 [5.12%]; HR, 1.22 [95% CI, 0.99-1.52]; P = .06). However, in those with recent MI (<=1 year), beta-blocker use was associated with a lower incidence of the secondary outcome (OR, 0.77 [95% CI, 0.64-0.92]). CONCLUSION: In this observational study of patients with either CAD risk factors only, known prior MI, or known CAD without MI, the use of beta-blockers was not associated with a lower risk of composite cardiovascular events. PMID- 23032551 TI - Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. AB - CONTEXT: Recent reports suggest that rheumatoid arthritis (RA) may be a risk factor for venous thromboembolism (VTE), particularly in conjunction with hospitalization. Using hospitalization data to identify RA and VTE may identify patients when they are at elevated risk for other reasons, obscuring the incompletely understood underlying association between RA and VTE and leading to inappropriate institution or timing of interventions. OBJECTIVE: To estimate risks for VTE in patients with RA, including the relation of these risks to disease duration and hospitalization. DESIGN, SETTING, AND PATIENTS: Prospective, population-based cohort study of 1 prevalent RA cohort (n = 37,856), 1 incident RA cohort (n = 7904), and matched general population comparison cohorts, all from Sweden, with follow-up from 1997 through 2010. MAIN OUTCOME MEASURE: First-time VTE. RESULTS: Patients with prevalent RA were at greater risk of VTE than the general population (rate, 5.9 [95% CI, 5.1-6.6] vs 2.8 [95% CI, 2.6-3.1] per 1000 person-years (adjusted hazard ratio [HR], 2.0 [95% CI, 1.9-2.2]; P < .001). By the time of RA symptom onset, there was no statistically significant association between a history of VTE and RA (odds ratio, 1.2 [95% CI, 1.0-1.4]; P = .08; 150 events in the RA cohort vs 587 in the comparison cohort). Counting from RA diagnosis, an increased rate in the RA cohort vs the comparison cohort (3.8 [95% CI, 2.5-5.2] vs 2.4 [95% CI, 1.9-2.9] per 1000 person-years; HR, 1.6 [95% CI, 1.1 2.5]; P = .02) was detected within the first year and did not increase further during the first decade. Although rates for VTE following hospitalization were higher, the 1-year rate of VTE per 1000 person-years was not higher in the RA cohort than in the comparison cohort after hospital discharge (11.8 [95% CI, 8.6 15.1] vs 13.1 [11.3-14.8]; HR, 1.0 [95% CI, 0.7-1.4]; P = .90). The rates of VTE increased with age but were largely similar across sex and rheumatoid factor status, as were the HRs for VTE across age, sex, and rheumatoid factor status. CONCLUSIONS: Compared with the general population, Swedish patients with RA had an elevated risk for VTE that was stable over the first 10 years after diagnosis. Although hospitalization was a risk factor for VTE the first year after discharge, the excess risk was not greater in patients with RA than in the general population. PMID- 23032553 TI - Pulmonary hypertension. AB - Pulmonary hypertension (PH), defined as elevated pulmonary artery pressure, is common in the general population and associated with increased mortality. Accordingly, physicians commonly encounter patients with dyspnea, exercise intolerance, and/or right heart failure who have elevated pulmonary artery systolic pressure (PASP) on echocardiography. Although pulmonary arterial vasodilators may often be considered in this setting, these drugs have been predominantly tested in the subset of PH patients with pulmonary arterial hypertension (PAH). Elevated PASP alone is not sufficient for the diagnosis of PAH, and secondary causes of PASP elevation, most commonly left heart disease, are far more prevalent than isolated PAH. Treatment of this more common group of patients with PH due to left heart disease is challenging because there are few evidence-based treatment options, and pulmonary vasodilator therapy may lead to worsening symptoms. Therefore, improving symptoms and avoiding adverse outcomes in patients with PH requires the following: (1) understanding the optimal use of echocardiography for the diagnosis of PH; (2) recognizing the utility and proper interpretation of invasive hemodynamic testing prior to starting pulmonary vasodilator therapy; (3) differentiating PAH from pulmonary venous hypertension due to left heart disease; and (4) understanding the appropriate treatment strategies for PH and resultant right heart failure. PMID- 23032554 TI - Vitamin D and the cure for the common cold. PMID- 23032552 TI - Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. AB - CONTEXT: Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. OBJECTIVE: To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network. INTERVENTION: Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. MAIN OUTCOME MEASURES: Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact). RESULTS: Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. CONCLUSION: In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00832000. PMID- 23032558 TI - JAMA patient page. Pulmonary hypertension. PMID- 23032555 TI - Mexiletine for treatment of myotonia: a trial triumph for rare disease networks. PMID- 23032559 TI - Water quality assessment using the AREc32 reporter gene assay indicative of the oxidative stress response pathway. AB - The reporter gene assay AREc32 is based on the induction of the Nrf2 mediated oxidative stress response pathway in the human breast cancer cell line MCF7, where eight copies of the antioxidant response element (ARE) are linked to a reporter gene encoding for luciferase. The Nrf2-ARE pathway is responsive to many chemicals that cause oxidative stress, among them a large number of pesticides and skin irritants. We adopted and validated the AREc32 bioassay for water quality testing. tert-Butylhydroquinone served as the positive control, phenol as the negative control and other reactive chemicals were assessed for their specificity. An environmentally relevant reference chemical, benzo(a)pyrene was the most potent inducer of all tested chemicals. The concentration causing an induction ratio (IR) of 1.5 (EC(IR1.5)) was chosen as the effect benchmark value. The assay was applied to 21 water samples ranging from sewage to drinking water, including secondary treatment and various tertiary treatment options (ozonation, biologically activated carbon filtration, membrane filtration, reverse osmosis, advanced oxidation, chlorination, chloramination). The samples were enriched by solid phase extraction. In most samples the oxidative stress response was far more sensitive than cytotoxicity. The primary and secondary treated effluent exceeded the effect threshold IR 1.5 at a relative enrichment factor (REF) of 1, i.e., the native samples were active. All tertiary treated samples were less potent and their EC(IR1.5) lay between REF 1 and 10. The Nrf2 pathway was induced at a REF of approximately 10 for surface waters and drinking water, and above this enrichment cytotoxicity took over in most samples and quenched the induction. The blank (ultrapure water run through the sample enrichment process) was cytotoxic at an REF of 100, which is the limit of concentrations range that can be evaluated. Treatment typically decreased both the cytotoxicity and oxidative stress response apart from drinking water treatment where chlorination caused an increase in oxidative stress response, presumably due to the formation of disinfection by-products. This study demonstrates the relevance and applicability of the oxidative stress response pathway for water quality monitoring. PMID- 23032560 TI - Changes in bone structure and the muscle-bone unit in children with chronic kidney disease. AB - The impact of pediatric chronic kidney disease (CKD) on acquisition of volumetric bone mineral density (BMD) and cortical dimensions is lacking. To address this issue, we obtained tibia quantitative computed tomography scans from 103 patients aged 5-21 years with CKD (26 on dialysis) at baseline and 12 months later. Gender, ethnicity, tibia length, and/or age-specific Z-scores were generated for trabecular and cortical BMD, cortical area, periosteal and endosteal circumference, and muscle area based on over 700 reference subjects. Muscle area, cortical area, and periosteal and endosteal Z-scores were significantly lower at baseline compared with the reference cohort. Cortical BMD, cortical area, and periosteal Z-scores all exhibited a significant further decrease over 12 months. Higher parathyroid hormone levels were associated with significantly greater increases in trabecular BMD and decreases in cortical BMD in the younger patients (significant interaction terms for trabecular BMD and cortical BMD). The estimated glomerular filtration rate was not associated with changes in BMD Z scores independent of parathyroid hormone. Changes in muscle and cortical area were significantly and positively associated in control subjects but not in CKD patients. Thus, children and adolescents with CKD have progressive cortical bone deficits related to secondary hyperparathyroidism and potential impairment of the functional muscle-bone unit. Interventions are needed to enhance bone accrual in childhood-onset CKD. PMID- 23032561 TI - Foamlike porous spinel Mn(x)Co(3-x)O4 material derived from Mn3[Co(CN)6]2?nH2O nanocubes: a highly efficient anode material for lithium batteries. AB - A new facile strategy has been designed to fabricate spinel Mn(x)Co(3-x)O(4) porous nanocubes, which involves a morphology-conserved and pyrolysis-induced transformation of Prussian Blue Analogue Mn(3)[Co(CN)(6)](2)?nH(2)O perfect nanocubes. Owing to the release of CO(2) and N(x)O(y) in the process of interdiffusion, this strategy can overcome to a large extent the disadvantage of the traditional ceramic route for synthesis of spinels, and Mn(x)Co(3-x)O(4) with foamlike porous nanostructure is effectively obtained. Importantly, when evaluated as an electrode material for lithium-ion batteries, the foamlike Mn(x)Co(3-x)O(4) porous nanocubes display high specific discharge capacity and excellent rate capability. The improved electrochemical performance is attributed to the beneficial features of the particular foamlike porous nanostructure and large surface area, which reduce the diffusion length for Li(+) ions and enhance the structural integrity with sufficient void space for buffering the volume variation during the Li(+) insertion/extraction. PMID- 23032562 TI - Luminescence lifetimes of neutral nitrogen-vacancy centres in synthetic diamond containing nitrogen. AB - The decay time of luminescence from neutral nitrogen-vacancy (NV(0)) centres in synthetic diamond is reported. The intrinsic luminescence lifetime of NV (0) is measured as tau(r) = 19 +/- 2 ns. Neutral substitutional nitrogen atoms (N(S)(0)) are shown to quench luminescence from NV(0) by dipole-dipole resonant energy transfer at a rate such that the transfer time would equal tau(r) if one (N(S)(0)) atom was ~3 nm from the NV(0). In chemical-vapour-deposited diamonds grown with a small nitrogen content, that are brown as a result of vacancy cluster defects, the decay time of NV(0) equals tau(r) in the as-grown material. However, after annealing at >=1700 degrees C to remove the brown colour, luminescence from the NV(0) centres is severely quenched. This effect is suggested to be a result of the destruction of NV(0) centres and the creation of new NV(0) centres localized in vacancy-rich regions of the crystals. PMID- 23032563 TI - Trace element reactivity in FeS-rich estuarine sediments: influence of formation environment and acid sulfate soil drainage. AB - Iron monosulfides (FeS) precipitate during benthic mineralisation of organic C and are well known to have a strong influence on trace element bioavailability in sediments. In this study we investigate the reactivity of trace elements (As, Cd, Co, Cr, Cu, Mn, Mo, Ni, Pb, Zn) in sediments containing abundant and persistent FeS stores, collected from a south-western Australian estuarine system. Our objective was to explore the influence of sediment formation conditions on trace element reactivity by investigating sediments collected from different environments, including estuarine, riverine and acid sulfate soil influenced sites, within a single estuarine system. In general, we found a higher degree of reactivity (defined by 1 mol/L HCl extractions) for Cd, Mn, Pb and Zn, compared with a lower reactivity of As, Co, Cr, Cu, Mo and Ni. Moderate to strong correlations (R(2)>0.4, P<0.05) were observed between AVS and reactive Cd, Co, Mn, Mo, Ni, Pb and Zn within many of the formation environments. In contrast, correlations between AVS and As, Cr and Cu were generally poor (not significant, R(2)<0.4, P>0.05). Based on their reactivity and correlations with AVS, it appears that interactions (sorption, co-precipitation) between FeS and Cd, Mn, Pb and Zn in many of the sediments from this study are probable. Our data also demonstrate that drainage from acid sulfate soils (ASS) can be a source of trace elements at specific sites. A principal components analysis of our reactive (1 mol/L HCl extractable) trace element data clearly distinguished sites receiving ASS drainage from the other non-impacted sites, by a high contribution from Fe-Co Mn-Ni along the first principal axis, and contributions from higher S-As/lower reactive Pb along the second axis. This demonstrates that trace element reactivity in sediments may provide a geochemical signature for sites receiving ASS drainage. PMID- 23032564 TI - Lost food, wasted resources: global food supply chain losses and their impacts on freshwater, cropland, and fertiliser use. AB - Reducing food losses and waste is considered to be one of the most promising measures to improve food security in the coming decades. Food losses also affect our use of resources, such as freshwater, cropland, and fertilisers. In this paper we estimate the global food supply losses due to lost and wasted food crops, and the resources used to produce them. We also quantify the potential food supply and resource savings that could be made by reducing food losses and waste. We used publically available global databases to conduct the study at the country level. We found that around one quarter of the produced food supply (614 kcal/cap/day) is lost within the food supply chain (FSC). The production of these lost and wasted food crops accounts for 24% of total freshwater resources used in food crop production (27 m(3)/cap/yr), 23% of total global cropland area (31 * 10(-3)ha/cap/yr), and 23% of total global fertiliser use (4.3 kg/cap/yr). The per capita use of resources for food losses is largest in North Africa & West-Central Asia (freshwater and cropland) and North America & Oceania (fertilisers). The smallest per capita use of resources for food losses is found in Sub-Saharan Africa (freshwater and fertilisers) and in Industrialised Asia (cropland). Relative to total food production, the smallest food supply and resource losses occur in South & Southeast Asia. If the lowest loss and waste percentages achieved in any region in each step of the FSC could be reached globally, food supply losses could be halved. By doing this, there would be enough food for approximately one billion extra people. Reducing the food losses and waste would thus be an important step towards increased food security, and would also increase the efficiency of resource use in food production. PMID- 23032565 TI - Hemocyte responses of Dreissena polymorpha following a short-term in vivo exposure to titanium dioxide nanoparticles: preliminary investigations. AB - The widespread use of titanium-based nanoparticles and their environmental release may pose a significant risk to aquatic organisms within freshwater ecosystems. Suspension-feeder invertebrates like bivalve molluscs represent a unique target group for nanoparticle toxicology. The aim of this work was to investigate the short-term responses of Dreissena polymorpha hemocytes after in vivo exposure to titanium dioxide nanoparticles (TiO(2) NP). For this purpose, freshwater mussels were exposed to P25 TiO(2) NP at the concentrations of 0.1, 1, 5 and 25mg/L during 24h. Viability, phagocytosis activity and mitogen activated protein kinase (MAPK) phosphorylation level of ERK 1/2 and p38 in hemocytes extracted from exposed mussels were compared to those from control specimens. Results demonstrated an inhibition of the phagocytosis activity after exposure to TiO(2) NP at 0.1 and 1mg/L. Similar trends, albeit less pronounced, were reported for higher concentrations of NP. Transmission electron microscopy showed for the first time the internalization of TiO(2) NP into Dreissena polymorpha hemocytes. Besides, exposure to NP increased the ERK 1/2 phosphorylation levels in all treatments. Concerning the phosphorylation level of p38, only exposures to 5 and 25mg/L of NP induced significant p38 activation in comparison to that of the control. Finally, these short-term effects observed at environmentally relevant concentrations highlighted the need for further studies concerning ecotoxicological evaluation of nanoparticle release into an aquatic environment. PMID- 23032566 TI - Assessing the impact of chemical pollution on benthic invertebrates from three different European rivers using a weight-of-evidence approach. AB - The aim of this study was to combine different lines of evidence on the impact of chemical pollution on benthic invertebrate communities in three European river basins (Elbe, Scheldt, and Llobregat). The study integrates chemical analyses, a battery of different sediment toxicity tests, and field data from soft-sediment meio- and macrobenthic fauna within a sediment-quality triad in which chironomids, oligochaetes, and nematodes are identified on the species level. The use of TU (toxic units) and msPAF (multi-substance potentially affected fraction) in an approach assessing the chemical impact as well as the integration of sediment toxicity tests with bacteria (Vibrio fischeri), benthic invertebrates (Caenorhabditis elegans, Potamopyrgus antipodarum, Lumbriculus variegatus, Chironomus riparius), and fish embryos (Danio rerio), together with univariate and non-parametric multivariate statistical analyses of the biological data revealed significant differences between unpolluted and polluted sites in all three river basins. To combine the different results obtained in the sediment quality triad, a scoring system was successfully developed based on a simple algorithm. This system provides an easily understandable scheme for non-experts among decision makers and water managers. PMID- 23032567 TI - Presence, fate and effects of the intense sweetener sucralose in the aquatic environment. AB - Sucralose (1,6-dichloro-1,6-dideoxy-b-D-fructo-furanosyl 4-chloro-4-deoxy-a-D galactopyranoside), sold under the trade name Splenda, has been detected in municipal effluents and surface waters in the United States and Europe. The environmental presence of sucralose has led to interest in the possibility of toxic effects in non-target species. This review presents an environmental risk assessment of sucralose based on available data concerning its presence, fate and effects in the environment. Sucralose, which is made by selective chlorination of sucrose, is a highly stable compound, which undergoes negligible metabolism in mammals, including humans, and displays a low biodegradation potential in the environment. This intense sweetener is highly soluble in water, displays a low bioaccumulation potential and a low sorption potential to soil and organic matter, and thus is predominantly present in the water column. The predicted environmental concentration (PEC) for sucralose, based on measured data in surface waters, was determined to be 10 MUg/L. Aquatic toxicity studies using standardized, validated protocols used in regulatory decision making indicate that sucralose does not alter survival, growth and reproduction of aquatic organisms (such as plants, algae, crustaceans and fish) at concentrations >9000 times higher than those detected in the environment. Some studies, using non standardized protocols, have reported behavioral and other non-traditional responses in aquatic organisms, but the relevance of these findings for assessing adverse effects on individuals and populations will require further investigation. In terms of traditional risk assessment, the proposed predicted no effect concentration for aquatic organisms (PNEC) was determined to be 0.93 mg/L, based on the lowest no effect concentration (NOEC) from a validated chronic study with mysid shrimp and an application factor of 100. The resultant PEC/PNEC quotient was determined to be well below 1 (PEC/PNEC=0.08), thus indicating a limited risk to the environment using traditional ecological risk assessment approaches. PMID- 23032568 TI - A social survey on the noise impact in open-plan working environments in China. AB - The aim of this study is to reveal noise impact in open-plan working environments in China, through a series of questionnaire surveys and acoustic measurements in typical open-plan working environments. It has been found that compared to other physical environmental factors in open-plan working environments, people are much less satisfied with the acoustic environment. The noise impact in the surveyed working environments is rather significant, in terms of sound level inside the office, understanding of colleagues' conversation, and the use of background music such as music players. About 30-50% of the interviewees think that various noise sources inside and outside offices are 'very disturbing' and 'disturbing', and the most annoying sounds include noises from outside, ventilation systems, office equipment, and keyboard typing. Using higher panels to separate work space, or working in enclosed offices, are regarded as effective improvement measures, whereas introducing natural sounds to mask unwanted sounds seems to be not preferable. There are significant correlations between the evaluation of acoustic environment and office symptoms, including hypersensitivity to loud sounds, easily getting tired and depression. There are also significant correlations between evaluation of various acoustics-related factors and certain statements relating to job satisfaction, including sensitivity to noise, as well as whether conversations could be heard by colleagues. PMID- 23032569 TI - Spherical-shell model for the van der Waals coefficients between fullerenes and/or nearly spherical nanoclusters. AB - Fullerene molecules such as C(60) are large nearly spherical shells of carbon atoms. Pairs of such molecules have a strong long-range van der Waals attraction that can produce scattering or binding into molecular crystals. A simplified classical-electrodynamics model for a fullerene is a spherical metal shell, with uniform electron density confined between outer and inner radii (just as a simplified model for a nearly spherical metallic nanocluster is a solid metal sphere or filled shell). For the spherical-shell model, the exact dynamic multipole polarizabilities are all known analytically. From them, we can derive exact analytic expressions for the van der Waals coefficients of all orders between two spherical metal shells. The shells can be identical or different, and hollow or filled. To connect the model to a real fullerene, we input the static dipole polarizability, valence electron number and estimated shell thickness t of the real molecule. Our prediction for the leading van der Waals coefficient C(6) between two C(60) molecules ((1.30 +/- 0.22) * 10(5) hartree bohr(6)) agrees well with a prediction for the real molecule from time-dependent density functional theory. Our prediction is remarkably insensitive to t. Future work might include the prediction of higher-order (e.g. C(8) and C(10)) coefficients for C(60), applications to other fullerenes or nearly spherical metal clusters, etc. We also make general observations about the van der Waals coefficients. PMID- 23032570 TI - The 'sticky business' of cleaning gas-phase membrane proteins: a detergent oriented perspective. AB - In recent years the properties of gas-phase detergent clusters have come under close scrutiny due in part to their participation in the analysis of intact membrane protein complexes by mass spectrometry. The detergent molecules that cover the protein complex are removed in the gas-phase by thermally agitating the ions by collision-induced dissociation. This process however, is not readily controlled and can frequently result in the disruption of protein structure. Improved methods of releasing proteins from detergent clusters are clearly required. To facilitate this the structural properties of detergent clusters along with the mechanistic details of their dissociation need to be understood. Pivotal to understanding the properties of gas-phase detergent clusters is the technique of ion mobility mass spectrometry. This technique can be used to assign polydisperse detergent clusters and provide information about their geometries and packing densities. In this article we consider the shapes of detergent clusters and show that these clusters possess geometries that are inconsistent with those in solution. We analyse the distributions of clusters in detail using tandem mass spectrometry and suggest that the mean charge of clusters formed from certain detergents is governed by electrostatic repulsion. We discuss the dissociation of detergent clusters and propose that detergent evaporation it a key process in the protection of protein complexes during high energy collisions in the gas-phase. PMID- 23032571 TI - Tana1, a new putatively active Tc1-like transposable element in the genome of sturgeons. AB - We report the discovery of a new putatively active Tc1-like transposable element (Tana1) in the genome of sturgeons, an ancient group of fish considered as living fossils. The complete sequence of Tana1 was first characterized in the 454 sequenced transcriptome of the Adriatic sturgeon (Acipenser naccarii) and then isolated from the genome of the same species and from 12 additional sturgeons including three genera of the Acipenseridae (Acipenser, Huso, Scaphirhynchus). The element has a total length of 1588bp and presents inverted repeats of 210bp, one of which partially overlapping the 3' region of the transposase gene. The spacing of the DDE motif within the catalytic domain in Tana1 is unique (DD38E) and indicates that Tana1 can be considered as the first representative of a new Tc1 subfamily. The integrity of the native form (with no premature termination codons within the transposase), the presence of all expected functional domains and its occurrence in the sturgeon transcriptome suggest a current or recent activity of Tana1. The presence of Tana1 in the genome of the 13 sturgeon species in our study points to an ancient origin of the element that existed before the split of the group 170 million years ago. The dissemination of Tana1 across sturgeon genomes could be interpreted by postulating vertical transmission from an ancestral Tana1 with a particularly slow evolutionary rate Horizontal transmission might have also played a role in the dissemination of Tana1 as evidenced by the presence of a complete copy in the genome of Atlantic salmon. Vertical and horizontal transmission are not mutually exclusive and may have concurred in shaping the evolution of Tana1. PMID- 23032572 TI - Stress, adaptation, and speciation in the evolution of the blind mole rat, Spalax, in Israel. AB - Environmental stress played a major role in the evolution of the blind mole rat superspecies Spalax ehrenbergi, affecting its adaptive evolution and ecological speciation underground. Spalax is safeguarded all of its life underground from aboveground climatic fluctuations and predators. However, it encounters multiple stresses in its underground burrows including darkness, energetics, hypoxia, hypercapnia, food scarcity, and pathogenicity. Consequently, it evolved adaptive genomic, proteomic, and phenomic complexes to cope with those stresses. Here I describe some of these adaptive complexes, and their theoretical and applied perspectives. Spalax mosaic molecular and organismal evolution involves reductions or regressions coupled with expansions or progressions caused by evolutionary tinkering and natural genetic engineering. Speciation of Spalax in Israel occurred in the Pleistocene, during the last 2.00-2.35 Mya, generating four species associated intimately with four climatic regimes with increasing aridity stress southwards and eastwards representing an ecological speciational adaptive trend: (Spalax golani, 2n=54->S. galili, 2n=52->S. carmeli, 2n=58->S. judaei, 2n=60). Darwinian ecological speciation occurred gradually with relatively little genetic change by Robertsonian chromosomal and genic mutations. Spalax genome sequencing has just been completed. It involves multiple adaptive complexes to life underground and is an evolutionary model to a few hundred underground mammals. It involves great promise in the future for medicine, space flight, and deep-sea diving. PMID- 23032573 TI - Robust and powerful tests for rare variants using Fisher's method to combine evidence of association from two or more complementary tests. AB - Many association tests have been proposed for rare variants, but the choice of a powerful test is uncertain when there is limited information on the underlying genetic model. Proposed methods use either linear statistics, which are powerful when most variants are causal and have the same direction of effect, or quadratic statistics, which are more powerful in other scenarios. To achieve robustness, it is natural to combine the evidence of association from two or more complementary tests. To this end, we consider the minimum-p and Fisher's methods of combining P values from linear and quadratic statistics. Extensive simulation studies show that both methods are robust across models with varying proportions of causal, deleterious, and protective rare variants, allele frequencies, and effect sizes. When the majority (>75%) of the causal effects are in the same direction (deleterious or protective), Fisher's method consistently outperforms the minimum p and the individual linear and quadratic tests, as well as the optimal sequence kernel association test, SKAT-O. When the individual test has moderate power, Fisher's test has improved power for 90% of the ~5000 models considered, with >20% relative efficiency gain for 40% of the models. The maximum absolute power loss is 8% for the remaining 10% of the models. An application to the GAW17 quantitative trait Q2 data based on sequence data of the 1000 Genomes Project shows that, compared with linear and quadratic tests, Fisher's test has comparable power for all 13 functional genes and provides the best power for more than half of them. PMID- 23032575 TI - Evaluation of pesticide-induced oxidative stress from a gene-environment interaction perspective. AB - Previously we reported that intensive agriculture workers exposed to pesticides had decreased levels of the intraerythrocyte enzymes delta-9-aminolevulinic acid dehydratase (ALA-D) and superoxide dismutase (SOD), very likely as a result of pesticide-induced oxidative stress. We have now examined in this population potential gene-environment interactions by modeling generalized estimating equations (GEE) adjusted for age, sex, body mass index and tobacco and alcohol consumption. Particularly, we assessed the interaction effects between plasma and erythrocyte cholinesterases (BChE and AChE, used as proxies for short- and long term pesticide exposure, respectively) and a number of genetic polymorphisms of pesticide metabolizing enzymes such as paraoxonase-1 (PON1), glutathione-S transferases (GST) and plasma cholinesterase variants (BCHE) on levels of erythrocyte antioxidant enzymes (SOD, catalase, glutathione peroxidase, glucose-6 phosphate dehydrogenase and ALA-D). We observed significant interaction effects between BChE activity and PON1192R allele on catalase, glutathione peroxidase and glucose-6-phosphate dehydrogenase activities. BChE also interacted significantly with GSM1 null genotype on ALA-D and SOD. Regarding long-term pesticide exposure, a significant interaction was found between AChE and genotypes PON1192QR and PON1108CC on GR; between AChE and PON1192RR on SOD, and between AChE and GSTM1, GSTT1 and unusual BCHE variants on catalase activity. These findings suggest relevant gene-pesticide interactions and highlight the potential role of genetic risk factors in the pathomechanism of oxidative stress-induced degenerative diseases following pesticide exposure. PMID- 23032576 TI - Cytochrome P1B1 (CYP1B1) polymorphisms and ovarian cancer risk: a meta-analysis. AB - CYP1B1 is a key P450 enzyme involved in the metabolism of exogenous and endogenous substrates and plays a key role in hormone-induced carcinogenesis. Risk factors for ovarian cancer are related to hormonal exposure and reproduction, and polymorphisms within genes involved in metabolism of oestrogen and certain xenobiotics may influence the risk of developing ovarian cancer. Current meta-analysis evaluated four CYP1B1 polymorphisms (Leu432Val, Arg48Gly, Ala119Ser and Asn453Ser) for their association with ovarian cancer risk. A search of the MEDLINE bibliographic database for the period up to April 2012 identified five relevant studies. With regards to Leu432Val polymorphism, all of the five studies were eligible (1199 cases and 2596 controls) for analysis, while for Arg48Gly (799 cases and 1169 controls), Ala119Ser (799 cases and 1172 controls) and Asn453Ser (361cases and 1577 controls) only two studies were eligible for analysis. Fixed-effect models were used to estimate pooled odds ratios (OR) with 95% confidence intervals (95% CI) and chi-square based Q-test was used to test for heterogeneity. The pooled OR (95% CI) for CYP1B1_Leu432Val polymorphism were 1.1 (0.84-1.31) for heterozygous subjects and 0.82 (0.57-1.17) for homozygous Val subjects. In a recessive model, homozygous carriers of Leu432Val showed a weak trend towards reduced risk as compared to 'wild type' and heterozygous carriers (OR 0.8, 95% CI; 0.66-0.99); however, this association was of limited significance. Regarding Arg48Gly, the pooled OR (95% CI) were 1.06 (0.89-1.27) for heterozygous and 0.98 (1.72-1.33) for homozygous Gly subjects. With respect to Ala119Ser and Asn453Ser, the pooled OR were 1.06 (0.87-1.29) and 1.24 (0.94 1.63) for heterozygous and 1.1 (0.8-1.52) and 1.09 (0.5-2.34) for homozygous respectively. In conclusion, this meta-analysis suggests that CYP1B1 polymorphisms are not associated with ovarian cancer risk. Studies evaluating CYP1B1_Leu432Val polymorphism are required to further elucidate the risk of ovarian cancer with this polymorphism. Additionally, studies amongst Asian and African subjects are required to estimate race-specific effects. PMID- 23032577 TI - A highly sensitive fluorescent probe based on simple pyrazoline for Zn2+ in living neuron cells. AB - We develop a pyrazoline-based fluorescent sensor for biological Zn(2+) detection. The sensor shows good binding selectivity for Zn(2+) over competing metal with 40 fold fluorescence enhancement in response to Zn(2+). The new probe is cell permeable and can be used to detect intracellular zinc ions in living neuron cells. PMID- 23032578 TI - Using biomarkers to "guide" heart failure management: current perspectives and future directions. AB - Over the last several years, cardiac biomarkers have proven to be increasingly useful for disease screening, diagnosis, and prognostication. The most widely used biomarkers in heart failure (HF) are natriuretic peptides (NPs), which can aid in diagnosing HF, while also identifying those who are at higher risk of adverse outcomes. Multiple clinical trials have investigated the role of NPs as therapeutic targets for HF management, but results have been conflicting. Collectively, however, the data suggest that NP levels may be useful in guiding HF management and improving HF-related morbidity and mortality. In this review, we summarize existing data investigating the use of NPs as targets for outpatient HF therapy, focusing on differences in study designs and lessons learned from the results. Although the results for this approach are promising overall, we propose that additional well-designed prospective randomized controlled trials specifically incorporating the relevant lessons learned from previous studies-are necessary to pivotally establish the role of NP-guided outpatient HF management. PMID- 23032579 TI - SPRECware: software tools for Standard PREanalytical Code (SPREC) labeling - effective exchange and search of stored biospecimens. AB - Biobanks provide stored material to basic, translational, and epidemiological research and this material should be transferred without institute-dependent intrinsic bias. The ISBER Biospecimen Science Working Group has released a "Standard PREanalytical Code" (SPREC), which is a proposal for a standard coding of the preanalytical options that have been adopted in order to track and make explicit the preanalytical variations in the collection, preparation, and storage of specimens. In this paper we address 2 issues arising in any biobank or biolaboratory aiming at adopting SPREC: (i) reducing the burden required to adopt this standard coding, and (ii) maximize the immediate benefits of this adoption by providing a free, dedicated software tool. We propose SPRECware, a vision encompassing tools and solutions for the best exploitation of SPREC based on information technology (www.sprecware.org). As a first step, we make available SPRECbase, a software tool useful for generating, storing, managing, and exchanging SPREC-related information associated to specimens. Adopting SPREC is useful both for internal purposes (such as finding the samples having some given preanalytical features), and for exchanging the preanalytical information associated to biological samples between Laboratory Information Systems. In case of a common adoption of this coding, it would be easy to find out whether and where, among the participating Biological Resource Centers, the specimens for a given study are available in order to carry out a planned experiment. PMID- 23032580 TI - Reduction of metal ions by boranephosphonate DNA. AB - Oligodeoxyribonucleotides bearing boranephosphonate linkages (bpDNA) were shown to reduce a number of metal ions and form nanoparticles through a novel reaction pathway that leads to phosphate diesters or phosphate triesters in water or alcohols respectively. The synthetic utility of this reaction was further demonstrated through the synthesis of oligodeoxyribonucleotides containing phosphate triester linkages. This new reactivity also makes bpDNA promising for use in construction of DNA templated metallic nanostructures. PMID- 23032581 TI - Navigators for motion detection during real-time MRI-guided radiotherapy. AB - An MRI-linac system provides direct MRI feedback and with that the possibility of adapting radiation treatments to the actual tumour position. This paper addresses the use of fast 1D MRI, pencil-beam navigators, for this feedback. The accuracy of using navigators was determined on a moving phantom. The possibility of organ tracking and breath-hold monitoring based on navigator guidance was shown for the kidney. Navigators are accurate within 0.5 mm and the analysis has a minimal time lag smaller than 30 ms as shown for the phantom measurements. The correlation of 2D kidney images and navigators shows the possibility of complete organ tracking. Furthermore the breath-hold monitoring of the kidney is accurate within 1.5 mm, allowing gated radiotherapy based on navigator feedback. Navigators are a fast and precise method for monitoring and real-time tracking of anatomical landmarks. As such, they provide direct MRI feedback on anatomical changes for more precise radiation delivery. PMID- 23032582 TI - Lead isotopes in marine surface sediments reveal historical use of leaded fuel. AB - Analyses of lead (Pb) isotopes have been performed in terrestrial and fresh water environments to estimate historical uses of leaded fuel, but so far this method has not been employed in studies of world-wide marine surface sediments. We analyzed Pb and its isotopes in 23 surface sediments from four continents collected during the Galathea 3 expedition in 2006-2007. To enhance the anthropogenic signal, a partial digestion using nitric acid was performed. The concentrations of Pb, Th, U and Al were determined with an ICP-Quadrupole MS, and Pb-isotope ratios with an ICP-multi-collector MS. The samples could be divided into three groups: Harbor areas in larger cities with concentrations of 150 to 265 mg kg(-1) dry weight, smaller towns with concentrations between 20 and 40 mg kg(-1) dry weight, and remotely located sites with concentrations below 15 mg kg( 1) dry weight. Pb-isotope ratios were compared to literature values for gasoline and local or geological background values, and the contribution of leaded gasoline to total concentrations was calculated for contaminated sites using both a one-dimensional and a novel two-dimensional (vector) method. The North American sites had Pb-isotope ratios corresponding to the US leaded gasoline, with 24-88% of the Pb from leaded gasoline. Samples from Oceania showed Pb-isotope ratios corresponding to Australian gasoline, with 60% attributed to leaded gasoline in Sydney and 21% in Christchurch. Outside Cape Town, 15 to 46% of Pb in sediments was from leaded gasoline. PMID- 23032583 TI - Induction of the columnar phase of unconventional dendrimers by breaking the C2 symmetry of molecules. AB - Two triazine-based unconventional dendrimers were prepared and characterized by (1)H and (13)C NMR spectroscopy, mass spectrometry, and elemental analysis. Differential scanning calorimetry, polarizing microscopy, and powder XRD studies showed that these dendrimers display columnar liquid-crystalline phases during thermal treatment. This is ascribable to breaking of their C(2) symmetry. The molecular conformations of prepared dendrimers were obtained by computer simulation with the MM3 model of the CaChe program in the gas phase. The simulation showed that the conformations of the prepared dendrimers are rather flat and disfavor formation of the LC phase. However, due to C(2)-symmetry breaking, the prepared dendrimers have structural isomers in the solid state and thus show the desired columnar phases. This new strategy should be applicable to other types of unconventional dendrimers with rigid frameworks. PMID- 23032584 TI - Rehabilitation after anterior cruciate ligament reconstruction: a systematic review. AB - BACKGROUND: Rigorous rehabilitation after anterior cruciate ligament (ACL) reconstruction is necessary for a successful surgical outcome. A large number of clinical trials continue to assess aspects of this rehabilitation process. Prior systematic reviews evaluated fifty-four Level-I and II clinical trials published through 2005. METHODS: Eighty-five articles from 2006 to 2010 were identified utilizing multiple search engines. Twenty-nine Level-I or II studies met inclusion criteria and were evaluated with use of the CONSORT (Consolidated Standards of Reporting Trials) criteria. Topics included in this review are postoperative bracing, accelerated strengthening, home-based rehabilitation, proprioception and neuromuscular training, and six miscellaneous topics investigated in single trials. RESULTS: Bracing following ACL reconstruction remains neither necessary nor beneficial and adds to the cost of the procedure. Early return to sports needs further research. Home-based rehabilitation can be successful. Although neuromuscular interventions are not likely to be harmful to patients, they are also not likely to yield large improvements in outcomes or help patients return to sports faster. Thus, they should not be performed to the exclusion of strengthening and range-of-motion exercises. Vibration training may lead to faster and more complete proprioceptive recovery but further evidence is needed. CONCLUSIONS: Several new modalities for rehabilitation after ACL reconstruction may be helpful but should not be performed to the exclusion of range-of-motion, strengthening, and functional exercises. Accelerated rehabilitation does not appear to be harmful but further investigation of rehabilitation timing is warranted. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 23032585 TI - Does subacromial injection of a local anesthetic influence strength in healthy shoulders?: a double-blinded, placebo-controlled study. AB - BACKGROUND: Subacromial injection of a local anesthetic is used to eliminate pain as a confounding factor in clinical assessment of abduction strength in shoulders with a suspected rotator cuff tear. If strength remains diminished despite pain relief, a rotator cuff tear is likely. The effect of injecting local anesthetic into the subacromial space on the strength of a normal shoulder is unknown, although it could affect strength by impairing suprascapular or axillary nerve function. We hypothesized that subacromial injection of a local anesthetic could decrease shoulder abduction and/or external rotation strength, resulting in physical examination findings that could mislead the clinician. METHODS: A double blinded, randomized, placebo-controlled design was used to evaluate the effect of subacromial injection of lidocaine on shoulder strength in ten healthy male volunteers. The contralateral shoulder served as the placebo control for each treated shoulder. Abduction and external rotation strength measurements and electromyographic assessment were performed before and after the subacromial injection. Ultrasonography was used to verify the integrity of the rotator cuff and to document the distribution pattern of the injected local anesthetic. RESULTS: The injection was subacromial in eighteen (90%) of twenty shoulders. There was no significant difference in pain or electromyographic parameters between shoulders injected with lidocaine and those injected with 0.9% saline solution (p > 0.05). In the Whipple position, placebo injection into the subacromial space decreased strength significantly compared with the pre injection state (95 +/- 17 to 84 +/- 20 N, p = 0.012), whereas a similar decrease observed in the lidocaine group did not reach significance (97 +/- 15 to 87 +/- 14 N, p = 0.092). In 90 degrees of abduction in the scapular plane (supraspinatus test position), there was no significant decrease in strength in either group. CONCLUSIONS: Subacromial injection reached the subacromial bursa in most cases (90%) without radiographic guidance. The injection of a local anesthetic into the subacromial bursa had no relevant effect on shoulder strength and did not falsify the clinical assessment of strength. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 23032586 TI - Comparison of ten-year survivorship of hip prostheses with use of conventional polyethylene, metal-on-metal, or ceramic-on-ceramic bearings. AB - BACKGROUND: To improve the long-term performance of hip prostheses, alternative bearings with metal-on-metal (MoM) and ceramic-on-ceramic (CoC) couples have been introduced. Although currently the results from the use of these bearings are in the midterm stage, there have been few comparative studies of these different bearings. METHODS: From 2000 to 2002, 487 total hip replacements were performed with use of a BICON-PLUS acetabular cup and an SL-PLUS femoral stem (Plus Orthopedics, Rotkreuz, Switzerland, now Smith & Nephew Orthopaedics). The patients were divided into three groups according to the type of bearing that was used: an MoM group (sixty-nine prostheses), a metal-on-polyethylene (MoP) group (200 prostheses), and a CoC group (218 prostheses). Patient demographic data and data with regard to revision operations were evaluated from the hospital computer database. The mean follow-up period was 8.5 years (range, 6.9 to 10.5 years). Patient activity was assessed with use of the University of California at Los Angeles activity scale. RESULTS: The mean patient age was sixty years at the time of the index arthroplasty in the MoM and CoC groups, and seventy-one years in the MoP group. Based on a scale of ten, the mean postoperative activity level was six in the CoC group, five in the MoM group, and four in the MoP group. Survival at ten years with regard to revision for any reason was 0.984, 0.956, and 0.879 for the MoP, CoC, and MoM groups, respectively. When revision for any reason was considered as the end point, survival of the MoM bearings was significantly worse than that of the MoP bearings (p = 0.005). Survival at ten years with regard to revision for aseptic loosening was 0.995, 0.990, and 0.894 for the MoP, CoC, and MoM groups, respectively. When revision for aseptic loosening was considered as the end point, survival of the MoM group was significantly worse than that of either the MoP group (p = 0.001) or the CoC group (p = 0.003). CONCLUSIONS: When comparing two groups of patients of similar mean age and mean activity level undergoing total hip arthroplasty with the use of alternative bearings, CoC bearings had better survival than did MoM bearings at the ten-year follow-up; the difference was significant when revision for aseptic loosening was defined as a failure. However, neither the CoC nor the MoM alternative bearings provided improved midterm results when compared with the results of the conventional MoP bearings. For older, less active patients, traditional metal-on-polyethylene bearings are the appropriate choice. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 23032587 TI - rhBMP-2/calcium phosphate matrix induces bone formation while limiting transient bone resorption in a nonhuman primate core defect model. AB - BACKGROUND: Transient bone resorption limits the use of recombinant human bone morphogenetic protein-2 (rhBMP-2)/absorbable collagen sponge in metaphyseal bone. The purpose of the present study was to evaluate the efficacy of rhBMP-2/calcium phosphate matrix (CPM) to induce bone formation while limiting transient bone resorption in nonhuman primate core defects. METHODS: Metaphyseal core defects were created in eighteen cynomolgus monkeys. rhBMP-2 retention was evaluated in the distal part of the radius. Bone formation was evaluated at eight weeks following treatment with 1.5 or 4.5-mg/mL rhBMP-2/CPM, CPM alone, or no treatment in the distal part of the radius, the proximal part of the tibia, and the proximal part of the femur; at twenty-four weeks following treatment with 1.5 mg/mL rhBMP-2/CPM or CPM alone in the proximal part of the tibia; and at one, two, and four weeks following treatment with 1.5-mg/mL rhBMP-2/CPM or no treatment in the distal part of the radius. Bone resorption was evaluated at four weeks following treatment with 1.5, 2.0, 3.0, and 4.5-mg/mL rhBMP-2/CPM or CPM alone in the distal part of the femur. Evaluations were performed with use of scintigraphy, radiographs, histological analysis, and computed tomography. RESULTS: Seventy-eight percent, 64%, 50%, 35%, and 12% of the rhBMP-2 was retained in the distal part of the radius at one, seven, fourteen, twenty-one, and forty-nine days after surgery. rhBMP-2/CPM increased bone formation within core defects and surrounding trabeculae compared with CPM alone or no treatment at all anatomic locations at eight weeks, and bone formation was ongoing in the rhBMP-2/CPM-treated proximal tibial sites at twenty-four weeks. Bone formation began in the trabeculae surrounding the core defects at one week and was observed adjacent to the resorbing CPM within the core defects and in the surrounding trabecular bone at two and four weeks in the rhBMP-2/CPM-treated distal radial sites. Bone formation was confined to the region immediately surrounding the core defects in the untreated distal radial sites at all time points. Transient bone resorption was only observed in the distal femoral sites treated with 4.5 mg/mL of rhBMP-2/CPM at two weeks. CONCLUSIONS: Treatment of nonhuman primate metaphyseal core defects with 1.5 to 3.0-mg/mL rhBMP-2/CPM resulted in bone formation without transient bone resorption. CLINICAL RELEVANCE: rhBMP-2/CPM may be useful to accelerate healing of metaphyseal bone defects in humans. PMID- 23032588 TI - Periprosthetic fractures associated with primary total shoulder arthroplasty and primary humeral head replacement: a thirty-three-year study. AB - BACKGROUND: The objective of this study was to assess the frequency of, and risk factors for, periprosthetic fractures during and after shoulder arthroplasty. METHODS: All adults treated with a primary total shoulder arthroplasty or humeral head replacement at the Mayo Clinic Medical Center from 1976 to 2008 were identified. Periprosthetic fractures were validated by medical record review. Univariate and multivariable-adjusted logistic regression analyses were used to assess the association of demographic factors (age, sex, and body mass index [BMI]), underlying diagnosis, implant fixation (cemented or uncemented), American Society of Anesthesiologists (ASA) class, and comorbidity as assessed with the Deyo-Charlson index. RESULTS: The cohort consisted of 2207 patients treated with a total of 2588 primary total shoulder arthroplasties and 1349 patients treated with 1431 humeral head replacements. Seventy-two medical-record-confirmed periprosthetic fractures occurred in association with the total shoulder arthroplasties. These consisted of forty-seven intraoperative fractures (forty humeral fractures, five glenoid fractures, and two fractures for which the site was unclear) and twenty-five postoperative fractures (twenty humeral fractures, three glenoid fractures, and two fractures for which the site was unclear). There were thirty-three fractures associated with the humeral head replacements. Fifteen were intraoperative (eight humeral fractures and seven glenoid fractures), and eighteen were postoperative (sixteen humeral fractures and two glenoid fractures). In the multivariable regression analysis of the total shoulder arthroplasties, female sex (odds ratio [OR], 4.19; 95% confidence interval [CI], 1.82 to 9.62; p < 0.001; a 2.4% rate for women versus 0.6% for men) and the underlying diagnosis (p = 0.04; posttraumatic arthritis: OR, 2.55; 95% CI, 0.92 to 7.12) were associated with a significantly higher risk of intraoperative humeral fracture in general, and female sex was associated with the risk of intraoperative humeral shaft fracture (OR, infinity; p < 0.001). In combined analyses of all patients (treated with either total shoulder arthroplasty or humeral head replacement), a higher Deyo-Charlson index was significantly associated with an increased risk of postoperative periprosthetic humeral shaft fracture (OR, 1.27; 95% CI, 1.11 to 1.45); p < 0.001), after adjusting for the type of surgery (total shoulder arthroplasty or humeral head replacement). CONCLUSIONS: The overall risk of periprosthetic fractures after total shoulder arthroplasty or humeral head replacement was low. Women had a significantly higher risk of intraoperative humeral shaft fracture. The underlying diagnosis (especially posttraumatic arthritis) was significantly associated with the risk of intraoperative humeral fracture, and comorbidity was significantly associated with the risk of postoperative humeral shaft fracture. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 23032590 TI - Landmarks for rotational alignment of the humeral component during elbow arthroplasty. AB - BACKGROUND: The reference points for rotational orientation of the humeral component during elbow arthroplasty typically are on the articular surface or the humeral epicondyles. With bone loss, these landmarks may be compromised. Our purpose was to assess whether the flat posterior humeral cortex proximal to the olecranon fossa is a reliable landmark with which to orient the humeral component during elbow arthroplasty. METHODS: Fifty cadaveric elbows (mean age [and standard deviation] at the time of death, 73 +/- 12 years) underwent computed tomography (CT) scans. The flexion-extension axis (FEA) was determined by sphere fitting the capitellar surface and circle-fitting the narrowest portion of the trochlea. The posterior humeral cortical line (PCL) was drawn on the flat posterior humeral cortex proximal to the olecranon fossa. The transepicondylar axis (TEA) was determined by a line between the most prominent points on the epicondyles. The angles between the PCL and FEA and the TEA and FEA were calculated and were compared by using two-tailed t tests. RESULTS: The PCL was externally rotated by a mean (and standard deviation) of 14.0 degrees +/- 4.2 degrees (p < 0.001) relative to the FEA (males: 12.6 degrees +/- 3.6 degrees , females: 16.4 degrees +/- 5.2 degrees ; p = 0.002). The TEA was externally rotated by a mean of 2.8 degrees +/- 3.5 degrees (p < 0.001) relative to the FEA (males: 2.7 degrees +/- 3.4 degrees , females: 2.6 degrees +/- 3.7 degrees ; p = 0.96). The intraobserver and interobserver reliability was >0.98 for the capitellar and trochlear centers, while the cumulative intraobserver and interobserver reliability was 0.8 and 0.5 for the FEA-PCL angle and 0.4 and 0.3 for the FEA-TEA angle. CONCLUSIONS: The posterior humeral cortex is a reproducible landmark that is externally rotated with respect to the flexion extension axis of the distal part of the humerus. The surgeon must be aware of the need for an internal rotation correction factor and consider the influence of the patient's sex on this correction when using the posterior humeral cortex as a landmark to avoid humeral component malrotation. CLINICAL RELEVANCE: While the PCL is better than the TEA as a reference point, neither is able to accurately identify the FEA because of considerable normal variation. Future studies are needed to evaluate the effectiveness of computer-assisted techniques or a preoperative CT scan of the contralateral, unaffected elbow in identifying rotational landmarks for the elbow undergoing arthroplasty. PMID- 23032592 TI - Total hip arthroplasty for adult hip dysplasia. AB - Preoperative planning is essential to define anatomy, clarify the operative approach and exposure, and ensure that suitable implants are available.Concerns exist regarding the long-term effectiveness and safety of hip resurfacing arthroplasty for the young dysplastic hip.In light of current evidence, concerns exist regarding the use of metal-on-metal articulations for hip arthroplasty in the young dysplastic hip.The ideal bearing surface is not known, although the longest data available support the use of metal-on-polyethylene. PMID- 23032591 TI - Outcome after sequential hip fracture in the elderly. AB - BACKGROUND: Hip fracture is a common cause of morbidity and mortality in the elderly. As the risk factors for hip fracture often persist after the original injury, patients remain at risk for sequential fractures. Our aim was to report the incidence, epidemiology, and outcome of sequential hip fracture in the elderly. METHODS: Data were collected during the acute hospital stay and at 120 days after admission from twenty-two acute orthopaedic units across Scotland between January 1998 and December 2005. These data were analyzed according to two separate time periods: by six-month intervals up to eight years after the primary fracture and by twenty-day intervals for the first two years after the primary fracture. RESULTS: The risk of sequential fracture was highest in the first twelve months, affecting 3% of surviving patients and decreasing to 2% per survival year thereafter. Survival to twelve months after sequential fracture was 63% compared with 68% for those with a single fracture (p = 0.03). Sequential hip fracture was also associated with greater loss of independent mobility and changes in residential status compared with single fractures. CONCLUSIONS: Sequential hip fracture is a relatively rare injury. Individuals who sustain this injury combination have poorer outcomes both in terms of survival and functional status. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 23032593 TI - Long-term results after distal rectus femoris transfer as a part of multilevel surgery for the correction of stiff-knee gait in spastic diplegic cerebral palsy. AB - BACKGROUND: The evidence for distal rectus femoris transfer as a part of multilevel surgery for the correction of stiff-knee gait in children with spastic diplegic cerebral palsy is limited because of inconsistent outcomes reported in various studies and the lack of long-term evaluations. METHODS: This study investigated the long-term results (mean, nine years) for fifty-three ambulatory patients with spastic diplegic cerebral palsy and stiff-knee gait treated with standardized distal rectus femoris transfer as a part of multilevel surgery. Standardized three-dimensional gait analysis and clinical examination were carried out before surgery and at one year and nine years after surgery. Patients with decreased peak knee flexion in swing phase who had distal rectus femoris transfer to correct the decreased peak knee flexion in swing phase (C-DRFT) were evaluated separately from those with normal or increased peak knee flexion in swing phase who had distal rectus femoris transfer done as a prophylactic procedure (P-DRFT). RESULTS: A significantly increased peak knee flexion in swing phase was found in the C-DRFT group one year after surgery, while a significant loss (15 degrees ) in peak knee flexion in swing phase was noted in the P-DRFT group. A slight but not significant increase in peak knee flexion in swing phase in both groups was noted at the time of the long-term follow-up. A significant improvement in timing of peak knee flexion in swing phase was only found for the C-DRFT group, and was maintained after nine years. Knee motion and knee flexion velocity were significantly increased in both groups and were maintained at long term follow-up in the C-DRFT group, while the P-DRFT showed a deterioration of knee motion. CONCLUSIONS: Distal rectus femoris transfer is an effective procedure to treat stiff-knee gait featuring decreased peak knee flexion in swing phase and leads to a long-lasting increase of peak knee flexion in swing phase nine years after surgery. Patients with more involvement showed a greater potential to benefit from distal rectus femoris transfer. However, 18% of the patients showed a permanently poor response and 15% developed recurrence. In patients with severe knee flexion who underwent a prophylactic distal rectus femoris transfer, a significant loss in peak knee flexion in swing phase was noted and thus a prophylactic distal rectus femoris transfer may not be indicated in these patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 23032594 TI - Optimization of leukocyte concentration in platelet-rich plasma for the treatment of tendinopathy. AB - BACKGROUND: Numerous methods are available for platelet-rich plasma (PRP) generation, but evidence defining the optimum composition is lacking. We hypothesized that leukocyte-reduced PRP would result in lower inflammatory cytokine expression compared with concentrated-leukocyte PRP and that maintaining the platelet:white blood cell (WBC) ratio would compensate for the effect of increased WBC concentration. METHODS: Blood and flexor digitorum superficialis tendons were collected from young adult horses. Three PRP groups were generated with the same platelet concentration but different WBC concentrations: intermediate-concentration standard PRP, leukocyte-reduced PRP, and concentrated leukocyte PRP. An additional high-concentration PRP group was generated with the same WBC concentration as the concentrated-leukocyte PRP group and the same platelet:WBC ratio as the standard PRP group. The PRP groups were used as media for flexor digitorum superficialis tendon explants in culture for seventy-two hours with 10% plasma in Dulbecco modified Eagle medium (DMEM) serving as control. Tendon gene expression for collagen types I (COL1A1) and III (COL3A1), cartilage oligomeric matrix protein (COMP), matrix metalloproteinase (MMP-13), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) was performed. RESULTS: The desired PRP groups were successfully generated. The expression of COMP, the COL1A1:COL3A1 ratio, and the expression of MMP-13 in flexor digitorum superficialis tendon explants was not different between PRP groups. The expression of COMP (p = 0.0027) and the COL1A1:COL3A1 ratio (p < 0.0001) were increased in the PRP groups as compared with the control group, and the expression of MMP-13 was decreased in the PRP groups as compared with the control group (p < 0.0001). The expression of IL-1beta was lowest in leukocyte reduced PRP and highest in concentrated-leukocyte PRP (p = 0.0001). The leukocyte reduced PRP group and the control group had the lowest TNF-alpha expression, whereas the high-concentration PRP and concentrated-leukocyte PRP groups had the highest expression (p = 0.0224). CONCLUSIONS: A high absolute WBC concentration in PRP contributes to the expression of inflammatory cytokines in flexor digitorum superficialis tendon explants, and maintenance of the platelet:WBC ratio is not able to counteract this effect. CLINICAL RELEVANCE: The optimum composition of PRP for the treatment of tendinopathy has not been directly investigated. Persistent inflammation results in inferior repair with scar tissue. The present study indicates that in an animal model, WBC in PRP contributes to inflammatory cytokine production. Therefore, leukocyte-reduced PRP may be the optimum preparation to stimulate superior healing without scar tissue formation. PMID- 23032595 TI - Treatment algorithm for dens fractures: non-halo immobilization, anterior screw fixation, or posterior transarticular C1-C2 fixation. AB - BACKGROUND: The appropriate treatment of dens fractures is unclear. We established a staged treatment protocol for dens fractures and conducted a prospective study to evaluate the outcome of treatment based on this protocol. METHODS: We prospectively evaluated sixty-nine consecutive patients who presented to our institution with a dens fracture. The mean duration of follow-up was 9.7 months (range, six to fifty-eight months). Fractures were categorized as stable or unstable. Stable fractures were treated by immobilization in a rigid collar. Patients seventy-five years or older with unstable fractures, patients with a neurological deficit, and patients with Anderson and D'Alonzo type-III fractures underwent posterior transarticular C1-C2 stabilization. Unstable fractures in patients younger than seventy-five years were stabilized with direct anterior screw fixation. Thirty-one patients were treated with a Philadelphia collar, twenty-five with posterior transarticular fixation, and thirteen with direct anterior screw fixation. RESULTS: Fracture-healing or solid fusion of C1-C2 was documented in sixty-eight of sixty-nine treated patients at final follow-up. The remaining patient had a stable nonunion of the dens. Secondary procedures were performed in five patients. CONCLUSIONS: Our treatment algorithm based on dens fracture type, fracture stability, and patient age was associated with a high success rate. Evaluating fracture stability is crucial when considering nonoperative treatment. External stabilization with a rigid cervical collar was adequate for stable fractures of the dens and was associated with a high healing rate. Posterior transarticular screw fixation of C1-C2 was associated with a high success rate, including in elderly patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 23032596 TI - Quality of life during orthopaedic training and academic practice: part 2: spouses and significant others. AB - BACKGROUND: Orthopaedic residents and attending physicians who report having a supportive spouse show lower levels of burnout and psychological distress than those without supportive spouses. However, little is known about the experiences of the spouses. This nationwide study examines burnout, psychological distress, and marital satisfaction of the spouses and significant others (collectively referred to hereafter as spouses) of orthopaedists in training and in orthopaedic practice in an academic setting. METHODS: Employing previously reported methodology, 259 spouses of orthopaedic residents and 169 spouses of full-time orthopaedic faculty completed a voluntary, anonymous survey. The survey included three validated instruments (the Maslach Burnout Inventory, the General Psychological Health Questionnaire-12, and the Revised Dyadic Adjustment Scale) and three novel question sets addressing demographic information, relationship issues, stress, and work/life balance. RESULTS: Psychological distress was noted in 18% of resident spouses compared with only 10% of faculty spouses (p = 0.014). Resident spouses reported greater loneliness (p < 0.0009) and stress (p = 0.03) than faculty spouses. Among working spouses, 30% of resident spouses and 13% of faculty spouses showed high levels of emotional exhaustion (p < 0.003). Twenty eight percent of employed resident spouses and 5% of employed faculty spouses showed problematic levels of depersonalization (p < 0.0001). Twenty-six percent of employed resident spouses and 12% of employed faculty spouses showed a diminished sense of personal accomplishment (p = 0.012). Marital satisfaction was high for both resident and faculty spouses. Decreased satisfaction correlated with excessive mate irritability and fatigue that precluded their mate's involvement in family activities. A gratifying sex life, full-time work outside the home, and spending more than ninety minutes a day with their mate correlated significantly with marital satisfaction. CONCLUSIONS: Many orthopaedic resident spouses showed elevated levels of burnout, and a substantial number showed psychological distress. Spouses of orthopaedic faculty surgeons showed low rates of burnout and psychological distress. While both resident and faculty spouses reported high levels of marital satisfaction, the engagement of their surgeon mates had a considerable impact on the well-being of the relationship. PMID- 23032597 TI - Medical student musculoskeletal education: an institutional survey. AB - BACKGROUND: Since the 1910 Flexner Report, medical education continues to undergo curriculum and graduation guideline reform to meet the needs of physicians and patients. Our aims were to (1) assess the quality of musculoskeletal education at our institution's School of Medicine by reporting the results of the Freedman and Bernstein examination among our medical students across all four years of training, and (2) stratify results according to medical school year, educational module, and intended career. METHODS: We surveyed the 460 2009-2010 School of Medicine students via e-mail. The survey contained a validated orthopaedic examination of musculoskeletal competency (passing grade, 70%), demographic questions (e.g., year in training, clinical area of interest, and time dedicated to musculoskeletal topics in medical school education), and a 10-point tool for determining confidence in assessing musculoskeletal disorders. There were 354 responses (77.0%); six were excluded for incompleteness, leaving 348 for analysis. Linear regression analysis was used to determine the association between test scores and days spent studying musculoskeletal material. The unpaired Student t test was used to compare performance among areas of interest and training years, with p < 0.05 being considered significant. RESULTS: The mean score was 51.1%; only sixty-seven (19.3%) of the students passed. Fourth-year students scored significantly higher (59.0%) compared with first-year students (37.3%), but >65% of students in both groups failed. Only 34.2% of the graduating students had completed a musculoskeletal elective. Students who participated in elective musculoskeletal education had a higher pass rate (67.5%) than those who did not (43.9%, p < 0.001). A minimum of fifteen days dedicated to elective study of musculoskeletal medicine significantly increased the chance of passing this examination. First-year through fourth-year students ranked their level of confidence in dealing with musculoskeletal issues as 3.18, 3.82, 3.57, and 4.77, respectively. CONCLUSIONS: To our knowledge, this is the first study to test this examination with medical school class years and have quantifiable results that advocate for incorporation of a dedicated musculoskeletal block in medical student education. PMID- 23032598 TI - What do we really know about rehabilitation after ACL reconstruction?: commentary on an article by L.M. Kruse, MD, et al.: "rehabilitation after anterior cruciate ligament reconstruction. a systematic review". PMID- 23032589 TI - Prognostic factors for predicting outcomes after intramedullary nailing of the tibia. AB - BACKGROUND: Prediction of negative postoperative outcomes after long-bone fracture treatment may help to optimize patient care. We recently completed the Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT), a large, multicenter trial of reamed and unreamed intramedullary nailing of tibial shaft fractures in 1226 patients. Using the SPRINT data, we conducted an investigation of baseline and surgical factors to determine any associations with an increased risk of adverse events within one year of intramedullary nailing. METHODS: Using multivariable logistic regression analysis, we investigated fifteen baseline and surgical factors for any associations with an increased risk of negative outcomes. RESULTS: There was an increased risk of negative events in patients with a high-energy mechanism of injury (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.05 to 2.35), a stainless steel compared with a titanium nail (OR = 1.52; 95% CI, 1.10 to 2.13), a fracture gap (OR = 2.40; 95% CI, 1.47 to 3.94), and full weight-bearing status after surgery (OR = 1.63; 95% CI, 1.00 to 2.64). There was no increased risk with the use of nonsteroidal anti-inflammatory agents, late or early time to surgery, or smoking status. Open fractures had a higher risk of events among patients treated with reamed nailing (OR = 3.26; 95% CI, 2.01 to 5.28) but not in patients treated with unreamed nailing (OR = 1.50; 95% CI, 0.92 to 2.47). Patients with open fractures who had wound management either without any additional procedures or with delayed primary closure had a decreased risk of events compared with patients who required subsequent, more complex reconstruction (OR = 0.18 [95% CI, 0.09 to 0.35] and 0.29 [95% CI, 0.14 to 0.62], respectively). CONCLUSIONS: We identified several baseline fracture and surgical characteristics that may increase the risk of adverse events in patients with tibial shaft fractures. Surgeons should consider the predictors identified in our analysis to inform patients treated for tibial shaft fractures. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 23032599 TI - Choosing a bearing material for hip arthroplasty: commentary on an article by Ingrid Milosev, PhD, et al.: "comparison of ten-year survivorship of hip prostheses with use of conventional polyethylene, metal-on-metal, or ceramic-on ceramic bearings". PMID- 23032600 TI - A systematic study of polarons due to oxygen vacancy formation at the rutile TiO2(110) surface by GGA + U and HSE06 methods. AB - The polaronic nature of excess electrons accompanying an oxygen vacancy in a TiO(2)(110) surface has been studied by several theoretical approaches. According to previous studies, DFT + U and hybrid functional methods predict different sites of localization of the polarons. In this paper, we conducted a thorough comparison of the results obtained by GGA + U (generalized gradient approximation + Hubbard U) and HSE06 (Heyd-Scuseria-Ernzerhof hybrid functional) approximations. Considering initial symmetry breaking in the geometry optimization process, we show that regardless of the approximations used, electrons localize at two particular subsurface Ti sites in a state with mixed d(x(2)-y(2))/d(z(2)) character in the global coordinate frame with a spatial extent of the order of 7 A. The lowest state of the polarons is a singlet, but the triplet is only about 0.1 meV higher in energy. Our results agree with previous experiments and calculations, wherever available. We stress that the hybrid functional has been first applied on this surface with a realistic coverage of oxygen vacancies corresponding to the experimental situation (~12.5%). PMID- 23032601 TI - Gene therapy through autologous transplantation of gene-modified hematopoietic stem cells. PMID- 23032602 TI - Perspectives on housing among homeless emerging adults. AB - Homeless emerging adults need the safety and stability of housing programs if they are to avoid the elements and victimization of the streets, however, barriers to obtaining housing are numerous. This study identified factors associated with perspectives of housing services among 29 homeless emerging adults (ages 18-23 years) through one-on-one interviews. Data were gathered and analyzed using grounded theory methodology for qualitative information. Major themes of peer support and positive personal and programmatic interactions in the context of emerging adult development were noted as important factors in housing service utilization. These major themes should be taken into consideration for current housing programs, due to homeless emerging adults' oscillation between their desire for formal support and personal independence. Greater emphasis on services that do not require long term commitments and are more flexible in addressing specific barriers to housing for homeless emerging adults may increase use. PMID- 23032603 TI - Response to 'Factors associated with the development of pressure ulcers after spinal cord injury'. PMID- 23032605 TI - Against all odds: a qualitative study of rehabilitation of persons with spinal cord injury in Afghanistan. AB - STUDY DESIGN: Cross-sectional, survey. OBJECTIVES: To describe the challenges in rehabilitating patients with spinal cord injury in the orthopaedic centres of the International Committee of the Red Cross in Afghanistan. SETTING: Afghanistan (Kabul, Herat, Mazar-i-Sharif, Jalalabad, Gulbahar), April 2012. METHODS: Semi structured interviews were conducted with managers and professional staff of ICRC and other concerned organizations/institutions (Ministries, hospitals, non governmental organizations), and with people with SCI and their families. Quantitative data were extracted from routine statistics. RESULTS: A reported annual incidence of roughly 21 SCI cases per million in Afghanistan could be established for the year 2011. Acts of violence were the most frequent cause, followed by spinal tuberculosis. Despite very elementary prehospital and hospital care, SCI individuals are rehabilitated within the limits set by available technology and socio-economic factors. Support to community reintegration is effective for the ones living within a radius determined by distance and security. CONCLUSION: Rehabilitation of SCI patients would be ineffective without covering at least part of the services usually provided during the phases of acute hospital care and community reintegration. The question of whether services currently provided by foreign-based or funded organizations can be extended into a potential postconflict period, and by whom, remains open. PMID- 23032606 TI - Dynamical screening of the van der Waals interaction between graphene layers. AB - The interaction between graphene layers is analyzed combining local orbital DFT and second order perturbation theory. For this purpose we use the linear combination of atomic orbitals-orbital occupancy (LCAO-OO) formalism, that allows us to separate the interaction energy as the sum of a weak chemical interaction between graphene layers plus the van der Waals interaction (Dappe et al 2006 Phys. Rev. B 74 205434). In this work, the weak chemical interaction is calculated by means of corrected-LDA calculations using an atomic-like sp(3)d(5) basis set. The van der Waals interaction is calculated by means of second order perturbation theory using an atom-atom interaction approximation and the atomic like-orbital occupancies. We also analyze the effect of dynamical screening in the van der Waals interaction using a simple model. We find that this dynamical screening reduces by 40% the van der Waals interaction. Taking this effect into account, we obtain a graphene-graphene interaction energy of 70 +/- 5 meV/atom in reasonable agreement with the experimental evidence. PMID- 23032607 TI - Inference of self-regulated transcriptional networks by comparative genomics. AB - The assumption of basic properties, like self-regulation, in simple transcriptional regulatory networks can be exploited to infer regulatory motifs from the growing amounts of genomic and meta-genomic data. These motifs can in principle be used to elucidate the nature and scope of transcriptional networks through comparative genomics. Here we assess the feasibility of this approach using the SOS regulatory network of Gram-positive bacteria as a test case. Using experimentally validated data, we show that the known regulatory motif can be inferred through the assumption of self-regulation. Furthermore, the inferred motif provides a more robust search pattern for comparative genomics than the experimental motifs defined in reference organisms. We take advantage of this robustness to generate a functional map of the SOS response in Gram-positive bacteria. Our results reveal definite differences in the composition of the LexA regulon between Firmicutes and Actinobacteria, and confirm that regulation of cell-division inhibition is a widespread characteristic of this network among Gram-positive bacteria. PMID- 23032608 TI - Efficiency of nuclear and mitochondrial markers recovering and supporting known amniote groups. AB - We have analysed the efficiency of all mitochondrial protein coding genes and six nuclear markers (Adora3, Adrb2, Bdnf, Irbp, Rag2 and Vwf) in reconstructing and statistically supporting known amniote groups (murines, rodents, primates, eutherians, metatherians, therians). The efficiencies of maximum likelihood, Bayesian inference, maximum parsimony, neighbor-joining and UPGMA were also evaluated, by assessing the number of correct and incorrect recovered groupings. In addition, we have compared support values using the conservative bootstrap test and the Bayesian posterior probabilities. First, no correlation was observed between gene size and marker efficiency in recovering or supporting correct nodes. As expected, tree-building methods performed similarly, even UPGMA that, in some cases, outperformed other most extensively used methods. Bayesian posterior probabilities tend to show much higher support values than the conservative bootstrap test, for correct and incorrect nodes. Our results also suggest that nuclear markers do not necessarily show a better performance than mitochondrial genes. The so-called dependency among mitochondrial markers was not observed comparing genome performances. Finally, the amniote groups with lowest recovery rates were therians and rodents, despite the morphological support for their monophyletic status. We suggest that, regardless of the tree-building method, a few carefully selected genes are able to unfold a detailed and robust scenario of phylogenetic hypotheses, particularly if taxon sampling is increased. PMID- 23032609 TI - Cloud computing for comparative genomics with windows azure platform. AB - Cloud computing services have emerged as a cost-effective alternative for cluster systems as the number of genomes and required computation power to analyze them increased in recent years. Here we introduce the Microsoft Azure platform with detailed execution steps and a cost comparison with Amazon Web Services. PMID- 23032610 TI - Evolution of Type II Antifreeze Protein Genes in Teleost Fish: A Complex Scenario Involving Lateral Gene Transfers and Episodic Directional Selection. AB - I examined hypotheses about lateral transfer of type II antifreeze protein (AFP) genes among "distantly" related teleost fish. The effects of episodic directional selection on amino acid evolution were also investigated. The strict consensus results showed that the type II AFP and type II antifreeze-like protein genes were transferred from Osmerus mordax to Clupea harengus, from the ancestral lineage of the Brachyopsis rostratus-Hemitripterus americanus clade to the ancestor of the Hypomesus nipponensis-Osmerus mordax group and from the ancestral lineage of Brachyopsis rostratus-Hemitripterus americanus-Siniperca chuatsi-Perca flavescens to Perca flavescens. At the present time, the available evidence is more consistent with the LGT hypothesis than with other alternative explanations. The overall results indicate that evolutionary history of the type II AFP gene is complex, and that episodic directional selection was instrumental in the evolution of this freeze-preventing protein from a C-type lectin precursor. PMID- 23032611 TI - Phylogenomic study of lipid genes involved in microalgal biofuel production candidate gene mining and metabolic pathway analyses. AB - Optimizing microalgal biofuel production using metabolic engineering tools requires an in-depth understanding of the structure-function relationship of genes involved in lipid biosynthetic pathway. In the present study, genome-wide identification and characterization of 398 putative genes involved in lipid biosynthesis in Arabidopsis thaliana Chlamydomonas reinhardtii, Volvox carteri, Ostreococcus lucimarinus, Ostreococcus tauri and Cyanidioschyzon merolae was undertaken on the basis of their conserved motif/domain organization and phylogenetic profile. The results indicated that the core lipid metabolic pathways in all the species are carried out by a comparable number of orthologous proteins. Although the fundamental gene organizations were observed to be invariantly conserved between microalgae and Arabidopsis genome, with increased order of genome complexity there seems to be an association with more number of genes involved in triacylglycerol (TAG) biosynthesis and catabolism. Further, phylogenomic analysis of the genes provided insights into the molecular evolution of lipid biosynthetic pathway in microalgae and confirm the close evolutionary proximity between the Streptophyte and Chlorophyte lineages. Together, these studies will improve our understanding of the global lipid metabolic pathway and contribute to the engineering of regulatory networks of algal strains for higher accumulation of oil. PMID- 23032613 TI - Concise and efficient syntheses of preQ1 base, Q base, and (ent)-Q base. AB - To thoroughly study the functional role of prokaryotic t-RNA-guanine transglycosylases which are essential in the pathogenesis of shigellosis, novel efficient, high-yielding synthetic approaches for preQ(1) base, Q base, as well as for (ent)-Q base mainly employing cheap and readily available starting materials have been developed. Q base as well as (ent)-Q base are accessible starting from preQ(1) base via nucleophilic substitution reactions with appropriately decorated halocyclopentenyl synthons, prior to that prepared from naturally occurring carbohydrates. PMID- 23032615 TI - Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B 18 and B-27. AB - PURPOSE: The limited information on predictors of locoregional recurrence (LRR) after neoadjuvant chemotherapy (NC) has resulted in controversy about the optimal use of adjuvant radiotherapy and the timing of sentinel lymph node biopsy. PATIENTS AND METHODS: We examined patterns and predictors of LRR as first event in combined analysis of two National Surgical Adjuvant Breast and Bowel Project (NSABP) neoadjuvant trials. NC was either doxorubicin/cyclophosphamide (AC) alone or AC followed by neoadjuvant/adjuvant docetaxel. Lumpectomy patients received breast radiotherapy alone; mastectomy patients received no radiotherapy. Pathologic complete response was defined as the absence of invasive tumor in the breast. Multivariate analyses were used to identify independent predictors of LRR. The primary end point was time to LRR as first event. RESULTS: In 3,088 patients, 335 LRR events had occurred after 10 years of follow-up. The 10-year cumulative incidence of LRR was 12.3% for mastectomy patients (8.9% local; 3.4% regional) and 10.3% for lumpectomy plus breast radiotherapy patients (8.1% local; 2.2% regional). Independent predictors of LRR in lumpectomy patients were age, clinical nodal status (before NC), and pathologic nodal status/breast tumor response; in mastectomy patients, they were clinical tumor size (before NC), clinical nodal status (before NC), and pathologic nodal status/breast tumor response. By using these independent predictors, groups at low, intermediate, and high risk of LRR could be identified. Nomograms that incorporate these independent predictors were created. CONCLUSION: In patients treated with NC, age, clinical tumor characteristics before NC, and pathologic nodal status/breast tumor response after NC can be used to predict risk for LRR and to optimize the use of adjuvant radiotherapy. PMID- 23032616 TI - Gleason score 6 adenocarcinoma: should it be labeled as cancer? PMID- 23032617 TI - Toward an improved definition of the tumor spectrum associated with BAP1 germline mutations. PMID- 23032618 TI - Phase I study of folate conjugate EC145 (Vintafolide) in patients with refractory solid tumors. AB - PURPOSE: EC145 (vintafolide), a conjugate of folic acid and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), is a ligand for the folate receptor (FR), with activity against FR-positive tumor xenografts in vivo. This phase I study determined the maximum-tolerated dose (MTD) of EC145 administered as a bolus intravenous injection or 1-hour infusion in patients with refractory solid tumors. PATIENTS AND METHODS: EC145 was administered as a bolus injection or 1 hour infusion on days 1, 3, and 5 and days 15, 17, and 19 of each 28-day cycle with dose escalation in cohorts of three to six patients until the MTD was identified. Plasma pharmacokinetics were determined on days 1 and 3 of the first cycle. RESULTS: The MTD of EC145 was 2.5 mg when administered as either a bolus injection or 1-hour infusion. Constipation was the dose-limiting toxicity with both routes. Constipation, nausea, fatigue, and vomiting were the most commonly reported adverse events. One partial response to therapy was observed in a patient with metastatic ovarian cancer. CONCLUSION: EC145 administered by bolus injection or as a 1-hour infusion at a dose of 2.5 mg on days 1, 3, and 5 and days 15, 17, and 19 of a 28-day cycle has an acceptable safety profile in patients with advanced cancer. On the basis of these findings, phase II studies of EC145 have been initiated in patients with advanced epithelial ovarian cancer and non-small-cell lung cancer. PMID- 23032619 TI - Failure to rescue as a source of variation in hospital mortality for ovarian cancer. AB - PURPOSE: Although the association between high surgical volume and improved outcomes from procedures is well described, the mechanisms that underlie this association are uncertain. There is growing recognition that high-volume hospitals may not necessarily have lower complication rates but rather may be better at rescuing patients with complications. We examined the role of complications, failure to rescue from complications, and mortality based on hospital volume for ovarian cancer. PATIENTS AND METHODS: The Nationwide Inpatient Sample was used to identify women who underwent surgery for ovarian cancer from 1988 to 2009. Hospitals were ranked on the basis of their procedure volume. We determined the risk-adjusted mortality, major complication rate, and "failure to rescue" rate (mortality in patients with a major complication) for each tertile. Univariate and multivariate associations were then compared. RESULTS: We identified 36,624 patients. The mortality rate for the cohort was 1.6%. The major complication rate was 20.4% at low-volume, 23.4% at intermediate volume, and 24.6% at high-volume hospitals (P < .001). However, the rate of failure to rescue (death after a complication) was markedly higher at low-volume (8.0%) compared with high-volume hospitals (4.9%; P < .001). After accounting for patient and hospital characteristics, women treated at low-volume hospitals who experienced a complication were 48% more likely (odds ratio [OR], 1.48; 95% CI, 1.11 to 1.99) to die than patients with a complication at a high-volume hospital. CONCLUSION: Mortality is lower for patients with ovarian cancer treated at high volume hospitals. The reduction in mortality does not appear to be the result of lower complications rates but rather a result of the ability of high-volume hospitals to rescue patients with complications. PMID- 23032620 TI - Questionable universal validity of PAX3/FOXO1 fusion gene status as molecular marker for improvement of risk stratification in rhabdomyosarcoma therapy. PMID- 23032621 TI - Children, adolescents, and young adults with leukemia: the empty half of the glass is growing. PMID- 23032622 TI - Is undetectable prostate-specific antigen always reliable to rule out prostate cancer recurrence after radical prostatectomy? PMID- 23032623 TI - Lymph node metastasis of osteosarcoma. PMID- 23032624 TI - Using chemotherapy response to personalize choices regarding locoregional therapy: a new era in breast cancer treatment? PMID- 23032626 TI - Should response to preoperative chemotherapy affect radiotherapy recommendations after mastectomy for stage II breast cancer? AB - A healthy 38-year-old woman presents with a palpable mass at the two o'clock position of the left breast. Mammography discloses a 3.2-cm spiculated lesion corresponding with the palpable abnormality, and ultrasonography confirms a solid mass in the breast and an enlarged, 2.1-cm lymph node with a thickened cortex in the ipsilateral axilla. Ultrasound-guided core needle biopsy of the breast mass diagnoses an invasive ductal carcinoma, poorly differentiated (grade 3), with lymphovascular invasion. Lymph node fine-needle aspiration is positive for malignant cells. Immunohistochemical studies on the breast specimen indicate that the tumor is triple negative, lacking estrogen and progesterone receptors and human epidermal growth factor 2 expression. The patient receives preoperative chemotherapy with doxorubicin and cyclophosphamide followed by paclitaxel. She has a dramatic clinical response; the breast and axillary masses shrink rapidly with chemotherapy. At the time of mastectomy, she is found to have several foci of residual invasive cancer in the breast (largest focus, 0.3 cm), located in a 3 cm tumor bed showing treatment effect (Figs 1A to 1C). The margins are negative, as are all 11 axillary lymph nodes. Her pathologic response to neoadjuvant treatment is judged Miller-Payne grade 4. She is referred for consideration of postmastectomy irradiation. PMID- 23032625 TI - Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. AB - PURPOSE: Molecular tumor profiling is a promising diagnostic technique to determine the tissue of origin in patients with carcinoma of unknown primary site (CUP). However, the clinical value of these molecular predictions is unknown. We used tumor profiling results to direct site-specific therapy for patients with CUP. PATIENTS AND METHODS: Tumor biopsy specimens from previously untreated patients with CUP were tested with a 92-gene reverse transcriptase polymerase chain reaction cancer classification assay. When a tissue of origin was predicted, patients who were treatment candidates received standard site-specific first-line therapy. RESULTS: Of 289 patients enrolled, 252 had successful assays performed, and 247 (98%) had a tissue of origin predicted. Sites most commonly predicted were biliary tract (18%), urothelium (11%), colorectal (10%), and non small-cell lung (7%). Two hundred twenty-three patients were treatment candidates, and 194 patients received assay-directed site-specific treatment. In these 194 patients, the median survival time was 12.5 months (95% CI, 9.1 to 15.4 months). When the assay predicted tumor types that were clinically more responsive, the median survival was significantly improved when compared with predictions of more resistant tumors (13.4 v 7.6 months, respectively; P = .04). CONCLUSION: In this large prospective trial, molecular tumor profiling predicted a tissue of origin in most patients with CUP. The median survival time of 12.5 months for patients who received assay-directed site-specific therapy compares favorably with previous results using empiric CUP regimens. Patients with CUP predicted to have more responsive tumor types had longer survival compared with patients with less responsive tumor types. Molecular tumor profiling contributes to the management of patients with CUP and should be a part of their standard evaluation. PMID- 23032627 TI - Unusual case of solitary intraparenchymal brain plasmacytoma. PMID- 23032628 TI - Longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation. AB - PURPOSE: To measure longitudinal changes in body mass and composition in survivors of childhood hematologic malignancies after allogeneic hematopoietic stem-cell transplantation (HSCT). PATIENTS AND METHODS: Body mass index (BMI) was analyzed in 179 survivors by category (underweight, healthy-weight, overweight, and obese) and by z score. Fat and lean body mass measured by dual-energy x-ray absorptiometry was analyzed as z scores. RESULTS: Over a median 6.6 years of follow-up, BMI z scores diminished significantly (0.32 pre-HSCT v -0.60 at 10 years post-HSCT; P < .001). Mean z scores for fat mass stayed within population norms, but those for lean mass remained below normal levels and diminished significantly over time (P = .018). Pre-HSCT BMI category and/or z score were strongly predictive of post-HSCT BMI (P < .001) and of fat and lean mass z scores (both P < .001). Survivors with extensive chronic graft-versus-host disease were more likely than others to have low BMI (P = .004) and low lean mass (P < .001) post-HSCT. Older age at HSCT (P = .015) and T-cell-depleted graft (P = .018) were predictive of lower post-HSCT BMI. Female patients had higher body fat (P = .002) and lower lean mass (P = .013) z scores than male patients, and black patients had higher fat mass z scores than white patients (P = .026). CONCLUSION: BMI declines significantly after allogeneic HSCT for childhood hematologic malignancies, reflecting primarily a substantial decrease in lean mass but not fat mass. Monitoring and preservation of BMI and lean mass are vital, especially in those with the identified risk factors. PMID- 23032630 TI - On thwarting the seeds of scientific fraud. PMID- 23032629 TI - Molecular cloning and biochemical characterization of two novel Neu3 sialidases, neu3a and neu3b, from medaka (Oryzias latipes). AB - Mammalian Neu3 sialidases are involved in various biological processes, such as cell death and differentiation, through desialylation of gangliosides. The enzymatic profile of Neu3 seems to be highly conserved from birds to mammals. In fish, the functional properties of Neu3 sialidase are not clearly understood, with the partial exception of the zebrafish form. To cast further light on the molecular evolution of Neu3 sialidase, we identified the encoding genes in the medaka Oryzias latipes and investigated the properties of the enzyme. PCR amplification using medaka brain cDNA allowed identification of two novel medaka Neu3 genes, neu3a and neu3b. The YRIP, VGPG motif and Asp-Box, characteristic of consensus motifs of sialidases, were well conserved in the both medaka Neu3 sialidases. When each gene was transfected into HEK293 to allow cell lysates for the use of enzymatic characterization, two Neu3 sialidases showed strict substrate specificity toward gangliosides, similar to mammalian Neu3. The optimal pH values were at pH 4.2 and pH 4.0, respectively, and neu3b in particular showed a broad optimum. Immunofluorescence assays indicated neu3a localization at plasma membranes, while neu3b was found in cytosol. The tissue distribution of two genes was then investigated by estimation of mRNA expression and sialidase activity, both being dominantly expressed in the brain. In neu3a gene-transfected neuroblastoma cells, the enzyme was found to positively regulate retinoic acid induced differentiation with the elongation of axon length. On the other hand, neu3b did not affect neurite formation. These results and phylogenetic analysis suggested that the medaka neu3a is an evolutionally conserved sialidase with regard to enzymatic properties, whereas neu3b is likely to have originally evolved in medaka. PMID- 23032631 TI - Urinary tract endometriosis. AB - Urinary endometriosis is a rare diagnosis which is becoming much more common at referral centres. The bladder and the pelvic ureter are the sites that can be affected, each posing to the urologist and gynecologist some specific diagnostic and therapeutic difficulties. Bladder endometriosis, indeed, usually causes lower urinary tract symptoms, has a typical appearance at imaging and can be an isolated presentation; ureteral location, at the contrary, often presents with a vague or aspecific symptomatology and is often associated to other pelvic locations, so that a careful evaluation of the urinary tract, preferably with NMR, is mandatory for severe pelvic endometriosis, also in the absence of symptoms. The treatment of bladder presentation is partial cystectomy, preferably via a laparoscopic approach, while ureteral endometriosis can require different surgical solutions, from ureterolysis to ureteral reimplantation, open, laparoscopic or robot-assisted, basing on its extent and on the need of additional procedures for other locations. PMID- 23032632 TI - [Urinary tract endometriosis: anatomopathology features]. AB - Endometriosis is a pathological entity characterized by the presence of endometrial glands and stroma in ectopic side, out of the uterus and the histological analysis represents the basic examination to a definitive diagnosis. The macroscopic and microscopic features to urological level are similar to those in the others sides and include not only the "usual" aspects of the pathology but also hyperplastic and metaplastic changes both in the glandular and stromal components. PMID- 23032633 TI - [BPH: state of the art in the surgical treatment]. AB - TURP has been considered the gold standard for surgical treatment of BPH for many years. Symptoms relief, improvement in maximum flow rate and reduction of post void residual urine have been reported in several experiences. Nevertheless, concerns have been reported in terms of safety outcomes: intracapsular perforation, TUR syndrome, bleeding. In the recent years the use of new forms of energy and devices such as bipolar resector, Ho: YAG and potassium-titanyl phosphate laser are challenging the role of traditional TURP for BPH surgical treatment. In 1999 TURP represented 81% of surgical treatment for BPH versus 39% in 2005. We have analyzed guidelines and recent literature to evaluate the role of the most relevant new surgical approaches compared to TURP for the treatment of BPH. PMID- 23032634 TI - Cytokine gene expression in the tunica albuginea of patients with Peyronie's disease. Pilot study with a control group. AB - INTRODUCTION AND OBJECTIVE: Cytokines may be involved in the pathogenesis of Peyronie's disease (PD). In this case, biological drugs, acting on specific cytokines, could be adopted in the pharmacological treatment of the disease. MATERIALS AND METHODS: Twenty PD patients and 8 patients affected by congenital recurvatum penis (control group) who underwent corporoplasty were enrolled in the study. Histological examination and measurement by Real Time PCR of the expression of the encoding genes for IL-2, IL-4, IL-6, IL-10, IL-13, TGF-beta, TNF-alpha and IFN-gamma were performed on the removed tunica albuginea (TA). For the normalization of data GAPDH (glucerldehyde-3fosfatehydrogenase) and GUSB (beta-glucuronidase), housekeeping genes were used. The analysis of the data was performed using the comparative method of DeltaCt. The results were reported with the Fold of induction (FOI) method. RESULTS: The histological exams of TA showed only fibrous tissue without cavernous tissue. The analysis of gene expression of IL-6, IL-10, IFN-gamma and TGF-beta1 showed in all samples very low levels. The levels were lower in PD patients although the differences were not statistically significant. An exception was represented by TGF-beta that showed a higher level in PD patients, although not statistically significant. The expression of IL-4, IL-13 and TNF-alpha was undetectable. CONCLUSIONS: The expressions of cytokines in TA of PD patients compared to those of the controls do not show any significant difference. A bias of our study is that the groups were not age matched. This is a bias already present in similar experiences and due to the different pathogenesis of the diseases. Cytokines promoting inflammation resulted undetectable and do not seem to be involved in PD pathogenesis. The higher level of TGF-beta, a pro-fibrotic cytokine, detected in PD could explain the presence of fibrotic tissue. Presently, there is no data suggesting a possible role of biological drugs in PD. PMID- 23032635 TI - [The efficacy of degarelix on LUTS (Lower urinary tract symptoms) relief in patients with prostate cancer]. AB - Hormonal therapy is one of the treatment options for prostate cancer patients. There are many hormonal treatments modality to block the testosterone effect on prostate cancer cell proliferation. Degarelix is an innovative molecule able to antagonize the GnRH receptor with comparable oncological results to GnRH agonist, but with less side effects, avoiding the flare up phase, and better efficacy in LUTS relief. These characteristics of degarelix can impact on the clinical decision making to choose a therapy instead of another. PMID- 23032636 TI - [Renal perforation due to the migration of metal cerclage in hip arthroplasty]. AB - Hip arthroplasty surgery allows the recovery of a good quality of life greatly enabling to resolve or alleviate the pain and improve physical and motor performance of the patient. However, this procedure is not without complications, which may occur at an earlier or later stage. In this work we report the only complication described in the literature of renal perforation due to the migration of metal cerclage in hip arthroplasty. PMID- 23032637 TI - Haploinsufficiency of Tumor Suppressor Genes is Driven by the Cumulative Effect of microRNAs, microRNA Binding Site Polymorphisms and microRNA Polymorphisms: An In silico Approach. AB - Haploinsufficiency of tumor suppressor genes, wherein the reduced production and activity of proteins results in the inability of the cell to maintain normal cellular function, is one among the various causes of cancer. However the precise molecular mechanisms underlying this condition remain unclear. Here we hypothesize that single nucleotide polymorphisms (SNPs) in the 3'untranslated region (UTR) of mRNAs and microRNA seed sequence (miR-SNPs) may cause haploinsufficiency at the level of proteins through altered binding specificity of microRNAs (miRNAs). Bioinformatics analysis of haploinsufficient genes for variations in their 3'UTR showed that the occurrence of SNPs result in the creation of new binding sites for miRNAs, thereby bringing the respective mRNA variant under the control of more miRNAs. In addition, 19 miR-SNPs were found to result in non-specific binding of microRNAs to tumor suppressors. Networking analysis suggests that the haploinsufficient tumor suppressor genes strongly interact with one another, and any subtle alterations in this network will contribute to tumorigenesis. PMID- 23032638 TI - CT to cone-beam CT deformable registration with simultaneous intensity correction. AB - Computed tomography (CT) to cone-beam CT (CBCT) deformable image registration (DIR) is a crucial step in adaptive radiation therapy. Current intensity-based registration algorithms, such as demons, may fail in the context of CT-CBCT DIR because of inconsistent intensities between the two modalities. In this paper, we propose a variant of demons, called deformation with intensity simultaneously corrected (DISC), to deal with CT-CBCT DIR. DISC distinguishes itself from the original demons algorithm by performing an adaptive intensity correction step on the CBCT image at every iteration step of the demons registration. Specifically, the intensity correction of a voxel in CBCT is achieved by matching the first and the second moments of the voxel intensities inside a patch around the voxel with those on the CT image. It is expected that such a strategy can remove artifacts in the CBCT image, as well as ensuring the intensity consistency between the two modalities. DISC is implemented on computer graphics processing units in compute unified device architecture (CUDA) programming environment. The performance of DISC is evaluated on a simulated patient case and six clinical head-and-neck cancer patient data. It is found that DISC is robust against the CBCT artifacts and intensity inconsistency and significantly improves the registration accuracy when compared with the original demons. PMID- 23032639 TI - Predictors of relapse in a bupropion trial for smoking cessation in recently abstinent alcoholics: preliminary results using an aggregate genetic risk score. AB - INTRODUCTION: Rates of smoking in the US population have decreased overall, but rates in some groups, including alcoholic smokers, remain high. Many newly sober alcoholics are concerned about their smoking and some attempt to quit. However, quit rates in this population are low. Prior studies suggest risk for relapse in this population may be genetically influenced and that genetic factors may moderate response to treatment. METHODS: IN THIS EXPLORATORY STUDY, WE HAD TWO SPECIFIC AIMS: (1) to investigate associations between genetic risk and outcome; (2) to investigate whether genetic risk moderates the efficacy of a medication intervention. Data are from a subsample of 90 participants from a clinical trial of smoking cessation treatment for smokers with between 2 and 12 months of alcohol abstinence. Subjects were randomly assigned to bupropion or placebo. All subjects received counseling and nicotine patches. To examine the possibility that bupropion may have been efficacious in participants with a specific genetic profile (ie, a pharmacogenetic approach), an aggregate genetic risk score was created by combining risk genotypes previously identified in bupropion treatment studies. RESULTS: Although medication efficacy was not moderated by the aggregate genetic risk score, there was an interaction between nicotine dependence and genetic risk in predicting smoking abstinence rates at the end of treatment (10 weeks). CONCLUSIONS: Results suggest an aggregate genetic risk score approach may have utility in treatment trials of alcoholics who smoke. Additionally, these findings suggest a strategy for understanding and interpreting conflicting results for single genetic markers examined as moderators of smoking cessation treatment. PMID- 23032640 TI - Many-body dynamic localization of strongly correlated electrons in ac-driven Hubbard lattices. AB - In the framework of the Hubbard model, it is shown that approximate dynamic localization for strongly correlated electrons hopping on a one-dimensional lattice and driven by a high-frequency sinusoidal field can be realized provided that periodic pi phase slips are impressed into the sinusoidal field. A possible experimental demonstration of the proposed driving scheme is presented for a photonic model system of the two-particle Hubbard model, based on light transport in a square waveguide lattice with a sinusoidally curved optical axis. PMID- 23032641 TI - Gold(I) and platinum(II) switch: a post-Ugi intramolecular hydroarylation to pyrrolopyridinones and pyrroloazepinones. AB - A regioselective approach for the synthesis of pyrrolopyridinones and pyrroloazepinones is reported employing an Ugi reaction followed by a gold(I) or platinum(II) catalyzed intramolecular hydroarylation. PMID- 23032642 TI - Effects of prebiotic inulin-type fructans on structure, quality, sensory acceptance and glycemic response of gluten-free breads. AB - The effect of adding increasing levels of prebiotic inulin-type fructans (ITFs) (0, 4, 8, 10 and 12%) on the sensory and nutritional quality of gluten-free bread (GFB) was assessed. ITFs can provide structure and gas retention during baking, thus improving GFB quality by yielding better specific volume, softer crumb, improved crust and crumb browning with enhanced sensory acceptance. During baking, approximately one-third of the ITFs was lost. The addition of 12% ITFs to the basic formulation is required in order to obtain GFB enriched with 8% ITFs (4 g of fructans per 50 g bread serving size), levels that can provide health benefits. 12% ITFs-addition level decreased GFB glycemic index (from 71 to 48) and glycemic load (from 12 to 8). Prebiotic ITFs are a promising improver for GFB that can provide nutritional (11% dietary fiber content, low glycemic response) and functional benefits to patients with celiac disease, since ITFs are prebiotic ingredients that can also increase calcium absorption. PMID- 23032643 TI - Nitric oxide as a mediator of fructose 1,6-bisphosphate protection in galactosamine-induced hepatotoxicity in rats. AB - Fructose 1,6-bisphosphate (F1,6BP) has been widely used as a therapeutic agent for different harmful conditions in a variety of tissues. The hypothesis of the present work was that the increase in nitric oxide production and the prevention of oxidative stress induced by exogenous F1,6BP mediate its protective effect against the hepatotoxic action of GalN. Experimental groups used were sham, F1,6BP (2g/kg bw i.p.), GalN (0.4g/kg bw i.p), l-NAME (10mg/kg bw i.v.), F1,6BP+GalN, l-NAME+GalN and l-NAME+F1,6BP+GalN. Animals were killed after 24h of bolus administration. F1,6BP induced an increase in NO and the redox ratio (GSH/GSSG) in liver. Western blot assays pointed to overexpression of liver eNOS in F1,6BP-treated rats. The hepatic injury induced by GalN increased transaminases in plasma and decreased the reduced/oxidized glutathione ratio in liver. The concomitant administration of F1,6BP reversed this damage, while the addition of l-NAME worsened the liver injury. We provided evidence that this F1,6BP-induced protection may be related to the increase in NO production through the positive modulation of eNOS, and the increase in intracellular reduced glutathione, thus providing a higher reducing capacity. PMID- 23032644 TI - Development and validation of prediction models for blood concentrations of dioxins and PCBs using dietary intakes. AB - BACKGROUND: Dioxins and PCBs accumulate in the food chain and might exert toxic effects in animals and humans. In large epidemiologic studies, exposure estimates of these compounds based on analyses of biological material might not be available or affordable. OBJECTIVES: To develop and then validate models for predicting concentrations of dioxins and PCBs in blood using a comprehensive food frequency questionnaire and blood concentrations. METHODS: Prediction models were built on data from one study (n=195), and validated in an independent study group (n=66). We used linear regression to develop predictive models for dioxins and PCBs, both sums of congeners and 33 single congeners (7 and 10 polychlorinated dibenzo-p-dioxins and furans (PCDDs/PCDFs), 12 dioxin-like polychlorinated biphenyls (PCBs: 4 non-ortho and 8 mono-ortho), sum of all the 29 dioxin-like compounds (total TEQ) and sum of 4 non dioxin-like PCBs (? CB-101, 138, 153, 183=PCB(4)). We used the blood concentration and dietary intake of each of the above as dependent and independent variables, while sex, parity, age, place of living, smoking status, energy intake and education were covariates. We validated the models in a new study population comparing the predicted blood concentrations with the measured blood concentrations using correlation coefficients and Weighted Kappa (K(W)) as measures of agreement, considering K(W)>0.40 as successful prediction. RESULTS: The models explained 78% (sum dioxin-like compounds), 76% (PCDDs), 76% (PCDFs), 74% (no-PCBs), 69% (mo-PCBs), 68% (PCB(4)) and 63% (CB-153) of the variance. In addition to dietary intake, age and sex were the most important covariates. The predicted blood concentrations were highly correlated with the measured values, with r=0.75 for dl-compounds 0.70 for PCB(4), (p<0.001) and 0.66 (p<0.001) for CB-153. K(W) was 0.68 for sum dl compounds 0.65 for both PCB(4) and CB-153. Out of 33 congeners 16 (13dl-compounds and 3 ndl PCBs) had K(W)>0.40. CONCLUSIONS: The models developed had high power to predict blood levels of dioxins and PCBs and to correctly rank subjects according to high or low exposure based on dietary intake and demographic information. These models underline the value of dietary intake data for use in investigations of associations between dioxin and PCB exposure and health outcomes in large epidemiological studies with limited biomaterial for chemical analysis. PMID- 23032645 TI - Dietary intake of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) by a population living in the vicinity of a hazardous waste incinerator: assessment of the temporal trend. AB - The concentrations of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) were determined in a number of foodstuffs purchased in various locations near a hazardous waste incinerator (HWI) in Tarragona County (Catalonia, Spain). The dietary intake of PCDD/Fs by the population of the area under potential influence of the HWI was subsequently estimated. The results were compared with previous surveys performed in the same area in 1998 (baseline), 2002 and 2006. In the present study, the highest WHO-TEQ corresponded to industrial bakery (0.183 ng/kg wet weight, ww), followed by fish (0.156 ng/kg ww), oils and fats (0.112 ng/kg fat weight), and seafood (0.065 ng/kg ww). In contrast, the lowest values were observed in pulses and tubers (0.003 ng/kg ww), and cereals and fruits (0.004 ng/kg ww). The dietary intake of PCDD/Fs by the general population was 33.1pg WHO-TEQ/day, having fish and seafood (11.6 pg WHO TEQ), oils and fats (4.61pg WHO-TEQ), dairy products (3.79 pg WHO-TEQ), and industrial bakery (3.49 pg WHO-TEQ) as the groups showing the highest contribution to the total TEQ. The lowest daily contributions corresponded to pulses (0.08 pg WHO-TEQ) and tubers (0.25 pg WHO-TEQ). This intake was considerably lower than that found in the baseline study, 210.1 pgI-TEQ/day, and also notably lower than that found in the 2002 survey (59.6 pgI-TEQ/day), but slightly higher than the intake estimated in the 2006 survey, 27.8 pgWHO-TEQ/day. The results of this study show that any increase potentially found in the biological monitoring of the general population living in the area under evaluation should not be attributed to dietary exposure to PCDD/Fs. PMID- 23032646 TI - A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). AB - Last century there was a short burst of interest in the tryptophan related disorders of pellagra and related abnormalities that are usually presented in infancy.1,2 Nutritional physiologists recognized that a severe human dietary deficiency of either tryptophan or the B group vitamins could result in central nervous system (CNS) sequelae such as ataxia, cognitive dysfunction and dysphoria, accompanied by skin hyperpigmentation.3,4 The current paper will focus on the emerging role of tryptophan in chronic fatigue syndrome (CFS) and fibromyalgia (FM). PMID- 23032647 TI - Influence of the solvent and the enantiomeric purity on the transition between different supramolecular polymers. AB - The self-assembly of two enantiomerically pure hexa(oligo(p-phenylene vinylene)) substituted benzenes having 24 stereocenters was studied in pure methylcyclohexane (MCH) and in a mixture of MCH/toluene (4:1). Irrespective of the solvent a cooperative supramolecular polymerization mechanism was determined for these star-shaped molecules by using temperature-dependent CD and UV/Vis spectroscopy. Quite remarkably, a transition from one helical supramolecular state (A) to a second more thermodynamically stable supramolecular helical assembly (B) was observed. The rate of the A->B transition was strongly dependent on the nature of the solvent; being faster in the solvent mixture than in pure MCH. By using size exclusion chromatography we could relate the increased rate to a decreased stability of the supramolecular A state in the solvent mixture. Next, we mixed the two enantiomerically pure hexa-substituted benzene derivatives in a so-called majority-rules experiment, which lead to the anitcipated chiral amplification in the A state. More importantly it appeared that the A->B transition was significantly hampered in these mixed systems. Furthermore, the absence of chiral amplification in the B state revealed the formation of separated enantiomerically pure assemblies. Therefore, by using a wide variety of spectroscopic and chromatographic techniques we determined the influence of solvent and enantiomeric purity on the transition between different supramolecular states. PMID- 23032648 TI - Examination of the relationship between antimicrobials and thrombocytosis. AB - OBJECTIVE: To evaluate whether there is a relationship between antimicrobial therapy and the development of thrombocytosis. DATA SOURCES: Literature was accessed through EMBASE (1977-June 2012) and MEDLINE (1977-June 2012) using the terms thrombocytosis and antimicrobial. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language publications identified were evaluated. For case reports, the Naranjo probability scale was used to calculate the likelihood of the drug causing the reaction. DATA SYNTHESIS: Thrombocytosis occurring during antimicrobial therapy is well documented, with several case reports and clinical trial observations. However, a direct causal relationship is not yet supported by the available literature. Platelets are well known to be an acute phase reactant, with an elevated count occurring after acute conditions such as blood loss, inflammation, or infection. Thrombocytosis during antimicrobial therapy may be the result of an infectious process and not an adverse drug event. CONCLUSIONS: Based on the current available literature, a definitive link cannot be established between antimicrobial therapy and occurrence of thrombocytosis. PMID- 23032649 TI - Paradoxical reaction of raynaud phenomenon following the repeated administration of iloprost in a patient with diffuse cutaneous systemic sclerosis. AB - OBJECTIVE: To report a paradoxical reaction of Raynaud phenomenon following the repeated administration of iloprost in a patient with diffuse cutaneous systemic sclerosis with vascular involvement. CASE SUMMARY: In January 2006, a 40-year-old male was diagnosed with diffuse cutaneous systemic sclerosis with pulmonary, esophageal, cutaneous, and vascular involvement (Raynaud phenomenon, with digital ulcers on his hands). In December 2008, treatment with iloprost was started due to worsening disease. Nine cycles of iloprost were administered at a rate of 0.5 1 ng/kg/min (6 hours per day, for 5 days every 6-8 weeks); the patient tolerated this treatment well. However, on the fourth day of cycles 10 and 11, the patient developed paradoxical Raynaud phenomenon in the hand with perfusion when the infusion was increased to 1 ng/kg/min, requiring treatment to be stopped. Treatment was continued during cycles 12 and 13 at 0.5 ng/kg/min; the patient tolerated the treatment well, although paradoxical Raynaud phenomenon occurred when the rate of infusion was increased. DISCUSSION: Raynaud phenomenon is extremely common in patients with scleroderma, and often is severe. Iloprost has vasodilating, antiplatelet, cytoprotective, and immunomodulating properties, and has been found to be an efficacious alternative to nifedipine for the treatment of Raynaud phenomenon in patients with scleroderma. The Naranjo probability scale indicated that iloprost was the probable cause of the paradoxical Raynaud phenomenon in this patient. CONCLUSIONS: This case demonstrates a probable relationship between the rate of infusion of iloprost and the paradoxical reaction of Raynaud phenomenon. PMID- 23032650 TI - Comment: planning a pharmacy-led medical mission trip, part 1: focus on medication acquisition. PMID- 23032651 TI - Proton pump inhibitor use and association with spontaneous bacterial peritonitis in patients with cirrhosis and ascites. AB - OBJECTIVE: To evaluate the literature regarding the efficacy and safety of proton pump inhibitors (PPIs) when they are used in patients with cirrhosis and ascites. DATA SOURCES: A literature search was conducted using MEDLINE (1966-May 2012) and Web of Science (1990-May 2012) with the terms proton pump inhibitor, antisecretory therapy, cirrhosis, ascites, spontaneous bacterial peritonitis, and Clostridium difficile. The search was restricted to articles published in English on the use of PPIs in humans. Reference citations from identified published articles were reviewed for relevant information. STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from the data sources were evaluated for inclusion. One case series, 8 retrospective case-control trials, and 1 meta-analysis were identified. DATA SYNTHESIS: Cirrhosis may cause complications such as portal hypertension, esophageal varices, and ascites. Patients may be prescribed PPIs without clear indications or because of their propensity to develop upper gastrointestinal symptoms and bleeding. However, gastric acidity is a major nonspecific defense mechanism and there is insufficient evidence on the need for chronic acid suppression in patients with cirrhosis. It is postulated that the portal hypertensive environment in cirrhosis and the acid suppression from PPIs can increase the risk of spontaneous bacterial peritonitis and C. difficile infection in patients with cirrhosis with ascites. Several retrospective studies and 1 meta-analysis have confirmed this association. CONCLUSIONS: Patients with cirrhosis and ascites should be monitored carefully while on PPIs for a possible increased risk of infection from spontaneous bacterial peritonitis and C. difficile. Prospective randomized trials are needed to confirm this association. Clinicians should be aware of this lesser known adverse effect of PPIs. PMID- 23032652 TI - Dyslipidemia: management using optimal lipid-lowering therapy. AB - OBJECTIVE: To evaluate current approaches and explore emerging research related to dyslipidemia management. DATA SOURCES: MEDLINE (2004-April 2012) was searched for randomized controlled trials using the terms dyslipidemia and lipid-lowering therapy or statin (>1000 hits). Separate searches (MEDLINE, Google) identified meta-analyses (2010-2011), disease prevalence statistics, and current consensus guidelines (2004-July 2011). Additional references were identified from the publications reviewed. STUDY SELECTION AND DATA EXTRACTION: English-language articles on large multicenter trials were evaluated. DATA SYNTHESIS: National Cholesterol Education Program Adult Treatment Panel III guidelines for the reduction of cardiovascular risk recommend the attainment of specific low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non HDL-C) target values, based on an individual's 10-year risk of coronary heart disease or global risk. For most patients unable to achieve recommended lipid level goals with therapeutic lifestyle changes, statins are the first option for treatment. Results of large, well-controlled clinical trials have demonstrated that statins are effective in primary and secondary prevention of cardiovascular disease in diverse populations, including patients with diabetes and the elderly, and that intensive statin therapy provides more effective lipid goal attainment and significantly greater risk reduction in patients with coronary artery disease. Statin therapy is generally well tolerated but may increase the risk of myopathy. Statin use has been associated with increases in hepatic transaminases and an increased risk of diabetes, although the absolute risk of diabetes is low compared with the risk reduction benefit. Combination therapy including a statin may be appropriate for certain populations, but the risk reduction benefits of combination therapy remain unclear. Ezetimibe is an important treatment option for patients with hypercholesterolemia who do not tolerate intensive statin therapy. Although fibrates or niacin improves overall lipid profiles in patients with hypertriglyceridemia or dyslipidemia who are receiving statin therapy, their efficacy in reducing cardiovascular risk remains questionable and their use raises safety and tolerability concerns. CONCLUSIONS: Intensifying lifestyle changes and statin dose should be utilized first in patients not achieving their LDL-C and non-HDL-C goals. PMID- 23032653 TI - Safety of intravenous hypertonic saline administration in severe traumatic brain injury. PMID- 23032654 TI - Sunitinib- and sorafenib-induced nephrotic syndrome in a patient with gastrointestinal stromal tumor. AB - OBJECTIVE: To report a case of nephrotic syndrome (NS) induced by both sunitinib and sorafenib therapy. CASE SUMMARY: A 61-year-old woman with metastatic gastrointestinal stromal tumor (GIST) presented with NS and hypertension following therapy with sunitinib 400 mg/day. Because of grade 3 toxicity, the drug was discontinued. After sunitinib discontinuation, NS and hypertension resolved. However, NS recurred on rechallenge. A similar picture developed following therapy with sorafenib 800 mg/day. A renal biopsy revealed a focal segmental glomerulosclerosis (FSGS). A few months after sorafenib cessation, resolution of NS and hypertension was again achieved. DISCUSSION: Several cases of NS have been reported among patients receiving sunitinib and sorafenib. However, renal histopathologic data were obtained in only a few patients. Although biopsy-proven cases of FSGS associated with sunitinib have been reported, this is, to our knowledge, the first reported case of biopsy-proven FSGS associated with sorafenib. The Naranjo probability scale indicated probable causality for NS developing with sorafenib, and definite causality with sunitinib. The clinical and histopathologic findings have led us to agree with the class effect proposal that all antiangiogenic drugs share a similar toxicity profile. Evidence supporting this hypothesis includes worsening of hypertension and proteinuria by both drugs, with full recovery occurring within a few months after cessation of the drugs, which favors the role of vascular endothelial growth factor receptor inhibition in FSGS development. CONCLUSIONS: The clinical adverse spectrum of antiangiogenic drugs may be broader than initially observed because of a lack of renal biopsy data and routine screening for proteinuria. It can be speculated that proteinuria, as well as hypertension, is a class effect of all antiangiogenic drugs. PMID- 23032655 TI - Inhibitory metabolic drug interactions with newer psychotropic drugs: inclusion in package inserts and influences of concurrence in drug interaction screening software. AB - BACKGROUND: Food and Drug Administration (FDA) regulations mandate that package inserts (PIs) include observed or predicted clinically significant drug-drug interactions (DDIs), as well as the results of pharmacokinetic studies that establish the absence of effect. OBJECTIVE: To quantify how frequently observed metabolic inhibition DDIs affecting US-marketed psychotropics are present in FDA approved PIs and what influence the source of DDI information has on agreement between 3 DDI screening programs. METHODS: The scientific literature and PIs were reviewed to determine all drug pairs for which there was rigorous evidence of a metabolic inhibition interaction or noninteraction. The DDIs were tabulated noting the source of evidence and the strength of agreement over chance. Descriptive statistics were used to examine the influence of source of DDI information on agreement among 3 DDI screening tools. Logistic regression was used to assess the influence of drug class, indication, generic status, regulatory approval date, and magnitude of effect on agreement between the literature and PI as well as agreement among the DDI screening tools. RESULTS: Thirty percent (13/44) of the metabolic inhibition DDIs affecting newer psychotropics were not mentioned in PIs. Drug class, indication, regulatory approval date, generic status, or magnitude of effect did not appear to be associated with more complete DDI information in PIs. DDIs found exclusively in PIs were 3.25 times more likely to be agreed upon by all 3 DDI screening tools than were those found exclusively in the literature. Generic status was inversely associated with agreement among the DDI screening tools (odds ratio 0.11; 95% CI 0.01 to 0.89). CONCLUSIONS: The presence in PIs of DDI information for newer psychotropics appears to have a strong influence on agreement among DDI screening tools. Users of DDI screening software should consult more than 1 source when considering interactions involving generic psychotropics. PMID- 23032656 TI - Drug-related problems and hospital admissions in cardiac transplant recipients. AB - BACKGROUND: Drug-related problems (DRPs) in the general population account for 15% of all hospital admissions, of which approximately 30% are preventable. Cardiac transplant patients may be at increased risk for DRPs because of their complicated medication regimens that include drugs with a narrow therapeutic index. OBJECTIVE: To determine the incidence and preventability of DRPs causing hospital admission in cardiac transplant patients at a single institution. METHODS: Between November 2009 and January 2010, a prospective longitudinal study investigated the incidence and preventability of DRPs in a single cardiac transplant center. Three independent reviewers used validated scoring systems to determine the incidence and preventability of drug-related hospital admissions. DRPs were classified by type, pharmacologic class, and impact on length of stay. RESULTS: During the 3-month study period, 48 cardiac transplant patients were hospitalized. DRPs accounted for 40% (19/48) of these admissions and 58% (11/19) were adjudicated to be preventable. Common DRPs included supratherapeutic (32%) and subtherapeutic (16%) dosage, adverse drug reaction (32%), drug interaction (5%), and nonadherence (5%). Pharmacologic classes implicated included immunosuppressant (63%), antimicrobial (11%), electrolyte/fluid (11%), and anticoagulant (5%). Average length of stay in drug-related compared to non-drug related admissions was 11.4 versus 8.5 days (p = 0.458). When annualized, 44 hospitalizations or 500 hospital days may have been prevented. CONCLUSIONS: Hospital admissions following cardiac transplantation are often drug related (40%) and preventable (58%). Incorporating this insight into the multidisciplinary transplant team may improve outcomes, assist in meeting national quality mandates by the United Network for Organ Sharing and Centers for Medicare Services, and lead to new benchmarks for transplant centers. PMID- 23032657 TI - Teratogenic risk of statins in pregnancy. AB - OBJECTIVE: To evaluate the teratogenic potential of statins in women of child bearing age. DATA SOURCES: A PubMed search (1980-September 2012) was performed using the search terms statin and pregnancy, then repeated using statin and teratogenicity. Results were limited to articles published in English reporting on use of statins in humans. STUDY SELECTION AND DATA EXTRACTION: All articles presenting data on pregnancy outcomes after statin use during any trimester of pregnancy were included. Three case reports, 2 case series, 2 systematic reviews, 2 registry-based studies, and 1 prospective observational cohort study were reviewed. DATA SYNTHESIS: Since initial premarketing studies of lovastatin in animals, teratogenesis has been assumed to be a classwide function of statins' mechanism of action. Data from human exposure during pregnancy have been gathered and analyzed in a variety of study formats to formulate useable conclusions on statins' actual teratogenic risk and pattern of associated birth defects. Although the current trend is that actual risk is lower than once thought, the available literature is limited by potential reporting bias, contains overlap in the data, and frequently lacks numbers of total exposures to statins during pregnancy with reported malformations. Additionally, no human studies included data on the 2 newest statins (rosuvastatin, pitavastatin); the more lipophilic statins (lovastatin, simvastatin) have the most experience and thus have more evidence related to teratogenic potential. CONCLUSIONS: Human teratogenic risk has not been proven nor has it been ruled out by the available data on statin use in pregnancy. Possible differences in risk between individual statins require further evaluation. Additional data, including prospective observational cohorts with inadvertent maternal exposure to statins during early weeks of gestation, should further help to clarify appropriate recommendations for statin use in this population. PMID- 23032658 TI - Continuous infusion vancomycin for treatment of methicillin-resistant Staphylococcus aureus in cystic fibrosis patients. AB - OBJECTIVE: To report 3 cases of methicillin-resistant Staphylococcus aureus (MRSA) in pediatric patients with cystic fibrosis (CF), all of whom had inadequate serum concentrations of vancomycin with conventional intermittent dosing and who achieved therapeutic serum concentrations with continuous infusions of vancomycin. CASE SUMMARY: In the first case, a 3-year-old patient failed to achieve therapeutic vancomycin trough concentrations despite 2 dose adjustments up to 19 mg/kg every 6 hours. A continuous infusion was initiated and a therapeutic steady-state level was obtained. The remaining case reports describe 2 patients who were readmitted to the hospital after having received intermittent dosing as outpatients. Continuous infusions were started upon readmission, and therapeutic serum concentrations were achieved in both patients. DISCUSSION: MRSA is a common pathogen in patients with CF. Intravenous vancomycin, a time-dependent antibiotic that is extensively eliminated by the kidneys, is frequently used to treat MRSA infections. Serum trough concentrations of 15-20 mg/L are considered therapeutic, but these levels are difficult to achieve in patients with CF because of increased renal clearance. Continuous infusions of vancomycin were successfully used in the patients described here and resulted in decreased total daily doses of vancomycin, clinical improvement, and no evidence of nephrotoxicity. CONCLUSIONS: Although more extensive studies are necessary, the cases presented here suggest that continuous infusion vancomycin is a safe and convenient therapy for MRSA infections. PMID- 23032660 TI - Readministration of calcineurin inhibitors for ulcerative colitis. AB - BACKGROUND: Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have been shown to be effective for treatment of patients with steroid-dependent or steroid-refractory ulcerative colitis (UC) with moderate to severe activity. However, it has not been determined whether readministration of CNIs is effective in patients who experience relapse after remission induced by CNIs. OBJECTIVE: To determine the effect of readministration of CNIs in patients who had initially responded to CNIs. METHODS: A review of the medical records of 46 patients with moderate to severe UC who were treated with a CNI at a single tertiary teaching hospital with 840 beds was conducted. Remission was defined as a clinical activity index (CAI) score of 3 or less within 2 months of starting CNI therapy. Response was defined as a CAI score of 4 or higher but had decreased by half from the start of CNI therapy. Relapse was defined as flare-up of symptoms that required an additional treatment or colectomy. RESULTS: Of the 46 patients, 37 (80%) achieved clinical remission or response with the initial CNI treatment. Among those 37 patients, 19 experienced relapse (median duration to relapse, 6.4 months), 12 of whom were readministered a CNI. Of the 12 patients, 2 achieved clinical remission, 2 had a response, and the remaining 8 had no response to the CNI. In addition, all patients who responded to CNI readministration experienced relapse within 6 months. CNI readministration was significantly less effective than the initial administration for treatment of UC (80% vs 33%; p = 0.0014). CONCLUSIONS: Readministration of CNIs for relapse after remission with CNI treatment does not seem to be successful. Alternative therapies such as anti tumor necrosis factor antibody should be used or colectomy should be considered. PMID- 23032661 TI - Levoleucovorin as replacement for leucovorin in cancer treatment. AB - OBJECTIVE: To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether levoleucovorin would be a reasonable alternative to the use of racemic leucovorin. DATA SOURCES: A MEDLINE search was conducted for English language human studies published between January 1980 and April 2012 using the terms l-LV, levoleucovorin, d,l-LV, leucovorin, folinic acid, folinate, 5 formyltetrahydrofolate, folic acid, folates, methotrexate, 5-fluorouracil, and clinical trials. STUDY SELECTION AND DATA EXTRACTION: Articles pertinent to clinical trials (Phase 1, 2, 3) related to evaluating the efficacy, interchangeability, and safety of levoleucovorin were collected and their contents reviewed. DATA SYNTHESIS: From these pharmacokinetics and clinical studies, information on the use of levoleucovorin as a modulator of fluorouracil as well as when combined with other antitumor agents were scrutinized and extracted for comparison with leucovorin whenever possible. Two randomized Phase 3 clinical studies comparing the efficacy and adverse effect profiles of leucovorin and levoleucovorin demonstrated that levoleucovorin is as effective as leucovorin in terms of response, toxicity, and survival. Six randomized Phase 3 clinical studies demonstrated the safety and efficacy of levoleucovorin as a modulator of fluorouracil in combination with/without other antitumor agents in colorectal cancer patients. Levoleucovorin has been studied in other cancers. These clinical Phase 1/2/3 studies demonstrated efficacy and safety of levoleucovorin in combination chemotherapeutic regimens comprising fluorouracil and other antitumor agents. CONCLUSIONS: The results of the clinical studies suggest that levoleucovorin is efficacious and can be used safely in combination with fluorouracil and other antitumor agents. Levoleucovorin can be used interchangeably with leucovorin for modulating fluorouracil. The current shortage of the supply of leucovorin centered in North America renders levoleucovorin a reasonable alternative in terms of efficacy and toxicity profile, but from the perspective of cost, leucovorin remains the drug of choice. PMID- 23032662 TI - Reflections shared at white coat ceremonies. PMID- 23032663 TI - Experimental video analysis of eye blink reflex in a primate model. AB - BACKGROUND: The establishment of reliable methods for functional assessment in experimental models of peripheral nerve regeneration is crucial. METHODS: We present a straightforward method for video analysis of the eye blink reflex in a model of facial nerve damage in a nonhuman primate (Callithrix sp.). RESULTS: Our 6-level dynamic analysis demonstrated good reproducibility between independent observers, as measured by Cohen's kappa index. Our static analysis, which was based on 4 semiautomated metric parameters, showed low correlation during the early stage of facial movement recovery (the first and second weeks), but the correlation was excellent during the later stage of recovery (the third and fourth weeks). CONCLUSION: Altogether, our results establish a viable and readily accessible method with good reproducibility and correlation for the analysis of functional facial nerve recovery in an experimental model and based on video images of the eye blink reflex. PMID- 23032664 TI - Hearing preservation in management of epidermoids of the cerebellopontine angle: CPA epidermoids and hearing preservation. AB - OBJECTIVES: Surgical approaches for epidermoid cysts of the cerebellopontine angle (CPA) are dictated by tumor location. Previous reports have advocated the sacrifice of usable hearing to achieve maximal tumor resection in a single operation. The aim of the current study is to demonstrate the applicability of hearing preservation approaches in the neurotologic management of epidermoids of the CPA. STUDY DESIGN: Retrospective chart review. METHODS: A search of archived surgical cases at a single institution between January 1, 1997, and December 31, 2011, revealed 18 cases of epidermoid cysts involving the CPA. RESULTS: Eighteen patients with a mean age 40.9 years underwent surgery. Average tumor size was 4.47 cm, and presenting symptoms included headache, vertigo, cranial neuropathies, and seizures. Thirteen patients underwent a retrosigmoid approach, 2 translabyrinthine, 2 pterional, and 1 retrolabyrinthine/presigmoid. Complications included CSF leak, pseudomeningocele, meningitis, cranial nerve dysfunction, and persistent imbalance. All but 5 patients had long-term follow-up imaging to chronicle tumor residua/recurrence, varying from 6 to 149 months postoperatively. The average length of follow-up was 71.4 months, and residual tumor was common, with most patients demonstrating a focal or small area of residual tumor on follow-up imaging. Two patients had undergone previous surgery for epidermoid excision elsewhere. Two patients required reoperation for epidermoid regrowth, and the times between surgeries were 44 and 78 months. Of the patients who underwent a retrosigmoid approach, 9 had postoperative audiograms. All of these patients maintained hearing at or near their preoperative level except for 2 patients whose hearing declined and one whose hearing significantly improved. CONCLUSION: Hearing preservation approaches for epidermoids of the CPA is a feasible option for long-term control of these tumors. Resection from a retrosigmoid approach can provide years of useful hearing, and the majority of patients do not require reoperation. PMID- 23032665 TI - Allograft tympanoplasty: a historical perspective. AB - OBJECTIVE: To present the rise and decline of allograft tympanoplasty and investigate how the challenges it has faced may inform us of its future. DATA SOURCES: Articles and books published over the last 48 years that refer to allograft tympanoplasty or its historical roots. HISTORY: The first published account of allograft tympanoplasty is by Ned Chalat in 1964; however, whether he was the first to use the technique is controversial. In 1966, Jean Marquet published the first clinically successful use of allograft tympanic membranes. Since that time, a number of surgeons have trialed both en bloc tympano-ossicular techniques and tympanomeatal techniques with separate ossicle interposition or columellar reconstruction, often with considerable success. The advent of the human immunodeficiency virus and Creutzfeldt-Jakob's disease resulted in a reduction in its application; however, a number of centers are still successfully using the technique in their current practice. CONCLUSION: Whether allograft tympanoplasty will have a place in the future of otology remains to be seen, but an understanding of the history of this technique is essential in evaluating its merit. PMID- 23032667 TI - Structural evolution of amino acid crystals under stress from a non-empirical density functional. AB - Use of the non-local correlation functional vdW-DF (from 'van der Waals density functional'; Dion M et al 2004 Phys. Rev. Lett. 92 246401) has become a popular approach for including van der Waals interactions within density functional theory. In this work, we extend the vdW-DF theory and derive the corresponding stress tensor in a fashion similar to the LDA and GGA approach, which allows for a straightforward implementation in any electronic structure code. We then apply our methodology to investigate the structural evolution of amino acid crystals of glycine and l-alanine under pressure up to 10 GPa-with and without van der Waals interactions-and find that for an accurate description of intermolecular interactions and phase transitions in these systems, the inclusion of van der Waals interactions is crucial. For glycine, calculations including the vdW-DF (vdW-DF-c09x) functional are found to systematically overestimate (underestimate) the crystal lattice parameters, yet the stability ordering of the different polymorphs is determined accurately, at variance with the GGA case. In the case of l-alanine, our vdW-DF results agree with recent experiments that question the phase transition reported for this crystal at 2.3 GPa, as the a and c cell parameters happen to become equal but no phase transition is observed. PMID- 23032668 TI - Steady-state voltammetry at a microdisc electrode in the absence of excess supporting electrolyte for reversible, quasi-reversible and irreversible electrode kinetics. AB - The steady-state voltammetry for a one electron reduction, A + e(-) [symbol:see text] B, is studied at a microdisc electrode in the absence of excess supporting electrolyte. For the first time, the full voltammetric waveshape is numerically simulated. Using a combination of theory and experiment, the voltammetry is investigated as a function of two variables: the concentration of the supporting electrolyte and the electrochemical rate constant. The 'hemispherical approximation' (in which a microdisc is assumed to be a hemisphere of 2/pi the radius) is shown to be valid under weakly supported conditions, for a range of electrochemical rate constants (K0(r(e))/D(A) = 10(-3) - 10(3)). The simulations were used, in conjunction with the Debye-Huckel theory, to rationalise the experimental steady-state voltammetry of two aqueous redox couples: hexaammineruthenium ([Ru(NH(3))(6)](3+)/[Ru(NH(3))(6)](2+)) and hexachloroiridate ([IrCl(6)](2-)/[IrCl(6)](3-)) (each with varying levels of KCl supporting electrolyte). This investigation provides evidence for ion pairing between [IrCl(6)](2-)/[IrCl(6)](3-) and K(+) from the supporting electrolyte. No observable ion pairing occurs between [Ru(NH(3))(6)](3+)/[Ru(NH(3))(6)](2+) and Cl(-). PMID- 23032670 TI - Stenosis of a reconstructed aorta caused a paradoxical diastolic pressure gradient after norwood operation. AB - An infant with hypoplastic left heart syndrome showed paroxysmal episodes of bradycardia, hypotension, and hypoxemia upon crying after modified Norwood operation. Echocardiography showed decreased right ventricular ejection with grade III tricuspid regurgitation, a markedly enlarged aortic arch, and accelerated blood flow distal to the enlarged aorta. Aortography demonstrated an aneurysmal neo-aorta with an apple-shaped appearance. The pressure measurements revealed intriguing aortic hemodynamics: the diastolic pressure of the ascending aorta was lower than that of the descending aorta (42 mmHg vs. 52 mmHg) despite no systolic pressure gradient. Markedly reduced compliance in the ascending aorta relative to that in the descending aorta, which was suggested by the difference in time constant of aortic pressure decay, may explain this hemodynamics. Impaired coronary circulation caused by lowered diastolic pressure in ascending aorta was indicated by reduced subendocardial viability ratio, and may account for her symptom and lowered ventricular ejection. The patient's condition was indeed significantly improved by surgical correction of the aortic shape. This case highlights the importance of aortic shape and properties after Norwood operation. PMID- 23032671 TI - Status of stigma, 2012. PMID- 23032673 TI - Law & psychiatry: punishing juveniles who kill. AB - Punishment of juvenile murderers forces policy makers to weigh the developmental immaturity of adolescents against the heinousness of their crimes. The U.S. Supreme Court has progressively limited the severity of punishments that can be imposed on juveniles, holding that their impulsivity, susceptibility to peer pressure, and more fluid character render them less culpable for their actions. Having eliminated the death penalty as a punishment, the Court recently struck down mandatory life sentences without prospect of parole. The decision is interesting for its emphasis on rehabilitation, opening the door to further restrictions on punitive sentences for juveniles-and perhaps for adults too. PMID- 23032674 TI - Personal accounts: reaching out. PMID- 23032676 TI - The antipsychiatry movement: dead, diminishing, or developing? AB - It has been argued recently that the antipsychiatry movement has transmogrified into a patient-based consumer movement. Instead, the author suggests, various activities and ideas that legitimately could be described as antipsychiatry, or, at least, as highly critical of psychiatry, are burgeoning. These activities include the works of intellectual scholars, such as disgruntled psychiatrists, critical social scientists, and humanistic psychologists; the analyses and writings of high-profile and prominent investigative journalists; blogs, Web sites, and social media that communicate a disdain for psychiatry among citizen Internet activists; and the ongoing, well-documented critique of followers of Scientology. The author concludes that a renewed yet amorphous critique of psychiatry is emerging, even though the tarnished name of antipsychiatry is studiously avoided by all. This critique may intensify, given the likely media and public interest surrounding the upcoming release of DSM-5. PMID- 23032675 TI - Challenging the public stigma of mental illness: a meta-analysis of outcome studies. AB - OBJECTIVE: Public stigma and discrimination have pernicious effects on the lives of people with serious mental illnesses. Given a plethora of research on changing the stigma of mental illness, this article reports on a meta-analysis that examined the effects of antistigma approaches that included protest or social activism, education of the public, and contact with persons with mental illness. METHODS: The investigators heeded published guidelines for systematic literature reviews in health care. This comprehensive and systematic review included articles in languages other than English, dissertations, and population studies. The search included all articles from the inception of the databases until October 2010. Search terms fell into three categories: stigma, mental illness (such as schizophrenia and depression), and change program (including contact and education). The search yielded 72 articles and reports meeting the inclusion criteria of relevance to changing public stigma and sufficient data and statistics to complete analyses. Studies represented 38,364 research participants from 14 countries. Effect sizes were computed for all studies and for each treatment condition within studies. Comparisons between effect sizes were conducted with a weighted one-way analysis of variance. RESULTS: Overall, both education and contact had positive effects on reducing stigma for adults and adolescents with a mental illness. However, contact was better than education at reducing stigma for adults. For adolescents, the opposite pattern was found: education was more effective. Overall, face-to-face contact was more effective than contact by video. CONCLUSIONS: Future research is needed to identify moderators of the effects of both education and contact. PMID- 23032677 TI - Characteristics of adults with serious mental illness in the United States household population in 2007. AB - OBJECTIVE: This study described the epidemiology of serious mental illness in the adult household population. METHODS: Data from the 2007 National Health Interview Survey of 23,393 adult respondents were used. Serious mental illness was defined when respondents reported that a health professional had told them that they had schizophrenia, bipolar disorder, mania, or psychosis. Sociodemographic and health characteristics, health care utilization, and participation in government assistance programs among adults with and without serious mental illness were compared. RESULTS: Over 2% of adults reported having received a diagnosis of serious mental illness. Thirty-five percent of adults with serious mental illness had a history of homelessness or of having been in jail. Fewer than two-thirds of adults with serious mental illness had seen a mental health professional in the past year. CONCLUSIONS: Adults with serious mental illness were socially disadvantaged and had worse health compared with adults without serious mental illness. PMID- 23032678 TI - Evaluation of a mentoring program for PTSD clinic managers in the U.S. Department of Veterans Affairs. AB - OBJECTIVE: This evaluation study elicited feedback from participants in a novel program intended to help posttraumatic stress disorder (PTSD) clinical managers address organizational challenges in providing services and improving care. METHODS: Program participants were invited to respond to an online survey developed for this study; 46% (N=121) responded. RESULTS: Two-thirds of survey respondents had engaged in mentoring program activities ten or more times in the past six months. Roughly half the respondents reported that the program helped them be more connected to other clinics, learn about innovations in care, and feel more supported. Those who participated more often (beta=.25, p<.01) and rated their mentors highly (beta=.59, p<.01) reported greater benefits from the program. CONCLUSIONS: Mentees who were actively engaged with the mentoring program reported significant benefits. Efforts are under way to enhance the program by strengthening mentor selection and training. PMID- 23032679 TI - AHRQ review finds evidence of the effectiveness of collaborative care interventions. PMID- 23032681 TI - History of anesthesia for ambulatory surgery. AB - PURPOSE OF REVIEW: Anesthesia for ambulatory surgery has come a long way since 1842 when James Venable underwent surgery for removal of a neck mass with Crawford W. Long administering ether and also being the surgeon. We examine major advances over the past century and a half. RECENT FINDINGS: The development of anesthesia as a medical specialty is perhaps the single most important improvement that has enabled advances in the surgical specialties. Moreover, improved equipment, monitoring, training, evaluation of patients, discovery of better anesthetic agents, pain control, and the evolution of perioperative care are the main reasons why ambulatory anesthesia remains so safe in modern times. The development of less invasive surgical techniques, economic factors, and patient preferences provided addition impetus to the popularity of ambulatory surgery. SUMMARY: Beyond the discovery in the mid-19th century that ether and nitrous oxide could be used to render patients unconscious during surgical procedures, subsequent developments in our specialty have added modestly, in a stepwise manner, to reduce mortality and morbidity associated with its use. These improvements have allowed us to safely meet the steadily increasing demand for ambulatory surgery. PMID- 23032680 TI - Religious coping and quality of life among individuals living with schizophrenia. AB - OBJECTIVE: This study investigated the relationship between positive and negative religious coping and quality of life among outpatients with schizophrenia. METHODS: Interviews were conducted with 63 adults in the southeastern United States. Religious coping was measured by the 14-item RCOPE and quality of life by the World Health Organization Quality of Life-BREF. Data were examined via descriptive bivariate statistics and controlled analyses. RESULTS: Most participants reported participation in private religious or spiritual activities (91%) and participation in public religious services or activities (68%). Positive religious coping was related to the quality-of-life facet of psychological health (r=.28, p=.03). Negative religious coping and quality of life were inversely related (r=-.30, p=.02). Positive religious coping was associated with psychological health in the reduced univariate general linear model (B=.72, p=.03, adjusted R(2)=.08). CONCLUSIONS: Greater awareness of the importance of religion in this population may improve cultural competence in treatment and community support. PMID- 23032682 TI - Recovery after orthopedic surgery: techniques to increase duration of pain control. AB - PURPOSE OF REVIEW: Ambulatory surgery continues to expand in scope and volume. Part of this development is supported by improvements in anesthesia care, especially in the realm of postoperative analgesia, which is often outlasted by the pain. The purpose of this review is to outline methods of increasing the duration of postoperative pain control. RECENT FINDINGS: There have been recent advances in the use of perineural catheters for the performance of continuous nerve blocks, the use of adjuvants to extend the duration of single dose blocks, methods to improve the technical performance of blocks, systemic multimodal analgesia, and novel or experimental agents. SUMMARY: The ideas and findings described in this review are taken from the most recent literature and show promise of aiding in the continued improvement of patient care through their dissemination and refinement by further research. Of the modalities reviewed in current use, the continuous perineural catheter combined with systemic multimodal analgesics represents the best combination of safety and efficacy to provide prolonged postoperative analgesia. PMID- 23032683 TI - The worsening of tibialis anterior muscle atrophy during recovery post immobilization correlates with enhanced connective tissue area, proteolysis, and apoptosis. AB - Sustained muscle wasting due to immobilization leads to weakening and severe metabolic consequences. The mechanisms responsible for muscle recovery after immobilization are poorly defined. Muscle atrophy induced by immobilization worsened in the lengthened tibialis anterior (TA) muscle but not in the shortened gastrocnemius muscle. Here, we investigated some mechanisms responsible for this differential response. Adult rats were subjected to unilateral hindlimb casting for 8 days (I8). Casts were removed at I8, and animals were allowed to recover for 10 days (R1 to R10). The worsening of TA atrophy following immobilization occurred immediately after cast removal at R1 and was sustained until R10. This atrophy correlated with a decrease in type IIb myosin heavy chain (MyHC) isoform and an increase in type IIx, IIa, and I isoforms, with muscle connective tissue thickening, and with increased collagen (Col) I mRNA levels. Increased Col XII, Col IV, and Col XVIII mRNA levels during TA immobilization normalized at R6. Sustained enhanced peptidase activities of the proteasome and apoptosome activity contributed to the catabolic response during the studied recovery period. Finally, increased nuclear apoptosis prevailed only in the connective tissue compartment of the TA. Altogether, the worsening of the TA atrophy pending immediate reloading reflects a major remodeling of its fiber type properties and alterations in the structure/composition of the extracellular compartment that may influence its elasticity/stiffness. The data suggest that sustained enhanced ubiquitin-proteasome-dependent proteolysis and apoptosis are important for these adaptations and provide some rationale for explaining the atrophy of reloaded muscles pending immobilization in a lengthened position. PMID- 23032684 TI - Truncated variants of pig somatostatin receptor subtype 5 (sst5) act as dominant negative modulators for sst2-mediated signaling. AB - Somatostatin (SST) and its related peptide cortistatin (CORT) exert their multiple actions through binding to the SST receptor (sst) family, generally considered to comprise five G protein-coupled receptors with seven transmembrane domains (TMD), named sst1-sst5, plus a splice sst2B variant. However, we recently discovered that human and rodent sst5 gene expression also generates, through noncanonical alternative splicing, novel truncated albeit functional sst5 variants with less than seven TMD. Here, we cloned and characterized for the first time the porcine wild-type sst5 (psst5, full-length) and identified two novel truncated psst5 variants with six and three TMD, thus termed psst5TMD6 and psst5TMD3, respectively. In line with that observed in human and rodent truncated sst5 variants, psst5TMD6 and psst5TMD3 are functional (e.g., activate calcium signaling), selectively respond to SST and CORT, respectively, and exhibit specific tissue expression profiles that differ from full-length psst5 and often overlaps with psst2 expression. Moreover, fluorescence resonance energy transfer analysis shows that psst5 truncated variants physically interact with psst2, thereby altering their localization at the plasma membrane and specifically disrupting the cellular response to SST and/or CORT. These results represent the first characterization of a key porcine SST receptor, psst5, and, together with our previous results, provide strong evidence that alternative splicing-derived, truncated sst5 variants with distinct functional capacities exist in the mammalian lineage, where they can act as dominant-negative receptors, by interacting directly with long, seven TMD variants, potentially contributing to modulate normal and pathological SST and CORT signaling. PMID- 23032685 TI - Use of (2)H(2)O for estimating rates of gluconeogenesis: determination and correction of error due to transaldolase exchange. AB - The use of deuterated water as a method to measure gluconeogenesis has previously been well validated and is reflective of normal human physiology. However, there has been concern since the method was first introduced that transaldolase exchange may lead to the overestimation of gluconeogenesis. We examined the impact of transaldolase exchange on the estimation of gluconenogenesis using the deuterated water method under a variety of physiological conditions in humans by using the gluconeogenic tracer [U-(13)C]propionate, (2)H(2)O, and (2)H/(13)C nuclear magnetic resonance (NMR) spectroscopy. When [U-(13)C]propionate was used, (13)C labeling inequality occurred between the top and bottom halves of glucose in individuals fasted for 12-24 h who were weight stable (n = 18) or had lost weight via calorie restriction (n = 7), consistent with transaldolase exchange. Similar analysis of glucose standards revealed no significant difference in the total (13)C enrichment between the top and bottom halves of glucose, indicating that the differences detected were biological, not analytical, in origin. This labeling inequality was attenuated by extending the fasting period to 48 h (n = 12) as well as by dietary carbohydrate restriction (n = 7), both conditions associated with decreased glycogenolysis. These findings were consistent with a transaldolase effect; however, the resultant overestimation of gluconeogenesis in the overnight-fasted state was modest (7-12%), leading to an error of 14-24% that was easily correctable by using either a simultaneous (13)C gluconeogenic tracer or a correction nomogram generated from data in the present study. PMID- 23032686 TI - Autoimmune-mediated glucose intolerance in a mouse model of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against self-antigens such as double-stranded DNA and phospholipids. Classical comorbidities of SLE include glomerulonephritis, infection, cardiovascular disease, arthritis, skin disorders, and neurological disease. In addition to these classical comorbidities, there is emerging evidence that SLE patients are at higher risk of developing insulin resistance and other components of the metabolic syndrome. Visceral adipose tissue inflammation is a central mediator of insulin resistance in the obese setting, but the mechanism behind the pathogenesis of metabolic disease in the SLE patient population is unclear. We hypothesize that lupus-associated changes in the adaptive immune system are associated with disruption in glucose homeostasis in the context of SLE. To test this hypothesis, we assessed the metabolic and immunological phenotype of SLE-prone B6.SLE mice. B6.SLE mice fed a low-fat diet had significantly worsened glucose tolerance, increased adipose tissue insulin resistance, increased beta-cell insulin secretion, and increased adipocyte size compared with their respective B6 controls. Independently of diet, B cells isolated from the white adipose tissue of B6.SLE mice were skewed toward IgG production, and the level of IgG1 was elevated in the serum of SLE-prone mice. These data show that B6.SLE mice develop defects in glucose homeostasis even when fed a low-fat diet and suggest that B cells may play a role in this metabolic dysfunction. PMID- 23032687 TI - Insulin receptor regulates photoreceptor CNG channel activity. AB - Photoreceptor cyclic nucleotide gated (CNG) channels are critical elements in phototransduction and light adaptation. Here we report that insulin receptor (IR), an integral membrane protein, directly phosphorylates the CNGA1 subunit of CNG channels that in turn affects the function of these channels negatively. The IR phosphorylates Tyr(498) and Tyr(503) residues on CNGA1 that are situated at the membrane-cytoplasmic interface. The IR tyrosine kinase activity is essential for the inhibition of CNG channel. To maintain the channels in an off state, it is necessary not only to have a precise balance of the cGMP levels but also to have a control on the cGMP sensitivity of the CNG channels itself. In this study, we observed that the channel opens at a lower concentration of cGMP in IR(-/-) mice. These studies suggest that IR regulates the modulation of CNG channel activity in vivo. PMID- 23032688 TI - In vivo imaging of lipid storage and regression in diet-induced obesity during nutrition manipulation. AB - Changes in adipose tissue distribution and ectopic fat storage in, liver and skeletal muscle tissue impact whole body insulin sensitivity in both humans and experimental animals. Numerous mouse models of obesity, insulin resistance, and diabetes exist; however, current methods to assess mouse phenotypes commonly involve direct harvesting of the tissues of interest, precluding the possibility of repeated measurements in the same animal. In this study, we demonstrate that whole body 3-D imaging of body fat composition can be used to analyze distribution as well as redistribution of fat after intervention by repeated assessment of intrahepatocellular lipids (IHCL), intra-abdominal, subcutaneous, and total adipose tissue (IAT, SAT, and TAT) and brown adipose tissue (BAT). C57BL/6J mice fed a cafeteria diet for 16 wk were compared with mice fed standard chow for 16 wk and mice switched from cafe diet to standard chow after 12 wk. MRI determinations were made at 9 and 15 wk, and autopsy was performed at 16 wk. There was a strong correlation between MRI-calculated weights in vivo at 15 wk and measured weights at 16 wk ex vivo for IAT (r = 0.99), BAT (r = 0.93), and IHCL (r = 0.97). IHCL and plasma insulin increased steeply relative to body weight at body weights above 45 g. This study demonstrates that the use of 3-D imaging to assess body fat composition may allow substantial reductions in animal usage. The dietary interventions indicated that a marked metabolic deterioration occurred when the mice had gained a certain fat mass. PMID- 23032689 TI - Current is better than energy as predictor of success for biphasic defibrillatory shocks in a porcine model of ventricular fibrillation. AB - OBJECTIVE: The evidence that monophasic defibrillation success is mainly determined by current is secure. However, modern defibrillators use biphasic waveforms. The aim of this study was to compare energy, peak voltage and peak current in predicting biphasic shock success in a porcine model of ventricular fibrillation (VF) where the impedance varies within a wide of ranges. METHODS: In 14 domestic male pigs weighing between 27 and 38 kg, VF was electrically induced and untreated for 15 s. Animals were randomized to receive defibrillation attempts from one of two defibrillators with different impedance compensation methods. A grouped up-and-down defibrillation threshold testing protocol was used to maintain the average success rate in the neighborhood of 50%. After a recovery interval of 5 min, the testing sequence was repeated for a total of 60 test shocks for each animal. RESULTS: A high defibrillation success was observed when high peak current was delivered. The area under ROC curve for predicting shock success was 0.681 for peak current, 0.585 for peak voltage and 0.562 for energy. The odds ratio revealed that peak current was a better predictor (OR=1.321, p<0.001) for defibrillation outcome compared with energy (OR=0.979, p<0.001) and peak voltage (OR=1.000, p=0.69) when multivariable logistic regression was conducted. CONCLUSION: In this porcine model of VF within a wide range of transthoracic impedance, peak current was a better indicator for shock success than the currently used energy for biphasic defibrillatory shocks. This finding may encourage design of new current-based biphasic defibrillators. PMID- 23032691 TI - Image-verified deep brain stimulation reduces risk and cost with no apparent impact on efficacy. PMID- 23032690 TI - The prognostic value of continuous amplitude-integrated electroencephalogram applied immediately after return of spontaneous circulation in therapeutic hypothermia-treated cardiac arrest patients. AB - INTRODUCTION: The purpose of this study was to examine the prognostic value of continuous amplitude-integrated electroencephalogram (aEEG) applied immediately after return of spontaneous circulation (ROSC) in therapeutic hypothermia (TH) treated cardiac arrest patients. METHODS: From September 2010 to August 2011, we prospectively studied comatose patients treated with TH after cardiac arrest who were monitored with aEEG. Monitoring at the forehead was applied as soon as possible after ROSC in the emergency department and continued until recovery of consciousness, death, or 72 h after ROSC. Neurological outcome was assessed with the Cerebral Performance Category (CPC) scale at hospital discharge, and good neurological outcome was defined as a CPC score of 1 or 2. RESULTS: A total of 55 TH-treated patients were included. Monitoring started at a median of 96 min after ROSC (interquartile range, 49-174). At discharge, 28 patients had a CPC of 1-2, and 27 patients had a CPC of 3-5. Seventeen patients had a continuous normal voltage (CNV) trace at the start of monitoring, and this voltage was strongly associated with a good outcome (16/17 [94.1%]; sensitivity and specificity of 57.1 and 96.3%, respectively). No development of a CNV trace within the recorded period accurately predicted a poor outcome (21/21 [100%]; sensitivity and specificity of 77.8 and 100%, respectively). CONCLUSIONS: An initial CNV trace in aEEG applied to forehead immediately after ROSC is a good early predictor of a good outcome in TH-treated cardiac arrest patients. Conversely, no development of a CNV trace within 72h is an accurate and reliable predictor of a poor outcome with a false-positive rate of 0%. PMID- 23032693 TI - Distinct patterns of gained chromosomes in high hyperdiploid acute lymphoblastic leukemia with t(1;19)(q23;p13), t(9;22)(q34;q22) or MLL rearrangements. PMID- 23032692 TI - Safety and efficacy of pralatrexate in the management of relapsed or refractory peripheral T-cell lymphoma. AB - Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas, with generally poor prognosis. Historically, there has been a lack of consensus regarding appropriate therapeutic measures for the disease, with conventional frontline chemotherapies being utilized in most cases. Following promising results obtained in 2009, the methotrexate analogue, pralatrexate, became the first drug to gain US FDA approval for the treatment of refractory PTCL. This antimetabolite was designed to have a higher affinity for reduced folate carrier (RFC) and folylpolyglutamate synthetase (FPGS). RFC is the principal transporter for cell entrance of folates and antifolates. Once inside the cell, pralatrexate is efficiently polyglutamated by FPGS. Pralatrexate has demonstrated varying degrees of efficacy in peripheral T-cell lymphoma, with response rates differing between the multiple subtypes of the disease. While phase III studies are still to be completed, early clinical trials indicate that pralatrexate is promising new therapeutic for PTCL. PMID- 23032694 TI - Randomized, dose-escalation study of the p38alpha MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome. PMID- 23032695 TI - High-throughput sequencing identifies an NFIA/CBFA2T3 fusion gene in acute erythroid leukemia with t(1;16)(p31;q24). PMID- 23032696 TI - Intrinsic crystal phase separation in the antiferromagnetic superconductor Rb(y)Fe(2-x)Se2: a diffraction study. AB - The crystal and magnetic structures of the superconducting iron-based chalcogenides Rb(y)Fe(2-x)Se(2) have been studied by means of single-crystal synchrotron x-ray and high-resolution neutron powder diffraction in the temperature range 2-570 K. The ground state of the crystal is an intrinsically phase-separated state with two distinct-by-symmetry phases. The main phase has the iron vacancy ordered ?5 * ?5 superstructure (I4/m space group) with AFM ordered Fe spins. The minority phase does not have ?5 * ?5-type of ordering and has a smaller in-plane lattice constant a and larger tetragonal c-axis and can be well described by assuming the parent average vacancy disordered structure (I4/mmm space group) with the refined stoichiometry Rb(0.60(5))(Fe(1.10(5))Se)(2). The minority phase amounts to 8-10% mass fraction. The unit cell volume of the minority phase is 3.2% smaller than the one of the main phase at T = 2 K and has quite different temperature dependence. The minority phase merges with the main vacancy ordered phase on heating above the phase separation temperature T(P) = 475 K. The spatial dimensions of the phase domains strongly increase above T(P) from 1000 to >2500 A due to the integration of the regions of the main phase that were separated by the second phase at low temperatures. Additional annealing of the crystals at a temperature T = 488 K, close to T(P), for a long time drastically reduces the amount of the minority phase. PMID- 23032697 TI - Reactive deposition of nano-films in deep polymeric microcavities. AB - We report the controlled diffusion of gas-phase high-reactivity chemical species into long polymeric microcavities to form glass-like, low-permeability barrier films on the interior surfaces of the microcavities. Reactive species created from fragmentation of O(2) and hexamethyldisiloxane (HMDSO) in a radio-frequency (RF) plasma environment are allowed to diffuse into the microcavities of polydimethylsiloxane (PDMS), where surface reactions lead to the formation of an effective, glass-like thin-film barrier. Reactive species including silicon radicals and elemental oxygen maintain their reactivity for sufficient times (up to 7000 s) and survive the random diffusional walk through the microcavities to form glass barriers as much as 65 mm from the cavity entrance. The barrier thickness and the growth length can be controlled by the reaction time and chamber operating pressure. Increasing the cross sectional area of the cavity inlet and/or decreasing the mean free path was found to increase the thickness of the barrier film. Optical emission spectroscopic analysis was used to characterize the reactive fragments formed from HMDSO, and energy-dispersive X ray analysis revealed that the barrier composition is consistent with oxides of silicon (SiO(x)). Formed inside PDMS microcavities, the glass barrier blocks the penetration or absorption of small molecules such as rhodamine B (RhB) and biotin, and also resists permeation of organic solvents such as toluene, preventing the PDMS microfluidic structures from swelling and deforming. Moreover, formation of glass-like thin films in PDMS microcavities enhances the stability of electroosmotic flow (EOF) relative to uncoated PDMS devices, in which EOF instabilities are significant; this enables separation by electrophoresis with reproducibility (relative standard deviation 3%, n = 5) and baseline peak resolution (R:1.3) comparable to that obtained in conventional fused-silica capillaries. PMID- 23032698 TI - The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic non-obese type 2 diabetic rats: a differential role of unfolded protein response (UPR) signaling proteins. AB - It has been well demonstrated that excessive blood glucose level could be detrimental to the myocardial function through the variety of mechanisms, of which endoplasmic reticulum stress (ERS) could play an unprecedented role through the activation of unfolded protein response (UPR). Recently, reports are coming out with the evidences that UPR signaling proteins are regulated differentially depend on the experimental conditions and cell types. In addition, ERS has been proposed to be closely associated with the regulation of lipogenesis. Therefore, in this study we tried to find out the expressions of myocardial UPR signaling proteins as well as proteins involved in lipid and glucose metabolism in non obese type 2 diabetic mellitus (DM) condition using Spontaneous Diabetic Torii (SDT) rat. We have found the significant up-regulation of oxidative, nitrosative and ERS marker proteins in the myocardium of the SDT rats, in comparison to its normal (Sprague-Dawley - SD) rats. In addition, the sub-arm of UPR signaling proteins, such as p-PERK, p-eIF2alpha, ATF6, CHOP/GADD153, TRAF2, apoptotic signaling proteins, such as BAD, cytochrome C, cleaved caspase-7 and -12, were significantly up-regulated in the SDT rats, in comparison to the SD rats. Interestingly, there were no significant changes in the phosphorylation of IRE 1alpha, and XBP-1 protein expression. In addition, the proteins involved in lipid and glucose metabolisms, such as PPARalpha, PPARgamma, CPT1, PGC-1alpha except GLUT4, and the proteins involved in insulin signaling, such as p-Akt and p-PI3K were shown significant attenuation in its expressions in the SDT rats, when compared with the SD rats. Taken together, it is suggested that the activation of PERK and ATF6 pathway are the major determinant rather than the IRE-1alpha-XBP1 pathway for the ERS-mediated metabolic dysfunction, which might eventually leads to diabetic cardiomyopathy in non-obese type 2 DM. PMID- 23032699 TI - Suppression of PRMT6-mediated arginine methylation of p16 protein potentiates its ability to arrest A549 cell proliferation. AB - The tumor suppressor p16(INK4A) (p16) blocks the cell cycle progression by inhibiting phosphorylation of the retinoblastoma protein. We describe here a novel aspect of the posttranslational control that has an important functional consequence on p16 protein. We first discovered that the p16 protein was methylated in various cell lineages. We then determined that the arginine 22, 131 and 138 of p16 were the main methylation sites. Western blotting and TUNEL analyses revealed that the p16 protein bearing these point mutations induced a higher apoptosis ratio than wild-type p16 in A549 cells. Furthermore, co immunoprecipitation assays suggested that decrease of p16 arginine methylation level promoted the association of p16 with CDK4. Additionally, we determined that the protein arginine methyltransferase 6 (PRMT6) was responsible for the p16 arginine methylation. Results from flow cytometric analysis demonstrated that PRMT6 overexpression counteracted the cell cycle arrest at G1 phase induced by wild-type p16 in A549 cells. We also provided evidence that PRMT6 was able to interact with p16, and that the intensity of p16-CDK4 association was reduced upon PRMT6 overexpression. Together, data presented in this report establish that methylation at specific arginine residues of p16 protein by PRMT6 may be critical for the activity of p16. PMID- 23032700 TI - Phospholipase D activation mediates cobalamin-induced downregulation of Multidrug Resistance-1 gene and increase in sensitivity to vinblastine in HepG2 cells. AB - Failure of cancer chemotherapy due to multidrug resistance is often associated with altered Multidrug Resistance-1 gene expression. Cobalamin is the cofactor of methionine synthase, a key enzyme of the methionine cycle which synthesizes methionine, the precursor of cell S-adenosyl-methionine synthesis. We previously showed that cobalamin was able to down-regulate Multidrug Resistance-1 gene expression. Herein we report that this effect occurs through cobalamin-activation of phospholipase D activity in HepG2 cells. Cobalamin-induced down-regulation of Multidrug Resistance-1 gene expression was similar to that induced by the phospholipase D activator oleic acid and was negatively modulated by the phospholipase D inhibitor n-butanol. Cobalamin increased cell S-adenosyl methionine content, which is the substrate for phosphatidylethanolamine methyltransferase-dependent phosphatidylcholine production. We showed that cobalamin-induced increase in cell phosphatidylcholine production was phosphatidylethanolamine-methyltransferase-dependent. Oleic acid-dependent activation of phospholipase D was accompanied by an increased sensitivity to vinblastine of HepG2 cells while n-butanol enhanced the resistance of the cells to vinblastine. These data indicate that cobalamin mediates down-regulation of Multidrug Resistance-1 gene expression through increased S-adenosyl-methionine and phosphatidylcholine productions and phospholipase D activation. This points out phospholipase D as a potential target to down-regulate Multidrug Resistance-1 gene expression for improving chemotherapy efficacy. PMID- 23032701 TI - Ex vivo measures of muscle mitochondrial capacity reveal quantitative limits of oxygen delivery by the circulation during exercise. AB - Muscle mitochondrial respiratory capacity measured ex vivo provides a physiological reference to assess cellular oxidative capacity as a component in the oxygen cascade in vivo. In this article, the magnitude of muscle blood flow and oxygen uptake during exercise involving a small-to-large fraction of the body mass will be discussed in relation to mitochondrial capacity measured ex vivo. These analyses reveal that as the mass of muscle engaged in exercise increases from one-leg knee extension, to 2-arm cranking, to 2-leg cycling and x-country skiing, the magnitude of blood flow and oxygen delivery decrease. Accordingly, a 2-fold higher oxygen delivery and oxygen uptake per unit muscle mass are seen in vivo during 1-leg exercise compared to 2-leg cycling indicating a significant limitation of the circulation during exercise with a large muscle mass. This analysis also reveals that mitochondrial capacity measured ex vivo underestimates the maximal in vivo oxygen uptake of muscle by up to ~2-fold. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. PMID- 23032702 TI - Assessment of a three-dimensional line-of-response probability density function system matrix for PET. AB - To achieve optimal PET image reconstruction through better system modeling, we developed a system matrix that is based on the probability density function for each line of response (LOR-PDF). The LOR-PDFs are grouped by LOR-to-detector incident angles to form a highly compact system matrix. The system matrix was implemented in the MOLAR list mode reconstruction algorithm for a small animal PET scanner. The impact of LOR-PDF on reconstructed image quality was assessed qualitatively as well as quantitatively in terms of contrast recovery coefficient (CRC) and coefficient of variance (COV), and its performance was compared with a fixed Gaussian (iso-Gaussian) line spread function. The LOR-PDFs of three coincidence signal emitting sources, (1) ideal positron emitter that emits perfect back-to-back gamma rays (gammagamma) in air; (2) fluorine-18 (18F) nuclide in water; and (3) oxygen-15 (15O) nuclide in water, were derived, and assessed with simulated and experimental phantom data. The derived LOR-PDFs showed anisotropic and asymmetric characteristics dependent on LOR-detector angle, coincidence emitting source, and the medium, consistent with common PET physical principles. The comparison of the iso-Gaussian function and LOR-PDF showed that: (1) without positron range and acollinearity effects, the LOR-PDF achieved better or similar trade-offs of contrast recovery and noise for objects of 4 mm radius or larger, and this advantage extended to smaller objects (e.g. 2 mm radius sphere, 0.6 mm radius hot-rods) at higher iteration numbers; and (2) with positron range and acollinearity effects, the iso-Gaussian achieved similar or better resolution recovery depending on the significance of positron range effect. We conclude that the 3D LOR-PDF approach is an effective method to generate an accurate and compact system matrix. However, when used directly in expectation-maximization based list-mode iterative reconstruction algorithms such as MOLAR, its superiority is not clear. For this application, using an iso Gaussian function in MOLAR is a simple but effective technique for PET reconstruction. PMID- 23032704 TI - [Treatment of lithiasis with infundibular axis at an acute angle to the calyx entry in PCNL]. AB - INTRODUCTION: In the treatment of pyelo multi calyceal renal lithiasis, although we utilize both rigid and flexible instruments, the greatest challenge when trying to achieve a stone-free status after the procedure with a single access, is represented by the presence of residual caliceal stones difficult to reach for the length of the infundibular system in which they are localized, and major axis of it at an acute angle with respect to the axis of the cannula entrance. We describe our technique of treatment in these cases with no second access. MATERIALS AND METHODS: 55 cases of multiple lithiasis of the lower calyx at the end of PCNL for complex lithiasis were treated with the following technique. Using ultrasound and fluoroscopic guidance a puncture of the calyx adjacent to the cannula was performed. A standard Lubriglide guide (0.038", right or J) was introduced until the renal pelvis. Through a nephroscopic guidance, the guide was retrieved with a clamp and was taken out from the cannula; then the two leaders were locked together by a mosquito-mounted clamp. The guide traction towards the cannula allowed identifying, through the rigid nephroscope, the infundibulum where the lithiasis was located. The infundibulum was sectioned with monopolar electrode and it was possible to access the calyx affected by the lithiasis. RESULTS: In all treated cases it was possible to reach the lithiasis from the single initial percutaneous access and to eliminate them. Small bleedings were dominated by monopolar electrode. The Urography or uro-CT performed after three months showed no residual lithiasis; the infundibulum resumed its morphological characteristics. DISCUSSION: The described technique allows for a complete resolution of the lithiasis with no need of a second access or a retrograde approach, in situations where the combined use of flexible instruments does not allow solving the pathology. PMID- 23032705 TI - [Use of TachoSil in laparoscopic enucleoresection of renal masses smaller than 4 cm: our preliminary experience of 41 cases]. AB - INTRODUCTION: In nephron-sparing surgery the use of new and various hemostatic materials has provided a significant support in the control of intraoperative hemostasis of resection bed. Objective of this study is to demonstrate the use of hemostatic material TachoSil in laparoscopic treatment of renal masses <4 cm. MATERIALS AND METHODS: 41 patients underwent laparoscopic renal enucleoresection. In all patients one or more hemostatic TachoSil sponges were used, affixed to the bed of resection; we retrospectively evaluated the efficacy and safety of this technique. Transperitoneal access in 39 patients with antero-lateral mass and retroperitoneoscopic access in 2 patients with middle-posterior mass. After performing a warm ischemia, we proceeded to mass enucleoresection by cold blade, and to hemostasis control by suturing open vessels on the resection bed with "central suturing" technique. After unclamping the renal artery, one or more hemostatic sponges of TachoSil were always used (fibrinogen and human thrombin) affixed to the bed section. RESULTS: No significant variations of Hb, BUN and Crs. 3 cases (6.9% of renal units) of intraoperative hemorrhage requesting blood transfusion, 2 cases (4.6% of renal units) of urinary leakage at low pressure, treated conservatively with retrograde application of ureteral stent DJ for 21 days; 2 patients underwent new laparoscopy and suture. The mean time to hemostasis, evaluated in terms of the absence of macroscopic intraoperative bleeding after the application of TachoSil, was 5.5 (3-16) minutes. Average hospital stay: 5.5 (4-11) days. FOLLOW-UP: 37.6 (5-84) months. DISCUSSION: The control of hemostasis is the key problem inherent to laparoscopic technique and can be approached using hemostatic agents. Currently hemostatic agents such as TachoSil (r) are used increasingly as an adjuvant agent in the control of bleeding, having an excellent application in laparoscopic renal enucleoresection, and proving safe and effective in the treatment of tumors below 4 cm. PMID- 23032706 TI - [Endoscopic combined intra renal surgery (ECIRS) in prone position]. AB - INTRODUCTION: E.C.I.R.S. is currently used in Galdakao-modified supine Valdivia position, since it is thought to be capable of allowing the retrograde approach to the high urinary diseases. Our school developed some good experience in percutaneous procedures in the prone position, with no significant anesthetic complications; we have performed an evaluation of flexible retrograde endoscopy with percutaneous nephrolithotripsy in this position. MATERIALS AND METHODS: 21 patients (14 M - 7 F), with a mean age 44.5 years (range 27-62), with complex urolithiasis, underwent percutaneous nephrolithotripsy associated with flexible retrograde endoscopy (E.C.I.R.S.) in the prone position. The technique has followed these steps: patient's positioning in the prone position; flexible cystoscopy and insertion of guide 0.038" stiff Lubriglide flexible tip; ureteral sheath 11/13 Ch until the lumbar ureter; fixing the end of the sheath to the surgical drape with sutures or surgical instrument; catheter Nelaton transurethral 10 Ch to the side of the sheath; renal puncture and routine procedure for the nephrolithotripsy assisted by the flexible instrumentation by retrograde approach. The procedure ended with the application of a Re-entry Malecot nephrostomy tube (Boston Scientific). RESULTS: The ureteral sheath was easily applicable in the prone position for all patients, with no difference between males and females; its presence made it easier to enter and the progression of the flexible instrument by retrograde approach. Idem come sopra. There was no lengthening of operative time associated with retrograde instrumentation. The "stone free" status was obtained in 100% of cases. There were no complications. DISCUSSION: The stabilized ureteral sheath allows for the comfortable and secure combined endorenal prone procedure, with flexible instruments both in men and women, through a safe and effective technique. PMID- 23032707 TI - The stereochemical outcome of allyl magnesium and indium additions to 5 substituted norbornen-7-ones and its application to cis fused carbocycle formation via ring rearrangement metathesis. AB - The addition of allyl magnesium and allyl indium reagents to a key TBS protected norbornenyl building block, synthesised in 6-steps from commercially available 1,1-dimethoxy-2,3,4,5-tetrachlorocyclopentadiene, has been achieved providing the syn addition products with high diastereoselectivity. The subsequent exposure of the addition products to metathesis conditions, in the presence of ethene, then provided cis fused[3.0.3]-carbocycles with very high regioselectivity, via a Ring Rearrangement Metathesis (RRM) transformation. PMID- 23032708 TI - Hearing impairment in Parkinson's disease: expanding the nonmotor phenotype. AB - The objective of this study was to evaluate hearing impairment in patients affected by Parkinson's disease compared with hearing scores observed in normal age- and sex-matched controls. One hundred eighteen consecutive patients with a clinical diagnosis of Parkinson's disease were screened. Severity of motor symptoms and staging were measured with the Unified Parkinson's Disease Rating Scale (section III) and the Hoehn and Yahr scale. Audiometric evaluation consisted of a comprehensive audiologic case history and questionnaire, visual otoscopic examination, acoustic immittance measures (tympanogram and acoustic reflexes), pure tone audiometry, and measurement of brain stem auditory-evoked potentials. Healthy age- and sex-matched subjects were selected as the control group. One hundred six of 118 patients were enrolled. Pure tone audiometry revealed age-dependent high-frequency hearing loss in patients with Parkinson's disease compared with both normative values and values for healthy age- and sex matched controls (75/106 [71%], chi(2) = 5.959, P = .02; 92/106 [86.8%] vs 60/106 [56.6%], chi(2) = 23.804, P < .001, respectively). Pure tone audiometry scores correlated with Hoehn and Yahr scale scores (P < .05). Brain stem auditory-evoked potentials were normal in all patients. Our patients with Parkinson's disease showed age-dependent peripheral, unilateral, or bilateral hearing impairment. Whether these auditory deficits are intrinsic to Parkinson's disease or secondary to a more complex impaired processing of sensorial inputs occurring over the course of illness remains to be determined. Because alpha-synuclein is located predominately in the efferent neuronal system within the inner ear, it could affect susceptibility to noise-induced hearing loss or presbycusis. It is feasible that the natural aging process combined with neurodegenerative changes intrinsic to Parkinson's disease might interfere with cochlear transduction mechanisms, thus anticipating presbycusis. PMID- 23032709 TI - Physisorption of nucleobases on graphene: a comparative van der Waals study. AB - The physisorption of the nucleobases adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) on graphene is studied using several variants of the density functional theory (DFT): the generalized gradient approximation with the inclusion of van der Waals interaction (vdW) based on the TS approach (Tkatchenko and Scheffer 2009 Phys. Rev. Lett. 102 073005) and our simplified version of this approach (here called sTS), the van der Waals density functional vdW-DF (Dion et al 2004 Phys. Rev. Lett. 92 246401) and vdW-DF2 (Lee et al 2010 Phys. Rev. B 82 081101), and DFT-D2 (Grimme 2006 J. Comput. Chem. 27 1787) and DFT-D3 (Grimme et al 2010 J. Chem. Phys. 132 154104) methods. The binding energies of nucleobases on graphene are found to be in the following order: G > A > T > C > U within TS, sTS, vdW-DF, and DFT-D2, and in the following order: G > A > T ~ C > U within DFT D3 and vdW-DF2. The binding separations are found to be different within different methods and in the following order: DFT-D2 < TS < DFT-D3 ~ vdW-DF2 < vdW-DF. We also comment on the efficiency of combining the DFT-D approach and vdW DF to study systems with van der Waals interactions. PMID- 23032710 TI - Crystal structures and emitting properties of trifluoromethylaminoquinoline derivatives: thermal single-crystal-to-single-crystal transformation of polymorphic crystals that emit different colors. AB - 2,4-Trifluoromethylquinoline (TFMAQ) derivatives that have amine (1), methylamine (2), phenylamine (3), and dimethylamine (4) substituents at the 7-position of the quinoline ring were prepared and crystallized. Six crystals including the crystal polymorphs of 2 (crystal GB and YG) and 3 (crystal B and G) were obtained and characterized by X-ray crystallography. In solution, TFMAQ derivatives emitted relatively strong fluorescence (lambda(max)(f)=418-469 nm and Phi(f)(s)=0.23 0.60) depending on the solvent polarity. From Lippert-Mataga plots, DeltaMU values in the range of 7.8-14 D were obtained. In the crystalline state, TFMAQ derivatives emitted at longer wavelengths (lambda(max)(f)=464-530 nm) with lower intensity (Phi(f)(c)=0.01-0.28) than those in n-hexane solution. The polymorphous crystals of 2 and 3 emitted different colors: 2, lambda(max)(f)=470 and 530 nm with Phi(f)(c)=0.04 and approximately 0.01 for crystal GB and YG, respectively; and 3, lambda(max)(f)=464 and 506 nm with Phi(f)(c)=0.28 and approximately 0.28 for crystal B and G, respectively. In both crystal polymorphs of 2 and 3, crystals GB and G showed emission color changes by heating/melting/cooling cycles that were representative. By following the color changes in heating at the temperature below the melting point with X-ray diffraction measurements and X-ray crystallography, the single-crystal-to-single-crystal transformations from crystal GB to YG for 2 and from crystal B to G for 3 were revealed. PMID- 23032711 TI - Medical therapy for peripheral arterial disease. AB - PURPOSE OF REVIEW: Peripheral arterial disease (PAD) is underdiagnosed, undertreated, and increasing in prevalence. Continued advances in understanding atherosclerosis, pathophysiology of vascular disease and risk factor modification emphasize the importance of a complete medical regimen. With the recently changed guidelines for PAD suggesting screening patients at an earlier age and the known benefits of using preventive therapies for PAD, this is the perfect time to review recent information and research on medical therapy for PAD, both for symptomatic patients and for secondary prevention. RECENT FINDINGS: PAD is a manifestation of systemic atherosclerosis. With the recent update of the ACC/AHA guidelines for the management of PAD, risk factor modification continues to be a major focus. Smoking is one of the most important modifiable risk factors in patients with PAD. New recommendations and therapeutic options exist for assisting patients in smoking cessation. Additionally, new evidence continues to support controlling hypertension, controlling lipids and use of antiplatelet agents. Evidence continues to evolve about the evidence of exercise therapy in symptomatic and asymptomatic PAD. SUMMARY: PAD is associated with increased risk of cardiovascular morbidity and mortality. Medical therapy is targeted toward systemic atherosclerosis and risk factor modification. Exercise therapy is the most studied and validated therapy for symptomatic peripheral arterial disease. PMID- 23032712 TI - Endoleaks after endovascular abdominal aortic aneurysm repair: what one needs to know. AB - PURPOSE OF REVIEW: To review the current state of diagnosis, treatment, and outcomes of the different types of endoleaks after endovascular abdominal aortic aneurysm repair (endovascular aneurysm repair, EVAR). RECENT FINDINGS: Endoleaks are the most frequent complication after EVAR, the most common indication for secondary interventions, and the most common cause of rupture after EVAR. Imaging is critical for detecting endoleaks. Type I and III endoleaks require urgent intervention to prevent aneurysm rupture. Intervention for other endoleaks or endotension is indicated if the aneurysm sac continues to grow during follow-up. The majority of endoleaks can be treated with endovascular techniques. Open surgical conversion may be considered if the risk of aneurysm rupture is high and if no endovascular options are available or if they have failed. SUMMARY: Endoleaks continue to be a challenge and this article discusses the different treatment options for endoleaks after EVAR. Long-term follow-up after EVAR is required to diagnose and treat endoleaks before they result in aneurysm rupture. The majority of endoleaks can be treated with endovascular techniques, although open surgical interventions may be required in selected patients. PMID- 23032713 TI - Optimal selection of STEMI treatment strategies in the current era: benefit of transferring STEMI patients for PCI compared with administration of onsite fibrinolytic therapy. AB - PURPOSE OF REVIEW: For patients presenting with ST-elevation myocardial infarction (STEMI), primary percutaneous coronary intervention (PPCI) is superior to onsite fibrinolytic therapy (O-FT) when administered in a timely fashion. This benefit diminishes as PCI-related delay increases. This review examines recent data exploring this relationship, offering insight into possible mechanisms for the time-dependent benefit of PCI. RECENT FINDINGS: The advantage of transfer for primary PCI (X-PCI) over O-FT was analyzed in a contemporary propensity-score matched cohort by evaluating outcomes based on PCI-related delay (door-to-balloon time minus door-to-needle time). In 19 012 matched STEMI patients from the National Registry of Myocardial Infarction database, the delay to PCI wherein the mortality advantage for X-PCI was nullified compared with O-FT was approximately 120 min. Extensive delays were found to attenuate the mortality benefit of X-PCI [number needed to treat (NNT) 23 for PCI-related delay >60 min; NNT 44 for PCI related delay 60-90 min; and NNT 250 for PCI-related delay >90 min]. SUMMARY: The benefit of PCI over O-FT appears to markedly decrease as PCI-related delay increases, particularly in the case of interhospital transfer, which can often lead to long reperfusion times. Various strategies can reduce PCI-related delays, including the establishment of STEMI systems of care and regionalization. Furthermore, alternate pharmacoinvasive strategies should be considered when significant delay to PCI is anticipated. PMID- 23032714 TI - Impact of in-hospital major bleeding on outcomes in acute coronary syndromes. AB - PURPOSE OF REVIEW: To describe the hazard of in-hospital major bleeding after acute coronary syndromes. RECENT FINDINGS: Long-term complications of early bleeding can extend to over 3 years beyond the index event. Nonaccess-site bleeding accounts for much of the higher risk associated with major in-hospital bleeding. SUMMARY: Bleeding complications after percutaneous coronary intervention are a consistent and independent predictor of adverse clinical outcomes. The majority of complications associated with major bleeding are attributable to in-hospital early bleeds. Whether the link between bleeding and increased mortality is causal has not been established. Bleeding may simply be a marker of higher comorbidity. When possible, bleeding should be avoided, and strategies such as use of risk scores, bivalirudin, vascular closure devices and radial access may decrease major bleeding. In the highest-risk patients, however, bleeding avoidance strategies may not be effective. PMID- 23032715 TI - Large vessel vasculitides: update for the cardiologist. AB - PURPOSE OF REVIEW: To evaluate new developments in the diagnosis and management of large vessel vasculitis, and to explore its relationship to atherosclerosis. RECENT FINDINGS: Although large vessel inflammatory disorders (giant cell arteritis and Takayasu arteritis) are the most common form of systemic vasculitis in adults, they remain incompletely understood and represent a challenge for rheumatologists and cardiologists. Diagnostic strategies rely on obtaining representative histological evidence of disease, or on using effective imaging techniques, that are only now being defined. The natural history of some of these conditions, such as Takayasu arteritis, includes a very long period of low level symptoms or even no symptoms, so that the diagnosis is made at an advanced stage of disease in many cases. Development of a robust system for evaluating disease activity is required in order to test the effectiveness of different therapies, ideally based on our understanding of their pathogenesis. A relatively newly recognized condition of IgG4-related disease includes inflammatory large vessel disease in a substantial number of cases; furthermore, better imaging techniques are being used to recognize the presence of isolated aortitis in patients with unexplained systemic disease. Long-term vascular complications are increasingly recognized, and this is blurring the margin between atherosclerosis and vasculitis, which may improve our understanding of both these conditions. SUMMARY: Large vessel vasculitis is the most common primary vasculitis. Better imaging and a wider understanding of its potential long-term complications should lead to improved quality of care in future. PMID- 23032716 TI - Do patients with heart failure benefit from coronary artery bypass grafting? AB - PURPOSE OF REVIEW: The purpose of this review is to examine the appropriateness of coronary artery bypass grafting (CABG) for the patient with ischemic cardiomyopathy and congestive heart failure. RECENT FINDINGS: CABG is the gold standard therapy for patients with advanced multivessel and left main coronary artery disease. A critical analysis of the Surgical Treatment of Ischemic Heart Failure (STICH) trial confirms the benefit of CABG for patients with ischemic cardiomyopathy. SUMMARY: CABG can be safely applied to patients with heart failure and provides benefit for appropriately selected patients. PMID- 23032717 TI - Incidence angle dependence of the enhancement factor in attenuated total reflection surface enhanced infrared absorption spectroscopy studied by numerical solution of the vectorial Maxwell equations. AB - The finite element method (FEM) was used to solve the time-harmonic Maxwell equations in a study of the effect of the incidence angle of infrared light on the surface enhancement caused by colloidal gold particles in attenuated total reflection surface enhanced infrared absorption spectroscopy (ATR-SEIRAS). The spectral enhancement factor was obtained from computations of absorbance from a thin organic layer in the presence and absence of the metal nanostructure. For computations of an isolated particle the enhancement factor is high around the critical angle and decreases with an increase in incidence angle. This trend was also observed in experiments performed with gold particles immobilised on a silane modified silicon ATR crystal. Computations where gold particles are touching each other show low enhancement factors around the critical angle and an increase with increasing incidence angle. These two opposing trends are analysed based on the electric field distribution around the particle. PMID- 23032718 TI - Biological applications of functionalized calixarenes. AB - The functionalized calixarene derivatives exhibit remarkable properties towards organic and bioorganic molecules. However, the ability of calixarene derivatives to form stable complexes with biomolecules allows them to be applied for the development of biosensors and in the field of biology, biotechnology, and drug discovery. The applications of the functionalized calixarenes are summarized in this review, and an outlook for the future developments is discussed. A brief survey (of the last 10 years) on their biological application in various fields is also considered (199 references). PMID- 23032719 TI - Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells. AB - The activation of signal transducer and activator of transcription signaling 3 (STAT3) has been linked with the survival, proliferation, angiogenesis and immunosuppression of hepatocellular carcinoma cells (HCCs). Agents that can suppress STAT3 activation have potential to be cancer therapeutics. In this study, we investigated the inhibitory effect of evodiamine on STAT3 pathway in vitro and the anti-tumor effect of evodiamine in vivo in HCC. We found that evodiamine suppressed both constitutive and interleukin-6 (IL-6)-induced activation of STAT3 tyrosine 705 (Tyr(705)) effectively. The phosphorylation of Janus-activated kinase 2 (JAK2), Src and extracellular regulated protein kinases 1/2 (ERK1/2) were also suppressed by evodiamine. Interestingly, treatment of cells with sodium pervanadate abrogated the inhibition of evodiamine on IL-6 induced STAT3 (Tyr(705)) activation indicating the involvement of protein tyrosine phosphatases. Indeed, further studies demonstrated that evodiamine induced the expression of phosphatase shatterproof 1 (SHP-1). Moreover, inhibition of SHP-1 gene by small interference RNA abolished the ability of evodiamine to inhibit IL-6-induced STAT3 (Tyr(705)) activation. Evodiamine also suppressed STAT3 DNA binding activity and down-regulated the expression of STAT3 mediated genes leading to the suppression of proliferation, induction of cell apoptosis and cell cycle arrest. In vivo, evodiamine significantly inhibited tumor growth in a subcutaneous xenograft model with HepG2 cells. In summary, evodiamine blocked STAT3 signaling pathway by inducing SHP-1 and exhibited anticancer effect in vitro and in vivo. PMID- 23032721 TI - Formation of donor and acceptor states of the divacancy-oxygen centre in p-type Cz-silicon. AB - The formation of the divacancy-oxygen centre (V(2)O) in p-type Czochralski-grown silicon has been investigated by means of deep level transient spectroscopy (DLTS). The donor state (+/0) of V(2)O is located at ~E(v) + 0.23 eV (E(v) denotes the valence band edge) and emerges during heat treatment above 200 degrees C at the expense of the divacancy centre (V(2)). A concurrent transition takes place between the single-acceptor states of V(2) and V(2)O, as unveiled by the injection of electrons through optical excitation during the trap filling sequence of the DLTS measurements. Further, a defect with an energy level at ~E(v) + 0.09 eV evolves in close correlation with the growth of V(2)O but at a factor of ~5-6 lower in concentration. In the literature, the E(v) + 0.09 eV level has previously been attributed to a double-donor state of V(2)O but this assignment can be ruled out by the present data favouring a complex formed between migrating V(2) centres and a competing interstitial oxygen trap. In addition, a level at ~E(v) + 0.24 eV occurs also during the heat treatment above 200 degrees C and is tentatively assigned to the trivacancy-oxygen centre (V(3)O). PMID- 23032720 TI - Combination therapy: histone deacetylase inhibitors and platinum-based chemotherapeutics for cancer. AB - One of the most promising strategies to increase the efficacy of standard chemotherapy drugs is by combining them with low doses of histone deacetylases inhibitors (HDACis). Regarded as chemosensitizers, the addition of well-tolerated doses of HDACis to platinum-based chemotherapeutics has been proven in vitro and in vivo in recent studies for many cancer types and stages. In this review, we discuss the most commonly used combinations of histone deacetylase inhibitors and platinum based drugs in the context of their possible mechanisms, efficiency, efficacy, and related drawbacks in preclinical and clinical studies. PMID- 23032722 TI - A pathway from leukemogenic oncogenes and stem cell chemokines to RNA processing via THOC5. AB - THOC5 is a member of the THO complex that is involved in processing and transport of mRNA. We have shown previously that hematopoietic stem cells have an absolute requirement for THOC5 for survival and that THOC5 is phosphorylated on tyrosine 225 as a consequence of leukemogenic protein tyrosine kinase (PTK) action. We have investigated pathways for THOC5 phosphorylation to develop an understanding of THO complex modulation by tyrosine kinase (TK) oncogenes in leukemias. We demonstrate that THOC5 phosphorylation is mediated by Src PTK and CD45 protein tyrosine phosphatase action and that this event is sensitive to oxidative status. We show that THOC5 phosphorylation is elevated in stem cells from patients with chronic myeloid leukemia (CML) and that this phosphorylation is sensitive to the frontline drugs used in CML treatment. Further we show that THOC5 Y225 phosphorylation governs mRNA binding. In addition, CXCL12 is shown to induce THOC5 Y225 phosphorylation, and site-directed mutagenesis demonstrates that this modulates motile response. In conclusion, we delineate a signaling pathway stimulated by leukemogenic PTKs, chemokines and oxidative stress that can affect THO complex mediation of gene expression describing mechanisms for post transcriptional regulation of protein levels. PMID- 23032723 TI - Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project. AB - The combination of serum beta2-microglobulin and albumin levels has been shown to be highly prognostic in myeloma as the International Staging System (ISS). The aim of this study was to assess the independent contributions of ISS stage and cytogenetic abnormalities in predicting outcomes. A retrospective analysis of international studies looking at both ISS and cytogenetic abnormalities was performed in order to assess the potential role of combining ISS stage and cytogenetics to predict survival. This international effort used the International Myeloma Working Group database of 12 137 patients treated worldwide for myeloma at diagnosis, of whom 2309 had cytogenetic studies and 5387 had analyses by fluorescent in situ hybridization (iFISH). Comprehensive analyses used 2642 patients with sufficient iFISH data available. Using the comprehensive iFISH data, combining both t(4;14) and deletion (17p), along with ISS stage, significantly improved the prognostic assessment in terms of progression-free survival and overall survival. The additional impact of patient age and use of high-dose therapy was also demonstrated. In conclusion, the combination of iFISH data with ISS staging significantly improves risk assessment in myeloma. PMID- 23032726 TI - Imaging in the cardiovascular and metabolic disease area. AB - There is a widely held belief that the use of non-invasive imaging can reduce the gap between basic science and clinical proof-of-concept, ultimately improving decision-making and therefore the efficiency of the drug development process. Imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) are routinely used in oncology and neuroscience drug development. However, less attention has been paid to the systematic use of imaging in the cardiovascular and metabolic disease area. Here, with an emphasis on 'early clinical' development, we discuss the application of imaging in those areas, highlighting opportunities and challenges. PMID- 23032727 TI - Advances and strategies in discovery of new antibacterials for combating metabolically resting bacteria. AB - Discovery of new antibacterial agents is crucial to counter the challenge of drug resistant bacterial infections. In this review we discuss the issue of bacterial metabolic resting states, observed for a variety of pathogenic bacteria, which display low susceptibility for most antibacterials. We present examples of how bacterial metabolic states may be controlled, target pathways may be validated and screening on metabolically resting bacteria can be designed. A deeper understanding of bacterial metabolic states may provide valuable input for the design of efficient screening approaches in the discovery of new antibacterial agents. PMID- 23032728 TI - A study of subtle motor signs in early Parkinson's disease. AB - BACKGROUND: The UPDRS is the most widely used rating scale for Parkinson's disease (PD). However, subtle features of early disease stages may be missed. METHODS: We studied 25 early PD patients using a newly compiled battery of motor tests focusing on subtle motor features. Focal dystonia patients (n = 31) and healthy individuals (n = 26) served as controls. Specifically, asymmetric shoulder null position and delayed shoulder shrugs, reduced arm swing, subtle tremor, and timed finger taps were assessed. Spiral drawings and writing were also studied. RESULTS: With a total mean of 9.8 +/- 4.9 (possible range: 0-94), PD patients scored significantly higher than dystonia patients (2.9 +/- 2.0) and healthy controls (1.9 +/- 2.0) (P < 0.001). Reduced arm swing and tremor of individual fingers best distinguished PD from the other groups. CONCLUSIONS: The battery was sensitive to detect subtle motor features missed by the UPDRS. For future revisions of an international motor score, further assessment of these items may be worthwhile. PMID- 23032729 TI - Suzuki coupling reactions in neat water as the solvent: where in the biphasic reaction mixture do the catalytic reaction steps occur? AB - Many reports on water-compatible palladium catalysts have appeared in the recent literature. For hydrophobic substrates, mixtures with pure water are biphasic, and it is widely not regarded that the elusive locality of the catalytic process (in water, the organic layer, or at the phase boundary) has an important impact on the mechanism and efficiency of the reaction. In the present work, for the first time systematic variation of reaction parameters has been performed for Suzuki coupling experiments with chloro- and bromoarenes in pure water. The investigations are not only aimed at the factors influencing the catalytic activity, but also at the effects that may occur particularly in water/organic biphasic media, and on the question as to in which of the two liquid phases the reaction takes place. These investigations have revealed that dilution of the base (in the aqueous layer) and the Pd species (in the organic layer) are detrimental to the reaction, and that phase-transfer processes play a major role in the overall mechanism. A series of experiments with variation of parameters like precatalyst hydrophilicity, organic and water phase volume, additives, stirring rate, base concentration, and so forth, indicate that for the systems under study the reaction occurs in the organic layer. The water phase needs to be present to dissolve and provide polar reactants, and re-absorb side products. The results encourage to pay more regard to the question of phase locality of coupling reactions in water in general. PMID- 23032730 TI - The role of van der Waals interactions in the adsorption of noble gases on metal surfaces. AB - Adsorption of noble gases on metal surfaces is determined by weak interactions. We applied two versions of the nonlocal van der Waals density functional (vdW-DF) to compute adsorption energies of Ar, Kr, and Xe on Pt(111), Pd(111), Cu(111), and Cu(110) metal surfaces. We compared our results with data obtained using other density functional approaches, including the semiempirical vdW-corrected DFT-D2. The vdW-DF results show considerable improvements in the description of adsorption energies and equilibrium distances over other DFT based methods, giving good agreement with experiments. We also calculated perpendicular vibrational energies for noble gases on the metal surfaces using vdW-DF data and found excellent agreement with available experimental results. Our vdW-DF calculations show that adsorption of noble gases on low-coordination sites is energetically favored over high-coordination sites, but only by a few meV. Analysis of the two-dimensional potential energy surface shows that the high coordination sites are local maxima on the two-dimensional potential energy surface and therefore unlikely to be observed in experiments; this provides an explanation of the experimental observations. The DFT-D2 approach with the standard parameterization was found to overestimate the dispersion interactions, and to give the wrong adsorption site preference for four of the nine systems we studied. PMID- 23032732 TI - Rectal microbicide development. AB - PURPOSE OF REVIEW: Individuals practicing unprotected receptive anal intercourse are at particularly high risk of HIV infection. Men who have sex with men (MSM) in the developed and developing world continue to have disproportionate and increasing levels of HIV infection. The past few years have seen important progress in demonstrating the efficacy of oral pre-exposure prophylaxis (PrEP), vaginal microbicides, and treatment as prevention, but there has also been significant progress in the development of rectal microbicides. The purpose of this review is to summarize the status of rectal microbicide research and to identify opportunities, challenges, and future directions in this important field of HIV prevention. RECENT FINDINGS: Recent phase 1 rectal microbicide studies have characterized the safety, acceptability, compartmental pharmacokinetics, and pharmacodynamics of both UC781 and tenofovir gels. The tenofovir gel formulation used in vaginal studies was not well tolerated in the rectum and newer rectal specific formulations have been developed and evaluated in phase 1 studies. SUMMARY: Complex phase 1 studies have provided important data on candidate rectal microbicides. Tenofovir gel is poised to move into phase 2 evaluation and it is possible that a phase 2B/3 effectiveness study could be initiated in the next 2-3 years. PMID- 23032733 TI - Next-generation oral preexposure prophylaxis: beyond tenofovir. AB - PURPOSE OF REVIEW: Clinical trials of oral preexposure prophylaxis (PrEP) have focused on regimens of tenofovir (TDF) with or without emtricitabine (FTC). However, TDF may be associated with toxicities (renal, bone), and FTC may select for drug resistance. Both are also first-line drugs for HIV treatment. In this review, we discuss agents that might serve as alternatives to TDF/FTC for HIV PrEP. RECENT FINDINGS: Several drug characteristics are important to consider when selecting agents for PrEP with the most critical being safety, tolerability, adequate penetration into target tissues for prevention of HIV infection, and long-lasting activity with convenient dosing. With these factors in mind, we review five potentially useful agents for PrEP. The first group includes drugs that are already Food and Drug Administration approved (maraviroc, raltegravir) with attributes that make them attractive for PrEP. The second group includes investigational agents with long-lasting activity that are being developed in parenteral form (rilpivirine-long acting, S/GSK1265744, ibalizumab). SUMMARY: Future PrEP drugs may give clinicians the flexibility to select agents on the basis of individual patient needs and preferences. PMID- 23032735 TI - Antiretrovirals and HIV prevention: new insights, challenges, and new directions. PMID- 23032734 TI - Antiretrovirals and safer conception for HIV-serodiscordant couples. AB - PURPOSE OF REVIEW: Many men and women living with HIV and their uninfected partners attempt to conceive children. HIV-prevention science can be applied to reduce sexual transmission risk while respecting couples' reproductive goals. Here we discuss antiretrovirals as prevention in the context of safer conception for HIV-serodiscordant couples. RECENT FINDINGS: Antiretroviral therapy (ART) for the infected partner and pre-exposure prophylaxis (PrEP) for the uninfected partner reduce the risk of heterosexual HIV transmission. Several demonstration projects suggest the feasibility and acceptability of antiretroviral (ARV)s as periconception HIV-prevention for HIV-serodiscordant couples. The application of ARVs to periconception risk reduction may be limited by adherence. SUMMARY: For male-infected (M+F-) couples who cannot access sperm processing and female infected (F+M-) couples unwilling to carry out insemination without intercourse, ART for the infected partner, PrEP for the uninfected partner, combined with treatment for sexually transmitted infections, sex limited to peak fertility, and medical male circumcision (for F+M couples) provide excellent, well tolerated options for reducing the risk of periconception HIV sexual transmission. PMID- 23032736 TI - Engaging healthcare providers to implement HIV pre-exposure prophylaxis. AB - PURPOSE OF REVIEW: Recent randomized controlled trials have demonstrated that HIV pre-exposure prophylaxis (PrEP) can decrease HIV incidence among several at-risk populations, including men who have sex with men, serodiscordant couples, and heterosexual men and women. As PrEP is a biomedical intervention that requires clinical monitoring and a high level of medication adherence, maximizing the public health effectiveness of PrEP in real-world settings will require the training of a cadre of healthcare providers to prescribe PrEP. Therefore it is critical to understand provider knowledge, practices, and attitudes towards PrEP prescribing, and to develop strategies for engaging and training providers to provide PrEP. RECENT FINDINGS: Limited numbers of studies have focused on PrEP implementation by healthcare providers. These studies suggest that some providers are knowledgeable about PrEP, but many are not, or express misgivings. Although many clinicians report willingness to provide PrEP, few have prescribed PrEP in clinical practice. Provider comfort and skills in HIV risk assessment are suboptimal, which could limit identification of individuals who are most likely to benefit from PrEP use. SUMMARY: Further studies to understand facilitators and barriers to HIV-risk assessment and PrEP prescribing by practicing clinicians are needed. Innovative training strategies and decision-support interventions for providers could optimize PrEP implementation and therefore merit additional research. PMID- 23032737 TI - Acceptability in microbicide and PrEP trials: current status and a reconceptualization. AB - PURPOSE OF REVIEW: Assessment of acceptability is a central component of most oral PrEP and microbicide trials. In this paper we review current definitions and frameworks employed in acceptability research, discuss findings from recent studies of product acceptability and summarize trends in acceptability research. We conclude by offering a new framework for investigating product acceptability within clinical trials, one which considers product acceptability to be conceptually distinct from adherence. RECENT FINDINGS: Although numerous studies have investigated product acceptability, a consensus is lacking regarding the definition and operationalization of the concept. In addition fewer than half of the studies reviewed investigated actual candidate products. To the extent that an overall measure of acceptability is considered, the consensus is that most participants find the products acceptable. However, it is the rare study that investigates whether product adherence is associated with acceptability. SUMMARY: Given that adherence is critical to the success of clinical trials, it is important to identify the extent to which acceptability is a factor in product usage and to ascertain which dimensions of acceptability - product attributes, dosing regimen, delivery mechanism, use attributes, partner's attitudes, effect of product on the sexual encounter, product-related norms - if any, affect adherence. PMID- 23032738 TI - Considerations regarding antiretroviral chemoprophylaxis and heterosexuals in generalized epidemic settings. AB - PURPOSE OF REVIEW: To discuss the factors pertinent to the use of pre-exposure prophylaxis (PrEP) by at-risk heterosexuals in countries with generalized HIV epidemics. RECENT FINDINGS: PrEP will have the greatest prevention effect if targeted to those at highest risk, but identifying and engaging such persons is challenging. Serodiscordant couples account for a high proportion of new infections and are an appropriate target for PrEP, but the proportion of people in such relationships is small and outside partnerships are common. Differences in adherence coupled to pharmacology of the drugs may account for differences in efficacy seen in the trials. Mathematical modeling indicates that the benefits of PrEP in highly endemic settings outweigh the risk of induced viral resistance. Behavioral risk compensation was not observed in the trials, but current open label studies will better determine if disinhibition will be an important problem. CONCLUSIONS: PrEP is a potentially useful HIV-prevention strategy for generalized heterosexual epidemics. Optimal implementation will require learning more about ways to improve acceptability and adherence and how best to deliver PrEP within the context of limited resource availability. PMID- 23032739 TI - Optical switching of the Dirac point in graphene multilayer field-effect transistors functionalized with spiropyran. AB - A facile method for achieving optical switching of the Dirac point and conductance in reduced graphene oxide multilayer FETs that are non-covalently functionalized with a photo-responsive spiropyran derivative is presented. The photoresponsive transition from spiropyran to merocyanine induces the reversible optical switching in graphene based FETs. PMID- 23032740 TI - In vivo phosphoantigen levels in bisphosphonate-treated human breast tumors trigger Vgamma9Vdelta2 T-cell antitumor cytotoxicity through ICAM-1 engagement. AB - PURPOSE: Nitrogen-containing bisphosphonates (N-BP) such as zoledronate and risedronate exhibit antitumor effects. They block the activity of farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway, leading to intracellular accumulation of mevalonate metabolites (IPP/ApppI), which are recognized as tumor phosphoantigens by Vgamma9Vdelta2 T cells. However, mechanisms responsible for Vgamma9Vdelta2 T-cell recognition of N-BP-treated tumors producing IPP/ApppI remain unclear. EXPERIMENTAL DESIGN: The effects of N-BPs on Vgamma9Vdelta2 T cell expansion and anticancer activity were evaluated in vitro and in animal models of human breast cancers. The modalities of recognition of breast tumors by Vgamma9Vdelta2 T cells in N-BP-treated animals were also examined. RESULTS: We found a strong correlation between Vgamma9Vdelta2 T-cell anticancer activity and intracellular accumulation of IPP/ApppI in risedronate-treated breast cancer cells in vitro. In addition, following risedronate treatment of immunodeficient mice bearing human breast tumors, human Vgamma9Vdelta2 T cells infiltrated and inhibited growth of tumors that produced high IPP/ApppI levels but not those expressing low IPP/ApppI levels. The combination of doxorubicin with a N-BP improved, however, Vgamma9Vdelta2 T-cell cytotoxicity against breast tumors expressing low IPP/ApppI levels. Moreover, Vgamma9Vdelta2 T-cell cytotoxicity in mice treated with risedronate or zoledronate did not only depend on IPP/ApppI accumulation in tumors but also on expression of tumor cell surface receptor intercellular adhesion molecule-1 (ICAM-1), which triggered the recognition of N BP-treated breast cancer cells by Vgamma9Vdelta2 T cells in vivo. CONCLUSION: These findings suggest that N-BPs can have an adjuvant role in cancer therapy by activating Vgamma9Vdelta2 T-cell cytotoxicity in patients with breast cancer that produces high IPP/ApppI levels after N-BP treatment. PMID- 23032741 TI - Redirecting gene-modified T cells toward various cancer types using tagged antibodies. AB - PURPOSE: To develop an adaptable gene-based vector that will confer immune cell specificity to various cancer types. EXPERIMENTAL DESIGN: Human and mouse T cells were genetically engineered to express a chimeric antigen receptor (CAR) that binds a fluorescein isothiocyanate (FITC) molecule, termed anti-FITC CAR T cells. Various antibodies (Ab) currently in clinical use including cetuximab (Ctx), trastuzumab (Her2), and rituximab (Rtx) were conjugated with FITC and tested for their ability to bind tumor cells, activate T cells, and induce antitumor effects in vitro and in vivo. RESULTS: Anti-FITC CAR T cells recognize various cancer types when bound with FITC-labeled Abs resulting in efficient target lysis, T cell proliferation, and cytokine/chemokine production. The treatment of immunocompromised mice with human anti-FITC CAR T cells plus FITC-labeled cetuximab (FITC-Ctx) delayed the growth of colon cancer but unexpectedly led to the outgrowth of EGF receptor (EGFR)-negative tumor cells. On the other hand, in a human pancreatic cancer cell line with uniform EGFR expression, anti-FITC CAR T cells plus FITC-Ctx eradicated preestablished late-stage tumors. In immunocompetent mice, anti-FITC CAR T cells exhibited potent antitumor activity against syngeneic mouse breast cancer expressing Her2 and B-cell lymphoma expressing CD20 by combining with FITC-Her2 and FITC-Rtx, respectively. In addition, the activity of anti-FITC CAR T cells could be attenuated by subsequent injections of nonspecific FITC-IgG. CONCLUSION: These studies highlight an applicability of anti-tag CAR technology to treat patients with different types of cancers and a possibility to regulate CAR T-cell functions with competing FITC molecules. PMID- 23032742 TI - Limited induction of tumor cross-reactive T cells without a measurable clinical benefit in early melanoma patients vaccinated with human leukocyte antigen class I-modified peptides. AB - PURPOSE: The progressive immune dysfunctions that occur in patients with advanced melanoma make them unlikely to efficiently respond to cancer vaccines. A multicenter randomized phase II trial was conducted to test whether immunization with modified HLA class I tumor peptides in the context of adjuvant therapy results in better immunologic responses and improved clinical outcomes in patients with early melanoma (stages IIB/C-III). EXPERIMENTAL DESIGN: Forty-three patients were enrolled to undergo vaccination (n = 22) or observation (n = 21). The vaccine included four HLA-A*0201-restricted modified peptides (Melan-A/MART 1([27L]), gp100([210M]), NY-ESO-1([165V]), and Survivin([97M])) emulsified in Montanide ISA51 and injected subcutaneously in combination with cyclophosphamide (300 mg/m(2)) and low-dose IL-2 (3 * 10(6) IU). The immune responses were monitored using ex vivo IFN-gamma-ELISpot, HLA/multimer staining, and in vitro short-term peptide sensitization assays. RESULTS: Vaccination induced a rapid and persistent increase in specific effector memory CD8(+) T cells in 75% of the patients. However, this immunization was not associated with any significant increase in disease-free or overall survival as compared with the observation group. An extensive immunologic analysis revealed a significantly reduced cross recognition of the corresponding native peptides and, most importantly, a limited ability to react to melanoma cells. CONCLUSIONS: Adjuvant setting is an appealing approach for testing cancer vaccines because specific CD8(+) T cells can be efficiently induced in most vaccinated patients. However, the marginal antitumor activity of the T cells induced by modified peptides in this study largely accounts for the observed lack of benefit of vaccination. These findings suggest reconsidering this immunization strategy, particularly in early disease. PMID- 23032743 TI - Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. AB - PURPOSE: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. EXPERIMENTAL DESIGN: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. RESULTS: Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8(+) T cells in the infusion product, a more differentiated effector phenotype of the CD8(+) population, and a higher frequency of CD8(+) T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. CONCLUSION: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8(+) T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. PMID- 23032744 TI - Establishment and characterization of novel cell lines from sinonasal undifferentiated carcinoma. AB - PURPOSE: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer. Despite the use of multimodality treatment, the overall prognosis remains poor. To better understand the biologic features of SNUC and help develop new therapies for the disease, we established SNUC cell lines and characterized their biologic behaviors. EXPERIMENTAL DESIGN: Cell lines were established from a patient with a T4N0M0 SNUC of the right maxillary sinus who was treated with surgical resection at our center. Tumor colonies were harvested and were sequentially replated onto larger plates. Two populations were developed and labeled MDA8788-6 and MDA8788-7. These cell lines were characterized with molecular, biomarker, functional, and histologic analyses. RESULTS: Short tandem repeat genotyping revealed that the cell line is isogenic to the parental tumor, and cytogenetic analysis identified 12 chromosomal translocations. The SNUC cell lines do not form colonies in soft agar but are tumorigenic and nonmetastatic in an orthotopic mouse model of sinonasal cancer. Western blot analysis revealed that both MDA8788 cell lines express epithelial markers but do not express mesenchymal markers or the endocrine marker synaptophysin. CONCLUSIONS: This is the first report of the establishment of stable human-derived SNUC cell lines. The lines were highly tumorigenic and maintain the histologic and molecular features of the original tumor. These cell lines should serve as useful tools for the future study of SNUC biology and the development and testing of novel therapies for this deadly disease. PMID- 23032745 TI - Phase I trial of overlapping long peptides from a tumor self-antigen and poly ICLC shows rapid induction of integrated immune response in ovarian cancer patients. AB - PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations. EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining). RESULTS: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were detected in all patients with greater frequency and polyclonality when Montanide ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1-specific immune responses. CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8(+) and CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants. PMID- 23032746 TI - A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission. AB - PURPOSE: Hedgehog pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor stromal interactions. Vismodegib is an orally available Hedgehog pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR). EXPERIMENTAL DESIGN: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: One hundred four patients were randomized to vismodegib (n = 52) or placebo (n = 52); median PFS was 7.5 months and 5.8 months, respectively [HR 0.79; 95% confidence interval (CI), 0.46-1.35]. The HR was 0.66 (95% CI, 0.36-1.20) for second CR patients (n = 84) and 1.79 (95% CI, 0.50-6.48) for third CR patients (n = 20). The most common adverse events in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues. CONCLUSIONS: In this study, the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hedgehog ligand expression was lower than expected. PMID- 23032747 TI - Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis, and tissue microarray validation. AB - PURPOSE: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap. EXPERIMENTAL DESIGN: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860). RESULTS: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup. CONCLUSIONS: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics. PMID- 23032748 TI - Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor. AB - PURPOSE: To evaluate CD4(+) helper functions and antitumor effect of promiscuous universal cancer peptides (UCP) derived from telomerase reverse transcriptase (TERT). EXPERIMENTAL DESIGN: To evaluate the widespread immunogenicity of UCPs in humans, spontaneous T-cell responses against UCPs were measured in various types of cancers using T-cell proliferation and ELISPOT assays. The humanized HLA DRB1*0101/HLA-A*0201 transgenic mice were used to study the CD4(+) helper effects of UCPs on antitumor CTL responses. UCP-based antitumor therapeutic vaccine was evaluated using HLA-A*0201-positive B16 melanoma that express TERT. RESULTS: The presence of a high number of UCP-specific CD4(+) T cells was found in the blood of patients with various types of cancer. These UCP-specific T cells mainly produce IFN-gamma and TNF-alpha. In HLA transgenic mice, UCP vaccinations induced high avidity CD4(+) T(H)1 cells and activated dendritic cells that produced interleukin-12. UCP-based vaccination breaks self-tolerance against TERT and enhances primary and memory CTL responses. Furthermore, the use of UCP strongly improves the efficacy of therapeutic vaccination against established B16-HLA A*0201 melanoma and promotes tumor infiltration by TERT-specific CD8(+) T cells. CONCLUSIONS: Our results showed that UCP-based vaccinations strongly stimulate antitumor immune responses and could be used to design efficient immunotherapies in multiple types of cancers. PMID- 23032749 TI - A novel, stable, helical scaffold as an alternative binder - construction of phage display libraries. AB - Specific, high affinity binding macromolecules are of great importance for biomedical and biotechnological applications. The most popular classical antibody based molecules have recently been challenged by alternative scaffolds with desirable biophysical properties. Phage display technology applied to such scaffolds allows generation of potent affinity reagents by in vitro selection. Here, we report identification and characterization of a novel helical polypeptide with advantageous biophysical properties as a template for construction of phage display libraries. A three-helix bundle structure, based on Measles virus phosphoprotein P shows a very favourable stability and solubility profile. We designed, constructed and characterized six different types of phage display libraries based on the proposed template. Their functional size of over 10(9) independent clones, balanced codon bias and decent display level are key parameters attesting to the quality and utility of the libraries. The new libraries are a promising tool for isolation of high affinity binders based on a small helical scaffold which could become a convenient alternative to antibodies. PMID- 23032750 TI - Properties of recombinant trehalose synthase from Deinococcus radiodurans expressed in Escherichia coli. AB - A trehalose synthase gene from Deinococcus radiodurans (DSMZ 20539) containing 1659 bp reading frame encoding 552 amino acids was amplified using PCR. The gene was finally ligated into pET30Ek/LIC vector and expressed after isopropyl beta-d thiogalactopyranoside induction in Escherichia coli (DE3) Rosetta pLysS. The recombinant trehalose synthase (DraTreS) containing a His(6)-tag at the C terminus was purified by metal affinity chromatography and characterized. The expressed enzyme is a homodimer with molecular mass of 126.9 kDa and exhibits the highest activity of 11.35 U/mg at pH 7.6 and at 30 degrees C. DraTreS activity was almost unchanged after 2 h preincubation at 45 degrees C and pH 7.6, and retained about 56% of maximal value after 8 h incubation at 50 degrees C. The DraTreS was strongly inhibited by Cu(2+), Hg(2+), Zn(2+), Al(3+) and 10 mM Tris. The K(m) value of maltose conversion was 290.7 mM. PMID- 23032752 TI - "Bump": using a mobile app to enhance learning in simulation scenarios. PMID- 23032751 TI - Comparative effectiveness of technology-enhanced simulation versus other instructional methods: a systematic review and meta-analysis. AB - To determine the comparative effectiveness of technology-enhanced simulation, we summarized the results of studies comparing technology-enhanced simulation training with nonsimulation instruction for health professions learners. We systematically searched databases including MEDLINE, Embase, and Scopus through May 2011 for relevant articles. Working in duplicate, we abstracted information on instructional design, outcomes, and study quality. From 10,903 candidate articles, we identified 92 eligible studies. In random-effects meta-analysis, pooled effect sizes (positive numbers favoring simulation) were as follows: satisfaction outcomes, 0.59 (95% confidence interval, 0.36-0.81; n = 20 studies); knowledge, 0.30 (0.16-0.43; n = 42); time measure of skills, 0.33 (0.00-0.66; n = 14); process measure of skills, 0.38 (0.24-0.52; n = 51); product measure of skills, 0.66 (0.30-1.02; n = 11); time measure of behavior, 0.56 (-0.07 to 1.18; n = 7); process measure of behavior, 0.77 (-0.13 to 1.66; n = 11); and patient effects, 0.36 (-0.06 to 0.78; n = 9). For 5 studies reporting comparative costs, simulation was more expensive and more effective. In summary, in comparison with other instruction, technology-enhanced simulation is associated with small to moderate positive effects. PMID- 23032753 TI - Resident education: patient safety and quality improvement in simulation. PMID- 23032755 TI - Effects of ultrasonic pre-treatment on sludge characteristics and anaerobic digestion. AB - In this work, the influence of an ultrasonic pre-treatment on anaerobic digestion of waste activated sludge is studied. Attention is paid to the solubilisation of the main organic (proteins, carbohydrates) and inorganic (heavy metals) sludge components during ultrasonic treatment and the influence of the dry solids content (DS) on the degree of solubilisation. The second part of the paper focuses on the relationship between the applied specific energy of the ultrasonic treatment and methane production. In general, a higher specific energy and a higher DS content are beneficial for the release of organic matter, resulting in an increased methane production. The efficiency of the subsequent anaerobic digestion is similar for both sludge types (2.1 and 3.2% DS). However, at lower DS contents (2.1%), the methane production increase was more significant. PMID- 23032754 TI - Preparation of single-walled carbon nanotubes/polyvinylchloride membrane and its antibacterial property. AB - Polyvinylchloride (PVC) ultrafiltration membranes were modified by blending with single-walled carbon nanotubes (SWCNTs) to improve the membranes' antibacterial property. Both modified and control samples were characterized for pore structure, roughness, hydrophilicity, permeability and mechanical properties. The membranes' antibacterial property was accessed with Escherichia coli as the model microbes by several methods. It was found that, after being blended with SWCNTs, the surface roughness of the modified membrane increased. Also, the surface hydrophilicity was improved. The membrane flux increased accordingly. But the membrane elongation decreased obviously with the SWCNTs addition. The modified membranes did not show the antibacterial property as expected in this research. There was no bacterial inhibition circle around the SWCNTs/PVC membrane coupons in the culture plates. There were no morphological differences of the cells on the control and the modified membranes. Hoechst 33342/propidium iodide stain test showed that there were more than 90% living bacterial cells which could grow on the SWCNTs/PVC membranes. This study suggests that the polymer wrapping may reduce the SWCNTs' antibacterial property greatly. PMID- 23032756 TI - Effect of coagulation mechanisms on the fouling and ultrasonic cleaning of PTFE membrane. AB - In this study, the effect of coagulation pretreatment on membrane fouling and ultrasonic cleaning efficiency was investigated using a dead-end polytetrafluoroethylene (PTFE) microfiltration system. The extent of membrane fouling was examined under different coagulation mechanisms such as charge neutralization (CN), electrostatic patch effect (EPE) and sweep flocculation (SW). Fouling through EPE mechanism provided the greatest flux decline and least permeate flux recovery over CN and SW. EPE produces more stable, smaller and more compact flocs while CN and SW have large, easily degraded and highly-branched structured flocs. The predominant fouling mechanism of EPE, CN and SW is pore blocking, a combination of pore blocking and cake formation, and cake formation, respectively. Better permeate flux recovery is observed with SW over CN and EPE, which implies formation of less dense and more porous cake deposits. The morphology of fouled membranes was examined using scanning electron microscopy (SEM). PMID- 23032757 TI - Evaluation of anaerobic biodegradability of wastewater from tebuconazole manufacturing. AB - This study aimed to verify the biological anaerobic treatability of tebuconazole effluent manufacturing. For this purpose, two preliminary batch tests were performed using an 'anaerobic respirometer' adjusting the initial pH of the effluent at 7.0 and 8.0, respectively (first phase). In addition, two tests (second phase) were run using sequential batch anaerobic fermenters, the first operated at different hydraulic detention times (10 and 16.7 days) and the second with different initial dilutions of the effluent (5 and 20%). The chemical oxygen demand (COD) removal observed on the anaerobic respirometer tests was in the range of 66-81%. According to the preliminary batch tests an optimal value of initial COD concentration and amount of biomass was identified, which was considered for the fermenters start up. However, it was observed that the optimal relation provided by the respirometer test was not a good parameter of operational control for the fermenters due to the accumulation of inhibitory substances, which affected the microbial activity and took the system to collapse. The initial dilution of the effluent (5 and 20%) was essential for the stability of the anaerobic system, allowing COD removals above 74% during this study. PMID- 23032758 TI - Molecular enrichment for detection of S. aureus in recreational waters. AB - The identification of rapid methods for the control of recreational water and of aquatic environments with similar characteristics is necessary to provide adequate levels of health safety for users. Molecular techniques have been proposed in recent years as a viable alternative to traditional microbiological methods, as they offer various advantages and are less time consuming than traditional tests. An innovative protocol based on molecular enrichment that allows the identification of low concentrations of Staphylococcus aureus in recreational water has been developed. The method is based on the specific amplification of prokaryotic genomic DNA by the usage of universal primers for 23S rDNA; subsequently, a second amplification step is performed with specific real-time polymerase chain reaction (PCR) primers and probe. This approach shows sensitivity levels similar to those observed with microbiological tests, with the additional benefits of the specificity typical of nucleic acids techniques. This methodology is easily applicable also to other microbiological parameters, representing an important milestone in hygiene monitoring by the detection of specific pollution indicators. PMID- 23032759 TI - A metabolic quotient for methanogenic Archaea. AB - Biogas production from renewable resources is an alternative to generate energy and concomitantly save fossil fuels and mitigate greenhouse gas emissions. As methanogenesis is a major bottleneck in the biogas process, the determination of the specific activity of methanogenic Archaea can be a good indicator of the process state. A new parameter, the metabolic quotient (MQ), was developed to evaluate the specific activity of methanogens. A standard was created from mesophilic maize-fed fermenters to calculate the expected concentration of methanogens for a given methane productivity at stable process stages. The MQ, the ratio of the predicted to the actual concentration of methanogens, defines their metabolic activity. The MQ was able to indicate methanogenic cell stress metabolism and imminent process failure before conventional chemical parameters. As a further approach, the methanogenic activity was determined by quantification of mRNA transcripts in relation to the mcrA/mrtA-gene, coding for a key enzyme subunit of methanogenesis. The cDNA/DNA ratio reflected the specific actual process activity of the methanogens. As both methods are potent parameters for the early detection of process failure, biogas plant operators may avoid economical losses by their preventive application. PMID- 23032760 TI - Analytical and numerical modelling of Newtonian and non-Newtonian liquid in a rotational cross-flow MBR. AB - Fouling is the main bottleneck of the widespread use of MBR systems. One way to decrease and/or control fouling is by process hydrodynamics. This can be achieved by the increase of liquid cross-flow velocity. In rotational cross-flow MBR systems, this is attained by the spinning of, for example, impellers. Validation of the CFD (computational fluid dynamics) model was made against laser Doppler anemometry (LDA) tangential velocity measurements (error less than 8%) using water as a fluid. The shear stress over the membrane surface was inferred from the CFD simulations for water. However, activated sludge (AS) is a non-Newtonian liquid, for which the CFD model was modified incorporating the non-Newtonian behaviour of AS. Shear stress and area-weighted average shear stress relationships were made giving error less that 8% compared with the CFD results. An empirical relationship for the area-weighted average shear stress was developed for water and AS as a function of the angular velocity and the total suspended solids concentration. These relationships can be linked to the energy consumption of this type of systems. PMID- 23032761 TI - Pretreatment methods for aquatic plant biomass as carbon sources for potential use in treating eutrophic water in subsurface-flow constructed wetlands. AB - Plant biomass is usually added to constructed wetlands (CW) to enhance denitrification. In this study, we investigated effects of different pretreatments on two common external plant carbon sources, cattail and reed litter. We determined the average ratio of chemical oxygen demand (COD) to total nitrogen (TN), designated as C/N, in water samples after addition of litter subjected to various pretreatments. The C/N in the water samples ranged from 4.8 to 6.4 after addition of NaOH-pretreated cattail litter, which was four to six times greater than that of water from the Yapu River and 3.84-39.15% higher than that of systems that received untreated cattail litter. The C/N of systems that received H(2)SO(4)-pretreated carbon sources varied from 1.7 to 3.6. These two methods resulted in TN and total phosphorus (TP) levels lower than those in river water. The C/N was 1.4-1.7 after addition of CH(3)COOH-pretreated reed litter, which was 34.87-53.83% higher than that of river water. The C/N was 2.5 in systems that received mild alkali/oxidation-pretreated reeds, which was 30.59% higher than that of systems that received non-pretreated reeds. The residue rates of cattail and reed litter subjected to various pretreatments were greater than 60%. Our results showed that NaOH, H(2)SO(4), and mild alkali/oxidation pretreatments were useful to rapidly improve the C/N of river water and enhance denitrification. PMID- 23032762 TI - Effect of increasing the organic loading rate on the co-digestion and mono digestion of cattle slurry and maize. AB - Co-digestion of cattle slurry and maize has been shown to have benefits for both, improving the biogas yield of the slurry and stability of digestion of the maize. The effect of increasing the total loading rate from 3 to 6 g VS l(-1) day(-1) on the co-digestion of cattle slurry and maize, mixed at equal volatile solids volumes, was investigated in laboratory-scale continuously stirred digesters. These were compared with similar digesters evaluating the increase of 1.5 to 3 g VS l(-1) day(-1) loading rates of slurry and maize digested separately. Compared with mono-digestion of the substrates, where the digestion of maize failed at loading rates greater than 2.5 g VS l(-1) day(-1), the co-digestion of cattle slurry and maize was feasible at all the loading rates tested with an increase in the volumetric methane yield occurring with loading rate. Even at the lowest rate of loading, the addition of equal amounts of volatile solids of maize to slurry leads to an increase in volumetric methane yield of 219%. PMID- 23032763 TI - Fundamental characteristics study of anion-exchange PVDF-SiO(2) membranes. AB - A new type of poly(vinylidene fluoride)(PVDF)-SiO(2) hybrid anion-exchange membrane was prepared by blending method. The anion-exchange groups were introduced by the reaction of epoxy groups with trimethylamine (TMA). Contact angle between water and the membrane surface was measured to characterize the hydrophilicity change of the membrane surface. The effects of nano-sized SiO(2) particles in the membrane-forming materials on the membrane mechanical properties and conductivity were also investigated. The experimental results indicated that PVDF-SiO(2) anion-exchange membranes exhibited better water content, ion-exchange capacity, conductivity and mechanic properties, and so may find potential applications in alkaline membrane fuel cells and water treatment processes. PMID- 23032764 TI - The oxidation of toluene sorbed on activated carbon in the presence of H(2)O(2) and manganese oxide. AB - We investigated the oxidation of toluene sorbed on activated carbon (AC) in the presence of hydrogen peroxide (H(2)O(2)) and pyrolusite (MnO(2)). Sorbed toluene was prepared by reacting a toluene-saturated solution and AC. The amounts of sorbed toluene (mg of toluene/g of AC) decreased as the amounts of AC were increased. The reaction was conducted in a gas-purging (GP) reactor and the gas flow at the outlet of a GP reactor was carefully maintained. As a result, the percentage of toluene captured by ORBO tube was 28% in the control system with pure water. When H(2)O(2) was catalyzed by AC (i.e. this forms a hydroxyl radical by electron transfer), approximately 17% of the desorbed toluene was oxidized and 68% of toluene remained on AC which was similar to the control system. However, when pyrolusite (650 mg/L) was added together with H(2)O(2) (10,000 mg/L), only 5% of toluene was captured by the ORBO tube and 55% of toluene remained on AC, which indicated that both desorbed and sorbed toluene was oxidized. Moreover, toluene oxidation increased when concentrations of pyrolusite and H(2)O(2) were increased. It was suggested that superoxide anion, which is generated by the reaction of H(2)O(2) and pyrolusite, might stimulate toluene desorption and then toluene in the aqueous phase could be oxidized by hydroxyl radical. PMID- 23032765 TI - Modification of SWAT model for simulation of organic matter in Korean watersheds. AB - The focus of water quality modeling of Korean streams needs to be shifted from dissolved oxygen to algae or organic matter. In particular, the structure of water quality models should be modified to simulate the biochemical oxygen demand (BOD), which is a key factor in calculating total maximum daily loads (TMDLs) in Korea, using 5-day BOD determined in the laboratory (Bottle BOD(5)). Considering the limitations in simulating organic matter under domestic conditions, we attempted to model total organic carbon (TOC) as well as BOD by using a watershed model. For this purpose, the Soil and Water Assessment Tool (SWAT) model was modified and extended to achieve better correspondence between the measured and simulated BOD and TOC concentrations. For simulated BOD in the period 2004-2008, the Nash-Sutcliffe model efficiency coefficient increased from a value of -2.54 to 0.61. Another indicator of organic matter, namely, the simulated TOC concentration showed that the modified SWAT adequately reflected the observed values. The improved model can be used to predict organic matter and hence, may be a potential decision-making tool for TMDLs. However, it needs further testing for longer simulation periods and other catchments. PMID- 23032766 TI - Identifying biases in deterioration models using synthetic sewer data. AB - The assessment and validation of sewer deterioration models is difficult because reliable data are missing. This makes it hard to find the most suitable model for a particular application. A network condition simulator (NetCoS) is used to generate synthetic sewer data for defined test scenarios. Thereby, the deterioration and replacement of pipes, the expansion of the sewer network, and classification errors are considered. Based on such synthetic data, deterioration models are calibrated and their results compared with the predefined scenario. While this approach is not capable of proving that a model performs correctly on a real application, it highlights the strengths and weaknesses of a model. The influence of condition classification errors and the age of the sewer system is investigated for two deterioration models. The results show, that classification errors can introduce substantial biases in the parameter estimation of the Markov model while in comparison the applied cohort model is fairly robust. Young sewer systems with fewer pipes in bad condition states on the other hand, have a very strong influence on the parameter uncertainties of the cohort model while the Markov model proved to be less sensitive. PMID- 23032767 TI - CFD analysis of sludge accumulation and hydraulic performance of a waste stabilization pond. AB - Sludge management in waste stabilization ponds (WSPs) is essential for safeguarding the system performance. Sludge accumulation patterns in WSPs are strongly influenced by the pond hydrodynamics. CFD modeling was applied to study the relation between velocity profiles and sludge deposition during 10 years of operation of the Ucubamba WSP in Cuenca (Ecuador). One tracer experiment was performed and three sludge accumulation scenarios based on bathymetric surveys were simulated. A residence time distribution (RTD) analysis illustrated the decrease of residence times due to sludge deposition. Sludge accumulation rates were calculated. The influence of flow pattern on the sludge deposition was studied, enabling better planning of future pond operation and desludging. PMID- 23032768 TI - Long-term hydrolytic capacity evaluation of a thermophilic anaerobic digester treating sewage sludge. AB - This study presents an evaluation of the hydrolytic activity of a continuous thermophilic anaerobic reactor in long-term operation. The hydrolytic coefficient was estimated by fitting a three-reaction model of the anaerobic digestion process with experimental data obtained from a pilot thermophilic digester operated for about 2 years. The model fitting and the cross-validation indicate that this model can represent the behavior of the system in a proper way; moreover, the results show a variation of the hydrolytic capacity of the system throughout the evaluation period. The increase in the hydrolytic coefficient is in agreement with the increase in the organic load applied to the reactor, which shows the capacity of the continuous reactor to select populations according to the input conditions of the system. PMID- 23032769 TI - Role of Escherichia coli strain subgroups, integrons, and integron-associated gene cassettes in dissemination of antimicrobial resistance in aquatic environments of Jinan, China. AB - Aquatic environments are known reservoirs of antibiotic-resistant bacteria, but little information is known about the role of Escherichia coli strain subgroups, integrons, and integron-associated gene cassettes in the prevalence of antimicrobial resistance. To address these knowledge gaps, the diversity and distribution of drug-resistant E. coli strains and their integrons in hospital wastewater (HWW) and XiaoQing River water (XQRW) in Jinan, China were compared. Phylogenetic assays showed that the isolates were distributed in every E. coli subgroup. The prevalence of antibiotic resistance in each E. coli subgroup from HWW was higher than in subgroups from XQRW, except for phylogenetic subgroup A(0). Classes 1 and 2 integrons were found in 327 strains (78.2% of the total 418 isolates) with a prevalence of 85.6% among the 209 isolates from HWW. Among 15 gene cassette arrays, dfrA17-aadA5 and dfrA12-orfF-aadA2 were the most prevalent. The prevalence of drug-resistance gene cassettes and diversity of arrays further proved that integrons were important contributors to the widespread occurrence of antibiotic resistance in E. coli among Jinan aquatic environments. PMID- 23032770 TI - A conceptual framework for addressing complexity and unfolding transition dynamics when developing sustainable adaptation strategies in urban water management. AB - To achieve a successful and sustainable adaptation to climate change we need to transform the way we think about change. Much water management research has focused on technical innovation with a range of new solutions developed to achieve a 'more sustainable and integrated urban water management cycle'. But Danish municipalities and utility companies are struggling to bring such solutions into practice. 'Green infrastructure', for example, requires the consideration of a larger range of aspects related to the urban context than the traditional urban water system optimization. There is the need for standardized methods and guidelines to organize transdisciplinary processes where different types of knowledge and perspectives are taken into account. On the basis of the macro-meso-micro pattern inspired by complexity science and transition theory, we developed a conceptual framework to organize processes addressing the complexity characterizing urban water management in the context of climate change. In this paper the framework is used to organize a research process aiming at understanding and unfolding urban dynamics for sustainable transition. The final goal is to enable local authorities and utilities to create the basis for managing and catalysing the technical and organizational innovation necessary for a sustainable transition towards climate change adaptation in urban areas. PMID- 23032771 TI - Using reverse phase high performance liquid chromatography as an alternative to resin fractionation to assess the hydrophobicity of natural organic matter. AB - Resin fractionation is the most widely used technique to isolate and characterize natural organic matter (NOM) based on its hydrophobicity and hydrophilicity, however, it is also recognized as a time consuming technique. This paper describes the use of reverse phase high performance liquid chromatography (RPHPLC) as a rapid assessment technique to determine the hydrophobicity/hydrophilicity of NOM. The optimum column separation condition was achieved and without the need for concentrating the sample prior to analysis and with good reproducibility of the peak retention time and the peak area. The characterization results were further compared with the traditional resin fractionation technique using DAX-8 and XAD-4 resins. The results demonstrated that the polarities defined by the two methods were different but consistent and also that the fractions absorbed onto XAD-4 were less hydrophobic than those absorbed onto DAX-8. The difference in definition between resin fractionation and RPHPLC were further investigated. PMID- 23032772 TI - A multi-objective optimisation model for sewer rehabilitation considering critical risk of failure. AB - A unique methodology for the optimal specification of sewer rehabilitation investment is presented in this paper. By accounting for the critical risk of asset failure, this methodology builds on previously successful work which explored the application of multi-objective optimisation tools to assist engineers with the specification of optimal rehabilitation strategies. The conventional sewerage rehabilitation specification process relies on the expertise of professional engineers to manually evaluate CCTV inspection information when determining the nature and extent of the rehabilitation solution. This process is not only tedious and subjective but it has no quantifiable means of identifying optimal solutions or possible combinations of optimal solutions in the delivery of catchment wide rehabilitation programmes. Therefore, the purely manual process of sewer rehabilitation design leaves a number of unanswered questions, such as: (1) Does the solution offer the greatest structural benefit to the network? (2) Is the solution the most cost-effective solution available? (3) Does the solution most greatly reduce the risk of critical asset failure? The application of a multi-objective genetic algorithm optimisation model, coupled with an enhanced critical risk methodology, has successfully answered these questions when applied to a case study data set provided by South West Water (UK). PMID- 23032773 TI - Comparison of two polarity measurements of hydrophobic organic matter for the evaluation of water treatment processes: XAD resin and PRAM. AB - Dissolved organic matter (DOM) is a mixture of thousands of organic molecules wide-ranging in molecular weight, polarity and physicochemical properties. DOM is responsible for multiple water treatment issues such as trihalomethane (THM) formation potential and membrane fouling. Two methods of evaluating the polarity of DOM are being used for water treatment application: a serial XAD resin adsorption method at acid pH and the polarity rapid assessment method (PRAM) by parallel solid phase extraction (SPE) cartridges at natural pH. These two methods have been described by their authors as able to define a hydrophobic fraction though they do so by sorption onto different types of material at different pHs. The first part of this study compared the PRAM and XAD methods and showed that the hydrophobic fractions defined by the two approaches were not correlated. This result highlighted the difficulties in defining fractions as 'hydrophobic material'. It appeared that the sorbents for XAD-8 (an acrylic polymer containing oxygen) at pH <3 and C-18 (a pure hydrocarbon polymer coating on silica particles) at neutral or pH <3 did not retain similar hydrophobic fractions. This hypothesis was verified by fluorescence spectroscopy of the effluent of the XAD-8 resin and PRAM C-18 SPE cartridge. Finally the study concentrated on the use of fluorescence and ultrafiltration methods in series with PRAM to gain more insight into the structure and characteristics of the hydrophobic DOM present in drinking water sources. This evaluation showed that the smaller molecular weight fraction of DOM (<1 kDa) had a higher percentage of hydrophobic character and that the fluorescence-defined aromatic protein fraction was the most hydrophilic. PMID- 23032774 TI - Bioremediation of acid mine drainage coupled with domestic wastewater treatment. AB - Acid mine drainage (AMD) - characterized by high acidity and elevated sulfate and metal concentrations - represents a big environmental concern. Biological sulfate reduction has become an alternative to the classical physicochemical methods. In this study, domestic wastewater (DW) was tested as a cost-effective carbon-source for the remediation of AMD. Sediments from Tinto River, an extreme acidic environment with an elevated concentration of metals, were used as inoculum. Three anaerobic bioreactors with different microbial supports were fed with a 1:10 (v:v) mixture of synthetic AMD:DW. Around 50% of the organic matter present in the DW co-precipitated with the metals from the AMD previous to feeding the reactor. Therefore, the reactors had to be supplemented with an extra carbon source (acetate) to achieve higher S elimination. Elevated removal efficiencies of chemical oxygen demand (COD) (>88%), sulfate (>75%), Fe (>85%) and other dissolved metals (>99% except for Mn) were achieved. Bacterial communities were examined through denaturing gradient gel electrophoresis and scanning electron microscopy. Higher biodiversity was found in the bioreactors compared with that of the inoculum. Dominant species belong to two metabolic groups: fermentative (Clostridium spp., Delftia spp., Paludibacter spp. and Pelotomaculum spp.) and sulfate-reducing bacteria (Desulfomonile spp., Desulfovibrio spp., Desulfosporosinus spp. and Desulfotomaculum spp.). PMID- 23032775 TI - IWRM decision support with material flow analysis: consideration of urban system input. AB - A review of material flow analysis (MFA) tools, comparison of case studies and analysis of approximately 20 MFA tools (static, semi-empirical models) are performed. The evaluation of the quantification procedures revealed several deficits in the approaches. The following principal complications for a reliable quantification of inputs from the urban water system are identified: (1) frequently insufficient data for urban system model validation (e.g. combined sewer overflow (CSO) discharges); (2) the necessity for additionally quantifying diffuse sources in order to verify modelling results at basin scale, where both input pathways occur, and (3) the contradictions arising when describing the highly dynamic urban system with the help of static MFA models. However, a wise selection of appropriate calculation procedures with regard to the concrete systems characteristics and available data can minimize the model deviations significantly. Criteria and suggestions for designing adapted quantification procedures are given. PMID- 23032776 TI - Occurrence, fate, and fluxes of perfluorochemicals (PFCs) in an urban catchment: Marina Reservoir, Singapore. AB - A study was carried out to characterize the occurrence, sources and sinks of perfluorochemicals (PFCs) in the Marina Catchment and Reservoir, Singapore. Salinity depth profiles indicated the reservoir was stratified with lower layers consisting of sea water (salinity ranging from 32 to 35 g L(-1)) and a brackish surface layer containing approximately 14-65% seawater. The PFC mixture detected in catchment waters contained perfluoroalkyl carboxylates (PFCAs), particularly perfluorooctanoate (PFOA), perfluorohexanoate (PFHpA), perfluorooctane sulfonate (PFOS) and PFC transformation products. PFC concentrations in storm runoff were generally higher than those in dry weather flow of canals and rivers. PFC concentration profiles measured during storm events indicated 'first flush' behavior, probably because storm water is leaching PFC compounds from non-point sources present in the catchment area. Storm runoff carries high concentrations of suspended solids (SS), which suggests that PFC transport is via SS. In Marina Bay, PFCs are deposited in the sediments along with the SS. In sediments, the total PFC concentration was 4,700 ng kg(-1), approximately 200 times higher than in the bottom water layers. Total perfluoroalkyl sulfonates (PFSAs), particularly PFOS and 6:2 fluoro telomer sulfonate (6:2 FtS) were dominant PFCs in the sediments. PFC sorption by sediments varied with perfluorocarbon chain length, type of functional group and sediment characteristics. A first approximation analysis based on SS transport suggested that the annual PFC input into the reservoir was approximately 35 +/- 12 kg y(-1). Contributions of SS, dry weather flow of river/canals, and rainfall were approximately 70, 25 and 5%, respectively. This information will be useful for improving strategies to protect the reservoir from PFC contamination. PMID- 23032777 TI - Sodium hydroxide pretreatment of ensiled sorghum forage and wheat straw to increase methane production. AB - The aim of this study was to determine the effect of sodium hydroxide pretreatment on the chemical composition and the methane production of ensiled sorghum forage and wheat straw. NaOH pretreatment was conducted in closed bottles, at 40 degrees C for 24 h. Samples were soaked in a NaOH solution at different dosages (expressed in terms of total solids (TS) content) of 1 and 10% gNaOH/gTS, with a TS concentration of 160 gTS/L. At the highest NaOH dosage the reduction of cellulose, hemicelluloses and lignin was 31, 66 and 44%, and 13, 45 and 3% for sorghum and wheat straw, respectively. The concentration of soluble chemical oxygen demand (CODs) in the liquid phase after the pretreatment was also improved both for wheat straw and sorghum (up to 24 and 33%, respectively). Total sugars content increased up to five times at 10% gNaOH/gTS with respect to control samples, suggesting that NaOH pretreatment improves the hydrolysis of cellulose and hemicelluloses. The Biochemical Methane Potential (BMP) tests showed that the NaOH pretreatment favoured the anaerobic degradability of both substrates. At 1 and 10% NaOH dosages, the methane production increased from 14 to 31% for ensiled sorghum forage and from 17 to 47% for wheat straw. The first order kinetic constant increased up to 65% for sorghum and up to 163% for wheat straw. PMID- 23032778 TI - Application of urea dosing for alkalinity supply during anaerobic digestion of vinasse. AB - Pushed by demand for renewable energy, the ethanol industry in Brazil is expanding. However, production of 1 m(3) of ethanol generates around 13 m(3) of liquid residues (vinasse), so this expansion results in an increasing need for a more adequate destination of these residues. Nowadays the vinasse is dispersed on the sugar cane fields in the practice of fertirrigation, but anaerobic digestion of this residue may be a better solution, additionally offering an alternative source of energy, able to complement hydroelectric power supply in the dry season. However, when trying to digest vinasse at reduced hydraulic retention times, complications arise from its strong tendency toward acidification, upsetting the fragile balance of transformations normally occurring under anaerobic conditions. For successful operation of an anaerobic treatment process with acceptable hydraulic residence times, increasing alkalinity levels inside the reactor is neces-sary. In the present work we show that pH regulation by means of urea dosing, in spite of the risk posed by ammonia toxicity towards methanogenic biomass, can be a viable alternative to avoid vinasse acidification. The ammonia formed in urea conversion remains in solution, rather than escaping to the biogas, and so its use as fertiliser can offset its cost of application in the process. PMID- 23032779 TI - Chitosan resins synthesised by improved drop-sphere-forming method for Cr(VI) removal from aqueous solutions. AB - An improved drop-sphere-forming (IDSF) method was applied to synthesise chitosan resin. Chitosan resin was synthesised by the self-made device and cross-linked with epichlorohydrin. The influences of concentration of chitosan-acetic acid solution, air flow, reaction time and the dosage of epichlorohydrin were investigated during synthesising. The satisfactory chitosan particles were prepared by chitosan-acetic acid solution (3%) under a controlled air flow of 0.6 m(3) h(-1), After 6 h of reaction at 80 degrees C with an epichlorohydrin dosage of 2 mL per 5 mL wet resin, the chitosan cross-linked resin has the best adsorption capacity. After 2 h of adsorption at pH = 3.0 and 25 degrees C with an adsorbent dosage of 2 g L(-1), the maximum adsorption capacity (112 mg g(-1)) was reached for an initial Cr(VI) concentration of 146 mg L(-1). Compared with other adsorbents, this synthesis method was simple and economic; moreover, the cross-linked chitosan resin can remove Cr(VI) efficiently. PMID- 23032780 TI - Electrochemical degradation of 4-chlorophenol in aqueous solution using modified PbO(2) anode. AB - The electrochemical oxidation of 4-chlorophenol (4-CP) in aqueous solution was studied by electrochemical oxidation using modified PbO(2) electrode as anode. The influence of several operating parameters, such as initial 4-CP concentration, applied current density, and supporting electrolyte (Na(2)SO(4)) concentration was investigated. Ultraviolet spectroscopy and total organic carbon (TOC) measurements were conducted to study the kinetics of 4-CP electrochemical reaction and the mineralization efficiency of 4-CP. The experimental results showed that the 4-CP degradation always followed a pseudo-first-order kinetics. The higher mineralization of 4-CP and the lower current efficiency (CE) were obtained by the lower initial 4-CP concentration. The applied current density showed a positive influence on the degradation of 4-CP and the removal of TOC, but a higher applied current density led to a lower CE. Although Na(2)SO(4) concentration of 0.05 M resulted in a higher 4-CP and TOC removal, the result of one-way analysis of variance (ANOVA) indicates that Na(2)SO(4) concentration is not the significant parameter for 4-CP removal in electrochemical oxidation. PMID- 23032781 TI - Microbiological quality assessment of sand and water from three selected beaches of South Coast, Sao Paulo State, Brazil. AB - This study aimed to assess the sanitary quality of water, and wet and dry sand from three beaches located in the South Coast region of Sao Paulo State, Brazil, selected taking into account the frequency of tourists and the water quality (good, fair and poor). Thirty-six water samples each of wet and dry sand and seawater were collected monthly over a period of one year and analyzed for fecal indicator bacteria (FIB: thermotolerant coliforms, Escherichia coli, and enterococci), presumptive Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans and dermatophytes. The results revealed FIB concentrations more elevated in dry sand followed by wet sand and water. P. aeruginosa and presumptive S. aureus were detected with a similar frequency in water and sand samples, but maximum concentrations and geometric means were higher in dry sand. C. albicans was detected only in water samples whereas the dermatophyte Microsporum sp. was isolated exclusively from dry and wet sand samples. This evaluation showed also that the environment had a significant influence on P. aeruginosa but not on presumptive S. aureus concentrations. According to threshold values proposed in the literature for E. coli and enterococci dry sand densities, none of the beaches would be considered of sufficient quality for recreational activities. PMID- 23032783 TI - Pilot-scale application of an online VFA sensor for monitoring and control of a manure digester. AB - A volatile fatty acids (VFA) sensor based on headspace chromatography was tested for online monitoring and control of a pilot-scale manure digester. The sensor showed satisfying results in terms of sensitivity and reliability for monitoring of the digester. The online VFA and biogas production data were used for automatic control of the digester based on feed flow manipulation. The control approach was based on optimization of biogas production while using VFA concentration as the alarm threshold. A rule-based supervisory system with a cascade controller was used to optimize the biogas production from the digester. The alarm state was set at 40 mM total VFA and 10 mM propionate concentration. The control algorithms could successfully maximize the biogas production without overloading the process. However, as the algorithm was based on a fixed biogas yield parameter and only used the biogas parameter for optimization, it could not distinguish between the decreases of biogas production from inhibition and from lower organic content in the substrate, which resulted in undesired decreasing of the control gas setpoint when the substrate was diluted. It was necessary to adjust the yield parameter in order to get this control approach to function properly, which is not suitable for the full-scale biogas plant where the organic content of waste streams can vary. An alternative approach could be a modified rule-based algorithm that includes VFA parameters to help distinguish between different process scenarios. PMID- 23032782 TI - Towards a benchmarking tool for minimizing wastewater utility greenhouse gas footprints. AB - A benchmark simulation model, which includes a wastewater treatment plant (WWTP) wide model and a rising main sewer model, is proposed for testing mitigation strategies to reduce the system's greenhouse gas (GHG) emissions. The sewer model was run to predict methane emissions, and its output was used as the WWTP model input. An activated sludge model for GHG (ASMG) was used to describe nitrous oxide (N(2)O) generation and release in activated sludge process. N(2)O production through both heterotrophic and autotrophic pathways was included. Other GHG emissions were estimated using empirical relationships. Different scenarios were evaluated comparing GHG emissions, effluent quality and energy consumption. Aeration control played a clear role in N(2)O emissions, through concentrations and distributions of dissolved oxygen (DO) along the length of the bioreactor. The average value of N(2)O emission under dynamic influent cannot be simulated by a steady-state model subjected to a similar influent quality, stressing the importance of dynamic simulation and control. As the GHG models have yet to be validated, these results carry a degree of uncertainty; however, they fulfilled the objective of this study, i.e. to demonstrate the potential of a dynamic system-wide modelling and benchmarking approach for balancing water quality, operational costs and GHG emissions. PMID- 23032784 TI - The time course of psychological stress as revealed by event-related potentials. AB - Psychological stress is common in everyday life and is believed to affect emotion, cognition and health. Previous brain imaging studies have been able to identify the brain regions involved in the stress response. However, our understanding of the temporal neurological response to psychological stress is limited. The present work aims to investigate the time course of psychological stress induced by a mental arithmetic task, utilizing event-related potentials (ERPs). The elicitation of stress was verified by self-reports of stress and increases in salivary cortisol levels. The subjective and physiological data showed that the stress-elicitation paradigm successfully induced a mild-to moderate level of psychological stress. The electrophysiological data showed that the amplitude of occipital N1 was more negative in the control task than in the stress task, and the latency of frontal P2 was shorter in the stress task than in the control task. Our results provide electrophysiological evidence that psychological stress occurs primarily at the early stage of cognitive processing. PMID- 23032785 TI - Gas phase low energy electron induced decomposition of the focused electron beam induced deposition (FEBID) precursor trimethyl (methylcyclopentadienyl) platinum(IV) (MeCpPtMe3). AB - Relative cross sections for dissociative electron attachment (DEA) and dissociative ionization (DI) of the FEBID precursor, trimethyl (methylcyclopentadienyl) platinum(iv), MeCpPtMe(3), are presented. The most pronounced DEA process is the loss of one methyl radical, while the loss of two or three methyl groups along with hydrogen is the main pathway in DI. Further fragments are formed in DEA and through DI by more complex rearrangement reactions but complete dissociation to bare Pt(-) in DEA or Pt(+) in DI is minor. The transient negative ion (TNI) formation in DEA is discussed and fragmentation mechanisms are proposed for individual processes. From the thermodynamics of the DEA processes we derive a lower limit for the electron affinity of the MeCpPtMe(2) radical (1.7 eV). Appearance energies (AE) of MeCpPtMe(3)(+) (7.7 eV) and Pt(+) (18.6 eV) formation through electron impact ionisation (EI) and through DI, respectively, are determined. Finally, the current DEA and DI results are compared and brought into context with earlier surface science studies on electron-induced decomposition of adsorbed MeCpPtMe(3) as well as gas phase and surface science studies on the FEBID precursors [Co(CO)(3)NO] and [Pt(PF(3))(4)]. These comparisons strongly indicate that DEA is an important process in the electron-induced decomposition of these molecules in FEBID. PMID- 23032786 TI - Spatially resolved investigation of the oil composition in single intact hyphae of Mortierella spp. with micro-Raman spectroscopy. AB - Zygomycetes are well known for their ability to produce various secondary metabolites. Fungi of the genus Mortierella can accumulate highly unsaturated lipids in large amounts as lipid droplets. However, no information about the spatial distribution or homogeneity of the oil inside the fungi is obtainable to date due to the invasive and destructive analytical techniques applied so far. Raman spectroscopy has been demonstrated to be well suited to investigate biological samples on a micrometre scale. It also has been shown that the degree of unsaturation of lipids can be determined from Raman spectra. We applied micro Raman spectroscopy to investigate the spatial distribution and composition of lipid vesicles inside intact hyphae. For Mortierella alpina and Mortierella elongata distinct differences in the degree of unsaturation and even the impact of growth conditions are determined from the Raman spectra. In both species we found that the fatty acid saturation in the vesicles is highly variable in the first 600 MUm of the growing hyphal tip and fluctuates towards a constant composition and saturation ratio in all of the remaining mycelium. Our approach facilitates in vivo monitoring of the lipid production and allows us to investigate the impact of cultivation parameters on the oil composition directly in the growing hyphae without the need for extensive extraction procedures. PMID- 23032788 TI - Mn-induced modifications of Ga 3d photoemission from (Ga, Mn)As: evidence for long range effects. AB - Using synchrotron based photoemission, we have investigated the Mn-induced changes in Ga 3d core level spectra from as-grown Ga(1-x)Mn(x)As. Although Mn is located in Ga substitutional sites, and therefore does not have any Ga nearest neighbors, the impact of Mn on the Ga core level spectra is pronounced even at Mn concentrations in the region of 0.5%. The analysis shows that each Mn atom affects a volume corresponding to a sphere with around 1.4 nm diameter. PMID- 23032787 TI - The G0/G1 switch gene 2 (G0S2): regulating metabolism and beyond. AB - The G0/G1 switch gene 2 (G0S2) was originally identified in blood mononuclear cells following induced cell cycle progression. Translation of G0S2 results in a small basic protein of 103 amino acids in size. It was initially believed that G0S2 mediates re-entry of cells from the G0 to G1 phase of the cell cycle. Recent studies have begun to reveal the functional aspects of G0S2 and its protein product in various cellular settings. To date the best-known function of G0S2 is its direct inhibitory capacity on the rate-limiting lipolytic enzyme adipose triglyceride lipase (ATGL). Other studies have illustrated key features of G0S2 including sub-cellular localization, expression profiles and regulation, and possible functions in cellular proliferation and differentiation. In this review we present the current knowledge base regarding all facets of G0S2, and pose a variety of questions and hypotheses pertaining to future research directions. PMID- 23032789 TI - Building on architectural principles for three-dimensional metallosupramolecular construction. AB - Over the last two decades the field of metallosupramolecular self-assembly has emerged as a promising research area for the development of intricate, three dimensional structures of increasing complexity and functionality. The advent of this area of research has strongly benefited from design principles that considered the ligand geometry and metal coordination geometry, thus opening up routes towards rationally designed classical (Archimedean or Platonic) architectures. In this tutorial review, we will focus on more recent developments in the design and synthesis of three-dimensional suprastructures which have non classical architectures (non-Archimedean/Platonic solids) and we will explicitly address the secondary effects responsible for their formation. Three classes of metallosupramolecular assemblies will be discussed: architectures formed through the combination of a single ligand and metal, heteroleptic structures and heterometallic structures. It is hoped that our exposition may suggest how different principles employed in these three classes of structures might be combined to create even greater complexity and potential for function. PMID- 23032790 TI - Induction of protective immunity against Mycobacterium tuberculosis by delivery of ESX antigens into airway dendritic cells. AB - As the Bacillus Calmette-Guerin (BCG) vaccine does not confer long-lasting protection against lung Mycobacterium tuberculosis infection, the development of more efficient vaccines is greatly needed. Here, we used mycobacterial low molecular weight proteins of the 6-kDa Early Secreted Antigenic Target (ESAT-6) protein family (ESX) antigens for the evaluation of a novel vaccine delivery strategy that enables versatile in vivo targeting of antigens into specialized dendritic cell (DC) subsets. ESX antigens were genetically fused to the tetramerizing core of streptavidin (SA) to form high-affinity complexes with biotin (biot)-conjugated antibodies recognizing DC surface receptors. When directed through the CD11b or CD11c beta2-integrins or diverse C-type lectins, the ESX-SA:biot-antibody complexes were efficiently captured and presented on major histocompatibility complex molecules of DCs to specific T-cell receptors. Robust ESX-specific T-cell responses were induced by immunization with as little as several picomoles of ESX-SA targeted to DC subsets. Moreover, directing of TB10.4-SA to airway CD205(+) cells enabled the induction of mucosal T-cell responses and provided significant protection against virulent M. tuberculosis. PMID- 23032791 TI - The Escherichia coli heat-labile enterotoxin B subunit protects from allergic airway disease development by inducing CD4+ regulatory T cells. AB - The B subunit of E. coli heat-labile enterotoxin (EtxB) protects against the development of T helper type 1 (Th1)-mediated autoimmune pathologies in mice. Protection was transferable with splenic CD4(+) T cells and was less effective following CD25 depletion; implying a T regulatory cell (Treg)-mediated process. We hypothesized that if this were the case, then EtxB would also control a Th2 mediated disorder. We tested the effect of EtxB treatment on asthma development in ovalbumin (OVA)-sensitized mice. EtxB treatment diminished eosinophilia in bronchoalveolar lavage samples, reduced OVA-specific immunoglobulin E and interleukin 4 production locally and systemically, and reduced airway hyper reactivity. EtxB induced a dose-dependent increase in Foxp3(+)CD4(+) T cells, and adoptive transfer of splenic CD4(+) T cells partially suppressed lung pathology. Importantly, EtxB treatment increased OVA-specific CD4(+)Foxp3(+) T cells in the lung and systemically. These data demonstrate that EtxB modulates the differentiation of allergen-specific T cells causing inducible Treg induction and preventing disease. PMID- 23032792 TI - Reliability of a new scale for essential tremor. AB - BACKGROUND: The objective of this study was to determine the reliability of a new scale for the clinical assessment of essential tremor. The Essential Tremor Rating Assessment Scale contains 9 performance items that rate action tremor in the head, face, voice, limbs, and trunk from 0 to 4 in half-point intervals. Head and limb tremor ratings are defined by specific amplitude ranges in centimeters. METHODS: Videos of 44 patients and 6 controls were rated by 10 specialists on 2 occasions 1-2 months apart. Inter- and intrarater reliability was assessed with a 2-way random-effects intraclass correlation, using an absolute agreement definition. RESULTS: Inter- and intrarater intraclass correlations for head and upper-limb tremor ranged from 0.86 to 0.96, and intraclass correlations for total score were 0.94 and 0.96. The intraclass correlations for voice, face, trunk, and leg were less robust. CONCLUSIONS: This scale is an exceptionally reliable tool for the clinical assessment of essential tremor. PMID- 23032793 TI - Dynamically controllable emission of polymer nanofibers: electrofluorescence chromism and polarized emission of polycarbazole derivatives. AB - Electrochemical polymerization of a series of N-alkyl-2,7-di(2-thienyl)carbazoles in acetonitrile was performed to obtain conjugated polymers with fluorescence. Scanning electron and atomic force microscopies revealed that the surface morphology of the polymer films significantly depends on the alkyl chain lengths of the polymers. Particularly, a homopolymer bearing hexyl groups and copolymers with an average alkyl chain length of six carbon atoms show nanofiber morphology. The polymer nanofibers were stacked on a substrate electrode. The fluorescence of the polymer nanofiber film was tunable with application of voltage, with good repeatability. The X-ray diffraction pattern of the fibers showed the structural order. The polymer nanofibers thus prepared showed an electrochemically driven change in polarized photoluminescence. PMID- 23032795 TI - Evaluation of a point-of-care test based on deamidated gliadin peptides for celiac disease screening in a large pediatric population. AB - OBJECTIVES: Celiac disease (CD) is nowadays known to be a common chronic enteropathy that is becoming a growing public health concern. Yet, it is estimated that more than 90% of patients remain undiagnosed. A point-of-care diagnostic test can be a rapid and cost-effective solution in the first-line screening of CD. The aim of this study is to evaluate the performance of a novel point-of-care screening test in a large pediatric population. MATERIALS AND METHODS: Serum samples were collected from a cohort of 250 children presenting either an increased risk or a clinical suspicion of CD. All sera were tested using the point-of-care test detecting IgA and IgG antibodies against a combination of three different deamidated gliadin peptides as well as total IgA. The results of the screening test were compared with an enzyme-linked tissue transglutaminase immunosorbent assay and with histology resulting from intestinal biopsies performed in patients with elevated titers of antitissue transglutaminase antibodies. RESULTS: The point-of-care test showed highly concordant results with the laboratory immunoassay, yielding a sensitivity of 93.1 (78-98.1%) and a specificity of 95% (91.2-97.2%), with a diagnostic accuracy of 94.8% (91.3-96.9%) and a negative predictive value of 99.1% (96.6-99.7%). The screening test identified all patients with celiac-type histology findings on biopsy, as well as all patients with concomitant IgA deficiency. CONCLUSION: With a high diagnostic accuracy, this novel point-of-care approach is an efficient tool for CD case finding in pediatric populations. It has the potential to improve the management of celiac patients in primary care by providing faster counseling and treatment. PMID- 23032797 TI - Desorption of n-alkanes from graphene: a van der Waals density functional study. AB - A recent study of temperature-programmed desorption (TPD) measurements of small linear alkane molecules (n-alkanes, with formula C(N)H(2N+2)) from C(0001) deposited on Pt(111) shows a linear relationship of the desorption energy with increasing n-alkane chain length N. We here present a van der Waals density functional study of the desorption barrier energy of the ten smallest n-alkanes (of carbon chain length N = 1-10) from graphene. We find linear scaling with N, including a non-zero intercept with the energy axis, i.e. an offset at the extrapolation to N = 0. This calculated offset is quantitatively similar to the results of the TPD measurements. From further calculations of the polyethylene polymer we offer a suggestion for the origin of the offset. PMID- 23032798 TI - Iguratimod: a new disease-modifying antirheumatic drug. AB - Iguratimod, a methanesulfonanilide, is a novel disease-modifying antirheumatic drug that has been developed exclusively in Japan and China. It inhibits the production of immunoglobulins and various inflammatory cytokines (interleukin-1, 6 and -8 and TNF), and exerts anabolic effects on bone metabolism by stimulating osteoblastic differentiation and inhibiting osteoclastogenesis. On the molecular level, it inhibits the nuclear transcription factor NF-kappaB but not its inhibitor, IkappaBalpha. In addition to these immunomodulatory and other long lasting effects, iguratimod inhibits cyclooxygenase-2, which provides a synergistic short-term action against pain and inflammation. Efficacy and tolerability are comparable to salazosulfapyridine, and probably also to methotrexate. Combination with methotrexate is synergistic in patients with insufficient response to methotrexate and does not significantly increase adverse events. Liver enzyme elevations and thrombocytopenia are the most significant side effects to watch for. In summary, iguratimod is a welcome addition to the small-molecule drug therapy of rheumatoid arthritis. PMID- 23032799 TI - Lucinactant for the treatment of respiratory distress syndrome in neonates. AB - Respiratory distress syndrome (RDS) is a leading cause of morbidity and mortality in premature neonates. This syndrome is caused by a lack of endogenous surfactant production in the lungs. Surfactant replacement was established as a safe and effective treatment in the 1990s and has become the standard of care for these infants. Surfactant products are either protein-free synthetic phospholipid compounds or animal-derived lung preparations. Currently, about 90,000 infants a year receive treatment with one of the commercially available animal-derived surfactants. Lucinactant (Surfaxin(r)) is a new synthetic surfactant with a pulmonary surfactant-associated protein B mimic that recently received FDA approval. The clinical trials that have been performed, although underpowered, may indicate that lucinactant is superior to phospholipid synthetic surfactant preparations and at least as effective as animal-derived surfactants in reducing morbidity and mortality from RDS. This review summarizes the current clinical knowledge about lucinactant. PMID- 23032800 TI - Spinosad for the treatment of head lice infestations. AB - Head lice infestations continue to be an issue in today's society, with an increase in economic cost and resistance. Spinosad 0.9% topical suspension was recently introduced in the U.S. market as a novel agent with both pediculicidal and ovicidal activity, approved in children 4 years of age and older for the treatment of head lice infestations. In clinical trials, it has demonstrated effectiveness against head lice with permethrin resistance. In two clinical trials comparing spinosad to permethrin, efficacy was observed in the spinosad treated groups at 84.6% and 86.7%, respectively, when compared to the permethrin treated groups (respective values of 44.9% and 42.9%; P < 0.001). Overall, spinosad was well tolerated in clinical trials. PMID- 23032802 TI - A report from the endocrine society's 94th annual meeting & expo (June 23-26 - Houston, Texas, USA). AB - At temperatures above 100 degrees Fahrenheit, but chilly air conditioning inside the George R. Brown convention center, Houston was the endocrine capital of America during June 2012, with the ENDO EXPO 2012 meeting calling attendees from all the states and abroad. Endocrinology is a highly varied specialty, ranging from hormonal disturbances of the pituitary (and in fact acromegaly and Cushing's syndrome were among the stars of this year's meeting therapy-wise) to diabetes, female hormonal disorders and endocrine-mediated malignancies, to mention only a few. New and investigational treatments for these conditions are summarized in the following report, based on the oral and poster presentations during the meeting. PMID- 23032801 TI - New and established tyrosine kinase inhibitors for chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is an uncommon malignancy, the treatment and prognosis of which have dramatically shifted over the last decade. Characterized by a translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, small-molecule tyrosine kinase inhibitors (TKIs) targeted against the oncogenic BCR-ABL fusion protein have changed this once fatal disease into the model of targeted therapy. This article will review the pharmacological and clinical data supporting the use of imatinib and the second-generation TKIs dasatinib and nilotinib, and the novel TKIs bosutinib and ponatinib. PMID- 23032803 TI - Reversible multistimuli-responsive vesicles formed by an amphiphilic cationic platinum(II) terpyridyl complex with a ferrocene unit in water. AB - An amphiphilic cationic platinum(II) terpyridyl complex 1 with a redox ferrocene unit has been demonstrated to form well-defined vesicular architectures that could be disrupted and regenerated reversibly by multi-stimuli in water. The hydrophobic and hydrophilic alternation of 1 was achieved via modulating its intramolecular ILCT state to MLCT state. PMID- 23032805 TI - Insuring the uninsured: potential impact of Health Care Reform Act of 2010 on trauma centers. AB - BACKGROUND: Viability of trauma centers is threatened by cost of care provided to patients without health insurance. The health care reform of 2010 is likely to benefit trauma centers by mandating universal health insurance by 2014. However, the financial benefit of this mandate will depend on the reimbursement provided. The study hypothesis was that compensation for the care of uninsured trauma patients at Medicare or Medicaid rates will lead to continuing losses for trauma centers. METHODS: Financial data for first hospitalization were obtained from an urban Level I trauma center for 3 years (n = 6,630; 2006-2008) and linked with clinical information. Patients were grouped into five payments categories: commercial (29%), Medicaid (8%), Medicare (20%), workers' compensation (6%), and uninsured (37%). Prediction models for costs and payments were developed for each category using multiple regression models, adjusting for patient demographics, injury characteristics, complications, and survival. These models were used to predict payments that could be expected if uninsured patients were covered by different insurance types. Results are reported as net margin per patient (payments minus total costs) for each insurance type, with 95% confidence intervals, discounted to 2008 dollar values. RESULTS: Patients were typical for an urban trauma center (median age of 43 years, 66% men, 82% blunt, 5% mortality, and median length of stay 4 days). Overall, the trauma center lost $5,655 per patient, totaling $37.5 million over 3 years. These losses were encountered for patients without insurance ($14,343), Medicare ($4,838), and Medicaid ($15,740). Patients with commercial insurance were profitable ($5,295) as were those with workers' compensation ($6,860). Payments for the care of the uninsured at Medicare/Medicaid levels would lead to continued losses at $2,267 to $4,143 per patient. CONCLUSION: The health care reforms of 2010 would lead to continued losses for trauma centers if uninsured are covered with Medicare/Medicaid-type programs. LEVEL OF EVIDENCE: Economic analysis, level II. PMID- 23032806 TI - Age-related trends in intracranial injury outcomes. AB - BACKGROUND: Age is an important prognostic indicator of outcomes following traumatic brain injuries. This study examines how outcomes for traumatic brain injuries in the acute care setting have changed during a recent 10-year period. METHODS: Population-level data broken down by age group was obtained from the Agency for Healthcare Research and Quality Web site for the years 2000 to 2009. Linear regression was used to determine trends in age-specific discharge volume, mortality rate, discharge disposition, and cost. Population and cost estimates were adjusted using census data and consumer price index. RESULTS: It was found that discharges for intracranial injuries have been increasing, with the most marked increase in the population older than 65 years, which cannot be accounted for by population age distribution changes. There were overall improvements in outcomes including decreased in-hospital mortality rates for all age groups and increased home discharges for those 18 to 44 years and older than 85 years. This came at an average annual cost increase of $1,071 dollars per patient. CONCLUSION: Acute care outcomes for intracranial injuries have been improving at a cost of $1,071 per patient per year. LEVEL OF EVIDENCE: Economic and decision analysis, level IV. PMID- 23032808 TI - Bedside thoracic ultrasonography of the fourth intercostal space reliably determines safe removal of tube thoracostomy after traumatic injury. AB - BACKGROUND: Thoracic ultrasonography is more sensitive than chest radiography (CXR) in detecting pneumothorax; however, the role of ultrasonography to determine resolution of pneumothorax after thoracostomy tube placement for traumatic injury remains unclear. We hypothesized that ultrasonography can be used to determine pneumothorax resolution and facilitate efficient thoracostomy tube removal. We sought to compare the ability of thoracic ultrasonography at the second through fifth intercostal space (ICS) to detect pneumothorax with that of CXR and determine which ICS maximizes the positive and negative predictive value of thoracic ultrasonography for detecting clinically relevant pneumothorax resolution. METHODS: A prospective, blinded clinical study of trauma patients requiring tube thoracostomy placement was performed at a university-based urban trauma center. A surgeon performed daily thoracic ultrasonographies consisting of midclavicular lung evaluation for pleural sliding in ICS 2 through 5. Ultrasonography findings were compared with findings on concurrently obtained portable CXR. RESULTS: Of the patients, 33 underwent 119 ultrasonographies, 109 of which had concomitant portable CXR results for comparison. Ultrasonography of ICS 4 or 5 was better than ICS 2 and 3 at detecting a pneumothorax, with a positive predictive value of 100% and a negative predictive value of 92%. The positive and negative predictive values for ICS 2 were 46% and 93% and for ICS 3 were 63% and 92%, respectively. CONCLUSION: Bedside, surgeon-performed, thoracic ultrasonography of ICS 4 for pneumothorax can safely and efficiently determine clinical resolution of traumatic pneumothorax and aid in the timely removal of thoracostomy tubes. LEVEL OF EVIDENCE: Diagnostic study, level II. PMID- 23032807 TI - Using trauma center data to identify missed bicycle injuries and their associated costs. AB - BACKGROUND: Recently, there has been a 58% increase in the number of observed cyclists in San Francisco. In 2009, 3.2% of commuters were traveling by bicycle in this city, which is well above the national average of less than 1%. Police reports are the industry standard for assessing transportation-related collisions and informing policies and interventions that address the issue. Previous studies have suggested that police reports miss a substantial portion of bicycle crashes not involving motor vehicles. No study to date has explored the health and economic impact of cyclist-only (CO) injuries for adults in the United States. Our objective was to use trauma registry data to investigate possible underrepresentation of certain cyclist injuries and characterize cost. METHODS: We reviewed hospital and police records for 2,504 patients treated for bicycle related injuries at San Francisco General Hospital (SFGH). We compared incidence, injury severity, admission rate, and cost of injury for CO and auto-versus bicycle (AVB) injuries treated at SFGH. We then calculated the cost of injury. RESULTS: Of all bicycle-related injuries at SFGH, 41.5% were CO injuries and 58.5% were AVB injuries. Those with CO injuries were more than four times as likely to be required of hospital admission compared with those with AVB injuries (odds ratio, 4.76; 95% confidence interval, 3.93-5.76; p < 0.0001). From 2000 to 2009, 54.5% of bicycle injuries treated at SFGH were not associated with a police report, revealing that bicycle crashes and injuries are underrecognized in San Francisco. Costs for care were significantly higher for AVB injuries and increased dramatically over time; total cost for CO and AVB injuries were $12.6 and $17.8 million. CONCLUSION: Based on this study, we conclude that trauma centers can play a key role in future collaborations to define issues and develop prevention strategies for CO crashes. LEVEL OF EVIDENCE: Epidemiologic study, level II. PMID- 23032809 TI - Combat-incurred bilateral transfemoral limb loss: a comparison of the Vietnam War to the wars in Afghanistan and Iraq. AB - BACKGROUND: This study is a comparison of the self-reported health status, quality of life, function, and prosthetic use of veterans with bilateral transfemoral limb loss following combat injury in either the Vietnam War or the recent conflicts in Afghanistan and Iraq, to learn what improvements in surgery, prosthetics, and rehabilitation have occurred. METHODS: Subjects were identified from Veteran's Administration and military databases. A cross-sectional survey was conducted of service members with bilateral transfemoral amputation who participated in a larger survey of service members with any type of amputation associated with a battlefield injury from the Vietnam War or Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF). The survey was conducted by mail, telephone, or Web site during 2007 to 2008. RESULTS: There were 501 subjects in the Vietnam group and 541 in the OIF/OEF group with any type of limb loss. Bilateral transfemoral amputation was reported in 23 (7.7%) of 298 of the Vietnam group and 10 (3.5%) of 283 of the OIF/OEF group (chi test, p = 0.04). Self reported health status was rated as good to excellent in 40% of the Vietnam group and 80% in the OIF/OEF group (p = 0.04). Quality of life was rated as good to excellent in 54.6% of the Vietnam group and 70% of the OIF/OEF group (not significant). Wheelchair use is reported by 22 of 23 subjects in the Vietnam group and all of the subjects of the OIF/OEF group. Of the Vietnam group, 8 (34.7%) of 23 currently use prostheses versus 7 (70%) of 10 of the OIF/OEF group (chi test, p = 0.13). The mean (SD) number of prostheses currently used is 1.0 (1.9) for the Vietnam group and 4.0 (5.2) for the OIF/OEF group (p = 0.022). CONCLUSION: Participants who served in OIF/OEF and those who served in Vietnam report comparable quality of life. Prosthetic use continues to be a problem, especially as the service member ages. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 23032810 TI - A prospective cohort study of 200 acute care gallbladder surgeries: the same disease but a different approach. AB - BACKGROUND: For patients who present to the emergency department (ED) with symptomatic cholelithiasis, surgery is indicated only if they are diagnosed of acute cholecystitis (AC). We hypothesized that, because preoperative signs and diagnostic tests are not sensitive enough to diagnose AC, coupled with the potential health care burden of non-AC gallbladder, surgery may be offered sooner. METHODS: We prospectively evaluated 200 patients who presented to ED with clinical suspicion of gallbladder disease, including a right upper quadrant/epigastric abdominal pain and cholelithiasis, and who underwent laparoscopic cholecystectomy. We correlated the preoperative clinical findings, including ultrasonography results, with the surgeon's intraoperative assessment (OR-GB) and with the pathology report (PA-GB). A multiple logistic regression model was performed. RESULTS: Of the gallbladders, 116 were declared AC by OR-GB but only 54 by PA-GB, (r = 0.31, p < 0.001). The median time to surgery was 17 hours; 75% of the patients underwent surgery within 24 hours. The sensitivity of ultrasonography for AC according to PA-GB was 38%, and 16% when combined all preoperative findings. Both figures dropped to 27% and 11% when correlated to OR GB. Our regression identified persistent abdominal pain, positive ultrasonography result, and a body mass index of greater than 40 to be significant predictors of AC according to PA-GB; however, only the persistent abdominal pain remained significant according to OR-GB. CONCLUSION: The study confirmed the lack of sensitivity of signs and diagnostic tools to diagnose AC. Because of the acute care surgery model, we believe that the approach to the patients who present to the ED with suspected gallbladder disease is to offer them surgery as soon as feasible, with or without AC. This approach will avoid an unnecessary delay as well as quickly relieve patient's pain and suffering; the health care system will benefit from a cost-effective reduction in number of outpatient referrals and repeated ED visits. LEVEL OF EVIDENCE: Diagnostic study, level II. PMID- 23032811 TI - Objective estimates of the probability of death in acute burn injury: a proposed Taiwan burn score. AB - BACKGROUND: This study aimed to develop an objective model for predicting mortality after burn injury in Taiwan. METHODS: From 1997 to 2010, 23,147 patients with acute burn injury in 44 hospitals were retrospectively reviewed. Variables examined were age, sex, depth and extent of burn, inhalation injury, flushing time, hospital admission and referral status, intensive care unit admission, and mortality. Logistic regression analyses were used to evaluate risk factors. Model performance and calibration was evaluated by measures of discrimination and goodness-of-fit statistic, respectively. A nomogram of four major risk factors was used to calculate the probability of mortality. RESULTS: Only 22,665 patients (mean [SD] age, 31.05 [22.67] years; mean second-degree and third-degree burn sizes, 8.67% [10.64%] and 3.25% [10.91%], respectively) survived until discharge, for a mortality rate of 2.08%. CONCLUSION: Burn depth is an important predictive factor for mortality. An objective model can help estimate the probability of death in acute burn injury. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 23032812 TI - Prostacyclin reduces plasma volume loss after skeletal muscle trauma in the rat. AB - BACKGROUND: Trauma induces transcapillary leakage of fluid and proteins because of increased microvascular permeability. Based on studies showing that prostacyclin (PGI2) has permeability-reducing properties, in the present study, we investigated whether PGI2 reduces plasma volume (PV) loss after a nonhemorrhagic trauma. METHODS: The study was performed on anesthetized Sprague Dawley rats exposed to a controlled standardized blunt trauma to the abdominal rectus muscle. Thereafter, the animals were randomized to treatment with either PGI2 (2 ng/kg per minute) or 0.9% NaCl. PV was estimated before and 3 hours after the trauma using I-albumin as tracer. In separate experiments, the transcapillary escape rate of I-albumin was calculated and plasma concentrations of cytokines were measured after both treatments. RESULTS: Average PV at baseline was 41.6 mL/kg +/- 2.5 mL/kg and 42.3 mL/kg +/- 1.7 mL/kg in the PGI2 and NaCl animals, respectively. PV was decreased by 22% +/- 8% in the NaCl animals and by 11% +/- 9% in the PGI2 animals 3 hours after the trauma (p < 0.05). Trauma induced a decrease in mean arterial blood pressure and an increase in hematocrit in both groups. There were no differences in urine production and mean arterial blood pressure between the PGI2 and NaCl animals. The transcapillary escape rate for albumin was calculated for one hour starting 30 minutes after the trauma and was 15.1% +/- 2.4% per hour in the PGI2 animals and 17.4% +/- 3.3% per hour in the NaCl animals (p = 0.09). Interleukin 6 concentration 3 hours after the trauma was lower in the PGI2 animals than in the NaCl animals (p < 0.05). CONCLUSION: We conclude that PGI2 attenuates PV loss after blunt muscle trauma. The vascular effects of PGI2 are associated with a modulation of the trauma-induced inflammatory response. PMID- 23032813 TI - Toward a better definition of massive transfusion: focus on the interval of hemorrhage control. AB - BACKGROUND: In clinical research, massive transfusion (MT) is commonly defined as transfusion of 10 or more red blood cell (RBC) units within 24 hours. However, the clinical relevance of this definition remains poorly understood. In this study, we evaluated whether patients who reach the MT threshold during hemorrhage control differ clinically from those who reach it after hemorrhage control (i.e., after intensive care unit [ICU] arrival) but before 24 hours. METHODS: Prospective data were collected on all Level I trauma resuscitations within 5.5 years. Patients transfused 10 or more RBCs in the first 24 hours of hospitalization were identified and stratified according to when the MT threshold was achieved: before ICU arrival (Pre-ICU) versus after ICU arrival but before 24 hours of hospitalization (Post-ICU). Clinical characteristics between groups were compared. RESULTS: Three hundred five patients received 10 or more units before ICU arrival, and 46 reached the MT threshold after ICU arrival but before 24 hours. Both groups were clinically similar with respect to age, sex, and Injury Severity Score, but the Post-ICU group had a larger proportion of blunt injuries (71 vs. 53%, p < 0.05), lower mean admission lactate (5.9 vs. 8.1 mmol/L, p < 0.05), and higher systolic blood pressure (112 vs. 96 mm Hg, p < 0.05) compared with the Pre-ICU group. Twenty-four-hour mortality was significantly lower in the Post-ICU group compared with the Pre-ICU group (9 vs. 33%, p < 0.05). In-hospital mortality was not significantly different between groups (33 vs. 46%, p = 0.11). CONCLUSION: Patients reaching the MT threshold after ICU arrival comprise a relatively small proportion of those that would be included by the traditional MT definition. However, they have a significantly decreased mortality risk at 24 hours and the potential to dilute the study cohort. For research purposes, restricting the MT definition to 10 or more RBCs during hemorrhage control may result in study cohorts with relatively more uniform mortality risks. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 23032814 TI - Flowers and inflorescences of the seagrass Posidonia (Posidoniaceae, Alismatales). AB - PREMISE OF THE STUDY: The predominantly aquatic order Alismatales displays a highly variable flower groundplan associated with a diverse range of developmental patterns. We present the first detailed description of flower anatomy and development in Posidonia, the sole genus of the seagrass family Posidoniaceae. Existing accounts provide conflicting interpretations of floral and inflorescence structure, so this investigation is important in clarifying morphological evolution within this early-divergent monocot order. * METHODS: We investigated two species of Posidonia using light microscopy and scanning electron microscopy. Our observations are interpreted in the framework of a recent molecular phylogeny. * KEY RESULTS: Partial inflorescences are bracteate spikes, which are arranged into a botryoid or a panicle. The flowers are perianthless. The gynoecium is monomerous with the ventral carpel side oriented abaxially. The carpel contains a single pendent bitegmic ovule with a nucellus and long chalaza, both extending along the carpel wall. The ovule develops an integumentary outgrowth. Each flower is supplied by a vascular bundle, whereas the flower-subtending bracts are nonvascularized. * CONCLUSIONS: Our data support a racemose interpretation for the partial inflorescence of Posidonia and the presence of flower-subtending bracts. In common with some other Alismatales, Posidonia has simultaneous development of the flower and its subtending bract and loss of the bract vascular supply accompanied by innervation of the flower by a single vascular strand. The unusual carpel orientation could be an evolutionary reduction of a formerly tricarpellate gynoecium. The ovule of Posidonia is campylotropous and unusual within Alismatales in possessing an integumentary outgrowth. PMID- 23032815 TI - Polyploidy in Indian paintbrush (Castilleja; Orobanchaceae) species shapes but does not prevent gene flow across species boundaries. AB - PREMISE OF STUDY: A difference in chromosome numbers (ploidy variation) between species is usually considered a major barrier to gene flow. Therefore, it is surprising that little is known about whether ploidy variation, both within and among species, influences spatial patterns of interspecific hybridization. The role that polyploidy plays in structuring gene flow patterns between three co occurring Indian paintbrush (Castilleja) species is investigated. * METHODS: Reciprocal hand pollinations were performed in populations where the three species co-occur with and without variable plants (previous data tested the ancestral "hybrid" history of these variable plants). I measured fruit set, seed production, seed germination, and the DNA content of parent plants and 26 synthesized F(1) hybrids. Data were combined with pollinator fidelity data to estimate the contribution of individual barriers to reproductive isolation. * KEY RESULTS: Interspecific gene flow could occur in all directions, but barriers were weaker for conspecific vs. heterospecific crosses. Species were nearly fixed for different ploidy levels, but some deviations occurred, primarily in populations with variable plants. Interspecific gene flow could occur across ploidy levels, but it was more likely when species had the same number of chromosomes or when resulting F(1) hybrids had even numbers of chromosomes. Postzygotic reproductive barriers were generally weaker than pollinator fidelity. * CONCLUSIONS: Polyploidy likely plays a large role in shaping contemporary and historical patterns of gene flow among these species. This study suggests that differences in chromosome numbers among closely related, compatible species might help structure spatial patterns of hybridization. PMID- 23032816 TI - Does mycorrhizal specificity affect orchid decline and rarity? AB - PREMISE OF THE STUDY: Orchids rely on mycorrhizal fungi for seed germination, and many species maintain associations during later stages in their life cycle. Because of the critical dependence of orchids on fungi it has been suggested that the degree of mycorrhizal specificity may be associated with rarity and long-term survival of orchid species, especially in highly degraded or fragmented landscapes. To test this hypothesis, we compared mycorrhizal communities in two species that differed significantly in decline in Belgium and other parts of Europe. * METHODS: Mycorrhizal associations were investigated in five populations of Anacamptis morio and Dactylorhiza fuchsii in Belgium. ITS-based DNA arrays were used for simultaneous detection and identification of a wide range of basidiomycetous mycorrhizal fungi. Mycorrhizal specificity, measured as phylogenetic diversity, was assessed for each population and compared between species. * KEY RESULTS: For both species, the degree of phylogenetic relatedness of the mycorrhizal partners was low, and both species were associated with a large number of fungal lineages related to clades of the Tulasnellaceae family. Contrary to expectations, the species that was apparently resilient to decline was associated with fewer fungal operational taxonomical units than the declining species was, and the phylogenetic relatedness of mycorrhizal communities among populations was higher in the stable than in the declining orchid. * CONCLUSIONS: Although our results do not present detailed insights into the causes of orchid persistence, they do suggest that orchid rarity and persistence are not necessarily related to fungal diversity and that other factors may be more important in determining orchid persistence. PMID- 23032817 TI - The Hippocratic oath: a comparative analysis of the ancient text's relevance to American and Indian modern medicine. AB - Hippocrates (460-375 B.C.), an ancient Greek physician considered the "Father of Medicine," constructed the groundwork for the principles of ethics in medicine over 2,500 years ago in his establishment of the Hippocratic Oath. One of the oldest binding documents in history, the text has remained the ethical template for physicians to this day. The changing cultural and social environment of modern society, accompanied by the advancement in scientific knowledge and therapeutic tools, has surfaced the need to reframe ethical perspective in modern medicine. Progress in aspects such as organ transplantation, stem cell technology, and genetic engineering has welcomed a new set of ethical dilemmas. These dilemmas have become intimately intertwined with the impact of commercialization, as seen by the interplay between legislation, health care, and pharmaceutical businesses. This paper seeks to dissect the principles of the original Hippocratic Oath and analyze the template in relation to the ethical dilemmas presented by contemporary medicine. Examination will provide a deeper understanding of the paradigm shift in modern medical ethics. Both the value of the Oath and the level of awareness of modern ethical dilemmas through the lens of American and Indian medical graduates will be assessed. PMID- 23032818 TI - Crystal violet stain as a selective stain for the assessment of mitotic figures in oral epithelial dysplasia and oral squamous cell carcinoma. AB - BACKGROUND: Assessment of mitotic figures (MFs) is routinely practiced as prognostic indicator in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), but identification of MFs poses a problem in terms of staining characteristics. AIM: To evaluate effectiveness of crystal violet stain for staining of MFs and its comparison with hematoxylin and eosin (H and E) stain. MATERIALS AND METHODS: Study sample includes archival tissues embedded in paraffin blocks diagnosed as OED (n = 30) and OSCC (n = 30). The control group comprised of tissue specimen from oral mucosa of healthy volunteers (n = 30). Two serial sections of each tissue specimen were stained separately with H and E stain and 1% crystal violet stain. The stained sections were observed under microscope for identification and counting of MFs. Data obtained was statistically analyzed by using the Man-Whitney U test. RESULTS: A significant increase in number of MFs was observed in OED and OSCC in comparison with normal oral mucosa. There was a highly significant increase in number of MFs in crystal violet stained tissue sections when compared with H and E stain. Metaphase is the most commonly observed phase of mitosis in crystal violet stain when compared with H and E stain for all three groups. CONCLUSION: Crystal violet stain can be considered as selective stain for mitotic figures. PMID- 23032819 TI - The expression and mutation of beta-catenin in colorectal traditional serrated adenomas. AB - CONTEXT: Exon 3 mutation of beta-catenin is associated with the carcinogenesis. AIMS: In this study we aimed to detect the expression of exon 3 mutations of beta catenin in colorectal TSA, TA/VTA, and CRC. MATERIALS AND METHODS: Immunohistochemistry staining for beta-catenin was performed for 30 TSA, 20 tubular adenomas (TA)/villous tubular adenomas (VTA), and 21 colorectal carcinoma (CRC) cases. DNA sequencing of the exon 3 of beta-catenin gene was performed for 8 TSA cases, 6 TA cases, 5 VTA cases, and 10 CRC cases with positive staining in the nuclei and cytoplasm. STATISTICAL ANALYSIS: A Fisher exact test and chi square test were used to analyze the differentiations of the expression of beta catenin in TSA, TA/VTA, and CRC. Results : The percentages of beta-catenin expression in TSA, TA/VTA, and CRC were 76.6% (23/30), 70.0% (14/20), and 95.2% (20/21), respectively, and were significantly different among these three types of tissue specimens (chi2 = 22.805, P < 0.001). Although beta-catenin expression levels in TSA were not related to it in TA/VTA, they were significantly different between TSA/TA/VTA and CRC. The degree of dysplasia was well correlated with beta catenin expression (TSA: P < 0.01; TA/VTA: P < 0.05). But beta-catenin exon 3 mutations were not detected in any of these tissue specimens. CONCLUSIONS: Aberrant beta-catenin expression is associated with the degree of dysplasia in TSA. beta-catenin likely plays an important role in the pathogenesis of colorectal TSA and conventional adenomas. PMID- 23032820 TI - Critical histopathological analysis of 25 dedifferentiated liposarcomas, including uncommon variants, reviewed at a Tertiary Cancer Referral Center. AB - BACKGROUND: De-differentiated liposarcomas (DDLSs) are uncommon tumors with a wide histopathological spectrum. MATERIALS AND METHODS: Over an 8-year period (2003-2011), 25 DDLSs, after review, were critically analyzed for histopathological features. RESULTS: Twenty-five tumors, in 14 men and 11 women (M: F = 1.2:1), with age range of 22-88 years (mean, 53.9), occurred in retroperitoneum (14) (56%), thigh (3) (12%), paratesticular region (3) (12%), chest wall (2) (8%), leg (1) (4%), shoulder (1) (4%), and groin (1) (4%). Tumor size (21 tumors) varied from 7.5 to 25 cm (mean, 17.5). Histopathologically, DD component was high grade in 19 (76%) and low grade in 6 (24%) tumors. Whereas the most common WD component was adipocytic type; the most common DD component was pleomorphic sarcomatous (13) (52%), followed by myxofibrosarcomatous (MFS)-type (6) (24%). Low-grade DD components included MFS (2), fibrosarcoma (2), myogenic/myofibroblastic type (1), and IMFT-type (1). Three tumors displayed meningothelial-like whorls and metaplastic bone formation. Heterologous elements, noted in 11 (44%) tumors, included bone (8) and rhabdomyoblastic differentiation (2). Two tumors displayed homologous differentiation, reinforced with MDM2 staining. S100-P was diffusely positive in WD components (5/7) and focally in DD components (2/9). All patients were treated with surgery, including 10, who underwent adjuvant radiotherapy. Outcomes (16 patients, 64%), over 1-48 months included 10 patients free of disease, 4 died of disease, and 2 patients alive with disease. CONCLUSIONS: This study forms the largest documentation of DDLSs, including its wide histopathological spectrum, from our country. Rare cases overlap with pleomorphic liposarcoma. S100-P and MDM2 are useful in substantiating adipocytic differentiation, especially in selected cases. Analysis of adequate tumor sections is vital for correct identification of a DDLS. Surgical excision with adjuvant RT forms optimal treatment. PMID- 23032821 TI - Glomerulogenesis: can it predict the gestational age? A study of 176 fetuses. AB - BACKGROUND: Accurate assessment of gestational age of fetuses is essential from both clinical and medico-legal point of view. Crown-rump length, crown-heel length, foot length, and the weight of the fetus are the commonly used parameters for fetal age assessment. However, this estimate often lacks accuracy and sometimes is necessary to combine other data. An analysis of the embryological development of nephrons in the kidney can assist in this determination. OBJECTIVE: To correlate the gestational age with the histological study of sequential development of nephrons in fetal kidney. MATERIALS AND METHODS: This study included 176 fetuses delivered between June 2009 and June 2011 and aged from 12 to 40 weeks. The number of glomerular generations counted in hematoxylin and eosin-stained microscopic sections of the kidneys were correlated with the reported period of gestation based on obstetrical methods. Regression analysis was used to determine the statistical significance of the correlation. RESULTS: A high degree of statistically significant correlation was observed between the period of gestation and the number of glomerular generations (P value < 0.0001). CONCLUSION: The histological assessment of the number of glomerular generations in kidney can be used as a reliable method of estimating fetal age. PMID- 23032822 TI - Correlation of p53 and KI-67 expression with grade and subtype of ependymoma. AB - INTRODUCTION: The morphological criteria for grading ependymomas were always felt subjective. Recently some studies have showed that Ki-67 and p53 immunolabeling are important prognostic markers in ependymomas. MATERIALS AND METHODS: All the cases of ependymomas diagnosed from 2005 to 2010 were graded according to WHO classification for central nervous system (CNS) tumors 2007. Two tissue microarray (TMA) blocks were prepared. Immunohistochemical analysis with glial fibrillary acidic protein (GFAP), epithelial membrane antigen (EMA), Ki-67 and p53 was performed. The difference in expression of p53 and Ki-67 in various tumor grades and subtypes was evaluated using Student's t test. RESULTS: There were 54 cases with a M: F ratio of 1.34 : 1, age ranging from 7 years to 65 years (mean 29.35 years). There were 33 intracranial and 21 spinal cases. There were 9 grade I ependymomas, 32 grade II ependymomas and 13 grade III ependymomas. GFAP immunopositivity was seen in all the cases and EMA was positive in 49% cases. The mean p53 indices were higher in grade III and grade II tumors (26.26% and 26.08%) as compared to subependymomas (7.25%). But these values did not show statistical significance (P = 0.2). The Ki-67 labeling index increased from grade I to grade III tumors. The difference was highly significant between grade II and grade III (0.5% vs. 2.75, P = 0.016). CONCLUSION: Ki-67 labeling index correlates with grade of ependymoma (P = 0.016). There is no correlation between p53 expression and grade of ependymomas. PMID- 23032823 TI - A novel tissue microarray instrumentation: the HT-1 tissue microarrayer. AB - BACKGROUND: Tissue microarray (TMA) is a novel and useful tool to efficiently analyze gene expression in histological tissues. AIM: Cost-efficient and easy to use automated tissue arrayers will provide a better instrumentation to generate TMAs. Thus, we designed and produced our tissue microarrayer to meet these needs. MATERIALS AND METHODS: The HT-1 tissue microarrayer we designed and manufactured consists primarily of four parts, including an instrument to make array pores for the recipient paraffin blocks, a punch needle, an instrument for negative pressure embedding, and a special manipulator. By using the HT-1, 14 different TMAs were made to accommodate 312 cases of tissues and TMA sections were tested by hematoxylin-eosin (H&E) staining, in situ hybridization, and immunohistochemistry. RESULTS: Expand: Hematoxylin and eosin staining showed that the tissue cylinders were similar, even, and in order on the slides. Most importantly, the HT-1 microarrayer can make array pores in the recipient paraffin block with a single application in seconds. The HT-1 also contains a unique negative pressure system for embedding TMA blocks. In addition, HT-1 can make tissue cylinders with the same levels and depth for equally embedded and sectioning. CONCLUSIONS: The HT-1 tissue microarrayer is a device that is simple, economical and easy to use. PMID- 23032824 TI - Genetic alterations in benign, preneoplastic and malignant breast lesions. AB - CONTEXT: The c-erbB-2 proto-oncogene is a member of the epidermal growth factor receptor family and has been associated with a more aggressive breast tumor biology and resistance to some types of treatments. AIMS: The aim is to investigate the correlation among bcl-2 and c-erbB-2 and the micronucleus (MN) formation in patients with early breast cancer (BC). MATERIALS AND METHODS: This study was conducted between May 2010 and December 2011. We analyzed the MN frequencies in 15 patients with invasive breast carcinoma (IBC), 13 patients with intraductal proliferative lesion (IDPL) and 12 benign breast lesion (BBL). The sample consisted of 40 formalin-fixed, paraffin-embedded blocks of benign and malignant breast tissue. The specimens were evaluated for bcl-2 or c-erbB-2 immunoreactivity was semi-quantitatively evaluated in at least 1000 cells examined under the microscope at 40Chi magnification and recorded as the percentage of c-erbB-2 and bcl-2 positive tumor cells over the total number of cells examined in the same area. The percentage scores were subsequently categorized using the 5% cut-off point for positive staining. RESULTS: The MN was significantly increased in IBC and in IDPL patients compared to BBL patients (3.82 +/- 0.17 and 2.37 +/- 0.52, respectively, vs. 1.61 +/- 0.40, P < 0.001). On other hand, the MN frequencies in IBC patients were higher than those in IDPL patients (3.82 +/- 0.17 vs. 2.37 +/- 0.52, P < 0.01). c-erbB-2, had the highest record in IBC (60%), and the score was not observed in both IDPL and BBL: bcl-2 immunostaining was also assessed, the lowest recorded score was in IBC (46.66%) and the highest in both BBL and IDPL (100%). Furthermore, there was a significantly difference in the mean MN frequency between c-erbB-2 positive IBC patients (4.06 +/- 0.48) and c-erbB-2 negative IBC patients (3.44 +/- 0.39) (P < 0.05). CONCLUSIONS: Our results suggest that increased chromosome / DNA instabilities may be associated with the pathogenesis of early BC. PMID- 23032825 TI - Clinicopathological spectrum of 19 adenosarcomas of female genital tract, including uncommon clinical associations and immunohistochemical profile, reviewed at a single institution. AB - BACKGROUND: Adenosarcomas of the female genital tract have been rarely documented as case series from our continent. MATERIALS AND METHODS: Over a seven-year period, 19 adenosarcomas were critically reviewed. RESULTS: Nineteen tumors occurred in the age range of 21-65 years (mean: 43), in the endometrium (8), endometrium and cervix (4), cervix (4), and ovary (3). Four cases displayed coexisting leiomyomas; two, adenomyosis; two on background endometriosis; and one in post-treated cervix carcinoma. Histopathologically, the tumors were low grade (10; 52.6%) and high grade (9; 47.3%), the latter with sarcomatous overgrowth (SO) (7/9 cases). Dedifferentiation (8, 42.1%) and conspicuous decidualization (2) were noted. Immunohistochemically, the tumors focally expressed CD10 (4/6), smooth muscle actin (SMA) (3/8), desmin (8/11); diffuse vimentin (7/7), and estrogen receptor/progesterone receptor (ER/PR) (2/4). Ki-67 (6 cases) varied 5 20%. Seventeen patients underwent surgery and four received adjuvant treatment (3/4 high-grade tumors). Five tumors recurred (4 high-grade tumors with SO) and one metastasized. Among 11 patients, five were alive with disease (AWD) (mean: 29.4 months) and six, free of disease (FOD) (mean: 15 months), the latter mostly with low-grade type tumors (83.3% cases). CONCLUSIONS: Diverse clinicopathological spectrum was noted within adenosarcomas. Low-grade tumors were less aggressive than high-grade ones, with SO. Immunohistochemically, lower CD10 and ER/PR positivity was noted in high-grade tumors. Surgery formed the mainstay of treatment. Adjuvant treatment was offered in high-grade subtypes, including in tumors with SO. PMID- 23032826 TI - Kikuchi-Fujimoto disease in fine needle aspiration smears: a clinico-cytologic study of 18 pediatric cases and correlation with 68 adult patients. AB - OBJECTIVE: Kikuchi-Fujimoto disease (KFD) is a self-limiting disorder which usually affects young women. There are only a few studies on pediatric KFD patients and their fine-needle aspiration (FNA) cytodiagnosis. We report a series of pediatric KFD patients diagnosed by FNA cytology and compare them with adults. MATERIALS AND METHODS: By routine FNA cytology and through retrospective review smears initially diagnosed as reactive hyperplasia of lymph node during the years 2004-2009, 18 pediatric and 68 adult KFD cases were detected. The clinico cytologic features of these two groups were compared. RESULTS: The age of the pediatric patients ranged from 6 to 18 years with a median of 13.5 years and adult cases were aged 19 to 54 years with a median of 30 years. Only 1 pediatric case (5.6%) and 20 (29.4%) adult cases were initially diagnosed as KFD (P = 0.0604). Arab:non-Arab ratios were 4.3:1 among the pediatric patients and 1:1.5 for the adults (P = 0.0043). FNA smears were highly cellular in 4 (22.2%) pediatric cases and 37 (54.4%) adult cases (P = 0.0180). More than 5% Kikuchi histiocytes was present in 8 (44.4%) pediatric and 49 (72.1%) adult cases (P = 0.0474). No significant difference was observed in male: female ratio, frequency of head & neck lymphadenopathy, time (season) of presentation, and presence of neutrophils and capillary networks, etc. CONCLUSIONS: Besides observation and interpretation errors, a significant difference between the two groups in respect of some clinico-cytomorphological features could have influenced the routine cytodiagnosis leading to lower pickup rate of pediatric KFD cases as compared to adults. PMID- 23032827 TI - The utility of p16 INK4a and Ki-67 to identify high-grade squamous intraepithelial lesion in adolescents and young women. AB - BACKGROUND: The repair of the immature squamous epithelium following HPV infection may mimic HSIL in adolescent women. AIM: to study the utility of p16 INK4a and Ki-67 in diagnosis of cervical squamous lesions in adolescents and young adults. MATERIALS AND METHODS: In a cross-sectional study, the evaluation of p16 INK4a and Ki-67 immunohistochemistry was performed on 72 cervical biopsies of adolescents and young adults women diagnosed as negative for malignancy and intraepithelial lesion (NML) (n = 18) or positive for low grade (LSIL) (n = 31) and high grade (HSIL) (n = 23) squamous intraepithelial lesions in two references services in Fortaleza-Brazil. Data was evaluated using Fisher's test and Kappa index. RESULTS: p16 INK4a was positive in 81% of HSIL, 19% of LSIL and in no NML (P < 0.0001). Ki-67 was positive in 74%, 32% and 5.5% of HSIL, LSIL and NML, respectively. p16 INK4a and Ki-67 in the diagnosis of HSIL showed high sensitivity and negative predictive value. Kappa index was very good for p16 INK4a (k = 0.72). CONCLUSIONS: In adolescents and young adults p16 INK4a alone or with Ki-67 represents important tool to reduce mistaken diagnosis of HSIL and to avoid overtreatment. PMID- 23032828 TI - Thrombophilic molecular markers in young patients (<40 years) with coronary artery disease. AB - BACKGROUND: There has been an alarming rise in the incidence of coronary artery disease (CAD) in India especially involving the age group of less than 45 years. In recent past, various studies focused on hemostatic aspects of CAD, but could not determine the significance of thrombophilic molecular marker in combination. The study was undertaken to investigate the association of thrombophilia related molecular markers in young patients with CAD. MATERIALS AND METHODS: Thirty diagnosed patients with CAD of either sex under 40 years were included. Thirty healthy age and sex matched control subjects without evidence of CAD formed the control group. Detailed history and clinical examination findings were recorded. In addition to routine investigations, polymerase chain reaction (PCR) based molecular analysis for Factor V Leiden (FVL), methyltetrahydrofolate reductase (MTHFR) gene, tumor necrosis factor receptor 2 (TNFR2) gene, and prothrombin gene mutation were carried out. RESULTS: The mean age (+/- SD) was 36.86 +/- 3.90 years in the patients. Smoking was the most prevalent risk factor. FVL, MTHFR and TNFR2 gene mutation were seen in nine (30%) patient. Three patients had presence of more than one mutation. FVL, MTHFR and TNFR2 gene mutation was found in 4 (13.3%), 3 (10%), and 5 (16.6%) patients respectively. Prothrombin gene mutation was not seen in any of the subjects. There was no significant difference in lipid profile, fibrinogen levels and CRP among the patients with mutation and patients without mutation. CONCLUSION: Almost one-third of the cases were positive for the various mutations in the study and the presence of at-least one or the other risk factor adds on to the risk of future thrombosis. There is a need to demonstrate or document these mutations in a larger group further based upon ethnicity and geographic distribution. PMID- 23032829 TI - Fluorescence in situ hybridization patterns of BCR/ABL1 fusion in chronic myelogenous leukemia at diagnosis. AB - BACKGROUND: Chronic myelogenous leukemia (CML) is characterised by the t(9;22)(q34;q11.2) which results in the formation of the BCR/ABL1 fusion gene. Occasionally, the t(9;22) may be associated with submicroscopic deletions of chromosomes 9 and/or 22 which appear to be associated with a worse prognosis. Three or four-way variant t(9;22) may also occur. All these changes as well as gain of the Philadelphia chromosome which represents disease progression can be detected by fluorescence in situ hybridization (FISH) analysis. FISH analysis at presentation is used to determine the number of cells with BCR/ABL1 fusion and establish whether the patterns are typical or atypical. Response to therapy can then be monitored by serial testing. PATIENTS AND METHODS: The study group consisted of all patients diagnosed or suspected to have CML who had interphase FISH analysis at presentation on peripheral blood/bone marrow using a commercially available BCR/ABL1 dual colour, dual fusion probe. The study was performed at a tertiary hospital in India between 2004 and 2010. RESULTS: There were 1076 diagnostic samples which were positive for BCR/ABL1 fusion. Typical dual fusion signals (two fusions, one red and one green, 2F1R1G) were seen in 801 cases (74 %). Atypical signal patterns were seen in 275 cases (26%). These were: 1F1R2G (4%), 1F2R1G (2.5%) and 1F1R1G (11%) representing deletions of the derivative 9 involving chromosome 9 sequences, chromosome 22 sequences, or both respectively; 3F1R1G (6.5%) usually representing gain of an additional Philadelphia chromosome and 1F2R2G (1%) representing a three- or four-way variant translocation. More than one signal pattern was seen in 1%. CONCLUSIONS: Our findings were similar to the literature with respect to the distribution of signal patterns except that we had a lower number of patients with variant translocations. While each signal pattern is typically associated with a particular abnormality, there can be more than one explanation for each pattern. Hence, metaphase FISH analysis is the "gold standard" for the interpretation of signal patterns. PMID- 23032830 TI - Colonization of hospital water systems by Legionella pneumophila, Pseudomonas aeroginosa, and Acinetobacter in ICU wards of Tehran hospitals. AB - BACKGROUND: Nosocomial infection caused by non-Enterobacteriaceae gram negative bacteria (GNB-NE) is increasing in intensive care units (ICU). AIM: The objective of this study was to determine whether potable water in ICU wards at Tehran hospitals is contaminated with L. pneomophila, P. aeroginosa and Acinetobacter spp. MATERIALS AND METHODS: A total of 52 water samples from shower bath and taps water in seven hospitals of Tehran were collected. The water sample concentrated by filtering through millipore cellulose filters and cultured on BCYE agar and tryptic soya agar media. The presence of Legionella pneumophila was confirmed by real time PCR assay using primers-probe designed for the mip gene. RESULTS: Legionella pneumophila, Pseudomonas aeroginosa and Acinetobacter were isolated from 5 (9.6%), 6 (11.4%) and 1 (1.8%) of the hospital water systems, respectively. This study demonstrated the presence of Legionella, Pseudomonas and Acinetobacter in water system in ICU wards of different hospitals in Tehran. CONCLUSIONS: Hot water from shower heads could be a potential source of infection for Legionella pneumophila. Water was also proved to contain Pseudomonas aeruginonsa, the main GNB-NE causing nosocomila pneumonia at Tehran hospitals. Care should be taken concerning cleanliness and decontamination of water supplies at ICUs for pathogenic organisms. PMID- 23032831 TI - Phenotypic method for differentiation of carbapenemases in Enterobacteriaceae: study from north India. AB - AIMS: Carbapenems are usually the choice of antimicrobials in infections caused by Enterobacteriaceae bacteria-producing ESBL (extended spectrum beta-lactamases) and Amp C. Resistance to carbapenems is mostly due to production of enzymes - Carbapenemases, which are divided into Ambler Classes A, B and D. Phenotypic detection and differentiation of types of Carbapenemases in carbapenem-resistant Enterobacteriaceae (CRE) is important for proper infection control and appropriate patient management. MATERIALS AND METHODS: The present study done in a tertiary care hospital from North India differentiates Class A (KPC type) and B (MBL type) carbapenemases among Enterobacteriaceae isolates by simple phenotypic method that uses both the inhibitors EDTA and phenylboronic acid. RESULTS: Total of 330 strains of Enterobacteriaceae were included in the study. Out of these 330 strains, 26 strains were resistant to carbapenems. The prevalence of CRE in our Institute is 7.87% (26/330). CONCLUSIONS: The prevalence of Enterobacteriaceae strains producing MBL type carbapenemase in our health care setup is 5.75% (19/330). None of the strains among the carbapenem-resistant bacterial isolates showed production of KPC enzyme. The need of the hour is simple, rapid and cost effective tests which will be able to identify and distinguish resistant pathogens for improved patient outcome, facilitating efficient infection control and reducing the escalation of resistance. PMID- 23032832 TI - Detection of resistance to linezolid in Staphylococcus aureus infecting orthopedic patients. AB - CONTEXT: In today's medical scenario, the human race is battling the most intelligent enemy who has unending alternatives to combat with the potent elements they have produced against it. AIM: To study the resistance to linezolid among Staphylococcus aureus isolated from pus samples of orthopedic patients. SETTINGS AND DESIGN: Pus samples were collected from dirty wounds of orthopedic patients undergoing long antimicrobial treatment programs. The sampling period was from July 2010 to June 2011. The samples were collected from different orthopedic hospitals of Nagpur (central India) representing a mixed sample of patients. MATERIALS AND METHODS: One hundred pus samples were screened for S. aureus, by growth on mannitol salt agar (MSA), Baird-Parker agar (BPA), deoxyribonuclease test, tube coagulase test, and HiStaph latex agglutination test. Fifty-one S. aureus isolates were obtained which were further subjected to antimicrobial susceptibility testing by Kirby-Bauer disc diffusion method (DDM). Minimal inhibitory concentrations (MICs) were determined by an automated system, the VITEK 2 system. Also, Ezy MIC strip method was carried out in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS AND CONCLUSION: Twelve linezolid-resistant S. aureus (LRSA) isolates were recovered from 51 S. aureus cultures tested for susceptibility to linezolid using the DDM, VITEK 2 system, and Ezy MIC strip method. The emergence of resistance suggests nosocomial spread and abuse of antibiotic. PMID- 23032833 TI - Analysis of clinical and biochemical spectrum of Wilson disease patients. AB - BACKGROUND AND AIMS: Wilson disease (WD) is autosomal recessive disorder of copper metabolism. Wilson disease patients usually suffer from hepatic or neuropsychiatric complications. The symptoms appear between ages five to 35 but it can vary from two years to 72 years. MATERIALS AND METHODS: Study was carried out from June 2008 to November 2010. This study included nine families with eleven cases of WD to determine clinical presentation, diagnostic findings (including laboratory results) and liver histology. It included 11 patients who presented with hepatic manifestations and/or Neuropsychiatric manifestations and/or family history suggesting features of WD. Patients with hepatitis B and C and those with history of taking antipsychotic drugs were excluded from the study. Patient's data was included in a well designed performa. Liver function test, serum ceruloplasmin, serum copper, 24 hour urinary copper, blood complete picture were analyzed. Quantitative data such as age, hemoglobin etc were expressed as mean with +/- SD and quantitative variables such as sex, movement disorders, hepatic involvement etc were expressed as frequency and percentage. RESULTS: There were five male and six female patients with evidence of various manifestations here (i) hepatic in which they had only liver dysfunction (ii) hepatic and neurological (iii) neurological. The mean age of presentation was 8.7+/-3.92 years (range 4-19 years) and 45% were male patients. Decreased serum ceruloplasmin, enhanced 24-h urinary copper excretion and signs of chronic liver damage were confirmed in all patients and Kayser-Fleischer rings (KF rings) in 72% of patients. In severe WD patients, serum prothrombin activity was less than 50%, serum ceruloplasmin were low and serum copper levels were high than those in non-severe WD patients. High degree of suspicion leads to early treatment with good outcome. CONCLUSIONS: The WD is rare but important cause of chronic liver disease. Clinical and biochemical analysis in cases of patients with unexplained liver disease with high degree of suspicion can lead to early treatment with good outcome. PMID- 23032834 TI - Primary squamous cell carcinoma of the renal parenchyma. AB - No case of a primary renal parenchymal squamous cell carcinoma (SCC) has been reported previously in the literature although renal pelvic SCCs are well known. We report an unusual case in a 60-year-old lady who presented with significant weight loss. She was found to have a mid and lower pole left renal tumor with enlarged para-aortic nodes. A left radical nephrectomy and nodal dissection was performed and the pathological stage was T4N1M0. No adjuvant therapy was given. She is alive at 13 months post-surgery. PMID- 23032835 TI - Huge uterine-cervical diverticulum mimicking as a cyst. AB - Here we report an incidental huge uterine-cervical diverticulum from a total abdominal hysterectomy specimen in a perimenopausal woman who presented with acute abdominal pain. The diverticulum was mimicking with various cysts present in the lateral side of the female genital tract. Histopathological examination confirmed this to be a cervical diverticulum with communication to uterine cavity through two different openings. They can attain huge size if left ignored for long duration and present a diagnostic challenge to clinicians, radiologists, as well as pathologists because of its extreme rarity. Therefore, diverticula should also be included as a differential diagnosis. Its histopathological confirmation also highlights that diverticula can present as an acute abdomen, requiring early diagnosis with appropriate timely intervention. Immunohistochemistry CD 10 has also been used to differentiate it from a mesonephric cyst. PMID- 23032836 TI - Urbach-Wiethe disease (lipoid proteinosis). AB - Lipoid proteinosis is a rare autosomal recessive disorder of variable severity that may involve the skin, mucous membranes of the upper respiratory tract and internal organs that may display different clinical manifestations based on the site of involvement. A 34-year-old male patient was admitted to our hospital with a complaint of hoarseness present since childhood but had worsened in recent years. A dermatological examination revealed light brown papillomatous skin lesions on the dorsum of both hands and elbows present for a long duration. Endoscopic examination of the larynx revealed widespread mucosal thickening and irregularity. Microscopic examination revealed acid Schiff (PAS) positive, Congo red negative eosinophilic hyaline material deposits in the dermis and submucosal regions. The final diagnosis was lipoid proteinosis with skin and larynx involvement. This typical case has been reported to draw attention to the fact that lipoid proteinosis should be included in the differential diagnosis of patients presenting with hoarseness in childhood. PMID- 23032837 TI - Bilharzial endocervical polyp. AB - Schistosomiasis still represents a major threat to women's health in many developing countries. The frequency in developed countries is increasing among immigrants and tourists who have a history of freshwater exposure in endemic areas. This is a case of 43-year-old immunocompetent Egyptian woman presented by abnormal vaginal bleeding. The gynecological examination revealed an endocervical polyp measuring 3 x 2 x 1 cm. Polypectomy was done. Histopathological examination revealed several granulomas containing viable eggs of Schistosoma hematobium. Schistosomiasis is rarely presented with endocervical polyp. In developing countries, schistosomiasis may be considered in differential diagnosis of patient with endocervical polyp. PMID- 23032838 TI - Abdominal cocoon: case report of a rare cause of intestinal obstruction. AB - Abdominal cocoon or sclerosing encapsulated peritonitis is a rare cause of intestinal obstruction often seen in adolescent girls. We present a case of an abdominal cocoon in a 14-year-old female presenting as a surgical emergency. The patient underwent excision of the involved segment of small bowel along with a part of ascending colon. Gross morphology revealed intestinal coils wrapped within a thick fibrous membrane. Diagnosis of this condition is seldom possible on radiological imaging. Characteristic gross appearance is showcased in our case, to create more awareness of this finding. PMID- 23032839 TI - Wilms' tumor with right heart extension: report of a post-chemotherapeutic fatality. AB - Wilms' tumor (WT) has a strong propensity to invade the vasculature in the form of tumor-thrombus, into the renal veins, and inferior vena cava and even into the right atrium. This cavo-atrial propagation does not alter the prognosis and pre operative chemotherapy produces shrinkage to the extent of even disappearance of caval or atrial extensions. We present a case of sudden death due to hemorrhagic expansion of the intra-atrial component of WT, immediately after commencement of chemotherapy, an uncommon incident. PMID- 23032840 TI - Invasive intestinal myiasis in a young male presenting as fungating rectal mass: an unusual presentation. AB - Intestinal myiasis is usually an accidental phenomenon which is transient and asymptomatic. It occurs due to intake of contaminated food or water containing fly larvae or eggs. We report a case of invasive intestinal myiasis presenting with complaint of pain, blood-mixed mucous discharge per rectum along with passage of maggots in stool. On proctoscopy an irregular fungating rectal growth with maggots was detected in rectum and anal canal. Excision of growth with diversion colostomy was done. On histopathology numerous variable-sized larvae in different stages of development were detected throughout the inflamed and necrosed bowel wall. No tumor was seen. With maintenance of proper hygiene, vermicide anti inflammatory and purgatives were given. Patient became alright after colostomy closure. The symptomatic presentation as a mass lesion and necessity for surgical intervention prompted us to report this rare case. PMID- 23032841 TI - Pantoea agglomerans infection behaving like a tumor after plant thorn injury: an unusual presentation. AB - Pantoea agglomerans infections in humans are uncommon. Most common infections reported are septic arthritis or synovitis. We report the case of a 25-year-old, healthy male, who presented with indurated swelling over the posterolateral aspect of his right thigh, associated with pain for one month. Magnetic resonance imaging (MRI) revealed muscle edema with cystic areas in the posterior-most part of the vastus lateralis of the right thigh. The condition was clinically diagnosed as a right-sided benign tumor of the vastus lateralis muscle. However, Pantoea agglomerans was isolated on a culture of the excised muscle tissue. On the basis of the awareness of the common association of Pantoea with penetrating trauma by vegetation, the patient was asked to recollect any prior such injury. He then gave a history of a fall in the field and a plant thorn prick in the thigh four years back, when he was an agricultural worker. We emphasize the importance of Pantoea agglomerans infection of the soft tissues that can have an atypical presentation as a non-suppurative, indurated, muscle cyst in our case. Thorn injuries are usually ignored as trivial incidents, however, Pantoea infections should always be borne in mind when encountering soft tissue lesions, as antibiotic treatment is required for complete resolution of the lesion. PMID- 23032842 TI - Left-sided giant adrenal myelolipoma secreting catecholamine. AB - Adrenal myelolipoma (AML) is a rare benign tumor composed of mature adipose and hematopoietic tissue. Most of these patients are asymptomatic and the tumors are non-secreting. We present a case with a large functional adrenal myelolipoma, wherein the patient was hypertensive and biochemistry revealed increase in 24 hours urinary Vanillylmandelic Acid (VMA), a metabolite of catecholamine. The mass was removed surgically and diagnosed as adrenal myelolipoma on histopathological examination. Both his blood pressure and urinary VMA returned to normal following surgery, which suggested that the mass was functioning and was secreting catecholamine. To the best of our knowledge, a catecholamine secreting adrenal myelolipoma has been reported in the literature only once previously. The association of hypertension and adrenal myelolipoma may not be entirely coincidental, as it may be associated with secreting catecholamine, as seen in our case. We also review the literature on functioning adrenal myelolipoma. PMID- 23032843 TI - Low grade mucoepidermoid carcinoma in a setting of Warthin's tumor. AB - Warthin's tumor also known as papillary cystadenoma lymphomatosum is a common benign salivary gland neoplasm that occurs exclusively in parotid gland. Rarely, the tumor can undergo carcinomatous or lymphomatous transformation of epithelial or lymphoid component, respectively. Herein, we describe a case of 55-year-old female who had undergone parotidectomy for a rapidly growing tumor in the right parotid gland. The case was diagnosed as mucoepidermoid carcinoma developed in a setting of Warthin's tumor based on the histomorphology, special staining characters, and immunohistochemical findings. The pathogenesis and differential diagnoses of such rare malignancy has been discussed briefly. PMID- 23032844 TI - Retroperitoneal sclerosing PEComa with melanin pigmentation and granulomatous inflammation-a rare association within an uncommon tumor. AB - PEComa, defined as a perivascular epithelioid cell tumor, displays a wide clinicopathological spectrum. Lately, a sclerosing PEComa has been identified as its distinct variant, but with limited documentation, in view of its rarity. Herein, we describe an uncommon case of a 53-year-old lady, who was referred to us with pain abdomen. Radiological imaging disclosed a well-defined, hypodense retroperitoneal mass. The excised tumor was a round, encapsulated soft tissue mass measuring 7 cm with a tan-brown cut surface. Microscopy showed uniform, epithelioid cells with clear cytoplasm, focal melanin pigmentation and mild nuclear atypia, arranged in sheets and nests around capillary-sized vessels in a dense sclerotic stroma. Additionally, co-existing epithelioid granulomas were noted. On immunohistochemistry (IHC), tumor cells were diffusely positive for HMB45; focally for desmin and smooth muscle actin (SMA), while negative for EMA, CD10, S100-P, Melan A, CD34, AMACR and CK MNF116. This case reinforces sclerosing PEComa as an uncommon, but a distinct clinicopathological entity and exemplifies diagnostic challenge associated with it; necessitating application of IHC markers for its correct identification. Presence of melanin pigment and granulomatous inflammation in the present tumor constitute as novel histopathological findings in a sclerosing PEComa. PMID- 23032845 TI - Vanishing bone disease (Gorham's disease) - a rare occurrence of unknown etiology. AB - A 20-year-old male patient presented with painful swelling around left elbow joint. Radiographic examination revealed osteolytic lesion with pathological fracture of lower end of humerus and upper radius. Upper end of ulna was completely absent along with bony erosion. Histopathology of the bony tissue revealed hemangioma-like lesion composed of vascular channels lined by benign endothelium replacing bone. The diagnosis of Gorham's massive osteolysis was made. Gorham's disease is a benign self-limiting condition affecting any age, may involve any part of the skeleton and is characterized by replacement of bone by hemangiomatous tissue resulting in formation of lesions exhibiting massive osteolysis, which may be to the extent of disappearance of the affected bone in radiograph. This nonhereditary case was not associated with nephropathy, which is often a coexistent condition. The case is being reported for its rarity. PMID- 23032846 TI - Cerebellar malignant fibrous histiocytoma. AB - Malignant fibrous histiocytoma (MFH) is uncommon within the central nervous system. MFH is a malignant tumor composed of a mixture of fibroblastic and histiocytic cells, and is also known as pleomorphic fibrous xanthoma, malignant fibrous xanthoma, and pleomorphic fibrous histiocytoma. It is a pleomorphic sarcoma originally found in soft tissue and there are few reported cases within the central nervous system, in particular the cerebellum. To the best of my knowledge, this is third case arising from the cerebellum. This tumor is difficult to diagnose and may be difficult to treat. PMID- 23032847 TI - Cutaneous metastasis of testicular choriocarcinoma, diagnosed by fine-needle aspiration cytology: a rare case report and review of the literature. AB - Skin metastasis of testicular choriocarcinoma is very rare. Until now about nine cases have been reported in the English literature; however, only one of them has been diagnosed by fine-needle aspiration (FNA) cytology. Herein, we report our experience with FNA cytology diagnosis of a metastatic testicular choriocarcinoma to the skin of chin. The combination of highly atypical mononuclear cells (cytotrophoblasts) and multinucleated malignant cells (syncytiotrophoblasts) are characteristic of metastatic tumor in a known case of choriocarcinoma of testis. PMID- 23032848 TI - Systemic mastocytosis with associated acute myeloid leukemia with t (8; 21) (q22; q22). AB - Systemic mastocytosis with associated clonal hematological nonmast cell lineage disease (SM-AHNMD) is a subtype of mastocytosis associated commonly with myeloid neoplasms, Non-Hodgkin's lymphoma, or other hematological neoplasms. In these conditions, mastocytosis needs to be differentiated from mast cell hyperplasia or mast cell activation states. Neoplastic nature of mastocytosis is proved either by morphology, aberrant immunophenotype, or detection of point mutation at codon 816 of c-kit gene. This is a rare entity, even more so in pediatric population. Herein, we report a case of 14-year-old girl with SM associated with acute myeloid leukemia with maturation with t(8;21). Multifocal dense infiltrate of spindle-shaped mast cells on bone marrow aspirate and biopsy with coexpression of CD2 and CD25 by flow cytometric analysis proved the SM component at the time of diagnosis and persistence at post induction status also. PMID- 23032849 TI - Inflammatory pseudotumor of the biliary tract. PMID- 23032850 TI - Lipoid proteinosis: a rare clinical entity. PMID- 23032851 TI - Gastric post transplant lymphoproliferative disorder in a cytomegalovirus positive live related renal allograft recipient: a single case study. PMID- 23032852 TI - Fetal immature teratoma causing intrauterine death. PMID- 23032853 TI - Nevus sebaceous at unusual location: a rare presentation. PMID- 23032855 TI - Dominant beta-thalassemia - a rare entity! PMID- 23032854 TI - Can multilocular cystic nephroma be a harbinger of multilocular cystic renal cell carcinoma? PMID- 23032856 TI - Thrombocytopenia, giant platelets and Leukocyte inclusion bodies in a patient presenting with vaginal bleeding. PMID- 23032857 TI - Myxoid chondrosarcoma of the cricoid cartilage. PMID- 23032858 TI - Transient myeloproliferative disorder in Down's syndrome. PMID- 23032859 TI - Benchmarking van der Waals density functionals with experimental data: potential energy curves for H2 molecules on Cu(111), (100) and (110) surfaces. AB - Detailed physisorption data from experiment for the H(2) molecule on low-index Cu surfaces challenge theory. Recently, density functional theory (DFT) has been developed to account for nonlocal correlation effects, including van der Waals (dispersion) forces. We show that the functional vdW-DF2 gives a potential-energy curve, potential-well energy levels and difference in lateral corrugation promisingly close to the results obtained by resonant elastic backscattering diffraction experiments. The backscattering barrier is sensitive to the choice of exchange functional approximation. Further, the DFT-D3 and TS-vdW corrections to traditional DFT formulations are also benchmarked, and deviations are analyzed. PMID- 23032860 TI - The effect of CNTs on structures and catalytic properties of AuPd clusters for H2O2 synthesis. AB - The structures and catalytic properties of AuPd clusters supported on carbon nanotubes (CNTs) for H(2)O(2) synthesis have been investigated by means of density functional theory calculations. Firstly, the structures of AuPd clusters are strongly influenced by CNTs, in which the bottom layers are mainly composed of Pd and the top layers are a mix of Au and Pd due to the stronger binding of Pd than Au on CNTs. Especially, it is found that O(2) adsorption on the Pd/CNTs interfacial sites is much weaker than that on the only Pd sites, which is in contrast to transition metal oxide (for example TiO(2), Al(2)O(3), CeO(2)) supported metal clusters. Furthermore, Pd ensembles on the interfacial sites have far superior catalytic properties for H(2)O(2) formation than those away from CNT supports due to the changes in electronic structures caused by the CNTs. Therefore, our study provides a physical insight into the enhanced role of carbon supports in H(2)O(2) synthesis over supported AuPd catalysts. PMID- 23032861 TI - Ligand and pathogen specificity of the Atlantic salmon serum C-type lectin. AB - BACKGROUND: An Atlantic salmon (Salmo salar) C-type lectin (SSL) binds to mannose and related sugars as well as to the surface of Aeromonas salmonicida. To characterize this lectin as a pathogen recognition receptor in salmon, aspects of its interaction with molecules and with intact pathogens were investigated. METHODS: SSL was isolated using whole-yeast-affinity and mannan-affinity chromatography. The binding of SSL to the two major surface molecules of A. salmonicida, lipopolysaccharide (LPS) and A-layer protein was investigated by western blotting and enzyme-linked immunosorbent assays. Microbial binding specificity of SSL was examined by whole cell binding assays using a range of species. Carbohydrate ligand specificity of SSL was examined using glycan array analysis and frontal affinity chromatography. RESULTS: SSL showed binding to bacteria and yeast including, Pseudomonas fluorescens, A. salmonicida, A. hydrophila, Pichia pastoris, and Saccharomyces cerevisiae, but there was no detectable binding to Yersinia ruckeri. In antimicrobial assays, SSL showed no activity against Escherichia coli, Bacillus subtilis, S. cerevisiae, or A. salmonicida, but it was found to agglutinate E. coli. The major surface molecule of A. salmonicida recognized by SSL was shown to be LPS and not the A-layer protein. LPS binding was mannose-inhibitable. Glycans containing N acetylglucosamine were shown to be predominant ligands. CONCLUSION: SSL has a distinct ligand preference while allowing recognition of a wide variety of related carbohydrate structures. GENERAL SIGNIFICANCE: SSL is likely to function as a wide-spectrum pattern recognition protein. PMID- 23032863 TI - Effect of oxygen stoichiometry in LuFe2O(4-delta) and its microstructure observed by aberration-corrected transmission electron microscopy. AB - A series of oxygen deficient LuFe(2)O(4-delta) materials have been prepared under a controlled oxygen partial-pressure atmosphere. Measurements of magnetization reveal that the increase of oxygen deficiencies could evidently depress the ferrimagnetic phase transition temperature (T(N)). In additional to the well known charge ordering within the (11(-)0) crystal plane, a visible structural modulation with q = (0,1/4.2,7/8) commonly appears on the (100) plane in the oxygen deficient samples. An aberration-corrected transmission electron microscopy study on the oxygen deficient samples demonstrates the presence of oxygen vacancies and local structural distortion. The atomic structural features in correlation with the structural modulation, distortion of the FeO(5) polyhedron and the (001) twinning domains have been also examined. PMID- 23032865 TI - The treatment of acute antibody-mediated rejection in kidney transplant recipients-a systematic review. AB - BACKGROUND: Antibody-mediated rejection (AMR) is a recognized cause of allograft loss in kidney transplant recipients. A range of therapies targeting removal of circulating donor-specific antibodies (DSAs), blocking their effect or reducing production have been reported. METHODS: We conducted a systematic review to determine the efficacy of treatments for acute AMR in renal allografts. Electronic databases, reference lists, and conference proceedings were searched for controlled trials. Nonrandomized publications were reviewed for the purpose of discussion. RESULTS: We identified 10,388 citations, including five randomized and seven nonrandomized controlled trials. The randomized studies were small (median, 13 patients/arm; range, 5-23), of which, four examined plasmapheresis (one suggested benefit) and one for immunoadsorption (also suggesting benefit). Marked heterogeneity was evident, including the definition and severity of AMR and the treatment regimen. The end point of graft survival was common to all studies. Small, nonrandomized controlled studies suggested benefit from rituximab or bortezomib. The effects of dose and regimen on the clinical response to any of the current treatments were not apparent from the available data. CONCLUSIONS: Data describing the efficacy of treatments for AMR in renal allografts are of low or very low quality. Larger randomized controlled trials and dose-response studies are required. PMID- 23032862 TI - Optimized negative-staining electron microscopy for lipoprotein studies. AB - BACKGROUND: Negative-staining (NS), a rapid, simple and conventional technique of electron microscopy (EM), has been commonly used to initially study the morphology and structure of proteins for half a century. Certain NS protocols however can cause artifacts, especially for structurally flexible or lipid related proteins, such as lipoproteins. Lipoproteins were often observed in the form of rouleau as lipoprotein particles appeared to be stacked together by conventional NS protocols. The flexible components of lipoproteins, i.e. lipids and amphipathic apolipoproteins, resulted in the lipoprotein structure being sensitive to the NS sample preparation parameters, such as operational procedures, salt concentrations, and the staining reagents. SCOPE OF REVIEW: The most popular NS protocols that have been used to examine lipoprotein morphology and structure were reviewed. MAJOR CONCLUSIONS: The comparisons show that an optimized NS (OpNS) protocol can eliminate the rouleau artifacts of lipoproteins, and that the lipoproteins are similar in size and shape as statistically measured from two EM methods, OpNS and cryo-electron microscopy (cryo-EM). OpNS is a high throughput, high-contrast and high-resolution (near 1nm, but rarely better than 1nm) method which has been used to discover the mechanics of a small protein, 53kDa cholesterol ester transfer protein (CETP), and the structure of an individual particle of a single protein by individual-particle electron tomography (IPET), i.e. a 14A-resolution IgG antibody three-dimensional map. GENERAL SIGNIFICANCE: It is suggested that OpNS can be used as a general protocol to study the structure of proteins, especially highly dynamic proteins with equilibrium-fluctuating structures. PMID- 23032866 TI - Zero-mismatch deceased-donor kidney versus simultaneous pancreas-kidney transplantation. AB - BACKGROUND: Patients with type 1 diabetes mellitus (T1DM) and end-stage renal disease may receive a simultaneous pancreas-kidney (SPK), living-donor kidney (LDK), or deceased-donor kidney (DDK) with possible pancreas after kidney transplantation. SPK is associated with superior patient and kidney graft survival compared with DDK, whereas SPK and LDK have comparable outcomes. It is unclear whether SPK and LDK offer a survival benefit over zero-mismatch (0MM) DDK. In this study, we compared the outcomes of T1DM recipients using data from the Organ Procurement and Transplant Network/United Network for Organ Sharing. METHODS: Adult (>=18 years) first-time transplant recipients with T1DM waitlisted for SPK and transplanted from 1995 to 2010 were included in this study. Patient and death-censored kidney graft survival were compared between 0MMDDK (n=228), mismatched (MM) DDK (n=964), 0MMSPK (n=215), MMSPK (n=11951), 2 haplotype identical (2hap) LDK (n=205), and non-2hapLDK (n=1719) recipients. Multivariate analysis was performed using stepwise Cox proportional hazards models. RESULTS: At 7 years, patient and death-censored graft survival of 0MMDDK recipients (85% and 81%, respectively) were not statistically different from that of 0MMSPK (81% and 85%; log-rank P value vs. 0MMDDK, 0.17 and 0.48, respectively) and 2hapLDK recipients (89% and 86%; log-rank P value vs. 0MMDDK, 0.34 and 0.18, respectively). Among all groups, MMDDK showed the worst patient survival (71%; log-rank P value vs. 0MMDDK, 0.001) CONCLUSION: Patient and kidney graft survival of 0MMDDK recipients were comparable to both SPK and LDK recipients. These findings suggest that T1DM patients awaiting SPK may consider accepting a 0MMDDK if an offer is available. PMID- 23032867 TI - Implantation and follow-up of totally subcutaneous versus conventional implantable cardioverter-defibrillators: a multicenter case-control study. AB - BACKGROUND: The approval of an entirely subcutaneous implantable-cardioverter defibrillator (ICD) system (S-ICD) has raised attention about this promising technology. It was developed to overcome lead failure and infection problems of conventional transvenous ICD systems. Nevertheless, lead migration of the initial design and inappropriate shock rates have raised concerns regarding its reliability and safety. OBJECTIVE: The purpose of this study was to report the largest multicenter series to date of patients with the new device in comparison with a matched conventional transvenous ICD collective with focus on perioperative complications, conversion of induced ventricular fibrillation (VF), and short-term follow-up. METHODS/RESULTS: Sixty-nine patients (50 male and 19 female; mean age 45.7 +/- 15.7 years) received an S-ICD in three German centers and were randomly assigned to 69 sex- and age-matched conventional ICD patients. The indication was primary prevention in 41 patients (59.4%) without difference between groups (34 control patients; P = .268). The predominant underlying heart disease was ischemic cardiomyopathy in 11 (15.9%), dilated cardiomyopathy in 25 (36.2%), and hypertrophic cardiomyopathy in 10 (14.5%) in the S-ICD group. Mean implantation time was 70.8 +/- 27.9 minutes (P = .398). Conversion rates of induced VF were 89.5% for 65 J (15-J safety margin) and 95.5% including reversed shock polarity (15-J safety margin) in the study group. Termination of induced VF was successful in 90.8% (10-J safety margin, device dependent) of the control patients (P = .815). Procedural complications were similar between the 2 groups. Mean follow-up was 217 +/- 138 days. During follow-up, 3 patients with S-ICD were appropriately treated for ventricular arrhythmias. Three inappropriate episodes (5.2%) occurred in 3 S-ICD patients due to T-wave oversensing, whereas atrial fibrillation with rapid conduction was the predominant reason for inappropriate therapy in conventional devices (P = .745). CONCLUSION: The novel S-ICD system can be implanted safely with similar perioperative adverse events compared with standard transvenous devices. Our case-control study demonstrates a 10.4% failure of conversion of induced VF with the S-ICD set to standard polarity and 15-J safety margin and comparable inappropriate shock rates during short-term follow up. PMID- 23032868 TI - To the Editor--Disease modification by autonomic nerve stimulation. PMID- 23032869 TI - Two-dimensional infrared spectroscopy reveals the structure of an Evans auxiliary derivative and its SnCl4 Lewis acid complex. AB - Determining the structure of reactive intermediates is the key to understanding reaction mechanisms. To access these structures, a method combining structural sensitivity and high time resolution is required. Here ultrafast polarization dependent two-dimensional infrared (P2D-IR) spectroscopy is shown to be an excellent complement to commonly used methods such as one-dimensional IR and multidimensional NMR spectroscopy for investigating intermediates. P2D-IR spectroscopy allows structure determination by measuring the angles between vibrational transition dipole moments. The high time resolution makes P2D-IR spectroscopy an attractive method for structure determination in the presence of fast exchange and for short-lived intermediates. The ubiquity of vibrations in molecules ensures broad applicability of the method, particularly in cases in which NMR spectroscopy is challenging due to a low density of active nuclei. Here we illustrate the strengths of P2D-IR by determining the conformation of a Diels Alder dienophile that carries the Evans auxiliary and its conformational change induced by the complexation with the Lewis acid SnCl(4), which is a catalyst for stereoselective Diels-Alder reactions. We show that P2D-IR in combination with DFT computations can discriminate between the various conformers of the free dienophile N-crotonyloxazolidinone that have been debated before, proving antiperiplanar orientation of the carbonyl groups and s-cis conformation of the crotonyl moiety. P2D-IR unequivocally identifies the coordination and conformation in the catalyst-substrate complex with SnCl(4), even in the presence of exchange that is fast on the NMR time scale. It resolves a chelate with the carbonyl orientation flipped to synperiplanar and s-cis crotonyl configuration as the main species. This work sets the stage for future studies of other catalyst substrate complexes and intermediates using a combination of P2D-IR spectroscopy and DFT computations. PMID- 23032870 TI - Joint effects of job strain and road-traffic and occupational noise on myocardial infarction. AB - OBJECTIVES: The aim of this study was to assess the joint effect of job strain and both road-traffic and occupational noise on myocardial infarction (MI). METHOD: We conducted a population based case-control study on first time MI in Stockholm County during 1992-1994. Participants answered a questionnaire and underwent a physical examination. Residential road-traffic noise exposure was based on residential history combined with information on traffic intensity and distance to nearby roads. Occupational noise exposure was assessed by occupational history combined with a job-exposure matrix derived from measurements. Job strain was based on questions regarding psychological demands and decision latitude. A total of 3050 study participants (1252 cases and 1798 controls) were included in the study. RESULTS: An increased risk of MI was indicated among participants exposed to road-traffic noise [odds ratio (OR) 1.23, 95% confidence interval (95% CI) 1.01-1.51], occupational noise (OR 1.17, 95% CI 0.98-1.41) and job strain (OR 1.39, 95% CI 1.17-1.65). Participants exposed to one, two, or three of these factors showed an increased risk (OR 1.16, 95% CI 0.97-1.40, OR 1.57, 95% CI 1.24-1.98, and OR 2.27, 95% CI 1.41-3.64, respectively). Exposure to two or three of these factors occurred among about 20% of the controls. CONCLUSION: Our results indicate that exposure to a combination of noise exposure and job strain increases the risk of MI substantially. Such exposures affect a considerable part of the population, which has relevance for prioritization of preventative measures. PMID- 23032871 TI - Paper-based nanobiosensors for diagnostics. AB - In this review we discuss how nanomaterials can be integrated in diagnostic paper based biosensors for the detection of proteins, nucleic acids and cells. In particular first the different types and properties of paper-based nanobiosensors and nanomaterials are briefly explained. Then several examples of their application in diagnostics of several biomarkers are reported. Finally our opinions regarding future trends in this field are discussed. PMID- 23032872 TI - Investigation of charge transfer in Au nanoparticle-ZnO nanosheet composite photocatalysts. AB - Ohmic contact formation at the interface of the Au nanoparticle (NP)-ZnO nanosheet (NS), which facilitates photoelectron transfer from ZnO NSs to Au NPs, is determined by scanning Kelvin microscopy for the first time. Reduction of charge recombination in the ZnO NSs confirmed by the quench of green band emission results in the enhancement of photocatalytic activity of the Au NP-ZnO NS composite. PMID- 23032874 TI - Effects of ZNF804A on neurophysiologic measures of cognitive control. PMID- 23032873 TI - Regulation of neuronal plasticity and fear by a dynamic change in PAR1-G protein coupling in the amygdala. AB - Fear memories are acquired through neuronal plasticity, an orchestrated sequence of events regulated at circuit and cellular levels. The conventional model of fear acquisition assumes unimodal (for example, excitatory or inhibitory) roles of modulatory receptors in controlling neuronal activity and learning. Contrary to this view, we show that protease-activated receptor-1 (PAR1) promotes contrasting neuronal responses depending on the emotional status of an animal by a dynamic shift between distinct G protein-coupling partners. In the basolateral amygdala of fear-naive mice PAR1 couples to Galphaq/11 and Galphao proteins, while after fear conditioning coupling to Galphao increases. Concurrently, stimulation of PAR1 before conditioning enhanced, but afterwards it inhibited firing of basal amygdala neurons. An initial impairment of the long-term potentiation (LTP) in PAR1-deficient mice was transformed into an increase in LTP and enhancement of fear after conditioning. These effects correlated with more frequent 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) receptor mediated miniature post synaptic events and increased neuronal excitability. Our findings point to experience-specific shifts in PAR1-G protein coupling in the amygdala as a novel mechanism regulating neuronal excitability and fear. PMID- 23032876 TI - Gait patterns in Parkinsonian patients with or without mild cognitive impairment. AB - Although in recent years the relationship between cognition and gait in Parkinson's disease (PD) has received increasing attention, the specific connections between gait patterns and cognitive features are not fully understood. The objective of this study was to describe the gait patterns in patients affected by PD with or without mild cognitive impairment (MCI+ and MCI-, respectively). We also sought to find an association between gait patterns and specific cognitive profiles. Using a gait analysis system, we compared the gait patterns among MCI+ patients (n = 19), MCI- patients (n - 24), and age- and sex matched healthy subjects (HS; n = 20) under the following conditions: (1) normal gait, (2) motor dual task, and (3) cognitive dual task. In PD patients, gait parameters were evaluated in both the off and on states. Memory, executive, and visuospatial domains were assessed using an extensive neuropsychological battery. Compared with MCI- PD and HS, MCI+ PD patients displayed reduced step length and swing time and impairment of measures of dynamic stability; these dysfunctions were only partially reversed by levodopa. We also found that dual-task conditions affected several walking parameters in MCI+ PD in the off and on states relative to MCI- PD and HS. Factor analysis revealed 2 independent factors, namely, pace and stability. The latter was strongly and directly correlated to the visuospatial domain. In conclusion, dysfunctions on specific gait parameters, which were poorly responsive to levodopa and highly sensitive to dual-task conditions, were associated with MCI in PD patients. Importantly, visuospatial impairment was strongly associated with the development of instability and more generally with the progression of PD. PMID- 23032875 TI - Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11. AB - Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5 HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5 HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5 HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders. PMID- 23032879 TI - Introduction of the thirty-fifth Lauriston S. Taylor Lecture in radiation protection and measurements. PMID- 23032882 TI - Eighth Warren K. Sinclair keynote address: Heavy ions in therapy and space: benefits and risks. AB - Heavy charged particles produce biological damage that is different from that normally produced by sparsely ionizing radiation, such as x- or gamma-rays, which are a large component of the natural radiation background. In fact, as a result of the different spatial distribution of the energy deposited along the core and penumbra of the track, DNA lesions are exquisitely complex and difficult to repair. Relative biological effectiveness (RBE) factors are normally used to scale from x-rays to heavy ion damage, but it should be kept in mind that RBE depends on several factors (dose, dose rate, endpoint, particle energy, and charge, etc.), and sometimes heavy ions produce special damages that just cannot be scaled by x-ray damage alone. These special characteristics of heavy ions can be used to treat tumors efficiently, as it is currently done in Japan and Germany, but they represent a threat for human space exploration. PMID- 23032883 TI - Physical interactions of charged particles for radiotherapy and space applications. AB - In this paper, the basic physics by which energetic charged particles deposit energy in matter is reviewed. Energetic charged particles are used for radiotherapy and are encountered in spaceflight, where they pose a health risk to astronauts. They interact with matter through nuclear and electromagnetic forces. Deposition of energy occurs mostly along the trajectory of the incoming particle, but depending on the type of incident particle and its energy, there is some nonzero probability for energy deposition relatively far from the nominal trajectory, either due to long-ranged knock-on electrons (sometimes called delta rays) or from the products of nuclear fragmentation, including neutrons. In the therapy setting, dose localization is of paramount importance, and the deposition of energy outside nominal treatment volumes complicates planning and increases the risk of secondary cancers as well as noncancer effects in normal tissue. Statistical effects are also important and will be discussed. In contrast to radiation therapy patients, astronauts in space receive comparatively small whole body radiation doses from energetic charged particles and associated secondary radiation. A unique aspect of space radiation exposures is the high-energy heavy ion component of the dose. This is not present in terrestrial exposures except in carbon-ion radiotherapy. Designers of space missions must limit exposures to keep risk within acceptable limits. These limits are, at present, defined for low Earth orbit, but not for deep-space missions outside the geomagnetosphere. Most of the uncertainty in risk assessment for such missions comes from the lack of understanding of the biological effectiveness of the heavy-ion component, with a smaller component due to uncertainties in transport physics and dosimetry. These same uncertainties are also critical in the therapy setting. PMID- 23032884 TI - DNA and cellular effects of charged particles. AB - Development of new radiotherapy strategies based on the use of hadrons, as well as reduction of uncertainties associated with radiation health risk during long term space flights, requires increasing knowledge of the mechanisms underlying the biological effects of charged particles. It is well known that charged particles are more effective in damaging biological systems than photons. This capability has been related to the production of spatially correlated and/or clustered DNA damage, in particular two or more double-strand breaks (DSB) in close proximity or DSB associated with other lesions within a localized DNA region. These kinds of complex damages are rarely induced by photons. They are difficult to repair accurately and are therefore expected to produce severe consequences at the cellular level. This paper provides a review of radiation induced cellular effects and will discuss the dependence of cell death and mutation induction on the linear energy transfer of various light and heavy ions. This paper will show the inadequacy of a single physical parameter for describing radiation quality, underlining the importance of the characteristics of the track structure at the submicrometer level to determine the biological effects. This paper will give a description of the physical properties of the track structure that can explain the differences in the spatial distributions of DNA damage, in particular DSB, induced by radiation of different qualities. In addition, this paper will show how a combined experimental and theoretical approach based on Monte Carlo simulations can be useful for providing information on the damage distribution at the nanoscale level. It will also emphasize the importance, especially for DNA damage evaluation at low doses, of the more recent functional approaches based on the use of fluorescent antibodies against proteins involved in the cellular processing of DNA damage. Advantages and limitations of the different experimental techniques will be discussed with particular emphasis on the still unsolved problem of the clustered DNA damage resolution. Development of biophysical models aimed to describe the kinetics of the DNA repair process is underway, and it is expected to support the experimental investigation of the mechanisms underlying the cellular radiation response. PMID- 23032880 TI - Lauriston S. Taylor Lecture on radiation protection and measurements: what makes particle radiation so effective? AB - The scientific basis for the physical and biological effectiveness of particle radiations has emerged from many decades of meticulous basic research. A diverse array of biologically relevant consequences at the molecular, cellular, tissue, and organism level have been reported, but what are the key processes and mechanisms that make particle radiation so effective, and what competing processes define dose dependences? Recent studies have shown that individual genotypes control radiation-regulated genes and pathways in response to radiations of varying ionization density. The fact that densely ionizing radiations can affect different gene families than sparsely ionizing radiations, and that the effects are dose- and time-dependent, has opened up new areas of future research. The complex microenvironment of the stroma and the significant contributions of the immune response have added to our understanding of tissue specific differences across the linear energy transfer (LET) spectrum. The importance of targeted versus nontargeted effects remains a thorny but elusive and important contributor to chronic low dose radiation effects of variable LET that still needs further research. The induction of cancer is also LET-dependent, suggesting different mechanisms of action across the gradient of ionization density. The focus of this 35th Lauriston S. Taylor Lecture is to chronicle the step-by-step acquisition of experimental clues that have refined our understanding of what makes particle radiation so effective, with emphasis on the example of radiation effects on the crystalline lens of the human eye. PMID- 23032885 TI - Space radiation protection issues. AB - The complex charged particle environments in space pose considerable challenges with regard to potential health consequences that can impact mission design and crew selection. The lack of knowledge of the biological effects of different ions in isolation and in combination is a particular concern because the risk uncertainties are very high for both cancer and non-cancer late effects. Reducing the uncertainties is of high priority. Two principal components of space radiation each raise different concerns. Solar particle events (SPE) occur sporadically and are comprised primarily of low- to moderate-energy protons. Galactic cosmic radiation (GCR) is isotropic and relatively invariant in dose rate. GCR is also dominated by protons, but the energy range is wider than in SPE. In addition, the contribution of other light and heavy ions to the health risks from GCR must be addressed. This paper will introduce the principal issues under consideration for space radiation protection. PMID- 23032886 TI - Animal studies of charged particle-induced carcinogenesis. AB - The distribution of energy deposition in cells and tissues by high-charge, high energy (HZE) nuclei differs considerably from that of low linear energy transfer (LET) radiation, raising concerns that charged particle exposure may be more efficient in inducing radiogenic cancers or may induce a different spectrum of tumors. The authors have performed a review of charged particle carcinogenesis in animals with the following observations. A limited number of animal studies with carcinogenesis endpoints have been performed to evaluate the effectiveness of HZE ions. These include the induction of skin and mammary tumors in the rat and Harderian gland tumors, acute myeloid leukemia (AML), and hepatocellular carcinomas in the mouse. In general, high relative biological effectiveness (RBE) has been reported for solid tumor induction. RBE dependence on HZE radiation quality has been most extensively characterized in studies of mouse Harderian gland tumorigenesis. In this model, the RBE increases with LET and plateaus in the 193-953 keV MUm(-1) range. Unlike the results of solid tumor studies, a leukemogenesis study found 1 GeV nucleon(-1) 56Fe ions no more efficient than gamma-rays for AML induction. No novel tumor types have been observed in HZE irradiated animals as compared with those that occur spontaneously or following low-LET radiation exposures. Genetic background of the irradiated animals is critical; the tumor types induced in HZE irradiated mice depend on their strain background, and the incidence of HZE ion-induced mammary carcinogenesis in the rat is also strain dependent. PMID- 23032887 TI - Risk of second cancers after photon and proton radiotherapy: a review of the data. AB - Control rates for pediatric and adult malignancies are now approximately 80 and 60%, respectively, due to dramatic improvements in surgery, chemotherapy, and radiotherapy. However, radiotherapy is responsible for many of the adverse late effects of treatment, which is now well documented in the literature. The most serious and life threatening side effect of radiotherapy that affects both children and adults is radiation-induced second primary cancers. PMID- 23032888 TI - Normal tissue complications from low-dose proton therapy. AB - Proton therapy is an attractive method to attenuate toxicities of radiotherapy because of the decrease of integral radiation dose to normal tissues, which should lead to fewer late side effects. This potential benefit is of particular interest in the pediatric population, since children are more vulnerable to the risks of radiation. In addition, overall survival rates for pediatric malignancies continue to improve, which will lead to more long-term survivors who will be at risk from the late effects of radiation therapy that was used for treatment. In this review, the potential benefits afforded by proton therapy in the low-dose area for radiosensitive organs will be evaluated. Because robust clinical information is not available for low-dose proton therapy, information from the experience of photon therapy in radiosensitive structures will be reviewed. In general, because the low-dose bath is reduced or on occasion eliminated with the use of proton therapy, a reduction of early and late toxicities related to low-dose radiotherapy such as vomiting, mucositis, cardiovascular complications, pulmonary injury, and developmental effects in children is expected. Other authors review the current evidence and potential benefits supporting the use of proton therapy for the reduction in neuro cognitive sequelae and secondary malignancies. Currently, a relative biological effectiveness of 1.1 is used in clinical situations to calculate the equivalent biologic dose for proton therapy relative to photon therapy. The unit of dose is commonly referred to as gray equivalent (GyEq). The interaction of a proton at a cellular level is postulated to lead to a higher frequency of double-strand breaks, so in theory there is a higher probability of cell kill and a lower probability of mutagenesis. At this time, however, once the physical properties of the interaction of proton with matter are accounted for, there is no definite data that 1 GyEq has any different biologic outcome than 1 Gy delivered with photon therapy. In the Bragg peak, there is greater uncertainty of dose deposition and associated biologic effect. In clinical practice, therefore, one avoids placing the Bragg peak on critical structures such as the brainstem, spinal cord, or optic chiasm. In summary, it appears that normal tissue tolerance of proton radiotherapy is likely to be similar to photon radiation for equivalent biologic doses. Overall, it is anticipated that there will be a lower risk of normal tissue toxicity associated with proton therapy because of a lower delivered dose outside of the target tissue. PMID- 23032889 TI - Track-structure simulations for charged particles. AB - Monte Carlo track-structure simulations provide a detailed and accurate picture of radiation transport of charged particles through condensed matter of biological interest. Liquid water serves as a surrogate for soft tissue and is used in most Monte Carlo track-structure codes. Basic theories of radiation transport and track-structure simulations are discussed and differences compared to condensed history codes highlighted. Interaction cross sections for electrons, protons, alpha particles, and light and heavy ions are required input data for track-structure simulations. Different calculation methods, including the plane wave Born approximation, the dielectric theory, and semi-empirical approaches are presented using liquid water as a target. Low-energy electron transport and light ion transport are discussed as areas of special interest. PMID- 23032891 TI - Genetic susceptibility: radiation effects relevant to space travel. AB - Genetic variation in the capacity to repair radiation damage is an important factor influencing both cellular and tissue radiosensitivity variation among individuals as well as dose rate effects associated with such damage. This paper consists of two parts. The first part reviews some of the available data relating to genetic components governing such variability among individuals in susceptibility to radiation damage relevant for radiation protection and discusses the possibility and extent to which these may also apply for space radiations. The second part focuses on the importance of dose rate effects and genetic-based variations that influence them. Very few dose rate effect studies have been carried out for the kinds of radiations encountered in space. The authors present here new data on the production of chromosomal aberrations in noncycling low passage human ATM+/+ or ATM+/- cells following irradiations with protons (50 MeV or 1 GeV), 1 GeV(-1) n iron ions and gamma rays, where doses were delivered at a high dose rate of 700 mGy(-1) min, or a lower dose rate of 5 mGy min(-1). Dose responses were essentially linear over the dose ranges tested and not significantly different for the two cell strains. Values of the dose rate effectiveness factor (DREF) were expressed as the ratio of the slopes of the dose response curves for the high versus the lower (5 mGy min(-1)) dose rate exposures. The authors refer to this as the DREF5. For the gamma ray standard, DREF5 values of approximately two were observed. Similar dose rate effects were seen for both energies of protons (DREF5 ~ 2.2 in both cases). For 1 GeV(-1) n iron ions [linear energy transfer (LET) ~ 150 keV MU(-1)], the DREF5 was not 1 as might have been expected on the basis of LET alone but was approximately 1.3. From these results and conditions, the authors estimate that the relative biological effectiveness for 1 GeV(-1) n iron ions for high and low dose rates, respectively, were about 10 and 15 rather than around 20 for low dose rates, as has been assumed by most recommendations from radiation protection organizations for charged particles of this LET. The authors suggest that similar studies using appropriate animal models of carcinogenesis would be valuable. PMID- 23032890 TI - Defining molecular and cellular responses after low and high linear energy transfer radiations to develop biomarkers of carcinogenic risk or therapeutic outcome. AB - The variability in radiosensitivity across the human population is governed in part by genetic factors. The ability to predict therapeutic response, identify individuals at greatest risk for adverse clinical responses after therapeutic radiation doses, or identify individuals at high risk for carcinogenesis from environmental or medical radiation exposures has a medical and economic impact on both the individual and society at large. As radiotherapy incorporates particles, particularly particles larger than protons, into therapy, the need for such discriminators, (i.e., biomarkers) will become ever more important. Cellular assays for survival, DNA repair, or chromatid/chromosomal analysis have been used to identify at-risk individuals, but they are not clinically applicable. Newer approaches, such as genome-wide analysis of gene expression or single nucleotide polymorphisms and small copy number variations within chromosomes, are examples of technologies being applied to the discovery process. Gene expression analysis of primary or immortalized human cells suggests that there are distinct gene expression patterns associated with radiation exposure to both low and high linear energy transfer radiations and that those most radiosensitive are discernible by their basal gene expression patterns. However, because the genetic alterations that drive radio response may be subtle and cumulative, the need for large sample sizes of specific cell or tissue types is required. A systems biology approach will ultimately be necessary. Potential biomarkers from cell lines or animal models will require validation in a human setting where possible and before being considered as a credible biomarker some understanding of the molecular mechanism is necessary. PMID- 23032892 TI - Description of transport codes for space radiation shielding. AB - Exposure to ionizing radiation in the space environment is one of the hazards faced by crews in space missions. As space radiations traverse spacecraft, habitat shielding, or tissues, their energies and compositions are altered by interactions with the shielding. Modifications to the radiation fields arise from atomic interactions of charged particles with orbital electrons and nuclear interactions leading to projectile and target fragmentation, including secondary particles such as neutrons, protons, mesons, and nuclear recoils. The transport of space radiation through shielding can be simulated using Monte Carlo techniques or deterministic solutions of the Boltzmann equation. To determine shielding requirements and to resolve radiation constraints for future human missions, the shielding evaluation of a spacecraft concept is required as an early step in the design process. To do this requires (1) accurate knowledge of space environmental models to define the boundary condition for transport calculations, (2) transport codes with detailed shielding and body geometry models to determine particle transmission into areas of internal shielding and at each critical body organ, and (3) the assessment of organ dosimetric quantities and biological risks by applying the corresponding response models for space radiation against the particle spectra that have been accurately determined from the transport code. This paper reviews current transport codes and analyzes their accuracy through comparison to laboratory and spaceflight data. This paper also introduces a probabilistic risk assessment approach for the evaluation of radiation shielding. PMID- 23032893 TI - Review of nuclear physics experimental data for space radiation. AB - The available nuclear fragmentation data relevant to space radiation studies are reviewed. It is found that there are serious gaps in the data. Helium data are missing in the intervals 280 MeV n-3 GeV n and >15 GeV n. Carbon data are missing >15 GeV n. Iron projectile data are missing at all energies except in the interval 280 MeV n-3 GeV n. PMID- 23032894 TI - Radiation carcinogenesis risk assessments for never-smokers. AB - Cigarette smoking, which is presently associated with more than 20% of adult deaths in the United States, is a large confounder to radiation risk estimates derived from epidemiology data. Astronauts and other exposed groups are classified as never-smokers (NS), defined as lifetime use of less than 100 cigarettes. In the past, radiation risk estimates have been made using average U.S. population rates for cancer and all causes of death, which may lead to overestimation of radiation risks for NS. In this report, age- and gender specific radiation carcinogenesis risk calculations for NS and the average U.S. population are compared. Lung is the major tissue site for smoking and radiation related cancer. However, other radiogenic cancers where tobacco has been shown to increase population cancer rates are esophagus, oral cavity, salivary gland, bladder, stomach, liver, colorectal, and leukemia. After adjusting U.S. cancer rates to remove smoking effects, radiation risks for lung and other cancers were estimated using the multiplicative risk model and a mixture model, with weighted contributions for additive and multiplicative risk transfer. Radiation mortality risks for NS were reduced compared to the average U.S. population by more than 20% and 50% in the mixture model and multiplicative transfer models, respectively. The authors discuss possible mechanisms of cancer risks from radiation and tobacco that suggest multiplicative effects could occur. These results suggest that improved understanding of possible synergisms between cancer initiators and promoters, such as radiation and tobacco, would greatly improve risk estimates and reduce uncertainties for differentially exposed groups, including NS. PMID- 23032896 TI - NCI support for particle therapy: past, present, future. AB - In light of the rising worldwide interest in particle therapy, and proton therapy specifically in the United States, the National Cancer Institute (NCI) is being asked more often about funding for such research and facilities. Many of the questions imply that NCI is naive to the exciting possibilities inherent in particle therapies, and thus they wish to encourage NCI to initiate and underwrite such programs. In fact, NCI has a long track record of support for the translation of hadrons from the physics laboratory to the therapy clinic by way of technology development and scientific investigations of physical and biological processes as well as clinical outcomes. Early work has included continuous funding since 1961 of proton treatments for more than 15,000 patients and facility construction at the Harvard/Massachusetts General Hospital (MGH) site; treatment of 227 patients with the pi-meson facility at Los Alamos between 1974 and 1981; funding of more than $69M for seven neutron therapy centers between 1971 and 1989; many funded projects in boron neutron capture radiation therapy through the present time; and numerous radiobiology projects over the past 50 y. NCI continues to play an active role in the incorporation of protons into randomized clinical trials through the Children's Oncology Group, Radiation Therapy Oncology Group, and the Program Project Grant (P01), which is co-directed by the MGH and MD Anderson Cancer Center. This has required funding development and implementation of guidelines that enable intercomparison of dosimetry and treatment between facilities. NCI has also funded recent efforts to develop new physical processes for the production of particles such as protons. With regard to the future, while it is true that there are no specific funding opportunity announcements directed to particle therapy research, it is also true that NCI remains open to reviewing any research that is compatible with an established mechanism. However, given the very substantial resources that these facilities currently require along with the highly competitive economic environment that now exists, it is clear that scientific review of such grant applications will look to leverage the scientific pursuits that are the NCI mandate with the reality of the clinical practices, just as is the case for photon radiation research. Such leveraging should be enhanced by the growing opportunities and need for international collaborations. On the other hand, these collaborations are complicated by the fact that these particle therapies are now fully reimbursable modalities, which makes it difficult to separate research (the NCI mission) from clinical practice development. This paper seeks to illuminate these new realities in order to encourage the pursuit and funding of the scientific underpinnings of physical methods, radiobiology, and clinical practice with particle therapy. PMID- 23032895 TI - Assessment of the risk for developing a second malignancy from scattered and secondary radiation in radiation therapy. AB - With the average age of radiation therapy patients decreasing and the advent of more complex treatment options comes the concern that the incidences of radiation induced cancer might increase in the future. The carcinogenic effects of radiation are not well understood for the entire dose range experienced in radiation therapy. Longer epidemiologic studies are needed to improve current risk models and reduce uncertainties of current risk model parameters. On the other hand, risk estimations are needed today to judge the risks versus benefits of modern radiation therapy techniques. This paper describes the current state-of the-art in risk modeling for radiation-induced malignancies in radiation therapy, distinguishing between two volumes: first, the organs within the main radiation field receiving low or intermediate doses (typically between 0.1 and 50 Gy); and second, the organs far away from the treatment volume receiving low doses mainly due to scattered and secondary radiation (typically below 0.1 Gy). The dosimetry as well as the risk model formalisms are outlined. Furthermore, example calculations and results are presented for intensity-modulated photon therapy versus proton therapy. PMID- 23032897 TI - Accelerators for America's Future Workshop: Medicine and Biology. AB - "Medicine and Biology" was one of five working groups of the "Accelerators for America's Future" Workshop held October 2009. The recently-released workshop report stresses that the leadership position of the United States in fields where accelerators play an important part is being seriously eroded because of lack of coordinated agency support for accelerator research and development. This is particularly true for biology and medicine. Radiation therapy with beams of protons and light ions was pioneered in the United States and has proven successful in the treatment of several different tumor sites in the body. Proton therapy is available in the United States in a number of centers; however, all but one contain accelerator and beam-delivery components manufactured abroad. Light-ion therapy is only available overseas. Why has the United States lost its lead in this field? The Working Group noted that in other countries, central governments are subsidizing construction and technology development by their industries, whereas in the United States funding for purchasing and building clinical facilities must be raised from private sources. As a result, most proton facilities in the United States, by virtue of having to recover investment costs, favor reimbursable treatments, detracting from the development of research protocols. The financial hurdle for starting a light-ion facility in the United States has been totally prohibitive for the private-equity market. While technological advances are being made that will provide some reduction in capital costs, the field will not flourish in the United States until effective funding means are developed that do not put the full burden on the private sector. PMID- 23032898 TI - ENLIGHT: The European Network for Light Ion Hadron Therapy. AB - The European Network for Light Ion Hadron Therapy (ENLIGHT) was established in 2002 to coordinate European efforts on hadron therapy (radiotherapy performed with protons and light ions instead of high-energy photons). The ENLIGHT network is formed by the European Hadron Therapy Community, with more than 300 participants from 20 different countries. A major success of ENLIGHT has been uniting traditionally separate communities so that clinicians, physicists, biologists, and engineers with experience and interest in particle therapy work together. ENLIGHT has been a successful initiative in forming a common European platform and bringing together people from diverse disciplines. ENLIGHT demonstrates the advantages of regular and organized exchanges of data, information, and best practices, as well as determining and following strategies for future needs in research and technological development in the hadron therapy field. PMID- 23032899 TI - Summary: achievements, critical issues, and thoughts on the future. AB - The number of individuals exposed to particle radiations in cancer treatment worldwide is increasing rapidly, and space agencies are developing plans for long duration, deep space missions in which humans could be exposed to significant levels of radiation from charged particles. Hence, the NCRP 47 th Annual Meeting on "Scientific and Policy Challenges of Particle Radiations in Medical Therapy and Space Missions" was a timely opportunity to showcase the current scientific knowledge regarding charged particles, enhance cross-fertilization between the oncology and space scientific communities, and identify common needs and challenges to both communities as well as ways to address those challenges. This issue of Health Physics contains papers from talks presented at that meeting and highlights provocative questions and the ample opportunities for synergism between space and particle-therapy research to further understanding of the biological impacts of particle radiations. PMID- 23032903 TI - First synthetic analogues of diphosphoinositol polyphosphates: interaction with PP-InsP5 kinase. AB - We synthesised analogues of diphosphoinositol polyphosphates (PP-InsPs) in which the diphosphate is replaced by an alpha-phosphonoacetic acid (PA) ester. Structural analysis revealed that 5-PA-InsP(5) mimics 5-PP-InsP(5) binding to the kinase domain of PPIP5K2; both molecules were phosphorylated by the enzyme. PA InsPs are promising candidates for further studies into the biology of PP-InsPs. PMID- 23032904 TI - Shoulder muscle isometric strength and active range of motion in patients with frozen shoulder syndrome after manipulation under anesthesia. AB - BACKGROUND AND OBJECTIVE: Frozen shoulder syndrome (FSS) causes pain and restriction of movement in the shoulder. The aim was to assess changes in shoulder muscle isometric maximal voluntary contraction (MVC) force and active range of motion (AROM) in patients with frozen shoulder syndrome (FSS) after manipulation under general anesthesia (MUA). MATERIAL AND METHODS: In total, 18 patients with FSS (9 women and 9 men) with a mean age of 53.6 years (SD, 9.7) participated in this study. MVC force of shoulder flexors, adductors, and internal and external rotators was measured by a handheld dynamometer. AROM in the same directions was measured goniometrically. The patients were screened according to the intensity of pain by day and at night. The data were collected before MUA and 1 and 6 months after MUA. A significant reduction in MVC force and AROM was noted before MUA in the involved extremity as compared with the uninvolved extremity (P<0.05). These parameters for the involved extremity were significantly increased 1 month after MUA (P<0.05). However, 6 months after MUA, MVC force and AROM did not differ significantly compared with the uninvolved extremity (P>0.05), whereas AROM of flexion and external rotation remained significantly reduced (P<0.05). A significant reduction in shoulder pain by day and at night was recorded 1 and 6 months after MUA (P<0.05). CONCLUSIONS: In the patients with FSS, the fastest improvement of MVC force and AROM occurred following the first month after MUA. However, 6 months after MUA, shoulder muscle MVC force for the involved extremity did not differ significantly as compared with the uninvolved extremity, whereas the shoulder AROM in flexion and external rotation remained lower. PMID- 23032905 TI - Behavioral problems in children with benign childhood epilepsy with centrotemporal spikes treated and untreated with antiepileptic drugs. AB - The aim of this study was to investigate behavioral problems in two groups of children with benign childhood epilepsy with centrotemporal spikes (BECTS), i.e., those treated with antiepileptic drugs and those not treated in order to identify the factors associated with behavioral problems. MATERIAL AND METHODS. In total, 20 newly diagnosed untreated, 23 treated patients with BECTS, and 20 patients with acute/subacute peripheral nervous system disorders as a comparison group (aged 6-11 years) were examined. The evaluation was performed using the Lithuanian version of the Child Behavior Checklist (CBCL). Schooling parameters, clinical parameters, EEG parameters, and their relation to the results of the CBCL were also investigated. RESULTS. The treated patients with BECTS had significantly higher scores in the subscales of Social Problems, Anxious/Depressed, Aggressive Behavior, and Attention Problems compared with the scores of the patients with peripheral nervous system disorders. A significant relationship was established between the scores of native language grades and Attention Problems; grades in mathematics and treatment duration; and age when the first seizure occurred and Delinquent Behavior in the group of treated patients. The duration of epilepsy was positively correlated with the scores in the subscales of Withdrawn and Delinquent Behavior. The presence of additional extrarolandic focus and spread of focal specific discharges to the centrofrontotemporal and centroparietotemporal areas were related to higher scores in Social Problems, Attention Problems, and Delinquent Behavior in the group of the treated patients with BECTS. CONCLUSIONS. Children with BECTS, especially those treated and with a longer epilepsy course, were found to be at risk of behavioral problems. Lower grades were associated with a longer disease course and medications. The presence of extrarolandic discharges was related to higher CBCL scores in the group of the treated patients with BECTS. PMID- 23032906 TI - Associations between TFPI-2 methylation and poor prognosis in glioblastomas. AB - BACKGROUND AND OBJECTIVE: The epigenetic silencing of tumor suppressor genes plays an important role in gliomagenesis. Recently, tissue factor pathway inhibitor 2 (TFPI-2) has been suggested as a tumor suppressor gene involved in tumorigenesis and metastasis in some cancers. However, to date, little is known about the methylation status of TFPI-2 gene in glioblastoma tissues. In this study, we aimed to investigate the methylation status of TFPI-2 promoter and its associations with patient prognosis in glioblastoma. MATERIAL AND METHODS: The methylation status of TFPI-2 was investigated by methylation-specific polymerase chain reaction in 99 glioblastoma patients. The associations between patients' clinical variables and overall survival time were assessed. RESULTS. TFPI-2 was aberrantly methylated in 22.2% (22/99) of glioblastoma tumors, but was not methylated in normal brain samples. The survival of patients with glioblastoma differed significantly between the methylated and unmethylated TFPI-2 groups (P=0.047). The 2-year survival among patients carrying methylated TFPI-2 tumors was significantly lower compared with that of patients with unmethylated TFPI-2 (27% versus 4.7%, P=0.037). CONCLUSIONS: The present work demonstrated that the epigenetic inactivation of TFPI-2 by promoter hypermethylation was a frequent and tumor-specific event in glioblastoma, and TFPI-2 promoter methylation might be considered as a prognostic marker in glioblastoma. PMID- 23032907 TI - Impedance cardiography and heart rate variability for long-term cardiovascular outcome prediction after myocardial infarction. AB - BACKGROUND AND OBJECTIVE: The objective of our study was to evaluate the predictive power of a combined assessment of heart rate variability (HRV) and impedance cardiography (ICG) measures in order to better identify the patients at risk of serious adverse events after ST-segment elevation myocardial infarction (STEMI): all-cause or cardiac mortality (primary outcomes) and in-hospital recurrent ischemia, recurrent nonfatal MI, and need for revascularization (secondary outcomes). MATERIAL AND METHODS: A total of 213 study patients underwent 24-hour electrocardiogram (used for HRV analysis) and thoracic bioimpedance monitoring (used for calculation of hemodynamic measures) immediately after admission. The patients were examined on discharge and contacted after 1 and 5 years. Cox regression analysis was used to determine the predictors of selected outcomes. RESULTS. The standard deviation of all normal-to normal intervals (SDNN) and cardiac power output (CPO) were found to be the significant determinants of 5-year all-cause mortality (SDNN <= 100.42 ms and CPO <= 1.43 W vs. others: hazard ratio [HR], 11.1; 95% CI, 4.48-27.51; P<0.001). The standard deviation of the averages of NN intervals (SDANN) and CPO were the significant predictors of 5-year cardiac mortality (SDANN <= 85.41 ms and CPO <= 1.43 W vs. others: HR, 11.05; 95% CI, 3.75-32.56; P<0.001). None of the ICG measures was significant in predicting any secondary outcome. CONCLUSIONS: The patients with both impaired autonomic heart regulation and systolic function demonstrated by decreased heart rate variability and impedance hemodynamic measures were found to be at greater risk of all-cause and cardiac death within a 5-year period after STEMI. An integrated analysis of electrocardiogram and impedance cardiogram helps estimate patient's risk of adverse outcomes after STEMI. PMID- 23032908 TI - Epileptic laughter: 2 case reports. AB - Two cases of gelastic epilepsy in a 6-year-old girl with attacks of mirthful laughter and a 38-year-old male patient with episodes of laughter without any positive emotions are presented. Temporal lobe epilepsy was diagnosed in the first case and possible frontal lobe epilepsy in the second case. It is concluded that that this rare form of epilepsy can be difficult to diagnose and treat, and can clinically be accompanied by urinary incontinence. PMID- 23032909 TI - Changes in caries prevalence and oral hygiene skills among preschool-aged children in Lithuania between 2000 and 2010. AB - The aim of the study was to evaluate the factors associated with the prevalence and severity of dental caries as well oral hygiene habits among 4- to 6-year-old children in Kaunas (Lithuania) in 2000 and 2010. MATERIAL AND METHODS: A repeated cross-sectional study was carried out to reveal the changes in dental caries prevalence in 2000 and 2010. The study population comprised 4- to 6-year-old children living in Kaunas city and attending kindergartens. The study consisted of two parts: questionnaires on oral health behavior and clinical examination of children's teeth by the World Health Organization methodology. RESULTS: A total of 941 4-6-year-old children were examined in 2000 and 2010. The prevalence of dental caries increased from 85.4% in 2000 to 88.4% in 2010; however, the difference was not significant (P=0.28). A significant increase in the dmf-t index, describing the severity of dental caries, was observed (from 7.42 in 2000 to 12.03 in 2010, P<0.001). The percentage of 4- to 5-year-old girls and 5-year old boys brushing their teeth regularly decreased in 2010. During the period of the study, a significant change in the accumulation of plaque on children's tooth surfaces was documented (P=0.001). CONCLUSIONS: Comparing 2000 and 2010, no significant difference in the prevalence of dental caries among 4- to 6-year-old children in Kaunas was observed; however, the severity of dental caries differed significantly. A significant decrease in regular toothbrushing skills was documented for 4- and 5-year-old girls and 5-year-old boys. The Silness-Loe oral hygiene index was assessed as satisfactory. PMID- 23032910 TI - Sources and reasons for seeking health information by Lithuanian adults. AB - The aim of this study was to assess the attitudes of Lithuanian adults aged 20-64 years toward the reasons for accessing health information and to determine the main health information sources and their relation to sociodemographic factors. MATERIAL AND METHODS: The data for this study were gathered in 2008 within the framework of the International Project Finbalt Health Monitor evaluating health behavior in a Lithuanian adult population. RESULTS: More than half of respondents searched for health information during the last year. Men were 2.7 times more likely to trust friends and family as a health information source compared with women. For each 1-year increase in age, the odds of using friends and family, and the Internet as the main sources of health information decreased, while the odds of using people with the same condition and different means of media increased. Marital status was associated with greater trust in health professionals and the Internet as health information sources. Higher education was positively associated with more frequent reporting courses and lectures, and the Internet as the sources of health information, while those with lower education preferred television and radio. CONCLUSIONS: This study revealed the characteristics of the "risk group" in terms of the sources of health information that people, assigned to it, tend to use, and it is especially important when providing health information. PMID- 23032911 TI - Paracetamol and simvastatin: a potential interaction resulting in hepatotoxicity. AB - The safety profile of paracetamol and simvastatin is sufficiently well known, although no interactions between these two medicinal products have been described in the scientific literature so far. A 66-year-old female patient who experienced myocardial infarction and underwent coronary artery bypass grafting 9 years ago was taking simvastatin at a daily dose of 10 mg. Liver enzyme tests were carried out regularly, and their results were always normal. Later on, the patient took 6 tablets of fixed combination medicinal product Gripex(TM) (paracetamol, pseudoephedrine, and dextromethorphan) per day due to a fever. The daily dose of paracetamol taken by the patient totaled 1.95 g. The patient developed severe jaundice, nausea, vomiting; blood bilirubin levels increased more than 3 times; alanine transaminase, more than 10 times; and asparagine transaminase, more than 5 times. Paracetamol is metabolized by CYP enzymes (CYP2E1, 1A2, 2A6, 3A4) to a reactive metabolite, N-acetyl-p-benzoquinone-imine (NAPQI). Under conditions of excessive NAPQI formation or reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of cellular proteins, forming NAPQI-protein adducts. Simvastatin is a substrate of CYP3A4 enzyme. Clinical and pharmacological data, available in the published literature, allow the assumption that simvastatin may induce CYP3A4 and result in increased hepatoxicity of paracetamol. PMID- 23032912 TI - Vibrational properties of the polymeric spin crossover (SCO) Fe(II) complexes [{Fe(4-amino-1,2,4-triazole)3}X2]n: a nuclear inelastic scattering (NIS), Raman and DFT study. AB - The vibrational properties of the cationic spin crossover (SCO) coordination polymers [{Fe(4-amino-1,2,4-triazole)(3)}(+2)](n) containing the anions chlorine, methanosulfonate and 1-naphthalenesulfonate have been studied via nuclear inelastic scattering of synchrotron radiation (NIS) as well as by Raman spectroscopy. Although the different anions have a strong influence on the spin crossover temperature, they have little effect on the positions of the spin marker bands in the NIS and Raman spectra. By comparing the line positions of the NIS spin marker bands with those observed by Raman spectroscopy, it has been possible to distinguish vibrations symmetry (A(u) or A(g)) because modes of A(u) and A(g) symmetries are NIS active, but only the A(g) modes are Raman active. The normal mode analysis of charge compensated cationic pentameric and hexameric model structures which have been obtained by density functional calculations reproduces the experimentally observed mode frequencies and the geometry optimization reproduces iron-ligand distances reported for these and related SCO coordination complexes. The effect of charge compensation appears to be independent of the choice of the functional and the basis set which shows that DFT calculations using B3LYP in conjunction with the basis set CEP-31G are a time effective approach in order to study vibrational properties of Fe(II) SCO compounds. PMID- 23032913 TI - Ab initio and semi-empirical van der Waals study of graphene-boron nitride interaction from a molecular point of view. AB - We have performed a systematic semi-empirical and ab initio van der Waals study to investigate the bonding mechanism of benzene (C(6)H(6)), triazine (C(3)N(3)H(3)) and borazine (B(3)N(3)H(6)) adsorbed on graphene and a single boron nitride (BN) sheet. The two semi-empirical approaches used to include the van der Waals (vdW) interactions in our density functional theory (DFT) calculations suggest that the strength of the molecule-surface interaction corresponds to a strong physisorption with no net charge transfer between the molecules and the corresponding substrates. This observation is strengthened by the use of first-principles non-local correlation vdW-DF functionals which provide a sound physical basis to include vdW interactions in DFT calculations. In particular we have employed two flavors of vdW-DF functionals which enabled us to determine the role of the non-local correlation effects in the molecule surface bonding mechanism which cannot be assessed by using only semi-empirical vdW methods. Our study also reveals that the strength of the molecule-surface interaction can be influenced by the electronegativity of the B, C and N atoms. PMID- 23032914 TI - Heart rate, age and the risk of progression to kidney failure in patients with CKD. AB - BACKGROUND AND METHODS: Since heart rate (HR) is a cardiovascular risk factor and a marker of sympathetic activity, we tested the predictive value of HR for progression to kidney failure in a well characterized cohort of 759 patients with stage 2-5 CKD followed up for 29 +/- 11 months. RESULTS: Overall, a total of 244 patients had renal events. In an unadjusted analysis by age tertiles the predictive value of HR for renal events was apparent only in patients in the third age tertile (older than 68 years) but not in those in the first two tertiles indicating effect modification by age of the HR--progression to kidney failure relationship. In a multiple Cox regression model adjusting for potential confounders, a 5 beats/min increase in HR entailed a 16% risk excess (Hazard Ratio = 1.16, P = .004) for renal events in patients in the third age tertile but no excess risk for the same events in patients in the first two tertiles. A statistically significant interaction (P<.001) was also found between age and the risk for renal events associated with proteinuria. CONCLUSIONS: Heart rate is an independent age-dependent effect modifier for progression to kidney failure in CKD patients. This observation generates the hypothesis that high sympathetic activity is a relevant risk factor for adverse renal outcomes in elderly patients with CKD. PMID- 23032915 TI - Heart failure and cardiorenal syndrome in the elderly. AB - In the view of the aging of the general population and particularly the aging of the dialysis population, it is of considerable interest to examine the combined effects of age and uremia on cardiovascular status. The effects of uremia per se interact with the effects of aging in cardiovascular end-organ damage and in the genesis of heart failure (HF) and cardiorenal syndrome (CRS). Structural abnormalities with fibrosis and calcification of the heart and central arteries, along with autonomic nervous system dysfunction, underlie reduced cardiac performance leading to cardiac decompensation and HF. HF in the elderly is characterized by the heart's inability to maintain an adequate cardiac output and may be the result of systolic dysfunction or reduced compliance and diastolic dysfunction. In the elderly, HF symptoms are generally light, upon admission to the hospital, while HF is sometimes in an advanced stage. The pathophysiology of CRS involves interrelated hemodynamic and neurohormonal mechanisms that in the elderly are often increased/emphasized because there is no compensatory response. The therapy of HF and CRS in the elderly with chronic kidney disease is almost entirely empirical since there are no large trials of drugs to reduce mortality and morbidity in this setting. This may lead nephrologists and cardiologists managing these patients toward a sort of "therapeutic nihilism." But this is not the attitude we should adopt in the elderly. Instead we should make a rather careful assessment of each patient and use a personalized treatment that takes into consideration the characteristics of the individual patient and his or her cardiac and renal history as well as social context. PMID- 23032917 TI - Adenoid ciliostimulation in children with chronic otitis media. AB - OBJECTIVE: Adenoid hypertrophy and chronic adenoiditis are associated with an increased incidence of chronic otitis media. This study intends to determine the relationship between chronic otitis media and dynamic ciliary beat frequency in children undergoing adenoidectomy. STUDY DESIGN: Prospective, controlled study. SETTING: Pediatric tertiary care hospital. SUBJECTS AND METHODS: Children undergoing adenoidectomy were enrolled. Patients were stratified according to their indication for surgery, including adenotonsillar hypertrophy with obstructive sleep apnea, chronic otitis media with effusion, or recurrent episodes of acute otitis media. Adenoids were harvested using the curette. Tissue was sectioned and allowed to equilibrate in basal media for 24 hours. Cilia bearing tissue was then stimulated using isoproterenol or methacholine. Ciliary beat frequency was serially reordered and analyzed using the Sisson-Ammons Video Analysis software program. RESULTS: Baseline ciliary beat frequency was similar in all groups (N = 47, total). Using isoproterenol, children with chronic otitis media with effusion demonstrated a blunted dynamic ciliary response at 2 and 3 hours relative to control (P = .0176 and P = .0282). Methacholine-stimulated ciliary beat frequency was not different between each group. CONCLUSION: At 2 and 3 hours following isoproterenol stimulation, there was a significant blunting of dynamic ciliary beat frequency in children with chronic otitis media with effusion. This ciliary dysfunction may provide a physiological explanation related to chronic adenoiditis in children with chronic otitis media. PMID- 23032918 TI - Role of NOD1-mediated signals in a mouse model of allergic rhinitis. AB - OBJECTIVES: The purpose of the present study was to investigate the effect of nucleotide-binding oligomerization domain 1 (NOD1), an innate immune sensor, on allergic inflammation and induction of regulatory T cells in a mouse model of allergic rhinitis. We also aimed to explore whether there were differences in the effect of NOD1 ligand according to the timing of administration. Study Design An in vivo study using an animal model. SETTING: Catholic Research Institutes of Medical Science. SUBJECTS AND METHODS: Forty BALB/c mice were divided into 4 groups: control, OVA, pre-NOD1, and post-NOD1. Ovalbumin (OVA) was used for sensitization and challenge. The pre-NOD1 group received NOD1 ligand intranasally before sensitization, whereas the post-NOD1 group received it after sensitization. The effects of allergic inflammation and regulatory T cells were compared among the groups. RESULTS: In the post-NOD1 group, serum OVA-specific IgE, eosinophil counts, interleukin (IL)-13 levels, and GATA-3 mRNA expression were significantly increased and Foxp3(+) mRNA expression and CD4(+) Foxp3(+) T cells were decreased compared with the OVA group. In the pre-NOD1 group, Foxp3 mRNA expression and CD4(+) Foxp3(+) T cells were significantly decreased compared with the OVA group. Although not significant, the pre-NOD1 group showed increases in serum OVA-specific IgE, eosinophil counts, IL-13 levels, and GATA-3 mRNA expression compared with the OVA group. CONCLUSION: The innate immune response through NOD1 enhances allergen-specific Th2 response and suppresses induction of regulatory T cells in a mouse model of allergic rhinitis, and the effects are different depending on the timing of exposure to NOD1 ligand. PMID- 23032919 TI - Pinning of elastic ferromagnetic/antiferromagnetic interfaces in phase-separated manganites. AB - We present a study of the magnetic properties of the Pr(0.5)Sr(0.5-x)Ca(x)MnO(3) manganite (x = 0.1 and 0.2) in the temperature region where phase separation occurs. This state is characterized by the presence of ferromagnetic (FM) inclusions inside an antiferromagnetic (AFM) matrix. The evolution of the magnetization (M) with magnetic field shows the existence of a critical field, H(C), above which M rapidly increases, indicating a sudden expansion of the FM volume against the AFM one. We analyze this behavior and the response of the magnetic susceptibility at low fields (H < H(C)) in terms of a thermally activated motion of pinned FM/AFM elastic interfaces. The pinning mechanism is likely to be related to the martensitic accommodation strain around the magnetic and structural interfaces. From this analysis we estimate the size of the FM domains and the parameters that characterize the pinning potential. PMID- 23032920 TI - A cellular lipidomic study on the Abeta-induced neurotoxicity and neuroprotective effects of EGCG by using UPLC/MS-based glycerolipids profiling and multivariate analysis. AB - The aim of this study was to investigate the cellular lipid metabolism associated with beta-amyloid peptide (Abeta)-induced neurotoxicity as well as the neuroprotective effect of (-)-epigallocatechin gallate (EGCG), a major polyphenol in green tea. An ultra-performance liquid chromatography-quadrupole-time-of flight mass spectrometry (UPLC-Q-TOF-MS)-based lipidomic approach was developed to screen and identify changes of the glycerolipids (GL) upon Abeta treatment with or without the presence of EGCG in PC12 cells. Principle component analysis (PCA) showed that the Abeta-treated group was well separated from the control group, whereas the EGCG group was closer to the control group. The GL levels were significantly elevated in Abeta-treated cells compared with the control group, but were restored near to normal levels after EGCG treatment. The elevated phosphatidylcholines (PCs) levels observed in the Abeta-treated PC12 cells were quite probably the integrated results of the reduced phospholipase A(2) (PLA(2)) activity and the enhanced activity of lysophospholipid acyltransferases. Moreover, an increased liberation of arachidonic acid (AA) from PCs was observed as another important response of PC12 cells to the Abeta aggregates, implying an active inflammatory process occurring in Abeta induced neurotoxicity. EGCG treatment can reverse the deregulated metabolism of PCs, which might be one of the biochemical mechanisms contributing to its neuroprotective effect. Collectively, results obtained from the current lipidomic analyses of PC12 cells provided important insight into the biochemical mechanisms underlying Abeta induced neurotoxicity and neuro protective effects of EGCG. This is the first report of the lipidomic study on the neuroprotective effect of EGCG. PMID- 23032921 TI - Interstitial 16p13.3 microduplication: case report and critical review of genotype-phenotype correlation. AB - We report on a patient with a recognizable phenotype of intellectual disability, multiple congenital anomalies, musculoskeletal anomalies and craniofacial dysmorphisms, carrying a de novo 0.4 Mb duplication of chromosome region 16p13.3 detected by SNP-array analysis. In addition, myopia, microcephaly and growth retardation were observed. The causal 16p13.3 duplication is one of the smallest reported so far, and includes the CREB binding protein gene (CREBBP, MIM 600140), whose haploinsufficiency is responsible for the Rubinstein-Taybi syndrome, and the adenylate cyclase 9 gene (ADCY9, MIM 603302). By comparing the clinical manifestations of our patient with those of patients carrying similar rearrangements, we confirmed that 16p13.3 microduplications of the Rubinstein Taybi region result in a recognizable clinical condition that likely represents a single gene disorder. In addition, our case allowed us to define with more precision the smallest region of overlap (SRO) in all patients reported so far, encompassing only the CREBBP gene, and is useful to confirm and further define the phenotypic characteristics due to duplication of the CREBBP gene, being the first case of interstitial duplication with microcephaly and growth defects reported to date. PMID- 23032922 TI - Indirect videolaryngoscopy with C-MAC D-Blade and GlideScope: a randomized, controlled comparison in patients with suspected difficult airways. AB - BACKGROUND: Recently, indirect videolaryngoscopes have become increasingly important devices in difficult airway management. The aim of the present study was to investigate laryngoscopic view and intubation success using the new C MAC(r) D-Blade in comparison to the established GlideScope(r) videolaryngoscope and conventional direct laryngoscopy in a randomized controlled trial. METHODS: Ninety-six adult patients with expected difficult airways undergoing elective ear, nose and throat surgery (ENT) requiring general anesthesia were investigated. Repeated laryngoscopy was performed using a conventional direct Macintosh laryngoscope (DL), C-MAC D-Blade (DB) and GlideScope (GS) in a randomized sequence before patients were intubated with the last device used. RESULTS: Both videolaryngoscopes showed significantly better C/L (Cormack-Lehane) classes than DL. Insufficient laryngoscopic view, defined as C/L >= III, was experienced in 18 patients (19.2%) with DL, in two patients with GS (2.1%) and in none with DB (0%). Time to best achievable laryngoscopic view did not differ between devices. Intubation time was significantly longer with both videolaryngoscopes (Median [Range] DB: 18 [8-33] s, and GS: 19 [9-34] s) than with DL (11 [5-26] s). However, intubation success was 100% for both DB and GS, whereas four patients could not be intubated using conventional direct laryngoscopy. CONCLUSION: Compared to direct Macintosh laryngoscopy, both C MAC(r) D-Blade and GlideScope(r) comparably resulted in an improved view of the glottic opening with successful tracheal intubation in all patients. PMID- 23032923 TI - Glucose and insulin administration while maintaining normoglycemia: the GIN concept. AB - The benefits of tight glucose control in critically ill and surgical patients remains a subject of debate. While some studies demonstrated a survival benefit associated with intensive insulin therapy, more recent studies have failed to demonstrate this correlation. On the contrary, the difficulty in achieving normoglycemia with the conventional insulin sliding scale protocols and a rising concern for severe hypoglycemic episodes associated with this strategy keep many clinicians skeptical. This article examines the use of hyperinsulinemic normoglycemic clamping, or glucose-insulin-normoglycemia (GIN) therapy, a novel approach to achieve normoglycemia in the perioperative period. If properly applied, this therapy potentially reduces the morbidity and mortality associated with hyperglycemia and confers the pharmacological advantages of hyperinsulinemia. Further understanding of the underlying molecular mechanisms, as well as the development of a continuous intravenous glucose monitoring device would facilitate the routine clinical use of GIN therapy. PMID- 23032924 TI - Biomarkers for acute kidney injury in critically ill patients. AB - Acute kidney injury (AKI) is a common and frequently fatal illness in critically ill patients, with a high associated-mortality. Early recognition of kidney injury and prompt corrective measures may improve outcome. Finding an early, accurate and reproducible biomarker for AKI is a research priority. In recent years, many urinary or plasma proteins have been investigated, some of them promising, but the ideal biomarker remains to be discovered. Cystatin C, neutrophil gelatinase-associated lipocalin, interleukin-18, fatty acid-binding proteins and kidney injury molecule 1 seem to be more accurate markers for AKI as compared with the traditional serum creatinine. However, their ability to predict worsening of AKI and need for renal replacement therapy (RRT) is not clear, and current available data are insufficient to recommend the use of these biomarkers routinely for clinical decision-making. Thus, using a combination of different urinary and plasma biomarkers and clinical observations, such as oliguria, may modify the clinical variability for therapeutic interventions, such as RRT initiation, and improve outcome. The purpose of this review was to summarize recent findings concerning biomarkers for AKI, especially in the intensive care unit setting, to highlight their strengths and weaknesses, and to determine their usefulness in clinical practice. PMID- 23032925 TI - Echocardiography and pulse contour analysis to assess cardiac output in trauma patients. AB - BACKGROUND: Echocardiography is a valuable technique to assess cardiac output (CO) in trauma patients, but it does not allow a continuous bedside monitoring. Beat-to-beat CO assessment can be obtained by other techniques, including the pulse contour method MostCare. The aim of our study was to compare CO obtained with MostCare (MC-CO) with CO estimated by transthoracic echocardiography (TTE CO) in trauma patients. METHODS: Forty-nine patients with blunt trauma admitted to an intensive care unit and requiring hemodynamic optimization within 24 hours from admission were studied. TTE-CO and MC-CO were estimated simultaneously at baseline, after a fluid challenge and after the start of vasoactive drug therapy. RESULTS: One hundred sixteen paired CO values were obtained. TTE-CO values ranged from 2.9 to 7.6 L.min(-1), and MC-CO ranged from 2.8 to 8.2 L.min(-1). The correlation between the two methods was 0.94 (95% confidence interval [CI]=0.89 to 0.97; P<0.001). The mean bias was -0.06 L.min(-1) with limits of agreements (LoA) of -0.94 to 0.82 L.min(-1) (lower 95% CI, -1.16 to -0.72; upper 95% CI, 0.60 to 1.04) and a percentage error of 18%. Changes in CO showed a correlation of 0.91 (95% CI=0.87 to 0.95; P<0.001), a mean bias of -0.01 L.min(-1) with LoA of -0.67 to 0.65 L.min(-1) (lower 95% CI, -0.83 to -0.51; upper 95% CI, 0.48 to 0.81). CONCLUSION: CO measured by MostCare showed good agreement with CO obtained by transthoracic echocardiography. Pulse contour analysis can complement echocardiography in evaluating hemodynamics in trauma patients. PMID- 23032926 TI - Prognostic indicators of mortality of mechanically ventilated patients with acute leukemia in a comprehensive cancer center. AB - BACKGROUND: The prognosis for adult acute leukemia patients that require intensive care unit (ICU) admission and invasive mechanical ventilation is poor. We aimed to identify prognostic indicators of 30-day hospital mortality in adult patients who had acute leukemia and respiratory failure, who had received invasive mechanical ventilation in the ICU but who had not received blood and marrow transplantation, were not admitted due to cardiopulmonary arrest or myocardial infarction and, had not recently undergone surgery. METHODS: In this case-control study, we retrospectively reviewed the medical records of relevant patients >16 year old who had been admitted to the ICU at our institution over a 4-year period. The main outcome measure was 30-day hospital mortality. Univariate and multivariate analyses were conducted to determine significant predictors of death. RESULTS: For the 167 patients meeting our eligibility criteria, the median age was 61 years. The majority was admitted due to respiratory insufficiency/failure (69%). The 30-day hospital mortality rate was 62%. Independent predictors of 30-day hospital mortality were advanced disease status (odds ratio [OR]=3.34; 95% confidence interval [CI], 1.65-6.77) and increased organ failure at the time of intubation (OR=1.17; 95% CI, 1.03-1.33) per point increase in the SOFA score. Patients who had received endotracheal intubation within the first 24 h of ICU admission were less likely than others to die (OR=0.46, 95% CI, 0.23-0.91) within the next 30 days after admission to the hospital. CONCLUSION: Advanced disease status and elevated SOFA scores at intubation are strong predictors of 30-day mortality in patients with acute leukemia and respiratory failure. The protective effect of early endotracheal intubation warrants further investigation. PMID- 23032927 TI - Practice of analgesia and sedation in Italian Paediatric Intensive Care Units: did we progress? AB - BACKGROUND: No strong recommendation was reported in management analgesia and sedation of critically ill children. The present study was performed to describe the current practice of analgesia and sedation in Pediatric Italian Intensive Care Units, in order to evaluate the adherence to last published pediatric guidelines. METHODS: A questionnaire was sent to 24 Italian Paediatric Intensive Care Units during 2010. RESULTS: One Hundred percent of contacted centers returned the filled form. All Pediatric Italian Intensive Care Units used the same combination (opioid plus benzodiazepine); 50% of centers referred to regularly monitor the level of sedation, but only 37% of them used validate tools. Withdrawal syndrome was regularly monitored in 25% of contacted Pediatric Italian Intensive Care Units; Finnegan scale was the only adopted scale. CONCLUSION: National pediatric intensivists identified the same drug strategy to obtain analgesia and sedation in their patients, according to last published guidelines. Assessment of analgesia and sedation was more diffuse but not regularly performed and different methods were used. Withdrawal syndrome was monitored in a minority of contacted centres. Considering our data the practice of analgesia and sedation in Italian Pediatric Intensive Care Units is improved but not yet completely adherent to last international recommendations. PMID- 23032928 TI - Diagnostic strategy for oncology patients with acute respiratory failure. AB - Acute respiratory failure (ARF) is frequent and often fatal in patients with a malignancy. However, there is not one type of "oncology patient", and it's high time that both clinical management and further studies consider specific populations rather than the heterogeneous and artificial group of "cancer patients". This individual-based approach will allow a relevant use of the numerous non invasive diagnostic tools developed during the past years: high resolution tomodensitometry, echocardiography, urine or serum antigen assays, polymerase chain reaction, serum biomarkers etc. These non invasive tools have reduced but not weakened the value of fiberoptic bronchoscopy and bronchoalveolar lavage: some subsets of patients may always benefit from this technique, particularly when new protective strategies such as non invasive mechanical ventilation and target-controlled infusion of sedative drugs are used. The present review focuses on the personalised approach required in "oncology patients" with ARF, based on first identifying the pattern of immunodeficiency, then listing the most probable hypotheses in the light of clinical and radiological findings in order to, finally, select the most accurate diagnostic tools. PMID- 23032929 TI - Long-term survival after ICU treatment. AB - BACKGROUND: The aim of this paper was to study long-term survival in patients treated in the Intensive Care Unit (ICU) and who survived to hospital discharge. METHODS: This was a single-center retrospective cohort study of patients admitted to a mixed intensivist-led 10 bed ICU in a teaching hospital between 2004 and 2009 and discharged alive from the hospital with complete follow-up until January 1, 2011. RESULTS: A total of 3477 individual patients were admitted to the ICU, 491 (14.1%) of whom died in the hospital while 2986 survived to hospital discharge. In the first year after discharge 436 out of 2986 (14.6%) patients died. Mortality after hospital discharge was highest in the first three months. For patients discharged alive from the hospital the risk of dying during the first year increased significantly with age, APACHE II score at admission and being discharged to a place other than home. Sepsis on ICU admission, mechanical ventilation, renal replacement therapy during ICU treatment or admission type had no effect on one-year mortality rate. CONCLUSION: Patients who survive ICU treatment have a high risk of dying during the next year. This risk is almost as great the risk of dying during ICU and hospital treatment and increases with age and illness severity on admission to the ICU. PMID- 23032930 TI - Effectiveness and predictors of success of noninvasive ventilation during H1N1 pandemics: a multicenter study. AB - BACKGROUND: The use of non-invasive ventilation (NIV) in acute hypoxemic respiratory failure (AHRF) due to H1N1 virus infection is controversial. In this multicenter study we aimed to assess the efficacy of NIV in avoiding endotracheal intubation (ETI) and to identify predictors of success or failure. METHODS: In this prospective multicenter study, 98 patients with new pulmonary infiltrate(s) sustained by H1N1 virus and a PaO(2)/FiO2<300 were eligible for study; 38/98 required immediate ETI, while the others received NIV as a first line therapy; 13/60 patients failed NIV and were intubated after 5.8+5.5 hours from enrolment. The remaining 47/60 patients were successfully ventilated with NIV. RESULTS: Hospital mortality was significantly higher in those patients who failed NIV vs. those who succeeded (53.8% vs. 2.1%; OR=0.52, P<0.001). ETI was associated with higher number of infectious complications, mainly sepsis and septic shock. The OR of having one of these events in the NIV failure group vs. NIV success was 16.7, P<0.001. According to logistic regression model, a SAPS II>29 and a PaO(2)/FIO(2)<=127 at admission and PaO2/FIO(2)<=149 after 1 hr of NIV were independently associated with the need for ETI. CONCLUSION: The early application of NIV, with the aim to avoid invasive ventilation, during the H1N1 pandemics was associated with an overall success rate of 47/98 (48%). Patients presenting at admission with an high SAPS II score and a low PaO(2)/FiO(2) ratio and/or unable to promptly correct gas exchange are at high risk of intubation and mortality. PMID- 23032931 TI - Proteome analysis of actin filament-associated proteins in the postnatal rat cerebellum. AB - The cerebellum contains more neurons than all other brain regions combined and these cells exhibit complex circuit development and dendritic elaboration during the postnatal period. Neural development, cellular morphogenesis, and synaptic plasticity are dependent on the dynamic regulation of the actin cytoskeleton by actin-binding proteins. The identification of the actin filament interactome, including proteins developmentally regulated in the postnatal cerebellum, could help define important regulators of actin cytoskeletal dynamics in developing cerebellar neurons. Affinity purification of cerebellar proteins on F-actin columns, combined with mass spectrometry, in total, 434 actin filament-associated proteins in postnatal rat cerebellum (P7) were identified. Furthermore, semi quantitative RT-PCR was performed to screening postnatal developmentally regulated genes involved in actin dynamics and membrane trafficking in rat cerebellum (P0-P56). As the result, nine genes encoding members of the cerebellar F-actin interactome were developmentally regulated in the transcriptional level and at least five of them exhibited a similar pattern at the protein expression level by Western blot analysis. Further fluorescent immunohistochemical observations demonstrated that the actin-associated proteins Lethal(2) giant larvae protein homolog 1 (LLGL1) and metastasis suppressor 1 (MTSS1) were specifically upregulated in granule neurons and Purkinje cells during morphogenesis of axons and dendrites. This work defines a provisional actin filament interactome in rat postnatal cerebellum and identifies several candidate proteins that may be involved in the postnatal development of the cerebellum. PMID- 23032933 TI - Aggregation-induced photoluminescent changes of naphthyridine-BF2 complexes. AB - Luminous boron: new 1,8-naphthyridine-BF(2) complexes with strong emissions both in solution and in the solid state have been developed. Aggregation-induced blueshifts of emissions in DMSO/water mixtures and solvent-influenced luminescence in crystalline states have been observed and are discussed. PMID- 23032932 TI - Intercellular K+ accumulation depolarizes Type I vestibular hair cells and their associated afferent nerve calyx. AB - Mammalian vestibular organs contain two types of sensory receptors, named Type I and Type II hair cells. While Type II hair cells are contacted by several small afferent nerve terminals, the basolateral surface of Type I hair cells is almost entirely enveloped by a single large afferent nerve terminal, called calyx. Moreover Type I, but not Type II hair cells, express a low-voltage-activated outward K(+) current, I(K,L), which is responsible for their much lower input resistance (Rm) at rest as compared to Type II hair cells. The functional meaning of I(K,L) and associated calyx is still enigmatic. By combining the patch-clamp whole-cell technique with the mouse whole crista preparation, we have recorded the current- and voltage responses of in situ hair cells. Outward K(+) current activation resulted in K(+) accumulation around Type I hair cells, since it induced a rightward shift of the K(+) reversal potential the magnitude of which depended on the amplitude and duration of K(+) current flow. Since this phenomenon was never observed for Type II hair cells, we ascribed it to the presence of a residual calyx limiting K(+) efflux from the synaptic cleft. Intercellular K(+) accumulation added a slow (tau>100ms) depolarizing component to the cell voltage response. In a few cases we were able to record from the calyx and found evidence for intercellular K(+) accumulation as well. The resulting depolarization could trigger a discharge of action potentials in the afferent nerve fiber. Present results support a model where pre- and postsynaptic depolarization produced by intercellular K(+) accumulation cooperates with neurotransmitter exocytosis in sustaining afferent transmission arising from Type I hair cells. While vesicular transmission together with the low Rm of Type I hair cells appears best suited for signaling fast head movements, depolarization produced by intercellular K(+) accumulation could enhance signal transmission during slow head movements. PMID- 23032934 TI - Optical switches with biplanemers obtained by intramolecular photocycloaddition reactions of tethered arenes. AB - The dimerization of anthracene by a [4pi + 4pi] cycloaddition is one of the oldest and best known reactions in photochemistry. In the series of tethered bichromophoric arenes, this reaction type could be extended to anthracene naphthalene, naphthalene-naphthalene and recently even to anthracene-benzene and naphthalene-benzene systems. Cyclophanes, which can be regarded as twofold or multiple tethered systems, are not discussed here. The cycloisomerizations are performed by irradiation at the long-wavelength absorption (lambda > 270 nm), whereas shorter wavelengths (lambda < 270 nm) lead to cycloreversions, which can be also achieved by a thermal route. The systems represent therefore a P- and T type photochromism, which can be used for optical or chiroptical switches. An acceleration of the switch is possible by a singlet energy transfer (light harvesting antenna effect) in dendritic compounds. In the past 5 to 10 years many applications of these switches were studied in the context of photonic devices, sensor techniques, lithographic processes, imaging techniques, data processing and data storage. PMID- 23032935 TI - Antibiotic resistance in acne treatment. AB - Propionibacterium acnes (P. acnes) is an anaerobic bacteria implicated in the pathogenesis of acne. The last 30 years have witnessed an alarming increase in resistance to antibiotics commonly employed to treat acne. Antibiotic resistance in acne represents a significant international public health concern because resistance can occur in more pathogenic bacteria than P. acnes, and an increase in pathogenic P. acnes has been reported. Current treatment guidelines offer strategies to limit the potential for resistance while achieving optimal outcome in the management of inflammatory and non-inflammatory acne. PMID- 23032936 TI - Device-based therapies for onychomycosis treatment. AB - Device-based therapies are promising alternatives for the treatment of onychomycosis because they can mitigate some of the negative factors associated with treatment failure. There are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis, and ultrasound. These therapeutic modalities are noninvasive procedures that are carried out by medical professionals, reduce the need for long-term patient adherence, and avoid adverse reactions associated with conventional systemic antifungal therapies. PMID- 23032937 TI - Dynamics due to combined buoyancy- and Marangoni-driven convective flows around autocatalytic fronts. AB - A reaction-diffusion-convection (RDC) model is introduced to analyze convective dynamics around horizontally traveling fronts due to combined buoyancy- and surface tension-driven flows in vertical solution layers open to the air. This isothermal model provides a means for a comparative study of the two effects via tuning two key parameters: the solutal Rayleigh number Ra, which rules the buoyancy influence, and the solutal Marangoni number Ma governing the intensity of surface effects at the interface between the reacting solution and air. The autocatalytic front dynamics is probed by varying the relative importance of Ra and Ma and the resulting RDC patterns are quantitatively characterized through the analysis of the front mixing length and the topology of the velocity field. Steady asymptotic regimes are found when the bulk and the surface contributions to fluid motions act cooperatively i.e. when Ra and Ma have the same sign. Complex dynamics may arise when these numbers are of opposite signs and the two effects thus compete in an antagonistic configuration. Typically, spatiotemporal oscillations are observed as the control parameters are set in the region (Ra < 0, Ma > 0). Periodic behaviour develops here even in the absence of any double diffusive interplay, which in previous literature was identified as a possible source of complexity. PMID- 23032938 TI - A subnanomolar fluorescent probe for protein kinase CK2 interaction studies. AB - Up-regulation of an acidophilic protein kinase, CK2, has been established in several types of cancer. This cognition has made CK2 an important target for drug development for cancer chemotherapy. The characterization of potential drug candidates, determination of the structure and clarification of the functions of CK2 could be facilitated by the application of small-molecule fluorescent probes that bind to the active site of the enzyme with high affinity and selectivity. We have used a bisubstrate approach for the development of a highly potent inhibitor of CK2. 4,5,6,7-Tetrabromo-1H-benzimidazole was conjugated with peptides containing multiple aspartate residues via different linkers. The design of the inhibitors was by crystallographic analysis of the complex of an inhibitor with the catalytic subunit of the enzyme (CK2alpha). The inhibitory potency of the synthesized compounds was established in a kinetic assay that used thin layer chromatography for the measurement of the rate of phosphorylation of fluorescently labelled peptide 5-TAMRA-RADDSDDDDD. The most potent inhibitor, ARC 1502 (K(i) = 0.5 nM), revealed high selectivity for CK2alpha in a panel of 140 protein kinases. Labelling of ARC-1502 with PromoFluor-647 gave the fluorescent probe ARC-1504 that possessed subnanomolar affinity towards both CK2alpha and the holoenzyme. The probe was used in a fluorescence anisotropy-based binding assay to measure the concentration of CK2alpha and characterize non-labelled ligands binding to the active site of CK2alpha. PMID- 23032939 TI - Predictors of visual-motor integration in children with intellectual disability. AB - The aim of this study was to assess the influence of sex, age, level and etiology of intellectual disability on visual-motor integration in children with intellectual disability. The sample consisted of 90 children with intellectual disability between 7 and15 years of age. Visual-motor integration was measured using the Acadia test of visual-motor integration. A multiple regression analysis was used for data analysis. The results of this study showed that sex, level of intellectual disability, and age were significant predictors of visual-motor integration. The etiology of intellectual disability did not play a significant role in predicting visual-motor integration. Visual-motor integration skills are very important for a child's overall level of functioning. Individualized programs for the remediation of visual-motor integration skills should be a part of the curriculum for children with intellectual disability. PMID- 23032940 TI - A chelating tetrapeptide rhodium complex comprised of a histidylidene residue: biochemical tailoring of an NHC-Rh hydrosilylation catalyst. AB - Coupling of a histidinium salt with a MetAlaAla amino acid sequence followed by metallation with [RhCl(cod)](2) yields a rhodium(I) NHC complex with a pending peptide residue. Methionine chelation, induced by chloride abstraction from the metal coordination sphere, affords an efficient hydrosilylation catalyst precursor comprised of a peptidic macrocyclic chelate backbone. PMID- 23032941 TI - Adherence to a Mediterranean diet and Alzheimer's disease risk in an Australian population. AB - The Mediterranean diet (MeDi), due to its correlation with a low morbidity and mortality for many chronic diseases, has been widely recognised as a healthy eating model. We aimed to investigate, in a cross-sectional study, the association between adherence to a MeDi and risk for Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large, elderly, Australian cohort. Subjects in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing cohort (723 healthy controls (HC), 98 MCI and 149 AD participants) completed the Cancer Council of Victoria Food Frequency Questionnaire. Adherence to the MeDi (0- to 9 point scale with higher scores indicating higher adherence) was the main predictor of AD and MCI status in multinominal logistic regression models that were adjusted for cohort age, sex, country of birth, education, apolipoprotein E genotype, total caloric intake, current smoking status, body mass index, history of diabetes, hypertension, angina, heart attack and stroke. There was a significant difference in adherence to the MeDi between HC and AD subjects (P < 0.001), and in adherence between HC and MCI subjects (P < 0.05). MeDi is associated with change in Mini-Mental State Examination score over an 18-month time period (P < 0.05) in HCs. We conclude that in this Australian cohort, AD and MCI participants had a lower adherence to the MeDi than HC participants. PMID- 23032942 TI - The association of attempted suicide with genetic variants in the SLC6A4 and TPH genes depends on the definition of suicidal behavior: a systematic review and meta-analysis. AB - The global prevalence of suicide has increased substantially over the last four decades. Suicidal behavior manifests owing to a combination of biological, behavioral and social factors; however, the etiology of suicidality remains elusive. Even though twin studies have reported a significant heritability of 30 50%, meta-analyses have not highlighted a common genetic variant associated with the spectrum of suicidal behavior. Here, we performed a systematic review of the literature (n = 112) to assess the association between serotonergic and non serotonergic genetic polymorphisms and suicidal behavior. Using an inverse variance random-effects model, we developed pooled odds ratios for the 10 most commonly studied genetic variants related to suicidal behavior, each with at least five independent studies that met our stringent inclusion criteria. Our pooled results indicate no significant correlation between genetic polymorphisms and overall suicidal behavior. However, subgroups of suicide attempts demonstrated actual significance with the serotonin transporter (SLC6A4) 5HTTLPR (OR = 1.13 (95% confidence interval = 1.05-1.21), P = 0.001) and reached nominal significance with the tryptophan hydroxylase rs1800532 (1.22 (1.05-1.41), P = 0.007) variant. Subgroups of suicidal behavior (completions and attempts) displayed reduced heterogeneity compared with the overall suicidal behavior spectrum. Our findings suggest that the 5HTTLPR and rs1800532 polymorphisms are significantly associated with suicide attempts, but not associated with completed suicides. The high degree of heterogeneity in past studies may be attributed to the lack of a phenotypic distinction between suicidal attempts and completions. Consequently, we have identified an important source of phenotypic heterogeneity that provides a rationale for the current lack of a common genetic variant associated with suicidal behavior. PMID- 23032943 TI - The association of white matter volume in psychotic disorders with genotypic variation in NRG1, MOG and CNP: a voxel-based analysis in affected individuals and their unaffected relatives. AB - We investigated the role of variation in putative psychosis genes coding for elements of the white matter system by examining the contribution of genotypic variation in three single-nucleotide polymorphisms (SNPs) neuregulin 1 (NRG1) SNP8NRG221533, myelin oligodendrocytes glycoprotein (MOG) rs2857766 and CNP (rs2070106) and one haplotype HAP(ICE) (deCODE) to white matter volume in patients with psychotic disorder and their unaffected relatives. Structural magnetic resonance imaging and blood samples for genotyping were collected on 189 participants including patients with schizophrenia (SZ) or bipolar I disorder (BDI), unaffected first-degree relatives of these patients and healthy volunteers. The association of genotypic variation with white matter volume was assessed using voxel-based morphometry in SPM5. The NRG1 SNP and the HAP(ICE) haplotype were associated with abnormal white matter volume in the BDI group in the fornix, cingulum and parahippocampal gyrus circuit. In SZ the NRG1 SNP risk allele was associated with lower white matter volume in the uncinate fasciculus (UF), right inferior longitudinal fasciculus and the anterior limb of the internal capsule. Healthy G-homozygotes of the MOG SNP had greater white matter volume in areas of the brainstem and cerebellum; this relationship was absent in those with a psychotic disorder and the unaffected relatives groups. The CNP SNP did not contribute to white matter volume variation in the diagnostic groups studied. Variation in the genes coding for structural and protective components of myelin are implicated in abnormal white matter volume in the emotion circuitry of the cingulum, fornix, parahippocampal gyrus and UF in psychotic disorders. PMID- 23032944 TI - The impact of the Great East Japan earthquake on mandatory psychiatric emergency hospitalizations in Tokyo: a retrospective observational study. AB - On 11 March 2011, the eastern part of Japan was struck by a magnitude 9.0 quake. About 20 000 people were killed or were missing, and a nuclear crisis followed. In Tokyo, people were indirectly exposed to the earthquake and nuclear crisis by TV broadcast. The aim of our study was to evaluate the potential effect of the series of catastrophes on psychiatric emergency hospitalizations in Tokyo. Clinical records of patients who were mandatorily admitted to Tokyo Metropolitan Matsuzawa Hospital by law because of urgent risk to self or others were reviewed. Records regarding the 2 years of investigation, which include the 6 months after the earthquake, were reviewed. The six months after the earthquake were compared with the eighteen months before the earthquake in clinical and demographic data using independent t-tests or chi(2) tests. During the 6 months before and after the earthquake, 97 and 127 people were mandatorily admitted. chi(2) Tests demonstrated a significant increase in the number of patients after the earthquake (P = 0.045), attributable to the significant increase in the number of patients with schizophrenia after the earthquake (P = 0.011, 32 vs 56), whereas there were no significant differences in the number of patients with other diagnoses between those two periods. Independent t-tests revealed that patients admitted after the earthquake had marginally significantly shorter periods of education compared with those admitted before the earthquake (13.78 vs 12.82 years, P = 0.084). This work suggests that patients with schizophrenia were more sensitive to indirect exposure to the earthquake and that a shorter period of education was a potential risk factor. PMID- 23032946 TI - Dual-tracer, non-equilibrium mixing cell modelling and uncertainty analysis for unsaturated bromide and chloride transport. AB - A model is presented for simulating one-dimensional advective dispersive solute transport in the vadose zone. The finite-volume, mixing-cell model uses drainage flux intervals as the index variable, which are calculated by a soil water balance model. The modelling approach considers solute transport from two different regions as well as a slow and a fast transport domain in each region as parallel transport processes. The model is applied to breakthrough curves of Cl( ) and Br(-) measured at different locations and different depths in the volcanic vadose zone of the Tutaeuaua subcatchment of Lake Taupo, New Zealand, following a dual tracer application. Estimates of transport parameter and model predictive uncertainty were derived using the differential evolution adaptive metropolis, DREAM(ZS) adaptive Markov chain Monte Carlo algorithm, a formal Bayesian likelihood function, observed leachate volumes, and Cl(-) breakthrough curves. The model was subsequently evaluated using Br(-) breakthrough curves from the dual tracer experiment and a previously conducted Br(-) tracer-only experiment. Uncertainty bounds derived by this MCMC method simultaneously capture the observed Br(-) and Cl(-) breakthrough curves and corresponding drainage volumes. Results suggest that the slow transport domain properties are relatively similar for different locations in the vadose zone and that the variability in contaminant fluxes is predominantly driven by structural variability of the vadose zone causing lateral flow. PMID- 23032945 TI - Genetic association of cyclic AMP signaling genes with bipolar disorder. AB - The genetic basis for bipolar disorder (BPD) is complex with the involvement of multiple genes. As it is well established that cyclic adenosine monophosphate (cAMP) signaling regulates behavior, we tested variants in 29 genes that encode components of this signaling pathway for associations with BPD type I (BPD I) and BPD type II (BPD II). A total of 1172 individuals with BPD I, 516 individuals with BPD II and 1728 controls were analyzed. Single SNP (single-nucleotide polymorphism), haplotype and SNP * SNP interactions were examined for association with BPD. Several statistically significant single-SNP associations were observed between BPD I and variants in the PDE10A gene and between BPD II and variants in the DISC1 and GNAS genes. Haplotype analysis supported the conclusion that variation in these genes is associated with BPD. We followed-up PDE10A's association with BPD I by sequencing a 23-kb region in 30 subjects homozygous for seven minor allele risk SNPs and discovered eight additional rare variants (minor allele frequency < 1%). These single-nucleotide variants were genotyped in 999 BPD cases and 801 controls. We obtained a significant association for these variants in the combined sample using multiple methods for rare variant analysis. After using newly developed methods to account for potential bias from sequencing BPD cases only, the results remained significant. In addition, SNP * SNP interaction studies suggested that variants in several cAMP signaling pathway genes interact to increase the risk of BPD. This report is among the first to use multiple rare variant analysis methods following common tagSNPs associations with BPD. PMID- 23032947 TI - The effects of auditory startle and nonstartle stimuli on step initiation in Parkinson's disease. AB - BACKGROUND: Auditory external cues enhance step initiation in Parkinson's disease (PD) patients. We wanted to explore whether a startle reaction has a comparable effect on step initiation in PD. METHODS: Thirteen PD patients and 13 aged matched controls participated in this study. Electromyography pattern and onset toe-off time during a step initiation task were recorded in response to three different stimuli: a visual imperative stimulus; visual stimulus simultaneous with a nonstartle auditory stimulus and with a startle auditory stimulus. RESULTS: In all subjects, onset of tibialis anterior was faster in the startle auditory condition, compared with the nonstartle auditory condition. However, in the patient group, there was no difference in onset of soleus and toe-off between the startle and nonstartle conditions. CONCLUSIONS: Startle reaction in PD patients demonstrates a disordered coupling between the anticipatory postural adjustments that initiate the weight shift and the movement to initiate toe-off during step initiation. PMID- 23032948 TI - Synthesis of highly active and stable Au-PtCu core-shell nanoparticles for oxygen reduction reaction. AB - Au-PtCu core-shell nanoparticles were successfully synthesized via galvanic replacement of Cu by Pt on hollow Au nano-spheres. Characterizations of the nanoparticles were conducted by X-ray diffraction (XRD), transmission electron microscopy (TEM), and electrochemical measurements. Results indicate 2-2.5 times higher specific activity and mass activity of the Au-PtCu catalysts than commercial Pt black and Pt/C in oxygen reduction reaction (ORR), measured in a rotating disk electrode system. Besides, thinner PtCu coating (25 nm thick, deposition time of 20 min) on the hollow Au nano-spheres demonstrated a pronounced CO oxidation peak shift (by 0.13 V) and long-term durability probably due to the unique core-shell structure and strong electronic coupling between the Au core and the PtCu shell. PMID- 23032950 TI - The clinical utility of vascular mapping with Doppler ultrasound prior to arteriovenous fistula construction for hemodialysis access. AB - PURPOSE: To compare the outcomes of vascular access (VA) procedures performed using physical examination (PE) alone to PE and ultrasound vein mapping for assessment of patients needing hemodialysis access. METHODS: Comparative analysis of data obtained by retrospective review of records of 63 patients who underwent PE and vascular mapping (VM) using colored Doppler ultrasonography (CDUS) and 76 patients assessed by physical examination alone to schedule vascular access surgery. The parameters assessed to study the impact of these two different pre operative assessment approaches included selection of surgical site, procedure, construction of arteriovenous fistulas (AVF) and grafts (AVG), negative surgical exploration rates and surgical outcomes (maturation and patency rates). RESULTS: The rate of successfully constructed AVF increased significantly from 75% to 97% (P=.001) with pre-operative ultrasonographic vascular mapping. In 22 patients (34.9%) the access planned with physical examination was modified based on CDUS examination. In 12 patients, the surgical site for AVF creation and type of surgical procedure were modified based on the CDUS results. Permanent access placement rates were significantly higher in patients assessed with CDUS (P=.001). All patients who underwent vascular mapping had successful VA construction while the PE group had a 18.4% negative surgical exploration rate. When fistulas were assessed at six months, the patency rate was 80.7% for the physical examination (PE) group and 93.4% for the vascular mapping (VM) group. CONCLUSIONS: Pre-operative vascular mapping using CDUS significantly increases the success of AVF construction and patency. PMID- 23032949 TI - Biodistribution studies with tumor-targeting bispecific antibodies reveal selective accumulation at the tumor site. AB - Bispecific antibodies are proteins that bind two different antigens and may retarget immune cells with a binding moiety specific for a leukocyte marker. A binding event in blood could in principle prevent antibody extravasation and accumulation at the site of disease. In this study, we produced and characterized two tetravalent bispecific antibodies that bind with high affinity to the alternatively-spliced EDB domain of fibronectin, a tumor-associated antigen. The bispecific antibodies simultaneously engaged the cognate antigens (murine T cell co-receptor CD3 and hen egg lysozyme) and selectively accumulated on murine tumors in vivo. The results, which were in agreement with predictions based on pharmacokinetic modeling and antibody binding characteristics, confirmed that bispecific antibodies can reach abluminal targets without being blocked by peripheral blood leukocytes. PMID- 23032951 TI - Patient-specific model of arterial circulation for surgical planning of vascular access. AB - PURPOSE: To report the technical aspects of a novel method to generate patient specific vascular network models of arterial vasculature for the surgical planning of vascular access (VA) for hemodialysis. METHODS: On the basis of literature data, we defined a set of rules for estimation of diameter, length and compliance of arterial network segments, at patient-specific level, as a function of general descriptors (i.e. sex, age, body size and pathology). Using this method we generated vascular network models of height hypothetical patients with different age, sex and body surface area and we computed pressures and blood flows along the arterial arm vasculature using a wave propagation model. RESULTS: Simulation results show that vascular geometry is influenced by sex, age and body size leading to important differences in hemodynamic function. Calculated wall shear stress is higher in women females as compared to men, regardless of body size and age. CONCLUSIONS: Our method facilitates estimating vascular network model parameters useful for patient-specific pre-operative assessment of blood flow distribution in the arterial arm circulation. PMID- 23032952 TI - First use of drug-eluting balloon for below-the-elbow artery occlusion in a hemodialysis patient: a 3-year follow-up. PMID- 23032953 TI - Emergency cephalic vein cut down for hemodialysis access. PMID- 23032954 TI - Vascular stent fracture and migration to pulmonary artery during arteriovenous shunt thrombectomy. AB - PURPOSE: Endovascular stent fracture and migration is an extremely rare complication of arteriovenous shunt thrombectomy. TECHNIQUE: We report a case of endovascular stent fracture following repeat arteriovenous graft thrombectomy, which was complicated by migration of a 26 millimeter stent fragment to the left main pulmonary artery. Attempts at percutaneous transvenous retrieval were unsuccessful, and an open thoracotomy to extract the stent fragment was performed. CONCLUSIONS: Although there is no consensus for the management of endovascular stents that have migrated to the pulmonary arteries, stent retrieval may be necessary in cases where arterial flow is compromised or heavy clot burden is a concern. Moreover, steps toward prevention of stent fracture and migration should be considered in order to preclude such occurrences--avoidance of puncturing the stent for hemodialysis access, discontinuation of use of the Arrow Trerotola device through or near stents, and consideration of short segment angioplasty for regional intrastent stenosis rather than typical long segment venous angioplasty. PMID- 23032955 TI - Arteriovenous thrombosis due to Aspergillus in a patient with hemodialysis. PMID- 23032956 TI - Preventive hemostasis for hemodialysis vascular access surgical reinterventions. AB - Surgical reinterventions for treatment of complications or ligation of haemodialysis vascular access (VA), when performed in or below the mid/lower part of the upper arm, could benefit from the use of preventive haemostasis with an inflatable tourniquet. This technique offers several advantages, such as the reduced risk of bleeding and the increased accuracy of dissection allowing for a minimally invasive approach. The use of preventive haemostasis is safe, economical and time-saving. All the secondary procedures on VA that could benefit from its use are reviewed. PMID- 23032957 TI - Rationale for switching to nonlocal functionals in density functional theory. AB - Density functional theory (DFT) has been steadily improving over the past few decades, becoming the standard tool for electronic structure calculations. The early local functionals (LDA) were eventually replaced by more accurate semilocal functionals (GGA) which are in use today. A major persisting drawback is the lack of the nonlocal correlation which is at the core of dispersive (van der Waals) forces, so that a large and important class of systems remains outside the scope of DFT. The vdW-DF correlation functional of Langreth and Lundqvist, published in 2004, was the first nonlocal functional which could be easily implemented. Beyond expectations, the nonlocal functional has brought significant improvement to systems that were believed not to be sensitive to nonlocal correlations. In this paper, we use the example of graphene nanodomes growing on the Ir(111) surface, where with an increase of the size of the graphene islands the character of the bonding changes from strong chemisorption towards almost pure physisorption. We demonstrate how the seamless character of the vdW-DF functionals makes it possible to treat all regimes self-consistently, proving to be a systematic and consistent improvement of DFT regardless of the nature of bonding. We also discuss the typical surface science example of CO adsorption on (111) surfaces of metals, which shows that the nonlocal correlation may also be crucial for strongly chemisorbed systems. We briefly discuss open questions, in particular the choice of the most appropriate exchange part of the functional. As the vdW-DF begins to appear implemented self-consistently in a number of popular DFT codes, with numerical costs close to the GGA calculations, we draw the attention of the DFT community to the advantages and benefits of the adoption of this new class of functionals. PMID- 23032958 TI - The breakfast effect: dogs (Canis familiaris) search more accurately when they are less hungry. AB - We investigated whether the consumption of a morning meal (breakfast) by dogs (Canis familiaris) would affect search accuracy on a working memory task following the exertion of self-control. Dogs were tested either 30 or 90 min after consuming half of their daily resting energy requirements (RER). During testing dogs were initially required to sit still for 10 min before searching for hidden food in a visible displacement task. We found that 30 min following the consumption of breakfast, and 10 min after the behavioral inhibition task, dogs searched more accurately than they did in a fasted state. Similar differences were not observed when dogs were tested 90 min after meal consumption. This pattern of behavior suggests that breakfast enhanced search accuracy following a behavioral inhibition task by providing energy for cognitive processes, and that search accuracy decreased as a function of energy depletion. PMID- 23032959 TI - Thicker is better? Synthesis and evaluation of well-defined polymer brushes with controllable catalytic loadings. AB - Polymer brushes (PBs) have been used as supports for the immobilization of palladium complexes on silicon surfaces. The polymers were grown by surface initiated atom-transfer radical polymerization (SI-ATRP) and postdecorated with dipyridylamine (dpa) ligands. The pendant dpa units were in turn complexed with [Pd(OAc)(2)] to afford hybrid catalytic surfaces. A series of catalytic samples of various thicknesses (ca. 20-160 nm) and associated palladium loadings (ca. 10 45 nmol cm(-2)) were obtained by adjusting the SI-ATRP reaction time and characterized by ellipsometry, X-ray reflectivity, X-ray photoelectron spectroscopy, and inductively coupled plasma mass spectrometry (ICP-MS). ICP-MS revealed a near-linear relationship between thickness of the polymer brush and palladium content, which confirmed the robustness of the preparation and postmodification sequence presented herein, rendering possible the creation of functional architectures with predefined catalytic potential. The activities of the catalytic PBs were determined by systematically exploring a full range of substrate-to-catalyst ratios in a model palladium(0)-catalyzed reaction. Quantitative transformations were observed for loadings down to 0.03 mol % and a maximum turnover number (TON) of around 3500 was established for the system. Comparison of the catalytic performances evidenced a singular influence of the thickness on conversions and TONs. The limited recyclability of the hairy catalysts has been attributed to palladium leaching. PMID- 23032960 TI - Statin use for nonrheumatic calcific aortic valve stenosis: a review with meta analysis. AB - AIMS: To synthesize by meta-analysis the findings of recent experimental studies focusing on possible therapeutic effectiveness of statins for nonrheumatic calcific aortic stenosis. METHODS: Observational studies and randomized controlled trials (RCTs) were selected from the Pubmed database to evaluate the hemodynamic progression of aortic stenosis in statin-treated patients compared with controls (i.e. patients with aortic stenosis taking placebo or no treatment). The endpoints were the annualized changes in one or more of the following ultrasonographic measurements: peak aortic valve jet velocity, peak aortic valve pressure gradient, mean aortic valve pressure gradient aortic valve area (AVA). For estimating the overall effect of statin therapy on each of the above-mentioned continuous variables across the considered studies, we used the weighted mean difference (WMD) as effect size measure. In addition, we calculated the odds of aortic valve replacement surgery and cardiovascular death in both statin-treated patients and controls for subsequently estimating the appropriate odds ratios. RESULTS: Nine studies were selected. A lower annualized increase in peak aortic valve jet velocity was found in statin-treated patients compared with controls (overall WMD: -0.09 m/s per year, 95% CI -0.16, -0.01 P = 0.018). Similarly, a smaller annualized increase in peak aortic valve pressure gradient was found in the statin group (overall WMD: -2.04 mmHg/year 95% CI: -3.56, -0.52, P = 0.0085). However, the overall effects in statin-treated patients on both annualized increases in mean aortic valve pressure gradient and decreases in AVA were not significantly different from those found in controls. Moreover, there was no significant difference in cardiovascular outcomes in the statin groups compared with placebo groups in each of the three analyzed RCTs and overall. CONCLUSION: Significant benefit of statin therapy in retarding hemodynamic deterioration was identified by favorable effects concerning annualized changes in peak aortic valve jet velocity and peak aortic valve pressure gradient; on the contrary, in statin-treated patients with aortic stenosis, no significant improvement was found for annualized changes in mean aortic valve pressure gradient and AVA and clinical outcomes. PMID- 23032961 TI - Dabigatran in atrial fibrillation: incremental benefit over a time horizon of 5 or 10 years. PMID- 23032962 TI - Remote ischemic preconditioning: the surgeon's perspective. AB - Since cardiac surgery began, surgeons have aimed to find methods of minimizing myocardial injury resulting from ischemia and reperfusion. The concept of somehow conditioning the heart in order to attenuate ischemia and reperfusion-related injury has evolved in cardiovascular research over decades, from ischemic preconditioning and postconditioning to, more recently, remote ischemic preconditioning (and postconditioning). Although many strategies have proven to be beneficial in the experimental arena, a few have been successfully translated into clinical practice. Remote ischemic preconditioning, with the use of brief episodes of ischemia and reperfusion of vascular territories remote from the heart, has been shown convincingly to decrease myocardial injury. To date, the translation of this powerful innate mechanism of myocardial and/or multiorgan protection from the animal lab to the operating theatre, using transient occlusion of blood flow to the upper limb with a blood-pressure cuff before cardiac surgery, has shown promising results, with several proof-of-principle and first randomized controlled clinical trials reporting benefits for patients undergoing cardiac surgery. If the efficacy of remote ischemic preconditioning can be conclusively proven, the clinical applications in cardiac surgery could be almost infinite, providing multiorgan protection in various surgical scenarios. PMID- 23032963 TI - Hyperuricaemia: more than just a cause of gout? AB - Traditionally, serum uric acid (SUA) has been implicated in acute gouty arthritis or chronic gouty arthropathy. However, SUA also plays a role in other pathological conditions especially in cardiovascular (CV), metabolic and renal disease. This narrative review considers the significant associations of SUA with kidney function, several CV risk factors and vascular diseases, supporting the concept of assessing hyperuricaemia for reasons other than just gout. Several drugs that reduce CV risk also decrease SUA levels, further improving vascular risk. Therefore, selecting SUA-lowering drugs to treat high-risk patients may prove beneficial in terms of reducing CV risk. PMID- 23032964 TI - Magnetically-induced lattice distortions and ferroelectricity in magnetoelectric GdMnO3. AB - In this work we investigate the magnetic field dependence of A(g) octahedra rotation (tilt) and B(2g) symmetric stretching modes frequencies at different temperatures. Our field-dependent Raman investigation at 10 K is interpreted by an ionic displacive nature of the magnetically-induced ferroelectric phase transition. The increasing frequency of the A(g) tilt mode with magnetic field gives evidence for the increase of the MnO(6) tilt angle, which in turn leads to a weakening of the ferromagnetic exchange interaction, yielding the necessary conditions for the onset of ferroelectricity on the basis of the inverse Dzyaloshinskii-Moriya interaction. The frequency change of the B(2g) symmetric stretching mode at the ferroelectric phase transition enables one to estimate the shift of oxygen ion positions and the corresponding spontaneous polarization of 480 MUC m(-2) in magnitude, which is of the same order as earlier reported values in single crystals. PMID- 23032965 TI - Thermodynamics and conformations in the formation of excited states and their interconversions for twisted donor-substituted tridurylboranes. AB - We synthesized a series of donor-substituted tridurylboranes containing different types and number of chromophores including 1-pyrene (PB1-3), 3-carbazole (CBC1 3), or substituted p-carbazol-N-phenyl (CBN3a-c) as various donor-acceptor (D-A) molecules. The photophysical and electrochemical properties of these twisted D-A molecules were investigated by means of UV/Vis absorption and fluorescence spectroscopy as well as cyclic voltammetry (CV). Solvent polarity, viscosity, and temperature effects on the fluorescence emission reveal the existence of three types of excited states, and their equilibria and interconversions between three excited states. In increasing order of the charge-separated extent and the conformational change, three excited states are the locally excited (LE) state, the more planar intramolecular charge-transfer (ICT) state, and the more twisted ICT (TICT) state as compared to the ground state. The TICT state undergoes a conformational change with a higher energy barrier over the ICT state. The solvent polarity effect on the state conversion is opposite to the viscosity effect, and temperature effects derive from its resulting changes of polarity and viscosity. For example, the increase of the polarity of the solvent results in excited-state conversions from the LE state to the ICT state, and/or from the ICT to the TICT state, and an increased viscosity leads to the opposite conversions. On the basis of electrochemical and spectral data, thermodynamics of a possible ICT process were estimated, and correlated with the excited-state character. Finally, three excited states have been characterized by the conformation, the photophysical properties, and the thermodynamics of the ICT processes. PMID- 23032966 TI - Peroxidase mimicking DNA-gold nanoparticles for fluorescence detection of the lead ions in blood. AB - Oligonucleotide (T30695) modified gold nanoparticles (T30695-Au NPs) have been prepared and employed for quantification of lead ions (Pb(2+)) in blood. The detection of Pb(2+) ions is through the formation of Au-Pb alloys and oligonucleotide-Pb(2+) complexes that catalyze the H(2)O(2)-mediated oxidation of non-fluorescent Amplex UltraRed (AUR) to form a highly fluorescent oxidized AUR product. Surface-assisted laser desorption/ionization time-of-flight mass spectrometry (SALDI-TOF MS) and inductively coupled plasma mass spectrometry (ICP MS) revealed the formation of Au-Pb alloys on the surfaces of the 40T30695-Au NPs (i.e., the system featuring 40 molecules of T30695 per Au NP) in the presence of Pb(2+) ions, leading to increased catalytic activity for the H(2)O(2)-mediated oxidation of AUR. The fluorescence intensity (excitation/emission maxima: ca. 540/584 nm) of the oxidized AUR product is proportional to the concentration of Pb(2+) ions over the range 0.1-100 nM, with a linear correlation (R(2) = 0.99). The 40T30695-Au NP/AUR probe is highly selective toward Pb(2+) ions (by at least 200-fold over other tested metal ions). The 40T30695-Au NPs/AUR probe provided limits of detection (LOD, at a signal-to-noise ratio 3) for Pb(2+) ions of 0.05 and 0.1 nM, in Tris-acetate solution (5 mM, pH 8.0) without and with salt (150 mM NaCl, 5 mM KCl, 1 mM MgCl(2), and 1 mM CaCl(2)), respectively. Without conducting tedious sample pretreatment, the approach allows detection of Pb(2+) ions in blood samples, showing the potential of the 40T30695-Au NPs/AUR assay for on-site and real-time detection of Pb(2+) ions in biological samples. PMID- 23032967 TI - A general route to make non-conjugated linear polymers luminescent. AB - Photoluminescent polymer dots (PDs) were prepared by a moderate hydrothermal treatment of poly(vinyl alcohol) (PVA). A single excited state was established in the PL mechanism by ultrafast spectroscopy. Moreover, the applied method be used to prepare fluorescent polymer dots from other non-conjugated polymers, and shows general universality. PMID- 23032968 TI - The evolution of sunscreen products in the United States--a 12-year cross sectional study. AB - Excessive exposure from ultraviolet (UV) radiation contributes to the development of skin cancers and photoaging. Topical sunscreen products remain one of the most widely used forms of protection for the majority of the public. The objective of this analysis was to examine photoprotection trends (e.g., SPF value) and the degree of UVA I protection from 1997 to 2009 in the United States. Sunscreen products purchased and evaluated in 1997 (N = 59), 2003 (N = 188) and again in 2009 (N = 330), totaling 577, were included in this analysis. Information regarding (1) the SPF value, (2) name and concentration of the active ingredients, (3) type of products (i.e., daily vs. recreational/beach), and (4) claims of UVA protection was recorded and analyzed. In addition, the critical wavelength (CW) of 330 products from 2009 was determined. The results showed an increase in the SPF values of products from 1997 to 2009. The percentage of low SPF products (SPF 4-14) decreased from 27% in 1997 to 6% in 2009. The number of products containing a known UVA-I filter (i.e., avobenzone or zinc oxide) increased from 5% in 1997 to 70% in 2009. Lastly, approximately, 225 (68%) of the products tested in 2009 attained CW > 370 nm. In the past decade, sunscreen products have undergone fundamental improvements, the most significant of which is the breadth of protection against UVA I. PMID- 23032969 TI - Potential of the smart balance master system to assess standing balance in people with incomplete spinal cord injury. AB - OBJECTIVES: The aim of this study was to investigate the concurrent validity of the Smart Balance Master (SBM) tests in individuals with incomplete spinal cord injury. DESIGN: Correlational study. SUBJECTS: A total of 32 individuals with an American Spinal Injury Association Impairment Scale D spinal cord injury able to walk 10 m independently, with or without walking assistive devices. METHODS: Outcome measures obtained from static and dynamic balance tests while standing using the SBM were compared to data obtained from the Berg Balance Scale (BBS) (14 items). RESULTS: No difference in performance between paraplegic and tetraplegic subjects was noted in the SBM tests. No ceiling effect was apparent in the SBM tests. The highest levels of association with the BBS was found for the limits of stability test (-0.416 < R < -0.752, p <= 0.05). The limits of stability test also correlated significantly with the majority of the other SBM tests and, except for the weight-shifting test, was completed by all but two participants. CONCLUSION: The limits of stability test of the SBM system appears to be useful for assessing dynamic standing-balance ability in spinal cord injury subjects and could potentially be used to complement the BBS. PMID- 23032970 TI - Peptides and peptidomimetics that behave as low molecular weight gelators. AB - Gelators may be divided into chemical gels and physical gels: the internal structure of chemical gels is made of chemical bonds, while physical gels are characterized by dynamic cross-links that are constantly created and broken. The gelator present in physical gels may be an inorganic or an organic compound, the latter having a molecular weight of <=500 amu. These compounds are generally called "low molecular weight gelators" (LMWGs). In this tutorial review we want to focus our attention on short peptides or peptidomimetics that behave as LMWGs. Peptidomimetics are small protein-like molecules designed to mimic natural peptides. To efficiently design a peptidomimetic, local constraints must be introduced into the skeleton, to induce the formation of preferred secondary structures. PMID- 23032971 TI - Evaluation of gait performance of a participant with Perthes disease while walking with and without a Scottish-Rite orthosis. AB - BACKGROUND: Scottish-Rite orthosis is one of the conservative methods used to treat Legg-Calve-Perthes disease. As there was not enough evidence to show the effects of using this orthosis on reducing the loads applied on the limb, this research aimed to find the influence of this orthosis. CASE DESCRIPTION AND METHODS: A participant with Perthes disease on the left hip joint was recruited into this study to walk with and without the orthosis. The kinetic and kinematic parameters were collected by a motion analysis system and a Kistler force platform. FINDINGS AND OUTCOMES: No significant differences were noted between the hip joint flexion/extension range of motion and the moments between the sound side and the side affected by Legg-Calve-Perthes disease. It may be concluded that use of orthosis may not have any positive effects to decrease the loads or to improve the alignment of the hip joint in participants with Perthes disease, as expected. CONCLUSIONS: The use of Scottish-Rite orthosis not only does not improve the containment of the hip joint, but also does not have any significant influence on loads applied on the joint during walking of the subject with Perthes disease. CLINICAL RELEVANCE: The results of this research can be used by clinicians involved in treatment of patients with Legg-Calve-Perthes disease. PMID- 23032972 TI - Buffering capacity and size of siRNA polyplexes influence cytokine levels. AB - Induction of cytokines by small interfering RNA (siRNA) polyplexes has been a significant concern of researchers attempting to minimize the toxicity of this promising therapy. Although cationic carriers of siRNA are known to increase cytokine levels, few systematic studies have been done to determine what properties of the carrier are important to modulate cytokines. Because branched histidine-lysine (HK) peptides are effective carriers of siRNA and their sequence can be readily modified, we selected this class of carrier to determine which sequences of the peptide were important for cytokine induction. With the use of peripheral blood mononuclear cells (PBMCs), the HK peptide with a higher number of histidines (H3K(+H)4b) in complex with siRNA induced lower levels of cytokines compared with other HK (e.g., H2K4b, H3K4b, H3K(+N)4b) siRNA nanoplexes. Notably, these peptides' siRNA polyplexes showed a similar pattern of cytokine induction when injected intravenously in a mouse model, i.e., the HK with higher content of histidines induced cytokines the least. As indicated by the pH-sensitive dye within acidic endosomes, the greater pH-buffering capacity of H3K(+H)4b compared with other HK peptides may explain why cytokine levels were reduced. In addition to buffering capacity, the size of HK polyplexes markedly influenced cytokine production. PMID- 23032973 TI - Induced pluripotent mesenchymal stromal cell clones retain donor-derived differences in DNA methylation profiles. AB - Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is an epigenetic phenomenon. It has been suggested that iPSC retain some tissue specific memory whereas little is known about interindividual epigenetic variation. We have reprogrammed mesenchymal stromal cells from human bone marrow (iP-MSC) and compared their DNA methylation profiles with initial MSC and embryonic stem cells (ESCs) using high-density DNA methylation arrays covering more than 450,000 CpG sites. Overall, DNA methylation patterns of iP-MSC and ESC were similar whereas some CpG sites revealed highly significant differences, which were not related to parental MSC. Furthermore, hypermethylation in iP-MSC versus ESC occurred preferentially outside of CpG islands and was enriched in genes involved in epidermal differentiation indicating that these differences are not due to random de novo methylation. Subsequently, we searched for CpG sites with donor-specific variation. These "epigenetic fingerprints" were highly enriched in non-promoter regions and outside of CpG islands-and they were maintained upon reprogramming. In conclusion, iP-MSC clones revealed relatively little intraindividual variation but they maintained donor-derived epigenetic differences. In the absence of isogenic controls, it would therefore be more appropriate to compare iPSC from different donors rather than a high number of different clones from the same patient. PMID- 23032975 TI - Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. AB - Despite the therapeutic potential of nucleic acid drugs, their clinical application has been limited in part by a lack of appropriate delivery systems. Exosomes or microvesicles are small endosomally derived vesicles that are secreted by a variety of cell types and tissues. Here, we show that exosomes can efficiently deliver microRNA (miRNA) to epidermal growth factor receptor (EGFR) expressing breast cancer cells. Targeting was achieved by engineering the donor cells to express the transmembrane domain of platelet-derived growth factor receptor fused to the GE11 peptide. Intravenously injected exosomes delivered let 7a miRNA to EGFR-expressing xenograft breast cancer tissue in RAG2(-/-) mice. Our results suggest that exosomes can be used therapeutically to target EGFR expressing cancerous tissues with nucleic acid drugs. PMID- 23032974 TI - Targeted expression of miR-34a using the T-VISA system suppresses breast cancer cell growth and invasion. AB - Recurrence and metastasis result in a poor prognosis for breast cancer patients. Recent studies have demonstrated that microRNAs (miRNAs) play vital roles in the development and metastasis of breast cancer. In this study, we investigated the therapeutic potential of miR-34a in breast cancer. We found that miR-34a is downregulated in breast cancer cell lines and tissues, compared with normal cell lines and the adjacent nontumor tissues, respectively. To explore the therapeutic potential of miR-34a, we designed a targeted miR-34a expression plasmid (T-VISA miR-34a) using the T-VISA system, and evaluated its antitumor effects, efficacy, mechanism of action, and systemic toxicity. T-VISA-miR-34a induced robust, persistent expression of miR-34a, and dramatically suppressed breast cancer cell growth, migration, and invasion in vitro by downregulating the protein expression levels of the miR-34a target genes E2F3, CD44, and SIRT1. In an orthotopic mouse model of breast cancer, intravenous injection of T-VISA-miR-34a:liposomal complex nanoparticles significantly inhibited tumor growth, prolonged survival, and did not induce systemic toxicity. In conclusion, T-VISA-miR-34a lead to robust, specific overexpression of miR-34a in breast cancer cells and induced potent antitumor effects in vitro and in vivo. T-VISA-miR-34a may provide a potentially useful, specific, and safe-targeted therapeutic approach for breast cancer. PMID- 23032976 TI - The possible "proton sponge " effect of polyethylenimine (PEI) does not include change in lysosomal pH. AB - Polycations such as polyethylenimine (PEI) are used in many novel nonviral vector designs and there are continuous efforts to increase our mechanistic understanding of their interactions with cells. Even so, the mechanism of polyplex escape from the endosomal/lysosomal pathway after internalization is still elusive. The "proton sponge " hypothesis remains the most generally accepted mechanism, although it is heavily debated. This hypothesis is associated with the large buffering capacity of PEI and other polycations, which has been interpreted to cause an increase in lysosomal pH even though no conclusive proof has been provided. In the present study, we have used a nanoparticle pH sensor that was developed for pH measurements in the endosomal/lysosomal pathway. We have carried out quantitative measurements of lysosomal pH as a function of PEI content and correlate the results to the "proton sponge " hypothesis. Our measurements show that PEI does not induce change in lysosomal pH as previously suggested and quantification of PEI concentrations in lysosomes makes it uncertain that the "proton sponge " effect is the dominant mechanism of polyplex escape. PMID- 23032977 TI - Infectivity-selective oncolytic adenovirus developed by high-throughput screening of adenovirus-formatted library. AB - Adenovirus (Ad) is a potent gene-delivery vehicle and has frequently been used for designing oncolytic viruses. However, lack of selectivity on infection has hampered the achievement of sufficient in vivo efficiency. Here, we developed a novel oncolytic virus system, infectivity-selective oncolytic adenovirus (ISOAd), via direct high-throughput screening of a high-diversity targeting-ligand library in adenoviral format. Through our newly designed rescue virus system, the high diversity Ad library carrying the random seven amino acid sequences ligand library in the AB-loop of its fiber-knob region (5 * 10(9) diversity) was successfully generated. During the screening of this library with the cells expressing the target molecule (mesothelin, MSLN), the AB-loop sequence of the virus clones converged to one dominant sequence and a novel MSLN-targeting sequence was isolated. The virus with the isolated motif showed selective infectivity to MSLN-positive cells in vitro. In vivo, it exhibited a selective and potent antitumor effect resulted from the viral replication in MSLN-positive xenografts. The ISOAd is a novel class of oncolytic Ad, which has selectivity at the step of transduction. The selectivity at the stage of infection can open new perspectives in oncolytic Ad therapy for various diseases. PMID- 23032979 TI - Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. AB - OBJECTIVES: Liver stiffness measurement (LSM) by transient elastography is a noninvasive test of liver fibrosis, but cannot be performed in a significant proportion of obese patients. The aim of this study was to evaluate the performance of the new XL probe in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: Liver biopsy and paired LSM by both the original M probe and XL probe were performed on 193 consecutive NAFLD patients in France and Hong Kong. RESULTS: Compared with M probe, XL probe was more likely to achieve 10 valid measurements (95% vs. 81%; P<0.001) and a success rate of over 60% (90% vs. 74%; P<0.001). The areas under receiver operating characteristics curves of XL probe for F2, F3, and F4 disease were 0.80, 0.85, and 0.91, respectively. XL probe tended to generate lower LSM than M probe in the same patient. At a cutoff of 7.2 kPa, the sensitivity, specificity, positive, and negative predictive values for F3 or greater disease were 78%, 78%, 60%, and 89%, respectively. Discordance of at least two stages between XL probe and histology was observed in 16 (9%) patients. Body mass index (BMI) over 35 kg/m(2) was independently associated with discordance (adjusted odds ratio 9.09; 95% confidence interval 1.10-75.43). Reliable measurements by XL probe were obtained in 75% of the overall population and 65% of patients with BMI over 30 kg/m(2). CONCLUSIONS: LSM by XL probe can be performed successfully in most NAFLD patients, but obesity is associated with less accurate and reliable measurements. PMID- 23032978 TI - Major complications of pneumatic dilation and Heller myotomy for achalasia: single-center experience and systematic review of the literature. AB - OBJECTIVES: Pneumatic dilation (PD) and laparoscopic Heller myotomy (LHM) can be definitive therapies for achalasia; recent data suggest comparable efficacy. However, risk must also be considered. We reviewed the major complication rate of PD and LHM in a high-volume center and reviewed the corresponding literature. METHODS: We reviewed 12 years of our institution's achalasia treatment experience. During this interval, a consistent technique of PD was used utilizing Rigiflex dilators. Medical records were reviewed for post-procedure complications. We administered a telephone survey and examined medical records to assess efficacy of treatment. We also performed a systematic review of the literature for comparable clinical data and examined 80 reports encompassing 12,494 LHM and PD procedures. RESULTS: At our center, 463 achalasia patients underwent 567 PD or LHM procedures. In all, 78% of the PDs used a 30-mm Rigiflex dilator. In all, 157/184 (85%) patients underwent 1 or 2 PD without any subsequent treatment. There were seven clinically significant perforations; one from PD and six from LHM. There were no resultant deaths from these perforations; two deaths occurred within 30 days of LHM from unrelated causes. Complications and deaths post-PD were significantly fewer than those post-LHM (P=0.02). CONCLUSIONS: Esophageal perforation from PD at our high-volume center was less common than often reported and lower than that associated with LHM. We conclude that, in the hands of experienced operators using conservative technique, PD has fewer major complications and deaths than LHM. PMID- 23032981 TI - Transcutaneous electrical tibial nerve stimulation in the treatment of fecal incontinence: a randomized trial (CONSORT 1a). AB - OBJECTIVES: The objective of this study was to show that although transcutaneous electrical tibial nerve stimulation (TENS) is being increasingly used to treat fecal incontinence (FI), its efficacy has never been proved using controlled trials. METHODS: In this randomized, double-blind, sham-controlled trial, 144 patients aged 30-82 years from nine centers were randomly assigned to receive either active or sham stimulations for 3 months. The primary end point was the response to treatment based on the number of incontinence and urgency episodes. Secondary end points were severity scores, quality of life scores, delay to postpone defecation, patient self-assessment of treatment efficacy, physician assessment of TENS efficacy, anorectal manometry, and adverse events. RESULTS: No statistically significant difference was seen between active and sham TENS in terms of an improvement in the median number of FI/urgency episodes per week. Thirty-four patients (47%) who received the active TENS treatment exhibited a >30% decrease in the FI severity score compared with 19 patients (27%) who received the sham treatment (odds ratio 2.4, 95% confidence interval 1.1-5.1, P=0.02). No differences in delay to postpone defecation, patient self-assessment of treatment efficacy, or anorectal manometry were seen between the two groups. The evaluating physicians rated the active stimulations as more effective than the sham stimulations (P=0.01). One minor therapy-related adverse event was observed (1.5%) (see Supplementary Consort 1b). CONCLUSIONS: We failed to demonstrate any benefit of TENS on our primary end-point. PMID- 23032980 TI - Association of nonalcoholic fatty liver disease with components of metabolic syndrome according to body mass index in Korean adults. AB - OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, and its prevalence is much higher in obese individuals. NAFLD is closely related to metabolic syndrome (MetS); however, most concepts about the relationship between NAFLD and MetS have emphasized obesity, although NAFLD is not a rare disease in the non-obese population. In the present study, we aim to determine the association between NAFLD and MetS and to compare this association between non-obese and obese individuals. METHODS: A total of 29,994 adults who underwent routine comprehensive health evaluations, including abdominal ultrasonography, were selected. We calculated the adjusted prevalence ratios (PRs) for components of MetS (high blood pressure (BP), impaired fasting glucose, low high-density lipoprotein cholesterol (HDL-C), and high triglycerides (TG)) according to NAFLD in non-obese and obese patients. RESULTS: NAFLD was found in 12.6% of non-obese subjects and 50.1% of obese subjects. NAFLD was associated with most components of MetS in both obese and non-obese subjects. However, non-obese NAFLD patients had significantly higher PRs for certain components of MetS than did obese patients, especially among women. Adjusted PRs (95% confidence interval) for components of MetS in non-obese women vs. obese women were as follows: (1) high BP: 1.41 (1.31-1.51) vs. 1.05 (0.89-1.22) (2) impaired fasting glucose: 2.04 (1.95-2.75) vs. 1.37 (1.21-1.53) (3) low HDL-C: 2.00 (1.92-2.08) vs. 1.40 (1.26-1.55), and (4) high TG: 3.36 (3.24-3.47) vs. 1.97 (1.76-2.17). CONCLUSIONS: NAFLD was associated with risk for components of MetS, and the association was stronger in non-obese than in obese individuals, especially in women. Therefore, NAFLD should be considered a meaningful predictor of metabolic diseases in the non-obese population. PMID- 23032982 TI - Prevalence of gastro-esophageal reflux-type symptoms in individuals with irritable bowel syndrome in the community: a meta-analysis. AB - OBJECTIVES: Irritable bowel syndrome (IBS) and gastro-esophageal reflux-type symptoms (GERS) are highly prevalent in the general population, and the two appear to be related. We conducted a systematic review and meta-analysis to estimate the prevalence of GERS in individuals with IBS, and to quantify the overlap between the two disorders. METHODS: MEDLINE, EMBASE, and EMBASE Classic were searched (up to October 2011) to identify population-based studies reporting the prevalence of IBS and GERS in adults (>= 15 years), defined using a specific symptom-based criteria or a questionnaire. The prevalence of IBS and GERS were extracted for all studies. Pooled prevalence, according to study location and criteria used to define IBS or GERS, as well as odds ratios (OR), with 95% confidence intervals (CIs) were calculated. The degree of overlap between the two was examined. RESULTS: Of 390 papers evaluated, 81 reported prevalence of IBS. Thirteen of these, containing 49,939 participants, reported the proportion of individuals with GERS. The prevalence of GERS in IBS was 42.0% (95% CI, 30.0 55.0). The pooled OR for GERS in individuals with IBS, compared with those without, was 4.17 (95% CI, 2.85-6.09). The OR for GERS in IBS remained significantly higher in all geographical regions studied, and for all diagnostic criteria used. The degree of overlap between the two conditions varied from 14.2, when the Rome II criteria for IBS were used, to 26.7% with the Manning criteria. CONCLUSIONS: The OR of GERS in individuals with IBS was four-fold that of individuals without IBS. Reasons for this remain speculative, but may include shared pathophysiological mechanisms or residual confounding. PMID- 23032983 TI - Prevalence and predictors of columnar lined esophagus in gastroesophageal reflux disease (GERD) patients undergoing upper endoscopy. AB - OBJECTIVES: Chronic gastroesophageal reflux disease (GERD) is a risk factor for Barrett's esophagus (BE), the most important surrogate marker for the development of esophageal adenocarcinoma (EAC). The need to document the presence of intestinal metaplasia in esophageal biopsies from a columnar lined esophagus (CLE) to diagnose BE is debated. The objective of this study was to prospectively evaluate the prevalence and risk factors of CLE in a large cohort of GERD patients undergoing upper endoscopy. METHODS: Consecutive patients presenting to the endoscopy unit at a tertiary referral center for their index upper endoscopy for evaluation of GERD symptoms were enrolled in this prospective cohort study. Patients were asked to complete a validated GERD questionnaire that documents the onset of GERD symptoms (heartburn and acid regurgitation) and grades the frequency and severity of symptoms experienced over the past year. Demographic information, body mass index, and use of aspirin/nonsteroidal antiinflammatory drugs were recorded. Endoscopic details including length of CLE, presence and size of hiatal hernia were noted. Patients with CLE (cases) were compared with those without CLE (controls) using Fischer's exact test and t-test. All factors that were statistically significant (P<0.05) were then entered into stepwise logistic regression to evaluate for independent predictors of CLE. RESULTS: A total of 1058 patients with GERD symptoms were prospectively enrolled. On index endoscopy, the prevalence of CLE was 23.3%, whereas of CLE with documented intestinal metaplasia was 14.1%. On univariate analysis, male gender, Caucasian race, heartburn duration of >5 years, presence and size of hiatal hernia were significantly associated with the presence of CLE compared with controls (P<0.05). On multivariate analysis, heartburn duration >5 years (odds ratio (OR): 1.50, 95% confidence interval (CI): 1.07-2.09, P=0.01), Caucasian race (OR: 2.40, 95% CI: 1.42-4.03, P=0.001), and hiatal hernia (OR: 2.07, 95% CI: 1.50-2.87, P<0.01) were found to be independent predictors for CLE. CLE length was significantly associated with the presence of intestinal metaplasia (P<0.001). CONCLUSIONS: If BE is defined by the presence of CLE alone on upper endoscopy, up to 25% of GERD patients are diagnosed with this lesion. Enrolling all these patients in surveillance programs would have significant ramifications on health care resources. PMID- 23032984 TI - T-cell non-Hodgkin's lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-alpha) inhibitors: results of the REFURBISH study. AB - OBJECTIVES: The risk of non-Hodgkin's lymphoma (NHL) with tumor necrosis factor alpha (TNF-alpha) inhibitors is unclear, whether related to concomitant thiopurines usage or due to the underlying inflammatory disease. We sought to review all cases of T-cell NHL reported to the Food and Drug Administration (FDA) in patients receiving TNF-alpha inhibitors for all approved indications and examine the risk of T-cell NHL with TNF-alpha inhibitors in comparison with the use of thiopurines in inflammatory bowel disease (IBD). METHODS: The FDA Adverse Event Reporting System (AERS) was queried for all lymphomas following treatment with the following TNF-alpha inhibitors: infliximab, adalimumab, certolizumab, etanercept, and their trade names. Full reports for T-cell NHL cases were identified using the Freedom of Information Act. In addition, T-cell NHL reported in patients IBD with the use of the thiopurines-azathioprine, 6-mercaptopurine, and their trade names were also collected. A search of MEDLINE was performed for additional T-cell NHL with TNF-alpha inhibitors or thiopurines, not reported to the FDA but available in published literature. The histological subtypes of T cell NHL reported with TNF-alpha inhibitors were compared with reported subtypes in Surveillance Epidemiology and End Results (SEER) -17 registry. Reported risk of T-cell NHL in IBD with TNF-alpha inhibitors, thiopurines, or concomitant use was calculated using Fisher's exact test using 5-aminosalicylates as control drugs. RESULTS: A total of 3,130,267 reports were downloaded from the FDA AERS (2003-2010). Ninety-one cases of T-cell NHL with TNF-alpha inhibitors were identified in the FDA AERS and nine additional cases were identified on MEDLINE search. A total of 38 patients had rheumatoid arthritis, 36 cases had Crohn's disease, 11 had psoriasis, 9 had ulcerative colitis, and 6 had ankylosing spondylitis. Sixty-eight of the cases (68%) involved exposure to both a TNF-alpha inhibitor and an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate, leflunomide, or cyclosporine). Hepatosplenic T-cell lymphoma (HSTCL) was the most common reported subtype, whereas mycosis fungoides/Sezary syndrome and HSTCL were identified as more common with TNF-alpha-inhibitor exposure compared with SEER-17 registry. Nineteen cases of T-cell NHL with thiopurines were identified in the FDA AERS and one additional case on MEDLINE. Reported risk of T-cell NHL was higher with TNF-alpha inhibitor use in combination with thiopurines (95% confidence interval (CI) 4.98-354.09; P<0.0001) and thiopurines alone (95% CI 8.32-945.38; P<0.0001) but not with TNF-alpha inhibitor use alone (95% CI 0.13 10.61; P=1.00). CONCLUSIONS: Risk of T-cell NHL is increased with TNF-alpha inhibitor use in combination with thiopurines but not with TNF-alpha inhibitors alone. PMID- 23032985 TI - The interaction of rs738409, obesity, and alcohol: a population-based autopsy study. AB - OBJECTIVES: The objective of this study was to access the prevalence of alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) histology in the general population, which had been otherwise difficult to access because of inherent misclassification bias in surrogate marker studies and referral bias in patient case series. The interaction among rs738409, obesity, and alcohol remains controversial. This population-based autopsy study investigated the histological prevalence of ALD and NAFLD, and interactions among rs738409, obesity, and alcoholism. METHODS: A total of 170 alcoholic and 235 nonalcoholic cases were selected from 1,034 adult car accident autopsies in 17 Kansas and Missouri counties from 2000 to 2010. The nonalcoholic group had undetectable blood alcohol concentration, while the alcoholic group had a blood alcohol concentration >=0.08%. RESULTS: The age-standardized prevalences of hepatic steatosis, steatohepatitis, and advanced fibrosis were 56, 6, and 18% among alcoholics and 36, 4, and 6% in nonalcoholics, respectively. The interaction terms among alcohol, body mass index (BMI), and genotype were not significant. rs738409 GC or GG genotype was associated with 1.9-fold odds (95% confidence interval (CI), 1.2 2.9) of a higher NAFLD Activity Score (NAS). Alcohol had 3.5-fold odds (95% CI, 2.0-5.9), while every 5-unit increase in BMI had 1.9-fold odds (95% CI, 1.7-2.5). A negative interaction between alcohol and BMI towards fibrosis had been observed (P=0.045). Every 5-unit increase in BMI had 2.2-fold odds (95% CI, 1.5-2.5) of fibrosis among nonalcoholics, but not in alcoholics. CONCLUSIONS: This study assessed the prevalence of fatty liver histology in the general population from an autopsy study perspective. The finding of an additive interaction among rs738409, obesity, and alcohol towards NAS may be useful in targeting preventative care to patients at highest risk for ALD. The negative interaction between alcohol and obesity towards fibrosis supported previous findings and suggests the need for future research to explore potential mechanisms that may improve treatment of nonalcoholic steatohepatitis-related fibrosis. PMID- 23032986 TI - Association between ambient ultraviolet radiation and risk of esophageal cancer. AB - OBJECTIVES: Ecological studies have suggested an inverse relationship between latitude and risks of some cancers. However, associations between solar ultraviolet radiation (UVR) exposure and esophageal cancer risk have not been fully explored. We therefore investigated the association between nevi, freckles, and measures of ambient UVR over the life-course with risks of esophageal cancers. METHODS: We compared estimated lifetime residential ambient UVR among Australian patients with esophageal cancer (330 esophageal adenocarcinoma (EAC), 386 esophago-gastric junction adenocarcinoma (EGJAC), and 279 esophageal squamous cell carcinoma (ESCC)), and 1471 population controls. We asked people where they had lived at different periods of their life, and assigned ambient UVR to each location based on measurements from NASA's Total Ozone Mapping Spectrometer database. Freckling and nevus burden were self-reported. We used multivariable logistic regression models to estimate the magnitude of associations between phenotype, ambient UVR, and esophageal cancer risk. RESULTS: Compared with population controls, patients with EAC and EGJAC were less likely to have high levels of estimated cumulative lifetime ambient UVR (EAC odds ratio (OR) 0.59, 95% confidence interval (CI) 0.35-0.99, EGJAC OR 0.55, 0.34-0.90). We found no association between UVR and risk of ESCC (OR 0.91, 0.51-1.64). The associations were independent of age, sex, body mass index, education, state of recruitment, frequency of reflux, smoking status, alcohol consumption, and H. pylori serostatus. Cases with EAC were also significantly less likely to report high levels of nevi than controls. CONCLUSIONS: These data show an inverse association between ambient solar UVR at residential locations and risk of EAC and EGJAC, but not ESCC. PMID- 23032987 TI - Stem cells for Parkinson's disease: advancing science but protecting patients. PMID- 23032989 TI - A review on nitrogen and organics removal mechanisms in subsurface flow constructed wetlands: dependency on environmental parameters, operating conditions and supporting media. AB - With the unique advantages of lower operational and maintenance cost, the applications of subsurface flow constructed wetlands for the treatment of wastewater have been increasing rapidly throughout the world. The removal of nitrogen and organics by such systems has gained substantial attention in recent years. In subsurface flow wetlands, the removal of pollutants often relies on a diverse range of co-existing physical, chemical and biological routes, which are vitally dependent on numerous environmental and operational parameters. This paper provides a comprehensive review of wetland structures, classic and novel nitrogen and organics removal mechanisms along with the key environmental parameters and operational conditions that enhance removal in subsurface flow wetland systems. The critical exploration identifies the major environmental parameters such as: pH, DO, and temperature, operational factors i.e. organic carbon availability, loading, feed mode, retention time, recirculation, harvesting, and the complex role (of both parameters) on classical nitrogen and organics removal pathways. Subsequently, the necessity of further extensive research on such factors, for promoting novel nitrogen removal routes in wetland systems has also been highlighted. The expansion of the review on the influence of the unconventional wetland matrix indicates that, the structural differences and inherent properties of these media can support substantial nitrogen and organics removal from wastewater, under optimal operating conditions. Overall, the critical review illustrates the necessity of a profound knowledge on the complicated inter-relationship between nitrogen and organics removal routes, governing environmental and operational parameters, and wetland matrix for improving the treatment performances of subsurface flow wetlands. PMID- 23032991 TI - Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters. AB - Roux-en-Y gastric bypass (RYGB) has become a prominent therapeutic option for long-term treatment of morbid obesity and type 2 diabetes mellitus (T2D). Cross talk and pathogenetic consequences of RYGB-induced profound effects on metabolism and gut microbiome are poorly understood. The aim of the present study therefore was to characterize intra-individual changes of gut microbial composition before and 3 months after RYGB by metagenomic sequencing in morbidly obese patients (body mass index (BMI)>40 kg m(-)(2)) with T2D. Subsequently, metagenomic data were correlated with clinical indices. Based on gene relative abundance profile, 1061 species, 729 genera, 44 phyla and 5127 KO (KEGG Orthology) were identified. Despite high diversity, bacteria could mostly be assigned to seven bacterial divisions. The overall metagenomic RYGB-induced shift was characterized by a reduction of Firmicutes and Bacteroidetes and an increase of Proteobacteria. Twenty-two microbial species and 11 genera were significantly altered by RYGB. Using principal component analysis, highly correlated species were assembled into two common components. Component 1 consisted of species that were mainly associated with BMI and C-reactive protein. This component was characterized by increased numbers of Proteobacterium Enterobacter cancerogenus and decreased Firmicutes Faecalibacterium prausnitzii and Coprococcus comes. Functional analysis of carbohydrate metabolism by KO revealed significant effects in 13 KOs assigned to phosphotransferase system. Spearmen's Rank correlation indicated an association of 10 species with plasma total- or low-density lipoprotein cholesterol, and 5 species with triglycerides. F. prausnitzii was directly correlated to fasting blood glucose. This is the first clinical demonstration of a profound and specific intra-individual modification of gut microbial composition by full metagenomic sequencing. A clear correlation exists of microbiome composition and gene function with an improvement in metabolic and inflammatory parameters. This will allow to develop new diagnostic and therapeutic strategies based on metagenomic sequencing of the human gut microbiome. PMID- 23032990 TI - A genetic basis for the variable effect of smoking/nicotine on Parkinson's disease. AB - Prior studies have established an inverse association between cigarette smoking and the risk of developing Parkinson's disease (PD), and currently, the disease modifying potential of the nicotine patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila. We identified SV2C, which encodes a synaptic-vesicle protein in PD-vulnerable substantia nigra (P=1 * 10(-7) for gene-smoking interaction on PD risk), and CG14691, which is predicted to encode a synaptic-vesicle protein in Drosophila (P=2 * 10(-11) for nicotine paraquat interaction on gene expression). SV2C is biologically plausible because nicotine enhances the release of dopamine through synaptic vesicles, and PD is caused by the depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful (P=5 * 10(-10)). Taken together, cross-validating evidence from humans and Drosophila suggests SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine. PMID- 23032988 TI - Structural basis of efficient electron transport between photosynthetic membrane proteins and plastocyanin in spinach revealed using nuclear magnetic resonance. AB - In the photosynthetic light reactions of plants and cyanobacteria, plastocyanin (Pc) plays a crucial role as an electron carrier and shuttle protein between two membrane protein complexes: cytochrome b(6)f (cyt b(6)f) and photosystem I (PSI). The rapid turnover of Pc between cyt b(6)f and PSI enables the efficient use of light energy. In the Pc-cyt b(6)f and Pc-PSI electron transfer complexes, the electron transfer reactions are accomplished within <10(-4) s. However, the mechanisms enabling the rapid association and dissociation of Pc are still unclear because of the lack of an appropriate method to study huge complexes with short lifetimes. Here, using the transferred cross-saturation method, we investigated the residues of spinach (Spinacia oleracea) Pc in close proximity to spinach PSI and cyt b(6)f, in both the thylakoid vesicle-embedded and solubilized states. We demonstrated that the hydrophobic patch residues of Pc are in close proximity to PSI and cyt b(6)f, whereas the acidic patch residues of Pc do not form stable salt bridges with either PSI or cyt b(6)f, in the electron transfer complexes. The transient characteristics of the interactions on the acidic patch facilitate the rapid association and dissociation of Pc. PMID- 23032992 TI - Cytochemistry of sialoglycoconjugates, lysozyme, and beta-defensin in eccrine glands of porcine snout skin as studied by electron microscopy. AB - In most mammals except for humanoid primates, eccrine glands are confined to the skin of a series of specific body regions. Sialic acids and antimicrobial substances exhibit various functional properties and serve as a component of nonspecific defense against micro-organisms, respectively. In this study, the distribution of these moieties was studied by electron microscopic histochemical methods. The eccrine glandular acini consisted of two types of dark cells as well as clear cells. The secretory granules and Golgi apparatus of both types of dark cells contained sialic acid residues linked to alpha2-6Gal/GalNAc. On the other hand, sialoglycoconjugates with Sialpha2-3Galbeta1-4GlcNAc sequence were confined to those of the Type II dark cells. In addition, lysozyme and beta-defensin were mainly detected in the secretory granules of the Type II dark cells. These secretory products may create a defensive barrier against microbial invasion and play an essential role in preservation of the integrity of porcine snout skin as a sensory organ. PMID- 23032993 TI - FCGR2C genotyping by pyrosequencing reveals linkage disequilibrium with FCGR3A V158F and FCGR2A H131R polymorphisms in a Caucasian population. AB - The FCGR3A-V158F and FCGR2A-H131R polymorphisms are associated with clinical responses to therapeutic mAbs and with immune thrombocytopenic purpura (ITP). The FCGR2C-ORF/STOP polymorphism, controlling FcgammaRIIC expression on natural killer cells and therefore FcgammaRIIC-mediated antibody dependent cell-mediated cytotoxicity, is also associated with ITP. Using a new pyrosequencing assay to determine this polymorphism in a control population, we observed the expected allele frequencies (ORF:12.6%) and percentages of individuals with a single copy (10.0%) or 3 copies (12.1%) of FCGR2C, or with at least one FCGR2C-ORF allele (20.1%). No association of FCGR2C copy number variations with the FCGR3A-V158F or FCGR2A-H131R genotype was detected. More importantly, our results demonstrate a strong and a weaker linkage disequilibrium associating the FCGR2C-ORF allele with the FCGR3A-158V and the FCGR2A-131H allele, respectively. PMID- 23032994 TI - Improved description of soft layered materials with van der Waals density functional theory. AB - The accurate description of van der Waals forces within density functional theory is currently one of the most active areas of research in computational physics and chemistry. Here we report results on the structural and energetic properties of graphite and hexagonal boron nitride, two layered materials where interlayer binding is dominated by van der Waals forces. Results from several density functionals are reported, including the optimized Becke88 van der Waals (optB88 vdW) and the optimized PBE van der Waals (optPBE-vdW) (Klimes et al 2010 J. Phys.: Condens. Matter 22 022201) functionals. Where comparison to experiment and higher-level theory is possible, the results obtained from the two new van der Waals density functionals are in good agreement. An analysis of the physical nature of the interlayer binding in both graphite and hexagonal boron nitride is also reported. PMID- 23032995 TI - Spin interactions in mineral libethenite series: evolution of low-dimensional magnetism. AB - Interesting magnetic properties and spin-exchange interactions along various possible pathways in the half-integral spin quantum magnetic tetramer system: A(2)PO(4)OH (A=Co, Cu) are investigated. Interplay of structural distortion and the magnetic properties with the evolution of localized band structure explain the gradual transition from a three-dimensional antiferromagnet to a low dimensional frustrated magnetic system along the series. A detailed study of the exchange mechanism in this system explores various possibilities of complex magnetic interaction. The electronic structure of this series, studied with the help of different appropriate density functional approaches such as Nth order muffin-tin orbital (NMTO) and plane-wave pseudopotential calculations incorporating onsite Coulomb repulsion (U), identifies the underlying magnetic exchange mechanism of this series. Thereafter a generalized minimal model spin Hamiltonian is constructed for the low-dimensional system. Solution of this model Hamiltonian within first-order perturbation theory results in the evaluation of spin-gap in the spin-tetramer system. In addition, the effects of size confinement and volume reduction on the relevant exchange integrals and spin-gap of the low-dimensional system are also discussed. PMID- 23032996 TI - Synthesis, characterization, electronic and gas-sensing properties towards H2 and CO of transparent, large-area, low-layer graphene. AB - Low-layered, transparent graphene is accessible by a chemical vapor deposition (CVD) technique on a Ni-catalyst layer, which is deposited on a <100> silicon substrate. The number of graphene layers on the substrate is controlled by the grain boundaries in the Ni-catalyst layer and can be studied by micro Raman analysis. Electrical studies showed a sheet resistance (R(sheet)) of approximately 1435 Omega per ?, a contact resistance (R(c)) of about 127 Omega, and a specific contact resistance (R(sc)) of approximately 2.8*10(-4) Omega cm(2) for the CVD graphene samples. Transistor output characteristics for the graphene sample demonstrated linear current/voltage behavior. A current versus voltage (I(ds)-V(ds)) plot clearly indicates a p-conducting characteristic of the synthesized graphene. Gas-sensor measurements revealed a high sensor activity of the low-layer graphene material towards H(2) and CO. At 300 degrees C, a sensor response of approximately 29 towards low H(2) concentrations (1 vol %) was observed, which is by a factor of four higher than recently reported. PMID- 23032997 TI - Calix[4]pyrrole-based heteroditopic ion-pair receptor that displays anion modulated, cation-binding behavior. AB - A new ditopic ion-pair receptor 1 was designed, synthesized, and characterized. Detailed binding studies served to confirm that this receptor binds fluoride and chloride ions (studied as their tetraalkylammonium salts) and forms stable 1:1 complexes in CDCl(3). Treatment of the halide-ion complexes of 1 with Group I and II metal ions (Li(+), Na(+), K(+), Cs(+), Mg(2+), and Ca(2+); studied as their perchlorate salts in CD(3)CN) revealed unique interactions that were found to depend on both the choice of the added cation and the precomplexed anion. In the case of the fluoride complex [1?F](-) (preformed as the tetrabutylammonium (TBA(+)) complex), little evidence of interaction with the K(+) ion was seen. In contrast, when this same complex (i.e., [1?F](-) as the TBA(+) salt) was treated with the Li(+) or Na(+) ions, complete decomplexation of the receptor-bound fluoride ion was observed. In sharp contrast to what was seen with Li(+), Na(+), and K(+), treating complex [1?F](-) with the Cs(+) ion gave rise to a stable, receptor-bound ion-pair complex [Cs?1?F] that contains the Cs(+) ion complexed within the cup-like cavity of the calix[4]pyrrole, which in turn was stabilized in its cone conformation. Different complexation behavior was observed in the case of the chloride complex [1?Cl](-). In this case, no appreciable interaction was observed with Na(+) or K(+). In addition, treating [1?Cl](-) with Li(+) produces a tightly hydrated dimeric ion-pair complex [1?LiCl(H(2)O)](2) in which two Li(+) ions are bound to the crown moiety of the two receptors. In analogy to what was seen in the case of [1?F](-), exposure of [1?Cl](-) to the Cs(+) ion gives rise to an ion-pair complex [Cs?1?Cl] in which the cation is bound within the cup of the calix[4]pyrrole. Different complexation modes were also observed when the binding of the fluoride ion was studied by using the tetramethylammonium and tetraethylammonium salts. PMID- 23032998 TI - Electronic structure and geometries of o-carborane derived cyclic structures [{MU 1,2-(C2B10H10)(n)M(n)}Ag(m)]z-, M = {Au, Hg}, n = {3, 4}, m = {0, 1, 2}, z = {n m, -m}. AB - To date, crystal structures of the cyclic mercury complexes [MU-1,2 (C(2)B(10)H(10))(n)Hg(n)], with n = {3, 4}, have been found. However, the same structures substituting Hg by Au, which implies a charge z = {-3, -4} for n = {3, 4} respectively, have not been found. In this work, we present geometrical and electronic structure properties of the title structures [MU-1,2 (C(2)B(10)H(10))(n)M(n)](z-), M = {Au, Hg}, n = {3, 4}, z = {n, 0}, and study the stability of structures with one and two added Ag(+) ions. PMID- 23032999 TI - A terbium(III)-organic framework for highly selective sensing of cytidine triphosphate. AB - Highly selective sensing of cytidine triphosphate (CTP) against other triphosphate nucleosides including ATP, GTP and UTP is successfully achieved with a luminescent terbium(III)-organic framework (TbOF) of [Tb(2)(2,3 pzdc)(2)(ox)(H(2)O)(2)](n) (2,3-pzdc(2-) = 2,3-pyrazinedicarboxylate, ox(2-) = oxalate). PMID- 23033000 TI - Genetic association study of tumor necrosis factor-alpha with sepsis and septic shock in Thai pediatric patients. AB - OBJECTIVES: To evaluate the association between the genetic polymorphism of the tumor necrosis factor-alpha (TNF-alpha) gene and the development of sepsis and septic shock in Thai pediatric patients and to investigate the clinical impacts of TNF-alpha polymorphisms in this population. METHODS: To perform this genetic association study, a prospective analysis of pediatric patients (age < 18 years) with clinical sepsis/septic shock was conducted. All clinical data were collected by pediatric intensive care experts, and genetic analyses were performed at a central laboratory. A single nucleotide polymorphism (SNP) located in the 5' promoter region at position -308 was genotyped and the results were associated with clinical phenotypes. RESULTS: A total of 167 Thai individuals were investigated, 66 of which were pediatric patients with sepsis/septic shock and 101 were healthy controls. Interestingly, we could not identify an association between sepsis and -308 (G/A) polymorphism, which have previously been demonstrated to be a major SNP associated with sepsis in several Caucasian populations, since there was no frequency difference between cases and controls. CONCLUSIONS: In this report, the major TNF-alpha polymorphism (-308) was not associated with clinical sepsis/septic shock in Thais. This information will be important for future analyses to identify the role of TNF-alpha as a genetic risk for the development of immunopathology underlying several diseases in Asia. PMID- 23033001 TI - Gold-catalyzed diastereoselective [2+2+2]-cycloaddition of 1,7-enynes with carbonyl compounds. AB - We report a gold-catalyzed [2+2+2]-cycloaddition of 1,7-enynes with carbonyl species; our experimental data suggest that the resulting oxacyclic cycloadducts arose from an interception of gold-containing cyclobutenium intermediates with carbonyl species. PMID- 23033002 TI - Ionising radiation and occupational cancer in Britain. PMID- 23033003 TI - Response in bone turnover markers during therapy predicts overall survival in patients with metastatic prostate cancer: analysis of three clinical trials. AB - BACKGROUND: The bone-forming metastases of prostate cancer result from complex stromal-epithelial interactions within the tumour microenvironment. Autocrine paracrine signalling pathways between prostate cancer epithelial cells, osteoblasts, and osteoclasts stimulate aberrant bone remodelling, and the activity of these three cell populations can be quantitatively measured using prostate-specific antigen (PSA), bone-specific alkaline phosphatase (BAP) and urine N-telopeptide (uNTx), respectively. The purpose of the present study was to test the hypothesis that serial measurements of BAP and uNTx during therapy would facilitate monitoring of disease activity and predict the overall survival (OS) in patients with metastatic prostate cancer receiving therapy. METHODS: Radionuclide bone scan, PSA, BAP, and uNTx data were retrospectively analysed from three clinical trials in patients with metastatic prostate cancer conducted at our institution. Qualitative changes in bone scans and quantitative changes in PSA, BAP, and uNTx concentrations during therapy were correlated with OS. RESULTS: Baseline levels of BAP, but not PSA, were prognostic for OS in both androgen-dependent and castrate-resistant disease. A reduction in PSA, BAP, uNTx, or BAP/uNTx on therapy was predictive of improved OS in both patient groups. Conversely, an increase in PSA, or BAP on therapy was predictive of worse OS in both patient groups. Baseline number of lesions and response on bone scan during therapy were neither prognostic nor predictive of OS in either patient group. CONCLUSION: These observations support the concept that serial measurements of bone turnover metabolites during therapy function as clinically informative predictive biomarkers in patients with advanced prostate cancer and skeletal metastases. PSA measurements and bone scans remain essential to monitor the overall disease activity and determine the anatomic distribution of skeletal metastases. PMID- 23033004 TI - Phase I/II trial of a biweekly combination of S-1 plus docetaxel in patients with previously treated non-small cell lung cancer (KRSG-0601). AB - BACKGROUND: Combination of S-1, an oral fluorouracil derivative, plus docetaxel against non-small cell lung cancer (NSCLC) showed promising efficacy but clinically problematic emesis. A phase I/II study utilising a new schedule for this combination was conducted. METHODS: A biweekly regimen of docetaxel on day 1 with oral S-1 on days 1-7 was administered to previously treated NSCLC patients. Doses of docetaxel/S-1 were escalated to 30/80, 35/80, and 40/80 mg m(-2), respectively, and its efficacy was investigated at the recommended dose below maximum tolerated dose (MTD). RESULTS: In phase I study employing 13 patients, dose-limiting toxicities were febrile neutropenia and treatment delay, with the respective MTDs for docetaxel 40 mg m(-2)/S-1 80 mg m(-2). In the phase II study, 34 patients were treated with docetaxel 35 mg m(-2)/S-1 80 mg m(-2) for a median cycle of 6. The response and disease control rates were 34.3% (95% confidence interval (CI), 18.6-50.0%) and 62.9% (95% CI, 46.8-72.9%), respectively. Median progression-free survival was 150.5 days. Haematologic grade 4 toxicities were observed in neutropenia (11.8%) and thrombocytopenia (2.9%). Regarding non haematologic toxicities, including emesis, there were no grade 3/4 side effects. CONCLUSION: Combination of 1-week administration of S-1 with biweekly docetaxel is safe and active for NSCLC. PMID- 23033005 TI - Capecitabine-associated hand-foot-skin reaction is an independent clinical predictor of improved survival in patients with colorectal cancer. AB - BACKGROUND: Hand-foot-skin reaction (HFSR) is an adverse event frequently observed during treatment with capecitabine (cape). In the present analysis, we sought to evaluate the potential association of HFSR and survival in German patients with metastatic colorectal cancer and locally advanced rectal cancer treated with cape in clinical trials. METHODS: Patients of the Arbeitsgemeinschaft fur Internistische Onkologie (AIO) KRK-0104 and the Mannheim rectal cancer trial were evaluated. HFSR was graded according to NCI-CTC criteria in both trials. Time to first occurrence of HFSR was described per cycle and HFSR developing during cycles 1 and 2 was defined as 'early HFSR'. Baseline characteristics between the patient groups with or without HFSR were compared using Mann-Whitney-U, Fisher's exact or chi(2)-test, as appropriate. Haematological and non-haematological toxicities observed in both groups were compared using Fisher's exact test. Progression-free (PFS) or disease-free (DFS) as well as overall survival (OS) data from both trials were pooled and the HFSR group was compared with the non-HFSR using Kaplan-Meier analysis. RESULTS: A total of 374 patients were included, of whom 29.3% developed any HFSR. Of these, 51% had early HFSR. Baseline characteristics were comparable between both HFSR groups concerning age, gender, ECOG performance status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFSR. The percentage of all-grade (and grade 3-4) haematological toxicities did not differ between both the groups. By contrast, patients exhibiting HFSR had a significantly higher rate of all-grade (but not grade 3-4) diarrhoea, stomatitis/mucositis and fatigue (P<0.01, respectively). Patients with HFSR had improved PFS/DFS (29.0 vs 11.4 months; P=0.015, HR 0.69) and OS (75.8 vs 41.0 months; P=0.001, HR=0.56). Within the HFSR group, PFS/DFS and OS were comparable between patients with early vs late HFSR. INTERPRETATION: The present analysis provides evidence for the association of HFSR and survival in patients with colorectal cancer. Baseline characteristics, with the exception of UICC stage, older age and ECOG performance status, and the time of occurrence of HFSR had no impact on survival. Patients with HFSR had a higher probability of developing any grade gastrointestinal toxicity and fatigue while no correlation with haematological toxicity was found. PMID- 23033006 TI - Prevalence and determinants of human papillomavirus infection and cervical lesions in HIV-positive women in Kenya. AB - BACKGROUND: We assessed the association of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) with various characteristics, CD4 count and use of combination antiretroviral therapy (cART) among HIV-positive women. METHODS: Cross-sectional study of 498 HIV-positive women who underwent HPV PCR-based testing, cytology, and systematic cervical biopsy. RESULTS: In all, 68.7% of women were HPV-positive, 52.6% had high-risk (hr) HPV, and 40.2% multiple type infections. High-risk human papillomavirus-positivity did not vary significantly by age but it was negatively associated with education level. The most frequent types in 113 CIN2/3 were HPV16 (26.5%), HPV35 (19.5%), and HPV58 (12.4%). CD4 count was negatively associated with prevalence of hrHPV (P<0.001) and CIN2/3 among non-users of cART (P=0.013). Combination antiretroviral therapies users (>=2 year) had lower hrHPV prevalence (prevalence ratio (PR) vs non-users=0.77, 95% confidence interval (CI): 0.61-0.96) and multiple infections (PR=0.68, 95% CI: 0.53-0.88), but not fewer CIN2/3. The positive predictive value of hrHPV-positivity for CIN2/3 increased from 28.9% at age <35 years to 53.3% in >=45 years. CONCLUSION: The burden of hrHPV and CIN2/3 was high and it was related to immunosuppression level. Combination antiretroviral therapies ( >=2 year) use had a favourable effect on hrHPV prevalence but cART in our population may have been started too late to prevent CIN2/3. PMID- 23033007 TI - Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH positive cancer-stem-like cells. AB - BACKGROUND: Glioblastoma multiforme (GBM) cells are resistant to anticancer drugs. Cancer stem cells (CSCs) are a key mediator of chemoresistance. We have reported that disulfiram (DS), an aldehyde dehydrogenase (ALDH) inhibitor, targets breast CSC-like cells. In this study, the effect of DS and combination of DS and gemcitabine (dFdC) on GBM cells and GBM stem-like cells was investigated. METHODS: 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI)-isobologram, western blot, luciferase reporter gene assay, electrophoretic mobility-shift assay and ALDH analysis were used in this study. RESULTS: Disulfiram is cytotoxic in GBM cell lines in a copper (Cu)-dependent manner. Disulfiram/copper enhances the cytotoxicity of dFdC. Combination index isobologram analysis indicates a synergistic effect between DS/Cu and dFdC. Disulfiram/copper induces reactive oxygen species (ROS), activates JNK and p38 pathways and inhibits nuclear factor-kappa B activity in GBM cell lines. Disulfiram/copper may trigger intrinsic apoptotic pathway via modulation of the Bcl2 family. Disulfiram/copper abolishes stem-like cell population in GBM cell lines. CONCLUSION: Our findings indicate that the cytotoxicity of DS/Cu and the enhancing effect of DS/Cu on the cytotoxicity of dFdC in GBM stem-like cells may be caused by induction of ROS and inhibition of both ALDH and the NFkB pathway. Both DS and dFdC can traverse the blood-brain barrier. Further study may lead them into GBM chemotherapy. PMID- 23033011 TI - Closed-form suboptimal maximum-likelihood sequence detection for free-space optical communications. AB - In this paper, a closed-form suboptimal maximum-likelihood sequence detection (MLSD) metric and its low-complexity version are proposed for free space optical communications systems operating over lognormal fading and high signal-to-noise channel. This algorithm provides a simplification to the algorithm reported by Riediger et al. In comparison, firstly, the parameters of this algorithm are independent of the scintillation index's variation, and secondly this algorithm just contains conventional computations; it saves computational time significantly. Bit error rate performance results confirm that the proposed algorithm performs comparably well as optimal MLSD. Moreover, the low-complexity version of this algorithm consumes much less time than the previously suboptimal MLSD metric presented by Riediger et al. PMID- 23033008 TI - Hookah smoking, nass chewing, and oesophageal squamous cell carcinoma in Kashmir, India. AB - BACKGROUND: Although cigarette smoking is an established risk factor for oesophageal squamous cell carcinoma (ESCC), there is little information about the association between other smoking and smokeless tobacco products, including hookah and nass, and ESCC risk. We conducted a case-control study in Kashmir Valley, India, where hookah smoking, nass chewing, and ESCC are common, to investigate the association of hookah smoking, nass use, and several other habits with ESCC. METHODS: We recruited 702 histologically confirmed ESCC cases and 1663 hospital-based controls, individually matched to the cases for age, sex, and district of residence from September 2008 to January 2012. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Ever-hookah smoking (OR=1.85; 95% CI, 1.41-2.44) and nass chewing (OR=2.88; 95% CI, 2.06-4.04) were associated with ESCC risk. These associations were consistent across different measures of use, including intensity, duration, and cumulative amount of use, and after excluding ever users of the other product and cigarette smokers. Our results also suggest an increased risk of ESCC associated with ever-gutka chewing and -bidi smoking. However, the latter associations were based on small number of participants. CONCLUSION: This study shows that hookah and nass use are associated with ESCC risk. As prevalence of hookah use seems to be increasing among young people worldwide, these results may have relevance not only for the regions in which hookah use has been a traditional habit, but also for other regions, including western countries. PMID- 23033009 TI - beta-catenin negatively regulates expression of the prostaglandin transporter PGT in the normal intestinal epithelium and colorectal tumour cells: a role in the chemopreventive efficacy of aspirin? AB - BACKGROUND: Levels of the pro-tumorigenic prostaglandin PGE(2) are increased in colorectal cancer, previously attributed to increased synthesis through COX-2 upregulation and, more recently, to decreased catabolism. The functionally linked genes 15-prostaglandin dehydrogenase (15-PGDH) and the prostaglandin transporter PGT co-operate in prostaglandin degradation and are downregulated in colorectal cancer. We previously reported repression of 15-PGDH expression by the Wnt/beta catenin pathway, commonly deregulated during early colorectal neoplasia. Here we asked whether beta-catenin also regulates PGT expression. METHODS: The effect of beta-catenin deletion in vivo was addressed by PGT immunostaining of beta catenin(-/lox)-villin-cre-ERT2 mouse tissue. The effect of siRNA-mediated beta catenin knockdown and dnTCF4 induction in vitro was addressed by semi quantitative and quantitative real-time RT-PCR and immunoblotting. RESULTS: This study shows for the first time that deletion of beta-catenin in murine intestinal epithelium in vivo upregulates PGT protein, especially in the crypt epithelium. Furthermore, beta-catenin knockdown in vitro increases PGT expression in both colorectal adenoma- and carcinoma-derived cell lines, as does dnTCF4 induction in LS174T cells. CONCLUSIONS: These data suggest that beta-catenin employs a two pronged approach to inhibiting prostaglandin turnover during colorectal neoplasia by repressing PGT expression in addition to 15-PGDH. Furthermore, our data highlight a potential mechanism that may contribute to the non-selective NSAID aspirin's chemopreventive efficacy. PMID- 23033012 TI - Characterization of a compressively sampled photonic link. AB - The emerging field of compressive sampling has potentially powerful implications for the design of analog-to-digital sampling systems. In particular, the mathematics of compressive sampling suggests that one can recover a signal at a smaller sampling interval than is dictated by the rate at which the samples are digitized. In a recent work the authors presented an all-photonic implementation of such a system and experimentally demonstrated the basic operating principles. This paper offers a more in-depth study of the system, including a more detailed description of the hardware, issues involved in real-time implementation, and how choice of signal model and model fidelity can influence the reconstruction. PMID- 23033013 TI - Analytical modeling and three-dimensional finite element simulation of line edge roughness in scatterometry. AB - The influence of edge roughness in angle-resolved scatterometry at periodically structured surfaces is investigated. A good description of the radiation interaction with structured surfaces is crucial for the understanding of optical imaging processes such as, e.g., in photolithography. We compared an analytical two-dimensional (2D) model and a numerical three-dimensional simulation with respect to the characterization of 2D diffraction of a line grating involving structure roughness. The results show a remarkably high agreement. The diffraction intensities of a rough structure can therefore be estimated using the numerical simulation result of an undisturbed structure and an analytically derived correction function. This work allows to improve scatterometric results for the case of practically relevant 2D structures. PMID- 23033014 TI - All-fiber passively mode-locked thulium/holmium laser with two center wavelengths. AB - We have demonstrated a self-starting, passively mode-locked Tm/Ho codoped fiber laser that lases at one of two center wavelengths. An amplified 1.56 MUm distributed feedback laser pumps a ring laser cavity which contains 1 m of Tm/Ho codoped silica fiber. Mode locking is obtained via nonlinear polarization rotation using a c-band polarization sensitive isolator with two polarization controllers. The laser is able to pulse separately at either 1.97 or 2.04 MUm by altering the intracavity polarization during the initiation of mode locking. The codoped fiber permits pulsing at one of two wavelengths, where the shorter is due to the Tm(3+) emission and the longer due to the Ho(3+) emission. The laser produces a stable pulse train at 28.4 MHz with 25 mW average power, and a pulse duration of 966 fs with 9 nm bandwidth. PMID- 23033015 TI - Method of excess fractions with application to absolute distance metrology: wavelength selection and the effects of common error sources. AB - Multiwavelength interferometry (MWI) is a well established technique in the field of optical metrology. Previously, we have reported a theoretical analysis of the method of excess fractions that describes the mutual dependence of unambiguous measurement range, reliability, and the measurement wavelengths. In this paper wavelength, selection strategies are introduced that are built on the theoretical description and maximize the reliability in the calculated fringe order for a given measurement range, number of wavelengths, and level of phase noise. Practical implementation issues for an MWI interferometer are analyzed theoretically. It is shown that dispersion compensation is best implemented by use of reference measurements around absolute zero in the interferometer. Furthermore, the effects of wavelength uncertainty allow the ultimate performance of an MWI interferometer to be estimated. PMID- 23033016 TI - Angular amplification by a diffraction grating for chiro-optical measurements. AB - The angles at which a light beam gets diffracted by a grating depend strongly on the direction of incidence for diffraction angles close to a right angle. Accordingly, it is possible to amplify small beam deflections by placing a grating at an optimal orientation to the light path. We use this principle to amplify small beam deviations arising out of a light beam refracting at the interface of an optically active medium, and demonstrate a new technique of enhancing the limit of detection of chiro-optical measurements. PMID- 23033017 TI - Positively and negatively large Goos-Hanchen lateral displacements from a single negative layered structure. AB - We study the electromagnetic beam reflection from layered structures that include the so-called epsilon-negative and the MU-negative materials, also called single negative materials. We predict that such structures can demonstrate a giant lateral Goos-Hanchen shift of the resonant excitation of surface waves at the interface between the conventional and single negative materials, as well as due to the excitation of leaky modes in the layered structures. Then we replace the conventional layer with a left-handed layer (a material with both epsilon<0 and MU<0). We show that the Goos-Hanchen shift can be positive and negative depending on the type of this layer (conventional or LH material), which can support TE or TM surface waves. PMID- 23033018 TI - Design of optically path-length-matched, three-dimensional photonic circuits comprising uniquely routed waveguides. AB - A method for designing physically path-length-matched, three-dimensional photonic circuits is described. We focus specifically on the case in which all the waveguides are uniquely routed from the input to output-a problem that has not been addressed to date and that allows for the waveguides to be used in interferometric measurements. Circuit elements were fabricated via the femtosecond laser direct-write technique. We demonstrate via interferometric methods that the fabricated circuits were indeed optically path-length matched to within 45 MUm, which is within the coherence length required for many applications. PMID- 23033019 TI - Effect of postdeposition annealing on the structure, composition, and the mechanical and optical characteristics of niobium and tantalum oxide films. AB - Optical, mechanical, and thermal properties of optical thin films are very important for a reliable device performance. In the present work, the effect of annealing on the stability and the characteristics of niobium and tantalum oxide films grown at room temperature (RT) by dual ion beam sputtering were studied. The refractive index (n(lambda)), extinction coefficient (k(lambda)), hardness (H), reduced Young's modulus (E(r)), and film stress (sigma) were investigated as a function of the annealing temperature (T(A)). X-ray diffraction analysis showed that all as-deposited films were amorphous, and crystallization was observed only after annealing at 700 degrees C. Compositional analyses confirmed that the atomic ratio of oxygen to metal in as-deposited and annealed films was close to 2.5, indicating that the films were stoichiometric pentoxides of Nb and Ta. The properties of Nb(2)O(5) and Ta(2)O(5) films were, respectively, affected by postdeposition annealing: n(lambda) values (at 550 nm) decreased from 2.30 to 2.20 and from 2.14 to 2.08, the average H and E(r) values increased from 5.6 to 7.4 GPa, and from 121 to 132 GPa for Nb(2)O(5), and from 6.5 to 8.3 GPa, and from 132 to 144 GPa for Ta(2)O(5), and the initial low compressive stress for both materials changed to tensile. We explain the variation of the coating material properties in terms of film stoichiometry, crystallinity, electronic structure, and possible reactions at the film-substrate interface. PMID- 23033020 TI - Influence of the tilting reflection mirror on the temperature and wind velocity retrieved by a polarizing atmospheric Michelson interferometer. AB - The principles of a polarizing atmospheric Michelson interferometer are outlined. The tilt of its reflection mirror results in deflection of the reflected beam and affects the intensities of the observed inteferogram. This effect is systematically analyzed. Both rectangular and circular apertures are considered. The theoretical expression of the modulation depth and phase of the interferogram are derived. These parameters vary with the inclination angle of the mirror and the distance between the deflection center and the optical axis and significantly influence the retrieved temperature and wind speed. If the wind and temperature errors are required to be less than 3 m/s and 5 K, the deflection angle must be less than 0.5 degrees . The errors are also dependent on the shape of aperture. If the reflection mirror is deflected in one direction, the temperature error is smaller for a circular aperture (1.3 K) than for a rectangular one (2.6 K), but the wind velocity errors are almost the same (less than 3 m/s). If the deflection center and incident light beam are coincident, the temperature errors are 3 * 10( 4) K and 0.45 K for circular and rectangular apertures, respectively. The wind velocity errors are 1.2 * 10(-3) m/s and 0.06 m/s. Both are small. The result would be helpful for theoretical research and development of the static polarization wind imaging interferometer. PMID- 23033021 TI - Understanding the effects of Doppler phenomena in white light Fabry-Perot interferometers for simultaneous position and velocity measurement. AB - In static tests, low-power (<5 mW) white light extrinsic Fabry-Perot interferometric position sensors offer high-accuracy (MUm) absolute measurements of a target's position over large (cm) axial-position ranges, and since position is demodulated directly from phase in the interferogram, these sensors are robust to fluctuations in measured power levels. However, target surface dynamics distort the interferogram via Doppler shifting, introducing a bias in the demodulation process. With typical commercial off-the-shelf hardware, a broadband source centered near 1550 nm, and an otherwise typical setup, the bias may be as large as 50-100 MUm for target surface velocities as low as 0.1 mm/s. In this paper, the authors derive a model for this Doppler-induced position bias, relating its magnitude to three swept-filter tuning parameters. Target velocity (magnitude and direction) is calculated using this relationship in conjunction with a phase-diversity approach, and knowledge of the target's velocity is then used to compensate exactly for the position bias. The phase-diversity approach exploits side-by-side measurement signals, transmitted through separate swept filters with distinct tuning parameters, and permits simultaneous measurement of target velocity and target position, thereby mitigating the most fundamental performance limitation that exists on dynamic white light interferometric position sensors. PMID- 23033022 TI - Magnetic field sensing based on capillary filled with magnetic fluids. AB - A kind of magnetic field sensing system based on capillary tube filled with magnetic fluids is developed in this work. The analytical expressions for the sensing system are derived in detail. The sensitivity and other sensing properties of the system are investigated numerically and experimentally. The focal line position of the emergent light after the capillary is related with the strength of the externally applied magnetic fields and recorded and judged by the CCD to sense the magnetic field indirectly. The sensing mechanism is analyzed and ascribed to the magnetically tunable refractive index of magnetic fluids. This kind of sensing unit has the advantages of miniaturization of device, easy operation, and lower dosage of sensing media. PMID- 23033023 TI - Method to evaluate beam quality of Gaussian beams with aberrations. AB - Zernike polynomials are commonly used to describe the aberration of light beams, and the beam quality of Gaussian beams with aberrations can be deduced when the order of Zernike polynomials is limited. In this paper, Hermite polynomials are utilized to reconstruct the aberrations of Gaussian beams. The beam quality factor is directly related to the coefficient and terms of Hermite polynomials and has no limit on its index. We analyzed the beam quality of a Gaussian beam with a quartic aberration and other former 11th Zernike aberrations by Hermite polynomial expansion. The result corresponds with the published research work. PMID- 23033024 TI - Polarization self-selection in a coherent beam combination system with an all optical feedback loop. AB - Polarization self-selection in passive phasing of four fiber amplifiers with an all-optical feedback loop is demonstrated. The polarization extinction ratio (PER) of the combined beam is increased, and the polarized direction is selected with the use of a polarization-maintaining (PM) isolator and some non-PM components. The best visibility of the interference patterns is observed at 95.2% and in the largest increment in the PER of the combined beam up to 7.4 dB. Results show that all PM components are unnecessary in the coherent beam combination with an all-optical feedback loop, whereas non-PM components have good potential to achieve high output power. PMID- 23033025 TI - Improved irradiances for use in ocean heating, primary production, and photo oxidation calculations. AB - Accurate calculation of underwater light is fundamental to predictions of upper ocean heating, primary production, and photo-oxidation. However, most ocean models simulating these processes do not yet incorporate radiative transfer modules for their light calculations. Such models are often driven by above surface, broadband, daily averaged irradiance or photosynthetically available radiation (PAR) values obtained from climatology or satellite observations, sometimes without correction for sea-surface reflectance, even though surface reflectance can reduce in-water values by more than 20%. We present factors computed by a radiative transfer code that can be used to convert above-surface values in either energy or quantum units to in-water net irradiance, as needed for calculations of water heating, and to in-water PAR, as needed for calculations of photosynthesis and photo-oxidation. PMID- 23033026 TI - Wave-atoms-based multipurpose scheme via perceptual image hashing and watermarking. AB - This paper presents a novel multipurpose scheme for content-based image authentication and copyright protection using a perceptual image hashing and watermarking strategy based on a wave atom transform. The wave atom transform is expected to outperform other transforms because it gains sparser expansion and better representation for texture than other traditional transforms, such as wavelet and curvelet transforms. Images are decomposed into multiscale bands with a number of tilings using the wave atom transform. Perceptual hashes are then extracted from the features of tiling in the third scale band for the purpose of content-based authentication; simultaneously, part of the selected hashes are designed as watermarks, which are embedded into the original images for the purpose of copyright protection. The experimental results demonstrate that the proposed scheme shows great performance in content-based authentication by distinguishing the maliciously attacked images from the nonmaliciously attacked images. Moreover, watermarks extracted from the proposed scheme also achieve high robustness against common malicious and nonmalicious image-processing attacks, which provides excellent copyright protection for images. PMID- 23033027 TI - Technique for in situ measurement of free spectral range and transverse mode spacing of optical cavities. AB - Length and g-factor are fundamental parameters that characterize optical cavities. We developed a technique to measure these parameters in situ by determining the frequency spacing between the resonances of fundamental and spatial modes of an optical cavity. Two laser beams are injected into the cavity, and their relative frequency is scanned by a phase-lock loop, while the cavity is locked to either laser. The measurement of the amplitude of their beat note in transmission reveals the resonances of the longitudinal and the transverse modes of the cavity and their spacing. This method proves particularly useful to characterize complex optical systems, including very long and/or coupled optical cavities, as in gravitational-wave interferometers. This technique and the results of its application to the coupled cavities of a 40 m-long gravitational wave interferometer prototype are presented here. PMID- 23033028 TI - Surface heating by optical beams and application to mid-infrared imaging. AB - Heating of surfaces by optical beams is investigated theoretically and compared with experimental results in the context of infrared imaging with vanadium dioxide thin films. Using known solutions for the diffusion of point heat sources at the interface between two semi-infinite media, the theory is extended to beams of Gaussian and flat profiles, for steady-state and dynamic regimes. Parameters relevant to imaging, such as spatial resolution and response time, are linked to thermal diffusivity, beam dimensions, and intensity. PMID- 23033029 TI - Three-wavelength parallel optical fiber dispersion measurement using dual heterodyne mixing. AB - We propose a novel optical dispersion measurement system using dual-heterodyne mixing to measure the relative phase. The system can realize parallel measurement of the relative phases between adjacent frequencies by introducing optical modulators to generate optical sidebands from a laser light source and an arrayed waveguide grating to separate the sidebands. To realize a wide dispersion range, different frequency intervals for the adjacent frequencies were combined in the system. One is the three-frequency optical dispersion measurement system (three frequency measurement), which has been developed to measure the relative phase between adjacent peaks of an optical frequency spectrum with intervals of 25 GHz generated without any frequency scanning. The other is the four-frequency optical dispersion measurement system (four-frequency measurement) with intervals of 2 GHz generated from the three-frequency sets to expand the measurement range. The experimental results using single-mode optical fibers of different lengths from 0 to 90 km indicated the dispersion slope to be 16.8 ps/nm/km with a measurement range of 2500 ps/nm and an uncertainty of less than 1 ps/nm. The proposed system provides advantages to enable parallel measurement on a frequency axis without a high-speed (GHz) photodetector, even though GHz spacing on the optical scale is used, thus reflecting the dual-heterodyne mixing. PMID- 23033030 TI - Traffic light to vehicle visible light communication channel characterization. AB - Outdoor visible light communication (VLC) between an LED traffic light and an automobile has been proposed for intelligent transportation system development. An unobstructed line-of-sight (LOS) channel has to be guaranteed for this communication system. In this paper, an analytical LOS path loss model is proposed and validated by the measurement results. Commercial-off-the-shelf (COTS) LED traffic lights are characterized for use as transmitters and possible interference sources are studied, such as background solar radiation and artificial lighting. Accordingly, the performance of an outdoor VLC system is evaluated using different modulation schemes. PMID- 23033031 TI - Micro-optical elements fabricated by metal-transparent-metallic-oxides grayscale photomasks. AB - One-step gray-tone lithography is the most effective approach to making three dimensional (3D) micro-optical elements (MOEs). Metal-transparent-metallic-oxide (MTMO) grayscale masks are novel and quite cost effective. In this paper, through the successful fabrication of 3D SiO(2) MOEs by gray-tone lithography and reactive ion etching, we thoroughly investigate the practical technique needs of MTMO grayscale masks on metallic nanofilms. Design calibration, pattern transfer, resolution, lifetime, and mask protection of grayscale masks have been verified. This work shows that the MTMO grayscale photomask has good practical applicability in the laboratory and in industry. PMID- 23033032 TI - Super-smooth surface fabrication technique and experimental research. AB - Wheel polishing, a new optical fabrication technique, is proposed for super smooth surface fabrication of optical components in high-precision optical instruments. The machining mechanism and the removal function contours are investigated in detail. The elastohydrodynamic lubrication theory is adopted to analyze the deformation of the wheel head, the pressure distribution, and the fluid film thickness distribution in the narrow machining zone. The pressure and the shear stress distributions at the interface between the slurry and the sample are numerically simulated. Practical polishing experiments are arranged to analyze the relationship between the wheel-sample distance and the machining rate. It is demonstrated in this paper that the wheel-sample distance will directly influence the removal function contours. Moreover, ripples on the wheel surface will eventually induce the transverse prints on the removal function contours. The surface roughness of fused silicon is reduced to less than 0.5 nm (rms) from initial 1.267 nm (rms). The wheel polishing technique is feasible for super-smooth surface fabrication. PMID- 23033033 TI - Simulation of electrowetting lens and prism arrays for wavefront compensation. AB - A novel application of electrowetting devices has been simulated: wavefront correction using an array of electrowetting lenses and prisms. Five waves of distortion can be corrected with Strehl ratios of 0.9 or higher, utilizing piston, tip-tilt, and curvature corrections from arrays of 19 elements and fill factors as low as 40%. Effective control of piston can be achieved by placing the liquid lens array at the focus of two microlens arrays. Seven waves of piston delay can be generated with variation in focal length between 1.5 and 500 mm. PMID- 23033034 TI - Proton irradiation damage mechanism of PANDA-type polarization-maintaining optical fibers. AB - The effects of proton irradiation with energies of 3.5 and 5 MeV on the optical properties of PANDA (polarization-maintaining and absorption-reducing) optical fiber were investigated. The displacement and the ionization damage in the fiber induced by proton irradiation at 3.5, 5, and 10 MeV were calculated, respectively, using a Stopping and Range of Ions in Matter code. The irradiation induced defects were analyzed by means of x-ray photoelectron spectroscopy, electron paramagnetic resonance, Fourier-transform infrared spectrometry, and broadband optical spectrum analysis. The results show that the proton irradiation leads to an increase of optical loss around 1310 nm and that the effect of 3.5 MeV protons is more severe than that of 5 MeV. PMID- 23033035 TI - Three-dimensional shape measurement with binary dithered patterns. AB - The previously proposed binary defocusing technique and its variations have proven successful for high-quality three-dimensional (3D) shape measurement when fringe stripes are relatively narrow, but they suffer if fringe stripes are wide. This paper proposes to utilize the binary dithering technique to conquer this challenge. Both simulation and experimental results show the phase error is always less than 0.6% even when the fringe stripes are wide and the projector is nearly focused. PMID- 23033036 TI - Implementing a grolishing process in Zeeko IRP machines. AB - The removal of mid-spatial-frequency errors is a challenging issue in most subaperture polishing technologies. A novel "grolishing" technology has been developed to deal with grinding errors of spatial wavelengths from 1 to 50 mm with the help of power spectral density analysis and filter theory. This grolishing process was implemented on Zeeko's IRP polishing machine, on which all the subsequent polishing was performed. This has greatly reduced the process time. Although different abrasive have been used, the process is self-contained. The process parameters have been optimized to leave an edge upstand of peak-to valley of 1 MUm over a width of 40 mm. PMID- 23033037 TI - Contour coding based rotating adaptive model for human detection and tracking in thermal catadioptric omnidirectional vision. AB - In this paper, we introduce a novel surveillance system based on thermal catadioptric omnidirectional (TCO) vision. The conventional contour-based methods are difficult to be applied to the TCO sensor for detection or tracking purposes due to the distortion of TCO vision. To solve this problem, we propose a contour coding based rotating adaptive model (RAM) that can extract the contour feature from the TCO vision directly as it takes advantage of the relative angle based on the characteristics of TCO vision to change the sequence of sampling automatically. A series of experiments and quantitative analyses verify that the performance of the proposed RAM-based contour coding feature for human detection and tracking are satisfactory in TCO vision. PMID- 23033038 TI - Photoinduced grating formation in a polymer containing azo-carbazole dyes. AB - Although some azo-carbazole derivatives attached on or doped into inert polymers are known to show photorefractive effect without external electric field, the origin of their asymmetric energy transfer in two-beam coupling experiments were unknown. We made the two-beam coupling experiment followed by sample translation and one-beam diffraction at 633 nm for thick films composed of 3-[(4 nitrophenyl)]azo-9H-carbazole-9-ethanol (NACzEtOH) and poly(methylmethacrylate), finding that photoinduced gratings grew in several minutes accompanied with phase displacement of the gratings, but the phase shift was not always synchronized with the refractive index modulation. We reformulated the Kogelnik's coupled-wave theory with strict energy conservation law for analysis. Comparison of the grating growth and erasure at 532 nm to Disperse Red 1 (DR1), the most well-known azo dye showed that the photoisomerization was dominant at this wavelength and that the azo-carbazole dyes were faster in response time and more resistive to erasure than DR1. PMID- 23033039 TI - Calculation of electromagnetic scattering by a large chiral sphere. AB - Expressions of scattering coefficients for calculating scattering by large chiral spheres are derived by using logarithmic derivatives and ratios of Riccati-Bessel functions. The improved expressions can be easily applied to the case of an arbitrarily shaped beam incidence. A simplified expression of the scattered field in the far field is obtained for the case of x-polarized plane-wave incidence. To verify the correctness and accuracy of the theory and codes, our results are compared with those in literature and those calculated by Mie theory. Radar cross sections of a large chiral sphere are numerically studied. It is found that the rainbow phenomenon of a chiral sphere is very different from that of an isotropic sphere. PMID- 23033040 TI - High-average-power and high-beam-quality Innoslab picosecond laser amplifier. AB - We demonstrated a laser-diode, end-pumped picosecond amplifier. With effective shaping of the seed laser, we achieved 73 W amplified laser output at the pump power of 255 W, and the optical-optical efficiency was about 28%. The beam propagation factors M(2) measured at the output power of 60 W in the horizontal direction and the vertical direction were 1.5 and 1.4, respectively. PMID- 23033041 TI - Influence of two typical defects on the near-field optical properties of multilayer dielectric compression gratings. AB - Internal electric-field enhancement is critical for the laser-induced damage properties of multilayer dielectric compression gratings (MDG) in high-energy laser systems. Due to the complex fabrication processes of MDGs, such as coating, interference lithography, etching, and cleaning, different kinds of defects in multilayers or profiles on MDG surfaces can't be practically avoided. Combined with a scanning electron microscope of some MDG samples, line-absence and added node seem to be two typical defects, according to which two defective MDG models are established, and numerical calculations are performed. From simulation results, the defect period and defect depth has little effect on the spectral response of the optical elements. However, they may produce large changes of internal electric-field distribution on the grating surface and even in multilayer structures, thus decreasing the damage threshold of MDG. To obtain a better understanding of the dependence of the internal electric-field enhancement on these defects, this work is focused on the near-field distributions of defective MDGs using the Fourier model method. PMID- 23033042 TI - Fiber-coupled ultraviolet planar laser-induced fluorescence for combustion diagnostics. AB - Multimode silica step-index optical fibers are examined for use in planar laser induced fluorescence (PLIF) for combustion diagnostics using ultraviolet (UV) laser sources. The multimode step-index fibers are characterized at UV wavelengths by examining their energy damage thresholds and solarization performance. The beam quality achievable with large clad step-index multimode fibers is also studied. Emphasis is placed on simultaneously achieving high output energy and beam quality (low output M(2)). The use of multimode fibers to deliver UV pulses at 283 nm for PLIF measurements of OH radicals in a Hencken burner is demonstrated. The fiber delivery capability of UV light will benefit combustion diagnostics in hostile environments, such as augmentor and combustor rigs. PMID- 23033043 TI - Identification and isolation of lantibiotics from culture: a bioorthogonal chemistry approach. AB - A distinguishing feature of the lantibiotic family of cyclic peptides is the presence of thioethers. Treatment of a lantibiotic with an alkaline solution at high pH gives rise to a beta-elimination reaction yielding the corresponding ring opened precursor, containing a dehydro-amino acid residue. We here reveal in a proof-of-concept study that a ring opened lantibiotic (mersacidin) can be captured for pull-down from a culture broth, subsequently released and identified by mass spectrometry. PMID- 23033044 TI - Science education reforms in the UK. AB - As children return to school at the end of the summer in the UK, planned reforms aim to increase their science and maths literacy. A comprehensive foundation in these essential subjects is necessary to ensure that the UK remains at the forefront of science and technology for decades to come. PMID- 23033045 TI - Pathway discovery: the road to Ras and MAP kinase. PMID- 23033046 TI - Integrating insulin secretion and ER stress in pancreatic beta-cells. AB - After food consumption, insulin-secreting pancreatic beta-cells detect increased glucose and incretin hormones, and respond by releasing insulin. Wolfram syndrome 1, a protein that mitigates endoplasmic reticulum (ER) stress, is now shown to regulate insulin synthesis and release--revealing a molecular point of convergence between the ER stress and insulin release pathways. PMID- 23033047 TI - Unanchoring integrins in focal adhesions. AB - Focal adhesions are large structures through which integrins and scaffold proteins link the actin cytoskeleton to the extracellular matrix. A detailed analysis of integrin dynamics now indicates that focal-adhesion-associated integrins constantly switch between active and immobilized, and unbound and free diffusing states, with different fibronectin-binding integrin heterodimers showing distinct focal-adhesion dynamics. PMID- 23033048 TI - Connecting membrane traffic to ESCRT and the final cut. AB - The ESCRT (endosomal sorting complex required for transport) machinery is responsible for scission of the cytokinetic bridge that connects daughter cells at the end of mitosis. Specific endosomes are now found to mediate local bridge constriction and actin clearance in human cells, which contribute to the recruitment of ESCRT components at the abscission site. PMID- 23033049 TI - Profilin phosphorylation as a VEGFR effector in angiogenesis. AB - Vascular endothelial growth factor (VEGF) signalling induces embryonic vascular development and angiogenesis in adult tissues. Direct phosphorylation of the actin-binding protein profilin by VEGF receptors is now shown to increase its affinity for actin, and to be essential for adult but not embryonic arteriogenesis. PMID- 23033050 TI - A potential link between obesity and neural stem cell dysfunction. AB - Given the important role of the hypothalamus in regulating feeding and metabolism, there has been considerable interest in a possible function for hypothalamic stem cells in modulating body weight in health and disease. Mice given a high-fat diet develop inflammation in the hypothalamus and lose key types of neurons. It now appears that another effect of a high-fat diet is to reduce neural stem cell numbers, as well as their ability to make new neurons--effects that are associated with activation of the IKKbeta/NF-kappaB pathway--thereby exacerbating the primary loss of neurons and resulting in altered feeding behaviour and obesity. PMID- 23033055 TI - Assessment of quality of life with the multiple system atrophy health-related quality of life scale. AB - BACKGROUND: Multiple system atrophy (MSA) has considerable effect on health related quality of life (Hr-QoL). The aim of this study was to prospectively evaluate Hr-QoL by using the MSA health-related Quality of Life (MSA-QoL) scale. METHODS: Evaluation of 100 patients at baseline and after a mean follow-up of 11.5 months was performed. Assessment was made of potential associations with established markers of disease progression. Calculation was performed of sample size estimates for various effect sizes. RESULTS: MSA-QoL scale scores were less responsive to change than Unified MSA Rating Scale (UMSARS) scores. Responsiveness was largely improved and reasonable sample-size estimates were obtained when limiting the analysis to items with significant change over time. CONCLUSIONS: The UMSARS remains the "gold standard" for disease modifying/neuroprotection trials. An MSA-QoL Change Scale, based on the most responsive items, may become a valuable tool. PMID- 23033056 TI - Self-weaving sulfur-carbon composite cathodes for high rate lithium-sulfur batteries. AB - Realization of a ubiquitous clean energy future depends critically on the efficient storage and utilization of renewable energies. Lithium-ion batteries are appealing in this regard, but low-cost, abundant, safe, high energy-density electrode materials need to be developed to adopt them. Here we present a sulfur multi-wall carbon nanotube (MWCNT) composite cathode with high-rate cyclability by a facile binder/current collector-free fabrication process. The composite cathode exhibits high capacities of 1352 mAh g(-1) at 1C rate and 1012 mAh g(-1) at 4C rate. Due to the self-weaving behavior of MWCNTs, extra cell components such as binders and current collectors are rendered unnecessary, thereby streamlining the electrode manufacturing process and decreasing the cell weight. While the highly conductive MWCNTs improve the active material utilization at high rates, the absorption ability of the cathode framework localizes the electrolyte and suppresses the migration of soluble polysulfides. The cathode design and facile synthesis enhance the feasibility of practical high rate Li-S batteries. PMID- 23033057 TI - Anxiety disorders and the quality of relationships with friends, relatives, and romantic partners. AB - OBJECTIVES: Though research suggests support for the association between marital quality and anxiety disorders, less is known about relationship quality with relatives and friends and anxiety disorders. METHOD: Using data from the Collaborative Psychiatric Epidemiology Surveys (n = 9912; mean age 44.8; 52.2% female), the association between relationship quality with relatives, friends, and romantic partners and anxiety disorders is examined for those who are divorced, single, or married. RESULTS: For those who are single or divorced, relationship quality with relatives and friends was associated with many anxiety disorders including agoraphobia, social phobia, and generalized anxiety disorder. For those who are married, relationship quality with relatives and partners was associated with generalized anxiety disorder and posttraumatic stress disorder. CONCLUSION: Given that those with anxiety disorders have higher rates of divorce and are more likely to be single, examining the relationship quality with relatives and friends, in addition to romantic partners, may be important for understanding the onset and course of anxiety disorders. PMID- 23033059 TI - Electron transfer in dye-sensitised semiconductors modified with molecular cobalt catalysts: photoreduction of aqueous protons. AB - A visible-light driven H(2) evolution system comprising of a Ru(II) dye (RuP) and Co(III) proton reduction catalysts (CoP) immobilised on TiO(2) nanoparticles and mesoporous films is presented. The heterogeneous system evolves H(2) efficiently during visible-light irradiation in a pH-neutral aqueous solution at 25 degrees C in the presence of a hole scavenger. Photodegradation of the self-assembled system occurs at the ligand framework of CoP, which can be readily repaired by addition of fresh ligand, resulting in turnover numbers above 300 mol H(2) (mol CoP)(-1) and above 200,000 mol H(2) (mol TiO(2) nanoparticles)(-1) in water. Our studies support that a molecular Co species, rather than metallic Co or a Co oxide precipitate, is responsible for H(2) formation on TiO(2). Electron transfer in this system was studied by transient absorption spectroscopy and time correlated single photon counting techniques. Essentially quantitative electron injection takes place from RuP into TiO(2) in approximately 180 ps. Thereby, upon dye regeneration by the sacrificial electron donor, a long-lived TiO(2) conduction band electron is formed with a half-lifetime of approximately 0.8 s. Electron transfer from the TiO(2) conduction band to the CoP catalysts occurs quantitatively on a 10 MUs timescale and is about a hundred times faster than charge-recombination with the oxidised RuP. This study provides a benchmark for future investigations in photocatalytic fuel generation with molecular catalysts integrated in semiconductors. PMID- 23033058 TI - Regional differences in the developmental trajectory of lateralization of the language network. AB - The timing and developmental factors underlying the establishment of language dominance are poorly understood. We investigated the degree of lateralization of traditional frontotemporal and modulatory prefrontal-cerebellar regions of the distributed language network in children (n = 57) ages 4 to 12--a critical period for language consolidation. We examined the relationship between the strength of language lateralization and neuropsychological measures and task performance. The fundamental language network is established by four with ongoing maturation of language functions as evidenced by strengthening of lateralization in the traditional frontotemporal language regions; temporal regions were strongly and consistently lateralized by age seven, while frontal regions had greater variability and were less strongly lateralized through age 10. In contrast, the modulatory prefrontal-cerebellar regions were the least strongly lateralized and degree of lateralization was not associated with age. Stronger core language skills were significantly correlated with greater right lateralization in the cerebellum. PMID- 23033060 TI - A new family of halogen-chelated Hoveyda-Grubbs-type metathesis catalysts. AB - Coordination, not insertion: New ruthenium benzylidenes with a chelating halogen atom were easily prepared and showed excellent stability and activity as metathesis catalysts (see figure). Structure-activity studies reveal that strength of the ruthenium-halogen interaction can be tuned across a wide range to set up a family of latent to active catalysts. PMID- 23033061 TI - Mechanical and electrical properties of epitaxial Si nanowires grown by pulsed laser deposition. AB - We report on the elastic and piezoresistive properties of individual epitaxial Si NWs grown on n-doped Si(111) by pulsed laser deposition. Using scanning probe microscopy, we obtained a Young's modulus between 82 and 900 GPa for the nanowires, unaffected by the nanowire shape. A relative resistivity change is observed in the prestrained (curved) Si-NWs, which we attribute to a large piezoresistance coefficient in the NW along its axis. Assuming that for the bent NWs the effect of longitudinal stress on resistivity is compensated, the piezoresistance coefficient originating in the shear strain alone, we found a piezoresistance gauge factor (GF) of 600, which is close to the values reported in literature for Si-NWs. PMID- 23033062 TI - Synthesis and photophysical properties of phosphorus(V) porphyrins functionalized with axial carbazolylvinylnaphthalimides. AB - We have synthesized new D-A-D type phosphorus(V) porphyrin derivatives and functionalized with axial carbazolylvinylnaphthalimide units. The absorption bands of the obtained phosphorus(V) porphyrins were in the range 250-640 nm with high molar absorption coefficients, meaning strong light-harvesting abilities. Notably, it is found that the devices based on phosphorus(V) porphyrins with a configuration structure of [ITO/PEDOT : PSS/organic active film/LiF/Al] give an incident-photon-to-current conversion efficiency (IPCE) response. The maximal IPCE value reaches 2.76% for the device based on compound , which is much higher than that of 0.20% for compound . The reason might be due to the low oxidation potential and the strong light-harvesting ability of the enlarged conjugation of the axial units in compound . Therefore, we deduced that photo-induced electron transfer happened in phosphorus(V) porphyrins bearing axial conjugated donor units, which would make them good candidates for photovoltaic materials that could be applied in solar cells. PMID- 23033063 TI - Catalyzed hydrogenation of condensed three-ring arenes and their N-heteroaromatic analogues by a bis(dihydrogen) ruthenium complex. AB - A series of anthracene and acridine derivatives were hydrogenated under mild reaction conditions (80 degrees C, 3 bar of H(2)) using the bis(dihydrogen) complex [RuH(2)(eta(2)-H(2))(2){P(C(6)H(11))(3)}(2)] (1) as a catalyst precursor. The influence of a methyl substituent on the substrate was studied. In all our systems, hydrogenation was only observed at the external rings leading to the corresponding 4H- or 8H-derivatives of anthracene and acridine. Three complexes resulting from the eta(4)(C,C)-coordination of the substrate to the unsaturated fragment [RuH(2){P(C(6)H(11))(3)}(2)] were characterized. In the case of 9-methyl acridine, the corresponding complex [RuH(2)(eta(4) C(14)H(11)N){P(C(6)H(11))(3)}(2)] (4) turned out to be an active catalyst precursor leading to 1,2,3,4,5,6,7,8-octahydro-9-methylacridine as the sole product after 24 h. Regeneration of 1 from 4 supports the role of complex 4 in the catalytic cycle. Three hydrogenated products, 1,2,3,4-tetrahydroanthracene (4H-Anth), 1,2,3,4-tetrahydro-9-methylanthracene (4H-9-Me-Anth) and 1,2,3,4 tetrahydroacridine (4H-Acr), were characterized by X-ray diffraction. PMID- 23033064 TI - Selective determination of cysteine using BSA-stabilized gold nanoclusters with red emission. AB - Gold nanoclusters (AuNCs) were synthesized by a macromolecules template using bovine serum albumin (BSA) as stabilizer which can emit red photoluminescence under illumination of ultraviolet light. The fluorescence intensity of AuNCs enhanced through decreasing the surface defects of AuNCs modified with cysteine, herein we present a novel fluorometry for determination of trace cysteine. This method with a wider linear range from 2.0 to 800 nmol mL(-1), higher sensitivity (detection limit was 1.2 nmol mL(-1)) and better selectivity has been utilized to determine cysteine content in real samples, and the results were in a good agreement with those determined by electrochemical biosensor. At the same time, the structures of AuNCs and AuNCs-cysteine were characterized by Fourier transform infrared spectroscopy (FTIR) and high resolution transmission electron microscopy (HRTEM) and the mechanism of the proposed assay for the detection of cysteine has been discussed. PMID- 23033065 TI - Accurate model-based reconstruction algorithm for three-dimensional optoacoustic tomography. AB - In many practical optoacoustic imaging implementations, dimensionality of the tomographic problem is commonly reduced into two dimensions or 1-D scanning geometries in order to simplify technical implementation, improve imaging speed or increase signal-to-noise ratio. However, this usually comes at a cost of significantly reduced quality of the tomographic data, out-of-plane image artifacts, and overall loss of image contrast and spatial resolution. Quantitative optoacoustic image reconstruction implies therefore collection of point 3-D (volumetric) data from as many locations around the object as possible. Here, we propose and validate an accurate model-based inversion algorithm for 3-D optoacoustic image reconstruction. Superior performance versus commonly-used backprojection inversion algorithms is showcased by numerical simulations and phantom experiments. PMID- 23033066 TI - Risk and protective factors for recidivism among juveniles who have offended sexually. AB - Literature on risk factors for recidivism among juveniles who have sexually offended (JSOs) is limited. In addition, there have been no studies published concerning protective factors among this population. The purpose of this study was to examine the relationship of risk and protective factors to sexual and nonsexual recidivism among a sample of 193 male JSOs (mean age = 15.26). Youths were followed for an average of 7.24 years following discharge from a residential sex offender treatment program. The risk factor opportunities to reoffend, as coded based on the Estimate of Risk of Adolescent Sexual Offense Recidivism, was associated with sexual recidivism. Several risk factors (e.g., prior offending; peer delinquency) were associated with nonsexual recidivism. No protective factors examined were associated with sexual recidivism, although strong attachments and bonds as measured by the Structured Assessment of Violence Risk in Youth was negatively related to nonsexual recidivism. These findings indicate that risk factors for nonsexual recidivism may be consistent across both general adolescent offender populations and JSOs, but that there may be distinct protective factors that apply to sexual recidivism among JSOs. Results also indicate important needs for further research on risk factors, protective factors, and risk management strategies for JSOs. PMID- 23033067 TI - Multichannel cavity optomechanics for all-optical amplification of radio frequency signals. AB - Optomechanical phenomena in photonic devices provide a new means of light-light interaction mediated by optical force actuated mechanical motion. In cavity optomechanics, this interaction can be enhanced significantly to achieve strong interaction between optical signals in chip-scale systems, enabling all-optical signal processing without resorting to electro-optical conversion or nonlinear materials. However, current implementation of cavity optomechanics achieves both excitation and detection only in a narrow band at the cavity resonance. This bandwidth limitation would hinder the prospect of integrating cavity optomechanical devices in broadband photonic systems. Here we demonstrate a new configuration of cavity optomechanics that includes two separate optical channels and allows broadband readout of optomechanical effects. The optomechanical interaction achieved in this device can induce strong but controllable nonlinear effects, which can completely dominate the device's intrinsic mechanical properties. Utilizing the device's strong optomechanical interaction and its multichannel configuration, we further demonstrate all-optical, wavelength multiplexed amplification of radio-frequency signals. PMID- 23033068 TI - Quantum correlations with no causal order. AB - The idea that events obey a definite causal order is deeply rooted in our understanding of the world and at the basis of the very notion of time. But where does causal order come from, and is it a necessary property of nature? Here, we address these questions from the standpoint of quantum mechanics in a new framework for multipartite correlations that does not assume a pre-defined global causal structure but only the validity of quantum mechanics locally. All known situations that respect causal order, including space-like and time-like separated experiments, are captured by this framework in a unified way. Surprisingly, we find correlations that cannot be understood in terms of definite causal order. These correlations violate a 'causal inequality' that is satisfied by all space-like and time-like correlations. We further show that in a classical limit causal order always arises, which suggests that space-time may emerge from a more fundamental structure in a quantum-to-classical transition. PMID- 23033069 TI - Protein encapsulation within synthetic molecular hosts. AB - Protein encapsulation has long attracted many chemists and biologists because of its potential to control the structure and functions of proteins, but has been a daunting challenge because of their incommensurably larger size compared with common synthetic hosts. Here we report the encapsulation of a small protein, ubiquitin, within giant coordination cages. The protein was attached to one bidentate ligand and, upon addition of Pd(II) ions (M) and additional ligands (L), M(12)L(24) coordination nanocages self-assembled around the protein. Because of the well-defined host framework, the protein-encapsulated structure could be analysed by NMR spectroscopy, ultracentrifugation and X-ray crystallography. PMID- 23033070 TI - Sound-induced length changes in outer hair cell stereocilia. AB - Hearing relies on mechanical stimulation of stereocilia bundles on the sensory cells of the inner ear. When sound hits the ear, each stereocilium pivots about a neck-like taper near their base. More than three decades of research have established that sideways deflection of stereocilia is essential for converting mechanical stimuli into electrical signals. Here we show that mammalian outer hair cell stereocilia not only move sideways but also change length during sound stimulation. Currents that enter stereocilia through mechanically sensitive ion channels control the magnitude of both length changes and bundle deflections in a reciprocal manner: the smaller the length change, the larger is the bundle deflection. Thus, the transduction current is important for maintaining the resting mechanical properties of stereocilia. Hair cell stimulation is most effective when bundles are in a state that ensures minimal length change. PMID- 23033072 TI - Top-down fabricated silicon nanowires under tensile elastic strain up to 4.5%. AB - Strained Si nanowires are among the most promising transistor structures for implementation in very large-scale integration due to of their superior electrostatic control and enhanced transport properties. Realizing even higher strain levels within such nanowires are thus one of the current challenges in microelectronics. Here we achieve 4.5% of elastic strain (7.6 GPa uniaxial tensile stress) in 30 nm wide Si nanowires, which considerably exceeds the limit that can be obtained using SiGe-based virtual substrates. Our approach is based on strain accumulation mechanisms in suspended dumbbell-shaped bridges patterned on strained Si-on-insulator, and is compatible with complementary metal oxide semiconductor fabrication. Potentially, this method can be applied to any tensile prestrained layer, provided the layer can be released from the substrate, enabling the fabrication of a variety of strained semiconductors with unique properties for applications in nanoelectronics, photonics and photovoltaics. This method also opens up opportunities for research on strained materials. PMID- 23033073 TI - Linear magnetoresistance due to multiple-electron scattering by low-mobility islands in an inhomogeneous conductor. AB - Linear transverse magnetoresistance is commonly observed in many material systems including semimetals, narrow band-gap semiconductors, multi-layer graphene and topological insulators. It can originate in an inhomogeneous conductor from distortions in the current paths induced by macroscopic spatial fluctuations in the carrier mobility and it has been explained using a phenomenological semiclassical random resistor network model. However, the link between the linear magnetoresistance and the microscopic nature of the electron dynamics remains unknown. Here we demonstrate how the linear magnetoresistance arises from the stochastic behaviour of the electronic cycloidal trajectories around low-mobility islands in high-mobility inhomogeneous conductors and that this process is only weakly affected by the applied electric field strength. Also, we establish a quantitative link between the island morphology and the strength of linear magnetoresistance of relevance for future applications. PMID- 23033071 TI - Robust photoregulation of GABA(A) receptors by allosteric modulation with a propofol analogue. AB - Photochemical switches represent a powerful method for improving pharmacological therapies and controlling cellular physiology. Here we report the photoregulation of GABA(A) receptors (GABA(A)Rs) by a derivative of propofol (2,6 diisopropylphenol), a GABA(A)R allosteric modulator, which we have modified to contain photoisomerizable azobenzene. Using alpha(1)beta(2)gamma(2) GABA(A)Rs expressed in Xenopus laevis oocytes and native GABA(A)Rs of isolated retinal ganglion cells, we show that the trans-azobenzene isomer of the new compound (trans-MPC088), generated by visible light (wavelengths ~440 nm), potentiates the gamma-aminobutyric acid-elicited response and, at higher concentrations, directly activates the receptors. cis-MPC088, generated from trans-MPC088 by ultraviolet light (~365 nm), produces little, if any, receptor potentiation/activation. In cerebellar slices, MPC088 co-applied with gamma-aminobutyric acid affords bidirectional photomodulation of Purkinje cell membrane current and spike-firing rate. The findings demonstrate photocontrol of GABA(A)Rs by an allosteric ligand, and open new avenues for fundamental and clinically oriented research on GABA(A)Rs, a major class of neurotransmitter receptors in the central nervous system. PMID- 23033074 TI - Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus. AB - Thymocyte trafficking has an important role in thymic selection. Here we show that the Hippo homologue Mst1 is required for thymocyte migration and antigen recognition by LFA-1 and ICAM-1 within the medulla. Using two-photon imaging of thymic tissues, we found that highly motile mature thymocytes arrest and are activated in the vicinity of rare populations of Aire(+) ICAM-1(hi) medullary thymic epithelia in a negatively selecting environment. Notably, Mst1 deficiency or blocking the cell adhesion molecules LFA-1 and ICAM-1 results in inefficient migration and antigen recognition of CD4(+) thymocytes within the medulla. Consistent with these defects, thymocyte selection is impaired in Mst1(-/-) mice, which display T cell-dependent inflammatory infiltrates in multiple organs and develop autoantibodies. Our results suggest that Mst1 has a key role in regulating thymocyte self-antigen recognition in the medulla. PMID- 23033075 TI - Cadherin selectivity filter regulates endothelial sieving properties. AB - The molecular basis of endothelial protein sieving, the critical vascular barrier function that restricts flow of large plasma proteins into tissues while allowing small molecules and water to pass, is not understood. Here, we address this issue using a novel assay to detect macromolecular penetrance at microdomains of endothelial adherens junctions. Adherens junctions, as detected by cadherin-GFP expression, were distributed in the cell perimeter as high- or low-density segments. Low but not high-density segments permitted penetrance of a 70-kDa fluorescent dextran, a molecule of equivalent size to albumin. Expression of a cadherin mutant that abrogates strand-swap adhesive binding in the cadherin EC1 ectodomain, or alternatively of an alpha-actinin-1 mutant that inhibits F-actin bundling, increased both cadherin mobility and 70 kDa dextran penetrance at high density segments. These findings suggest that adhesive interactions in the cadherin EC1 domain, which underlie adherens junction structure, are critical determinants of endothelial macromolecular sieving. PMID- 23033076 TI - Ultrafast optical demagnetization manipulates nanoscale spin structure in domain walls. AB - During ultrafast demagnetization of a magnetically ordered solid, angular momentum has to be transferred between the spins, electrons, and phonons in the system on femto- and picosecond timescales. Although the intrinsic spin-transfer mechanisms are intensely debated, additional extrinsic mechanisms arising due to nanoscale heterogeneity have only recently entered the discussion. Here we use femtosecond X-ray pulses from a free-electron laser to study thin film samples with magnetic domain patterns. We observe an infrared-pump-induced change of the spin structure within the domain walls on the sub-picosecond timescale. This domain-topography-dependent contribution connects the intrinsic demagnetization process in each domain with spin-transport processes across the domain walls, demonstrating the importance of spin-dependent electron transport between differently magnetized regions as an ultrafast demagnetization channel. This pathway exists independent from structural inhomogeneities such as chemical interfaces, and gives rise to an ultrafast spatially varying response to optical pump pulses. PMID- 23033077 TI - Highly transparent nonvolatile resistive memory devices from silicon oxide and graphene. AB - Transparent electronic memory would be useful in integrated transparent electronics. However, achieving such transparency produces limits in material composition, and hence, hinders processing and device performance. Here we present a route to fabricate highly transparent memory using SiO(x) as the active material and indium tin oxide or graphene as the electrodes. The two-terminal, nonvolatile resistive memory can also be configured in crossbar arrays on glass or flexible transparent platforms. The filamentary conduction in silicon channels generated in situ in the SiO(x) maintains the current level as the device size decreases, underscoring their potential for high-density memory applications, and as they are two-terminal based, transitions to three-dimensional memory packages are conceivable. As glass is becoming one of the mainstays of building construction materials, and conductive displays are essential in modern handheld devices, to have increased functionality in form-fitting packages is advantageous. PMID- 23033078 TI - Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing. AB - Voltage-gated sodium channels are vital membrane proteins essential for electrical signalling; in humans, they are key targets for the development of pharmaceutical drugs. Here we report the crystal structure of an open-channel conformation of NavMs, the bacterial channel pore from the marine bacterium Magnetococcus sp. (strain MC-1). It differs from the recently published crystal structure of a closed form of a related bacterial sodium channel (NavAb) by having its internal cavity accessible to the cytoplasmic surface as a result of a bend/rotation about a central residue in the carboxy-terminal transmembrane segment. This produces an open activation gate of sufficient diameter to allow hydrated sodium ions to pass through. Comparison of the open and closed structures provides new insight into the features of the functional states present in the activation cycles of sodium channels and the mechanism of channel opening and closing. PMID- 23033079 TI - Magnesium-free self-assembly of multi-layer DNA objects. AB - Molecular self-assembly with DNA offers a route for building user-defined nanoscale objects, but an apparent requirement for magnesium in solution has limited the range of conditions for which practical utility of such objects may be achieved. Here we report conditions for assembling templated multi-layer DNA objects in the presence of monovalent ions, showing that neither divalent cations in general or magnesium in particular are essential ingredients for the successful assembly of such objects. The percentage of DNA strands in an object that do not form thermally stable double-helical DNA domains (T(m)>45 degrees C) with the template molecule correlated with the sodium requirements for obtaining folded objects. Minimizing the fraction of such weakly binding strands by rational design choices enhanced the yield of folding. The results support the view that DNA-based nanodevices may be designed and produced for a variety of target environments. PMID- 23033080 TI - Arrays of giant octagonal and square cylinders by liquid crystalline self assembly of X-shaped polyphilic molecules. AB - Nanopatterning by molecular self-assembly has been a topic of intense research in pursuit of 'bottom-up' methods of generating structures for use in nanotechnology. The systems most widely studied have been two- and three dimensional morphologies of block copolymers. However, T- and X-shaped polyphilic liquid crystals have recently been shown to have great potential for generating soft honeycomb-like structures, surpassing those of polymers in both complexity and degree of order. The cell cross-section of the liquid crystals honeycombs has so far been limited by small molecular size. Here we overcome this limitation by exploiting the inability of the polyphiles to simultaneously achieve optimal packing and complete nanophase separation. This frustration results in a two dimensional periodic honeycomb consisting of giant octagonal and square cylinders with circumferences of 12 and 8 molecules, respectively. In addition to forming large cells, the two-molecule-long bendy walls give this structure extra versatility and stability. PMID- 23033081 TI - Food web expansion and contraction in response to changing environmental conditions. AB - Macroscopic ecosystem properties, such as major material pathways and community biomass structure, underlie the ecosystem services on which humans rely. While ecologists have long sought to identify the determinants of the trophic height of food webs (food chain length), it is somewhat surprising how little research effort is invested in understanding changes among other food web properties across environmental conditions. Here we theoretically and empirically show how a suite of fundamental macroscopic food web structures respond, in concert, to changes in habitat accessibility using post-glacial lakes as model ecosystems. We argue that as resource accessibility increases in coupled food webs, food chain length contracts (that is, reduced predator trophic position), habitat coupling expands (that is, increasingly coupled macrohabitats) and biomass pyramid structure becomes more top heavy. Our results further support an emerging theoretical view of flexible food webs that provides a foundation for generally understanding ecosystem responses to changing environmental conditions. PMID- 23033082 TI - Cobweb-weaving spiders produce different attachment discs for locomotion and prey capture. AB - Spiders' cobwebs ensnare both walking and flying prey. While the scaffolding silk can entangle flying insects, gumfoot silk threads pull walking prey off the ground and into the web. Therefore, scaffolding silk needs to withstand the impact of the prey, whereas gumfoot silk needs to easily detach from the substrate when contacted by prey. Here we show that spiders accomplish these divergent demands by creating attachment discs of two distinct architectures using the same pyriform silk. A 'staple-pin' architecture firmly attaches the scaffolding silk to the substrate and a previously unknown 'dendritic' architecture weakly attaches the gumfoot silk to the substrate. Gumfoot discs adhere weakly, triggering a spring-loaded trap, while the strong adhesion of scaffolding discs compels the scaffolding threads to break instead of detaching. We describe the differences in adhesion for these two architectures using tape peeling models and design synthetic attachments that reveal important design principles for controlled adhesion. PMID- 23033084 TI - Multiwavelength-integrated local model fitting method for interferometric surface profiling. AB - The local model fitting (LMF) method is a useful single-shot surface profiling algorithm that features fast measurement speed and robustness against vibration. However, the measurement range of the LMF method (i.e., measurable height difference between two neighboring pixels) is limited up to a quarter of the light source wavelength. To cope with this problem, the multiwavelength-matched LMF(MM-LMF) method was proposed, where the plain LMF method is first applied individually to interference images obtained from multiple light sources with different wavelengths, and then the LMF solutions are matched to obtain a range extended solution. Although the MM-LMF method was shown to provide high measurement accuracy under moderate noise, phase unwrapping errors can occur if individual LMF solutions are erroneous. In this paper, we propose the multiwavelength-integrated LMF (MI-LMF) method, which directly computes a range extended solution from multiple interference images in an integrated way. The effectiveness of the proposed MI-LMF method is demonstrated through simulations and actual experiments. PMID- 23033083 TI - Monosynaptic inputs to new neurons in the dentate gyrus. AB - Adult hippocampal neurogenesis is considered important for cognition. The integration of newborn dentate gyrus granule cells into the existing network is regulated by afferent neuronal activity of unspecified origin. Here we combine rabies virus-mediated retrograde tracing with retroviral labelling of new granule cells (21, 30, 60, 90 days after injection) to selectively identify and quantify their monosynaptic inputs in vivo. Our results show that newborn granule cells receive afferents from intra-hippocampal cells (interneurons, mossy cells, area CA3 and transiently, mature granule cells) and septal cholinergic cells. Input from distal cortex (perirhinal (PRH) and lateral entorhinal cortex (LEC)) is sparse 21 days after injection and increases over time. Patch-clamp recordings support innervation by the LEC rather than from the medial entorhinal cortex. Mice with excitotoxic PRH/LEC lesions exhibit deficits in pattern separation but not in water maze learning. Thus, PRH/LEC input is an important functional component of new dentate gyrus neuron circuitry. PMID- 23033085 TI - Polarization-induced noise in resonator fiber optic gyro. AB - An optical fiber ring resonator (OFRR) is the key rotation-sensing element in the resonator fiber optic gyro (R-FOG). In comparing between different OFRR types, a simulation model that can apply to all cases is set up. Both the polarization crosstalk and polarization-dependent loss in the coupler are fully investigated for the first time to our knowledge. Three different splicing schemes, including a single 0 degrees , a single 90 degrees , and twin 90 degrees polarization axis rotated spices, are compared. Two general configurations of the OFRR are considered. One is a reflector OFRR, the other is a transmitter OFRR. This leads to six different OFRR types. The output stability of the R-FOG with six OFRR types is fully investigated theoretically and experimentally. Additional Kerr noise due to the polarization fluctuation is discovered. The OFRR with twin 90 degrees polarization axis rotated splices is of lower additional Kerr noise and hence has better temperature stability. As the coupler is polarization dependent, we notice that in a reflector OFRR, the straight-through component of the output lightwave, which can be isolated by a transmitter configuration, would produce large polarization fluctuation-induced noise. The experimental results show that the bias stability of the transmitter OFRR is 8 times improved over that of the reflector OFRR, which is in accord with the theoretical analysis. By the analysis and experiments above, it is reasonable to make a conclusion that an R-FOG based on a transmitter OFRR with twin 90 degrees polarization axis rotated splices is of better temperature stability and smaller additional Kerr effect noise. PMID- 23033086 TI - Using adaptive weighted least squares approximation for coupling thermal and optical simulation. AB - Thermo-optical simulation is a mandatory enhancement of classical ray tracing, since nowadays many fields in the branch of optical technology have to deal with thermal effects. This paper discusses an approach for coupling the finite element method (FEM) and ray tracing simulation by processing finite element (FE) data using scattered data approximation techniques, particularly with an adaptive weighted least squares approximation algorithm in two dimensions. The validation of the implemented interface is being conducted by comparing approximated data to analytical functions. Finally, FEM data are being processed by the developed algorithm to demonstrate the applicability on appropriate problems. PMID- 23033087 TI - Arbitrary scanning of the Airy beams using additional phase grating with cubic phase mask. AB - To controllably deflect the Airy beam in a wide range dynamic, the method of combining the classical Airy cubic phase with a diffraction blazed grating phase was adopted in this paper. By dynamically adjusting the grating parameters, the transverse self-accelerating Airy beam allows arbitrary deflection, and the deflected position can be controlled precisely. The mathematical model of the Airy beam optical field distributions generated by the combined phase patterns were proposed to explain the feasibility. Its correctness was ultimately demonstrated by the experimental results. It is significant to use this method for the Airy beam deflection control in high-precision closed-loop aiming systems. PMID- 23033088 TI - Visible light Laue diffraction from woodpile photonic crystals. AB - Bragg diffraction is often used as a tool to assess the structural quality of two dimensional and three-dimensional (3D) photonic crystals. However, direct conclusions from the Laue diagrams to the underlying crystals structure cannot be drawn, as multiple scattering due to the high index contrast takes place. Here we systematically study the scattering of visible light by 3D woodpile photonic crystals with varying internal refractive index contrast Deltan, to determine the limits of the single (kinematic) scattering approach. We aim to describe the intensity distribution of diffracting Bragg peaks with analytic expressions similarly to x-ray scattering at electronic crystals. Measured scattering curves of selected Bragg reflections are classified in terms of Deltan. We find that the kinematic approach describes the shape and intensity distribution of experimental scattering curves in acceptable accuracy as long as Deltan<0.15. The transition between single and multiple scattering is observed for Deltan~0.16-0.25 before multiple scattering dominates for larger Deltan. The classification of the scattering regimes is confirmed by simulations in terms of numerical solution of Maxwell's equations. PMID- 23033089 TI - Three-dimensional terahertz computed tomography of human bones. AB - Three-dimensional terahertz computed tomography has been used to investigate dried human bones such as a lumbar vertebra, a coxal bone, and a skull, with a direct comparison with standard radiography. In spite of lower spatial resolution compared with x-ray, terahertz imaging clearly discerns a compact bone from a spongy one, with strong terahertz absorption as shown by additional terahertz time-domain transmission spectroscopy. PMID- 23033090 TI - Using a fuzzy system in the study of the luminescence and potency of neodymium ions. AB - The processes of energy transfer and diffusion of photons emitted by Nd(3+) ions embedded into a glass sample were investigated. The luminescence resolved in space allowed the observation of the photons' spatial distribution. In this paper, we propose a fuzzy mathematical model that permits carrying out calculations based on the neighborhood luminescence intensity of the excitation spot laser. This proposed model differs from other well-known ones in the literature because it shows clearly the luminescence intensity profile on the sample surface. PMID- 23033091 TI - Order-of-scattering point spread and modulation transfer functions for natural waters. AB - The point spread and modulation transfer functions for natural waters are derived using the small-angle approximation to radiative transfer theory. The functional forms are expanded into a summation of terms that represent each order-of scattering contribution to the total. The beam spread function is shown to be a product of an angle function that depends only on the phase function of the medium and a weighting factor that depends only on the optical properties and depth. The modulation transfer function is similarly shown as a product of a function depending only on the spatial frequency and a weighting function. These results are compared with Monte Carlo calculations using two different phase functions, with excellent agreement. The results suggest the small-angle approximation to be valid over a much larger angular range than previously thought. PMID- 23033093 TI - Influence of composition and seed dimension on the structure and laser damage of nodular defects in HfO2/SiO2 high reflectors. AB - Seeds are the sources for forming nodular defects that largely limit the improvement of laser-induced damage threshold of 1omega laser mirrors in the nanosecond pulse regime. To shed more light of the composition and sizes of seeds on the associated structure of nodular defects and laser damage sensitivity, nodular defects were generated in 1064 nm HfO(2)/SiO(2) high reflectors with different sizes of absorbing Au and nonabsorbing SiO(2) nanoparticles located on the surfaces of substrates. The width dimensions, inner structures, and damage morphologies of nodular defects were characterized by an atomic force microscope, a field emission scanning electron microscope, and a focused ion beam. It was found that the composition and size both influenced the structure and the laser damage of nodular defects. The width of nodules from SiO(2) seeds were larger than that formed by the same size of Au seed. A nodule grown from a small seed generally tends to have a continuous and stable boundary. The ejection fluences of nodules generated from different size absorbing Au and nonabsorbing SiO(2) seeds were totally different. The results were interpreted from the aspects of absorption cross sections of seeds and mechanical stability of nodular structures. PMID- 23033092 TI - Thermal luminescence spectroscopy chemical imaging sensor. AB - The authors present a pseudo-active chemical imaging sensor model embodying irradiative transient heating, temperature nonequilibrium thermal luminescence spectroscopy, differential hyperspectral imaging, and artificial neural network technologies integrated together. We elaborate on various optimizations, simulations, and animations of the integrated sensor design and apply it to the terrestrial chemical contamination problem, where the interstitial contaminant compounds of detection interest (analytes) comprise liquid chemical warfare agents, their various derivative condensed phase compounds, and other material of a life-threatening nature. The sensor must measure and process a dynamic pattern of absorptive-emissive middle infrared molecular signature spectra of subject analytes to perform its chemical imaging and standoff detection functions successfully. PMID- 23033094 TI - Mid-infrared optical properties of thin films of aluminum oxide, titanium dioxide, silicon dioxide, aluminum nitride, and silicon nitride. AB - The complex refractive index components, n and k, have been studied for thin films of several common dielectric materials with a low to medium refractive index as functions of wavelength and stoichiometry for mid-infrared (MIR) wavelengths within the range 1.54-14.29 MUm (700-6500 cm(-1)). The materials silicon oxide, silicon nitride, aluminum oxide, aluminum nitride, and titanium oxide are prepared using room temperature reactive sputter deposition and are characterized using MIR variable angle spectroscopic ellipsometry. The investigation shows how sensitive the refractive index functions are to the O2 and N2 flow rates, and for which growth conditions the materials deposit homogeneously. It also allows conclusions to be drawn on the degree of amorphousness and roughness. To facilitate comparison of the materials deposited in this work with others, the index of refraction was also determined and provided for the near-IR and visible ranges of the spectrum. The results presented here should serve as a useful information base for designing optical coatings for the MIR part of the electromagnetic spectrum. The results are parameterized to allow them to be easily used for coating design. PMID- 23033095 TI - Generation of dipole vortex array using spiral Dammann zone plates. AB - We propose a new diffractive optical element, called a spiral Dammann zone plate (SDZP), to generate a series of dipole vortices along the optical axis in the focal region of a focusing objective. By combining this SDZP and another Dammann grating, we describe the generation of three-dimensional dipole vortex arrays in the focal volume of an objective. For experimental demonstration, a 1*5 SDZP with base charge of l=1 is fabricated by using lithography and wet-etching techniques, and a 1*5 coaxial dipole vortex array is achieved for an objective of NA=0.127. Furthermore, by combining the 1*5 SDZP and another 5*5 Dammann grating, a 5*5*5 dipole vortex array is also experimentally demonstrated. The results show that topological charges of these 5*5 vortex arrays on five coaxial planes could be tunable by selecting a vortex beam carrying different charge as the incident field. PMID- 23033096 TI - Mueller matrix polarimetry with four photoelastic modulators: theory and calibration. AB - A spectroscopic Mueller matrix polarimeter with four photoelastic modulators (PEMs) and no moving parts is introduced. In the 4-PEM polarimeter, all the elements of the Mueller matrix are simultaneously determined from the analysis of the frequencies of the time-dependent intensity of the light beam. PMID- 23033097 TI - Optimization of intersatellite microwave photonic links by utilizing an optical preamplifier under dual-tone modulation. AB - An optical preamplifier is utilized to improve the signal-to-noise and distortion ratio (SNDR) of intersatellite microwave photonic links employing a Mach-Zehnder modulator under dual-tone modulation. The resulting SNDR at an appropriate direct current (DC) bias phase shift is additionally investigated without small-signal approximation in order to optimize the performance of all the links. It is observed that the most limiting factor degrading the SNDR performance is changed, and the fundamental power is seen to increase more compared with the power of third-order intermodulation (IM3) plus noise due to the optical preamplifier. Thus, SNDR can be improved with respect to the case of a nonoptical preamplifier. For the preamplifier gain of 20 dB and noise figure of 3 dB, an increase of about 24 dB in optimum SNDR is accessible. In addition, the optimum DC bias phase shift is found to be insensitive to the preamplifier gain and noise figure, while the optimum SNDR is sensitive to the preamplifier gain and noise figure. PMID- 23033098 TI - A translational polarization rotator. AB - We explore a free-space polarization modulator in which a variable phase is introduced between the right- and left-handed circular polarization components and used to rotate the linear polarization of the outgoing beam relative to that of the incoming beam. In this device, the polarization states are separated by a circular polarizer that consists of a quarter-wave plate in combination with a wire grid. A movable mirror is positioned behind and parallel to the circular polarizer. As the polarizer-mirror distance is changed, an incident linear polarization will be rotated through an angle that is proportional to the introduced phase delay. We demonstrate a prototype device that modulates Stokes Q and U over a 20% bandwidth, from 77 to 94 GHz. PMID- 23033099 TI - Two-step phase-shift interferometry with known but arbitrary reference waves: a graphical interpretation. AB - There are many applications in biology and metrology where it is important to be able to measure both the amplitude and phase of an optical wave field. There are several different techniques for making this type of measurement, including digital holography and phase retrieval methods. In this paper we propose an analytical generalization of this two-step phase-shifting algorithm. We investigate how to reconstruct the object signal if both reference waves are different in phase and amplitude. The resulting equations produce two different solutions and hence an ambiguity remains as to the correct solution. Because of the complexity of the generalized analytical expressions we propose a graphical vectorial method for solution of this ambiguity problem. Combining our graphical method with a constraint on the amplitude of the object field we can unambiguously determine the correct result. The results of the simulation are presented and discussed. PMID- 23033100 TI - Porous anodic alumina with low refractive index for broadband graded-index antireflection coatings. AB - Materials with very low refractive index are essential to prepare broadband graded-index antireflection (AR) coatings. However, the availability of such materials is very limited. In this study, large-area (4 cm*4 cm) low refractive index porous anodic alumina (PAA) coatings on glass substrate were prepared successfully by electron-beam evaporation, electrochemical oxidation, and chemical etching method. The nanopore size of PAA film is smaller than 40 nm, and the refractive index of PAA film is n=1.08. Besides, five-layered graded-index broadband PAA coatings with refractive indices following the Gaussian profile were also prepared to noticeably eliminate the reflectance of glass over a broadband wavelength, and the lowest reflectivity is 0.64% at the wavelength of 534 nm at normal incidence. The PAA AR coatings having an omnidirectional nature are likely to have practical applications in photovoltaic cells and optical devices. PMID- 23033101 TI - Study on the absorption uniformity of optical thin films based on the photothermal detuning technique. AB - Absorption loss in optical components, particularly in optical coatings, is a limiting factor in high-power laser applications. The uniformity of optical coatings becomes more and more important as large-diameter optical devices are used widely. In this paper, the photothermal detuning technique used for absorption uniformity measurement of optical thin films is developed for the first time. Experiments are conducted with a highly reflective coating used in 514 nm to measure the photothermal detuning signal and to evaluate the absorption at 514 nm by detecting the spectral shift with a probe beam at a wavelength of 632.8 nm. The relative absorption at different points on the sample surface can be measured by moving the sample two-dimensionally, and we use the measured data to make the absorption image. The results show that the designed experimental system can be used to analyze the absorption uniformity of optical coatings. The obtained images reflect the absorption uniformity of the sample well. The absorption uniformities of the two samples analyzed in this experiment are different. The film coated on fused silica is better. The research provides a powerful and convenient tool for absorption uniformity measurement of optical thin film. PMID- 23033102 TI - Planar waveguide concentrator used with a seasonal tracker. AB - Solar concentrators offer good promise for reducing the cost of solar power. Planar waveguides equipped with a microlens slab have already been proposed as an excellent approach to produce medium to high concentration levels. Instead, we suggest the use of a cylindrical microlens array to get useful concentration without tracking during the day. To use only a seasonal tracking system and get the highest possible concentration, cylindrical microlenses are placed in the east-west orientation. Our new design has an acceptance angle in the north-south direction of +/-9 degrees and +/-54 degrees in the east-west axis. Simulation of our optimized system achieves a 4.6* average concentration level from 8:30 to 16:30 with a maximum of 8.1* and 80% optical efficiency. The low-cost advantage of waveguide-based solar concentrators could support their use in roof-mounted solar panels and eliminate the need for an expensive and heavy active tracker. PMID- 23033103 TI - Design of a flat field concave-grating-based micro-Raman spectrometer for environmental applications. AB - In order to simplify the design process of microfabricated concave gratings, simplified algorithms for fast characterization of the concave grating were developed. These algorithms can be used to assist system designers using ray tracing software in the determination of optimum design parameters considering the requirements and restrictions for specific applications. According to the algorithms, it is feasible to design a flat field microconcave grating with a 4 mm grating radius as a key component in a micro-Raman spectrometer system for inline environmental monitoring applications. This microspectrometer operates over the spectral wavelength band from 785 nm to 1000 nm and has a spectral resolution of 2 nm at 900 nm. The total size of the system is 1 mm*4 mm*3.7 mm, making it one of the smallest for this wavelength range and spectrum resolution. PMID- 23033104 TI - Flame temperature measurements by radar resonance-enhanced multiphoton ionization of molecular oxygen. AB - Here we report nonintrusive local rotational temperature measurements of molecular oxygen, based on coherent microwave scattering (radar) from resonance enhanced multiphoton ionization (REMPI) in room air and hydrogen/air flames. Analyses of the rotational line strengths of the two-photon molecular oxygen C(3)Pi(v=2)<-X(3)Sigma(v'=0) transition have been used to determine the hyperfine rotational state distribution of the ground X(3)Sigma(v'=0) state. Rotationally resolved 2+1 REMPI spectra of the molecular oxygen C(3)Pi(v=2)<-X(3)Sigma(v'=0) transition at different temperatures were obtained experimentally by radar REMPI. Rotational temperatures have been determined from the resulting Boltzmann plots. The measurements in general had an accuracy of ~+/-60 K in the hydrogen/air flames at various equivalence ratios. Discussions about the decreased accuracy for the temperature measurement at elevated temperatures have been presented. PMID- 23033105 TI - Fast measurement of automotive headlamps based on high dynamic range imaging. AB - The headlamp of the automobile is a very important device for the safety of driving in the dark. Therefore, the distribution of the light designed to provide forward and lateral illumination needs to meet the requirements of various regulations. Traditional measurement of the distribution has been based on a point-by-point approach using a goniophotometer. In this paper, an imaging photometer is developed by combining a regular digital camera and a high dynamic range imaging technique to achieve faster and more complete measurement of the entire distribution. The experimental results indicate that errors of the measurements are within 10% of the true values, which is better than the 20% requirements of the industry. PMID- 23033106 TI - High-power multichannel PPMgLN-based optical parametric oscillator pumped by a master oscillation power amplification-structured Q-switched fiber laser. AB - We experimentally demonstrated a compact fiber laser-pumped multichannel PPMgLN based optical parametric oscillator (OPO) generating total OPO output power of 15.8, 15.2, 14.2, 12.9, and 8.8 W with idler output power of 4.7, 4.3, 4.1, 3.3, and 2.1 W at the wavelength of 3.43, 3.63, 3.72, 3.83, and 3.99 MUm, respectively. The OPO was pumped by a fully fiberized polarization maintaining (PM) ytterbium-doped pulsed fiber master oscillation power amplifier (MOPA) operating at 1064 nm at a repetition rate of 65 kHz with effective pump power of 28.7 W. The MOPA system was constructed with an acousto-optic Q-switched fiber laser seed and only one stage PM fiber amplifier without any free space components, which makes the pump system compact and stable in the long-term. Comparisons on efficiencies and signal wavelength shifts between different channels showed that the idler absorption was the main factor preventing high average-power OPO operation with long idler wavelength. PMID- 23033107 TI - Self-repairing, interferometric waveguide sensor with a large strain range. AB - We demonstrate a polymer waveguide, Fabry-Perot interferometer strain sensor fabricated through a self-writing process in a photopolymerizable resin bath between two silica optical fibers. The measurable strain range is extended through sensor self-repair and strain measurements are demonstrated up to 150% applied tensile strain. The sensor fabrication and repair is performed in the ultraviolet wavelength range, while the sensor interrogation is performed in the near-infrared wavelength range. A hybrid sensor is fabricated by splicing a short segment of multimode optical fiber to the input single-mode optical fiber. The hybrid sensor provides the high quality of waveguide fabrication previously demonstrated through self-writing between multimode optical fibers with the high fringe visibility of single-mode propagation. The peak frequency shift of the reflected spectrum Fabry-Perot sensor is extremely linear with applied strain for the hybrid sensor, with a sensitivity of 2.3*10(-3) per nanometer per percent strain. The calibrated peak frequency shift with applied strain is the same for both the original sensor and the repaired sensor; therefore, the fact that the sensor has self-repaired does not need to be known. Additionally, this calibration is the same between multiple sensor fabrications. In contrast to a conventional air gap Fabry-Perot cavity sensor, no decrease in the fringe visibility is observed over the measurable strain range. PMID- 23033108 TI - Design of nonlinear photonic crystal fibers with a double-cladded coaxial core for zero chromatic dispersion. AB - Photonic crystal fiber (PCF) with a double-cladded coaxial core (CC) is proposed and analyzed to obtain propagation characteristics such as chromatic dispersion, field distribution, and effective area. Only by doubling the number of air holes to 12 in the inner hexagonal cladding layer with one pitch (Lambda) value can the chromatic dispersion shift close to zero be achieved at 1.55 MUm operation wavelength. The fundamental mode field for the double-cladded CCPCF is tightly confined to the central core region. Therefore, the effective area is normally very small, while it tends to be larger rather rapidly as the operating wavelength is longer than around 1.7 MUm. PMID- 23033109 TI - Evolution of an editor. PMID- 23033110 TI - Free and open-source software application for the evaluation of coronary computed tomography angiography images. AB - BACKGROUND: The standardization of images used in Medicine in 1993 was performed using the DICOM (Digital Imaging and Communications in Medicine) standard. Several tests use this standard and it is increasingly necessary to design software applications capable of handling this type of image; however, these software applications are not usually free and open-source, and this fact hinders their adjustment to most diverse interests. OBJECTIVE: To develop and validate a free and open-source software application capable of handling DICOM coronary computed tomography angiography images. METHODS: We developed and tested the ImageLab software in the evaluation of 100 tests randomly selected from a database. We carried out 600 tests divided between two observers using ImageLab and another software sold with Philips Brilliance computed tomography appliances in the evaluation of coronary lesions and plaques around the left main coronary artery (LMCA) and the anterior descending artery (ADA). To evaluate intraobserver, interobserver and intersoftware agreements, we used simple and kappa statistics agreements. RESULTS: The agreements observed between software applications were generally classified as substantial or almost perfect in most comparisons. CONCLUSION: The ImageLab software agreed with the Philips software in the evaluation of coronary computed tomography angiography tests, especially in patients without lesions, with lesions < 50% in the LMCA and < 70% in the ADA. The agreement for lesions > 70% in the ADA was lower, but this is also observed when the anatomical reference standard is used. PMID- 23033111 TI - Blood pressure and interpersonal discrimination: systematic review of epidemiologic studies. AB - The relationship between blood pressure and discrimination has been recently investigated, and there are conflicting debates in literature devoted to the topic. The objective of this study was to update previous literature reviews on discrimination and blood pressure. A bibliographic search was conducted in PubMed between January/2000 and December/2010, including epidemiological studies, assessing the relationship between interpersonal discrimination and blood pressure/hypertension. The 22 studies included originated from the United States; 96% of them used the cross-sectional design with convenience sample, comprising, in 59% of the studies, exclusively Black participants. The Everyday Discrimination Scale and the Perceived Racism Scale were the most frequently used instruments, emphasizing lifetime or chronic/everyday racial/ethnic discrimination. In the 22 studies assessed, the association between discrimination and blood pressure/hypertension was assessed 50 times. Twenty results (40%) showed no association between them, and only 15 (30%) revealed global positive associations, of which 67% were statistically significant. Eight negative associations were also observed, suggesting that higher exposure to discrimination would be associated with lower blood pressure/hypertension. The studies did not consistently support the hypothesis that discrimination is associated with higher blood pressure. These findings can be partially attributed to the limitations of the studies, especially those related to the measurement of discrimination and of factors that might modify its association with outcomes. To establish discrimination as an epidemiological risk factor, more rigorous methodological strategies should be used, and the theoretical frameworks that postulate causal relationships between discrimination and blood pressure should be reviewed. PMID- 23033112 TI - Cardiorespiratory optimal point: a submaximal variable of the cardiopulmonary exercise testing. AB - BACKGROUND: At the maximal Cardiopulmonary Exercise Testing (CPET), several ventilatory variables are analyzed, including the ventilatory equivalent for oxygen (VE/VO2). The minimum VE/VO2 value reflects the best integration between the respiratory and cardiovascular systems and may be called "Cardiorespiratory Optimal Point (COP)". OBJECTIVE: To determine the behavior of the COP according to gender and age in healthy adults and verify its association with other CPET variables. METHODS: Of 2,237 individuals, 624 were selected (62% men and 48 +/- 12 years), non- athletes, healthy, who were submitted to maximal CPET. COP or minimum VE/VO2 was obtained from the analysis of ventilation and oxygen consumption in every minute of CPET. We investigated the association between age and COP for both genders, as well as associations with: VO(2)max, VO(2) at anaerobic threshold (VO(2)AT), oxygen uptake efficiency slope (OUES) and with maximum VE. We also compared the intensity of exertion (MET) at the COP, AT and VO(2)max. RESULTS: COP increases with age, being 23.2 +/- 4.48 and 25.0 +/- 5.14, respectively, in men and women = (p < 0.001). There are moderate and inverse associations with VO(2)max (r = -0.47; p < 0.001), with VO(2)AT (r = -0.42; p < 0.001) and with OUES (r = -0.34; p < 0.001). COP occurred, on average, at 44% do VO(2)max and before AT (67% of VO(2)max) (p < 0.001). CONCLUSION: COP, a submaximal variable, increases with age and is slightly higher in women. Being modestly associated with other ventilation measures, there seems to be an independent contribution to the interpretation of the cardiorespiratory response to CPET. PMID- 23033113 TI - Parkinson's disease and the risk of cerebrovascular pathology. PMID- 23033114 TI - Fruit juices as perpetrators of drug interactions: the role of organic anion transporting polypeptides. AB - Grapefruit juice is widely recognized to cause important drug interactions via inhibition of CYP3A4, and a wider variety of fruit juices have been shown to inhibit influx transporters in enterocytes known as organic anion-transporting polypeptides (OATPs). Fruit juice coadministration significantly reduces the oral bioavailability of numerous important medicines relying on this anion transporter pathway for absorption. This article reviews the current literature on interactions between clinically used OATP substrates and fruit juice consumption. PMID- 23033117 TI - Sulfate-selective binding and sensing of a fluorescent [3]rotaxane host system. AB - The chloride-templated synthesis of a novel [3]rotaxane, capable of binding anionic guests, and incorporating a naphthalene group for fluorescence sensing is reported. Extensive (1)H NMR titration studies were used to probe the anion binding selectivity of the system. The rotaxane selectively recognises sulfate, undergoing an induced conformational change upon sulfate binding to form a 1:1 stoichiometric sandwich-type complex, concomitant with significant quenching of the fluorescence. Binding of mono-anionic guests results in the formation of a 2:1 stoichiometric guest-host complex, and a modest enhancement of the emission. Addition of an excess of sulfate in non-competitive solvent also results in a 2:1 emissive complex. PMID- 23033119 TI - Ionic compound containing iron phthalocyanine (Fe(I)Pc)(-) anions and (C70(-))2 dimers. Optical and magnetic properties of (Fe(I)Pc)(-) in the solid state. AB - Ionic compounds containing the anion of iron phthalocyanine (Fe(I)Pc)(-), {(Fe(I)Pc)(-)}.(cryptand[2,2,2].[Na(+)]).(C(6)H(4)Cl(2)) (1), and the fullerene C(70)(-) and Fe(I)Pc(-) anions, (C(70)(-))(2).{(Fe(I)Pc)( )}(6).(cryptand[2,2,2].[Na(+)])(8).(C(6)H(4)Cl(2))(8.65).(C(6)H(14))(0.35) (2), were obtained as single crystals. Their crystal structures and optical and magnetic properties were analyzed. Spectra of 1 and 2 manifest intense bands in visible-NIR range at 820, 690, 555, 528, 449, 400 and 316 nm attributed to (Fe(I)Pc)(-). The four-coordinate (Fe(I)Pc)(-) anions show an EPR signal with perpendicular and parallel components at g(?) = 2.487 and g(||) = 2.353 in 1 and g(?) = 2.328 and g(||) = 2.230 in 2. According to magnetic measurements the (Fe(I)Pc)(-) anions have low spin (S = 1/2) state indicating d(7) configuration for the Fe(I) atoms with the odd electron on the d(z(2)) orbital. Fullerene anions form singly bonded (C(70)(-))(2) dimers in 2, the shape of which efficiently fitted with the large planar phthalocyanine anions to be surrounded completely by eight (Fe(I)Pc)(-) anions. The (C(70)(-))(2) dimers are diamagnetic and EPR silent up to 350 K. Both complexes contain channels formed by four (Fe(I)Pc)(-) planes in 1 or four (Fe(I)Pc)(-) planes and two (C(70)(-))(2) dimers in 2. The channels are occupied by double chains of alternating cryptand[2,2,2].[Na(+)] cations and solvent C(6)H(4)Cl(2) molecules. PMID- 23033116 TI - Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients. AB - We investigated population pharmacokinetics and pharmacogenetics of ritonavir boosted atazanavir (ATV), using drug intake times exactly recorded by the Medication Event Monitoring System. The ANRS 134-COPHAR 3 trial was conducted in 35 HIV-infected treatment-naive patients. ATV (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg), in bottles with MEMS caps, were taken once daily for 6 months. Six blood samples were collected at week 4 to measure drug concentrations, and trough levels were measured bimonthly. A model integrating ATV and ritonavir pharmacokinetics and pharmacogenetics used nonlinear mixed effects. Use of exact dosing data halved unexplained variability in ATV clearance. The ritonavir-ATV interaction model suggested that optimal boosting effect is achievable at lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 28% higher oral clearance. We provide evidence that variability in ATV pharmacokinetics is defined by adherence, CYP3A5 genotype, and ritonavir exposure. PMID- 23033120 TI - The influence of positive and negative emotional associations on semantic processing in depression: an fMRI study. AB - In depression, patients suffer from emotional and cognitive deficits, among others in semantic processing. If these semantic deficits are cognitive or interact with emotional dysfunctions, is still an open question. The aim of the current study was to investigate the influence of emotional valence on the neural correlates of semantic priming in major depression. In a lexical decision task, positive, negative, and neutral word pairs were presented during fMRI measurement. Nineteen inpatients and 19 demographically matched controls were recruited. Behaviorally, positive and neutral valence induced a priming effect whereas negative valence induced no effect (controls) or even inhibition (slower RT for related stimuli) in patients. At the neural level, the semantic relation effect revealed similar neural activation in right middle frontal regions for patients and controls. Group differences emerged in the right fusiform gyrus and the ACC. Activity associated with positive valence differed at the DLPFC and amygdala and for negative valence at putamen and cerebellum. The activation of amygdala and DLPFC correlated negatively with the severity of depression. To conclude, semantic processing deficits in depression are modulated by emotional valence of the stimulus on the behavioral as well as on neural level in right lateralized prefrontal areas and the amygdala. The results highlighted an influence of depression severity on emotion information processing as the severity of symptoms correlated negatively with neural responses to positively and negatively valenced information. Hence, the dysfunctional emotion processing may further enhance the cognitive deficits in depression. PMID- 23033121 TI - Cu(II)-promoted three-component coupling sequence for the efficient synthesis of substituted quinolines. AB - The copper-promoted three-component coupling sequence for substituted quinoline formation from aldehydes, anilines and acetone is described. Various 2 arylquinolines were selectively obtained in good yields under mild conditions. The reaction tolerated a wide range of functionalities. PMID- 23033122 TI - Access to an unexplored chiral C82 cage by encaging a divalent metal: structural elucidation and electrochemical studies of Sm@C2(5)-C82. AB - Access to a chiral C(82) cage: Encaging a divalent samarium atom has provided access to an unexplored chiral cage of C(2)(5)-C(82) that has never been reported for trivalent M@C(82) or empty fullerenes. Inside this cage, a wandering Sm atom has been identified using crystallographic methods. In addition, electrochemical studies of Sm@C(2)(5)-C(82) have been performed to explore its oxidation properties (see figure). PMID- 23033123 TI - A community-based participatory diabetes prevention and management intervention in rural India using community health workers. AB - PURPOSE: The purpose of this study was to test the effectiveness of a 6-month community-based diabetes prevention and management program in rural Gujarat, India. METHODS: A community-based participatory research method was used to plan and tailor the intervention by engaging trained community health workers as change agents to provide lifestyle education, serve as community advocates, and collect data from 1638 rural Indians (81.9% response rate). Ten culturally and linguistically appropriate health education messages were provided in face-to face individual and group sessions (demonstrations of model meals and cooking techniques). RESULTS: Mean age was 41.9 +/- 15.9 years. Overall point prevalence of diabetes, prediabetes, obesity, and hypertension were 7.2%, 19.3%, 16.7%, and 28%, respectively, with significant differences between the low socioeconomic status (SES) participants (agricultural workers) and the high SES participants (business community) due to differing diet and activity levels. The intervention significantly reduced blood glucose levels by 5.7 and 14.9 mg/dL for individuals with prediabetes and diabetes, respectively, and systolic and diastolic blood pressure by 8 mm Hg and 4 mm Hg, respectively, in the overall population. Knowledge of diabetes and cardiovascular disease improved by 50% in the high SES group and doubled in the low SES group; general and abdominal obesity also decreased by <= 1%. High rates of undiagnosed hypertension (26.1%) were surprising. Among individuals with diabetes, metabolic complications such as diabetic nephropathy and chronic kidney disease were noted. CONCLUSIONS: Through collective engagement of the community, participatory programs can serve as a prototype for future prevention and management efforts, which are rare and underutilized in India. PMID- 23033124 TI - A new paradigm in viral resistance. AB - The rapid mutation of RNA viruses allows for the acquisition of resistance to drugs directly targeting viral proteins. Therefore, a novel approach to the development of antivirals centers on targeting host factors critical to viral replication. A recent report has brought to light the potential for RNA viruses to also develop resistance against compounds targeting crucial host factors, suggesting that a combination of drugs with various targets may be necessary for preventing resistance. PMID- 23033125 TI - Psychogenic facial movement disorders: clinical features and associated conditions. AB - The facial phenotype of psychogenic movement disorders has not been fully characterized. Seven tertiary-referral movement disorders centers using a standardized data collection on a computerized database performed a retrospective chart review of psychogenic movement disorders involving the face. Patients with organic forms of facial dystonia or any medical or neurological disorder known to affect facial muscles were excluded. Sixty-one patients fulfilled the inclusion criteria for psychogenic facial movement disorders (91.8% females; age: 37.0 +/- 11.3 years). Phasic or tonic muscular spasms resembling dystonia were documented in all patients most commonly involving the lips (60.7%), followed by eyelids (50.8%), perinasal region (16.4%), and forehead (9.8%). The most common pattern consisted of tonic, sustained, lateral, and/or downward protrusion of one side of the lower lip with ipsilateral jaw deviation (84.3%). Ipsi- or contralateral blepharospasm and excessive platysma contraction occurred in isolation or combined with fixed lip dystonia (60.7%). Spasms were reported as painful in 24.6% of cases. Symptom onset was abrupt in most cases (80.3%), with at least 1 precipitating psychological stress or trauma identified in 57.4%. Associated body regions involved included upper limbs (29.5%), neck (16.4%), lower limbs (16.4%), and trunk (4.9%). There were fluctuations in severity and spontaneous exacerbations and remissions (60%). Prevalent comorbidities included depression (38.0%) and tension headache (26.4%). Fixed jaw and/or lip deviation is a characteristic pattern of psychogenic facial movement disorders, occurring in isolation or in combination with other psychogenic movement disorders or other psychogenic features. PMID- 23033126 TI - Effects of angico extract (Anadenanthera colubrina var. cebil) in cutaneous wound healing in rats. AB - PURPOSE: To study the effects of the angico extract (Anadenanthera colubrina var. cebil) on the healing of rat skin. METHODS: Twenty adult rats were divided into four groups of five animals each, the G4, G7, G14 and G21, which corresponds to the respective postoperative days. Each group received two incisions on skin and subcutaneous tissue in the right and left antimere of the thoracic region, separated by a distance of 2 cm. The right lesion was treated daily with saline and the left with the angico alcoholic extract (5%). At the end of each experimental period, animals were euthanized and fragments of the wound area, together with the edges were removed, fixed in 10% formaldehyde solution and processed for paraffin embedding. In the histological sections with 5 um of thickness, were carried out immunohistochemical methods for detection of blood vessels (VEGF) and stained with hematoxylin and eosin for morphological analysis. Statistical analysis was done by ANOVA and Tukey test (p<0.05). RESULTS: Morphological analysis showed larger fibroblasts and a higher concentration of collagen fibers in days 7 and 14 in wounds treated with the angico extract. Morphometric analysis demonstrated a significant increase in the number of blood vessels in both the seventh and 14th days (p<0.01) in wounds treated with the angico extract. CONCLUSION: The angico alcoholic extract (Anadenanthera colubrina var. cebil) induces the acceleration of wound healing in skin wounds of rats. PMID- 23033127 TI - Nonwoven polypropylene prosthesis in large abdominal wall defects in rats. AB - PURPOSE: To evaluate, in large abdominal wall defects surgically shaped in rats, if a synthetic polypropylene nonwoven prosthesis could be used as a therapeutic option to conventional polypropylene mesh. METHODS: Twenty four (24) Wistar rats were enrolled into three groups. Group 1 (Simulation group) with an abdominal wall defect of 3 X 3 left untreated and Groups 2 and 3, respectively treated with a conventional polypropylene mesh and a polypropylene nonwoven (NWV) prosthesis to cover the breach. At the 45th postoperatively day, adhesion (area and strength) and vascularization of Groups 2 and 3 were evaluated. The histological preparations with Hematoxylin-Eosin, Tricromium of Masson, Pricrosirius red and polarization with birefringence, and also the structural analysis of the prostheses carried on by Thermogravimetry and Differential Scanning Calorimetry were also assessed. RESULTS: There were no significant differences between the Groups 2 and 3. CONCLUSION: In rats, the polypropylene nonwoven prosthesis showed to be safe and has to be considered as an alternative to conventional mesh manufactured by weaving in the treatment of great defects of the abdominal wall. PMID- 23033128 TI - An experimental model for the study of collagen fibers in skeletal muscle. AB - PURPOSE: To examine histological and histomorphometric techniques for measuring collagen in skeletal muscle. METHODS: The following staining methods were used in the study: hematoxylin and eosin, Masson's trichrome, reticulin, and picrosirius red, and immunostaining for collagen types I, II, III, IV, and V. Histomorphometric measurements were performed using Corel PhotoPaint and UTHSCSA Image Tool 3.0 software. RESULTS: Both the Masson's trichrome and picrosirius red staining provided the best visualization for the measurement of collagen content. CONCLUSION: This methodology is important for the identification and quantification of the different types of collagen in muscles and can be used in the investigation of the qualitative and quantitative influence of collagen on physical activities, aging, and diseases. PMID- 23033129 TI - Lung morphology and growth of rats exposed to tobacco smoke and alcohol. AB - PURPOSE: Investigate the morphological effects of chronic exposure to tobacco smoke inhalation and alcohol consumption on the lungs and on the growth of rats. METHODS: Sixty male Wistar rats were divided into four groups: control, tobacco, alcohol, tobacco + alcohol, for a period of study 260 days. Morphological analysis was conducted by optical and electron microscopy. Rat growth was investigated by measuring the snout-anus length, body mass index and body weight. RESULTS: The three groups exposed to the drugs presented lower growth and lower weight than the control group. The percentages of alveolitis, bronchiolitis and the mean alveolar diameter were greater, particularly in the groups exposed to tobacco smoke, but were not significantly different from the control group. Electron microscopy revealed more intense apoptotic and degenerative lesions in the smoking group, while degenerative lesions in the lamellar bodies were more intense with the association of both drugs. CONCLUSIONS: This experimental model showed morphological alterations observed by electron microscopy, principally due to tobacco smoke exposure. Alcohol and tobacco hindered the growth of rats, such that tobacco showed a greater effect on body length and alcohol on body weight. PMID- 23033130 TI - Combination of poly L-lactic acid nanofiber scaffold with omentum graft for bone healing in experimental defect in tibia of rabbits. AB - PURPOSE: To investigate the osteoconductive properties and biological performance of Poly L-lactic acid (PLLA) with omentum in bone defects. METHODS: PLLA nanofiber scaffolds were prepared via electrospinning technique. Forty four New Zealand white female rabbits randomly divided into three groups of 18 rabbits each. Created defects in right tibias were filled in group I with omentum, in group II with PLLA nanofiber scaffold and in group III with combination of the omentum and PLLA. The same defects were created in left tibia of all groups but did not receive any treatment (control group). Histological and histomorphometric evaluations were performed at two, four and six weeks after the implantation. RESULTS: Histological changes on all groups along with the time course were scored and statistical analysis showed that the average scores in group III were significantly higher than the other groups. CONCLUSION: Histomorphometric analysis of bone healing was shown to be significantly improved by the combined PLLA with omentum compared with the other groups, suggesting this biomaterial promote the healing of cortical bone, presumably by acting as an osteoconductive scaffold. PMID- 23033132 TI - Effects of chitosan on healing and strength of colonic anastomosis in rats. AB - PURPOSE: To investigate whether chitosan application over colonic anastomosis line, provide reinforcement, and subsequently improve anastomotic healing. METHODS: Forty eight Wistar albino female rats were used and were randomly divided into four groups, 12 rats in each: The control groups (1 and 3) received no further treatment. The experimental groups (2 and 4) received chitosan application over the colonic anastomosis. After sacrifying rats at the end of the experiment (either on day three or on day seven, depending on the group), colonic bursting pressure, a hihydroxyproline level and histopathologic characteristics of the perianastomotic tissue were examined. RESULTS: At three days, chitosan and control groups had similar values for histopathologically. On day seven, chitosan group had significantly higher mean score of collagenization (p=0.007) and a significantly higher bursting pressure (p=0.038). CONCLUSION: Our study emphasizes the positive effect of chitosan in the process of collagenation in colonic anastomosis healing. PMID- 23033131 TI - The effects of anesthetic regimen in 90% hepatectomy in rats. AB - PURPOSE: To evaluate the influence of the anesthetic regimen on anesthetic recovery, survival, and blood glucose levels following a 90% partial hepatectomy in rats. METHODS: Thirty adult male Wistar rats were divided into two groups according to their anesthetic regimens: intraperitoneal ketamine and xylazine or inhaled isoflurane. In order to prevent hypoglycemia, glucose was administered intraperitoneally and glucose (20%) was added to the drinking water. RESULTS: Anesthetic recovery time was longer in the ketamine and xylazine group. The survival rate after 72 hours was lower (log rank=0.0001) in the ketamine and xylazine group (0.0%) than in the isoflurane group (26.7%). The blood glucose after six hours was lower (p=0.017) in the ketamine and xylazine group (63 +/- 31.7 mg/dL) than in the isoflurane group (98 +/- 21.2 mg/dL). The prolonged anesthesia recovery time associated with ketamine and xylazine decreased the survival rate and blood glucose levels after 90% hepatectomy. CONCLUSION: Isoflurane anesthesia reduced the recovery time and incidence of hypoglycemia and increased the survival rate in the early hours, providing a therapeutic window that is suitable for experimental studies. PMID- 23033133 TI - Modified technique to increase nostril cross-sectional area after using rib and septal cartilage graft over alar nasal cartilages. AB - PURPOSE: Describe a modified technique to increase nostril cross-sectional area using rib and septal cartilage graft over alar nasal cartilages. METHODS: A modified surgical technique was used to obtain, carve and insert cartilage grafts over alar nasal cartilages. This study used standardized pictures and measured 90 cadaveric nostril cross-sectional area using Autocad((r)); 30 were taken before any procedure and 60 were taken after grafts over lateral crura (30 using costal cartilage and 30 using septal cartilage). Statistical analysis were assessed using a model for repeated measures and ANOVA (Analysis of Variance) for the variable "area". RESULTS: There's statistical evidence that rib cartilage graft is more effective than septal cartilage graft. The mean area after the insertion of septal cartilage graft is smaller than the mean area under rib graft treatment (no confidence interval for mean difference contains the zero value and all P values are below the significance level of 5%). CONCLUSIONS: The technique presented is applicable to increase nostril cross section area in cadavers. This modified technique revealed to enhance more nostril cross section area with costal cartilage graft over lateral crura rather than by septal graft. PMID- 23033134 TI - Evaluation of Langerhans cells counts comparing HIV-positive and negative anal squamous cell-carcinoma patients. AB - PURPOSE: To investigate the differences in Langerhans cells (LCs) populations between HIV-positive and negative anal squamous cell carcinomas patients. METHODS: Twenty five patients (14 HIV-positive and 11 HIV-negative) were evaluated. Paraffin-block transversal thin sections from biopsies of anal squamous cell carcinomas (ASCC) were stained using the anti-CD1A antibody that identifies activated LCs. LCs counts were performed using histometry at 20 different sites, at baseline in the ASCC cases. These were then compared with LCs counts in anal canal specimens from HIV-negative and positive patients without ASCC (controls groups). RESULTS: In patients with ASCC, the LC count was greater among HIV-negative individuals than among HIV-positive individuals (p<0.05). The LC count was greater in the control HIV-negative group than in HIV-positive patients with ASCC (p<0.05). CONCLUSION: There was a lower amount of activated LCs in HIV-positive patients with anal squamous cell carcinomas than in HIV negative patients, thereby suggesting worsening of the immune response. PMID- 23033135 TI - Comparison on different strategies for treatments of hypertensive hemorrhage in the basal ganglia region with a volume of 25 to 35 ml. AB - PURPOSE: To compare curative effect of different treatments for hypertensive cerebral hemorrhage of 25 to 35 ml. METHODS: In this study, 595 cases were enrolled and grouped regarding treatments including conservative treatment, evacuation with microinvasive craniopuncture technique within 6h and 6-48 h after the attack. RESULTS: After follow up for three months after the attack, the assessment based on the Activity of Daily Living (ADL) indicated no significant difference among conservative treatment and surgical interventions (p>0.05). However, surgical interventions showed advantages of shorter hospitalization, quick removal of hematoma and obvious reduction of cost. CONCLUSION: The microinvasive craniopuncture technique to drain the hematoma within 6-48 h may be a good way in treating hypertensive hemorrhage of basal ganglia region. PMID- 23033136 TI - Conjunctival inflammation in patients under topical glaucoma treatment with indication to surgery. AB - PURPOSE: To compare the frequency of conjunctival HLA-DR expression (a surrogate marker for inflammation) in eyes treated with topical prostaglandin analogues versus eyes treated with other topical antiglaucomatous drugs. METHODS: Patients diagnosed with primary open-angle glaucoma presenting indication for trabeculectomy were divided in groups according to the use or not of prostaglandin analogues. All subjects were treated with the maximum tolerated dose of antiglaucomatous drugs until the date of the surgery. At the beginning of the surgical procedure, a 5 x 5 mm biopsy of the bulbar conjunctiva was collected, incubated with monoclonal anti-HLA-DR antibody and processed for histological analysis. RESULTS: Of the 31 eyes included (31 patients), 25 were under topical prostaglandin analogues (Group 1) and six under other topical pharmacological agents (Group 2). Fourteen eyes of Group 1 (56%) and three of Group 2 (50 %) were positive for the inflammatory marker HLA-DR (P=1.0). The percentage of stained cells ranged from 15.49 to 48.09% (median: 27.61) in Group 1, and from 18.35 to 28 (median: 20.71) in Group 2, with no differences statistically significant (p=0.33). CONCLUSION: The use of prostaglandin analogues did not increase conjunctival expression of HLA-DR compared to other topical antiglaucomatous agents. PMID- 23033137 TI - Influence of aging on the quality of the skin of white women: the role of collagen. AB - PURPOSE: Evaluate the influence of aging on the quality of the skin of white women, analyzing the dermal collagen. METHODS: Pre-auricular flaps were collected for histological and morphometric analysis of 218 white women who underwent spontaneous facial aesthetic plastic surgery. Picrosirius ultrared stain was used for analysis and quantification of collagen in five age groups (<40 years, 40 to 49 years, 50 to 59 years, 60 to 69 years and 70 to 79 years) . RESULTS: Histological analysis showed changes suggestive of skin aging (fragmentation and disorganization of collagen fibers), especially in patients over 60 years. There were no significant changes in the relationship of age with the thickness of the dermis and epidermis, but there was with the percentage of the collagen I, III and total (p<0.001), which decreased with increasing aging. CONCLUSION: There is reduction in collagen with increasing age, and an increase in its degradation, leading to fragmentation of the fibers. PMID- 23033138 TI - New experimental model for training in videosurgery. AB - PURPOSE: To develop a new experimental model of lower cost for training in videosurgery. METHODS: This project was performed at the Nucleus of Experimental Surgery of the Bahiana School of Medicine and Public Health, based on previous models described in the literature and under the supervision of the full professor of Operative Technique and Experimental Surgery II. It was made a model cube-shaped, made of wood, with holes distributed in various locations, rubber stoppers for the holes and lined externally with carpet, and internally with laminate. RESULTS: The new experimental model is of low cost and reproduces quite faithfully several videosurgical procedures. CONCLUSION: Medical schools interested in the subject may adopt the new model for training in videosurgery without the need of high costs for making and using these models. PMID- 23033139 TI - Organocatalyzed enantioselective desymmetrization of diols in the preparation of chiral building blocks. AB - Desymmetrization of diols is a powerful tool to the synthesis of chiral building blocks. Among the different approaches to perform discrimination between both enantiotopic hydroxyl groups, the organocatalytic approach has gained importance in the last years. A diverse range of organocatalysts has been used to efficiently promote this enantioselective transformation and this Minireview examines the different contributions in this field. PMID- 23033140 TI - Designed synthesis of a metal cluster-pillared coordination cage. AB - An unprecedented polynuclear metal cluster-pillared triangular prism was built by a macrocycle-directing strategy. Discrete architectures of three silver cluster involved metallosupramolecules were characterized by single crystal X-ray crystallography and spectroscopy studies. PMID- 23033141 TI - A comparative study of iron uptake mechanisms in marine microalgae: iron binding at the cell surface is a critical step. AB - We investigated iron uptake mechanisms in five marine microalgae from different ecologically important phyla: the diatoms Phaeodactylum tricornutum and Thalassiosira pseudonana, the prasinophyceae Ostreococcus tauri and Micromonas pusilla, and the coccolithophore Emiliania huxleyi. Among these species, only the two diatoms were clearly able to reduce iron, via an inducible (P. tricornutum) or constitutive (T. pseudonana) ferrireductase system displaying characteristics similar to the yeast (Saccharomyces cerevisiae) flavohemoproteins proteins. Iron uptake mechanisms probably involve very different components according to the species, but the species we studied shared common features. Regardless of the presence and/or induction of a ferrireductase system, all the species were able to take up both ferric and ferrous iron, and iron reduction was not a prerequisite for uptake. Iron uptake decreased with increasing the affinity constants of iron-ligand complexes and with increasing ligand-iron ratios. Therefore, at least one step of the iron uptake mechanism involves a thermodynamically controlled process. Another step escapes to simple thermodynamic rules and involves specific and strong binding of ferric as well as ferrous iron at the cell surface before uptake of iron. Binding was paradoxically increased in iron-rich conditions, whereas uptake per se was induced in all species only after prolonged iron deprivation. We sought cell proteins loaded with iron following iron uptake. One such protein in O. tauri may be ferritin, and in P. tricornutum, Isip1 may be involved. We conclude that the species we studied have uptake systems for both ferric and ferrous iron, both involving specific iron binding at the cell surface. PMID- 23033143 TI - The effect of parenterally administered cyclodextrins on the pharmacokinetics of coadministered drugs. AB - Cyclodextrins are used increasingly to formulate otherwise poorly soluble molecules for clinical use. Cyclodextrins, such as 2-hydroxypropyl-beta cyclodextrin (HPbetaCD) and sulfobutylether beta-cyclodextrin (SBEbetaCD), are found in marketed parenteral drug formulations. Depending upon the relative affinities of a coadministered medication for cyclodextrin and plasma proteins, complexation with HPbetaCD or SBEbetaCD may alter its pharmacokinetics (PK). To explore this possibility, we applied a previously developed model for competitive binding of drugs with HPbetaCD and human serum albumin to a variety of commonly administered medications. We modeled this potential interaction in medications chosen on the basis of a hypothetical detrimental effect of HPbetaCD complexation with their therapeutic action (e.g., antibiotics), supplemented by a composite listing of concurrent medications. Stability constant (K(1:1)) values for drug HPbetaCD 1:1 inclusion complexes were extracted from our own data and the literature. The K(1:1) values for the drugs tested ranged from 2 to 40,000 M(-1) and the plasma protein binding from about 20% to over 99%. None of the 63 drugs examined in the present study had a sufficiently high K(1:1) value for HPbetaCD complexation to affect plasma protein binding to a degree that would be expected to alter their PK substantively, for example, to require increased doses. PMID- 23033142 TI - Steady-state phosphorylation of light-harvesting complex II proteins preserves photosystem I under fluctuating white light. AB - According to the "state transitions" theory, the light-harvesting complex II (LHCII) phosphorylation in plant chloroplasts is essential to adjust the relative absorption cross section of photosystem II (PSII) and PSI upon changes in light quality. The role of LHCII phosphorylation upon changes in light intensity is less thoroughly investigated, particularly when changes in light intensity are too fast to allow the phosphorylation/dephosphorylation processes to occur. Here, we demonstrate that the Arabidopsis (Arabidopsis thaliana) stn7 (for state transition7) mutant, devoid of the STN7 kinase and LHCII phosphorylation, shows a growth penalty only under fluctuating white light due to a low amount of PSI. Under constant growth light conditions, stn7 acquires chloroplast redox homeostasis by increasing the relative amount of PSI centers. Thus, in plant chloroplasts, the steady-state LHCII phosphorylation plays a major role in preserving PSI upon rapid fluctuations in white light intensity. Such protection of PSI results from LHCII phosphorylation-dependent equal distribution of excitation energy to both PSII and PSI from the shared LHCII antenna and occurs in cooperation with nonphotochemical quenching and the proton gradient regulation5-dependent control of electron flow, which are likewise strictly regulated by white light intensity. LHCII phosphorylation is concluded to function both as a stabilizer (in time scales of seconds to minutes) and a dynamic regulator (in time scales from tens of minutes to hours and days) of redox homeostasis in chloroplasts, subject to modifications by both environmental and metabolic cues. Exceeding the capacity of LHCII phosphorylation/dephosphorylation to balance the distribution of excitation energy between PSII and PSI results in readjustment of photosystem stoichiometry. PMID- 23033144 TI - An important role of prostanoid receptor EP2 in host resistance to Mycobacterium tuberculosis infection in mice. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis, resides and replicates within susceptible hosts by inhibiting host antimicrobial mechanisms. Prostaglandin E(2) (PGE(2)), produced by M. tuberculosis-infected macrophages, exerts a variety of immunomodulatory functions via 4 receptors (EP1-EP4), each mediating distinct PGE(2) functions. Here, we show that M. tuberculosis infection selectively upregulates EP2 messenger RNA expression in CD4(+) T cells. We found that EP2 deficiency in mice increases susceptibility to M. tuberculosis infection, which correlated with reduced antigen-specific T-cell responses and increased levels of CD4(+)CD25(+)Foxp3(+) T-regulatory cells. These findings have revealed an important role for EP2 in host immune defense against tuberculosis. As a G protein-coupled receptor, EP2 could serve as a target for immunotherapy of tuberculosis. PMID- 23033145 TI - Eicosanoids, prostaglandins, and the progression of tuberculosis. PMID- 23033146 TI - Candida albicans biofilms do not trigger reactive oxygen species and evade neutrophil killing. AB - Neutrophils are found within Candida albicans biofilms in vivo and could play a crucial role in clearing the pathogen from biofilms forming on catheters and mucosal surfaces. Our goal was to compare the antimicrobial activity of neutrophils against developing and mature C. albicans biofilms and identify biofilm-specific properties mediating resistance to immune cells. Antibiofilm activity was measured with the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)2H tetrazolium-5-carboxanilide assay and a molecular Candida viability assay. Reactive oxygen species generation was assessed by measuring fluorescence of 5 (and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester in preloaded neutrophils. We found that mature biofilms were resistant to leukocytic killing and did not trigger reactive oxygen species, even though neutrophils retained their viability and functional activation potential. Beta-glucans found in the extracellular matrix negatively affected antibiofilm activities. We conclude that these polymers act as a decoy mechanism to prevent neutrophil activation and that this represents an important innate immune evasion mechanism of C. albicans biofilms. PMID- 23033147 TI - Childhood tuberculosis and malnutrition. AB - Despite the burden of both malnutrition and tuberculosis in children worldwide, there are few studies on the mechanisms that underlie this relationship. From available research, it appears that malnutrition is a predictor of tuberculosis disease and is associated with worse outcomes. This is supported through several lines of evidence, including the role of vitamin D receptor genotypes, malnutrition's effects on immune development, respiratory infections among malnourished children, and limited work specifically on pediatric tuberculosis and malnutrition. Nutritional supplementation has yet to suggest significant benefits on the course of tuberculosis in children. There is a critical need for research on childhood tuberculosis, specifically on how nutritional status affects the risk and progression of tuberculosis and whether nutritional supplementation improves clinical outcomes or prevents disease. PMID- 23033148 TI - Influenza viral RNA detection in blood as a marker to predict disease severity in hematopoietic cell transplant recipients. AB - Influenza RNA in blood (viremia) was detected in 9 of 79 (11.4%) hematopoietic cell transplant recipients with influenza, and was less frequently observed in patients with upper respiratory tract disease only and more frequently in patients infected with 2009 pandemic influenza A/H1N1 strain (versus seasonal strains). Viremia increased the risk of progression to lower respiratory tract disease (LRD), hypoxemia, respiratory failure, and overall and influenza-related death. Among patients with LRD, viremia was associated with increased hazards of overall and influenza-associated death (hazard ratio 3.5, 1.1-12). Thus, influenza viremia may serve as marker for overall poor outcome. PMID- 23033149 TI - Scope whac-a-mole. AB - TMA doesn't always oppose scope-of-practice expansion by nonphysicians. It believes it's appropriate when it improves patient care and nonphysicians are properly trained, when a physician heads the health care team, and when there is proper Texas Medical Board oversight. PMID- 23033150 TI - Rebuilding relationships. PMID- 23033151 TI - Preventing injury. PMID- 23033152 TI - Vital connections. PMID- 23033153 TI - Clinical service characteristics and initiation of the human papillomavirus vaccination series in an academic clinic setting. AB - Investigators examined billing records from 4 university-affiliated primary care clinics for encounters with females aged 8-26 years from October 2007 to May 2008 to determine clinical service characteristics of initiating the human papillomavirus (HPV) vaccination series. A total of 5538 services were rendered to 1365 patients within 2550 visits. Sixteen percent of those who received HPV vaccination were adults. Statistically significant predictors of initiating the vaccination series included type of visit (ie, nurse visit and preventive visit) and the patient being a minor. PMID- 23033155 TI - General one-pot synthesis of alkynyliodonium salts and alkynyl benziodoxolones from aryl iodides. AB - I: hyperfond of a triple bond! The first one-pot synthesis of alkynyl(aryl)iodonium salts directly from aryl iodides has been developed. The reaction is fast and high yielding, and can be extended to the synthesis of alkynyl benziodoxolones (see scheme). The developed methodology is expected to greatly facilitate the access to this interesting class of hypervalent iodine reagents, and many new application areas are foreseen. PMID- 23033154 TI - Increased resting state functional connectivity in the default mode network in recovered anorexia nervosa. AB - Functional brain imaging studies have shown abnormal neural activity in individuals recovered from anorexia nervosa (AN) during both cognitive and emotional task paradigms. It has been suggested that this abnormal activity which persists into recovery might underpin the neurobiology of the disorder and constitute a neural biomarker for AN. However, no study to date has assessed functional changes in neural networks in the absence of task-induced activity in those recovered from AN. Therefore, the aim of this study was to investigate whole brain resting state functional connectivity in nonmedicated women recovered from anorexia nervosa. Functional magnetic resonance imaging scans were obtained from 16 nonmedicated participants recovered from anorexia nervosa and 15 healthy control participants. Independent component analysis revealed functionally relevant resting state networks. Dual regression analysis revealed increased temporal correlation (coherence) in the default mode network (DMN) which is thought to be involved in self-referential processing. Specifically, compared to healthy control participants the recovered anorexia nervosa participants showed increased temporal coherence between the DMN and the precuneus and the dorsolateral prefrontal cortex/inferior frontal gyrus. The findings support the view that dysfunction in resting state functional connectivity in regions involved in self-referential processing and cognitive control might be a vulnerability marker for the development of anorexia nervosa. PMID- 23033156 TI - Multifunctional organic fluorescent materials derived from 9,10 distyrylanthracene with alkoxyl endgroups of various lengths. AB - A series of remarkable multifunctional 9,10-distyrylanthracene derivatives (DSA(n), n = 7-12) was synthesized. All derivatives possess typical aggregation induced emission (AIE) property. Some of the derivatives exhibit multifunctional properties, including AIE, mechanofluorochromism, vapochromism, thermochromism, and mesomorphism, which are rarely found to exist simultaneously in a single compound. PMID- 23033157 TI - Bicyclic core estrogens as full antagonists: synthesis, biological evaluation and structure-activity relationships of estrogen receptor ligands based on bridged oxabicyclic core arylsulfonamides. AB - Compounds that block estrogen action through the estrogen receptor (ER) or downregulate ER levels are useful for the treatment of breast cancer and endocrine disorders. In our search for structurally novel estrogens having three dimensional core scaffolds, we found some compounds with a 7 oxabicyclo[2.2.1]heptene core that bound well to the ERs. The best of these compounds, a phenyl sulfonate ester (termed OBHS for oxabicycloheptene sulfonate), was a partial antagonist on both ERalpha and ERbeta. Although OBHS bears no structural resemblance to other estrogen antagonists, it appears to achieve its partial antagonist character by stabilizing a novel conformation of the ER that involves a significant distortion of helix-11. To enhance the antagonist properties of these oxabicyclo[2.2.1]heptane core ligands, we expanded the functional diversity of OBHS by replacing the sulfonate with secondary or tertiary sulfonamides (-SO(2)NR-), isoelectronic and potentially isostructural molecular replacements. An array of 16 OBHS sulfonamide analogues were prepared through a Diels-Alder reaction of a 3,4-diarylfuran using various N-aryl vinyl sulfonamide dienophiles. While the more polar secondary sulphonamides were weak ligands, certain of the tertiary sulfonamides had very good ER binding affinity. In HepG2 cell reporter gene assays, the sulphonamides had moderate potency, but they showed lower intrinsic transcriptional activity on ERalpha than the selective estrogen receptor modulator (SERM) hydroxytamoxifen or OBHS, and they were inverse agonists on ERbeta. Thus, the behaviour of these OBH-sulfonamides more closely mirrors the activity of full antagonists like the drug fulvestrant (ICI 182 780), and their greater antagonist biocharacter appears to arise from an accentuated distortion of helix-11. PMID- 23033158 TI - Formal total synthesis of palmerolide A. AB - A formal total synthesis of the 20-membered marine macrolide, palmerolide A from chiral pool tartaric acid is described. Elaboration of a gamma-hydroxy amide, which is derived from the desymmetrization of tartaric acid amide, and Boord olefination are the pivotal reactions employed for the synthesis of the chiral building blocks, and Stille coupling and ring-closing metathesis (RCM) are used to assemble the macrolactone. PMID- 23033159 TI - One-pot solvothermal synthesis of uniform layer-by-layer self-assembled ultrathin hexagonal Gd2O2S nanoplates and luminescent properties from single doped Eu3+ and codoped Er3+, Yb3+. AB - Uniform Gd(2)O(2)S flower-like nano-assemblies were prepared through one-pot mild solvothermal synthesis. The parallel nanoplates are the building blocks, ~3 nm in thickness and 20-30 in diameter. Ethanediamine, the main solvent, plays an important role in dissolving a large amount of sulphur and producing active S(2-) ions, which results in the direct formation of Gd(2)O(2)S. Oleylamine, the capping agent, controls the growth of the plate-like structure. Under UV excitation, the Gd(2)O(2)S:Eu(3+) nano-phosphor shows good red luminescence with a main emission peak at 627 nm. Under 980 nm laser excitation, Gd(2)O(2)S:xYb(3+),1%Er(3+) nano-phosphors exhibit a tuneable emission, shifting from greenish-yellow to orange-yellow, with increasing Yb(3+) content. PMID- 23033160 TI - An evidence base for noradrenergic deficits in Parkinson's disease. PMID- 23033161 TI - Crosslinked redox polymer enzyme electrodes containing carbon nanotubes for high and stable glucose oxidation current. AB - Co-immobilisation approaches for preparation of glucose-oxidising films of [Os(2,2'-bipyridine)(2)(poly-vinylimidazole)(10)Cl] and glucose oxidase on glassy carbon electrodes are compared. Electrodes prepared by crosslinking using glutaraldehyde vapour, without and with a NaBH(4) reduction, provide higher glucose oxidation current than those prepared using a well-established diepoxide method. Addition of multi walled carbon nanotubes to the film deposition solutions produces an enhanced glucose oxidation current density of 5 mA cm(-2) at 0.35 V vs. Ag/AgCl, whilst improving the operational stability of the current signal. Carbon nanotube, glutaraldehyde vapour crosslinked, films on electrodes, reduced by NaBH(4), retain 77% of initial catalytic current over 24 hours of continuous amperometric testing in a 37 degrees C, 50 mM phosphate buffer solution containing 150 mM NaCl and 100 mM glucose. Potential application of this approach to implantable enzymatic biofuel cells is demonstrated by production of glucose oxidation currents, under pseudo-physiological conditions, using mediating films with lower redox potentials. PMID- 23033162 TI - Depressed nNOS expression during spine transition in the developing hippocampus of FMR1 KO mice. AB - Nitric oxide (NO), synthesized as needed by NO synthase (NOS), is involved in spinogenesis and synaptogenesis. Immature spine morphology is characteristic of fragile X syndrome (FXS). The objective of this research was to investigate and compare changes of postnatal neuronal NOS (nNOS) expression in the hippocampus of male fragile X mental retardation 1 gene knockout mice (FMR1 KO mice, the animal model of FXS) and male wild-type mice (WT) at postnatal day 7 (P7), P14, P21, and P28. nNOS mRNA levels were analyzed by real-time quantitative PCR (N = 4-7) and nNOS protein was estimated by Western blot (N = 3) and immunohistochemistry (N = 1). In the PCR assessment, primers 5'-GTGGCCATCGTGTCCTACCATAC-3' and 5' GTTTCGAGGCAGGTGGAAGCTA-3' were used for the detection of nNOS and primers 5' CCGTTTCTCCTGGCTCAGTTTA-3' and 5'-CCCCAATACCACATCATCCAT-3' were used for the detection of beta-actin. Compared to the WT group, nNOS mRNA expression was significantly decreased in FMR1 KO mice at P21 (KO: 0.2857 +/- 0.0150, WT: 0.5646 +/- 0.0657; P < 0.05). Consistently, nNOS immunoreactivity also revealed reduced staining intensity at P21 in the FMR1 KO group. Western blot analysis validated the immunostaining results by demonstrating a significant reduction in nNOS protein levels in the FMR1 KO group compared to the WT group at P21 (KO: 0.3015 +/- 0.0897, WT: 1.7542 +/- 0.5455; P < 0.05). These results suggest that nNOS was involved in the postnatal development of the hippocampus in FXS and impaired NO production may retard spine maturation in FXS. PMID- 23033163 TI - [Neuraminidase inhibitors: effects still unclear]. PMID- 23033164 TI - [The common cold: are non-steroidal antiinflammatory drugs effective?]. PMID- 23033165 TI - [Does interferon beta slow the progression of multiple sclerosis? Long-term effect of IFN-beta on progression of physical disability is still not proven]. PMID- 23033166 TI - [Functional activity of autonomous adenoma in Germany]. AB - BACKGROUND: The American (ATA) and the European Thyroid Association (ETA) recommend a thyroid scintiscan for the detection of a suspected autonomy only when serum thyrotropin (TSH) levels are low or suppressed. If ultrasound reveals a thyroid nodule > 1.0 cm and TSH is normal, a fine-needle biopsy is recommended without a preceding scintiscan as the next step. The aim of this prospective study was to evaluate the incidence of reduced or suppressed TSH in 100 autonomous adenoma > 1.0 cm and to clarify, if normal TSH does substantially exclude a focal autonomy. When the study was conducted no data of German patients were available. PATIENTS AND METHODS: An unselected group of 496 patients with a nodular goiter was continuously screened by scintiscan in order to detect 100 autonomous adenoma > 1.0 cm for the study. The following investigations were carried out: ultrasound, scintiscan and laboratory tests (fT3, fT4, TSH, TPO antibodies). The reference range of TSH was 0.4 to 4.0 uU/ml. RESULTS: 21% of patients (100/476) with a nodular goiter had a focal autonomy. 32 % (32/100) of autonomous adenoma revealed a reduced (< 0.4 uU/ml) or completely suppressed TSH, while in 68 % (68/100) normal TSH level were found. CONCLUSION: In Germany autonomous adenoma are still frequent (21 % of all thyroid nodules). Most of them (68 %) reveal normal TSH levels. Our data demonstrate, that there is no relevant connection between TSH level and autonomous adenoma detected by scintiscan. In most cases, TSH is not able to discriminate, whether a nodule is autonomous or not. Biopsy of undetected autonomous nodules should not be performed, as they often show cytological features of follicular neoplasias. In thyroid nodules > 1.0 cm a scintiscan should routinely be performed in primary diagnostics to avoid unnecessary fine-needle biopsy of autonomous adenoma. PMID- 23033167 TI - [Myocardial contrast echocardiography guided alcohol septal ablation in hypertrophic obstructive cardiomyopathy with a new echocardiographic contrast agent]. AB - HISTORY AND ADMISSION FINDINGS: Myocardial contrast echocardiography guided alcohol septal ablation (PTSMA) is an established treatment for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). Most important properties of the optimal echocardiographic contrast agent are good contrast imaging and sufficient stability without fast washing out. HOCM was diagnosed in a 49-year-old female patient 4 years before first admission. Despite optimal medical treatment the patient was highly symptomatic with angina pectoris and dyspnoea NYHA II III.Investigations, treatment and course: ECG showed signs of left ventricular hypertrophy. Echocardiography revealed asymmetric septal hypertrophy, dynamic LVOT obstruction with pronounced SAM and associated moderate mitral valve regurgitation. Coronary angiography performed in the catheterization laboratory showed coronary atherosclerosis and haemodynamic measurements verified a significant LVOT obstruction. An atypical septal branch, originating from the intermediate artery, was regarded as target branch and was occluded with a balloon catheter. For the contrast echocardiography guided septal ablation cold, agitated Gelafundin(r) was used. This led to a good subaortic septal contrast demarcation with confirmation of the correct choice of target branch. No arrhythmias were recorded during the administration of contrast medium. Injection of Levovist(r) in the same septal branch for comparison resulted in opacification of the same myocardial area without any sign of misplacement. After alcohol injection in the balloon-occluded septal branch, an effective elimination of the LVOT gradient could be haemodynamically documented. CONCLUSION: For contrast echocardiography guided PTSMA a good myocardial opacification with an appropriate contrast agent is essential, not only to recognize the obstruction dependent region but also to identify any possible misplacement. Gelafundin(r) seems to offer similarly sufficient contrast potential as Levovist(r), so that Gelafundin(r) could be a possible alternative. PMID- 23033168 TI - [48-year-old patient with progressive dyspnoea and recurrent syncope]. PMID- 23033169 TI - [Focal liver lesion, incidental finding]. AB - The differential diagnosis of incidentally found Focal Liver Lesions (FLL) is complex. Screening procedures so far are only defined for patients with liver cirrhosis. Characterization of a FLL begins as soon as it is detected. Taking patients history and thorough clinical examination are essential. An imaging procedure that is used to detect liver masses should also allow the examiner to determine whether the lesion is benign or malignant. Conventional B-mode US and colour Doppler imaging are effective at detecting and characterizing typical liver cysts and calcifications. Laboratory data, computed tomography, magnetic resonance imaging and imaging guided liver biopsy are complementary methods.Contrast Enhanced Ultrasound (CEUS) is a well established diagnostic imaging technique for a variety of indications and applications. One of the most important applications is in the liver where it is frequently a first-line technique for the detection and diagnosis (characterization) of focal liver lesions (FLL). In this setting the accurate differentiation of benign from malignant lesions is critical to ensure the patient undergoes the appropriate therapeutic option. This has been documented in recently published guidelines, in particular in terms of the enhancement patterns of the most common FLL hemangioma, focal nodular hyperplasia hepatocellular adenoma and their differentiation from malignant lesions. In this article the role of CEUS in the characterization of incidentally found FLL is described. PMID- 23033170 TI - [Testosterone in old age: an up-date]. AB - Contrasting the relatively abrupt hormonal changes during female menopause, male reproductive function gradually declines during aging. This leads to the formal diagnosis of androgen deficiency in many apparently healthy 80-year-old men, when conventional thresholds are applied, and consequently to the question of androgen substitution in geriatric medicine. Although many clinical studies have documented a correlation between low plasma testosterone levels and mortality a clear causal relationship - which would imply immanent substitution therapy - has not been demonstrated. With this in mind, the diagnosis of late-onset hypogonadism (LOH) should only be made when testosterone-deficiency related symptoms concur with low testosterone levels. Which exact symptoms justify the diagnosis of LOH, however, is not sharply defined. Using criteria defined in the recent EMAS study, LOH might even be an over-diagnosed entity without huge relevance in geriatrics. Low testosterone levels are associated with frailty, but testosterone supplementation has only shown limited effects on age-related sarcopenia. Moreover: the increased incidence of cardiovascular events in the TOM study should be a caveat and lead to a moratorium for uncritical testosterone supplementation in aging men with cardiovascular diseases. PMID- 23033171 TI - pH-induced outward movement of star centers within coumarin-centered star-block polymer micelles. AB - A novel coumarin-centered amphiphilic star-block polymer of C-(PDMAEMA(80)-b PS(8))(3) has been designed to investigate the pH-induced accompanying outward movement of hydrophobic coumarin centers within the polymer micelles upon protonation. PMID- 23033172 TI - Total synthesis of (29S,37S)-isomer of malevamide E, a potent ion-channel inhibitor. AB - The first total synthesis of (29S,37S)-malevamide E (1), a potent ion channel inhibitor, has been achieved in a convergent fashion involving Julia-Kocienski olefination, Urpi acetal aldol and Shiina macrolactonization reactions as the key steps. The strategy developed herein is amenable for the synthesis of the other possible isomers in search for the correct stereoisomer of the naturally occurring molecule. PMID- 23033173 TI - Synthesis of the originally proposed structure of palmerolide C. AB - A stereoselective synthesis of the proposed structure of palmerolide C (1), a cytotoxic marine macrolide isolated from the Antarctic tunicate Synoicum adareanum, utilizes a convergent carbonyl-based coupling strategy to construct the C1-C24 carbon skeleton (see scheme). Compound 1 was shown to be a diastereomer of palmerolide C, and the structural revision of the natural product is proposed. PMID- 23033174 TI - A synthetic peptide derived from the parasite Toxoplasma gondii triggers human dendritic cells' migration. AB - The migration of DCs is a critical function, enabling information to be carried to where the immunological response occurs. Parasites are known to weaken host immunity by interfering with the functions of DCs and thus, may be a source of molecules with immunomodulatory properties. Here, we demonstrate that the soluble protein, GRA5, specific to Toxoplasma gondii, is able to increase the migration of human CD34-DCs toward CCL19. A synthetic Pep29 derived from the GRA5 hydrophilic NT region (Pep29) was found to be internalized by macropinocytosis and to trigger in vitro migration of CD34-DCs via CCR7 expression without activating DCs. Pep29 also induced a decrease in the number of LCs from human skin epidermis. As local depletion of DCs and migration of immature DCs lead to a disruption of the specific innate response, our results highlight the potential of using pathogen-derived synthetic peptides as novel cell modulators with a therapeutic potential to reduce symptoms in inflammatory disorders. PMID- 23033175 TI - Crystal structure determination and mutagenesis analysis of the ene reductase NCR. AB - The crystal structure of the "ene" nicotinamide-dependent cyclohexenone reductase (NCR) from Zymomonas mobilis (PDB ID: 4A3U) has been determined in complex with acetate ion, FMN, and nicotinamide, to a resolution of 1.95 A. To study the activity and enantioselectivity of this enzyme in the bioreduction of activated alpha,beta-unsaturated alkenes, the rational design methods site- and loop directed mutagenesis were applied. Based on a multiple sequence alignment of various members of the Old Yellow Enzyme family, eight single-residue variants were generated and investigated in asymmetric bioreduction. Furthermore, a structural alignment of various ene reductases predicted four surface loop regions that are located near the entrance of the active site. Four NCR loop variants, derived from loop-swapping experiments with OYE1 from Saccharomyces pastorianus, were analysed for bioreduction. The three enzyme variants, P245Q, D337Y and F314Y, displayed increased activity compared to wild-type NCR towards the set of substrates tested. The active-site mutation Y177A demonstrated a clear influence on the enantioselectivity. The loop-swapping variants retained reduction efficiency, but demonstrated decreased enzyme activity compared with the wild-type NCR ene reductase enzyme. PMID- 23033176 TI - Palladium(II)-catalyzed oxidative cyclization of allylic tosylcarbamates: scope, derivatization, and mechanistic aspects. AB - A highly selective oxidative palladium(II)-catalyzed (Wacker-type) cyclization of readily available allylic tosylcarbamates is reported. This operationally simple catalytic reaction furnishes tosyl-protected vinyl-oxazolidinones, common precursors to syn-1,2-amino alcohols, in high yield and excellent diasteroselectivity (>20:1). It is demonstrated that both stoichiometric amounts of benzoquinone (BQ) as well as aerobic reoxidation (molecular oxygen) is suitable for this transformation. The title reaction is shown to proceed through overall trans-amidopalladation of the olefin followed by beta-hydride elimination. This process is scalable and the products are suitable for a range of subsequent transformations such as: kinetic resolution (KR) and oxidative Heck , Wacker-, and metathesis reactions. PMID- 23033177 TI - Lung cancer and smoking trends in Brazil. PMID- 23033178 TI - Phenylketonuria, congenital hypothyroidism and haemoglobinopathies: public health issues for a Brazilian newborn screening program. AB - In this study, the frequency of detected congenital hypothyroidism, phenylketonuria and haemoglobinopathies in the State of Rio de Janeiro's (Brazil) Newborn Screening Program (NBSP) was analyzed between the years of 2005 and 2007. There were two Newborn Screening Reference Centers (named NSRC A and B) with programmatic differences. In 2007, overall detection coverage reached 80.7%. The increase in the incidence of congenital hypothyroidism (1:1,030 in 2007) was attributed to the reduction of neonatal TSH value limits over time. The incidence discrepancy of phenylketonuria between NSRC A (1:28,427) and B (1:16,522) might be partially explained by the small number of cases. The incidence of sickle cell disease and its traits were uniformly high (1:1,288 and 1:21, respectively). This was coherent with the ethnic composition of the population. The differences in laboratory methods and critical values, in addition to other programmatic issues, may explain the variances in the results and limited analysis of the role of biological and environmental determinants in the occurrence of these diseases. PMID- 23033179 TI - Physical and psychosocial risk factors for musculoskeletal disorders in Brazilian and Italian nurses. AB - As part of the international CUPID investigation, we compared physical and psychosocial risk factors for musculoskeletal disorders among nurses in Brazil and Italy. Using questionnaires, we collected information on musculoskeletal disorders and potential risk factors from 751 nurses employed in public hospitals. By fitting countryspecific multiple logistic regression models, we investigated the association of stressful physical activities and psychosocial characteristics with site-specific and multisite pain, and associated sickness absence. We found no clear relationship between low back pain and occupational lifting, but neck and shoulder pain were more common among nurses who reported prolonged work with the arms in an elevated position. After adjustment for potential confounding variables, pain in the low back, neck and shoulder, multisite pain, and sickness absence were all associated with somatizing tendency in both countries. Our findings support a role of somatizing tendency in predisposition to musculoskeletal disorders, acting as an important mediator of the individual response to triggering exposures, such as workload. PMID- 23033180 TI - Is there a crack epidemic among students in Brazil?: comments on media and public health issues. AB - In the past year, the Brazilian Federal Government and society have reported and acted on a crack use epidemic, which has been exacerbated by the media. This study hypothesized that crack use has not increased at the rate suggested by the Brazilian media. A cross-sectional survey was carried out in 2010 using a multistage probabilistic representative sample of Brazilian middle and high school students in the country's 27 state capitals. A total of 50,890 valid questionnaires were weighted, analyzed and results compared to the 2004 national school survey dataset. Considering lifetime and past year crack use, no change in consumption was found between 2004 and 2010. Official data in Brazil on middle and high school students does not support the assertion of a crack epidemic widely publicized by the media. Government measures to treat and prevent crack use are encouraged; however, the term epidemic has been inappropriately used to represent the static prevalence of crack consumption among students. PMID- 23033181 TI - [Prenatal patient cards and quality of prenatal care in public health services in Greater Metropolitan Vitoria, Espirito Santo State, Brazil]. AB - This study aimed to assess the completeness of prenatal care information on the patients' prenatal care cards, according to coverage by various public health services: Family Health Strategy (FHS), Community-Based Health Workers' Program (CBHWP), and traditional Primary Care Units (PCU) in Greater Metropolitan Vitoria, Espirito Santo State, Brazil. In a cross-sectional study, 1,006 prenatal cards were randomly selected from postpartum women at maternity hospitals in the metropolitan area. Completeness of the cards was assessed according to the criteria proposed by Romero & Cunha, which measure the quality on a scale from excellent (< 5% incomplete cards) to very bad (> 50% incomplete cards). In general, completion of information on the cards was bad (> 20% incomplete), but cards were filled out better in the FHS than in the CBHWP and PCU, especially for tetanus vaccination (p = 0.016) and gestational weight (p = 0.039). In conclusion, the quality of prenatal care in the public health system in Greater Metropolitan Vitoria fails to meet the Brazilian national guidelines for maternal and child health. PMID- 23033182 TI - [Social inequality in morbidity and mortality from oral and oropharyngeal cancer in the city of Sao Paulo, Brazil: 1997-2008]. AB - Occupation of geographical space is historically determined by the socioeconomic model and the dynamism of its social, political, and ideological relations. This study aimed to evaluate the spatial distribution of morbidity and mortality from cancer of the mouth and oropharynx and related socioeconomic variables in the city of Sao Paulo, Brazil, from 1997 to 2008. Data were collected from the Population-Based Cancer Registry and the Program for Improvement of Mortality Data (PRO-AIM) and were georeferenced using Terraview and GeoDa. The theoretical framework for evaluating the results was the work of Milton Santos. The incidence rates showed spatial autocorrelation with a Global Moran index of 0.226 and mortality rates of 0.337. Incidence of cancer of the mouth and oropharynx did not show a well-defined spatial pattern in the city of Sao Paulo, but mortality rates were highly unequal, concentrating the lowest rates in the central area of the city, which is wealthier and economically less unequal. PMID- 23033183 TI - Sleep duration and health status self-assessment (SF-36) in the elderly: a population-based study (ISA-Camp 2008). AB - The aim of this study was to determine the association between sleep duration and health status among the elderly. A population-based study was carried out with 1,418 elderly individuals using data from the health survey of Campinas, Sao Paulo State, Brazil (ISA-Camp 2008). Linear regression models were used to determine associations between the physical and mental components and subscales of the SF-36 and sleep duration. Elderly male individuals who slept <= 6 hours obtained lower mean SF-36 scores for the vitality and mental health scales and the mental component summary than those who slept for seven to eight hours. All scales were negatively associated with sleep duration >= 10 hours, except bodily pain. Scores for the mental health, vitality and role-emotional subscales were lower among women who slept for less than five hours. Mental health was negatively associated with >= 10 hours of sleep. Sleep deprivation and excessive sleep were associated with poorer health status, with differences between genders, principally in the long duration sleep categories. PMID- 23033184 TI - [Leprosy diagnosis in municipalities other than the patients' place of residence: spatial analysis, 2001-2009]. AB - The study analyzed the flow of persons with leprosy from their municipality (county) of residence to that of their diagnosis in a highly endemic area in Brazil. The study was based on data from the National Information System for Notifiable Diseases from 2001 to 2009 in the States of Maranhao, Para, Tocantins, and Piaui. Of the 373 municipalities, 349 (93.6%) had at least one resident with leprosy that had been diagnosed in a different municipality (4,325 cases, or 5.2% of the total). The municipalities with the most cases reported elsewhere were Timon (248) and Sao Jose de Ribamar (201), Maranhao State. The municipalities that received the most exogenous cases for diagnosis were Sao Luis (719), capital of Maranhao, and Teresina (516), capital of Piaui. Goiania (146), capital of Goias, and the Federal District (42) also reported numerous cases, even though they are located more than 1,000 km from the endemic area. The flow indicates gaps in the decentralization of comprehensive care for persons with leprosy and calls attention to the difficulties associated with patient monitoring during and after multidrug therapy. PMID- 23033185 TI - [Thirty years of homicides in Medellin, Colombia, 1979-2008]. AB - In Medellin, Colombia, homicides have been the leading cause of death since 1986. Their proportion among total deaths increased from 3.5% in 1976 to 42% in 1991 and subsequently decreased to 7% in 2006. From 1979 to 2008, there were 81,166 homicides (annual mean, 2,706). The homicide rates per 100,000 inhabitants were 44 in 1979 and 47 in 2008, with a peak of 388 in 1991. The current article analyzes homicides in 30 years (1979-2008) using a random sample of 3,414 forensic autopsy reports. The vast majority of victims were males, 92.8% (95%CI: 91.8%; 93.6%), mostly low-income young people from 27 to 33 years of age. Most homicides involved revenge, fights, or armed robberies. The study showed different periods in the homicide epidemic: the first 15 years, with a rapid increase, the second, with a steady decline until 1998, and the third, with a fluctuating but overall steep decline in the last 10 years. This long-term study on violence in Medellin opens possibilities for analyzing and identifying more consistent policies for intervention. PMID- 23033186 TI - [Adverse events following vaccination against pandemic influenza A (H1N1) 2009 in children]. AB - The aim of this study was to estimate the frequency of adverse events following vaccination against pandemic influenza A (H1N1) 2009 and associated factors in children from six months to two years of age (n = 156). Multivariate Cox regression was used to assess the independent associations between covariates and complaints of at least one adverse event. Strength of association was measured by hazard ratios and respective 95% confidence intervals. Following the first dose, 40.3% of parents reported one or more adverse events in their children, compared to 35.5% after the second dose. Systemic adverse events, specifically irritation, diarrhea, and fever, were more frequent than local reactions at the vaccination site. Incidence rates for adverse events in general and systemic reactions following the first dose were higher in children with concomitant illness or allergies (HR = 3.43, 95%CI: 1.34-8.77 and HR = 2.76, 95%CI: 1.11-6.89). Most events were mild. Cases of high fever, vomiting, and diarrhea prompted parents to seek care for their children at health services. PMID- 23033187 TI - [Association between physical violence, consumption of alcohol and other drugs, and bullying among Brazilian adolescents]. AB - This study aimed to identify the association between alcohol and drug consumption and bullying on the one hand and involvement in situations of physical violence among adolescents 13 to 15 years in public and private schools in State capitals and the Federal District of Brazil. The study analyzed data from the National School Health Survey (PeNSE) for the year 2009. Data analysis used logistic regression. Prevalence of involvement in physical violence was 12.9% more common in boys than girls. Both genders showed associations between physical violence or being a victim of bullying and use of illegal drugs, plus the heightened effect of the combined consumption of alcohol and other drugs. In boys, alcohol consumption showed a significant association with physical violence. Having the father or both parents living at home was inversely associated with physical violence in girls. Knowledge of factors associated with physical violence among adolescents is important for supporting health promotion strategies and a culture of peace, thereby counteracting the idea of taking teenage violence for granted. PMID- 23033188 TI - The impact of atmospheric particulate matter on cancer incidence and mortality in the city of Sao Paulo, Brazil. AB - This study aimed to verify the impact of inhalable particulate matter (PM(10)) on cancer incidence and mortality in the city of Sao Paulo, Brazil. Statistical techniques were used to investigate the relationship between PM(10) on cancer incidence and mortality in selected districts. For some types of cancer (skin, lung, thyroid, larynx, and bladder) and some periods, the correlation coefficients ranged from 0.60 to 0.80 for incidence. Lung cancer mortality showed more correlations during the overall period. Spatial analysis showed that districts distant from the city center showed higher than expected relative risk, depending on the type of cancer. According to the study, urban PM(10) can contribute to increased incidence of some cancers and may also contribute to increased cancer mortality. The results highlight the need to adopt measures to reduce atmospheric PM(10) levels and the importance of their continuous monitoring. PMID- 23033189 TI - [Challenges for dealing with cases of domestic violence against children and adolescents through the Family Health Program in a medium-sized city in Rio de Janeiro state, Brazil]. AB - This qualitative case study aimed to analyze the challenges faced by the Family Health Program (FHP) teams in dealing with domestic violence against children and adolescents in Teresopolis, Rio de Janeiro State, Brazil. The sample consisted of 25 professionals from three family health teams. Data were collected through face to-face semi-structured thematic interviews and submitted to content analysis. Findings included the health professionals' detection of cases of domestic violence among families enrolled in the program, often associated with drug use and drug dealing, alcoholism, family breakdown, and poverty. Collaboration with the community and difficulty in inter-sector actions were identified as challenges for detecting, reporting, and monitoring cases. Most professionals felt insecure in dealing with such cases, due to lack of appropriate knowledge and skills. The study concludes that it is essential to managers, staff and community discuss the problem and means to approach it in the context of the territories. PMID- 23033190 TI - [Food consumption Brazilian children by 6 to 59 months of age]. AB - The aim of this study was to assess food consumption in Brazilian children 6 to 59 months of age by region of the country and area of residence. This was a descriptive cross-sectional study of 4,322 children in the National Demographic and Health Survey (2006-2007). The data showed low daily consumption of leafy vegetables (12.7%), vegetables (21.8%), and meat (24.6%) and high consumption (1 3 times a week) of soft drinks (40.5%), fried foods (39.4%), salty snacks (39.4%), and sweets (37.8%). Comparing the regions of Brazil, children in the South, Southeast, and Central-West consumed more rice, bread, potatoes, beans, greens, vegetables, and meat, but they also ate more foods not recommended for their age, like sweets and soft drinks (soda). Rural children showed lower consumption of foods recommended for their age and also those not recommended for their age, as compared to their urban counterparts. According to this study, food consumption in these young children fails to meet the recommendations for healthy eating in this age bracket. PMID- 23033191 TI - [Quality assessment of primary care by health professionals: a comparison of different types of services]. AB - In Porto Alegre, Rio Grande do Sul State, Brazil, public primary healthcare (PHC) is provided by traditional Basic Health Units (BHU), the Family Health Strategy (FHS), the Murialdo Health Center (MHC), and the Community Health Service (CHS) of Grupo Hospitalar Conceicao. This study compares the quality of adult healthcare among these different types of services. Quality of care was measured by interviews focusing on the experience of physicians and nurses in the services (n = 340), using the Primary Care Assessment Tool. Overall scores for the FHS, MHC, and CHS were significantly higher than for the BHU. The CHS also showed a significantly higher overall score compared to the FHS and MHC. In the multivariate analysis, the variables "specialized training in PHC" and "continuing education" were associated with high overall score. Thus, expansion of FHS coverage and investment in professional training are important potential strategies for improving PHC in Porto Alegre. PMID- 23033192 TI - [Epidemiological study of scorpion stings in Belo Horizonte, Minas Gerais State, Brazil, 2005-2009]. AB - This retrospective epidemiological study focused on scorpion stings in Belo Horizonte, Minas Gerais State, Brazil, from 2005 to 2009. Data on reported scorpion stings were taken from the National System for Notifiable Diseases (SINAN) and the Epidemiological Surveillance System (SISVE) and patient records from the Joao XXIII Hospital. There were 2,769 cases of scorpion stings in Belo Horizonte (114.7 cases per 100,000 inhabitants), with a downward trend over time and the highest incidence from August to January. Tityus serrulatus was the species involved in most of the stings. There was no statistical difference in the incidence between male and female victims, and the most frequently affected age bracket was 55 to 64 years. Ninety-six percent of cases evolved to cure, and there were two deaths. It is necessary to improve the reporting process for scorpion stings and to consider the determinants of scorpion stings in order to plan and implement effective public health interventions. PMID- 23033193 TI - [Test-retest reliability of the scale silhouettes figures of body image in Brazilian Longitudinal Study of Adult Health]. AB - We applied silhouette scales for assessing body image on two occasions with a 7 to 14 day interval in 281 participants in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Intraclass correlation coefficient (ICC) was used to measure test-retest reliability. The item "how participants see their current body size" showed ICC from 0.92 to 0.97, with no difference by gender, age, or schooling. "Ideal body size" showed ICC from 0.86 to 0.92 and was lower among men. Temporal stability was satisfactory, allowing for use of the scales in studies on body image in the ELSA-Brasil and similar populations. PMID- 23033194 TI - [Cross-cultural adaptation of the Tilburg Frailty Indicator (TFI) for use in the Brazilian population]. AB - The current study aimed to adapt the Tilburg Frailty Indicator (TFI), used to assess frailty in the elderly, to the Brazilian population. Conceptual, item, and semantic equivalences were analyzed and the summary version was pre-tested. In the evaluation of conceptual equivalence, the construct for frailty adopted in Brazil demonstrated the same conceptualization as in other cultures where this condition has been investigated. All items included in the original version also showed similarity in the two cultures. High semantic equivalence was observed in the analysis of the items' referential and general meanings. The pre-test showed a high percentage of understanding of items and good acceptance of items by elderly individuals. The results suggest that the TFI version adapted to the Brazilian culture can be a useful tool for assessing health conditions in older Brazilians. PMID- 23033195 TI - Diversity of containers and buildings infested with Aedes aegypti in Puerto Iguazu, Argentina. AB - Aedes aegypti is the main domestic vector of the dengue virus. Control measures to prevent dengue transmission focus on the treatment and elimination of this vector's oviposition sites. There is limited biological information on Ae. aegypti in Argentina. The aim of this study was to characterize Ae. aegypti oviposition sites in the city of Puerto Iguazu, Argentina. We surveyed an area covering nine neighborhoods in 2005. We identified 191 premises as positive for Ae. aegypti, giving a general house index of 9.6%. Premises classified as residential and vacant lots presented the highest number of infested premises, with 9% and 22% respectively. The total number of surveyed containers was 29,600. The overall container index (CI) was 1.1. The most frequently infested containers were water tanks (CI = 37). These preliminary results suggest that vacant lots and water tanks provide suitable breeding areas and environmental conditions, improving the chances of Ae. aegypti survival in Puerto Iguazu. PMID- 23033196 TI - [Towards a transdisciplinary approach and social determinants for the study of infant mortality]. PMID- 23033198 TI - Reproducibility study of crown-rump length and biparietal diameter measurements in the first trimester. AB - OBJECTIVE: This study aims to investigate the intra-observer and inter-observer variability of crown-rump length (CRL) and biparietal diameter (BPD) measurements in the first trimester. METHODS: A prospective observational study on 592 fetuses between 8 and 14 gestational weeks was conducted. Intra-class correlation coefficients (ICCs) were computed, and Bland-Altman analysis was carried out. RESULTS: The ICCs (95% confidence interval) and the 95% limits of agreement, expressed as a percentage of the average, for CRL's intra-observer and inter observer variability were 0.979 (0.974-0.982, p < 0.001), +8.53% to -8.376%, and 0.968 (0.952-0.978, p < 0.001), +9.06% to -7.69%, respectively. The corresponding figures for BPD were 0.981 (0.977-0.984, p < 0.001), +7.41% to -7.51%, and 0.968 (0.952-0.978, p < 0.001), +6.65% to -7.25%. After conversion in days, the ICCs and 95% limits of agreement for CRL's intra-observer and inter-observer variability were 0.983 (0.980-0.986, p < 0.001), +2.88% to -2.84%, and 0.971 (0.957-0.980, p < 0.001), 2.83% to -2.60%, respectively. The corresponding figures for BPD were 0.982 (0.979-0.986, p < 0.001), +3.36% to -3.40%, and 0.968 (0.953-0.978, p < 0.001), +3.06% to -3.38%. CRL's standard deviation of the differences increased with gestation for intra-observer (r = 0.289, p < 0.001) and inter-observer (r = 0.197, p = 0.023) variability. CONCLUSION: The BPD and CRL are highly reproducible measurements. CRL's measurement error increased with the magnitude of CRL, whereas BPD's reproducibility was not affected by gestational age. PMID- 23033199 TI - Sensitive SERS detection of DNA and lysozyme based on polymerase assisted cross strand-displacement amplification. AB - A novel surface-enhanced Raman scattering (SERS) assay is demonstrated by developing a cross strand-displacement amplification (CSDA) method to enhance the SERS signals. Highly sensitive and selective detection of any single-stranded DNA is achieved and an aptasensor for proteins is constructed. PMID- 23033200 TI - Sterically crowding the bridge of dithienylcyclopentenes for enhanced photoswitching performance. AB - Better switching: The introduction of bulky substituents into the bridge moiety of dithienylethenes led to derivatives exhibiting high photocyclization quantum yields. This novel and versatile form of substitution facilitated tuning of the switching performance without compromising on the optical and redox properties of the ring-open and ring-closed forms (see scheme). PMID- 23033201 TI - [More physical activity: pedometers for our patients]. PMID- 23033202 TI - [Parkinson's disease: current standards in diagnostics and therapy]. AB - Idiopathic Parkinson's disease is still a clinical diagnosis. However, modern imaging and nuclear techniques allow very early diagnosis and lead to higher security in the differential diagnosis between idiopathic Parkinson's disease and atypical Parkinson syndromes. At early stages of the disease, modification of disease progression and symptom control are key factors of the therapy. Continuous dopaminergic stimulation is even more important at later stages with first fluctuations. In stages where conservative medical options have been exhausted continuous pump therapies with Duodopa and apomorphine are attractive options. Deep brain stimulation in the subthalamic nucleus has turned out in the last years, especially in younger patients, to be a highly successful treatment option. Deep drain stimulation requires, however, a close preoperative work-up and individual consideration of potential effects and side effects. PMID- 23033203 TI - [Interventions in people at risk of developing first episode psychosis: a survey of current randomised controlled studies]. AB - Early and valid detection of the psychosis risk syndrome, and indicated prevention aim at preventing, delaying or ameliorating frank psychosis, improving current symptoms as well as emerging psychosocial disability. In a systematic literature search we identified seven completed randomised controlled trials of interventions for individuals at high risk of developing first episode psychosis. These studies evaluated antipsychotics, neuroprotective agents, cognitive behavioural and integrated treatment approaches. All trials reported advantages for specific interventions as compared to the respective control conditions (although not significant in each of the studies), which proved to be significant in the first meta-analysis of the studies. However, the current results do not allow recommendations for any specific treatment. Therefore, interventions should be thoroughly reviewed based on their risk/benefit ratio. The level of individual clinical risk, assumed benefits and side effects of interventions are critical determinants for these considerations. Future research is needed with sufficiently powered, methodologically sound replication studies, which are designed to explore differential efficacy of the interventions. PMID- 23033204 TI - [Neurological complex treatment: impact on mortality in the first year and costs for statutory health insurance]. AB - BACKGROUND: The purpose of this study was to compare standard treatment of strokes with a complex form, defined by the German procedure classification. PATIENTS AND METHODS: 3827 patients in 2005 were compared with 4315 patients in 2007 concerning mortality within hospital and 30, 90 and 360 days after hospital admission. Furthermore, the costs for the statutory health insurances were linked to the mortality rates. 2005 was set as proxy for the standard treatment and 2007 as proxy for the neurological complex treatment. RESULTS: There were significant differences in the 1-year mortality with a 3.11 percentage point reduction (p < 0.0373). For the other periods, there were no significant deviations. The cost for the statutory health insurance per case rose with an average of 0.4809 cost weights. CONCLUSION: There are hints of an improvement in the long-term mortality after the introduction of complex neurological treatment. For the health insurance significant additional costs ensue, which are in an international published range. On the other hand, savings by improving the morbidity must be taken into account. PMID- 23033205 TI - [Cerebral venous thrombosis and subdural haematoma: complications of spontaneous intracranial hypotension]. AB - We report on the case of a spontaneous intracranial hypotension with subdural hygroma, as well as cerebral venous thrombosis (CVT), both known complications of intracranial hypotension. The 45-year-old patient was subsequently treated - according to current guidelines for CVT - with anticoagulation, but developed subdural haematoma (SDH), which required neurosurgical treatment. Our case highlights the complex pathophysiological sequelae of intracranial hypotension, as well as the occasionally difficult treatment decisions. Subdural hygroma probably predisposes patients to SDH during anticoagulation. Thus, the potential benefit of anticoagulation needs to be weighed against the risk of SDH on an individual basis. PMID- 23033206 TI - [Dysthymia]. PMID- 23033207 TI - Photochemistry of N-methylformamide: matrix isolation and nonadiabatic dynamics. AB - The photochemistry of N-methylformamide (MF) is elucidated by investigating its photodissociation products generated by UV irradiation (248 nm) in an argon matrix (10 K). We find that, starting from trans-MF, prolonged irradiation produces cis-MF, CH3NH2 and CO fragments as major products. Another photoproduct is identified as methylformimidic acid (FIA). Nonadiabatic dynamics simulations starting from both MF conformers revealed that the internal conversion occurs within 1 ps through a C-N dissociation channel. The major product is a weakly bound complex between CH3NH and HCO radicals. This complex owes its existence to the cage effect of the matrix which allows for H-transfer reactions and recombination. By identifying the primary photoisomerization and photodissociation pathways of MF, we gain new insights into the photochemistry of peptide bonds in general, which is a prerequisite for a better understanding of the effect of UV irradiation on living systems. PMID- 23033208 TI - Characterization of serotonin transporter gene (SLC6A4) polymorphisms and its association with drug dependence in a Jordanian Arab population. AB - Drug dependence is a pattern of repeated self-administration of a drug, which can result in tolerance, withdrawal and compulsive drug-taking behaviour. It has been recently suggested that 5-HTTLPR (LL/LS/SS) variants and rs25531 (A/G) polymorphism in the serotonin transporter gene (SLC6A4) may play a role in drug dependence. The current study aimed to (1) identify allelic, haplotypic and genotypic frequencies of the 5-HTTLPR variants and rs25531 polymorphisms of SLC6A4 gene in drug and nondrug-dependent Jordanian Arab population and (2) determine whether there is an association of these variants in a drug-dependent population from the same area. Jordanian drug male addicts of Arab descent (n = 192) meeting the Diagnostic and Statistical Manual of Mental Disorders - Fourth edition criteria for drug dependence and 230 healthy male controls from an ethnically homogenous Jordanian Arab population were examined. Genotyping was performed using the restriction fragment length polymorphism-polymerase chain reaction-based method to genotype the 5-HTTLPR variants and detect the A/G polymorphism at position rs25531. The biallelic analysis revealed that the frequency of 5-HTTLPR (LL/LS/SS) genotypes was statistically significant different between drug-dependent individuals and controls (chi (2) (2, N = 422), p = 0.04). Drug-dependent subjects had a higher frequency of 'L' allele. However, using the triallelic approach, the estimated frequency of haplotypes (SA , SG , LA and LG ) and phased genotypes (LA /LA , LA /SA , LA /LG , SA /SA and SA /SG) did not show significant association with drug dependence (chi (2) (3, N = 422), p = 0.53 and chi (2) (4, N = 422), p = 0.06, respectively). This study suggests a putative role of the 5-HTTLPR for drug dependence in the Jordanian Nationals of Arab ancestry. PMID- 23033209 TI - Arsenic residue in the products and by-products of chicken and ducks: a possible concern of avian health and environmental hazard to the population in West Bengal, India. AB - Arsenicosis caused due to drinking of arsenic contaminated ground water is a major environmental health hazard throughout the world. We evaluated the ecotoxicological effect of arsenic on chicken and duck in an arsenic endemic zone. The concentration of arsenic was higher in chicken and duck feed and their by-products than that in the respective samples of control area. Arsenic concentration in the eggs of both chicken and duck was higher than that in the respective samples of control area. Thus, we concluded that arsenic enters into food chain through the intake of contaminated eggs. Furthermore, adverse health effect of arsenic on avian population is due to the alteration in haematobiochemical indices. PMID- 23033210 TI - Low concentration of mercury induces autophagic cell death in rat hepatocytes. AB - In the present study, we attempted to elucidate the induction of autophagy in rat hepatocytes by a low concentration of mercury. Hepatocytes treated with different doses of mercuric chloride (HgCl2; 1, 2.5, 5 and 10 uM) and at different time intervals (0 min, 30 min, 1 h, 2 h and 4 h) show autophagic cell death only at 5 uM HgCl2 within 30 min of incubation. At 1 and 2.5 uM HgCl2, no cell death is recorded, while apoptosis is found at 10 uM HgCl2, as evidenced by the activation of caspase 3. Autophagic cell death is confirmed by the presence of monodansylcadaverine (MDC) positive hepatocytes which is found to be highest at 1 h. Atg5-Atg12 covalent-conjugation triggers the autophagic pathway within 30 min of 5 uM HgCl2 treatment and continues till 4 h of incubation. In addition, damage regulated autophagy modulator (DRAM) expression gradually increases from 30 min to 4 h of treatment with mercury and a corresponding linear decrease in p53 has been observed. It is concluded that a low concentration (5 uM HgCl2) of mercury induces autophagy or nonapoptotic programmed cell death following an Atg5-Atg12 covalent-conjugation pathway, which is modulated by DRAM in a p53-dependent manner. PMID- 23033211 TI - Functionalized periodic mesoporous organosilica: a highly enantioselective catalyst for the Michael addition of 1,3-dicarbonyl compounds to nitroalkenes. AB - A functionalized periodic mesoporous organosilica with incorporated chiral bis(cyclohexyldiamine)-based Ni(II) complexes within the silica framework was developed by the co-condensation of (1R,2R)-cyclohexyldiamine-derived silane and ethylene-bridge silane, followed by the complexation of NiBr(2) in the presence of (1R,2R)-N,N'-dibenzylcyclohexyldiamine. Structural characterization by XRD, nitrogen sorption, and TEM disclosed its orderly mesostructure, and FTIR and solid-state NMR spectroscopy demonstrated the incorporation of well-defined single-site bis(cyclohexyldiamine)-based Ni(II) active centers within periodic mesoporous organosilica. As a chiral heterogeneous catalyst, this functionalized periodic mesoporous organosilica showed high catalytic activity and excellent enantioselectivity in the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroalkenes, comparable to those with homogeneous catalysts. In particular, this heterogeneous catalyst could be recovered easily and reused repeatedly up to nine times without obviously affecting its enantioselectivity, thus showing good potential for industrial applications. PMID- 23033212 TI - Possible effects of reduced conductance in delayed-rectifier K+ current on neuronal firing. PMID- 23033213 TI - STARD4 knockdown in HepG2 cells disrupts cholesterol trafficking associated with the plasma membrane, ER, and ERC. AB - STARD4, a member of the evolutionarily conserved START gene family, has been implicated in the nonvesicular intracellular transport of cholesterol. However, the direction of transport and the membranes with which this protein interacts are not clear. We present studies of STARD4 function using small hairpin RNA knockdown technology to reduce STARD4 expression in HepG2 cells. In a cholesterol poor environment, we found that a reduction in STARD4 expression leads to retention of cholesterol at the plasma membrane, reduction of endoplasmic reticulum-associated cholesterol, and decreased ACAT synthesized cholesteryl esters. Furthermore, D4 KD cells exhibited a reduced rate of sterol transport to the endocytic recycling compartment after cholesterol repletion. Although these cells displayed normal endocytic trafficking in cholesterol-poor and replete conditions, cell surface low density lipoprotein receptor (LDLR) levels were increased and decreased, respectively. We also observed a decrease in NPC1 protein expression, suggesting the induction of compensatory pathways to maintain cholesterol balance. These data indicate a role for STARD4 in nonvesicular transport of cholesterol from the plasma membrane and the endocytic recycling compartment to the endoplasmic reticulum and perhaps other intracellular compartments as well. PMID- 23033214 TI - Pituitary function in patients with hereditary haemochromatosis. AB - Haemochromatosis may impair the function of endocrine organs, amongst others the pituitary gland. It was the aim of this study to determine pituitary function in adult patients with genetically defined hereditary haemochromatosis in a prospective diagnostic study using a standardised stimulation test. Therefore, 22 patients (7 females, 15 males; age at diagnosis of haemochromatosis 48.1 +/- 7.9 years; age at study inclusion 50.7 +/- 7.7 years) with genetically defined hereditary haemochromatosis were investigated by a combined pituitary stimulation test (CRH, GHRH/arginine, GnRH, TRH). In 11 patients (50% of the study population; 2 females, 9 males), pituitary insufficiencies were detected [isolated corticotrophic insufficiency (peak cortisol < 181.25 MUg/l/500 nmol/l) n=10 (2 females, 8 males); combined corticotrophic and borderline gonadotrophic insufficiency (basal testosterone 2.4-3.0 MUg/l without basal LH-elevation) in 1 male]. Somatotrophic pituitary insufficiencies were not found. IFG-1 concentrations below -2 standard deviations in 7 patients (32%) may be attributed to impaired hepatic IGF-1 synthesis. Hypopituitarism, particularly corticotrophic insufficiency, seems to be prevalent in a considerable number of middle-aged patients with hereditary haemochromatosis. Despite normal somatotrophic function, low IGF-1 serum concentrations may be found in a subgroup of haemochromatosis patients. PMID- 23033215 TI - NMR of hyperpolarised probes. AB - Increasing the sensitivity of NMR experiments is an ongoing field of research to help realise the exquisite molecular specificity of this technique. Hyperpolarisation of various nuclei is a powerful approach that enables the use of NMR for molecular and cellular imaging. Substantial progress has been achieved over recent years in terms of both tracer preparation and detection schemes. This review summarises recent developments in probe design and optimised signal encoding, and promising results in sensitive disease detection and efficient therapeutic monitoring. The different methods have great potential to provide molecular specificity not available by other diagnostic modalities. PMID- 23033216 TI - Advanced geometries of PEDOT formed in titania nanotubes. AB - In and out of tube: Robust poly-3,4-ethylene-dioxythiophene nanostructures in the form of nanopore arrays and inverse nanotube arrays are obtained by site selective deposition into TiO(2) nanotubes. The deposition process critically depends on the applied potential and is in line with three-dimensional (3D) progressive and 3D instantaneous nucleation-growth mechanism, leading to the construction of polymer blocks or polymer/semiconductor hybrids. PMID- 23033217 TI - Refolding of urea-denatured alpha-chymotrypsin by protein-folding liquid chromatography. AB - An approach for re-folding denatured proteins during proteome research by protein folding liquid chromatography (PFLC) is presented. Standard protein, alpha chymotrypsin (alpha-Chy), was selected as a model protein and hydrophobic interaction chromatography was performed as a typical PFLC; the three different alpha-Chy states - urea-denatured (U state), its folded intermediates (M state) and nature state (N state) - were studied during protein folding. Based on the test by matrix-assisted laser desorption/ionization time of flight mass spectrometry and bioactivity, only one stable M state of the alpha-Chy was identified and then it was prepared for further investigation. The specific bioactivity of the refolded alpha-Chy was found to be higher than that of commercial alpha-Chy as the urea concentration in the sample solution ranged from 1.0 to 3.0 m; the highest specific bioactivity at urea concentration was 1.0 m, indicating the possibility for re-folding some proteins that have partially or completely lost their bioactivity, as a dilute urea solution was employed for dissolving the sample. The experiment showed that the peak height of its M state increased with increasing urea concentration, and correspondingly decreased in the amount of the refolded alpha-Chy. When the urea concentration reached 6.0 m, the unfolded alpha-Chy could not be refolded at all. PMID- 23033218 TI - Synthesis of amino, azido, nitro, and nitrogen-rich azole-substituted derivatives of 1H-benzotriazole for high-energy materials applications. AB - The amino, azido, nitro, and nitrogen-rich azole substituted derivatives of 1H benzotriazole have been synthesized for energetic material applications. The synthesized compounds were fully characterized by (1)H and (13)C NMR spectroscopy, IR, MS, and elemental analysis. 5-Chloro-4-nitro-1H benzo[1,2,3]triazole (2) and 5-azido-4,6-dinitro-1H-benzo[1,2,3]triazole (7) crystallize in the Pca2(1) (orthorhombic) and P2(1)/c (monoclinic) space group, respectively, as determined by single-crystal X-ray diffraction. Their densities are 1.71 and 1.77 g cm(-3), respectively. The calculated densities of the other compounds range between 1.61 and 1.98 g cm(-3). The detonation velocity (D) values calculated for these synthesized compounds range from 5.45 to 8.06 km s( 1), and the detonation pressure (P) ranges from 12.35 to 28 GPa. PMID- 23033219 TI - Beyond spheres: Murphy's silver nanorods and nanowires. AB - In this viewpoint we discuss the early work of Murphy et al. on the colloidal synthesis of silver nanorods and nanowires, which represents a milestone in the controllable synthesis of anisotropic metal nanoparticles. We present here an overview of the impact of this pioneering work on the later drastic development of solution phase synthesis of shape-controlled metal nanostructures. PMID- 23033221 TI - The speech gene FOXP2 is not imprinted. PMID- 23033222 TI - Findings in Historical Control Harlan RCCHanTM: WIST Rats from 4-, 13-, 26-Week Studies. AB - Vehicle control Harlan RCCHanTM: WIST rats were examined to provide control data for subsequent studies. Sixty male and 60 female rats were sacrificed after 4, 13, and 26 weeks (360 animals total) of daily oral gavage dosing with reverse osmosis water. At necropsy, body weights, organ weights, and macroscopic findings were recorded, and tissues were collected for histopathology. Mean terminal body and organ weight data demonstrated expected age-related trends. Macroscopic findings occurred sporadically, generally at singular or at very low incidence, and with no observable age-related trend. The most frequent observation was discoloration of the stomach mucosa. Neoplastic microscopic findings were uncommon (one endometrial stromal polyp; one hepatocellular adenoma; one C-cell adenoma; and one sarcoma, NOS). The most common and/or notable nonneoplastic microscopic findings included basophilic tubules and mononuclear cell infiltration in the kidney, macrophage infiltration in pulmonary alveoli, and mononuclear infiltration in the liver of males and females, and myocardial degeneration/necrosis and mononuclear cell infiltration in the heart of males. Female reproductive tracts were staged to establish a representative baseline distribution. Diestrus, proestrus, estrus, and metestrus were diagnosed 45.8%, 11.9%, 30.5%, and 11.9%, respectively, at 4 weeks and 27.6%, 13.8%, 50.0%, and 8.6%, respectively, at 13 weeks. PMID- 23033224 TI - Collaborative development of teaching scripts: an efficient faculty development approach for a busy clinical teaching unit. AB - BACKGROUND: Exemplary teachers have been shown to use teaching scripts, ways of organizing the content and instructional approach for commonly encountered teachable moments. This study describes a busy hospitalist unit's early experience with the collaborative development of teaching scripts. METHODS: In 2010, during monthly workshops, 10 faculty members each prepared and presented a teaching script for a different commonly encountered diagnosis. Open-ended surveys assessing the impact on faculty were analyzed using an iterative approach. Changes in faculty self-efficacy, and the frequency and applicability of teaching were measured. RESULTS: The program required 10 hours of attendance time and a mean of 4.3 hours for each faculty member who prepared a teaching script. No significant differences in quantity or applicability of teaching were detected, but faculty self-efficacy improved significantly. In addition, faculty described beneficial effects in their individual professional development, development of a shared mental model of professional responsibility, and interpersonal relationships. A majority of comments were positive; negative comments focused on the time required to prepare scripts, and apprehension about presenting to peers. CONCLUSIONS: The program was an efficient approach to improve self-rated teaching skills, enhance professional development, and build collegiality among clinician-teachers. PMID- 23033223 TI - Dynamics and functional differences between dendroaspin and rhodostomin: insights into protein scaffolds in integrin recognition. AB - Dendroaspin (Den) and rhodostomin (Rho) are snake venom proteins containing a PRGDMP motif. Although Den and Rho have different 3D structures, they are highly potent integrin inhibitors. To study their structure, function, and dynamics relationships, we expressed Den and Rho in Pichia pastoris. The recombinant Den and Rho inhibited platelet aggregation with the K(I) values of 149.8 and 83.2 nM. Cell adhesion analysis showed that Den was 3.7 times less active than Rho when inhibiting the integrin alphaIIbbeta3 and 2.5 times less active when inhibiting the integrin alphavbeta3. In contrast, Den and Rho were similarly active when inhibiting the integrin alpha5beta1 with the IC50 values of 239.8 and 256.8 nM. NMR analysis showed that recombinant Den and Rho have different 3D conformations for their arginyl-glycyl-aspartic acid (RGD) motif. However, the comparison with Rho showed that the docking of Den into integrin alphavbeta3 resulted in a similar number of contacts. Analysis of the dynamic properties of the RGD loop in Den and Rho showed that they also had different dynamic properties. These results demonstrate that protein scaffolds affect the function, structure, and dynamics of their RGD motif. PMID- 23033225 TI - Development of the Pediatric Research in Inpatient Settings (PRIS) Network: lessons learned. PMID- 23033226 TI - Impact of a pharmacist-led warfarin self-management program on quality of life and anticoagulation control: a randomized trial. AB - STUDY OBJECTIVE: To evaluate the impact of a pharmacist-led warfarin patient self management program on quality of life and anticoagulation control compared with management in a physician-led specialized anticoagulation clinic. DESIGN: Prospective, randomized, controlled, open-label trial. SETTING: Tertiary care academic medical center. PATIENTS: A total of 114 patients aged 18-75 years who were followed at a specialized anticoagulation clinic, had received warfarin for at least 6 months, and were expected to continue warfarin for a minimum of 4 months. INTERVENTION: All patients attended an educational session on anticoagulation provided by a pharmacist. Patients randomized to the self management group (58 patients) also received practical training to use the CoaguChek XS device and a self-management dosing algorithm. Patients in the control group (56 patients) continued to undergo standard management at the anticoagulation clinic. MEASUREMENTS AND MAIN RESULTS: Patients completed a validated quality-of-life questionnaire and the validated Oral Anticoagulation Knowledge test at the beginning and end of the study. The quality of anticoagulation control was evaluated by using the time spent in therapeutic range. After 4 months of follow-up, a significant improvement in the self management group was observed compared with the control group in four of the five quality-of-life topics (p<0.05). Improvements in knowledge were observed in both groups after the training session and persisted after 4 months (p<0.05 for all). The time spent in the therapeutic range (80.0% in the self-management group vs 75% in the control group, p=0.79) and in the extended therapeutic range ([target international normalized ratio +/- 0.3] 93.2% in the self-management group vs 91.1% in the control group, p=0.30) were similar between groups. CONCLUSION: A self-management warfarin program led by pharmacists resulted in significant improvement in the quality of life of patients receiving warfarin therapy as well as a reduction in the time required for anticoagulation monitoring, while maintaining a level of anticoagulation control similar to a high-quality specialized anticoagulation clinic. PMID- 23033227 TI - Performance of compliance and persistence measures in predicting clinical and economic outcomes using administrative data from German sickness funds. AB - STUDY OBJECTIVE: To compare the performance of various compliance and persistence measures in predicting schizophrenia-related hospitalization rates and inpatient costs. DESIGN: Retrospective, nonrandomized cohort study. DATA SOURCE: Prescription claims databases from three German sickness funds (public health insurance programs). PATIENTS: A total of 1484 patients who were hospitalized in 2003 for a schizophrenia-related episode and subsequently received long-term antipsychotic pharmacotherapy. MEASUREMENTS AND MAIN RESULTS: Data on age, sex, schizophrenia, prescription drugs, hospitalizations, and inpatient expenditures were collected for each patient from the three German sickness funds. Refill compliance measures based on single-interval availability and multiple-interval availability, as well as refill persistence, were calculated for each patient over 1 year. Ten measurement variables were compared with respect to their performance in predicting disease-related hospitalization and inpatient expenditure, using multivariate logistic regression and gamma regression, respectively. C-statistics were calculated to determine each measure's predictive performance. Likelihood ratio tests showed that inclusion of compliance and persistence measures significantly improved (p<0.05) outcomes prediction in 6 of 10 hospitalization models and in 3 of 10 inpatient cost models compared with a baseline model that included only age, sex, and disease severity covariates. Refill compliance as a continuous variable of drug persistence, including transfer of oversupplies into subsequent periods, performed best in predicting hospitalization (C = 0.669). Availability ratios, capped at 100%, were superior to default availability ratios in predicting hospitalization. Allowing for cross period carryover improved the discriminatory performance of the persistence models. CONCLUSION: Refill persistence measures appear sufficiently flexible to account for hospitalizations common in schizophrenia and other psychiatric diseases. A continuous refill persistence measure should be used to assess compliance in psychiatric conditions when working with administrative data. PMID- 23033228 TI - Cost of invasive fungal infections in the era of new diagnostics and expanded treatment options. AB - STUDY OBJECTIVE: To determine the true institutional cost of treating invasive fungal infections in light of recent advances in diagnostic techniques and antifungal therapies for both treatment and prophylaxis of these infections. DESIGN: Economic analysis. SETTING: Academic medical center. PATIENTS: A total of 200 patients discharged from the hospital during 2004-2005 with a diagnosis of proven, probable, or possible aspergillosis, cryptococcosis, invasive candidiasis, or zygomycosis (cases). Patients were matched in a 1:1 fashion with patients having similar underlying disease states but no invasive fungal infections (controls). MEASUREMENTS AND MAIN RESULTS: Data on demographic and clinical characteristics were collected from patients' medical records. In addition, information concerning each patient's hospitalization was recorded. Resource utilization data for a patient's entire hospitalization were collected from the hospital's charge databases and converted to costs. These data were compared between the cases and the controls. After adjusting for race-ethnicity, sex, age, and comorbid illnesses, mean total hospital cost for cases was $32,196 more than for controls (p<0.0001). Nonpharmacy costs accounted for the majority (63%) of this difference, and an additional $3996 was attributed to systemic antifungal drugs. The mean length of hospital stay was longer for cases than controls (25.8 vs 18.4 days). CONCLUSION: Treatment of patients with invasive fungal infections was associated with a significantly higher inpatient hospital cost compared with controls. However, due to new diagnostic techniques and effective antifungal therapy, the relative cost of these infections appears to be at least stable compared with the previous decade. These findings can help assess the utility of cost-avoidance strategies such as antifungal prophylaxis and application of appropriate treatment. PMID- 23033229 TI - Thrombotic events associated with C1 esterase inhibitor products in patients with hereditary angioedema: investigation from the United States Food and Drug Administration adverse event reporting system database. AB - STUDY OBJECTIVE: To investigate reports of thrombotic events associated with the use of C1 esterase inhibitor products in patients with hereditary angioedema in the United States. DESIGN: Retrospective data mining analysis. SOURCE: The United States Food and Drug Administration (FDA) adverse event reporting system (AERS) database. MEASUREMENTS AND MAIN RESULTS: Case reports of C1 esterase inhibitor products, thrombotic events, and C1 esterase inhibitor product-associated thrombotic events (i.e., combination cases) were extracted from the AERS database, using the time frames of each respective product's FDA approval date through the second quarter of 2011. Bayesian statistical methodology within the neural network architecture was implemented to identify potential signals of a drug-associated adverse event. A potential signal is generated when the lower limit of the 95% 2-sided confidence interval of the information component, denoted by IC025 , is greater than zero. This suggests that the particular drug associated adverse event was reported to the database more often than statistically expected from reports available in the database. Ten combination cases of thrombotic events associated with the use of one C1 esterase inhibitor product (Cinryze) were identified in patients with hereditary angioedema. A potential signal demonstrated by an IC025 value greater than zero (IC025 = 2.91) was generated for these combination cases. CONCLUSION: The extracted cases from the AERS indicate continuing reports of thrombotic events associated with the use of one C1 esterase inhibitor product among patients with hereditary angioedema. The AERS is incapable of establishing a causal link and detecting the true frequency of an adverse event associated with a drug; however, potential signals of C1 esterase inhibitor product-associated thrombotic events among patients with hereditary angioedema were identified in the extracted combination cases. PMID- 23033230 TI - Psychological and physical impact of anabolic-androgenic steroid dependence. AB - STUDY OBJECTIVE: To contrast the characteristics of two groups of anabolic androgenic steroid (AAS) users-those with versus those without AAS dependence. DESIGN: Subanalysis of data from the Anabolic 500, a cross-sectional survey. PARTICIPANTS: One hundred twelve male AAS-dependent users and 367 AAS nondependent users who completed an online survey between February 19 and June 30, 2009. MEASUREMENTS AND MAIN RESULTS: Respondents were recruited from the Internet discussion boards of 38 fitness, bodybuilding, weightlifting, and steroid Web sites. The respondents provided online informed consent and completed the Anabolic 500, a 99-item Web-based survey. Self-reported data included demographics, exercise patterns, use of AAS and other performance-enhancing agents, adverse effects of AAS use, behavior consistent with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for AAS dependence, history of illicit drug and alcohol use, history of sexual or physical abuse, and psychiatric conditions diagnosed according to the DSM-IV-TR. Behavior consistent with AAS dependence was identified in 23.4% of the survey participants. These AAS-dependent users were more excessive in their AAS use (e.g., higher doses, higher quantity of agents, longer duration of use), more likely to report a history of illicit heroin use in the last 12 months (5.4% vs 1.9%, p=0.049), and more likely to report a diagnosis of an anxiety disorder (16.1 vs 8.4%, p=0.020) or major depressive disorder (15.2% vs 7.4%, p=0.012) than AAS-nondependent users. CONCLUSION: Data from the Anabolic 500 survey showed that almost one quarter of AAS users were dependent on these drugs. These AAS dependent users had a higher rate of heroin use as well as anxiety and major depressive disorders compared with AAS-nondependent users. These findings can help clinicians and researchers better understand and address the potential illicit drug use and psychiatric comorbidities that may be present among AAS dependent users. PMID- 23033232 TI - Drug-drug interactions between warfarin and psychotropics: updated review of the literature. AB - As the number of psychotropics on the market expands, the likelihood increases that a patient requiring anticoagulation with warfarin will receive concurrent treatment with a psychotropic drug. Because warfarin undergoes hepatic metabolism and is highly protein bound, it is particularly prone to drug interactions; in addition, its relatively narrow therapeutic window places patients at risk of either hemorrhagic or thrombotic complications. Although warfarin's interactions with other drugs have long been studied, the most recent review of the literature of warfarin's interactions with psychotropics was over a decade ago. Thus, we conducted a systematic review of the literature documenting the interaction between warfarin and psychotropics, with a focus on interactions mediated through the cytochrome P450 system and protein binding. A search of the MEDLINE database was performed, and reports of warfarin interactions with psychotropics were identified. The results suggest that interactions between warfarin and psychotropic drugs are important and likely underrecognized. They also have notable implications for both safety and drug compliance. When certain psychotropics are started or discontinued in patients receiving warfarin therapy, or when warfarin is introduced to a patient receiving a stable dose of a psychotropic, clinicians should monitor a patient's international normalized ratio (INR) closely to ensure it remains within therapeutic range. Psychotropics that pose a particular risk of increasing the INR when used with warfarin include fluoxetine, fluvoxamine, quetiapine, and valproic acid. Psychotropics that may significantly decrease the INR when used with warfarin include trazodone, St. John's wort, carbamazepine, and the polycyclic aromatic carbons in tobacco cigarettes; however, nicotine itself, as in nicotine replacement strategies, is not known to alter warfarin's anticoagulant effect. In certain cases, the need for anticoagulation may also necessitate switching to a different psychotropic. PMID- 23033231 TI - Effects of tobacco smoking and nicotine on cancer treatment. AB - A substantial number of the world's population continues to smoke tobacco, even in the setting of a cancer diagnosis. Studies have shown that patients with cancer who have a history of smoking have a worse prognosis than nonsmokers. Modulation of several physiologic processes involved in drug disposition has been associated with long-term exposure to tobacco smoke. The most common of these processes can be categorized into the effects of smoking on cytochrome P450 mediated metabolism, glucuronidation, and protein binding. Perturbation in the pharmacokinetics of anticancer drugs could result in clinically significant consequences, as these drugs are among the most toxic, but potentially beneficial, pharmaceuticals prescribed. Unfortunately, the effect of tobacco smoking on drug disposition has been explored for only a few marketed anticancer drugs; thus, little prescribing information is available to guide clinicians on the vast majority of these agents. The carcinogenic properties of several compounds found in tobacco smoke have been well studied; however, relatively little attention has been given to the effects of nicotine itself on cancer growth. Data that identify nicotine's effect on cancer cell apoptosis, tumor angiogenesis, invasion, and metastasis are emerging. The implications of these data are still unclear but may lead to important questions regarding approaches to smoking cessation in patients with cancer. PMID- 23033233 TI - Pharmacotherapy for acute respiratory distress syndrome. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a continuum of a clinical syndrome of respiratory failure due to refractory hypoxia. Acute respiratory distress syndrome is differentiated from ALI by a greater degree of hypoxemia and is associated with higher morbidity and mortality. The mortality for ARDS ranges from 22-41%, with survivors usually requiring long-term rehabilitation to regain normal physiologic function. Numerous pharmacologic therapies have been studied for prevention and treatment of ARDS; however, studies demonstrating clear clinical benefit for ARDS-related mortality and morbidity are limited. In this focused review, controversial pharmacologic therapies that have demonstrated, at minimum, a modest clinical benefit are discussed. Three pharmacologic treatment strategies are reviewed in detail: corticosteroids, fluid management, and neuromuscular blocking agents. Use of corticosteroids to attenuate inflammation remains controversial. Available evidence does not support early administration of corticosteroids. Additionally, administration after 14 days of disease onset is strongly discouraged. A liberal fluid strategy during the early phase of comorbid septic shock, balanced with a conservative fluid strategy in patients with ALI or ARDS during the postresuscitation phase, is the optimum approach for fluid management. Available evidence supports an early, short course of continuous-infusion cisatracurium in patients presenting with severe ARDS. Evidence of safe and effective pharmacologic therapies for ARDS is limited, and clinicians must be knowledgeable about the areas of controversies to determine application to patient care. PMID- 23033234 TI - Vilazodone for the treatment of major depressive disorder. AB - Major depressive disorder (MDD) affects 121 million people globally and is one of the leading causes of functional disability worldwide. As a recurrent disorder, MDD is associated with significant morbidity and functional disability as well as high direct and indirect costs to the health care system. Although several drug therapies are available for treating MDD, many patients do not achieve a sustained remission. Vilazodone was approved by the United States Food and Drug Administration in 2011 and has a distinctive pharmacology profile, as the drug is a selective serotonin reuptake inhibitor and serotonin 5-HT(1A) receptor partial agonist. In two 8-week, double-blind, placebo-controlled trials, vilazodone's overall rate of response was similar to other antidepressants for the treatment of MDD. Compared with placebo, remission rates were not significantly different in one trial and were not reported in the second trial. Vilazodone was generally well tolerated, with nausea and diarrhea being the most frequent adverse events reported. Postmarketing studies and further active comparative studies will provide additional insight to the potential benefits and safety of this novel drug. PMID- 23033236 TI - Ethnic differences in the prevalence of diabetic retinopathy in persons with diabetes when first presenting at a diabetes clinic in South Africa. AB - OBJECTIVE: To describe the prevalence and associated risk factors for diabetic retinopathy (DR) within a multiethnic population at presentation to a diabetes clinic in South Africa. RESEARCH DESIGN AND METHODS: Retinal photography was conducted using a nonmydriatic digital camera without mydriasis and graded by one of three senior graders. Logistic regression analyses were used to assess the association between any DR, referable DR, and clinical risk factors. RESULTS: A total of 1,537 persons with type 1 and 3,978 with type 2 diabetes were included. Prevalence of any DR in type 1 diabetes was 35.2% (background DR 26% and referable DR 9.2%) and in type 2 diabetes was 20.5% (14.1 and 6.4%, respectively). In type 1 diabetes, there was an increased risk of any DR in Asian Indians, whereas the risk of referable DR was increased for indigenous Africans compared with Caucasians. In type 2 diabetes, the risk was increased for all non Caucasians compared with Caucasians. Longer duration of diabetes and elevated HbA(1c) were independently associated with any and referable DR in both type 1 and type 2 diabetes, with the addition of hypertension and smoking in type 1 diabetes when adjusted for age at diagnosis of diabetes, sex, and ethnicity. CONCLUSIONS: The prevalence of DR in this population from South Africa was similar to that reported globally; however, ethnic differences were observed. Increasing duration of diabetes and poor glycemic control were the strongest risk factors associated with any and referable DR in both type 1 and type 2 diabetes. PMID- 23033237 TI - Closed-loop insulin therapy improves glycemic control in children aged <7 years: a randomized controlled trial. AB - OBJECTIVE: To assess the possibility of improving nocturnal glycemic control as well as meal glycemic response using closed-loop therapy in children aged <7 years. RESEARCH DESIGN AND METHODS: This was a randomized controlled crossover trial comparing closed-loop with standard open-loop insulin pump therapy performed in an inpatient clinical research center. Ten subjects aged <7 years with type 1 diabetes for >6 months treated with insulin pump therapy were studied. Closed-loop therapy and standard open-loop therapy were compared from 10:00 p.m. to 12:00 p.m. on 2 consecutive days. The primary outcome was plasma glucose time in range (110-200 mg/dL) during the night (10:00 p.m.-8:00 a.m.). Secondary outcomes included peak postprandial glucose levels, incidence of hypoglycemia, degree of hyperglycemia, and prelunch glucose levels. RESULTS: A trend toward a higher mean nocturnal time within target range was noted for closed- versus open-loop therapy, although not reaching statistical significance (5.3 vs. 3.2 h, P = 0.12). There was no difference in peak postprandial glucose or number of episodes of hypoglycemia. There was significant improvement in time spent >300 mg/dL overnight with closed-loop therapy (0.18 vs. 1.3 h, P = 0.035) and the total area under the curve of glucose >200 mg/dL (P = 0.049). Closed-loop therapy returned prelunch blood glucose closer to target (189 vs. 273 mg/dL on open loop, P = 0.009). CONCLUSIONS: Closed-loop insulin delivery decreases the severity of overnight hyperglycemia without increasing the incidence of hypoglycemia. The therapy is better able to reestablish target glucose levels in advance of a subsequent meal. Younger children with type 1 diabetes may reap significant benefits from closed-loop therapy. PMID- 23033238 TI - Serum levels of the adipokine progranulin depend on renal function. AB - OBJECTIVE: Progranulin has recently been introduced as a novel adipokine inducing insulin resistance and obesity. In the current study, we investigated renal elimination, as well as association of the adipokine with markers of the metabolic syndrome. RESEARCH DESIGN AND METHODS: Progranulin serum levels were quantified by enzyme-linked immunosorbent assay and correlated to anthropometric and biochemical parameters of renal function and glucose and lipid metabolism, as well as inflammation, in 532 patients with stages 1-5 of chronic kidney disease (CKD). RESULTS: Median serum progranulin levels adjusted for age, sex, and BMI were significantly different between CKD stages with highest values detectable in stage 5 (stage 1, 58.3 ug/L; stage 2, 63.0 ug/L; stage 3, 65.4 ug/L; stage 4, 68.8 ug/L; and stage 5, 90.6 ug/L). Furthermore, CKD stage was the strongest independent predictor of circulating progranulin in our cohort. In addition, high sensitivity interleukin-6 and adiponectin remained significantly and independently correlated with the adipokine. CONCLUSIONS: We demonstrate that progranulin serum levels increase with deteriorating renal function. These findings are in accordance with the hypothesis that renal clearance is a major elimination route for circulating progranulin. Furthermore, the adipokine is positively and independently associated with markers of inflammation and adiponectin. PMID- 23033239 TI - High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. AB - OBJECTIVE: Low vitamin D levels predict the development of diabetes. This double blind, randomized, control study in subjects with prediabetes and hypovitaminosis D evaluated whether high doses of vitamin D for 1 year affected insulin secretion, insulin sensitivity, and the development of diabetes. RESEARCH DESIGN AND METHODS: A total of 1,551 subjects >=40 years of age not known to have diabetes were screened with A1C levels. Subjects with A1C levels of 5.8-6.9% underwent an oral glucose tolerance test (OGTT). Subjects with prediabetes and 25 OH vitamin D (25-OHD) levels <30 ng/mL were randomized to receive weekly placebo (n = 53) or vitamin D (n = 56) with doses based on body weight and baseline 25 OHD levels. OGTTs were performed 3, 6, 9, and 12 months later. Insulin secretion and sensitivity were measured, and the proportion of subjects developing diabetes was assessed. RESULTS: 25-OHD levels rapidly rose from 22 to nearly 70 ng/mL after vitamin D supplementation with a mean weekly dose of 88,865 IU. There were no differences between the placebo and vitamin D groups regarding fasting plasma glucose, 2-h glucose, or insulin secretion and sensitivity or in the percent developing diabetes or returning to normal glucose tolerance. No subjects experienced increased serum or urinary calcium levels. At 12 months, A1C levels were significantly slightly less (0.2%) in the vitamin D group. CONCLUSIONS: In individuals with prediabetes and hypovitaminosis D, doses of vitamin D supplementation designed to raise serum 25-OHD levels into the upper-normal range for 1 year had no effect on insulin secretion, insulin sensitivity, or the development of diabetes compared with placebo administration. PMID- 23033240 TI - Moderate-intensity physical activity ameliorates the breast cancer risk in diabetic women. AB - OBJECTIVE: To evaluate the association between self-reported diabetes and the risk of breast cancer (BC) and its interaction with moderate-intensity physical activity in pre- and postmenopausal Mexican women. RESEARCH DESIGN AND METHODS: A population-based case-control study was conducted using 1,000 incident case subjects and 1,074 control subjects. Blood samples and information on health, diet, physical activity, and anthropometric measurements were obtained. RESULTS: The association between diabetes and BC risk decreased with increasing tertiles of moderate-intensity physical activity (odds ratio [OR] = 4.9 [95% CI 2.3-10.8]; 3.0 [1.3-6.9]; and 1.0 [0.1-9.2], respectively, for each tertile) (test for interaction = 0.04). Compared with the women in the lowest tertiles, increased risk was observed in those premenopausal women with the highest serum C-peptide, IGF-1, and IGF-1 binding protein 3 levels. CONCLUSIONS: Moderate-intensity physical activity can substantially ameliorate the increased BC risk in diabetic women. PMID- 23033241 TI - Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: This placebo-controlled study assessed long-term efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes and severe renal impairment (RI). RESEARCH DESIGN AND METHODS: In this 1 year, double-blind study, 133 patients with type 2 diabetes (HbA(1c) 7.0-10.0%) and severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m(2)) at screening were randomized to linagliptin 5 mg (n = 68) or placebo (n = 65) once daily, added to existing background therapy. The primary efficacy end point was HbA(1c) change from baseline to week 12. Efficacy and safety end points were assessed after 1 year. RESULTS: At week 12, adjusted mean HbA(1c) decreased by 0.76% with linagliptin and -0.15% with placebo (treatment difference, -0.60%; 95% CI -0.89 to -0.31; P < 0.0001). HbA(1c) improvements were sustained with linagliptin (-0.71%) over placebo (0.01%) at 1 year (treatment difference -0.72%, -1.03 to -0.41; P < 0.0001). Mean insulin doses decreased by -6.2 units with linagliptin and -0.3 units with placebo. Overall adverse event incidence was similar over 1 year (94.1 vs. 92.3%). Incidence of severe hypoglycemia with linagliptin and placebo was comparably low (three patients per group). Linagliptin and placebo had little effect on renal function (median change in eGFR, -0.8 vs. -2.2 mL/min/1.73 m(2)), and no drug-related renal failure occurred. CONCLUSIONS: In patients with type 2 diabetes and severe RI, linagliptin provided clinically meaningful improvements in glycemic control with very low risk of severe hypoglycemia, stable body weight, and no cases of drug related renal failure. The potential for linagliptin to spare insulin and provide long-term renal safety warrants further investigations. PMID- 23033242 TI - Can ultrasound of the tibial nerve detect diabetic peripheral neuropathy? A cross sectional study. AB - OBJECTIVE: Peripheral nerve imaging by portable ultrasound (US) may serve as a noninvasive and lower-cost alternative to nerve conduction studies (NCS) for diagnosis and staging of diabetic sensorimotor polyneuropathy (DSP). We aimed to examine the association between the size of the posterior tibial nerve (PTN) and the presence and severity of DSP. RESEARCH DESIGN AND METHODS: We performed a cross-sectional study of 98 consecutive diabetic patients classified by NCS as subjects with DSP or control subjects. Severity was determined using the Toronto Clinical Neuropathy Score. A masked expert sonographer measured the cross sectional area (CSA) of the PTN at 1, 3, and 5 cm proximal to the medial malleolus. RESULTS: Fifty-five patients had DSP. The mean CSA of the PTN in DSP compared with control subjects at distances of 1 (23.03 vs. 17.72 mm(2); P = 0.004), 3 (22.59 vs. 17.69 mm(2); P < 0.0001), and 5 cm (22.05 vs. 17.25 mm(2); P = 0.0005) proximal to the medial malleolus was significantly larger. Although the area under the curve (AUC) for CSA measurements at all three anatomical levels was similar, the CSA measured at 3 cm above the medial malleolus had an optimal threshold value for identification of DSP (19.01 mm(2)) with a sensitivity of 0.69 and a specificity of 0.77 by AUC analysis. CONCLUSIONS: This large study of diabetic patients confirms that the CSA of the PTN is larger in patients with DSP than in control subjects, and US is a promising point-of-care screening tool for DSP. PMID- 23033243 TI - Metabolic and inflammatory links to depression in youth with diabetes. AB - OBJECTIVE: Youth with diabetes are at increased risk for depression. The objectives of this study were to provide preliminary evidence that this at-risk status for depression is associated with metabolic and inflammatory markers and to inform future, more stringent examinations of the directionality of these associations. RESEARCH DESIGN AND METHODS: Data from SEARCH for Diabetes in Youth (SEARCH), an observational study of U.S. children diagnosed with diabetes at <20 years of age, were used for these analyses. SEARCH participants were drawn from four geographically defined populations in Ohio, Washington, South Carolina, and Colorado; health plan enrollees in Hawaii and California; and Indian Health Service beneficiaries from four Native American populations. Participants were 2,359 youth with diabetes from the 2001 prevalent and 2002-2004 incident SEARCH cohorts. Depression was measured with the Center for Epidemiologic Studies Depression scale. Eight metabolic and inflammatory markers were measured: adiponectin, leptin, C-reactive protein, serum amyloid A, apolipoprotein B (apoB), lipoprotein A, interleukin-6, and LDL. RESULTS: Six of eight markers were significantly (P < 0.006) associated with depression in youth with diabetes in bivariate analyses. In general, higher levels of depression were associated with indicators of worse metabolic or inflammatory functioning. In regression models stratified by diabetes type and accounting for demographic and clinical characteristics, only higher levels of apoB remained associated with higher levels of depression in youth with type 1 diabetes. CONCLUSIONS: These data suggest that depression reported by youth with diabetes is partially associated with metabolic abnormalities and systemic inflammation. PMID- 23033244 TI - Prospective associations between emotional distress and poor outcomes in type 2 diabetes. AB - OBJECTIVE: Cross-sectional studies link both depressive symptoms (DS) and diabetes-related distress (DRD) to diabetes self-management and/or glycemic control. However, longitudinal studies of these variables are rare, and their results are somewhat conflicting. The study objective was to compare DS and DRD as longitudinal predictors of medication adherence, self-care behavior, and glycemic control in type 2 diabetes. RESEARCH DESIGN AND METHODS: Primary care patients with type 2 diabetes reported DS, DRD, and other variables at baseline were studied. Medication adherence, self-care behaviors (diet, physical activity, and glucose testing), and glycemic control (HbA(1c)) were assessed 6 months later (n = 253). Cross-sectional and longitudinal regression analyses were used to model behavioral and medical outcomes as a function of baseline confounders, DS, and DRD. RESULTS: Adjusted cross-sectional and longitudinal analyses yielded very similar results. In the latter, only DS were significantly associated with future diet behavior (P = 0.049), physical activity (P = 0.001), and glucose testing (P = 0.018). In contrast, only DRD predicted future glycemic control (P < 0.001) and medication adherence (P = 0.011). CONCLUSIONS: Distress-outcome associations seem to vary by type of distress under consideration. Only DS predicts future lifestyle-oriented self-management behaviors. In contrast, only DRD predicts glycemic control, perhaps by decreasing medication adherence. Clinical assessment and intervention should encompass both types of distress, unless the goal is to narrowly target a highly specific outcome. PMID- 23033245 TI - Extended family history of type 1 diabetes and phenotype and genotype of newly diagnosed children. AB - OBJECTIVE: To determine the frequency of newly diagnosed diabetic children with first- and second-degree relatives affected by type 1 diabetes and to characterize the effects of this positive family history on clinical markers, signs of beta-cell autoimmunity, and HLA genotype in the index case. RESEARCH DESIGN AND METHODS: Children (n = 1,488) with type 1 diabetes diagnosed under 15 years of age were included in a cross-sectional study from the Finnish Pediatric Diabetes Register. Data on family history of diabetes and metabolic decompensation at diagnosis were collected using a questionnaire. Antibodies to beta-cell autoantigens (islet cell antibodies, insulin autoantibodies, GAD antibodies, and antibodies to the islet antigen 2 molecule) and HLA genotypes were analyzed. RESULTS: A total of 12.2% of the subjects had a first-degree relative with type 1 diabetes (father 6.2%, mother 3.2%, and sibling 4.8%) and 11.9% had an affected second-degree relative. Children without affected relatives had lower pH (P < 0.001), higher plasma glucose (P < 0.001) and beta hydroxybutyrate concentrations (P < 0.001), a higher rate of impaired consciousness (P = 0.02), and greater weight loss (P < 0.001). There were no differences in signs of beta-cell autoimmunity. The familial cases carried the HLA DR4-DQ8 haplotype more frequently than sporadic cases (74.0 vs. 67.0%, P = 0.02). CONCLUSIONS: When the extended family history of type 1 diabetes is considered, the proportion of sporadic diabetes cases may be reduced to <80%. A positive family history for type 1 diabetes associates with a less severe metabolic decompensation at diagnosis, even when only second-degree relatives are affected. Autoantibody profiles are similar in familial and sporadic type 1 diabetes, suggesting similar pathogenetic mechanisms. PMID- 23033246 TI - Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD lipid trial. AB - OBJECTIVE: The Action to Control Cardiovascular Risk in Diabetes lipid study (ACCORD Lipid), which compared the effects of simvastatin plus fenofibrate (FENO S) versus simvastatin plus placebo (PL-S) on cardiovascular disease outcomes, measured only fasting triglyceride (TG) levels. We examined the effects of FENO-S on postprandial (PP) lipid and lipoprotein levels in a subgroup of ACCORD Lipid subjects. RESEARCH DESIGN AND METHODS: We studied 139 subjects (mean age of 61 years, 40% female, and 76% Hispanic or black) in ACCORD Lipid, from a total 529 ACCORD Lipid subjects in the Northeast Clinical Network. PP plasma TG, apolipoprotein (apo)B48, and apoCIII were measured over 10 h after an oral fat load. RESULTS: The PP TG incremental area under the curve (IAUC) above fasting (median and interquartile range [mg/dL/h]) was 572 (352-907) in the FENO-S group versus 770 (429-1,420) in the PL-S group (P = 0.008). The PP apoB48 IAUC (mean +/ SD [MUg/mL/h]) was also reduced in the FENO-S versus the PL-S group (23.2 +/- 16.3 vs. 35.2 +/- 28.6; P = 0.008). Fasting TG levels on the day of study were correlated with PP TG IAUC (r = 0.73 for FENO-S and r = 0.62 for PL-S; each P < 0.001). However, the fibrate effect on PP TG IAUC was a constant percentage across the entire range of fasting TG levels, whereas PP apoB48 IAUC was only reduced when fasting TG levels were increased. CONCLUSIONS: FENO-S lowered PP TG similarly in all participants compared with PL-S. However, levels of atherogenic apoB48 particles were reduced only in individuals with increased fasting levels of TG. These results may have implications for interpretation of the overall ACCORD Lipid trial, which suggested benefit from FENO-S only in dyslipidemic individuals. PMID- 23033247 TI - Does elevated plasma triglyceride level independently predict impaired fasting glucose?: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - OBJECTIVE: Elevated plasma triglycerides (TGs) have been included in diabetes risk prediction models. This study examined whether elevated TGs predict risk for impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: This study used the baseline and longitudinal follow-up data from the Multi-Ethnic Study of Atherosclerosis (MESA). The analysis included non-Hispanic whites, African Americans, Hispanics, and Chinese Americans 45-84 years of age who had fasting glucose <100 mg/dL at baseline and who did not have clinically evident cardiovascular disease or diabetes. Cox proportional regression models were used to examine the association of elevated TGs with incidence of IFG adjusting for central obesity, low HDL cholesterol, elevated blood pressure, baseline fasting glucose, and BMI. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity of elevated TGs in predicting IFG were calculated. RESULTS: The incidence rate of developing IFG was 59.1 per 1,000 person-years during the median 4.75 years of follow-up. African Americans and Hispanics had a higher incidence rate of IFG compared with non-Hispanic whites among people with normal TG concentrations. Elevated TGs (>150 mg/dL) at baseline were independently associated with the incidence of IFG with an adjusted hazard ratio of 1.19 (95% CI 1.04-1.37). However, its predictive value for identifying people at risk for IFG was poor, with <57% AUC. Interactions of elevated TGs with race/ethnicity in predicting IFG were not statistically significant. CONCLUSIONS: Elevated TGs were moderately associated with risk for IFG, and it was a poor risk prediction tool for IFG. PMID- 23033248 TI - Prospective associations of B-type natriuretic peptide with markers of left ventricular function in individuals with and without type 2 diabetes: an 8-year follow-up of the Hoorn Study. AB - OBJECTIVE: Heart failure is common in individuals with type 2 diabetes, and early detection of individuals at risk may offer opportunities for prevention. We aimed to explore 1) prospective associations of B-type natriuretic peptide (BNP) levels in a non-heart failure range with changes in markers of left ventricular (LV) function and 2) possible effect modification by type 2 diabetes in a population based cohort. RESEARCH DESIGN AND METHODS: Echocardiographic measurements were performed at baseline (2000-2001) and follow-up (2007-2009), together with standardized physical examinations and BNP measurements on 300 individuals (mean age 66 years, 32% with type 2 diabetes) of the longitudinal Hoorn Study. Multivariate linear regression analyses were performed to investigate associations of baseline BNP (<100 pg/mL) in individuals without prevalent heart failure at baseline with changes in LV mass index, LV ejection fraction, left atrial volume index, and ratio of early diastolic LV inflow velocity (E) to early diastolic lengthening velocity (e') (E/e'). RESULTS: In all individuals, higher BNP was associated with 8-year increases in left atrial volume index. Higher BNP was also associated with increasing LV mass index and E/e'. These associations were significantly stronger in individuals with type 2 diabetes compared with the nonsignificant associations in individuals without type 2 diabetes. CONCLUSIONS: This 8-year follow-up study shows that higher BNP levels in a non-heart failure range were associated with an increased LV mass and deteriorated LV diastolic function, particularly in individuals with type 2 diabetes. This implies that the presence or absence of type 2 diabetes should be taken into account if BNP levels are used to assess future heart failure risk. PMID- 23033249 TI - Predicting the glycemic response to gastric bypass surgery in patients with type 2 diabetes. AB - OBJECTIVE: To find clinically meaningful preoperative predictors of diabetes remission and conversely inadequate glycemic control after gastric bypass surgery. Predicting the improvement in glycemic control in those with type 2 diabetes after bariatric surgery may help in patient selection. RESEARCH DESIGN AND METHODS: Preoperative details of 154 ethnic Chinese subjects with type 2 diabetes were examined for their influence on glycemic outcomes at 1 year after gastric bypass. Remission was defined as HbA(1c) <=6%. Analysis involved binary logistic regression to identify predictors and provide regression equations and receiver operating characteristic curves to determine clinically useful cutoff values. RESULTS: Remission was achieved in 107 subjects (69.5%) at 12 months. Diabetes duration <4 years, body mass >35 kg/m(2), and fasting C-peptide concentration >2.9 ng/mL provided three independent preoperative predictors and three clinically useful cutoffs. The regression equation classification plot derived from continuous data correctly assigned 84% of participants. A combination of two or three of these predictors allows a sensitivity of 82% and specificity of 87% for remission. Duration of diabetes (with different cutoff points) and C-peptide also predicted those cases in which HbA(1c) <=7% was not attained. Percentage weight loss after surgery was also predictive of remission and of less satisfactory outcomes. CONCLUSIONS: The glycemic response to gastric bypass is related to BMI, duration of diabetes, fasting C-peptide (influenced by insulin resistance and residual beta-cell function), and weight loss. These data support and refine previous findings in non-Asian populations. Specific ethnic and procedural regression equations and cutoff points may vary. PMID- 23033250 TI - Determination of amyloid core structure using chemical shifts. AB - Amyloid fibrils are the pathological hallmark of a large variety of neurodegenerative disorders. The structural characterization of amyloid fibrils, however, is challenging due to their non-crystalline, heterogeneous, and often dynamic nature. Thus, the structure of amyloid fibrils of many proteins is still unknown. We here show that the structure calculation program CS-Rosetta can be used to obtain insight into the core structure of amyloid fibrils. Driven by experimental solid-state NMR chemical shifts and taking into account the polymeric nature of fibrils CS-Rosetta allows modeling of the core of amyloid fibrils. Application to the Y145X stop mutant of the human prion protein reveals a left-handed beta-helix. PMID- 23033251 TI - Kinetic template-guided tethering of fragments. AB - Birds of a tether: A tethering strategy for the site-directed discovery of low molecular-weight fragments that bind weakly to defined protein surfaces is described. A solvent-exposed protein thiol captures acrylamide-modified fragments in a conjugate addition reaction that requires a template to produce a measureable quantity of protein-fragment adduct, which can be rapidly identified by mass spectrometry. PMID- 23033252 TI - A highly porous metal-organic framework, constructed from a cuboctahedral super molecular building block, with exceptionally high methane uptake. AB - A highly porous metal-organic framework Cu(2)(BBCDC) (BBCDC = 9,9'-([1,1' b[combining low line]iphenyl]-4,4'-diyl)b[combining low line]is(9H-c[combining low line]arbazole-3,6-d[combining low line]ic[combining low line]arboxylate) (DUT 49) with a specific surface area of 5476 m(2) g(-1), a pore volume of 2.91 cm(3) g(-1), a H(2) excess uptake of 80 mg g(-1) (77 K, 50 bar), a CO(2) excess uptake of 2.01 g g(-1) (298 K, 50 bar) and an exceptionally high excess methane storage capacity of 308 mg g(-1) (298 K, 110 bar) was obtained using an extended tetratopic linker. PMID- 23033253 TI - Identification of Cys255 in HIF-1alpha as a novel site for development of covalent inhibitors of HIF-1alpha/ARNT PasB domain protein-protein interaction. AB - The heterodimer HIF-1alpha (hypoxia inducible factor)/HIF-beta (also known as ARNT-aryl hydrocarbon nuclear translocator) is a key mediator of cellular response to hypoxia. The interaction between these monomer units can be modified by the action of small molecules in the binding interface between their C terminal heterodimerization (PasB) domains. Taking advantage of the presence of several cysteine residues located in the allosteric cavity of HIF-1alpha PasB domain, we applied a cysteine-based reactomics "hotspot identification" strategy to locate regions of HIF-1alpha PasB domain critical for its interaction with ARNT. COMPOUND 5 was identified using a mass spectrometry-based primary screening strategy and was shown to react specifically with Cys255 of the HIF-1alpha PasB domain. Biophysical characterization of the interaction between PasB domains of HIF-1alpha and ARNT revealed that covalent binding of COMPOUND 5 to Cys255 reduced binding affinity between HIF-1alpha and ARNT PasB domains approximately 10-fold. Detailed NMR structural analysis of HIF-1alpha-PasB-COMPOUND 5 conjugate showed significant local conformation changes in the HIF-1alpha associated with key residues involved in the HIF-1alpha/ARNT PasB domain interaction as revealed by the crystal structure of the HIF-1alpha/ARNT PasB heterodimer. Our screening strategy could be applied to other targets to identify pockets surrounding reactive cysteines suitable for development of small molecule modulators of protein function. PMID- 23033254 TI - Enzyme immobilization and direct electrochemistry based on a new matrix of phospholipid-monolayer-functionalized graphene. AB - A new nanocomposite material for enzyme immobilization and subsequent direct electrochemistry and electrocatalysis was developed by using 1,2-dimyristoyl-sn glycero-3-phospho-(1-rac-glycerol)-phospholipid-monolayer-membrane-modified graphene (DMPG-G). Microperoxidase-11 (MP11) was chosen as a model enzyme to investigate the composite system. Owing to the improved conductivity and biocompatible microenvironment, MP11 that was immobilized in the matrix of the DMPG-G nanocomposite (DMPG-G-MP11) effectively retained its native structure and bioactivity. DMPG-G-MP11-modified glassy carbon electrode (DMPG-G-MP11/GCE) exhibited a pair of well-defined quasi-reversible redox peaks of MP11 and showed high electrocatalytic activity towards hydrogen peroxide (H(2)O(2)). The linear response of the developed biosensor for the determination of H(2)O(2) ranged from 2.0*10(-6) to 4.5*10(-4) M with a detection limit of 7.2*10(-7) M. This biosensor exhibited high reproducibility and long-term storage stability. The promising features of this biosensor indicate that these lipid-graphene nanocomposites are ideal candidate materials for the direct electrochemistry of redox proteins and that they could serve as a versatile platform for the construction of a third-generation biosensor. PMID- 23033255 TI - Discovery and characterization of novel, potent, and selective cytochrome P450 2J2 inhibitors. AB - Cytochrome P450 (CYP) 2J2 is one of the human CYPs involved in phase I xenobiotics metabolism. It is mainly expressed in extrahepatic tissues, including intestine and cardiovascular systems. The general role of CYP2J2 in drug metabolism is not yet fully understood, and the recent discovery that CYP2J2 can metabolize a wide range of structurally diverse drugs and its primary distribution in the intestine suggest its potentially indispensable role in first pass intestinal metabolism and involvement in drug-drug interaction. To fully characterize its role in drug metabolism, selective and potent inhibitors of CYP2J2 are necessary tools. In the current study, 69 known drugs were screened for the inhibition of CYP2J2, and we discovered a number of marketed drugs as potent and selective CYP2J2 inhibitors. In particular, telmisartan and flunarizine have CYP2J2 inhibition IC(50) values of 0.42 MUM and 0.94 MUM, respectively, which are at least 10-fold more selective against all other major metabolizing CYPs; moreover, they are not substrates of CYP2J2 and show no time dependent inhibition toward this CYP. The results of enzyme kinetics studies, supported by molecular modeling, have also elucidated that telmisartan is a mixed type inhibitor, and flunarizine competitively inhibits CYP2J2. The K(i) for telmisartan is 0.19 MUM, with an alpha value, an indicator of the type of inhibition mechanism, of 2.80, and flunarizine has a K(i) value of 0.13 MUM. These newly discovered CYP2J2 inhibitors can be potentially used as a tool to study CYP2J2 in drug metabolism and interaction in a clinical setting. PMID- 23033256 TI - DNA methylation and histone modification profiles of mouse organic anion transporting polypeptides. AB - Organic anion transporting polypeptides (rodents, Oatps; human, OATPs) are primarily involved in the transmembrane transportation of a wide range of endogenous and exogenous compounds. Multiple mouse Oatp1 isoforms are closely located on chromosome 6, where each isoform shows distinct tissue distribution; Oatp1b2, Oatp1a6, and Oatp1c1 are expressed exclusively in the liver, kidney, and cerebrum, respectively; Oatp1a1 in the liver and kidney; and Oatp1a4 in the liver and cerebrum. We have identified tissue-dependent differentially methylated region (T-DMR) around the transcriptional start site (TSS) of Oatp1b2, which correlates with its liver-specific expression. Bisulfite sequencing also demonstrated the presence of T-DMRs around the TSS in other Oatp1 genes: CpG dinucleotides at +149 relative to the TSS for Oatp1c1; -48, +101, and +356 for Oatp1a4; -572 and -550 for Oatp1a1; and -122 and +216 for Oatp1a6 were differentially methylated among the liver, kidney, and cerebrum. These methylation profiles were largely consistent with the tissue distribution of Oatp1 mRNAs. Chromatin immunoprecipitation assay revealed that the mRNA expression of Oatp1 genes was accompanied by acetylated histone H3. Human OATP1B1 and OATP1B3 are located on chromosome 12p12 in the OATP1 cluster; both show predominant expression in the liver. These genes also contained T-DMRs that were hypomethylated in the liver, compared with kidney cortex: -511, -411, and +92 relative to the TSS for OATP1B1 and -331, +70, and +73 for OATP1B3. These results suggest that the difference in epigenetic profiles comprising DNA methylation and histone acetylation determines the distinct tissue distribution of Oatp/OATP mRNAs. PMID- 23033257 TI - Post-market drug safety evidence sources: an analysis of FDA drug safety communications. PMID- 23033258 TI - Retraction. Direct to consumer advertising of statins: an assessment of safety. PMID- 23033259 TI - Limitation of discharge capacity and mechanisms of air-electrode deactivation in silicon-air batteries. AB - The electrocatalytical process at the air cathode in novel silicon-air batteries using the room-temperature ionic liquid hydrophilic 1-ethyl-3-methylimidazolium oligofluorohydrogenate [EMI?2.3 HF?F] as electrolyte and highly doped silicon wafers as anodes is investigated by electrochemical means, X-ray photoelectron spectroscopy (XPS), and electron paramagnetic resonance (EPR) spectroscopy. The results obtained by XPS and EPR provide a model to describe the limited discharge capacity by means of a mechanism of air-electrode deactivation. In that respect, upon discharge the silicon-air battery's cathode is not only blocked by silicon oxide reduction products, but also experiences a major modification in the MnO2 catalyst nature. The proposed modification of the MnO2 catalyst by means of a MnF2 surface layer greatly impacts the Si-air performance and describes a mechanism relevant for other metal-air batteries, such as the lithium-air. Moreover, the ability for this deactivation layer to form is greatly impacted by water in the electrolyte. PMID- 23033260 TI - Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism. AB - OBJECTIVE: Primary aldosteronism (PA) has deleterious effects on kidney function independent of blood pressure levels. Up to now, data on effectiveness of different PA therapies regarding renal function are scarce. DESIGN AND METHODS: This prospective multi-center study included 29 patients with newly diagnosed PA evaluated before and 1 year after treatment initiation, and a second cohort including 119 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Glomerular filtration rate (GFR), spot urine albumin excretion/urinary creatinine (UAE/Ucrea) ratio, biochemical parameters, and 24-h blood pressure were measured. In a larger cross-sectional cohort, renal function was evaluated depending on the type of treatment (adrenalectomy (ADX; n=86); spironolactone (n=65); and eplerenone (n=18)). RESULTS: GFR and UAE/Ucrea ratio significantly decreased in newly diagnosed PA patients after treatment initiation. In the second cohort, GFR and UAE/Ucrea ratio did not change during study period, and blood pressure was well controlled. In the larger cross sectional cohort, no differences were seen in GFR and UAE/Ucrea ratio between PA patients on different treatment regimens. However, eplerenone treatment showed lower potassium levels and higher number of required antihypertensive medications. CONCLUSIONS: Renal dysfunction with elevated albuminuria was seen in PA patients and was reversible after treatment initiation. Medical therapies with spironolactone or eplerenone seem to be as effective as ADX regarding renal function and blood pressure; however, sufficient daily doses need to be given. PMID- 23033261 TI - The facial evolution: looking backward and moving forward. AB - Three-dimensional (3D) facial analysis is ideal for high-resolution, nonionizing, noninvasive objective, high-throughput phenotypic, and phenomic studies. It is a natural complement to (epi)genetic technologies to facilitate advances in the understanding of rare and common diseases. The face is uniquely reflective of the primordial tissues, and there is evidence supporting the application of 3D facial analysis to the investigation of variation and disease including studies showing that the face can reflect systemic health, provides diagnostic clues to disorders, and that facial variation reflects biological pathways. In addition, facial variation has been related to evolutionary factors. The purpose of this review is to look backward to suggest that knowledge of human evolution supports, and may instruct, the application and interpretation of studies of facial morphology for documentation of human variation and investigation of its relationships with health and disease. Furthermore, in the context of advances of deep phenotyping and data integration, to look forward to suggest approaches to scalable implementation of facial analysis, and to suggest avenues for future research and clinical application of this technology. PMID- 23033262 TI - Carbon dioxide insertion into diamines: a computational study of solvent effects. AB - We studied computationally, on the model compound ethylenediamine, the insertion of carbon dioxide into diamines, yielding cyclic urea compounds. Two mechanisms were elaborated, depending on the value of the dielectric constant (DC) of the solvent. Accordingly, reaction mixtures with a high DC lead to carbamates, whereas lower DC values result in the preferred product cyclic urea. Additives behaving as "proton shuttles" act as catalysts, significantly reducing the activation barriers of insertion and ring closure to surmountable values. CO(2) insertion into diamines may also occur by autocatalysis, even without further additives, but under less favorable conditions, for example, lower yields. Amine reagents are most efficient at proton shuttling, followed by alcohols. The activation barrier of the rate-limiting step is lowered in a reaction mixture with higher values of DC, up to a critical value epsilon(cr) ~ 18. Hence, in a suitably optimized reaction mixture, ring closure is suggested to occur under milder conditions than those previously applied experimentally. The two roles of the additive, that is, acting as proton shuttling agent and adjusting the effective DC of the reaction mixture, do not have to be assigned to a single compound, possibly affording a handle on process optimization. PMID- 23033263 TI - Whole exome sequencing reveals uncommon mutations in the recently identified Fanconi anemia gene SLX4/FANCP. AB - Fanconi anemia (FA) is a rare genetic disorder characterized by congenital malformations, progressive bone marrow failure (BMF), and susceptibility to malignancies. FA is caused by biallelic or hemizygous mutations in one of 15 known FA genes, whose products are involved in the FA/BRCA DNA damage response pathway. Here, we report on a patient with previously unknown mutations of the most recently identified FA gene, SLX4/FANCP. Whole exome sequencing (WES) revealed a nonsense mutation and an unusual splice site mutation resulting in the partial replacement of exonic with intronic bases, thereby removing a nuclear localization signal. Immunoblotting detected no residual SLX4 protein, which was consistent with abrogated interactions with XPF/ERCC1 and MUS81/EME1. This cellular finding did not result in a more severe clinical phenotype than that of previously reported FA-P patients. Our study additionally exemplifies the versatility of WES for the detection of mutations in heterogenic disorders such as FA. PMID- 23033264 TI - Long-term survival of anoxia despite rapid ATP decline in embryos of the annual killifish Austrofundulus limnaeus. PMID- 23033265 TI - Has MRD monitoring superseded other prognostic factors in adult ALL? AB - Significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL) during the past 2 decades, and measurement of submicroscopic (minimal) levels of residual disease (MRD) is increasingly used to monitor treatment efficacy. For a better comparability of MRD data, there are ongoing efforts to standardize MRD quantification using real-time quantitative PCR of clonal immunoglobulin and T-cell receptor gene rearrangements, real-time quantitative-based detection of fusion gene transcripts or breakpoints, and multiparameter flow cytometric immunophenotyping. Several studies have demonstrated that MRD assessment in childhood and adult ALL significantly correlates with clinical outcome. MRD detection is particularly useful for evaluation of treatment response, but also for early assessment of an impending relapse. Therefore, MRD has gained a prominent position in many ALL treatment studies as a tool for tailoring therapy with growing evidence that MRD supersedes most conventional stratification criteria at least for Ph-negative ALL. Most study protocols on adult ALL follow a 2-step approach with a first classic pretherapeutic and a second MRD-based risk stratification. Here we discuss whether and how MRD is ready to be used as main decisive marker and whether pretherapeutic factors and MRD are really competing or complementary tools to individualize treatment. PMID- 23033266 TI - A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. AB - Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose-escalated cohorts (0.0003-3 mg/kg) for up to 4 cycles. Pharmacokinetic, pharmacodynamic, and correlative immunologic studies were completed. A total of 32 patients were enrolled. The biologic endpoint of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. One severe adverse event was noted. Pharmacokinetic and pharmacodynamic findings approximated preclinical predictions, and IPH2101 enhanced ex vivo patient-derived NK cell cytotoxicity against MM. No objective responses were seen. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation, and this approach warrants further development in MM. This trial was registered at www.clinicaltrials.gov as #NCT00552396. PMID- 23033268 TI - Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). AB - Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO)-defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis-derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events. PMID- 23033269 TI - SOCS3 promotes interleukin-17 expression of human T cells. AB - SOCS3 is a feedback regulator of cytokine signaling that affects T-cell polarization. Human tuberculosis is accompanied by increased SOCS3 expression in T cells, and this may influence susceptibility against Mycobacterium tuberculosis. Because the role of SOCS3 in human T-cell function is not well defined, we characterized cytokine expression and proliferation of human T cells with differential SOCS3 expression in the present study. We established a flow cytometry-based method for SOCS3 protein quantification and detected higher SOCS3 levels induced by M tuberculosis specific T-cell activation and a transient decrease of SOCS3 expression in the presence of mycobacteria-infected macrophages. Notably increased SOCS3 expression was detected in IL-17-expressing T-cell clones and in CD161(+) T helper type 17 cells ex vivo. Ectopic SOCS3 expression in primary CD4(+) T cells by lentiviral transduction induced increased IL-17 production but diminished proliferation and viability. Recombinant IL-7 inhibited SOCS3 expression and reduced IL-17-expressing T-cell proportions. We concluded that higher SOCS3 expression in human T cells favors T helper type 17 cells. Therefore, increased SOCS3 expression in human tuberculosis may reflect polarization toward IL-17-expressing T cells as well as T-cell exhaustion marked by reduced proliferation. PMID- 23033267 TI - The signal transducers STAT5 and STAT3 control expression of Id2 and E2-2 during dendritic cell development. AB - Cytokines and transcription factors play key roles in dendritic cell (DC) development, yet information about regulatory interactions between these signals remains limited. Here we show that the cytokines GM-CSF and Flt3L induce the transcriptional mediators Id2 and E2-2 and control DC lineage diversification by STAT-dependent pathways. We found that STAT5 is required for tissue CD103(+) DC generation and plasmacytoid DC (pDC) suppression in steady state or response to GM-CSF. STAT5 stimulates GM-CSF-dependent expression of Id2, which controls CD103(+) DC production and pDC inhibition. By contrast, pDCs, but not CD103(+) DCs, are dependent on STAT3. Consistently, STAT3 stimulates Flt3L-responsive expression of the pDC regulator Tcf4 (E2-2). These data suggest that STATs contribute to DC development by controlling transcription factors involved in lineage differentiation. PMID- 23033270 TI - Memory CD4(+)CCR5(+) T cells are abundantly present in the gut of newborn infants to facilitate mother-to-child transmission of HIV-1. AB - Despite potential clinical importance, target cells for mother-to-child transmission of HIV-1 have not yet been identified. Cord blood-derived CD4(+) T cells are largely naive and do not express CCR5, the mandatory coreceptor for transmitted HIV-1 R5 strains in infants. In the present study, we demonstrate that in the human fetal and infant gut mucosa, there is already a large subset of mucosal memory CD4(+)CCR5(+) T cells with predominantly a Th1 and Th17 phenotype. Using next-generation sequencing of the TCRbeta chain, clonally expanded T cells as a hallmark for memory development predominated in the gut mucosa (30%), whereas few were found in the lymph nodes (1%) and none in cord blood (0%). The gut mucosal fetal and infant CD4(+) T cells were highly susceptible to HIV-1 without any prestimulation; pol proviral DNA levels were similar to infected phytohemagglutinin-stimulated adult PBMCs. In conclusion, in the present study, we show that extensive adaptive immunity is present before birth and the gut mucosa is the preferential site for memory CD4(+) T cells. These CD4(+)CCR5(+) T cells in the infant mucosa provide a large pool of susceptible cells for ingested HIV-1 at birth and during breastfeeding, indicating a mucosal route of mother-to child transmission that can be targeted in prevention strategies. PMID- 23033271 TI - S1P1 expression is controlled by the pro-oxidant activity of p66Shc and is impaired in B-CLL patients with unfavorable prognosis. AB - Although intrinsic apoptosis defects are causal to the extended survival of chronic lymphocytic leukemia (CLL) B cells, several lines of evidence support a contribution of the peripheral lymphoid organs and BM microenvironment to the extended lifespan of leukemic B cells. Lymphocyte trafficking is controlled by homing signals provided by stromal cell-derived chemokines and egress signals provided by sphingosine-1-phosphate (S1P). In the present study, we show that expression of S1P1, the S1P receptor responsible for lymphocyte egress, is selectively reduced in CLL B cells with unmutated IGHV. Expression of S1P2, which controls B-cell homeostasis, is also impaired in CLL B cells but independently of the IGHV mutational status. We provide evidence herein that p66Shc, a Shc adaptor family member the deficiency of which is implicated in the apoptosis defects of CLL B cells, controls S1P1 expression through its pro-oxidant activity. p66Shc also controls the expression of the homing receptor CCR7, which opposes S1P1 by promoting lymphocyte retention in peripheral lymphoid organs. The results of the present study provide insights into the regulation of S1P1 expression in B cells and suggest that defective egress caused by impaired S1P1 expression contributes to the extended survival of CLL B cells by prolonging their residency in the prosurvival niche of peripheral lymphoid organs. PMID- 23033272 TI - Epigenetic changes through DNA methylation contribute to uterine stromal cell decidualization. AB - Embryo-uterine interaction during early pregnancy critically depends on the coordinated expression of numerous genes at the site of implantation. The epigenetic mechanism through DNA methylation (DNM) plays a major role in the control of gene expression, although this regulatory event remains unknown in uterine implantation sites. Our analysis revealed the presence of DNA methyltransferase 1 (Dnmt1) in mouse endometrial cells on the receptive d 4 of pregnancy and early postattachment (d 5) phase, whereas Dnmt3a had lower abundant expression. Both Dnmt1 and Dnmt3a were coordinately expressed in decidual cells on d 6-8. 5-Methycytosine showed a similar expression pattern to that of Dnmt1. The preimplantation inhibition of DNM by 5-aza-2'-deoxycytodine was not antagonistic for embryonic attachment, although endometrial stromal cell proliferation at the site of implantation was down-regulated, indicating a disturbance with the postattachment decidualization event. Indeed, the peri- or postimplantation inhibition of DNM caused significant abrogation of decidualization, with concomitant loss of embryos. We next identified decidual genes undergoing alteration of DNM using methylation-sensitive restriction fingerprinting. One such gene, Chromobox homolog 4, an epigenetic regulator in the polycomb group protein family, exhibited hypomethylation in promoter DNA and increased expression with the onset of decidualization. Furthermore, inhibition of DNM resulted in enhanced expression of hypermethylated genes (Bcl3 and Slc16a3) in the decidual bed as compared with control, indicating aberration of gene expression may be associated with DNM-inhibition-induced decidual perturbation. Overall, these results suggest that uterine DNM plays a major role for successful decidualization and embryo development during early pregnancy. PMID- 23033274 TI - Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis. AB - Acrodysostosis is characterized by nasal hypoplasia, peripheral dysostosis, variable short stature, and intellectual impairment. Recently, mutations in PRKAR1A were reported in patients with acrodysostosis and hormone resistance. Subsequently, mutations in a phosphodiesterase gene (PDE4D) were identified in seven sporadic cases. We sequenced PDE4D in seven acrodysostosis patients from five families. Missense mutations were identified in all cases. Families showed de novo inheritance except one family with three affected children whose father was subsequently found to have subtle features of acrodysostosis. There were no recurrent mutations. Short stature and endocrine resistance are rare in this series; however, cognitive involvement and obesity were frequent. This last finding is relevant given PDE4D is insulin responsive and potentially involved in lipolysis. PDE4D encodes a cyclic AMP regulator and places PDE4D-related acrodysostosis within the same family of diseases as pseudohypoparathyroidism, pseudopseudohypoparathyroidism, PRKAR1A-related acrodysostosis and brachydactyly mental retardation syndrome; all characterized by cognitive impairment and short distal extremities. PMID- 23033273 TI - Suppression of food intake by glucagon-like peptide-1 receptor agonists: relative potencies and role of dipeptidyl peptidase-4. AB - Administration of the glucagon-like peptide-1 (GLP-1) receptor agonists GLP-1 and exendin-4 (Ex-4) directly into the central nervous system decreases food intake. But although Ex-4 potently suppresses food intake after peripheral administration, the effects of parenteral GLP-1 are variable and not as strong. A plausible explanation for these effects is the rapid inactivation of circulating GLP-1 by dipeptidyl peptidase-4 (DPP-4), an enzyme that does not alter Ex-4 activity. To test this hypothesis, we assessed the relative potency of Ex-4 and GLP-1 under conditions in which DPP-4 activity was reduced. Outbred rats, wild type mice, and mice with a targeted deletion of DPP-4 (Dpp4(-/-)) were treated with GLP-1 alone or in combination with the DPP-4 inhibitor vildagliptin, Ex-4, or saline, and food intake was measured. GLP-1 alone, even at high doses, did not affect feeding in wild-type mice or rats but did reduce food intake when combined with vildagliptin or given to Dpp4(-/-) mice. Despite plasma clearance similar to DPP-4-protected GLP-1, equimolar Ex-4 caused greater anorexia than vildagliptin plus GLP-1. To determine whether supraphysiological levels of endogenous GLP-1 would suppress food intake if protected from DPP-4, rats with Roux-en-Y gastric bypass and significantly elevated postprandial plasma GLP-1 received vildagliptin or saline. Despite 5-fold greater postprandial GLP-1 in these animals, vildagliptin did not affect food intake in Roux-en-Y gastric bypass rats. Thus, in both mice and rats, peripheral GLP-1 reduces food intake significantly less than Ex-4, even when protected from DPP-4. These findings suggest distinct potencies of GLP-1 receptor agonists on food intake that cannot be explained by plasma pharmacokinetics. PMID- 23033275 TI - Paraneoplastic syndromes with connective tissue involvement. "It's not always lupus!". AB - Paraneoplastic syndromes (PNS) are remote effects of cancer that are, by definition, caused neither by invasion of the tumor or its metastases nor by infection, ischemia, metabolic and nutritional deficits, surgery or other forms of tumor treatment. The purpose of the current review was to present the challenging elements of differential diagnosis in oncology, as they may represent the main clinical problem in a patient diagnosed with cancer, even though the complete knowledge of both their clinical aspects and pathogenesis remain quite poor. This review focuses on the paraneoplastic syndromes related to dermatology and rheumatology, as the most frequent manifestations come from connective tissues that might determine a patient to ask for consultation by a general practitioner. PMID- 23033276 TI - Primary prevention of cervical cancer: prophylactic human papillomavirus vaccines. AB - Human papillomavirus (HPV) is one of the most common sexually transmitted diseases worldwide. Cervical and anal intraepithelial neoplasia, genital warts, and recurrent respiratory papillomatosis such as cervical and other anogenital cancers, are HPV-associated diseases. Prophylactic HPV vaccines are composed of HPV L1 capsid protein that self-assembles into virus-like particles (VLPs) when expressed in recombinant systems. The two types of prophylactic vaccines are designed a bivalent vaccine to protect against high-risk HPV types 16 and 18 and a quadrivalent vaccine designed to protect against HPV 16 and 18, and low-risk, genital wart-causing HPV 6 and 11. Proof-of-principle trials have suggested that intramuscular injections of VLPs result in strong adaptive immune responses that are capable of neutralizing subsequent natural infections. Recent research on the safety and efficacy of candidate prophylactic vaccines against HPV have shown very promising results with nearly 100% efficacy in preventing the development of persistent infections and cervical precancerous lesions in vaccinated individuals. PMID- 23033277 TI - Case-control design as investigative approach to assessing cancer etiology: development and future perspectives. AB - The case-control method evolved out of analyses of series of cases. The analytic form of the case-control study can be found in the 19th century medical literature, but did not appear to be viewed as a special or distinct methodology. The first modern case-control study was the Janet Lane-Claypon's study of breast cancer in 1926, but the design was used only sporadically in medicine until 1950, when 4 published casecontrol studies linked smoking and lung cancer. These 1950s studies synthesized the essential elements of the case-control comparison, produced a conceptual shift within epidemiology, and laid the foundation for the rapid development of the case-control design in the subsequent half century. The powerful consistency of these case-control studies, and the replication of their findings in later prospective studies, promoted the general acceptance of the case-control study as a scientific tool in clinical research. Newer case-control studies have benefited from the advances in design, execution and analysis since 1950s. These advances include more rigorous selection and matching of case and control population, improved interviewing techniques, location of the design within a general framework of epidemiologic strategies for relating exposure to disease, understanding of the measures of effect, and application of increasingly sophisticated statistical procedures to findings. This review traces the development and future perspectives of the case-control design to assessing cancer etiology. With illustrations drawn primarily from the literature on its use and the value of its results to unravelling the etiology of malignant diseases, we tried to explore if the case-control approach firmly ensconced in epidemiology as investigational tool and rivals in importance the more straightforward cohort approach. PMID- 23033278 TI - Palliative treatments for advanced osteosarcoma. AB - Advances in diagnostic imaging, interventional radiology, chemotherapy and surgery greatly improved the outcome of patients with osteosarcoma, and made limb salvage possible without compromising survival. In these patients, the prognosis is influenced by the site and resectability of the tumor, prior malignancy, and histological response to preoperative chemotherapy. Unfortunately, the progress has not been as significant in the treatment of advanced osteosarcoma, namely metastatic, recurrent and unresectable tumor. Yet, although advanced and forecasting a dismal prognosis, advanced osteosarcoma is not necessarily untreatable. Aggressive local and medical treatments, including surgical removal of primary and/or metastatic disease are currently available; however, yet, most treatments aim at palliation. Palliative local treatments including isolated limb perfusion, radiation therapy, embolization, chemoembolization, thermal ablation and cryoablation, all have an important role for these patients. The aim of palliative treatments is to achieve a mild response by offering the least discomfort to the patient with the minimum possible complications, and possibly increase of survival. PMID- 23033279 TI - Cytopathologic interpretation of ascites due to malignancy. AB - The diagnosis of metastatic cancer in peritoneal fluid is of great importance for the patient and the attending physician. A cytopathologist's responsibility is twofold: (1) to accurately identify malignant cells; (2) to interpret tumor type and if possible the site of its origin even in the absence of complete clinical history of other clues. The difficulty in the diagnosis of metastatic neoplasms in peritoneal fluid is due to 2 factors: (1) abnormal mesothelial cells or macrophages may simulate cancer cells, or may conceal tumor cells; and (2) peritoneal fluid constitutes a natural and hitherto inadequately explored medium of cell culture, in which neoplastic cells may proliferate free of the boundaries imposed upon them by the framework of organs and tissues. Immunocytochemistry (ICC) and molecular techniques are essential to establish an accurate diagnosis. From a great many points of view malignant peritoneal fluid is suitable for continuous study of cancer cells, thus providing knowledge about biologic aspects of human solid tumors. PMID- 23033280 TI - Significance of the resection margin and risk factors for close or positive resection margin in patients undergoing breast-conserving surgery. AB - PURPOSE: While positive resection margin (RM) in women undergoing breast conserving surgery (BCS) represents a clear indication for re-resection, there is no unequivocal recommendation regarding the extent of the clear RM. The aim of this study was to define the optimal extent of the RM and the risk factors for close or positive RM. METHODS: Patients scheduled for BCS had diagnosis confirmed before BCS (lumpectomy and quadrantectomy) by core biopsy. Sentinel lymph node biopsy followed BCS, and in case of positive findings axillary lymph node dissection followed. According to RM patients were categorized into 4 groups: 1) Patients with positive RM; 2) Clear RM < 2 mm; 3) Clear RM of 2-5 mm; and 4) RM > 5 mm. In the first 3 groups where re-resection was indicated, the presence of tumor cells in the re-resection specimen was determined. All patients were followed for local recurrence. RESULTS: 330 patients undergoing BCS were studied. Median follow up was 39.6 months (range 12-70). Lumpectomy was performed in 111 cases and quadrantectomy in 219. In 19 cases the final procedure was mastectomy due to the impossibility to achieve negative RM. In 78 cases re-resection followed the primary procedure due to close or positive RM. Clear RM was < 2 mm in 12 cases (15%), 2-5 mm in 56 (72%) and positive margin in 10 (13%). Positive re-resection specimen was detected in 31 cases (39.7%) (in 10 cases with positive RM after primary procedure, in 3 with negative margin < 2 mm and in 18 with 2-5 mm margin). The re-resection rate according to the location of the primary tumor was 77% (n=60) in the upper outer quadrant, 8% (n=6) in the lower outer quadrant, 6% (n=5) in the upper inner quadrant, 4% (n=3) in the lower inner quadrant, and 5% (n=4) in centrally located tumors. Multicentric/ multifocal tumor was diagnosed in 16 cases from which re-resection was indicated in 12 cases (75%). The number of re-resection according to tumor size was as follows: Tis 8 cases (30.7%), T1a none, T1b 14 (20.2%), T1c 34 (22.5%), T2 22 (28%). Re-resection was performed in 8 cases (31%) of ductal carcinoma in situ (DCIS), in 53 (22%) of ductal carcinoma, in 10 (37%) of lobular carcinoma, and in 7 (15%) of other histology. Five cases with local relapse were detected during follow up. CONCLUSION: The generally recommended clear RM of 1-5 mm is not sufficient because of the high number of positive specimens in the case of clear RM of 2-5 mm. The risk factors for close or positive RM are multicentric tumors and upper outer location of the primary tumor. Longer follow up will be needed to analyze local relapse rate according to RM status. PMID- 23033281 TI - ABO and Rh blood groups frequency in women with HER2 positive breast cancer. AB - PURPOSE: The role of genetic factors in the development of cancer is widely accepted. Data on the role of ABO blood group and Rh factor in breast cancer is inconclusive. The aim of this study was to investigate the presence of a possible association between HER2 (+) breast cancer in Turkish women and ABO blood groups and Rh factor. METHODS: In 294 female patients with HER2 (+) breast cancer, ABO blood groups and Rh factor were examined. The relationship of blood groups with age, menopausal status, and family history of cancer, estrogen receptor (ER), progesterone receptor (PR) and HER2 status of these patients was evaluated. Blood groups distribution of 22,821 healthy blood donors was also assessed and compared with the patients' blood groups distribution. RESULTS: The median patient age was 47 years (range 20-80) and 56% of the patients were premenopausal. ER and PR were positive in 50 and 60% of the patients, respectively. Overall, the ABO blood group distribution of the 294 HER2 (+) breast cancer patients was similar to that of the healthy blood donors (p=0.36). Likewise there was no correlation between blood type and ER, PR and menopausal status. Rh (-) patients had more frequent family cancer history and this difference was significant for patients with blood group B Rh (-) and O Rh (-) (p = 0.04). CONCLUSION: In the present study we didn't find any relationship between HER2 status and ABO blood group and Rh factor. However, further studies with larger number of patients are needed to establish the role (if any) of blood groups in patients with breast cancer. PMID- 23033282 TI - Granulosa cell tumors of the ovary: review of 43 cases. AB - PURPOSE: Granulosa cell tumors of the ovary (OGCT) are rarely seen tumors and display a quite interesting behavior profile. The purpose of this study was to evaluate the impact of stage, histological type (juvenile or adult type) and treatment on the prognosis of this disease. METHODS: Forty-three females with OGCT operated between January 1990 and June 2007 were retrospectively evaluated. Radical surgery was performed to 37 patients (86%) without fertility desire, whereas conservative surgery was performed to 6 patients with early-stage disease and fertility desire. RESULTS: Thirty-nine (90.6%) patients had stage I disease, whereas 4 (9.4%) had advanced-disease stage (stage II 2 and stage III 2 patients). All of the patients were surgically treated, but conservative surgery was applied to only 6 cases. Postoperative chemotherapy was administered to 18 cases and the remaining 25 cases were put under follow-up without chemotherapy. Recurrence was observed in 8 cases and 1 of these cases was of juvenile type. Mean time to recurrence was 55.14+/-32.18 months (range 15-122). Tumor stage was the most important prognostic factor, with 5-year overall survival of 96.77% in local disease, and 66.67% in advanced-stage disease (p<0.01). CONCLUSION: OGCT can recur many years after primary therapy. Consequently these patients must be followed-up for long periods of time. Disease stage at diagnosis was the most important factor affecting the recurrence rate and prognosis. The evaluation of all factors affecting survival needs further studies with larger numbers of patients. PMID- 23033283 TI - Reirradiation for recurrent head and neck carcinoma. AB - PURPOSE: To present the outcome and toxicity profile of reirradiation (re-RT) in patients with recurrent head and neck cancer (HNC). METHODS: From 1995 to 2009, 35 patients underwent re-RT at our institution. Twenty-seven (77%) patients were initially diagnosed with stage III/IV disease. The median total doses of irradiation -first and second courses- were 66.0 Gy (range 54.0-70.0) and 55.8 Gy (range 32.5-66.6), respectively. The median time from the first course of irradiation to re-RT was 25.2 months (range 8-136). Six (17%) patients underwent salvage surgery before reirradiation. Concurrent chemotherapy was administered to 18 (51%) patients. RESULTS: With a median follow-up of 12.9 months (range 2.5 109.6), the 1- and 2-year locoregional control (LRC) rates were 41 and 9%, respectively. The 1- and 2-year disease free survival (DFS) rates were 30 and 7%, respectively. The 1- and 2-year overall survival (OS) rates were 42.9 and 7.9%, respectively. Grade 3 acute toxicity was reported in 7 (20%) patients while grade 3-4 late radiation-induced complications were seen in 8 (23%) patients. In univariate analysis, an improvement in OS was observed in patients with initial N0/N1 stage vs. those with N2/N3 stage (p=0.004). Prior neoadjuvant chemotherapy was associated with significantly inferior OS (p=0.028), while neoadjuvant chemotherapy in recurrence was predictive of improved LRC (p=0.041). CONCLUSION: re-RT in HN cancer is associated with poor prognosis, especially in patients with inoperable disease. Complications due to treatment are not infrequent. Nonetheless, our outcomes remain encouraging and applicable to a carefully selected patient population. PMID- 23033284 TI - Definitive radiochemotherapy with weekly cisplatin in patients with head and neck cancer; single institution outcome analysis. AB - PURPOSE: The objective of this study was to evaluate the feasibility, toxicity and efficacy of definitive radiochemotherapy with weekly cisplatin in head and neck cancer in a single institutional setting. METHODS: Previously untreated patients with stage II-IV head and neck cancer were included. Radiotherapy consisted of 70 Gy/7 weeks/35 fractions. All patients received concurrent cisplatin 40 mg/m(2) weekly. RESULTS: Between 2/2002 and 8/2009, 148 consecutive patients (WHO <= 2, male to female ratio 6/1, median age 56 years) were treated. The mean follow-up was 40 months. Tumors of the oropharynx were the most frequent (46%) and stage IV predominated (80%). Eighty-nine percent of the patients had received the full radiation treatment as planned. Omission of weekly cisplatin occurred frequently, mainly because of hematological toxicity. Only 64% of the patients completed at least 5 cycles of chemotherapy. Grade 3/4 mucosal toxicity developed in 32% of the patients. The late toxicities were acceptable: 74% of the patients were able to eat solid food during the 1st post-treatment year, 4 patients were not able to swallow at all during the 1st post-treatment year, requiring thus permanent feeding tube. Five cases of osteoradionecrosis of the mandible were reported. Three-year overall survival, locoregional control, time to progression and disease free survival were 34, 60, 52 and 29%, respectively. CONCLUSION: Definitive radiochemotherapy with weekly cisplatin was toxic, with high rate of morbidity and mortality in this patient population. Five weekly cycles of 40 mg/m(2) cisplatin seem to be the dose limit for most patients. Three year survival was significantly reduced despite the promising high initial response and locoregional control. PMID- 23033285 TI - Postlaryngectomy vocal rehabilitation in Albania. AB - PURPOSE: To assess short and midterm results with consistent use of indwelling voice prostheses (Provox 1 and Provox 2 valves) for vocal rehabilitation after total laryngectomy. METHODS: From May 2008 to June 2010 106 patients (104 men, 2 women, median age 62.32 years) with total laryngectomy underwent vocal prosthesis insertion and replacement procedures as needed. Patients were prosthesized primarily or secondarily and follow-up was performed monthly. RESULTS: Median patient-device follow-up was 279 days (range 184-995). Leakage through the prosthesis, mainly caused by Candida deposits on the valve, was the most common cause of failure of the Provox valves. CONCLUSION: Compared to other European countries, like the Netherlands (100 days) and France (150 days) Albania has the longest device half life. This relatively long prosthesis' lifetime in our country is perhaps related with the use of spicy food (a common custom in our country), and the use of antifungal and antacid agents. PMID- 23033286 TI - Elective bladder preservation with multimodality treatment for bladder cancer. AB - PURPOSE: To observe the outcome of maximal transurethral resection of bladder tumor (TURBT) followed by induction chemotherapy and concurrent chemoradiotherapy in medically inoperable patients with bladder cancer. METHODS: This study included 30 patients with stage T 2-4 bladder cancer. The patients were first treated with TURBT, and then received 2 cycles of induction chemotherapy with gemcitabine and cisplatin, followed by concurrent chemoradiotherapy with gemcitabine. RESULTS: Median follow up was 28.9 months. Radiologically, complete and partial response rates were 60 and 36.7%, while cystoscopically they were 40 and 30%, respectively. Local progression (4 cases) and distant metastasis (11 cases) were noted. Median overall survival and progressionfree survival were 32 and 21 months, respectively. One -and 2-year overall survival and progression free survival rates were 97.60% and 83.49%, respectively. CONCLUSION: The multimodal treatment performed in this study was well tolerated and achieved a high rate of bladder preservation in selected patients with bladder cancer. PMID- 23033287 TI - Research on and clinical importance of duplications in various chromosomal regions in addition to Philadelphia chromosome in chronic myeloid leukemia. AB - PURPOSE: To investigate the chromosomal aberrations in chronic myelogenous leukemia (CML), particularly in chromosomal regions which carried 67 genes pertaining to oncogenes, transcription factors, signal transduction, tumor suppressors, apoptosis etc, in addition to Philadelphia (Ph+) chromosome by multiplex ligation-dependent probe amplification (MLPA) method and to compare them with clinical parameters. METHODS: The aberrations were investigated in 48 CML patients receiving imatinib therapy and a group of 15 healthy controls, by using the MLPA method between 2000 and 2009. The obtained results were compared both between patient and control groups and with clinical parameters. RESULTS: Duplication was detected in the fibroblast growth factor receptor 1 (FGFR1) gene of 2 patients, inosine 5' monophosphate dehydrogenase 1 (IMPDH1) gene of 4, postmeiotic segregation increased S. Cerevisiae 2 (PMS2) gene of 1, nuclear factor kappa beta (NFKB) of 5 and T-cell translocation 2 (LMO2) gene of 1 patient. Univariate analysis showed that splenomegaly, advanced age, Sokal risk score (SRS) and the duplications in IMPDH1 and FGFR1 genes significantly shortened 7-year event-free survival (EFS); multivariate analysis showed that only the duplications in IMPDH1 and FGFR1 genes were the factors that significantly affected EFS. No statistically significant correlations were detected between duplications and other clinical parameters. CONCLUSION: Duplications in 4 genes (FGFR1, IMPDH1, PMS2, LMO2) in addition to Ph+ chromosome in CML patients were detected for the first time. This study indicates that chromosomes 7 and 8 should be particularly investigated in more detail in addition to the Ph+ chromosome for better determination of disease prognosis and selection of alternative treatments. PMID- 23033288 TI - Significance of tumor burden, vascular endothelial growth factor, lactate dehydrogenase and beta-2 microglobulin serum levels in advanced diffuse large B cell lymphoma. AB - PURPOSE: Lactate dehydrogenase (LDH) and beta-2 microglobulin (B2M) are incorporated in the so-called "serologic staging system", as independent parameters for predicting time to treatment failure (TTF) and overall survival (OS) for aggressive non-Hodgkin's lymphoma (NHL) patients. Elevated values of serum vascular endothelial growth factor (sVEGF) was associated with poor survival in the largest histological subgroup, the diffuse large B cell (DLBCL) and immunoblastic lymphomas. sVEGF has independent influence on survival in multivariate models when tested together with the components of the International Prognostic Index (IPI). The purpose of this study was to define possible correlations between LDH, B2M levels and the novel prognostic parameter sVEGF, with assessed tumor burden, as another parameter of aggressiveness for advanced stage DLBCLs. METHODS: Serum samples were collected from 29 patients with DLBCL, Ann Arbor clinical stages III and IV, to measure pretreatment serum levels of LDH, B2M and sVEGF. Tumor burden was defined as low and high according to criteria's defined by Jagannath and colleagues. RESULTS: A trend toward significant correlation between high initial levels of sVEGF and high tumor burden was observed (p=0.077). High serum LDH level was strongly associated with high tumor burden (p=0.0091), but B2M correlation with either low or high tumor burden was not confirmed (p=0.249). Complete response (CR) rates (CR vs. non CR) and OS according to tumor burden (low vs. high) showed no statistically significant differences (p=0.245 and p=0.202). CONCLUSION: Our preliminary data confirmed association between serum LDH level and DLBCL burden with a satisfactory sensitivity-specificity relationship. The other two parameters, sVEGF and B2M, failed to demonstrate significant relationship with tumor burden. PMID- 23033289 TI - The prevalence and significance of autoantibodies in patients with non-Hodgkin's lymphoma: are they correlated with clinicopathological features? AB - PURPOSE: It is well known that an association exists between the pathogenesis of lymphomas and autoimmune diseases. Autoantibodies are detected at higher frequency in lymphoproliferative diseases, but neither the precise role of the immune system nor the cause of this is comprehensively understood. In this study we evaluated the presence and significance of some autoantibodies for patients with non- Hodgkin's lymphoma (NHL). METHODS: 150 patients with NHL who had either newly diagnosed disease, or active disease being under chemotherapy or were disease-free during follow-up, were analyzed. The frequency of autoantibodies and the relationship between autoantibodies and several clinicopathological factors were evaluated. RESULTS: The majority of the patients (50%) had diffuse large B cell lymphoma (DLBCL). Thirty-two patients (21.4%) were newly diagnosed, 81 (54%) had active disease and were receiving chemotherapy and 37 (24.6%) were disease free and followed-up. Fifty-one patients (34%) had stage IV disease. Antinuclear antibodies (ANA) were found in 7 (4.7%) patients, perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) in 10 (6.7%), anti dsDNA in 1 (0.7%), anti ssDNA in 16 (10.7%), anti Jo-1 in 3 (2%), anti-scleroderma antibody (anti Scl-70) in 4 (2.7%), and rheumatoid factor (RF) in 85 (56.7%) patients. No c7horbar;ANCA positivity was found. The mean levels of anti Jo-1 (p=0.028), anti ssDNA (p=0.014), c-ANCA (p=0.015), ANA (p=0.026) and RF (p=0.046) were significantly higher in cases with DLBCL compared to patients with non-DLBCL. In addition, in patients with newly diagnosed NHL the mean levels of anti Scl- 70 (p=0.023), anti Jo-1 (p7equals;0.017), and RF (p=0.046) were significantly higher than the other patient groups. No significant correlation was detected between the presence of autoantibodies and other clinicopathological factors. CONCLUSION: Our results show that the frequency of autoantibodies is high in NHL patients, especially in DLBCL and newly diagnosed cases. Autoantibodies may be helpful for the diagnosis of autoimmune diseases, but regular and long follow-up is needed in NHL patients with high levels of autoantibodies. PMID- 23033290 TI - External beam radiotherapy versus brachytherapy in the management of malignant oesophageal dysphagia: a retrospective study. AB - PURPOSE: Dysphagia is a prominent symptom of oesophageal cancer which may be palliated by stent, external beam radiation (EBRT) or intraluminal brachytherapy (ILBT). Brachytherapy is not widely practised in the UK. The aim of this study was to compare the efficacy of ILBT and EBRT in relieving malignant dysphagia. METHODS: The radiotherapy database at Northampton Cancer Centre (NCC) was used to identify patients who underwent ILBT or EBRT for malignant dysphagia between 1.1.2008 and 31.3 2010. Data was collected on patient demographics, tumour characteristics, treatment received and dysphagia score pre- and post- treatment. Serial assessment of dysphagia was used to determine the duration of symptomatic improvement. EBRT involved 20-30 Gy in 5-10 fractions. Brachytherapy applicator placement was done by an experienced endoscopist at the high dose rate (HDR) suite and a single treatment dose of 12 Gy was prescribed at 1 cm depth. Oesophageal dilation was performed prior to brachytherapy treatment if needed. RESULTS: 44 patients were included in this study (EBRT: 21; ILBT: 23). Patient characteristics were well balanced between the two groups. The average dysphagia scores in the EBRT group prior to treatment were 3, and at 4, 8 and 16 weeks following treatment they were 3.4, 2.4, 2.1 and 2.1, respectively. The corresponding dysphagia scores in the ILBT group were 3.5 before treatment and 2.2, 2.1 and 2.3 following treatment, respectively. There was significant improvement in dysphagia in both groups at 4 weeks (p<0.0001), and the benefit was sustained after 8 and 16 weeks. No major complications were reported from either EBRT or oesophageal brachytherapy. CONCLUSION: ILBT is an effective alternative to multifractionated EBRT for palliation of malignant dysphagia providing a convenient one-stop treatment for patients who live a long distance from their cancer centre. Our model of performing the endoscopically guided procedure in the brachytherapy unit is comparable in cost to fractionated EBRT and can be adopted by other centres. PMID- 23033291 TI - Different radiation treatment in esophageal carcinoma: a clinical comparative study. AB - PURPOSE: Conventional fractionation radiation therapy (CFRT), 3-dimensional conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT), are always applied to treat esophageal carcinoma. The purpose of this study was to analyse the therapeutic results and acute radiation side effects of radiotherapy in the treatment of esophageal carcinoma. METHODS: From March 2008 to May 2010, 117 patients with esophageal carcinoma treated at our hospital were included into this study. Thirty-eight (32.48%?) patients were treated with CFRT, 32 with 3DCRT and 47 with IMRT. The data were retrospectively collected and analysed. RESULTS: The objective response rates (complete/CR plus partial response/PR) in the CFRT group, 3DCRT group and IMRT group were 96.88, 92.11, and 91.49%, respectively (p=0.617). Furthermore, the one-year survival of the 3 groups was 77.9, 87.5 and 86.7%, respectively (p=0.193), and the 2-year survival 38.6, 55.1 and 57.7%, respectively (p=0.211). The incidence of acute radiation esophagitis in the IMRT+3DCRT groups was significantly higher compared with the CFRT group (p=0.012) and the incidence of acute radiation- induced pneumonitis, bronchitis and myelosuppression in the IMRT+3DCRT groups were lower compared with the CFRT group (p<0.01, p=0.028, and p=0.01, respectively). CONCLUSION: Both IMRT and 3DCRT methods can improve the clinical therapeutic outcome of patients with esophageal carcinoma and decrease the incidence of acute radiation pneumonitis, radiation bronchitis and bone marrow suppression. PMID- 23033292 TI - Identification of prognostic factors in patients with metastatic gastrointestinal stromal tumors. AB - PURPOSE: Gastrointestinal stromal tumors (GISTs) have a complex biology which is reflected by a marked clinical heterogeneity. Thus, there has been great interest in identifying prognostic factors influencing tumor recurrence and survival. The aim of this study was to identify potential clinical and immunohistochemical prognostic factors that may affect survival and treatment outcomes in patients with metastatic GISTs. METHODS: Between 2000 and September 2011, a total of 41 patients with metastatic GISTs (29 males and 12 females; mean age: 57.4+/-11.8 years; range 29-74) were referred to the Department of Oncology, Uludag University Medical School. Survival analysis for a number of potential prognostic factors was made with the main outcome results of progression-free survival (PFS) and overall survival (OS7rpar;. RESULTS: The most common sites of isolated metastases comprised the liver (n=18), followed by lymph nodes (n=5), the omentum (n=1), and the mesothelium (n=1). The remaining patients had metastases at multiple sites. Cox regression analysis identified ileal location as the only significant predictor of poor PFS both after first-line (p=0.023) and second-line therapy (p=0.016). Tumor location in the ileum (p=0.025) and S100 immunoreactivity (p=0.041) were both independent predictors of OS. CONCLUSION: Tumor site and S100 positivity were the main significant independent predictors of clinical outcomes in patients with metastatic GISTs treated by standard of care. PMID- 23033293 TI - Reoperation combining re-cytoreductive surgery and re-HIPEC for recurrent peritoneal carcinomatosis. AB - PURPOSE: Cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the proper treatment for resectable peritoneal carcinomatosis (PC). The aim of this study was to evaluate the postoperative course and long-term outcome of repeat CS (reCS) plus repeat HIPEC (reHIPEC) in patients with recurrent disease, after primary CS plus primary HIPEC. METHODS: From 2004 to 2012 85 patients were subjected to primary CS + HIPEC. Fourteen of those patients developed recurrent PC and were subjected to reCS+reHIPEC during the same time period. Eligibility criteria included limited extent of the peritoneal disease, and interval of more than 12 months from the primary CS+HIPEC. The origins of the tumors were ovarian cancer (n=7) colorectal cancer (n=3), pseudomyxoma peritonei (n=3), and uterine sarcoma (n=1). RESULTS: At second laparotomy, mean peritoneal cancer index (PCI) was 5.3 + 2.8. Among the 14 procedures, HIPEC was used in all patients. The postoperative mortality was 0% and grade 3-4 postoperative complications occurred in 4 patients. The overall 1-, 2- and 3- year overall survival rate was 90, 40 and 30%, respectively. CONCLUSION: ReCS+reHIPEC is feasible and yields an accepted survival in highly selected patients. PMID- 23033294 TI - Dosimetric consequences of pancreatic tumor motion when predetermined treatment margins are employed during intensity-modulated radiation therapy. AB - PURPOSE: To quantify the dosimetric consequences of pancreatic tumor motion on the pancreatic intensity-modulated radiation therapy (IMRT) plans. METHODS: Dose map of IMRT plans for 5 patients with pancreatic cancer were measured using a 2D diode array placed on a computer-controlled platform to simulate 2D pancreatic tumor motion. Dosimetric analysis was then performed to obtain IMRT quality assurance (QA) passing rates. The convolution method, which used a motion kernel to simulate 2D pancreatic motion, was also applied to the treatment and phantom verification plans for a wide range of magnitudes of motion (0.8-2.0 cm). The resulting motion-convolved verification dose maps (VDMs) were compared with the dynamic measurements to evaluate IMRT QA passing rates as well as the dose-volume histogram, the V95% of the planning target volume (PTV) and V98% of the clinical target volume (CTV). RESULTS: While CTV coverage was maintained when the simulated pancreatic tumor drifted inside the PTV with magnitudes of 1.0 cm and 1.5 cm, the V95% of the PTV was reduced by 10% and 17%, respectively. We also found that the differences between the measurements and the static VDMs increased proportional to the amplitude of motion, while the agreement between the measurements and the motion-convolved VDMs was excellent for any magnitude of motion. CONCLUSIONS: When the 4D technique is not available, predetermined margins must be used carefully to avoid possible under-dose to the target. Additionally, the phantom results show that the kernel convolution method provides an accurate evaluation of the dosimetric impact due to tumor motion and it should be employed in the planning process. PMID- 23033295 TI - Prognostic factors in elderly patients with advanced non-small cell lung cancer treated with first-line cisplatin-based chemotherapy: a retrospective analysis of single institution. AB - PURPOSE: Non-small cell lung cancer (NSCLC) makes up 80-85% of all lung cancers cases. Lung cancer in older individuals is frequently undertreated. Patients eligible for cisplatin- based chemotherapy should be selected carefully. The aim of this retrospective single-center study was to evaluate prognostic factors for overall survival (OS) in elderly (>=65 years) patients with advanced NSCLC who received first-line cisplatin-based chemotherapy. METHODS: We retrospectively reviewed 110 elderly patients with locally advanced or metastatic NSCLC who had been administered cisplatin-based first-line chemotherapy between December 2004 and November 2011. Seventeen potential prognostic variables were chosen for analysis. Univariate and multivariate analyses were conducted to identify prognostic factors associated with OS. RESULTS: Among the 17 variables of univariate analysis, 4 were identified to have prognostic significance for OS: comorbidities (p<0.001), Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p=0.02), first-line chemotherapy cycles (p<0.001) and serum albumin level (p=0.04). Multivariate analysis showed that only ECOG PS (p=0.01) was independent prognostic factor for OS. CONCLUSION: PS was important prognostic factor in elderly patients with advanced NSCLC. The findings of this study may facilitate pretreatment prediction of OS and therefore can be used for selecting the most appropriate treatment for elderly patients. PMID- 23033296 TI - The clinical value of scintigraphy of neuroendocrine tumors using (99m)Tc-HYNIC TOC. AB - PURPOSE: To assess the value of whole body scintigraphy using (99m)Tc-HYNIC-TOC (Tektrotyd) and with single photon emission computerized tomography (SPECT) in the detection of primary and metastatic neuroendocrine tumors (NETs). METHODS: Thirty patients with different neuroendocrine tumors, mainly gastroenteropancreatic (GEP), were investigated. Whole body scintigraphy was performed 2 h (if necessary 10 min and 24h) after i.v. administration of 740 Mbq (99m)Tc-Tektrotyd, Polatom. In cases of unclear findings obtained by whole body scintigraphy, investigation was followed by SPECT. RESULTS: From 12 patients with NETs of unknown origin, there were 10 true positive (TP), and 2 false negative (FN) findings. Diagnosis was made with SPECT in 6 patients. From 8 patients with gut carcinoids, there were 4 TP, 2 true negative (TN), one FN, and one false positive (FP) finding. Diagnosis was made with SPECT in 2 patients. From 7 patients with neuroendocrine pancreatic carcinomas there were 4 TP and 3 TN findings. Diagnosis was made with SPECT in 2 patients. From 3 patients with gastrinomas there were 2 TP findings and one TN findings. Diagnosis was made with SPECT findings in 2 patients. Sensitivity of (99m)Tc-HYNIC-TOC was 87%, specificity 86%, positive predictive value 95%, negative predictive value 67% and accuracy 87%. CONCLUSION: We concluded that scintigraphy with (99m)Tc-Tektrotyd is an useful method for diagnosis, staging and follow up of the patients with NETs. PMID- 23033297 TI - Mitral valve myxoma: a large-scale collective review. AB - PURPOSE: Despite the review articles repeatedly published with respect to mitral valve myxomas, hardly could we find one based upon complete literature retrieval. We took an effort on complete literature retrieval and made a comprehensive review of the mitral valve myxomas. METHODS: An instant thorough literature retrieval of the heart myxoma was made by using the MEDLINE and EMBASE databases, as well as secondary references cited in the articles obtained from the MEDLINE search. In addition, we searched the Google and HighWire Press. RESULTS: The patients with mitral valve myxoma were young. Their major symptoms were cerebrovascular, cardiovascular, or constitutional. The tumors had small sizes, predilection of mitral leaflet location, solitary and pedicled nature, and good response to surgical resection. CONCLUSION: These clinical characteristics of mitral valve myxoma may help the differential diagnosis between mitral valve myxoma and other valvular lesions, and help making a decision of a surgical treatment. PMID- 23033298 TI - The value of expression of EGFR, telomerase and topoisomerase IIalpha in malignant effusion smears before and after chemotherapy. AB - PURPOSE: To evaluate the significance of expression of epidermal growth factor receptor (EGFR), telomerase and topoisomerase IIalpha (topo IIalpha) in cells of malignant effusions of patients under chemotherapy. METHODS: We studied the expression of EGFR, telomerase and topo IIalpha in malignant effusion smears of 95 cancer patients before and after chemotherapy. Immunocytochemical and in situ hybridization techniques were applied. RESULTS: Positive expression before chemotherapy of telomerase, topo IIalpha and EGFR was found in 64.2, 63.2 and 69.5% of the cases, respectively; the expression of these markers following chemotherapy was 43.6, 28.2 and 53.8%, respectively. The stronger prognostic factor affecting survival before chemotherapy was telomerase (p=0.0002), whereas after chemotherapy the strongest factor was EGFR (p<0.0001). A positivity for all three markers following chemotherapy was associated with shorter survival compared with positivity for only 1 or 2 markers (p<0.0001) or with a negative expression. CONCLUSION: It seems that expression of EGFR, telomerase and topo IIalpha in malignant effusion smears is adversely affecting prognosis and survival. PMID- 23033300 TI - Nurse-assisted education and exercise decrease the prevalence and morbidity of lymphedema following breast cancer surgery. AB - PURPOSE: To evaluate an educational and exercise program for the prevention and progression of post-mastectomy lymphedema of the arm and shoulder. METHODS: Fifty five patients who had undergone mastectomy and axillary lymph node dissection between June 2009 and January 2010 were included in this study. The patients were informed by a trainer nurse about the precautions they should take to prevent the development of lymphedema. The patients were also trained for the appropriate exercises and were given written educational material prepared by the investigators. RESULTS: Among the participants, 96.4% underwent modified radical mastectomy (MRM) and 3.6% breast-conserving (BCS) surgery. The mean postoperative follow-up period was 9.87 +/- 17.55 months. The degree of lymphedema was found lower, even within 6 months, in the patients that exercised as compared to the patients that did not (p<0.05). CONCLUSIONS: The results indicate that the risk of development and progression of mastectomy-related lymphedema was reduced with education and exercise provided by trained nurses at an early stage. PMID- 23033299 TI - Comparison of foam dressings with silver versus foam dressings without silver in the care of malodorous malignant fungating wounds. AB - PURPOSE: To investigate the effectiveness of foam dressings with silver vs. foam dressings without silver to reduce malodorous and septic phenomena in malignant fungating wounds (MFWs). METHODS: The study included 26 patients with malodorous MFWs at home care. Thirteen patients formed the intervention group A (foam dressings with silver), and another 13 patients formed the control group B (foam dressings without silver). The patients' selection was random. The dressing changes were carried out according to the needs of the ulcer and depending on the exudates' level. The evaluation of the odor was 4 weeks after the start of the study. The patients' evaluation was excluded due to familiarization with the odor. RESULTS: In group A 10/13 (76.9%) patients showed a significant reduction of the odor compared with 4/13 (30.8%) patients in group B (p = 0.049). CONCLUSION: Microbial activity and septic phenomena in the ulcerated surface of MFWs are the causes of unpleasant odor. This study provided evidence that the antimicrobial property of silver dressings is very useful in the treatment of microbial activity and can reduce malodorous and septic phenomena. PMID- 23033301 TI - Science ethics education: effects of a short lecture on plagiarism on the knowledge of young medical researchers. AB - PURPOSE: Plagiarism is the most common form of scientific fraud. It is agreed that the best preventive measure is education of young scientists on basic principles of responsible conduct of research and writing. The purpose of this article was to contribute to the students' knowledge and adoption of the rules of scientific writing. METHODS: A 45 min lecture was delivered to 98 attendees during 3 courses on science ethics. Before and after the course the attendees fulfilled an especially designed questionnaire with 13 questions, specifically related to the definition and various types of plagiarism and self-plagiarism. RESULTS: Although considering themselves as insufficiently educated in science ethics, the majority of the attendees responded correctly to almost all questions even before the course, with percentages of correct responses to the specific question varying from 45.9-85.7%. After completion of the course, these percentages were significantly (p<0.01) higher, ranging from 66.3-98.8%. The percentage of improvement of the knowledge about plagiarism ranged from 9.18- 42.86%. The percentage of impairment ranged from 1.02- 16.33%, the latter being related to the question on correct citing unpublished materials of other people; only for this question the percentage of impairment (16.33%) was greater than the percentage of improvement (11.22%). CONCLUSION: Even a short lecture focused on plagiarism contributed to the students' awareness that there are many forms of plagiarism, and that plagiarism is a serious violation of science ethics. This result confirms the largely accepted opinion that education is the best means in preventing plagiarism. PMID- 23033302 TI - KRAS and BRAF mutations in Serbian patients with colorectal cancer. AB - PURPOSE: Mutations of KRAS and BRAF genes represent molecular biomarkers of response to targeted therapy in patients with metastatic colorectal cancer (mCRC). Since these mutations have been shown to exert different biological effects and impacts on patients' outcome, there is a need to determine reliably the frequency and types of KRAS mutations for diagnostic and individual therapeutic purposes. Despite having a wild type (wt) KRAS, some patients fail to respond to treatment. BRAF V600E mutation is an additional molecular determinant of response to the same therapy. In this study we described the KRAS and the BRAF V600E mutation spectra and frequencies in a group of Serbian mCRC specimens. METHODS: KRAS mutations were determined with DxS TheraScreen(r) K-RAS Mutation Kit and KRAS StripAssay(TM), and for the BRAF V600E mutation we applied High Resolution Melting (HRM) analysis. RESULTS: KRAS mutations were present in 34.7% of 190 analyzed samples. The 7 most frequent mutation types observed were: G12D 43.9%, G12V 21.2%, G12A 10.6%, G12C 7.6%, G12S 4.5%, G12R 1.5%, G13D 10.6%. Among the wt KRAS patients, 17.8% carried the BRAF V600E mutation. CONCLUSIONS: We have shown that the spectrum and frequency distribution of the identified KRAS and BRAF mutations in Serbian study population are in good accordance with literature data. We believe that our results are significant concerning aspects related to tumor molecular biology as well as to patient selection in the diagnostic settings. PMID- 23033303 TI - Effect of continuous and pulsed therapeutic ultrasound in the appearance of local recurrence of mammary cancer in rats. AB - PURPOSE: Ultrasound (US) therapy is an electrothermotherapeutic modality that uses US energy to provoke physical and chemical alterations. US therapy has been widely used in physical therapy. However, in clinical practice, it is contraindicated in cancer patients due to the possibility of exacerbating tumor growth. METHODS: Sixty-eight female Sprague-Dawley rats bred in UNIFAE vivarium were studied. At 50 days of age, 7,12-dimetylbenz(a)anthracene (7,12-DMBA) was administered to 35 rats by gastric gavage to induce mammary cancer. After 90 days the mammary glands of the rats belonging to the group with mammary cancer induction and stimulated by US were removed. Animals received either continuous or pulsed US. US waves were generated at a frequency of 1 MHz during 10 days, with an intensity dose of 0.5 W in the continuous group, and 0.9 W (duty cycle: 20%) in the pulsed group. RESULTS: Among the rats treated with continuous US, 44.4% developed local recurrence, while among the rats treated with pulsed US, 22.2% had local tumor recurrence (p<0.05). No evidence of distant metastases was shown in any of the rats studied. CONCLUSION: The use of continuous and pulsed therapeutic US promoted the development of local recurrence of mammary cancer in female Sprague-Dawley rats in the postoperative period. PMID- 23033304 TI - A new semiquantitative method for evaluation of metastasis progression. AB - PURPOSE: Although recent technical advancements are directed toward developing novel assays and methods for detection of micro and macro metastasis, there are still no reports of reliable, simple to use imaging software that could be used for the detection and quantification of metastasis in tissue sections. We herein report a new semiquantitative method for evaluation of metastasis progression in a well established 4T1 orthotopic mouse model of breast cancer metastasis. METHODS: The new semiquantitative method presented here was implemented by using the Autodesk AutoCAD 2012 program, a computer-aided design program used primarily for preparing technical drawings in 2 dimensions. RESULTS: By using the Autodesk AutoCAD 2012 software- aided graphical evaluation we managed to detect each metastatic lesion and we precisely calculated the average percentage of lung and liver tissue parenchyma with metastasis in 4T1 tumor-bearing mice. The data were highly specific and relevant to descriptive histological analysis, confirming reliability and accuracy of the AutoCAD 2012 software as new method for quantification of metastatic lesions. CONCLUSION: The new semiquantitative method using AutoCAD 2012 software provides a novel approach for the estimation of metastatic progression in histological tissue sections. PMID- 23033305 TI - Trabectedin in advanced soft tissue sarcoma: case series. AB - The prognosis of advanced soft tissue sarcomas (STS) is poor. The median overall survival (OS) is 6 months in unresectable and metastatic STS that progress after treatment with anthracyclines and ifosfamide. Trabectedin is an alkylating agent, effective in advanced STS, especially in leiomyosarcoma and liposarcoma. In the present study, the effectiveness and safety of trabectedin was retrospectively evaluated in 8 unresectable and metastatic STS patients. Their median age was 47 years. The median progression free survival (PFS) was 3.75 months and the median OS 15 months in relapse or progression after anthracyclines and/or ifosfamide. Toxicities were mainly hematologic. In the present study, trabectedin showed efficacy in different histological subtypes of sarcomas like liposarcoma and leiomyosarcoma. PMID- 23033306 TI - Gene numerical imbalances in cytological specimens based on fluorescence/chromogenic in situ hybridization analysis. AB - Design and development of novel targeted therapeutic strategies is an innovation in handling patients with solid malignancies including breast, colon, lung, head & neck or even pancreatic and hepatocellular carcinoma. For a long time, immunohistocytochemistry (IHC/ICC) has been performed as a routine method in almost all labs for evaluating protein expression. Modern molecular approaches show that identification of specific structural and numerical imbalances regarding genes involved in signal transduction pathways provide important data to the oncologists. Alterations in molecules such as epidermal growth factor receptor (EGFR), HER2/neu, PTEN or Topoisomerase IIa affect the response rates to specific chemotherapeutic agents modifying also patients' prognostic rates. In situ hybridization (ISH) techniques based on fluorescence and chromogenic variants (FISH/CISH) or silver in situ hybridization (SISH) are applicable in both tissue and cell substrates. Concerning cytological specimens, FISH/CISH analysis appears to be a fast and very accurate method in estimating gene/chromosome ratios. In this paper, we sought to evaluate the usefulness of FISH/ CISH analysis in cytological specimens, describing also the advantages and disadvantages of these methods from the technical point of view. PMID- 23033307 TI - Nasopharyngeal carcinoma with synchronous breast cancer; possible role of Epstein Barr virus infection in the carcinogenesis of both cancers. PMID- 23033308 TI - Solid pseudopapillary tumor of the pancreas: a case series of 7 patients. PMID- 23033309 TI - Can bevacizumab be a new treatment approach in metastatic melanoma? PMID- 23033310 TI - Rituximab-related cryptogenic organizing pneumonia and late onset neutropenia in a patient with non-Hodgkin lymphoma: report of two rare complications and review of the literature. PMID- 23033311 TI - Case detection rates of basal cell carcinoma by gender and age in Greek population. PMID- 23033312 TI - The quarrel between iatromechanists and animists about the cause of cancer: lymph's role in oncogenesis. AB - In the 17th century, iatromechanists based to the solidist theory for the lymphatic system and lymph established a new speculation for the essential role of lymph in oncogenesis, while animists gave their own views in relation to the cause of cancer. Gradually, with the rise of pathological anatomy, new more rational theories have emerged. PMID- 23033314 TI - Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer. AB - Oxidative stress caused by an increase in reactive oxygen species levels or a decrease in cellular antioxidant capacity can evoke the modulation of various cellular events including androgen receptor (AR) signaling via direct or indirect interactions. In this review, we summarize the mechanisms of AR activation by oxidative stress including: i) AR overexpression; ii) AR activation by AR co regulators or intracellular signal transduction pathways; iii) generation of AR mutations or splice variants; and iv) de novo androgen synthesis. AR signaling augmented by oxidative stress appears to contribute to pro-survival and anti apoptotic effects in prostate cancer cells in response to androgen deprivation therapy. In addition, AR signaling suppresses anti-survival and pro-apoptotic effects in prostate cancer cells in response to various cytotoxic and tumor suppressive interventions including taxanes and radiation through the modulation of betaIII-tubulin and ataxia telangiectasia-mutated kinase expression respectively. Taken together, AR signaling appears to render prostate cancer cells refractory to various therapeutic interventions including castration, taxanes, and radiation, indicating that AR signaling is a comprehensive resistant factor and crucial target for prostate cancer treatment. PMID- 23033313 TI - Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability. AB - OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability. PMID- 23033315 TI - Case-control study of markers of insulin resistance and endometrial cancer risk. AB - Markers of insulin resistance such as the adiponectin:leptin ratio (A:L) and the homeostasis model assessment ratio (HOMA-IR) are associated with obesity and hyperinsulinemia, both established risk factors for endometrial cancer, and may therefore be informative regarding endometrial cancer risk. This study investigated the association between endometrial cancer risk and markers of insulin resistance, namely adiponectin, leptin, the A:L ratio, insulin, fasting glucose, and the HOMA-IR. We analyzed data from 541 incident endometrial cancer cases and 961 frequency age-matched controls in a population-based case-control study in Alberta, Canada from 2002 to 2006. Participants completed interview administered questionnaires were assessed for anthropometric measures, and provided 8-h fasting blood samples either pre- or postoperatively. Blood was analyzed for concentrations of leptin, adiponectin, and insulin by immunoassay, and fasting plasma glucose levels were determined by fluorimetric quantitative determination. Compared with the lowest quartile, the highest quartile of insulin and HOMA-IR was associated with 64% (95% confidence intervals (CI): 1.12-2.40) and 72% (95% CI: 1.17-2.53) increased risks of endometrial cancer, respectively, and the highest quartile of adiponectin was associated with a 45% (95% CI: 0.37 0.80) decreased risk after multivariable adjustments. Null associations were observed between fasting glucose, leptin and A:L, and endometrial cancer risk. This population-based study provides evidence for a role of insulin resistance in endometrial cancer etiology and may provide one possible pathway whereby obesity increases the risk of this common cancer. Interventions aimed at decreasing both obesity and insulin resistance may decrease endometrial cancer risk. PMID- 23033316 TI - Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models. AB - The rate at which nonsynonymous single nucleotide polymorphisms (nsSNPs) are being identified in the human genome is increasing dramatically owing to advances in whole-genome/whole-exome sequencing technologies. Automated methods capable of accurately and reliably distinguishing between pathogenic and functionally neutral nsSNPs are therefore assuming ever-increasing importance. Here, we describe the Functional Analysis Through Hidden Markov Models (FATHMM) software and server: a species-independent method with optional species-specific weightings for the prediction of the functional effects of protein missense variants. Using a model weighted for human mutations, we obtained performance accuracies that outperformed traditional prediction methods (i.e., SIFT, PolyPhen, and PANTHER) on two separate benchmarks. Furthermore, in one benchmark, we achieve performance accuracies that outperform current state-of-the-art prediction methods (i.e., SNPs&GO and MutPred). We demonstrate that FATHMM can be efficiently applied to high-throughput/large-scale human and nonhuman genome sequencing projects with the added benefit of phenotypic outcome associations. To illustrate this, we evaluated nsSNPs in wheat (Triticum spp.) to identify some of the important genetic variants responsible for the phenotypic differences introduced by intense selection during domestication. A Web-based implementation of FATHMM, including a high-throughput batch facility and a downloadable standalone package, is available at http://fathmm.biocompute.org.uk. PMID- 23033317 TI - Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome. AB - Mutations in the gene encoding the iron-sulfur-containing DNA helicase DDX11 (ChlR1) were recently identified as a cause of a new recessive cohesinopathy, Warsaw breakage syndrome (WABS), in a single patient with severe microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Here, using homozygosity mapping in a Lebanese consanguineous family followed by exome sequencing, we identified a novel homozygous mutation (c.788G>A [p.R263Q]) in DDX11 in three affected siblings with severe intellectual disability and many of the congenital abnormalities reported in the WABS original case. Cultured lymphocytes from the patients showed increased mitomycin C-induced chromosomal breakage, as found in WABS. Biochemical studies of purified recombinant DDX11 indicated that the p.R263Q mutation impaired DDX11 helicase activity by perturbing its DNA binding and DNA-dependent ATP hydrolysis. Our findings thus confirm the involvement of DDX11 in WABS, describe its phenotypical spectrum, and provide novel insight into the structural requirement for DDX11 activity. PMID- 23033318 TI - SEM-EDX and microFTIR studies on evaluation of protection capacity of some thin phosphate layers. AB - This article presents the SEM-EDX and microFTIR study and the corrosion behavior of new five types of phosphated coatings obtained by coprecipitation in acid aqueous medium of some metal cations, pursuing the influence of the addition of other cations and a moderator of precipitation, on the uniformity and compactness of the layers and on the morphology of dendritic structure of Zn(II) and Fe(II) phosphates. PMID- 23033319 TI - Association of the smoothelin (SMTN) gene with cerebral infarction in men: a haplotype-based case-control study. AB - Smoothelin is a specific type of cytoskeletal protein found in smooth muscle cells (SMCs). Several previous research studies have examined the relationship between smoothelin and atherosclerotic plaque. The aim of the present study was to further assess the association between the human SMTN gene and cerebral infarction (CI) using a haplotype-based case-control study. A total of 168 CI patients and 259 supercontrols were genotyped for the five single-nucleotide polymorphisms (SNPs) used as genetic markers for the human SMTN gene (rs2074738, rs5997872, rs56095120, rs9621187 and rs10304). Data were analyzed for three separate groups that included total subjects, men and women. The genotypic distribution of rs10304 for men showed a significant difference between the control and CI groups. In addition, the frequency of the C-T-T-A haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) was significantly higher in the CI versus the control group (p = 0.013), while the frequency of the C-A-T-G haplotype (established by rs5997872, rs56095120, rs9621187 and rs10304) in the CI group was significantly lower than that seen in the controls (p = 0.021). In conclusion, we confirmed that the haplotype constructed using rs5997872, rs56095120, rs9621187 and rs10304 was a useful genetic marker of CI in Japanese men. PMID- 23033320 TI - Resisting sarcolemmal rupture: dystrophin repeats increase membrane-actin stiffness. AB - Dystrophin is an essential part of a membrane protein complex that provides flexible support to muscle fiber membranes. Loss of dystrophin function leads to membrane fragility and muscle-wasting disease. Given the importance of cytoskeletal interactions in strengthening the sarcolemma, we have focused on actin-binding domain 2 of human dystrophin, constituted by repeats 11 to 15 of the central domain (DYS R11-15). We previously showed that DYS R11-15 also interacts with membrane lipids. We investigated the shear elastic constant (MU) and the surface viscosity (eta(s)) of Langmuir phospholipid monolayers mimicking the inner leaflet of the sarcolemma in the presence of DYS R11-15 and actin. The initial interaction of 100 nM DYS R11-15 with the monolayers slightly modifies their rheological properties. Injection of 0.125 MUM filamentous actin leads to a strong increase of MU and eta(s,) from 0 to 5.5 mN/m and 2.4 * 10(-4) N . s/m, respectively. These effects are specific to DYS R11-15, require filamentous actin, and depend on phospholipid nature and lateral surface pressure. These findings suggest that the central domain of dystrophin contributes significantly to the stiffness and the stability of the sarcolemma through its simultaneous interactions with the cytoskeleton and lipid membrane. This mechanical link is likely to be a major contributing factor to the shock absorber function of dystrophin and muscle sarcolemmal integrity on mechanical stress. PMID- 23033321 TI - Fully synthetic polymer vesicles for intracellular delivery of antibodies in live cells. AB - There is an emerging need both in pharmacology and within the biomedical industry to develop new tools to target intracellular mechanisms. The efficient delivery of functionally active proteins within cells is potentially a powerful research strategy, especially through the use of antibodies. In this work, we report on a nanovector for the efficient encapsulation and delivery of antibodies into live cells with no significant loss of cell viability or any deleterious effect on cell metabolic activity. This delivery system is based on poly[2 (methacryloyloxy)ethyl phosphorylcholine]-block-[2-(diisopropylamino)ethyl methacrylate] (PMPC-PDPA), a pH-sensitive diblock copolymer that self-assembles to form nanometer-sized vesicles, also known as polymersomes, at physiological pH. Polymersomes can successfully deliver relatively high antibody payloads within different types of live cells. We demonstrate that these antibodies can target their respective epitope showing immunolabeling of gamma-tubulin, actin, Golgi protein, and the transcription factor NF-kappaB in live cells. Finally, we demonstrate that intracellular delivery of antibodies can control specific subcellular events, as well as modulate cell activity and proinflammatory processes. PMID- 23033322 TI - alphaB-Crystallin regulates expansion of CD11b+Gr-1+ immature myeloid cells during tumor progression. AB - The molecular chaperone alphaB-crystallin has emerged as a target for cancer therapy due to its expression in human tumors and its role in regulating tumor angiogenesis. alphaB-crystallin also reduces neuroinflammation, but its role in other inflammatory conditions has not been investigated. Here, we examined whether alphaB-crystallin regulates inflammation associated with tumors and ischemia. We found that CD45(+) leukocyte infiltration is 3-fold increased in tumors and ischemic myocardium in alphaB-crystallin-deficient mice. Notably, alphaB-crystallin is prominently expressed in CD11b(+) Gr-1(+) immature myeloid cells (IMCs), known as regulators of angiogenesis and immune responses, while lymphocytes and mature granulocytes show low alphaB-crystallin expression. alphaB Crystallin deficiency results in a 3-fold higher accumulation of CD11b(+) Gr-1(+) IMCs in tumors and a significant rise in CD11b(+) Gr-1(+) IMCs in spleen and bone marrow. Similarly, we noted a 2-fold increase in CD11b(+) Gr-1(+) IMCs in chronically inflamed livers in alphaB-crystallin-deficient mice. The effect of alphaB-crystallin on IMC accumulation is limited to pathological conditions, as CD11b(+) Gr-1(+) IMCs are not elevated in naive mice. Through ex vivo differentiation of CD11b(+) Gr-1(+) cells, we provide evidence that alphaB crystallin regulates systemic expansion of IMCs through a cell-intrinsic mechanism. Our study suggests a key role of alphaB-crystallin in limiting expansion of CD11b(+) Gr-1(+) IMCs in diverse pathological conditions. PMID- 23033323 TI - Toward an EEG-based recognition of music liking using time-frequency analysis. AB - Affective phenomena, as reflected through brain activity, could constitute an effective index for the detection of music preference. In this vein, this paper focuses on the discrimination between subjects' electroencephalogram (EEG) responses to self-assessed liked or disliked music, acquired during an experimental procedure, by evaluating different feature extraction approaches and classifiers to this end. Feature extraction is based on time-frequency (TF) analysis by implementing three TF techniques, i.e., spectrogram, Zhao-Atlas-Marks distribution and Hilbert-Huang spectrum (HHS). Feature estimation also accounts for physiological parameters that relate to EEG frequency bands, reference states, time intervals, and hemispheric asymmetries. Classification is performed by employing four classifiers, i.e., support vector machines, k-nearest neighbors (k -NN), quadratic and Mahalanobis distance-based discriminant analyses. According to the experimental results across nine subjects, best classification accuracy {86.52 (+/-0.76)%} was achieved using k-NN and HHS-based feature vectors ( FVs) representing a bilateral average activity, referred to a resting period, in beta (13-30 Hz) and gamma (30-49 Hz) bands. Activity in these bands may point to a connection between music preference and emotional arousal phenomena. Furthermore, HHS-based FVs were found to be robust against noise corruption. The outcomes of this study provide early evidence and pave the way for the development of a generalized brain computer interface for music preference recognition. PMID- 23033324 TI - Reconstruction of high-resolution tongue volumes from MRI. AB - Magnetic resonance images of the tongue have been used in both clinical studies and scientific research to reveal tongue structure. In order to extract different features of the tongue and its relation to the vocal tract, it is beneficial to acquire three orthogonal image volumes--e.g., axial, sagittal, and coronal volumes. In order to maintain both low noise and high visual detail and minimize the blurred effect due to involuntary motion artifacts, each set of images is acquired with an in-plane resolution that is much better than the through-plane resolution. As a result, any one dataset, by itself, is not ideal for automatic volumetric analyses such as segmentation, registration, and atlas building or even for visualization when oblique slices are required. This paper presents a method of superresolution volume reconstruction of the tongue that generates an isotropic image volume using the three orthogonal image volumes. The method uses preprocessing steps that include registration and intensity matching and a data combination approach with the edge-preserving property carried out by Markov random field optimization. The performance of the proposed method was demonstrated on 15 clinical datasets, preserving anatomical details and yielding superior results when compared with different reconstruction methods as visually and quantitatively assessed. PMID- 23033325 TI - Improved localization accuracy in magnetic source imaging using a 3-D laser scanner. AB - Brain source localization accuracy in magnetoencephalography (MEG) requires accuracy in both digitizing anatomical landmarks and coregistering to anatomical magnetic resonance images (MRI). We compared the source localization accuracy and MEG-MRI coregistration accuracy of two head digitization systems-a laser scanner and the current standard electromagnetic digitization system (Polhemus)-using a calibrated phantom and human data. When compared using the calibrated phantom, surface and source localization accuracy for data acquired with the laser scanner improved over the Polhemus by 141% and 132%, respectively. Laser scan digitization reduced MEG source localization error by 1.38 mm on average. In human participants, a laser scan of the face generated a 1000-fold more points per unit time than the Polhemus head digitization. An automated surface-matching algorithm improved the accuracy of MEG-MRI coregistration over the equivalent manual procedure. Simulations showed that the laser scan coverage could be reduced to an area around the eyes only while maintaining coregistration accuracy, suggesting that acquisition time can be substantially reduced. Our results show that the laser scanner can both reduce setup time and improve localization accuracy, in comparison to the Polhemus digitization system. PMID- 23033326 TI - Spatial variability of the 12-lead surface ECG as a tool for noninvasive prediction of catheter ablation outcome in persistent atrial fibrillation. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. Radiofrequency catheter ablation (CA) is increasingly employed to treat this disease, yet the selection of persistent AF patients who will benefit from this treatment remains a challenging task. Several parameters of the surface electrocardiogram (ECG) have been analyzed in previous works to predict AF termination by CA, such as fibrillatory wave (f-wave) amplitude. However, they are usually manually computed and only a subset of electrodes is inspected. In this study, a novel perspective of the role of f-wave amplitude as a potential noninvasive predictor of CA outcome is adopted by exploring ECG interlead spatial variability. An automatic procedure for atrial amplitude computation based on cubic Hermite interpolation is first proposed. To describe the global f-wave peak-to-peak amplitude distribution, signal contributions from multiple leads are then combined by condensing the most representative features of the atrial signal in a reduced-rank approximation based on principal component analysis (PCA). We show that exploiting ECG spatial diversity by means of this PCA-based multilead approach does not only increase the robustness to electrode selection, but also substantially improves the predictive power of the amplitude parameter. PMID- 23033327 TI - Effect of permeability on the performance of elastographic imaging techniques. AB - Elastography is a well-established imaging modality. While a number of studies aimed at evaluating the performance of elastographic techniques are retrievable in the literature, very little information is available on the effects that the presence of an underlying permeability contrast in the tissue may have on the resulting elastograms. Permeability is a fundamental tissue parameter, which characterizes the ease with which fluid can move within a tissue. This parameter plays a central role both biomechanically in the description of the temporal behavior of fluid-filled tissues and clinically in the development of a number of diagnostic and therapeutic modalities. In this paper, we present a simulation study that investigates selected elastographic image quality factors in nonhomogeneous materials, modeled as poroelastic media with different geometries and permeability contrasts. The results of this study indicate that the presence of an underlying permeability contrast may create a new contrast mechanism in the spatial and temporal distributions of the axial strains and the effective Poisson's ratios experienced by the tissue and as imaged by the corresponding elastograms. The effect of permeability on the elastographic image quality factors analyzed in this study was found to be a nonsymmetric function of the underlying mechanical contrast between background and target, the geometry of the material and the boundary conditions. PMID- 23033328 TI - Activity discovery and activity recognition: a new partnership. AB - Activity recognition has received increasing attention from the machine learning community. Of particular interest is the ability to recognize activities in real time from streaming data, but this presents a number of challenges not faced by traditional offline approaches. Among these challenges is handling the large amount of data that does not belong to a predefined class. In this paper, we describe a method by which activity discovery can be used to identify behavioral patterns in observational data. Discovering patterns in the data that does not belong to a predefined class aids in understanding this data and segmenting it into learnable classes. We demonstrate that activity discovery not only sheds light on behavioral patterns, but it can also boost the performance of recognition algorithms. We introduce this partnership between activity discovery and online activity recognition in the context of the CASAS smart home project and validate our approach using CASAS data sets. PMID- 23033329 TI - A semi-infinite programming approach to preoperative planning of robotic cardiac surgery under geometric uncertainty. AB - In this paper, a computational framework for patient-specific preoperative planning of Robotics-Assisted Minimally Invasive Cardiac Surgery (RAMICS) is presented. It is expected that preoperative planning of RAMICS will improve the success rate by considering robot kinematics, patient-specific thoracic anatomy, and procedure-specific intraoperative conditions. Given the significant anatomical features localized in the preoperative computed tomography images of a patients thorax, port locations and robot orientations (with respect to the patients body coordinate frame) are determined to optimize qualities such as dexterity, reachability, tool approach angles and maneuverability. To address intraoperative geometric uncertainty, the problem is formulated as a Generalized Semi-Infinite Program (GSIP) with a convex lower-level problem to seek a plan that is less sensitive to geometric uncertainty in the neighborhood of surgical targets. It is demonstrated that with a proper formulation of the problem, the GSIP can be replaced by a tractable constrained nonlinear program that uses a multi-criteria objective function to balance between the nominal task performance and robustness to collisions and joint limit violations. Finally, performance of the proposed formulation is demonstrated by a comparison between the plans generated by the algorithm and those recommended by an experienced surgeon for several case studies. PMID- 23033330 TI - Asynchronous BCI based on motor imagery with automated calibration and neurofeedback training. AB - A new multiclass brain-computer interface (BCI) based on the modulation of sensorimotor oscillations by imagining movements is described. By the application of advanced signal processing tools, statistics and machine learning, this BCI system offers: 1) asynchronous mode of operation, 2) automatic selection of user dependent parameters based on an initial calibration, 3) incremental update of the classifier parameters from feedback data. The signal classification uses spatially filtered signals and is based on spectral power estimation computed in individualized frequency bands, which are automatically identified by a specially tailored AR-based model. Relevant features are chosen by a criterion based on Mutual Information. Final recognition of motor imagery is effectuated by a multinomial logistic regression classifier. This BCI system was evaluated in two studies. In the first study, five participants trained the ability to imagine movements of the right hand, left hand and feet in response to visual cues. The accuracy of the classifier was evaluated across four training sessions with feedback. The second study assessed the information transfer rate (ITR) of the BCI in an asynchronous application. The subjects' task was to navigate a cursor along a computer rendered 2-D maze. A peak information transfer rate of 8.0 bit/min was achieved. Five subjects performed with a mean ITR of 4.5 bit/min and an accuracy of 74.84%. These results demonstrate that the use of automated interfaces to reduce complexity for the intended operator (outside the laboratory) is indeed possible. The signal processing and classifier source code embedded in BCI2000 is available from https://www.brain project.org/downloads.html. PMID- 23033331 TI - Sparse optimal motor estimation (SOME) for extracting commands for prosthetic limbs. AB - It is possible to replace amputated limbs with mechatronic prostheses, but their operation requires the user's intentions to be detected and converted into control signals to the actuators. Fortunately, the motoneurons (MNs) that controlled the amputated muscles remain intact and capable of generating electrical signals, but these signals are difficult to record. Even the latest microelectrode array technologies and targeted motor reinnervation can provide only sparse sampling of the hundreds of motor units that comprise the motor pool for each muscle. Simple rectification and integration of such records is likely to produce noisy and delayed estimates of the actual intentions of the user. We have developed a novel algorithm for optimal estimation of motor pool excitation based on the recruitment and firing rates of a small number (2-10) of discriminated motor units. We first derived the motor estimation algorithm from normal patterns of modulated MN activity based on a previously published model of individual MN recruitment and asynchronous frequency modulation. The algorithm was then validated on a target motor reinnervation subject using intramuscular fine-wire recordings to obtain single motor units. PMID- 23033332 TI - EMG signal decomposition using motor unit potential train validity. AB - A system to resolve an intramuscular electromyographic (EMG) signal into its component motor unit potential trains (MUPTs) is presented. The system is intended mainly for clinical applications where several physiological parameters of motor units (MUs), such as their motor unit potential (MUP) templates and mean firing rates, are of interest. The system filters an EMG signal, detects MUPs, and clusters and classifies the detected MUPs into MUPTs. Clustering is partially based on the K-means algorithm, and the supervised classification is implemented using a certainty-based algorithm. Both clustering and supervised classification algorithms use MUP shape and MU firing pattern information along with signal dependent assignment criteria to obtain robust performance across a variety of EMG signals. During classification, the validity of extracted MUPTs are determined using several supervised classifiers; invalid trains are corrected and the assignment threshold for each train is adjusted based on the estimated validity (i.e., adaptive classification). Performance of the developed system in terms of accuracy (A(c)), assignment rate (A(r)), correct classification rate (CC(r)) , and the error in estimating the number of MUPTs represented in the set of detected MUPs (E(NMUPTs)) was evaluated using 32 simulated and 30 real EMG signals comprised of 3-11 and 3-15 MUPTs, respectively. The developed system, with average CC(r) of 86.4% for simulated and 96.4% for real data, outperformed a previously developed EMG decomposition system, with average CC(r) of 71.6% and 89.7% for simulated and real data, by 14.7% and 6.7%, respectively. In terms of E(NMUPTs), the new system, with average E(NMUPTs) of 0.3 and 0.2 for simulated and real data respectively, was better able to estimate the number of MUPTs represented in a set of detected MUPs than the previous system, with average E(NMUPTs) of 2.2 and 0.8 for simulated and real data respectively. For both the simulated and real data used, variations in A(c), A(r), and E(NMUPTs) for the newly developed system were lower than for the previous system, which demonstrates that the new system can successfully adjust the assignment criteria based on the characteristics of a given signal to achieve robust performance across a wide variety of EMG signals, which is of paramount importance for successfully promoting the clinical application of EMG signal decomposition techniques. PMID- 23033333 TI - Design of a virtual reality based adaptive response technology for children with autism. AB - Children with autism spectrum disorder (ASD) demonstrate potent impairments in social communication skills including atypical viewing patterns during social interactions. Recently, several assistive technologies, particularly virtual reality (VR), have been investigated to address specific social deficits in this population. Some studies have coupled eye-gaze monitoring mechanisms to design intervention strategies. However, presently available systems are designed to primarily chain learning via aspects of one's performance only which affords restricted range of individualization. The presented work seeks to bridge this gap by developing a novel VR-based interactive system with Gaze-sensitive adaptive response technology that can seamlessly integrate VR-based tasks with eye-tracking techniques to intelligently facilitate engagement in tasks relevant to advancing social communication skills. Specifically, such a system is capable of objectively identifying and quantifying one's engagement level by measuring real-time viewing patterns, subtle changes in eye physiological responses, as well as performance metrics in order to adaptively respond in an individualized manner to foster improved social communication skills among the participants. The developed system was tested through a usability study with eight adolescents with ASD. The results indicate the potential of the system to promote improved social task performance along with socially-appropriate mechanisms during VR-based social conversation tasks. PMID- 23033335 TI - Novel vibration-exercise instrument with dedicated adaptive filtering for electromyographic investigation of neuromuscular activation. AB - Vibration exercise (VE) has been suggested as an effective methodology to improve muscle strength and power performance. Several studies link the effects of vibration training to enhanced neuromuscular demand, typically ascribed to involuntary reflex mechanisms. However, the underlying mechanisms are still unclear, limiting the identification of the most appropriate vibration training protocols. This study concerns the realization of a new vibration exercise system for the upper limbs. Amplitude, frequency, and baseline of the vibrating force, which is generated by an electromechanical actuator, can be adjusted independently. A second order model is employed to identify the relation between the generated force and the input voltage driving the actuator. Our results show a high correlation (0.99) between the second order model fit and the measured data, ensuring accurate control on the supplied force. The level of neuromuscular demand imposed by the system on the targeted muscles can be estimated by electromyography (EMG). However, EMG measurements during VE can be severely affected by motion artifacts. An adaptive least mean square algorithm is proposed to remove motion artifacts from the measured EMG data. Preliminary validation with seven volunteers showed excellent motion artifact removal, enabling reliable evaluation of the neuromuscular activation. PMID- 23033334 TI - A novel myoelectric pattern recognition strategy for hand function restoration after incomplete cervical spinal cord injury. AB - This study presents a novel myoelectric pattern recognition strategy towards restoration of hand function after incomplete cervical spinal cord Injury (SCI). High density surface electromyogram (EMG) signals comprised of 57 channels were recorded from the forearm of nine subjects with incomplete cervical SCI while they tried to perform six different hand grasp patterns. A series of pattern recognition algorithms with different EMG feature sets and classifiers were implemented to identify the intended tasks of each SCI subject. High average overall accuracies (> 97%) were achieved in classification of seven different classes (six intended hand grasp patterns plus a hand rest pattern), indicating that substantial motor control information can be extracted from partially paralyzed muscles of SCI subjects. Such information can potentially enable volitional control of assistive devices, thereby facilitating restoration of hand function. Furthermore, it was possible to maintain high levels of classification accuracy with a very limited number of electrodes selected from the high density surface EMG recordings. This demonstrates clinical feasibility and robustness in the concept of using myoelectric pattern recognition techniques toward improved function restoration for individuals with spinal injury. PMID- 23033340 TI - Spatiotemporal clustering of the epigenome reveals rules of dynamic gene regulation. AB - Spatial organization of different epigenomic marks was used to infer functions of the epigenome. It remains unclear what can be learned from the temporal changes of the epigenome. Here, we developed a probabilistic model to cluster genomic sequences based on the similarity of temporal changes of multiple epigenomic marks during a cellular differentiation process. We differentiated mouse embryonic stem (ES) cells into mesendoderm cells. At three time points during this differentiation process, we used high-throughput sequencing to measure seven histone modifications and variants--H3K4me1/2/3, H3K27ac, H3K27me3, H3K36me3, and H2A.Z; two DNA modifications--5-mC and 5-hmC; and transcribed mRNAs and noncoding RNAs (ncRNAs). Genomic sequences were clustered based on the spatiotemporal epigenomic information. These clusters not only clearly distinguished gene bodies, promoters, and enhancers, but also were predictive of bidirectional promoters, miRNA promoters, and piRNAs. This suggests specific epigenomic patterns exist on piRNA genes much earlier than germ cell development. Temporal changes of H3K4me2, unmethylated CpG, and H2A.Z were predictive of 5-hmC changes, suggesting unmethylated CpG and H3K4me2 as potential upstream signals guiding TETs to specific sequences. Several rules on combinatorial epigenomic changes and their effects on mRNA expression and ncRNA expression were derived, including a simple rule governing the relationship between 5-hmC and gene expression levels. A Sox17 enhancer containing a FOXA2 binding site and a Foxa2 enhancer containing a SOX17 binding site were identified, suggesting a positive feedback loop between the two mesendoderm transcription factors. These data illustrate the power of using epigenome dynamics to investigate regulatory functions. PMID- 23033342 TI - Sirtuin activation: a role for plasma membrane in the cell growth puzzle. AB - For more than 20 years, the observation that impermeable oxidants can stimulate cell growth has not been satisfactorily explained. The discovery of sirtuins provides a logical answer to the puzzle. The NADH-dependent transplasma membrane electron transport system, which is stimulated by growth factors and interventions such as calorie restriction, can transfer electrons to external acceptors and protect against stress-induced apoptosis. We hypothesize that the activation of plasma membrane electron transport contributes to the cytosolic NAD(+) pool required for sirtuin to activate transcription factors necessary for cell growth and survival. PMID- 23033343 TI - New firework caused severe eye injuries at a public display. PMID- 23033341 TI - Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. AB - Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole-genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and three lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators, including KDM6A, ASH1L, SMARCA4, and ATAD2, are frequently altered by mutations or copy number changes. A systematic survey of splice-site mutations identified 106 splice site mutations associated with cancer specific aberrant splicing, including mutations in several known cancer-related genes. RAC1b, an isoform of the RAC1 GTPase that includes one additional exon, was found to be preferentially up-regulated in lung cancer. We further show that its expression is significantly associated with sensitivity to a MAP2K (MEK) inhibitor PD 0325901. Taken together, these data present a comprehensive genomic landscape of a large number of lung cancer samples and further demonstrate that cancer specific alternative splicing is a widespread phenomenon that has potential utility as therapeutic biomarkers. The detailed characterizations of the lung cancer cell lines also provide genomic context to the vast amount of experimental data gathered for these lines over the decades, and represent highly valuable resources for cancer biology. PMID- 23033344 TI - Toward the neurovascular unit. A journey in clinical translation: 2012 Thomas Willis Lecture. AB - The Nobel laureate Max Delbruck often said that it is the crossover between disciplines where advances are possible in science. This certainly has been true for our understanding of the vascular biology of the central nervous system in the setting of ischemic stroke. The ability to cross the boundaries of hemostasis, neurology, hematology, and neuroscience has facilitated our research direction to define the relation of the microvasculature to neuron function. Work begun with the clinical scientific exploration of the contributions of arterial thrombosis to the acute injury processes initiated by focal cerebral ischemia has led to an increased understanding of the effects of ischemia on microvessel integrity. PMID- 23033345 TI - High rate of magnetic resonance imaging stroke recurrence in cryptogenic transient ischemic attack and minor stroke patients. AB - BACKGROUND AND PURPOSE: Cryptogenic stroke is common in patients with transient ischemic attack (TIA) and minor stroke. It is likely that the imaging recurrence risk is higher than the clinical recurrence rate. We sought to determine the rate of clinical and radiographic stroke recurrence in a population of cryptogenic TIA and minor stroke. METHODS: Patients with TIA/minor stroke (National Institutes of Health Stroke Scale score<=3) were prospectively enrolled and imaged within 24 hours of symptom onset as part of 2 cohorts. Patients were assessed at 3 months to document any clinical recurrence and underwent repeat magnetic resonance imaging (MRI) at either 30 or 90 days. Stroke mechanism was categorized as cryptogenic after standard etiologic work-up was completed and was negative. Follow-up MRI was assessed for any new lesions in comparison with baseline imaging. RESULTS: Three hundred thirty-three of 693 (48%) patients had cryptogenic stroke. Of these cryptogenic patients, 207 (62%) had follow-up imaging. At 30-day MRI follow-up, 6.6% (5/76) had new lesions (3 in a remote arterial territory). At 90-day MRI follow-up, 14.5% (19/131) had new lesions (9 in a remote arterial territory). Clinical recurrent stroke was seen in 1.2% (4/333) of patients within 90 days. CONCLUSIONS: Cryptogenic etiology is common in a TIA/minor stroke population. This population shows a high rate of silent radiographic recurrence, suggesting active disease. Use of MRI as a surrogate marker of disease activity is 1 potential way of assessing efficacy of new treatments in this population with reduced sample size. PMID- 23033346 TI - Impact of an electronic medical record-based clinical decision support tool for dysphagia screening on care quality. AB - BACKGROUND AND PURPOSE: Dysphagia screening (DS) before oral intake in patients with acute stroke is a hospital-level performance measure. We report outcomes of an initiative to improve compliance to this quality measure. METHODS: The design was a pre- versus postintervention comparison study. The Intervention was an electronic medical record-based clinical DS system embedded within stroke admission orders. The clinical DS was designed to facilitate DS in patients with stroke. The primary outcome was compliance to a process measure in patients with ischemic stroke: performance of a swallow screen before oral intake. RESULTS: DS measure compliance increased from 36% to 74% (P=0.001). Chart audits found screened patients were more likely to have clinical DS-embedded admission orders initiated or stroke unit admission. CONCLUSIONS: The electronic medical record offers a ready platform for clinical DS implementation. DS is a difficult performance measure to improve. The described clinical DS has the potential for improving performance on this challenging care quality measure. PMID- 23033347 TI - Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial. AB - BACKGROUND AND PURPOSE: Apixaban reduces stroke with comparable bleeding risks when compared with aspirin in patients with atrial fibrillation who are unsuitable for vitamin k antagonist therapy. This analysis explores patterns of bleeding and defines bleeding risks based on stroke risk with apixaban and aspirin. METHODS: The Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial fibrillation and risk factors to receive either apixaban or aspirin. Bleeding events were defined as the first occurrence of either major bleeding or clinically relevant nonmajor bleeding. RESULTS: The rate of a bleeding event was 3.8%/year with aspirin and 4.5%/year with apixaban (hazard ratio with apixaban, 1.18; 95% CI, 0.92-1.51; P=0.19). The anatomic site of bleeding did not differ between therapies. Risk factors for bleeding common to apixaban and aspirin were use of nonstudy aspirin>50% of the time and a history of daily/occasional nosebleeds. The rates of both stroke and bleeding increased with higher CHADS2 scores but apixaban compared with aspirin was associated with a similar relative risk of bleeding (P interaction 0.21) and a reduced relative risk of stroke (P interaction 0.37) irrespective of CHADS2 category. CONCLUSIONS: Anatomic sites and predictors of bleeding are similar for apixaban and aspirin in these patients. Higher CHADS2 scores are associated with increasing rates of bleeding and stroke, but the balance between risks and benefits of apixaban compared with aspirin is favorable irrespective of baseline stroke risk. Clinical Trial Registration Information- www.clinicaltrials.gov. Unique identifier: NCT 00496769. PMID- 23033348 TI - Antihypertensive treatment prolongs tissue plasminogen activator door-to treatment time: secondary analysis of the INSTINCT trial. AB - BACKGROUND AND PURPOSE: Identifying modifiable tissue plasminogen activator treatment delays may improve stroke outcomes. We hypothesized that prethrombolytic antihypertensive treatment (AHT) may prolong door-to-treatment time (DTT). METHODS: We performed an analysis of consecutive tissue plasminogen activator-treated patients at 24 randomly selected community hospitals in the Increasing Stroke Treatment through Interventional Behavior Change Tactics (INSTINCT) trial between 2007 and 2010. DTT among stroke patients who received prethrombolytic AHT were compared with those who did not receive prethrombolytic AHT. We then calculated a propensity score for the probability of receiving prethrombolytic AHT using logistic regression with demographics, stroke risk factors, home medications, stroke severity (National Institutes of Health Stroke Scale), onset-to-door time, admission glucose, pretreatment blood pressure, emergency medical service transport, and location at time of stroke as independent variables. A paired t test was performed to compare the DTT between the propensity-matched groups. RESULTS: Of 534 tissue plasminogen activator treated stroke patients analyzed, 95 received prethrombolytic AHT. In the unmatched cohort, patients who received prethrombolytic AHT had a longer DTT (mean increase, 9 minutes; 95% confidence interval, 2-16 minutes) than patients who did not. After propensity matching, patients who received prethrombolytic AHT had a longer DTT (mean increase, 10.4 minutes; 95% confidence interval, 1.9-18.8) than patients who did not receive prethrombolytic AHT. CONCLUSIONS: Prethrombolytic AHT is associated with modest delays in DTT. This represents a potential target for quality-improvement initiatives. Further research evaluating optimum prethrombolytic hypertension management is warranted. PMID- 23033349 TI - State differences in the reporting of 'unspecified stroke' on death certificates: implications for improvement. AB - BACKGROUND AND PURPOSE: Little is known about the comparability of stroke subtype mortality across states. We conducted a cross-sectional descriptive study to examine state differences in the reporting of "unspecified stroke" on death certificates in the United States. METHODS: The number of deaths from different subtypes of stroke in each state for the years 2007 to 2009 were obtained from the CDC WONDER online databases. We calculated the percentage of stroke deaths classified as unspecified stroke (International Classification of Diseases, 10th Revision [ICD-10] code I64) among all stroke deaths (ICD-10 codes I60-I69) for each state. RESULTS: Of 398 942 people who died from stoke in the United States between 2007 and 2009, in 209 933 (53%) cases, the medical certifier did not specify whether the stroke was hemorrhage or infarction on the death certificate. There were 44 states in which the percentage of unspecified stroke among all strokes was >=50 and 20 states in which the percentage was >=55%. The percentage was lowest in the District of Columbia (46%) and highest in Oklahoma (64%). The state variation in the proportion of unspecified stroke decreased with age of the deceased. The state percentage of unspecified stroke correlated most with the state percentage of cerebral infarction and other and sequelae of cerebrovascular disease. CONCLUSIONS: Owing to the high percentage and state variation in the reporting of unspecified stroke on death certificates, the comparability of stroke subtype mortality is threatened. Querying of medical certifiers for more specific information for better coding is needed. PMID- 23033350 TI - Stent-based thrombectomy versus intravenous tissue plasminogen activator in patients with acute middle cerebral artery occlusion. AB - BACKGROUND AND PURPOSE: Our goal was to compare outcomes of patients with proximal middle cerebral artery occlusions treated with intravenous tissue plasminogen activator (tPA) with those of patients treated with stent-based thrombectomy (SBT). METHODS: Patients with proximal middle cerebral artery occlusions included in our prospective stroke registry were identified. Patients presenting with moderate to severe stroke defined as National Institutes of Health Stroke Scale score>=10 were included. Patients treated with tPA were compared with those treated with SBT. Disability was measured with the modified Rankin Scale and shifts toward favorable outcomes (modified Rankin Scale<=2) were analyzed. Logistic regression was used to determine outcome modifiers. RESULTS: We included 22 patients treated with SBT and 66 treated with tPA. Patients treated with SBT had higher admission National Institutes of Health Stroke Scale scores (median 21 vs 14.5; P<0.001) and prolonged symptom onset-to-treatment times (median 240 vs 95 minutes; P<0.001). At discharge, the magnitude of change in National Institutes of Health Stroke Scale was larger in the thrombectomy group (median 12 vs 6 points; P<0.001). At 90 days poststroke there was a shift toward favorable outcome in the thrombectomy group (60% vs 37.5%; P=0.001). Treatment allocation did not impact outcome in the regression analysis. CONCLUSIONS: Treatment of patients with proximal middle cerebral artery occlusions with SBT resulted in a shift toward more favorable outcomes compared with tPA. Randomized controlled studies are needed to explore whether treatment with SBT should be used in patients presenting within the first hours after stroke. PMID- 23033351 TI - Association between socioeconomic status and functional impairment 3 months after ischemic stroke: the Berlin Stroke Register. AB - BACKGROUND AND PURPOSE: We aimed to analyze the association between patient socioeconomic status and functional impairment 3 months after ischemic stroke and to identify factors that influence this association. METHODS: Data were obtained from the Berlin Stroke Register, a network of 14 stroke units in Berlin. Ischemic stroke patients consecutively admitted to 1 of the hospitals in the Berlin Stroke Register between June 2010 and September 2011, were followed-up 3 months after the index event by postal or telephone interview. We used multivariable logistic regression to examine the association between highest education as marker of socioeconomic status and functional impairment after stroke defined by Barthel Index categories. We adjusted for age, sex, prestroke dependency, stroke severity, functional deficit after stroke onset, and comorbidities as possible confounding factors. RESULTS: A total of 1688 ischemic stroke patients who were alive at 3 months and completed the questionnaire were included in the analysis; 40% of the patients were female and 50% of the patients were 70 years or older. Age, prestroke dependency, stroke severity, and the absence of comorbidities were significantly associated with good functional outcome at 3 months. In multivariable analysis, a higher probability of good outcome was observed in patients with college or university degree (odds ratio, 2.18; 95% confidence interval, 1.39-3.42) compared with patients with no completed education. CONCLUSIONS: Patients with lower education have considerably lower rates of good functional outcome after stroke that cannot be fully explained by variations in the patients' clinical and demographic characteristics. PMID- 23033352 TI - How does ALS spread between neurones in the CNS? PMID- 23033353 TI - Is language impairment more common than executive dysfunction in amyotrophic lateral sclerosis? AB - BACKGROUND: Systematic explorations of language abilities in patients with amyotrophic lateral sclerosis (ALS) are lacking in the context of wider cognitive change. METHODOLOGY: Neuropsychological assessment data were obtained from 51 patients with ALS and 35 healthy controls matched for age, gender and IQ. Composite scores were derived for the domains of language and executive functioning. Domain impairment was defined as a composite score <=5th centile relative to the control mean. Cognitive impairment was also classified using recently published consensus criteria. RESULTS: The patients with ALS were impaired on language and executive composite scores. Language domain impairment was found in 43% of patients with ALS, and executive domain impairment in 31%. Standardised language and executive composite scores correlated in the ALS group (r=0.68, p<0.001). Multiple regression analyses indicated that scores on the executive composite accounted for 44% of the variance in language composite scores. CONCLUSIONS: Language impairments are at least as prevalent as executive dysfunction in ALS. While the two domains are strongly associated, executive dysfunction does not fully account for the profile of language impairments observed, further highlighting the heterogeneity of cognitive impairment in non demented patients with ALS. PMID- 23033354 TI - The role of the subgenual cingulate cortex in self-appraisal. PMID- 23033355 TI - Factors associated with early outcome in patients with large-vessel carotid strokes. AB - OBJECTIVE: To describe the severity and early neurological deterioration (END) in patients with symptomatic carotid stenosis and to analyse the influence of related factors. METHODS: Observational cohort study of patients with ischaemic stroke, ipsilateral carotid stenosis and without evidence of cardiac sources of embolism prospectively recorded since January 2003 to January 2012. Initial severity was categorised as mild (NIH stroke scale (NIHSS) <=7), moderate (NIHSS 8-14) or high (NIHSS >14). Logistic ordinal and regression analyses were performed for stroke severity and END risk. RESULTS: Of 2332 ischaemic strokes attended, 338 patients were included. Stroke severity was mild in 254 (75.1%) cases, moderate in 53 (15.7%) and severe in 31 (9.2%). Adjusted ORs (95% CI) for stroke severity were: degree of carotid stenosis, 2.20 (1.55 to 3.11, p<0.001); intracranial disease, 1.93 (1.18 to 3.17, p=0.009); plasma glucose, 1.01 (1.003 to 1.02, p<0.001); and previous transient ischaemic attack (TIA), 0.37 (0.17 to 0.82, p=0.014). 78 patients (23.1%) had END. Multivariate analysis showed independent association between END and degree of carotid stenosis (OR 1.64, 1.14 to 2.34, p=0.007), previous TIA (OR 2.40, 1.25 to 4.57, p=0.008) and mean arterial pressure (OR 1.02, 1.01 to 1.04, p=0.003). CONCLUSIONS: Strokes due to large vessel disease in the carotid artery are in general of mild severity and have a high rate of END. The degree of stenosis has a clear association with higher severity and END risk. PMID- 23033356 TI - Social contacts and receipt of help among older people in England: are there benefits of having more children? AB - OBJECTIVES: To investigate whether number of children and, among parents, having a daughter is associated with older people's likelihood of at least weekly face to-face social contact and later receipt of help if needed. METHOD: Multivariate analysis of data from Waves 1 and 2 of the English Longitudinal Study of Ageing (ELSA). RESULTS: Older parents in England had higher chances of at least weekly face-to-face social contact than their childless counterparts but larger family size had only a slight additional effect. For parents, having at least one daughter was more important than number of children. Larger family size was positively associated with receipt of help from a child by parents with activities of daily living (ADL) or instrumental activities of daily living (IADL) limitations. Childless women were more likely than mothers to receive help from friends but even so had lower odds of receiving help from any informal source. Contact with a child in 2002 predicted receipt of help 2 years later. DISCUSSION: These results show some advantages for older parents compared with childless individuals in terms of social contact and receipt of help and, among parents, an additional effect of having a daughter. Changes in family size distributions have implications for the support of older people and for planners of formal services. PMID- 23033357 TI - Coordinated analysis of age, sex, and education effects on change in MMSE scores. AB - OBJECTIVES: We describe and compare the expected performance trajectories of older adults on the Mini-Mental Status Examination (MMSE) across six independent studies from four countries in the context of a collaborative network of longitudinal studies of aging. A coordinated analysis approach is used to compare patterns of change conditional on sample composition differences related to age, sex, and education. Such coordination accelerates evaluation of particular hypotheses. In particular, we focus on the effect of educational attainment on cognitive decline. METHOD: Regular and Tobit mixed models were fit to MMSE scores from each study separately. The effects of age, sex, and education were examined based on more than one centering point. RESULTS: Findings were relatively consistent across studies. On average, MMSE scores were lower for older individuals and declined over time. Education predicted MMSE score, but, with two exceptions, was not associated with decline in MMSE over time. CONCLUSION: A straightforward association between educational attainment and rate of cognitive decline was not supported. Thoughtful consideration is needed when synthesizing evidence across studies, as methodologies adopted and sample characteristics, such as educational attainment, invariably differ. PMID- 23033358 TI - Caregiving strain and all-cause mortality: evidence from the REGARDS study. AB - OBJECTIVES: Using a large, national sample, this study examined perceived caregiving strain and other caregiving factors in relation to all-cause mortality. METHOD: The REasons for Geographic and Racial Differences in Stroke (REGARDS) study is a population-based cohort of men and women aged 45 years and older. Approximately 12% (n = 3,710) reported that they were providing ongoing care to a family member with a chronic illness or disability. Proportional hazards models were used for this subsample to examine the effects of caregiving status measures on all-cause mortality over the subsequent 5-year period, both before and after covariate adjustment. RESULTS: Caregivers who reported high caregiving strain had significantly higher adjusted mortality rates than both no strain (hazard ratio [HR] = 1.55, p = .02) and some strain (HR = 1.83, p = .001) caregivers. The mortality effects of caregiving strain were not found to differ by race, sex, or the type of caregiving relationship (i.e., spouse, parent, child, sibling, and other). DISCUSSION: High perceived caregiving strain is associated with increased all-cause mortality after controlling for appropriate covariates. High caregiving strain constitutes a significant health concern and these caregivers should be targeted for appropriate interventions. PMID- 23033360 TI - Recent advances in the molecular imaging of programmed cell death: part I- pathophysiology and radiotracers. AB - In humans, apoptosis (programmed cell death) is the most common form of cell death after necrosis. Apoptosis is a series of genetically preprogrammed biochemical and morphologic energy-requiring events that, after a specific external or internal stimulus, results in the physiologic disappearance of a cell via its self-disintegration and packaging of its contents into membrane vesicles called apoptotic bodies. Apoptotic bodies can readily be ingested, with their nutrients and even organelles recycled by neighboring cells or phagocytes without local inflammation. In contrast, necrosis is characterized by the primary loss of plasma membrane integrity and the uncontrolled release of a cell's contents, often causing local inflammation, tissue damage, and scarring. Alternate forms of cell death also exist, associated with specific molecular mechanisms involving enzymes, organelles, genes, external stimuli, or blockade of normal cell proliferation. In this review we will briefly outline the molecular mechanisms of apoptosis that can be imaged with radiotracers now under development. PMID- 23033362 TI - Heterogeneous time-dependent response of adipose tissue during the development of cancer cachexia. AB - Cancer cachexia induces loss of fat mass that accounts for a large part of the dramatic weight loss observed both in humans and in animal models; however, the literature does not provide consistent information regarding the set point of weight loss and how the different visceral adipose tissue depots contribute to this symptom. To evaluate that, 8-week-old male Wistar rats were subcutaneously inoculated with 1 ml (2*10(7)) of tumour cells (Walker 256). Samples of different visceral white adipose tissue (WAT) depots were collected at days 0, 4, 7 and 14 and stored at -80 degrees C (seven to ten animals/each day per group). Mesenteric and retroperitoneal depot mass was decreased to the greatest extent on day 14 compared with day 0. Gene and protein expression of PPARgamma2 (PPARG) fell significantly following tumour implantation in all three adipose tissue depots while C/EBPalpha (CEBPA) and SREBP-1c (SREBF1) expression decreased over time only in epididymal and retroperitoneal depots. Decreased adipogenic gene expression and morphological disruption of visceral WAT are further supported by the dramatic reduction in mRNA and protein levels of perilipin. Classical markers of inflammation and macrophage infiltration (f4/80, CD68 and MIF-1alpha) in WAT were significantly increased in the later stage of cachexia (although showing a incremental pattern along the course of cachexia) and presented a depot-specific regulation. These results indicate that impairment in the lipid-storing function of adipose tissue occurs at different times and that the mesenteric adipose tissue is more resistant to the 'fat-reducing effect' than the other visceral depots during cancer cachexia progression. PMID- 23033361 TI - Low levels of tissue factor lead to alveolar haemorrhage, potentiating murine acute lung injury and oxidative stress. AB - BACKGROUND: Systemic blockade of tissue factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown. We used mice with complete knockout of mouse TF and low levels (~1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury. METHODS: LTF mice were treated with 10 MUg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal injection and studied at 24 h. RESULTS: Contrary to our hypothesis, LTF mice had increased lung inflammation and injury as measured by bronchoalveolar lavage cell count (3.4*10(5) wild-type (WT) LPS vs 3.3*10(5) LTF LPS, p=0.947) and protein (493 MUg/ml WT LPS vs 1014 MUg/ml LTF LPS, p=0.006), proinflammatory cytokines (TNF-alpha, IL-10, IL-12, p<0.035 WT LPS vs LTF LPS) and histology compared with WT mice. LTF mice also had increased haemorrhage and free haemoglobin in the airspace accompanied by increased oxidant stress as measured by lipid peroxidation products (F(2) isoprostanes and isofurans). CONCLUSIONS: These findings indicate that global TF deficiency does not confer protection in a direct lung injury model. Rather, TF deficiency causes increased intra-alveolar haemorrhage following LPS leading to increased lipid peroxidation. Strategies to globally inhibit TF may be deleterious in patients with ALI. PMID- 23033364 TI - Why this love for antibiotics in India? PMID- 23033363 TI - Pain catastrophizing in youths with physical disabilities and chronic pain. AB - OBJECTIVE: The current study examined the associations between catastrophizing and pain intensity, psychological adjustment, functional ability, and community participation in youths with physical disability and chronic pain. METHODS: Participants consisted of 80 youths, aged 8-20 years, with cerebral palsy (n = 34), neuromuscular disease (n = 22), or spina bifida (n = 24). Measures from a cross-sectional survey included demographic, pain, and disability information, the Pain Catastrophizing Scale, the Child Health Questionnaire, and the Functional Disability Inventory. RESULTS: Results suggested that catastrophizing was significantly associated with pain intensity and psychological adjustment; however, catastrophizing did not demonstrate significant associations with functional ability or community participation. CONCLUSIONS: The study extends previous findings of significant associations between catastrophizing and both pain intensity and psychological adjustment to samples of youths with chronic pain and disabilities not previously examined. Further research that examines the causal association between catastrophizing and outcomes in youths with chronic pain and physical disability is warranted. PMID- 23033365 TI - Headache and visual aura in an immunocompromised patient. PMID- 23033366 TI - Charity calls for NHS to commission services to improve health of homeless people. PMID- 23033367 TI - Dutch court finds gynaecologist guilty of "culpable homicide" after baby dies. PMID- 23033368 TI - US Supreme Court is asked to rule on validity of patents on BRCA1 and BRCA2 genes. PMID- 23033369 TI - GMC investigates government's director of commissioning development. PMID- 23033370 TI - Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice. AB - Infiltration of macrophages into the artery wall plays detrimental roles during hypertension by promoting vascular inflammation and endothelial dysfunction, and it occurs via a chemo-attractant action of chemokines on macrophage cytokine receptors. We sought to identify the key chemokine receptors associated with macrophage infiltration into the vascular wall during deoxycorticosterone acetate (DOCA)/salt-induced hypertension in mice and to evaluate the impact of pharmacological inhibition of these receptors on blood pressure and leukocyte accumulation. Mice treated with DOCA/salt for 21 days displayed markedly elevated systolic blood pressure (158 +/- 2 versus 114 +/- 5 mm Hg in sham group; P<0.0001). Polymerase chain reaction screening via a gene array of 20 chemokine receptors indicated an increased expression of CCR2 in aortas of DOCA/salt treated mice. Real-time polymerase chain reaction confirmed mRNA upregulation of CCR2 in aortas from DOCA/salt-treated animals and of the CCR2 ligands CCL2, CCL7, CCL8, and CCL12 (all >2-fold versus sham; P<0.05). Flow cytometry revealed 2.9 fold higher macrophage numbers (ie, CD45(+) CD11b(+) F4/80(+) cells) in the aortic wall of DOCA/salt versus sham-treated mice. Intervention with a CCR2 antagonist, INCB3344 (30 mg/kg per day, IP), 10 days after the induction of hypertension with DOCA/salt treatment, reduced the aortic expression of CCR2 mRNA and completely reversed the DOCA/salt-induced influx of macrophages. Importantly, INCB3344 substantially reduced the elevated blood pressure in DOCA/salt-treated mice. Hence, our findings highlight CCR2 as a promising therapeutic target to reduce both macrophage accumulation in the vascular wall and blood pressure in hypertension. PMID- 23033371 TI - Low-sodium dietary approaches to stop hypertension diet reduces blood pressure, arterial stiffness, and oxidative stress in hypertensive heart failure with preserved ejection fraction. AB - Recent studies suggest that oxidative stress and vascular dysfunction contribute to heart failure with preserved ejection fraction (HFPEF). In salt-sensitive HFPEF animal models, diets low in sodium and high in potassium, calcium, magnesium, and antioxidants attenuate oxidative stress and cardiovascular damage. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would have similar effects in human hypertensive HFPEF. Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD for 21 days (all food/most beverages provided). The DASH/SRD reduced clinic systolic (155-138 mm Hg; P=0.02) and diastolic blood pressure (79-72 mm Hg; P=0.04), 24-hour ambulatory systolic (130-123 mm Hg; P=0.02) and diastolic blood pressure (67-62 mm Hg; P=0.02), and carotid-femoral pulse wave velocity (12.4-11.0 m/s; P=0.03). Urinary F2-isoprostanes decreased by 31% (209-144 pmol/mmol Cr; P=0.02) despite increased urinary aldosterone excretion. The reduction in urinary F2-isoprostanes closely correlated with the reduction in urinary sodium excretion on the DASH/SRD. In this cohort of HFPEF patients with treated hypertension, the DASH/SRD reduced systemic blood pressure, arterial stiffness, and oxidative stress. These findings are characteristic of salt sensitive hypertension, a phenotype present in many HFPEF animal models and suggest shared pathophysiological mechanisms linking these 2 conditions. Further dietary modification studies could provide insights into the development and progression of hypertensive HFPEF. PMID- 23033372 TI - Enhanced adipose afferent reflex contributes to sympathetic activation in diet induced obesity hypertension. AB - We recently found that adipose afferent reflex (AAR) induced by chemical stimulation of white adipose tissue (WAT) increased sympathetic outflow and blood pressure in normal rats. The study was designed to test the hypothesis that AAR contributes to sympathetic activation in obesity hypertension. Male rats were fed with a control diet (12% kcal as fat) or high-fat diet (42% kcal as fat) for 12 weeks to induce obesity hypertension. Stimulation of WAT with capsaicin increased renal sympathetic nerve activity and mean arterial pressure. Both AAR and WAT afferent activity were enhanced in obesity hypertension (OH) compared with obesity nonhypertension (ON) and in ON compared with obesity-resistant or control diet rats. WAT sensory denervation induced by resiniferatoxin caused greater decreases in renal sympathetic nerve activity and mean arterial pressure in OH than ON and in ON than obesity-resistant or control. The depressor effect of resiniferatoxin lasted >= 3 weeks in OH. Leptin antagonist in WAT reduced renal sympathetic nerve activity and mean arterial pressure in OH. WAT injection of capsaicin increased plasma renin, angiotensin II, and norepinephrine levels in OH and caused more c-fos expression in paraventricular nucleus in OH than ON and in ON than obesity-resistant or control rats. Inhibiting paraventricular nucleus neurons with lidocaine attenuated renal sympathetic nerve activity in OH and ON, decreased mean arterial pressure in OH, and abolished the capsaicin-induced AAR in all groups. The results indicate that enhanced AAR contributes to sympathetic activation in OH, and paraventricular nucleus plays an important role in the enhanced AAR and sympathetic activation in OH. PMID- 23033374 TI - Anti-inflammatory functions of apolipoprotein A-I and high-density lipoprotein are preserved in trimeric apolipoprotein A-I. AB - Raising high-density lipoprotein (HDL) levels is proposed as an attractive target to treat cardiovascular disease. However, a number of clinical studies examining the effect of HDL-raising therapies have been prematurely halted due to futility. Therefore there is a need for alternative therapies. Infusion of reconstituted HDL (rHDL) particles is still considered as a viable approach to increasing HDL levels. In this study we have profiled the anti-inflammatory effects of a trimeric-HDL particle. We show that trimeric apoA-I and rHDL particles promote cholesterol efflux to a similar rate as native apoA-I particles in both ABCA1 dependent and -independent pathways. Trimeric particles inhibited ICAM-1 and VCAM 1 expression and the ability of the endothelium to capture monocytes under shear flow. Monocyte activation, CD11b-dependent adhesion, and monocyte recruitment under shear flow conditions were perturbed by the trimeric particles. Our data suggest that trimeric rHDL particles can be constructed without any loss of function, preserving the anti-inflammatory effects of HDL that are key to its in vivo actions. PMID- 23033373 TI - Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin. AB - We have documented recently that bradykinin (BK) directly inhibits activity of the epithelial Na(+) channel (ENaC) via the bradykinin B2 receptor (B2R)-G(q/11) phospholipase C pathway. In this study, we took advantage of mice genetically engineered to lack bradykinin receptors (B1R, B2R(-/-)) to probe a physiological role of BK cascade in regulation of ENaC in native tissue, aldosterone-sensitive distal nephron. Under normal sodium intake (0.32% Na(+)), ENaC open probability (P(o)) was modestly elevated in B1R, B2R(-/-) mice compared with wild-type mice. This difference is augmented during elevated Na(+) intake (2.00% Na(+)) and negated during Na(+) restriction (<0.01% Na(+)). Saturation of systemic mineralocorticoid status with deoxycorticosterone acetate similarly increased ENaC activity in both mouse strains, suggesting that the effect of BK on ENaC is independent of aldosterone. It is accepted that angiotensin-converting enzyme represents the major pathway of BK degradation. Systemic inhibition of angiotensin-converting enzyme with captopril (30 mg/kg of body weight for 7 days) significantly decreases ENaC activity and P(o) in wild-type mice, but this effect is diminished in B1R, B2R(-/-) mice. At the cellular level, acute captopril (100 MUmol/L) treatment sensitized BK signaling cascade and greatly potentiated the inhibitory effect of 100 nmol/L of BK on ENaC. We concluded that BK cascade has its own specific role in blunting ENaC activity, particularly under conditions of elevated sodium intake. Augmentation of BK signaling in the aldosterone-sensitive distal nephron inhibits ENaC-mediated Na(+) reabsorption, contributing to the natriuretic and antihypertensive effects of angiotensin-converting enzyme inhibition. PMID- 23033375 TI - FDA given new powers over data reporting to national clinical trials registry. PMID- 23033377 TI - Germany opposes EU plans for regulating clinical trials owing to lack of ethical standards. PMID- 23033376 TI - Marketing of antipsychotic drugs targeted doctors of Medicaid patients, report says. PMID- 23033378 TI - US Institute of Medicine urges fitness standards for young people. PMID- 23033379 TI - Fraud, not error, is why two thirds of biomedical papers are withdrawn. PMID- 23033380 TI - Pathology service run jointly with Serco is "in turmoil," claims report. PMID- 23033381 TI - The UCP1 -3826A/G polymorphism is associated with diabetic retinopathy and increased UCP1 and MnSOD2 gene expression in human retina. AB - PURPOSE: Uncoupling protein 1 (UCP1) reduces mitochondrial production of reactive oxygen species (ROS). ROS overproduction is related to diabetic retinopathy (DR), a chronic complication of diabetes mellitus (DM). Therefore, deleterious polymorphisms in the UCP1 gene are candidate risk factors for DR. We investigated the relationships between the UCP1 -3826A/G polymorphism and risk of DR and UCP1 gene expression in human retina. Considering that superoxide dismutase-2 (MnSOD2) enzyme is the first line of defense against oxidative stress in mitochondria, we also analyzed MnSOD2 gene expression in retinal samples according to different UCP1 -3826A/G genotypes. METHODS: In a case-control study, frequencies of 3826A/G polymorphisms were analyzed in 257 type 1 DM patients (154 cases with DR and 103 controls without DR). In a cross-sectional study comprising cadaveric cornea donors, UCP1 and MnSOD2 gene expressions were evaluated in 107 retinal samples differentiated according to different -3826A/G genotypes. RESULTS: In the type 1 DM group, multivariate analysis confirmed that the G/G genotype was an independent risk factor for DR (OR = 3.503; P = 0.043). In cornea donors, G allele carriers had higher UCP1 cDNA and protein concentrations than A/A carriers (P = 0.034 and P = 0.039, respectively). Interestingly, G allele carriers exhibited increased MnSOD2 expression (P = 0.001). CONCLUSIONS: This study suggests that the -3826A/G polymorphism is associated with DR in type 1 DM patients. This is the first report demonstrating UCP1 gene expression in human retinas and indicates that the -3826A/G polymorphism influences its expression. In addition, the -3826G allele was associated with increased MnSOD2 expression; thus, suggesting that this allele could be a marker of oxidative stress. PMID- 23033382 TI - Interleukin-10 gene-transfected mature dendritic cells suppress murine experimental autoimmune optic neuritis. AB - PURPOSE: We have reported that calcitonin gene-related peptide gene-transfected mature dendritic cells (mDC) suppress murine experimental autoimmune optic neuritis (EAON) and experimental autoimmune encephalitis (EAE) via interleukin-10 (IL-10) production. In our study, we examined whether IL-10-transfected mDC prevent development of EAON and EAE. METHODS: A plasmid expressing mouse IL-10 was constructed and used to transfect C57BL/6 mouse bone marrow-derived mDC by electroporation methods. C57BL/6 mice (with or without GFP expression) were immunized with myelo-oligodendrocyte glycoprotein35-55 (MOG35-55), and injected intravenously with IL-10-transfected mDC either in the induction or effector phase. RESULTS: When IL-10-transfected mDC were injected in the induction phase, EAE developed clinically in 60% of mice in the IL-10-transfected group compared to 100% in the mock-transfected group (P < 0.05), and mean pathologic score for EAON was 1.1 in the IL-10-transfected group compared to 2.1 in the mock transfected group (P < 0.05). When IL-10-transfected mDC were injected in the effector phase, mean EAE clinical scores were not significantly different between the two groups (2.0 vs. 3.0), while the mean EAON pathologic score was lower in the IL-10-transfected group compared to the mock-transfected group (1.0 vs. 2.7, P < 0.05). Delayed hypersensitivity was suppressed significantly in the IL-10 transfected group. Interestingly, the proportions of CD80/86+ and MHC class II+ cells decreased significantly (P < 0.05), whereas Foxp3+ cells increased significantly in the spleen and lymph node in the IL-10-transfected group by flow cytometry analysis. Immunohistochemical analysis demonstrated the localization of IL-10-transfected GFP-expressing mDC not only in the spleen and lymph nodes but also in the inflamed optic nerve. CONCLUSIONS: Treatment with IL-10-expressing mDC was effective in suppressing the development of EAON and EAE. PMID- 23033383 TI - Phototoxicity of indocyanine green and Brilliant Blue G under continuous fluorescent illumination on cultured human retinal pigment epithelial cells. AB - PURPOSE: We compared the phototoxicity of indocyanine green (ICG) and Brilliant Blue G (BBG) in cultured RPE cells under fluorescent lamp illumination imitating ambient light. METHODS: Cultured human RPE line cells were stained with ICG or BBG solution at concentrations of clinical use, and cultured in a colorless medium for 24 hours in the dark or under illumination from a fluorescent lamp. After culture, cell morphology and TUNEL-positive apoptotic cells were observed. Cell viability and cell death rate were evaluated. Absorption spectral changes of BBG before and after incubation were measured. RESULTS: ICG-stained cells cultured under illumination changed to an oval morphology with increased number of apoptotic cells, whereas ICG-stained cells cultured in the dark, and BBG stained cells cultured under illumination and dark conditions maintained a flat morphology without increase in apoptotic cells. Cell viability decreased and cell death rate increased only in cells stained by ICG followed by culture under illumination. Staining cells with ICG at one-tenth concentration of clinical usage induced no cytotoxicity after culture under illumination. Approximately 30% of total BBG retained in the stained cells was released into the culture supernatant after incubation for 24 hours. The absorption spectrum of BBG did not change after fluorescent light irradiation. CONCLUSIONS: Illumination with a fluorescent lamp caused cell death via apoptosis in ICG-exposed, but not in BBG exposed cultured RPE cells. BBG may be a safer dye than ICG because of low light induced cytotoxicity and rapid elution from stained cells. PMID- 23033384 TI - Innate immune regulation of Serratia marcescens-induced corneal inflammation and infection. AB - PURPOSE: Serratia marcescens is frequently isolated from lenses of patients with contact lens-associated corneal infiltrates. In the current study, we examined the role of toll-like receptors (TLRs) and interleukin-1 receptor type 1 (IL-1R1) in S. marcescens-induced corneal inflammation and infection. METHODS: The central corneal epithelium of C57BL/6 and gene knockout mice was abraded, and 1 * 10(7) S. marcescens were added in the presence of a silicone hydrogel contact lens, and we examined corneal inflammation by confocal microscopy and neutrophil enumeration. Viable bacteria were quantified by colony-forming units (CFU). RESULTS: S. marcescens induced neutrophil recruitment to the corneal stroma, and increased corneal thickness and haze in C57BL/6 mice. Conversely, CFU was significantly lower by 48 hours post infection. In contrast, MyD88(-/-), IL-1R(-/ ), TLR4(-/-), and TLR4/5(-/-) corneas infected with S. marcescens had significantly increased CFU, indicating impaired clearance. However, there was no significant difference in CFU among C57BL/6, TIRAP(-/-), and TRIF(-/-) mice. Tobramycin-killed S. marcescens induced corneal inflammation in C57BL/6 mice, which was impaired significantly in MD-2(-/-) mice and in C57BL/6 mice pretreated topically with the MD-2 antagonist eritoran tetrasodium. CONCLUSIONS: S. marcescens induces corneal inflammation by activation of TLR4/MD-2/MyD88 and the IL-1R1/MyD88 pathways, which are potential therapeutic targets for inhibition of S. marcescens-induced corneal inflammation. PMID- 23033385 TI - Observations of vascular structures within and posterior to sclera in eyes with pathologic myopia by swept-source optical coherence tomography. AB - PURPOSE: We examined the intrascleral and retrobulbar blood vessels in highly myopic eyes by swept-source optical coherence tomography (swept-source OCT). METHODS: We included in the study 662 of 357 patients with pathologic myopia (spherical equivalent of myopic refractive error >= 8.00 diopters or axial length > 26.5 mm). A swept-source OCT system that uses a wavelength sweeping laser with A-scan repetition rate of 100,000 Hz and 1 MUm wavelength was used. Radial scans along 12 meridians of 12 mm scan length centered on the fovea were made. Indocyanine green angiography (ICGA) also was performed to identify the intrascleral and retrobulbar vessels that were observed by swept-source OCT. RESULTS: Intrascleral and retrobulbar blood vessels were observed in the macular area of the highly myopic eyes. Linear hyporeflective structures running in the sclera were observed in 474 of the 662 myopic eyes, and ICGA confirmed that these structures were the long posterior ciliary arteries (LPCAs) or the short posterior ciliary arteries (SPCAs) whose entry sites into the eye were displaced toward the temporal edge of the posterior staphyloma in 50 eyes. In 36 of the 662 eyes (5.4%), cross sections of the blood vessels were seen coursing through the scleral layer. In 177 of these 443 eyes, the retrobulbar posterior ciliary arteries (PCAs) also were observed as a cluster of circular or curved hyporeflectant structures just posterior to the sclera. CONCLUSIONS: Swept-source OCT is a high-quality method to detect intrascleral and retroscleral blood vessels in the eyes with pathologic myopia. These findings and longitudinal studies of these vessels will help in investigating how they are altered in pathologic myopia, and how such alterations are related to the complications in the retina-choroid and optic nerve. PMID- 23033386 TI - Impaired mesopic visual acuity in eyes with early age-related macular degeneration. AB - PURPOSE: To determine photopic and mesopic distance high-contrast visual acuity (HC-VA) and low-contrast visual acuity (LC-VA) in eyes with early age-related macular degeneration (AMD). METHODS: Measurements were made in 22 subjects with early AMD and 28 healthy control subjects. Inclusion criteria included a photopic HC-VA of 20/25 or better. Distance VA was measured using HC (96%) and LC (10%) Bailey-Lovie logMAR letter charts under photopic (85 cd/m(2)) and mesopic (0.1 0.2 cd/m(2)) luminance conditions. RESULTS: Mean mesopic distance HC-VA and LC-VA were significantly worse (0.1 logMAR and 0.28 logMAR, respectively) in the early AMD group than in the control group. Under mesopic conditions, the mean difference between LC-VA and HC-VA was significantly greater in the early AMD (0.45 logMAR) than the control group (0.27 logMAR). Mean differences between mesopic versus photopic HC-VA and mesopic versus photopic LC-VA were significantly greater in the early AMD than the control group (0.13 and 0.32 logMAR of difference between the means, respectively). Sensitivity and specificity were significantly greater for mesopic LC-VA than for mesopic HC-VA (Receiver Operating Characteristics, area under the curve [AUC], 0.94 +/- 0.030 and 0.76 +/- 0.067, respectively). AUC values for photopic HC-VA and LC-VA were below 0.70. CONCLUSIONS: Visual acuity testing under low luminance conditions emerged as an optimal quantitative measure of retinal function in early AMD. PMID- 23033387 TI - Analysis of higher-order aberrations in a large clinical population. AB - PURPOSE: To use a large wave-front database of a clinical population to investigate relationships between refractions and higher-order aberrations and between aberrations of right and left eyes. METHODS: Third- and fourth-order aberration coefficients and higher-order root-mean-squared aberrations (HO RMS), scaled to a pupil size of 4.5-mm diameter, were analyzed in a population of approximately 24,000 patients from Carl Zeiss Vision's European wave-front database. Correlations were determined between the aberrations and the variables of refraction, near addition, and cylinder. RESULTS: Most aberration coefficients were significantly dependent upon these variables, but the proportion of aberrations that could be explained by these factors was less than 2% except for spherical aberration (12%), horizontal coma (9%), and HO RMS (7%). Near addition was the major contributor for horizontal coma (8.5% out of 9.5%) and spherical equivalent was the major contributor for spherical aberration (7.7% out of 11.6%). Interocular correlations were highly significant for all aberration coefficients, varying between 0.16 and 0.81. Anisometropia was a variable of significance for three aberrations (vertical coma, secondary astigmatism, and tetrafoil), but little importance can be placed on this finding because of the small proportion of aberrations that can be explained by refraction (all <1.0%). CONCLUSIONS: Most third- and fourth-order aberration coefficients were significantly dependent upon spherical equivalent, near addition, and cylinder, but only horizontal coma (9%) and spherical aberration (12%) showed dependencies greater than 2%. Interocular correlations were highly significant for all aberration coefficients, but anisometropia had little influence on aberration coefficients. PMID- 23033388 TI - Influence of the interposition of a nonhollow probe during cannula extraction on sclerotomy vitreous incarceration in sutureless vitrectomy. AB - PURPOSE: To evaluate the effect of the cannula removal technique on postoperative vitreous incarceration using an experimental model of vitrectomized eye. METHODS: In a prospective, experimental, randomized, and observer-masked study, 118 cadaveric pig eyes were vitrectomized through 23-gauge transconjunctival sclerotomies. Once vitrectomy was finished, one of the superior cannulas was extracted with the illumination probe inserted through it, and the other cannula was removed with a cannula plug inserted. Postoperative incisional vitreous entrapment was evaluated by direct visualization. No vitreous incarceration was classified as grade 0 (G0), thin vitreous entrapment was classified as grade 1 (G1), and thick vitreous strands as grade 2 (G2). RESULTS: Considering the sclerotomies whose cannulas were extracted with the light probe inside, vitreous incarceration was detected in 93.2% (73.7% G1, 19.5% G2) of the incisions. In turn, vitreous entrapment was observed in 95.8% (43.2% G1, 52.6% G2) of the entry sites whose cannulas were extracted with the plug inserted. Statistical analysis showed significant differences when comparing postvitrectomy vitreous incarceration grades in sclerotomies according to the cannula extraction technique (P < 0.0001). CONCLUSIONS: Interposing the light probe through the cannula during its removal reduces vitreous incarceration grade in our experimental model. This simple maneuver may decrease complications related to vitreous entrapment, such as peripheral retinal tears and acute endophthalmitis. PMID- 23033389 TI - The shape of the ganglion cell plus inner plexiform layers of the normal human macula. AB - PURPOSE: To use surfaces generated by two-dimensional penalized splines (2D P splines) to characterize the shape of the macular ganglion cell plus inner plexiform layers (GCL+IPL) in a group of normal humans. METHODS: Macular images of the right eyes of 23 normal subjects ranging in age from 18 to 75 years were obtained with spectral-domain optical coherence tomography (SD-OCT). The thickness of GCL+IPL was determined by manual segmentation, areas with blood vessels were removed, and the resulting maps were fit by smooth surfaces in polar coordinates centered on the fovea. RESULTS: Smooth surfaces based on 2D P-splines could precisely represent GCL+IPL thickness data, with errors comparable to the axial resolution of the SD-OCT instrument. Metrics were developed for the size, shape, and slope of the edge of the foveal depression and size and shape of the surrounding macular ridge. The slope of the foveal edge was negatively correlated with foveal size (r = -0.60). The size of the macular ridge was positively correlated with foveal size (r = 0.75), with a slope near unity (0.90 +/- 0.18). The centroids of the foveal edge and macular ridge clustered near the foveal center. The foveal edge and macular ridge were well fit by ellipses. The mean GCL+IPL thickness formed an elliptical annulus elongated by approximately 30% in the horizontal direction. CONCLUSIONS: The methods developed here provide precise characterization of retinal layers for the study of glaucoma, foveal development, and other applications. PMID- 23033390 TI - Comparison of single versus multiple injections of the protein saratin for prolonging bleb survival in a rabbit model. AB - PURPOSE: We compared the anti-fibrotic effects of single versus multiple postoperative injections of saratin following glaucoma filtration surgery (GFS) in the rabbit model. METHODS: The experiment was in two parts. To determine the optimal frequency for postoperative therapy, seven New Zealand White (NZW) rabbits received an injection of saratin under the superior conjunctiva bilaterally, and ocular tissue concentration was determined using Western blot and bicinchoninic acid (BCA) assay. Next, 32 additional NZW rabbits underwent filtration surgery and received either single or multiple-dose saratin treatments. Mitomycin-C (MMC) and balanced saline solution (BSS) treatment acted as positive and negative controls, respectively. RESULTS: Rabbits receiving only one perioperative saratin injection had a mean bleb survival time of 29.8 +/- 5.3 days, while those receiving multiple (either 3 or 5+) injections of saratin had mean bleb survival times of 26.3 +/- 8.1 and 26.4 +/- 4.2 days, respectively. Analysis of variance with post-hoc testing showed the single injection group had a statistically favorable effect on bleb survival duration compared to BSS controls and was not significantly different from MMC. The conjunctivas of the saratin-treated rabbits did not show the thinning or avascularity that was seen in the MMC treatment group. Rabbits receiving more than three injections of saratin suffered temporary conjunctival redness and two rabbits had upper eyelid edema. CONCLUSIONS: A single postoperative injection of saratin was able to prolong the duration of bleb elevation when compared to BSS controls. Additional treatments of saratin seemed to reduce effectiveness and caused short-term eye inflammation. PMID- 23033391 TI - Assessment of retinal morphology with spectral and time domain OCT in the phase III trials of enzymatic vitreolysis. AB - PURPOSE: To determine the relative ability of time domain (TD)-optical coherence tomography (OCT) compared with spectral domain (SD)-OCT to assess vitreoretinal interface abnormalities and pharmacologic treatment of symptomatic vitreomacular adhesion (VMA)/traction (VMT) with or without full-thickness macular hole (FTMH), and the reproducibility of trained readers' evaluation of these images in an interventional phase III program of ocriplasmin. METHODS: Eyes from the MIVI TRUST program with concurrent SD-OCT and TD-OCT at baseline and day 28 were included. Pairwise intermodality agreement frequency and interreader reproducibility were calculated for baseline OCT features and the study endpoints of VMA resolution and FTMH closure. RESULTS: A total 186 eyes (186 patients) met the inclusion criteria for this study. There was excellent agreement between TD OCT and SD-OCT for the reader-determined presence or absence of VMA (96.7%), FTMH (97.1%), and all other baseline parameters except epiretinal membrane (84.3%), which was detected at a significantly greater rate with SD-OCT than TD-OCT (44.6% vs. 35.3%, P < 0.001). There was excellent agreement for the study endpoints of VMA resolution (95.4%) and FTMH closure (100%) at day 28. Interreader reproducibility was similar but consistently greater with SD-OCT than TD-OCT to detect baseline VMA (kappa 0.6 vs. 0.52); FTMH (kappa 0.9 vs. 0.78); and epiretinal membrane (kappa 0.65 vs. 0.45). CONCLUSIONS: Readers using SD-OCT or TD-OCT have similar ability to assess vitreoretinal interface abnormalities and outcomes of enzymatic vitreolysis. SD-OCT may be superior for formal clinical trial grading due to greater interreader reproducibility and, therefore, decreased need for arbitration of discrepant values. (ClinicalTrials.gov numbers,NCT00781859, NCT00798317.). PMID- 23033394 TI - Dynamic changes in anterior segment morphology during the Valsalva maneuver assessed with ultrasound Biomicroscopy. AB - PURPOSE: We evaluated dynamic changes in anterior segment morphology during the Valsalva maneuver with ultrasound biomicroscopy (UBM). METHODS: For this prospective observational study, a group of patients with narrow angles and a group of normal subjects were recruited. The anterior segment of subjects was imaged and analyzed quantitatively using UBM before and during the Valsalva maneuver. Changes in anterior segment parameters from baseline and during the Valsalva maneuver, and the differences in parameters between the narrow angle and control groups were analyzed. RESULTS: Of 151 subjects recruited for the study, 68 (45.0%) were men and 83 (54.9%) had narrow angles. For the overall group, during Valsalva maneuver, the subjects' central anterior chamber depth (ACD) became shallower (from 2.286-2.262 mm, P < 0.001), and the anterior chamber angle became narrower (from 14.673-13.370 degrees, P = 0.004), the angle opening distance became smaller (from 0.158-0.140 mm, P = 0.014), and the peripheral iris thickness became thicker (from 0.494-0.508 mm, P = 0.041), while the central iris thickness did not change. Compared to normal controls, narrow angle subjects had shallower ACD and thicker iris at baseline, but there was no significant difference between the 2 groups in dynamic changes in the anterior segment after the Valsalva maneuver. CONCLUSIONS: The Valsalva maneuver, performed frequently in daily activities, can lead to significant narrowing of the angles in subjects with open and narrow angles. This factor may be important in eyes at risk for angle closure glaucoma. PMID- 23033393 TI - Analysis of spectral-domain optical coherence tomography in preterm children: retinal layer thickness and choroidal thickness profiles. AB - PURPOSE: To compare retinal layer thickness and choroidal thickness profiles in preterm and full-term children using spectral-domain optical coherence tomography (SD-OCT). METHODS: We performed horizontal and vertical SD-OCT crosshair scans through the fovea with and without an enhanced depth technique in 31 premature and 30 full-term children. Retinal layer and choroidal thicknesses were measured at various locations including the fovea and 1.0 and 3.0 mm nasal, temporal, superior, and inferior to the fovea. After adjusting for age and the child's axial length, we compared retinal layer and choroidal thicknesses at the measurement points. RESULTS: Total retinal thickness and outer nuclear layer (ONL) thickness at the foveal center in preterm children (256.00 +/- 30.71 MUm, 141.87 +/- 28.75 MUm, respectively) were larger than those in full-term children (217.57 +/- 10.64 MUm, 101.22 +/- 10.90 MUm, respectively, P < 0.001). Gestational age at birth was inversely correlated with both total retinal and ONL thicknesses (P < 0.001). Choroidal thickness 3.0 mm temporal to the fovea in preterm children (283.75 +/- 60.47 MUm) was significantly less than that in full term children (339.89 +/- 90.32, P = 0.010). Retinopathy of prematurity staging showed a marginal inverse correlation with choroidal thickness 3.0 mm temporal to the fovea (P = 0.053). Visual acuity in preterm children was not correlated with retinal thickness or choroidal thickness. CONCLUSIONS: Our SD-OCT data demonstrated an increased total retinal thickness and ONL thickness at the foveal center and decreased choroidal thickness 3.0 mm temporal to the fovea in preterm children. Further studies are needed to better understand the association between these structural changes and visual functions in preterm children. PMID- 23033392 TI - Dorsomedial/Perifornical hypothalamic stimulation increases intraocular pressure, intracranial pressure, and the translaminar pressure gradient. AB - PURPOSE: Intraocular pressure (IOP) fluctuation has recently been identified as a risk factor for glaucoma progression. Further, decreases in intracranial pressure (ICP), with postulated increases in the translaminar pressure gradient across the lamina cribrosa, has been reported in glaucoma patients. We hypothesized that circadian fluctuations in IOP and the translaminar pressure gradient are influenced, at least in part, by central autonomic regulatory neurons within the dorsomedial and perifornical hypothalamus (DMH/PeF). This study examined whether site-directed chemical stimulation of DMH/PeF neurons evoked changes in IOP, ICP, and the translaminar pressure gradient. METHODS: The GABA(A) receptor antagonist bicuculline methiodide (BMI) was stereotaxically microinjected into the DMH/PeF region of isoflurane-anesthetized male Sprague-Dawley rats (n = 19). The resulting peripheral cardiovascular (heart rate [HR] and mean arterial pressure [MAP]), IOP, and ICP effects were recorded and alterations in the translaminar pressure gradient calculated. RESULTS: Chemical stimulation of DMH/PeF neurons evoked significant increases in HR (+69.3 +/- 8.5 beats per minute); MAP (+22.9 +/- 1.6 mm Hg); IOP (+7.1 +/- 1.9 mm Hg); and ICP (+3.6 +/- 0.7 mm Hg) compared with baseline values. However, the peak IOP increase was significantly delayed compared with ICP (28 vs. 4 minutes postinjection), resulting in a dramatic translaminar pressure gradient fluctuation. CONCLUSIONS: Chemical stimulation of DMH/PeF neurons evokes substantial increases in IOP, ICP, and the translaminar pressure gradient in the rat model. Given that the DMH/PeF neurons may be a key effector pathway for circadian regulation of autonomic tone by the suprachiasmatic nucleus, these findings will help elucidate novel mechanisms modulating circadian fluctuations in IOP and the translaminar pressure gradient. PMID- 23033395 TI - Topographic changes of retinal layers after resolution of acute retinal detachment. AB - PURPOSE: To investigate changes in thickness profiles of retinal layers after resolution of recent onset rhegmatogenous retinal detachment METHODS: Spectral domain optical coherence tomography (SD-OCT) scans were performed for 28 patients diagnosed with unilateral inferior half or superior half retinal detachment who underwent retinal reattachment surgery. The thickness of each retinal layer was measured at 3000 MUm and 2800 MUm in the superior and inferior directions from the foveal center. The thicknesses of each retinal layer of the reattached retina were compared with those of the undetached region of the retina of the same eye. RESULTS: Sixteen patients were diagnosed with superior half and 12 patients were diagnosed with inferior half retinal detachment. The mean duration of retinal detachment was 6.9 +/- 3.9 days. SD-OCT scans were performed 10.4 +/- 6.9 months after the surgery. The thicknesses of the outer nuclear layer and photoreceptor layer in the reattached retina were significantly thinner than those of the undetached retina (P = 0.012, and P = 0.018, respectively). CONCLUSIONS: Our findings suggest that prominent retinal structural sequelae, especially in outer nuclear layer and photoreceptor layer, can be induced by a short duration of retinal detachment. Our findings also underscore the important role of initial retinal injuries that occur within the first several days on the long term structural prognosis. (ClinicalTrials.gov number, NCT01587794). PMID- 23033396 TI - Clinical profile of concurrent dengue fever and Plasmodium vivax malaria in the Brazilian Amazon: case series of 11 hospitalized patients. AB - Malaria and dengue fever are the most prevalent vector-borne diseases worldwide. This study aims to describe the clinical profile of patients with molecular diagnosis of concurrent malaria and dengue fever in a tropical-endemic area. Eleven patients with concurrent dengue virus (DENV) and Plasmodium vivax infection are reported. Similar frequencies of DENV-2, DENV-3, and DENV-4 were found, including DENV-3/DENV-4 co-infection. In eight patients, the World Health Organization (WHO) criteria for severe malaria could be fulfilled (jaundice being the most common). Only one patient met severe dengue criteria, but warning signs were present in 10. Syndromic surveillance systems must be ready to identify this condition to avoid misinterpretation of severity attributed to a single disease. PMID- 23033397 TI - Prevalence and risk factors for Chagas disease in pregnant women in Casanare, Colombia. AB - Knowledge of the prevalence and risk factors associated with maternal infection is the first step to develop a surveillance system for congenital transmission of Chagas disease. We conducted a cross-sectional study in Casanare, a disease endemic area in Colombia. A total of 982 patients were enrolled in the study. A global prevalence of Trypanosoma cruzi infection of 4.0% (95% confidence interval [CI] = 2.8-5.3%) was found. Multivariate analysis showed that the most important risk-associated factors were age > 29 years (adjusted odds ratio [aOR] = 3.4, 95% CI = 0.9-12.4), rural residency (aOR = 2.2, 95% CI = 1.0-4.6), low education level (aOR = 10.2, 95% CI = 1.6-82.7), and previous knowledge of the vector (aOR = 2.2, 95% CI = 1.0-4.9). Relatives and siblings of infected mothers showed a prevalence of 9.3%. These findings may help physicians to investigate congenital cases, screen Chagas disease in siblings and relatives, and provide early treatment to prevent the chronic complications of Chagas disease. PMID- 23033398 TI - Prevalence of raised intracranial pressure in cerebral malaria detected by optic nerve sheath ultrasound. AB - We aimed to use optic nerve sheath (ONS) ultrasound to determine the prevalence of raised intracranial pressure (ICP) in African children with cerebral malaria (CM); and if increased ONS diameter is associated with poor outcome. We measured ONS diameter in 101 children with CM and 11 children with malaria and impaired consciousness in Malawi. The prevalence of raised ICP detected by increased ONS diameter was 49%. Case fatality was similar in children with increased ONS diameter on admission (9/55) and those children without increased ONS diameter (11/57). Neurological sequelae were more common in those children with increased ONS diameter (7/46 versus 2/46, P < 0.05). Lumbar puncture (LP) opening pressure was elevated in 95% of 46 children who underwent LP. In Malawian children with CM, raised ICP is less commonly detected by ONS ultrasound than LP. This study suggests that raised ICP is not universal in CM and that other mechanisms may account for coma. PMID- 23033399 TI - Association of Schistosomiasis and HIV infection in Tanzania. AB - Animal and human studies suggest that Schistosoma mansoni infection may increase risk of human immunodeficiency virus (HIV) acquisition. Therefore, we tested 345 reproductive age women in rural Tanzanian villages near Lake Victoria, where S. mansoni is hyperendemic, for sexually transmitted infections (STIs) and schistosomiasis by circulating anodic antigen (CAA) serum assay. Over one-half (54%) had an active schistosome infection; 6% were HIV-seropositive. By univariate analysis, only schistosome infection predicted HIV infection (odds ratio [OR] = 3.9, 95% confidence interval = [1.3-12.0], P = 0.015) and remained significant using multivariate analysis to control for age, STIs, and distance from the lake (OR = 6.2 [1.7-22.9], P = 0.006). HIV prevalence was higher among women with more intense schistosome infections (P = 0.005), and the median schistosome intensity was higher in HIV-infected than -uninfected women (400 versus 15 pg CAA/mL, P = 0.01). This finding suggests that S. mansoni infection may be a modifiable HIV risk factor that places millions of people worldwide at increased risk of HIV acquisition. PMID- 23033400 TI - Malaria risk mapping for control in the republic of Sudan. AB - Evidence shows that malaria risk maps are rarely tailored to address national control program ambitions. Here, we generate a malaria risk map adapted for malaria control in Sudan. Community Plasmodium falciparum parasite rate (PfPR) data from 2000 to 2010 were assembled and were standardized to 2-10 years of age (PfPR(2-10)). Space-time Bayesian geostatistical methods were used to generate a map of malaria risk for 2010. Surfaces of aridity, urbanization, irrigation schemes, and refugee camps were combined with the PfPR(2-10) map to tailor the epidemiological stratification for appropriate intervention design. In 2010, a majority of the geographical area of the Sudan had risk of < 1% PfPR(2-10). Areas of meso- and hyperendemic risk were located in the south. About 80% of Sudan's population in 2011 was in the areas in the desert, urban centers, or where risk was < 1% PfPR(2-10). Aggregated data suggest reducing risks in some high transmission areas since the 1960s. PMID- 23033401 TI - Occurrence of Japanese encephalitis virus mosquito vectors in relation to urban pig holdings. AB - Japanese encephalitis virus (JEV) is transmitted to humans from pigs or birds by mosquitoes. In this study, the association between urban pig keeping and mosquito vectors was analyzed. A total of 7, 419 mosquitoes were collected overnight in urban households with and without pigs in Can Tho City, Vietnam. The most prevalent vectors were Culex tritaeniorhynchus (36%), Cx. gelidus (24%), and Cx. quinquefasciatus (15%), which were present in all parts of the city. Pigs were associated with increased numbers of Cx. tritaeniorhynchus. Traps close to pigs had higher numbers of Cx. tritaeniorhynchus and Cx. gelidus than traps close to humans. Increased number of persons in the household was associated with increased numbers of Cx. quinquefasciatus. We demonstrate that JEV vector species are present at urban households with and without pigs, and show that keeping pigs in an urban area increase the number of mosquitoes competent as vectors for JEV. PMID- 23033402 TI - Amebic liver abscess diagnosed by polymerase chain reaction in 14 returning travelers. AB - Amebic liver abscesses (ALA) are not commonly described in travelers. The ALA diagnosis is usually based on serology and Entamoeba histolytica polymerase chain reaction (PCR) is a new tool. We retrospectively reviewed all ALA cases diagnosed by PCR on the liver abscess pus aspirate of patients admitted in 4 teaching hospitals in Paris, France between 2007 and 2011. Fourteen cases (10 male, median age 48 years) were included. The median lag time between return and onset of symptoms was 23 days among 10 patients (interquartile range [IQ] 18-24) whereas the remaining patients had travelled over 2 years ago.All patients had an elevated C-reactive protein level, and 11 had leukocytosis. The ALA was multiple in five patients, localized in the right lobe in 12, and higher than 5 cm in 11. Serology was initially negative in one patient, whereas PCR was positive. There was bacterial co-infection in one patient. The outcome was good. Liver puncture allows a rapid diagnosis of ALA with PCR and helps identify the association with a bacterial dual infection [corrected].. PMID- 23033403 TI - Outcomes of patients with melioidosis treated with cotrimoxazole alone for eradication therapy. AB - We retrospectively reviewed a 10-year experience of administration of cotrimoxazole alone in 31 patients compared with 109 patients who received conventional eradication therapy (cotrimoxazole plus doxycycline). The baseline characteristics, the clinical manifestations, the initial intravenous antibiotic treatments, and the mean duration of eradication therapy between the two groups were similar. The culture-confirmed recurrences among the patients who received cotrimoxazole alone and those who received the conventional regimen were not significantly different (1/31 [3.2%] versus 5/109 [4.5% odds ratio = 0.69 [95% confidence interval [CI] = 0.08-6.17]). Gastrointestinal side effects were more common among the conventional regimen group (28/109 [25.7%] versus 2/31 [6.5%], P = 0.02) and the proportion of patients who could complete at least 20 weeks of therapy without having switched to the other regimen was significantly lower (91/109 [83.5%] versus 31/31 [100.0%] P = 0.01). Cotrimoxazole alone is as effective as and better tolerated than cotrimoxazole plus doxycycline for the eradication treatment of melioidosis. PMID- 23033404 TI - Use of multiple data sources to estimate the economic cost of dengue illness in Malaysia. AB - Dengue represents a substantial burden in many tropical and sub-tropical regions of the world. We estimated the economic burden of dengue illness in Malaysia. Information about economic burden is needed for setting health policy priorities, but accurate estimation is difficult because of incomplete data. We overcame this limitation by merging multiple data sources to refine our estimates, including an extensive literature review, discussion with experts, review of data from health and surveillance systems, and implementation of a Delphi process. Because Malaysia has a passive surveillance system, the number of dengue cases is under reported. Using an adjusted estimate of total dengue cases, we estimated an economic burden of dengue illness of US$56 million (Malaysian Ringgit MYR196 million) per year, which is approximately US$2.03 (Malaysian Ringgit 7.14) per capita. The overall economic burden of dengue would be even higher if we included costs associated with dengue prevention and control, dengue surveillance, and long-term sequelae of dengue. PMID- 23033405 TI - Detection of eastern equine encephalomyelitis virus RNA in North American snakes. AB - The role of non-avian vertebrates in the ecology of eastern equine encephalomyelitis virus (EEEV) is unresolved, but mounting evidence supports a potential role for snakes in the EEEV transmission cycle, especially as over wintering hosts. To determine rates of exposure and infection, we examined serum samples from wild snakes at a focus of EEEV in Alabama for viral RNA using quantitative reverse transcription polymerase chain reaction. Two species of vipers, the copperhead (Agkistrodon contortrix) and the cottonmouth (Agkistrodon piscivorus), were found to be positive for EEEV RNA using this assay. Prevalence of EEEV RNA was more frequent in seropositive snakes than seronegative snakes. Positivity for the quantitative reverse transcription polymerase chain reaction in cottonmouths peaked in April and September. Body size and sex ratios were not significantly different between infected and uninfected snakes. These results support the hypothesis that snakes are involved in the ecology of EEEV in North America, possibly as over-wintering hosts for the virus. PMID- 23033406 TI - A PAUC-based estimation technique for disease classification and biomarker selection. AB - The partial area under the receiver operating characteristic curve (PAUC) is a well-established performance measure to evaluate biomarker combinations for disease classification. Because the PAUC is defined as the area under the ROC curve within a restricted interval of false positive rates, it enables practitioners to quantify sensitivity rates within pre-specified specificity ranges. This issue is of considerable importance for the development of medical screening tests. Although many authors have highlighted the importance of PAUC, there exist only few methods that use the PAUC as an objective function for finding optimal combinations of biomarkers. In this paper, we introduce a boosting method for deriving marker combinations that is explicitly based on the PAUC criterion. The proposed method can be applied in high-dimensional settings where the number of biomarkers exceeds the number of observations. Additionally, the proposed method incorporates a recently proposed variable selection technique (stability selection) that results in sparse prediction rules incorporating only those biomarkers that make relevant contributions to predicting the outcome of interest. Using both simulated data and real data, we demonstrate that our method performs well with respect to both variable selection and prediction accuracy. Specifically, if the focus is on a limited range of specificity values, the new method results in better predictions than other established techniques for disease classification. PMID- 23033407 TI - New recommendation for malaria treatment in Indonesia. PMID- 23033410 TI - More evidence of harms of sunbed use, particularly for young people. PMID- 23033409 TI - Indoor tanning and non-melanoma skin cancer: systematic review and meta-analysis. AB - OBJECTIVE: To synthesise the literature on indoor tanning and non-melanoma skin cancer. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed (1966 to present), Embase (1974 to present), and Web of Science (1898 to present). STUDY SELECTION: All articles that reported an original effect statistic for indoor tanning and non-melanoma skin cancer were included. Articles that presented no data, such as review articles and editorials, were excluded, as were articles in languages other than English. DATA EXTRACTION: Two investigators independently extracted data. Random effects meta-analysis was used to summarise the relative risk of ever use versus never use of indoor tanning. Dose-response effects and exposure to indoor tanning during early life were also examined. The population attributable risk fraction for the United States population was calculated. RESULTS: 12 studies with 9328 cases of non-melanoma skin cancer were included. Among people who reported ever using indoor tanning compared with those who never used indoor tanning, the summary relative risk for squamous cell carcinoma was 1.67 (95% confidence interval 1.29 to 2.17) and that for basal cell carcinoma was 1.29 (1.08 to 1.53). No significant heterogeneity existed between studies. The population attributable risk fraction for the United States was estimated to be 8.2% for squamous cell carcinoma and 3.7% for basal cell carcinoma. This corresponds to more than 170 000 cases of non-melanoma skin cancer each year attributable to indoor tanning. On the basis of data from three studies, use of indoor tanning before age 25 was more strongly associated with both squamous cell carcinoma (relative risk 2.02, 0.70 to 5.86) and basal cell carcinoma (1.40, 1.29 to 1.52). CONCLUSIONS: Indoor tanning is associated with a significantly increased risk of both basal and squamous cell skin cancer. The risk is higher with use in early life (<25 years). This modifiable risk factor may account for hundreds of thousands of cases of non-melanoma skin cancer each year in the United States alone and many more worldwide. These findings contribute to the growing body of evidence on the harms of indoor tanning and support public health campaigns and regulation to reduce exposure to this carcinogen. PMID- 23033411 TI - Unnecessary care: are doctors in denial and is profit driven healthcare to blame? PMID- 23033412 TI - The need to distinguish between group A streptococcus and polymicrobial causes in necrotising fasciitis. PMID- 23033413 TI - The ability to stand is not diagnostic in vertigo. PMID- 23033415 TI - Bioethicists do participate in everyday practice. PMID- 23033416 TI - "Ethics Man" misses mark: most bioethicists are not thugs. PMID- 23033417 TI - A tax on indoor tanning would reduce demand in Europe. PMID- 23033418 TI - Reductions in specialist chronic illness management fuel emergency hospital admissions. PMID- 23033419 TI - Keep general practice and secondary care separate. PMID- 23033420 TI - If facts do not fit theory, the theory is wrong. PMID- 23033421 TI - Neither off the peg nor made to measure calculations are fit for purpose. PMID- 23033422 TI - An unorthodox approach to calculating sample size. PMID- 23033423 TI - "If everybody's somebody, then no one's anybody". PMID- 23033424 TI - Teledermatology is the answer. PMID- 23033425 TI - Predicting polyp location on optical colonoscopy from CT colonography by minimal energy curve modeling of the colonoscope path. AB - The ability to accurately locate a polyp found on computed tomographic colonography (CTC) at subsequent optical colonoscopy (OC) is an important task in colorectal cancer screening. We present a method to more accurately match polyp locations at CTC and OC. A colonoscope was modeled as a flexible tube with negligible stretch and minimal strain. The path of the colonoscope was estimated using a minimal-energy curve method. The energy function was defined and optimized by a subdivision scheme. The prediction of polyp locations at OC from CTC was converted to an optimization problem. The prediction performance was evaluated on 134 polyps by comparing the predicted with the true polyp locations at OC. The method can accurately predict polyp locations at OC to within +/-0.5 colonoscope mark (5 cm) for more than 58% of polyps and to within +/-1 colonoscope mark (10 cm) for more than 96% of polyps, significantly improving upon previously published methods. This method can be easily incorporated into routine OC practice and allow the colonoscopist to begin the examination by targeting locations of potential polyps found at CTC. PMID- 23033426 TI - Conformal hyperthermia of superficial tumor with left-handed metamaterial lens applicator. AB - With proper source spacing, low loss left-handed metamaterial (LHM) lens should be useful for hyperthermia treatment of large area tumors. With a flat LHM lens applicator, conformal hyperthermia can be performed by joint heating of multiple microwave sources (antennas). In the hyperthermia, we restrict distance of two neighboring sources within a critical source interval, arrange the sources in a specific array of general shape in accord with the tumor, and adjust the source to-lens distance to acquire desired inclination of the heating zone for better fit to tumor region. It is shown that inclination can also be adjusted by the phases of microwave sources. A maneuverable LHM-based hyperthermia scheme is thus proposed to generate a relatively large and even tilted heating pattern in tissue. PMID- 23033427 TI - An interactive approach to multiobjective clustering of gene expression patterns. AB - Some recent studies have posed the problem of data clustering as a multiobjective optimization problem, where several cluster validity indices are simultaneously optimized to obtain tradeoff clustering solutions. A number of cluster validity index measures are available in the literature. However, none of the measures can perform equally well in all kinds of datasets. Depending on the dataset properties and its inherent clustering structure, different cluster validity measures perform differently. Therefore, it is important to find the best set of validity indices that should be optimized simultaneously to obtain good clustering results. In this paper, a novel interactive genetic algorithm-based multiobjective approach is proposed that simultaneously finds the clustering solution as well as evolves the set of validity measures that are to be optimized simultaneously. The proposed method interactively takes the input from the human decision maker (DM) during execution and adaptively learns from that input to obtain the final set of validity measures along with the final clustering result. The algorithm is applied for clustering real-life benchmark gene expression datasets and its performance is compared with that of several other existing clustering algorithms to demonstrate its effectiveness. The results indicate that the proposed method outperforms the other existing algorithms for all the datasets considered here. PMID- 23033428 TI - Greater cardiac cell excitation efficiency with rapidly switching multidirectional electrical stimulation. AB - Electric field (E) stimulation is widely used in experiments with myocardial preparations and in the clinical setting (e.g., defibrillation). As a rule, stimuli are applied in a single direction, which limits excitatory cell recruitment because myocytes are disposed in different directions and their sensitivity to E depends on the stimulus orientation with respect to the cell major axis. Here, we propose a stimulatory approach, namely rapidly switching multidirectional stimulation (RSMS), in which stimuli are delivered in three directions within the electric refractory period. In populations of randomly oriented isolated rat cardiomyocytes, RSMS doubled the percentage of cells excited by near-threshold E (P < 0.001), which was more than the increase in recruitment in a single direction achieved by doubling E intensity. This effect was similar for monophasic and biphasic pulses, but for the latter, a given percent recruitment was obtained with 20-30% lower E intensity ( P < 0.01), so that RSMS with biphasic pulses allowed at least 60% reduction of E intensity for recruitment of >70% of the cells. RSMS can be applied to improve stimulation efficiency in experiments with isolated cardiac myocytes, and may be a promising alternative for decreasing shock intensity requirements for cardioversion and defibrillation. PMID- 23033430 TI - Reducing the complexity of the N-FINDR algorithm for hyperspectral image analysis. AB - The N-FINDR algorithm for unmixing hyperspectral data is both popular and successful. However, opportunities for improving the algorithm exist, particularly to reduce its computational expense. Two approaches to achieve this are examined. First, the redundancy inherent in the determinant calculations at the heart of N-FINDR is reduced using an LDU decomposition to form two new algorithms, one based on the original N-FINDR algorithm and one based on the closely related Sequential N-FINDR algorithm. The second approach lowers complexity by reducing the repetition of the volume calculations by removing pixels unlikely to represent pure materials. This is accomplished at no additional cost through the reuse of the volume calculations inherent in the Sequential N-FINDR algorithm. Various thresholding methods for excluding pixels are considered. The impact of these modifications on complexity and the accuracy is examined on simulated and real data showing that the LDU-based approaches save considerable complexity, while pixel reduction methods, with appropriate threshold selection, can produce a favorable complexity-accuracy trade-off. PMID- 23033429 TI - System identification of physiological systems using short data segments. AB - System identification of physiological systems poses unique challenges, especially when the structure of the system under study is uncertain. Nonparametric techniques can be useful for identifying system structure, but these typically assume stationarity and require large amounts of data. Both of these requirements are often not easily obtained in the study of physiological systems. Ensemble methods for time-varying nonparametric estimation have been developed to address the issue of stationarity, but these require an amount of data that can be prohibitive for many experimental systems. To address this issue, we developed a novel algorithm that uses multiple short data segments. Using simulation studies, we showed that this algorithm produces system estimates with lower variability than previous methods when limited data are present. Furthermore, we showed that the new algorithm generates time-varying system estimates with lower total error than an ensemble method. Thus, this algorithm is well suited for the identification of physiological systems that vary with time or from which only short segments of stationary data can be collected. PMID- 23033431 TI - Image noise level estimation by principal component analysis. AB - The problem of blind noise level estimation arises in many image processing applications, such as denoising, compression, and segmentation. In this paper, we propose a new noise level estimation method on the basis of principal component analysis of image blocks. We show that the noise variance can be estimated as the smallest eigenvalue of the image block covariance matrix. Compared with 13 existing methods, the proposed approach shows a good compromise between speed and accuracy. It is at least 15 times faster than methods with similar accuracy, and it is at least two times more accurate than other methods. Our method does not assume the existence of homogeneous areas in the input image and, hence, can successfully process images containing only textures. PMID- 23033432 TI - Neural PID Control of Robot Manipulators With Application to an Upper Limb Exoskeleton. AB - In order to minimize steady-state error with respect to uncertainties in robot control, proportional-integral-derivative (PID) control needs a big integral gain, or a neural compensator is added to the classical proportional-derivative (PD) control with a large derivative gain. Both of them deteriorate transient performances of the robot control. In this paper, we extend the popular neural PD control into neural PID control. This novel control is a natural combination of industrial linear PID control and neural compensation. The main contributions of this paper are semiglobal asymptotic stability of the neural PID control and local asymptotic stability of the neural PID control with a velocity observer which are proved with standard weight training algorithms. These conditions give explicit selection methods for the gains of the linear PID control. An experimental study on an upper limb exoskeleton with this neural PID control is addressed. PMID- 23033433 TI - Toward Efficient Computation of the Dempster-Shafer Belief Theoretic Conditionals. AB - Dempster-Shafer (DS) belief theory provides a convenient framework for the development of powerful data fusion engines by allowing for a convenient representation of a wide variety of data imperfections. The recent work on the DS theoretic (DST) conditional approach, which is based on the Fagin-Halpern (FH) DST conditionals, appears to demonstrate the suitability of DS theory for incorporating both soft (generated by human-based sensors) and hard (generated by physics-based sources) evidence into the fusion process. However, the computation of the FH conditionals imposes a significant computational burden. One reason for this is the difficulty in identifying the FH conditional core, i.e., the set of propositions receiving nonzero support after conditioning. The conditional core theorem (CCT) in this paper redresses this shortcoming by explicitly identifying the conditional focal elements with no recourse to numerical computations, thereby providing a complete characterization of the conditional core. In addition, we derive explicit results to identify those conditioning propositions that may have generated a given conditional core. This "converse" to the CCT is of significant practical value for studying the sensitivity of the updated knowledge base with respect to the evidence received. Based on the CCT, we also develop an algorithm to efficiently compute the conditional masses (generated by FH conditionals), provide bounds on its computational complexity, and employ extensive simulations to analyze its behavior. PMID- 23033434 TI - Corrections to "Finite-Time Attitude Tracking Control for Spacecraft Using Terminal Sliding Model and Chebyshev Neural Network". PMID- 23033435 TI - Decision Making and Finite-Time Motion Control for a Group of Robots. AB - This paper deals with the problem of odor source localization by designing and analyzing a decision-control system (DCS) for a group of robots. In the decision level, concentration magnitude information and wind information detected by robots are used to predict a probable position of the odor source. Specifically, the idea of particle swarm optimization is introduced to give a probable position of the odor source in terms of concentration magnitude information. Moreover, an observation model of the position of the odor source is built according to wind information, and a Kalman filter is used to estimate the position of the odor source, which is combined with the position obtained by using concentration magnitude information in order to make a decision on the position of the odor source. In the control level, two types of the finite-time motion control algorithms are designed; one is a finite-time parallel motion control algorithm, while the other is a finite-time circular motion control algorithm. Precisely, a nonlinear finite-time consensus algorithm is first proposed, and a Lyapunov approach is used to analyze the finite-time convergence of the proposed consensus algorithm. Then, on the basis of the proposed finite-time consensus algorithm, a finite-time parallel motion control algorithm, which can control the group of robots to trace the plume and move toward the probable position of odor source, is derived. Next, a finite-time circular motion control algorithm, which can enable the robot group to circle the probable position of the odor source in order to search for odor clues, is also developed. Finally, the performance capabilities of the proposed DCS are illustrated through the problem of odor source localization. PMID- 23033436 TI - Accurate coronary centerline extraction, caliber estimation and catheter detection in angiographies. AB - Segmentation of coronary arteries in X-Ray angiography is a fundamental tool to evaluate arterial diseases and choose proper coronary treatment. The accurate segmentation of coronary arteries has become an important topic for the registration of different modalities which allows physicians rapid access to different medical imaging information from Computed Tomography (CT) scans or Magnetic Resonance Imaging (MRI). In this paper, we propose an accurate fully automatic algorithm based on Graph-cuts for vessel centerline extraction, caliber estimation, and catheter detection. Vesselness, geodesic paths, and a new multi scale edgeness map are combined to customize the Graph-cuts approach to the segmentation of tubular structures, by means of a global optimization of the Graph-cuts energy function. Moreover, a novel supervised learning methodology that integrates local and contextual information is proposed for automatic catheter detection. We evaluate the method performance on three datasets coming from different imaging systems. The method performs as good as the expert observer w.r.t. centerline detection and caliber estimation. Moreover, the method discriminates between arteries and catheter with an accuracy of 96.5%, sensitivity of 72%, and precision of 97.4%. PMID- 23033437 TI - Distributed system for cognitive stimulation over interactive TV. AB - This paper details the full design, implementation and validation of an e-health service in order to improve the community health care services for patients with cognitive disorders. Specifically, the new service allows Parkinson's disease patients benefit from the possibility of doing Cognitive Stimulation Therapy at home by using a familiar device such as a TV set. Its use instead a PC could be a major advantage for some patients whose lack of familiarity with the use of a PC means that they can do therapy only in the presence of a therapist. For these patients this solution could bring about a great improvement in their autonomy. At the same time, this service provides therapists with the ability to conduct follow-up of therapy sessions via the web, benefiting from greater and easier control of the therapy exercises performed by patients and allowing them to customize new exercises in accordance with the particular needs of each patient. As a result, this kind of cognitive stimulation therapy is considered to be a complement of other therapies oriented to Parkinson patients. Further, with small changes, the system could be useful for patients with a different cognitive disease such as Alzheimers or Mild Cognitive Impairment. PMID- 23033438 TI - Regenerative scaffold electrodes for peripheral nerve interfacing. AB - Advances in neural interfacing technology are required to enable natural, thought driven control of a prosthetic limb. Here, we describe a regenerative electrode design in which a polymer-based thin-film electrode array is integrated within a thin-film sheet of aligned nanofibers, such that axons regenerating from a transected peripheral nerve are topographically guided across the electrode recording sites. Cultures of dorsal root ganglia were used to explore design parameters leading to cellular migration and neurite extension across the nanofiber/electrode array boundary. Regenerative scaffold electrodes (RSEs) were subsequently fabricated and implanted across rat tibial nerve gaps to evaluate device recording capabilities and influence on nerve regeneration. In 20 of these animals, regeneration was compared between a conventional nerve gap model and an amputation model. Characteristic shaping of regenerated nerve morphology around the embedded electrode array was observed in both groups, and regenerated axon profile counts were similar at the eight week end point. Implanted RSEs recorded evoked neural activity in all of these cases, and also in separate implantations lasting up to five months. These results demonstrate that nanofiber-based topographic cues within a regenerative electrode can influence nerve regeneration, to the potential benefit of a peripheral nerve interface suitable for limb amputees. PMID- 23033439 TI - Artificial redirection of sensation from prosthetic fingers to the phantom hand map on transradial amputees: vibrotactile versus mechanotactile sensory feedback. AB - This work assesses the ability of transradial amputees to discriminate multi-site tactile stimuli in sensory discrimination tasks. It compares different sensory feedback modalities using an artificial hand prosthesis in: 1) a modality matched paradigm where pressure recorded on the five fingertips of the hand was fed back as pressure stimulation on five target points on the residual limb; and 2) a modality mismatched paradigm where the pressures were transformed into mechanical vibrations and fed back. Eight transradial amputees took part in the study and were divided in two groups based on the integrity of their phantom map; group A had a complete phantom map on the residual limb whereas group B had an incomplete or nonexisting map. The ability in localizing stimuli was compared with that of 10 healthy subjects using the vibration feedback and 11 healthy subjects using the pressure feedback (in a previous study), on their forearms, in similar experiments. Results demonstrate that pressure stimulation surpassed vibrotactile stimulation in multi-site sensory feedback discrimination. Furthermore, we demonstrate that subjects with a detailed phantom map had the best discrimination performance and even surpassed healthy participants for both feedback paradigms whereas group B had the worst performance overall. Finally, we show that placement of feedback devices on a complete phantom map improves multi-site sensory feedback discrimination, independently of the feedback modality. PMID- 23033440 TI - Quantitative approaches of dynamic FDG-PET and PET/CT studies (dPET/CT) for the evaluation of oncological patients. AB - OBJECTIVES: The use of dynamic positron emission tomography/computed tomography (dPET/CT) studies with [18F]deoxyglucose (FDG) in oncological patients is limited and primarily confined to research protocols. A more widespread application is, however, desirable, and may help to assess small therapeutic effects early after therapy as well as to differentiate borderline differences between tumour and non tumour lesions, e.g., lipomas versus low-grade liposarcomas. The aim is to present quantification approaches that can be used for the evaluation of dPET/CT series in combination with parametric imaging and to demonstrate the feasibility with regard to tumour diagnostics and therapy management. METHODS: A 60-min data acquisition and short acquisition protocols (20-min dynamic series and a static image 60 min post injection) are discussed. A combination of a modified two tissue compartment model and non-compartmental approaches from the chaos theory (fractal dimension of the time-activity curves) are presented. Fused PET/CT images as well as regression-based parametric images fused with CT or with PET/standardised uptake value images are demonstrated for the exact placement of volumes of interest. RESULTS: The two-tissue compartmental method results in the calculation of 5 kinetic parameters, the fractional blood volume VB (known also as the distribution volume), and the transport rates k1 to k4. Furthermore, the influx according to Patlak can be calculated from the transport rates. The fractal dimension of the time-activity curves describes the heterogeneity of the tracer distribution. The use of the regression-based parametric images of FDG helps to visualise the transport/perfusion and the transport/phosphorylation dependent FDG uptake, and adds a new dimension to the existing conventional PET or PET/CT images. CONCLUSIONS: More sophisticated quantification methods and dedicated software as well as high computational power and faster acquisition protocols can facilitate the assessment of dPET/CT, and may find use in clinical routine, in particular for the assessment of early therapeutic effects or new treatment protocols in combination with the new generation of PET/CT scanners. PMID- 23033441 TI - Unexpected dissemination patterns in lymphoma progression revealed by serial imaging within a murine lymph node. AB - Non-Hodgkin lymphoma (NHL) is a heterogeneous and highly disseminated disease, but the mechanisms of its growth and dissemination are not well understood. Using a mouse model of this disease, we used multimodal imaging, including intravital microscopy (IVM) combined with bioluminescence, as a powerful tool to better elucidate NHL progression. We injected enhanced green fluorescent protein and luciferase-expressing EMU-Myc/Arf(-/-) (Cdkn2a(-/-)) mouse lymphoma cells (EL Arf(-/-)) into C57BL/6NCrl mice intravenously. Long-term observation inside a peripheral lymph node was enabled by a novel lymph node internal window chamber technique that allows chronic, sequential lymph node imaging under in vivo physiologic conditions. Interestingly, during early stages of tumor progression we found that few if any lymphoma cells homed initially to the inguinal lymph node (ILN), despite clear evidence of lymphoma cells in the bone marrow and spleen. Unexpectedly, we detected a reproducible efflux of lymphoma cells from spleen and bone marrow, concomitant with a massive and synchronous influx of lymphoma cells into the ILN, several days after injection. We confirmed a coordinated efflux/influx of tumor cells by injecting EL-Arf(-/-) lymphoma cells directly into the spleen and observing a burst of lymphoma cells, validating that the burst originated in organs remote from the lymph nodes. Our findings argue that in NHL an efflux of tumor cells from one disease site to another, distant site in which they become established occurs in discrete bursts. PMID- 23033442 TI - Characterizing intonation deficit in motor speech disorders: an autosegmental metrical analysis of spontaneous speech in hypokinetic dysarthria, ataxic dysarthria, and foreign accent syndrome. AB - PURPOSE: The autosegmental-metrical (AM) framework represents an established methodology for intonational analysis in unimpaired speaker populations but has found little application in describing intonation in motor speech disorders (MSDs). This study compared the intonation patterns of unimpaired participants (CON) and those with Parkinson's disease (PD), ataxic dysarthria (AT), and foreign accent syndrome (FAS) to evaluate the approach's potential for distinguishing types of MSDs from each other and from unimpaired speech. METHOD: Spontaneous speech from 8 PD, 8 AT, 4 FAS, and 10 CON speakers were analyzed in relation to inventory and prevalence of pitch patterns, accentuation, and phrasing. Acoustic-phonetic baseline measures (maximum-phonation-duration, speech rate, and F0-variability) were also performed. RESULTS: The analyses yielded differences between MSD and CON groups and between the clinical groups in regard to prevalence, accentuation, and phrasing. AT and FAS speakers used more rising and high pitch accents than PD and CON speakers. The AT group used the highest number of pitch accents per phrase, and all 3 MSD groups produced significantly shorter phrases than the CON group. CONCLUSIONS: The study succeeded in differentiating MSDs on the basis of intonational performances by using the AM approach, thus, demonstrating its potential for charting intonational profiles in clinical populations. PMID- 23033443 TI - Apraxia of speech: concepts and controversies. AB - PURPOSE: This article was written as an editorial to a collection of original articles on apraxia of speech (AOS) in which some of the more recent advancements in the understanding of this syndrome are discussed. It covers controversial issues concerning the theoretical foundations of AOS. Our approach was motivated by a change of perspective on motor speech that has taken place in neurobiology, neurolinguistics, phonology, and phonetics during the past few decades. METHOD: The literature on AOS is reviewed from 3 different but overlapping perspectives that is, a disconnection, a motor memory, and a fine motor skill perspective. Separate sections are devoted to the delimitations of AOS from oral facial apraxia, dysarthria, and phonological impairment. CONCLUSIONS: We conclude that many of the still unresolved conceptual issues about AOS arise from an underspecification of existing models of spoken language production. We suggest that phonological and motor impairments of sound production should be studied by an integrated approach. PMID- 23033444 TI - Toward a quantitative basis for assessment and diagnosis of apraxia of speech. AB - PURPOSE: We explored the reliability and validity of 2 quantitative approaches to document presence and severity of speech properties associated with apraxia of speech (AOS). METHOD: A motor speech evaluation was administered to 39 individuals with aphasia. Audio-recordings of the evaluation were presented to 3 experienced clinicians to determine AOS diagnosis and to rate severity of 11 speech dimensions. Additionally, research assistants coded 11 operationalized metrics of articulation, fluency, and prosody in the same speech samples and in recordings from 20 neurologically healthy participants. RESULTS: Agreement among the 3 clinicians was limited for both AOS diagnosis and perceptual scaling, but inter-observer reliability for the operationalized metrics was strong. The relationships between most operationalized metrics and mean severity ratings for corresponding perceptual dimensions were moderately strong and statistically significant. Both perceptual scaling and operationalized quantification approaches were sensitive to the presence or absence of AOS. CONCLUSIONS: Perceptual scaling and operationalized metrics are promising quantification techniques that can help establish diagnostic transparency for AOS. However, because satisfactory reliability cannot be assumed for scaling techniques, effective training and calibration procedures should be implemented. Operationalized metrics show strong potential for enhancing diagnostic objectivity and sensitivity. PMID- 23033445 TI - The diagnosis and understanding of apraxia of speech: why including neurodegenerative etiologies may be important. AB - PURPOSE: To discuss apraxia of speech (AOS) as it occurs in neurodegenerative disease (progressive AOS [PAOS]) and how its careful study may contribute to general concepts of AOS and help refine its diagnostic criteria. METHOD: The article summarizes our current understanding of the clinical features and neuroanatomical and pathologic correlates of PAOS and its relationship to primary progressive aphasia (PPA). It addresses similarities and differences between PAOS and stroke-induced AOS that may be relevant to improving our understanding of AOS in general. CONCLUSIONS: PAOS is clinical disorder that should be distinguished from PPA. Its recognition is important to clinical care provided by speech language pathologists, but it also has implications for neurologic localization and diagnosis as well as prediction of underlying pathology and histochemistry. The clinical features of PAOS and stroke-induced AOS have not been explicitly compared, but they may not be identical because PAOS does not follow a vascular distribution, the brunt of cortical pathology is in the premotor and supplementary motor area, and its onset (rather than acute) is slowly progressive with potential for adaptation to gradual impairment. Careful description and study of PAOS may be a valuable source of information for refining our understanding of AOS in general. PMID- 23033446 TI - Speech planning happens before speech execution: online reaction time methods in the study of apraxia of speech. AB - PURPOSE: The purpose of this article is to present an argument for the use of online reaction time (RT) methods to the study of apraxia of speech (AOS) and to review the existing small literature in this area and the contributions it has made to our fundamental understanding of speech planning (deficits) in AOS. METHOD: Following a brief description of limitations of offline perceptual methods, we provide a narrative review of various types of RT paradigms from the (speech) motor programming and psycholinguistic literatures and their (thus far limited) application with AOS. CONCLUSION: On the basis of the review of the literature, we conclude that with careful consideration of potential challenges and caveats, RT approaches hold great promise to advance our understanding of AOS, in particular with respect to the speech planning processes that generate the speech signal before initiation. A deeper understanding of the nature and time course of speech planning and its disruptions in AOS may enhance diagnosis and treatment for AOS. RESULTS: Only a handful of published studies on apraxia of speech have used reaction time methods. However, these studies have provided deeper insight into speech planning impairments in AOS based on a variety of experimental paradigms. PMID- 23033447 TI - Patterns of impairments in AOS and mechanisms of interaction between phonological and phonetic encoding. AB - PURPOSE: One reason why the diagnosis of apraxia of speech (AOS) and its underlying impairment are often debated may lie in the fact that most patients do not display pure patterns of AOS. Mixed patterns are clearly acknowledged at other levels of impairment (e.g., lexical-semantic and lexical-phonological), and they have contributed to debate about the degree of interaction between encoding levels; by contrast, mixed impairments and mechanisms of interaction are less acknowledged at the levels of phonological and phonetic processes. Here, the author aims at bringing together empirical evidence in favor of an interaction between phonological and phonetic encoding and of the predominance of mixed patterns of impairment over pure phonetic impairment. METHOD: The author reviews empirical results from acoustic and psycholinguistic studies, both with healthy speakers and speakers with brain damage, favoring independent phonological and phonetic encoding and separable impairments as well as recent research pointing to an interaction between phonological and phonetic encoding processes and overlapping patterns of impairments. CONCLUSIONS: Acknowledging interaction between phonological and phonetic processing has clear consequences on the definition of patterns of impairment. In particular, phonetic errors have not necessarily a phonetic origin, and most patterns of impairment are bound to display both phonological and phonetic features. PMID- 23033448 TI - Error variability in apraxia of speech: a matter of controversy. AB - PURPOSE: Error variability has traditionally been considered a hallmark of apraxia of speech (AOS). However, in some of the current AOS literature, relatively invariable error patterns are claimed as a mandatory criterion for a diagnosis of AOS. This paradigm shift has far-reaching consequences for our understanding of the disorder and for its (differential) diagnosis. Against the background of this controversy, the present article aims to further examine error variability in AOS. METHOD: Four patients with relatively pure, mild-to-moderate AOS participated in the study. They repeated 8 target words in 2 different phrase contexts, 10 times each. Error analyses were based on phonetic transcription. Error variability was determined using several measures of (a) consistency of error occurrence and (b) consistency of error type. RESULTS: All patients produced highly inconsistent reactions across multiple trials in some of the target words. However, other words were more consistently accurate or inaccurate. Several factors influencing error variability were identified. CONCLUSIONS: Because this study has disclosed clear indications of variable behavior in AOS, diagnostic guidelines claiming error consistency as a mandatory criterion cannot be maintained. Because error variability is difficult to operationalize, we recommend to no longer use (in)consistency as a strict diagnostic marker of AOS. PMID- 23033449 TI - Apraxia of speech and phonological errors in the diagnosis of nonfluent/agrammatic and logopenic variants of primary progressive aphasia. AB - PURPOSE: The International Consensus Criteria for the diagnosis of primary progressive aphasia (PPA; Gorno-Tempini et al., 2011) propose apraxia of speech (AOS) as 1 of 2 core features of nonfluent/agrammatic PPA and propose phonological errors or absence of motor speech disorder as features of logopenic PPA. We investigated the sensitivity and specificity of AOS and phonological errors as markers for these variants and also investigated the relationship between AOS, phonological errors, and findings on C-labeled Pittsburgh Compound B (PiB)-positron emission tomography (PET) imaging associated with putative Alzheimer-type pathology. METHOD: Connected speech and word repetition in 23 people with PPA who underwent PiB-PET imaging were rated for apraxic versus phonological disruption by 1 rater who was blind to diagnosis and by 2 raters who were blind to PiB-PET results. RESULTS: Apraxic characteristics had high sensitivity for nonfluent/agrammatic PPA, and phonological errors had high sensitivity for logopenic PPA; however, phonological errors showed lower specificity for logopenic PPA. On PiB imaging, 8 of 9 people with predominant AOS returned negative results, whereas participants with no or questionable AOS with and without phonological errors returned positive results. CONCLUSIONS: Attention to AOS and phonological errors may help counter some of the inherent limitations of diagnosis-by-exclusion in the current International Consensus Criteria for diagnosing PPA. PMID- 23033450 TI - Phonological and motor errors in individuals with acquired sound production impairment. AB - PURPOSE: This study aimed to compare sound production errors arising due to phonological processing impairment with errors arising due to motor speech impairment. METHOD: Two speakers with similar clinical profiles who produced similar consonant cluster simplification errors were examined using a repetition task. We compared both overall accuracy and acoustic details of hundreds of productions with target consonant clusters to tokens with singletons. Changes in accuracy over the course of the study were also compared. RESULTS: In target words with consonant cluster simplification, the individual whose errors reflected phonological impairment produced articulatory timing consistent with singleton onsets. These productions improved when resyllabification was possible, but error rates were not affected by exposure. In contrast, the individual with motoric-based errors produced simplifications that contained the articulatory timing associated with clusters. Accuracy was not affected by the ability to resyllabify, but it did significantly improve following repeated production. CONCLUSIONS: Our findings reveal clear differences between errors arising in phonological processing and in motor planning that reflect the underlying systems. The changes over the course of the study suggest that error types with different sources are responsive to different intervention strategies. PMID- 23033451 TI - Imaging paradigms in assessment of rectal carcinoma: loco-regional and distant staging. AB - The role of imaging in the management of rectal malignancy has progressively evolved and undergone several paradigm shifts. Unlike a few decades ago when the role of a radiologist was restricted at defining the longitudinal extent of the tumour with barium enema, recent advances in imaging techniques permit highly accurate locoregional and distant staging of the disease as well as prognostication on those who are likely to have a postoperative recurrence. Computed tomography (CT) has always been the mainstay of imaging when evaluating for distant metastasis, with the advent of positron emission tomography/CT improving its specificity. In rectal malignancy, it is the local extent of the disease that often influences the surgical decision making and need for neoadjuvant therapy. Although endoscopic ultrasound has been the traditional technique for determining the depth of tumour invasion, over the last decade magnetic resonance imaging (MRI) has emerged as a very effective tool for accurate T-staging. This review intends to address the status of various imaging modalities and their advantages and limitations in detection, pretreatment staging, and assessment of therapeutic efficacy in rectal cancer, with emphasis on MRI of high spatial resolution. PMID- 23033452 TI - Animal use and lessons learned in the U.S. High Production Volume Chemicals Challenge Program. AB - BACKGROUND: Launched by the U.S. Environmental Protection Agency (EPA) in 1998, the High Production Volume (HPV) Challenge Program was developed to address the perceived gap in basic hazard information for the 2,800 chemicals produced or imported into the United States in quantities of >= 1 million pounds per year. Health and environmental effects data obtained from either existing information or through new vertebrate animal testing were voluntarily submitted by chemical companies (sponsors) to the U.S. EPA. Despite the potential for extensive animal testing, animal welfare guidelines were not provided until after the start of the program. OBJECTIVES: We evaluated compliance with the animal welfare principles that arose from an agreement reached between the U.S. EPA and animal protection organizations and tracked the HPV program's use of animals for testing. DISCUSSION: Under a worst-case scenario, the HPV program had the potential to consume 3.5 million animals in new testing. After application of animal-saving measures, approximately 127,000 were actually used. Categorization of chemicals based on similar structure-activity and application of read-across, along with use of existing test data, were the most effective means of reducing animal testing. However, animal-saving measures were inconsistently used by both sponsors and the U.S. EPA. CONCLUSIONS: Lessons learned from the HPV program can be applied to future programs to minimize animal testing and promote more human relevant chemical risk assessment. PMID- 23033453 TI - Meat and heme iron intake and risk of squamous cell carcinoma of the upper aero digestive tract in the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - BACKGROUND: Evidence from prospective studies on intake of meat and fish and risk of squamous cell carcinoma (SCC) of the upper aero-digestive tract (UADT) is scarce. We prospectively investigated the association of meat and fish intake with risk of SCC of the UADT and the possible mechanism via heme iron in the large multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: Multivariable proportional hazards models were used to estimate relative risks (RR) of SCC of the UADT in relation to intake of total meat, as well as subtypes of meat, fish, and heme iron among 348,738 individuals from 7 European countries. RESULTS: During an average follow-up of 11.8 years, a total of 682 incident cases of UADT SCC were accrued. Intake of processed meat was positively associated with risk of SCC of the UADT in the total cohort [highest vs. lowest quintile: RR = 1.41; 95% confidence interval (CI) = 1.03 1.94], however, in stratified analyses, this association was confined to the group of current smokers (highest vs. lowest quintile: RR = 1.89; 95% CI = 1.22 2.93). Red meat, poultry, fish, and heme iron were not consistently related to UADT SCC. CONCLUSION: Higher intake of processed meat was positively associated with SCC of the UADT among smokers. Although this finding was stable in various sensitivity analyses, we cannot rule out residual confounding by smoking. Confirmation in future studies and identification of biologic mechanisms is warranted. IMPACT: Smokers may further increase their risk for SCC of the UADT if they additionally consume large amounts of processed meat. PMID- 23033454 TI - Variation in genes related to obesity, weight, and weight change and risk of contralateral breast cancer in the WECARE Study population. AB - BACKGROUND: Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation, and altered levels of adipose-derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight, and weight change are associated with CBC risk. METHODS: Variants in 20 genes [182 single-nucleotide polymorphisms (SNP)] involved in adipose tissue metabolism, energy balance, insulin resistance, and inflammation, as well as those identified through genome-wide association studies (GWAS) of BMI and type II-diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants [643 cases with CBC and 1,271 controls with unilateral breast cancer (UBC)] in the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression. RESULTS: After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor (ER) status did not alter these findings. CONCLUSION: Among women with early onset disease who survive a first breast cancer diagnosis, there was no association between variation in obesity-related genes and risk of CBC. IMPACT: Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer. PMID- 23033455 TI - Gender difference in systemic oxidative stress and antioxidant capacity in current and former heavy smokers. AB - BACKGROUND: Several studies suggested that women may be more susceptible to oxidative damage induced by cigarette smoking, but the role of smoking status and antioxidant capacity in gender difference in susceptibility to oxidative damage has not been well studied. METHODS: We conducted a cross-sectional analysis of the baseline data from 146 current and former heavy smokers enrolled in a chemoprevention trial to determine the gender difference in oxidative damage and antioxidant capacity. Oxidative DNA and lipid damage were assessed by urinary 8 hydroxy-2'-deoxyguanosine (8OHdG) and 8-isoprostaglandin F(2alpha) (8-iso PGF(2alpha)), respectively. The erythrocyte antioxidant enzymes and serum fat soluble antioxidants were measured to assess antioxidant capacity. RESULTS: Female smokers had significantly greater levels of 8OHdG and 8-iso-PGF(2alpha) than males but the gender difference was only significant in current smokers. No gender difference was noted in erythrocyte antioxidant enzymes, although female current smokers had significantly lower or a trend for lower antioxidant enzymes. Female smokers had higher serum beta-carotene than males. Biomarkers of oxidative damage did not correlate significantly with the antioxidant enzymes. Urinary 8OHdG did not correlate significantly with fat-soluble antioxidants. Inverse correlations were observed between urinary 8-iso-PGF(2alpha) and several serum carotenoids. CONCLUSION: Female current smokers have a greater extent of oxidative damage despite having higher serum levels of fat-soluble antioxidants. Lower erythrocyte antioxidant enzymes in female current smokers may contribute to the greater extent of oxidative damage. IMPACT: The study may help identify appropriate high-risk populations for interventions that attenuate oxidative damage and appropriate biomarkers for clinical studies in smokers. PMID- 23033456 TI - Comparison of geostatistical interpolation and remote sensing techniques for estimating long-term exposure to ambient PM2.5 concentrations across the continental United States. AB - BACKGROUND: A better understanding of the adverse health effects of chronic exposure to fine particulate matter (PM2.5) requires accurate estimates of PM2.5 variation at fine spatial scales. Remote sensing has emerged as an important means of estimating PM2.5 exposures, but relatively few studies have compared remote-sensing estimates to those derived from monitor-based data. OBJECTIVE: We evaluated and compared the predictive capabilities of remote sensing and geostatistical interpolation. METHODS: We developed a space-time geostatistical kriging model to predict PM2.5 over the continental United States and compared resulting predictions to estimates derived from satellite retrievals. RESULTS: The kriging estimate was more accurate for locations that were about 100 km from a monitoring station, whereas the remote sensing estimate was more accurate for locations that were > 100 km from a monitoring station. Based on this finding, we developed a hybrid map that combines the kriging and satellite-based PM2.5 estimates. CONCLUSIONS: We found that for most of the populated areas of the continental United States, geostatistical interpolation produced more accurate estimates than remote sensing. The differences between the estimates resulting from the two methods, however, were relatively small. In areas with extensive monitoring networks, the interpolation may provide more accurate estimates, but in the many areas of the world without such monitoring, remote sensing can provide useful exposure estimates that perform nearly as well. PMID- 23033457 TI - Climate change and older Americans: state of the science. AB - BACKGROUND: Older adults make up 13% of the U.S. population, but are projected to account for 20% by 2040. Coinciding with this demographic shift, the rate of climate change is accelerating, bringing rising temperatures; increased risk of floods, droughts, and wildfires; stronger tropical storms and hurricanes; rising sea levels; and other climate-related hazards. Older Americans are expected to be located in places that may be relatively more affected by climate change, including coastal zones and large metropolitan areas. OBJECTIVE: The objective of this review is to assess the vulnerability of older Americans to climate change and to identify opportunities for adaptation. METHODS: We performed an extensive literature survey and summarized key findings related to demographics; climate stressors relevant to older adults; factors contributing to exposure, sensitivity, and adaptive capacity; and adaptation strategies. DISCUSSION: A range of physiological and socioeconomic factors make older adults especially sensitive to and/or at risk for exposure to heat waves and other extreme weather events (e.g., hurricanes, floods, droughts), poor air quality, and infectious diseases. Climate change may increase the frequency or severity of these events. CONCLUSIONS: Older Americans are likely to be especially vulnerable to stressors associated with climate change. Although a growing body of evidence reports the adverse effects of heat on the health of older adults, research gaps remain for other climate-related risks. We need additional study of the vulnerability of older adults and the interplay of vulnerability, resilience, and adaptive responses to projected climate stressors. PMID- 23033458 TI - Antimicrobial resistance and pharmacodynamics of canine and feline pathogenic E. coli in the United States. AB - Percent resistance and minimum inhibitory concentrations (MIC) were described for canine (n = 301) and feline (n = 75) pathogenic Escherichia coli (E. coli) isolates solicited during May 2005 to Sep 2005 from the Clinical Pharmacology Laboratory at Auburn University (n = 165) or commercial diagnostic laboratories ([CDL]; n = 211) from four regions in the USA. Drugs tested were amoxicillin (AMX), amoxicillin trihydrate/clavulanate potassium (AMXC), cefpodoxime (CFP), doxycycline (DXY), enrofloxacin (ENR), gentamicin (GM) and trimethoprim sulfamethoxazole (TMS). Urinary isolates were most common (n = 174). Percent resistance was greatest for isolates from the respiratory tract, urine, and skin compared with the ear. Resistance was also greatest for samples sent from the south and central states compared with the western states (P <= 0.001). Percent resistance by drug was AMX (46 +/- 2.6%) > AMXC (37 +/- 2.5%) > CFP (21.8 +/- 2%) = DXY (22 +/- 2.1%) = ENR (20 +/- 2.1%) = TMS (19 +/- 2%) > GM (12 +/- 1.7%). There was a significant difference in resistance between the different antibiotic drugs (P <= 0.001). Population MIC distributions were bimodal, and MICs were highest in samples from the southern states (P <= 0.001). E. coli resistance may limit its empirical treatment. For susceptible isolates, AMX and AMXC may be least effective and TMS most effective. PMID- 23033459 TI - Ectopic ureters in male dogs: review of 16 clinical cases (1999-2007). AB - Ureteral ectopia is a well-described cause of urinary incontinence in female dogs, but this condition has not been completely characterized in male dogs. Sixteen male dogs with ectopic ureters were evaluated between Jan 1999 and Mar 2007. Male dogs were similar to female dogs with ectopic ureters in terms of breed, presenting complaint, age of onset, and bilateral nature of the ectopia. Diagnosis was made by expert interpretation of imaging techniques such as excretory urography and contrast-enhanced computed tomography (CT). Overall, 11 of 13 dogs that had surgical correction of ectopic ureters were incontinent preoperatively. Urinary continence was restored in 82% of those dogs. PMID- 23033460 TI - Systemic mycosis in three dogs from nonendemic regions. AB - Three dogs were examined for clinical signs ultimately attributed to systemic fungal infections. One dog was evaluated for chronic, ulcerated dermal lesions and lymphadenomegaly; one dog was examined for acute onset of unilateral blepharospasm; and one dog had diarrhea and hematochezia. Two of the dogs were diagnosed with blastomycosis (one with disseminated disease and the other with the disease localized to the left eye). The third dog was diagnosed with disseminated histoplasmosis. None of the dogs originated from, or had traveled to, typical regions endemic for these fungal diseases. All diagnoses were established from histopathology and either polymerase chain reaction (PCR) or cytology and culture. The two dogs diagnosed with blastomycosis were treated with either itraconazole or ketoconazole with apparent resolution of the infections. The dog with ocular involvement had an enucleation prior to beginning therapy. The dog diagnosed with histoplasmosis was euthanized without treatment. In patients with characteristic clinical features, systemic fungal infections should still be considered as differential diagnoses regardless of their travel history. PMID- 23033461 TI - Toxic shock syndrome in two dogs. AB - Two young, unrelated, spayed female Labrador retrievers were evaluated for severe, diffuse, generalized erythema and edema of the skin. Both dogs exhibited signs of disseminated intravascular coagulopathy and were euthanized. On postmortem examination, toxic shock syndrome (TSS) was diagnosed based on histopathology and supported by skin cultures. TSS is a rarely reported disease in veterinary medicine and can cause acute and profound clinical signs. Rapid recognition of this disease process and immediate treatment may improve the clinical outcome. PMID- 23033462 TI - Ultrasonographic evaluation of canine supraspinatus calcifying tendinosis. AB - Supraspinatus calcifying tendinosis is an uncommon finding in dogs. Although its radiographic appearance has been described previously, radiographs alone do not provide detailed information about the tendon parenchyma. Tendon ultrasonography has been widely applied for the diagnosis of human tendinosis, but it remains underused in dogs. This article reviews the ultrasonographic technique and variable appearance of canine supraspinatus calcifying tendinosis observed in 33 tendons. The ultrasonographic findings are described. The most common ultrasonographic finding was a hyperechoic area accompanied by distal acoustic shadowing. No relationship with bicipital tenosynovitis was found. A color Doppler examination was possible in only five of the tendons, revealing no blood flow in those tendons. There was evidence that the presence of a hypoechoic area surrounding the calcification was related to clinical signs of pain, suggesting an active inflammatory process. Ultrasonography was an excellent technique to evaluate lesions of the supraspinatus tendon and it revealed details not apparent on radiographs. PMID- 23033463 TI - Adrenocortical carcinoma in a dog with incomplete excision managed long-term with metastasectomy alone. AB - A 10 yr old bichon frise presented with a 3 mo history of polyuria, polydipsia, and hind limb weakness. Serum biochemistry revealed persistent hypokalemia. A left adrenal gland mass with right adrenal atrophy was detected ultrasonographically. Basal serum cortisol concentration was at the low end of normal (30 nmol/L; reference range, 30-140 nmol/L) and adrenocorticotropic hormone (ACTH)-stimulated cortisol concentration was low (199 nmol/L; reference range, 220-470 nmol/L). Basal serum 17-alpha-OH progesterone concentration was also low (0.03 ng/mL; reference range, 0.06-0.30 ng/mL), but the aldosterone concentration 2 hr after the ACTH stimulation was elevated (> 3,000 pmol/L; reference range, 197-2,103 pmol/L). A left adrenalectomy and nephrectomy were performed. Histopathology revealed an adrenocortical zona glomerulosa carcinoma. Surgical excision was considered incomplete; however, clinical signs resolved. Two years later, basal and ACTH-stimulated aldosterone concentrations were elevated. Computed tomography demonstrated a mass effect in the liver. The left lateral and left medial hepatic lobes were removed. Histopathology confirmed metastatic endocrine carcinoma. The patient was stable 1,353 days postsurgically (when this report was prepared). This is the first case report of a metastatic adrenal carcinoma that was successfully managed surgically for > 3 yr. PMID- 23033464 TI - A review of 18 cases of feline colonic adenocarcinoma treated with subtotal colectomies and adjuvant carboplatin. AB - Feline colonic adenocarcinoma is a locally invasive, highly metastatic tumor that is most often treated with wide surgical excision (subtotal colectomy) and systemic chemotherapy either with or without nonsteroidal anti-inflammatory medications. In this retrospective study, the outcome of subtotal colectomy and adjuvant carboplatin in 18 client-owned cats is described. The median carboplatin dose was 200 mg/m(2) (range, 200-254 mg/m(2)) q 4 wk with a median of five doses/cat (range was two to seven doses/cat). Limited toxicities were noted. Positive prognostic factors for the disease-free interval included cats that had weight loss as a presenting sign (P < 0.036) and negative prognostic factors for median survival included nodal and distant metastasis (178 versus 328 days and 200 versus 340 days, respectively). The median disease-free interval was 251 days (range, 37-528 days) and the median survival time was 269 days (range, 40-533 days). Subtotal colectomy and adjuvant carboplatin is a safe and potentially effective treatment for cats with colonic adenocarcinoma. PMID- 23033465 TI - Biomechanical testing of locking and nonlocking plates in the canine scapula. AB - Locking plates have been shown to offer improved fixation in fractures involving either osteoporotic bone or bone with lesser screw pullout strength, such as thin and flat bones. Fractures of the scapular body are one type of fracture where the screw pullout strength using conventional plate fixation may not be sufficient to overcome physiologic forces. The purpose of this study was to compare the pullout strengths of locking plates to conventional nonlocking plates in the canine scapula. A 2.7 mm string of pearls plate (SOP) and a 2.7 mm limited contact dynamic compression plate (LC-DCP) were applied with similar divergent screws to the supraspinatus fossa of the scapula. Forces perpendicular to the plates were applied and both the loads at failure and modes of failure were recorded. No differences were noted in loads at failure between the two plating systems. Although the modes of failure were not significantly different, the SOP constructs tended to fail more often by bone slicing and coring, whereas the LC DCP constructs failed primarily by screw stripping. Neither of the plate systems used in this study demonstrated a distinct mechanical advantage. The application and limitations of locking plate systems in various clinical situations require further study. PMID- 23033466 TI - Use of procainamide for conversion of acute onset AF following pericardiocentesis in a dog. AB - A 9 yr old spayed female golden retriever was evaluated for anorexia and suspected gastric dilatation. Subsequent evaluation the following day determined the dog to have pericardial effusion. Muffled heart sounds and jugular pulses were noted on physical exam, and the dog was diagnosed with pleural and pericardial effusion. A sinus rhythm with a rate of 142 beats/min was documented on a surface electrocardiogram (EKG). Following pericardiocentesis, the heart rate increased to 260 beats/min, the rhythm became irregular, and the systemic blood pressure decreased. Atrial fibrillation (AF) was confirmed by EKG. Procainamide was administered IV over 15 min, resulting in successful conversion of AF to sinus rhythm and clinical improvement. Procainamide is one of several antiarrhythmic medications that are used for the conversion of acute AF in humans; however, its utility and efficacy in dogs in the setting of AF has not previously been reported. This case highlights a unique complication of performing a pericardiocentesis that requires immediate treatment and describes a potential treatment option for the conversion of acute AF in dogs. PMID- 23033467 TI - Primary ovarian teratoma and GCT with intra-abdominal metastasis in a dog. AB - This report describes the simultaneous occurrence of an ovarian teratoma and a granulosa cell tumor (GCT) with intra-abdominal metastasis in a 1.5 yr old female Doberman pinscher. At surgery, a 20 cm, smooth, intact mass associated with the left ovary and multiple 1-2 cm irregular masses in the broad ligament were found. The masses were surgically removed and submitted for histopathology. A histologic diagnosis of a teratoma and a GCT with broad ligament metastasis was made. Further treatment was elected by the owner and included two cycles of carboplatin therapy. The dog was euthanized 6 wk postoperatively for signs related to metastasis and dyspnea. Teratoma of the ovary, although it contains derivatives of all three embryonic germ cell layers, rarely presents together with either ovarian epithelial or sex cord-stromal tumors. To the authors' knowledge, this is the first reported case of an ovarian teratoma coexisting with a primary GCT with intra-abdominal metastasis in the same ovary in a dog. PMID- 23033468 TI - Mineralocorticoid before glucocorticoid deficiency in a dog with primary hypoadrenocorticism and hypothyroidism. AB - A dog with an unexpected presentation of primary hypoadrenocorticism was evaluated for clinical signs and electrolyte abnormalities characteristic of Addison's disease. Although the initial adrenocorticotropic hormone (ACTH) stimulation test documented serum cortisol concentrations within the reference range, subsequent assessments confirmed hypoaldosteronism. Mineralocorticoid replacement promptly normalized electrolytes and transiently improved clinical illness. Six weeks after initial ACTH stimulation testing, the dog became glucocorticoid deficient. Concurrent primary hypothyroidism was also documented. Hypoaldosteronism preceding hypocortisolemia is a unique presentation of canine Addison's disease. PMID- 23033469 TI - Thermal control of microbial development and virulence: molecular mechanisms of microbial temperature sensing. AB - Temperature is a critical and ubiquitous environmental signal that governs the development and virulence of diverse microbial species, including viruses, archaea, bacteria, fungi, and parasites. Microbial survival is contingent upon initiating appropriate responses to the cellular stress induced by severe environmental temperature change. In the case of microbial pathogens, development and virulence are often coupled to sensing host physiological temperatures. As such, microbes have developed diverse molecular strategies to sense fluctuations in temperature, and nearly all cellular molecules, including proteins, lipids, RNA, and DNA, can act as thermosensors that detect changes in environmental temperature and initiate relevant cellular responses. The myriad of molecular mechanisms by which microbes sense and respond to temperature reveals an elegant repertoire of strategies to orchestrate cellular signaling, developmental programs, and virulence with spatial and temporal environmental cues. PMID- 23033470 TI - Role of CTR4 in the Virulence of Cryptococcus neoformans. AB - While research has identified an important contribution for metals, such as iron, in microbial pathogenesis, the roles of other transition metals, such as copper, remain mostly unknown. Recent evidence points to a requirement for copper homeostasis in the virulence of Cryptococcus neoformans based on a role for a CUF1 copper regulatory factor in mouse models and in a human patient cohort. C. neoformans is an important fungal pathogen that results in an estimated 600,000 AIDS-related deaths yearly. In the present studies, we found that a C. neoformans mutant lacking the CUF1-dependent copper transporter, CTR4, grows normally in rich medium at 37 degrees C but has reduced survival in macrophages and attenuated virulence in a mouse model. This reduced survival and virulence were traced to a growth defect under nutrient-restricted conditions. Expression studies using a full-length CTR4-fluorescent fusion reporter construct demonstrated robust expression in macrophages, brain, and lung, the latter shown by ex vivo fluorescent imaging. Inductively coupled mass spectroscopy (ICP-MS) was used to probe the copper quota of fungal cells grown in defined medium and recovered from brain, which suggested a role for a copper-protective function of CTR4 in combination with cell metallothioneins under copper-replete conditions. In summary, these data suggest a role for CTR4 in copper-related homeostasis and subsequently in fungal virulence. IMPORTANCE: Crytococcus neoformans is a significant global fungal pathogen, and copper homeostasis is a relatively unexplored aspect of microbial pathogenesis that could lead to novel therapeutics. Previous studies correlated expression levels of a Ctr4 copper transporter to development of meningoencephalitis in a patient cohort of solid organ transplants, but a direct role for Ctr4 in mammalian pathogenesis has not been demonstrated. The present studies utilize a Deltactr4 mutant strain which revealed an important role for CTR4 in C. neoformans infections in mice and relate the gene product to homeostatic control of copper and growth under nutrient-restricted conditions. Robust expression levels of CTR4 during fungal infection were exploited to demonstrate expression and lung cryptococcal disease using ex vivo fluorescence imaging. In summary, these studies are the first to directly demonstrate a role for a copper transporter in fungal disease and provide an ex vivo imaging tool for further study of cryptococcal gene expression and pathogenesis. PMID- 23033471 TI - Occurrence and evolution of the paralogous zinc metalloproteases IgA1 protease, ZmpB, ZmpC, and ZmpD in Streptococcus pneumoniae and related commensal species. AB - The distribution, genome location, and evolution of the four paralogous zinc metalloproteases, IgA1 protease, ZmpB, ZmpC, and ZmpD, in Streptococcus pneumoniae and related commensal species were studied by in silico analysis of whole genomes and by activity screening of 154 representatives of 20 species. ZmpB was ubiquitous in the Mitis and Salivarius groups of the genus Streptococcus and in the genera Gemella and Granulicatella, with the exception of a fragmented gene in Streptococcus thermophilus, the only species with a nonhuman habitat. IgA1 protease activity was observed in all members of S. pneumoniae, S. pseudopneumoniae, S. oralis, S. sanguinis, and Gemella haemolysans, was variably present in S. mitis and S. infantis, and absent in S. gordonii, S. parasanguinis, S. cristatus, S. oligofermentans, S. australis, S. peroris, and S. suis. Phylogenetic analysis of 297 zmp sequences and representative housekeeping genes provided evidence for an unprecedented selection for genetic diversification of the iga, zmpB, and zmpD genes in S. pneumoniae and evidence of very frequent intraspecies transfer of entire genes and combination of genes. Presumably due to their adaptation to a commensal lifestyle, largely unaffected by adaptive mucosal immune factors, the corresponding genes in commensal streptococci have remained conserved. The widespread distribution and significant sequence diversity indicate an ancient origin of the zinc metalloproteases predating the emergence of the humanoid species. zmpB, which appears to be the ancestral gene, subsequently duplicated and successfully diversified into distinct functions, is likely to serve an important but yet unknown housekeeping function associated with the human host. IMPORTANCE: The paralogous zinc metalloproteases IgA1 protease, ZmpB, ZmpC, and ZmpD have been identified as crucial for virulence of the human pathogen Streptococcus pneumoniae. This study maps the presence of the corresponding genes and enzyme activities in S. pneumoniae and in related commensal species of the genera Streptococcus, Gemella, and Granulicatella. The distribution, genome location, and sequence diversification indicate that zmpB is the ancestral gene predating the evolution of today's humanoid species. The ZmpB protease may play an important but yet unidentified role in the association of streptococci of the Mitis and Salivarius groups with their human host, as it is ubiquitous in these two groups, except for a fragmented gene in Streptococcus thermophilus, the only species not associated with humans. The relative sequence diversification of the IgA1 protease, ZmpB, and ZmpD is striking evidence of differences in selection for diversification of these surface-exposed proteins in the pathogen S. pneumoniae compared to the closely related commensal streptococci. PMID- 23033472 TI - Toward a semisynthetic stress response system to engineer microbial solvent tolerance. AB - Strain tolerance to toxic metabolites is an important trait for many biotechnological applications, such as the production of solvents as biofuels or commodity chemicals. Engineering a complex cellular phenotype, such as solvent tolerance, requires the coordinated and tuned expression of several genes. Using combinations of heat shock proteins (HSPs), we engineered a semisynthetic stress response system in Escherichia coli capable of tolerating high levels of toxic solvents. Simultaneous overexpression of the HSPs GrpE and GroESL resulted in a 2 fold increase in viable cells (CFU) after exposure to 5% (vol/vol) ethanol for 24 h. Co-overexpression of GroESL and ClpB on coexisting plasmids resulted in 1,130%, 78%, and 25% increases in CFU after 24 h in 5% ethanol, 1% n-butanol, and 1% i-butanol, respectively. Co-overexpression of GrpE, GroESL, and ClpB on a single plasmid produced 200%, 390%, and 78% increases in CFU after 24 h in 7% ethanol, 1% n-butanol, or 25% 1,2,4-butanetriol, respectively. Overexpression of other autologous HSPs (DnaK, DnaJ, IbpA, and IbpB) alone or in combinations failed to improve tolerance. Expression levels of HSP genes, tuned through inducible promoters and the plasmid copy number, affected the effectiveness of the engineered stress response system. Taken together, these data demonstrate that tuned co-overexpression of GroES, GroEL, ClpB, and GrpE can be engaged to engineer a semisynthetic stress response system capable of greatly increasing the tolerance of E. coli to solvents and provides a starting platform for engineering customized tolerance to a wide variety of toxic chemicals. IMPORTANCE: Microbial production of useful chemicals is often limited by the toxicity of desired products, feedstock impurities, and undesired side products. Improving tolerance is an essential step in the development of practical platform organisms for production of a wide range of chemicals. By overexpressing autologous heat shock proteins in Escherichia coli, we have developed a modular semisynthetic stress response system capable of improving tolerance to ethanol, n-butanol, and potentially other toxic solvents. Using this system, we demonstrate that a practical stress response system requires both tuning of individual gene components and a reliable framework for gene expression. This system can be used to seek out new interacting partners to improve the tolerance phenotype and can be used in the development of more robust solvent production strains. PMID- 23033473 TI - An evolutionary link between natural transformation and CRISPR adaptive immunity. AB - Natural transformation by competent bacteria is a primary means of horizontal gene transfer; however, evidence that competence drives bacterial diversity and evolution has remained elusive. To test this theory, we used a retrospective comparative genomic approach to analyze the evolutionary history of Aggregatibacter actinomycetemcomitans, a bacterial species with both competent and noncompetent sister strains. Through comparative genomic analyses, we reveal that competence is evolutionarily linked to genomic diversity and speciation. Competence loss occurs frequently during evolution and is followed by the loss of clustered regularly interspaced short palindromic repeats (CRISPRs), bacterial adaptive immune systems that protect against parasitic DNA. Relative to noncompetent strains, competent bacteria have larger genomes containing multiple rearrangements. In contrast, noncompetent bacterial genomes are extremely stable but paradoxically susceptible to infective DNA elements, which contribute to noncompetent strain genetic diversity. Moreover, incomplete noncompetent strain CRISPR immune systems are enriched for self-targeting elements, which suggests that the CRISPRs have been co-opted for bacterial gene regulation, similar to eukaryotic microRNAs derived from the antiviral RNA interference pathway. IMPORTANCE: The human microbiome is rich with thousands of diverse bacterial species. One mechanism driving this diversity is horizontal gene transfer by natural transformation, whereby naturally competent bacteria take up environmental DNA and incorporate new genes into their genomes. Competence is theorized to accelerate evolution; however, attempts to test this theory have proved difficult. Through genetic analyses of the human periodontal pathogen Aggregatibacter actinomycetemcomitans, we have discovered an evolutionary connection between competence systems promoting gene acquisition and CRISPRs (clustered regularly interspaced short palindromic repeats), adaptive immune systems that protect bacteria against genetic parasites. We show that competent A. actinomycetemcomitans strains have numerous redundant CRISPR immune systems, while noncompetent bacteria have lost their CRISPR immune systems because of inactivating mutations. Together, the evolutionary data linking the evolution of competence and CRISPRs reveals unique mechanisms promoting genetic heterogeneity and the rise of new bacterial species, providing insight into complex mechanisms underlying bacterial diversity in the human body. PMID- 23033474 TI - Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. AB - New treatments are needed for extensively drug-resistant (XDR) Gram-negative bacilli (GNB), such as Acinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance of GNB, including A. baumannii. However, here we have shown that 100% of wild-type mice versus 0% of TLR4-deficient mice died of septic shock due to A. baumannii infection, despite having similar tissue bacterial burdens. The strain lipopolysaccharide (LPS) content and TLR4 activation by extracted LPS did not correlate with in vivo virulence, nor did colistin resistance due to LPS phosphoethanolamine modification. However, more-virulent strains shed more LPS during growth than less-virulent strains, resulting in enhanced TLR4 activation. Due to the role of LPS in A. baumannii virulence, an LpxC inhibitor (which affects lipid A biosynthesis) antibiotic was tested. The LpxC inhibitor did not inhibit growth of the bacterium (MIC>512 ug/ml) but suppressed A. baumannii LPS-mediated activation of TLR4. Treatment of infected mice with the LpxC inhibitor enhanced clearance of the bacteria by enhancing opsonophagocytic killing, reduced serum LPS concentrations and inflammation, and completely protected the mice from lethal infection. These results identify a previously unappreciated potential for the new class of LpxC inhibitor antibiotics to treat XDR A. baumannii infections. Furthermore, they have far-reaching implications for pathogenesis and treatment of infections caused by GNB and for the discovery of novel antibiotics not detected by standard in vitro screens. IMPORTANCE: Novel treatments are needed for infections caused by Acinetobacter baumannii, a Gram-negative bacterium that is extremely antibiotic resistant. The current study was undertaken to understand the immunopathogenesis of these infections, as a basis for defining novel treatments. The primary strain characteristic that differentiated virulent from less-virulent strains was shedding of Gram-negative lipopolysaccharide (LPS) during growth. A novel class of antibiotics, called LpxC inhibitors, block LPS synthesis, but these drugs do not demonstrate the ability to kill A. baumannii in vitro. We found that an LpxC inhibitor blocked the ability of bacteria to activate the sepsis cascade, enhanced opsonophagocytic killing of the bacteria, and protected mice from lethal infection. Thus, an entire new class of antibiotics which is already in development has heretofore-unrecognized potential to treat A. baumannii infections. Furthermore, standard antibiotic screens based on in vitro killing failed to detect this treatment potential of LpxC inhibitors for A. baumannii infections. PMID- 23033475 TI - EspZ of enteropathogenic and enterohemorrhagic Escherichia coli regulates type III secretion system protein translocation. AB - Translocation of effector proteins via a type III secretion system (T3SS) is a widespread infection strategy among Gram-negative bacterial pathogens. Each pathogen translocates a particular set of effectors that subvert cell signaling in a way that suits its particular infection cycle. However, as effector unbalance might lead to cytotoxicity, the pathogens must employ mechanisms that regulate the intracellular effector concentration. We present evidence that the effector EspZ controls T3SS effector translocation from enteropathogenic (EPEC) and enterohemorrhagic (EHEC) Escherichia coli. Consistently, an EPEC espZ mutant is highly cytotoxic. Following ectopic expression, we found that EspZ inhibited the formation of actin pedestals as it blocked the translocation of Tir, as well as other effectors, including Map and EspF. Moreover, during infection EspZ inhibited effector translocation following superinfection. Importantly, while EspZ of EHEC O157:H7 had a universal "translocation stop" activity, EspZ of EPEC inhibited effector translocation from typical EPEC strains but not from EHEC O157:H7 or its progenitor, atypical EPEC O55:H7. We found that the N and C termini of EspZ, which contains two transmembrane domains, face the cytosolic leaflet of the plasma membrane at the site of bacterial attachment, while the extracellular loop of EspZ is responsible for its strain-specific activity. These results show that EPEC and EHEC acquired a sophisticated mechanism to regulate the effector translocation. IMPORTANCE: Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) are important diarrheal pathogens responsible for significant morbidity and mortality in developing countries and the developed world, respectively. The virulence strategy of EPEC and EHEC revolves around a conserved type III secretion system (T3SS), which translocates bacterial proteins known as effectors directly into host cells. Previous studies have shown that when cells are infected in two waves with EPEC, the first wave inhibits effector translocation by the second wave in a T3SS-dependent manner, although the factor involved was not known. Importantly, we identified EspZ as the effector responsible for blocking protein translocation following a secondary EPEC infection. Interestingly, we found that while EspZ of EHEC can block protein translocation from both EPEC and EHEC strains, EPEC EspZ cannot block translocation from EHEC. These studies show that EPEC and EHEC employ a novel infection strategy to regulate T3SS translocation. PMID- 23033476 TI - Dynamics of ribosomal protein S1 on a bacterial ribosome with cross-linking and mass spectrometry. AB - Ribosomal protein S1 has been shown to be a significant effector of prokaryotic translation. The protein is in fact capable of efficiently initiating translation, regardless of the presence of a Shine-Dalgarno sequence in mRNA. Structural insights into this process have remained elusive, as S1 is recalcitrant to traditional techniques of structural analysis, such as x-ray crystallography. Through the application of protein cross-linking and high resolution mass spectrometry, we have detailed the ribosomal binding site of S1 and have observed evidence of its dynamics. Our results support a previous hypothesis that S1 acts as the mRNA catching arm of the prokaryotic ribosome. We also demonstrate that in solution the major domains of the 30S subunit are remarkably flexible, capable of moving 30-50A with respect to one another. PMID- 23033478 TI - Rolling back the bureaucracies of ethics review. AB - Dyck and Allen's criticisms of current systems of governance are well founded, at least in some jurisdictions. Their desire to halt the expansion and intensification of research ethics governance is to be applauded. However, their listed categories of research to be exempted from mandatory review may not create a better system. PMID- 23033477 TI - High resolution quantitative proteomics of HeLa cells protein species using stable isotope labeling with amino acids in cell culture(SILAC), two-dimensional gel electrophoresis(2DE) and nano-liquid chromatograpohy coupled to an LTQ OrbitrapMass spectrometer. AB - The proteomics field has shifted over recent years from two-dimensional gel electrophoresis (2-DE)-based approaches to SDS-PAGE or gel-free workflows because of the tremendous developments in isotopic labeling techniques, nano-liquid chromatography, and high-resolution mass spectrometry. However, 2-DE still offers the highest resolution in protein separation. Therefore, we combined stable isotope labeling with amino acids in cell culture of controls and apoptotic HeLa cells with 2-DE and the subsequent analysis of tryptic peptides via nano-liquid chromatography coupled to an LTQ-Orbitrap mass spectrometer to obtain quantitative data using the methods with the highest resolving power on all levels of the proteomics workflow. More than 1,200 proteins with more than 2,700 protein species were identified and quantified from 816 Coomassie Brilliant Blue G-250 stained 2-DE spots. About half of the proteins were identified and quantified only in single 2-DE spots. The majority of spots revealed one to five proteins; however, in one 2-DE spot, up to 23 proteins were identified. Only half of the 2-DE spots represented a dominant protein with more than 90% of the whole protein amount. Consequently, quantification based on staining intensities in 2 DE gels would in approximately half of the spots be imprecise, and minor components could not be quantified. These problems are circumvented by quantification using stable isotope labeling with amino acids in cell culture. Despite challenges, as shown in detail for lamin A/C and vimentin, the quantitative changes of protein species can be detected. The combination of 2-DE with high-resolution nano-liquid chromatography-mass spectrometry allowed us to identify proteomic changes in apoptotic cells that would be unobservable using any of the other previously employed proteomic workflows. PMID- 23033479 TI - Calretinin regulates Ca2+-dependent inactivation and facilitation of Ca(v)2.1 Ca2+ channels through a direct interaction with the alpha12.1 subunit. AB - Voltage-gated Ca(v)2.1 Ca(2+) channels undergo dual modulation by Ca(2+), Ca(2+) dependent inactivation (CDI), and Ca(2+)-dependent facilitation (CDF), which can influence synaptic plasticity in the nervous system. Although the molecular determinants controlling CDI and CDF have been the focus of intense research, little is known about the factors regulating these processes in neurons. Here, we show that calretinin (CR), a Ca(2+)-binding protein highly expressed in subpopulations of neurons in the brain, inhibits CDI and enhances CDF by binding directly to alpha(1)2.1. Screening of a phage display library with CR as bait revealed a highly basic CR-binding domain (CRB) present in multiple copies in the cytoplasmic linker between domains II and III of alpha(1)2.1. In pulldown assays, CR binding to fusion proteins containing these CRBs was largely Ca(2+)-dependent. alpha(1)2.1 coimmunoprecipitated with CR antibodies from transfected cells and mouse cerebellum, which confirmed the existence of CR-Ca(v)2.1 complexes in vitro and in vivo. In HEK293T cells, CR significantly decreased Ca(v)2.1 CDI and increased CDF. CR binding to alpha(1)2.1 was required for these effects, because they were not observed upon substitution of the II-III linker of alpha(1)2.1 with that from the Ca(v)1.2 alpha(1) subunit (alpha(1)1.2), which lacks the CRBs. In addition, coexpression of a protein containing the CRBs blocked the modulatory action of CR, most likely by competing with CR for interactions with alpha(1)2.1. Our findings highlight an unexpected role for CR in directly modulating effectors such as Ca(v)2.1, which may have major consequences for Ca(2+) signaling and neuronal excitability. PMID- 23033480 TI - Soluble amyloid precursor protein 770 is released from inflamed endothelial cells and activated platelets: a novel biomarker for acute coronary syndrome. AB - BACKGROUND: Separate monitoring of the cleavage products of different amyloid beta precursor protein (APP) variants may provide useful information. RESULTS: We found that soluble APP770 (sAPP770) is released from inflamed endothelial cells and activated platelets as judged by ELISA. CONCLUSION: sAPP770 is an indicator for endothelial and platelet dysfunctions. SIGNIFICANCE: How sAPP770 is released in vivo has been shown. Most Alzheimer disease (AD) patients show deposition of amyloid beta (Abeta) peptide in blood vessels as well as the brain parenchyma. We previously found that vascular endothelial cells express amyloid beta precursor protein (APP) 770, a different APP isoform from neuronal APP695, and produce Abeta. Since the soluble APP cleavage product, sAPP, is considered to be a possible marker for AD diagnosis, sAPP has been widely measured as a mixture of these variants. We hypothesized that measurement of the endothelial APP770 cleavage product in patients separately from that of neuronal APP695 would enable discrimination between endothelial and neurological dysfunctions. Using our newly developed ELISA system for sAPP770, we observed that inflammatory cytokines significantly enhanced sAPP770 secretion by endothelial cells. Furthermore, we unexpectedly found that sAPP770 was rapidly released from activated platelets. We also found that cerebrospinal fluid mainly contained sAPP695, while serum mostly contained sAPP770. Finally, to test our hypothesis that sAPP770 could be an indicator for endothelial dysfunction, we applied our APP770 ELISA to patients with acute coronary syndrome (ACS), in which endothelial injury and platelet activation lead to fibrous plaque disruption and thrombus formation. Development of a biomarker is essential to facilitate ACS diagnosis in clinical practice. The results revealed that ACS patients had significantly higher plasma sAPP770 levels. Furthermore, in myocardial infarction model rats, an increase in plasma sAPP preceded the release of cardiac enzymes, currently used markers for acute myocardial infarction. These findings raise the possibility that sAPP770 can be a useful biomarker for ACS. PMID- 23033481 TI - S-nitrosylation inhibits pannexin 1 channel function. AB - S-nitrosylation is a post-translational modification on cysteine(s) that can regulate protein function, and pannexin 1 (Panx1) channels are present in the vasculature, a tissue rich in nitric oxide (NO) species. Therefore, we investigated whether Panx1 can be S-nitrosylated and whether this modification can affect channel activity. Using the biotin switch assay, we found that application of the NO donor S-nitrosoglutathione (GSNO) or diethylammonium (Z)-1 1(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA NONOate) to human embryonic kidney (HEK) 293T cells expressing wild type (WT) Panx1 and mouse aortic endothelial cells induced Panx1 S-nitrosylation. Functionally, GSNO and DEA NONOate attenuated Panx1 currents; consistent with a role for S-nitrosylation, current inhibition was reversed by the reducing agent dithiothreitol and unaffected by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a blocker of guanylate cyclase activity. In addition, ATP release was significantly inhibited by treatment with both NO donors. To identify which cysteine residue(s) was S nitrosylated, we made single cysteine-to-alanine substitutions in Panx1 (Panx1(C40A), Panx1(C346A), and Panx1(C426A)). Mutation of these single cysteines did not prevent Panx1 S-nitrosylation; however, mutation of either Cys-40 or Cys 346 prevented Panx1 current inhibition and ATP release by GSNO. This observation suggested that multiple cysteines may be S-nitrosylated to regulate Panx1 channel function. Indeed, we found that mutation of both Cys-40 and Cys-346 (Panx1(C40A/C346A)) prevented Panx1 S-nitrosylation by GSNO as well as the GSNO mediated inhibition of Panx1 current and ATP release. Taken together, these results indicate that S-nitrosylation of Panx1 at Cys-40 and Cys-346 inhibits Panx1 channel currents and ATP release. PMID- 23033482 TI - The cytosolic GH loop regulates the phosphatidylinositol 4,5-bisphosphate-induced gating kinetics of Kir2 channels. AB - Inwardly rectifying K(+) (Kir) channels set the resting membrane potential and regulate cellular excitability. The activity of Kir channels depends critically on the phospholipid PIP(2). The molecular mechanism by which PIP(2) regulates Kir channel gating is poorly understood. Here, we utilized a combination of computational and electrophysiological approaches to discern structural elements involved in regulating the PIP(2)-induced gating kinetics of Kir2 channels. We identify a novel role for the cytosolic GH loop. Mutations that directly or indirectly affect GH loop flexibility (e.g. V223L, E272G, D292G) increase both the on- and especially the off-gating kinetics. These effects are consistent with a model in which competing interactions between the CD and GH loops for the N terminus regulate the gating of the intracellular G loop gate. PMID- 23033483 TI - Neuregulin-4 is a survival factor for colon epithelial cells both in culture and in vivo. AB - Expression of the ErbB4 tyrosine kinase is elevated in colonic epithelial cells during inflammatory bowel disease, whereas ErbB4 overexpression in cultured colonocytes blocks TNF-induced apoptosis in a ligand-dependent manner. Together, these observations suggest that ErbB4 induction may be a protective response. However, the effects of ErbB4 signaling in the colonic epithelium in vivo are not known. Furthermore, previous work on ErbB4 used ligands shared with other receptors, raising the question of whether the observed responses are explicitly due to ErbB4. In this study, we used the ErbB4-specific ligand neuregulin-4 (NRG4) to activate ErbB4 and define its role in colonocyte biology. NRG4 treatment, either in cultured cells or in mice, blocked colonic epithelial apoptosis induced by TNF and IFN-gamma. It was also protective in a murine experimental colitis model. NRG4 stimulated phosphorylation of ErbB4 but not other ErbB receptors, indicating that this is a specific response. Furthermore, in contrast to related ligands, NRG4 enhanced cell survival but not proliferation or migration, and stimulated phosphorylation of the anti-apoptotic mediator Akt but not ERK MAPK. Pharmacological inhibition of PI3K/Akt signaling reversed the anti-apoptotic effects of NRG4, confirming the role of this cascade in NRG4 induced cell survival. With regard to the potential clinical importance of this pathway, NRG4 expression was decreased in human inflammatory bowel disease samples and mouse models of colitis, suggesting that activation of ErbB4 is altered in disease. Thus, exogenous NRG4 may be beneficial for disorders in which epithelial apoptosis is part of the pathology. PMID- 23033484 TI - Identification of amino acid residues responsible for the selectivity of tadalafil binding to two closely related phosphodiesterases, PDE5 and PDE6. AB - The 11 families of the Class I cyclic nucleotide phosphodiesterases (PDEs) are critical for regulation of cyclic nucleotide signaling. PDE5 (important in regulating vascular smooth muscle contraction) and PDE6 (responsible for regulating visual transduction in vertebrate photoreceptors) are structurally similar but have several functional differences whose structural basis is poorly understood. Using evolutionary trace analysis and structural homology modeling in conjunction with site-directed mutagenesis, we have tested the hypothesis that class-specific differences between PDE5 and PDE6 account for the biochemical and pharmacological differences in the two enzyme families. Replacing human PDE5 residues in the M-loop region of the binding site for the PDE5-selective inhibitor tadalafil (Cialis(r)) with the corresponding class-specific cone PDE6 residues (P773E, I778V, E780L, F787W, E796V, D803P, L804M, N806D, I813L, S815K) reduces tadalafil binding affinity to levels characteristic of PDE6. These mutations fail to alter vardenafil (Levitra(r)) affinity for the active site. Class-specific differences in PDE5 versus cone PDE6 that contribute to the accelerated catalytic efficiency of PDE6 were identified but required heterologous expression of full-length PDE5 constructs. Introduction of PDE6 residues into the background of the PDE5 protein sequence often led to loss of catalytic activity and reduced protein solubility, supporting the idea that multiple structural elements of PDE6 are highly susceptible to misfolding during heterologous expression. This work validates the use of PDE5 as a template to identify functional differences between PDE5 and PDE6 that will accelerate efforts to develop the next generation of PDE5-selective inhibitors with fewer adverse side effects resulting from PDE6 inhibition. PMID- 23033486 TI - Pickpocket1 is an ionotropic molecular sensory transducer. AB - The molecular transformation of an external stimulus into changes in sensory neuron activity is incompletely described. Although a number of molecules have been identified that can respond to stimuli, evidence that these molecules can transduce stimulation into useful neural activity is lacking. Here we demonstrate that pickpocket1 (ppk1), a Drosophila homolog of mammalian Degenerin/epithelial sodium channels, encodes an acid-sensing sodium channel that conducts a transient depolarizing current in multidendritic sensory neurons of Drosophila melanogaster. Stimulation of Ppk1 is sufficient to bring these sensory neurons to threshold, eliciting a burst of action potentials. The transient nature of the neural activity produced by Ppk1 activation is the result of Ppk1 channel gating properties. This model is supported by the observation of enhanced bursting activity in neurons expressing a gain of function ppk1 mutant harboring the degenerin mutation. These findings demonstrate that Ppk1 can function as an ionotropic molecular sensory transducer capable of transforming the perception of a stimulus into phasic neuronal activity in sensory neurons. PMID- 23033485 TI - Identification and characterization of a compound that protects cardiac tissue from human Ether-a-go-go-related gene (hERG)-related drug-induced arrhythmias. AB - The human Ether-a-go-go-related gene (hERG)-encoded K(+) current, I(Kr) is essential for cardiac repolarization but is also a source of cardiotoxicity because unintended hERG inhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that diminishes I(Kr) block by a known hERG antagonist would constitute a first step toward preventing hERG-related arrhythmias and facilitating drug discovery. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC(70) of dofetilide, a well characterized hERG blocker. One compound, VU0405601, with the desired activity was further characterized. In isolated, Langendorff-perfused rabbit hearts, optical mapping revealed that dofetilide-induced arrhythmias were reduced after pretreatment with VU0405601. Patch clamp analysis in stable hERG-HEK cells showed effects on current amplitude, inactivation, and deactivation. VU0405601 increased the IC(50) of dofetilide from 38.7 to 76.3 nM. VU0405601 mitigates the effects of hERG blockers from the extracellular aspect primarily by reducing inactivation, whereas most clinically relevant hERG inhibitors act at an inner pore site. Structure-activity relationships surrounding VU0405601 identified a 3-pyridiyl and a naphthyridine ring system as key structural components important for preventing hERG inhibition by multiple inhibitors. These findings indicate that small molecules can be designed to reduce the sensitivity of hERG to inhibitors. PMID- 23033488 TI - New directions for biologic targets in urothelial carcinoma--letter. PMID- 23033487 TI - GCN5 protects vertebrate cells against UV-irradiation via controlling gene expression of DNA polymerase eta. AB - By UV-irradiation, cells are subjected to DNA damage followed by mutation, cell death and/or carcinogenesis. DNA repair systems such as nucleotide excision repair (NER) and translesion DNA synthesis (TLS) protect cells against UV irradiation. To understand the role of histone acetyltransferase GCN5 in regulation of DNA repair, we studied the sensitivity of GCN5-deficient DT40, GCN5(-/-), to various DNA-damaging agents including UV-irradiation, and effects of GCN5-deficiency on the expression of NER- and TLS-related genes. After UV irradiation, cell death and DNA fragmentation of GCN5(-/-) were appreciably accelerated as compared with those of DT40. Interestingly, GCN5(-/-) showed a remarkable sensitivity to only UV-irradiation but not to other DNA-damaging agents tested. Semiquantitative RT-PCR showed that transcription of DNA polymerase eta (POLH) gene whose deficiency is responsible for a variant form of xeroderma pigmentosum was drastically down-regulated in GCN5(-/-) (to ~25%). In addition, ectopic expression of human POLH in GCN5(-/-) dramatically reversed the sensitivity to UV-irradiation of GCN5(-/-) to almost the same level of wild type DT40. Moreover, chromatin immunoprecipitation assay revealed that GCN5 binds to the chicken POLH gene 5'-flanking region that contains a typical CpG island and acetylates Lys-9 of histone H3, but not Lys-14 in vivo. These data suggest that GCN5 takes part in transcription regulation of POLH gene through alterations in the chromatin structure by direct interaction with its 5'-flanking region, and protects vertebrate cells against UV-induced DNA damage via controlling POLH gene expression. PMID- 23033490 TI - Contrary regulation of bladder cancer cell proliferation and invasion by dexamethasone-mediated glucocorticoid receptor signals. AB - In patients with advanced bladder cancer, glucocorticoids are frequently given to reduce acute toxicity, particularly hyperemesis, during chemotherapy, as well as to improve cachectic conditions. However, it remains unclear whether glucocorticoids directly affect the development and progression of bladder cancer through the glucocorticoid receptor pathway. Glucocorticoid receptor expression was first investigated in human bladder cancer lines and tissue microarrays. Then, the effects of dexamethasone on glucocorticoid receptor transcription, cell proliferation, apoptosis/cell cycle, and invasion were examined in bladder cancer lines. Finally, mouse xenograft models for bladder cancer were used to assess the efficacy of dexamethasone on tumor progression. All the cell lines and tissues examined were found to express glucocorticoid receptor. Dexamethasone increased glucocorticoid receptor-mediated reporter activity and cell proliferation, and inhibited apoptosis in the presence or absence of cisplatin. In contrast, dexamethasone suppressed cell invasion, the expression of its related genes [MMP 2/MMP-9, interleukin (IL)-6, VEGF], and the activity of MMP-2/MMP-9, and also induced mesenchymal-to-epithelial transition. In addition, dexamethasone increased IkappaBalpha protein levels and cytosolic accumulation of NF-kappaB. In xenograft-bearing mice, dexamethasone slightly augmented the growth of the inoculated tumors but completely prevented the development of bloody ascites, suggestive of peritoneal dissemination of tumor cells, and actual metastasis. In all these assays, dexamethasone effects were abolished by a glucocorticoid receptor antagonist or glucocorticoid receptor knockdown via RNA interference. Thus, glucocorticoid receptor activation resulted in promotion of cell proliferation via inhibiting apoptosis yet repression of cell invasion and metastasis. These results may provide a basis of developing improved chemotherapy regimens, including or excluding glucocorticoid receptor agonists/antagonists, for urothelial carcinoma. PMID- 23033491 TI - Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder. AB - We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor alpha-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in gamma-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1 activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers. PMID- 23033492 TI - Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. AB - Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSC-induced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones. We also show that LOX is an essential component of the CD44-Twist signaling axis, in which extracellular hyaluronan causes nuclear translocation of CD44 in the cancer cells, thus triggering LOX transcription by associating with its promoter. Processed and enzymatically active LOX, in turn, stimulates Twist transcription, which mediates the MSC-triggered epithelial-to-mesenchymal transition (EMT) of carcinoma cells. Surprisingly, although induction of EMT in breast cancer cells has been tightly associated with the generation of cancer stem cells, we find that LOX, despite being critical for EMT, does not contribute to the ability of MSCs to promote the formation of cancer stem cells in the carcinoma cell populations. Collectively, our studies highlight a critical role for LOX in cancer metastasis and indicate that the signaling pathways controlling stroma induced EMT are distinct from pathways regulating the development of cancer stem cells. PMID- 23033493 TI - Tibet is one of the centers of domestication of cultivated barley. AB - The Near East Fertile Crescent is well recognized as a primary center of barley origin, diversity, and domestication. A large number of wild barleys have been collected from the Tibetan Plateau, which is characterized by an extreme environment. We used genome-wide diversity array technology markers to analyze the genotypic division between wild barley from the Near East and Tibet. Our results confirmed the existence of Tibetan wild barley and suggested that the split between the wild barleys in the Near East and those in Tibet occurred around 2.76 million years ago (Mya). To test the concept of polyphyletic domestication of barley, we characterized a set of worldwide cultivated barley. Some Chinese hulless and six-rowed barleys showed a close relationship with Tibetan wild barley but showed no common ancestor with other cultivated barley. Our data support the concept of polyphyletic domestication of cultivated barley and indicate that the Tibetan Plateau and its vicinity is one of the centers of domestication of cultivated barley. The current results may be highly significant in exploring the elite germplasm for barley breeding, especially against cold and drought stresses. PMID- 23033494 TI - Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. AB - Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB) regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases. PMID- 23033496 TI - Role of protons in sugar binding to LacY. AB - WT lactose permease of Escherichia coli (LacY) reconstituted into proteoliposomes loaded with a pH-sensitive fluorophore exhibits robust uphill H(+) translocation coupled with downhill lactose transport. However, galactoside binding by mutants defective in lactose-induced H(+) translocation is not accompanied by release of an H(+) on the interior of the proteoliposomes. Because the pK(a) value for galactoside binding is ~10.5, protonation of LacY likely precedes sugar binding at physiological pH. Consistently, purified WT LacY, as well as the mutants, binds substrate at pH 7.5-8.5 in detergent, but no change in ambient pH is observed, demonstrating directly that LacY already is protonated when sugar binds. However, a kinetic isotope effect (KIE) on the rate of binding is observed, indicating that deuterium substitution for protium affects an H(+) transfer reaction within LacY that is associated with sugar binding. At neutral pH or pD, both the rate of sugar dissociation (k(off)) and the forward rate (k(on)) are slower in D(2)O than in H(2)O (KIE is ~2), and, as a result, no change in affinity (K(d)) is observed. Alkaline conditions enhance the effect of D(2)O on k(off), the KIE increases to 3.6-4.0, and affinity for sugar increases compared with H(2)O. In contrast, LacY mutants that exhibit pH-independent high affinity binding up to pH 11.0 (e.g., Glu325 -> Gln) exhibit the same KIE (1.5 1.8) at neutral or alkaline pH (pD). Proton inventory studies exhibit a linear relationship between k(off) and D(2)O concentration at neutral and alkaline pH, indicating that internal transfer of a single H(+) is involved in the KIE. PMID- 23033498 TI - Co-occurrence of dermatomyositis and Hashimoto's thyroiditis in a type I diabetic patient. PMID- 23033499 TI - Comparison of digital screening mammography and screen-film mammography in the early detection of clinically relevant cancers: a multicenter study. AB - PURPOSE: To compare screen-film mammography with digital mammography in a breast cancer screening program, with a focus on the clinical relevance of detected cancers. MATERIALS AND METHODS: The study was approved by the regional medical ethics review board. Informed consent was not required. Before the nationwide transition to digital mammography in the Dutch biennial screening program, the performance of digital mammography was studied in three screening regions. For initial screening examinations, mediolateral oblique and craniocaudal views were obtained of each breast. In subsequent examinations, the mediolateral oblique view was standard. A craniocaudal view was added if indicated. Screening outcomes obtained with screen-film mammography and digital mammography, including radiologic and pathologic characteristics, were compared for initial and subsequent examinations. RESULTS: A total of 1,198,493 screening examinations were performed between 2003 and 2007. Recall was indicated in 18 896 cases (screen-film mammography: 2.6% at initial examinations, 1.3% at subsequent examinations; digital mammography: 4.4% at initial examinations, 2.1% at subsequent examinations; P < .001 for both). Breast cancer was diagnosed in 6410 women (detection rate per 1000 women with screen-film mammography: 5.6 at initial examinations, 5.2 at subsequent examinations; detection rate per 1000 women with digital mammography: 6.8 at initial examinations, 6.1 at subsequent examinations; P = .02 and P < .001, respectively). Digital mammography depicted significantly more ductal carcinoma in situ (DCIS) lesions, irrespective of screening round. Invasive carcinoma was detected significantly more often in subsequent examinations, particularly when associated with microcalcifications (P = .047). The distribution of the histopathologic differentiation grades for DCIS and invasive carcinoma were similar with both modalities. However, with digital mammography more high-grade DCIS lesions were detected at subsequent examinations (P = .013). CONCLUSION: In a population-based breast screening program, the performance of digital mammography in the detection of DCIS and invasive carcinoma was substantially better than that of screen-film mammography. There is no sign of an increase in detection of low-grade DCIS lesions-indicative of possible overdiagnosis-with digital breast cancer screening. Rather, digital mammography appears to add to the detection of high-grade DCIS. PMID- 23033502 TI - Recurrent parotid pseudogout. PMID- 23033500 TI - Nonmalignant breast lesions: ADCs of benign and high-risk subtypes assessed as false-positive at dynamic enhanced MR imaging. AB - PURPOSE: To evaluate the diffusion-weighted (DW) imaging characteristics of nonmalignant lesion subtypes assessed as false-positive findings at conventional breast magnetic resonance (MR) imaging. MATERIALS AND METHODS: This HIPAA compliant retrospective study had institutional review board approval, and the need for informed patient consent was waived. Lesions assessed as Breast Imaging Reporting and Data System category 4 or 5 at clinical dynamic contrast material enhanced MR imaging that subsequently proved nonmalignant at biopsy were retrospectively reviewed. One hundred seventy-five nonmalignant breast lesions in 165 women were evaluated. Apparent diffusion coefficients (ADCs) from DW imaging (b = 0, 600 sec/mm(2)) were calculated for each lesion and were compared between subtypes and with an ADC threshold of 1.81 * 10(-3) mm(2)/sec (determined in a prior study to achieve 100% sensitivity). RESULTS: Eighty-one (46%) lesions exhibited ADCs greater than the predetermined threshold. The most prevalent lesion subtypes with mean ADCs above the threshold were fibroadenoma ([1.94 +/- 0.38 {standard deviation}] * 10(-3) mm(2)/sec; n = 30), focal fibrosis ([1.84 +/- 0.48] * 10(-3) mm(2)/sec; n = 19), normal tissue ([1.81 +/- 0.47] * 10(-3) mm(2)/sec; n = 13), apocrine metaplasia ([2.01 +/- 0.38] * 10(-3) mm(2)/sec; n = 13), usual ductal hyperplasia ([1.83 +/- 0.49] * 10(-3) mm(2)/sec; n = 12), and inflammation ([1.95 +/- 0.46] * 10(-3) mm(2)/sec; n = 10). Atypical ductal hyperplasia ([1.48 +/- 0.36] * 10(-3) mm(2)/sec; n = 23) was the most common lesion subtype with ADC below the threshold. Lymph nodes exhibited the lowest mean ADC of all nonmalignant lesions ([1.28 +/- 0.23] * 10(-3) mm(2)/sec; n = 4). High-risk lesions (atypical ductal hyperplasia and lobular neoplasia) showed significantly lower ADCs than other benign lesions (P < .0001) and were the most common lesions with ADCs below the threshold. CONCLUSION: Assessing ADC along with dynamic contrast-enhanced MR imaging features may decrease the number of avoidable false-positive findings at breast MR imaging and reduce the number of preventable biopsies. The ability of DW imaging to help differentiate high-risk lesions requiring additional work-up from other nonmalignant subtypes may further improve patient care. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112672/-/DC1. PMID- 23033503 TI - An introduction to the International Brain Research Organization: IBRO's beginnings. PMID- 23033504 TI - Reviewing the genetic causes of spastic-ataxias. AB - Although the combined presence of ataxia and pyramidal features has a long differential, the presence of a true spastic-ataxia as the predominant clinical syndrome has a rather limited differential diagnosis. Autosomal recessive ataxia of Charlevoix-Saguenay, late-onset Friedreich ataxia, and hereditary spastic paraplegia type 7 are examples of genetic diseases with such a prominent spastic ataxic syndrome as the clinical hallmark. We review the various causes of spastic ataxic syndromes with a focus on the genetic disorders, and provide a clinical framework, based on age at onset, mode of inheritance, and additional clinical features and neuroimaging signs, that could serve the diagnostic workup. PMID- 23033505 TI - "Bright tongue sign" in ALS. PMID- 23033506 TI - Opinion & special articles: a guide from fellowship to faculty: Nietzsche and the academic neurologist. AB - The role of the physician scientist in biomedical research is increasingly threatened. Despite a clear role in clinical advances in translational medicine, the percentage of physicians engaged in research has steadily declined. Several programmatic efforts have been initiated to address this problem by providing time and financial resources to the motivated resident or fellow. However, this decline in physician scientists is due not only to a lack of time and resources but also a reflection of the uncertain path in moving from residency or postdoctoral training toward junior faculty. This article is a practical guide to the milestones and barriers to successful faculty achievement after residency or fellowship training. PMID- 23033507 TI - Clinical reasoning: a unique case of acute onset, progressive left hemiparesis. PMID- 23033508 TI - Teaching NeuroImages: mitochondrial encephalopathy, lactic acidosis, and stroke like episodes. PMID- 23033509 TI - Occupational exposure to cleaning products and asthma in hospital workers. AB - OBJECTIVE: Cleaning products may cause work-related asthma, but information regarding the specific exposures involved is scarce. We aimed to determine the associations between asthma and occupational exposure to cleaning agents in hospital workers. METHODS: Analyses were conducted in 179 (136 women) hospital workers and a reference population of 545 subjects (18-79 years) from the French case-control and familial Epidemiological study on the Genetics and Environment of Asthma (2003-2007). Exposures to cleaning agents were estimated using three methods: self-report, expert assessment and an asthma-specific job-exposure matrix (JEM). Associations between cleaning products and current asthma were evaluated by logistic regressions, stratified by sex and adjusted for age and smoking status. RESULTS: According to expert assessment, 55% of male and 81% of female hospital workers were exposed to cleaning/disinfecting tasks weekly (p<0.001). No association was observed between cleaning/disinfecting tasks and current asthma in men or in women whatever the assessment method used. In women, exposure to decalcifiers (expert assessment) was associated with current asthma (OR (95% CI):2.38 (1.06 to 5.33)). In hospital workers classified as exposed according to both the expert assessment and the JEM, additional associations were observed for exposure to ammonia (3.05 (1.19 to 7.82)) and to sprays with moderate/high intensity (2.87 (1.02 to 8.11)). CONCLUSIONS: Female hospital workers are often exposed to numerous cleaning products, some of which were markedly associated with current asthma. Low numbers prevented a meaningful analysis in men. Objective and more accurate estimates of occupational exposure to cleaning products are needed to better understand the adverse effects of cleaning products. PMID- 23033510 TI - European guideline for the organization of a consultation for sexually transmitted infections, 2012. AB - This guideline is intended to serve as a framework for those working in any location where sexually transmitted infections (STIs) are managed. It offers recommendations which will need to be adapted depending on local facilities and policies, and is not intended to be all encompassing. This guideline should be read in conjunction with other European guidelines on the management of specific infections (see http://www.iusti.org/). PMID- 23033511 TI - Herpes simplex virus and HIV: genital infection synergy and novel approaches to dual prevention. AB - Sexual transmission of HIV-1, in the absence of co-factors, is poorly efficient. Data support that herpes simplex virus type-2 (HSV-2) may increase a woman's susceptibility to HIV-1. Potential mechanisms by which HSV-2 serves as an HIV-1 enhancing co-factor include (1) initiation of a clinical or subclinical mucosal inflammatory response, (2) alteration of innate mucosal immunity and (3) weakening or breaching the protective genital epithelia. No clinical trial has examined prevention of primary HSV-2 infection to eliminate the major morbidities of this recurrent disease and as a strategy to reduce HIV-1 transmission. Topical administration of potent antivirals can achieve local concentrations that are orders of magnitude higher than those obtained with oral administration. This paper reviews major advances in oral and topical pre-exposure prophylaxis of HIV 1 and HSV-2 and, based on these data, hypothesizes that simultaneous prevention of sexual acquisition of HSV-2 and HIV-1 via topical antiretroviral agents will have a synergistic impact on both epidemics. PMID- 23033512 TI - Testicular microlithiasis: is it significant? AB - Previously considered to be a benign finding on scrotal ultrasonography, testicular microlithiasis (TM) is now recognized as a condition associated with the development of testicular neoplasia. Despite this the management of TM remains unclear. We review the evidence for this association and suggested management strategies. PMID- 23033513 TI - Anal cytology screening in HIV-positive men who have sex with men: experience in a city centre HIV clinic. AB - The objectives of this study were to describe the findings of anal cytology screening during the first year of a unit protocol offering yearly screening to all HIV-positive men who have sex with men (MSM). Of 285 patients seen, 75% were offered anal cytology screening. Sixty-two percent of patients offered screening accepted and 21% of anal smears performed were reported as abnormal. Anal cytology screening may lead to earlier detection of anal intraepithelial neoplasia allowing for treatment before progression to cancer. This study revealed potential difficulties in follow-up of patients with high-grade precancerous disease and highlighted potential resource implications of implementing a routine screening programme. PMID- 23033514 TI - The value of testing multiple anatomic sites for gonorrhoea and chlamydia in sexually transmitted infection centres in the Netherlands, 2006-2010. AB - National surveillance data from 2006 to 2010 of the Dutch sexually transmitted infection (STI) centres were used to analyse current practices on testing extragenital sites for chlamydia and gonorrhoea in men who have sex with men (MSM) and women. In MSM, 76.0% and 88.9% were tested at least at one extragenital site (pharyngeal and/or anorectal) for chlamydia and gonorrhoea, respectively; for women this was 20.5% and 30.2%. Testing more than one anatomic site differed by STI centre, ranging from 2% to 100%. In MSM tested at multiple sites, 63.0% and 66.5% of chlamydia and gonorrhoea diagnoses, respectively, would have been missed if screened at the urogenital site only, mainly anorectal infections. For women tested at multiple sites, the proportions of missed chlamydia and gonorrhoea diagnoses would have been 12.9% and 30.0%, respectively. Testing extragenital sites appears warranted, due to the numerous infections that would have been missed. Adding anorectal screening to urogenital screening for all MSM visiting an STI centre should be recommended. Since actual testing practices differ by centre, there is a need for clearer guidelines. Routine gonorrhoea and chlamydia screening at multiple sites in STI centres should be investigated further as this might be a more effective approach to reduce transmission than current practice. PMID- 23033515 TI - The outcome of treatment of early syphilis with different benzathine penicillin regimens in HIV-infected and -uninfected patients. AB - The evolution of treatment guidelines for early syphilis to single-dose benzathine penicillin regardless of HIV status has been controversial in the UK. We describe the treatment response in patients treated by current and previous regimens of benzathine penicillin for early syphilis. We found no difference in treatment efficacy between single-dose benzathine and previously recommended benzathine treatment courses in HIV co-infected patients. HIV-positive status did alter treatment efficacy as evidenced by increased serological cure rates at 12 months, although this was not statistically significant. This may be due to the loss to follow-up in HIV-negative patients. HIV-infected patients were increasingly likely to be re-infected with syphilis compared to HIV-negative patients. Our findings also justify the screening of HIV patients with syphilis serology at each routine HIV follow-up. PMID- 23033516 TI - Eosinophilia: clinical significance in HIV-infected individuals. AB - This study was conducted to determine the relationship between eosinophilia and parasitic infection in HIV-infected individuals. HIV-positive patients attending an HIV clinic in Birmingham were recruited and classified as either eosinophilic (>400 eosinophils/mm(3)) or non-eosinophilic. A demographic and parasitic risk history was taken and clinical examination was performed. Urine and stool were examined for parasites, and blood samples taken for parasite serology. A total of 266 patients (96 eosinophilic and 170 non-eosinophilic) were recruited. Of 64 eosinophilic patients who had a stool examination, one (1.6%) was positive for both Strongyloides larvae and schistosomal eggs. Urine microscopy was negative in the 245 patients (88 eosinophilic, 157 non-eosinophilic) from whom a sample was available. Two hundred and sixty-three patients underwent serological investigation (96 eosinophilic and 167 non-eosinophilic): 13 (4.9%) were positive for schistosomiasis and three (1.1%) positive for Strongyloides. A significant association between eosinophilia and positive schistosomal serology was found (P = 0.003): 11 (10.5%) were eosinophilic patients, while only four (2.3%) were non eosinophilic patients. Eosinophilia was associated with a low nadir CD4 count (P = 0.021) and prior AIDS-defining illness (P = 0.041). In all, 7.8% of patients from a developing country and 5.3% of patients from a developed country with a travel history had positive parasitic serology. Eosinophilia in HIV-infected patients was significantly associated with positive serology for schistosomiasis, low nadir CD4 count and prior AIDS-defining illness. Geographical exposure is also an important determinant of positive parasitic serology. PMID- 23033517 TI - Seroprevalence of hepatitis C, hepatitis B virus and syphilis in HIV-1 infected patients in Shandong, China. AB - To determine the seroprevalence of hepatitis C virus (HCV), hepatitis B virus (HBV) and syphilis in HIV-1-infected patients and related risk factors in Shandong province, China, we tested all eligible participants between 2000 and 2010 for the presence of anti-HCV antibody, hepatitis B surface antigen (HBsAg) and non-treponemal antibodies for syphilis after informed consent. Among 2087 HIV infected patients, anti-HCV antibody was present in 41.2%, HBsAg in 12.6% and rapid plasma reagin (RPR) reactivity in 19.6%. In the multivariate logistic regression model, male gender (adjusted odds ratio [aOR] = 1.41), minority ethnicity (aOR = 1.72), syphilis infection (aOR = 1.40), former paid blood donors (aOR = 3.36), blood transfusion recipients (aOR = 2.91) and injection drug users (aOR = 1.98) were significantly associated with HCV infection. HCV infection (aOR = 1.40) and being men who have sex with men (aOR = 2.38) were significantly associated with syphilis infection. Co-infection with HCV, HBV and syphilis was observed frequently in all described subgroups of HIV infection. The results of this study suggest that it is necessary to screen for these viruses and syphilis in all Chinese HIV-infected patients. PMID- 23033518 TI - Rapid HIV testing using DetermineTM HIV 1/2 antibody tests: is there a difference between the visual appearance of true- and false-positive tests? AB - HIV point-of-care tests (POCTs) give occasional false positive results, causing unnecessary patient anxiety. We aimed to elicit whether false- and true-positive POCTs differed visually. Seventeen false- and 17 true-positive serum samples were randomized into pairs, comprising one false- and one true-positive sample. Two independent readers identified each POCT as negative or positive and compared line strength between pairs. Six further readers graded line strength, 0-5, from POCT photographs. All true-positive samples were identified positive and 8/17 false-positive samples negative, on repeat testing of stored sera. Eight out of the 9 remaining false-positive tests were described as having weaker pigment uptake than their paired true-positive POCT. Mean grade of line strength was 4.2 in true- and 0.9 in false-positive samples, on photographic evaluation. These results suggest false-positive POCTs may differ visually from true-positive POCTs. If larger studies confirm these findings, we may be able to alleviate anxiety in low risk patients with faintly positive POCTs awaiting their confirmatory laboratory result, where the possibility of a false-positive result could be emphasized. PMID- 23033519 TI - What do HIV-positive patients in Plymouth think about sharing details of their HIV status with other health-care workers? AB - We carried out a prospective structured interview with 71% of the HIV cohort in Plymouth to establish patients' views on recording HIV status and details of HIV care in routine hospital and primary care notes. Forty-nine percent of patients did not want their HIV status routinely documented in hospital notes and 57% did not want hospital staff to have access to results of sexual health screens (SHSs). In light of these results, we plan to offer patients the option to opt out of using hospital notes for documentation of their HIV care and will be providing SHSs under a separate genitourinary medicine (GU) patient number. PMID- 23033520 TI - Discrepancies in diagnosis of incident HIV infection between antibody- and DNA based tests in a phase III prevention trial in southern Africa. AB - Dried blood spots (DBS) are widely used to test for HIV in a variety of research and service delivery settings; however, uniform guidelines regarding collection, storage and DNA extraction processes have neither been developed nor evaluated. Previously published reports suggested DBS may be stored at room temperature for up to 60 days, and intensive stability tests have shown that DBS can withstand high temperatures, humidity and freeze-thawing. During the implementation of a large randomized controlled trial (RCT) in southern Africa, with HIV acquisition as the primary endpoint, we observed 65 instances when DBS samples collected from the same day as a positive HIV antibody test yielded negative DNA polymerase chain reaction (PCR) results. The source of this discrepancy may have been due to inadequate specimen volume, filter paper or DNA extraction procedures, but were most likely due to storage conditions that have been reported as acceptable in other settings. PMID- 23033521 TI - A community-based study to examine the effect of a youth HIV prevention programme in South Africa. AB - The aim of this study was to examine the relationships among changes in self reported HIV and sexually transmitted infection (STI) and exposure to the loveLife youth HIV prevention programmes. A cross-sectional population-based household survey was conducted using a multistage stratified cluster sampling approach. The total sample included 3123 participants, aged 18-24, 54.6% men and 45.4% women, from four provinces (Eastern Cape, Gauteng, KwaZulu-Natal and Mpumalanga). Results indicate a self-reported STI past-year prevalence of 2.6%, experienced genital sores or ulcers in the past year prevalence of 3.9% and an HIV self-reported prevalence of 7.4%. In multivariable analyses it was found that knowing a person living with HIV and a person who has died from AIDS, lower education, having had two or more sexual partners in the past year, not having talked with a partner about condom use, difficulty of getting condoms and not having been male circumcised were associated with having been diagnosed with an STI in the past 12 months and/or HIV. Face-to-face and multimedia youth HIV prevention programmes had limited effect. PMID- 23033522 TI - Olympic outreach: testing for sexually transmitted infections in construction workers. AB - Concerns have been voiced in the national press that the surge in migrant construction workers leading up to the 2012 Olympics Games would increase the levels of sexual ill health in East London. Between 2009 and 2011, we sent a sexual health outreach team to the Olympic Park and Village. A total of 614 clients were tested, of whom 91% were men and 46% reported English/Scottish/Welsh ethnicity. The age range was 17-73 years and median age 30 years. Reported sexual risk factors were low, including use of commercial sex workers. Prevalence of sexually transmitted infections was low, with Chlamydia trachomatis found in 20 clients (3%), and hepatitis B diagnosed in one client. This study, although small, did not support the image of construction workers presenting a higher than average sexual health risk. PMID- 23033523 TI - Barriers to contraception among HIV-positive women in a periurban district of Uganda. AB - This study explored perceptions and care-seeking practices for HIV testing and contraception in order to obtain data for designing effective interventions to increase contraception among HIV-positive women. A triangulation of methods (household survey, focus group discussions and key informant interviews) were conducted in Wakiso district, central Uganda from January to April 2009. Results show that a majority of women, 2062/2896 (71.2%) would like to have an HIV test, while access to antiretroviral therapy (ART) was low at 237/879 (27%). Of the women who were on ART, 133/266 (50.0%) could not use contraception due to negative perceptions that a combination of ART and contraceptives would weaken them, as these drugs were perceived to be 'strong'. Fear of side-effects for contraceptives and resistance from spouses were other main reasons. Constraints to HIV testing included fear of clients knowing their own HIV status and fear of their spouses' reactions to the test results. Private midwives were identified as a potential outlet for delivering contraception to HIV-positive women. PMID- 23033524 TI - Pre-elective HIV postexposure prophylaxis clinic for medical students: design, protocol, uptake and effectiveness. AB - We sought to evaluate medical student need for HIV postexposure prophylaxis (PEP) prior to their elective and introduce a 'Pilot PEP Clinic'. We undertook a survey of 388 medical students to assess their elective plans. All were offered an appointment in a clinic, assessed via a protocol and provided a PEP 'starter pack' prescription if criteria were met. A follow-up questionnaire was sent to assess the acceptability of the clinic. The pre-elective questionnaire response rate was 232/388 (60%); 72/232 (31%) of respondents planned their elective in areas of high HIV prevalence and, of these, 32/72 (45%) attended the clinic. Of 32, 31 (97%) met the clinic protocol criteria and received a prescription for PEP. Of 32, 29 (90%) completed the follow-up questionnaire and every respondent rated the clinic as acceptable. The main concern was the cost of antiretroviral medications. We conclude that a 'Pre-elective HIV PEP Clinic' is an acceptable way to provide students with safe access to PEP prior to their elective. PMID- 23033525 TI - Dynamics of the HIV epidemic in southern China: sexual and drug-using behaviours among female sex workers and male clients in Yunnan. AB - To examine the HIV/sexually transmitted infection (STI)-related risk behaviours among community-based female sex workers (FSWs) and their clients in Yunnan Province, China, we performed a cross-sectional study of 705 FSWs and 100 male clients. We found that HIV seroprevalence among FSWs was 13.0% and the most prevalent STI was herpes simplex virus type 2 (HSV-2) (71.1%), followed by Chlamydia trachomatis (18.1%) and syphilis (8.8%). The 20% of FSWs who reported injection drug use also reported needle-sharing behaviours in the last three months. Drug-using FSWs had substantially higher HIV and HSV-2 prevalence, serviced more clients and had a longer history of sex work than non-using FSWs. In total, 57.0% of male clients did not consistently use condoms with FSWs, 2.0% reported illicit drug use and 17.0% had STI symptoms in the last year. The dual risk behaviours of drug-using FSWs and clients place them at greater risk of HIV infection. Intervention programmes must adopt comprehensive methods. PMID- 23033526 TI - Long-term neurological follow-up of HIV-positive patients diagnosed with syphilis. AB - No cerebrospinal fluid (CSF) abnormalities are found in HIV-positive patients in long-term follow-up after standard syphilis treatment. Syphilis has been reported to have immunological effects on HIV infection and HIV is known to modulate both the manifestations of syphilis and the serological response to therapy. HIV positive patients who had been diagnosed with and treated for syphilis prior to 2007 were identified. Patients were consented for lumbar puncture. Serum HIV viral load, CD4 count and CSF were recorded. Thirty-five patients with previously diagnosed and treated syphilis underwent lumbar puncture. Thirty-four patients had a normal neurological exam. Only one patient had an abnormal mean white cell count (10.7 cells per high-power field). The finding that those with previously diagnosed syphilis had normal CSF and clinical findings is reassuring and supports the practice of using standard syphilis therapy in HIV-positive patients. PMID- 23033527 TI - Cutaneous aspergillosis associated with HIV infection. AB - Primary cutaneous aspergillosis is rare but has been described in immunosuppressed individuals. Cutaneous aspergillosis associated with HIV infection, to date, has primarily been described in hospitalized individuals with advanced HIV following skin trauma. We describe a case of primary cutaneous aspergillosis in a HIV-infected, antiretroviral therapy naive patient with moderate immunosuppression. PMID- 23033528 TI - A presentation of penile Mondor's disease. AB - Mondor's disease can manifest itself in the penile dorsal vein. It is a rare complaint with a quoted incidence of 1.39%. We report a case of a 41-year-old man who has sex with men (MSM), who presented with penile swelling and painful erections following intensive and vigorous sexual activity. He was found to have a thrombosis of the penile dorsal veins. He was managed with non-steroidal anti inflammatory drugs and sexual abstinence and his symptoms resolved in the following two weeks. Practitioners need to beware of Mondor's disease as a differential diagnosis in the presence of penile swelling and not underestimate the anxiety it can cause the patient. PMID- 23033529 TI - Recurrent vulval ulceration: could it be Behcet's disease? AB - This report describes a young black Caribbean woman with a three-year history of recurrent genital ulceration initially diagnosed as genital herpes. This diagnosis had been made clinically by the general practitioner but never confirmed on culture or nucleic acid amplification testing; sequential treatment with aciclovir and famciclovir over a four-month period did not alleviate her genital symptoms. Presentation to our genitourinary (GU) medicine clinic identified painful aphthous genital and oral ulcers, erythema nodosum bilaterally and a history of eye irritation. A clinical diagnosis of Behcet's disease was made. Treatment with hydrocortisone mouth pellets and dermovate ointment was initiated in addition to dermatology and ophthalmology referral. This report reminds clinicians to consider alternative diagnoses in clinical practice when faced with patients who are resistant to treatment. It also highlights the importance of recognizing systemic disease and maintaining a holistic approach when treating patients. PMID- 23033531 TI - What do we need to learn for policy decision-making on sexually transmitted infections prevention and treatment in Israel? AB - The rising trend of sexually transmitted infections (STIs) reported in several western countries has also affected Israel. To review epidemiological trends and to address additional issues needed for a wider overview on STIs in Israel, we analysed notified data on infectious syphilis, gonorrhoea, Chlamydia trachomatis and HIV/AIDS during 1998-2007, by age groups, and each available publication on STIs in Israel. The trend of each disease had a unique pattern, probably influenced by different screening procedures, case definition, mix of populations and better access to care for high-risk populations. Higher rates were found among patients aged 25-34 years. Rates found in different peak years for gonorrhoea, HIV, chlamydia and infectious syphilis reached 43.6, 18.9, 10.8 and 8.1 cases per 100,000 population, respectively. We compare trends to those of countries from World Health Organization (WHO) European Region and discuss interventions for subpopulations on which additional data are needed for evidence based policy-making. Incidence rates of syphilis, gonorrhoea, chlamydia and HIV/AIDS are still low in Israel. We propose additional components needed for a more comprehensive evidence-based policy on STIs. PMID- 23033530 TI - Treatment outcome, mortality and their predictors among HIV-associated tuberculosis patients. AB - The risk of death is significantly higher in HIV-infected patients with tuberculosis (TB). This study aims to evaluate the impact of demographic, clinical and laboratory characteristics on the treatment outcome and mortality of TB/HIV co-infected patients in a tertiary TB centre in Iran. In total, 111 patients were recruited from 2004 to 2007. Mycobacteriological studies and demographic, clinical, and laboratory data from all patients were analysed and predictors of unsuccessful outcomes as well as mortality were determined. The mean age for all 111 TB-HIV patients was 38 +/- 9 years (range 22-70) and 107 (96.3%) were men; 104 (93.7%) had a history of drug abuse and 96 (86.4%) had a history of imprisonment. The method of HIV transmission was intravenous drug use in 88 (79.3%). Twenty-three (20.7%) had a history of Category 1 (CAT I) TB treatment and six (5.4%) Category 2 (CAT II) treatment. Combination antiretroviral therapy (cART) was given to 48 (43.2%). No significant associations were found between treatment outcomes or mortality and gender, smoking, drug and alcohol abuse, imprisonment, method of transmission, history of CAT I and CAT II treatments, CD4 counts or adverse effects (P > 0.05). Administration of cART led to significantly better outcomes (P < 0.001). Lower serum albumin levels and low body weight were significantly associated with mortality. PMID- 23033532 TI - Correlation of HIV/AIDS prevalence with social, economic and demographic measures in Andhra Pradesh, India. AB - In this study, the spatial distribution of HIV/AIDS is investigated with several socioeconomic variables. Results of exploratory analysis of correlations have been reported between the prevalence of HIV/AIDS as it is the dependent variable against a range of socioeconomic and demographic measures in Andhra Pradesh, India. The state ranks among the top six states for HIV prevalence in the country. This study offers an insight to the distribution of HIV prevalence and the potential impacts of the epidemic on the high-, medium- and low-risk groups determined through cluster analyses of population and cumulative HIV infections. The impacts have been addressed through selective social and economic measures as HIV/AIDS is considered more of a social epidemic. These results help in identifying factors that are contributing more towards the spread of HIV and so guide policies to counteract dominant factors in order to control the disease. Future investigations are necessary to elucidate characterization of the rates of infection according to gender, age groups and regions. PMID- 23033533 TI - Effect of condom-use measures in predicting sexually transmitted diseases: variation by individual and contextual factors of sexual risk. AB - Inconsistent findings in the global literature regarding the effectiveness of condom use against sexually transmitted diseases (STDs) may result from variations in the measurement of condom use. In this study, we assess the sensitivity and specificity of six condom-use measures in predicting STD infection, and assess the difference in sensitivity and specificity by type of sexual partner (clients versus stable partners), type of STD, ethnicity (Han versus non-Han), years of formal schooling (<=6 versus >6 years) and level of risk of STD exposure (high versus low). Cross-sectional data were obtained from 454 female sex workers (FSWs) in Guangxi, China. Measurements of condom use were created along types of use (any use, consistent use, correct use, or the combination of consistent and correct use) and periods of recall (life time, last month or recent three sexual episodes). Measures of consistent use had higher sensitivity and lower specificity than measures of any use in predicting STDs among FSWs, regardless of the recall period and type of sexual partner. Incorporating correct use improved the measures of consistent use. Measures of consistent use and the combination of consistent and correct use demonstrated high sensitivity in predicting particular STDs. They showed higher sensitivity in predicting STDs among FSWs who reported higher risk for STD exposure than among FSWs who reported lower risk of exposure to STDs. In conclusion, the findings suggest the superiority of consistent use and correct use of condoms in predicting STD infection. The findings also underscore the importance of considering the context of sexual risk such as type of sexual partner and risk of exposure to STD infection when we measure condom use. Future studies of condom effectiveness should collect and quantify these contextual and individual factors among the target population. PMID- 23033534 TI - Human papillomavirus genotype distribution and risk factors for infection in women from a small municipality in north east Brazil. AB - In order to assess the prevalence of human papillomavirus (HPV) infection, the HPV genotypes and factors associated with infection, we conducted a population based survey in a small municipality in north east Brazil among women aged between 12 and 49 years. A questionnaire regarding socioeconomic variables, reproductive life and sexual behaviour was used, and women were examined gynaecologically, followed by collection of vaginal lavage with saline solution for HPV DNA determination. HPV DNA was detected by the Digene((r)) SHARP Signal(TM)-System, and further genotyped by INNO-LiPA Genotyping System((r)). Of 579 women, HPV infection was present in 68 (prevalence: 11.7%; 95% CI: 9.3-14.7). The most common HPV types were 16, 31 and 74, each accounting for 14.7% of infections. Of all HPV-positive women, 35.3% showed multiple HPV genotypes. Variables independently associated with HPV infection were: >=3 partners in life (adjusted OR [aOR]: 3.06; 95% CI: 1.68-5.60) and the use of oral contraception in the last 12 months (aOR: 2.39; 95% CI: 1.33-4.30). Previous participation in a cervical cancer screening programme was protective (aOR: 0.28; 95% CI: 0.13 0.60). HPV infection is common among women from rural Brazil, and HPV genotypes identified indicate that immunization could be an important preventive measure in this population. PMID- 23033536 TI - HCN1 channels: a new therapeutic target for depressive disorders? AB - The hyperpolarization-activated cyclic nucleotide-gated channels are cation channels that are activated by hyperpolarizing potentials. These channels are concentrated in cortical and hippocampal pyramidal cell dendrites, where they play an important role in determining synaptic input integration and thus neuronal output. These channels have thus been suggested to be involved in physiological processes such as cognition as well as pathophysiological states such as epilepsy. Recent evidence suggests that these channels may also be therapeutic targets for treatment of depressive disorders. PMID- 23033535 TI - Rho GEFs and cancer: linking gene expression and metastatic dissemination. AB - Guanine nucleotide exchange factors (GEFs) that promote GTP loading onto the guanosine triphosphatases (GTPases) Rho and Rac are prominent players in cancer progression. Recent studies have highlighted the relevance of several GEFs, including the phosphatidylinositol 3,4,5-trisphosphate Rac exchangers P-Rex1 and P-Rex2a, in breast tumorigenesis. New evidence suggests that the exchange factors Vav2 and Vav3 play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and metastasis. The identification of a Vav-regulated transcriptome and Vav-related genes that control specific steps of metastatic dissemination of breast cancer cells to the lungs highlights the complexities of the signaling networks regulated by Rho/Rac GTPases and may lead to novel therapeutic targets. PMID- 23033537 TI - Inflammatory factors contribute to depression and its comorbid conditions. AB - New perspectives have emerged regarding the processes associated with depressive disorders and their many comorbid conditions. Particular attention has been paid to the potential role of inflammatory factors in promoting these illnesses. These inflammatory responses include those elicited by pathogenic stimuli, as well as sterile inflammatory processes, such as those related to severe or chronic stress. These diverse challenges may activate common processes in which cytokines, which are inflammatory signaling molecules, provoke the dysregulation of several growth factors, including brain-derived neurotrophic factor, fibroblast growth factor-2, macrophage migration inhibitory factor, and erythropoietin. The result of such dysregulation favors the development of depressive disorders and their comorbid illnesses, such as heart disease, diabetes, autoimmune conditions, and poststroke depression. PMID- 23033539 TI - Primary generalized glucocorticoid resistance and hypersensitivity: the end-organ involvement in the stress response. AB - Primary generalized glucocorticoid resistance (PGGR or Chrousos syndrome) and primary generalized glucocorticoid hypersensitivity (PGGH) are rare genetic disorders characterized by generalized, partial target-tissue insensitivity or hypersensitivity to glucocorticoids, respectively, while also causing compensatory alterations in the activity of the hypothalamic-pituitary-adrenal axis. The molecular basis of Chrousos syndrome and PGGH has been ascribed to mutations in the gene encoding the human glucocorticoid receptor (hGR), which impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. Alterations in hGR action may have important implications for many critical biological processes, such as the behavioral and physiologic responses to stress, immune responses, growth, and reproduction. This Presentation summarizes the pathophysiology, clinical manifestations, and molecular mechanisms of the PGGR and PGGH states. PMID- 23033538 TI - Circadian rhythms of glucocorticoid hormone actions in target tissues: potential clinical implications. AB - Organisms face unforeseen short- and long-term changes in the environment (stressors). To defend against these changes, organisms have developed a stress system that includes the hypothalamic-pituitary-adrenal (HPA) axis, which employs glucocorticoids and the glucocorticoid receptor (GR) for signal transduction. In addition, organisms live under the strong influence of day-night cycles and, hence, have also developed a highly conserved circadian clock system for adjusting their activities to recurring environmental changes. This regulatory system creates and maintains internal circadian rhythmicity by employing a self oscillating molecular pacemaker composed of the Clock-Bmal1 heterodimer and other transcription factors. The circadian clock consists of a central master clock in the suprachiasmatic nucleus of the brain hypothalamus and peripheral slave clocks in virtually all organs and tissues. The HPA axis and the circadian clock system communicate with each other at multiple levels. The central clock controls the HPA axis, creating the diurnal oscillation of circulating adrenocorticotropic hormone and cortisol, and the HPA axis adjusts the circadian rhythmicity of the peripheral clocks in response to various stressors through the GR. Further, Clock Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the GR, possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. Importantly, dysregulation in the clock system and the HPA axis may cause similar pathologic manifestations--including obesity, metabolic syndrome, and cardiovascular disease--by uncoupling circulating cortisol concentrations from tissue sensitivity to glucocorticoids. PMID- 23033540 TI - The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells. AB - The guanosine triphosphatases of the Rho and Rac subfamilies regulate protumorigenic pathways and are activated by guanine nucleotide exchange factors (Rho GEFs), which could be potential targets for anticancer therapies. We report that two Rho GEFs, Vav2 and Vav3, play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and many of the steps involved in lung specific metastasis. The involvement of Vav proteins in these processes did not correlate with Rac1 and RhoA activity or cell migration, implying the presence of additional biological programs. Microarray analyses revealed that Vav2 and Vav3 controlled a vast transcriptional program in breast cancer cells through mechanisms that were shared between the two proteins, isoform-specific or synergistic. Furthermore, the abundance of Vav-regulated transcripts was modulated by Rac1-dependent and Rac1-independent pathways. This transcriptome encoded therapeutically targetable proteins that played nonredundant roles in primary tumorigenesis and lung-specific metastasis, such as integrin-linked kinase (Ilk), the transforming growth factor-beta family ligand inhibin betaA, cyclooxygenase-2, and the epithelial cell adhesion molecule Tacstd2. It also contained gene signatures that predicted disease outcome in breast cancer patients. These results identify possible targets for treating breast cancer and lung metastases and provide a potential diagnostic tool for clinical use. PMID- 23033541 TI - An interaction between BZR1 and DELLAs mediates direct signaling crosstalk between brassinosteroids and gibberellins in Arabidopsis. AB - Plant growth and development are coordinated by several groups of small-molecule hormones, including brassinosteroids (BRs) and gibberellins (GAs). Physiological and molecular studies have suggested the existence of crosstalk between BR and GA signaling. We report that BZR1, a key transcription factor activated by BR signaling, interacts in vitro and in vivo with REPRESSOR OF ga1-3 (RGA), a member of the DELLA family of transcriptional regulators that inhibits the GA signaling pathway in Arabidopsis thaliana. Genetic analyses of plants with mutations in the genes encoding RGA and BZR1 revealed that RGA suppressed root and hypocotyl elongation of the gain-of-function mutant bzr1-1D. Ectopic expression of proteins of the DELLA family reduced the abundance and transcriptional activity of BZR1. Reporter gene analyses further indicated that BZR1 and RGA antagonize each other's transcriptional activity. Our data indicated that BZR1 and RGA served as positive and negative regulators, respectively, of both the BR and the GA signaling pathways and establish DELLAs as mediators of signaling crosstalk between BRs and GAs in controlling cell elongation and regulation of plant growth. PMID- 23033542 TI - Impact of pharmacist discharge medication therapy counseling and disease state education: Pharmacist Assisting at Routine Medical Discharge (project PhARMD). AB - Many patients experience adverse events after discharge; numerous are medication related and preventable. The objective of this study is to evaluate the impact of pharmacist medication counseling and disease education at discharge. Pharmacist Assisting at Routine Medical Discharge is a prospective study of English- or Spanish-speaking adults discharged from internal medicine. Control patients received usual hospital discharge care; intervention patients received usual care with discharge counseling and a follow-up phone call. Evaluated outcomes included the following: 30-day hospital reutilization (combined readmissions/emergency department visits), pharmacist interventions, predictors for hospital utilization, patient satisfaction, and primary medication adherence. In all, 279 patients were enrolled: 139 in the control and 140 in the intervention group. Pharmacists made 198 interventions. The rate of hospital reutilization was 20.7% and similar between the intervention and control groups. Patients receiving the pharmacist intervention demonstrated improved primary medication adherence and increased patient satisfaction. Pharmacist-provided discharge counseling resulted in medication interventions, improved patient satisfaction, and increased medication adherence. PMID- 23033543 TI - Medical research in China: where does it go? PMID- 23033545 TI - Age- and sex-related effects on ankle-brachial index in a screened cohort of Japanese: the Okinawa Peripheral Arterial Disease Study (OPADS). AB - AIMS: Age-related change of ankle-brachial index (ABI) within the general population, especially <40 years, has not been determined in large population studies. We evaluated the value of the ABI by age- and sex-related differences in a screened cohort. METHODS AND RESULTS: The ABI was examined in 13,211 participants (aged 21-89 years) in a health evaluation programme. The mean ABI was lower in women than in men at all ages. The ABI was lowest at <40 years, and increased with age; the maximum was at 60-69 years in both sexes. In participants <40 years, 186 (22%) of women and 108 (9.8%) of men had a borderline ABI (0.9 1.0). The prevalence of an ABI <=0.9 in men increased with age, and sharply rose to 3.3% at >=70 years. Conversely, women demonstrated a J-curve relationship, where the prevalence of an ABI <=0.9 was lowest at 60-69 years (0.2%), and increased at <40 (0.9%) and >=70 years (1.6%). The prevalence of atherosclerotic risk factors was higher in participants with an ABI <=0.9 than those with an ABI >0.9 in men, both <=60 and >60 years, and in women >60 years. In women <=60 years, however, the prevalence of atherosclerotic risk factors in participants with an ABI >0.9 was as small as those with an ABI <=0.9. CONCLUSION: The ABI increased with age until 60-69 years, and was lower in women than in men. It is unlikely that a low ABI in younger healthy women always indicate that existence of arterial stenosis. PMID- 23033546 TI - Initiation and maintenance of cardiovascular medications following cardiovascular risk assessment in a large primary care cohort: PREDICT CVD-16. AB - AIM: To examine whether use of a standardized cardiovascular disease (CVD) risk assessment recommended by national guidelines is associated with appropriate initiation and maintenance of medication in a large primary care cohort. METHODS AND DESIGN: A total of 90,631 people aged 30-80 years were followed for up to 3 years after a formal CVD risk assessment was undertaken between January 2006 and October 2009, during routine primary care visits in New Zealand. Patients either had prior CVD or had their CVD risk estimated using a modified Framingham prediction equation for fatal or non-fatal CVD events. The individual risk profiles were anonymously linked to national dispensing data for blood-pressure lowering and lipid-lowering medications in the 6-month period before and in consecutive 6-month blocks after the baseline CVD risk assessment. RESULTS: At baseline, a combination of blood-pressure-lowering and lipid-lowering therapy was already being used by about two-thirds of patients with prior CVD, one-quarter with a 5-year CVD risk greater than 10% (approximately 20% 10-year risk), and one tenth with CVD risk below this level. Among these previously treated patients, dispensing rates for blood-pressure-lowering, lipid-lowering, or both medications together declined by only 4?16% up to 3 years after baseline assessment, irrespective of risk category. Among patients untreated at baseline, combination therapy was initiated within 6 months for 21% with prior CVD, 16% with 5-year CVD risk greater than 15% (approximately 30% 10-year risk and the national drug treatment threshold), 10% with 5-year CVD risk between 10 and 14% (approximately 20?29% 10-year risk), and 3% in the lowest risk category. Across the study population, patients with prior CVD had the highest dispensing rates for each category of medication, and incrementally higher dispensing rates were noted as CVD risk group increased. CONCLUSIONS: In this primary care cohort, most patients already using CVD medications at the time of the baseline CVD risk assessment maintained treatment over a maximum of 3 years follow up, irrespective of their estimated baseline risk. Among patients untreated at baseline, subsequent dispensing rates were strongly related to estimated CVD risk group. Around 15?20% of untreated patients meeting national drug-treatment criteria commenced combination pharmacotherapy within 6 months of CVD risk assessment. PMID- 23033547 TI - Barriers to therapeutic clinical trials enrollment: differences between African American and white cancer patients identified at the time of eligibility assessment. AB - BACKGROUND: Clinical trials (CTs) are the mechanism by which research is translated into standards of care. Low recruitment among underserved and minority populations may result in inequity in access to the latest technology and treatments, compromise the generalizability, and lead to failure in identification of important positive or negative treatment effects among under represented populations. METHODS: Data were collected over a 39-month period on patient eligibility for available therapeutic cancer CTs. Reasons for ineligibility and refusal were collected. The data were captured using an automated software tool for tracking eligibility pre-enrollment. We examined characteristics associated with being evaluated for a trial, and reasons for ineligibility and refusal, overall and by patient race. RESULTS: African Americans (AAs) were more likely than Whites to be ineligible (odds ratio, (OR) = 1.26, 95% confidence interval (CI) = 1.0-1.58) and if eligible, to refuse participation (OR = 1.79, 95% CI = 1.27-2.52), even after adjusting for insurance, age, gender, study phase, and cancer type. White patients were more likely to be ineligible due to study-specific or cancer characteristics. AAs were more likely to be ineligible due to mental status or perceived noncompliance. Whites were more likely to refuse due to extra burden, due to concerns with randomization and toxicity, or because they express a positive treatment preference. AAs were more likely to refuse because they were not interested in CTs, because of family pressures, or they felt overwhelmed (NS)). DISCUSSION: This study is the first to directly compare ineligibility and refusal rates and reasons captured prospectively in AA and White cancer patients. The data are consistent with earlier studies that indicated that AA patients more often are deemed ineligible and, when eligible, more often refuse participation. However, differences in reasons for ineligibility and refusal by race have implications for a cancer center to participate in CTs appropriate for the population of patients served. On a broader scale, consideration should be given to modifying eligibility criteria and other design aspects to permit broader participation of minority and other underserved groups. PMID- 23033549 TI - Oral Health Disparities and the Future Face of America. AB - The 4th Annual AADR Fall Focused Symposium (FFS), "Oral Health Disparities Research and the Future Face of America", took place on November 3-4, 2011 in Washington, DC. The FFS strategy was developed by the AADR to help provide additional opportunities for members to engage in research discussions during the year by identifying specific research topics of interest among the 21 Scientific Groups and 4 Networks of the IADR and targeting a focused topic area for the FFS. The conference attracted an international group of approximately 120 registrants, including participants from Canada, India, Mexico, and China; 4 oral sessions and 32 poster presentations were offered. PMID- 23033548 TI - Spiritually based intervention to increase colorectal cancer screening among African Americans: screening and theory-based outcomes from a randomized trial. AB - Colorectal cancer screening has clear benefits in terms of mortality reduction; however, it is still underutilized and especially among medically underserved populations, including African Americans, who also suffer a disproportionate colorectal cancer burden. This study consisted of a theory-driven (health belief model) spiritually based intervention aimed at increasing screening among African Americans through a community health advisor-led educational series in 16 churches. Using a randomized design, churches were assigned to receive either the spiritually based intervention or a nonspiritual comparison, which was the same in every way except that it did not contain spiritual/religious content and themes. Trained and certified peer community health advisors in each church led a series of two group educational sessions on colorectal cancer and screening. Study enrollees completed a baseline, 1-month, and 12-month follow-up survey at their churches. The interventions had significant pre-post impact on awareness of all four screening modalities, and self-report receipt of fecal occult blood test, flexible sigmoidoscopy, and colonoscopy. There were no significant study group differences in study outcomes, with the exception of fecal occult blood test utilization, whereas those in the nonspiritual intervention reported significantly greater pre-post change. Both of these community-engaged, theory driven, culturally relevant approaches to increasing colorectal cancer awareness and screening appeared to have an impact on study outcomes. Although adding spiritual/religious themes to the intervention was appealing to the audience, it may not result in increased intervention efficacy. PMID- 23033550 TI - Too much salt in your diet? If you're like most Americans, you consume way too much sodium. PMID- 23033551 TI - Update on osteoporosis treatment. Should you stay on bisphosphonate drugs long term? PMID- 23033552 TI - Could a few daily cups of coffee help you live longer? PMID- 23033553 TI - Calcium supplements could increase heart attack risks. PMID- 23033554 TI - Arthritis, anxiety and depression: frequent companions. Treating emotional issues aids in improving arthritis pain. PMID- 23033555 TI - Living with restless legs syndrome. PMID- 23033556 TI - Do you really need that test? Experts point to overuse of screening and diagnostic tests. PMID- 23033557 TI - Does PSA testing hurt or help? PMID- 23033558 TI - Heart disease and gum disease: cutting the ties. PMID- 23033559 TI - Can people exposed to radiation during scans or therapy spread the radiation to others? PMID- 23033560 TI - How can I protect myself against MRSA, the "flesh-eating" virus? PMID- 23033561 TI - Taking a shot at shingles. PMID- 23033562 TI - [Q & A. A case with concave lesions of the lower gastric corpus and the gastric angle]. PMID- 23033563 TI - Patrick William Cotter. PMID- 23033565 TI - [The public health as social economic system]. AB - The article considers the public health as a social system because its main elements are human beings and their relationships. The conceptual foundations of characteristics of medical services are discussed as kinds of public benefits and nonmaterial values. PMID- 23033564 TI - Returning the mouth to the body: integrating oral health & primary care. PMID- 23033566 TI - [On the issue of development of state-private partnership in public health of Russia]. AB - The article considers possible directions of development of organizational technologies of state-private partnership in public health of Russia. Such directions are emphasized as management of operational activities of medical institutions, development of infrastructure of population medical care system, implementation of innovative technologies, organization of interaction with international clinical institutions, joint development of legal and low decisions in the area of interactions oa state and business relating to public health. The factors interfering with development of effective state-private partnership are demonstrated and possible ways of overcoming are proposed. PMID- 23033567 TI - [The primary disability of children population in Kaluga oblast]. AB - The article considers the primary disability of children population of Kaluga oblast at the age up to 18 years during period of last five years. On the oblast and district levels primary cases, prevalence, dynamics and characteristics of children disability indicators in total and according classes of diseases were detected. The indicators of primary disability in children depending of age and gender were calculated and comparatively analyzed. It is established that primary disability of children population has a distinct trend to increase, especially in adolescents. PMID- 23033568 TI - [The prevalence on diseases of thyroid gland in Tver oblast]. AB - The results of study of dynamics of prevalence of diseases of thyroid gland in Tverskaya oblast for 2006-2009 are presented. The analysis demonstrated the increase of prevalence of diseases of thyroid gland in the region that corresponds to the general trend in the Russian Federation. The tendency of decreasing of prevalence and primary morbidity of diffused euthyroid goiter is established which can be a result of mass iodine prevention in the region. The analytic data can be used as a basis for development of target regional programs focused on the enhancement of curative preventive institutions functioning (primary health care level included) to organize the effective medical care of patients suffering from diseases of thyroid gland. PMID- 23033569 TI - [The evaluation of morbidity, physical health of students and the formation of self-protecting behavior]. AB - The article presents the graded analysis of morbidity of students in comparison with adolescents and adults with consideration for gender age and trends in physical health. With maturation, the number of students with good physical health conditions decreases almost twice. The process of education in university can be considered as one of the factors negatively impacting the youth's health. The information indicators of students' health (weight/height indicator; test of Genchi and Ruffier) and organization of health information data bank considered as evaluation criteria in the development of complex target program of students' health promotion during education process. PMID- 23033570 TI - [The medical social aspects of health of students of medical college (the Ryazan oblast example)]. AB - The article presents the results of studying the main parameters impacting health of students of medical social college and in most instances providing self preserving behavior. Among these risk factors - health attitude, medical activity, health risk habits. The situation is most probably caused by the negative tendencies in health of both the Russian Federation population and students' youth. PMID- 23033571 TI - [The evaluation of physical development of students]. AB - The article demonstrates that physical health of university students is conditioned by the aggregate of morpho-functional indices and depends on the development of physical qualities of students. The evaluation of mass/height indicators of female students demonstrates the increase of total body size and weakness of body build. The testing of physical readiness testified the ambiguity of high-speed and high-speed/power qualities and results of stamina evaluation. PMID- 23033572 TI - [On the risk factors of population healthy population of Irkutsk oblast]. AB - The article presents the results of sociologic survey of Irkutsk women to reveal the factors impacting health - environment pollution, harmful habits, diet, health self-assessment, prevention measures. The results of questionnaire survey can be applied as a useful element in the system of social hygienic monitoring. PMID- 23033573 TI - [The medical social aspects of childhood traumatism accounting the family type]. AB - In the Russian Federation the childhood traumatism is considered as one of progressing social dangers. The interest in studying the impact of family type on childhood morbidity formation is increased during last years. The family is a fundamental principle of mechanisms of public health formation. The questionnaire poll of parents of children suffered from traumas provides the data concerning the medical social risk factors impacting the level of childhood traumatism. The one of the most important prevention measures is the impact on the family. PMID- 23033574 TI - [The preventable losses because of rural population mortality]. AB - The common and special issues of mortality in the Republic of Bashkortostan are established The analysis of tendencies and ratio of leading causes of gender proportions of mortality of urban and rural population established that in comparison with the national data the characteristics of the Republic of Bashkortostan are determined by higher life span rate of rural population and lower share in the structure of mortality due to traumas and intoxications, digestive apparatus diseases and neoplasms. At the same time, the quality of diagnostics in the Republic of Bashkortostan is inadequate due to large share of inaccurately specified states. The expertise survey revealed high degree of preventability of losses related to high mortality of rural population. The reserves to decrease preventable mortality of rural population are established on the basis of calculated preventability coefficients. The possibility of decreasing mortality of main classes of death causes based on the mathematical modeling is analyzed. It is demonstrated that in the Republic of Bashkortostan the mortality rate will significantly decrease only concerning cardiovascular disease and external causes. The coefficients of preventability of death main causes of rural population of the Republic of Bashkortostan are analyzed. PMID- 23033575 TI - [The organization and rendering of ambulatory surgical medical care to the population of the Russian Federation]. AB - The article deals with the results of analysis of official statistic data concerning the rendering of ambulatory surgical care to the population of the Russian Federation. The main volumes of surgical care rendered to the population (including children) in ambulatory polyclinic institutions, day-time in-patient establishment of ambulatory polyclinic institutions are demonstrated. The structure of ambulatory surgical operations according the localization and applied medical equipment is analyzed. The research data testify the necessity of further development of organization and rendering of ambulatory surgical care including enhancement of its significance, availability and effectiveness at the expense of reallocation of surgical care volumes to the ambulatory stage. PMID- 23033576 TI - [The organizational aspects of emergency care in the conditions of central district hospital]. AB - The article presents the results of analysis of dynamics of level of emergency hospital care to different age groups of population of municipality for five year period. The effectiveness of implementation of the new organizational form of day and night personnel support of emergency specialized hospital care in the conditions of central district hospital is analyzed. The study results indicates the possibility to resolve the problem of increase of effectiveness of emergency specialized hospital care under organization of day and night physicians' teams of specialists at the expense of reserves of the system of capitation financing of municipal health system. PMID- 23033577 TI - [The training of administration personnel for private medical organizations]. AB - The training of administration personnel for medical institutions is an integral part of the restructuring of health care. The authors proposed a system approach during the development of business-competences needed for modem medicine to provide the corresponding level of activity in the conditions of market economy and modernization of health care system. PMID- 23033578 TI - [The functioning of feldsher-midwife stations]. AB - The article presents the materials based on the statistical data and results of sociological survey. They characterize the condition of feldsher-midwife stations, their field of services, personnel issues and certain issues of everyday life of feldshers of Perm kray. The proposals concerning the development of feldsher-midwife stations functioning are analyzed. The comparative analysis with the data of similar survey of 1982 is done. The study results support the necessity to maintain and develop feldsher-midwife stations in the system of primary medical sanitary care of rural population, especially on the territories with low population density. PMID- 23033579 TI - [The analysis of opinions of physicians-experts concerning the organization of military medical expertise]. AB - The article presents the main results of sociological survey of physicians of military medical commissions of Kirov oblast. It is established that presently the training of students and physicians on the issues of military medical expertise factually does not carry out. Mainly, physicians-experts are trained on their work places. This condition can testify that theory and practice aspects of military medical expertise are not provided in needed proportions. At the same time, the collegiate style in work of physicians of military medical commissions is underdeveloped. The physicians emphasize the need to develop the normative legal base of military medical expertise. PMID- 23033580 TI - [The characteristics of ambulatory polyclinic care in case of cardiovascular pathology]. AB - The article deals with results of studying the awareness of population concerning the main risk factors, prevention of cardiologic pathology blood pressure self control in the Republic of Dagestan. The importance and priority of resource support of medical institutions and enhancement of health education of population concerning cardiovascular diseases are emphasized. PMID- 23033581 TI - [The modern international public health and globalization challenges]. AB - The article deals with the issues of impact of globalization on population health and public health. The positive and negative aspects of this process are analyzed. The role of international organizations (UN, WHO, UNESCO, ILO, UNISEF) is demonstrated in the area of management of globalization impact on public health of different countries, Russia included. PMID- 23033582 TI - [The characteristics of activities of general practice physician in the Republic of Uzbekistan]. AB - The article demonstrates that during the last decade in the Republic of Uzbekistan the reform of health system and restructuring of medical institutions of primary medical care have been implemented. At that, the landmark transition to organization and provision of medical care using general practitioner principle is accepted as the most important reform direction. PMID- 23033583 TI - [The origination of preventive medicine in the process of reforming of practical medicine in XVII-XIX centuries. Report 1. The traditional concepts concerning health preservation and diseases prevention]. AB - The present report is dedicated to short description of complex of concepts concerning issues of "health preservation and diseases prevention" elaborated by Galen and prevailed in medicine during fifteen centuries. The characteristics and main causes of revision of these concepts during the first scientific revolution are discussed. PMID- 23033584 TI - [On the medical and publishing activities of the community of Saint Eugene]. AB - The article deals with the role the physicians played in organization and functioning of the Community of Saint Eugene in St. Petersburg in 1882-1918. The typography production of the Community being of interest for history of medicine is examined. PMID- 23033585 TI - [The development of idea of psychiatric care decentralization in late XIX - early XX centuries]. AB - The article demonstrates that over a period of many years the development of national psychiatric care in Russia followed the course of centralization. During the Zemstvo self government period the principle of decentralization was proposed on purpose to make the psychiatric care more accessible for population. PMID- 23033586 TI - [Surgical treatment of patients with supratentorial cavernomas manifested with seizures]. AB - Supratentorial compartment is the most frequent cavernomas location associated with seizures in 50-79% cases. Surgical removal of some cavernomas remains a delicate decision. To assess long-term epilepsy results in consecutive series of patients treated for supratentorial cavernomas. PATIENTS AND METHODS: Single center retrospective study of 302 patients (2002-2010) with operated supratentorial cavernomas was performed. Male: female ratio= 139:163, age ranged 1 to 68 years, mean: 26.4. Multiple lesion were diagnosed in 27 (8.9%) patients, eloquent in 77 (24.9%) cases. Mean follow up was 55.2 months. Functional outcomes using modified Rankin scale and epilepsy outcomes using Engel scale were assessed. Data were statistically analyzed in respect to natural history, lesion type, location, size, extent of resection, use of anti-epileptic drugs, etc. Seizures suffered 74.8% of patients, generalized seizures--79.6% from those who have an epilepsy. In 34.5% of patients epileptic symptoms tended to worsen over time. Seizures improved in 78.2% patients post op, 62.3%--became seizure-free. Early surgery and less than 5 seizures in history were found a reliable predictors of better epilepsy outcome. Drug-resistant subgroup was associated with worse outcomes. Resection of gliosis and tailored ECoG-guided resection with respect to epilepsy outcome were not proved beneficial. Long-term disability was 9%, 3% in non-eloquent and 21% in eloquent and deep cavernomas group. One patient died (0.3%). Surgery remains an effective treatment for recurrent hemorrhage prevention and seizure control with acceptable morbidity. The benefits of surgery for eloquent and deep-seated cavernomas must be accurately weighted with higher risks. For symptomatic non-eloquent cavernomas surgical excision should be considered as soon as possible after disease onset. PMID- 23033587 TI - [First experience of photodynamic diagnosis and laser spectroalanysis in surgery of intracranial meningiomas]. AB - Photodynamic diagnosis (PDD) has been actively implemented into neurooncological practice, especially in cerebral gliomas surgery. This paper describes our first experience of PDD combined with laser spectroanalysis in intracranial meningiomas. The study included 21 patients (8 male and 13 female patients, mean age was 58 years, range--between 37 and 74 years) with intracranial meningiomas operated with PDD in Burdenko Neurosurgical Institute between 2008 and 2011. In 14 cases laser spectroanalysis was used. Tumor fluorescence was present in all but one cases (95%). Spectroanalysis demonstrated that peaks of fluorescence varied between 5 and 46 (mean level was 18.5). These data correlated with visual impression of fluorescence and confirmed that meningioma is a tumor with bright fluorescence. Radical removal (Simpson grade I-II) was achieved in 10 cases, subtotal resection was performed in the rest of the patients. Application of PDD and laser spectroanalysis allows gaining complete information about accumulation of photosensibilizer in the tissue. To our opinion, these methods may be the most useful for determination of the borders of dural and bony invasion which directly affects the surgical tactics and degree of radical removal. Further studies are needed to evaluate the influence of PDD and laser spectroanalysis on long-term surgical outcomes. PMID- 23033588 TI - [Initial experience of treatment of primary intraocular lymphomas associated with primary CNS lymphomas]. AB - Methods of diagnostics of primary intraocular lymphomas associated with primary CNS lymphomas are described. This article demonstrates the value of neurophtalmological assessment before surgery in patients with intracranial space occupying lesions. Three cases with bilateral primary intraocular lymphomas are presented. Authors analyzed initial results of intraocular lymphomas treatment with intravitreal methotrexate injections. PMID- 23033589 TI - [Analysis of thyroid homeostasis disorders in patients with severe traumatic brain injury]. AB - Aim of the study was to investigate the status of thyroid homeostasis and the relationship between severe traumatic brain injury (TBI) and thyroid disorders. The study included 56 patients. Protocol of the study concluded: noninvasive and invasive hemodynamic monitoring, including PICCO, transcranial Doppler ultrasonography, measurement of intracranial pressure (ICP), indirect calorimetry, levels of thyroid stimulating hormone (TSH), T3, T4 and free fractions. Patients were divided into three groups. Group 1--with normal thyroid hormones (n = 20), Group 2--with the low T3 (n = 23) and Group 3 with the low T3 and T4 (n = 13). Correlation between the Glasgow Coma Scale (GCS) and thyroid hormone levels was obtained: the first group between GCS and T4 (r = 0.50), GCS, and free fraction T4 (r = 0.51); between the GCS and TSH (r = 0.51), T3 (r = 0.48) and T4 (r = 0.57) in the second group, and the third--with TSH (r = 0.67). Poor outcomes in the first group compound 15%, in the second group--39.2%, and in the third group--62.5% of patients. Doses of vasopressors were significantly higher in groups 2 and 3 compared with a first group. ICP was significantly higher in the group with the low T3 and T4. Development of intracranial hypertension correlated with the formation of thyroid insufficiency. Deficiency of thyroid hormones, especially the simultaneous reduction and T3, and T4 is associated with poor outcome in patients with severe TBI. Doses of sympathomimetic drugs used to optimize the parameters of systemic hemodynamics in acute severe head injury were higher in patients with deficiency of thyroid hormones. PMID- 23033590 TI - [Protein malnutrition in patient in the early postoperative period after uncomplicated removal of the brain tumors]. AB - Malnutrition leads to adverse effects and may worsen clinical outcome. Surgery as a stress factor activates pathological reactions changing metabolism structure. The aim of this study was to evaluate changes of protein metabolism in patients after elective neurosurgical operation. 24 patients were prepared for elective surgery and were enrolled in this study. Evaluation of each patient included: measurement of anthropometric indices--height, weight, arm circumference and the triceps skinfold thickness, the definition of protein loss by determining the loss of nitrogen in the urine, assessment of protein catabolism, determining the violations of nutritional status upon the base of laboratory parameters. During the course of the conducted investigation significant (p < 0.05) decrease in the indices of total protein, albumin, transferrin and the absolute numbers of lymphocytes in the postoperative period was revealed. All the patients developed severe protein catabolism. It became clear that uncomplicated elective surgical intervention, together with the adopted scheme of the nutritional therapy leads to severe protein catabolism in all patients. PMID- 23033591 TI - [Pain syndrome relapse following herniated disc surgery (diagnosis and treatment)]. AB - The aim of this study was to improve results of treatment of patients with degenerative disc disease at the long-term period after microdiscectomy by developing unique algorithm for diagnosis and treatment of persisting pain syndrome. Patients were divided into two groups. First one included 198 patients with reflex-pain syndromes. In the main subgroup (97 patients) consecutive denervation of spinal facet joints and intervertebral discs was performed to detect referred-pain syndromes. The second group included 64 patients who suffered recurrent nerve-root compression. The main cause was relapse of disc herniation. We used anterior retroperitoneal approach in 34 patients to remove herniated disc and stabilize the segment. Surgery results were assessed by visual analogue scale and Oswestry index. Consecutive chemical denervation of spinal facet joints and intervertebral discs allowed not only to discover referred-pain syndromes, but enabled to control them. Stepwise surgical treatment resulted in clinical recovery and better outcome in 88.7% of our patients. Decompressive stabilizing surgery with anterior interbody fusion is a pathogenetic and technically adequate treatment. The long-term follow up results of surgical treatment were better at the group of our patients operated with anterior retroperitoneal approach and anterior foraminotomy. Excellent and good results were obtained at 79.3% cases. PMID- 23033592 TI - [Botulotoxin type A (lantox) for inducing temporal ptosis in neurosurgical patients]. AB - The aim of our study was to assess the effectiveness of the ptosis induced by injection of Lantox (botulotoxin type A) into levator muscle projection in neurosurgical patients with lagophthalmos and trophic keratitis. The study included 66 patients at the age from 11 to 67 years. Lantox dose used was 10-25 U. Ptosis appeared after 1-7 days. Complete induced ptosis developed in 1-17 days and remained within 6-150 days. Full induced eyelid ptosis developed in 44 patients. Incomplete ptosis was observed in 19 patients. Drug resistance was seen in 3 patients. Our study results demonsrated effectiveness of the induced ptosis: complete recourse of trophic keratitis at development was seen in patients with complete drug-induced ptosis and significant decrease of trophic keratitis was observed in patients with semi-ptosis. PMID- 23033593 TI - [Aneurysm of abdominal aorta resulting in vertebral body destruction. Simultaneous prosthetic repair of aorta bifurcation and anterior lumbar fusion with mesh implant]. AB - This case report describes unique situation of dissecting aneurysm of aorta resulting in L3 vertebral body destruction. Diagnostic work-up that helped to elicit proper diagnosis and surgical management is described. Clinical and neuroimaging results of treatment, as well as detailed literature review are given. PMID- 23033594 TI - [Stepwise treatment of a patient with seven bilateral cerebral aneurysms]. AB - This case report describes successful multistage combined treatment of a female patent with seven bilateral cerebral aneurysms. PMID- 23033595 TI - [Variations of transpedicular screw fixation and spinal dura opening]. AB - The paper presents modified treatment protocols for spinal trauma and degenerative disease--transpedicular screw fixation based upon biomechanical adjustment and spinal dura opening. Both methods help to improve results of surgical treatment and decrease complication rate. PMID- 23033596 TI - [Evidence-based medicine methods and critical reading of the paper devoted to degenerative lumbar and sacral spinal stenosis (comment to the article)]. AB - The paper provides critical analysis of the article "Correlated analysis of radiologic criteria's referred to central degenerative spinal canal stenosis and intensity of clinical implications". Critical analysis was carried out by the 5 step evidence cycle. First step is supposed to formulate primary goal of the research and identify its type. This investigation belongs to prognostic studying of certain patient's characteristics and their impact on the state of disease and the treatment outcome. According to Oxford evidence based center of medicine gradation, this study is attributed to level IV (clinical series). Analysis performed allowed to state that investigation sampling might be considered as representative, but nonhomogeneous. Absence of blind evaluation of the treatment results could alter treatment outcomes when compared by two different scales. Multifactor analysis was not held in the present study. Analyzed investigation has low methodological level, however, it has no major disadvantages. Statistical significance between various factors and clinical effect can be achieved when study is based upon database analysis of many patients, which however cannot be managed by efforts of a single medical institution. Organizing investigations by registration treatment outcomes with follow up evaluation nationwide could be a problem solution. In particular, vertebrological register might be a very useful tool for development prognostic risk scales and predictive models in degenerative spine disease surgery. PMID- 23033597 TI - [Adjuvant therapy of brain tumors in young infants. Review article (Part two)]. PMID- 23033598 TI - Who says risk has to be scary? PMID- 23033599 TI - If it wasn't done, don't document it: tackling E&M coding errors in the age of EHRs. PMID- 23033600 TI - Walking the walk on patient-centered care. PMID- 23033602 TI - Grab it and run! Keep basic insurance information in a place you can get to- fast. PMID- 23033601 TI - 5 unexpected ways of getting sued. PMID- 23033603 TI - Medical group gets 600 percent ROI on self-pay plan. PMID- 23033604 TI - Navigating the ADA labyrinth: Changes to disability laws might be disorienting. PMID- 23033605 TI - For busy medical practices, planning is the only way to stay ahead of a crisis. PMID- 23033606 TI - Navigate RAC audits with exclusive new tool. PMID- 23033607 TI - How fair is fair-market value when it comes to physician compensation? PMID- 23033608 TI - Out to lunch? Patient-centered practices provide more access. PMID- 23033609 TI - Man's best friend. Understanding service dogs. PMID- 23033610 TI - Take notice of nice. And then act upon it. PMID- 23033611 TI - Cancer complications. Heart and electrolyte problems befall a weakened patient. PMID- 23033612 TI - Cardiac zebras. Diagnosing Wellens and Brugada syndromes on 12-lead ECGs. PMID- 23033613 TI - It takes a system to make a save. PMID- 23033614 TI - Current events in cardiac arrest research. PMID- 23033615 TI - Non-ACS chest pain. Some etiologies are life-threatening, and you should know them. PMID- 23033616 TI - 10 Steps for smarter intubation. When to intubate, how to do it quickly and when to do something else. PMID- 23033617 TI - Spirituality in EMS. The relationship between EMS providers and patients is a unique one and spirituality, for some, is part of that connection. PMID- 23033618 TI - The value of EMS. The time to change EMS reimbursement models is now. PMID- 23033619 TI - The most interesting medic in the world. We might not maintain much mystique, but that's OK. PMID- 23033620 TI - Integrated care models: if patients benefit, so will bottom line. PMID- 23033621 TI - SGR reform and nephrology: difficult problems, potential solutions. AB - In light of the massive uncertainty with both the federal government in general and health policy priorities specifically, it is probably constructive to focus on the things we know for sure. In Medicare Part B reimbursement, the SGR system is fundamentally flawed, and must be replaced. All of Congress has recognized this fact, and there is legislation in the House that would move the ball forward on SGR repeal and replacement. Likewise, coordinated care models like ACOs offer a logical process for achieving a triple aim: improving individual health care, improving population health, and promoting cost efficiency in health care. Hopefully, policy makers in Washington will recognize and act on these truths as well. PMID- 23033622 TI - Is it time for a new renal diet? Reevaluating the role of plant-based foods in the dialysis diet. PMID- 23033623 TI - HIPAA: privacy, security and the consequences of a breach for dialysis providers. PMID- 23033624 TI - Education cuts "disaster". PMID- 23033626 TI - "Wielding his magic water, the new health secretary steps in". PMID- 23033625 TI - "Employers have to bring the South West back into line". PMID- 23033627 TI - "Moving patients is far more than just inconvenient". PMID- 23033629 TI - Transforming nursing leadership development. PMID- 23033628 TI - Supporting people living with and beyond cancer. AB - The number of people living with cancer in the UK is increasing by 3.2% per year. The current system of follow-up is not meeting needs and this will worsen if the number of people living with cancer continues to increase at this rate. Emerging models of aftercare show that care needs should be assessed at key transition points and care plans developed to reflect the levels of risk. We cannot afford to double the workforce to meet future needs, so we will have to do things differently. Over the next two years Macmillan Cancer Support will be piloting four new roles across the UK and will later publish the full evaluation results. PMID- 23033630 TI - Raising cancer awareness in minority ethnic groups. AB - Awareness of cancer and uptake of screening is lower among some black and minority ethnic groups than in the white British population, yet incidence of some cancers is higher. The National Cancer Action Team has set up a pilot with a number of BME communities to improve screening uptake and understanding of early signs and symptoms of cancer by increasing cancer awareness and dispelling myths and misconceptions. PMID- 23033631 TI - Introducing care rounds using rapid spread. AB - Rapid Spread is designed to introduce evidence-based practice in a nonincremental style so that all affected areas implement the changes at the same time. This article describes how care rounds were introduced to all inpatient wards in a large acute trust using a Rapid Spread approach. It discusses the rationale for, responses to, and the sustainability of, the care round concept. PMID- 23033632 TI - Ethical issues around continuous deep sedation without hydration. AB - By reviewing the literature on the subject, this article examines whether continuous deep sedation without hydration--in the context of palliative care for patients with advanced cancer at the end of life--could be seen as a moral and clinical equivalent of so-called "slow euthanasia". It focuses on length of survival, fluid retention and thirst, and reviews the evidence and lack of it that supports or questions the practice of withholding parenteral fluids at the sedated and palliated end of life. PMID- 23033633 TI - Moving forward in arthritis care. PMID- 23033634 TI - The secret of success. PMID- 23033635 TI - Ambient air sulphur dioxide and sulphate accumulation in deciduous and evergreen plants. AB - Present study is an attempt to evaluate the difference in rate of sulphur dioxide (SO2) absorption by deciduous (Ficus religiosa) and evergreen (Carica papaya) plants, under elevated concentration of the gas in ambient air. Two-way ANOVA for SO2 in air and sulphate (SO4) accumulation in both the selected plants showed significant difference (p<0.01) at different study sites; different months as well as interaction effect of both site and months. The linear correlation coefficient among ambient air SO2 and SO4 in leaves was always significant (p<0.001) in case of deciduous plant; however, the same in evergreen plants showed heterogeneous result. Air pollution tolerance index (APTI) of F. religiosa (deciduous) and C. papaya (evergreen) was found to be 19.73 and 81.10 respectively, proving that the former has low tolerance capacity and is sensitive, while the latter is resistant to the elevated ambient air SO2. PMID- 23033636 TI - Optimization of solid state fermentation conditions for the production of cellulase by Trichoderma reesei. AB - Cellulase production studies have been carried out using the fungal strain Trichoderma reesei NCIM 992 by using three different lignocellulosic materials by solid state fermentation (SSF). The effect of basic fermentation parameters (pH, temperature, moisture content, particle size of substrate and moistening agent) on enzyme production was studied. Maximum cellulase production was 2.63 U ml(-1) using wheat bran as substrate. The optimal conditions forcellulase production forwheat bran were found to be: initial moisture content - 70%, initial medium pH 5.0, temperature-30 degrees C, moistening agents (MSS) and particle size of substrate (500 microm).The optimal incubation time for production was six days. Results indicate the scope for further optimization of the production conditions to obtain higher cellulase titres using the strain under SSF. PMID- 23033637 TI - Comparative studies on antioxidant enzyme action and ion accumulation in soybean cultivars under salinity stress. AB - Plant biomass, antioxidant enzymes activity, ions accumulation and proline level in four soybean cultivars were investigated atdifferent NaCl concentrations (20, 40, 60, 80 and 100 mM) applied to plants 15 days after sowing. There was a significant decrease in plant biomass and soluble protein content with each NaCl treatment. Accumulation of Na+ and Cl- was maximum in roots, followed by the stem and leaves in all the treated cultivars; Pusa 9712 being the top accumulator. On the contrary, K+ and Ca2+ ion concentrations were inhibited in all the treated cultivars. Activities of antioxidant enzymes (superoxide dismutase, ascorbate peroxidase and glutathione reductase) and proline content increased significantly in all the cultivars with each NaCl treatment. The maximum increase was found in Pusa 9712. However, catalase activity decreased in all the cultivars except in Pusa 9712. On the whole, Pusa 9712 was most efficient in managing protection against salinity stress. PMID- 23033638 TI - Phytotoxic effect of 2-benzoxazolinone (BOA) against some vegetable crops. AB - Benzoxazolin-2(3H)-one (BOA) is a well known allelochemical that is being explored for its herbicidal activity. However, not much is known about its effect on crop plants. The present study investigated the effect of BOA on germination and early growth of four vegetable crops viz. Pisum sativum L., Raphanus sativus L., Brassica oleracea L. var. botrytis and Brassica oleracea L. var. capitata. At 1000 microM, germination of P. sativum, R. sativus and B. oleracea var. botrytis was reduced by more than 50%, whereas that of B. oleracea var. capitata was completely suppressed. Further, BOA reduced the root and shoot length of the test plants by approximately 40-82% and approximately 55-85%, respectively. In general, the effect was more pronounced on the root (approximately 82% in B. oleracea var. botrytis) than on the shoot growth (approximately 73% B. oleracea var, botrytis). 2-Benzoxazolinone significantly enhanced the contents of proteins (by 6-28%) and carbohydrates (by 61-189%) in B. oleracea var. capitata and decreased the activities of related enzymes like proteases (by 13-36%), alpha amylases (19-60%) and beta-amylase (25-70%). The observed decline in the activities of hydrolytic enzymes amylases suggest that BOA interferes with the vital metabolic processes in the germinating seedlings leading to growth reduction. The study reveals that BOA interferes with the germination and early seedling growth of vegetable crops and induces biochemical alterations. PMID- 23033639 TI - Removal of heavy metals by biosorption using freshwater alga Spirogyra hyalina. AB - The use of biosorbents for heavy metal removal has revealed enormous potential of algae for biosorption. The dried biomass of Spirogyra hyalina was used as biosorbent for removal of cadmium (Cd), mercury (Hg), lead (Pb), arsenic (As) and cobalt (Co) from aqueous solutions atdifferent initial concentrations of the heavy metals and contact time of the biomass. The results showed that highest amount of Cd, Hg and As was adsorbed when the initial heavy metal concentration was 40 mg l(-1) whereas Pb and Co exhibited greatest removal at 80 mg l(-1). The value of Freundlich model constant (1/n) for different metals ranged from 0.342 to 0.693 and the values of Langmuir separation factor values (R(L)) varied between 0.114 and 0.719 that indicated favorable biosorption by the biomass. The order of metal uptake for the dried biomass was found to be Hg>Pb>Cd>As>Co. The finding of the study revealed that dried biomass of S. hyalina has much potential as a biosorbent for the sorption of Cd, Hg, Pb, As and Co. PMID- 23033640 TI - Effect of methomyl formulation, a carbamate pesticide on ovarian follicular development and fertility in albino mice. AB - Administration of 5 mg methomyl (40%) kg(-1) b.wt. mouse(-1) (equal to 50% of LD50 dose), every day for 90 days to adult female mice resulted in a significant decrease in body weight, relative weight of the ovary, uterus and fallopian tube; mean number of small, preantral, antral and pre-ovulatory follicles and fertility compared to controls. On the other hand, total duration of the estrous cycle was significantly increased compared to controls. One month after the cessation of the treatment (a commercial methomyl preparation-lannate) the effect on estrous cycle and organ weight was not restored. Treatment of 2.5 mg or 1 mg lannate kg( 1) b. wt., although did not alter duration of the estrous cycle; relative weight of the ovary, uterus, and fallopian tube and fertility, caused a significant decrease in mean number of small follicles compared to controls. All the groups of mice treated with lannate showed loss in body weight (15.15% in 1 mg, 6.61% in 2 mg and 12.16% in 5 mg treated groups) whereas controls showed a gain in body weight (20.02%) during the period of experimentation. The results indicate that 5 mg lannate kg(-1) b. wt causes loss of follicles and infertility, whereas lower dosages (2.5 and 1 mg) reduce the number of small follicles which might shorten reproductive life span of mice. PMID- 23033641 TI - Effect of leather industry effluents on soil microbial and protease activity. AB - Release of leather industry effluents into the agricultural fields causes indicative changes in nutrient cycling and organic matter processing. In the present study, leather industry effluent discharged soil (test) and undischarged soil(control) were collected from the surrounding areas of industry. The physico chemical, biological properties and soil protease activity were examined. The study reflected the average mean value of pH, electrical conductivity and water holding capacity of the test soil was found to be 7.94, 0.89 microMhos cm(-1) and 0.51 ml g(-1), respectively. In chemical parameters, organic matter, total nitrogen, phosphorus and potassium has the mean of 6.73%, 0.23 g kg(-1), 4.28 mg g(-1) and 28 microg g(-1), respectively. In all the respects, the test soil showed higher values than the control. The soil protease enzyme activity was determined by using substrate casein and the activity was found to be higher (180 microg TE g(-1) 24 hr(-1)) in test soil than the control soil (63 microg TE g(-1) 24 hr(-1)). PMID- 23033642 TI - Conservation of soil, water and nutrients in surface runoff using riparian plant species. AB - Three riparian plant species viz. Cynodon dactylon (L.) Pers., Saccharum bengalensis Retz. and Parthenium hysterophorus L. were selected from the riparian zone of Kali river at Aligarh to conduct the surface runoff experiment to compare their conservation efficiencies for soil, water and nutrients (phosphorus and nitrogen). Experimental plots were prepared on artificial slopes in botanical garden and on natural slopes on study site. Selected riparian plant species showed the range of conservation values for soil and water from 47.11 to 95.22% and 44.06 to 72.50%, respectively on artificial slope and from 44.53 to 95.33% and 48.36 to 73.15%, respectively on natural slope. Conservation values for phosphorus and nitrogen ranged from 40.83 to 88.89% and 59.78 to 82.22%, respectively on artificial slope and from 50.01 to 90.16% and 68.07 to 85.62%, respectively on natural slope. It was observed that Cynodon dactylon was the most efficient riparian species in conservation of soil, water and nutrients in surface runoff. PMID- 23033643 TI - Remediation of nitrite contamination in ground and surface waters using aquatic macrophytes. AB - The study was carried out to determine the seasonal variation of nitrite levels in drinking and surface waters of urban, peri-urban and rural areas of Lucknow, during 2007-2008, and to evaluate the nitrite removal and accumulation potential of certain native aquatic macrophytes. Most of the drinking and surface water samples were collected from urbanized region of the city. All drinking water samples detected, showed higher nitrite level in winter, when compared with that in summer and rainy seasons. However, in drinking water samples nitrite level was below the permissible limit i.e. 3.29 mg l(-1) NO2. The surface water showed more than 3 fold higher levels of nitrite over the permissible level i.e. 0.06 mg l( 1), and the level was higher during rainy season than in summer and winterseasons. Eight macrophytes viz. Peltandra virginica, Utricularia vulgaris, Eichhomia crassipes, Trapa natans, Mimulus glabratus, Marsilea quadrifolia, Pistia stratiotes and Polygonum persicaria were studied for phytoremediation potential of nitrite from the water under simulated laboratory conditions. The gradual diminution in the level of nitrite in the water and simultaneously it's increase in the plant tissues was recorded at 5th, 10th and 15th d after plant culture. All the plants selected, removed nitrite from water but Polygonum persicaria, Mimulus glabratus, Trapa natans and Pistia stratiotes were found more efficient and removed nitrite upto 60.91, 58.09, 60.97 and 72.28%, respectively. Observations revealed that Pistia stratiotes can be used forthe effective removal of nitrite from the contaminated water. PMID- 23033644 TI - Development of polyvinyl chloride biofilms for succession of selected marine bacterial populations. AB - Present investigation was made to bring out the pattern of biofilm formation by heterotrophic bacteria on nontoxic material, polyvinyl chloride (PVC) sheet fitted wooden rack that was immersed in seawater and the study was conducted in Tuticorin coast. Samplings were made over a period of 7 days with the following time period intervals: 30 min, 1, 2, 4, 24, 48, 72, 96, 120 and 144 hr. Bacterial enumeration was made by spread plate method on nutrient agar medium and characterization of bacterial isolates up to generic level was done. Gram negative bacteria like Pseudomonas sp., Enterobacter sp., Aeromonas sp., Cytophaga sp. and Flavobacterium sp. were found to be the pioneer in colonizing the surface within 30 min and seven genera were represented in the biofilm. Among them two genera were found belonging to Gram-positive groups which included Micrococcus and Bacillus sp. The early stage biofilm i.e. up to 24th hr was wholly constituted by Gram-negative groups. However, the population density of Pseudomonas sp. was found to be higher (315 CFU) when compared to other Gram negative forms. Occurrence of Gram-positive group was noted only at 48th hr old biofilm (28 to 150 CFU). The period between 48 and 96th hr was the transition where both the Gram-negative and Gram-positive groups co- existed. After 96th hr, the biofilm was found constituted only by Gram-positive groups. The isolates of early stage biofilm were found to produce allelopathic substance like bacteriocin. PMID- 23033645 TI - Distribution of potentially pathogenic enteric bacteria in coastal sea waters along the Southern Kerala Coast, India. AB - This study evaluated the relationship between the traditional indicators of faecal pollution, total coliforms (TC), faecal coliforms (FC) and Faecalstreptococci (FS), and the presence of few potentially pathogenic enteric bacteria, Vibrio cholerae (VC), Vibrio parahaemolyticus (VP), Shigella spp. (SH) and Salmonella spp. (SL) in coastal sea water. The distributional statuses of these bacteria were also studied along the Southern Kerala coast. Cluster analyses were done to identify similar groups of indicator as well as enteric pathogenic bacteria. Kochi was found to be highly polluted with enteric pathogens and indicator bacteria (TC of 4700, VC of 820, FC of 920 and FS of 410 CFU ml( 1)). Percentage incidence of VC (97.42%) was comparatively higher than the traditional indicator bacteria (TC 95.04%, FC of 63.64% and FS of 47.64%). VC found to be rather stable and showed significant relationship with all the traditional indicator bacteria (R2 > 0.370), suggests that both quantitatively and qualitatively the abundance of Vibrio cholerae can determine faecal pollution, could be used as a faecal pollution indicator bacterium, especially in the marine environment where traditional indicator bacteria failed to survive. It would be advisable to always perform the detection of SH and VP beside the traditional indicators as no significant relationship (R2< or =0.076, p>0.05) exists among them. PMID- 23033646 TI - Characterization of light gaseous hydrocarbons of the surface soils of Krishna Godavari basin, India. AB - Several techniques are used for the exploration of hydrocarbons, of which; the geochemical techniques involving the microbiological technique use the principle of detecting the light hydrocarbon seepage activities for indication of sub surface petroleum accumulations. Asurvey was carried out to characterize the light gaseous hydrocarbons seeping in oil and gas fields of Krishna-Godavari basin ofAndhra Pradesh. Aset of 50 sub-soil samples were collected at depths of about 3 m for geochemical analyses and 1m for microbiological analysis. The microbial prospecting studies showed the presence of high bacterial population for methane 2.5 x 10(2) to 6.0 x 10(6) cfu g(-1), propane 1x10(2) to 8.0 x 10(6) cfu g(-1) in soil samples. The adsorbed soil gas analysis showed the presence of moderate to low concentrations of methane (26 to 139 ppb), ethane (0 to 17 ppb), propane (0 to 8 ppb), butane (0 to 5 ppb) and pentane (0 to 2 ppb) in the soil samples of the study area. Carbon isotope analysis for methane ('13C1) ranging from -36.6 to -22.7 per hundred Pee Dee Belemnite (PDB) suggests these gases are of thermogenic origin. Geo-microbial prospecting method coupled with adsorbed soil gas and carbon isotope ratio analysis have thus shown good correlation with existing oil/gas fields of Krishna-Godavari basin. PMID- 23033647 TI - Production and characterization of carboxymethyl cellulase from Paenibacillus polymyxa using mango peel as substrate. AB - Mango peel, a solid mango processing waste, comprises 15-20% of total fruit weight. This, being a rich source of lignocelluloses, was used as substrate for carboxymethyl cellulase (CMCase) production using Paenibacillus polymyxa. Maximum CMCase production (7.814 U mg(-1)) was observed in a medium containing 7% mango peel (w/v) with 1.5% ammonium sulphate (w/v) at 37 degrees C and pH 5.5. Purification to an extent of 28.24 fold was achieved by affinity column chromatography. Bands corresponding to 26.5 and 34.0 kDa molecular sizes were observed on 12% denaturing Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) while of 72 kDa on 10% non-denaturing Native-PAGE, proving its heteromeric multienzyme nature. The enzyme was stable over a range of 20-60 degrees C and pH of 4.0-7.5. Michaelis-Menten equation constant (Km and Vmax) values of purified CMCase were 8.73 mg ml(-1) and 17.805 mM ml(-1) min(-1), respectively. PMID- 23033648 TI - Influence of drying of biosludge on organochlorine compounds from pulp and paper industry. AB - Pulp and paper industry is one of the major sources of man-made generation of organochlorine compounds. During biological treatment of wastewater, part of organochlorine compounds is discharged with treated effluent and part is retained on biomass and disposed of as waste activated sludge. Due to presence of these compounds, the disposal of biosludge from pulp and paper industry has become an issue. The estimation of adsorbable organic halogen (AOX) compounds after drying and grinding resulted in 49% lower concentration of AOX due to stripping of purgeable compounds. These purgeable compounds are not released at 60 degrees C in aqueous medium during estimation of purgeable organic halogen (POX) compounds. Dispersion of sludge by sonication overcomes the loss of POX compounds and results in higher concentration ofAOX compounds. The drying of biosludge samples at 45, 100 degrees C and in presence of sun light resulted in 20.1, 49.0 and 29.6% removal of purgeable AOX compounds, respectively. The lab scale sorption study using dichloromethane (as volatile organochlorine compound) reveal that biosludge from pulp and paper industry is a good adsorbent of volatile organochlorine compounds and results in poor release of these compounds during estimation of POX compounds. PMID- 23033649 TI - Steroidal feedback on photoperiodic induction of testicular growth and development in two bird species. AB - Present study was performed to demonstrate the effect of exogenous administration of testosterone propionate on photoperiodic induction of testicular growth and development in brahminy myna (Sturnus pagodarum) and baya weaver (Ploceus philippinus). Two groups of brahminy myna and baya weaver (n=5 each) were exposed to 15L:9D (group-I) and 9L:15D (group-II), and received 30 microg of TP bird(-1) for 15 days. Then, the photoperiod was reversed; the one receiving 15L was exposed to 9L and vice versa. Observations on body mass and testis volume were taken at the beginning and at 15 days interval. In brahminy myna, a significant change in body mass occurred under 9L:15D, transfer to 15L:9D, but not under 15L:9D group, transfer to 9L:15D. Also, testes were stimulated under 15L:9D transferred to 9L:15D, but not under 9L:15D transferred to 15L:9D. In baya weaver, body mass increased under 15L:9D and 9L:15D for first 15 days and was maintained until the end of the experiment. Testes enlarged gradually in both groups (15L:9D and 9L:15D transfer to vice versa), but it regressed in 15L:9D group, transferred to 9L:15D after 45 days. Taken together it appears that body mass response indicates the photoperiodic effect and gonadal response indicates the hormonal effect. Finally results conclude that the photoperiod and circulating testosterone levels feedback on to hypothalamus regulates reproductive cycle in these birds. PMID- 23033650 TI - Studies on effects of Emblica officinalis (Amla) on oxidative stress and cholinergic function in scopolamine induced amnesia in mice. AB - Emblica officinalis, commonly known as amla, is an important medicinal plant of India. Its fruits have potent antioxidant activity due to the presence of tannoids, tannins, vitamin C and flavonoids. The aim of this study was to investigate the beneficial effect of the hydroalcoholic extract of the fruits of Emblica officinalis (EO) on memory impairment in Swiss albino mice. Scopolamine (1 mg kg(-1), i.p)was administered to induce amnesia and the memory was evaluated by using elevated plus-maze and passive avoidance tests. Piracetam (200 mg kg( 1), i.p.) was used as a standard nootropic agent. The EO extract was administered intraperitoneally in four graded doses (150, 300, 450 and 600 mg kg(-1)) for 7 consecutive days to different groups of mice. The mice were sacrificed on the 8th day following assessment of memory. The brain malondialdehyde (MDA) and glutathione (GSH) as well as acetylcholinesterase (AchE)) activity was determined. It was observed that EO extract reversed the amnesia induced by scopolamine. The mean transfer latency and retention latency in the EO extract 600 mg kg(-1) group vs the vehicle treated scopolamine group was 13.46 sec (p<0.001) and 134.4 sec (p<0.001) vs 23.99 sec and 44.55 sec, respectively. EO extract treatment also significantly (p<0.001) ameliorated the oxidative stress induced by scopolamine administration. The mice brain MDA and GSH levels in the EO extract 600 mg kg(-1) group vs the scopolamine group were 29.95 nmol g(-1) of wet tissue and 51.87 microg g(-1) tissue vs 55.22 nmol g(-1) of wet tissue and 28.33 microg g(-1) tissue, respectively. Further, EO extract (300, 450 and 600 mg kg(-1), i.p) significantly (p<0.001) reversed the rise in brain acetyl cholinesterase (AchE) level induced by scopolamine. The mice brain Ach E levels in the EO extract 600 mg kg(-1) group as compared to the scopolamine group was 70.23 vs 151.49 U mg(-1) protein(-1), respectively. These results suggestthat EO possesses memory enhancing, antioxidant and anti-cholinesterase activity. It may be useful for the treament of cognitive impairments induced by cholinergic dysfunction. Its potential in the management of dementia and Azheimer disease needs to be further explored. PMID- 23033651 TI - Studies on spatio-temporal dynamics of phytoplankton in El-Umum drain in west of Alexandria, Egypt. AB - Phytoplankton was assessed quantitatively and qualitatively in regard to their abundance in the northern part of El-Umum drain, west of Alexandria at four stations to study the spatial, temporal, dominance and abundance of the phytoplankton community. The samples were collected monthly from April 2003 to April 2004. Atotal of 152 phytoplankton taxa were identified belonging to Bacillariophyceae (60), Chlorophyceae (46), Cyanophyceae (20), Euglenophyceae (17) and Dinophyceae (9). A limited number of these were recorded throughout the year, and showed an indication of organic pollution. The total densities (333.8x10(3) units l(-1)) were mainly a reflection of the trends in counts of Bacillariophyceae and Chlorophyceae (138.1 x 10(3) and 131.6 x 10(3) units l(-1), respectively). Monthly differences in the quantitative (18 x 10(3) to 1645 x 10(3) units l(-1)) and qualitative composition (41 to 113 taxa) of the phytoplankton communities in the different stations were marked, with recurrent high abundance in spring (910.4 x 10(3) units l(-1)), whereas lowest densities occurred in autumn (99.7x10(3) units l(-1)). Cyanophyceae was most abundant in July (67.5 x 10(3) units l(-1)), whereas Euglenophyceae in December (32.0x10(3) units l(-1)). Species diversity (H') gave a signal of the area is light to moderate polluted. The present study emphasized the need to use phytoplankton community as index of water quality. PMID- 23033652 TI - Temporal and spatial distribution of physico-chemical parameters in an anoxic lagoon, Aitoliko, Greece. AB - Temporal and spatial distribution of physico-chemical and water quality parameters and their correlation with meteorological and hydrological data, was investigated for anoxic lagoons, in Greece. Monthly variations of parameters like temperature, salinity, dissolved oxygen, chlorophyll-a, total phosphorus etc., along the Aitoliko lagoon water column, were recorded and studied at 14 stations. Throughout the sampling period, in lagoon's water column three layers were determined: the surface low density layer (11.49-16.15), the layer with the steep density gradient and the deep dense (19.78-20.62) water below the depth of 20 m. The depth of the surface and pycnocline layers depends on seasonal surface salinity (20.53-22.43 per hundred) and temperature (12.48-28.40 degrees C) alterations. Lagoon's monimolimnion was extended, below the depth of 20 m and had constant temperature and salinity equal to about 13 degrees C and 27 per hundred respectively. Meteorological conditions control temperature (R2=0.845) and dissolved oxygen (R2=0.576) monthly changes, in lagoon's epilimnion, while salinity seems to be related with the salt/fresh water budget into Aitoliko lagoon. Epilimnetic chlorophyll-a (3.29-14.89 microg l(-1)) and total phosphorus (13.33-36.31 microg l(-1)) concentrations classify Aitoliko lagoon as a mesotrophic environment (40400,000 cells ml(-1), respectively. Data were analyzed by SPSS, and no statistical difference was found in each parameter by SCC thresholds. However, significant (P<0.01) difference was determined among MD means by NM groups. Estimated correlation (r=0.47; P<0.01) indicated that lower NM causes to shorter MD during milking activity. The results of the study suggest that dairy farmers should focus on milking factors to obtain more quality milk. PMID- 23033655 TI - Macroenvironmental influence on Hepatozoon lacertilis infectivity to lizard Hemidactylus flaviviridis. AB - Hemidactylus flaviviridis Ruppell, 1835 (n= 199) sampled during different seasons from Bareilly (Uttar Pradesh, India) were infected with a sporozoan parasite belonging to the genus Hepatozoon Miller, 1908. Four morphovariants of the parasite, Type I, II, III and IV were identified on their growing pattern. When compared with earlier reported species, the parasite could be characterized taxonomically by its comparatively greater length 17.35 (13.57-21.30) microm and width 7.51 (5.59-10.11) microm, unusual larger size of parasite nuclear length 8.86 (4.75-15.83) microm and width 3.55 (2.14-5.11) microm and cytomorphological differences. These characteristics warrant creation of a new species and was named Hepatozoon lacertilis sp. nov. The morpho-variants, their effect on hostcell and host nuclei are clearly illustrated. The influence of macroenvironmental factor (host sex) on parasitic infectivity indicated that it was 7.14% prevalant in male and 6.25% in female Hemidactylus flaviviridis. PMID- 23033656 TI - Glutathione S-transferase and metallothionein levels in the freshwater prawn Macrobrachium malcolmsonhi exposed to mercury. AB - Healthy juveniles of M. malcolmsoniiwere exposed to 24.1 microg l(-1) of mercury (96 hr LC50: 145 microg l(-1) Hg) for a period of 21 days. The hepatopancreas and gills of the prawns were sampled on 8th, 15th and 22nd day of exposure. Accumulation and elimination of Hg, activity of glutathione S-transferase (GST), content of glutathione (GSH) and metallothionein (MT) level were studied. Mercury accumulation was found to be higher in the hepatopancreas (88.60 microg g(-1)) and lower in the gills (67.8 microg g(-1)). However, Hg elimination was found to be faster in the gills (62%) and slower in the hepatopancreas (58%). Therefore, the rate of Hg elimination did not match the rate of its uptake. The activity of GST was found to be higher in tissues of test prawns (5.94-9.13 nmol mg(-1) protein min(-1)) on all sampling days when compared with controls (3.454.23 nmol mg(-1) protein min(-1)). Similarly, the content of GSH was found to be higher in tissues of test prawns (0.80-1.43 micromol g(-1) protein) on all sampling days when compared with controls (0.55-1.00 micromol g(-1) protein). These results indicate the formation of glutathione conjugate in test prawns to eliminate Hg. The induction of MT level was also found to be higher in tissues of test prawns (57.50-75.76 nmol g(-1) protein) on all sampling days when compared with control (20.24-45.22 nmol g(-1) protein). This indicates the fact that sequestration of Hg has occurred for its easy elimination. Thus, induction of GST-GSH and MT ensured protection and adaptation of test prawns to thrive in Hg contaminated environment. PMID- 23033657 TI - Acute and chronic toxicity of copper on aquatic insect Chironomus ramosus from Assam, India. AB - Acute toxicity of copper (Cu) on Chironomus ramosus was determined by exposing third-instar larvae to graded concentrations of copper sulphate (CuSO4 x 5H2O). Median lethal concentrations (LC50) of Cu as CuSO4 at 24, 48, 72 and 96 hr were determined as 3280, 1073.33,780 and 183 microg l(-1), respectively. For determining the effects of chronic toxicity, small first-instar larvae were individually exposed to sublethal concentrations of copper sulphate (1.0-18.0 microg l(-1)) for a period of 21 days. Discoloration and thinning of body were detected at 1 microg l(-1) and ventilation movements, pupation and adult emergence were significantly affected at 1.8 microg l(-1). At 10 microg l(-1) CuSO4 concentration, growth and tube-building activities of the larva were significantly different from the control. PMID- 23033658 TI - Studies on the distribution of bacterial isolates in rare earth environment. AB - Rare earth soil is precious, but very common across Arabian coast especially in Chavara, (Quilon district, Kerala) south west coast of India. They are widely distributed but usually occur in small amounts and enhance the soil properties. In the present study, 18 different bacterial isolates were identified from three different samples such as soil and biofilm formed on metal surfaces from the rare earth environment of Chavara using 16S rDNA gene sequencing. The accumulation of rare earth elements (REE) by microbes was studied using FT-IR analysis. In the FTIR spectrum of the test system, a peak at 1548 and 1449 cm(-1) indicates the presence of aromatic nuclei (carboxylic acid), while C=C stretch for C-O-C group was noticed at 1237 cm(-1). Thus significant variations in the peak position confirm the presence of carboxyl group and thus it was confirmed that rare earth elements induce the bacteria to produce carboxylic acid and thereby accumulate rare earth elements. PMID- 23033659 TI - Time-dependent FTIR spectral changes in rats of massive hemorrhage death during the later postmortem period. AB - The aim of the current study was to investigate the spectra in the different organs of the rats which died of massive hemorrhage; to explore their spectral changes 15 days postmortem and the best mathematical model with different band absorption ratio changes to postmortem interval(PMI); and to compare the spectral changes of different temperature. Thirty male Sprague-Dawley rats were sacrificed by cutting abdominal aorta, and the cadavers were divided equally and kept at 4 degrees C, 20 degrees C and 30 degrees C in the control chamber. From the same rat, seven different organs were sampled at intervals of 1-15 days postmortem, and then measured by Fourier transfom infrared (FTIR) spectrometer. Six mathematical model functions were explored. The absorbance of bands and band absorbance ratios of absorption peak in each organ showed a time-dependent increase or decrease, most band absorbance ratios remaining stable for 7-15 days postmortem. Cubic model functions of the various bands absorbance ratios against PMI showed a stronger related coefficient. The absorbance bands with obvious changes at 20 degrees C showed stabilized tendencies at 4 degrees C and significant changes at 30 degrees C within 15 days postmortem. In addition, FTIR spectroscopy revealed a time-dependent metabolic process, with potential of being used to estimate PMI during 7 days postmortem, which merits further investigation. PMID- 23033661 TI - [Expression of fas protein of myocardium in dilated cardiomyopathy]. AB - OBJECTIVE: To investigate Fas protein expression of the myocardium in dilated cardiomyopathy (DCM) and its relationship with occurrence of sudden death caused by DCM. METHODS: Nine autopsy cases of sudden death caused by DCM along with the heart samples were chosen from the archives in the Department of Forensic Medicine, Tongji Medical College, HUST from 1997 to 2007. Other 11 cases which died of violence and other diseases were selected as the control group. Expressions of myocardial Fas protein in the samples were quantitatively detected by immunohistochemistry and computerized imaging analysis. RESULTS: Myocardial Fas protein expression increased significantly in the DCM group. Positive color showed brown-yellow granulated or striped distribution in the longitudinal section of myocardial within the cell membrane and cytoplasm, and showed circular brown granules in the cross section of the cell membrane, while these changes were not observed in the control group though there was focal weak staining noted. Statistical significance was observed between the experimental and control groups (P = 0.002), but no statistical significance was found for the average optical density value between these two groups (P = 0.675). CONCLUSION: The expression of Fas protein increased obviously in the DCM group. Such alteration in expression quantity and distribution of myocardial Fas protein may be related to arrhythmia and heart failure in the patients with DCM. PMID- 23033660 TI - [Changes of left ventricular myocardial collagen fibers and osteopontin expression in hypertrophic cardiomyopathy]. AB - OBJECTIVE: To investigate the changes of collagen fibers and the expression of osteopontin in the left ventricle in cases of hypertrophic cardiomyopathy (HCM), along with the significance of their potential forensic application. METHODS: Fifteen cases of HCM, 15 cases of coronary heart disease with cardiac hypertrophy and 20 cases of traffic accidents were selected as HCM group, coronary heart disease group and control group, respectively. Collagen volume fraction and osteopontin expression were observed and compared by HE staining, Masson trichrome staining and immunohistochemistry methods. Imaging and statistical methods were used for quantitative analysis. RESULTS: Collagen volume fraction in left ventricle of HCM and coronary heart disease were significantly higher than that in the control group (P < 0.05), which was not significantly different between the HCM group and the coronary heart disease group. The integral light density value of osteopontin in left ventricular cardiomyocytes of the HCM group and the coronary heart disease group were significantly higher than that of the control group (P< 0.05), and the value of the HCM group was also significantly higher than that of coronary heart disease group (P < 0.05). CONCLUSION: The increased contents of collagen fibers and the overexpression of osteopontin may play an important role in myocardial fibrosis, and they can be used as markers in aid of diagnosing sudden death due to HCM. PMID- 23033662 TI - [Magnetic resonance diffusion tensor imaging for diagnosis of pyramidal tract damage in rats]. AB - OBJECTIVE: To explore the applicability of magnetic resonance diffusion tensor imaging (DTI) for diagnosis of pyramidal tract damage in rats. METHODS: Marmarou's model was set up, followed by DTI scanning at 3, 12, 24 and 72 h post trauma to acquire the dispersion parameter of bilateral pyramidal tracts. Moreover, axonal varicosities per square millimeter and the percentage of positive area of axons demonstrated by beta-amyloid precursor protein (beta-APP) immunostaining were obtained, as well as the mean density and sum density of neurofilament (NF) 68 immunostaining. RESULTS: Axial diffusivity (AD), fraction anisotropy (FA) and relative anisotropy (RA) in the pyramidal tract were significantly and continuously reduced and reached to the bottom at 72h post trauma (P < 0.05) in accord with the gradient of axonal damage verified by beta APP and NF68 immunostaining. Furthermore, the changes of AD, FA and RA showed a significant negative correlation with the beta-APP immunohistochemical results. CONCLUSION: DTI has important value for early diagnosis in pyramidal tract damage. PMID- 23033663 TI - [Different expression of TNF-alpha in brain and peripheral organs after cerebral contusion of rats]. AB - OBJECTIVE: To compare the expression of tumor necrosis factor-alpha (TNF-alpha) between brain and peripheral organs after cerebral contusion in order to provide the scientific theoretical basis for forensic pathological diagnosis and wound age estimation. METHODS: Brain and peripheral organs including heart, liver, spleen, lung, kidney tissues of 45 SD rats after the cerebral contusion were obtained and TNF-alpha of these tissues were analyzed with immunohistochemistry methods. RESULTS: TNF-alpha was detected at 1 h in brain, reaching maximum at 6 h and 3 d after the cerebral contusion, and then decreased but still kept at high expression level at 7 d. TNF-alpha was detected at 1 h after the cerebral contusion in heart, liver, spleen, lung and kidney tissues. The number of cells expressing TNF-alpha increased gradually, reaching maximum at 3 d after the contusion of brain, and then decreased but still kept at high expression level at 7 d. CONCLUSION: Besides the change of cerebral contusion, this study considered both the brain and peripheral organs. It is helpful for forensic pathological diagnosis and wound age estimation after contusion of brain. PMID- 23033664 TI - [Distribution of diatoms in central city of Beijing]. AB - OBJECTIVE: To explore the quantity and distribution of diatoms in main rivers and lakes in Xicheng, Dongcheng, Chaoyang, Haidian, Fengtai and Shijingshan Districts of the city of Beijing. METHODS: Water samples were examined through the method of disorganizing, which were collected from 16 rivers and lakes in the central city of Beijing in September and October 2011. Diatom species and proportions of water samples were analyzed using DotSlide microscope station. RESULTS: A total of 10 species of diatoms were detected. Cyclotella, Synedra and Melosira etc. were found to be the dominant species via quantitative analysis. Significant differences were observed for diatom species and proportions among the different rivers and lakes. Melosira was found to be the dominant species in the Chang River; Synedra, in the Zhuan River, the Kunyu River and the Taoranting Park; Cyclotella, in the East Moat River, the Ba River, the Liangshui River and the Yongding River; and Navicula, in the Liangma River; Nitzschia, in the diversion canal of the Yongding River. CONCLUSION: The features of distribution of diatoms in the central city of Beijing are outlined. The morphological and relative constituent ratio database of diatoms are established in central city of Beijing. PMID- 23033665 TI - Long-term trend of bone development in the contemporary teenagers of Chinese Han nationality. AB - OBJECTIVE: To further improve the accuracy of bone age identification using the time of secondary ossification center appearance and epiphyseal fusion of 7 joints to estimate the age of living individuals. METHODS: DR films were taken from 7 parts including sternal end of clavical and the left side of shoulder, elbow, carpal, hip, knee and ankle joints of 1 709 individuals who came from eastern China, central China and southern China, whose ages were between 11.0 and 20.0 years. From those 7 joints 24 osteal loci were selected as bone age indexes, which could better reflect age growth of teenagers. The characteristics of secondary ossification center appearance and epiphyseal fusion were observed, and the mean and age range of secondary ossification center appearance and epiphyseal fusion were calculated. RESULTS: The fusion time of the 24 epiphyses were advanced at different degrees, the most obvious epiphyses the sternal end of clavicle, scapular acromial end, distal end of the radius, distal end of the ulna, iliac crest, ischial tuberosity, the upper and lower end of tibia and fibula. The appearance time of sternal end of clavicle, scapular acromial end, iliac crest and ischial tuberosity epiphyses were all found to be after the age of 12, and the female's age, approximately 1 year ahead of schedule in comparison with the male's. CONCLUSION: The relevant forensic information and data for bone age identification should be updated every 10-15 years so as to provide accurate and objective evidence for court testimony, conviction and sentencing. PMID- 23033666 TI - [Application of needle electromyography and nerve conduction study in forensic appraisal]. AB - OBJECTIVE: To explore the application value of needle electromyography (EMG) and nerve conduction study (NCS) in the forensic appraisal; to provide scientific basis for establishing normative and unified assessment methods of the peripheral nerve study in forensic medicine. METHODS: One hundred and sixty-four samples with injured peripheral nerve (injury group) and 138 samples with normal peripheral nerve (control group) were collected and tested with methods of EMG and NCS respectively. The relevance rate of two methods were compared and statistical analysis was performed. RESULTS: In the injury group, there was no statistical difference on the relevance rate between the application of EMG and that of NCS (P > 0.05). In the control group, there was no statistical difference on the negative rate between the two methods (P > 0.05). The false negative rate of the injury group and the false positive rate of the control group were both 0% when using the two methods together. CONCLUSION: When the injured peripheral nerve in forensic appraisal is in doubt, application of both EMG and NCS could disclose truth from falsehood. The accuracy and credibility of identification results could be enhanced. PMID- 23033667 TI - [Analysis on work related fatigue among prison police and mental medical staffs]. AB - OBJECTIVE: To investigate the work related fatigue among prison police and mental medical staffs; to compare the social support between two groups; to develop specific intervention strategies in the future. METHODS: The Chinese Maslach Burnout Inventory (CMBI) and the Social Support Rating Scale (SSRS) were applied to 100 prison police and 100 mental medical staffs respectively. Their status of work related fatigue and relevant social support were analyzed accordingly. RESULTS: 1) The level of fatigue among prison police was higher than mental medical staffs (P < 0.05); 2) The factor scores of "emotional burnout" and "depersonalization" among prison police were higher than that among mental medical staffs (P < 0.05). There was no significant difference between the two groups on the "decreased sense of achievement" (P > 0.05); 3) The level of social support in the prison police was higher than that in the mental medical staffs (P < 0.05). CONCLUSION: Both prison police and mental medical staffs were vulnerable to suffering from fatigue. However, the details and relevant social support between these two groups were different. Active intervention should be taken for different occupation. PMID- 23033668 TI - [Identification of sarcosaphagous Calliphorid flies by analyzing the sequence of 16S rDNA]. AB - OBJECTIVE: To explore the application of a 289bp fragment of the 16S rDNA gene to identify various species of sarcosaphagous Calliphorid flies. METHODS: Twenty-six Calliphorid flies were collected from 14 Chinese provinces. All specimens were properly assigned into three genera and six species. The DNA of the pectoralis was extracted using CTAB method. Then PCR amplification was done for the 289 bp fragment of the 16S rDNA gene. The PCR products were then purified and sequenced, and the obtained sequences were uploaded to GenBank. The phylogenetic tree was built by the neighbor-joining method and intraspecific and interspecific divergences were calculated by sequence analysis. RESULTS: The above 26 sarcosaphagous flies could be well clustered according to different genera and species. The evolutional intraspecific values were all zero, the evolutional interspecific variations varied from 0.3% to 6.5%. CONCLUSION: The 289 bp fragment of the 16S rDNA of sarcosaphagous flies can be effectively used to identify most of the flies at species level. This method appears to be fast and low dissipative, which might be used to estimate postmortem interval by sarcosaphagous flies. PMID- 23033669 TI - [Latest progress in postmortem interval estimation]. AB - Accurate estimation of the postmortem interval (PMI) has been one of the most important and complicated issues in the forensic practice. In order to provide novel perspectives for the future research concerning PMI, the advantages and disadvantages of related traditional methods, postmortem degradation of nucleic acid and tissue, the componential change of vitreous humor and histological biochemistry since 2002 have been introduced and compared in this review. PMID- 23033670 TI - [Progress in standard assessment on competency to stand trial of mentally disordered offenders]. AB - Competency to stand trial relates directly to legal rights of the appraised individual as well as whether criminal procedure can be carried out smoothly. Foreign scholars have conducted a large number of theoretical researches, and developed a series of standardized evaluation tools. However, the assessment on competency to stand trial has mainly focused on medical criteria in China for a long time, and most cases were judged by forensic psychiatrists' experience. Recently, Chinese scholars have started the initial research on standardized evaluation. This paper reviews the notion of competency to stand trial, the evaluation criteria, and the assessment tools domestically and abroad. The main focus is on foreign assessment tools, which included three categories. First category includes checklist, self-report questionnaires and sentence-completion tasks. Second category is the interview-based instruments without criterion-based scoring. Last category is the interview-based instruments with criterion-based scoring. This literature may be helpful for further research and standardization on assessment tools of competency to stand trial of mentally disordered offenders. PMID- 23033671 TI - [Association and its forensic significance between COMT gene and schizophrenia]. AB - Catechol-O-methyltransferase (COMT) gene encodes catechol-O-methyltransferase, the variant of this gene may affect the expression and metabolic activity of COMT. As the result of the changes of the effective concentration of the catecholamine neurotransmitter in the central nervous system, central nervous system dysfunctions associated with schizophrenia. This review summarizes genetic polymorphism and diversity of COMT gene. It also elaborates the relation between SNP and haplotype of COMT gene and three aspects, which including schizophrenia, attacking and violent tendency, and the frontal cognitive function of the schizophreniac. The correlativity study between genetic variation of the COMT gene and schizophrenia in patients with attacking and violent tendency may be helpful for the assessment of forensic psychiatry. PMID- 23033672 TI - Effects of "short" photoperiods on seedling growth of Pinus brutia. AB - This study investigated how nurseries could benefit by inducing "short" photoperiods as low as 4 hr to produce "better" seedlings characterized by more vigorous roots; a substantial feature to overcome transplanting stress. The carryover effect of the photoperiod was also investigated on seedlings that grew for 30 days more underthe consistent 14 hr photoperiod. Seedlings of Pinus brutia were subjected to 4, 6, 8 and 14 hr photoperiod for 3 week. Fifteen seedlings were used to evaluate the leaf area, the root and shoot dry weight and their ratio. Six and sixteen seedlings were used to evaluate the shoot electrolyte leakage and the root growth potential, respectively. Based on the results, the 6 and 8 hr photoperiod indicated greater root allocation (4.8 and 4.9 mg, respectively) and chlorophyll content (3.7 and 4.4, respectively). They also indicated greater leaf area values (3.3 and 3.5 cm2, respectively) along with the 14 hr (3.4 cm2). The photoperiod effect continued even after seedlings were subjected at consistent photoperiod. Overall, "short" photoperiods could provide "better" P. brutia seedlings to accommodate immediate massive reforestation and afforestation needs. PMID- 23033673 TI - Pandemic influenza A/H1N1 virus in a swine farm house in Sicily, Italy. AB - This report describes a pandemic A/H1N1 (H1N1 pdm) virus outbreak occurred in December, 2009 in a swine farm used as research facility (Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione) for preclinical studies, located in Sicily, Italy. All the 13 pigs of the farm, showed cough, fever, inappetence and weakness. At the same time, an unvaccinated worker of the stabling showed influenza-like symptoms. RNAv extracted from two swabs collected from infected pigs resulted positive by Real Time RT-PCR for Influenza A virus. Furthermore, after growth on embryonated eggs, viral isolates were identified by Real Time RT PCR specific for H1N1 pdm virus and characterized antigenically. Sequencing of the whole genome was also performed. All sera taken from animals and from the worker were tested by a competitive influenza A ELISA and by the haemoagglutination inhibition test. Serological findings confirmed the circulation of influenza virus H1N1 pdm in pigs and the presence of specific antibodies against H1N1 pdm in human serum. The results of this study seem to support a H1N1 pdm transmission from man to animals showing the importance of serological and virological investigation to control the pig farms and the importance of close cooperation between the different authorities like veterinarian and human public. PMID- 23033674 TI - Comparison of PCR based marker systems for genetic analysis in different cultivars of mango. AB - Native diversity is well represented in northern and eastern parts of India for mango. We evaluated three important polymerase chain reaction (PCR) based marker techniques viz., random amplified polymorphic DNA (RAPD), inter simple sequence repeat (ISSR) and directed amplified mini satellite DNA (DAMD) and examined their suitability for depicting genetic relationships and discrimination among closely related group of 46 mango varieties grown in the different agro-ecological zones in Uttar Pradesh, Bihar and West Bengal. Nine RAPD, eleven ISSR and four DAMD primers generated 110, 160 and 43 discrete fragments, respectively, accounting for polymorphism of 87.3, 79.83 and 83.72%, respectively. Cumulative analysis of these markers resulted in comprehensive UPGMA based dendrogram where in native mangoes representing important breeding lines and varieties from Uttar Pradesh fall more or less in separate cluster, while Bihar and West Bengal cultivars represent genetically different lineage forming distinct separate cluster. The prime focus on the study was towards identification of genetic variability that warrants establishing origin and molecular evolution of mango cultivars of eastern and northern India because they are the rich gene pool for conservation. Highest diversity index (DI) and polymorphic information content (PIC) values were found in DAMD indicating it to be more informative than others. Similarly, high effective multiplex ratio (EMR) and marker index (MI) were recorded by ISSR reflecting ability to simultaneously detect a large number of bands. The study accomplished establishing genetic relationship and also DNA fingerprint development. The data is also useful for mapping studies for gene identification. PMID- 23033675 TI - Assessment of the toxicity of waste water from a textile industry to Cyprinus carpio. AB - Static, short-term, acute toxicity tests were performed over a period of 96 hrs using different concentrations of influent and effluent of textile industry waste water with the objective of evaluating their acute toxicity on fresh water fish, Cyprinus carpio (common carp). The LC50 24, 48, 72 and 96 hr of influent and effluent were 25.9, 21.10, 15.66, 11.11% (v/v) and 63.18, 54.89, 48.62, 36.04% (v/v), respectively. The acute toxic unit TUa values for 24, 48, 72, 96 hr for influent and effluent are 3.85, 4.73, 6.38, 8.99 and 1.58, 1.82, 2.05, 2.77, respectively. Correspondingly, the TF was found to be 1, 1.22, 1.65 and 2.33 for influent, and for effluent 1, 1.15, 1.29 and 1.75. Total efficiency of the treatment was 69.16% and the safe concentration of effluent is set to be 3.60%. These data are highly useful in establishing limits of acceptability by the aquatic animals. The need to introduce toxicity evaluation assay for confirming the quality of effluent from the point view of effective environmental safe limits and to ensure integrity of aquatic environment, is stressed. PMID- 23033676 TI - Effects of cadmium on growth and metabolism of Phaseolus mungo. AB - An attempt has been made to assess the response of Phaseolus mungo L. under influence of cadmium chloride (Cd Cl2) with special reference to growth, morphology, yield and biochemical aspects. Surface sterilized seeds of Phaseolus mungo L. cv. T-9 were exposed to various concentrations of Cd Cl2 solution (10( 2) M, 10(-4) M, 10(-5) M, 10(-8) M and control) for 12 hr at room temperature and these seeds were transferred to petriplates and polythene bags in triplicate. 10( 2) M conconcentration was found to have deleterious effects on seed germination, germination relative index, length and dry weight of root and shoot, shoot root ratio and seedling vigour index, plant height, phytomass, number of leaves and branches, leaf area and chlorophyll contents while 10(-8) M revealed slightly promotory effects. Phytotoxicity percentage and chlorophyll stability index were maximum in (10(-2) M) concentration, while minimum in 10(-8) M conconcentration of Cd Cl2. Nitrate and nitrite reductase activity was markedly inhibited at higherconconcentration. Low dose of Cd (10(-8) M) did not affect soluble sugar contents of seeds but it induced a significant increase at higher conconcentration (10(-2) M). It however, did not affect protein contents of seeds accept at higher concentration. PMID- 23033677 TI - Seasonal distribution of Isotomina thermophilan in a secondary succession and a homegarden in Cachar, Assam. AB - Present investigation was carried out in Cachar district of Assam over a period of two years (May 2007-April 2009) to understand the seasonal ecology of Isotomina thermophila (Axelson, 1900) in secondary succession and homegarden ecosystems. Population was found to be maximum during July 2008 (7949.05 No. m( 2)) and September 2008 (7949.05 No. m(-2)) in homegarden whereas the peak was recorded in secondary succession during September 2008 (13656.05 No. m(-2)). Least population was encountered during March 2008 (1222.93 No. m(-2)) and April 2008 (1630.57 No. m(-2)) in homegarden and secondary succession, respectively. It may be due to the fact that, vital activity of this species effected in the dry period or migrate towards lower soil profile in search of food and moisture. Linear regression analysis established the hypothesis that all the environmental variables showed positive and significant influence on the population dynamics whereas in homegarden, rainfall (r = 0.36, p > 0.05) did not show any influence. In multiple regression analysis positive and significant influences (p < 0.05) were recorded for both the investigated sites. Rainfall, relative humidity and temperature facilitated the soil moisture, microbial activity, litter decomposition may favour the reproduction and growth rate of the species. Among microclimatic conditions except soil pH all other parameters exhibited significant correlations (p < 0.05) with population. Based on the present investigation, it can be concluded that I. thermophilia does not differ much with the general ecology of collembolans in this sub humid climate. PMID- 23033678 TI - Plasmid profiles of mercuric chloride tolerant rhizobia from horse gram (Macrotyloma uniflorum). AB - Thirty two rhizobia were isolated from the fresh healthy root nodules of horse gram. They were found to be highly salt tolerant. They were identified as rhizobia by cultural, biochemical and 16S rRNA sequence. The sequences of the four selected isolates were deposited in the NCBI GenBank. The obtained accession numbers were GQ483457, GQ483458, GQ483459 and GQ483460. All the rhizobia were able to grow at 10 ppm mercuric chloride concentration. Four isolates HGR-11, 16, 30 and 31 were used to study the effect of different concentrations of mercuric chloride on the growth of rhizobia. These isolates were able to grow at 30 ppm concentration also. In these isolates, HGR-11 and HGR-30 showed maximum growth at 20 ppm than at control. These isolates contained one mega plasmid (-22 kb) at 20 ppm mercuric chloride concentration. PMID- 23033679 TI - Observation on an isopod parasitizing the edible fish Parastromateus niger in the Parangipettai coast of India. AB - Cymothoidae are big parasites on fishes and often they are host specific. This study reports that in India, the Black pomfret (Parastromateus niger), a highly edible marine fish belonging to the family Carangidae, is the type host of Cymothoa eremita (Isopoda, Cymothoidae). Among one hundred and sixty fish examined from April to July, 2010 in Parangipettai coastal waters, only three female specimens were infested in June, 2010. It seems that such parasitism depends particularly on the season and on the host sex. PMID- 23033680 TI - Population dynamics of a parasite Pallisentis in two species of fish Channa punctatus and Channa striatus. AB - In an aquatic environment, there is a profound and inverse relationship between environment quality and disease status of fish. Parasites are one of the most serious limiting factors in aquaculture. Therefore, the present investigation has been undertaken to sort out the population dynamics of Pallisentis (Acanthocephala), in relation to host sex from freshwater fishes, Channa of Rohilkhand region. A total of 517 fishes (Channa punctatus, n = 198 and C. striatus, n = 319) were examined regularly from August 2006 to February 2010. Overall prevalence of Pallisentis in C. striatus was higher in females (67.78%) as compared to males (63.52%). In case of C. punctatus, overall prevalence of Pallisentis was higher in males (53.77%) as compared to females (52.17%) whereas, relative density was higher in females (61.41%) than in males (52.72%). Intensity (2-3 parasite/host, in both sexes), density (1.36 in males and 1.69 in females) and infection index (0.73 in males and 0.88 in females) were recorded. PMID- 23033681 TI - Studies on antioxidative enzymes induced by cadmium in pea plants (Pisum sativum). AB - Pea plants (Pisum sativum cv. Swati) exposed to different concentration of cadmium (50,100, 200 microM Cd) under controlled glass house conditions were quantified for different physiological parameters and antioxidative enzymes. In pea plants, Cd produced a significant inhibition of growth and induced chlorosis, marginal yellowing and necrosis in young leaves, the effect being most pronounced at 200 microM Cd supply. An alteration in the activated oxygen metabolism of pea plants were also detected as evidenced by an increase in concentration of H2O2 and TBARS along with decrease in the chlorophyll and carotenoid concentration in leaves. Cadmium toxicity induced an increase in non-protein thiol, ascorbate, proline and cysteine concentration. A significant increment in the activity of SOD, APX and GR, and a decrease in CAT was observed as a result of Cd treatment. The enhanced activity of SOD and inhibition of CAT and POD produces a high build up of H2O2 which appears to be the main cause of oxidative stress due to Cd toxicity in pea plants. PMID- 23033682 TI - Growth, biomass production and remediation of copper contamination by Jatropha curcas plant in industrial wasteland soil. AB - The survival, biomass production and copper (Cu) remediation efficiency of Jatropha curcas L. was evaluated in Cu rich industrial wasteland soil (IWLS), collected from a local town, Sandila (Hardoi), Uttar Pradesh, India. The IWLS had high bulk density, water holding capacity (WHC), pH, electrical conductivity (EC), organic carbon and NPK. The Cu and Mn contents in IWLS were about 3 and 2 fold higher than that in the normal field soil (control). Stem cuttings of the J. curcas clones (BTP-A, BTP-N and BTP-K) were planted in IWLS as well as the same amended with cowdung or sand. The percent survival, net elongations and biomass accumulation of J. curcas were decreased slightly in IWLS, as compared to the control soil. The translocation of Cu from soil to the plants was higher in IWLS grown plants, which was more pronounced in IWLS amended with cowdung. J. curcas clones BTP-N, showed better survival and Cu removal efficiency from IWLS. PMID- 23033683 TI - Variation in wood fibre traits among eight populations of Dipterocarpus indicus in Western Ghats, India. AB - Wood elements and anatomical ratio of Dipterocarpus indicus were studied to evaluate variation among populations and to recommend for end selection. The variation of wood element [fibre length (FL), fibre diameter (FD), lumen diameter (LD), cell wall thickness (CWT), double wall thickness (DWT), and lumen volume (LV)] and anatomical ratio [fibre lumen area (FLA), slenderness ratio (SR) and runkel ratio (RR)] were investigated in a girth class of 100 - 120 cm among eight populations of Dipterocarpus indicus in Western Ghats, India. The study revealed a significant variations in FL (0.2426), FD (4.7019), LD (3.1689), CWT (2.7104), DWT and (5.4298) among populations. The variations in anatomical ratios were significant among populations except in case of LV. The causes of variations among populations in their wood traits were attributed to the site factors. The interaction between genetic makeup of wood traits combined with effects of edaphic, local and regional climatic conditions reflect the amount of variation among populations. The highest coefficient of variation (CV %) for FL, FD, CWT and DWT was recorded in population of Gundya whereas low coefficient of variation were recorded in the population of Makuta (FL), Devimane (FD, CWT and DWT), and Sampaje (LD). The wood of Dipterocarpus indicus was found undesirable for pulp wood but can be utilized for plywood timbers. PMID- 23033684 TI - Novel application of fungal Phanerochaete sp. and xylanase for reduction in pollution load of paper mill effluent. AB - Four different strategies of pulping and bleaching were carried out to develop alternative mechanistic ecoenvironmental friendly approaches and generated effluent was characterised. Strategy-I included Phanerochaete sp. fungal pretreatment followed by conventional bleaching, whereas in strategy-II, fungal pretreatment was followed by enzyme xylanase aided bleaching. Strategy-III also included xylanase supplement but without prior fungal pretreatment. Chemically driven pulping and bleaching was the IV strategy. Conventional C(D)E(OP)D1D2 sequence of bleaching was used for strategy-I and IV whereas XC(D)E(OP)D1D2 sequence was applied to strategy-I and III. Strategy-II was responsible for 27.5% reduction in Kappa no. whereas the maximum (27.5%) reduction in refining energy was observed with strategy-II. Biobleaching strategies-II and III were helpful in saving 37.3 and 20.3% of elemental chlorine (Cl2) and 30.8 and 23.1% of chlorine dioxide (ClO2) respectively. In comparison to control (strategy-IV), strategy II resulted in maximum pollution load reduction of chemical oxygen demand (COD), biological oxygen demand (BOD), color and adsorbable organic halides (AOX) up to 57, 60, 30 and 43.6%, respectively. PMID- 23033685 TI - Effect of physico-chemical treatments on ripening behavior and post-harvest quality of Amrapali mango (Mangifera indica L.) during storage. AB - An experiment was done to assess the effect of various physico-chemical treatments on ripening behavior and post harvest quality of mango cv. Amrapali. The experiment was planned under completely randomized design (CRD) with three replications. The treatment units was five fruits per replication. Total 14 treatments were applied. Out of these, ethrel 750 ppm treated fruits showed better results in respect of specific gravity (0.88), moisture loss (8.45%), decay (2.5%), total soluble solids (TSS, 20.7 degrees brix), sugar content (14.39%) and acidity content (0.32) followed by ethrel 500 ppm; specific gravity (0.90), moisture loss (8.82%), decay (3.5%), TSS (20.7 degrees brix), sugar content (13.99%) and acidity content (0.36%). The pedicellate fruits and ethrel+bavistin (750+1000 ppm) were also found to be significantly superior over control in respect of specific gravity (0.88 and 0.86), moisture loss (9.10 and 9.33%), decay (4.0 and 5.33%), TSS (20.1 and 20.4 degrees brix), sugar content (12.70 and 12.80%) and acidity content (0.42 and 0.38%), respectively. Based on results of this study, it can be concluded that ethrel 750 ppm was found to be the most suitable treatment in improving physico-chemical traits i.e. ripening, storage, quality and shelf-life for commercial purpose in mango. PMID- 23033686 TI - Dose related effects of nicotine on oxidative injury in young, adult and old rats. AB - Nicotine affects a variety of cellular process ranging from induction of gene expression to secretion of hormones and modulation of enzymatic activities. The objective of the present study was to study the dose dependent toxicity of nicotine on the oxidative stress in young, adult and old rats which were administered 0.75, 3 and 6 mg kg(-1) nicotine as nicotine hydrogen tartarate intraperitoneally for a period of seven days. No changes were observed in blood catalase (CAT) activity and level of blood reactive oxygen species (ROS) in any of the age group at the lowest dose of nicotine. However, at the highest dose (6 mg kg(-1) nicotine) ROS level increased significantly from 1.17 to 1.41 microM ml(-1) in young rats and from 1.13 to 1.40 microM ml(-1) in old rats. However, no change was observed in blood ROS levels of adult rats. Administration of 3 mg kg( 1) nicotine resulted in an increase in level of reduced glutathione (GSH) in rats of all the age groups. The young animals were the most sensitive as a dose of 6 mg kg(-1) resulted in decline in the levels of reduced GSH to 0.89 mg ml(-1) as compared to normal control (1.03 mg ml(-1)). The antioxidant enzymes SOD and CAT were sensitive to a dose of 6 mg kg(-1) as it resulted in decline of the enzymatic activity in all age group animals. Also, administration of nicotine at a lower dose of 3 mg kg(-1) inhibited SOD activity from 1.48 to 1.20 units min( 1) mg(-1) protein in old rats. Catalase activity showed a similar trend at a dose of 3 mg kg(-1). Administration of nicotine also increased the blood lipid peroxidation levels at all three doses in young and old rats dose dependently. Nicotine exposure also increased ROS in brain at the doses of 3 and 6 mg kg(-1) in all the three age groups. Brain GSH decreased significantly at high dose of nicotine (6 mg kg(-1) b.wt.) in adult rats (4.27 mg g(-1)) and old rats (3.68 mg g(-1)) but in young rats level increased to 4.40 mg g(-1) at the lower dose (0.75 mg kg nicotine). Brain lipid peroxidation increased at all three doses of nicotine in young as well as old rats as compared to their respective normal control. The SOD activity increased significantly in young (2.88 units min(-1) mg(-1) protein) and old rats (1.81 units min(-1) mg(-1) protein) as compared to their respective normal at a dose of 6 mg kg(-1). Interestingly, the SOD activity decreased in adult rats (2.18 units min(-1) mg(-1) protein) as compared to its normal control. Catalase activity decreased at the dose of 3 mg kg(-1) and 6 mg kg(-1) nicotine in young and old rats but no effect was observed in adult rats at any of the doses. Acetylcholine esterase (AchE) activity decreased in a dose dependent manner in adult and old rats. Overall, the results of the study indicate that young and old rats are more sensitive to nicotine induced oxidative stress as compared to the adult ones. PMID- 23033687 TI - Chromium-induced alterations in photosynthesis and associated attributes in Indian mustard. AB - Contamination of soil and water by chromium (Cr) is increasing enormously due to anthropogenic activities. The potential of plants to accumulate or stabilize Cr compounds forthe purpose of remediation of Cr contamination has been recognized in recent years. We conducted pot experiments to study photosynthesis and associated attributes in cv Pusa Jai Kisan of Indian mustard under natural as well as Cr-loaded environmental conditions. High doses of Cr caused toxic effects in plants, as evident by a reduction in photosynthetic rate (24.3 to 8.7 micromol CO2 m(-2)s(-1) at 80 DAS), nitrate reductase activity (3.76 to 1.30 micromol nitrite g(-1) f. wt. h(-1) at 80 DAS) and the contents of chlorophyll (1.49 to 0.86 mg g(-1) f. wt. at 80 DAS) and soluble protein (2.96 to 1.93 mg g(-1) f. wt. at 80 DAS). Since plants lack a specific Cr-transport system, mineral nutrient contents also changed due to Cr toxicity. Cr accumulation in different plant parts was affected by both duration and dose of Cr treatments, with a maximal localization of Cr in roots (up to 0.77 mg g(-1) d. wt) at initial stages (40 DAS) and in stem (up to 4.19 mg g(-1) d. wt) at the later stage (80 DAS) of plant growth. Thus, Indian mustard was able to withstand Cr stress and protect itself from Cr toxicity by altering various metabolic processes. Owing to its ability to accumulate large amounts of Cr, it may be useful in the process of land reclamation. PMID- 23033688 TI - Impact of seawater on development and reproduction of red cotton bug, Dysdercus cingulatus (Fab.). AB - Distribution pattern of animals, modification of their life cycle and behaviours have been governed by climatic changes. It affects the insect from egg to adults. Eggs always face lot of stress either from biotic or abiotic threats. This study examined the flooding of Dysdercus cingulatus eggs with seawater alone and in combination with fresh water on the egg hatchability, survival and development, fecundity and hatchability of the hatched nymphs and adults, respectively under laboratory conditions. Flooding of egg in salt water, slightly and insignificantly increased the nymphal developmental period (24.2 days) of the insect. However, treatment has no impact on the survival of nymphs (95.4%). Fecundity (135.2 eggs female(-1)), hatchability (77.51%) has been gradually decreased while the amount of sea water increased in the treated water. Results revealed that entering of seawater into the agriculture fields alter the reproduction of insects subsequently change the food web in the ecosystem. PMID- 23033690 TI - Chemopreventive potential of geraniol in 7,12-dimethylbenz(a) anthracene (DMBA) induced skin carcinogenesis in Swiss albino mice. AB - The present study investigated the chemopreventive potential of geraniol, an acyclic monoterpene alcohol, by monitoring the tumor incidence and analyzing the status of phase II detoxification agents, lipid peroxidation by products and antioxidants in 7,12-dimethylbenz(a)anthracene (DMBA) induced mouse skin carcinogenesis. Skin tumor was developed by painting DMBA (25 microg in 0.1 ml acetone mouse(-1)) in the shaved back of the mice, twice weekly for 8 weeks. We noticed 100% skin tumor formation in mice treated with DMBA alone. The status of phase II detoxification agents and antioxidants were decreased where as lipid peroxidation by products were increased in tumor bearing mice. Oral administration of geraniol at a dose of 250 mg kg(-1) body weight significantly prevented the tumor formation as well as brought back the status of phase II detoxification agents, lipid peroxidation by products and antioxidants to near normal range in DMBAtreated mice. Present results suggest that geraniol might have inhibited abnormal cell proliferation occurring in skin carcinogenesis by modulating the activities of phase II detoxification agents and through its free radical scavenging potential. PMID- 23033689 TI - A novel method of sludge pretreatment using the combination of alkalis. AB - The present study aims to utilise the advantage of higher sludge solubilisation potential of sodium hydroxide (NaOH) and sludge management properties of lime to achieve sludge pretreatment and its subsequent management. The optimum dosage and time required for sludge pretreatment using NaOH was found to be 1.6 g l(-1) and 3 hr, respectively. At the optimized condition, lime was added at varying concentration (0.3 to 1.6 g l(-1)) to study its effect on capillary suction time, soluble chemical oxygen demand (SCOD) release and total phosphorous (TP) removal. A lime dosage of 0.7g l(-1) was found to be beneficial for soluble chemical oxygen demand (COD) release. When compared to control, the combination of alkalis (NaOH and lime) reduced the TP and capillary suction time (CST) in the supernatant of the sludge. The TP removal was from 100 to 40 mg l(-1) and CST reduction was from 1360 to 350 sec, respectively. The combined alkali pretreatment not only prevent the subsequent TP increase in the effluent, but also decreased the time to filter the sludge, thus makes the digested sludge easier to manage. PMID- 23033691 TI - Stock assessment of fish species Labeo rohita, Tor tor and Labeo calbasu in the rivers of Vindhyan region, India. AB - A study was conducted on the economically important fishes Labeo rohita (Hamilton 1822), Tortor (Hamilton 1822) and Labeo calbasu (Hamilton 1822) stocks from the Ken, the Paisuni and the Tons rivers in the Vindhyan region. Asymptotic length was maximum in L. rohita (946, 833 and 962 mm) as compared with T. tor (822, 787 and 946 mm) and minimum in L. calbasu (567, 612 and 692 mm) in the Ken, the Paisuni and the Tons rivers, respectively. The growth coefficient and total mortality was maximum in T. torcompared to L. rohita and minimum in L. calbasu. Fishing mortality was maximum in T. tor (2.9, 4.57 and 3.44) and minimum in L. calbasu (0.51, 1.21 and 1.18) while natural mortality was maximum in L. rohita (0.74, 0.94 and 1.86) and minimum in L. calbasu (0.47, 0.65 and 0.68). Natural mortality indicated that the habitat was more suitable for L. calbasu. Comparatively, fishing pressure was very high in T. tor than L. rohita and L. calbasu. Exploitation rate was maximum in T. tor (0.71, 0.82 and 0.84) compared to L. rohita (0.77, 0.74 and 0.56) and minimum in L. calbasu (0.52, 0.65 and 0.63) in the Ken, Paisuni and Tons rivers, respectively. PMID- 23033692 TI - Growth, photosynthetic activity and oxidative stress in wheat (Triticum aestivum) after exposure of lead to soil. AB - The present study was conducted to assess quantitative information about lead (Pb) contamination in soil on the growth and physiology of wheat. Solutions with three different concentrations of Pb as [Pb(NO3)2 at 500, 1000 and 2500 microM] were incorporated into the soil to achieve Pb-stressed conditions in comparison to unstressed, water treated, control variant. Wheat growth measured in terms of root length, shoot length and dry weight exhibited a significant decline with increasing Pb concentrations in the soil. Root and shoot length and seedling weight declined in the range of -23-51, -17-44, and -21-44% in response to 500 to 2500 microM Pb. In addition, there was a significant reduction in the levels of photosynthetic pigments-chlorophyll a (16-66%) and b (10-24%) and total chlorophyll content (by 14-39%) in plants growing in Pb-contaminated soil. It indicated a negative effect on photosynthetic activity in wheat and was confirmed by reduced photochemical efficiency of PSII (Fv/Fm) in the range of - 3-37% in response to 500 to 2500 microM Pb. The reduction in wheat growth in Pb contaminated soil was accompanied by induction of oxidative stress as indicated by enhanced lipid peroxidation ir. terms of malondialdehyde (MDA) content (by 18 40%) and hydrogen peroxide (H2O2) content (by 34-123%) and alterations in the activity of enzymes, superoxide dismutases (SOD) and guaiacol peroxidases (GPX) in wheat roots. The study concludes that Pb in soil inhibits growth and phototsynthetic activity in wheat through induction of oxidative stress. PMID- 23033693 TI - Removal of nutrients in denitrification system using coconut coir fibre for the biological treatment of aquaculture wastewater. AB - Ideal bacterial support medium for fixed film denitrification processes/bioreactors must be inexpensive, durable and possess large surface area with sufficient porosity. The present study has been focussed on removing nitrate nitrogen at two different nitrate nitrogen loading rates (60 (NLR I) and 120 (NLR II) mg l(-1)) from simulated aquaculture wastewater. Coconut coir fibre and a commercially available synthetic reticulated plastic media (Fujino Spirals) were used as packing medium in two independent upflow anaerobic packed bed column reactors. Removal of nitrate nitrogen was studied in correlation with other nutrients (COD, TKN, dissolved orthophosphate). Maximum removal of 97% at NLR-I and 99% at NLR - II of nitrate nitrogen was observed in with either media. Greater consistency in the case of COD removal of upto 81% was observed at NLR II where coconut coir was used as support medium compared to 72% COD removal by Fujino Spirals. The results observed indicate that the organic support medium is just as efficient in nitrate nitrogen removal as conventionally used synthetic support medium. The study is important as it specifically focuses on denitrification of aquaculture wastewater using cheaper organic support medium in anoxic bioreactors for the removal of nitrate nitrogen; which is seldom addressed as a significant problem. PMID- 23033694 TI - Estimating soil erosion in Natura 2000 areas located on three semi-arid Mediterranean Islands. AB - A major initiative in Europe is the protection of its biodiversity. To accomplish this, specific areas from all countries of the European Union are protected by the establishment of the "Natura 2000" network. One of the major threats to these areas and in general to ecosystems is soil erosion. The objective of this study was to quantitatively estimate surface soil losses for three of these protected areas that are located on semi-arid islands of the Mediterranean. One Natura 2000 area was selected from each of the following islands: Sicily in Italy, Cyprus and Rhodes in Greece. To estimate soil losses, Gerlach troughs were used. These troughs were established on slopes that ranged from 35-40% in four different vegetation types: i) Quercus ilex and Quercus rotundifolia forests, ii) Pinus brutia forests, iii) "Phrygana" shrublands and iv) vineyards. The shrublands had the highest soil losses (270 kg ha(-1) yr(-1)) that were 5-13 times more than the other three vegetation types. Soil losses in these shrublands should be considered a major concern. However, the other vegetation types also had high soil losses (21-50 kg ha(-1) yr(-1)). Conclusively, in order to enhance and conserve the biodiversity of these Natura 2000 areas protective management measures should be taken into consideration to decrease soil losses. PMID- 23033695 TI - Urban and country level greenhouse gas emissions and carbon footprints: A comparative study of a megacity, Delhi and India. AB - This paper describes the contribution and comparison of carbon footprints of megacity Delhi with that of India over the period from 1990 to 2000. Two published studies were taken as base to calculate carbon footprint in terms of CO2 equivalents (CO(2)-e) by taking into account CO2, CH4 and N2O emissions mainly from transport, power plants, domestic, industries, agriculture and waste sectors. It is found that carbon footprints have increased more in India (-45%) in comparison to Delhi (-33%) between 1990-2000. However, the average per capita carbon footprints at India level is less than for Delhi. Also, carbon footprint per km area in Delhi is - 40 times to that for India. In India (2000) the contribution to carbon footprint's share primarily comes from power plants, industries and agriculture sector whereas it comes from power plants and transport in case of Delhi. Various control measures taken into account in Delhi during 1990-2000 have resulted in decreasing share of CO2 in the total greenhouse gas (GHG) emissions in comparison to what appears at India level. It indicates that suitable policy measures and norms are required to be implemented at India level to control other GHGs along with CO2 to reduce net carbon footprints at the country level. PMID- 23033696 TI - GIS based water quality indexing of Malad creek, Mumbai (India): an impact of sewage discharges. AB - Malad creek is one of the most heavily polluted water bodies in Mumbai, India. Presently, creek receives wastewater and sewage from open drains and nallahs as well as partially treated wastewater from treatment facilities. The objective of the present study was to assess and classify the water quality zones spatially and temporally based on physico-chemical and bacteriological analysis. For this, GIS based methodology was integrated with water quality indexing, according to National Sanitation Foundation. Nine water quality parameters were considered to generate the indices that represent the overall status of creek water quality. Based on field observations and spatial distribution of water quality, various options were suggested for improvement in water quality of the creek. PMID- 23033697 TI - Hydrochemical investigations and correlation analysis of groundwater quality. AB - A study was conducted to evaluate the water quality of Sambhar lake city (India) and its adjoining areas. Groundwater samples from hand pumps and tube wells of fifteen sampling stations were analyzed during post-monsoon session with the help of standard methods of APHA. The analytical results showed higher concentrations of TDS, EC, Sodium, Nitrate, Sulphate and Fluoride, which indicate signs of deterioration but values of pH, Calcium, Magnesium, TH and Carbonate were found within permissible limits as per the WHO standards. From correlation analysis it was observed that very strong correlations exist between Na+ and Cl- (0.99) as well as EC and Cl-. From Hill-piper trilinear diagram it is observed that the majority of groundwater from sampling stations was sodium-potassium-chloride sulphate type water. The values of sodium absorption ratio and EC of groundwater were plotted in the US salinity laboratory diagram of irrigation water. Only one sample was found to fall in C3S1 quality with high salinity hazard and low sodium hazard. Another samples were found to fall in high salinity hazard and high sodium hazard. Chemical analysis of groundwater showed that mean concentration of cation is in order sodium > magnesium > calcium > potassium while for the anion it is chloride > bicarbonate > nitrate > sulphate. PMID- 23033699 TI - Adsorptive removal of nickel and lead ions from aqueous solutions using phosphorylated tamarind nut carbon. AB - The adsorption of Ni(II) and Pb(II) from aqueous solutions by Phosphorylated Tamarind Nut Carbon (PTNC) was investigated. The effects of contact time, pH and carbon dose were studied in batch experiments at 30 degrees C. The equilibrium process was determined by Freundlich and Langmuir isotherm models. The kinetic studies showed good correlation for a pseudo-second-order kinetic model. Column studies were conducted in 2.5cm diameter columns. The applicability of PTNC for wastewaters containing Ni(II) and Pb(II) was evaluated. The mechanism of adsorption of metals on PTNC was found to follow ion exchange process predominantly and was supported by FTIR. The metal removal was also confirmed by SEM studies. PMID- 23033698 TI - Analysis, assessment and mapping of groundwater quality of Chandigarh (India). AB - Chandigarh (India) has been depending on groundwater resources to meet its water requirements in addition to the surface water source (Bhakra Main Canal). With a view to assess the groundwater quality, samples were collected from geo referenced tube wells in different localities of the city. Samples were analysed for conventional parameters indicative of the physico-chemical quality of groundwater. The groundwater quality mapping was attempted using the ARCGIS 9.0. Thematic maps were generated for each parameter of groundwater quality. This paper presents the spatial distribution of groundwater quality of Chandigarh city. The quality of groundwater was found to be varying with geology of the area as well as the land use and land cover. PMID- 23033700 TI - Effect of shape of brushes on oxygen transfer for horizontal shaft rotor. AB - Mechanical aerators used in wastewater treatment are the largest energy consumers in biological reactors. The main aim of aeration process control in biological reactors for wastewater treatment is to provide the necessary oxygen supply at different working conditions of reactors. The effect of geometric parameters of brush aeration system on the oxygen transfer coefficient (Kla) was studied with the help of experiments carried out in the laboratory. The phenomenon was examined by conducting 150 experiments with brush rotors with five different geometric shapes of blades in which submergence of the blades, distance of the shaft of the rotor from water level and temperature range were varied over fairly wide range. It was found that geometric parameters of brush rotor affect the oxygen transfer coefficient significantly. The maximum value of oxygen transfer coefficient was obtained for blades with angled (triangular) brushes. PMID- 23033701 TI - Phytoremediation of domestic wastewater using Eichhornia crassipes. AB - Safe, economic and effective treatment of domestic wastewater is the biggest challenge the world experienced in modern times. Phytoremediation studies were undertaken in a laboratory scale using shallow pond water hyacinth (Echhornia crassipes) system and analytical data was collected before and after treatment. The studies also include microbial flora present in the system by isolating and identifying the microorganisms. At optimum hydraulic retention time (HRT) of 21 h, approximately 81% chemical oxygen demand (COD), 91% biological oxygen demand (BOD5), 16% total dissolved solids (TDS), 70% total suspended solids (TSS), 4% Chlorides, 74% ammonia nitrogen (NH3-N), 41% phosphate (PO4-P), 96% most probable number (MPN) and 98% total viable count (TVC) reduction was achieved in shallow pond water hyacinth system. The shallow pond water hyacinth system shows better treatment efficiency compared to conventional water hyacinth system. The process indicates a possibility of development of a substantially effective shallow pond water hyacinth system for domestic wastewater treatment. PMID- 23033702 TI - Investigation of the electrochemical treatment for distillery wastewater. AB - The treatability study of distillery wastewater by electrochemical (EC) oxidation technique as pretreatment has been carried out. Batch experiments were conducted using stainless steel plates as electrodes to assess the effects of operating parameters such as pH, electrolysis duration (ED) and current density (CD). The EC treatment removed 58% COD at current density 0.12 A cm(-2) and at wastewater pH 3 with 120 min of ED. The BOD to COD ratio increased from 0.25 to 0.76 indicating considerable improvement in wastewater biodegradability. The maximum anodic efficiency and minimum energy consumption observed were 7.44 kg COD h(-1) A(-1) m(-2) and 0.19 kWh kg(-1) COD respectively. PMID- 23033703 TI - Performance evaluation of the Common Effluent Treatment Plant at Vapi (Gujarat, India). AB - Small scale industries cannot afford to treat their effluents individually, so they adopt Common Effluent Treatment Plant (CETP) for the same. To evaluate the performance of the CETP at Vapi industrial area of South Gujarat (India), effluent samples were collected from inlet of CETP, after primary treatment and after secondary treatment for assessing various parameters like pH, color, total dissolved solids (TDS), total suspended solids (TSS), chemical oxygen demand (COD), biochemical oxygen demand (BOD), phenol, chloride and metals like copper (Cu), lead (Pb) and manganese (Mn). It was observed that COD is reduced by 69%, BOD by 78%, color by 35% and TSS by 58% in secondary treatment. PMID- 23033704 TI - Wastewater pollution remediation: an experimental investigation with aquatic macrophyte Lemna minor. AB - The freshwater resources are shrinking rapidly due to rise in population and discharge of untreated wastewater into fresh water bodies making them unfit for public use in many developing countries. Effective and affordable wastewater treatment has become a challenge, hence various alternatives are being investigated by researchers to tackle the problem. In this study, laboratory scale experiments on duckweed covered domestic sewage were carried out to evaluate the removal efficiency of duckweed species Lemna minor as a domestic wastewater stripper. The outdoor experiments were conducted in 4 mini ponds at Jodhpur, popularly known as Sun City of India. The physico-chemical properties of domestic wastewater were evaluated before and after inoculation of culture for wastewater quality improvement. Various parameters, namely pH, DO, TSS, TDS, Turbidity, BOD, COD, Total Nitrogen and Total Phosphorus were analysed for varying detention periods. The result indicated that the treated effluent can be used for irrigation. PMID- 23033705 TI - Wastewater treatment of pulp and paper industry: a review. AB - Pulp and paper industries generate varieties of complex organic and inorganic pollutants depending upon the type of the pulping process. A state-of-art of treatment processes and efficiencies of various wastewater treatment is presented and critically reviewed in this paper. Process description, source of wastewater and their treatment is discussed in detail. Main emphasis is given to aerobic and anaerobic wastewater treatment. In pulp and paper mill wastewater treatment aerobic treatment includes activated sludge process, aerated lagoons and aerobic biological reactors. UASB, fluidized bed, anaerobic lagoon and anaerobic contact reactors are the main technologies for anaerobic wastewater treatment. It is found that the combination of anaerobic and aerobic treatment processes is much efficient in the removal of soluble biodegradable organic pollutants. Color can be removed effectively by fungal treatment, coagulation, chemical oxidation, and ozonation. Chlorinated phenolic compounds and adsorable organic halides (AOX) can be efficiently reduced by adsorption, ozonation and membrane filtration techniques. PMID- 23033706 TI - Aspects of legislative cognizance of noise pollution in India. AB - The impacts of noise pollution are associated with the mental, physical, emotional and psychological well-being of an individual. Its damaging effects from various natural and man-made sources are potential hazards that need to be checked at the planning, executive and judicial levels. The paper presents an overview of the technological aspects of noise pollution, and seeks to visit its legislative aspects with respect to India. Excerpts from international laws are presented for a meaningful discussion. References are made from the conclusions of studies carried out by researchers and legislative cases involving noise pollution to make this paper useful for researchers, planners and administrators. PMID- 23033707 TI - Food poisoning and house gecko: myth or reality? AB - The reason behind the food-poisoning due to felling of house geckos in eatables is described in this paper. House geckos are known to carry various types of pathogens in their bodies which cause food-poisoning after consuming the contaminated foods. Since these geckos are non-poisonous, the food poisoning due to their presence in food is not possible. PMID- 23033708 TI - Caring for strangers: the challenge for health policy. PMID- 23033709 TI - Evaluation of the North Carolina Violent Death Reporting System, 2009. AB - BACKGROUND: Violence is a leading cause of death in North Carolina. The North Carolina Violent Death Reporting System (NC-VDRS) is part of the National Violent Death Reporting System (NVDRS), which monitors violent deaths and collects information about injuries and psychosocial contributors. Our objective was to describe and evaluate the quality, timeliness, and usefulness of the system. METHODS: We used the Centers for Disease Control and Prevention's guidelines for evaluating public health surveillance systems to assess the system. We performed subjective assessment of system attributes by reviewing system documents and interviewing stakeholders. We estimated NC-VDRS's reporting completeness using a capture-recapture method. RESULTS: Stakeholders considered data provided by NC VDRS to be of high quality. Reporting to the national system has taken place before the specified 6-month and 18-month deadlines, but local stakeholder reports have been delayed up to 36 months. Stakeholders reported using NC-VDRS data for program planning and community education. The system is estimated to capture all NVDRS-defined cases, but law enforcement officers report only 61% of suicides. LIMITATIONS: The law enforcement agencies we interviewed may not be representative of all participating agencies in the state. Data sources used to assess completeness were not independent. CONCLUSION: NC-VDRS is useful and well accepted. However, completeness of suicide reporting is limited, and reporting to local stakeholders has been delayed. Improving these limitations might improve the usefulness of the system for planning and appropriately targeting violence prevention interventions. PMID- 23033711 TI - Promoting healthy and sustainable communities. Introduction. PMID- 23033710 TI - The cost of Medicaid coverage for the uninsured: evidence from Buncombe County, North Carolina. AB - BACKGROUND: The Affordable Care Act gives states the option to expand state Medicaid programs to cover many who are currently uninsured. The potential financial impact has not been thoroughly examined. We characterized the health risk of uninsured adults in Buncombe County, North Carolina, relative to that of local Medicaid recipients, to estimate the cost of expanding Medicaid coverage to include the uninsured. METHODS: We obtained de-identified patient enrollment and claims data for 2008 from the Division of Medical Assistance, North Carolina Department of Health and Human Services and from the 3 safety-net providers who care for most of the county's low-income uninsured adults. We used the Chronic Illness and Disability Payment System (CDPS) risk-adjustment tool to measure the relative health risk of the two populations. Based on actual spending in the Medicaid group and its health risk relative to that of the uninsured, we then projected how much it would have cost to provide Medicaid coverage for these uninsured in 2008. RESULTS: We estimated, based on CDPS adjustment for demographics and diagnoses, that these uninsured adults would have incurred costs 13% greater than those of the actual nondisabled adult Medicaid population. The projected cost of providing Medicaid coverage to these uninsured would have been $4,320 per person. LIMITATIONS: Data were drawn from only the 3 major safety-net organizations and therefore excluded care obtained from other safety-net providers. Also, this sample of uninsured people included some who are ineligible for Medicaid because of their citizenship status. Furthermore, Medicaid enrollment might lead to increased utilization, revealing a greater burden of illness than we detected. CONCLUSION: In Buncombe County, uninsured adults who enroll in expanded Medicaid are likely to have somewhat more costly health problems than do currently enrolled nondisabled adults. PMID- 23033712 TI - Forging new partnerships to build healthier communities for a healthier state. AB - Building healthy communities is critical to reducing the rates of chronic diseases impacting millions of North Carolinians. In 2011, North Carolina's overall health status ranking was 32nd in the nation (with 1 being the best). It is well recognized that health is impacted by a variety of individual, social, environmental, and economic factors, which are complex, interrelated, and influenced by a variety of other factors. Creating healthy communities provides options for people to make health-promoting choices. Such communities include transportation alternatives, access to healthy foods and places to be active, opportunities for economic growth and education, and clean air and water. Creating communities that provide these types of options requires the work of different sectors, many of which may not have health as their main mission, such as those that focus on commerce, planning, transportation, and environmental and natural resources. This article outlines the need for healthier communities and highlights the innovative partnerships and work being done by individuals and agencies at the state, local, and national levels to build healthier communities across North Carolina. PMID- 23033713 TI - The North Carolina Department of Transportation's vision for healthy communities through sustainable transportation. AB - The North Carolina Department of Transportation increasingly includes the health of North Carolinians in its transportation decision-making. With an expanded mission that now includes health, the agency is integrating public health considerations into its initiatives, plans, and policies, as well as exploring the use of health impact assessments. PMID- 23033714 TI - The North Carolina Department of Commerce: a healthy workforce promotes economic security. AB - To thrive economically, North Carolina needs a healthy, productive workforce. The public and private sectors should collaborate on the prevention and management of chronic diseases, which significantly impact the state's economy. Evidence-based prevention strategies should be prioritized, and communities should be designed with public health considerations in mind. PMID- 23033715 TI - The North Carolina Department of Environment and Natural Resources: clean land, water, and air for healthy people and communities. AB - The North Carolina Department of Environment and Natural Resources works with communities and other agencies to sustain clean air, water, and land. Sustainability efforts include protecting air quality through community design, community enhancement through brownfields revitalization, community development strategies to protect water resources, and the integration of natural resource conservation. PMID- 23033716 TI - The North Carolina Division of Public Health's vision for healthy and sustainable communities. AB - The North Carolina Division of Public Health is working to improve access to physical activity through changes in the built environment by participating in the Healthy Environments Collaborative and by leading the state's Communities Putting Prevention to Work project and the Shape Your World movement. PMID- 23033717 TI - Tobacco-free parks: maximizing health impact in built environment planning. PMID- 23033718 TI - Shape your world. PMID- 23033719 TI - Planners and public health professionals need to partner...again. AB - The planning profession traces its origins to the efforts of 19th century reformers to improve public health by addressing problems resulting from urbanization. So it is fitting that in the 21st century, planners are once again working with public health professionals to make communities healthier, this time by addressing problems caused by suburbanization. PMID- 23033720 TI - The Blue Ridge Corridor experience. PMID- 23033721 TI - Economics, physical activity, and community design. PMID- 23033722 TI - Health impact assessments in North Carolina: promoting public health through informed decisions. AB - Health impact assessment (HIA), a systematic way of incorporating health considerations into the public policy decision-making process, has been set into motion in North Carolina. The state's public health and planning fields are well positioned to become leaders of HIA and should prepare to take proactive measures to promote health in their communities. PMID- 23033723 TI - North Carolina tomorrow: building communities for tomorrow's jobs. AB - The North Carolina Tomorrow initiative develops the North Carolina Strategy for Economic Development based on economic development planning best practices, which can serve as a blueprint for creating an economically sustainable economy. It is made possible through government agency and private sector collaboration. Thought leaders from all sectors, including health care, are involved at the regional level. PMID- 23033724 TI - Two North Carolina public health departments taking steps toward sustainable communities. AB - Communities Putting Prevention to Work grant funding, provided to the state through the Centers for Disease Control and Prevention since 2010, is aimed at impacting obesity. This has enabled 2 local health departments-Pitt County and the Appalachian District-to make broad, sustainable environmental changes that foster improvements in health outcomes. PMID- 23033725 TI - Active living by design: collaborating to build healthy communities in North Carolina. PMID- 23033726 TI - Local food systems for a healthy population. AB - Working together across disciplines and organizational boundaries, North Carolina is leading national efforts to foster environments that increase access to healthy foods and raise awareness about the complexity and benefits of local food systems. PMID- 23033727 TI - Appalachian sustainable agriculture project: growing minds and healthy communities. PMID- 23033728 TI - North Carolina pedestrian crash facts. PMID- 23033729 TI - Building healthier communities to support healthier individuals. PMID- 23033730 TI - Jo Morgan. PMID- 23033732 TI - The development of an indoor mobility course for the evaluation of electronic mobility aids for persons who are visually impaired. AB - PURPOSE: To develop a suitable mobility course for the assessment of mobility performance as part of a user evaluation of Electronic Mobility Aids (EMA) aimed at obstacle detection and orientation. METHOD: A review of the literature led to a list of critical factors for the assessment of mobility performance of persons who are visually impaired. Based upon that list, method, test situations, and determining elements were selected and presented to Dutch orientation and mobility experts. Due to expert advice and a pilot study, minor changes were made and the final version was used for the evaluation of two EMA by eight persons who are visually impaired. RESULTS: The results of the literature study are summarized in an overview of critical factors for the assessment of the mobility performance of persons who are visually impaired. Applied to the requirements of the above mentioned user evaluation a replicable indoor mobility course has been described in detail and tested. CONCLUSION: Based upon evidence from literature an indoor mobility course has been developed, which was sensitive to assess differences in mobility incidents and obstacle detection when using an EMA compared to the regular mobility aid. Experts' opinion confirmed its face and content validity. PMID- 23033731 TI - Choose your words carefully, please. PMID- 23033733 TI - Factors associated with provision of wheelchairs in older adults. AB - The objectives of this study were: to identify the factors that are associated with prescription of wheeled mobility devices for older adults, and to determine the effect that living setting has on the types of devices that older adults receive. Retrospective medical chart review at the Center for Assistive Technology on 337 older individuals. These individuals were aged >60 years, and each of them received a new wheeled mobility device from the center during 2007 or 2008. Data were analyzed in three tiers: tier 1 (manual versus powered mobility devices); tier 2 (motorized scooters versus power wheelchairs); and tier 3 (customized versus standard power wheelchairs). For tier 1, the factor associated with higher odds for receipt of manual wheelchairs versus powered were: cognitive limitations (OR = .03). For tier 2, diagnosis of cardio-vascular and pulmonary conditions were associated with prescription of motorized scooters (OR = 3.9). For tier 3, neurological conditions (OR = 3.1), male gender (OR = .37), institutional living (OR = .23), and lower age (OR = .96) were associated with receipt of customized power wheelchairs. This study objectively describes factors associated with prescription of wheeled mobility for older adults. This information can aid in development of guidelines and improving standards of practice for prescription of wheelchairs for older adults. PMID- 23033734 TI - How older adults make decisions regarding smart technology: an ethnographic approach. AB - Comparatively little research has been conducted regarding the smart technology needs of the older adult population despite the proliferation of smart technology prototypes. The purpose of this study was to explore the perceived smart technology needs of older adults with mobility impairments while using an ethnographic research approach to construct a preliminary decision tree model of how these smart technology decisions are made. In-depth individual interviews with 11 older adults aged 65 and older with mobility impairments provided insight into how older adults perceived smart technology. Audio-taped interviews were transcribed verbatim, then analyzed for key phrases that represented participant decision criteria. Decision criteria concepts were combined to construct an older adult smart technology decision tree model. The model consisted of a preliminary decision stage that participants engaged in to make the decision of whether a change was needed in their current pattern of behavior; followed by an evaluation stage that included five potential barriers (i.e., not easy to use/learn) and seven potential facilitators (i.e., decreasing imposition on family/friends) to the smart technology need decision process. Future designers could use this decision model to create appropriately matched technological devices to promote independence of aging baby boomers with mobility impairments. PMID- 23033735 TI - Driving performance among bioptic telescope users with low vision two years after obtaining their driver's license: a quasi-experimental study. AB - This study sought to compare road safety of new drivers with low vision who have followed a specific pilot bioptic training program with other groups of drivers all matched for age and driving experience. A quasi-experimental design was used two years after drivers obtained their license. Drivers were classified in the experimental group (n = 10, they followed a pilot bioptic training program and had license restrictions: weight of the car, requirement of a yearly medical exams, requirement to wear glasses/contacts, use of a bioptic telescope), the comparison group (n = 17, similar license restrictions except the use of a bioptic telescope) and the regional population (n = 1,690, no license restriction). The number of new drivers involved in at least one accident and who committed at least one offense is not greater for users of a bioptic telescope than for drivers of in the other groups. The results of this study indicate that driving with a bioptic telescope does not increase the risk of accidents and offenses, with more scientific evidence than in previous studies, among drivers aged between 25 and 35 who have a congenital visual impairment and who have completed an eight-week pilot bioptic training program. PMID- 23033736 TI - Evaluation of a neural network-based control strategy for a cost-effective externally-powered prosthesis. AB - This paper presents a control strategy that compensates for the nonlinearity in the inexpensive sensors and hardware of a cost effective prosthetic hand. The control strategy uses neural network-based force control and sensory feedback to detect disturbance induced by slippage. The neural network approach is chosen over other nonlinear models because it is easy to implement and it offered the additional advantage of having its parameters easily adjusted over the life span of the device. The proposed strategy was evaluated on a functional multi-digit underactuated prosthetic hand. The initial and incremental forces exerted from each finger were adjusted to balance the amount of disturbance and the deformation of the objects. Experiments were conducted to test the performance of the protocol in situations encountered in activities of daily living. The displacement of each object under three grasping configurations was measured as a performance criterion while the object's mass was changed. The results showed that with the adjusted parameters for each grasping configuration, the control strategy was able to detect the dynamic changes in mass of the object and was also able to successfully adjust the grasping force before the object drops from the hand. PMID- 23033737 TI - The application of a telemedicine management system: the case of a Moroccan hospital unit. AB - This study is a contribution to the ongoing debate on the application of informatics in medicine. It attempts to outline a theoretical framework supported by a software application of a telemedicine management system. The proposed model is based on a detailed benchmarking of Telecom environments, hardware environments, and content management systems. This approach, which uses open source technologies, helps to create an interface with two entities: web and medical care USB. In sum, for the proposed telemedicine model to be successful, health professionals, telecom operators and research medical informatics laboratories must play an active role in the conception and implementation of telemedicine applications. PMID- 23033738 TI - Investigating the effects of varying the angle of application and increasing the ignition source flow rate during ISO ignitability testing on foam and vinyl. AB - To investigate how, and to what extent, the following factors influence burn damage: (1) the angle of application of the ignition source to the sample surface, and (2) the flow rate for the ignition source, when assessing samples in accordance with ISO 8191-2:1988. Varying the ignition source flow rate and the angle of application of the ignition source to the sample undergoing testing, which are both variations on the existing procedure outlined in the Standard ISO 8191-2:1988. Burn damage as measured by the depth (if applicable) and greatest horizontal and vertical dimensions. Increasing the ignition source gas flow rate (from 45 ml/min to 240 ml/min) increased the measured burn damage for both foam and vinyl samples. The increased damage factor was at least two-fold (and up to five-fold). Changing the angle of application of the ignition source (45 degrees compared to 0 degrees) did not significantly affect the measured burn damage for either sample. These findings indicate that the direction of application of a match-flame equivalent ignition source has no significant affect on the resulting burn damage, but that increasing the ignition source flow rate increases the burn damage for both foam and vinyl samples. PMID- 23033739 TI - Validating a change of technique proposed in draft ISO7176-16 ignitability testing on wheelchair materials. AB - To investigate whether (1) the changes to the angle of application of the ignition source to the sample surface, and (2) more precise failure criteria, would result in similar outcomes (in terms of pass/fail criteria) when assessing samples in accordance with ISO CD 7176-16:2010. Time before smouldering/fire/smoke had ceased following withdrawal of the flame as well as area of burn damage were recorded. Changing the angle of application of the ignition source (45 degrees compared to 0 degrees) did not appreciably affect the ongoing smouldering/smoking of samples, but did result in increased measured burn damage for most samples. Thin structures showed more variable outcomes especially in the vertical orientation. The direction of application of a match-flame equivalent ignition source has only a moderate affect on the resulting burn damage, and that pass/fail results from the proposed revision would be consistent with the existing ISO7176-16 with the exception of the proposed burn damage criterion. It is suggested that the burn damage area be moderately increased in the draft standard to maintain consistency under the existing standard. Some benefits were identified in fixing thin coverings to underlying materials, and little value in any cleaning or laundering pre-test. PMID- 23033740 TI - Speed of mental addition in an abacus expert, estimated by eye movements and neural activities. AB - A grand expert of abacus looked at a display on which three-digit numbers were aligned vertically with constant spacing, for sequentially adding the numbers mentally. His eye regularly moved downward by alternating a fixation to one of the numbers with a saccade to another below it, with the average period of the alternations at 271 msec. His magnetoencephalogram averaged with respect to start of the fixations revealed activity in the right superior parietal cortex. This finding not only supported the previous view that abacus experts mentally calculate by manipulating spatial representations of numbers, but also showed that the calculation was synchronized with the periodic eye movements. Thus, each process of the mental sequential addition, which starts with visual recognition of an addend, was estimated to require less than 271 msec. on average. PMID- 23033741 TI - Musical training effect on reading musical notation: evidence from event-related potentials. AB - Musical training enhances a range of non-musical cognitive functions, including visuospatial abilities. The aim of this study was to explore which event-related potential (ERP) components were enhanced or reduced as a result of musical training. Both electrophysiological and behavioral methods were used to compare musicians and non-musicians in the processing of pitch and duration when reading single musical notes. It was observed that in the early stage of note reading, the musician/non-musician differences emerged in the latency range of the N1 and N2. The N1 component was enhanced; in contrast, the N2 component was reduced in musicians. It is possible that musicians receive auditory meanings from visual music notations, so they therefore did not find it necessary to spend more resources on executing spatial attention than non-musicians do during pitch processing. PMID- 23033742 TI - Effects of the order of reading text or viewing a film and L1/L2 captions on reading comprehension. AB - The purpose of the study was to investigate the effects of order of reading text or viewing a film and L1/L2 captions on participants' comprehension. The participants were college freshmen (N = 236) enrolled in English as a Foreign Language (EFL) courses. In the experiment, there were four conditions: the text was read first, and then the film version viewed with either Chinese or English subtitles, or the film version was viewed first with Chinese or English subtitles. Pre-test and post-test scores on the General English Proficiency Test (GEPT) indicated that the read-first group viewing the film with Chinese subtitles outperformed the read-first and view-first groups viewing the film version with English subtitles. PMID- 23033743 TI - Further tests of pigeons' (Columba livia) planning behavior using a computerized plus-shaped maze task. AB - Miyata and Fujita in 2008 reported that pigeons, trained to move a target square to a goal square by pecking, plan one step ahead while performing on a plus shaped maze, that is, the birds frequently made errors to move the target toward the previous goal direction after the goal jumped to another arm. In the present study, pigeons' planning using this maze was further examined. In Experiment 1, when goals appeared at all three of the arms during solution, the birds did not choose the old goal at above chance. Reaction time data suggested that the birds decided which goal to choose after crossing the center point. In Experiment 2, after the goal jumped to another arm following a preview phase, some birds frequently moved in the direction of the old goal. These results suggest that pigeons may plan one step ahead but might have updated plans for each movement. PMID- 23033744 TI - Measurement invariance of working memory measures across two Arab cultures. AB - A confirmatory factor analysis was performed to examine the factorial structure of a battery of working memory measures across two Arab cultures (Kuwait and Egypt). The battery of tests was administered to a sample of 384 children: 192 primary-school Kuwaiti children (96 boys, 96 girls; M age = 10.0 yr., SD = 1.0) and 192 primary-school Egyptian children (96 boys, 96 girls; M age = 10.0 yr., SD = 1.2). The multi-group confirmatory factor analysis revealed configural, metric, scalar, and strict invariances across the two cultures. This implies that working memory can be conceptualized similarly by Kuwaiti and Egyptian children and was measured in the same way in both cultures. Both within-groups individual differences and between-groups differences in means reflected differences in the underlying latent construct. PMID- 23033745 TI - Inhibition of irrelevant information is not necessary to performance of expert chess players. AB - Some studies on expertise have demonstrated that the difference between novices and experts can be partly due to a lack of knowledge about which information is relevant for a given situation. This lack of knowledge seems to be associated with the selection of correct information and with inhibitory processes. However, while the efficiency of inhibitory processes can lead to better performance in the normal population, it seems that experts in chess do not base their performance on this process but rather on an automatic and parallel encoding of information. Two experiments investigated the processes involved in a check detection task. The congruence of the information was manipulated in a Stroop situation similar to Reingold, Charness, Scheltetus, & Stampe (2001). The results showed that the experts did not benefit from cuing with a congruent cue and that they did not show any interference effect by the incongruent cue, contrary to less skilled chess players who benefited from cuing (Exp. 1). An attentional priming procedure confirmed the automatic encoding of chess relations in the more skilled chess players by showing no advantage from the prime in this group (Exp. 2). Taken together, the results indicate that the processing was serial for the less skilled chess players and that it was automatic and parallel for the more expert chess players. The inhibition of irrelevant information does not seem necessary to process information rapidly and efficiently. PMID- 23033746 TI - Electrophysiological indicators of visuomotor planning: delay-dependent changes. AB - A visuomotor task was used to investigate the influence of a varying response delay on the evoked activity measured during motor planning. Participants performed one-dimensional hand movements to visual targets after 200-, 1,000-, and 5,000- msec. delays with respect to the target offset. In response to an imperative go signal, similar deflections were observed over motor areas in all delay conditions. In contrast, activity at posterior electrodes was strongly delay-dependent. During the shortest delay condition, evoked alpha oscillations were pronounced at occipitoparietal recording sites and were accompanied by P300 like positive waves. In contrast, when the delay was either 1,000 or 5,000 msec., lateral occipitotemporal deflections (N1) were observed. Also, during the longest delay condition another P300-like component was measured, which was entirely absent when the delay was 1,000 msec. These results suggest that neurophysiological processes underlie motor planning, change depending on the time of response. PMID- 23033747 TI - Color of light-source and background luminance on perceived convexity and concavity of a blurred 3-D hemisphere. AB - In the present study, the effect of light-source color, size, background luminance, and blur on the perceived convexity and concavity of a 3-D hemisphere was investigated. The sample consisted of 84 undergraduates divided into Experience and No-experience groups based on experience working with 3D software. Participants were asked to adjust the angle of light in a clockwise direction until a convex hemisphere appeared concave. Analysis indicated that the color of light had a statistically significant effect on the angle of adjusted light, and the Experience group adjusted the angle of light less than did the No-experience group. The angle of the adjusted light was significantly smaller under the high background luminance condition compared with the medium and low luminance conditions. The angle of adjusted light under the low blur condition was greater than that under the high and medium blur conditions. These results have implications for graphics-based interface design. PMID- 23033748 TI - Exploration time of static images implying different body movements causes time distortions. AB - Studies of subjective time have adopted different methods to understand different processes of time perception. Four sculptures, with implied movement ranked as 1.5-, 3.0-, 4.5-, and 6.0-point stimuli on the Body Movement Ranking Scale, were randomly presented to 42 university students untrained in visual arts and ballet. Participants were allowed to observe the images for any length of time (exploration time) and, immediately after each image was observed, recorded the duration as they perceived it. The results of temporal ratio (exploration time/time estimation) showed that exploration time of images also affected perception of time, i.e., the subjective time for sculptures representing implied movement were overestimated. PMID- 23033749 TI - Relationship between writing skills and visual-motor control in low-vision students. AB - The purpose of this study was to investigate the relationship between handwriting skills and visual motor control among students with low vision and to compare this with the performance of their normal sighted peers. 42 students with low vision and 26 normal sighted peers participated. The Bruininks-Oseretsky Motor Proficiency Test-Short Form (BOTMP-SF), Jebsen Taylor Hand Function Test's writing subtest, and a legibility assessment were administered. Significant differences were found between groups for students' writing speed, legibility, and visual motor control. Visual motor control was correlated both writing speed and legibility. Students with low vision had poorer handwriting performance, with lower legibility and slower writing speed. Writing performance time was related to visual motor control in students with low vision. PMID- 23033750 TI - Charpentier's papers of 1886 and 1891 on weight perception and the size-weight illusion. AB - The French physiologist Augustin Charpentier (1852-1916) published the first accounts of the size-weight illusion-the observation that if two objects differ in size but have equal mass, the smaller will feel heavier when lifted. In the current paper, translations are presented of Charpentier's much-cited 1891 paper on weight perception and the size-weight illusion, and his little-known brief 1886 paper which contains the earliest experimental data on the illusion. Charpentier explained weight illusions in terms of the sense of effort involved in lifting the object and the contrast with the expected effort. Modern research shows that people quickly adapt and use the appropriate force to pick up objects, but the illusion persists even when appropriate force is used; expectations therefore affect the perceptual system more strongly than the motor system. PMID- 23033751 TI - Association of force steadiness of plantar flexor muscles and postural sway during quiet standing by young adults. AB - This study was conducted to assess the relations of force fluctuations during isometric plantar-flexion and postural sway during quiet standing. Twelve healthy men (M age = 21 yr., SD = 1) performed unilateral plantar flexion measured by a strain gauge force transducer. Participants performed force-matching tasks; sustained plantar flexion for 20 sec. at levels corresponding to 10% and 20% of maximum voluntary contraction with the visual feedback. Also, participants were asked to stand quietly with their eyes open, and then the center of mass displacement and velocity in the anteroposterior were measured. In analysis, postural sway was associated with force fluctuation at only 10% of maximum voluntary contraction. The statistically significant correlation between variables was found only at corresponding contraction intensities for plantar flexor muscles. From this one may infer neural strategies in plantar-flexor muscles during quiet standing may be characteristics similar to those controlling the plantar-flexion force in young adults. PMID- 23033752 TI - A developmental perspective of intermanual performance asymmetry in aiming. AB - This study compared intermanual performance asymmetry between adults and children of different ages in timing components of an aiming task. Participants manipulated a computer mouse with either hand, aiming to rapidly reach targets of different widths with a pointer on a monitor. Results showed longer deceleration movements with the left hand in children, leading to increased intermanual performance asymmetry when aiming at narrower targets. Increased intermanual performance asymmetry in children is conceptualized to derive from planning to minimize trajectory variability when controlling the nondominant hand. PMID- 23033753 TI - Association of relative age effects in sports with number of years in school. AB - The present study investigated the association of the relative age effect, a biased distribution of birth dates, with a high school versus university background in Japanese professional soccer and baseball players. The number of athletes born in the first quarter (April-June) was larger than the number born in the fourth quarter (January-March) for both soccer and baseball; however, the magnitude of the relative age effect differed with years in school. The skew of birth dates was stronger among players who only graduated high school than those who graduated university or college. This phenomenon was confirmed in both baseball and soccer players. The findings suggest relative age effects in professional sports to be related to years of age and years in school. PMID- 23033754 TI - Interrelations between three fine motor skills in young adults. AB - Motor skills are typically considered to be highly specific, although some researchers have attempted to identify evidence for general motor aptitude. The present study tested these contentions by assessing the extent of relationship between fine motor tasks, using correlations between selected performance measures for three fine motor skills. University students ages 18 to 35 years (N = 305; 147 men, 158 women) completed three fine motor tasks with both right and left hands (placing pegs, posting coins, and placing bricks). Performance was assessed by time to complete each individual task. The intercorrelations between the three tasks were generally low and at a level that can be expected by chance (r < or = .3), indicating that performance was quite specific to the individual skills rather than attributable to a general ability. As a further test for evidence for a general motor ability, the dimensionality of the data set was analyzed using a principal component analysis on the correlation matrix. A three factor solution explaining approximately 80% of the total variance in performance on the fine motor tasks was identified, where each factor could be associated with each fine motor task. These findings provide further support for the high specificity in fine motor skills and against the existence of a general aptitude for motor ability. PMID- 23033755 TI - Sex differences in relative age effects among Japanese athletes. AB - The present study investigated the relative age effect (RAE), a biased distribution of elite athletes' birthdates, in Japanese female athletes. Japan applies a unique annual-age grouping for sport and education, which is from April 1 to March 31 of the following year. A total of 1,335 female athletes were evaluated from six sports: softball, soccer, volleyball, basketball, badminton, and track and field (long distance), and compared with male athletes. All athletes played in the top level of Japanese leagues for each sport in 2010. Distribution of the birth dates in each female sport showed a significant RAE only in volleyball. For males, significant RAEs were observed in baseball, soccer, and track and field. Findings suggest that the determinants of RAEs in sports may differ between males and females. PMID- 23033756 TI - Optimal combination of auxiliary device size and its location on chopsticks for food-gripping performances. AB - Chopsticks are the main utensils for daily dining in Asia. Lee and Chen (2008) designed a novel auxiliary device for chopsticks that successfully converts people experienced in scissor-pinching to the correct method: pincer-pinching. This study attempts to assess the optimal combination of auxiliary size and location on chopstick stems for food-gripping performance. Twenty-four male participants experienced in scissor-pinching were recruited for the experiment. They were requested to perform 3 simulated tasks (force, precision, and stability) using 6 auxiliary combinations of 3 sizes (15, 25, and 35 mm) of chopsticks and 2 locations (on top of the stems and 1/3 stem-length from the top). Results indicate that auxiliary device size influenced simulated task performance and the user's subjective rating of chopsticks use. The auxiliary device measuring 15 mm wide showed the best performance in pinching force, precision, stability, and subjective rating. The location of the auxiliary device only affected the pinching force. The auxiliary device produced greater force when located at the top of the stems. This finding improves the application of auxiliary devices to chopstick operation. PMID- 23033757 TI - Children's locomotion on slopes given visual, acoustic, and tactile information. AB - The effects of visual, acoustic, and tactile information on 5 blind and 5 sighted children's locomotion on slopes (10 degrees, 15 degrees, 20 degrees, 25 degrees, and 30 degrees) were investigated. Children's ages ranged from 5.8 to 7.7 years (M= 6.8, SD= 0.7). The sighted children performed the task of walking up and down different slopes blindfolded and with full vision. Locomotion modes, locomotor skill, gait deviation, and time to complete the task were analyzed. Walking was the preferred locomotion mode up to 20 degrees, but steeper slopes were perceived as "non-walkable." Doubly multivariate MANOVAs revealed an effect of visual information (blindfolded vs full vision) on the sighted children's gait patterns, and a significant interaction between cue condition and group (blind vs blindfolded), underlining a distinct influence of the cues in the gait patterns of the two groups of children. Acoustic and tactile cues were generally more effective for the blind than for the sighted blindfolded children. PMID- 23033758 TI - Observer effects on the rating of perceived exertion and affect during exercise in recreationally active males. AB - This study examined the effect of introducing either a male or female observer on the ratings of perceived exertion (RPE) and affect of male runners during a moderate intensity running task. 10 moderately active men completed three 20-min. moderate intensity running trials at 60% of their peak treadmill running speed. Each participant completed three trials in random order: control, male-observed, and female-observed, where either the male or female observer joined the trial after 10 min. of the trial had elapsed, during which RPE and affect were monitored. The introduction of a female observer caused a significant decrease in RPE, whereas the introduction of a male observer caused a significant increase in RPE compared to the control trial. Affect was higher in the presence of both a male and female observer compared to control. It was concluded that there is a social, interpersonal, psychological dimension to RPE during exercise. PMID- 23033759 TI - Sex differences in electromechanical delay during a punch movement. AB - This study assessed how sex of participant is related to electromechanical delay during a karate punch. Ten male (M age = 25.00 yr., SD = 3.02; M height=174.9 cm, SD=6.3; M weight = 71.13 kg, SD=9.35) and 8 female (M age = 27.4 yr., SD = 6.0; M height = 161.4 cm, SD = 5.1; M weight = 59.09 kg, SD = 7.00) karate athletes performed 10 ballistic punches to a target as hard as possible. Kinematic analysis and surface electromyographic (EMG) activity of the upper-limb muscles were recorded. Men had a significantly shorter electromechanical delay in the anterior portion of the deltoid, showing a larger effectiveness in the transfer of the contractile force for the beginning of movement. Agonist and antagonist relationships show intermuscular coordination differences between the sexes. Results revealed the existence of a different neuromuscular coordination pattern of motor control between men and women, although a similar kinematic pattern was expected due to karate practice. PMID- 23033760 TI - Coactivation of lower leg muscles during body weight-supported treadmill walking decreases with age in adolescents. AB - The kinematics of children's walking are nearly adult-like by about age 3-4 years, but metabolic efficiency of walking does not reach adult values until late in adolescence or early adulthood, perhaps due to higher coactivation of agonist/antagonist muscle pairs in adolescents. Additionally, it is unknown how use of a body weight-supported treadmill device affects coactivation, but because unloading will alter the activity of anti-gravity muscles, it was hypothesized that muscle coactivation will be altered as well. Muscle coactivation during treadmill walking was evaluated for adolescents (ages 10 to 17 years, M = 13.2, SD = 2.2) and adults (ages 22 to 35 years, M = 25.2, SD = 4.3), for thigh muscles (vastus lateralis/biceps femoris) and lower leg muscles (tibialis anterior/gastrocnemius). Conditions included body weight unloadings from nearly 0% to 80% of body weight, while walking at a preferred speed (self-selected, overground speed) or a reduced speed. Unloading was accomplished using a lower body positive pressure support system. Coactivation was found to be higher in adolescents than in adults, but only for the lower leg muscles. PMID- 23033761 TI - Effects of sensory information, movement direction, and hand use on fine motor precision. AB - The differences in fine motor precision over line model in different sensorial conditions (visual-proprioceptive and proprioceptive only) for different movement directions (transverse, frontal, and sagittal) and both hands were measured digitally with use of special software. The observed variables were directional (D) and formal (F) deviations, together with changes of line length (LL) from the base model. Analysis indicated non-significant differences for all measured variables for hand use, while for the remaining factors (sensory test condition and movement direction), the differences were significant for all levels. Both sensory information and movement directions are important for hand-drawing precision, not just the specific hand used. PMID- 23033762 TI - Effects of rest interval length on rating of perceived exertion during a multiple set resistance exercise. AB - This investigation analyzed the effect of rest interval length on the rating of perceived exertion (RPE) during a resistance exercise session. Nineteen males performed two experimental sessions: resistance exercise with 30-sec. rest intervals (E30) and 90-sec. rest intervals (E90). In both sessions, five exercises (bench press, knee extension, seated row, knee curl, and frontal rise) were performed at 50% 1RM in three sets of 12, 9, and 6 repetitions, respectively. In the E30 session, the RPE increased between sets in all exercises, while in the E90 session, the RPE increased from the first set to the second set in three exercises. RPE in the E30 session was higher than that in the E90 session in the third set. The results suggest that RPE increases for shorter rest intervals than for longer rest intervals. Therefore, the RPE could be considered an indicator of muscle recovery during resistance exercise. PMID- 23033763 TI - Comparison between recreational male Ironman triathletes and marathon runners. AB - Recent investigations described a personal best marathon time as a predictor variable for an Ironman race time in recreational male Ironman triathletes. Similarities and differences in anthropometry and training were investigated between 83 recreational male Ironman triathletes and 81 recreational male marathoners. Ironman triathletes were significantly taller and had a higher body mass and a higher skin-fold thickness of the calf compared to the marathoners. Weekly training volume in hours was higher in Ironman triathletes. In the Ironman triathletes, percent body fat was related to overall race time and both the split time in cycling and running. The weekly swim kilometres were related to the split time in swimming, and the speed in cycling was related to the bike split time. For the marathoners, the calf skin-fold thickness and running speed during training were related to marathon race time. Although personal best marathon time was a predictor of Ironman race time in male triathletes, anthropometric and training characteristics of male marathoners were different from those of male Ironman triathletes, probably due to training of different muscle groups and metabolic endurance beyond marathon running, as the triathletes are also training for high-level performance in swimming and cycling. Future studies should compare Olympic distance triathletes and road cyclists with Ironman triathletes. PMID- 23033764 TI - Assessment of beginners' front-crawl stroke efficiency. AB - Efficiency in front-crawl stroke has been inferred primarily by means of the analysis of arm actions, specifically, stroke frequency and stroke length. The objective of the present study was to investigate whether swimming efficiency could be better assessed in children still learning the front-crawl stroke by analyzing the movement pattern as a whole. Forty-two children enrolled in private swimming programs volunteered to participate in the study. The task consisted of swimming 30 m as fast as possible. Three experts analyzed the movement pattern of the participants using a checklist. Both stroke frequency and stroke length were calculated. The correlation coefficients between the time taken to swim and both the stroke frequency and stroke length were not significant, but the total and components of the checklist scores were. Results indicate that the swimming efficiency of children learning the front-crawl stroke can be better assessed by analyzing their whole movement pattern. PMID- 23033765 TI - Effect of walking speed on typing performance using an active workstation. AB - This study tested the effect of treadmill walking speed on typing performance when these tasks were performed simultaneously. 24 research participants (M age = 23.2 yr.) performed a typing test under each of four conditions including the control (seated), treadmill walking at 1.3 km/hr., 2.25 km/hr., and 3.2 km/hr. Results indicated that treadmill walking had a detrimental effect on typing performance, but that the walking speed of 2.25 km/hr. would result in better typing performance than the slower and faster speeds. Seated typing was better than typing while walking at 1.3 km/hr. and typing while walking at 3.2 km/hr. Typing performance while walking at 2.25 km/hr. was not different than seated typing performance. The results support the potential of treadmill walking at 2.25 km/hr. to provide low-intensity physical activity without compromising typing performance. PMID- 23033766 TI - Peer-victimization during physical education and enjoyment of physical activity. AB - This study examined the relations between peer-victimization during sport practice and physical activity enjoyment. 395 students (219 boys, 176 girls) from a middle school, ages 12 to 13 years (M = 12.2), were surveyed. Few correlations between peer-victimization during sport practice and physical activity enjoyment variables were negative. Linear regression analysis was also conducted, highlighting a subtle influence of peer-victimization during practice of sports on enjoyment of physical activity. Peer-victimization during practice of sports seems to be a poor predictor of low enjoyment of physical activity. PMID- 23033767 TI - Perceptions of instructor's verbal aggressiveness and physical education students' affective learning. AB - The study examined the effects of perceptions of instructor's verbal aggressiveness on students' affective learning, and, in particular, students' affect toward the course, course-related behaviour, the instructor, as well as students' satisfaction as a function of perceived verbal aggressiveness by the instructor. Furthermore, the study aimed to examine the psychometric integrity of the affective learning scale employed. The sample comprised 146 physical education undergraduate students (18-22 years old, M = 18.9, SD = 1.0). Results of a confirmatory factor analysis provided support for the factorial validity of the affective learning measure. Correlational analysis revealed a negative relationship between perceived verbal aggressiveness of the instructor and students' affect toward the course, course-related behaviour and the instructor, and students' satisfaction. The results of regression analysis revealed that perceived verbal aggression could significantly predict all the dependent variables; the prediction was particularly high for students' affect towards the instructor and students' satisfaction. Findings and implications for teachers' type of communication were discussed and future research suggestions were made. PMID- 23033768 TI - [Efficacy of surgical treatment of medullary thyroid carcinoma in patients with regional and distant metastases]. AB - Results of surgical treatment of 93 primary patients with medullary thyroid carcinoma within 1995-2009 years, including 26 (28%) - with hereditary disease (MEN2 syndrome) were analyzed. The best long-term results were observed in group of noninvasive tumor without metastases at the time of operation (39% - clinical and biochemical recovery, 32% - clinical remission). No one patient with extrathyroid tumor invasion and regional/distant metastases has completely recovered. Hereditary forms of disease are more aggressiveness in comparison with sporadic carcinomas with higher rate of distant metastases (31 and 21%) and worse survival. In sporadic group 3 (6%) patients and in hereditary group - 4 (12%) died from progression of distant metastases within 8-15 years after primary operation. Complete recovery was seen only after radical primary operations. Repeated surgery was palliative. Implementation of calcitonine screening and genetic testing for Ret-protooncogene mutation is an important task for Ukraine medicine to improve results of medullary carcinoma treatment. PMID- 23033769 TI - ["Incidental" thyroid carcinoma among patients in surgical treatment for nontumors thyroid desease]. AB - Incidence of unexpected diagnosis of thyroid carcinoma among operations on benign thyroid surgical diseases (nodular goiter and Graves' disease) was studied in 608 patients within 2008-2009 years in specialized clinic of endocrine surgery. In 56 (9.2%) patients the "incidental" thyroid carcinoma including 43 (77%) - papillary microcarcinoma were diagnosed in histological investigations. In 10 (18%) patients which were performed within the first postoperative week. Repeated surgery demonstrates increased risk of complication (damage of parathyroid glands, recurrent laryngeal nerves and other anatomic structures of neck) considering less favoring conditions for secondary operations, it is worth to implement wider indications to frozen section, radical primary operation (total thyroidectomy at multi-nodular bilateral goiter and Graves' disease), and also maximal complete examination prior to surgery. PMID- 23033770 TI - [Lazer-inducted interstitial thermotherapy in the treatment of solid nodulus of thyroid]. AB - The results of treatment 272 patients with a nodular colloid goiter with the use of lazerinducted termotherapy (LITT) are analysed. I is established that in the developed modes of LITT application does not cause destructive changes in paranodular tissue and disorders of thyroid gland hormonal function. Duration of reverse development and substituting of nodular for a connecting tissue is determined by echogene and volume. With it increase the intensity of nodulus substituting for a connecting tissue goes down, extended the terms of nodulus regress. The indication to the repeated application of termotherapy is remaining tissue in the projections of nodulus scope from 42% and more an initial volume through 6 ms treatment. Absolute indications to repeated LITT is a presence of thyroid epithelium in remaining tissue of nodulus. PMID- 23033771 TI - [Minimally invasive and endoscopic methods in surgical treatment of patients with primary hyperparathyroidism: advantages and limitations]. AB - Results of surgical treatment of 212 patients with primary hyperparathyroidism (PHPT) within 2007-2009 years were analyzed. In 183 patients have been performed the conventional approach with revision of all 4 parathyroid glands, in 29- using minimally invasive methods (in 18 - endoscopic operations, in 11 - targeted operations through mini incision). Multi-glandular disease was observed in 5.2 % of all cases. Comparison of conventional and minimally invasive surgery demonstrates advantages of the endoscopic and targeted operations in cosmetic results and recovery time having the same rate of complications. The obligatory conditions for effective minimally invasive operations in patients with PHPT include undoubtful localisation of adenoma, diameter of tumor no more 3 cm, absence of thyroiditis, low risk of multiglandular disease, availability of quick parathyroid hormon assay (at least--one day result). PMID- 23033772 TI - [Application of video-assisted parathyroidectomy for treatment of primary hyperparathyroidism]. AB - During the last years for surgical treatment of primary hyperparathyroidism minimally invasive operations were applied. The results of the introduction of video-assisted parathyroidectomy in the clinic in 8 (32%) of 25 patients with primary hyperparathyroidism, who were operated during the 2010-2012 were analysed. Video-assisted parathyroidectomy compared to conventional operation allowed to reduce significantly the duration of the operation, to reduce the incidence of postoperative complications, to achieve a better cosmetic effect. PMID- 23033773 TI - [Carcinoids of pancreas and digestion canal clinical signs, diagnostics and surgical treatment]. AB - The review of the literature is presented and results of diagnostics and treatment of 28 patients with carcinoid tumours of the digestion canal of various localization are analysed. Carcinoids were both hormone-active, and hormone inactive. Before the operation the diagnosis of carcinoid syndrome has been established only for two patients. Carcinoid tumours of a liver were in 4 patients, a gall bladder - in 1, a pancreas - in 5, a stomach - in 1, a duodenum in 1. Results of methods of laboratory and instrumental examination are given and corresponding conclusions are made. PMID- 23033774 TI - [Application of high frequency electric welding in adrenal surgery. Current state and prospects]. AB - In 14 patients underwent open adrenalectomy with high-frequency electric welding application (I group), in 8 - open adrenalectomy (II group). The two groups were compared: duration of surgery, blood loss, postoperative pain intensity, duration of postoperative hospitalization, the frequency of intra-and postoperative complications, histological changes in tissues. The advantages of open adrenalectomy with high-frequency electric welding application feel less duration of surgery and estimated blood loss, lack of necrosis in the surrounding tissues and foreign bodies in the wound, reducing the trauma of surgery, improving rehabilitation. PMID- 23033775 TI - [Adrenal tumours: diagnosis and modern surgical methods of treatment, including minimale invasive]. AB - The results of diagnosis and treatment of 759 patients (aged from 8 to 78 years) with adrenal diseases were analyzed. A variety of clinical symptoms depended on the adrenal layer lesion. We analyzed the results of biochemical and instrumental methods of examination of patients, hormone levels in the blood, methods of preoperative preparation of patients, postoperative complications. The results of minimally invasive surgery of adrenal tumors were presented. From 1997 till 2010 endoscopic adrenalectomies performed in 81 patients. PMID- 23033776 TI - [The influence of ozone therapy to some immunological parameters in patients with generalized peritonitis]. AB - The immune status of the surgical treatment of 103 patients with generalized peritonitis (GP) were discussed. Patients were divided into two groups. Comparison group included 60 patients who received conventional combined therapy, main group - 43 patients, who, along with the standard complex treatment measures, were used local and systemic intravenous ozone therapy (OT). The severity state of patients evaluated by Mannheim peritoneal index (MPI). To assess the immune status in blood of the patients with GP were studied the level of lymphocyte subpopulations (CD3+, CD4+, CD8+, CD11a+, CD19+), the phagocytic activity of neutrophilic granulocytes, concentration of immunoglobulin A, M, G, and the content of circulating immune complexes (CIC). Studies have shown that GP is accompanied by changes in the functioning of the immune system, the severity and extent of which depends on the severity of MPI. The conventional basic therapy is not effective in correcting of these disturbances. Using the local and systemic OT in the complex of therapeutic measures in individually selected patients with GP have a positive effect on some level of immunity with a tendency to restore the immune system dysfunction. PMID- 23033777 TI - [Dynamics of cytokine profile in patients with postoperative hernias the abdominal wall in prosthesis with polytetrafluoroethylene and polyvinylidene fluoride application]. AB - The results of experimental and clinical studies for the comparative evaluation of implants used in herniology of polytetrafluoroethylene (PTFE) and polyvinylidene fluoride (PVDF) are presented. Experimental investigations conducted on 200 mice, which in the anterior abdominal wall mesh prosthesis implanted. All animals, regardless of the type of implanted prosthesis, deduced from the experiment at 10, 30 th and 60 th day. Histological investigation of the submissions received. The clinical part is based on an analysis of surgical treatment results of postoperative abdominal wall hernia (POGBS) in 121 patients during the period from 2003 to 2011 patients were divided into 2 groups. The control group included 73 patients who were operated during the period 2005-2007, used PTFE graft "Ecoflon", in the main - 48 patients who from 2008 to 2011 the prosthesis was implanted PVDF - "Uniflex" firm "Linteks". In each group, selected patients whom have examined the profile of cytokines. The results of the studies found that both the material cause marked inflammatory reaction with a characteristic stepwise increased levels of proinflammatory and antiinflammatory cytokines, the dynamics of cytokines indicative of a less pronounced local inflammatory reaction to the prosthesis from the PVDF. In the application of the implant "Uniflex" a lower incidence of exudative complications in comparison with that when using the prosthesis "Ecoflon" it is preferable in clinical use. PMID- 23033778 TI - [Application of essential phospholipids in the treatment and prophylaxis of postcholecystectomy syndrome]. AB - The experience of drug use in the clinic Enerliv (of "Berlin - Chemie Menarini" Germany) in 58 patients is the complex treatment of postcholecystectomy syndrome in generalised. The drug has hepatoprotective and cholesterol-lowering effect, effectively eliminates pain and dyspeptic symptoms, normalize biochemical parameters. PMID- 23033779 TI - [Modern minimal invasive combine surgical approach in varicose disease of lower limbs patients]. AB - The analysis of combine endovenous laser coagulations in 167 patients, treated from 2007 to 2011 with different types of chronic venous insufficiency of superficial veins of lower limbs varicous disease were analysed. The high efficiency of minimal invasive combine surgical treatment, using high energetic diode laser Dornier Medilas Fibertom with wave length of 940 nm was done. PMID- 23033780 TI - [Thoracoscopic fenestration of pericardium during the treatment of patients, suffering exudative pericarditis]. AB - There were examined 67 patients, treated in the Thoracic Department of Rural Ivano-Frankivsk Clinical Hospital for exudative pericarditis in 2005-2009 yrs. In 27 (40.2%) patients a fenestration of pericardium was performed, using videoassisted thoracoscopy (VATHS), and in 40 (59.8%) - a pericardium cavity puncture according to Larrey method. The results of surgical treatment were analyzed, comparative estimation of the every method efficacy was conducted. The advantages of VATHS application with pericardium fenestration in patients, suffering exudative pericarditis, were proved. Indications for the VATHS application in patients, suffering exudative pericarditis, were determined. PMID- 23033781 TI - [Inhibition of pancreatic stellate cell activation by lisinopril for prevention fibrogenesis in experimental chronic alcoholic pancreatitis]. AB - Lisinopril (angiotensin-converting enzyme inhibitor) attenuates fibrotic changes in pancreas after distal pancreatectomy in rats with experimental alcohol induced chronic pancreatitis. Lisinopril was administered after distal pancreatectomy in rats with experimental alcohol induced chronic pancreatitis. The animals were treated with lisinopril at the dose of 10 mg/kg body weight per day for 21 days after operation. To estimate the efficacy of the treatment on activity and number of pancreatic stellate cells the immunohistochemical investigation was made with alpha-smooth muscle actin (alpha-SMA), desmin, vimentin, glial fibrillary acidic protein (GFAP), matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-2 (TIMP-2) using. The treatment of rats after operation with lisinopril inhibite activity of pancreatic stellate cells and characterized by significant decrease of the alpha-SMA, desmin, GFAP, vimentin and TIMP-2 expression. The ratio of MMP-1/TIMP-2 was greater in the group with treatment then in the control group. This therapy had a trend to alleviate the fibrotic changes in pancreas. PMID- 23033782 TI - [Use of high-temperature methods of coagulation in parenchymal organs surgery]. AB - The results of the experimental resection of the liver and spleen, which are used for high-temperature devices of various types of coagulation are presented. It is established that the application of various high-technology the biological tissues carbonation is typically process. The morphological investigation revealed that carbonized tissue surrounded by a connective tissue capsule with the formation of a large number of giant cells of foreign bodies and macroscopic appear as granulomas foreign bodies. In the late stages of observation granulomas can transforme of chronic aseptic abscesses. PMID- 23033783 TI - [Simultaneus intervention for ishemic heart disease and rectal tumor]. PMID- 23033784 TI - [Castleman's disease: the problems of diagnosis and treatment]. PMID- 23033785 TI - [Gut bacteria and antimicrobial resistance--what to worry about]. AB - Gram negative and anaerobic bacteria from gut microbiota are important pathogens both in community-acquired and hospital infections. Escherichia coli is the the most common cause of adult bacteraemias in Finland. Antimicrobial resistance in these bacteria is a threatening phenomenon. Enterobacteriacae producing extended spectrum beta-lactamase (ESBL) have spead worldwide. The use of antimicrobial agents shifts the balance in gut microbiota and induces and selects bacterial resistance. When resistant bacteria cause infections, empiric antimicrobial therapy may not cover them, which may increase lenght of hospital stay, costs and mortality due to infections. PMID- 23033786 TI - [Common vulvar dermatologic conditions]. AB - A wide range of cutaneous diseases can affect genital area. Some of these dermatoses are predominantly present in vulvar area while others primarily occur in extra-genital skin areas. Genital area is susceptible to maceration and the combination of moisture and warmth together with the increased penetration of topical agents make the region vulnerable for mechanical and chemical irritation. Lichen simplex chronicus (LSC) is a secondary condition precipitated by chronic itching and scratching. Scratching may be caused by some dermatoses or candida infection. Chronic systemic dermatoses most commonly affecting vulval area are various eczemas, psoriasis, lichen sclerorus and lichen planus. PMID- 23033787 TI - [When is ankle fracture treatable without surgery?]. AB - Stability of a fractured ankle is the most important factor when considering the choice between operative and non-operative treatment. Depending on the mechanism of injury, the most common type of ankle fracture, spiral fracture of the lateral malleolus (Weber B) may be stable or unstable. It can be treated conservatively, provided that the shape of the ankle joint has remained intact in both projections and there is neither significant injury of deep deltoid ligament nor another fracture within the ankle region. In cases of suspected unstable ankle fracture the patients should be referred to a clinic having experience of surgical therapy of ankle fractures. PMID- 23033788 TI - [Treatment of plantar fasciopathy]. AB - Plantar fasciopathy is the most frequent reason for foot pain. It is characterized by degeneration of the insertion of the plantar fascia on the medial process of the calcaneal tuberosity. Palpation over plantar fascia insertion reproduces the pain and may reveal swelling. Conservative treatment is almost always successful. Initial treatment consists of anti-inflammatory medication, stretching exercises, night splints and shoe inserts. If these fail, steroid injections, custom made orthotics, and extra corporeal shock wave therapy may be tried. If disabling pain persists for more than one year, surgery may be indicated. PMID- 23033789 TI - [Treatment of hemangiomas]. AB - Hemangioma is the most common benign tumor in infancy. Over 90% of hemangiomas require no treatment, but there is a need to recognize those that may require even quick measures to secure vital functions or normal development of organs. Propranolol has established itself as the first-line treatment. Pulsed dye laser has proven effective in the treatment of ulcerated hemangiomas. Corticosteroid therapy is applied only rarely, but surgical treatment or angiography and embolization therapy associated with it may sometimes be indicated. PMID- 23033790 TI - [Treatment of common warts]. AB - Spontaneous healing of warts should be followed up for at least for six months, preferably one or two years. Salicylic acid products, i.e. anti-wart drops, gel and salicylic acid plaster, are still the cornerstones of the treatment of warts. Approximately four out of five warts are healed up in 1 to 3 months. The therapeutic value of formic acid solution or trichloroacetic acid products is not established. Other options available for the doctor include cryotherapy with liquid nitrogen and in cases of difficult, isolated plantar warts, removal of the lesion with a punch and diathermy which may be applied to selected hand warts also. PMID- 23033791 TI - [A guest worker's multistage skin disease--a dermatologist's headache]. AB - A Bangladeshi man had suffered for four years from dermatitis that turned out to be caused by a dermatophyte infection masked by the use of strong corticosteroid ointments. After starting internal antifungal medication he developed a painful kerion reaction in the bearded region. Two systemic corticosteroid courses were required to calm it down. After discontinuation of corticosteroids he developed extensive psoriasis. PMID- 23033792 TI - [Concurrent subacute thyroiditis and Graves disease]. AB - The diagnosis of subacute thyroiditis is based on typical symptoms and findings, including thyroid pain, high fever, tenderness on palpating the thyroid gland, transient symptoms of thyrotoxicosis, and hypersedimentation. The doctor responsible for the diagnosis is in most cases able to treat the illness without special examinations. In cases with an atypical clinical picture or a poor therapeutic response a specialist consultation is recommended. Diseases of the thyroid gland may exist concurrently. Concurrent occurrence of the Hashimoto disease and Graves disease is well known. In this paper, a patient with concurrent subacute thyroiditis and Graves disease is described. PMID- 23033793 TI - [Update on current care guidelines: Treatment of drug abuse]. AB - The Finnish treatment guarantee includes people with drug problems. The incidence of drug abuse has been stable during the last five years in Finland, with only lifetime prevalence of cannabis use increasing up to 17%. All substance abusers are treated within the health-care system, in special service units of substance abuse treatment services, and within the social welfare system. Psychosocial treatment and rehabilitation methods, as well as supporting medications are reviewed and recommended. For maintenance treatment of opiate dependence either buprenorphine-naloxone or methadone is recommended. PMID- 23033794 TI - [The disturbances of the relationship between oxidative homeostasis and the immune status of lymphocytes in liquidators of the consequences of the Chernobyl accident]. AB - We investigated into the relations between the immune status of individuals who took part in liquidating the consequences of the Chernobyl accident (liquidators) and the level of active oxygen forms in peripheral blood lymphocytes, as well as the level of the genome damage in lymphocytes (frequency of cells with micronuclei). The results show that the immune status changes as the level of the genome damage increases: the content of some markers increases and others decreases. It has also been shown that a) active oxygen forms participate in forming some indexes of the immunological lymphocyte status and b) the exposure of liquidators to irradiation many years ago almost completely changes the characteristics of the relation between the concentration of active oxygen forms and immunological status indexes. It has been shown that there are many more immunological indexes that experienced changes in their relation with the concentration of active oxygen forms than the amount of indexes associated with the genome damage. It has been found that a) there is little difference in the concentration of active oxygen forms in donors and liquidators and b) the concentration is not associated with the level of the genome damage. Taking this into account, the authors speculate that the changes in the relation between the concentration of active oxygen forms and the immunological indexes are reflection of how irradiation influences the level of the immune status formation based on the relation between the concentration of active oxygen forms and the appearance of a marker in the immune status. The obtained results point to the new, previously unknown aspects of how the primary injuries which are the result of the low dose irradiation influence the health of irradiated individuals. The changes in relations that can be seen in liquidators in comparison with donors lead to a different set of immunological indexes as well as to different immune status, and may become the reason for the deterioration in their health. The authors suppose that the above results could be a substantial contribution to the research into the fundamental mechanisms of the human immune status formation and human health. PMID- 23033795 TI - [Radiation biology of structurally different Drosophila genes. Report 2. The vestigial gene: molecular characteristics of chromosome mutations]. AB - The results of the PCR-assay of mutation lesions at each of 16 fragments overlapping the entire vestigial (vg) gene of Drosophila melanogaster in 52 gamma ray-, neutron- and neutron + gamma-ray-induced vg mutants having the inversion or translocation breakpoint within the vg microregion are presented. 4 from 52 mutants studied were found to have large deletions of about 200 kb covering the entire vg gene and adjacent to sca and l(2)C gene-markers as well. 23 mutants from 48 (47.9%) were found to have a wild-type gene structure showing that the exchange breakpoints are located outside of the vg gene. 25 others display the intragenic lesions of different complexity detected by PCR as the absence of(i) either one fragment or (ii) two or more (6-7) adjacent fragments and (iii) simultaneously several (i) or (i) and (ii) types separated by normal gene regions. It is important that 6 from 25 mutants have the breakpoint inside the vg gene and display the (i) or (ii) type of lesions at the gene regions containing the putative break whereas 5 others from 25 with the above lesions have the exchange breakpoint outside the vg gene. Therefore, the breakpoints underlying either inversions or translocations induced by low- and high-LET radiation are likely to be located within and outside the gene under study. Thereby, the formation of exchanges is accompanied by DNA deletions of various sizes at the exchange breakpoints. The molecular model of formation of such exchange-deletion rearrangements is elaborated and presented. Also, conception of the predominately clustered action of both low- and high-LET radiation on the germ cell genome is suggested as the summing-up of the presented results. The ability of ionizing radiation to induce the clusters of genetic alterations in the form of hidden DNA damages as well as gene/chromosome mutations is determined by the track structure and hierarchical organization of the genome. To detect the quality and frequency patterns of all components of the cluster, joint molecular, genetic and cytological techniques need to be used. PMID- 23033797 TI - [Polymorphism of superoxiddismutase in chronically irradiated Scots pine populations]. AB - Polymorphism ofsuperoxidedismutase in Scots pine populations from the Bryansk region radioactively contaminated as a result of the Chernobyl accident was studied. The frequency of mutations in the isozyme loci, the effective number of alleles, intrapopulation diversity, as well as the frequency of rare morphs were significantly increased along with the level of radioactive contamination. Changes in the genetic makeup of the populations under study were due to the increased frequency of rare alleles. PMID- 23033796 TI - Potential of Piper guineense and Aframomum longiscapum to reduce radiation induced hepatic damage in male Wistar rats. AB - The ameliorative effect of aqueous extracts of Piper guineense and Aframomum longiscapum on radiation-induced hepatic damage was evaluated. Rats were treated with a single dose of 600 rads (6 Gy) y-radiation to induce hepatic damage. Aqueous extracts of Piper guineense and Aframomum longiscapum (200 and 400 mg/kg b. wt) were administered orally to rats for two weeks prior to radiation and four weeks after radiation. Hepatic malondialdehyde (MDA), glutathione (GSH) levels and glutathione peroxidase (GPx) and catalase (CAT) activities were determined for their antioxidant capacity. The activities of serum markers such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the histological changes were examined to evaluate potential ameliorative effects. Results from this study confirmed that exposure of animals to radiation led to induction of lipid peroxidation (LPO), reduced the level of GSH as well as CAT and GPx activities while simultaneously a significant elevation in the activities of serum ALT and AST was observed. Administration of varying doses of P.G. and A.L. before and after irradiation inhibited the elevated levels of LPO, restored the GSH level and enhanced CAT and GPx activities as well as significantly decreased the elevated levels of serum ALT and AST activities. This findings demonstrated that aqueous extracts of Piper guineense and Aframomum longiscapum might mitigate the liver gamma-radiation-induced damage probably by increasing antioxidant activities. PMID- 23033798 TI - [Adaptation to extreme environmental conditions and radiosensitivity of Yakutian plants]. AB - The aim of the long-term research was to assess the influence of physiological, cytological and biochemical adaptations of the plants formed in conditions of extreme continental climate and permafrost on the radiosensitivity of their seed progeny. The obtained data were analyzed using comprehensive cytological and biochemical methods (author's) of the differential assessment of genome stability in reparation reactions and its overall activity. The data on the radiosensitivity of plants growing under permafrost conditions were obtained for the first time. Radiosensitivity of 50 species of wild plants in Central Yakutia was investigated and their classification into 4 groups of radiosensitivity was suggested. The correlation between the totality of biochemical properties of cells providing antioxidant and genomic protection and resistance to ionizing radiation was established. PMID- 23033799 TI - [Experimental justification of possible mechanisms of action of low intensity electromagnetic radiation (EMR) on animals' behavior]. AB - Effects of EMR on the behavior of Wistar rats (196 males, 180-240 g of mass) under the conflict of opposed motivations: strong positive, drinking, motivation, and strong negative, pain, motivation were studied. The animals were exposed to low intensity EMR (40 microW/cm2) produced by two independent sources, 475 MHz (Albatross) with two orthogonal E vectors, and synchronization of rhythm modulation in the range of electroencephalography (EEG) frequency. The effect on behavior was observed during 10 min: 1) following the 5-minute exposure to EMR and 2) during the 10-minute exposure. Low intensity EMR of the above mentioned parameters and pulse modulation of 4, 8, 10 and 13 Hz was found to inhibit development of phobia to pain, increase the number of punishable contacts. It testifies to the existence of a weak anxiolytic effect which is similar to the effect of tranquilizers. If animals were exposed to EMR following administration of phenazepam, the radiation was shown to produce potentiation of the anxiolytic effect ofphenazepam. Effect of phenazepam is associated with activation ofbenzdiazipine receptors in the structure ofGABA-ergic receptor complex, which regulates neural membrane chloride channel conductance. We can suggest that anxiolytic and neurodepressive effects of EMR are realized to some extent at the level of ionophore and regulatory receptor complexes. PMID- 23033800 TI - [Non-thermal effect of GSM electromagnetic radiation on quality of pea seeds]. AB - The seeds with low level of room temperature phosphorescence (RTP) were selected from a lot of air-dry peas (Pisum sativum) with 62% germination. These strong seeds (95-97% germination percentage) in air-dry, imbibed or emerged states were exposed to 905 MHz GSM-band electromagnetic radiation (EMR). The following effects of EMR were observed. Fraction II with higher RTP level appeared in the air-dry seeds. The germination rate decreased 2-3 fold in the air-dry, swollen and sprouting seeds due to an increase in the ratio of the seedlings with morphological defects (from 3 to 38%) and suffocated seeds (from 1 to 15%). We suggest tentative mechanisms to account for the decreased fitness of peas under GSM-band EMR (905 MHz); also discussed is the role of non-enzymatic hydrolysis of carbohydrates and amino-carbonyl reaction in this process. PMID- 23033801 TI - [Estimation of the involvement of 137Cs in biological cycle of pine biogeocenoses]. AB - The estimation of accumulated radionuclides in the biological cycle was carried out on the basis of long-term studies of distribution of 137Cs in the aboveground phytomass of pine plantations. The two main stages which differ from each other in the intensity of the involvement of 137Cs have been defined: the most intensive accumulation of 137Cs in the phytomass of pine plantations in the early 1990s (up to 2.3% of the total activity in biogeocoenose) and quasi-equilibrium distribution of 137Cs in the ecosystem since the 2000s when phytomass has received about 1% of the total activity. The accumulation of the radionuclide during the current year mainly occurs due to its transfer through the needles. PMID- 23033802 TI - [Radiation ecological environment in the Republic of Kazakhstan in the vicinity of the reactors and on the territory of the Semipalatinsk Test Site]. AB - The results of research into the environmental conditions in the regions of location of the pressurized water reactor WWR-K, fast neutron breeder BN-350 and on the territory of the Semipalatinsk Test Site are represented. The effects of the exposure to aerosol emissions from WWR-K and BN-350 reactors on the environment are summarized. We present some arguments in favor of the safe operation of fission reactors in compliance with the rules and norms of nuclear and radiation protection and the efficient disposal of radioactive waste on the territory of the Republic. PMID- 23033803 TI - [Phytoplankton and zooplankton of the industrial reservoir R-9 (Lake Karachay)]. AB - Planktonic communities of the Reservoir-9 (Lake Karachay, storage reservoir of liquid medium-level radioactive waste of the Mayak Production Association) are exposed to the severe radioactive forcing (in 2010 the total beta-activity of the water was 1.8 x 10(7) Bq/L, total alpha-activity was 1.1 x 10(4) Bq/L), aswell as to the chemical contamination (level of nitrates in water 4.1 g/L). The calculated values of the absorbed dose rate were 130 Gy/day for phytoplankton and 4.0 Gy/day for zooplankton. Extremely low species diversity, the overwhelming dominance of one species (phytoplankton is close to a monoculture of ubiquitous cyanobacteria Geitlerinema amphibium, zooplankton--to a monoculture of rotifers Hexarthrafennica), wide fluctuations in numbers of algae, a low number of zooplankton were the most substantial characteristics of the plankton communities in Lake Karachay. So, plankton communities status is a sign of environmental retrogress in this ecosystem. PMID- 23033804 TI - [Possible mechanisms of aftereffects of GSM electromagnetic radiation on air-dry seeds]. AB - Some physical treatments, such as microwave- and gamma-radiation and magnetic field, induce long-term transition of air-dry seeds from the fraction of strong seeds into the weak seed fraction, due to non-enzymatic hydrolysis ofbiomacromolecules. These physical factors make water molecules more active, which is followed by the release of water molecules from the hydration layer, disturbance of this layer structure, further activation of water molecules by means of the "domino effect," and accumulation of hydrolysis products. PMID- 23033805 TI - Band-selective coupling-induced enhancement of two-photon photoluminescence in gold nanocubes and its application as turn-on fluorescent probes for cysteine and glutathione. AB - We have demonstrated that cysteine and glutathione induced edge-to-edge coupling of gold nanocubes (Au NCs) caused a band-selective enhancement of two-photon photoluminescence (TPPL). The photoluminescence intensity of the X-band of Au NCs was found to be enhanced up to 60-fold and 46-fold upon addition of cysteine and glutathione, respectively, while the intensity of L-band remained almost unchanged. This band-selective enhancement behavior is totally different from the previously observed aggregation enhanced TPPL of spherical metal nanoparticles (NPs). The band-selective enhancement was ascribed to preferential enhancement of the X-band emission through resonant coupling with longitudinal surface plasmon resonance (SPR) band of the Au NCs assembly. This phenomenon was utilized to develop a new two-photon fluorescence turn-on sensing platform for detection of cysteine and glutathione. This method displayed high sensitivity and excellent selectivity over the other 19 amino acids. Together with the advantage of deep tissue penetration and localized excitation of two-photon near-infrared excitation, this strategy has promising applications in in vivo biosensing and imaging. PMID- 23033806 TI - Inhibitory effect of chondroitin sulfate type E on the binding step of human T cell leukemia virus type 1. AB - Cell surface heparan sulfate proteoglycans (HSPGs) are involved in the binding and entry of human T-cell leukemia virus type 1 (HTLV-1) into host cells, while sulfated polysaccharides such as heparin inhibit HTLV-1 infection. Chondroitin sulfate proteoglycans (CSPGs) are classified as another major type of proteoglycans. Here, we examined the effect of four types of chondroitin sulfate (CS) on HTLV-1 infection. Accordingly, a human T cell line, MOLT-4, was inoculated with cell-free HTLV-1 in the presence or absence of soluble CS, and the synthesis of reverse-transcribed HTLV-1 DNA within cells 20 h after inoculation was detected using polymerase chain reaction (PCR). Among the four types of CS (A, C, D, and E), the E type (CSE), which was derived from the squid cartilage, exhibited anti-HTLV-1 activity. Furthermore, we observed that CSE directly interacted with recombinant HTLV-1 envelope (Env) proteins and inhibited the binding of HTLV-1 virions to MOLT-4 cells, indicating that the interaction between Env and CSE plays a significant role in its anti-HTLV-1 activity. In addition, CSE inhibited syncytium formation that was induced by HTLV-1-producing cells. When CSE was mixed with the synthetic fusion inhibitor peptide corresponding to the ectodomain of the Env transmembrane subunit (TM) gp21, the HTLV-1 infection was further inhibited when compared with the inhibitory effect of each compound alone. Thus, further elucidation of the in vitro antiviral mechanism of CSE shown in this study will lead to the development of CSE-like molecules for the entry inhibition of HTLV-1. PMID- 23033807 TI - Iloprost inhalation in mild asthma. AB - OBJECTIVE: To determine the feasibility of administering iloprost by inhalation in patients with mild atopic asthma. METHODS: Volunteers underwent supervised inhalation of iloprost in the clinic with measurement of spirometry and blood pressure for 2 hours. The volunteers then inhaled iloprost four times daily at a dose of 2.5 or 5 MUg for 14 days. Spirometry, asthma questionnaires, peak flow diaries, measurement of methacholine responsiveness, and exhaled nitric oxide concentrations were obtained prior to and after the treatment period. RESULTS: Chronic inhalation of iloprost (2.5-5 MUg) did not alter spirometry or methacholine responsiveness. CONCLUSION: Inhaled iloprost in carefully selected volunteers with mild asthma appears to be a suitable intervention to explore the effects of prostacyclin in human asthma. PMID- 23033808 TI - The impact of hospital-based skilled nursing facility closures on rehospitalizations. AB - OBJECTIVE: To examine the effect of reductions in hospital-based (HB) skilled nursing facility (SNF) bed supply on the rate of rehospitalization of patients discharged to any SNF from zip codes that lost HB beds. DATA SOURCE: We used Medicare enrollment records, Medicare hospital and SNF claims, and nursing home Minimum Dataset assessments and characteristics (OSCAR) to examine nearly 10 million Medicare fee-for-service hospital discharges to SNFs between 1999 and 2006. STUDY DESIGN: We calculated the number of HB and freestanding (FS) SNF beds within a 22 km radius from the centroid of all zip codes in which Medicare beneficiaries reside in all years. We examined the relationship between HB and FS bed supply and the rehospitalization rates of the patients residing in corresponding zip codes in different years using zip code fixed effects and instrumental variable methods including extensive sensitivity analyses. PRINCIPAL FINDINGS: Our estimated coefficients suggest that closure of 882 HB homes during our study period resulted in 12,000-18,000 extra rehospitalizations within 30 days of discharge. The effect was largely concentrated among the most acutely ill, high-need patients. CONCLUSIONS: SNF patient-based prospective payment resulted in closure of higher cost HB facilities that had served most postacute patients. As other, less experienced SNFs replaced HB facilities, they were less able to manage high acuity patients without rehospitalizing them. PMID- 23033809 TI - Sexual dimorphism of thyroid reactive oxygen species production due to higher NADPH oxidase 4 expression in female thyroid glands. AB - BACKGROUND: Dual oxidases (DUOX1 and DUOX2) are NADPH oxidases (NOX) involved in hydrogen peroxide production necessary for thyroid hormonogenesis, but recently, the NOX4 has also been described in the thyroid gland. The prevalence of thyroid disease is higher in women, and the basis for this difference might involve a higher oxidative stress level in the female thyroid gland. Hence, we aimed at evaluating whether the function and the expression of enzymes involved in the thyroid redox balance differ between females and males. METHODS: DUOX1, DUOX2, NOX4, glutathione peroxidase (GPx), and catalase activities and expression levels were evaluated in the thyroids of prepubertal and adult male and female rats. The mRNA levels of DUOXA1 and DUOXA2, the DUOX maturation factors, and of p22phox and Poldip2 (subunits of NOX4) were also determined. RESULTS: A higher calcium independent H(2)O(2) production was detected in the adult female rat thyroid, being higher in the estrous phase of the cycle. Moreover, the expression of NOX4 and Poldip2 mRNA was higher in the thyroids of adult female rats, as well as in PCCL3 cells treated with 17beta-estradiol. The GPx1 mRNA expression was higher in adult female thyroids, while GPx2 and GPx3 mRNA and total GPx activity were not significantly different. Catalase mRNA expression and activity, together with thyroid thiol levels were significantly lower in the adult female rat thyroid. CONCLUSIONS: Taken together, our results show that the thyroid gland of female rats is exposed to higher oxidative stress levels due both to increased reactive oxygen species (ROS) production through NOX4, and decreased ROS degradation. PMID- 23033810 TI - Amyoplasia: a case report of an old woman. AB - PURPOSE: Little information exists about the long-term outcome of amyoplasia. In this article, a case report of a 93-year old woman is presented including both the development of the physical limitations and coping strategies. METHOD: The medical records, physical examinations and personal interviews during the last 10 years, autobiographical essays and personal photographs were included. RESULTS: Eleven surgical procedures were performed during childhood and ten during adulthood. Ambulation without aids was possible up to the age of 37 years. Thereafter, the muscular force declined gradually, first in the legs and later in the arms. Musculoskeletal pain decreased during ageing. There was an increasing demand to use technical aids. Seniority brought about several diseases, which complicated the quality of life. The woman stayed 32 years of her life in work. CONCLUSIONS: A high age can be achieved with amyoplasia although the disability increases due to a gradual deterioration of muscular force. The personal experiences of the woman suggest that her active and creative attitude towards her disability may have contributed to the quality of her life. This may encourage people with amyoplasia and their care givers. IMPLICATIONS FOR REHABILITATION: * There are no data about ageing and life-long prognosis of amyoplasia. * Severe physical limitations in amyoplasia are compatible with a long and meaningful life. * Muscular force decreases during adult life. Therefore, a potential risk of overtraining should be considered. PMID- 23033811 TI - Study of Sangiovese Wines Pigment Profile by UHPLC-MS/MS. AB - The metabolic pigment composition of Sangiovese wines produced from grapes harvested at 20 different vineyards in Montalcino over three consecutive years (2008-2010) on a semi-industrial scale and of 55 commercial Brunello di Montalcino wines (2004-2007) was studied, using a targeted method capable of analyzing 90 pigments in an 11 min UHPLC-MS/MS chromatographic run. Interesting correlations were shown between various pigments formed during wine aging and those present in Sangiovese grapes. Vitisin B-like pigment and vitisin A-like pigment concentrations would seem to have a good correlation with ethyl-linked and direct-linked flavanol-anthocyanin concentrations, respectively. Moreover, the anthocyanic pattern recognition, genetically controlled by the plant variety, was shown to be inherited by the pigments formed during wine aging. PMID- 23033812 TI - The psychosocial work environment among physicians employed at Danish oncology departments in 2009. A nationwide cross-sectional study. AB - Working as a physician at an oncology department has some distinctive characteristics that may lead to a stressful work environment. The present study was conducted to provide a nationwide description of the work conditions of all oncologists in Denmark. By comparing the results of the present study with those of a similar study carried out in 2006, the aim was furthermore to elucidate changes in the psychosocial work environment over time. MATERIAL AND METHODS: From May to September 2009, 330 physicians employed at six oncology centres and seven community based oncology departments were invited to participate in a survey based on the short version of the COPSOQ II questionnaire. The results were compared with data from a representative section of Danish employees and with data from the 2006 survey. RESULTS: Two hundred and twenty of the 330 invited physicians returned the questionnaire (response rate 67%). Concerning the aspects quantitative demands, work pace, emotional demands, influence, burnout and stress, the oncologists reported worse work conditions than the average Danish employee. However, with regard to possibilities for development, meaning of work and commitment to workplace, the oncologists reported better work conditions. Between 2006 and 2009, substantial improvement was seen concerning several of the assessed work environment aspects within the group of young physicians at the oncology centres. CONCLUSION: Though substantial improvement of the work conditions has been achieved between 2006 and 2009, certain aspects of the psychosocial work environment at Danish oncology departments still require attention. PMID- 23033813 TI - Expressions of C5a and its receptor CD88 after spinal cord injury in C3-deficient mice. AB - The activation of complement system can aggravate the secondary injury after spinal cord injury (SCI). Our previous study indicates that the interception of complement activation by C3 deficiency can reduce the secondary injury and improve the regeneration and functional recovery after SCI. However, recently, it was reported that C5a which was generated during the complement activation pathways also had a protective effect on neurons, but whether it has the similar effect after SCI is unknown. To investigate the possibility and mechanism of the protective effect of C5a on neurons, it is necessary to study the expression profiles of C5a and its receptor CD88 after SCI and the influence on their expression when C3 was knocked out. By immunohistochemistry and Western blot, we found that in wild-type (WT) mice, both the expression of C5a and its receptor CD88 increased significantly, and there were two peaks during their expression after SCI. However, in C3-deficient mice, the expression of C5a still increased after SCI, although it was lower than that in WT group at every time points after SCI, and the expression of CD88 remained stable. Our study suggests that the expressions of C5a and CD88 can be inhibited in different degrees after SCI when the activation of complement system is blocked through C3 deficiency, which can reduce the secondary injury caused by C5a after SCI on one hand but deprive neurons of the possible protective effect from C5a on the other hand. PMID- 23033814 TI - Action imitation at 11/2 years is better than pointing gesture in predicting late development of language production at 3 years of age. AB - This study examined whether poor pointing gestures and imitative actions at 18 months of age uniquely predicted late language production at 36 months, beyond the role of poor language at 18 months of age. Data from the Norwegian Mother and Child Cohort Study were utilized. Maternal reports of the children's nonverbal skills and language were gathered for 42,517 children aged 18 months and for 28,107 of the same children at 36 months. Panel analysis of latent variables revealed that imitative actions, language comprehension, and language production uniquely contributed to predicting late development of language production, while pointing gestures did not. It is suggested that the results can be explained by underlying symbolic representational skills at 18 months. PMID- 23033815 TI - Prevalence and nature of dentoalveolar injuries among patients with maxillofacial fractures. AB - OBJECTIVE: Although not previously reported, experience suggests that dentoalveolar injury is -common among patients with maxillofacial fractures. The objective of this study was to evaluate and describe the prevalence and nature of dentoalveolar injuries in patients identified with maxillofacial fractures. METHODS: Medical records of 43 dogs and cats diagnosed with maxillofacial fractures between 2005 and 2012 were reviewed to identify patients with concurrent dentoalveolar injury. Medical records of patients with dentoalveolar injury were abstracted for the following information: signalment (including sex, age and skull type), mechanism of maxillofacial trauma, location and number of maxillofacial fractures, dentoalveolar injury type and location and the number of dentoalveolar injury per patient. Statistical evaluation was performed to determine associations between signalment, mechanism of trauma, location and number of maxillofacial fractures and the prevalence and nature of concurrent dentoalveolar injury. RESULTS: Dentoalveolar injuries are common among patients with maxillofacial trauma. Age and mechanism of trauma are significant predictors of the presence of dentoalveolar injuries in patients with maxillofacial trauma. CONCLUSIONS AND CLINICAL RELEVANCE: The findings of this study serve to encourage veterinarians to fully assess the oral cavity in patients with maxillofacial fractures as dentoalveolar injuries are common and can be predicted by age and mechanism of trauma. PMID- 23033816 TI - Effects of dietary red pepper on egg yolk colour and histological intestinal morphology in laying hens. AB - To evaluate the effect of three kinds of red pepper supplementation 'Kagawa Hontaka' produced at Shiwaku Islands (KHS), Miki (KHM) and Takanotsume (TKT) on production performance, egg quality and intestinal histology in laying hens. A total of 32 laying hens (39 weeks of age) were randomly allotted to four groups, each comprising eight hens. Birds were fed a basal diet supplemented with red pepper at 0% (control), 0.5% KHS, 0.5% KHM and 0.5% TKT, respectively. Compared with the control group, no significant difference (p > 0.05) in feed consumption, final body weight, hen-day production, egg mass, feed efficiency, shell-breaking strength, shell thickness, shell ratio, albumen ratio, yolk ratio and Haugh units was observed among the experimental groups. Roche yolk colour fan (RYCF) value increased significantly in all experimental groups (p < 0.05). Furthermore, the KHS and KHM groups showed higher RYCF values than the TKT group (p < 0.05). Spectrophotometric measurements of yolk colour, redness (a*) and yellow index (YI) values were higher in the KHS and KHM groups (p < 0.0001). The yellowness (b*) value was lower in the TKT group (p < 0.05). The lightness (L*) value was lower in the KHS and KHM groups (p < 0.05). Villus height, villus area, cell area and cell mitosis in all intestinal segments tended to be higher in all experimental groups. Jejunal cell area and cell mitosis were higher in experimental groups than in the control group (p < 0.05). The cells on the villus tip surface were protuberated in all experimental groups. In conclusion, the KHS, KHM and TKT groups showed hypertrophied intestinal villi and epithelial cell functions. These results indicate that dietary red pepper has stimulating effect on intestinal villi and the structure of epithelial cells, and the 0.5% KHS and KHM groups improved in egg yolk colour. PMID- 23033817 TI - Transformational leadership in nursing: towards a more critical interpretation. AB - Effective nurse leadership is positioned as an essential factor in achieving optimal patient outcomes and workplace enhancement. Over the last two decades, writing and research on nursing leadership has been dominated by one conceptual theory, that of transformational leadership. This theoretical framework has provided insight into various leader characteristics, with research findings presented as persuasive evidence. While elsewhere there has been robust debate on the merits of the transformational model of leadership, in the nursing literature, there has been little critical review of the model and the commonly used assessment instruments. In this article, we critically review more than a decade of nursing scholarship on the transformational model of leadership and its empirical evidence. Applying a critical lens to the literature, the conceptual and methodological weaknesses of much nursing research on this topic, we question whether the uncritical adoption of the transformational model has resulted in a limited interpretation of nursing leadership. Given the limitations of the model, we advocate embracing new ways of thinking about nursing leadership. PMID- 23033818 TI - Expanded dengue syndrome: subacute thyroiditis and intracerebral hemorrhage. AB - BACKGROUND: Although most symptomatic dengue infections follow an uncomplicated course, complications and unusual manifestations are increasingly being reported due to rising disease burden. Expanded dengue syndrome is a new entity added into World Health Organization (WHO) classification system to incorporate this wide spectrum of unusual manifestations. We report a case of expanded dengue syndrome with subacute thyroiditis and intracerebral hemorrhage. This is the first case report of thyroiditis in dengue infection. CASE PRESENTATION: A 20 years old man presented with fever, myalgias, arthralgias, retro-orbital pain, vomiting and gum bleeding during a large dengue outbreak in Lahore, Pakistan. On 7th day of illness patient became afebrile, but he developed severe headaches, unconsciousness followed by altered behavior. On 9th day of illness patient developed painful neck swelling accompanied by fever, tremors, palpitations, hoarseness of voice and odynophagia. Examination revealed acutely swollen, tender thyroid gland along with features of hyperthyroidism. Laboratory evaluation revealed stable hematocrit, thrombocytopenia and leukopenia. Patient had seroconverted for anti-dengue IgM antibodies on the 10th day of illness. A non contrast Computed Tomogram (CT) of the brain showed right frontal lobe hematoma. Thyroid profile showed increased free T3 and T4 and low TSH. Technetium thyroid scan showed reduced tracer uptake. He was diagnosed as having subacute thyroiditis and treated with oral prednisolone and propranolol. Follow up CT brain showed resolving hematoma. Patient's recovery was uneventful. CONCLUSION: Subacute thyroiditis may develop during the course of dengue fever and should be included as a manifestation of expanded dengue syndrome. It should be suspected in patients with dengue fever who develop painful thyroid swelling and clinical features of hyperthyroidism. PMID- 23033819 TI - The prevalence of physical, sexual and mental abuse among adolescents and the association with BMI status. AB - BACKGROUND: Studies among adults show an association between abuse and Body Mass Index (BMI) status. When an aberrant BMI status as a consequence of abuse is already prevalent in adolescence, early detection and treatment of abuse might prevent these adolescents from developing serious weight problems and other long term social, emotional and physical problems in adulthood. Therefore, this study investigated the prevalence of physical, sexual and mental abuse among adolescents and examined the association of these abuse subtypes with BMI status. METHODS: In total, data of 51,856 secondary school students aged 13-16 who had completed a questionnaire on health, well-being and lifestyle were used. BMI was classified into four categories, underweight, normal weight, overweight and obesity. Adolescents reported if they had ever been physically, sexually or mentally abused. Crude and adjusted General Estimation Equation (GEE) analyses were performed to investigate the association between abuse subtypes and BMI status. Analyses were adjusted for ethnicity and parental communication, and stratified for gender and educational level. RESULTS: Eighteen percent of the adolescents reported mental abuse, 7% reported sexual abuse, and 6% reported physical abuse. For underweight, overweight and obese adolescents these percentages were 17%, 25%, and 44%; 7%, 8%, and 16%; and 6%, 8%, 18% respectively. For the entire population, all these subtypes of abuse were associated with being overweight and obese (OR=3.67, 1.79 and 1.50) and all but sexual abuse were associated with underweight (OR=1.21 and 1.12). Stratified analyses showed that physical and sexual abuse were significantly associated with obesity among boys (OR=1.77 and 2.49) and among vocational school students (OR=1.60 and 1.69), and with underweight among girls (OR=1.26 and 0.83). CONCLUSION: Mental abuse was reported by almost half of the obese adolescents and associated with underweight, overweight and obesity. Longitudinal analyses are recommended to explore the causality of and the mechanisms explaining this association between abuse and overweight. PMID- 23033820 TI - The topography of awareness: a classification of intra-operative cognitive states. PMID- 23033821 TI - Anaphylaxis and blue urticaria associated with Patent Blue V injection. PMID- 23033822 TI - Comparing intubation performance of indirect laryngoscopes: study design is crucial. PMID- 23033823 TI - Difficult Airway Society guidelines for the management of tracheal extubation. PMID- 23033825 TI - Conversion from regional to general anaesthesia for caesarean section: are we meeting the standards? PMID- 23033826 TI - Conversion from regional to general anaesthesia for caesarean section: we are meeting the standards! PMID- 23033827 TI - Tension gastrothorax presenting with dramatic ECG changes. PMID- 23033828 TI - Theatre efficiency: confounding factors for surrogate measures. PMID- 23033829 TI - Theatre efficiency: starting on time. PMID- 23033831 TI - Unexpected behaviour of BIS in brain injury and the value of intra-operative computed tomography. PMID- 23033832 TI - Rapid sequence spinal anaesthesia - a survey of current use. PMID- 23033833 TI - EVAR fever - response from the Vascular Anaesthesia Society of Great Britain and Ireland. PMID- 23033834 TI - Rural mobile phone coverage is an issue for the NHS. PMID- 23033835 TI - Observational trials and airway devices: more to it than just sample size. PMID- 23033837 TI - Effect of doping on single-walled carbon nanotubes network of different metallicity. AB - Effects of doping on single-walled carbon nanotubes (SWNT) networks with different metallicity are reported through the study of sheet resistance changes upon annealing and acid treatment. SWNT film with high metallic tube content is found to have relatively good chemical stability against post treatments, as demonstrated from its stable film performance in ambient after annealing, and merely 15% reduction in sheet resistance upon sulfuric acid treatment. Conversely, film stability of SWNT film with low metallic content which comprises largely of semiconducting SWNT varies with days in ambient, and its sheet resistance changes drastically after treated with acid, indicating the extreme sensitivity of semiconducting SWNT to surrounding environment. The results suggest that annealing removes unintentional oxygen doping from the ambient and shifts the Fermi level towards the intrinsic Fermi level. Acid treatment, on the other hand, introduces physisorbed and chemisorbed oxygen and shifts the Fermi level away from the intrinsic level and increases the hole doping. PMID- 23033838 TI - Autonomic nervous control of the urinary bladder. AB - The autonomic nervous system plays an important role in the regulation of the urinary bladder function. Under physiological circumstances, noradrenaline, acting mainly on beta(3) -adrenoceptors in the detrusor and on alpha(1) (A) adrenoceptors in the bladder outflow tract, promotes urine storage, whereas neuronally released acetylcholine acting mainly on M(3) receptors promotes bladder emptying. Under pathophysiological conditions, however, this system may change in several ways. Firstly, there may be plasticity at the levels of innervation and receptor expression and function. Secondly, non-neuronal acetylcholine synthesis and release from the urothelium may occur during the storage phase, leading to a concomitant exposure of detrusor smooth muscle, urothelium and afferent nerves to acetylcholine and noradrenaline. This can cause interactions between the adrenergic and cholinergic system, which have been studied mostly at the post-junctional smooth muscle level until now. The implications of such plasticity are being discussed. PMID- 23033839 TI - Functional traits explain phytoplankton community structure and seasonal dynamics in a marine ecosystem. AB - A fundamental yet elusive goal of ecology is to predict the structure of communities from the environmental conditions they experience. Trait-based approaches to terrestrial plant communities have shown that functional traits can help reveal the mechanisms underlying community assembly, but such approaches have not been tested on the microbes that dominate ecosystem processes in the ocean. Here, we test whether functional traits can explain community responses to seasonal environmental fluctuation, using a time series of the phytoplankton of the English Channel. We show that interspecific variation in response to major limiting resources, light and nitrate, can be well-predicted by lab-measured traits characterising light utilisation, nitrate utilisation and maximum growth rate. As these relationships were predicted a priori, using independently measured traits, our results show that functional traits provide a strong mechanistic foundation for understanding the structure and dynamics of ecological communities. PMID- 23033841 TI - Matrix metalloproteinases: do they play a role in mucosal pathology of the oral cavity? AB - Matrix metalloproteinases (MMPs) are critical factors in maintaining the integrity of mucosa and mediating normal biological processes. An imbalance between tissue levels of these mediators and their natural inhibitors is believed to underlie the pathophysiology of many diseases, including those affect the gastrointestinal and oral mucosae. The ongoing development of synthetic inhibitors of these mediators may provide opportunities to develop treatment modalities for patients suffering from these diseases. Understanding the role of MMPs in the pathophysiology of many diseases, however, is far from complete, and the improvement of pharmaceutical management strategies can only be achieved if the underlying process of these diseases is completely comprehended. This paper reviews the functions of matrix metalloproteinases and addresses their role in mediating mucosal pathologies with emphasis on oral mucosa. PMID- 23033840 TI - Plasma NT-proBNP and white matter hyperintensities in type 2 diabetic patients. AB - Elevated plasma N-terminal (NT)-proBNP from the heart as well as white matter hyperintensities (WMH) in the brain predict cardiovascular (CV) mortality in the general population. The cause of poor prognosis associated with elevated P-NT proBNP is not known but WMH precede strokes in high risk populations. We assessed the association between P-NT-proBNP and WMH or brain atrophy measured with magnetic resonance imaging (MRI) in type 2 diabetic patients, and age-matched controls. METHODS AND RESULTS: We measured P-NT-proBNP(ng/l) in 20 diabetic patients without prior stroke but with(n=10) or without(n=10) asymptomatic coronary artery disease(CAD) in order to include patients with a wide-ranging CV risk profile. All patients and 26 controls had a 3D MRI and brain volumes(ml) with WMH and brain parenchymal fraction(BPF), an indicator of brain atrophy, were determined.P-NT-proBNP was associated with WMH in linear regression analysis adjusted for CV risk factors(r=0.94, p=0.001) and with BPF in univariate analysis(r=0.57, p=0.009). Patients divided into groups of increased P-NT-proBNP levels were paralleled with increased WMH volumes(geometric mean[SD];(2.86[5.11] ml and 0.76[2.49] ml compared to patients with low P-NT-proBNP 0.20[2.28] ml, p=0.003)) and also when adjusted for age, sex and presence of CAD(p=0.017). The association was strengthened by CV risk factors and we did not find a common heart or brain specific driver of both P-NT-proBNP and WMH. Patients and particular patients with CAD had higher WMH, however no longer after adjustment for age and sex. CONCLUSION: P-NT-proBNP was associated with WMH in type 2 diabetic patients, suggesting a linkage between heart and brain disease. PMID- 23033842 TI - Trigeminal neuralgia: diagnostic criteria, clinical aspects and treatment outcomes. A retrospective study. AB - OBJECTIVE: The aim of this study was to investigate the diagnostic criteria and clinical presentations and compare the different treatment modalities in relation to prognosis in a sample of patients with the neuropathic disorder trigeminal neuralgia (TN). METHODS: A retrospective review study of clinical records was conducted of 92 patients diagnosed with TN. RESULTS: The mean age[+/-standard deviation (SD)] of the patients was 67.3+/-12.7 years with an average TN duration of 7.1+/-6 years and a female predominance (M:F=1:2.5). The maxillary branch was the most involved nerve (in 45% of patients). Twelve patients underwent CT scans, while thirty-six patients had MRIs. Carbamazepine used by 92.4% of patients was the most commonly used drug in the management of the disorder. Twenty-two patients had microvascular decompression (MVD). TN symptoms were completely relieved following surgery in 73% of patients who underwent neurosurgery. CONCLUSIONS: MRI is highly sensitive in the exclusion of central intracranial lesions and recommended as a routine consideration during the assessment of TN patients. Despite the side effects, carbamazepine is the drug therapy of choice. MVD produces satisfactory relief of TN symptoms in the majority of cases and should be offered to young healthy patients. PMID- 23033843 TI - A scalable method for identifying frequent subtrees in sets of large phylogenetic trees. AB - BACKGROUND: We consider the problem of finding the maximum frequent agreement subtrees (MFASTs) in a collection of phylogenetic trees. Existing methods for this problem often do not scale beyond datasets with around 100 taxa. Our goal is to address this problem for datasets with over a thousand taxa and hundreds of trees. RESULTS: We develop a heuristic solution that aims to find MFASTs in sets of many, large phylogenetic trees. Our method works in multiple phases. In the first phase, it identifies small candidate subtrees from the set of input trees which serve as the seeds of larger subtrees. In the second phase, it combines these small seeds to build larger candidate MFASTs. In the final phase, it performs a post-processing step that ensures that we find a frequent agreement subtree that is not contained in a larger frequent agreement subtree. We demonstrate that this heuristic can easily handle data sets with 1000 taxa, greatly extending the estimation of MFASTs beyond current methods. CONCLUSIONS: Although this heuristic does not guarantee to find all MFASTs or the largest MFAST, it found the MFAST in all of our synthetic datasets where we could verify the correctness of the result. It also performed well on large empirical data sets. Its performance is robust to the number and size of the input trees. Overall, this method provides a simple and fast way to identify strongly supported subtrees within large phylogenetic hypotheses. PMID- 23033844 TI - Microarray evaluation of specific IgE to allergen components in elite athletes. AB - BACKGROUND: Allergic sensitization and diseases have been reported to have a very high and increasing prevalence in elite athletes. Over 80% of allergic athletes are poly-sensitized. OBJECTIVE: This study aims at evaluating the potential diagnostic added value of a microarray technology (ImmunoCAP ISAC, Phadia AB [at present Thermo Fisher Scientific] Uppsala, Sweden which detects IgE antibodies to specific or cross-reacting allergen components. METHODS: Seventy-two poly sensitized athletes according to skin prick test (SPT) with different allergic phenotypes (asthma n = 19; rhino-conjunctivitis n = 20; food allergy and/or oral allergy syndrome n = 13; no clinical symptoms n = 20) and two different control populations (20 poly-sensitized sedentary subjects with respiratory allergy and 20 healthy athletes with negative SPT) were studied for detecting specific IgE (sIgE) both to allergen extracts (ImmunoCAPsIgE) and to allergen components (ImmunoCAP ISAC). RESULTS: ImmunoCAP ISAC detected the presence of sIgE in 90% of poly-sensitized athletes--in 96% with symptoms and in 75% without symptoms--and in 100% of allergic controls. The pattern of positivity towards the 103 components tested differed from subject to subject, even in those with the same sensitization to allergen extract SPT or sIgE. Based on the ISAC results, poly sensitized athletes were classified into the following prototypical patterns, differently represented in the clinical phenotypes studied (P = 0.03): (1) One single predominant specific allergen positivity; (2) sIgE to two or more non cross-reacting allergens; (3) sIgE to cross-reacting allergens; and (4) sIgE to components potentially responsible for severe allergic reactions. CONCLUSIONS: The ImmunoCAP ISAC represents a useful additional tool for diagnosis and management of poly-sensitized athletes. PMID- 23033845 TI - Novel splice-site mutation in ATP8B1 results in atypical progressive familial intrahepatic cholestasis type 1. AB - BACKGROUND AND AIM: Our objective was to identify the molecular genetic basis of an Alagille-like condition not linked to JAG1 or NOTCH2 in two related sibships. METHODS: Because of common ancestry, and an autosomal recessive mode of inheritance, it was hypothesized that all affected and no unaffected individuals would be homozygous for the same haplotype in the region of the causative gene. Single nucleotide polymorphism arrays were therefore used to genotype 3 affected individuals from two sibships, their mothers and four unaffected siblings, to identify regions of homozygosity. Genes within the largest regions were prioritized and sequenced for mutations. Mutant RNA transcripts were also sequenced. RESULTS: A novel splice acceptor site mutation in the ATP8B1 gene was identified (a G-C preceding exon 16 resulting in a 4 bp deletion and frameshift from the 5' end of exon 16). This result was unexpected because ATP8B1 mutations are associated with progressive familial intrahepatic cholestasis type 1 (PFIC1). Intrahepatic bile duct paucity, cardiac anomalies, renal tubular acidosis and hypothyroidism led to an initial diagnosis of Alagille syndrome. However, in retrospect, abnormal sweat chloride, normal gamma-glutamyl transferase, normal to low cholesterol, and an autosomal recessive mode of inheritance were consistent with PFIC1. Renal tubular acidosis, hypothyroidism and cardiac anomalies have not previously been associated with PFIC1. CONCLUSION: This work expands the phenotypic spectrum of PFIC1, and highlights the overlap in clinical phenotype between Alagille syndrome and PFIC1. Knowledge of the causative mutation allows for carrier testing and prenatal diagnosis in this community. PMID- 23033846 TI - Randomized controlled trial of a self-management intervention in persons with spinal cord injury: design of the HABITS (Healthy Active Behavioural Intervention in SCI) study. AB - PURPOSE: To evaluate the effectiveness of a 16-week self-management intervention on physical activity level and self-management skills (self-efficacy, proactive coping and problem solving skills) in persons with chronic SCI. METHOD AND DESIGN: Multicenter randomized controlled trial (RCT). Eighty persons with a SCI for at least 10 years and aged 18 to 65 will randomly be assigned to the intervention (self-management) or the control group (information provision). During the 16-week self-management intervention (one home-visit, five group and five individual sessions) active lifestyle will be stimulated and self-management skills will be taught. Data will be collected at baseline (T0), 16 (T1) and 42 (T2) weeks after baseline. Primary outcome measure is level of daily physical activity (self-report/objectively measured). Secondary outcome measures are self managements skills, stage of behaviour change and attitude. CONCLUSION: This is the first RCT on self-management in people with chronic spinal cord injury. This trial will provide knowledge on the effects of a self-management intervention on physical active lifestyle in persons with a long-term SCI. PMID- 23033847 TI - High screen time is associated with asthma in overweight Manitoba youth. AB - OBJECTIVE: Low physical activity and high sedentary behavior are associated with adverse health outcomes, including asthma. The purposes were to (1) determine if low physical activity and/or high screen time increase the risk of asthma and airway hyperresponsiveness (AHR) in youth and (2) determine if weight status modifies these associations. METHODS: This is a prospective cohort study of healthy weight and overweight Canadian youth. In 2003-2005, 723 youth (8.6 +/- 0.5 years; 34.0% asthma, 55.9% boys) were recruited from the 1995 Manitoba Prospective Cohort Study. In 2008-2010, 489 returned for follow-up measures (30.9% asthma, 56.6% boys). The primary exposure variables were parent-reported physical activity and screen time at 8-10 years of age. The primary outcome measures were pediatric allergist-defined asthma and AHR defined as the provocative concentration of methacholine required to induce a 20% fall in forced expiratory volume in 1 second (FEV(1)). RESULTS: Low physical activity (<=2 times weekly) was not associated with asthma or AHR. However, high screen time (>=1 hour/day) was associated with a greater odds of asthma at baseline (odds ratio (OR) = 2.01, 95% confidence interval (CI) = 1.20-3.37, p < .01) and follow-up (OR = 2.11, 95% CI = 1.14-3.89, p < .02) versus low screen time. This association was more pronounced among overweight youth (baseline: OR = 3.95, 95% CI = 1.70-9.12, p < .0001; follow-up: OR = 3.22, 95% CI = 1.17-8.86, p < .02). Screen time was not associated with AHR at baseline or follow-up. CONCLUSIONS: High screen time increases the risk of asthma, particularly among overweight youth. Screen time, in addition to physical activity, should be included in clinical assessments of youth with asthma. PMID- 23033848 TI - Delayed entry into and failure to remain in HIV care among HIV-infected adolescents. AB - Prompt entry into care and retention in care are critical for improving outcomes among HIV-infected individuals. This study identified factors associated with HIV infected adolescents who delayed entry into HIV care (DEC) after diagnosis of HIV or who fail to remain in care afterward (FRC). We reviewed clinical, demographic, and social data from the records of 202 HIV-positive adolescents (13-21 years old) infected via high-risk behaviors. Strength of association between clinical and social factors and DEC or FRC were estimated with log-linear regression models. DEC occurred in 38% (76/202) of adolescents. Factors independently associated with DEC were unstable residence (RR 1.5; CI: 1.0-2.1) and, compared with less education, college attendance (RR 2.1; CI: 1.5-3.2). FRC occurred in 29% (52/177) of adolescents established in care. Compared with college attendees, high school students (RR: 4.5; CI: 1.2-17.3) and those who dropped out of high school (RR: 4.0; CI: 1.1-15) were more likely to FRC. Compared with adolescents with private insurance, adolescents without insurance (despite access to free care) were more likely to FRC (RR: 2.8; CI: 1.1-6.9). Controlling for sex, adolescents with children were more likely to FRC (RR: 1.8; CI: 1.0-3.1). Interventions to avoid DEC that target HIV-infected adolescents with unstable residences or those diagnosed while attending college are warranted. Among patients engaged in care, those with only high school education or without insurance-which may be markers for socioeconomic status-need additional attention to keep them in care. PMID- 23033849 TI - Dispersion and exposure to a cough-generated aerosol in a simulated medical examination room. AB - Few studies have quantified the dispersion of potentially infectious bioaerosols produced by patients in the health care environment and the exposure of health care workers to these particles. Controlled studies are needed to assess the spread of bioaerosols and the efficacy of different types of respiratory personal protective equipment (PPE) in preventing airborne disease transmission. An environmental chamber was equipped to simulate a patient coughing aerosol particles into a medical examination room, and a health care worker breathing while exposed to these particles. The system has three main parts: (1) a coughing simulator that expels an aerosol-laden cough through a head form; (2) a breathing simulator with a second head form that can be fitted with respiratory PPE; and (3) aerosol particle counters to measure concentrations inside and outside the PPE and at locations throughout the room. Dispersion of aerosol particles with optical diameters from 0.3 to 7.5 MUm was evaluated along with the influence of breathing rate, room ventilation, and the locations of the coughing and breathing simulators. Penetration of cough aerosol particles through nine models of surgical masks and respirators placed on the breathing simulator was measured at 32 and 85 L/min flow rates and compared with the results from a standard filter tester. Results show that cough-generated aerosol particles spread rapidly throughout the room, and that within 5 min, a worker anywhere in the room would be exposed to potentially hazardous aerosols. Aerosol exposure is highest with no personal protective equipment, followed by surgical masks, and the least exposure is seen with N95 FFRs. These differences are seen regardless of breathing rate and relative position of the coughing and breathing simulators. These results provide a better understanding of the exposure of workers to cough aerosols from patients and of the relative efficacy of different types of respiratory PPE, and they will assist investigators in providing research-based recommendations for effective respiratory protection strategies in health care settings. PMID- 23033850 TI - Solid-state characterization and dissolution properties of Fluvastatin sodium salt hydrates. AB - The present study reports the solid-state properties of Fluvastatin sodium salt crystallized from different solvents for comparison with crystalline forms of the commercially available raw material and United States Pharmacopeia (USP) reference standard. Fluvastatin (FLV) samples were characterized by several techniques; such as X-ray powder diffractometry, differential scanning calorimetry, thermogravimetry, liquid and solid-state nuclear magnetic resonance spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, and scanning electron microscopy. In addition, intrinsic dissolution rate (IDR) of samples was performed in order to study the influence of crystalline form and other factors on rate and extent of dissolution. Three different forms were found. The commercial raw material and Fluvastatin-Acetonitrile (ACN) were identified as "form I" hydrate, the USP reference standard as "form II" hydrate and an ethanol solvate which presented a mixture of phases. Form I, with water content of 4%, was identified as monohydrate. PMID- 23033851 TI - Client-provider relationships in a community health clinic for people who are experiencing homelessness. AB - Recognizing the importance of health-promoting relationships in engaging people who are experiencing homelessness in care, most research on health clinics for homeless persons has involved some recognition of client-provider relationships. However, what has been lacking is the inclusion of a critical analysis of the policy context in which relationships are enacted. In this paper, we question how client-provider relationships are enacted within the culture of community care with people who are experiencing homelessness and how clinic-level and broader social and health policies shape relationships in this context. We explore these questions within a critical theoretical perspective utilizing a critical ethnographic methodology. Data were collected using multiple methods of document review, participant observation, in-depth interviews and focus groups. The participants include both clients at a community health clinic, and all clinic service providers. We explore how clients and providers characterized each other as 'good' or 'bad'. For providers, this served as a means by which they policed behaviours and enforced social norms. The means by which both providers' and clients' negotiated relationships are explored, but this is couched within both local and system-level policies. This study highlights the importance of healthcare providers and clients being involved in broader policy and systemic change. PMID- 23033852 TI - Follow-up study comparing necropsy rates and discrepancies between clinical and pathologic diagnoses at a veterinary teaching hospital: 2009 versus 1989 and 1999. AB - OBJECTIVES: A follow-up, retrospective study to determine whether the proportion of discrepancies between clinical and pathological diagnoses made during 2009, 1999 and 1989 and the proportion of dogs necropsied have changed. METHODS: Medical records of 148 hospitalised dogs that died or were euthanased in a veterinary medical teaching hospital during 2009 were reviewed. Clinical and pathological diagnoses were recorded, categorised and compared to historical controls using a data set of 623 dogs from a previous study. RESULTS: The proportion of discrepancies was significantly (P<0.001) lower in 2009 (14.9%), compared to both 1999 (37%) and 1989 (39.8%). There was also a significant (P<0.001) decrease in the number of necropsies performed during 2009 (21.4%) compared to both 1999 (48.4%) and 1989 (58.9%). CLINICAL SIGNIFICANCE: There was a marked improvement in the ante-mortem diagnosis of patients in 2009 compared with both 1989 and 1999 as evidenced by the decrease in the proportion of discrepancies between the clinical and pathological diagnoses. Necropsies should still be regarded as a vital tool for teaching, determining the pathological basis of disease, identification of new and emerging diseases, and for an individual animal determining the cause of death. PMID- 23033853 TI - Task-dependent uncertainty modulation of perceptual decisions in the human brain. AB - Perceptual judgments are frequently made during uncertain situations. Previous human brain imaging studies have revealed multiple cortical and subcortical areas that are activated when decision uncertainty is linked to outcome probability. However, the neural mechanisms of uncertainty modulation in different perceptual decision tasks have not been systematically investigated. Uncertainty of perceptual decision can originate either from highly similar object categories (e.g. tasks based on criterion comparison) or from noise being added to visual stimuli (e.g. tasks based on signal detection). In this study, we used functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms of task dependent modulation of uncertainty in the human brain during perceptual judgements. We observed correlations between uncertainty levels and fMRI activity in a network of areas responsible for performance monitoring and sensory evidence comparison in both tasks. These areas are associated with late stages of perceptual decision, and include the posterior medial frontal cortex, dorsal lateral prefrontal cortex, and intraparietal sulcus. When the modulation of uncertainty on the two tasks was compared, dissociable cortical networks were identified. Uncertainty in the criterion comparison task modulated activity in the left lateral prefrontal cortex related to rule retrieval. In the signal detection task, uncertainty modulated activity in higher visual processing areas thought to be sensory information 'accumulators' that are active during early stages of perceptual decision. These findings offer insights into the mechanism of information processing during perceptual decision-making. PMID- 23033854 TI - Genotyping and antifungal susceptibility testing of Cryptococcus neoformans isolates from Cameroonian HIV-positive adult patients. AB - Cryptococcus neoformans is the most common cause of meningitis amongst adult Africans with HIV/AIDS. The widespread use of fluconazole may lead to the emergence of isolates with reduced susceptibility. We studied C. neoformans isolates from HIV-infected patients with cryptococcal meningitis. Genotyping and antifungal testing were performed to assess the genetic diversity, occurrence of mixed infections and in vitro activity of antifungal agents. Isolates were recovered from cerebrospinal fluid prior to systemic antifungal treatment. Six isolates were studied for each sample (a total of 114 isolates from 19 patients). Serotyping was performed via LAC 1 and CAP 64 gene amplification and genotyping was performed using phage M13 core, (GACA)4 and (GTG)5 primers and restriction polymorphism analysis of the URA5 gene. Susceptibilities for amphotericin B, flucytosine, fluconazole, voriconazole and posaconazole were tested by the Sensititre YeastOne(r) method. All strains were identified as C. neoformans var. grubii serotype A. We identified nine major genotypes. Up to two genotypes were identified in the same sample. None of the isolates were resistant to the studied drugs. However, 13 of 114 strains exhibited a reduced susceptibility to fluconazole and 13 of 114 strains exhibited a reduced susceptibility to flucytosine. No correlation was found between the genotype and susceptibility. This study confirms the prevalence of C. neoformans serotype A in Cameroon. Two genotypes may be responsible for a single episode of cryptococcosis. The possibility of mixed infection and diminished susceptibility to fluconazole or flucytosine must be considered for the management of cryptococcosis. PMID- 23033855 TI - Site directed mutagenesis as a tool to understand the catalytic mechanism of human cytidine deaminase. AB - Cytidine deaminase (CDA), is one of the enzymes involved in the pyrimidine salvage pathways, which catalyzes the formation of uridine and deoxyuridine by the hydrolytic deamination of cytidine and deoxycytidine, respectively. Human CDA is a tetrameric enzyme of identical 15 kDa subunits, each containing an essential zinc atom in the active site. The substrate binds to each active site independently and the cooperativity between subunits has not been reported. CDA is able to recognize as substrates some antitumor and antiviral cytidine analogs rendering them pharmacologically inactive. In light of the role played by this enzyme, a deep knowledge of CDA active site and mechanism of catalysis is required. Site-directed mutagenesis, associated with molecular modeling studies, may be an important tool to discover the active site structure of an enzyme and consequently its mechanism of action. In this review are summarized the site directed mutagenesis experiments performed on human CDA: through these studies it was possible to understand the role exerted by specific amino acid residues in CDA active site and in the contacts between subunits. The obtained results may open a way for designing new cytidine based drugs or more potent CDA inhibitors. PMID- 23033856 TI - Inherent aggregation propensity of flanking residues attached to polyglutamines: implication to aggregation inhibition. AB - Expansion of polyglutamine (polyQ) sequence in some proteins leads to their aggregation, which is responsible for neurodegenerative diseases like Huntington's disease, ataxia etc. A flanking domain is usually fused at the N terminal to polyQ in these proteins. On linking the flanking residues to polyQ, they accelerate aggregation of the proteins, which initiates from the flanking residues. In this report the inherent propensity of the flanking residues towards aggregation in six aggregating proteins has been elucidated from their primary sequences with the help of Betascan and PASTA programs and explored unambiguously. This will provide a molecular mechanism of this process. Suppression of aggregation using chaperones like alphaB-crystallin by masking the exposed hydrophobic surface of flanking residues is also documented through molecular docking, which could be applied for inhibition of aggregation of this type of proteins. PMID- 23033857 TI - Structure of starch binding domains of halophilic alpha-amylase at low pH. AB - The solubility and structural properties of halophilic proteins are ascribed to their abundant acidic residues, resulting in large net negative charges at neutral pH. This study examined the effects of low pH, i.e., reduction of net negative charges on the structural properties of starch binding domain (SBD) of halophilic Kocuria varians alpha-amylase. Titration to pH 2.1 caused loss of 233 nm peak characteristic of aromatic interactions present in the native SBD at neutral pH and resulted in the spectrum with a 216 nm valley characteristic of beta-sheet. The low pH beta-sheet structure was stable against heat treatment. The addition of NaCl and trifluoroethanol resulted in decrease and increase of the 216 nm signal, without altering the spectral shape. These structural properties were significantly different from those of the native protein. PMID- 23033858 TI - To sign or not to sign? The impact of encouraging infants to gesture on infant language and maternal mind-mindedness. AB - Findings are presented from the first randomized control trial of the effects of encouraging symbolic gesture (or "baby sign") on infant language, following 40 infants from age 8 months to 20 months. Half of the mothers were trained to model a target set of gestures to their infants. Frequent measures were taken of infant language development and dyadic interactions were scrutinized to assess mind mindedness. Infants exposed to gesture did not differ from control conditions on language outcomes; thus, no support was found for previous claims that encouraging gesturing with infants accelerates linguistic development. Microgenetic analysis revealed mothers in the gesture training conditions were more responsive to their infants' nonverbal cues and encouraged more independent action by their infant. PMID- 23033859 TI - A meta-analysis of magnesium for tetanus. AB - Uncontrolled studies suggest that magnesium sulphate controls spasms in patients with established tetanus. We performed a meta-analysis of controlled trials that compared magnesium sulphate with placebo or diazepam for the treatment of patients with tetanus. We searched PubMed, Scopus, Embase and the Cochrane clinical trials registry. Three studies met the inclusion criteria, containing 275 participants (199 male patients, 72.4%). Magnesium sulphate did not reduce mortality, relative risk (95% CI): vs placebo, 0.80 (0.41-1.58); vs diazepam, 1.11 (0.70-1.75). The data on duration of total intensive care unit stay, total hospital stay and the need for ventilatory support were conflicting and pooling of results could not be done due to methodological differences of individual trials. More controlled trials are needed to assess the effect of magnesium sulphate on reducing autonomic instability, spasms, duration of intensive care and hospital stays and the need for mechanical ventilation. PMID- 23033860 TI - Nocturia: current concepts and future perspectives. AB - Nocturia is a prevalent highly bothersome urinary symptom that may significantly detriment the health and well-being of sufferers. It is characterized by waking at night to void, each void preceded and followed by sleep, hence leading to fragmentation of sleep and day-time tiredness. This may result in reduced productivity in the workplace, which contributes to the significant burden to the wider society that nocturia incurs. Nocturia was traditionally viewed as one of the many urinary tract symptoms that occur due to lower urinary tract dysfunction. However, recently it has been recognized that due to its multi factorial aetio-pathogenesis, nocturia should be viewed as distinct clinical condition in its own right. Careful assessment of the nocturic patient is essential so that treatment strategies are guided by the likely causes. Much research is currently being undertaken into the underlying causes and the optimal management approaches. This review will explore the contemporary status of research on nocturia with a focus on the current and newly available pharmacotherapies. PMID- 23033861 TI - Oral insecticidal activity of plant-associated pseudomonads. AB - Biocontrol pseudomonads are most known to protect plants from fungal diseases and to increase plant yield, while intriguing aspects on insecticidal activity have been discovered only recently. Here, we demonstrate that Fit toxin producing pseudomonads, in contrast to a naturally Fit-deficient strain, exhibit potent oral activity against larvae of Spodoptera littoralis, Heliothis virescens and Plutella xylostella, all major insect pests of agricultural crops. Spraying plant leaves with suspensions containing only 1000 Pseudomonas cells per ml was sufficient to kill 70-80% of Spodoptera and Heliothis larvae. Monitoring survival kinetics and bacterial titres in parallel, we demonstrate that Pseudomonas fluorescens CHA0 and Pseudomonas chlororaphis PCL1391, two bacteria harbouring the Fit gene cluster colonize and kill insects via oral infection. Using Fit mutants of CHA0 and PCL1391, we show that production of the Fit toxin contributes substantially to oral insecticidal activity. Furthermore, the global regulator GacA is required for full insecticidal activity. Our findings demonstrate the lethal oral activity of two root-colonizing pseudomonads so far known as potent antagonists of fungal plant pathogens. This adds insecticidal activity to the existing biocontrol repertoire of these bacteria and opens new perspectives for applications in crop pest control and in research on their ecological behaviour. PMID- 23033862 TI - Systemic contact dermatitis to corticosteroids. AB - BACKGROUND: Although unexpected and paradoxical, allergic hypersensitivity to corticosteroids is a common finding, delayed-type reactions being much more frequently encountered than the immediate-type ones. Although the skin is the main sensitization and elicitation route, other routes, amongst them systemic administration of corticosteroids may exceptionally be involved. OBJECTIVE: To determine the frequency, clinical presentation and cross-reactivity patterns for allergic reactions following systemic administration of corticosteroids amongst patients with identified and investigated 'contact allergy' to corticosteroids. METHODS: We reviewed clinical data, patch test results and sensitization sources in patients who reacted positively to corticosteroids tested in the K.U. Leuven Dermatology department during an 18-year period. RESULTS: Sixteen subjects (out of 315 with CS delayed-type hypersensitivity) presented with allergic manifestations due to systemic administration of corticosteroids. Most patients reacted to molecules from the three groups of the recently reappraised classification. CONCLUSION: The reactions observed seem to be in most cases 'systemic contact dermatitis' due to oral or parenteral re-exposure of sensitized individuals with the respective corticosteroids previously applied topically. Moreover, most patients seem to be able to react to any corticosteroid molecules and therefore need a systematic individualized evaluation of their sensitization/tolerance profile. PMID- 23033863 TI - Effect of posture-control insoles on function in children with cerebral palsy: randomized controlled clinical trial. AB - INTRODUCTION: Cerebral palsy (CP) is a posture and movement disorder and different therapeutic modalities, such as the use of braces, have sought to favor selective motor control and muscle coordination in such patients. The aim of the proposed study is to determine the effect of the combination of posture-control insoles and ankle-foot orthoses (AFOs) improving functional limitation in children with CP. METHODS/DESIGN: The sample will be composed of 24 children with CP between four and 12 years of age. After the signing of the statement of informed consent, the children will be randomly allocated to two groups: a control group using AFOs alone and an experimental group using both posture control insoles and AFOs. Evaluations will be performed on five occasions: without any accessory (insoles or AFOs), immediately after, one month after, six months after and one year after AFOs or insole and AFOs use. The evaluation will involve the analysis of gait, static and functional balance, mobility and hypertonia. The three-dimensional assessment of gait will involve the eight camera SMART-D SMART-D 140(r) system (BTS Engineering), two Kistler force plates (model 9286BA) and an eight-channel, wireless FREEEMG(r) electromyography (BTS Engineering). Static balance will be assessed using a Kistler force plate (model 9286BA). Clinical functional balance and mobility will be assessed using the Berg Balance Scale, Timed Up-and-Go Test and Six-Minute Walk Test. The posture-control insoles will be made of ethylene vinyl acetate, with thermal molding for fixation. The fixed orthoses will be made of polypropylene and attached to the ankle region (AFO). The results will be analyzed statistically, with the level significance set to 5% (p < 0.05). TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: RBR6d342s (http://www.ensaiosclinicos.gov.br/news/). PMID- 23033864 TI - Sources and transfers of methylmercury in adjacent river and forest food webs. AB - Nearly all ecosystems are contaminated with highly toxic methylmercury (MeHg), but the specific sources and pathways leading to the uptake of MeHg within and among food webs are not well understood. In this study, we report stable mercury (Hg) isotope compositions in food webs in a river and an adjacent forest in northern California and demonstrate the utility of Hg isotopes for studying MeHg sources and cross-habitat transfers. We observed large differences in both delta(202)Hg (mass-dependent fractionation) and Delta(199)Hg (mass-independent fractionation) within both food webs. The majority of isotopic variation within each food web could be accounted for by differing proportions of inorganic Hg [Hg(II)] and MeHg along food chains. We estimated mean isotope values of Hg(II) and MeHg in each habitat and found a large difference in delta(202)Hg between Hg(II) and MeHg (~2.70/00) in the forest but not in the river (~0.250/00). This is consistent with in situ Hg(II) methylation in the study river but suggests Hg(II) methylation may not be important in the forest. In fact, the similarity in delta(202)Hg between MeHg in forest food webs and Hg(II) in precipitation suggests that MeHg in forest food webs may be derived from atmospheric sources (e.g., rainfall, fog). Utilizing contrasting delta(202)Hg values between MeHg in river food webs (-1.00/00) and MeHg in forest food webs (+0.70/00), we estimate with a two-source mixing model that ~55% of MeHg in two riparian spiders is derived from riverine sources while ~45% of MeHg originates from terrestrial sources. Thus, stable Hg isotopes can provide new information on subtle differences in sources of MeHg and trace MeHg transfers within and among food webs in natural ecosystems. PMID- 23033865 TI - Alternative investigations for irritable bowel syndrome. AB - BACKGROUND AND AIM: Alternative and complementary medical practitioners have long advocated alternative treatments for irritable bowel syndrome. A more recent development has been the use of alternative investigations by these practitioners and, in the era of internet advertising, directly by patients themselves. The aim of the present study was to examine the alternative investigations that are advocated for the assessment of gastrointestinal disease and that are available through mainstream laboratories in Australia. METHODS: A comprehensive literature review was undertaken for each investigation, which was then evaluated on the basis of ACCE criteria for diagnostic tests. The ACCE criteria consider the analytical and clinical validity, clinical utility and ethical implications of the test. RESULTS: Serum immunoglobulin G (IgG) to food antigens, salivary IgA, intestinal permeability, fecal short-chain fatty acids and fecal microbial analysis were identified as readily available. None of the investigations satisfied the ACCE criteria. The tests were deficient in one or more areas of analytical validity, clinical application, validity and ethical usage standards. CONCLUSION: Alternative investigations lack reliability and direct clinical applications, and should not be recommended for the investigation of gastrointestinal symptoms. PMID- 23033866 TI - Synthesis route and three different core-shell impacts on magnetic characterization of gadolinium oxide-based nanoparticles as new contrast agents for molecular magnetic resonance imaging. AB - Despite its good resolution, magnetic resonance imaging intrinsically has low sensitivity. Recently, contrast agent nanoparticles have been used as sensitivity and contrast enhancer. The aim of this study was to investigate a new controlled synthesis method for gadolinium oxide-based nanoparticle preparation. For this purpose, diethyleneglycol coating of gadolinium oxide (Gd2O3-DEG) was performed using new supervised polyol route, and small particulate gadolinium oxide (SPGO) PEGylation was obtained with methoxy-polyethylene-glycol-silane (550 and 2,000 Da) coatings as SPGO-mPEG-silane550 and 2,000, respectively. Physicochemical characterization and magnetic properties of these three contrast agents in comparison with conventional Gd-DTPA were verified by dynamic light scattering transmission electron microscopy, Fourier transform infrared spectroscopy, inductively coupled plasma, X-ray diffraction, vibrating sample magnetometer, and the signal intensity and relaxivity measurements were performed using 1.5-T MRI scanner.As a result, the nanoparticle sizes of Gd2O3-DEG, SPGO-mPEG-silane550, and SPGO-mPEG-silane2000 could be reached to 5.9, 51.3, 194.2 nm, respectively. The image signal intensity and longitudinal (r1) and transverse relaxivity (r2) measurements in different concentrations (0.3 to approximately 2.5 mM), revealed the r2/r1 ratios of 1.13, 0.89, 33.34, and 33.72 for Gd-DTPA, Gd2O3-DEG, SPGO mPEG-silane550, and SPGO-mPEG-silane2000, respectively.The achievement of new synthesis route of Gd2O3-DEG resulted in lower r2/r1 ratio for Gd2O3-DEG than Gd DTPA and other previous synthesized methods by this and other groups. The smaller r2/r1 ratios of two PEGylated-SPGO contrast agents in our study in comparison with r2/r1 ratio of previous PEGylation (r2/r1 = 81.9 for mPEG-silane 6,000 MW) showed that these new three introduced contrast agents could potentially be proper contrast enhancers for cellular and molecular MR imaging. PMID- 23033867 TI - Direct-acting DNA alkylating agents present in aqueous extracts of areca nut and its products. AB - Areca nut is a carcinogen to humans and has been strongly associated with oral premalignant and malignant diseases. Previous studies speculated the presence of unknown direct-acting mutagens present in aqueous extracts of areca nut. We hypothesized whether any direct-acting alkylating agents are present in areca nut and its commercial products. In this study, calf thymus DNA was treated with four different aqueous extracts obtained from unripe and ripe areca nuts or their commercial products, namely, pan masala (without tobacco) and gutkha (with tobacco). Three N-alkylated purines including N7-methylguanine (N7-MeG), N3 methyladenine (N3-MeA), and N7-ethylguanine (N7-EtG) were detected using sensitive and specific isotope-dilution liquid chromatography-tandem-mass spectrometry (LC-MS/MS) methods. The results showed that four types of aqueous extracts significantly induced the formation of N7-MeG and N3-MeA in a linear dose-response manner. Extracts from unripe areca nut exhibited higher methylating potency than those of ripe areca nut, while gutkha had higher methylating potency than pan masala. Meanwhile, gutkha made with areca nut and tobacco, was the only extract found to induce the formation of N7-EtG. Overall, this study first demonstrated that the presence of direct-acting alkylating agents in areca nut and its commercial products exist at a level that is able to cause significant DNA damage. Our findings may provide another mechanistic rationale for areca nut mediated oral carcinogenesis and also highlight the importance and necessity of the identification of these direct-acting alkylating agents. PMID- 23033868 TI - Fiber optic micro sensor for the measurement of tendon forces. AB - A fiber optic sensor developed for the measurement of tendon forces was designed, numerically modeled, fabricated, and experimentally evaluated. The sensor incorporated fiber Bragg gratings and micro-fabricated stainless steel housings. A fiber Bragg grating is an optical device that is spectrally sensitive to axial strain. Stainless steel housings were designed to convert radial forces applied to the housing into axial forces that could be sensed by the fiber Bragg grating. The metal housings were fabricated by several methods including laser micromachining, swaging, and hydroforming. Designs are presented that allow for simultaneous temperature and force measurements as well as for simultaneous resolution of multi-axis forces.The sensor was experimentally evaluated by hydrostatic loading and in vitro testing. A commercial hydraulic burst tester was used to provide uniform pressures on the sensor in order to establish the linearity, repeatability, and accuracy characteristics of the sensor. The in vitro experiments were performed in excised tendon and in a dynamic gait simulator to simulate biological conditions. In both experimental conditions, the sensor was found to be a sensitive and reliable method for acquiring minimally invasive measurements of soft tissue forces. Our results suggest that this sensor will prove useful in a variety of biomechanical measurements. PMID- 23033870 TI - Homoeolog expression bias and expression level dominance in allopolyploids. PMID- 23033869 TI - High-gradient nanomagnets on cantilevers for sensitive detection of nuclear magnetic resonance. AB - Detection of magnetic resonance as a force between a magnetic tip and nuclear spins has previously been shown to enable sub-10 nm resolution 1H imaging. Maximizing the spin force in such a magnetic resonance force microscopy (MRFM) experiment demands a high field gradient. In order to study a wide range of samples, it is equally desirable to locate the magnetic tip on the force sensor. Here we report the development of attonewton-sensitivity cantilevers with high gradient cobalt nanomagnet tips. The damage layer thickness and saturation magnetization of the magnetic material were characterized by X-ray photoelectron spectroscopy and superconducting quantum interference device magnetometry. The coercive field and saturation magnetization of an individual tip were quantified in situ using frequency-shift cantilever magnetometry. Measurements of cantilever dissipation versus magnetic field and tip-sample separation were conducted. MRFM signals from protons in a polystyrene film were studied versus rf irradiation frequency and tip-sample separation, and from this data the tip field and tip field gradient were evaluated. Magnetic tip performance was assessed by numerically modeling the frequency dependence of the magnetic resonance signal. We observed a tip-field gradient ?B(z)(tip)/?z estimated to be between 4.4 and 5.4 MT m(-1), which is comparable to the gradient used in recent 4 nm resolution 1H imaging experiments and larger by nearly an order of magnitude than the gradient achieved in prior magnet-on-cantilever MRFM experiments. PMID- 23033871 TI - The experience of amputation and prosthesis use for adults: a metasynthesis. AB - PURPOSE: To identify and synthesize qualitative literature on the experience of amputation and prosthesis use for adults, and to make recommendations based on these findings for rehabilitation services. METHODS: A systematic search of three databases for qualitative research exploring the experience of amputation and prosthesis use for adults was undertaken. Included papers were evaluated using the Critical Appraisal Skills Programme (CASP) quality guidelines. Data were extracted and themes synthesized in accordance with accepted procedures for qualitative metasyntheses. RESULTS: From the 15 papers (13 studies) included in there view, five concepts were identified: (i) Becoming an amputee and facing prosthesis use; (ii) Adjustment to and coping with amputation and prosthesis use; (iii) The role of valued relationships in recovery; (iv) Amputation and prosthesis use in social interaction; and (v) Prosthetically enabled identities. CONCLUSIONS: The findings provide a base from which to make suggestions regarding the provision of health rehabilitation services for this population. It is recommended that such services make greater use of psychological interventions and education, include patients' social support networks, use psychotherapy to support and develop positive coping strategies, and facilitate peer support from those who have already made positive adjustments to amputation and prosthesis use. PMID- 23033872 TI - Alacrity of cells engaged in the immune response. AB - A hypothesis is postulated and experimental findings are given that a special kind of cell heterogeneity exists that renders cells differentially sensitive to the epitopal stimulus with the consequence that only a portion of ligand-specific cells engages in the response. The differential sensitivity is based on epigenetically driven cell-to-cell variations in the expressed gene products, such that every cell becomes unique in its molecular profile, and will preserve its individuality in 'sensing' the boundary conditions of the response milieu. The readiness of cells to engage in the response will be termed alacrity. High alacrity cells are ready to respond under given conditions because their molecular expression pattern - both in qualitative and in quantitative terms - matches the response milieu. This heterogeneity has little to do with the BCR and TCR specificity, that is, not all antigen-specific cells respond to a stimulus, and cells failing to respond do so because their overall molecular pattern is inadequate to the conditions of the response milieu. The corollary to this proposition is that whatever physiological conditions prevail, some ligand specific cells will likely be ready to engage in the response, because their uniqueness makes them differentially reactive to external signals. Although the pool of cells available for any response is restricted under any given boundary condition, some idle cells are saved to be 'in reserve'. Experiments are described that are compatible with this proposition, and approaches are suggested to elucidate the mechanism of developing and maintaining alacrity. This paper is a contribution to the Centennial conference in honour of Niels Kaj Jerne, held in Lisbon November 2011. PMID- 23033874 TI - Practice-related reduction of electromyographic mirroring activity depends on basal levels of interhemispheric inhibition. AB - Paired-pulse transcranial magnetic stimulation (TMS) is used to measure the excitability of interhemispheric inhibition (IHI) between the hand areas of the two motor cortices. It varies from person to person, and is highly predictive of individual differences in callosal anatomy (fractional anisotropy) and even motor behaviour, e.g. the amount of involuntary electromyographic (EMG) 'mirroring' in one hand during rapid contraction of the other. The present experiments tested whether it also predicts how well individuals can improve motor performance in a task involving the two hands. Healthy participants were given 100 trials to maximize the initial acceleration of a ballistic finger movement made with one hand while trying to maintain a tonic low level of EMG activity in the other hand. Initially, each movement was accompanied by additional unwanted EMG mirroring in the other hand. However, after practice, participants had on average increased acceleration by approximately one-third without changing the amount of EMG mirroring in the contralateral hand; indeed, in some individuals EMG mirroring activity declined. TMS measures showed that there was an increase in corticospinal excitability in the trained hemisphere, but there was no change in the excitability of short- or long-latency IHI from the trained to non-trained hemisphere. Nevertheless, in each individual, the baseline (pre-practice) excitability of short-latency IHI was highly predictive (r = 0.65; P = 0.0019) of the change in EMG mirroring. The implication is that a physiological measure of brain excitability at rest can predict behaviour in response to training. PMID- 23033875 TI - Postpartum HELLP syndrome--the case of lost battle. AB - Unexpected rapid maternal death after delivery due to HELLP syndrome is rarely encountered and may become the subject of forensic expertise. Unexpectedness, suddenness, and fulminant course of this syndrome as well as absence of classical signs of pre-eclampsia can confuse physicians and lead to diagnostic delay. A definitive post-mortem diagnosis of HELLP syndrome in questionable cases of maternal death should be based on accepted laboratory criteria and characteristic histopathological alterations. We present a case of acute postpartum HELLP syndrome complicated by disseminated intravascular coagulation and acute renal failure which caused rapid maternal death only 20 hours after a caesarean section following an uncomplicated pregnancy. PMID- 23033876 TI - Formation of high-molecular-weight angiotensinogen during pregnancy is a result of competing redox reactions with the proform of eosinophil major basic protein. AB - The plasma concentration of the placentally derived proMBP (proform of eosinophil major basic protein) increases in pregnancy, and three different complexes containing proMBP have been isolated from pregnancy plasma and serum: a 2:2 complex with the metalloproteinase, PAPP-A (pregnancy-associated plasma protein A), a 2:2 complex with AGT (angiotensinogen) and a 2:2:2 complex with AGT and complement C3dg. In the present study we show that during human pregnancy, all of the circulating proMBP exists in covalent complexes, bound to either PAPP-A or AGT. We also show that the proMBP-AGT complex constitutes the major fraction of circulating HMW (high-molecular weight) AGT in late pregnancy, and that this complex is able to further associate with complement C3 derivatives post sampling. Clearance experiments in mice suggest that complement C3-based complexes are removed faster from the circulation compared to monomeric AGT and the proMBP-AGT complex. Furthermore, we have used recombinant proteins to analyse the formation of the proMBP-PAPP-A and the proMBP-AGT complexes, and we demonstrate that they are competing reactions, depending on the same cysteine residue of proMBP, but differentially on the redox potential, potentially important for the relative amounts of the complexes in vivo. These findings may be important physiologically, since the biochemical properties of the proteins change as a consequence of complex formation. PMID- 23033878 TI - Coalescent: an open-source and scalable framework for exact calculations in coalescent theory. AB - BACKGROUND: Currently, there is no open-source, cross-platform and scalable framework for coalescent analysis in population genetics. There is no scalable GUI based user application either. Such a framework and application would not only drive the creation of more complex and realistic models but also make them truly accessible. RESULTS: As a first attempt, we built a framework and user application for the domain of exact calculations in coalescent analysis. The framework provides an API with the concepts of model, data, statistic, phylogeny, gene tree and recursion. Infinite-alleles and infinite-sites models are considered. It defines pluggable computations such as counting and listing all the ancestral configurations and genealogies and computing the exact probability of data. It can visualize a gene tree, trace and visualize the internals of the recursion algorithm for further improvement and attach dynamically a number of output processors. The user application defines jobs in a plug-in like manner so that they can be activated, deactivated, installed or uninstalled on demand. Multiple jobs can be run and their inputs edited. Job inputs are persisted across restarts and running jobs can be cancelled where applicable. CONCLUSIONS: Coalescent theory plays an increasingly important role in analysing molecular population genetic data. Models involved are mathematically difficult and computationally challenging. An open-source, scalable framework that lets users immediately take advantage of the progress made by others will enable exploration of yet more difficult and realistic models. As models become more complex and mathematically less tractable, the need for an integrated computational approach is obvious. Object oriented designs, though has upfront costs, are practical now and can provide such an integrated approach. PMID- 23033879 TI - Effects of temperature and photoperiod on yield and chemical composition of northern and southern clones of bilberry (Vaccinium myrtillus L.). AB - After pollination outdoors, individual bilberry plants from two Northern and two Southern clones were studied for climatic effects on berry yield and quality in a controlled phytotrone experiment at 12 and 18 degrees C. At each temperature, the following light treatments were tested: (1) 12 h natural light, (2) 24 h natural light, and (3) 24 h natural light plus red light. The first experimental year there was no difference in yield between temperatures; however, the second experimental year the berry yields was significantly higher at 18 degrees C. Berry ripening was faster in the Northern than in the Southern clones at 12 degrees C. Northern clones also showed significantly higher contents of total anthocyanins, all measured anthocyanin derivatives, total phenolics, malic acid and sucrose. Metabolic profiling revealed higher levels of flavanols, hydroxycinnamic acids, quinic acid and carbohydrates at 12 degrees C. PMID- 23033877 TI - Organization of the neural switching circuitry underlying reflex micturition. AB - The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain and spinal cord that coordinates the activity of the bladder and urethral outlet. Experimental studies in animals indicate that urine storage is modulated by reflex mechanisms in the spinal cord, whereas voiding is mediated by a spinobulbospinal pathway passing through a coordination centre in the rostral brain stem. Many of the neural circuits controlling micturition exhibit switch like patterns of activity that turn on and off in an all-or-none manner. This study summarizes the anatomy and physiology of the spinal and supraspinal micturition switching circuitry and describes a computer model of these circuits that mimics the switching functions of the bladder and urethra at the onset of micturition. PMID- 23033880 TI - In-vitro analysis of the microbicidal activity of 6 contact lens care solutions. AB - BACKGROUND: Contact lens-related infections are often associated with inadequate contact lens hygiene, and therefore, contact lens care products should be able to sufficiently minimise the amount of pathogens that are responsible for these infections. In 2001, the EN ISO 14729 was introduced to ensure adequate disinfection efficacy of contact lens care solutions, but this norm has recently been criticised. METHODS: In this study, six frequently used contact lens care solutions were retested according to the Stand Alone Test of the EN ISO 14729 (2001). The Stand Alone Test is a quantitative suspension test. In addition, the products were tested in a modified setting adding an organic load. The load was a mixture of human blood serum, lysozyme, and mucine, which resembles tear fluid. RESULTS: The criteria of the Stand Alone Test recommended in EN ISO 14729 were only met by Aosept Plus. This 3% hydrogen-peroxide-based contact lens care solution attained a reduction factor of > 5 log units for bacteria and > 4 for fungi in all cases. Two further contact lens care solutions, Blue Vision and Optifree Replenish, met the criteria of a reduction factor of > 3 log units for bacteria and > 1 log unit for fungi, but only in the presence of artificial tear fluid. The three remaining products did not exhibit adequate disinfecting efficacy, at least against one of the tested microorganisms. CONCLUSIONS: Through the observation that the artificial tear fluid used in this study influences the disinfecting efficacy of contact lens care solutions, especially that of multi purpose solutions, in a different way than does albumin, mucine, or even the organic load suggested in EN ISO 14729, it becomes obvious that the test conditions in the EN ISO 14729 should be revised in order to create more realistic conditions, e.g., by using a more realistic artificial tear fluid. Furthermore, we suggest adapting the EN ISO 14729 to the European test hierarchy for chemical disinfectants and antiseptics, which consists of three test phases and also requests meeting stricter criteria in order to pass the test. Unless the test conditions guarantee a sufficient reduction of potential pathogens, the risk of contact lens-related microbial keratitis and other infections will remain for the users. PMID- 23033881 TI - Design and statistical optimization of osmotically driven capsule based on push pull technology. AB - In present investigation attempt was made to develop and statistically optimize osmotically active capsule tailor made from the concept of bilayer (push-pull) osmotic tablet technology. The capsule was comprised of active (drug) and push (osmogen) layer. Active layer was compressed in form of tablet by mixing known amount of drug and formulation excipients. Similarly push layer was made by compressing Mannitol with formulation excipients. Finally, both layers were packed in hard gelatin capsule having small aperture at top and coated with semipermeable membrane to form osmotically active capsule. Formulated and optimized capsules were characterized for Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetric (DSC), scanning electron microscopy, In-vitro drug release study and Release models and kinetics. Statistically optimized formulation showed good correlation between predicted and experimented results, which further confirms the practicability and validity of the model. PMID- 23033882 TI - Assessing production of the ubiquitous archaeal diglycosyl tetraether lipids in marine subsurface sediment using intramolecular stable isotope probing. AB - The membrane lipids diglycosyl-glycerol dibiphytanyl glycerol tetraethers (2G GDGTs) in marine subsurface sediments are believed to originate from uncultivated benthic archaea, yet the production of 2G-GDGTs from subseafloor samples has not been demonstrated in vitro. In order to validate sedimentary biosynthesis of 2G GDGTs, we performed a stable carbon isotope probing experiment on a subseafloor sample with six different (13) C-labelled substrates (bicarbonate, methane, acetate, leucine, glucose and Spirulina platensis biomass). After 468 days of anoxic incubation, only glucose and S. platensis resulted in label uptake in lipid moieties of 2G-GDGTs, indicating incorporation of carbon from these organic substrates. The hydrophobic moieties of 2G-GDGTs showed minimal label incorporation, with up to 40/00 (13) C enrichment detected in crenarchaeol derived tricyclic biphytane from the S. platensis-supplemented slurries. The 2G GDGT-derived glucose or glycerol moieties also showed (13) C incorporation (Deltadelta(13) C = 18-380/00) in the incubations with glucose or S. platensis, consistent with a lipid salvage mechanism utilized by marine benthic archaea to produce new 2G-GDGTs. The production rates were nevertheless rather slow, even when labile organic matter was supplied. The 2G-GDGT turnover times of 1700 20,500 years were much longer than those estimated for subseafloor microbial communities, implying that sedimentary 2G-GDGTs as biomarkers of benthic archaea are cumulative records of past and present generations. PMID- 23033883 TI - A comparison of chemical enhancements for the detection of latent blood. AB - Luminol, Bluestar((r)), and Hemascein((r)) were tested to compare detection sensitivities to latent blood. Untreated, EDTA-treated human blood, and a catalytically similar blood substitute were diluted (neat to 1:1,000,000) and pipetted onto a variety of substrates. Luminol and Bluestar((r)) performed similarly on all surfaces and fabrics. Hemascein((r)) yielded poor results on wood surfaces, but performed well in the detection of latent blood on fabrics. Results from untreated, EDTA-treated, and synthetic blood results indicate that EDTA-treated blood is similar or slightly less sensitive than untreated blood at all dilutions and on all substrates, and the synthetic blood is less sensitive than real blood, but consistent in detection threshold and thus is useful as a training aid. Additionally, some foods and household chemicals that have previously been shown to cross-react were tested with Bluestar((r)), Hemascein((r)), and luminol. Hemascein((r)) cross-reacted with many substances, while both luminol reagents were more discriminating. PMID- 23033884 TI - Effects of ezetimibe on visceral fat in the metabolic syndrome: a randomised controlled study. AB - BACKGROUND: Although visceral obesity, a key abnormality in the metabolic syndrome, is an important risk for cardiovascular diseases, reduction in visceral fat is hard to achieve despite intensive efforts directed at lifestyle modification. The present study was designed to investigate whether ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann Pick C1-like 1, reduces visceral fat in patients with metabolic syndrome. MATERIALS AND METHODS: Seventy-eight outpatients (63.7 +/- 10.4 years old) with metabolic syndrome were enroled and randomly assigned to receive either ezetimibe (10 mg/day) or nothing for 6 months. Changes in visceral fat were assessed by computed tomography. RESULTS: Treatment with ezetimibe significantly improved lipid profiles. Visceral fat was decreased 7.2%, from 161.3 +/- 58.6 cm(2) to 148.4 +/- 52.7 cm(2) (P < 0.05), and adiponectin was increased 7.7%, from 3.61 +/ 3.10 MUg/mL to 3.86 +/- 3.62 MUg/mL (P < 0.05), after ezetimibe therapy; these beneficial effects were not observed in the control group. The increase in the adiponectin level was correlated with the reduction in visceral fat after ezetimibe treatment. Furthermore, ezetimibe reduced fasting insulin levels (P < 0.05) and improved the homoeostasis model assessment of insulin resistance (HOMA IR) (P < 0.05). CONCLUSIONS: Ezetimibe reduces visceral fat with beneficial effects on adiponectin and insulin resistance in patients with metabolic syndrome, suggesting a new therapeutic approach in such patients. PMID- 23033885 TI - An electronic diary is shown to be more reliable than a paper diary: results from a randomized crossover study in patients with persistent asthma. AB - OBJECTIVES: Test-retest reliability of an asthma paper diary versus an electronic diary (e-diary) with an integrated peak flow meter was investigated. The equivalence of the two modes was also evaluated. METHODS: Prospective, randomized crossover study design in adolescents (12-17 years) and adults (>=18 years). Key inclusion criteria were persistent asthma, Asthma Control Test (ACT) scores >=16, use of inhaled corticosteroid with or without long-acting beta-agonist for >=12 weeks, nocturnal awakenings <2 times in the past week, and activity limitations <1 per week. Participants were randomized to either paper then e-diary or e-diary then paper, to be completed for 14 days each. RESULTS: Forty-seven participants completed all study visits. Weekly percentage of symptom-free days (SFDs) and rescue-free days (RFDs) were calculated. Intraclass correlation coefficients (ICCs) of Week 1 mean SFD and RFD (test) and Week 2 mean SFD and RFD (retest), respectively, were estimated in three groups defined as stable: (i) minimal changes in asthma symptoms, as measured by the global patient reported symptom change question, (ii) less than 15% change (absolute value) in 1 second FEV(1) at adjacent study visits, and (iii) changes in ACT scores less than three points for each mode. SFD demonstrated acceptable ICC (>=0.70) using all three definitions of asthma stability for both modes. CONCLUSION: Acceptable reproducibility of the percentage of RFD (ICC = 0.78) was only observed for the e-diary using the FEV(1) stability criterion. The ICCs for SFD and RFD were acceptable, 0.84 and 0.70, respectively, suggesting better reliability for the e-diary. PMID- 23033886 TI - Organic selenium supplementation increases mercury excretion and decreases oxidative damage in long-term mercury-exposed residents from Wanshan, China. AB - Due to a long history of extensive mercury mining and smelting activities, local residents in Wanshan, China, are suffering from elevated mercury exposure. The objective of the present study was to study the effects of oral supplementation with selenium-enriched yeast in these long-term mercury-exposed populations. One hundred and three volunteers from Wanshan area were recruited and 53 of them were supplemented with 100 MUg of organic selenium daily as selenium-enriched yeast while 50 of them were supplemented with the nonselenium-enriched yeast for 3 months. The effects of selenium supplementation on urinary mercury, selenium, and oxidative stress-related biomarkers including malondialdehyde and 8-hydroxy-2 deoxyguanosine were assessed. This 3-month selenium supplementation trial indicated that organic selenium supplementation could increase mercury excretion and decrease urinary malondialdehyde and 8-hydroxy-2-deoxyguanosine levels in local residents. PMID- 23033887 TI - A design process for using normative models in shared decision making: a case study in the context of prenatal testing. AB - BACKGROUND: Shared decision making (SDM) encourages the patient to play a more active role in the process of medical consultation and its primary objective is to find the best treatment for a specific patient. Recent findings, however, show that patient preferences cannot be easily or accurately judged on the basis of communicative exchange during routine office visits, even for patients who seek to expand their role in medical decision making (MDM). OBJECTIVE: The objective of this study is to improve the quality of patient-physician communication by developing a novel design process for SDM and then demonstrating, through a case study, the applicability of this process in enabling the use of a normative model for a specific medical situation. DESIGN: Our design process goes through the following stages: definition of medical situation and decision problem, development/identification of normative model, adaptation of normative model, empirical analysis and development of decision support systems (DSS) tools that facilitate the SDM process in the specific medical situation. CASE STUDY: This study demonstrates the applicability of the process through the implementation of the general normative theory of MDM under uncertainty for the medical-financial dilemma of choosing a physician to perform amniocentesis. DISCUSSION: The use of normative models in SDM raises several issues, such as the goal of the normative model, the relation between the goals of prediction and recommendation, and the general question of whether it is valid to use a normative model for people who do not behave according to the model's assumptions. PMID- 23033888 TI - Anti-cancer activity of novel dibenzo[b,f]azepine tethered isoxazoline derivatives. AB - BACKGROUND: Dibenzoazepine (DB) derivatives are important and valuable compounds in medicinal chemistry. The synthesis and chemotherapeutic properties of naturally occurring DBs and different heterocyclic moiety tethered DBs are reported. Herein, we report the DB-fused hybrid structure that containing isoxazolines (DBIs) and their anti-cancer activity, which could throw light on the structural and functional features of new molecules. RESULTS AND CONCLUSION: The synthesis and characterization of novel ring DB tethered isoxazoline derivatives (DBIs) were carried out. After the detailed structural characterization using 2D-NMR experiments, the compounds were identified as 5 substituted isoxazolines. The effect of newly synthesized DBIs against the invasion of murine osteosarcoma (LM8G7) cells was studied. Among the tested molecules, compound 4g (5-[-3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f]azepine), was found to inhibit the invasion of LM8G7 cells strongly, when compared to other structurally related compounds. Cumulatively, the compound 4g inhibited the invasion MDA-MB-231 cells completely at 10 MUM. In addition to anti-invasion property the compound 4g also inhibited the migration of LM8G7 and human ovarian cancer cells (OVSAHO) dose-dependently. Compound 4g inhibited the proliferation of LM8G7, OVSAHO, human breast cancer cells (MCF-7) and human melphalan-resistant multiple myeloma (RPMI8226-LR5) cells that are comparable to cisplatin and suramin. PMID- 23033889 TI - Clinical and molecular characterization of Thai patients with Wiskott-Aldrich syndrome. AB - Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder caused by mutations in the gene encoding the WAS protein (WASP). Classic WAS is characterized by thrombocytopenia with small-sized platelets, recurrent infections, eczema and increased susceptibility to autoimmune diseases and haematologic malignancies. Here, we reported on seven unrelated Thai individuals with classic WAS. In addition to clinical and immunologic characterization, mutation analysis by PCR-sequencing the entire coding region of WASP was performed. Recurrent and novel mutations were successfully identified. A nonsense mutation, the c.55C>T (p.Q19X), has not been previously described, expanding the mutational spectrum of WASP. The patient with this newly described mutation developed cow's milk allergy manifesting as angioedema and urticaria and had cytomegalovirus infection that was successfully treated with long-term ganciclovir. This study reported long-term follow-up of seven patients with molecular confirmation of WAS and infrequent features in the patient with classic WAS carrying the novel nonsense mutation. PMID- 23033890 TI - Is there a role for tirapazamine in the treatment of cervical cancer? AB - INTRODUCTION: Cervical cancer is the second-most common malignancy in women worldwide. Cisplatin was introduced as a radiosensitizer in 1999 to improve chances of survival. Tumor cell hypoxia, however, remains a major limiting factor in the treatment of solid tumors with chemotherapy and radiation. There has since been significant interest in the use of bioreductive agents to overcome the hypoxia and improve survival. The addition of tirapazamine (TPZ) to conventional chemoradiation protocols in the management of cervical cancer held promise in the initial Phase I and II clinical trials in delaying recurrence and improving survival. However, GOG recently announced early closure of the Phase III trial of tirapazamine in cervical cancer due to a lack of increased survival. AREAS COVERED: This article covers the definition of hypoxic tumor cells, the markers of tumor hypoxia, methods for measuring hypoxia as well as the pharmacologic action of tirapazamine in hypoxic media. Furthermore, it critically evaluates TPZ's role in cervical cancer treatment and the drawbacks to the GOG study. The authors review all clinical trials published to date with special emphasis on cervical cancer. A systematic review of the literature was also undertaken with PubMed and Ovid. EXPERT OPINION: Despite the promising results from early clinical trials, it has been shown that the addition of tirapazamine appears to confer no benefits on progression-free or overall survival in patients with cervical cancer. Success in the future will require smaller randomized trials with biologic targets that have acceptable toxicity and efficacy. PMID- 23033891 TI - Chains, sheets, and droplets: assemblies of hydrophobic gold nanocrystals with saturated phosphatidylcholine lipid and squalene. AB - Assemblies of saturated 1,2-diacylphosphatidylcholine lipid and hydrophobic dodecanethiol-capped 1.8 nm diameter gold nanocrystals were studied as a function of lipid chain length and the addition of the naturally occurring oil, squalene. The gold nanocrystals formed various lipid-stabilized agglomerates, sometimes fusing with lipid vesicle bilayers. The nanocrystal assembly structure depended on the hydrocarbon chain length of the lipid fatty acids. The lipid with the shortest fatty acid length studied, dilauroylphosphatidylcholine, created extended chains of gold nanocrystals. The lipid with slightly longer fatty acid chains created planar sheets of nanocrystals. Further increases of the fatty acid chain length led to spherical agglomerates. The inclusion of squalene led to lipid- and nanocrystal-coated oil droplets. PMID- 23033892 TI - Automated, semi-automated, and manual analyses of anti-cardiolipin and anti-beta2 glycoprotein I antibodies in women with a history of miscarriage. AB - INTRODUCTION: Anti-cardiolipin and beta2-glycoprotein I antibodies represent important diagnostic parameters in routine hematology. In this study, five different automated, semi-automated, and manual immunoassays detecting IgG/IgM anti-cardiolipin and anti-beta2 -glycoprotein I antibodies were tested. METHODS: A total of 162 samples from women with a history of miscarriage were recruited from 110 different G&O outpatient centers in Germany. RESULTS: For both anti cardiolipin and anti-beta2 -glycoprotein I antibodies, considerable differences in the percentage of positive results were seen between all five methods, and itemization of all positive test results revealed a poor accordance. These findings were confirmed by Cohen's kappa coefficients. CONCLUSION: Our study revealed a moderate to poor accordance between five different test systems for anti-cardiolipin and anti-beta2 -glycoprotein I antibodies. Such deviations may result in clinical misinterpretation of data and may lead to wrong therapeutic consequences. Therefore, further standardization of all tests for anti phospholipid antibodies should be achieved. PMID- 23033893 TI - Formation of Ga droplets on patterned GaAs (100) by molecular beam epitaxy. AB - In this paper, the formation of Ga droplets on photo-lithographically patterned GaAs (100) and the control of the size and density of Ga droplets by droplet epitaxy using molecular beam epitaxy are demonstrated. In extension of our previous result from the journal Physical Status Solidi A, volume 209 in 2012, the sharp contrast of the size and density of Ga droplets is clearly observed by high-resolution scanning electron microscope, atomic force microscope, and energy dispersive X-ray spectrometry. Also, additional monolayer (ML) coverage is added to strength the result. The density of droplets is an order of magnitude higher on the trench area (etched area), while the size of droplets is much larger on the strip top area (un-etched area). A systematic variation of ML coverage results in an establishment of the control of size and density of Ga droplets. The cross-sectional line profile analysis and root mean square roughness analysis show that the trench area (etched area) is approximately six times rougher. The atomic surface roughness is suggested to be the main cause of the sharp contrast of the size and density of Ga droplets and is discussed in terms of surface diffusion. PMID- 23033894 TI - A validation of ground ambulance pre-hospital times modeled using geographic information systems. AB - BACKGROUND: Evaluating geographic access to health services often requires determining the patient travel time to a specified service. For urgent care, many research studies have modeled patient pre-hospital time by ground emergency medical services (EMS) using geographic information systems (GIS). The purpose of this study was to determine if the modeling assumptions proposed through prior United States (US) studies are valid in a non-US context, and to use the resulting information to provide revised recommendations for modeling travel time using GIS in the absence of actual EMS trip data. METHODS: The study sample contained all emergency adult patient trips within the Calgary area for 2006. Each record included four components of pre-hospital time (activation, response, on-scene and transport interval). The actual activation and on-scene intervals were compared with those used in published models. The transport interval was calculated within GIS using the Network Analyst extension of Esri ArcGIS 10.0 and the response interval was derived using previously established methods. These GIS derived transport and response intervals were compared with the actual times using descriptive methods. We used the information acquired through the analysis of the EMS trip data to create an updated model that could be used to estimate travel time in the absence of actual EMS trip records. RESULTS: There were 29,765 complete EMS records for scene locations inside the city and 529 outside. The actual median on-scene intervals were longer than the average previously reported by 7-8 minutes. Actual EMS pre-hospital times across our study area were significantly higher than the estimated times modeled using GIS and the original travel time assumptions. Our updated model, although still underestimating the total pre-hospital time, more accurately represents the true pre-hospital time in our study area. CONCLUSIONS: The widespread use of generalized EMS pre-hospital time assumptions based on US data may not be appropriate in a non-US context. The preference for researchers should be to use actual EMS trip records from the proposed research study area. In the absence of EMS trip data researchers should determine which modeling assumptions more accurately reflect the EMS protocols across their study area. PMID- 23033895 TI - On the morphology of a discotic liquid crystalline charge transfer complex. AB - Discotic liquid crystalline (DLC) charge transfer (CT) complexes, which combine visible light absorption with rapid charge transfer characteristics within the CT complex, can have a great potential for photovoltaic applications when they can be made to self-assemble in a bulk heterojunction arrangement with separate channels for electron and hole conduction. However, the morphology of some liquid crystalline CT complexes has been under debate for many years. In particular, the liquid crystalline CT complex built from the electron acceptor 2,4,7-trinitro-9 fluorenone (TNF) and discotic molecules has been reported to have the TNF "sandwiched" either between the discotic molecules within the same column or between the columns within the aliphatic tails of the discotic molecules. We present a detailed structural study of the prototypic 1:1 mixture of the discotic 2,3,6,7,10,11-hexakis(hexyloxy)triphenylene (HAT6) and TNF. Nuclear magnetic resonance (NMR) line widths and cross-polarization rates are consistent with the picosecond time scale anisotropic thermal motions of the HAT6 and TNF molecules previously observed. By computational integration of Rietveld refinement analyses of neutron diffraction patterns with density experiments and short-range structural constraints from heteronuclear 2D NMR, we determine that the TNF molecules are vertically oriented between HAT6 columns. The data provide the insight that a morphology of separate hole conducting channels of HAT6 molecules can be realized in the liquid crystalline CT complex. PMID- 23033896 TI - Construction and analysis of a high-density genetic linkage map in cabbage (Brassica oleracea L. var. capitata). AB - BACKGROUND: Brassica oleracea encompass a family of vegetables and cabbage that are among the most widely cultivated crops. In 2009, the B. oleracea Genome Sequencing Project was launched using next generation sequencing technology. None of the available maps were detailed enough to anchor the sequence scaffolds for the Genome Sequencing Project. This report describes the development of a large number of SSR and SNP markers from the whole genome shotgun sequence data of B. oleracea, and the construction of a high-density genetic linkage map using a double haploid mapping population. RESULTS: The B. oleracea high-density genetic linkage map that was constructed includes 1,227 markers in nine linkage groups spanning a total of 1197.9 cM with an average of 0.98 cM between adjacent loci. There were 602 SSR markers and 625 SNP markers on the map. The chromosome with the highest number of markers (186) was C03, and the chromosome with smallest number of markers (99) was C09. CONCLUSIONS: This first high-density map allowed the assembled scaffolds to be anchored to pseudochromosomes. The map also provides useful information for positional cloning, molecular breeding, and integration of information of genes and traits in B. oleracea. All the markers on the map will be transferable and could be used for the construction of other genetic maps. PMID- 23033897 TI - Beneficial effects of microwave-assisted heating versus conventional heating in noble metal nanoparticle synthesis. AB - An extensive comparative study of the effects of microwave versus conventional heating on the nucleation and growth of near-monodisperse Rh, Pd, and Pt nanoparticles has revealed distinct and preferential effects of the microwave heating method. A one-pot synthetic method has been investigated, which combines nucleation and growth in a single reaction via precise control over the precursor addition rate. Using this method, microwave-assisted heating enables the convenient preparation of polymer-capped nanoparticles with improved monodispersity, morphological control, and higher crystallinity, compared with samples heated conventionally under otherwise identical conditions. Extensive studies of Rh nanoparticle formation reveal fundamental differences during the nucleation phase that is directly dependent on the heating method; microwave irradiation was found to provide more uniform seeds for the subsequent growth of larger nanostructures of desired size and surface structure. Nanoparticle growth kinetics are also markedly different under microwave heating. While conventional heating generally yields particles with mixed morphologies, microwave synthesis consistently provides a majority of tetrahedral particles at intermediate sizes (5-7 nm) or larger cubes (8+ nm) upon further growth. High-resolution transmission electron microscopy indicates that Rh seeds and larger nanoparticles obtained from microwave-assisted synthesis are more highly crystalline and faceted versus their conventionally prepared counterparts. Microwave-prepared Rh nanoparticles also show approximately twice the catalytic activity of similar sized conventionally prepared particles, as demonstrated in the vapor-phase hydrogenation of cyclohexene. Ligand exchange reactions to replace polymer capping agents with molecular stabilizing agents are also easily facilitated under microwave heating, due to the excitation of polar organic moieties; the ligand exchange proceeds with excellent retention of nanoparticle size and structure. PMID- 23033898 TI - p63 as a prognostic marker for giant cell tumor of bone. AB - BACKGROUND AND PURPOSE: Giant cell tumor of bone (GCT) is sometimes difficult to distinguish from other giant-cell-rich tumors such as chondroblastoma (CHB) and aneurysmal bone cyst (ABC). The usefulness of p63 as a diagnostic marker for GCT is controversial. While there have been no reports about p63 as a prognostic marker for local recurrence, various p63-positive rates in GCT have been reported. The purpose of this study was to investigate retrospectively whether p63 is useful as a diagnostic marker and/or a prognostic marker for local recurrence of GCT. METHODS: This study included 36 patients diagnosed with either GCT (n = 16), CHB (n = 9), ABC (n = 7), or non-ossifying fibroma (NOF) (n = 4). p63 immunostaining was performed for all specimens. The mean p63-positive rate was compared with the four diseases and between the recurrent and non-recurrent cases of GCT. RESULTS: Although the mean p63-positive rate for GCT (36.3%) was statistically higher than that of all other diseases examined (CHB: 15.2%; ABC: 5.8%; NOF: 3.4%), p63 was not specific for GCT. The mean p63-positive rate for recurrent GCT cases (73.6%) was statistically higher than that for non-recurrent cases (29.1%). CONCLUSION: In the diagnosis of GCT, p63 is a useful but not a conclusive marker. However, p63 did appear to indicate the biological aggressiveness of GCT. Therefore, p63 may help surgeons to estimate the risk of recurrence after surgery and help them to choose the best treatment for each GCT case. PMID- 23033899 TI - Clinical features of autoimmune hepatitis and comparison of two diagnostic criteria in Korea: a nationwide, multicenter study. AB - BACKGROUND AND AIM: As a rare liver disease, little is known about autoimmune hepatitis (AIH). This study investigated the clinical features and compared two diagnostic criteria of AIH in Korea. METHODS: A nationwide, multicenter, retrospective analysis was done of data of adult patients diagnosed with AIH from January 2005 to December 2009. RESULTS: The enrolled patients (n = 343; mean age, 52.8 years; range, 19-87 years; 12% male, 88% female) met diagnostic criteria of AIH according to the revised original criteria (n = 311) or the simplified criteria (n = 250). At diagnosis, 30.6% were asymptomatic, 22.7% were cirrhotic, and 4.3% displayed hepatic decompensation. The positive results for anti-nuclear antibody, smooth muscle antibody, and anti-liver/kidney microsomal antibody were 94.2%, 23.0%, and 2.9%, respectively. Definite AIH and probable AIH according to the revised original criteria were 24.8% and 65.3%, respectively, while those according to the simplified criteria were 34.4% and 38.5%, respectively. The diagnostic sensitivity and positive predictive value of simplified criteria in comparison with the revised original criteria were 69.9% and 86.4%, respectively. As an initial therapy, corticosteroid (37.7%) or corticosteroid with azathioprine (36.8%) was administered. Remission, incomplete response, and treatment failure were noted with 85.7%, 10.5%, and 3.9% of patients, respectively. CONCLUSIONS: Autoimmune hepatitis in Korea is mostly type I, showing a mean age of 53 years with comparable clinical features to other countries. The concordant rate of the two diagnostic criteria was rather low with modest sensitivity of the simplified criteria. Further studies on the validation of the diagnostic criteria are warranted. PMID- 23033901 TI - Determining postmortem interval using glycoproteinous adhesion deposits by Balanus improvisus on human skeletal and dental remains. AB - An anthropological analysis was conducted on skeletal and dental remains brought to the Galveston County Medical Examiner's office. The skeletal remains were dry, fragmented, and absent of typical fluvial characteristics. During microscopic examination, semitransparent, circular objects were discovered on the dentition, the mandible, tibial plateau, and distal femur. The objects were glycoproteinous adhesions deposited by the acorn barnacle, Balanus improvisus. B. improvisus is an intertidal barnacle found in estuaries in Galveston Bay. Basal diameter of the adhesions on the dentition were significantly smaller than those found on the postcranial bones (p = 0.010), indicating two consecutive cohorts adhered to the bone and dentition. As settlement typically occurs once a year, this would indicate that the remains were in the fluvial environment for at least 375-410 days. It is important in geographic areas that have prevalent fluvial environments that human remains, particularly dentition, are microscopically examined for marine life evidence. PMID- 23033903 TI - Effect of dirty-hold time on cleaning process of pharmaceutical equipment. AB - The work was aimed at the evaluation of a cleanliness of pharmaceutical equipments after the end of the production and subsequent cleaning process. The influence of a dirty-hold time, a time interval between the end of the production period and the beginning of the cleaning process on its efficiency and the cleanliness of the equipment has been studied. The evaluation was performed for commercial tablet antihypertensive formulation with API losartan potassium. Sampling was carried out by a wet-swabbing method from the equipments and consequently obtained samples were analytically evaluated using HPLC. In the production of the concerned pharmaceutical, it has been found that the cleaning process is properly designed and validated. Despite the concentration of losartan in swabs from the equipment was in all cases within the limits of acceptance criteria, the effect of the dirty-hold time was proved. In the equipments with long hold-time period, the monitored substance was found in substantially higher concentrations. PMID- 23033904 TI - Reduced incidence of end stage renal disease among the elderly in Denmark: an observational study. AB - BACKGROUND: A number of studies during the nineties have shown that antihypertensive therapy, particularly using RAS blockade, can reduce uremia progression, and ESRD incidence. METHODS: National incidence rates were studied of end stage renal disease (ESRD) for Denmark between 1990 and 2011, and of national prescription of antihypertensive drugs between 1995 and 2010, in order to investigate whether prescription rates had changed, and whether the expected change in ESRD had materialized. The Danish Nephrology Registry (DNR) is incident and comprehensive. Incidence rates were classified according to renal diagnosis. RESULTS: ESRD incidence was constant for age groups <60 years. Incidence rates rose during the nineties for all cohorts >60 years. Since 2001 rates for subjects 60-70 years have fallen from 400 ppm/yr to 234, and since 2002 for subjects 70-80 years from 592 to 398. The incidence of patients >80 years has increased to 341. The falling incidence for patients 60-80 years was distributed among a number of diagnoses. Since 1995 national antihypertensive drug therapy has increased from 24.5 defined daily doses (DDD)/citizen/yr to 101.3, and the proportion using renin-angiotensin system (RAS) blockade from 34 to 58%. CONCLUSIONS: This national study has shown a reduction in actively treated ESRD incidence among patients aged 60-80 years. It is possible that this is the result of increased antihypertensive prescription rates, particularly with RAS blockade. If it is assumed that therapeutic intervention is the cause of the observed reduced incidence, ESRD incidence has been reduced by 33.8 ppm/yr, prevalence by 121 ppm, and ESRD expenditure by 6 ?/citizen/yr. PMID- 23033902 TI - Trans-Golgi proteins participate in the control of lipid droplet and chylomicron formation. AB - LDs (lipid droplets) carrying TAG (triacylglycerol) and cholesteryl esters are emerging as dynamic cellular organelles that are generated in nearly every cell. They play a key role in lipid and membrane homoeostasis. Abnormal LD dynamics are associated with the pathophysiology of many metabolic diseases, such as obesity, diabetes, atherosclerosis, fatty liver and even cancer. Chylomicrons, stable droplets also consisting of TAG and cholesterol are generated in the intestinal epithelium to transport exogenous (dietary) lipids after meals from the small intestine to tissues for degradation. Defective chylomicron formation is responsible for inherited lipoprotein deficiencies, including abetalipoproteinaemia, hypobetalipoproteinaemia and chylomicron retention disease. These are disorders sharing characteristics such as fat malabsorption, low levels of circulating lipids and fat-soluble vitamins, failure to thrive in early childhood, ataxic neuropathy and visual impairment. Thus understanding the molecular mechanisms governing the dynamics of LDs and chylomicrons, namely, their biogenesis, growth, maintenance and degradation, will not only clarify their molecular role, but might also provide additional indications to treatment of metabolic diseases. In this review, we highlight the role of two small GTPases [ARFRP1 (ADP-ribosylation factor related protein 1) and ARL1 (ADP-ribosylation factor-like 1)] and their downstream targets acting on the trans-Golgi (Golgins and Rab proteins) on LD and chylomicron formation. PMID- 23033905 TI - The Legionella pneumophila orphan sensor kinase LqsT regulates competence and pathogen-host interactions as a component of the LAI-1 circuit. AB - Legionella pneumophila is an amoeba-resistant opportunistic pathogen that performs cell-cell communication through the signalling molecule 3 hydroxypentadecane-4-one (LAI-1, Legionella autoinducer-1). The lqs (Legionella quorum sensing) gene cluster encodes the LAI-1 autoinducer synthase LqsA, the cognate sensor kinase LqsS and the response regulator LqsR. Here we show that the Lqs system includes an 'orphan' homologue of LqsS termed LqsT. Compared with wild type L. pneumophila, strains lacking lqsT or both lqsS and lqsT show increased salt resistance, greatly enhanced natural competence for DNA acquisition and impaired uptake by phagocytes. Sensitive novel single round growth assays and competition experiments using Acanthamoeba castellanii revealed that DeltalqsT and DeltalqsS-DeltalqsT, as well as DeltalqsA and other lqs mutant strains are impaired for intracellular growth and cannot compete against wild-type bacteria upon co-infection. In contrast to the DeltalqsS strain, DeltalqsT does not produce extracellular filaments. The phenotypes of the DeltalqsS-DeltalqsT strain are partially complemented by either lqsT or lqsS, but are not reversed by overexpression of lqsA, suggesting that LqsT and LqsS are the sole LAI-1 responsive sensor kinases in L. pneumophila. In agreement with the different phenotypes of the DeltalqsT and DeltalqsS strains, lqsT and lqsS are differentially expressed in the post-exponential growth phase, and transcriptome studies indicated that 90% of the genes, which are downregulated in absence of lqsT, are upregulated in absence of lqsS. Reciprocally regulated genes encode components of a 133 kb genomic 'fitness island' or translocated effector proteins implicated in virulence. Together, these results reveal a unique organization of the L. pneumophila Lqs system comprising two partially antagonistic LAI-1 responsive sensor kinases, LqsT and LqsS, which regulate distinct pools of genes implicated in pathogen-host cell interactions, competence, expression of a genomic island or production of extracellular filaments. PMID- 23033907 TI - Diet-dependent modulation of hippocampal expression of endocannabinoid signaling related proteins in cannabinoid antagonist-treated obese rats. AB - Diet-induced obesity produces changes in endocannabinoid signaling (ECS), influencing the regulation of energy homeostasis. Recently, we demonstrated that, in high-fat-diet-fed rats, blockade of CB1 receptor by AM251 not only reduced body weight but also increased adult neurogenesis in the hippocampus, suggesting an influence of diet on hippocampal cannabinoid function. To further explore the role of hippocampal ECS in high-fat-diet-induced obesity, we investigated whether the immunohistochemical expression of the enzymes that produce (diacylglycerol lipase alpha and N-acyl phosphatidylethanolamine phospholipase D) and degrade (monoacylglycerol lipase and fatty acid amino hydrolase) endocannabinoids may be altered in the hippocampus of AM251 (3 mg/kg)-treated rats fed three different diets: standard diet (normal chow), high-carbohydrate diet (70% carbohydrate) and high-fat diet (60% fat). Results indicated that AM251 reduced caloric intake and body weight gain, and induced a modulation of the expression of ECS-related proteins in the hippocampus of animals exposed to hypercaloric diets. These effects were differentially restricted to either the 2-arachinodoyl glycerol or anandamide signaling pathways, in a diet-dependent manner. AM251-treated rats fed the high-carbohydrate diet showed a reduction of the diacylglycerol lipase alpha : monoacylglycerol lipase ratio, whereas AM251-treated rats fed the high-fat diet showed a decrease of the N-acyl phosphatidylethanolamine phospholipase D : fatty acid amino hydrolase ratio. These results are consistent with the reduced levels of hippocampal endocannabinoids found after food restriction. Regarding the CB1 expression, AM251 induced specific changes focused in the CA1 stratum pyramidale of high-fat-diet-fed rats. These findings indicated that the cannabinoid antagonist AM251 modulates ECS-related proteins in the rat hippocampus in a diet specific manner. Overall, these results suggest that the hippocampal ECS participates in the physiological adaptations to different caloric diets. PMID- 23033908 TI - Intratesticular and subcutaneous lidocaine alters the intraoperative haemodynamic responses and heart rate variability in male cats undergoing castration. AB - OBJECTIVE: To evaluate the usefulness of intratesticular and subcutaneous lidocaine in alleviating the intraoperative nociceptive response to castration, measured by pulse rate (PR) and mean arterial pressure (MAP), and to test the applicability of heart rate variability (HRV) analysis in assessing this response. STUDY DESIGN: Randomized, controlled, observer-blinded experimental trial. ANIMALS: Thirty-nine healthy male cats admitted for castration. METHODS: One group received general anaesthesia and served as control group (GA), while the treatment group (LA) additionally received local anaesthesia (lidocaine 2 mg kg(-1)) intratesticularly and subcutaneously. PR and MAP were recorded at anaesthesia baseline (T0), treatment (T1), incision left testicle (T2), traction on spermatic cord (T3), tightening of the autoligature and resection of the cord (T4), incision on the right side (T5), traction on spermatic cord (T6), and tightening of the autoligature and resection of cord (T7). HRV analysis was divided into three 5-minute intervals: baseline (H0), treatment (H1), and surgery (H2). RESULTS: There were significant increases in PR and MAP for both groups during surgery from T3 onwards; however, the increase in the treatment group (LA) was significantly lower than for the control group (GA). For HRV analysis, significant differences were found between groups in the following parameters during surgery: TP (total power), VLF (very low frequency), SDNN (standard deviation of NN intervals [= the interval between two consecutive R-waves in the ECG]), and TI (triangular index), which were lower in the LA group. Mean NN was significantly lower in the GA group, whereas LF (low frequency) and LFn (low frequency, normalized value) were lower in the LA group. HF (high frequency) and HFn (high frequency, normalized value) decreased significantly from H1 to H2 in both groups. CONCLUSIONS AND CLINICAL RELEVANCE: The study showed that the nociceptive response to surgery was alleviated by the use of intratesticular and subcutaneous lidocaine and that HRV analysis is a promising research tool to estimate intraoperative nociception in cats during general anaesthesia. PMID- 23033909 TI - The entropies of adsorbed molecules. AB - Adsorbed molecules are involved in many reactions on solid surface that are of great technological importance. As such, there has been tremendous effort worldwide to learn how to predict reaction rates and equilibrium constants for reactions involving adsorbed molecules. Theoretical calculation of both the rate and equilibrium constants for such reactions requires knowing the entropy and enthalpy of the adsorbed molecule. While much effort has been devoted to measuring and calculating the enthalpies of well-defined adsorbates, few measurements of the entropies of adsorbates have been reported. We present here a new way to determine the standard entropies of adsorbed molecules (S(ad)(0)) on single crystal surfaces from temperature programmed desorption data, prove its accuracy by comparison to entropies measured by equilibrium methods, and apply it to published data to extract new entropies. Most importantly, when combined with reported entropies, we find that at high coverage, they linearly track the entropy of the gas-phase molecule at the same temperature (T), such that S(ad)(0)(T) = 0.70 S(gas)(0)(T) - 3.3R (R = the gas constant), with a standard deviation of only 2R over a range of 50R. These entropies, which are ~2/3 of the gas, are huge compared to most theoretical predictions. This result can be extended to reliably predict prefactors in the Arrhenius rate constant for surface reactions involving such species, as proven here for desorption. PMID- 23033911 TI - Influence of in vitro hemolysis on nucleated red blood cells and reticulocyte counts. AB - INTRODUCTION: Nucleated red blood cells (NRBCs) and reticulocytes are early and important measures of red blood cells' (RBCs) turnover, but little is known on how spurious hemolysis may affect the reliability of these parameters. MATERIALS AND METHODS: Ten EDTA-anticoagulated samples were divided into three aliquots. The first was immediately tested, where-as the others (defined A and B) were mechanically hemolyzed by aspiration 5 and 10 times through a small-gauge needle. RBC, NRBC, and reticulocyte counts were performed on Sysmex XE-2100. RESULTS: An increasing amount of hemolysis was produced in hemolyzed aliquots A and B. The RBC and reticulocyte counts progressively decreased from the nonhemolyzed sample to hemolyzed aliquots 'A' and 'B'. The NRBC count increased in 3 of the 10 samples and decreased in the remaining seven. CONCLUSIONS: Hemolysis of venous blood samples may seriously jeopardize NRBC and reticulocyte counts. PMID- 23033910 TI - Patients' engagement in primary care: powerlessness and compounding jeopardy. A qualitative study. AB - BACKGROUND: Primary health care does not adequately respond to populations known to have high needs such as those with compounding jeopardy from chronic conditions, poverty, minority status and age; as such populations report powerlessness. OBJECTIVE: To explore what poor older adults with chronic conditions who mostly belong to ethnic minority groups say they want from clinicians. SETTING AND PARTICIPANTS: Participants were older adults whose chronic conditions were severe enough to require hospital admission more than twice in the previous 12 months. All participants lived in poor localities in Auckland, New Zealand's largest city. METHODS: Forty-two in-depth interviews were conducted and analysed using qualitative description. RESULTS: An outward acceptance of health care belied an underlying dissatisfaction with low engagement. Participants did not feel heard and wanted information conveyed in a way that indicated clinicians understood them in the context of their lives. Powerlessness, anger, frustration and non-concordance were frequent responses. DISCUSSION AND CONCLUSIONS: Despite socio-cultural and disease-related complexity, patients pursue the (unrealised) ideal of an engaged therapeutic relationship with an understanding clinician. Powerlessness means that the onus is upon the health system and the clinician to engage. Engagement means building a relationship on the basis of social, cultural and clinical knowledge and demonstrating a shift in the way clinicians choose to think and interact in patient care. Respectful listening and questioning can deepen clinicians' awareness of patients' most important concerns. Enabling patients to direct the consultation is a way to integrate clinician expertise with what patients need and value. PMID- 23033912 TI - Interferon regulation factor-3 is a critical regulator of the mature of dendritic cells from mice. AB - Interferon regulatory factor-3 (IRF-3) plays an important role in virus and double-stranded RNA-mediated induction of type I interferon and RANTES (regulated on activation normal T cell expressed and secreted), DNA damage signalling, tumour suppression and virus-induced apoptosis. IRF-3 had recently been shown to contribute to T-cell activation in response to pathogens, which implicated an extensive immunological role for IRF-3. Dendritic cells (DCs) played critical roles as professional APCs in the development of immune responses. However, it was unclear whether IRF-3 had any effect on phenotype or function of DCs. In this study, it was shown that IRF-3 acted as a promoter of DC maturation. The level of IRF-3 expression was transiently upregulated and accumulated in the nucleus in TNF-alpha-induced immune maturation of mice DC cells. Knockdown of IRF-3 by small interfering RNA in DC cells resulted in both phenotypic and functional immaturation, even without TNF-alpha treatment. Overall, our data demonstrated for the first time that IRF-3 was a critical regulator of mice DC maturation. PMID- 23033913 TI - Quantitative PCR of ear discharge from Indigenous Australian children with acute otitis media with perforation supports a role for Alloiococcus otitidis as a secondary pathogen. AB - BACKGROUND: Otitis media is endemic in remote Indigenous communities of Australia's Northern Territory. Alloiococcus otitidis is an outer ear commensal and putative middle ear pathogen that has not previously been described in acute otitis media (AOM) in this population. The aims of this study were to determine the presence, antibiotic susceptibility and bacterial load of A. otitidis in nasopharyngeal and ear discharge swabs collected from Indigenous Australian children with AOM with perforation. METHODS: Paired nasopharyngeal and ear discharge swabs from 27 children with AOM with perforation were tested by A. otitidis quantitative PCR (qPCR). Positive swabs were cultured for 21 days. Total and respiratory pathogen bacterial loads in A. otitidis-positive swabs were determined by qPCR. RESULTS: A. otitidis was detected by qPCR in 11 ear discharge swabs from 10 of 27 (37%) children, but was not detected in paired nasopharyngeal swabs. A. otitidis was cultured from 5 of 11 qPCR-positive swabs from four children. All A. otitidis isolates had minimum inhibitory concentrations consistent with macrolide resistance. All A. otitidis qPCR-positive swabs were culture-positive for other bacteria. A. otitidis bacterial load ranged from 2.2 * 104-1.1 * 108 cells/swab (median 1.8 * 105 cells/swab). The relative abundance of A. otitidis ranged from 0.01% to 34% of the total bacterial load (median 0.7%). In 6 of 11 qPCR-positive swabs the A. otitidis relative abundance was <1% and in 5 of 11 it was between 2% and 34%. The A. otitidis bacterial load and relative abundance measures were comparable to that of Haemophilus influenzae. CONCLUSIONS: A. otitidis can be a dominant species in the bacterial communities present in the ear discharge of Indigenous children with AOM with perforation. The absence of A. otitidis in nasopharyngeal swabs suggests the ear canal as the likely primary reservoir. The significance of A. otitidis at low relative abundance is unclear; however, at higher relative abundance it may be contributing to the associated inflammation. Further studies to better understand A. otitidis as a secondary otopathogen are warranted, particularly in populations at high-risk of progression to chronic suppurative otitis media and where macrolide therapies are being used. PMID- 23033914 TI - Phosphate handling in CKD-MBD from stage 3 to dialysis and the three strengths of lanthanum carbonate. AB - INTRODUCTION: High phosphate levels are associated with unfavorable outcomes in ESRD. Recent data suggested that phosphate levels within the normal range are equally associated with poor outcomes in the community and CKD stage 3 - 4. Several concept papers support the potential role of phosphate load as a first line toxin in the beginning of CKD-MBD processes via the activation of FGF23 cascade. Phosphate load is thereafter involved in the progression of vascular calcification (VC) and bone disorder typical of CKD-MBD. AREAS COVERED: Herein the authors cover the recent evidence on the pathophysiology of phosphate handling through the natural history of CKD, with particular emphasis on FGF23 cascade, its potential surrogate markers, VC and bone disorder. The major characteristics of lanthanum carbonate are therefore discussed, focusing on its potential advantages for the treatment of difficult cases in CKD-MBD. EXPERT OPINION: Lanthanum carbonate, being the most potent calcium-free phosphate binder available in clinical practice, could be decisive for those cases where controlling phosphate load is complicated by poor compliance to medications, stubborn high phosphorus intake, extended VC and bone disorders. PMID- 23033915 TI - SERE: single-parameter quality control and sample comparison for RNA-Seq. AB - BACKGROUND: Assessing the reliability of experimental replicates (or global alterations corresponding to different experimental conditions) is a critical step in analyzing RNA-Seq data. Pearson's correlation coefficient r has been widely used in the RNA-Seq field even though its statistical characteristics may be poorly suited to the task. RESULTS: Here we present a single-parameter test procedure for count data, the Simple Error Ratio Estimate (SERE), that can determine whether two RNA-Seq libraries are faithful replicates or globally different. Benchmarking shows that the interpretation of SERE is unambiguous regardless of the total read count or the range of expression differences among bins (exons or genes), a score of 1 indicating faithful replication (i.e., samples are affected only by Poisson variation of individual counts), a score of 0 indicating data duplication, and scores >1 corresponding to true global differences between RNA-Seq libraries. On the contrary the interpretation of Pearson's r is generally ambiguous and highly dependent on sequencing depth and the range of expression levels inherent to the sample (difference between lowest and highest bin count). Cohen's simple Kappa results are also ambiguous and are highly dependent on the choice of bins. For quantifying global sample differences SERE performs similarly to a measure based on the negative binomial distribution yet is simpler to compute. CONCLUSIONS: SERE can therefore serve as a straightforward and reliable statistical procedure for the global assessment of pairs or large groups of RNA-Seq datasets by a single statistical parameter. PMID- 23033917 TI - Docking of ubiquitin to gold nanoparticles. AB - Protein-nanoparticle associations have important applications in nanoscience and nanotechnology such as targeted drug delivery and theranostics. However, the mechanisms by which proteins recognize nanoparticles and the determinants of specificity are still poorly understood at the microscopic level. Gold is a promising material in nanoparticles for nanobiotechnology applications because of the ease of its functionalization and its tunable optical properties. Ubiquitin is a small, cysteine-free protein (ubiquitous in eukaryotes) whose binding to gold nanoparticles has been characterized recently by nuclear magnetic resonance (NMR). To reveal the molecular basis of these protein-nanoparticle interactions, we performed simulations at multiple levels (ab initio quantum mechanics, classical molecular dynamics and Brownian dynamics) and compared the results with experimental data (circular dichroism and NMR). The results provide a model of the ensemble of structures constituting the ubiquitin-gold surface complex, and insights into the driving forces for the binding of ubiquitin to gold nanoparticles, the role of nanoparticle surfactants (citrate) in the association process, and the origin of the perturbations in the NMR chemical shifts. PMID- 23033916 TI - A mathematical modeling approach to quantify the role of phlebotomy losses and need for transfusions in neonatal anemia. AB - BACKGROUND: Very preterm infants commonly develop anemia requiring multiple red blood cell transfusions (RBCTx). This is in part attributable to heavy laboratory phlebotomy loss. Quantification of the extent to which laboratory blood loss contributes to anemia sufficient to prompt RBCTx has not been examined. STUDY DESIGN AND METHODS: Twenty-six preterm infants weighing less than 1500 g at birth requiring ventilator support who received one or more RBCTx were intensively studied during the first month of life. Hemoglobin (Hb) loss via laboratory blood loss and RBC senescence and Hb gain from RBCTx were precisely accounted for in a Hb mass balance mathematical model developed to assess the impact of phlebotomy on RBCTx when restrictive RBCTx criteria were applied. RESULTS: Study subjects had a birth weight of 880 +/- 240 g (mean +/- SD) and a Hb level of 14.4 +/- 2.4 g/dL at birth and received 3.81 +/- 2.15 RBCTx during the study period. Modeling indicated that even with the total elimination of laboratory phlebotomy loss, a reduction of 41% to 48% in RBCTx was achievable. CONCLUSION: The present modeling results indicate that while phlebotomy reduction can significantly decrease the number of RBCTx administered to preterm infants, total elimination of all RBCTx will likely require other approaches, for example, stimulation of erythropoiesis with erythropoiesis-stimulating agents. PMID- 23033918 TI - Controlled suppression of the photoluminescence superlinear dependence on excitation density in quantum dots. AB - : We have shown that it is possible to tune, up to complete suppression, the photoluminescence superlinear dependence on the excitation density in quantum dot samples at high temperatures by annealing treatments. The effect has been attributed to the reduction of the defectivity of the material induced by annealing. PMID- 23033920 TI - Regulation of JAK2 activation by Janus homology 2: evidence from molecular dynamics simulations. AB - Janus kinase 2 (JAK2) is a protein tyrosine kinase implicated in signaling by specific members of the cytokine receptor family. Although it has been established that the JAK2 tyrosine kinase is negatively regulated by the JAK homology 2 (JH2) pseudokinase domain, the underlying mechanism of JH2 mediated regulation remains elusive. To elucidate the regulation of JAK2 kinase, we have built a structural model for the kinase and pseudokinase domains of JAK2. An asymmetric dimer is proposed, in which the kinase domain JH1 occupies a position where it could not be activated. We investigate the dynamic and energetic properties of the dimer by molecular dynamics simulation. JAK2 activation requires the two domains to be dissociated and rearranged in a form such that the JH1 kinase domain can adopt an active conformation. The significance of the above mechanism is emphasized by the finding that the activating V617F mutation destabilizes JH1-JH2 association in the proposed asymmetric dimer. Thus abrogation of the domain-domain interaction seems to be a possible first step for the structural rearrangement of the two domains, resulting in constitutive activation of JAK2 by the V617F mutation. PMID- 23033919 TI - The effect of a dietary supplement (N-oleyl-phosphatidyl-ethanolamine and epigallocatechin gallate) on dietary compliance and body fat loss in adults who are overweight: a double-blind, randomized control trial. AB - BACKGROUND: A dietary supplement containing a blend of 170 mg of N-oleyl phosphatidylethanolamine (NOPE) and 100 mg of epigallocatechin-3-gallate (EGCG) has been shown to improve compliance to low caloric diets. Considering the cost of dietary ingredients, many manufacturers attempt to determine the lowest efficacious dose. Thus, the purpose of this study was to evaluate the efficacy of 8-weeks of supplementation with a daily intake of 120 mg of NOPE and 105 mg of EGCG in conjunction with a low caloric diet and regular, moderate exercise on dietary compliance in healthy, overweight adults. An additional purpose was to examine the effect of this supplement/diet/exercise paradigm on changes in body composition, sensation of appetite, mood and severity of binge eating. METHODS: Fifty healthy, overweight (BMI > 25 m.kg2) men (15) and women (35) (SUP; n = 25; 32.7 +/- 13.75 y; BMI = 33.4 +/- 6.2; PLA; n = 25, 34.3 +/- 12.7 years; BMI = 33.2 +/- 6.8) were recruited for a double-blind, placebo controlled study. Each volunteer was randomly assigned to either the supplement (SUP; n = 25) or placebo group (PLA; n = 25). Based upon a self-reported 3-day dietary recall all volunteers were recommended a 500 kcal or 30% (maximum of 1000 kcal) reduction in caloric intake. Volunteers were also encouraged to exercise 30 minutes per day, three times per week. RESULTS: Subjects in SUP were significantly more compliant (x2 = 3.86, p = 0.049) in maintaining a low caloric diet at week 4, but this was not able to be maintained through the 8-week study. In addition, a significant difference in mood, feelings of fatigue and confusion were noted between the groups at week 4, but again not maintained by week 8 where only feelings of tension were improved. No differences between groups (p > 0.05) were observed for body mass, body composition, feelings of hunger, and binge eating after eight weeks. CONCLUSION: Supplementing with a combination of 120 mg of NOPE and 105 mg of EGCG does appear to enhance compliance to a low caloric diet and improve mood for 4 -weeks, but loses its effectiveness by week 8. PMID- 23033921 TI - Single cell analysis of gene expression patterns during carbon starvation in Bacillus subtilis reveals large phenotypic variation. AB - How cells dynamically respond to fluctuating environmental conditions depends on the architecture and noise of the underlying genetic circuits. Most work characterizing stress pathways in the model bacterium Bacillus subtilis has been performed on bulk cultures using ensemble assays. However, investigating the single cell response to stress is important since noise might generate significant phenotypic heterogeneity. Here, we study the stress response to carbon source starvation and compare both population and single cell data. Using a top-down approach, we investigate the transcriptional dynamics of various stress-related genes of B. subtilis in response to carbon source starvation and to increased cell density. Our data reveal that most of the tested gene regulatory networks respond highly heterogeneously to starvation and cells show a large degree of variation in gene expression. The level of highly dynamic diversification within B. subtilis populations under changing environments reflects the necessity to study cells at the single cell level. PMID- 23033922 TI - A novel local recycling mechanism that enhances enteric bioavailability of flavonoids and prolongs their residence time in the gut. AB - Recycling in the gastrointestinal tract is important for endogenous substances such as bile acids and for xenobiotics such as flavonoids. Although both enterohepatic and enteric recycling mechanisms are well recognized, no one has discussed the third recycling mechanism for glucuronides: local recycling. The intestinal absorption and metabolism of wogonin and wogonoside (wogonin-7 glucuronide) was characterized by using a four-site perfused rat intestinal model, and hydrolysis of wogonoside was measured in various enzyme preparations. In the perfusion model, the wogonoside and wogonin were interconverted in all four perfused segments. Absorption of wogonoside and conversion to its aglycon at the upper small intestine was inhibited in the presence of a glucuronidase inhibitor (saccharolactone) but was not inhibited by lactase phlorizin hydrolase (LPH) inhibitor gluconolactone or antibiotics. Further investigation indicated that hydrolysis of wogonoside in the blank intestinal perfusate was not correlated with bacterial counts. Kinetic studies indicated that K(m) values from blank duodenal and jejunal perfusate were essentially identical to the K(m) values from intestinal S9 fraction but were much higher (>2-fold) than those from the microbial enzyme extract. Lastly, jejunal perfusate and S9 fraction share the same optimal pH, which was different from those of fecal extract. In conclusion, local recycling of wogonin and wogonoside is the first demonstrated example that this novel mechanism is functional in the upper small intestine without significant contribution from bacteria beta-glucuronidase. PMID- 23033924 TI - Effect of fixed aqueous layer thickness of polymeric stabilizers on zeta potential and stability of aripiprazole nanosuspensions. AB - The aim of this study was to evaluate the effect of the thickness of adsorbed polymer layer (also known as Fixed Aqueous Layer Thickness, FALT) of polymeric stabilizers on zeta potential and stability of nanoparticles in a suspension. Aripiprazole, a poorly water soluble drug was used as a model drug to evaluate rationale for increased FALT and to understand the effect of hydrophilicity and hydrophobicity of polymeric stabilizers on FALT of aripiprazole nanosuspensions. The nanosuspensions were prepared by media milling and Pluronic F68, Pluronic F127, Hydroxypropyl methylcellulose (HPMC) and Hydroxypropyl cellulose (HPC) were used as polymeric stabilizers. The particle size (immediately after preparation and after 1 week of storage at 25 degrees C) and zeta potential of aripiprazole nanosuspensions were determined. For Pluronics, FALT was determined theoretically whereas for HPMC and HPC it was calculated as Debye Huckel parameter from the zeta potential dependence on the ionic strength. An increase in FALT resulted in reduced zeta potential. With an increase in FALT of polymers used, the stability of nanosuspensions showed improvement. Furthermore, a linear correlation was shown to exist between the FALT and length of hydrophilic chains in Pluronics. PMID- 23033925 TI - Description of two novel HLA-B alleles, B*37:34 and B*44:152. AB - Two novel HLA-B alleles were characterized. HLA-B*37:34 shows two nucleotide differences regarding B*37:10 at codons 79 (CGC>CGG) and 80 (ACC>ATC), resulting in one amino acid replacement at position 80 (T>I). HLA-B*44:152 differs from B*44:02:01 in one nucleotide at codon 81 (GCG>ACG) giving rise to a leucine to threonine substitution at position 81. PMID- 23033926 TI - Epoetin administrated after cardiac surgery: effects on renal function and inflammation in a randomized controlled study. AB - BACKGROUND: Experimentally, erythropoietin (EPO) has nephroprotective as well as immunomodulatory properties when administered after ischemic renal injury. We tested the hypothesis that different doses of recombinant human EPO administered to patients after cardiac surgery would minimize kidney lesions and the systemic inflammatory response, thereby decreasing acute kidney injury (AKI) incidence. METHODS: In this double-blinded randomized control study, 80 patients admitted to the ICU post-cardiac surgery were randomized by computer to receive intravenously isotonic saline (n = 40) versus alpha-Epoetin (n = 40): either 40000 IU (n = 20) or 20000 IU (n = 20). The study lasted one year. The primary outcome was the change in urinary NGAL concentration from baseline and 48 h after EPO injection. Creatinine, cystatine C and urinary NGAL levels were measured on the day of randomization and 2-4 days after EPO injection. To assess acute inflammatory response, serum cytokines (IL6 and IL8) were measured at randomization and four days after r-HuEPO injection. Patients and care-takers were blinded for the assignment. RESULTS: No patient was excluded after randomization. Patient groups did not differ in terms of age, gender, comorbidities and renal function at randomization. The rate of AKI assessed by AKIN criteria was 22.5% in our population. EPO treatment did not significantly modify the difference in uNGAl between 48 hours and randomization compared to placebo [2.5 ng/ml (-17.3; 22.5) vs 0.7 ng/ml (-31.77; 25.15), p = 0.77] and the incidence of AKI was similar. Inflammatory cytokines levels were not influenced by EPO treatment. Mortality and hospital stays were similar between the groups and no adverse event was recorded. CONCLUSION: In this randomized-controlled trial, alpha-Epoetin administrated after cardiac surgery, although safe, demonstrated neither nephroprotective nor anti-inflammatory properties. TRIAL REGISTRATION NUMBER: NCT00676234. PMID- 23033927 TI - Insect-bite-like reaction in patients with chronic lymphocytic leukemia: a study from the Israeli Chronic Lymphocytic Leukemia Study Group. AB - An insect-bite-like reaction is known to occur in patients with chronic lymphocytic leukemia (CLL). Most of the literature, however, consists of isolated case reports or small case series. The aim of this retrospective study was to review the national experience with insect-bite-like reaction in a large group of patients with CLL. The study cohort of patients with these skin reactions consisted of 48 patients (25 males, 23 females) of mean age 64.8 yr (range 33-89) at skin eruption. Data on clinical, histologic, immunophenotypic, and cytogenetic characteristics, treatment, and outcome were collected from the medical files. Mean time between diagnosis of CLL and appearance of the skin lesions was 3.1 yr (range -4 to 14 yr). The eruption was not related to disease activity or the course of the hematological disease. The eruption preceded the diagnosis of CLL in 10 patients (by 0-4 yr); and followed the diagnosis in 36; in 11 patients, it occurred during therapy for CLL and in nine after therapy. Mean duration of the skin findings was 21.5 months (range 0.3-132). The eruption usually presented in summer, although it occurred also at other times of the year, and predominantly affected the upper and lower limbs, although it also appeared on unexposed areas. Treatment included local ointments, antihistaminics, oral steroids, antibiotics, phototherapy, and dapsone with varying responses. Insect-bite-like reactions is a relatively common and disturbing skin reaction in CLL patients, it may be related to the immune dysregulation accompanying CLL and further exacerbated by external factors, including actual insect bites, chemoimmunotherapy, and pyogenic infection. PMID- 23033928 TI - Phosphorylated p38 and JNK MAPK proteins in hepatocellular carcinoma. AB - BACKGROUND: The p38 and JNK MAPK proteins function as key mediators in cellular responses to extracellular stimuli. Deregulated p38 and JNK expressions have been associated with cancer development. This study aimed to investigate the association of p-p38 and p-JNK levels of the cancerous tissues with hepatocellular carcinoma (HCC) development. MATERIALS AND METHODS: One hundred and four liver cancer tissues of patients with HCC who underwent curative resection were prospectively collected. The levels of activated/p-p38 and p-JNK were determined by the enzyme-linked immunosorbent assay. The associations of results with clinicopathological characteristics and overall survival were further statically analysed using chi-squared test, two-tailed Student's t-test and Kaplan-Meier survival curve. RESULTS: The p-p38 levels were significantly higher in the HCC patients with a larger tumour (>= 3 cm) and satellite tumour, and significantly correlated with the p-JNK levels. High p-p38 and low p-JNK expressions were associated with a poor survival in the patients with HCC (odds ratio, 4.24 and 0.20; P = 0.03 and 0.03, respectively). The Kaplan-Meier survival analysis showed that the HCC patients with high p-p38 expressions had a poor overall survival than those with low p-p38 expressions (P = 0.04), and a coexistent and high p-JNK expression remarkably improved this trend. CONCLUSIONS: Increasing p-p38 levels in HCC tissues were associated with tumour size and the formation of satellite tumours. High p-p38 expression could serve as a predictor for a poor survival for the patients with HCC. Simultaneous expression of p-JNK in HCC tissues might antagonize the promoting effect of p-p38 in human liver cancer. PMID- 23033929 TI - Release kinetics of calcium and quercetin from chewing gum as a novel antiplaque and antimicrobial device. AB - There is a growing interest in the use of anticariogenic and antimicrobial agents to prevent demineralization and promote remineralization of dental enamel for the prevention of oral diseases. The purpose of this study was to develop a novel chewing-system containing as Casein-Phosphopeptides-Amorphous-Calcium-Phosphate (CPP-ACP) as Quercetin (Qt) and evaluate their release using in vitro and in vivo experiments. In vitro and in vivo experimental protocols were designed to test the percentages of Ca from CPP-ACP and Qt released with time and their delivery rate from a chewing gum. The in vitro experiments were performed using a specifically designed chewing apparatus to test the release of Ca and Qt in artificial saliva in function of chewed time, while the in vivo experiments required a chew-out method with volunteers and the residual CPP-ACP and Qt present in the chewed gums was analyzed. This study demonstrated that both CPP ACP'Ca and Qt were released during chewing although CPP-ACP'Ca was released from the chewing gum in a slower and more controlled manner than Qt. They were also both effectively retained in the oral cavity for all the investigated chewing time and according to their monitored release concentrations they were able to serve as a novel antiplaque agent. This research concludes that both drugs were efficiently released during the mastication process to fully exploit their anti carious activity. PMID- 23033930 TI - Elucidation of pathophysiology and treatment of neuropathic pain. AB - Neuropathic pain, pain arising as a direct consequence of a lesion or disease affecting the somatosensory system, is relatively common, occurring in about 1% of the population. Studies in animal models describe a number of peripheral and central pathophysiological processes after nerve injury that would be the basis of underlying neuropathic pain mechanism. Additionally, neuro-imaging (positron emission tomography and functional magnetic resonance imaging) provides insights in brain mechanisms corresponding with mechanistic processes including allodynia, hyperalgesia, altered sensation, and spontaneous pain. A change in function, chemistry, and structures of neurons (neural plasticity) underlie the production of the altered sensitivity characteristics of neuropathic pain. Peripheral processes in neuropathic pain involve production of mediators (cytokines, protons, nerve growth factor), alterations in calcium channels, sodium channels, hyperpolarisation-activated nucleotide-gated ion channels, and potassium channels, phenotypic switches and sprouting of nerves endings, and involvement of the sympathetic nervous system. Stimulation of the N-Methyl-D-Aspartate receptor, activation of microglia, oligodendrocytes, and astrocytes, increased production of nerve growth factor and brain-derived neurotrophic factor together with loss of spinal inhibitory control are responsible for central neuron hyperexcitability and maintenance of neuropathic pain. Recent advances, including functional imaging techniques, in identification of peripheral and central sensitization mechanisms related to nervous system injury have increased potential for affecting pain research from both diagnostic as well as therapeutic view. Key brain regions involved in generating pharmacologically induced analgesia may be identified. Despite the progress in pain research, neuropathic pain is challenge to manage. Although numerous treatment options are available for relieving neuropathic pain, there is no consensus on the most appropriate treatment. However, recommendations can be proposed for first-line, second-line, and third line pharmacological treatments based on the level of evidence for the different treatment strategies. Available therapies shown to be effective in managing neuropathic pain include opioids and tramadol, anticonvulsants, antidepressants, topical treatments (lidocaine patch, capsaicin), and ketamine. Tricyclic antidepressants are often the first drugs selected to alleviate neuropathic pain (first-line pharmacological treatment). Although they are very effective in reducing pain in several neuropathic pain disorders, treatment may be compromised (and outweighed) by their side effects. In patients with a history of cardiovascular disorders, glaucoma, and urine retention, pregabalin and gabapentine are emerging as first-line treatment for neuropathic pain. In addition these anti-epileptic drugs have a favourable safety profile with minimal concerns regarding drug interactions and showing no interference with hepatic enzymes. Alternatively, opioids (oxycodone and methadone) and tramadol may alleviate nociceptive and neuropathic pain. Despite the numerous treatment options available for relieving neuropathic pain, no more than half of patients experience clinically meaningful pain relief, which is almost always partial but not complete relief. In addition, patients frequently experience burdensome adverse effects and as a consequence are often unable to tolerate the treatment. In the remaining patients, combination therapies using two or more analgesics with different mechanisms of action may also offer adequate pain relief. Although combination treatment is clinical practice and may result in greater pain relief, trials regarding different combinations of analgesics (which combination to use, occurrence of additive or supra-additive effects, sequential or concurrent treatment, adverse-event profiles of these analgesics, alone and in combination) are scarce. If medical treatments have failed, invasive therapies such as intrathecal drug administration and neurosurgical stimulation techniques (spinal cord stimulation, deep brain stimulation, and motor cortex stimulation) may be considered. PMID- 23033931 TI - Are there socioeconomic disparities in women having discussions on human papillomavirus vaccine with health care providers? AB - BACKGROUND: Human papillomavirus (HPV) vaccine recommendation by a health care provider (HCP) is an important predictor of vaccine receipt. We examined whether being of a minority race/ethnicity, having lower income and education, and the lack of health insurance and a regular HCP are each associated with a lower likelihood of a discussion on HPV vaccine occurring between a woman and her HCP. METHODS: A sample of 1,631 women aged 18 years and older was drawn from the 2007 Health Information National Trends Survey. Given that only a subgroup of women who were aware of the HPV vaccine were asked if they had a discussion with their HCPs, we estimated a probit model correcting for sample selection. RESULTS: Among those aware of the HPV vaccine, 17.3% of respondents reported having discussions on the vaccine with their HCPs. Compared with Whites, African Americans were less likely to be aware of the HPV vaccine but more likely to have discussions with their HCPs concerning the vaccine. A statistically significant association between lower income and education levels and a lower likelihood of HPV vaccine awareness was observed, but low levels of income and education did not appear to affect the probability of having HPV vaccine discussions with HCPs. CONCLUSIONS: Socioeconomically disadvantaged women did not show a lower propensity to have vaccine discussions with their HCPs, suggesting that HCPs can be a major catalyst in increasing vaccine receipt among the higher risk group. The results of the study suggest a two-pronged approach that seeks to raise vaccine awareness among socioeconomically disadvantaged women at the population level and encourages HCPs to intensify discussions about the HPV vaccine with patients. PMID- 23033932 TI - A Phase II study of pulse dose imatinib mesylate and weekly paclitaxel in patients aged 70 and over with advanced non-small cell lung cancer. AB - BACKGROUND: In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra tumoral delivery of paclitaxel, increasing response rate (RR). METHODS: This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged >= 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes. RESULTS: Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail. CONCLUSIONS: The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01011075. PMID- 23033933 TI - 'Talking the talk or walking the walk?' A bibliometric review of the literature on public involvement in health research published between 1995 and 2009. AB - OBJECTIVES: To characterise the literature on public involvement in health research published between 1995 and 2009. METHODS: Papers were identified from three systematic reviews, one narrative review and two bibliographies. The analysis identified journals where papers were published; countries of lead authors; types of public involved; health topic areas; and stages of research involving the public. Papers were also classified as to whether they were literature reviews or empirical studies; focused on participatory/action research; were qualitative, quantitative or mixed-method. The number of papers published per year was also examined. FINDINGS: Of the 683 papers identified, 297 were of USA origin and 223 were of UK origin. Of the 417 empirical papers: (i) participatory/action research approach was dominant, together with qualitative data collection methods; (ii) the stage of research the public was most involved was question identification; (iii) indigenous groups were most commonly involved; (iv) mental health was the most common health topic. Published studies peaked in 2006. CONCLUSIONS: The present study identifies publication patterns in public involvement in health research and provides evidence to suggest that researchers increasingly are 'walking the walk' with respect to public involvement, with empirical studies consistently out-numbering literature reviews from 1998. PMID- 23033935 TI - Erythrocyte and reticulocyte indices in the assessment of erythropoiesis activity and iron availability. AB - INTRODUCTION: Consequence of the imbalance between the erythroid marrow iron requirements and the actual supply is a reduction in red cell hemoglobin content, which causes hypochromic mature red cells and reticulocytes. Sysmex XE 5000 analyzer (Sysmex Corporation, Kobe, Japan) reports reticulocyte hemoglobin equivalent (Ret-He) and the percentages of erythrocyte subsets, including the hypochromic fraction (%Hypo-He). We study the value of these parameters of hemoglobinization in the evaluation of erythropoiesis and iron availability. METHODS: Ninety healthy subjects, 85 patients with chronic kidney disease (CKD) and 65 patients on dialysis (HD) receiving therapy and 91 patients with iron deficiency (IDA) were analyzed. Pearson's correlation, t-test for independent, and receiver operating characteristic (ROC) curve analysis were utilized. RESULTS: The results in the IDA group reflected the state of iron depletion (low ferritin), low iron availability (low MCH and high percentage of hypochromic red cells (%Hypo-He)), and iron-restricted erythropoiesis (low Ret-He). In the HD and CKD, the reticulocyte percentage showed the increased erythropoiesis, maintained due to treatment (Ret-He over 30 pg) and good iron availability, MCH within reference range and %Hypo-He slightly increased. The results of ROC curves analysis for the diagnosis of iron deficiency (gold standard sTfR > 21 nm) were as follows: Ret-He area under curve (AUC) 0.935 cutoff 29.8 pg, sensitivity 90.7%, specificity 83.1%. % Hypo-He AUC 0.925 cutoff 3.5%, sensitivity 87.3%, specificity 88.0%. CONCLUSIONS: Percentage of hypochromic red cells and Ret-He provide information about individual cell characteristics, so the hypochromic cells are detected and quantitated improving the evaluation of erythropoiesis and iron status. PMID- 23033934 TI - Systematic and searchable classification of cytochrome P450 proteins encoded by fungal and oomycete genomes. AB - BACKGROUND: Cytochrome P450 proteins (CYPs) play diverse and pivotal roles in fungal metabolism and adaptation to specific ecological niches. Fungal genomes encode extremely variable "CYPomes" ranging from one to more than 300 CYPs. Despite the rapid growth of sequenced fungal and oomycete genomes and the resulting influx of predicted CYPs, the vast majority of CYPs remain functionally uncharacterized. To facilitate the curation and functional and evolutionary studies of CYPs, we previously developed Fungal Cytochrome P450 Database (FCPD), which included CYPs from 70 fungal and oomycete species. Here we present a new version of FCPD (1.2) with more data and an improved classification scheme. RESULTS: The new database contains 22,940 CYPs from 213 species divided into 2,579 clusters and 115 clans. By optimizing the clustering pipeline, we were able to uncover 36 novel clans and to assign 153 orphan CYP families to specific clans. To augment their functional annotation, CYP clusters were mapped to David Nelson's P450 databases, which archive a total of 12,500 manually curated CYPs. Additionally, over 150 clusters were functionally classified based on sequence similarity to experimentally characterized CYPs. Comparative analysis of fungal and oomycete CYPomes revealed cases of both extreme expansion and contraction. The most dramatic expansions in fungi were observed in clans CYP58 and CYP68 (Pezizomycotina), clans CYP5150 and CYP63 (Agaricomycotina), and family CYP509 (Mucoromycotina). Although much of the extraordinary diversity of the pan-fungal CYPome can be attributed to gene duplication and adaptive divergence, our analysis also suggests a few potential horizontal gene transfer events. Updated families and clans can be accessed through the new version of the FCPD database. CONCLUSIONS: FCPD version 1.2 provides a systematic and searchable catalogue of 9,550 fungal CYP sequences (292 families) encoded by 108 fungal species and 147 CYP sequences (9 families) encoded by five oomycete species. In comparison to the first version, it offers a more comprehensive clan classification, is fully compatible with Nelson's P450 databases, and has expanded functional categorization. These features will facilitate functional annotation and classification of CYPs encoded by newly sequenced fungal and oomycete genomes. Additionally, the classification system will aid in studying the roles of CYPs in the evolution of fungal adaptation to specific ecological niches. PMID- 23033936 TI - English vowels produced by Cantonese-English bilingual speakers. AB - The present study attempted to test the postulate that sounds of a foreign language that are familiar can be produced with less accuracy than sounds that are new to second language (L2) learners. The first two formant frequencies (F1 and F2) were obtained from the 11 English monophthong vowels produced by 40 Cantonese-English (CE) bilingual and 40 native American English monolingual speakers. Based on F1 and F2, compact-diffuse (C-D) and grave-acute (G-A) values, and Euclidean Distance (ED) associated with the English vowels were evaluated and correlated with the perceived amount of accent present in the vowels. Results indicated that both male and female CE speakers exhibited different vowel spaces compared to their AE counterparts. While C-D and G-A indicated that acquisition of familiar and new vowels were not particularly different, ED values suggested better performance in CE speakers' productions of familiar vowels over new vowels. In conclusion, analyses based on spectral measurements obtained from the English vowel sounds produced by CE speakers did not provide favourable evidence to support the Speech Learning Model (SLM) proposed by Flege (1995) . Nevertheless, for both familiar and new sounds, English back vowels were found to be produced with greater inaccuracy than English front vowels. PMID- 23033937 TI - Chirality enriched (12,1) and (11,3) single-walled carbon nanotubes for biological imaging. AB - The intrinsic band gap photoluminescence of semiconducting single-walled carbon nanotubes (SWNTs) makes them promising biological imaging probes in the second near-infrared (NIR-II, 1.0-1.4 MUm) window. Thus far, SWNTs used for biological applications have been a complex mixture of metallic and semiconducting species with random chiralities, preventing simultaneous resonant excitation of all semiconducting nanotubes and emission at a single well-defined wavelength. Here, we developed a simple gel filtration method to enrich semiconducting (12,1) and (11,3) SWNTs with identical resonance absorption at ~808 nm and emission near ~1200 nm. The chirality sorted SWNTs showed ~5-fold higher photoluminescence intensity under resonant excitation of 808 nm than unsorted SWNTs on a per-mass basis. Real-time in vivo video imaging of whole mouse body and tumor vessels was achieved using a ~6-fold lower injected dose of (12,1) and (11,3) SWNTs (~3 MUg per mouse or ~0.16 mg/kg of body weight vs 1.0 mg/kg for unsorted SWNTs) than a previous heterogeneous mixture, demonstrating the first resonantly excited and chirality separated SWNTs for biological imaging. PMID- 23033939 TI - Fluoride and silver concentrations of silver diammine fluoride solutions for dental use. AB - OBJECTIVE: To determine the short-term stability of free fluoride ion concentrations and acidity (pH values) of three commercially available SDF solutions over time. METHODS: Three SDF products for caries control were studied: Cariestop-12%, Cariestop-30% and Saforide-38%. Their expected fluoride ion concentrations were 14,200, 35,400 and 44,800 ppm, respectively. The fluoride ion concentrations were determined with an ion-selective electrode. The acidity was determined with a pH electrode. The measurements were performed when open and at 7 and 28 days. RESULTS: The mean fluoride ion concentrations of the freshly opened bottles were 12,525 +/- 450, 13,200 +/- 2060 and 55,800 +/- 2536 ppm, respectively. The mean pH values were 9.4 +/- 0.1, 10.4 +/- 0.1 and 10.2 +/- 0.2, respectively. No significant change (P > 0.05) in the fluoride ion concentrations or the acidity was detected after 7 or 28 days. CONCLUSION: The three SDF tested solutions were alkaline. The fluoride ion concentrations of Cariestop-30% and Saforide-38% were considerably different. The fluoride ion concentrations and acidity of the products demonstrated a short-term stability over 28 days. PMID- 23033938 TI - Fabrication and properties of capsicum extract-loaded PVA and CA nanofiber patches. AB - The aim of this study was to prepare, characterize and evaluate electrospun polyvinyl alcohol (PVA) and cellulose acetate (CA) nanofibers loaded with capsicum extract (CE) for use in topical skin treatments. CE, 0.5, 1 or 2 wt %, was loaded into PVA and CA electrospun fiber mats. Various properties of the CE loaded fiber mats as well as release and skin permeation were investigated. The average diameters of these fibers ranged from 251-368 nm. The release rate of capsaicin from CE-loaded as-spun PVA was faster than that of the CA fiber mats and increased as the CE content in CE-loaded as-spun PVA and CA increased. The release kinetics of the CA and PVA fibers followed the Higuchi equation. The percentages of CE that permeated the shed snake skin with PVA and CA fiber mats containing 2 wt % CE after 24 h were 60% and 20%, respectively. The results suggest a potential use of PVA and CA nanofibers being used to control skin permeation of capsicum extract. Our research suggests the potential application of CE-loaded PVA electrospun mats as transdermal drug delivery systems. PMID- 23033940 TI - Porphyromonas gingivalis displays a competitive advantage over Aggregatibacter actinomycetemcomitans in co-cultured biofilm. AB - BACKGROUND AND OBJECTIVE: Biofilm formation occurs through the events of cooperative growth and competitive survival among multiple species. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans are important periodontal pathogens. The aim of this study was to demonstrate competitive or cooperative interactions between these two species in co-cultured biofilm. MATERIAL AND METHODS: P. gingivalis strains and gingipain mutants were cultured with or without A. actinomycetemcomitans. Biofilms formed on glass surfaces were analyzed by crystal violet staining and colony counting. Preformed A. actinomycetemcomitans biofilms were treated with P. gingivalis culture supernatants. Growth and proteolytic activities of gingipains were also determined. RESULTS: Monocultured P. gingivalis strains exhibited a range of biofilm-formation abilities and proteolytic activities. The ATCC33277 strain, noted for its high biofilm-formation ability and proteolytic activity, was found to be dominant in biofilm co-cultured with A. actinomycetemcomitans. In a time resolved assay, A. actinomycetemcomitans was primarily the dominant colonizer on a glass surface and subsequently detached in the presence of increasing numbers of ATCC33277. Detachment of preformed A. actinomycetemcomitans biofilm was observed by incubation with culture supernatants from highly proteolytic strains. CONCLUSION: These results suggest that P. gingivalis possesses a competitive advantage over A. actinomycetemcomitans. As the required biofilm-formation abilities and proteolytic activities vary among P. gingivalis strains, the diversity of the competitive advantage is likely to affect disease recurrence during periodontal maintenance. PMID- 23033941 TI - Adenosine receptor stimulation by polynucleotides (PDRN) reduces inflammation in experimental periodontitis. AB - AIM: Adenosine receptors modulate inflammation in periodontal tissues. No data are available regarding the effects of adenosine A(2A) receptor stimulation in experimental periodontitis (EPD). The aim of this study was to investigate the effects of polynucleotides (also known as polydeoxyribonucleotide, PDRN), a ligand of A(2A) receptor, in EPD in rats. MATERIALS AND METHODS: EPD was induced ligating the cervix of the lower left first molar. Sham-EPD had no ligature. After 7 days, EPD animals were randomized to a daily treatment with vehicle gel or 0.75% PDRN gel or PDRN gel with a specific A(2A) antagonist (DMPX). Treatments lasted 7 days. Animals were then euthanized and the periodontium and surrounding gingival tissue were excised for histological evaluation and bio molecular analysis of inflammatory (p-JNK, p-ERK, TNF-alpha, IL-6, HMGB-1) and apoptotic proteins (BAX and Bcl-2). RESULTS: Vehicle-treated EPD rats showed severe inflammatory infiltrate in both gingival and periodontal ligament, as well as an enhanced expression of p-JNK, p-ERK, TNF-alpha, IL-6, HMGB-1 and BAX and a reduction in Bcl-2. PDRN gel restored the histological features, blunted inflammatory and apoptotic proteins expression and preserved Bcl-2 expression. DMPX abrogated PDRN positive effects. CONCLUSION: Our data suggest that adenosine receptor stimulation by PDRN might represent a new therapeutic strategy for periodontitis. PMID- 23033942 TI - Different mechanisms causing loss of mismatched human leukocyte antigens in relapsing t(6;11)(q27;q23) acute myeloid leukemia after haploidentical transplantation. AB - Mismatched human leukocyte antigens (HLAs) on leukemic cells can be targeted by donor T cells in HLA-mismatched/haploidentical stem cell transplantation. In two cases of acute myeloid leukemia with t(6;11)(q27;q23) abnormality presented here, flow cytometry analysis showed a lack of HLA-A unshared between recipients and donors in relapsing leukemic cells after HLA-haploidentical transplantation. However, high-resolution HLA genotyping showed that one case lacked a corresponding HLA haplotype, whereas the other preserved it. These cases suggest that leukemic cells, which lacked mismatched HLA expression, might have an advantage in selective expansion under donor T-cell immune surveillance after HLA haploidentical transplantation. Most importantly, down-regulation of unshared HLA expression potentially occurs by genetic alterations other than loss of HLA alleles. PMID- 23033943 TI - Influence of tip wear of piezoelectric ultrasonic scalers on root surface roughness at different working parameters. A profilometric and atomic force microscopy study. AB - Roughness on tooth surfaces is reported to facilitate the reestablishment of microbial dental plaque. Hence, the main goal of dental scaling is to remove bacterial plaque and obtain smoother tooth surfaces. This study was aimed to assess the influence of tip wear of ultrasonic scaler inserts on root surface roughness at different working parameters. Twenty piezoelectric ultrasonic scaler inserts (10 worn/10 new) were selected to examine the erosion ratio (ER) on the scaler tips and to assess the influence of tip wear on root surface roughness. Erosion on the tip surfaces was evaluated under atomic force microscopy (AFM). Root samples were prepared and instrumented by new (Group I) and worn (Group II) inserts at different working parameters. Roughness change (Rc) on root surfaces after instrumentation was examined under profilometer and compared between and within the groups. Statistically significant differences were found between the mean ERs of new and worn tips (P < 0.01). The results of this study showed that tip angulation and instrument power strongly influenced the Rc values on instrumented samples (P < 0.05). It was also revealed that tip wear influenced the Rc values on root surfaces especially at 45 degrees tip angulation (P < 0.05). Therefore, tip wear should also be considered as much as the other parameters to minimize the surface roughness during ultrasonic treatment. PMID- 23033944 TI - Residual risk of transfusion-transmitted hepatitis B virus (HBV) infection caused by blood components derived from donors with occult HBV infection in Japan. AB - BACKGROUND: Nucleic acid amplification testing (NAT) for hepatitis B virus (HBV) during blood screening has helped to prevent transfusion-transmitted HBV infection (TT-HBV) in Japan. Nevertheless, 4 to 13 TT-HBV infections arise annually. STUDY DESIGN AND METHODS: The Japanese Red Cross (JRC) analyzed repository samples of donated blood for TT-HBV that was suspected through hemovigilance. Blood donations implicated in TT-HBV infections were categorized as either window period (WP) or occult HBV infection (OBI) related. In addition, we analyzed blood from 4742 donors with low antibody to hepatitis B core antigen (anti-HBc) and antibody to hepatitis B surface antigen (anti-HBs) titers using individual-donation NAT (ID-NAT) to investigate the relationship between anti-HBc titer and proportion of viremic donors. RESULTS: Introduction of a more sensitive NAT method for screening minipools of 20 donations increased the OBI detection rate from 3.9 to 15.2 per million, while also the confirmed OBI transmission rate increased from 0.67 to 1.49 per million. By contrast the WP transmission rate decreased from 0.92 to 0.46 per million. Testing repository samples of donations missed by minipools of 20 donations NAT showed that 75 and 85% of TT-HBV that arose from WP and OBI donations, respectively, would have been interdicted by ID NAT. The ID-NAT trial revealed that 1.94% of donations with low anti-HBc and anti HBs titers were viremic and that anti-HBc titers and the frequency of viremia did not correlate. CONCLUSIONS: The JRC has elected to achieve maximal safety by discarding all units with low anti-HBc and anti-HBs titers that account for 1.3% of the total donations. PMID- 23033945 TI - Internalization and intracellular trafficking of poly(propylene imine) glycodendrimers with maltose shell in melanoma cells. AB - The diagnosis and treatment of malignant melanoma by means of the formulation of active principles with dendrimeric nanoparticles is an area of great current interest. The identification and understanding of molecular mechanisms which ensure the integration of particular dendrimeric nanostructures in tumor cellular environment can provide valuable guidance in their coupling strategies with antitumor or diagnostic agents. Two structurally distinct maltose-shell modified 5th generation (G5) poly(propylene imine) (PPI) glycodendrimers fluorescently labeled, (a) with open maltose shell, cationic charged G5-PPI-OS and (b) with dense maltose shell and nearly neutral G5-PPI-DS, were tested in relation with several melanoma cell lines. We found that three melanoma cell lines internalize G5-PPI-DS structure more efficiently than non tumoral HEK297T cells. Furthermore, the internalization pathways of G5-PPI-OS and G5-PPI-DS are characteristic for each tumor cell phenotype and include more than one mechanism. As a general trend, large amounts of both G5-PPI-OS and G5-PPI-DS are internalized on cholesterol-dependent pathway in MJS primary melanoma cells and on non conventional pathways in SK28 metastatic melanoma cells. G5-PPI-OS, temporarily retained at plasma membrane in both cell lines, is internalized slower in metastatic than in primary phenotype. Unlike G5-PPI-OS, G5-PPI-DS is immediately endocytosed in both cell lines. The unconventional internalization pathway and trafficking, exclusively used by G5-PPI-DS in metastatic cells, is described at molecular level. The decay kinetics of fluorescent labeled G5-PPI-OS and G5-PPI DS is distinct in the two cellular phenotypes. Both cationic and neutral maltose G5-PPI glycodendrimeric structures represent molecules based on which designing of new formulations for therapy or/and diagnosis of melanoma can be further developed. PMID- 23033946 TI - Molecular properties of lysine dendrimers and their interactions with Abeta peptides and neuronal cells. AB - Prevention of amyloidosis by chemical compounds is a potential therapeutic strategy in Alzheimer's, prion and other neurodegenerative diseases. Regularly branched dendrimers and less regular hyperbranched polymers have been suggested as promising inhibitors of amyloid aggregation. As demonstrated in our previous studies, some widely used dendrimers (PAMAM, PPI) could not only inhibit amyloid aggregation in solution but also dissolve mature fibrils. In this study we have performed computer simulation of polylysine dendrimers of 3rd and 5th generations (D3 and D5) and analysed the effect of these dendrimers and some hyperbranched polymers on a lysine base (HpbK) on aggregation of amyloid peptide in solution. The effects of dendrimers on cell viability and their protective action against Abeta-induced cytotoxicity and alteration of K+channels was also analysed using human neuroblastoma SH-SY5Y cells. In addition, using fluorescence microscopy, we analysed uptake of FITC-conjugated D3 by SH-SY5Y cells and its distribution in the brain after intraventricular injections to rats. Our results demonstrated that dendrimers D3 and D5 inhibited amyloid aggregation in solution while HpbK enhanced amyloid aggregation. Cell viability and patch-clamp studies have shown that D3 can protect cells against Abeta-induced cytotoxicity and K+channel modulation. In contrast, HpbK had no protective effect against Abeta. Fluorescence microscopy studies demonstrated that FITC-D3 accumulates in the vacuolar compartments of the cells and can be detected in various brain structures and populations of cells after injections to the brain. As such, polylysine dendrimers D3 and D5 can be proposed as compounds for developing antiamyloidogenic drugs. PMID- 23033947 TI - Obesity-driven inflammation and colorectal cancer. AB - Visceral obesity is characterized by increased risk of cardiovascular disease as well as higher incidence of malignancies, including colorectal cancer (CRC), although the mechanisms linking excess adiposity with cancer are only partly characterized. Visceral obesity is currently acknowledged as a chronic inflammatory disorder and a growing body of evidence demonstrates the interconnections between obesity-related secretion pattern of adipo/cytokines and CRC. Specific molecules derived from the visceral adipose tissue (VAT), including adiponectin, leptin and resistin, are able to establish a positive feedback loop, thus increasing the proinflammatory and insulin resistant state and promoting tumorigenesis. Interestingly, these molecules have emerged as novel prognostic factors and therapeutic targets. This review will focus on current molecular and clinical evidence linking VAT-related inflammation to CRC initiation and progression, and summarize the role of dietary factors and lifestyle interventions aimed at promoting weight control and physical activity on CRC prevention and prognosis. PMID- 23033948 TI - Reproductive effects of low-to-moderate medical radiation exposure. AB - Medical radiation from x-rays and nuclear medicine is the largest man-made source of radiation exposure in Western countries, accounting for a mean effective dose of 3.0 mSv per capita per year, comparable to the radiologic risk of 150 chest x rays, and in many cases gonads fall in the imaging field, with > 20 millions examinations per year in US being abdominal and pelvic CT, and > 0.5 million barium enema. Of the over 7 million workers exposed to medical radiation, special attention has been paid to those working in the interventional cardiology and radiology labs, with high and increasing professional exposures, two-to three times higher than diagnostic radiologists. Thus, adverse effects of radiation exposure are well worth of the scientific community's interest. Aims of this review are: 1) to assess gonad dose to patients undergoing diagnostic testing or interventional fluoroscopy therapy and in professionally exposed interventional fluoroscopists; and 2) to evaluate the evidence linking radiation exposure in the low-to-moderate range (besides the radiotherapy high dose range) to adverse reproductive effects. In patients, the gonad radiation exposure can reach 5 mSv for a lower limb angiography, 20 mSv for a CT pelvis and hips, and 36 (in females) to 90 mSv (for males) for a lower gastrointestinal series. For interventional cardiologists, the gonad dose (below lead apron) is in the same order of magnitude of the shielded thyroid dose, with a median of 50 to 100 microSievert per cine-angiography procedure. The dose can be ten-fold higher for a complex interventional procedure. This leads to a cumulative exposure in the 0.5-1 Sv range over a professional lifetime of 30 years. At present, the epidemiological approach provided inconclusive results, inadequate for a robust evidence-based advice to exposed subjects, since large groups followed-up for decades would be required to detect a small increase in risk. A molecular epidemiology approach and/or the use of integrated biomarkers of reproductive health (e.h., reproductive hormone balance, sperm quality, sperm DNA damage) might be more fruitful in future research focused in the low-to-moderate dose range (< 1000 mSv) of greatest interest for diagnostic and professional exposures. PMID- 23033949 TI - Signal transduction pathways of the epidermal growth factor receptor in colorectal cancer and their inhibition by small molecules. AB - While prognostic factors can help to classify the standard risk of subpopulations of patients with the same tumor entity, it is still not possible to predict the response of individual patients to specific therapies. The reason for such wide variation in cancer therapy responses remains largely unknown. The field of chemotherapy is currently undergoing a paradigm shift from classical cytotoxic chemotherapy to targeted therapy in order to kill tumor cells more efficiently with fewer side effects on normal tissue. In the present review, we focus on colorectal carcinoma, which is one of the most frequent tumor types worldwide and represents a leading cause of cancer-related deaths. The signaling pathways downstream of epidermal growth factor receptor (EGFR) are central to the biology of colorectal cancer. A considerable achievement during the past years was the development of targeted therapies against EGFR using monoclonal antibodies and small molecule inhibitors. Two major pathways mediate signal transduction through EGFR: the RAS/RAF/MAPK/ERK and the PI3K/AKT/ PTEN/mTOR pathways. Sometimes, predictive biomarkers can provide information on the expected response of tumors to standard chemotherapy. Such molecular markers for EGFR-targeted treatment have been described. However, disease progression and resistance towards EGFR-directed drugs frequently develop due to mutations in genes downstream of EGFR. In this review, we describe the mechanisms by which colorectal cancers gain resistance against EGFR-targeted therapies as well as strategies to bypass mutationinduced resistance in these two signaling pathways. PMID- 23033950 TI - Dendrimers in biomedical applications. PMID- 23033951 TI - Increased Akt signaling resulting from the loss of androgen responsiveness in prostate cancer. AB - The mechanisms responsible for the switch of prostate cancer from androgen sensitive (AS) to androgen-insensitive (AI) form are not well understood. Regulation of androgen receptor (AR), through which androgens control the expression of genes involved in prostate cells proliferation, migration and death also involves its cross-talk with the other signaling pathways, transcription factors and coregulatory proteins, such as beta-catenin. With the aim to determine their possible contribution in triggering the switch from AS to AI form, which occurs upon androgen deprivation therapy - AR, Akt and beta-catenin expression were knocked-down with respective siRNAs. Treatment of LNCaP prostate cells with siRNA for AR significantly reduced their proliferation (45-70%), expression of nuclear beta- catenin, cyclin-D1, cyclin-G1, c-Myc as well as activity of metalloproteinases (MMPs) -2,-7,-9 and cell migration. Surprisingly, after longer (over 72 hrs) silencing of AR in LNCaP cells, elevated levels of p Akt were detected and enhanced proliferation as well as expression of nuclear beta-catenin, cyclin-D1, c-Myc and activity of MMPs were observed. Such effects were not observed in either PC-3 or DU145 AI cells. However, silencing of Akt and /or beta-catenin in those as well as in LNCaP cells led to their decreased proliferation and migration. Our findings suggest that in prostate cancer cells, either AR or Akt signaling prevails, depending on their initial androgen sensitivity and its availability. In AI prostate cancer cells, Akt takes over the role of AR and more effectively contributes through the same signaling molecule, beta-catenin, to AI cancer progression. PMID- 23033952 TI - DNA methyltransferase inhibitors in cancer: a chemical and therapeutic patent overview and selected clinical studies. AB - INTRODUCTION: DNA methylation is an epigenetic modification that modulates gene expression without altering the DNA base sequence. It plays a crucial role in cancer by silencing tumor suppressor genes (TSG). The DNA methyltransferases (DNMT) are the enzymes that catalyze DNA methylation and they are interesting therapeutical targets since DNA methylation is reversible such that an aberrant hypermethylation of DNA can be reverted by inhibition of DNMTs. Today, two drugs are on the market for the treatment of myelodysplastic syndrome, azacitidine and decitabine. AREAS COVERED: Here, we present a review of the patents describing the chemistry and biological activities of novel DNMT inhibitors and discuss select clinical studies. EXPERT OPINION: DNMT inhibitors have shown efficacy in clinics. However, highly efficient and specific DNMT inhibitors have not yet been identified. Improving methods will certainly lead to the prediction of novel directly binding inhibitors in the future. PMID- 23033953 TI - Sequencing of two novel HLA-A*29 alleles, A*29:39 and A*29:40. AB - A*29:39 differs from A*29:02:01 by three clustered amino acid replacements at alpha1 domain, T73>I73, A76>V76 and N77>D77. A*29:40 shows one nucleotide difference regarding A*29:02:01 allele, resulting in one amino acid substitution at position 154, E154>G154. PMID- 23033954 TI - Graded exercise therapy (GET)/cognitive behavioural therapy (CBT) is often counterproductive in myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). PMID- 23033955 TI - Differential regulation of tissue thiol-disulfide redox status in a murine model of peritonitis. AB - BACKGROUND: Glutathione (GSH)/glutathione disulfide (GSSG) and cysteine (Cys)/cystine (CySS) are major redox pools with important roles in cytoprotection. We determined the impact of septic peritonitis on thiol-disulfide redox status in mice. METHODS: FVB/N mice (6-12 week old; 8/group) underwent laparotomy with cecal ligation and puncture (CLP) or laparotomy alone (control). Sections of ileum, colon, lung and liver were obtained and GSH, GSSG, Cys and CySS concentrations determined by HPLC 24 h after laparotomy. Redox potential [Eh in millivolts (mV)] of the GSH/GSSG and Cys/CySS pools was calculated using the Nernst equation. Data were analyzed by ANOVA (mean +/- SE). RESULTS: GSH/GSSG Eh in ileum, colon, and liver was significantly oxidized in septic mice versus control mice (ileum: septic -202+/-4 versus control -228+/-2 mV; colon: -195+/-8 versus -214+/-1 mV; and liver: -194+/-3 vs. -210+/-1 mV, all P<0.01). Lung GSH/GSSG redox was similar in each group (-191+/-3 versus -190+/-2 mV). In contrast, ileal and colonic Cys/CySS Eh was unchanged with CLP, while liver and lung Cys/CySS Eh became significantly more reducing (liver: septic = -103+/-3 versus control -90+/-2 mV; lung: -101+/-5 versus -81+/-1 mV, each P<0.05). CONCLUSIONS: Septic peritonitis induced by CLP oxidizes ileal and colonic GSH/GSSG redox but Cys/CySS Eh remains unchanged in these intestinal tissues. In liver, CLP oxidizes the GSH/GSSG redox pool and CyS/CySS Eh becomes more reducing; in lung, CLP does not alter GSH/GSSG Eh, and Cys/CySS Eh is less oxidized. CLP-induced infection/inflammation differentially regulates major thiol disulfide redox pools in this murine model. PMID- 23033956 TI - Pregnancy following uterine artery embolization: an update. AB - OBJECTIVE: This paper seeks to evaluate the ability to conceive and deliver term pregnancies following uterine artery embolization. METHODS: We conducted a retrospective chart review of patients under the age of 40 who indicated a desire for fertility prior to embolization. Patients were questioned regarding attempts to conceive, subsequent pregnancies, and outcomes of those pregnancies. Patients who identified fertility as a desired outcome were studied. All patients who conceived were asked about the details of the pregnancy. RESULTS: Forty-four women under the age of 40 embolized between 1996 and 2010 stated a desire for fertility. Twenty-two of these women have reported 28 pregnancies. Of these pregnancies, 20 live births, three miscarriages, and three instances of premature labor were reported. Seventeen of these pregnancies were delivered by caesarean section and six pregnancies were vaginal deliveries. And one woman is currently pregnant. No perfusion problems, either during pregnancy or labor, were reported. CONCLUSION: The course of pregnancy and delivery was largely normal after embolization with three cases of premature labor and three miscarriages reported. Forty-eight percent of women who were under 40 and desired pregnancies were able to have successful term pregnancies. PMID- 23033957 TI - Internal retraction in single-port laparoscopic cholecystectomy: initial experience and learning curve. AB - INTRODUCTION: We report our experience and learning curve in single-port laparoscopic cholecystectomy (SPLC) using an internal anchored retraction system. METHODS: Usefulness of the retraction system was analysed in 18 SPLC. The first eight, the following ten SPLC and 20 consecutive four-port laparoscopic cholecystectomies (4PLC) were compared. Duration of operation, burns on nontarget tissue and gallbladder perforations were assessed by reviewing videotapes recorded during the procedures. RESULTS: Use of the retraction system failed in three out of five patients (60%) with intraoperative signs of chronic inflammation and in one out of 13 (7.1%) without such signs (p = 0.0441). Median operation time was 90 (45-120) in the first eight and 55 (40-180) minutes in the following ten SPLC (p = 0.0361). Whereas the first eight SPLC lasted longer compared to 4PLC (70 (40-140) minutes, p = 0.0435) the difference disappeared after eight procedures (p = 0.2076). Median number of burns to nontarget tissue was seven (1-16) in the first eight and one (0-8) in the following ten SPLC (p = 0.0049). There was no difference in perforation of the gallbladder. DISCUSSION: Internal retraction enables a safe exposure of the Calot triangle avoiding bile spillage in cholecystectomies without intraoperative signs of inflammation. Familiarisation with SPLC was rapidly achieved. Operation time and dexterity were equal to 4PLC after eight SPLC. PMID- 23033958 TI - Kirschner wire placement in scaphoid bones using intraoperative CT-guided stereotaxy. AB - BACKGROUND: Minimally invasive ostesynthesis of scaphoid fractures may reduce the risk of fracture non-union and shorten the duration of illness. The aim of this study was to analyze the technical feasibility and targeting accuracy of computed tomography (CT) - guided stereotactic Kirschner (K)-wire positioning in the scaphoid. METHODS: Nineteen Formalin preserved cadaveric upper extremities (10 right, 9 left) were fixed in 90 degree dorsal extension for percutaneous access from palmar. An ideal central position of the K-wire was planned on the computer adapted from intraoperative CT data. A 3D navigation system and stereotactic targeting device were used for K-wire placement. Target positioning errors were evaluated by fusion of the control CT with the K-wire in place with the planning CT. RESULTS: The procedure allowed for an easy and rigid wrist fixation. K-wire placement showed mean +/- SD lateral targeting errors of 0.9 +/- 0.5 mm at the scaphoid bone entry and 1.2 +/- 0.7 mm at the K-wire tip. The mean angular error was 1.3 degrees +/- 1.1 degrees . Total duration of the intervention ranged between 19 and 23 min. CONCLUSION: CT-guided stereotactic K-wire placement in scaphoid bones is highly accurate. The technique may guide minimally invasive screw-osteosynthesis of scaphoid fractures. PMID- 23033959 TI - Model-based analysis of an adaptive evolution experiment with Escherichia coli in a pyruvate limited continuous culture with glycerol. AB - : Bacterial strains that were genetically blocked in important metabolic pathways and grown under selective conditions underwent a process of adaptive evolution: certain pathways may have been deregulated and therefore allowed for the circumvention of the given block. A block of endogenous pyruvate synthesis from glycerol was realized by a knockout of pyruvate kinase and phosphoenolpyruvate carboxylase in E. coli. The resulting mutant strain was able to grow on a medium containing glycerol and lactate, which served as an exogenous pyruvate source. Heterologous expression of a pyruvate carboxylase gene from Corynebacterium glutamicum was used for anaplerosis of the TCA cycle. Selective conditions were controlled in a continuous culture with limited lactate feed and an excess of glycerol feed. After 200-300 generations pyruvate-prototrophic mutants were isolated. The genomic analysis of an evolved strain revealed that the genotypic basis for the regained pyruvate-prototrophy was not obvious. A constraint-based model of the metabolism was employed to compute all possible detours around the given metabolic block by solving a hierarchy of linear programming problems. The regulatory network was expected to be responsible for the adaptation process. Hence, a Boolean model of the transcription factor network was connected to the metabolic model. Our model analysis only showed a marginal impact of transcriptional control on the biomass yield on substrate which is a key variable in the selection process. In our experiment, microarray analysis confirmed that transcriptional control probably played a minor role in the deregulation of the alternative pathways for the circumvention of the block. PMID- 23033960 TI - Hepatitis B virus infection is associated with deletion of chromosome 8p in multiple myeloma. AB - Serological analyses within epidemiological cohort and case-control studies indicate to an association between HBV infection and risk of multiple myeloma (MM). To verify the relationship with an independent approach, we investigated the correlation between HBV positivity and chromosomal aberrations within 680 patients of the National Center for Tumor Diseases Heidelberg for which the serological HBV status (HBsAg and anti-HBc) and FISH data for five gains (1q21, 9q34, 11q23, 15q22, 19q13), five losses (6q21, 8p21, 13q14, 17p13, 22q11), and three IgH translocations [t(4,14), t(11,14), t(14,16)] were available. Deletion of 8p21 and 13q14 were shown associated with HBV positivity within hepatocellular carcinoma in other investigations. In the present evaluation, the odds ratio for loss of 8p21 was significantly elevated (OR = 2.74, 95% CL = 1.36-5.50, P = 0.0048) and for loss of 13q14 non-significantly increased (OR = 1.40, 95% CL = 0.74-2.65) in anti-HBc positive patients. The results provide further support for a role of HBV infection in the pathogenesis of MM. PMID- 23033961 TI - Case report and literature review of chronic neuropathic pain associated with peripheral venous cannulation. AB - We report a case of neuropathic pain following peripheral venous cannulation for an elective surgical procedure and discuss the various mechanisms by which this could occur. The mostly likely trigger in this case is phlebitis as the onset of symptoms coincided with the local infection. Neuropathic pain can occur following innocent interventions and its impact on the patient's quality of life may be reduced by timely recognition and management. PMID- 23033962 TI - The nature of lithium battery materials under oxygen evolution reaction conditions. AB - Transition-metal oxide and phosphate materials, commonly used for lithium battery devices, are active as oxygen evolution reaction (OER) catalysts under alkaline and neutral solution conditions. Electrodes composed of LiCoO(2) and LiCoPO(4) exhibit progressive deactivation and activation for OER catalysis, respectively, upon potential cycling at neutral pH. The deactivation of LiCoO(2) and activation of LiCoPO(4) are coincident with changes in surface morphology and composition giving rise to spinel-like and amorphous surface structures, respectively. The amorphous surface structure of the activated LiCoPO(4) is compositionally similar to that obtained from the electrodeposition of cobalt oxide materials from phosphate-buffered electrolyte solutions. These results highlight the importance of a combined structural and electrochemical analysis of the materials surface when assessing the true nature of the OER catalyst. PMID- 23033963 TI - Na+-K+-ATPase, a potent neuroprotective modulator against Alzheimer disease. AB - Alzheimer disease (AD) is a neurodegenerative disorder clinically characterized by progressive cognitive and memory dysfunction, which is the most common form of dementia. Although the pathogenesis of neuronal injury in AD is not clear, recent evidences suggest that Na+-K+-ATPase plays an important role in AD, and may be a potent neuroprotective modulator against AD. This review aims to provide readers with an in-depth understanding of Na+-K+-ATPase in AD through these modulations of some factors that are as follows, which leads to the change of learning and memory in the process of AD. 1. The deficiency in Na+, K+-ATPase alpha1, alpha2 and alpha3 isoform genes induced learning and memory deficits, and alpha isoform was evidently changed in AD, revealing that Na+, K+-ATPase alpha isoform genes may play an important role in AD. 2. Some factors, such as beta-amyloid, cholinergic and oxidative stress, can modulate learning and memory in AD through the mondulation of Na+-K+-ATPase activity. 3. Some substances, such as Zn, s Ethyl cysteine, s-propyl cysteine, citicoline, rivastigmine, Vit E, memantine, tea polyphenol, curcumin, caffeine, Alpinia galanga (L.) fractions, and Bacopa monnieri could play a role in improving memory performance and exert protective effects against AD by increasing expression or activity of Na+, K+-ATPase. PMID- 23033964 TI - Infectious diseases in Iran: a bird's eye view. AB - Thanks to improved health standards in Iran over the past three decades, we have witnessed a shift in the causes of death in Iran from infectious causes to non communicable diseases-mainly cardiovascular disorders, cancers, and road traffic injuries. The incidence and prevalence of many infectious diseases, such as many parasitic infections, have fallen significantly; there have been no reported cases of dracunculiasis in Iran since the mid-1970s. Great strides have also been made towards the elimination of schistosomiasis in Iran. However, we still have some problems with cutaneous leishmaniasis, hepatitis C, human immunodeficiency virus, tuberculosis, infections among immunocompromised hosts, hospital-acquired infections, and antibiotic-resistant bacterial strains. We need to emphasize improvements in sanitation, good clinical practice, and education about the rational administration of antibiotics. PMID- 23033965 TI - Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease. AB - Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM). PMID- 23033966 TI - LRpath analysis reveals common pathways dysregulated via DNA methylation across cancer types. AB - BACKGROUND: The relative contribution of epigenetic mechanisms to carcinogenesis is not well understood, including the extent to which epigenetic dysregulation and somatic mutations target similar genes and pathways. We hypothesize that during carcinogenesis, certain pathways or biological gene sets are commonly dysregulated via DNA methylation across cancer types. The ability of our logistic regression-based gene set enrichment method to implicate important biological pathways in high-throughput data is well established. RESULTS: We developed a web based gene set enrichment application called LRpath with clustering functionality that allows for identification and comparison of pathway signatures across multiple studies. Here, we employed LRpath analysis to unravel the commonly altered pathways and other gene sets across ten cancer studies employing DNA methylation data profiled with the Illumina HumanMethylation27 BeadChip. We observed a surprising level of concordance in differential methylation across multiple cancer types. For example, among commonly hypomethylated groups, we identified immune-related functions, peptidase activity, and epidermis/keratinocyte development and differentiation. Commonly hypermethylated groups included homeobox and other DNA-binding genes, nervous system and embryonic development, and voltage-gated potassium channels. For many gene sets, we observed significant overlap in the specific subset of differentially methylated genes. Interestingly, fewer DNA repair genes were differentially methylated than expected by chance. CONCLUSIONS: Clustering analysis performed with LRpath revealed tightly clustered concepts enriched for differential methylation. Several well-known cancer-related pathways were significantly affected, while others were depleted in differential methylation. We conclude that DNA methylation changes in cancer tend to target a subset of the known cancer pathways affected by genetic aberrations. PMID- 23033968 TI - Evaluation of strategies for the eradication of Pseudorabies virus (Aujeszky's disease) in commercial swine farms in Chiang-Mai and Lampoon Provinces, Thailand, using a simulation disease spread model. AB - Several strategies for eradicating Pseudorabies virus (Aujeszky's disease) in Chiang-Mai and Lampoon Provinces, Thailand, were compared using a computer simulation model, the North American Animal Disease Spread Model (NAADSM). The duration of the outbreak, the number of affected herds and the number of destroyed herds were compared during these simulated outbreaks. Depopulation, zoning for restricted movement and improved detection and vaccination strategies were assessed. The most effective strategies to eradicate Pseudorabies as per the findings from this study are applying depopulation strategies with MOVEMENT RESTRICTIONS in 3-, 8- and 16-km ZONES surrounding infected herds and enhancing the eradication with vaccination campaign on 16-km radius surrounding infected herds. PMID- 23033967 TI - Novel anti-HER2 monoclonal antibodies: synergy and antagonism with tumor necrosis factor-alpha. AB - BACKGROUND: One-third of breast cancers display amplifications of the ERBB2 gene encoding the HER2 kinase receptor. Trastuzumab, a humanized antibody directed against an epitope on subdomain IV of the extracellular domain of HER2 is used for therapy of HER2-overexpressing mammary tumors. However, many tumors are either natively resistant or acquire resistance against Trastuzumab. Antibodies directed to different epitopes on the extracellular domain of HER2 are promising candidates for replacement or combinatorial therapy. For example, Pertuzumab that binds to subdomain II of HER2 extracellular domain and inhibits receptor dimerization is under clinical trial. Alternative antibodies directed to novel HER2 epitopes may serve as additional tools for breast cancer therapy. Our aim was to generate novel anti-HER2 monoclonal antibodies inhibiting the growth of breast cancer cells, either alone or in combination with tumor necrosis factor alpha (TNF-alpha). METHODS: Mice were immunized against SK-BR-3 cells and recombinant HER2 extracellular domain protein to produce monoclonal antibodies. Anti-HER2 antibodies were characterized with breast cancer cell lines using immunofluorescence, flow cytometry, immunoprecipitation, western blot techniques. Antibody epitopes were localized using plasmids encoding recombinant HER2 protein variants. Antibodies, either alone or in combination with TNF-alpha, were tested for their effects on breast cancer cell proliferation. RESULTS: We produced five new anti-HER2 monoclonal antibodies, all directed against conformational epitope or epitopes restricted to the native form of the extracellular domain. When tested alone, some antibodies inhibited modestly but significantly the growth of SK-BR-3, BT-474 and MDA-MB-361 cells displaying ERBB2 amplification. They had no detectable effect on MCF-7 and T47D cells lacking ERBB2 amplification. When tested in combination with TNF-alpha, antibodies acted synergistically on SK-BR-3 cells, but antagonistically on BT-474 cells. A representative anti-HER2 antibody inhibited Akt and ERK1/2 phosphorylation leading to cyclin D1 accumulation and growth arrest in SK-BR-3 cells, independently from TNF-alpha. CONCLUSIONS: Novel antibodies against extracellular domain of HER2 may serve as potent anti-cancer bioactive molecules. Cell-dependent synergy and antagonism between anti-HER2 antibodies and TNF-alpha provide evidence for a complex interplay between HER2 and TNF-alpha signaling pathways. Such complexity may drastically affect the outcome of HER2-directed therapeutic interventions. PMID- 23033969 TI - Adipokines: a novel link between adiposity and carotid plaque vulnerability. AB - BACKGROUND: In patients with carotid stenosis, we prospectively investigated the association of novel adipokines, apelin and visfatin, with gray-scale median (GSM) score, a valid index of carotid plaque vulnerability. We also assessed the impact of atorvastatin therapy on the above biochemical and imaging markers. MATERIALS AND METHODS: Seventy-four overweight [body-mass index (BMI) > 25 kg/m(2) , fat-mass > 30%], statin-free patients, with carotid stenosis, but without indications for intervention were enrolled. Thirty-eight age-, sex- and BMI-matched healthy subjects served as healthy controls (HC). All patients received gradual titrated (10-80 mg) atorvastatin therapy to target LDL-C < 100 mg/dL. GSM score, blood pressure (BP), fat-mass, lipid profile, and serum high sensitivity C-reactive protein (hsCRP), apelin and visfatin levels were obtained at baseline and after 24 months. RESULTS: At baseline, patients with carotid atherosclerosis had worse lipid profile, lower apelin and higher systolic BP, hsCRP, visfatin levels compared with HC (P < 0.05). Notably, decreased apelin (P < 0.001) and GSM score (P = 0.010), while increased visfatin (P = 0.019) and hsCRP (P = 0.039) levels were found in symptomatic rather than asymptomatic patients. At baseline, GSM score correlated with fat-mass, BMI, LDL-C, visfatin and apelin (P < 0.05). Apelin, visfatin and fat-mass remained independent determinants of baseline GSM score (R(2) = 0.391, P = 0.007). In parallel, we found that apelin increment and LDL-C reduction were independently associated with the atorvastatin-induced GSM increase (R(2) = 0.411, P = 0.011). CONCLUSION: Increased fat-mass, low apelin and high visfatin serum levels seem to correlate with carotid plaque vulnerability in patients with carotid stenosis. The atorvastatin-induced modification of apelin and LDL-C may beneficially affect carotid plaque stability. PMID- 23033970 TI - Bradykinin B1 receptor antagonists: a patent update 2009 - 2012. AB - INTRODUCTION: Due to the role of bradykinin B1 receptor (B1R) in pain and inflammation, B1R antagonists have been suggested as promising drug candidates in chronic pain states. The first disclosed B1R antagonists were peptidomimetics, however, during the last few years, novel chemotypes with improved pharmacodynamic and pharmacokinetic properties have been identified. AREAS COVERED: In this review, we aim to give an overview on B1R antagonists published in patent applications between January 2009 and July 2012. EXPERT OPINION: Extensive research on B1R antagonists resulted in basically two chemotypes including sulfonamides and carboxamides. The most important achievement is that these scaffolds show improved PK profile relative to previous compounds. Several B1R antagonists entered clinical trials and the results from proof-of-concept Phase II clinical study is expected to be disclosed soon. PMID- 23033971 TI - Representing spatial structure through maps and language: Lord of the Rings encodes the spatial structure of middle Earth. AB - Spatial mental representations can be derived from linguistic and non-linguistic sources of information. This study tested whether these representations could be formed from statistical linguistic frequencies of city names, and to what extent participants differed in their performance when they estimated spatial locations from language or maps. In a computational linguistic study, we demonstrated that co-occurrences of cities in Tolkien's Lord of the Rings trilogy and The Hobbit predicted the authentic longitude and latitude of those cities in Middle Earth. In a human study, we showed that human spatial estimates of the location of cities were very similar regardless of whether participants read Tolkien's texts or memorized a map of Middle Earth. However, text-based location estimates obtained from statistical linguistic frequencies better predicted the human text based estimates than the human map-based estimates. These findings suggest that language encodes spatial structure of cities, and that human cognitive map representations can come from implicit statistical linguistic patterns, from explicit non-linguistic perceptual information, or from both. PMID- 23033973 TI - Resistance of a subset of red blood cells to clearance by antibodies in a mouse model of incompatible transfusion. AB - BACKGROUND: Alloimmunization to antigens on transfused red blood cells (RBCs) represents a major barrier to chronic transfusion. In extreme cases of multiple alloimmunization, clinicians may be faced with the decision of transfusing incompatible RBCs or risking death from lack of transfusion. The disastrous results of hemolytic transfusion reactions are well understood, and major pathways of clearance have been described. However, well described but poorly understood is the survival of a subset of incompatible donor RBCs during hemolysis, despite antibody binding. STUDY DESIGN AND METHODS: We utilize a tractable murine model of incompatible transfusion in which RBCs from transgenic donor mice expressing human glycophorin A (hGPA) are transfused into recipients passively immunized with anti-hGPA. RESULTS: As in humans, the majority of RBCs are cleared but a subset of incompatible donor RBCs persist in circulation, despite being bound by antibodies. Data contained herein reject the hypothesis that lack of clearance is due to insufficient antibody or overwhelming of phagocytic machinery; rather, we establish that surviving RBCs represent a distinct population resistant to clearance. CONCLUSIONS: These studies demonstrate that surviving RBCs during incompatible transfusion can represent a population that is resistant to clearance. PMID- 23033972 TI - Working memory ability predicts trajectories of early alcohol use in adolescents: the mediational role of impulsivity. AB - AIMS: (i) To evaluate the role of pre-existing weakness in working memory ability (WM) as a risk factor for early alcohol use as mediated by different forms of impulsivity and (ii) to assess the adverse effects of progressive alcohol use on variations in WM over time. DESIGN, SETTING AND PARTICIPANTS: A community sample of 358 adolescents [48% males, mean(age) (baseline) = 11.4 +/- 0.87 years] from a longitudinal cohort design, assessed annually over 4 consecutive years with less than 6% attrition. MEASUREMENTS: Repeated assessments were conducted for the following key variables: WM (based on performance on four separate tasks), frequency of alcohol use (AU) and three forms of impulsivity, namely sensation seeking (SS), acting without thinking (AWT) and delay discounting (DD). Latent growth curve modeling procedures were used to identify individual trajectories of change for all key variables. FINDINGS: Weakness in WM (at baseline) predicted significantly both concurrent alcohol use and increased frequency of use over the four waves (P < 0.05). This effect was entirely mediated by two forms of impulsivity, AWT and DD, both of which were characterized by underlying weakness in WM. No individual variation was observed in the slopes of WM, which suggests that individual variations in alcohol use were not associated with changes in WM in our early adolescent sample. CONCLUSIONS: Early adolescent alcohol use may be a consequence of (pre-existing) weaknesses in working memory (WM) rather than a cause of it. Efforts to reduce early alcohol use should consider the distinct roles of different impulsivity dimensions, in addition to WM, as potential targets of intervention. PMID- 23033974 TI - Melatonin levels in periodontal health and disease. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to measure melatonin levels in the gingival crevicular fluid and saliva of subjects with healthy periodontal tissues, plaque-induced gingival inflammation, chronic periodontitis and aggressive periodontitis. MATERIAL AND METHODS: A total of 70 subjects were examined and assigned to four groups: healthy periodontium (10 subjects); plaque induced gingival inflammation (20 subjects); chronic periodontitis (20 subjects); and aggressive periodontitis (20 subjects). Gingival crevicular fluid and saliva samples were collected from each subject and analyzed using ELISAs. RESULTS: The melatonin levels in both gingival crevicular fluid and saliva were lower in patients with chronic periodontitis (10.4 and 12.8 pg/mL, respectively) and aggressive periodontitis (8.4 and 8.8 pg/mL, respectively) than in patients with gingivitis (13.9 and 17.6 pg/mL, respectively) and in healthy subjects (16.6 and 22.9 pg/mL, respectively). The mean melatonin levels in both gingival crevicular fluid and saliva were statistically significantly higher in healthy patients compared with patients with chronic periodontitis and aggressive periodontitis; however, there was no significant difference in the plaque-induced gingival inflammation between the study groups. CONCLUSIONS: The melatonin levels in gingival crevicular fluid and saliva are decreased in diseased periodontal tissues, especially periodontitis. The melatonin level was lowest in the aggressive periodontitis group. PMID- 23033975 TI - Plasma soluble urokinase plasminogen activator receptor (suPAR) levels in systemic lupus erythematosus. AB - OBJECTIVE: Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of systemic inflammation. We aimed to characterize plasma suPAR levels in SLE patients. METHODS: We measured plasma suPAR, C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in 89 SLE patients and 29 healthy controls. RESULTS: suPAR and ESR values were higher in SLE than in controls, while CRP levels were comparable. ROC analysis of suPAR levels indicated a cut-off value of 5.70 ng/mL to distinguish patients with high disease activity (SLEDAI >8). CONCLUSION: suPAR might be an objective marker for identifying SLE patients with active disease. PMID- 23033976 TI - ICU-acquired weakness: what is preventing its rehabilitation in critically ill patients? AB - Intensive care unit-acquired weakness (ICUAW) has been recognized as an important and persistent complication in survivors of critical illness. The absence of a consistent nomenclature and diagnostic criteria for ICUAW has made research in this area challenging. Although many risk factors have been identified, the data supporting their direct association have been controversial. Presently, there is a growing body of literature supporting the utility and benefit of early mobility in reducing the morbidity from ICUAW, but few centers have adopted this into their ICU procedures. Ultimately, the implementation of such a strategy would require a shift in the knowledge and culture within the ICU, and may be facilitated by novel technology and patient care strategies. The purpose of this article is to briefly review the diagnosis, risk factors, and management of ICUAW, and to discuss some of the barriers and novel treatments to improve outcomes for our ICU survivors. PMID- 23033977 TI - Diagnostic exome sequencing--are we there yet? PMID- 23033978 TI - Diagnostic exome sequencing in persons with severe intellectual disability. AB - BACKGROUND: The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity. METHODS: We evaluated patients with intellectual disability to exclude known causes of the disorder. We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series). All mutations were evaluated by molecular geneticists and clinicians in the context of the patients' clinical presentation. RESULTS: We identified 79 de novo mutations in 53 of 100 patients. A total of 10 de novo mutations and 3 X linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients. Potentially causative de novo mutations in novel candidate genes were detected in 22 patients. Additional de novo mutations in 3 of these candidate genes were identified in patients with similar phenotypes in the confirmation series, providing support for mutations in these genes as the cause of intellectual disability. We detected no causative autosomal recessive inherited mutations in the discovery series. Thus, the total diagnostic yield was 16%, mostly involving de novo mutations. CONCLUSIONS: De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection. (Funded by the European Union and others.). PMID- 23033979 TI - Moneyball and medicine. PMID- 23033981 TI - Levosimendan's effect on platelet function in a rat sepsis model. AB - Although studies have evaluated the efficacy of levosimendan in heart failure during sepsis, it still is a subject of controversy whether levosimendan produces an effect on platelets. In this study, the short- and long-term effects of levosimendan on platelet aggregation were investigated in untreated animals and in a rat model of sepsis. Therefore, adult rats (n = 40) were randomly divided into four groups with n = 10 per group: (I) sham, (II) levosimendan (bolus 53 ug/kg + 285 ug/kg/hour, intravenously (i.v.) injected), (III) LPS (lipopolysaccharide, 8 mg/kg body weight intraperitoneally injected), and (IV) LPS + levosimendan. Levosimendan was given 24 hours after LPS injections. The number of platelets was determined. Platelet aggregation was measured using venous blood from rats 10 minutes and 5 days after levosimendan application with Dynabyte Multiplate system. Aggregation responses were evaluated with adenosine diphosphate (10 uM) and collagen (5 ug/ml). In addition to clinical dosage, the in vitro effect of high-dosage levosimendan on platelet function was investigated. The results clearly showed that LPS significantly reduced the platelet aggregation 1 day after injection compared to controls; 6 days after LPS, a marked increase (p < 0.01) was noted. This result is associated with numbers of platelets. Levosimendan (bolus 53 ug/kg + 285 ug/kg/hour i.v.) had no significant effect on the platelets of rats in contrast to the high-dosage in vitro findings. Thus, the in vivo use of levosimendan does not affect blood coagulation significantly in this rat model. This also applies under the conditions of decreased and increased numbers of platelets during mild sepsis. PMID- 23033980 TI - Individuals with increased inflammatory response to ozone demonstrate muted signaling of immune cell trafficking pathways. AB - BACKGROUND: Exposure to ozone activates innate immune function and causes neutrophilic (PMN) airway inflammation that in some individuals is robustly elevated. The interplay between immuno-inflammatory function and genomic signaling in those with heightened inflammatory responsiveness to ozone is not well understood. OBJECTIVES: Determine baseline predictors and post exposure discriminators for the immuno-inflammatory response to ozone in inflammatory responsive adult volunteers. METHODS: Sputum induction was performed on 27 individuals before and after a two hour chamber exposure to 0.4 ppm ozone. Subjects were classified as inflammatory responders or non-responders to ozone based on their PMN response. Innate immune function, inflammatory cell and cytokine modulation and transcriptional signaling pathways were measured in sputum. RESULTS: Post exposure, responders showed activated innate immune function (CD16: 31,004 MFI vs 8988 MFI; CD11b: 44,986 MFI vs 24,770 MFI; CD80: 2236 MFI vs 1506 MFI; IL-8: 37,603 pg/ml vs 2828 pg/ml; and IL-1beta: 1380 pg/ml vs 318 pg/ml) with muted signaling of immune cell trafficking pathways. In contrast, non-responders displayed decreased innate immune activity (CD16, CD80; phagocytosis: 2 particles/PMN vs 4 particles/PMN) post exposure that was accompanied by a heightened signaling of immune cell trafficking pathways. CONCLUSIONS: Inflammatory responsive and non responsive individuals to ozone show an inverse relationship between immune cell trafficking and immuno-inflammatory functional responses to ozone. These distinct genomic signatures may further our understanding about ozone-induced morbidity in individuals with different levels of inflammatory responsiveness. PMID- 23033982 TI - Quality of life, immunomodulation and safety of adjuvant mistletoe treatment in patients with gastric carcinoma - a randomized, controlled pilot study. AB - BACKGROUND: Mistletoe (Viscum album L.) extracts are widely used in complementary cancer therapy. Aim of this study was to evaluate safety and efficacy of a standardized mistletoe extract (abnobaVISCUM((r)) Quercus, aVQ) in patients with gastric cancer. PATIENTS AND METHODS: 32 operated gastric cancer patients (stage Ib or II) who were waiting for oral chemotherapy with the 5-FU prodrug doxifluridine were randomized 1:1 to receive additional therapy with aVQ or no additional therapy. aVQ was injected subcutaneously three times per week from postoperative day 7 to week 24 in increasing doses. EORTC QLQ-C30 and -STO22 Quality of Life questionnaire, differential blood count, liver function tests, various cytokine levels (tumor necrosis factor (TNF)-alpha, interleukin (IL)-2), CD 16(+)/CD56(+) and CD 19(+) lymphocytes were analyzed at baseline and 8, 16 and 24 weeks later. RESULTS: Global health status (p <0.01), leukocyte- and eosinophil counts (p <=0.01) increased significantly in the treatment group compared to the control group. Diarrhea was less frequently reported (7% vs. 50%, p=0.014) in the intervention group. There was no significant treatment effect on levels of TNF-alpha, IL-2, CD16(+)/CD56(+) and CD 19(+) lymphocytes and liver function tests measured by ANOVA. CONCLUSION: Additional treatment with aVQ is safe and was associated with improved QoL of gastric cancer patients. ClinicalTrials.Gov Registration number NCT01401075. PMID- 23033983 TI - Comparison of non-invasive and invasive blood pressure in aeromedical care. AB - Blood pressure measurement is an essential physiological measurement for all critically ill patients. Previous work has shown that non-invasive blood pressure is not an accurate reflection of invasive blood pressure measurement. In a transport environment, the effects of motion and vibration may make non-invasive blood pressure less accurate. Consecutive critically ill patients transported by a dedicated aeromedical retrieval and critical care transfer service with simultaneous invasive and non-invasive blood pressure measurements were analysed. Two sets of measurements were recorded, first in a hospital environment before departure (pre-flight) and a second during aeromedical transport (in-flight). A total of 56 complete sets of data were analysed. Bland-Altman plots showed limits of agreement (precision) for pre-flight systolic blood pressure were -37.3 mmHg to 30.0 mmHg, and for pre-flight mean arterial pressure -20.5 mmHg to 25.0 mmHg. The limits of agreement for in-flight systolic blood pressure were -40.6 mmHg to 33.1 mmHg, while those for in-flight mean blood pressure in-flight were -23.6 mmHg to 24.6 mmHg. The bias for the four conditions ranged from 0.5 to -3.8 mmHg. There were no significant differences in values between pre-flight and in-flight blood pressure measurements for all categories of blood pressure measurement. Thus, our data show that non-invasive blood pressure is not a precise reflection of invasive intra-arterial blood pressure. Mean blood pressure measured non invasively may be a better marker of invasive blood pressure than systolic blood pressure. Our data show no evidence of non-invasive blood pressures being less accurate in an aeromedical transport environment. PMID- 23033984 TI - Microbial culturomics: paradigm shift in the human gut microbiome study. AB - Comprehensive determination of the microbial composition of the gut microbiota and the relationships with health and disease are major challenges in the 21st century. Metagenomic analysis of the human gut microbiota detects mostly uncultured bacteria. We studied stools from two lean Africans and one obese European, using 212 different culture conditions (microbial culturomics), and tested the colonies by using mass spectrometry and 16S rRNA amplification and sequencing. In parallel, we analysed the same three samples by pyrosequencing 16S rRNA amplicons targeting the V6 region. The 32 500 colonies obtained by culturomics have yielded 340 species of bacteria from seven phyla and 117 genera, including two species from rare phyla (Deinococcus-Thermus and Synergistetes, five fungi, and a giant virus (Senegalvirus). The microbiome identified by culturomics included 174 species never described previously in the human gut, including 31 new species and genera for which the genomes were sequenced, generating c. 10 000 new unknown genes (ORFans), which will help in future molecular studies. Among these, the new species Microvirga massiliensis has the largest bacterial genome so far obtained from a human, and Senegalvirus is the largest virus reported in the human gut. Concurrent metagenomic analysis of the same samples produced 698 phylotypes, including 282 known species, 51 of which overlapped with the microbiome identified by culturomics. Thus, culturomics complements metagenomics by overcoming the depth bias inherent in metagenomic approaches. PMID- 23033985 TI - Rectosigmoid adenocarcinoma revealed by metastatic anal fistula. The visible part of the iceberg: a report of two cases with literature review. AB - Colonic adenocarcinoma revealed by metastatic anorectal fistula is rare, with few cases in the literature. Such lesions can be taken for the more common manifestation of a benign perianal abscess or fistula. Once diagnosed, the management of such conditions remains controversial. We herein report two cases with perianal fistula that were subsequently found to have developed perianal adenocarcinoma on biopsy. Further colonic investigation revealed a rectosigmoid adenocarcinoma. Histology and immunohistochemical staining was identical in both primary and metastatic tumors. Preoperative chemoradiation with further rectal low anterior resection and local excision of metastatic anal fistula was performed. There is no recurrence after 3 years of follow-up. PMID- 23033986 TI - A novel TRB@/NOTCH1 fusion gene in T-cell lymphoblastic lymphoma with t(7;9)(q34;q34). AB - BACKGROUND: In T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), activating mutations of NOTCH1 are observed in more than 50% of cases, whereas the t(7;9)(q34;q34) involving NOTCH1 at 9q34 and TRB@ at 7q34 is an extremely rare but recurrent translocation. PATIENT: A 41-year-old male with a large mediastinal mass, pleural effusion, and lymphadenopathy was diagnosed as having T LBL. Lymphoma cells were positive for CD4, CD8, CD2, CD3, CD5, CD7, CD10, and TdT. RESULTS: G-banding and spectral karyotyping of pleural effusion cells showed 47,XY,dup(1)(q21q32),t(7;9)(q34;q34),+20. Genomic polymerase chain reaction (PCR) revealed that the 5' end of TRB@ J1-5 was connected with the middle of NOTCH1 exon 25 (434 bp downstream from its 5' end) in a 'head-to-head' configuration on the der(9)t(7;9), although nine extra bases were inserted between the two genes. Reverse transcription-PCR confirmed expression of the TRB@/NOTCH1 fusion transcripts. Similarly, the 5' end of J1-5 was fused to the shortened exon 25 with nine extra bases. The NOTCH1 breakpoint in exon 25 was very close to transcription start sites of deleted Notch1 in murine T-ALL. CONCLUSIONS: The TRB@/NOTCH1 fusion gene with a NOTCH1 breakpoint in exon 25, which has not previously been detected in four other reported cases with t(7;9), could lead to aberrant expression of the truncated NOTCH1 by TRB@ enhancer elements. The resultant NOTCH1 receptor deleting most of the extracellular domain may be implicated in the pathogenesis of T-LBL by ligand-independent, constitutive activation of the NOTCH1 pathway, suggesting avenues for future therapy with gamma-secretase inhibitors. PMID- 23033987 TI - The involvement of K(ATP) channels in morphine-induced antinociception and hepatic oxidative stress in acute and inflammatory pain in rats. AB - This study investigated the role of K(ATP) channels in morphine-induced antinociception and hepatic oxidative stress in acute and inflammatory pain. The K(ATP) channel modulators (K(ATP) channel opener, diazoxide 100 mg/kg, p.o, and K(ATP) channel blocker, glibenclamide, 3 mg/kg i.p.) were administered with morphine (80 mg/kg, i.p.). Antinociception was assessed by the tail-flick and formalin tests in rats and measured by the area under the curve values and the maximum percent effect for 3 h. The indices of hepatic oxidative stress: glutathione, glutathione peroxidase, and malondialdehyde were then determined in the liver homogenates obtained from the treated animals. In both tests, glibenclamide antagonized morphine-induced antinociception, whereas diazoxide augmented it in the tail-flick test only. In the formalin test, glibenclamide alone has a significant hyperalgesic effect, whereas diazoxide decreased the number of flinches. Coadministration of glibenclamide with morphine antagonized the hepatotoxic effect of morphine in both animal models. In the tail-flick test, glibenclamide administered alone significantly increased malondialdehyde's level. Coadministration of diazoxide with morphine increased glutathione level in the formalin test. Diazoxide administered alone exacerbated the hepatic oxidative stress in both animal models. These findings suggest a role of K(ATP) channel modulators on morphine-induced antinociception and hepatic oxidative stress. The administration of glibenclamide may prevent morphine-induced hepatotoxicity. The effectiveness of diazoxide in the management of pain is limited due to its deleterious effect on the liver. However, the interaction of the K(ATP) channel modulators with morphine depends on the differential sensitivity to the pain stimulus. PMID- 23033988 TI - Implications of surfactant-induced flow for miscible-displacement estimation of air-water interfacial areas in unsaturated porous media. AB - Surfactant miscible-displacement experiments represent a conventional means of estimating air-water interfacial area (A(I)) in unsaturated porous media. However, changes in surface tension during the experiment can potentially induce unsaturated flow, thereby altering interfacial areas and violating several fundamental method assumptions, including that of steady-state flow. In this work, the magnitude of surfactant-induced flow was quantified by monitoring moisture content and perturbations to effluent flow rate during miscible displacement experiments conducted using a range of surfactant concentrations. For systems initially at 83% moisture saturation (S(W)), decreases of 18-43% S(W) occurred following surfactant introduction, with the magnitude and rate of drainage inversely related to the surface tension of the surfactant solution. Drainage induced by 0.1 mM sodium dodecyl benzene sulfonate, commonly used for A(I) estimation, resulted in effluent flow rate increases of up to 27% above steady-state conditions and is estimated to more than double the interfacial area over the course of the experiment. Depending on the surfactant concentration and the moisture content used to describe the system, A(I) estimates varied more than 3-fold. The magnitude of surfactant-induced flow is considerably larger than previously recognized and casts doubt on the reliability of A(I) estimation by surfactant miscible-displacement. PMID- 23033989 TI - Perhaps unidimensional is not unidimensional. AB - Miller (1956) identified his famous limit of 7 +/- 2 items based in part on absolute identification-the ability to identify stimuli that differ on a single physical dimension, such as lines of different length. An important aspect of this limit is its independence from perceptual effects and its application across all stimulus types. Recent research, however, has identified several exceptions. We investigate an explanation for these results that reconciles them with Miller's work. We find support for the hypothesis that the exceptional stimulus types have more complex psychological representations, which can therefore support better identification. Our investigation uses data sets with thousands of observations for each participant, which allows the application of a new technique for identifying psychological representations: the structural forms algorithm of Kemp and Tenenbaum (2008). This algorithm supports inferences not possible with previous techniques, such as multidimensional scaling. PMID- 23033990 TI - Functional connectivity profile of the human inferior frontal junction: involvement in a cognitive control network. AB - BACKGROUND: The human inferior frontal junction area (IFJ) is critically involved in three main component processes of cognitive control (working memory, task switching and inhibitory control). As it overlaps with several areas in established anatomical labeling schemes, it is considered to be underreported as a functionally distinct location in the neuroimaging literature. While recent studies explicitly focused on the IFJ's anatomical organization and functional role as a single brain area, it is usually not explicitly denominated in studies on cognitive networks. However based on few analyses in small datasets constrained by specific a priori assumptions on its functional specialization, the IFJ has been postulated to be part of a cognitive control network. Goal of this meta-analysis was to establish the IFJ's connectivity profile on a high formal level of evidence by aggregating published implicit knowledge about its co activations. We applied meta-analytical connectivity modeling (MACM) based on the activation likelihood estimation (ALE) method without specific assumptions regarding functional specialization on 180 (reporting left IFJ activity) and 131 (right IFJ) published functional neuroimaging experiments derived from the BrainMap database. This method is based on coordinates in stereotaxic space, not on anatomical descriptors. RESULTS: The IFJ is significantly co-activated with areas in the dorsolateral and ventrolateral prefrontal cortex, anterior insula, medial frontal gyrus / pre-SMA, posterior parietal cortex, occipitotemporal junction / cerebellum, thalamus and putamen as well as language and motor areas. Results are corroborated by an independent resting-state fMRI analysis. CONCLUSIONS: These results support the assumption that the IFJ is part of a previously described cognitive control network. They also highlight the involvement of subcortical structures in this system. A direct line is drawn from works on the functional significance of brain activity located at the IFJ and its anatomical definition to published results related to distributed cognitive brain systems. The IFJ is therefore introduced as a convenient starting point to investigate the cognitive control network in further studies. PMID- 23033991 TI - Reversible photoswitching of spiropyran-conjugated semiconducting polymer dots. AB - Semiconducting polymer dots (Pdots) recently have emerged as a new class of ultrabright fluorescent probes with promising applications in biological detection and imaging. We developed photoswitchable Pdots by conjugating photochromic spiropyran molecules onto poly[9,9-dioctylfluorenyl-2,7-diyl)-co-1,4 benzo-{2,1'-3}-thiadiazole)] (PFBT). The modulation of fluorescence was achieved by ultraviolet irradiation, which converted spiropyran into its visible-absorbing merocyanine form. The merocyanine efficiently quenched the fluorescence of PFBT via Forster resonance energy transfer (FRET). We then reversed the quenching by subsequent irradiation with visible light to get back the fluorescence of PFBT. This FRET-based photomodulation of Pdot fluorescence could be repeated multiple times. We next conjugated biomolecules onto the surface of these photoswitchable Pdots and demonstrated their specific cellular and subcellular labeling to different types of cells without any noticeable nonspecific binding. We anticipate these photoswitchable and biocompatible Pdots will be useful in developing bioimaging techniques in the future. PMID- 23033992 TI - The effect of pre-exercise diesel exhaust exposure on cycling performance and cardio-respiratory variables. AB - PURPOSE: To determine the effect of pre-exercise exposure to diesel exhaust (DE) on 20-km cycling performance, pulmonary function, and cardio-respiratory variables during exercise. METHODS: Eight endurance-trained males participated in the study. Test days consisted of a 60-min exposure to either filtered air (FA) or DE, followed by a 20 km cycling time trial. Exposures to DE were at a concentration of 300 ug/m3 of PM(2.5). Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured before and after exposure, and after exercise. Oxygen consumption (VO2) and carbon dioxide production (VCO2), minute ventilation (V(E)), tidal volume (V(T)), breathing frequency (F(B)), heart rate and oxyhemoglobin saturation (SpO2), were collected during the time trials. The effect of condition on time trial duration, an order effect, and mean cardio respiratory variables were each analysed using paired T-tests. Repeated-measures ANOVA were used to assess the effect of DE exposure on pulmonary function. RESULTS: There was a main effect of condition (FA vs. DE) on the change in FEV1 from baseline, and in exercise heart rate. Post hoc tests revealed that exercise induced bronchodilation was significantly attenuated following DE compared to FA. There were no main effects of condition on 20 km cycling performance, or VO2, VCO2, V(E), V(T), F(B) and SpO2 during a 20 km time trial. CONCLUSION: A 60-min exposure to DE prior to exercise significantly attenuated exercise-induced bronchodilation and significantly increased heart rate during exercise. Pre exercise exposure to diesel exhaust did not significantly impair 20 km cycling time trial performance. PMID- 23033993 TI - Synergistic effects of exposure to concentrated ambient fine pollution particles and nitrogen dioxide in humans. AB - CONTEXT: Exposure to single pollutants e.g. particulate matter (PM) is associated with adverse health effects, but it does not represent a real world scenario that usually involves multiple pollutants. OBJECTIVES: Determine if simultaneous exposure to PM and NO2 results in synergistic interactions. MATERIALS AND METHODS: Healthy young volunteers were exposed to clean air, nitrogen dioxide (NO2, 0.5 ppm), concentrated fine particles from Chapel Hill air (PM(2.5)CAPs, 89.5 +/- 10.7 ug/m3), or NO2+PM(2.5)CAPs for 2 h. Each subject performed intermittent exercise during the exposure. Parameters of heart rate variability (HRV), changes in repolarization, peripheral blood endpoints and lung function were measured before and 1 and 18 h after exposure. Bronchoalveolar lavage (BAL) was performed 18 h after exposure. RESULTS: NO2 exposure alone increased cholesterol and HDL 18 h after exposure, decreased high frequency component of HRV one and 18 h after exposure, decreased QT variability index 1 h after exposure, and increased LDH in BAL fluid. The only significant change with PM(2.5)CAPs was an increase in HDL 1 h after exposure, likely due to the low concentrations of PM(2.5)CAPs in the exposure chamber. Exposure to both NO2 and PM(2.5)CAPs increased BAL alpha1-antitrypsin, mean t wave amplitude, the low frequency components of HRV and the LF/HF ratio. These changes were not observed following exposure to NO2 or PM(2.5)CAPs alone, suggesting possible interactions between the two pollutants. DISCUSSION AND CONCLUSIONS: NO2 exposure may produce and enhance acute cardiovascular effects of PM(2.5)CAPs. Assessment of health effects by ambient PM should consider its interactions with gaseous copollutants. PMID- 23033994 TI - Multi-walled carbon nanotubes: sampling criteria and aerosol characterization. AB - This study intends to develop protocols for sampling and characterizing multi walled carbon nanotube (MWCNT) aerosols in workplaces or during inhalation studies. Manufactured dry powder containing MWCNT's, combined with soot and metal catalysts, form complex morphologies and diverse shapes. The aerosols, examined in this study, were produced using an acoustical generator. Representative samples were collected from an exposure chamber using filters and a cascade impactor for microscopic and gravimetric analyses. Results from filters showed that a density of 0.008-0.10 particles per um2 filter surface provided adequate samples for particle counting and sizing. Microscopic counting indicated that MWCNT's, resuspended at a concentration of 10 mg/m3, contained 2.7 * 104 particles/cm3. Each particle structure contained an average of 18 nanotubes, resulting in a total of 4.9 * 105 nanotubes/cm3. In addition, fibrous particles within the aerosol had a count median length of 3.04 um and a width of 100.3 nm, while the isometric particles had a count median diameter of 0.90 um. A combination of impactor and microscopic measurements established that the mass median aerodynamic diameter of the mixture was 1.5 um. It was also determined that the mean effective density of well-defined isometric particles was between 0.71 and 0.88 g/cm3, and the mean shape factor of individual nanotubes was between 1.94 and 2.71. The information obtained from this study can be used for designing animal inhalation exposure studies and adopted as guidance for sampling and characterizing MWCNT aerosols in workplaces. The measurement scheme should be relevant for any carbon nanotube aerosol. PMID- 23033995 TI - Change in agglomeration status and toxicokinetic fate of various nanoparticles in vivo following lung exposure in rats. AB - The deposition characteristics in lungs following inhalation, the potential toxic effects induced and the toxicokinetic fate including a possible translocation to other sites of the body are predominantly determined by the agglomeration status of nanoscaled primary particles. Systemic particle effects, i.e. effects on remote organs besides the respiratory tract are considered to be of relevant impact only for de-agglomerated particles with a nanoscaled aspect. Rats were exposed to various types of nanoscaled particles, i.e. titanium dioxide, carbon black and constantan. These were dispersed in physiologically compatible media, e.g. phosphate buffer, sometimes including auxiliaries. Rats were treated with aqueous nanoparticle dispersions by intratracheal instillation or were exposed to well-characterized nanoparticle aerosols. Subsequently, alterations in the particle size distribution were studied using transmission electron microscopy (TEM) as well as the bronchoalveolar lavage (BAL) technique. Based on the results in various approaches, a tendency of nanoscaled particles to form larger size agglomerates following deposition and interaction with cells or the respiratory tract is predominant. The contrary trend, i.e. the increase of particle number due to a disintegration of agglomerates seems not to be of high relevance. PMID- 23033996 TI - Effects of outdoor air pollutants on platelet activation in people with type 2 diabetes. AB - Exposure to air pollution is associated with increased morbidity and mortality from cardiovascular disease. We hypothesized that increases in exposure to ambient air pollution are associated with platelet activation and formation of circulating tissue factor-expressing microparticles. We studied 19 subjects with type 2 diabetes, without clinical evidence of cardiovascular disease, who had previously participated in a human clinical study of exposure to ultrafine particles (UFP). Blood was obtained for measurements of platelet activation following an overnight stay in the Clinical Research Center, prior to each of their two pre-exposure visits. Air pollution and meteorological data, including UFP counts, were analyzed for the 5 days prior to the subjects' arrival at the Clinical Research Center. Contrary to expectations, increases in UFP were associated with decreases in surface expression of platelet activation markers. The number of platelet-leukocyte conjugates decreased by -80 (95% confidence interval (CI) -123 to -37, p = 0.001) on the first lag day (20-44 h prior to the blood draw) and by -85 (CI -139 to -31, p = 0.005) on combined lag days 1 to 5, per interquartile range (IQR) increase in UFP particle number (2482). However, levels of soluble CD40L increased 104 (CI 3 to 205, p = 0.04) pg/ml per IQR increase in UFP on lag day 1, a finding consistent with prior platelet activation. We speculate that, in people with diabetes, exposure to UFP activates circulating platelets within hours of exposure, followed by an increase in soluble CD40L and a rebound reduction in circulating platelet surface markers. PMID- 23033997 TI - Industrial worker exposure to airborne particles during the packing of pigment and nanoscale titanium dioxide. AB - CONTEXT: Titanium dioxide (TiO2) factory workers' source specific exposure and dose to airborne particles was studied extensively for particles between 5 nm and 10 MUm in size. OBJECTIVE: We defined TiO2 industry workers' quantitative inhalation exposure levels during the packing of pigment TiO2 (pTiO2) and nanoscale TiO2 (nTiO2) material from concentrations measured at work area. METHODS: Particle emissions from different work events were identified by linking work activity with the measured number size distributions and mass concentrations of particles. A lung deposit model was used to calculate regional inhalation dose rates in units of particles min-1 and MUg min-1 without use of respirators. RESULTS: Workers' average exposure varied from 225 to 700 MUg m-3 and from 1.15 * 104 to 20.1 * 104 cm-4. Over 90% of the particles were smaller than 100 nm. These were mainly soot and particles formed from process chemicals. Mass concentration originated primarily from the packing of pTiO2 and nTiO2 agglomerates. The nTiO2 exposure resulted in a calculated dose rate of 3.6 * 106 min-1 and 32 MUg min-1 where 70% of the particles and 85% of the mass was deposited in head airways. CONCLUSIONS: The recommended TiO2 exposure limits in mass by NIOSH and in particle number by IFA were not exceeded. We recommend source-specific exposure assessment in order to evaluate the workers' risks. In nTiO2 packing, mass concentration best describes the workers' exposure to nTiO2 agglomerates. Minute dose rates enable the simulation of workers' risks in different exposure scenarios. PMID- 23033998 TI - Comparison of the effects of e-cigarette vapor and cigarette smoke on indoor air quality. AB - CONTEXT: Electronic cigarettes (e-cigarettes) have earned considerable attention recently as an alternative to smoking tobacco, but uncertainties about their impact on health and indoor air quality have resulted in proposals for bans on indoor e-cigarette use. OBJECTIVE: To assess potential health impacts relating to the use of e-cigarettes, a series of studies were conducted using e-cigarettes and standard tobacco cigarettes. METHODS AND MATERIALS: Four different high nicotine e-liquids were vaporized in two sets of experiments by generic 2-piece e cigarettes to collect emissions and assess indoor air concentrations of common tobacco smoke by products. Tobacco cigarette smoke tests were conducted for comparison. RESULTS: Comparisons of pollutant concentrations were made between e cigarette vapor and tobacco smoke samples. Pollutants included VOCs, carbonyls, PAHs, nicotine, TSNAs, and glycols. From these results, risk analyses were conducted based on dilution into a 40 m3 room and standard toxicological data. Non-cancer risk analysis revealed "No Significant Risk" of harm to human health for vapor samples from e-liquids (A-D). In contrast, for tobacco smoke most findings markedly exceeded risk limits indicating a condition of "Significant Risk" of harm to human health. With regard to cancer risk analysis, no vapor sample from e-liquids A-D exceeded the risk limit for either children or adults. The tobacco smoke sample approached the risk limits for adult exposure. CONCLUSIONS: For all byproducts measured, electronic cigarettes produce very small exposures relative to tobacco cigarettes. The study indicates no apparent risk to human health from e-cigarette emissions based on the compounds analyzed. PMID- 23033999 TI - Long-range transported Asian Dust and emergency ambulance dispatches. AB - Asian Dust (AD) particles transported from source areas contribute to sharp increases in coarse particles in Japan. We examined the association of exposure to AD events with emergency ambulance dispatches in Nagasaki city. We also examined whether AD transported at different altitude routes from source areas influenced dispatch rates. Using lidar (light detection and ranging), we determined moderate AD days (0.066/km AUCbrain > AUClung > AUCspleen > AUCheart > AUCkidney, while the SWW group is AUCliver > AUClung > AUCspleen > AUCheart > AUCbrain > AUCspleen. Especially, the AUC value in brain region (AUCbrain) of ME is 6.06-fold of SWW. The drug relative overall targeting efficiency (RTE) are calculated: heart (7.49%), liver (3.54%), spleen (12.60%), lung (6.02%), kidney (2.86%) and brain (12.51%). The results from ME directly showed obvious targeting transport to the brain. These results indicated that this new family of pharmaceutical carriers can be used for the solubilization and targeted delivery of poorly soluble drugs to various pathological sites in the body. PMID- 23034009 TI - Pediatric and adolescent migraine. PMID- 23034010 TI - Response letter to D. Singh-franco et al. PMID- 23034011 TI - Response letter. Effects of linagliptin. PMID- 23034013 TI - Anti-bacterial factors secreted from cumulus cells of ovulated COCs enhance sperm capacitation during in vitro fertilization. AB - PROBLEM: The aim of this study was to find immune-related genes expressed in cumulus cells of ovulated cumulus oocyte complexes (COCs) and to clear the functional roles during fertilization process. METHOD OF STUDY: Ovulated COCs were collected from oviduct 16 hr after the hCG injections followed by eCG priming. The cumulus cells were used for RT-PCR or western blotting study. COCs were also used for in vitro fertilization study. RESULTS: Cramp, Trf, Lyz2, S100a8, and S100a9 were expressed in cumulus cells during ovulation process. The protein levels of CRAMP or transferrin were detected in ovulated COCs and then secreted into hyaluronan-rich matrix. The high dose of these factors reduced the proliferative activity of E. coli; however, the lower levels of them significantly increased the rate of fertilization in in vitro via the induction of sperm capacitation. CONCLUSION: Cumulus-secreted anti-bacterial factors act on sperm to induce sperm capacitation. PMID- 23034014 TI - Association of vitamin D receptor gene polymorphisms with severe atopic dermatitis in adults. AB - BACKGROUND: Vitamin D mediates immunomodulatory functions, and beneficial functions in allergic diseases have been suggested. Vitamin D receptor gene (VDR) polymorphisms are known but have not been studied in patients with atopic dermatitis (AD). OBJECTIVES: To investigate the frequency of four common VDR gene polymorphisms in patients with AD, and their potential functional relevance. METHODS: In this case-control study, 265 patients with AD [n=142 severe AD, Scoring AD index (SCORAD) > 40; n=123 moderate AD, SCORAD 15-40] and 265 healthy controls were genotyped for four common VDR gene polymorphisms by restriction fragment length polymorphism analysis. The VDR haplotype sequences were analysed in silico. Baseline and activation-induced gene expression of VDR and the vitamin D metabolizing enzyme CYP24A1 were analysed in monocytes of homozygous VDR haplotype carriers by quantitative reverse transcription-polymerase chain reaction. RESULTS: In patients with severe AD, the VDR BsmI (rs1544410) G allele, ApaI (rs7975232) C allele and TaqI (rs731236) T alleles were over-represented compared with healthy controls. These single nucleotide polymorphisms (SNP) were tightly linked, and the VDR haplotype GCT was correlated with severe AD and complementary AAC with protection from AD. The VDR haplotype GCT region is evolutionarily conserved. The VDR FokI (rs2228570) SNP was not associated with AD. Baseline VDR expression in monocytes and short-term activation were haplotype independent. CONCLUSION: A specific VDR haplotype is more frequent in patients with severe AD. These data indicate that VDR contributes to the control of AD, e.g. by regulation of the epidermal barrier function and/or local immune response. PMID- 23034015 TI - Are obstetric anal sphincter ruptures preventable?-- large and consistent rupture rate variations between the Nordic countries and between delivery units in Norway. AB - OBJECTIVE: To study changes in the incidence of obstetric anal sphincter rupture (OASR) during recent years in Denmark, Finland, Sweden and Norway and hospital based incidence in recent years in Norway. DESIGN: Retrospective birth register study. SETTING: Unselected population of delivering women in four Nordic countries. SAMPLE: All deliveries (574 175) registered in Denmark, Finland, Norway and Sweden, 2004-2010. METHODS: Parity data, including maternal, obstetrical and fetal characteristics, were obtained. The incidence of OASR was calculated from vaginal deliveries. A chi-squared test was used to analyse differences between countries and time periods. MAIN OUTCOME MEASURES: Incidence of OASR. RESULTS: During the study period, the OASR incidence in Finland was notably lower (0.7-1.0%) than in the other three Nordic countries (4.2-2.3%). A significant and constant reduction in OASR incidence was observed in Norway only (from 4.1 to 2.3%, from 2004 to 2010, p < 0.001). This reduction occurred simultaneously with introduction of a national intervention program of improved delivery techniques that aimed to reduce the incidence of OASR. No major alterations in maternal or fetal risk factors for OASR or registration routines could explain this rapid reduction in the rate of OASR. Differences in the incidence of OASR between Norwegian delivery units were significant, with a threefold difference when comparing the units with lowest and highest incidences. CONCLUSIONS: Obstetric anal sphincter rupture seems to be preventable to a considerable extent, as indicated by the rapid and lasting reduction of OASR incidence after implementation of perineal protection programs in Norway. Improved delivery techniques should be implemented in all delivery units to prevent OASR as much as possible. PMID- 23034016 TI - Gastric carcinoma associated with Menetrier's-like disease in a West Highland white terrier. AB - A seven-year-old West Highland white terrier was presented for chronic vomiting associated with mild regenerative anaemia and hypoalbuminaemia. Further examination showed a giant polypoid cerebriform mass located in the lesser curvature of the stomach. Partial gastrectomy was performed and histology was consistent with hypertrophic gastritis with typical features of Menetrier's disease. Five years after surgery, the dog was re-examined for recurrence of vomiting episodes. Endoscopy showed ulceration of the lesser curvature of the stomach and histological analysis revealed a poorly differentiated superficial gastric carcinoma surrounded by hypertrophic gastritis. To the authors' knowledge, this is the second time that coexistence of these two types of lesions is reported, suggesting that recurrence of gastritis could be the starting point of the tumoural process. PMID- 23034018 TI - France's new framework for regulating off-label drug use. PMID- 23034017 TI - User fees and beyond--the FDA Safety and Innovation Act of 2012. PMID- 23034019 TI - Head and shoulder. PMID- 23034021 TI - The past 200 years in diabetes. PMID- 23034022 TI - Images in clinical medicine. Mydriasis in the garden. PMID- 23034023 TI - Clinical problem-solving. An intricate interplay. PMID- 23034025 TI - The prevention and treatment of missing data in clinical trials. PMID- 23034026 TI - The shear stress of busting blood clots. PMID- 23034029 TI - MEK inhibition in BRAF-mutated melanoma. PMID- 23034028 TI - MEK inhibition in BRAF-mutated melanoma. PMID- 23034031 TI - Early surgery for infective endocarditis. PMID- 23034032 TI - Early surgery for infective endocarditis. PMID- 23034033 TI - Early surgery for infective endocarditis. PMID- 23034035 TI - Vitamin D dose requirements for fracture prevention. PMID- 23034020 TI - C-reactive protein, fibrinogen, and cardiovascular disease prediction. AB - BACKGROUND: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. METHODS: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. RESULTS: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (>=20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of >=20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. CONCLUSIONS: In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.). PMID- 23034036 TI - Vitamin D dose requirements for fracture prevention. PMID- 23034037 TI - Vitamin D dose requirements for fracture prevention. PMID- 23034040 TI - Management of opioid analgesic overdose. PMID- 23034038 TI - Vitamin D dose requirements for fracture prevention. PMID- 23034041 TI - Management of opioid analgesic overdose. PMID- 23034042 TI - Management of opioid analgesic overdose. PMID- 23034043 TI - Management of opioid analgesic overdose. PMID- 23034044 TI - Four-year follow-up after two-year dietary interventions. PMID- 23034045 TI - Images in clinical medicine. Mites in the external auditory canal. PMID- 23034046 TI - Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. AB - Mesenchymal stem cells (MSCs) have opposite effects on tumor growth, being able either to favor angiogenesis and tumor initiation or to inhibit progression of established tumors. Factors produced by MSCs within the tumor microenvironment may be relevant for their biological effects. Recent studies demonstrated that microvesicles (MVs) are an integral component of inter-cellular communication within the tumor microenvironment. In the present study, we evaluated whether MVs derived from human bone marrow MSCs may stimulate or inhibit in vitro and in vivo growth of HepG2 hepatoma, Kaposi's sarcoma, and Skov-3 ovarian tumor cell lines. We found that MVs inhibited cell cycle progression in all cell lines and induced apoptosis in HepG2 and Kaposi's cells and necrosis in Skov-3. The observed activation of negative regulators of cell cycle may explain these biological effects. In vivo intra-tumor administration of MVs in established tumors generated by subcutaneous injection of these cell lines in SCID mice significantly inhibited tumor growth. In conclusion, MVs from human MSCs inhibited in vitro cell growth and survival of different tumor cell lines and in vivo progression of established tumors. PMID- 23034047 TI - Neuronal Toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro. AB - BACKGROUND: The innate immune response in the brain is initiated by pathogen associated molecular patterns (PAMPS) or danger-associated molecular patterns (DAMPS) produced in response to central nervous system (CNS) infection or injury. These molecules activate members of the Toll-like receptor (TLR) family, of which TLR4 is the receptor for bacterial lipopolysaccharide (LPS). Although neurons have been reported to express TLR4, the function of TLR4 activation in neurons remains unknown. METHODS: TLR4 mRNA expression in primary mouse glial and neuronal cultures was assessed by RT-PCR. Mouse mixed glial, neuronal or endothelial cell cultures were treated with LPS in the absence or the presence of a TLR4 specific antagonist (VIPER) or a specific JNK inhibitor (SP600125). Expression of inflammatory mediators was assayed by cytometric bead array (CBA) and ELISA. Activation of extracellular-signal regulated kinase 1/2 (ERK1/2), p38, c-Jun-N-terminal kinase (JNK) and c-Jun was assessed by Western blot. The effect of conditioned media of untreated- versus LPS-treated glial or neuronal cultures on endothelial activation was assessed by neutrophil transmigration assay, and immunocytochemistry and ELISA were used to measure expression of intercellular cell adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1). RESULTS: LPS induces strong release of the chemokines RANTES and CXCL1 (KC), tumor necrosis factor-alpha (TNFalpha) and IL-6 in primary mouse neuronal cultures. In contrast, LPS induced release of IL-1alpha, IL-1beta and granulocyte colony stimulating factor (G-CSF) in mixed glial, but not in neuronal cultures. LPS-induced neuronal KC expression and release were completely blocked by VIPER. In glial cultures, LPS induced activation of ERK1/2, p38 and JNK. In contrast, in neuronal cultures, LPS activated JNK but not ERK1/2 or p38, and the specific JNK inhibitor SP600125 significantly blocked LPS-induced KC expression and release. Finally, conditioned medium of LPS-treated neuronal cultures induced strong expression of ICAM-1 and VCAM-1 on endothelial cells, and induced infiltration of neutrophils across the endothelial monolayer, which was inhibited by VIPER. CONCLUSION: These data demonstrate for the first time that neurons can play a role as key sensors of infection to initiate CNS inflammation. PMID- 23034048 TI - The effect of clinical experience, judgment task difficulty and time pressure on nurses' confidence calibration in a high fidelity clinical simulation. AB - BACKGROUND: Misplaced or poorly calibrated confidence in healthcare professionals' judgments compromises the quality of health care. Using higher fidelity clinical simulations to elicit clinicians' confidence 'calibration' (i.e. overconfidence or underconfidence) in more realistic settings is a promising but underutilized tactic. In this study we examine nurses' calibration of confidence with judgment accuracy for critical event risk assessment judgments in a high fidelity simulated clinical environment. The study also explores the effects of clinical experience, task difficulty and time pressure on the relationship between confidence and accuracy. METHODS: 63 student and 34 experienced nurses made dichotomous risk assessments on 25 scenarios simulated in a high fidelity clinical environment. Each nurse also assigned a score (0-100) reflecting the level of confidence in their judgments. Scenarios were derived from real patient cases and classified as easy or difficult judgment tasks. Nurses made half of their judgments under time pressure. Confidence calibration statistics were calculated and calibration curves generated. RESULTS: Nurse students were underconfident (mean over/underconfidence score -1.05) and experienced nurses overconfident (mean over/underconfidence score 6.56), P = 0.01. No significant differences in calibration and resolution were found between the two groups (P = 0.80 and P = 0.51, respectively). There was a significant interaction between time pressure and task difficulty on confidence (P = 0.008); time pressure increased confidence in easy cases but reduced confidence in difficult cases. Time pressure had no effect on confidence or accuracy. Judgment task difficulty impacted significantly on nurses' judgmental accuracy and confidence. A 'hard-easy' effect was observed: nurses were overconfident in difficult judgments and underconfident in easy judgments. CONCLUSION: Nurses were poorly calibrated when making risk assessment judgments in a high fidelity simulated setting. Nurses with more experience tended toward overconfidence. Whilst time pressure had little effect on calibration, nurses' over/underconfidence varied significantly with the degree of task difficulty. More research is required to identify strategies to minimize such cognitive biases. PMID- 23034050 TI - A generic method for rational scalable synthesis of monodisperse metal sulfide nanocrystals. AB - A rational synthetic method is developed to produce monodisperse metal sulfide nanocrystals (NCs) in organic nonpolar solutions by using (NH(4))(2)S as a sulfide precursor. (NH(4))(2)S is stabilized in an organic primary amine solution and exhibits high reactivity toward metal complexes. This novel technique exhibits wide applicability for organic phase metal sulfide NC synthesis: a large variety of monodisperse NCs have been synthesized, including Cu(2)S, CdS, SnS, ZnS, MnS, Ag(2)S, and Bi(2)S(3). The stoichiometric reactions between (NH(4))(2)S and metal salts afford high conversion yields, and large-scale production of monodisperse NCs (more than 30 g) can be synthesized in a single reaction. The high reactivity of (NH(4))(2)S enables low temperature (<100 degrees C) syntheses, and the air-stable materials (such as CdS NCs) can be produced in air. Moreover, this low-temperature technique can be used to produce small size NCs which are difficult to be synthesized by the conventional high temperature methods, such as sub-5 nm Ag(2)S and Bi(2)S(3) quantum dots. PMID- 23034049 TI - Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies. AB - BACKGROUND: Activated mast cells are present within airway smooth muscle (ASM) bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide), long-acting beta2-agonists (salmeterol, formoterol) and thiazolidinediones (ciglitazone, rosiglitazone) on CXCL10 production by ASM cells (ASMC) from people with and without asthma were investigated in vitro. METHODS: Confluent serum-deprived cells were treated with the agents before and during cytokine stimulation for 0-24 h. CXCL10 protein/mRNA, IkappaB-alpha levels and p65 activity were measured using ELISA, RT PCR, immunoblotting and p65 activity assays respectively. Data were analysed using ANOVA followed by Fisher's post-hoc test. RESULTS: Fluticasone and/or salmeterol at 1 and 100 nM inhibited CXCL10 release induced by IL-1beta and TNF-alpha, but not IFNgamma or all three cytokines (cytomix). The latter was also not affected by budesonide and formoterol. In asthmatic ASMC low salmeterol, but not formoterol, concentrations increased cytomix-induced CXCL10 release and at 0.01 nM enhanced NF-kappaB activity. Salmeterol 0.1 nM together with fluticasone 0.1 and 10 nM still increased CXCL10 release. The thiazolidinediones ciglitazone and rosiglitazone (at 25 and 100 MUM) inhibited cytomix-induced CXCL10 release but these inhibitory effects were not prevented by the PPAR-g antagonist GW9662. Ciglitazone did not affect early NF-kappaB activity and CXCL10 mRNA production. CONCLUSIONS: Thus the thiazolidinediones inhibited asthmatic ASMC CXCL10 release under conditions when common asthma therapies were ineffective or enhanced it. They may provide an alternative strategy to reduce mast cell-ASM interactions and restore normal airway physiology in asthma. PMID- 23034051 TI - The microarray technology: facts and controversies. AB - Molecular diagnostic techniques for viral testing have undergone rapid development in recent years. They are becoming more widely used than the classical virological assays in the majority of clinical virology laboratories, and now represent a new method for the diagnosis of human viral infections. Recently, new techniques based on multiplex RT-PCR amplification followed by microarray analysis have been developed and evaluated. On the basis of amplification of viral genome-specific fragments by multiplex RT-PCR and their subsequent detection via hybridization with microorganism-specific binding probes on solid surfaces, they allow simultaneous detection and identification of multiple viruses in a single clinical sample. The management of viral central nervous system and respiratory tract infections currently represents the two main applications of the microarrays in routine virological practice. Microarrays have shown reliable results in comparison with those of referenced (RT)-PCR assays, and appear to be of major interest for the detection of a broad range of respiratory and neurotropic viruses, assessment of the pathogenicity of newly discovered or neglected viruses, and identification of multiple viral infections in clinical samples. Despite several limitations observed during the different studies performed, this new technology might improve the clinical management of patients by enlarging the range of the viruses detected, in particular in cases of severe infections leading to patient hospitalization in the intensive-care unit. They might also help in the prevention of nosocomial transmission in hospital departments by contributing to the development of new epidemiological surveillance systems for viral infections. PMID- 23034052 TI - Mechanistic and structural analyses of the roles of active site residues in yeast polyamine oxidase Fms1: characterization of the N195A and D94N enzymes. AB - Flavoprotein Fms1 from Saccharomyces cerevisiae catalyzes the oxidation of spermine in the biosynthetic pathway for pantothenic acid. The same reaction is catalyzed by the mammalian polyamine and spermine oxidases. The active site of Fms1 contains three amino acid residues positioned to interact with the polyamine substrate, His67, Asn195, and Asp94. These three residues form a hydrogen-bonding triad with Asn195 being the central residue. Previous studies of the effects of mutating His67 are consistent with that residue being important both for interacting with the substrate and for maintaining the hydrogen bonds in the triad [Adachi, M. S., Taylor, A. B., Hart, P. J., and Fitzpatrick, P. F. (2012) Biochemistry 51, 4888-4897]. The N195A and D94N enzymes have now been characterized to evaluate their roles in catalysis. Both mutations primarily affect the reductive half-reaction. With N(1)-acetylspermine as the substrate, the rate constant for flavin reduction decreases ~450-fold for both mutations; the effects with spermine as the substrate are smaller, 20-40-fold. The k(cat)/K(amine)- and k(cat)-pH profiles with N(1)-acetylspermine are only slightly changed from the profiles for the wild-type enzyme, consistent with the pK(a) values arising from the amine substrate or product and not from active site residues. The structure of the N195A enzyme was determined at a resolution of 2.0 A. The structure shows a molecule of tetraethylene glycol in the active site and establishes that the mutation has no effect on the protein structure. Overall, the results are consistent with the role of Asn195 and Asp94 being to properly position the polyamine substrate for oxidation. PMID- 23034053 TI - Hypocupremia associated cytopenia and myelopathy: a national retrospective review. AB - Copper is an essential trace element that is involved in a number of important enzymatic processes throughout the body. Recent single case reports and small studies have shown that deficiency of copper can cause reversible haematological changes and irreversible neurological injury. We chose to undertake a national study, looking at all cases of copper deficiency in Scotland over a 5-yr period using information from a national reference laboratory. From 16 identified patients, we determined that 86% had both haematological and neurological features of copper deficiency, while 18% had haematological features only at presentation. Twelve of the sixteen patients had high serum zinc concentrations (>18 MUm/L) nine patients were using zinc-containing dental fixatives at time of diagnosis. 94% of patients had haematological features as an initial manifestation of copper deficiency, which included anaemia, thrombocytopenia and neutropenia. Patients who underwent later bone marrow testing had appearances in keeping with refractory cytopenia with multilineage dysplasia, refractory anaemia with excess of blasts, unclassified marrow dysplasia or probable myelodysplasia (MDS). 75% of patients had neurological symptoms or signs, including progressive walking difficulties and paraesthesia, or gait difficulties without sensory signs. Clinical examination was in keeping with spastic paraparesis (either with or without sensory neuropathy). Magnetic resonance imaging (MRI) showed multifocal T2 hyper intense foci in the subcortical white matter, and atrophy of the cerebrum and cerebellum was also seen on computerised tomography (CT). MRI of the spinal cord showed signal change in the dorsal columns in either the cervical or thoracic cord. 93% of cytopenias responded to copper replacement and addressing the original cause of the copper deficiency, but only 25% of patients had improvement in their neurological function, while 33% deteriorated and 42% remained unchanged. Our study demonstrates that copper deficiency is an under recognised cause of several types of cytopenia, which are reversible but can progress to significant neurological injury if left untreated. We illustrate the importance of identifying these patients early to prevent irreversible neurological injury. PMID- 23034054 TI - Comparative breeding and behavioral responses to ethinylestradiol exposure in wild and laboratory maintained zebrafish (Danio rerio) populations. AB - Genetic variation has a significant effect on behavior, fitness, and response to toxicants; however, this is rarely considered in ecotoxicological studies. We compared fitness-related behavioral traits, breeding activity, and the effects of exposure to the environmental estrogen ethinylestradiol (EE(2)) on reproduction in a laboratory (Wild Indian Karyotype, WIK) strain and a wild-caught population (Bangladesh, BLD01) of Danio rerio (zebrafish). In WIK fish, males with higher observed heterozygocity were more active reproductively and more successful in securing parentage, but these relationships were not apparent in the BLD01 fish. The frequency of reproductive behaviors increased in WIK zebrafish for exposure to 0.4 ng/L EE(2), which was not apparent in the BLD01 zebrafish. The different strains showed the same threshold for hepatic vitellogenin gene (vtg) induction (2.2 ng EE(2)/L), but results suggested an elevated response level in the BLD01. There were no effects on total egg production up to 2.2 ng EE(2)/L in either population; however, there was reduced egg fertilization rate at 2.2 ng EE(2)/L in the BLD01 fish. These results show consistency in the general responses to EE(2) between these two genetically divergent strains of zebrafish, but also illustrate differences in their breeding biology and response sensitivities. These findings highlight the need for due consideration of the source (and genetics) of populations used in ecological risk assessment for accurate comparisons among studies. PMID- 23034055 TI - Resolving the growth of 3D colloidal nanoparticle superlattices by real-time small-angle X-ray scattering. AB - The kinetics and intricate interactions governing the growth of 3D single nanoparticle (NP) superlattices (SLs, SNSLs) and binary NP SLs (BNSLs) in solution are understood by combining controlled solvent evaporation and in situ, real-time small-angle X-ray scattering (SAXS). For the iron oxide (magnetite) NP SLs studied here, the larger the NP, the farther apart are the NPs when the SNSLs begin to precipitate and the closer they are after ordering. This is explained by a model of NP assembly using van der Waals interactions between magnetite cores in hydrocarbons with a ~21 zJ Hamaker constant. When forming BNSLs of two different sized NPs, the NPs that are in excess of that needed to achieve the final BNSL stoichiometry are expelled during the BNSL formation, and these expelled NPs can form SNSLs. The long-range ordering of these SNSLs and the BNSLs can occur faster than the NP expulsion. PMID- 23034056 TI - Creating a Knowledge Translation Platform: nine lessons from the Zambia Forum for Health Research. AB - The concept of the Knowledge Translation Platform (KTP) provides cohesion and leadership for national-level knowledge translation efforts. In this review, we discuss nine key lessons documenting the experience of the Zambia Forum for Health Research, primarily to inform and exchange experience with the growing community of African KTPs. Lessons from ZAMFOHR's organizational development include the necessity of selecting a multi-stakeholder and -sectoral Board of Directors; performing comprehensive situation analyses to understand not only the prevailing research-and-policy dynamics but a precise operational niche; and selecting a leader that bridges the worlds of research and policy. Programmatic lessons include focusing on building the capacity of both policy-makers and researchers; building a database of local evidence and national-level actors involved in research and policy; and catalyzing work in particular issue areas by identifying leaders from the research community, creating policy-maker demand for research evidence, and fostering the next generation by mentoring both up-and coming researchers and policy-makers. Ultimately, ZAMFOHR's experience shows that an African KTP must pay significant attention to its organizational details. A KTP must also invest in the skill base of the wider community and, more importantly, of its own staff. Given the very real deficit of research-support skills in most low-income countries - in synthesis, in communications, in brokering, in training - a KTP must spend significant time and resources in building these types of in-house expertise. And lastly, the role of networking cannot be underestimated. As a fully-networked KTP, ZAMFOHR has benefited from the innovations of other KTPs, from funding opportunities and partnerships, and from invaluable technical support from both African and northern colleagues. PMID- 23034057 TI - Move for Change Part II: a European survey evaluating the impact of the EPDA Charter for people with Parkinson's disease. AB - BACKGROUND AND PURPOSE: The Move for Change campaign is a three-part series of pan-European surveys designed by the European Parkinson's Disease Association (EPDA) to assess the impact that the EPDA Charter for People with Parkinson's disease (PD) has had since its launch in 1997. Here, we report results from the second survey, focusing on the third right of the Charter; that is, 'all patients have the right to have access to support services'. Although the level of evidence for different support services varies, it is important to ensure that patients can access services with clinically proven benefits. METHODS: This survey comprised nine questions administered online via the EPDA and PD organization Web sites. Accessibility of support services was defined as 'services/medication/multidisciplinary healthcare professionals, etc. being available and on hand to patients when required'. RESULTS: Neurologists and general practitioners (GPs) received highest accessibility results (90.0 and 87.0% of respondents, respectively), with moderate results for physiotherapists (68.0%) and PD organizations (72.0%) and lower results for PD specialist nurses (26.0%), occupational therapists (23.0%), and counselors (27.0%). Support provided by neurologists and PD specialists was considered to be 'very helpful' by 59.0 and 55.7%, respectively, whilst only 31.8% of respondents gave such favorable ratings to GPs. Funding of services was variable across Europe. CONCLUSIONS: These data demonstrate the challenges faced by PD patients in accessing the adequate care and support required throughout the course of their disease. These findings can assist healthcare professionals and policymakers in improving access to support services for patients and their families across Europe. PMID- 23034058 TI - The social paediatrics initiative: a RICHER model of primary health care for at risk children and their families. AB - BACKGROUND: The Responsive Interdisciplinary Child-Community Health Education and Research (RICHER) initiative is an intersectoral and interdisciplinary community outreach primary health care (PHC) model. It is being undertaken in partnership with community based organizations in order to address identified gaps in the continuum of health services delivery for 'at risk' children and their families. As part of a larger study, this paper reports on whether the RICHER initiative is associated with increased: 1) access to health care for children and families with multiple forms of disadvantage and 2) patient-reported empowerment. This study provides the first examination of a model of delivering PHC, using a Social Paediatrics approach. METHODS: This was a mixed-methods study, using quantitative and qualitative approaches; it was undertaken in partnership with the community, both organizations and individual providers. Descriptive statistics, including logistic regression of patient survey data (n=86) and thematic analyses of patient interview data (n=7) were analyzed to examine the association between patient experiences with the RICHER initiative and parent-reported empowerment. RESULTS: Respondents found communication with the provider clear, that the provider explained any test results in a way they could understand, and that the provider was compassionate and respectful. Analysis of the survey and in-depth interview data provide evidence that interpersonal communication, particularly the provider's interpersonal style (e.g., being treated as an equal), was very important. Even after controlling for parents' education and ethnicity, the provider's interpersonal style remained positively associated with parent reported empowerment (p<0.01). CONCLUSIONS: This model of PHC delivery is unique in its purposeful and required partnerships between health care providers and community members. This study provides beginning evidence that RICHER can better meet the health and health care needs of people, especially those who are vulnerable due to multiple intersecting social determinants of health. Positive interpersonal communication from providers can play a key role in facilitating situations where individuals have an opportunity to experience success in managing their and their family's health. PMID- 23034059 TI - Cluster randomized trial in the general practice research database: 2. Secondary prevention after first stroke (eCRT study): study protocol for a randomized controlled trial. AB - BACKGROUND: The purpose of this research is to develop and evaluate methods for conducting pragmatic cluster randomized trials in a primary care electronic database. The proposal describes one application, in a less frequent chronic condition of public health importance, secondary prevention of stroke. A related protocol in antibiotic prescribing was reported previously. METHODS/DESIGN: The study aims to implement a cluster randomized trial (CRT) using the electronic patient records of the General Practice Research Database (GPRD) as a sampling frame and data source. The specific objective of the trial is to evaluate the effectiveness of a computer-delivered intervention at enhancing the delivery of stroke secondary prevention in primary care. GPRD family practices will be allocated to the intervention or usual care. The intervention promotes the use of electronic prompts to support adherence with the recommendations of the UK Intercollegiate Stroke Working Party and NICE guidelines for the secondary prevention of stroke in primary care. Primary outcome measure will be the difference in systolic blood pressure between intervention and control trial arms at 12-month follow-up. Secondary outcomes will be differences in serum cholesterol, prescribing of antihypertensive drugs, statins, and antiplatelet therapy. The intervention will continue for 12 months. Information on the utilization of the decision-support tools will also be analyzed. DISCUSSION: The CRT will investigate the effectiveness of using a computer-delivered intervention to reduce the risk of stroke recurrence following a first stroke event. The study will provide methodological guidance on the implementation of CRTs in electronic databases in primary care. TRIAL REGISTRATION: Current Controlled Trials ISRCTN35701810. PMID- 23034060 TI - Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? A review of clinicopathological features of 27 cases. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) describes a heterogeneous group of severe adverse reactions to medications. The cutaneous phenotype has a number of guises, accompanied by a variety of systemic features including fever, haematological abnormalities and visceral involvement, most commonly the liver. Clinical markers of prognosis have not been identified. OBJECTIVES: To assess the cutaneous signs and dermatopathological features of DRESS in order to identify potential prognostic markers. METHODS: We reviewed the clinical features, dermatopathology and outcomes of 27 consecutive cases of DRESS presenting to a single unit. RESULTS: Four distinct patterns of cutaneous involvement were identified: an urticated papular exanthem (13/27 patients), a morbilliform erythema (three of 27), an exfoliative erythroderma (three of 27) and an erythema multiforme-like (EM-like) reaction consisting of atypical targets (eight of 27). All patients mounted a fever, most developed lymphadenopathy (24/27) and peripheral eosinophilia (25/27) and the most common organ involved was the liver (27/27). Review of the dermatopathic features of patients with DRESS demonstrated a superficial spongiotic dermatitis in the majority of cases (16/27). A smaller number of cases showed basal cell vacuolar degeneration and necrotic keratinocytes (nine of 27). The patients with these biopsy findings more commonly had an EM-like cutaneous phenotype, and more severe hepatic involvement. Three patients died, two following failed liver transplants. CONCLUSIONS: Our series is the first in which a detailed dermatological assessment has been made of consecutive patients presenting with DRESS, and the largest U.K. series to date. Our results suggest a possible prognostic role of the cutaneous and dermatopathic findings in DRESS in predicting the severity of visceral involvement in this syndrome. What's already known about this topic? * Drug reaction with eosinophilia and systemic symptoms (DRESS) has a heterogeneous clinical presentation, with a skin eruption of variable morphology. * DRESS carries considerable morbidity and mortality, usually hepatic in origin, although renal, pulmonary and pericardial involvement can be seen. What does this study add? * The cutaneous phenotype in DRESS can be categorized as an urticated papular exanthem, a morbilliform erythema, exfoliative erythroderma or erythema multiforme-like (EM-like). * An EM-like eruption DRESS may be prognostic of more severe hepatic involvement. PMID- 23034061 TI - Development and characterization of gelatin and ethylcellulose microparticles designed as platforms to delivery fluoride. AB - PURPOSE: To develop and characterize microparticles containing fluoride sources (FS) from sodium fluoride, sodium monofluorophosphate (MFP) or aminofluoride and evaluate their characteristics as fluoride delivery systems. METHODS: Ethylcellulose microparticles containing fluoride (EM) were prepared by emulsification of ethyl acetate dispersion containing polymer and FS (ethylcellulose:FS ratio of 1:0.25 wt/wt) with aqueous external phase containing polysorbate 80 (0.8% vol/vol) using the volume ratio (organic:aqueous) of 1:5. The organic solvent was evaporated; microparticles were collected by centrifuging, washed with deionized water and freeze-dried. Gelatin microparticles containing FS (GM) was obtained by dispersion of the natural polymer in water, adding FS (6:1 wt/wt) and 20% (wt/wt) of mannitol. The final dispersions were spray-dried. Particle morphology and size were investigated using optical microscopy. The content of fluoride ions in the microparticles was quantified using a potentiometric method. The encapsulation efficiency and in vitro release profile of fluoride was also determined. RESULTS: Microparticles exhibited polydispersity and mean diameters <145.35 and <124.22 um for EM and GM, respectively. Considering the entrapment efficiency, the spray-drying technique exhibited greater values than microencapsulation by emulsification and solvent evaporation. The release profile of fluoride ions from microparticles was shown to be modified, fitted first order and guided by Fickian diffusion. CONCLUSIONS: Microparticles prepared with ethylcellulose or gelatin can be used as platform for oral delivery of fluoride, providing a means to increase the local supply of this ion in a controlled manner, providing an increased protection against caries. Moreover, further investigations are needed to demonstrate this property in vivo. PMID- 23034062 TI - Callose plug deposition patterns vary in pollen tubes of Arabidopsis thaliana ecotypes and tomato species. AB - BACKGROUND: The pollen grain contains the male gametophyte that extends a pollen tube that grows through female tissues in order to deliver sperm to the embryo sac for double fertilization. Growing pollen tubes form periodic callose plugs that are thought to block off the older parts of the tube and maintain the cytoplasm near the growing tip. The morphology of callose plugs and the patterns of their deposition were previously shown to vary among species, but variation within a species had not been examined. We therefore systematically examined callose plug deposition in Arabidopsis thaliana ecotypes, tested for heritability using reciprocal crosses between ecotypes that had differing deposition patterns, and investigated the relationship between callose plugs and pollen tube growth rate. We also surveyed callose plug deposition patterns in different species of tomato. RESULTS: We used in vitro grown pollen tubes of 14 different A. thaliana ecotypes and measured the distance from the pollen grain pore to the first callose plug (termed first interval). This distance varied among Arabidopsis ecotypes and in some cases even within an ecotype. Pollen tubes without a callose plug were shorter than those with a callose plug, and tubes with a callose plug near the grain were, on average, longer than those with the first callose plug farther from the grain. Variations in the first callose plug position were also observed between different species of tomato. CONCLUSIONS: We showed that the position of the first callose plug varied among Arabidopsis ecotypes and in tomato species, and that callose plug deposition patterns were heritable. These findings lay a foundation for mapping genes that regulate callose plug deposition or that determine pollen tube length or growth rate. PMID- 23034064 TI - Determination of the cause of selected canine urolith formation by advanced analytical methods. AB - OBJECTIVE: The goal of this study was to determine the cause of selected canine urolith formation using less conventional but more advanced analytical methods. METHODS: A routine laboratory specialising in urinary calculi analysis noticed a special type of core zone in some canine uroliths, which was typically made up of cylindrical holes. Of 4028 canine samples analysed, non-absorbable suture material was detected in 9 (0.22%) cases. A hollow cylindrical central area was found in a further 13 (0.32%) samples. X-ray microtomography (MUCT) was utilised in order to reveal the channel structure inside this urolith sample. Matrix assisted laser desorption-ionisation - time of flight mass spectrometry was used in order to assess the cause of this urinary stone formation. RESULTS: The diameter of the channel structure corresponded with the diameter of the previously utilised suture material and indicated that this urolith was formed around residual suture material. Further confirmation was provided by the comparative matrix-assisted laser desorption-ionisation - time of flight mass spectrometry chemical analysis. This channel structure is formed by a surgical thread that serves as a base for the urolith growth. CLINICAL SIGNIFICANCE: Results of this study confirm the causative role of absorbable suture material in the pathogenesis of hollow channel structures in some canine compound uroliths. PMID- 23034063 TI - Immunobiology of genital tract trauma: endocrine regulation of HIV acquisition in women following sexual assault or genital tract mutilation. AB - Studies on HIV acquisition and transmission in women exposed to sexual trauma throughout their life cycle are lacking, but some findings suggest that rates of HIV acquisition through coercive sex are significantly higher than that seen in consensual sex. Sexual trauma can also occur as a result of female genital mutilation, which makes sex extremely painful and can cause increased abrasions, lacerations, and inflammation, which enhances the risk of HIV acquisition. This review presents an overview of the immune system in the human female reproductive tract (FRT) from adolescence, through puberty to pregnancy and menopause. What is clear is that the foundation of information on immune protection in the FRT throughout the life cycle of women is extremely limited and at some stages such as adolescence and menopause are grossly lacking. Against this backdrop, forced or coercive sexual intercourse as well as genital mutilation further complicates our understanding of the biological risk factors that can result in transmission of HIV and other sexually transmitted infections. PMID- 23034065 TI - Double balloon enteroscopy can be safely done in elderly patients with significant co-morbidities. AB - BACKGROUND AND AIM: Performance of double balloon enteroscopy (DBE) on older patients with comorbidities is a matter of safety. We aimed to investigate the utility and safety of DBE in older patients. METHODS: We retrospectively reviewed the medical records of patients 75 years or older who underwent DBE in our open access endoscopy unit in a tertiary center. We analyzed the diagnostic yield, therapeutic intervention, and safety including complications of DBE. RESULTS: Four scheduled DBEs were canceled because of poor conditions. Two hundred and fourteen DBEs were performed in 167 elderly patients. All DBEs were performed under monitored anesthesia care using intravenous propofol administered by anesthesiologists. One half of the patients were male (female : male = 80:87). The mean age of patients was 80.1 +/- 3.7 years. Co-morbidity of significant chronic diseases was noted in 208 (97.2%) DBEs. Fifty-one (23.8%) DBEs were performed in patients with American Society of Anesthesiologists (ASA) physical status II, 151 (70.6%) DBEs with ASA class III, and 12 (5.6%) DBEs with ASA class IV. The most common indication was obscure gastrointestinal bleeding. The mean DBE procedure time was 131 +/- 51 min. Abnormalities were detected in 129 (60.3%) DBEs with therapeutic interventions performed in 83 (38.8%) cases. Pancreatitis, hypoxia, and aspiration pneumonia developed after three (1.4%), three (1.4%), and two (0.9%) DBEs, respectively, all of which resolved with conservative care. CONCLUSIONS: Double balloon enteroscopy can be done with acceptable safety in the elderly with high ASA class. DBE shows a high diagnostic yield and can deliver many therapeutic applications. PMID- 23034066 TI - Cross cultural validation of the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) and the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). AB - The available instruments for cognitive assessment in multiple sclerosis (MS) require considerable time and resources, and are not readily available in all countries. The study aimed to examine validity of the Czech translation of the Minimal Assessment of Cognitive Function in MS (MACFIMS), to validate the Brief International Cognitive Assessment for MS (BICAMS), and to compare their outcomes. We evaluated 367 MS patients and 134 healthy controls with the MACFIMS battery, which comprises the three tests of the BICAMS (Symbol Digit Modalities Test, Brief Visuospatial Memory Test-Revised, California Verbal Learning Test, second edition). The most accurate BICAMS criterion of cognitive deficit was that of at least one of the overall three tests outside the normal range (sensitivity = 94%, specificity = 86%, p = 10(-28)). Outcomes of the Czech translation of the MACFIMS were comparable to its original. The MACFIMS and the BICAMS identified cognitive deficit in 55% and 58% of the MS patients, respectively. Both batteries predicted patient self-reported vocational status. This is the first study to show that the BICAMS is highly sensitive and specific to cognitive impairment in MS as defined by the MACFIMS. This impairment is associated with vocational status. Czech versions of the studied batteries have now been validated. PMID- 23034067 TI - The appropriate cone depth to avoid endocervical margin involvement is dependent on age and disease severity. AB - OBJECTIVE: To analyse factors associated with endocervical cone margin involvement and suggest appropriate cone depth for the conization procedure. DESIGN: Retrospective cohort study. SETTING: Gynecological oncology center. POPULATION: One thousand two hundred and twenty women undergoing conization for cervical intraepithelial neoplasia (CIN) II or III or stage IA1 microinvasive cervical carcinoma. METHODS: The following factors were analysed: age, parity, gravida, conization type, margin status, disease severity and specimen depth. Receiver operating characteristic curve analyses were used to determine the best cut-off points to define appropriate cone depth. MAIN OUTCOME MEASURES: Cone depth to avoid endecervical margin involvement. RESULTS: Ninety-one women had endocervical margin involvement (7.5%). This was positively associated with disease severity and age and inversely related to cone depth. In women under 50 years of age, the cut-off value was achieved at 1.8 cm cone depth, with high sensitivity and relatively low specificity [area under the curve (AUC) 0.64, sensitivity 0.86, specificity 0.27, p= 0.005]. For a subset of CIN II patients aged <=50 years, the cut-off value was 1.2 cm (AUC 0.75, sensitivity 0.90, specificity 0.47, p= 0.008). In women <40 years of age, the cut-off value was 1.8 cm (AUC 0.60, sensitivity 0.88, specificity 0.25, p= 0.036). In a subset of CIN II, the cut-off value was 0.9 cm (AUC 0.87, sensitivity 0.83, specificity 0.69, p= 0.002). CONCLUSIONS: Age, disease severity and cone depth are predictive factors for endocervical margin involvement. In women of reproductive age, the appropriate cone depth to avoid endocervical margin involvement can be changed depending on age and disease severity. PMID- 23034068 TI - Short communication: HIV incidence among vulnerable populations in Honduras: results from an integrated behavioral and biological survey among female sex workers, men who have sex with men, and Garifuna in Honduras, 2006. AB - Honduras has one of the highest HIV prevalence rates in Central America. Data on HIV incidence are needed to identify groups at greatest need of prevention interventions to inform the national HIV response. We applied a test for recent infection to HIV-positive specimens from a biological and behavioral survey to estimate assay-derived incidence among men who have sex with men (MSM), female sex workers (FSW), and the Garifuna population in Honduras. Assay-derived estimates were compared to the mathematically modeled estimates in the same populations to assess plausibility of the assay-based estimates. Assay-derived incidence was 1.1% (95% CI 0.2-2.0) among MSM, 0.4% (95% CI 0.1-0.8) among the Garifuna, and 0% (95% CI 0-0.01) among FSWs. The modeled incidence estimates were similar at 1.03% among MSM, 0.30% among the Garifuna, and 0.23% among FSWs. HIV incidence based on the assay was highest among MSM in Honduras, lowest among FSWs, and similar to modeled incidence in these groups. Targeted programs on HIV prevention, care, and treatment are urgently needed for the MSM population. Continued support for existing prevention programs for FSWs and Garifuna are recommended. PMID- 23034069 TI - A systematic review of statin efficacy in asthma. AB - BACKGROUND: Statins are known for their lipid-lowering effects and role in the treatment of atherosclerotic disease. They also have anti-inflammatory and immunomodulatory properties which could benefit asthma patients. We aimed to review the evidence on the efficacy and safety of statins in asthma-related outcomes. METHODS: A systematic review of the literature on the effects of statins on asthma-related outcomes was performed following a search of the National Guideline Clearinghouse, Cochrane, Scopus, and Pubmed Medline databases in January 2012. Randomized controlled trials (RCTs) and observational studies (cohort/case-control design) assessing the effect of statins were included. The Grading of Recommendations Assessment Development and Evaluation (GRADE) system was used to rate the levels of evidence and grade of recommendation. RESULTS: Twenty-four of the 379 articles retrieved electronically and one article identified by hand search were selected for full-text scrutiny by two independent reviewers. Eight studies were included: six RCTs and two observational studies. Statin use was not associated with consistent, statistical significant improvements in patient outcomes (asthma control, quality of life, steroid sparing effects) or disease outcomes (lung function, airway responsiveness), and all the studies analyzed had low or very low quality of evidence. Inflammatory outcome improvements were observed in mild allergic asthma. CONCLUSION: Statins do not seem to have any additional benefit in asthma control or steroid-sparing effect in asthma treatment. Considering the prevalence of both statin use and asthma, more, better designed studies are needed to determine whether a specific phenotype of asthma exists that could benefit from statin treatment. PMID- 23034070 TI - Stability of Coxiella burnetii in stored human blood. AB - BACKGROUND: Coxiella burnetii, an obligate intracellular organism, is the causative agent of the zoonotic disease Q fever. The seroprevalence rate for Q fever in the United States is 3.1%, suggesting a high number of infections each year. However, fewer than 200 cases of Q fever are reported to the CDC annually. This discrepancy is likely the result of underutilized diagnostics and a high percentage (>50%) of asymptomatic infections. The detection of C. burnetii in patient blood during the first 2 to 3 weeks of infection raises the possibility that the organism could be present in donated human blood. The purpose of this study was to determine if extracellular C. burnetii would be stable in blood under normal storage conditions. STUDY DESIGN AND METHODS: Donated human blood was separated into whole blood, leukoreduced whole blood, red blood cells, and plasma. Each component was spiked with purified, extracellular C. burnetii strain Nine Mile Phase 1, and the viability and infectivity of the organisms were tested weekly. RESULTS: C. burnetii did not decrease in viability or the ability to infect cells after storage in any of the blood products, even after 6 weeks of storage at 1 to 6 degrees C. CONCLUSIONS: Extracellular C. burnetii can survive and remain infectious in donated blood products. PMID- 23034071 TI - Molecular epidemiology of Acinetobacter baumannii and Acinetobacter nosocomialis in Germany over a 5-year period (2005-2009). AB - To investigate the species distribution within the Acinetobacter calcoaceticus Acinetobacter baumannii complex and the molecular epidemiology of A. baumannii and Acinetobacter nosocomialis, 376 Acinetobacter isolates were collected prospectively from hospitalized patients at 15 medical centres in Germany during three surveillance studies conducted over a 5-year period. Species identification was performed by molecular methods. Imipenem minimum inhibitory concentrations (MIC) were determined by broth microdilution. The prevalence of the most common carbapenemase-encoding genes was investigated by oxacillinase (OXA) -multiplex polymerase chain reaction (PCR). The molecular epidemiology was investigated by repetitive sequence-based PCR (rep-PCR; DiversiLabTM). Acinetobacter pittii was the most prevalent Acinetobacter species (n = 193), followed by A. baumannii (n = 140), A. calcoaceticus (n = 10) and A. nosocomialis (n = 8). The majority of A. baumannii was represented by sporadic isolates (n = 70, 50%) that showed unique rep-PCR patterns, 25 isolates (18%) clustered with one or two other isolates, and only 45 isolates (32%) belonged to one of the previously described international clonal lineages. The most prevalent clonal lineage was international clone (IC) 2 (n = 34) and IC 1 (n = 6). According to CLSI, 25 A. baumannii isolates were non susceptible to imipenem (MIC >= 8 mg/L), all of which produced an OXA-58-like or OXA-23-like carbapenemase. The rate of imipenem susceptibility among A. baumannii isolates decreased from 96% in 2005 to 76% in 2009. All other Acinetobacter isolates were susceptible to imipenem. The population structure of carbapenem susceptible A. baumannii in Germany is highly diverse. Imipenem non susceptibility was strongly associated with the clonal lineages IC 2 and IC 1. These data underscore the high clonality of carbapenem-resistant A. baumannii isolates. PMID- 23034072 TI - Why do some primary care practices engage in practice improvement efforts whereas others do not? AB - OBJECTIVE: To understand what motivates primary care practices to engage in practice improvement, identify external and internal facilitators and barriers, and refine a conceptual framework. DATA SOURCES: In-depth interviews and structured telephone surveys with clinicians and practice staff (n = 51), observations, and document reviews. STUDY DESIGN: Comparative case study of primary care practices (n = 8) to examine aspects of the practice and environment that influence engagement in improvement activities. DATA COLLECTION METHODS: Three on-site visits, telephone interviews, and two surveys. PRINCIPAL FINDINGS: Pressures from multiple sources create conflicting forces on primary care practices' improvement efforts. Pressures include incentives and requirements, organizational relationships, and access to resources. Culture, leadership priorities, values set by the physician(s), and other factors influence whether primary care practices engage in improvement efforts. CONCLUSIONS: Most primary care practices are caught in a cross fire between two groups of pressures: a set of forces that push practices to remain with the status quo, the "15-minute per patient" approach, and another set of forces that press for major transformations. Our study illuminates the elements involved in the decision to stay with the status quo or to engage in practice improvement efforts needed for transformation. PMID- 23034073 TI - Incidence rates and trends of lip, oral and oro-pharyngeal cancers in Portugal. AB - OBJECTIVES: To analyse the trends and patterns of lip, oral and oro-pharyngeal cancer incidence in Portugal between 1998 and 2007. PATIENTS AND METHODS: Data on lip, oral and oro-pharyngeal cancers was collected from the databases maintained at the three main Regional Cancer Registries of Portugal (1998-2007). The data were analysed by gender, age and by site. Incidence rates were age standardized by the direct method, and joinpoint regression was used to estimate trends in incidence. RESULTS: During this 10-year period, a total of 9623 cases of lip, oral and oropharynx cancers were reported, 7565 (78.6%) in males and 2058 (21.4%) in females. There was an increase in the age-standardized incidence of oral cancers by 1.96% per year for both sexes grouped together and an increase of 4.34% per year for the female group. Oro-pharyngeal cancer showed an increase incidence trend of 3.49% per year for both sexes grouped together and an increase of 3.49% per year for male group among the sites analysed. Lip cancer showed a decrease in its incidence rate. CONCLUSION: In view of rising trends, it is necessary to implement policies on oral cancer control by initiating campaigns on oral cancer awareness and screening and to harness political measures on tobacco and alcohol control for the Portuguese population. PMID- 23034074 TI - Bladder interstitial cells: an updated review of current knowledge. AB - The field of bladder research has been energized by the study of novel interstitial cells (IC) over the last decade. Several subgroups of IC are located within the bladder wall and make structural interactions with nerves and smooth muscle, indicating integration with intercellular communication and key physiological functions. Significant progress has been made in the study of bladder ICs' cellular markers, ion channels and receptor expression, electrical and calcium signalling, yet their specific functions in normal bladder filling and emptying remain elusive. There is increasing evidence that the distribution of IC is altered in bladder pathophysiologies suggesting that changes in IC may be linked with the development of bladder dysfunction. This article summarizes the current state of the art of our knowledge of IC in normal bladder and reviews the literature on IC in dysfunctional bladder. PMID- 23034076 TI - Time-shift experiments and patterns of adaptation across time and space. AB - Time-shift experiments provide measures of the mean fitness of a population in environments of different points in time. Here, we show how to use this type of data to decompose mean fitness into (1) the effect of the environment in which the population is transplanted, (2) the effect of the genetic composition of the population and (3) 'temporal adaptation', which measures how the population fits the environment at that time. We derive analytical results for the pattern of 'temporal adaptation' and show that it is in general maximal in the recent past. The link between 'temporal adaptation' and 'local adaptation' is discussed, and we show when patterns of adaptation in time and space are expected to be similar. Finally, we illustrate the potential use of this approach using a data set measuring the adaptation of HIV to the immune response of several recently infected patients. PMID- 23034075 TI - Pharmacokinetics and modeling of immune cell trafficking: quantifying differential influences of target tissues versus lymphocytes in SJL and lipopolysaccharide-treated mice. AB - BACKGROUND: Immune cell trafficking into the CNS and other tissues plays important roles in health and disease. Rapid quantitative methods are not available that could be used to study many of the dynamic aspects of immune cell tissue interactions. METHODS: We used pharmacokinetics and modeling to quantify and characterize the trafficking of radioactively labeled lymphocytes into brain and peripheral tissues. We used variance from two-way ANOVAs with 2 * 2 experimental designs to model the relative influences of lymphocytes and target tissues in trafficking. RESULTS: We found that in male CD-1 mice, about 1 in 5,000 intravenously injected lymphocytes entered each gram of brain. Uptake by brain was 2 to 3 times higher in naive SJL females, but uptake by spleen and clearance from blood was lower, demonstrating a dichotomy in immune cell distribution. Treatment of CD-1 mice with lipopolysaccharide (LPS) increased immune cell uptake into brain but decreased uptake by spleen and axillary nodes. CONCLUSIONS: Differences in brain uptake and in uptake by spleen between SJL and CD-1 mice were primarily determined by lymphocytes, whereas differences in uptake with LPS were primarily determined by lymphocytes for the brain but by the tissues for the spleen and the axillary lymph node. These results show that immune cells normally enter the CNS and that tissues and immune cells interact in ways that can be quantified by pharmacokinetic models. PMID- 23034078 TI - Remarkable disparity in mechanical response among the extracellular domains of type I and II cadherins. AB - Cadherins, a large family of calcium-dependent adhesion molecules, are critical for intercellular adhesion. While crystallographic structures for several cadherins show clear structural similarities, their relevant adhesive strengths vary and their mechanisms of adhesion between types I and II cadherin subfamilies are still unclear. Here, stretching of cadherins was explored experimentally by atomic force microscopy and computationally by steered molecular dynamics (SMD) simulations, where partial unfolding of the E-cadherin ectodomains was observed. The SMD simulations on strand-swapping cadherin dimers displayed similarity in binding strength, suggesting contributions of other mechanisms to explain the strength differences of cell adhesion in vivo. Systematic simulations on the unfolding of the extracellular domains of type I and II cadherins revealed diverse pathways. However, at the earliest stage, a remarkable similarity in unfolding was observed for the various type I cadherins that was distinct from that for type II cadherins. This likely correlates positively with their distinct adhesive properties, suggesting that the initial forced deformation in type I cadherins may be involved in cadherin-mediated adhesion. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:25. PMID- 23034077 TI - The short-term effect on alliance and satisfaction of using patient feedback scales in mental health out-patient treatment. A randomised controlled trial. AB - BACKGROUND: The main aim was to investigate the effect of using two brief feedback scales in mental health out-patient treatment six weeks after starting treatment, compared to treatment as usual. Hypotheses were that use of feedback scales would improve treatment alliance and patient satisfaction. METHODS: An open parallel-group randomised controlled trial was conducted in an out-patient unit in a mental health hospital in Central Norway. Eight therapists trained in using the feedback scales in the Partners for Change Outcome Management System (PCOMS) treated the intervention group. Seventeen therapists treated the controls, providing treatment without using feedback scales. The main outcome measures were treatment alliance and patient satisfaction. RESULTS: Seventy-five patients participated. There were no differences between the groups in the intention to treat (ITT) analyses on alliance (mean difference = 0.08, 95% CI 0.44, 0.59, p = 0.760) or satisfaction (mean difference = 0.24, 95% CI -1.85, 2.32, p = 0.819), and no statistically significant differences between the groups in the per protocol (PP, n = 58) analyses on alliance (mean difference = 0.32, 95% CI -0.84, 3.16, p = 0.137) or satisfaction (mean difference = 1.16, 95% CI 0.84, 3.16, p = 0.248) six weeks after the treatment started. The effect size in favour of the PCOMS group increased from 0.07 for alliance and 0.06 for satisfaction in the intention to treat analysis to 0.40 on alliance and 0.31 for satisfaction in the per protocol analysis. Among the other outcomes, the PCOMS group had better motivation for treatment (estimated mean difference ITT: 0.29, 95% CI 0.00 to 0.57, p = 0.05, PP: 0.28, 95% CI 0.04, 0.52, p = 0.024). CONCLUSION: Six weeks after starting treatment, there were no effects on alliance and satisfaction from using two brief feedback scales. Since the per protocol analyses showed higher effect sizes, future investigations in a larger study with longer follow-up are warranted. PMID- 23034079 TI - Neuropsychiatric features of C9orf72-associated behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease. AB - Earlier reports of chromosome 9p-linked frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS) kindreds observed psychosis as a prominent feature in some patients. Since the discovery of chromosome 9 open reading frame 72 (C9orf72) hexanucleotide expansions as a cause of FTD and ALS, research groups and consortia around the world have reported their respective observations of the clinical features associated with this mutation. We reviewed the recent literature on C9orf72-associated FTD and ALS with focus on the neuropsychiatric features associated with this mutation, as well as the experience at University of California, San Francisco. The results and methodologies varied greatly across studies, making comparison of results challenging. Four reports found that psychotic features (particularly delusions) were frequent among mutation carriers, particularly when present early during the disease course, suggesting that this symptom category may be a marker for the mutation. Disinhibition and apathy were the most commonly reported early behavioral symptoms, but these may not be helpful in distinguishing carriers and noncarriers because of the symptoms' frequency in sporadic behavioral variant FTD. Other neuropsychiatric features were reported in different frequencies across studies, suggesting either a similar behavioral phenotype in carriers and noncarriers or reflecting the heterogeneity in clinical presentation of behavioral variant FTD due to C9orf72 expansions. Further studies with larger cohorts will be necessary to determine the neuropsychiatric presentation associated with this mutation. PMID- 23034080 TI - Cerebral venous sinus thrombosis presenting with diplopia in pregnancy: a case report. AB - INTRODUCTION: Cerebral venous sinus thrombosis is a rare condition. The most frequent symptoms and signs are headache, focal seizures with or without secondary generalization, unilateral or bilateral paresis and papilledema. We report a case of transverse sinus and superior sagittal sinus thrombosis that presented with diplopia in a pregnant woman. CASE PRESENTATION: A 34-year-old Malay woman, gravida 3 para 2 at 8 weeks of pregnancy, was admitted for hyperemesis gravidarum, presented with sudden onset of diplopia, blurring of vision and headache. A magnetic resonance scan of her brain showed the presence of cerebral edema with no space occupying lesion, but magnetic resonance venography ultimately revealed right transverse sinus and superior sagittal sinus thrombosis. The patient was treated with anticoagulation for 1 year, after which the patient recovered fully. CONCLUSION: Due to its diverse and varied neurological presentation, cerebral venous sinus thrombosis should be considered in almost any brain syndrome. PMID- 23034081 TI - Iron-catalyzed chemo- and stereoselective hydromagnesiation of diarylalkynes and diynes. AB - Diarylalkynes are chemo- and stereoselectively hydromagnesiated in high yields at room temperature with an iron species generated in situ from FeCl(2)and EtMgBr. Functional groups such as bromide, iodide, amine, phenoxide, and alkene are well tolerated. Under similar conditions, diynes are chemo-, regio-, and stereoselectively hydromagnesiated. The resulting alkenylmagnesium compounds are a platform for further functionalization as a one-pot reaction. PMID- 23034082 TI - Microbial diversity in the oral cavity of healthy Chinese Han children. AB - OBJECTIVE: This study aimed to identify the oral microbial diversity of healthy Chinese Han children. METHODS: Dental plaques were sampled from the oral cavity of ten healthy Chinese Han children. The oral microbiome was examined using the 16S rRNA-based Human Oral Microbe Identification Microarray. The microbial diversity and similarity were analyzed using the Chao-Jaccard similarity index. RESULTS: A total of 112 species, which belonged to nine bacterial phyla and 41 genera, were detected. Each individual harbored an average of 54.1 microbial species (ranging from 37 to 69) and 26.2 genera (ranging from 21 to 31), with interindividual variations both at the species and genus level. Thirteen genera were conserved among all individuals. The Chao-Jaccard similarity index averages, at the genus and species level, were 0.642 (ranging from 0.485 to 0.871) and 0.506 (ranging from 0.338 to 0.676), respectively, suggesting that the healthy oral community was more conserved at the genus level than at the species level. CONCLUSION: Although there was interindividual variation in the oral microflora, some bacterial genera were conserved among individuals, supporting the existence of a core microbiome in the oral cavity of healthy Chinese Han children. PMID- 23034083 TI - Effect of HIV type 1 subtype on virological and immunological response to combination antiretroviral therapy: evidence for a more rapid viral suppression for subtype A than subtype B-infected Greek individuals. AB - Whether response to combination antiretroviral therapy (cART) differs between those infected with HIV-1 subtype A or B remains unclear. We compared virological and immunological response to cART in individuals infected with subtype A or B in an ethnically homogeneous population. Data derived from the Athens Multicenter AIDS Cohort Study (AMACS) and analysis were restricted to those of Greek origin. Time to virological response (confirmed HIV-RNA <500 copies/ml) and time to failure (>500 copies/ml at any time or no response by month 6) were analyzed using survival models and CD4 changes after cART initiation using piecewise linear mixed effects models. Of the 571 subjects included in the analysis, 412 (72.2%) were infected with subtype B and 159 (27.8%) with subtype A. After adjusting for various prognostic factors, the rate of virological response was higher for those infected with subtype A versus B (adjusted HR: 1.35; 95% CI: 1.08-1.68; p=0.009). Subtype A was also marginally associated with a lower hazard of virological failure compared to subtype B (HR=0.73; 95% CI: 0.53-1.02; p=0.062). Further adjustment for treatment adherence did not substantially changed the main results. No significant differences were observed in the rates of CD4 increases by subtype. The overall median (95% CI) CD4 increase at 2 years of cART was 193 (175, 212) cells/MUl. Our study, based on one of the largest homogeneous groups of subtype A and B infections in Europe, showed that individuals infected with subtype A had an improved virological but similar immunological response to cART compared to those infected with subtype B. PMID- 23034084 TI - Diarrhea and dengue control in rural primary schools in Colombia: study protocol for a randomized controlled trial. AB - BACKGROUND: Diarrheal diseases and dengue fever are major global health problems. Where provision of clean water is inadequate, water storage is crucial. Fecal contamination of stored water is a common source of diarrheal illness, but stored water also provides breeding sites for dengue vector mosquitoes. Poor household water management and sanitation are therefore potential determinants of both diseases. Little is known of the role of stored water for the combined risk of diarrhea and dengue, yet a joint role would be important for developing integrated control and management efforts. Even less is known of the effect of integrating control of these diseases in school settings. The objective of this trial was to investigate whether interventions against diarrhea and dengue will significantly reduce diarrheal disease and dengue entomological risk factors in rural primary schools. METHODS/DESIGN: This is a 2*2 factorial cluster randomized controlled trial. Eligible schools were rural primary schools in La Mesa and Anapoima municipalities, Cundinamarca, Colombia. Eligible pupils were school children in grades 0 to 5. Schools were randomized to one of four study arms: diarrhea interventions (DIA); dengue interventions (DEN); combined diarrhea and dengue interventions (DIADEN); and control (C). Schools were allocated publicly in each municipality (strata) at the start of the trial, obviating the need for allocation concealment. The primary outcome for diarrhea is incidence rate of diarrhea in school children and for dengue it is density of adult female Aedes aegypti per school. Approximately 800 pupils from 34 schools were enrolled in the trial with eight schools in the DIA arm, nine in the DEN, eight in the DIADEN, and nine in the control arms. The trial status as of June 2012 was: completed baseline data collections; enrollment, randomization, and allocation of schools. The trial was funded by the Research Council of Norway and the Lazos de Calandaima Foundation. DISCUSSION: This is the first trial investigating the effect of a set of integrated interventions to control both dengue and diarrhea. This is also the first trial to study the combination of diarrhea-dengue disease control in school settings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN40195031. PMID- 23034085 TI - Exciton dynamics in disordered poly(p-phenylenevinylene). 1. Ultrafast interconversion and dynamical localization. AB - The disordered Frenkel-Holstein model is introduced to investigate dynamical relaxation and localization of photoexcited states in conformationally disordered poly(p-phenylenevinylene). It is solved within the Ehrenfest approximation, in which the excited state is treated fully quantum mechanically, but the nuclear displacements are treated classically. The following are shown: (i) Lower energy local exciton ground states (LEGSs) adiabatically relax to vibrationally relaxed states (VRSs) in the time scale of one or two vibrational periods (ca. 40 fs). The relaxation of LEGSs is accompanied by localization and fluorescence depolarization, as the transition dipole moment reduces and rotates. The amount of dynamical localization increases as the torsional disorder decreases, causing an increase in the fluorescence depolarization. (ii) Higher energy quasi-extended exciton states (QEESs) interconvert to VRSs via three distinct episodes. A brief initial period of adiabatic relaxation is followed by the time-evolving eigenstate becoming a linear superposition of instantaneous eigenstates of the Frenkel-Holstein Hamiltonian. Typically, after a few hundred femtoseconds, one of the instantaneous eigenstates dominates the linear superposition, and the remaining dynamics is again adiabatic relaxation to a VRS. (iii) Very high energy QEESs, which are delocalized over many chromophores, sometimes exhibit a splitting of the wave function into more than one VRS. This self-localization onto more than one chromophore is assumed to be a failure of the Ehrenfest approximation, as this approximation neglects quantum mechanical coherences between the electronic and nuclear degrees of freedom. (iv) QEESs exhibit larger, but slower, fluorescence depolarization than LEGSs. Thus, ultrafast fluorescence depolarization is a function of excitation energy and conformational disorder. PMID- 23034087 TI - Challenges of alloimmunization in patients with haemoglobinopathies. AB - Red blood cell (RBC) transfusions can be life-sustaining in chronic inherited anaemias, such as thalassaemia, and the indications for blood transfusions in patients with sickle cell disease continue to expand. Complications of transfusions, such as allosensitization, can create significant medical challenges in the management of patients with haemoglobinopathies. This review summarizes key findings from the medical literature related to alloimmunization in haemoglobinopathies and examines potential measures to mitigate these risks. Areas where future studies are needed are also addressed. PMID- 23034086 TI - methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles. AB - DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit. PMID- 23034088 TI - Effects of candesartan in hypertensive patients with type 2 diabetes mellitus on inflammatory parameters and their relationship to pulse pressure. AB - BACKGROUND: Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress in patients without arteriosclerosis. This study aimed to evaluate (1) whether an ARB (candesartan) decreases values for inflammatory parameters in hypertensive patients with type 2 diabetes mellitus of long duration accompanied by arteriosclerosis and (2) whether there any predictors of which patients would receive the benefits of organ protection by candesartan. METHODS: We administered candesartan therapy (12 mg daily) for 6 months and evaluated whether there was improvement in serum inflammatory parameters high molecular weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1) in serum and urinary 8-hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of lowering of blood pressure and inflammatory factors and the relationship between pulse pressure and inflammatory factors. Finally, we analyzed predictive factors in patients who received the protective benefit of candesartan. RESULTS: After 6 months of treatment, significant improvements from baseline values were observed in all patients in HMW-ADN and PAI-1 but not in Hs CRP, VCAM-1 and U-8-OHdG. Multilinear regression analysis was performed to determine which factors could best predict changes in HMW-ADN and PAI-1. Changes in blood pressure were not significant predictors of changes in metabolic factors in all patients. We found that the group with baseline pulse pressure <60 mmHg had improved HMW-ADN and PAI-1 values compared with the group with baseline pulse pressure >= 60 mmHg. These results suggest that pulse pressure at baseline could be predictive of changes in HMW-ADN and PAI-1. CONCLUSIONS: Candesartan improved inflammatory parameters (HMW-ADN and PAI-1) in hypertensive patients with type 2 diabetes mellitus of long duration independent of blood pressure changes. Patients with pulse pressure <60 mmHg might receive protective benefits by candesartan. TRIAL REGISTRATION: UMIN000007921. PMID- 23034089 TI - EpiExplorer: live exploration and global analysis of large epigenomic datasets. AB - Epigenome mapping consortia are generating resources of tremendous value for studying epigenetic regulation. To maximize their utility and impact, new tools are needed that facilitate interactive analysis of epigenome datasets. Here we describe EpiExplorer, a web tool for exploring genome and epigenome data on a genomic scale. We demonstrate EpiExplorer's utility by describing a hypothesis generating analysis of DNA hydroxymethylation in relation to public reference maps of the human epigenome. All EpiExplorer analyses are performed dynamically within seconds, using an efficient and versatile text indexing scheme that we introduce to bioinformatics. EpiExplorer is available at http://epiexplorer.mpi inf.mpg.de. PMID- 23034090 TI - Identification of a high risk gastric cancer group using serum pepsinogen after successful eradication of Helicobacter pylori. AB - BACKGROUND AND AIM: Pepsinogen (PG) method is widely used to identify high risk groups of gastric cancer. It is very useful before Helicobacter pylori eradication, but after eradication the method becomes useless because the PGI, PGII, PGI/II ratios change. Therefore, we aimed to identify a high risk group for gastric cancer using serum pepsinogen after successful eradication of H. pylori. METHODS: A total of 261 participants were enrolled after successful eradication of H. pylori in Hokkaido University Hospital from 1995 to 2010. Participants with renal failure, taking proton pump inhibitors, and those with advanced gastric cancer were excluded. Serum levels of PGI and II were measured using chemiluminescent immunoassay method. RESULTS: Receiver operating characteristic curves using cancerous and non-cancerous data in post-eradication determined the optimal cut-off value of PGI/II as 4.5. The sensitivity and the specificity were 65.9% and 79.3%, respectively. The usual PG method includes 48.9% of cancer cases, and the PGI/II <= 4.5 in post-eradication includes 65.9% of them, and it includes approximately half of the high risk group of diffuse type cancer. PGI/II <= 4.5 in post-eradication included many gastric cancer cases detected after eradication (12/16 = 75%). CONCLUSION: In the identification of a high risk group for gastric cancer, we suggest that the optimal cut-off value of PGI/II after successful eradication of H. pylori is 4.5. PGI/II <= 4.5 in post-eradication includes more gastric cancer cases compared with the traditional PG method, and 75% of gastric cancer cases detected after eradication. PMID- 23034091 TI - A 20-year multi-follow-up of hallucinations in schizophrenia, other psychotic, and mood disorders. AB - BACKGROUND: Hallucinations are a major aspect of psychosis and a diagnostic feature of both psychotic and mood disorders. However, the field lacks information regarding the long-term course of hallucinations in these disorders. Our goals were to determine the percentage of patients with hallucinations and the relationship between hallucinations and recovery, and work attainment. Method The present study was a prospective evaluation of the 20-year trajectory of hallucinations in 150 young patients: 51 schizophrenia, 25 schizoaffective, 25 bipolar with psychosis, and 49 unipolar depression. The patients were studied at an index phase of hospitalization for hallucinations, and then reassessed longitudinally at six subsequent follow-ups over 20 years. RESULTS: The longitudinal course of hallucinations clearly differentiated between schizophrenia and bipolar disorder with psychosis, and suggested some diagnostic similarities between schizophrenia and schizoaffective disorder, and between bipolar disorder and schizoaffective disorder and depression. Frequent or persistent hallucinatory activity over the 20-year period was a feature of 40-45% of schizophrenia patients. The early presence of hallucinations predicted the lack of future periods of recovery in all patients. Increased hallucinatory activity was associated with reduced work attainment in all patients. CONCLUSIONS: This study provides data on the prospective longitudinal course of hallucinations, which were previously unavailable to the field, and are one of the key features of psychosis in major psychiatric disorders. This information on the clinical course of major psychiatric disorders can inform accurate classification and diagnosis. PMID- 23034092 TI - Risk of infections subsequent to pyogenic liver abscess: a nationwide population based study. AB - This nationwide study aimed to provide risk estimates for a panel of infections subsequent to pyogenic liver abscesses (PLA) in Taiwan. In this study, we selected 12 050 patients diagnosed with PLA as our study cohort and 60 250 non PLA patients as our comparison cohort. We individually tracked each subject for a 1-year period beginning with their index date to identify those who were subsequently diagnosed with any of the following infections: pneumonia, endophthalmitis, septic pulmonary embolism, pulmonary abscess, pleural empyema, meningitis, abscess of prostate, renal and perinephric abscess, epidural spinal abscess, osteomyelitis, necrotizing fasciitis, splenic abscess, psoas abscess and infectious endocarditis. We found that during the 1-year follow-up period, the subjects with PLA had a consistently higher incidence of all types of infections than comparison subjects. In particular, compared with subjects without PLA, the adjusted hazard ratios (HR) of pulmonary abscess, pleural empyema, renal and perinephric abscess, epidural spinal abscess and splenic abscess were 26.71, 18.56, 43.21, 51.32 and 126.51, respectively. We further analysed the HR of extra hepatic Klebsiella pneumoniae infections among patients with PLA caused by K. pneumoniae. We found that the HR was higher for 12 of the 15 analysed extra hepatic infections after restricting the analysis to only infections with K. pneumoniae aetiologies. PMID- 23034093 TI - Healthy younger and older adults control foot placement to avoid small obstacles during gait primarily by modulating step width. AB - BACKGROUND: Falls are a significant problem in the older population. Most falls occur during gait, which is primarily regulated by foot placement. Variability of foot placement has been associated with falls, but these associations are inconsistent and generally for smooth, level flooring. This study investigates the control of foot placement and the associated gait variability in younger and older men and women (N=7/group, total N=28) while walking at three different speeds (slow, preferred, and fast) across a control surface with no obstacles and surfaces with multiple (64) small (10 cm long *13 mm high) visible and hidden obstacles. RESULTS: Minimum obstacle distance between the shoe and nearest obstacle during each footfall was greater on the visible obstacles surface for older subjects because some of them chose to actively avoid obstacles. This obstacle avoidance strategy was implemented primarily by modulating step width and to a lesser extent step length as indicated by linear regressions of step width and length variability on minimum obstacle distance. Mean gait speed, step length, step width, and step time did not significantly differ by subject group, flooring surface, or obstacle avoidance strategy. CONCLUSIONS: Some healthy older subjects choose to actively avoid small obstacles that do not substantially perturb their gait by modulating step width and, to a lesser extent, step length. It is not clear if this obstacle avoidance strategy is appropriate and beneficial or overcautious and maladaptive, as it results in fewer obstacles encountered at a consequence of a less efficient gait pattern that has been shown to indicate increased fall risk. Further research is needed on the appropriateness of strategy selection when the environmental demands and/or task requirements have multiple possible completion strategies with conflicting objectives (i.e. perceived safety vs. efficiency). PMID- 23034094 TI - Bioassay-guided isolation of anti-inflammatory components from the root of Rehmannia glutinosa and its underlying mechanism via inhibition of iNOS pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root of Rehmannia glutinosa (RR) is commonly used to reduce inflammation in various traditional Chinese herbal formulae; however, little is known regarding its active component(s). AIM OF STUDY: The objective of the present study was to examine the active component(s) responsible for the anti-inflammatory activity of RR via anti-nitric oxide production assay guided fractionation; and the underlying anti-inflammatory mechanism of action of such component(s) was further investigated. MATERIALS AND METHODS: Anti-nitric oxide (NO) activities with lipopolysaccharides (LPS)-stimulated RAW264.7 murine macrophages was used as screening platform. Gene, protein and inflammatory mediators' expression were also studied using real-time PCR, western blotting and ELISA, respectively. RESULTS: Using anti-NO assay-guided fractionation, sub fraction C3 (from 31.25 to 62.5 MUg/ml, p=0.001 to 0.01) possessed 100-fold more potent anti-inflammatory effect than that of the aqueous extract of RR. Characterization of C3 showed that the anti-inflammatory effect could be partly due to the presence of rehmapicrogenin, which could significantly inhibit NO production (p<0.001). C3 was further demonstrated in blocking inflammation by inhibiting gene (p<0.001) and protein expression of inducible NO synthase (iNOS) dose-dependently. Besides, C3 also significantly inhibited the production of prostaglandin E(2) (p<0.001 to 0.01), IL-6 (p<0.001 to 0.05) and COX-2 (p<0.05). CONCLUSIONS: Rehmapicrogenin was, for the first time, shown to possess nitric oxide inhibitory activities. Bioassay-guided fractionation demonstrated that rehmapicrogenin-containing subfraction C3 exhibited potent anti-inflammatory effect by inhibiting iNOS, COX-2 and IL-6, while rehmapicrogenin was only partially responsible for the anti-inflammatory effect of RR. PMID- 23034096 TI - Pathologic tumor response of invasive lobular carcinoma to neo-adjuvant chemotherapy. AB - Neo-adjuvant chemotherapy is used for locally advanced breast cancer patients with significant variation in tumor response. Our objective is to determine the clinicopathologic effect of neo-adjuvant chemotherapy on invasive lobular carcinoma. A review of a single-institution data base of women diagnosed with breast cancer identified 30 patients from 1999 to 2009 with operable invasive lobular carcinoma who received neo-adjuvant chemotherapy. Patient demographics and clinicopathologic data were reviewed. Cases were reviewed by a single pathologist (NNE). Residual cancer burden class was determined for each case. Median patient age was 50 years (range 25-79). All tumors were hormone receptor positive and clinical stage II or III carcinomas. Most patients (53.3%) had combination anthracycline- and taxane-based chemotherapy. Therapy-related changes were noted within the tumor bed in 25 (83.3%) patients. Six (30%) of 20 patients with residual axillary disease had therapy-related nodal changes. There were 11 patients with moderate residual disease (class II) and 18 (60%) with extensive (class III); there were no complete pathologic responses (class 0). Only one patient (3.3%) converted from mastectomy to breast-conserving surgery. Four (13.3%) patients developed distant metastases; all had pleomorphic-type, clinical stage III tumors with residual cancer burden III classification and developed distant disease in the 2 years after surgery (range 0-26 months). Median follow up time was 29.5 months (range 7-132). Patients with locally advanced pleomorphic type lobular carcinoma appear to develop early post-treatment metastatic disease. Neo-adjuvant chemotherapy did not appear to have significant impact on the surgical treatment of patients with invasive lobular carcinoma. PMID- 23034097 TI - Validation of a home food inventory among low-income Spanish- and Somali-speaking families. AB - OBJECTIVE: To refine and validate an existing home food inventory (HFI) for low income Somali- and Spanish-speaking families. DESIGN: Formative assessment was conducted using two focus groups, followed by revisions of the HFI, translation of written materials and instrument validation in participants' homes. SETTING: Twin Cities Metropolitan Area, Minnesota, USA. SUBJECTS: Thirty low-income families with children of pre-school age (fifteen Spanish-speaking; fifteen Somali-speaking) completed the HFI simultaneously with, but independently of, a trained staff member. Analysis consisted of calculation of both item-specific and average food group kappa coefficients, specificity, sensitivity and Spearman's correlation between participants' and staff scores as a means of assessing criterion validity of individual items, food categories and the obesogenic score. RESULTS: The formative assessment revealed the need for few changes/additions for food items typically found in Spanish-speaking households. Somali-speaking participants requested few additions, but many deletions, including frozen processed food items, non-perishable produce and many sweets as they were not typical food items kept in the home. Generally, all validity indices were within an acceptable range, with the exception of values associated with items such as 'whole wheat bread' (k = 0.16). The obesogenic score (presence of high-fat, high energy foods) had high criterion validity with k = 0.57, sensitivity = 91.8%, specificity = 70.6% and Spearman correlation = 0.78. CONCLUSIONS: The revised HFI is a valid assessment tool for use among Spanish and Somali households. This instrument refinement and validation process can be replicated with other population groups. PMID- 23034095 TI - 'Placement budgets' for supported employment--improving competitive employment for people with mental illness: study protocol of a multicentre randomized controlled trial. AB - BACKGROUND: Vocational integration of people with mental illness is poor despite their willingness to work. The 'Individual Placement and Support' (IPS) model which emphasises rapid and direct job placement and continuing support to patient and employer has proven to be the most effective vocational intervention programme. Various studies have shown that every second patient with severe mental illness was able to find competitive employment within 18 months. However, the goal of taking up employment within two months was rarely achieved. Thus, we aim to test whether the new concept of limited placement budgets increases the effectiveness of IPS. METHODS/DESIGN: Six job coaches in six out-patients psychiatric clinics in the Canton of Zurich support unemployed patients of their clinic who seek competitive employment. Between June 2010 and May 2011 patients (N=100) are randomly assigned to three different placement budgets of 25h, 40h, or 55h working hours of job coaches. Support lasts two years for those who find a job. The intervention ends for those who fail to find competitive employment when the respective placement budgets run out. The primary outcome measure is the time between study inclusion and first competitive employment that lasted three months or longer. Over a period of three years interviews are carried out every six months to measure changes in motivation, stigmatization, social network and social support, quality of life, job satisfaction, financial situation, and health conditions. Cognitive and social-cognitive tests are conducted at baseline to control for confounding variables. DISCUSSION: This study will show whether the effectiveness of IPS can be increased by the new concept of limited placement budgets. It will also be examined whether competitive employment leads in the long term to an improvement of mental illness, to a transfer of the psychiatric support system to private and vocational networks, to an increase in financial independence, to a reduction of perceived and internalized stigma, and to an increase in quality of life and job satisfaction of the patient. In addition, factors connected with fast competitive employment and holding that job down in the long term are being examined (motivation, stigmatization, social and financial situation). TRIAL REGISTER: ISRCTN89670872. PMID- 23034098 TI - Natural selection, plasticity and the emergence of a behavioural syndrome in the wild. AB - Individuals often show consistent behavioural differences where behaviours can form integrated units across functionally different contexts. However, the factors causing and maintaining behavioural syndromes in natural populations remain poorly understood. In this study, we provide evidence for the emergence of a behavioural syndrome during the first months of life in wild brown trout (Salmo trutta). Behavioural traits of trout were scored before and after a 2-month interval covering a major survival bottleneck, whereupon the consistency and covariance of behaviours were analysed. We found that selection favoured individuals with high activity levels in an open-field context, a personality trait consistent throughout the duration of the experiment. In addition, a behavioural syndrome emerged over the 2 months in the wild, linking activity to aggressiveness and exploration tendency. These novel results suggest that behavioural syndromes can emerge rapidly in nature from interaction between natural selection and behavioural plasticity affecting single behaviours. PMID- 23034099 TI - Differences in characteristics between healthcare-associated and community acquired infection in community-onset Klebsiella pneumoniae bloodstream infection in Korea. AB - BACKGROUND: Healthcare-associated (HCA) infection has emerged as a new epidemiological category. The aim of this study was to evaluate the impact of HCA infection on mortality in community-onset Klebsiella pneumoniae bloodstream infection (KpBSI). METHODS: We conducted a retrospective study in two tertiary care hospitals over a 6-year period. All adult patients with KpBSI within 48 hours of admission were enrolled. We compared the clinical characteristics of HCA and community-acquired (CA) infection, and analyzed risk factors for mortality in patients with community-onset KpBSI. RESULTS: Of 553 patients with community onset KpBSI, 313 (57%) were classified as HCA- KpBSI and 240 (43%) as CA-KpBSI. In patients with HCA-KpBSI, the severity of the underlying diseases was higher than in patients with CA-KpBSI. Overall the most common site of infection was the pancreatobiliary tract. Liver abscess was more common in CA-KpBSI, whereas peritonitis and primary bacteremia were more common in HCA-KpBSI. Isolates not susceptible to extended-spectrum cephalosporin were more common in HCA- KpBSI than in CA-KpBSI (9% [29/313] vs. 3% [8/240]; p = 0.006). Overall 30-day mortality rate was significantly higher in HCA-KpBSI than in CA-KpBSI (22% [70/313] vs. 11% [27/240]; p = 0.001). In multivariate analysis, high Charlson's weighted index of co-morbidity, high Pitt bacteremia score, neutropenia, polymicrobial infection and inappropriate empirical antimicrobial therapy were significant risk factors for 30-day mortality. CONCLUSIONS: HCA-KpBSI in community-onset KpBSI has distinctive characteristics and has a poorer prognosis than CA-KpBSI, but HCA infection was not an independent risk factor for 30-day mortality. PMID- 23034101 TI - Paraparesis caused by a cyst in the spinal canal from a pseudarthrosis 22 years following Harrington rod procedure for scoliosis: a case report. AB - INTRODUCTION: This case demonstrates very late neurological deterioration due to a pseudarthrosis in the fusion mass after scoliosis surgery. Though not the first case in the literature, it is the first case in which pre-operative magnetic resonance imaging revealed that the compression was due to a cyst arising from the pseudarthrosis. CASE PRESENTATION: Twenty-two years after a successful correction and fusion for scoliosis, a 38-year-old Caucasian man presented with progressive numbness and significant weakness. As revealed by imaging, a cyst relating to an old pseudarthrosis was compressing the spinal cord. This was removed, and the cord decompressed, resulting in resolution of all symptoms. CONCLUSIONS: Lifetime care of patients with scoliosis is required for very late complications of surgery. Asymptomatic pseudarthroses have the potential to cause symptoms many years after surgery. PMID- 23034100 TI - Evidence that women meeting physical activity guidelines do not sit less: an observational inclinometry study. AB - BACKGROUND: The inactivity physiology paradigm proposes that sedentary behaviors, including sitting too much, are independent of the type of physical activity delineated for health in the Physical Activity Guidelines for Americans. Thus, we hypothesized that, when accounting for behaviors across the entire day, variability in the amount of time spent sitting would be independent of the inter and intra-individual time engaged in sustained moderate-to-vigorous physical activity (MVPA). METHODS: Ninety-one healthy women, aged 40-75 years, completed a demographic questionnaire and assessment of height and weight. Participants wore the activPAL activity monitor for one week and time (minutes/day) spent sitting, standing, stepping, and in sustained bouts (bouts >=10 minutes) of MVPA were quantified. The women were then stratified into groups based on weekly sustained MVPA. Additionally, each day of data collection for each participant was classified as either a "sufficient" MVPA day (>= 30 min of MVPA) or an "insufficient" MVPA day for within-participant analyses. RESULTS: Time spent sitting, standing, and in incidental non-exercise stepping averaged 64, 28, and 11 hrs/week, respectively, and did not differ between groups with individuals meeting/exceeding the current exercise recommendation of 150 min/week of sustained MVPA in >=10 minutes bouts (M = 294 min/week, SD = 22) compared to those with none or minimal levels (M= 20 min/week, SD = 4). Time spent sitting (M = 9.1 hr/day, SD = 0.19 vs. M = 8.8 hr/day, SD = 0.22), standing (M = 3.9 hr/day, SD = 0.16 vs. M = 3.9 hr/day, SD = 0.15), and in intermittent stepping (M = 1.6 hr/day, SD = 0.07 vs. M = 1.6 hr/day, SD = 0.06) did not differ between days with (~55 min/day) and without recommended MVPA. CONCLUSIONS: This study provides the first objective evidence that participation in sustained MVPA is unrelated to daily sitting duration in relatively healthy, middle and older-aged women. More research is needed to extend these findings to other populations and to inform distinct behavioral recommendations focused on sedentary time. PMID- 23034102 TI - Expression signature in peripheral blood cells for molecular diagnosis of head and neck squamous cell carcinoma. AB - Patients with head and neck squamous cell carcinoma (HNSCC) have a poor prognosis due to the development of locoregional recurrences, distant metastases, and second primary tumors. There is an urgent need for biomarkers that enable detection and monitoring of the disease to provide adequate therapeutic strategies. In this study, we have investigated markers in peripheral blood cells (PBC) of 28 HNSCC patients who underwent surgery by means of expression profiling. Our hypothesis is that nucleated blood cells circulate continuously, also pass the tumor, and change their expression profile in response to tumor cell factors. For comparison, we enrolled a control group of 11 patients who underwent surgery in the head and neck region for non-HNSCC reasons. A set of 2949 genes was found to be statistically different between the groups (P < 0.05, false discovery rate-corrected) and the most prominently different pathways were EIF2, EIF4, and mTOR signaling. These preliminary results are promising and warrant further studies on the definitive role of PBC gene expression as a biomarker for HNSCC detection and monitoring. PMID- 23034103 TI - Effect of non-clinical inter-hospital critical care unit to unit transfer of critically ill patients: a propensity-matched cohort analysis. AB - INTRODUCTION: No matter how well resourced, individual hospitals cannot expect to meet all peaks in demand for adult general critical care. However, previous analyses suggest that patients transferred for non-clinical reasons have worse outcomes than those who are not transferred, but these studies were underpowered and hampered by residual case-mix differences. The aim of this study was to evaluate the effect of transferring adult general critical care patients to other hospitals for non-clinical reasons. METHODS: We carried out a propensity-matched cohort analysis comparing critical care patients who underwent a non-clinical critical care unit to unit transfer to another hospital with those who were not transferred. The primary outcome measure was mortality at ultimate discharge from acute hospital. Secondary outcomes were mortality at ultimate discharge from critical care, plus length of stay in both critical care and acute hospital. RESULTS: A total of 308,323 patients were admitted to one of 198 adult general critical care units in England and Wales between January 2008 and September 2011. This included 759 patients who underwent a non-clinical transfer within 48 hours of admission to the unit and 1,518 propensity-matched patients who were not transferred. The relative risk of ultimate acute hospital mortality was 1.01 (95% confidence interval = 0.87 to 1.16) for the non-clinical transfer group, compared with patients who were not transferred but had a similar propensity for transfer. There was no statistically significant difference in ultimate critical care unit mortality. Transferred patients received on average three additional days of critical care (P < 0.001) but the difference in length of acute hospital stay was of only borderline significance (P = 0.05). CONCLUSION: In our analysis the difference in mortality between non-clinical transferred and nontransferred patients was not statistically significant. Nevertheless, non-clinical transfers received, on average, an additional 3 days of critical care. This has potential ramifications in terms of distress, inconvenience and cost for patients, their families, and the National Health Service. We therefore need further evidence, including qualitative data from family members and cost-effective analyses, to better understand the broader effects of non-clinical transfer. PMID- 23034104 TI - The reality of rurality: rural parents' experiences of early years services. AB - This study examined the experiences of rural parents accessing early years support services through a specific service delivery strategy in Ontario, Canada. Nine focus groups and five interviews were conducted in two rural communities as part of a larger research project exploring parent experiences in both urban and rural communities. Thematic analysis, informed by a critical ecological systems perspective, revealed that certain factors related to rural life and location affected parents' experiences. Services must be accessible in terms of location and social and psychological dimensions for parents to attend and make use of supports. These supports, in turn, foster healthy child development and healthy communities. PMID- 23034105 TI - Applying proteomic technology to clinical virology. AB - Developing antiviral drugs, vaccines and diagnostic markers is still the most ambitious challenge in clinical virology. In the past few decades, data from high throughput technologies have allowed for the rapid development of new antiviral therapeutic strategies, thus making a profound impact on translational research. Most of the current preclinical studies in virology are aimed at evaluating the dynamic composition and localization of the protein platforms involved in various host-virus interactions. Among the different possible approaches, mass spectrometry-based proteomics is increasingly being used to define the protein composition in subcellular compartments, quantify differential protein expression among samples, characterize protein complexes, and analyse protein post translational modifications. Here, we review the current knowledge of the most useful proteomic approaches in the study of viral persistence and pathogenicity, with a particular focus on recent advances in hepatitis C research. PMID- 23034106 TI - Identification accuracy for single- and double-perpetrator crimes: does accomplice gender matter? AB - There is an important mismatch between empirical research on the accuracy of eyewitness identification and the real world of criminal investigation. Most research models single-perpetrator crimes, but in the real world, most crimes involve multiple perpetrators. This study examined how the number of perpetrators affects eyewitness identification by manipulating the gender of accomplices. Observers viewed a video of a staged crime. The crime was committed by a male or female perpetrator, who was presented alone or with an accomplice of the same or the opposite gender. The observers were then asked to identify the perpetrators from target-present or target-absent line-ups. The results revealed a double perpetrator disadvantage, which was manifested in reduced identification accuracy on target-present line-ups. Importantly, however, the gender of the perpetrator or the accomplice had no effect on this disadvantage. This double-perpetrator disadvantage is attributed to the need to divide attention between two concurrent people, compared to single-culprit crimes, rather than an impairment of visual encoding processes. The implications of these findings are discussed. PMID- 23034107 TI - "Lights on at the end of the party": are lads' mags mainstreaming dangerous sexism? AB - Research has suggested that some magazines targeted at young men - lads' mags - are normalizing extreme sexist views by presenting those views in a mainstream context. Consistent with this view, young men in Study 1 (n = 90) identified more with derogatory quotes about women drawn from recent lads' mags, and from interviews with convicted rapists, when those quotes were attributed to lads' mags, than when they were attributed to convicted rapists. In Study 2, 40 young women and men could not reliably judge the source of those same quotes. While these participants sometimes voiced the belief that the content of lads' mags was 'normal' while rapists' talk was 'extreme', they categorized quotes from both sources as derogatory with equal frequency. Jointly, the two studies show an overlap in the content of convicted rapists' talk and the contents of contemporary lads' mags, and suggest that the framing of such content within lads' mags may normalize it for young men. PMID- 23034108 TI - Are systemizing and autistic traits related to talent and interest in mathematics and engineering? Testing some of the central claims of the empathizing systemizing theory. AB - In two experiments, we tested some of the central claims of the empathizing systemizing (E-S) theory. Experiment 1 showed that the systemizing quotient (SQ) was unrelated to performance on a mathematics test, although it was correlated with statistics-related attitudes, self-efficacy, and anxiety. In Experiment 2, systemizing skills, and gender differences in these skills, were more strongly related to spatial thinking styles than to SQ. In fact, when we partialled the effect of spatial thinking styles, SQ was no longer related to systemizing skills. Additionally, there was no relationship between the Autism Spectrum Quotient (AQ) and the SQ, or skills and interest in mathematics and mechanical reasoning. We discuss the implications of our findings for the E-S theory, and for understanding the autistic cognitive profile. PMID- 23034109 TI - Workplace mavericks: how personality and risk-taking propensity predicts maverickism. AB - We examine the relationship between lateral preference, the Five-Factor Model of personality, risk-taking propensity, and maverickism. We take an original approach by narrowing our research focus to only functional aspects of maverickism. Results with 458 full-time workers identify lateral preference as a moderator of the neuroticism-maverickism relationship. Extraversion, openness to experience, and low agreeableness were also each found to predict maverickism. The propensity of individuals high in maverickism to take risks was also found to be unaffected by task feedback. Our results highlight the multifaceted nature of maverickism, identifying both personality and task conditions as determinants of this construct. PMID- 23034110 TI - Aberrant first fixations when looking at inverted faces in various poses: the result of the centre-of-gravity effect? AB - Face recognition is essential in everyday human life, and all faces are encountered in different poses. However, when a face is inverted, difficulties arise for recognition and eye movements may (Barton, Radcliffe, Cherkasova, Edleman, & Intriligator, 2006) or may not be disrupted (Williams & Henderson, 2007). The present study explored the effects of orientation and pose on recognition and eye movements during a standard old/new recognition task in order to resolve whether inversion disrupts eye movements. Eye-tracking data looked at the first fixations, the number of fixations, and the duration of fixations over a face. A standard inversion effect was observed, but the three-quarter view advantage was not observed. Eye-movement data revealed that the eyes were the most sampled feature (in terms of first fixation, number of fixations, and duration of fixation) for all upright faces, however, other features were sampled first for inverted faces. These results are consistent with Barton et al.'s (2006) but not Williams and Henderson's (2007) findings: possible explanations for this are discussed with the caveat that the same images were used from learning to test. PMID- 23034111 TI - The role of movement exaggeration in the anticipation of deceptive soccer penalty kicks. AB - Human movement containing deception about the true outcome is thought to be perceived differently compared to the non-deceptive version. Exaggeration in the movement is thought to change the perceiver's mode of functioning from an invariant to a cue-based mode. We tested these ideas by examining anticipation in skilled and less skilled soccer players while they viewed temporally occluded ( 240 ms, -160 ms, -80 ms, 0 ms, +80 ms) deceptive, non-deceptive, and non deceptive-exaggerated penalty kicks. Kinematic analyses were used to ascertain that the kicking actions differed across conditions. The accuracy of judging the direction of an opponent's kick as well as response confidence were recorded. Players were over confident when anticipating deceptive penalty kicks compared to non-deceptive kicks, suggesting a cue-based mode was used. Furthermore, there was a significant relationship between less skilled players' confidence ratings and their accuracy 80 ms before ball-foot contact in the deceptive and non-deceptive exaggerated conditions, but not the non-deceptive condition. Because both deceptive and non-deceptive-exaggerated kicks contained exaggeration, results suggest exaggerated movements in the kickers' action at 80 ms before ball-foot contact explains why a cue-based mode prevails when anticipating deceptive kicks at this time point. PMID- 23034112 TI - Personality differences in mental imagery and the effects on verbal memory. AB - This study examined the effects of extraversion and neuroticism on participants' reported vividness of visual imagery and on their memory performance for concrete and abstract nouns. Groups of extraverts (n = 15) and introverts (n = 15) were selected from a larger original sample and asked to remember a series of concrete and abstract nouns, including a set of lexically ambiguous concrete homonyms (e.g., earth = 1. planet, 2. soil). Extraverts reported more vivid imagery than introverts but this did not translate into better recall for extraverts, even for concrete stimuli. Recall was best for unambiguous concrete nouns, followed by concrete homonyms, then abstract nouns. While initial analyses suggested that there was an interaction between extraversion and the type of word presented, later analyses revealed that neuroticism was the main driver in differences in recall between different word types. While differences in recall were best explained by context availability theory (Schwanenflugel, 1991) rather than dual coding theory (Paivio, 1991), questions remain about the power of either theory to explain the role of individual differences in personality on recall, particularly given that imagery vividness effects were related to extraversion while differences in recall were related to neuroticism. The implications of these findings for future research and theoretical development are discussed. PMID- 23034113 TI - Metabolomics in food science. AB - Metabolomics, the newest member of the omics techniques, has become an important tool in agriculture, pharmacy, and environmental sciences. Advances in compound extraction, separation, detection, identification, and data analysis have allowed metabolomics applications in food sciences including food processing, quality, and safety. This chapter discusses recent advances and applications of metabolomics in food science. PMID- 23034114 TI - Implications of light energy on food quality and packaging selection. AB - Light energy in the ultraviolet and visible light regions plays a critical role in overall food quality, leading to various degradation and oxidation reactions. Food degradation and oxidation result in the destruction of nutrients and bioactive compounds, the formation of off odors and flavors, the loss of food color, and the formation of toxic substances. Food compounds are sensitive to various light wavelengths. Understanding the effect that specific light wavelengths have on food compounds will allow the development of novel food packaging materials that block the most damaging light wavelengths to photostability of specific food compounds. Future research should focus more specifically on the effect of specific light wavelengths on the quality of specific food products, as there is limited published information on this particular topic. This information also can be directly related to the selection of food packaging materials to retain both high quality and visual clarity of food products exposed to light. PMID- 23034115 TI - Antioxidant activity and protecting health effects of common medicinal plants. AB - Medicinal plants are traditionally used in folk medicine as natural healing remedies with therapeutic effects such as prevention of cardiovascular diseases, inflammation disorders, or reducing the risk of cancer. In addition, pharmacological industry utilizes medicinal plants due to the presence of active chemical substances as agents for drug synthesis. They are valuable also for food and cosmetic industry as additives, due to their preservative effects because of the presence of antioxidants and antimicrobial constituents. To commonly used medicinal plants with antioxidant activity known worldwide belong plants from several families, especially Lamiaceae (rosemary, sage, oregano, marjoram, basil, thyme, mints, balm), Apiaceae (cumin, fennel, caraway), and Zingiberaceae (turmeric, ginger). The antioxidant properties of medicinal plants depend on the plant, its variety, environmental conditions, climatic and seasonal variations, geographical regions of growth, degree of ripeness, growing practices, and many other factors such as postharvest treatment and processing. In addition, composition and concentration of present antioxidants, such as phenolic compounds, are related to antioxidant effect. For appropriate determination of antioxidant capacity, the extraction technique, its conditions, solvent used, and particular assay methodology are important. PMID- 23034116 TI - Fatty acid profile of unconventional oilseeds. AB - The continued increase in human population has resulted in the rise in the demand as well as the price of edible oils, leading to the search for alternative unconventional sources of oils, particularly in the developing countries. There are hundreds of un- or underexplored plant seeds rich in oil suitable for edible or industrial purposes. Many of them are rich in polyunsaturated essential fatty acids, which establish their utility as "healthy oils." Some agrowaste products such as rice bran have gained importance as a potential source of edible oil. Genetic modification has paved the way for increasing the oil yields and improving the fatty acid profiles of traditional as well as unconventional oilseeds. Single cell oils are also novel sources of edible oil. Some of these unconventional oils may have excellent potential for medicinal and therapeutic uses, even if their low oil contents do not promote commercial production as edible oils. PMID- 23034117 TI - Modern approaches in probiotics research to control foodborne pathogens. AB - Foodborne illness is a serious public health concern. There are over 200 known microbial, chemical, and physical agents that are known to cause foodborne illness. Efforts are made for improved detection, control and prevention of foodborne pathogen in food, and pathogen associated diseases in the host. Several commonly used approaches to control foodborne pathogens include antibiotics, natural antimicrobials, bacteriophages, bacteriocins, ionizing radiations, and heat. In addition, probiotics offer a potential intervention strategy for the prevention and control of foodborne infections. This review focuses on the use of probiotics and bioengineered probiotics to control foodborne pathogens, their antimicrobial actions, and their delivery strategies. Although probiotics have been demonstrated to be effective in antagonizing foodborne pathogens, challenges exist in the characterization and elucidation of underlying molecular mechanisms of action and in the development of potential delivery strategies that could maintain the viability and functionality of the probiotic in the target organ. PMID- 23034118 TI - Bacteriophages for detection and control of bacterial pathogens in food and food processing environment. AB - This chapter presents recent advances in bacteriophage research and their application in the area of food safety. Section 1 describes general facts on phage biology that are relevant to their application for control and detection of bacterial pathogens in food and environmental samples. Section 2 summarizes the recently acquired data on application of bacteriophages to control growth of bacterial pathogens and spoilage organisms in food and food-processing environment. Section 3 deals with application of bacteriophages for detection and identification of bacterial pathogens. Advantages of bacteriophage-based methods are presented and their shortcomings are discussed. The chapter is intended for food scientist and food product developers, and people in food inspection and health agencies with the ultimate goal to attract their attention to the new developing technology that has a tremendous potential in providing means for producing wholesome and safe food. PMID- 23034119 TI - Carbon dioxide and ethanol release from champagne glasses, under standard tasting conditions. AB - A simple glass of champagne or sparkling wine may seem like the acme of frivolity to most people, but in fact, it may rather be considered as a fantastic playground for any fluid physicist or physicochemist. In this chapter, results obtained concerning various steps where the CO2 molecule plays a role (from its ingestion in the liquid phase during the fermentation process to its progressive release in the headspace above the tasting glass) are gathered and synthesized to propose a self-consistent and global overview of how gaseous and dissolved CO2 impact champagne and sparkling wine science. Some recent investigations, conducted through laser tomography techniques, on ascending bubbles and ascending bubble-driven flow patterns found in champagne glasses are reported, which illustrate the fine interplay between ascending bubbles and the fluid around under standard tasting conditions. The simultaneous monitoring of gaseous CO2 and ethanol in the headspace of both a flute and a coupe filled with champagne was reported, depending on whether or not the glass shows effervescence. Both gaseous CO2 and ethanol were found to be enhanced by the presence of ascending bubbles, thus confirming the close link between ascending bubbles, ascending-bubble-driven flow patterns, and the release of gaseous CO2 and volatile organic compounds. PMID- 23034120 TI - Chromatin accessibility reveals insights into androgen receptor activation and transcriptional specificity. AB - BACKGROUND: Epigenetic mechanisms such as chromatin accessibility impact transcription factor binding to DNA and transcriptional specificity. The androgen receptor (AR), a master regulator of the male phenotype and prostate cancer pathogenesis, acts primarily through ligand-activated transcription of target genes. Although several determinants of AR transcriptional specificity have been elucidated, our understanding of the interplay between chromatin accessibility and AR function remains incomplete. RESULTS: We used deep sequencing to assess chromatin structure via DNase I hypersensitivity and mRNA abundance, and paired these datasets with three independent AR ChIP-seq datasets. Our analysis revealed qualitative and quantitative differences in chromatin accessibility that corresponded to both AR binding and an enrichment of motifs for potential collaborating factors, one of which was identified as SP1. These quantitative differences were significantly associated with AR-regulated mRNA transcription across the genome. Base-pair resolution of the DNase I cleavage profile revealed three distinct footprinting patterns associated with the AR-DNA interaction, suggesting multiple modes of AR interaction with the genome. CONCLUSIONS: In contrast with other DNA-binding factors, AR binding to the genome does not only target regions that are accessible to DNase I cleavage prior to hormone induction. AR binding is invariably associated with an increase in chromatin accessibility and, consequently, changes in gene expression. Furthermore, we present the first in vivo evidence that a significant fraction of AR binds only to half of the full AR DNA motif. These findings indicate a dynamic quantitative relationship between chromatin structure and AR-DNA binding that impacts AR transcriptional specificity. PMID- 23034123 TI - A bumpy road to maintenance hemodialysis. PMID- 23034122 TI - Aging effects on DNA methylation modules in human brain and blood tissue. AB - BACKGROUND: Several recent studies reported aging effects on DNA methylation levels of individual CpG dinucleotides. But it is not yet known whether aging related consensus modules, in the form of clusters of correlated CpG markers, can be found that are present in multiple human tissues. Such a module could facilitate the understanding of aging effects on multiple tissues. RESULTS: We therefore employed weighted correlation network analysis of 2,442 Illumina DNA methylation arrays from brain and blood tissues, which enabled the identification of an age-related co-methylation module. Module preservation analysis confirmed that this module can also be found in diverse independent data sets. Biological evaluation showed that module membership is associated with Polycomb group target occupancy counts, CpG island status and autosomal chromosome location. Functional enrichment analysis revealed that the aging-related consensus module comprises genes that are involved in nervous system development, neuron differentiation and neurogenesis, and that it contains promoter CpGs of genes known to be down regulated in early Alzheimer's disease. A comparison with a standard, non-module based meta-analysis revealed that selecting CpGs based on module membership leads to significantly increased gene ontology enrichment, thus demonstrating that studying aging effects via consensus network analysis enhances the biological insights gained. CONCLUSIONS: Overall, our analysis revealed a robustly defined age-related co-methylation module that is present in multiple human tissues, including blood and brain. We conclude that blood is a promising surrogate for brain tissue when studying the effects of age on DNA methylation profiles. PMID- 23034121 TI - Efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. Brave dreams study (brain venous drainage exploited against multiple sclerosis): study protocol for a randomized controlled trial. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a disabling progressive course. Chronic cerebrospinal venous insufficiency (CCSVI) has recently been described as a vascular condition characterized by restricted venous outflow from the brain, mainly due to blockages of the internal jugular and azygos veins. Despite a wide variability among studies, it has been found to be associated with MS. Data from a few small case series suggest possible improvement of the clinical course and quality of life by performing percutaneous balloon angioplasty (PTA) of the stenotic veins. STUDY DESIGN AND METHODS: This is a multicenter, randomized, parallel group, blinded, sham-controlled trial to assess the efficacy and safety of PTA. Participants with relapsing remitting MS or secondary progressive MS and a sonographic diagnosis of CCSVI will be enrolled after providing their informed consent. Each participant will be centrally randomized to receive catheter venography and PTA or catheter venography and sham PTA. Two primary end points with respect to efficacy at 12 months are (1) a combined end point obtained through the integration of five functional indicators, walking, balance, manual dexterity, bladder control, and visual acuity, objectively measured by instruments; and (2) number of new brain lesions measured by T2-weighted MRI sequences. Secondary end points include annual relapse rate, change in Expanded Disability Status Scale score, proportion of patients with zero, one or two, or more than two relapses; fatigue; anxiety and depression; general cognitive state; memory/attention/calculus; impact of bladder incontinence; and adverse events. Six hundred seventy-nine patients will be recruited. The follow-up is scheduled at 12 months. Patients, treating neurologists, trained outcome assessors, and the statistician in charge of data analysis will be masked to the assigned treatment. DISCUSSION: The study will provide an answer regarding the efficacy of PTA on patients' functional disability in balance, motor, sensory, visual and bladder function, cognitive status, and emotional status, which are meaningful clinical outcomes, beyond investigating the effects on inflammation. In fact, an important part of patients' expectations, sustained and amplified by anecdotal data, has to do precisely with these functional aspects. TRIAL REGISTRATION: Clinicaltrials.gov NCT01371760. PMID- 23034125 TI - The emergence of multidrug-resistant Klebsiella pneumoniae of international clones ST13, ST16, ST35, ST48 and ST101 in a teaching hospital in the Paris region. AB - Despite infection control measures, an important increase in the extended spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae incidence density occurred in our hospital from 2006 onwards. This study, focusing on the 2005-2007 period, was performed in an attempt to explain this increase. ESBLs were characterized, isolates were typed by ERIC2-PCR, and sequence type (ST) of clustered isolates was determined. Temporal-spatial relationships of patients were analysed to assess possible cross-contamination. Of the 74 ESBL-producing isolates, 30 (40%) were detected at admission, 53 (71?5%) produced CTX-M enzymes, 40 displayed unique ERIC2-PCR profiles and 34 were assigned into six clusters: ST16 (n=21), ST101, ST48, ST35, ST13, and ST436. Relationships were identified in 22 of the 34 patients harbouring clustered isolates. This study highlights the complex epidemiology of ESBL-producing K. pneumoniae in the mid-2000s with potential cross-contamination for only 30% of the 74 patients in our hospital, and the emergence of clones that are currently spreading worldwide. PMID- 23034126 TI - Efficacy of nasal irrigation in the treatment of acute sinusitis in atopic children. AB - BACKGROUND: Nasal irrigation has been used as adjunctive therapy for sinonasal disease but is under-researched in children. The study aim was to evaluate the effectiveness of nasal irrigation with normal saline in the management of acute sinusitis in atopic children. METHODS: We enrolled 60 atopic children with acute sinusitis, of whom 29 received nasal irrigation with normal saline and 31 did not receive nasal irrigation. All participants underwent a nasal peak expiratory flow rate (nPEFR) test, a nasal smear examination, and radiography (Water's projection) and were requested to complete a Pediatric Rhinoconjunctivitis Quality-of-Life Questionnaire (PRQLQ) during the baseline visit. All participants were requested to record symptoms in a daily diary and were followed up at 1-week intervals. A physical examination, nasal smear, and nPEFR were performed at each visit, and all daily diaries were collected. At the final visit (after 3 weeks), the symptom diaries were reviewed and participants were requested to complete the PRQLQ again. nPEFR, radiography, and a nasal smear were also repeated. RESULTS: There were significant improvements in mean PRQLQ and nPEFR values (p < 0.05) for the irrigation compared to the non-irrigation group. There was no significant difference in radiographic findings between the groups (p > 0.05). The irrigation group recorded significant improvements in eye congestion, rhinorrhea, nasal itching, sneezing, and cough symptoms compared with the non-irrigation group. CONCLUSION: Nasal irrigation is an effective adjunctive treatment for acute sinusitis in atopic children. PMID- 23034127 TI - Climatic effects in Central Europe on the frequency of medical treatments of dairy cows. AB - In the present study, the relationship between the temperature-humidity index (THI) and the incidence of medical treatments in lactating dairy cows in Lower Saxony, Germany, was investigated. Records of all veterinary-treated cases over 2 years (2003 and 2005) from eight Holstein-Friesian dairy herds raised in loose housing systems (55 to 170 cows per herd) were evaluated. After exclusion of management-dependent and climate-independent cases, a total of 5547 treatments were analyzed. Treatments were clustered into the following groups: metabolism, fertility, udder and foot/leg. Meteorological data were compiled from the nearest weather station (average distance +/- s.d. 39 +/- 13 km). Hourly temperatures and relative humidity values were used to calculate the THI, which was divided into classes. Out of the total number of treatments, 37.4%, 32.9%, 21.6% and 8.1% belonged to metabolism, udder, fertility and foot/leg, respectively. Data were analyzed with a mixed model that included THI class, season and year as fixed effects and farm as random effect. In general, incidences were neither affected by the year (P > 0.05) and season (P > 0.05) nor by THI classes (P > 0.05). In tendency, incidences of metabolic treatments increased with increasing THI and incidences of udder treatments increased with decreasing THI. In conclusion, indications of moderate heat stress during summer months in Central Europe were found in the present study, although THI and season did not affect the different disease complexes significantly. PMID- 23034128 TI - Treatment of non-alcoholic steatohepatitis with Phyllanthus urinaria: a randomized trial. AB - BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is a common liver disease that may progress to cirrhosis and hepatocellular carcinoma. There is currently no approved pharmacological treatment for NASH. Phyllanthus urinaria is a commonly used hepatoprotective herb that ameliorates NASH in animal studies. We aimed to test the hypothesis that Phyllanthus was superior to placebo in improving histological non-alcoholic fatty liver disease (NAFLD) activity score. METHODS: This was a placebo-controlled parallel-group double-blind randomized controlled trial. Patients with histology-proven NASH were randomized to receive Phyllanthus or placebo for 24 weeks. The primary endpoint was change in NAFLD activity score from baseline to week 24. Secondary endpoints included changes in individual histological parameters, liver biochemistry and metabolic profile. RESULTS: We enrolled 60 patients (40 received Phyllanthus and 20 received placebo). The change in NAFLD activity score was -0.8 +/- 1.4 in the Phyllanthus group and -0.3 +/- 1.3 in the placebo group (P = 0.24). The change in steatosis, lobular inflammation, ballooning and fibrosis was also similar between the two groups. Within the Phyllanthus group, although there was reduction in hepatic steatosis (-0.2 +/- 0.7; P = 0.039) and ballooning grades (-0.4 +/- 0.5; P < 0.001), the change was small and of limited clinical significance. Furthermore, there was no significant difference in the changes in alanine aminotransferase, aspartate aminotransferase, fasting glucose and lipid profile between the two groups. CONCLUSIONS: Phyllanthus is not superior to placebo in improving NAFLD activity score in NASH patients. PMID- 23034129 TI - Health- related quality of life and self-worth in 10-year old children with congenital hypothyroidism diagnosed by neonatal screening. AB - BACKGROUND: Much is written about cognitive and motor development; less is known about social and emotional consequences of growing up with congenital hypothyroidism (CH).The objectives of the study were: (1) to compare health related quality of life (HRQoL) and self-worth of 10 year old patients with CH with the general population; (2) to explore associations of disease factors, IQ and motor skills with the outcomes. METHODS: Children with CH and their parents completed several questionnaires. Patients were classified to 'severe CH, n = 41' or 'moderate/mild CH, n = 41' based on pre-treatment FT4 concentration.Differences between CH and the general population were tested by analysis of covariance and one sample t-tests (mean scale scores HRQoL and self worth), chi-square tests and binomial tests (% at risk of impaired HRQoL and self worth). Linear regression analyses corrected for gender were conducted to explore associations of the outcomes with disease factors, IQ and motor skills. RESULTS: Patients with CH reported lower mean HRQoL on motor, cognitive and social functioning, and on autonomy and positive emotions (p < 0.0001). Patients were also more often at risk for impaired HRQoL and self-worth. No differences were found between the severity groups. Lower IQ was only significant associated with worse cognitive HRQoL. Initial FT4 plasma, age at onset of therapy, initial T4 dose and motor skills were not significantly associated with HRQoL and self worth. CONCLUSIONS: Negative consequences in terms of HRQoL and self-worth are prevalent in children with CH, independent of disease factors, IQ and motor skills. Physicians should to be attentive to these consequences and provide attention and supportive care. PMID- 23034130 TI - Cancer classification using the Immunoscore: a worldwide task force. AB - Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). PMID- 23034131 TI - Association between craniofacial asymmetry and unilateral temporomandibular joint sounds in adult patients using 3D-computed tomography. AB - OBJECTIVES: The purpose of this study was to investigate the possible relationship between unilateral temporomandibular joint (TMJ) sounds and craniofacial asymmetry, using 3D-computed tomography (CT) measurements. SUBJECTS AND METHODS: Forty-one reconstructed 3D-CT models of adult subjects were measured to analyze craniofacial asymmetry. Subjects were divided into two groups depending on the presence (n = 20) or absence (n = 21) of unilateral joint sounds, and the results compared using the Mann-Whitney U-test. To investigate the association between these parameters, the Pearson correlation coefficient was calculated. RESULTS: Asymmetries in the maxillary and mandibular structures were statistically significant (P < 0.05) for subjects with unilateral TMJ sounds and for controls, except in the case of maxillary rotation and mandibular ramus height (P > 0.05). The highest deviations found were frontal and lateral ramal inclination, goniac angle and canting of occlusal plane. CONCLUSIONS: Adult patients with unilateral joint sounds may have skeletal jaw asymmetry and a canted occlusal plane. PMID- 23034132 TI - A longitudinal study of emotion regulation, emotion lability-negativity, and internalizing symptomatology in maltreated and nonmaltreated children. AB - The longitudinal contributions of emotion regulation and emotion lability negativity to internalizing symptomatology were examined in a low-income sample (171 maltreated and 151 nonmaltreated children, from age 7 to 10 years). Latent difference score models indicated that for both maltreated and nonmaltreated children, emotion regulation was a mediator between emotion lability-negativity and internalizing symptomatology, whereas emotion lability-negativity was not a mediator between emotion regulation and internalizing symptomatology. Early maltreatment was associated with high emotion lability-negativity (age 7) that contributed to poor emotion regulation (age 8), which in turn was predictive of increases in internalizing symptomatology (from age 8 to 9). The results imply important roles of emotion regulation in the development of internalizing symptomatology, especially for children with high emotion lability-negativity. PMID- 23034133 TI - Metformin overdose causes platelet mitochondrial dysfunction in humans. AB - INTRODUCTION: We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in vitro and ex vivo. METHODS: Human platelets were incubated for 72 hours with saline or increasing doses of metformin (in vitro experiments). Lactate production, respiratory chain complex activities (spectrophotometry), mitochondrial membrane potential (flow-cytometry after staining with JC-1) and oxygen consumption (Clark type electrode) were then measured. Platelets were also obtained from ten patients with lactic acidosis (arterial pH 6.97 +/- 0.18 and lactate 16 +/- 7 mmol/L) due to accidental metformin intoxication (serum drug level 32 +/- 14 mg/L) and ten healthy volunteers of similar sex and age. Respiratory chain complex activities were measured as above (ex vivo experiments). RESULTS: In vitro, metformin dose-dependently increased lactate production (P < 0.001), decreased respiratory chain complex I activity (P = 0.009), mitochondrial membrane potential (P = 0.003) and oxygen consumption (P < 0.001) of human platelets. Ex vivo, platelets taken from intoxicated patients had significantly lower complex I (P = 0.045) and complex IV (P < 0.001) activity compared to controls. CONCLUSIONS: Depending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in vitro and, possibly, in vivo. TRIAL REGISTRATION: NCT 00942123. PMID- 23034134 TI - An unusual device-related complication: multiple painful stones after explantation of a subcutaneous Holter system. PMID- 23034135 TI - Proton pump inhibitor therapy predisposes to community-acquired Streptococcus pneumoniae pneumonia. AB - BACKGROUND: The pathophysiological mechanisms which contribute to an increased risk of community-acquired pneumonia (CAP) in patients using proton pump inhibitors are not well established. AIM: To examine differences in microbial etiology in patients with CAP between patients with and without proton pump inhibitor (PPI) therapy and its possible impact on disease severity. METHODS: All individuals consulting the emergency care unit were prospectively registered and underwent chest radiography. Sputum, urine, nose-throat swabs and blood samples were obtained for microbial evaluation. We evaluated the association between use of proton pump inhibitors, etiology of CAP and severity of illness with multivariate regression analysis. RESULTS: The final cohort comprised 463 patients, 29% using proton pump inhibitors (PPIs). Pathogens regarded as oropharyngeal flora were more common in CAP patients using PPI therapy compared to those who did not (adjusted OR: 2.0; 95% CI: 1.22-3.72). Patients using proton pump inhibitors more frequently had an infection with Streptococcus pneumoniae (28% vs. 14%) and less frequently with Coxiella burnetii (8% vs. 19%) compared to nonuser of PPI. Adjusted for baseline differences, the risk of PPI users being infected with S. pneumonia was 2.23 times (95% CI: 1.28-3.75) higher compared to patients without PPI's. No risk between PPI use and any other microbial pathogen was found. There was no difference in severity of CAP between patients with and without using PPI therapy. CONCLUSIONS: Proton pump inhibitor therapy was associated with an approximately 2-fold increased risk to develop community acquired pneumonia possibly as a result of S. pneumoniae infection. PMID- 23034137 TI - Epigenetic interplay between mouse endogenous retroviruses and host genes. AB - BACKGROUND: Transposable elements are often the targets of repressive epigenetic modifications such as DNA methylation that, in theory, have the potential to spread toward nearby genes and induce epigenetic silencing. To better understand the role of DNA methylation in the relationship between transposable elements and genes, we assessed the methylation state of mouse endogenous retroviruses (ERVs) located near genes. RESULTS: We found that ERVs of the ETn/MusD family show decreased DNA methylation when near transcription start sites in tissues where the nearby gene is expressed. ERVs belonging to the IAP family, however, are generally heavily methylated, regardless of the genomic environment and the tissue studied. Furthermore, we found full-length ETn and IAP copies that display differential DNA methylation between their two long terminal repeats (LTRs), suggesting that the environment surrounding gene promoters can prevent methylation of the nearby LTR. Spreading from methylated ERV copies to nearby genes was rarely observed, with the regions between the ERVs and genes apparently acting as a boundary, enriched in H3K4me3 and CTCF, which possibly protects the unmethylated gene promoter. Furthermore, the flanking regions of unmethylated ERV copies harbor H3K4me3, consistent with spreading of euchromatin from the host gene toward ERV insertions. CONCLUSIONS: We have shown that spreading of DNA methylation from ERV copies toward active gene promoters is rare. We provide evidence that genes can be protected from ERV-induced heterochromatin spreading by either blocking the invasion of repressive marks or by spreading euchromatin toward the ERV copy. PMID- 23034138 TI - Reproductive disorders in relation to Neospora caninum, Brucella spp. and bovine viral diarrhoea virus serostatus in breeding and dairy farms of central and southern Ethiopia. AB - Abortion and stillbirth are important reproductive disorders in the dairy industry and are often caused by infectious agents. This study investigated whether bovine viral diarrhoea virus (BVDV), Brucella spp., and Neospora caninum are associated with abortion and/or stillbirth in dairy cattle in Ethiopia. Dairy cattle from 99 farms were categorized as cases (n=134) or controls (n=268) according to reproductive data. Blood samples were screened for antibodies for these infectious agents. The overall proportion of cattle that were seropositive for BVDV, Brucella spp., and N. caninum was 11?7%, 3?2%, and 17?2%, respectively. Seropositivity for BVDV and Brucella spp. was similar for cases and controls, but significantly more cases were seropositive for N. caninum (29?8%) than controls (10?8%). This is the first report demonstrating N. caninum is common in dairy cattle in Ethiopia, and is probably a greater impediment to reproductive success in Ethiopian dairy farms than either BVDV or Brucella spp. PMID- 23034139 TI - Design of tumor biomarker-monitoring trials: a proposal by the European Group on Tumor Markers. AB - A major application of tumor biomarkers is in serial monitoring of cancer patients, but there are no published guidelines on how to evaluate biomarkers for this purpose. The European Group on Tumor Markers has convened a multidisciplinary panel of scientists to develop guidance on the design of such monitoring trials. The panel proposes a 4-phase model for biomarker-monitoring trials analogous to that in use for the investigation of new drugs. In phase I, biomarker kinetics and correlation with tumor burden are assessed. Phase II evaluates the ability of the biomarker to identify, exclude, and/or predict a change in disease status. In phase III, the effectiveness of tumor biomarker guided intervention is assessed by measuring patient outcome in randomized trials. Phase IV consists of an audit of the long-term effects after biomarker monitoring has been included into standard patient care. Systematic well-designed evaluations of biomarkers for monitoring may provide a stronger evidence base that might enable their earlier use in evaluating responses to cancer therapy. PMID- 23034140 TI - Evidence-based laboratory medicine in oncology drug development: from biomarkers to diagnostics. AB - BACKGROUND: The promise of targeted therapies in molecularly defined subsets of cancer has led to a transformation of the process of drug development in oncology. To target cancer successfully and precisely requires high-quality translational data. Such data can be generated by the use of biomarkers that answer key questions in drug development. CONTENT: Translational data for aiding in decision-making and driving cancer drug development can be generated by systematic assessments with biomarkers. Types of biomarkers that support decisions include: pharmacodynamic assessments for selecting the best compound or dosage; assessment of early tumor response with tissue biomarkers and imaging, mutation, and other assessment strategies for patient selection; and the use of markers of organ injury to detect toxicity and improve safety. Tactics used to generate biomarker data include fit-for-purpose assay validation and real-time biomarker assessments. Successfully translated and clinically informative biomarkers can mature into novel companion diagnostic tests that expand the practice of laboratory medicine. SUMMARY: Systematic biomarker assessments are a key component of the clinical development of targeted therapies for cancer. The success of these biomarker assessments requires applying basic principles of laboratory medicine to generate the data required to make informed decisions. Successful biomarkers can transition into diagnostic tests that expand the laboratory medicine armamentarium. PMID- 23034141 TI - Host predilection and transmissibility of vesicular stomatitis New Jersey virus strains in domestic cattle (Bos taurus) and swine (Sus scrofa). AB - BACKGROUND: Epidemiologic data collected during epidemics in the western United States combined with limited experimental studies involving swine and cattle suggest that host predilection of epidemic vesicular stomatitis New Jersey virus (VSNJV) strains results in variations in clinical response, extent and duration of virus shedding and transmissibility following infection in different hosts. Laboratory challenge of livestock with heterologous VSNJV strains to investigate potential viral predilections for these hosts has not been thoroughly investigated. In separate trials, homologous VSNJV strains (NJ82COB and NJ82AZB), and heterologous strains (NJ06WYE and NJOSF [Ossabaw Island, sand fly]) were inoculated into cattle via infected black fly bite. NJ82AZB and NJ06WYE were similarly inoculated into swine. RESULTS: Clinical scores among viruses infecting cattle were significantly different and indicated that infection with a homologous virus resulted in more severe clinical presentation and greater extent and duration of viral shedding. No differences in clinical severity or extent and duration of viral shedding were detected in swine. CONCLUSIONS: Differences in clinical presentation and extent and duration of viral shedding may have direct impacts on viral spread during epidemics. Viral transmission via animal-to-animal contact and insect vectored transmission are likely to occur at higher rates when affected animals are presenting severe clinical signs and shedding high concentrations of virus. More virulent viral strains resulting in more severe disease in livestock hosts are expected to spread more rapidly and greater distances during epidemics than those causing mild or inapparent signs. PMID- 23034142 TI - Effect of perennial ryegrass (Lolium perenne L.) cultivars on the milk yield of grazing dairy cows. AB - The objective of this experiment was to investigate the effect of four perennial ryegrass cultivars: Bealey, Astonenergy, Spelga and AberMagic on the milk yield and milk composition of grazing dairy cows. Two 4 * 4 latin square experiments were completed, one during the reproductive and the other during the vegetative growth phase of the cultivars. Thirty-two Holstein-Friesian dairy cows were divided into four groups, with each group assigned 17 days on each cultivar during both experiments. Within each observation period, milk yield and milk composition, sward morphology and pasture chemical composition were measured. During the reproductive growth phase, organic matter digestibility (OMD) was greater for Bealey and Astonenergy (P < 0.001; +1.6%). AberMagic contained a higher stem proportion (P < 0.01; +0.06) and a longer sheath height (P < 0.001; +1.9 cm). Consequently, cows grazing AberMagic recorded a lower milk yield (P < 0.001; -1.5 kg/day) and a lower milk solids yield (P < 0.001; -0.13 kg/day). During the vegetative growth phase, OMD was greater (P < 0.001; +1.1%) for Bealey, whereas the differences between the cultivars in terms of sward structure were smaller and did not appear to influence animal performance. As a result, cows grazing Bealey recorded a higher milk yield (P < 0.001; +0.9 kg/day) and a higher milk solids yield (P < 0.01; +0.08 kg/day). It was concluded that grass cultivar did influence milk yield due to variations in sward structure and chemical composition. PMID- 23034143 TI - Autoimmune cholangitis and cholangiocarcinoma. AB - Autoimmune cholangitis, immunoglobulin G4-associated cholangitis (IAC), is a part of multiorgan IgG4-related systemic disease, which was recognized as a new clinicopathological entity in recent years. IAC is defined as a biliary stricture that responds to steroid therapy, frequently is associated with other fibrosing conditions, especially autoimmune pancreatitis and is characterized by elevation of IgG4 in serum and infiltration of IgG4 positive plasma cells in bile ducts. Since IAC shares a number of clinical, biochemical, and imaging features with cholangiocarcinoma (CCA), it is often misdiagnosed as CCA, and unnecessary surgery was performed. In this compact review, we clarify the disease of IAC, summarize criteria for diagnosis of IAC, discuss the role of CA 19-9, and provide key information to differentiate diagnosis of IAC from CCA. IAC should be highly suspected in unexplained biliary stricture associated with increased IgG4 (in serum especially in bile) and other organ involvement (kidney, retroperitoneum etc. especially pancreas in which there are abundant IgG4-positive plasmocytes infiltration). Correct diagnosis of IAC will avoid unnecessary surgery because IAC responds well to steroid therapy. In a word, increased IgG4 levels, other organ involvement and response to steroids are keys to distinguishing IAC from CCA. PMID- 23034144 TI - Molecular network analysis of human microRNA targetome: from cancers to Alzheimer's disease. AB - MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs, mediate posttranscriptional regulation of protein-coding genes by binding chiefly to the 3' untranslated region of target mRNAs, leading to translational inhibition, mRNA destabilization or degradation. A single miRNA concurrently downregulates hundreds of target mRNAs designated "targetome", and thereby fine-tunes gene expression involved in diverse cellular functions, such as development, differentiation, proliferation, apoptosis and metabolism. Recently, we characterized the molecular network of the whole human miRNA targetome by using bioinformatics tools for analyzing molecular interactions on the comprehensive knowledgebase. We found that the miRNA targetome regulated by an individual miRNA generally constitutes the biological network of functionally-associated molecules in human cells, closely linked to pathological events involved in cancers and neurodegenerative diseases. We also identified a collaborative regulation of gene expression by transcription factors and miRNAs in cancer-associated miRNA targetome networks. This review focuses on the workflow of molecular network analysis of miRNA targetome in silico. We applied the workflow to two representative datasets, composed of miRNA expression profiling of adult T cell leukemia (ATL) and Alzheimer's disease (AD), retrieved from Gene Expression Omnibus (GEO) repository. The results supported the view that miRNAs act as a central regulator of both oncogenesis and neurodegeneration. PMID- 23034145 TI - Inflammatory histopathogenesis of nasopalatine duct cyst: a clinicopathological study of 41 cases. AB - OBJECTIVE: The aim of this study is to characterize immunohistochemical profiles of lining epithelia of nasopalatine duct cyst (NPC) as well as to correlate those findings with their clinicopathological features to understand the histopathogenesis of NPC. MATERIALS AND METHODS: Forty-one surgical specimens from NPC were examined for clinical profiles and expression of keratin-7, 13, MUC 1, and P63 by immunohistochemistry, compared to radicular cyst (RC) and maxillary sinusitis. RESULTS: Nasopalatine duct cyst was clinically characterized by male predominant occurrence: 44% of the cases involved tooth roots, and 70% with inflammatory backgrounds. Lining epithelia of NPCs without daughter cysts were immunohistochemically distinguished into three layers: a keratin 7-positive (+) ciliated cell layer in the surface, a keratin-13+ middle layer, and a MUC-1+/P63+ lower half, indicating that they were not respiratory epithelia, and the same layering pattern was observed in RC. However, those immunolocalization patterns of the main cyst lining with daughter cyst were exactly the same as those of daughter cyst linings as well as duct epithelia of mucous glands. CONCLUSIONS: Two possible histopathogenesis of NPC were clarified: one was inflammatory cyst like RC and the other was salivary duct cyst-like mucocele. PMID- 23034146 TI - Association between ambient ultraviolet radiation and risk of epithelial ovarian cancer. AB - Evidence is accumulating to suggest that higher exposure to solar ultraviolet radiation (UVR) is associated with decreased risk of internal cancers, but data for ovarian cancer are unclear. We aimed to examine the association between lifetime ambient UVR and ovarian cancer in a population-based-case-control study. The study included women aged 18 to 79 years with a new diagnosis of invasive (n = 1,215) or borderline (n = 285) epithelial ovarian cancer identified through a network of clinics and state cancer registries throughout Australia. Controls (n = 1,459), frequency matched to cases by age (5-year groups) and state of residence, were randomly selected from the National Electoral Roll. We asked participants to report where they had lived at different periods of their life and assigned an estimate of UVR using data from NASA's Total Ozone Mapping Spectrometer database (1997-2003). We estimated the association between ambient UVR and risk of ovarian cancer using conditional logistic regression adjusted for potential confounders. Women in the highest third of average daily ambient UVR over their lifetime were at significantly lower risk of all epithelial ovarian cancers than those in the lowest third [OR, 0.70; 95% confidence interval (CI), 0.56-0.88]. The inverse association was stronger for borderline tumors (0.47, 0.31-0.71) than invasive tumors (0.78, 0.61-1.00). The effect sizes for overall and borderline tumors were unchanged after adjusting for confounders, whereas the inverse association for invasive tumors was attenuated. These data suggest that exposure to ambient UVR may reduce the risk of ovarian cancer. PMID- 23034148 TI - The landscape of DNA repeat elements in human heart failure. AB - BACKGROUND: The epigenomes of healthy and diseased human hearts were recently examined by genome-wide DNA methylation profiling. Repetitive elements, heavily methylated in post-natal tissue, have variable methylation profiles in cancer but methylation of repetitive elements in the heart has never been examined. RESULTS: We analyzed repetitive elements from all repeat families in human myocardial samples, and found that satellite repeat elements were significantly hypomethylated in end-stage cardiomyopathic hearts relative to healthy normal controls. Satellite repeat elements are almost always centromeric or juxtacentromeric, and their overexpression correlates with disease aggressiveness in cancer. Similarly, we found that hypomethylation of satellite repeat elements correlated with up to 27-fold upregulation of the corresponding transcripts in end-stage cardiomyopathic hearts. No other repeat family exhibited differential methylation between healthy and cardiomyopathic hearts, with the exception of the Alu element SINE1/7SL, for which a modestly consistent trend of increased methylation was observed. CONCLUSIONS: Satellite repeat element transcripts, a form of non-coding RNA, have putative functions in maintaining genomic stability and chromosomal integrity. Further studies will be needed to establish the functional significance of these non-coding RNAs in the context of heart failure. PMID- 23034147 TI - Obesity, energy balance, and cancer: new opportunities for prevention. AB - Obesity is associated with increased risk and poor prognosis for many types of cancer. The mechanisms underlying the obesity-cancer link are becoming increasingly clear and provide multiple opportunities for primary to tertiary prevention. Several obesity-related host factors can influence tumor initiation, progression and/or response to therapy, and these have been implicated as key contributors to the complex effects of obesity on cancer incidence and outcomes. These host factors include insulin, insulin-like growth factor-I, leptin, adiponectin, steroid hormones, cytokines, and inflammation-related molecules. Each of these host factors is considered in the context of energy balance and as potential targets for cancer prevention. The possibility of prevention at the systems level, including energy restriction, dietary composition, and exercise is considered as is the importance of the newly emerging field of stem cell research as a model for studying energy balance and cancer prevention. PMID- 23034149 TI - Framework for research on children's reactions to disasters and terrorist events. AB - Clinical work and research relative to child mental health during and following disaster are especially challenging due to the complex child maturational processes and family and social contexts of children's lives. The effects of disasters and terrorist events on children and adolescents necessitate diligent and responsible preparation and implementation of research endeavors. Disasters present numerous practical and methodological barriers that may influence the selection of participants, timing of assessments, and constructs being investigated. This article describes an efficient approach to guide both novice and experienced researchers as they prepare to conduct disaster research involving children. The approach is based on five fundamental research questions: "Why?, Who?, When?, What?, and How?" Addressing each of the "four Ws" will assist researchers in determining "How" to construct and implement a study from start to finish. A simple diagram of the five questions guides the reader through the components involved in studying children's reactions to disasters. The use of this approach is illustrated with examples from disaster mental health studies in children, thus simultaneously providing a review of the literature. PMID- 23034150 TI - Living with side effects from cancer treatment--a challenge to target information. AB - BACKGROUND: Patients with cancer experience side effects related to their antineoplastic treatment. Demands for efficiency limit the time patients spend with health professionals. This requires that professionals are able to offer adequate support to patients in coping with side effects of treatment in everyday life. However, it appears that the level of information about and support in living with side effects may be insufficient. OBJECTIVE: To explore patients' experiences of how side effects from chemotherapy and radiotherapy impact everyday life as well as the information needs in coping with these side effects. METHODS: Nine patients' experiences were analysed and interpreted using a phenomenological-hermeneutical approach. Data were collected through semi structured interviews. FINDINGS: The patients are deeply impacted by side effects in their everyday life. They struggle to take power but experience loss of control. They feel inexperienced without knowledge in an 'ongoing system', and because of lack of continuity, they do not come up with their real needs. To avoid pitfalls in the information, the patients need individualized support from the professionals. CONCLUSION: If the patients have to be supported during everyday life with side effects from cancer treatment in an individualized way, the professional must be aware that the patients risk adapting to the busy healthcare system. To empower the patient, the professional must be able to sense the patients' appeal for help and enter into caring relationships. IMPLICATIONS FOR PRACTICE: To ensure targeted information, the relationship between nurse and patient must build on nursing values including the patients' illness - perspective. However, the professionals must take a critical look at how they provide information and how they act to empower the patients. PMID- 23034151 TI - Characterization of the variable cow's age at last calving as a measurement of longevity by using the Kaplan-Meier estimator and the Cox model. AB - In most studies on beef cattle longevity, only the cows reaching a given number of calvings by a specific age are considered in the analyses. With the aim of evaluating all cows with productive life in herds, taking into consideration the different forms of management on each farm, it was proposed to measure cow longevity from age at last calving (ALC), that is, the most recent calving registered in the files. The objective was to characterize this trait in order to study the longevity of Nellore cattle, using the Kaplan-Meier estimators and the Cox model. The covariables and class effects considered in the models were age at first calving (AFC), year and season of birth of the cow and farm. The variable studied (ALC) was classified as presenting complete information (uncensored = 1) or incomplete information (censored = 0), using the criterion of the difference between the date of each cow's last calving and the date of the latest calving at each farm. If this difference was >36 months, the cow was considered to have failed. If not, this cow was censored, thus indicating that future calving remained possible for this cow. The records of 11 791 animals from 22 farms within the Nellore Breed Genetic Improvement Program ('Nellore Brazil') were used. In the estimation process using the Kaplan-Meier model, the variable of AFC was classified into three age groups. In individual analyses, the log-rank test and the Wilcoxon test in the Kaplan-Meier model showed that all covariables and class effects had significant effects (P < 0.05) on ALC. In the analysis considering all covariables and class effects, using the Wald test in the Cox model, only the season of birth of the cow was not significant for ALC (P > 0.05). This analysis indicated that each month added to AFC diminished the risk of the cow's failure in the herd by 2%. Nonetheless, this does not imply that animals with younger AFC had less profitability. Cows with greater numbers of calvings were more precocious than those with fewer calvings. PMID- 23034152 TI - Methodological quality of systematic reviews in subfertility: a comparison of Cochrane and non-Cochrane systematic reviews in assisted reproductive technologies. AB - STUDY QUESTION: Are there differences in the methodological quality of Cochrane systematic reviews (CRs) and non-Cochrane systematic reviews (NCRs) of assisted reproductive technologies? SUMMARY ANSWER: CRs on assisted reproduction are of higher methodological quality than similar reviews published in other journals. WHAT IS KNOWN ALREADY: The quality of systematic reviews varies. STUDY DESIGN, SIZE AND DURATION: This was a cross-sectional study of 30 CR and 30 NCR systematic reviews that were randomly selected from the eligible reviews identified from a literature search for the years 2007-2011. MATERIALS, SETTING AND METHODS: We extracted data on the reporting and methodological characteristics of the included systematic reviews. We assessed the methodological quality of the reviews using the 11-domain Measurement Tool to Assess the Methodological Quality of Systematic Reviews (AMSTAR) tool and subsequently compared CR and NCR systematic reviews. MAIN RESULTS AND THE ROLE OF CHANCE: The AMSTAR quality assessment found that CRs were superior to NCRs. For 10 of 11 AMSTAR domains, the requirements were met in >50% of CRs, but only 4 of 11 domains showed requirements being met in >50% of NCRs. The strengths of CRs are the a priori study design, comprehensive literature search, explicit lists of included and excluded studies and assessments of internal validity. Significant failings in the CRs were found in duplicate study selection and data extraction (67% meeting requirements), assessment for publication bias (53% meeting requirements) and reporting of conflicts of interest (47% meeting requirements). NCRs were more likely to contain methodological weaknesses as the majority of the domains showed <40% of reviews meeting requirements, e.g. a priori study design (17%), duplicate study selection and data extraction (17%), assessment of study quality (27%), study quality in the formulation of conclusions (23%) and reporting of conflict of interests (10%). LIMITATIONS, REASONS FOR CAUTION: The AMSTAR assessment can only judge what is reported by authors. Although two of the five authors are involved in the production of CRs, the risk of bias was reduced by not involving these authors in the assessment of the systematic review quality. WIDER IMPLICATIONS OF THE FINDINGS: Not all systematic reviews are equal. The reader needs to consider the quality of the systematic review when they consider the results and the conclusions of a systematic review. STUDY FUNDING/COMPETING INTEREST(S): There are no conflicts with any commercial organization. Funding was provided for the students by the summer studentship programme of the Faculty of Medical and Health Sciences of the University of Auckland. PMID- 23034153 TI - Maternal smoking during pregnancy and reproductive health of daughters: a follow up study spanning two decades. AB - STUDY QUESTION: Does in utero exposure to constituents of cigarette smoke have a programming effect on daughters' age of menarche and markers of long-term reproductive health? SUMMARY ANSWER: In utero exposure to constituents of cigarette smoke was associated with earlier age of menarche and--to a lesser extent--changes in the testosterone profile of the young women. WHAT IS KNOWN ALREADY: Studies observe potential effects of in utero exposure to constituents of cigarette smoke on the intrauterine formation of female gonads, but the consequences on long-term reproductive health in daughters remain unclear. STUDY DESIGN, SIZE AND DURATION: A prospective cohort study was designed using data from 965 pregnant women enrolled prior to a routine 30th-week antenatal examination at a midwifery practice in Denmark from 1988 to 1989 and a follow-up of their 19-21-year-old daughters in 2008. PARTICIPANTS/MATERIALS, SETTING AND METHODS: The pregnant women provided information on lifestyle factors during pregnancy, including the exact number of cigarettes smoked per day during the first and the second trimesters. A total of 438 eligible daughters were asked to complete a web-based questionnaire on reproductive health and subsequently invited to participate in a clinical examination during 2008. Of the 367 daughters (84%) who answered the questionnaire, 267 (61%) agreed to further examination. Information on menstrual pattern was provided at examination, blood samples were drawn to be analyzed for serum levels of reproductive hormones [FSH, LH, estradiol (E(2)), sex hormone-binding globulin, anti-Mullerian hormone, dehydroepiandrosterone-sulphate (DHEAS), free testosterone and free E(2)] and number of follicles (2-9 mm) were examined by transvaginal ultrasound. The daughters were divided into three exposure groups according to the level of maternal smoking during first trimester [non-exposed (reference), low-exposed (mother smoking >0-9 cigarettes/day) and high-exposed (mother smoking >= 10 cigarettes/day)]. Data were analyzed by multiple regression analyses in which we adjusted for potential confounders. Both crude and adjusted test for trend were carried out using maternal smoking during the first trimester as a continuous variable. MAIN RESULTS AND THE ROLE OF CHANCE: We observed an inverse association between in utero exposure to constituents of cigarette smoke and age of menarche (P = 0.001). Daughters exposed to >0-9 cigarettes/day debuted with -2.7 [95% confidence interval (CI) -5.2 to -0.1] percentage earlier age of menarche, whereas daughters exposed to >= 10 cigarettes/day had -4.1 (95% CI: -6.6 to -1.5) percentage earlier age of menarche corresponding to 6.5 (95% CI: -10.7 to -2.2) months. There was a non-significant tendency towards lower levels of testosterone and DHEAS with increasing in utero exposure to constituents of cigarette smoke but no associations with follicle number, cycle length or serum levels of the other reproductive hormones were observed. LIMITATIONS AND REASONS FOR CAUTION: We collected information on age of menarche retrospectively but the recall time was relatively short (2-10 years) and the reported values were within the normal range of Caucasians. Analyses of reproductive hormones are presented only for the group of daughters who were non-users of hormonal contraceptives because users were excluded, leaving only a low number of daughters available for the analyses (n = 75), as reflected in the wide CIs. The analyses of hormones were further adjusted for menstrual phase at time of clinical examination (follicular, ovulation and luteal phase) because blood samples were not collected on a specific day of the menstrual cycle. WIDER IMPLICATIONS OF THE FINDINGS: This study supports the limited evidence of an inverse association between maternal smoking during pregnancy and age of menarche and further addresses to what extent reproductive capacity and hormones may be programmed by maternal smoking during pregnancy. A trend toward earlier maturation of females is suggested to have implications on long-term reproductive function. STUDY FUNDING/COMPETING INTEREST(S): Supported by a scholarship from The Lundbeck Foundation (R93-A8476). No conflict of interest declared. PMID- 23034154 TI - Donor identification 'kills gamete donation'? A response. AB - Two Australian government inquiries have recently called for the release of information to donor-conceived people about their gamete donors. A national inquiry, recommended 'as a matter of priority' that uniform legislation to be passed nationwide. A state-based inquiry argued that all donor-conceived people should have access to information and called for the enactment of retrospective legislation that would override donor anonymity. This paper responds to an opinion piece published in Human Reproduction in October 2012 by Professor Pennings in which he criticized such recommendations and questioned the motives of people that advocate for information release. I answer the arguments of Pennings, and argue that all parties affected by donor conception should be considered, and a compromise reached. The contact veto system is one such compromise. I discuss the education and support services recommended by the Victorian government and question Pennings' assertions that legislation enabling information release will lead to a decrease in gamete donation. Finally, I rebut Pennings' assertion that there is a 'hidden agenda' behind the call for information release. There is no such agenda in my work. If there is from others, then it is their discriminatory views that need to be addressed, not the move toward openness and honesty or the call for information by donor-conceived people. PMID- 23034155 TI - Acute renal failure in cirrhotic patients with severe sepsis: value of urinary interleukin-18. AB - BACKGROUND AND AIM: Acute renal failure (ARF) is a common complication of liver cirrhosis and severe sepsis. Differentiating functional renal failure from acute tubular necrosis (ATN) has been difficult in this clinical setting. It has been shown that urinary interleukin 18 (IL-18) can serve as a sensitive marker for ARF and ATN. This study was aimed to investigate the diagnostic and prognostic values of urinary IL-18 in ARF associated with liver cirrhosis and severe sepsis. METHODS: We prospectively evaluated the relationship between urinary IL-18 and clinical outcomes in 168 consecutive cirrhotic patients with severe sepsis. RESULTS: One hundred and eight patients (64.3%) developed ARF at admission to the intensive care unit. ARF was associated with higher urinary IL-18 and impaired effective arterial volume. Renal failure was functional in 64 (59.2%), due to acute tubular necrosis (ATN) in 30 (27.7%), and mixed type in 14 (12.9%). Patients with ATN had significantly higher levels of urinary IL-18, rates of vasopressor dependency, and hospital mortality than those with functional renal failure. By using the areas under receiver operating characteristic (AUROC) curve, urinary IL-18 demonstrated an excellent discriminative power (AUROC 0.882) for diagnosing tubular injury in those with ARF. Meanwhile, hospital survivors had significantly lower urinary and serum IL-18 levels, compared to non survivors. In multivariate analysis, urinary IL-18, international normalized ratio, and mean arterial pressure were independent factors to predict hospital mortality. CONCLUSIONS: Urinary IL-18 can serve as a diagnostic and prognostic marker in cirrhotic patients with severe sepsis. PMID- 23034156 TI - The role of hypoxia and hypoxia-inducible factor-1alpha in preeclampsia pathogenesis. AB - Preeclampsia affects 5%-8% of pregnancies and is the leading worldwide cause of maternal and fetal morbidity and mortality. Preeclampsia is associated with shallow trophoblast invasion and inadequate spiral artery remodeling, which are widely believed to lead to placental hypoxia, the putative culprit initiating the cascade of events that ultimately results in the maternal manifestations of the disease. Despite extensive research, however, the pathophysiology of this disease remains poorly understood, no effective prevention exists, and treatment is limited to symptomatic therapy. Recent research has introduced exciting new theories regarding the pathogenesis of preeclampsia. Clinical and experimental evidence implicating the circulating antiangiogenic molecules soluble Fms-like tyrosine kinase-1 (sFLT-1) and soluble endoglin (sENG), as well as endothelin-1 and the angiotensin II receptor type I autoimmune antibody (AT-1AA), have been especially promising. This review collates evidence for a role of hypoxia and hypoxia-inducible factor-1alpha (HIF1A; referred to as HIF-1alpha throughout) in the pathogenesis of preeclampsia and discusses possible molecular links between hypoxia and the newly reported potential mediators of the disease's manifestations. PMID- 23034158 TI - Pivotal role for monocytes/macrophages and dendritic cells in maternal immune response to the developing embryo in cattle. AB - In mammals, successful pregnancy is dependent in part on the adaptation or regulation of the maternal immune system to prevent the rejection of the embryonic semiallograft. A modification in Th cell function and secretion is a requirement for the establishment and maintenance of pregnancy. Although there is strong evidence from studies in humans and mice linking successful pregnancy with the predominance of Th2-type immunity, the situation in cattle remains unclear. This study describes the characterization of the immune response of the bovine maternal endometrium to the presence of a developing embryo, with specific emphasis on the macrophage and dendritic cell populations and associated factors, using quantitative real-time PCR, in situ hybridization, and immunohistochemistry. Furthermore, in vivo and in vitro models were developed to investigate the potential role of progesterone and interferon-tau (IFNT) in the regulation of these immune factors. There was a marked increase in the population of CD14(+) cells and CD172a-CD11c(+) cells in the endometrium in response to pregnancy, which was paralleled by increased mRNA expression of a number of non Th-associated factors, including IL12B and IL15, and downregulation of IL18. In addition, we identified several novel IFNT- and progesterone-regulated factors, including IL12B, MCP1, MCP2, PTX3, RSAD2, and TNFA, whose regulation may be critical to pregnancy outcome. Our findings give center stage to non-Th cells, such as monocytes/macrophages and dendritic cells, in the bovine immune response to the semiallogenic embryo. In conclusion, we propose that in cattle, successful pregnancy establishment is associated with a dramatic regulation of the cytokine network, primarily by endometrial monocytes/macrophages and dendritic cells. PMID- 23034157 TI - Molecular profiling of postnatal development of the hypothalamus in female and male rats. AB - Reproductive function is highly dynamic during postnatal developmental. Here, we performed molecular profiling of gene expression patterns in the hypothalamus of developing male and female rats to identify which genes are sexually dimorphic, to gain insight into a more complex network of hypothalamic genes, and to ascertain dynamic changes in their relationships with one another and with sex steroid hormones during development. Using a low-density PCR platform, we quantified mRNA levels in the preoptic area (POA) and medial basal hypothalamus (MBH), and assayed circulating estradiol, testosterone, and progesterone at six ages from birth through adulthood. Numerous genes underwent developmental change, particularly postnatal increases, decreases, or peaks/plateaus at puberty. Surprisingly, there were few sex differences; only Esr1, Kiss1, and Tac2 were dimorphic (higher in females). Cluster analysis of gene expression revealed sexually dimorphic correlations in the POA but not the MBH from P30 (Postnatal Day 30) to P60. Hormone measurements showed few sex differences in developmental profiles of estradiol; higher levels of progesterone in females only after P30; and a developmental pattern of testosterone with a nadir at P30 followed by a dramatic increase through P60 (males). Furthermore, bionetwork analysis revealed that hypothalamic gene expression profiles and their relationships to hormones undergo dynamic developmental changes that differ considerably from adults. These data underscore the importance of developmental stage in considering the effects of hormones on the regulation of neuroendocrine genes in the hypothalamus. Moreover, the finding that few neuroendocrine genes are sexually dimorphic highlights the need to consider postnatal development from a network approach that allows assessment of interactions and patterns of expression. PMID- 23034159 TI - SRY induced TCF21 genome-wide targets and cascade of bHLH factors during Sertoli cell differentiation and male sex determination in rats. AB - Male sex determination is initiated through the testis-determining factor SRY that promotes Sertoli cell differentiation and subsequent gonadal development. The basic helix-loop-helix (bHLH) gene Tcf21 was identified as one of the direct downstream targets of SRY. The current study was designed to identify the downstream targets of TCF21 and the potential cascade of bHLH genes that promote Sertoli cell differentiation. A modified ChIP-Chip comparative hybridization analysis identified 121 direct downstream binding targets for TCF21. The gene networks and cellular pathways potentially regulated by these TCF21 targets were identified. One of the main bHLH targets for TCF21 was the bHLH gene scleraxis (Scx). An embryonic ovarian gonadal cell culture was used to examine the functional role of Sry, Tcf21, and Scx to promote an in vitro sex reversal and induction of Sertoli cell differentiation. SRY and TCF21 were found to induce the initial stages of Sertoli cell differentiation, whereas SCX was found to induce the later stages of Sertoli cell differentiation associated with pubertal development using transferrin gene expression as a marker. Therefore, a cascade of SRY followed by TCF21 followed by SCX appears to promote, in part, Sertoli cell fate determination and subsequent differentiation. The current observations help elucidate the initial molecular events involved in the induction of Sertoli cell differentiation and testis development. PMID- 23034160 TI - Risk factors for porcine reproductive and respiratory syndrome virus infection and resulting challenges for effective disease surveillance. AB - BACKGROUND: This study aimed to identify risk factors for active porcine reproductive and respiratory syndrome virus (PRRSV) infection at farm level and to assess the probability of an infected farm being detected through passive disease surveillance in England. Data were obtained from a cross-sectional study on 147 farrow-to-finish farms conducted from April 2008-April 2009. The risk factors for active PRRSV infection were identified using multivariable logistic regression analysis. The surveillance system was evaluated using a stochastic scenario tree model. RESULTS: Evidence of PRRSV circulation was confirmed on 35.1% (95%CI: 26.8-43.4) of farms in the cross sectional study, with a higher proportion of infected farms in areas with high pig density (more than 15000 pigs within 10 km radius from the farm). Farms were more likely to have active PRRSV infection if they used the live virus vaccine-Porcilis PRRS (OR=7.5, 95%CI: 2.5 22.8), were located in high pig density areas (OR=2.9, 95%CI: 1.0-8.3) or had dead pigs collected (OR=5.6, 95%CI: 1.7-18.3). Farms that weaned pigs at 28 days of age or later had lower odds of being PRRSV positive compared to those weaning at 21-27 days (OR=0.2, 95%CI: 0.1-0.7). The probability of detecting an infected farm through passive surveillance for disease was low (mode=0.074, 5th and 95th percentiles: 0.067; 0.083 respectively). In particular farms which used live virus vaccine had lower probabilities for detection compared to those which did not. CONCLUSIONS: Risk factors identified highlight the importance of biosecurity measures for the incursion of PRRSV infection. The results further indicate that a combined approach of surveillance for infection and disease diagnosis is needed to assist effective control and/or elimination of PRRSV from the pig population. PMID- 23034161 TI - Design and process evaluation of an informative website tailored to breast cancer survivors' and intimate partners' post-treatment care needs. AB - BACKGROUND: On-line provision of information during the transition phase after treatment carries great promise in meeting shortcomings in post-treatment care for breast cancer survivors and their partners. The objectives of this study are to describe the development and process evaluation of a tailored informative website and to assess which characteristics of survivors and partners, participating in the feasibility study, are related to visiting the website. METHODS: The development process included quantitative and qualitative assessments of survivors' and partners' care needs and preferences. Participants' use and evaluation of the website were explored by conducting baseline and post measurements. During the intervening 10-12 weeks 57 survivors and 28 partners were granted access to the website. RESULTS: Fifty-seven percent (n=21) of survivors who took part in the post-measurement indicated that they had visited the website. Compared to non-visitors (n=16), they were more likely to have a partner and a higher income, reported higher levels of self-esteem and had completed treatment for a longer period of time. Partners who consulted the on line information (42%, n=8) were younger and reported lower levels of social support compared to partners who did not visit the website (n=11). Visitors generally evaluated the content and lay-out positively, yet some believed the information was incomplete and impersonal. CONCLUSIONS: The website reached only about half of survivors and partners, yet was mostly well-received. Besides other ways of providing information and support, a website containing clear-cut and tailored information could be a useful tool in post-treatment care provision. PMID- 23034162 TI - BatMeth: improved mapper for bisulfite sequencing reads on DNA methylation. AB - DNA methylation plays a crucial role in higher organisms. Coupling bisulfite treatment with next generation sequencing enables the interrogation of 5 methylcytosine sites in the genome. However, bisulfite conversion introduces mismatches between the reads and the reference genome, which makes mapping of Illumina and SOLiD reads slow and inaccurate. BatMeth is an algorithm that integrates novel Mismatch Counting, List Filtering, Mismatch Stage Filtering and Fast Mapping onto Two Indexes components to improve unique mapping rate, speed and precision. Experimental results show that BatMeth is faster and more accurate than existing tools. BatMeth is freely available at http://code.google.com/p/batmeth/. PMID- 23034164 TI - The International Code of Marketing of Breast-milk Substitutes: lessons learned and implications for the regulation of marketing of foods and beverages to children. AB - OBJECTIVE: To identify lessons learned from 30 years of implementing the International Code of Marketing of Breast-milk Substitutes ('the Code') and identify lessons learned for the regulation of marketing foods and beverages to children. DESIGN: Historical analysis of 30 years of implementing the Code. SETTING: Latin America and the Caribbean. SUBJECTS: None. RESULTS: Legislation to restrict marketing of breast-milk substitutes is necessary but not sufficient; equally important are the promulgation of implementing regulations, effective enforcement and public monitoring of compliance. A system of funding for regular monitoring of compliance with legislation should be explicitlyd eveloped and funded from the beginning. Economic sanctions, while important, are likely to be less effective than reports that affect a company's public image negatively. Non governmental organizations play a critical role in leveraging public opinion and galvanizing consumer pressure to ensure that governments adopt regulations and companies adhere to them. Continual clinical, epidemiological and policy research showing the link between marketing and health outcomes and between policy and better health is essential. CONCLUSIONS: Implementation of the Code has not come easily as it places the interests of underfinanced national governments and international and non-governmental organizations promoting breast-feeding against those of multinational corporations that make hundreds of millions of dollars annually marketing infant formulas. Efforts to protect, promote and support breast-feeding have been successful with indicators of breast-feeding practices increasing globally. The lessons learned can inform current efforts to regulate the marketing of foods and beverages to children. PMID- 23034163 TI - Epigenetic transgenerational inheritance of somatic transcriptomes and epigenetic control regions. AB - BACKGROUND: Environmentally induced epigenetic transgenerational inheritance of adult onset disease involves a variety of phenotypic changes, suggesting a general alteration in genome activity. RESULTS: Investigation of different tissue transcriptomes in male and female F3 generation vinclozolin versus control lineage rats demonstrated all tissues examined had transgenerational transcriptomes. The microarrays from 11 different tissues were compared with a gene bionetwork analysis. Although each tissue transgenerational transcriptome was unique, common cellular pathways and processes were identified between the tissues. A cluster analysis identified gene modules with coordinated gene expression and each had unique gene networks regulating tissue-specific gene expression and function. A large number of statistically significant over represented clusters of genes were identified in the genome for both males and females. These gene clusters ranged from 2-5 megabases in size, and a number of them corresponded to the epimutations previously identified in sperm that transmit the epigenetic transgenerational inheritance of disease phenotypes. CONCLUSIONS: Combined observations demonstrate that all tissues derived from the epigenetically altered germ line develop transgenerational transcriptomes unique to the tissue, but common epigenetic control regions in the genome may coordinately regulate these tissue-specific transcriptomes. This systems biology approach provides insight into the molecular mechanisms involved in the epigenetic transgenerational inheritance of a variety of adult onset disease phenotypes. PMID- 23034166 TI - Comparison of clinical characteristics of combined hepatocellular cholangiocarcinoma and other primary liver cancers. AB - BACKGROUND AND AIM: Combined hepatocellular-cholangiocarcinoma (CHC) is a rare liver malignancy. In this study, we compared patient characteristics and outcomes for primary CHC, intrahepatic cholangiocarcinoma (ICC), and hepatocellular carcinoma (HCC). METHODS: Medical records of patients with tissue-proven CHC (65 cases) treated at the Chang Gung Memorial Hospital between 1991 and 2005 were retrospectively reviewed. These records were compared to records of patients diagnosed with tissue-proven HCC (1985 cases) and ICC (127 cases) during the same period. RESULTS: Hepatitis B and C are major causes of CHC. CHC patients exhibited greater similarity to HCC than to ICC patients with respect to cirrhotic changes, age, and positive serology for hepatitis B surface antigen and anti-hepatitis C antibody. Survival was related to tumor characteristics and intervention therapies, but not to etiologies. CONCLUSIONS: The clinical characteristics of CHC are similar to those of HCC, but overall survival is more similar to that of ICC; survival may be related to tumor biology rather than the cause. Multimodal treatment with an initial aggressive therapeutic approach can improve survival. PMID- 23034167 TI - Elevated levels of anti inflammatory IL-10 and pro inflammatory IL-17 in malignant pleural effusions. AB - BACKGROUND: Pleural effusions can be caused by highly different underlying diseases and are characterized by complex interactions of various local and circulating cells as well as numerous soluble parameters like interleukins (IL). Knowledge of this complex network can be helpful in order to make the differential diagnosis in known malignant pleural effusions and understand the underlying immunochemistry of each disease or condition. METHODS: We investigated immunoreactive concentrations of Interleukin 10 (IL-10) and Interleukin 17 (IL 17) in malignant pleural effusions and peripheral blood from patients with bronchial carcinomas and other carcinomas, excluding other conditions such as congestive heart failure (CHF) and pneumonias in twenty four (24) patients (9 men/15 women), 37-74 years (mean:61) with already diagnosed malignant pleural effusions applying the ELISA method. RESULTS: The SPSS 15 program for Windows was used. Quantitative analysis showed high concentrations of IL-10 and IL-17 in pleural fluid and blood. Even though IL-17 levels -both blood and pleural- were lower than IL-10's, statistical correlation between blood and pleural concentations was proven, confirming once more the systematic action of these cytokines. At the same time high IL-17 levels in malignant effusions shows maybe a new perspective in understanding the pathophysiology of malignant pleural effusions. CONCLUSIONS: Our results confirm the pathogenetic role of these cytokines in malignant pleural effusions combining for the first time a pro- and an anti- inflammatory cytokine. The observation that IL-17 is elevated in malignant pleural effusions may give a new meaning in Virchow's remarks 100 years ago. Larger number of patients is needed to confirm our hypothesis. PMID- 23034168 TI - Small beta2-glycoprotein I peptides protect from intestinal ischemia reperfusion injury. AB - Intestinal ischemic events, which are followed by reperfusion, induce significant tissue damage and frequently result in multiple organ failure, with >70% mortality. Upon reperfusion, excessive inflammation leads to exacerbated tissue damage. Previous studies indicated that binding of the serum protein, beta2 glycoprotein I, to the endothelium initiates a cascade of inflammatory molecules that is required for damage. We hypothesized that peptides derived from the binding domain (domain V) of beta2-glycoprotein I would attenuate ischemia/reperfusion-induced damage and inflammation in a therapeutic manner. Using a mouse model of intestinal ischemia/reperfusion, we administered peptides either prior to ischemia or at clinically relevant time points during reperfusion and evaluated intestinal tissue damage and inflammation after 2 h of reperfusion. We demonstrate that multiple peptides attenuate injury and inflammation in a dose dependent manner and, perhaps more significantly, are efficacious when administered up to 30 min after the onset of reperfusion. In addition, an all D amino acid retro-inverso peptide was biologically active. Thus, the beta2 glycoprotein I-derived peptides attenuate injury and inflammation when administered in a therapeutic manner in intestinal ischemia/reperfusion injury. PMID- 23034169 TI - Mouse CD11b+Gr-1+ myeloid cells can promote Th17 cell differentiation and experimental autoimmune encephalomyelitis. AB - Myeloid-derived suppressor cells (MDSCs) have been a focus of recent study on tumor-mediated immune suppression. However, its role in Th17 cell differentiation and the pathogenesis of autoimmune diseases (e.g., multiple sclerosis) has not been determined. We show in this study that development of experimental autoimmune encephalomyelitis (EAE) in mice is associated with a profound expansion of CD11b(+)Gr-1(+) MDSCs, which display efficient T cell inhibitory functions in vitro. Unexpectedly, these MDSCs enhance the differentiation of naive CD4(+) T cell precursors into Th17 cells in a highly efficient manner under Th17-polarizing conditions, as indicated by significantly increased number of Th17 cells, elevation of IL-17A production, and upregulation of the orphan nuclear receptor RORA and RORC. Mechanistic studies show that IL-1beta represents a major mediator of MDSC-facilitated Th17 differentiation, which depends on the IL-1 receptor on CD4(+) T cells but not MDSCs. Selective depletion of MDSCs using gemcitabine results in a marked reduction in the severity of EAE (e.g., decreased clinical scores and myelin injury), which correlates with reduced Th17 cells and inflammatory cytokines (IL-17A and IL-1beta) in the lymphoid tissues and spinal cord. Adoptive transfer of MDSCs after gemcitabine treatment restores EAE disease progression. Together, we demonstrate for the first time, to our knowledge, that excessive and prolonged presence of MDSCs can drive a Th17 response and consequently contributes to the pathogenesis of EAE. These new findings provide unique insights into the pleiotropic functions of MDSCs and may help explain the failure of immunosuppressive MDSCs to control Th17/IL-17-dependent autoimmune disorders. PMID- 23034170 TI - Tumor-infiltrating gammadelta T lymphocytes predict clinical outcome in human breast cancer. AB - Understanding and dissecting the role of different subsets of regulatory tumor infiltrating lymphocytes (TILs) in the immunopathogenesis of individual cancer is a challenge for anti-tumor immunotherapy. High levels of gammadelta regulatory T cells have been discovered in breast TILs. However, the clinical relevance of these intratumoral gammadelta T cells is unknown. In this study, gammadelta T cell populations were analyzed by performing immunohistochemical staining in primary breast cancer tissues from patients with different stages of cancer progression. Retrospective multivariate analyses of the correlations between gammadelta T cell levels and other prognostic factors and clinical outcomes were completed. We found that gammadelta T cell infiltration and accumulation in breast tumor sites was a general feature in breast cancer patients. Intratumoral gammadelta T cell numbers were positively correlated with advanced tumor stages, HER2 expression status, and high lymph node metastasis but inversely correlated with relapse-free survival and overall survival of breast cancer patients. Multivariate and univariate analyses of tumor-infiltrating gammadelta T cells and other prognostic factors further suggested that intratumoral gammadelta T cells represented the most significant independent prognostic factor for assessing severity of breast cancer compared with the other known factors. Intratumoral gammadelta T cells were positively correlated with FOXP3(+) cells and CD4(+) T cells but negatively correlated with CD8(+) T cells in breast cancer tissues. These findings suggest that intratumoral gammadelta T cells may serve as a valuable and independent prognostic biomarker, as well as a potential therapeutic target for human breast cancer. PMID- 23034171 TI - Reconstitution of protective immune responses against cytomegalovirus and varicella zoster virus does not require disease development in pediatric recipients of umbilical cord blood transplantation. AB - CMV and varicella zoster virus (VZV) are significant causes of morbidity and mortality following umbilical cord blood transplantation (UCBT). However, the kinetics of reconstitution and protective potential of antiviral cell-mediated immune responses following UCBT remain poorly characterized. In this study, the reconstitution of CMV- and VZV-specific T cell responses was assessed using IFN gamma ELISPOT in 28 children who underwent UCBT to treat hematological or inherited disorders. Barely detectable in the first 3 mo posttransplantation, CMV and VZV-specific T cell responses were observed in 30.4% and 40.3% of study subjects after 36 mo of follow-up. Four of five CMV-seropositive subjects developed detectable levels of circulating CMV DNA (DNAemia), and 5 of 17 VZV seropositive patients experienced herpes zoster during the posttransplant period. Four CMV-seronegative subjects developed IFN-gamma responses against CMV, and four subjects developed a VZV-specific IFN-gamma response without clinical signs of infection. No CMV- or VZV-related events were observed in study subjects following the development of CMV- or VZV-specific responses > 150 spot-forming units/10(6) PBMCs, consistent with T cell-mediated protection. Finally, famciclovir prophylaxis did not strictly prevent the reconstitution of the VZV specific T cell repertoire, because the frequency of T cells producing IFN-gamma in response to VZV Ags reached levels consistent with protection in two nonzoster subjects. Monitoring of CMV- and VZV-specific cell-mediated immunity could inform immunocompetence and guide the initiation and cessation of antiherpetic prophylaxis in UCBT recipients. PMID- 23034172 TI - In the eye of the beholder: visual mate choice lateralization in a polymorphic songbird. AB - Birds choose mates on the basis of colour, song and body size, but little is known about the mechanisms underlying these mating decisions. Reports that zebra finches prefer to view mates with the right eye during courtship, and that immediate early gene expression associated with courtship behaviour is lateralized in their left hemisphere suggest that visual mate choice itself may be lateralized. To test this hypothesis, we used the Gouldian finch, a polymorphic species in which individuals exhibit strong, adaptive visual preferences for mates of their own head colour. Black males were tested in a mate choice apparatus under three eye conditions: left-monocular, right-monocular and binocular. We found that black male preference for black females is so strongly lateralized in the right-eye/left-hemisphere system that if the right eye is unavailable, males are unable to respond preferentially, not only to males and females of the same morph, but also to the strikingly dissimilar female morphs. Courtship singing is consistent with these lateralized mate preferences; more black males sing to black females when using their right eye than when using their left. Beauty, therefore, is in the right eye of the beholder for these songbirds, providing, to our knowledge, the first demonstration of visual mate choice lateralization. PMID- 23034173 TI - Histology shows that elongated neck ribs in sauropod dinosaurs are ossified tendons. AB - The histology of cervical ribs of Sauropoda reveals a primary bone tissue, which largely consists of longitudinally oriented mineralized collagen fibres, essentially the same tissue as found in ossified tendons. The absence of regular periosteal bone and the dominance of longitudinal fibres contradict the ventral bracing hypothesis (VBH) postulated for sauropod necks. The VBH predicts histologically primary periosteal bone with fibres oriented perpendicular to the rib long axis, indicative of connective tissue between overlapping hyperelongated cervical ribs. The transformation of the cervical ribs into ossified tendons makes the neck more flexible and implies that tension forces acted mainly along the length of the neck. This is contrary to the VBH, which requires compressive forces along the neck. Tension forces would allow important neck muscles to shift back to the trunk region, making the neck much lighter. PMID- 23034174 TI - Mesothelin regulates growth and apoptosis in pancreatic cancer cells through p53 dependent and -independent signal pathway. AB - Mesothelin, a secreted protein, is overexpressed in some cancers, including pancreatic cancer. Rescent studies have shown that overexpression of mesothelin significantly increased tumor cell proliferation, and downregulation of mesothelin inhibited cell proliferation in pancreatic cancer cells, but its exact function and mechanism remains unclear. The aim of the present study was to evaluate the effects of mesothelin on proliferation and apoptosis in pancreatic cancer cells with different p53 status and to explore its signal pathway. Mesothelin levels were detected by western blot and RT-PCR assay in human pancreatic cancer AsPC-1, HPAC and Capan-2, Capan-1 and MIA PaCa-2 cell lines. Mesothelin was slienced by shRNA in AsPC-1, Capan-2 and Capan-1 cells with rich mesothelin level, and mesothelin was overexpressed in the HPAC and Capan-2 cells with less mesothelin level. We observed that in the AsPC-1 and Capan-1cells with mt-p53, and Capan-2 cells with wt-p53, shRNA mediated sliencing of the mesothelin significantly increased PUMA and Bax expression and caspase-3 activity, and decreased bcl-2 expression, followed by the reduced proliferation and colony forming capability and increased cell apoptosis. When PUMA was slienced by siRNA in the stable mesothelin shRNA transfected cells, proliferative capability was significantly increased, and apoptosis was decreased. However, in the Capan-2 cells with wt-p53, suppression of the mesothelin significantly increased wt-p53 levels. When p53 was blocked by siRNA in the stable mesothelin shRNA transfected Capan-2 cells, PUMA was inhibited, followed by increased proliferative capability and decreased cell apoptosis. In the HPAC and Capan-2 cells with wt-p53 and in the MIA PaCa-2 cells with mt-p53, overexpression of the mesothelin significantly decreased bax levels and increased bcl-2 levels, followed by increased proliferative and colony forming capability. Furthermore, mesothelin-shRNA transfected cells exhibited a reduced rate of tumor growth under in vivo conditions. However, mesothelin-transfected cells exhibited a increased rate of tumor growth under in vivo conditions. Our data demonstrated that mesothelin promotes proliferation and inhibited apoptosis through p53-dependent pathway in pancreatic cancer cells with wt-p53, and p53-independent pathway in pancreatic cancer cells with mt-p53. Targeting mesothelin by shRNA is the important method for pancreatic cancer therapy. PMID- 23034175 TI - BSmooth: from whole genome bisulfite sequencing reads to differentially methylated regions. AB - DNA methylation is an important epigenetic modification involved in gene regulation, which can now be measured using whole-genome bisulfite sequencing. However, cost, complexity of the data, and lack of comprehensive analytical tools are major challenges that keep this technology from becoming widely applied. Here we present BSmooth, an alignment, quality control and analysis pipeline that provides accurate and precise results even with low coverage data, appropriately handling biological replicates. BSmooth is open source software, and can be downloaded from http://rafalab.jhsph.edu/bsmooth. PMID- 23034176 TI - Gel-free multiplexed reduced representation bisulfite sequencing for large-scale DNA methylation profiling. AB - Sequencing-based approaches have led to new insights about DNA methylation. While many different techniques for genome-scale mapping of DNA methylation have been employed, throughput has been a key limitation for most. To further facilitate the mapping of DNA methylation, we describe a protocol for gel-free multiplexed reduced representation bisulfite sequencing (mRRBS) that reduces the workload dramatically and enables processing of 96 or more samples per week. mRRBS achieves similar CpG coverage to the original RRBS protocol, while the higher throughput and lower cost make it better suited for large-scale DNA methylation mapping studies, including cohorts of cancer samples. PMID- 23034177 TI - Body fatness or anthropometry for assessment of unhealthy weight status? Comparison between methods in South African children and adolescents. AB - OBJECTIVE: A variety of methods are available for defining undernutrition (thinness/underweight/under-fat) and overnutrition (overweight/obesity/over-fat). The extent to which these definitions agree is unclear. The present cross sectional study aimed to assess agreement between widely used methods of assessing nutritional status in children and adolescents, and to examine the benefit of body composition estimates. DESIGN: The main objective of the cross sectional study was to assess underweight, overweight and obesity using four methods: (i) BMI-for-age using WHO (2007) reference data; (ii) BMI-for-age using Cole et al. and International Obesity Taskforce cut-offs; (iii) weight-for-age using the National Centre for Health Statistics/WHO growth reference 1977; and (iv) body fat percentage estimated by bio-impedance (body fat reference curves for children of McCarthy et al., 2006). Comparisons were made between methods using weighted kappa analyses. SETTING: Rural South Africa. SUBJECTS: Individuals (n 1519) in three age groups (school grade 1, mean age 7 years; grade 5, mean age 11 years; grade 9, mean age 15 years). RESULTS: In boys, prevalence of unhealthy weight status (both under- and overnutrition) was much higher at all ages with body fatness measures than with simple anthropometric proxies for body fatness; agreement between fatness and weight-based measures was fair or slight using Landis and Koch categories. In girls, prevalence of unhealthy weight status was also higher with body fatness than with proxies, although agreement between measures ranged from fair to substantial. CONCLUSIONS: Methods for defining under and overnutrition should not be considered equivalent. Weight-based measures provide highly conservative estimates of unhealthy weight status, possibly more conservative in boys. Simple body composition measures may be more informative than anthropometry for nutritional surveillance of children and adolescents. PMID- 23034178 TI - Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Abeta generation in Alzheimer's disease. AB - BACKGROUND: One of the best-characterized causative factors of Alzheimer's disease (AD) is the generation of amyloid-beta peptide (Abeta). AD subjects are at high risk of epileptic seizures accompanied by aberrant neuronal excitability, which in itself enhances Abeta generation. However, the molecular linkage between epileptic seizures and Abeta generation in AD remains unclear. RESULTS: X11 and X11-like (X11L) gene knockout mice suffered from epileptic seizures, along with a malfunction of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. Genetic ablation of HCN1 in mice and HCN1 channel blockage in cultured Neuro2a (N2a) cells enhanced Abeta generation. Interestingly, HCN1 levels dramatically decreased in the temporal lobe of cynomolgus monkeys (Macaca fascicularis) during aging and were significantly diminished in the temporal lobe of sporadic AD patients. CONCLUSION: Because HCN1 associates with amyloid-beta precursor protein (APP) and X11/X11L in the brain, genetic deficiency of X11/X11L may induce aberrant HCN1 distribution along with epilepsy. Moreover, the reduction in HCN1 levels in aged primates may contribute to augmented Abeta generation. Taken together, HCN1 is proposed to play an important role in the molecular linkage between epileptic seizures and Abeta generation, and in the aggravation of sporadic AD. PMID- 23034179 TI - The yeast homologue of the microtubule-associated protein Lis1 interacts with the sumoylation machinery and a SUMO-targeted ubiquitin ligase. AB - Microtubules and microtubule-associated proteins are fundamental for multiple cellular processes, including mitosis and intracellular motility, but the factors that control microtubule-associated proteins (MAPs) are poorly understood. Here we show that two MAPs-the CLIP-170 homologue Bik1p and the Lis1 homologue Pac1p interact with several proteins in the sumoylation pathway. Bik1p and Pac1p interact with Smt3p, the yeast SUMO; Ubc9p, an E2; and Nfi1p, an E3. Bik1p interacts directly with SUMO in vitro, and overexpression of Smt3p and Bik1p results in its in vivo sumoylation. Modified Pac1p is observed when the SUMO protease Ulp1p is inactivated. Both ubiquitin and Smt3p copurify with Pac1p. In contrast to ubiquitination, sumoylation does not directly tag the substrate for degradation. However, SUMO-targeted ubiquitin ligases (STUbLs) can recognize a sumoylated substrate and promote its degradation via ubiquitination and the proteasome. Both Pac1p and Bik1p interact with the STUbL Nis1p-Ris1p and the protease Wss1p. Strains deleted for RIS1 or WSS1 accumulate Pac1p conjugates. This suggests a novel model in which the abundance of these MAPs may be regulated via STUbLs. Pac1p modification is also altered by Kar9p and the dynein regulator She1p. This work has implications for the regulation of dynein's interaction with various cargoes, including its off-loading to the cortex. PMID- 23034180 TI - NMI mediates transcription-independent ARF regulation in response to cellular stresses. AB - The ARF tumor suppressor is a product of the INK4a/ARF locus, which is frequently mutated in human cancer. The expression of ARF is up-regulated in response to certain types of DNA damage, oncogene activation, and interferon stimuli. Through interaction with the p53 negative regulator MDM2, ARF controls a well-described p53/MDM2-dependent checkpoint. However, the mechanism of ARF induction is poorly understood. Using a yeast two-hybrid screen, we identify a novel ARF-interacting protein, N-Myc and STATs interactor (NMI). Previously, NMI was known to be a c Myc-interacting protein. Here we demonstrate that through competitive binding to the ARF ubiquitin E3 ligase (ubiquitin ligase for ARF [ULF]), NMI protects ARF from ULF-mediated ubiquitin degradation. In response to cellular stresses, NMI is induced, and a fraction of NMI is translocated to the nucleus to stabilize ARF. Thus our work reveals a novel NMI-mediated, transcription-independent ARF induction pathway in response to cellular stresses. PMID- 23034181 TI - POS-1 and GLD-1 repress glp-1 translation through a conserved binding-site cluster. AB - RNA-binding proteins (RBPs) coordinate cell fate specification and differentiation in a variety of systems. RNA regulation is critical during oocyte development and early embryogenesis, in which RBPs control expression from maternal mRNAs encoding key cell fate determinants. The Caenorhabditis elegans Notch homologue glp-1 coordinates germline progenitor cell proliferation and anterior fate specification in embryos. A network of sequence-specific RBPs is required to pattern GLP-1 translation. Here, we map the cis-regulatory elements that guide glp-1 regulation by the CCCH-type tandem zinc finger protein POS-1 and the STAR-domain protein GLD-1. Our results demonstrate that both proteins recognize the glp-1 3' untranslated region (UTR) through adjacent, overlapping binding sites and that POS-1 binding excludes GLD-1 binding. Both factors are required to repress glp-1 translation in the embryo, suggesting that they function in parallel regulatory pathways. It is intriguing that two equivalent POS-1-binding sites are present in the glp-1 3' UTR, but only one, which overlaps with a translational derepression element, is functional in vivo. We propose that POS-1 regulates glp-1 mRNA translation by blocking access of other RBPs to a key regulatory sequence. PMID- 23034182 TI - Analysis of substrate specificity of human DHHC protein acyltransferases using a yeast expression system. AB - Palmitoylation plays important roles in the regulation of protein localization, stability, and activity. The protein acyltransferases (PATs) have a common DHHC Cys-rich domain. Twenty-three DHHC proteins have been identified in humans. However, it is unclear whether all of these DHHC proteins function as PATs. In addition, their substrate specificities remain largely unknown. Here we develop a useful method to examine substrate specificities of PATs using a yeast expression system with six distinct model substrates. We identify 17 human DHHC proteins as PATs. Moreover, we classify 11 human and 5 yeast DHHC proteins into three classes (I, II, and III), based on the cellular localization of their respective substrates (class I, soluble proteins; class II, integral membrane proteins; class III, lipidated proteins). Our results may provide an important clue for understanding the function of individual DHHC proteins. PMID- 23034183 TI - RhoD activated by fibroblast growth factor induces cytoneme-like cellular protrusions through mDia3C. AB - The small GTPase RhoD regulates actin cytoskeleton to collapse actin stress fibers and focal adhesions, resulting in suppression of cell migration and cytokinesis. It also induces alignment of early endosomes along actin filaments and reduces their motility. We show here that a constitutively activated RhoD generated two types of actin-containing thin peripheral cellular protrusions distinct from Cdc42-induced filopodia. One was longer, almost straight, immotile, and sensitive to fixation, whereas the other was shorter, undulating, motile, and resistant to fixation. Moreover, cells expressing wild-type RhoD extended protrusions toward fibroblast growth factor (FGF) 2/4/8-coated beads. Stimulation of wild-type RhoD-expressing cells with these FGFs also caused formation of cellular protrusions. Nodules moved through the RhoD-induced longer protrusions, mainly toward the cell body. Exogenously expressed FGF receptor was associated with these moving nodules containing endosome-like vesicles. These results suggest that the protrusions are responsible for intercellular communication mediated by FGF and its receptor. Accordingly, the protrusions are morphologically and functionally equivalent to cytonemes. RhoD was activated by FGF2/4/8. Knockdown of RhoD interfered with FGF-induced protrusion formation. Activated RhoD specifically bound to mDia3C and facilitated actin polymerization together with mDia3C. mDia3C was localized to the tips or stems of the protrusions. In addition, constitutively activated mDia3C formed protrusions without RhoD or FGF stimulation. Knockdown of mDia3 obstructed RhoD-induced protrusion formation. These results imply that RhoD activated by FGF signaling forms cytoneme-like protrusions through activation of mDia3C, which induces actin filament formation. PMID- 23034184 TI - Inactivation of Bacillus cereus vegetative cells by gastric acid and bile during in vitro gastrointestinal transit. AB - BACKGROUND: The foodborne pathogen Bacillus cereus can cause diarrhoeal food poisoning by production of enterotoxins in the small intestine. The prerequisite for diarrhoeal disease is thus survival during gastrointestinal passage. METHODS: Vegetative cells of 3 different B. cereus strains were cultivated in a real composite food matrix, lasagne verde, and their survival during subsequent simulation of gastrointestinal passage was assessed using in vitro experiments simulating transit through the human upper gastrointestinal tract (from mouth to small intestine). RESULTS: No survival of vegetative cells was observed, despite the high inoculum levels of 7.0 to 8.0 log CFU/g and the presence of various potentially protective food components. Significant fractions (approx. 10% of the consumed inoculum) of B. cereus vegetative cells survived gastric passage, but they were subsequently inactivated by bile exposure in weakly acidic intestinal medium (pH 5.0). In contrast, the low numbers of spores present (up to 4.0 log spores/g) showed excellent survival and remained viable spores throughout the gastrointestinal passage simulation. CONCLUSION: Vegetative cells are inactivated by gastric acid and bile during gastrointestinal passage, while spores are resistant and survive. Therefore, the physiological form (vegetative cells or spores) of the B. cereus consumed determines the subsequent gastrointestinal survival and thus the infective dose, which is expected to be much lower for spores than vegetative cells. No significant differences in gastrointestinal survival ability was found among the different strains. However, considerable strain variability was observed in sporulation tendency during growth in laboratory medium and food, which has important implications for the gastrointestinal survival potential of the different B. cereus strains. PMID- 23034185 TI - Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. AB - BACKGROUND: Aberrant CpG island promoter DNA hypermethylation is frequently observed in cancer and is believed to contribute to tumor progression by silencing the expression of tumor suppressor genes. Previously, we observed that promoter hypermethylation in breast cancer reflects cell lineage rather than tumor progression and occurs at genes that are already repressed in a lineage specific manner. To investigate the generality of our observation we analyzed the methylation profiles of 1,154 cancers from 7 different tissue types. RESULTS: We find that 1,009 genes are prone to hypermethylation in these 7 types of cancer. Nearly half of these genes varied in their susceptibility to hypermethylation between different cancer types. We show that the expression status of hypermethylation prone genes in the originator tissue determines their propensity to become hypermethylated in cancer; specifically, genes that are normally repressed in a tissue are prone to hypermethylation in cancers derived from that tissue. We also show that the promoter regions of hypermethylation-prone genes are depleted of repetitive elements and that DNA sequence around the same promoters is evolutionarily conserved. We propose that these two characteristics reflect tissue-specific gene promoter architecture regulating the expression of these hypermethylation prone genes in normal tissues. CONCLUSIONS: As aberrantly hypermethylated genes are already repressed in pre-cancerous tissue, we suggest that their hypermethylation does not directly contribute to cancer development via silencing. Instead aberrant hypermethylation reflects developmental history and the perturbation of epigenetic mechanisms maintaining these repressed promoters in a hypomethylated state in normal cells. PMID- 23034187 TI - Medication costs across the hospice stay: an evaluation of medication costs in response to the MedPAC proposed reimbursement model. AB - The Medicare Payment Advisory Committee (MedPAC) recommended that the per diem reimbursement for the Medicare Hospice Benefit change to a U-shaped scheme reflecting spending based on nursing visit frequency. This study investigated the change in drug cost over patients' length of stay (LOS) as current drug cost trends are unknown and were not evaluated in the MedPAC proposed reimbursement scheme. An analysis of patient utilizers of a national pharmacy claims database from 2007 to 2010 was completed to determine the trend in average daily pharmaceutical cost per utilizer (PCPU) over the patient's LOS. The average daily PCPU for 144,119 patients demonstrated a U-shaped curve. Indexed values in the first and last periods were significantly higher than in all other periods overall and by diagnosis (P < .001). Although indexed medication costs showed a U shaped curve, it is imperative that hospice reimbursement be adequately evaluated for all medication costs including variations within the diagnosis mix. Payer sources and hospices must work together to determine adequate reimbursement models that will provide patients with effective and efficient high-quality care through the end of life. PMID- 23034188 TI - Four-item fatigue screen: replacing the Brief Fatigue Index. AB - INTRODUCTION: To develop a shorter and less burdensome cancer-related fatigue (CRF) questionnaire, the Four-Item Fatigue Scale (FIFS) was tested for validity against the Brief Fatigue Index (BFI). METHODS: On day 1, patients with cancer completed the BFI and FIFS in a random order and the reverse on day 7. Sixty-five patients were needed for an 80% power and a Spearman correlation of .7 or greater. The FIFS was compared with the BFI in fatigue severity and changes in fatigue over time. Bonferroni corrections were made for multiple comparisons with International Classification of Diseases, Tenth Revision (ICD-10) fatigue criteria. RESULTS: Seventy-nine patients were enrolled, 65 patients completed both surveys. Spearman correlation between FIFS and BFI for day 1 was 0.69 (95% confidence interval [CI] 0.50-0.87) and 0.73 (95% CI 0.56-0.90) 1 week later. Fatigue severity did not predict survival with either questionnaire. Brief Fatigue Index severity correlated with ICD-10 items 1, 3, 7, and 10B. Regression analysis showed that on day 7 BFI correlated with ICD-10 items 1, 7, and 10. When the model was adjusted for day 1, only the ICD-10 item 5 correlated well in BFI over 1 week. The ICD-10 items 7 and 10 significantly correlated with day 1 FIFS fatigue changes over 7 days after adjustment for FIFS baseline score. CONCLUSIONS: Four-Item Fatigue Scale has concurrent validity for fatigue using the BFI. The FIFS and BFI correlated modestly over time. Certain ICD-10 items correlated with CRF severity depending on the questionnaire. PMID- 23034186 TI - Non-genotoxic carcinogen exposure induces defined changes in the 5 hydroxymethylome. AB - BACKGROUND: Induction and promotion of liver cancer by exposure to non-genotoxic carcinogens coincides with epigenetic perturbations, including specific changes in DNA methylation. Here we investigate the genome-wide dynamics of 5 hydroxymethylcytosine (5hmC) as a likely intermediate of 5-methylcytosine (5mC) demethylation in a DNA methylation reprogramming pathway. We use a rodent model of non-genotoxic carcinogen exposure using the drug phenobarbital. RESULTS: Exposure to phenobarbital results in dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter regions of a cohort of genes that are transcriptionally upregulated. This reprogramming of 5mC/5hmC coincides with characteristic changes in the histone marks H3K4me2, H3K27me3 and H3K36me3. Quantitative analysis of phenobarbital-induced genes that are involved in xenobiotic metabolism reveals that both DNA modifications are lost at the transcription start site, while there is a reciprocal relationship between increasing levels of 5hmC and loss of 5mC at regions immediately adjacent to core promoters. CONCLUSIONS: Collectively, these experiments support the hypothesis that 5hmC is a potential intermediate in a demethylation pathway and reveal precise perturbations of the mouse liver DNA methylome and hydroxymethylome upon exposure to a rodent hepatocarcinogen. PMID- 23034189 TI - A comparison of cancer and noncancer patients who receive palliative care consultation services. AB - This study aimed to compare multiaspect characteristics in cancer and noncancer patients who received palliative care. Totally, 226 patients with cancer and 115 noncancer patients received palliative care consultation service in Taiwan from September 2007 through December 2009 were retrospectively analyzed. Noncancer patients were older (81 vs 67 years, P < .001), more likely to be enrolled from an intensive care unit (51% vs 5%, P < .001), and waited longer to be referred for admission to a palliative care (8 vs 3 days, P < .001) than patients with cancer. Cancer and noncancer patients presented as polysymptomatics in both physical and psychosocial symptoms at the end of life. Such physical and psychosocial characteristics should be taken into account in providing appropriate end-of-life care in the same way as it is for the patients with cancer. PMID- 23034190 TI - Consumption of soda and other sugar-sweetened beverages by 2-year-olds: findings from a population-based survey. AB - OBJECTIVE: To determine risk factors for consumption of soda and other sugar sweetened beverages (SSB) among 2-year-old children. DESIGN: The analysis was performed using three linked data sets: the 2004-2005 Oregon Pregnancy Risk Assessment Monitoring Survey (PRAMS); its longitudinal follow-up, 2006-2007 Oregon PRAMS-2; and 2004-2005 Oregon birth certificates. SETTING: PRAMS is a surveillance programme supported by the federal Centers for Disease Control and Prevention and implemented by participating state health departments. Using mixed methods, PRAMS surveys women 2-6 months after a live birth. Oregon PRAMS-2 re interviews respondents shortly after the index child's second birthday. Oregon PRAMS oversamples minority women. SUBJECTS: Using monthly cohorts, we randomly selected 5851 women from the 2004-2005 birth certificates. In total 1911 women completed both PRAMS and PRAMS-2. The weighted response rate of PRAMS-2 was 43.5%. RESULTS: Almost half of mothers (49.9%) reported that their child drank SSB on at least 1 d/week. Mothers whose children drank SSB at least once weekly were more likely to have low income (adjusted OR=2.83, 95% CI 2.09, 3.83) and to eat out on >=2 d/week (OR=2.11 %, 95% CI 1.66, 2.70). Hispanic and non-Hispanic black women were most likely to report that their child drank SSB at least once weekly. CONCLUSIONS: Half of mothers reported that their 2-year-old children drank SSB at least once weekly. Public health interventions and policies should address childhood SSB consumption including educating health-care providers and parents. PMID- 23034191 TI - A cyanoacrylate and silastic patch to reduce the risk of opening of the tumor: technical note. AB - BACKGROUND: Wide surgery is the main factor influencing survival in muscular skeletal tumor. Sometimes the margin can be very thin and the contamination risk can be very high because of manipulation of the mass. MATERIALS AND METHODS: A patch of cyanoacrylate and a silastic mesh are applied on tumor surface. In order to demonstrate the tumor sealing an histologic exam was performed. DISCUSSION: The application of protective patch can decrease the risk of accidental tumor rupture and neoplastic cells spreading. PMID- 23034193 TI - [Not Available]. PMID- 23034192 TI - Hippo signaling in mammalian stem cells. AB - Over the past decade, the Hippo signaling cascade has been linked to organ size regulation in mammals. Indeed, modulation of the Hippo pathway can have potent effects on cellular proliferation and/or apoptosis and a deregulation of the pathway often leads to tumor development. Importantly, emerging evidence indicates that the Hippo pathway can modulate its effects on tissue size by the regulation of stem and progenitor cell activity. This role has recently been associated with the central position of the pathway in sensing spatiotemporal or mechanical cues, and translating them into specific cellular outputs. These results provide an attractive model for how the Hippo cascade might sense and transduce cellular 'neighborhood' cues into activation of tissue-specific stem or progenitors cells. A further understanding of this process could allow the development of new therapies for various degenerative diseases and cancers. Here, we review current and emerging data linking Hippo signaling to progenitor cell function. PMID- 23034194 TI - Comparing the efficacy of long-acting pharmaceutical forms (depot) versus oral pharmaceutical forms of atypical and conventional antipsychotics used in Spain for treating patients with schizophrenia. AB - INTRODUCTION AND OBJECTIVES: Currently in Spain, 4 depot antipsychotics are available: flufenazine, pipotiazine, zuclopentixol and risperidone. The objectives of the present study are: a) to evaluate the efficacy of depot vs. oral forms of typical and atypical antipsychotics available in Spain for treating patients with schizophrenia; b) to compare the efficacy of different depot antipsychotics; c) to evaluate cost-effectiveness of typical and atypical depot and oral antipsychotics. METHODS: Systematic review of the literature between January 1980 and March 2007. Pharmaceutical companies of depot preparations were contacted aiming to include unpublished material. RESULTS: A total of 15 studies were included (13 journal manuscripts and 2 posters provided by the industry). Concordance between evaluators was moderate-high. The quality of selected studies was moderate-low. There were no differences in the efficacy between depot and oral risperidone. Efficacy of depot risperidone was higher than oral olanzapine (there were no differences regarding tolerability) and higher and better tolerated than oral zuclopentixol. The evidence was controversial when comparing the efficacy of depot and oral flufenazine. There were no differences when comparing the efficacy between depot flufenazine and oral pimozide. Depot zuclopentixol was more efficient than the oral preparation for treating patients with schizophrenia and violent behaviour. Finally, there were no differences regarding the efficacy and tolerability between depot pipotiazine and depot flufenazine and between depot clopentixol and depot flufenazine. CONCLUSIONS: There is few high-quality scientific evidence comparing depot and oral antipsychotics or different depot antipsychotics available in Spain. Selected evidence does not allow to conclude that depot antipsychotics are more effective and better tolerated than oral ones. PMID- 23034195 TI - Age at onset in bipolar I disorder: two may be better than three subgroups. AB - INTRODUCTION AND OBJECTIVE: Age at onset in bipolar disorder is related to prognosis and to treatment response. However, it is not clear if there are three or two subgroups in relation to age at onset. The objective of this study is to analyze the number of subgroups in relation to age at the beginning of the disease in a representative sample of bipolar I patients and to compare the subgroups in relation to clinical variables. METHOD: We included 169 patients diagnosed with bipolar I disorder. Normal mixture analysis was performed. The subgroups of patients formed above were compared regarding clinical characteristics. Patients were followed-up during six years. RESULTS: We found three ages at onset subgroups. The early onset group (18.2+/-2 years) included 34% of the patients. The second group (26.1+/-5.5 years) included 44% of the patients. The third group (50.9+/-9.1 years) included 22% of the patients. Early and intermediate onset groups were not significantly different, and had more family history of affective disorders, more psychotic symptoms, more history of suicide attempts and more history of drug abuse history than the late onset group. CONCLUSIONS: Our results suggest that there are three groups of age at onset but early and intermediate groups are similar in relation to clinical variables. The late onset group includes almost a quartile of patients and has different clinical profile. PMID- 23034196 TI - Role of serotonergic polymorphisms in the clinical severity of the panic disorder. AB - OBJECTIVES: To investigate the association between three serotonergic polymorphisms (A-1438G [rs6311] of the HTR2A gene, STin2 VNTR and 5-HTTLPR of the SLC6A4 gene) and the severity of panic and depression symptomatology among mental health outpatients with diagnosis of panic disorder (PD). METHODS: 92 unrelated PD outpatients (DSM-IV criteria) from a homogeneous Spanish Caucasian population (mean age+/-SD, 35.9+/-12.4 years; 28 [30.4%] males) were assessed using the Panic and Agoraphobia Scale (PAS), and the Hamilton Depression Rating Scale (HDRS), and genotyped using standard methods. RESULTS: Age of onset of PD varied by STin2 VNTR genotype (F=3.21; p=0.045). On average, onset of PD occurred earlier for those with the 10/10 than for those with the 12/12 genotype (25.1 nus 33.3; p=0.043). No relationship was found between A-1438G, 5-HTTLPR, and STin2 VNTR genotypes and PAS or HDRS total scores. Variation in scores on the HDRS Anxiety subscale by A-1438G genotype almost reached statistical significance (F=3.03; p=0.053). Post hoc pairwise comparisons showed higher anxiety levels among A/G than among A/A carriers (4.1 nus 2.9; p=0.043). Finally, variation in scores on the Preoccupied with Health subscale of the PAS by 5-HTTLPR genotype approached statistical significance (F=2.56; p=0.083). Post hoc pairwise comparisons showed higher scores among L/S than among L/L carriers (2.4 nus 1.4; p=0.078). CONCLUSIONS: Our data provide support of an involvement of the serotonin system, particularly, the HTR2A gene in the severity of PD. PMID- 23034197 TI - Bipolar disorder: What effect does treatment adherence have on risk of suicidal behavior? AB - Bipolar disorder is associated with high risk for suicidal behavior. Lack of adherence to treatment is one factor that may be partly responsible for this common complication. We searched MEDLINE with the combination of the key words "compliance" or "adherence" with "suicide" and "bipolar", limited to English language papers published between 1990 and July 2008.We evaluate the existent literature studying the influence of treatment adherence on suicidality among these patients. Our findings show a limited number of studies addressing this issue, mostly conducted with patients enrolled in lithium clinics. Results suggest an association between non-adherence and an increased risk of suicidal behavior among bipolar patients. Whether non-adherence leads to increase risk of suicidality due to specific properties of interventions such as lithium treatment or simply is secondary to mood stabilization is still an open question. PMID- 23034198 TI - Cardiovascular disease and diabetes in people with severe mental illness. AB - Position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). People with severe mental illnesses, such as schizophrenia, depression or bipolar disorder, have worse physical health and reduced life expectancy compared to the general population. The excess cardiovascular mortality associated with schizophrenia and bipolar disorder is attributed to an increased risk of the modifiable coronary heart disease risk factors, obesity, smoking, diabetes, hypertension, and dyslipidaemia. Antipsychotic medication and possibly other psychotropic medication like antidepressants can induce weight gain and further increase the risk of adverse metabolic effects which may result in further increased incidence of cardiovascular disease. Patients have limited access to general healthcare with less opportunity for cardiovascular risk screening and prevention than would be expected in a non-psychiatric population. The European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC) published this statement aiming to improve the care of patients suffering from severe mental illness. The intention is to initiate co-operation and shared care between the different health care professionals and to increase the awareness of psychiatrists caring for patients suffering from severe mental illness to screen and treat increased cardiovascular risk factors and diabetes. PMID- 23034199 TI - Time does not heal all wounds: very late stent thrombosis eight years after implantation of a sirolimus-eluting stent due to positive remodelling, saccular evaginations and marked vascular inflammation. PMID- 23034202 TI - Poor maternal outcomes: a factor of poor professional systems design. AB - South Africa is struggling to improve maternal and perinatal outcomes, resulting in failure to achieve the Millennium Goal for maternal health. Staff attitudes and skills have been identified as a factor affecting deaths and adverse outcomes in mothers. Huge training efforts are required from health departments to ensure that staff have the required skills to provide the services. The integrated approach to training of nurse professionals, which includes midwifery as a part of undergraduate training, has a devastating effect on the quality of midwifery. Training of midwifery is unfocused and forced upon those who have no interest in improving maternal outcomes. Maternal care is provided in professional silos by professionals who are not equipped with appropriate skills. Unless this systems design error is corrected, and a single-output training model introduced to professionals providing maternal care, we are unlikely to see a a major change in our maternal outcomes. New models based on inter-professional training and task sharing need to be developed for the country, including redefining of professional accountability for maternal care. PMID- 23034203 TI - Addressing poor maternal and fetal outcomes. PMID- 23034204 TI - Unforeseen ethical/legal complications with screening tests in the capitation model of medical aid schemes. AB - In the South African health care system patients/consumers are divided into those who can afford private care and those who rely on state medical assistance. The system is under pressure to fund delivery of medical care to its beneficiaries. We consider the effects of different funding models on medicolegal liability of health professionals serving the private sector. Medical reasons should determine the service rendered. However, financial implications of services rendered and defensive practice of medicine also contribute to treatment received by a patient and its remuneration. Practitioners who commit to delivering a predetermined set of services within a particular time for a predetermined 'lump sum' are only paid for the service specifically requested. Should disease be found other than those contracted for, we argue that inaction with regard to that disease would be deemed to be negligent or unethical according to legal and ethical considerations. PMID- 23034205 TI - Blood-brain barrier integrity in a zolpidem-responder patient. AB - A 27-year-old neurologically disabled but fully conscious male zolpidem-responder patient was investigated for blood brain barrier (BBB) dysfunction 5 years after a traumatic brain injury. A baseline single-photon emission computed tomography (SPECT) technetium-99m-labelled hexamethylpropylene amine oxime (99mTcHMPAO) brain scan was performed and the patient was administered 10 mg zolpidem daily. The patient was rescanned 2 weeks later when 99mTcHMPAO was injected 1 hour after zolpidem application. SPECT technetium-99m-labelled diethylene-triamine pentacetic acid (99mTcDTPA) BBB scans were also performed before and after zolpidem treatment. There was decreased uptake of 99mTcHMPAO in the left frontoparietal brain region, left temporal region and left thalamus on baseline scanning; this improved within 1 hour after zolpidem treatment at the follow-up scan. The 99mTcDTPA scan remained within normal limits before and after zolpidem treatment. The patient's neurological disabilities, especially coordination, speech and gait, improved markedly. The Barthel Index remained normal, but the Tinetti falls efficacy scale improved from 21/100 to 15/100. The results implied that the underlying cause for the patient's long-term neurological disability and brain suppression was not due to a long-term dysfunctional BBB. PMID- 23034206 TI - Sexuality, disability and human rights: strengthening healthcare for disabled people. PMID- 23034207 TI - Introducing a national health insurance system in South Africa: a general practitioner's bottom-up approach to costing. AB - BACKGROUND: The introduction of national health insurance (NHI) is an important debate in South Africa, with affordability and institutional capacity being the key issues. NHI costing has been dominated by estimates of exorbitant cost. However, capitation is not only a different payment system but also a different service delivery model, and as a result there are opportunities for risk management and efficiencies. OBJECTIVE: This study explores how private general practitioners (GPs) may choose to embrace these service delivery concepts and deal with the cost implications to meet NHI requirements. METHODS: Data were collected from 598 solo private GPs through a self-administered online questionnaire survey across South Africa. RESULTS: In spite of poor engagement with the public sector, and some challenges in costing and organisation, GPs appear to have an affordable and pro-active response to NHI capitation costing and fee setting. On average, they would accept a minimum global fee of R4.03 million to look after a population of 10 000 people for personal healthcare services. CONCLUSION: At a total cost to the country of R16.9 billion, government could affordably use GPs to develop the primary health care part of NHI to cover the entire South African uninsured population. It is anticipated that a similar approach would be successful in other developing countries. PMID- 23034208 TI - Challenges with using estimates when calculating ART need among adults in South Africa. AB - BACKGROUND: The Foundation for Professional Development (FPD) collects information annually on HIV/AIDS service provision and estimates service needs in the City of Tshwane Metropolitan Municipality (CTMM). METHODS: Antiretroviral therapy (ART) data from the Department of Health and Statistics South Africa (SSA) mid-year population estimates were used to approximate the ART need among adults in the CTMM. RESULTS: According to SSA data, ART need decreased dramatically from 2010 to 2011 and was lower than the number of adults receiving ART. Although the noted difference was probably due to changes in the calculations by SSA, no detailed or confirmed explanation could be offered. CONCLUSIONS: We provide a constructive contribution to the discussion about the use of model-derived estimates of ART need. PMID- 23034209 TI - Reasons why patients with primary health care problems access a secondary hospital emergency centre. AB - BACKGROUND: Many patients present to an emergency centre (EC) with problems that could be managed at primary healthcare (PHC) level. This has been noted at George Provincial Hospital in the Western Cape province of South Africa. AIM: In order to improve service delivery, we aimed to determine the patient-specific reasons for accessing the hospital EC with PHC problems. METHODS: A descriptive study using a validated questionnaire to determine reasons for accessing the EC was conducted among 277 patients who were triaged as green (routine care), using the South African Triage Score. The duration of the complaint, referral source and appropriateness of referral were recorded. RESULTS: Of the cases 88.2% were self referred and 30.2% had complaints persisting for more than a month. Only 4.7% of self-referred green cases were appropriate for the EC. The three most common reasons for attending the EC were that the clinic medicine was not helping (27.5%), a perception that the treatment at the hospital is superior (23.7%), and that there was no PHC service after-hours (22%). CONCLUSIONS: Increased acceptability of the PHC services is needed. The current triage system must be adapted to allow channelling of PHC patients to the appropriate level of care. Strict referral guidelines are needed. PMID- 23034210 TI - Tuberculosis in an inflammatory bowel disease cohort from South Africa. AB - BACKGROUND: Potent immunosuppressive therapy is standard treatment for inflammatory bowel disease (IBD) but carries a risk of reactivating latent tuberculosis (TB). No data exist on the burden of TB in South African patients with IBD. OBJECTIVE: To evaluate the burden of TB in IBD patients attending a large tertiary IBD clinic. METHODS: A retrospective analysis was performed on data pertaining to patients attending the Groote Schuur Hospital IBD clinic. Data were extracted from an existing IBD database, patient notes, the National Health Laboratory Services database and chest X-ray analysis. RESULTS: Of 614 patients, 72 (11.7%) were diagnosed with TB; 40 (55.6%) developed TB prior to the diagnosis of IBD. On regression analysis, coloured IBD patients were at increased risk for TB development (p=0.004, odds ratio (OR) 3.57, 95% confidence interval (CI) 1.49 8.56), as were patients with extensive Crohn's disease (CD) compared with those with less extensive disease (p=0.001,OR 2.84, 95% CI 1.27 - 6.33). No other risk factors, including the use of immunosuppressive agents, were identified for the development of TB. CONCLUSIONS: Of over 600 patients, 12% had TB either before or after IBD diagnosis. The high rate of previous TB and positive association with ethnicity probably reflects the high burden of TB in a socio-economically disadvantaged community. We recommend that IBD patients should be screened actively and monitored for TB when immunosuppressive medications are used. PMID- 23034211 TI - Implementation of Xpert MTB/RIF for routine point-of-care diagnosis of tuberculosis at the primary care level. AB - Xpert MTB/RIF (Xpert) offers rapid detection of Mycobacterium tuberculosis and rifampicin resistance. However, little is known about routine point-of-care (POC) use in high TB/HIV burden settings. We describe our experiences of launching Xpert as the POC, initial diagnostic for all TB suspects at a primary healthcare clinic in Johannesburg, South Africa. Noted important benefits of POC Xpert were fewer clinic visits, rapid detection of TB and rifampicin resistance, real-time assessment of accompanying household members of new TB cases, and increased staff motivation for TB screening. While Xpert results are available within 2 hours, actual turn-around time was longer for most patients because of sample preparation time and clinic congestion. Consequently, a GX4 instrument did not result in a 16-test capacity during an 8-hour working day, and some patients did not receive same-day results. Loss to follow-up was an unforeseen challenge, overcome by clinic flow changes, marking of clinic files, documenting patients' physical description and locating patients in the clinic by cell phone. Staff with high school education successfully performed the assay after minimal training. Human resource requirements were considerable, with a minimum of 2 staff needed to supervise sputum collection, process sputum, perform assays, and document results for an average of 15 TB suspects daily. POC placement of the instrument transferred logistical responsibilities to the clinic, including quality assurance, maintenance, stock control and cartridge disposal. POC use of Xpert is feasible at the primary healthcare level but must be accompanied by financial, operational and logistical support. PMID- 23034212 TI - Determinants of mortality in Nigerian children with severe anaemia. AB - BACKGROUND: Severe anaemia (haemoglobin concentration less than 50 g/l) is a major cause of paediatric hospital admissions and deaths in the tropics. OBJECTIVES: To examine the pattern and predictors of mortality among severely anaemic children. METHODS: A prospective cross-sectional study was conducted among children with severe anaemia at the Children's Emergency Room of the University Teaching Hospital, Ado-Ekiti, Nigeria. Socio-demographic characteristics, clinical features, laboratory findings and co-morbidities of the survivors and those who died were compared by logistic regression analysis. RESULTS: Of the 1 735 children admitted, 311 (17.9%) had severe anaemia, with a case - fatality rate of 9.3%. The presence of respiratory distress (95% confidence interval (CI) 2.1 - 3.6, p=0.031); acidosis (95% CI 1.8 - 2.7, p=0.010); coma (95% CI 0.1 - 0.3, p=0.001); hypotension (95% CI 2.0 - 4.2, p=0.020); and bacteraemia (95% CI 3.1 - 3.9; p=0.008) were the significant independent predictors of death with regression analysis. CONCLUSION: Early recognition with prompt and appropriate anticipatory intervention is essential to reduce mortality from severe anaemia. PMID- 23034213 TI - TGF-beta-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury. AB - Transforming growth factor-beta (TGFbeta) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFbeta regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFbeta expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter beta (OSTbeta) expression were markedly decreased in Smad3-null mice, whereas TGFbeta induced LPCAT4 and OSTbeta expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFbeta-induced LPCAT4 and OSTbeta expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFbeta-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury. PMID- 23034214 TI - Lipid mediator metabolic profiling demonstrates differences in eicosanoid patterns in two phenotypically distinct mast cell populations. AB - Mast cells are inflammatory cells that play key roles in health and disease. They are distributed in all tissues and appear in two main phenotypes, connective tissue and mucosal mast cells, with differing capacities to release inflammatory mediators. A metabolic profiling approach was used to obtain a more comprehensive understanding of the ability of mast cell phenotypes to produce eicosanoids and other lipid mediators. A total of 90 lipid mediators (oxylipins) were characterized using liquid chromatography-tandem mass spectrometry (LC-MS/MS), representing the cyclooxygenase (COX), lipoxygenase (LO), and cytochrome P450 (CYP) metabolic pathways. In vitro-derived murine mucosal-like mast cells (MLMC) and connective tissue-like mast cells (CTLMC) exhibited distinct mRNA expression patterns of enzymes involved in oxylipin biosynthesis. Oxylipins produced by 5-LO and COX pathways were the predominant species in both phenotypes, with 5-LO products constituting 90 +/- 2% of the CTLMCs compared with 58 +/- 8% in the MLMCs. Multivariate analyses demonstrated that CTLMCs and MLMCs secrete differing oxylipin profiles at baseline and following calcium ionophore stimulation, evidencing specificity in both a time- and biosynthetic pathway-dependent manner. In addition to the COX-regulated prostaglandin PGD(2) and 5-LO-regulated cysteinyl-leukotrienes (e.g., LTC(4)), several other mediators evidenced phenotype-specificity, which may have biological implications in mast cell mediated regulation of inflammatory responses. PMID- 23034216 TI - Population diversity of ORFan genes in Escherichia coli. AB - The origin and evolution of "ORFans" (suspected genes without known relatives) remain unclear. Here, we take advantage of a unique opportunity to examine the population diversity of thousands of ORFans, based on a collection of 35 complete genomes of isolates of Escherichia coli and Shigella (which is included phylogenetically within E. coli). As expected from previous studies, ORFans are shorter and AT-richer in sequence than non-ORFans. We find that ORFans often are very narrowly distributed: the most common pattern is for an ORFan to be found in only one genome. We compared within-species population diversity of ORFan genes with those of two control groups of non-ORFan genes. Patterns of population variation suggest that most ORFans are not artifacts, but encode real genes whose protein-coding capacity is conserved, reflecting selection against nonsynonymous mutations. Nevertheless, nonsynonymous nucleotide diversity is higher than for non-ORFans, whereas synonymous diversity is roughly the same. In particular, there is a several-fold excess of ORFans in the highest decile of diversity relative to controls, which might be due to weaker purifying selection, positive selection, or a subclass of ORFans that are decaying. PMID- 23034215 TI - Weak 5'-mRNA secondary structures in short eukaryotic genes. AB - Experimental studies of translation have found that short genes tend to exhibit greater densities of ribosomes than long genes in eukaryotic species. It remains an open question whether the elevated ribosome density on short genes is due to faster initiation or slower elongation dynamics. Here, we address this question computationally using 5'-mRNA folding energy as a proxy for translation initiation rates and codon bias as a proxy for elongation rates. We report a significant trend toward reduced 5'-secondary structure in shorter coding sequences, suggesting that short genes initiate faster during translation. We also find a trend toward higher 5'-codon bias in short genes, suggesting that short genes elongate faster than long genes. Both of these trends hold across a diverse set of eukaryotic taxa. Thus, the elevated ribosome density on short eukaryotic genes is likely caused by differential rates of initiation, rather than differential rates of elongation. PMID- 23034218 TI - Wegener's granulomatosis in a middle-aged woman presenting with dyspnea, rash, hemoptysis and recurrent eye complaints: a case report. AB - INTRODUCTION: Wegener's granulomatosis presenting as diffuse alveolar hemorrhage is uncommon. However, the recognition of multisystem disease involving joints, kidney, eye and lung is critical for diagnosing Wegener's vasculitis. This is not the first report of this kind in the literature. CASE PRESENTATION: A 51-year-old Croatian woman presented to our Emergency Department with a history of progressively worsening productive cough and shortness of breath, epistaxis and two episodes of hemoptysis. She developed respiratory failure due to diffuse alveolar hemorrhage, which was successfully treated with high-dose steroids, cyclophosphamide and plasmapheresis. Her clinical course was complicated with methicillin-resistant Staphyloccocus aureus pneumonia, which has been associated with Wegener's granulomatosis flares. CONCLUSION: The recognition of multisystem disease is critical for diagnosing Wegener's vasculitis. Diffuse alveolar hemorrhage can be a fulminant manifestation of Wegener's granulomatosis, in which case immediate and aggressive treatment with pulse steroids, high-dose cyclophosphamide and plasma exchange can be life-saving. PMID- 23034217 TI - Incomplete sex chromosome dosage compensation in the Indian meal moth, Plodia interpunctella, based on de novo transcriptome assembly. AB - Males and females experience differences in gene dose for loci in the nonrecombining region of heteromorphic sex chromosomes. If not compensated, this leads to expression imbalances, with the homogametic sex on average exhibiting greater expression due to the doubled gene dose. Many organisms with heteromorphic sex chromosomes display global dosage compensation mechanisms, which equalize gene expression levels between the sexes. However, birds and Schistosoma have been previously shown to lack chromosome-wide dosage compensation mechanisms, and the status in other female heterogametic taxa including Lepidoptera remains unresolved. To further our understanding of dosage compensation in female heterogametic taxa and to resolve its status in the lepidopterans, we assessed the Indian meal moth, Plodia interpunctella. As P. interpunctella lacks a complete reference genome, we conducted de novo transcriptome assembly combined with orthologous genomic location prediction from the related silkworm genome, Bombyx mori, to compare Z-linked and autosomal gene expression levels for each sex. We demonstrate that P. interpunctella lacks complete Z chromosome dosage compensation, female Z-linked genes having just over half the expression level of males and autosomal genes. This finding suggests that the Lepidoptera and possibly all female heterogametic taxa lack global dosage compensation, although more species will need to be sampled to confirm this assertion. PMID- 23034219 TI - Building the case for independent monitoring of food advertising on Australian television. AB - OBJECTIVE: To provide an independent monitoring report examining the ongoing impact of Australian self-regulatory pledges on food and drink advertising to children on commercial television. DESIGN: Analysis of food advertisements across comparable sample time periods in April/May 2006, 2007, 2009, 2010 and 2011. The main outcome measure comprised change in the mean rate of non-core food advertisements from 2006 to 2011. SETTING: Sydney free-to-air television channels. SUBJECTS: Televised food advertisements. RESULTS: In 2011 the rate of non-core food advertisements was not significantly different from that in 2006 or 2010 (3.2/h v. 4.1/h and 3.1/h), although there were variations across the intervening years. The rate of fast-food advertising in 2010 was significantly higher than in 2006 (1.8/h v. 1.1/h, P < 0.001), but the same as that in 2011 (1.5/h). CONCLUSIONS: The frequency of non-core food advertising on Sydney television has remained essentially unchanged between 2006 and 2011, despite the implementation of two industry self-regulatory pledges. The current study illustrates the value of independent monitoring as a basic requirement of any responsive regulatory approach. PMID- 23034220 TI - Early manifestations in a cohort of children prenatally diagnosed with 47,XYY. Role of multidisciplinary counseling for parental guidance and prevention of aggressive behavior. AB - BACKGROUND: An increasing number of foetuses are recognized as having double Y because of the widespread use of prenatal screening using chorionic villus sampling and amniocentesis. 47, XYY karyotype occurs in about one out of 1,000 newborn males, but it is not often detected unless it is diagnosed during prenatal testing. Despite the fact that unbiased follow-up studies demonstrate largely normal post-natal development of young men with 47, XYY, there is a scarcity of controlled studies about the neurological, cognitive and behavioural phenotype which remains the main reason for anxiety and anticipatory negative attitudes of parents. Furthermore, prejudices still exist among professionals and the general population concerning the relationship between this sex chromosome aneuploidy and aggressive and antisocial behaviours. METHODS: We report on the clinical follow-up of children diagnosed prenatally with a 47,XYY karyotype, whose parents received multidisciplinary counselling and support at time of diagnosis. The specific focus of our study is on auxology, facial features, developmental milestones, behaviour, detection of aggressiveness as well as the evaluation of parental attitudes toward prenatal counselling. Clinical evaluations including auxological measurements and dysmorphological descriptions were as conducted on 13 boys aged 9 month -7 years. The Child Behavior Check List test specific for age and a 15 item questionnaire were administered to both parents. An update of ongoing problems was carried out by means of a telephone interview two years later. RESULTS: Our results show that, from birth, weight, height and head circumference were above average values while some facial features such mild hypertelorism are overrepresented when compared to parents' facial features. Language delay was detected in 8 out of 11 children older than 20 months. Parental attitudes were found to be favourable toward prenatal diagnoses of sexual chromosome aneuploidies. CONCLUSIONS: Our data, although limited, is similar to other observational studies, and serves to alert clinicians about opportunities to delineate new and appropriate educational interventions that target the specific learning challenges of XYY boys. Our experience better defines the early manifestation of XYY and should aid those involved in prenatal counselling and paediatric surveillance. PMID- 23034221 TI - In vivo production of thiopeptide variants. AB - Thiopeptides are a family of highly modified peptide metabolites, characterized by a macrocycle bearing a central piperidine/dehydropiperidine/pyridine ring, multiple thiazole rings, and several dehydrated amino acid residues. Thiopeptides have useful antibacterial, antimalarial, and anticancer properties but have not been adapted for human clinical applications, owing in part to their poor water solubility. In 2009, it was revealed that the thiopeptide scaffold is derived from a ribosomally synthesized precursor peptide subjected to extensive posttranslational modifications. Shortly thereafter, three groups developed two types of in vivo strategies to generate thiopeptide variants: precursor peptide mutagenesis and gene inactivation. The thiopeptide analogs and biosynthetic intermediates obtained from these studies provide much-needed insight into the biosynthetic process for these complicated metabolites. Furthermore, the in vivo production of variants can be employed to interrogate thiopeptide structure activity relationships and may be useful to address the bioavailability issues plaguing these otherwise promising lead molecules. This chapter discusses the in vivo systems developed to generate thiopeptide variants. PMID- 23034222 TI - Microviridin biosynthesis. AB - The microviridins are a group of ribosomally synthesized and subsequently posttranslationally modified peptides. The structural modifications introduced during maturation are the formation of two intramolecular esters and one amide bond accompanied by dehydration. The two ester bonds are introduced by one GRASP like ligase (ATP-dependent carboxylate-amine/thiol ligase) (Galperin & Koonin, 1997) and the amide bond is formed by a second such enzyme, which shows strong homology to the ligase introducing the ester bonds. Action of these two enzymes gives microviridins an overall tricyclic topography. Further maturation of the peptide is achieved by leader peptide cleavage and N-terminal acetylation. Members of this group have been isolated and characterized by spectroscopic methods exclusively from the cyanobacteria, specifically the genera Microcystis, Nostoc, and Planktothrix (Oscillatoria). Expression of two genes encoding GRASP like ATP-binding proteins has made it possible to study the cyclization reaction in vitro and to define the minimal sequence requirements for cross-linking in the C-terminal region comprising the structural peptide. Heterologous expression of the microviridin gene cluster of Microcystis in Escherichia coli and analysis of the cell mass of the heterologous host has allowed the analysis of motifs in the leader peptide important for posttranslational modification. PMID- 23034223 TI - Cyclotide isolation and characterization. AB - Cyclotides are disulfide-rich cyclic peptides produced by plants with the presumed natural function of defense agents against insect pests. They are present in a wide range of plant tissues, being ribosomally synthesized via precursor proteins that are posttranslationally processed to produce mature peptides with a characteristic cyclic backbone and cystine knot motif associated with their six conserved cysteine residues. Their processing is not fully understood but involves asparaginyl endoproteinase activity. In addition to interest in their defense roles and their unique topologies, cyclotides have attracted attention as potential templates in peptide-based drug design applications. This chapter provides protocols for the isolation of cyclotides from plants, their detection and sequencing by mass spectrometry, and their structural analysis by NMR, as well as describing methods for the isolation of nucleic acid sequences that encode their precursor proteins. Assays to assess their membrane-binding interactions are also described. These protocols provide a "starter kit" for researchers entering the cyclotide field. PMID- 23034224 TI - Ribosomally encoded cyclic peptide toxins from mushrooms. AB - The cyclic peptide toxins of poisonous Amanita mushrooms are chemically unique among known natural products. Furthermore, they differ from other fungal cyclic peptides in being synthesized on ribosomes instead of by nonribosomal peptide synthetases. Because of their novel structures and biogenic origins, elucidation of the biosynthetic pathway of the Amanita cyclic peptides presents both challenges and opportunities. In particular, a full understanding of the pathway should lead to the ability to direct synthesis of a large number of novel cyclic peptides based on the Amanita toxin scaffold by genetic engineering of the encoding genes. Here, we highlight some of the principal methods for working with the Amanita cyclic peptides and the known steps in their biosynthesis. PMID- 23034225 TI - The Pictet-Spengler mechanism involved in the biosynthesis of tetrahydroisoquinoline antitumor antibiotics: a novel function for a nonribosomal peptide synthetase. AB - The core scaffold of microbial tetrahydroisoquinoline antitumor antibiotics is biosynthesized by a nonribosomal peptide synthetase (NRPS) with novel functions, which catalyzes a highly unusual seven-step transformation involving multiple reductions of thioester intermediates and two rounds of the Pictet-Spengler reaction. The reaction mechanism of saframycin NRPS SfmC has been firmly established by a series of in vitro experiments using various substrate analogs, SfmC domain-deletion mutants and (2)H-labeled NADH and NADPH. The Pictet-Spengler reaction found in the biosynthesis of saframycin heavily relies on the chain length of the cryptic long acyl chain in the peptide substrates. This chapter describes protocols for biochemical characterization of the saframycin NRPS SfmC. They include (1) bioinformatic analysis of related gene clusters, (2) synthesis of intermediate analogs, and (3) enzymatic reactions for both analytical and preparative scale. PMID- 23034226 TI - Discovery and biosynthesis of phosphonate and phosphinate natural products. AB - The P-C bonds in phosphonate and phosphinate natural products endow them with a high level of stability and the ability to mimic phosphate esters and carboxylates. As such, they have a diverse range of enzyme targets that act on substrates containing such functionalities. Recent years have seen a renewed interest in discovery efforts focused on this class of compounds as well as in understanding their biosynthetic pathways. This chapter focuses on current knowledge of these biosynthetic pathways as well as tools for phosphonate discovery. PMID- 23034227 TI - RlmN and AtsB as models for the overproduction and characterization of radical SAM proteins. AB - An explosion of remarkable chemical transformations has been witnessed in the past decade as a result of the radical S-adenosyl-l-methionine (SAM) (RS) superfamily of proteins. These proteins share the ability to cleave SAM reductively to l-methionine and a 5'-deoxyadenosyl 5'-radical (5'-dA(*)). The 5' dA(*) initiates >40 distinct reaction types by abstracting target hydrogen atoms on small-molecule and macromolecular substrates. All RS enzymes contain a [4Fe 4S] cluster coordinated by SAM that supplies the electron for SAM cleavage. A subset of RS enzymes contains additional iron-sulfur (Fe/S) clusters that serve alternative purposes, many remaining to be defined. The oxygen lability of their [4Fe-4S] clusters causes RS enzymes to be more tedious to purify, characterize, and study. Moreover, the type(s) and stoichiometry of Fe/S clusters in RS enzymes has often been a source of debate. Herein, we use RlmN and AtsB as models to highlight methods for purifying and characterizing RS enzymes, focusing on using Mossbauer spectroscopy in concert with methods for quantifying iron and acid labile sulfide to assign cluster content accurately. PMID- 23034228 TI - Fe(II)-dependent, uridine-5'-monophosphate alpha-ketoglutarate dioxygenases in the synthesis of 5'-modified nucleosides. AB - Several nucleoside antibiotics from various actinomycetes contain a high-carbon sugar nucleoside that is putatively derived via C-5'-modification of the canonical nucleoside. Two prominent examples are the 5'-C-carbamoyluridine- and 5'-C-glycyluridine-containing nucleosides, both families of which were discovered using screens aimed at finding inhibitors of bacterial translocase I involved in the assembly of the bacterial peptidoglycan cell wall. A shared open reading frame was identified whose gene product is similar to enzymes of the nonheme, Fe(II)-, and alpha-ketoglutarate-dependent dioxygenases. The enzyme LipL from the biosynthetic pathway for A-90289, a 5'-C-glycyluridine-containing nucleoside, was functionally characterized as an UMP:alpha-ketoglutarate dioxygenase, providing the enzymatic imperative for the generation of a nucleoside-5'-aldehdye that serves as a downstream substrate for an aldol or aldol-type reaction leading to the high-carbon sugar scaffold. The functional assignment of LipL and the homologous enzymes-including bioinformatic analysis, iron detection and quantification, and assay development for biochemical characterization-is presented herein. PMID- 23034229 TI - Tailoring reactions catalyzed by heme-dependent enzymes: spectroscopic characterization of the L-tryptophan-nitrating cytochrome P450 TxtE. AB - There is a truly vast quantity of research articles and textbooks, aimed at a variety of audiences, on cytochromes P450. However, a large amount of specialized terminology has become associated with these enzymes, which can be daunting to those new to the field. The aim of this chapter is to give a brief overview of the functions and importance of cytochromes P450 with particular emphasis on their roles as tailoring enzymes in natural product biosynthetic pathways. Differences between the biosynthetic enzymes and their catabolic counterparts are highlighted. Assays used to investigate substrate binding to cytochromes P450 are described using TxtE, a recently discovered unique nitrating enzyme involved in thaxtomin A biosynthesis, as an example. PMID- 23034230 TI - Oxidative tailoring reactions catalyzed by nonheme iron-dependent enzymes: streptorubin B biosynthesis as an example. AB - Tailoring enzymes catalyze reactions that modify natural product backbone structures before, during, or after their biosynthesis to create a final product with specific biological activities. Such reactions can be catalyzed by a myriad of different enzyme families and are responsible for a wide variety of transformations including regio- and/or stereospecific acylation, alkylation, glycosylation, halogenation, and oxidation. Within a broad group of oxidative tailoring enzymes, there is a rapidly growing family of nonheme iron- and oxygen dependent enzymes that catalyze a variety of remarkable hydroxylation, desaturation, halogenation, and oxidative cyclization reaction in the biosynthesis of several important metabolites, including carbapenems, penicillins, cephalosporins, clavams, prodiginines, fosfomycin, syringomycin, and coronatine. In this chapter, we report an expedient method for analyzing tailoring enzymes that catalyze oxidative cyclization reactions in prodiginine biosynthesis via expression of the corresponding genes in a heterologous host, feeding of putative biosynthetic intermediates to the resulting strains, and liquid chromatography-mass spectrometry analyses of the metabolites produced. PMID- 23034231 TI - The rare fluorinated natural products and biotechnological prospects for fluorine enzymology. AB - Nature has hardly evolved a biochemistry of fluorine although there is a low level occurrence of fluoroacetate found in selected tropical and subtropical plants. This compound, which is generally produced in low concentrations, has been identified in the plants due to its high toxicity, although to date the biosynthesis of fluoroacetate in plants remains unknown. After that, fluorinated entities in nature are extremely rare, and despite increasingly sophisticated screening and analytical methods applied to natural product extraction, it has been 25 years since the last bona fide fluorinated natural product was identified from an organism. This was the reported isolation of the antibiotic 4 fluorothreonine and the toxin fluoroacetate in 1986 from Streptomyces cattleya. This bacterium has proven amenable to biochemical investigation, the fluorination enzyme (fluorinase) has been isolated and characterized, and the biosynthetic pathway to these bacterial metabolites has been elucidated. Also the fluorinase gene has been cloned into a host bacterium (Salinispora tropica), and this has enabled the de novo production of a bioactive fluorinated metabolite from fluoride ion, by genetic engineering. Biotechnological manipulation of the fluorinase offers the prospects for the assembly of novel fluorinated metabolites by fermentation technology. This is particularly attractive, given the backdrop that about 15-20% of pharmaceuticals licensed each year (new chemical entities) contain a fluorine atom. PMID- 23034232 TI - Enzymatic chlorination and bromination. AB - Our knowledge about the enzymes catalyzing the incorporation of halide ions during the biosynthesis of halometabolites has increased tremendously during the last 15 years. Between 1960 and 1995, haloperoxidases were the only halogenating enzymes known. However, absolute proof for the connection of haloperoxidases to the biosynthesis of halometabolites is still missing. In 1997, FADH(2)-dependent halogenases were identified as the type of halogenating enzymes responsible for the incorporation of chloride and bromide atoms into aromatic and aliphatic compounds activated for electrophilic attack. FADH(2)-dependent halogenases are two-component systems consisting of a flavin reductase providing the FADH(2) required by the halogenase. Elucidation of the three-dimensional structure of FADH(2)-dependent halogenases led to the understanding of the reaction mechanism, which involves the formation of hypohalous acids. Unactivated carbon atoms were found to be halogenated by nonheme iron, alpha-ketoglutarate- and O(2)-dependent halogenases. The reaction mechanism of this type of halogenase was shown to involve the formation of a substrate radical. These two types of halogenating enzymes, together with the much less common fluorinases, are the major types of halogenating enzymes. However, the existence of other types of halogenating enzymes, yet not detected, cannot be completely ruled out. Here, we describe the detection, purification, characterization, and reaction mechanisms of flavin dependent halogenases and of nonheme iron, alpha-ketoglutarate- and O(2) dependent halogenases. PMID- 23034233 TI - Prenyltransferases of the dimethylallyltryptophan synthase superfamily. AB - Prenylated natural products often have interesting biological and pharmacological activities clearly distinct from their nonprenylated precursors. Prenyltransferases are responsible for the attachment of prenyl moieties to a number of acceptors and contribute significantly to structural and biological diversity of these compounds in nature. In the past 8 years, significant progress has been achieved in the molecular biological, biochemical, and structural biological investigation of the prenyltransferases of the dimethylallyltryptophan synthase (DMATS) superfamily. These soluble enzymes are involved in the biosynthesis of fungal secondary metabolites and mainly catalyze prenylation of diverse indole derivatives, including tryptophan and tryptophan-containing cyclic dipeptides. The members of the DMATS superfamily show promising flexibility toward their aromatic substrates and catalyze highly regio- and stereoselective prenyltransfer reactions. These features were successfully used for chemoenzymatic synthesis, not only for production of prenylated simple indoles and cyclic dipeptides but also for prenylated hydroxynaphthalenes and flavonoids, which are usually found in bacteria and plants, respectively. PMID- 23034234 TI - Serine carboxypeptidase-like acyltransferases from plants. AB - Serine carboxypeptidase-like (SCPL) acyltransferases facilitate transacylation reactions using energy-rich 1-O-beta-glucose esters in the synthesis of an array of bioactive compounds and are associated with the diversification of plant natural products. SCPL acyltransferases have evolved from a hydrolytic ancestor by adapting functional elements of the proteases such as the catalytic triad, oxyanion hole, and substrate recognition H-bond network to their new function. As vacuolar proteins, SCPL acyltransferases define an alternative cellular route of transacylation spatially separated from the cytoplasmic enzymes of the BAHD acyltransferase family named according to the first characterized members (BEAT, AHCT, HCBT, and DAT). Recent efforts in cloning and characterization led to the identification of diagnostic peptides for SCPL acyltransferases, enabling the detection of candidate genes in several plant genomes. Detailed biochemical analysis of SCPL acyltransferases is strongly dependent on comprehensive heterologous expression systems, efficient protein purification protocols, and the supply of appropriate substrates. This chapter describes some useful techniques and strategies for identification and characterization of SCPL acyltransferases. PMID- 23034235 TI - 4-methylideneimidazole-5-one-containing aminomutases in enediyne biosynthesis. AB - Many natural products contain unusual aromatic beta-amino acids or moieties derived therefrom. The biosynthesis of these beta-amino acids was first elucidated during a biosynthetic study of the enediyne antitumor antibiotic C 1027, when an enzyme, SgcC4, was discovered to convert L-tyrosine to (S)-beta tyrosine. SgcC4 is similar in sequence and structure to 4-methylideneimidazole-5 one (MIO)-containing ammonia lyases. Whereas the ammonia lyases use the electrophilic power of the MIO group to catalyze the release of ammonia from aromatic amino acids to generate alpha,beta-unsaturated carboxylic acids as final products, SgcC4 retains the alpha,beta-unsaturated carboxylic acid and amine as intermediates and reappends the amino group to the beta-carbon, affording a beta amino acid as the final product. The study of SgcC4 led to the subsequent discovery of other MIO-containing aminomutases with altered substrate specificity and product stereochemistry, including MdpC4 from the biosynthetic pathway of the enediyne antitumor antibiotic maduropeptin. This chapter describes protocols for the enzymatic and structural characterization of these MIO-containing aminomutases as exemplified by SgcC4 and MdpC4. These protocols are applicable to the study of other aminomutases. PMID- 23034236 TI - Tailoring enzymes acting on carrier protein-tethered substrates in natural product biosynthesis. AB - Carrier proteins (CPs) are integral components of fatty acid synthases, polyketide synthases, and nonribosomal peptide synthetases and play critical roles in the biosynthesis of fatty acids, polyketides, and nonribosomal peptides. An emerging role CPs play in natural product biosynthesis involves tailoring enzymes that act on CP-tethered substrates. These enzymes provide a new opportunity to engineer natural product diversity by exploiting CPs to increase substrate promiscuity for the tailoring steps. This chapter describes protocols for in vitro biochemical characterization of SgcC3 and SgcC that catalyze chlorination and hydroxylation of SgcC2-tethered (S)-beta-tyrosine and analogues in the biosynthesis of the enediyne chromophore of the chromoprotein C-1027. These protocols are applicable to mechanistic characterization and engineered exploitation of other tailoring enzymes that act on CP-tethered substrates in natural product biosynthesis and structural diversification. The ultimate goal is to use the in vitro findings to guide in vivo engineering of designer natural products. PMID- 23034237 TI - High-throughput colorimetric assays for nucleotide sugar formation and glycosyl transfer. AB - Glycosyltransferases are ubiquitous in nature, catalyzing glycosidic bond formation in the context of an enormous range of substrates, which include all major classes of biological molecules. Because this wide range of substrates lacks a shared, distinguishable feature that can be altered by glycosyl transfer, general assays for detection of glycosyltransferase activity have long been largely limited to low-throughput methods. Of those high-throughput assays reported in the literature, many are confined to specific glycosyl transfer reactions with modified aglycon acceptors selected for their unique analytical properties. Herein are described a series of protocols centered on the use of 2 chloro-4-nitrophenyl glycoside donors and the reversibility of glycosyltransferase-catalyzed reactions to enable a colorimetric assay for the formation of sugar nucleotides, coupled reaction systems for the glycodiversification of small molecules, and a general colorimetric assay for glycosyltransfer, applicable to drug discovery, protein engineering, and other fundamental sugar nucleotide-dependent investigations. PMID- 23034238 TI - Methods in Enzymology. Natural product biosynthesis by microorganisms and plants, part B. Preface. PMID- 23034239 TI - Reconceptualizing psychiatric nosology: the case of suicidal behaviour. PMID- 23034240 TI - Telephone assessment of behavioral inhibition and activation systems. AB - INTRODUCTION AND OBJECTIVES: The activity of behavioral inhibition and activation systems (BIS and BAS) has been related to several mental disorders. The availability of a validated questionnaire to assess BIS and BAS over the telephone could aid research. The objective of the present study was to evaluate the procedural validity of telephone administration of the sensitivity to punishment/sensitivity to reward questionnaire (SPSRQ) as a measure of BIS and BAS activity (by means of its two scales: the sensitivity to punishment [SP] scale and the sensitivity to reward [SR] scale). METHODS: A total of 231 participants were assessed with the SPSRQ twice (over the telephone and in a self administered format). Intraclass correlation coefficients and kappa indices were calculated. Additionally, possible differences between the mean scores obtained with the two assessment procedures and internal consistency were explored. RESULTS: Telephone and self-assessment of BIS and BAS, by means of the SPSRQ, provided similar results, supporting the procedural validity of telephone administration. A slight but statistically significant tendency (estimated betha = 0.62; 95% CI, 0.33-0.92; p<0.001) toward lower scores was observed for the telephone-administered SP scale and for the interaction "first or second assessment/telephone or self-administered SPSRQ" for the SR scale (p=0.023). CONCLUSIONS: The results of the present study support the reliability of telephone assessment of BIS and BAS by means of the SPSRQ. PMID- 23034241 TI - An empirical study of psychosocial and clinical correlates of delusional disorder: the DELIREMP study. AB - OBJECTIVE: We aim to describe psychosocial and clinical correlates of delusional disorder (DD) and its types. This approach is important because most knowledge on DD does not come from empirical data collected using a validated systematic research method. METHODS: A cross-sectional study was conducted in a sample of 86 patients fulfilling DSM-IV criteria for DD as established using the SCID-I. Variables were evaluated using a systematic methodology and standardized instruments, and included possible psychosocial risk factors (low socioeconomic status or social isolation, immigration, sensory deficits, older age at onset), family history of psychiatric disorders and premorbid personality (SAP), psychotic psychopathology (PANSS), depressive syndrome (MADRS), global cognitive functioning (MMSE), axis I comorbidity (MINI) and other clinical aspects such as global functionality (GAF), and disability (SDI). A sociodemographic and clinical questionnaire was also completed. RESULTS: The mean age at onset was 39.6 years and 61.6% of the cases were female. The most frequent DD types were persecutory (59.3%) and jealous (22.1%). Nearly 21% had a family history of schizophrenia and 17.4% had DD (significantly higher among those with the jealous subtype). Sixty four percent had a premorbid personality disorder (38.4% paranoid, 12.8% schizoid). The grandiose type was significantly associated with higher scores on the PANSS positive subscale and the mixed type with lower scores on the PANSS negative subscale. Depression affected 45.3% of subjects (mainly mild depression) and 45.3% had hallucinations (20.9% tactile, 16.3% olfactory), which were more common among somatic cases. The mean MMSE was 27.6+/-2.5 suggesting a preserved cognitive function. Mean GAF was 63.9+/-11.3 indicating a moderate degree of disability, which was significantly worse amongst grandiose cases. CONCLUSIONS: This study provides unique empirical and reliable evidence on the real psychosocial, clinical, and psychopathological correlates of DD and its types. PMID- 23034242 TI - Clinical predictors of interpersonal functioning in patients with bipolar disorder. AB - OBJECTIVE: Functional impairment has been repeatedly reported in patients with bipolar disorder even during clinical remission. Less is known about specific domains, such as interpersonal relationships. The aim of this study was to identify clinical predictors of poor interpersonal relationships. METHODS: Using a specific subscale of the Functioning Assessment Short Test (FAST), we assessed the interpersonal relationships of a sample of 71 euthymic bipolar (Hamilton Depression Rating Scale [HAM-D] < 8; Young Mania Rating Scale [YMRS] < 5) patients. The sample was divided into two categories: low vs. high level functioning in interpersonal relationships according to the median of the sample. Multivariate analyses were applied to identify significant predictors of interpersonal functioning. RESULTS: Age (p=0.026), the number of previous depressive and mixed episodes and HAM-D scores differed significantly between the two groups (p<0.05). For manic episodes, only a tendency was detected (p=0.064). After running multivariate analyses, age (p=0.026), depressive symptoms (p=0.055) and the number of previous manic episodes (p=0.033) could be considered predictors of poor interpersonal functioning. The model predicted 83.3% of the variance (R=0.59; gl=1; p<0.001). DISCUSSION: Our results indicate a link between greater impairment in interpersonal relationships and being older and having more residual symptoms and a higher number of previous manic episodes. Patients with these features should be carefully monitored and specific psychosocial interventions should be implemented to improve their outcome. PMID- 23034243 TI - Variability in the COMT gene and modification of the risk of schizophrenia conferred by cannabis consumption. AB - INTRODUCTION: The risk of schizophrenia conferred by cannabis has recently been proposed to be modulated by the Val158Met polymorphism (rs4680) at the COMT gene. To date, these findings have not been replicated in independent samples. MATERIAL AND METHODS: We tested the potential gene-by-environment interaction between Val158Met genotype at the COMT gene and previous use of cannabis in schizophrenia in 192 healthy controls and 91 inpatients with DSM-IV schizophrenia. The functional COMT Val158Met polymorphism was analyzed using TaqMan technology. Cannabis use was measured by taking into account the frequency of intake during the previous month. Logistic regression models were used to test the interaction between genetic and environment factors. RESULTS: Cannabis use was strongly associated with the case condition (p<0.0001). The Val158Met polymorphism at the COMT gene was not associated with schizophrenia, although Val/Val homozygosity tended to be more frequent in the case group than in the control group (34% vs 27%; OR=1.39; 95% CI, 0.78-2.47). Finally, in women we found a non-significant trend toward the association when we tested for the interaction between cannabis use, the number of Val alleles and susceptibility to schizophrenia (p=0.152). CONCLUSIONS: Our results tend to support recent findings suggesting that the Val158Met polymorphism at the COMT gene modifies the risk of schizophrenia conferred by cannabis use. In our study, this possible effect was only detected in women. PMID- 23034244 TI - Bipolar anxiety. PMID- 23034245 TI - Psychological care of critically ill patients. PMID- 23034246 TI - Support to the relatives of patients admitted to intensive care units. PMID- 23034247 TI - Angiography alone versus angiography plus optical coherence tomography to guide decision-making during percutaneous coronary intervention: the Centro per la Lotta contro l'Infarto-Optimisation of Percutaneous Coronary Intervention (CLI OPCI) study. AB - AIMS: Angiographic guidance for percutaneous coronary intervention (PCI) has substantial limitations. The superior spatial resolution of optical coherence tomography (OCT) could translate into meaningful clinical benefits. We aimed to compare angiographic guidance alone versus angiographic plus OCT guidance for PCI. METHODS AND RESULTS: Patients undergoing PCI with angiographic plus OCT guidance (OCT group) were compared with matched patients undergoing PCI with angiographic only guidance (Angio group) within 30 days. The primary endpoint was the one-year rate of cardiac death or myocardial infarction (MI). A total of 670 patients were included, 335 in the OCT group and 335 in the Angio group. OCT disclosed adverse features requiring further interventions in 34.7%. Unadjusted analyses showed that the OCT group had a significantly lower one-year risk of cardiac death (1.2% vs. 4.5%, p=0.010), cardiac death or MI (6.6% vs. 13.0%, p=0.006), and the composite of cardiac death, MI, or repeat revascularisation (9.6% vs. 14.8%, p=0.044). Angiographic plus OCT guidance was associated with a significantly lower risk of cardiac death or MI even at extensive multivariable analysis adjusting for baseline and procedural differences between the groups (OR=0.49 [0.25-0.96], p=0.037) and at propensity-score adjusted analyses. CONCLUSIONS: This observational study, the first ever formally to appraise OCT guidance for PCI decision-making, suggests that the use of OCT can improve clinical outcomes of patients undergoing PCI. PMID- 23034248 TI - Could sterile males be used to vector a microbiological control agent? The case of Rhynchophorus ferrugineus and Beauveria bassiana. AB - Rhynchophorus ferrugineus (Coleoptera, Curculionidae) is the most threatening pest of palms worldwide. The potential of gamma-irradiated males to spread a pathogenic strain of the entomopathogenic fungus Beauveria bassiana (Ascomycota: Clavicipitaceae) to control this pest was studied. First, the effects of gamma irradiation (15 and 25 Gy) on the mating success and performance of adult males irradiated at age one day were studied in the laboratory. Although male longevity decreased after irradiation (118.6 vs. 244.7 days for irradiated and control males, respectively) and their testes suffered from the treatment, fecundity of mated females did not depend on the irradiation status of the male (86.8 +/- 5.5 eggs in 15 days). However, egg hatching was significantly lower in couples with irradiated males (31.4% vs. 86.5% for irradiated and control couples, respectively), and this value decreased after a second mating (6.1% vs. 85.9%). Therefore, irradiation did not affect male sexual competiveness but sperm quality. Second, a semi-field assay was carried out to evaluate infestation in young Phoenix canariensis caused by different combinations of couples with irradiated and/or B. bassiana-challenged males. The number of immature stages found in infested palms was significantly higher when females mated with untreated males and lower when mated with irradiated males (either B. bassiana infected or not). Some females from the fungus-challenged treatments showed post mortem hyphal growth, and this horizontal transmission proves that irradiated males could act as a vector for B. bassiana and should be considered as a new method to improve the biological control of R. ferrugineus. PMID- 23034250 TI - Role of Th17 in the pathogenesis of cutaneous inflammatory diseases. AB - Th17 cells are a new T-cell subtype characterized by the capability of producing IL-17. They are reported to be involved in a wide range of cutaneous immune mediated conditions and, particularly in this review, we sought to elucidate the Th17 role in the pathogenesis of some common inflammatory diseases including psoriasis, allergic contact dermatitis and atopic dermatitis. PMID- 23034251 TI - Interleukin-9 and mast cells. AB - Mast cells are granulated hematopoietic cells derived from stem cells that reside in nearly all tissues and are involved in protection of a host from bacterial infection with a protective and pathogenic activity. Mast cells are important for both innate and adaptive immunity in tissues which are in close contact with the environment. These cells express proinflammatory cytokines such as IL-1, IL-6, IL 8 and tumor necrosis factor which are necessary for innate immunity. Mast cells also produce interleukin-9 and enhance mast cell expression of several cytokines including IL-1beta, IL-5, IL-6, IL-9 and IL-13. In addition, IL-9 can induce mast cell production of TGF-beta which can have proinflammatory downstream effects. IL 9 can function as either a positive or a negative regulator of immune responses and can have a detrimental role in allergy and autoimmunity. Furthermore, IL-9 contributes to disease by promoting mast cell expansion and production of IL-13 which in turn contributes to airway hyperresponsiveness. Here, in this editorial we review the interrelationship between IL-9 and mast cells. PMID- 23034252 TI - Effective properties of a sturgeon-based bioactive compound on stress-induced hippocampal degeneration and on in vitro neurogenesis. AB - The aim of this study is to test the activity of a marine bioactive compound containing high-purity caviar-derived DNA, collagen elastin and protein extracts from sturgeon (LD-1227, Caviarlieri, Laboratoires Dom, Switzerland) to exert neuroprotective properties in an experimental setting while also being potential triggers of neurogenesis in a separate in vitro study. Supplementation with high DHA mixture of LD-1227 was applied for 30 days to stress model rats. Both supplementations significantly mitigated the histological brain damage when analyzing hippocampal subregions and corticosterone level. However, LD-1227 was most significantly efficient in preventing SOD, Catalase and ascorbic acid decrease in brain tissue. Both supplementations stimulated neurogenesis in vitro and neuron markers in particular but og olygodendrocyte markers and glia increased only in LD-1227-enriched medium. Taken together, these data suggest that LD-1227 is able to significantly protect the brain structure redox system to higher degree than DHA. Moreover, from in vitro study it appears that marine bioactive compound, through it wide array of small unsaturated fatty acids, phospholipids and neurotransmitter precursors, is likely to influence neuronal and glial lineage to act differently from a DHA-rich mixture. PMID- 23034253 TI - Beneficial effect of a sturgeon-based bioactive compound on gene expression of tumor necrosis factor-alpha, matrix metalloproteinases and type-10 collagen in human chondrocytes. AB - In the present study, we examined the effect of a marine bioactive compound containing high-purity caviar-derived DNA, collagen elastin and protein extracts from sturgeon (LD-1227, Caviarlieri, Laboratoires Dom, Switzerland) on IL-1beta induced activation and production of TNFalpha and MMP-13 in human osteo-arthritis (OA) chondrocytes and intracellular signaling factors. Human chondrocytes were derived from OA cartilage and stimulated with IL-1beta. Gene expression of TNFalpha, MMP-13, MMP-1 and Col10A1 was measured by quantitative RT-PCR. TNFalpha protein in culture medium was determined using cytokine-specific ELISA. Western immunoblotting was used to analyze the MMP-13 production in the culture medium and the activation of NF-kB. DNA binding activity of NF-kB p65 was determined using a highly sensitive and specific ELISA. MMP-13 activity in the culture medium was assayed by gelatine zymography. LD-1227 significantly decreased IL 1beta-stimulated gene expression and production of TNFalpha, MMP-1, MMP-13 and Col10A1 in human chondrocytes. The inhibitory effect of LD-1227 on the IL-1beta induced expression of these genes was mediated at least in part via suppression of NF-kB p65. These data show that LD-1227 can inhibit IL-1beta-induced proliferation and inflammatory reactions via inhibited activation of the transcription factor NF-kB pathway in human chondrocytes derived from OA patients. These novel pharmacological actions of LD-1227 on IL-1beta-stimulated human OA chondrocytes provide suggestions that this marine biology compound may inhibit cartilage degradation by suppressing IL-1beta-mediated activation and the catabolic response in human chondrocytes. PMID- 23034254 TI - Nerve growth factor and brain-derived neurotrophic factor concentrations in schizophrenia: a review. AB - There is growing interest in the role of neurotrophins in the pathophysiology of schizophrenia. Neurotrophins are a large family of dimeric polypeptides that promote the growth and the differentiation of developing neurons in the central and peripheral nervous systems as well as the survival of neuronal cells in response to stress. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) concentrations are here reviewed in relation to medication-naive early psychotic patients and in medicated chronic schizophrenic patients. Most data point to decreased plasma and serum NGF and BDNF concentrations in naive drug and in medicated schizophrenic patients compared to healthy controls. Higher BDNF levels were observed in patients with the paranoid subtype of schizophrenia. Low serum BDNF levels were associated with reduction in hippocampal volume (HV) at the onset of schizophrenia. Evidence on the correlation between BDNF levels and positive and negative schizophrenic symptoms were ambiguous. There are contrasting results on a possible correlation between increase in BDNF concentrations and treatment with antipsychotics. Antipsychotic treatment can elevate NGF values, specifically atypical. Growth factors might be good candidates as prognostically and diagnostically useful markers in schizophrenia. PMID- 23034256 TI - Effect of chronic forced running on gene expression of catecholamine biosynthetic enzymes in stellate ganglia of rats. AB - The sympathoneural system has a profound influence on the heart function. Sympathetic neurons are the major contributors to the huge rise of circulating noradrenaline (NA) level in response to stressful stimuli. Treadmill training in rats is forced exercise which has the propensity to induce both psychological and physical stress. The aim of this study is to examine how chronic forced running (CFR) affects the expression of catecholamine biosynthetic enzymes (tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine N methyltransferase (PNMT)) and cAMP response element-binding (CREB) in stellate ganglia, as well as the concentrations of catecholamines, adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in the plasma of rats. Also, we investigated how the additional acute immobilization stress changes the mentioned parameters. The rat training program consisted of 12 weeks running on a treadmill (20 m/min, 20 min/day). We found that CFR increases TH and DBH mRNA and protein levels in stellate ganglia, which is followed by increased NA concentration in the plasma. CFR reduces the level of PNMT mRNA, while the level of PNMT protein remains unchanged in stellate ganglia. The increased expression of TH and DBH genes positively correlates with the expression of CREB in stellate ganglia and with plasma ACTH level, while reduced level of PNMT mRNA in stellate ganglia correlates with reduced plasma CORT level. The additional acute immobilization stress increased gene expression of catecholamine biosynthetic enzymes in stellate ganglia, as well as catecholamines, ACTH and CORT levels in the plasma. The results presented here suggest that the continuous increase of the noradrenaline biosynthetic enzyme expression in stellate ganglia due to CFR may play a role in growing risk of cardiovascular diseases. PMID- 23034255 TI - TGF-beta signaling in T cells is not essential for Th17 cell development in the mouse. AB - Th17 cells are potent pro-inflammatory effectors crucial for defense against extracellular bacteria. However, in this context and in the context of autoimmune disorders Th17 cells have been demonstrated to be key contributors to destructive pathological mechanism. A number of trials report TGF-beta to be involved in Th17 cell development. Nevertheless, to date, the role that TGF-beta plays in Th17 cell generation remains unclear. In this paper we highlight the role of TGF-beta in Th17 cell development in the mouse. The effects of likewise T cell specific over-expression of TGF-beta or inhibition of TGF-beta signal transduction in these cells on Th17 cell development were investigated by means of transgenic mouse models. The T cell specific insensitivity to TGF-beta does not prevent Th17 cell development ex vivo or in vitro in the murine system. In contrast, stimulation of T cells over-expressing TGF-beta actually results in decreased Th17 cell numbers in comparison to the wild type. Thus, our data indicate that TGF-beta signaling in T cells is dispensable or even inhibitory for generation of Th17 cells in the mouse. Moreover, we could show TGF-beta to inhibit a LPS driven Th1 cell development suggesting the cytokine to act as an indirect effector in Th17 cell differentiation. PMID- 23034257 TI - Influence of different oxygen supply on metabolic markers and gene response in murine adipocytes. AB - Obese subjects often present a low-grade chronic inflammation in the white adipose tissue, which seems to play an important role in the initiation and development of obesity-related diseases. It has been reported that this inflammatory process may be due to a hypoxic state occuring within this tissue. Oxygen is used in current medicine as a treatment for several conditions. The aim of this study is to analyze the effects of 95 percent O2 on specific metabolic variables and on the expression of some genes on murine adipocytes. 3T3-L1 adipocytes were exposed during 48 h to different treatments: 95 percent O2 hyperoxia (HPx group), CoCl2 (CoCl2 group), hyperoxia with CoCl2 (HPx+CoCl2 group) and 1 percent O2 hypoxia (Hx group). Cell viability, intracellular ROS content, glucose utilization, lactate and glycerol concentrations were measured. Also, mRNA expression of HIF-1alpha, GLUT-1, ANGPTL4, PPAR-gamma, adiponectin, IL 6 and MCP-1 genes was analyzed. Importantly, 95 percent O2 decreased cell viability and increased intracellular ROS production. Also, glycerol and lactate release were significantly increased and decreased, respectively, in HPx treated cells. This treatment also provoked a down-regulation of GLUT-1 and ANGPTL-4, while IL-6 and MCP-1 were up-regulated. Exposure to a hyperoxia of 95 percent O2 provoked an inflammatory response in adipocytes. The two hypoxia-inducing conditions (CoCl2 and 1 percent O2) produced different outcomes in metabolic measurements as well as in the expression of some genes (GLUT-1, ANPGTL4, PPAR gamma and adiponectin), while it remained similar in others (HIF-1alpha, IL-6 and MCP-1). Indeed, hyperoxia increased significantly the ROS levels and the lipolytic activity, while it reduced lactate production. In addition to the effects on inflammation, the changes in GLUT-1, ANGPTL4 and PPAR-gamma genes lead to suppose that hyperoxia may be beneficial for the hypertrophied adipose tissues of obese subjects and for improving insulin sensitivity. PMID- 23034258 TI - Rat model of burn wound healing: effect of Botox. AB - Animal models of burn play a crucial role in studying the mechanisms of burn wound progression and the factors that regulate various stages of healing. In this study, using a rat model, we assessed the effect of Botox in the healing process through parameters like transepidermal water loss (TEWL), histological alterations, transforming growth factor beta (TGF-beta1) and tumor necrosis factor alpha (TNF-alpha). Fifty Sprague-Dawley rats were inflicted with 5 cm2 second degree burn and divided into 2 groups; one group was injected intralesionally with Botox and the other with saline. Daily observation and transepidermal water loss measurement were performed. Biopsies were taken on days 0, 3, 8, 14, and 28 for histology and polymerase chain reaction, testing TGF-beta and TNF-alpha. The results showed no significant difference in TEWL except for slightly better preservation of moisture with Botox. Histology revealed relatively better and faster regeneration with Botox, delayed lower grade inflammation, and increase in fibroblasts. TNF-alpha had an acute increase of 21 fold then tapered down while TGF-beta levels increased on day 3 after TNF-alpha, peaked on day 8 and then started to decrease until complete healing. Botox improved the healing process and the cosmetic appearance of burn scar. PMID- 23034259 TI - Association analysis of dopaminergic gene variants (Comt, Drd4 And Dat1) with Alzheimer s disease. AB - Defects in dopaminergic transmission play important roles in the disturbance of synaptic plasticity and even in advanced cognitive behavior. However, the relationship between genes involved in the regulation of dopamine levels and predisposition for Alzheimer s disease (AD) remains unclear. The potential association of dopamine-modulating gene polymorphisms with AD was evaluated. We performed a case-control study with 120 patients and 86 healthy controls. Two catechol-O-methyltransferase (COMT) single-nucleotide polymorphisms (SNPs) (rs2020917 and rs4646312), two dopamine D4 receptor (DRD4) SNPs (rs3758653 and rs916455), and four dopamine transporter (DAT1) SNPs (rs2937639, rs6347, rs12516948 and rs11133762) were investigated. The T allele at the DRD4 SNP (rs3758653) was found to be significantly associated with AD. Our results also showed that haplotype frequencies, observed from the analyzed SNPs, were distributed significantly differently in AD patients vs control subjects. Moreover, a strong association was observed between the A allele at rs6347 of DAT1 and moderate stage of dementia. These observations suggest that genetic variations in the dopamine-modulating genes, COMT, DRD4 and DAT1, may contribute to AD pathogenesis in the Taiwanese population. PMID- 23034260 TI - Obese visceral adipose tissue grafted in lean mice can alter glucose homeostasis and energy efficiency. AB - Fat transplantation experiments have previously shown regulatory properties of lean adipose tissue on glucose homeostasis in the whole animal. In the current study, we addressed whether obese visceral white adipose tissue grafted in lean mice could alter glucose homeostasis. Obese visceral fat (VF) tissue was effective in increasing body weight gain and energy efficiency but not energy intake, when transplanted into the epididymal VF depot in lean recipient mice. These changes were accompanied by impaired glucose and insulin tolerance tests, showing altered glucose homeostasis. None of these effects were observed when transplants were grafted subcutaneously. These effects show that both physiologic state of donor VF (obese vs lean) and graft location (epididymal vs subcutaneous) in the recipient animal are critical to express deleterious effects of VF on glucose homeostasis in the whole organism. PMID- 23034261 TI - Cocaine- and amphetamine-regulated transcript : identification and distribution in human gastrointestinal tract. AB - Cocaine- and amphetamine-regulated transcript (CART) was identified in the central and peripheral nervous system, including the gastrointestinal tract of rodents and pig. CART was also expressed in neuroendocrine cells of the rats stomach antral mucosa. The knowledge of the presence and functional role of CART peptide in the human alimentary tract is very limited due to difficulties in obtaining human samples (especially from healthy individuals). The presence of CART peptide in the gastrointestinal tract of the human was investigated immunohistochemically. CART-immunoreactive (IR) neural structures were observed in all studied fragments of alimentary tract. CART-like immunoreactive nerve fibers were numerous within the muscle in layers of muscularis externa and in the myenteric plexus of all gastrointestinal segments (from esophagus to colon), while they were moderate or few in density in other layers of gastrointestinal tract. The presence of CART peptides in the neuroendocrine cells was demonstrated predominantly in the pyloric, duodenum and fundus, and only few in the rest parts of the small intestine. CART-IR neuroendocrine cells could not be detected in the mucosa of large intestine. The present study reports for the first time a detailed description of the CART distribution pattern within the human alimentary tract. Our findings may hopefully provide some contribution towards a more complete and comprehensive understanding of the function and role of the CART peptide in the alimentary system. PMID- 23034262 TI - The effect of PGE administration on the activity of oxidative system in erythrocytes and platelets during ischemia reperfusion injury and on postoperative renal function in patients undergoing open abdominal aortic aneurysm reconstruction. AB - Postoperative decline of renal function remains a common and unpredictable complication after abdominal aortic aneurysm (AAA) reconstruction. The oxidative stress that occurs during perioperative ischemia/reperfusion injury (I/R) may contribute to the development of this complication. In this study, the influence of intraoperative prostaglandin E (alprostadil) administration on erythrocyte and platelet antioxidants as well as postoperative kidney function modulation were verified. AAA patients were randomly divided into control and study/alprostadil groups. Blood samples were collected directly before aortic clamping and 5 min after aortic declamping. Superoxide dismutase, catalase, glutathione, glutathione peroxidase (GPx), and glutathione transferase (GST) were measured using spectrophotometry. During I/R, the activity of catalase (57.14+/-30.65 vs 128.35+/-91.94 U/mg protein; P < 0.009), GPx (0.21+/-0.18 vs 0.35+/-0.21 mU/g protein; P = 0.028), and GST (217.49+/-101.39 vs 310.66+/-88.86 mU/g protein; P = 0.0006) significantly increased in the control group. GST activity before the aortic clamping was significantly lower in the study/alprostadil group (2.84+/ 2.28 vs 3.48+/-2.30 U/g Hb; P = 0.05). The activity of the selected antioxidants proved to be of a diagnostic value for predicting postoperative decline in renal function. In conclusion, during I/R after AAA reconstruction, activation of various erythrocyte and platelet antioxidants occurs. Perioperative administration of alprostadil is associated with disruption of this activation. PMID- 23034263 TI - Perception of occupational risk by rural workers in an area of central Italy. AB - The aim of this study is to analyze the subjective perception of risks for rural workers in Abruzzo, an area of central Italy. A group of 273 workers were asked to fill in a questionnaire which included, apart from general information, questions relative to six different types of risks normally found in the field of agriculture. The types of risks considered were: falling from a height, manually moving loads, overturning/accident whilst driving an agricultural tractor, noise and vibration, use of pesticides, the risk of being cut/injured. The workers were requested to assess, on a scale of 1 to 3, both the probability of an accident taking place and the consequent damage which could result from each of the risks considered. The assessment of the risks provided by the workers was related to the objective assessment of the risks carried out by the study group, also on the basis of objective data provided by INAIL (Italian insurance company) indexes, to highlight the eventual under/over estimations of risk. Furthermore, the possible correlation was evaluated between having received specific training regarding work safety and the workers perception of the risk. The results showed that approximately 11 percent of the workers do not consider their job as being dangerous; the risk perceived by the workers is higher for accidents that cause an immediate injury compared to those which cause professional illnesses, except the risk deriving from noise/vibrations. A direct correlation was found between the job as being dangerous and having attended courses on accident prevention. PMID- 23034264 TI - Nanotechnology and vascular neurosurgery: an in vivo experimental study on microvessels repair using laser photoactivation of a nanostructured hyaluronan solder. AB - Sealing tissues by laser in neurosurgical procedures may overcome problems related to the use of conventional suturing methods which can be associated with various degrees of vascular wall damage. Despite the significant experimental and clinical achievements of the past, a standardized clinical application of laser welding technology has not yet been implemented. The main problem is related to the use of common organic chromophores. A substantial breakthrough in the laser welding of biological tissues may come from the advent of nanotechnologies. In this paper we describe an experimental study, to confirm the feasibility of an innovative laser-assisted vascular repair (LAVR) technique based on diode laser irradiation and subsequent photoactivation of a hyaluronan solder embedded with near infrared (NIR) absorbing gold nanorods (GNRs), and to analyze the induced closuring effect in a follow-up study performed in animal model. Twenty New Zealand rabbits underwent closure of a 3-mm longitudinal incision performed on the common carotid artery (CCA) by means of 810 nm diode laser irradiation, in conjunction with the topical application of an optimized GNR composite. Effective closure of the arterial wound was accomplished by using very low laser intensity (30 W/cm2). The average CCA occlusion time was as low as 50 sec. Animals underwent different follow-up periods (2, 8, 30 days). After follow-up, they were re-anesthetized, the patency of the treated vessels was tested (Doppler analysis) and then the irradiated vessels were excised and subjected to histological evaluations. Morphological examinations of the samples documented the integrity of the vascular wall. No host reaction to nanoparticles occurred. Collagen and elastic fibers returned to their normal architecture 30 days after treatment. A Scanning Electron Microscopy (SEM) examination and immuno-histochemical analysis demonstrated a full re-endothelization of the vessel walls. We thus confirmed that a laser-based approach is technically easy to perform, and provides several advantages, such as a simplification of the surgical procedure, a reduction in the operative time, and the suppression of bleeding. The use of GNRs improves the selectivity of welding and minimizes the surgical trauma to vessels, resulting in an optimal healing process. PMID- 23034265 TI - Viral sequence analysis of occult HBV infection and its reactivation in immunosuppressed patients. AB - Mechanisms associated with reactivation of hepatitis B virus (HBV) in patients with occult HBV infection (OBI) remain unclear. In some cases immunosuppression is an enhancer of viral replication. However, not all patients with OBI who undergo immunosuppression experience reactivation. This study explores the role of viral heterogeneity as a determinant of occult HBV reactivation. HBV genotype, mutation patterns and quasispecies were assessed by sequencing the PreS/S region of 16 patients with OBI undergoing chemotherapy, 3 of whom experienced a OBI reactivation. The latter were also assessed at the time of reactivation. Phylogenetic analysis identified low nucleotide and amino acid diversity rates. There were no differences in the viral quasispecies, or common mutation patterns, detected between patients who underwent reactivation of OBI, and those who did not. Furthermore, upon reactivation, the quasispecies evolved towards a loss of most of the variants present during the initial OBI stage, probably representing the fittest version of the virus. The genetic variability of HBV alone did not account for the transition from occult to overt infection, which appears to be governed principally by the host immune response. PMID- 23034266 TI - Treatment of radiculopathies: a study of efficacy and tollerability of paravertebral oxygen-ozone injections compared with pharmacological anti inflammatory treatment. AB - The study was performed to evaluate the effectiveness of lumbar paravertebral injections of a gas mixture of Oxygen and Ozone in patients with lumbar radiculopathies caused by L4-L5 or L5-S1 disk herniations compared to a pharmacological therapy based on non-steroidal anti-inflammatory drugs. Lumbar radiculopathy caused by disc herniation is widely spread. Many therapeutic options are available before steering patients to the surgery. Low back pain and sciatica represent some of the most frequent causes of antinflammatory-analgesic drugs overuse. Recent findings have shown that medical Ozone can be used in the treatment of radicular syndrome caused by herniated intervertebral discs. Although widely spread, there are insufficient published data supporting the effectiveness of this approach in clinical practice. We studied 38 affected patients with acute L5 or S1 radicolopathy. The patients were randomly divided in two groups: A) 20 patients treated with lumbar paravertebral injections of Oxygen and Ozone; B) 18 patients treated pharmacologically with antinflammatory analgesic drugs. All patients underwent a clinical and neurological examination at baseline (T1) and after 1 (T2), 2 (T3), 4 weeks (T4) and after 3 (T5) and 6 months (T6). An MRI and EMG examination were performed at baseline and after 6 months. The intensity of pain and the outcome of treatments were evaluated in all patients with the Visual Analogue Scale and with the Oswestry Disability Index. We found a reduction of pain and discomfort soon after one week with oxygen-ozone injections compared with pharmacological treatment, but this difference of response became statistically significant after two weeks (50 percent vs 16.6 percent) and is confirmed after 3 and 6 months, when 80 percent of patients treated with injections turned out pain free compared with half of the patients treated pharmacologically. No statistical difference were found in MRI and EMG examinations. No adverse effects were found in any patient of group A. We hypothesize that oxygen-ozone injections in paravertebral regions can induce a direct reduction of root inflammation with a corresponding reduction of pain. The paravertebral injections of oxygen-ozone represent a rapidly effective therapy, easily practicable and secure, in patients with lumbar radicolopathies secondary to disc herniation. PMID- 23034267 TI - Platelet rich fibrin matrix effects on skeletal muscle lesions: an experimental study. AB - Even though muscle injuries are very common, few scientific data on their effective treatment exist. Growth Factors (GFs) may have a role in accelerating muscle repair processes and a currently available strategy for their delivery into the lesion site is the use of autologous platelet-rich plasma (PRP). The present study is focused on the use of Platelet Rich Fibrin Matrix (PRFM), as a source of GFs. Bilateral muscular lesions were created on the longissimus dorsi muscle of Wistar rats. One side of the lesion was filled with a PRFM while the contralateral was left untreated (controls). Animals were sacrificed at 5, 10, 40 and 60 days from surgery. Histological, immunohistochemical and histomorphometric analyses were performed to evaluate muscle regeneration, neovascularization, fibrosis and inflammation. The presence of metaplasia zones, calcifications and heterotopic ossification were also assessed. PRFM treated muscles exhibited an improved muscular regeneration, an increase in neovascularization, and a slight reduction of fibrosis compared with controls. No differences were detected for inflammation. Metaplasia, ossification and heterotopic calcification were not detected. This preliminary morphological experimental study shows that PRFM use can improve muscle regeneration and long-term vascularization. Since autologous blood products are safe, PRFM may be a useful and handy product in clinical treatment of muscle injuries. PMID- 23034268 TI - Assessment of NGAL as an early biomarker of acute kidney injury in adult cardiac surgery patients. AB - Early and predictive acute kidney injury (AKI) markers may be decisive for the clinical outcome of heart surgery. Hence, this study set out to evaluate the biological variability of urinary neutrophil gelatinase-associated lipocalin (uNGAL) levels in adult cardiac surgery patients, to test their feasibility as a biomarker of early AKI in a routine laboratory setting. uNGAL levels were measured with an automated immunoassay in urine samples from patients undergoing cardiac surgery using cardiopulmonary bypass, at the time of admission (T0) and 4 hours (T1) and 24 hours (T2) after surgery. Patients without post-operative AKI did not show significant differences in urine NGAL levels after surgery. In contrast, patients developing AKI displayed a significant increase (P=0.011) in uNGAL levels compared to T0. This increase was detectable at an earlier time point (T1, 4 hours) with respect to serum creatinine (T2, 24 hours). Confirming its utility as a biomarker, at T1 the uNGAL levels were significantly higher in AKI patients than in non-AKI patients (P=0.021). A receiver operating characteristic curve analysis of the uNGAL assay gave a sensitivity of 55.3 (95percent confidence interval, 26.59-78.73), a specificity of 72.9 (95 percent CI, 55.88-86.21), and a cut-off value for AKI prediction of 55.2. These results support the notion that urinary NGAL is an earlier marker of AKI than serum creatinine. However, the cut-off value of the assay was too low to consider it as a positive or negative diagnostic marker in AKI patients with moderate degree of severity. Likewise, its sensitivity and specificity were not high enough for it to be considered better than the others currently in use. PMID- 23034269 TI - Inhibition of P-glycoprotein-mediated transport by S-adenosylmethionine and cynarin in multidrug-resistant human uterine sarcoma MES-SA/Dx5 cells. AB - Multidrug resistance (MDR) to anticancer chemotherapy is often mediated by the overexpression of the plasma membrane drug transporter P-glycoprotein (Pgp) encoded by multidrug resistance gene (MDR1). Various chemosensitizing agents are able to inhibit Pgp activity but their clinical application is limited by their toxicity. Furthermore, hepatotoxicity related to chemotherapy causes delays of treatment in cancer patients and often requires supplementation of anti-tumour therapy with hepatoprotective agents. In this in vitro study, we investigated the effectiveness of an endogenous hepatoprotective agent, S-adenosylmethionine (SAMe), and a natural hepatoprotective compound, Cynarin (Cyn), to inhibit Pgp activity in order to evaluate their potential use as chemosensitizing agents. Human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) expressing high levels of Pgp were treated with two hepatoprotectors at various concentrations (1, 5 and 10 microM) that are clinically achievable, in the presence or absence of three different concentrations of doxo (2, 4 and 8 microM). In order to evaluate the effects of both hepatoprotectors, we measured the intracellular accumulation and cytotoxicity of doxo, the cellular GSH level, ROS production and catalase (CAT) activity. We found that treatment with 2, 4 and 8 microM doxo in the presence of SAMe or Cyn significantly increased the doxo accumulation and cytotoxicity on MES-SA/Dx5 cells, when compared to control cells receiving doxo alone. Moreover, treatment with SAMe or Cyn significantly increased GSH content, greater than 80 percent and 60 percent, respectively) and CAT activity greater than 60 and 150 percent, respectively) in resistant cancer cells, while ROS production was below the values of corresponding untreated control cells. Our in vitro findings provide a rationale for the potential clinical use of these hepatoprotectors both as chemosensitizing agents, to reverse Pgp-mediated MDR, and as antioxidants to protect normal cells from chemotherapy-induced cytotoxixity. PMID- 23034270 TI - Influence of titanium laser surface geometry on proliferation and on morphological features of human mandibular primary osteoblasts. AB - The aim of this study is to assess in vitro the proliferation and the morphological changes of primary osteoblast-like cells (HOst) seeded on titanium dish grade 4 and 5 with different roughness and different titanium grade: machined (M), sandblasted (SBT), laser-treated with pitches of 20-microm diameter and 30-microm interpore distance. The titanium disks were divided into two groups: group A (titanium grade 4) and Group B (titanium Grade 5), respectively. Proliferation rate of attached cells was evaluated at different time (24, 48, 72 h and 1 week) by the quantitative colorimetric MTT assay. Our results showed a cell growth decrease evident in M titanium surfaces in both Groups A and B, while the cells seeded on the STB and laser disks displayed an increase of cells growth, more evident in laser titanium surfaces in groups A and B. Morphological changes of the biocomplex cells/titanium was assessed by light, scanning and confocal microscopy. In fact, the microscopic analysis helped to clarify the behavior of the cells in contact with the titanium surfaces, in particular the M surface induced significant morphological changes, which were less evident in the SBT surfaces. Laser-engineered porous titanium surfaces promoted viability and proliferation of the osteoblasts. In particular, hemispherical porosity of 20 microm could be responsible for the higher HOst activation, in terms of cells proliferation, adhesion and morphological features. PMID- 23034271 TI - Enteropathogenic e.coli sustains iodoacetamide-induced ulcerative colitis-like colitis in rats: modulation of IL-1beta, IL-6, TNF-alpha, COX-2, and apoptosisi. AB - Pathogenic or non-pathogenic bacteria from flora may play a key role in inflammatory bowel disease (IBD) pathogenesis. However, a specific infectious agent causing IBD has not been identified. This study assessed the impact of enteropathogenic E. coli (EPEC) on the modulation of IL-1beta, IL-6, TNF- alpha, COX-2, BAX and Bcl-2 expression, in sustaining inflammation of a rat colitis model. Two hundred male Sprague-Dawley rats (4 groups) were inoculated weekly or bi-weekly for 70 days, with 1 percent methylcellulose (MC), (b) 6 percent iodoacetamide (IA) in 1 percent MC, (c) 4x108 CFU of EPEC, and (d) IA+EPEC. After a month, treatment was stopped in half of the animals in each group. IL-1beta, IL 6, TNF-alpha, COX-2, BAX and Bcl-2 expression were measured in colonic mucosa scrapings. IL-1beta, IL-6, TNF-alpha, and COX-2 were significantly increased in colonic mucosa of the IA+EPEC group and to a lesser but significant level in the IA group compared to controls, or EPEC alone, both in continued and discontinued treatment groups. Additionally, the BAX/Bcl-2 ratio decreased, indicating less apoptosis in the IA+EPEC group which exhibited more necrosis. These effects increased with experiment duration. This work provides new arguments favouring the role of bacteria in IBD pathogenesis. PMID- 23034272 TI - Correlation between viral load, plasma levels of CD4 - CD8 T lymphocytes and AIDS related oral diseases: a multicentre study on 30 HIV+ children in the HAART era. AB - This experimental retrospective multicenter study carried out on 30 seropositive children treated with Highly Active Antiretroviral Therapy (HAART), between the ages of 18 months and 14 years, in the clinical categories Centers for Disease Control (CDC) classification 1993 A (mildly symptomatic), B (moderately symptomatic) and C (severely symptomatic) aims to: 1) clinically and immunologically demonstrate the therapeutic benefits of HAART; 2) monitor the frequency of AIDS-related oral diseases in seropositive children with HAART therapy; 3) monitor the plasma levels of total CD4, CD4 percent, CD8 percent, CD4 CD8 lymphocytes and viral load from 1997 to 30 April, 2011. The statistic methods used are the analysis of covariance and the Bonferroni Test. More than 100 AIDS related oral diseases were found in the study samples, the most frequent being: oral candidiasis, oropharyngeal candidiasis, HSV-1 herpetic esophagyitis, herpetic gingivolstomatitis (RHOG), recurrent aphthous stomatitis (RAS), parotid swelling, oral hairy leukoplakia (OHL), Herpes simplex 1 (HSV-1), linear gingival erythema (LGE), necrotizing gingivitis (NUG), facial lipodistrophy, facial cervical lymphadenopathy (FCL), xerostomia, dysgeusia, hyposmia, oral mucosa hyperpigmentation (OMP). The Bonferroni test showed a significant difference between the mean plasma values (mpVTL) of total CD4, CD4 percentage, CD4-CD8 T lymphocytes and Viral Load (VL) of the various oral diseases found in the study samples. The therapeutic benefits of HAART are: immune reconstitution; reduction of the HIV/AIDS-related stomatology diseases; prevention and cure of the AIDS correlated neoplasias; reduction in maternal-fetal transmission of the HIV virus. The negative effects of HAART in relation to odontostomatolgy are: increase in oral lesions from HPV; xerostomia; dysgeusia/ageusia, hyposmia, perioral paresthesia; hyperpigmentation of oral mucosa; facial lipodystrophy, recurrent aphthous stomatitis (RAS). No case of immune reconstitution inflammatory syndrome or human papillomavirus (HPV)-related oral diseases were found in this study. PMID- 23034273 TI - Postoperative pain management at Tirana university hospital center -Mother Teresa , Tirana, Albania. AB - There is no or little evidence on postoperative pain assessment and treatment in Albanian hospitals. This study is based on our every day work and aims to highlight our experience. We conducted a descriptive drug utilization study which implied data collection over 6 months. Evidence of the enrolled patients was kept by maintaining records and the completed structured questionnaires. Postoperative pain was assessed through a five-category verbal rating scale (VRS). Metamizole was the most prescribed and administered analgesic drug as single therapy and in combination therapy, and acetaminophen was the least prescribed drug. The compliance between the prescribed dosages and those administered was higher in patients treated with a single analgesic compared to multiple therapies. A few patients reported adverse events (4.2 percent). There is much variability in postoperative pain management methods used by medical staff within the Tirana University Hospital. In Albania to date there is no standard protocol for postoperative pain treatment. This study shows that there are no essential differences in patient outcomes in terms of efficacy of analgesic treatment. This leads to the conclusion that a postoperative protocol/guideline for pain management should be prepared, based on our local study findings and also on international experience. Moreover, the guidelines should consider use of balanced analgesia. PMID- 23034274 TI - Enterococcus faecalis leakage of root canal sealers: an ex vivo study. AB - The aim of this ex vivo study was to evaluate bacterial penetration after filling root canals using 3 different techniques. Three experimental groups of 25 teeth each, obturated with lateral-warm-vertical condensation of gutta-percha, Microseal technique and EndoREZ system, respectively, were tested in a split chamber model system using Enterococcus faecalis and monitored for 180 days to determine bacterial penetration. A statistical analysis was performed using the Kaplan-Meier method. Median survival time was 25 days for Microseal system, 41 for lateral-warm-vertical condensation and 81 for EndoREZ(r). Significant differences were demonstrated between Microseal and EndoREZ (p less than 0.001) and between Microseal and lateral-warm-vertical condensation technique (p less than 0.05). No statistically significant differences were observed between EndoREZ and lateral-warm-vertical condensation. After 180 days of assessment, 20 percent of the EndoREZ samples resisted bacterial penetration and furthermore, the EndoREZ system has the potential to be a filler system compatible with other currently used systems. PMID- 23034275 TI - Dental and periodontal complications of labial and tongue piercing. AB - Piercing is the practice of puncturing some parts of the body to apply ornamental objects. The presence of oral and perioral piercings are a risk factor for many acute and chronic complications, such as chipping of the dental enamel, periodontal lesions and infection. The aim of this study is to assess the prevalence of lip and tongue piercing complications in the dental and periodontal tissues in a sample of young adults. Twenty-five adult patients were examined (test group: 11 males and 14 females with an average age of 23.4+/-3.6 years) who had had a minimum of one labial or tongue piercing for at least 1 year and were compared with 25 subjects (control group: 11 males - 44 percent, and 14 females - 56 percent) without any lingual or labial piercing. A questionnaire was compiled for each patient and a clinical examination was performed. The following parameters were examined by the same operator: abnormal toothwear, tooth chipping or cracking, clinical attachment loss (CAL), probing pocket depth (PD) and gingival recession (GR, classified by using Miller s classification). The data were analyzed using X2 or Fisher s exact test for small numbers and non parametric Mann-Whitney or Kruskal-Wallis tests to examine for differences in continuity; the level of significance was p less than 0.05. According to the results found in the present study the prevalence of abnormal tooth wear and tooth chipping was higher in the subjects with labial or lingual piercing. Moreover, patients with tongue or labial piercing exhibited a higher GR in comparison to control subjects without any oral piercing. No differences were observed between the two groups as regards CAL and PD. A significant association between the duration of piercing and dental defects was found in the group of patients with piercings with greater prevalence of tooth and periodontal defects in the group of 13 subjects who had had the piercings for a period less than or equal to 4 years. PMID- 23034276 TI - ADMA, SDMA, L-Arginine and nitric oxide in allergic pediatric bronchial asthma. AB - Published data regarding asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), L-arginine (L-ARG) and nitric oxide fraction in exhaled air (FeNO) in pediatric bronchial asthma are limited. Many question remain open about plasma concentration of these substances. The aim of this study is to evaluate ADMA, SDMA, L-ARG and FeNO concentration in allergic pediatric mild asthmatic patients in respect to healthy subjects. In this case-control study 60 children (50 asthmatics and 10 healthy) underwent a complete clinical visit, baseline respiratory function, allergy tests and biochemical analyses. The statistical significance of the different concentrations between the two groups were studied using one-way analysis of variance (ANOVA). A p value less than 0.05 was considered statistically significant. The mean plasma ADMA (0.58 vs 0.68 micromol/L), SDMA (0.40 vs 0.45 micromol/L) and L-ARG (52.2 vs 74.13 micromol/L) concentration were significantly lower (p less than 0.001) in the asthmatic patients in respect to healthy subjects (control group). The concentration of FeNO was significantly higher in the asthmatic subjects in respect to the control group (9.18 vs 4.2 micromol/L; p less than 0.001). Low plasma concentrations of ADMA, SDMA, L-ARG and high concentration of FeNO are associated with bronchial asthma and indicate an important role in airway disease through NO metabolism. PMID- 23034277 TI - Prion search and cellular prion protein expression in stranded dolphins. AB - The recent description of a prion disease (PD) case in a free-ranging bottlenose dolphin (Tursiops truncatus) prompted us to carry out an extensive search for the disease-associated isoform (PrPSc) of the cellular prion protein (PrPC) in the brain and in a range of lymphoid tissues from 23 striped dolphins (Stenella coeruleoalba), 5 bottlenose dolphins and 2 Risso s dolphins (Grampus griseus) found stranded between 2007 and 2012 along the Italian coastline. Three striped dolphins and one bottlenose dolphin showed microscopic lesions of encephalitis, with no evidence of spongiform brain lesions being detected in any of the 30 free ranging cetaceans investigated herein. Nevertheless, we could still observe a prominent PrPC immunoreactivity in the brain as well as in lymphoid tissues from these dolphins. Although immunohistochemical and Western blot investigations yielded negative results for PrPSc deposition in all tissues from the dolphins under study, the reported occurrence of a spontaneous PD case in a wild dolphin is an intriguing issue and a matter of concern for both prion biology and intra/inter-species transmissibility, as well as for cetacean conservation medicine. PMID- 23034278 TI - Solitary plasmacytoma of the tonsillar site associated with actinomyces infection: the possible role of IL-6. AB - ExtraMedullary Plasmacytoma (EMP) is a rare plasma cell tumor. It can occur in the upper aerodigestive tract and presents as a large nodule causing local compressive symptoms. A 79-year old woman presented to Otorhinolaryngology Department with progressive hearing loss and no other symptoms. Following PET/TC examination due to the suspicion of a lymphoproliferative disease, the patient underwent tonsillectomy and the diagnosis of solitary EMP was formulated. In addition to that, the histological examination of the tonsillar tissue revealed large colonies of filamentous bacteria, showing abundant sulphur granules and Splendore-Hoeppli phenomenon; these evidences indicating the presence of a chronic Actinomyces infection. Immunohistochemical analysis demonstrated a marked IL-6 immunoreactivity of the neoplastic plasma cells. Interestingly, a marked IL 6 immunoreactivity was also found in the tissue surrounding the Actinomyces colonies. In the present study we report for the first time a solitary EMP associated with Actinomycosis. It is tempting to speculate that the unsuspected and untreated Actinomyces infection, through chronic IL-6 production, could contribute to the neoplastic transformation of plasma cells. PMID- 23034279 TI - Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of subsequent cardiovascular disease. AB - Hematopoietic cell transplantation (HCT) recipients may be at an increased risk of developing hypertension, diabetes, and dyslipidemia (referred to as cardiovascular risk factors [CVRFs]); and these factors can potentially increase the risk of cardiovascular disease (CVD). We examined the incidence and predictors of CVRFs and subsequent CVD in 1885 consecutive 1+year survivors of HCT performed at City of Hope between 1995 and 2004. Ten-year cumulative incidence of hypertension, diabetes, dyslipidemia, and multiple (>= 2) CVRFs was 37.7%, 18.1%, 46.7%, and 31.4%, respectively. The prevalence of CVRFs was significantly higher among HCT recipients compared with the general population; contributed to largely by allogeneic HCT recipients. Older age and obesity at HCT were associated with increased risk of CVRFs. History of grade II-IV acute graft versus host disease was associated with an increased risk for hypertension (relative risk [RR] = 9.1, P < .01), diabetes (RR = 5.8, P < .01), and dyslipidemia (RR = 3.2, P < .01); conditioning with total body irradiation was associated with an increased risk of diabetes (RR = 1.5, P = .01) and dyslipidemia (RR = 1.4, P < .01). There was an incremental increase in 10-year incidence of CVD by number of CVRFs (4.7% [none], 7.0% [1 CVRF], 11.2% [>= 2 CVRFs], P < .01); the risk was especially high (15.0%) in patients with multiple CVRFs and pre-HCT exposure to anthracyclines or chest radiation. PMID- 23034280 TI - The transcription factor Th-POK negatively regulates Th17 differentiation in Valpha14i NKT cells. AB - The majority of mouse Valpha14 invariant natural killer T (Valpha14i NKT) cells produce several cytokines, including IFNgamma and IL-4, very rapidly after activation. A subset of these cells, known as NKT17 cells, however, differentiates in the thymus to preferentially produce IL-17. Here, we show that the transcription factor-known as T helper, Poxviruses, and Zinc-finger and Kruppel family, (Th-POK)-represses the formation of NKT17 cells. Valpha14i NKT cells from Th-POK-mutant helper deficient (hd/hd) mice have increased transcripts of genes normally expressed by Th17 and NKT17 cells, and even heterozygosity for this mutation leads to dramatically increased numbers of Valpha14i NKT cells that are poised to express IL-17, especially in the thymus and lymph nodes. In addition, using gene reporter mice, we demonstrate that NKT17 cells from wild type mice express lower amounts of Th-POK than the majority population of Valpha14i NKT cells. We also show that retroviral transduction of Th-POK represses the expression of the Th17 master regulator RORgammaT in Valpha14i NKT cell lines. Our data suggest that NKT17-cell differentiation is intrinsically regulated by Th-POK activity, with only low levels of Th-POK permissive for the differentiation of NKT17 cells. PMID- 23034281 TI - Mouse natural killer cell development and maturation are differentially regulated by SHIP-1. AB - The SH2-containing inositol phosphatase-1 (SHIP-1) is a 5' inositol phosphatase known to negatively regulate the product of phosphoinositide-3 kinase (PI3K), phosphatidylinositol-3.4,5-trisphosphate. SHIP-1 can be recruited to a large number of inhibitory receptors expressed on natural killer (NK) cells. However, its role in NK cell development, maturation, and functions is not well defined. In this study, we found that the absence of SHIP-1 results in a loss of peripheral NK cells. However, using chimeric mice we demonstrated that SHIP-1 expression is not required intrinsically for NK cell lineage development. In contrast, SHIP-1 is required cell autonomously for NK cell terminal differentiation. These findings reveal both a direct and indirect role for SHIP-1 at different NK cell development checkpoints. Notably, SHIP-1-deficient NK cells display an impaired ability to secrete IFN-gamma during cytokine receptor mediated responses, whereas immunoreceptor tyrosine-based activation motif containing receptor-mediated responses is not affected. Taken together, our results provide novel insights on how SHIP-1 participates in the development, maturation, and effector functions of NK cells. PMID- 23034283 TI - Acute psychiatric inpatient care: a cross-cultural comparison between two hospitals in Germany and Japan. AB - BACKGROUND: Intercultural differences influence acute inpatient psychiatric care systems. AIMS: To evaluate characteristics of acute inpatient care in a German and a Japanese hospital. METHOD: Based on a sample of 465 admissions to the Psychiatric State Hospital Regensburg (BKR) and 91 admissions to the Hirakawa Hospital (HH) over a six-month period in 2008, data from the psychiatric basic documentation system (BADO) were analysed with regard to socio-demographic characteristics, treatment processes and outcome indicators. RESULTS: Schizophrenia and related psychosis was the most common diagnosis in both hospitals. Cases at the BKR were admitted more quickly after onset of the present episode. Global Assessment of Psychosocial Functioning (GAF) ratings at admission were lower at the HH. Most admissions to both hospitals received psychopharmacological treatment, but more at the HH received psychotherapy. Length of stay was significantly longer at the HH (75 days) than at the BKR (28 days). Admissions to the HH were more improved with regard to GAF and clinical global impression (CGI). CONCLUSIONS: Acute admissions in Germany provide intensive care with short hospitalization as crisis intervention. For acute admissions in Japan, comprehensive care for severe mental illness precedes emergency admissions and achieves greater improvement with longer hospitalization. PMID- 23034282 TI - Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. AB - The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1 targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the EMU-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies. PMID- 23034284 TI - Physical illness in psychiatric inpatients: comparison of patients with and without substance use disorders. AB - BACKGROUND: Physical comorbidities and substance use are commonly reported in patients with mental disorders. AIM: To examine somatic comorbidity in patients with substance use disorders (SUD) compared to patients with mental disorders but no SUD. METHODS: Lifetime prevalence data on mental and physical health status were collected from inpatients in 12 mental health care facilities in five different countries. Differences in somatic comorbidity were examined by means of logistic regression analysis controlling for age and gender. RESULTS: Of 2,338 patients, 447 (19%) had a primary or secondary SUD diagnosis. In comparison to patients with other mental disorders, patients with SUD had a higher prevalence of infectious and digestive diseases but a lower prevalence of endocrine, nutritional and metabolic disorders. Patterns of physical comorbidities differed according to type of substance used (alcohol use - cardiovascular; tobacco use - respiratory, neoplasms; cannabinoid use - injuries; opioid use - infectious, digestive; benzodiazepine use - endocrine, nutritional, metabolic; stimulants - urogenital). CONCLUSIONS: SUD are related to specific somatic health risks while some of our findings point to potentially protective effects. The widespread prescription of benzodiazepines requires research on physical health effects. Early detection of SUD and their integration into programmes targeting physical comorbidity should be a priority in organizing mental health care. PMID- 23034285 TI - The etiology of mental disorders: public endorsement of traditional Chinese beliefs in Macau. AB - BACKGROUND: Public beliefs concerning the causes of mental disorders are important in their effective treatment. The relative importance of public beliefs related to the etiology of mental disorders among Chinese populations and their relationship to other attitudes to mental disorders are poorly understood. AIMS: To investigate the endorsement of beliefs related to the etiology of mental disorders in Macau, in particular, traditional Chinese beliefs, and to explore their relationship to general attitudes towards mental disorders. METHODS: A survey of 361 members of the public measured attitudes towards 32 possible causes of mental disorders as well as contact with and social distance from individuals with a mental disorder. RESULTS: The results indicated that traditional Chinese beliefs were ranked with relatively low importance compared with psychosocial causes. Traditional beliefs related to two underlying factors and were significantly higher in participants with lower education levels. There was a significant negative correlation between endorsement of traditional beliefs and contact with individuals with a mental disorder and a significant positive correlation between endorsement of traditional beliefs and desired social distance from individuals with a mental disorder. CONCLUSION: Factors underlying traditional Chinese beliefs concerning the causes of mental disorders are associated with more negative attitudes towards individuals with a mental disorder, with such beliefs more strongly endorsed by those with relatively lower education levels. PMID- 23034286 TI - Duration of untreated illness (DUI) and schizophrenia sub-types: a collaborative study between the universities of Milan and Moscow. AB - BACKGROUND: Several studies show an association between a long duration of untreated illness (DUI) and poor outcome in schizophrenic patients. DUI, in turn, may be influenced by different variables including specific illness-related factors as well as access to local psychiatric services. AIMS: The purposes of the present study were to detect differences in terms of DUI among schizophrenics coming from different geographic areas and to evaluate differences in DUI across diagnostic sub-types. METHOD: One hundred and twenty-five (125) schizophrenic patients of the Psychiatric Clinic of Milan (n = 51) and Moscow (n = 74) were enrolled. SCID-I was administered to all patients and information about DUI was obtained by consulting clinical charts and health system databases, and by means of clinical interviews with patients and their relatives. DUI was defined as the time between the onset of illness and the administration of the first antipsychotic drug. One-way analyses of variance (ANOVAs) were performed to find eventual differences in terms of DUI across diagnostic sub-types. RESULTS: Italian patients showed a longer DUI (M = 4.14 years, SD = 4.95) than Russians (M = 1.16 years, SD = 1.43) (F = 24.03, p < .001). DUI was found to be longer in paranoid schizophrenics (M = 3.47 years, SD = 4.19) compared to catatonic patients (M = 0.96 years, SD = 0.94) (F = 3.56, p = .016). CONCLUSIONS: The results of the present study suggest that the different schizophrenic sub-types may differ in terms of DUI, likely due to different clinical severity and social functioning. Studies with larger samples are needed to confirm the data of the present study. PMID- 23034287 TI - Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. AB - The therapeutic benefits of adrenocorticotropic hormone in multiple sclerosis are usually ascribed to its corticotropic actions. Evidence is presented that adrenocorticotropic hormone, approved for multiple sclerosis relapses, acts via corticosteroid-independent melanocortin pathways to engender down-modulating actions on immune-system cells and the cytokines they synthesize. Immune response dampening effects are also brought about by agent-induced neurotransmitters that inhibit immunocytes. The likelihood that adrenocorticotropic hormone promotes microglial quiescence and counteracts glucocorticoid-mediated bone resorption is discussed. PMID- 23034288 TI - Association between parental motives for food choice and eating patterns of 12- to 13-year-old Norwegian children. AB - OBJECTIVE: To determine (i) the importance of parents' motives for everyday family food choices; and (ii) the relationship between parental food choice motives and eating patterns of 12- to 13-year-old children. DESIGN: Cross sectional study. A modified version of the Food Choice Questionnaire was used to determine parental motives for food choices. The children's food and drink intake was reported by their parents using a retrospective FFQ. Eating patterns were derived using principal component analysis. The association between food choice motives and eating patterns was examined using multiple linear regression analysis. SETTING: Primary schools, Telemark County, Norway. SUBJECTS: In total, 1095 children aged 12-13 years and their parents. RESULTS: The parental motive 'sensory appeal' was the most important for food choice, followed by 'health', 'convenience', 'natural content' and 'weight control'. The food choice motives were associated with the eating patterns of the children, independent of background variables. The motive 'health' was most strongly associated with a 'varied Norwegian' eating pattern, representing a diverse diet and regular meals, while the motive 'convenience' appeared to be the most important barrier to this eating pattern. 'Weight control' was not associated with the 'varied Norwegian' eating pattern. CONCLUSIONS: To encourage parents to make healthy food choices for their children, health promotion activities should focus on the health benefits of a diverse diet and regular meals, rather than weight control. Recommended food products should be made more convenient and easily available for families with children. PMID- 23034289 TI - Assessment of tumour size in PET/CT lung cancer studies: PET- and CT-based methods compared to pathology. AB - BACKGROUND: Positron emission tomography (PET) may be useful for defining the gross tumour volume for radiation treatment planning and for response monitoring of non-small cell lung cancer (NSCLC) patients. The purpose of this study was to compare tumour sizes obtained from CT- and various more commonly available PET based tumour delineation methods to pathology findings. METHODS: Retrospective non-respiratory gated whole body [18F]-fluoro-2-deoxy-D-glucose PET/CT studies from 19 NSCLC patients were used. Several (semi-)automatic PET-based tumour delineation methods and manual CT-based delineation were used to assess the maximum tumour diameter. RESULTS: 50%, adaptive 41% threshold-based and contrast oriented delineation methods showed good agreement with pathology after removing two outliers (R2=0.82). An absolute SUV threshold of 2.5 also showed a good agreement with pathology after the removal of 5 outliers (R2: 0.79), but showed a significant overestimation in the maximum diameter (19.8 mm, p<0.05). Adaptive 50%, relative threshold level and gradient-based methods did not show any outliers, provided only small, non-significant differences in maximum tumour diameter (<4.7 mm, p>0.10), and showed fair correlation (R2>0.62) with pathology. Although adaptive 70% threshold-based methods showed underestimation compared to pathology (36%), it provided the best precision (SD: 14%) together with good correlation (R2=0.81). Good correlation between CT delineation and pathology was observed (R2=0.77). However, CT delineation showed a significant overestimation compared with pathology (3.8 mm, p<0.05). CONCLUSIONS: PET-based tumour delineation methods provided tumour sizes in agreement with pathology and may therefore be useful to define the (metabolically most) active part of the tumour for radiotherapy and response monitoring purposes. PMID- 23034290 TI - Examinations and ophthalmic education. PMID- 23034291 TI - Free autologous conjunctival grafts. PMID- 23034292 TI - Refractive stability after phaco-DSAEK. PMID- 23034293 TI - Teaching manual cataract extraction. PMID- 23034294 TI - Intraretinal tuberculosis. PMID- 23034295 TI - Bilateral corneal ulceration in keratoconus. PMID- 23034296 TI - Periorbital discoid lupus erythematosus. PMID- 23034297 TI - Trabeculectomy success rates. PMID- 23034299 TI - Limbus vs. fornix-based trabeculectomy results. PMID- 23034301 TI - Acute corneal hydrops. PMID- 23034302 TI - Regional corticosteroids for scleritis. PMID- 23034305 TI - Smartphone photography safety. PMID- 23034308 TI - [Not Available]. PMID- 23034307 TI - Mechanical buckling of arterioles in collateral development. AB - Collateral arterioles enlarge in both diameter and length, and develop corkscrew like tortuous patterns during remodeling. Recent studies showed that artery buckling could lead to tortuosity. The objective of this study was to determine arteriole critical buckling pressure and buckling pattern during arteriole remodeling. Arterioles were modeled as elastic cylindrical vessels with an elastic matrix support and underwent axial and radial growth. Our results demonstrated that arteriole critical buckling pressure decreased with increasing axial growth ratio and radius growth ratio, but increased with increasing wall thickness. Arteriole buckling mode number increased (wavelength decreased) with increasing axial growth ratio, but decreased with increasing radius growth ratio and wall thickness. Our study suggests that axial growth in arterioles makes them prone to buckling and that buckling leads to tortuous collaterals. These results shed light on the mechanism of collateral arteriole tortuosity. PMID- 23034309 TI - Cost-effectiveness simulation analysis of schizophrenia at the Instituto Mexicano del Seguro Social: Assessment of typical and atypical antipsychotics. AB - INTRODUCTION: Estimation of the economic costs of schizophrenia is a fundamental tool for a better understanding of the magnitude of this health problem. The aim of this study was to estimate the costs and effectiveness of five antipsychotic treatments (ziprasidone, olanzapine, risperidone, haloperidol and clozapine), which are included in the national formulary at the Instituto Mexicano del Seguro Social, through a simulation model. METHODS: Type of economic evaluation: complete economic evaluation of cost-effectiveness. STUDY PERSPECTIVE: direct medical costs. TIME HORIZON: 1 year. Effectiveness measure: number of months free of psychotic symptoms. ANALYSIS: to estimate cost-effectiveness, a Markov model was constructed and a Monte Carlo simulation was carried out. RESULTS: Effectiveness: the results of the Markov model showed that the antipsychotic with the highest number months free of psychotic symptoms was ziprasidone (mean 9.2 months). The median annual costs for patients using ziprasidone included in the hypothetical cohort was 194,766.6 Mexican pesos (MXP) (95% CI, 26,515.6-363,017.6 MXP), with an exchange rate of 1 ? = 17.36 MXP. The highest costs in the probabilistic analysis were estimated for clozapine treatment (260,236.9 MXP). CONCLUSIONS: Through a probabilistic analysis, ziprasidone showed the lowest costs and the highest number of months free of psychotic symptoms and was also the most costeffective antipsychotic observed in acceptability curves and net monetary benefits. PMID- 23034310 TI - Gender differences in major depressive disorder: somatic symptoms and quality of life. AB - INTRODUCTION: Few findings in the literature have been as widely studied and consistently verified as the higher prevalence of depression among women. However, doubts remain on the distinguishing features of female depression. The available studies concur in the higher prevalence of somatizations among women and in the possibility that the impact of these symptoms on quality of life could be underestimated. In this study, all these aspects were analyzed in a sample of depressive patients. MATERIAL AND METHODS: We performed an epidemiologic, cross sectional, non-intervention study. The final sample of 1164 patients with major depressive disorder (DSM-VI) (629 women and 535 men) was recruited in outpatient Mental Health Services in Spain. Assessments were performed using the Hamilton (HAM-D17), the Quality of Life for Depression Scale (QLDS) and the Patient Health Questionnaire 15-Item Somatic Symptom Severity Scale (PHQ-15) to measure somatic symptoms. Differences were analyzed by Chi-square and ANOVA or Student's t-test, depending on the variable. RESULTS AND CONCLUSIONS: Somatic symptoms were significantly more prevalent among women. A positive correlation was found between somatic symptoms and worse quality of life. Clinical variables measured by the Hamilton scale showed significant differences in some items but no strong conclusions could be drawn. These results suggest gender differences in depression, which should be replicated in other samples. Other risk or clinical factors could also be included. PMID- 23034311 TI - Bipolar patients in community mental health centers and specialized units. Could they be pooled? AB - INTRODUCTION: Bipolar patients recruited for studies are usually picked from Bipolar Disorder Units, which only contain a fraction of the total population of patients with bipolar disorder. The purpose of this study was to determine whether the course of the illness is comparable in patients from a Community Mental Health Center (CMHC) and those from a Bipolar Disorder Unit (BDU). METHODS: This study was carried out at the La Fe Teaching Hospital BDU and two CMCH. Data were collected from the patients' clinical records and were completed by a face-toface interview. When the latter was not possible, a telephone interview was carried out. Demographic, clinical and course-of-illness variables were gathered. RESULTS: There were no differences in demographic characteristics between the two patient groups. Differences were found in clinical data: BDU patients were younger at illness onset (p<0.005), were admitted more frequently (p<0.05), and stayed longer in the hospital (p<0.005). CONCLUSIONS: Bipolar patients treated at a CMHC show clear differences compared with those from a BDU. Consequently, care should be exercised when generalizing the clinical course of bipolar patients using BDU samples. These patients are not representative of the total bipolar patient population, as their clinical course is more complicated. PMID- 23034312 TI - Effects of (RS)-3,4-DCPG, a mixed AMPA antagonist/mGluR8 agonist, on aggressive behavior in mice. AB - INTRODUCTION: Ionotropic and metabotropic (mGlu) receptors of glutamate have been suggested to be involved in the modulation of aggression. Thus, recent studies found reduced aggression in AMPA-type glutamate receptor GluR-A subunit-deficient mice. Likewise, mGlu1 and 5 receptors have also been implicated in aggression regulation. (RS)-3,4-DCPG is a mixed antagonist of AMPA receptors and an agonist of mGluR8. The AMPA antagonist activity of this compound is determined by its R isomer while the S isomer is responsible for its mGluR8 agonistic properties. METHODS: We analyzed the effects of (RS)-3,4-DCPG (5, 10 and 20mg/kg, ip) on agonistic encounters between male mice. Individually housed mice were exposed to anosmic opponents 30 min after drug administration. Ten min of dyadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to 10 broad behavioral categories was estimated using an ethologically based analysis. RESULTS AND CONCLUSIONS: The results indicated that (RS)-3,4-DCPG produced no significant behavioral changes, suggesting that antagonism of AMPA receptors by the R isomer and stimulation of mGluR8 by the S isomer do not act synergistically on aggression in the racemic form of 3,4-DCPG. PMID- 23034313 TI - Use of antipsychotics during pregnancy and breastfeeding. AB - There is growing acceptance that pregnancy itself is not a protective factor against mental disorders. Indeed, some mental disorders such as psychotic and bipolar disorders may become worse during pregnancy and the immediate postpartum period. In pregnant women with a mental disorder that can be treated with antipsychotics, the known risks -teratogenic, obstetric, neonatal and those affecting the mother- indicate that, in general, the risk of the non-treated disorder is higher than that resulting from the use of antipsychotics and that the reduction in psychoticism improves the overall prognosis of these women. All the antipsychotics marketed in Spain are included in category C of the US Food and Drug Administration, with the exception of clozapine and piperazine, which are included in category B. The use of all of these drugs should be avoided during breast feeding as far as possible. The most reliable current recommendations indicate that optimal control of severe mental disorders should be maintained during pregnancy, the postpartum and subsequent periods. These recommendations also indicate that women with mental disorders must be considered as high risk and that both these women and their pregnancies should be constantly monitored. The currently available scientific information does not allow more than relatively secure individually-tailored recommendations to be made. When taking the decision of whether or not to treat with antipsychotics, the use of a risk-benefit relationship is crucial, with the participation of the woman's partner or legal representative, other physicians and even the clinical pharmacist if necessary. PMID- 23034316 TI - A rare case of primary otoscleroma of the middle ear. AB - OBJECTIVE: We report an extremely rare case of primary otoscleroma. METHOD: We present a case report and a review of the world literature concerning otoscleroma. RESULTS: An adult woman presented with chronic suppurative otitis media with tubotympanic disease and conductive hearing loss. On mastoid exploration, dark granulations were seen, which were identified as otoscleroma on histopathological examination. The patient responded well to streptomycin. CONCLUSION: To the best of our knowledge, this is the first report of primary otoscleroma in the world literature. This case indicates that Frisch's bacillus can also spread to the middle ear. PMID- 23034317 TI - Diagnostic and prognostic role of biomarkers for pulmonary hypertension in interstitial lung disease. AB - BACKGROUND: Pulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the relation of NT-proBNP, fibrin D-dimer, troponin-T, uric acid and exhaled nitric oxide (NO) to the presence of PH and mortality in ILD. METHODS: In a previously described cohort of 212 ILD patients of whom 29 had PH, levels of the above mentioned biomarkers were analyzed as routine tests. RESULTS: A value of NT proBNP below 95 ng/l had a negative predictive value for PH of 99% (95% CI: 94 100). Values of troponin-T were higher in patients with PH (median (inter quartile range) = 9 (9-20) vs. 9(9-10) ng/l), and the odds ratio (OR) for PH was increased in patients with abnormal levels of uric acid (OR (95% CI) = 3.1(1.1 8.8)). NT-proBNP and troponin-T values above the 50(th) percentile, and uric acid and fibrin D-dimer values above the 90th percentile were each associated with increased mortality. CONCLUSIONS: A value of NT-proBNP below 95 ng/l may be used as a rule-out test for PH in ILD, while an abnormal value of uric acid is a risk factor for PH. NT-proBNP, troponin-T, uric acid and fibrin D-dimer have prognostic value in ILD patients, while exhaled levels of NO do not seem to predict PH or mortality. PMID- 23034320 TI - Optimising cardiovascular outcomes using optical coherence tomography-guided percutaneous coronary interventions. PMID- 23034321 TI - Helminth infections and host immune regulation. AB - Helminth parasites infect almost one-third of the world's population, primarily in tropical regions. However, regions where helminth parasites are endemic record much lower prevalences of allergies and autoimmune diseases, suggesting that parasites may protect against immunopathological syndromes. Most helminth diseases are spectral in nature, with a large proportion of relatively asymptomatic cases and a subset of patients who develop severe pathologies. The maintenance of the asymptomatic state is now recognized as reflecting an immunoregulatory environment, which may be promoted by parasites, and involves multiple levels of host regulatory cells and cytokines; a breakdown of this regulation is observed in pathological disease. Currently, there is much interest in whether helminth-associated immune regulation may ameliorate allergy and autoimmunity, with investigations in both laboratory models and human trials. Understanding and exploiting the interactions between these parasites and the host regulatory network are therefore likely to highlight new strategies to control both infectious and immunological diseases. PMID- 23034322 TI - New approaches to sepsis: molecular diagnostics and biomarkers. AB - Sepsis is among the most common causes of death in hospitals. It arises from the host response to infection. Currently, diagnosis relies on nonspecific physiological criteria and culture-based pathogen detection. This results in diagnostic uncertainty, therapeutic delays, the mis- and overuse of antibiotics, and the failure to identify patients who might benefit from immunomodulatory therapies. There is a need for new sepsis biomarkers that can aid in therapeutic decision making and add information about screening, diagnosis, risk stratification, and monitoring of the response to therapy. The host response involves hundreds of mediators and single molecules, many of which have been proposed as biomarkers. It is, however, unlikely that one single biomarker is able to satisfy all the needs and expectations for sepsis research and management. Among biomarkers that are measurable by assays approved for clinical use, procalcitonin (PCT) has shown some usefulness as an infection marker and for antibiotic stewardship. Other possible new approaches consist of molecular strategies to improve pathogen detection and molecular diagnostics and prognostics based on transcriptomic, proteomic, or metabolic profiling. Novel approaches to sepsis promise to transform sepsis from a physiologic syndrome into a group of distinct biochemical disorders and help in the development of better diagnostic tools and effective adjunctive sepsis therapies. PMID- 23034323 TI - West Nile Virus: biology, transmission, and human infection. AB - West Nile Virus was introduced into the Western Hemisphere during the late summer of 1999 and has been causing significant and sometimes severe human diseases since that time. This article briefly touches upon the biology of the virus and provides a comprehensive review regarding recent discoveries about virus transmission, virus acquisition, and human infection and disease. PMID- 23034324 TI - Eosinophilic pneumonias. AB - This review starts with discussions of several infectious causes of eosinophilic pneumonia, which are almost exclusively parasitic in nature. Pulmonary infections due specifically to Ascaris, hookworms, Strongyloides, Paragonimus, filariasis, and Toxocara are considered in detail. The discussion then moves to noninfectious causes of eosinophilic pulmonary infiltration, including allergic sensitization to Aspergillus, acute and chronic eosinophilic pneumonias, Churg-Strauss syndrome, hypereosinophilic syndromes, and pulmonary eosinophilia due to exposure to specific medications or toxins. PMID- 23034328 TI - Altered endometrial immune gene expression in beef heifers with retarded embryos. AB - The aim of the present study was to compare endometrial gene expression profiles in a group of beef heifers yielding viable or retarded embryos on Day 7 after oestrus as a means of potentially explaining differences in embryo survival rates. Heifers were classified as either: (1) viable, when the embryo collected on Day 7 after oestrus was at the correct developmental stage (i.e. morula/early blastocyst); or (2) retarded, when the embryo was arrested at the 2-16-cell stage. The focus of the present study was on genes that were associated with either the pro- or anti-inflammatory immune response. Endometrial gene expression was determined using quantitative real-time polymerase chain reaction analysis. Expression of the beta-defensin (DEFB1), interferon (IFN)-alpha (IFNA), IFN-gamma (IFNG), interleukin (IL)-6 (IL6), IL-10 (IL10), forkhead box P3 (FOXP3) and natural cytotoxicity triggering receptor 1 (NCR1) genes was lower in endometria from viable than retarded heifers. Expression of the nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (NKFB1), transforming growth factor (TGF)-beta (TGFB), IFN-gamma-inducible protein 16 (IFI16) and IL-21 (IL21) genes was higher in viable than retarded heifers. We propose that small disturbances in the expression of immune genes in the endometrium on Day 7 after oestrus can have detrimental effects on embryo survival. PMID- 23034327 TI - Mixed-strain mycobacterium tuberculosis infections and the implications for tuberculosis treatment and control. AB - Numerous studies have reported that individuals can simultaneously harbor multiple distinct strains of Mycobacterium tuberculosis. To date, there has been limited discussion of the consequences for the individual or the epidemiological importance of mixed infections. Here, we review studies that documented mixed infections, highlight challenges associated with the detection of mixed infections, and discuss possible implications of mixed infections for the diagnosis and treatment of patients and for the community impact of tuberculosis control strategies. We conclude by highlighting questions that should be resolved in order to improve our understanding of the importance of mixed-strain M. tuberculosis infections. PMID- 23034325 TI - Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. AB - The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms. PMID- 23034326 TI - Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. AB - SUMMARY: The spread of Enterobacteriaceae, primarily Klebsiella pneumoniae, producing KPC, VIM, IMP, and NDM carbapenemases, is causing an unprecedented public health crisis. Carbapenemase-producing enterobacteria (CPE) infect mainly hospitalized patients but also have been spreading in long-term care facilities. Given their multidrug resistance, therapeutic options are limited and, as discussed here, should be reevaluated and optimized. Based on susceptibility data, colistin and tigecycline are commonly used to treat CPE infections. Nevertheless, a review of the literature revealed high failure rates in cases of monotherapy with these drugs, whilst monotherapy with either a carbapenem or an aminoglycoside appeared to be more effective. Combination therapies not including carbapenems were comparable to aminoglycoside and carbapenem monotherapies. Higher success rates have been achieved with carbapenem-containing combinations. Pharmacodynamic simulations and experimental infections indicate that modification of the current patterns of carbapenem use against CPE warrants further attention. Epidemiological data, though fragmentary in many countries, indicate CPE foci and transmission routes, to some extent, whilst also underlining the lack of international collaborative systems that could react promptly and effectively. Fortunately, there are sound studies showing successful containment of CPE by bundles of measures, among which the most important are active surveillance cultures, separation of carriers, and assignment of dedicated nursing staff. PMID- 23034329 TI - Early otic development depends on autophagy for apoptotic cell clearance and neural differentiation. AB - Autophagy is a highly regulated program of self-degradation of the cytosolic constituents that has key roles during early development and in adult cell growth and homeostasis. To investigate the role of autophagy in otic neurogenesis, we studied the expression of autophagy genes in early stages of chicken (Gallus gallus) inner ear development and the consequences of inhibiting the autophagic pathway in organotypic cultures of explanted chicken otic vesicles (OVs). Here we show the expression of autophagy-related genes (Atg) Beclin-1 (Atg6), Atg5 and LC3B (Atg8) in the otocyst and the presence of autophagic vesicles by using transmission electron microscopy in the otic neurogenic zone. The inhibition of the transcription of LC3B by using antisense morpholinos and of class III phosphatidylinositol 3-kinase with 3-methyladenine causes an aberrant morphology of the OV with accumulation of apoptotic cells. Moreover, inhibition of autophagy provokes the misregulation of the cell cycle in the otic epithelium, impaired neurogenesis and poor axonal outgrowth. Finally, our results indicate that autophagy provides the energy required for the clearing of neuroepithelial dying cells and suggest that it is required for the migration of otic neuronal precursors. Taken together, our results show for the first time that autophagy is an active and essential process during early inner ear development. PMID- 23034330 TI - Gamma-ray irradiation promotes premature meiosis of spontaneously differentiating testis-ova in the testis of p53-deficient medaka (Oryzias latipes). AB - In this study, the roles of p53 in impaired spermatogenic male germ cells of p53 deficient medaka were investigated by analyzing histological changes, and gene expressions of 42Sp50, Oct 4 and vitellogenin (VTG2) by RT-PCR or in situ hybridization in the testes. We found that a small number of oocyte-like cells (testis-ova) differentiated spontaneously in the cysts of type A and early type B spermatogonia in the p53-deficient testes, in contrast to the wild-type (wt) testes in which testis-ova were never found. Furthermore, ionizing radiation (IR) irradiation increased the number of testis-ova in p53-deficient testes, increased testis-ova size and proceeded up to the zygotene or pachytene stages of premature meiosis within 14 days after irradiation. However, 28 days after irradiation, almost all the testis-ova were eliminated presumably by p53-independent apoptosis, and spermatogenesis was restored completely. In the wt testis, IR never induced testis-ova differentiation. This is the first study to demonstrate the pivotal role of the p53 gene in the elimination of spontaneous testis-ova in testes, and that p53 is not indispensable for the restoration of spermatogenesis in the impaired testes in which cell cycle regulation is disturbed by IR irradiation. PMID- 23034331 TI - CXCR4 inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells in NOG mouse model. AB - The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates in pathogenesis is unclear. Here, we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4 (high) from CXCR4(neg/low) AML patients. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOD/Shi-scid/IL-2Rgamma(null) (NOG) leukemia initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to chemokine CXC motif ligand 12 (CXCL12). Functional analysis showed a greater mobilization of leukemic cells and LICs in response to drugs, suggesting that they target the interaction between leukemic cells and their supportive bone marrow microenvironment. In addition, increased apoptosis of leukemic cells in vitro and in vivo was observed. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs. PMID- 23034332 TI - Proliferation and tissue remodeling in cancer: the hallmarks revisited. AB - Although cancers are highly heterogeneous at the genomic level, they can manifest common patterns of gene expression. Here, we use gene expression signatures to interrogate two major processes in cancer, proliferation and tissue remodeling. We demonstrate that proliferation and remodeling signatures are partially independent and result in four distinctive cancer subtypes. Cancers with the proliferation signature are characterized by signatures of p53 and PTEN inactivation and concomitant Myc activation. In contrast, remodeling correlates with RAS, HIF-1alpha and NFkappaB activation. From the metabolic point of view, proliferation is associated with upregulation of glycolysis and serine/glycine metabolism, whereas remodeling is characterized by a downregulation of oxidative phosphorylation. Notably, the proliferation signature correlates with poor outcome in lung, prostate, breast and brain cancer, whereas remodeling increases mortality rates in colorectal and ovarian cancer. PMID- 23034333 TI - MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is a heterogeneous disease despite its seemingly uniform pathology. Deconvolution of The Cancer Genome Atlas's GBM gene expression data has unveiled the existence of distinct gene expression signature underlying discrete GBM subtypes. Recent conflicting findings proposed that microRNA (miRNA) 10b exclusively regulates glioma growth or invasion but not both. We showed that silencing of miRNA-10b by baculoviral decoy vectors in a glioma cell line resembling the mesenchymal subtype of GBM reduces its growth, invasion and angiogenesis while promoting apoptosis in vitro. In an orthotopic human glioma mouse model, inhibition of miRNA-10b diminishes the invasiveness, angiogenicity and growth of the mesenchymal subtype-like glioma cells in the brain and significantly prolonged survival of glioma-bearing mice. We demonstrated that the pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10 and NOTCH1. In particular, siRNA-mediated knockdown experiments identified TP53, PAX6, NOTCH1 and HOXD10 as invasion regulatory genes in our mesenchymal subtype-like glioma cells. By interrogating the REMBRANDT, we noted that dysregulation of many direct targets of miRNA-10b was associated with significantly poorer patient survival. Thus, our study uncovers a novel role for miRNA-10b in regulating angiogenesis and suggests that miRNA-10b may be a pleiotropic regulator of gliomagenesis. PMID- 23034335 TI - Vision therapy management for dissociated horizontal deviation. AB - PURPOSE: Dissociated horizontal deviation (DHD), a rare subtype of strabismus, is a change in horizontal eye alignment that does not obey Hering's law. The variation is unrelated to a change in accommodation and depends on which eye is fixating. Both esotropia (ET) and exotropia (XT) can manifest in the same patient with DHD. Surgery has been reported to manage DHD, but often a second or third surgery is necessary. We report two cases of DHD that were managed with vision therapy (VT). CASE REPORTS: Case one: A 9-year-old girl presented for eye examination with her parents noting an eye drifting out. Cover test showed a DHD that varied from 15Delta left ET to 15Delta alternating XT. A 40Delta XT manifested when she was inattentive. Antisuppression, vergence, accommodation, and oculomotility were addressed with VT. Upon completion of VT, binocular vision functions were normal except for appreciation of global stereopsis. No strabismus was observed during the examination. These findings were stable at a 7-month follow-up visit. Case two: A 40-year-old man presented for eye examination with the complaint of double vision and eye strain. Cover test revealed a DHD that varied from 5Delta ET to 15Delta XT, along with DVD. A 30 to 40Delta XT was observed during visual inattention. Antisuppression and vergence skills were addressed with VT. At the end of VT, most binocular vision functions were normal. No strabismus was observed on cover test. Follow-up examination 16 years later showed no strabismus by cover test, although XT manifested when he was inattentive. CONCLUSIONS: In two DHD cases, control of eye alignment improved with VT. To the best of our knowledge, these are the first case reports to describe management of DHD with VT. Eye care practitioners should be aware that a long period of VT may be necessary to successfully manage DHD. PMID- 23034334 TI - Remnant living cells that escape cell loss in late-stage tumors exhibit cancer stem cell-like characteristics. AB - A balance between cell proliferation and cell loss is essential for tumor progression. Although up to 90% of cells are lost in late-stage carcinomas, the progression and characteristics of remnant living cells in tumor mass are unclear. Here we used molecular imaging to track the progression of living cells in a syngeneic tumor model, and ex vivo investigated the properties of this population at late-stage tumor. The piggyBac transposon system was used to stably introduce the dual reporter genes, including monomeric red fluorescent protein (mRFP) and herpes simplex virus type-1 thymidine kinase (HSV1-tk) genes for fluorescence-based and radionuclide-based imaging of tumor growth in small animals, respectively. Iodine-123-labeled 5-iodo-2'-fluoro-1-beta-D arabinofuranosyluracil was used as a radiotracer for HSV1-tk gene expression in tumors. The fluorescence- and radionuclide-based imaging using the single-photon emission computed tomography/computed tomography revealed that the number of living cells reached the maximum at 1 week after implantation of 4T1 tumors, and gradually decreased and clustered near the side of the body until 4 weeks accompanied by enlargement of tumor mass. The remnant living cells at late-stage tumor were isolated and investigated ex vivo. The results showed that these living cells could form mammospheres and express cancer stem cell (CSC)-related biomarkers, including octamer-binding transcription factor 4, SRY (sex determining region Y)-box 2, and CD133 genes compared with those cultured in vitro. Furthermore, this HSV1-tk-expressing CSC-like population was sensitive to ganciclovir applied for the suicide therapy. Taken together, the current data suggested that cells escaping from cell loss in late-stage tumors exhibit CSC like characteristics, and HSV1-tk may be considered a theranostic agent for targeting this population in vivo. PMID- 23034336 TI - Visual performance of a multifocal toric soft contact lens. AB - PURPOSE: To evaluate the visual performance of the Proclear multifocal toric contact lens (CL; CooperVision, US) for both presbyopia and astigmatism correction. METHODS: In this crossover study design, 20 presbyopic subjects with astigmatism were fitted in a random order with either Proclear multifocal toric CL or Proclear toric single vision distance CL (DCL) combined with reading spectacles. After 1 month, high-contrast distance visual acuity, near high contrast visual acuity, distance contrast sensitivity (CS) under photopic and mesopic conditions without and with glare, near CS, defocus curve, and stereopsis were measured. Subjects were then refitted with the alternative correction, and the procedure was repeated. RESULTS: Repeated measures analysis of variance revealed differences in visual acuity and CS (p < 0.001) between groups. Mean binocular distance visual acuity and near visual acuity obtained with multifocal toric CL were -0.01 +/- 0.03 logMAR and -0.04 +/- 0.06 logMAR, respectively. The mean distance CS with the multifocal toric CL was within normal limits under photopic and mesopic conditions. Under photopic conditions, distant CS was better with distance CL than with multifocal toric CL only at 18 cycles/degree. Under mesopic conditions without and with glare, there were differences between both CLs in distant CS for all spatial frequencies. There were differences between the two CLs in near CS for all spatial frequencies. Mean values of stereopsis obtained with multifocal toric CLs and with the DCL combined with reading glasses were 62 +/- 12 sec of arc and 59 +/- 12 sec of arc, respectively (p = 0.06). Near range of clear vision with the multifocal toric CLs was 1.55 +/- 0.33D. CONCLUSIONS: The results of this study suggest that the multifocal toric CL studied is a good option to compensate both presbyopia and astigmatism, providing an optimal distance and near visual quality without compromising the stereopsis. PMID- 23034337 TI - Prolactinomas and the eye: a clinical case and review. AB - PURPOSE: Elevated prolactin levels may have several etiologies, one of which is a prolactinoma. Prolactinomas, the most prevalent pituitary tumors, may be more common than once described. These tumors can result in ocular complications such as vision loss and visual field defects. Prolactinomas are easily treated but need to be identified early in order to prevent more serious systemic complications. CASE REPORT: A 24-year-old Pacific Islander male presented with sudden blurred vision and an associated visual field defect in the right eye for 4 to 6 months. After performing a magnetic resonance imaging and consultation with an endocrinologist, the patient was diagnosed with a prolactinoma. The patient was treated and demonstrated a complete recovery of visual acuity and visual field defect. CONCLUSIONS: Prolactinomas are a common pituitary tumor characterized by an increase in prolactin levels. This review describes how prolactinomas are classified, their etiology, subsequent complications, and treatments. PMID- 23034338 TI - Smoking and age-related macular degeneration: biochemical mechanisms and patient support. AB - A small percentage of the population associates smoking with ocular disease. Most optometrists do not stress the importance of smoking cessation to their patients, and the centrality of smoking regarding the risk for ocular disease is not emphasized in optometric education. Age-related macular degeneration has strong epidemiological associations with smoking, and so serves as an appropriate model for the adverse effects of cigarette smoke on the eye. This article aims to provide basic scientific information to optometrists and optometry students so that they can better understand the pathogenesis of age-related macular degeneration and provide education and support to their patients wishing to stop smoking. PMID- 23034339 TI - Using optical coherence tomography to assess corneoscleral morphology after soft contact lens wear. AB - PURPOSE: To evaluate the use of optical coherence tomography (OCT) for assessing the effect of different soft contact lenses on corneoscleral morphology. METHODS: Ten subjects had anterior segment OCT B-scans taken in the morning and again after 6 h of soft contact lens wear. For each subject, three different contact lenses were used in the right eye on non-consecutive days, including a hydrogel sphere, a silicone hydrogel sphere, and a silicone hydrogel toric. After image registration and layer segmentation, analyses were performed of the first hyper reflective layer (HRL), the epithelial basement membrane (EBL), and the epithelial thickness (HRL to EBL). A root mean square difference (RMSD) of the layer profiles and the thickness change between the morning and afternoon measurements were used to assess the effect of the contact lens on the corneoscleral morphology. RESULTS: The soft contact lenses had a statistically significant effect on the morphology of the anterior segment layers (p < 0.001). The average amounts of change for the three lenses (average RMSD values) for the corneal region were lower (3.93 +/- 1.95 MUm for the HRL and 4.02 +/- 2.14 MUm for the EBL) than those measured in the limbal/scleral region (11.24 +/- 6.21 MUm for the HRL and 12.61 +/- 6.42 MUm for the EBL). Similarly, averaged across the three lenses, the RMSD in epithelial thickness was lower in the cornea (2.84 +/- 0.84 MUm) than the limbal/scleral (5.47 +/- 1.71 MUm) region. Post hoc analysis showed that ocular surface changes were significantly smaller with the silicone hydrogel sphere lens than both the silicone hydrogel toric (p < 0.005) and hydrogel sphere (p < 0.02) for the combined HRL and EBL data. CONCLUSIONS: In this preliminary study, we have shown that soft contact lenses can produce small but significant changes in the morphology of the limbal/scleral region and that OCT technology is useful in assessing these changes. The clinical significance of these changes is yet to be determined. PMID- 23034340 TI - Perceived stress and ADHD symptoms in adults. AB - OBJECTIVE: Given that ADHD has been linked to dysfunction across development and in many life domains, it is likely that individuals experiencing these symptoms are at increased risk for experiencing stress. The current study examines the association between ADHD and other psychiatric symptoms and perceived stress in a community sample of adults. METHOD: Perceived stress data collected from 983 participants (M(age) = 45.6 years) were analyzed primarily via hierarchical multiple regression using ADHD symptom clusters, demographic variables, and anxiety and depression scale variables as predictors. RESULTS AND CONCLUSION: ADHD symptoms positively associated with perceived stress. Inattention and sluggish cognitive tempo (SCT), as opposed to hyperactivity-impulsivity and newly proposed executive dysfunction symptoms, were the most consistent predictors. These findings reinforce that the experience of ADHD symptoms in adulthood is associated with stress and suggest that SCT could play an important role in assessing risk for negative adult outcomes. PMID- 23034341 TI - Improving awareness, identification, and management of meibomian gland dysfunction. AB - Ocular surface disorder--and dry eye, in particular--is a leading reason for visits to eye care professionals. It has been generally accepted that meibomian gland dysfunction (MGD) is a leading cause of evaporative dry eye, as well as being associated with aqueous-deficient dry eye. Yet, researchers and clinicians have lacked a global consensus on the definition of MGD, its epidemiology, pathophysiology, and management. Various systemic diseases and medications have been associated with the progression of both dry eye and MGD, as have several ocular disorders beyond those directly affecting the surface. It is in the best interest of patients for clinicians to be able to better identify and diagnose MGD, differentiating it from other ocular surface disorders, and to recognize the effects of MGD on the ocular surface, and thus initiate appropriate therapy. This CME activity provides expert insight into the Tear Film and Ocular Surface Society's International Workshop on MGD consensus report, offering practical application of its findings to better manage MGD patient care, particularly for those patients facing or undergoing ocular surgery. PMID- 23034342 TI - The x-ray magnetic circular dichroism spin sum rule for 3d4 systems: Mn3+ ions in colossal magnetoresistance manganites. AB - The colossal magnetoresistance manganites La(0.87+/-0.02)Sr(0.12+/ 0.02)MnO(3+delta), La(0.78+/-0.02)Sr(0.17+/-0.02)MnO(3+delta), and La(0.66+/ 0.02)Sr(0.36+/-0.02)MnO(3+delta) (delta close to 0) were investigated by using soft x-ray magnetic circular dichroism (XMCD) and magnetometry. Very good agreement between the values for the average Mn magnetic moments determined with these two methods was achieved by correcting the XMCD spin sum rule results by means of charge transfer multiplet calculations, which also suggest a charge transfer of ~50% for Mn(4+) and approximately equal to 30% for Mn(3+). The magnetic moment was found to be localized at the Mn ions for x = 0.17 and 0.36 at 80 K and for x = 0.12 in the temperature range from 80 to 300 K. We discuss our findings in the light of previously published data, confirming the validity of our approach. PMID- 23034343 TI - Psychiatrists and the pharmaceutical industry: a current topic. PMID- 23034344 TI - Adaptation and validation of the Spanish version of the Strauss and Carpenter Prognostic Scale for Schizophrenia. AB - INTRODUCTION: The aim of this study was to validate the Spanish version of the Strauss and Carpenter Prognostic Scale for Schizophrenia (Strauss and Carpenter, 1977). METHOD: We performed a multicenter, longitudinal, descriptive study. Forward and backtranslation of the original scale was performed. The sample was composed of persons diagnosed with schizophrenia aged between 18 and 65 years. We calculated interrater reliability, construct validity according to the Global Assessment Scale (GAS), Satisfaction with Life Domains Scale (SLDS), the Global Clinical Impression-Schizophrenia (GCI) scale, The World Health. Organization Short Disability Assessment Schedule (WHO-DAS) and the Positive and Negative Syndrome Scale (PANSS), and predictive validity at the 1-year follow-up using three criterion measures of the GCI, WHO-DAS and GAS scales. RESULTS: The internal consistency coefficient (Cronbach's alpha) was 0.70. The intraclass correlation coefficient ranged from 0.54 to 0.99, except for item 5 (resources for the current treatment), which was -0.13. The correlation between the distinct scales (measuring construct validity) was significant, with a p-value of < 0.01, except for the SLDS, which showed a higher p-value (p<0.05). The Strauss Carpenter score correlated with all three scores at 1 year (GCI, GAS and WHO-DAS) with an alpha of less than 0.01, showing good predictive validity. CONCLUSIONS: The Spanish adaptation of the Strauss and Carpenter prognostic scale is reliable and valid and allows a more severe disease course to be predicted. PMID- 23034345 TI - Validity of the cognitive factor of the Positive and Negative Syndrome Scale as a measure of cognitive functioning in schizophrenia. AB - INTRODUCTION: The Positive and Negative Syndrome Scale (PANSS) is a widely used instrument for measuring symptomatology in patients with schizophrenia. Numerous studies have analyzed the factorial structure of this scale and have suggested a fivefactor model, namely: negative, positive, excited, anxiety/depression, and disorganized (or cognitive). The latter factor has been related to neuropsychological tests, with a view to analyzing its utility as a measure of cognitive functioning in schizophrenia, but data are inconclusive. The aim of the present study was to analyze the factorial structure of the PANSS and to assess the relationships between factors and neurocognitive tests. MATERIAL AND METHODS: The sample comprised 235 outpatients diagnosed with schizophrenia. To investigate the factorial structure of the PANSS, a principal component factor analysis was performed. Cognitive functioning was measured with a shortened version of the Barcelona Test. RESULTS: Unlike previous studies, our study obtained a six-factor model, with disorganized and cognitive symptoms separated in two different factors. The cognitive factor obtained in this study was related to all subtests of the Barcelona Test. The disorganized factor, however, was only related to two of these subtests. CONCLUSIONS: Our results support the use of a six-factor model and suggest that the cognitive factor could be a valid measure of cognitive deficits in schizophrenia, although the use of a standard neuropsychological battery is advisable. PMID- 23034346 TI - Psychometric performance of the Oviedo Sleep Questionnaire in patients with severe mental disorder. AB - INTRODUCTION: The prevalence of sleep disturbances among patients with severe mental disorder ranges from 30 to 80%. Since the impact of these disturbances on patients' lives is substantial, there is a need for their evaluation and management. The aim of this study was to examine the reliability and validity of the Oviedo Sleep Questionnaire (OSQ) in patients with severe mental disorder. MATERIAL AND METHODS: We performed an observational, prospective (3-month), multicenter study. A total of 259 individuals (184 patients with severe mental disorder and 75 controls) were included. EVALUATION: the OSQ, the sleep items of the Bech- Rafaelsen's Scales for Depression (MES item 3) and Mania (MAS item 5), and the Clinical Global Impression Scales for Severity of Mental Disorder (CGI SMD) and Sleep Disorder (CGI-SSD). RESULTS: a) Factorial structure: two factors accounted for 57.65% of the variance; factor 1 (insomnia) accounted for 44.65% and factor 2 (hypersomnia) for 13%; b) internal consistency: total OSQ=0.90, insomnia scale=0.91, hypersomnia scale=0.88; c) testretest reliability=0.87; d) convergent validity: Pearson's correlation coefficients were 0.632 with item 3 of the MES, 0.619 with item 5 of the MAS, and 0.630 with the CGI-SS (p<0.001); e) discriminant validity: the OSQ was able to differentiate between patients and controls (p=0.018), and among distinct degrees of mental disorder severity (CGISMD) (p<0.001) and sleep disorder severity (CGI-SSD) (p<0.001); f) responsiveness: the OSQ, like the CGI-SSD (p=0.004), identified a significant decrease in the insomnia severity score after 3 months (p=0.005). CONCLUSIONS: The OSQ is a valid and reliable method for measuring the sleep/wake cycle in patients with severe mental disorder. PMID- 23034347 TI - Comorbidity in pathological gambling: clinical variables, personality and treatment response. AB - INTRODUCTION: Pathological gambling shows high comorbidity rates, especially with substance use disorders, although affective, anxiety and other impulse control disorders, as well as personality disorders, are also frequently associated. OBJECTIVES: To explore comorbidity in pathological gambling with other mental disorders in a consecutive sample of patients attending a unit specialized in pathological gambling, and specifically the relationship between substance related disorders, on the one hand, and personality and clinical variables in pathological gamblers, on the other. METHOD: A total of 498 patients with a DSM IV-TR diagnosis of Pathological Gambling (11.8% women) were assessed with a semi structured clinical interview and several clinical and personality scales. RESULTS: Higher comorbidity with affective disorders was found in women (30.5%), while higher comorbidity with substance-related disorders was found in men (11.2%). A positive association was also detected between a history of psychiatric disorders and current comorbidity with substance-use disorders, as well as between alcohol abuse and age. Finally, some personality traits such as low reward dependence (OR=0.964) and high impulsivity (OR=1.02) predicted other substance abuse (not alcohol). High selftranscendence scores predicted both alcohol and other substance abuse (OR=1.06). CONCLUSIONS: Our results suggest a high prevalence of comorbid disorders in pathologic gambling, mainly with affective and substance-related disorders. The results of the present study, conducted in a broad sample of consecutively admitted pathologic gamblers, may contribute to understanding of this complex disorder and treatment improvement. PMID- 23034348 TI - Etiology of pedophilia from a neurodevelopmental perspective: markers and brain alterations. AB - DEVELOPMENT: Distinct signs have been associated with a wide range of neurodevelopmental disorders and warning signs of neural developmental problems have also been observed in pedophiles. Continuing this line of research, several neuroimaging studies have found neural alterations in this disorder. CONCLUSIONS: Pedophilia has been related to distinct indicators of neurodevelopmental alterations such as low intelligence quotient, left-handedness and smaller stature, among others. In addition, pedophiles show several neural alterations and a predominantly subcortical pattern of cerebral activation to sexual stimuli. The results of these studies suggest that the origin of pedophilia may partly lie in brain alterations due to problems during neural development, although these alterations do not absolve these persons of responsibility for their actions. PMID- 23034349 TI - Ribozyme-based insulator parts buffer synthetic circuits from genetic context. AB - Synthetic genetic programs are built from circuits that integrate sensors and implement temporal control of gene expression. Transcriptional circuits are layered by using promoters to carry the signal between circuits. In other words, the output promoter of one circuit serves as the input promoter to the next. Thus, connecting circuits requires physically connecting a promoter to the next circuit. We show that the sequence at the junction between the input promoter and circuit can affect the input-output response (transfer function) of the circuit. A library of putative sequences that might reduce (or buffer) such context effects, which we refer to as 'insulator parts', is screened in Escherichia coli. We find that ribozymes that cleave the 5' untranslated region (5'-UTR) of the mRNA are effective insulators. They generate quantitatively identical transfer functions, irrespective of the identity of the input promoter. When these insulators are used to join synthetic gene circuits, the behavior of layered circuits can be predicted using a mathematical model. The inclusion of insulators will be critical in reliably permuting circuits to build different programs. PMID- 23034350 TI - A mechanistic model for bromodeoxyuridine dilution naturally explains labelling data of self-renewing T cell populations. AB - Bromodeoxyuridine (BrdU) is widely used in immunology to detect cell division, and several mathematical models have been proposed to estimate proliferation and death rates of lymphocytes from BrdU labelling and de-labelling curves. One problem in interpreting BrdU data is explaining the de-labelling curves. Because shortly after label withdrawal, BrdU+ cells are expected to divide into BrdU+ daughter cells, one would expect a flat down-slope. As for many cell types, the fraction of BrdU+ cells decreases during de-labelling, previous mathematical models had to make debatable assumptions to be able to account for the data. We develop a mechanistic model tracking the number of divisions that each cell has undergone in the presence and absence of BrdU, and allow cells to accumulate and dilute their BrdU content. From the same mechanistic model, one can naturally derive expressions for the mean BrdU content (MBC) of all cells, or the MBC of the BrdU+ subset, which is related to the mean fluorescence intensity of BrdU that can be measured in experiments. The model is extended to include subpopulations with different rates of division and death (i.e. kinetic heterogeneity). We fit the extended model to previously published BrdU data from memory T lymphocytes in simian immunodeficiency virus-infected and uninfected macaques, and find that the model describes the data with at least the same quality as previous models. Because the same model predicts a modest decline in the MBC of BrdU+ cells, which is consistent with experimental observations, BrdU dilution seems a natural explanation for the observed down-slopes in self renewing populations. PMID- 23034351 TI - Autonomous Boolean modelling of developmental gene regulatory networks. AB - During early embryonic development, a network of regulatory interactions among genes dynamically determines a pattern of differentiated tissues. We show that important timing information associated with the interactions can be faithfully represented in autonomous Boolean models in which binary variables representing expression levels are updated in continuous time, and that such models can provide a direct insight into features that are difficult to extract from ordinary differential equation (ODE) models. As an application, we model the experimentally well-studied network controlling fly body segmentation. The Boolean model successfully generates the patterns formed in normal and genetically perturbed fly embryos, permits the derivation of constraints on the time delay parameters, clarifies the logic associated with different ODE parameter sets and provides a platform for studying connectivity and robustness in parameter space. By elucidating the role of regulatory time delays in pattern formation, the results suggest new types of experimental measurements in early embryonic development. PMID- 23034352 TI - Insect wet steps: loss of fluid from insect feet adhering to a substrate. AB - Reliable attachment ability of insect adhesive pads is proposed to be due to pad secretion. It has been shown that surface roughness strongly reduces adhesion forces of insect pads. This effect has been explained by decreased contact area and rapid fluid absorption from the pad surface by rough surfaces. However, it remains unclear how the fluid flows on rough substrates having different roughness parameters and surface energy. In this paper, we numerically studied the fluid flow on rough substrates during contact formation. The results demonstrate that an increase in the density of the substrate structures leads to an increase in fluid loss from the pad: substrates with a fine roughness absorb pad fluid faster. Decreased affinity of the solid substrate to the fluid has a more remarkable effect on the fluid loss and leads to a decrease in the fluid loss. With an increase in the aspect ratio of the substrate irregularities (porosity), the fluid loss is decreased. The numerical results obtained agree well with previous observations on insects and experimental results on nanoporous substrata. The significance of the obtained results for understanding biological wet adhesives is discussed. PMID- 23034353 TI - Inferring population-level contact heterogeneity from common epidemic data. AB - Models of infectious disease spread that incorporate contact heterogeneity through contact networks are an important tool for epidemiologists studying disease dynamics and assessing intervention strategies. One of the challenges of contact network epidemiology has been the difficulty of collecting individual and population-level data needed to develop an accurate representation of the underlying host population's contact structure. In this study, we evaluate the utility of common epidemiological measures (R0, epidemic peak size, duration and final size) for inferring the degree of heterogeneity in a population's unobserved contact structure through a Bayesian approach. We test the method using ground truth data and find that some of these epidemiological metrics are effective at classifying contact heterogeneity. The classification is also consistent across pathogen transmission probabilities, and so can be applied even when this characteristic is unknown. In particular, the reproductive number, R0, turns out to be a poor classifier of the degree heterogeneity, while, unexpectedly, final epidemic size is a powerful predictor of network structure across the range of heterogeneity. We also evaluate our framework on empirical epidemiological data from past and recent outbreaks to demonstrate its application in practice and to gather insights about the relevance of particular contact structures for both specific systems and general classes of infectious disease. We thus introduce a simple approach that can shed light on the unobserved connectivity of a host population given epidemic data. Our study has the potential to inform future data-collection efforts and study design by driving our understanding of germane epidemic measures, and highlights a general inferential approach to learning about host contact structure in contemporary or historic populations of humans and animals. PMID- 23034354 TI - Modelling mechanical characteristics of microbial biofilms by network theory. AB - In this contribution, we present a constitutive model to describe the mechanical behaviour of microbial biofilms based on classical approaches in the continuum theory of polymer networks. Although the model is particularly developed for the well-studied biofilms formed by mucoid Pseudomonas aeruginosa strains, it could easily be adapted to other biofilms. The basic assumption behind the model is that the network of extracellular polymeric substances can be described as a superposition of worm-like chain networks, each connected by transient junctions of a certain lifetime. Several models that were applied to biofilms previously are included in the presented approach as special cases, and for small shear strains, the governing equations are those of four parallel Maxwell elements. Rheological data given in the literature are very adequately captured by the proposed model, and the simulated response for a series of compression tests at large strains is in good qualitative agreement with reported experimental behavior. PMID- 23034355 TI - Three-dimensional tracking and behaviour monitoring of multiple fruit flies. AB - The increasing interest in the investigation of social behaviours of a group of animals has heightened the need for developing tools that provide robust quantitative data. Drosophila melanogaster has emerged as an attractive model for behavioural analysis; however, there are still limited ways to monitor fly behaviour in a quantitative manner. To study social behaviour of a group of flies, acquiring the position of each individual over time is crucial. There are several studies that have tried to solve this problem and make this data acquisition automated. However, none of these studies has addressed the problem of keeping track of flies for a long period of time in three-dimensional space. Recently, we have developed an approach that enables us to detect and keep track of multiple flies in a three-dimensional arena for a long period of time, using multiple synchronized and calibrated cameras. After detecting flies in each view, correspondence between views is established using a novel approach we call the 'sequential Hungarian algorithm'. Subsequently, the three-dimensional positions of flies in space are reconstructed. We use the Hungarian algorithm and Kalman filter together for data association and tracking. We evaluated rigorously the system's performance for tracking and behaviour detection in multiple experiments, using from one to seven flies. Overall, this system presents a powerful new method for studying complex social interactions in a three dimensional environment. PMID- 23034356 TI - Behavioural mapping of a pelagic seabird: combining multiple sensors and a hidden Markov model reveals the distribution of at-sea behaviour. AB - The use of miniature data loggers is rapidly increasing our understanding of the movements and habitat preferences of pelagic seabirds. However, objectively interpreting behavioural information from the large volumes of highly detailed data collected by such devices can be challenging. We combined three biologging technologies-global positioning system (GPS), saltwater immersion and time-depth recorders-to build a detailed picture of the at-sea behaviour of the Manx shearwater (Puffinus puffinus) during the breeding season. We used a hidden Markov model to explore discrete states within the combined GPS and immersion data, and found that behaviour could be organized into three principal activities representing (i) sustained direct flight, (ii) sitting on the sea surface, and (iii) foraging, comprising tortuous flight interspersed with periods of immersion. The additional logger data verified that the foraging activity corresponded well to the occurrence of diving. Applying this approach to a large tracking dataset revealed that birds from two different colonies foraged in local waters that were exclusive, but overlapped in one key area: the Irish Sea Front (ISF). We show that the allocation of time to each activity differed between colonies, with birds breeding furthest from the ISF spending the greatest proportion of time engaged in direct flight and the smallest proportion of time engaged in foraging activity. This type of analysis has considerable potential for application in future biologging studies and in other taxa. PMID- 23034357 TI - Evaluation of accuracy and reliability of the plaque reduction neutralization test (micro-PRNT) in detection of yellow fever virus antibodies. AB - Yellow fever is a disease caused by the prototype virus of the genus Flavivirus and remains endemic in tropical forest regions from Africa and South America, despite the availability of effective vaccines. These are capable of inducing a rapid specific immune response, with the formation of neutralizing antibodies that appear early, are protective and long lasting. The Plaque Reduction Neutralization Test is considered the most sensitive and specific test for quantification of neutralizing antibodies, and the reference method for assessing the protective immune response after vaccination. This study evaluated the reliability (repeatability and reproducibility) and accuracy (sensitivity, specificity and overall accuracy) of micro-PRNT50 and compared its performance with the micro-PRNT90. Although the micro-PRNT50 has showed satisfactory levels of reliability (ICCs ranged from 0.62 to 0.NorNormas e Manuais Tecnicosas e Manuais Tecnicos6 for repeatability and 0.72 for reproducibility) and accuracy (sensitivity of 91.1%, specificity of 72.9% and overall accuracy of 78%), the micro-PRNT90 showed higher performance, with ICCs for repeatability ranged from 0.78 to 0.79 and 0.81 for reproducibility, sensitivity of 100%, specificity of 94.7% and overall accuracy of 95%. Modifications in the test methodology and changes in the classification criteria in the readings of the results obtained will be important to improve the accuracy of micro-PRNT. PMID- 23034358 TI - Facile functionalization of HTC-derived carbon microspheres. AB - Surfaces of HTC-derived carbons were functionalized using dienophiles such as maleimide (MI), tetracyanoethylene (TCNE), and 4,5-dicyano-1,3-dithiol-2-one (DCDTO). DCDTO-functionalized carbons were then hydrolyzed to yield thiol functionalized carbons, which were used to perform conjugate addition on the carbon surface. PMID- 23034362 TI - Activity of pectoral fin motoneurons during two swimming gaits in the larval zebrafish (Danio rerio) and localization of upstream circuit elements. AB - In many animals, limb movements transition between gait patterns with increasing locomotor speed. While for tetrapod systems several well-developed models in diverse taxa (e.g., cat, mouse, salamander, turtle) have been used to study motor control of limbs and limb gaits, virtually nothing is known from fish species, including zebrafish, a well-studied model for axial motor control. Like tetrapods, fish have limb gait transitions, and the advantages of the zebrafish system make it a powerful complement to tetrapod models. Here we describe pectoral fin motoneuron activity in a fictive preparation with which we are able to elicit two locomotor gaits seen in behaving larval zebrafish: rhythmic slow axial and pectoral fin swimming and faster axis-only swimming. We found that at low swim frequencies (17-33 Hz), fin motoneurons fired spikes rhythmically and in coordination with axial motoneuron activity. Abductor motoneurons spiked out of phase with adductor motoneurons, with no significant coactivation. At higher frequencies, fin abductor motoneurons were generally nonspiking, whereas fin adductor motoneurons fired spikes reliably and nonrhythmically, suggesting that the gait transition from rhythmic fin beats to axis-only swimming is actively controlled. Using brain and spinal cord transections to localize underlying circuit components, we demonstrate that a limited region of caudal hindbrain and rostral spinal cord in the area of the fin motor pool is necessary to drive a limb rhythm while the full hindbrain, but not more rostral brain regions, is necessary to elicit the faster axis-only, fin-tucked swimming gait. PMID- 23034363 TI - High-performance execution of psychophysical tasks with complex visual stimuli in MATLAB. AB - Behavioral, psychological, and physiological experiments often require the ability to present sensory stimuli, monitor and record subjects' responses, interface with a wide range of devices, and precisely control the timing of events within a behavioral task. Here, we describe our recent progress developing an accessible and full-featured software system for controlling such studies using the MATLAB environment. Compared with earlier reports on this software, key new features have been implemented to allow the presentation of more complex visual stimuli, increase temporal precision, and enhance user interaction. These features greatly improve the performance of the system and broaden its applicability to a wider range of possible experiments. This report describes these new features and improvements, current limitations, and quantifies the performance of the system in a real-world experimental setting. PMID- 23034364 TI - Theories of pain: from specificity to gate control. AB - Several theoretical frameworks have been proposed to explain the physiological basis of pain, although none yet completely accounts for all aspects of pain perception. Here, we provide a historical overview of the major contributions, ideas, and competing theories of pain from ancient civilizations to Melzack and Wall's Gate Control Theory of Pain. PMID- 23034366 TI - Review of health and health service improvements in Nepal. AB - Nepal has made great progress regarding maternal and childhood mortality over the past two decades. A visionary leadership, coupled with the implementation of targeted interventions and programmes have resulted in improved MNCH indicators and marked decline in mortality. Maternal deaths have dropped by almost half from 539 per 100,000 live births in 1996 to 281 in 2006. Although neonatal mortality rates have stagnated in recent years, the overall childhood mortality has improved. This article tracks changes made in key indicators (mortality, fertility and service indicators including immunisation, family planning, maternal, neonatal and child over time and provides an overview of successful programmes that have led to this accomplishment. PMID- 23034365 TI - Changes in corticospinal excitability during reach adaptation in force fields. AB - Both abrupt and gradually imposed perturbations produce adaptive changes in motor output, but the neural basis of adaptation may be distinct. Here, we measured the state of the primary motor cortex (M1) and the corticospinal network during adaptation by measuring motor-evoked potentials (MEPs) before reach onset using transcranial magnetic stimulation of M1. Subjects reached in a force field in a schedule in which the field was introduced either abruptly or gradually over many trials. In both groups, by end of the training, muscles that countered the perturbation in a given direction increased their activity during the reach (labeled as the on direction for each muscle). In the abrupt group, in the period before the reach toward the on direction, MEPs in these muscles also increased, suggesting a direction-specific increase in the excitability of the corticospinal network. However, in the gradual group, these MEP changes were missing. After training, there was a period of washout. The MEPs did not return to baseline. Rather, in the abrupt group, off direction MEPs increased to match on direction MEPs. Therefore, we observed changes in corticospinal excitability in the abrupt but not gradual condition. Abrupt training includes the repetition of motor commands, and repetition may be the key factor that produces this plasticity. Furthermore, washout did not return MEPs to baseline, suggesting that washout engaged a new network that masked but did not erase the effects of previous adaptation. Abrupt but not gradual training appears to induce changes in M1 and/or corticospinal networks. PMID- 23034367 TI - Early initiation of community-based programmes in Nepal: a historic reflection. AB - Community-based programmes have long been an integral part of Nepal's health sector strategy and has contributed to the progress seen in maternal and child health. This paper reviews three early community-based programmes - the acute respiratory infection programme and its evolution to the fully scaled-up community-based integrated management of childhood illness programme, the national vitamin A programme and the female community health volunteer programme and how the Government of Nepal rapidly accepted them to address pressing maternal and child health issues in an evidence-informed manner, moving rapidly from research to feasibility studies, to implementation and scale-up. PMID- 23034368 TI - Exploration and innovation in addressing maternal, infant and neonatal mortality. AB - The Government of Nepal has been remarkably progressive in introducing innovative community-based maternal newborn and child health interventions in an effort to address the major causes of maternal and child mortality in the country. This article describes the introduction of innovative interventions, including a review of the landmark research that precipitated the discussion and provided evidence of practical feasibility, the acceptance of the intervention concept and validity, the approval process and the introduction and results from the pilot interventions. These interventions, which include the use of misoprostol to prevent post partum haemorrhage during homebirths, Morang Innovative Neonatal Intervention, gentamicin in Uniject and for the management of neonatal sepsis and newborn vitamin A supplementation, are in various stages and demonstrate the responsiveness of the Government to new approaches that address the major causes of maternal and child mortality. PMID- 23034369 TI - Developing, piloting and scaling-up of Nepal's neonatal care program. AB - The Community-based Newborn Care Package is a set of neonatal care interventions to be delivered through the existing government system of facility-based health workers and community based volunteers in Nepal. The package was developed by the government of Nepal in 2007 based on the evidence from Nepal and neighboring countries and designed to be implemented as a comprehensive package to improve newborn survival. This paper reviews the process, progress, and lessons learned from the program design, early-implementation and monitoring and provides future directives to improve upon this integrated package that uses a continuum of care approach from the pre-pregnancy to neonatal periods by involving the communities, health workers and the private sector. PMID- 23034370 TI - Strengthening national health systems for improving efficiency of health service delivery in Nepal. AB - The success of Nepal's community-based health programmes in promoting maternal and child health has been achieved due to an overall improvement in service delivery facilities and health support systems. This article assesses the progress made by the Government of Nepal in improving health service delivery by introducing three key components: an improved health logistics management, facility-based maternal and neonatal health services, and decentralized health facility management. PMID- 23034371 TI - Emerging challenges in family planning programme in Nepal. AB - Family planning is a priority program of the Government of Nepal. Despite political instability in the last two decades, Nepal has achieved remarkable progress in the overall status of reproductive health, including family planning. Married women of reproductive age have been increasingly using contraceptive from 1980s to 2006. However, Nepal Demographic Health Survey 2011 has shown unexpected results on contraceptive prevalence rate. There had been a notable decline in the prevalence rate between 2006 and 2011, creating concerns among various stakeholders working in family planning programs. This paper analyzes this situation and identifies possible reasons for the stagnated contraceptive prevalence rate in Nepal. High proportion of spousal separation, an increased use of traditional methods, abortion, emergency contraception, and a lack of innovative approaches to cater services to difficult-to-reach or special sub groups are possible reasons. To improve the contraceptive prevalence, the family planning program should be implemented more strategically. Further data analysis, initiation of best practices to fulfill family planning needs of special groups, functional integration of family planning services into general health services, effective counseling and behavior change communication to prevent unwanted pregnancies, and increased access to modern family planning methods could be the stepping stones to improve contraceptive prevalence rate and the overall FP program in Nepal. PMID- 23034372 TI - Magnesium sulphate in management of severe pre-eclampsia and eclampsia. AB - BACKGROUND: Pre-eclampsia and eclampsia (PE/E) are the second leading cause of maternal mortality in Nepal accounting for 21% of all maternal deaths and 30% of all facility based maternal deaths. For treatment of severe pre-eclampsia and eclampsia (SPE/E), WHO has identified magnesium sulphate (MgSO4) as the most effective and low cost medication. The objective of the study was to explore current situation of SPE/E management using MgSO4 in 10 health facilities of Mid Western Development Region. METHODS: Descriptive and single group pre-test, post test study design was used for the study. Data were collected by reviewing records, taking interviews and through observation. Knowledge and skills of service provider was assessed and scored (0-100%) before and after the educational intervention. RESULTS: One year records indicate that 0.5% SPE/E cases were found in Dang Sub Regional Hospital and Pyuthan District Hospital; 0.4% in Bheri Zonal Hospital; 0.9% in Mehelkuna PHCC and 0.5% in Rajapur PHCC. In most of the hospitals, these cases were managed with MgSO4. During pre-testing none of the health facility was able to get standard score (80%) but in post test, 50% health facilities were able to get 80% or higher score. CONCLUSIONS: Establishing national standard and providing one-time training is not sufficient, it requires refresher onsite training for propermanagement of SPE/E on time to improve maternal and neonatal health. PMID- 23034373 TI - An assessment of the safe delivery incentive program at a tertiary level hospital in Nepal. AB - BACKGROUND: Maternity incentive program of Nepal known as Safe Delivery Incentive Program (SDIP) was introduced nationwide in 2005 with the intention of increasing utilization of professional care at childbirth. The program provided both childbirth service as well as 'cash' to women giving birth in a health facility in addition to incentives to health provider for each delivery attended, either at home or the facility. Due to a lack of uniformity in its implementation and administrative delays, the program was reformed and even extended to many not-for profit health institutions in early 2007, and implemented as a 'Safer Mother Program' popularly known as "Aama-Suraksha-Karyakram" since January 2009. METHODS: This is a system research with observational and analytical components. Plausibility design is selected to evaluate the performance-based funding (PBF) as a system level intervention of maternity care using two instruments: Pay-For Performance and Conditional-Cash-Transfer. It uses interrupted time-series to control for the natural trend. Research tools used are interviews, the focus group discussions and literature review. Numerical data are presented in simple graphs. While online random number generator was used partly, the purposive sampling was used for qualitative data. RESULTS: There is a gross discrepancy in non-targeted service delivery at the tertiary level health facility. Overflooding of maternity cases has hampered gynecological admission and surgical management delaying subspecialty care and junior physicians' training. With the same number and quality of physical facility and human resource, the additional program has put more strains to service providers and administrators. CONCLUSIONS: There should be adequate planning and preparation at all levels of health facilities; implementing a new program should not adversely affect another existing service delivery system. For the optional implementation, hospital organogram should be revised; and physical facilities and the low-risk birthing-centers with referral linkages should be expanded. PMID- 23034374 TI - Environmental burden of diarrhoeal diseases due to unsafe water supply and poor sanitation coverage in Nepal. AB - BACKGROUND: Unsafe water and poor sanitation are major contributing factors of diarrhoea. Most of the water supply systems in urban and rural area of Nepal do not have basic water treatment facilities. This has resulted in frequent reports of fecal contamination in drinking water and outbreaks of waterborne diseases. The purpose of this study was to find out the burden of diarrhoeal diseases at different scenario of water supply system and sanitation status in Nepalese context. METHODS: A cross-sectional study was conducted in four different districts of Nepal analyzing six different scenarios based on availability of water supply and sanitation status. Village Development Committees (VDCs) and community selection was made purposively and 360 households, 60 from each scenario were selected conveniently to achieve the required number. Within the selected household, the head of the household or any member above 18 years of age was interviewed using a structured questionnaire. Observation was done for toilet and water sources besides questionnaire method. RESULTS: Incidence of diarrhoea per 1000 population was found to be the highest in scenario-IV (Spring without toilet) with 204.89 followed by scenario-VI (Tube well without toilet) with 145.30, while it was less in scenario-I (Tap water with toilet) with 46.05. Accordingly, the burden of disease (YLD) was also found to be the highest in scenario-IV and the lowest in scenario-I. Most of the households didn't treat water before drinking. Hand washing practice was found to be more than 90% regardless of toilet availability. CONCLUSIONS: The greater risk of acquiring diarrhoeal disease and higher burden of disease in situation of unprotected water source and absence of toilet shows that these are still important contributing factors for diarrhoeal disease in Nepal. Use of sanitary toilets and protected water source are the important measures for diarrhoeal disease prevention in Nepal. PMID- 23034375 TI - Hospital-based study in children with rotavirus gastroenteritis and other enteropathogens. AB - BACKGROUND: Rotavirus is the most common cause of life threatening gastroenteritis in infants and young children in the world. The objective of the study is to find out current trends and incidents of rotavirus, including other enteropathogens related with children diarrhoea and lastly identify the most common rotavirus serotypes that circulate in Nepal. METHODS: A total of 1721 stool samples from less than 5 years of children were collected. Rotavirus in the stool samples were detected by Enzyme Immuno Assay (EIA) and strains were genotyped by Reverse-Transcription Polymerase Chain Reaction (RT-PCR). Bacteria and parasites were detected by following standard microbiological procedures. RESULTS: In between 2009 to 2010, of the total 1721, the prevalence of rotavirus was 24.7%. Of them, 906 (52.6%) were collected in the year 2009 and 815(47.5%) in the year 2010. Rotavirus was frequently detected in inpatients (31.6%) than outpatient (16.8%). Rotavirus detection was higher in female (26.4%) than male (23.7%). The prevalence was seen higher in age group 0-23 months in both years. Among six different bacterial isolates, Escherichia coli was most frequently isolated (6.5%). Similarly, Giardia lamblia (1.3%) was most common among six different parasites detected. A total of rotavirus positive 425 stool samples were detected over 2 years (2009-230, and 2010-195), G12P6 was the predominant strain circulating in both (45% in 2009 and 28% in 2010) years. G9P6 emerged in 2010 (6%). There were significant numbers of mixed infections (14.0% in 2009 and 29.8% in 2010). Thirty five samples were partially typed and 15 were completely untyped over the two year period. CONCLUSIONS: The study helps comprehend the prevalence of rotavirus along with other intestinal pathogens including bacteria and parasites. Major genotypes of rotavirus are also introduced in the study. PMID- 23034376 TI - Perceived discrimination among people living with HIV in Nepal. AB - BACKGROUND: HIV is one of the major public health problems in Nepal, fuelled by several socio-economic factors. The objective of this study was to explore perceived discrimination among people living with HIV in their own family, society and health facilities. METHODS: A qualitative descriptive cross-sectional study was conducted with semi-structured face-to-face in-depth interview of 18 people (10 men, 8 women) living with HIV in four districts of Nepal. RESULTS: Perceived discriminations among people living with HIV were found among family, society and health facilities. In families, the major forms of perceived discrimination were restriction to go outside, exposure to media and use of different utensils for eating purpose. Female HIV positive perceived more violence at household level than males. Financial restriction was also found imposed upon some respondents by the family for being HIV positive. Similarly, restriction to participate in social work, restriction to buy from shops, social harassment and insult were the main forms of discrimination. Perceived discrimination experienced in the health facility yielded very bitter experiences to some respondents, while many had refused treatment because of their HIV status. CONCLUSIONS: People living with HIV faced different forms of perceived discrimination within family, society and health facility which are thought to be crucial in supporting a person at the time of crisis. Intensive programs that can reduce social stigma and discrimination faced by people living with HIV are a most. PMID- 23034377 TI - Infant and young child feeding practices in Chepang communities. AB - BACKGROUND: Infant and young child feeding (IYCF) practices differ in communities due to difference in knowledge, culture, health service utilization, and other socio-economic factors. The objective of this study was to explore the knowledge and practices of Chepang mothers on ICYF and their correlates. METHODS: Cross sectional descriptive study was conducted in Chepang communities of Makawanpur district. Quantitative methodology was used in which 360 mothers of under children under two were randomly selected. Logistic regression analysis of selected child feeding indicators were done to find their association with socio economic and health related factors. RESULTS: Feeding practices of mothers were found better than their knowledge level. About 35% had knowledge about early initiation of breastfeeding. Exclusive breastfeeding and introduction of complementary foods at the age of six months were 81% and 90% respectively. Literate mothers were found initiating breastfeeding early than the illiterate (OR=2.61, 95% CI, 1.59-4.27). Growth monitoring service utilization was found to have significant association with exclusive breastfeeding practices (OR= 2.75; 95% CI, 1.30-5.78). Feeding diverse complementary foods was associated with average monthly family income and duration of food sufficiency. CONCLUSIONS: Feeding practices in Chepang community were associated with health and socioeconomic determinants. Some of the feeding practices were found good however, meal frequency for the children 9-23 months of age and feeding diverse foods for children 6-23 months were found lower which needs to be improved through health education programs. Qualitative studies are needed to explore cultural factors. PMID- 23034378 TI - Factors associated with dropout between Bacille Calmette Guerin (BCG) and measles vaccination in a village development committee of a district. AB - BACKGROUND: The Expanded Programme on Immunization is one of the first priorities of the Government of Nepal. The high national dropout rate (11.3%) demonstrates that immunization opportunities are lost as approximately one of every nine children in contact with immunization services are slipping "out of the system" before the age of 12 months. This study is an attempt to explore the situation of the enhancing factors for dropout. OBJECTIVES: The main objective of the study was to identify the reasons of dropout between BCG and Measles vaccination in Kapan Village Development Committee (VDC) of Kathmandu district. METHODS: This was a descriptive study. of children ranging from 12 to 23 months of age residing in Kapan VDC. (N=81) mothers were interviewed to obtain the information. RESULTS: The study revealed that Magar/Gurung in the area were found to dropout more (78.6%). Female children were more likely to dropout than male children. About 70% of children dropout were from labor class, and/or illiterate families. Majority of the mothers (42.5 %) said that the child was ill so they did not go for routine vaccination. However, 50.7% of dropout children received quality care. These findings were corroborated with the findings of key informant interview. CONCLUSIONS: The major reason of dropout of measles vaccine was found to be the perceived contraindication regarding the immunization. PMID- 23034379 TI - Dengue in western Terai region of Nepal. AB - BACKGROUND: Dengue Fever (DF) is an emerging mosquito-borne disease. It is a nagging public health problem in the low lands of Terai, expanding to new areas of Nepal in recent years. METHODS: A cross-sectional study was conducted to determine anti-Dengue IgM positive rate in Mahendranagar, Dhangadi and Dang between August 2008 and November 2009. Serum samples were collected from 283 patients visiting hospitals with history of fever, headache and suspected DF. The samples were examined by ELISA. RESULTS: The anti-Dengue IgM positivity was found to be 9.8 %. The positive rate was highest in Mahendranagar (13.3 %) followed by Dhangadi (9.8 %) (P<0.05). The Dengue positive cases were higher in female (10.9 %) than males (9.0 %). The positivity was higher in Ethnic group Brahman/Chherti (13.1%) as compared to Janajati (5.6 %). The highest positive cases (10.7 %) were from age group above 50 years. The highest numbers of Dengue positive cases were observed in occupation group of agriculture (18.2 %) (P>0.05). CONCLUSIONS: Dengue has substantial expansion in Western and Far Western Terai region of Nepal which was limited to the middle Terai region in the past and mostly infects older people. PMID- 23034380 TI - Malnutrition in children aged 6-59 months in Mugu district. AB - BACKGROUND: Malnutrition is one of the leading causes of child morbidity and mortality. The severity of hunger in mountain and hill districts of Mid- and Far Western Development Regions is a serious concern. Mugu, is one of the most remote and least developed districts of Nepal, periodically facing food insufficiency. This study was carried out to evaluate the malnutrition status of the most vulnerable group of children (6-59 months age group) in Mugu district. METHODS: This study conducted in Mugu district was prospective and observational. Nutritional status of children aged 6-59 months were assessed by measuring mid upper arm circumference by using MUAC tape and data was collected by interviewing caretakers. The data were analyzed and compared to the national figure. RESULTS: Altogether 198 children aged 6-59 months were recruited for this study. Among them 49% were boys and 51% were girls. According to MUAC criteria, 1% of children had suffered from Severe Acute Malnutrition (SAM), 17% had Moderate Acute Malnutrition (MAM) and 82% had adequate nutritional status. CONCLUSIONS: The prevalence of Acute Malnutrition is high in Mugu district. The important factors, among numerous others are food scarcity, poor hygiene and environmental practices, lack of care of the mother towards her child due to priority given to work and lack of knowledge about proper child feeding/care. PMID- 23034381 TI - Intrauterine growth curves for singleton live babies in Paropakar Maternity and Women's Hospital in Nepal. AB - BACKGROUND: To construct birth weight, crown heel length and head circumference centile chart referenced to gestational age for Nepalese infants. METHODS: The study was conducted over a period of six months. It included consecutive live births from 28 to 42 weeks of gestation. Their birth weight, crown-heel length and head circumference were recorded. Smoothed percentile values along with curves were created using the Lambda Mu Sigma (LMS) method. The curves were compared with one of the Indian study. RESULTS: A total of 9710 newborns were measured. The mean birth weight, crown-heel length, head circumference at 40 weeks were 3023g, 49.22cm and 33.61cm respectively. Smoothed percentile values calculated gave the cutoffs for defining small and large gestational age for Nepalese newborns. Comparison with Indian study showed significant difference (p<0.01) in weight. The Indian babies weighed less than Nepalese babies. CONCLUSIONS: The referenced growth standards help in clinical assessment, defining and identifying high risk newborns, thus, leading to improved care and management of neonates. It should help public health policy makers to track population difference due to several factors, intervene and find response over time. PMID- 23034382 TI - Impact evaluation of uterine prolapse surgery in Nepalese women. AB - BACKGROUND: The problem of uterine prolapse exists throughout Nepal and negatively affects women's health and quality of life (QOL). The Government of Nepal recognizes it as a priority problem. METHODS: This study was conducted in eight districts to examine the status and problems of women who have undergone prolapse surgery. Qualitative and quantitative methods were used to examine the issues of prolapse. Survey method was used to administer the questionnaire. RESULTS: Sixty-six percent women reported pelvic organ prolapse at an early age. The mean age of its occurrence was 28 years. In the hill/mountain districts, 52% women among the non-poor and 72% among the poor went to health camps for surgery indicating that the camps were fulfilling the demands of the poor. Majority (>75%) of them from remote districts went to health camps for surgery indicating the camps were more beneficial to women in remote areas. Counseling was weak in the health camps and the use of IEC materials was minimal. Majority had improved health status after surgery. The incidence of post-surgery problems were as follows: 10.1% in government hospitals, 11.1% in non-government hospitals and 15.1% in health camps. CONCLUSIONS: Despite improved performance of health camps, the program for prolapse management still seems weak due to lack of ownership of local health institutions and lack of proper coordination among the stakeholders/ partners. However, these camps need to be scaled up for the benefit of the unreached population. PMID- 23034383 TI - Comment on "risk factors associated with low birth weight". AB - In 2011 Oct issue, Journal of Nepal Health Research Council published an article "risk factors associated with low birth weight" by Yadav DK affiliated to School of Health and Allied Sciences, Pokhara University, Chaudhary U affiliated to Child Welfare Scheme, Kaski, and Shrestha N from CIST College, Kathmandu, Nepal. As a result, comments were sent to JNHRC, and are published below. PMID- 23034384 TI - Comment on "status of pathology professionals". AB - In 2012 Jan issue, Journal of Nepal Health Research Council published an article "Status of Pathology Professionals" by Mishra SK affiliated to Concern for Public Health and Development (C-PHD), Kathmandu, Tiwari BR affiliated to Department of Clinical Microbiology, People's Dental College, Tribhuwan University and Yadav BK from Department of Clinical Biochemistry, Institute of Medicine, Kathmandu, TribhuwanUniversity, Nepal.As a result, comments were sent to JNHRC, and are published below. PMID- 23034385 TI - Phylogenetic analysis using Levy processes: finding jumps in the evolution of continuous traits. AB - Gaussian processes, a class of stochastic processes including Brownian motion and the Ornstein-Uhlenbeck process, are widely used to model continuous trait evolution in statistical phylogenetics. Under such processes, observations at the tips of a phylogenetic tree have a multivariate Gaussian distribution, which may lead to suboptimal model specification under certain evolutionary conditions, as supposed in models of punctuated equilibrium or adaptive radiation. To consider non-normally distributed continuous trait evolution, we introduce a method to compute posterior probabilities when modeling continuous trait evolution as a Levy process. Through data simulation and model testing, we establish that single rate Brownian motion (BM) and Levy processes with jumps generate distinct patterns in comparative data. We then analyzed body mass and endocranial volume measurements for 126 primates. We rejected single-rate BM in favor of a Levy process with jumps for each trait, with the lineage leading to most recent common ancestor of great apes showing particularly strong evidence against single-rate BM. PMID- 23034386 TI - K+-Cl- cotransporter-2 KCC2 in chicken cardiomyocytes. AB - Using antibodies prepared against a unique region (exon 22-24) of rat K(+)-Cl(-) cotransporter-2 (KCC2), we confirmed that the ~140-kDa KCC2 protein is exclusively expressed in rat brain, but in chicken, we observed strong reactivity not only with the ~140-kDa KCC2 protein in brain but also a slightly larger ~145 kDa protein in heart. In silico analysis showed that while exon 22 of KCC2 is unique to this isoform in therian mammals, it is retained in KCC2's closest paralog, KCC4, of lower vertebrates, including chicken. To eliminate potential cross-reactivity with chicken KCC4, the antibodies were preadsorbed with blocking peptides prepared over the only two regions showing significant sequence identity to chicken KCC4. This completely eliminated antibody recognition of exogenously expressed chicken KCC4 but not of the ~145-kDa protein in chicken heart, indicating that chicken heart expresses KCC2. Real-time PCR confirmed robust KCC2 transcript expression in both chicken brain and heart. Chicken heart expressed predominantly the longer KCC2a splice variant consistent with the larger ~145-kDa protein in chicken heart. Immunofluorescence microscopy revealed prominent plasma membrane KCC2 labeling in chicken ventricular cardiomyocytes. We hypothesize that KCC2 is an important Cl(-) extrusion pathway in avian cardiomyocytes that counters channel-mediated Cl(-) loading during high heart rates with beta adrenergic stimulation. While KCC2 is absent from mammalian cardiomyocytes, understanding the role that the other KCC isoforms play in Cl(-) homeostasis of these cells represents a nascent area of research. PMID- 23034387 TI - Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. AB - The neuropeptides orexins and their G protein-coupled receptors, OX(1) and OX(2), were discovered in 1998, and since then, their role has been investigated in many functions mediated by the central nervous system, including sleep and wakefulness, appetite/metabolism, stress response, reward/addiction, and analgesia. Orexins also have peripheral actions of less clear physiological significance still. Cellular responses to the orexin receptor activity are highly diverse. The receptors couple to at least three families of heterotrimeric G proteins and other proteins that ultimately regulate entities such as phospholipases and kinases, which impact on neuronal excitation, synaptic plasticity, and cell death. This article is a 10-year update of my previous review on the physiology of the orexinergic/hypocretinergic system. I seek to provide a comprehensive update of orexin physiology that spans from the molecular players in orexin receptor signaling to the systemic responses yet emphasizing the cellular physiological aspects of this system. PMID- 23034388 TI - TRPC1 and Orai1 interact with STIM1 and mediate capacitative Ca(2+) entry caused by acute hypoxia in mouse pulmonary arterial smooth muscle cells. AB - Previous studies in pulmonary artery smooth muscle cells (PASMCs) showed that acute hypoxia activates capacitative Ca(2+) entry (CCE) but the molecular candidate(s) mediating CCE caused by acute hypoxia remain unclear. The present study aimed to determine if transient receptor potential canonical 1 (TRPC1) and Orai1 interact with stromal interacting molecule 1 (STIM1) and mediate CCE caused by acute hypoxia in mouse PASMCs. In primary cultured PASMCs loaded with fura-2, acute hypoxia caused a transient followed by a sustained rise in intracellular Ca(2+) concentration ([Ca(2+)](i)). The transient but not sustained rise in [Ca(2+)](i) was partially inhibited by nifedipine. Acute hypoxia also increased the rate of Mn(2+) quench of fura-2 fluorescence that was inhibited by SKF 96365, Ni(2+), La(3+), and Gd(3+), exhibiting pharmacological properties characteristic of CCE. The nifedipine-insensitive rise in [Ca(2+)](i) and the increase in Mn(2+) quench rate were both inhibited in cells treated with TRPC1 antibody or TRPC1 small interfering (si)RNA, in STIM1 siRNA-transfected cells and in Orai1 siRNA transfected cells. Moreover, overexpression of STIM1 resulted in a marked increase in [Ca(2+)](i) and Mn(2+) quench rate caused by acute hypoxia, and they were reduced in cells treated with TRPC1 antibody and in cells transfected with Orai1 siRNA. Furthermore, TRPC1 and Orai1 coimmunoprecipitated with STIM1 and the precipitation levels of TRPC1 and Orai1 were increased in cells exposed to acute hypoxia. Immunostaining showed colocalizations of TRPC1-STIM1 and Orai1-STIM1, and the colocalizations of these proteins were more apparent in acute hypoxia. These data provide direct evidence that TRPC1 and Orai1 channels mediate CCE through activation of STIM1 in acute hypoxic mouse PASMCs. PMID- 23034389 TI - Calcium-binding protein 39 facilitates molecular interaction between Ste20p proline alanine-rich kinase and oxidative stress response 1 monomers. AB - X-ray crystallography of the catalytic domain of oxidative stress response 1 (OSR1) has provided evidence for dimerization and domain swapping. However, the functional significance of dimer formation or domain swapping has yet to be addressed. In this study, we used nine glutamine residues to link the carboxyl end of one SPAK (related Ste20 kinase) monomer to the amino end of another SPAK monomer to assess the role of kinase monomers versus dimers in Na-K-2Cl cotransporter 1 (NKCC1) activation. Transport studies in Xenopus laevis oocytes show that forcing dimerization of two wild-type SPAK molecules results in cotransporter activation when calcium-binding protein 39 (Cab39) is coexpressed, indicating that the presence of Cab39 can bypass the upstream phosphorylation requirement of SPAK normally associated with kinase activation. We determined that monomers are the functional units of the kinase as concatamers consisting of an active and various inactive monomers were still functional. Furthermore, we found that two different nonfunctional SPAK mutants could be linked together in a concatamer and activated, presumably by domain swapping, indicating that dimerization and domain swapping are both important components of kinase activation. Finally, we demonstrate rescue of a nonfunctional SPAK mutant by domain swapping with wild-type OSR1, indicating that heterodimers of the two Ste20-related kinases are possible and therefore potentially relevant to the regulation of NKCC1 activity. PMID- 23034391 TI - miR-141 as a regulator of the mitochondrial phosphate carrier (Slc25a3) in the type 1 diabetic heart. AB - Dysfunctional mitochondria are central in the pathogenesis of diabetic cardiomyopathy. Mitochondrial proteomic alterations resulting from diabetes mellitus have been reported although the mechanisms driving changes in proteomic signatures are unknown. microRNAs (miRNAs) have been considered as potential regulators of proteins. The goal of this study was to determine whether miRNAs play a role in diabetes-induced mitochondrial proteomic alterations. Quanitative RT-PCR miRNA screening in diabetic mice, 5 wk following multiple low-dose streptozotocin treatment was associated with alteration in the expression of 29 miRNAs in the diabetic heart compared with control. Among those miRNAs upregulated in the diabetic heart was miR-141 (P < 0.002). miRNA target prediction analyses identified miR-141 as a potential regulator of the inner mitochondrial membrane phosphate transporter, solute carrier family 25 member 3 (Slc25a3), which provides inorganic phosphate to the mitochondrial matrix and is essential for ATP production. With the use of a luciferase reporter construct with a Slc25a3 3'-untranslated region (UTR) target sequence, overexpression of miR-141 downregulated luciferase activity levels confirming miR-141/Slc25a3 3' UTR binding. miR-141 overexpression in HL-1 cells elicited a decrease in Slc25a3 protein content, ATP production and a decrease in ATP synthase activity, similar to the diabetic phenotype (P < 0.05, for both). Diabetic interfibrillar mitochondria (IFM) displayed decreased Slc25a3 protein content, which was inversely correlated with increased miR-141 expression. Further, diabetic IFM ATP synthase activity was also decreased (P < 0.05). Together these results indicate that miR-141 can regulate Slc25a3 protein expression in the diabetic heart. Further, diabetes-induced miRNA changes may influence mitochondrial proteomes and functional processes such as mitochondrial ATP production. PMID- 23034390 TI - Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension. AB - Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca(2+) levels in pulmonary hypertension (PH). Whether the functional properties and expression of Ca(2+)-activated Cl- channels (Cl(Ca)), an important excitatory mechanism in PASMCs, are altered in PH is unknown. The potential role of Cl(Ca) channels in PH was investigated using the monocrotaline (MCT)-induced PH model in the rat. Three weeks postinjection with a single dose of MCT (50 mg/kg ip), the animals developed right ventricular hypertrophy (heart weight measurements) and changes in pulmonary arterial flow (pulse-waved Doppler imaging) that were consistent with increased pulmonary arterial pressure and PH. Whole cell patch experiments revealed an increase in niflumic acid (NFA) sensitive Ca(2+)-activated Cl(-) current [I(Cl(Ca))] density in PASMCs from large conduit and small intralobar pulmonary arteries of MCT-treated rats vs. aged matched saline-injected controls. Quantitative RT-PCR and Western blot analysis revealed that the alterations in I(Cl(Ca)) were accompanied by parallel changes in the expression of TMEM16A, a gene recently shown to encode for Cl(Ca) channels. The contraction to serotonin of conduit and intralobar pulmonary arteries from MCT-treated rats exhibited greater sensitivity to nifedipine (1 MUM), an l-type Ca(2+) channel blocker, and NFA (30 or 100 MUM, with or without 10 MUM indomethacin to inhibit cyclooxygenases) or T16A(Inh)-A01 (10 MUM), TMEM16A/Cl(Ca) channel inhibitors, than that of control animals. In conclusion, augmented Cl(Ca)/TMEM16A channel activity is a major contributor to the changes in electromechanical coupling of PA in this model of PH. TMEM16A-encoded channels may therefore represent a novel therapeutic target in this disease. PMID- 23034393 TI - Small carbides of third-row main group elements: structure and bonding in C3X compounds (X = K-Br). AB - The molecular structures of third-row main group tricarbides C(3)X (X = K-Br) have been studied by quantum chemical methods. It is found that less electronegative elements (K, Ca, Ga, Ge) favor either fan or rhombic structures (resulting from side interactions with either linear or triangular C(3) units), whereas the more electronegative elements (As, Se, Br) favor linear or three membered ring structures (resulting from sigma-type interactions with either linear or triangular C(3) units). The predicted global minima are of fan type for C(3)K, rhombic for C(3)Ca, C(3)Ga, and C(3)Ge, linear for C(3)As and C(3)Se, and a three-membered ring for C(3)Br. In order to aid in their possible experimental identification the molecular geometries, vibrational frequencies, IR intensities, and dipole moments have been provided. The nature of the interactions has been characterized through an analysis of the electronic charge density. In addition, the relative stability of the different isomers has been also rationalized in terms of an energy decomposition analysis. PMID- 23034392 TI - [Compensable occupational disease and cancer: how to improve the recognition rate? "Cursus Laboris" Project in Midi-Pyrenees: feasibility study]. AB - Five to ten percent of cancers are of occupational origin but only 0.5% of cancers are compensable occupational diseases recognized in 2001. The project "Curriculum Laboris" was launched in Midi-Pyrenees with the objective to establish an organization to improve the identification, reporting and recognition of occupational cancers. The project consisted firstly in creating an online training module for professionals. Furthermore, a pilot has identified patients with lung, bladder, head and neck or hematologic cancer. Afterwards, four investigators realized an interview with the patients "marked" to define their careers. Finally, a group of experts produced advice, providing the general practitioner, the aid element in drafting the initial medical certificate (CMI) as part of the recognition process. Twenty-three patients were identified, 21 surveys were carried out. Six returns were filed and actually recognized. The generalization of our device measures meet the Cancer Plan II 2009 to 2013 and may improve the number of cancers recognized as compensable occupational diseases. PMID- 23034394 TI - Resonance-Raman microspectroscopy for quality assurance of dye-sensitized NiO(x) films with respect to dye desorption kinetics in water. AB - Resonance Raman microspectroscopy is used to investigate dye-sensitized NiO(x) nanoparticle films to be used as photocathodes in tandem dye-sensitized solar cells. It is shown that rR microspectroscopy has potential for applications in quality assurance in such systems and also in integrated dye-sensitized solar cell modules. Here, ruthenium dye-sensitized NiO(x) nanoparticle layers were produced both as single and double NiO(x) films using a one or two-step deposition process, respectively. The distribution of the sensitizer on the surfaces was investigated by rR microspectroscopy. The chemical images obtained from rR microspectroscopy yield complementary information to bright field microscope pictures and provide detailed insight into the sensitization pattern e.g. in the vicinity of surface vacancies and other inhomogeneities. Furthermore, based on the mapping results the dye desorption kinetics upon addition of water has been analysed. Desorption on the single NiO(x) film is faster and more efficient than on the double film. These changes are attributed to binding sites on the NiO(x) surface that are passivated with regard to water penetration. This passivation is introduced by the second synthesis step in building the second film of NiO(x) on the glass substrate. Both findings highlight the potential of rR microspectroscopy for quality assurance of dye-sensitized solar cell electrodes. PMID- 23034397 TI - Legislation direction for implementation of health information exchange in Korea. AB - Facing national implementation of standardized health information exchange (HIE), the need for a robust e-governance system has also been emerging in Korea. Based on the Guidelines for Personal Health Information in Health Care Organizations, this article examines how recent governance encourages meaningful use of HIE technology in health care and suggests legislative directions relevant to appropriate health information sharing and the rights and responsibilities of stakeholders regarding the details of the guidelines. PMID- 23034398 TI - Attitudes toward nonsmoking policies and tobacco tax increases: a cross-sectional study among Vietnamese adults. AB - Following the 2009 update of the 2005 Framework Convention on Tobacco Control, Vietnam issued a new policy to ban smoking at workplaces and public places. This cross-sectional survey explored public attitudes toward this new regulation and provides evidence to inform future laws. Using stratified cluster sampling, 10 383 Vietnamese people older than 15 years were drawn from 11 142 selected households. Policies mandating "no smoking at workplaces" were supported by 88.7% of Vietnamese adults, whereas "no smoking in public places" and "increasing the tobacco tax" received less support. Educational level, knowledge of health effects, access to information on quitting and smoking health risks, smoking status, ethnicity, and region had significant associations with positive attitudes toward all 3 tobacco control policies. Adults belonging to the non-Kinh ethnic group, those who do not live in the Red river delta, people with lower educational levels, and current smokers should be targeted in tobacco control communication programs. PMID- 23034399 TI - Estimation of the direct cost of treating people aged more than 60 years infected by influenza virus in Shanghai. AB - BACKGROUND: Influenza is a common, vaccine preventable, viral respiratory infection with potentially serious consequences in persons aged 60 years and above. In China, influenza vaccination is recommended but not reimbursed for people. Therefore, we studied management of influenza episode, healthcare resource use and costs associated with influenza infection in people aged over 60 in Shanghai. METHODS: A prospective, observational study was conducted over the 2008-2009 influenza season. Persons aged 60 years and above presenting to a study center with acute onset of influenza-like illness (ILI) were enrolled and tested by PCR for influenza virus. Laboratory confirmed influenza (LCI) patients were visited 2 weeks later for detail information. RESULTS: From January 2009 to December 2009, 1,946 subjects were recruited. Among them 1,777 patients met the inclusion criteria, 395 (22.2%) tested positive. 341 (86%) patients received ambulatory care only while 54 (14%) were hospitalized. Most patients had been prescribed at least one medication (94%), and had had at least one laboratory test (92%). An outpatient cost a mean of USD 47 per case. Once hospitalized, the average length of stay was 17.0 days (SD = 13.82) and the mean total inpatient cost reached USD 1,601. The public health insurance paid 69% and 79% of the mean outpatient and inpatient costs per patient respectively. CONCLUSION: This study described the management of a LCI case in people aged more than 60 years in Shanghai and estimated the economic burden in particular from the public healthcare system perspective, showing expensive consequences among hospitalized patients. PMID- 23034400 TI - Developing a tool for assessing public health law in countries. AB - At present, the World Health Organization (WHO) is in the process of developing a tool designed to assess the status of public health legislation in a given country. An Expert Consultation on Public Health Law was convened in Manila, Philippines, in May 2011. The participants agreed that the tool could serve as a guide for a regional approach to assist Member States in assessing the scope, completeness, and adequacy of their public health law. Given the broad definition of "public health" and the laws that affect health, directly or indirectly, the participants further agreed to narrow the field to 4 areas based on significant WHO works/policies, each organized into an independent module: (1) International Digest on Health Law, (2) Primary Health Care, (3) International Health Regulations 2005, and (4) Framework Convention on Tobacco Control. The tool would be drafted in a questionnaire format that asks the respondent to determine whether primary and/or subsidiary legislation exists in the country on a specific topic and, if so, to cite the relevant law, describe the pertinent points, and attach and/or link to the full text where available. The participants agreed that the respondents should include government officials and/or academics with legal competency. Version 1 of the tool was piloted in the Philippines, the Republic of Korea, Samoa, and Vanuatu. At a 2nd Expert Consultation on Public Health Law, convened in Incheon, Republic of Korea, in October 2011, in conjunction with the 43rd Conference of the Asia-Pacific Academic Consortium on Public Health, the participants determined that the tool was generally usable, certain concerns notwithstanding, such as the risk of standardizing compliance with WHO policies. The agreed next step is to finalize the analysis tool by August 2012, marking the end of stage I in the development process. Stage II will consist of team building and networking of responsible officers and/or professionals in the countries. The tool will be further developed to reflect specific in-country situations. PMID- 23034401 TI - Humanitarian responses and their ethical implications. AB - As the frequency and seriousness of natural disasters increase, humanitarian response gains interests. Disaster, as a threat to a society, exposes the weaknesses of that society and aids from agents other than that society are needed in the disaster situation. This nature of humanitarian response makes ethical consideration necessary, but as the context is different, ethical concerns and principles are also different from those of conventional medical ethics. Ethical justification is essential to humanitarian responses, and ethical standards and ideals should be considered during the humanitarian responses. PMID- 23034402 TI - Nuclear envelope-associated dynein drives prophase centrosome separation and enables Eg5-independent bipolar spindle formation. AB - The microtubule motor protein kinesin-5 (Eg5) provides an outward force on centrosomes, which drives bipolar spindle assembly. Acute inhibition of Eg5 blocks centrosome separation and causes mitotic arrest in human cells, making Eg5 an attractive target for anti-cancer therapy. Using in vitro directed evolution, we show that human cells treated with Eg5 inhibitors can rapidly acquire the ability to divide in the complete absence of Eg5 activity. We have used these Eg5 independent cells to study alternative mechanisms of centrosome separation. We uncovered a pathway involving nuclear envelope (NE)-associated dynein that drives centrosome separation in prophase. This NE-dynein pathway is essential for bipolar spindle assembly in the absence of Eg5, but also functions in the presence of full Eg5 activity, where it pulls individual centrosomes along the NE and acts in concert with Eg5-dependent outward pushing forces to coordinate prophase centrosome separation. Together, these results reveal how the forces are produced to drive prophase centrosome separation and identify a novel mechanism of resistance to kinesin-5 inhibitors. PMID- 23034404 TI - Implanted cardiac pacemaker pulses as recorded from the body surface. AB - This study investigates the characteristics of contemporary pacemaker pulses as recorded from the body surface. Twelve-lead paced ECGs from 140 patients (68 +/- 12 years, 71% males) were collected at 32,000 samples per second. Pacer pulses were manually annotated based on the high-sampling rate data stream. The results show that durations of the various pulses are stable, while amplitudes exhibit large variations. Also, more than 50% of pulses have either durations <0.5 ms or amplitudes <2 mV, which are the AAMI/IEC thresholds for detection and marking of pacemaker pulses on an ECG report. Therefore the current standards for pacemaker pulse detection are not fit for purpose and require to be updated. Further, this study suggests that a high-sampling rate database should be used as a standard test for pacemaker annotation and detection from body surface ECGs. PMID- 23034403 TI - Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. AB - Cancers and tissue stem cells (SCs) share similar molecular pathways for their self-renewal and differentiation. The race is on to identify unique pathways to specifically target the cancer, while sparing normal SCs. Here, we uncover the transcription factor Runx1/AML1, a known haematopoietic and leukaemia factor, albeit dispensable for normal adult SC homeostasis, as being important for some mouse and human epithelial cancers. We implicate Runx1 as a SC-intrinsic gene in mouse hair follicle and oral epithelia by genetic lineage tracing in adulthood. Runx1-expressing SCs, but not other cells that ectopically upregulate Runx1 by injury and inflammation, are at the skin tumour origin. Runx1 loss impairs tumour initiation and maintenance and the growth of oral, skin, and ovarian epithelial human cancer cells. Runx1 stimulates Stat3 signalling via direct transcriptional repression of SOCS3 and SOCS4 and this is essential for cancer cell growth. Thus, Runx1 is a broader epithelial SC and cancer factor than previously recognized, and qualifies as an attractive potential target for both prevention and therapy of several epithelial cancers. PMID- 23034405 TI - A retrospective review of antiemetic use for chemotherapy-induced nausea and vomiting in pediatric oncology patients at a tertiary care center. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting are the most dreaded and distressing side effects for cancer patients undergoing chemotherapy treatment. These side effects have a significant impact on the patients' quality of life and can interfere with their ability to receive intensive chemotherapy regimens. With the recent advances in antiemetic pharmacotherapy and supportive care, the current treatments for chemotherapy-induced nausea and vomiting, when used appropriately, have become highly effective in mitigating these adverse effects. OBJECTIVE: The aim of this study was to evaluate the current practice involving antiemetic treatment in newly diagnosed pediatric oncology patients at our center. METHODS: This was a retrospective cohort study of newly diagnosed pediatric oncology patients who were less than 14 years of age receiving their first cycle of inpatient chemotherapy. The data abstracted included the following: age, gender, type of cancer, chemotherapy regimen, emetogenic risk and level, prescribed prophylactic antiemetic regimen, incidence of breakthrough emesis, and breakthrough antiemetic medications used. Emetogenic risk was classified based on published guidelines into low, moderate, or high emetogenic chemotherapy, and a scoring system to determine the emetogenic level of combined chemotherapy agents was followed to monitor the efficacy of the antiemetic regimens. Clinical effectiveness was assessed based on breakthrough emesis. RESULTS: A total of 49 patients were eligible for the study. High emetogenic chemotherapy was administered in 28/49 (57.1%) and moderate emetogenic chemotherapy was administered in 21/49 (42.9%) patients. Only 10/49 (20.4%) received appropriate antiemetic prophylaxis, whereas 39/49 (79.6%) received inadequate antiemetic prophylaxis; 14/49 (28.6%) patients experienced breakthrough emesis. Breakthrough emesis occurred in 11/28 (39.3%) patients receiving high emetogenic chemotherapy and 3/21 (14.3%) patients receiving moderate emetogenic chemotherapy. The use of an inadequate antiemetic regimen was found in 14/14 (100%) patients with breakthrough emesis. Thus, inadequate prophylaxis resulted in a 35.9% (14/39) risk of breakthrough emesis. This risk was higher in patients receiving high emetogenic chemotherapy versus those receiving moderate emetogenic chemotherapy (39.3% versus 14.3%). CONCLUSION: Inadequate antiemetic prophylaxis is associated with a high risk of breakthrough emesis particularly with high emetogenic chemotherapy regimens. Standardizing antiemetic prophylaxis based on emetogenic level could reduce breakthrough emesis and improve the quality of life in pediatric oncology patients. PMID- 23034406 TI - Tyrosine kinase inhibitor induced pancreatitis. AB - Sorafenib and sunitinib are oral tyrosine kinase inhibitors, commonly used in the treatment of metastatic renal cell carcinoma. Known adverse events associated with tyrosine kinase inhibitors include hypertension and palmarplantar erythrodysesthesia. We report two cases of acute pancreatitis associated with tyrosine kinase inhibitors. PMID- 23034407 TI - Is there still a role for mitomycin-based combination chemotherapy in treating patients with nonsmall cell lung cancer? A single institution experience. AB - BACKGROUND: Mitomycin and irinotecan are widely used in the treatment of colorectal cancer, furthermore both of these drugs are active agents against nonsmall cell lung cancer and their combination has shown synergism in preclinical studies. The aim of the study was to evaluate the efficacy and safety of mitomycin- and irinotecan-based chemotherapy combination in patients with advanced nonsmall cell lung cancer progressing after previous antineoplastic therapies. METHODS: Thirty-one consecutive patients suffering from nonsmall cell lung cancer, who underwent mitomycin- plus irinotecan-based chemotherapy as salvage treatment after failure of at least two previous systemic treatments, were retrospectively identified in our database. Between September 2003 and March 2011, 31 patients with histologically proven stage IIIB or IV nonsmall cell lung cancer, received mitomycin 5 mg/m(2) on day 1 followed by irinotecan 150 mg/m(2) on day 2. Cycles were repeated at 2-week interval. RESULTS: A total of 164 cycles of treatment were given with a median of five per patient (range 1-10). The objective responses included partial response in 6 patients (19.3%), stable disease in 4 (13%), and progressive disease in 21 (67.7%). Median time to disease progression was 4 months, and median survival was 9+ months. Twelve patients (38%) reached 1-year survival. Grade 3-4 toxicities occurred in seven patients (22.5%), mainly myelosuppression (neutropenia, anemia, and thrombocytopenia), mucositis, and diarrhea. No treatment-related death was recorded. CONCLUSION: The mitomycin- and irinotecan-based combination chemotherapy seems to be tolerated and active in this subset of heavily pretreated patients with advanced nonsmall cell lung cancer. However, evaluation or recruitment of a larger number of patients would be needed to provide more adequate data on safety and activity of the described combination. PMID- 23034408 TI - Availability of supervised exercise programs and the role of structured home based exercise in peripheral arterial disease. AB - OBJECTIVES: The effectiveness of supervised exercise programs (SEPs) for the management of peripheral arterial disease (PAD) can be hampered by low accessibility and poor compliance. The current international availability and use of SEPs was evaluated and the evidence on alternative approaches such as structured, home-based exercise programs (HEPs) was reviewed. METHODS-MATERIALS: International survey on SEP availability among vascular surgeons using an online questionnaire. A systematic review on structured-HEPs effectiveness was also performed. RESULTS: A total of 378 responses were collected from 43 countries, with the majority (95%) from Europe. Only 30.4% of the participants had access to SEPs and within this group there was significant heterogeneity on the way SEPs were implemented. This systematic review identified 12 studies on the effectiveness of HEPs. In 3 studies SEPs were superior to HEPs in improving functional capacity or equivalent in improving quality of life (QoL). HEPs significantly improved most of the functional capacity and QoL markers when compared to the "go home and walk" advice and baseline measurements. CONCLUSIONS: SEPs remain an underutilized tool despite recommendations. Structured HEPs may be effective and can be useful alternatives when SEPs are not available. Further research is warranted to establish cost-effectiveness. PMID- 23034416 TI - The changing world of medically complex dental patients: electronic health records and more. PMID- 23034409 TI - Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder. AB - An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development. PMID- 23034410 TI - Birth and expression evolution of mammalian microRNA genes. AB - MicroRNAs (miRNAs) are major post-transcriptional regulators of gene expression, yet their origins and functional evolution in mammals remain little understood due to the lack of appropriate comparative data. Using RNA sequencing, we have generated extensive and comparable miRNA data for five organs in six species that represent all main mammalian lineages and birds (the evolutionary outgroup) with the aim to unravel the evolution of mammalian miRNAs. Our analyses reveal an overall expansion of miRNA repertoires in mammals, with threefold accelerated birth rates of miRNA families in placentals and marsupials, facilitated by the de novo emergence of miRNAs in host gene introns. Generally, our analyses suggest a high rate of miRNA family turnover in mammals with many newly emerged miRNA families being lost soon after their formation. Selectively preserved mammalian miRNA families gradually evolved higher expression levels, as well as altered mature sequences and target gene repertoires, and were apparently mainly recruited to exert regulatory functions in nervous tissues. However, miRNAs that originated on the X chromosome evolved high expression levels and potentially diverse functions during spermatogenesis, including meiosis, through selectively driven duplication-divergence processes. Overall, our study thus provides detailed insights into the birth and evolution of mammalian miRNA genes and the associated selective forces. PMID- 23034417 TI - Clinical performance of all-ceramic cantilever fixed dental prostheses: results of a 2-year randomized pilot study. AB - OBJECTIVE: To evaluate the clinical performance of zirconia-based cantilever fixed dental prostheses (FDPs). METHOD AND MATERIALS: Twenty-one cantilever FDPs with three or four units were designed to replace one premolar or incisor (no canines). The FDPs were divided into 11 zirconia cantilever FDPs (test group) and 10 metal-ceramic cantilever FDPs (control group) and randomly assigned to patients. The results documented included failures, complications, plaque accumulation, and esthetic performance. Statistical analysis was performed using the Mann-Whitney U and chi-square tests. RESULTS: During the 2-year observation period, a total of five clinically relevant complications in four patients occurred: three endodontic problems (two in the test group and one in the control group) and two veneer chippings (both in the test group). Plaque accumulation on the abutment teeth was not significantly different among groups. The esthetic performance of all FDPs was acceptable. CONCLUSION: Stability and esthetic performance were acceptable for all-ceramic cantilever FDPs fabricated with zirconia. A longer observation period and larger sample size are necessary to make valid predictions about the longevity of these restorations. PMID- 23034418 TI - A systematic review of visual and instrumental measurements for tooth shade matching. AB - OBJECTIVE: Common methods for matching tooth shade can be classified into two categories: visual and instrumental measurements. This systematic review evaluated these two methods in terms of precision and accuracy using the agreement percentage rate. METHOD AND MATERIALS: The following databases were searched for studies comparing different shade-matching methods: MEDLINE (PubMed), Embase, and Google Scholar. Reference lists of relevant articles were also searched. Screening, data abstraction, and quality assessment were conducted independently and in duplicate. RESULTS: Twenty-six studies were included. Seventeen studies provided data on the precision of the evaluated shade-matching methods, eight provided data on accuracy, and one provided data on both precision and accuracy. CONCLUSION: Instrumental measurements using a spectrophotometer may provide the most precise and accurate shade-matching outcomes. However, the limitations of the available articles suggest that high-quality studies are still needed verify this claim. PMID- 23034419 TI - Esthetic and functional rehabilitation of crowded mandibular anterior teeth using ceramic veneers: a case report. AB - The use of ceramic veneers to restore crowded teeth in the maxilla has been widely discussed in the literature. However, the use of this technique in the mandible has received little attention. Therefore, this case report describes the treatment of crowded mandibular anterior teeth using ceramic veneers. The primary treatment challenge in this region is the reduced tooth structure available for rehabilitation. Proper communication between the clinician and dental technician is required to achieve clinical success. This article presents a straightforward treatment plan and restorative technique that includes both the clinical and laboratory sequences necessary for predictable and stable postoperative outcomes. PMID- 23034420 TI - Clinical and metabolic evaluation of one-stage, full-mouth, ultrasonic debridement as a therapeutic approach for uncontrolled type 2 diabetic patients with periodontitis. AB - OBJECTIVE: To evaluate the therapeutic potential of one-stage, full-mouth, ultrasonic debridement (FMUD) as a treatment for type 2 diabetic patients with generalized severe chronic periodontitis. METHOD AND MATERIALS: Sixteen patients diagnosed with generalized severe chronic periodontitis and type 2 diabetes mellitus were allocated to the diabetic group; another 15 subjects with periodontitis but without metabolic disorders were placed in the nondiabetic group. Both groups were treated using the FMUD protocol, a unique 45-minute session of ultrasonic debridement of all sites presenting periodontal disease. Patients were analyzed for the following parameters: plaque and bleeding indices, gingival recession, probing depth, and clinical attachment level. Further, diabetic subjects were assessed using fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) tests. Patients were evaluated at 3 and 6 months for all parameters. ANOVA and the Tukey test were used for data analysis (P < .05). RESULTS: Both groups showed improved periodontal health after treatment. There were no significant differences between the groups for any of the parameters assessed (P > .05). Diabetic subjects treated with FMUD had a clinical response similar to that of nondiabetic subjects at all pocket depths. No adverse effects or medical disturbances were observed in either group during treatment. FPG and HbA1c levels remained unaltered after treatment. CONCLUSION: Within the limitations of this study, FMUD promoted clinical improvements in patients with type 2 uncontrolled diabetes and generalized severe chronic periodontitis. PMID- 23034421 TI - Randomized clinical trial of the efficacy, tolerability, and long-term color stability of two bleaching techniques: 18-month follow-up. AB - OBJECTIVE: To investigate the efficacy, tolerability, and long-term color stability of tooth whitening using two different bleaching techniques: an at-home tray technique (5.0% H2O2) and an over-the-counter strip technique (5.3% H2O2). METHOD AND MATERIALS: Thirty subjects were included in this two-cell, parallel, examiner-blinded, randomized clinical trial. Shade evaluations were performed with a value-oriented VITA shade guide. The null hypothesis was that there would be no differences between the groups and no improvements from baseline with regard to tooth shade. Bleaching sensitivity, gingival irritation, and patient acceptance were recorded on a visual analog scale (VAS). Scanning electron microscopy (SEM) was performed to detect any enamel surface changes. RESULTS: After bleaching, both treatments demonstrated significant improvements in tooth shade (P < .001 for both groups). At the 18-month recall, tooth shade remained significantly lighter than at baseline (P = .006 for tray group; P = .001 for strip group). However, a relapse of the tooth shade was observed compared with the immediate postbleaching result (P < .05). VAS data yielded no significant differences between groups regarding bleaching sensitivity and gingival irritation. None of the teeth studied showed detectable enamel surface changes. Patient acceptance was statistically significantly higher in the tray group compared with the strip group (P < .05). CONCLUSION: Both techniques demonstrated significant and comparable levels of tooth shade improvement after 2 weeks and 18 months. Each treatment caused similar, transient oral adverse effects. PMID- 23034423 TI - In vitro microbiologic evaluation of PTFE and cotton as spacer materials. AB - OBJECTIVE: To microbiologically evaluate the efficacy of cotton and polytetrafluoroethylene (PTFE) tape used as spacer materials. METHOD AND MATERIALS: Twenty-six extracted human molars were restored using either cotton or PTFE tape as spacers under a standardized provisional restorative material (Cavit). The teeth were incubated for 7 days in a culture of Streptococcus gordonii or in liquid media alone. The spacers were removed and tested for bacterial contamination. The access cavities were also evaluated for bacterial contamination. RESULTS: Nine of 10 teeth with cotton spacers and one of 10 teeth with PTFE spacers were positive for S gordonii growth. The nine teeth in the cotton group also showed contamination of the access cavities. CONCLUSION: Even under optimal conditions, cotton spacers may cause leakage into the access cavities. Cotton fibers may serve as a route for bacterial contamination of the access cavities and root canal space. In contrast, PTFE tape did not provide an avenue for bacterial contamination. PMID- 23034422 TI - A systematic review of acupuncture or acupoint injection for management of burning mouth syndrome. AB - OBJECTIVE: Burning mouth syndrome (BMS) is a common chronic pain condition that lacks a satisfactory treatment approach. This systematic review was designed to examine the effects of acupuncture or acupoint injection on the management of BMS and to evaluate the evidence supporting the use of acupuncture therapy for BMS in clinical practice. METHOD AND MATERIALS: The following databases were searched for relevant articles: Cochrane Oral Health Group Trials Register (July 2011), Cochrane Central Register of Controlled Trials (issue 7, 2011), MEDLINE (1966 to June 2011), and electronic medical database from the China-National Knowledge Infrastructure (1979 to June 2011). Articles were screened, and the quality of the included trials was assessed independently by two reviewers. RESULTS: After screening, nine studies with 547 randomized patients were included in this review. All nine articles were published in Chinese and were clinical trial studies with a Jadad score < 3. Their results showed that acupuncture/acupoint injection may benefit patients with BMS. The evidence supported the efficacy of acupuncture/acupoint injection therapy in reducing BMS pain and related symptoms. CONCLUSION: In light of the positive outcomes reported, the use of acupuncture therapy for BMS patients warrants further research. PMID- 23034424 TI - Clinical efficacy of a new tooth and tongue gel applied with a tongue cleaner in reducing oral halitosis. AB - OBJECTIVE: The short-term and overnight effect of three treatment regimens on oral halitosis were investigated: toothbrushing with a reference toothpaste, toothbrushing with reference toothpaste and tongue cleaning, and toothbrushing and tongue cleaning with a tooth-and-tongue gel. METHOD AND MATERIALS: Fifty-four subjects meeting the inclusion criteria for bad breath were enrolled in the study. All subjects received each of the three treatment regimens in a balanced design. Efficacy was assessed by organoleptic ratings and volatile sulfur compound (VSC) measurements 5 and 60 minutes after first application and overnight after 7 days of repeated use. RESULTS: The combination of toothbrushing and tongue cleaning with tooth-and-tongue gel provided the best results in terms of organoleptic ratings and VSC measurements at all time points compared to the other treatment regimens. CONCLUSION: The use of tooth and tongue gel for both toothbrushing and tongue cleaning showed a positive short-term and overnight effects after 7 days of use. This treatment regimen is a promising approach to control halitosis. PMID- 23034425 TI - Genotoxicity of digital panoramic radiography on oral epithelial tissues. AB - OBJECTIVE: To evaluate the genotoxic effects of x-rays on gingival and buccal epithelial cells during panoramic dental radiography using the micronucleus test. METHOD AND MATERIALS: Eighty otherwise healthy subjects who required a diagnostic panoramic radiograph and met the selection criteria were included in the study. Epithelial cells were obtained from the maxillary anterior gingiva and buccal mucosa by gentle scraping with a wooden spatula immediately before exposure and again 10 days after exposure. Cytologic preparations were made according to the Papanicolaou staining method and analyzed under a light microscope for micronucleus count. RESULTS: The mean +/- SD micronucleus count of gingival epithelial cells was 1.08 +/- 0.76 before radiographic exposure and 1.6 +/- 0.93 after exposure. This increase was statistically significant (P < .05). Similarly, there was an increase in the postexposure micronucleus count in the buccal mucosa, but this increase was not significant (P > .05). A significant correlation was observed between the age of subjects and micronucleus count, although no such correlation was found between sex and micronucleus count. CONCLUSION: Although radiation-related effects from panoramic radiography were reduced compared with full-mouth intraoral periapical radiographs or radiotherapy, the results of this study show that genotoxic effects do take place. Thus, radiographs should be taken with adequate protection measures and only when the potential benefit outweighs the potential risk. PMID- 23034427 TI - Gut microbiota: married to our gut microbiota. PMID- 23034426 TI - Variables of host response in saliva of patients with periodontitis: a pilot study. AB - OBJECTIVE: Periodontitis is an infection that results from an imbalance between periodontopathic microorganisms and the local and systemic host defense. This study analyzed saliva samples of patients with periodontitis for several biomarkers of host response. METHOD AND MATERIALS: Saliva was collected from 13 patients with chronic periodontitis, seven patients with aggressive periodontitis, and 13 periodontally healthy control subjects. Diverse markers of host response representing innate and adaptive immune response as well as antioxidative variables were determined. RESULTS: Patients with aggressive periodontitis had significantly higher values of lipid peroxidation and cathepsin C activity in saliva. The highest activities of neutrophil elastase, proteinase 3, and superoxide dismutase were measured in chronic periodontitis patients. Levels of antimicrobial peptides HNPs 1-3 were significantly highest in chronic periodontitis patients than in aggressive periodontitis or control subjects. Immunoglobulin G levels directed against Aggregatibacter actinomycetemcomitans were highest in aggressive periodontitis patients, while those directed against Porphyromonas gingivalis were highest in chronic periodontitis patients. Immunoglobulin A levels directed against these periodontopathogens did not differ among the groups. CONCLUSION: Chronic periodontitis patients showed higher levels of markers primarily associated with combating infection. The levels of markers known mainly for tissue damage were higher in aggressive periodontitis patients. Neutrophil-related markers may be able to identify and differentiate patients with periodontitis. PMID- 23034428 TI - Plasma frequency and dielectric function dependence on doping and temperature for p-type indium phosphide epitaxial films. AB - The optical properties of p-type InP epitaxial films with different doping concentrations are investigated by infrared absorption measurements accompanied by reflection and transmission spectra taken from 25 to 300 K. A complete dielectric function (DF) model, including intervalence band (IVB) transitions, free-carrier and lattice absorption, is used to determine the optical constants with improved accuracy in the spectral range from 2 to 35 MUm. The IVB transitions by free holes among the split-off, light-hole, and heavy-hole bands are studied using the DF model under the parabolic-band approximation. A good understanding of IVB transitions and the absorption coefficient is useful for designing high operating temperature and high detectivity infrared detectors and other optoelectronic devices. In addition, refractive index values reported here are useful for optoelectronic device designing, such as implementing p-InP waveguides in semiconductor quantum cascade lasers. The temperature dependence of hole effective mass and plasma frequency is also reported. PMID- 23034429 TI - [Consistency in the analysis and reporting of PEPs in oncology randomized controlled trials from registration to publication: a systematic review]. AB - To improve the quality of reporting of randomized clinical trials (RCTs), international registries for RCTs and guidelines for primary endpoint (PEP) analysis were established. The objectives of this systematic review were to evaluate concordance of PEP between publication and the corresponding registry and to assess the intrapublication consistency in PEP reporting. All adult oncology RCTs in solid tumors published in 10 journals between 2005 and 2009 were reviewed. Registration information was extracted from international trial registries. A total 366 RCTs were identified. Trial registration was found for 215 trials and the rate increased from 43% in 2005 to 82% in 2009 (P < 0.001). There were 134 RCTs with clearly defined PEPs in registry, with the rate increasing from 15 to 67% (P < 0.001). PEP differs between registration and final publication in 14% trials with clearly defined PEPs. Reporting issues in methodology were found in 15% RCTs, mainly due to inadequate reporting of PEP or of sample size calculation. Problems with the interpretation of trial results were found in 22% publications, mostly due to negative superiority studies being interpreted as showing equivalence. The rates of trial registration and of trials with clearly defined PEP have improved over time, however 14% of these trials reported a different PEP in the final publication. Intrapublication inconsistencies in PEP reporting are frequent. Our findings highlight the need for investigators, peer reviewers and readers for increased awareness and scrutiny of reporting outcomes of oncology RCTs. PMID- 23034430 TI - At a loss. AB - When someone is very ill or has lost a loved one, this may be the hardest time to say the right words. Guidance is given on communication during these times. PMID- 23034432 TI - Hospital status admission determination: the use of Boolean logic, set theory, and information theory to improve accuracy. AB - PURPOSE: To evaluate methods of logic, set theory, and information theory in developing a conceptual framework that would be useful in an educational process as well as in developing a consistent and rational method for hospital status determination. OBJECTIVES: To implement these methods on a daily basis in interaction with nurse case managers, physicians, and in documentation of the process. PRIMARY PRACTICE SETTING: A tertiary private, not-for-profit institution within the department of case management and utilization review. FINDINGS: These methods were well accepted by those involved in the decision process and allowed a Case Management Assignment Protocol to function well in the hospital environment with a low level of disagreement and conflict. CONCLUSIONS: Medical information can be processed effectively with conceptual models of logic and information theory. The used commercial screening systems are described well by set theory and are intersecting sets of patient variables and characteristics. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: These methods can be used in educational processes in practice settings apart from those using the Case Management Assignment Protocol. It provides a basis for evaluation of patients' presentations that use important factors such as clinical uncertainty, patient specific data, and reference to preexisting admission criteria. PMID- 23034434 TI - Community-based case management for uninsured patients with chronic diseases: effects on acute care utilization and costs. AB - PURPOSE OF THE STUDY: To examine the effects of a community-based case management program on acute health care utilization and associated costs in uninsured patients with 1 or more chronic diseases. PRIMARY PRACTICE SETTING: Large regional academic medical center that provides health care services for the vast majority of indigent patients in the area. METHODOLOGY AND SAMPLE: This was a retrospective study of 83 patients who enrolled in a case management program between April 2007 and August 2008 on the basis of 1 or more emergency department visits or acute hospitalizations. Paired t tests were used to compare utilization and costs before and after enrollment. RESULTS: Overall, acute outpatient encounters decreased by 62% and inpatient admissions by 53%, whereas primary care visits increased by 162%. Participation in the case management program was also associated with a 41% reduction in overall aggregate costs, from $16,208 preintervention to $9,541 postintervention (p = .004). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The results of this study suggest that intensive case management can reduce acute care utilization and costs and increase primary care follow-up among uninsured patients with certain chronic diseases. PMID- 23034436 TI - Barriers to care and service needs among chronically homeless persons in a housing first program. AB - PURPOSE: In 2010, more than 600,000 people in the United States experienced homelessness. Efficient and cost-effective housing methods that reduce homelessness need to be implemented. Housing Ready programs are the standard method that often has set requirements including earned income and sobriety, among others. These programs enable a subset of the homeless to become housed. However, chronically homeless persons, who use the most resources, are often not successful at enrollment or maintaining enrollment. Housing First (H1) is a method focusing on chronically homeless persons. Housing First places a client in housing and provides services after stabilization. This article assessed differences between chronically homeless persons in a H1 program and chronically homeless persons who are not in H1. METHOD AND SAMPLE: A case-control study imbedded within a homeless service program collected sociodemographic and service variables, including access and barriers to care. RESULTS: Although the sample was 100% native English speaking, 22% of homeless persons reported that their providers do not speak their same language. All (100%) of participants had a disabling condition under HUD guidelines, but only 17.78% of homeless controls reported having a disabling condition. There were no differences on housing status based on income, gender, race, or age. The lack of differences between these groups indicates that a H1 program can be a clear derivation from the more common Housing Ready programs that have specific requirements for participation. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Provider communication may negatively impact an individual's ability to transition from homelessness. Furthermore, chronically homeless persons not in intensive case management are less likely to understand the eligibility requirements for housing and, therefore, self disqualify because of this lack of knowledge. Intentional communication and education for chronically homeless persons are 2 examples where case managers could improve the ability of the chronically homeless to obtain housing. PMID- 23034437 TI - From acute care to postdischarge: extending the reach of the multidisciplinary team. PMID- 23034438 TI - The blessing of finding your passion. PMID- 23034439 TI - Legal & regulatory issues. PMID- 23034440 TI - The role of case management and care coordination in improving employee health and productivity. PMID- 23034441 TI - Documentation in workers' compensation case management: RU@RISK? PMID- 23034442 TI - The coefficient of determination: what determines a useful R2 statistic? PMID- 23034443 TI - Author response: retinal vein pulsation is in phase with intracranial pressure and not intraocular pressure. PMID- 23034445 TI - Alglucosidase alfa and Pompe disease: still going strong? PMID- 23034447 TI - Bioelectrode-based approach for enhancing nitrate and nitrite removal and electricity generation from eutrophic lakes. AB - Nitrate and nitrite contamination of surface waters (e.g. lakes) has become a severe environmental and health problem, especially in developing countries. The recent demonstration of nitrate reduction at the cathode of microbial fuel cell (MFC) provides an opportunity to develop a new technology for nitrogen removal from surface waters. In this study, a sediment-type MFC based on two pieces of bioelectrodes was employed as a novel in situ applicable approach for nitrogen removal, as well as electricity production from eutrophic lakes. Maximum power density of 42 and 36 mW/m(2) was produced respectively from nitrate- and nitrite rich synthetic lake waters at initial concentration of 10 mg-N/L. Along with the electricity production a total nitrogen removal of 62% and 77% was accomplished, for nitrate and nitrite, respectively. The nitrogen removal was almost 4 times higher under close-circuit condition with biocathode, compared to either the open circuit operation or with abiotic cathode. The mass balance on nitrogen indicates that most of the removed nitrate and nitrite (84.7 +/- 0.1% and 81.8 +/- 0.1%, respectively) was reduced to nitrogen gas. The nitrogen removal and power generation was limited by the dissolved oxygen (DO) level in the water and acetate level injected to the sediment. Excessive oxygen resulted in dramatically decrease of nitrogen removal efficiency and only 7.8% removal was obtained at DO level of 7.8 mg/l. The power generation and nitrogen removal increased with acetate level and was nearly saturated at 0.84 mg/g-sediment. This bioelectrode based in situ approach is attractive not only due to the electricity production, but also due to no need of extra reactor construction, which may broaden the application possibilities of sediment MFC technology. PMID- 23034448 TI - TGF-beta-associated miR-27a inhibits dendritic cell-mediated differentiation of Th1 and Th17 cells by TAB3, p38 MAPK, MAP2K4 and MAP2K7. AB - The alterations induced in dendritic cells (DCs) in the cancer microenvironment have not been extensively explored. We found that the tumor-associated factor TGF beta may selectively upregulate the expression of miR-27a via the SP1 transcription factor. Importantly, miR-27a altered the activity of NF-kappaB and MAPKs (mitogen-activated protein kinases) p38, JNK (c-Jun N-terminal kinases) and ERK (extracellular signal-regulated kinase 1/2). It influences the production of proinflammatory cytokines by targeting TAB3, p38 MAPK, MAP2K4 and MAP2K7. As a consequence, miR-27a hampered the DC-mediated differentiation of Th1 and Th17 cells in vitro and in vivo, but it promoted the DC-mediated accumulation of Tr1 (CD4(+)IL-10(+)) and Treg (CD4(+)CD25(+)Foxp3(+)) cells in vivo. The repeated infusion of miR-27a-engineered DCs into tumor tissues accelerated tumor growth, indicating that miR-27a is a potential target for tumor immunotherapy. PMID- 23034449 TI - Antioxidant properties and cytotoxic effects on human cancer cell lines of aqueous fermented and lipophilic quince (Cydonia oblonga Mill.) preparations. AB - In the course of a screening program on quince phytochemicals, two complex preparations were in the focus of the present study, i.e., a lipophilic quince wax extract (QWE) and an aqueous fermented one (QAFE). While the phytochemical composition has been described earlier, the intention of the current investigation was to complement these data with an extensive antioxidant screening of these preparations including their radical scavenging and reductive power as well as their antilipoperoxidative properties. The Quince Aqueous Fermented Extract (QAFE) effectively scavenged the radical target species exhibiting ID(50) values equal to 68.8 MUg/mL towards DPPH. and 73.7 MUg/mL towards the anion superoxide radical. Quince wax extract (QWE) was more effective at preventing the formation of thiobarbituric reactive species than QAFE exhibiting an ID(50) value equal to 48.9 MUg/mL. Moreover the cytotoxic effects towards human HepG2, A549, and HeLa cell lines were evaluated. The two preparations exerted a different effect on the proliferation of the three tested cell lines. Noteworthy, QAFE was almost always more active than QWE but, sometimes, its effects seemed to be strongly dependent on exposure time. Data obtained demonstrate clearly that both hydrophilic and lipophilic quince preparations are non-toxic and exert health-promoting properties. PMID- 23034450 TI - Comparing the Youth Psychopathic Traits Inventory (YPI) and the Psychopathy Checklist-Youth Version (PCL-YV) among offending girls. AB - Using a multimeasure longitudinal research design, we measured psychopathy with the Youth Psychopathic Traits Inventory (YPI) and the Psychopathy Checklist-Youth Version (PCL-YV) among 122 offending girls. We examined the psychometric properties of the YPI, investigated the association between the YPI and the PCL YV, and assessed their concurrent and longitudinal association with externalizing problems on the Youth/Adult Self-Report and violent and delinquent behaviors on the Self-Report of Offending. Alphas for the YPI were adequate and there were small to moderate correlations between the YPI and PCL-YV, suggesting that each assesses distinctive personality features. The YPI and the PCL-YV were approximately equivalent in their association with concurrent and longitudinal outcomes with two exceptions, where the YPI demonstrated a stronger association with antisocial behavior. Concurrently, there was a divergent relationship between the psychopathy factor scores and antisocial outcomes. Within 2 years, the psychopathy affective factor, which constrained the YPI and PCL-YV to be equivalent, was associated with externalizing behaviors and the YPI affective factor was associated with violent offending. Approximately 41/2 years later, neither measure was significantly related to antisocial behavior after accounting for past behavior. Reasons for continuity and discontinuity in risk identification are discussed. PMID- 23034451 TI - Cell death: Some like it hot. PMID- 23034452 TI - DNA replication: It's a matter of time. PMID- 23034454 TI - Development: Knowing left from right. PMID- 23034455 TI - Dynamic phase transition properties and hysteretic behavior of a ferrimagnetic core-shell nanoparticle in the presence of a time dependent magnetic field. AB - We have presented dynamic phase transition features and stationary-state behavior of a ferrimagnetic small nanoparticle system with a core-shell structure. By means of detailed Monte Carlo simulations, a complete picture of the phase diagrams and magnetization profiles has been presented and the conditions for the occurrence of a compensation point T(comp) in the system have been investigated. According to Neel nomenclature, the magnetization curves of the particle have been found to obey P-type, N-type and Q-type classification schemes under certain conditions. Much effort has been devoted to investigating the hysteretic response of the particle, and we observed the existence of triple hysteresis loop behavior, which originates from the existence of a weak ferromagnetic core coupling J(c)/J(sh), as well as a strong antiferromagnetic interface exchange interaction J(int)/J(sh). Most of the calculations have been performed for a particle in the presence of oscillating fields of very high frequencies and high amplitudes in comparison with exchange interactions, which resembles a magnetic system under the influence of ultrafast switching fields. Particular attention has also been paid to the influence of the particle size on the thermal and magnetic properties, as well as magnetic features such as coercivity, remanence and the compensation temperature of the particle. We have found that, in the presence of ultrafast switching fields, the particle may exhibit a dynamic phase transition from paramagnetic to a dynamically ordered phase with increasing ferromagnetic shell thickness. PMID- 23034453 TI - Induced pluripotent stem cells: the new patient? AB - Worldwide increases in life expectancy have been paralleled by a greater prevalence of chronic and age-associated disorders, particularly of the cardiovascular, neural and metabolic systems. This has not been met by commensurate development of new drugs and therapies, which is in part owing to the difficulty in modelling human diseases in laboratory assays or experimental animals. Patient-specific induced pluripotent stem (iPS) cells are an emerging paradigm that may address this. Reprogrammed somatic cells from patients are already applied in disease modelling, drug testing and drug discovery, thus enabling researchers to undertake studies for treating diseases 'in a dish', which was previously inconceivable. PMID- 23034456 TI - Functional selectivity in serotonin receptor 2A (5-HT2A) endocytosis, recycling, and phosphorylation. AB - G protein-coupled receptor (GPCR) signaling is modulated by endocytosis and endosomal sorting of receptors between degradation and recycling. Differential regulation of these processes by endogenous ligands and synthetic drugs is a poorly understood area of GPCR signaling. Here, we describe remarkable diversity in the regulation of trafficking of GPCR induced by multiple ligands. We show that the serotonin receptor 2A (5-HT(2A)), a prototypical GPCR in the study of functional selectivity at a signaling receptor, is functionally selective in endocytosis and recycling in response to five ligands tested: endogenous agonists serotonin (5-HT) and dopamine (DA), synthetic agonist 1-(2,5-dimethoxy-4 iodophenyl)-aminopropane (DOI), antagonist ketanserin, and inverse agonist and antipsychotic drug clozapine. Only four ligands (5-HT, DA, DOI, and clozapine) bring about receptor endocytosis. As we have earlier described with 5-HT and DA, there is ligand-specific requirement for protein kinase C (PKC) in endocytosis. We now show 5-HT(2A) phosphorylation by PKC is necessary for 5-HT-mediated and DOI-mediated receptor endocytosis, but DA-mediated and clozapine-mediated internalization is not affected if PKC is inhibited. Internalized receptors are recycled to the cell surface, but there is variability in the time course of recycling. 5-HT- and DA-internalized receptors are recycled in 2.5 hours while agonist DOI and antagonist clozapine bring about recycling in 7.5 hours. Recycling in response to those ligands that require PKC activation to effect receptor endocytosis is dependent on receptor dephosphorylation by protein phosphatase 2A (PP2A). Thus, internalization and phosphorylation/dephosphorylation cycles may play a significant role in the regulation of 5-HT(2A) by functionally and therapeutically important ligands. PMID- 23034457 TI - Effect of continuous blood purification on concentrations of plasma vasoactive substances and cardiac function in endotoxic shock. AB - OBJECTIVE: To evaluate the effect of continuous blood purification on cardiac function and plasma vasoactive substances in endotoxic shock in piglets. DESIGN: This was a randomized controlled trial in an animal laboratory in a tertiary care pediatric center. MATERIALS AND METHODS: Twenty-three healthy Shanghai white piglets weighing 8-14 kg were randomly assigned to one of the four groups: control group (n = 5), continuous blood purification without lipopolysaccharide infusion group (continuous blood purification, n = 6), lipopolysaccharide-induced endotoxin shock without continuous blood purification group (lipopolysaccharide, n = 6), and lipopolysaccharide-induced endotoxin shock with continuous blood purification group (continuous blood purification/lipopolysaccharide, n = 6). INTERVENTIONS: The lipopolysaccharide and continuous blood purification/lipopolysaccharide groups were injected intravenously with Escherichia coli endotoxin to induce septic shock. The continuous blood purification and continuous blood purification/lipopolysaccharide groups received continuous venovenous hemodiafiltration right after model establishment. At baseline state (T0), following the injection of lipopolysaccharide (T), 1 hr later (T1), 3 hrs later (T3), and 5 hrs later (T5) after model establishment, clinical systemic inflammatory response syndrome parameters, hemodynamic indexes, and plasma concentration of vasoactive substances were obtained. Plasma concentration of dopamine was measured by enzyme-linked immunosorbent assay (DSL Company) and endothelin-1 by enzyme-linked immunosorbent assay (R&D Company). Nitric oxide synthase activity was measured by chromatometry (Nanjing Jiancheng Bioengineering Institute, China). MEASUREMENTS AND MAIN RESULTS: In continuous blood purification/lipopolysaccharide group, after treatment with CPB, heart rate decreased significantly (p < .05) and pulse contour cardiac index, systematic vascular resistance index, and stroke volume index increased significantly (p < .05) when compared with lipopolysaccharide and continuous blood purification groups. After treatment with continuous blood purification, dopamine and endothelin-1 level increased and nitric oxide synthase activities decreased in continuous blood purification/lipopolysaccharide group when compared with the lipopolysaccharide group. In the continuous blood purification/lipopolysaccharide group, improvement in hemodynamic indexes was strongly correlated with increases in plasma dopamine and endothelin-1 level and decreases in nitric oxide synthase activity (r > .9, p < .05). CONCLUSIONS: The adverse cardiovascular effects of lipopolysaccharide-induced endotoxin shock can be improved by continuous blood purification. Improvement is correlated with increases in the concentration of plasma vasoactive substances (endothelin and dopamine) and decreases in nitric oxide synthase activity. PMID- 23034458 TI - "What would you do if this were your child?": practitioners' responses during enacted conversations in the United States. AB - OBJECTIVE: To explore how practitioners in the United States respond to the question "What would you do if this were your child?" during realistic enactments with professional actors. DESIGN: Descriptive study of realistic pediatric critical care enactments. SETTING: Pediatric critical care. SUBJECTS: Interprofessional practitioners who enrolled in the Program to Enhance Relational and Communication Skills at Children's Hospital Boston and engaged in realistic simulated enactments. INTERVENTION: During the Program to Enhance Relational and Communication Skills workshops, practitioners met with parent-actors faced with life-support decisions for their 5-yr-old son who had suffered a near-drowning incident. Parent-actors were directed to naturally pose the question, "What would you do if this were your child?" The enactments were videotaped and practitioners' verbal responses to the question were qualitatively analyzed using content analysis. MEASUREMENTS AND MAIN RESULTS: From 2003 to 2008, we offered 20 Program to Enhance Relational and Communication Skills workshops and analyzed 20 realistic enactments during which interprofessional teams engaged in conversations about life-support decisions with parent-actors. In 50% of the meetings, the physician responded to the question, in 25% both the physician and the nurse or social worker, in 20% the nurse, and in 5% the physical therapist. The content of practitioners' responses yielded six themes: acknowledgment; discomfort and/or reluctance; values and decision-making approaches; focus on medical information; emotional and practical support; and personal response and self-disclosure. Eighty percent of practitioners' responses included more than one theme. CONCLUSIONS: Practitioners demonstrated a wide repertoire of responses that varied in their degree of relational engagement and responsiveness. Future research should explore parents' perspectives and preferences regarding such communication to further refine recommendations and educational experiences. PMID- 23034459 TI - Trial of shift scheduling with standardized sign-out to improve continuity of care in intensive care units. AB - BACKGROUND: Since 2003, the Accreditation Council for Graduate Medical Education requires residency programs to restrict to 80 hrs/wk, averaged over 4 wks to improve patient safety. These restrictions force training programs with night call responsibilities to either maintain a traditional program with alternative night float schedules or adopt a "shift" model, both with increased handoffs. OBJECTIVE: To assess whether a 65 hrs/wk shift-work schedule combined with structured sign-out curriculum is equivalent to a 65 hrs/wk traditional day coverage with night call schedule, as measured by multiple assessments. DESIGN: Eight-month trial of shift-work schedule with structured sign-out curriculum (intervention) vs. traditional call schedule without curriculum (control) in alternating 1-2 month periods. SETTING: A mixed medical-surgical intensive care unit at a tertiary care academic center. SUBJECTS: Primary subjects: 19 fellows in a Multidisciplinary Critical Care Training Program; Secondary subjects: intensive care unit nurses and attending physicians, families of intensive care unit patients. INTERVENTIONS: Implementation of shift-work schedule, combined with structured sign-out curriculum. MEASUREMENTS: Workplace perception assessment through Continuity of Care Survey evaluation by faculty, fellows, and nurses through structured surveys; family assessment by the Critical Care Family Needs Index survey; clinical assessment through intensive care unit mortality, intensive care unit length of stay, and intensive care unit readmission within 48 hrs; and educational impact assessment by rate of fellow didactic lecture attendance. MAIN RESULTS: There were no statistically significant differences in surveyed perceptions of continuity of care, intensive care unit mortality (8.5% vs. 6.0%, p = .20), lecture attendance (43% vs. 42%), or family satisfaction (Critical Care Family Needs Index score 24 vs. 22) between control and intervention periods. There was a significant decrease in intensive care unit length of stay (8.4 vs. 5.7 days, p = .04) with the shift model. Readmissions within 48 hrs were not different (3.6% vs. 4.9%, p = .39). Nurses preferred the intervention period (7% control vs. 73% intervention, n = 30, p = .00), and attending faculty preferred the intervention period and felt continuity of care was maintained (15% control vs. 54% intervention, n = 11, p = .15). CONCLUSIONS: A shift-work schedule with structured sign-out curriculum is a viable alternative to traditional work schedules for the intensive care unit in training programs. PMID- 23034462 TI - Timing perception and motor coordination on rope jumping in children with attention deficit hyperactivity disorder. AB - OBJECTIVES: To evaluate timing perception ability and motor coordination in children with ADHD (Attention Deficit Hyperactivity Disorder) while rope jumping at different rates. DESIGN AND SETTING: Rope jumping at (1) a constant tempo of 100 for 15 s (RJ-C) and (2) two randomly permutated tempos (80, 100, or 120) for 15 s (RJ-V). MAIN OUTCOME MEASURES: The "timing variation while jumping", "timing variation while whirling", and "hand-foot deviation time" in each rope jumping cycle were recorded, to assess the time estimation ability. PARTICIPANTS: 10 children with ADHD (9.65 +/- 1.27 years) and 10 children without ADHD (9.93 +/- 1.54 years) were recruited. RESULTS: The ADHD group showed greater variation in time between the foot jumping and the rope whirling tasks. Also, the median value of hand-foot deviation time was greater in the ADHD group (3.34 ms) than in the control group (1.75 ms). In RJ-V, the control group was able to modify their pace and respond to the target speed in the post-phase, while the ADHD group could not. CONCLUSION: Impaired timing perception leads to less accurate performance during rope jumping for ADHD children. The findings also reveal that poor hand foot coordination results in poor control of simultaneous movements of the upper and lower limbs during rope jumping. PMID- 23034460 TI - Current approaches to the diagnosis of bacterial and fungal bloodstream infections in the intensive care unit. AB - Healthcare systems spend considerable resources collecting and processing blood cultures for the detection of blood stream pathogens. The process is initiated with the collection of blood cultures that depend upon proper skin disinfection, collection of an adequate number of specimens and volume of blood, and prompt processing in a sensitive culture system. Complementing blood cultures and gaining in use are techniques such as nucleic acid amplification tests and mass spectroscopy that allow clinical laboratories to detect and identify organisms from blood cultures substantially faster than conventional systems. Furthermore, certain resistance mutations can be detected within hours of organism detection, thus providing valuable guidance to clinicians who strive to initiate the appropriate antimicrobial therapy as rapidly as possible, and who wish to discontinue unnecessary drugs expeditiously. Molecular and mass spectroscopy techniques are changing sepsis diagnosis rapidly and will provide far more specific information far more quickly, but the performance characteristics of these systems must be understood by intensivists who use such information to guide their patient management. PMID- 23034465 TI - Is fetuin-A a biomarker of preclinical atherosclerosis in essential hypertension? PMID- 23034464 TI - Unique binding behavior of the recently approved angiotensin II receptor blocker azilsartan compared with that of candesartan. AB - The angiotensin II type 1 (AT(1)) receptor blocker (ARB) candesartan strongly reduces blood pressure (BP) in patients with hypertension and has been shown to have cardioprotective effects. A new ARB, azilsartan, was recently approved and has been shown to provide a more potent 24-h sustained antihypertensive effect than candesartan. However, the molecular interactions of azilsartan with the AT(1) receptor that could explain its strong BP-lowering activity are not yet clear. To address this issue, we examined the binding affinities of ARBs for the AT(1) receptor and their inverse agonist activity toward the production of inositol phosphate (IP), and we constructed docking models for the interactions between ARBs and the receptor. Azilsartan, unlike candesartan, has a unique moiety, a 5-oxo-1,2,4-oxadiazole, in place of a tetrazole ring. Although the results regarding the binding affinities of azilsartan and candesartan demonstrated that these ARBs interact with the same sites in the AT(1) receptor (Tyr(113), Lys(199) and Gln(257)), the hydrogen bonding between the oxadiazole of azilsartan-Gln(257) is stronger than that between the tetrazole of candesartan Gln(257), according to molecular docking models. An examination of the inhibition of IP production by ARBs using constitutively active mutant receptors indicated that inverse agonist activity required azilsartan-Gln(257) interaction and that azilsartan had a stronger interaction with Gln(257) than candesartan. Thus, we speculate that azilsartan has a unique binding behavior to the AT(1) receptor due to its 5-oxo-1,2,4-oxadiazole moiety and induces stronger inverse agonism. This property of azilsartan may underlie its previously demonstrated superior BP lowering efficacy compared with candesartan and other ARBs. PMID- 23034466 TI - We need more evidence for antihypertensive treatment guided by home blood pressure. PMID- 23034467 TI - Conflicting effect of alcohol on cardiovascular risk: a clue to understand the different etiologies of coronary artery disease, stroke and peripheral artery disease. PMID- 23034468 TI - Comparison of the efficacy between hydrochlorothiazide and chlorthalidone on central aortic pressure when added on to candesartan in treatment-naive patients of hypertension. AB - Thiazide-type diuretics are the most commonly used blood pressure (BP)-lowering drug for patients with uncomplicated hypertension. However, it has remained unclear whether hydrochlorothiazide (HCTZ) or chlorthalidone (CTD) shows better improvement in central aortic pressure. We conducted an open-label, randomized, prospective cross-over study with an 8-week active treatment (HCTZ of 25 mg with candesartan of 8 mg or CTD of 12.5 mg with candesartan of 8 mg) with a 4-week washout period (only candesartan during this period). Twenty-eight treatment naive patients of hypertension were enrolled (mean age: 50+/-9 years, male: 44.4%). Central aortic pressure, pulse wave velocity (PWV), augmentation index (AIx) and other BP-derived parameters were measured. After 8 weeks of active treatment, there was no significant difference in changes of central aortic pressure between HCTZ and CTD treatments (Delta=-14+/-8 vs. -16+/-7 mm Hg, P=0.645). However, CTD treatment showed a significant reduction in PWV compared with baseline (1321+/-194 vs. 1439+/-190 cm s(-1), P=0.007) and HCTZ treatment (Delta=-118+/-82 vs. Delta=5+/-72 cm s(-1), P=0.033), whereas HCTZ treatment showed a marginal, but not a significant reduction in AIx compared with baseline. In conclusion, CTD of 12.5 mg is as potent as HCTZ of 25 mg, when combined with candesartan of 8 mg, in lowering central aortic pressure. In addition, CTD treatment resulted in a significant reduction of PWV. PMID- 23034469 TI - The Vicorder device compared with SphygmoCor in the assessment of carotid-femoral pulse wave velocity in patients with peripheral arterial disease. AB - To assess the reliability and reproducibility of the Vicorder's carotid-femoral pulse wave velocity (cfPWV) measurements in patients with peripheral arterial disease (PAD) and to compare between cfPWV measurements obtained using the Vicorder with those obtained using the SphygmoCor device as a reference. Some 30 patients with PAD (23 men, mean age 64.9+/-7.5) underwent cfPWV measurement twice by a single investigator during one visit using the Vicorder and the SphygmoCor according to the manufacturer's instructions. Intra-rater reproducibility for each device was assessed using intraclass correlation coefficients (ICC) and Bland-Altman method. The latter was also used to compare between the two devices. The mean difference (s.d.) between repeated measurements was 0.03+/-0.92 m s(-1), P=0.85 and 0.01+/-0.54 m s(-1), P=0.91 for the SphygmoCor and Vicorder, respectively. Measurements of cfPWV were highly reproducible using both devices (ICC=0.94 and 0.92, for the Vicorder and SphygmoCor, respectively). Limits of Agreement using the Bland-Altman method were -1.07 to 1.09 m s(-1) and -1.79 to 1.85 m s(-1) for the Vicorder and the SphygmoCor, respectively. Bland-Altman plots indicated that 90% of the cfPWV measurements using the Vicorder and 93% of the measurements using the SphygmoCor fell within two s.d.s of the mean difference. Transit time (TT) differed significantly between the two devices (mean difference 30+/-9.2 m s, P<0.001), with the Vicorder recording higher values. Nevertheless, the two devices recorded nearly similar cfPWV measurements (mean difference -0.69+/-1.6 m s(-1), P=0.02) with 97% of cfPWV values falling within two s.d. values of the mean difference on Bland-Altman plot. Both devices generated highly reproducible cfPWV measurements in patients with PAD and were in good agreement when compared with each other. However, the discrepancy in TT between the two devices lead to the Vicorder producing lower values of cfPWV at high values produced by the SphygmoCor. PMID- 23034470 TI - The physical and mental health of lesbian, gay male, and bisexual (LGB) older adults: the role of key health indicators and risk and protective factors. AB - PURPOSE: Based on resilience theory, this paper investigates the influence of key health indicators and risk and protective factors on health outcomes (including general health, disability, and depression) among lesbian, gay male, and bisexual (LGB) older adults. DESIGN AND METHODS: A cross-sectional survey was conducted with LGB older adults, aged 50 and older (N = 2,439). Logistic regressions were conducted to examine the contributions of key health indicators (access to health care and health behaviors), risk factors (lifetime victimization, internalized stigma, and sexual identity concealment), and protective factors (social support and social network size) to health outcomes, when controlling for background characteristics. RESULTS: The findings revealed that lifetime victimization, financial barriers to health care, obesity, and limited physical activity independently and significantly accounted for poor general health, disability, and depression among LGB older adults. Internalized stigma was also a significant predictor of disability and depression. Social support and social network size served as protective factors, decreasing the odds of poor general health, disability, and depression. Some distinct differences by gender and sexual orientation were also observed. IMPLICATIONS: High levels of poor general health, disability, and depression among LGB older adults are of major concern. These findings highlight the important role of key risk and protective factors, which significantly influences health outcomes among LGB older adults. Tailored interventions must be developed to address the distinct health issues facing this historically disadvantaged population. PMID- 23034471 TI - Physical impairment is associated with nursing home admission for older adults in disadvantaged but not other neighborhoods: results from the UAB study of aging. AB - OBJECTIVES: Aging adults face an increased risk of adverse health events as well as risk for a decrease in personal competencies across multiple domains. These factors may inhibit the ability of an older adult to age in place and may result in a nursing home admission (NHA). This study combines insights from Lawton's environmental press theory with the neighborhood disadvantage (ND) literature to examine the interaction of the neighborhood environment and individual characteristics on NHA. METHODS: Characteristics associated with the likelihood of NHA for community-dwelling older adults were examined using data collected for 8.5 years from the UAB Study of Aging. Logistic regression models were used to test direct effects of ND on NHA for all participants. The sample was then stratified into 3 tiers of ND to examine differences in individual-level factors by level of ND. RESULTS: There was no direct link between living in a disadvantaged neighborhood environment and likelihood of NHA, but physical impairment was associated with NHA for older adults living highly disadvantaged neighborhood environments in contrast to older adults living in less disadvantaged neighborhood environments, where no association was observed. DISCUSSION: These outcomes highlight (a) the usefulness of linking Lawton's theories of the environment with the ND literature to assess health-related outcomes and (b) the importance of neighborhood environment for older adults' ability to age in place. PMID- 23034474 TI - Impact of vitamin D supplementation during a resistance training intervention on body composition, muscle function, and glucose tolerance in overweight and obese adults. AB - BACKGROUND & AIMS: The impact of vitamin D supplementation in overweight and obese adults during resistance training on body composition, muscle function, and glucose tolerance was investigated. METHODS: Twenty-three overweight and obese (age: 26.1+/-4.7 y; BMI: 31.3+/-3.2 kg/m(2); 25-hydroxyvitamin D: 19.3+/-7.2 ng/mL) adults were recruited for participation in a double-blind, placebo controlled trial. Participants were randomly divided into vitamin D (VitD, 4000 IU/d; 5 females, 5 males) and placebo (PL; 7 females, 6 males) groups. Both groups completed 12 weeks of resistance training. 25-hydroxyvitamin D, parathyroid hormone, body composition, and glucose tolerance were assessed at baseline and 12 weeks. Muscle function (strength and power) was assessed at baseline, 4, 8, and 12 weeks. RESULTS: During the intervention, 25-hydroxyvitamin D increased and parathyroid hormone decreased in the VitD group (P<0.05). Peak power was significantly increased at 4 weeks in the VitD group only (P<0.05). Regression analysis revealed an inverse association between the change in 25 hydroxyvitamin D with the change in waist-to-hip ratio (R(2)=0.205, P=0.02). No other improvements were observed with supplementation. CONCLUSIONS: Vitamin D supplementation in overweight and obese adults during resistance training induced an early improvement in peak power, and elevated vitamin D status was associated with reduced waist-to-hip ratio. CLINICAL TRIAL REGISTRATION NUMBER: NCT01199926. PMID- 23034475 TI - Porphyromonas gingivalis entry into gingival epithelial cells modulated by Fusobacterium nucleatum is dependent on lipid rafts. AB - Host cell invasion by a major periodontal pathogen, Porphyromonas gingivalis, has been proposed as an important mechanism involved in host-pathogen interactions in periodontal and cardiovascular diseases. The present study sought to gain insight into the underlying mechanism(s) involved in previously demonstrated fusobacterial modulation of host cell invasion by P. gingivalis. An immortalized human gingival cell line Ca9-22 was dually infected with P. gingivalis ATCC 33277 and Fusobacterium nucleatum TDC 100, and intracellular invasion was assessed by scanning electron microscopy (SEM) and confocal scanning laser microscopy (CSLM). SEM observation showed that P. gingivalis and F. nucleatum formed consortia and were in the process of penetrating into Ca9-22 by 30-60 min after infection. In CSLM, Ca9-22 cells that contained both P. gingivalis and F. nucleatum were frequently observed after 2 h, although cells that contained exclusively P. gingivalis were also found. Infection by P. gingivalis and/or F. nucleatum revealed evident colocalization with a lipid raft marker, GM1-containing membrane microdomains. In an antibiotic protection assay, depletion of epithelial plasma membrane cholesterol resulted in a significant reduction of recovered P. gingivalis or F. nucleatum (~33% of untreated control; p < 0.001). This inhibition was also confirmed by CSLM. Sequential infection experiments showed that timing of infection by each species could critically influence the invasion profile. Co-infection with F. nucleatum significantly enhanced host cell invasion by P. gingivalis 33277, its serine phophatase SerB mutant and complemented strains, suggesting that the SerB does not play a major role in this fusobacterial enhancement of P. gingivalis invasion. Thus, the interaction between F. nucleatum and host cells may be important in the fusobacterial enhancement of P. gingivalis invasion. Collectively, these results suggest that lipid raft-mediated process is at least one of the potential mechanisms involved in fusobacterium-modulated host cell invasion by P. gingivalis. PMID- 23034476 TI - Contribution of the epigenetic mark H3K27me3 to functional divergence after whole genome duplication in Arabidopsis. AB - BACKGROUND: Following gene duplication, retained paralogs undergo functional divergence, which is reflected in changes in DNA sequence and expression patterns. The extent of divergence is influenced by several factors, including protein function. We examine whether an epigenetic modification, trimethylation of histone H3 at lysine 27 (H3K27me3), could be a factor in the evolution of expression patterns after gene duplication. Whereas in animals this repressive mark for transcription is deposited on long regions of DNA, in plants its localization is gene-specific. Because of this and a well-annotated recent whole genome duplication, Arabidopsis thaliana is uniquely suited for studying the potential association of H3K27me3 with the evolutionary fate of genes. RESULTS: Paralogous pairs with H3K27me3 show the highest coding sequence divergence, which can be explained by their low expression levels. Interestingly, they also show the highest similarity in expression patterns and upstream regulatory regions, while paralogous pairs where only one gene is an H3K27me3 target show the highest divergence in expression patterns and upstream regulatory sequence. These trends in divergence of expression and upstream regions are especially pronounced for transcription factors. CONCLUSIONS: After duplication, a histone modification can be associated with a particular fate of paralogs: H3K27me3 is linked to lower expression divergence yet higher coding sequence divergence. Our results show that H3K27me3 constrains expression divergence after duplication. Moreover, its association with higher conservation of upstream regions provides a potential mechanism for the conserved H3K27me3 targeting of the paralogs. PMID- 23034477 TI - H2A.Z landscapes and dual modifications in pluripotent and multipotent stem cells underlie complex genome regulatory functions. AB - BACKGROUND: The histone variant H2A.Z has been implicated in nucleosome exchange, transcriptional activation and Polycomb repression. However, the relationships among these seemingly disparate functions remain obscure. RESULTS: We mapped H2A.Z genome-wide in mammalian ES cells and neural progenitors. H2A.Z is deposited promiscuously at promoters and enhancers, and correlates strongly with H3K4 methylation. Accordingly, H2A.Z is present at poised promoters with bivalent chromatin and at active promoters with H3K4 methylation, but is absent from stably repressed promoters that are specifically enriched for H3K27 trimethylation. We also characterized post-translational modification states of H2A.Z, including a novel species dually-modified by ubiquitination and acetylation that is enriched at bivalent chromatin. CONCLUSIONS: Our findings associate H2A.Z with functionally distinct genomic elements, and suggest that post-translational modifications may reconcile its contrasting locations and roles. PMID- 23034478 TI - Neurodevelopment: isolation reduces myelination. PMID- 23034479 TI - Behavioural genetics: to bee or not to bee...a nurse. PMID- 23034480 TI - Signal transduction: hair cells go out with a bang. PMID- 23034481 TI - Translating upwards: linking the neural and social sciences via neuroeconomics. AB - The social and neural sciences share a common interest in understanding the mechanisms that underlie human behaviour. However, interactions between neuroscience and social science disciplines remain strikingly narrow and tenuous. We illustrate the scope and challenges for such interactions using the paradigmatic example of neuroeconomics. Using quantitative analyses of both its scientific literature and the social networks in its intellectual community, we show that neuroeconomics now reflects a true disciplinary integration, such that research topics and scientific communities with interdisciplinary span exert greater influence on the field. However, our analyses also reveal key structural and intellectual challenges in balancing the goals of neuroscience with those of the social sciences. To address these challenges, we offer a set of prescriptive recommendations for directing future research in neuroeconomics. PMID- 23034482 TI - The Zalpha domain of fish PKZ facilitates the B-Z conformational transition of oligonucleotide DNAs with d(GC)(n) inserts. AB - PKZ (PKR-like) was discovered as a member of elF2alpha kinase family in fish, which possesses a conserved catalytic domain of an eIF2alpha kinase in C-terminal and also two Z-DNA-binding domains (Zalpha1 and Zalpha2) in N-terminal. PKZ can be activated through binding of Zalpha to Z-DNA. However, the regulatory function of PKZ Zalpha still remains unclear. To investigate a molecular mechanism of how PKZ Zalpha interacts with Z-DNA, we expressed Zalpha polypeptide Zalpha1alpha2 in Escherichia coli Rosetta strain and purified by affinity chromatography on Ni-NTA resin. Different lengths of oligonucleotide DNAs with various inserts, namely d(GC)(n) (n = 6, 8, 10, 13), d(TA)(n) (n = 6, 10), non-d(GC), and non-d(TA), were designed and synthesized. Circular dichroism spectrum and gel mobility shift assays were used to investigate the effects of Zalpha1alpha2 on the conformational transition of different oligonucleotide DNAs. Results showed that oligonucleotide DNAs retained a conventional B-DNA conformation in the absence of Zalpha1alpha2. With the increasing amount of Zalpha1alpha2 titration, d(GC)(n) were recognized and converted to Z-DNA conformation to some degree. With increasing the repeat number (from n = 6 to n = 13), the tendency of conformational transition became more obvious. However, the conformation of oligonucleotides with d(TA)(n) inserts changed a little in the presence of Zalpha1alpha2, and Zalpha1alpha2 had no effect on conformational transition of oligonucleotides with non-d(GC) or non-d(TA) inserts. Gel mobility shift assays further showed that Zalpha1alpha2 could bind to oligonucleotide with d(GC)(10). In other words, Zalpha1alpha2 can turn oligonucleotides with d(GC)(n) inserts into Z-DNA conformation and bind to it with high affinity. PMID- 23034483 TI - A method mediated AAVS1 recombination with Rep mRNA and homologous arms. AB - The adeno-associated virus (AAV) genome can be stably integrated into the AAVS1 region of human chromosome 19 (19q13.4-qter) with the assistance of Rep68/78 protein. In the current models of AAV integration in a locus-specific manner, the foreign genes were randomly inserted into the AAVS1 region, which contains several functional genes. As random integration in this region may lead to insertion mutations and disrupt normal gene expression or critical signaling pathways of the host cells, it is necessary to find a precise insertion site in the AAVS1 region. Homologous recombination is the most accurate and versatile mechanism for such site-specific integration. To investigate site-specific integration in the AAVS1 region, a targeted vector containing two homologous arms derived from AAVS1 and a reporter gene was transfected into HeLa cells with or without Rep68/78 mRNA. The results indicated that transient expression of Rep68/78 in HeLa cells improved integration of the gene of interest at the AAVS1 locus in a site-specific manner. Compared with locus-specific integration reported in previous studies, site-specific integration may minimize the risk associated with random DNA integration in the AAVS1 region, which might be helpful for gene therapy. PMID- 23034485 TI - A highly permeable and selective zeolitic imidazolate framework ZIF-95 membrane for H2/CO2 separation. AB - Making use of the preferred adsorption affinity and capacity to CO(2) as well as the highly porous structure with huge cavities of 2.4 nm, a highly permeable and selective ZIF-95 molecular sieve membrane was developed for the separation of H(2) from CO(2). PMID- 23034484 TI - Connecting the (quantum) dots: towards hybrid photovoltaic devices based on chalcogenide gels. AB - CdSe(ZnS) core(shell) aerogels were prepared from the assembly of quantum dots into mesoporous colloidal networks. The sol-gel method produces inorganic particle interfaces with low resistance to electrical transport while maintaining quantum-confinement. The photoelectrochemical properties of aerogels and their composites with poly(3-hexylthiophene) are reported for the first time. PMID- 23034491 TI - The 2011 PEMpix photo competition award winner: Vanessa Perez, MD: An unusual case of pallor, the eyes have it! AB - This is a case report of 7-year-old boy who presented with diplopia. Physical examination was remarkable for pallor and right-eye proptosis. Differential diagnosis of this chief complaint and the management of the suspected condition are discussed. This case was presented at the Section of Emergency Medicine Meeting at the National Conference and Exhibition of the American Academy of Pediatrics in 2011 and was awarded first place in the PEMpix photo competition. PMID- 23034492 TI - A 15-year-old female with amenorrhea, abdominal distention, and elevated human chorionic gonadotropin: pregnancy, right? Not so fast.... AB - Nongestational choriocarcinoma, a rare ovarian tumor, may present in young women with amenorrhea, abdominal distention, and elevated urine human chorionic gonadotropin (hCG), all of which may be mistaken for pregnancy. A 15-year-old Hispanic female, who reported no sexual activity, presented with 6 months of amenorrhea, abdominal pain, and progressive abdominal distension. Initially, suspicion of pregnancy was considered. Physical examination was significant for abdominal distension, but no uterine fundus or fetal anatomy could be palpated, and auscultation did not reveal any fetal heart sounds or bruits. Laboratory values showed elevated urine hCG, cancer antigen 125, and cancer antigen 19.9 levels but normal serum hCG level and was inconsistent with pregnancy. Computed tomographic scans revealed a large abdominal heterogeneous mass and pleural effusions. Salpingo-oophorectomy with total omentectomy and inversion appendectomy removed a 21 * 20.5 * 16.5-cm tumor. Pathological testing determined it to be a nongestational choriocarcinoma. This rare tumor is more common in the pediatric adolescent population than in adults. Surgical resection and chemotherapy often result in a positive prognosis. In female adolescent patients presenting with elevated hCG level, amenorrhea, and abdominal distention, choriocarcinoma should be considered, especially in those with no history of sexual activity or before menarche. PMID- 23034493 TI - Treatment of guanfacine toxicity with naloxone. AB - We describe a 4-year-old boy who presents to the emergency department with lethargy, bradycardia, and initial hypertension followed by hypotension due to guanfacine toxicity after ingestion of standard doses of the extended release formulation. This is the first case report to describe the use of naloxone to treat these symptoms and document improvements in level of consciousness, blood pressure, and heart rate associated with this therapy. PMID- 23034494 TI - Beneficial effects of levosimendan in infants with sepsis-associated cardiac dysfunction: report of 2 cases. AB - Although international guidelines for hemodynamic support of pediatric septic shock suggest considering the potent calcium sensitizer inodilator levosimendan as a second-line inotropic agent to treat cold hypodynamic shock resistant to catecholamines, clinical experience in septic infants is lacking. We report the beneficial effects of levosimendan infusion in 2 infants (39 and 64 days old) with low cardiac output septic shock (ejection fraction, 29% and 33%; fractional shortening, 10% and 16% respectively) refractory to volume replacement and to the catecholamines dopamine and dobutamine. Levosimendan infusion (0.15 ug/kg/min) promptly increased both patients' myocardial contractility and improved tissue perfusion, thereby reducing lactate levels and increasing urine output. The only adverse effect was moderate hypotension in one infant, who reversed by adding norepinephrine to levosimendan. This clinical experience confirms the potential beneficial effects of levosimendan infusion to restore hemodynamics in infants with low cardiac output septic shock resistant to catecholamines. PMID- 23034495 TI - Significant toxicity in a young female after low-dose tricyclic antidepressant ingestion. AB - BACKGROUND: Tricyclic antidepressant (TCA) ingestions are a relatively common pediatric ingestion, with significant potential for both cardiac and neurological toxicity. Previous studies on pediatric TCA ingestions have found the threshold of toxicity to be 5 mg/kg. CASE: We report a case of an 8-year-old girl who presented to the emergency department with depressed mental status and seizure like movements. An extensive workup was pursued to evaluate the cause of her mental status, which only revealed a positive urine toxicology screen for TCA. Quantified serum levels of amitriptyline were 121 ng/mL (therapeutic range, 50 300 ng/mL) and nortriptyline were 79 ng/mL (therapeutic range 70-170 ng/mL), 18 hours after onset of symptoms. Subsequent history obtained after her mental status returned to normal revealed that she had ingested amitriptyline at a dose of 0.8 mg/kg. CONCLUSIONS: Tricyclic antidepressant ingestion has a high potential for toxicity in pediatric patients. This case suggests, contrary to previous literature, that toxicity may occur even with small doses. PMID- 23034496 TI - Mastoiditis and meningitis complicating an aural foreign body. AB - Children commonly present to emergency departments with foreign bodies in the ear. In addition, physicians place wicks in the ear canal as part of the treatment of otitis externa. Usually, these foreign bodies are easily removed, but occasionally, removal must be deferred or is delayed by parents. Therefore, the dangers of retained foreign bodies are important for the emergency physician to be aware of. We report the highly unusual case of a 12-year-old girl who presented with ear pain for 3 weeks. She was found to have an ear wick in place as part of the treatment of otalgia. She was subsequently diagnosed with mastoiditis and meningitis. This is first time mastoiditis and meningitis has been reported as a complication of ear wick placement, although not the only case of an intracranial complication of an aural foreign body. PMID- 23034497 TI - Early repair of large infant ventricular septal defect despite respiratory syncytial virus-induced respiratory failure with postrepair chylous pericardial effusion requiring pleuropericardial window: a case report and review of the literature. AB - The surgical correction of congenital cardiac lesions that are complicated by intercurrent respiratory syncytial virus (RSV) pneumonitis has traditionally been deferred for at least 6 to 8 weeks. The presumption is that using cardiopulmonary bypass will increase the risk of postoperative pulmonary complications. We present an infant who developed acute respiratory failure related to RSV pneumonitis and required urgent mechanical ventilation. Cardiac evaluation revealed a large nonrestrictive ventricular septal defect (VSD), aortic arch hypoplasia, normally functioning bicuspid aortic valve, and hemodynamic instability associated with markedly increased pulmonary blood flow. Separation from mechanical ventilation was unsuccessful preoperatively. He underwent VSD repair with cardiopulmonary bypass less than 4 weeks after initial RSV infection. He was extubated successfully within 72 hours of VSD repair. Approximately 6 weeks postoperatively, he developed a circumferential chylous pericardial effusion of unclear etiology--an exceedingly rare complication of VSD repair in early infancy in a non-Down syndrome patient. The chylous effusion was initially managed unsuccessfully with Portogen/Monogen and a percutaneously placed pericardial drain. Two weeks later, he underwent creation of a pleuropericardial window with successful resolution of the chylous effusion. It is of interest to pediatricians to be able to correctly time the repair of congenital heart disease lesions after RSV infection to minimize post-bypass pulmonary complications and yet avoid morbidity from undue delays in repair. In addition, chylopericardium can occur in infants after VSD repair, and dietary modification and catheter drainage may not be adequate. PMID- 23034498 TI - Gastric volvulus complication in an infant with undiagnosed congenital diaphragmatic hernia presenting with acute respiratory distress. AB - INTRODUCTION: Congenital diaphragmatic hernia is an embryologic defect that creates a passage for herniation of abdominal structures into the thoracic cavity. This can lead to a variety of complications, including gastric volvulus that can present acutely with epigastric distention and vomiting. In cases of late-onset congenital diaphragmatic hernia, symptoms may be vague and often necessitate further investigation. CASE: Our patient is a 12-month-old previously healthy female infant who presented to the emergency department with a history of vomiting and acute onset respiratory distress. Her SaO(2) was 94% to 98% on room air, her respiratory rate was in the 80s breaths per minute, and she was noted to have severe retractions. Her chest examination revealed absent breath sounds on the left side. Her abdominal examination was unremarkable. The acute presentation of respiratory distress was initially concerning for a foreign body aspiration, but a chest radiograph demonstrated left-sided opacification and mediastinal shift to the right. The patient required intubation for respiratory decompensation and a subsequent computed tomographic scan showed diaphragmatic hernia with gastric volvulus. CONCLUSIONS: This patient's presentation highlights one of the complications that may occur owing to congenital diaphragmatic hernia. Computed tomographic scan is the confirmatory test for diaphragmatic hernia and, in this case, also uncovered a concomitant gastric volvulus. Treatment includes early resuscitation, a definitive airway, and emergent surgery to prevent ischemic necrosis of the stomach owing to strangulation, gastric perforation, and serious cardiorespiratory decompensation. PMID- 23034499 TI - Pediatric posttraumatic headache: two cases using steroids as abortive therapy. AB - Pediatric traumatic brain injury is a common occurrence, and even an ostensibly mild injury may result in disabling posttraumatic headaches. The headache may result in a number of subsequent unremitting symptoms refractory to many standard headache therapies. Current treatment recommendations are sparse because there is a lack of clinical trial data recommendations and outcomes. From these 2 cases, we report the effectiveness of steroids for severe posttraumatic headache, along with recommended treatment strategies for acute pain management and prevention. PMID- 23034500 TI - Sudden unexpected infant death: differentiating natural from abusive causes in the emergency department. AB - Sudden unexpected infant deaths (SUIDs) are deaths in infants younger than 12 months that occur suddenly, unexpectedly, and without obvious cause in the emergency department (ED). Sudden infant death syndrome, the leading cause of SUID in the United States, is much more common, but fatal child abuse and neglect have been sometimes mistaken for sudden infant death syndrome. The distinction between these 2 entities can only be made after a thorough investigation of the scene, interview of caregivers, and a complete forensic autopsy. Development of ED guidelines for the reporting and evaluation of SUID, in collaboration with the local medical examiner and child death review teams, will enable ED practitioners to collect important information in a compassionate manner that will be valuable to the investigating personnel. PMID- 23034502 TI - Bedside ultrasonography in the pediatric emergency department: the focused assessment with sonography in trauma examination uncovers an occult intra abdominal tumor. AB - We present a case of a 3-year-old male with history of minor trauma, who was brought in by ambulance from the playground where he had an acute mental status change and was noted to be hypotensive on initial evaluation. History and examination did not indicate a clear etiology of his symptoms. Point-of-care emergency ultrasonography revealed free fluid in the abdomen and expedited the care of the child's unexpected intra-abdominal hemorrhage from an occult abdominal tumor. This case demonstrates the ability of practitioners to expedite and focus care with the use of rapid assessment with ultrasonography in the pediatric emergency department. PMID- 23034503 TI - Legal briefs. PMID- 23034504 TI - ECGs in the ED. PMID- 23034505 TI - The anaphase-promoting complex/cyclosome in control of plant development. AB - Temporal controlled degradation of key cell division proteins ensures a correct onset of the different cell cycle phases and exit from the cell division program. In light of the cell cycle, the Anaphase-Promoting Complex/Cyclosome (APC/C) is an important conserved multi-subunit ubiquitin ligase, marking targets for degradation by the 26S proteasome. However, whereas the APC/C has been studied extensively in yeast and mammals, only in the last decade has the plant APC/C started to unveil its secrets. Research results have shown the importance of the APC/C core complex and its activators during gametogenesis, growth, hormone signaling, symbiotic interactions, and endoreduplication onset. In addition, recently, the first plant APC/C inhibitors have been reported, allowing a fine tuning of APC/C activity during the cell cycle. Together with the identification of the first APC/C targets, a picture emerges of APC/C activity being essential for many different developmental processes. PMID- 23034506 TI - Molecular analysis of the breast cancer genes BRCA1 and BRCA2 using amplicon based massive parallel pyrosequencing. AB - The aim of this study was to implement the massively parallel sequencing technology for diagnostic applications. We evaluated an amplicon-based method for the analysis of the BRCA1 and BRCA2 genes on the Roche 454 GS-FLX sequencer, to identify disease-causing mutations in breast and/or ovarian cancer patients. A first evaluation relied on the analysis of DNA fragments containing known mutations. Secondly, the entire coding regions of the BRCA1 and BRCA2 genes were interrogated in more than 400 patient samples, using a multiplex PCR-based assay. Variants were filtered on the basis of their frequency (20%) and sequencing depth (>25*). Special attention was given to sequencing accuracy in homopolymers. In the initial evaluation, all known heterozygous mutations were detected. The percentage of mutant reads ranged from 22% to 62%. For the multiplex assay, 95% sensitivity and 91% specificity were obtained. In addition, we were able to reliably distinguish mutations from noise through the analysis of the raw signal intensities in homopolymers. This work presents an evaluation of the next generation sequencing for use in diagnostics, based on a relatively high number of samples and experiments. We anticipate that the technique would further improve, and would allow reducing the costs per analysis and the turn-around time, to benefit patients who undergo BRCA molecular testing. PMID- 23034508 TI - Child health in the United States: recent trends in racial/ethnic disparities. AB - In the United States, race and ethnicity are considered key social determinants of health because of their enduring association with social and economic opportunities and resources. An important policy and research concern is whether the U.S. is making progress toward reducing racial/ethnic inequalities in health. While race/ethnic disparities in infant and adult outcomes are well documented, less is known about patterns and trends by race/ethnicity among children. Our objective was to determine the patterns of and progress toward reducing racial/ethnic disparities in child health. Using nationally representative data from 1998 to 2009, we assessed 17 indicators of child health, including overall health status, disability, measures of specific illnesses, and indicators of the social and economic consequences of illnesses. We examined disparities across five race/ethnic groups (non-Hispanic white, non-Hispanic black, Hispanic, non Hispanic Asian, and non-Hispanic other). We found important racial/ethnic disparities across nearly all of the indicators of health we examined, adjusting for socioeconomic status, nativity, and access to health care. Importantly, we found little evidence that racial/ethnic disparities in child health have changed over time. In fact, for certain illnesses such as asthma, black-white disparities grew significantly larger over time. In general, black children had the highest reported prevalence across the health indicators and Asian children had the lowest reported prevalence. Hispanic children tended to be more similar to whites compared to the other race/ethnic groups, but there was considerable variability in their relative standing. PMID- 23034509 TI - Phosphodiesterase-9 (PDE9) inhibition with BAY 73-6691 increases corpus cavernosum relaxations mediated by nitric oxide-cyclic GMP pathway in mice. AB - Phosphodiesterase-9 (PDE9) specifically hydrolyzes cyclic GMP, and was detected in human corpus cavernosum. However, no previous studies explored the selective PDE9 inhibition with BAY 73-6691 in corpus cavernosum relaxations. Therefore, this study aimed to characterize the PDE9 mRNA expression in mice corpus cavernosum, and investigate the effects of BAY 73-6691 in endothelium-dependent and -independent relaxations, along with the nitrergic corpus cavernosum relaxations. Male mice received daily gavage of BAY 73-6691 (or dimethylsulfoxide) at 3 mg kg(-1) per day for 21 days. Relaxant responses to acetylcholine (ACh), nitric oxide (NO) (as acidified sodium nitrite; NaNO2 solution), sildenafil and electrical-field stimulation (EFS) were obtained in corpus cavernosum in control and BAY 73-6691-treated mice. BAY 73-6691 was also added in vitro 30 min before construction of concentration-responses and frequency curves. PDE9A and PDE5 mRNA expression was detected in the mice corpus cavernosum in a similar manner. In vitro addition of BAY 73-6691 neither itself relaxed mice corpus cavernosum nor changed the NaNO2, sildenafil and EFS-induced relaxations. However, in mice treated chronically with BAY 73-6691, the potency (pEC50) values for ACh, NaNO2 and sildenafil were significantly greater compared with control group. The maximal responses (Emax) to NaNO2 and sildenafil were also significantly greater in BAY 73-6691-treated mice. BAY 73-6691 treatment also significantly increased the magnitude and duration of the nitrergic corpus cavernosum relaxations (8-32 Hz). In conclusion, murine corpus cavernosum expresses PDE9 mRNA. Prolonged PDE9 inhibition with BAY 73-6691 amplifies the NO cGMP-mediated cavernosal responses, and may be of therapeutic value for erectile dysfunction. PMID- 23034511 TI - Current world literature. PMID- 23034510 TI - A coculture system of cavernous endothelial and smooth muscle cells. AB - In erectile dysfunction (ED) research, monocultures of cavernous endothelial cells (CECs) and smooth muscle cells (CSMCs) have been reported, but a CEC-CSMC coculture system is still lacking. In the present study, we wished to investigate the feasibility of setting up such a system and test whether it can be used for diabetic ED research. Cavernous tissues were obtained from patients undergoing surgery for penile prosthesis. CSMCs were isolated by explant culture and verified by calponin staining. CECs were isolated by binding to CD31 antibody, followed by magnetic capture. These CECs were nearly 100% pure endothelial cells as determined by flow cytometric analysis for endothelial markers CD31, vWF and eNOS. Functional analyses, that is, low-density lipoprotein (LDL) uptake and capillary tube formation, also confirmed their endothelial phenotype. When cocultured with CSMCs, CECs formed capillary-like structures, and based on the extent of this capillary-like network, it was determined that a ratio of 1:4 in cell number between CECs and CSMCs was better than ratios of 1:1 and 1:9. It was also found that direct contact between CECs and CSMCs was necessary and a coculture period of 3 weeks was optimal. Autologous CSMCs were better than allogeneic CSMCs, and fibroblasts were completely incompetent. When treated with high glucose (25 mM), the CEC-CSMC coculture expressed significantly lower level of CD31 but significantly higher level of collagen-IV (Col-IV), and the diameter of the capillaries increased significantly, when compared with normal glucose (5 mM)-treated cocultures. These data are consistent with previously observed changes in the cavernous tissues of diabetic patients and thus suggest that the coculture system could be utilized for diabetic ED research. PMID- 23034513 TI - Hearing outcomes in stapes surgery: a comparison of fat, fascia, and vein tissue seals. AB - OBJECTIVE: To compare short- and long-term hearing results following stapedectomy using 3 different oval window grafting materials with the same stapes prosthesis. STUDY DESIGN: Database review. SETTING: Tertiary referral private practice. SUBJECTS AND METHODS: Subjects were ears that underwent stapedectomy for otosclerosis, with placement of fat, fascia, or vein as an oval window seal and reconstruction with a titanium bucket handle prosthesis. A total of 365 procedures met these inclusion criteria: 98 fat grafts, 135 fascia grafts, and 132 vein grafts. Outcome measures included short-term (<1 year) and long-term follow-up air-bone gap. We compared the preoperative and postoperative amount of change in air-bone gap and preoperative and postoperative amount of change in the high-frequency bone conduction average. RESULTS: Overall median times to short term and long-term follow-ups were 2.2 months and 36.1 months, respectively. There were no statistically significant differences between the 3 tissue seal groups in the amount of change in air-bone gap. There was no significant difference in amount of change in high-frequency bone conduction (representing sensorineural hearing level) between the 3 tissue seal groups. Most patients in all 3 groups had an air-bone gap at long-term follow-up of <= 10 dB (fat, 79.5%; fascia, 78.8%; and vein, 75.6%), with 90.3% of all patients at <= 20 dB. CONCLUSIONS: In both the short-term postoperative period and long-term follow-up, there were no significant differences in hearing results among 3 types of tissue seals of the oval window in stapes surgery. Fat, fascia, and vein grafts all provide satisfactory hearing outcomes in stapedectomy. PMID- 23034514 TI - Management of pathologic fractures of the mandible secondary to osteoradionecrosis. AB - OBJECTIVE: To review our experience with late Marx stage III osteoradionecrosis (ORN) of the mandible in patients who present with pathologic fracture. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care center. SUBJECTS AND METHODS: Thirty-seven patients were identified from June 1998 to August 2010 who underwent treatment of Marx grade III osteoradionecrosis with pathologic fracture of the mandible. All patients underwent reconstruction with osteocutaneous free tissue transfer and when possible underwent hyperbaric oxygen therapy Marx protocol. RESULTS: The average time between completion of radiation therapy and presentation of ORN-induced pathologic fracture was 3.2 years. Sixteen patients developed ORN following tooth extraction. Sixteen patients had no previous documented ORN prior to presenting with pathologic fracture. Follow up after surgery averaged 4.5 years with no recurrence of disease. The overall complication rate was 24% with no total flap loss. Of the patients, 95% returned to prefracture dietary intake. Twenty-six patients underwent a staged protocol, in which after resection and plate reconstruction, they underwent 20 hyperbaric oxygen (HBO) dives. They then underwent free tissue transfer followed by a further 10 HBO dives. There were no flaps lost or nonbony unions. Eleven patients did not receive HBO therapy as part of their surgical treatment plan. Again, there was no total flap loss, but 2 skin paddles were lost and 4 bony nonunions occurred. CONCLUSIONS: Pathologic fracture in conjunction with ORN has a relatively high treatment complication rate. Free tissue transfer and HBO are the treatment of choice for this population. PMID- 23034515 TI - Practical guide to understanding multivariable analyses: Part A. AB - Multivariable analyses are complex statistical methods to evaluate the impact of multiple variables on outcomes of interest. Books have been written on each of these methods detailing the mathematical and statistical objectives and processes. However, we have found very little in the way of brief reports that help the nonstatistically trained physician obtain a basic understanding of multivariable analyses in order to have some understanding of the increasing literature using these methods. This work is organized in 2 parts. This article, Part A, addresses the "big 4" algebraic methods of multivariable analysis. The primary focus of Part A is to present a brief "primer" to help the reader understand the methods and uses; it expressly avoids the many details of statistical assumptions, calculations, and myriad branching alternatives. Part B will concentrate on conjunctive consolidation and will focus on enough information to allow the interested reader to actually perform the analysis. For the statistical scholar, we have included references to several voluminous serious works. PMID- 23034517 TI - 5-HTTLPR-environment interplay and its effects on neural reactivity in adolescents. AB - It is not known how 5-HTTLPR genotype x childhood adversity (CA) interactions that are associated with an increased risk for affective disorders in population studies operate at the neural systems level. We hypothesized that healthy adolescents at increased genetic and environmental risk for developing mood disorders (depression and anxiety) would demonstrate increased amygdala reactivity to emotional stimuli compared to those with only one such risk factor or those with none. Participants (n=67) were classified into one of 4 groups dependent on being homozygous for the long or short alleles within the serotonin transporter-linked polymorphic region (5-HTTLPR) of the SLC6A4 gene and exposure to CA in the first 11 years of life (present or absent). A functional magnetic resonance imaging investigation was undertaken which involved viewing emotionally salient face stimuli. In addition, we assessed the role of other variables hypothesized to influence amygdala reactivity, namely recent negative life-events (RNLE) assessed at ages 14 and 17, current anxiety symptoms and psychiatric history. We replicated prior findings demonstrating moderation by gene variants in 5-HTTLPR, but found no support for an effect of CA on amygdala reactivity. We also found a significant effect of RNLE aged 17 with amygdala reactivity demonstrating additive, but not interactive effects with 5-HTTLPR. A whole-brain analysis found a 5-HTTLPR*CA interaction in the lingual gyrus whereby CA appears to differentially modify neural reactivity depending on genotype. These results demonstrate that two different forms of environmental adversities interplay with 5-HTTLPR and thereby differentially impact amygdala and cortical reactivity. PMID- 23034518 TI - Role of fusiform and anterior temporal cortical areas in facial recognition. AB - Recent fMRI studies suggest that cortical face processing extends well beyond the fusiform face area (FFA), including unspecified portions of the anterior temporal lobe. However, the exact location of such anterior temporal region(s), and their role during active face recognition, remain unclear. Here we demonstrate that (in addition to FFA) a small bilateral site in the anterior tip of the collateral sulcus ('AT'; the anterior temporal face patch) is selectively activated during recognition of faces but not houses (a non-face object). In contrast to the psychophysical prediction that inverted and contrast reversed faces are processed like other non-face objects, both FFA and AT (but not other visual areas) were also activated during recognition of inverted and contrast reversed faces. However, response accuracy was better correlated to recognition-driven activity in AT, compared to FFA. These data support a segregated, hierarchical model of face recognition processing, extending to the anterior temporal cortex. PMID- 23034520 TI - The ELISA-measured increase in cerebrospinal fluid tau that discriminates Alzheimer's disease from other neurodegenerative disorders is not attributable to differential recognition of tau assembly forms. AB - Elevated cerebrospinal fluid concentrations of tau discriminate Alzheimer's disease from other neurodegenerative conditions. The reasons for this are unclear. While commercial assay kits are widely used to determine total-tau concentrations, little is known about their ability to detect different aggregation states of tau. We demonstrate that the leading commercial enzyme linked immunosorbent assay reliably detects aggregated and monomeric tau and evinces good recovery of both species when added into cerebrospinal fluid. Hence, the disparity between total-tau levels encountered in Alzheimer's disease and other neurodegenerative conditions is not due to differential recognition of tau assembly forms or the extent of degeneration. PMID- 23034519 TI - Genome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers. AB - BACKGROUND: Accurate outcome prediction in neuroblastoma, which is necessary to enable the optimal choice of risk-related therapy, remains a challenge. To improve neuroblastoma patient stratification, this study aimed to identify prognostic tumor DNA methylation biomarkers. RESULTS: To identify genes silenced by promoter methylation, we first applied two independent genome-wide methylation screening methodologies to eight neuroblastoma cell lines. Specifically, we used re-expression profiling upon 5-aza-2'-deoxycytidine (DAC) treatment and massively parallel sequencing after capturing with a methyl-CpG-binding domain (MBD-seq). Putative methylation markers were selected from DAC-upregulated genes through a literature search and an upfront methylation-specific PCR on 20 primary neuroblastoma tumors, as well as through MBD- seq in combination with publicly available neuroblastoma tumor gene expression data. This yielded 43 candidate biomarkers that were subsequently tested by high-throughput methylation-specific PCR on an independent cohort of 89 primary neuroblastoma tumors that had been selected for risk classification and survival. Based on this analysis, methylation of KRT19, FAS, PRPH, CNR1, QPCT, HIST1H3C, ACSS3 and GRB10 was found to be associated with at least one of the classical risk factors, namely age, stage or MYCN status. Importantly, HIST1H3C and GNAS methylation was associated with overall and/or event-free survival. CONCLUSIONS: This study combines two genome-wide methylation discovery methodologies and is the most extensive validation study in neuroblastoma performed thus far. We identified several novel prognostic DNA methylation markers and provide a basis for the development of a DNA methylation-based prognostic classifier in neuroblastoma. PMID- 23034521 TI - Longitudinal stability of cerebrospinal fluid biomarker levels: fulfilled requirement for pharmacodynamic markers in Alzheimer's disease. AB - The current treatment for Alzheimer's disease (AD) is purely symptomatic, but medications interfering with underlying pathophysiological processes are being developed. To evaluate a possible disease-modifying effect, cerebrospinal fluid (CSF) biomarkers with a direct link to the underlying pathophysiology, such as amyloid-beta(1-42) (Abeta(1-42)), total tau protein (T-tau), and hyperphosphorylated tau (P-tau(181P)), may play an important role. If intra individual fluctuations in biomarker levels are small, the difference between two samples could serve as a pharmacodynamic measure. The aim of this study was to evaluate the longitudinal stability of CSF Abeta(1-42), T-tau, and P-tau(181P) levels in AD patients and control subjects. Serial CSF samples of 28 AD patients and 23 controls with a minimum time interval of 30 days were included in this study. Serial CSF samples from 10 progressive patients (7 mild cognitive impairment (MCI) patients and 3 controls progressing to MCI or AD) were also analyzed. Intra-individual CSF Abeta(1-42) and P-tau(181P) levels were stable in AD and controls. Intra-individual CSF T-tau levels differed significantly in AD patients, but not in controls. Change in biomarker concentrations per time unit was also significant between groups, but not within groups. The difference in biomarker levels in samples from progressive patients was not significant. In conclusion, CSF levels of Abeta(1-42), T-tau, and P-tau(181P) are relatively stable over time. Only T-tau increased in AD patients in comparison to controls, which does not preclude its use as a diagnostic marker, nor as a potential pharmacodynamic marker. PMID- 23034522 TI - Soy-based diet exacerbates seizures in mouse models of neurological disease. AB - Seizures are a common phenotype in many neurological disorders including Alzheimer's disease, Down syndrome, and fragile X syndrome. Mouse models of these disorders overexpress amyloid-beta protein precursor (AbetaPP) and amyloid-beta (Abeta) and are highly susceptible to audiogenic-induced seizures (AGS). We observed decreased AGS in these mice fed a casein-based, purified diet (D07030301) as opposed to a standard soy protein-containing, non-purified diet (Purina 5015). Our objective in this manuscript was to determine if soy protein, and in particular soy isoflavones, in the Purina 5015 were contributing to the seizure phenotype. Wild running, AGS, and death rates were assessed in juvenile mice fed Purina 5015, D07030301, D07030301 containing soy protein, or D07030301 supplemented with individual isoflavones (750 mg/kg daidzein or genistein). A short treatment (3 days) with Purina 5015 induced wild running and AGS in Alzheimer's disease mice. A 3-day treatment with daidzein-supplemented diet, but not genistein, induced wild running in wild type mice. To understand the mechanism underlying daidzein activity, we assessed dendritic AbetaPP expression in primary, cultured, wild type neurons treated with daidzein or genistein. In vitro, daidzein significantly increased dendritic AbetaPP. Thus, the soy isoflavone daidzein recapitulated seizure induction in vivo and altered AbetaPP expression in vitro. These results have important implications for individuals on soy-based diets as well as for rodent model research. PMID- 23034524 TI - Episodic-like memory for what-where-which occasion is selectively impaired in the 3xTgAD mouse model of Alzheimer's disease. AB - Episodic memory loss is a defining feature of early-stage Alzheimer's disease (AD). A test of episodic-like memory for the rat, the What-Where-Which occasion task (WWWhich), requires the association of object, location, and contextual information to form an integrated memory for an event. The WWWhich task cannot be solved by use of non-episodic information such as object familiarity and is dependent on hippocampal integrity. Thus, it provides an ideal tool with which to test capacity for episodic-like memory in the 3xTg murine model for AD. As this model captures much of the human AD phenotype, we hypothesized that these mice would show a deficit in the WWWhich episodic-like memory task. To test the specificity of any episodic-like deficit, we also examined whether mice could perform components of the WWWhich task that do not require episodic-like memory. These included object (Novel Object Recognition), location (Object Location Task, What-Where task), and contextual (What-Which) memory, as well as another three component task that can be solved without reliance on episodic recall (What-Where When; WWWhen). The results demonstrate for the first time that control 129sv/c57bl6 mice could form WWWhich episodic-like memories, whereas, 3xTgAD mice at 6 months of age were impaired. Importantly, while 3xTgAD mice showed some deficit on spatial component tasks, they were unimpaired in the more complex WWWhen combination task (which includes a spatial component and is open to non episodic solutions). These results strongly suggest that AD pathology centered on the hippocampal formation mediates a specific deficit for WWWhich episodic-like memory in the 3xTgAD model. PMID- 23034523 TI - Clinically asymptomatic vascular brain injury: a potent cause of cognitive impairment among older individuals. AB - Cerebrovascular risk factors and stroke are highly prevalent with advancing age, and stroke may be more common than Alzheimer's disease, particularly among older men. While stroke mortality continues to decline, the prevalence of individuals with various vascular risk factors continues to rise and many are undiagnosed or undertreated. Asymptomatic cerebrovascular brain injury that includes asymptomatic brain infarction and white matter hyperintensities as well as accelerated brain atrophy is even more frequent than clinical stroke. Moreover, the impact of cerebrovascular risk factors on brain injury appears to begin in middle life and additively increases the likelihood of later life dementia. This review focuses on the use of neuroimaging and genetics to understand the impact of asymptomatic vascular risk factors on the trajectories of cognitive aging as well as incident cognitive impairment, stroke, and mortality. Results of this review emphasize the need for early detection and treatment of vascular risk factors to improve the cognitive health of our rapidly aging population. PMID- 23034526 TI - Unique reactivity of Fe nanoparticles-defective graphene composites toward NH(x) (x = 0, 1, 2, 3) adsorption: a first-principles study. AB - We investigated the electronic structure of Fe nanoparticle-graphene composites and the impact of the interfacial interaction on NH(x) (x = 0, 1, 2, 3) adsorption by first-principles based calculations. We found that Fe(13) nanoparticles can be stabilized by the sp(2) dangling bonds on single vacancy graphene substrate with a binding energy up to -7.07 eV. This interaction not only deformed the carbon atoms around the defect and gave rise to the stability of the Fe nanoparticle against sintering, but also had significant impact on the adsorption of NH(x) that is related to the catalytic performance of these composites in NH(3) decomposition. Doping of the single vacancy graphene with N or B can finely tune the adsorption of NH(x). Further analysis revealed that the calculated adsorption energies of NH(x) on these composites correlated well with the shift of the average d-band center of the Fe nanoparticles and they were around the peak of the activity-adsorption energy curve for NH(3) decomposition catalysts, especially when doped with B. The optimal adsorption of NH(x) on Fe nanoparticles deposited on boron-doped defective graphene suggests the possible high stability and superior catalytic performance of these composites in the low temperature catalytic decomposition of NH(3). PMID- 23034525 TI - Enhanced top-down characterization of histone post-translational modifications. AB - Post-translational modifications (PTMs) of core histones work synergistically to fine tune chromatin structure and function, generating a so-called histone code that can be interpreted by a variety of chromatin interacting proteins. We report a novel online two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) platform for high-throughput and sensitive characterization of histone PTMs at the intact protein level. The platform enables unambiguous identification of 708 histone isoforms from a single 2D LC-MS/MS analysis of 7.5 ug purified core histones. The throughput and sensitivity of comprehensive histone modification characterization is dramatically improved compared with more traditional platforms. PMID- 23034527 TI - An aerosol-seed-assisted hybrid chemical route to synthesize anisotropic bimetallic nanoparticles. AB - Herein we report the development of anisotropic bimetallic nanoparticles where aerosol gold nanoparticles served as the seeds for the continuous deposition of silver atoms on their surfaces. Initially, aerosol gold nanoparticles were formed by spark discharge and then injected into a silver precursor solution in an impinging device. The gold nanoparticles acted as the seed particles, and catalyzed the reduction of the added silver ions in the presence of ultrasound to yield bimetallic (gold core-silver shell) anisotropic nanoparticles. PMID- 23034528 TI - The association of early transfusion with acute lung injury in patients with severe injury. AB - BACKGROUND: Packed red blood cell (PRBC) transfusion is associated with acute lung injury (ALI) development after trauma, but this risk may not be constant through time after trauma. We hypothesized that the relationship between PRBC delivery and ALI risk varies through time after injury. METHODS: Data were collected prospectively from 1999 to 2006. Inclusion criteria include the following: older than 13 years, surgical intensive care unit admission, and Injury Severity Score of 16 or greater. Exclusion criteria included discharge/death within 24 hours of admission. Patients were followed up prospectively for ALI development for 5 days after trauma. Discrete time models were fit to test the association of timing of PRBC delivery with the development of ALI while controlling for patient demographics, resuscitation variables, Injury Severity Score, and Acute Physiology and Chronic Health Evaluation III scores. RESULTS: At total of 602 patients were included. Median age was 33 years, 77% were male, and 50% were African American. Using a discrete time-survival model, the relation between transfusion and ALI development was found to vary by transfusion time window (p < 0.0001). The major effect of PRBC delivery on ALI risk occurred in the first 24 hours after trauma; this finding persisted in multivariable modeling (adjusted odds ratio, 1.07 per unit; 95% confidence interval, 1.02-1.11, p < 0.001). Cumulative incidence of ALI approached 50% in patients receiving 6 U of PRBC or more in the first 24 hours. CONCLUSION: The association between PRBC transfusion and ALI development in patients with trauma is time dependent, with PRBC delivery in the first 24 hours after injury driving the overall relation. Each PRBC unit during this period increases odds of subsequent ALI development by 7%. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level II. PMID- 23034529 TI - In vivo transfection of nuclear factor kappaB decoy protects pulmonary function against acute lung contusion in rabbits. AB - BACKGROUND: The transcription factor nuclear factor kappaB (NF-kappaB) regulates the expression of numerous proinflammatory factors that may exacerbate the response to acute injury. We investigated the effect of an inhibitory NF-kappaB decoy oligodeoxynucleotide on proinflammatory factor expression and pulmonary function after acute lung contusion in rabbits. METHODS: Thirty-minutes after acute lung contusion, the NF-kappaB decoy or a scrambled control oligodeoxynucleotide was injected via the jugular vein. Blood samples were collected for blood gas analysis and plasma tumor necrosis factor alpha, interleukin 1beta (IL-1beta), IL-13, and IL-10 were measured by enzyme-linked immunosorbent assay at 1, 2, 3, and 4 hours after contusion. In addition, NF kappaB protein expression in lung tissue was detected by Western blot analysis. RESULTS: The blood PO2 decreased immediately after lung contusion, whereas PAO2 increased significantly, indicative of disrupted respiratory function. Respiratory function improved after sense NF-kappaB decoy injection but not after injection of the inactive scrambled form. Injection of NF-kappaB decoy resulted in significant inhibition of NF-kappaB protein expression in lung tissue and a reduction in the serum concentrations of proinflammatory cytokines tumor necrosis factor alpha and IL-1beta compared with those of control rabbits injected with the scrambled decoy. In contrast, serum levels of the anti-inflammatory cytokines IL-10 and IL-13 increased after decoy injection compared with those of control animals and rabbits injected with the scrambled decoy. CONCLUSION: The sense NF kappaB decoy protected respiratory function and reduced serum proinflammatory factor secretion after acute lung contusion. Inhibition of NF-kappaB may allow for preservation of pulmonary function for patients with acute lung injury. PMID- 23034530 TI - Different influence of outdoor temperature on traumatic and nontraumatic injuries. AB - BACKGROUND: Injuries are affected by weather conditions, which influence various human activities. However, only a few studies have reported an association between injuries and weather conditions despite the fact that extreme weather conditions can occur more frequently with climate change. The goal of this study was to evaluate the association between outdoor temperature and traumatic and nontraumatic injury using emergency ambulance delivery. METHODS: We designed a prognostic study to evaluate the different effects of outdoor temperature depending on types of injury. Using a generalized additive model, we examined the association between outdoor temperatures and injuries in Korea from 2006 to 2008, adjusting for confounders such as relative humidity, day of the week, and long term time trends. A random effects model was used to estimate combined effects across all areas. RESULTS: The city-combined effect estimate for nontraumatic injuries was 1.95% (95% confidence interval, 1.28-2.62%) corresponding to a 1 degrees C increase in mean temperature, whereas the relationship for traumatic injuries was not linear. The risk of nontraumatic injury related to temperature for males and elderly individuals was higher than for females and younger people. CONCLUSION: The risk of injury attributable to outdoor temperature was found to vary according to the injury type. This information may be useful for developing adaptation strategies related to climate change. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 23034531 TI - Distally based perforator-plus sural fasciocutaneous flap for reconstruction of complex soft tissue defects caused by motorcycle spoke injury in children. PMID- 23034532 TI - Synthesis and comparative study of Co(pym)(VO3)2 and [Co(H2O)2(VO3)2].2H2O. AB - The three-dimensional Co(pym)(VO(3))(2), 1, hybrid compound, where pym is pyrimidine, has been synthesized under mild hydrothermal conditions at 120 degrees C. The compound has been characterized by FT-IR spectroscopy, elemental analysis, thermogravimetric measurements, thermodiffractometry, UV-Vis spectroscopy, temperature-dependent magnetic susceptibility and magnetization, and finally a study of specific heat has been performed. The crystal structure of 1 was solved using single-crystal X-ray diffraction data, taking into account that the crystals of this compound are twins of two components. It crystallizes in the monoclinic system, space group C2/c, a = 12.899(5) A, b = 9.859(2) A, c = 7.051(1) A, beta = 111.41(3) degrees , Z = 4. The crystal structure is built up from edge sharing VO(5) trigonal bipyramid double chains and [CoO(4)pym](n) chains. This resembles the structure of the [Co(H(2)O)(2)(VO(3))(2)].2H(2)O compound, 2. For this reason a comparative study of their properties was carried out. Magnetic measurements of 1, performed in the 2.0 to 300 K range, reveal the existence of a weak ferromagnetic order near 3 K. This fact was confirmed with magnetization measurements, which show irreversibility characteristic of soft ferromagnets. Magnetic measurements of 2 show a 3D antiferromagnetic ordering at 2.5 K. The magnetization shows a small change of curvature indicating the occurrence of a metamagnetic transition. Specific heat measurements of both compounds confirm the 3D nature of the magnetic order. The comparative study of the magneto-structural correlations reveals that the pyrimidine molecules are responsible for the different magnetic behaviour between 1 and 2. PMID- 23034533 TI - Cycloaddition reactions of polyenic donor-pi-acceptor systems with an electron rich alkyne: access to new chromophores with second-order optical nonlinearities. AB - The formal [2 + 2] cycloaddition-cycloreversion (CA-CR) between 4-ethynyl-N,N dimethylaniline and polyenic Donor-pi-Acceptor (D-pi-A) systems takes place to yield compounds bearing two donors and one acceptor. Structural, linear and second-order nonlinear optical (NLO) properties of the new molecules reveal the stronger polarization of these systems when compared to analogous merocyanines lacking the dimethylaminophenyl (DMA) ring. PMID- 23034534 TI - All-polymer solar cells with bulk heterojunction nanolayers of chemically doped electron-donating and electron-accepting polymers. AB - We report the improved performance of all-polymer solar cells with bulk heterojunction nanolayers of an electron-donating polymer (poly(3-hexylthiophene) (P3HT)) and an electron-accepting polymer (poly(9,9-dioctylfluorene-co benzothiadiazole) (F8BT)), which were both doped with 4-ethylbenzenesulfonic acid (EBSA). To choose the doping ratio of P3HT for all-polymer solar cells, various EBSA doping ratios (0, 1, 3, 5, 10, 20 wt%) were tested by employing optical absorption spectroscopy, photoluminescence spectroscopy, photoelectron yield spectroscopy, and space-charge-limited current (SCLC) mobility measurement. The doping reaction of P3HT with EBSA was followed by observing the colour change in solutions. The final doping ratio for P3HT was chosen as 1 wt% from the best hole mobility measured in the thickness direction, while that for F8BT was fixed as 10 wt% (F8BT-EBSA). The polymer:polymer solar cells with bulk heterojunction nanolayers of P3HT-EBSA (EBSA-doped P3HT) and F8BT-EBSA (EBSA-doped F8BT) showed greatly improved short circuit current density (J(SC)) and open circuit voltage (V(OC)), compared to the undoped solar cells. As a result, the power conversion efficiency (PCE) was enhanced by ca. 300% for the 6 : 4 (P3HT-EBSA : F8BT-EBSA) composition and ca. 400% for the 8 : 2 composition. The synchrotron-radiation grazing incidence angle X-ray diffraction (GIXD) measurement revealed that the crystallinity of the doped nanolayers significantly increased by EBSA doping owing to the formation of advanced phase segregation morphology, as supported by the surface morphology change measured by atomic force microscopy. Thus the improved PCE can be attributed to the enhanced charge transport by the formation of permanent charges and better charge percolation paths by EBSA doping. PMID- 23034535 TI - Use of alternative promoters may hide genetic effects on phenotypic traits. AB - Genome-wide association studies have identified a multitude of single-nucleotide polymorphisms (SNPs) associated with a wide spectrum of human phenotypic traits. However, the SNPs identified so far do not explain much of the expected genetic variation and they are poor predictors of the occurrence of disease. I recently advanced the hypothesis that there is person-to-person variation in the use of alternative regulatory elements (for example, gene promoters) and this new source of variation may explain in part the low genetic variation accounted for known genetic variants. In the present report a simple mathematical model is developed to explore the biological consequences of the proposed hypothesis. The model predicts that in presence of person-to-person variation in the use of alternative promoters the observable effects of genetic variants located inside promoters will be smaller than their actual effects. As a consequence, genetic variation because of those observed polymorphisms will be reduced. The present report suggests new paths of research to elucidate the genetic basis of human complex traits. PMID- 23034536 TI - The diagnostic utility of exome sequencing in Joubert syndrome and related disorders. AB - Joubert syndrome (JS) and related disorders (JSRD) are autosomal recessive and X linked disorders characterized by hypoplasia of the cerebellar vermis with a characteristic 'molar tooth sign' on brain imaging and accompanying neurological symptoms including episodic hyperpnoea, abnormal eye movements, ataxia and intellectual disability. JSRD are clinically and genetically heterogeneous, and, to date, a total of 17 causative genes are known. We applied whole-exome sequencing (WES) to five JSRD families and found mutations in all: either CEP290, TMEM67 or INPP5E was mutated. Compared with conventional Sanger sequencing, WES appears to be advantageous with regard to speed and cost, supporting its potential utility in molecular diagnosis. PMID- 23034537 TI - Behavioral risk factors and mental health: single and cluster associations in Spanish adolescents. AB - OBJECTIVE: The risk factors associated with mental health in adolescents are not well known in the general population of Mediterranean countries. Therefore, this study aimed to identify individual and clustered behavioral risk factors for psychological distress. METHODS: Cross-sectional study conducted between 2008 and 2009 among 4054 students representative of those in the fourth year of secondary education in the region of Madrid (Spain). Mental health was assessed using the General Health Questionnaire, with psychological distress defined as a score >=3. The analyses were performed with logistic regression and adjusted for the main confounders. RESULTS: Psychological distress was more frequent in those who did insufficient physical activity (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.03-1.47), smokers (OR, 1.30; 95% CI, 1.07-1.59), and users of illegal drugs (OR, 1.46; 95% CI, 1.21-1.76). Psychological distress also showed a positive dose-response relationship with the number of risk behaviors for eating disorders (p for linear trend <0.001). Moreover, it was associated with both thin (OR, 1.37; 95% CI, 1.16-1.62) or very thin body image (OR, 2.15; 95% CI, 1.39 3.32) and perceived overweight (OR, 1.74; 95% CI, 1.40-2.15) or obesity (OR, 3.12; 95% CI, 2.23-4.37). Compared with individuals without classic risk behaviors (low physical activity, low consumption of fruits/vegetables, smoking, high-risk alcohol consumption), frequency of psychological distress was higher in those with 2 risk behaviors (OR, 1.47; 95% CI, 1.19-1.82) and was even greater in those with 3 or 4 risk behaviors (OR, 1.56; 95% CI, 1.21-2.01). CONCLUSIONS: During adolescence, psychological distress is associated with lifestyles, body image, and eating behaviors. Clustering of classic risk behaviors increases the likelihood of poor mental health. PMID- 23034538 TI - A new way of thinking about complications of prematurity. AB - The morbidity and mortality of preterm infants are impacted by their ability to maintain physiologic homeostasis using metabolic, endocrine, and immunologic mechanisms independent of the mother's placenta. Exploring McEwen's allostatic load model in preterm infants provides a new way to understand the altered physiologic processes associated with frequently occurring complications of prematurity such as bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity. The purpose of this article is to present a new model to enhance understanding of the altered physiologic processes associated with complications of prematurity. The model of allostatic load and complications of prematurity was derived to explore the relationship between general stress of prematurity and complications of prematurity. The proposed model uses the concepts of general stress of prematurity, allostasis, physiologic response patterns (adaptive-maladaptive), allostatic load, and complications of prematurity. These concepts are defined and theoretical relationships in the proposed model are interpreted using the four maladaptive response patterns of repeated hits, lack of adaptation, prolonged response, and inadequate response. Empirical evidence for cortisol, inflammation, and oxidative stress responses are used to support the theoretical relationships. The proposed model provides a new way of thinking about physiologic dysregulation in preterm infants. The ability to describe and understand complex physiologic mechanisms involved in complications of prematurity is essential for research. Advancing the knowledge of complications of prematurity will advance clinical practice and research and lead to testing of interventions to reduce negative outcomes in preterm infants. PMID- 23034539 TI - Success in blinding to group assignment with sham-CPAP. AB - This study evaluated the success of sham-continuous positive airway pressure (CPAP) as a placebo in a 4-week clinical trial of adults with sleep apnea. Participants (n = 23) were previously undiagnosed for obstructive sleep apnea, had no one in their household on sleep apnea therapy, and were willing to be randomly assigned to either active or sham-CPAP. Before final debriefing, participants were asked to "guess" their group assignment. When questioned, 10 of the 23 participants (44%) were incorrect in their guess of group assignment; 2 of these participants stated that their guess was "random." The active CPAP group's average usage was significantly longer when compared to participants on the sham device (293 +/- 117 min/day vs. 188 +/- 110 min/day, p = .046). The results suggest that participants remained blinded to group assignment and that sham-CPAP is an appropriate placebo control device. Participants' lower adherence to the sham device may be a potential problem that requires attention in the use of sham CPAP as a placebo during clinical trials. PMID- 23034540 TI - Synergistic effects of low-intensity exercise conditioning and beta-blockade on cardiovascular and autonomic adaptation in pre- and postmenopausal women with hypertension. AB - The effects of a 12-week low-intensity exercise conditioning program (walking) on blood pressure (BP), heart rate (HR), rate-pressure product (RPP), and cardiac autonomic function were measured in 40 sedentary women with hypertension. Women were assigned to either an exercise group (n = 20) or a control group (n = 20), matched for beta-blockade treatment. They underwent testing at the beginning and at the end of the 12-week study period in three conditions: supine rest, standing, and low-intensity steady state exercise. The exercise group participated in a 12-week, low-intensity walking program, while the control group continued with usual sedentary activity. Compared with the control group, women in the exercise group showed reductions in systolic and diastolic BP and RPP (i.e., the estimated cardiac workload). beta-Blockers increased baroreflex sensitivity and lowered BP and HR in all participants; however, those in the exercise group showed the effects of both treatments: a greater reduction in HR and RPP. The combination of exercise training and beta-blockade produces cardiac and autonomic adaptations that are not observed with either treatment alone, suggesting that beta-blockade enhances the conditioning effects of low-intensity exercise in women with hypertension. PMID- 23034541 TI - [Clinical nursing education]. AB - Nursing is a clinical profession influenced by social and environmental change. Facing the continuing evolution of the medical practice environment, nursing educators should take into account both current issues and future trends. As nursing clinical education undergoes radical reform, it must address both current and future healthcare demands. Relevant articles in the literature indicate that students continue to face significant difficulties applying classroom knowledge to clinical practice. This article describes the meanings, purposes, elements and models of nursing clinical education as well as relevant factors of influence. We also offer suggestions for meeting future societal demands. PMID- 23034542 TI - [Challenges and strategies for nursing education in Taiwan from a public health needs perspective]. AB - An increasingly elderly population and prevalence of chronic health problems have transformed the healthcare landscape in Taiwan and necessitated a shift in the focus of healthcare toward chronic rather than acute illnesses. This is a challenge to the domestic healthcare system, which was initially designed to address and cure primarily acute illness. Traditional nursing education and training programs are no longer adequate to meet current population healthcare needs. The first part of this article highlights the challenges posed by changing healthcare needs, e.g., the rise in prevalence of age-related chronic conditions and the increased acuity of hospitalized patients. Such developments are making new demands and expectations of nurses in terms of education, skills and roles. The second part of this article explores the weaknesses of current nursing education. Recommendations for the future include: making high school graduation a minimum requirement for entering nursing college and university programs, restructuring the nursing master's education program to prepare advanced nurse practitioners, redesigning curriculum content, and teaching approaches based on public healthcare needs. Upgrading clinical competencies and increasing nursing school faculty numbers are issues of the most immediate priority. PMID- 23034543 TI - [A Taiwan nursing perspective on current imbalances in educating, licensing and hiring new nurses]. AB - Level of development in the nursing profession affects healthcare quality and safety. The nursing profession in Taiwan today faces myriad external pressures such as the global financial crisis and rapidly changing national health insurance policies and social issues. For example, cutbacks in nursing manpower at medical institutions and increasingly difficult healthcare working conditions are increasing nurse workloads and turnover, conflict in the workplace, and difficulties in recruiting new nursing staff. Such negative developments directly and negatively impact professional development, healthcare quality, healthcare safety, and workplace morale. In terms of maintaining and enhancing the quality of new nurses entering the profession, rapid growth in numbers of technology schools and nursing students have severely strained insufficient resources and resulted in teaching quality and education outcomes below expectations. Poor passing rates on the national nursing license examination and increasingly high new nurse turnover are now significant negative factors influencing clinical manpower availability. Imbalances among education, licensing, and hiring clearly and negatively impact nursing professional development and social needs and cause the inefficient allocation of limited education resources. This article discusses and analyzes the causes underlying current imbalances in nurse hiring, licensing, and education. We provide the following suggestions: (1) Integrate education and licensing activities based on professional recruitment considerations to promote nursing competent and manpower stability; (2) revise the focus and content of the national license examination to resolve the current disconnect between license examination and hiring needs; (3) redesign curricula, update teaching material, and adjust teaching methods based on professional competencies in order to resolve key education and recruitment problems. All nursing schools should prepare their students well to pass the license examination in order to resolve the current state of inconsistent educational standards, and (4) train international nursing talent to address and reflect international medical care trends and policies in Taiwan. This paper is intended to serve as reference for both policymakers and professionals in the nursing and healthcare fields. PMID- 23034544 TI - [Response of Taiwan nursing education to today's nursing shortage]. AB - The shortage of nursing manpower has recently attracted significant attention from Taiwan society. Government efforts to improve the nursing practice environment have challenged the quality of current domestic nursing education. This article provides an overview of Taiwan nursing education in terms of its development under current nursing shortage conditions and in light of Taiwan's low birthrate, ageing society. A few suggestions for nursing education are listed at the end of the article. PMID- 23034545 TI - [A qualitative study of physical experiences associated with cervical screenings]. AB - BACKGROUND: Papnicolauo (Pap) smear screening is an invasive examination that intrudes upon women's privacy, forcing them to physically perceive both inner and external worlds. This subjective physical experience has rarely been explored in the literature. PURPOSE: This article explores the subjective physical experiences of patients undergoing cervical screening. METHODS: This phenomenological study employed purposive sampling; five females were recruited. All provided informed consent and were enrolled as participants. The content analysis method analyzed and categorized interview content. RESULTS: The 3 main themes associated with participant experiences were: Loss of physical control (e. g., negative feelings, body unresponsive to mental commands); interaction between the subjective and objective body (e.g., objectification of the body, subjectification of gender); experiencing the spatial dimensions of the body (e.g., bodily exposure, protection). CONCLUSION: Findings recommend healthcare providers help pap smear recipients strengthen "inter-subjectivity" and focus on "body space" to enhance patients' "physical consciousness" and "physical emotions." PMID- 23034546 TI - [Cancer nursing care education programs: the effectiveness of different teaching methods]. AB - BACKGROUND: In-service education affects the quality of cancer care directly. Using classroom teaching to deliver in-service education is often ineffective due to participants' large workload and shift requirements. PURPOSE: This study evaluated the learning effectiveness of different teaching methods in the dimensions of knowledge, attitude, and learning satisfaction. METHODS: This study used a quasi-experimental study design. Participants were cancer ward nurses working at one medical center in northern Taiwan. Participants were divided into an experimental group and control group. The experimental group took an e learning course and the control group took a standard classroom course using the same basic course material. Researchers evaluated the learning efficacy of each group using a questionnaire based on the quality of cancer nursing care learning effectiveness scale. All participants answered the questionnaire once before and once after completing the course. RESULTS: (1) Post-test "knowledge" scores for both groups were significantly higher than pre-test scores for both groups. Post test "attitude" scores were significantly higher for the control group, while the experimental group reported no significant change. (2) after a covariance analysis of the pre-test scores for both groups, the post-test score for the experimental group was significantly lower than the control group in the knowledge dimension. Post-test scores did not differ significantly from pre-test scores for either group in the attitude dimension. (3) Post-test satisfaction scores between the two groups did not differ significantly with regard to teaching methods. The e-learning method, however, was demonstrated as more flexible than the classroom teaching method. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Study results demonstrate the importance of employing a variety of teaching methods to instruct clinical nursing staff. We suggest that both classroom teaching and e-learning instruction methods be used to enhance the quality of cancer nursing care education programs. We also encourage that interactivity between student and instructor be incorporated into e-learning course designs to enhance effectiveness. PMID- 23034547 TI - [Validation of the Chinese-version Self-Efficacy in Smoking Cessation Service Scale (SE-SCS) for clinical psychiatric professionals]. AB - BACKGROUND: Smoking cessation has been an important issue of concern for Taiwan's psychiatric nurses since promulgation of the Tobacco Hazards Prevention Act. However, Taiwan has lacked a qualified tool to evaluate the self-efficacy of nurses in providing smoking cessation services. PURPOSE: The purpose of this study was to validate the Chinese version of the Self- Efficacy in Smoking Cessation Service Scale (SE-SCS). METHODS: A back translation approach was used to develop the SE-SCS Chinese version. We enrolled 193 psychiatric nurses from two psychiatric centers in central and southern Taiwan to assess the reliability and validity of the Chinese version scale using internal consistency, test retest, factor analysis, and concurrent criteria validity. RESULTS: The reliability of the SE-SCS Chinese version was assessed as good (Cronbach's alpha = .85) and the Pearson correlation for total test-retest score was acceptable (r = .65, p = .004). Explanatory factor analysis revealed that one factor explained 63.4% of total variance. As to the criteria validity, frequency of smoking cessation service provision was the main criterion, with a correlation of 0.25 0.26. We identified a low, but significant correlation (p < .001). CONCLUSION: The SE-SCS Chinese version appears to be a valid measure for assessing psychiatric nurse self-efficacy in providing smoking cessation services. PMID- 23034548 TI - [Family function and depression in relatives of earthquake victims: a survey conducted one year after China's Wenchuan Earthquake]. AB - BACKGROUND: The Wenchuan Earthquake that hit Sichuan, China in 2008 not only caused huge losses in terms of human life and economic damage. It also caused psychological trauma in survivors, especially those who had lost relatives and close friends (bereaved). In the aftermath of earthquakes, bereaved individuals require family and spiritual renewal in addition to material assistance. PURPOSE: This study investigated the status of and relationship between family function and depression in bereaved individuals living in areas devastated by the Wenchuan Earthquake. Results provide baseline information for post-disaster family reconstruction. METHODS: This cross-sectional study surveyed 264 qualified bereaved individuals who lived in an area hard hit by the Wenchuan Earthquake. Face-to-face interviews were administered based on the family APGAR(adaptation, partnership, growth, affection, resolve) index and Hamilton depression (HAMD) scale. RESULTS: The mean family function score for participants was 6.52 +/- 2.65. Results for half (50.0%) of participants indicated "good" family function. Results indicated marital status, family structure and status of having another baby as factors that significantly influence family function (p < .05). Participants' mean depression score was 40.41 +/- 9.35, with all (100%) of participants demonstrating symptoms of depression. The 5 most prevalent depressive symptoms were: depressed mood, decreased interest in work, mental anxiety, diminished capacity and agitation. Results showed marital status, leisure frequency, economic status, and having another baby as factors that significantly influenced family function (p < .05). A Pearson's correlation analysis indicated no significant relationship between level of depression and family function (p >.05). CONCLUSION: Family functions of the bereaved living in areas hard hit by the Wenchuan Earthquake were all undermined to varying degrees. Although participants all exhibited depressive symptoms, this study found no affect of such symptoms on family functions. Interventions delivered in the months and years after an earthquake should be tailored to address each individual's depression status. Interventions should also help these individuals learn to improve and enhance family functions to effectively reduce negative behaviors and reactions in order to better promote physical and mental health. PMID- 23034549 TI - [Enhancing self-care behavior to empower diabetes patients: the MAGIC strategy]. AB - Good self-care behaviors can control diabetes and its complications effectively. Today, it is estimated that less than 20% of diabetes patients adhere to the self care behavior regimens suggested by their healthcare providers. The World Health Organization advocates incorporating empowerment strategies into diabetes education to enhance patient abilities to control their disease and improve overall care efficacy. This article reviews the literature to develop the MAGIC strategy empowerment approach. MAGIC is an acronym for: Motivating patient self awareness (M); assessing the causes of the problem (A); goal setting (G); individual self-care plan development (I) and Checking whether goals or plans have been achieved (C). The MAGIC empowerment process, involving interaction between healthcare professionals and patients, has the potential to work like "magic" to help patients implement effective self-care behavior. Guidelines and practice are necessary to shift professionals from the traditional education model to the empowerment approach. This article is a useful reference for clinical practice. PMID- 23034550 TI - [Applying fatigue practice guidelines in clinical care: examples of adult leukemia patients]. AB - Cancer-related fatigue is one of the most prevalent symptoms experienced by cancer patients. The high-dose chemotherapy regimen given to those with hematological malignancies makes this group in particularly urgent need of fatigue management during hospitalization. The National Comprehensive Cancer Network (NCCN) has published practice guidelines for cancer-related fatigue. However, the complexity of these guidelines has prevented their widespread application in Taiwan. Most healthcare providers remain uncertain as to how and when to assess fatigue. This article summarizes 2011 NCCN fatigue practice guidelines, including those related to assessing fatigue patterns, intensity, and causes and choosing appropriate interventions based on patient fatigue level. The authors further share their experiences using the guideline in caring for adult hematological patients with different fatigue levels. Through these examples, we hope healthcare providers will properly apply practice guidelines and provide better care to patients experiencing fatigue. PMID- 23034551 TI - [Application of spaced retrieval training on patients with dementia]. AB - Dementia causes semantic and episodic memory impairments that limit patients' activities of daily living (ADL) and increase caregiver burden. Spaced retrieval training uses repetitive retrieval to strengthen cognitive and motor skills intuitively in mild / moderate dementia patients who retain preserved implicit / non-declarative memory. This article describes and discusses the operative mechanism, influencing variables, and practical applications of spaced retrieval training. We hope this article increases professional understanding and application of this training approach to improve dementia patient ADL and improve quality of life for both caregivers and patients. PMID- 23034552 TI - [Preliminarily application of content analysis to qualitative nursing data]. AB - Content analysis is a methodology for objectively and systematically studying the content of communication in various formats. Content analysis in nursing research and nursing education is called qualitative content analysis. Qualitative content analysis is frequently applied to nursing research, as it allows researchers to determine categories inductively and deductively. This article examines qualitative content analysis in nursing research from theoretical and practical perspectives. We first describe how content analysis concepts such as unit of analysis, meaning unit, code, category, and theme are used. Next, we describe the basic steps involved in using content analysis, including data preparation, data familiarization, analysis unit identification, creating tentative coding categories, category refinement, and establishing category integrity. Finally, this paper introduces the concept of content analysis rigor, including dependability, confirmability, credibility, and transferability. This article elucidates the content analysis method in order to help professionals conduct systematic research that generates data that are informative and useful in practical application. PMID- 23034553 TI - [Clinical evaluation and nursing management of a patient with decreased intracranial adaptive capacity]. AB - Decreased intracranial adaptive capacity is one of the most common neurological problems in critically ill patients. It is the main cause of intracranial hypertension and, if not handled properly, is likely to negatively affect patient prognoses and may lead to further brain injury or death. This article describes concepts related to the mechanisms that cause decreased intracranial adaptive capacity and related factors. This article may provide a guide for clinical evaluation and nursing management. We hope to increase nursing staff knowledge to ensure they take the clinical management action necessary to prevent intracranial hypertension and provide optimal patient treatment and prognosis. PMID- 23034554 TI - [Experience assisting an AIDS-infected homosexual patient and his same-sex partner make a do-not-resuscitate decision]. AB - Family members play an important role in the process of writing advance directives. Homosexual men infected with HIV often wish to authorize their intimate same-sex partner or friends rather than immediate family members to make medical decisions on their behalf. Although same-sex marriage is currently illegal in Taiwan, HIV infected homosexual patients are able to write advance directives appointing their same-sex partner to be their surrogate decision maker for end-of-life medical decisions. This case report describes an experience assisting a homosexual patient with HIV to write his advance directives. The nurse assisted the patient and his partner to make a self-determined decision not to resuscitate. Family conferences held to discuss the patient's decisions regarding resuscitation helped legitimize his partner's primary role in making end-of-life healthcare decisions on his behalf. As an advocate for patient rights, nurses should understand the law as it relates to homosexuality and end of-life decision making, inform patients on the durable power of autonomy, and help execute their advance directives. PMID- 23034555 TI - [Pedlar inexpensive ergometer-based exercise program improves activity intolerance in a heart failure case]. AB - This paper reports on the efficacy of a pedlar inexpensive ergometer-based structured exercise program in improving activity intolerance in a heart failure case. Data were collected between May 15, 2010 and May 20, 2010 using physical assessments, observations, and interviews. Several home visits were conducted after hospital discharge until August 8. Health problems identified included disease-related weakness, inability to complete daily activities, activity intolerance, malnutrition, and ineffective tissue perfusion. In addition to providing nutrition and dietary guidance, we designed an exercise rehabilitation program to improve activity intolerance both during hospitalization and after hospital discharge. Outcome measurements included the six-minute walk test, blood pressure, heart rate, oxygen saturation, and self-perceived improvement. Improvements achieved by the 12th week of the exercise training program included: (1) Able to complete the six-minute walk test (initially unable). (2) Walking distance increased by 54 meters. (3) Target heart rate achieved 40-60% of the maximum heart rate. (4) Resting systolic blood pressure and heart rates decreased tremendously, and (5) Fatigue and shortness of breath improved greatly. Results indicate the pedlar inexpensive ergometer exercise program may help improve the health of heart failure cases suffering from activity intolerance. PMID- 23034556 TI - Vacuum-ultraviolet circular dichroism reveals DNA duplex formation between short strands of adenine and thymine. AB - Absorbance spectroscopy is used extensively to tell when two DNA single strands come together and form a double strand. Here we show that circular dichroism in the vacuum ultraviolet region provides an even stronger indication for duplex formation in the case of short strands of adenine and thymine (4 to 16 bases in each strand). Indeed, our results show that a strong positive CD band appears at 179 nm when double strands are formed. Melting experiments were done in aqueous solution with and without added Na(+) counter ions. With additional salt present a huge increase in the 179 nm CD band was observed when lowering the temperature. A 179 nm CD marker band for duplex formation can be used to measure the kinetics for the association of two single strands. Such experiments rely on large changes at one particular wavelength since it is too time-consuming to record a full wavelength spectrum. PMID- 23034557 TI - Elderly men with renal dysfunction are most at risk for poor outcome after neck of femur fractures. AB - BACKGROUND: both acute and chronic renal dysfunction (ARD and CRD) have been reported to influence outcomes after neck of femur fractures. We have examined the relationship between the length of stay, mortality and renal dysfunction using biomarkers. These included pre-operative (admission) serum concentrations of urea, creatinine and albumin, and estimated glomerular filtration rates (eGFR) derived from four- and six-variable Modification of Diet in Renal Disease (MDRD) study equations. METHODS: complete outcomes data for 566 patients and the patterns of variations in the biomarkers were analysed using generalised linear models. Cox-proportional hazard analyses investigated the association between kidney function (as assessed by the above-mentioned biochemical data) and post operative length of stay and mortality. All patients were stratified for CRD according to their eGFR. RESULTS: serum urea and creatinine were significantly, positively correlated with age. After adjusting for age and sex, risk of mortality was positively related to six-variable eGFR and creatinine, and marginally so for urea. One-year mortality risk thus worsened with stages of CRD (1-4), increasing age and male gender. Risk of discharge from trauma ward, the length of stay in trauma ward and the overall length of stay were not related to urea and creatinine, but were negatively related to both four- and six-variable eGFR. CONCLUSIONS: the study has identified elderly renal-impaired males as the subgroup of patients most at risk for poor survival. This subgroup may require a more targeted approach to the management of their fluid and electrolyte homoeostasis to help improve their outcomes. PMID- 23034558 TI - An investigation into which individual instrumental activities of daily living are affected by a home visiting nurse intervention. AB - BACKGROUND: to our knowledge no research has investigated the effect of home visiting nurse (HVN) interventions on individual instrumental activities of daily living (IADL). OBJECTIVE: to investigate the effects of an HVN intervention on the difficulty or dependence in six individual IADLs. DESIGN: a secondary analysis of a randomised controlled study comparing an HVN intervention (n = 237) with usual care (n = 262) at 22 months after study entry. SETTING: home care linked to primary care. SUBJECTS: a total of 499 Medicare patients needing or receiving help with at least three IADLs or two ADLs, who had recent significant health-care use. METHODS: the intervention consisted of monthly home visits by trained nursing staff. Unadjusted and adjusted (binary and multinomial logistic regression) analyses were performed. RESULTS: unadjusted analyses found less difficulty or dependence for the HVN group for meal preparation, telephone use, shopping and ordinary housework, and more difficulty or dependence for medication management. After adjustment, in addition to an effect through health-care services use, the HVN group had less difficulty or dependence for meal preparation and shopping and more difficulty or dependence for medication management. CONCLUSIONS: an HVN intervention had mixed results for individual IADLs. The negative effect on medication management questions the validity of a total IADL score as an outcome measure, and implies that other medication management measures should be considered for outcome evaluation. Future research is needed to confirm and better understand these findings. PMID- 23034559 TI - Non-HLA antibodies targeting vascular receptors enhance alloimmune response and microvasculopathy after heart transplantation. AB - BACKGROUND: Non-human leukocyte antigen antibodies (Abs) targeting vascular receptors are implicated in the pathogenesis of renal allograft vascular rejection and in progressive vasculopathy in patients with systemic sclerosis. METHODS: We prospectively tested in 30 heart transplant recipients the impact of Abs directed against endothelin-1 type A (ET(A)R) and angiotensin II type 1 receptors (AT(1)R, cell-enzyme-linked immunosorbent assay) at time of transplantation and during the first posttransplantation year on cellular and Ab mediated rejection (immunohistochemistry, C3d, and immunoglobulins) and microvasculopathy in endomyocardial biopsy. RESULTS: Cellular rejection, Ab mediated rejection, and microvasculopathy was found in 40% and 13%, 57% and 18%, and 37% and 40% of biopsies at 1 month and 1 year posttransplantation, respectively. Maximum levels of AT(1)R and ET(A)R Abs were higher in patients with cellular (16.5+/-2.6 vs. 9.4+/-1.3; P=0.021 and 16.5+/-2.5 vs. 9.9+/-1.9; P=0.041) and Ab-mediated rejection (19.0+/-2.6 vs. 10.0+/-1.3; P=0.004 and 19.4+/ 2.7 vs. 9.0+/-1.7; P=0.002), as compared with patients who had no rejection. Patients with elevated AT(1)R Abs (53% [16/30]) or ETAR Abs (50% [15/30]; pretransplantation prognostic rejection cutoff >16.5 U/L) presented more often with microvasculopathy (both, 67% vs. 23%; P=0.048) than patients without. CONCLUSIONS: Elevated levels of AT(1)R and ET(A)R Abs are associated with cellular and Ab-mediated rejection and early onset of microvasculopathy and should be routinely monitored after heart transplantation. PMID- 23034560 TI - How to avoid graft thrombosis requiring graftectomy: immediate posttransplant CT angiography in pancreas transplantation. AB - BACKGROUND: Graft thrombosis immediately after surgery remains a problem for successful pancreas transplantation. The present study evaluated the efficacy of computed tomography (CT) angiography for monitoring of graft patency in the immediate postoperative period. METHODS: The study involved 119 patients who underwent pancreas transplantation between July 1992 and December 2009 in a single center. The anticoagulation strategy was heparin during and after transplantation and then oral warfarin for 1 to 6 months. Graft thrombosis was monitored using color Doppler ultrasonography until July 2005 (group A) and, thereafter, using CT angiography (group B). We retrospectively analyzed the efficacy of diagnosis of graft thrombosis in two groups. Graft survival was assessed using Kaplan-Meier analysis. RESULTS: Group A comprised 51 patients, and group B comprised 68 patients. Total vascular thrombosis was diagnosed in three (5.9%) group A and one (1.4%) group B patients, and partial venous thrombosis was diagnosed in 1 (2.0%) group A and 19 (31.6%) group B patients. Eighteen of the 19 grafts with partial thrombosis in group B were successfully treated using heparin based anticoagulant therapy. There were no CT contrast media-related complications in group B. In group B, graft survival rates were the same for grafts with partial thrombosis and grafts without thrombosis. CONCLUSIONS: CT angiography was safe and effective for evaluating graft patency after pancreas transplantation. Partial vascular thrombosis in the immediate posttransplantation period showed no effect on graft survival under intensive anticoagulation and monitoring by CT angiography. PMID- 23034561 TI - The causes, risk factors, and outcomes of early relaparotomy after living-donor liver transplantation. AB - BACKGROUND: Although early relaparotomy of the recipient after living-donor liver transplantation (LDLT) is a significant event, its causes, risk factors, and outcomes are still unclear. METHODS: A retrospective analysis of 284 cases of adult-to-adult LDLT was performed. RESULTS: The incidence of early relaparotomy of the recipient was 9.2% (n=26). The reasons for relaparotomy were divided into three groups: postoperative bleeding (n=11, 42.3%), insufficient portal venous flow (n=5, 19.2%), and other (n=10, 38.5%). The 6-month graft survival rates of patients in the early laparotomy and nonlaparotomy groups were 61.5% and 88.4%, respectively (P<0.0001). Patients with postoperative bleeding experienced a significantly higher mortality rate (54.6%) than those with other reasons for early relaparotomy (13.3%; P=0.0231). Multivariate analysis showed that a model for end-stage liver disease score of greater than 20 (odds ratio [OR], 9.06; P=0.0434) and an operative blood loss of greater than 15 L (OR, 9.06; P=0.0434) were significant risk factors for graft loss after early relaparotomy. In patients with patent major shunt vessels (>1 cm in diameter, n=31), portal venous flow of less than 1.0 L/min at the end of surgery was a significant risk factor for early relaparotomy to ligate the remaining shunt vessels (OR, 50.5; P=0.0188). CONCLUSIONS: Early relaparotomy of the recipient is significantly associated with poor graft survival after LDLT. Massive intraoperative blood loss and high model for end-stage liver disease score were associated with poor graft survival in the relaparotomy group. PMID- 23034562 TI - No evidence for recipient-derived hepatocytes in serial biopsies of sex mismatched liver transplants. AB - BACKGROUND: Bone marrow-derived hematopoietic stem cells (BM-HSCs) have been shown to act as source for hepatic regeneration in rodent models; however, their ability to participate in human liver regeneration remains controversial. The aim of this study was to investigate the origin of hepatocytes in sex-mismatched cases of orthotopic liver transplantation in longitudinally performed liver biopsies. METHODS: Paraffin-embedded liver biopsy samples of 14 patients after sex-mismatched (female-to-male) liver transplantation were investigated. Biopsies were taken at multiple time points and subjected to histologic examination. Immunohistochemical staining with a hepatocyte-specific antibody and fluorescent in situ hybridization for visualization of Y chromosomes were performed to analyze the presence of recipient-derived hepatocytes. RESULTS: We analyzed 30 liver biopsy samples ranging from 1 week to more than 3 years after transplantation. There was no evidence for recipient-derived hepatocytes in liver transplants at any time point. We were able to detect recipient-specific chromosomal status in inflammatory cells within the liver but not within hepatocytes. Results were independent of liver injury at the time of biopsy, caused by hepatitis C recurrence or rejection episodes. CONCLUSIONS: Our results show no evidence for involvement of BM-HSCs in liver regeneration after orthotopic liver transplantation. We think that recipient BM-HSC-derived hepatocyte repopulation is a very rare event at best and is not of clinical relevance. PMID- 23034564 TI - Nanomechanical identification of proteins using microcantilever-based chemical sensors. AB - We have developed a microcantilever based sensor array which can be functionalized with mercapto-compounds to detect proteins. Linear discriminant analysis (LDA) is used to differentiate the cantilever deflection patterns. It is concluded that more sensors give better separating capacity and the COOH and Si OCH(3) groups are important factors in protein recognition. PMID- 23034563 TI - Electronically excited states of DNA oligonucleotides with disordered base sequences studied by fluorescence spectroscopy. AB - DNA double-stranded oligomers are studied by steady-state and time-resolved fluorescence spectroscopy from the femtosecond to the nanosecond time-scale, following excitation at 267 nm. It is shown that emission arises from three types of excited states. (i) Bright pipi* states emitting around 330 nm and decaying on the sub-picosecond time-scale with an average lifetime of ca. 0.4 ps and a quantum yield lower than 4 * 10(-6). (ii) Excimers/exciplexes emitting around 430 nm and decaying on the sub-nanosecond time-scale. (iii) Excited states emitting mainly at short wavelengths (lambda < 330 nm) and decaying on the nanosecond time scale, possibly correlated to GC pairs. The properties of the examined duplexes, exhibiting significant disorder with respect to the nearest neighbour base sequence, are radically different than those of the much longer and disordered calf thymus DNA. Such behaviour suggests that long range and/or sequence effects play a key role in the fate of excitation energy. PMID- 23034565 TI - A novel amplification strategy for genotyping with liquid chromatography electrospray ionization mass spectrometry. AB - Among numerous available genotyping techniques, mass spectrometry (MS) based methods play a major role in providing high quality genotype data at reasonable costs for research and diagnostics, e.g. for pharmacogenetic applications. Ion pair reversed-phase liquid chromatography hyphenated to electrospray ionization time-of-flight MS (ICEMS) is, for example, a powerful instrument that allows a direct characterization of complex mixtures of polymerase chain reaction (PCR) amplified DNA fragments. Current limitations of PCR-ICEMS genotyping are mainly concerned with the multiplex PCR set-up. Assay development often requires time consuming primer design and intensive optimization of PCR conditions. To overcome this restraint, a robust amplification strategy originally combined with arrayed primer extension genotyping was transferred and adapted to ICEMS genotyping. The modifications involved limitation of the primer length, application of two universal sequences and amplification with an appropriate DNA polymerase. To demonstrate the applicability of the novel amplification strategy for ICEMS, a 23 plex pharmacogenetic genotyping assay was developed. After slight optimization steps, an efficient and quantitatively balanced amplification of all targeted markers was achieved, resulting in a convenient characterization of the multiplexed PCR fragments with ICEMS. Expenditure of time, costs and hands-on work associated with assay design and optimization was dramatically lowered compared to previous multiplex PCR-ICEMS assays. The developed 23-plex assay was applied in a pharmacogenetic study including 284 individuals (genotype call rate 99.0%). A total of 399 SNPs were retyped by Sanger sequencing (concordance rate 99.8%). The PCR-ICEMS assay turned out to be an accurate, reliable, cost effective and a ready-to-use tool for pharmacogenetic genotyping. PMID- 23034566 TI - Multiple-choice tests exonerated, at least of some charges: fostering test induced learning and avoiding test-induced forgetting. AB - Among the criticisms of multiple-choice tests is that-by exposing the correct answer as one of the alternatives-such tests engage recognition processes rather than the productive retrieval processes known to enhance later recall. We tested whether multiple-choice tests could trigger productive retrieval processes provided the alternatives were made plausible enough to enable test takers to retrieve both why the correct alternatives were correct and why the incorrect alternatives were incorrect. In two experiments, we found not only that properly constructed multiple-choice tests can indeed trigger productive retrieval processes, but also that they had one potentially important advantage over cued recall tests. Both testing formats fostered retention of previously tested information, but multiple-choice tests also facilitated recall of information pertaining to incorrect alternatives, whereas cued-recall tests did not. Thus, multiple-choice tests can be constructed so that they exercise the very retrieval processes they have been accused of bypassing. PMID- 23034567 TI - Air-stable and efficient inorganic-organic heterojunction solar cells using PbS colloidal quantum dots co-capped by 1-dodecanethiol and oleic acid. AB - PbS colloidal quantum dot (CQD)-sensitized inorganic-organic heterojunction solar cells fabricated by using the PbS CQDs co-capped by the oleic acid (OA) and 1 dodecanethiol (DT) ligand showed better device stability with aging time under ambient conditions without encapsulation. Furthermore, the device performance is better than the cell fabricated from PbS CQDs without DT ligand. The enhancement of performance in OA and DT co-capped systems is investigated by impedance spectroscopy. An upward displacement of the TiO(2) conduction band, with a consequent increase of V(oc), results in the improved performance when CQD with DT are employed. PMID- 23034568 TI - Quantum chemical studies on the enantiomerization mechanism of several [Zn(py)3(tach)]2+ derivatives. AB - The enantiomerization mechanism of the trigonal-prismatic [Zn(py)(3)(tach)](2+) complex and several derivatives has been studied by applying DFT calculations (B3LYP/LANL2DZp). The enantiomerization pathways of [Zn(py(3)tach-X)](2+) (X = C, Si, Ge, N, P, As, O, S and Se) start from a distorted trigonal-prismatic C(3) symmetric ground state via an ideal trigonal-prismatic C(3v) structure to end up in a C(3)' symmetric image of the ground state. The activation energy and structural data of the complexes depend on electronic and steric factors. The activation barriers of the complexes decrease in the order [Zn(py(3)tach-Ge)](2+) > [Zn(py(3)tach-Si)](2+) > [Zn(py(3)tach-As)](2+) > [Zn(py(3)tach-Se)](2+) > [Zn(py(3)tach-P)](2+) > [Zn(py(3)tach-S)](2+) > [Zn(py(3)tach-C)](2+) > [Zn(py(3)tach-N)](2+) > [Zn(py(3)tach-O)](2+). PMID- 23034569 TI - Trinuclear Mn(II) complex with paramagnetic bridging 1,2,3-dithiazolyl ligands. AB - The first metal coordination complex of a radical ligand based on the 1,2,3 dithiazolyl heterocycle is reported. 6,7-Dimethyl-1,4-dioxo-naphtho[2,3 d][1,2,3]dithiazolyl acts as a bridging ligand in the volatile trinuclear Mn(hfac)(2)-Rad-Mn(hfac)(2)-Rad-Mn(hfac)(2) complex (hfac = 1,1,1,5,5,5 hexafluoroacetylacetonato-). The Mn(II) and radical ligand spins are coupled anti ferromagnetically (AF) resulting in an S(T) = 13/2 spin ground state. PMID- 23034570 TI - Religion and spirituality and psychiatry. PMID- 23034571 TI - Cognitive behavioral therapy for schizophrenia: an empirical review. AB - Early case studies and noncontrolled trial studies focusing on the treatment of delusions and hallucinations have laid the foundation for more recent developments in comprehensive cognitive behavioral therapy (CBT) interventions for schizophrenia. Seven randomized, controlled trial studies testing the efficacy of CBT for schizophrenia were identified by electronic search (MEDLINE and PsychInfo) and by personal correspondence. After a review of these studies, effect size (ES) estimates were computed to determine the statistical magnitude of clinical change in CBT and control treatment conditions. CBT has been shown to produce large clinical effects on measures of positive and negative symptoms of schizophrenia. Patients receiving routine care and adjunctive CBT have experienced additional benefits above and beyond the gains achieved with routine care and adjunctive supportive therapy. These results reveal promise for the role of CBT in the treatment of schizophrenia although additional research is required to test its efficacy, long-term durability, and impact on relapse rates and quality of life. Clinical refinements are needed also to help those who show only minimal benefit with the intervention. PMID- 23034572 TI - Cognitive behavioral therapy and Aaron Beck. PMID- 23034573 TI - Report from England I: innovative approaches to reducing mental health disparities related to ethnicity. PMID- 23034574 TI - Religion, spirituality, and mental health: current controversies and future directions. AB - Although studies examining religion, spirituality, and mental health generally indicate positive associations, there is a need for more sophisticated methodology, greater discrimination between different cultures and traditions, more focus on situated experiences of individuals belonging to particular traditions, and, in particular, greater integration of theological contributions to this area. We suggest priorities for future research based on these considerations. PMID- 23034575 TI - Absolute and relative short-term stability of interpersonal dependency in suicide attempters. AB - Previous studies have reported an association between suicide and interpersonal dependency (IPD), but no study has examined whether IPD constitutes a state dependent phenomenon or an enduring personality trait in this association. The aims of the present study were, firstly, to evaluate both the absolute and the relative stability of IPD as well as depression in suicide attempters and, secondly, to examine whether the relative stability of IPD was related to the depressive level rated on admission and/or at follow-up. The sample consisted of 41 suicide attempters evaluated on admission and 1 month later. The subjects filled in the Interpersonal Dependency Inventory (IDI) and the Beck Depression Inventory-II (BDI-II). The absolute and the relative stability of depression and IPD were analyzed using paired t-tests and Pearson's or intraclass correlation coefficients, respectively. The relative stability of IPD, taking into account the changes of the depressive level, was tested by two regression analyses. In the first regression analysis follow-up, the IDI scores were the dependent variable and the baseline IDI scores and BDI-II scores were the predictors. In the second regression analysis, the IDI change scores were the dependent variable and the BDI-II change scores were the predictors. Absolute and relative stability were demonstrated for IPD, whereas depression presented only relative stability. The IPD scores on admission were also significant predictors of the follow-up IPD scores after controlling for depression level. The 1-month duration of follow-up may be too brief to detect any decrease in the level of IPD. In conclusion, in contrast with the depression scores, the IPD scores presented short-term absolute and relative stability, and these results support the view that IPD is a stable personality trait in suicide attempters. The stability of IPD in suicide attempters suggests the interest of specific therapeutic approaches of this personality trait. PMID- 23034576 TI - Cognitive insight in schizophrenia: the missing link between insight and neurocognitive complaint? AB - The aim of this study was to explore the associations between cognitive insight, clinical insight, and neurocognitive complaint in a sample of 54 outpatients with schizophrenia spectrum disorders. Cognitive insight assessed using the Beck Cognitive Insight Scale (BCIS) was not associated with clinical insight assessed using the Scale to Assess Unawareness of Mental Disorder. Associations were found between the BCIS scores and the neurocognitive complaints assessed using the Subjective Scale to Investigate Cognition in Schizophrenia. A high level of neurocognitive complaints was positively associated with self-reflectiveness and negatively associated with self-certainty about beliefs and judgments. These results provide further support for the construct validity of the BCIS. The data also suggest that cognitive insight and neurocognitive complaint are close constructs that should be differentiated from awareness of having a mental illness. PMID- 23034577 TI - More than 60 years later: the mediating role of trauma and posttraumatic stress disorder for the association of forced displacement in world war II with somatization in old age. AB - Up to now, it has remained unclear whether displacement itself is the pathogenetic factor for the impairment of mental health in uprooted individuals or whether the effect is mediated by the amount of traumatic events experienced during forced displacement and/or by the development of posttraumatic stress disorder (PTSD). A total of 1657 participants were included in this population based study, who were then administered with the Patient Health Questionnaire, a modified trauma list of the PTSD module of the Munich Composite International Diagnostic Interview, and the Posttraumatic Diagnostic Scale. Displacement was associated with increased rates of traumatic events. The displaced participants were significantly more affected by somatoform symptoms and PTSD than the nondisplaced population. It was not displacement itself but the amount of trauma experienced during displacement that predicts current somatization in the population-based sample. The results highlight the necessity for prevention and treatment of posttraumatic conditions in displaced individuals and underpin the importance to understand somatization as one condition of the posttraumatic symptoms spectrum in the elderly. PMID- 23034578 TI - Autotransplantation for renovascular hypertension in children with solitary functioning kidney. PMID- 23034579 TI - Interpreting results from Factor V Leiden mutation analysis: a cautionary note. PMID- 23034580 TI - A primer in macromolecular linguistics. AB - Polymeric macromolecules, when viewed abstractly as strings of symbols, can be treated in terms of formal language theory, providing a mathematical foundation for characterizing such strings both as collections and in terms of their individual structures. In addition this approach offers a framework for analysis of macromolecules by tools and conventions widely used in computational linguistics. This article introduces the ways that linguistics can be and has been applied to molecular biology, covering the relevant formal language theory at a relatively nontechnical level. Analogies between macromolecules and human natural language are used to provide intuitive insights into the relevance of grammars, parsing, and analysis of language complexity to biology. PMID- 23034581 TI - Metal-insulator transition in V(1-x)W(x)O2: structural and electronic origin. AB - The driving mechanism of the metal-insulator transition (MIT) in VO(2) has always attracted attention, in particular with regards to understanding if and how the doping mechanism may tune the MIT transition temperature. However, due to the lack of detailed local structural information, in this oxide the underlying MIT mechanism is still matter of debate. In this contribution on the V(1-x)W(x)O(2) system, we attempt to clarify the origin of the MIT induced by tungsten doping. Combining W L(3)-edge and V K-edge extended X-ray absorption fine-structure (EXAFS) spectroscopy, the local structures around both V and W have been obtained. The data point out the occurrence of internal stress along the V-V chains induced by doping. It reaches a critical value that remains constant during the transition. The main effect of the internal stress on the vanadium local structure has also been identified. Actually, upon increasing the dopant concentration, the tilt of the V-V pairs towards the apex oxygen atoms in the VO(6) octahedron decreases while the V-V bond lengths remain unchanged. The electronic structure has also been investigated by O K-edge X-ray absorption near edge structure (XANES) spectroscopy. Actually, at high doping concentrations the interaction of O(2p) and the V d(?) state increases, while the hybridization of O(2p) and V pi* decreases. The O(2p)-V(3d) hybridization is therefore an essential parameter correlated with the decreasing transition temperature in the V(1-x)W(x)O(2) system. PMID- 23034582 TI - Clobazam : in patients with Lennox-Gastaut syndrome. AB - Clobazam, as with other benzodiazepines, has a long history of use in the treatment of epilepsy. More recently, it was approved in the USA as adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome in patients aged >=2 years. In the pivotal, placebo-controlled CONTAIN trial in paediatric and adult patients with Lennox-Gastaut syndrome (n = 217 evaluable), adjunctive therapy with clobazam 5-40 mg/day for 12 weeks significantly reduced mean weekly drop seizure rates from baseline compared with adjunctive placebo (primary endpoint), with a significant dosage-dependent improvement in these rates. Results from a dosage-ranging, double-blind, multi-centre, phase II trial add further support for the efficacy of clobazam in paediatric and adult patients with Lennox-Gastaut syndrome (n = 61 evaluable). Improvements in mean weekly drop seizure rates with adjunctive clobazam treatment in these short-term trials was maintained in an ongoing, open-label extension study, with a 91.6 % reduction in mean weekly drop seizure rates from baseline (at randomization in the initial trials) to 24 months in the overall population. Treatment with adjunctive clobazam was generally well tolerated in these clinical trials and after at least 2 years of treatment in an open-label extension study. Most adverse events were mild or moderate and similar to those typically observed with other benzodiazepines. PMID- 23034583 TI - Sublingual zolpidem (EdluarTM; SublinoxTM). AB - Zolpidem is a non-benzodiazepine hypnotic used in the short-term treatment of insomnia. A sublingual orally disintegrating tablet formulation of zolpidem (EdluarTM; SublinoxTM) has been developed to provide a more rapid onset of action than oral immediate-release zolpidem. Sublingual zolpidem has demonstrated bioequivalence to oral zolpidem. In a randomized, double-blind, double-dummy, crossover, multi-centre study in adult patients with primary insomnia (n = 70), a single 10-mg dose of sublingual zolpidem significantly reduced latency to persistent sleep (primary endpoint) compared with a single 10-mg dose of oral immediate-release zolpidem. Sleep-onset latency and latency to stage 1 sleep were also significantly shorter with sublingual zolpidem than with oral zolpidem. Moreover, compared with the oral formulation, sublingual zolpidem was noninferior in terms of total sleep time and did not significantly differ in terms of duration of wake after sleep onset. Sublingual zolpidem was generally well tolerated in this trial, with most adverse events being of mild or moderate severity. The overall tolerability profile of sublingual zolpidem was similar to that of oral zolpidem. PMID- 23034584 TI - U.S-acquired human rabies with symptom onset and diagnosis abroad, 2012. AB - On July 8, 2012, a U.S. resident was admitted to a hospital in Dubai, United Arab Emirates, for evaluation of right arm spasticity, anxiety, and malaise. By the next day, the patient had become comatose following a period of agitation. On July 31, he died. Investigators from CDC, state, and local health departments determined that the patient acquired rabies from contact in March with a bat in California. Person-to-person transmission of rabies has been documented in cases of organ and tissue transplantation and is theoretically possible if infectious saliva or tears are introduced into fresh open wounds or onto mucous membranes. Once symptoms begin, rabies is almost always fatal. While he was potentially infectious, during June 11-July 31, the patient traveled on eight international flights through six countries. To date, 59 persons have been identified as contacts, and 23 persons have been administered postexposure prophylaxis (PEP); no secondary cases have been identified. Bites or scratches from bats or other animals suspected of having rabies should be regarded seriously; victims should promptly seek consultation with public health practitioners and medical-care providers. This report highlights the need for collaboration to 1) identify persons who potentially had contact with infectious materials from a person infected with rabies, 2) conduct a risk assessment, and 3) provide prophylaxis to all those with a reasonable risk for contact with infectious materials (e.g., tears, saliva, or neural tissue from a person with rabies contacting open wounds or mucous membranes of an uninfected person). PMID- 23034585 TI - Botulism from drinking prison-made illicit alcohol - Utah 2011. AB - Foodborne botulism is a rare, potentially fatal paralytic illness caused by eating food contaminated by Clostridium botulinum toxin. It occurs most often as a single case not linked to others by a common food source. As a result of improvements in food canning, when outbreaks do occur, they typically involve fewer than five persons. During October 2-4 2011, eight maximum security inmates at the Utah State Prison in Salt Lake County were diagnosed with foodborne botulism. An investigation by Salt Lake Valley Heath Department, Utah Department of Health, and CDC identified pruno, an illicit alcoholic brew, as the vehicle. The principal ingredients in pruno are fruit, sugar, and water. Many additional ingredients, including root vegetables, are sometimes added, depending on the availability of foods in prison. A baked potato saved from a meal served weeks earlier and added to the pruno was the suspected source of C. botulinum spores. Many of the affected inmates suffered severe morbidity, and some required prolonged hospitalizations. Knowing the link between pruno and botulism might help public health and correctional authorities prevent future outbreaks, respond quickly with appropriate health-care to inmates with acute descending paralysis and/or other symptoms, and reduce associated treatment costs to states. PMID- 23034586 TI - Update: influenza activity - United States and worldwide, May 20-September 22, 2012. AB - During May 20-September 22, 2012, the United States experienced low levels of seasonal influenza activity overall; however, more seasonal influenza viruses were detected than in the summer months of previous years. Influenza A (H1N1)pdm09 (pH1N1), influenza A (H3N2), and influenza B viruses were detected worldwide and were identified sporadically in the United States. In July, influenza A (H3N2) variant viruses (H3N2v) were first detected in Indiana, and since July 12, a total of 306 cases have been reported from 10 states. This report summarizes influenza activity in the United States and worldwide since May 20, 2012. PMID- 23034587 TI - Progress toward poliomyelitis eradication - Afghanistan and Pakistan, January 2011-August 2012. AB - In 1988, the World Health Assembly resolved to eradicate polio, which led to the establishment of the Global Polio Eradication Initiative (GPEI). In 2012, however, the transmission of indigenous wild poliovirus (WPV) continued uninterrupted in Afghanistan, Pakistan, and Nigeria, leading the World Health Assembly to declare completion of polio eradication a programmatic emergency for global public health. This report updates previous reports and describes polio eradication activities and progress in Afghanistan and Pakistan during January 2011-August 2012, as of September 9, 2012. During 2011, 80 WPV cases were confirmed in Afghanistan, compared with 25 WPV cases in 2010; 17 WPV cases were confirmed during January-August 2012, compared with 34 WPV cases for the same period in 2011. In Pakistan, 198 WPV cases were confirmed in 2011, compared with 144 WPV cases in 2010; 30 WPV cases were confirmed during January-August 2012, compared with 88 WPV cases during the same period in 2011. During January 2011 August 2012, no WPV type 3 (WPV3) cases were confirmed in Afghanistan, and four confirmed WPV3 cases and one case with coinfection of WPV3 and WPV type 1 (WPV1) were reported in Pakistan. Violence targeting vaccinators has occurred previously in Afghanistan and recently in Pakistan. To progress further toward interruption of WPV transmission within their countries and across their shared border, the governments of Afghanistan and Pakistan might consider reviewing the implementation of their national emergency action plans and determine how to enhance the safety of vaccination teams within conflict-affected areas of both countries. PMID- 23034588 TI - Vital signs: drinking and driving among high school students aged >=16 years - United States, 1991-2011. AB - BACKGROUND: Although every state prohibits persons aged <21 years from driving with any measurable amount of blood alcohol, many young persons still drink and drive. Additionally, fatal crash data indicate that most teen drivers with positive (>0.00%) blood alcohol concentrations (BACs) who are involved in fatal crashes have BACs >=0.08%, the level designated as illegal for adult drivers. METHODS: CDC analyzed data from the 1991-2011 national Youth Risk Behavior Surveys (YRBS) to describe the trend in prevalence of drinking and driving (defined as driving one or more times when they had been drinking alcohol during the 30 days before the survey) among U.S. high school students aged >=16 years. The 2011 national YRBS data were used to describe selected subgroup differences in drinking and driving, and 2011 state YRBSs data were used to describe drinking and driving prevalence in 41 states. RESULTS: During 1991-2011, the national prevalence of self-reported drinking and driving among high school students aged >=16 years declined by 54%, from 22.3% to 10.3%. In 2011, 84.6% of students who drove after drinking also binge drank. Drinking and driving prevalence varied threefold across 41 states, from 4.6% in Utah to 14.5% in North Dakota; higher prevalences were clustered among states in the upper Midwest and along the Gulf Coast. CONCLUSIONS: Although substantial progress has been made during the past 2 decades to reduce drinking and driving among teens, in 2011, one in 10 students aged >=16 years reported driving after drinking during the past 30 days. Most students who drove after drinking alcohol also binge drank. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Effective interventions to reduce drinking and driving among teens include enforcement of minimum legal drinking age laws, zero tolerance laws (i.e., no alcohol consumption allowed before driving for persons aged <21 years), and graduated driver licensing systems. PMID- 23034589 TI - Notes from the field: tuberculosis outbreak in a long-term-care facility for mentally ill persons - Puerto Rico, 2010-2012. AB - During January 2012, the Puerto Rico Department of Health (PRDOH) detected a tuberculosis (TB) outbreak among residents of a long-term-care facility in the San Juan metropolitan area. The same rare Mycobacterium tuberculosis genotype was identified in isolates from four patients. This facility housed 40 men, aged 40 71 years, with severe mental illness. During April 2012, CDC assisted PRDOH with the investigation to describe outbreak epidemiology, identify and prioritize contacts for evaluation and treatment, and provide recommendations on interventions aimed at stopping TB transmission. PMID- 23034591 TI - Determination of catalytic reaction mechanisms by isotopic frequency response. AB - Efficient catalysts are of extraordinary importance for the development of efficient chemical processes as well as applications such as energy storage. Rational development of catalysts requires a mechanistic understanding of the catalytic reaction. Since steady-state investigations are insufficient to gain mechanistic understanding, transient methods such as SSITKA and frequency response have been developed. In this paper we provide a theoretical basis for a frequency response method based on variations in the isotopic composition of the reactant. This approach is particularly useful, since it permits transient investigations under quasi-steady state conditions and because the response is linear. PMID- 23034592 TI - Single-nucleotide polymorphisms in GALNT8 are associated with the response to interferon therapy for chronic hepatitis C. AB - New anti-hepatitis C virus (HCV) therapeutics developed recently are more effective and lead to improvements in sustained viral response. However, interferon (IFN) monotherapy is still used to a limited extent for fear of adverse effects. This study investigated host genetic factors affecting the IFN response in patients with chronic hepatitis C (CHC). Using a two-step design, a large-scale association screening including 1088 Japanese CHC patients treated with IFN was performed employing ~70 000 gene-based single-nucleotide polymorphisms (SNPs). Replication was tested in an independent Japanese cohort of 328 patients. Fine-mapping and functional analyses were also performed. Through two-step screening, it was found that rs2286580 in intron 6 of the gene encoding N-acetylgalactosaminyltransferase 8 (GALNT8) on chromosome 12 was significantly associated with a sustained viral response (combined P = 3.9*10(-6), odds ratio 1.52, 95 % confidence interval 1.29-1.82). The association was replicated in an additional cohort of 328 Japanese patients. In subgroup analysis, GALNT8 variants were associated with treatment outcome independently of HCV genotype. By contrast, the outcome of pegylated IFN and ribavirin combined therapy was not affected by the SNP. Fine-mapping analysis revealed that the association peak was at rs10849138 in intron 6 of GALNT8. Allele-specific transcription analysis demonstrated that GALNT8 expression was upregulated by an unfavourable allele of the variant. A luciferase reporter assay demonstrated that overexpression of GALNT8 attenuated IFN-alpha-induced gene transcription via the IFN-stimulated response element. These results suggest that GALNT8 variants contribute to the response to IFN therapy against CHC, providing a new insight into antiviral mechanisms of IFN. PMID- 23034593 TI - CD4+ T-cell responses to foot-and-mouth disease virus in vaccinated cattle. AB - We have performed a series of studies to investigate the role of CD4(+) T-cells in the immune response to foot-and-mouth disease virus (FMDV) post-vaccination. Virus neutralizing antibody titres (VNT) in cattle vaccinated with killed FMD commercial vaccine were significantly reduced and class switching delayed as a consequence of rigorous in vivo CD4(+) T-cell depletion. Further studies were performed to examine whether the magnitude of T-cell proliferative responses correlated with the antibody responses. FMD vaccination was found to induce T cell proliferative responses, with CD4(+) T-cells responding specifically to the FMDV antigen. In addition, gamma interferon (IFN-gamma) was detected in the supernatant of FMDV antigen-stimulated PBMC and purified CD4(+) T-cells from vaccinated cattle. Similarly, intracellular IFN-gamma could be detected specifically in purified CD4(+) T-cells after restimulation. It was not possible to correlate in vitro proliferative responses or IFN-gamma production of PBMC with VNT, probably as a consequence of the induction of T-independent and T dependent antibody responses and antigen non-specific T-cell responses. However, our studies demonstrate the importance of stimulating CD4(+) T-cell responses for the induction of optimum antibody responses to FMD-killed vaccines. PMID- 23034594 TI - Accumulation of nucleotide substitutions occurring during experimental transmission of foot-and-mouth disease virus. AB - Analysis of full-genome sequences was previously used to trace the origin and transmission pathways of foot-and-mouth disease virus (FMDV) outbreaks in the UK in 2001 and 2007. Interpretation of these data was sometimes at variance with conventional epidemiological tracing, and was also used to predict the presence of undisclosed infected premises that were later discovered during serological surveillance. Here we report the genome changes associated with sequential passage of a highly BHK-21-cell-adapted (heparan sulphate-binding) strain of FMDV arising from two independent transmission chains in cattle. In vivo virus replication rapidly selected for a wild-type variant with an amino acid substitution at VP3(56). Full-genome sequence analysis clearly demonstrated sequence divergence during parallel passage. The genetic diversity generated over the course of infection and the rate at which these changes became fixed and were transmitted between cattle occurred at a rate sufficient to enable reliable tracing of transmission pathways at the level of the individual animal. However, tracing of transmission pathways was only clear when sequences from epithelial lesions were compared. Sequences derived from oesophageal-pharyngeal scrapings were problematic to interpret, with a varying number of ambiguities suggestive of a more diverse virus population. These findings will help to correctly interpret full-genome sequence analyses to resolve transmission pathways within future FMDV epidemics. PMID- 23034596 TI - Structure and luminescence properties of 10-BN sheets. AB - Isotopic (10)BN sheets were first prepared using graphene sheets as templates to react with (10)B(2)O(3). The edge-areas of BN sheets have much higher oxygen doping ratios compared to other areas. The emission peak of X-ray excited optical luminescence spectra of the (10)BN-sheets is broader and red-shifted because of the isotopic effect. A broad violet-blue emission at a wavelength centered at ~400 nm is assigned to the defect emission due to oxygen-doping and defects in the BN network. PMID- 23034595 TI - Genomic analysis of two novel human enterovirus C genotypes found in respiratory samples from Peru. AB - We report the discovery of two enteroviruses detected in nasopharyngeal samples obtained from subjects with respiratory disease in Peru. Phylogenetic analysis indicated that both viruses belong to a clade within the species Human enterovirus C, which includes the recently characterized human enteroviruses 109 and 104. Members of this clade have undergone significant genomic rearrangement, as indicated by deletions in the hypervariable region of the 5' UTR and the VP1 protein, as well as recombination within the non-structural genes. Our findings and review of published sequences suggests that several novel human enterovirus C serotypes are currently circulating worldwide. PMID- 23034597 TI - Solid-state reactivity and structural transformations involving coordination polymers. AB - This tutorial review discusses recent literature on coordination polymers and metal-organic frameworks (MOFs) that exhibit solid-state reactivity and structural transformation under various experimental conditions. Removal or exchange of solvents and guest molecules, exposure to reactive vapours, and external stimuli such as heat, light or mechanochemical force cause such structural transformations and these are often manifested by various physical properties such as colour, magnetism, luminescence, chirality, porosity, etc. due to change in coordination number and geometry, dimensionality, interpenetration, etc. More drastic transformations related to the exchange of metal ions, pillar ligands and insertion of additional ligands between the layers have also been demonstrated. The vast area of dynamic behaviour of coordination polymers and their stimuli-responsive properties have also been addressed briefly. PMID- 23034598 TI - Study of indoor radon concentrations and associated health risks in the five districts of Hazara division, Pakistan. AB - A total of 200 indoor air samples were collected to measure radon concentration levels and its contribution to the mean effective doses during different seasons of the period 2009-2010 at different sites of the five districts of Hazara division, Pakistan. The major portion of the region is mountainous and is full of thick forests which receives heavy snow fall in winter. The need for conducting the present survey relied on the fact that occupants spend their lives in poorly ventilated indoor environments of the region, especially in the winter season when they use wood fire inside their residences. The measurements of indoor air samples were taken with RAD-7, a solid state alpha-detector. Radon concentrations in the whole region range from 41 Bq m(-3) to 254 Bq m(-3) with a geometric mean of 128 Bq m(-3). Radon progenies were measured with a surface barrier detector through alpha spectroscopy from which the Equilibrium Factor (EF) for radon and Radon Decay Products (RDPs) for the smoke-bearing as well as smoke-free indoor environments were deduced. The respective mean values of EF were calculated as 0.49 +/- 0.08 and 0.40 +/- 0.07. The mean effective doses from indoor air of Abbottabad, Mansehra, Haripur, Battgram and Kohistan districts were calculated as 3.5 +/- 1.2, 3.7 +/- 0.7, 3.9 +/- 1.0, 3.6 +/- 1.1 and 3.9 +/- 0.7 mSv a(-1) respectively, with the maximum value of 5.1 +/- 1.8 mSv a(-1) in Kohistan district during winter and the minimum value of 2.9 +/- 1.0 mSv a(-1) in Abbottabad district during summer. The annual exposure dose to the inhabitants of the locality lies below the upper bound of 10 mSv a(-1), as recommended by ICRP 65, and may not pose any significant threat to the public health. PMID- 23034599 TI - Vapor-based synthesis of maleimide-functionalized coating for biointerface engineering. AB - Chemical vapor deposition polymerization was used to deposit a novel maleimide functionalized poly-p-xylylene coating on various substrates. The coated substrates are readily able to undergo thiol-maleimide click reaction under mild conditions. Applications using this coating technology are highlighted in low protein-fouling modification as well as manipulated attachments and growth of bovine arterial endothelial cells. PMID- 23034602 TI - Mesoporous ferrihydrite with incorporated manganese for rapid removal of organic contaminants in air. AB - Mesoporous ferrihydrite nanoparticles with incorporated Mn (MMnFh) were prepared for the first time, and MMnFh exhibits excellent performance in removing organic contaminants (CH(3)CHO and toluene) in air. The interesting physico-chemical properties and remarkable activity of MMnFh give great commercial potential in air purification application in diverse sectors. PMID- 23034600 TI - Genome-wide technology for determining RNA stability in mammalian cells: historical perspective and recent advantages based on modified nucleotide labeling. AB - Changing the abundance of transcripts by regulated RNA degradation is a critical step in the control of various biological pathways. Recently, genome-wide inhibitor-free technologies for determining RNA stabilities in mammalian cells have been developed. In these methods, endogenous RNAs are pulse labeled by uridine analogs [e.g., 4-thiouridine (4sU), 5-etyniluridine (EU) and 5'-bromo uridine (BrU)], followed by purification of labeled de novo RNAs. These technologies have revealed that the specific half-life of each mRNA is closely related to its physiological function. Genes with short-lived mRNAs are significantly enriched among regulatory genes, while genes with long-lived mRNAs are enriched among housekeeping genes. This review describes the recent progress of experimental procedures for measuring RNA stability. PMID- 23034604 TI - The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation? AB - One hypothesis for the etiology of inflammatory bowel disease is that an altered or pathogenic microbiota causes inflammation in a genetically susceptible individual. Understanding the microbiota's role in the pathogenesis of the disease could lead to new IBD treatments aimed at shifting the bacteria in the gut back to eubiosis. Probiotics have some efficacy in the treatment of ulcerative colitis (UC), but our current repertoire is limited in potency. Fecal microbiota therapy (FMT) is an emerging treatment for several gastrointestinal and metabolic disorders. It has demonstrated efficacy in treating refractory Clostridium difficile infection, and there are case reports of FMT successfully treating UC. Further clinical studies are justified, and could be complemented by mouse models of fecal transplantation, in which variables can be controlled and manipulated. PMID- 23034606 TI - Tips for better colonoscopy from two experts. PMID- 23034605 TI - Efficacy of hepatitis B vaccination and revaccination and factors impacting on response in patients with inflammatory bowel disease. AB - OBJECTIVES: We assessed the effectiveness of hepatitis B virus (HBV) vaccine in inflammatory bowel disease (IBD) patients, evaluated the impact of immunosuppressors and anti-tumor necrosis factor (anti-TNF) agents, and assessed the effectiveness of revaccination. METHODS: IBD patients were vaccinated against HBV with a quick (0, 1, and 2 months) and double-dose schedule (Engerix B). A second vaccination was administered to nonresponders. RESULTS: Of 241 vaccinated patients, anti-HBs was >10 IU/l in 59% and >100 IU/l in 39%. The response rate (anti-HBs >10 IU/l) was lower among patients under anti-TNF therapy: 46% vs. 62%. In the multivariate analysis, a lower response rate was demonstrated in older patients and those receiving anti-TNFs. The response rate (anti-HBs >100 IU/l) after revaccination was 42%. CONCLUSIONS: The response rate to the HBV vaccination--even with a double-dose schedule--is very low in IBD patients, mainly in those receiving anti-TNFs. However, treatment with immunosuppressors did not affect the efficacy of the vaccine. A considerable--albeit insufficient- success rate may be obtained when two consecutive vaccination courses, each with a three-dose vaccine series, are administered. PMID- 23034607 TI - Images of the month: Giant fibrovascular polyp of the esophagus. PMID- 23034608 TI - "Irritable bowel symptoms" in inflammatory bowel disease: diagnostic uncertainty meets pathological reality. AB - Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are common, chronic, relapsing, and potentially disabling disorders in the West which are increasing in prevalence in the rest of the world. They typically afflict young adults in the prime of their lives and, consequently, may inflict a considerable emotional, personal, and socioeconomic toll. Not surprisingly, therefore, their management requires considerable clinical acumen and a fundamental commitment to the many dimensions of the patient-doctor relationship. There the similarities end. Despite a considerable body of recent data reporting a number of abnormalities (both upregulation and downregulation) in various components of the mucosal and systemic immune response in IBS, none of these findings come even close to the inflammatory processes that typify IBD. Furthermore, there is little evidence that those with an established diagnosis of IBS (in contrast to those with IBS-type symptoms in which IBD may have been missed (1)) can evolve into IBD; IBS, regardless of immunological or microbiological findings, should not be considered as a part of the spectrum of IBD. If IBS and IBD are distinct entities, then can they co-exist and lead to diagnostic confusion for the clinician? PMID- 23034613 TI - Case description of cap retention in the submucosal tunnel during peroral endoscopic myotomy. PMID- 23034615 TI - Darwinian dyspepsia, a more definitive diagnosis. PMID- 23034617 TI - Ten-year outcome of radiofrequency thermal ablation for hepatocellular carcinoma: an Italian experience. PMID- 23034618 TI - Is injecting absolute alcohol a safe and effective therapy for bleeding ulcers? PMID- 23034620 TI - Stepwise endoscopic therapy for a large duodenal papillary polyp. PMID- 23034622 TI - Treatment of intractable rectal stump drainage with cryoablation. PMID- 23034623 TI - Benefits of Beta blockade beyond bleeding prophylaxis and the role of adherence. PMID- 23034624 TI - Double trouble: two cases of squamous carcinoma arising from Barrett's dysplasia after endoscopic mucosal resection. PMID- 23034627 TI - Complexes of earth-abundant metals for catalytic electrochemical hydrogen generation under aqueous conditions. AB - Growing global energy demands and climate change motivate the development of new renewable energy technologies. In this context, water splitting using sustainable energy sources has emerged as an attractive process for carbon-neutral fuel cycles. A key scientific challenge to achieving this overall goal is the invention of new catalysts for the reductive and oxidative conversions of water to hydrogen and oxygen, respectively. This review article will highlight progress in molecular electrochemical approaches for catalytic reduction of protons to hydrogen, focusing on complexes of earth-abundant metals that can function in pure aqueous or mixed aqueous-organic media. The use of water as a reaction medium has dual benefits of maintaining high substrate concentration as well as minimizing the environmental impact from organic additives and by-products. PMID- 23034628 TI - BMP, Wnt and FGF signals are integrated through evolutionarily conserved enhancers to achieve robust expression of Pax3 and Zic genes at the zebrafish neural plate border. AB - Neural crest cells generate a range of cells and tissues in the vertebrate head and trunk, including peripheral neurons, pigment cells, and cartilage. Neural crest cells arise from the edges of the nascent central nervous system, a domain called the neural plate border (NPB). NPB induction is known to involve the BMP, Wnt and FGF signaling pathways. However, little is known about how these signals are integrated to achieve temporally and spatially specific expression of genes in NPB cells. Furthermore, the timing and relative importance of these signals in NPB formation appears to differ between vertebrate species. Here, we use heat shock overexpression and chemical inhibitors to determine whether, and when, BMP, Wnt and FGF signaling are needed for expression of the NPB specifiers pax3a and zic3 in zebrafish. We then identify four evolutionarily conserved enhancers from the pax3a and zic3 loci and test their response to BMP, Wnt and FGF perturbations. We find that all three signaling pathways are required during gastrulation for the proper expression of pax3a and zic3 in the zebrafish NPB. We also find that, although the expression patterns driven by the pax3a and zic3 enhancers largely overlap, they respond to different combinations of BMP, Wnt and FGF signals. Finally, we show that the combination of the two pax3a enhancers is less susceptible to signaling perturbations than either enhancer alone. Taken together, our results reveal how BMPs, FGFs and Wnts act cooperatively and redundantly through partially redundant enhancers to achieve robust, specific gene expression in the zebrafish NPB. PMID- 23034629 TI - Parathyroid hormone-related protein activates Wnt signaling to specify the embryonic mammary mesenchyme. AB - Parathyroid hormone-related protein (PTHrP) regulates cell fate and specifies the mammary mesenchyme during embryonic development. Loss of PTHrP or its receptor (Pthr1) abolishes the expression of mammary mesenchyme markers and allows mammary bud cells to revert to an epidermal fate. By contrast, overexpression of PTHrP in basal keratinocytes induces inappropriate differentiation of the ventral epidermis into nipple-like skin and is accompanied by ectopic expression of Lef1, beta-catenin and other markers of the mammary mesenchyme. In this study, we document that PTHrP modulates Wnt/beta-catenin signaling in the mammary mesenchyme using a Wnt signaling reporter, TOPGAL-C. Reporter expression is completely abolished by loss of PTHrP signaling and ectopic reporter activity is induced by overexpression of PTHrP. We also demonstrate that loss of Lef1, a key component of the Wnt pathway, attenuates the PTHrP-induced abnormal differentiation of the ventral skin. To characterize further the contribution of canonical Wnt signaling to embryonic mammary development, we deleted beta-catenin specifically in the mammary mesenchyme. Loss of mesenchymal beta-catenin abolished expression of the TOPGAL-C reporter and resulted in mammary buds with reduced expression of mammary mesenchyme markers and impaired sexual dimorphism. It also prevented the ectopic, ventral expression of mammary mesenchyme markers caused by overexpression of PTHrP in basal keratinocytes. Therefore, we conclude that a mesenchymal, canonical Wnt pathway mediates the PTHrP-dependent specification of the mammary mesenchyme. PMID- 23034630 TI - Analysis of nephric duct specification in the avian embryo. AB - Vertebrate kidney tissue exhibits variable morphology that in general increases in complexity when moving from anterior to posterior along the body axis. The nephric duct, a simple unbranched epithelial tube, is derived in the avian embryo from a rudiment located in the anterior intermediate mesoderm (IM) adjacent to somites 8 to 10. Using quail-chick chimeric embryos, the current study finds that competence to form nephric duct is fixed when IM precursor cells are still located in the primitive streak, significantly before the onset of duct differentiation. In the primitive streak, expression of the gene HoxB4 is associated with prospective duct IM, whereas expression of the more posterior Hox gene HoxA6 is associated with more posterior, non-duct-forming IM. Misexpression of HoxA6, but not of HoxB4, in prospective duct-forming regions of the IM resulted in repression of duct formation, suggesting a mechanism for the restriction of duct formation to the anterior-most IM. The results are discussed with respect to their implications for anterior-posterior patterning of kidney tissue and of mesoderm in general, and for the loss of duct-forming ability in more posterior regions of the IM that has occurred during vertebrate evolution. PMID- 23034631 TI - APETALA2 negatively regulates multiple floral organ identity genes in Arabidopsis by recruiting the co-repressor TOPLESS and the histone deacetylase HDA19. AB - The development and coordination of complex tissues in eukaryotes requires precise spatial control of fate-specifying genes. Although investigations of such control have traditionally focused on mechanisms of transcriptional activation, transcriptional repression has emerged as being equally important in the establishment of gene expression territories. In the angiosperm flower, specification of lateral organ fate relies on the spatial regulation of the ABC floral organ identity genes. Our understanding of how the boundaries of these expression domains are controlled is not complete. Here, we report that the A class organ identity gene APETALA2 (AP2), which is known to repress the C-class gene AGAMOUS, also regulates the expression borders of the B-class genes APETALA3 and PISTILLATA, and the E-class gene SEPALLATA3. We show that AP2 represses its target genes by physically recruiting the co-repressor TOPLESS and the histone deacetylase HDA19. These results demonstrate that AP2 plays a broad role in flower development by controlling the expression domains of numerous floral organ identity genes. PMID- 23034632 TI - Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis. AB - Abnormal activation of Hedgehog (Hh) signaling leads to basal cell carcinoma (BCC) of the skin, the most common human cancer. Gli2, the major transcriptional activator of Hh signaling, is essential for hair follicle development and its overexpression in epidermis induces BCC formation and maintains tumor growth. Despite its importance in skin development and tumorigenesis, little is known about the molecular regulation of Gli2. Sufu and Kif7 are two evolutionarily conserved regulators of Gli transcription factors. Here, we show that Sufu and Kif7 regulate Gli2 through distinct mechanisms in keratinocytes. Sufu restricts the activity of Gli2 through cytoplasmic sequestration. Kif7 possesses Sufu dependent and -independent regulatory functions in Hh signaling: while it promotes Hh pathway activity through the dissociation of Sufu-Gli2 complex, it also contributes to the repression of Hh target genes in the absence of Sufu. Deletion of both Sufu and Kif7 in embryonic skin leads to complete loss of follicular fate. Importantly, although inactivation of Sufu or Kif7 alone in adult epidermis cannot promote BCC formation, their simultaneous deletion induces BCC. These studies establish Sufu and Kif7 as crucial components in the regulation of Gli2 localization and activity, and illustrate their overlapping functions in skin development and tumor suppression. PMID- 23034633 TI - Smad4 is required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors in mouse limb buds. AB - SMAD4 is an essential mediator of canonical TGFbeta/BMP signal transduction and we inactivated Smad4 in mouse limb buds from early stages onward to study its functions in the mesenchyme. While this Smad4 inactivation did not alter the early Sox9 distribution, prefiguring the chondrogenic primordia of the stylopod and zeugopod, it disrupted formation of all Sox9-positive digit ray primordia. Specific inactivation of Smad4 during handplate development pointed to its differential requirement for posterior and anterior digit ray primordia. At the cellular level, Smad4 deficiency blocked the aggregation of Sox9-positive progenitors, thereby preventing chondrogenic differentiation as revealed by absence of collagen type II. The progressive loss of SOX9 due to disrupting digit ray primordia and chondrogenesis was paralleled by alterations in genes marking other lineages. This pointed to a general loss of tissue organization and diversion of mutant cells toward non-specific connective tissue. Conditional inactivation of Bmp2 and Bmp4 indicated that the loss of digit ray primordia and increase in connective tissue were predominantly a consequence of disrupting SMAD4-mediated BMP signal transduction. In summary, our analysis reveals that SMAD4 is required to initiate: (1) formation of the Sox9-positive digit ray primordia; and (2) aggregation and chondrogenic differentiation of all limb skeletal elements. PMID- 23034634 TI - Wapl antagonizes cohesin binding and promotes Polycomb-group silencing in Drosophila. AB - Wapl protein regulates binding of the cohesin complex to chromosomes during interphase and helps remove cohesin from chromosomes at mitosis. We isolated a dominant mutation in wapl (wapl(AG)) in a screen for mutations that counteract silencing mediated by an engrailed Polycomb-group response element. wapl(AG) hemizygotes die as pharate adults and have an extra sex combs phenotype characteristic of males with mutations in Polycomb-group (PcG) genes. The wapl gene encodes two proteins, a long form and a short form. wapl(AG) introduces a stop codon at amino acid 271 of the long form and produces a truncated protein. The expression of a transgene encoding the truncated Wapl-AG protein causes an extra-sex-comb phenotype similar to that seen in the wapl(AG) mutant. Mutations in the cohesin-associated genes Nipped-B and pds5 suppress and enhance wapl(AG) phenotypes, respectively. A Pds5-Wapl complex (releasin) removes cohesin from DNA, while Nipped-B loads cohesin. This suggests that Wapl-AG might exert its effects through changes in cohesin binding. Consistent with this model, Wapl-AG was found to increase the stability of cohesin binding to polytene chromosomes. Our data suggest that increasing cohesin stability interferes with PcG silencing at genes that are co-regulated by cohesin and PcG proteins. PMID- 23034635 TI - Endogenous Nodal signaling regulates germ cell potency during mammalian testis development. AB - Germ cells, the embryonic precursors of sperm or oocytes, respond to molecular cues that regulate their sex-specific development in the fetal gonads. In males in particular, the balance between continued proliferation and cell fate commitment is crucial: defects in proliferation result in insufficient spermatogonial stem cells for fertility, but escape from commitment and prolonged pluripotency can cause testicular germ cell tumors. However, the factors that regulate this balance remain unidentified. Here, we show that signaling by the TGFbeta morphogen Nodal and its co-receptor Cripto is active during a crucial window of male germ cell development. The Nodal pathway is triggered when somatic signals, including FGF9, induce testicular germ cells to upregulate Cripto. Germ cells of mutant mice with compromised Nodal signaling showed premature differentiation, reduced pluripotency marker expression and a reduced ability to form embryonic germ (EG) cell colonies in vitro. Conversely, human testicular tumors showed upregulation of NODAL and CRIPTO that was proportional to invasiveness and to the number of malignant cells. Thus, Nodal signaling provides a molecular control mechanism that regulates male germ cell potency in normal development and testicular cancer. PMID- 23034636 TI - Migration of cardiomyocytes is essential for heart regeneration in zebrafish. AB - Adult zebrafish possess a significant ability to regenerate injured heart tissue through proliferation of pre-existing cardiomyocytes, which contrasts with the inability of mammals to do so after the immediate postnatal period. Zebrafish therefore provide a model system in which to study how an injured heart can be repaired. However, it remains unknown what important processes cardiomyocytes are involved in other than partial de-differentiation and proliferation. Here we show that migration of cardiomyocytes to the injury site is essential for heart regeneration. Ventricular amputation induced expression of cxcl12a and cxcr4b, genes encoding a chemokine ligand and its receptor. We found that cxcl12a was expressed in the epicardial tissue and that Cxcr4 was expressed in cardiomyocytes. We show that pharmacological blocking of Cxcr4 function as well as genetic loss of cxcr4b function causes failure to regenerate the heart after ventricular resection. Cardiomyocyte proliferation was not affected but a large portion of proliferating cardiomyocytes remained localized outside the injury site. A photoconvertible fluorescent reporter-based cardiomyocyte-tracing assay demonstrates that cardiomyocytes migrated into the injury site in control hearts but that migration was inhibited in the Cxcr4-blocked hearts. By contrast, the epicardial cells and vascular endothelial cells were not affected by blocking Cxcr4 function. Our data show that the migration of cardiomyocytes into the injury site is regulated independently of proliferation, and that coordination of both processes is necessary for heart regeneration. PMID- 23034638 TI - Mesoscale simulations of biomolecular transport through nanofilters with tapered and cylindrical geometries. AB - Molecular transport properties in short cylindrical and pyramidal nanopores are investigated by mesoscale dissipative particle dynamics simulations. We examine the effect of pore geometry, size, flow direction, particle diameter and electrostatic forces on membrane flux, selectivity and fouling. Biomolecules of various sizes are represented by spherical particles as they move through nanopores. The highest molecular concentration in pores is obtained with a cylindrical geometry, whereas the lowest concentration is obtained with a pyramidal geometry when the molecular transport direction is from large to small pore opening. This reveals a higher tendency for fouling in cylindrical pores relative to pyramidal pores. In general, increasing pore size and decreasing molecular diameter increase diffusion and fluxes, as expected, and the highest fluxes are achieved when the molecule is in neutral state. For large, short pores, higher diffusion rates are achieved with a cylindrical geometry compared to a pyramidal geometry. For pore: particle diameter ratios below 10, highly restricted motion is observed. In the presence of electrostatic forces, the molecular separation potential of pyramidal pores is 1.5* higher relative to short cylindrical pores, although the diffusion rate with cylindrical pores is 1.8* higher. Finally, we demonstrate that decreasing the pore size by a factor of 1.2 can reduce the pore molecular concentration by at least a factor of 3 for all pore types. This finding is consistent with a surprising recent experimental study in which larger ceramic pores were observed to foul much faster than smaller pores. PMID- 23034637 TI - Age-related changes in expression and function of Toll-like receptors in human skin. AB - Toll-like receptors (TLRs) initiate innate immune responses and direct subsequent adaptive immunity. They play a major role in cutaneous host defense against micro organisms and in the pathophysiology of several inflammatory skin diseases. To understand the role of TLRs in the acquisition of immunological competence, we conducted a comprehensive study to evaluate TLR expression and function in the developing human skin before and after birth and compared it with adults. We found that prenatal skin already expresses the same spectrum of TLRs as adult skin. Strikingly, many TLRs were significantly higher expressed in prenatal (TLRs 1-5) and infant and child (TLRs 1 and 3) skin than in adult skin. Surprisingly, neither dendritic cell precursors in prenatal skin nor epidermal Langerhans cells and dermal dendritic cells in adult skin expressed TLRs 3 and 6, whereas the staining pattern and intensity of both TLRs in fetal basal keratinocytes was almost comparable to those of adults. Stimulation of primary human keratinocytes from fetal, neonatal and adult donors with selected TLR agonists revealed that the synthetic TLR3 ligand poly (I:C) specifically, mimicking viral double stranded RNA, induced a significantly enhanced secretion of CXCL8/IL8, CXCL10/IP 10 and TNFalpha in fetal and neonatal keratinocytes compared with adult keratinocytes. This study demonstrates quantitative age-specific modifications in TLR expression and innate skin immune reactivity in response to TLR activation. Thus, antiviral innate immunity already in prenatal skin may contribute to protect the developing human body from viral infections in utero in a scenario where the adaptive immune system is not yet fully functional. PMID- 23034639 TI - Maximal aerobic and anaerobic exercise responses in children with cerebral palsy. AB - PURPOSE: The objective of this study is to compare the maximal aerobic and anaerobic exercise responses of children with cerebral palsy (CP) by level of motor impairment and in comparison with those of typically developing children (TD). METHODS: Seventy children with CP, with varying levels of motor impairment (Gross Motor Function Classification System (GMFCS) I-III), and 31 TD performed an incremental continuous maximal aerobic exercise test and a 20-s anaerobic Wingate test on a cycle ergometer. Peak oxygen uptake (VO2peak), anaerobic threshold (AT), peak ventilation (VEpeak), peak oxygen pulse (peak O2 pulse), peak ventilatory equivalent of oxygen (peak VE/VO2) and carbon dioxide (peak VE/VCO2), peak aerobic power output (POpeak), and mean anaerobic power (P20mean) were measured. Isometric leg muscle strength was determined as a secondary outcome. RESULTS: Analysis revealed a lower VO2peak for CP (I: 35.5 +/- 1.2 (SE); II: 33.9 +/- 1.6; III: 29.3 +/- 2.5 mL.kg-1.min-1) compared with TD (41.0 +/- 1.3, P < 0.001) and a similar effect for AT (I: 19.4 +/- 0.9; II: 19.2 +/- 1.2; III: 15.5 +/- 1.9; TD: 24.1 +/- 1.0 mL.kg-1.min-1, P < 0.001). VEpeak and peak O2 pulse were also lower, whereas peak VE/VCO2 was higher in CP compared with TD (P < 0.05) and peak VE/VO2 similar between groups. All these variables showed no differences for different motor impairment levels. POpeak was lower for CP (I: 2.4 +/- 0.1; II: 1.8 +/- 0.1; III: 1.4 +/- 0.2 W.kg-1) versus TD (3.0 +/- 0.1, P < 0.001), together with a lower P20mean in CP (I: 4.6 +/- 0.2; II: 3.3 +/- 0.2; III: 2.5 +/- 0.4 W.kg-1) versus TD (6.4 +/- 0.2, P < 0.001), and both decreased significantly with increasing motor impairment. CONCLUSION: Children with CP have decreased aerobic and anaerobic exercise responses, but decreases in respiratory and aerobic exercise responses were not as severe as predicted by motor impairment. Future research should reveal the role of inactivity on the exercise responses of children with CP and possibilities for improvement through training interventions. PMID- 23034640 TI - Effect of BMI on pedometers in early adolescents under free-living conditions. AB - PURPOSE: Pedometers may provide valuable information regarding the ambulatory patterns of adolescents, but the effects of body mass index (BMI) on pedometer accuracy in this population are unknown.The purpose of this study was twofold: 1) to determine whether the New Lifestyles NL-2000 (NL) and the Digi-Walker SW-200 (DW) (New Lifestyles, Inc., Lees Summit, MO) yield similar step counts as compared with an ankle-mounted criterion, StepWatch 3, when worn by early adolescents in a free-living environment and 2) to study whether BMI percentile affects the accuracy of waist-mounted pedometers in adolescents. METHODS: Seventy four early adolescents (13.0 +/- 1.1 yr) wore the devices during one weekday. The study population included 33 normal weight, 21 overweight, and 20 obese participants. Two-way repeated-measures ANOVA was used to determine whether the BMI and the device were related to the number of steps per day and percentage of actual steps. RESULTS: The NL and DW recorded fewer steps than the StepWatch 3 in each BMI category (P < 0.05). In the obese group, the DW underestimated the steps more than the NL (P < 0.001). For the normal weight, overweight, and obese groups, the NL counted 89.1%, 89.1%, and 91.6% of the steps, respectively, whereas the DW counted 86.7%, 84.6%, and 72.7%, respectively. CONCLUSION: Researchers must be cognizant of the limitations of waist-mounted pedometers and carefully choose a device that suits the needs of their investigations. Because of the inaccuracies of the DW when measuring steps in obese adolescents, careful consideration must be given before choosing this device for research and interventions. The NL is a better device for assessment of adolescents' steps than the DW, especially for those who are obese. PMID- 23034641 TI - Joint mobilization acutely improves landing kinematics in chronic ankle instability. AB - PURPOSE: The objective of this study is to examine the acute effect of ankle joint mobilizations akin to those performed in everyday clinical practice on sagittal plane ankle joint kinematics during a single-leg drop landing in participants with chronic ankle instability (CAI). METHODS: Fifteen participants with self-reported CAI (defined as <24 on the Cumberland Ankle Instability Tool) performed three single-leg drop landings under two different conditions: 1) premobilization and, 2) immediately, postmobilization. The mobilizations performed included Mulligan talocrural joint dorsiflexion mobilization with movement, Mulligan inferior tibiofibular joint mobilization, and Maitland anteroposterior talocrural joint mobilization. Three CODA cx1 units (Charnwood Dynamics Ltd., Leicestershire, UK) were used to provide information on ankle joint sagittal plane angular displacement. The dependent variable under investigation was the angle of ankle joint plantarflexion at the point of initial contact during the drop landing. RESULTS: There was a statistically significant acute decrease in the angle of ankle joint plantarflexion from premobilization (34.89 degrees +/- 4.18 degrees ) to postmobilization (31.90 degrees +/- 5.89 degrees ), t(14) = 2.62, P < 0.05 (two-tailed). The mean decrease in the angle of ankle joint plantarflexion as a result of the ankle joint mobilization was 2.98 degrees with a 95% confidence interval ranging from 0.54 to 5.43. The eta squared statistic (0.32) indicated a large effect size. CONCLUSION: These results indicate that mobilization acted to acutely reduce the angle of ankle joint plantarflexion at initial contact during a single-leg drop landing. Mobilization applied to participants with CAI has a mechanical effect on the ankle joint, thus facilitating a more favorable positioning of the ankle joint when landing from a jump. PMID- 23034642 TI - Effect of recovery duration between two bouts of running on bone metabolism. AB - PURPOSE: Strenuous endurance exercise increases biochemical markers of bone resorption but not formation, although the effect of recovery duration between consecutive bouts of exercise is unknown. We examined the effect of recovery duration on the bone metabolic response to two bouts of running. METHODS: Ten physically active men completed two 9-d trials. On days 4 and 5 (D4 and D5), participants completed two 60-min bouts of running at 65% VO2max separated by either a 23-h (LONG) or a 3-h (SHORT) recovery period. Osteoprotegerin (OPG), parathyroid hormone (PTH), albumin-adjusted calcium (ACa), and phosphate (PO4) were measured from blood samples obtained before and for 3 h after exercise and on four follow-up days (D6-D9). Markers of bone resorption (C-terminal telopeptide region of collagen type 1) and bone formation (N-terminal propeptides of procollagen type 1 and bone alkaline phosphatase) were measured in early morning fasted samples on D4-D9. RESULTS: There were no significant changes in C terminal telopeptide region of collagen type 1, N-terminal propeptides of procollagen type 1, or bone alkaline phosphatase with either protocol. OPG, PTH, ACa, and PO4 concentrations increased with all exercise bouts, but the response to the second bout was not altered by recovery duration. CONCLUSIONS: Two 60-min bouts of running at 65% VO2max separated by either 23 or 3 h had no effect on the markers of bone resorption or formation from 1 to 4 d after exercise. Reducing recovery duration from 23 to 3 h between two bouts of running did not alter the increase in OPG, PTH, ACa, and PO4 to the second bout. PMID- 23034643 TI - Former male elite athletes have lower incidence of fragility fractures than expected. AB - PURPOSE: Physical activity during growth is associated with high peak bone mass and may, as a result, prevent osteoporosis later in life. It is therefore possible that athletic activity during youth could lower the risk of fragility fractures in old age. Although this is currently unclear and based on evaluations of surrogate skeletal end point variables in former athletes, we hypothesized that this is not the case. METHODS: In a retrospective matched controlled cohort study design, we calculated the lifetime incidence of fractures from the results of a mailed questionnaire sent to 709 former male elite athletes with a mean age of 69 yr (range = 50-93 yr) who had given up regular sports activity a mean of 34 yr (range = 1-63 yr) earlier, and to 1368 matched controls. Estimates of time to first fracture were analysed using Poisson regression, and for analyses of covariance, Cox Regression was used. Data are presented as rate ratios (RR) with 95% confidence interval (CI). RESULTS: After retirement from sports, the former athletes had an RR of 0.70 (0.52-0.93) for any fracture, an RR of 0.50 (0.27 0.89) for any fragility fracture, and an RR of 0.29 (0.09-0.74) for distal radius fractures. When adjusting for occupation, smoking, alcohol, disease, and medication the hazard ratio (HR) of any fracture after an active career was 0.73 (95% CI = 0.54-0.99) and the hazard ratio of any fragility fracture after age 50 yr was 0.63 (95% CI = 0.35-1.16). CONCLUSIONS: In men, elite sports during adolescence are associated with a lower fracture risk after career end. The former athletes were overall healthier, which may have influenced the results. PMID- 23034644 TI - Exercise-induced insulin-like growth factor I system concentrations after training in women. AB - INTRODUCTION: This study examined the effects of short-term physical training on the acute hormonal response (i.e., growth hormone, total and free insulin-like growth factor I [IGF-I], and IGF binding proteins [IGFBP]-1, IGFBP-2, and IGFBP 3) to resistance exercise (RE) in women. METHODS: Forty-six women (20.3 +/- 0.3 yr, mass = 64.1 +/- 7.3 kg, height = 165.7 +/- 1.0 cm) were randomly assigned to an endurance training (E), resistance training (R), combined training (R + E), or control (C) group for 8wk. Subjects completed a standardized bout of RE (six sets of back squats at 10 repetition maximum) before and after training. Blood samples were obtained at rest (PRE), after the third set, immediately postexercise (POST), and at 15 min and 30 min after exercise. RESULTS: Acute RE significantly increased (P < 0.05) serum growth hormone (mean +/- SD; change from PRE to POST = +10.9 +/- 7.5 MUg.L-1), total IGF-I (+66.1 +/- 25.4 MUg.L-1), IGFBP-1 (+2.5 +/- 3.1 MUg.L-1), IGFBP-2 (+86.0 +/- 86.8 MUg.L-1), and IGFBP-3 (+0.69 +/- 0.25 mg.L 1) concentrations and decreased free IGF-I concentrations (-0.14 +/- 0.21 MUg.L 1). After 8 wk of training, total IGF-I concentrations were significantly increased (change in POST concentrations from week 0 to week 8 = +82.5 +/- 120.8 MUg.L-1), and IGFBP-1 concentrations were significantly decreased (-6.7 +/- 13.6 MUg.L-1) during exercise in groups that participated in resistance training (R and R + E); no significant changes were seen after E or C. CONCLUSIONS: Participation in resistance training increased total IGF-I and reduced IGFBP-1 concentrations during acute RE, indicating exercise mode-specific adaptations in the circulating IGF-I system. PMID- 23034645 TI - Altered landing mechanics in ACL-reconstructed patients. AB - PURPOSE: This longitudinal study aimed to examine whether patients with anterior cruciate ligament (ACL) reconstruction show a similar landing strategy during the single-leg hop test (SLHT) postsurgery analog to that previously identified when ACL deficient. It is hypothesized that ACL-reconstructed patients demonstrate greater trunk flexion to reduce knee joint moments at the cost of postural dynamic stability at their involved leg compared to their uninvolved leg. METHODS: Ten ACL-reconstructed patients performed a bilateral SLHT 6 and 12 months after surgery. Landing mechanics were determined by means of a soft tissue artifact optimized, rigid, full-body model, and the margin of stability was quantified using an inverted pendulum approach. Knee extensor muscular strength (KS) was assessed during isometric maximal voluntary knee extension contractions. RESULTS: ACL-reconstructed patients showed similar landing strategies as previously reported in their ACL-deficient state. By flexing their trunk, patients repositioned the ground reaction force vector more anteriorly in relation to the joints of the lower extremity (P < 0.05) and, in doing so, were able to transfer joint moments from the knee to the adjacent joints (P < 0.05). This upper body strategy reduced the margin of stability in the ACL-reconstructed leg during landing (P < 0.05). Twelve months after surgery, the ACL-reconstructed leg showed lower KS compared to the uninvolved leg (P < 0.05), and knee joint moment output during landing was significantly correlated to KS. CONCLUSIONS: The results highlight the important role of KS on the interaction between trunk angle, joint kinetics, and postural dynamic stability during landing and show that ACL-reconstructed patients use an analogous feedforward strategy (e.g., more flexed trunk) to that used in their ACL-deficient state, aiming to compensate for KS deficits and thereby sacrificing postural dynamic stability and increasing the risk of loss of balance during landing maneuvers. PMID- 23034646 TI - SenseWear-determined physical activity and sedentary behavior and metabolic syndrome. AB - PURPOSE: The aim of this study was to examine the associations of multiple, objectively measured parameters of physical activity and sedentary behavior with metabolic syndrome (MetS) and its individual components. METHODS: Physical activity was measured in 370 Flemish adults (age = 41.7 +/- 9.8 yr; mean +/- SD) for 7 d using a SenseWear Armband. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Logistic regressions examined the associations between the subcomponents of physical activity and sedentary behavior and the odds of having MetS or individual risk factors. RESULTS: MetS was observed in 10.2% of men and 5.2% of women. Adults who spent >=60 min.d-1 in moderate-to-vigorous physical activity (MVPA) were 68%-81% less likely to have abdominal obesity, hypertriglyceridemia, and low HDL cholesterol compared with those with <30 min.d MVPA, independent of sex, age, education, smoking, alcohol consumption, and total sedentary time. The total sedentary time and the average duration of a sedentary bout were positively associated with MetS and most of its individual risk factors (odds ratio [OR] = 1.07-1.47). Breaks in sedentary time were inversely associated with abdominal obesity (OR = 0.71, 95% confidence interval [CI] = 0.55-0.91) and hypertriglyceridemia (OR = 0.79, 95% CI 0.63-0.99). These associations were no longer significant after adjustment for MVPA (and total sedentary time). Light physical activity was not associated with MetS or any of the individual risk factors. Time spent in moderate, vigorous, total MVPA, and bouts of MVPA were associated with a reduced likelihood of abdominal obesity (OR = <0.01-0.48), hypertriglyceridemia (OR = 0.14-0.63), and low HDL cholesterol (OR = 0.02-0.43), independent of potential confounders and total sedentary time. CONCLUSIONS: Engagement in MVPA may be essential to prevent MetS and individual risk factors. PMID- 23034647 TI - A map of rice genome variation reveals the origin of cultivated rice. AB - Crop domestications are long-term selection experiments that have greatly advanced human civilization. The domestication of cultivated rice (Oryza sativa L.) ranks as one of the most important developments in history. However, its origins and domestication processes are controversial and have long been debated. Here we generate genome sequences from 446 geographically diverse accessions of the wild rice species Oryza rufipogon, the immediate ancestral progenitor of cultivated rice, and from 1,083 cultivated indica and japonica varieties to construct a comprehensive map of rice genome variation. In the search for signatures of selection, we identify 55 selective sweeps that have occurred during domestication. In-depth analyses of the domestication sweeps and genome wide patterns reveal that Oryza sativa japonica rice was first domesticated from a specific population of O. rufipogon around the middle area of the Pearl River in southern China, and that Oryza sativa indica rice was subsequently developed from crosses between japonica rice and local wild rice as the initial cultivars spread into South East and South Asia. The domestication-associated traits are analysed through high-resolution genetic mapping. This study provides an important resource for rice breeding and an effective genomics approach for crop domestication research. PMID- 23034648 TI - Delayed build-up of Arctic ice sheets during 400,000-year minima in insolation variability. AB - Knowledge of the past variability of climate at high northern latitudes during astronomical analogues of the present interglacial may help to inform our understanding of future climate change. Unfortunately, long-term continuous records of ice-sheet variability in the Northern Hemisphere only are scarce because records of benthic (18)O content represent an integrated signal of changes in ice volume in both polar regions. However, variations in Northern Hemisphere ice sheets influence the Siberian High (an atmospheric pressure system), so variations in the East Asian winter monsoon (EAWM)--as recorded in the aeolian dust deposits on the Chinese Loess Plateau--can serve as a useful proxy of Arctic climate variability before the ice-core record begins. Here we present an EAWM proxy record using grain-size variations in two parallel loess sections representative of sequences across the whole of the Chinese Loess Plateau over the past 900,000 years. The results show that during periods of low eccentricity and precessional variability at approximately 400,000-year intervals, the grain-size-inferred intensity of the EAWM remains weak for up to 20,000 years after the end of the interglacial episode of high summer monsoon activity and strong pedogenesis. In contrast, there is a rapid increase in the EAWM after the end of most other interglacials. We conclude that, for both the 400,000-year interglacials, the weak EAWM winds maintain a mild, non-glacial climate at high northern latitudes for much longer than expected from the conventional loess and marine oxygen isotope records. During these times, the less-severe summer insolation minima at 65 degrees N (ref. 4) would have suppressed ice and snow accumulation, leading to a weak Siberian High and, consequently, weak EAWM winds. PMID- 23034649 TI - The molecular basis of phosphate discrimination in arsenate-rich environments. AB - Arsenate and phosphate are abundant on Earth and have striking similarities: nearly identical pK(a) values, similarly charged oxygen atoms, and thermochemical radii that differ by only 4% (ref. 3). Phosphate is indispensable and arsenate is toxic, but this extensive similarity raises the question whether arsenate may substitute for phosphate in certain niches. However, whether it is used or excluded, discriminating phosphate from arsenate is a paramount challenge. Enzymes that utilize phosphate, for example, have the same binding mode and kinetic parameters as arsenate, and the latter's presence therefore decouples metabolism. Can proteins discriminate between these two anions, and how would they do so? In particular, cellular phosphate uptake systems face a challenge in arsenate-rich environments. Here we describe a molecular mechanism for this process. We examined the periplasmic phosphate-binding proteins (PBPs) of the ABC type transport system that mediates phosphate uptake into bacterial cells, including two PBPs from the arsenate-rich Mono Lake Halomonas strain GFAJ-1. All PBPs tested are capable of discriminating phosphate over arsenate at least 500 fold. The exception is one of the PBPs of GFAJ-1 that shows roughly 4,500-fold discrimination and its gene is highly expressed under phosphate-limiting conditions. Sub-angstrom-resolution structures of Pseudomonas fluorescens PBP with both arsenate and phosphate show a unique mode of binding that mediates discrimination. An extensive network of dipole-anion interactions, and of repulsive interactions, results in the 4% larger arsenate distorting a unique low barrier hydrogen bond. These features enable the phosphate transport system to bind phosphate selectively over arsenate (at least 10(3) excess) even in highly arsenate-rich environments. PMID- 23034651 TI - Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. AB - The substantia nigra pars compacta and ventral tegmental area contain the two largest populations of dopamine-releasing neurons in the mammalian brain. These neurons extend elaborate projections in the striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output through the release of dopamine to promote and reinforce motor action. Here we show that activation of dopamine neurons in striatal slices rapidly inhibits action potential firing in both direct- and indirect-pathway striatal projection neurons through vesicular release of the inhibitory transmitter GABA (gamma-aminobutyric acid). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead, GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for dopamine. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms used by dopamine neurons to influence basal ganglia circuits, show a new substrate whose transport is dependent on VMAT2 and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons. PMID- 23034650 TI - Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. AB - Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of beta-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumour-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL 23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth. PMID- 23034653 TI - Probing graphene grain boundaries with optical microscopy. AB - Grain boundaries in graphene are formed by the joining of islands during the initial growth stage, and these boundaries govern transport properties and related device performance. Although information on the atomic rearrangement at graphene grain boundaries can be obtained using transmission electron microscopy and scanning tunnelling microscopy, large-scale information regarding the distribution of graphene grain boundaries is not easily accessible. Here we use optical microscopy to observe the grain boundaries of large-area graphene (grown on copper foil) directly, without transfer of the graphene. This imaging technique was realized by selectively oxidizing the underlying copper foil through graphene grain boundaries functionalized with O and OH radicals generated by ultraviolet irradiation under moisture-rich ambient conditions: selective diffusion of oxygen radicals through OH-functionalized defect sites was demonstrated by density functional calculations. The sheet resistance of large area graphene decreased as the graphene grain sizes increased, but no strong correlation with the grain size of the copper was revealed, in contrast to a previous report. Furthermore, the influence of graphene grain boundaries on crack propagation (initialized by bending) and termination was clearly visualized using our technique. Our approach can be used as a simple protocol for evaluating the grain boundaries of other two-dimensional layered structures, such as boron nitride and exfoliated clays. PMID- 23034652 TI - Black mamba venom peptides target acid-sensing ion channels to abolish pain. AB - Polypeptide toxins have played a central part in understanding physiological and physiopathological functions of ion channels. In the field of pain, they led to important advances in basic research and even to clinical applications. Acid sensing ion channels (ASICs) are generally considered principal players in the pain pathway, including in humans. A snake toxin activating peripheral ASICs in nociceptive neurons has been recently shown to evoke pain. Here we show that a new class of three-finger peptides from another snake, the black mamba, is able to abolish pain through inhibition of ASICs expressed either in central or peripheral neurons. These peptides, which we call mambalgins, are not toxic in mice but show a potent analgesic effect upon central and peripheral injection that can be as strong as morphine. This effect is, however, resistant to naloxone, and mambalgins cause much less tolerance than morphine and no respiratory distress. Pharmacological inhibition by mambalgins combined with the use of knockdown and knockout animals indicates that blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b containing channels in nociceptors is involved in the analgesic effect of mambalgins. These findings identify new potential therapeutic targets for pain and introduce natural peptides that block them to produce a potent analgesia. PMID- 23034654 TI - Monitoring the occurrence of PAHs in Irish wastewater effluent. AB - Polycyclic aromatic hydrocarbons (PAHs) are commonly occurring environmental pollutants, 8 of which have been chosen from the list of priority substances in the EU Water Framework Directive (WFD). The levels of PAHs in the environment are affected by a number of emission factors including anthropogenic activities, population equivalents, and weather, all of which must be taken into account when monitoring levels of PAHs being released into the environment via waste water treatment plant effluent. Effluent samples have been collected from nine different wastewater treatment plants in 2 areas of Ireland (Dublin and Cork) over a period of 3 years (2009-2011), including several weeks of high intensity sampling. Solid phase extraction is used in the sample preparation process with subsequent analysis by gas chromatography with mass spectrometric detection (GCMS). All samples analysed contained the priority PAHs in this study; however levels detected do not exceed environmental quality standards (EQSs). Herein these results are related to a number of key emission factors affecting the levels of PAHs present in wastewater treatment plant effluent. This study aims to complement storm water studies and inform future targeted priority substance monitoring programmes. PMID- 23034656 TI - Roles of CdS quantum dots in 1,1'-oxalyldiimidazole chemiluminescence. AB - The roles of CdS nanocrystals (quantum dots) stabilized by oleic acid ligands in toluene were investigated in the 1,1'-oxalyldiimidazole chemiluminescence (ODI CL) reaction generated under various environmental conditions. CdS excited by high-energy intermediates formed in ODI-CL reaction emitted dim CL. Also, CdS acted as a catalyst to enhance the yield of high-energy intermediates, capable of transferring energy to fluorescent molecules, in aqueous ODI-CL reactions, whereas it acted as a strong quencher, capable of inhibiting the CL emission of excited fluorescent molecules, in non-aqueous ODI-CL reactions. Based on the role of CdS in the aqueous ODI-CL reaction, the limit of detection (LOD = signal/noise = 3, 0.1 MUM) determined to quantify glucose using aqueous ODI-CL reaction in the presence of 2.75 MUM CdS was four times lower than that in the absence of CdS. The range of recovery determined in the aqueous ODI-CL reaction in the presence of CdS was 91.7-104%. We expect that the aqueous ODI-CL reaction in the presence of CdS can be applied as a highly sensitive sensor in various research fields such as bioanalytical chemistry, environmental engineering, homeland security, and toxicology. PMID- 23034655 TI - Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. AB - OBJECTIVE: Elevated presynaptic striatal dopaminergic function is a robust feature of schizophrenia. However, the relationship between this dopamine abnormality and the response to dopamine-blocking antipsychotic treatments is unclear. The authors tested the hypothesis that in patients with schizophrenia the response to antipsychotic treatment would be related to the severity of presynaptic dopamine dysfunction, as indexed using [(18)F]-DOPA uptake positron emission tomography (PET). METHOD: Twelve patients with treatment-resistant schizophrenia, twelve patients with schizophrenia who had responded to antipsychotics, and twelve healthy volunteers matched for gender, age, ethnicity, weight, and cigarette smoking underwent [(18)F]-DOPA PET scanning. [(18)F]-DOPA influx rate constants (K(i)(cer) values) were measured in the striatum and its functional subdivisions. RESULTS: Patients who had responded to antipsychotic treatment showed significantly higher K(i)(cer) striatal values than did patients with treatment-resistant illness (effect size=1.11) and healthy volunteers (effect size=1.12). The elevated [(18)F]-DOPA uptake was most marked in the associative (effect size=1.31) and the limbic (effect size=1.04) striatal subdivisions. There were no significant differences between patients with treatment-resistant illness and healthy volunteers in the whole striatum or any of its subdivisions. CONCLUSIONS: In some patients with schizophrenia, antipsychotic treatment may be ineffective because they do not exhibit the elevation in dopamine synthesis capacity that is classically associated with the disorder; this may reflect a different underlying pathophysiology or a differential effect of antipsychotic treatment. PMID- 23034657 TI - Prussian blue nanospheres synthesized in deep eutectic solvents. AB - A novel route for controlled synthesis of Prussian blue nanospheres (PB NSs) with different sizes by using deep eutectic solvents (DES) as both solvent and template provider was demonstrated. The size-controlled PB NSs were obtained directly by the coordination of Fe(CN)(6)(4-) ion with Fe(3+) ion in the DES. The probable mechanism of formation of PB NSs was discussed based on the characterization results of UV-visible, X-ray diffraction, X-ray photoelectronic spectrum and transfer electron microscopy. Furthermore, the electrochemical and electrocatalytic properties of the synthesized PB NSs were investigated, and it has demonstrated that the PB NSs exhibited excellent catalytic activity for H(2)O(2) reduction, and then extended this strategy to glucose sensing, by detecting H(2)O(2) formed from the enzymatic reaction of glucose oxidase with its substrate glucose. The linear calibration range for glucose was from 0.9 MUM to 0.12 mM, with a correlation coefficient of 0.998. The limit of detection was 0.3 MUM and the sensitivity was 61.7 A cm(-2) M(-1). The present study provides a general platform for the controlled synthesis of novel nanomaterials in DES and can be extended to other optical, electronic and magnetic nanocompounds. PMID- 23034658 TI - Systematic review of predictors of surgical performance. AB - BACKGROUND: Selection criteria for surgical training are not scientifically proven. There is a need to define which attributes predict future surgical performance. The aim of this study was to examine the predictive value of specific attributes that impact on surgical performance. METHODS: All studies assessing the predictive power of specified attributes with regard to outcome measures of surgical performance in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Educational Resources Information Centre databases, and bibliographies of selected articles from 1950 to November 2010 were considered for inclusion by two independent reviewers. Information on study identifiers, participant characteristics, predictors assessed, evaluation methods for predictors, outcome measures, results and statistical analysis was collected. Quality assessment was carried out using the Hayden criteria. RESULTS: Visual spatial perception correlated with both subjective and objective assessments of surgical performance, including rate of skill acquisition. Visual-spatial perception did not correlate with operative ability in experts, although it did with operative ability at the end of a training programme. Psychomotor aptitude, assessed collectively, correlated with rate of skill acquisition. Academic achievement predicted completion of a training programme and passing end-of training examinations, but did not predict clinical performance during the training programme. CONCLUSION: Intermediate- and high-level visual-spatial perception, as well as psychomotor aptitude, can be used as criteria for assessing candidates for surgical training. Academic achievement is an effective predictor of successful completion of training programmes and should continue to form part of the assessment of surgical candidates. PMID- 23034674 TI - Heterologous production of the lantibiotic Ala(0)actagardine in Escherichia coli. AB - We report the heterologous production of Ala(0)actagardine in E. coli by co expression of the substrate peptide GarA and its modification enzymes GarM and GarO. The activity of GarO, a luciferase-like monooxygenase that introduces the unique sulfoxide group of actagardine, was also investigated in vitro. PMID- 23034675 TI - Ultracold fluorine production via Doppler cooled BeF. AB - Large parts of the periodic table cannot be cooled by current laser-based methods. We investigate whether zero energy fragmentation of laser cooled fluorides is a potential source of ultracold fluorine atoms. We report new ab initio calculations on the lowest electronic states of the BeF diatomic molecule including spin-orbit coupling, the calculated minima for the valence electronic states being within 1 pm of the spectroscopic values. A four colour cooling scheme based on the A(2)Pi<- X(2)Sigma(+) transition is shown to be feasible for this molecule. Multi-Reference Configuration Interaction (MRCI) potentials of the lowest energy Rydberg states are reported for the first time and found to be in good agreement with experimental data. A series of multi-pulse excitation schemes from a single rovibrational level of the cooled molecule are proposed to produce cold fluorine atoms. PMID- 23034676 TI - Exploiting FOXM1-orchestrated molecular network for early squamous cell carcinoma diagnosis and prognosis. AB - Histopathological discordance with molecular phenotype of many human cancers poses clinically challenging tasks for accurate cancer diagnosis, which impacts on treatment strategy and patient outcome. Hence, an objective, accurate and quantitative method is needed. A quantitative Malignancy Index Diagnostic System (qMIDS) was developed based on 14 FOXM1 (isoform B)-associated genes implicated in the regulation of the cell cycle, differentiation, ageing, genomic stability, epigenetic and stem cell renewal, and two reference genes. Their mRNA expression levels were translated via a prospectively designed algorithm, into a metric scoring system. Subjects from UK and Norway (n = 299) provided 359 head and neck tissue specimens. Diagnostic test performance was assessed using detection rate (DR) and false-positive rate (FPR). The median qMIDS scores were 1.3, 2.9 and 6.7 in healthy tissue, dysplasia and head and neck squamous cell carcinomas (HNSCC), respectively (UK prospective dataset, p<0.001); 1.4, 2.3 and 7.6 in unaffected, oral lichen planus, or HNSCC, respectively (Norwegian retrospective dataset with up to 19 years survival data, p<0.001). At a qMIDS cut-off of 4.0, DR was 94% and FPR was 3.2% (Norwegian dataset); and DR was 91% and FPR was 1.3% (UK dataset). We further demonstrated the transferability of qMIDS for diagnosing premalignant human vulva (n = 58) and skin (n = 21) SCCs, illustrating its potential clinical use for other cancer types. This study provided evidence that qMIDS was able to quantitatively diagnose and objectively stratify cancer aggressiveness. With further validation, qMIDS could enable early HNSCC detection and guide appropriate treatment. Early treatment intervention can lead to long-term reduction in healthcare costs and improve patient outcome. PMID- 23034678 TI - Dynamic cyclen-metal complexes for molecular sensing and chirality signaling. AB - Structural dynamism plays important roles in artificial and biological systems, because it controls structures and functions of various molecules and assemblies. In this review, molecular recognition and self-assembling behavior of dynamic armed cyclen-metal complexes are discussed at the molecular and supramolecular levels. These metal complexes provide useful platforms for molecular receptors, supramolecules, and molecular assemblies that can respond rapidly to guest molecules and environments. Since armed cyclens have many structural and geometrical variations, they form a wide variety of metal complexes having specific sensing and signaling functions. The Lewis acidity of the metal cations plays an essential role in anion binding and in hydrolytic catalysis of phosphate esters. Characteristic luminescence and magnetic properties of lanthanides also enable techniques for effective bio-imaging. They also serve as chiral building blocks for self-assembled architectures, which offer chirality integration effective for chirality sensing and signaling at the supramolecular level. PMID- 23034677 TI - A microfluidic device to investigate axon targeting by limited numbers of purified cortical projection neuron subtypes. AB - While much is known about general controls over axon guidance of broad classes of projection neurons (those with long-distance axonal connections), molecular controls over specific axon targeting by distinct neuron subtypes are poorly understood. Corticospinal motor neurons (CSMN) are prototypical and clinically important cerebral cortex projection neurons; they are the brain neurons that degenerate in amyotrophic lateral sclerosis (ALS) and related motor neuron diseases, and their injury is central to the loss of motor function in spinal cord injury. Primary culture of purified immature murine CSMN has been recently established, using either fluorescence-activated cell sorting (FACS) or immunopanning, enabling a previously unattainable level of subtype-specific investigation, but the resulting number of CSMN is quite limiting for standard approaches to study axon guidance. We developed a microfluidic system specifically designed to investigate axon targeting of limited numbers of purified CSMN and other projection neurons in culture. The system contains two chambers for culturing target tissue explants, allowing for biologically revealing axonal growth "choice" experiments. This device will be uniquely enabling for investigation of controls over axon growth and neuronal survival of many types of neurons, particularly those available only in limited numbers. PMID- 23034679 TI - Morphology study of progesterone polymorphs prepared by polymer-induced heteronucleation (PIHn). AB - In this article, morphology of progesterone polymorphs prepared by polymer induced heteronucleation (PIHn) technique was studied. Hydroxypropyl methylcellulose(HPMC), such as dextran T-500 and gelatin G-9382, polyisoprene (PI), and acrylonitrile/butadiene copolymer (NBR) were used as substrates. The crystallizations were performed by solvent evaporation at room temperature from 0.5, 10, and 40 mg/ml solutions in chloroform and acetone. Progesterone polymorphs were identified by X-ray diffraction. Differential scanning calorimetry and total attenuated reflectance infrared spectroscopy were used as complementary techniques in the identification. Depending on the polymeric matrix and the concentration used, form 1, form 2, or mixture of both polymorphs were obtained. Scanning electron microscopy pictures evidenced difference in morphology and in homogeneity of the two progesterone polymorphs. These polymorphs prepared by PIHn, did not present a distinctive morphology that allows identifying polymorph by its crystal habit. Hence, polymeric matrix induced the crystallization, affecting polymorphism and morphology. PMID- 23034680 TI - Endonasal endoscopic retrieval of lodged silicone punctal plugs: a case report. AB - We present the case of a 59-year-old woman whose silicone punctal plugs migrated distally causing lacrimal obstruction. The plugs were removed from the lacrimal sac during endoscopic endonasal dacrocystorhinostomy and is illustrated by endoscopic photographs and videos taken at the time of surgery. This case highlights the potential complications of punctal plugs and the difficulties posed in retrieving them. PMID- 23034681 TI - The sigmoid upper eyelid blepharoplasty: redefining beauty. AB - PURPOSE: A youthful female upper eyelid contour includes a concave medial portion of the upper eyelid along with a fuller, convex lateral eyelid. The skin in the lateral eyelid is tight without hooding. This is a sigmoid shape in 3-dimensional terms. With aging, fatty herniation medially along with redundant, hooded, ptotic lateral skin creates the exact opposite eyelid curve. The sigmoid blepharoplasty is a novel surgical technique that recreates a youthful upper eyelid. METHOD: A retrospective chart review of 142 female patients who underwent the sigmoid blepharoplasty was conducted. To recreate a youthful eyelid in 3 dimensions, the medial eyelid concavity is achieved by removing a strip of medial orbicularis oculi muscle along with selective medial fat removal. Excess skin and hooding is removed, and fat grafts from the medial eyelid are placed laterally below the muscle to achieve a fullness and tight skin. RESULTS: All patients achieved a pleasant, rejuvenated upper eyelid as assessed by photographs and chart records. The sigmoid blepharoplasty restored a youthful eyelid appearance by recreating a concave medial eyelid and fuller lateral eyelid. There were no infections, and fat grafts took uniformly. CONCLUSIONS: The sigmoid upper eyelid blepharoplasty technique recreates a truly youthful eyelid with novel eyelid concepts. The surgery is safe and reproducible, and consistent results are achievable. PMID- 23034682 TI - External dacryocystorhinostomy surgery in patients with Wegener granulomatosis. AB - PURPOSE: To determine surgical outcomes after external dacryocystorhinostomy (DCR) surgery in patients with Wegener granulomatosis (WG). METHODS: The authors retrospectively reviewed the charts of consecutive patients with WG who underwent primary or secondary external DCR surgery between January 2001 and January 2010. Clinical data reviewed included patient demographics, systemic disease involvement and immunosuppression therapy, intraoperative biopsy findings, and postoperative outcomes and complications. Success was defined as resolution of epiphora. RESULTS: Sixteen primary external DCRs were performed on 9 patients with WG, and 2 secondary external DCRs were performed on 2 patients. At the time of surgery, all patients with WG were on systemic immunosuppressive agents including methotrexate, rapamycin, sirolimus, tacrolimus, azathioprine, cyclophosphamide, rituximab, and prednisone, and no patients received increased corticosteroids after surgery. Intraoperative biopsy in patients with WG revealed chronic inflammation (4 patients) and fibrosis (1 patient). Silicone stents were removed at an average of 5.8 months (range, 3-12 months). All surgeries were successful in resolving epiphora with an average follow up of 3.5 years (range, 10 months-6 years) and no complications. CONCLUSIONS: Primary and secondary external DCR surgery successfully treats nasolacrimal duct obstruction in patients with WG on systemic immunosuppression. PMID- 23034683 TI - Sixteen-year experience with the Putterman-Gladstone tube for conjunctival dacryocystorhinostomy. AB - PURPOSE: To determine whether the Putterman-Gladstone tube is a safe and effective lacrimal bypass tube in conjunctival dacryocystorhinostomy surgery. METHODS: The authors retrospectively reviewed the charts of patients who underwent conjunctival dacryocystorhinostomy with the Putterman-Gladstone tube between January 1994 and December 2010. Clinical data reviewed included demographics, ocular and surgical history, epiphora symptoms, complications, and repeat surgery information. Success was defined as resolution of epiphora or greatly improved symptoms of epiphora at last follow up. RESULTS: Twenty-five patients and 29 eyes of patients undergoing conjunctival dacryocystorhinostomy surgery with Putterman-Gladstone were identified. Mean follow up was 35.61 months. Complications of surgery included occlusion in 10.3%, malposition in 17.2%, discomfort in 24.1%, and extrusion in 37.9%. Median time to extrusion was 8 months. Repeat operative intervention was required in 41.4% of patients. Twenty five of 29 (86.2%) patients had complete resolution of epiphora or only mild residual epiphora at last follow up. CONCLUSION: This retrospective chart review demonstrates the efficacy and safety of the Putterman-Gladstone tube in conjunctival dacryocystorhinostomy surgery. PMID- 23034684 TI - Diesel fuel injury to the orbit. AB - A 48-year-old man was seen in the Wills Eye Institute emergency room for pain and decreased vision after having a diesel engine fuel cylinder explosion in his face. Clinical examination showed proptosis, decreased extraocular motility, and increased intraocular pressure; CT scan imaging revealed hypodense areas within the orbit. His orbital signs rapidly worsened despite aggressive antibiotics, steroids, and surgical intervention. Two orbitotomies revealed diesel fuel infiltration of the intraconal and extraconal spaces that proved impossible to evacuate completely. The patient ended up losing vision from an intense chemical cellulitis with subsequent orbital compartment syndrome and optic neuropathy. This case highlights the severity of orbital chemical injuries and their variable prognoses despite aggressive management. PMID- 23034685 TI - Primary adenoid cystic carcinoma of the orbital apex. AB - Adenoid cystic carcinoma is an uncommon malignant tumor of epithelial origin typically arising from salivary glands. Orbital involvement may occur via direct or perineural spread from a lacrimal gland or sinonasal source. Primary orbital adenoid cystic carcinoma without involvement of the lacrimal gland is rare. The authors report a 53-year-old woman who was examined for insidious monocular vision loss and was found to have a primary adenoid cystic carcinoma of the orbital apex and cavernous sinus. Systemic workup for a primary source, including ipsilateral lacrimal gland biopsy, was negative. One must maintain a high index of suspicion for adenoid cystic carcinoma when evaluating orbital tumors. PMID- 23034686 TI - The orientation of the lacrimal fossa to the bony nasolacrimal canal: an anatomical study. AB - PURPOSE: To examine the relative positions of the lacrimal fossa (LF) and the bony nasolacrimal canal (BNLC) in relation to each other and a reference plane. METHODS: Forty-two orbits and BNLCs from 21 Asian cadavers (9 men and 12 women; average age at death, 84.4 years; range, 70-99 years) had been fixed in 10% buffered formalin before use. After exposing the LF and the medial half of the BNLC, the authors measured the angles of the longitudinal axis of the LF and the BNLC relative to the aesthetic horizontal plane respectively. Based on these values, the relative orientation of the LF and the BNLC was determined and defined in terms of Delta BNLC-LF. A positive Delta BNLC-LF represents a nasolacrimal canal that descends posteriorly relative to the LF. RESULTS: The mean LF, BNLC, and Delta BNLC-LF were 9.5 degrees , 19.8 degrees , and 10.3 degrees , respectively. In 39 passages (92.9%), the Delta BNLC-LF was positive, representing a nasolacrimal canal that is more posteriorly oriented than the LF. In 3 passages (7.1%), the Delta BNLC-LF was equal to or less than 0 degrees ; 2 of them (4.8%) had a straight course and 1 passage (2.4%) had a negative value. CONCLUSIONS: In most patients, the BNLC is directed more posteriorly than the LF. This finding may help in preventing an inadvertent false passage during probing and intubation in patients with epiphora. PMID- 23034687 TI - Primary subconjunctival ganglioneuroma. AB - A ganglioneuroma is an extremely rare benign neoplasm composed of neural elements, including mature ganglion cells that originate from the sympathetic ganglia. It is located most frequently in the posterior mediastinum and can be found in the retroperitoneum, including the adrenal medulla. It may evolve from a differentiating neuroblastoma or may be diagnosed as a primary ganglioneuroma. Primary orbital ganglioneuromas are extremely rare, with only 2 reported cases in young otherwise-healthy individuals. A single, reported case of bulbar conjunctival ganglioneuromas has been described in water buffalos. This is the first report of a primary subconjunctival ganglioneuroma in a young healthy person. PMID- 23034688 TI - PROSE treatment for lagophthalmos and exposure keratopathy. AB - Prosthetic replacement of the ocular surface ecosystem is a treatment developed by the Boston Foundation for Sight that uses a Food and Drug Administration approved prosthetic device for the treatment of severe ocular surface disease to improve vision and discomfort in addition to supporting the ocular surface. Facial nerve paralysis has multiple causes including trauma, surgery, tumor, stroke, and congenital lagophthalmos. Subsequent lagophthalmos leading to exposure keratitis has been treated with copious lubrication, tarsorrhapy, eyelid weights, chemodenervation to yield protective ptosis, and palpebral spring insertion. Each of these treatments, however, has limitations and potential complications. The prosthetic replacement of the ocular surface ecosystem device provides a liquid bandage to protect the cornea from eyelid interaction and dessication in addition to improving vision. This report describes 4 patients with exposure keratitis who were successfully treated with prosthetic replacement of the ocular surface ecosystem devices at 2 clinical sites. PMID- 23034689 TI - Late complications of hydrogel scleral buckle implants and a technique for effective removal. AB - PURPOSE: The aim of this article is to describe complications of hydrogel (MIRAgel) scleral buckle implants that may appear many years after implantation, and to describe an effective technique to facilitate safe removal of these implants, which become extremely friable with time. METHODS: Four case reports of patients with complications of hydrogel orbital implants and a technique for removal of the implants are described with review of the literature. The technique involves a conjunctival incision into each involved quadrant, followed by use of blunt instrumentation for "push" and a Frasier suction handpiece for "pull" to allow segmental removal. This technique limits the tendency of the implant to fragment, which has been a problem described with previous techniques. RESULTS: Cases typically present simulating an orbital tumor or infection, with the diagnosis not immediately apparent, as was the case in 3 of 4 cases in our series. The technique we used allowed for expeditious removal and prompt recovery in all 4 patients. CONCLUSIONS: Hydrogel scleral buckle implants can produce late complications that may be difficult to diagnose and manage. The "push-pull" technique described in this article facilitates effective removal, and may have implications for other types of orbital hydrogel implants as well. PMID- 23034690 TI - Periocular abscesses following brow epilation. AB - PURPOSE: The aim of this article was to report the clinical presentation, radiography, culture results, treatment modalities, and outcomes of periocular abscesses associated with brow epilation. METHODS: This was a retrospective case series including 26 patients referred for periocular abscess following brow epilation. RESULTS: Twenty-six female patients with a median age of 20.5 (range, 12-73) years were referred for oculoplastic evaluation of periocular abscesses related to recent brow epilation. All patients were treated with incision and drainage along with systemic antibiotics. Culture results revealed 16 cases of methicillin-resistant Staphylococcus aureus, 3 of methicillin-sensitive Staphylococcus aureus, and 7 cultures that showed no growth. All patients had resolution of their abscesses at 1-month follow-up visits without progression to orbital cellulitis. CONCLUSIONS: Periocular abscess formation after brow epilation has been previously described in only a single case report in the literature. The authors believe this entity is underreported given their current report describing 26 such cases. Given the high prevalence of cosmetic brow epilation in females, the authors believe a careful history regarding brow epilation in any patient presenting with a periocular abscess or preseptal cellulitis is essential to explore the possible cause of their infection. The majority of patients in the current study's cohort had methicillin-resistant Staphylococcus aureus-related abscesses, and treatment with antibiotics with methicillin-resistant Staphylococcus aureus coverage may be a prudent first line choice in such patients. PMID- 23034691 TI - Infantile inflammatory myofibroblastic tumor of the orbit with apical bone involvement. AB - Inflammatory myofibroblastic tumors of the orbit are uncommon lesions with unique histopathological features and uncertain pathogenesis. The authors report a case of an 8-month-old male infant who presented with approximately a 5-week history of left upper eyelid painless swelling that progressively grew in size. The patient underwent surgical debulking of the superior orbital mass through an upper eyelid crease incision. Review of the pathology slides revealed the tumor to be of myofibroblastic origin based on both histopathological and immunohistochemical examinations. Although the parents declined postoperative orbital irradiation or systemic corticosteroids, no recurrence was noted after 2 years of follow up. PMID- 23034692 TI - Odontogenic myxoma with orbital involvement. AB - A 15-month-old female child presented with progressive right-sided facial swelling, nasal obstruction, and deviation of the nose to the left. Computed tomography revealed a cystic mass in the maxillary sinus with disruption of the medial orbital floor. Incisional biopsy of this mass was nondiagnostic and the mass continued to grow rapidly. The mass was removed by excisional biopsy and curettage with conservative margins via combined lateral rhinotomy and sublabial approaches. Intraoperatively, a large defect of the floor that extended to the orbital apex was noted. Histopathology revealed an odontogenic myxoma. Odontogenic myxomas are uncommon tumors that are usually seen in adults. Our case is unique because to the best of our knowledge, it is the first reported case with orbital involvement in the pediatric population. PMID- 23034693 TI - A positive sentinel lymph node in periocular invasive squamous cell carcinoma: a case series. AB - PURPOSE: The aim of this article was to describe positive sentinel lymph node biopsy (SLNB) findings in patients with periocular invasive squamous cell carcinoma (SCC). METHODS: This was a retrospective chart review of 5 patients with invasive SCC of the periocular region who underwent SLNB and were found to have regional metastasis. RESULTS: All patients had large (2.0-4.3 cm) primary tumors with poor differentiation on pathology. In all 5 patients, SLNB was positive in the absence of other signs or evidence of regional or systemic metastasis. While tumor cells may drain to the preauricular or the submandibular basin, the preauricular lymph node was identified as the sentinel lymph node on lymphoscintigraphy in all 5 patients. With a positive sentinel lymph node, the results of SLNB changed the clinical staging and influenced subsequent treatment recommendations for each patient. We identified no complications related to SLNB including facial nerve damage, lymphedema, or allergic reaction to radioactive tracing material. CONCLUSIONS: In this series of patients with periocular invasive SCC, SLNB was well tolerated and uncovered regional metastasis in patients with no clinical signs of metastasis otherwise. The SLNB findings influenced subsequent oncologic management recommendations. The usefulness of SLNB for poorly differentiated SCC remains uncertain. Further research is necessary to establish the role of SLNB in periocular SCC. PMID- 23034694 TI - Simplified Muller's muscle-conjunctival resection internal ptosis repair. AB - PURPOSE: To describe and evaluate a modified technique for blepharoptosis repair via Muller's muscle-conjunctival resection. METHODS: An observational case series is reported. Records of 29 consecutive patients (42 eyelids) with blepharoptosis undergoing internal ptosis repair between January 2008 and December 2010 were reviewed including detailed preoperative and postoperative evaluations, eyelid measurements, surgical outcome, and complications. The procedure performed was a modified Muller's muscle-conjunctival resection with simple measurements, no traction sutures, a double-opposing mattress suture, and single external knot. Main outcome measures included success of ptosis repair surgery defined by improvement in margin reflex distance, symmetry of upper eyelid position, and incidence of complications. RESULTS: The described modified Muller's muscle conjunctival resection procedure achieved improvement in eyelid position in all patients with mean margin reflex distance change of 2.3 mm (p < 0.001). No patient experienced significant complications, and all procedures resulted in objective eyelid symmetry (within 1 mm) and satisfactory cosmetic appearance. CONCLUSIONS: The procedure described is an efficient, safe, and successful technique for internal blepharoptosis repair. PMID- 23034696 TI - Formal C-H amination of cyclopropenes. AB - A novel C(sp(3))-H amination of trimethylsilyl-substituted cyclopropenes is described. This C-H amination proceeds via a tandem regioselective ene reaction between cyclopropenes and azodicarboxylate to generate a hydrazodicarboxylate intermediate followed by its site-selective allylic transposition. PMID- 23034697 TI - Characterization of differential cocaine metabolism in mouse and rat through metabolomics-guided metabolite profiling. AB - Rodent animal models have been widely used for studying neurologic and toxicological events associated with cocaine abuse. It is known that the mouse is more susceptible to cocaine-induced hepatotoxicity (CIH) than the rat. However, the causes behind this species-dependent sensitivity to cocaine have not been elucidated. In this study, cocaine metabolism in the mouse and rat was characterized through LC-MS-based metabolomic analysis of urine samples and were further compared through calculating the relative abundance of individual cocaine metabolites. The results showed that the levels of benzoylecgonine, a major cocaine metabolite from ester hydrolysis, were comparable in the urine from the mice and rats treated with the same dose of cocaine. However, the levels of the cocaine metabolites from oxidative metabolism, such as N hydroxybenzoylnorecgonine and hydroxybenzoylecgonine, differed dramatically between the two species, indicating species-dependent cocaine metabolism. Subsequent structural analysis through accurate mass analysis and LC-MS/MS fragmentation revealed that N-oxidation reactions, including N-demethylation and N-hydroxylation, are preferred metabolic routes in the mouse, while extensive aryl hydroxylation reactions occur in the rat. Through stable isotope tracing and in vitro enzyme reactions, a mouse-specific alpha-glucoside of N hydroxybenzoylnorecgonine and a group of aryl hydroxy glucuronides high in the rat were identified and structurally elucidated. The differences in the in vivo oxidative metabolism of cocaine between the two rodent species were confirmed by the in vitro microsomal incubations. Chemical inhibition of P450 enzymes further revealed that different P450-mediated oxidative reactions in the ecgonine and benzoic acid moieties of cocaine contribute to the species-dependent biotransformation of cocaine. PMID- 23034698 TI - Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, multicenter, double-blinded, controlled study. AB - BACKGROUND: Chronic migraine (CM) is a debilitating neurological disorder with few treatment options. Peripheral nerve stimulation (PNS) of the occipital nerves is a potentially promising therapy for CM patients. METHODS: In this randomized, controlled multicenter study, patients diagnosed with CM were implanted with a neurostimulation device near the occipital nerves and randomized 2:1 to active (n = 105) or sham (n = 52) stimulation. The primary endpoint was a difference in the percentage of responders (defined as patients that achieved a >=50% reduction in mean daily visual analog scale scores) in each group at 12 weeks. RESULTS: There was not a significant difference in the percentage of responders in the Active compared with the Control group (95% lower confidence bound (LCB) of -0.06; p = 0.55). However, there was a significant difference in the percentage of patients that achieved a 30% reduction (p = 0.01). Importantly, compared with sham-treated patients, there were also significant differences in reduction of number of headache days (Active Group = 6.1, baseline = 22.4; Control Group = 3.0, baseline = 20.1; p = 0.008), migraine-related disability (p = 0.001) and direct reports of pain relief (p = 0.001). The most common adverse event was persistent implant site pain. CONCLUSION: Although this study failed to meet its primary endpoint, this is the first large-scale study of PNS of the occipital nerves in CM patients that showed significant reductions in pain, headache days, and migraine-related disability. Additional controlled studies using endpoints that have recently been identified and accepted as clinically meaningful are warranted in this highly disabled patient population with a large unmet medical need. TRIAL REGISTRATION: Clinical trials.gov (NCT00615342). PMID- 23034699 TI - Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication. AB - BACKGROUND: A systematic review and network meta-analysis was undertaken to consider the evidence for the efficacy and tolerability of placebo, cilostazol, naftidrofuryl oxalate and pentoxifylline in patients with intermittent claudication due to peripheral arterial disease (PAD). METHODS: MEDLINE, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings, BIOSIS, National Research Register and MetaRegister databases were searched. Eligible studies were randomized controlled trials (RCTs) and published systematic reviews of patients with intermittent claudication due to PAD and whose symptoms persisted despite a period of conservative management. Study selection was conducted by one reviewer with involvement from a clinician. Data were extracted by one reviewer with no blinding to authors or journal, and checked by a second reviewer. Outcome measures were maximum walking distance (MWD) and pain-free walking distance (PFWD). RESULTS: The review identified 1876 citations; 26 RCTs met the inclusion criteria for the systematic review. Eleven trials provided data relevant for the meta-analysis. Naftidrofuryl oxalate was ranked first for both MWD and PFWD (probability of 0.947 and 0.987, respectively, of being the best treatment) followed by cilostazol and pentoxifylline. For naftidrofuryl oxalate, cilostazol and pentoxifylline, MWD increased by 60 (95 per cent credible interval 20 to 114) per cent, 25 (11 to 40) per cent and 11 (-1 to 24) per cent respectively relative to placebo, and PFWD increased by 49, 13 and 9 per cent. CONCLUSION: Naftidrofuryl oxalate and cilostazol are both effective treatments for claudication; naftidrofuryl oxalate is likely to be the most effective, with minimal serious adverse events. PMID- 23034700 TI - The life-history trade-off between fertility and child survival. AB - Evolutionary models of human reproduction argue that variation in fertility can be understood as the local optimization of a life-history trade-off between offspring quantity and 'quality'. Child survival is a fundamental dimension of quality in these models as early-life mortality represents a crucial selective bottleneck in human evolution. This perspective is well-rehearsed, but current literature presents mixed evidence for a trade-off between fertility and child survival, and little empirical ground to evaluate how socioecological and individual characteristics influence the benefits of fertility limitation. By compiling demographic survey data, we demonstrate robust negative relationships between fertility and child survival across 27 sub-Saharan African countries. Our analyses suggest this relationship is primarily accounted for by offspring competition for parental investment, rather than by reverse causal mechanisms. We also find that the trade-off increases in relative magnitude as national mortality declines and maternal somatic (height) and extrasomatic (education) capital increase. This supports the idea that socioeconomic development, and associated reductions in extrinsic child mortality, favour reduced fertility by increasing the relative returns to parental investment. Observed fertility, however, falls considerably short of predicted optima for maximizing total offspring survivorship, strongly suggesting that additional unmeasured costs of reproduction ultimately constrain the evolution of human family size. PMID- 23034701 TI - Diverse pollinator communities enhance plant reproductive success. AB - Understanding the functional consequences of biodiversity loss is a major goal of ecology. Animal-mediated pollination is an essential ecosystem function and service provided to mankind. However, little is known how pollinator diversity could affect pollination services. Using a substitutive design, we experimentally manipulated functional group (FG) and species richness of pollinator communities to investigate their consequences on the reproductive success of an obligate out crossing model plant species, Raphanus sativus. Both fruit and seed set increased with pollinator FG richness. Furthermore, seed set increased with species richness in pollinator communities composed of a single FG. However, in multiple FG communities, highest species richness resulted in slightly reduced pollination services compared with intermediate species richness. Our analysis indicates that the presence of social bees, which showed roughly four times higher visitation rates than solitary bees or hoverflies, was an important factor contributing to the positive pollinator diversity-pollination service relationship, in particular, for fruit set. Visitation rate at different daytimes, and less so among flower heights, varied among social bees, solitary bees and hoverflies, indicating a niche complementarity among these pollinator groups. Our study demonstrates enhanced pollination services of diverse pollinator communities at the plant population level and suggests that both the niche complementarity and the presence of specific taxa in a pollinator community drive this positive relationship. PMID- 23034702 TI - Cost of autotomy drives ontogenetic switching of anti-predator mechanisms under developmental constraints in a land snail. AB - Autotomy of body parts offers various prey animals immediate benefits of survival in compensation for considerable costs. I found that a land snail Satsuma caliginosa of populations coexisting with a snail-eating snake Pareas iwasakii survived the snake predation by autotomizing its foot, whereas those out of the snake range rarely survived. Regeneration of a lost foot completed in a few weeks but imposed a delay of shell growth. Imprints of autotomy were found in greater than 10 per cent of S. caliginosa in the snake range but in only less than 1 per cent out of it, simultaneously demonstrating intense predation by the snakes and high efficiency of autotomy for surviving snake predation in the wild. However, in experiments, mature S. caliginosa performed autotomy less frequently. Instead of the costly autotomy, they can use defensive denticles on the inside of their shell apertures. Owing to the constraints from the additive growth of shells, most pulmonate snails can produce these denticles only when they have fully grown up. Thus, this developmental constraint limits the availability of the modified aperture, resulting in ontogenetic switching of the alternative defences. This study illustrates how costs of adaptation operate in the evolution of life history strategies under developmental constraints. PMID- 23034703 TI - Bat echolocation calls facilitate social communication. AB - Bat echolocation is primarily used for orientation and foraging but also holds great potential for social communication. The communicative function of echolocation calls is still largely unstudied, especially in the wild. Eavesdropping on vocal signatures encoding social information in echolocation calls has not, to our knowledge, been studied in free-living bats so far. We analysed echolocation calls of the polygynous bat Saccopteryx bilineata and found pronounced vocal signatures encoding sex and individual identity. We showed experimentally that free-living males discriminate approaching male and female conspecifics solely based on their echolocation calls. Males always produced aggressive vocalizations when hearing male echolocation calls and courtship vocalizations when hearing female echolocation calls; hence, they responded with complex social vocalizations in the appropriate social context. Our study demonstrates that social information encoded in bat echolocation calls plays a crucial and hitherto underestimated role for eavesdropping conspecifics and thus facilitates social communication in a highly mobile nocturnal mammal. PMID- 23034704 TI - The influence of male age and simulated pathogenic infection on producing a dishonest sexual signal. AB - In recent years, studies have shown that reproductive effort decelerates in response to pathogenic infection. If infection substantially reduces a host's residual reproductive value (RRV), however, then an acceleration of effort may instead occur (e.g. terminal investment). Reproductive acceleration would theoretically allow hosts to maintain or exaggerate their sexual signal upon infection. This would create a deceptive message from the perspective of the chooser, who may unwittingly copulate with an infected mate to their detriment. Using the cricket Allonemobius socius, we assessed the potential for reduced RRV to accelerate male reproductive effort and create a dishonest signal. RRV was manipulated through male age and simulated pathogenic insult. Reproductive effort was measured as calling song energetics, mating success, latency to mate and nuptial gift size. We show that males adopted either an accelerated or decelerated reproductive strategy upon infection, and that this decision was probably mediated by RRV. Moreover, males who accelerated their effort produced a dishonest signal by increasing their song energetics while providing fewer paternal resources (i.e. smaller gifts). Our study is one of the few to document the existence of dishonest signals and relate dishonesty to a potential reduction in female fitness, underscoring the conflict inherent in sexual reproduction. PMID- 23034705 TI - Constraints on the coevolution of contemporary human males and females. AB - Because autosomal genes in sexually reproducing organisms spend on average half their time in each sex, and because the traits that they influence encounter different selection pressures in males and females, the evolutionary responses of one sex are constrained by processes occurring in the other sex. Although intralocus sexual conflict can restrict sexes from reaching their phenotypic optima, no direct evidence currently supports its operation in humans. Here, we show that the pattern of multivariate selection acting on human height, weight, blood pressure and glucose, total cholesterol, and age at first birth differs significantly between males and females, and that the angles between male and female linear (77.8 +/- 20.5 degrees ) and nonlinear (99.1 +/- 25.9 degrees ) selection gradients were closer to orthogonal than zero, confirming the presence of sexually antagonistic selection. We also found evidence for intralocus sexual conflict demonstrated by significant changes in the predicted male and female responses to selection of individual traits when cross-sex genetic covariances were included and a significant reduction in the angle between male- and female predicted responses when cross-sex covariances were included (16.9 +/- 15.7 degrees ), compared with when they were excluded (87.9 +/- 31.6 degrees ). We conclude that intralocus sexual conflict constrains the joint evolutionary responses of the two sexes in a contemporary human population. PMID- 23034706 TI - Unprecedented ichneumonid parasitoid wasp diversity in tropical forests. AB - The megadiverse parasitoid wasp family Ichneumonidae (Hymenoptera) is classically considered an exception to the extensively studied latitudinal diversity gradient: the majority of ichneumonid species are described from temperate regions. The gradient has been hypothesized to be dependent on the biology of the wasps, but recently questions of sampling and description biases have been raised. Here, we show with primary data that the species richness of Ichneumonidae is markedly underestimated in tropical areas and that latitudinal diversity patterns in the family remain uncharacterized. We discovered a startling 177 likely undescribed orthocentrine species with relatively low sampling effort in the forests of Central America and Amazonian Ecuador, over three times the previously known orthocentrine diversity in the world's tropics. Species accumulation curves reveal that we are just beginning to unveil the true extent of tropical orthocentrine diversity. We also found evidence for cryptic species; our DNA analysis revealed additional species not easily distinguishable using morphological characteristics. The difficulty in establishing species richness patterns of Ichneumonidae probably follows from the relative lack of taxonomic expertise and the low density of ichneumonid species throughout the landscape. PMID- 23034707 TI - Quorum-sensing and cheating in bacterial biofilms. AB - The idea from human societies that self-interest can lead to a breakdown of cooperation at the group level is sometimes termed the public goods dilemma. We tested this idea in the opportunistic bacterial pathogen, Pseudomonas aeruginosa, by examining the influence of putative cheats that do not cooperate via cell-to cell signalling (quorum-sensing, QS). We found that: (i) QS cheating occurs in biofilm populations owing to exploitation of QS-regulated public goods; (ii) the thickness and density of biofilms was reduced by the presence of non-cooperative cheats; (iii) population growth was reduced by the presence of cheats, and this reduction was greater in biofilms than in planktonic populations; (iv) the susceptibility of biofilms to antibiotics was increased by the presence of cheats; and (v) coercing cooperator cells to increase their level of cooperation decreases the extent to which the presence of cheats reduces population productivity. Our results provide clear support that conflict over public goods reduces population fitness in bacterial biofilms, and that this effect is greater than in planktonic populations. Finally, we discuss the clinical implications that arise from altering the susceptibility to antibiotics. PMID- 23034708 TI - Inferring subjective states through the observation of actions. AB - Estimating another person's subjective confidence is crucial for social interaction, but how this inference is achieved is unknown. Previous research has demonstrated that the speed at which people make decisions is correlated with their confidence in their decision. Here, we show that (i) subjects are able to infer the subjective confidence of another person simply through the observation of their actions and (ii) this inference is dependent upon the performance of each subject when executing the action. Crucially, the latter result supports a model in which motor simulation of an observed action mediates the successful understanding of other minds. We conclude that kinematic understanding allows access to the higher-order cognitive processes of others, and that this access plays a central role in social interactions. PMID- 23034709 TI - Evidence for determinism in species diversification and contingency in phenotypic evolution during adaptive radiation. AB - Adaptive radiation (AR) theory predicts that groups sharing the same source of ecological opportunity (EO) will experience deterministic species diversification and morphological evolution. Thus, deterministic ecological and morphological evolution should be correlated with deterministic patterns in the tempo and mode of speciation for groups in similar habitats and time periods. We test this hypothesis using well-sampled phylogenies of four squamate groups that colonized the New World (NW) in the Late Oligocene. We use both standard and coalescent models to assess species diversification, as well as likelihood models to examine morphological evolution. All squamate groups show similar early pulses of speciation, as well as diversity-dependent ecological limits on clade size at a continental scale. In contrast, processes of morphological evolution are not easily predictable and do not show similar pulses of early and rapid change. Patterns of morphological and species diversification thus appear uncoupled across these groups. This indicates that the processes that drive diversification and disparification are not mechanistically linked, even among similar groups of taxa experiencing the same sources of EO. It also suggests that processes of phenotypic diversification cannot be predicted solely from the existence of an AR or knowledge of the process of diversification. PMID- 23034711 TI - The VanE operon in Enterococcus faecalis N00-410 is found on a putative integrative and conjugative element, Tn6202. AB - OBJECTIVES: To date no complete genetic structure of acquired DNA harbouring a d Ala-d-Ser operon in an Enterococcus is known. We wished to characterize the acquired DNA harbouring the vanE operon located in the Enterococcus faecalis N00 410 chromosome. METHODS: Whole genome sequencing of E. faecalis N00-410 was conducted by massively parallel sequencing. Two sequence contigs harbouring the vanE region were linked by PCR and the acquired DNA harbouring the vanE operon was completely characterized. Excision/integration of the region was determined by PCR and transfer attempted by conjugation. RESULTS: The regions flanking the vanE operon were analysed and a total of 42 open reading frames were identified in a region flanked by inverted terminal and direct repeats (Tn6202). Tn6202 could be excised from the chromosome, circularized and the target site rejoined, but transfer could not be demonstrated. CONCLUSIONS: The vanE operon was found on the putative integrative and conjugative element Tn6202 in the E. faecalis N00 410 chromosome. This represents the first characterization of acquired DNA harbouring a D-Ala-D-Ser operon. PMID- 23034712 TI - Evaluation of the EUCAST disc diffusion susceptibility testing method for Haemophilus influenzae based on the resistance mechanism to beta-lactam antibiotics. AB - OBJECTIVES: EUCAST developed an antibiotic susceptibility testing method for Haemophilus influenzae. We assessed the EUCAST testing method and EUCAST clinical breakpoints and newly proposed epidemiological cut-off values against H. influenzae clinical isolates with known molecular mechanisms of resistance to beta-lactam antibiotics. METHODS: In total, 89 clinical isolates were used: 30 were beta-lactamase negative with PBP3 mutations (gBLNAR), 20 were beta-lactamase positive without PBP3 mutations (gBLPAR), 15 were beta-lactamase positive with PBP3 mutations (gBLPACR), and 24 were beta-lactamase negative without resistance mechanism (gBLNAS). Twelve different beta-lactam antibiotics and disc charges were tested. RESULTS: None of the discs tested fully separated between gBLNAS and gBLNAR populations. According to EUCAST clinical zone diameter breakpoints, overall the best values of sensitivity and specificity were obtained with cefuroxime 30 MUg and amoxicillin/clavulanic acid 2/1 MUg discs for detection of gBLNAR and gBLPACR populations, although a previous beta-lactamase test was needed. Other antibiotic discs could be suitable for epidemiological purposes, such us penicillin 10 U for separating gBLNAR isolates and cefoxitin 30 MUg for detection of gBLPACR isolates. By Etest using the EUCAST method, the EUCAST MIC clinical breakpoints for ampicillin and amoxicillin/clavulanic acid showed high specificity, but low sensitivity, for the detection of genotypes with mutations in PBP3. CONCLUSIONS: The main genotypes of beta-lactam-resistant H. influenzae can be separated by using the EUCAST disc diffusion method, although it should be noted that overlapping between populations with and without PBP3 mutations is common. PMID- 23034713 TI - Salmonella enterica subsp. enterica producing VIM-1 carbapenemase isolated from livestock farms. PMID- 23034714 TI - Emergence of OXA-48-producing Klebsiella pneumoniae and the novel carbapenemases OXA-244 and OXA-245 in Spain. AB - OBJECTIVES: To describe the molecular and population-level characterization of a selected group of OXA-48-like-producing Klebsiella pneumoniae isolates collected in Spain between January 2011 and May 2012. METHODS: During the study period, 151 OXA-48-like-producing K. pneumoniae isolates were collected from 10 hospitals in six different Spanish regions. From these, a representative sample of 21 isolates that caused hospital outbreaks and single infections was selected for further in depth analysis. Molecular epidemiology was investigated using PFGE and multilocus sequence typing (MLST). Resistance genes were characterized by PCR and sequencing. Plasmids carrying bla(OXA-48-like) were studied by PFGE with S1 nuclease digestion. RESULTS: All 21 isolates had ertapenem MICs >= 1 mg/L, but 47.6% remained susceptible to imipenem and meropenem; bla(OXA-48) was identified in 19 isolates (90.5%) and the novel bla(OXA-244) and bla(OXA-245) genes were detected in 1 isolate each. With one exception, all isolates that contained bla(OXA-48-like) also contained bla(CTX-M-15). PFGE typing revealed six clusters comprising isolates that belonged to MLST types ST11, ST16, ST392, ST405, ST437 and ST663, respectively. Two main clusters were identified: PFGE cluster 1 (12 isolates, belonging either to ST405 or ST663, from seven hospitals), and PFGE cluster 2 (4 ST16 isolates from two hospitals). Six of seven donor isolates conjugated successfully; bla(OXA-48-like) (but not bla(CTX-M-15)) was carried on ~ 60 kb Inc L/M plasmids. CONCLUSIONS: Multidrug-resistant K. pneumoniae producing OXA-48-like carbapenemase are emerging as important pathogens in Spain due to intra- and inter-hospital, clonal and non-clonal dissemination. PMID- 23034716 TI - Molecular, functional, and gene expression analysis of zebrafish hypoxia inducible factor-3alpha. AB - Hypoxia-inducible factors 1-3 (HIF1-3) are transcription factors that regulate gene expression in response to hypoxia. Compared with our extensive understanding of HIF-1 and HIF-2, our knowledge of HIF-3 is limited. In this study, we characterized the zebrafish hif-3alpha gene and determined its temporal and spatial expression, physiological regulation, and biological activity. We show that the chromosomal location, gene structure, and protein structure of zebrafish hif-3alpha are similar to its mammalian orthologs. When tagged with enhanced green fluorescent protein and transfected into cultured cells, zebrafish Hif 3alpha was localized in the nucleus and stimulated reporter gene expression in a hypoxia response element-dependent manner. During early development, hif-3alpha mRNA was detected in all tissues with higher levels in the head. This expression pattern became more apparent in larvae at the 72, 96, and 120 hours post fertilization stages. In the adult stage, hif-3alpha mRNA was detected in all examined tissues with the highest levels in the ovary. Hypoxia treatment increased Hif-3alpha protein levels in both embryos and adults. Hypoxia also increased hif-3alpha mRNA expression levels, and this regulation was tissue specific. Expression of a stabilized form of Hif-1alpha in zebrafish embryos increased the expression of igfbp-1a, a Hif-1 target gene, whereas it did not change hif-3alpha mRNA levels, suggesting that hif-3alpha is not a Hif-1alpha target. These results provide new information about the structural and functional conservation, spatial and temporal expression, and physiological regulation of hif-3alpha in a teleost model organism. PMID- 23034715 TI - Sodium-retaining effect of insulin in diabetes. AB - Insulin has long been hypothesized to cause sodium retention, potentially of enough magnitude to contribute to hypertension in obesity, metabolic syndrome, and Type II diabetes. There is an abundance of supportive evidence from correlational analyses in humans, acute insulin infusion studies in humans and animals, and chronic insulin infusion studies in rats. However, the absence of hypertension in human insulinoma patients, and negative results for sodium retaining or blood pressure effects of chronic insulin infusion in a whole series of dog studies, strongly refute the insulin hypothesis. We recently questioned whether the euglycemic, hyperinsulinemia model used for most insulin infusion studies, including the previous chronic dog studies, was the most appropriate model to test the renal actions of insulin in obesity, metabolic syndrome, and Type II diabetes. In those circumstances, hyperinsulinemia coexists with hyperglycemia. Therefore, we tested the sodium-retaining effect of insulin in chronically instrumented, alloxan-treated diabetic dogs. We used 24 h/day intravenous insulin infusion to regulate plasma insulin concentration. Induction of diabetes (~400 mg/dl) caused sustained natriuresis and diuresis. However, if we clamped insulin at baseline, control levels, i.e., prevented it from decreasing, then the sustained natriuresis and diuresis were completely reversed, despite the same level of hyperglycemia. We also found that 24 h/day intrarenal insulin infusion had the same effect in diabetic dogs but had no sodium-retaining action in normal dogs. This new evidence that insulin has a sodium-retaining effect during hyperglycemia may have implications for maintaining sodium balance in uncontrolled Type II diabetes. PMID- 23034718 TI - The influences of the transfer method and particle surface chemistry on the dispersion of nanoparticles in nanocomposites. AB - The synthesis via in situ polymerization and characterization of nanocomposites (NCs) made from silica (SiO(2)) nanoparticles in a methyl methacrylate (MMA) monomer matrix is reported. We first investigate the transfer of well-defined spherical silica nanoparticles (NPs) (average radius R = 24.2 +/- 3.2 nm) into the monomer solvent. We study the influence of two transfer methods and different surface chemistries on the resulting colloidal stability. The first transfer method consists of drying the silica particles into powder before dispersing them via ultrasonication in the MMA matrix. The second is based on repetitive centrifugations to exchange NPs from their synthetic milieu to pure MMA, avoiding the dried powder state. These transfer methods are compared for two kinds of NP surface chemistry, natural silanol (Si-OH) groups of the silica NPs and an additional silane coupling agent, namely 3-(trimethoxysilyl)propyl methacrylate (TPM), which mimics the monomeric group of the MMA dispersing milieu. We then characterize the morphology of the resulting nanocomposites prepared via in situ polymerization at a fixed amount of dispersed NPs (2.2 wt%; 1 vol%) using a combination of transmission electron microscopy (TEM) from ultramicrotomed nanocomposite films, thermogravimetry (TGA) and small angle X-ray scattering (SAXS). PMID- 23034717 TI - Arginine plus proline supplementation elicits metabolic adaptation that favors wound healing in diabetic rats. AB - Diabetic patients with wounds are at risk of protein malnutrition, have low arginine plasma levels, and suffer from delayed wound healing. We sought to determine the efficacy of arginine plus proline supplementation on protein and amino acid metabolism and on wound repair in a model of diabetic rats. Eighteen 11-wk-old Zucker diabetic fatty fa/fa male rats underwent a 7-cm abdominal skin incision with implantation of sponges and daily excision of full-thickness round sections of dorsal skin for 5 days. They were randomized to be fed with either a standard formula (S group, Clinutren Iso), a high-protein and arginine (ARG) plus proline (PRO)-enriched formula (ARG+PRO group, Clinutren Repair), or an isonitrogenous isoenergetic control formula (IC group). Nitrogen balance was calculated daily. The rats were euthanized on day 5, and plasma glucose, insulin, amino acids, skin epithelialization, and angiogenesis were measured. In macrophages, we assessed inducible nitric oxide synthase (iNOS) and arginase expression, production of nitric oxide (NO) and amino acid metabolism. Both the ARG+PRO and IC groups showed improved nitrogen balance. ARG plus PRO supplementation increased proline and branched-chain amino acid plasma concentrations and improved angiogenesis. Arginase and iNOS expressions in macrophages were reduced, together with NO and citrulline production. In diabetic rats, ARG plus PRO supplementation improves wound angiogenesis and favors whole body protein metabolism. Low macrophage iNOS expression at day 5 may reflect a low inflammatory state in the wounds, favoring wound closure. PMID- 23034719 TI - Transient IR spectroscopy and ab initio calculations on ESIPT in 3-hydroxyflavone solvated in acetonitrile. AB - Femtosecond polarization resolved UV/Vis and mid-infrared spectroscopy was used to thoroughly identify and characterize the relevant elementary chemical and physical processes in the photocycle of 3-hydroxyflavone (3-HF) in solution. In one set of experiments with the polar aprotic solvent acetonitrile-d(3), for the first time excited state intramolecular proton transfer (ESIPT), vibrational cooling/relaxation and rotational diffusion could be separated, and furthermore mid IR vibrational spectra of 3-HF excited states in solution phase were obtained. UV/Vis transient absorption data yield the time constant tau(Rot) = 22 ps for rotational diffusion and the time constant tau(VR) = 8.5 ps for vibrational cooling/relaxation in the tautomer excited state (S(1)'). Biphasic ESIPT with tau < 120 fs and tau = 2.4 ps as well as slow ground state recovery with tau > 500 ps was found. The time resolved mid IR data yield a time constant of ~3.4 ps for the slow ESIPT step as well as the vibrational frequencies of S(0,) S(1)' and, in particular those of the short lived excited state S(1). Via quantum chemical calculations, structural parameters of these states are obtained. Various models were used, namely for the isolated molecule, aggregates with solvent as well as a polarizable continuum, that allow us to correlate the two ESIPT components with two mechanisms. Results are compared to those from previously published gas-phase experiments and indicate that the observed slow ESIPT is mediated by solute-solvent interaction via a hydrogen bond with the hydroxyl group of 3-HF. PMID- 23034720 TI - Retracted: Predicting protein folding rates using the concept of Chou's pseudo amino acid composition. PMID- 23034722 TI - Combined symptomatology of psychosis, pica syndrome, and hippocampal sclerosis: a case report. AB - Pica is the developmentally and culturally inappropriate eating of nonnutritive substances for at least 1 month. Herein, we present the case of a male patient that suddenly showed behavioral changes including aggressiveness, withdrawal, and perceptional disturbances at the age of 12. About 7 years later, pica symptoms emerged additionally. Neither pharmacotherapy nor electroconvulsive therapy led to success. Magnetic resonance imaging showed bilateral sclerosis of the hippocampus. The therapy with carbamazepine, clozapine, diazepam, and zinc finally improved the symptoms including the pica symptoms. PMID- 23034721 TI - Imaging of genetically engineered T cells by PET using gold nanoparticles complexed to Copper-64. AB - Adoptive transfer of primary T cells genetically modified to have desired specificity can exert an anti-tumor response in some patients. To improve our understanding of their therapeutic potential we have developed a clinically appealing approach to reveal their in vivo biodistribution using nanoparticles that serve as a radiotracer for imaging by positron emission tomography (PET). T cells electroporated with DNA plasmids from the Sleeping Beauty transposon transposase system to co-express a chimeric antigen receptor (CAR) specific for CD19 and Firefly luciferase (ffLuc) were propagated on CD19(+) K562-derived artificial antigen presenting cells. The approach to generating our clinical grade CAR(+) T cells was adapted for electro-transfer of gold nanoparticles (GNPs) functionalized with (64)Cu(2+) using the macrocyclic chelator (1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA) and polyethyleneglycol (GNP-(64)Cu/PEG2000). MicroPET/CT was used to visualize CAR(+)EGFPffLucHyTK(+)GNP (64)Cu/PEG2000(+) T cells and correlated with bioluminescence imaging. These data demonstrate that GNPs conjugated with (64)Cu(2+) can be prepared as a radiotracer for PET and used to image T cells using an approach that has translational implications. PMID- 23034723 TI - Propargyl Claisen rearrangement: allene synthesis and beyond. AB - The propargyl Claisen rearrangement is a known protocol to gain access to functionalized allenes through the [3,3]-sigmatropic transformation of propargyl vinyl ethers. The correct use of appropriate propargyl vinyl ethers as starting materials coupled with suitable reaction conditions can aid in the development of new domino methodologies in which the allenes are valuable intermediates in route to a wide range of important classes of organic compounds. PMID- 23034724 TI - The risk of Barrett's esophagus associated with abdominal obesity in males and females. AB - Esophageal adenocarcinoma arises from Barrett's esophagus (BE). Both occur predominantly in males. The role of abdominal obesity in this sex distribution is uncertain. Our study aimed to determine whether there is an association between abdominal obesity and risk of BE and if present was it modified by sex. A structured interview and anthropometric measures were conducted within a population-based case-control study. We recruited 237 BE cases (70% male) and 247 population controls, frequency matched by age and sex. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression analysis. In the overall group and males, all measures of abdominal obesity [waist circumference (WC), waist-hip ratio (WHR), sagittal abdominal diameter (SAD) and waist-height ratio (WHtR)] were strongly associated with risk of BE (Overall: WC OR 2.2 95% CI 1.4-3.5, WHR 1.8 95% CI 1.2-2.9, SAD 2.3 95% CI 1.4 3.7, WHtR 1.9 95% CI 1.2-3.0, males WC 2.5 95% CI 1.4-4.3, WHR 2.4 95% CI 1.3 4.2, SAD 2.5 95% CI 1.4-4.3, WHtR 1.9 95% CI 1.1-3.4). These associations were minimally attenuated by adjusting for ever-symptoms of gastroesophageal reflux (GER). These findings suggest in males, non-GER factors related to abdominal obesity may be important in the development of BE. In females, there was modest association between measures of abdominal obesity and risk of BE but these were all abolished after adjusting for ever-symptoms of GER. The power to detect differences between sexes in the risk of BE associated with abdominal obesity was limited by the number of females in the study. PMID- 23034725 TI - Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine. AB - Depletion of cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) in adult rats increases the locomotor activating effects of amphetamine. It also impairs sensorimotor gating processes, an effect reversed by the antipsychotic haloperidol. These behavioral effects are suggestive of pronounced hyper-responsiveness of the mesolimbic dopamine (DA) projection to the N.Acc. However, it is unclear whether local cholinergic depletion results predominantly in exaggerated presynaptic DA release or a postsynaptic upregulation of DAergic function. The purpose of the present study is to test the former possibility by employing in vivo voltammetry to examine changes in the levels of extracellular DA within the N.Acc. in response to either mild tail pinch stress or amphetamine administration. While both cholinergic-lesioned and control rats showed reliable stress-induced increases in extracellular DA on two consecutive test days, those in the lesioned rats were significantly less pronounced. In response to amphetamine, a separate cohort of lesioned rats also exhibited smaller increases in extracellular DA release than controls, despite showing greater locomotor activity. Moreover, the increased behavioral response to amphetamine in lesioned rats coincided temporally with decreasing levels of DA in the N.Acc. The results confirm that cholinergic depletion within the N.Acc. suppresses presynaptic DA release and suggest that lesion-induced behavioral effects are more likely due to postsynaptic DA receptor upregulation. The results are also discussed in the context of schizophrenia, where post mortem studies have revealed a selective loss of cholinergic interneurons within the ventral striatum. PMID- 23034726 TI - High pressure structures of "111" type iron-based superconductors predicted from first-principles. AB - The high-pressure crystal structures of the "111" type iron-based superconductors: NaFeAs, LiFeP and LiFeAs have been systematically explored by using particle-swarm structural searches. It was found that though these iron based superconductors are chemically similar, they adopted distinct structural phase transitions: P4/nmm->Cmcm->P3m1 for NaFeAs, P4/nmm->Cmcm->I4mm for LiFeP, and P4/nmm->P3m1 ->I4mm->P6(3)/mmc for LiFeAs under high pressure. The high pressure orthorhombic Cmcm phase preserved the structural features of FeX(4)(X = As, P) tetrahedral layers present in the ambient-pressure P4/nmm structure. However, the FeX(4) tetrahedrons in the Cmcm phase were clearly distorted, leading to changes in the electronic behavior around the Fermi level. Under higher pressures, the FeX(4) layered structural features were no longer persistent and three-dimensional crystal structures were stabilized in other P3m1, I4mm, and P6(3)/mmc phases, which featured FeAs(5)/FeAs(6) hexahedron and octahedrons, FeX(5) tetragonal pyramids, and FeAs(6) octahedrons, respectively. Analysis of the electronic density of states suggests that most of the high pressure phases are metallic except for the tetragonal I4mm phase, which possesses a narrow band gap. This semiconducting state might relate to the tetragonal pyramid structure formed by FeX(5) unit, which might be favorable for charge localization. PMID- 23034727 TI - Rats use hippocampus to recognize positions of objects located in an inaccessible space. AB - Rat hippocampus plays a crucial role in many spatial tasks, including recognition of position of objects, which can be approached and explored. Whether hippocampus is also necessary for recognizing positions of objects located in an inaccessible part of the environment remains unclear. To address this question, we conditioned rats to press a lever when an object displayed on a distant computer screen was in a particular position ("reward position") and not to press the lever when the object was in other positions ("nonreward positions"). After the rats had reached an asymptotic performance, the role of the dorsal hippocampus was assessed by blocking its activity with muscimol. The rats without functional dorsal hippocampus did not discriminate the reward position from the nonreward positions. Then the same rats were trained to discriminate light and dark conditions. The hippocampal inactivation did not disrupt the ability to discriminate these two conditions. It indicated that the inactivation itself had no major effect on the operant behavior and its control by visual stimuli. We conclude that rats use dorsal hippocampus for recognizing positions of objects located in an inaccessible part of the environment. PMID- 23034728 TI - Reconfiguration: putting the patient first. AB - Increasing sub-specialization in the less-common conditions is leading to better outcomes for patients. Yet the way we provide the service has not changed. Is it time to consider doing things differently? Do we need to reconfigure service provision both within and between units? PMID- 23034729 TI - Final follow-up of the Multicentre Aneurysm Screening Study (MASS) randomized trial of abdominal aortic aneurysm screening. AB - BACKGROUND: The long-term effects of abdominal aortic aneurysm (AAA) screening were investigated in extended follow-up from the UK Multicentre Aneurysm Screening Study (MASS) randomized trial. METHODS: A population-based sample of men aged 65-74 years were randomized individually to invitation to ultrasound screening (invited group) or to a control group not offered screening. Patients with an AAA (3.0 cm or larger) detected at screening underwent surveillance and were offered surgery after predefined criteria had been met. Cause-specific mortality data were analysed using Cox regression. RESULTS: Some 67 770 men were enrolled in the study. Over 13 years, there were 224 AAA-related deaths in the invited group and 381 in the control group, a 42 (95 per cent confidence interval 31 to 51) per cent reduction. There was no evidence of effect on other causes of death, but there was an overall reduction in all-cause mortality of 3 (1 to 5) per cent. The degree of benefit seen in earlier years of follow-up was slightly diminished by the occurrence of AAA ruptures in those with an aorta originally screened normal. About half of these ruptures had a baseline aortic diameter in the range 2.5-2.9 cm. It was estimated that 216 men need to be invited to screening to save one death over the next 13 years. CONCLUSION: Screening resulted in a reduction in all-cause mortality, and the benefit in AAA-related mortality continued to accumulate throughout follow-up. REGISTRATION NUMBER: ISRCTN37381646 (http://www.controlled-trials.com). PMID- 23034730 TI - Facile synthesis of novel tunable highly porous CuO nanorods for high rate lithium battery anodes with realized long cycle life and high reversible capacity. AB - Various CuO nanostructures have been well studied as anode materials for lithium ion batteries (LIBs); however, there are few reports on the synthesis of porous CuO nanostructures used for anode materials, especially one-dimensional (1D) porous CuO. In this work, novel 1D highly porous CuO nanorods with tunable porous size were synthesized in large-quantities by a new, friendly, but very simple approach. We found that the pore size could be controlled by adjusting the sintering temperature in the calcination process. With the rising of calcination temperature, the pore size of CuO has been tuned in the range of ~0.4 nm to 22 nm. The porous CuO materials have been applied as anode materials in LIBs and the effects of porous size on the electrochemical properties were observed. The highly porous CuO nanorods with porous size in the range of ~6 nm to 22 nm yielded excellent high specific capacity, good cycling stability, and high rate performance, superior to that of most reported CuO nanocomposites. The CuO material delivers a high reversible capacity of 654 mA h g(-1) and 93% capacity retention over 200 cycles at a rate of 0.5 C. It also exhibits excellent high rate capacity of 410 mA h g(-1) even at 6 C. These results suggest that the facile synthetic method of producing a tunable highly porous CuO nanostructure can realize a long cycle life with high reversible capacity, which is suitable for next-generation high-performance LIBs. PMID- 23034731 TI - CovalentDock: automated covalent docking with parameterized covalent linkage energy estimation and molecular geometry constraints. AB - Covalent linkage formation is a very important mechanism for many covalent drugs to work. However, partly due to the limitations of proper computational tools for covalent docking, most covalent drugs are not discovered systematically. In this article, we present a new covalent docking package, the CovalentDock, built on the top of the source code of Autodock. We developed an empirical model of free energy change estimation for covalent linkage formation, which is compatible with existing scoring functions used in docking, while handling the molecular geometry constrains of the covalent linkage with special atom types and directional grid maps. Integrated preparation scripts are also written for the automation of the whole covalent docking workflow. The result tested on existing crystal structures with covalent linkage shows that CovalentDock can reproduce the native covalent complexes with significant improved accuracy when compared with the default covalent docking method in Autodock. Experiments also suggest that CovalentDock is capable of covalent virtual screening with satisfactory enrichment performance. In addition, the investigation on the results also shows that the chirality and target selectivity along with the molecular geometry constrains are well preserved by CovalentDock, showing great capability of this method in the application for covalent drug discovery. PMID- 23034733 TI - Exploring copper(I)-based dye-sensitized solar cells: a complementary experimental and TD-DFT investigation. AB - The structures and properties of the homoleptic copper(I) complexes [Cu(1)(2)][PF(6)] and [Cu(2)(2)][PF(6)] (1 = 6,6'-dimethyl-2,2'-bipyridine, 2 = 6,6'-bis{2-[4-(N,N'-diphenylamino)phenyl]ethenyl}-2,2'-bipyridine) are compared, and a strategy of ligand exchange in solution has been used to prepare eight TiO(2) surface-bound heteroleptic complexes incorporating ligands with bpy metal binding domains and carboxylate or phosphonate anchoring groups. The presence of the extended pi-system in 2 significantly improves dye performance, and the most efficient sensitizers are those with phosphonate or phenyl-4-carboxylate anchoring units; a combination of [Cu(2)(2)](+) with the phosphonate anchoring ligand gives a very promising performance (eta = 2.35% compared to 7.29% for standard dye N719 under the same conditions). The high-energy bands in the electronic absorption spectrum of [Cu(2)(2)](+) which arise from ligand-based transitions dominate the spectrum, whereas that of [Cu(1)(2)](+) exhibits both MLCT and ligand pi* <- pi bands. Both [Cu(1)(2)][PF(6)] and [Cu(2)(2)][PF(6)] are redox active; while the former exhibits both copper-centred and ligand-based processes, [Cu(2)(2)][PF(6)] shows only ligand-based reductions. Results of TD DFT calculations support these experimental data. They predict an electronic absorption spectrum for [Cu(1)(2)](+) with an MLCT band and high-energy ligand based transitions, and a spectrum for [Cu(2)(2)](+) comprising transitions involving mainly contributions from orbitals with ligand 2 character. We have assessed the effects of the atomic orbital basis set on the calculated absorption spectrum of [Cu(1)(2)](+) and show that a realistic spectrum is obtained by using a 6-311++G** basis set on all atoms, or 6-311++G** on copper and 6-31G* basis set on all other atoms; a smaller basis set on copper leads to unsatisfactory results. Electronic absorption spectra of six heteroleptic complexes have been predicted using TD-DFT calculations, and the transitions making up the dominant bands analysed in terms of the character of the HOMO-LUMO manifold. The calculational data reveal dominant phosphonate ligand character in the LUMO for the dye found to function most efficiently in practice, and also reveal that the orbital character in the HOMOs of the two most efficient dyes is dominated by the non-anchoring ligand 2, suggesting that ligand 2 enhances the performance of the sensitizer by minimizing back-migration of an electron from the semiconductor to the dye. PMID- 23034732 TI - Aspects of forward scattering from the compression paddle in the dosimetry of mammography. AB - The best compression paddle position during air kerma measurement in mammography dosimetry was studied. The amount of forward scattering as a function of the compression paddle distance was measured with different X-ray spectra and different types of paddles and dose meters. The contribution of forward scattering to the air kerma did not present significant dependency on the beam quality or of the compression paddle type. The tested dose meter types detected different amounts of forward scattering due to different internal collimation. When the paddle was adjusted to its maximum clinical distance, the proportion of the detected forward scattering was only 1 % for all dose meter types. The most consistent way of performing air kerma measurements is to position the compression paddle at the maximum distance from the dose meter and use a constant forward scattering factor for all dose meters. Thus, the dosimetric uncertainty due to the forward scatter can be minimised. PMID- 23034734 TI - Effects of non-catalytic, distal amino acid residues on activity of E. coli DinB (DNA polymerase IV). AB - DinB is one of two Y family polymerases in E. coli and is involved in copying damaged DNA. DinB is specialized to bypass deoxyguanosine adducts that occur at the N(2) position, with its cognate lesion being the furfuryl adduct. Active site residues have been identified that make contact with the substrate and carry out deoxynucleotide triphosphate (dNTP) addition to the growing DNA strand. In DNA polymerases, these include negatively charged aspartate and glutamate residues (D8, D103, and E104 in E. coli DNA polymerase IV DinB). These residues position the essential magnesium ions correctly to facilitate nucleophilic attack by the primer hydroxyl group on the alpha-phosphate group of the incoming dNTP. To study the contribution of DinB residues to lesion bypass, the computational methods THEMATICS and POOL were employed. These methods correctly predict the known active site residues, as well as other residues known to be important for activity. In addition, these methods predict other residues involved in substrate binding as well as more remote residues. DinB variants with mutations at the predicted positions were constructed and assayed for bypass of the N(2) -furfuryl dG lesion. We find a wide range of effects of predicted residues, including some mutations that abolish damage bypass. Moreover, most of the DinB variants constructed are unable to carry out the extension step of lesion bypass. The use of computational prediction methods represents another tool that will lead to a more complete understanding of translesion DNA synthesis. PMID- 23034736 TI - Attaching molecular hydrogen to metal cations: perspectives from gas-phase infrared spectroscopy. AB - In this perspective article we describe recent infrared spectroscopic investigations of mass-selected M(+)-H(2) and M(+)-D(2) complexes in the gas phase, with targets that include Li(+)-H(2), B(+)-H(2), Na(+)-H(2), Mg(+)-H(2), Al(+)-H(2), Cr(+)-D(2), Mn(+)-H(2), Zn(+)-D(2) and Ag(+)-H(2). Interactions between molecular hydrogen and metal cations play a key role in several contexts, including in the storage of molecular hydrogen in zeolites, metal-organic frameworks, and doped carbon nanostructures. Arguably, the clearest view of the interaction between dihydrogen and a metal cation can be obtained by probing M(+) H(2) complexes in the gas phase, free from the complicating influences of solvents or substrates. Infrared spectra of the complexes in the H-H and D-D stretch regions are obtained by monitoring M(+) photofragments as the excitation wavelength is scanned. The spectra, which feature full rotational resolution, confirm that the M(+)-H(2) complexes share a common T-shaped equilibrium structure, consisting essentially of a perturbed H(2) molecule attached to the metal cation, but that the structural and vibrational parameters vary over a considerable range, depending on the size and electronic structure of the metal cation. Correlations are established between intermolecular bond lengths, dissociation energies, and frequency shifts of the H-H stretch vibrational mode. Ultimately, the M(+)-H(2) and M(+)-D(2) infrared spectra provide a comprehensive set of benchmarks for modelling and understanding the M(+)...H(2) interaction. PMID- 23034735 TI - Comparison of specialist and nonspecialist care pathways for adolescents with anorexia nervosa and related eating disorders. AB - OBJECTIVE: To explore the role of specialist outpatient eating disorders services and investigate how direct access to these affects rates of referral, admissions for inpatient treatment, and continuity of care. METHOD: Services beyond primary care in Greater London retrospectively identified adolescents who presented with an eating disorder over a 2-year period. Data concerning service use were collected from clinical casenotes. RESULTS: In areas where specialist outpatient services were available, 2-3 times more cases were identified than in areas without such services. Where initial outpatient treatment was in specialist rather than nonspecialist services, there was a significantly lower rate of admission for inpatient treatment and considerably higher consistency of care. DISCUSSION: Developing specialist outpatient services with direct access from primary care is likely to lead to improvements in treatment and reduce overall costs. PMID- 23034737 TI - The effect of oxygen vacancies on the binding interactions of NH3 with rutile TiO2(110)-1 * 1. AB - A series of NH(3) temperature-programmed desorption (TPD) spectra were taken after dosing NH(3) at 70 K on rutile TiO(2)(110)-1 * 1 surfaces with oxygen vacancy (V(O)) concentrations of ~0% (p-TiO(2)) and 5% (r-TiO(2)), respectively, to study the effect of V(O)s on the desorption energy of NH(3) as a function of coverage, theta. Our results show that in the zero coverage limit, the desorption energy of NH(3) on r-TiO(2) is 115 kJ mol(-1), which is 10 kJ mol(-1) less than that on p-TiO(2). The desorption energy from the Ti(4+) sites decreases with increasing theta due to repulsive NH(3)-NH(3) interactions and approaches ~55 kJ mol(-1) upon the saturation of Ti(4+) sites (theta = 1 monolayer, ML) on both p- and r-TiO(2). The absolute monolayer saturation coverage is determined to be about 10% smaller on r-TiO(2) than that on p-TiO(2). Additionally, the trailing edges of the NH(3) TPD spectra on the hydroxylated TiO(2)(110) (h-TiO(2)) appear to be the same as that on r-TiO(2) while those on oxidized TiO(2)(110) (o-TiO(2)) shift to higher temperatures. We present a detailed analysis of the results and reconcile the observed differences based on the repulsive adsorbate-adsorbate dipole interactions between neighboring NH(3) molecules and the surface charge associated with the presence of V(O)s. PMID- 23034739 TI - The role of the dentate gyrus in the formation of contextual representations. AB - The hippocampus is involved in encoding and integrating contextual information. Recently, it has been suggested that the dorsal dentate gyrus (dDG) hippocampal subregion may mediate the formation of contextual representations of the spatial environment through a conjunctive encoding process whereby incoming multimodal information is integrated into a single higher-order representation. Despite anatomical evidence in support of this claim, behavioral evidence is limited. Therefore, a contextual associative learning paradigm was used to determine whether the dDG supports the formation of integrated contextual representations. Male Long-Evans rats were randomly assigned as controls or to receive bilateral intracranial infusions of colchicine into the dDG. Following recovery from surgery, each rat was tested on an appetitive task that required animals to form an association between a cue (odor) and a context to receive a food reward. Each rat received 10 trials per day and was tested for 10 consecutive days. Upon completion of testing, animals were tested on an additional two-choice olfactory and contextual discrimination task. The testing order was counterbalanced across animals. Results showed that control animals successfully acquired the contextual associative learning task for olfactory stimuli as indicated by improved performance across the 10 testing days. In contrast, animals with dDG lesions were impaired in the ability to acquire the odor-context associations. Results from follow-up odor and context discrimination tests indicated that both groups acquired the discriminations at similar rates. Therefore, it is unlikely that deficits in performance on the contextual associative learning task were due to an inability to discriminate between odors or contexts. The present findings provide further support for DG involvement in the formation of conjunctive contextual representations. PMID- 23034740 TI - Multifaceted prismatic silver nanoparticles: synthesis by chloride-directed selective growth from thiolate-protected clusters and SERS properties. AB - We describe the synthetic preparation of well-defined symmetric multifaceted prismatic silver nanoparticles with chemically controlled faceting advantageous for strong and tunable surface-enhanced Raman scattering, SERS. These silver nanoparticles, that have been termed nanoflowers, AgNFls for their characteristic morphologies, have been prepared by a one-pot aqueous reaction under ambient conditions. AgNFl faceting is synthetically controlled by selective nanoparticle growth driven by chloride ions. Selective chloride binding to the surface of growing AgNFls results in nanoparticle enlargement predominantly at the points of their highest energy. These growth points are located at the tips of prismatic polygons in precursor prismatic morphologies that have been produced from thiolate-protected silver clusters whose coalescence is triggered with a strong base. For the practical aspects of AgNFl synthesis, concentrations of thiol and a strong base were found to be the key variables reliably controlling the extent of AgNFl faceting, as well as the kinetics of AgNFl formation and their stability. The selective growth of AgNFls progresses slower compared to that of non-faceted prisms: fewer nuclei can form leading to larger AgNFls with the diameter ranging from 130 to 2250 nm and asperity sizes on the order of 20 to 100 nm. Self assembly of AgNFls yields columnar stacking. AgNFls were demonstrated to function as a promising substrate for surface-enhanced Raman scattering. SERS measurements were performed for a series of AgNFls with variable faceting, where the enhancement factors of 4.6 * 10(8) and 425 have been achieved for dry solid films and aqueous dispersions of non-aggregated AgNFls with single-particle enhancement, respectively. These SERS results are promising, especially in combination with that AgNFl nanoscale asperities can be conveniently tailored synthetically. Overall, AgNFls offer valuable opportunities for a system with synthetically variable nanoscale asperities. PMID- 23034738 TI - Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer. AB - The prognostic impact of CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) on the treatment outcome of colon cancer patients receiving adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) is unclear. We investigated CIMP and MSI status in colorectal cancer patients treated with adjuvant FOLFOX. Stages II and III sporadic colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Eight CpG island loci (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, CDKN2A (p16), RUNX3 and SOCS1) and five microsatellite markers were examined. Disease free survival (DFS) was analyzed according to CIMP and MSI status. A total of 322 patients were included: male/female 192/130, median age 61 years (range 30-78), proximal/distal location 118/204 and Stages II/III 43/279. CIMP status was high in 25 patients (7.8%) and 21 patients (6.5%) had MSI-high tumor. CIMP/MSI status was not significantly associated with DFS: 3-year DFS 100% in CIMP(-)/MSI(+), 84% in CIMP(-)/MSI(-), 82% in CIMP(+)/MSI(-) and 75% in CIMP(+)/MSI(+) (p = 0.33). Results of exploratory analysis showed that concurrent methylation at NEUROG1 and CDKN2A (p16) was associated with shorter DFS: 3-year DFS 69% in NEUROG1(+)/CDKN2A (p16)(+) versus 87% in NEUROG1(-)/CDKN2A (p16)(-) (p = 0.006). In conclusion, concurrent methylation of NEUROG1 and CDKN2A (p16) is associated with recurrence following adjuvant FOLFOX in Stages II/III colorectal cancer. PMID- 23034741 TI - Meta-analysis of laparoscopic versus open cholecystectomy for patients with liver cirrhosis and symptomatic cholecystolithiasis. AB - BACKGROUND: Open cholecystectomy (OC) is often preferred over laparoscopic cholecystectomy (LC) in patients with liver cirrhosis and portal hypertension, but evidence is lacking to support this practice. This meta-analysis aimed to clarify which surgical technique is preferable for symptomatic cholecystolithiasis in patients with liver cirrhosis. METHODS: A meta-analysis was conducted according to the PRISMA guidelines. Articles published between January 1990 and October 2011 were identified from MEDLINE, Embase and the Cochrane Library. Randomized clinical trials (RCTs) comparing outcomes of OC versus LC for cholecystolithiasis in patients with liver cirrhosis were included. The quality of the RCTs was assessed using the Jadad criteria. RESULTS: Following review of 1422 papers by title and abstract, a meta-analysis was conducted of four RCTs comprising 234 surgical patients. They provided evidence of at least level 2b on the Oxford Level of Evidence Scale, but scored poorly according to the Jadad criteria. Some 97.0 per cent of the patients had Child-Turcotte-Pugh (CTP) grade A or B liver cirrhosis. In all, 96.6 per cent underwent elective surgery. No postoperative deaths were reported. LC was associated with fewer postoperative complications (risk ratio 0.52, 95 per cent confidence interval (c.i.) 0.29 to 0.92; P = 0.03), a shorter hospital stay (mean difference -3.05 (95 per cent c.i. -4.09 to -2.01) days; P < 0.001) and quicker resumption of a normal diet (mean difference -27.48 (-30.96 to -23.99) h; P < 0.001). CONCLUSION: Patients with CTP grade A or B liver cirrhosis who undergo LC for symptomatic cholecystolithiasis have fewer overall postoperative complications, a shorter hospital stay and resume a normal diet more quickly than those who undergo OC. PMID- 23034742 TI - Assessment of the posterior brain at 11-14 weeks for the prediction of open neural tube defects. AB - OBJECTIVE: To evaluate the routine midsagittal view of the posterior brain at the 11-13 weeks' ultrasound examination, for predicting open neural tube defects. METHODS: Posterior brain was examined midsagittally for normality of the four line view (upper and lower border of the brain stem, the choroid plexus of the fourth ventricle and the occipital bone). Intracranial translucency and cisterna magna (CM) were measured. RESULTS: The posterior brain was assessed in 1330 cases. The four-line view was normal in all but one case. In the two cases of open spina bifida contained in the study population, intracranial translucency was within normal range. The CM and the four-line view were normal in the first case, whereas in the second case, the four-line view was abnormal, and CM was obliterated and impossible to measure. No other cases of abnormal four-line view were observed in the study population. CONCLUSION: Obliteration of the CM appears to be the most consistent early sign of open neural tube defects. Attention should focus on either measuring the cisterna magna or simply observing the presence of four lines in the midsagittal view of the posterior brain. However, these early signs of brain herniation are not present in all abnormal cases. PMID- 23034743 TI - Ab initio, density functional theory, and semi-empirical calculations. AB - This chapter introduces the theory and applications of commonly used methods of electronic structure calculation, with particular emphasis on methods applicable for modelling biomolecular systems. This chapter is sectioned as follows. We start by presenting ab initio methods, followed by a treatment of density functional theory (DFT) and some recent advances in semi-empirical methods. Treatment of excited states as well as basis sets are also presented. PMID- 23034744 TI - Ab initio molecular dynamics. AB - In this chapter, an introduction to ab initio molecular dynamics (AIMD) has been given. Many of the basic concepts, like the Hellman-Feynman forces, the difference between the Car-Parrinello molecular dynamics and AIMD, have been explained. Also a very versatile AIMD code, the CP2K, has been introduced. On the application, the emphasis was on the aqueous systems and chemical reactions. The biochemical applications have not been discussed in depth. PMID- 23034745 TI - Introduction to QM/MM simulations. AB - Hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have become a popular tool for investigating chemical reactions in condensed phases. In QM/MM methods, the region of the system in which the chemical process takes place is treated at an appropriate level of quantum chemistry theory, while the remainder is described by a molecular mechanics force field. Within this approach, chemical reactivity can be studied in large systems, such as enzymes. In the first part of this contribution, the basic methodology is briefly reviewed. The two most common approaches for partitioning the two subsystems are presented, followed by a discussion on the different ways of treating interactions between the subsystems. Special attention is given on how to deal with situations in which the boundary between the QM and MM subsystems runs through one or more chemical bonds. The second part of this contribution discusses what properties of larger system can be obtained within the QM/MM framework and how. Finally, as an example of a QM/MM application in practice, the third part presents an overview of recent QM/MM molecular dynamics simulations on photobiological systems. In addition to providing quantities that are experimentally accessible, such as structural intermediates, fluorescence lifetimes, quantum yields and spectra, the QM/MM simulations also provide information that is much more difficult to measure experimentally, such as reaction mechanisms and the influence of individual amino acid residues. PMID- 23034746 TI - Computational enzymology. AB - Techniques for modelling enzyme-catalyzed reaction mechanisms are making increasingly important contributions to biochemistry. They can address fundamental questions in enzyme catalysis and have the potential to contribute to practical applications such as drug development. PMID- 23034747 TI - QM and QM/MM simulations of proteins. AB - Molecular dynamics simulations of biomolecules have matured into powerful tools of structural biology. In addition to the commonly used empirical force field potentials, quantum mechanical descriptions are gaining popularity for structure optimization and dynamic simulations of peptides and proteins. In this chapter, we introduce methodological developments such as the QM/MM framework and linear scaling QM that make efficient calculations on large biomolecules possible. We identify the most common scenarios in which quantum descriptions of peptides and proteins are employed, such as structural refinement, force field development, treatment of unusual residues, and predicting spectroscopic and exited state properties. The benefits and shortcomings of QM potentials, in comparison to classical force fields, are discussed, with special emphasis on the sampling problems of protein conformational space. Finally, recent examples of QM/MM calculations in light-sensitive membrane proteins illustrate typical applications of the reviewed methods. PMID- 23034748 TI - Classical molecular dynamics in a nutshell. AB - This chapter provides an overview of the various techniques that are commonly used in classical molecular dynamics simulations. It describes suitable algorithms for the integration of Newton's equation of motion over many time steps for systems containing a large number of particles, different choices of boundary conditions as well as available force fields for biological systems, that is, the mathematical description of the interactions of atoms and molecules with each other. It also illustrates algorithms used to simulate systems at constant temperature and/or pressure and discusses their advantages and disadvantages. It presents a few methods to save CPU time and a summary of popular software for biomolecular molecular dynamics simulations. PMID- 23034749 TI - Enhanced sampling algorithms. AB - In biomolecular systems (especially all-atom models) with many degrees of freedom such as proteins and nucleic acids, there exist an astronomically large number of local-minimum-energy states. Conventional simulations in the canonical ensemble are of little use, because they tend to get trapped in states of these energy local minima. Enhanced conformational sampling techniques are thus in great demand. A simulation in generalized ensemble performs a random walk in potential energy space and can overcome this difficulty. From only one simulation run, one can obtain canonical-ensemble averages of physical quantities as functions of temperature by the single-histogram and/or multiple-histogram reweighting techniques. In this article we review uses of the generalized-ensemble algorithms in biomolecular systems. Three well-known methods, namely, multicanonical algorithm, simulated tempering, and replica-exchange method, are described first. Both Monte Carlo and molecular dynamics versions of the algorithms are given. We then present various extensions of these three generalized-ensemble algorithms. The effectiveness of the methods is tested with short peptide and protein systems. PMID- 23034751 TI - Polarizable force fields. AB - This chapter provides an overview of the most common methods for including an explicit description of electronic polarization in molecular mechanics force fields: the induced point dipole, shell, and fluctuating charge models. The importance of including polarization effects in biomolecular simulations is discussed, and some of the most important achievements in the development of polarizable biomolecular force fields to date are highlighted. PMID- 23034750 TI - Force fields for classical molecular dynamics. AB - In this chapter we review the basic features and the principles underlying molecular mechanics force fields commonly used in molecular modeling of biological macromolecules. We start by summarizing the historical background and then describe classical pairwise additive potential energy functions. We introduce the problem of the calculation of nonbonded interactions, of particular importance for charged macromolecules. Different parameterization philosophies are then presented, followed by a section on force field validation. We conclude with a brief overview on future perspectives for the development of classical force fields. PMID- 23034752 TI - Electrostatics interactions in classical simulations. AB - Electrostatic interactions are crucial for both the accuracy and performance of atomistic biomolecular simulations. In this chapter we review well-established methods and current developments aiming at efficiency and accuracy. Specifically, we review the classical Ewald summations, particle-particle particle-method particle-method Ewald algorithms, multigrid, fast multipole, and local methods. We also highlight some recent developments targeting more accurate, yet classical, representation of the molecular charge distribution. PMID- 23034753 TI - An introduction to best practices in free energy calculations. AB - Free energy calculations are extremely useful for investigating small-molecule biophysical properties such as protein-ligand binding affinities and partition coefficients. However, these calculations are also notoriously difficult to implement correctly. In this chapter, we review standard methods for computing free energy via simulation, discussing current best practices and examining potential pitfalls for computational researchers performing them for the first time. We include a variety of examples and tips for how to set up and conduct these calculations, including applications to relative binding affinities and small-molecule solvation free energies. PMID- 23034754 TI - Recipes for free energy calculations in biomolecular systems. AB - During the last decade, several methods for sampling phase space and calculating various free energies in biomolecular systems have been devised or refined for molecular dynamics (MD) simulations. Thus, state-of-the-art methodology and the ever increasing computer power allow calculations that were forbidden a decade ago. These calculations, however, are not trivial as they require knowledge of the methods, insight into the system under study, and, quite often, an artful combination of different methodologies in order to avoid the various traps inherent in an unknown free energy landscape. In this chapter, we illustrate some of these concepts with two relatively simple systems, a sugar ring and proline oligopeptides, whose free energy landscapes still offer considerable challenges. In order to explore the configurational space of these systems, and to surmount the various free energy barriers, we combine three complementary methods: a nonequilibrium umbrella sampling method (adaptively biased MD, or ABMD), replica exchange molecular dynamics (REMD), and steered molecular dynamics (SMD). In particular, ABMD is used to compute the free energy surface of a set of collective variables; REMD is used to improve the performance of ABMD, to carry out sampling in space complementary to the collective variables, and to sample equilibrium configurations directly; and SMD is used to study different transition mechanisms. PMID- 23034755 TI - Molecular docking methodologies. AB - Molecular docking represents an important technology for structure-based drug design. Docking is a computational technique aimed at the prediction of the most favorable ligand-target spatial configuration and an estimate of the corresponding complex free energy, although as stated at the beginning accurate scoring methods remain still elusive. In this chapter, the state of art of molecular docking methodologies and their applications in drug discovery is summarized. PMID- 23034756 TI - Simulation studies of the mechanism of membrane transporters. AB - Membrane transporters facilitate active transport of their specific substrates, often against their electrochemical gradients across the membrane, through coupling the process to various sources of cellular energy, for example, ATP binding and hydrolysis in primary transporters, and pre-established electrochemical gradient of molecular species other than the substrate in the case of secondary transporters. In order to provide efficient energy-coupling mechanisms, membrane transporters have evolved into molecular machines in which stepwise binding, translocation, and transformation of various molecular species are closely coupled to protein conformational changes that take the transporter from one functional state to another during the transport cycle. Furthermore, in order to prevent the formation of leaky states and to be able to pump the substrate against its electrochemical gradient, all membrane transporters use the widely-accepted "alternating access mechanism," which ensures that the substrate is only accessible from one side of the membrane at a given time, but relies on complex and usually global protein conformational changes that differ for each family of membrane transporters. Describing the protein conformational changes of different natures and magnitudes is therefore at the heart of mechanistic studies of membrane transporters. Here, using a number of membrane transporters from diverse families, we present common protocols used in setting up and performing molecular dynamics simulations of membrane transporters and in analyzing the results, in order to characterize relevant motions of the system. The emphasis will be on highlighting how optimal design of molecular dynamics simulations combined with mechanistically oriented analysis can shed light onto key functionally relevant protein conformational changes in this family of membrane proteins. PMID- 23034757 TI - Molecular dynamics simulations of lipid bilayers: simple recipe of how to do it. AB - Simulations based on molecular dynamics (MD) are an important tool in structural biology. In the field of lipid membrane research, MD represents a major tool as it grant access to atomic level features of the membrane difficult to access by experimental means. In this chapter we describe step by step how to simulate a membrane in silico. The explanation comprehends from the initial set up of a membrane system to its analysis passing through the simulation itself. Most of the tasks described here are performed using the Gromacs simulation suite, a widely used software for molecular modeling and simulations. In the selected example the attention is focused on a single component lipid bilayer composed of DPPC, one of the most studied lipid species. PMID- 23034758 TI - Simulations of lipid monolayers. AB - A lipid monolayer lining a boundary between two immiscible phases forms a complex interface with inhomogeneous distribution of forces. Unlike lipid bilayers, monolayers are formed in asymmetric environment and their properties depend strongly on lipid surface density. The monolayer properties are also affected significantly by the representation of the pure interface. Here we give a brief theoretical introduction and describe methods to simulate lipid monolayers starting from force-fields and system setup to reproducing state points on the surface tension (pressure)-area isotherms and transformations between them. PMID- 23034759 TI - Simulating DNA by molecular dynamics: aims, methods, and validation. AB - The structure and dynamics of the B-DNA double helix involves subtle sequence dependent effects which are decisive for its function, but difficult to characterize. These structural and dynamic effects can be addressed by simulations of DNA sequences in explicit solvent. Here, we present and discuss the state-of-art of B-DNA molecular dynamics simulations with the major force fields in use today. We explain why a critical analysis of the MD trajectories is required to assess their reliability, and estimate the value and limitations of these models. Overall, simulations of DNA bear great promise towards deciphering the structural and physical subtleties of this biopolymer, where much remains to be understood. PMID- 23034760 TI - Simulation of carbohydrates, from molecular docking to dynamics in water. AB - Modeling of carbohydrates is particularly challenging because of the variety of structures resulting for the high number of monosaccharides and possible linkages and also because of their intrinsic flexibility. The development of carbohydrate parameters for molecular modeling is still an active field. Nowadays, main carbohydrates force fields are GLYCAM06, CHARMM36, and GROMOS 45A4. GLYCAM06 includes the largest choice of compounds and is compatible with the AMBER force fields and associated. Furthermore, AMBER includes tools for the implementation of new parameters. When looking at protein-carbohydrate interaction, the choice of the starting structure is of importance. Such complex can be sometimes obtained from the Protein Data Bank-although the stereochemistry of sugars may require some corrections. When no experimental data is available, molecular docking simulation is generally used to the obtain protein-carbohydrate complex coordinates. As molecular docking parameters are not specifically dedicated to carbohydrates, inaccuracies should be expected, especially for the docking of polysaccharides. This issue can be addressed at least partially by combining molecular docking with molecular dynamics simulation in water. PMID- 23034761 TI - Systematic methods for structurally consistent coarse-grained models. AB - This chapter provides a primer on theories for coarse-grained (CG) modeling and, in particular, reviews several systematic methods for determining effective potentials for CG models. The chapter first reviews a statistical mechanics framework for relating atomistic and CG models. This framework naturally leads to a quantitative criterion for CG models that are "consistent" with a particular atomistic model for the same system. This consistency criterion is equivalent to minimizing the relative entropy between the two models. This criterion implies that a many-body PMF is the appropriate potential for a CG model that is consistent with a particular atomistic model. This chapter then presents a unified exposition of the theory and numerical methods for several approaches for approximating this many-body PMF. Finally, this chapter closes with a brief discussion of a few of the outstanding challenges facing the field of systematic coarse-graining. PMID- 23034762 TI - The Martini coarse-grained force field. AB - The Martini force field is a coarse-grained force field suited for molecular dynamics simulations of biomolecular systems. The force field has been parameterized in a systematic way, based on the reproduction of partitioning free energies between polar and apolar phases of a large number of chemical compounds. In this chapter the methodology underlying the force field is presented together with details of its parameterization and limitations. Then currently available topologies are described with a short overview of the key elements of their parameterization. These include the new polarizable Martini water model. A set of three selected ongoing studies using the Martini force field is presented. Finally the latest lines of development are discussed. PMID- 23034763 TI - Multiscale molecular modeling. AB - We review the basic theoretical principles of the adaptive resolution simulation scheme (AdResS). This method allows to change molecular resolution on-the-fly during a simulation by changing the number of degrees of freedom in specific regions of space where the required resolution is higher than in the rest of the system. We also report about recent extensions of the method to the continuum and quantum regimes. PMID- 23034764 TI - Coarse-grained models for protein folding and aggregation. AB - Coarse-grained models for protein folding and aggregation are used to explore large dimension scales and timescales that are inaccessible to all-atom models in explicit aqueous solution. Combined with enhanced configuration search methods, these simplified models with various levels of granularity offer the possibility to determine equilibrium structures, compare folding kinetics and thermodynamics with experiments for single proteins and understand the dynamic assembly of amyloid proteins leading to neurodegenerative diseases. I shall describe recent progress in developing such models, and discuss their potentials and limitations in probing the folding and misfolding of proteins with computer simulations. PMID- 23034765 TI - Elastic network models: theoretical and empirical foundations. AB - Fifteen years ago, Monique Tirion showed that the low-frequency normal modes of a protein are not significantly altered when nonbonded interactions are replaced by Hookean springs, for all atom pairs whose distance is smaller than a given cutoff value. Since then, it has been shown that coarse-grained versions of Tirion's model are able to provide fair insights on many dynamical properties of biological macromolecules. In this chapter, theoretical tools required for studying these so-called Elastic Network Models are described, focusing on practical issues and, in particular, on possible artifacts. Then, an overview of some typical results that have been obtained by studying such models is given. PMID- 23034766 TI - An introduction to dissipative particle dynamics. AB - Dissipative particle dynamics (DPD) is a particle-based mesoscopic simulation method, which facilitates the studies of thermodynamic and dynamic properties of soft matter systems at physically interesting length and time scales. In this method, molecule groups are clustered into the dissipative beads, and this coarse graining procedure is a very important aspect of DPD as it allows significant computational speed-up. In this chapter, we introduce the DPD methodology, including its theoretical foundation and its parameterization. With this simulation technique, we can study complex behaviors of biological systems, such as the formation of vesicles and their fusion and fission processes, and the phase behavior of lipid membranes. PMID- 23034767 TI - Multiscale molecular dynamics simulations of membrane proteins. AB - The time and length scales accessible by biomolecular simulations continue to increase. This is in part due to improvements in algorithms and computing performance, but is also the result of the emergence of coarse-grained (CG) potentials, which complement and extend the information obtainable from fully detailed models. CG methods have already proven successful for a range of applications that benefit from the ability to rapidly simulate spontaneous self assembly within a lipid membrane environment, including the insertion and/or oligomerization of a range of "toy models," transmembrane peptides, and single- and multi-domain proteins. While these simplified approaches sacrifice atomistic level detail, it is now straightforward to "reverse map" from CG to atomistic descriptions, providing a strategy to assemble membrane proteins within a lipid environment, prior to all-atom simulation. Moreover, recent developments have been made in "dual resolution" techniques, allowing different molecules in the system to be modeled with atomistic or CG resolution simultaneously. PMID- 23034768 TI - Vesicles and vesicle fusion: coarse-grained simulations. AB - Biological cells are highly dynamic, and continually move material around their own volume and between their interior and exterior. Much of this transport encapsulates the material inside phospholipid vesicles that shuttle to and from, fusing with, and budding from, other membranes. A feature of vesicles that is crucial for this transport is their ability to fuse to target membranes and release their contents to the distal side. In industry, some personal care products contain vesicles to help transport reagents across the skin, and research on drug formulation shows that packaging active compounds inside vesicles delays their clearance from the blood stream. In this chapter, we survey the biological role and physicochemical properties of phospholipids, and describe progress in coarse-grained simulations of vesicles and vesicle fusion. Because coarse-grained simulations retain only those molecular details that are thought to influence the large-scale processes of interest, they act as a model embodying our current understanding. Comparing the predictions of these models with experiments reveals the importance of the retained microscopic details and also the deficiencies that can suggest missing details, thereby furthering our understanding of the complex dynamic world of vesicles. PMID- 23034769 TI - Regression patterns in treated retinoblastoma with chemotherapy plus focal adjuvant therapy. AB - PURPOSE: The aim of this study was evaluation of the regression patterns after 3, 6, and 8 months of treatment. METHODS: A total of 100 retinoblastoma tumors (57 eyes of 35 patients) were treated with 6 (n = 8) or 8 (n = 92) cycles of systemic chemoreduction and tumor consolidation (transpupillary thermotherapy [TTT] or cryotherapy) during this prospective study. RESULTS: After 3 months of treatment, type 3 was the predominant pattern (n = 57%, 57%), while after 6 and 8 months of treatment the tumors regressed to type 4 most often (44% and 52%, respectively). Smaller tumors and the peripheral tumors were likely to regress to type 4, whereas larger tumors and those nearer to fovea were more likely to become type 1 pattern. Tumors consolidated with cryotherapy mostly showed type 4 regression (3rd month: 40%, 6th month: 90%, and 8th month: 87.5%). Whereas, those treated with TTT rather regressed to type 3 after 3 months (57.9%) and to type 4 after 6 and 8 months of treatment (51.4% and 59.5%, respectively). Recurrence of the tumor was 40% in our cases with defined correlation with tumor location, size, and subretinal seeds. CONCLUSION: We conclude that regression patterns of tumors in patients undergoing systemic chemoreduction with focal adjuvant treatments predominantly changed over time and their changes are dependent on tumor size, location, and type of treatment. It appears that subretinal seeds, tumor size, and location of tumors are the most important factors predicting tumor recurrence. PMID- 23034770 TI - Comparison between splines and fractional polynomials for multivariable model building with continuous covariates: a simulation study with continuous response. AB - In observational studies, many continuous or categorical covariates may be related to an outcome. Various spline-based procedures or the multivariable fractional polynomial (MFP) procedure can be used to identify important variables and functional forms for continuous covariates. This is the main aim of an explanatory model, as opposed to a model only for prediction. The type of analysis often guides the complexity of the final model. Spline-based procedures and MFP have tuning parameters for choosing the required complexity. To compare model selection approaches, we perform a simulation study in the linear regression context based on a data structure intended to reflect realistic biomedical data. We vary the sample size, variance explained and complexity parameters for model selection. We consider 15 variables. A sample size of 200 (1000) and R(2) = 0.2 (0.8) is the scenario with the smallest (largest) amount of information. For assessing performance, we consider prediction error, correct and incorrect inclusion of covariates, qualitative measures for judging selected functional forms and further novel criteria. From limited information, a suitable explanatory model cannot be obtained. Prediction performance from all types of models is similar. With a medium amount of information, MFP performs better than splines on several criteria. MFP better recovers simpler functions, whereas splines better recover more complex functions. For a large amount of information and no local structure, MFP and the spline procedures often select similar explanatory models. PMID- 23034772 TI - Prediction and control of number of cells in microdroplets by stochastic modeling. AB - Manipulation and encapsulation of cells in microdroplets has found many applications in various fields such as clinical diagnostics, pharmaceutical research, and regenerative medicine. The control over the number of cells in individual droplets is important especially for microfluidic and bioprinting applications. There is a growing need for modeling approaches that enable control over a number of cells within individual droplets. In this study, we developed statistical models based on negative binomial regression to determine the dependence of number of cells per droplet on three main factors: cell concentration in the ejection fluid, droplet size, and cell size. These models were based on experimental data obtained by using a microdroplet generator, where the presented statistical models estimated the number of cells encapsulated in droplets. We also propose a stochastic model for the total volume of cells per droplet. The statistical and stochastic models introduced in this study are adaptable to various cell types and cell encapsulation technologies such as microfluidic and acoustic methods that require reliable control over number of cells per droplet provided that settings and interaction of the variables is similar. PMID- 23034773 TI - Unbiased estimates of long-term net survival of hematological malignancy patients detailed by major subtypes in France. AB - Long-term population-based survival data detailed by cancer subtype are important to measure the overall outcomes of malignancy managements. We provide net survival estimates at 1, 3, 5 and 10-year postdiagnosis on 37,549 hematological malignancy (HM) patients whose ages were >15 years, diagnosed between 1989 and 2004 and actively followed until 2008 by French population-based cancer registries. These are, to our knowledge, the first unbiased estimates of 10-year net survival in HMs detailed by subtypes. HMs were classified according to the International Classification of Diseases-Oncology 3. Net survival was estimated with the unbiased Pohar-Perme method. The results are reported by sex and age classes. The changes of these indicators by periods of diagnosis were tabulated and the trends of the net mortality rates over time since diagnosis graphed. In all, 5- and 10-year age-standardized net survivals after HMs varied widely from 81 and 76% for classical Hodgkin lymphoma (CHL) to 18 and 14% for acute myeloid leukemia (AML). Even in HMs with the most favorable prognoses, the net survival decreased between 5- and 10-year postdiagnosis. Women had better prognoses than men and age at diagnosis was an unfavorable prognostic factor for most HMs. In patients <55 years old, the net mortality rate decreased to null values 5-year postdiagnosis in AML and 10-year postdiagnosis in CHL, precursor non-HL, chronic myelogenous leukemia, diffuse large B-cell lymphoma and follicular lymphoma. The prognoses improved for various HMs over the study period. The obtained unbiased indicators are important to evaluate national cancer plans. PMID- 23034771 TI - Dynamic coding of dorsal hippocampal neurons between tasks that differ in structure and memory demand. AB - Hippocampal place fields show remapping between environments that contain sufficiently different contextual features, a phenomenon that may reflect a mechanism for episodic memory formation. Previous studies have shown that place fields remap to changes in the configuration of visual landmarks in an environment. Other experiments have demonstrated that remapping can occur with experience, even when the visual features of an environment remain stable. A special case of remapping may be trajectory coding, the tendency for hippocampal neurons to exhibit different firing rates depending upon recently visited or upcoming spatial locations. To further delineate the conditions under which different task features elicit remapping, we recorded from place cells in dorsal CA1 of hippocampus while rats switched between tasks that differed in memory demand and task structure; continuous spatial alternation (CA), delayed spatial alternation (DA), and tactile-visual conditional discrimination (CD). Individual hippocampal neurons and populations of simultaneously recorded neurons showed coherent remapping between CA and CD. However, task remapping was rarely seen between DA and CD. Analysis of individual units revealed that even though the population retained a coherent representation of task structure across the DA and CD tasks, the majority of individual neurons consistently remapped at some point during recording sessions. In contrast with previous studies, trajectory coding on the stem of the T-maze was virtually absent during all of the tasks, suggesting that experience with multiple tasks in the same environment reduces the likelihood that hippocampal neurons will represent distinct trajectories. Trajectory coding was, however, observed during the delay period of DA. Whether place fields change in response to task or trial type or remain stable within the same environment may depend on which aspects of the context are most salient or relevant to behavior. PMID- 23034774 TI - The impact of incarceration on women's mental health: responses from women in a maximum-security prison. AB - Many women enter prison with significant mental health conditions. Without appropriate intervention during incarceration, there is the potential for these conditions to worsen during confinement. As a result, women, most of whom will eventually be released from prison, might return to their families and communities with even more complex mental health needs. We examined women's perceptions of how incarceration had affected their mental health. Our study approach included descriptive surveys and focus groups with women in prison. Our analysis revealed that women's mental health might worsen, might improve, or might remain the same as a result of incarceration. Women's accounts also provide evidence to support the need for all women's correctional institutions to adopt a trauma-informed approach to care of this vulnerable population. PMID- 23034775 TI - Research ethics in accessing hospital staff and securing informed consent. AB - Qualitative researchers cannot rely on research ethics to be a static practice. In this article we discuss how observation of guidelines for inquiry and international agreements on the dignity of health care research are not sufficient on their own to ensure that the challenges inherent in the everyday management of a project are regulated. We focus in particular on ethics in accessing participants and the construction of informed consent. During our study, important contrasts emerged between the ideal presented for the standard ethics review process and practical ethics. As a result, we focused on building open communication with the participants through rigorous project management. We analyzed the data and wrote this article collaboratively to represent the empirical reality of a team of researchers aiming to take ethical challenges seriously while collecting data in three National Health Service Trusts in the United Kingdom. PMID- 23034776 TI - Complex posttraumatic stress disorder: voices of healing. AB - In this article, we report on a phenomenological study of experiences of recovery of 7 women with histories of childhood maltreatment. We propose a model that recalls the Anglo-Franc etymological origins of rekeverer: to regain consciousness, health, or strength. Dimensions include development of a selfhood; tasks of connection and separation; regulation of overwhelming emotions; management of choices; and internalization of therapeutic relational dynamics. Based on the findings, we suggest that theory and research need to extend concepts of healing, add methodologies privileging victim/survivor voices, and revisit concepts such as neutrality and resistance as they apply to dissociative disorders. Practitioners should have specific training in trauma models, although they need to hold these theories lightly because therapeutic goals and pathways of change might well differ for each client. Integrated whole-of-government initiatives need to identify those at risk of abuse as early as possible, and provide response funding beyond assessment services. PMID- 23034777 TI - What do psychotic experiences mean to Chinese schizophrenia patients? AB - In this study we explored the perceptions of Chinese patients with schizophrenia about their treatment, mental state, social relationships, and daily life throughout the psychotic episodes. A purposive sample of 16 schizophrenia patients with heterogeneous demographic backgrounds was recruited. We collected data through face-to-face semistructured interviews. We conducted a qualitative data analysis and identified three central themes inductively: (a) negative experiences, (b) sense of powerlessness, and (c) ambivalent therapeutic relationship. Several subthemes were derived under each central theme. The participants' narratives revealed a complex picture of disadvantage and difficulties throughout their psychotic episodes and rehabilitation processes. The themes identified are explored in detail, and their links with existing research and potential clinical implications are considered. PMID- 23034778 TI - Dancing around death: hospitalist-patient communication about serious illness. AB - Hospital physicians care for most seriously ill patients in the United States. We employed dimensional analysis to describe communication about death and dying in audio-recorded admission encounters between seriously ill patients and hospitalists. Acknowledging or not acknowledging the possibility of dying emerged as a key process. Acknowledgment was rare, and depended on synergistic communication behaviors between patient and physician. Facilitators included patients cuing for information and disclosing emotional distress, and physicians exploring the patient's understanding of his or her illness and emotional distress. When hospitalists focused on acute issues, stated that they were awaiting test results, and deferred to other physicians, discussion moved away from acknowledgment. Meaningful discussion of end-of-life issues, including goals and values, fears about death and dying, prognosis, and options for palliative care followed open acknowledgment. This acknowledgment process can serve as a guide for providers to sensitively and honestly discuss essential end-of-life issues. PMID- 23034779 TI - Modifying the diary interview method to research the lives of people with dementia. AB - Debates about involving people with dementia in qualitative research are extensive, yet the range of methods used is limited. Researchers tend to rely on interview and/or observation methods to collect data, even though these tools might preclude participation. I modified the conventional diary interview method to include photo and audio diaries in an effort to investigate the lives of people with dementia in a participatory way. Sixteen people with dementia kept a diary-written, photo, or audio, whichever suited them best-for 1 month. The purposes of this article are to share the methodological insights gained from this process in the context of emerging literature on sensory ethnography, and to argue for the broader application of the diary interview method in dementia related research, on the grounds that it mediates an equal relationship and makes visible the "whole person," including the environment in which that person lives. PMID- 23034780 TI - Undetected sex chromosome aneuploidy by chromosomal microarray. AB - We report on a case of a female fetus found to be mosaic for Turner syndrome (45,X) and trisomy X (47,XXX). Chromosomal microarray analysis (CMA) failed to detect the aneuploidy because of a normal average dosage of the X chromosome. This case represents an unusual instance in which CMA may not detect chromosomal aberrations. Such a possibility should be taken into consideration in similar cases where CMA is used in a clinical setting. PMID- 23034781 TI - A template-based automatic skull-stripping approach for mouse brain MR microscopy. AB - Small animal magnetic resonance microscopy (MRM) has been widely used today in computational neuroanatomy. Accurate identification of brain tissue in a mouse MRM is a critical fundamental step in neuroimaging processing, which is given less attention. This study presents an automatic skull-stripping technique based on template models and histogram analysis. Results were evaluated by calculating the Jaccard similarity index (JSI) and boundary concordance ratio (BCR) between the automatically segmented and manually traced brain volumes. Results demonstrate that this technique accurately extracts the brain volume (mean JSI = 97.1%, BC = 94.4%). The brain extraction method presented in this study will greatly facilitate analysis of neuroimaging studies of rodent animals in neurodegenerative diseases. PMID- 23034782 TI - An observational study of the initial management of hypothyroidism in France: the ORCHIDEE study. AB - OBJECTIVE: To document the initial management of hypothyroidism in France with respect to diagnostic setting, investigations, and therapeutic approach. DESIGN: Observational study of the management by primary care practitioners (PCPs) and endocrinologists of patients diagnosed with, and treated for, hypothyroidism during the enrollment period or the previous 6 months. METHODS: A representative sample of PCPs and endocrinologists enrolled up to five consecutive patients and reported sociodemographic, clinical, therapeutic, and laboratory data. Data were submitted at baseline and at the first measurement of TSH after starting the treatment. RESULTS: The analysis population comprised 1255 patients (mean (s.d.) age 52.8 (16.3) years; 84% female). Hypothyroidism was suspected on clinical grounds in 77% of patients, with goiter in 16%. Autoimmune thyroiditis, supported by positive anti-thyroid antibodies, was the most frequent diagnosis (59%), followed by iatrogenic causes (28%), of which thyroidectomy was the most common. The median baseline TSH was 8.6 mIU/l, suggesting a high incidence of subclinical hypothyroidism. Imaging studies were requested in over 75% of patients, with ultrasound performed in 98% and scintigraphy performed in 19% of these patients. Both groups of physicians treated their patients almost exclusively with levothyroxine. Endocrinologists were more likely than PCPs to provide counseling on how to take medication correctly. CONCLUSIONS: This observational study of a large cohort of patients with newly diagnosed hypothyroidism in France illustrates current practice and indicates some areas where physician education may be required to optimize adherence to guidelines and cost-effectiveness. PMID- 23034783 TI - Assessment of glucocorticoid therapy with salivary cortisol in secondary adrenal insufficiency. AB - CONTEXT: Appropriate glucocorticoid replacement therapy in adrenal insufficiency (AI) is crucial, given the risks of chronic under- or overtreatment, particularly in patients on multiple medications. Salivary sampling allows for non-invasive, stress-free cortisol measurement. OBJECTIVE: To determine whether salivary cortisol measurement is helpful in assessing the adequacy of glucocorticoid therapy with cortisone acetate (CA) in patients with secondary AI. DESIGN: A prospective cohort study at the Endocrinology Unit of Padua University Hospital. METHODS: Six samples of salivary cortisol were collected from 28 patients with secondary AI on CA treatment and from 36 healthy volunteers at fixed times of the day, and used to calculate salivary cortisol levels at each time point and the area under the curve (AUC) across the different sampling times. RESULTS: Salivary cortisol levels were lower in patients than in controls in the morning but no differences were found in the afternoon or at night before resting. Salivary cortisol levels were higher in patients immediately following CA administration. Ten patients showed an AUC above the 97.5th percentile of controls, without clinical signs of hypercortisolism, and salivary cortisol levels 90 min after each dose of CA predict the AUC. All patients had severe GH deficiency and there were no differences in salivary cortisol levels or AUC between patients treated or not with GH. CONCLUSIONS: Two salivary cortisol determinations, able to predict the daily AUC, may allow for assessing the adequacy of glucocorticoid replacement therapy in secondary AI and for identifying cases of over- or undertreatment. PMID- 23034785 TI - Safety critical work, ageing and cognitive decline. PMID- 23034786 TI - John Gilroy: Unloading in the Malt Store Guinness Brewery 1951. PMID- 23034787 TI - Non-cancer occupational health risks in firefighters. AB - BACKGROUND: Firefighters are exposed to a number of different workplace hazards. As a result of this and the perception of increased ill-health symptoms, a systematic review was carried out to identify significant associations. AIMS: To carry out a systematic review of evidence relating to non-cancer occupational health risks in firefighters. METHODS: Systematic literature searches were conducted using a predetermined search strategy that encompassed terms describing the population of interest and health outcomes. Titles and abstracts identified were subjected to an initial screening process using specified guidelines. Included papers were reviewed and data extracted. Additional material, in the form of papers cited by those selected for review, was also obtained and, where relevant, added to the review. Extracted data were then collated into evidence tables to support the narrative review. RESULTS: Relatively few papers were identified that addressed forms of ill-health in firefighters other than cancer. Nine papers were considered covering each of coronary heart disease and respiratory health. Other ill-health outcomes studied were hearing loss (five studies); hip osteoarthritis (two studies); and sarcoidosis (two studies). None of these sets of papers provided conclusive evidence of a consistent relationship between the specified disease outcomes and the occupation as a firefighter; although, in some instances (hearing loss, respiratory health, and hip and knee osteoarthritis), there were limited indications of some effect. CONCLUSIONS: None of the sets of papers reviewed showed any consistent association between the occupation of firefighter and any of a number of non-cancer disease and ill health outcomes. PMID- 23034788 TI - The oldest sick note. PMID- 23034789 TI - Why I became an occupational physician... PMID- 23034790 TI - Risk assessments: good and bad. PMID- 23034792 TI - Mortality from asbestosis and mesothelioma in Britain by birth cohort. AB - BACKGROUND: Analysis of occupational mortality in England and Wales during 1991 2000 showed no decline in work-attributable deaths from asbestosis. AIMS: To explore why there was no decline in mortality from asbestosis despite stricter controls on asbestos exposure over recent decades. METHODS: Using data from registers of all deaths in Great Britain with mention of mesothelioma or asbestosis on the death certificate, we plotted death rates by 5 year age group within 5 year birth cohorts for(a) mesothelioma and (b) asbestosis without mention of mesothelioma. RESULTS: Analysis was based on a total of 33,751 deaths from mesothelioma and 5396 deaths from asbestosis. For both diseases, mortality showed a clear cohort effect; within birth cohorts, death rates increased progressively with age through to 85 years and older. However, highest mortality from mesothelioma was in men born during 1939-43, whereas, mortality from asbestosis peaked in men born during 1924-38. CONCLUSIONS: Our findings suggest that mortality, in Britain, from asbestosis has been determined mainly by cumulative exposure to asbestos before 45 years of age and that the effect of such exposure continues through to old age. That mortality from asbestosis peaked in earlier birth cohorts than mortality from mesothelioma may reflect a difference in exposure-response relationships for the two diseases. The discrepancy could be explained if risk of asbestosis increased more steeply than that of mesothelioma at higher levels of exposure to asbestos and if the highest prevalence of heavy exposure occurred in earlier birth cohorts than the highest prevalence of less intense exposures. PMID- 23034794 TI - Re: Substance misuse among health care workers: national survey of occupational physicians. PMID- 23034795 TI - Keeping folk in work for longer. PMID- 23034796 TI - 64-slice coronary computed tomography angiography using low tube voltage of 80 kV in subjects with normal body mass indices: comparative study using 120 kV. AB - BACKGROUND: The radiation dose of coronary computed tomography (CT) angiography (CCTA) is generally higher than that of CT scans of other parts of the body, and there is concern that the high radiation dose may result in increased cancer risk. Although various techniques have recently been introduced to lower the radiation dose of CCTA, there has been no direct comparison between protocols with 80 and 120 kV. PURPOSE: To assess the image quality and radiation dose of 80 kV electrocardiography (ECG)-gated CCTA in subjects with a normal body mass index (BMI), compared to 120-kV ECG-gated CCTA. MATERIAL AND METHODS: This retrospective study was approved by our local ethics board, and the requirement of written informed consent was waived. We analyzed the CCTA images of 100 subjects with BMIs <25 kg/m(2). Fifty subjects underwent 120-kV CCTA, and the other 50 subjects underwent 80-kV CCTA. Two blinded observers independently evaluated the subjective image quality of the coronary arteries. The objective image quality (signal-to-noise ratio [SNR] and contrast-to-noise ratio [CNR]) and radiation dose were also measured in each group. RESULTS: Although the objective image quality of the 80-kV protocol images was significantly poorer than that of 120-kV protocol images (mean SNR, 14.9 +/- 4.7 vs. 19.8 +/- 4.4, P < 0.0001; mean CNR, 15.2 +/- 4.8 vs. 21.6 +/- 4.7, P < 0.0001), there was no significant difference in the subjective image quality between the two groups (mean image score, 4.7 +/- 1.1 vs. 4.5 +/- 0.7 for radiologist 1, P = 0.273; 5.0 +/- 1.0 vs. 4.8 +/- 1.0 for radiologist 2, P = 0.197). The radiation dose was reduced by 70% with the 80-kV protocol and by 88% with the 80-kV and ECG-based tube current modulation than with the 120-kV protocol (3.42 +/- 1.16 and 2.9 +/- 0.8 vs. 11.49 +/- 3.62 mSv, P < 0.0001). CONCLUSION: The low tube voltage CCTA protocol using 80 kV allows significant reduction of the radiation dose without impairing the subjective image quality in subjects with normal BMIs. PMID- 23034797 TI - Cefotaxime-eluting covered self-expandable stents in a canine biliary model: scanning electron microscopic study of biofilm formation. AB - BACKGROUND: As bacterial attachment and subsequent biofilm formation on the surface of a stent lumen may be important in initiating sludge formation and subsequent stent blockage, there is a need for antibiotic-eluting stents to prevent sludge formation by bacterial attachment and colonization. PURPOSE: To evaluate the antimicrobial effects of cefotaxime-eluting covered self-expandable stents (CE-CSEMS) in a canine biliary model by using scanning electron microscopy (SEM) to analyze biofilm formation on the inner surface of the stents. MATERIAL AND METHODS: Three 10% (wt/vol) CE-CSEMS, three 20% (wt/vol) CE-CSEMS, and three control stents (CS) were endoscopically inserted into the bile ducts of nine mongrel dogs, which were followed up for 8 weeks. Gross and SEM examinations were performed to access the development and degree of biofilm formation in dogs with CS and CE-CSEMS. RESULTS: All stents were successfully inserted into canine bile ducts without any procedure-related complications. All nine dogs remained in good health without jaundice over the next 8 weeks. The degree of biofilm was similar in dogs implanted with CS and CE-CSEMS using two concentrations of cefotaxime either by gross inspection or SEM. All stent types showed a similar biofilm structure with relatively uniform thickness on SEM. CONCLUSION: Cefotaxime does not prevent biofilm development in a canine biliary model. Biofilm formation on the inner surface of biliary stents may be prevented by using broad-spectrum antimicrobial agents and stents that maintain a steady release of these agents for a long time, thus prolonging stent patency. PMID- 23034798 TI - Ift88 regulates Hedgehog signaling, Sfrp5 expression, and beta-catenin activity in post-natal growth plate. AB - Primary cilia are present on most cell types including chondrocytes. Dysfunction of primary cilia results in pleiotropic symptoms including skeletal dysplasia. Previously, we showed that deletion of Ift88 and subsequent depletion of primary cilia from chondrocytes resulted in disorganized columnar structure and early loss of growth plate. To understand underlying mechanisms whereby Ift88 regulates growth plate function, we compared gene expression profiles in normal and Ift88 deleted growth plates. Pathway analysis indicated that Hedgehog (Hh) signaling was the most affected pathway in mutant growth plate. Expression of the Wnt antagonist, Sfrp5, was also down-regulated. In addition, Sfrp5 was up-regulated by Shh in rib chondrocytes and regulation of Sfrp5 by Shh was attenuated in mutant cells. This result suggests Sfrp5 is a downstream target of Hh and that Ift88 regulates its expression. Sfrp5 is an extracellular antagonist of Wnt signaling. We observed an increase in Wnt/beta-catenin signaling specifically in flat columnar cells of the growth plate in Ift88 mutant mice as measured by increased expression of Axin2 and Lef1 as well as increased nuclear localization of beta-catenin. We propose that Ift88 and primary cilia regulate expression of Sfrp5 and Wnt signaling pathways in growth plate via regulation of Ihh signaling. PMID- 23034799 TI - Laser synthesized super-hydrophobic conducting carbon with broccoli-type morphology as a counter-electrode for dye sensitized solar cells. AB - A laser photochemical process is introduced to realize superhydrophobic conducting carbon coatings with broccoli-type hierarchical morphology for use as a metal-free counter electrode in a dye sensitized solar cell. The process involves pulsed excimer laser irradiation of a thin layer of liquid haloaromatic organic solvent o-dichlorobenzene (DCB). The coating reflects a carbon nanoparticle-self assembled and process-controlled morphology that yields solar to electric power conversion efficiency of 5.1% as opposed to 6.2% obtained with the conventional Pt-based electrode. PMID- 23034800 TI - Human herpesvirus 6-associated encephalopathy in a child with Dravet syndrome. AB - Dravet syndrome presents with generalized and unilateral clonic or clonic-tonic seizures that occur during the first year of life, followed by severe epilepsy. Prolonged seizures are often provoked by fever and usually followed by recovery of the previous condition. We describe the case of a 13-month-old girl with Dravet syndrome who experienced severe neurological sequelae as a result of human herpesvirus 6-associated encephalopathy. Biphasic clinical course was observed, with fever and prolonged seizures at onset and late seizures refractory against antiepileptic agents. Serum concentrations of proinflammatory cytokines and matrix metalloproteinase-9, which have been associated with development of acute encephalopathy, were not markedly increased in this patient, suggesting that these molecules were not the main causes of neuronal damage in this patient. Instead, seizure susceptibility due to SCN1A mutation may have contributed to acute encephalopathy in our patient. PMID- 23034801 TI - SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response. AB - Survival time-associated plant homeodomain (PHD) finger protein in Ovarian Cancer 1 (SPOC1, also known as PHF13) is known to modulate chromatin structure and is essential for testicular stem-cell differentiation. Here we show that SPOC1 is recruited to DNA double-strand breaks (DSBs) in an ATM-dependent manner. Moreover, SPOC1 localizes at endogenous repair foci, including OPT domains and accumulates at large DSB repair foci characteristic for delayed repair at heterochromatic sites. SPOC1 depletion enhances the kinetics of ionizing radiation-induced foci (IRIF) formation after gamma-irradiation (gamma-IR), non homologous end-joining (NHEJ) repair activity, and cellular radioresistance, but impairs homologous recombination (HR) repair. Conversely, SPOC1 overexpression delays IRIF formation and gammaH2AX expansion, reduces NHEJ repair activity and enhances cellular radiosensitivity. SPOC1 mediates dose-dependent changes in chromatin association of DNA compaction factors KAP-1, HP1-alpha and H3K9 methyltransferases (KMT) GLP, G9A and SETDB1. In addition, SPOC1 interacts with KAP-1 and H3K9 KMTs, inhibits KAP-1 phosphorylation and enhances H3K9 trimethylation. These findings provide the first evidence for a function of SPOC1 in DNA damage response (DDR) and repair. SPOC1 acts as a modulator of repair kinetics and choice of pathways. This involves its dose-dependent effects on DNA damage sensors, repair mediators and key regulators of chromatin structure. PMID- 23034802 TI - MiRmap: comprehensive prediction of microRNA target repression strength. AB - MicroRNAs, or miRNAs, post-transcriptionally repress the expression of protein coding genes. The human genome encodes over 1000 miRNA genes that collectively target the majority of messenger RNAs (mRNAs). Base pairing of the so-called miRNA 'seed' region with mRNAs identifies many thousands of putative targets. Evaluating the strength of the resulting mRNA repression remains challenging, but is essential for a biologically informative ranking of potential miRNA targets. To address these challenges, predictors may use thermodynamic, evolutionary, probabilistic or sequence-based features. We developed an open-source software library, miRmap, which for the first time comprehensively covers all four approaches using 11 predictor features, 3 of which are novel. This allowed us to examine feature correlations and to compare their predictive power in an unbiased way using high-throughput experimental data from immunopurification, transcriptomics, proteomics and polysome fractionation experiments. Overall, target site accessibility appears to be the most predictive feature. Our novel feature based on PhyloP, which evaluates the significance of negative selection, is the best performing predictor in the evolutionary category. We combined all the features into an integrated model that almost doubles the predictive power of TargetScan. miRmap is freely available from http://cegg.unige.ch/mirmap. PMID- 23034803 TI - The C-terminus of Dpb2 is required for interaction with Pol2 and for cell viability. AB - DNA polymerase epsilon (Pol epsilon) participates in the synthesis of the leading strand during DNA replication in Saccharomyces cerevisiae. Pol epsilon comprises four subunits: the catalytic subunit, Pol2, and three accessory subunits, Dpb2, Dpb3 and Dpb4. DPB2 is an essential gene with unclear function. A genetic screen was performed in S. cerevisiae to isolate lethal mutations in DPB2. The dpb2-200 allele carried two mutations within the last 13 codons of the open reading frame, one of which resulted in a six amino acid truncation. This truncated Dpb2 subunit was co-expressed with Pol2, Dpb3 and Dpb4 in S. cerevisiae, but this Dpb2 variant did not co-purify with the other Pol epsilon subunits. This resulted in the purification of a Pol2/Dpb3/Dpb4 complex that possessed high specific activity and high processivity and holoenzyme assays with PCNA, RFC and RPA on a single primed circular template did not reveal any defects in replication efficiency. In conclusion, the lack of Dpb2 did not appear to have a negative effect on Pol epsilon activity. Thus, the C-terminal motif of Dpb2 that we have identified may instead be required for Dpb2 to fulfill an essential structural role at the replication origin or at the replication fork. PMID- 23034804 TI - Demethylation initiated by ROS1 glycosylase involves random sliding along DNA. AB - Active DNA demethylation processes play a critical role in shaping methylation patterns, yet our understanding of the mechanisms involved is still fragmented and incomplete. REPRESSOR OF SILENCING 1 (ROS1) is a prototype member of a family of plant 5-methylcytosine DNA glycosylases that initiate active DNA demethylation through a base excision repair pathway. As ROS1 binds DNA non-specifically, we have critically tested the hypothesis that facilitated diffusion along DNA may contribute to target location by the enzyme. We have found that dissociation of ROS1 from DNA is severely restricted when access to both ends is obstructed by tetraloops obstacles. Unblocking any end facilitates protein dissociation, suggesting that random surface sliding is the main route to a specific target site. We also found that removal of the basic N-terminal domain of ROS1 significantly impairs the sliding capacity of the protein. Finally, we show that sliding increases the catalytic efficiency of ROS1 on 5-meC:G pairs, but not on T:G mispairs, thus suggesting that the enzyme achieves recognition and excision of its two substrate bases by different means. A model is proposed to explain how ROS1 finds its potential targets on DNA. PMID- 23034805 TI - A SUMO-interacting motif activates budding yeast ubiquitin ligase Rad18 towards SUMO-modified PCNA. AB - SUMO-targeted ubiquitin ligases (STUbLs) recognize sumoylated proteins as substrates for ubiquitylation and have been implicated in several aspects of DNA repair and the damage response. However, few physiological STUbL substrates have been identified, and the relative importance of SUMO binding versus direct interactions with the substrate remains a matter of debate. We now present evidence that the ubiquitin ligase Rad18 from Saccharomyces cerevisiae, which monoubiquitylates the sliding clamp protein proliferating cell nuclear antigen (PCNA) in response to DNA damage, exhibits the hallmarks of a STUbL. Although not completely dependent on sumoylation, Rad18's activity towards PCNA is strongly enhanced by the presence of SUMO on the clamp. The stimulation is brought about by a SUMO-interacting motif in Rad18, which also mediates sumoylation of Rad18 itself. Our results imply that sumoylated PCNA is the physiological ubiquitylation target of budding yeast Rad18 and suggest a new mechanism by which the transition from S phase-associated sumoylation to damage-induced ubiquitylation of PCNA is accomplished. PMID- 23034806 TI - The methylomes of six bacteria. AB - Six bacterial genomes, Geobacter metallireducens GS-15, Chromohalobacter salexigens, Vibrio breoganii 1C-10, Bacillus cereus ATCC 10987, Campylobacter jejuni subsp. jejuni 81-176 and C. jejuni NCTC 11168, all of which had previously been sequenced using other platforms were re-sequenced using single-molecule, real-time (SMRT) sequencing specifically to analyze their methylomes. In every case a number of new N(6)-methyladenine ((m6)A) and N(4)-methylcytosine ((m4)C) methylation patterns were discovered and the DNA methyltransferases (MTases) responsible for those methylation patterns were assigned. In 15 cases, it was possible to match MTase genes with MTase recognition sequences without further sub-cloning. Two Type I restriction systems required sub-cloning to differentiate their recognition sequences, while four MTase genes that were not expressed in the native organism were sub-cloned to test for viability and recognition sequences. Two of these proved active. No attempt was made to detect 5 methylcytosine ((m5)C) recognition motifs from the SMRT(r) sequencing data because this modification produces weaker signals using current methods. However, all predicted (m6)A and (m4)C MTases were detected unambiguously. This study shows that the addition of SMRT sequencing to traditional sequencing approaches gives a wealth of useful functional information about a genome showing not only which MTase genes are active but also revealing their recognition sequences. PMID- 23034807 TI - DNA-binding determinants promoting NHEJ by human PolMU. AB - Non-homologous end-joining (NHEJ), the preferred pathway to repair double-strand breaks (DSBs) in higher eukaryotes, relies on a collection of molecular tools to process the broken ends, including specific DNA polymerases. Among them, Polu is unique as it can catalyze DNA synthesis upon connection of two non-complementary ends. Here, we demonstrate that this capacity is intrinsic to Polu, not conferred by other NHEJ factors. To understand the molecular determinants of its specific function in NHEJ, the interaction of human Polu with DNA has been directly visualized by electromobility shift assay and footprinting assays. Stable interaction with a DNA gap requires the presence of a recessive 5'-P, thus orienting the catalytic domain for primer and nucleotide binding. Accordingly, recognition of the 5'-P is crucial to align the two DNA substrates of the NHEJ reaction. Site-directed mutagenesis demonstrates the relevance of three specific residues (Lys(249), Arg(253) and Arg(416)) in stabilizing the primer strand during end synapsis, allowing a range of microhomology-induced distortions beneficial for NHEJ. Moreover, our results suggest that the Polu BRCT domain, thought to be exclusively involved in interaction with NHEJ core factors, has a direct role in binding the DNA region neighbor to the 5'-P, thus boosting Polu mediated NHEJ reactions. PMID- 23034808 TI - SR1--a small RNA with two remarkably conserved functions. AB - SR1 is a dual-function sRNA that acts as a base-pairing regulatory RNA on the ahrC mRNA and as a peptide-encoding mRNA on the gapA operon. The SR1-encoded peptide SR1P binds GapA thereby stabilizing gapA mRNA. Under glycolytic conditions, SR1 transcription is repressed by CcpN and CcpA. A computer-based search identified 23 SR1 homologues in Bacillus, Geobacillus, Anoxybacillus and Brevibacillus species. All homologues share a high structural identity with Bacillus subtilis SR1, and the encoded SR1P peptides are highly similar. In the Bacillus cereus group, the sr1p region is present in triplicate or duplicate resulting in longer SR1 species. In all cases, sr1 expression is under control of CcpN, and transcriptional lacZ fusions of nine examined SR1 homologues were sensitive to glucose. Two homologues showed an additional glucose-independent repression by CcpN and an unknown factor. A total of 10 out of 11 tested SR1P homologues complemented a B. subtilis Deltasr1 strain in their ability to stabilize gapA mRNA, but only five of them bound GapA tightly. In vitro binding assays with six SR1/ahrC pairs suggest that-despite divergent primary sequences the base-pairing function is also preserved. In summary, SR1 is an sRNA with two functions that have been conserved over ~1 billion years. PMID- 23034809 TI - MsDetector: toward a standard computational tool for DNA microsatellites detection. AB - Microsatellites (MSs) are DNA regions consisting of repeated short motif(s). MSs are linked to several diseases and have important biomedical applications. Thus, researchers have developed several computational tools to detect MSs. However, the currently available tools require adjusting many parameters, or depend on a list of motifs or on a library of known MSs. Therefore, two laboratories analyzing the same sequence with the same computational tool may obtain different results due to the user-adjustable parameters. Recent studies have indicated the need for a standard computational tool for detecting MSs. To this end, we applied machine-learning algorithms to develop a tool called MsDetector. The system is based on a hidden Markov model and a general linear model. The user is not obligated to optimize the parameters of MsDetector. Neither a list of motifs nor a library of known MSs is required. MsDetector is memory- and time-efficient. We applied MsDetector to several species. MsDetector located the majority of MSs found by other widely used tools. In addition, MsDetector identified novel MSs. Furthermore, the system has a very low false-positive rate resulting in a precision of up to 99%. MsDetector is expected to produce consistent results across studies analyzing the same sequence. PMID- 23034810 TI - CAF-1-induced oligomerization of histones H3/H4 and mutually exclusive interactions with Asf1 guide H3/H4 transitions among histone chaperones and DNA. AB - Anti-silencing function 1 (Asf1) and Chromatin Assembly Factor 1 (CAF-1) chaperone histones H3/H4 during the assembly of nucleosomes on newly replicated DNA. To understand the mechanism of histone H3/H4 transfer among Asf1, CAF-1 and DNA from a thermodynamic perspective, we developed and employed biophysical approaches using full-length proteins in the budding yeast system. We find that the C-terminal tail of Asf1 enhances the interaction of Asf1 with CAF-1. Surprisingly, although H3/H4 also enhances the interaction of Asf1 with the CAF-1 subunit Cac2, H3/H4 forms a tight complex with CAF-1 exclusive of Asf1, with an affinity weaker than Asf1-H3/H4 or H3/H4-DNA interactions. Unlike Asf1, monomeric CAF-1 binds to multiple H3/H4 dimers, which ultimately promotes the formation of (H3/H4)(2) tetramers on DNA. Thus, transition of H3/H4 from the Asf1-associated dimer to the DNA-associated tetramer is promoted by CAF-1-induced H3/H4 oligomerization. PMID- 23034811 TI - Vacuum and mesh-mediated fascial traction for primary closure of the open abdomen in critically ill surgical patients. AB - BACKGROUND: Several temporary abdominal closure techniques have been used in the management of open abdomen. Failure to achieve delayed primary fascial closure results in a large ventral hernia. This retrospective analysis evaluated whether the use of vacuum-assisted closure and mesh-mediated fascial traction (VACM) as temporary abdominal closure improved the delayed primary fascial closure rate compared with non-traction methods. METHODS: Patients treated with an open abdomen between 2004 and 2010 were analysed. RESULTS: Among 50 patients treated with VACM and 54 using non-traction techniques (control group), the delayed primary fascial closure rate was 78 and 44 per cent respectively (P < 0.001); rates among those who survived to abdominal closure were 93 and 59 per cent respectively. Independent predictors of delayed primary fascial closure in multivariable logistic regression analysis were the use of VACM (odds ratio (OR) 4.43, 95 per cent confidence interval 1.64 to 11.99) and diagnosis other than peritonitis, severe acute pancreatitis or ruptured abdominal aortic aneurysm (OR 3.45, 1.07 to 11.04), which represented the main diagnoses. Prophylactic open abdomen was used to inhibit the development of intra-abdominal hypertension more frequently in the VACM group (28 versus 7 per cent; P = 0.008). Twelve per cent of patients in the VACM group developed an enteroatmospheric fistula compared with 19 per cent of control patients. Among survivors, three of 31 treated with VACM and 17 of 36 controls were left with a planned ventral hernia (P = 0.001). CONCLUSION: The indication for open abdomen contributed to the probability of delayed primary fascial closure. VACM resulted in a higher fascial closure rate and lower planned hernia rate than methods that did not provide fascial traction. PMID- 23034812 TI - Isotope effects in lithium hydride and lithium deuteride crystals by molecular dynamics simulations. AB - Molecular dynamics (MD) simulations have been carried out to study isotope effects in lithium hydride and lithium deuteride crystals. Quantum effects on nuclear motion have been included through a quantum thermal bath (QTB). The interatomic forces were described either within the density functional theory (DFT) in the generalized gradient approximation (GGA) or by the phenomenological approach using the shell model. For both models, the isotopic shift in the lattice parameter can be successfully predicted by QTB-MD simulations. The slope of the experimental isotopic shift in pressure is satisfactorily reproduced by QTB-MD within DFT-GGA, in contrast to both density functional perturbation theory and QTB-MD with the shell model. We have analyzed the reasons for these discrepancies through the vibrational densities of states and the isotopic shifts in bulk modulus. The results illustrate the importance of anharmonic contributions to vibrations and to the isotopic pressure shift between LiH and LiD. PMID- 23034813 TI - Influence of radiotherapy for the first tumor on aggressiveness of contralateral breast cancer. AB - We aimed to investigate if characteristics of contralateral breast cancer (CBC) are influenced by adjuvant radiotherapy for the first breast cancer. Using information from population-based registers and medical records, we analyzed two cohorts comprising all women with CBC diagnosed >3 months after their first cancer (809 patients in Stockholm 1976-2005 and 750 patients in South Sweden 1977 2005). We used Poisson regression to calculate risk of distant metastasis after CBC, comparing patients treated and not treated with radiotherapy for the first cancer. Logistic regression was used to estimate odds ratio (OR) of more aggressive tumor characteristics in the second cancer, compared to the first. For patients with CBC in Stockholm with <5 years between the cancers radiotherapy for the first cancer conferred a nearly doubled risk of distant metastasis [incidence rate ratio (IRR) = 1.91; 95% confidence interval (CI): 1.27-2.88], compared to those not treated with radiotherapy. This was replicated in the South Swedish cohort [IRR = 2.12 (95% CI: 1.40-3.23)]. In Stockholm, we found an increased odds that, following radiotherapy, a second cancer was of more advanced TNM-stage [OR 2.16 (95% CI 1.13-4.11)] and higher histological grade [OR = 2.00 (95% CI 1.08 3.72)] compared to the first, for patients with CBC with <5 years between the cancers. No effect on any of the investigated outcomes was seen for patients diagnosed with CBC >5 years from the first cancer. In conclusion, patients diagnosed with CBC within 5 years had worse prognosis and more aggressive tumor characteristics of the second cancer, if they had received radiotherapy for their first cancer, compared to no radiotherapy. PMID- 23034815 TI - Effects of treatment of the fat body trophocytes of Melipona quadrifasciata anthidioides nurse workers and virgin queens in culture by juvenile hormone III and ecdysterone (20-HE). AB - The fat body (FB) consists of two types of cells: throphocytes and oenocytes. Throphocytes are related to intermediary metabolism storing lipids, carbohydrates, and proteins while oenocytes play role in the lipids and lipoproteins production. The vitellogenin is the precursor of egg yolk (vitelline) and is synthesized on FB. The aim of this work was to analyze the effects of hormones acting in bee reproduction, as juvenile hormone (JH) and ecdisteroids (20 HE) on FB cells, where vitellogenin is synthesized. For the study were chose nurse workers that in Melipona quadrifasciata anthidioides present activated ovaries and produce eggs, and virgin queens whose ovaries are not yet activated, presenting only previtellogenic follicles. FB trophocytes from these classes of bees were cultivated in media containing different amounts of JH and 20-HE. The effects on trophocytes cytoplasm reserves of lipids, proteins, and activity of acid phosphatase were compared by observing preparations from cultured FB, treated and control, by transmission electron microscopy (TEM). The results showed that the hormones effects are related to the bee's caste and functional ovary stage. The role of acid phosphatase on mobilization of the trophocyte reserves was also determined. PMID- 23034814 TI - Overt cleft palate phenotype and TBX1 genotype correlations in velo-cardio facial/DiGeorge/22q11.2 deletion syndrome patients. AB - Velo-cardio-facial syndrome/DiGeorge syndrome, also known as 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome, with an estimated incidence of 1/2,000-1/4,000 live births. Approximately 9-11% of patients with this disorder have an overt cleft palate (CP), but the genetic factors responsible for CP in the 22q11DS subset are unknown. The TBX1 gene, a member of the T-box transcription factor gene family, lies within the 22q11.2 region that is hemizygous in patients with 22q11DS. Inactivation of one allele of Tbx1 in the mouse does not result in CP, but inactivation of both alleles does. Based on these data, we hypothesized that DNA variants in the remaining allele of TBX1 may confer risk to CP in patients with 22q11DS. To test the hypothesis, we evaluated TBX1 exon sequencing (n = 360) and genotyping data (n = 737) with respect to presence (n = 54) or absence (n = 683) of CP in patients with 22q11DS. Two upstream SNPs (rs4819835 and rs5748410) showed individual evidence for association but they were not significant after correction for multiple testing. Associations were not identified between DNA variants and haplotypes in 22q11DS patients with CP. Overall, this study indicates that common DNA variants in TBX1 may be nominally causative for CP in patients with 22q11DS. This raises the possibility that genes elsewhere on the remaining allele of 22q11.2 or in the genome could be relevant. PMID- 23034816 TI - Comparing ROC curves derived from regression models. AB - In constructing predictive models, investigators frequently assess the incremental value of a predictive marker by comparing the ROC curve generated from the predictive model including the new marker with the ROC curve from the model excluding the new marker. Many commentators have noticed empirically that a test of the two ROC areas often produces a non-significant result when a corresponding Wald test from the underlying regression model is significant. A recent article showed using simulations that the widely used ROC area test produces exceptionally conservative test size and extremely low power. In this article, we demonstrate that both the test statistic and its estimated variance are seriously biased when predictions from nested regression models are used as data inputs for the test, and we examine in detail the reasons for these problems. Although it is possible to create a test reference distribution by resampling that removes these biases, Wald or likelihood ratio tests remain the preferred approach for testing the incremental contribution of a new marker. PMID- 23034817 TI - In vivo spatially localized high resolution 1H MRS via intermolecular single quantum coherence of rat brain at 7 T. AB - PURPOSE: To compare the conventional localized point-resolved spectroscopy (PRESS) with localized 2D intermolecular single-quantum coherence (iSQC) magnetic resonance spectroscopy (MRS) and obtain in vivo MRS spectrum of rat brain using the latter technique. MATERIALS AND METHODS: A brain phantom, an intact pig brain tissue, and mature Sprague-Dawley rat were studied by PRESS, Nano magic-angle spinning spectroscopy, and iSQC MRS. RESULTS: Using PRESS, high-resolution MRS can be obtained from the brain phantom and pig brain tissue with a small voxel in a relatively homogeneous field. When a large voxel is selected, the field homogeneity is distinctly reduced. No useful information is obtained from the PRESS spectra. However, using the iSQC MRS, high-resolution spectra can be obtained from the two samples with a relatively large voxel. In the same way, an iSQC MRS spectrum can be obtained from a relatively large voxel of in vivo rat brain with a comparable resolution to the PRESS spectrum with a small voxel. CONCLUSION: Compared to PRESS, the iSQC MRS may be more feasible and promising for detection of strongly structured tissues with relatively large voxels. PMID- 23034818 TI - Nanoparticles assembled by aptamers and crystal violet for arsenic(III) detection in aqueous solution based on a resonance Rayleigh scattering spectral assay. AB - Aptamer-assembled nanomaterials have captured much attention from the field of analytical chemistry in recent years. Although they have been regarded as a promising tool for heavy metal monitoring, report involving aptamer-based biosensors for arsenic detection are rare. Herein we developed a highly sensitive and selective aptamer biosensor for As(iii) detection based on a Resonance Rayleigh Scattering (RRS) spectral assay. Prior to As(iii) detection, we firstly assembled a variety of nanoparticles with different sizes via controlling the concentration of arsenic-binding aptamers in crystal violet (CV) solutions. The results of photon correlation spectroscopy (PCS) and scanning probe microscope (SPM) testified that the introduction of As(iii) had indeed changed the size of nanoparticles, which caused a great variation in the RRS intensity at 310 nm. In the presence of 100 ppb As(iii), a maximum decline in the ratio of RRS intensity was achieved for large nanoparticles assembled from 200 nM of aptamers and CV molecules, where the average size of nanoparticles had decreased from 273 nm to 168 nm. In the case of small nanoparticles, the maximum increase ratio of the RRS intensity was obtained when the concentration of aptamer was over 600 nM. Combined with an RRS spectral assay, an effective biosensor has been developed for As(iii) detection, using the above large and small nanoparticles as the target recognition element. The present biosensor has a detection limit as low as 0.2 ppb, a dynamic range from 0.1 ppb to 200 ppb, and high selectivity over other metal ions. Such an efficient biosensor will play an important role in environmental detection. PMID- 23034819 TI - A model for the controlled assembly of semiconductor peptides. AB - The self-assembly of small molecules provides a potentially powerful method to create functional nanomaterials for many applications ranging from optoelectronics to oncology. However, the design of well-defined nanostructures via molecular assembly is a highly empirical process, which severely hampers efforts to create functional nanostructures using this method. In this review, we describe a simple strategy to control the assembly of functionalized peptides by balancing attractive hydrophobic effects that drive assembly with opposing electrostatic repulsions. Extended pi-pi contacts are created in the nanostructures when assembly is driven by pi-stacking interactions among chromophores that are appended to the peptide. The formation of insoluble beta sheet aggregates are mitigated by incorporating charged side-chains capable of attenuating the assembly process. Although the application of this approach to the assembly of organic semiconductors is described, we expect this strategy to be effective for many other functional organic materials. PMID- 23034820 TI - Fabrication of graphene sheets intercalated with manganese oxide/carbon nanofibers: toward high-capacity energy storage. AB - Herein, 3D nanohybrid architectures consisting of MnO(x) nanocrystals, carbon nanofibers (CNFs), and graphene sheets are fabricated. MnO(x) -decorated CNFs (MCNFs) with diameters of about 50 nm are readily obtained via single-nozzle co electrospinning, followed by heat treatment. The MCNFs are then intercalated between graphene sheets, yielding the ternary nanohybrid MCNF/reduced graphene oxide (RGO). This straightforward synthesis process readily affords product on a scale of tens of grams. The ultrathin CNFs, which might be a promising alternative to carbon nanotubes (CNTs), overcome the low electrical conductivity of the excellent pseudocapacitive component, MnO(x) . Furthermore, the graphene sheets separated by the MCNFs boost the electrochemical performance of the nanohybrid electrodes. These nanohybrid electrodes exhibit enhanced specific capacitances compared with a sheet electrode fabricated of MCNF-only or RGO-only. Evidently, the RGO sheet acts as a conductive channel inside the nanohybrid, while the intercalated MCNFs increase the efficiency of the ion and charge transfer in the nanohybrid. The proposed nanohybrid architectures are expected to lay the foundation for the design and fabrication of high-performance electrodes. PMID- 23034821 TI - Light emission from tryptophan oxidation by hypobromous acid. AB - The emission of ultraweak light from cells is a phenomenon associated with the oxidation of biomolecules by reactive oxygen species. The indole moiety present in tryptophan, serotonin and melatonin is frequently associated with the emission of light during the oxidation of these metabolites. This study presents results for hypobromous acid (HOBr) oxidation of tryptophan as a putative endogenous source of ultraweak light emission. We found that chemiluminescence elicited by the oxidation of tryptophan by HOBr was significantly higher than by hypochlorous acid (HOCl). This difference was related to secondary oxidation reactions, which were more intense using HOBr. The products identified during oxidation by HOCl, but depleted by using HOBr, were N-formylkynurenine, kynurenine, 1,2,3,3a,8,8a hexahydro-3a-hydroxypyrrolo[2,3-b]-indole-2-carboxylic acid, oxindolylalanine and dioxindolylalanine. The emission of light is dependent on the free alpha-amino group of tryptophan, and hence, the indole of serotonin and melatonin, although efficiently oxidized, did not produce chemiluminescence. The emission of light was even greater using taurine monobromamine and dibromamine as the oxidant compared to HOBr. A mechanism based on bromine radical intermediates is suggested for the higher efficiency in light emission. Altogether, the experimental evidence described in the present study indicates that the oxidation of free tryptophan or tryptophan residues in proteins is an important source of ultraweak cellular emission of light. This light emission is increased in the presence of taurine, an amino acid present in large amounts in leukocytes, where this putative source of ultraweak light emission is even more relevant. PMID- 23034822 TI - Repeatability of ultrashort echo time-based two-component T2* measurements on cartilages in human knee at 3 T. AB - Repeatability of in vivo measurement of multicomponent T2* relaxation in articular cartialges in human knee is important to clinical use. This study evaluated the repeatability of two-component T2* relaxation on seven healthy human subjects. The left knee was scanned once a day in three consecutive days, on a clinical 3T MRI scanner with eight-channel knee coil and ultrashort echo time pulse sequence at 11 echo times=0.6-40 ms. The intrasubject and intersubject repeatability was evaluated via coefficient of variation (CV=standard deviation/mean) in four typical cartilage regions: patellar, anterior articular, femoral, and tibial regions. It was found that the intrasubject repeatability was good, with CV<10% for the short- and long-T2* relaxation time in the layered regions in the four cartilages (with one exception) and CV<13% for the component intensity fraction (with two exceptions). The intersubject repeatability was also good, with CV~8% (range 1-15%) for the short- and long-T2* relaxation time and CV~10% (range 2-20%) for the component intensity fraction. The long-T2* component showed significantly better repeatability (CV~8%) than the short-T2* component (CV~12%) (P<0.005). These CV values suggest that in vivo measurement of two component T2* relaxation in the knee cartilages is repeatable on clinical scanner at 3 T, with a signal-to-noise ratio of 90. PMID- 23034823 TI - The discovery of stereoselectivity at biological receptors: Arnaldo Piutti and the taste of the asparagine enantiomers--history and analysis on the 125th anniversary. AB - In 1886, Italian chemist Arnaldo Piutti isolated, for the first time, d asparagine, the enantiomer of the known l-asparagine. He obtained 100 g of D asparagine from 6500 kg of vetches. Using an ingenious synthetic scheme, Piutti established the chemical structure of asparagine and demonstrated that his isolation of D-asparagine from plants was not the result of the racemization of L asparagine during the extraction procedure. He found a striking difference in the taste of asparagine: L-asparagine was without taste, while D-asparagine was intensely sweet. This was the first example of enantioselectivity in a receptor mediated biological activity. Receptors constitute one of the most important and most intensively studied phenomena in biology, and enantioselectivity in receptor mediated activity, including at the sweetness receptor, is today an important and commonly seen aspect of receptor function. Therefore, Piutti's discovery, although made ca. 15 years before the emergence of the receptor concept, was a milestone. The publication of Piutti's asparagine work prompted several eminent scientists, including Louis Pasteur and Arthur Cushny, a leading pharmacologist of the time, to remark on the importance of the discovery. Piutti also carried out investigations in many other fields, e.g., other organic compounds and reactions, pharmaceuticals, alimentary products, radioactivity, noble gases, and spectroscopy. Considerable progress has been made in recent decades concerning the biology and chemistry of sweet taste, but the details of the interactions of chiral molecules with the sweetness receptor remain poorly understood. Piutti and his discovery are largely forgotten today; they deserve the attention of the chirality and receptor "communities." PMID- 23034824 TI - Diagnosis and management of high platelet reactivity on treatment with clopidogrel. AB - Clopidogrel is an antithrombotic drug that inhibits the P2Y(12) platelet receptor for adenosine diphosphate. Wide interindividual variability of responses to clopidogrel were reported in several studies: about one-third of treated patients exhibit high on-treatment platelet reactivity. Genetic and environmental factors influence the absorption and/or the extent of metabolism of clopidogrel (which is a prodrug) to its active metabolite and this contributes to the observed variability of response. Tailored treatment based on the results of laboratory tests of platelet function was proposed as a solution to this problem. However, we still need to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness, before monitoring clopidogrel therapy can be recommended in clinical practice. When possible, the use of alternative drugs with more uniform and predictable bioavailability and with favorable profiles in terms of risk/benefit and cost/benefit ratios should be preferred. PMID- 23034825 TI - Novel and emerging therapies: thrombus-targeted fibrinolysis. AB - Thrombolytic therapy by infusion of analogs of tissue plasminogen activator (tPA), other recombinant-based plasminogen activators (e.g., alteplase, reteplase, and tenecteplase), streptokinase, and urokinase (uPA) aims to clear blood clots and restore blood flow in occluded blood vessels. Thrombolytic therapy is thereby frequently used in patients with myocardial infarction, stroke, peripheral arterial disease, and massive pulmonary embolism. The leading drawbacks of thrombolysis and associated therapy are represented by a significant burden of inefficacy combined with a high risk of bleeding complications. Recent advances in understanding the complex pathophysiology of vascular occlusions, combined with important technological innovations, are notably improving the therapeutic armamentarium against thrombotic and occlusive disorders. Most of the past and ongoing research in this area have entailed thrombus-targeted fibrinolytic therapy with either tissue- and fibrin-specific immunoconjugates, fibrinolytic-bearing erythrocytes, or fibrinolytic-bearing nanoparticles. The greatest advantages of thrombus-targeted fibrinolysis, especially with biocompatible nanoparticles, are represented by their preferential localization within developing clots, effectual thrombolysis and enhanced safety due to substantial reduction of the dosage of fibrinolytic agents, and reduced onstream adverse effects. These positive biological features, coupled with minimal extravasation and favorable clearance from the circulation, appear advantageous for obtaining more efficacious and durable thrombolytic effects while concomitantly lowering or even eliminating the risk of systemic bleeding complications that typically accompany the injection of free or soluble plasminogen activators. Although an ideal technique has not been definitely established so far, tPA-bearing nanoparticles exhibiting affinity for clot specific cells and biomolecules coupled with low-frequency ultrasound seem to bear the greatest advantages for prevention and therapy of acute thrombosis, with the possibility to specifically guide and concentrate the thrombolytic agent at the site of pathologic thrombi and clear preexisting clots by a series of mechanisms combining mechanical stress and increased penetration and effectiveness of the drugs employed. PMID- 23034826 TI - Perioperative management of patients having noncardiac surgery who are receiving anticoagulant or antiplatelet therapy: an evidence-based but practical approach. AB - Patients receiving anticoagulant or antiplatelet therapy who require noncardiac surgery represent a common yet challenging clinical problem. Clinicians must balance the risk of thromboembolic and major adverse cardiovascular events that are associated with interrupting these therapies, against the risk of bleeding from continuing these drugs in the perioperative period. Identifying patients at highest risk for such complications requires particular attention to the role of bridging therapy and the optimal timing and duration of drug withdrawal and resumption with surgery. Patients with coronary stents represent a population that requires specific considerations, due to the added risk and significant mortality associated with perioperative stent thrombosis. Minimizing this risk is dependent on several patient- and stent-specific factors. This review provides clinicians with a summary of the available evidence to facilitate a practical approach to the management of these patients while highlighting the need for continued research in this field. PMID- 23034827 TI - Common management issues in pediatric patients with mild bleeding disorders. AB - Type 1 von Willebrand disease and mild platelet function defects are among the most common disorders seen by pediatric hematologists. The management and prevention of bleeding in these patients can be challenging, as there are limited published data to guide clinical practice, and a complete lack of randomized clinical trials. Desmopressin (DDAVP) and antifibrinolytics are the mainstays of treatment in these patients, yet the optimal dosing and timing of these agents to prevent or resolve bleeding, while minimizing adverse side effects, is sometimes unclear. DDAVP-induced hyponatremia is a particularly under-recognized complication in children with bleeding disorders who undergo surgery. Clinicians need to be aware of local measures that are equally important in treating problems such as epistaxis and surgical bleeding. This review will discuss the published literature and provide practical suggestions regarding four common management issues in the care of children and adolescents with mild bleeding disorders: epistaxis, heavy menstrual bleeding, dental extractions, and tonsillectomy. PMID- 23034828 TI - Diagnosis and management of deep venous thrombosis and pulmonary embolism in neonates and children. AB - Neonates and children represent a specific population that can suffer from deep venous thrombosis (DVT) and pulmonary embolism (PE). In considering how the diagnosis and management of DVT/PE in neonates and children differs from adults, one has to consider the fundamental differences in the general characteristics of the patient population, the specific differences in the disease entity, the differences in sensitivity or specificity of diagnostic strategies and risk/benefit profile of therapeutic options available, and then finally the practical applications of therapies, using an evidence-based approach. This review will articulate the key differences in the patient population, disease entity, diagnostic strategies, and drug therapies that must be understood to apply a rigorous evidence-based approach to diagnosis and management of DVT and PE in neonates and children. Finally, there will be a brief discussion of the latest American College of Chest Physician guidelines for antithrombotic treatment in neonates and children. PMID- 23034829 TI - The diagnosis of venous thromboembolism. AB - Venous thromboembolism (VTE) is a serious and potentially fatal medical condition. Correct diagnosis and early treatment of VTE with anticoagulant drugs are critical steps in preventing further complications and recurrence. Evidence suggests that patients with suspected deep vein thrombosis (DVT) or pulmonary embolism (PE) should be managed with a diagnostic strategy that includes clinical pretest probability assessment, D-dimer test, and imaging. Clinical probability scoring, complemented by selective D-dimer testing, has become the recommended strategy for diagnosis. The reason is that overwhelming evidence suggests that patients with suspected VTE are better managed with a diagnostic strategy. If diagnostic algorithms are followed correctly, the chances of adverse events are extremely low (< 1%) in patients in whom VTE has been ruled out, whereas incomplete strategies leads to an increased risk of recurrent VTE or death. This review focuses on the application of diagnostic strategies with suspected DVT or PE into daily clinical practice while discussing the benefits and disadvantages of different approaches. PMID- 23034830 TI - Approaches to diagnosing and managing anticoagulant-related bleeding. AB - Anticoagulant therapy reduces deaths and disability in patients with or at risk of both arterial and venous thromboembolism. Highly effective antithrombotic therapies now exist that reduce the risk of both arterial thrombosis and venous thrombosis. Anticoagulant strategies include platelet inhibition, using a variety of potent platelet inhibitors, and antithrombotic therapy, designed to interfere with thrombosis by blocking activation of the coagulation cascade. All anticoagulants increase the risk of bleeding. Older antithrombotic agents have, in most cases, effective antidotes and well-developed (although perhaps not very evidence-based) treatment strategies. Newer anticoagulants, and most antiplatelet drugs, do not have effective antidotes or well-tested reversal strategies. This narrative review will provide advice on the diagnosis and management of anticoagulant bleeding with a particular focus on the antithrombotic drugs, including warfarin, heparin, and the novel agents. PMID- 23034831 TI - Major early complications following open, laparoscopic and robotic gastrectomy. AB - BACKGROUND: Laparoscopic and robotic gastrectomy have been adopted rapidly despite lack of evidence concerning technical safety and controversy regarding additional benefits. This study aimed to compare clinically relevant complications after open, laparoscopic and robotic gastrectomy. METHODS: This was a retrospective analysis of prospectively collected data on surgical complications in patients undergoing gastrectomy with curative intent for histologically proven adenocarcinoma between 2005 and 2010 at the Department of Surgery, Yonsei University College of Medicine in Seoul, Korea. Complications were categorized into wound infection, bleeding, anastomotic leak, obstruction, fluid collection and other. RESULTS: In a total of 5839 patients (4542 open, 861 laparoscopic and 436 robotic gastrectomies), overall complication, reoperation and mortality rates were 10.5, 1.0 and 0.4 per cent respectively. There were no significant differences between the three groups. Ileus (P = 0.001) and intra abdominal fluid collections (P = 0.013) were commoner after conventional open surgery. However, tumour stage was higher and more complex resections were performed in the open group. Anastomotic leak, the leading cause of death, occurred more often after a minimally invasive approach (P = 0.017). CONCLUSION: Laparoscopic and robotic gastrectomy had overall complication and mortality rates similar to those of open surgery, but anastomotic leaks were more common with the minimally invasive techniques. PMID- 23034832 TI - Waiting list-controlled evaluation of a participatory arts course for people experiencing mental health problems. AB - AIMS: The potential for participation in creative activity to promote recovery from mental ill health is highlighted in mental health policy and guidance, alongside a perceived dearth of robust evidence of effectiveness. Open Arts has run participatory arts courses in South Essex since 2008 and a course waiting list has developed with increasing demand for places. Given the waiting list and the need to improve the evidence base for the utility of participatory arts groups in mental health, the aim of this project was to conduct a naturalistic waiting list-controlled evaluation of the 12-week courses routinely provided and to explore participants' experiences of their course. It was expected that people on the waiting list who were allocated places on a course would gain improvements in well-being and social inclusion, whereas those not allocated places would show no changes over the same time period. METHODS: Measures included the Warwick Edinburgh Mental Well-being Scale (WEMWBS) and the Social Inclusion Scale (SIS). People on the Open Arts waiting list who had been allocated a place on the courses formed an intervention group; those remaining on the waiting list were asked to complete the same measures over the same time period (forming a control group). Participants in the intervention group were asked to rate the service and were offered the opportunity to join a focus group. RESULTS: Thirty-two people in the control group and 26 people in the intervention group could be included in the final analyses. There were no significant differences between the two groups on either measure at baseline. Intervention group total mean scores were significantly higher after the Open Arts course than at baseline on both the WEMWBS and SIS, but no significant differences across time were found for the control group. Of the intervention group 96% reported enjoying the course and most of those providing feedback reported gains in confidence (81%) and motivation (88%). Nineteen participants in the control group completed an Open Arts course later in the year and similar improvements between baseline and follow-up scores on the WEMWBS and SIS were then found in this group. CONCLUSIONS: This service evaluation of Open Arts has provided some preliminary evidence that participatory arts groups are likely to have benefits for mental health service users in terms of improved well-being and social inclusion. The evaluation justifies a future randomised controlled trial and economic appraisal of participatory arts projects. PMID- 23034834 TI - Salivaomics. AB - BACKGROUND: The ability to monitor health and wellness, as well as detect oral and systemic illnesses early through noninvasive means, are highly desirable goals in health care promotion and delivery. Saliva is an emerging medium to be explored for health and disease surveillance, as well as for personalized medicine. A major mandate is to demonstrate clinicians' ability to use saliva to detect and monitor systemic diseases. METHODS: To realize the translational and clinical vision of salivary diagnostics, two prerequisites are essential. The first is the need to develop and optimize diagnostic tools tailored to saliva. The second is the need to substantiate the scientific underpinnings of salivary biomarkers reflecting systemic diseases. RESULTS: The author describes five diagnostic alphabets (proteome, transcriptome, microRNA, metabolome and microbiome) and point-of-care technology platforms that are in place to advance the translational and clinical path. For mechanistic studies (that is, basic science studies), animal models are in place to elucidate the scientific mechanisms of systemic diseases reflected in saliva. CONCLUSIONS: Significant advancements have been made in the development of salivary diagnostic tools. The translation of the scientific mechanisms of systemic diseases reflected in saliva is in progress. CLINICAL IMPLICATIONS: On the scientific credentialing of salivary biomarkers for the detection of systemic diseases, salivary diagnostics will have an effect on access to care, health disparities and global health. Dentistry can advance into the realm of primary health care with integration of chairside screening for medical conditions. PMID- 23034833 TI - Detecting viruses by using salivary diagnostics. AB - BACKGROUND: Diagnostics that involve the use of oral fluids have become increasingly available commercially in recent years and are of particular interest because of their relative ease of use, low cost and noninvasive collection of oral fluid for testing. TYPES OF STUDIES REVIEWED: The authors discuss the use of salivary diagnostics for virus detection with an emphasis on rapid detection of infection by using point-of-care devices. In particular, they review salivary diagnostics for human immunodeficiency virus, hepatitis C virus and human papillomavirus. Oral mucosal transudate contains secretory immunoglobulin (Ig) A, as well as IgM and IgG, which makes it a good source for immunodiagnostic-based devices. CLINICAL IMPLICATIONS: Because patients often visit a dentist more regularly than they do a physician, there is increased discussion in the dental community regarding the need for practitioners to be aware of salivary diagnostics and to be willing and able to administer these tests to their patients. PMID- 23034835 TI - Salivary diagnostic tests. PMID- 23034843 TI - Glutathione S-transferase A1, M1, P1 and T1 null or low-activity genotypes are associated with enhanced oxidative damage among haemodialysis patients. AB - BACKGROUND: Increased oxidative stress is a hallmark of end-stage renal disease (ESRD). Glutathione S-transferases (GST) are involved in the detoxification of xenobiotics and protection of oxidative damage. We hypothesized that genetic polymorphism in antioxidant enzymes GSTA1, GSTM1, GSTP1 and GSTT1 is more frequent in ESRD and modulates the degree of oxidative stress in these patients. METHODS: GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 ESRD patients and 199 age- and gender-matched controls. Markers of protein and lipid oxidative damage [thiol groups, carbonyl groups, advanced oxidative protein products, nitrotyrosine, malondialdehyde (MDA) and MDA adducts], together with total oxidant status and pro-oxidant-antioxidant balance were determined. RESULTS: Individual GST polymorphisms influence vulnerability to both protein and lipid oxidation, with GSTM1-null gene variant having the most pronounced effect. Furthermore, a strong combined effect of null/low-activity GSTM1, GSTT1, GSTA1 and GSTP1 genotypes in terms of susceptibility towards oxidative and carbonyl stress was found in ESRD patients. When patients were stratified according to GSTM1 and GSTT1, the highest oxidant damage was noted in those with the GSTM1 null/GSTT1-null genotype. The observed effect was even stronger in patients with the third low-activity GSTP1 or GSTA1 genotype. Finally, the level of oxidative and carbonyl stress was most pronounced in the subgroup of patients with all four null or low-activity GSTM1, GSTT1, GSTP1 and GSTA1 genotypes. CONCLUSIONS: According to the GST genotype, ESRD patients may be stratified in terms of the level of oxidative and carbonyl stress that might influence cardiovascular prognosis, but could also improve efforts towards individualization of antioxidant treatment. PMID- 23034844 TI - Cardiopulmonary resuscitation. PMID- 23034845 TI - Improving targeted screening for hepatitis C in the UK. PMID- 23034846 TI - A woman with neck pain and shortness of breath. PMID- 23034847 TI - The problem of diagnosis. PMID- 23034849 TI - Demand for knee replacement surgery rises steadily in the US. PMID- 23034848 TI - Fewer road crashes in the year after a medical warning. PMID- 23034850 TI - Brief counselling reduces hazardous drinking. PMID- 23034851 TI - Patients report benefits from online access to doctors' notes. PMID- 23034852 TI - Hazards of poor renal function are independent of diabetes and hypertension. PMID- 23034853 TI - Not curing the common cold. PMID- 23034854 TI - Who needs beta blockers? PMID- 23034855 TI - Is the USA's problem ours too? PMID- 23034856 TI - Spinal injury patients get a place of escape. PMID- 23034857 TI - India's capping of drug prices will leave drugs costing near the market price. PMID- 23034858 TI - Nuclear transfer to prevent maternal transmission of mitochondrial DNA disease. PMID- 23034859 TI - Doctors leaders, charities, and hospices back Liverpool Care Pathway. PMID- 23034860 TI - Scientists debunk idea that rise in allergic diseases is due to homes becoming "too clean". PMID- 23034861 TI - Tax calories to end the buffet syndrome. PMID- 23034862 TI - Failure rates of Birmingham hip implant exceed recommended level. PMID- 23034863 TI - Nicklinson's widow is refused right to appeal to higher court. PMID- 23034864 TI - Prevalence and viral load of 51 genital human papillomavirus types and three subtypes. AB - Of the 120 known human papillomaviruses (HPV), 51 HPV types infect the genital mucosa. Very little is known about the prevalence and viral load of the majority of these low-risk (Lr-) HPV types in screening populations. We determined the prevalence of 51 HPV types and three subtypes in 999 consecutive BD-SurePathTM liquid-based cervical cytology samples collected during routine gynecological health checks from Belgian women. This series of screening samples was enriched with ASC-US (n = 100), low-grade squamous intraepithelial lesion LSIL (n = 100) and high-grade squamous intraepithelial lesion (HSIL) (n = 97) and analyzed by BSGP5+/6+-PCR/MPG assay for 51 HPV types and three subtypes. In consecutive screening samples, any of the 54 genital HPV (sub)types was found in 37.1%; Hr HPV types were detected more frequently (26.8%) than the 31 Lr-HPV types (16.4%) and the six possibly high-risk types (6.6%). High viral load infections were present in 17.0% of the screening population. Among the women with cytological abnormalities, the prevalence of high viral loads of Hr-HPV types increased from negative for intraepithelial lesion or malignancy (NIL/M) over ASC-US, LSIL to HSIL (5.3, 47.1, 84.2 and 91.8%, respectively). The prevalence of possibly Hr and Lr-HPV types increased from NIL/M to LSIL but declined to HSIL. From NIL/M to HSIL, Hr-HPV infections showed an increasing frequency of high viral loads compared to total DNA positivity, but the increase between LSIL and HSIL was small. Type-specific analyses revealed substantial differences between individual HPV types in these groups. Our study provides quantitative data for the whole spectrum of genital HPV in a Belgian screening population and in a representative set of women with cervical abnormalities. PMID- 23034865 TI - Consumption of a durable termite bait matrix by subterranean termites (Isoptera: Rhinotermitidae) and resulting insecticidal activity. AB - BACKGROUND: A novel durable termite bait was developed to enable continuous bait availability and lengthen the monitoring interval to 1 year. Laboratory studies were conducted to determine the palatability and insecticidal activity of this bait to Reticulitermes flavipes (Kollar), R. virginicus (Banks), R. hesperus Banks, Coptotermes formosanus Shiraki and Heterotermes aureus (Synder). RESULTS: Consumption of the blank durable bait matrix was significantly higher than consumption of a blank preferred textured cellulose matrix (PTC) by R. virginicus, R. flavipes and C. formosanus. R. flavipes, R. hesperus and H. aureus consumed significantly more durable bait than PTC when both contained the active ingredient noviflumuron. All bait treatments resulted in significant mortality relative to the untreated controls. Survivorship of R. virginicus, C. formosanus and H. aureus was 2% or less and not significantly different between the durable bait and PTC treatments containing noviflumuron. The durable bait matrix lagged behind the PTC matrix in mortality over time for all species tested except H. aureus. CONCLUSION: The durable bait was highly palatable and effective in inducing mortality to R. flavipes, R. virginicus, R. hesperus, C. formosanus and H. aureus in the laboratory. This unique bait matrix will be available to termites continuously and allows for an annual monitoring interval. The durability of this bait matrix is unprecedented, allowing for bait to remain active for years and thus providing continuous structural protection. PMID- 23034866 TI - Effect of cerebral spinal fluid suppression for diffusional kurtosis imaging. AB - PURPOSE: To evaluate the cerebral spinal fluid (CSF) partial volume effect on diffusional kurtosis imaging (DKI) metrics in white matter and cortical gray matter. MATERIALS AND METHODS: Four healthy volunteers participated in this study. Standard DKI and fluid-attenuated inversion recovery (FLAIR) DKI experiments were performed using a twice-refocused-spin-echo diffusion sequence. The conventional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, D[symbol in text], D[symbol in text] together with DKI metrics of mean, axial, and radial kurtosis (MK, K[symbol in text], K[symbol in text], were measured and compared. Single image slices located above the lateral ventricles, with similar anatomical features for each subject, were selected to minimize the effect of CSF from the ventricles. RESULTS: In white matter, differences of less than 10% were observed between diffusion metrics measured with standard DKI and FLAIR-DKI sequences, suggesting minimal CSF contamination. For gray matter, conventional DTI metrics differed by 19% to 52%, reflecting significant CSF partial volume effects. Kurtosis metrics, however, changed by 11% or less, indicating greater robustness with respect to CSF contamination. CONCLUSION: Kurtosis metrics are less sensitive to CSF partial voluming in cortical gray matter than conventional diffusion metrics. The kurtosis metrics may then be more specific indicators of changes in tissue microstructure, provided the effect sizes for the changes are comparable. PMID- 23034867 TI - Deriving age-specific incidence from prevalence with an ordinary differential equation. AB - This article describes new relationships between the age-specific incidence of, the prevalence of and mortality from a chronic disease. We express these relationships in terms of an ordinary differential equation and form the methodological basis for a novel approach to estimating incidences from age specific prevalence data. We examine practical aspects of the relationships and a comparison with a known stochastic method in a simulation study. Finally, we apply the novel method to a data set of renal replacement therapy recorded from patients with chronic kidney failure in a region of Germany with approximately 310,000 inhabitants from 2002 to 2010. PMID- 23034868 TI - A homozygous balanced reciprocal translocation suggests LINC00237 as a candidate gene for MOMO (macrosomia, obesity, macrocephaly, and ocular abnormalities) syndrome. AB - Macrosomia, obesity, macrocephaly, and ocular abnormalities syndrome (MOMO syndrome) has been reported in only four patients to date. In these sporadic cases, no chromosomal or molecular abnormality has been identified thus far. Here, we report on the clinical, cytogenetic, and molecular findings in a child of healthy consanguineous parents suffering from MOMO syndrome. Conventional karyotyping revealed an inherited homozygous balanced reciprocal translocation (16;20)(q21;p11.2). Uniparental disomy testing showed bi-parental inheritance for both derivative chromosomes 16 and 20. The patient's oligonucleotide array comparative genomic hybridization profile revealed no abnormality. From the homozygous balanced reciprocal translocation (16;20)(q21;p11.2), a positional cloning strategy, designed to narrow 16q21 and 20p11.2 breakpoints, revealed the disruption of a novel gene located at 20p11.23. This gene is now named LINC00237, according to the HUGO (Human Genome Organization) nomenclature. The gene apparently leads to the production of a non-coding RNA. We established that LINC00237 was expressed in lymphocytes of control individuals while normal transcripts were absent in lymphocytes of our MOMO patient. LINC00237 was not ubiquitously expressed in control tissues, but it was notably highly expressed in the brain. Our results suggested autosomal recessive inheritance of MOMO syndrome. LINC00237 could play a role in the pathogenesis of this syndrome and could provide new insights into hyperphagia-related obesity and intellectual disability. PMID- 23034869 TI - Silk fibers and silk-producing organs of Harpactea rubicunda (C. L. Koch 1838) (Araneae, Dysderidae). AB - Scanning electron microscopy and atomic force microscopy were used to study the silk spinning apparatus and silks of Harpactea rubicunda spiders. Three types of silk secretions that are produced by three kinds of silk spinning glands (ampullate, piriform, and pseudaciniform) and released through three types of spigots, were confirmed for both adult and juvenile spiders. Silk secretions for the construction of spider webs for shelter or retreat are produced by the pseudaciniform silk glands. Silk secretions that are released from spigots in the course of web construction are not processed by the legs during the subsequent process of hardening. Pairs of nanofibril bundles seemed to be part of the basic microarchitecture of the web silk fibers as revealed by AFM. These fiber bundles frequently not only overlap one another, but occasionally also interweave. This structural variability may strengthen the spider web. High-resolution AFM scans of individual nanofibrils show a distinctly segmented nanostructure. Each globular segment is ~30-40 nm long along the longitudinal axis of the fiber, and resembles a nanosegment of artificial fibroin described by Perez-Rigueiro et al. (2007). PMID- 23034870 TI - Inverse correlation of intracellular calcium and cyclic AMP levels in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common renal tumour in adults. Altered levels of secondary messengers, that is, intracellular calcium and cyclic AMP (cAMP), have been implicated in the pathogenesis of various malignancies. In the present study, we measured levels of intracellular calcium and cAMP in RCC. The intracellular calcium level was significantly reduced, whereas the cAMP level was significantly augmented in RCC as compared with adjacent grossly normal renal parenchyma. PMID- 23034871 TI - Determination of chemotherapeutic agents in fish and shellfish by matrix solid phase dispersion and liquid chromatography-tandem mass spectrometry. AB - Chemicals are widely used in aquaculture and one of the main recipients of these analytes is the aquatic environment. The aim of this work was to develop and validate a simple and sensitive method for the determination of multiclass chemotherapeutic agents in farmed fish and shellfish using matrix solid-phase dispersion and liquid chromatography-tandem mass spectrometry. Residues of azamethiphos, three avermectins, two carbamates, and two benzoylureas were extracted from samples using silica gel as clean-up adsorbent and 0.5% acetic acid in acetonitrile as elution solvent. The extraction conditions were investigated and optimized using an experimental design. Mass spectrometry detection was carried out in positive electrospray ionization mode with multiple reaction monitoring scan (except for benzoylurea family). Matrix-matched standards were used for the drugs quantification. Good linearity (R(2) >= 0.996) was observed in the range of 5-500 MUg kg(-1). Limits of detection were in the range of 1.5-3.7 MUg kg(-1). Recoveries from salmon samples spiked with veterinary drugs were in the range 84.9-118%. Precision was satisfactory since relative standard deviations were lower than 10.6%. The method can be successfully applied for the analysis of fish and shellfish from aquaculture. PMID- 23034872 TI - Psychomotor car-driving abilities after robotically assisted totally endoscopic coronary artery bypass grafting. AB - OBJECTIVE: Postoperative cognitive decline is a common complication after coronary artery bypass graft surgery. As robotically assisted totally endoscopic coronary artery bypass grafting (TECAB) has shown several positive impacts on recovery and quality of life, the aim of this study was to assess psychomotor functioning relevant for car-driving abilities before and after this intervention. METHODS: A total of 20 patients who underwent TECAB completed a neuropsychological test battery including conventional and computerized assessments [Trail Making Test (TMT A + B), Leeds Psychomotor Tester (LPT), Test System for Attentional Performance (TAP 2.1)] before surgery (T0) and 1 week (T1) and 3 months (T2) after surgery. RESULTS: Data show no significant cognitive decline between T0, T1, and T2 following TECAB. Significant improvements were measured from T0 to T2 for psychomotoric function and visual attention (TMT A; p = 0.038) and for reaction time, which was significantly shorter after 3 months in comparison with T0 and T1; p = 0.001). CONCLUSION: Data of our preliminary study show no relevant cognitive decline caused from TECAB and therefore do not contradict the practice of early car driving after this procedure. PMID- 23034873 TI - Surgical therapy for necrotizing pneumonia and lung gangrene. AB - OBJECTIVE: Necrotizing pneumonia, pulmonary abscess, and lung gangrene are rare complications of severe pulmonary infection with devitalization and sloughing of lung tissue. Pulmonary necrosis is often associated with alcoholism and other chronic disorders with known immunodeficiency. Mortality is significant and both treatment strategies as well as the role of surgery are controversially debated. METHODS: In a retrospective review at a German tertiary referral hospital, 20 patients with pulmonary resection for necrotizing lung disorders were identified since 2008. At hospital admission, all patients suffered from pulmonary sepsis and despite adequate medical treatment progressing parenchymal destruction and devitalization took place. The majority of the patients sustained pleural empyema (13/20) and five patients a persisting air leak. On account of failing medical therapy, eight patients (40%) developed severe sepsis with septic shock and four patients (20%) were already preoperatively ventilated. Chronic alcoholism was present in 10 patients (50%). RESULTS: Gangrene of a complete lung was seen in four cases. Lobar gangrene or necrotizing pneumonia complicated by fulminate abscess was seen in the right lower lobe (8/20), middle lobe (4/20), right upper lobe (2/20), and left lower lobe (2/20). Procedures included pneumectomy (4/20), lobectomy (13/20), and limited resection (3/20). The bronchial stump was reinforced with a pedicle muscle flap in seven cases. There were three postoperative deaths due to septic shock with multiorgan failure. The remaining 17 patients (85%) recovered well and were transferred to rehabilitation clinics specialized on pulmonary disorders. CONCLUSION: Necrotizing pulmonary infections are infrequent but are life-threatening disease entities. Patients often present with severe comorbidity and chronic disorders causing immunodeficiency. If initial medical therapy fails surgery offers a reasonable therapeutic approach. Aim of surgical therapy is resection of all gangrenous lung parenchyma and effective drainage of pleural empyema. Then recovery is feasible in up to 80%. PMID- 23034874 TI - Coronary artery fistula between left coronary artery and coronary sinus in newborn. AB - Aneurysmal circumflex coronary artery fistula connected to the coronary sinus is a rare clinical entity that usually remains asymptomatic until later in life. The timing of surgical treatment for asymptomatic patients is crucial. The decision to leave or exclude the aneurysmatic coronary artery following ligation of the fistula is controversial. Herein, we report the successful management of a coronary fistula between the circumflex artery and the coronary sinus without using cardiopulmonary bypass during the newborn period. PMID- 23034875 TI - Temporary epicardial pacemaker wires: significance of position and electrode type. AB - OBJECTIVE: To determine the pacing and sensing properties of different temporary epicardial pacemaker electrodes after cardiac surgery depending on position at the heart and time after surgery. METHODS: From September 2009 to October 2010, 60 patients undergoing cardiac surgery were prospectively randomized into two groups: group O: Osypka-electrodes (n = 30), group M: Medtronic-electrodes (n = 30). In position 1, the bipolar electrodes were inserted onto the anterior wall of the right ventricle and at the right atrial auricle, in position 2, onto the diaphragmal wall of the right ventricle and at the aortic aspect of the superior vena cava medial close to the atrium. Sensing values and pacing thresholds were measured for all electrodes during surgery, on day 1 and every second day up to day 10 after surgery. RESULTS: In both groups, pacing thresholds (both positions) were higher during surgery (ventricle 3.1 +/- 0.6 V, atrium 3.1 +/- 0.3 V) than at day 1 (ventricle 2.4 +/- 0.7 V, atrium 2.4 +/- 0.3 V) and increased during the perioperative course until day 10 (ventricle 4.7 +/- 1.0 V, atrium 4.9 +/- 1.1 V, p = 0.04, p = 0.02). P and R wave amplitudes did not change over time (atrium 5.1 +/- 0.1 mV initially, 4.2 +/- 0.1 mV at removal (p = ns); ventricle 10.4 +/- 0.2 mV vs. 10.1 +/- 0.25 mV). Group M had better median pacing thresholds compared with group O (atrium: 2.9 +/- 0.6 V vs. 3.9 +/- 0.7 V, p = 0.04 and ventricle: 2.6 +/- 0.6 V vs. 3.9 +/- 0.6 V, p = 0.045). Atrial position 1 was superior to position 2 concerning pacing thresholds of Medtronic electrodes (2.1 +/- 0.3 mV vs. 3.4 +/- 0.4 mV, p = 0.02). Osypka-electrodes were easier to handle due to their more pliable texture. CONCLUSIONS: 1. Up to postoperative day 10, adequate pacing and sensing performance was achieved by both electrode types in each position. 2. Medtronic electrodes had better pacing thresholds in atrium and ventricle after day 5. 3. Positioning of pacemaker electrodes does not alter functionality. 4. Handling of Osypka electrodes was easier than that of Medtronic electrodes. PMID- 23034876 TI - A strange bullet which caused chylomediastinum and chyloptysis. AB - Chyloptysis and chylomediastinum are uncommon complications of various kinds of thoracic operations, malign and nonmalign diseases. In the English language medical literature, there were no cases of both chylomediastinum and chyloptysis following trauma. We discuss a case of chylomediastinum and chyloptysis after penetrating trauma. The patient sustained a bullet wound that caused chylomediastinum and chyloptysis without damaging major structures apart from the thoracic duct in the mediastinum. Following surgical intervention, the patient has remained problem-free for 5 months. PMID- 23034877 TI - AtAPY1 and AtAPY2 function as Golgi-localized nucleoside diphosphatases in Arabidopsis thaliana. AB - Nucleoside triphosphate diphosphohydrolases (NTPDases; apyrases) (EC 3.6.1.5) hydrolyze di- and triphosphate nucleotides, but not monophosphate nucleotides. They are categorized as E-type ATPases, have a broad divalent cation (Mg(2+), Ca(2+)) requirement for activation and are insensitive to inhibitors of F-type, P type and V-type ATPases. Among the seven NTPDases identified in Arabidopsis, only APYRASE 1 (AtAPY1) and APYRASE 2 (AtAPY2) have been previously characterized. In this work, either AtAPY1 or AtAPY2 tagged with C-terminal green fluorescent protein (GFP) driven by their respective native promoter can rescue the apy1 apy2 double knockout (apy1 apy2 dKO) successfully, and confocal microscopy reveals that these two Arabidopsis apyrases reside in the Golgi apparatus. In Saccharomyces cerevisiae, both AtAPY1 and AtAPY2 can complement the Golgi localized GDA1 mutant, rescuing its aberrant protein glycosylation phenotype. In Arabidopsis, microsomes of the wild type show higher substrate preferences toward UDP compared with other NDP substrates. Loss-of-function Arabidopsis AtAPY1 mutants exhibit reduced microsomal UDPase activity, and this activity is even more significantly reduced in the loss-of-function AtAPY2 mutant and in the AtAPY1/AtAPY2 RNA interference (RNAi) technology repressor lines. Microsomes from wild-type plants also have detectable GDPase activity, which is significantly reduced in apy2 but not apy1 mutants. The GFP-tagged AtAPY1 or AtAPY2 constructs in the apy1 apy2 dKO plants can restore microsomal UDP/GDPase activity, confirming that they both also have functional competency. The cell walls of apy1, apy2 and the RNAi-silenced lines all have an increased composition of galactose, but the transport efficiency of UDP-galactose across microsomal membranes was not altered. Taken together, these results reveal that AtAPY1 and AtAPY2 are Golgi-localized nucleotide diphosphatases and are likely to have roles in regulating UDP/GDP concentrations in the Golgi lumen. PMID- 23034878 TI - Non-functionalization of two CYP82E nicotine N-demethylase genes abolishes nornicotine formation in Nicotiana langsdorffii. AB - Nornicotine is formed from nicotine by nicotine N-demethylase, a CYP82E family monooxygenase, and accumulates to high levels in some tobacco (Nicotiana tabacum) cultivars and many wild Nicotiana species. Nicotiana langsdorffii does not form nornicotine, whereas the closely related species N. alata accumulates this alkaloid abundantly. We show here that the two nicotine N-demethylase genes in N. langsdorffii have been inactivated by different molecular mechanisms. We identified four N. alata CYP82E genes that encode functional nicotine N demethylases. In N. langsdorffii, however, one CYP82E gene encoding a functional enzyme was not expressed at all, whereas the other was weakly expressed but contained a one-nucleotide deletion in the first exon, yielding a truncated protein. Expression analysis of interspecific F(1) hybrids between N. alata and N. langsdorffii indicated that cis-acting polymorphisms abolish expression of the otherwise functional CYP82E gene in N. langsdorffii. Segregation analysis of tobacco alkaloids and individual CYP82E alleles in F(2) progeny revealed that duplicated CYP82E genes in both species are genetically linked, and provide genetic evidence that CYP82E genes are solely responsible for nornicotine formation in these wild Nicotiana species. PMID- 23034879 TI - Atomic layer engineering of perovskite oxides for chemically sharp heterointerfaces. AB - Atomic layer engineering enables fabrication of a chemically sharp oxide heterointerface. The interface formation and strain evolution during the initial growth of LaAlO(3) /SrTiO(3) heterostructures by pulsed laser deposition are investigated in search of a means for controlling the atomic-sharpness of the interface. This study shows that inserting a monolayer of LaAlO(3) grown at high oxygen pressure dramatically enhances interface abruptness. PMID- 23034880 TI - Role of standardized and study-specific human brain diffusion tensor templates in inter-subject spatial normalization. AB - PURPOSE: To investigate the effect of standardized and study-specific human brain diffusion tensor templates on the accuracy of spatial normalization, without ignoring the important roles of data quality and registration algorithm effectiveness. MATERIALS AND METHODS: Two groups of diffusion tensor imaging (DTI) datasets, with and without visible artifacts, were normalized to two standardized diffusion tensor templates (IIT2, ICBM81) as well as study-specific templates, using three registration approaches. The accuracy of inter-subject spatial normalization was compared across templates, using the most effective registration technique for each template and group of data. RESULTS: It was demonstrated that, for DTI data with visible artifacts, the study-specific template resulted in significantly higher spatial normalization accuracy than standardized templates. However, for data without visible artifacts, the study specific template and the standardized template of higher quality (IIT2) resulted in similar normalization accuracy. CONCLUSION: For DTI data with visible artifacts, a carefully constructed study-specific template may achieve higher normalization accuracy than that of standardized templates. However, as DTI data quality improves, a high-quality standardized template may be more advantageous than a study-specific template, because in addition to high normalization accuracy, it provides a standard reference across studies, as well as automated localization/segmentation when accompanied by anatomical labels. PMID- 23034882 TI - Laboratory tests of insect growth regulators as bait sprays for the control of the olive fruit fly, Bactrocera oleae (Diptera: Tephritidae). AB - BACKGROUND: Insect growth regulators (IGRs) act specifically on arthropods. This selectivity makes them an interesting alternative to traditional insecticides for pest control. The aim of this work was to test the IGRs azadirachtin, cyromazine, flufenoxuron, lufenuron and pyriproxyfen as useful pesticides for the control of the olive fruit fly, Bactrocera oleae (Rossi), a key pest of olive crops. RESULTS: Of the products tested, the chitin-synthesis inhibitor lufenuron showed the highest efficacy. The life parameter showing the strongest effect was the egg hatch, because lufenuron caused nearly 100% egg mortality 7 days after treatment. However, sterility was not transmitted from the treated males to the untreated females. The LC50 and LC90 values for a 7 day evaluation period were 19.3 and 86.2 ug AI mL(-1) respectively. Azadirachtin, cyromazine and flufenoxuron also caused significant increases in egg mortality. However, these increases were less than those produced by lufenuron. Pyriproxyfen had a stimulatory effect on B. oleae fecundity. CONCLUSION: Applied as a bait treatment, a procedure used frequently in the field for the control of B. oleae, lufenuron is potentially useful against this important pest. PMID- 23034881 TI - SMAD7 directly converts human embryonic stem cells to telencephalic fate by a default mechanism. AB - Human embryonic stem cells (hESCs) provide a valuable window into the dissection of the molecular circuitry underlying the early formation of the human forebrain. However, dissection of signaling events in forebrain development using current protocols is complicated by non-neural contamination and fluctuation of extrinsic influences. Here, we show that SMAD7, a cell-intrinsic inhibitor of transforming growth factor-beta (TGFbeta) signaling, is sufficient to directly convert pluripotent hESCs to an anterior neural fate. Time course gene expression revealed downregulation of MAPK components, and combining MEK1/2 inhibition with SMAD7-mediated TGFbeta inhibition promoted telencephalic conversion. Fibroblast growth factor-MEK and TGFbeta-SMAD signaling maintain hESCs by promoting pluripotency genes and repressing neural genes. Our findings suggest that in the absence of these cues, pluripotent cells simply revert to a program of neural conversion. Hence, the "primed" state of hESCs requires inhibition of the "default" state of neural fate acquisition. This has parallels in amphibians, suggesting an evolutionarily conserved mechanism. PMID- 23034883 TI - Measurement of fundamental chromatography parameters in conventional and split flow comprehensive two-dimensional gas chromatography-mass spectrometry: A focus on the importance of second-dimension injection efficiency. AB - The present manuscript reports a comparative study between conventional and split flow comprehensive GC*GC-MS. Conventional GC*GC-MS was performed by using a single GC oven, and with a widely employed apolar (30 m * 0.25 mm id)-polar (1 m * 0.10 mm id) column combination. Split-flow GC*GC-MS experiments were carried out by using the same first and second analytical columns, and by diverting part of the primary-capillary flow to waste, via a waste line. The latter was located at the conjunction point between the two dimensions. The measurement of fundamental gas chromatography parameters (efficiency, resolution), in both dimensions and under different experimental conditions, enabled the attainment of detailed information related to GC*GC-MS method optimization. Finally, the results derived from the present investigation highlight an important GC*GC issue, namely the efficiency of band reinjection onto the second-dimension capillary. PMID- 23034884 TI - Neuronavigation in endonasal pituitary and skull base surgery using an autoregistration mask without head fixation: an assessment of accuracy and practicality. AB - BACKGROUND: Intraoperative navigation is an important tool used during endonasal surgery, which typically requires rigid head fixation. Herein we describe a navigational technique using an autoregistration mask without head fixation. MATERIAL AND METHODS: Prospective evaluation of a surface autoregistration mask used without rigid head fixation in 12 consecutive endonasal endoscopic skull base procedures was performed with patients positioned in a horseshoe head holder. We assessed the accuracy by recording the surface registration error (SRE) and target registration error (TRE). We also noted the time required for installation and the occurrence of system failure. The system's accuracy was validated using a deep target simultaneously viewed with endoscopic. RESULTS: In 12 consecutive endonasal cases performed by a neurosurgeon and ENT team, pathologies included pituitary macroadenomas (9), chordoma (1), craniopharyngioma (1), and sinonasal melanoma (1). Median time required for the registration and accuracy verification was 84 seconds (interval 64 to 129 seconds). The mask stayed on the patient throughout the procedure. The mean SRE was 0.8 mm (interval 0.6 to 0.9 mm). The mean TRE was 0.9 +/- 0.7 mm and 1.0 +/- 0.8 mm measured respectively at the beginning and end of the case. In every case, the system was judged accurate by the surgical team using the sphenoid keel or an intrasphenoidal bony septation as a deep target for internal validation. No system failure occurred during these 12 cases. CONCLUSION: A facial surface autoregistration mask maintained in place throughout surgery without rigid head fixation allows excellent operational accuracy in endonasal pituitary and skull base surgery. This navigation system is practical, reliable, and noninvasive. PMID- 23034885 TI - Endoscopic extracapsular dissection for resection of pituitary macroadenomas: technical note. AB - OBJECTIVE: With the increasing use of the endoscope in neurosurgery, transsphenoidal surgery has undergone a considerable technical evolution. However, most recently reported advances relate to the approach to the sella turcica or to extended transsphenoidal approaches, whereas the dissection technique for pituitary tumor removal itself has received more limited attention. A notable exception is Oldfield's elegant description of an extracapsular dissection of functional pituitary microadenomas. Our objective is to describe and illustrate our technique for endoscopic extracapsular resection of pituitary macroadenomas. METHODS: Influenced by Oldfield's description, we have adopted an extracapsular dissection technique in the endoscopic resection of pituitary macroadenomas. After carefully opening the dura without disrupting the macroadenoma pseudocapsule, the pseudocapsule is dissected inferiorly and laterally. The tumor is then internally debulked and the extracapsular dissection is extended circumferentially; the resection is then complete. RESULTS: The enhanced visualization and illumination afforded by the endoscope enables the identification and surgical dissection of the pseudocapsule at the periphery of the macroadenomas under direct vision in most cases. As demonstrated in the illustrative case, working around the macroadenoma pseudocapsule allows for a definitive and complete macroadenoma resection with direct visual confirmation and with preservation of the normal gland and diaphragma. CONCLUSION: The endoscopic transsphenoidal approach permits an extracapsular dissection of many pituitary macroadenomas. In our preliminary experience, this technique appears to result in a high rate of complete resection without an increase in complications. PMID- 23034886 TI - An unusual sacral osteomyelitis due to an occult anterior sacral meningocele. AB - OBJECTIVE: We present the extremely rare case of sacral osteomyelitis due to an anterior sacral meningocele (ASM) with fistula to the skin. We also discuss the case's clinical significance and the importance of imaging in diagnosis. METHODS: A 28-year-old female patient was referred to our clinic due to back and hip pain, erythema, and purulent discharge from the right gluteal region. Neurological examination was normal except for pain in the gluteal region. Physical examination revealed a porus lateral to the right gluteal region. Lumbar magnetic resonance imaging (MRI)showed osteomyelitis and a minimal occult sacral meningocele in the anterior sacral region. Contrast-enhanced radiographic imaging clearly showed the fistula tract. The patient underwent surgery via the posterior approach; debridement of the sacral osteomyelitis was performed and the fistula tract toward the skin was closed. RESULTS: She was pain free after surgery. There were no postoperative complications. CONCLUSION: Although vertebral osteomyelitis due to ASMs is extremely rare, the risk of infection increases in cases of a fistula to the skin. When investigating the etiology of treatment-resistant infections, especially of the skin, sacral osteomyelitis and an underlying anomaly must be kept in mind. PMID- 23034887 TI - Transnasal endoscopic removal of intraorbital wooden foreign body. AB - INTRODUCTION: Traditionally retrobulbar lesions localized in the medial part of the orbit are removed using rather extensive extracranial approaches. A few cases were recently reported in which lesions of a certain type were removed using a transnasal endoscopic approach. We describe a patient in whom we managed to remove a sizable piece of wood from the orbit endoscopically after two former unsuccessful attempts. CASE REPORT: A 30-year-old male with a wooden foreign body localized medially behind the globe was operated on 5 days after trauma. His vision was preserved but motility of the eye globe was heavily restricted. An endoscopic transnasal, transethmoidal approach with neuronavigated tools was used to remove the foreign body successfully, using a "bimanual technique." The patient was discharged on day 1 postoperatively with intact vision. Movement restriction gradually resolved, and after 2 weeks he recovered completely. CONCLUSION: Foreign bodies localized close to the medial wall of the orbit can be safely removed using an endoscopic transnasal approach. The use of neuronavigation is essential for the precision, safety, and effectiveness of the procedure. PMID- 23034888 TI - Surgical instrument tracking optimizes trans-sphenoidal endoscopic treatment of petrous apex cholesterol granuloma. AB - During endoscopic trans-sphenoidal treatment of petrous apex cholesterol granuloma, the challenge for the surgeon is to drill the posterior wall of the sphenoid sinus to reach the lesion while attempting to avoid the internal carotid artery (ICA). A refined neuronavigation technique is presented that diminishes bonework needed for exposure and marsupialization, and simultaneously minimizes risks of accidental harm to the ICA. The technique utilizes real-time intraoperative instrument tracking of a drill, enabling safe creation of a direct canal toward the cyst just medial to the paraclival ICA and of a curette for entirely image-guided marsupialization of the cyst's deep areas through the canal. PMID- 23034889 TI - Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy. AB - Lung cancer is the leading cause of cancer death worldwide as well as in Taiwan. Interleukin-6 (IL-6) is a multifunctional cytokine and has been implicated in tumor progression. This study recruited 245 patients with advanced (Stage 3B/4) nonsmall cell lung cancer (NSCLC) that had received chemotherapy, to evaluate associations between IL-6 and lung cancer-specific survival. Among these subjects, 112 gave blood samples before and 133 after the start of chemotherapy. Plasma IL-6 was measured using an enzyme linked-immunosorbent assay. The 33rd and 66th percentiles of IL-6 concentrations were 2.01 and 25.16 for the 245 patients and were defined as the cutoff points for dividing the patients into low, intermediate and high groups. Kaplan-Meier and Cox proportional-hazard models were used to evaluate the relationship between the IL-6 level and survival time. Results after adjusting for age, sex, smoking history, histologic type and stage of lung cancer revealed a significant relationship. For all patients, the hazard ratio with high IL-6 levels for lung cancer-specific survival was 2.10 [95% confidence interval (CI) = 1.49 - 2.96] compared with low IL-6 levels. The hazard ratio for patients who were recruited before and after the start of chemotherapy was1.25 (95% CI = 0.73 - 2.13) and 3.66 (95% CI = 2.18 - 6.15), respectively. Patients with high circulating IL-6 also responded poorly to chemotherapy. Therefore, a high level of circulating IL-6 was associated with an inferior response and survival outcome in NSCLC patients treated with chemotherapy. PMID- 23034891 TI - Imatinib assay by high-performance liquid chromatography in tandem mass spectrometry with solid-phase extraction in human plasma. AB - We have developed a method of liquid chromatography in tandem with mass spectrometry to monitor therapeutic levels of imatinib in plasma, a selective inhibitor of protein tyrosine kinase. After solid-phase extraction of plasma samples, imatinib and its internal standard, imatinib-D8, were eluted with Zorbax SB-C18 at 60 degrees C, under isocratic conditions through a mobile phase consisting of 4 mm ammonium formate, pH: 3.2 (solution A) and acetonitrile solution B. The flow rate was 0.8 mL/min with 55% solution A + 45% solution B. Imatinib was detected and quantified by mass spectrometry with electrospray ionization operating in selected-reaction monitoring mode. The calibration curve was linear in the range 10-5000 ng/mL, the lower limit of quantitation being 10 ng/mL. The method was validated according to the recommendations of the Food and Drug Administration, including tests of matrix effect (bias < 10%) and recovery efficiency (>80 and <120%). The method is precise (coefficient of variance intra day <2% and inter-day <7%), accurate (95-108%), sensitive and specific. It is a simple method with very fast recording time (1.2 min) that is applicable to clinical practice. This will permit improvement of the pharmacological treatment of patients. PMID- 23034892 TI - Maximum likelihood pedigree reconstruction using integer linear programming. AB - Large population biobanks of unrelated individuals have been highly successful in detecting common genetic variants affecting diseases of public health concern. However, they lack the statistical power to detect more modest gene-gene and gene environment interaction effects or the effects of rare variants for which related individuals are ideally required. In reality, most large population studies will undoubtedly contain sets of undeclared relatives, or pedigrees. Although a crude measure of relatedness might sometimes suffice, having a good estimate of the true pedigree would be much more informative if this could be obtained efficiently. Relatives are more likely to share longer haplotypes around disease susceptibility loci and are hence biologically more informative for rare variants than unrelated cases and controls. Distant relatives are arguably more useful for detecting variants with small effects because they are less likely to share masking environmental effects. Moreover, the identification of relatives enables appropriate adjustments of statistical analyses that typically assume unrelatedness. We propose to exploit an integer linear programming optimisation approach to pedigree learning, which is adapted to find valid pedigrees by imposing appropriate constraints. Our method is not restricted to small pedigrees and is guaranteed to return a maximum likelihood pedigree. With additional constraints, we can also search for multiple high-probability pedigrees and thus account for the inherent uncertainty in any particular pedigree reconstruction. The true pedigree is found very quickly by comparison with other methods when all individuals are observed. Extensions to more complex problems seem feasible. PMID- 23034890 TI - Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome. AB - Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in 925 Finnish breast cancer patients and further analyzed five single nucleotide polymorphisms (SNPs) in PRKAG2 (rs1029946, rs4726050, rs6464153, rs7789699) and PPP2R2B (rs10477313) for 10-year survival in breast cancer patients, interaction with TP53 R72P and MDM2-SNP309, outcome after specific adjuvant therapy and correlation to tumor characteristics in 4,701 invasive cases from four data sets. We found evidence for carriers of PRKAG2 rs1029946 and PRKAG2-rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.3-0.9; p = 0.023 for homozygous carriers of the rare G-allele and HR 0.85, 95% CI 0.7-0.9; p = 0.049 for carriers of the rare G allele, respectively). PRKAG2-rs4726050 showed a significant interaction with MDM2 SNP309, with PRKAG2-rs4726050 rare G-allele having a dose-dependent effect for better breast cancer survival confined only to MDM2 SNP309 rare G-allele carriers (HR 0.45, 95% CI 0.2-0.7; p = 0.001). This interaction also emerged as an independent predictor of better survival (p = 0.047). PPP2R2B-rs10477313 rare A allele was found to predict better survival (HR 0.82, 95% CI 0.6-0.9; p = 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.5-0.9; p = 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as PRKAG2 and PPP2R2B might affect prognosis and treatment outcome in breast cancer patients. PMID- 23034893 TI - Purification and characterization of an antitumor protein with deoxyribonuclease activity from edible mushroom Agrocybe aegerita. AB - SCOPE: Mushrooms are well known for their nutritional and medicinal value. Agrocybe aegerita has been used as a nutritious food around the world and for its herbal medicinal properties in Asia. In recent years, several antitumor proteins have been identified from A. aegerita. The objective of this study was to purify a novel antitumor protein from A. aegerita. METHODS AND RESULTS: A novel antitumor protein A. aegerita deoxyribonuclease (AAD) was purified through a two step chromatographic procedure and was shown to possess antitumor activity against different cancer cell lines. Cells treated with AAD produced typical apoptotic morphological changes, which include chromatin condensation, the accumulation of sub-G1 cells and caspase-8 cleavage. Biochemical characterization of AAD showed that it was a member of the DNase I family and that it possessed divalent metal ion-dependent endonuclease activity. The optimal temperature for AAD activity was 50 degrees C and its optimal pH was 8.5. The MS-identified peptides of AAD were found to match to Unigene3821, which has 97% homology with Aa-Pri1, in our A. aegerita transcriptome. CONCLUSION: We have identified a novel antitumor protein from A. aegerita. This fuller understanding of A. aegerita would help us to enhance its use in nutritional and medical applications. PMID- 23034894 TI - Modeling seasonality in space-time infectious disease surveillance data. AB - Infectious disease data from surveillance systems are typically available as multivariate times series of disease counts in specific administrative geographical regions. Such databases are useful resources to infer temporal and spatiotemporal transmission parameters to better understand and predict disease spread. However, seasonal variation in disease notification is a common feature of surveillance data and needs to be taken into account appropriately. In this paper, we extend a time series model for spatiotemporal surveillance counts to incorporate seasonal variation in three distinct components. A simulation study confirms that the different types of seasonality are identifiable and that a predictive approach suggested for model selection performs well. Application to surveillance data on influenza in Southern Germany reveals a better model fit and improved one-step-ahead predictions if all three components allow for seasonal variation. PMID- 23034895 TI - Purification of transthyretin as nutritional biomarker of selenium status. AB - Transthyretin has been proposed as nutritional biomarker of selenium intake. Previous transthyretin purification methods used different procedures to isolate transthyretin either from plasma or from pathological urine of humans. In general, the procedure for purification of transthyretin is laborious and expensive, and extensive sample recycling is necessary for purification in appreciable amounts. This work proposes a new, promissory, and cheap two-step process to purify transthyretin from blood plasma, composed by a first aqueous two-phase system fractionation followed by affinity chromatography, using thyroxine-immobilized on epoxy-activated Sepharose CL-6B. The aqueous two-phase system fractionation was demonstrated to perform better than commercial immunoaffinity-based kits for albumin depletion in blood plasma samples and is an effective first step for transthyretin purification. Thyroxine affinity chromatography was designed to bind transthyretin with high affinity, and was demonstrated to be useful to purify transthyretin, but was unable to completely resolve transthyretin from thyroxine-binding globulin and serum albumin, although the relative amount of albumin was lowered in the eluates. This purification process could be used in nutritional diagnosis tools or as a first step in structural and functional studies. PMID- 23034896 TI - Spatial structure of heptapeptide Abeta(16-22) (beta-amyloid Abeta(1-40) active fragment) in solution and in complex with a biological membrane model. AB - The spatial structure of an active fragment of beta-amyloid Abeta(1-40) heptapeptide Abeta(16-22) (Lys-Leu-Val-Phe-Phe-Ala-Glu) in aqueous buffer solution and in complex with sodium dodecyl sulfate micelles as a model membrane system was investigated by (1)H NMR spectroscopy and two-dimensional NMR (TOCSY, HSQC-HECADE (Heteronuclear Couplings from ASSCI-domain experiments with E.COSY type crosspeaks), NOESY) spectroscopy. Complex formation was confirmed by the chemical shift changes of the heptapeptide's (1)H NMR spectra, as well as by the signs and values of the NOE effects in different environments. We compared the spatial structure of the heptapeptide in borate buffer solution and in complex with a model of the cell surface membrane. PMID- 23034897 TI - Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis. AB - Tumor tropism of human bone marrow-derived mesenchymal stem cells (MSC) has been exploited for the delivery of therapeutic genes for anticancer therapy. However, the exact contribution of these cells in the tumor microenvironment remains unknown. In this study, we examined the biological effect of MSC on tumor cells. The results showed that MSC inhibited the growth of human glioma cell lines and patient-derived primary glioma cells in vitro. Coadministration of MSC and glioma cells resulted in significant reduction in tumor volume and vascular density, which was not observed when glioma was injected with immortalized normal human astrocytes. Using endothelial progenitor cells (EPC) from healthy donors and HUVEC endothelial cells, the extent of EPC recruitment and capacity to form endothelial tubes was significantly impaired in conditioned media derived from MSC/glioma coculture, suggesting that MSC suppressed tumor angiogenesis through the release of antiangiogenic factors. Further studies using antibody array showed reduced expression of platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1beta in MSC/glioma coculture when compared with controls. In MSC/glioma coculture, PDGF-BB mRNA and the corresponding proteins (soluble and membrane bound forms) as well as the receptors were found to be significantly downregulated when compared with that of glioma cocultured with normal human astrocytes or glioma monoculture. Furthermore, IL-1beta, phosphorylated Akt, and cathepsin B proteins were also reduced in MSC/glioma. Taken together, these data indicated that the antitumor effect of MSC may be mediated through downregulation of PDGF/PDGFR axis, which is known to play a key role in glioma angiogenesis. STEM Cells2013;31:146-155. PMID- 23034898 TI - Epitope-specificity of recombinant antibodies reveals promiscuous peptide-binding properties. AB - Protein-peptide interactions are a common occurrence and essential for numerous cellular processes, and frequently explored in broad applications within biology, medicine, and proteomics. Therefore, understanding the molecular mechanism(s) of protein-peptide recognition, specificity, and binding interactions will be essential. In this study, we report the first detailed analysis of antibody peptide interaction characteristics, by combining large-scale experimental peptide binding data with the structural analysis of eight human recombinant antibodies and numerous peptides, targeting tryptic mammalian and eukaryote proteomes. The results consistently revealed that promiscuous peptide-binding interactions, that is, both specific and degenerate binding, were exhibited by all antibodies, and the discovery was corroborated by orthogonal data, indicating that this might be a general phenomenon for low-affinity antibody-peptide interactions. The molecular mechanism for the degenerate peptide-binding specificity appeared to be executed through the use of 2-3 semi-conserved anchor residues in the C-terminal part of the peptides, in analogue to the mechanism utilized by the major histocompatibility complex-peptide complexes. In the long term, this knowledge will be instrumental for advancing our fundamental understanding of protein-peptide interactions, as well as for designing, generating, and applying peptide specific antibodies, or peptide-binding proteins in general, in various biotechnical and medical applications. PMID- 23034899 TI - Genetic variants of p21 and p27 and hepatocellular cancer risk in a Chinese Han population: a case-control study. AB - The p21 (Cip1/CDKN1A) and p27 (Kip1/CDKN1B) are members of the Cip/Kip family of cyclin-dependent kinase inhibitors, which can arrest cell proliferation and serve as tumour suppressors. We hypothesized that genetic variants in p21 and p27 may modify individual susceptibility to hepatocellular carcinoma (HCC). To test this hypothesis, we evaluated the associations of the polymorphisms of Ser31Arg and C+20T in p21 and C-79T and Gly109Val in p27, as well as their combinations, with HCC risk in a case-control study of 476 HCC cases and 526 cancer-free controls in a Chinese population. The matrix-assisted laser desorption ionisation time-of flight (MALDI-TOF) mass spectrometry method was performed to detect these polymorphisms. We found that the variant genotypes of p21 Ser31Arg and p27 C-79T were individually associated with a significantly increased risk of HCC, but no associations were observed for other variant genotypes. Moreover, the combined variant genotypes of the four loci were associated with a significantly increased HCC risk (adjusted OR = 2.24, 95% CI = 1.72, 2.91 among subjects carrying 3 or more variant alleles), especially among HbsAg-positive individuals (adjusted OR = 3.09, 95% CI = 1.86, 5.14). Furthermore, the combined variant genotypes of the four loci (carrying three or more variant alleles) increased a 1.93-fold (95% CI = 1.20, 3.09) and 1.76-fold (95% CI = 1.17, 2.64) risk of HCC among smokers and nonsmokers. The variant genotypes of the two genes in this study have negative correlation with the clinicopathologicals observed. These results suggest that p21 polymorphisms individually or in combination with p27 polymorphisms increases risk of HCC, particularly among HbsAg-positive individuals. PMID- 23034900 TI - [6]-Gingerol induces bone loss in ovary intact adult mice and augments osteoclast function via the transient receptor potential vanilloid 1 channel. AB - SCOPE: [6]-Gingerol, a major constituent of ginger, is considered to have several health beneficial effects. The effect of 6-gingerol on bone cells and skeleton of mice was investigated. METHODS AND RESULTS: The effects of 6-gingerol on mouse bone marrow macrophages and osteoblasts were studied. 6-Gingerol-stimulated osteoclast differentiation of bone marrow macrophages but had no effect on osteoblasts. Capsazepine, an inhibitor of TRPV1 (transient receptor potential vanilloid 1) channel, attenuated the pro-osteoclastogenic effect of 6-gingerol or capsaicin (an agonist of TRPV1). Similar to capsaicin, 6-gingerol stimulated Ca(2) + influx in osteoclasts. The effect of daily feeding of 6-gingerol for 5 wk on the skeleton of adult female Balb/cByJ mice was investigated. Mice treated with capsaicin and ovariectomized (OVx) mice served as controls for osteopenia. 6 Gingerol caused increase in trabecular osteoclast number, microarchitectural erosion at all trabecular sites and loss of vertebral stiffness, and these effects were comparable to capsaicin or OVx group. Osteoclast-specific serum and gene markers of 6-gingerol-treated mice were higher than the OVx group. Bone formation was unaffected by 6-gingerol. CONCLUSION: Daily feeding of 6-gingerol to skeletally mature female mice caused trabecular osteopenia, and the mechanism appeared to be activation of osteoclast formation via the TRPV1 channel. PMID- 23034901 TI - Novel application of T1-weighted BLADE sequences with fat suppression compared to TSE in contrast-enhanced T1-weighted imaging of the neck: cutting-edge images? AB - PURPOSE: To evaluate if the use of BLADE sequences might overcome some limitations of magnetic resonance imaging (MRI) in the extracranial head and neck, which is a diagnostically challenging area with a variety of artifacts and a broad spectrum of potential lesions. MATERIALS AND METHODS: After informed consent and Institutional Review Board approval, two different BLADE sequences with (BLADE IR) and without inversion pulse (BLADE) were compared to turbo-spin echo (TSE) with fat saturation for coronal T1-weighted postcontrast imaging of the extracranial head and neck region in 40 individuals of a routine patient collective. Visual evaluation of image sharpness, motion artifacts, vessel pulsation, contrast of anatomic structures, contrast of pathologies to surrounding tissue as well as BLADE-specific artifacts was performed by two experienced, independent readers. Statistical evaluation was done by using the Wilcoxon test. RESULTS: Both BLADE and BLADE IR were significantly superior to TSE regarding pulsation artifacts and delineation of thoracic structures. TSE provided better results concerning contrast muscle/fat tissue and contrast lymph nodes/fat. More important, it showed significantly better contrast of several lesions, facilitating the detection of patient pathology. CONCLUSION: T1-weighted coronal imaging of the extracranial head and neck region is demanding. T1 weighted BLADE sequences still have drawbacks in anatomical contrast and lesion detection but offer possibilities to achieve reasonable image quality in difficult cases with a variety of artifacts. PMID- 23034902 TI - Genetic and environmental influences on thin-ideal internalization. AB - OBJECTIVE: Current research on the etiology of thin-ideal internalization focuses on psychosocial influences (e.g., media exposure). The possibility that genetic influences also account for variance in thin-ideal internalization has never been directly examined. This study used a twin design to estimate genetic effects on thin-ideal internalization and examine if environmental influences are primarily shared or nonshared in origin. METHOD: Participants were 343 postpubertal female twins (ages: 12-22 years; M = 17.61) from the Michigan State University Twin Registry. Thin-ideal internalization was assessed using the Sociocultural Attitudes toward Appearance Questionnaire-3. RESULTS: Twin modeling suggested significant additive genetic and nonshared environmental influences on thin-ideal internalization. Shared environmental influences were small and non-significant. DISCUSSION: Although prior research focused on psychosocial factors, genetic influences on thin-ideal internalization were significant and moderate in magnitude. Research is needed to investigate possible interplay between genetic and nonshared environmental factors in the development of thin-ideal internalization. PMID- 23034903 TI - Determination of baseline susceptibility of European populations of Tuta absoluta (Meyrick) to indoxacarb and chlorantraniliprole using a novel dip bioassay method. AB - BACKGROUND: Tuta absoluta(Meyrick) is one of the most serious pests of tomato recently introduced in the Mediterranean region. A novel bioassay method designed for the accurate determination of insecticide toxicity on T. absoluta (IRAC method No. 022) was validated by three different laboratories [Greece (NAGREF), Italy (UC) and Spain (UPCT)] on European populations. RESULTS: The insecticides indoxacarb and chlorantraniliprole were used as reference products. The IRAC leaf dip method is easy to perform, producing repeatable, homogeneous responses. LC(50) values for indoxacarb ranged between 1.8 and 17.9 mg L(-1) (NAGREF), 0.93 and 10.8 mg L(-1) (UC) and 0.20 and 0.70 mg L(-1) (UPCT), resulting in a tenfold, 12-fold and fourfold difference between the least and most susceptible populations at each laboratory respectively. For chlorantraniliprole, LC(50) values ranged between 0.10 and 0.56 mg L(-1) (NAGREF), 0.23 and 1.34 mg L(-1) (UC) and 0.04 and 0.24 mg L(-1) (UPCT), resulting in a sixfold difference in all three cases. Overall, UPCT reported lower mean LC(50) to indoxacarb, while UC reported higher LC(50) to chlorantraniliprole. CONCLUSIONS: The new bioassay is reliable, providing a useful tool in the design of IRM strategies. Within each country/lab, the variability observed in the results for both indoxacarb and chlorantraniliprole can be attributed to natural variation. Future research is necessary to determine the extent to which it is possible to compare results among laboratories. PMID- 23034905 TI - Common polymorphisms for the time of living and death? PMID- 23034906 TI - Posterior medial corticothalamic connectivity and consciousness. PMID- 23034907 TI - Brain-computer interfaces for communication with nonresponsive patients. AB - A substantial number of patients who survive severe brain injury progress to a nonresponsive state of wakeful unawareness, referred to as a vegetative state (VS). They appear to be awake, but show no signs of awareness of themselves, or of their environment in repeated clinical examinations. However, recent neuroimaging research demonstrates that some VS patients can respond to commands by willfully modulating their brain activity according to instruction. Brain computer interfaces (BCIs) may allow such patients to circumvent the barriers imposed by their behavioral limitations and communicate with the outside world. However, although such devices would undoubtedly improve the quality of life for some patients and their families, developing BCI systems for behaviorally nonresponsive patients presents substantial technical and clinical challenges. Here we review the state of the art of BCI research across noninvasive neuroimaging technologies, and propose how such systems should be developed further to provide fully fledged communication systems for behaviorally nonresponsive populations. PMID- 23034909 TI - A role for the default mode network in the bases of disorders of consciousness. AB - OBJECTIVE: Functional connectivity in the default mode network (DMN) is known to be reduced in patients with disorders of consciousness, to a different extent depending on their clinical severity. Nevertheless, the integrity of the structural architecture supporting this network and its relation with the exhibited functional disconnections are very poorly understood. We investigated the structural connectivity and white matter integrity of the DMN in patients with disorders of consciousness of varying clinical severity. METHODS: Fifty-two patients--19 in a vegetative state (VS), 27 in a minimally conscious state (MCS), and 6 emerging from a minimally conscious state (EMCS)--and 23 healthy volunteers participated in the study. Structural connectivity was assessed by means of probabilistic tractography, and the integrity of the resulting fibers was characterized by their mean fractional anisotropy values. RESULTS: Patients showed significant impairments in all of the pathways connecting cortical regions within this network, as well as the pathway connecting the posterior cingulate cortex/precuneus with the thalamus, relative to the healthy volunteers. Moreover, the structural integrity of this pathway, as well as that of those connecting the posterior areas of the network, was correlated with the patients' behavioral signs for awareness, being higher in EMCS patients than those in the upper and lower ranges of the MCS patients, and lowest in VS patients. INTERPRETATION: These results provide a possible neural substrate for the functional disconnection previously described in these patients, and reinforce the importance of the DMN in the genesis of awareness and the neural bases of its disorders. PMID- 23034908 TI - A common polymorphism near PER1 and the timing of human behavioral rhythms. AB - OBJECTIVE: Circadian rhythms influence the timing of behavior, neurological diseases, and even death. Rare mutations in homologs of evolutionarily conserved clock genes are found in select pedigrees with extreme sleep timing, and there is suggestive evidence that certain common polymorphisms may be associated with self reported day/night preference. However, no common polymorphism has been associated with the timing of directly observed human behavioral rhythms or other physiological markers of circadian timing at the population level. METHODS: We performed a candidate gene association study with replication, evaluating associations between polymorphisms in homologs of evolutionarily conserved clock genes and the timing of behavioral rhythms measured by actigraphy. For validated polymorphisms, we evaluated associations with transcript expression and time of death in additional cohorts. RESULTS: rs7221412, a common polymorphism near period homolog 1 (PER1), was associated with the timing of activity rhythms in both the discovery and replication cohorts (joint p = 2.1 * 10(-7) ). Mean activity timing was delayed by 67 minutes in rs7221412(GG) versus rs7221412(AA) homozygotes. rs7221412 also showed a suggestive time-dependent relationship with both cerebral cortex (p = 0.05) and CD14+ CD16- monocyte (p = 0.02) PER1 expression and an interesting association with time of death (p = 0.015) in which rs7221412(GG) individuals had a mean time of death nearly 7 hours later than rs7221412(AA/AG) . INTERPRETATION: A common polymorphism near PER1 is associated with the timing of human behavioral rhythms, and shows evidence of association with time of death. This may be mediated by differential PER1 expression. These results may facilitate individualized scheduling of shift work, medical treatments, or monitoring of vulnerable patient populations. PMID- 23034910 TI - Cognitive impairment in lacunar strokes: the SPS3 trial. AB - OBJECTIVE: Lacunar strokes are a leading cause of cognitive impairment and vascular dementia. However, adequate characterization of cognitive impairment is lacking. The aim of this study was to estimate the prevalence and characterize the neuropsychological impairment in lacunar stroke patients. METHODS: All English-speaking participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (National Clinical Trial 00059306) underwent neuropsychological testing at baseline. Raw scores were converted to z scores using published norms. Those with impairment (z <= -1.5) in memory and/or nonmemory domains were classified as having mild cognitive impairment (MCI). RESULTS: Among the 1,636 participants, average z scores on all tests were < 0, with the largest deficits seen on tests of episodic memory (range of means, -0.65 to -0.92), verbal fluency (mean, -0.89), and motor dexterity (mean, -2.5). Forty seven percent were classified as having MCI (36% amnestic, 37% amnestic multidomain, 28% nonamnestic). Of those with modified Rankin score 0-1 and Barthel score = 100, 41% had MCI. Younger age (odds ratio [OR] per 10-year increase, 0.87), male sex (OR, 1.3), less education (OR, 0.13-0.66 for higher education levels compared to 0-4 years education), poststroke disability (OR, 1.4), and impaired activities of daily living (OR, 1.8) were independently associated with MCI. INTERPRETATION: In this large, well-characterized cohort of lacunar stroke patients, MCI was present in nearly half, including many with minimal or no physical disabilities. Cognitive dysfunction in lacunar stroke patients may commonly be overlooked in clinical practice but may be as important as motor and sensory sequelae. PMID- 23034911 TI - Neuromyelitis optica lesions may inform multiple sclerosis heterogeneity debate. AB - OBJECTIVE: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are considered inflammatory demyelinating diseases with distinguishing pathological characteristics. NMO pathology shows perivascular immunoglobulin G and complement deposition, as well as an astrocytopathy with aquaporin-4 (AQP4) loss. MS lesions reveal a profound, interindividual heterogeneity in immunopathological patterns of active demyelination, which has been challenged by the description of stage dependent sequences of pathological features. The aim of our study was to compare the histological characteristics of early active demyelinating NMO and MS brain lesions. METHODS: Thirteen cases with supraspinal active demyelinating NMO lesions were analyzed using immunohistochemistry. Results were compared with the published characteristics of MS lesions. RESULTS: A subset of supraspinal lesions from AQP4-IgG-seropositive NMO patients revealed both (1) complement activation products within macrophages at sites of active demyelination and (2) oligodendrocyte apoptosis and a preferential loss of myelin-associated glycoprotein. These characteristics resemble features previously associated with MS lesion patterns II and III, and were present in addition to characteristic histopathological NMO features, namely loss of AQP4 and astrocytes. INTERPRETATION: Early active demyelinating NMO lesions may show complement within macrophages and oligodendrocyte apoptosis associated with a selective loss of minor myelin proteins, in addition to typical NMO features. We hypothesize these findings occur simultaneously only in a subset of active demyelinating NMO lesions. These observations plausibly explain the findings of Barnett and Prineas and further support the concept of interindividual heterogeneity in MS. PMID- 23034913 TI - Schwann cell glycogen selectively supports myelinated axon function. AB - OBJECTIVE: Interruption of energy supply to peripheral axons is a cause of axon loss. We determined whether glycogen was present in mammalian peripheral nerve, and whether it supported axon conduction during aglycemia. METHODS: We used biochemical assay and electron microscopy to determine the presence of glycogen, and electrophysiology to monitor axon function. RESULTS: Glycogen was present in sciatic nerve, its concentration varying directly with ambient glucose. Electron microscopy detected glycogen granules primarily in myelinating Schwann cell cytoplasm, and these diminished after exposure to aglycemia. During aglycemia, conduction failure in large myelinated axons (A fibers) mirrored the time course of glycogen loss. Latency to compound action potential (CAP) failure was directly related to nerve glycogen content at aglycemia onset. Glycogen did not benefit the function of slow-conducting, small-diameter unmyelinated axons (C fibers) during aglycemia. Blocking glycogen breakdown pharmacologically accelerated CAP failure during aglycemia in A fibers, but not in C fibers. Lactate was as effective as glucose in supporting sciatic nerve function, and was continuously released into the extracellular space in the presence of glucose and fell rapidly during aglycemia. INTERPRETATION: Our findings indicated that glycogen is present in peripheral nerve, primarily in myelinating Schwann cells, and exclusively supports large-diameter, myelinated axon conduction during aglycemia. Available evidence suggests that peripheral nerve glycogen breaks down during aglycemia and is passed, probably as lactate, to myelinated axons to support function. Unmyelinated axons are not protected by glycogen and are more vulnerable to dysfunction during periods of hypoglycemia. . PMID- 23034912 TI - Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination. AB - OBJECTIVE: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that presents with variable pathologies that may reflect different disease-causing mechanisms. Existing animal models of MS induce pathology using either local injection of gliotoxins or stimulation of the immune system with myelin-related peptides. In none of these models is the primary cellular target well characterized, and although demyelination is a hallmark pathological feature in MS, it is unclear to what extent this reflects local oligodendrocyte loss. To unambiguously identify the effects of oligodendrocyte death in the absence of inflammatory stimulation, we developed a method for experimentally inducing programmed cell death selectively in mature oligodendrocytes and assessed the effects on demyelination, immunological stimulation, and gliosis. The resulting pathology is discussed relative to observed MS pathologies. METHODS: Oligodendrocyte apoptosis was induced in the adult rat brain using a lentivirus to express experimentally inducible caspase 9 (iCP9) cDNA under transcriptional control of the promoter for myelin basic protein, which is oligodendrocyte specific. Activation of iCP9 was achieved by distal injection of a small molecule dimerizer into the lateral ventricle resulting in localized, acute oligodendrocyte apoptosis. RESULTS: Induced oligodendrocyte apoptosis resulted in rapid demyelination and robust, localized microglial activation in the absence of peripheral immune cell infiltration. Lesion borders showed layers of preserved and degraded myelin, whereas lesion cores were demyelinated but only partially cleared of myelin debris. This resulted in local proliferation and mobilization of the oligodendrocyte progenitor pool. INTERPRETATION: This approach provides a novel model to understand the pathological changes that follow from localized apoptosis of myelinating oligodendrocytes. It provides the first direct proof that initiation of apoptosis in oligodendrocytes is sufficient to cause rapid demyelination, gliosis, and a microglial response that result in lesions sharing some pathological characteristics with a subset of MS lesions. PMID- 23034914 TI - Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. AB - OBJECTIVE: Failure of remyelination is a critical impediment to recovery in multiple sclerosis (MS). Chondroitin sulfate proteoglycans (CSPGs) have been reported to accumulate in MS lesions, and we thus examined the functional roles of CSPGs on oligodendrocyte precursor cells (OPCs), oligodendrocytes, and remyelination. METHODS: We evaluated the expression of CSPGs in lysolecithin injected mouse spinal cord, an animal model of demyelination and spontaneous remyelination. The functional impact of CSPGs on OPCs and remyelination was investigated using cultured adult murine and human OPCs and by treating demyelinated mice with xyloside to reduce the CSPG deposition that occurred following injury. RESULTS: Early and robust upregulation of CSPGs following lysolecithin-induced demyelination was cleared during remyelination. In culture, CSPGs anchored onto the substratum reduced the adhesion of mouse and human OPCs and their subsequent morphological differentiation into process-bearing oligodendrocytes. Soluble CSPGs added to already adherent OPCs reduced the development of processes, whereas the acquisition of mature myelin proteins was unimpeded. Stripe assays of alternating CSPG and control substrata confirmed the nonpermissive nature of CSPGs for OPC adhesion and morphological differentiation. Enzymatic degradation of CSPGs with chondroitinase ABC was sufficient to overcome CSPG-dependent inhibition of human oligodendrocytes. Finally, in vivo xyloside treatment to reduce CSPG synthesis in lysolecithin-demyelinated mice increased numbers of OPCs and oligodendrocytes in lesions, and culminated in improved remyelination. INTERPRETATION: These results identify CSPGs as a nonpermissive substrate for OPCs and oligodendrocytes, and as a prominent impediment to remyelination. The data suggest the requirement for the neutralization of CSPGs for repair after demyelination. PMID- 23034915 TI - Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings. AB - OBJECTIVE: Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy characterized by neurogenic bladder, progressive spastic gait, and peripheral neuropathy. Polyglucosan bodies accumulate in the central and peripheral nervous systems and are often associated with glycogen branching enzyme (GBE) deficiency. To improve clinical diagnosis and enable future evaluation of therapeutic strategies, we conducted a multinational study of the natural history and imaging features of APBD. METHODS: We gathered clinical, biochemical, and molecular findings in 50 APBD patients with GBE deficiency from Israel, the United States, France, and the Netherlands. Brain and spine magnetic resonance images were reviewed in 44 patients. RESULTS: The most common clinical findings were neurogenic bladder (100%), spastic paraplegia with vibration loss (90%), and axonal neuropathy (90%). The median age was 51 years for the onset of neurogenic bladder symptoms, 63 years for wheelchair dependence, and 70 years for death. As the disease progressed, mild cognitive decline may have affected up to half of the patients. Neuroimaging showed hyperintense white matter abnormalities on T2 and fluid attenuated inversion recovery sequences predominantly in the periventricular regions, the posterior limb of the internal capsule, the external capsule, and the pyramidal tracts and medial lemniscus of the pons and medulla. Atrophy of the medulla and spine was universal. p.Y329S was the most common GBE1 mutation, present as a single heterozygous (28%) or homozygous (48%) mutation. INTERPRETATION: APBD with GBE deficiency, with occasional exceptions, is a clinically homogenous disorder that should be suspected in patients with adult onset leukodystrophy or spastic paraplegia with early onset of urinary symptoms and spinal atrophy. PMID- 23034917 TI - Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. AB - OBJECTIVE: Mutations in the glucocerebrosidase gene (GBA) represent a significant risk factor for developing Parkinson disease (PD). We investigated the enzymatic activity of glucocerebrosidase (GCase) in PD brains carrying heterozygote GBA mutations (PD+GBA) and sporadic PD brains. METHODS: GCase activity was measured using a fluorescent assay in cerebellum, frontal cortex, putamen, amygdala, and substantia nigra of PD+GBA (n = 9-14) and sporadic PD brains (n = 12-14). Protein expression of GCase and other lysosomal proteins was determined by western blotting. The relation between GCase, alpha-synuclein, and mitochondria function was also investigated in vitro. RESULTS: A significant decrease in GCase activity was observed in all PD+GBA brain areas except the frontal cortex. The greatest deficiency was in the substantia nigra (58% decrease; p < 0.01). GCase activity was also significantly decreased in the substantia nigra (33% decrease; p < 0.05) and cerebellum (24% decrease; p < 0.05) of sporadic PD brains. GCase protein expression was lower in PD+GBA and PD brains, whereas increased C/EBP homologous protein and binding immunoglobulin protein levels indicated that the unfolded protein response was activated. Elevated alpha-synuclein levels or PTEN-induced putative kinase 1 deficiency in cultured cells had a significant effect on GCase protein levels. INTERPRETATION: GCase deficiency in PD brains with GBA mutations is a combination of decreased catalytic activity and reduced protein levels. This is most pronounced in the substantia nigra. Biochemical changes involved in PD pathogenesis affect wild-type GCase protein expression in vitro, and these could be contributing factors to the GCase deficiency observed in sporadic PD brains. PMID- 23034916 TI - 5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease. AB - OBJECTIVE: The 5-lipoxygenase (5LO) enzyme is upregulated in Alzheimer disease (AD), and its genetic absence reduces Abeta levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated. METHODS: To this end, we generated triple transgenic mice (3xTg-AD) overexpressing neuronal 5LO and investigated their phenotype. RESULTS: Compared with controls, 3xTg-AD mice overexpressing 5LO manifested an exacerbation of memory deficits, plaques, and tangle pathologies. The elevation in Abeta was secondary to an upregulation of gamma-secretase pathway, whereas tau hyperphosphorylation resulted from an activation of the Cdk5 kinase. In vitro study confirmed the involvement of this kinase in the 5LO-dependent tau phosphorylation, which was independent of the effect on Abeta. INTERPRETATION: Our findings highlight the novel functional role that neuronal 5LO plays in exacerbating AD-related tau pathologies. They provide critical preclinical evidence to justify testing selective 5LO inhibitors for AD treatment. PMID- 23034918 TI - Subthalamic discharges as a causal determinant of parkinsonian motor deficits. AB - OBJECTIVE: We have reported that intrinsic membrane properties, especially T-type Ca2+ channels, play a key role in the genesis of burst discharges in the subthalamic nucleus (STN) and parkinsonian locomotor symptoms. Whether deep brain stimulation (DBS) exerts its clinical benefits on Parkinson disease (PD) with changes in T currents or other conductances, however, remains elusive. METHODS: Different stimulation protocols, including constant currents of opposite polarity, were applied to STN in vivo or in vitro, and the electrophysiological and behavioral effects were documented in normal and parkinsonian rodents. The effect of correlatively adjusted DBS protocols was also explored in 3 PD patients. RESULTS: Delivery of negative constant current into STN dramatically ameliorated locomotor deficits in parkinsonian rats. It also depolarized STN neurons and decreased T-channel availability as well as burst discharges. In contrast, delivery of positive constant currents to STN induced PD-like locomotor deficits and increased STN burst discharges in normal rats. In addition, the therapeutic effect of DBS was greatly improved in 3 PD patients simply by increasing the pulse width from 60 to 240 microseconds, even at a lower stimulation frequency of 60 Hz. INTERPRETATION: The increased tendency of STN burst discharges may by itself serve as a direct cause of parkinsonian locomotor deficits, even in the absence of deranged dopaminergic innervation. Effective DBS therapy in PD very likely relies on adequate depolarization, and consequent modification of the relevant ionic currents and discharge patterns, of STN neurons. PMID- 23034920 TI - Beaten into action: a perspective on blood sports. PMID- 23034921 TI - Neurology's chronic pain challenge. PMID- 23034922 TI - HEADACHE: a neurology success story--and a funding frustration. PMID- 23034923 TI - CCAAT/enhancer binding protein beta is expressed in satellite cells and controls myogenesis. AB - Upon injury, muscle satellite cells become activated and produce skeletal muscle precursors that engage in myogenesis. We demonstrate that the transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) is expressed in the satellite cells of healthy muscle. C/EBPbeta expression is regulated during myogenesis such that C/EBPbeta is rapidly and massively downregulated upon induction to differentiate. Furthermore, persistent expression of C/EBPbeta in myoblasts potently inhibits differentiation at least in part through the inhibition of MyoD protein function and stability. As a consequence, myogenic factor expression, myosin heavy chain expression, and fusogenic activity were reduced in C/EBPbeta-overexpressing cells. Using knockout models, we demonstrate that loss of Cebpb expression in satellite cells results in precocious differentiation of myoblasts in growth conditions and greater cell fusion upon differentiation. In vivo, loss of Cebpb expression in satellite cells resulted in larger muscle fiber cross-sectional area and improved repair after muscle injury. Our results support the notion that C/EBPbeta inhibits myogenic differentiation and that its levels must be reduced to allow for activation of MyoD target genes and the progression of differentiation. PMID- 23034924 TI - Restore ward rounds to former glory to improve patient care, say colleges. PMID- 23034925 TI - Screening for type 2 diabetes doesn't affect mortality at 10 years. PMID- 23034926 TI - Poly(2-oxazoline)s--are they more advantageous for biomedical applications than other polymers? AB - Poly(2-alkyl-2-oxazoline)s are biocompatible polymers with polypeptide-isomeric structures that are attracting increasing interest as biomaterials for drug, gene, protein, and radionuclide delivery. They are, however, still relatively new in comparison to other classes of hydrophilic water-soluble polymers already established for such use, including poly(ethylene oxide), polyvinylpyrrolidone, and polymethacrylamides such as poly[N-(2-hydroxypropyl)methacrylamide]. This feature article critically compares the synthetic aspects and physicochemical and biological properties of poly(2-alkyl-2-oxazoline)s and these commonly studied polymers in terms of their suitability for biomedical applications. PMID- 23034927 TI - Deaths involving 1,1-difluoroethane at the San Diego County Medical Examiner's Office. AB - Intentional abuse of 1,1-difluoroethane has been reported to cause transient symptoms such as confusion, tremors, pulmonary irritation, loss of consciousness and, rarely, coma. In the last five years, 17 cases from the San Diego County Medical Examiner's Office showed the presence of 1,1-difluoroethane in postmortem tissues, and the gas was cited in the cause of death in 13 of those cases. Detected during routine ethanol screening, 1,1-difluoroethane was evaluated for concentrations in peripheral blood, central blood and vitreous humor by a slightly modified method published by Avella et al. In many cases, death from abuse of 1,1-difluoroethane seemed to occur within minutes of intentional abuse; large concentrations (>100 mg/L) of the gas were still in the blood. It is important that forensic toxicology laboratories have routine screening procedures to detect 1,1-difluoroethane because cases exist in which evidence of use from cans may not be present in proximity to the decedent, or may be undiscovered in the debris of a motor vehicle accident. It is also important to quantify concentrations of 1,1-difluoroethane in both peripheral blood and central blood, whose ratio may be useful in interpreting how recently the use of the 1,1 difluoroethane occurred. PMID- 23034928 TI - Concentration ratios of methamphetamine to amphetamine in blood can help to distinguish use of methamphetamine from various mixtures of the two stimulants. AB - Using a forensic toxicology database, the authors investigated cases of driving under the influence of drugs (DUID) if methamphetamine (MA) was identified in the blood samples (N = 9,310). The concentrations of MA and amphetamine (AM) in blood were determined after liquid-liquid extraction by gas chromatography-mass spectrometry at limits of quantitation of 0.03 mg/L for both stimulants. In 814 cases, AM was negative in blood and MA was positive at mean (median) and highest concentrations of 0.19 mg/L (0.11 mg/L) and 3.4 mg/L, respectively. Both amines were present in blood in 8,496 cases at concentrations of 0.54 mg/L (0.35 mg/L) and 10.4 mg/L for AM and 0.41 mg/L (0.22 mg/L) and 5.6 mg/L for MA. However, the correlation between AM and MA was low and insignificant (r = -0.13) in the whole material. The coefficient of correlation increased to r = 0.41 (P < 0.001) when the MA/AM concentration ratio was >1. When MA/AM ratios were selected at intervals of 1.0 (e.g., >3.0 and <4.0 up to >9.0 and <10.0), the correlation between AM and MA was r = 0.99 (P < 0.001). Such cases represent the use of MA without contamination from AM, and the mean (median) and highest concentrations of this secondary amine in blood of DUID suspects were 0.72 mg/L (0.56 mg/L) and 4.2 mg/L, respectively. PMID- 23034929 TI - Chemical imaging beyond the diffraction limit: experimental validation of the PTIR technique. AB - Photothermal induced resonance (PTIR) has recently attracted great interest for enabling chemical identification and imaging with nanoscale resolution. In this work, electron beam nanopatterned polymer samples are fabricated directly on 3D zinc selenide prisms and used to experimentally evaluate the PTIR lateral resolution, sensitivity and linearity. It is shown that PTIR lateral resolution for chemical imaging is comparable to the lateral resolution obtained in the atomic force microscopy height images, up to the smallest feature measured (100 nm). Spectra and chemical maps are produced from the thinnest sample analyzed (40 nm). More importantly, experiments show for the first time that the PTIR signal increases linearly with thickness for samples up to ~ 1 MUm (linearity limit); a necessary requirement towards the use of the PTIR technique for quantitative chemical analysis at the nanoscale. Finally, the analysis of thicker samples provides the first evidence that the previously developed PTIR signal generation theory is correct. It is believed that the findings of this work will foster nanotechnology development in disparate applications by proving the basis for quantitative chemical analysis with nanoscale resolution. PMID- 23034930 TI - Longitudinal study of parent caregiving self-efficacy and parent stress reactions with pediatric cancer treatment procedures. AB - BACKGROUND: Pain/distress during pediatric cancer treatments has substantial psychosocial consequences for children and families. We examined relationships between parents' caregiving self-efficacy, parents' affect in response to their children's cancer-related treatment procedures, and parents' symptoms of post traumatic stress at follow-up. METHODS: Participants were 75 pediatric cancer patients and parents. On the day of each of three procedures (i.e., port-start, lumbar puncture, or bone marrow aspiration), parents rated their self-efficacy for six caregiving goals. Parents also self-reported their negative affect (i.e., state anxiety, negative mood, and distress) in response to each procedure. Three months after the last procedure, parents reported their level of post-traumatic stress symptoms (PTSS). RESULTS: Higher parent self-efficacy about keeping children calm before treatment and/or keeping children calm during the procedure was associated with lower state anxiety. Self-efficacy for keeping the child calm during procedures was significantly correlated with distress in parents at the time of procedures, and self-efficacy for keeping the child calm before procedures was significantly correlated with PTSS. All three negative affect measures significantly mediated the effects of parents' caregiving self-efficacy for both goals on parents' PTSS 3 months later. CONCLUSIONS: Parents' caregiving self-efficacy influences their immediate and longer-term distress reactions to their children's treatment procedures. These findings provide a more nuanced understanding of how parents' cognitions contribute to their ability to cope with their children's treatment and suggest the benefit of an intervention that targets parents' procedure-specific caregiver self-efficacy. PMID- 23034931 TI - Interplay between protein carbonylation and nitrosylation in plants. AB - ROS and reactive nitrogen species (RNS) are key regulators of redox homeostasis in living organisms including plants. As control of redox homeostasis plays a central function in plant biology, redox proteomics could help in characterizing the potential roles played by ROS/RNS-induced posttranslational modification in plant cells. In this review, we focus on two posttranslational modifications: protein carbonylation (a marker of protein oxidation) and protein S nitrosylation, both of which having recently emerged as important regulatory mechanisms during numerous fundamental biological processes. Here, we describe the recent progress in proteomic analysis of carbonylated and nitrosylated proteins and highlight the achievements made in understanding the physiological basis of these oxy/nitro modifications in plants. In addition, we document the existence of a relationship between ROS-based carbonylation and RNS-based nitrosylation thus supporting the finding that crosstalk between cellular signaling stress pathways induced by ROS and RNS could be mediated by specific protein modifications. PMID- 23034932 TI - Acceptability and feasibility of a virtual intervention to help people living with HIV manage their daily therapies. AB - We conducted a study of the acceptability and feasibility of a web application which was designed to empower people living with HIV to manage their daily antiretroviral therapies. The application (VIH-TAVIE) consists of four interactive computer sessions with a virtual nurse who guides the user through a learning process aimed at enhancing treatment management capacities. The information furnished and the strategies proposed by the nurse are tailored, based on the responses provided by the user. The application was evaluated in a hospital setting as an adjunct to usual care. The participants (n = 71) had a mean age of 47 years (SD = 7.6). There were 59 men and 12 women. They had been diagnosed with HIV some 15 years earlier and had been on antiretroviral medication for a mean duration of 11 years. Data were collected by acceptability questionnaires, field notes and observations. Most participants found the application easy to use. They learned tips for taking their medication, diminishing adverse side-effects and maintaining a positive attitude towards treatment. Many participants deemed their experience with the application highly satisfactory and felt that it met their needs with respect to strategies and proficiencies despite their long experience of medication use. The results of the study support the feasibility and acceptability of the intervention. PMID- 23034933 TI - A pilot study using interactive SMS support groups to prevent mother-to-child HIV transmission in South Africa. AB - We investigated the feasibility of using mobile phone text messaging (SMS) to promote adherence to antiretroviral therapy among HIV-infected pregnant women recently diagnosed with HIV. Seven HIV-positive women (15-33 weeks gestation) from two urban antenatal clinics received mobile phones and were invited to use text messaging to discuss HIV, health and pregnancy over a 12-week period. All participants were connected to each other and to a clinician who guided the group and answered questions via group SMS messaging. A total of 1018 individual messages were sent regarding medical and psychosocial topics related to HIV and mother-to-child HIV transmission. Participants sent an average of 16 messages per enrolled, technology-problem-free week. Half the messages (51%) concerned medical information, and the remainder concerned social comments or addressed psychological matters. Four post-intervention interviews with participants revealed overall satisfaction and participants recommended that the group be offered in the future. The pilot project's anonymity, non-rigid nature and remote access allowed it to overcome stigma and logistical challenges where a conventional support intervention would probably have failed. PMID- 23034934 TI - Thrombolysis to stroke mimics in telestroke. AB - Stroke mimics are patients diagnosed initially with stroke who finally receive a different diagnosis, such as seizure, conversion disorder or encephelopathy. We compared the number of stroke mimics receiving thrombolytic therapy via a telestroke network and via a conventional primary stroke centre. We reviewed the data on all patients who received intravenous t-PA through the ARSAVES statewide telestroke network or at the University of Arkansas for Medical Sciences (UAMS) stroke centre between November 2008 and January 2012. During the study period there were 252 patients (46 UAMS, 206 ARSAVES). Of the 206 telestroke patients, 141 patients (68%) were transferred to the UAMS and were examined there by a vascular neurologist where a diagnosis of stroke or stroke mimic was made; 65 patients (32%) stayed at the peripheral site and were excluded from the present study. Of the 189 study patients, 3-month outcome data were available on 166 (89%), 43 from UAMS (94%) and 123 from ARSAVES (87%). The mean door to needle time was significantly shorter at the UAMS (72 min vs. 91 min, P = 0.001). However, the percentage of good outcomes was similar in both groups (70% vs. 58%, P = 0.21) and both groups had similar total time from symptom onset to treatment (154 min vs. 156 min, P = 0.81) and similar baseline characteristics. The percentage of stroke mimics was similar in the two groups: UAMS 4.3% and ARSAVES 7.8% (P = 0.53). Although making a diagnosis of stroke mimic may be challenging on face-to-face encounter, our study shows that this challenge does not increase if telemedicine is used instead. Larger prospective studies are now required to confirm the findings of our study. PMID- 23034935 TI - User engagement with and attitudes towards an interactive SMS reminder system for patients with tuberculosis. AB - We conducted a qualitative study to understand user perceptions, acceptability and engagement with an interactive SMS reminder system designed to improve treatment adherence for patients with tuberculosis (TB). Patients received daily reminders and were asked to respond after taking their medication. Non-responsive patients were sent up to three reminders a day. We enrolled 30 patients with TB who had access to a mobile phone and observed their engagement with the system for a one-month period. We also conducted semi-structured interviews with 24 patients to understand their experience with the system. Most patients found the reminders helpful and encouraging. The average response rate over the study period was 57%. However, it fell from a mean response rate of 62% during the first ten days to 49% during the last ten days. Response rates were higher amongst females, participants with some schooling, and participants who had sent an SMS message the week prior to enrolment. Non-responsiveness was associated with a lack of access to the owner of the mobile phone, problems with the mobile phone itself and literacy. Our pilot study suggests that interactive SMS reminders are an acceptable and appreciated method of supporting patients with TB in taking their medication. PMID- 23034936 TI - The story of a new insecticidal chemistry class: the diamides. AB - This paper describes the story of the invention of the diamides, a novel chemical class of insecticides. It starts with the pioneering work by Nihon Nohyaku researchers, who developed a herbicide lead with weak insecticidal activity to flubendiamide, a highly potent lepidoptericide. The journey continues with Nissan's isoxazolines and the invention of the anthranilamides by DuPont, culminating in the discovery of the blockbuster chlorantraniliprole and its analogue cyantraniliprole. The next steps are Syngenta's sulfoximines and bicyclic anthranilamides, Ishihara Sangyo Kaisha's cyclopropylamides, Sumitomo's hydrazides, Bayer's pyrazoles and tetrazoles, BASF's sulfoximines and more recent contributions from Chinese agrochemical companies and academic institutions. The diamides affect calcium homeostasis by binding to ryanodine receptors and releasing calcium from the intracellular stores. Investigations at Nihon Nohyaku, DuPont and Bayer on the action of the diamides on ryanodine receptors will be briefly reported. PMID- 23034937 TI - Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling. AB - Augmented Wnt signaling has been implicated in many fibrotic diseases including obstructive nephropathy. Soluble form Klotho has been reported to function as a secreted Wnt antagonist. In this study, we tested whether Klotho protein could reduce renal fibrosis by inhibition of Wnt signaling. Transgenic mice that overexpressed Klotho, wild-type mice, and Klotho hetero mutant mice underwent unilateral ureteral obstruction (UUO). In some Klotho hetero mutant mice, Klotho encoding plasmid was transferred into the skeletal muscle by electroporation. UUO induced activation of Wnt signaling in wild-type but less in Klotho transgenic mice. Enhanced tubulointerstitial fibrosis in wild-type mice was also attenuated in Klotho transgenic mice. In contrast, Wnt signaling and concomitant tubulointerstitial fibrosis were further augmented in Klotho hetero mutant mice after UUO compared with wild-type mice. In Klotho-encoding plasmid-transfected Klotho hetero mutant mice, however, Wnt signaling was markedly reduced accompanied by a decrease in extracellular matrix deposition after UUO. In vitro studies showed that stimulation of Wnt3a induced prolonged cell cycle arrest at G(2)/M phase, with a resultant increase in production of fibrogenic cytokines. Cotreatment with Klotho bypassed the G(2)/M arrest and reduced fibrogenic cytokine production. In conclusion, Klotho is a critical negative regulator of Wnt signaling and a suppressor of renal fibrosis in the obstructed kidney model. PMID- 23034938 TI - Zona occludens-2 protects against podocyte dysfunction induced by ADR in mice. AB - Zona occludens-2 (ZO-2) is a protein present at the tight junction and nucleus of epithelial cells. ZO-2 represses the transcription of genes regulated by the Wnt/beta-catenin pathway. This pathway plays a critical role in podocyte injury and proteinuria. Here, we analyze whether the overexpression of ZO-2 in the glomerulus, by hydrodynamics transfection, prevents podocyte injury mediated by the Wnt/beta-catenin pathway in the mouse model of adriamycin (ADR) nephrosis. By immunofluorescence and immunogold electron microscopy, we show that ZO-2 is present in mice glomerulus, not at the slit diaphragms where nephrin concentrates, but in the cytoplasm and at processes of podocytes. Our results indicate that in the glomeruli of mice treated with ADR, ZO-2 overexpression increases the amount of phosphorylated beta-catenin, inhibits the expression of the transcription factor snail, prevents nephrin and podocalyxin loss, reduces podocyte effacement and massive fusions, restrains proteinuria, and supports urea and creatinine clearance. These results suggest that ZO-2 could be a new target for the regulation of hyperactive Wnt/beta-catenin signaling in proteinuric kidney diseases. PMID- 23034939 TI - Multiple mechanisms of ligand interaction with the human organic cation transporter, OCT2. AB - OCT2 is the entry step for organic cation (OC) secretion by renal proximal tubules. Although many drugs inhibit OCT2 activity, neither the mechanistic basis of their inhibition nor their transport status is generally known. Using representatives of several structural classes of OCT2-inhibitory ligands described recently (Kido Y, Matsson P, Giacomini KM. J Med Chem 54: 4548-4558, 2011), we determined the kinetic basis of their inhibition of 1-methyl-4 phenylpyridinium (MPP) transport into Chinese hamster ovary cells that stably expressed hOCT2. The "cluster II" inhibitors (which contain known OCT2 substrates) metformin and cimetidine interacted competitively with MPP. However, other cluster II compounds, including tetraethylammonium (TEA), diphenidol and phenyltoloxamine, were mixed-type inhibitors of MPP transport (i.e., decreasing J(max) and increasing K(t)). A cluster III (neutral steroid) representative, adrenosterone, and a cluster I (large, flexible cation) representative, carvedilol, displayed noncompetitive inhibitory profiles. Competitive counterflow (CCF) was used to determine whether the inhibitory ligands served as substrates of hOCT2. Carvedilol (cluster I) and adrenosterone (cluster III) did not support CCF, consistent with the prediction that members of these structural classes are likely to be nontransported inhibitors of OCT2. The cluster II representatives MPP, metformin, cimetidine, and TEA all supported CCF, consistent with independent assessments of their OCT2-mediated transport. However, the other cluster II representatives, diphenidol and phenyltoloxamine, failed to support CCF, suggesting that neither compound is transported by OCT2. An independent assessment of diphenidol transport (using liquid chromatography with tandem mass spectroscopy) confirmed this observation. The results underscore the caution required for development of predictive models of ligand interaction with multidrug transporters. PMID- 23034940 TI - A regulated NH2-terminal Sgk1 variant with enhanced function is expressed in the collecting duct. AB - Sgk1 is a relatively unstable kinase that regulates epithelial Na(+) transport in the distal nephron of the kidney. We identified a 5' variant alternate transcript of human Sgk1 (Sgk1_v3) that is expressed in the connecting tubule and collecting duct, is regulated by aldosterone and insulin, and is predicted to encode an NH(2)-terminal variant Sgk1 isoform, Sgk1_i3. Sgk1_i3 contains a polybasic motif, KKR, in its NH(2) terminus that regulates ubiquitination and stability of the expressed protein in HEK293 cells. In Fisher rat thyroid, and mpkCCD(c14) cells, Sgk1_i3 had a significantly greater effect on Na(+) transport compared with Sgk1 and its stimulatory effect was dependent on the kinase domain. Sgk1_i3 increased the abundance of cleaved epithelial Na(+) channel (ENaC) subunits at the cell surface, which was inhibited by coexpression of Nedd4-2. Together, the data demonstrate that a renally expressed Sgk1 isoform, Sgk1_i3, shows improved stability, is regulated by insulin and aldosterone, and stimulates ENaC activity when heterologously expressed in collecting duct cells. PMID- 23034941 TI - Novel signaling mechanisms of intracellular angiotensin II-induced NHE3 expression and activation in mouse proximal tubule cells. AB - Expression of a cytosolic cyan fluorescent fusion protein of angiotensin II (ECFP/ANG II) in proximal tubules increases blood pressure in rodents. To determine cellular signaling pathways responsible for this response, we expressed ECFP/ANG II in transport-competent mouse proximal convoluted tubule cells (mPCT) from wild-type (WT) and type 1a ANG II receptor-deficient (AT(1a)-KO) mice and measured its effects on intracellular ANG II levels, surrogates of Na/H exchanger 3 (NHE3)-dependent Na(+) absorption, as well as MAP kinases and NF-kappaB signaling. In WT mPCT cells, ECFP/ANG II expression doubled ANG II levels, increased NHE3 expression and membrane phospho-NHE3 proteins threefold and intracellular Na(+) concentration by 65%. These responses were associated with threefold increases in phospho-ERK 1/2 and phospho-p38 MAPK, fivefold increases in p65 subunit of NF-kappaB, and threefold increases in phospho-IKKalpha/beta (Ser 176/180) proteins. These signaling responses to ECFP/ANG II were inhibited by losartan (AT(1) blocker), PD123319 (AT(2) blocker), U0126 (MEK1/MEK2 inhibitor), and RO 106-9920 (NF-kappaB inhibitor). In mPCT cells of AT(1a)-KO mice, ECFP/ANG II also increased the levels of NHE3, p-ERK1/2, and p65 proteins above their controls, but considerably less so than in WT cells. In WT mice, selective expression of ECFP/ANG II in vivo in proximal tubules significantly increased blood pressure and indices of sodium reabsorption, in particular levels of phosphorylated NHE3 protein in the membrane fraction and proton gradient stimulated (22)Na(+) uptake by proximal tubules. We conclude that intracellular ANG II may induce NHE3 expression and activation in mPCTs via AT(1a)- and AT(2) receptor-mediated activation of MAP kinases ERK 1/2 and NF-kappaB signaling pathways. PMID- 23034943 TI - Superoxide in AVF dysfunction: a new target for intervention. PMID- 23034942 TI - Regulation of the renal Na+-Cl- cotransporter by phosphorylation and ubiquitylation. AB - The activity of the renal thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule plays a key role in defining arterial blood pressure levels. Increased or decreased activity of the NCC is associated with arterial hypertension or hypotension, respectively. Thus it is of major interest to understand the activity of NCC using in vivo models. Phosphorylation of certain residues of the amino-terminal domain of NCC has been shown to be associated with its activation. The development of phospho-specific antibodies against these sites provides a powerful tool that is helping to increase our understanding of the molecular physiology of NCC. Additionally, NCC expression in the plasma membrane is modulated by ubiquitylation, which represents another major mechanism for regulating protein activity. This work presents a review of our current knowledge of the regulation of NCC activity by phosphorylation and ubiquitylation. PMID- 23034944 TI - Diagnostic evaluation in children with developmental delay: a cautionary tale for genetic testing. PMID- 23034945 TI - Fever, severe mucositis, and conjunctivitis in a 15-year-old male. PMID- 23034946 TI - Pediatric obesity and depression: a cross-sectional analysis of absolute BMI as it relates to children's depression index scores in obese 7- to 17-year-old children. AB - Depression and obesity are important in children because they affect health in childhood and later life. The exact relationship between obesity and depression, especially in children, remains undefined. PATIENTS AND METHODS: Using a cross sectional chart review design, our study looked at a weight management clinic based sample of 117 obese children, 7 to 17 years old, to determine the relationship between absolute BMI and depression as measured by the Children's Depression Index (CDI) while accounting for confounders, such as the child's medical problems, physical activity, and family structure. RESULTS: There was no correlation between depression as measured by the CDI and increasing BMI in obese children seeking weight management. However, we did demonstrate a positive correlation between depression and paternal absence and daily television/computer/video game time. CONCLUSIONS: Clinicians should encourage decreasing screen time and might consider family therapy for obese children in families that lack paternal involvement. PMID- 23034948 TI - Parental preference for short- versus long-course corticosteroid therapy in children with asthma presenting to the pediatric emergency department. AB - Asthma is the most common chronic condition affecting children and a prominent chief complaint in pediatric emergency departments (ED). We aimed to determine parental preference between short- and long-term courses of oral corticosteroids for use in children with mild to moderate asthma presenting to our pediatric ED with acute asthma exacerbations. We surveyed parents of asthmatic children who presented to our pediatric ED from August 2011 to April 2012. Questions characterized each patient's asthma severity, assessed parental preference among systemic steroid and inhaled medication delivery options for acute asthma management, and inquired about compliance, medication costs, and intention to follow up. The majority of our parents prefer the use of 1 to 2 days of steroids to 5 days for acute asthma exacerbations in the ED. Thus, dexamethasone is an attractive alternative to prednisone/prednisolone and should be considered in the management of acute asthma exacerbations in the ED. PMID- 23034947 TI - Adolescents and type 2 diabetes mellitus: a qualitative analysis of the experience of social support. AB - OBJECTIVE: Research on how adolescents with type 2 diabetes mellitus (T2DM) understand and use social support is limited. Therefore, we explored how adolescents with T2DM experience and perceive social support. METHODS: Adolescents with T2DM were interviewed, and data were qualitatively analyzed using Consensual Qualitative Research methodology. RESULTS: Four themes emerged: support for nondiabetes and diabetes-specific behaviors, feelings of belonging, and disclosure. All participants expressed emotional and self-care-specific support. For some, disclosure and a sense of belonging with others who had diabetes often led to support elicitation. Participants also expressed a fear of disclosing their diabetes to others. DISCUSSION: Adolescents with T2DM value tangible and emotional support for behaviors both related and not related to diabetes. Fear of disclosure was a typical experience with disclosure often limited to close friends and family. Recommendations for health professionals to assist adolescents in promoting appropriate disclosure and means of requesting support are discussed. PMID- 23034949 TI - Restructuring the Morbidity and Mortality Conference in a Department of Pediatrics to serve as a vehicle for system changes. AB - PURPOSE: Morbidity and Mortality conference (MMC) serves an important role in medical care and education. We restructured our Department of Pediatrics MMC to focus on multidisciplinary participation and improved communication among disciplines, quality improvement, and system changes for safer clinical care and enhanced learning from adverse outcomes. METHOD: The structure and philosophy of the Department of Pediatrics MMC was changed. We present guiding principles for the restructuring process and evaluation results postrestructuring, which examined achievement of conference goals, including quality improvement. RESULTS: The MMC led to system changes within the Department of Pediatrics as well as other parts of the hospital. Satisfaction with these changes was high among conference participants, who felt that the conference achieved its goals of including multiple disciplines and creating system changes. CONCLUSIONS: The successful change in the focus of the pediatric MMC conference resulted in significant hospital-wide system changes, quality improvements, enhanced education, and departmental satisfaction. PMID- 23034950 TI - Serial procalcitonin levels to detect bacteremia in febrile neutropenia. AB - BACKGROUND: Our objective was to evaluate serial procalcitonin (PCT) levels compared with an initial PCT level at admission in predicting bacteremia in pediatric febrile neutropenic oncology patients. PROCEDURE: Serum PCT levels were measured at admission (t0) and within 24 hours of admission (t1) in pediatric oncology patients presenting with fever and neutropenia. A blood culture was collected at t0 and monitored for 5 days for bacterial growth. PCT value of 0.5 ng/mL at either t0 or t1 was considered predictive for bacteremia. RESULTS: PCT levels were significantly higher in children with positive blood cultures than with negative blood cultures. Serial PCT values mirrored t1 values. Serial PCT showed 76% specificity and negative predictive value of 93% in ruling out bacteremia. CONCLUSION: Elevated PCT levels are predictive of bacteremia. Using serial PCT levels within 24 hours allowed a better prediction of bacteremia than the PCT level at t0. PMID- 23034951 TI - DNA methylation profiles define stem cell identity and reveal a tight embryonic extraembryonic lineage boundary. AB - Embryonic (ES) and epiblast (EpiSC) stem cells are pluripotent but committed to an embryonic lineage fate. Conversely, trophoblast (TS) and extraembryonic endoderm (XEN) stem cells contribute predominantly to tissues of the placenta and yolk sac, respectively. Here we show that each of these four stem cell types is defined by a unique DNA methylation profile. Despite their distinct developmental origin, TS and XEN cells share key epigenomic hallmarks, chiefly characterized by robust DNA methylation of embryo-specific developmental regulators, as well as a subordinate role of 5-hydroxymethylation. We also observe a substantial methylation reinforcement of pre-existing epigenetic repressive marks that specifically occurs in extraembryonic stem cells compared to in vivo tissue, presumably due to continued high Dnmt3b expression levels. These differences establish a major epigenetic barrier between the embryonic and extraembryonic stem cell types. In addition, epigenetic lineage boundaries also separate the two extraembryonic stem cell types by mutual repression of key lineage-specific transcription factors. Thus, global DNA methylation patterns are a defining feature of each stem cell type that underpin lineage commitment and differentiative potency of early embryo-derived stem cells. Our detailed methylation profiles identify a cohort of developmentally regulated sequence elements, such as orphan CpG islands, that will be most valuable to uncover novel transcriptional regulators and pivotal "gatekeeper" genes in pluripotency and lineage differentiation. PMID- 23034953 TI - From bare metal powders to colloidally stable TCO dispersions and transparent nanoporous conducting metal oxide thin films. PMID- 23034952 TI - Increase in multiple sclerosis activity after assisted reproduction technology. AB - OBJECTIVE: Our objective was to evaluate risk of exacerbations in multiple sclerosis (MS) patients undergoing assisted reproduction technology (ART) infertility treatment. METHODS: Sixteen patients with relapsing-remitting MS subjected to 26 ART treatment cycles receiving gonadotropin-releasing hormone (GnRH) agonists and recombinant follicle-stimulating hormone were studied prospectively. The baseline study period encompassed 12 months prior to the first cycle and 9 months after final ART cycle. Neurological examinations, brain magnetic resonance imaging (MRI), and immunology testing were conducted every 3 months. Anti-myelin-oligodendrocyte glycoprotein (MOG) antibody production, interleukin (IL)-4, IL-8, IL-10, IL-12, IL-17, interferon (IFN)-gamma, and transforming growth factor (TGF)-beta secretion by myelin basic protein- and MOG peptide-specific T cells, as well as ex vivo isolated peripheral blood mononuclear cells (PBMCs), were studied using enzyme-linked immunospot. vascular endothelial growth factor (VEGF) production by PBMCs was assessed using enzyme linked immunosorbent assay. RESULTS: ART was associated with a 7-fold increase in risk of MS exacerbation, and a 9-fold increase in risk of enhanced disease activity on MRI. Worsening was associated with higher number of cells producing IL-8, IL-12, IFN-gamma, and TGF-beta, as well as increased VEGF production by CD4(+) T cells and CXCL-12 plasma levels, all GnRH-mediated effects. A rise in 17 beta estradiol production associated with ART increased anti-MOG antibody titers, as well as B-cell survival factor BAFF (B-cell activating factor) and antiapoptotic molecule Bcl-2 levels from purified CD19(+) B cells. Finally, ART facilitated PBMC transmigration across an in vitro blood-brain barrier model, an effect mediated by IL-8, VEGF, and CXCL-12. INTERPRETATION: Results indicate a significant increase in MS disease activity in patients receiving ART, a risk that neurologists should be aware of. Reproductive hormones appear to exert an important role in regulating immune responses during the course of autoimmune diseases. PMID- 23034954 TI - Limbic system structures differentially contribute to exploratory trip organization of the rat. AB - The role of limbic system structures in spatial orientation continues to be debated. The hippocampus (HPC) has been implicated in encoding symbolic representations of environments (i.e., cognitive map), whereas entorhinal cortex (EC) function has been implicated in self-movement cue processing (i.e., dead reckoning). These distinctions largely depend on the electrophysiological characteristics of cells within these regions and behavioral tasks that typically fail to dissociate environmental and self-movement cue processing. Topographic and kinematic characteristics of exploratory trip organization have been shown to differentially depend on environmental and self-movement cue processing. The present study examines the effects of either HPC or EC lesions on exploratory trip organization under varying lighting conditions. HPC lesions selectively impaired all measures of performance under dark conditions, but spared all measures of performance under light conditions. EC lesions impaired kinematic measures related to distance estimation under all conditions and impaired all measures of performance under light conditions. These results provide evidence that the HPC is involved in processing self-movement cues but not environmental cues, and EC is involved in processing distance estimates generated from either self-movement or environmental cues. These observations provide further support for serial processing of self-movement cues through limbic system structures that converge on the HPC. PMID- 23034955 TI - MRT letter: Quantum noise removal and classification of breast mammogram images. AB - Because of the limitations of the X-ray hardware systems in mammogram machines, the quality of the breast mammogram images may undergo from poor resolution or low contrast. Quantum noise occurs in the mammogram images during acquisition due to low-count X-ray photons. In this work, an adaptive frost filter has been used to remove quantum noise. Local binary patterns have been extracted to classify breast mammograms into benign and malignant using different classifiers. Results show the superiority of the proposed algorithm in terms of sensitivity, specificity, and accuracy. Mammographic Institute Society Analysis database of mammography has been used for experimentation. Peak signal-to-noise ratio and structural similarity index measure are used to test the validity of adaptive frost filter. Experiment results show that proposed technique produces better results. PMID- 23034956 TI - Weight of the nation: moving forward, reversing the trend using medical care. PMID- 23034958 TI - Prognostic implications for insulin-sensitive and insulin-resistant normal-weight and obese individuals from a population-based cohort. AB - BACKGROUND: There are few prospective data on the prognosis of insulin-sensitive and insulin-resistant normal-weight (NW) or obese individuals. OBJECTIVES: The estimated liver fat content, incidences of hyperglycemia and cardiovascular disease, and all-cause and cardiovascular mortality rates were investigated in a population-based cohort of 1658 individuals who were categorized according to BMI and insulin resistance as defined by HOMA-IR values >=2.5 and the presence of metabolic syndrome. DESIGN: This was a prospective cohort study with a 9-y follow up. Anthropometric values, blood pressure, and blood metabolic variables were measured, and information on vital status was collected from demographic files at follow-up. RESULTS: A total of 137 of 677 NW individuals (20%) were classified as insulin resistant and normal weight (IR-NW), and 72 of 330 obese individuals (22%) were classified as insulin sensitive and obese (IS-obese). Incidences of diabetes, impaired fasting glucose, and cardiovascular events were 0.4%, 6.3%, and 3.3%, respectively, in insulin-sensitive and normal-weight (IS-NW) individuals (reference category); 5.8%, 10.2%, and 6.6%, respectively, in IR-NW individuals; and 5.6%, 8.3%, and 8.3%, respectively, in IS-obese individuals. In a multiple logistic regression model, risks of incident hyperglycemia and cardiovascular events increased in both groups compared with in the reference category [HR (95% CI): 2.54 (1.42, 4.55) and 1.98 (0.86, 4.54) in IR-NW subjects; 2.16 (1.01, 4.63) and 2.76 (1.05, 7.28) in IS-obese subjects]. The estimated liver fat content significantly increased during follow-up only in the IR-NW group in the same model. Cardiovascular mortality was 2-3-fold higher in IR-NW and IS-obese than in IS-NW individuals in a Cox regression model. CONCLUSIONS: Our data refute the existence of healthy obese phenotypes because IS-obese individuals showed increased cardiometabolic risk. The existence of unhealthy NW phenotypes is supported by their increased risk of incident hyperglycemia, fatty liver, cardiovascular events, and death. PMID- 23034957 TI - TCF7L2 genetic variants modulate the effect of dietary fat intake on changes in body composition during a weight-loss intervention. AB - BACKGROUND: TCF7L2 gene variants have been associated with increased risk of type 2 diabetes and higher adiposity. Observational studies and short-term trials have suggested that macronutrients may modify these effects. However, to our knowledge, this has yet to be verified in long-term interventions. OBJECTIVE: In a long-term intervention setting, we investigated the effects of TCF7L2 polymorphisms rs7903146 and rs12255372 and dietary total fat on changes in body composition and subsequent glycemic control. DESIGN: Data were analyzed for 591 participants in the Preventing Overweight Using Novel Dietary Strategies (Pounds Lost) trial, which is a 2-y weight-loss randomized clinical trial of diets that differed in macronutrient proportions. Adjusted means for changes in body composition at 6 and 24 mo were obtained for gene main effects and interactions with a low-fat diet (20% from energy) compared with a high-fat diet (40% from energy). Interactions with protein and carbohydrate intakes were also tested. Predicted changes in glycemic control from changes in adiposity were determined by genotype and diet type. RESULTS: Significant interactions were observed for rs12255372 TT (risk genotype) and fat intake for changes in BMI, total fat mass, and trunk fat mass (all P/q < 0.05) at 6 mo, with nonsignificant larger decreases for TT carriers on a low-fat diet. No significant associations were observed at 24 mo or for other macronutrients. Changes in body composition for TT carriers predicted reductions in plasma glucose and insulin only on the low-fat diet. CONCLUSIONS: Individuals with the TCF7L2 rs12255372 risk genotype may reduce body adiposity by consuming a diet lower in total fat. These reductions may induce better glycemic control for such individuals predisposed to type 2 diabetes. The Pounds Lost trial was registered at clinicaltrials.gov as NCT00072995. PMID- 23034960 TI - Dietary intake and dietary quality of low-income adults in the Supplemental Nutrition Assistance Program. AB - BACKGROUND: The Supplemental Nutrition Assistance Program (SNAP) aims to alleviate hunger among its beneficiaries by providing benefits to purchase nutritious foods. OBJECTIVE: We conducted a comprehensive dietary analysis of low income adults and examined differences in dietary intake between SNAP participants and nonparticipants. DESIGN: The study population comprised 3835 nonelderly adults with a household income <=130% of the federal poverty level from the 1999-2008 NHANES. The National Cancer Institute method was used to estimate the distributions of usual intake for dietary outcomes. Relative differences in dietary intake by SNAP participation were estimated with adjustment for sociodemographic characteristics and household food security. RESULTS: Few low-income adults consumed recommended amounts of whole grains, fruit, vegetables, fish, and nuts/seeds/legumes. Conversely, many low-income adults exceeded recommended limits for processed meats, sweets, and bakery desserts and sugar-sweetened beverages. Approximately 13-22% of low-income adults did not meet any food and nutrient guidelines; virtually no adults met all of the guidelines. Compared with nonparticipants, SNAP participants consumed 39% fewer whole grains (95% CI: -57%, -15%), 44% more 100% fruit juice (95% CI: 0%, 107%), 56% more potatoes (95% CI: 18%, 106%), 46% more red meat (95% CI: 4%, 106%), and, in women, 61% more sugar-sweetened beverages (95% CI: 3%, 152%). SNAP participants also had lower dietary quality scores than did nonparticipants, as measured by a modified Alternate Healthy Eating Index. CONCLUSION: Although the diets of all low-income adults need major improvement, SNAP participants in particular had lower-quality diets than did income-eligible nonparticipants. PMID- 23034959 TI - Demographic and socioeconomic correlates of adiposity assessed with dual-energy X ray absorptiometry in US children and adolescents. AB - BACKGROUND: Associations between demographic-socioeconomic characteristics and childhood obesity are complex in the United States. OBJECTIVE: We examined associations between demographic-socioeconomic characteristics (age, sex, race ethnicity, family income, household size, and birthplace) and adiposity measured by dual-energy X-ray absorptiometry in US children. DESIGN: Data were from 8-19-y old US children enrolled in NHANES 2001-2004 (n = 5436). Adiposity was expressed as the fat mass index (FMI = fat mass/height(2); in kg/m(2)), percentage body fat (%BF), and prevalence of normal, overfat, and excess fat corresponding to %BF <25%, 25-29.9%, and >=30% in boys and <30%, 30-34.9%, and >=35% in girls, respectively. We used sex-specific linear and multinomial logistic regression models adjusted for demographic-socioeconomic factors. RESULTS: The prevalence of excess fat was higher in Mexican American (36%) than in white (28%; P <= 0.10) and black (21%; P < 0.05) boys; higher in Mexican American (44%) than in white (36%; P <= 0.10) and black (35%; P < 0.05) girls; and higher in US-born (38%) than in foreign-born (29%; P <= 0.10) Mexican American boys. In boys, %BF was higher in Mexican Americans and lower in blacks than in whites (P < 0.05). Adiposity was negatively associated with family income in white boys and girls and in Mexican American girls (P < 0.05). Racial-ethnic disparities in adiposity persisted (P < 0.001) after control for demographic-socioeconomic factors available in NHANES. The R(2) for sex-specific models of %BF or FMI regressed on age, race-ethnicity, family income, household size, and birthplace ranged from 2% to 11%. CONCLUSION: The association between demographic-socioeconomic factors and adiposity among US children varied substantially by age, sex, and race-ethnicity. PMID- 23034961 TI - Introduction of a school fruit program is associated with reduced frequency of consumption of unhealthy snacks. AB - BACKGROUND: A diet high in fruit and vegetables (FV) is inversely related to chronic diseases, and some studies suggest that increasing the intake of FV reduces the intake of unhealthy snacks. OBJECTIVES: The objectives were to analyze changes in the frequency of consumption of unhealthy snacks (soda, candy, and potato chips) from 2001 to 2008 in Norwegian children, to assess whether being part of a school fruit program reduces the frequency of unhealthy snack consumption, and to explore differences in sex and socioeconomic status. DESIGN: Within the project Fruits and Vegetables Make the Marks, 1488 sixth- and seventh grade pupils from 27 Norwegian elementary schools completed a questionnaire in 2001, and 1339 sixth- and seventh-grade pupils from the same schools completed the same questionnaire in 2008. In 2001, none of the schools had any organized school fruit program. In 2008, 15 schools participated in a program and 12 did not participate in any program. RESULTS: From 2001 to 2008, the frequency of unhealthy snack consumption decreased from 6.9 to 4.6 times/wk (P < 0.001). The decrease was largest in the schools that had been included in the national free school fruit program (-2.8 times/wk). The effect of the school fruit programs was significant in reducing the frequency of unhealthy snack consumption in children of parents without higher education (from 7.8 to 4.0 times/wk; P = 0.004). CONCLUSIONS: The frequency of unhealthy snack consumption decreased from 2001 to 2008 in schoolchildren in Norway. The decrease was most evident among children at schools participating in the national free school fruit program and in children with a low socioeconomic status. PMID- 23034962 TI - Dietary phylloquinone intake and risk of type 2 diabetes in elderly subjects at high risk of cardiovascular disease. AB - BACKGROUND: Limited evidence from human and animal studies has suggested that vitamin K has a potentially beneficial role in glucose metabolism and insulin resistance. OBJECTIVE: We analyzed the cross-sectional and longitudinal associations between dietary phylloquinone intake and type 2 diabetes in elderly subjects at high cardiovascular risk. DESIGN: Cross-sectional associations were tested in 1925 men and women in the Prevention with the Mediterranean Diet trial. A longitudinal analysis was conducted on 1069 individuals free of diabetes at baseline (median follow-up: 5.5 y). Biochemical and anthropometric variables were obtained yearly. Dietary intake was collected during each annual visit by using a food-frequency questionnaire, and phylloquinone intake was estimated by using the USDA database. The occurrence of type 2 diabetes during follow-up was assessed by using American Diabetes Association criteria. RESULTS: Dietary phylloquinone at baseline was significantly lower in subjects who developed type 2 diabetes during the study. After adjustment for potential confounders, risk of incident diabetes was 17% lower for each additional intake of 100 MUg phylloquinone/d. Moreover, subjects who increased their dietary intake of vitamin K during the follow-up had a 51% reduced risk of incident diabetes compared with subjects who decreased or did not change the amount of phylloquinone intake. CONCLUSION: We conclude that dietary phylloquinone intake is associated with reduced risk of type 2 diabetes. This trial was registered at http://www.controlled-trials.com as ISRCTN35739639. PMID- 23034963 TI - Malnutrition self-screening by using MUST in hospital outpatients: validity, reliability, and ease of use. AB - BACKGROUND: Although nutritional screening with a tool such as the Malnutrition Universal Screening Tool (MUST) is recommended for outpatients, staff are under pressure to undertake a variety of other tasks. Little attention has been paid to the validity of patient self-screening with MUST. OBJECTIVE: This study in 205 outpatients with a mean (+/-SD) age of 55 +/- 17 y (56% male) assessed the practicalities of self-screening, its agreement with screening undertaken by a trained health care professional (HCP), and its test-retest reliability. DESIGN: After the participants provided consent, screening was undertaken by the patients themselves and then by a trained HCP who was unaware of the self-screening results. All patients completed an ease-of-use questionnaire. Test-retest reliability of self-screening was established in a subset of 60 patients. RESULTS: A total of 19.6% of patients categorized themselves as "at risk" of malnutrition (9.8% medium, 9.8% high). For the 3-category classification of MUST (low, medium, high), agreement between self-screening and HCP screening was 90% (kappa = 0.70; SE = 0.058, P < 0.001). For the 2-category classification (low risk, medium + high risk), agreement was 93% (kappa = 0.78, SE = 0.057, P < 0.001). Disagreements were not systematically under- or overcategorized. Test retest reliability was almost perfect (kappa = 0.94, P < 0.001). Most patients (71%) completed self-screening in <5 min. Patients found the tool easy or very easy to understand (96%) and complete (98%), with 94% reporting that they were happy to screen themselves. CONCLUSION: Self-screening involving MUST in outpatients is acceptable to patients, user-friendly, reliable, and associated with good agreement with HCP screening. This trial was registered at clinicaltrials.gov as NCT00714324. PMID- 23034964 TI - Dietary balance during pregnancy is associated with fetal adiposity and fat distribution. AB - BACKGROUND: The prenatal environment can induce permanent changes in offspring phenotype. Thinness at birth is associated with adult risk of cardiometabolic disease. OBJECTIVE: The objective was to investigate the association between maternal nutrition during pregnancy and intrauterine development of fetal body composition. DESIGN: We used prospective data from 179 Australian women with singleton pregnancies from the Women and Their Children's Health Study. A validated food-frequency questionnaire was used at 18-24 wk and 36-40 wk of gestation to quantify maternal diet during the previous 3 mo of pregnancy. Fetal body-composition measurements were ascertained from abdominal and midthigh sites by ultrasound performed at 19, 25, 30, and 36 wk. The subcutaneous fat area at each site was calculated by subtracting the lean/visceral area from the total area. RESULTS: In linear mixed-model regressions, maternal intakes of protein (b = -0.13; P = 0.04) and starch (b = 0.10; P = 0.02) and the protein:carbohydrate ratio (b = -3.61; P = 0.02) were associated with the percentage of abdominal fat, whereas SFA (b = 0.27; P = 0.04) and PUFA (b = -0.48; P = 0.03) were associated with the percentage of midthigh fat. Response surfaces for fetal adiposity were maximized at different macronutrient intakes. Abdominal fat was highest with low protein intakes (<16% of energy), and midthigh fat was highest at intermediate protein (18-21% of energy), high fat (>40% of energy), and low carbohydrate (<40% of energy) intakes. CONCLUSION: Fetal body composition may be modifiable via nutritional intervention in the mother and thus may play an important role in influencing the offspring's risk of future disease. PMID- 23034966 TI - Effect of tumor burden and subsequent surgical resection on skeletal muscle mass and protein turnover in colorectal cancer patients. AB - BACKGROUND: Cachexia is a consequence of tumor burden caused by ill-defined catabolic alterations in muscle protein turnover. OBJECTIVE: We aimed to explore the effect of tumor burden and resection on muscle protein turnover in patients with nonmetastatic colorectal cancer (CRC), which is a surgically curable tumor that induces cachexia. DESIGN: We recruited the following 2 groups: patients with CRC [n = 13; mean +/- SEM age: 66 +/- 3 y; BMI (in kg/m(2)): 27.6 +/- 1.1] and matched healthy controls (n = 8; age: 71 +/- 2 y; BMI: 26.2 +/- 1). Control subjects underwent a single study, whereas CRC patients were studied twice before and ~6 wk after surgical resection to assess muscle protein synthesis (MPS), muscle protein breakdown (MPB), and muscle mass by using dual-energy X-ray absorptiometry. RESULTS: Leg muscle mass was lower in CRC patients than in control subjects (6290 +/- 456 compared with 7839 +/- 617 g; P < 0.05) and had an additional decline after surgery (5840 +/- 456 g; P < 0.001). Although postabsorptive MPS was unaffected, catabolic changes with tumor burden included the complete blunting of postprandial MPS (0.038 +/- 0.004%/h in the CRC group compared with 0.065 +/- 0.006%/h in the control group; P < 0.01) and a trend toward increased MPB under postabsorptive conditions (P = 0.09). Although surgical resection exacerbated muscle atrophy (-7.2%), catabolic changes in protein metabolism had normalized 6 wk after surgery. The recovery in postprandial MPS after surgery was inversely related to the degree of muscle atrophy (r = 0.65, P < 0.01). CONCLUSIONS: CRC patients display reduced postprandial MPS and a trend toward increased MPB, and tumor resection reverses these derangements. With no effective treatment of cancer cachexia, future therapies directed at preserving muscle mass should concentrate on alleviating proteolysis and enhancing anabolic responses to nutrition before surgery while augmenting muscle anabolism after resection. PMID- 23034965 TI - Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial. AB - BACKGROUND: Chronic adipose tissue inflammation is a hallmark of obesity, triggering the development of associated pathologies, particularly type 2 diabetes. Long-chain n-3 PUFAs reduce cardiovascular events and exert well established antiinflammatory effects, but their effects on human adipose tissue inflammation are unknown. OBJECTIVE: We investigated whether n-3 PUFAs reduce adipose tissue inflammation in severely obese nondiabetic patients. DESIGN: We treated 55 severely obese nondiabetic patients, scheduled to undergo elective bariatric surgery, with 3.36 g long-chain n-3 PUFAs/d (EPA, DHA) or an equivalent amount of butterfat as control, for 8 wk, in a randomized open-label controlled clinical trial. The primary efficacy measure was inflammatory gene expression in visceral and subcutaneous adipose tissue samples (subcutaneous adipose tissue and visceral adipose tissue), collected during surgery after the intervention. Secondary efficacy variables were adipose tissue production of antiinflammatory n 3 PUFA-derived eicosanoids, plasma concentrations of inflammatory markers, metabolic control, and the effect of the Pro12Ala PPARG polymorphism on the treatment response. RESULTS: Treatment with n-3 PUFAs, which was well tolerated, decreased the gene expression of most analyzed inflammatory genes in subcutaneous adipose tissue (P < 0.05) and increased production of antiinflammatory eicosanoids in visceral adipose tissue and subcutaneous adipose tissue (P < 0.05). In comparison with control subjects who received butterfat, circulating interleukin-6 and triglyceride concentrations decreased significantly in the n-3 PUFA group (P = 0.04 and P = 0.03, respectively). The Pro12Ala polymorphism affected the serum cholesterol response to n-3 PUFA treatment. CONCLUSIONS: Treatment with long-chain n-3 PUFAs favorably modulated adipose tissue and systemic inflammation in severely obese nondiabetic patients and improved lipid metabolism. These effects may be beneficial in the long-term treatment of obesity. This trial was registered at clinicaltrials.gov as NCT00760760. PMID- 23034967 TI - Assessment of dietary patterns in nutritional epidemiology: principal component analysis compared with confirmatory factor analysis. AB - BACKGROUND: In the field of nutritional epidemiology, principal component analysis (PCA) has been used to derive patterns, but the robustness of interpretation might be an issue when the sample size is small. The authors proposed the alternative use of confirmatory factor analysis (CFA) to define such patterns. OBJECTIVE: The aim was to compare dietary patterns derived through PCA and CFA used as equivalent approaches in terms of stability and relevance. DESIGN: PCA and CFA were performed in 2 different studies: the Epidemiological Study on the Genetics and Environment of Asthma 2-France (EGEA2-France; n = 1236) and the Phenotype and Course of Chronic Obstructive Pulmonary Disease study-Spain (n = 274). To check for stability, PCA and CFA were also performed in 2 subsamples from the EGEA2 study (n = 618 and 309). Statistical proprieties were evaluated by 1000 bootstrapped random sets of observations for each of the 4 subsamples. For each random set of observations, the distribution of the factor loading for each pattern was obtained and represented by using box-plots. To check for relevance, partial correlations between different nutrients and the different patterns derived by either PCA or CFA were calculated. RESULTS: With the use of CFA, 2 consistent dietary patterns were derived in each subsample (the Prudent and the Western patterns), whereas dietary factors were less interpretable with the use of PCA (smaller median of factor loadings and higher dispersion), especially for the smallest subsample. Higher correlations were reported among total fiber, vitamins, minerals, and total lipids with patterns derived by using CFA than with patterns derived by using PCA. CONCLUSION: The current study shows that CFA may be a useful alternative to PCA in epidemiologic studies, especially when the sample size is small. PMID- 23034968 TI - Effects of supplementation with essential amino acids on intrahepatic lipid concentrations during fructose overfeeding in humans. AB - BACKGROUND: A high dietary protein intake has been shown to blunt the deposition of intrahepatic lipids in high-fat- and high-carbohydrate-fed rodents and humans. OBJECTIVE: The aim of this study was to evaluate the effect of essential amino acid supplementation on the increase in hepatic fat content induced by a high fructose diet in healthy subjects. DESIGN: Nine healthy male volunteers were studied on 3 occasions in a randomized, crossover design after 6 d of dietary intervention. Dietary conditions consisted of a weight-maintenance balanced diet (control) or the same balanced diet supplemented with 3 g fructose . kg(-1) . d( 1) and 6.77 g of a mixture of 5 essential amino acids 3 times/d (leucine, isoleucine, valine, lysine, and threonine) (HFrAA) or with 3 g fructose . kg(-1) . d(-1) and a maltodextrin placebo 3 times/d (HFr); there was a washout period of 4 to 10 wk between each condition. For each condition, the intrahepatocellular lipid (IHCL) concentration, VLDL-triglyceride concentration, and VLDL [(13)C]palmitate production were measured after oral loading with [(13)C]fructose. RESULTS: HFr increased the IHCL content (1.27 +/- 0.31 compared with 2.74 +/- 0.55 vol %; P < 0.05) and VLDL-triglyceride (0.55 +/- 0.06 compared with 1.40 +/- 0.15 mmol/L; P < 0.05). HFr also enhanced VLDL-[(13)C]palmitate production. HFrAA significantly decreased IHCL compared with HFr (to 2.30 +/- 0.43 vol%; P < 0.05) but did not change VLDL-triglyceride concentrations or VLDL [(13)C]palmitate production. CONCLUSIONS: Supplementation with essential amino acids blunts the fructose-induced increase in IHCL but not hypertriglyceridemia. This is not because of inhibition of VLDL-[(13)C]palmitate production. This trial was registered at www.clinicaltrials.gov as NCT01119989. PMID- 23034969 TI - Poorer survival in women with advanced ovarian cancer explains the UK's lower overall survival. PMID- 23034970 TI - Symptom interval in pediatric patients with solid tumors: adolescents are at greater risk of late diagnosis. AB - BACKGROUND: The awareness that adolescents can have cancer is probably insufficient, not only among teenagers and their families, but also among physicians, and adolescent patients are reportedly often referred to qualified cancer institutes after a considerable delay. PROCEDURE: A prospective series of 425 patients (28% of them adolescents) with solid tumors was analyzed to investigate the correlation between symptom interval and age, and the different contributions to symptom interval in terms of the time from symptom onset to the first contact with a doctor (patient delay), referral to the oncologist (referral delay), and final diagnosis (oncologist delay). RESULTS: The median symptom interval was 47 days for 0 to 14-year-old patients and 137 for those >=15 years (P < 0.001). The greatest delay in the adolescent group related to the patient delay (63.3% of the total symptom interval). CONCLUSION: Adolescents are often diagnosed with longer delay as compared to children. The main contribution to symptom interval in adolescents appears to be due to the time they first go to a doctor; however, also the time taken by the physician to the patient to a specialist (oncologist or surgeon) able to define the diagnosis of cancer was longer for adolescents than for younger patients. PMID- 23034971 TI - Dealing responsibly with the alcohol industry in London. AB - The 2012 UK Government's Alcohol Strategy for England and Wales has been welcomed broadly and resulted only in muted criticism within the UK public health community. This is despite strong continuities with previous alcohol industry constructions of the nature of the problem and preferred policy responses. This is probably because the strategy shows progress on the public health lobby's key issue of pricing of alcohol beverages. There are, however, many problems with the wider content of the strategy, showing little interest in much needed industry regulation other than on price, and an absence of commitment to investment in research. Some dilemmas posed for the research community are discussed. PMID- 23034973 TI - Seizure occurrence following nonoptimal anticonvulsant medication management during the transition into the hospital. AB - Previous work has shown that medication errors related to anticonvulsants are common during the transition into the hospital for pediatric patients. The purpose of this work was to evaluate whether children with epilepsy admitted for reasons other than epilepsy experience nonoptimal care in anticonvulsant medication management preceding the occurrence of seizures. Using a retrospective cohort of children with epilepsy admitted for reasons other than epilepsy, we created timelines from data in the medical record for the children who experienced seizures. These timelines included the timing and concentration of anticonvulsant administration and seizure occurrence. Three child neurologists independently identified whether nonoptimal care preceded the occurrence of seizures and potentially contributed to the occurrence of the seizure. Of 120 children, 18 experienced seizures and 12 experienced nonoptimal care in anticonvulsant management preceding seizure occurrence. Nonoptimal care that occurred during the transition into the hospital included missed doses of anticonvulsants, delays in administration during which seizures occurred, and patients inadvertently not receiving their home dosing of medication. Anticonvulsant medication errors are known to occur during the transition into the hospital. Here we present a case series of children who experienced nonoptimal care in anticonvulsant medication management who subsequently experienced seizures. Further work to identify how likely the outcome of seizures is following anticonvulsant medication errors, specifically focusing on timing as well as interventions to change the system issues that lead to these errors, is indicated. PMID- 23034972 TI - Cathodal transcranial direct current stimulation in children with dystonia: a pilot open-label trial. AB - Studies suggest that dystonia is associated with increased motor cortex excitability. Cathodal transcranial direct current stimulation can temporarily reduce motor cortex excitability. To test whether stimulation of the motor cortex can reduce dystonic symptoms in children, we measured tracking performance and muscle overflow using an electromyogram tracking task before and after stimulation. Of 10 participants, 3 showed a significant reduction in overflow, and a fourth showed a significant reduction in tracking error. Overflow decreased more when the hand contralateral to the cathode performed the task than when the hand ipsilateral to the cathode performed the task. Averaged over all participants, the results did not reach statistical significance. These results suggest that cathodal stimulation may allow a subset of children to control muscles or reduce involuntary overflow activity. Further testing is needed to confirm these results in a blinded trial and identify the subset of children who are likely to respond. PMID- 23034974 TI - Case report of subacute cerebellar ataxia of adolescence with long-term sequelae. AB - Acute ataxia is not an uncommon childhood complaint. It most commonly occurs in young patients secondary to a postinfectious cerebellitis, which is typically associated with a very good prognosis and recovery. In adolescence, acute cerebellar ataxia is more often the product of an etiology likely to progress into a chronic disorder without recovery to preillness baseline. In the present case, the authors describe a 15-year-old girl with subacute cerebellar ataxia of presumed immune-mediated etiology that advanced into a chronic cerebellar ataxia. Due to a family history, celiac disease was suspected as the origin of the ataxia; biopsy ruled out enteropathy, and the severe, abrupt radiological changes to the patient's cerebellum are inconsistent with the reported sequelae of gluten ataxia. This case serves as a discussion for diagnostic challenges in adolescent patients with acute cerebellar ataxia with long-term sequelae as well as providing an adjunct discussion on the neurological complications of celiac disease. PMID- 23034975 TI - Acquired demyelinating and other autoimmune disorders of the central nervous system in children. PMID- 23034976 TI - Basilar Artery Thrombosis in a Child Treated With Intravenous Tissue Plasminogen Activator and Endovascular Mechanical Thrombectomy. AB - Basilar artery occlusion in children is rare. It has a high mortality and morbidity if recanalization is not achieved before extensive brainstem infarction has occurred. An 11-year-old boy presented with a clinical and radiological "top of-the-basilar" syndrome. Intravenous tissue plasminogen activator was administered, and the patient was immediately referred to the regional stroke center. Subsequent mechanical thrombectomy using a Solitaire stent (Solitaire FR stent; ev3, Irvine, CA, USA) resulted in clot removal and recanalization of the basilar artery 4 hours after stroke onset. The patient made a full clinical recovery. To the authors' knowledge this is the first report on basilar artery occlusion in a child treated with "bridging" therapy, the combination of intravenous thrombolysis and endovascular thrombectomy. If the diagnosis can be made within the time window for intravenous thrombolysis (4.5 hours), the present case suggests that bridging therapy in pediatric basilar artery occlusion can be safe and effective. PMID- 23034977 TI - An Unusual Presentation of Chiari I Malformation. AB - The most typical symptom of Chiari malformation type I in children is headache. The authors describe a 14-year-old girl who presented with a 3-year history of gait decline and no headache, which is very unusual. After surgery to correct the Chiari I malformation, the patient's gait improved; however, she went on to develop decreased hand use with joint deformities. She was diagnosed with a probable connective tissue disorder. Patients with connective tissue disorders are at increased risk for developing Chiari I malformation. The authors discuss the possible reasons for the unusual presentation of the Chiari I malformation and possible mechanisms. The unusual presentation of Chiari I delayed this young patient's diagnosis and treatment. PMID- 23034978 TI - Leigh Syndrome and the Mitochondrial m.13513G>A Mutation: Expanding the Clinical Spectrum. AB - The mitochondrial DNA m.13513G>A mutation in the ND5 subunit gene is a frequent cause of Leigh syndrome. Patients harboring this mutation typically present with ptosis and cardiac conduction abnormalities, particularly Wolff-Parkinson-White syndrome, and have a late clinical onset, which contrasts with the typical infantile form. The authors describe a patient presenting with intrauterine growth retardation and visual impairment at 3 months of age, followed by infantile spasms, severe gastrointestinal dysmotility, and neurological regression. The patient had hyperlactacidemia and bilateral basal ganglia and brainstem lesions on MRI. Although he did not present cardiac conduction abnormalities, his mother had been diagnosed with Wolff-Parkinson-White syndrome. The m.13513G>A mutation was found in the patient's muscle and in several tissues of his mother. The present results expand the phenotype of Leigh syndrome associated with the m.13513G>A mutation, which should be suspected in patients with early-onset mitochondrial encephalopathy with infantile spasms or prominent gastrointestinal smooth muscle involvement. PMID- 23034979 TI - Diabetic Ketoacidosis in an Adult Patient With Spinal Muscular Atrophy Type II: Further Evidence of Extraneural Pathology Due to Survival Motor Neuron 1 Mutation? AB - Spinal muscular atrophy is an autosomal recessive neurodegenerative disease caused by homozygous mutation to the survival motor neuron 1 (SMN1) gene. Historically, spinal muscular atrophy has been considered to almost exclusively affect the function and survival of alpha motor neurons of the spinal cord and brainstem. With the development of animal models of spinal muscular atrophy, the presence of widespread systemic abnormalities affecting the brain, heart, and pancreas has been repeatedly noted among animals with diminished survival motor neuron protein expression. While these observations suggest similar possible effects in humans, reports of primary systemic disease manifestations among humans affected by spinal muscular atrophy are strikingly lacking. Here we report a case of a 29-year-old man with genetically confirmed spinal muscular atrophy type II who presented with new onset diabetes mellitus and diabetic ketoacidosis. PMID- 23034980 TI - Novel mutation in Sjogren-Larsson syndrome is associated with divergent neurologic phenotypes. AB - Sjogren-Larsson syndrome is an inherited disorder of lipid metabolism caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase, which results in accumulation of fatty aldehydes and alcohols and is characterized by ichthyosis, intellectual disability, and spastic diplegia/quadriplegia. The authors describe 2 unrelated Honduran patients who carried the same novel homozygous nonsense mutation (c.1309A>T, p.K437X) and ALDH3A2 DNA haplotype, but widely differed in disease severity. One patient exhibited spastic quadriplegia with unusual neuroregression, whereas the other patient had the usual static form of spastic diplegia with neurodevelopmental disabilities. Biochemical analyses showed a similar profound deficiency of fatty aldehyde dehydrogenase activity and impaired fatty alcohol metabolism in both patients' cultured fibroblasts. These results indicate that variation in the neurologic phenotype of Sjogren-Larsson syndrome is not strictly determined by the ALDH3A2 mutation or the biochemical defect as expressed in cultured fibroblasts, but by unidentified epigenetic/environmental factors, gene modifiers, or other mechanisms. PMID- 23034981 TI - A Startling Case of Neonatal Hyperekplexia Responsive to Levetiracetam: A New Alternative in Management? AB - The authors report a case of hyperekplexia presenting in the neonatal period resistant to clonazepam that responded subsequently to levetiracetam. Hyperekplexia is often misdiagnosed as epilepsy and can be difficult to manage with a particular concern over neonatal apnea and an increased risk of sudden infant death syndrome. The mainstay of therapy to date has been with clonazepam. The authors describe the salient features of their case, clinical diagnosis, and issues pertaining to management. The authors believe this is the first reported case of the use of levetiracetam for effectively treating hyperekplexia within the neonatal and infant period. PMID- 23034982 TI - The optic disc is minimal in children with idiopathic intracranial hypertension. AB - This study sought to characterize the optic disc morphology, particularly the cup to-disc ratio of the optic nerve head in children with idiopathic intracranial hypertension. The medical charts and digital optic disc photos of children with confirmed diagnosis of idiopathic intracranial hypertension were reviewed retrospectively. The optic disc area, cup area, and cup-to-disc ratio were measured digitally using VISUPAC software, and the mean values of those parameters were compared to the published norms. Of children with idiopathic intracranial hypertension, 83% had absence of the physiological cup of the optic disc, compared to 10% of children in the general population of the same age. The median disc area was 2.2 mm(2), and median cup area was 0.0mm(2), compared to the published norms of 2.69 mm(2) and 0.44 mm(2), respectively. There is very significantly high prevalence of small optic disc cups in children with idiopathic intracranial hypertension, with the cup being absent on majority of cases in our patient cohort. This may signal an underlying systemic predisposition to the development of intracranial hypertension. PMID- 23034983 TI - Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects. AB - Bone marrow mesenchymal stem cells (BM-MSCs) have multiple therapeutic potentials for regenerative, anti-inflammatory, and immunomodulatory purposes and also show promise as vehicles for gene therapy of various metastatic cancers based on their tumor-tropic capacity. However, BM-MSCs are also a source of carcinoma-associated fibroblasts (CAFs) and may promote growth and metastasis of cancer. Transforming growth factor beta (TGF-beta) signaling is required to induce CAF differentiation of mouse BM-MSCs in vivo and can induce expression of some CAF markers in human BM-MSCs in vitro. To determine whether inhibiting TGF-beta signaling in human BM MSCs can block their differentiation to CAFs induced by tumor microenvironments and the consequent protumor effects, we transduced human BM-MSCs with a lentiviral vector encoding bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a decoy TGF-beta receptor. BAMBI transduction significantly inhibited TGF-beta/Smad signaling and expression of CAF markers in human BM-MSCs treated with TGF-beta1 or tumor-conditioned medium or cocultured with cancer cells, but did not alter the stem cell properties and the tumor-tropic property of MSCs. In addition, BAMBI transduction disrupted the cytokine network mediating the interaction between MSCs and breast cancer cells. Consequently, BAMBI transduction abolished protumor effects of BM-MSCs in vitro and in an orthotopic breast cancer xenograft model, and instead significantly inhibited growth and metastasis of coinoculated cancer. These results indicated that TGF-beta signaling is essential for differentiation of human BM-MSCs to CAFs in tumor microenvironments and the consequent protumor effects, and inhibiting TGF beta/Smad pathway may improve the safety of MSC-based therapies in cancer patients. PMID- 23034984 TI - Synthesis of few-layer MoS2 nanosheet-coated TiO2 nanobelt heterostructures for enhanced photocatalytic activities. AB - MoS(2) nanosheet-coated TiO(2) nanobelt heterostructures--referred to as TiO(2)@MoS(2)--with a 3D hierarchical configuration are prepared via a hydrothermal reaction. The TiO(2) nanobelts used as a synthetic template inhibit the growth of MoS(2) crystals along the c-axis, resulting in a few-layer MoS(2) nanosheet coating on the TiO(2) nanobelts. The as-prepared TiO(2)@MoS(2) heterostructure shows a high photocatalytic hydrogen production even without the Pt co-catalyst. Importantly, the TiO(2)@MoS(2) heterostructure with 50 wt% of MoS(2) exhibits the highest hydrogen production rate of 1.6 mmol h(-1) g(-1). Moreover, such a heterostructure possesses a strong adsorption ability towards organic dyes and shows high performance in photocatalytic degradation of the dye molecules. PMID- 23034986 TI - Do we know enough about the health care use of adolescents with low back pain? PMID- 23034985 TI - Adolescent perspectives on phase I cancer research. AB - BACKGROUND: The aim of this study was to examine adolescent patients' perspectives on their understanding and decision making about a pediatric phase I cancer study. PROCEDURE: Participants included adolescents ages 14-21 years with cancer (N = 20), all of whom attended a phase I study consent conference. Participants responded to closed- and open-ended questions on a verbally administered structured interview, which assessed aspects of understanding and decision making about the phase I study. RESULTS: All participants decided to enroll in the phase I study. The majority of participants understood that participation was voluntary, entailed risks, and that they could withdraw. Most also believed that participation in the phase I study would increase the length of their lives. The most frequent reasons for enrolling were positive clinical benefit, needing an option, impact on quality of life, and few side effects or fewer than those of current or past treatments. Eighty-five percent of participants reported that they themselves made the final decision about enrollment in the phase I study. CONCLUSIONS: Most participants hoped or expected that the phase I study would provide a direct benefit (increased survival time or cure) and reported that they themselves were the final decision-maker about enrollment. Clinicians may underestimate the role of adolescents, especially if they believe that parents typically make such decisions. Future research should assess the actual participation of children and adolescents during the informed consent process and explore the role of hope in their decision making about phase I studies. PMID- 23034987 TI - Left ventricular contractile reserve after arterial switch operation for complete transposition of the great arteries: an exercise echocardiographic study. AB - AIMS: This study tested the hypothesis that left ventricular (LV) contractile reserve is altered in patients after arterial switch operation (ASO) for complete transposition of the great arteries (TGA) by non-invasive determination of LV force-frequency relationship (FFR). METHODS AND RESULTS: Thirty-two patients aged 16.2 +/- 2.1 years and 22 healthy controls were studied. M-mode parameters, transmitral early (E) and late (A) diastolic velocities, and tissue Doppler derived systolic (sm), early (em), and late (am) diastolic mitral annular velocities were determined at baseline and during submaximal exercise testing. The LV myocardial isovolumic acceleration (IVA) was measured at different heart rates during exercise for derivation of LV FFR and the average slope of IVA increment with heart rate. At baseline, patients had significantly greater E velocity, E/A and E/em ratios, shorter E deceleration time, and reduced mitral annular sm, em, and am velocities (all P < 0.05), but similar IVA (P = 0.29) compared with controls. During exercise, sm and em remained significantly reduced (P < 0.001), and LV IVA became lower (P < 0.001) in patients. The average FFR slope was significantly lower in patients (0.039 +/- 0.019 vs. 0.070 +/- 0.024 m/s(2) bpm, P < 0.001). The weighted average FFR curve of patients was flattened compared with the reported positive FFR reference curve based on a healthy paediatric cohort (P < 0.0001). Patients with variant compared with those with usual coronary arterial anatomy had significant flattening of FFR (P < 0.001) and a reduced FFR slope (P = 0.007). CONCLUSION: In adolescents and young adults after ASO, exercise stress revealed reduced LV contractile reserve, which is worse in those having variant coronary arterial anatomy. PMID- 23034988 TI - A rare consequence of blunt chest trauma: dumbbell heart with calcified pericardial band at the mid-ventricular level. PMID- 23034989 TI - Revascularization in patients with chronic ischaemic myocardial dysfunction: insights from cardiovascular magnetic resonance imaging. AB - In patients with chronic ischaemic left ventricular dysfunction, revascularization may lead to symptomatic and prognostic improvement. Cardiovascular magnetic resonance (CMR) imaging with its high spatial resolution provides the qualitative and quantitative, global and regional information on myocardial anatomy and function. In combination with a gadolinium-based contrast agent, CMR allows an accurate quantification of the myocardial scar and predicts the likelihood of functional recovery after revascularization. The aim of this review is to summarize our current understanding of the detection of myocardial viability using CMR, and why it may be the preferred technique in the assessment of patients with ischaemic cardiomyopathy. PMID- 23034990 TI - Diastolic fluttering of the aortic valve: pathognomonic M-mode features of flail cusp. PMID- 23034991 TI - Effects of late REopening of Coronary total Occlusion on micRovascular perfusion and myocarDial function: the RECORD study. AB - AIMS: The effects of the reopening of a coronary total occlusion (CoTO) on microvascular perfusion in subacute or chronic coronary syndromes are actually unclear. We aimed at evaluating the microvascular perfusion pattern by myocardial contrast echocardiography (MCE), in addition to contractile function, before and after CoTO reopening. METHODS: Twenty four patients with subacute and chronic coronary syndromes and CoTO datable >7 days underwent evaluation of microvascular perfusion and left ventricular (LV) function by MCE (Acuson Sequoia, with Sonovue, Bracco) before the reopening of the CoTO and at 9 +/- 3 months of follow up. Microvascular perfusion was semi-quantitatively assessed by the contrast score index (CSI), whereas the endocardial length of the perfusion defect [contrast defect length (CDL)], measured in three apical views and averaged, was expressed as a percentage of the total LV endocardial border. The wall motion score index (WMSI), LV volumes, and ejection fraction were also calculated. RESULTS: At baseline, a mild impairment of LV contractile function was observed, which corresponded to a similar impairment of the coronary microvascular perfusion in the overall study population. At follow-up, a significant reduction of CDL% [8.23 (0-19.63) vs. 0 (0-3.68), P = 0.005], improvement of the CSI (1.41 +/- 0.29 vs. 1.12 +/- 0.17, P = 0.001) and the WMSI (1.73 +/- 0.41 vs. 1.33 +/- 0.34, P = 0.0004), and increase in the ejection fraction (47.48% +/- 8.66 vs. 55.60% +/- 8.29, P = 0.0001) were found. CONCLUSION: Reopening of a CoTO in patients with clinical indications to myocardial revascularization is associated with the improvement of coronary microvascular perfusion and the recovery of contractile function. PMID- 23034992 TI - Early impairment of systolic right ventricular function parameters in patients with primary systemic amyloidosis. PMID- 23034993 TI - Onion-like masses in the left ventricle. PMID- 23034994 TI - Pericardial cystic lymphangioma. PMID- 23034995 TI - A large blood cyst of the mitral valve: late presentation in an 80-year-old female. PMID- 23034996 TI - Efficacy and safety of transdermal buprenorphine in the management of children with cancer-related pain. AB - BACKGROUND: The current study investigated the efficacy, safety, tolerability, and compliance of a transdermal buprenorphine delivery system for the management of chronic cancer pain in the pediatric population. PROCEDURE: Sixteen pediatric patients with moderate to severe cancer-related pain not satisfactorily controlled with previous non-opioid therapies were enrolled. Transdermal buprenorphine was administered following a 72 hour schedule and rescue medication (tramadol) was allowed for breakthrough pain. Pain intensity was assessed using the Wong-Baker faces pain rating scale (WBS) and other parameters related to the global quality of life were evaluated. Children's evaluations of efficacy, compliance, and tolerability were recorded using numerical scales. Adverse events were monitored during the study and the medications needed to control opioid related nausea and constipation were recorded. RESULTS: Eleven patients (68.75%) responded to transdermal buprenorphine after 2 weeks of treatment. Pain intensity measured with WBS decreased from 6.25 at baseline to 1.38 at Day +60 (P < 0.001). All outcome measures of global quality of life (quality of sleep, alimentation, play and activity, speech, and crying) significantly improved over the 60-day study period. Children's evaluations of compliance and tolerability of the drug were always positive over the entire period of treatment. No severe adverse events were recorded. Opioid-related nausea was well controlled with medication on request, and the need for laxative therapy was greater at the end of the second month of treatment. CONCLUSIONS: Transdermal buprenorphine was found to represent an efficient, safe and well tolerated approach to the management of children's chronic cancer pain. PMID- 23034997 TI - A transparent nanowire-based cell impalement device suitable for detailed cell nanowire interaction studies. AB - A method to fabricate inexpensive and transparent nanowire impalement devices is invented based on CuO nanowire arrays grown by thermal oxidation. By employing a novel process the nanowires are transferred to a transparent, cell-compatible epoxy membrane. Cargo delivery and detailed cell-nanowire interaction studies are performed, revealing that the cell plasma membrane tightly wraps the nanowires, while cell membrane penetration is not observed. The presented device offers an efficient investigation platform for further optimization, leading towards a simple and versatile impalement delivery system. PMID- 23035002 TI - Finger tourniquets: a review of National Patient Safety Agency recommendations, available devices and current practice. PMID- 23035003 TI - Palmar reconstruction of the triangular fibrocartilage complex for instability of the distal radioulnar joint: a biomechanical study. AB - We developed a new triangular fibrocartilage complex reconstruction technique for distal radioulnar joint instability in which the palmar portion of the triangular fibrocartilage complex was predominantly reconstructed, and evaluated whether such reconstruction can restore stability of the distal radioulnar joint in seven fresh cadaver upper extremities. Distal radioulnar joint instability was induced by cutting all soft-tissue stabilizers around the distal ulna. Using a palmar approach, a palmaris longus tendon graft was sutured to the remnant of the palmar radioulnar and ulnocarpal ligaments. The graft was then passed through a bone tunnel created at the fovea and was sutured. Loads were applied to the radius, and dorsopalmar displacements of the radius relative to the ulna were measured using an electromagnetic tracking device in neutral rotation, 60 degrees supination and 60 degrees pronation. We compared the dorsopalmar displacements before sectioning, before reconstruction and after reconstruction. Dorsopalmar instability produced by sectioning significantly improved in all forearm positions after reconstruction. PMID- 23035004 TI - Effects of a single session of whole body vibration on ankle plantarflexion spasticity and gait performance in patients with chronic stroke: a randomized controlled trial. AB - OBJECTIVE: To investigate the effects of a single session of whole body vibration training on ankle plantarflexion spasticity and gait performance in chronic stroke patients. DESIGN: Randomized controlled trial. SETTING: Rehabilitation unit in university hospital. PARTICIPANTS: Thirty subjects with chronic stroke were randomized into either a control group (n = 15) or a group receiving a single session of whole body vibration (n = 15). INTERVENTION: The intervention group was actually treated with whole body vibration while the control group was treated with placebo treatment. MAIN MEASURES: The spastic changes were measured clinically and neurophysiologically. Subjective evaluation of ankle spasticity was performed via a visual analogue scale. Gait performances were evaluated by the timed up and go test, 10-meter walk test and cadence. A forceplate was used for measuring foot pressure. RESULTS: The changes between whole body vibration and control groups were significantly different in Modified Ashworth Scale (1.33, 95% confidence interval (CI) = 1.06~1.60). The H (max)/M (max) ratio (0.14, 95% CI = 0.01~0.26) and visual analogue scale (1.87, 95% CI = 1.15~2.58) were significantly decreased. Whole body vibration could significantly improve gait velocity, timed up and go test (6.03, 95% CI = 3.17~8.89) and 10-meter walk test (1.99, 95% CI = 0.11~3.87). The uneven body weight posture on bilateral feet was also improved after vibration. CONCLUSION: These results suggest that a single session of whole body vibration training can reduce ankle plantarflexion spasticity in chronic stroke patients, thereby potentially increasing ambulatory capacity. PMID- 23035005 TI - Comparison of the therapeutic effects of ultrasound-guided platelet-rich plasma injection and dry needling in rotator cuff disease: a randomized controlled trial. AB - OBJECTIVE: To compare the effects of platelet-rich plasma injection with those of dry needling on shoulder pain and function in patients with rotator cuff disease. DESIGN: A single-centre, prospective, randomized, double-blinded, controlled study. SETTING: University rehabilitation hospital. PARTICIPANTS: Thirty-nine patients with a supraspinatus tendon lesion (tendinosis or a partial tear less than 1.0 cm, but not a complete tear) who met the inclusion criteria recruited between June 2010 and February 2011. INTERVENTION: Two dry needling procedures in the control group and two platelet-rich plasma injections in the experimental group were applied to the affected shoulder at four-week intervals using ultrasound guidance. MEASUREMENTS: The Shoulder Pain and Disability Index, passive range of motion of the shoulder, a physician global rating scale at the six-month follow-up, adverse effects monitoring and an ultrasound measurement were used as outcome measures. RESULTS: The clinical effect of the platelet-rich plasma injection was superior to the dry needling from six weeks to six months after initial injection (P < 0.05). At six months the mean Shoulder Pain and Disability Index was 17.7 +/- 3.7 in the platelet-rich plasma group versus 29.5 +/- 3.8 in the dry needling group (P < 0.05). No severe adverse effects were observed in either group. CONCLUSIONS: Autologous platelet-rich plasma injections lead to a progressive reduction in the pain and disability when compared to dry needling. This benefit is certainly still present at six months after treatment. These findings suggest that treatment with platelet-rich plasma injections is safe and useful for rotator cuff disease. PMID- 23035006 TI - Short-term effects of interferential current electro-massage in adults with chronic non-specific low back pain: a randomized controlled trial. AB - OBJECTIVES: To analyse the effectiveness of a combined procedure of massage and electrotherapy with interferential current in individuals with chronic non specific low back pain of mechanical aetiology. DESIGN: A single blinded randomized controlled trial. SETTING: Clinical setting. PARTICIPANTS: Sixty-two individuals with chronic non-specific low back pain were randomly assigned to an experimental or control group. For 10 weeks the experimental group underwent treatment comprising 20 sessions (twice a week) of massage with interferential current in the lumbar and dorsal-lumbar area, and the control group received superficial lower back massage (effleurage, superficial pressure and skin rolling). MAIN OUTCOME VARIABLES: Oswestry Disability Index, pain visual analogue scale, Tampa Scale for Kinesiophobia, Roland Morris Disability Questionnaire, McQuade Test, Side Bridge Test, quality of life scores and the range of trunk anteflexion motion, which were all assessed before the treatment and immediately after the last treatment session. RESULTS: The 2 * 2 mixed model ANOVA with repeated measurements showed statistically significant group * time interactions for the visual analogue scale (F = 12.839; P = 0.001), Oswestry Disability Index (F = 5.850; P = 0.019), Roland Morris Disability Questionnaire (F = 8.237; P = 0.006) and quality of life (physical function (F = 16.792; P = 0.001), physical role (F = 14.839; P = 0.001) and body pain (F = 11.247; P = 0.001)). CONCLUSIONS: In individuals with chronic non-specific low back pain, interferential current electro-massage achieved a significantly greater improvement in disability, pain and quality of life in comparison to superficial massage after 20 treatment sessions. PMID- 23035007 TI - The association between popliteal vein compression and deep venous thrombosis: results of a pilot study. AB - OBJECTIVE: A pilot study to clarify the association between popliteal vein compression (PVC) and deep venous thrombosis (DVT). METHOD: It is assumed that PVC and the associated change in blood flow increases the likelihood of DVT. We have selected patients who were referred to a vascular laboratory for a DVT duplex and scanned for both DVT and PVC. Duplex criteria for the diagnosis of a DVT were lack of flow and inability to compress the vein. The study was performed over 12 weeks. RESULTS: Of the 54 eligible patients, 16 had a DVT. Five of 18 patients with PVC had a distal DVT (27.7%), while five of 36 patients without PVC had distal DVT (16.7%). The difference was statistically significant (relative risk 2.9, P < 0.05). CONCLUSION: There appears to be an association between the presence of PVC and an increased likelihood of developing a DVT. If confirmed in larger studies, this will have strong implications for patient positioning in theatres, as there is a high incidence of PVC in supine anaesthetized patients. PMID- 23035008 TI - Great saphenous vein stump thrombosis after harvesting for coronary artery bypass graft surgery. AB - OBJECTIVES: To determine the rate of superficial venous thrombosis in patients undergoing great saphenous vein (GSV) harvesting for coronary artery bypass surgery (CABG). METHODS: Post-CABG patients with suspected lower-extremity thrombosis underwent duplex scanning. Thrombus in the saphenofemoral junction stump was noted, and thrombus extension and associated complications collected. RESULTS: Out of 2335 patients who underwent CABG in five years, 98 patients presented with signs and symptoms of lower-extremity thrombosis. Thrombosis was present in 19 (19.4%) of these patients, 15 of which had a thrombus in the GSV. Five patients had significant signs and symptoms of pulmonary embolism (PE). On objective diagnostic imaging, three of them had a PE. CONCLUSION: Patients undergoing great saphenous vein harvesting for CABG are at an increased risk of developing superficial vein thrombosis especially at the saphenous stump. Given the increased risk of deep vein thrombosis and PE, further studies investigating this topic are warranted. PMID- 23035009 TI - Local cooling effect on perforation rates comparing the 980-1470 nm laser wavelengths used with endovenous laser ablation: double blind in vitro experimental study. AB - OBJECTIVE: Endovenous laser treatment (EVLA) is fast gaining acceptance as an alternative to open surgery for the treatment of saphenous vein incompetence. The method of action of these techniques is based on heat, making tumescence anaesthesia necessity. Heat-induced complications may occur with inadequate application of tumescent anaesthesia. Our hypothesis was, local cooling effect of tumescent anaesthesia on tunica adventitia might be kept undamaged from disruption due to the thermal injury. METHODS: We experimented with two popular laser wavelengths (980 and 1470 nm) and with two different thermal media (+4 and +24) in vitro for perforation. Twenty different 12 cm length vein pieces were numbered randomly to set up four groups of the experiment. Endovenous laser procedures were applied in same manner in a unique design test tube with same energy density per pieces on same duration (10 W/second) (linear endovenous energy density 60 J/cm). Procedure video was recorded for macroscopic perforations. All postprocedure vein segments were examined microscopically. RESULTS: Activities of both wavelengths were much better in cold medium (P < 0.05). Cold tumescent anaesthesia reduces the bleeding complication rate. But the performance of 1470 nm laser was better than that of 980 nm in cold environment (P = 0.0136). CONCLUSIONS: It can be commented that reducing the ambient temperature is more beneficial than modifying the laser wavelength on perforation rates. Therefore we suppose tumescent anaesthesia temperature is effective on perforation independently from the wavelengths or type of the laser fibre. PMID- 23035010 TI - Venous filling time using air-plethysmography correlates highly with great saphenous vein reflux time using duplex. AB - OBJECTIVES: Venous filling time (VFT90) is the time taken to reach 90% of the venous volume in the calf. It is recorded by air-plethysmography (APG((r))) and is assumed to measure global venous reflux duration. However, this has never been confirmed by duplex. The aim of the study was to compare VFT on APG to venous reflux time/duration (RT) measured simultaneously with duplex on the same patients. METHOD: Twenty-six consecutive patients, M:F = 16:10, age (25-78), C1 = 1, C2 = 4, C3 = 8, C4a = 6, C4b = 4, C5 = 2, C6 = 1, underwent simultaneous APG with duplex. The venous filling index (VFI, mL/second), VFT90 (seconds), great saphenous vein (GSV) RT on duplex, averaged thigh GSV diameter and thigh length (length) between the APG sensor air-cuff and duplex transducer were recorded. The VFT100 was calculated by VFT90/0.9. The additional time taken to fill the thigh was achieved using the VFI, length and deep vein diameter (d), to determine the corrected reflux duration: CRD = VFT100 + (length * pid(2)/4 (1/VFI)). RESULTS: Twenty-five patients are presented. One patient with very mild reflux (VFT90 = 55.9 seconds) had an indeterminate endpoint on duplex and was excluded. The median (range) VFI and GSV diameter was 4.9(1.3-15.5) mL/second and 7(4-17) mm, respectively. The VFT90 and VFT100 both correlated with RT on duplex (Spearman, P < 0.0005) at: r = 0.933, r(2) linear = 0.72 and r = 0.933, r(2) linear = 0.68, respectively. The median (interquartile range) filling time with VFT90 was less than the duplex RT at 24 (16.9) versus 28 (20) seconds respectively, P < 0.0005 (Wilcoxon). The median percentage underestimation improved from 24% to 16% and then 4% using the VFT90, VFT100 and CRD, respectively. CONCLUSIONS: This is the first study to compare APG parameters with duplex by performing simultaneous measurements. There was an excellent correlation between the VFT90 versus duplex RT, thereby comparing reverse flow in a single superficial vein against the legs overall venous haemodynamic status. These tests can both be used in the quantification of reflux. PMID- 23035011 TI - Diabetes increases the risk of breast cancer: a meta-analysis. AB - The aim of this meta-analysis was to collate and analyse all primary observational studies investigating the risk of breast cancer (BC) associated with diabetes. In addition, we aimed to complete subgroup analyses by both type of diabetes and gender of study participants to further clarify the origin of any such association between the two. Studies were obtained from a database search of MEDLINE, EMBASE, PubMed, Current Contents Connect and Google Scholar with additional cross-checking of reference lists. Collated data were assessed for heterogeneity and a pooled odds ratio (OR) calculated. Forty-three studies were included in the meta-analysis with 40 studies investigating BC in women and six studies investigating BC in men. Overall, we found a significantly increased risk of BC associated with diabetes in women (OR 1.20, 95% confidence interval (CI) 1.13-1.29). After subgroup analysis by type of diabetes, the association was unchanged with type 2 diabetes (OR 1.22, 95% CI 1.07-1.40) and nullified with gestational diabetes (OR 1.06, 95% CI 0.79-1.40). There were insufficient studies to calculate a pooled OR of the risk of BC associated with type 1 diabetes. There was an increased risk of BC in males with diabetes mellitus; however, the results did not reach statistical significance (OR 1.29, 95% CI 0.99-1.67). In conclusion, diabetes increases the risk of BC in women. This association is confirmed in women with type 2 diabetes and supports the hypothesis that diabetes is an independent risk factor for BC. PMID- 23035012 TI - The interaction between Siglec-15 and tumor-associated sialyl-Tn antigen enhances TGF-beta secretion from monocytes/macrophages through the DAP12-Syk pathway. AB - We previously demonstrated that Siglec-15, a member of the Siglec family of glycan-recognition proteins, is expressed on a subset of macrophages and preferentially recognizes the sialyl-Tn (sTn) antigen, a tumor-associated glycan structure. In this study, we report on the biological significance of the Siglec 15-mediated interaction between monocytes/macrophages and cancer cells. Siglec-15 is expressed on tumor-associated macrophages (TAMs) in various human tumor tissues. We further demonstrated that its expression is substantially elevated in macrophage colony-stimulating factor-induced M2-like macrophages, which produced more transforming growth factor-beta (TGF-beta) in response to sTn-positive cells than to negative cells. We designed a co-culture model of THP-1 (human monocytic leukemia) cells and H157 (human lung carcinoma) cells mimicking the interaction between monocytes/macrophages and cancer cells that recapitulated the enhanced TGF-beta production in Siglec-15 expressing THP-1 cells by the cellular interaction with sTn expressing H157 cells. The enhanced TGF-beta production required a direct interaction between the two cell lines through sialic acids. Siglec-15 associates with adaptor protein DNAX activation protein of 12 kDa (DAP12) at the binding determinant Lys(274) in the transmembrane domain and transduces a signal to spleen tyrosine kinase (Syk). The enhanced TGF-beta secretion was significantly attenuated by Syk inhibitor treatment of THP-1 cells or by substitution of the Siglec-15 Lys(274) to Ala, which disrupts the molecular interaction between Siglec15 and DAP12. These findings indicate that Siglec-15 recognizes the tumoral sTn antigen and transduces a signal for enhanced TGF-beta secretion in TAMs and further suggest that Siglec-15 on macrophages may contribute to tumor progression by the TGF-beta-mediated modulation of intratumoral microenvironments. PMID- 23035013 TI - Utility of the new rheumatoid arthritis 2010 ACR/EULAR classification criteria in routine clinical care. AB - OBJECTIVES: The new 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for rheumatoid arthritis (RA) have been designed to classify early onset RA, but has not been studied to identify RA in patients with arthritis seen in routine clinical care where correct 'classification' of patients, when they are not selected for having RA would be important. DESIGN: Prospective, consecutive patients cohort. SETTING: Outpatient clinic of a university rheumatology centre. PARTICIPANTS: A total of 126 patients with joint symptoms were consecutively recruited. INTERVENTIONS: The ACR/EULAR RA criteria were applied, with questions followed by a targeted musculoskeletal exam. The gold standard for the diagnosis of RA was the primary rheumatologist's diagnosis. PRIMARY OUTCOME MEASURE: Number of patients with non-RA diagnosis who were classified as having RA by the new classification criteria. RESULTS: The sensitivity and specificity of the 2010 criteria in classifying RA were 97% and 55%, respectively, compared with the 1987 RA criteria which were 93% and 76%, respectively. The 2010 criteria as applied to this group of patients had a poorer positive predictive (44% vs 61%) and a similar negative predictive value (98% vs 97%) compared with the 1987 criteria. More specifically, 66.7% of systemic lupus erythematosus patients, 50% of osteoarthritis, 37.5% of psoriatic arthritis and 27.2% of others fulfilled the new criteria and could have been classified as RA. CONCLUSIONS: In this, we believe, the first study to examine the new 2010 ACR/EULAR RA criteria among consecutive patients seen in routine care, we found the criteria to have low specificity, and therefore incorrectly label those as having RA when, in fact, they may have a different type of inflammatory arthritis. Physicians need to be aware of this when applying the new criteria for classifying their patients for any purpose. PMID- 23035014 TI - Utilisation of primary total knee joint replacements across socioeconomic status in the Barwon Statistical Division, Australia, 2006-2007: a cross-sectional study. AB - OBJECTIVES: There are few Australian data that examine the association between total knee joint replacement (TKR) utilisation and socioeconomic status (SES). This study examined TKR surgeries with a diagnosis of osteoarthritis (OA) performed for residents of Barwon Statistical Division (BSD) for 2006-2007. DESIGN: Cross-sectional. SETTING: BSD, South-eastern Victoria, Australia PARTICIPANTS: All patients who underwent a TKR for OA, 2006-2007, and whose residential postcode was identified as within the BSD of Australia, and for whom SES data were available, were eligible for inclusion. PRIMARY OUTCOME MEASURE: Primary TKR data ascertained from the Australian Orthopaedic Association National Joint Replacement Registry. Residential addresses were matched with the Australian Bureau of Statistics census data, and the Index of Relative Socioeconomic Disadvantage was used to determine SES, categorised into quintiles whereby quintile 1 indicated the most disadvantaged and quintile 5 the least disadvantaged. Age-specific and sex-specific rates of TKR utilisation per 1000 person-years were reported for 10-year age bands. RESULTS: Females accounted for 62.7% of the 691 primary TKR surgeries performed during 2006-2007. The greatest utilisation rates of TKR in males was 7.6 observed in those aged >79 years, and in 10.2 in females observed in those aged 70-79 years. An increase in TKR was observed for males in SES quintile four compared to quintile 1 in which the lowest utilisation which was observed (p=0.04). No differences were observed in females across SES quintiles. CONCLUSIONS: Further investigation is warranted on a larger scale to examine the role that SES may play in TKR utilisation, and to determine whether any social disparities in TKR utilisation reflect health system biases or geographic differences. PMID- 23035015 TI - Does prognosis and socioeconomic status impact on trust in physicians? Interviews with patients with coronary disease in South Australia. AB - OBJECTIVES: There is concern across a range of healthcare settings worldwide that trust in physicians is declining. Decreased trust may lead to lesser tolerance of prognosis uncertainty and an increased demand for tests, referrals and second opinions. Literature suggests that there has been a recent cultural shift towards decreased trust in, and increased questioning of, medical advice. We investigated the impact of varying prognosis and socioeconomic status (SES) on trust in physicians, and patient questioning of medical advice. DESIGN: Semistructured, audio-recorded transcribed interviews were conducted. The interview schedule was developed with reference to the Health Belief Model. Interviews were conducted between October 2008 and September 2009. SETTING: Participants were recruited via general practitioner clinics and hospital cardiac rehabilitation programmes. PARTICIPANTS: Participants consisted of patients either receiving preventive treatment or active treatment for established cardiovascular disease. OUTCOME MEASURES: A coding structure was developed based on the aim of the research, to investigate the impact of varying prognosis and SES on trust in physicians. RESULTS: Older participants are more likely than their younger counterparts to be unquestioning of medical advice. Higher SES participants are more likely to question medical advice than lower SES participants. Also, unlike primary prevention participants, established pathology increased participants' trust, or decreased questioning behaviour. Participants who perceived themselves at risk of a poor or uncertain outcome were unlikely to doubt medical advice. CONCLUSIONS: Blind trust in physicians remains strong in older participants, participants who perceive their prognosis to be uncertain and a proportion of lower SES participants. This is important for practitioners in terms of patient agency and points to the importance of moral and ethical practice. However, physicians also need to be aware that there are a growing proportion of patients for whom trust needs to be developed, and cannot be assumed. PMID- 23035016 TI - Discrepancy in patient-rated and oncologist-rated performance status on depression and anxiety in cancer: a prospective study protocol. AB - OBJECTIVE: Psychological distress is common in patients with cancer. We need a rapid means of screening for and identifying depression and anxiety in patients with cancer. The present study evaluates the potential of the Eastern Cooperative Oncology Group (ECOG) performance status (PS) scoring as a brief screening tool to assess psychological distress in routine cancer care. The ECOG PS is widely used by oncologists and the WHO, as a standardised measure to assess general well being in patients with cancer and quality of life in cancer trials. We examine the discrepancy between patient-rated and oncologist-rated PS scores on the ECOG in a comparative assessment against the Hospital Anxiety and Depression Scale (HADS). METHODS AND DESIGN: This is a prospective evaluation of approximately 500 ambulatory adult cancer patients from a large academic medical centre. Participants will be asked to assess their own ECOG PS on a scale of 0-4, which will be compared to ECOG PS as rated by their oncologists. Higher ECOG PS scores indicate poorer daily functioning. Both patient-rated and oncologist-rated ECOG PS and their absolute differences will be tested for predictive and concurrent validity against the HADS. A HADS cut-off >=15 will be used. Ethics approval for this study has been secured from the institutional ethics board. Outcomes are re evaluated at 4-week to 6-week and 1-year follow-up. CONCLUSION: This study holds practical significance for rapid screening of psychological distress in the cancer clinic with the use of the ECOG PS scoring. Given the high prevalence of anxiety and depression in patients with cancer, screening is important to increase its recognition, which will, in turn, help to direct referrals and deliver appropriate intervention. This study also generates greater insight into the association between psychosomatic complaints and psychological distress. TRIAL REGISTRATION NUMBER: MEC 896.52. PMID- 23035018 TI - Invited commentary: Shift work and cancer. AB - In this issue of the Journal, Parent et al. (Am J Epidemiol. 2012;176(9):751-759) report significant associations between night-shift work and risk of cancer at several sites among men. These findings not only address the need for shift-work studies that evaluate cancers other than breast and prostate cancer but also support the increasing concern that the negative effects of shift work may be broadly applicable to risk of many cancers via the direct oncostatic properties of melatonin. Studies of shift work have been limited by a lack of detailed data for determining which aspects of this multifaceted exposure may be associated with increased cancer risk. Additionally, the influence of individual-level characteristics, such as preference for daytime activity versus nighttime activity or chronotype, has not been considered. In moving forward, launching new cohort studies of shift work and cancer risk is the most tenable approach, though it will be limited by the years of follow-up required in order to accrue adequate numbers of cancer cases. Studies incorporating biomarkers of effect are useful for providing immediate information that can aid not only in identifying the underlying mechanisms of the shift-work-cancer association but also in interpreting existing epidemiologic data and informing the design of future epidemiologic studies of cancer risk. PMID- 23035017 TI - TLR3 activation efficiency by high or low molecular mass poly I:C. AB - Toll-like receptor 3 (TLR3) plays a critical role in initiating type I IFN mediated innate immunity against viral infections. TLR3 recognizes various forms of double stranded (ds) RNA, including viral dsRNA and a synthetic mimic of dsRNA, poly I:C, which has been used extensively as a TLR3 ligand to induce antiviral immunity. The activation efficiency of TLR3 by poly I:C is influenced by various factors, including size of the ligands, delivery methods and cell types. In this study, we examined the stimulatory effect of two commercially available poly I:Cs [high molecular mass (HMM) and low molecular mass (LMM)] on TLR3 activation in various human cell types by determining the induction of type I and type III IFNs, as well as the antiviral effect. We demonstrated that the direct addition of both HMM- and LMM-poly I:C to the cultures of primary macrophages or a neuroplastoma cell line could activate TLR3. However, the transfection of poly I:C was necessary to induce TLR3 activation in other cell types studied. In all the cell lines tested, the efficiency of TLR3 activation by HMM-poly I:C was significantly higher than that by LMM-poly I:C. These observations indicate the importance and necessity of developing effective TLR3 ligands for antiviral therapy. PMID- 23035019 TI - Night work and the risk of cancer among men. AB - Night work might influence cancer risk, possibly via suppression of melatonin release. In a population-based case-control study conducted in Montreal, Quebec, Canada, between 1979 and 1985, job histories, including work hours, were elicited from 3,137 males with incident cancer at one of 11 anatomic sites and from 512 controls. Compared with men who never worked at night, the adjusted odds ratios among men who ever worked at night were 1.76 (95% confidence interval (CI): 1.25, 2.47) for lung cancer, 2.03 (95% CI: 1.43, 2.89) for colon cancer, 1.74 (95% CI: 1.22, 2.49) for bladder cancer, 2.77 (95% CI: 1.96, 3.92) for prostate cancer, 2.09 (95% CI: 1.40, 3.14) for rectal cancer, 2.27 (95% CI: 1.24, 4.15) for pancreatic cancer, and 2.31 (95% CI: 1.48, 3.61) for non-Hodgkin's lymphoma. Equivocal evidence or no evidence was observed for cancers of the stomach (odds ratio (OR) = 1.34, 95% CI: 0.85, 2.10), kidney (OR = 1.42, 95% CI: 0.86, 2.35), and esophagus (OR = 1.51, 95% CI: 0.80, 2.84) and for melanoma (OR = 1.04, 95% CI: 0.49, 2.22). There was no evidence of increasing risk with increasing duration of night work, with risks generally being increased across all duration categories. Results suggest that night work may increase cancer risk at several sites among men. PMID- 23035021 TI - Insulin resistance and the risk of stroke and stroke subtypes in the nondiabetic elderly. AB - Insulin resistance, which plays a key role in the development of diabetes mellitus, is a putative modifiable risk factor for stroke. The aim of this study was to investigate if markers of insulin resistance were associated with risk of stroke in the general elderly population. This study was part of the large population-based Rotterdam Study and included 5,234 participants who were aged 55 years or older and stroke free and diabetes free at baseline (1997-2001). Fasting insulin levels and homeostasis model assessment for insulin resistance were used as markers for insulin resistance. Cox regression was used to determine associations between insulin resistance markers and stroke risk, adjusted for age, sex, and potential confounders. During 42,806 person-years of follow-up (median: 8.6 years), 366 first-ever strokes occurred, of which 225 were cerebral infarctions, 42 were intracerebral hemorrhages, and 99 were unspecified strokes. Fasting insulin levels were not associated with risk of any stroke, cerebral infarction, or intracerebral hemorrhage. Homeostasis model assessment for insulin resistance, which almost perfectly correlated with fasting insulin levels, was also not associated with risk of stroke or stroke subtypes. In conclusion, in this population-based cohort study among nondiabetic elderly, insulin resistance markers were not associated with risk of stroke or any of its subtypes. PMID- 23035022 TI - Guidelines on similar biologics: regulatory requirements for marketing authorization in India. PMID- 23035023 TI - Pre-use/Post-sterilization Integrity Testing of Sterilizing Grade Filters. PMID- 23035024 TI - Considerations on Auditing and GxP Requirements along the Product Lifecycle. AB - The purpose of this article is to summarize the current GxP standards which need to be applied by global pharmaceutical manufacturers in order to achieve compliance with global regulatory requirements. Companies need to follow and audit against relevant global/regional and domestic laws as well as focusing on the lifecycle aspects of the product and processes involved from development through to routine commercial manufacture. This article was written under the auspices of PDA's Paradigm Change for Manufacturing Operations (PCMO(SM)) task force on risk-based auditing. PMID- 23035025 TI - Mass extraction container closure integrity physical testing method development for parenteral container closure systems. AB - Container closure integrity (CCI) is a critical factor to ensure that product sterility is maintained over its entire shelf life. Assuring the CCI during container closure (C/C) system qualification, routine manufacturing and stability is important. FDA guidance also encourages industry to develop a CCI physical testing method in lieu of sterility testing in a stability program. A mass extraction system has been developed to check CCI for a variety of container closure systems such as vials, syringes, and cartridges. Various types of defects (e.g., glass micropipette, laser drill, wire) were created and used to demonstrate a detection limit. Leakage, detected as mass flow in this study, changes as a function of defect length and diameter. Therefore, the morphology of defects has been examined in detail with fluid theories. This study demonstrated that a mass extraction system was able to distinguish between intact samples and samples with 2 MUm defects reliably when the defect was exposed to air, water, placebo, or drug product (3 mg/mL concentration) solution. Also, it has been verified that the method was robust, and capable of determining the acceptance limit using 3sigma for syringes and 6sigma for vials. LAY ABSTRACT: Sterile products must maintain their sterility over their entire shelf life. Container closure systems such as those found in syringes and vials provide a seal between rubber and glass containers. This seal must be ensured to maintain product sterility. A mass extraction system has been developed to check container closure integrity for a variety of container closure systems such as vials, syringes, and cartridges. In order to demonstrate the method's capability, various types of defects (e.g., glass micropipette, laser drill, wire) were created in syringes and vials and were tested. This study demonstrated that a mass extraction system was able to distinguish between intact samples and samples with 2 MUm defects reliably when the defect was exposed to air, water, placebo, or drug product (3 mg/mL concentration) solution. Also, it was verified that the method showed consistent results, and was able to determine the acceptance limit using 3sigma for syringes and 6sigma for vials. PMID- 23035026 TI - A survey of quality attributes of virus spike preparations used in clearance studies. AB - Demonstration of effective and consistent viral clearance by small scale models of downstream processing, typically cited as logarithmic reduction value (LRV), is an important safety requirement for biotech products. LRVs have anecdotally been reported to be inconsistent in these small-scale studies, even under controlled conditions when all process parameters are held constant. It was postulated that the quality of virus spike preparations used can in some cases adversely affect performance of these studies, which, from a regulatory standpoint, would be undesirable. This, along with topics discussed in PDA's Technical Report 47 (TR47), "Virus Preparations Used in Viral Clearance Studies," suggests that improving the quality and consistency of virus spike quality and utilizing testing procedures as described within should make these studies more reliable. However, an extensive survey to assess overall quality attributes to date has not been performed. To scout the landscape of spike preparation quality, we systematically characterized 18 commercially available virus preparations, focusing on key attributes identified in TR47: (1) infectious/total- and infectious/particle-associated copy numbers, (2) exogenous DNA/protein content and banding patterns, and (3) presence of aggregates. We found substantial variation across many of the preparations tested, often in more than one category. By modeling small-virus retentive filtration and low-pH inactivation unit operations, we show that virus preparation quality can potentially affect unit operation performance and viral clearance outcome. Our data supports the notion that during early-phase development, characterization of virus stock quality may provide an added level of control. LAY ABSTRACT: Demonstration of effective and consistent viral clearance is an important safety requirement for biotech products. However, accumulating evidence suggests that the quality of virus preparations used in clearance studies often vary, and thus potentially affect their performance. To scout the landscape of virus preparation quality, we systematically characterized 18 commercially available virus preparations, focusing on key attributes identified in PDA's Technical Report 47 (TR47). Virus Preparations Used in Viral Clearance Studies. We found substantial variation across many of the preparations tested, often in more than one attribute category. By performing small-virus retentive filtration and low-pH inactivation unit operations on a small scale, we also show that virus preparation quality can affect unit operation performance and viral clearance outcome. Our data supports the notion that during early-phase development, characterization of virus stock quality may provide an added level of control. PMID- 23035027 TI - Development of a nondestructive leak testing method utilizing the head space analyzer for ampoule products containing ethanol-based solutions. AB - The application of a head space analyzer for oxygen concentration was examined to develop a novel ampoule leak test method. Studies using ampoules filled with ethanol-based solution and with nitrogen in the headspace demonstrated that the head space analysis (HSA) method showed sufficient sensitivity in detecting an ampoule crack. The proposed method is the use of HSA in conjunction with the pretreatment of an overpressurising process known as bombing to facilitate the oxygen flow through the crack in the ampoule. The method was examined in comparative studies with a conventional dye ingress method, and the results showed that the HSA method exhibits sensitivity superior to the dye method. The results indicate that the HSA method in combination with the bombing treatment provides potential application as a leak test for the detection of container defects not only for ampoule products with ethanol-based solutions, but also for testing lyophilized products in vials with nitrogen in the head space. LAY ABSTRACT: The application of a head space analyzer for oxygen concentration was examined to develop a novel ampoule leak test method. The proposed method is the use of head space analysis (HSA) in conjunction with the pretreatment of an overpressurising process known as bombing to facilitate oxygen flow through the crack in the ampoule for use in routine production. The result of the comparative study with a conventional dye leak test method indicates that the HSA method in combination with the bombing treatment can be used as a leak test method, enabling detection of container defects. PMID- 23035028 TI - Application of flow cytometry for rapid bioburden screening in vaccine virus production. AB - Sensitive and timely detection of bioburden in presterile filtration product in aseptic processing of biologics is a critical parameter for microbial control and assurance of final product sterility. An application of automated flow cytometry system was developed for rapid microbial assessment and in-process control in vaccine virus production. In order to minimize the background signal caused by the components of the chicken egg substrate sample matrix, a sample processing method to clear somatic cell debris was included. The sample processing and the automated analysis take approximately 5 to 7 min per test sample and the method provides objective results in real time, enabling uninterrupted processing. The flow cytometry method was compared with the standard aerobic plate count method using tryptic soy agar in a parallel study of 1566 independent production-scale samples. The method was further characterized by spike recovery of five model bacterial organisms in representative sample matrix. In comparison to the culture method, the flow cytometry method was shown to be 96.2% sensitive and 98.2% specific for the detection of bioburden at a level of sensitivity suitable for the process stage requirement with the advantage of a nearly instantaneous time to result. LAY ABSTRACT: In-process bioburden control in the manufacturing of biopharmaceuticals is essential for final product sterility and integrity. In manufacturing contexts where an in-process hold time is infeasible or in cases where uninterrupted processing is desired, conventional culture-based bioburden detection methods cannot be used, as they require significant time to results that may not fit within the time constraints. In this case study we demonstrate the use of flow cytometry as an alternative rapid method that provides real-time results to enable uninterrupted processing. PMID- 23035029 TI - Container/Closure Integrity Testing and the Identification of a Suitable Vial/Stopper Combination for Low-Temperature Storage at -80 {degrees}C. AB - It was recently found that after storage of a live viral vaccine at -80 degrees C in glass vials closed with rubber stoppers, a phenomenon was revealed which had not been observed before with other viral products stored at -20 degrees C: overpressure in the vials. As this phenomenon poses a serious safety problem for medical personnel as well as for the product itself, an investigation was initiated to identify the root cause of the overpressure. After exclusion of possible root causes (differences in air temperature or atmospheric air pressure during filling and quality control testing, outgassing from the formulation buffer) the remaining hypothesis involved a possible container closure integrity issue at low temperature. The glass transition temperatures (T(g)) of many rubber stopper formulations are in the range -55 to -70 degrees C. At storage temperatures below T(g), the rubber stopper loses its elastic properties and there is a risk that the seal integrity of the vial could be compromised. Loss of seal integrity of the vials near storage temperatures of -80 degrees C would result in an ingress of cold dense gas into the vial headspace. After removal of the vials from storage at -80 degrees C, the rubber stoppers could regain their elastic properties and the vials would quickly reseal, thereby trapping the ingressed gas, which leads to overpressure in the vial headspace. Nondestructive laser-based headspace analysis was used to investigate the maintenance of container closure integrity as a function of the filling and capping/crimping process, storage and transport conditions, and vial/stopper designs. This analytical method is based on frequency modulation spectroscopy (FMS) and can be used for noninvasive headspace measurements of headspace pressure and headspace gas composition. Changes in the vial headspace composition and/or pressure are a clear marker for vials that have lost container closure integrity. LAY ABSTRACT: After storage of a live viral vaccine at -80 degrees C in glass vials closed with rubber stoppers, overpressure in some of the vials was observed, posing a serious safety problem for medical personnel as well as for the product. A working hypothesis to explain this phenomenon involved a possible container closure integrity issue at these low temperatures. The glass transition temperatures (T(g)) of many rubber stopper formulations are in the range -55 to 70 degrees C. At storage temperatures below T(g), the rubber stopper loses its elastic properties, resulting in compromised seal integrity of the vial and ingress of cold dense gas into the vial headspace. Upon thawing, the rubber stoppers regain their elastic properties and the vials quickly reseal, thereby trapping the ingressed gas, which leads to overpressure in the vial headspace. Nondestructive, laser-based headspace analysis, which is able to detect changes in headspace pressure and gas composition, was used to investigate the maintenance of container closure integrity. Changes in the vial headspace composition and/or pressure are a clear marker for vials that have lost container closure integrity. PMID- 23035030 TI - Drug delivery from the oral cavity: a focus on mucoadhesive buccal drug delivery systems. AB - Since the early 1980s the concept of mucoadhesion has gained considerable interest in pharmaceutical technology. The various advantages associated with these systems made buccal drug delivery as a novel route of drug administration. It prolongs the residence time of the dosage form at the site of application. These systems remain in close contact with the absorption tissue, the mucous membrane, and thus contribute to improved and/or better therapeutic performance of the drug and of both local and systemic effects. This review highlights the anatomy and structure of oral mucosa, mechanism and theories of mucoadhesion, factors affecting mucoadhesion, characteristics and properties of desired mucoadhesive polymers, various types of dosage forms, and general considerations in design of mucoadhesive buccal dosage forms, permeation enhancers, and evaluation methods. LAY ABSTRACT: Over the past few decades the mucoadhesive buccal drug delivery system has received a great deal of attention to develop mucoadhesive dosage forms to enable the prolonged retention at the site of action, providing a controlled release of drug for improved therapeutic outcome. Mucoadhesive drug delivery gives facility to include a permeation enhancer/enzyme inhibitor or pHmodifier in the formulation and versatility in designing as multidirectional or unidirectional release systems for local and systemic action. Local delivery to tissues of the oral cavity has a number of applications, including treatment of local conditions such as periodontal disease, bacterial and fungal infections, and aphthous stomatitis and vesiculo bullous diseases. For the treatment of chronic diseases, the mucoadhesive buccal drug delivery system allows easily accessibility and is generally well-accepted for administeringdrugs by systemic action. PMID- 23035031 TI - Multiple antidepressant potential modes of action of curcumin: a review of its anti-inflammatory, monoaminergic, antioxidant, immune-modulating and neuroprotective effects. AB - Curcumin is the principal curcuminoid of the popular Indian spice turmeric and has attracted increasing attention for the treatment of a range of conditions. Research into its potential as a treatment for depression is still in its infancy, although several potential antidepressant mechanisms of action have been identified. Research completed to date on the multiple effects of curcumin is reviewed in this paper, with a specific emphasis on the biological systems that are compromised in depression. The antidepressant effects of curcumin in animal models of depression are summarised, and its influence on neurotransmitters such as serotonin and dopamine is detailed. The effects of curcumin in moderating hypothalamus-pituitary-adrenal disturbances, lowering inflammation and protecting against oxidative stress, mitochondrial damage, neuroprogression and intestinal hyperpermeability, all of which are compromised in major depressive disorder, are also summarised. With increasing interest in natural treatments for depression, and efforts to enhance current treatment outcomes, curcumin is presented as a promising novel, adjunctive or stand-alone natural antidepressant. PMID- 23035032 TI - Reducing harm from tobacco use. AB - If current trends in smoking prevalence continue, even with the implementation of enhanced tobacco control measures, millions of smokers will continue to fall ill and die as a direct result of their smoking. Many of these will be from the most deprived groups in society - smoking continues to be one of the strongest drivers of health inequalities. The personal costs of this morbidity and mortality, as well as costs to business and the economy, are unequalled and will therefore remain high for several decades to come. However, there is an addition to the tobacco control armoury that could have a marked impact on public health, but it requires radical action to be taken. This would be to embrace harm reduction, but this approach is as controversial in the case of tobacco as it is in the case of illicit drugs from where it derives. However, harm reduction remains the Cinderella of the three major strategies for reducing smoking-related harm, the others being prevention and cessation. Here we make the case that harm reduction has an important role to play in reducing the health burden of tobacco use. PMID- 23035033 TI - The bi-annual meeting GEOMED was held in October 2011 in Victoria, British Columbia, Canada. Introduction. PMID- 23035034 TI - Bayesian point event modeling in spatial and environmental epidemiology. AB - This paper reviews the current state of point event modeling in spatial epidemiology from a Bayesian perspective. Point event (or case event) data arise when geo-coded addresses of disease events are available. Often, this level of spatial resolution would not be accessible due to medical confidentiality constraints. However, for the examination of small spatial scales, it is important to be capable of examining point process data directly. Models for such data are usually formulated based on point process theory. In addition, special conditioning arguments can lead to simpler Bernoulli likelihoods and logistic spatial models. Goodness-of-fit diagnostics and Bayesian residuals are also considered. Applications within putative health hazard risk assessment, cluster detection, and linkage to environmental risk fields (misalignment) are considered. PMID- 23035035 TI - Relationship between average leucocyte telomere length and the presence or severity of idiopathic dilated cardiomyopathy in black Africans. AB - AIMS: A reduced average leucocyte telomere length is associated with ischaemic heart failure. Whether this relationship represents a cause or consequence of heart failure or is attributed to associated risk factors and coronary artery disease is uncertain. We evaluated if average leucocyte telomere length is associated with idiopathic dilated cardiomyopathy (IDC) or its severity. METHODS AND RESULTS: We compared average leucocyte telomere length in 223 patients with heart failure due to IDC and 227 healthy controls of black African ancestry. We also evaluated the relationship between average leucocyte telomere length and left ventricular ejection fraction (LVEF). LVEF was determined using echocardiography and radionuclide multiple-gated acquisition (MUGA) scan in patients with IDC. Relative leucocyte telomere length (T/S) was measured using a quantitative real-time polymerase chain reaction assay. Log T/S was negatively correlated with age in patients with IDC (P = 0.0007) and in controls (P = 0.030), and with alcohol consumption (P = 0.032) and regular smoking (P = 0.021) in patients with IDC. Log T/S did not differ between IDC and control groups either before (P = 0.11) or after (IDC = 0.071 +/- 0.187, control = 0.071 +/- 0.187, P = 0.99) adjustments for confounders. Log T/S was not associated with echocardiographic (P = 0.47) or MUGA (P = 0.99) LVEF or LV end-diastolic diameter (LVEDD) (P = 0.34) in patients with IDC. With adjustments for age, sex, alcohol consumption, and smoking, log T/S was similarly not associated with echocardiographic (P = 0.60) or MUGA (P = 0.91) LVEF or LVEDD (P = 0.53) in patients with IDC. CONCLUSIONS: Average relative leucocyte telomere length is not associated with IDC or its severity in groups of black African ancestry. PMID- 23035036 TI - A simulation shows limited savings from meeting quality targets under the Medicare Shared Savings Program. AB - The Medicare Shared Savings Program, created under the Affordable Care Act, will reward participating accountable care organizations that succeed in lowering health care costs while improving performance. Depending on how the organizations perform on several quality measures, they will "share savings" in Medicare Part A and B payments-that is, they will receive bonus payments for lowering costs. We used a simulation model to analyze the effects of the Shared Savings Program quality measures and performance targets on Medicare costs in a simulated population of patients ages 65-75 with type 2 diabetes. We found that a ten percentage-point improvement in performance on diabetes quality measures would reduce Medicare costs only by up to about 1 percent. After the costs of performance improvement, such as additional tests or visits, are accounted for, the savings would decrease or become cost increases. To achieve greater savings, accountable care organizations will have to lower costs by other means, such as through improved use of information technology and care coordination. PMID- 23035037 TI - Does low-dose acetylsalicylic acid prevent cognitive decline in women with high cardiovascular risk? A 5-year follow-up of a non-demented population-based cohort of Swedish elderly women. AB - OBJECTIVE: The aim of this study was to examine whether low-dose acetylsalicylic acid (ASA) influences the rate of cognitive change in elderly women. DESIGN: Prospective, population-based cohort study. SETTING: The city of Gothenburg, Sweden, including those living in private households as well as in residential care. PARTICIPANTS: The sample was derived from the Prospective Population Study of Women and from the H70 Birth Cohort Study in Gothenburg, Sweden. Both samples were obtained from the Swedish Population Register, based on birth date, and included 789 (response rate 71%) women aged 70-92 years. After the exclusion of individuals with dementia and users of warfarin, clopidogrel or heparin at baseline, 681 women were examined. Among all participants, 95.4% (N=601) had a high cardiovascular risk (CVD), defined as 10% or higher 10-year risk of any CVD event according to the Framingham heart study and 129 used low-dose ASA (75-160 mg daily) at baseline. After 5 years a follow-up was completed by 489 women. PRIMARY OUTCOME AND SECONDARY OUTCOME MEASURES: Cognitive decline and dementia incidence in relation to the use of low-dose ASA and cardiovascular risk factors. Cognition was measured using the Mini Mental State Examination (MMSE), word fluency, naming ability and memory word tests. Dementia was diagnosed according to the DSM-III-R criterion. As secondary outcome incidence of stroke and peptic ulcer in relation to low-dose ASA use was studied. RESULTS: Women on regular low dose ASA declined less on MMSE at follow-up than those not on ASA. This difference was even more pronounced in those who had ASA at both examinations (p=0.004 compared with never users; n=66 vs n=338). All other cognitive tests showed the same trends. There were no differences between the groups regarding short-term risk for dementia (N=41). CONCLUSION: Low-dose ASA treatment may have a neuroprotective effect in elderly women at high cardiovascular risk. PMID- 23035038 TI - Biodrying of municipal solid waste under different ventilation modes: drying efficiency and aqueous pollution. AB - Ventilation is very important during the biodrying process because it affects the biodrying efficiency and secondary pollution. In this study, three ventilation modes-intermittent negative ventilation (IN), continuous negative ventilation (CN) and intermittent positive ventilation (IP)-were used to provide the same amount of total air during biodrying of municipal solid waste (MSW). During the entire 16-day experiment, 68.4%, 68.7% and 67.2% of water contained in the initial waste was removed under IN, CN and IP trials respectively. The ratio of water loss to volatile solid loss was used to evaluate the biodrying efficiency, with values of 5.35, 5.93 and 4.82 being observed for IN, CN and IP trials respectively. The total organic carbon concentrations of the leachate generated from the biodrying of waste were as high as 25,000 mg/l, while those of the condensate were not higher than 3500 mg/l. During the entire process, the average ammonia concentrations of leachate and condensate were 1350 mg/l and 2140 mg/l respectively. From the aspect of biodrying efficiency, continuous negative ventilation was the most preferable ventilation mode for biodrying of MSW, while special care should be taken to prevent aqueous pollution if it is used in a MSW treatment plant. PMID- 23035039 TI - Achieving organizational change: findings from a case study of health promoting hospitals in Taiwan. AB - The Taiwanese Network of Health Promoting Hospitals (HPH) has been in place since 2006 and developing rapidly. The criticism of inadequate evaluation of the HPH approach taken elsewhere also holds true for the Taiwan HPH Network. Organizational change is a key to sustainable and effective health promotion, and it is also an important aspect in the European HPH movement. Therefore, this study aims to evaluate changes in organizational capacity for the implementation of HPH in Taiwan. All 55 HPH coordinators were invited to participate in the study, and 52 of them completed the questionnaires. The survey covered seven dimensions of HPH organizational capacity, and a total score of each dimension was calculated and converted to a figure on a scale of 10. This study has shown that HPH made a positive impact on HP hospitals in Taiwan regarding organizational change in capacity building for HPH. Leadership, organization culture and mission and strategy received the top three highest mean scores (8.19 +/- 1.25, 8.08 +/- 1.39, 7.99 +/- 1.42), while staff participation received the lowest score (7.62 +/- 1.26). The high level of organizational change was associated with the high satisfaction levels of organizational support from the viewpoint of the HPH coordinators. Based on a cluster analysis, a majority of the HP hospitals in Taiwan seemed to have adopted the addition model in putting the HPH initiative into practice; a few hospitals appeared to have accepted HPH initiative well through the integration model. These results presented evidence that HPH contributed to organizational capacity building of hospitals for health promotion. PMID- 23035040 TI - Molecular analysis and biochemical classification of TDP-43 proteinopathy. AB - Amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TAR DNA binding protein of 43 kDa pathology are progressive neurodegenerative diseases that are characterized by intracytoplasmic aggregates of hyperphosphorylated TAR DNA-binding protein of 43 kDa. These TAR DNA-binding protein 43 proteinopathies can be classified into subtypes, which are closely correlated with clinicopathological phenotypes, although the differences in the molecular species of TAR DNA-binding protein 43 in these diseases and the biological significance thereof, remain to be clarified. Here, we have shown that although the banding patterns of abnormally phosphorylated C-terminal fragments of TAR DNA-binding protein 43 differ between the neuropathological subtypes, these are indistinguishable between multiple brain regions and spinal cord in individual patients. Immunoblot analysis of protease-resistant TAR DNA-binding protein 43 demonstrated that the fragment patterns represent different conformations of TAR DNA-binding protein 43 molecular species in the diseases. These results suggest a new clinicopathological classification of TAR DNA-binding protein 43 proteinopathies based on their molecular properties. PMID- 23035041 TI - Therapeutic resistance in autoimmune diseases. PMID- 23035042 TI - The diagnostic role of cardiac magnetic resonance imaging in detecting myocardial inflammation in systemic lupus erythematosus. Differentiation from viral myocarditis. AB - OBJECTIVE: The objective of this paper is to evaluate the diagnostic role of cardiac magnetic resonance imaging (CMR) in detecting myocardial inflammation in systemic lupus erythematosus (SLE) and its differentiation from viral myocarditis. PATIENTS AND METHODS: Fifty patients with suspected infective myocarditis (IM), with chest pain, dyspnoea or altered ECG, increase in troponin I and/or NT-pro BNP, with or without a history of flu-like syndrome or gastroenteritis and elevated C-reactive protein (CRP) within three to five (median four) weeks before admission, 25 active SLE patients, aged 38 +/- 3 years, and 20 age-matched controls were prospectively evaluated by clinical assessment, ECG, echocardiogram and CMR. All patients underwent coronary angiography, and those with significant coronary artery disease (CAD) were excluded. CMR was performed using STIR T2-W (T2W), early T1-W (EGE) and late T1-W (LGE). Endomyocardial biopsies were performed when clinically indicated by current guidelines. Specimens were examined by immunohistological and polymerase chain reaction (PCR) analysis. RESULTS: Positive coronary angiography for CAD excluded 10/50 suspected IM and 5/25 active SLE. Positive clinical criteria for acute myocarditis were fulfilled by 28/40 suspected IM and only 5/20 active SLE. CMR was positive for myocarditis in 35/40 suspected IM and in 16/20 active SLE. Endomyocardial biopsy (EMB), performed in 25/35 suspected IM and 7/16 active SLE with positive CMR, showed positive immunohistology in 18/25 suspected IM and 3/7 active SLE. Infectious genomes were identified in 24/25 suspected IM and 1/7 active SLE. CONCLUSIONS: CMR-positive IM patients were more symptomatic than active SLE. More than half of CMR-positive patients also had positive EMB. PCR was positive in almost all IM, but unusual in SLE. Due to the subclinical presentation of SLE myocarditis and the limitations of EMB, CMR presents the best alternative for the diagnosis of SLE myocarditis. PMID- 23035043 TI - "What great creation". Interview by Alisa M. Clyne. AB - In this case study, an early-career mechanical engineer interviews an established translational bioscientist about mechanisms for merging engineering and biomedicine to pursue clinically informed research questions. PMID- 23035044 TI - The battlefield of rare diseases: where uncommon insights are common. PMID- 23035045 TI - A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates. AB - Over decades, all attempts to translate acute stroke neuroprotectants from discovery in lower-order species to human clinical use have failed. This raised concerns about the predictive validity of preclinical studies in animals for outcomes in human stroke trials. To bridge this translational gap, we used high order gyrencephalic nonhuman primates subjected to an experimental protocol that mimicked that of a corresponding, separately reported, clinical trial in which the human subjects underwent endovascular cerebral aneurysm repair. Both placebo controlled studies tested neuroprotection by Tat-NR2B9c, a prospective therapeutic compound, in anesthetized subjects. Embolic strokes were produced by small intra-arterial emboli caused by the endovascular procedure. We show that primates treated with Tat-NR2B9c after the onset of embolic strokes exhibited significantly reduced numbers and volumes of strokes, as visualized by diffusion- and T2-weighted magnetic resonance imaging. These results correctly anticipated the outcome of the corresponding human trial, thus validating this study design as a predictor of neuroprotective efficacy in humans. This strategy may facilitate the evaluation of promising neuroprotectants before undertaking similar studies in human subjects. PMID- 23035046 TI - Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). AB - Pulmonary lymphangioleiomyomatosis (LAM) is a rare genetic disease characterized by neoplastic growth of atypical smooth muscle-like LAM cells, destruction of lung parenchyma, obstruction of lymphatics, and formation of lung cysts, leading to spontaneous pneumothoraces (lung rupture and collapse) and progressive loss of pulmonary function. The disease is caused by mutational inactivation of the tumor suppressor gene tuberous sclerosis complex 1 (TSC1) or TSC2. By injecting TSC2 null cells into nude mice, we have developed a mouse model of LAM that is characterized by multiple random TSC2-null lung lesions, vascular endothelial growth factor-D expression, lymphangiogenesis, destruction of lung parenchyma, and decreased survival, similar to human LAM. The mice show enlargement of alveolar airspaces that is associated with progressive growth of TSC2-null lesions in the lung, up-regulation of proinflammatory cytokines and matrix metalloproteinases (MMPs) that degrade extracellular matrix, and destruction of elastic fibers. TSC2-null lesions and alveolar destruction were differentially inhibited by the macrolide antibiotic rapamycin (which inhibits TSC2-null lesion growth by a cytostatic mechanism) and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin (which inhibits growth of TSC2-null lesions by a predominantly proapoptotic mechanism). Treatment with simvastatin markedly inhibited MMP-2, MMP-3, and MMP-9 levels in lung and prevented alveolar destruction. The combination of rapamycin and simvastatin prevented both growth of TSC2-null lesions and lung destruction by inhibiting MMP-2, MMP-3, and MMP-9. Our findings demonstrate a mechanistic link between loss of TSC2 and alveolar destruction and suggest that treatment with rapamycin and simvastatin together could benefit patients with LAM by targeting cells with TSC2 dysfunction and preventing airspace enlargement. PMID- 23035047 TI - Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. AB - Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants. Because disease progression is extremely rapid, albeit heterogeneous, in newborns, molecular diagnoses must occur quickly to be relevant for clinical decision making. We describe 50-hour differential diagnosis of genetic disorders by whole genome sequencing (WGS) that features automated bioinformatic analysis and is intended to be a prototype for use in neonatal intensive care units. Retrospective 50-hour WGS identified known molecular diagnoses in two children. Prospective WGS disclosed potential molecular diagnosis of a severe GJB2-related skin disease in one neonate; BRAT1-related lethal neonatal rigidity and multifocal seizure syndrome in another infant; identified BCL9L as a novel, recessive visceral heterotaxy gene (HTX6) in a pedigree; and ruled out known candidate genes in one infant. Sequencing of parents or affected siblings expedited the identification of disease genes in prospective cases. Thus, rapid WGS can potentially broaden and foreshorten differential diagnosis, resulting in fewer empirical treatments and faster progression to genetic and prognostic counseling. PMID- 23035048 TI - Vacuolar-type H+-ATPase V1A subunit is a molecular partner of Wolfram syndrome 1 (WFS1) protein, which regulates its expression and stability. AB - Wolfram syndrome is an autosomal recessive disorder characterized by neurodegeneration and diabetes mellitus. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER)-resident transmembrane protein that also localizes to secretory granules in pancreatic beta cells. Although its precise functions are unknown, WFS1 protein deficiency affects the unfolded protein response, intracellular ion homeostasis, cell cycle progression and granular acidification. In this study, immunofluorescent and electron-microscopy analyses confirmed that WFS1 also localizes to secretory granules in human neuroblastoma cells. We demonstrated a novel interaction between WFS1 and the V1A subunit of the H(+) V-ATPase (proton pump) by co-immunoprecipitation in human embryonic kidney (HEK) 293 cells and with endogenous proteins in human neuroblastoma cells. We mapped the interaction to the WFS1-N terminal, but not the C-terminal domain. V1A subunit expression was reduced in WFS1 stably and transiently depleted human neuroblastoma cells and depleted NT2 (human neuron committed teratocarcinoma) cells. This reduced expression was not restored by adenoviral overexpression of BiP (immunoglobulin-binding protein) to correct the ER stress. Protein stability assays demonstrated that the V1A subunit was degraded more rapidly in WFS1 depleted neuroblastoma cells compared with wild type; however, proteosomal inhibition did not restore the expression of the V1A subunit. Cell cycle assays measuring p21(cip) showed reduced levels in WFS1 depleted cells, and an inverse association between p21(cip) expression and apoptosis. We conclude that WFS1 has a specific interaction with the V1A subunit of H(+) ATPase; this interaction may be important both for pump assembly in the ER and for granular acidification. PMID- 23035050 TI - Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasiveness. AB - The gene encoding protein kinase WNK2 was recently identified to be silenced by promoter hypermethylation in gliomas and meningiomas, suggesting a tumour suppressor role in these brain tumours. Following experimental depletion in cell lines, WNK2 was further found to control GTP-loading of Rac1, a signalling guanosine triphosphatase involved in cell migration and motility. Here we show that WNK2 promoter methylation also occurs in 17.5% (29 out of 166) of adult gliomas, whereas it is infrequent in its paediatric forms (1.6%; 1 out of 66). Re expression of WNK2 in glioblastoma cells presenting WNK2 gene silencing reduced cell proliferation in vitro, tumour growth in vivo and also cell migration and invasion, an effect correlated with reduced activation of Rac1. In contrast, when endogenous WNK2 was depleted from glioblastoma cells with unmethylated WNK2 promoter, changes in cell morphology, an increase in invasion and activation of Rac1 were observed. Together, these results validate the WNK2 gene as a recurrent target for epigenetic silencing in glia-derived brain tumours and provide first mechanistic evidence for a tumour-suppressing role of WNK2 that is related to Rac1 signalling and tumour cell invasion and proliferation. PMID- 23035051 TI - Evidence-based analysis of risk factors for postoperative nausea and vomiting. AB - BACKGROUND: /st> In assessing a patient's risk for postoperative nausea and vomiting (PONV), it is important to know which risk factors are independent predictors, and which factors are not relevant for predicting PONV. METHODS: /st> We conducted a systematic review of prospective studies (n>500 patients) that applied multivariate logistic regression analyses to identify independent predictors of PONV. Odds ratios (ORs) of individual studies were pooled to calculate a more accurate overall point estimate for each predictor. RESULTS: /st> We identified 22 studies (n=95 154). Female gender was the strongest patient specific predictor (OR 2.57, 95% confidence interval 2.32-2.84), followed by the history of PONV/motion sickness (2.09, 1.90-2.29), non-smoking status (1.82, 1.68 1.98), history of motion sickness (1.77, 1.55-2.04), and age (0.88 per decade, 0.84-0.92). The use of volatile anaesthetics was the strongest anaesthesia related predictor (1.82, 1.56-2.13), followed by the duration of anaesthesia (1.46 h(-1), 1.30-1.63), postoperative opioid use (1.39, 1.20-1.60), and nitrous oxide (1.45, 1.06-1.98). Evidence for the effect of type of surgery is conflicting as reference groups differed widely and funnel plots suggested significant publication bias. Evidence for other potential risk factors was insufficient (e.g. preoperative fasting) or negative (e.g. menstrual cycle). CONCLUSIONS: /st> The most reliable independent predictors of PONV were female gender, history of PONV or motion sickness, non-smoker, younger age, duration of anaesthesia with volatile anaesthetics, and postoperative opioids. There is no or insufficient evidence for a number of commonly held factors, such as preoperative fasting, menstrual cycle, and surgery type, and using these factors may be counterproductive in assessing a patient's risk for PONV. PMID- 23035049 TI - Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone photoreceptor vision correlates with biochemical properties of the mutants. AB - The GUCY2D gene encodes retinal membrane guanylyl cyclase (RetGC1), a key component of the phototransduction machinery in photoreceptors. Mutations in GUCY2D cause Leber congenital amaurosis type 1 (LCA1), an autosomal recessive human retinal blinding disease. The effects of RetGC1 deficiency on human rod and cone photoreceptor structure and function are currently unknown. To move LCA1 closer to clinical trials, we characterized a cohort of patients (ages 6 months 37 years) with GUCY2D mutations. In vivo analyses of retinal architecture indicated intact rod photoreceptors in all patients but abnormalities in foveal cones. By functional phenotype, there were patients with and those without detectable cone vision. Rod vision could be retained and did not correlate with the extent of cone vision or age. In patients without cone vision, rod vision functioned unsaturated under bright ambient illumination. In vitro analyses of the mutant alleles showed that in addition to the major truncation of the essential catalytic domain in RetGC1, some missense mutations in LCA1 patients result in a severe loss of function by inactivating its catalytic activity and/or ability to interact with the activator proteins, GCAPs. The differences in rod sensitivities among patients were not explained by the biochemical properties of the mutants. However, the RetGC1 mutant alleles with remaining biochemical activity in vitro were associated with retained cone vision in vivo. We postulate a relationship between the level of RetGC1 activity and the degree of cone vision abnormality, and argue for cone function being the efficacy outcome in clinical trials of gene augmentation therapy in LCA1. PMID- 23035052 TI - Sequence capture and massively parallel sequencing to detect mutations associated with malignant hyperthermia. AB - BACKGROUND: Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disorder in which intracellular calcium homeostasis in the skeletal muscle of susceptible individuals is disrupted upon exposure to halogenated anaesthetics. While MH is linked to the ryanodine receptor (RYR1) on chromosome 19 and the alpha1S subunit of the voltage-dependent L-type calcium channel (CACNA1S) on chromosome 1, mutations have been found in only 50-70% of patients, and subsequently, there is a need for a more powerful screening tool. METHODS: Genomic DNA capture and next-generation sequencing was used to screen 32 genes involved in excitation-contraction coupling, skeletal muscle calcium homeostasis, or immune response in two MH patients. Lymphoblastoid cell lines were used to functionally characterize candidate RYR1 mutations in one family. RESULTS: Sequence analysis revealed two putative causative mutations in RYR1 in one patient. Segregation analysis and functional analysis support a causative role of the detected variants. The amount of Ca(2+) released after stimulation with 4 chloro-m-cresol from B lymphocytes of the MH-susceptible patients in the family was significantly greater compared with that of Ca(2+) released from cells of an MH-negative family member. In the other patient, no causative mutations were identified in the 32 genes screened. CONCLUSIONS: In this study, we successfully demonstrate the use of genomic DNA capture and next-generation sequencing for identification of putative mutations causing MH. We also suggest that whole exome sequencing may be necessary to identify MH causing mutations in patients where no mutations in RYR1 and CACNA1S have been identified thus far. PMID- 23035053 TI - Does warm-up using mental practice improve crisis resource management performance? A simulation study. AB - BACKGROUND: Mental practice (MP) is defined as the 'symbolic rehearsal of a physical activity in the absence of any gross-muscular movements' and has been used in sport and music to enhance performance. In healthcare, MP has been demonstrated to improve technical skill performance of surgical residents. However, its effect on crisis resource management (CRM) skills has yet to be determined. We aimed to investigate the effect of warm-up with MP on CRM skill performance during a simulated crisis scenario. METHODS: Following ethics board approval, 40 anaesthesia residents were randomized. The intervention group performed 20 min of MP of a script based on CRM principles. The control group received a 20 min didactic teaching session on an unrelated topic. Each subject then managed a simulated cardiac arrest. Two CRM experts rated the video recordings of each performance using the previously validated Ottawa GRS. The time to start chest compressions, administer epinephrine, and give blood was recorded. RESULTS: There was no significant difference between the intervention and control groups: total Ottawa GRS score was 24.50 (18.63-28.88 [6.50-34.50]) (median (inter-quartile range [range]) vs 20.50 (13.00-29.13 [6.50-34.50]) (P=0.53); the time to start chest compressions 146.0 s (138.0-231.0 [115.0 323.0]) vs 162.5 s (138.0-231.0 [100.0-460.0]) (P=0.27), the time to epinephrine administration 163.0 s (151.0-187.0 [111.0-337.0]) vs 187.0 s (164.0-244.0 [115.0 310.0]) (P=0.09), and the time to blood administration 220.5 s (130.8-309.0 [92.0 485.0]) vs 252.5 (174.5-398.8 [65.0-527.0]) (P=0.48). CONCLUSION: Unlike technical skills, warm-up with MP does not seem to improve CRM skills in simulated crisis scenarios. PMID- 23035054 TI - Left ventricular volume and ejection fraction assessment with transoesophageal echocardiography: 2D vs 3D imaging. AB - BACKGROUND: Developments in transducer technology have enabled the use of three dimensional transoesophageal echocardiography (3D TOE) in the operating theatre. Transthoracic echocardiography (TTE) 3D left ventricular (LV) volumes and ejection fraction (EF) agree better with magnetic resonance imaging (MRI) measurements, with less intra- and inter-observer variability compared with 2D. This has not been validated with 3D TOE. The aim of this study was to assess the bias, limits of agreement, and reproducibility of 3D TOE and 2D TOE LV volumes and EF in cardiac surgical patients. METHODS: Sixty-three patients having cardiac surgery with TOE were evaluated. LV volumes and EF were calculated using modified Simpson's method on 2D mid-oesophageal four- and two-chamber views, xPlane, and from a 3D full-volume data set. Intra- and inter-observer variability were assessed in a subset of 17 patients. RESULTS: Real-time 3D TOE volume and EF assessment was possible in 59 of the 63 patients. Median end-diastolic volumes (EDVs) as measured by 2D, xPlane, and 3D techniques were 98.5, 94, and 97 ml. Median ESVs were 38.5, 40 and 35.6 ml. Median EFs were 58, 54 and 62.2%. There were no significant pairwise differences between these measurements. The limits of agreement for all comparisons were wide, and there were no statistically significant differences between the three methods in intra- or inter-observer variability. CONCLUSION: The intraoperative use of 3D TOE to estimate LV volumes and EF has small bias compared with 2D assessments, wide limits of agreement, and no clear advantages compared with standard 2D TOE imaging in terms of LV volume and EF assessment. PMID- 23035055 TI - What is shared in shared decision making? Complex decisions when the evidence is unclear. AB - Patient involvement in decisions is central to patient-centered care. Yet many important decisions must be made in complex, ambiguous clinical situations in which all possible options cannot be known, evidence is inadequate to inform patients' preferences fully, and/or patients are unclear about their desired level of involvement. In these situations, preferences are shaped by affect, framing, and "collaborative cognition" among clinicians, patients, and their families; thus, decisions are often relational, dynamic, iterative, provisional, and/or conditional. Clinicians can help patients achieve greater autonomy by engaging both intuitive and deliberative decision-making processes ("whole mind") and involving others in exploring, clarifying, and co-constructing patients' preferences ("shared mind"). Clinical and interpersonal relationships can promote effective decision making through developing a shared attentional focus, tailoring information, and identifying conditions under which provisional preferences might change. Information technology and health systems offer untapped potential to deepen the relationships and conversations within which decisions are made. PMID- 23035056 TI - The effect of community pharmacy-based interventions on patient health outcomes: a systematic review. AB - Many studies have demonstrated the beneficial effects that pharmacist-provided patient care services can have on patient health outcomes. However, the effectiveness of patient care services delivered by pharmacists in community pharmacy settings, where organizational barriers may affect service implementation or limit effectiveness, remains unclear. The authors systematically reviewed the literature on the effectiveness of pharmacist delivered patient care services in community pharmacy settings in the United States. Of the 749 articles retrieved, 21 were eligible for inclusion in the review. Information concerning 134 outcomes was extracted from the included articles. Of these, 50 (37.3%) demonstrated statistically significant, beneficial intervention effects. The percentage of studies reporting favorable findings ranged from 50% for blood pressure to 0% for lipids, safety outcomes, and quality of life. Our findings suggest that evidence supporting the effectiveness of pharmacist-provided direct patient care services delivered in the community pharmacy setting is more limited than in other settings. PMID- 23035057 TI - State deregulation and Medicare costs for acute cardiac care. AB - Past literature suggests that Certificate of Need (CON) regulations for cardiac care were ineffective in improving quality, but less is known about the effect of CON on patient costs. We analyzed Medicare data for 1991-2002 to test whether states that dropped CON experienced changes in costs or reimbursements for coronary artery bypass graft (CABG) surgery or percutaneous coronary interventions. We found that states that dropped CON experienced lower costs per patient for CABG but not for percutaneous coronary intervention. Average Medicare reimbursement was lower for both procedures in states that dropped CON. The cost savings from removing CON regulations slightly exceed the total fixed costs of new CABG facilities that entered after deregulation. Assuming continued cost savings past 2002, the savings from deregulating CABG surgery outweigh the fixed costs of new entry. Thus, CON regulations for CABG may not be justified in terms of either improving quality or controlling cost growth. PMID- 23035058 TI - Fingolimod and multiple sclerosis: four cautionary tales. PMID- 23035059 TI - Hypertensive disorders in pregnancy and cognitive decline in the offspring up to old age. AB - OBJECTIVE: We tested whether maternal hypertensive disorders in pregnancy predict age-related change in cognitive ability in the offspring up to old age. METHODS: Using mothers' blood pressure and urinary protein measurements from the maternity clinics and birth hospitals, we defined normotensive or hypertensive pregnancies in mothers of 398 men, who participated in the Helsinki Birth Cohort 1934-1944 Study. The men underwent the Finnish Defence Forces basic ability test twice: first during compulsory military service at age 20.1 (SD = 1.4) years and then in a retest at age 68.5 (SD = 2.9) years. The test yields a total score and subscores for tests measuring verbal, arithmetic, and visuospatial reasoning. RESULTS: Men born after pregnancies complicated by a hypertensive disorder, compared with men born after normotensive pregnancies, scored 4.36 (95% confidence interval, 1.17-7.55) points lower on total cognitive ability at 68.5 years and displayed a greater decline in total cognitive ability (2.88; 95% confidence interval, 0.07-5.06) after 20.1 years. Of the subscores, associations were strongest for arithmetic reasoning. CONCLUSION: Maternal hypertensive disorders in pregnancy predict lower cognitive ability and greater cognitive decline up to old age. A propensity to lower cognitive ability and decline up to old age may have prenatal origins. PMID- 23035060 TI - Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. AB - OBJECTIVE: This study aims to evaluate protective effects of brief repetitive bilateral arm ischemic preconditioning (BAIPC) on stroke recurrence in patients with symptomatic atherosclerotic intracranial arterial stenosis (IAS). METHODS: A total of 68 consecutive cases with symptomatic IAS, diagnosed by imaging, were enrolled in this prospective and randomized study. All patients received standard medical management. Patients in the BAIPC group (n = 38) underwent 5 brief cycles consisting of bilateral upper limb ischemia followed by reperfusion. The BAIPC procedure was performed twice daily over 300 consecutive days. Incidence of recurrent stroke and cerebral perfusion status in BAIPC-treated patients were compared with the untreated control group (n = 30). RESULTS: In the control group, incidence of recurrent stroke at 90 and 300 days were 23.3% and 26.7%, respectively. In the BAIPC group, incidence of recurrent stroke was reduced to 5% and 7.9% at 90 and 300 days (p < 0.01), respectively. The average time to recovery (modified Rankin Scale score 0-1) was also shortened by BAIPC. Cerebral perfusion status, measured by SPECT and transcranial Doppler sonography, improved remarkably in BAIPC-treated brain than in control (p < 0.01). CONCLUSION: This study provides a proof-of-concept that BAIPC may be an effective way to improve cerebral perfusion and reduce recurrent strokes in patients with IAS. Further investigation of this therapeutic approach is warranted as some patients were excluded after randomization. PMID- 23035061 TI - Reliability and accuracy of skeletal muscle imaging in limb-girdle muscular dystrophies. AB - OBJECTIVE: To evaluate the reliability and accuracy of skeletal muscle CT to correctly identify different muscular dystrophies manifesting with limb-girdle weakness. METHODS: Four evaluators assessed scans from 118 patients with limb girdle muscular dystrophy (LGMD) caused by mutations in 7 different genes and from 32 controls. The conditions studied were scans of genetically confirmed cases of Becker muscular dystrophy (BMD) (n = 28), LGMD2C-F (sarcoglycanopathies) (n = 11), LGMD2I (n = 4), LGMD1B (n = 26), LGMD2A (n = 24), Bethlem myopathy (n = 14), and LGMD2L (n = 11). The control group (n = 32) consisted of patients with neuromuscular disorders manifesting with limb-girdle weakness in which the aforementioned muscular dystrophies were excluded. The scans were compared with the characteristic patterns described in literature. RESULTS: The overall interobserver agreement was poor (kappa = 0.27), with markedly higher scores for BMD (kappa = 0.51) and Bethlem myopathy (kappa = 0.59). The sensitivity to detect selective patterns in relation to the genetic diagnosis was 40% if all LGMDs were taken together. The specificity was 58%, positive predictive value (PPV) 77%, and 1 - negative predictive value (NPV) 79%. Markedly better scores were observed for BMD (sensitivity 91%, PPV 66%, 1 - NPV 3%) and Bethlem myopathy (sensitivity 90%, PPV 69%, 1 - NPV 1%). CONCLUSIONS: Our findings suggest that muscle CT might be an adjunct to the clinical diagnosis of BMD and Bethlem myopathy. However, pattern recognition was cumbersome in the other LGMDs. PMID- 23035062 TI - "Untangling" the relationship between Alzheimer disease and dementia with Lewy bodies. PMID- 23035063 TI - Severe relapses under fingolimod treatment prescribed after natalizumab. PMID- 23035064 TI - Assessment of cortical and striatal involvement in 523 Huntington disease brains. AB - OBJECTIVE: To evaluate the relationship of striatal involvement in Huntington disease (HD) to involvement in other brain regions, CAG repeat size, onset age, and other factors. METHODS: We examined patterns of neuropathologic involvement in 664 HD brains submitted to the Harvard Brain Tissue Resource Center. Brains with concomitant Alzheimer or Parkinson changes (n = 82), more than 20% missing data (n = 46), incomplete sample submission (n = 12), or CAG repeat less than 36 (n = 1) were excluded, leaving 523 cases. Standardized ratings from 0 (absent) to 4 (severe) of gross and microscopic involvement were performed for 50 regions. Cluster analysis reduced the data to 2 main measures of involvement: striatal and cortical. RESULTS: The clusters were correlated with each other (r = 0.42) and with disease duration (striatal: r = 0.35; cortical: r = 0.31). The striatal cluster was correlated with HD repeat size (r = 0.50). The cortical cluster showed a stronger correlation with decreased brain weight (r = -0.52) than the striatal cluster (r = -0.33). The striatal cluster was correlated with younger death age (r = -0.31) and onset age (r = -0.46) while the cortical cluster was not (r = 0.09, r = -0.04, respectively). CONCLUSIONS: The 2 brain clusters had different relationships to the HD CAG repeat size, onset age, and brain weight, suggesting that neuropathologic involvement does not proceed in a strictly coupled fashion. The pattern and extent of involvement varies substantially from one brain to the next. These results suggest that regional involvement in HD brain is modified by factors which, if identified, may lend insight into novel routes to therapeutics. PMID- 23035066 TI - Generalized periodic discharges: more light shed on the old "GPEDs". PMID- 23035065 TI - Tumefactive multiple sclerosis lesions under fingolimod treatment. PMID- 23035067 TI - Detection of IDH1 mutation in the plasma of patients with glioma. AB - OBJECTIVE: The IDH1(R132H) mutation is both a strong prognostic predictor and a diagnostic hallmark of gliomas and therefore has major clinical relevance. Here, we developed a new technique to detect the IDH1(R132H) mutation in the plasma of patients with glioma. METHODS: Small-size DNA (150-250 base pairs) was extracted from the plasma of 31 controls and 80 patients with glioma with known IDH1(R132H) status and correlated with MRI data. The IDH1(R132H) mutation was detected by a combination of coamplification at lower denaturation temperature and digital PCR. RESULTS: The small size DNA concentration was 1.2 ng/mL (range 0.1-6.6) in controls vs 1.2 ng/mL (range 0.1-50.3) in patients with glioma (p = not significant) and 0.9 ng/mL (0.0-3.0) in low-grade gliomas vs 1.5 ng/mL in high grade gliomas (p < 0.01). The small size DNA concentration correlated with enhancing tumor volume (1.6 ng/mL [0.4-24.9] when <10 cm(3) and 14.0 ng/mL [0.6 50.3] when >=10 cm(3)). The IDH1(R132H) mutation was detected in 15 out of 25 plasma DNA mixtures (60%) from patients with mutated tumors and in none of the 14 patients with a nonmutated tumor. The sensitivity increased with enhancing tumor volume (3/9 in nonenhancing tumors, 6/10 for enhancing volume <10 cm(3), and 6/6 for enhancing volume >=10 cm(3)). CONCLUSION: With a specificity of 100% and a sensitivity related to the tumor volume and contrast enhancement, IDH1(R132H) identification has a valuable diagnostic accuracy in patients not amenable to biopsy. PMID- 23035068 TI - Generalized periodic discharges in the critically ill: a case-control study of 200 patients. AB - OBJECTIVE: Generalized periodic discharges are increasingly recognized on continuous EEG monitoring, but their relationship to seizures and prognosis remains unclear. METHODS: All adults with generalized periodic discharges from 1996 to 2006 were matched 1:1 to controls by age, etiology, and level of consciousness. Overall, 200 patients with generalized periodic discharges were matched to 200 controls. RESULTS: Mean age was 66 years (range 18-96); 56% were comatose. Presenting illnesses included acute brain injury (44%), acute systemic illness (38%), cardiac arrest (15%), and epilepsy (3%). A total of 46% of patients with generalized periodic discharges had a seizure during their hospital stay (almost half were focal), vs 34% of controls (p = 0.014). Convulsive seizures were seen in a third of both groups. A total of 27% of patients with generalized periodic discharges had nonconvulsive seizures, vs 8% of controls (p < 0.001); 22% of patients with generalized periodic discharges had nonconvulsive status epilepticus, vs 7% of controls (p < 0.001). In both groups, approximately half died or were in a vegetative state, one-third had severe disability, and one fifth had moderate to no disability. Excluding cardiac arrest patients, generalized periodic discharges were associated with increased mortality on univariate analysis (36.8% vs 26.9%; p = 0.049). Multivariate predictors of worse outcome were cardiac arrest, coma, nonconvulsive status epilepticus, and sepsis, but not generalized periodic discharges. CONCLUSION: Generalized periodic discharges were strongly associated with nonconvulsive seizures and nonconvulsive status epilepticus. While nonconvulsive status epilepticus was independently associated with worse outcome, generalized periodic discharges were not after matching for age, etiology, and level of consciousness. PMID- 23035070 TI - Preconditioning reaches clinical practice in intracranial arterial stenosis. PMID- 23035069 TI - Growth failure and outcome in Rett syndrome: specific growth references. AB - OBJECTIVES: Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes. METHODS: A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Student's t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression. RESULTS: Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X). CONCLUSIONS: RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations. PMID- 23035071 TI - Dysembryoplastic neuroepithelial tumors: an MRI-based scheme for epilepsy surgery. AB - OBJECTIVE: To determine optimal resections in the 3 dysembryoplastic neuroepithelial tumor (DNT) histologic subtypes (simple, complex, and nonspecific) based on MRI features. METHODS: In 78 consecutive epilepsy patients operated for DNT, MRI features were classified as follows: type 1 (cystic/polycystic-like, well-delineated, strongly hypointense T1), type 2 (nodular-like, heterogeneous), or type 3 (dysplastic-like, iso/hyposignal T1, poor delineation, gray-white matter blurring). Correlations between histology, neurophysiologic findings, and surgical outcome were established for each MRI subtype. RESULTS: Type 1 MRI (25 cases, in temporal and extratemporal areas) always corresponded to simple or complex DNTs. Type 2 MRI (25 cases, predominantly in neocortical areas) and type 3 MRI (28 cases, mainly in the mesial temporal lobe) corresponded to nonspecific forms. The epileptogenic zone (EZ) differed significantly according to the MRI subtype (p = 0.0029). It colocalized with the tumor in type 1 MRI, included perilesional cortex in type 2 MRI, and involved extensive areas in type 3 MRI. Cortical dysplasia was predominantly found in type 3 MRI (p < 0.0001). The main prognostic factors for seizure-free outcome (83%) were complete tumor (p < 0.0001) and EZ (p = 0.0115) removal. Other factors favorably influencing the outcome were a short epilepsy duration (p = 0.013) and absence of cortical-subcortical damage at the resection site (p = 0.053). Age at surgery was not related to outcome; however, cortical subcortical damage was correlated with old age (p = 0.021). Treatment discontinuation was correlated with young age at surgery (p = 0.004) and short epilepsy duration (p = 0.001). CONCLUSION: We propose that resection might be restricted to the tumor in type 1 MRI and be more extensive in other MRI subtypes, especially in type 3 MRI. Early surgery and clean surgical margins are crucial for curing epilepsy. PMID- 23035072 TI - Varicella-zoster virus encephalitis and vasculopathy in a patient treated with fingolimod. PMID- 23035073 TI - Spontaneous intracerebral hemorrhage in Urbach-Wiethe disease. PMID- 23035074 TI - Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. PMID- 23035076 TI - Increased resting state network connectivity in synesthesia: evidence for a neural basis of synesthetic consistency. PMID- 23035075 TI - GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. AB - OBJECTIVES: Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both. METHODS: We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD). RESULTS: Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8-31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2-17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2-6.6; p = 0.92). There was a highly significant trend test across groups (chi(2)(1) = 19.3; p = 1.1 * 10(-5)), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB. CONCLUSIONS: GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD. PMID- 23035077 TI - Influence of highly distinctive structural properties on the excitability of pyramidal neurons in monkey visual and prefrontal cortices. AB - Whole-cell patch-clamp recordings and high-resolution 3D morphometric analyses of layer 3 pyramidal neurons in in vitro slices of monkey primary visual cortex (V1) and dorsolateral granular prefrontal cortex (dlPFC) revealed that neurons in these two brain areas possess highly distinctive structural and functional properties. Area V1 pyramidal neurons are much smaller than dlPFC neurons, with significantly less extensive dendritic arbors and far fewer dendritic spines. Relative to dlPFC neurons, V1 neurons have a significantly higher input resistance, depolarized resting membrane potential, and higher action potential (AP) firing rates. Most V1 neurons exhibit both phasic and regular-spiking tonic AP firing patterns, while dlPFC neurons exhibit only tonic firing. Spontaneous postsynaptic currents are lower in amplitude and have faster kinetics in V1 than in dlPFC neurons, but are no different in frequency. Three-dimensional reconstructions of V1 and dlPFC neurons were incorporated into computational models containing Hodgkin-Huxley and AMPA receptor and GABA(A) receptor gated channels. Morphology alone largely accounted for observed passive physiological properties, but led to AP firing rates that differed more than observed empirically, and to synaptic responses that opposed empirical results. Accordingly, modeling predicts that active channel conductances differ between V1 and dlPFC neurons. The unique features of V1 and dlPFC neurons are likely fundamental determinants of area-specific network behavior. The compact electrotonic arbor and increased excitability of V1 neurons support the rapid signal integration required for early processing of visual information. The greater connectivity and dendritic complexity of dlPFC neurons likely support higher level cognitive functions including working memory and planning. PMID- 23035078 TI - Light-mediated control of rhodopsin movement in mosquito photoreceptors. AB - Multiple mechanisms contribute to a photoreceptor's ability to adapt to ambient light conditions. The mosquito Aedes aegypti expresses the long-wavelength rhodopsin Aaop1 in all R1-R6 photoreceptors and most R8 photoreceptors. These photoreceptors alter the cellular location of Aaop1 and reorganize their photosensitive rhabdomeric membranes on a daily basis. During daylight periods, Aaop1 is excluded from the light-sensitive rhabdomeres and localized to multivesicular bodies (MVBs) within the photoreceptor cytoplasm. In the dark, Aaop1 accumulates in the rhabdomeres and no Aaop1-containing MVBs are present in the cytoplasm. Manipulation of light treatments shows the cellular movement of Aaop1 in and out of the rhabdomere is directly controlled by light. In a separate process, the photoreceptors reduce Aaop1 protein content during a time period spanning from late afternoon into the first 2 h of the dark period. Aaop1 levels then gradually increase through the dark period and remain high following movement of Aaop1 to the cytoplasm at dawn. These results demonstrate that mosquito photoreceptors control rhodopsin availability during the daily light dark cycle by novel mechanisms not discerned from analysis of traditional invertebrate models. These mechanisms will maximize a photoreceptor's light sensitivity range and therefore may be common in organisms active in low light conditions. PMID- 23035079 TI - Opioids disrupt pro-nociceptive modulation mediated by raphe magnus. AB - In anesthetized rats, opioid analgesia is accompanied by a specific pattern of tonic activity in two neuronal populations within the medullary raphe magnus (RM): opioids silence pain-facilitatory ON cells and produce sustained discharge in pain-inhibitory OFF cells. These tonic activity patterns, hypothesized to generate a tonic analgesic state, have not been observed in recordings made without anesthesia. Therefore, we recorded ON and OFF cell activity before and after an analgesic dose of morphine in unanesthetized mice. The tonic activity of ON and OFF cells was unchanged by morphine. Rather, morphine suppressed the phasic ON cell excitation and OFF cell inhibition evoked by noxious stimulation. Before morphine, the magnitude of the noxious stimulus-evoked burst in ON cells correlated with motor withdrawal magnitude, suggesting that ON cells facilitate nocifensive motor reactions. Contrary to model prediction, OFF cell activity was greater before stimulus trials that evoked withdrawals than those without withdrawals. Since withdrawals only occurred when OFF cell activity was suppressed, a decrease in OFF cell activity appears to serve as a pro-nociceptive signal that synchronizes and therefore strengthens the ensuing motor reaction. We further propose that morphine acts in RM to suppress ON and OFF cell phasic responses and thereby disable RM's pro-nociceptive output. Thus, RM cells produce antinociception by failing to exert the pro-nociceptive effects normally engaged by noxious stimulation. These findings revise the conventional understanding of supraspinal opioid analgesia and demonstrate that RM produces on demand rather than state modulation, allowing RM cells to serve other functions during pain free periods. PMID- 23035081 TI - Change in choice-related response modulation in area MT during learning of a depth-discrimination task is consistent with task learning. AB - What are the neural mechanisms underlying improvement in perceptual performance due to learning? A recent study using motion-direction discrimination suggested that perceptual learning is due to improvements in the "readout" of sensory signals in sensory-motor cortex and not to improvements in neural sensitivity of the sensory cortex. To test the generality of this hypothesis, we examined this in a similar but different task. We recorded from isolated neurons in the middle temporal (MT) area while monkeys were trained in a depth-discrimination task. Consistent with earlier reports using direction discrimination, we found no long term improvement in MT neuron sensitivity to depth, although monkey performance improved over months with extensive training, even when taking out the effect of behavioral biases. We further addressed improvement in the readout of sensory signals by focusing on choice-related response modulation [choice probability (CP)]. CP increased with training, suggesting an improvement in the readout of sensory signals from MT. CP, however, correlated more strongly with lapse rate than psychophysical threshold, suggesting that changes in readout may be restricted to early phases of learning. To test how behavioral learning, as well as the magnitude of CP, transferred across visual fields, we measured CP variation in one hemifield after training monkeys on the depth-discrimination task in the opposite hemifield. CP was large from the beginning of training in the untrained hemifield, even though a small but significant improvement in sensitivity was observed behaviorally. Overall, our findings are consistent with the idea that increases in CP reflect task learning. PMID- 23035080 TI - Zfp423/OAZ mutation reveals the importance of Olf/EBF transcription activity in olfactory neuronal maturation. AB - Zfp423/OAZ, a multi-zinc finger protein, is proposed to participate in neuronal differentiation through interactions with the Olf/EBF (O/E) family of transcription factors and mediate extrinsic BMP signaling pathways. These activities are associated with distinct domains of the Olf/EBF-associated zinc finger (OAZ) protein. Sustained OAZ expression arrests olfactory sensory neurons (OSNs) at an immature state and alters olfactory receptor expression, but the mechanism remains elusive. We show here that constitutive expression of a C terminal mutant OAZ (OAZDeltaC) in mice that selectively disrupts OAZ-O/E interaction while retaining other activities, exhibits apparently normal OSN differentiation. Additionally, interfering with potential BMP signaling pathways by inducible Follistatin expression in adult mice does not alter the neuronal lineage or differentiation status. Our results indicate that O/E-mediated processes are essential for the differentiation of OSNs and the establishment of a mature phenotype. BMP signaling pathways, if they are active in normal adult olfactory epithelium, may play a minor role in this tissue. PMID- 23035082 TI - Glucagon-like peptide-1 cleavage product GLP-1(9-36) amide rescues synaptic plasticity and memory deficits in Alzheimer's disease model mice. AB - Glucagon-like peptide-1 (GLP-1) is an endogenous intestinal peptide that enhances glucose-stimulated insulin secretion. Its natural cleavage product GLP-1(9 36)(amide) possesses distinct properties and does not affect insulin secretion. Here we report that pretreatment of hippocampal slices with GLP-1(9-36)(amide) prevented impaired long-term potentiation (LTP) and enhanced long-term depression induced by exogenous amyloid beta peptide Abeta((1-42)). Similarly, hippocampal LTP impairments in amyloid precursor protein/presenilin 1 (APP/PS1) mutant mice that model Alzheimer's disease (AD) were prevented by GLP-1(9-36)(amide). In addition, treatment of APP/PS1 mice with GLP-1(9-36)(amide) at an age at which they display impaired spatial and contextual fear memory resulted in a reversal of their memory defects. At the molecular level, GLP-1(9-36)(amide) reduced elevated levels of mitochondrial-derived reactive oxygen species and restored dysregulated Akt-glycogen synthase kinase-3beta signaling in the hippocampus of APP/PS1 mice. Our findings suggest that GLP-1(9-36)(amide) treatment may have therapeutic potential for AD and other diseases associated with cognitive dysfunction. PMID- 23035083 TI - Double dissociation between regulation of conditioned disgust and taste avoidance by serotonin availability at the 5-HT(3) receptor in the posterior and anterior insular cortex. AB - A taste associated with emetic drugs produces conditioned disgust reactions in rats (predominantly gaping), unlike nonemetic drugs that can still produce conditioned taste avoidance but not conditioned disgust. That difference suggests nausea is a prerequisite for learning disgust reactions to tastes. Depletion of forebrain serotonin (5-HT) by 5,7-dihydroxytryptamine (5,7-DHT) lesions of the dorsal raphe nucleus and median raphe nucleus prevents LiCl-induced conditioned disgust reactions (Limebeer et al., 2004). Here we demonstrate that partial depletion of 5-HT in the insular cortex (IC) prevents LiCl-induced conditioned disgust reactions. Furthermore, a double dissociation occurred in the partial regulation of disgust and taste avoidance by selective 5-HT(3) receptor antagonism/agonism in the posterior (granular) region of the IC and the anterior (dorsal agranular) region of the IC, respectively. Intracranial administration of the 5-HT(3) receptor antagonist, ondansetron (OND), to the posterior IC impaired the establishment of LiCl-induced conditioned gaping reactions, but not LiCl induced conditioned taste avoidance (CTA). Likewise, posterior IC administration of the 5-HT(3) receptor agonist m-chlorophenylbiguanide (mCPBG) enhanced the establishment of LiCl-induced conditioned gaping and produced conditioned gaping on its own (which was prevented by intracranially administered OND), with no effect on CTA. On the other hand, anterior IC administration of OND partially reduced the establishment of LiCl-induced CTA, and mCPBG produced a weak CTA, both without effect on gaping. These results suggest that activation of 5-HT(3) receptors in the posterior IC is important for the production of nausea-induced conditioned disgust reactions, while activation of 5-HT(3) receptors in the anterior IC are involved in the production of CTA. PMID- 23035084 TI - Proliferation of external globus pallidus-subthalamic nucleus synapses following degeneration of midbrain dopamine neurons. AB - The symptoms of Parkinson's disease (PD) are related to changes in the frequency and pattern of activity in the reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN). In idiopathic and experimental PD, the GPe and STN exhibit hypoactivity and hyperactivity, respectively, and abnormal synchronous rhythmic burst firing. Following lesion of midbrain dopamine neurons, abnormal STN activity emerges slowly and intensifies gradually until it stabilizes after 2-3 weeks. Alterations in cellular/network properties may therefore underlie the expression of abnormal firing. Because the GPe powerfully regulates the frequency, pattern, and synchronization of STN activity, electrophysiological, molecular, and anatomical measures of GPe-STN transmission were compared in the STN of control and 6-hydroxydopamine-lesioned rats and mice. Following dopamine depletion: (1) the frequency (but not the amplitude) of mIPSCs increased by ~70%; (2) the amplitude of evoked IPSCs and isoguvacine-evoked current increased by ~60% and ~70%, respectively; (3) mRNA encoding alpha1, beta2, and gamma2 GABA(A) receptor subunits increased by 15-30%; (4) the density of postsynaptic gephyrin and gamma2 subunit coimmunoreactive structures increased by ~40%, whereas the density of vesicular GABA transporter and bassoon coimmunoreactive axon terminals was unchanged; and (5) the number of ultrastructurally defined synapses per GPe-STN axon terminal doubled with no alteration in terminal/synapse size or target preference. Thus, loss of dopamine leads, through an increase in the number of synaptic connections per GPe-STN axon terminal, to substantial strengthening of the GPe-STN pathway. This adaptation may oppose hyperactivity but could also contribute to abnormal firing patterns in the parkinsonian STN. PMID- 23035085 TI - A role for atypical cadherin Celsr3 in hippocampal maturation and connectivity. AB - Atypical cadherin Celsr3, a regulator of planar cell polarity, is critical for the development of the axonal blueprint. We previously showed that expression of Celsr3 is necessary to establish forebrain connections such as the anterior commissure and thalamocortical and corticospinal tracts. The requirement for Celsr3 during hippocampal wiring and its action in the hippocampus remain largely unexplored. Here, we compared the connectivity and maturation of the hippocampal formation in Celsr3|Foxg1 and Celsr3|Dlx mice. Celsr3 is inactivated in the whole telencephalon, including the hippocampal primordium, in Celsr3|Foxg1 mice, and in the early basal telencephalon, including ganglionic eminences and ventral diencephalon, in Celsr3|Dlx mice. Behavioral tests showed that both mutants were hyperactive and had impaired learning and memory. Abnormal cytoarchitecture of CA1, CA3, and dentate gyrus was found in the Celsr3|Foxg1 mutant, in which afferent and efferent hippocampal pathways, as well as intrinsic connections, were dramatically disrupted. In Celsr3|Dlx mutant mice, hippocampal cytoarchitecture was mildly affected and extrinsic and intrinsic connectivity moderately disturbed. In both mutants, pyramidal neurons in CA1 harbored atrophic dendritic trees, with decreased synapse density and increased proportion of symmetric versus asymmetric synapses, and long-term potentiation was altered. In contrast, mutant hippocampal neurons extended neurites that were normal, even longer than those of control neurons, indicating that anomalies in vivo are secondary to defective connections. Postnatal neurogenesis was preserved and mutant interneurons were able to migrate to the hippocampus. Thus, like in neocortex, Celsr3 is required for hippocampal development, connectivity and function, and for pyramidal cell maturation. PMID- 23035086 TI - Rapid simultaneous enhancement of visual sensitivity and perceived contrast during saccade preparation. AB - Humans and other animals with foveate vision make saccadic eye movements to prioritize the visual analysis of behaviorally relevant information. Even before movement onset, visual processing is selectively enhanced at the target of a saccade, presumably gated by brain areas controlling eye movements. Here we assess concurrent changes in visual performance and perceived contrast before saccades, and show that saccade preparation enhances perception rapidly, altering early visual processing in a manner akin to increasing the physical contrast of the visual input. Observers compared orientation and contrast of a test stimulus, appearing briefly before a saccade, to a standard stimulus, presented previously during a fixation period. We found simultaneous progressive enhancement in both orientation discrimination performance and perceived contrast as time approached saccade onset. These effects were robust as early as 60 ms after the eye movement was cued, much faster than the voluntary deployment of covert attention (without eye movements), which takes ~300 ms. Our results link the dynamics of saccade preparation, visual performance, and subjective experience and show that upcoming eye movements alter visual processing by increasing the signal strength. PMID- 23035087 TI - Inhibition of protein kinase Mzeta disrupts the stable spatial discharge of hippocampal place cells in a familiar environment. AB - It is widely held that spatial computations in the rodent hippocampus require the location-specific discharge of place cells that together form a stable cognitive map used to solve and perform spatial tasks. It is not known, however, if map stability requires persistent hippocampal synaptic strength changes that are vulnerable to blockade of protein kinase Mzeta (PKMzeta) phosphorylation activity, a manipulation that reverses hippocampal LTP and disrupts multiple forms of long-term memory. Here we report that acute intrahippocampal inhibition of PKMzeta disrupts place cell activity in a familiar environment, where the map is expected to be stable. After this disruption, new, stable spatial firing patterns can later form, but the new and original maps are unrelated even though the rat is exposed to a constant environment. We therefore propose that the previously demonstrated erasure of stored spatial memory and the disruption of place cell firing are parallel effects of PKMzeta blockade. We similarly propose that the known sparing of new spatial memory formation depends on the sparing of new map formation. On these bases, we argue that the loss of the map used to perform a practiced spatial task leads to behavioral performance deficits, and that synaptic plasticity maintained by PKMzeta, which stabilizes the map, is essential for the proper expression of spatial memory. PMID- 23035088 TI - Extinction of aversive memories associated with morphine withdrawal requires ERK mediated epigenetic regulation of brain-derived neurotrophic factor transcription in the rat ventromedial prefrontal cortex. AB - Recent evidence suggests that histone deacetylase (HDAC) inhibitors facilitate extinction of rewarding memory of drug taking. However, little is known about the role of chromatin modification in the extinction of aversive memory of drug withdrawal. In this study, we used conditioned place aversion (CPA), a highly sensitive model for measuring aversive memory of drug withdrawal, to investigate the role of epigenetic regulation of brain-derived neurotrophic factor (BDNF) gene expression in extinction of aversive memory. We found that CPA extinction training induced an increase in recruiting cAMP response element-binding protein (CREB) to and acetylation of histone H3 at the promoters of BDNF exon I transcript and increased BDNF mRNA and protein expression in the ventromedial prefrontal cortex (vmPFC) of acute morphine-dependent rats and that such epigenetic regulation of BDNF gene transcription could be facilitated or diminished by intra-vmPFC infusion of HDAC inhibitor trichostatin A or extracellular signal-regulated kinase (ERK) inhibitor U0126 (1,4-diamino-2,3 dicyano-1,4-bis(methylthio)butadiene) before extinction training. Correspondingly, disruption of the epigenetic regulation of BDNF gene transcription with U0126 or suppression of BDNF signaling with Trk receptor antagonist K252a or BDNF scavenger tyrosine kinase receptor B (TrkB)-Fc blocked extinction of CPA behavior. We also found that extinction training-induced activation of ERK and CREB and extinction of CPA behavior could be potentiated or suppressed by intra-vmPFC infusion of d-cycloserine, a NMDA receptor partial agonist or aminophosphonopentanoic acid, a NMDA receptor antagonist. We conclude that extinction of aversive memory of morphine withdrawal requires epigenetic regulation of BDNF gene transcription in the vmPFC through activation of the ERK CREB signaling pathway perhaps in a NMDA receptor-dependent manner. PMID- 23035089 TI - Analysis of synaptic growth and function in Drosophila with an extended larval stage. AB - The Drosophila larval neuromuscular junction (NMJ) is a powerful system for the genetic and molecular analysis of neuronal excitability, synaptic transmission, and synaptic development. However, its use for studying age-dependent processes, such as maintenance of neuronal viability and synaptic stability, are temporally limited by the onset of pupariation and metamorphosis. Here we characterize larval NMJ growth, growth regulation, structure, and function in a developmental variant with an extended third instar (ETI). RNAi-knockdown of the prothoracicotropic hormone receptor, torso, in the ring gland of developing larvae leaves the timing of first and second instar molts largely unchanged, but triples duration of the third instar from 3 to 9.5 d (McBrayer et al., 2007; Rewitz et al., 2009). During this ETI period, NMJs undergo additional growth (adding >50 boutons/NMJ), and this growth remains under the control of the canonical regulators Highwire and the TGFbeta/BMP pathway. NMJ growth during the ETI period occurs via addition of new branches, satellite boutons, and interstitial boutons, and continues even after muscle growth levels off. Throughout the ETI, organization of synapses and active zones remains normal, and synaptic transmission is unchanged. These results establish the ETI larval system as a viable model for studying motor neuron diseases and for investigating time dependent effects of perturbations that impair mechanisms of neuroprotection, synaptic maintenance, and response to neural injury. PMID- 23035090 TI - Acetylcholine facilitates recovery of episodic memory after brain damage. AB - Episodic memory depends on a network of interconnected brain structures including the inferior temporal cortex, hippocampus, fornix, and mammillary bodies. We have previously shown that a moderate episodic memory impairment in monkeys with transection of the fornix is exacerbated by prior depletion of acetylcholine from inferotemporal cortex, despite the fact that depletion of acetylcholine from inferotemporal cortex on its own has no effect on episodic memory. Here we show that this effect occurs because inferotemporal acetylcholine facilitates recovery of function following structural damage within the neural circuit for episodic memory. Episodic memory impairment caused by lesions of the mammillary bodies, like fornix transection, was exacerbated by prior removal of temporal cortical acetylcholine. However, removing temporal cortical acetylcholine after the lesion of the fornix or mammillary bodies did not increase the severity of the impairment. This lesion order effect suggests that acetylcholine within the inferior temporal cortex ordinarily facilitates functional recovery after structural lesions that impair episodic memory. In the absence of acetylcholine innervation to inferotemporal cortex, this recovery is impaired and the amnesia caused by the structural lesion is more severe. These results suggest that humans with loss of cortical acetylcholine function, for example in Alzheimer's disease, may be less able to adapt to memory impairments caused by structural neuronal damage to areas in the network important for episodic memory. PMID- 23035091 TI - Calcium-dependent isoforms of protein kinase C mediate glycine-induced synaptic enhancement at the calyx of Held. AB - Depolarization of presynaptic terminals that arises from activation of presynaptic ionotropic receptors, or somatic depolarization, can enhance neurotransmitter release; however, the molecular mechanisms mediating this plasticity are not known. Here we investigate the mechanism of this enhancement at the calyx of Held synapse, in which presynaptic glycine receptors depolarize presynaptic terminals, elevate resting calcium levels, and potentiate release. Using knock-out mice of the calcium-sensitive PKC isoforms (PKC(Ca)), we find that enhancement of evoked but not spontaneous synaptic transmission by glycine is mediated primarily by PKC(Ca). Measurements of calcium at the calyx of Held indicate that deficits in synaptic modulation in PKC(Ca) knock-out mice occur downstream of presynaptic calcium increases. Glycine enhances synaptic transmission primarily by increasing the effective size of the pool of readily releasable vesicles. Our results reveal that PKC(Ca) can enhance evoked neurotransmitter release in response to calcium increases caused by small presynaptic depolarizations. PMID- 23035092 TI - Effects of decision variables and intraparietal stimulation on sensorimotor oscillatory activity in the human brain. AB - To decide effectively, information must not only be integrated from multiple sources, but it must be distributed across the brain if it is to influence structures such as motor cortex that execute choices. Human participants integrated information from multiple, but only partially informative, cues in a probabilistic reasoning task in an optimal manner. We tested whether lateralization of alpha- and beta-band oscillatory brain activity over sensorimotor cortex reflected decision variables such as the sum of the evidence provided by observed cues, a key quantity for decision making, and whether this could be dissociated from an update signal reflecting processing of the most recent cue stimulus. Alpha- and beta-band activity in the electroencephalogram reflected the logarithm of the likelihood ratio associated with the each piece of information witnessed, and the same quantity associated with the previous cues. Only the beta-band, however, reflected the most recent cue in a manner that suggested it reflected updating processes associated with cue processing. In a second experiment, transcranial magnetic stimulation-induced disruption was used to demonstrate that the intraparietal sulcus played a causal role both in decision making and in the appearance of sensorimotor beta-band activity. PMID- 23035093 TI - Optimization of a GCaMP calcium indicator for neural activity imaging. AB - Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Recent efforts in protein engineering have significantly increased the performance of GECIs. The state-of-the art single-wavelength GECI, GCaMP3, has been deployed in a number of model organisms and can reliably detect three or more action potentials in short bursts in several systems in vivo. Through protein structure determination, targeted mutagenesis, high-throughput screening, and a battery of in vitro assays, we have increased the dynamic range of GCaMP3 by severalfold, creating a family of "GCaMP5" sensors. We tested GCaMP5s in several systems: cultured neurons and astrocytes, mouse retina, and in vivo in Caenorhabditis chemosensory neurons, Drosophila larval neuromuscular junction and adult antennal lobe, zebrafish retina and tectum, and mouse visual cortex. Signal to-noise ratio was improved by at least 2- to 3-fold. In the visual cortex, two GCaMP5 variants detected twice as many visual stimulus-responsive cells as GCaMP3. By combining in vivo imaging with electrophysiology we show that GCaMP5 fluorescence provides a more reliable measure of neuronal activity than its predecessor GCaMP3. GCaMP5 allows more sensitive detection of neural activity in vivo and may find widespread applications for cellular imaging in general. PMID- 23035094 TI - Regulated vesicular trafficking of specific PCDH15 and VLGR1 variants in auditory hair cells. AB - Usher syndrome is a genetically heterogeneous disorder characterized by hearing and balance dysfunction and progressive retinitis pigmentosa. Mouse models carrying mutations for the nine Usher-associated genes have splayed stereocilia, and some show delayed maturation of ribbon synapses suggesting these proteins may play different roles in terminal differentiation of auditory hair cells. The presence of the Usher proteins at the basal and apical aspects of the neurosensory epithelia suggests the existence of regulated trafficking through specific transport proteins and routes. Immature mouse cochleae and UB/OC-1 cells were used in this work to address whether specific variants of PCDH15 and VLGR1 are being selectively transported to opposite poles of the hair cells. Confocal colocalization studies between apical and basal vesicular markers and the different PCDH15 and VLGR1 variants along with sucrose density gradients and the use of vesicle trafficking inhibitors show the existence of Usher protein complexes in at least two vesicular subpools. The apically trafficked pool colocalized with the early endosomal vesicle marker, rab5, while the basally trafficked pool associated with membrane microdomains and SNAP25. Moreover, coimmunoprecipitation experiments between SNAP25 and VLGR1 show a physical interaction of these two proteins in organ of Corti and brain. Collectively, these findings establish the existence of a differential vesicular trafficking mechanism for specific Usher protein variants in mouse cochlear hair cells, with the apical variants playing a potential role in endosomal recycling and stereocilia development/maintenance, and the basolateral variants involved in vesicle docking and/or fusion through SNAP25-mediated interactions. PMID- 23035095 TI - Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment. AB - Excitatory-inhibitory imbalance has been identified within specific brain microcircuits in models of Rett syndrome (RTT) and other autism spectrum disorders (ASDs). However, macrocircuit dysfunction across the RTT brain as a whole has not been defined. To approach this issue, we mapped expression of the activity-dependent, immediate-early gene product Fos in the brains of wild-type (Wt) and methyl-CpG-binding protein 2 (Mecp2)-null (Null) mice, a model of RTT, before and after the appearance of overt symptoms (3 and 6 weeks of age, respectively). At 6 weeks, Null mice exhibit significantly less Fos labeling than Wt in limbic cortices and subcortical structures, including key nodes in the default mode network. In contrast, Null mice exhibit significantly more Fos labeling than Wt in the hindbrain, most notably in cardiorespiratory regions of the nucleus tractus solitarius (nTS). Using nTS as a model, whole-cell recordings demonstrated that increased Fos expression in Nulls at 6 weeks of age is associated with synaptic hyperexcitability, including increased frequency of spontaneous and miniature EPSCs and increased amplitude of evoked EPSCs in Nulls. No such effect of genotype on Fos or synaptic function was seen at 3 weeks. In the mutant forebrain, reduced Fos expression, as well as abnormal sensorimotor function, were reversed by the NMDA receptor antagonist ketamine. In light of recent findings that the default mode network is hypoactive in autism, our data raise the possibility that hypofunction within this meta-circuit is a shared feature of RTT and other ASDs and is reversible. PMID- 23035096 TI - Stochastic generation of gamma-band activity in primary visual cortex of awake and anesthetized monkeys. AB - Oscillatory neural activity within the gamma band (25-90 Hz) is generally thought to be able to provide a timing signal for harmonizing neural computations across different brain regions. Using time-frequency analyses of the dynamics of gamma band activity in the local field potentials recorded from monkey primary visual cortex, we found identical temporal characteristics of gamma activity in both awake and anesthetized brain states, including large variability of peak frequency, brief oscillatory epochs (<100 ms on average), and stochastic statistics of the incidence and duration of oscillatory events. These findings indicate that gamma-band activity is temporally unstructured and is inherently a stochastic signal generated by neural networks. This idea was corroborated further by our neural-network simulations. Our results suggest that gamma-band activity is too random to serve as a clock signal for synchronizing neuronal responses in awake as in anesthetized monkeys. Instead, gamma-band activity is more likely to be filtered neuronal network noise. Its mean frequency changes with global state and is reduced under anesthesia. PMID- 23035097 TI - Signals from the deep: reach-related activity in the human superior colliculus. AB - Neurophysiological studies in nonhuman species indicated that neurons in the superior colliculus (SC) are involved in the control of upper limb movements. These findings suggested that the SC represents a crucial hub in a general sensorimotor network, including skeletomotor as much as oculomotor functions. In contrast to the SC in the various animal models, the human SC is largely unknown territory. In particular, it is unknown whether findings of reach-related activity in the nonhuman SC can be extrapolated to humans. Using fMRI we found signal increases at superficial/intermediate and deep locations at the SC during the execution of arm movements. In contrast, signals related to saccade execution were confined to the superficial and intermediate locations. Although targets for reaching were presented in the left and right hemifields under central fixation, we found a lateralization of reach-related signals with respect to the active arm. In contrast, saccade-related activity was bilateral, in agreement with the bilateral target presentation and the resulting directions of saccades. Our results suggest that the human SC not only contributes to the coordination of eye movements and spatial shifts of attentions but also to the sensorimotor control of arm movements. PMID- 23035098 TI - Neuregulin directly decreases voltage-gated sodium current in hippocampal ErbB4 expressing interneurons. AB - The Neuregulin 1 (NRG1)/ErbB4 signaling pathway has been genetically and functionally implicated in the etiology underlying schizophrenia, and in the regulation of glutamatergic pyramidal neuron function and plasticity. However, ErbB4 receptors are expressed in subpopulations of GABAergic interneurons, but not in hippocampal or cortical pyramidal neurons, indicating that NRG1 effects on principal neurons are indirect. Consistent with these findings, NRG1 effects on hippocampal long-term potentiation at CA1 pyramidal neuron synapses in slices are mediated indirectly by dopamine. Here we studied whether NRG/ErbB signaling directly regulates interneuron intrinsic excitability by pharmacologically isolating ErbB4-expressing neurons in rat dissociated hippocampal cultures, which lack dopaminergic innervation. We found that NRG1 acutely attenuates ErbB4 expressing interneuron excitability by depolarizing the firing threshold; neurons treated with the pan-ErbB inhibitor PD158780 or negative for ErbB4 were unaffected. These effects of NRG1 are primarily attributable to decreased voltage gated sodium channel activity, as current density was attenuated by ~60%. In stark contrast, NRG1 had minor effects on whole-cell potassium currents. Our data reveal the direct actions of NRG1 signaling in ErbB4-expressing interneurons, and offer novel insight into how NRG1/ErbB4 signaling can impact hippocampal activity. PMID- 23035099 TI - Interleukin-1beta causes anxiety by interacting with the endocannabinoid system. AB - Interleukin-1beta (IL-1beta) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-1beta-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-1beta-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-1beta caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-1beta-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-1beta-CB1R coupling, and TRPV1-/- mice were indeed insensitive to the synaptic and behavioral effects of both IL 1beta and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-1beta on CB1Rs only in control mice, while the same treatment was ineffective in slices prepared from TRPV1-/- mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety. PMID- 23035100 TI - Microtubule plus-end tracking protein CLASP2 regulates neuronal polarity and synaptic function. AB - Microtubule organization and dynamics are essential during axon and dendrite formation and maintenance in neurons. However, little is known about the regulation of microtubule dynamics during synaptic development and function in mammalian neurons. Here, we present evidence that the microtubule plus-end tracking protein CLASP2 (cytoplasmic linker associated protein 2) is a key regulator of axon and dendrite outgrowth that leads to functional alterations in synaptic activity and formation. We found that CLASP2 protein levels steadily increase throughout neuronal development in the mouse brain and are specifically enriched at the growth cones of extending neurites. The short-hairpin RNA mediated knockdown of CLASP2 in primary mouse neurons decreased axon and dendritic length, whereas overexpression of human CLASP2 caused the formation of multiple axons, enhanced dendritic branching, and Golgi condensation, implicating CLASP2 in neuronal morphogenesis. In addition, the CLASP2-induced morphological changes led to significant functional alterations in synaptic transmission. CLASP2 overexpression produced a large increase in spontaneous miniature event frequency that was specific to excitatory neurotransmitter release. The changes in presynaptic activity produced by CLASP2 overexpression were accompanied by increases in presynaptic terminal circumference, total synapse number, and a selective increase in presynaptic proteins that are involved in neurotransmitter release. Also, we found a smaller increase in miniature event amplitude that was accompanied by an increase in postsynaptic surface expression of GluA1 receptor localization. Together, these results provide evidence for involvement of the microtubule plus-end tracking protein CLASP2 in cytoskeleton-related mechanisms underlying neuronal polarity and interplay between microtubule stabilization and synapse formation and activity. PMID- 23035101 TI - Sustaining sleep spindles through enhanced SK2-channel activity consolidates sleep and elevates arousal threshold. AB - Sleep spindles are synchronized 11-15 Hz electroencephalographic (EEG) oscillations predominant during nonrapid-eye-movement sleep (NREMS). Rhythmic bursting in the reticular thalamic nucleus (nRt), arising from interplay between Ca(v)3.3-type Ca(2+) channels and Ca(2+)-dependent small-conductance-type 2 (SK2) K(+) channels, underlies spindle generation. Correlative evidence indicates that spindles contribute to memory consolidation and protection against environmental noise in human NREMS. Here, we describe a molecular mechanism through which spindle power is selectively extended and we probed the actions of intensified spindling in the naturally sleeping mouse. Using electrophysiological recordings in acute brain slices from SK2 channel-overexpressing (SK2-OE) mice, we found that nRt bursting was potentiated and thalamic circuit oscillations were prolonged. Moreover, nRt cells showed greater resilience to transit from burst to tonic discharge in response to gradual depolarization, mimicking transitions out of NREMS. Compared with wild-type littermates, chronic EEG recordings of SK2-OE mice contained less fragmented NREMS, while the NREMS EEG power spectrum was conserved. Furthermore, EEG spindle activity was prolonged at NREMS exit. Finally, when exposed to white noise, SK2-OE mice needed stronger stimuli to arouse. Increased nRt bursting thus strengthens spindles and improves sleep quality through mechanisms independent of EEG slow waves (<4 Hz), suggesting SK2 signaling as a new potential therapeutic target for sleep disorders and for neuropsychiatric diseases accompanied by weakened sleep spindles. PMID- 23035102 TI - Biasing amacrine subtypes in the Atoh7 lineage through expression of Barhl2. AB - Within the developing vertebrate retina, particular subtypes of amacrine cells (ACs) tend to arise from progenitors expressing the basic helix-loop-helix (bHLH) transcription factor, Atoh7, which is necessary for the early generation of retinal ganglion cells (RGCs). All ACs require the postmitotic expression of the bHLH pancreas transcription factor Ptf1a; however, Ptf1a alone is not sufficient to give subtype identities. Here we use functional and in vivo time-lapse studies in the zebrafish retina to investigate on the developmental programs leading to ACs specification within the subsequent divisions of Atoh7-positive progenitors. We find evidences that the homeobox transcription factor Barhl2 is an AC subtype identity-biasing factor that turns on within Atoh7-positive descendants. In vivo lineage tracing reveals that particular modes of cell division tend to generate Barhl2-positive precursors from sisters of RGCs. Additionally, Atoh7 indirectly impacts these division modes to regulate the right number of barhl2-expressing cells. We finally find that Atoh7 itself influences the subtypes of Barhl2 dependent ACs. Together, the results from our study uncover lineage-related and molecular logic of subtype specification in the vertebrate retina, by showing that specific AC subtypes arise via a particular mode of cell division and a transcriptional network cascade involving the sequential expression of first atoh7 followed by ptf1a and then barhl2. PMID- 23035104 TI - p53 Regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury. AB - Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53(-/-) versus wild-type mice. p53(-/-) spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss- and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53(-/-) mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53(-/-) mice, while, similarly, p53 expression in p53(-/-) cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury. PMID- 23035103 TI - Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activation of caspase 1. AB - After hypoxia, a critical adverse outcome is the inability to create new memories. How anterograde amnesia develops or resolves remains elusive, but a link to brain-based IL-1 is suggested due to the vital role of IL-1 in both learning and brain injury. We examined memory formation in mice exposed to acute hypoxia. After reoxygenation, memory recall recovered faster than memory formation, impacting novel object recognition and cued fear conditioning but not spatially cued Y-maze performance. The ability of mice to form new memories after hypoxia/reoxygenation was accelerated in IL-1 receptor 1 knockout (IL-1R1 KO) mice, in mice receiving IL-1 receptor antagonist (IL-1RA), and in mice given the caspase 1 inhibitor Ac-YVAD-CMK. Mechanistically, hypoxia/reoxygenation more than doubled caspase 1 activity in the brain, which was localized to the amygdala compared to the hippocampus. This reoxygenation-dependent activation of caspase 1 was prevented by broad-spectrum adenosine receptor (AR) antagonism with caffeine and by targeted A1/A2A AR antagonism with 8-cyclopentyl-1,3-dipropylxanthine plus 3,7-dimethyl-1-propargylxanthine. Additionally, perfusion of adenosine activated caspase 1 in the brain, while caffeine blocked this action by adenosine. Finally, resolution of anterograde amnesia was improved by both caffeine and by targeted A1/A2A AR antagonism. These findings indicate that amygdala-based anterograde amnesia after hypoxia/reoxygenation is sustained by IL-1beta generated through adenosine-dependent activation of caspase 1 after reoxygenation. PMID- 23035105 TI - Population response to natural images in the primary visual cortex encodes local stimulus attributes and perceptual processing. AB - The primary visual cortex (V1) is extensively studied with a large repertoire of stimuli, yet little is known about its encoding of natural images. Using voltage sensitive dye imaging in behaving monkeys, we measured neural population response evoked in V1 by natural images presented during a face/scramble discrimination task. The population response showed two distinct phases of activity: an early phase that was spread over most of the imaged area, and a late phase that was spatially confined. To study the detailed relation between the stimulus and the population response, we used a simple encoding model to compute a continuous map of the expected neural response based on local attributes of the stimulus (luminance and contrast), followed by an analytical retinotopic transformation. Then, we computed the spatial correlation between the maps of the expected and observed response. We found that the early response was highly correlated with the local luminance of the stimulus and was sufficient to effectively discriminate between stimuli at the single trial level. The late response, on the other hand, showed a much lower correlation to the local luminance, was confined to central parts of the face images, and was highly correlated with the animal's perceptual report. Our study reveals a continuous spatial encoding of low- and high-level features of natural images in V1. The low level is directly linked to the stimulus basic local attributes and the high level is correlated with the perceptual outcome of the stimulus processing. PMID- 23035106 TI - TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. AB - Traf2 and NcK interacting kinase (TNiK) contains serine-threonine kinase and scaffold domains and has been implicated in cell proliferation and glutamate receptor regulation in vitro. Here we report its role in vivo using mice carrying a knock-out mutation. TNiK binds protein complexes in the synapse linking it to the NMDA receptor (NMDAR) via AKAP9. NMDAR and metabotropic receptors bidirectionally regulate TNiK phosphorylation and TNiK is required for AMPA expression and synaptic function. TNiK also organizes nuclear complexes and in the absence of TNiK, there was a marked elevation in GSK3beta and phosphorylation levels of its cognate phosphorylation sites on NeuroD1 with alterations in Wnt pathway signaling. We observed impairments in dentate gyrus neurogenesis in TNiK knock-out mice and cognitive testing using the touchscreen apparatus revealed impairments in pattern separation on a test of spatial discrimination. Object location paired associate learning, which is dependent on glutamatergic signaling, was also impaired. Additionally, TNiK knock-out mice displayed hyperlocomotor behavior that could be rapidly reversed by GSK3beta inhibitors, indicating the potential for pharmacological rescue of a behavioral phenotype. These data establish TNiK as a critical regulator of cognitive functions and suggest it may play a regulatory role in diseases impacting on its interacting proteins and complexes. PMID- 23035107 TI - TrkB downregulation is required for dendrite retraction in developing neurons of chicken nucleus magnocellularis. AB - The chick embryo (Gallus domesticus) is one of the most important model systems in vertebrate developmental biology. The development and function of its auditory brainstem circuitry is exceptionally well studied. These circuits represent an excellent system for genetic manipulation to investigate mechanisms controlling neural circuit formation, synaptogenesis, neuronal polarity, and dendritic arborization. The present study investigates the auditory nucleus, nucleus magnocellularis (NM). The neurotrophin receptor TrkB regulates dendritic structure in CNS neurons. TrkB is expressed in NM neurons at E7-E8 when these neurons have dendritic arbors. Downregulation of TrkB occurs after E8 followed by retraction of dendrites and by E18 most NM cells are adendritic. Is cessation of TrkB expression in NM necessary for dendritic retraction? To answer this question we combined focal in ovo electroporation with transposon mediated gene transfer to obtain stable expression of Doxycycline (Dox) regulated transgenes, specifically TrkB coexpressed with EGFP in a temporally controlled manner. Electroporation was performed at E2 and Dox added onto the chorioallointoic membrane from E7.5 to E16. Expression of EGFP had no effect on development of the embryo, or cell morphology and organization of auditory brainstem nuclei. NM cells expressing EGFP and TrkB at E17-E18 had dendrites and biophysical properties uncharacteristic for normal NM cells, indicating that cessation of TrkB expression is essential for dendrite retraction and functional maturation of these neurons. These studies indicate that expression of transposon based plasmids is an effective method to genetically manipulate events in mid to late embryonic brain development in chick. PMID- 23035108 TI - Effortful listening: the processing of degraded speech depends critically on attention. AB - The conditions of everyday life are such that people often hear speech that has been degraded (e.g., by background noise or electronic transmission) or when they are distracted by other tasks. However, it remains unclear what role attention plays in processing speech that is difficult to understand. In the current study, we used functional magnetic resonance imaging to assess the degree to which spoken sentences were processed under distraction, and whether this depended on the acoustic quality (intelligibility) of the speech. On every trial, adult human participants attended to one of three simultaneously presented stimuli: a sentence (at one of four acoustic clarity levels), an auditory distracter, or a visual distracter. A postscan recognition test showed that clear speech was processed even when not attended, but that attention greatly enhanced the processing of degraded speech. Furthermore, speech-sensitive cortex could be parcellated according to how speech-evoked responses were modulated by attention. Responses in auditory cortex and areas along the superior temporal sulcus (STS) took the same form regardless of attention, although responses to distorted speech in portions of both posterior and anterior STS were enhanced under directed attention. In contrast, frontal regions, including left inferior frontal gyrus, were only engaged when listeners were attending to speech and these regions exhibited elevated responses to degraded, compared with clear, speech. We suggest this response is a neural marker of effortful listening. Together, our results suggest that attention enhances the processing of degraded speech by engaging higher-order mechanisms that modulate perceptual auditory processing. PMID- 23035109 TI - Motor-sensory confluence in tactile perception. AB - Perception involves motor control of sensory organs. However, the dynamics underlying emergence of perception from motor-sensory interactions are not yet known. Two extreme possibilities are as follows: (1) motor and sensory signals interact within an open-loop scheme in which motor signals determine sensory sampling but are not affected by sensory processing and (2) motor and sensory signals are affected by each other within a closed-loop scheme. We studied the scheme of motor-sensory interactions in humans using a novel object localization task that enabled monitoring the relevant overt motor and sensory variables. We found that motor variables were dynamically controlled within each perceptual trial, such that they gradually converged to steady values. Training on this task resulted in improvement in perceptual acuity, which was achieved solely by changes in motor variables, without any change in the acuity of sensory readout. The within-trial dynamics is captured by a hierarchical closed-loop model in which lower loops actively maintain constant sensory coding, and higher loops maintain constant sensory update flow. These findings demonstrate interchangeability of motor and sensory variables in perception, motor convergence during perception, and a consistent hierarchical closed-loop perceptual model. PMID- 23035110 TI - Mitotic motors coregulate microtubule patterns in axons and dendrites. AB - Microtubules are nearly uniformly oriented in the axons of vertebrate neurons but are non-uniformly oriented in their dendrites. Studies to date suggest a scenario for establishing these microtubule patterns whereby microtubules are transported into the axon and nascent dendrites with plus-ends-leading, and then additional microtubules of the opposite orientation are transported into the developing dendrites. Here, we used contemporary tools to confirm that depletion of kinesin 6 (also called CHO1/MKLP1 or kif23) from rat sympathetic neurons causes a reduction in the appearance of minus-end-distal microtubules in developing dendrites, which in turn causes them to assume an axon-like morphology. Interestingly, we observed a similar phenomenon when we depleted kinesin-12 (also called kif15 or HKLP2). Both motors are best known for their participation in mitosis in other cell types, and both are enriched in the cell body and dendrites of neurons. Unlike kinesin-12, which is present throughout the neuron, kinesin-6 is barely detectable in the axon. Accordingly, depletion of kinesin-6, unlike depletion of kinesin-12, has no effect on axonal branching or navigation. Interestingly, depletion of either motor results in faster growing axons with greater numbers of mobile microtubules. Based on these observations, we posit a model whereby these two motors generate forces that attenuate the transport of microtubules with plus-ends-leading from the cell body into the axon. Some of these microtubules are not only prevented from moving into the axon but are driven with minus-ends-leading into developing dendrites. In this manner, these so-called "mitotic" motors coregulate the microtubule patterns of axons and dendrites. PMID- 23035111 TI - The hexameric structure of a conjugative VirB4 protein ATPase provides new insights for a functional and phylogenetic relationship with DNA translocases. AB - VirB4 proteins are ATPases essential for pilus biogenesis and protein transport in type IV secretion systems. These proteins contain a motor domain that shares structural similarities with the motor domains of DNA translocases, such as the VirD4/TrwB conjugative coupling proteins and the chromosome segregation pump FtsK. Here, we report the three-dimensional structure of full-length TrwK, the VirB4 homologue in the conjugative plasmid R388, determined by single-particle electron microscopy. The structure consists of a hexameric double ring with a barrel-shaped structure. The C-terminal half of VirB4 proteins shares a striking structural similarity with the DNA translocase TrwB. Docking the atomic coordinates of the crystal structures of TrwB and FtsK into the EM map revealed a better fit for FtsK. Interestingly, we have found that like TrwB, TrwK is able to bind DNA with a higher affinity for G4 quadruplex structures than for single stranded DNA. Furthermore, TrwK exerts a dominant negative effect on the ATPase activity of TrwB, which reflects an interaction between the two proteins. Our studies provide new insights into the structure-function relationship and the evolution of these DNA and protein translocases. PMID- 23035112 TI - Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. AB - BACKGROUND: Uric acid is an independent risk factor in fructose-induced fatty liver, but whether it is a marker or a cause remains unknown. RESULTS: Hepatocytes exposed to uric acid developed mitochondrial dysfunction and increased de novo lipogenesis, and its blockade prevented fructose-induced lipogenesis. CONCLUSION: Rather than a consequence, uric acid induces fatty liver SIGNIFICANCE: Hyperuricemic people are more prone to develop fructose-induced fatty liver. Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states. PMID- 23035113 TI - The stem region of premembrane protein plays an important role in the virus surface protein rearrangement during dengue maturation. AB - BACKGROUND: Dengue virus surface proteins, envelope (E) and pre-membrane (prM), undergo rearrangement during the maturation process at acidic condition. RESULTS: prM-stem region binds tighter to both E protein and lipid membrane when environment becomes acidic. CONCLUSION: At acidic condition, E proteins are attracted to the membrane-associated prM-stem. SIGNIFICANCE: prM-stem region induces virus structural changes during maturation. Newly assembled dengue viruses (DENV) undergo maturation to become infectious particles. The maturation process involves major rearrangement of virus surface premembrane (prM) and envelope (E) proteins. The prM-E complexes on immature viruses are first assembled as trimeric spikes in the neutral pH environment of the endoplasmic reticulum. When the virus is transported to the low pH environment of the exosomes, these spikes rearrange into dimeric structures, which lie parallel to the virus lipid envelope. The proteins involved in driving this process are unknown. Previous cryoelectron microscopy studies of the mature DENV showed that the prM-stem region (residues 111-131) is membrane-associated and may interact with the E proteins. Here we investigated the prM-stem region in modulating the virus maturation process. The binding of the prM-stem region to the E protein was shown to increase significantly at low pH compared with neutral pH in ELISAs and surface plasmon resonance studies. In addition, the affinity of the prM-stem region for the liposome, as measured by fluorescence correlation spectroscopy, was also increased when pH is lowered. These results suggest that the prM-stem region forms a tight association with the virus membrane and attracts the associated E protein in the low pH environment of exosomes. This will lead to the surface protein rearrangement observed during maturation. PMID- 23035114 TI - Inhibition of the ethanol-induced potentiation of alpha1 glycine receptor by a small peptide that interferes with Gbetagamma binding. AB - BACKGROUND: Gbetagamma interaction with GlyR is an important determinant in ethanol potentiation of this channel. RESULTS: A small peptide, RQH(C7), can inhibit ethanol potentiation of GlyR currents. CONCLUSION: Results with RQH(C7) indicate that ethanol mediated potentiation of GlyR is in part by Gbetagamma activation. SIGNIFICANCE: Molecular interaction between Gbetagamma and GlyR could be used as a target for pharmacological modification of ethanol effects. Previous studies indicate that ethanol can modulate glycine receptors (GlyR), in part, through Gbetagamma interaction with basic residues in the intracellular loop. In this study, we show that a seven-amino acid peptide (RQH(C7)), which has the primary structure of a motif in the large intracellular loop of GlyR (GlyR-IL), was able to inhibit the ethanol-elicited potentiation of this channel from 47 +/- 2 to 16 +/- 4%, without interfering with the effect of Gbetagamma on GIRK (G protein activated inwardly rectifying potassium channel) activation. RQH(C7) displayed a concentration-dependent effect on ethanol action in evoked and synaptic currents. A fragment of GlyR-IL without the basic amino acids did not interact with Gbetagamma or inhibit ethanol potentiation of GlyR. In silico analysis using docking and molecular dynamics allowed to identify a region of ~350A(2) involving aspartic acids 186, 228, and 246 in Gbetagamma where we propose that RQH(C7) binds and exerts its blocking action on the effect of ethanol in GlyR. PMID- 23035115 TI - Regulation of autophagy and its associated cell death by "sphingolipid rheostat": reciprocal role of ceramide and sphingosine 1-phosphate in the mammalian target of rapamycin pathway. AB - The role of "sphingolipid rheostat" by ceramide and sphingosine 1-phosphate (S1P) in the regulation of autophagy remains unclear. In human leukemia HL-60 cells, amino acid deprivation (AA(-)) caused autophagy with an increase in acid sphingomyleinase (SMase) activity and ceramide, which serves as an autophagy inducing lipid. Knockdown of acid SMase significantly suppressed the autophagy induction. S1P treatment counteracted autophagy induction by AA(-) or C(2) ceramide. AA(-) treatment promoted mammalian target of rapamycin (mTOR) dephosphorylation/inactivation, inducing autophagy. S1P treatment suppressed mTOR inactivation and autophagy induction by AA(-). S1P exerts biological actions via cell surface receptors, and S1P(3) among five S1P receptors was predominantly expressed in HL-60 cells. We evaluated the involvement of S1P(3) in suppressing autophagy induction. S1P treatment of CHO cells had no effects on mTOR inactivation and autophagy induction by AA(-) or C(2)-ceramide. Whereas S1P treatment of S1P(3) overexpressing CHO cells resulted in activation of the mTOR pathway, preventing cells from undergoing autophagy induced by AA(-) or C(2) ceramide. These results indicate that S1P-S1P(3) plays a role in counteracting ceramide signals that mediate mTOR-controlled autophagy. In addition, we evaluated the involvement of ceramide-activated protein phosphatases (CAPPs) in ceramide-dependent inactivation of the mTOR pathway. Inhibition of CAPP by okadaic acid in AA(-)- or C(2)-ceramide-treated cells suppressed dephosphorylation/inactivation of mTOR, autophagy induction, and autophagy associated cell death, indicating a novel role of ceramide-CAPPs in autophagy induction. Moreover, S1P(3) engagement by S1P counteracted cell death. Taken together, these results indicated that sphingolipid rheostat in ceramide-CAPPs and S1P-S1P(3) signaling modulates autophagy and its associated cell death through regulation of the mTOR pathway. PMID- 23035116 TI - Glucose-regulated protein 94 triage of mutant myocilin through endoplasmic reticulum-associated degradation subverts a more efficient autophagic clearance mechanism. AB - BACKGROUND: Mutant myocilin accumulates in the endoplasmic reticulum for unknown reasons. RESULTS: Glucose-regulated protein (Grp) 94 depletion reduces mutant myocilin by engaging autophagy. CONCLUSION: Grp94 triages mutant myocilin through ER-associated degradation, subverting autophagy. SIGNIFICANCE: Treating glaucoma could be possible by inhibiting Grp94 and reducing its novel client, mutant myocilin. Clearance of misfolded proteins in the endoplasmic reticulum (ER) is traditionally handled by ER-associated degradation (ERAD), a process that requires retro-translocation and ubiquitination mediated by a luminal chaperone network. Here we investigated whether the secreted, glaucoma-associated protein myocilin was processed by this pathway. Myocilin is typically transported through the ER/Golgi network, but inherited mutations in myocilin lead to its misfolding and aggregation within trabecular meshwork cells, and ultimately, ER stress induced cell death. Using targeted knockdown strategies, we determined that glucose-regulated protein 94 (Grp94), the ER equivalent of heat shock protein 90 (Hsp90), specifically recognizes mutant myocilin, triaging it through ERAD. The addition of mutant myocilin to the short list of Grp94 clients strengthens the hypothesis that beta-strand secondary structure drives client association with Grp94. Interestingly, the ERAD pathway is incapable of efficiently handling the removal of mutant myocilin, but when Grp94 is depleted, degradation of mutant myocilin is shunted away from ERAD toward a more robust clearance pathway for aggregation-prone proteins, the autophagy system. Thus ERAD inefficiency for distinct aggregation-prone proteins can be subverted by manipulating ER chaperones, leading to more effective clearance by the autophagic/lysosomal pathway. General Hsp90 inhibitors and a selective Grp94 inhibitor also facilitate clearance of mutant myocilin, suggesting that therapeutic approaches aimed at inhibiting Grp94 could be beneficial for patients suffering from some cases of myocilin glaucoma. PMID- 23035117 TI - delta-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. AB - Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that delta-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a delta-tocopherol-induced intracellular Ca(2+) response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that delta tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases. PMID- 23035118 TI - Tissue specificity of a human mitochondrial disease: differentiation-enhanced mis splicing of the Fe-S scaffold gene ISCU renders patient cells more sensitive to oxidative stress in ISCU myopathy. AB - BACKGROUND: ISCU myopathy is a disease caused by muscle-specific deficiency of the Fe-S cluster scaffold protein ISCU. RESULTS: MyoD expression enhanced ISCU mRNA mis-splicing, and oxidative stress exacerbated ISCU depletion in patient cells. CONCLUSION: ISCU protein deficiency in patients results from muscle specific mis-splicing as well as oxidative stress. SIGNIFICANCE: Oxidative stress negatively influences the mammalian Fe-S cluster assembly machinery by destabilization of ISCU. Iron-sulfur (Fe-S) cluster cofactors are formed on the scaffold protein ISCU. ISCU myopathy is a disease caused by an intronic mutation that leads to abnormally spliced ISCU mRNA. We found that two predominant mis spliced ISCU mRNAs produce a truncated and short-lived ISCU protein product in multiple patient cell types. Expression of the muscle-specific transcription factor MyoD further diminished normal splicing of ISCU mRNA in patient myoblasts, demonstrating that the process of muscle differentiation enhances the loss of normal ISCU mRNA splicing. ISCU protein was nearly undetectable in patient skeletal muscle, but was higher in patient myoblasts, fibroblasts, and lymphoblasts. We next treated patient cells with pro-oxidants to mimic the oxidative stress associated with muscle activity. Brief hydrogen peroxide treatment or incubation in an enriched oxygen atmosphere led to a marked further reduction of ISCU protein levels, which could be prevented by pretreatment with the antioxidant ascorbate. Thus, we conclude that skeletal muscle differentiation of patient cells causes a higher degree of abnormal ISCU splicing and that oxidative stress resulting from skeletal muscle work destabilizes the small amounts of normal ISCU protein generated in patient skeletal muscles. PMID- 23035119 TI - Opposite effects of KCTD subunit domains on GABA(B) receptor-mediated desensitization. AB - GABA(B) receptors assemble from principle and auxiliary subunits. The principle subunits GABA(B1) and GABA(B2) form functional heteromeric GABA(B(1,2)) receptors that associate with homotetramers of auxiliary KCTD8, -12, -12b, or -16 (named after their K(+) channel tetramerization domain) subunits. These auxiliary subunits constitute receptor subtypes with distinct functional properties. KCTD12 and -12b generate desensitizing receptor responses while KCTD8 and -16 generate largely non-desensitizing receptor responses. The structural elements of the KCTDs underlying these differences in desensitization are unknown. KCTDs are modular proteins comprising a T1 tetramerization domain, which binds to GABA(B2), and a H1 homology domain. KCTD8 and -16 contain an additional C-terminal H2 homology domain that is not sequence-related to the H1 domains. No functions are known for the H1 and H2 domains. Here we addressed which domains and sequence motifs in KCTD proteins regulate desensitization of the receptor response. We found that the H1 domains in KCTD12 and -12b mediate desensitization through a particular sequence motif, T/NFLEQ, which is not present in the H1 domains of KCTD8 and -16. In addition, the H2 domains in KCTD8 and -16 inhibit desensitization when expressed C-terminal to the H1 domains but not when expressed as a separate protein in trans. Intriguingly, the inhibitory effect of the H2 domain is sequence-independent, suggesting that the H2 domain sterically hinders desensitization by the H1 domain. Evolutionary analysis supports that KCTD12 and -12b evolved desensitizing properties by liberating their H1 domains from antagonistic H2 domains and acquisition of the T/NFLEQ motif. PMID- 23035120 TI - PACSIN1, a Tau-interacting protein, regulates axonal elongation and branching by facilitating microtubule instability. AB - Tau is a major member of the neuronal microtubule-associated proteins. It promotes tubulin assembly and stabilizes axonal microtubules. Previous studies have demonstrated that Tau forms cross-bridges between microtubules, with some particles located on cross-bridges, suggesting that some proteins interact with Tau and might be involved in regulating Tau-related microtubule dynamics. This study reports that PACSIN1 interacts with Tau in axon. PACSIN1 blockade results in impaired axonal elongation and a higher number of primary axonal branches in mouse dorsal root ganglia neurons, which is induced by increasing the binding ability of Tau to microtubules. In PACSIN1-blocked dorsal root ganglia neurons, a greater amount of Tau is inclined to accumulate in the central domain of growth cones, and it promotes the stability of the microtubule network. Taken together, these results suggest that PACSIN1 is an important Tau binding partner in regulating microtubule dynamics and forming axonal plasticity. PMID- 23035121 TI - The N-terminal capping propensities of the D-helix modulate the allosteric activation of the Escherichia coli cAMP receptor protein. AB - Transduction of biological signals at the molecular level involves the activation and/or inhibition of allosteric proteins. In the transcription factor cAMP receptor protein (CRP) from Escherichia coli, the allosteric activation, or apo holo transition, involves rigid body motions of domains and structural rearrangements within the hinge region connecting the cAMP- and DNA-binding domains. During this apo-holo transition, residue 138 is converted as part of the elongated D-helix to the position of the N-terminal capping residue of a shorter D-helix. The goal of the current study is to elucidate the role of residue 138 in modulating the allostery between cAMP and DNA binding. By systematically mutating residue 138, we found that mutants with higher N-terminal capping propensities lead to increased cooperativity of cAMP binding and a concomitant increase in affinity for lac-DNA. Furthermore, mutants with higher N-terminal capping propensity correlate with properties characteristic of holo-CRP, particularly, increase in protein structural dynamics. Overall, our results provide a quantitative characterization of the role of residue 138 in the isomerization equilibrium between the apo and holo forms of CRP, and in turn the thermodynamic underpin to the molecular model of allostery revealed by the high resolution structural studies. PMID- 23035122 TI - Identification of the catalytic site of phospholipase D2 (PLD2) newly described guanine nucleotide exchange factor activity. AB - We have demonstrated that phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for Rac2 and determined the PLD2 domains and amino acid site(s) responsible for its GEF activity. Experiments using GST fusion proteins or GST-free counterparts, purified proteins revealed that the PX domain is sufficient to exert GEF activity similar to full-length PLD2. The PLD2-GEF catalytic site is formed by a hydrophobic pocket of residues Phe-107, Phe-129, Leu-166, and Leu-173, all of which are in the PX domain. A nearby Arg-172 is also important in the overall activity. PX mutants altering any of those five amino acids fail to have GEF activity but still bind to Rac2, while their lipase activity was mostly unaffected. In addition to the PX domain, a region in the pleckstrin homology domain (Ile-306-Ala-310) aids in the PX-mediated GEF activity by providing a docking site to hold Rac2 in place during catalysis. We conclude that PLD2 is a unique GEF, with the PX being the major catalytic domain for its GEF activity, whereas the pleckstrin homology domain assists in the PX-mediated activity. The physiological relevance of this novel GEF in cell biology is demonstrated here in chemotaxis and phagocytosis of leukocytes, as the specific PX and PH mutants abolished cell function. Thus, this study reveals for the first time the catalytic site that forms the basis for the mechanism behind the GEF activity of PLD2. PMID- 23035123 TI - Mitotic regulator SKAP forms a link between kinetochore core complex KMN and dynamic spindle microtubules. AB - Chromosome segregation in mitosis is orchestrated by the dynamic interactions between the kinetochore and spindle microtubules. Our recent study shows that mitotic motor CENP-E cooperates with SKAP to orchestrate an accurate chromosome movement in mitosis. However, it remains elusive how kinetochore core microtubule binding activity KMN (KNL1-MIS12-NDC80) regulates microtubule plus-end dynamics. Here, we identify a novel interaction between MIS13 and SKAP that orchestrates accurate interaction between kinetochore and dynamic spindle microtubules. SKAP physically interacts with MIS13 and specifies kinetochore localization of SKAP. Suppression of MIS13 by small interfering RNA abrogates the kinetochore localization of SKAP. Total internal reflection fluorescence microscopic assays demonstrate that SKAP exhibits an EB1-dependent, microtubule plus-end loading and tracking in vitro. Importantly, SKAP is essential for kinetochore oscillations and dynamics of microtubule plus-ends during live cell mitosis. Based on those findings, we reason that SKAP constitutes a dynamic link between spindle microtubule plus-ends and mitotic chromosomes to achieve faithful cell division. PMID- 23035124 TI - Glutathionylation state of uncoupling protein-2 and the control of glucose stimulated insulin secretion. AB - The role of reactive oxygen species (ROS) in glucose-stimulated insulin release remains controversial because ROS have been shown to both amplify and impede insulin release. In regard to preventing insulin release, ROS activates uncoupling protein-2 (UCP2), a mitochondrial inner membrane protein that negatively regulates glucose-stimulated insulin secretion (GSIS) by uncoupling oxidative phosphorylation. With our recent discovery that the UCP2-mediated proton leak is modulated by reversible glutathionylation, a process responsive to small changes in ROS levels, we resolved to determine whether glutathionylation is required for UCP2 regulation of GSIS. Using Min6 cells and pancreatic islets, we demonstrate that induction of glutathionylation not only deactivates UCP2 mediated proton leak but also enhances GSIS. Conversely, an increase in mitochondrial matrix ROS was found to deglutathionylate and activate UCP2 leak and impede GSIS. Glucose metabolism also decreased the total amount of cellular glutathionylated proteins and increased the cellular glutathione redox ratio (GSH/GSSG). Intriguingly, the provision of extracellular ROS (H(2)O(2), 10 MUM) amplified GSIS and also activated UCP2. Collectively, our findings indicate that the glutathionylation status of UCP2 contributes to the regulation of GSIS, and different cellular sites and inducers of ROS can have opposing effects on GSIS, perhaps explaining some of the controversy surrounding the role of ROS in GSIS. PMID- 23035125 TI - Epigenetic silencing of the chaperone Cosmc in human leukocytes expressing tn antigen. AB - Cosmc is the specific molecular chaperone in the endoplasmic reticulum for T synthase, a Golgi beta3-galactosyltransferase that generates the core 1 O-glycan, Galbeta1-3GalNAcalpha-Ser/Thr, in glycoproteins. Dysfunctional Cosmc results in the formation of inactive T-synthase and consequent expression of the Tn antigen (GalNAcalpha1-Ser/Thr), which is associated with several human diseases. However, the molecular regulation of expression of Cosmc, which is encoded by a single gene on Xq24, is poorly understood. Here we show that epigenetic silencing of Cosmc through hypermethylation of its promoter leads to loss of Cosmc transcripts in Tn4 cells, an immortalized B cell line from a male patient with a Tn-syndrome like phenotype. These cells lack T-synthase activity and express the Tn antigen. Treatment of cells with 5-aza-2'-deoxycytidine causes restoration of Cosmc transcripts, restores T-synthase activity, and reduces Tn antigen expression. Bisulfite sequencing shows that CG dinucleotides in the Cosmc core promoter are hypermethylated. Interestingly, several other X-linked genes associated with glycosylation are not silenced in Tn4 cells, and we observed no correlation of a particular DNA methyltransferase to aberrant methylation of Cosmc in these cells. Thus, hypermethylation of the Cosmc promoter in Tn4 cells is relatively specific. Epigenetic silencing of Cosmc provides another mechanism underlying the abnormal expression of the Tn antigen, which may be important in understanding aberrant Tn antigen expression in human diseases, including IgA nephropathy and cancer. PMID- 23035127 TI - Identifying individual changes in performance with composite quality indicators while accounting for regression to the mean. AB - Almost a decade ago Morton and Torgerson indicated that perceived medical benefits could be due to "regression to the mean." Despite this caution, the regression to the mean "effects on the identification of changes in institutional performance do not seem to have been considered previously in any depth" (Jones and Spiegelhalter). As a response, Jones and Spiegelhalter provide a methodology to adjust for regression to the mean when modeling recent changes in institutional performance for one-variable quality indicators. Therefore, in our view, Jones and Spiegelhalter provide a breakthrough methodology for performance measures. At the same time, in the interests of parsimony, it is useful to aggregate individual quality indicators into a composite score. Our question is, can we develop and demonstrate a methodology that extends the "regression to the mean" literature to allow for composite quality indicators? Using a latent variable modeling approach, we extend the methodology to the composite indicator case. We demonstrate the approach on 4 indicators collected by the National Database of Nursing Quality Indicators. A simulation study further demonstrates its "proof of concept." PMID- 23035126 TI - The TspanC8 subgroup of tetraspanins interacts with A disintegrin and metalloprotease 10 (ADAM10) and regulates its maturation and cell surface expression. AB - A disintegrin and metalloprotease 10 (ADAM10) is a ubiquitous transmembrane metalloprotease that cleaves the extracellular regions from over 40 different transmembrane target proteins, including Notch and amyloid precursor protein. ADAM10 is essential for embryonic development and is also important in inflammation, cancer, and Alzheimer disease. However, ADAM10 regulation remains poorly understood. ADAM10 is compartmentalized into membrane microdomains formed by tetraspanins, which are a superfamily of 33 transmembrane proteins in humans that regulate clustering and trafficking of certain other transmembrane "partner" proteins. This is achieved by specific tetraspanin-partner interactions, but it is not clear which tetraspanins specifically interact with ADAM10. The aims of this study were to identify which tetraspanins interact with ADAM10 and how they regulate this metalloprotease. Co-immunoprecipitation identified specific ADAM10 interactions with Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33/Penumbra. These are members of the largely unstudied TspanC8 subgroup of tetraspanins, all six of which promoted ADAM10 maturation. Different cell types express distinct repertoires of TspanC8 tetraspanins. Human umbilical vein endothelial cells express relatively high levels of Tspan14, the knockdown of which reduced ADAM10 surface expression and activity. Mouse erythrocytes express predominantly Tspan33, and ADAM10 expression was substantially reduced in the absence of this tetraspanin. In contrast, ADAM10 expression was normal on Tspan33 deficient mouse platelets in which Tspan14 is the major TspanC8 tetraspanin. These results define TspanC8 tetraspanins as essential regulators of ADAM10 maturation and trafficking to the cell surface. This finding has therapeutic implications because focusing on specific TspanC8-ADAM10 complexes may allow cell type- and/or substrate-specific ADAM10 targeting. PMID- 23035128 TI - Lysine racemase from a lactic acid bacterium, Oenococcus oeni: structural basis of substrate specificity. AB - Oenococcus oeni, a lactic acid bacterium, possesses a lysine racemase, which has a specific activity towards basic amino acids. A comparison of amino acid residues around the active site suggested that Ile222 and Tyr354 of the Geobacillus stearothermophilus alanine racemase, which shares 60% sequence similarity with lysine racemase, were replaced by Thr224 and Trp355 in the O. oeni lysine racemase. T224I/W355Y double mutations significantly decreased the activity of lysine racemase, whereas I222T/Y354W double mutations endowed alanine racemase with lysine racemization activity. These results suggest that the two residues play an important role in lysine racemization. PMID- 23035129 TI - Not-so-random errors: randomized controlled trials are not the only evidence of the value of PET. PMID- 23035130 TI - Static sound timing alters sensitivity to low-level visual motion. AB - Visual motion processing is essential to survival in a dynamic world and is probably the best-studied facet of visual perception. It has been recently discovered that the timing of brief static sounds can bias visual motion perception, an effect attributed to "temporal ventriloquism" whereby the timing of the sounds "captures" the timing of the visual events. To determine whether this cross-modal interaction is dependent on the involvement of higher-order attentive tracking mechanisms, we used near-threshold motion stimuli that isolated low-level pre-attentive visual motion processing. We found that the timing of brief sounds altered sensitivity to these visual motion stimuli in a manner that paralleled changes in the timing of the visual stimuli. Our findings indicate that auditory timing impacts visual motion processing very early in the processing hierarchy and without the involvement of higher-order attentional and/or position tracking mechanisms. PMID- 23035131 TI - Local contextual interactions can result in global shape misperception. AB - Adaptation in the visual system frequently results in properties of subsequently presented stimuli being repelled along identifiable axes. Adaptation to radial frequency (RF) patterns, patterns deformed from circular by a sinusoidal modulation of radius, results in a circle taking on the appearance of having modulation in opposite phase. Here we used paths of spatially localized gratings (Gabor patches) to examine the role of local orientation adaptation in this shape aftereffect. By applying the tilt aftereffect (TAE) as a function of the local orientation difference between adaptor and test, concomitant with adjustment of local position to accommodate the orientation change and preserve path continuity (Euler's method), we show that a TAE field can account for this misperception of shape. Spatial modulation is also observed spontaneously in a circular path of Gabor patches when the local patch orientations are rotated from tangential to the path. This illusory path modulation is consistent with the path orientation being attracted to the orientation of the patches. This consistent local rule implies a local explanation for the global effect and is consistent with a known illusion with a local cause, the Fraser illusion (FI). A similar analysis to that used for the TAE shows that the Fraser illusion can account for this particular alteration of perceived shape. A model which proposes that local orientations are encoded after considering the activation in a population of neurons with differing orientation tuning can accommodate both effects. It is proposed that these distinct processes rely on the same neural architecture. PMID- 23035132 TI - What should public health be doing for disabled people, and why aren't we? PMID- 23035133 TI - Tulane University School of Public Health and Tropical Medicine 100th anniversary. Introduction. From hygiene and tropical medicine to global health. AB - The author reviews the history of the Tulane School of Public Health and Tropical Medicine. In 1912, Dr. Creighton Wellman published a groundbreaking paper entitled "The New Orleans School of Tropical Medicine and Hygiene," outlining a clear plan for a new independent school of public health. He became the founding dean of the Tulane School of Hygiene and Tropical Medicine. Dr. Wellman had spent 9 years practicing medicine in Angola and graduated from the London School of Tropical Medicine before launching a career in tropical medicine in the United States. Tulane already had a formal course of hygiene established as early as 1881. The founding of Tulane School of Hygiene and Tropical Medicine was made possible by a gift from Samuel Zemurray, who would become the president of the United Fruit Company. In January of 1914, Dr. Wellman abruptly left New Orleans to live in Brazil. The school lost its independence in 1919 and again became part of the School of Medicine until 1967. The school initiated by Dr. Wellman is the foundation on which today's Tulane School of Public Health and Tropical Medicine is built. PMID- 23035135 TI - Absolute humidity, temperature, and influenza mortality: 30 years of county-level evidence from the United States. AB - Recent research exploring associations between environmental factors and influenza outcomes has devoted substantial attention to the role of absolute humidity. However, the existing literature provides very little quantitative epidemiologic evidence on the relations between absolute humidity and other weather variables and influenza outcomes in human populations. In the present study, the authors helped fill this gap by analyzing longitudinal weather and influenza mortality data, observed every month between January 1973 and December 2002, for each of 359 urban US counties. A flexible regression model was used to simultaneously explore fully nonlinear relations between absolute humidity and influenza outcomes and temperature and influenza outcomes. Results indicated that absolute humidity was an especially critical determinant of observed human influenza mortality, even after controlling for temperature. There were important nonlinear relations; humidity levels below approximately 6 g of water vapor per kilogram of air were associated with increases in influenza mortality. Model predictions suggested that approximately half of the average seasonal differences in US influenza mortality can be explained by seasonal differences in absolute humidity alone. Temperature modestly influenced influenza mortality as well, although results were less robust. PMID- 23035134 TI - Physical activity reduces salt sensitivity of blood pressure: the Genetic Epidemiology Network of Salt Sensitivity Study. AB - Salt sensitivity of blood pressure (BP) is influenced by genetic and environmental factors. A dietary feeding study was conducted from October 2003 to July 2005 that included a 7-day low-sodium intervention (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) among 1,906 individuals who were 16 years of age or older and living in rural northern China. Salt sensitivity of BP was defined as mean BP change from the low-sodium intervention to the high-sodium intervention. Usual physical activity during the past 12 months was assessed at baseline using a standard questionnaire. The multivariable-adjusted means of systolic BP responses to high-sodium intervention were 5.21 mm Hg (95% confidence interval (CI): 4.55, 5.88), 4.97 mm Hg (95% CI: 4.35, 5.59), 5.02 mm Hg (95% CI: 4.38, 5.67), and 3.96 mm Hg (95% CI: 3.29, 4.63) among participants from the lowest to the highest quartiles of physical activity, respectively (P = 0.003 for linear trend). The multivariable-adjusted odds ratio of high salt sensitivity of systolic BP was 0.66 (95% CI: 0.49, 0.88) for persons in the highest quartile of physical activity compared with those in the lowest quartile. Physical activity is significantly, independently, and inversely related to salt sensitivity of BP and may be particularly effective in lowering BP among salt-sensitive individuals. PMID- 23035136 TI - Short-term outdoor temperature change and emergency department visits for asthma among children: a case-crossover study. AB - Although weather changes are known to cause asthma symptoms, their impact on asthma-related health-care utilization is poorly understood. The objective of the present study was to determine the association between short-term outdoor temperature change and asthma-related emergency department (ED) visits among children 3-18 years of age in Detroit, Michigan, in 2000-2001. Descriptive analyses of patient and ED visit characteristics were performed. A case-crossover study utilizing time-stratified controls was conducted to determine the impact of maximum temperature change and change rate measured during 4-, 8-, 12-, and 24 hour periods. Multivariable conditional logistic regression demonstrated the relation between ED visits and temperature change after controlling for other weather and pollutant measures. There were 4,804 asthma-related ED visits during the study period, and they occurred most frequently in the fall and during morning hours. The case-crossover study showed a statistically significant inverse relation between ED visits and maximum 24-hour temperature change after adjustment for climatic factors (for temperature change, odds ratio = 0.992, P = 0.04; for temperature change rate, odds ratio 0.972, P = 0.01). The association persisted after air pollutant measures were added to the model, although the association was not significant. Despite the finding that a greater 24-hour temperature change decreased the risk of asthma-related ED visits, the overall results suggested a negligible association with short-term temperature change. PMID- 23035137 TI - GIS-modeled indicators of traffic-related air pollutants and adverse pulmonary health among children in El Paso, Texas. AB - Investigators examined 5,654 children enrolled in the El Paso, Texas, public school district by questionnaire in 2001. Exposure measurements were first collected in the late fall of 1999. School-level and residence-level exposures to traffic-related air pollutants were estimated using a land use regression model. For 1,529 children with spirometry, overall geographic information system (GIS) modeled residential levels of traffic-related ambient air pollution (calibrated to a 10-ppb increment in nitrogen dioxide levels) were associated with a 2.4% decrement in forced vital capacity (95% confidence interval (CI): -4.0, -0.7) after adjustment for demographic, anthropomorphic, and socioeconomic factors and spirometer/technician effects. After adjustment for these potential covariates, overall GIS-modeled residential levels of traffic-related ambient air pollution (calibrated to a 10-ppb increment in nitrogen dioxide levels) were associated with pulmonary function levels below 85% of those predicted for both forced vital capacity (odds ratio (OR) = 3.10, 95% CI: 1.65, 5.78) and forced expiratory volume in 1 second (OR = 2.35, 95% CI: 1.38, 4.01). For children attending schools at elevations above 1,170 m, a 10-ppb increment in modeled nitrogen dioxide levels was associated with current asthma (OR = 1.56, 95% CI: 1.08, 2.50) after adjustment for demographic, socioeconomic, and parental factors and random school effects. These results are consistent with previous studies in Europe and California that found adverse health outcomes in children associated with modeled traffic-related air pollutants. PMID- 23035138 TI - Relation of childhood obesity/cardiometabolic phenotypes to adult cardiometabolic profile: the Bogalusa Heart Study. AB - Not all obese adults have cardiometabolic abnormalities. It is unknown whether this is true in children and, if true, whether children who have metabolically healthy overweight/obesity (MHO) will also have favorable cardiometabolic profiles in adulthood. These aspects were examined in 1,098 individuals who participated as both children (aged 5-17 years) and adults (aged 24-43 years) in the Bogalusa Heart Study between 1997 and 2002 in Bogalusa, Louisiana. MHO was defined as being in the top body mass index quartile, while low density lipoprotein cholesterol, triglycerides, mean arterial pressure, and glucose were in the bottom 3 quartiles, and high density lipoprotein cholesterol was in the top 3 quartiles. Forty-six children (4.2%) had MHO, and they were more likely to retain MHO status in adulthood compared with children in other categories (P < 0.0001). Despite markedly increased obesity in childhood and in adulthood, these same MHO children and adults showed a cardiometabolic profile generally comparable to that of nonoverweight/obese children (P > 0.05 in most cases). Moreover, there was no difference in carotid intima-media thickness in adulthood between MHO children and nonoverweight/obese children. Further, carotid intima media thickness in adulthood was lower in MHO children than in metabolically abnormal, overweight/obese children (P = 0.003). In conclusion, the MHO phenotype starts in childhood and continues into adulthood. PMID- 23035139 TI - Predictors of birth weight and gestational age among adolescents. AB - Although pregnant adolescents are at high risk of poor birth outcomes, the majority of adolescents go on to have full-term, healthy babies. Data from the National Longitudinal Study of Adolescent Health, a longitudinal study of a nationally representative sample of adolescents in grades 7-12 in the United States who were surveyed from 1994-1995 through 2008, were used to examine the epidemiology of preterm birth and low birth weight within this population. Outcomes of pregnancies were reported by participants in the fourth wave of data collection (when participants were 24-32 years of age); data were compared between female participants who reported a first singleton livebirth at less than 20 years of age (n = 1,101) and those who were 20 years of age or older (n = 2,846). Multivariable modeling was used to model outcomes; predictors included demographic characteristics and maternal health and behavior. Among black adolescents, low parental educational levels and older age at pregnancy were associated with higher birth weight, whereas low parental educational levels and being on birth control when one got pregnant were associated with higher gestational age. In nonblack adolescents, lower body mass index was associated with lower birth weight, whereas being unmarried was associated with lower gestational age. Predictors of birth outcomes may differ by age group and social context. PMID- 23035140 TI - Cumulative neighborhood risk of psychosocial stress and allostatic load in adolescents. AB - The authors examined the impact of cumulative neighborhood risk of psychosocial stress on allostatic load (AL) among adolescents as a mechanism through which life stress, including neighborhood conditions, may affect health and health inequities. They conducted multilevel analyses, weighted for sampling and propensity score-matched, among adolescents aged 12-20 years in the National Health and Nutrition Examination Survey (1999-2006). Individuals (first level, n = 11,886) were nested within families/households (second level, n = 6,696) and then census tracts (third level, n = 2,191) for examination of the contextual effect of cumulative neighborhood risk environment on AL. Approximately 35% of adolescents had 2 or more biomarkers of AL. A significant amount of variance in AL was explained at the neighborhood level. The likelihood of having a high AL was approximately 10% higher for adolescents living in medium-cumulative-risk neighborhoods (adjusted odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.08, 1.09), 28% higher for those living in high-risk neighborhoods (adjusted OR = 1.28, 95% CI: 1.27, 1.30), and 69% higher for those living in very-high-risk neighborhoods (adjusted OR = 1.69, 95% CI: 1.68, 1.70) as compared with adolescents living in low-risk areas. Effect modification was observed by both individual- and neighborhood-level sociodemographic factors. These findings offer support for the hypothesis that neighborhood risks may culminate in a range of biologically mediated negative health outcomes detectable in adolescents. PMID- 23035142 TI - Dietary protein intake and blood pressure: a meta-analysis of randomized controlled trials. AB - The authors conducted a meta-analysis of randomized controlled trials to evaluate the association of dietary protein intake with blood pressure. To identify articles published before April 2011, the authors searched electronic databases, conducted a manual bibliography review, and consulted experts in the field. Forty trials (including 3,277 participants in total) met the eligibility criteria and were included. Using a standardized form, 2 investigators independently abstracted data on study design, participant characteristics, and treatment outcomes. Net change estimates were pooled across trials using random-effects models. Compared with carbohydrate, dietary protein intake was associated with significant changes in mean systolic and diastolic blood pressure of -1.76 mm Hg (95% confidence interval (CI): -2.33, -1.20) and -1.15 mm Hg (95% CI: -1.59, 0.71), respectively (both P 's < 0.001). Both vegetable protein and animal protein were associated with significant blood pressure changes of -2.27 mm Hg (95% CI: -3.36, -1.18) and -2.54 mm Hg (95% CI: -3.55, -1.53), respectively, for systolic blood pressure (both P 's < 0.001) and -1.26 mm Hg (95% CI: -2.26, 0.26) and -0.95 mm Hg (95% CI: -1.72, -0.19), respectively, for diastolic blood pressure (both P 's = 0.014). Blood pressure reduction was not significantly different when vegetable protein was compared directly with animal protein. These findings indicate that partially replacing dietary carbohydrate with protein may be important for the prevention and treatment of hypertension. PMID- 23035141 TI - Sickle cell trait protects against Plasmodium falciparum infection. AB - Although sickle cell trait protects against severe disease due to Plasmodium falciparum, it has not been clear whether sickle trait also protects against asymptomatic infection (parasitemia). To address this question, the authors identified 171 persistently smear-negative children and 450 asymptomatic persistently smear-positive children in Bancoumana, Mali (June 1996 to June 1998). They then followed both groups for 2 years using a cohort-based strategy. Among the 171 children with persistently negative smears, the median time for conversion to smear-positive was longer for children with sickle trait than for children without (274 vs. 108 days, P < 0.001; Cox hazard ratio = 0.56, 95% confidence interval: 0.33, 0.96; P = 0.036). Similar differences were found in the median times to reinfection after spontaneous clearance without treatment (365 days vs. 184 days; P = 0.01). Alternatively, among the 450 asymptomatic children with persistently positive smears, the median time for conversion to smear-negative (spontaneous clearance) was shorter for children with sickle trait than for children without (190 vs. 365 days; P = 0.02). These protective effects of sickle trait against asymptomatic P. falciparum infection under conditions of natural transmission were demonstrable using a cohort-based approach but not when the same data were examined using a cross-sectional approach. PMID- 23035143 TI - The New Orleans School of Tropical Medicine and Hygiene. 1912. PMID- 23035144 TI - Effects of low-carbohydrate diets versus low-fat diets on metabolic risk factors: a meta-analysis of randomized controlled clinical trials. AB - The effects of low-carbohydrate diets (<=45% of energy from carbohydrates) versus low-fat diets (<=30% of energy from fat) on metabolic risk factors were compared in a meta-analysis of randomized controlled trials. Twenty-three trials from multiple countries with a total of 2,788 participants met the predetermined eligibility criteria (from January 1, 1966 to June 20, 2011) and were included in the analyses. Data abstraction was conducted in duplicate by independent investigators. Both low-carbohydrate and low-fat diets lowered weight and improved metabolic risk factors. Compared with participants on low-fat diets, persons on low-carbohydrate diets experienced a slightly but statistically significantly lower reduction in total cholesterol (2.7 mg/dL; 95% confidence interval: 0.8, 4.6), and low density lipoprotein cholesterol (3.7 mg/dL; 95% confidence interval: 1.0, 6.4), but a greater increase in high density lipoprotein cholesterol (3.3 mg/dL; 95% confidence interval: 1.9, 4.7) and a greater decrease in triglycerides (-14.0 mg/dL; 95% confidence interval: -19.4, 8.7). Reductions in body weight, waist circumference and other metabolic risk factors were not significantly different between the 2 diets. These findings suggest that low-carbohydrate diets are at least as effective as low-fat diets at reducing weight and improving metabolic risk factors. Low-carbohydrate diets could be recommended to obese persons with abnormal metabolic risk factors for the purpose of weight loss. Studies demonstrating long-term effects of low carbohydrate diets on cardiovascular events were warranted. PMID- 23035145 TI - Maternal history of hypertension and blood pressure response to potassium intake: the GenSalt Study. AB - The relation between parental history of hypertension and blood pressure response to potassium intake is unknown. A 7-day high-sodium followed by a 7-day high sodium plus potassium dietary-feeding study was conducted from 2003 to 2005 among 1,871 Chinese participants. Those with a maternal history of hypertension had larger systolic blood pressure responses to potassium compared with those without: -4.31 (95% confidence interval (CI): -4.99, -3.62) mm Hg versus -3.35 (95% CI: -4.00, -2.70) mm Hg, respectively (P(difference) = 0.002). A consistent trend was observed for diastolic blood pressure responses: -1.80 (95% CI: -2.41, 1.20) mm Hg versus -1.35 (95% CI: -1.95, -0.74) mm Hg, respectively (P = 0.07). Stronger associations between early onset maternal hypertension and blood pressure responses were noted, with systolic blood pressure decreases of -4.80 (95% CI: -5.65, -3.95) mm Hg versus -3.55 (95% CI: -4.17, -2.93) mm Hg and diastolic blood pressure decreases of -2.25 (95% CI: -3.01, -1.50) mm Hg versus 1.42 (95% CI: -1.99, -0.85) mm Hg among those with early onset maternal hypertension versus those without, respectively (P = 0.001 and 0.009, respectively). Odds ratios for high potassium sensitivity were 1.36 (95% CI: 0.96, 1.92) and 1.60 (95% CI: 1.08, 2.36) for those with maternal hypertension and early onset maternal hypertension, respectively (P = 0.08 and 0.02, respectively). Potassium supplementation could help to reduce blood pressure among those with a maternal history of hypertension. PMID- 23035146 TI - Life events, coping, and antihypertensive medication adherence among older adults: the cohort study of medication adherence among older adults. AB - The authors examined the association between life events and antihypertensive medication adherence in older adults and the moderating role of coping. A cross sectional analysis was conducted by using data (n = 1,817) from the Cohort Study of Medication Adherence among Older Adults (recruitment conducted from August 2006 through September 2007). Life events occurring in the 12 months preceding the study interview were assessed via the Holmes Rahe Social Readjustment Rating Scale (SRRS), and coping levels were assessed via an adapted version of the John Henry Active Coping Scale. Low adherence to antihypertensive medication was defined as scores less than 6 on the 8-item Morisky Medication Adherence Scale (known as "MMAS-8"). Of study participants, 13.2% had low adherence, and 27.2% and 5.0% had medium (150-299) and high (>=300) SRRS scores, respectively. After multivariable adjustment, the odds ratios for low adherence associated with medium and high, versus low, SRRS were 1.50 (95% confidence interval: 1.11, 2.02) and 2.11 (95% confidence interval: 1.24, 3.58), respectively. When multivariable models were stratified by coping level, the association between life events and adherence was evident only among participants with low coping levels. PMID- 23035147 TI - The role of the kallikrein-kinin system genes in the salt sensitivity of blood pressure: the GenSalt Study. AB - The current study comprehensively examined the association between common genetic variants of the kallikrein-kinin system (KKS) and blood pressure salt sensitivity. A 7-day low-sodium followed by a 7-day high-sodium dietary intervention was conducted among 1,906 Han Chinese participants recruited from 2003 to 2005. Blood pressure was measured by using a random-zero sphygmomanometer through the study. A total of 205 single nucleotide polymorphisms (SNPs) covering 11 genes of the KKS were selected for the analyses. Genetic variants of the bradykinin receptor B2 gene (BDKRB2) and the endothelin converting enzyme 1 gene (ECE1) showed significant associations with the salt-sensitivity phenotypes even after adjustment for multiple testing. Compared with the major G allele, the BDKRB2 rs11847625 minor C allele was significantly associated with increased systolic blood pressure responses to low-sodium intervention (P = 0.0001). Furthermore, a haplotype containing allele C was associated with an increased systolic blood pressure response to high-sodium intervention (P = 0.0009). Seven highly correlated ECE1 SNPs were shown to increase the diastolic blood pressure response to low-sodium intervention (P values ranged from 0.0003 to 0.002), with 2 haplotypes containing these 7 SNPs also associated with this same phenotype (P values ranged from 0.0004 to 0.002). In summary, genetic variants of the genes involved in the regulation of KKS may contribute to the salt sensitivity of blood pressure. PMID- 23035148 TI - Reproducibility of blood pressure response to the cold pressor test: the GenSalt Study. AB - An elevated blood pressure (BP) response to the cold pressor test (CPT) is associated with increased risk of hypertension and cardiovascular disease. However, it is still unclear whether BP response to the CPT is a stable and reproducible trait over time. Using the same study protocol, the authors repeated the CPT 4.5 years after initial administration among 568 Han Chinese in rural northern China (2003-2005 and 2008-2009). BP was measured using a standard mercury sphygmomanometer prior to and 0, 1, 2, and 4 minutes after the participants immersed their hand in ice water (3 degrees C-5 degrees C) for 1 minute. Absolute BP levels and BP responses during the CPT in the initial and repeated administrations were highly correlated. For example, the correlation coefficients were 0.67, 0.73, 0.71, and 0.72 for absolute systolic BP levels at 0, 1, 2, and 4 minutes after ice-water immersion (all P 's < 0.0001). The correlation coefficients for systolic BP response were 0.41 at 0 minutes, 0.37 at 1 minute, 0.42 for maximum response, and 0.39 for the area under the curve during CPT (all P 's < 0.0001). These data indicate that BP response to the CPT is a long-term reproducible and stable characteristic in the general population. PMID- 23035149 TI - Low birth weight is associated with higher blood pressure variability from childhood to young adulthood: the Bogalusa Heart Study. AB - The association between birth weight and long-term within-individual variability of blood pressure (BP) was examined in a longitudinal cohort of 1,454 adults (939 whites and 515 blacks; adulthood age = 19-50 years) enrolled in the Bogalusa Heart Study in Bogalusa, Louisiana, in 1973-2010. BP variability was depicted as standard deviation, coefficient of variation, and deviation from age-predicted values using 6-15 serial BP measurements from childhood to adulthood over an average of 25.7 years. Birth weight was significantly and negatively associated with adulthood BP levels, long-term BP levels, and rate of change. Importantly, low birth weight was significantly associated with increased BP variability in terms of standard deviation, coefficient of variation, and deviation. As evaluated using the regression coefficients, a 1-kg lower birth weight was associated with increases in systolic BP variability measures (-0.38 mm Hg, P = 0.04 for standard deviation; -0.004 mm Hg, P = 0.01 for coefficient of variation; and -0.16 mm Hg, P = 0.04 for deviation) after adjustment for race, age, sex, mean BP levels, and gestational age; similar trends in the associations were noted for diastolic BP variability measures. In conclusion, these findings suggest that birth weight affects not only BP levels but also the magnitude of within-individual BP fluctuations over time through fetal programming in BP regulation mechanisms. PMID- 23035150 TI - Anterior cruciate ligament reconstruction in adolescent patients: limb asymmetry and functional knee bracing. AB - BACKGROUND: Anterior cruciate ligament (ACL) reinjury rates are high in adolescent patients. Knee braces are commonly used after ACL reconstruction to prevent reinjury during return to sports. HYPOTHESIS: Adolescent patients following ACL injury would demonstrate a decreased vertical ground-reaction force, knee extension moment, knee flexion angle, and knee flexion velocity on the surgical limb when compared with the nonsurgical limb during a side-cutting task. A functional knee extension-resistant brace would decrease the limb asymmetries. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-three adolescent patients 6 months after ACL reconstruction were recruited for this study. Three-dimensional kinematic and kinetic data were collected bilaterally (surgical, nonsurgical) during a 35 degrees side-cutting task while the patient was wearing and not wearing a functional knee extension-resistant brace (nonbraced, braced) on the surgical limb. RESULTS: The surgical limb demonstrated a significant decrease in peak impact vertical ground-reaction force (2.55 body weight [BW] vs 2.8 BW; P < .01), peak propulsion vertical ground-reaction force (2.15 BW vs 2.3 BW; P < .01), peak knee extension moment (0.13 BW * body height [BH] vs 0.17 BW * BH; P < .01), knee flexion angle at peak knee flexion velocity (27.8 degrees vs 30.0 degrees ; P = .01), peak knee flexion angle (44.1 degrees vs 48.5 degrees ; P < .01), and peak knee flexion velocity (571.3 deg/sec vs 640.1 deg/sec; P < .01) when compared with the nonsurgical limb during both nonbraced and braced conditions. Bracing increased the initial knee flexion velocity (42.4 deg/sec vs -40.2 deg/sec; P = .01) and decreased the initial knee flexion angle on the surgical limb (13.1 degrees vs 15.7 degrees ; P < .01). Bracing also affected kinematics of the nonsurgical limb. Bracing did not decrease the asymmetry between surgical and nonsurgical limbs. CONCLUSION: Adolescent patients 6 months after ACL reconstruction demonstrated significant kinematic and kinetic asymmetries between the surgical and nonsurgical limbs. The limb asymmetries persisted when the patients were wearing a functional knee brace. There were changes in the surgical knee kinematics with and without bracing, especially near initial ground contact. CLINICAL RELEVANCE: The limb asymmetries are of concern with regard to injuring the graft or the contralateral limb when the patients return to sport. PMID- 23035151 TI - EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer. AB - BACKGROUND: In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed. PATIENTS AND METHODS: We assigned risk groups to 1702 ER-positive/HER2 negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan-Meier survival analysis. RESULTS: After 10 years, absolute risk reductions (ARR) between the high- and low risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%-61% of women classified as high /intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years. CONCLUSION: The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors. PMID- 23035152 TI - Incidence of transformation to aggressive lymphoma in limited-stage follicular lymphoma treated with radiotherapy. AB - BACKGROUND: The established treatment of limited-stage follicular lymphoma is radiotherapy (RT). There is an inherent risk of transformation of follicular lymphoma to aggressive lymphoma; however, the frequency and impact on the outcome are unknown in limited-stage patients. MATERIALS AND METHODS: We identified 237 patients with limited-stage follicular lymphoma treated with curative intent RT. Cases were reviewed to determine the frequency of transformation and subsequent survival. RESULTS: With a median follow-up of 7.4 years, the 10-year risk of transformation was 18.5%. With a median follow-up after transformation of 4.7 years, the 3-year post-transformation progression-free survival (PFS) and overall survival (OS) were 42% and 44%, respectively. The addition of rituximab improved the 3-year post-transformation PFS and OS compared with combination chemotherapy alone (78% versus 15%, P < 0.00001) and (87% versus 38.5%, P < 0.00001), respectively. In multivariate analysis, only rituximab was associated with OS [HR 0.07 (95% CI 0.015-0.312, P = 0.001)] and PFS [HR 0.19 (95% CI 0.55-0.626, P = 0.007)] following transformation. CONCLUSIONS: There is a moderate risk of transformation in limited-stage follicular lymphoma treated with curative intent RT, and it substantially impacts outcome in these patients. Treatment with rituximab at the time of transformation appears to improve survival in this otherwise poor-risk population. PMID- 23035153 TI - Cutaneous effects of BRAF inhibitor therapy: a case series. AB - BACKGROUND: The cutaneous effects of rapidly accelerated fibrosarcoma kinase B (BRAF) inhibitors are not well understood. Squamous cell carcinoma (SCC), keratoacanthoma, and photosensitivity have been described in patients taking BRAF inhibitors. PATIENTS AND METHODS: To characterize the timing and frequency of skin lesions in patients receiving BRAF inhibitor therapy, we utilized a retrospective case review of 53 patients undergoing treatment with BRAF inhibitors for 4-92 weeks of therapy. Patients were evaluated at baseline, and then followed at 4- to 12-week intervals. Charts were retrospectively reviewed, and the morphology and timing of cutaneous events were recorded. RESULTS: Thirty three of the 53 charts met exclusion/inclusion criteria, 15 were treated with vemurafenib, and 18 were treated with GSK 2118436/GSK 1120212. Of 33 patients treated with BRAF inhibitor, 13 developed photosensitivity (39.4%), 10 developed actinic keratoses (30.3%), 10 developed warts (30.3%), and 6 developed SCC (18.2%). CONCLUSIONS: Multiple cutaneous findings were observed in the 33 patients taking BRAF inhibitors. The previously described association with SCC and photosensitivity was observed in these patients as well. Over half of the observed SCCs were invasive in nature. Photosensitivity continues to be frequent with BRAF inhibitors. Patients taking BRAF inhibitors should have regular full body skin exams. Further studies are necessary to better elucidate the rates of these adverse cutaneous effects. PMID- 23035154 TI - Eosinophilic fasciitis. AB - A 57-year-old woman presented with malaise and heaviness in her extremities. At first there were no clues of an inflammatory disease, but the patient developed slowly progressive oedema of her arms and legs with induration of the skin. Blood tests showed eosinophilia. Additional analysis revealed generalised lymphadenopathy. After excluding an infectious or malignant cause, the clinical diagnosis of eosinophilic fasciitis was made, this was confirmed by the results of a full thickness skin biopsy. PMID- 23035155 TI - Intracranial mass of multiple myeloma with good response to chemotherapy. PMID- 23035156 TI - Secondary hypokalaemic paralysis. AB - A 28-year-old man presented with acute onset, ascending-type and bilateral symmetrical areflexic motor paralysis. There was a history of fever 3 days prior to paralysis, multiple episodes of vomiting, chloroquine use and intravenous dextrose administration. Investigations revealed metabolic alkalosis with normal serum potassium level but ECG showed characteristic changes of hypokalaemia based on which patient was managed successfully. This case highlights the importance of ECG findings of hypokalaemia in the presence of non-confirmatory laboratory values while evaluating a case of acute flaccid quadriplegia. PMID- 23035157 TI - T-wave inversions and the role of de-training in the differentiation of athlete's heart from pathology: is 6 months too long? AB - Electrocardiographic changes are common in athletes. Differentiation of a physiological from a pathological substrate is important as ECG changes may indicate underlying cardiac disease placing the athlete at increased risk of sudden cardiac death. Deep T-wave inversions are uncommon in Caucasian athletes however; appear more prevalent in black athletes. Irrespective of the ethnic origin of the athlete, deep T-wave inversions require thorough follow-up. At present, 6 months de-training is recommended to assist in the differentiation of physiologic and pathologic changes where a definitive diagnosis is elusive through standard diagnostic techniques. This case study examines findings from a black and a Caucasian athlete presenting with deep T-wave inversions following a brief (ca.3 week) period of de-training resulting in normalisation of T-wave. These cases suggest that a shorter period of time may be sufficient in differentiating physiological from pathological mechanisms for deep T-wave inversions. PMID- 23035158 TI - Thoracic ectopia cordis. AB - Ectopia cordis is defined as complete or partial displacement of the heart outside the thoracic cavity. It is a rare congenital defect in fusion of the anterior chest wall resulting in extra thoracic location of the heart. Its estimated prevalence is 5.5-7.9 per million live births. The authors had one such case of a 15-h-old full-term male neonate weighing 2.25 kg with an externally visible, beating heart over the chest wall. The neonate had difficulty in respiration with peripheral cyanosis. Patient died of cardiorespiratory arrest before any surgical intervention could be undertaken inspite of best possible resuscitative measures. PMID- 23035159 TI - Subarachnoid block in a case of rheumatoid arthritis with severe pulmonary fibrosis. AB - Rheumatoid arthritis (RA) is the most common chronic inflammatory arthritis, of unknown aetiology and a propensity to involve almost all organ systems. The anaesthesiologists should be aware of the associated airway pathologies, pain management techniques and adverse effects of drug therapies being used to treat RA. In this respect, we describe a 60-year-old female patient who presented with a diagnosis of RA with pulmonary fibrosis, and was scheduled for orthopaedic surgery for subcapital fracture of femur which was successfully managed using intrathecal bupivacaine and midazolam. PMID- 23035160 TI - Ketamine bladder syndrome: an important differential diagnosis when assessing a patient with persistent lower urinary tract symptoms. AB - The recreational use of ketamine is increasing in popularity due to its dissociative and paralytic effects, ease of availability and low cost. However, serious and frequently irreversible damage to the urinary tract is a recently recognised side effect of recreational ketamine use. The authors present a case of a young male patient with a 2-year history of troublesome lower urinary tract symptoms and a 5-year history of ketamine consumption. Medical management of such patients is largely limited to analgesia alone, and cessation of ketamine use before irreversible damage occurs remains the best means of avoiding the radical reconstructive surgery required in end-stage disease. This case and an accompanying review of the available literature illustrate the importance of early recognition of ketamine bladder syndrome in recreational users. PMID- 23035161 TI - Kidney infarction in Friedreich's ataxia with dilated cardiomyopathy. AB - A 37-year-old man with advanced Friedreich's ataxia was referred to our emergency department with acute exacerbated abdominal pain of unclear aetiology. Laboratory tests showed slightly increased inflammatory parameters, elevated troponin and B type natriuretic peptide, as well as minimal proteinuria. Transthoracic echocardiography revealed a pre-existing dilated cardiomyopathy. Abdominal sonography showed no pathological alterations. Owing to persistent pain under analgesia, a contrast-enhanced CT-abdomen was performed, which revealed a non homogeneous perfusion deficit of the right kidney, although neither abdominal vascular alteration, cardiac thrombus, deep vein thrombosis nor a patent foramen ovale could be detected. Taking all clinical and radiological results into consideration, the current incident was diagnosed as a thromboembolic kidney infarction. As a consequence, lifelong oral anticoagulation was initiated. PMID- 23035162 TI - Abnormal head movement in a patient with tuberculous meningitis. AB - The bobble-head doll syndrome is characterised by abnormal head movements. These head movements are usually 'yes-yes' (up and down) type; rarely, head movements are 'no-no' (side-to-side) type. Commonly described causes of the bobble-head doll syndrome include third ventricular tumours, suprasellar arachnoid cysts, aqueductal stenosis and other lesions in the region of the third ventricle of the brain. We report a case of tuberculous meningitis with hydrocephalus; in this patient bobble-head doll syndrome developed following external ventricular drainage. In our patient, placement of intraventricular drain led to massive dilatation of the frontal horn of the left lateral ventricle because of blocked foramina of Monro on the left side. The bobble-head doll syndrome, presumably, developed because of the pressure effect of the dilated third ventricle on the dorsomedial nucleus of the thalamus, red nucleus and dentatorubrothalamic pathways. We think that distortion of the third ventricle was responsible for the impairment of the functions of all these structures. PMID- 23035164 TI - An unusual cause of haemoptysis: a diagnostic challenge for clinicians. AB - A 32-year-old male patient presented with haemoptysis in the background of high grade fever for 3 weeks. Chest examination and x-ray were suggestive of right sided moderate pleural effusion. On finding tender hepatomegaly in abdominal examination, an ultrasonography of abdomen was performed which was suggestive of ruptured hepatic abscess. Cytological examination of both sputum and aspirate from hepatic abscess showed neutrophilic debris mixed with red blood cells. The serological test for antibody to Entamoeba histolytica was positive. Computerised tomography-guided trans-tracheal fistulogram demonstrated presence of hepato bronchial fistula. Our case responded to conservative management. Follow-up ultrasonography after 6 months showed total abolition of abscess cavity and sealing of bronchial connection. Amoebic liver abscess complicating into hepato bronchial fistula is thought to be an obsolete entity in contemporary world. But possibility of amoebic liver abscess should be kept in mind while managing a patient of haemoptysis in appropriate clinical setting in endemic areas. PMID- 23035163 TI - An autopsy case of acute cor pulmonale and paradoxical systemic embolism due to tumour cell microemboli in a patient with breast cancer. AB - A 62-year-old woman was admitted to our hospital because of severe respiratory distress. Diagnostic imaging studies suggested the existence of inexplicable cor pulmonale. Although we immediately sought the aetiology of her severe condition, she died suddenly on the fourth day after admission. Postmortem autopsy revealed tumour cell microemboli in the small pulmonary arteries. In addition, tumour cell embolisation identical to that in primary breast cancer cells was also observed in microvessels in systemic multiple organs, such as the liver, brain, kidneys, spleen, uterus, bone marrow and adrenal glands-with simultaneous findings of peripheral infarction. Systemic tumour cell embolism mediated through the patent foramen ovale superimposed on pulmonary tumour cell emboli (PTCE) is considered to be the mechanism underlying inexplicable cor pulmonale. The rapid aggravation of her condition terminated in death. PMID- 23035165 TI - Clues to diagnosing culture negative Listeria rhombencephalitis. AB - A previously healthy 35-year-old Caucasian woman developed left body (including facial) hemianaesthesia, asymmetrical lower cranial nerve palsies and cerebellar signs after a 4-day history of headache, nausea and vomiting. Serial blood and cerebrospinal fluid (CSF) cultures returned negative for a culprit organism. CSF examination revealed a lymphocytic pleocytosis and an elevated protein count. CSF cytological examination identified plasma cells. MRI of brain showed multiple ring-enhancing 'abscess-like' lesions in the brainstem and upper cervical cord together with abnormal meningeal enhancement. A decision was made to treat her empirically for Listeria rhombencephalitis to which she responded completely. CSF PCR eventually returned positive for Listeria monocytogenes. This case illustrates the utility of clinical features, MRI, CSF cytology and PCR in diagnosis and treatment of culture negative L monocytogenes rhombencephalitis in an immunocompetent individual. PMID- 23035166 TI - Reactive amyloidosis complicated by end-stage renal disease 28 years after liquid silicone injection in the buttocks. AB - Silicone ganulomas usually arise from the rupture of silicone implants. Until the 1980s, however, underground care providers used to inject liquid and unapproved silicone directly into human tissues, in the absence of a containing capsule. We report here the case of a man who ultimately developed end-stage renal disease (ESRD) because of a chronic glomerulosclerosis that was attributed to a glomerular AA amyloidosis diagnosed 28 years after a buttock injection of liquid silicone. To our knowledge, this is the first case of a silicone-induced AA amyloidosis irreversibly affecting the kidneys, and leading to ESRD. An interleukin 1 receptor antagonist was started to prevent the extension of amyloidosis, but to no avail as far as the kidneys are concerned. We want to draw the attention of health professionals about the risk of developing AA amyloidosis secondary to a long-lasting inflammation induced by silicone leakage, after a long latency period. PMID- 23035167 TI - Premature ovarian failure 3 years after menarche in a 16-year-old girl following human papillomavirus vaccination. AB - Premature ovarian failure in a well adolescent is a rare event. Its occurrence raises important questions about causation, which may signal other systemic concerns. This patient presented with amenorrhoea after identifying a change from her regular cycle to irregular and scant periods following vaccinations against human papillomavirus. She declined the oral contraceptives initially prescribed for amenorrhoea. The diagnostic tasks were to determine the reason for her secondary amenorrhoea and then to investigate for possible causes of the premature ovarian failure identified. Although the cause is unknown in 90% of cases, the remaining chief identifiable causes of this condition were excluded. Premature ovarian failure was then notified as a possible adverse event following this vaccination. The young woman was counselled regarding preservation of bone density, reproductive implications and relevant follow-up. This event could hold potential implications for population health and prompts further inquiry. PMID- 23035168 TI - Giant left atrium with spontaneous echo contrast: a harbinger of thromboembolic phenomenon. PMID- 23035169 TI - Bulbous urethral stricture: a rare and grave complication of suprapubic catheterisation. AB - We report a very rare complication of bulbous urethral stricture following suprapubic catheterisation (SPC). A 67-year-old paraplegic man underwent SPC for urethral trauma. During SPC, the catheter slipped across the bladder neck into the bulbous urethra where the balloon was inflated. Follow-up retrograde urethrograms showed the gradual evolution of stricture at the same site. This report highlights yet another pitfall of the SPC procedure. We also describe the ways to avoid this complication. PMID- 23035170 TI - Tumour-seeding: a rare complication of ablative therapy for clinically localised renal cell carcinoma. AB - Current evidence-based clinical practice guidelines identify surgical resection as the recommended treatment of small renal masses. Ablative approaches such as laparoscopic and percutaneous cryoablation and radiofrequency ablation offer the promise of complete tumour destruction by a less-invasive approach with regard to outcomes such as anaesthesia requirements, blood loss, length of stay and time to recovery, making them appealing to patients. However, evidence of therapeutic benefits, harms and costs for these methods remains limited. We report a case of applicator tract seeding by tumour following percutaneous cryoablation of renal cell carcinoma; a rare and potentially under-reported, yet catastrophic complication of ablative therapy. PMID- 23035171 TI - Haemophagocytic lymphohistiocytosis: a cause for rare but fatal outcome in tuberculosis. AB - Haemophagocytic lymphohistiocytosis (HLH), also called haemophagocytic syndrome (HPS) is characterised by a dysregulated activation and proliferation of macrophages, leading to uncontrolled phagocytosis of platelets, erythrocytes, lymphocytes and their haematopoietic precursors throughout the reticuloendothelial system. Mycobacterium tuberculosis-associated HPS is a rare and underdiagnosed association. We report a 34-year-old male patient diagnosed with tubercular pleural effusion responding poorly to antitubercular treatment. Patient later developed generalised lymphadenopathy, pancytopaenia and liver dysfunction and was eventually diagnosed as HLH. Despite being treated as per HLH protocol 2004 he could not be saved. PMID- 23035172 TI - Widely separated composite split cord malformation. AB - We are reporting a rare case of 18-month-old child with split cord malformations (SCMs) at two different levels, one in the upper thoracic (T2) and the other in the lumbar (L2) region. Only few case reports of such wide separation of SCM are available in the published literature. PMID- 23035173 TI - Laryngeal actinomycosis mimicking relapse of laryngeal carcinoma in a 67-year-old man. PMID- 23035174 TI - MIC1-MAG1-SAG1 chimeric protein, a most effective antigen for detection of human toxoplasmosis. AB - This study describes a Toxoplasma gondii IgG enzyme-linked immunosorbent assay based on a new chimeric antigen containing three immunodominant regions from the MIC1, MAG1, and SAG1 proteins of the parasite and shows that this test is useful for diagnostic purposes and may replace the lysed and whole-cell antigens. PMID- 23035175 TI - The oral, live attenuated enterotoxigenic Escherichia coli vaccine ACE527 reduces the incidence and severity of diarrhea in a human challenge model of diarrheal disease. AB - An oral, live attenuated, three-strain recombinant bacterial vaccine, ACE527, was demonstrated to generate strong immune responses to colonization factor and toxin antigens of enterotoxigenic Escherichia coli (ETEC) in human volunteers. The vaccine was safe and well tolerated at doses of up to 10(11) CFU, administered in each of two doses given 21 days apart. These observations have now been extended in a phase 2b study with a total of 70 subjects. Fifty-six of these subjects were challenged 28 days after the second dose of vaccine with the highly virulent ETEC strain H10407 to obtain preliminary indicators of efficacy against disease and to support further development of the vaccine for both travelers and infants in countries where ETEC is endemic. The vaccine had a significant impact on intestinal colonization by the challenge strain, as measured by quantitative fecal culture 2 days after challenge, demonstrating the induction of a functional immune response to the CFA/I antigen. The incidence and severity of diarrhea were also reduced in vaccinees as measured by a number of secondary and ad hoc endpoints, although the 27% reduction seen in the primary endpoint, moderate to severe diarrhea, was not statistically significant. Together, these observations support the hypothesis that the ACE527 vaccine has a dual mode of action, targeting both colonization factors and the heat-labile enterotoxin (LT), and suggest that it should be further developed for more advanced trials to evaluate its impact on the burden of ETEC disease in field settings. PMID- 23035176 TI - Protection by a recombinant Mycobacterium bovis Bacillus Calmette-Guerin vaccine expressing Shiga toxin 2 B subunit against Shiga toxin-producing Escherichia coli in mice. AB - We have developed a novel vaccine against Shiga toxin (Stx)-producing Escherichia coli (STEC) infection using a recombinant Mycobacterium bovis BCG (rBCG) system. Two intraperitoneal vaccinations with rBCG expressing the Stx2 B subunit (Stx2B) resulted in an increase of protective serum IgG and mucosal IgA responses to Stx2B in BALB/c mice. When orally challenged with 10(3) CFU of STEC strain B2F1 (O91: H21), the immunized mice survived statistically significantly longer than the nonvaccinated mice. We suggest that intraperitoneal immunization with rBCG expressing Stx2B would be a potential vaccine strategy for STEC. PMID- 23035177 TI - Antibody responses to norovirus genogroup GI.1 and GII.4 proteases in volunteers administered Norwalk virus. AB - An assay was developed to detect antibodies against two norovirus proteases among participants in a Norwalk virus (GI.1) challenge study. Prechallenge seroprevalence was lower against the protease from the homologous GI.1 virus than against protease from a heterologous GII.4 strain. Seroresponses were detected for 14 of 19 (74%) infected persons. PMID- 23035179 TI - Prospective study of Helicobacter pylori biomarkers for gastric cancer risk among Chinese men. AB - BACKGROUND: Helicobacter pylori is the leading risk factor for gastric cancer, yet only a fraction of infected individuals ever develop neoplasia. METHODS: To identify potential predictive biomarkers, we assessed the association of 15 antibodies to H. pylori proteins and gastric cancer in a nested case-control study. Blood levels of antibodies were assessed using multiplex serology for 226 incident cases and 451 matched controls from the Shanghai Men's Health Study. ORs and 95% confidence intervals (CI) were calculated using conditional logistic regression. RESULTS: Seropositivity to four (Omp, HP0305, HyuA, and HpaA) proteins was associated with a 1.5- to 3-fold increased risk for gastric cancer. When excluding cases diagnosed within 2 years of study enrollment, seropositivity to two additional proteins (CagA and VacA) showed significant associations with risk. Compared with individuals with three or fewer seropositive results to the six virulent proteins identified in this population, individuals with four to five seropositive results were at a 2-fold increased risk (OR, 2.08; 95% CI, 1.31 3.30) and individuals seropositive to all six proteins had a 3.5-fold increase in risk (OR, 3.49; 95% CI, 2.00-6.11) for gastric cancer. Among individuals diagnosed at least 2 years after study enrollment, these associations were even stronger (ORs, 2.79 and 4.16, respectively). CONCLUSIONS: Increasing number of seropositives to six H. pylori proteins may be a risk marker for distal gastric cancer in China. IMPACT: In a population with a 90% prevalence of CagA-positive H. pylori infection, assessment of additional virulent H. pylori proteins might better identify individuals at high risk for gastric cancer. PMID- 23035178 TI - Human papillomavirus DNA methylation as a potential biomarker for cervical cancer. AB - Sexually transmitted carcinogenic human papillomavirus (HPV) infections are extraordinarily prevalent worldwide. However, most incident HPV infections clear within a few years, whereas a small minority persists to invasive cancer. Recent studies indicate that detection of methylated viral DNA may distinguish women with cervical intraepithelial neoplasia grade 2+ (CIN2+) from those with a carcinogenic HPV-type infection that shows no evidence of CIN2+. Several studies have reported a positive association between methylation of CpG sites in the L1 gene and CIN2+, although there are inconclusive results about methylation of CpG sites in the upstream regulatory region (URR). In this review, we summarize the current state of knowledge on HPV DNA methylation in cervical carcinogenesis, and discuss the merits of different methods used to measure HPV DNA methylation. To follow the promising leads, we suggest future studies to validate the use of methylated carcinogenic HPV DNA as a predictive and/or diagnostic biomarker for risk of cervical cancer among HPV-positive women. PMID- 23035180 TI - Application of the Rosner-Colditz risk prediction model to estimate sexual orientation group disparities in breast cancer risk in a U.S. cohort of premenopausal women. AB - BACKGROUND: Lesbian and bisexual women may be at greater risk of breast cancer than heterosexual women during the premenopausal period due to disparities in risk factors. METHODS: With 16 years of prospective data from a large cohort of U.S. women ages 25-58 years, we conducted a breast cancer risk assessment for 87,392 premenopausal women by applying the Rosner-Colditz biomathematical risk prediction model to estimate breast cancer risk based on known risk factors. On the basis of each woman's comprehensive risk factor profile, we calculated the predicted 1-year incidence rate (IR) per 100,000 person-years and estimated incidence rate ratios (IRR) and 95% confidence intervals (CI) for lesbian and bisexual women compared with heterosexual women. RESULTS: A total of 87,392 premenopausal women provided 1,091,871 person-years of data included in analyses. Mean predicted 1-year breast cancer IRs per 100,000 person-years for each sexual orientation group were heterosexual, 122.55; lesbian, 131.61; and bisexual, 131.72. IRs were significantly elevated in both lesbian (IRR, 1.06; 95% CI, 1.06 1.06) and bisexual (IRR, 1.10; 95% CI, 1.10-1.10) women compared with heterosexual women. CONCLUSIONS: Our findings suggest that both lesbian and bisexual women have slightly elevated predicted breast cancer incidence compared with heterosexual women throughout the premenopausal period. IMPACT: Health professionals must ensure that breast cancer prevention efforts are reaching these women. As more health systems around the country collect data on patient sexual orientation, the National Cancer Institute's SEER cancer registry should add this information to its data system to monitor progress in reducing sexual orientation-related disparities in cancer incidence and mortality. PMID- 23035181 TI - Influence of quercetin-rich food intake on microRNA expression in lung cancer tissues. AB - BACKGROUND: Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined. METHODS: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR-based analyses, we compared the expression of miRs (n = 198) between lung cancer cases consuming high versus low quercetin-rich food intake using multivariate ANOVA tests. In family-miR-based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miR families. We accounted for multiple testing using 10,000 global permutations (significance at P(global) < 0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers). RESULTS: Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (P(FCS) < 0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (P (FCS) < 0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest and lowest quercetin-rich food consumers (23 expected by chance; P(global) = 0.047). CONCLUSIONS: We observed differential expression of key biologically functional miRs between high versus low consumers of quercetin-rich foods in adenocarcinoma cases. IMPACT: Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis. PMID- 23035182 TI - Lower-sensitivity and avidity modifications of the vitros anti-HIV 1+2 assay for detection of recent HIV infections and incidence estimation. AB - Recent-infection testing assays/algorithms (RITAs) have been developed to exploit the titer and avidity of HIV antibody evolution following seroconversion for incidence estimation. The Vitros Anti-HIV 1+2 assay (Ortho-Clinical Diagnostics) was approved by the FDA to detect HIV-1 and HIV-2 infections. We developed a less sensitive (LS) and an avidity-modified version of this assay to detect recent HIV infection. Seroconversion panels (80 subjects, 416 samples) were tested to calculate the mean duration of recent infection (MDR) for these assays. A panel from known long-term (2+ years) HIV-infected subjects on highly active antiretroviral therapy (HAART) (n = 134) and subjects with low CD4 counts (AIDS patients [n = 140]) was used to measure the false-recent rate (FRR) of the assays. Using a signal-to-cutoff ratio of 20 and the LS-Vitros assay gave a RITA MDR of 215 days (95% confidence interval [95% CI], +/- 65 days) and using an avidity index (AI) of 0.6 gave an MDR of 170 days (+/- 44 days), while a combination of the two assays yielded a MDR of 146 days (+/- 38.6) and an FRR of 8%. Misclassifying subjects with known long-term infection as recently infected occurred in 14% of AIDS patients and 29% (95% CI, 22, 38) of HAART subjects and 3% (95% CI, 0.8, 7.2) and 42% (95% CI, 33, 51), respectively, for the LS- and avidity-modified Vitros assays, with a misclassification rate of 15% (95% CI, 11, 20) overall using a dual-assay algorithm. Both modified Vitros assays can be used to estimate the length of time since seroconversion and in calculations for HIV incidence. Like other RITAs, they are subject to high FRR in subjects on HAART or with AIDS. PMID- 23035183 TI - First isolation of Dietzia cinnamea from a dog bite wound in an adult patient. AB - We report the first case of deep-wound colonization by Dietzia cinnamea in a patient who had been bitten by a dog. PMID- 23035184 TI - Comparative assessment of a commercial kit and two laboratory-developed PCR assays for molecular diagnosis of congenital toxoplasmosis. AB - Toxoplasmosis is a worldwide infection that may cause severe disease and is regarded as a serious health problem in France. Detection of the parasite by molecular methods is crucial for diagnosing the disease. The extreme diversity of methods and performances of Toxoplasma PCR assays makes the use of commercial PCR kits an attractive alternative, as they offer a chance for standardization. We compared the performances of three molecular methods for the detection of Toxoplasma gondii DNA in amniotic fluid: a commercial method using nested PCR and two laboratory-developed methods, one using conventional PCR and the other one real-time PCR. This evaluation was based upon a T. gondii DNA serial dilution assay, three amniotic fluid samples spiked with T. gondii at different concentrations, and a clinical cohort of 33 amniotic fluid samples. The T. gondii DNA serial dilution assay showed a much lower sensitivity for the commercial kit than for the laboratory-developed methods. Moreover, out of 12 proven congenital toxoplasmosis cases, 91.7% were detected by the laboratory-developed assays, whereas only 50% were detected by the commercial kit. A lack of sensitivity of the method, partly due to the presence of PCR inhibitors, was the main drawback of the commercial method. This study emphasizes that commercial PCR diagnostic kits do not systematically perform better than carefully optimized laboratory developed methods. There is a need for thorough evaluation of such kits by proficient groups, as well as for performance standards that commercial kits can be tested against to improve confidence in those selected by health care providers. PMID- 23035185 TI - A novel method for genotyping the Helicobacter pylori vacA intermediate region directly in gastric biopsy specimens. AB - The present report describes a novel method for genotyping the virulence associated vacA intermediate (i) region of Helicobacter pylori in archive material. vacA i-region genotypes as determined by the novel method were completely concordant with those of sequence analysis and with those of functional vacuolation activity. The method was further validated directly in gastric biopsy specimens of 386 H. pylori-positive cases, and effective characterization of the vacA i region was obtained in 191 of 192 (99.5%) frozen and in 186 of 194 (95.9%) formalin-fixed paraffin-embedded gastric biopsy specimens, respectively. The genotyping method was next used to address the relationship between the vacA genotypes and the cagA status. The vacA i1 genotype was associated with vacA s1 (where s indicates signal region), vacA m1 (where m indicates middle region), and cagA-positive genotypes (P < 0.0001), while the vacA i2 genotype was closely related with vacA s2, vacA m2, and cagA-negative genotypes (P < 0.0001). The relationship between H. pylori vacA i-region genotypes and gastric disease development was subsequently evaluated in the Portuguese population. Patients infected with vacA i1 strains showed an increased risk for gastric atrophy and for gastric carcinoma, with odds ratios of 8.0 (95% confidence interval [CI], 2.3 to 27) and of 22 (95% CI, 7.9 to 63), respectively. Taken together, the results show that this novel H. pylori vacA i-region genotyping method can be applied directly to archive material, providing a fast evaluation of strain virulence determinants without the need of culture. The results further emphasize that the characterization of the vacA i region may be useful to identify patients at higher risk of gastric carcinoma development. PMID- 23035186 TI - Carriage of Neisseria lactamica in 1- to 29-year-old people in Burkina Faso: epidemiology and molecular characterization. AB - Neisseria lactamica is a true commensal bacterium occupying the same ecological niche as the pathogenic Neisseria meningitidis, which is responsible for outbreaks and large epidemics, especially in sub-Saharan Africa. To better understand the epidemiology of N. lactamica in Africa and its relationship to N. meningitidis, we studied N. lactamica carriage in 1- to 29-year-old people living in three districts of Burkina Faso from 2009 to 2011. N. lactamica was detected in 18.2% of 45,847 oropharyngeal samples. Carriage prevalence was highest among the 2-year-olds (40.1%) and decreased with age. Overall prevalence was higher for males (19.1%) than females (17.5%) (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.04 to 1.18), while among the 18- to 29-year-olds, carriage prevalence was significantly higher in women (9.1%) than in men (3.9%) (OR, 2.49; 95% CI, 1.94 to 3.19). Carriage prevalence of N. lactamica was remarkably homogeneous in the three districts of Burkina Faso and stable over time, in comparison with carriage of N. meningitidis (P. A. Kristiansen et al., Clin. Vaccine Immunol. 18:435-443, 2011). There was no significant seasonal variation of N. lactamica carriage and no significant change in carriage prevalence after introduction of the serogroup A meningococcal conjugate vaccine, MenAfriVac. Multilocus sequence typing was performed on a selection of 142 isolates. The genetic diversity was high, as we identified 62 different genotypes, of which 56 were new. The epidemiology of N. lactamica carriage and the molecular characteristics of carried isolates were similar to those reported from industrialized countries, in contrast to the particularities of N. meningitidis carriage and disease epidemiology in Burkina Faso. PMID- 23035187 TI - Disseminated Trichosporon mycotoxinivorans, Aspergillus fumigatus, and Scedosporium apiospermum coinfection after lung and liver transplantation in a cystic fibrosis patient. AB - Trichosporon mycotoxinivorans is a novel pathogen recently found in cystic fibrosis patients. We report the first case of a disseminated fatal infection with T. mycotoxinivorans associated with invasive Aspergillus fumigatus and Scedosporium apiospermum infection after lung and liver transplantation in a cystic fibrosis patient. PMID- 23035188 TI - Identification of Streptococcus intermedius central nervous system infection by use of PCR and electrospray ionization mass spectrometry. AB - We describe the utility of PCR and electrospray ionization with mass spectrometry (PCR/ESI-MS) of culture-negative cerebrospinal fluid (CSF) in order to identify Gram-positive cocci noted on a Gram stain of CSF from a previously healthy 26 year-old man with community-acquired pneumonia (CAP) and multiple brain abscesses. CSF samples were obtained 2 weeks apart, first by lumbar puncture and 2 weeks later from an external ventricular drain that was inserted into the right ventricle. Both CSF cultures were negative. A Gram stain of bronchoalveolar lavage (BAL) fluid was notable for many Gram-positive cocci (GPC), but cultures of BAL fluid and subcarinal lymph node biopsy tissue were negative. PCR/ESI-MS detected Streptococcus intermedius, a common cause of brain abscesses, in both CSF samples as well as in the fixed tissue from the biopsy. This unique case confirms S. intermedius pulmonary infection as the source of metastatic CNS infection and reveals the potential of PCR/ESI-MS to detect a streptococcal pathogen not captured by conventional cultures. PMID- 23035189 TI - Recovery of Bordetella pertussis from PCR-positive nasopharyngeal samples is dependent on bacterial load. AB - Viable Bordetella pertussis isolates are essential for surveillance purposes. We performed culture of 223 PCR-positive nasopharyngeal samples. B. pertussis was recovered from 45 (20.2%) of the samples. Growth was associated with a high bacterial load, as determined by PCR. Culture from PCR-positive samples is a feasible approach to recover B. pertussis isolates, and culture can be limited to samples with a high bacterial load. PMID- 23035190 TI - Direct detection and genotyping of Klebsiella pneumoniae carbapenemases from urine by use of a new DNA microarray test. AB - Klebsiella pneumoniae carbapenemases (KPCs) are considered a serious threat to antibiotic therapy, as they confer resistance to carbapenems, which are used to treat extended-spectrum beta-lactamase (ESBL)-producing bacteria. Here, we describe the development and evaluation of a DNA microarray for the detection and genotyping of KPC genes (bla(KPC)) within a 5-h period. To test the whole assay procedure (DNA extraction plus a DNA microarray assay) directly from clinical specimens, we compared two commercial DNA extraction kits (the QIAprep Spin miniprep kit [Qiagen] and the urine bacterial DNA isolation kit [Norgen]) for the direct DNA extraction from urine samples (dilution series spiked in human urine). Reliable single nucleotide polymorphism (SNP) typing was demonstrated using 1 * 10(5) CFU/ml urine for Escherichia coli (Qiagen and Norgen) and 80 CFU/ml urine, on average, for K. pneumoniae (Norgen). This study presents, for the first time, the combination of a new KPC microarray with commercial sample preparation for detecting and genotyping microbial pathogens directly from clinical specimens; this paves the way toward tests providing epidemiological and diagnostic data, enabling better antimicrobial stewardship. PMID- 23035191 TI - Hexaplex PCR detection system for identification of five human Plasmodium species with an internal control. AB - Malaria remains one of the major killers of humankind and persists to threaten the lives of more than one-third of the world's population. Given that human malaria can now be caused by five species of Plasmodium, i.e., Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and the recently included Plasmodium knowlesi, there is a critical need not only to augment global health efforts in malaria control but also, more importantly, to develop a rapid, accurate, species-sensitive/species-specific, and economically effective diagnostic method for malaria caused by these five species. Therefore, in the present study, a straightforward single-step hexaplex PCR system targeting five human Plasmodium 18S small-subunit rRNAs (ssu rRNAs) was designed, and the system successfully detected all five human malaria parasites. In addition, this system enables the differentiation of single infection as well as mixed infections up to the two-species level. This assay was validated with 50 randomly blinded test and 184 clinical samples suspected to indicate malaria. This hexaplex PCR system is not only an ideal alternative for routine malaria diagnosis in laboratories with conventional PCR machines but also adds value to diagnoses when there is a lack of an experienced microscopist or/and when the parasite morphology is confusing. Indeed, this system will definitely enhance the accuracy and accelerate the speed in the diagnosis of malaria, as well as improve the efficacy of malaria treatment and control, in addition to providing reliable data from epidemiological surveillance studies. PMID- 23035193 TI - Characterization of a verocytotoxin-producing enteroaggregative Escherichia coli serogroup O111:H21 strain associated with a household outbreak in Northern Ireland. AB - A strain of Escherichia coli O111:H21 recently isolated in the United Kingdom harbored the phage-encoded vtx2c gene and the aggregative adherence plasmid. Although exhibiting the same pathogenic profile as the E. coli O104:H4 strain linked to the outbreak in Germany, there were important differences in strain characteristics and in the epidemiological setting. PMID- 23035192 TI - Swab protocol for rapid laboratory diagnosis of cutaneous anthrax. AB - The clinical laboratory diagnosis of cutaneous anthrax is generally established by conventional microbiological methods, such as culture and directly straining smears of clinical specimens. However, these methods rely on recovery of viable Bacillus anthracis cells from swabs of cutaneous lesions and often yield negative results. This study developed a rapid protocol for detection of B. anthracis on clinical swabs. Three types of swabs, flocked-nylon, rayon, and polyester, were evaluated by 3 extraction methods, the swab extraction tube system (SETS), sonication, and vortex. Swabs were spiked with virulent B. anthracis cells, and the methods were compared for their efficiency over time by culture and real-time PCR. Viability testing indicated that the SETS yielded greater recovery of B. anthracis from 1-day-old swabs; however, reduced viability was consistent for the 3 extraction methods after 7 days and nonviability was consistent by 28 days. Real-time PCR analysis showed that the PCR amplification was not impacted by time for any swab extraction method and that the SETS method provided the lowest limit of detection. When evaluated using lesion swabs from cutaneous anthrax outbreaks, the SETS yielded culture-negative, PCR-positive results. This study demonstrated that swab extraction methods differ in their efficiency of recovery of viable B. anthracis cells. Furthermore, the results indicated that culture is not reliable for isolation of B. anthracis from swabs at >= 7 days. Thus, we recommend the use of the SETS method with subsequent testing by culture and real-time PCR for diagnosis of cutaneous anthrax from clinical swabs of cutaneous lesions. PMID- 23035194 TI - Comparison of hybrid capture II, linear array, and a bead-based multiplex genotyping assay for detection of human papillomavirus in women with negative pap test results and atypical squamous cells of undetermined significance. AB - Many methods with different levels of analytical sensitivity and clinical specificity have been developed to detect the presence of high-risk (HR) types of the human papillomavirus (HPV) in cervical samples. The Hybrid Capture II (HC-II) assay is broadly used for primary screening. In addition, several HPV genotyping assays, based on PCR methods, display higher sensitivity than the HC-II and are also used in screening programs. We evaluated the performance of three HPV DNA tests, namely, the HC-II, the Linear Array (LA) HPV genotyping assay, and an HPV type-specific E7 PCR bead-based multiplex genotyping assay (TS-MPG) that is a laboratory-developed method for the detection of HPV, in 94 women with atypical squamous cells of undetermined significance (ASC-US) and in cytological samples from 86 women with a negative Pap test. The HPV prevalence with the TS-MPG assay was increased compared to the prevalence with the LA and HC-II assays. The HPV DNA prevalence in women with ASC-US was greater with the TS-MPG assay (46.2%) than with the LA (36.3%) and HC-II (29.7%) assays. The HPV DNA prevalence in the control group was greater with the TS-MPG assay (32.1%) than with the LA assay (10.7%). Two women with ASC-US who were HPV DNA negative by the HC-II and positive by the TS-MPG or/and LA assays had lesions that progressed to low-grade squamous intraepithelial and high-grade squamous intraepithelial lesions. This study shows that the TS-MPG assay exhibited higher analytical sensitivity than the LA and HC-II assays for the detection of HPV DNA, which reduces the potential to incorrectly identify a woman's HPV infection status. PMID- 23035195 TI - Atypical H-type bovine spongiform encephalopathy in a cow born after the reinforced feed ban on meat-and-bone meal in Europe. AB - The significance of atypical bovine spongiform encephalopathies (BSE) in cattle for controlling the BSE epidemic is poorly understood. Here we report a case of atypical H-type BSE in a cow born after the implementation of the reinforced feed ban in Europe. This supports an etiology of H-type BSE unrelated to that of classical BSE. PMID- 23035196 TI - Unusual "flesh-eating" strains of Escherichia coli. AB - Monomicrobial necrotizing fasciitis (type II) is typically caused by group A streptococcus alone or in combination with Staphylococcus aureus. Escherichia coli has been isolated from polymicrobial or Fournier's gangrene but has rarely been reported in monomicrobial necrotizing fasciitis. We describe the clinical characteristics and outcomes of seven cases of monomicrobial E. coli necrotizing fasciitis and/or severe soft tissue infection diagnosed at a single institution during an 18-month period. Four isolates from three patients and two isolates from two patients with type I polymicrobial severe soft tissue infection (controls) were assayed by the randomly amplified polymorphic DNA (RAPD) analysis for fingerprinting and PCR amplification of primers in order to detect cytotoxic necrotizing factor 1 and 2 (cnf1 and cnf2) genes. All patients had some type of immune suppression. The limb was the most commonly involved organ. In all cases, E. coli was isolated as a monomicrobial pathogen from blood, fascia, or both. All patients died during hospitalization, three within the first 48 h. The RAPD amplification assay showed a high degree of genetic diversity among the "flesh eating" strains and controls. The cnf1 toxin gene was identified in two out of three cases, but not in the controls. cnf2 was not detected in any of the patients. E. coli may be responsible for life-threatening necrotizing fasciitis. Further research is needed to reveal relevant risk factors, reservoirs, and modes of transmission of cnf1 E. coli. PMID- 23035197 TI - Similarity and divergence of phylogenies, antimicrobial susceptibilities, and virulence factor profiles of Escherichia coli isolates causing recurrent urinary tract infections that persist or result from reinfection. AB - In order to obtain a better molecular understanding of recurrent urinary tract infection (RUTI), we collected 75 cases with repeatedly occurring uncomplicated UTI. The genetic relationships among uropathogenic Escherichia coli (UPEC) isolates were analyzed by pulsed-field gel electrophoresis. While 39 (52%) of the RUTI cases were defined as "persistence" of the same strain as the primary infecting strain, 36 (48%) were characterized by "reinfection" with a new strain that is different from the primary strain. We then examined the antimicrobial susceptibilities and phylogenetic backgrounds of 39 persistence and 86 reinfection UPEC isolates, and screened 44 virulence factor (VF) genes. We found that isolates had significant differences in the following: placement in phylogenetic group B2 (41% versus 21%; P = 0.0193) and the presence of adhesin genes iha (49% versus 28%; P = 0.0233) and papG allele I' (51% versus 24%; P = 0.003), iron uptake genes fyuA (85% versus 58%; P = 0.0037), irp-2 (87% versus 65%; P = 0.0109), and iutA (87% versus 58%; P = 0.0014), and an aggregate VF score (median, 11 versus 9; P = 0.0030). In addition, 41% of persistence strains harbored three adhesin genes simultaneously, whereas 22% of reinfection isolates did (P = 0.0289). Moreover, 59% versus 29% (P = 0.0014) of persistence and reinfection isolates contained seven types of iron uptake genes. Taken together, the antimicrobial susceptibilities of UPEC isolates had little effect on the RUTI. Compared with reinfection strains, persistence UPEC isolates exhibited higher VF scores and carried more VF genes than may be involved in the development and progression of RUTI. PMID- 23035198 TI - Comparison of SpectraCell RA typing and multilocus sequence typing for extended spectrum-beta-lactamase-producing Escherichia coli. AB - Multilocus sequence typing (MLST) is one of the most reliable methods for typing of Escherichia coli, including extended-spectrum-beta-lactamase-producing E. coli (ESBL-EC). We investigated the performance of a new typing method, SpectraCell RA (River Diagnostics, Madison, WI), in comparison on MLST on a well-defined collection of ESBL-EC isolates obtained from chicken meat and humans. Ninety-two ESBL-EC isolates obtained from meat and 59 ESBL-EC isolates obtained from human rectal swabs and clinical blood cultures were typed using MLST and SpectraCell RA. The sensitivity and specificity of SpectraCell RA were calculated, using MLST as a reference method. Subsequently, the results of SpectraCell RA were used to determine the relatedness of ESBL-EC isolates from chicken and humans. Using MLST as the gold standard, the performance of SpectraCell RA was evaluated for 3 different cutoff values: 0.99975, 0.99955, and 0.99935. Depending on the cutoff value, the sensitivity was mediocre to unacceptably low, with values of 9.4%, 43.9%, and 66.7%, respectively. When sensitivity increased, the specificity decreased rapidly, from 95.6% to 69.8% and 34.4%, respectively. Also, the number of clusters containing both human and meat samples varied from 0 (0.0%) to 14 (38.9%). Our study shows that SpectraCell RA is not a suitable typing method for ESBL-EC when evaluating relationships of ESBL-EC at the population level. PMID- 23035199 TI - Use of clustered regularly interspaced short palindromic repeat sequence polymorphisms for specific detection of enterohemorrhagic Escherichia coli strains of serotypes O26:H11, O45:H2, O103:H2, O111:H8, O121:H19, O145:H28, and O157:H7 by real-time PCR. AB - We explored the genetic diversity of the clustered regularly interspaced short palindromic repeat (CRISPR) regions of enterohemorrhagic Escherichia coli (EHEC) to design simplex real-time PCR assays for each of the seven most important EHEC serotypes worldwide. A panel of 958 E. coli strains investigated for their CRISPR loci by high-throughput real-time PCR showed that CRISPR polymorphisms in E. coli strongly correlated with both O:H serotypes and the presence of EHEC virulence factors (stx and eae genes). The CRISPR sequences chosen for simplex real-time PCR amplification of EHEC strains belonging to the top 7 EHEC serogroups differentiated clearly between EHEC and non-EHEC strains. Specificity estimates for the CRISPR PCR assays varied from 97.5% to 100%. Sensitivity estimates for the assays ranged from 95.7% to 100%. The assays targeting EHEC O145:H28, O103:H2, and O45:H2 displayed 100% sensitivity. The combined usage of two simplex PCR assays targeting different sequences of the O26 CRISPR locus allowed detection of EHEC O26:H11 with 100% sensitivity. By combining two simplex PCR assays targeting different sequences of the EHEC O157 CRISPR locus, EHEC O157:H7 was detected with 99.56% sensitivity. EHEC O111:H8 and EHEC O121:H19 were detected with 95.9% and 95.7% sensitivity, respectively. This study demonstrates that the identification of EHEC serotype-specific CRISPR sequences is more specific than the mere identification of O-antigen gene sequences, as is used in current PCR protocols for detection of EHEC strains. PMID- 23035200 TI - Association between an emerging disseminated form of leishmaniasis and Leishmania (Viannia) braziliensis strain polymorphisms. AB - Leishmania (Viannia) braziliensis causes three main types of American tegumentary leishmaniasis (ATL), localized cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and disseminated leishmaniasis (DL). All forms are observed among individuals of Corte de Pedra, Brazil. We previously used random amplified markers to identify a multiclonal population among L. (V.) braziliensis isolates from ATL patients, defining parasite clades associated with different clinical syndromes. Herein we compared sequences of random amplified markers to identify genotypes of L. (V.) braziliensis recovered from lesions of CL, ML, and DL patients. Six polymorphic genomic loci were sequenced from 35 parasite isolates. Single-nucleotide polymorphisms (SNPs) and insertions-deletions (indels) at each locus allowed us to segregate the L. (V.) braziliensis population according to haplotypes. Several SNPs, indels, and haplotypes were significantly associated with an increased risk of DL. Molecular genotyping may provide markers to identify L. (V.) braziliensis strains likely to cause this emerging, hard-to treat form of ATL. PMID- 23035201 TI - Novel interpretation of molecular diagnosis of congenital toxoplasmosis according to gestational age at the time of maternal infection. AB - From a prospective cohort of 344 women who seroconverted for toxoplasmosis during pregnancy, 344 amniotic fluid, 264 placenta, and 216 cord blood samples were tested for diagnosis of congenital toxoplasmosis using the same PCR assay. The sensitivity and negative predictive value of the PCR assay using amniotic fluid were 86.3% and 97.2%, respectively, and both specificity and positive predictive value were 100%. Using placenta and cord blood, sensitivities were 79.5% and 21.2%, and specificities were 92% and 100%, respectively. In addition, the calculation of pretest and posttest probabilities and the use of logistic regression allowed us to obtain curves that give a dynamic interpretation of the risk of congenital toxoplasmosis according to gestational age at maternal infection, as represented by the three sample types (amniotic fluid, placenta, and cord blood). Two examples are cited here: for a maternal infection at 25 weeks of amenorrhea, a negative result of prenatal diagnosis allowed estimation of the probability of congenital toxoplasmosis at 5% instead of an a priori (pretest) risk estimate of 33%. For an infection at 10 weeks of amenorrhea associated with a pretest congenital toxoplasmosis risk of 7%, a positive PCR result using placenta at birth yields a risk increase to 43%, while a negative result damps down the risk to 0.02%. Thus, with a molecular diagnosis performing at a high level, and in spite of the persistence of false negatives, posttest risk curves using both negative and positive results prove highly informative, allowing a better assessment of the actual risk of congenital toxoplasmosis and finally an improved decision guide to treatment. PMID- 23035202 TI - Fatal case of Weeksella virosa sepsis. AB - Weeksella virosa is an aerobic Gram-negative rod that has rarely been reported to cause infection. We describe a fatal case of W. virosa sepsis in a young female with end-stage renal disease, report three additional cases of W. virosa infection, and review the literature regarding this infection. PMID- 23035203 TI - Should varicella-zoster virus culture be eliminated? A comparison of direct immunofluorescence antigen detection, culture, and PCR, with a historical review. AB - A comparison of direct fluorescent-antibody assay (DFA), culture, and two PCR assays disclosed sensitivities of 87.8%, 46.3%, and 97.6% and 100%, respectively. We reviewed 1,150 results for clinical specimens submitted for DFA and culture and found that only 17 were culture positive/DFA negative. The incremental cost to detect these 17 positives was $3,078/specimen. PMID- 23035205 TI - Chemometric approach to selectivity in TLC with densitometric detection. AB - A recent study showed that spectral correlation cannot be considered as a reliable method for spot purity of thin-layer chromatography (TLC). The current paper discusses limitations of possible chemometric techniques performed on diode array detection or multiwavelength densitograms of spots. The primary difference between high-performance liquid chromatography and TLC is the nonlinearity of the detector response. The discussion is based on two examples: a spot of decomposed aspirin and sixteen spots with different concentrations and contaminations of ciprofibrate and clofibric acid. It is concluded that only visual inspection of principal component analysis (PCA) scores can detect inhomogeneity in the cases of nonlinearity, spectral similarity and high overlap. The objective values and other methods can be affected by these phenomena and detect nonlinear artifacts as other compounds, or can be insensitive to a second compound with similar spectra. Therefore, PCA analysis of the spot is the recommended procedure for spot purity checking at the stage of method development. PMID- 23035204 TI - In vitro susceptibilities of yeast species to fluconazole and voriconazole as determined by the 2010 National China Hospital Invasive Fungal Surveillance Net (CHIF-NET) study. AB - We conducted active, laboratory-based surveillance for isolates from patients with invasive infections across China from August 2009 to July 2010. DNA sequencing methods were used to define species, and susceptibility to fluconazole and voriconazole was determined by the Clinical and Laboratory Standards Institute M44-A2 disk diffusion method but using up-to-date clinical breakpoints or epidemiological cutoff values. Candida spp. made up 90.5% of the 814 yeast strains isolated, followed by Cryptococcus neoformans (7.7%) and other non Candida yeast strains (1.7%). Bloodstream isolates made up 42.9% of the strains, isolates from ascitic fluid made up 22.1%, but pus/tissue specimens yielded yeast strains in <5% of the cases. Among the Candida isolates, Candida albicans was the most common species from specimens other than blood (50.1%) but made up only 23% of the bloodstream isolates (P < 0.001). C. parapsilosis complex species were the most common Candida isolates from blood (33.2%). Uncommon bloodstream yeast strains included Trichosporon spp., C. pelliculosa, and the novel species C. quercitrusa, reported for the first time as a cause of candidemia. Most (>94%) of the isolates of C. albicans, C. tropicalis, and the C. parapsilosis complex were susceptible to fluconazole and voriconazole, as were all of the Trichosporon strains; however, 12.2% of the C. glabrata sensu stricto isolates were fluconazole resistant and 17.8% had non-wild-type susceptibility to voriconazole. Seven C. tropicalis strains were cross-resistant to fluconazole and voriconazole; six were from patients in the same institution. Resistance to fluconazole and voriconazole was seen in 31.9% and 13.3% of the uncommon Candida and non-Candida yeast strains, respectively. Causative species and azole susceptibility varied with the geographic region. This study provided clinically useful data on yeast strains and their antifungal susceptibilities in China. PMID- 23035206 TI - Analysis of rutin in the extract and gel of Viola tricolor. AB - Heartsease, also known as wild pansy (Viola tricolor L.), contains considerable amounts of polyphenols: 109.32 +/- 1.29 mg of Gallic acid equivalent/g of extract. This study investigates their phytoconstituents and antioxidant capacity and validates a method for the quantification of rutin in the crude extract of the flowers of V. tricolor and in the extract incorporated in gel. Much better antioxidant capacity was found for the extract [inhibition concentration (IC50) of 16.00 +/- 0.78 ug/mL] than the standard ascorbic acid (IC50 of 16.57 +/- 0.95 ug/mL); these excellent results may be attributable to the amounts of polyphenols, flavonoids and condensed tannins. The high-performance liquid chromatography method for the quantification of rutin in the extract and gel was linear, sensitive, precise, specific, accurate and robust. This validated method can be used to control the quality of the extract and the gel. PMID- 23035207 TI - Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions. AB - BACKGROUND: The inhibition of dipeptidyl peptidase-4 (DPP4) protects the heart from acute myocardial ischemia. However, the role of DPP4 in chronic heart failure independent of coronary artery disease remains unclear. METHODS AND RESULTS: We first localized the membrane-bound form of DPP4 to the capillary endothelia of rat and human heart tissue. Diabetes mellitus promoted the activation of the membrane-bound form of DPP4, leading to reduced myocardial stromal cell-derived factor-1alpha concentrations and resultant angiogenic impairment in rats. The diabetic rats exhibited diastolic left ventricular dysfunction (DHF) with enhanced interstitial fibrosis caused partly by the increased ratio of matrix metalloproteinase-2 to tissue inhibitor of metalloproteinase-2 in a DPP4-dependent fashion. Both genetic and pharmacological DPP4 suppression reversed the stromal cell-derived factor-1alpha-dependent microvasculopathy and DHF associated with diabetes mellitus. Pressure overload induced DHF, which was reversed by DPP4 inhibition via a glucagon-like peptide 1/cAMP-dependent mechanism distinct from that for diabetic heart. In patients with DHF, the circulating DPP4 activity in peripheral veins was associated with that in coronary sinus and with E/e', an echocardiographic parameter representing DHF. Comorbid diabetes mellitus increased the circulating DPP4 activities in both peripheral veins and coronary sinus. CONCLUSIONS: DPP4 inhibition reverses DHF via membrane-bound DPP4/stromal cell-derived factor-1alpha-dependent local actions on angiogenesis and circulating DPP4/glucagon-like peptide-1-mediated inotropic actions. Myocardium-derived DPP4 activity in coronary sinus can be monitored by peripheral vein sampling, which partly correlates with DHF index; thus, circulating DPP4 may potentially serve as a biomarker for monitoring DHF. PMID- 23035208 TI - Homeostatic and tissue reparation defaults in mice carrying selective genetic invalidation of CXCL12/proteoglycan interactions. AB - BACKGROUND: Interaction with heparan sulfate proteoglycans is supposed to provide chemokines with the capacity to immobilize on cell surface and extracellular matrix for accomplishing both tissue homing and signaling of attracted cells. However, the consequences of the exclusive invalidation of such interaction on the roles played by endogenous chemokines in vivo remain unascertained. METHODS AND RESULTS: We engineered a mouse carrying a Cxcl12 gene (Cxcl12(Gagtm)) mutation that precludes interactions with heparan sulfate structures while not affecting CXCR4-dependent cell signaling of CXCL12 isoforms (alpha, beta, gamma). Cxcl12(Gagtm/Gagtm) mice develop normally, express normal levels of total and isoform-specific Cxcl12 mRNA, and show increased counting of circulating CD34(+) hematopoietic precursor cells. After induced acute ischemia, a marked impaired capacity to support revascularization was observed in Cxcl12(Gagtm/Gagtm) animals associated with a reduced number of infiltrating cells in the ischemic tissue despite the massive expression of CXCL12 isoforms. Importantly, exogenous administration of CXCL12gamma, which binds heparan sulfate with the highest affinity ever reported for a cytokine, fully restores vascular growth, whereas heparan sulfate-binding CXCL12gamma mutants failed to promote revascularization in Cxcl12(Gagtm/Gagtm) animals. CONCLUSION: These findings prove the role played by heparan sulfate interactions in the functions of CXCL12 in both homeostasis and physiopathological settings and document for the first time the paradigm of chemokine immobilization in vivo. PMID- 23035209 TI - Nationwide improvements in survival from out-of-hospital cardiac arrest in Japan. AB - BACKGROUND: Little is known about the nationwide trend in the survival of out-of hospital cardiac arrest (OHCA) in Japan and the differences in incidence and survival by age group and origin of arrest. METHODS AND RESULTS: A nationwide, prospective, population-based observation covering the whole population of Japan and involving consecutive OHCA patients with resuscitation attempts was conducted from January 2005 to December 2009. The main outcome measure was 1-month survival with favorable neurological outcome. The nationwide trends in OHCA incidence and outcome by age and origin of arrest were assessed. Multiple logistic regression analysis for bystander-witnessed OHCA was used to adjust for factors that were potentially associated with favorable neurological outcome. During 5 years, 547 153 overall OHCAs and 169 360 bystander-witnessed OHCAs were enrolled. The annual incidence significantly increased among overall OHCAs and bystander-witnessed OHCAs. Neurologically favorable survival significantly increased from 1.6% (1676/102 737) in 2005 to 2.8% (3280/115 250) in 2009 (P<0.001), from 2.1% (638/30 556) to 4.3% (1558/36 361) (P<0.001), and from 9.8% (437/4461) to 20.6% (1215/5906) (P<0.001) among overall OHCA, bystander-witnessed OHCA, and bystander witnessed ventricular fibrillation OHCA, respectively. Public-access automated external defibrillator use, either bystander-initiated chest compression-only cardiopulmonary resuscitation or conventional cardiopulmonary resuscitation, and earlier emergency medical services response time were associated with a better neurological outcome. Favorable neurological outcome among adult OHCA subjects significantly improved, but the outcome among younger children and very elderly subjects did not improve and was poor irrespective of origin of OHCA. CONCLUSIONS: Nationwide improvements of favorable neurological outcome from OHCA were observed in Japan and differed by age group and origin of OHCA. PMID- 23035210 TI - Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence. AB - PURPOSE: Deregulated expression of miRNAs has been shown in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a. EXPERIMENTAL DESIGN: Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo. RESULTS: Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6, and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in severe combined immunodeficient (SCID) mice. The anti-MM activity of lipidic-formulated miR-34a was further shown in vivo in two different experimental settings: (i) SCID mice bearing nontransduced MM xenografts; and (ii) SCID-synth-hu mice implanted with synthetic 3-dimensional scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity. CONCLUSIONS: Our findings provide a proof-of principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients. PMID- 23035211 TI - A small-RNA enhancer of viral polymerase activity. AB - Influenza A virus (IAV) is an unremitting virus that results in significant morbidity and mortality worldwide. Key to the viral life cycle is the RNA dependent RNA polymerase (RdRp), a heterotrimeric complex responsible for both transcription and replication of the segmented genome. Here, we demonstrate that the viral polymerase utilizes a small RNA enhancer to regulate enzymatic activity and maintain stoichiometric balance of the viral genome. We demonstrate that IAV synthesizes small viral RNAs (svRNAs) that interact with the viral RdRp in order to promote genome replication in a segment-specific manner. svRNAs localize to the nucleus, the site of IAV replication, are synthesized from the positive-sense genomic intermediate, and interact within a novel RNA binding channel of the polymerase PA subunit. Synthetic svRNAs promote polymerase activity in vitro, while loss of svRNA inhibits viral RNA synthesis in a segment-specific manner. Taking these observations together, we mechanistically define svRNA as a small regulatory enhancer RNA, which functions to promote genome replication and maintain segment balance through allosteric modulation of polymerase activity. PMID- 23035212 TI - A novel group of avian astroviruses in wild aquatic birds. AB - Using a pan-astrovirus reverse transcription-PCR assay, a great diversity of novel avastroviruses was detected from wild bird and poultry samples. Two groups of astroviruses detected from wild birds are genetically related or highly similar to previously known viruses in poultry. Most interestingly, a novel group of astroviruses was detected in wild aquatic birds. Our results also reveal that different groups of astroviruses might have difference host ranges. This study has expanded our understanding regarding avastrovirus ecology. PMID- 23035213 TI - Structural basis of rotavirus strain preference toward N-acetyl- or N glycolylneuraminic acid-containing receptors. AB - The rotavirus spike protein domain VP8* is essential for recognition of cell surface carbohydrate receptors, notably those incorporating N-acylneuraminic acids (members of the sialic acid family). N-Acetylneuraminic acids occur naturally in both animals and humans, whereas N-glycolylneuraminic acids are acquired only through dietary uptake in normal human tissues. The preference of animal rotaviruses for these natural N-acylneuraminic acids has not been comprehensively established, and detailed structural information regarding the interactions of different rotaviruses with N-glycolylneuraminic acids is lacking. In this study, distinct specificities of VP8* for N-acetyl- and N glycolylneuraminic acids were revealed using biophysical techniques. VP8* protein from the porcine rotavirus CRW-8 and the bovine rotavirus Nebraska calf diarrhea virus (NCDV) showed a preference for N-glycolyl- over N-acetylneuraminic acids, in contrast to results obtained with rhesus rotavirus (RRV). Crystallographic structures of VP8* from CRW-8 and RRV with bound methyl-N-glycolylneuraminide revealed the atomic details of their interactions. We examined the influence of amino acid type at position 157, which is proximal to the ligand's N-acetyl or N glycolyl moiety and can mutate upon cell culture adaptation. A structure-based hypothesis derived from these results could account for rotavirus discrimination between the N-acylneuraminic acid forms. Infectivity blockade experiments demonstrated that the determined carbohydrate specificities of these VP8* domains directly correlate with those of the corresponding infectious virus. This includes an association between CRW-8 adaption to cell culture, decreased competition by N-glycolylneuraminic acid for CRW-8 infectivity, and a Pro157-to Ser157 mutation in VP8* that reduces binding affinity for N-glycolylneuraminic acid. PMID- 23035214 TI - Interaction of the hepatitis B spliced protein with cathepsin B promotes hepatoma cell migration and invasion. AB - Hepatitis B spliced protein (HBSP) is involved in the pathogenicity and/or persistence of hepatitis B virus (HBV). Chronic HBV infection is one of the most important risk factors for the development of hepatocellular carcinoma (HCC). However, whether or not HBSP contributes to the progression of HBV-associated HCC remains unknown. This study reports that overexpression of HBSP in human hepatoma cells increased cell invasion and motility. Conversely, small interfering RNA (siRNA)-mediated knockdown of HBSP expression inhibited migration and invasion. By glutathione S-transferase (GST) pulldown, coimmunoprecipitation, and a mammalian two-hybrid assay, HBSP was found to directly interact with cathepsin B (CTSB). Similar to HBSP knockdown, knocking down CTSB also reduced cell migration and invasion. Furthermore, the HBSP-overexpressing hepatoma cells were shown to have increased expression and activity of matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (uPA), and overexpression of HBSP significantly enhanced tumor-induced vascularization of endothelial cells. In contrast, knockdown of either HBSP or CTSB by siRNA resulted in inhibition of the two proteolytic enzymes and of the in vitro angiogenesis. Expression of HBSP in the hepatoma cells appeared to activate the mitogen-activated protein kinase (MAPK) and Akt signaling pathway, as evidenced by increases in phosphorylation of p38, Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinase (ERK), and Akt. Taken together, these findings imply that interaction of HBSP with CTSB may promote hepatoma cell motility and invasion and highlight new molecular mechanisms for HBSP-induced HCC progression that involve the secretion and activation of proteolytic enzymes, increased tumor-induced angiogenesis, and activation of the MAPK/Akt signaling, thereby leading to the aggressiveness of hepatoma cells. PMID- 23035215 TI - Recognition of the different structural forms of the capsid protein determines the outcome following infection with porcine circovirus type 2. AB - Porcine circovirus type 2 (PCV2) capsid protein (CP) is the only protein necessary for the formation of the virion capsid, and recombinant CP spontaneously forms virus-like particles (VLPs). Located within a single CP subunit is an immunodominant epitope consisting of residues 169 to 180 [CP(169 180)], which is exposed on the surface of the subunit, but, in the structural context of the VLP, the epitope is buried and inaccessible to antibody. High levels of anti-CP(169-180) activity are associated with porcine circovirus associated disease (PCVAD). The purpose of this study was to investigate the role of the immune response to monomer CP in the development of PCVAD. The approach was to immunize pigs with CP monomer, followed by challenge with PCV2 and porcine reproductive and respiratory syndrome virus (PRRSV). To maintain the CP immunogen as a stable monomer, CP(43-233) was fused to ubiquitin (Ub-CP). Size exclusion chromatography showed that Ub-CP was present as a single 33-kDa protein. Pigs immunized with Ub-CP developed a strong antibody response to PCV2, including antibodies against CP(169-180). However, only low levels of virus neutralizing activity were detected, and viremia levels were similar to those of nonimmunized pigs. As a positive control, immunization with baculovirus-expressed CP (Bac-CP) resulted in high levels of virus neutralizing activity, small amounts of anti CP(169-180) activity, and the absence of viremia in pigs following virus challenge. The data support the role of CP(169-180) as an immunological decoy and illustrate the importance of the structural form of the CP immunogen in determining the outcome following infection. PMID- 23035216 TI - HIV-1 antisense transcription is preferentially activated in primary monocyte derived cells. AB - In this study, an antisense luciferase-expressing human immunodeficiency virus type 1 (HIV-1) molecular clone was used to infect primary cells. We found that antisense transcription activity from the 3' long terminal repeat (LTR) was significantly more abundant in monocyte-derived cells than in activated T lymphocytes. Moreover, by analyzing antisense transcription in infected monocyte derived dendritic cells (MDDCs), we observed that the majority of HIV-1-infected MDDCs with significant antisense transcription activity did not produce Gag. We also confirmed that the negative-strand-encoded antisense protein (ASP) was expressed in monocyte-derived cells. PMID- 23035217 TI - Reduced infectivity of adenovirus type 5 particles and degradation of entering viral genomes associated with incomplete processing of the preterminal protein. AB - To investigate further the contribution of the adenovirus type 5 (Ad5) E1B 55-kDa protein to genome replication, viral DNA accumulation was examined in primary human fibroblasts and epithelial cells infected with Ad5 or the E1B 55-kDa-null mutant Hr6. Unexpectedly, all cell types were observed to contain a significantly higher concentration of entering Hr6 than of Ad5 DNA, as did an infectious unit of Hr6. However, the great majority of the Hr6 genomes were degraded soon after entry. As this unusual phenotype cannot be ascribed to the Hr6 E1B frameshift mutation (J. S. Chahal and S. J. Flint, J. Virol. 86:3064-3072, 2012), the sequences of the Ad5 and Hr6 genomes were compared by using high-throughput sequencing. Seven previously unrecognized mutations were identified in the Hr6 genome, two of which result in substitutions in virion proteins, G315V in the preterminal protein (preTP) and A406V in fiber protein IV. Previous observations and the visualization by immunofluorescence of greater numbers of viral genomes entering the cytosol of Hr6-infected cells than of Ad5-infected cells indicated that the fiber mutation could not be responsible for the low-infectivity phenotype of Hr6. However, comparison of the forms of terminal protein present in purified virus particles indicated that the production of mature terminal protein from a processing intermediate is impaired in Hr6 particles. We therefore propose that complete processing of preTP within virus particles is necessary for the ability of viral genomes to become localized at appropriate sites and persist in infected cells. PMID- 23035218 TI - Infection and propagation of human rhinovirus C in human airway epithelial cells. AB - Human rhinovirus species C (HRV-C) was recently discovered using molecular diagnostic techniques and is associated with lower respiratory tract disease, particularly in children. HRV-C cannot be propagated in immortalized cell lines, and currently sinus organ culture is the only system described that is permissive to HRV-C infection ex vivo. However, the utility of organ culture for studying HRV-C biology is limited. Here, we report that a previously described HRV-C derived from an infectious cDNA, HRV-C15, infects and propagates in fully differentiated human airway epithelial cells but not in undifferentiated cells. We demonstrate that this differentiated epithelial cell culture system supports infection and replication of a second virus generated from a cDNA clone, HRV-C11. We show that HRV-C15 virions preferentially bind fully differentiated airway epithelial cells, suggesting that the block to replication in undifferentiated cells is at the step of viral entry. Consistent with previous reports, HRV-C15 utilizes a cellular receptor other than ICAM-1 or LDLR for infection of differentiated epithelial cells. Furthermore, we demonstrate that HRV-C15 replication can be inhibited by an HRV 3C protease inhibitor (rupintrivir) but not an HRV capsid inhibitor previously under clinical development (pleconaril). The HRV-C cell culture system described here provides a powerful tool for studying the biology of HRV-C and the discovery and development of HRV-C inhibitors. PMID- 23035220 TI - Baculoviruses modulate a proapoptotic DNA damage response to promote virus multiplication. AB - The baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) initiates apoptosis in diverse insects through events triggered by virus DNA (vDNA) replication. To define the proapoptotic pathway and its role in antivirus defense, we investigated the link between the host's DNA damage response (DDR) and apoptosis. We report here that AcMNPV elicits a DDR in the model insect Drosophila melanogaster. Replication of vDNA activated DDR kinases, as evidenced by ATM-driven phosphorylation of the Drosophila histone H2AX homolog (H2Av), a critical regulator of the DDR. Ablation or inhibition of ATM repressed H2Av phosphorylation and blocked virus-induced apoptosis. The DDR kinase inhibitors caffeine and KU55933 also prevented virus-induced apoptosis in cells derived from the permissive AcMNPV host, Spodoptera frugiperda. This block occurred at a step upstream of virus-mediated depletion of the cellular inhibitor-of-apoptosis protein, an event that initiates apoptosis in Spodoptera and Drosophila. Thus, the DDR is a conserved, proapoptotic response to baculovirus infection. DDR inhibition also repressed vDNA replication and reduced virus yields 100,000-fold, demonstrating that the DDR contributes to virus production, despite its recognized antivirus role. In contrast to virus-induced phosphorylation of Drosophila H2Av, AcMNPV blocked phosphorylation of the Spodoptera H2AX homolog (SfH2AX). Remarkably, AcMNPV also suppressed SfH2AX phosphorylation following pharmacologically induced DNA damage. These findings indicate that AcMNPV alters canonical DDR signaling in permissive cells. We conclude that AcMNPV triggers a proapoptotic DDR that is subsequently modified, presumably to stimulate vDNA replication. Thus, manipulation of the DDR to facilitate multiplication is an evolutionarily conserved strategy among DNA viruses of insects and mammals. PMID- 23035221 TI - Distribution and dynamics of transcription-associated proteins during parvovirus infection. AB - Canine parvovirus (CPV) infection leads to reorganization of nuclear proteinaceous subcompartments. Our studies showed that virus infection causes a time-dependent increase in the amount of viral nonstructural protein NS1 mRNA. Fluorescence recovery after photobleaching showed that the recovery kinetics of nuclear transcription-associated proteins, TATA binding protein (TBP), transcription factor IIB (TFIIB), and poly(A) binding protein nuclear 1 (PABPN1) were different in infected and noninfected cells, pointing to virus-induced alterations in binding dynamics of these proteins. PMID- 23035219 TI - Critical role for interferon regulatory factor 3 (IRF-3) and IRF-7 in type I interferon-mediated control of murine norovirus replication. AB - Human noroviruses (HuNoV) are the major cause of epidemic, nonbacterial gastroenteritis in the world. The short course of HuNoV-induced symptoms has implicated innate immunity in control of norovirus (NoV) infection. Studies using murine norovirus (MNV) confirm the importance of innate immune responses during NoV infection. Type I alpha and beta interferons (IFN-alpha/beta) limit HuNoV replicon function, restrict MNV replication in cultured cells, and control MNV replication in vivo. Therefore, the cell types and transcription factors involved in antiviral immune responses and IFN-alpha/beta-mediated control of NoV infection are important to define. We used mice with floxed alleles of the IFNAR1 chain of the IFN-alpha/beta receptor to identify cells expressing lysozyme M or CD11c as cells that respond to IFN-alpha/beta to restrict MNV replication in vivo. Furthermore, we show that the transcription factors IRF-3 and IRF-7 work in concert to initiate unique and overlapping antiviral responses to restrict MNV replication in vivo. IRF-3 and IRF-7 restrict MNV replication in both cultured macrophages and dendritic cells, are required for induction of IFN-alpha/beta in macrophages but not dendritic cells, and are dispensable for the antiviral effects of IFN-alpha/beta that block MNV replication. These studies suggest that expression of the IFN-alpha/beta receptor on macrophages/neutrophils and dendritic cells, as well as of IRF-3 and IRF-7, is critical for innate immune responses to NoV infection. PMID- 23035222 TI - Characterization of ectromelia virus deficient in EVM036, the homolog of vaccinia virus F13L, and its application for rapid generation of recombinant viruses. AB - The orthopoxvirus (OPV) vaccinia virus (VACV) requires an intact F13L gene to produce enveloped virions (EV) and to form plaques in cell monolayers. Simultaneous introduction of an exogenous gene and F13L into F13L-deficient VACV results in expression of the foreign gene and restoration of plaque size. This is used as a method to rapidly generate VACV recombinants without the need for drug selection. However, whether other OPVs require the orthologs of F13L to generate EV and form plaques, whether F13L orthologs and EV are important for OPV pathogenesis in natural hosts, and whether a system based on F13L ortholog deficiency can be used to generate recombinant OPVs other than VACV have not been reported. The F13L ortholog in ectromelia virus (ECTV), the agent of mousepox, is EVM036. We show that ECTV lacking EVM036 formed small plaques and was highly attenuated in vivo but still induced strong antibody responses. Reintroduction of EVM036 in tandem with the DsRed gene resulted in a virus that expressed DsRed in infected cells but was indistinguishable from wild-type ECTV in terms of plaque size and in vivo virulence. Thus, our data show that, like F13L in VACV, EVM036 is required for ECTV plaque formation and that EVM036 and EV are important for ECTV virulence. Our experiments also suggest that OPVs deficient in F13L orthologs could serve as safer anti-OPV vaccines. Further, our results demonstrate that ECTV deficient in EVM036 can be exploited for the rapid generation of fully virulent ECTV expressing foreign genes of interest. PMID- 23035223 TI - Lack of methylation in the upstream region of human papillomavirus type 6 from aerodigestive tract papillomas. AB - Methylation of the high-risk human papillomavirus type 16 (HPV16) upstream regulatory region (URR) has been described, but whether methylation is present among low-risk HPVs is unknown. The methylation status of the HPV6 URR was analyzed in papillomas from the upper aerodigestive tract of six adult patients. All CpGs in the URR were unmethylated, from both basal/intermediate and superficial cells, suggesting that methylation is not involved in the regulation of transcription from the HPV6 URR, regardless of epithelial differentiation. PMID- 23035224 TI - Inhibition of Marburg virus budding by nonneutralizing antibodies to the envelope glycoprotein. AB - The envelope glycoprotein (GP) of Marburg virus (MARV) and Ebola virus (EBOV) is responsible for virus entry into host cells and is known as the only target of neutralizing antibodies. While knowledge about EBOV-neutralizing antibodies and the mechanism for the neutralization of infectivity is being accumulated gradually, little is known about antibodies that can efficiently regulate MARV infectivity. Here we show that MARV GP-specific monoclonal antibodies AGP127-8 (IgG1) and MGP72-17 (IgM), which do not inhibit the GP-mediated entry of MARV into host cells, drastically reduced the budding and release of progeny viruses from infected cells. These antibodies similarly inhibited the formation of virus like particles (VLPs) consisting of GP, the viral matrix protein, and nucleoprotein, whereas the Fab fragment of AGP127-8 showed no inhibitory effect. Morphological analyses revealed that filamentous VLPs were bunched on the surface of VLP-producing cells cultured in the presence of the antibodies. These results demonstrate a novel mechanism of the antibody-mediated inhibition of MARV budding, in which antibodies arrest unformed virus particles on the cell surface. Our data lead to the idea that such antibodies, like classical neutralizing antibodies, contribute to protective immunity against MARV and that the "classical" neutralizing activity is not the only indicator of a protective antibody that may be available for prophylactic and therapeutic use. PMID- 23035225 TI - Development of neurological disease is associated with increased immune activation in simian immunodeficiency virus-infected macaques. AB - Simian immunodeficiency virus (SIV) infection of macaques can result in central nervous system disorders, such as meningitis and encephalitis. We studied 10 animals inoculated with brain-derived virus from animals with SIV encephalitis. Over half of the macaques developed SIV-induced neurologic disease. Elevated levels of systemic immune activation were observed to correlate with viral RNA in the cerebral spinal fluid but not with plasma viral load, consistent with a role for SIV in the pathogenesis of neurologic disease. PMID- 23035226 TI - Severe acute respiratory syndrome coronavirus protein nsp1 is a novel eukaryotic translation inhibitor that represses multiple steps of translation initiation. AB - Severe acute respiratory syndrome (SARS) coronavirus nonstructural protein 1 (nsp1) binds to the 40S ribosomal subunit and inhibits translation, and it also induces a template-dependent endonucleolytic cleavage of host mRNAs. nsp1 inhibits the translation of cap-dependent and internal ribosome entry site (IRES) driven mRNAs, including SARS coronavirus mRNAs, hepatitis C virus (HCV), and cricket paralysis virus (CrPV) IRES-driven mRNAs that are resistant to nsp1 induced RNA cleavage. We used an nsp1 mutant, nsp1-CD, lacking the RNA cleavage function, to delineate the mechanism of nsp1-mediated translation inhibition and identify the translation step(s) targeted by nsp1. nsp1 and nsp1-CD had identical inhibitory effects on mRNA templates that are resistant to nsp1-induced RNA cleavage, implying the validity of using nsp1-CD to dissect the translation inhibition function of nsp1. We provide evidence for a novel mode of action of nsp1. nsp1 inhibited the translation initiation step by targeting at least two separate stages: 48S initiation complex formation and the steps involved in the formation of the 80S initiation complex from the 48S complex. nsp1 had a differential, mRNA template-dependent, inhibitory effect on 48S and 80S initiation complex formation. nsp1 inhibited different steps of translation initiation on CrPV and HCV IRES, both of which initiate translation via an IRES 40S binary complex intermediate; nsp1 inhibited binary complex formation on CrPV IRES and 48S complex formation on HCV IRES. Collectively, the data revealed that nsp1 inhibited translation by exerting its effect on multiple stages of translation initiation, depending on the mechanism of initiation operating on the mRNA template. PMID- 23035227 TI - Utilization of sialylated glycans as coreceptors enhances the neurovirulence of serotype 3 reovirus. AB - Mammalian reoviruses display serotype-specific patterns of tropism and disease in the murine central nervous system (CNS) attributable to polymorphisms in viral attachment protein sigma1. While all reovirus serotypes use junctional adhesion molecule-A as a cellular receptor, they differ in their utilization of carbohydrate coreceptors. This observation raises the possibility that carbohydrate binding by sigma1 influences reovirus pathology in the CNS. In this study, we sought to define the function of carbohydrate binding in reovirus neuropathogenesis. Newborn mice were inoculated intramuscularly with wild-type strain type 3 Dearing (T3D) and T3D-sigma1R202W, a point mutant T3D derivative that does not bind sialic acid (SA). Infected mice were monitored for survival, and viral loads at the sites of primary and secondary replication were quantified. Fewer mice inoculated with the wild-type virus survived in comparison to those inoculated with the mutant virus. The wild-type virus also produced higher titers in the spinal cord and brain at late times postinoculation but lower titers in the liver in comparison to those produced by the mutant virus. In addition, the wild-type virus was more virulent and produced higher titers in the brain than the mutant following intracranial inoculation. These animal infectivity studies suggest that T3D-sigma1R202W harbors a defect in neural growth. Concordantly, compared with the wild-type virus, the mutant virus displayed a decreased capacity to infect and replicate in primary cultures of cortical neurons, a property dependent on cell surface SA. These results suggest that SA binding enhances the kinetics of reovirus replication in neural tissues and highlight a functional role for sialylated glycans as reovirus coreceptors in the CNS. PMID- 23035228 TI - Activation of the phosphatidylinositol 3-kinase/Akt signaling pathway during porcine circovirus type 2 infection facilitates cell survival and viral replication. AB - Virus infection activates host cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which regulates diverse cellular activities related to cell growth, survival, and apoptosis. The present study demonstrated for the first time that porcine circovirus type 2 (PCV2), a major causative agent of postweaning multisystemic wasting syndrome, which is an emerging and important swine disease, can transiently induce the PI3K/Akt pathway in cultured cells at an early step during PCV2 infection. Activation of the PI3K/Akt signal was also induced by UV-irradiated PCV2, indicating that virus replication was not required for this induction. Inhibition of PI3K activation leads to reduced virus yield, which is associated with decreased viral DNA replication and lower virus protein expression. However, inhibition of PI3K activation greatly enhanced apoptotic responses as evidenced by the cleavage of poly-ADP ribose polymerase and caspase-3 as well as DNA fragmentation using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining during the early stage of PCV2 infection. Furthermore, the pancaspase inhibitor zVAD.fmk alleviated the reduction in Akt phosphorylation levels by inhibiting PI3K activation, indicating that the signaling promotes cell survival and thereby favors viral replication. These results reveal that an antiapoptotic role for the PI3K/Akt pathway induced by PCV2 infection to suppress premature apoptosis for improved virus growth after infection, extending our understanding of the molecular mechanism of PCV2 infection. PMID- 23035229 TI - Hepatitis C virus induces epithelial-mesenchymal transition in primary human hepatocytes. AB - Hepatitis C virus (HCV)-mediated liver disease progression may reflect distinct molecular mechanisms for increased hepatocyte growth and hepatic stellate cell activation. In this study, we have observed that primary human hepatocytes, when infected in vitro with cell culture-grown HCV genotype 1a or 2a, display viral RNA and protein expression. Infected hepatocytes displayed a fibroblast-like shape and an extended life span. To understand the changes at the molecular level, we examined epithelial-mesenchymal transition (EMT) markers. Increased mRNA and protein expression levels of vimentin, snail, slug, and twist and a loss of the epithelial cell marker E-cadherin were observed. Snail and twist, when examined separately, were upregulated in chronically HCV-infected liver biopsy specimens, indicating an onset of an active EMT state in the infected liver. An increased expression level of fibroblast-specific protein 1 (FSP-1) in the infected hepatocytes was also evident, indicating a type 2 EMT state. Infected hepatocytes had significantly increased levels of phosphorylated beta-catenin (Ser(552)) as an EMT mediator, which translocated into the nucleus and activated Akt. The phosphorylation level of beta-catenin at Thr(41)/Ser(45) moieties was specifically higher in control than in HCV-infected hepatocytes, implicating an inactivation of beta-catenin. Together, these results suggested that primary human hepatocytes infected with cell culture-grown HCV display EMT via the activation of the Akt/beta-catenin signaling pathway. This observation may have implications for liver disease progression and therapeutic intervention strategies using inhibitory molecules. PMID- 23035230 TI - Genetic subpopulations of Rift Valley fever virus strains ZH548 and MP-12 and recombinant MP-12 strains. AB - Rift Valley fever virus strain MP-12 was generated by serial plaque passages of parental strain ZH548 12 times in MRC-5 cells in the presence of a chemical mutagen, 5-fluorouracil. As a result, MP-12 encoded 4, 9, and 10 mutations in the S, M, and L segments, respectively. Among them, mutations in the M and L segments were responsible for attenuation, while the MP-12 S segment still encoded a virulent phenotype. We performed high-throughput sequencing of MP-12 vaccine, ZH548, and recombinant MP-12 (rMP-12) viruses. We found that rMP-12 contains very low numbers of viral subpopulations, while MP-12 and ZH548 contain 2 to 4 times more viral genetic subpopulations than rMP-12. MP-12 genetic subpopulations did not encode the ZH548 sequence at the 23 MP-12 consensus mutations. On the other hand, 4 and 2 mutations in M and L segments of MP-12 were found in ZH548 subpopulations. Thus, those 6 mutations were no longer MP-12-specific mutations. ZH548 encoded several unique mutations compared to other Egyptian strains, i.e., strains ZH501, ZH1776, and ZS6365. ZH548 subpopulations shared nucleotides at the mutation site common with those in the Egyptian strains, while MP-12 subpopulations did not share those nucleotides. Thus, MP-12 retains unique genetic subpopulations and has no evidence of reversion to the ZH548 sequence in the subpopulations. This study provides the first information regarding the genetic subpopulations of RVFV and shows the genetic stability of the MP-12 vaccine manufactured in MRC-5 cells. PMID- 23035231 TI - Incorporation of antigens into viral capsids augments immunogenicity of adeno associated virus vector-based vaccines. AB - Genetic modification of adeno-associated virus (AAV) capsids has previously been exploited to redirect viral tropism. Here we demonstrate that engineering of AAV capsids as scaffolds for antigen display augments antigen-specific immunogenicity. Combining antigen display with vector-mediated overexpression resulted in a single-shot prime-boost vaccine. This new class of vaccines induced immune responses significantly faster and an IgG antibody pool of higher avidity than conventional vectors, highlighting the potency of capsid modification in vaccine development. PMID- 23035232 TI - Acid-activated structural reorganization of the Rift Valley fever virus Gc fusion protein. AB - The entry of the enveloped Rift Valley fever virus (RVFV) into its host cell is mediated by the viral glycoproteins Gn and Gc. We investigated the RVFV entry process and, in particular, its pH-dependent activation mechanism using our recently developed nonspreading-RVFV-particle system. Entry of the virus into the host cell was efficiently inhibited by lysosomotropic agents that prevent endosomal acidification and by compounds that interfere with dynamin- and clathrin-dependent endocytosis. Exposure of plasma membrane-bound virions to an acidic pH (> or the loss of the natural variant of inertness (<> of the labyrinth capsule)]. AB - The author suggests an original hypothesis of otosclerosis based on the analyses of the literature publications for many years and his personal clinical observations. The normal labyrinth capsule is considered to be bradytrophic, i.e. inert and showing an extremely low level of metabolic processes. The disturbance of bradytrophicity under the action of individual factors and/or especially their combination make it involved in the maintenance of calcium homeostasis in the body. The validity of this conjecture is confirmed by the results of histological investigations, viz. the appearance of diquide or xplasma-like, bone in the labyrinth of the patients suffering otosclerosis. Such bone resorption is known to occur in other parts of the bony skeletontoo and should be regarded as a normal physiological process contributing to the replenishment of blood calcium deficiency.The subsequent reorganization (remodeling) of any part of the bony skeleton is physiologically neutral. In the labyrinth capsule,with its small size and delicate structure, such reorganization induces the otosclerotic process responsible for dysfunction of the membranaceous labyrinth. The surgical treatment of the patients presenting with otosclerosis should be supplemented by conservative treatment intended to slow down the otosclerotic reorganization and to restore bradytrophicity of the labyrinth capsule. PMID- 23035269 TI - How rigid should you be when employees want flexible hours? PMID- 23035268 TI - [Ototoxicity of cisplatin]. AB - The objective of this publication is to summarize "classical" and modern concepts of pathogenesis, clinical features of cisplatin ototoxicity, its screening, and prophylaxis. It is argued that pathogenesis of a cisplatin-induced injury to the inner ear shares common features with the ototoxic mechanisms of action of other pharmaceuticals even though it is characterized by certain important differences. The authors consider the mechanisms of ototropicity, specific cytochemical aspects of cisplatin cytotoxicity that aggravate risk factors, and genetic predisposition to the development of iatrogenic problems. The data are presented on monitoring and experimental aspects of otoprotection for the prevention of cisplatin-induced damage to the auditory analyzer. PMID- 23035270 TI - Analysis of the 2013 proposed Medicare physician fee schedule. PMID- 23035271 TI - What do you do with that data? NEMSIS is power--learn how to take advantage. PMID- 23035320 TI - Boost your memory by eating right. How diet can help--or harm--your cognitive fitness. PMID- 23035321 TI - What's the beef with meat? Why too many burgers and steaks might shorten your life. PMID- 23035322 TI - Ask the doctor. I have high blood pressure. Is it worth it to buy a blood pressure monitor to check my pressure at home? PMID- 23035323 TI - Ask the doctor. I often fly on business from Chicago to Europe. Do you have any tips for managing jet lag? PMID- 23035324 TI - Vitamin D and calcium supplements: take them or leave them? How to follow the changing recommendations without making yourself dizzy. PMID- 23035325 TI - An apple a day--plus a walk--might contribute to a longer life. PMID- 23035326 TI - Surviving cancer--what happens next? Learning you're cancer-free is only the first step in a lifelong process. PMID- 23035327 TI - Weight-loss drug review. Before you try these medicines, know what they can do and if they are really for you. PMID- 23035328 TI - Making smart screening decisions. Part 1: colon cancer screening. Learn which colorectal cancer tests you need, and how often you need them. PMID- 23035329 TI - Unique stroke risks in women with atrial fibrillation. PMID- 23035330 TI - Still smoking? Study find quitting has benefits at any age. PMID- 23035331 TI - Staying fit might lower your odds of getting breast cancer. PMID- 23035332 TI - Abortion: women's health. PMID- 23035333 TI - [Q & A. A case with intra-hepatic bile duct dilatation]. PMID- 23035334 TI - [Lactoferrin in complex treatment of dental diseases]. PMID- 23035335 TI - [Present-day methods treatment and prevention of periodontal disease]. PMID- 23035336 TI - [Current status and future prospect of pre- and post-operative adjuvant therapy of pancreatic cancer: discussion]. PMID- 23035337 TI - [Social actors and phenomenologic modelling]. AB - The phenomenological approach has a quasi-monopoly in the individual and subjectivity analyses in social sciences. However, the conceptual apparatus associated with this approach is very restrictive. The human being has to be understood as rational, conscious, intentional, interested, and autonomous. Because of this, a large dimension of human activity cannot be taken into consideration: all that does not fit into the analytical categories (nonrational, nonconscious, etc.). Moreover, this approach cannot really move toward a relational analysis unless it is between individuals predefined by its conceptual apparatus. This lack of complexity makes difficult the establishment of links between phenomenology and systemic analysis in which relation (and its derivatives such as recursiveness, dialectic, correlation) plays an essential role. This article intends to propose a way for systemic analysis to apprehend the individual with respect to his complexity. PMID- 23035338 TI - Normalizing denominational statistics with demographic data: the case of the United Church of Canada. AB - In the Canadian context, one type of data has been underutilized in the study of contemporary religious trends: church collected statistics. The present article explores the advantages and limitations of such data by analyzing the evolution of key church indicators of the United Church of Canada over the past four decades. Figures regarding church membership, child baptisms, and funerals are examined and compared with demographic data from four Canadian regions. Results show that virtually all United Church statistics are in decline with regard to larger society since the 1970s. However, there are regional variations, most notably in the Atlantic provinces, which show later and lesser rates of decline. PMID- 23035339 TI - Safe spaces: gay-straight alliances in high schools. AB - In activists' circles as in sociology, the concept "safe space" has been applied to all sorts of programs, organizations, and practices. Few studies have specified clearly what safe spaces are and how they support the people who occupy them. We examine one social location typically understood to be a safe space: gay straight alliance groups in high schools. Using qualitative interviews with young adults in the United States and Canada who have participated in gay-straight alliances, we unpack this complex concept to consider some of the dimensions along which safe spaces might vary. Based on interviews with participants, we derive three interrelated dimensions of safe space: social context, membership, and activity. PMID- 23035340 TI - Technical considerations for measurement of median nerve conduction velocity at wrist. AB - Nerve conduction velocity (NCV) testing for the median nerve is the gold standard for diagnosing carpal tunnel syndrome (CTS), which affects about 6% of the general population. However, NCV equipment is relatively expensive and not always available at outpatient clinics. This study investigated the effects of different sampling rates and electrode placements on the NCV values of the median nerve to establish the practical significance of those specifications. The NCV of the median nerve at the wrist was measured in 30 healthy subjects with sampling rates of 2 kHz or 10 kHz and wide or narrow spacing of the electrode; Paired t-tests were used to compare the NCV values acquired by the different testing protocols. We found that the sampling rate had a statistically significant effect on the NCV values (P < 0.01), while the electrode placements did not significantly affect the NCV values (P > 0.05). The findings of this study have implications for improving the cost-effectiveness and technical applicability of NCV instruments. PMID- 23035341 TI - Erythema annulare centrifugum associated with herpes zoster. AB - Erythema annulare centrifugum (EAC) presents as erythematous or urticarial papules, each with an annular shape, that exhibit peripheral extension. Internal malignancies are occasionally associated with EAC, and infectious diseases, including fungal, bacterial or viral infections, have also been regarded as possible causes of EAC. A 35-year-old man had a 1-week history of a painful vesicular eruption over the trunk corresponding to dermatomes Th8-10. Concomitantly, he developed several annular eruptions over the trunk. We diagnosed the former lesions as herpes zoster and the latter as EAC associated with herpes zoster. Although DNA was extracted from the EAC region, no varicella zoster virus DNA was detected. We consider that this is Wolf's isotopic response, which is caused by an alteration of the local immunity due to viral infection. An etiologic relationship between EAC and herpes zoster is strongly suggested by the present case and by our review. PMID- 23035342 TI - [Recovery of bone conduction hearing level after stapes surgery in otosclerosis]. AB - Although otosclerosis is essentially a middle ear disease, patients with this disease often exhibit mixed hearing loss. This discrepancy is thought to be explained by the following mechanism: the resonance of the ossicular chain is disturbed by the fixation of stapes, leading to the attenuation of inertial bone conduction. The bone-conduction hearing level usually recovers after stapes surgery. We herein studied the change in air- and bone-conduction hearing after stapes surgery in patients with otosclerosis. Six consecutive patients with otosclerosis who underwent stapes surgery in our department were enrolled. They were 2 men and 4 women, ranging in age from 16 to 74 with an average of 57.2 years. Stapedotomy was performed in 5 patients, and the other patient underwent partial stapedectomy. Their pure tone hearing levels of air and bone conduction were measured before and after surgery. In the air conduction, the hearing levels at 125, 250, 500, 1000, 2000, and 4000 Hz significantly improved after surgery, but showed no significant change at 8000 Hz. On the other hand, in the bone conduction, the hearing levels at 500 and 1000 Hz significantly improved after surgery, whereas those at 250, 2000, and 4000 Hz showed no significant change. The recovery of the bone conduction hearing at 500 and 1000 Hz is explained by the resonance of the ossicular chain. However, the unimproved bone conduction hearing at 2000 Hz is unexplainable, and remains to be further investigated in future studies. PMID- 23035343 TI - [Possibility of exacerbation of allergy by lunar regolith]. AB - Japan, U.S.A. and other foreign space agencies have plans for the construction of a lunar base and long-term stay of astronauts on the moon. The surface of the moon is covered by a thick layer of soil that includes fine particles called "lunar regolith", which is formed by meteorite impact and space weathering. Risk assessment of particulate matter on the moon is important for astronauts working in microgravity on the moon. However, there are few investigations about the biological influences of lunar regolith. Especially, there is no investigation about allergic activity to lunar regolith. The main chemical components of lunar regolith are SiO2, Al2O3, CaO, FeO, etc. Of particular interest, approximately 50% of lunar regolith consists of SiO2. There is a report that the astronauts felt hay fever-like symptoms from the inhalation of the lunar regolith. Yellow sand, whose chemical components are similar to lunar regolith, enhances allergenic reactions, suggesting the possibility that lunar regolith has an adjuvant-like activity. Although intraperitoneal administration of lunar regolith with ovalbumin to mouse did not show enhancement of allergenic reactions, further evaluation of lunar regolith's potential to exacerbate the effects of allergies is essential for development of the moon. PMID- 23035344 TI - [Advances in research on cognitive function related to temporal lobe epilepsy: focus on social cognitive function]. AB - Research on cognitive function related to temporal lobe epilepsy has thus far focused on memory, language, and general intelligence. Recently, however, the concept of social cognitive function has been proposed in the field of neuropsychology. Social cognitive function refers collectively to the higher cognitive functions that are essential in our social lives, and its representative aspects are facial expression recognition and decision-making. Emotional processing centered around the amygdala is thought to play a key role in the neural mechanism of this function. We conducted a study on the social cognitive function (decision-making) of patients with temporal lobe epilepsy, and found that this function is reduced in these patients, and that the right amygdalo-hippocampal complexes play an important role. In order to ensure the best possible treatment for epilepsy patients, it is necessary not only to make an accurate diagnosis and provide appropriate treatment, but also to provide support for enabling a smoother social life from the perspective of social cognitive function. Future research developments in this field are expected to contribute to total management in medical care for epilepsy patients. PMID- 23035345 TI - [A case of accidental hypothermia caused by cervical spinal cord injury]. AB - Accidental hypothermia is the state in which body temperature falls due for exposure to a chilly environment. In accidental hypothermia, the mortality rate is higher the lower the body temperature. We report a case of a consciousness disorder and severe hypothermia, with a body temperature below 28 degrees C, in which it later became clear that a cervical spinal cord injury had been caused by a small external force. A 70-year-old woman was transported to our hospital in an ambulance for consciousness disturbance and severe hypothermia. At the time of arrival, her rectal temperature was 26.2 degrees C. We promptly performed rewarming. Her consciousness level became clear, but paralysis and diminished sensation were observed below the C5 domain. We suspected cervical spinal cord injury and performed cervical magnetic resonance imaging. She was diagnosed as having C5 cervical spinal cord injury. When there is a consciousness disorder due to accidental hypothermia, it might not be possible to evaluate the neurological value of the cervical spinal cord injury correctly. The presence of cervical spinal cord injury should be considered when patients have a decreased consciousness level due to hypothermia. PMID- 23035346 TI - [A case of malakoplakia of the urinary bladder]. AB - This is a case report of a 65-year-old female with malakoplakia in the urinary bladder. An ultrasound scan showed many tumor-like polyp lesions, where a transurethral resection was performed. Since the lesions revealed gross papillary neoplasms, malignancy was suspected. However, histpathological examination showed an aggregation of many infiltrating histiocytes containing characteristic Michaelis-Gutmann bodies positively reactive with von Kossa staining, indicating a typical case of malakoplakia of the urinary bladder. Immunohistochemical study demonstrated that the cytoplasms of the histiocytes were focally positive for an anti-Escherichia coli antibody. One of the etiologies of malakoplakia is infection by Escherichia coli, which is supported by our data. PMID- 23035347 TI - [Possibilities and problems in the development of forensic nursing in Japan: a questionnaire survey of clinical nurses]. AB - Forensic nursing scientifically obtains and preserves the criminal damage from victims of domestic violence, child abuse, elder abuse, sexual violence and other related forms of violence. This was developed in North America in the 1980s, and has carried out appropriate nursing care while protecting the human rights of victims. Serious crime in Japan has been increasing, and it would seem that forensic nursing opportunities should expand as well. However, in Japan, there hasn't been much discussion about forensic nursing. Theorizing that support for clinical forensic nursing should be recognized and relevant, we carried out a survey of 581 clinical nurses to investigate the development of forensic nursing in Japan. 93 clinical nurses (16.0%) had a low level of familiarity with forensic nursing; however, 324 nurses (56.3%) had encountered patients who had suffered violence. 264 nurses (45.4%) had a feeling of wanting to be involved in forensic nursing, but were not confident with the knowledge and technology, while 144 nurses (24.8%) were concerned about the larger responsibility they would have. 400 nurses (68.8%) hoped to receive specialized knowledge and technical education. It is necessary to establish an education system for forensic nursing in accordance with the educational status-quo while considering the present state of forensic nursing education. PMID- 23035348 TI - [Automatic monitoring of the chest compression parameters during human cardiopulmonary resuscitation]. PMID- 23035350 TI - [Improvement of procedures for monitoring parameters of electrocardiographs]. PMID- 23035349 TI - [Improvement of plasma coatings used in medicine]. PMID- 23035351 TI - [A chromatographic system for determination of biomarkers of dangerous diseases of humans]. PMID- 23035352 TI - [Application of LabView software for improving the quality of evaluation of parameters of electroencephalograms and evoked potentials]. PMID- 23035353 TI - [A procedure for formation of signs of the radial artery pulse signal]. PMID- 23035354 TI - [Diagnosis of breast cancer based on electrical impedance tomography]. PMID- 23035355 TI - [Simulation of acoustic fields of ultrasonic phased-array sector transducers]. PMID- 23035356 TI - [A boosting-based method for automatic detection of leukocytes in blood smear images]. PMID- 23035357 TI - [Specific features of use of medical equipment in air ambulance service]. PMID- 23035358 TI - [Assessment of quality of bench testing of an auxiliary axial pump for blood circulation]. PMID- 23035359 TI - The role of the cysteine-rich domain and netrin-like domain of secreted frizzled related protein 4 in angiogenesis inhibition in vitro. AB - Secreted frizzled-related protein 4 (sFRP4) is a Wnt signaling antagonist. Classically, sFRP4 antagonizes the canonical Wnt signaling pathway, resulting in decreased cellular proliferation and increased apoptosis. Recent research from our laboratory has established that sFRP4 inhibits angiogenesis by decreasing proliferation, migration, and tube formation of endothelial cells. The objective of this study was to examine the role of sFRP4's cysteine-rich domain (CRD) and netrin-like domain (NLD) in angiogenesis inhibition. Experiments were carried out to examine cell death and tube formation of endothelial cells after treatment with the CRD and the NLD. The CRD was seen to inhibit tube formation of endothelial cells, which suggests that this domain is important to sFRP4's antiangiogenesis property. In addition, the NLD promoted endothelial cell death and may also inhibit angiogenesis. Furthermore, treatment with the CRD and the NLD increased endothelial intracellular calcium levels. Our findings implicate a role for both the CRD and NLD in angiogenesis inhibition by sFRP4. It is suggestive of alternative antiangiogenic downstream targets of canonical Wnt signaling and a possible importance of the noncanonical Ca2+ Wnt signaling pathway in sFRP4-mediated angiogenesis inhibition. PMID- 23035360 TI - Structure-activity relationship of 9-methylstreptimidone, a compound that induces apoptosis selectively in adult T-cell leukemia cells. AB - We previously reported that 9-methylstreptimidone, a piperidine compound isolated from a culture filtrate of Streptomyces, induces apoptosis selectively in adult T cell leukemia cells. It was screened for a compound that inhibits LPS-induced NF kappaB and NO production in mouse macrophages. However, 9-methystreptimidone is poorly obtained from the producing microorganism and difficult to synthesize. Therefore, in the present research, we studied the structure-activity relationship to look for new selective inhibitors. We found that the structure of the unsaturated hydrophobic portion of 9-methylstreptimidone was essential for the inhibition of LPS-induced NO production. Among the 9-methylstreptimidone related compounds tested, (+/-)-4,alpha-diepi-streptovitacin A inhibited NO production in macrophage-like cells as potently as 9-methylstreptimidone and without cellular toxicity. Moreover, this compound selectively induced apoptosis in adult T-cell leukemia MT-1 cells. PMID- 23035361 TI - TLR4 signaling promotes immune escape of human colon cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. AB - This study investigated the expression and biological role of TLR4 in human colon cancer cells' growth and survival, and its potential as a target for colon cancer therapy. Reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry (FCM) were used to detect the expression level of TLR4. MTT analysis was performed to evaluate cell proliferation and enzyme-linked immunosorbent assay (ELISA) to test the production of IL-8, VEGF, and TGF-beta. MAPKs and NF kappaB were analyzed by Western blotting. Apoptosis was analyzed by flow cytometry with Annexin V and propidium iodide staining. The results showed that the human colon cancer cells HT-29, SW480, and Lovo all expressed TLR4 at both mRNA and protein levels, and TLR4 ligand LPS could not affect the expression of TLR4 and the proliferation of colon cancer cells. LPS increased phosphorylation of ERK1/2 and p38 and activated NF-kappaB. LPS promoted cytokine production, such as IL-8, VEGF, and TGF-beta. In addition, LPS induced resistance of human colon cancer cells to TRAIL-induced apoptosis and NF-kappaB activation was necessary for apoptosis resistance. The study identified the expression level of TLR4 in human colon cancer cells and TLR4 was functionally active. TLR4 may play important roles in promoting immune escape of human colon cancer cells by inducing immunosuppressive factors and apoptosis resistance. PMID- 23035362 TI - Lack of association of genetic variations of deoxycytidine kinase with toxicity or survival of non-small-cell lung cancer patients treated with gemcitabine plus cisplatin. AB - The aim of this study was to determine whether tagging polymorphisms (tSNPs) of deoxycytidine kinase (DCK) have an effect on toxicity or prognosis in patients with non-small-cell lung cancer (NSCLC) treated with gemcitabine plus cisplatin. Three tSNPs (-201 C>T, rs2306744; IVS2+9846 G>A, rs12648166; IVS6+1392 T>C, rs4694362) were chosen using the international HapMap Project and Japanese Single Nucleotide Polymorphisms. We evaluated the associations of the tSNPs with hematologic toxicity or overall survival of 139 NSCLC patients at stages IIIA/IIIB (59) and IV (80). Hematologic toxicity such as neutropenia, thrombocytopenia, and anemia were not different by the three tSNPs or haplotypes (CGT, CAT, and CAC) of DCK. The genetic variations did not affect survival of the patients (log-rank p: 0.248 for -201 C>T, 0.571 for IVS2+9846 G>A, 0.686 for IVS6+1392 T>C, 0.556 for CGT, 0.453 for CAT, and 0.845 for CAC). In a Cox model, these tSNPs and haplotypes did not reveal prognostic relevance (aHR and 95% CI: 0.954 and 0.611 to 1.489 for -201 C>T; 1.193 and 0.719 to 1.979 for IVS2+9846 G>A; 1.072 and 0.674 to 1.706 for IVS6+1392 T>C, 0,668 and 0.205 to 2.175 for CGT, 1.043 and 0.713 to 1.525 for CAT, and 1.043 and 0.701 to 1.550 for CAC). This is the first study to focus on the association of tSNPs and their haplotypes of DCK with toxicity and survival in NSCLC patients. This suggests that genetic variations of DCK have no effect on the outcomes in the patients treated with gemcitabine-based chemotherapy. PMID- 23035363 TI - Energy controllable steep pulse (ECSP) treatment suppresses tumor growth in rats implanted with Walker 256 carcinosarcoma cells through apoptosis and an antitumor immune response. AB - Electrochemotherapy has been widely used for the treatment of solid tumors, although the underlying mechanism remains unclear. We aimed to investigate the effects of energy controllable steep pulse (ECSP) on the regulation of tumor growth and apoptosis in rats implanted with Walker 256 carcinosarcoma cells. A rat tumor model was established by injection of Walker 256 carcinosarcoma cells into the inguinal area. H&E staining, transmission electron microscopy, and the TUNEL assay were used to detect apoptosis. Concanavalin A-induced lymphocyte transformation and MTT assays were used to assess lymphocyte proliferation. ELISA was used to determine serum cytokine levels. After 2 weeks of ECSP treatment, tumor growth in rats was effectively suppressed, while tumor cell apoptosis was significantly induced compared to the control tumor group. Moreover, ECSP treatment enhanced proliferation and activation of lymphocytes and natural killer (NK) cells. Serum IL-2 and IFN-gamma levels were significantly decreased, and IL 4 and 1-10 levels dramatically increased in rats with control tumors compared to rats without tumors and lacking treatment (p < 0.05). In contrast, ECSP treatment increased IL-2 and IFN-gamma levels, but reduced IL-4 and IL-10 levels to normal values. Moreover, ECSP also increased TNF-alpha production, possibly from peritoneal microphages. Our current study demonstrates that ECSP treatment is able to effectively reduce tumors in rats via induction of apoptosis and activation of the rat antitumor immune response. These data provide insightful information for the future application of ECSP-based electrochemotherapy in clinical trials against solid tumors. PMID- 23035365 TI - Nurses left to fill in cleaning. PMID- 23035364 TI - Nimotuzumab increases chemosensitivity of human lung adenocarcinoma cell lines to docetaxel. AB - Overexpression of epidermal growth factor receptor (EGFR) is common in non-small cell lung cancer (NSCLC) and has been recently shown to contribute to cancer chemoresistance. It has been reported that the EGFR antibodies such as cetuximab in combination with chemotherapy could lead to an absolute benefit of overall survival (OS) compared with chemotherapy alone. In this study, we investigated the effects of nimotuzumab (h-R3), a humanized anti-EGFR antibody, in combination with docetaxel (DTX), on DTX-resistant human lung adenocarcinoma cell line SPC-A1 (SPC-A1/DTX) both in vitro and in vivo. Immunohistochemistry and FCM assays demonstrated that SPC-A1/DTX cells had a relatively higher rate of EGFR overexpression than SPC-A1 cells. Accordingly, SPC-A1/DTX cells were approximately 13.7 times resistant to DTX than SPC-A1 cells. The combined therapy of h-R3 and DTX showed strong synergistic suppressive effect on cell proliferation of SPC-A1/DTX cells in vitro. The synergistic antitumor effect was also observed in SPC-A1/DTX xenograft-bearing nude mice. Further study showed that h-R3 could lead to a significant cell arrest at G1 phase of cell cycle in both SPC-A1DTX and SPC-A1 cells. A dramatic increase of apoptosis rate was detected in h-R3-treated SPC-A1/DTX but not SPC-A1 cells. Moreover, when combined with DTX, h-R3 brought higher apoptosis rate in SPC-A1/DTX cells rather than in SPC-A1 cells. In conclusion, our results suggested that h-R3 could significantly enhance chemosensitivity of human lung adenocarcinoma cells to DTX, at least partially by induction of G1 phase arrest and cell apoptosis. PMID- 23035367 TI - "New initiative will tell the public that nurses are remarkable". PMID- 23035366 TI - One in 10 patients experience some form of avoidable harm. PMID- 23035368 TI - "Expand HCA role to focus on older people's rehabilitation". PMID- 23035369 TI - Dementia care: focusing on daily experiences. AB - Dementia care is emerging as a national priority. It is affecting younger people and as many as one million could be living with the condition by 2015. This article describes the development of the Kitwood Plus model, which was specifically designed to care for people with dementia. Based on Kitwood (1997), the model fosters high-quality interaction from high-quality carers to enhance relationships and daily living experiences. Smile, touch, eye contact and positive talk (STEP) are the basic tools needed to connect with people with the condition. PMID- 23035370 TI - Using negative pressure therapy in wound healing. AB - Negative pressure wound therapy, also referred to as topical negative pressure therapy, is a useful treatment for a variety of acute and chronic wounds and, unlike many other wound treatments and dressings, has a relatively good evidence base to demonstrate its effectiveness. This article considers its application in both primary and acute care. PMID- 23035371 TI - Silver tube coatings in pneumonia prevention. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a common hospital-acquired infection that is associated with higher mortality rates, increased healthcare costs and longer hospitalisations. One intervention that has recently been used to reduce the prevalence of VAP is a new type of endotracheal tube impregnated with silver sulfadiazine. AIM: To investigate whether the use of silver-coated endotracheal tubes reduces VAP in adult intubated patients. METHOD: A thorough evidence-based literature review was conducted to investigate whether the use of silver-coated endotracheal tubes reduces the incidence of VAP. The following databases were consulted: CINAHL; Medline; Health Source: Nursing and Academic edition; ProQuest Nursing and Allied Health Source; Cochrane Database of Systematic Reviews; TRIP Database; and National Guideline Clearinghouse. RESULTS: The use of silver-coated endotracheal tubes reduces the prevalence of VAP in intubated patients but should not be used as an isolated intervention. CONCLUSION: More research is needed to assess whether the benefits of silver coated endotracheal tubes, coupled with additional VAP prevention strategies, outweigh the costs incurred. PMID- 23035373 TI - VTE: its diagnosis and management. PMID- 23035372 TI - Collaborative working to reduce VTE. AB - The thrombosis team at King's College Hospital used innovative methods to bring about a change in the trust's VTE prevention practice. The team took a structured approach with a focus on positive aspects of practice. The aim was to involve clinical staff by forming partnerships rather than using a dictatorial approach. The creation of a nurse and midwife link network and valuing the individuality of clinical areas were fundamental to successful change. PMID- 23035374 TI - Recalling sporting heroes. PMID- 23035375 TI - Survey of Canadian critical care nurses' experiences of conflict in intensive care units. AB - The purpose of this study was to enhance our understanding of Canadian critical care nurses' experiences of and responses to situations of conflict in the ICU. Through a 35-item web-based survey, members of the Canadian Association of Critical Care Nurses were asked questions regarding the types, causes and frequency of conflict experienced, the nursing interventions found most helpful in situations of conflict, and the resources found most helpful in responding to situations of conflict. A total of 241 nurses responded to the survey. The mean age of the nurses was 43 years, and the majority were female (89.2%), direct care providers (66.4%), with greater than 11 years of experience in critical care (58.3%), and working in medical/surgical ICUs (66.4%) in tertiary care hospitals (67.2%). Approximately 51% of the nurses reported being involved in at least one situation of conflict related to the management of a patient in the last week worked. The most common types of conflict encountered were disagreements between the team and family (46.5%) or within the team (35.3%). The nurses acknowledged the importance of clear, consistent and honest communication with patients and families when conflict arises and rank-ordered the resources found most helpful to patients, families, and nurses in conflict situations. Implications for practice and education are discussed and recommendations for future research are outlined. PMID- 23035376 TI - BiVADs: a bridge to the future for patients and their families: the art and science of nursing combined in the face of technology. AB - Approximately 500,000 Canadians live with heart failure (Ross et al., 2006). These numbers continue to rise due to advancing technology and successes in treating cardiac conditions and potentially fatal events such as myocardial infarctions. According to Carrier (2005), individuals with damaged hearts are living longer, and lives are being successfully saved with the surge of cardiovascular assist devices developed in recent years, which are increasingly used as a bridge to transplant. Despite the lifesaving capabilities of ventricular-assist devices, these innovations pose risks and complications that can be debilitating for patients and their families (Carrier, 2005). As this complex trajectory is navigated, nurses provide care and support to the patient and family while playing a unique role in the assessment and monitoring of these devices. A family-centred nursing model provides a framework for practice when nursing patients and families are in crisis. The foundations of the McGill Model of Nursing are focused on a strengths-based approach, revolving around collaboration between patients, family resources, and tailored interventions (Gottlieb & Feeley, 2005). As students placed in a critical care setting, we began to realize the complexity of care required to nurse these patients and their families. In this paper, a case study is used to describe and share our learning experiences of caring for a patient with a biventricular assist device, as well as the principles that guided our interventions. PMID- 23035377 TI - Hunt warned not to alienate nurses. PMID- 23035378 TI - "Stories of fantastic work will build public confidence". PMID- 23035379 TI - "You can nurse with dyscalculia--but know your limitations". PMID- 23035380 TI - Appropriate glove use in dermatitis prevention. AB - Work-related skin problems in nursing staff have risen in recent years, and inspections by the Health and Safety Executive in 2011 found a number of NHS trusts failing in their duties to prevent and manage the risks of work-related dermatitis. In response, the Royal College of Nursing issued guidelines on glove use and the prevention of contact dermatitis in nursing (RCN, 2012). These involved close collaboration between the professional and trade union parts of the RCN because failure to prevent and manage skin problems affects the safety of both staff and patients. PMID- 23035381 TI - Dyscalculia: awareness and student support. AB - Dyscalculia is a learning need that requires assessment and provision of reasonable adjustments. Although there have been numerous discussions about how to identify, assess and support dyscalculic children, there is less information available covering further and higher education, and even less concerned with the education of health professionals. This article aims to address this deficit, to discuss the disparity often felt by educators, and to raise awareness of the impact of dyscalculia on student nurses. PMID- 23035382 TI - Methods of skin antisepsis for preventing SSIs. AB - Surgical site infections increase morbidity and mortality rates and raise costs to healthcare providers. Surgical skin antisepsis is one element in a bundle of interventions designed to prevent SSIs. This article summarises the most recent evidence and guidance on skin antisepsis. PMID- 23035383 TI - Overcoming barriers to influenza vaccination. AB - Healthcare professionals face an ongoing challenge in overcoming barriers to influenza vaccination. This article explores the external and internal influences related to the uptake of flu vaccination with regard to both healthcare workers and their patients. The article discusses the ways in which nurses can help patients eligible for free flu vaccinations to make informed choices. PMID- 23035384 TI - Using Rapid Spread to achieve change in practice. AB - This article describes the development of Rapid Spread, a method of bringing about rapid changes in practice, and gives a step-by-step guide to using it to manage change. Trusts using Rapid Spread have seen measurable improvements in patient outcomes. Our experience shows that nurses are keen to embrace new practice that improves patient care. PMID- 23035385 TI - Aiming for flu immunity in all. PMID- 23035386 TI - What can the NHS learn from the private sector? PMID- 23035387 TI - The human capacity to reflect and decide: bioethics and the reconfiguration of the research subject in the British biomedical sciences. AB - This article examines how a fundamental element of the British bioethical assemblage - the literature on informed consent published between 1980 and 2000, a period when bioethics became a powerful force in the UK--has influenced contemporary understandings of the research subject. Drawing on Foucault, the article argues that this corpus of texts has created a sphere of possibilities in which research subjects can imagine themselves as human beings who reflect and decide whether they want to participate in medical experimentation. In particular, it shows how the narratives found in these texts portray relationships between researchers and their human subjects as 'paternalistic', and calls for their replacement by new, more ethical relationships characterized by both 'dialogue' and 'respect' and articulated around subjects who can 'think and take decisions'. It also discusses the different strategies- using patient information sheets, a list of possible questions and invitations to take time to reflect--which the bioethical literature has developed in order to realise these new, ethical relationships. As the article suggests, these narratives and strategies provide researchers and research subjects with models and examples of how to interact with each other that are very different from the ones that prevailed before the emergence of bioethics. PMID- 23035388 TI - Evolution of the human lifespan, past, present, and future: phases in the evolution of human life expectancy in relation to the inflammatory load. PMID- 23035389 TI - Human skin pigmentation as an example of adaptive evolution. PMID- 23035390 TI - [Freud's "Critical Introduction to Neuropathology" (1885-87): context and significance]. AB - Freud's "Critical Introduction" has many of the markers of a purely neuroanatomical text. But a comparison with contemporary anatomical writings as well as an analysis of the larger scientific, clinical and institutional context of Freud's work suggests important differences. Freud's manuscript was an ambitious enterprise to reform the brain sciences of the 1880s to open them up towards nervous conditions that were only poorly accounted for by the predominant German model of a somatically informed psychiatry. It marks an attempt to bridge the two cultures of French and German-speaking neurology, as well as scientific and clinical medicine. By navigating these different contexts, it provides a clue to the relationship between Freud's early scientific work and his developing psychoanalysis. PMID- 23035391 TI - [Critical Introduction to Neuropathology (1885 - 1887). Sigmund Freud. Published by Katja Guenther, Gerhard Fichtner and Albrecht Hirschmuller]. PMID- 23035392 TI - [On Freud's contributions to Villaret's Handworterbuch der Gesamten Medizin (1888 91)]. AB - Starting from an unpublished list of contributors to the handbook, Freud's authorship is established for three unsigned articles about the cranial nerves abducens, accessorius and (in parts) facialis. His authorship of the "Aphasia" article which has been disputed by Scherrer is confirmed. The section "II. physiology" of the article on the brain which has come to be ascribed to him is positively attributed to the physiologist Johannes Gad, the article on infantile paralysis to Alfred Goldscheider. PMID- 23035393 TI - [Susmann Galant (1896-1978). A Russian-Swiss supporter and opponent of Sigmund Freud]. AB - The scientific activity of this Russian psychiatrist is depicted in a short biography. His ambivalent attitude to Freud's dream theory is emphasized. At the end of his medical career he became full professor of psychiatry at Khabarovsk. PMID- 23035394 TI - ["Professor is well". The correspondence between Max Schur and Marie Bonaparte]. AB - The correspondence between Freud's doctor and his "Princess" spans the period 1929-1962, and comprises over 90 letters, mostly concerned with Freud's health but also touching upon Schur's permanent dilemma--to emigrate or to stay with Freud--and upon the dire situation of his family and friends on behalf of whom he appeals to Marie for help. After Freud's death the letters change in focus. PMID- 23035395 TI - [Karl Landauer's fate after the German occupation of the Netherlands]. AB - This paper documents Landauer's hesitation, prior to May 1940 when the Germans invaded the country, whether to emigrate a second time, and it reconstructs how he lost his positions as training analyst and psychoanalytic teacher after falling in love with a patient and starting an intimate relationship with her. PMID- 23035396 TI - [Jean-Jacques Rosseau the vitalist. The moralization of medical hygiene between diet and ethical food]. AB - The historiographical prejudice that sees in Jean-Jacques Rousseau an implacable opponent of scientific knowledge has long prevented an objective evaluation of the important influence that medical thought exerted over his philosophy. The aim of this paper is to show not only Rousseau's familiarity with the most important expressions of eighteenth-century medical literature, but also his willingness to incorporate some medical suggestions in his philosophical and literary production. In the first part of this article, I try to show how Rousseau's sensibility theory presupposes precise medical ideals, related to Montpellier School of vitalism. In the second part, I stress how Rousseau's philosophy of alimentation (which has clear anthropological and political implications) can be regarded as a genuine application of an ambition typical of vitalism: to use medical hygiene, also and above all, for moral purpose. PMID- 23035397 TI - Science on the fringe of the empire: the Academy of the Linceans in the early nineteenth century. AB - The article treats the Academy of the Linceans in the early nineteenth century, and more particularly during the Napoleonic domination of Rome in 1809-14. For the French regime, the Academy was instrumental to turning intellectuals into notables; pursuing the advancement of knowledge; stimulating industry; fostering secularization and orientating public opinion. But these goals did not always harmonize one with the other. Moreover, the local agenda was subordinated to strategic and ideological considerations pertaining to the organization of the Empire, relations with the Papacy, and internal politics. Hence, support to the Academy was subject to changes and contradictions. Within the Empire, the small local scientific elite found a place within international networks of science. Men of science increased their visibility and social standing, and greater symbolic and material resources were granted to the practice of science. The Academy, however, was left in the unclear status of a semi-public establishment, and it eventually imploded after the Restoration. The article analyses the Academy's scientific activity and its role in public life, focusing on material history as a key element to understand the ambiguous nature of Roman scientific institutions both under the papal government and the French regime. PMID- 23035398 TI - Penfield's homunculus and other grotesque creatures from the Land of If. AB - The neurosurgeon Wilder Graves Penfield (1891-1976) helped to develop a surgical treatment for epilepsy and used his results to investigate the functional organization of the brain. He was instrumental in founding the Montreal Neurological Institute at McGill University, which he directed from 1934 to 1960. There he studied, with his collaborators, the effects of stimulation and surgical ablation on different parts of the brain in order to localize their somatosensory functions. To visualize the results of this research, Hortense Pauline Cantlie drew images of a homunculus whose proportions reflected the extent of the cortical areas controlling different parts of the body. These images were published by Penfield in 1937; a modified version followed in 1950, opening the way for such developments as the diagrams of mammalian brains drawn by the neurophysiologist Clinton N. Woolsey in 1958. This article will reconstruct the history of Penfield's map of the human brain, which was utilized in medical texts for many decades, but which eventually would be severely criticized. PMID- 23035399 TI - Imaging the experiments on respiration and transpiration of Lavoisier and Seguin: two unknown drawings by Madame Lavoisier. AB - This paper presents two hitherto unknown drawings by Marie-Anne-Pierrette Lavoisier dating to the early 1790s that illustrate the experiments on respiration and transpiration of her husband Antoine-Laurent Lavoisier and his assistant Armand Seguin. These works may be associated with the well-known sepia drawings that were published for the first time by Edouard Grimaux in 1888. Details contained in these newly discovered drawings by M.me Lavoisier provide fresh evidence as to the nature and aims of Lavoisier's innovative experiments. As we will show, these drawings were intended to illustrate the collection of papers on respiration being prepared by Lavoisier for his Memoires de physique et de chimie (1792-1805). PMID- 23035400 TI - [Medical translations and practical compilations: a necessary coincidence?]. AB - Fourteenth- and fifteenth-century medicine is characterised by a trickle-down effect which led to an increasing dissemination of knowledge in the vernacular. In this context, translations and compilations appear to be two similar endeavours aiming to provide access to contents pertaining to the particulars of medical practice. Nowhere is this phenomenon seen more clearly than in vernacular manuscripts on surgery. Our study proposes to compare for the first time two corpora of manuscripts of surgical compilations, in Middle French and Middle English respectively, in order to discuss form and matter in this type of book production. PMID- 23035401 TI - [The mark of envy: metaphysics and embryology according to Descartes]. AB - This paper explores the interaction between medicine and metaphysics in modern natural philosophy and especially in Descartes' philosophy. I argue that Descartes hypothetical account of birthmarks in connection with his embryology provides an argumentative proof of the metaphysical necessity of a substantial union between mind and body, which however does not threaten his doctrine of the real distinction between these two substances. It would appear that his argument relies on a temporal conception of alethic modalities and provides a new answer to Henricus Regius who in 1641 claimed that, for Descartes, the human being is an ensper accidens. PMID- 23035402 TI - [Humanistic medicine and cryptocalvinism. Introduction]. PMID- 23035403 TI - [Life and works of Caspar Peucer]. PMID- 23035404 TI - [Peucer's medical manuscripts]. PMID- 23035405 TI - [The relationship of Peucer to Paracelsimism - ["Against fraudulent alchemists and shameless empiricists"]. PMID- 23035406 TI - [Humanistic medicine and cryptocalvinism. Summary]. PMID- 23035407 TI - The technology of medieval water management at the charterhouse of Bourgfontaine. PMID- 23035408 TI - Development of biosensors based on the one-dimensional semiconductor nanomaterials. AB - Biosensors are becoming increasingly important due to their applications in biological and chemical analyses, food safety industry, biomedical diagnostics, clinical detection, and environmental monitoring. Recent years, nanostructured semiconductor materials have been used to fabricate biosensors owing to their biocompatibility, low toxicity, high electron mobility, and easy fabrication. In the present study, we focus on recent various biosensors based on the one dimensional semiconductor nanomaterials such as electrochemical biosensor, field effect transistors biosensor, and label-free optical biosensor. In particular, the development of the electrochemical biosensor is discussed detailedly. PMID- 23035409 TI - Labeling of hematopoietic stem cells by Tat peptide conjugated quantum dots for cell tracking in mouse body. AB - Fluorescent quantum dots have great potential to act as labeling tools in biological research, especially cellular tracking and imaging. Tat peptide conjugated quantum dots were introduced into living human hematopoietic stem cells (HSCs). The internalized quantum dots were assessed by laser confocal microscope and flow cytometer. The quantum dots labeled HSCs were injected intravenously into the tail veins of NOD/SCID beta2M null mice. The tissue collections in the major organs were examined with fluorescence microscope to assess the distribution of transplanted stem cells. HSCs with internalized quantum dots offer a promising approach for stem cell transplantation, which will hold a significant impact on stem cell based therapy for several disorders, especially to cure leukemia in current China. PMID- 23035410 TI - A low-cost hydrogel chip for SNP typing by the incorporation of Cy5-dCTP into label-free allele-specific probes hybridizing to gel-immobilized targets. AB - A 3-dimensional (3-D) polyacrylamide gel microarray based on dual-color fluorescence hybridization was an efficient SNP typing method with a high throughput, but it is expensive to use dual dye-labeled allele-specific probes to type various SNPs. To lower the typing cost on 3-D polyacrylamide gel microarray, we propose a novel method by incorporating Cy5-dCTP into label-free allele specific probes hybridizing to gel-immobilized targets. The method is much simple. At first, raw PCR products without any purification was spotted on the acryl-modified slides to copolymerize with acrylamide monomers. Then a pair of allele-specific probes were respectively added into two different areas of a hydrogel chip to hybridize with the single-stranded DNA targets immobilized in the gel-pads. Before extension reaction with Cy5-dCTP, electrophoresis was performed on the gel chip to remove non-specific allele-specific probes, and a high specificity was thus obtained. After the extension reaction, electrophoresis was used once more to remove the unincorporated Cy5-dCTP absorbed in the gel pads, and a low background image was achieved. The method was successfully employed to type the SNP (C14417G) in the OLR-1 gene for 40 different samples, and the typing results were consistent with those by pyrosequencing, indicating that the proposed method is accurate and specific in SNP typing. As no use of dye modified probes, the typing cost is significantly decreased in comparison with the conventional typing method based on dual-color fluorescence hybridization, in particular when typing multiple SNPs. In addition to the low cost, our method has a low risk of cross-contamination from PCR amplicons due to no need of purification step of PCR products. Although only proof-of-concept results were given, we believe that the proposed method should be very useful for screening the biomarkers related to disease-susceptibility and personalized medicine where detection of many SNPs in different genes is required. PMID- 23035411 TI - Surface functionalized gold nanorods: tracking and observing live cell via three optical signals. AB - Surface functionalized gold nanorods (GNRs) with three optical signals and the ability to track and observe live cells was investigated. The Cetyltrimethyl Ammonium Bromide (CTAB) was used as the shape-directing agent to develop GNRs with uniform size and aspect ratio. The as-synthesized GNRs can strongly enhance the Raman signal of the attached MGITC on the GNRs. Polyethylene glycol (SH-PEG COOH) and SH-PEG-FITC were attached with GNRs through ligand exchange with CTAB. They can stabilize the GNRs, reduce the cytotoxicity and provide fluorescence signal. A cell-penetrating peptide was covalently conjugated with SH-PEG-COOH to assist the GNRs to enter living cell. After cultured with the MCF-7 cells, the surfaced functionalized Au nanorods can enter the MCF-7 cells and be tracking with enhanced MGITC Raman signal, FITC fluorescence, and Rayleigh scatter signal. PMID- 23035412 TI - A comparative study of CdTe quantum dots and CdTe@SiO2 nanoparticles: fabrication and cytotoxicity in HEK293 cells. AB - Quantum Dots have shown remarkable potentials in biomedical research. Herein, we reported the effects of CdTe quantum dots (QDs) and CdTe@SiO2 nanoparticles (NPs) on human embryonic kidney 293 (HEK 293A) cells with the aim of investigating their in vitro cytotoxicity. The CdTe@SiO2 particles were prepared by reverse microemulsion method. The structural morphology of the CdTe and hydrophilic silica-coated CdTe particles were characterized by transmission electron microscopy (TEM), ultraviolet-visible (UV-vis) spectrometry and photoluminescence (PL) spectrometry. The in vitro cytotoxicity of CdTe QDs and CdTe@SiO2 nanoparticles was assessed in 293A cells using standard MTT assay, western blot and fluorescent microscopy. The results showed that the CdTe and CdTe@SiO2 particles were relatively uniform with the diameter of about 3.8 nm, 75 nm respectively. The cell viability and the adhesion ability were similar to the control 293A cells. The level of the fibronectin protein expression was decreased with the increasing concentration of CdTe while the no effects were observed on expression of beta-actin in CdTe as well as CdTe@SiO2 treated cells even at highest concentration of 45 microg/mL which demonstrated their good biocompatibility to 293A cells. The results indicate that the CdTe@SiO2 nanoparticles are attractive candidates for biological imaging studies as expected. PMID- 23035414 TI - Hybrid low resistance ultracapacitor electrodes based on 1-pyrenebutyric acid functionalized centimeter-scale graphene sheets. AB - Ultracapacitors are promising candidates for alternative energy storage applications since they can store and deliver energy at relatively high rates. Here, we present hybrid nanocarbon ultracapacitor electrodes with a low equivalent series resistance (ESR) of 7 ohms. 1-pyrenebutyric acid treated large area single layer graphene (SLG) sheets covered with shortened multi-walled carbon nanotubes (MWNTs) have been utilized as highly conductive and percolated networks of hybrid carbon nanomaterial composites or thin films as ultracapacitor electrodes. Uniform centimeter scale single layer graphene sheets were produced via low pressure chemical vapor deposition using copper foil substrates and then subsequently modified by 1-pyrenebutyric acid functionalization. Chemically shortened MWNTs ranging in length of 200-500 nm, were deposited by drop casting on 1-pyrenebutyric acid functionalized SLG films. SLG/MWNT nancomposite hybrid films of different thicknesses were obtained by controlling the density of MWNT suspension. Surface morphology and nanostructure of the hybrid nanocomposites indicated relatively dense and homogeneous web-like networks. Specific capacitance values of the hybrid electrodes were substantially increased by 200% compared to those ultracapacitors fabricated using buckypaper electrodes. Average values of specific capacitance and energy density obtained were 140.64 F/g and 21.54 Wh/kg respectively. SLG/MWNT nanocomposite electrodes are very promising for future ultracapacitor devices with their low ESR value that is 95% lower than that of buckypaper based ultracapacitors. PMID- 23035413 TI - Preparation of magnetite-fullerene nanocomposite with enzyme immobilization. AB - This study presents modification of magnetite nanoparticles and fullerene for biocompatibility. It show also specific fabrication of magnetite-carbon nanocomposite with immobilized biomolecule. The composites were created by joining individual components step-by-step manner (fullerene to magnetite and glucose oxidase or glucose oxidase to magnetite and fullerene). The resulting nanocomposites were characterized by infrared spectroscopy (IR) and transmission electron microscopy (TEM). PMID- 23035415 TI - A facile hydrothermal strategy for synthesis of SnO2 nanorods-graphene nanocomposites for high performance photocatalysis. AB - In this study, we report a facilely hydrothermal process for synthesizing SnO2 nanorods-graphene (SnO2 nanorods-GR) composite using graphite oxide and SnCl4 as raw materials. The SnO2 nanorods-GR composite was characterized by X-ray diffraction, electron microscopy, Xray photoelectron spectroscopy, and thermogravimetric analysis. Compared to commercial TiO2 nanoparticles P25 and neat SnO2 nanorods, the SnO2 nanorods-GR composite exhibits higher photocatalytic activity under UV light irradiation. The mechanism of its high photocatalytic activity is mainly ascribed to the synergy effect between SnO2 and graphene, in which graphene acts as an adsorbent and electron acceptor due to its large structure of pi-pi conjugation from sp2 hybrid carbon atoms. The results demonstrated in this study provide a promising way to enhance the photocatalytic activity by compounding semiconductive nanocrystals with graphene. PMID- 23035416 TI - Improvement of electrical conductivity while maintaining a high-transmittance of graphene oxide/MWCNT film by hydrazine reduction. AB - In this study, we attempted to synthesize a transparent electrode with a composite of along graphene with multi-walled carbon nanotubes (MWCNT). Hydrazine was used for the reduction process. After the treatment with hydrazine, the sheet resistance was reduced from over 10 Momega/sq. The longest dip time sample (reduced GO/MWCNT-5, RGO/MWCNT-5) had the lowest sheet resistance (114 komega/sq). The reason for this decrease is likely due to the fact that the concentration of MWCNT in the deposited film increased with increases in the deposition time based on the higher density of the MWCNT. Although the transmittance decreased with decreases in the sheet resistance, the transmittances of all the samples were approximately 80% at 550 nm. We succeed in synthesizing a film that maintains transmittance (80%) despite a decreasing sheet resistance. PMID- 23035417 TI - Chemical vapor deposition synthesis of carbon nanotube-graphene nanosheet hybrids and their application in polymer composites. AB - Both carbon nanotubes (CNTs) and graphene nanosheets (GNs) have potential applications in polymer composites. Combining them may induce a synergistic effect on enhancing the properties of composites. Herein, CNT-GN 3D hybrids were prepared by liquid injection chemical vapor deposition through a spray containing both carbon feedstocks and catalyst precursors. Vertically aligned CNTs were self organized on the GNs. The morphology of hybrids could be well controlled as a function of the synthesis parameters. The unique 3D geometry of the CNT-GN hybrids provided composites with a higher electrical conductivity as compared to composites solely reinforced by CNTs or GNs. However, the thermal stability of the neat poly(vinylidene fluoride) matrix was found to decrease upon the addition of these hybrid fillers. PMID- 23035418 TI - Vertically aligned carbon nanotubes for microelectrode arrays applications. AB - In this work a methodology to fabricate carbon nanotube based electrodes using plasma enhanced chemical vapour deposition has been explored and defined. The final integrated microelectrode based devices should present specific properties that make them suitable for microelectrode arrays applications. The methodology studied has been focused on the preparation of highly regular and dense vertically aligned carbon nanotube (VACNT) mat compatible with the standard lithography used for microelectrode arrays technology. PMID- 23035419 TI - Fabrication and characterization of solution processed n-ZnO nanowire/p-Si heterojunction device. AB - This paper reports the results on the fabrication and characterization of n-ZnO nanowire/p-Si heterojunction devices. ZnO nanowires were grown on p-Si substrates by two step chemical solution process at low temperature. The ZnO nanowires grown vertically on silicon substrates were characterized by FESEM, EDX and PL. Heterojunction devices of n-ZnO nanowires/p-Si were fabricated and characterized for their photo, thermal and electrical responses. The ZnO nanowires grown were found to show piezoelectric nature and its effect has also been demonstrated. I-V characteristics of the fabricated n-ZnO/p-Si hetero-junction device showed rectifying behavior at different temperatures. The turn-on voltage of the fabricated ZnO nanowire/silicon devices was 0.45 V in the ambient condition. The ideality factor of the devices determined at low bias voltage is about 7.5, which indicates the defects induced tunneling of the junction. PMID- 23035420 TI - Study of ink paper sensor based on aluminum/carbon nanotubes agglomerated nanocomposites. AB - Agglomerated nanocomposites based on Aluminum/Carbon Nanotubes (AI/CNT) were produced by an arc discharge technique under argon/acetone atmosphere and ultrasonically dispersed in distilled water to form an ink-like composite. This ink was spread onto commercial paper to produce a conductive thick film. Experimental results show that the electrical resistance of Al/CNT nanocomposite on paper changes when a mechanical stress and/or heat is applied. The multi sensory properties obtained are the following: (i) piezoresistive effect, electrical resistance shows linear dependence with pressure intensity at room temperature; (ii) polynomial relationship between electrical resistance and temperature; and (iii) high accuracy thermal sensor compared to a K type thermocouple at 25 degrees C. The nanocomposite and paper morphology was analyzed by Scanning Electron Microscopy with Energy Dispersive Spectrometry (SEM/EDS) and a favorable surface for physisorption was observed. Transmission Electron Microscopy (TEM) was utilized for Al/CNT agglomerated indicating that the ink paper based on nanocomposite shows good performance as a thermo-piezoresistive sensor. PMID- 23035421 TI - Influence of silver concentrations on structural and magnetic properties of Ag Fe3O4 heterodimer nanoparticles. AB - In the present work, we have reported the effect of Ag NPs seeds on the growth and magnetic properties of Ag-Fe3O4 heterodimer nanoparticles prepared using a two step chemical approach. Three different Ag NPs concentrations have been tried and thoroughly characterized using small angle X-ray scattering (SAXS), transmission electron microscopy (TEM), X-ray diffraction (XRD), dc magnetization, and X-ray absorption near edge spectroscopy (XANES). It is observed that at low concentration, the "flower" types of nanoparticles are more favorable whereas the higher concentration of Ag NPs seeds promotes the growth of dimer type of structures. Our dc magnetization results are well correlated to the structural ones. The sample with lower amount of starting Ag NPs seeds possesses highest blocking and irreversibility temperature. On the other hand, the sample with highest concentration of Ag NPs seeds, the blocking temperature is lowered. PMID- 23035422 TI - Ordered assembly of sorted single-walled carbon nanotubes by drying an aqueous droplet on a meshed substrate. AB - We report on the ordered assembly of sorted single-walled carbon nanotubes (SWCNTs) (95% semiconducting tubes) by drying aqueous droplets on meshed grids with an enhanced evaporation rate. Besides the commonly observed "coffee ring" deposit of aligned SWCNTs on the droplet contact line after water evaporation, tubes self-organized in the central area of a grid and covered up to -1/3 of the whole surface area of a grid. In addition, parallel-aligned and straightened SWCNTs were seen to span across cracks in the SWCNT-surfactant film. The evaporation-driven assembly of sorted SWCNTs has the potential to produce ordered SWCNT structures that are attractive for the fabrication of electronic devices comprising mostly semiconducting or metallic tubes. PMID- 23035423 TI - Ultrasound assisted synthesis and properties of ZnO:B nanorods and micro flowers. AB - Nanopowders of ZnO pure and doped with boron have been synthesized through sonochemical method using acetate of the material as starting reagent. The incorporation of boron has been confirmed by inductively coupled plasma-optical emission spectroscopy (ICP-OES) analysis. Continuous (CS) and pulsed (PS) mode syntheses have shown interesting structural and optical properties such as photoluminescence (PL) and ultra-violet (UV) absorption. X-ray diffraction (XRD) studies showed broadening and shifting of peaks with boron incorporation in ZnO leading to size reduction in doped samples. The structure of the nanoparticles was found to be rod like and these rod like structure coalesce in boron doped ZnO. This has been explained on the basis of nucleation of octahedral units in the beginning leading it to tetrahedral structure. Electron microscopy has been used to explain these results. Definite peak shifts towards low wavelength side in absorption band and photoluminescence spectra have been observed for smaller particle size in pulsed mode powder. The blue shift due to particle size has been explained in the light of quantum confinement effect. PMID- 23035424 TI - Study of delta phase on static recrystallization behavior of Inconel 718 alloy. AB - The mechanical properties of Inconel 718 alloy depend on its microstructural features. Controlling the grain size during manufacturing is currently achieved through the use of a powerful hot forming process performed at a temperature sufficiently high to induce dynamic recrystallization. The present study proposes an alternative technique to achieve a uniform fine grain structure by using static recrystallization and a proper control of delta precipitation. The results show that a fine structure with an average grain size of ASTM No. 7 can be achieved. And in this study the finest grains yet achievable is ca. 200 nm. As a result, the proposed technique provides a feasible means of controlling the grain size without the need for an energy consumption and technically sophisticated hot forming process. PMID- 23035425 TI - Enhanced photocatalytic properties of nanoclustered P-doped TiO2 films deposited by advanced atmospheric plasma jet. AB - A facile preparation of P-doped TiO2 nanoclusters onto fluorine-doped tin oxide (FTO) glass by an advanced atmospheric plasma jet (AAP jet) is reported here. Titanium tetrachloride (TiCl4) and phosphorus trichloride (PCl3) were used as precursors. Radio frequencies were used to generate plasma at fix powder with Argon as carrier gas. Films were deposited at 500 degrees C for 10 minutes. For comparison, as-prepared, annealed and deposited at 500 degrees C samples were studied for chemical/physical properties by scanning electron microscopy (SEM), X ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). Optical properties were studied by using UV-Vis spectroscopy which indicated a reduction in optical band with P-doping. The rhodamine B (Rh-B) degradation by P-doped TiO2 deposited at 500 degrees C showed enhanced degradation efficiency than that of annealed TiO2. The suggested deposition method appears to be suitable for the synthesis of photocatalyst with proper control over dopants. PMID- 23035426 TI - Nanoporous activated carbon derived from Lapsi (Choerospondias axillaris) seed stone for the removal of arsenic from water. AB - Activated carbons were prepared from Lapsi (Choerospondias axillaris) seed stone by zinc chloride (ZnCl2) activation at three different Lapsi seed powder (LSP):ZnCl2 ratios: 1:0.5 (AC-0.5), 1:1 (AC-1), and 1:2 (AC-2). The properties of these activated carbons (ACs), including effective surface areas, pore volumes, and pore size distributions were characterized from N2 adsorption-desorption isotherms. The ACs obtained were essentially nanoporous (including both micro- and mesoporous) with effective surface area ranging from 1167 to 1328 m2/g. Fourier-transform infrared (FTIR) spectroscopy showed the presence of functional groups on the surface of ACs. Scanning electron microscopy (SEM) images showed a high pore development in the ACs. X-ray diffraction (XRD) patterns showed that, in addition to the amorphous structure, ACs contains crystalline ZnO formed during the carbonization. Presence of amorphous carbon is further confirmed by Raman scattering, where we observed only D and G bands. Iron impregnated nanoporous AC has been found to be very effective for arsenic removal from ground water; amount of arsenic is decreased from ca. 200 ppb to 10 ppb. These experimental results indicate the potential use of Lapsi seed as a precursor material for the preparation of high surface area nanoporous activated carbons. PMID- 23035427 TI - Molecular architecture and electrical properties in evaporated films of cobalt phthalocyanine. AB - Thin films of cobalt phthalocyanine (CoPc) were deposited onto solid substrates through physical vapor deposition (PVD) by thermal evaporation up to 60 nm thick to determine their molecular architecture and electrical properties. The growth was monitored using UV-Vis absorption spectroscopy, revealing a linear increase for absorbance versus thickness. PVD films were found in the crystalline alpha phase and with the CoPc molecules forming ca. 45 degrees in relation to the substrate surface. The film surface was fairly homogeneous at the micro and nanoscales, with the roughness at ca. 3 nm. DC and AC electrical measurements were carried out for devices built with distinct structures. Perpendicular contact was established by depositing 60 nm CoPc PVD films between indium tin oxide (ITO) and Al, forming a sandwich-type structure (ITO/CoPc/Al). The current versus DC voltage curve indicated a Schottky diode behavior with a rectification factor of 4.2. The AC conductivity at low frequencies increased about 2 orders of magnitude (10(-9) to 10(-7) S/m) with increasing DC bias (0 to 5 V) and the dielectric constant at 1 kHz was 3.45. The parallel contact was obtained by depositing 120 nm CoPc PVD film onto interdigitated electrodes, forming an IDE structured device. The latter presented a DC conductivity of 5.5 x 10(-10) S/m while the AC conductivity varied from 10(-9) to 10(-1) S/m between 1 Hz and 1 MHz, respectively, presenting no dependence on DC bias. As proof-of-principle, the IDE-structured device was applied as gas sensor for trifluoroacetic acid (TFA). PMID- 23035428 TI - Defect complexes in carbon and boron nitride nanotubes. AB - The effect of defect complexes on the stability, structural and electronic properties of single-walled carbon nanotubes and boron nitride nanotubes is investigated using the ab initio pseudopotential density functional method implemented in the Castep code. We found more substantial atomic relaxations in the zig-zag carbon nanotube than the armchair one. We find that the B(C)B(c) defect introduced in both zig-zag and armchair carbon nanotubes results in a semimetallic system. Similarly to the carbon nanotubes, the relaxation energies in the zig-zag boron nitride nanotubes are lower than in the armchair system. We find that creating a C(B)B(N) in the boron nitride nanotube, changes the system to metallic. The zig-zag configuration is energetically more stable than the armchair one in both the boron-rich and nitrogen-rich environments. The interaction between the carbon impurity and the antisite was investigated: we find that C(B)B(N) is preferable in the B-rich environment, and C(N)N(B) is preferable in the N-rich environment. We determine that in both zig-zag and armchair systems, B(N)N(B) is stable with the heats of formation of -5.77 eV and 8.69 eV, respectively. PMID- 23035429 TI - Ab initio studies of vacancies in (8,0) and (8,8) Single-walled carbon and boron nitride nanotubes. AB - A systematic study of vacancies in single-walled carbon nanotubes and boron nitride nanotubes was carried out. First principles calculations within the framework of density functional theory using the CASTEP code are used to optimize fully the geometries of the systems. The generalized gradient approximation is used for the exchange-correlation functional. We find that the pristine single walled carbon nanotubes have lower heats of formation compared with the boron nitride nanotubes, consistent with other findings. The zig-zag (8,0) carbon nnaotube has a slightly lower (-3.32 eV) heat of formation compared to the armchair (8,8) configuration (-3.25 eV). Comparison of the heats of formation of the vacancy systems is made and we draw conclusions about the relative stability of these defects. The heats of formation and atomic relaxations of the vacancies are explained as resulting from the tendency of the affected ions to recover the lost electronic coordination. For the boron nitride nanotube, we find that the vacancies on the nitrogen and boron site, namely V(N), and V(B), are respectively the more stable vacancies in the B- and N-rich environments. The electronic structure of the single vacancies also depends on the nanotube chirality. PMID- 23035430 TI - Laser collimation of Cr atoms with 3-D simulation analysis. AB - Based on two-level atomic theory and Doppler Effect, the laser collimation of Cr atoms with 3-D simulation analysis has been studied in this paper. By analyzing the 3-D force on chromium atom, a theoretical 3-D model is built and the accurate 3-D trajectory of chromium atoms in laser cooling field has been achieved. The final 3-D distribution of atoms with different parameters has also been described. PMID- 23035431 TI - One-atmosphere aqueous-solution synthesis of trimolybdate nanomaterials and the feasibility for mass production. AB - Mass production of low-cost functional nanomaterials is an important issue for the development of nanoscience and nanotechnology. With rich structural, physical and chemical properties, polyoxometalates are important functional materials for both industrial applications and fundamental research. We presented a family of alkali trimolybdate nanowires and nanorods that were synthesized by a one atmosphere aqueous solution method from a mixture of two solutions, one consisting of (NH4)6Mo7O24 x 4H2O and the other of Li+, Na+, K+ and Rb+ ions, respectively. This family showed clear similarities in their Raman and infrared spectra. By systematic characterizations, we have figured out a universal formula theta(m)(NH4)(2-m)Mo3O10 x nH2O (theta = Li, Na, K, Rb; m = 1,2) for this family of hydrate nanomaterials. Among them, two new phases, namely Li2Mo3O10 x H2O and Rb2Mo3O10 x 3 x 4H2O were recognized. The method was also applied to synthesizing Ag-doped trimolybdate nanowires, and the feasibility for mass production of these nanomaterials with a continuous synthesis experiment was also clear demonstrated. The results of this work offered interesting experimental data for theoretical analysis of the unique growth mechanism. PMID- 23035432 TI - Improved the electrochemical performance of LiCe(1-x)Ni(x)O2 cathode material for rechargeable lithium ion battery. AB - Cerium substituted LiCe(1-x)Ni(x)O2 (0.00 < X < 0.20) (Ce = 0.00 < X < 0.20) nano particles were synthesized by sol-gel method using nitrate as precursor at 800 degrees C for 12 hrs. XRD studies were revealed a well defined layer structure and a linear variation of lattice parameters with the addition of Cerium confirmed phase pure compounds in a rhombohedral structure for all materials. The surface morphological and particles agglomeration changes by the substitution of Cerium in LiNiO2 particles were examined by scanning electron microscope technique and TEM techniques. Ce3+ has prevented Jahn-Teller distortion and contained the NiO6 in LiCe(1-x)Ni(x)O2 through charge transfer from Ce-3d orbital to nearby Ni-3d orbital. The preferential occupation of Ce3+ in the Li sites was decreased the mixing of Ni2+ into the Li sites and improved the electrochemical properties of LiNiO2. The galvanostatic charge/discharge studies using assembled cells were carried out at 0.5 C rates. Cyclic voltammetric studies were carried out in the potential range between 3.5 V and 4.7 V at a scan rate of 0.1 mV s( 1). Electrochemical impedance spectroscopy revealed that, LiCe0.15Ni0.85O2 augmented charge transfer resistance upon cycling. The variations of cerium mixing and hexagonal ordering with the element (increase in R-factor) were favoured the first discharge capacity with the substituted element. LiCe0.15Ni0.85O2 nano cathode materials have superior electrochemical performances, such as, high charge-discharge capacity, high coulombic efficiency, high electrical conductivity and low irreversible capacity loss. PMID- 23035433 TI - Morphology controllable self-assembly of hierarchical hexaphenylsilole structures and their properties. AB - Morphology controllable hexaphenylsilole hierarchical homo-aggregations have been prepared by the self-assembly method in this paper. Tuning the solvent parameters can significantly affect the morphologies of the resulting HPS aggregations. The solvent properties play an important role in the shape-controlled synthesis of nanostructures. The possible self-assembly mechanism was also discussed. All of the different hierarchical structures aggregated from different solvents show different florescence and different absorption spectra properties, which could be of importance and have potential applications in the fields of optoelectronic functional materials. PMID- 23035434 TI - Pulse laser ablation in water fragmentation of amorphous silica in water with optional NaCI spiking. AB - Amorphous SiO2 powders having two kinds of medium range order (MRO) were subjected to pulse laser ablation in water (PLAL) for X-ray diffraction, transmission electron microscopy and spectroscopy characterization. The powders fragmented down to 10-20 nm in size are mainly hydrogenated amorphous phase retaining Si-2nd O but not Si-2nd Si MRO. There are minor co-existing crystallites of beta-cristobalite, H2Si2O5 as well as additional alpha-tridymite and Na2SiO3 when water is spiked with NaCI for PLAL. Na-signature also caused lower vibration frequency of the hydrogenated silica network. The opal-like hydrogenated phase assemblage of amorphous phase, cristobalite and tridymite thus formed have a minimum band gap at ca. 5 eV for potential optoelectronic and catalytic applications in UV range and shed light on natural occurrence in dynamic settings such as meteorite impact and lightening strike on silicate enrich crustal rocks. PMID- 23035435 TI - Synthesis of Pt nanoparticles decorated 1,5-diaminoanthraquinone nanofibers and their application toward catalytic reduction of 4-nitrophenol. AB - The present communication reports on the rapid preparation of 1,5 diaminoanthraquinone nanofibers (DAAQNFs) on a large scale by a reprecipitation method and their subsequent decoration with small platinum nanoparticles (PtNPs) using tannic acid (TA) as a reducing agent. It suggests the resultant PtNP/DAAQNF composites exhibit a good catalytic activity toward reduction of 4-nitrophenol (4 NP) to 4-aminophenol (4-AP) by NaBH4. It also suggests that the composites exhibit higher catalytic activity than the PtNPs due to that the DAAQNF support may play an active part in the catalysis, yielding a synergistic effect. The possible mechanism involved has also been discussed. PMID- 23035436 TI - Impedance study of tea with added taste compounds using conducting polymer and metal electrodes. AB - In this study the sensing capabilities of a combination of metals and conducting polymer sensing/working electrodes for tea liquor prepared by addition of different compounds using an impedance mode in frequency range 1 Hz-100 KHz at 0.1 V potential has been carried out. Classification of six different tea liquor samples made by dissolving various compounds (black tea liquor + raw milk from milkman), (black tea liquor + sweetened clove syrup), (black tea liquor + sweetened ginger syrup), (black tea liquor + sweetened cardamom syrup), (black tea liquor + sweet chocolate syrup) and (black tea liquor + vanilla flavoured milk without sugar) using six different working electrodes in a multi electrode setup has been studied using impedance and further its PCA has been carried out. Working electrodes of Platinum (Pt), Gold (Au), Silver (Ag), Glassy Carbon (GC) and conducting polymer electrodes of Polyaniline (PANI) and Polypyrrole (PPY) grown on an ITO surface potentiostatically have been deployed in a three electrode set up. The impedance response of these tea liquor samples using number of working electrodes shows a decrease in the real and imaginary impedance values presented on nyquist plots depending upon the nature of the electrode and amount of dissolved salts present in compounds added to tea liquor/solution. The different sensing surfaces allowed a high cross-selectivity in response to the same analyte. From Principal Component Analysis (PCA) plots it was possible to classify tea liquor in 3-4 classes using conducting polymer electrodes; however tea liquors were well separated from the PCA plots employing the impedance data of both conducting polymer and metal electrodes. PMID- 23035437 TI - Artemisia capillaris extracts as a green factory for the synthesis of silver nanoparticles with antibacterial activities. AB - We report a green synthesis of silver nanoparticles that uses extracts from the aerial part of Artemisia capillaris. Both water and 70% ethanol extracts successfully generated silver nanoparticles. The formation of silver nanoparticles was confirmed by surface plasmon resonance bands, Fourier transform infrared spectra, high resolution-transmission electron and atomic force microscopic images. Various shapes of silver nanoparticles were generated with an average diameter of 29.71 nm with water extract and 29.62 nm with 70% ethanol extract. An improvement in antibacterial activity (MIC 8.35-16.7 microg/mL) was observed against a total of twenty different strains of Gram-negative and Gram positive bacteria. A remarkable enhancement (approximately 12-fold) was observed against Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, and Klebsiella areogenes when compared with the extract alone. Silver nanoparticles produced by the 70% ethanol extract showed slightly higher antibacterial activity than those generated with the water extract. The correlation between total flavonoid content of each extract and the antibacterial activity did not exert any significant relationships. This report suggests that plant extracts have the potential to be used as powerful reducing agents for the production of biocompatible silver nanoparticles possessing enhanced antibacterial activities. PMID- 23035438 TI - Synthesis and magnetic property of iron ions-doped hydroxyapatite. AB - Magnetic Hydroxyapatite (HAP) particles were successfully synthesized at different concentration of Fe2+ by a co-precipitation method. The influences of concentration of doped ions and calcination temperature on the morphology and magnetic property were studied. The iron ions-doped HAP still kept its structure similar to conventional HAP and no second phases were detected. Results indicated that the doping of iron ions decreased the crystallinity and inhibited the c-axis growth and promoted the a-axis growth. HAP particles incorporated with 10% and 50% iron ions exhibited superparamagnetic and with 30% iron ions exhibited weak ferromagnetic characters. In addition, calcination temperature also increased the remnant. PMID- 23035439 TI - Nanowire dimensions effect on ON/OFF current ratio and sub-threshold slope in silicon nanowire transistors. AB - This paper shows the effect of the dimensions of nanowires on threshold voltage, ON/OFF current ratio, and sub-threshold slope. These parameters are critical factors of the characteristics of silicon nanowire transistors. The MuGFET simulation tool was used to investigate the characteristics of a transistor. Current-voltage characteristics with different dimensions were simulated. Results show that long nanowires with low diameter and oxide thickness tend to have the best transistor characteristics. PMID- 23035440 TI - Antimicrobial activity of zirconia (ZrO2) nanoparticles and zirconium complexes. AB - The antimicrobial activities of zirconia (ZrO2) nanoparticles and zirconium mixed ligand complexes were studied on bacterial strains of E. coli, S. aureus and fungal strain of A. niger. The nanoparticles of zirconia and Zr(IV) complexes with different amino acids as ligands were synthesized by hydrothermal method. X ray diffraction (XRD) and HRTEM confirmed the crystalline nature and morphology of the synthesized products. The antimicrobial studies revealed that the zirconia exhibits activity only against the E. coli, whereas, the Zr(IV) complexes exhibits activity against both the bacteria: gram -ve E. coli and gram +ve S. aureus as well as fungal strains. The Zr(IV) complexes are found to possess significant antifungal activity against A. niger. The results are indicative of crystal plane-dependent antimicrobial activity of zirconia nanoparticles and complexes. The observed difference in the antibacterial activity of ZrO2 crystals and Zr(IV) complexes may be ascribed to the atomic arrangements of different exposed surfaces. On the basis of the study, it could be speculated that the ZrO2 nanoparticles with the same surface areas but with different shapes i.e., different active facets will show different antimicrobial activity. PMID- 23035441 TI - Enhancing high-rate and elevated-temperature performances of nano-sized and micron-sized LiMn2O4 in lithium-ion batteries with ultrathin surface coatings. AB - LiMn2O4 suffers from severe capacity degradation when used as a cathode material in rechargeable lithium-ion batteries, especially when cycled at high rates and elevated temperatures. To enhance its high-rate electrochemical performance at elevated temperature (55 degrees C), we use atomic layer deposition (ALD) to deposit ultrathin and highly conformal Al2O3 coatings (as thin as 0.72 nm) onto micron-sized and nano-sized LiMn2O4 with precise thickness-control at atomic scale. All ALD-modified electrodes exhibit significantly improved capacities and cycling stability compared to bare electrodes. In particular, the effect of ALD coating to improve electrochemical performance of LiMn2O4 is more distinct for nano-sized LiMn2O4 than for micron-sized LiMn2O4, and more distinct for electrochemical cycling at higher charge/discharge rates. For example, nano LiMn2O4 electrode coated with 6 Al2O3 ALD layers delivers higher initial capacity (124.7 mA h/g) and final capacity (106.7 mA h/g) after 100 cycles than bare electrode with an initial capacity of 112.3 mA h/g and a final capacity of only 95.5 mA h/g, when cycled at a very high rate of 5 C at 55 degrees C. In addition, nano-LiMn2O4 electrodes show much better rate performance than micron-LiMn2O4 electrodes at 5 C. The enhanced electrochemical performance of ALD-modified LiMn2O4 is ascribed to high-quality ALD oxide coatings that are highly conformal, dense, complete, and thus protect active material from severe dissolution, and to a formed robust glass layer on the surface of LiMn2O4 that suppress its crystallographic transformation during electrochemical cycling. Surface modifications of LiMn2O4 are also carried out by either ALD coating directly onto the entire LiMn2O4/carbon/PVDF composite electrode or coating only on LiMn2O4 particles in electrode. The former results in more significantly improved electrochemical performance of cathode, possibly because ALD coating onto entire electrode provides better mechanical integrity and preserves contact between LiMn2O4 particles and carbon/poly-vinylidenefluoride network. PMID- 23035442 TI - A single-source hydrothermal route to synthesize porous hematite particles and their photocatalytic activity. AB - In this work, we have successfully synthesized porous hematite (alpha-Fe2O3) particles with reasonable surface area by the hydrothermal treatment of iron(II) D-gluconate aqueous solution and the calcination at 550 degrees C. These porous alpha-Fe2O3 particles were characterized by X-ray diffraction, transmission electron microscopy, scanning electron microcopy and N2 adsorption-desorption technique. The results indicated that these alpha-Fe2O3 particles have high porosity at mesoscale, and the specific surface area can reach 35.1 m2/g. The evaluation of photocatalytic activities of porous alpha-Fe2O3 particles for photocatalytic degradation of rhodamine B (RhB) aqueous solution in the presence of H2O2, indicated that porous alpha-Fe2O3 particles exhibit good visible-light photocatalytic activities. Therefore, the prepared porous alpha-Fe2O3 particles are of great interest in photocataytic degradation of dyes. PMID- 23035443 TI - Influence of calcium ions on the structural and magnetic properties of Cd-Mg ferrites nanoparticles. AB - Cadmium magnesium ferrites doped with calcium having the chemical formula Cd0.5Mg0.5-x Ca(x)Fe2O4 (0.0 < or = x < or = 0.3) were prepared by the Co precipitation method. X-ray diffraction analysis confirmed the formation of a single phase with spinel crystal structure for the samples. The lattice parameter is determined for each composition and has been found to increase from 8.505 angstroms to 8.626 angstroms with increasing calcium concentration. Cation distribution for the studied ferrite system is proposed in terms of the structural and magnetic properties by means of X-ray diffraction (XRD), infrared spectroscopy (IR), vibrating sample magnetometer (VSM) and is found to be reliable. The experimental and theoretical lattice constants show the same trend with increasing calcium concentration indicating the validity of the proposed cation distribution. The analysis of infrared spectra indicates the presence of splitting in the absorption band which may be attributed to the presence of small amounts of Fe2+ ions in the ferrite system. The appearance of a shoulder around 700 cm(-1) suggests the presence of calcium ions in the tetrahedral site. The addition of non magnetic calcium ions in the ferrites suppressed the A interaction and developed a B-B interaction, which is reflected in reducing the saturation magnetization in the present samples. The coercive field (H(c)) is also found to increase by increasing of Ca2+ concentration and has been explained on the bases of direct relationship with anisotropy constant. PMID- 23035444 TI - Antibacterial effects of zinc oxide nanorod surfaces. AB - Antibacterial coating approaches are being investigated to modify implants to reduce bacterial adhesion and viability in order to reduce implant-associated infection. Nanostructured materials possess unique surface properties, and nanotopographic surfaces have been reported to modulate bacterial adhesion. Zinc oxide (ZnO) films presenting well-controlled nanorod surface structures have recently been developed. To assess the efficacy of ZnO nanorod surfaces as an anti-bacterial coating, we evaluated bacterial adhesion and viability, compared to sputtered ZnO substrates (a relatively flat control) and glass substrates (as a reference). Common implant-associated pathogens, Pseudomonas aeruginosa and Staphylococcus epidermidis were investigated. The number of adherent P. aeruginosa on ZnO nanorod surfaces was found to be reduced compared to glass and sputtered ZnO, while the adherent number of S. epidermidis on the ZnO nanorods was equivalent to glass. Regarding bacteria viability, the ZnO nanorod and sputtered ZnO surfaces demonstrated a modest, but significant bactericidal effect on adherent P. aeruginosa, killing 2.5-fold and 1.7-fold more over the number of dead P. aeruginosa on glass, respectively. A greater bactericidal effect of ZnO substrates on S. epidermidis was found, with sputtered ZnO and ZnO nanorod substrates killing -20-fold and 30-fold more over the number of dead S. epidermidis on glass, respectively. These data support the further investigation and optimization of ZnO nanorod coatings with potential for bacterial adhesion resistance and bactericidal properties. PMID- 23035445 TI - Investigating chiral recognizability of diastereomeric crystallization of mandelic acid and L-phenylalanine. AB - The present study investigated the mechanism of the chiral recognition of the resolving agent (L-phenylalanine) to the chiral isomers (D/L-mandelic acid). According the NMR analysis, the distinctive chemical shifts of between two diastereomer crystals (L-mandelic acid-L-phenlyalanine and D-mandelic acid-L phenylalanine) were observed even though there was no difference of the chemicals shift of the two diastereomer solutions. This result indicated that the chiral recognition of the resolving agent mainly occurred during the crystallization of the diastereomers in the solution. Then, the chiral recognition of the diastereomers was confirmed by using thermal analysis and AFM. The diastereomer crystal of L-mandelic acid-L-phenylalanine was much more thermally stable due to the higher lattice energy than the diastereomer crystals of D-mamdelic acid-L phenylalanine. Also, the adhesive force measured with AFM exhibited a stronger molecular interaction between L-mandelic acid and 4-amino-L-phenylalanine than between D-mandelic acid and 4-amino-L-phenylalanine. Plus, the AFM results implied that the hydroxyl group abundance on the mandelic acid surface was a possible explanation for the different chiral selectivity of the L-phenylalanine. PMID- 23035446 TI - Thermochemical vapor growth of beta-SiC nanospheres. AB - SiC nanospheres have been grown successfully via thermochemical decomposition of tetramethylsilane as a single molecular precursor for Si and C free from halogen. The growth temperature was varied from 700 to 900 degrees C in presence of H2, Ar, and N2 as process gases. XRD analyses showed that the synthesized nanoparticles under various experimental conditions are mainly composed of SiC phase and have broad and low intensity diffraction peaks implying its tiny size characteristics. SEM and TEM images confirmed the formation of SiC nanospheres in the size range of 100-250 nm. Denser cluster formation was observed for the sample deposited in presence of N2 gas. FTIR spectrum showed that the stretching vibration band corresponding to Si-O bond was observed whereas that corresponding to Si-H bond disappeared for the sample deposited in presence of N2 gas. This indicated the formation of oxygen-containing SiC layer on the nanospheres surface. Slight positive and negative weight changes (1.5-7 wt.%) were observed upon heating of SiC nanospheres in dynamic nitrogen atmosphere upto 500 degrees C. This slight changes might be due to the removal of residual un disproportionated materials and/or formation of N2-dopped SiC nanospheres. PMID- 23035448 TI - Theoretical modeling of diffusional release of a dispersed solute from a cylindrical polymeric matrix. AB - We present an analytical treatment of diffusional release of a dispersed solute from a cylindrical non-erodible polymeric matrix and study the mechanism of diffusional release of solute from the matrix system as a function of solute loading parameter. The diffusion equation is solved exactly under perfect sink condition for certain concentration of solute in the form of cylindrical geometry. The numerical solution of diffusional release function as a function of time is found to be increased initially and then remain constant after certain time, tau(c). This tac(c) is found to be as a function of solute loading parameter. The asymptotic solutions of the diffusional release function is also presented. PMID- 23035447 TI - Characterization and evaluation of poly(epsilon-caprolactone) nanoparticles containing 2-ethylhexyl-p-methoxycinnamate, octocrylene, and benzophenone-3 in anti-solar preparations. AB - Ultraviolet radiation can bring both harm and benefits to human health. Among those harms are erythemas, photosensitivity, photoaging, and the most worrying, skin cancer. Nanoencapsulation of sunscreen agents (SA) by using a biocompatible and biodegradable polymer such as poly(epsilon-caprolactone) (PCL) is advantageous as it increases the retention of UV absorbers in the skin, avoids systemic absorption, and consequently, improves water resistance and stability of the preparation. The aim of this work is to develop, characterize, and study the encapsulation of 3 different SA: 2-ethylhexyl-p-methoxycinnamate, benzophenone-3, and octocrylene in PCL nanoparticles (Nps). Nps were prepared by the solvent emulsification and evaporation method. The process yield was calculated, and the Nps were characterized in terms of size, polydispersity index (PI), morphology, zeta potential (ZP), encapsulation efficiency (EE) (%), and sunscreen agent content (SAC). The final formulations were submitted to the hen's egg test chorioallantoic membrane (HET-CAM), chorioallantoic membrane-trypan blue staining (CAM-TBS), red blood cell (RBC), Draize tests, in vitro release, in vitro sun protection factor (SPF), UVA protection factor (PF-UVA), and photostability. All the Nps were in the nanometric scale. PI showed monodisperse systems. ZP became more negative as the Np were lyophilized and were added to the formulations. EE varied from 84 to 90%. The SAC went from 44 to 65 microg of sunscreen agents by milligram of Np. The process yield went from 60 to 76%. Nps were predominantly spherical and elliptical forms. The addition of Np diminished the release of the SA. The SPF increased with Np presence and helped to maintain the PF-UVA after irradiation. The HET-CAM assay evaluated the formulation as slightly irritant, CAM-TBS and RBC tests as non irritant, and the Draize test as moderately irritant. PMID- 23035449 TI - Poly(3-methylthiophene)/graphene composite: in-situ synthesis and its electrochemical characterization. AB - Poly(3-methylthiophene)/Graphene composites (G-PMT) and poly(3-methylthiophene) (PMT) were synthesized by in-situ chemical oxidative polymerization and investigated as electrode material for supercapacitors. The interaction between graphene and polymer chains was characterized by Fourier Transform Infrared (FTIR) spectroscopy. The morphology of the nanocomposites was characterized by Scanning Electron Microscopy (SEM) and High Resolution Transmission Electron Microscopy (TEM). The thermal stability of the composite and the polymer was studied by Thermogravimetric Analysis (TGA) which shows G-PMT has higher thermal stability than PMT. The electrochemical properties were investigated by Cyclic Voltammetry (CV), Cyclic Charging-discharging tests (CC) and Electrochemical Impedance Spectroscopy (EIS) in a three-electrode system. G-PMT resulted in higher specific capacitance of 240 F/g. The specific capacitance retention after 500 cycles on G-PMT was also higher compared with PMT. These results indicate that G-PMT has good electrochemical performance than PMT hence it is useful for the making of electrode in supercapacitor application. PMID- 23035450 TI - Efficient degradation of Methylene Blue dye over highly reactive Cu doped strontium titanate (SrTiO3) nanoparticles photocatalyst under visible light. AB - Visible light induced photocatalysts of Cu doped SrTiO3 (Cu/SrTiO3) nanoparticles with the size -60-75 nm were prepared via facile sol-gel method. The morphological, optical, crystalline properties and compositions of synthesized Cu/SrTiO3 nanoparticles were thoroughly characterized by field emission scanning electron microscopy (FE-SEM), powder X-ray diffraction (XRD), ultra violet visible spectroscopy (UV-Vis) and energy dispersive X-ray (EDX). A significant red shift in the UV-diffused reflectance spectrum was observed and the absorption edge shifted to visible region by the Cu doping. Surprisingly, the band gap of SrTiO3 was changed from 3.2 eV drop to 2.96 eV. The photocatalytic activity of the synthesized Cu/SrTiO3 nanoparticles was demonstrated for the degradation of Methylene Blue dye under visible light irradiation. The formation of new acceptor region in Cu/SrTiO3 was responsible for high photocatalytic activity of Cu/SrTiO3 nanoparticles. The results showed that the Methylene Blue dye was degraded by 66% within time span of 2 h over the Cu/SrTiO3 nanoparticles. This dye degradation reaction followed the Langmuir-Hinshelwood kinetics and also exhibited first order reaction rate. The calculated rate constant for the degradation reaction following first order kinetics was k = 0.0016 min(-1). PMID- 23035451 TI - Nanoscale gelatinase A (MMP-2) inhibition on human skin fibroblasts of Longkong (Lansium domesticum Correa) leaf extracts for anti-aging. AB - Leaves of Longkong which collected from Chantaburi in Thailand were extracted by the hot and cold processes using three different solvents including water, chloroform and methanol. The crude extracts were tested for antioxidative activities, tyrosinase inhibition and in vitro cytotoxicity as well as the MMP-2 inhibition activity on human skin fibroblasts for anti-aging evaluation. The hot water crude extract showed the highest antioxidative activities (DPPH radical scavenging, metal ion chelating and lipid peroxidation inhibition) with the SC50, CC50 and IPC50 values of 5.40 +/- 1.23, 32.31 +/- 0.84 and 3.29 +/- 0.30 mg/ml, respectively, and the highest tyrosinase inhibition activity with the IC50 value of 0.49 +/- 0.23 mg/ml. The extract also showed no cytotoxicity on human skin fibroblasts with the cell viability of 80.52 +/- 15.16%. It demonstrated the anti aging potential by having the pro and active MMP-2 inhibition activity, but lower than ascorbic acid of 1.28 and 1.12 times, respectively. The semi-purified extracts were prepared from this crude extract by solvent-solvent partition. The ethyl acetate soluble fraction showed higher activities (DPPH radical scavenging, metal ion chelating and tyrosinase inhibition) than the crude extract of 23.48, 71.80 and 2.58 times, respectively. This fraction exhibited similar pro and active MMP-2 inhibitory effect to the crude extract. The results from this study have indicated the possible application of the ethyl acetate fraction of the hot water crude extract from leaves of Longkong to be developed as an anti-aging product. PMID- 23035452 TI - 12P-conjugated PEG-modified gold nanorods combined with near-infrared laser for tumor targeting and photothermal therapy. AB - Gold nanorods have been reported as potential tumor photothermal therapy in vivo and in vitro. However, development of the safe and efficient tumor-targeting gold nanorods for in vivo localized tumor therapy is still a challenge. In our present study, we synthesized the PEG modified gold nanorods and demonstrated its negligible cytotoxicity in vitro. These nanorods also have been demonstrated to efficiently ablate the different kinds of tumor cells in vitro after exposure to the near-infrared laser. When the PEG modified gold nanorods conjugated with the 12P (sequence: TACHQHVRMVRP), this conjugate showed great tumor-targeting and hyperthermia effects on the human liver cancer cell line HepG2 in vitro when coupled with the near-infrared laser treatment. To determine the potential hyperthermia effect of PEG modified gold nanorods or 12P conjugate on tumor cells in vivo, the mice hepatic cancer cells were used to induce the subcutaneous tumor bearing model in ICR mice. The significant inhibition effects of near-infrared laser mediated PEG modified gold nanorods or 12P conjugate on the tumor growth were observed. These composite results suggest that the 12P-conjugated PEG modified gold nanorods exhibit great biocompatible, particular tumor-targeting and effective photothermal ablation of tumor cells, which warrant the potential therapeutic value of this conjugate for further application in in vivo localized tumor therapy. PMID- 23035453 TI - Preparation and characterization of polystyrene microspheres in the presence of beta-cyclodextrin. AB - Using styrene as raw material, potassium persulfate as an initiator, beta cyclodextrin as a stabilizer, polystyrene microspheres were successfully prepared with nice monodisperse feature by means of soap-free emulsion polymerization method. Experimental studies were performed in detail to check the effect of the synthesis process of the microspheres, the stabilizer dosage, monomer concentration, and initiator dosage on the particle size and distribution, the microstructures were characterized with SEM, TEM, infrared (IR) and the particle size distribution investigation. The results show that the appropriate changes in amount of stabilizer and monomer concentration and dosage of initiator can result in a different particle size and polystyrene microspheres with good monodispersity were finally obtained. PMID- 23035454 TI - Carbon nanotube exposure sensitize human ovarian cancer cells to paclitaxel. AB - With the rapid development in design and synthesis, carbon nanotubes (CNTs) are being studied for potential applications in a variety of biomedical fields, such as site-directed drug delivery, tumor-targeted imaging, and anticancer drug development. In the present study, we observed that SWCNTs could significantly induce cell death of human ovarian cancer OVCAR3 cells. More importantly, we demonstrated that SWCNTs could sensitize OVCAR3 cells to the chemotherapeutic compound paclitaxel (PTX), resulting increased cell death. Mechanistic investigations suggested that SWCNTs provoked cell death in the absence or presence of PTX mainly via apoptosis. Taken together, our results suggest that SWCNTs contribute to regulating the chemosensitivity of ovarian cancer cells to the anticancer drug. Co-exposure of SWCNTs and chemotherapeutic drugs might thus stand for a promising approach to improve the cancer treatment. PMID- 23035455 TI - Hierarchically assembled one-dimensional TiO2 nanostructures: echinoid- and labyrinth-shaped TiO2 crystals for dye sensitized solar cell. AB - TiO2 nanostructures have been studied intensively for decades for their photocatalytic properties. Recently, several interesting TiO2 nanostructures with controlled surface facets or shapes were reported. However, systemic approaches to obtain designed nanostructures are still rare. Here, various hierarchical 1D TiO2 nanostructures, including TiO2 nanorods, echinoid-shaped TiO2, and labyrinth structured TiO2, were fabricated by a one-pot hydrothermal process. Concentrated HCl was added to a solution having a Ti4+/H+ ratio that ranged from 1/4 to 1/8. The highly concentrated acid stabilized hydrolysis and hindered condensation, thereby balancing nucleation and growth of TiO2 nanostructures in the hydrothermal treatment step. Dye-sensitized solar cells prepared using the hierarchical 1D TiO2 nanostructures have shown higher photon to current conversion efficiency in the wavelength over 600 nm compared to those prepared with TiO2 nanoparticles. PMID- 23035456 TI - Bio-inspired superhydrophobic polyphenylene sulfide/polytetrafluoroethylene coatings with high performance. AB - Bio-inspired superhydrophobic Polyphenylene sulfide/Polytetrafluoroethylene (PPS/PTFE) coatings were prepared by a simple curing process. The surface morphology characterization by SEM shows that these superhydrophobic coatings have the similar macro-nano-structures to that of lotus leaf. Effect of the content of PTFE as well as the curing condition on the water contact angle of the superhydrophobic coating surface was then systematically studied. A series of tests show that the superhydrophobic coatings exhibit high cohesional strength, excellent impact resistance and high thermal stability. Moreover, we studied the stability of chemical resistance of the as-prepared superhydrophobic PPS/PTFE coatings, and the electrochemical impedance values kept on a high level even after 8 days. The superhydrophobic PPS/PTFE coatings with high performance have potential applications in some specific fields. PMID- 23035457 TI - A novel synthesis of a CuInSe2 thin film from electrodeposited Cu-Se-In-Se precursors with three steps annealing. AB - In this study, copper indium diselenide (CIS) films were synthesized from electrodeposited Cu-Se-In-Se precursors by three step annealing. The Se layer between Cu and In layer was grown to prevent the formation of Cu/In compound. The Cu-Se precursors were first annealed to grow uniform and conductive Cu2Se surface. After deposition of the four layers precursors, two steps annealing was employed to form Cu2Se-In2Se3 precursors. Transforming Cu2Se-In2Se3 to CIS required less thermal energy. Therefore, high quality CIS film can be synthesized by two steps annealing due to its high crystallinity. The properties of the CIS films were characterized by scanning electron microscopy (SEM), X-ray Diffraction (XRD), and Raman Spectra. PMID- 23035458 TI - Synthesis and characterization of Gd@C82-PVK and C60-PVK--a kind of fullerene grafted polymer. AB - Different fullerene-grafted poly(N-vinylcarbazole) was synthesized by free radical polymerization and the influence of the amount of initiator, the reaction time and the reaction temperature on the polymerization was studied. Metallofullerene-grafted polymer (Gd@C82-PVK) was firstly synthesized and characterized by GPC, UV-vis, FTIR, DSC, XPS. The results demonstrated that the fullerenes had chemically combined with PVK. Fluorescence spectra suggested that the grafted fullerenes had certain influence on the fluorescence properties of the polymer. This is due to the better electron-attractive ability of fullerenes, which contributed a lot to form the electron donor-acceptor systems in fullerene grafted poly(N-vinylcarbazole). Potential applications of this kind of materials in optical and memory devices were expected. PMID- 23035459 TI - The complete control for the nanosize of spherical MCM-41. AB - In this work, we present a systematic study on the complete control over the sphere diameters of MCM-41 nanospheres with different pore sizes. The mesoporous silica nanospheres with diameter range from 40 nm to 160 nm are synthesized by using cationic quaternary ammonium surfactants as template and TEOS as silicon source in sodium hydroxide aqueous solution via sol-gel supermolecular method. Nanospheres with fixed diameter can be obtained through the precise control over the molar ratio of NaOH/TEOS and other synthetic conditions. The range of sphere diameter for each sample prepared under adjustable reaction conditions is in a sharp distribution. Moreover, the formation mechanism for nanospheres with controlled morphological and structural features is proposed, and we suggest the optimal synthesis conditions of the MCM-41 nanospheres for the minimization of the Gibbs free energy deltaG. Besides, after depositing vanadium species on the MCM-41 support, the catalytic performance of V-MCM-41 for the selective oxidation of styrene by hydroperoxide increases with the diameter of the supports decreasing. PMID- 23035460 TI - Study on the adsorption of chromium (VI) by hydrolyzed keratin/polyamide 6 blend nanofibres. AB - In this study, nanofibre mats for chemical adsorption of heavy metals were prepared by electrospinning blends of hydrolyzed keratin (HK) and polyamide 6 (PA6) in formic acid. Viscosity measurements of the spinning solutions and morphological analyses of the fracture sections of the same polymer blends cast into films, suggested intermolecular interactions and good compatibility between HK and PA6. The mats made of continuous randomly oriented blend nanofilaments of HK/PA6 50/50 wt, with a mean diameter of about 200 nm, were tested as chromium (VI) ion adsorbents. The parameters investigated included initial chromium ion concentration, pH, contact time and adsorbent dosage. The maximum adsorption capacity occurred at acidic pH. The pseudo-first order, the pseudo-second order and the intraparticle diffusion models were used to describe the kinetics of adsorption process. It was found that kinetic data fit the pseudo-second order model and follow the intraparticle diffusion model, although diffusion is not the only rate control step. Adsorption data fit well the Freundlich isotherm model and the maximum adsorption capacity was found 55.9 mg/g. Moreover, the mean free energy (E) of adsorption ranges between 8 and 16 kJ/mol, so that the adsorption mechanism for HK-based nanofibres was explained as an ion-exchange process. PMID- 23035461 TI - Electrodeposition of macroporous nickel coating by employing nano-silica as template. AB - A novel method of preparing the macrporous nickel coating was described. The macrporous nickel coating was fabricated by employing nano-silica as the template. The effects of technological conditions and the concentration of the additives on the surface quality of coating were investigated, the nano-silica was characterized transmission electron microscopy (TEM) and laser particle size analyzer, and the macrporous nickel coating was characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The experimental results showed that nano-silica particles were about 100 nm, the optimal technological conditions of electrodepositing nickel were that the cathode current density was 12 A/dm2, the temperature was 30 degrees C and the pH value was 2.0, the concentration of lauryl sodium sulfate was 0.15 g/L and the concentration of glucide was 3 g/L, the macrporous nickel coating was obtained when the adding nano-SiO2 content in the electroplating bath was 6 g/L and its structure was crystalline. PMID- 23035462 TI - Fabrication of ringlike and disclike nano-structures with surface-enhanced Raman scattering activity. AB - Functional gold nanoparticles with tunable surface ligands were used to assemble ringlike and disclike nano-structures. The adjustable formation mechanism was deduced, and important assembling processes happened such as evaporation, cooling, Marangoni flow and drying. With its hydrophobic nature, butanethiol monolayer-protected gold nanoparticles were arranged to form ringlike nano assemblies. Well-defined disclike nano-structures were obtained as a result of the change of hydrophilic-hydrophobic property and the aggregation of carboxyl group functionalized gold nanoparticles induced by tris(2-aminoethyl)amine. Surface-enhanced Raman spectroscopy (SERS) activities of nano-assemblies were examined. These nano-assemblies showed strong SERS enhancement occurred with the increase of localized surface plasmon resonance. The efficient technique will open a new avenue for fabricating organized nanoparticle structures in a convenient manner. It may be potentially applied for the biosensor due to SERS activities of those structures. PMID- 23035463 TI - Adsorption behavior of pazufloxacin mesilate on amino-functionalized carbon nanotubes. AB - In this study, the interaction between amino-functionalized multi-walled carbon nanotubes (e-MWNTs) and antibacterial agents was investigated and the drug loading ability of e-MWNTs was evaluated. The e-MWNTs were prepared and characterized, then were used as adsorbents for loading an antibacterial agent, pazufloxacin mesilate (PZFX). The adsorption behavior of PZFX on e-MWNTs in water was investigated. The results showed that e-MWNTs were able to form supramolecular complexes with PZFX and could be used as drug carriers with high drug-loading efficiency. Compared with pristine multi-walled carbon nanotubes (MWNTs), the adsorption efficiency of e-MWNTs was better. In kinetic studies, the pseudo-second-order model showed satisfactory fitting and good adsorption process. Langmuir model was successfully employed to describe the adsorption isotherms of PZFX on e-MWNTs and higher drug-loading ability were observed from e MWNTs with smaller diameter. The adsorption process of e-MWNTs was sensitive to the pH and it was observed that the neutral pH gave the best adsorption. Low temperatures facilitated the adsorption process. In addition, the release process of PZFX from e-MWNTs occurred in two stages: a rapid release, then followed by a slow release, in which acidic solution favored the release process. In summary, our technique developed for the adsorption of PZFX on e-MWNTs is satisfactory. PMID- 23035464 TI - One-pot low temperature synthesis of monodisperse silver nanoparticles. AB - A facile one-pot route for the synthesis of monodisperse Ag nanocrystals with a narrow size distribution is described. Uniform Ag nanoparticles with the size of around 12 nm were obtained by reduction of AgNO3 in the presence of oleylamine and polymer polyvinylpyrrolidone (PVP) at low temperature. It is found that temperature has a significant effect on the sizes and the size distributions of the nanoparticles. Because irregular Ag nanoparticles are produced easily due to Ostwald ripening or kinetic control at both high temperature and low temperature, respectively, uniform nanocrystals can be obtained at an appropriate temperature (70 degrees C). PMID- 23035465 TI - Electrospinning-directed one-dimensional alignment of core-shell silica/polymer nanoparticles in nanofibers. AB - Nanofibers with ordered inorganic nanoparticles inside are great interesting for their potential applications in biomedical and photonics. In this work, yardlong bean shaped nanofibers were fabricated by the combined technology of surface initiated atom transfer radical polymerization (ATRP) and coaxial electrospinning process. Initially, the core-shell nanospheres were prepared by surface-initiated ATRP of glycidyl methacrylate (GMA) from silica nanoparticles with ATRP initiators on surface. Subsequent coaxial electrospinning allows prepare cross linked nanofibers with a linear-single-particle-array structure. Removal of the inorganic cores gave rise to nanofibers with uniformly dispersed-close-pore structure, which would be useful to drug delivery and catalyst carrying. PMID- 23035466 TI - Structure, thermal stability and electrical properties of reduced graphene/poly(vinylidene fluoride) nanocomposite films. AB - The reduced graphene/poly(vinylidene fluoride) nanocomposite films were prepared by the solution casting-thermal reduction process using graphene oxide (GO) and poly(vinylidene fluoride) (PVDF) resin. With the presence of reduced graphene (RG) nano sheets in the nanocomposite, the structure of PVDF is transformed from alpha to beta phase, and the beta phase fraction and its crystallinity are largely affected by the RG content. The PVDF thermal stability is improved by the RG introduction, with about 15 degrees C increase of the half-life of PVDF decomposition temperature. The RG/PVDF nanocomposites show a better electrical conductivity than that for the GO/PVDF nanocomposites. At a low RG content (0.8 wt.%), the dielectric constant of RG/PVDF nanocomposite film with a very low loss tangent is dramatically increased from about 6 to 23. The mechanisms for the thermal stability and electrical property improvements are discussed. PMID- 23035467 TI - Preparation and morphology of polyethylene/clay nanocomposite with novel MgCl2/montmorillonite (MMT) bi-supported Ziegler-Natta catalyst. AB - In the present article, the spherical and high activity TiCl4/MgCI2/MMT intercalated catalyst was successfully prepared. The active centers of obtained catalyst well dispersed in the MMT through electron probe micro-analysis (EPMA). The d-spacing of MMT was broadened from 0.97 nm to 1.42 nm after addition of MgCl2 and the space between MMT layers was 1.60 nm after treated with excess TiCl4. In addition, the catalyst shows a very high activity toward ethylene polymerization. During the ethylene polymerization, the MMT layers were exfoliated by the polymerization force arising from the propagation of ethylene chain. Interestingly, the macro-scale morphology of the obtained polyethylene (PE)/MMT nanocomposite still retained the spherical shape of precursor catalyst; while the PE particles contain MMT platelets take the shape of "flower petal" in the micro-scale. Transmission electron microscopy (TEM) photographs showed that the MMT homogeneously dispersed in the PE. PMID- 23035468 TI - Progress in preparation and application of nanostructured neurotransmitters microsensors/microelectrodes. AB - This paper gives an introduction of preparation and application of neurotransmitters-based bioelectrochemical microsensors/microelectrode with the help of nanotechnology, and illustrates various methods to measure neurotransmitter (including L-glutamate (Glu), acetylcholine, dopamine, etc.) microsensors/microelectrode and the prospects in the future of the sensors. PMID- 23035469 TI - The structure of polycaprolactone-clay nanocomposites investigated by 1H NMR relaxometry. AB - Nanocomposites based on polycaprolactone (PCL), containing concentrations of 1, 3 and 5 wt% of sodium montmorillonite (NT-25) and organo-modified montmorillonite clay, with three different salts (Viscogel B7, Viscogel S4 and Viscogel B8), were prepared employing the solution intercalation method using chloroform. The PCL nanocomposites were characterized by relaxometry, through determination of the hydrogen spin-lattice relaxation times using low-field nuclear magnetic resonance (NMR). Conventional X-ray diffraction (XDR) was also used to measure the basal space of the nanoclay. The proton spin-lattice relaxation parameters showed that hybrid nanocomposites were formed, containing different parts of intercalated and exfoliated organoclay. The proton T1rhoH also indicated changes in the microstructure, organization and the molecular mobility of the hybrid materials. NMR relaxometry is a good way to evaluate nanomaterials because it provides complementary information, since it is measured in a different time scale. Furthermore, differential scanning calorimetry and thermogravimetric analysis were also used to investigate the crystallization and thermal behavior of the nanocomposites, respectively. All materials had low crystallization temperature (Tc) and the melting temperature (Tm) were very close to that of the PCL matrix, but the degree of crystallinity of the nanocomposites decreased. TGA analysis demonstrated that montmorillonite accelerates PCL's decomposition while unmodified montmorillonite has the opposite effect. PMID- 23035470 TI - Crystallization kinetics and thermal property of biodegradable poly(3 hydroxybutyrate)/graphene oxide nanocomposites. AB - Biodegradable poly(3-hydroxybutyrate)/graphene oxide (PHB/GO) nanocomposites were prepared successfully via a solution mixing method. Transmission electron microscopy and wide angle X-ray diffraction results indicate that the GO sheets were homogeneously dispersed in the PHB matrix. Effect of GO on the thermal stability, nonisothermal melt crystallization behavior, isothermal melt crystallization kinetics, spherulitic morphology, and crystal structure of PHB in the nanocomposites was investigated in detail with various techniques. The observed decomposition temperature of PHB has been improved dramatically in the PHB/GO nanocomposites relative to neat PHB. Both nonisothermal and isothermal melt crystallization of PHB have also been enhanced significantly in the nanocomposites because of the efficient nucleating agent effect of GO. However, the presence of GO does not change the crystallization mechanism and crystal structure of PHB in the PHB/GO nanocomposites. PMID- 23035471 TI - Photoluminescent enhancement of CdSe/Cd(1-x) Zn(x)S quantum dots by hexadecylamine at room temperature. AB - CdSe/Cd(1-x) Zn(x)S core/shell quantum dots (QDs) were fabricated in 1-octadecene via a two step synthesis. CdSe cores were first prepared using CdO, trioctylphosphine (TOP) selenium, and stearic acid. Subsquently, a Cd(1-x) Zn(x)S shell coating was carried out using zinc acetate dihydrate, cadmium acetate dihydrate, TOPS, and hexadecylamine (HDA) starting materials in the friendly organic system under relatively low temperature. The absorption and photoluminescence (PL) spectra have a significant red shift after the coverage of Cd(1-x)Zn(x)S shell on CdSe cores. The X-ray diffraction analysis of samples confirmed the formation of core/shell structure. The PL quantum yields (QYs) of CdSe/Cd(1-x)Zn(x)S QDs were improved gradually with time at room temperature. This is ascribed to the surface passivation of HDA to the QDs during store. This phenomenon was confirmed by the Fourier transform infrared spectrum of samples. Namely, HDA does not capped on the surface of as-prepared QDs, in which a low PL QYs was observed (less than 10%). Being storing for certain time, HDA attached to the surface of the QDs, in which the PL QYs increased (up to 31%) and the full width at half maximum of PL spectra decreased. Moreover, the fluorescence decay curve of the core/shell QDs is closer to a biexponential decay profile and has a longer average PL lifetime. The variation of average PL lifetime also indicated the influence of HDA during store. PMID- 23035472 TI - NbN and NaNbN2 particles: selective solid state synthesis and conduction performance. AB - Starting from Nb2O5, NaN3 and different metallic reductants such as magnesium or aluminum, cubic NbN and hexagonal NaNbN2 were selectively synthesized in a stainless steel autoclave at 400-700 degrees C. When magnesium was used as a metallic reductant, NbN can be synthesized at 400 degrees C for 10 h. If the metallic reductant was replaced by aluminum, NaNbN2 was obtained at 700 degrees C for 40 h. The structures and morphologies of the samples were derived from X-ray powder diffraction (XRD), transmission electron microscopy (TEM) and field emission-scanning electron microscopy (FE-SEM). FE-SEM images showed that the NbN sample consisted of particles with an average size of about 100 nm, and the NaNbN2 sample is composed of with an average size of 500 nm. Furthermore, the electric resistivity of the obtained samples reveals the obtained NbN sample is a superconductor with transition temperature of 17 K, and the obtained NaNbN2 sample can be classified as a semiconductor. PMID- 23035473 TI - MnCO3 microstructures assembled with nanoparticles: shape-controlled synthesis and their application for Li-ion batteries. AB - MnCO3 ellipsoids and twinborn spheres have been synthesized by a hydrothermal process and a room temperature synthesis approach, respectively. The structures and morphologies of the products are investigated by X-ray powder diffraction (XRD) and field emission-scanning electron microscopy (FE-SEM). XRD patterns indicate the MnCO3 ellipsoids display higher crystallinity than twinborn spheres. SEM images show that both the MnCO3 ellipsoids and twinborn spheres have a similar size of about 1 microm and consist of nanoscale primary particles. Brunauer-Emmett-Teller (BET) surface areas of MnCO3 ellipsoids and twinborn spheres are 33.93 and 59.35 m2/g, respectively. Furthermore, the lithium storage properties of these MnCO3 samples with distinct morphologies have been investigated. When used as anode materials in lithium-ion batteries, MnCO3 ellipsoids and twinborn spheres exhibit the initial discharge capacities of 1375 and 1650 mAh/g, respectively. After charged/discharged for 50 cycles at a current density of 500 mA/g, the remaining discharge capacities for MnCO3 ellipsoids and twinborn spheres are 663 and 305 mAh/g, respectively. PMID- 23035474 TI - Physico-chemical properties of cationic niosomes loaded with fraction of rice (Oryza sativa) bran extract. AB - The aim of this study was to investigate the physico-chemical properties of cationic niosomes (Tween61/cholesterol/CTAB) loaded with fraction No. 3 of Oryza sativa bran extract (OSF3) at 0.1, 0.5, 1.0 and 2.0% (w/v), respectively, before and after ultra-centrifugation. More white milky translucent appearance of the niosomes was observed at the higher loaded amount of OSF3. The entrapment efficiency of 0.5% OSF3 in niosomes was 86.22 +/- 1.43%. The sizes of the niosomes were slightly increased (120-220 nm) and the zeta potential values were decreased from 80 to the range of 40-60 mV after loaded with OSF3. All niosomes both blank and loaded with OSF3 were in the uni-lamellar structures determined by FF-TEM and SAXS. The transitions temperature (T(c)) of niosomes significant increased from 75 to 80 degrees C when loaded with OSF3 at 0.1 and 0.5%. Moreover, blank niosomes showed the highest microviscosity with the most rigid membrane at 25 degrees C, followed by the niosomes loaded with 0.1, 0.5, 1.0 and 2.0% of OSF3, respectively. The fluorescence polarizations of all niosomal formulations indicated the sharp descending phases at about 40 and 70 degrees C. After ultra-centrifugation to eliminate the non-loaded negatively charged OSF3, the increased vesicular sizes and zeta potential values of the blank, loaded niosomes with 0.1 and 0.5% OSF3 were observed. All niosomal formulations gave the same transition temperatures at about 71 degrees C and the same microviscosities at 25 degrees C. The results from this study can be applied for the niosomal formulation development of the rice bran semi-purified fraction for anti-hair loss products. PMID- 23035475 TI - Effects of different pH conditions on enamel erosion repair by nano fluorapatite pastes. AB - The effects of different pH conditions on enamel erosion repair by nano fluorapatite (n-FA) pastes were evaluated in this study. Eighteen human dental enamel blocks with artificially-induced erosion were randomly divided into three groups that were coated with n-FA pastes with 3 different pH values (pH < 1, pH = 4.5 and pH = 7.5, respectively) for 15 minutes. SEM, XRD, XPS, Vickers microhardness test and mass measurement were performed for the enamels before and after treatment. A layer of enamel-like fluoride substituted hydroxyapatite was observed on the surface of all the samples. After treatment by n-FA pastes with 3 different pH values (pH < 1, pH = 4.5 and pH = 7.5), the Vickers micro-hardness value was respectively changed to 125.9 HV, 252.1 HV and 304.9 HV from 241.3 HV of the artificial enamel erosion, and mass loss was 0.75 mg/mm2, 0.41 mg/mm2 and 0.30 mg/mm2, respectively. SEM analysis showed that the surface of the enamels treated by n-FA pastes with pH 7.5 and pH 4.5 was smoother than those treated by n-FA pastes with pH < 1. These results suggested that the pH value had significant effects for the repairment of enamel erosion with n-FA pastes. This study demonstrated that the n-FA paste with neutral pH value (7.5) for enamel erosion repair would not only significantly enhance the enamel surface hardness, but also avoid the enamel mass loss and increased surface roughness. PMID- 23035476 TI - Amidoxime-grafted hydrothermal carbon microspheres for highly selective separation of uranium. AB - A new amidoxime-functionalized carbonaceous sorbent has been successfully prepared using hydrothermal carbon microsphere as solid matrix and diaminomaleonitrile as precursor of amidoxime ligand. Effects of pH, sorbent dosage, contact time, temperature, initial U(VI) concentration and ionic strength on U(VI) sorption were investigated in detail through batch experiments. Sorption of U(VI) on the sorbent was pH-dependent. Sorption equilibrium was reached in 5 min. Distinctively, higher temperature was beneficial to the sorption of U(VI) in the range of 15-60 degrees C, high ionic strength up to 1 mol L(-1) NaNO3 had almost no effect on the sorption, and the maximum U(VI) sorption capacity of 466 mg g(-1) was observed under the conditions tested. The as-synthesized sorbent exhibited a high selectivity for U(VI) over other 12 competing ions coexisting in a simulated nuclear industrial effluent sample and the U(VI) sorption amount reached up to 1.09 mmol g(-1), accounting for about 52% of the total sorption amount. PMID- 23035477 TI - Formation of ethylene-silica nanofibers with concentric circular mesopores inside and lamellar mesopores on the surfaces. AB - Ethylene-silica nanofibers with concentric circular mesopores inside and lamellar mesopores outside were prepared using stearyltrimethylammonium bromide (STAB) as template and (S)-beta-citronellol as a co-structure-directing agent. They were formed at the (S)-beta-citronellol/STAB molar ratio range of 3:1 to 4:1. Field emission scanning electron microscopy and transmission electron microscopy images taken after different reaction times revealed a phase transition from hexagonal to lamellar phase on the surface of the organic-inorganic hybrid silica nanofibers. The nanofibers with concentric circular pore channels were proposed to be formed from spherical micelles. With increasing the (S)-beta citronellol/STAB molar ratio from 0.5:1 to 5:1, the morphology changed from short hexagonal rod to long nanofiber, and then to shrunk multilamellar vesicle. Moreover, 1,4-phenylene-silica nanofibers and nanoparticles with concentric circular mesopores inside and lamellar mesopores outside were also prepared. PMID- 23035478 TI - In situ conversion of ZnO microsphere from ZnS complex microstructure and photocatalytic study. AB - Precursor ZnS complex microstructure, synthesized under concentrated NaOH solution, was annealed at different temperatures to fabricate self-supported ZnO microstructure with large-scale yield. The crystal structure, morphology and chemical compositions of the as-prepared ZnO nanoparticles were examined by X-ray powder diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), scanning electron microscopy (SEM), Brunauer-Emmett Teller specific surface area (BET). The experimental results show that the obtained ZnO microsphere keeps an intact self-supported structure even after high temperature annealing and the XRD observation indicates that the crystal lattice becomes more integrated along with the elevation of annealing temperature. We further investigated the photocatalytic property towards eosin B and found that the photocatalytic property seems to be closely related to crystallinity of the lattice. As the crystallinity enhances, the photocatalytic performance of the ZnO self-supported microsphere becomes significantly better. Overall, the investigation indicates that we have prepared a novel kind of self-supported ZnO microsphere photocatalyst with the merit of mass production and high catalytic efficiency. PMID- 23035479 TI - Controllable deposition of platinum nanoparticles on single-wall carbon nanohorns as catalyst for direct methanol fuel cells. AB - Uniform and well dispersed platinum nanoparticles were successfully deposited on single-walled carbon nanohorns with the assistance of 4,4-dipydine and ion liquids, respectively. In particular, the size of platinum nanoparticles could be controlled in a very narrow range (2.2 to 2.5 nm) when ion liquids were applied. The crystalline nature of these platinum nanoparticles was confirmed by high resolution transmission electron microscopy observation and X-ray power diffraction analysis, and two species of platinum Pt(0) and Pt(II) were detected by X-ray photoelectron spectroscopy. Electrochemical studies revealed that thus obtained nanocomposites had much better electrocatalytic activity for the methanol oxidation than those prepared with carbon nanotubes as supporter. PMID- 23035480 TI - Growth mechanism of hydrophilic CdTe nanocrystals with green to dark red emission. AB - A modified method has been developed to fabricate high-quality CdTe nanocrystals (NCs) with a tunable photoluminescence (PL) range between green and dark red using thioglycolic acid (TGA). Namely, CdTe NCs with dark red emission (PL peak wavelength of 672 nm) and a PL quantum yield (QY) of 46% were created by controlling the NC growth kinetics. The molar ratio of TGA/Cd2+ in solutions and the concentration of starting materials play important roles in creating the NCs with a large size for long PL peak wavelength and decreased surface defects for a target of a high PLQY. Lifetime measurement indicated that the average lifetime of the NCs decreased at the beginning of a reflux and then converted to increase with time. This means that long reflux time resulted in a CdS-like shell formed on CdTe NCs. The X-ray diffraction analysis of the NCs illustrated that CdS-like layer were created on CdTe NCs, in which S(2-) ions generated by the decomposition of TGA during a long reflux period. PMID- 23035481 TI - Synthesis, characterization and adsorption behavior of molecularly imprinted nanospheres for erythromycin using precipitation polymerization. AB - Preparation of uniform size molecularly imprinted nanospheres for erythromycin with good selectivity and high binding capacity by precipitation polymerization were presented, in which erythromycin, methacrylic acid and ethylene glycol dimethacrylate are used as template molecule, functional monomer and cross linker, respectively. The synthesis conditions of molecularly imprinted nanospheres were optimized and the optimal molar ratio of erythromycin to functional monomer is 1:3. The molecularly imprinted polymers were characterized by scanning electron microscope, laser particle size analyzer and BET, respectively. The results suggested that molecularly imprinted nanospheres for erythromycin exhibited spherical shape and good monodispersity. Selectivity analysis indicated that the imprinted nanospheres could specifically recognize erythromycin from its structure analogues. Furthermore, adsorption kinetics and adsorption isotherm of the imprinted nanospheres were employed to investigate the binding characteristics of the imprinted nanospheres. The results showed that the imprinted nanospheres have high adsorption capacity for erythromycin, and the maximum theoretical static binding capacity is up to 267.0188 mg g(-1). PMID- 23035482 TI - Attenuated total reflectance Fourier transform infrared spectroscopy method to differentiate between normal and cancerous breast cells. AB - Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) is used to find the structural differences between cancerous breast cells (MCF-7 line) and normal breast cells (MCF-12F line). Gold nanoparticles were prepared and the hydrodynamic diameter of the gold nanoparticles found to be 38.45 nm. The Gold nanoparticles were exposed to both MCF-7 and MCF-12F cells from lower to higher concentrations. Spectroscopic studies founds nanoparticles were within the cells, and increasing the nanoparticles concentration inside the cells also resulted in sharper IR peaks as a result of localized surface Plasmon resonance. Asymmetric and symmetric stretching and bending vibrations between phosphate, COO , CH2 groups were found to give negative shifts in wavenumbers and a decrease in peak intensities when going from noncancerous to cancerous cells. Cellular proteins produced peak assignments at the 1542 and 1644 cm(-1) wavenumbers which were attributed to the amide I and amide II bands of the polypeptide bond of proteins. Significant changes were found in the peak intensities between the cell lines in the spectrum range from 2854-2956 cm(-1). Results show that the concentration range of gold nanoparticles used in this research showed no significant changes in cell viability in either cell line. Therefore, we believe ATR-FTIR and gold nanotechnology can be at the forefront of cancer diagnosis for some time to come. PMID- 23035483 TI - Visualization of focused proton beam dose distribution by atomic force microscopy using blended polymer films based on polyacrylic acid. AB - A simple and sensitive sub-micrometer scale method for visualization of the dose distribution of a focused proton beam (FPB) was developed, taking advantage of the formation of a bulky crosslinked structure induced by FPB irradiation of a common polymer and cross-linker, polyacrylic acid-N, N'-methylene bisacrylamide, blend film surface. The irradiated part of the film swelled as a peak, and the height of swelling increased with increasing FPB fluence. The film was used as a proton beam-sensitive polymer film by analysis of the irradiated film surface using atomic force microscopy. The method was successfully applied to confirm the FPB pattern. Typical misaligned spot shape of FPB gave clear 3-dimensional structures, and the half-solenoidal nanostructures are visualized clearly by use of crescent shaped beam. PMID- 23035484 TI - Controllable synthesis of 6H-1,4-diazepine-2,3-dicarbonitrile nanocrystals and their optical properties. AB - Organic nanostructures of 6H-1,4-Diazepine-2,3-dicarbonitrile (HDD) ranging from nanoparticles to nanoribbons have been controllably prepared. Changes in morphologies are observed to be accompanied with changes in optical properties. The HDD nanoparticles show a main emission at ca. 710 nm with a very weak shoulder at 625 nm, as nanoparticles gradually grow into nanoribbons, the predominant emission shifts to be centered at 625 nm at the expense of that at 710 nm. Shifts in the emission are proposed to come from different charge distributions of highest occupied molecular orbits (HOMO) induced by changing of intermolecular interactions, which is also evidenced by the quantum mechanics calculations. PMID- 23035485 TI - Effect of a pinning field on the critical current density for current-induced domain wall motion in perpendicular magnetic anisotropy nanowires. AB - In this study, the effect of a pinning field on the critical current density for current-induced domain wall motion in nanowires with perpendicular magnetic anisotropy was investigated using micromagnetic simulations. In order to estimate the pinning field in notched nanowires, we conducted wall energy calculations for nanowires with various saturation magnetizations. The pinning field increased as the notch size increased. The pinning field decreased as the saturation magnetization decreased. As a result, the decreased in the pinning field causes the reduction of the critical current density. Therefore, a significant reduction of the critical current density can be obtained by decreasing the saturation magnetization, even if wall pinning occurs. PMID- 23035486 TI - A two-population analysis of the magnetic dipolar interaction in superparamagnetic systems: a Monte Carlo study. AB - To understand the influence of the magnetic dipolar interaction on the blocking temperature (T(B)) of superparamagnetic systems, usual models treat the dipolar energy as an additional term to the single-particle anisotropy energy barrier. However, such approaches cannot describe non-monotonic T(B)(c) dependences as reported both experimental and theoretically. Therefore, alternative approaches should be explored. For such a purpose, in this work we investigate a simple approach based on splitting the total population of the system into two subgroups, depending on its relative orientation (parallel- or antiparallel aligned) with respect to the applied magnetic field direction. The suitability of such approach was explored by means of a Monte Carlo technique that provided us with a good insight into the properties of the system. Our results indicate that this two-population analysis can be a promising way to understand the SPM behaviour of interacting nanomagnetic systems. PMID- 23035487 TI - Micromagnetic simulations of Pac-man-like nanomagnets for memory applications. AB - In this work we study magnetic properties of nanomagnets with lateral dimensions 50-100 nm. These structures have a potential of producing static memories with high storage densities. If simple disk is used as basic nanomagnet, its chirality and polarity cannot be read/write easily by in-plane magnetic field. Based on micromagnetic calculations, we have designed "Pac-man-like" (PL) nanomagnet and calculated its magnetic properties using the oommf code. It solves the micromagnetic problem using the Landau-Lifshitz-Gilbert equation. The calculations have shown, that in the PL shape both, the chirality and the polarity, can be controlled by the in-plane magnetic field with x, y components. The PL shape opens straight channel for the energy relaxation towards stable vortex state with defined chirality and polarity for thickness 32-48 nm, and diameter 50-78 nm. PMID- 23035489 TI - Magnetic multilayers as a way to increase the magnetic field responsiveness of magnetocaloric materials. AB - The magnetocaloric response of Ni-Cu based multilayers has been studied with the aim of optimizing their magnetic field dependence. In contrast to the behavior of single phase materials, whose peak magnetic entropy change follows a power law with exponents close to 0.75, multilayering leads to exponents of -1 for an extended temperature span close to the transition temperature. This demonstrates that nanostructuring can be a good strategy to enhance the magnetic field responsiveness of magnetocaloric materials. PMID- 23035488 TI - Phase transitions, magnetotransport and magnetocaloric effects in a new family of quaternary Ni-Mn-In-Z Heusler alloys. AB - The magnetic, magnetotransport, and magnetocaloric properties near compound phase transitions in Ni50Mn35In14Z (Z = In, Ge, Al), and Ni48Co2Mn35In15 Heusler alloys have been studied using VSM and SQUID magnetometers (at magnetic fields (H) up to 5 T), four-probe method (at H = 0.005-1.5 T), and an adiabatic magnetocalorimeter (for H changes up to deltaH = 1.8 T), respectively. The martensitic transformation (MT) is accompanied by large magnetoresistance (up to 70%), a significant change in resistivity (up to 200%), and a sign reversal of the ordinary Hall effect coefficient, all related to a strong change in the electronic spectrum at the MT. The field dependences of the Hall resistance are complex in the vicinity of the MT, indicating a change in the relative concentrations of the austenite and martensite phases at strong fields. Negative and positive changes in adiabatic temperatures of about -2 K and +2 K have been observed in the vicinity of MT and Curie temperatures, respectively, for deltaH = 1.8 T. PMID- 23035490 TI - Fabrication and magnetic characterization of cobalt antidot arrays: effect of the surrounding continuous film. AB - We have performed an experimental study on the influence of a ferromagnetic continuous film in the magnetization reversal processes in discrete submicrometric antidot arrays fabricated on it. In order to compare the magnetic properties, two sets of antidot arrays have been fabricated over a cobalt thin film: embedded in the continuous film, and isolated by a trench surrounding the array. X-ray photoemission electron microscopy images of the virgin state show the same magnetic domain distribution in both sets of samples, finding no evidence of any effect of the surrounding film. This result is supported by the hysteresis loops measured with magneto-optical Kerr effect, as isolated and non isolated arrays present almost coincident loops. A huge increase of the coercivity of the film is achieved, and the expected dependence on the geometrical parameters of the array is found, connecting the previous studies on the micro- and nanometric scales. PMID- 23035491 TI - Structural and magnetization changes at high temperature in Co50Mn30In20 alloy. AB - In this work we report on microstructural and magnetic characterization of Co50Mn30In20 alloy melt-spun ribbons in its as-cast state and after being annealed at 923 K during 5 h. Microstructure was analysed by means of differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM) techniques, while magnetic measurements (hysteresis loop and magnetization) were performed in the temperature range 1.8-1000 K. XRD measurements confirm the presence of Heusler phase Co2MnIn in the annealed material with crystallites sizing around 35 nm. Ferromagnetic ordering temperatures in Co-based Heusler systems (Co2MnIn) are considerably higher than in the corresponding Ni2MnIn ones. In this case, T(c) = 520 K for the annealed sample is lower than the corresponding one (T(c) = 550 K) for the as-cast ribbon. At around 840 K, the very abrupt magnetization change for the annealed sample is higher than the one obtained for the as-cast ribbon. This temperature value is the same than the recrystallization phase transition temperature detected in the DSC measurement. PMID- 23035492 TI - Temperature dependences of magnetoimpedance of nanocrystalline Fe-based ribbons. AB - The influence of a magnetic field or the mechanical stresses on the impedance of the Fe73.5Si16.5B6Nb3Cu1 and Fe73.5Si13.5B9Nb3Cu1 ribbons was investigated in the (297 divided by 433) K temperature range. It is shown that impedance changes, which are observed under the application of mechanical stresses and temperature, are conditioned by the structural features and magnetic properties of the alloys. The temperature increase leads to a decrease of the saturation magnetostriction constant, an increase of the anisotropy axis dispersion and a decrease of the anisotropy effective value. It was determined that the maximum sensitivity of impedance to the mechanical stresses reaches the value of about 2%/MPa for the Fe73.5Si16.5B6Nb3Cu1 and Fe73.5Si13.5B9Nb3Cu1 samples. PMID- 23035493 TI - Specific absorption rate of magnetite nanoparticle powders with and without surrounding organic ligands. AB - Magnetite nanoparticles have been synthesized at different temperatures in order to get nanoparticles of different average sizes. Powders of the synthesized nanoparticles were introduced in a radio frequency electromagnetic apparatus built to perform hyperthermia measurements in laboratory animals. The nanoparticles synthesized at 80 degrees C, the ones giving the largest specific absorption rate values, have been functionalized with different organic ligands to study the influence of functionalization on specific absorption rate values. In all the synthesized nanoparticles, with and without organic surroundings, specific absorption rate measurements have been performed to study the influence of applied magnetic field intensity an frequency. PMID- 23035494 TI - Microbeads detection using spin-valve planar Hall effect sensors. AB - In this paper we present a micromagnetic approach to describe the detection of magnetic nanobeads using planar Hall effect sensors. The magnetic beads polarized by a dc magnetic field generate a field, which can affect the magnetization state of spin-valve sensor, leading in principle, to a detectable signal. For magnetic nanobeads we assumed a superparamagnetic behaviour. Three detection geometries are discussed and some specific behaviours were highlighted by micromagnetic simulations. We found that when the polarising field is applied parallel with the sensor surface a very weak signal can be obtained. This is because at working fields, for which the magnetic nanobeads are magnetised, the sensor saturates. We identified other setups that can overcome this shortcoming and deliver a net signal. PMID- 23035495 TI - Fast magnetization switching by linear vertical microwave-assisted spin-transfer torque. AB - The effect of vertical microwave magnetic field on spin-transfer torque switching in elliptical magnetic spin valve has been investigated by performing micromagnetic simulations including a spin-transfer torque term. The speed of magnetization switching can be accelerated by applying a vertical microwave magnetic field. Magnetization switching time decreases with the increase of the amplitude of vertical microwave magnetic field for both the fixed microwave frequency and current density. When the frequency of the microwave magnetic field coincides with the natural ferromagnetic resonance frequency of the elliptical spin valve, magnetization switching time is reduced to the minimum. Magnetization switching time can be reduced from 9.44 to 2.4 ns due to an effect of vertical microwave magnetic field. In addition, critical current density of magnetization reversal is strongly lowered in the presence of vertical microwave magnetic field. PMID- 23035496 TI - Domain wall dynamics in amorphous and nanocrystalline FeCoMoB microwires. AB - We have studied the domain wall dynamics in amorphous and nanocrystalline FeCoMoB microwires. The domain wall propagation velocity has been found very fast (up to 5000 m/s) for the as-cast sample. Annealing at 575 K/1 h leads to the stress relief and sample homogenization and the domain wall velocity even increases to 5300 m/s. However, the domain wall dynamics is highly sensible to the temperature of a measurement. Annealing at 775 K/1 h leads to the appearance of the nanocrystalline structure with much higher temperature stability. The maximum domain wall velocity decreases (2800 m/s), however the domain wall dynamics is much stable with the temperature. PMID- 23035497 TI - Nano Superconducting QUantum Interference Device sensors for magnetic nanoparticle detection. AB - In this paper, Superconducting QUantum Interference Devices (SQUIDs) based on single layer Nb nanobridge Josephson junctions are described. Devices, with loop area ranging from 4 to 0.5 microm2, have been patterned by Electron Beam Lithography (EBL) in a 20 nm thick Nb layer, achieving a responsivity of about 30 microA/phi0. Magnetization measurements have been performed via switching current measurements at a temperature T = 4.2 K. Preliminary detection of Silica magnetite (Fe3O4-SiO2) core/shell nanoparticle cluster has been proven. PMID- 23035498 TI - Influence of the interactions on the magnetotransport properties of Fe-Ag granular thin films. AB - Fe(x)Ag(100-x) granular thin films, 25 < or = x < or = 40, have been prepared by DC-Magnetron sputtering deposition. These samples are composed of small Fe nanoparticles (2.5-3 nm) embedded in an Ag matrix, and their size remains nearly constant with increasing Fe content. A crossover in the collective magnetic behaviour of the samples near x = 35, had been previously reported for these samples. In this article, we show that the transport and magnetotransport properties are clearly correlated with these magnetic behaviours, and that the resistivity, the magnetoresistance and the Hall resistivity depend on the nature of the most relevant interactions, dipolar or direct exchange, as a function of the thermal evolution and the Fe content. PMID- 23035499 TI - Influence of magnetic anisotropy on laser-induced precession of magnetization in ferromagnetic semiconductor (Ga, Mn)As. AB - The laser-induced precession of magnetization in (Ga, Mn)As samples with different magnetic anisotropy was studied by the time-resolved magneto-optical method. We observed that the dependence of the precession amplitude on the external magnetic field depends strongly on the magnetic anisotropy of (Ga, Mn)As and we explain this phenomenon in terms of competing cubic and uniaxial anisotropies. We also show that the corresponding anisotropy fields can be deduced from the magnetic field dependence of the precession frequency. PMID- 23035500 TI - Magnetic properties of TbAl2 nanometric alloys. AB - The magnetic properties of nanometric TbAI2 alloys have been investigated. The Curie temperature (T(c)) of these nanometric alloys is strongly size dependent and decreases from 103 K for the bulk alloy down to 98 K for the 14 nm alloy, as the particle volume is reduced. This reduction of T(c) has been explained by a finite-size scaling law of type [T(c)(D) -T(c)(infinity)]/T(c)(infinity) = (D/D0)-(1/vp), with v = 0.7 and D0 = 2.2a (a, the lattice parameter), in agreement with the three-dimensional Heisenberg model. The size dependence of the coercivity has also been established. An increase of the coercivity from 0.08 kOe (bulk) to 1 kOe for 10 h milled alloy, indicates the crossover from multidomain to single domain behavior around 85 nm, as expected from the estimate of the critical size of monodomain particles. The field dependence of the magnetization indicates a faster thermal reduction of the magnetization of the nanosized alloys (17% in 300 h milled alloy with mean particle size of 14 nm) related to the bulk (3%), in the temperature range between 5 K and 30 K. The results can be explained as a direct consequence of the competing effects of the surface and the purely finite-size effects, in an ensemble of nanometric particles suffering interactions. PMID- 23035501 TI - Probing the quality of Ni filled nanoporous alumina templates by magnetic techniques. AB - Pulsed electrodeposition prepared porous alumina templates with Ni nanowires pore filling ranged from 1 to 100%, depending on the alumina barrier-layer thickness, were probed by continuous wave ferromagnetic resonance at room temperature. For completely filled samples, a single resonance peak was observed in the whole range of angles between the applied magnetic field and normal to the sample plane. Its position was described by Kittel formula that takes into account shape anisotropy of individual Ni wires and dipolar interactions between them. For the samples with lower pore filling the effective anisotropy field decreased and the resonance linewidth in the perpendicular configuration increased. Also a quite intense second peak was observed at lower fields for these samples. These changes are associated with reduction of pore filling percentage that can lead to decrease of dipolar interactions between nanowires and to appearance of magnetic inhomogeneities inside wires. PMID- 23035502 TI - Super MI sensor: recent advances of amorphous wire and CMOS-IC magneto-impedance sensor. AB - We indicate that the Magneto-Impedance sensor using amorphous wires has reached a new stage to view "Super MI sensor technology" based on three main advantageous factors of (i) micro sized head and micro power consumption chip, (ii) ultra-high sensitivity micro magnetic sensor with 1 pico-Tesla resolution at the room temperature without any electromagnetic shielding, and (iii) ultra-quick response magnetic sensor with GHz operation. We summarize systematically the magneto impedance technology with the basic principle and mechanisms of three advantageous features for constitution of various high performance new sensor devices such as the electronic compass chip for mobile phones and smart phones and portable sensors for the magneto-encephalography, the magneto-spinography, and various bio-cell magnetic measurements. Possibility of new application to MI antenna in magnetic telecommunications is also discussed. PMID- 23035503 TI - High performance magnetoimpedance in FeNi/Ti nanostructured multilayers with opened magnetic flux. AB - Magnetic [FeNi (170 nm)/Ti (6 nm)]3/Cu (L(cu) = 250 or 500 nm)/[Ti (6 nm)/FeNi (170 nm)]3 multilayers were designed with focus on high frequency applications. They were deposited onto glass or a microfluidic system compatible flexible Ciclo Olefin Copolymer substrate and comparatively tested. A maximum sensitivity for the total impedance of 110%/Oe was obtained for a driving current frequency of 30 MHz for [FeNi/Ti]3/Cu (L(cu) = 500 nm)/[Ti/FeNi]3 multilayers deposited onto a glass substrate and 45%/Oe for a driving current frequency of 65 MHz for the same multilayers deposited onto the flexible polymer substrate, a very promising result for applications. The possibility of using flexible substrate/[FeNi/Ti],/Cu/[Ti/FeNi]3 multilayers as MI pressure-sensitive elements was also demonstrated. PMID- 23035504 TI - Magnetic properties of (Fe, Co)-Pd nanowire arrays. AB - Ordered arrays of ferromagnetic nanowires with (Fe, Co)-Pd compositions have been fabricated from chloride based electrochemical baths by means of template assisted electrodeposition into self-assembled nanopores of anodic alumina membranes. The nanowires have a diameter and inter-spacing distance of 72 nm and 105 nm, respectively, and around 0.6-1.6 microm in length. Their microstructure and basic magnetic properties are reported. Coercivity, remanence and respective angular dependences on the applied field up to +/- 3 T have been determined from room temperature hysteresis loops measured in a VSM. The study has been performed paying particular attention to the influence of increasing from about 27 up to 63 percent the Pd content in the nanowire alloy. PMID- 23035505 TI - Magnetic properties of epitaxial discontinuous Fe/MgO multilayers. AB - We report magnetic, dynamic and transport properties of discontinuous metal insulator multilayers Fe/MgO grown on amorphous Corning glass and single crystalline MgO (001) substrates. The films of structure Substrate/MgO (3 nm)/[Fe (0.6 nm)/MgO (3.0 nm)] x 10 were prepared in ultra-high vacuum conditions using Pulsed Laser Deposition. It was shown that conditions of epitaxial growth are favorable for MgO substrates. As a result a substantial increase of tunneling magnetoresistance caused by spin-filtering effect was observed and reasonably theoretically explained. The value of TMR - 9.2% at room temperature in 18 kOe magnetic field is three times higher comparing to that for the samples grown on Corning glass substrates. PMID- 23035506 TI - Magnetic behavior of high density arrays of Co bars with strong magnetostatic coupling. AB - Magnetization reversal processes have been analyzed by Magnetic Force Microscopy in dense arrays of Co bars with well defined shape anisotropy and strong magnetostatic interactions. Two different geometries have been used: rectangular and rhombic so that the sign of dipolar interactions between adjacent chains of bars is changed from antiferromagnetic (rectangular array) to ferromagnetic (rhombic array), having a profound influence on the shape of a nucleus of inversion at the magnetization reversal. PMID- 23035507 TI - Noncollinear magnetism in ultrathin films with strong spin-orbit coupling from Ab Initio. AB - Fe and Pt are paradigms for ferromagnetism and strong spin-orbit coupling, respectively. Their combination--in an ultrathin Fe film on a Pt(111) substrate- is thus expected to modify the magnetic structures. We report on a theoretical investigation of a monolayer of Fe on Pt(111), using a generalized Heisenberg model that includes the complete spin interaction matrices I(ij) computed from first principles. We find a noncollinear periodic configuration that is strongly determined by the Dzyaloshinskii-Moriya interaction. Taking into account a magnetic field to mimic recent experiments, this noncollinear structure solves the disagreement between the experimental magnetization and the average magnetization for a ferromagnetic system. The critical temperature decreases from 670 K to 590 K due to spin-orbit coupling. PMID- 23035508 TI - Dependence of spin torque switching probability on electric current. AB - Dependence of the thermally assisted spin torque switching probability on the sweep electric current was investigated theoretically. The analytical expressions of the switching times for b = 1 and b = 2 are derived based on the rate equation, where b is the exponent of the current term in the switching rate. The switching current is approximately proportional to the temperature T and the logarithm of the sweep rate v for both b = 1 and b = 2 in the experimentally performed ranges of T and v. Experiments in very low temperature range are required to determine the exponent b. PMID- 23035509 TI - Spin-dependent transport through graphene quantum dots. AB - We analyze theoretically transport properties of graphene quantum dots weakly coupled to normal and ferromagnetic leads. The calculations are performed by using the real-time diagrammatic technique in the first-order approximation with respect to tunneling processes. First, we analyze the energy spectrum of graphene dots of different shape. Then, we determine the current flowing through the system and the differential conductance. We show that the structure of the Coulomb diamonds of graphene quantum dots greatly depends on energy spectrum and therefore on the shape of the dots. In the case of ferromagnetic leads we also determine the tunnel magnetoresistance, which displays a nontrivial behavior depending on the number of charge states taking part in transport, and on particular shape of the graphene flake. PMID- 23035510 TI - Evolution of the magnetic properties of Co10Cu90 nanoparticles prepared by wet chemistry with thermal annealing. AB - Nanoparticles of Co10Cu90 alloy have been prepared by sonochemical wet method. According to transmission electron microscopy, bimetallic particles with typical diameter of 50-100 nm consisting of nanocrystallites with average diameter of 15 20 nm were obtained. The samples were annealed at 300 degrees C and 450 degrees C. Zero field cooled and field cooled temperature dependences of magnetization in the temperature range of 5-400 K at 50 Oe, as well as magnetization hysteresis loops at 15, 100 and 305 K were measured by vibrating sample magnetometry. Presence of antiferromagnetic phase, most probably of the oxide Co3O4, was observed in as-prepared sample. The lowest coercivity was found for the CoCu sample annealed at-300 degrees C, whereas for as prepared sample and the one annealed at 450 degrees C it was significantly higher. The samples were additionally probed by continuous wave ferromagnetic resonance at room, temperature using a standard X-band electron spin resonance spectrometer. A good correspondence between evolution of the coercivity and the microwave resonance fields with annealing temperature was observed. PMID- 23035511 TI - Spin tunneling and manipulation in nanostructures. AB - The results for joint effects of tunneling and spin-orbit coupling on spin dynamics in nanostructures are presented for systems with discrete and continuous spectra. We demonstrate that tunneling plays the crucial role in the spin dynamics and the abilities of spin manipulation by external electric field. This result can be important for design of nanostructures-based spintronics devices. PMID- 23035512 TI - Above room temperature ferromagnetism in Si:Mn and TiO(2-delta)Co. AB - We present recent experimental results on the structural, electrical, magnetic, and magneto-optical properties of Mn-implanted Si and Co-doped TiO(2-delta) magnetic oxides. Si wafers, both n- and p-type, with high and low resistivity, were used as the starting materials for implantation with Mn ions at the fluencies up to 5 x 10(16) cm(-2). The saturation magnetization was found to show the lack of any regular dependence on the Si conductivity type, type of impurity and the short post-implantation annealing. According to XMCD Mn impurity in Si does not bear any appreciable magnetic moment at room temperature. The obtained results indicate that above room temperature ferromagnetism in Mn-implanted Si originates not from Mn impurity but rather from structural defects in Si. The TiO(2-delta):Co thin films were deposited on LaAlO3 (001) substrates by magnetron sputtering in the argon-oxygen atmosphere at oxygen partial pressure of 2 x 10( 6)-2 x 10(-4) Torr. The obtained transverse Kerr effect spectra at the visible and XMCD spectra indicate on intrinsic room temperature ferromagnetism in TiO(2 delta):Co thin films at low (< 1%) volume fraction of Co. PMID- 23035513 TI - Analysing surface structures on (Ga, Mn)As by atomic force microscopy. AB - Using atomic force microscopy, we have studied the surface structures of high quality molecular beam epitaxy grown (Ga, Mn)As compound. Several samples with different thickness and Mn concentration, as well as a few (Ga, Mn)(As, P) samples have been investigated. All these samples have shown the presence of periodic ripples aligned along the [110] direction. From a detailed Fourier analysis we have estimated the period (-50 nm) and the amplitude of these structures. PMID- 23035514 TI - Current driven domain wall motion in rare-earth transition metal alloys with perpendicular magnetic anisotropy. AB - The domain wall movement behaviors under current combining with magnetic field in perpendicularly magnetized TbFeCo wire were studied by a polar magneto-optical Kerr effect microscope. The velocity for domain wall creeping along electrons flowing direction was found to be apparently higher than that of domain wall creeping against electrons flowing, which is the signature of the spin transfer torque effect. By employing the modified field-driven creep motion law, a spin transfer efficiency of 2.7 Oe cm2/10(6) A was determined for TbFeCo wire by treating the spin transfer torque as an effective field adding to the external field. The high spin transfer efficiency suggests that perpendicularly magnetized system with sharp domain walls in TbFeCo film shows high superiorities for applications in spin transfer torque based devices compared with in-plane magnetized systems. PMID- 23035515 TI - Transport properties of Fe/GaAs/Ag(001) system. AB - We present results of ab initio transport calculations for epitaxial magnetic tunnel junctions Fe/GaAs/Ag(001). The electronic structure is calculated by means of the tight-binding linear muffin-tin orbital method and the ballistic conductances are evaluated within the Kubo-Landauer formalism which includes the effect of the spin-orbit interaction. Particular attention is paid to the dependence of the conductances on the orientation of magnetization direction of the Fe electrode with respect to the crystal lattice and on the thickness of the tunneling barrier. We have found that the in-plane tunneling anisotropic magnetoresistance (TAMR) exhibits a non-monotonic thickness dependence with a maximum around 7.5 nm of GaAs. This behavior is ascribed to a hybridization of interface resonances formed on both sides of the junction and manifested as hot spots in k[]-resolved conductances. For thicker GaAs barriers, the relative intensity of the hot spots is reduced on account of the contribution from a narrow central region of the two-dimensional Brillouin zone which leads to the final decrease of the TAMR effect. PMID- 23035516 TI - Low hysteresis FeMn-based top spin valve. AB - FeMn-based top spin valves Ta/[FeNi/CoFe]/Cu/CoFe/FeMn/Ta with different Cu and FeMn layers thicknesses were prepared by DC magnetron sputtering at room temperature. It was shown that low field hysteresis due to free layer magnetization reversal can be reduced down to (0.1 divided by 0.2) Oe keeping the GMR ratio higher 8% by using both layers thicknesses optimization and non collinear geometry of magnetoresistance measurements. Dependence of low field hysteresis and GMR ratio on the angle between applied magnetic field and pinning direction are presented. PMID- 23035517 TI - Diffusion mechanism of exchange bias formation in permalloy-manganese nanostructures at thermo-magnetic treatment. AB - A mechanism of unidirectional exchange anisotropy formation at thermo-magnetic treatment of permalloy-manganese bilayers has been studied. A shift of hysteresis loops appears at annealing beginning from 230 degrees C. The maximal exchange field of 155 Oe is reached after the 250 degrees C annealing for 2 h. As demonstrated by transmission electron microscopy, the exchange bias and the coercivity growth result from an ordered anti-ferromagnetic NiFeMn phase formation due to the diffusion interaction of permalloy and manganese at annealing. PMID- 23035518 TI - Influence of temperature on structure and magnetic properties of exchange coupled TbCo/FeNi bilayers. AB - Among amorphous films of rare earth-transition metal (RE-TM) alloys as exchange biasing layers in magnetoresistive heads and spin-valve sensors, the amorphous Tb Co films have most high practical potential. In the present work the influence of the temperature and the heat treatment parameters on the structure and magnetic properties was studied for exchange bias FeNi/Tb35Co65 bilayers annealed in vacuum or a nitrogen flow. A simple explanation of the dependence of the magnetic properties on the temperature and the heat treatment parameters connected with structural changes in each one of the layers was proposed. PMID- 23035519 TI - Morin transition in hematite nanocrystals self-assembled into three-dimensional structures. AB - The Morin transition (i.e., the first-order weak ferromagnetic (WF)/antiferromagnetic (AF) transition) in tridimensional (3D) nanoarchitectures constituted by self-organized hematite nanocrystals with controlled crystal size has been investigated. These intricate structures were prepared by the thermally induced hydrolysis of iron (III) solutions in presence of urea. The variation of the aging time from 1 hour up to 7 days leads to the formation of hematite crystal aggregates with crystallite sizes ranging between 7 and 42 nm. As the crystallite size decreases, it is observed that a superparamagnetic contribution, ascribed to the spins of the crystal surface, gains importance. This emergent contribution progressively hides the abrupt change of the magnetization associated to the Morin transition which, in turn, occurs at decreasing temperatures. The Morin transition found in the bigger particles exhibits thermal hysteresis. This fact has been tentatively explained by considering that in absence of crystal defects, the nucleation of the AF --> WF transition occurs in areas near to the outer spin layers, whereas the nucleation of the WF --> AF occurs in the inner of the crystal. In the outer spin layers, the AFM order is frustrated and therefore this transition is suppressed. In fact, the uncompensated surface spins can be magnetically coupled with the core spins at low temperatures when the sample is field cooled, inducing exchange anisotropy in the system. PMID- 23035520 TI - Shape anisotropy and exchange bias in magnetic flattened nanospindles with metallic/oxide core/shell structures. AB - A preliminary study of the magnetic phenomenology of Fe and Fe90Co10 nanospindles with axial ratio equal to 5 is presented. These nanospindles are constituted by single-domains single-crystals coated by oxide surface layer and assembled in chains into the nanospindle. The thermal dependence of the coercive field and the saturation magnetization in the temperature range from 4 K up to room temperature indicates that the coercive field is roughly proportional to the saturation magnetization (which follows the T3/2 Bloch law) at temperatures above the blocking temperature of the oxide. This suggests that the predominant source of magnetic anisotropy in this temperature range is the shape anisotropy. However, at temperatures below the oxide blocking temperature, the magnetic coupling between the spins of the oxide and the nanocrystals is produced at the interface. This exchange coupling enhances the effective anisotropy of the nanospindles and the coercive field increases more abruptly than the saturation of magnetization as temperature decreases. PMID- 23035521 TI - Magnetoelastic contribution in domain wall propagation of micrometric wires. AB - We report on studies of domain wall propagation of magnetically-bistable Fe-Co rich microwires paying attention on the effect of applied and internal stresses. We measured magnetic domain propagation in various magnetic Fe-Co-rich amorphous microwires with metallic nucleus diameters (from 2.8 microm to 18 microm) using Sixtus Tonks-like experiments. We found that application of applied stresses and increasing of internal stresses result in decreasing of domain wall (DW) velocity. We assume that in order to achieve higher DW propagation velocity at the same magnetic field and enhanced DW mobility, special attention should be paid to the decrease of magnetoelastic energy. PMID- 23035522 TI - [Bubbles induced fluctuations of some properties of aqueous solutions]. AB - A mathematical model of the air diffusion process through the water surface, taking into account the reverse flow of bubbles was proposed. The numerical solving gives self-oscillation of the dissolved air concentration. Spectral density of these oscillations has the 1/f-noise form, which explains the fluctuating nature of the observed properties of water and biological effects, which depend on the amount of dissolved air. A mechanism of spontaneous water luminescence observed after laser irradiation was suggested. The calculated luminescence self-oscillations have the form of a fractal with an infinite sequence of periods, which evolve in time and that is qualitatively consistent with the experiment. PMID- 23035523 TI - [Study of elongation complexes for T7 RNA polymerase]. AB - Complexes of bacteriophage T7 RNA polymerase with a DNA template for transcription elongation were visualized by atomic force microscopy. Images for complexes of T7 RNA polymerase with terminal fragments of DNA template were obtained for single molecules. Complexes of a single DNA template molecule with several T7 RNA polymerase molecules corresponding to stages of initiation, elongation and termination of transcription were visualized under the elimination of unspecific DNA-protein binding. Immobilized on the amino mica RNA transcripts form rod-like condensed structures. Detailes of specific and unspecific complex formation for the T7 RNA polymerase-DNA system during initiation and transcription elongation are discussed. PMID- 23035524 TI - [New method for calculating the dissipation parameters in ultrafast biochemical reactions from protein crystal structure data]. AB - A new method of calculating the spectral function of system-bath interaction during elementary biochemical reaction is proposed. This method was applied to the primary electron transfer in the photosynthetic reaction center of purple bacteria Rh. Sphaeroides. The calculated spectral functions differ significantly from the commonly used ohmic function. It is shown that the unidirectionality of the electron transfer along the A-branch in the reaction center of Rh. Sphaeroides can be caused by the asymmetry or reaction system interaction with the protein environment. PMID- 23035525 TI - [Energy of a ligand-RNA complex formation]. AB - This work presents an energetic analysis of complex formation of eleven ligands with different structure and charge with RNA aptamers. The most entire set of the components of the total Gibbs energy of complex formation has been first calculated using different physical factors: van der Waals, electrostatic and hydrophobic interactions, hydrogen bonds and specific factors being predominantly of entropic character. The calculated Gibbs energy is found to be in a good agreement with experimental data. Different energy components which stabilize and destabilize complexes are lined up according to the degree of importance. The results obtained provide an understanding of the role of different physical interactions in a ligand-RNA complex formation. PMID- 23035526 TI - [Investigation of exciting light and plant leaves age effects on chlorophyll fluorescense of radish plants]. AB - The effect of exciting light intensity and leaves age on characteristics of slow stage of chlorophyll fluorescence induction (CFI) of radish leaves has been investigated. Light dependence of the relationship of maximum fluorescence intensity in the peak P and the stationary fluorescence level (F(P)/F(S)) and also light dependence of temporal characteristics of CFI (T0.5 - half decrease of chlorophyll fluorescence intensity during slow stage of fluorescence induction and tmin - summarized CFI characteristics derived by calculating via integral proportional to variable part of illuminated in the result of chlorophyll fluorescence energy during slow stage of CFI) have been studied. Plants were grown in controlled conditions of light culture at 100 Wt/m2 of photosynthetic active radiation (PAR). It has been shown that variability of the characteristics under study, associated with the effect of leaves age, significantly decreases at exciting light intensity equal to 40 Wt/m2 of PAR and more. The lowest effect of leaves age on the value of fluorescence characteristics for T0.5 and tmin and also for F(P)/F(S) ratio was observed at the intensity of exciting fluorescence light of 60 Wt/m2 of PAR. In the researched range of light intensities the temporal characteristics of T0.5 and tmin for uneven-aged radish leaves appeared to be by an order less responsive to the intensity changes of exciting fluorescence light as compared with F(P)/F(S) ratio. PMID- 23035527 TI - [Collective movement of ions in cytoplasm]. AB - Theoretical model of transmission in cytoplasm of self consistent electric-and magnetic waves of millimeter-infrared range have been developed; cytoplasm ions surrounded by water molecule "fur-coats" being the main carriers of these waves. It has been discovered that not only own long-wave transverse waves, but also linear waves which are not able to leave cytoplasm can exist in tissues of living organisms. Frequencies and logarithmic decrements of such perturbation have been found, and it has been shown that these frequencies approach the ion fluctuation frequencies inside the "fur-coats". Laser radiation movement in bioobjects on the indicated frequencies has been analyzed, and it was detected the existence of no penetrative stripes of waves into bodies. The new mechanism of swinging of cytoplasm own fluctuation based on the existence of the extreme border of the ion movement area has been proposed. It has been shown that having this mechanism the electric field magnitude of linear waves is six-seven degrees larger than Plank fluctuation level. PMID- 23035528 TI - [On the theory of action potential propagation in plant cells]. AB - The distribution of an electric field in plant cells and zooblasts has been investigated at propagation of the action potential. The behavior of ions in the cytoplasm and in the extracellular fluid has been described with the equations of electric charge motion in the electrolytes. It has been shown that the action potential causes an electric potential change not only in the depth of the cytoplasm but also in the extracellular area far from the lipidic bilayer. The biomembrane resistance has been expressed by physical parameters of a cell, such as ionic diffusion coefficient in fluid, Debye-Huckel radius, dielectric conductivity etc. The presence of breakings in the action potential diagrams has been explained as a result of insufficient resolving power of the measuring devices at the instant the sodium ionic canals of the bilayer opens. PMID- 23035529 TI - [Ways of apoptosis development in human lymphocytes, induced by UV-irradiation]. AB - The level of DNA damage and cytochrome c content in human lymphocytes in the dynamics of apoptosis induced by UV-light (240-390 nm) at doses of 151, 1510 and 3020 J/m2 is studied. DNA fragmentation is revealed in 20 h after UV-irradiation of lymphocytes at doses mentioned above. It is shown that DNA damages (single strand breaks) appear immediately after UV-irradiation of lymphocytes at doses of 1510 and 3020 J/m2 (comets of C1 type) and reach their maximum 6 h after cell modification (comets of C2 and C3 types). It is concluded that p53-dependent and receptor caspase pathways are involved in apoptosis development in the human lymphocytes, modified after UV-irradiation. PMID- 23035530 TI - [Membrane-modifying effect of taurine]. AB - The effect of taurine on the membrane-bound processes in rat erythrocytes and peritoneal mast cells was studied. By EPR method using spin probe 5-DS a significant decrease in the order parameter S of erythrocyte membrane phospholipid acyl chains in in vitro experiments after incubation with taurine (10 mM, 1 h) was shown. The increase of erythrocyte membrane response to peroxide hemolysis was also observed, that was apparently induced by decrease of membrane viscosity as a result of lessening the solidity of the erythrocyte membrane phospholipid packing. The different effects of taurine on ionophore A23187 and compound 48/80-stimulated functional activity of the peritoneal rat mast cells by various modes of administration (peroral, intraperitoneal, intramuscular) were shown. This makes it possible to conclude that the mechanism of taurine activity at the organism level seems to be a mediated process and systemic by nature. PMID- 23035531 TI - [Increase in resistance of A431 cancer cells to TRAIL-induced apoptosis in confluent cultures]. AB - It was shown that cancer cells acquired resistance to TRAIL-induced apoptosis in confluent cultures. Recombinant protein izTRAIL induced apoptosis of human carcinoma A431 cells in the first hours after cell plating at a concentration of 3-10 ng/ml, while in confluent cultures these cells acquire resistance to protein izTRAIL even at the concentration of 2 mkg/ml. Detachment and suspending of the cells of confluent cultures immediately suppressed the resistance to izTRAIL. The cells of confluent cultures, being resistant to TRAIL-induced apoptosis continue progression through the cell cycle, as evidenced by the DNA cytograms and the Ki67p-GFP reporter system. Thus, the results showed that tumor A431 cells can acquire resistance to TRAIL-induced apoptosis in confluent cultures, while continue progression through the cell cycle, keeping the proliferative potential. PMID- 23035532 TI - [Multikinase inhibitor sorafenib and HDAC inhibitor suberoylanilide hydroxamic acid suppress confluent resistance of cancer cells to recombinant protein izTRAIL]. AB - Suppression of human tumor cell resistance to TRAIL-induced apoptosis in confluent cultures, using molecular target drugs (sorafenib and SAHA) at non toxic concentrations was studied. Sorafenib, a multikinase inhibitor, and SAHA, an inhibitor of histone deacetylase, effectively suppressed resistance of confluent human cells derived from the skin carcinoma (A431 cell line) and fibrosarcoma (HT-1080 cell line). The effectiveness of suppression of confluent resistance with these inhibitors for human carcinoma A431 cells was significantly higher than that for the human ovarian carcinoma OVCAR-3 cells. For all cell lines studied, suppression of confluent resistance with SAHA was more effective than when sorafenib was used. The possible reason for increasing tumor cell resistance in confluent cultures and the importance of this phenomenon for understanding drug resistance of cells in the tumor tissue are discussed. PMID- 23035533 TI - [Slow fluorescence induction and productivity of barley treated with supercritical fluid extract of amaranth]. AB - It is shown that treatment of barley plants with supercritical fluid extract of amaranth results in the increased fluorescence parameter (F(M) - F(T))/F(T) of slow fluorescence induction curve of the leaf. Barley treated with the extract showed higher productivity and higher indices of the yield. PMID- 23035534 TI - [Spin-lattice relaxation of water protons in plant and animal cells]. AB - NMR-spin echo method has been used to study spin-lattice relaxation time of protons T1 in plant and animal cells - muscle tissue of fish, the cells of which unlike plant cells have no developed system of vacuoles, plastids and a solid cell wall. According to the values of T1 time a new NMR parameter K, a coefficient of relaxation effectiveness of a cell structure, has been calculated. This parameter can be used for quantitative characterization of the influence of different cell structures, the tissue water interact with, for a time of spin lattice relaxation of water protons. It has been ascertained that the values of K coefficient in animal tissue and in storing tissues of some plants differ little; it may be stipulated by permanent transmembrane water exchange which occurs at high rate in the living cell. It has been concluded that there exists a certain similarity between water state in protoplast of plant and animal cells. PMID- 23035535 TI - [Experimental and modelling investigation of the mechanism of synaptic vesicles recycling]. AB - Under the condition of microelectrode recording and fluorescence microscopy with dye FM 1-43 the research of exo- endocytosis of synaptic vesicle in motor nerve terminals (NT) of frog cutaneous pectoris and white mice diaphragm muscles during high frequency stimulation (20 imp/s) was carried out. A mathematical modeling allowed us to conclude that the obtained experimental data can be explained in the following framework. Three pools of synaptic vesicles are involved in neurotransmitter release in the frog motor NT. Recovery of these pools is provided by endocytosis of two types: fast endocytosis with limited capacity and slow endocytosis. Fast-reconstructing vesicles refills the mobilization pool and slow endocytosis recovers the reserve pool. Our modelling investigation has revealed in frog NT independent recruiting of reserve and mobilization pools to the neurotransmitter secretion, i.e. this pools work concurrently. Experimental data, obtained on mice preparations, are well described with the framework of two pools model including single type of endocytosis (fast endocytosis). PMID- 23035536 TI - [Contractile properties, transversal stiffness and cytoskeletal protein content in Mongolian gerbils soleus fibers under long-term hindlimb suspension]. AB - Structural and functional changes in Mongolian gerbil soleus fibers were analyzed after a 31-day hindlimb suspension. Contractile properties of muscle fibers were studied by means of tensometry; the transversal stiffness of different parts of the contractile apparatus was measured by atomic force microscopy, resting calcium level was estimated by fluorescence microscopy by using Fluo-4-AM; cytoskeletal protein content was determined by western blotting. It was shown that after gravitational unloading the maximal force of contraction and specific tension of fiber were significantly reduced, as well as calcium sensitivity actually lowered. At the same time, the transversal stiffness of Z-disk in the relaxed and activated state was decreased significantly compared to the control group. Desmin content was at the control level, but alpha-actinin-2, main structural protein of Z-disk, became considerably less after a 31-day hindlimb suspension. Besides, resting calcium level remained at control values during the simulated gravitational unloading. The data suggest that Z-disk destruction, as a result of alpha-actinin-2 content reduction, leads to changes in the lattice spacing and decreases contractile properties. PMID- 23035537 TI - [Viscoelastic properties of relaxed papillary muscle at physiological hypertrophy]. AB - Viscoelastic properties of relaxed rat papillary muscles at physiological hypertrophy (intensive swimming for 5 weeks) have been obtained. It has been ascertained that viscoelastic properties of hypertrophied muscles are not significantly distinguished from those of control papillary muscles. A three dimensional model of myocardial fascicle has been verified in compliance with experimental data of biomechanical tests of hypertrophied muscles. Elastic and viscous parameters of structural elements of the model negligibly differ from the parameters of the model of a control muscle. It is shown that physiological hypertrophy has a slight influence on viscoelastic properties of papillary muscles. PMID- 23035538 TI - [The wavelet-analysis of non-stationary heart rate variability during out head-up tilt test]. AB - Heart rate variability (HRV) during the head-up tilt test (HUT) was investigated using an automated set of dynamic positioning in the gravitational field. The theory of wavelets is applied to find the dynamics of changes in the spectral properties of rhythmogran during the transitional phases of HUT. Quantitative parameters (spectral integrals, instantaneous maximal frequencies, nonstationarity factors), that describe transitive stages of such non-stationary head-up tilt test, are calculated. PMID- 23035539 TI - [Study of mutual synchronization of self-oscillations of cellular density in skin lesions caused by psoriasis based on paracrine regulation of epidermal proliferation with participation of T-lymphocytes]. AB - This paper represents the results of research of mutual synchronization of self oscillations of epidermal cellular density in skin lesions caused by psoriasis under strong limited noise conditions by the method of computing experiment. As an initial model the system of three ordinary nonlinear differential equations, presumably describing principles of paracrine regulation of epidermal proliferation with participation of populations functionally activated by CD4+/CD8+ T-lymphocytes is used. The results of research have shown, that if epidermal proliferation is considered as an attribute determining pathomorphologic features of dermatoses, synchronization can appear to be responsible for development of linear, annular, arcuate, geographical, and also the limited and common forms of disease. It is shown, that strong noise is capable of providing different duration for clinical manifestation of ensembles of synchronously connected lesions of psoriatic skin within several days, as to phase slip - it is up to several tens of days, and distinction of physical parameters - it is from several hours up to about several days. PMID- 23035540 TI - [Wavelet analysis and its application in investigation of brain potentials during verbal task solving]. AB - The components of event-related brain potentials during verbal tasks were investigated with the help of a new method--wavelet analysis. Using this method in 415 ms from the beginning of the stimulus maximum values of the higher frequent components were revealed in the left parietal zone. During a repetition of verbal task a tendency for a decrease of amplitude values of the higher frequent components was observed. PMID- 23035541 TI - [On structure and function of "chlorosoma" of green bacteria]. AB - An assertion is substantiated that what is widely termed as chlorosoma of green bacteria--is not a bioparticle, but simply microscopic bacteriochlorophyll-c crystals. Apparently the creation of "chlorosoma" represents the first mostly unsuccessful evolutionary attempt to produce the regulatory mechanism in photosynthesis, which should react to the variations in the intensity of solar light reaching earth surface. It could not be successful without bacteriochlorophyll cooperation with proteins. PMID- 23035542 TI - Comparative analysis of the role of JNK signaling pathway in regulating cell proliferation and apoptosis of rat liver regeneration and rat acute hepatic failure. AB - To compare the role of JNK signaling pathway in rat liver regeneration (LR) and in rat acute hepatic failure (AHF) occurrence at the gene transcription level, Rat Genome 230 2.0 array was used to detect the gene expression profiles of the two processes, and bioinformatics and systems biology methods were applied to analyze the physiological activities uncovered by their gene expression profiles in this study. The results showed that 240 genes were included in the array above, though there were 302 genes related to forty two paths of JNK signaling pathway. Array detection results demonstrated that 52 genes were significantly expressed during LR, 20 genes in AHF occurrence, and 15 genes in both of above two processes. Synergy values of these genes were calculated using a mathematical model established by our lab, which revealed the following. The cell proliferation-promoting effects of paths 1, 16 and paths 1-17 of JNK signaling pathway were stronger than the control at 6-12 h and 72 h of LR, respectively, while the cell proliferation-promoting effects of paths 1-17 and the cell proliferation-inhibiting effects of path 34-35 were weaker at 6h of AHF occurrence. The cell apoptosis-promoting effects of paths 22-23 were much stronger at 6, 12 and 72 h of LR and at 12, 24 h of AHF occurrence. In conclusion, thirty eight paths of JNK signaling pathway regulate cell proliferation and apoptosis in both LR and AHF occurrence. PMID- 23035543 TI - [Chromosomal polymorphism of Acremonium chrysogenum strains producing cephalosporin C]. AB - Using pulse electrophoresis in controlled homogenous electric field we conducted molecular karyotyping of highly-productive and laboratory strains of Acremonium chrysogenum generating antibiotic cephalosporin C (cefC). Differences in size of several chromosomes of highly active strain CB26/8 compared to the wild-type strain ATCC 11550 were revealed. It was shown that chromosomal polymorphism in the highly active strain was not associated with alteration of localization and copy number ofcephalosporin C biosynthesis and transport genes. A cluster of "early" cefC biosynthesis genes is located on chromosome VI (4.4 Mb); a cluster of the "late genes", on chromosome II (2.3 Mb). Both clusters are presented as a single copy perA. chrysogenum genome in the wild-type and in CB26/8 producer strains. Based on comparative analysis of laboratory and industrial cefC producers, a karyotype scheme for A. chrysogenum strains of various origins was designed. PMID- 23035544 TI - [A cytogenetic study of the blue-grain line of the common wheat cultivar Saratovskaya 29]. AB - The chromosome composition of the blue-grain line i:S29Ba of the cultivar Saratovskaya 29 was identified by cytological, GISH, and microsatellite analyses and C-banding. It was found that common wheat chromosome 4B of the cultivar Saratovskaya 29 was substituted with the Agropyron elongatum Host. chromosome carrying the gene for blue grain (s:S294Ag(4B)) during the construction of this nearly isogenic line. The blue-grain line was tested for productivity. The substitution of total chromosome 4B of the cultivar Saratovskaya 29 by Ag. elongatum chromosome 4 did not significantly affect the spike productivity parameters and grain quality with the exception of spike length (plus effect), spike density, and vitreousness (minus effects). The blue-grain line with s:S294Ag(4B) can be used in further studies associated with chromosome engineering in cereals and wheat breeding. PMID- 23035545 TI - [Polymorphism of hordein-coding loci in barley (Hordeum vulgare L.) populations from the countries of East Asia (China, Nepal, Pakistan, India)]. AB - In this study, starch gel electrophoresis was used to examine polymorphism of hordeins encoded by the Hrd A, Hrd B, and Hrd Floci in 201 accessions of barley landraces from China (including Tibet), Nepal, Pakistan, and India. Altogether, 50 alleles with the frequencies of 0.001-0.2269 were determined for the Hrd A locus, 65 alleles with the frequencies of 0.001-0.1612 were determined for the Hrd B locus, and five alleles with the frequencies of 0.001-0.4537 were determined for the Hrd Flocus. In barley populations from these countries, irregular distribution of alleles and allele frequencies was observed. Cluster analysis of the matrix of allele frequencies in populations from known sampling sites revealed cluster structure of local barley populations within each country. Local populations formed five differently sized clusters in Nepal, four such clusters in India, three clusters in China, and three clusters, in Pakistan. These results suggest that variation and allele frequency distribution of the hordein-coding loci in the countries of East Asia resulted from the introduction and spreading of barley forms through the husbandmen migrations. PMID- 23035546 TI - Morphological characteristics and chromosome behaviour in F1, F2 and BC1 progenies between Chrysanthemum x morifolium and Ajania pacifica. AB - The garden chrysanthemum (Chrysanthemum x morifolium) variety 'Aoyunhuoju' (2n = 6x = 54) was crossed as female with Ajania pacifica (2n = 10x = 90) to produce an intergeneric F1 hybrid, which was used both as a source ofF2 progeny and as a parent for a first back-cross with 'Aoyunhuoju'. The morphology of all of the F1 hybrids and hybrid derivatives was intermediate with respect to the two parents, although the BC1 progenies resembled 'Aoyunhuoju' more closely than any of the F1 and F2 progenies did. In the F1 hybrid, the density of silvery hairs on the lower leaf surface and along the margin of the leaf was lower than in A. pacifica, while that in the BC1 generation, this trait was less prominent than in the F1. The somatic chromosome number of the F1, F2 (with an exception of F2-6 of a mainly 63) and BC1 generations was 2n = 8x = 72, 2n = 8x = 72 and 2n = 7x = 63 respectively, as expected. The hybrids and their derivatives retained a variable degree of fertility. There was a low frequency of meiotic chromosome pairing failure in all three hybrid generations, with most of the chromosomes involved as bivalents. Some BC1 individuals show potential for commercialization thanks both to their flower shape and the inheritance of the silvery leaf trait from A. pacifica. PMID- 23035547 TI - [Variation of the BoLA-DRB3 gene in dairy cattle and its effect on the viability parameters]. AB - Genotyping of the BoLA-DRB3 alleles was performed in dairy cattle of Krasnodar krai and Holstein stud bulls. Loss of heterozygosity, which decreased the reproductive parameters, was observed. It was proposed that stud bulls be selected on the basis of their genotyping at the BoLA-DRB3 gene to prevent further decay of cattle viability. PMID- 23035548 TI - [Phenotypic variation of spermatogenesis and a search for associations with genetic polymorphism in 13 inbred mouse strains]. AB - Adult mice of the BALB/cLac, PT, CBA/Lac, DD/He, A/He, SWR, NZB, GR, DBA/2J, CC57Br, C57 B1/6J, A/Sn, and YT inbred strains were tested for the count, motility, and morphology of sperms from the caudal region of the epididymis. The protein-coding regions of the cytochrome P450 aromatase (CYP19a1), estrogen receptor 2 (ESR2), steroidogenic factor 1 (Nr5a1), and sex-determining (Sry) gene were sequenced. A substantial genetic heterogeneity for the genes was observed, as well as a phenotypic variation in spermatogenetic parameters, but the variation was rather discordant. The specifics of the interstrain variation in spermatogenetic parameters indicated that a physiological compensatory mechanism increases certain spermatogenetic parameters when other ones are low to maintain male fertility at a level sufficient for successful reproduction. For instance, a high sperm production compensated for a low sperm motility in DD/He males. In the issue of the protein-coding regions sequencing of the analyzed genes, 16 various mutations were observed. The decreases in proportion of motile sperms and in their velocity were attributed to mutations (I63T and W133L) of the Sry gene in the DD/He strain. PMID- 23035549 TI - [A panel of microsatellite loci for population studies of Sakhalin taimen Parahucho perryi (Brevoort)]. AB - Using DNA samples of Sakhalin taimen and a set of microsatellite loci, earlier reported for other salmonid fishes (Salmonidae), successful cross-species amplification was performed. A total of 56 Sakhalin taimen (Parahucho perryi) samples from the Daga, Nabil, Poronai, and Agnevo rivers (Sakhalin Island) were examined at 36 microsatellite loci, most ofwhich were described for other species and first tested in taimen. Among the 21 loci first tested in taimen, two loci produced no amplification products. The remaining 19 loci were successfully amplified (for some loci, new primers were generated). Thirteen of these loci were monomorphic, while six loci were polymorphic and used in further population genetic analysis. In addition, with the purpose of modification of the allele sizes and optimization of the research technique, new primers for the already known 12 loci of Sakhalin taimen were designed. Three more loci were included in analysis without changes. As a result, ajoint panel consisting of 21 polymorphic microsatellite markers was suggested for analysis of Sakhalin taimen. This panel was tested with four population samples from the rivers of Sakhalin Island. The results showed that this panel of markers could be used in detailed population studies for evaluation of the level of genetic differentiation, inbreeding, and migrations in Sakhalin taimen, an endangered species with a fragmented range. Using this approach in further studies will make it possible to isolate basic populations, which is necessary for conservation of this rare species. PMID- 23035550 TI - [Heterozygous carrier rate for type I-IV proximal spinal muscular atrophy in Chuvashes, Udmurts, and residents of the Moscow region]. AB - The first estimation of the heterozygous carrier rates for the SMN1 gene deletions and SMN2 gene duplications in populations of Russia has been performed. The numbers of SMNgene copies have been determined in samples from Chuvash and Udmurt populations, as well the population of the Moscow region, by means of multiplex ligation-dependent probe amplification. The heterozygous carrier rates for the CMA gene were 2.7% (1 : 37 people), 2.8% (1 : 36 people), and 2.8% (1 : 36 people) in Chuvashes, Udmurts, and residents of the Moscow region, respectively. The SMN2 duplication frequencies have been determined in the studied groups. It is 1.5, 4, and 2.5% in Chuvashes, Udmurts, and residents of the Moscow region, respectively. The high SMN2 duplication frequency in Udmurts may explain why the SMN1 heterozygous carriage frequency in this population was overestimated in earlier PCR-RFLP analyses. PMID- 23035551 TI - [Association of the insulin-like growth factor II (IGF2) gene with human cognitive functions]. AB - Active search for candidate genes whose polymorphisms are associated with human cognitive functions has been in progress in the past years. The study focused on the role that the insulin-like growth factor II (IGF2) gene may play in the variation of cognitive processes related to executive functions. The ApaI polymorphism of the IGF2 gene was tested for association with selective attention during visual search, working memory/mental control, and semantic verbal fluency in a group of 182 healthy individuals. The ApaI polymorphism was associated with the general cognitive index and selective attention measure. Carriers of genotype AA displayed higher values of the two parameters than carriers of genotype GG. It was assumed that the ApaI polymorphism of the IGF2 gene influences the human cognitive functions, acting possibly via modulation of the IGF-II level in the central nervous system. PMID- 23035552 TI - [Role of DopR in the molecular mechanism of the dopamine control of juvenile hormone metabolism in female Drosophila]. AB - The effect of a decreased availability of the D1-like dopamine receptor (DopR) in Drosophila (caused by DopR antagonist added into food) on the juvenile hormone (JH) synthesis rate in young female D. melanogaster has been studied. The JH degradation rate and the alkaline phosphatase (ALP) and tyrosine decarboxylase (TDC) activities were used as indicators of the JH synthesis rate. Treatment of the flies with butaclamol, a specific DopR antagonist, has been demonstrated to increase the JH degradation rate, and the stress reactivity of the system of JH metabolism and decrease the ALP activity and stress reactivity, and increase the TDC activity and stress reactivity. As shown earlier, all this indicates a decrease in the JH synthesis rate in young female drosophila with a decreased DopR availability. It is concluded that the activating effect of dopamine on JH synthesis in Drosophila is mediated by D1-like receptors. PMID- 23035553 TI - [Diversity of 16S rRNA genes in metagenomic community of the freshwater sponge Lubomirskia baicalensis]. AB - Phylogenetic analysis of the nucleotide sequences of 16S rRNA genes in the metagenomic community of Lubomirskia baicalensis has revealed taxonomic diversity of bacteria associated with the endemic freshwater sponge. Fifty-four operational taxonomic units (OTUs) belonging to six bacterial phyla (Actinobacteria, alpha Proteobacteria, beta-Proteobacteria, Verrucomicrobia, Bacteroidetes, Cyanobacteria, and Nitrospiracea) have been identified. Actinobacteria, whose representatives are known as antibiotic producers, is the dominant phylum of the community (37%, 20 OTUs). All sequences detected shared the maximal homology with unculturable microorganisms from freshwater habitats. The wide diversity of bacteria closely coexisting with the Baikal sponge indicate the complex ecological relationships in the community formed under the unique conditions of Lake Baikal. PMID- 23035554 TI - Population genetic structure of wild boars in the West Balkan region. AB - We investigated the population genetic structure of wild boars from Vojvodina (Serbia), Slavonija (Croatia) and Bosnia using four microsatellite markers. All loci presented a high degree of polymorphism and a total of 76 alleles (mean 19 alleles per locus) were detected. Average observed heterozygosity (Ho) value was 0.60. Deviation from Hardy-Weinberg equilibrium was found due to significant heterozygote deficiency detected for three of the four analyzed loci and for all populations. F(IS) value over all loci and all populations was 0.29, and the effective number of migrants based on private alleles was 1.64. Sufficient levels of gene flow were found between all populations and the spatial structure showed slightly closer nuclear gene pool affinity of Vojvodina and Slavonija populations in relation of Bosnia population. PMID- 23035555 TI - [Nuclear envelope attachment sites of interphase chromosomes: barrier elements but not insulators]. AB - A neDNA fragment that protects a transgene from position effect variegation when flanking it was tested for insulator properties. The fragment did not act as an insulator. A similarity of neDNA and various barrier elements was examined, and Drosophila melanogaster and Mus musculus chromosome DNA regions homologous to neDNA were analyzed. Additional conserved sites and DNA duplex destabilization sites were found in the neDNA sequence, and DNA conformational specifics were assumed for the chromosomal neighborhood of neDNA sites of the D. melanogaster and M. musculus genomes. PMID- 23035556 TI - [Possible mechanisms for orexin effects on the functioning of the hippocampus and spatial learning (analytical review)]. AB - We analyzed possible mechanisms for the influence of the "wakening hormone" orexin on spatial learning acting via changes in the functioning of the hippocampus and connected structures. The literature data point out that, firstly, orexin can directly potentiate excitation of neurons in different hippocampal areas by acting on Gq/11-protein-coupled postsynaptic OX1 and OX2 receptors. Due to facilitation of induction of the long-term potentiation of excitatory transmission at each stage of trisynaptic pathway through the hippocampus, orexin can promote transduction of information through this structure and formation of neural representations of object-place associations. Secondly, orexin can increase the release of acetylcholine, GABA and glutamate in the hippocampus by enhancing activity of neurons in the medial septum that have OX1 and OX2 receptors. This could lead to changes in intensity and frequency of the hippocampal theta rhythm. Thirdly, orexin can influence the functioning of reinforcing networks that include neurons of the hippocampus, prefrontal cortex, amygdala, ventral striatum, and ventral tegmental area by direct modulation of their activity through OX receptors. By enhancing the activity of dopaminergic neurons and increasing dopamine release, orexin can improve the functioning of reinforcing networks and facilitate spatial learning. PMID- 23035557 TI - [Functional heterogeneity of gamma-band cortical potentials]. AB - A review. The problem of the functional significance of gamma-band EEG in different cognitive paradigms, including the aspect of the gamma-band heterogeneity (different origin and functional significance of "low gamma" and "high gamma"). PMID- 23035558 TI - [Adolescents under conditions of chronic family stress]. AB - The influence of the type of the nervous system on psychophysiological stress reaction was studied in a group of adolescents at the age of 15-17 years with chronic stress. Adolescents with the weak type of the nervous system were to a greater extent subject to psychological disorders; adolescents with the intermediate type of the nervous system suffered more from disorders in physiological sphere, whereas persons with the strong type appeared to be most stable in the situation of chronic family stress. PMID- 23035559 TI - [Learning of reproduction of random sequences by the right and the left hand movements: coding of positions or movements]. AB - Positional and movement errors during reproduction of memorized sequences of six random hand movements were analyzed. The task was performed by two groups of subjects: during six days by one hand (right/left) and during next six days by another hand (left/right). Mean values of accuracy errors decreases during learning only in a group which begins to work by the right hand. The quantity of transposition errors depends on type of error: positional or movement one. Subjects transpose the positions of the right hand more often when it begins to perform the task. Subjects transpose the movements of the left hand more often when it begins to perform the task. The results are evident in favor of the hypothesis about two type of movement coding: positional and vector coding (coding of positions or of changing of positions) specific in the right and the left hemispheres and suggest that learning of reproduction of movement sequences is provided by vector coding. PMID- 23035560 TI - [Functional asymmetry of monkeys' hand movements (Macaca mulatta)]. AB - Three Macaca mulatta were tested in two different tasks. In the naturalistic behavioral experiment, a monkey had to grasp a piece of food from a hollow cube with an asymmetric position of an aperture. The preferable hand was determined. In the second experiment, a monkey performed a more difficult instrumental task: it pulled the lever by the right or by the left hand depending on the position of a trigger stimulus in a corresponding visual hemifield. It was shown that, in the second task, the preferable hand to some extent is characterized by the following: 1) it was mainly used if the trigger stimulus was presented in the contralateral midline region of the visual field, 2) shorter latencies, 3) higher maximum speed of the movement. On the basis of the results obtained a hand preference criterion can be developed in monkey laboratory experiments. PMID- 23035561 TI - [Specific modulation of neuronal responses to light of different intensities by sound in the rabbit's primary visual cortex]. AB - Changes in activity of 92 neurons in the primary visual cortex of four rabbits (Orictolagus cuniculus) were analyzed. In the first series of experiments, we recorded discharges of 63 neurons in response to replacement of visual stimuli in pairs (pairs of 0.28 - 1, 1 - 3, 3 - 6, 6 - 8.5, 8.5 - 14, 14 - 17, 17 - 20 cd/m2). Then the same stimuli were presented simultaneously with sound (70 dB, 2000 Hz, 40 ms). Neurons did not respond directly to the sound. Two groups of neurons were found. In the first group of neurons (31%), responses to the complex "light and sound" (40-100 ms from the moment of substitution of stimuli) increased on average by 41% (p < 0.0001) under conditions of the lowest stimuli intensities. With increasing light intensities, discharges to the complex were reduced to the background level of responses to light and even lower. The second group of neurons (19%) showed the opposite properties: at low intensities, responses to the complex were comparable to responses to light (or even lower). At high intensities (14-20 cd/m2), discharges to the complex were significantly (p < 0.05) different from the responses to light (20% and higher, up to 39%). In the second series of experiments, we reconstructed vector sensory spaces on the basis of responses of 29 neurons to light of different intensities and eight complexes of "light and sound." It was found that the sound had also a dual effect on the sensory space of complexes. Some neurons showed an enhancement of the angular distance between the two lowest light intensities (0.28 and 1 cd/m2). Other neurons showed an increase in the angular distance between the highest intensities. Such changes in the space structure are consistent with the groups of neurons revealed in the first two series of the experiments. Comparison of the dynamics of neuronal responses and the amplitudes of evoked potentials under the same conditions of stimulation revealed their considerable similarity. Thus, modulation of neuronal activity in the visual cortex by sound is a complex nonlinear process. PMID- 23035562 TI - [Influence of changes in the state of brain neurotransmitter and peptidergic systems on circadian rhythms and behavior of rats]. AB - The influence of changes in the state of a number of neurotransmitter and peptidergic brain systems on the circadian rhythms and behaviour of rats was studied. Prolylleucine (oxytocine dipeptide fragment) eliminates disorders of circadian motility rhythm in SHR rats induced by "injection" stress, impedes dysrhythmias caused by application of cholinergic and glutamatergic modulators in SHR and WKY rats, and prevents cognitive disorders in SHR rats produced by REM sleep deprivation. PMID- 23035563 TI - [Effect of the selective ligands 5-HT(1A) receptors administration on the impulsive and self-control behavior in rats]. AB - The influence of drugs, agonist and antagonist of serotonin receptors 5-HT(1A) on the behavior of rats tested by the method of choice to the value of reinforcement was investigated. Depending on their preferences in food reinforcement rats were divided into self-monitoring (choosing more valuable, delayed reinforcement) and impulsive (low value, immediate reinforcement). An hour before the test animals were administrated i.p. agonist 5-HT(1A) receptors 8-OH-DPAT, [(+)-8-Hydroxy-2 (dipropylamino)tetralin] in a dose of 0.1 mg/kg or antagonist WAY-100635, [N-[2 [4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleat salt] at a dose of 0.2 mg/kg. Evaluated parameters, such as number of clicks on a particular pedal, the latencies and number of omitted responses. The results showed that the administration of drugs to modify individual behavior parameters both groups of animals. The introduction of 5-HT(1A) agonist receptors in impulsive animals caused an increase in the number of clicks on the pedal for more valuable reinforcement, and administration of an antagonist did not have any significant effect to behavior. PMID- 23035564 TI - [Signals of danger inhibit exploration-induced activation of the nitrergic system of the nucleus accumbens]. AB - In Sprague-Dawley rats it was shown by means of in vivo microdialysis combined with HPLC analysis that exploratory behavior in a new chamber produced an increase in the extracellular level of citrulline (an NO co-product) in the medial n. accumbens, which was prevented by intra-accumbal infusions of 7 nitroindazole (0.5 mM), a neuronal NO synthase inhibitor. When presented during exploratory activity, a tone previously pared with footshock, firstly, inhibited the exploration and, secondly, prevented the exploration-induced increase in accumbal extracellular citrulline level. These changes did not occur in control animals (the same procedure but without footshock or unpaired tone and footshock presentation). The data obtained indicate for the first time that the n. accumbens could be implicated in fear transfer to exploratory behavior and show the involvement of the nitrergic system inhibition in this process. PMID- 23035565 TI - [C57BL/6 mice open field behaviour qualitatively depends on arena size]. AB - Open field behavior is well known to depend on physical characteristics of the apparatus. However many of such effects are poorly described especially with using of modern methods of behavioral registration and analysis. The previous results of experiments on the effect of arena size on behavior are not numerous and contradictory. We compared the behavioral scores of four groups of C57BL/6 mice in round open field arenas of four different sizes (diameter 35, 75, 150 and 220 cm). The behavior was registered and analyzed using Noldus EthoVision, WinTrack and SegmentAnalyzer software. A significant effect of arena size was found. Traveled distance and velocity increased, but not in proportion to increase of arena size. Moreover a significant effect on segment characteristics of the trajectory was revealed. Detailed behavior analysis revealed drastic differences in trajectory structure and number of rears between smaller (35 and 75 cm) and bigger (150 and 220 cm) arenas. We conclude, that the character of exploration in smaller and bigger arenas depends on relative size of central open zone in arena. Apparently its extension increases the motivational heterogeneity of space, that requires another than in smaller arenas, strategy of exploration. PMID- 23035567 TI - [Stress effect on the development of hemorrhagic stroke]. AB - The objective of this work was to study how stress, activity in the open field test, and conformational properties of albumin-binding sites are associated with experimental hemorrhagic stroke in rats. The open-field behavioral pattern in rats was characterized by the previously developed by us activity index. In accordance with this activity index, rats were divided into two groups, i.e., active and passive animals. The animals were subjected to experimental hemorrhagic stroke with or without previous emotional stress. It was shown that the previous stress affected the stroke development. Stress loading before experimental stroke changed albumin conformational properties in rats with active and passive behavioral patterns in different ways. It was associated with different ability of the albumin globule to undergo pH-induced transition N-F and in different accessibility of albumin-bound fluorescent probe CAPIDAN to nitrate induced fluorescence quenching. PMID- 23035566 TI - [Detection of c-fos expression in animal brain in a pilocarpine model of temporal lobe epilepsy]. AB - The dynamics of the involvement of different brain structures in a pathological process is very important for decoding the mechanisms of temporal lobe epilepsy. In this work, the experimental model of temporal lobe epilepsy induced by lithium chloride and pilocarpine was used. The method of immunochemical detection of the immediate early gene c-fos was used as an indicator of functioning neurons in the brain. The c-fos expression was determined at different time points (30, 60 and 90 min) after the pilocarpine injection. An increase in the c-fos expression was observed in neuronal populations during the development of the status epilepticus, the time and degree of involvement of different brain structures being different. The expression of c-fos was first observed in the piriform cortex, the olfactory tubercle, thalamic nuclei, lateral habenular nuclei, and the caudate putamen. Then the hippocampus, the septal formation, the amygdala, and basal ganglia were involved in the activation process. In the hypothalamic areas, c-fos expression was observed latest. These data contribute to understanding the mechanisms of temporal lobe epilepsy and searching for the ways of its therapy. PMID- 23035568 TI - [Coupled biological hydrogen-producing systems: a review]. AB - Possible ways for combining various biological processes of biohydrogen production are described. Some of these processes are being intensively studied now, whereas others are theoretically feasible, but as yet have not been studied. A special focus is on the factors that influence the efficiency of coupled systems. PMID- 23035569 TI - [Isolation and functional characterization of lipase from the thermophilic alkali tolerant bacterium Thermosyntropha lipolytica]. AB - As a result of sequencing the genome of the termophilic alkali-tolerant lipolytic bacterium Thermosyntropha lipolytica, the gene encoding a lipase secreted into the medium was identified. The recombinant enzyme was expressed in Escherichia coli. It was isolated, purified, and functionally characterized. The lipase exhibited hydrolytic activity toward para-nitrophenyl esters of various chain lengths, as well as triglycerides, including vegetable oils. The optimal reaction conditions were achieved at temperatures from 70 to 80 degrees C and pH 8.0. Enzyme saved more than 80% of its activity in the presence of 10% methanol. This new thermostable lipase may be a promising biocatalyst for organic synthesis; it may find application in the food and detergent industry and biodiesel production. PMID- 23035570 TI - [1-butanol synthesis by Escherichia coli cells through butyryl-CoA formation by heterologous enzymes of clostridia and native enzymes of fatty acid beta oxidation]. AB - Anaerobic biosynthesis of 1-butanol from glucose is investigated in recombinant Escherichia coli strains which form butyryl-CoA using the heterologous enzyme complex of clostridia or as a result of a reversal in the action of native enzymes of the fatty acid beta-oxidation pathway. It was revealed that when the basic pathways of acetic and lactic acid formation are inactivated due to deletions in the ackA, pta, poxB, and ldhA genes, the efficiency of butyryl-CoA biosynthesis and its reduced product, i.e., 1-butanol, by two types of recombinant stains is comparable. The limiting factor for 1-butanol production by the obtained strains is the low substrate specificity of the basic CoA-dependent alcohol/aldehyde AdhE dehydrogenase from E. coli to butyryl-CoA. It was concluded that, in order to construct an efficient 1-butanol producer based on a model strain synthesizing butyryl-CoA as a result of a reversal in fatty acid beta oxidation enzymes, it is necessary to provide intensive formation of acetyl-CoA and enhanced activity of alternative alcohol and aldehyde dehydrogenases in the cells of a strain. PMID- 23035571 TI - Putative down-stream signaling molecule of GTPase in Porphyromonas gingivalis. AB - Porphyromonas gingivalis is a strict anaerobic bacterium mainly responsible for periodontal disease in oral cavity. Putative GTPase gene (pgp) of this bacterium was cloned and its recombinant protein (rPGP) was produced in Escherichia coli. Based on the amino acid sequence of SGP that is a GTP-binding protein of Streptococcus mutans, putative GTPase amino acid sequence was deduced in the data base of genome sequences of Porphyromonas gingivalis. A 900-bp PCR fragment was amplified with P. gingivalis genomic DNA as a template and cloned into E. coli JM 109. Then pgp was transferred into pQE-30 expression vector to make pQE-PGP for production of rPGR. This protein was produced and purified by Ni-NTA affinity column chromatography. Anti-PGP antibody was also produced in Sprague Dawley rats. Using Westernblot analysis with this antibody, it was confirmed that the rPGP produced in E. coli was identical to that of donor strain. Furthermore, by Southernblot analysis it was revealed that the pgp was originated from P. gingivalis. By immunoprecipitation with anti-PGP antibody and N-terminal amino acid sequence analysis it was found that PGP was able to bind to acetate kinase, which was reported to be a secondary signaling-molecule in anaerobic microorganisms. Therefore, these results imply that P. gingivalis produces putative GTPase and this protein might play a potential role in signaling pathway in oral biofilm formation. PMID- 23035572 TI - [Role of allelopathic compositions in the regulation and development of legume rhizobial symbiosis]. AB - It was discovered that aromatic compounds isolated from root exudates of three legume species (Pisum sativum L., Vicia faba L. var. major Hartz, and Glycine max L. MERR) and identified as N-phenyl-2-naphthyl amine, dibutyl, and dioctyl esters of orthophthalic acid, which are known to work as negative allelopathic substances, are involved in the regulation of legume-rhizobial symbiosis formation after the inoculation of roots with rhizobia under unfavorable conditions for symbiosis. PMID- 23035573 TI - Biofilm, ice recrystallization inhibition and freeze-thaw protection in an epiphyte community. AB - Microbial communities found on the surface of overwintering plants may be exposed to low temperatures as well as multiple freeze-thaw events. To explore the adaptive mechanisms of these epiphytes, with the objective of identifying products for freeze-protection, enrichment libraries were made from frost-exposed leaves. Of 15 identified bacteria from 60 individual clones, approximately half had ice-association activities, with the great majority showing high freeze-thaw resistance. Isolates with ice nucleation activity and ice recrystallization inhibition activity were recovered. Of the latter, two (Erwinia billingiae J10, and Sphingobacterium kitahiroshimense Y2) showed culture and electron microscopic evidence of motility and/or biofilm production. Mass spectrometric characterization of the E. billingiae extracellular polymeric substance (EPS) identified the major proteins as 35 kDa outer membrane protein A and F, supporting its biofilm character. The addition of the EPS preparation increased the freeze-thaw survival of the more susceptible bacteria 1000-10000 times, and protection was at least partially dependent on the protein component. PMID- 23035574 TI - Microbial activity in the landfill soil. AB - The research objective was to determine the activity of microorganisms in the soil exposed to direct influence of a landfill, as well as in the soil beyond its influence. Fluorescein diacetate (FDA) hydrolytic activity and respiration in the soil were determined. The highest number of cultivated bacteria was recorded at the site located within the zone of direct influence exerted by the landfill, whereas the least amount was found at a distance of 1000 metres from the landfill. In contrast, the largest numbers of molds were observed in the soil at a distance of 1000 m from the headquarters of the landfill. The highest FDA hydrolytic activity and biological oxygen demand (BOD5) were recorded in the soil by the headquarters of the landfill, and the least parameters were revealed at a distance of 1000 m from the landfill. It was found a high correlation between the number of bacteria and FDA hydrolytic activity of soil and BOD5 in the north eastern of the landfill. However, in the same place, there is a low correlation between the number of molds, and FDA hydrolytic activity of soil and BOD5. PMID- 23035575 TI - [Biogas production by microbial communities via decomposition of cellulose and food waste]. AB - Several active microbial communities that form biogas via decomposition of cellulose and domestic food waste were identified among 24 samples isolated from different natural and anthropogenic sources. The methane yield was 90-260 ml CH4/g from microbial communities grown on cellulose substrates, office paper, and cardboard at 37 degrees C without preprocessing. Under mesophilic conditions, bioconversion of paper waste yields biogas with a methane content from 47 to 63%; however, the rate of biogas production was 1.5-2.0 times lower than under thermophilic conditions. When microbial communities were grown on DFW under thermophilic conditions, the most stable and effective of them produced 230-353 ml CH4/g, and the methane content in biogas was 54-58%. These results demonstrated the significance of our studies for the development of a technology for the biotransformation of paper waste into biogas and for the need of selection of microbial communities to improve the efficiency of the process. PMID- 23035576 TI - [Elimination of volatile compounds of leaf tobacco from air emissions using biofiltration]. AB - The composition of the volatile organic compounds (VOCs) of various leaf tobacco brands and their blends has been studied. The differences in the content of nicotine, solanone, tetramethyl hexadecenol, megastigmatrienones, and other compounds, determining the specific tobacco smell, have been revealed. A microbial consortium, which is able to deodorize simulated tobacco emissions and decompose nicotine, has been formed by long-term adaptation to the VOCs of tobacco leaves in a laboratory reactor, functioning as a trickle-bed biofilter. Such a biofilter eliminates 90% of the basic toxic compound (nicotine) and odor active compounds; the filtration efficiency does not change for tobacco brands with different VOC concentrations or in the presence of foreign substances. The main strains, isolated from the formed consortium and participating in the nicotine decomposition process, belong to the genera Pseudomonas, Bacillus, and Rhodococcus. An examination of the biofilter trickling fluid has shown full decomposition of nicotine and odor-active VOCs. The compounds, revealed in the trickling fluid, did not have any odor and were nontoxic. The obtained results make it possible to conduct scaling of the biofiltration process to eliminate odor from air emissions in the tobacco industry. PMID- 23035577 TI - [EDTA degradation by cells of Chelativorans oligotrophicus immobilized on a biofilter]. AB - A biofilter based on light expanded clay aggregate (LECA) and cells of the obligate ethylenediamine tetraacetate (EDTA) destructor Chelativorans oligotrophicus LPM-4 has been developed. The culture steadily maintained a high level of EDTA monooxygenase activity of 180-200 nmol/min/mg of protein during three months. EDTA was converted completely or by 80% at initial concentrations of 0.5-0.7 or 2.0 g/l, respectively, in a 2-dm2 biofilter at a flow rate of 20 ml/h. PMID- 23035578 TI - [Extracellular beta-D-glucosidase of the Penicillium canescens marine fungus]. AB - Extracellular beta-D-glucosidase was isolated in a homogeneous state from the Penicillium canescens marine fungus. According to SDS-electrophoresis, the molecular weight of the enzyme was 64 kDa and the maximal activity was observed at pH 5.2 and 70 degrees C. Glucosidase catalyzed the hydrolysis of beta glycosidic bonds both in glycosides and in glucose disaccharides and had transglycosylation activity. The enzyme can be used for the deglycosylation of natural glycosides and in enzymatic synthesis of new carbon-containing compounds. PMID- 23035579 TI - Fusant Trichoderma HF9 with enhanced extracellular chitinase and protein content. AB - Strain improvement was carried out to obtain higher chitinase and protein by inter-specific protoplast fusion between Trichoderma harzianum and Trichoderma viride. Fusant HF9 and parental strains of Trichoderma were compared for chitinase and protein production. 1% of glucose, sucrose and fungal cell wall (Rhizoctonia solani), were used as carbon source for cultivation of Trichoderma and fungal cell wall was the best to induce chitinase and protein. Usage of 0.5% colloidal chitin for the fungal growth under aerated conditions at pH 6.5 and 28 degrees C led to higher chitinase and protein production. In these conditions fusant Trichoderma HF9 in comparison with parent strains had 3-, 2.5- and 1.5 fold increase of total chitinase, specific chitinase and protein, respectively. SDS-PAGE analysis revealed that it had 9 major protein bands with up-regulation compared to parent strains. Amino acid analysis showed that protein of culture filtrate of T. harzianum, T. viride and fusant Trichoderma HF9 had 8, 6 and 10 amino acids, respectively. The results obtained suggested that fusant HF9 could be an integration of T. harzianum and T. viride through protoplast fusion. PMID- 23035580 TI - [Purification of the chimeric protein Alburon16 from a culture medium of the yeast Pichia pastoris]. AB - Conditions have been created for the isolation of the chimeric protein Alburonl6 (human albumin-interferon-alpha 16) from a culture medium of the yeast Pichia pastoris, under which there is no aggregation of the protein and its biological activity is maintained. The proposed scheme can be used for the isolation and purification of a chimeric protein in laboratory conditions. The obtained results may be useful for improving the purification methods of various recombinant proteins synthesized and secreted by the yeast P. pastoris. PMID- 23035581 TI - [Changes in phenolic acids during maturation and lignification of Scots pine xylem]. AB - The content and fractional composition of alcohol soluble phenolic acids (PhA) in cells with different degree maturation and lignification in the course of early and late timber formation in the pine (Pinus sylvestris) during vegetation were studied. Phenolic compounds (PhC), extracted by 80% ethanol, were divided into free and bound fractions of PhA. In turn, the esters and ethers were isolated from bound PhA. The contents of all substances were calculated per dry weight and per cell. Considerable differences have been found to exist in both the contents and the composition of the fractions PhA on successive stages oftracheid maturation of early and late xylem. Early timber tracheids at all secondary wall thickening steps contained PhC less and free PhA more than late timber tracheids. Throughout early timber tracheid maturation, the pool of free PhA per cell declined at the beginning oflignification and then increased gradually while that of bound PhA decreased. The maturation of late timber trecheids were accompanied by the rise of free PhA pool and the diminution of bound PhA pool. In the composition of bound PhA, the ethers were always dominant, and the amount of that in early timber cells was less than in late timber cells. The cells of early xylem at all steps of maturation contained more of ester. The sum total of free hydroxycinnamic acids, precursors of monolignols, gradually decreased during early xylem lignification as the result of the reduction of the pools of p coumaric, caffeic, ferulic and synapic acids, while that of their ester rised. In the course of late xylem lignification, the pools of free p-coumaric, ferulic and, especially, synapic acids increased. Simultaneously, the amount of ferulic acid ester and synapic acid ether increased too. According to the data, lignin biosynthesis in early xylem and late xylem occurs with different dynamics and the structure of lignins of two xylem types might be different too. PMID- 23035582 TI - [Induction of cytomixis affects microsporogenesis in Sesamum indicum L. (Pedaliaceae)]. AB - Cytomixis was recorded during microsporogenesis in sesame (Sesamum indicum L.), a member of the family Pedaliaceae. The phenomenon of cytomixis was observed at various stages of meiosis in 0.5% Sodium azide (SA) treated populations of Sesamum indicum L. Cytomixis was observed to occur through various methods, i.e., by forming cytoplasmic channels and direct fusion of pollen mother cells (PMCs), the former was more frequent than the latter. The migration of nuclear content involved all the chromatin/chromosomes or part of it from donor to recipient cell/cells. Some completely empty meiocytes were also observed. Stickiness, precocious movement, laggards, unorientation and micronuclei were observed in almost all the sets treated with various doses of SA. Increase in the doses of SA had a positive effect on the percentage of PMCs showing cytomixis and chromosomal abnormalities. The impact ofcytomixis on meiotic behaviour, reduced pollen viability and heterogeneous sized pollen grains were observed. PMID- 23035583 TI - [Antiproliferative and cytotoxic effects of different type cytostatics on mouse pluripotent stem and teratocarcinoma cells]. AB - Pluripotent stem cells are able to proliferate indefinitely and differentiate in vitro into various cell types. However, in most cases in vitro differentiation of the pluripotent stem cells is asynchronous and incomplete, and the residual undifferentiated cells can initiate teratoma development after transplantation into recipients. These features of the pluripotent stem cells are the major issue for development of safe cell therapy technologies based on pluripotent stem cells. Considering significant resemblance of growth rates of pluripotent stem and cancer cells we investigated antiproliferative and cytotoxic effects of different type cytostatics (mitomycin C, etoposide, vinblastine and cycloheximide) on the undifferentiated and differentiating mouse embryonic stem cells, embryonic germ cells, blastocyst and on mouse embryonal teratocarcinoma cells and mouse embryonic fibroblasts. The findings showed that all cytostatics used induced both antiproliferative effects and acute toxic processes in undifferentiated pluripotent stem cells and embryonal teratocarcinoma cells whereas these effects were less in differentiating embryonic stem cells and embryonic fibroblast. Moreover, the trophoblast cells of mouse blastocysts were less sensitive to damaging effects of cytostatics than inner cell mass cells. The examination of deferred effects ofcytostatics revealed that the effects ofmitomycin C, etoposide and vinblastine, but not cycloheximide, were irreversible because survived cells were not able to proliferate. Nevertheless, the numbers of embryonic fibroblasts exposed to etoposide or vinblastine remained unchanged while vast majority of undifferentiated pluripotent cells treated underwent apoptosis. Thus, diverse effects of etoposide and vinblastine on the undifferentiated pluripotent stem cells and differentiated embryonic cells allow us to consider these cytostatics and their analogs as drug-candidates for selective elimination of the residual undifferentiated pluripotent stem cells from population of differentiating cells. These findings demonstrate for the first time the possibility of selective elimination of undifferentiated pluripotent stem cells using cytostatic drugs approved for clinic practice. However, to improve effectiveness and safety of this approach and to prevent mutagenic, carcinogenic and teratogenic effects on undifferentiated pluripotent stem cells and their differentiated cell derivatives large-scale studies ofcytostatic effects using different experimental design and active doses must be performed. PMID- 23035584 TI - [Influence of activator and inhibitors of Ca2+ channels on proliferative activity in Tetrahymena pyriformis infusoria]. AB - It was determined that change in DNA content in macronuclei occurs in the T. pyriformis infusoria under the influence of an activator (caffeine) and inhibitors of Ca2+ channels (verapamil), NiCl2, and CdCl2. Caffeine (10 mM) stimulates DNA synthesis. Verapamil (5 microM), CdCl2 (125 microM), and NiCl2 (100 microM) decrease DNA content in macronuclei by 30 min after proliferative stimulation. By 4 h of incubation, there is, on average, 10% less DNA in macronuclei of Tetrahymena preprocessed with verapamil than in the control cells. The cells preprocessed with CdCl2 and NiCl2 differ from the control cells by lower DNA content almost at all studied periods, but they restore the level of nuclear DNA by 4 h. It is assumed that transmission of proliferative signals in the T. pyriformis has a Ca2+ -dependent character. PMID- 23035585 TI - [Age changes in the sexual size dimorphism in sables in nature and captivity]. AB - Inter-sexual differences in craniometric parameters were studied in sables of varying sex and age in natural (n = 2338) and farm (n = 516) populations. In nature, the differences between the skull size in males and females are, as a rule, high (p < 0.001) and the size dynamics correlate well with age. In the cell population, the difference in the skull size between the sexes is statistically significant (p < 0.01), but the correlation of sizes with age is absent. In natural populations, parameters of sexual dimorphism (SD) correlate positively with age, with a maximum correlation found in the animals aged nine and a minimum found in yearlings. The index of sexual dimorphism grows considerably until three years of age, after which the dynamics resemble a cyclical process with a repetition of maximum values each fourth year with a general trend of growth in the parameter. The highest values of SD in cell sables are registered at 3-5 years of age, while the minimum ones are noted in the age groups of 6-9 and 13-14 years of age. In nature, yearlings aged 6-10 months are characterized by a tendency to general growth (which is not manifested in the introduced population from the basin of the Vakh River) and increase in the SD index with age. The Vakh population is characterized by a decrease in the SD index. The specific rate of skull growth in males is 1.8-fold higher than in females. The age dynamics of the sizes and the vectors of rates between the sexes are not in accordance, as a rule. The results of our study correspond to the theory by Geodakyan (1991) about dichronomorphism. In our opinion, the differences in age manifestations of sexual dimorphism and postnatal skull growth in natural and farm sable populations are determined by the different directions of selection. PMID- 23035586 TI - [Early embryonic mortality in water vole (Arvicola terrestris L.)]. AB - A morphological study of forty-eight 3-4-day embryos from eight females of the water vole (Arvicola terrestris L.) was conducted. The data obtained demonstrated that early embryonic losses in the water vole can be 30-35%, and the main cause of these losses is anomalies of oogenesis. PMID- 23035587 TI - Inhaled chemotherapy in lung cancer: safety concerns of nanocomplexes delivered. PMID- 23035588 TI - Potential of drug-loaded nanoparticles for Alzheimer's disease: diagnosis, prevention and treatment. PMID- 23035589 TI - Encapsulated cell systems: the future of insulin delivery? PMID- 23035590 TI - Delivery of custom-purposed colloidal nanocrystals to cancer cells. AB - Colloidal inorganic nanocrystals are abound with magnetic, luminescent and plasmonic properties that are attractive for medical diagnostics and therapy. Our group, among others, have been interested in conferring nanocrystals, by design, with new capabilities that are not possible with conventional materials approaches. Two areas where the fruits of these efforts are paying dividends are in their implementation as in vivo imaging probes and as biosensors that dynamically respond to the local chemical or physical environment in cells and tissues. For applications in medical imaging, nanocrystal probes with unusual shapes are showing exceptional promise over existing technologies, while for environment-responsive probes, a hybrid approach involving tailored organic coatings is being implemented alongside the nanocrystals for the realization of dynamic, information-rich optical outputs. PMID- 23035591 TI - Predicting feasibility and characterizing performance of extended-release formulations using physiologically based pharmacokinetic modeling. AB - This review presents nine case studies where physiologically based pharmacokinetic modeling has been used in the design and development of extended release formulations. While the approaches for creating the models were similar, in each case a product-development or drug-delivery problem unique to each compound was solved so that the drug-release rate could be optimized to achieve the best clinical performance. Examples presented include understanding the relationship between colonic absorption and efflux, effect of drug release and gastric emptying on maximum achieved drug concentration in plasma and area under the plasma concentration-time curve for a Biopharmaceutics Classification System class 3 compound, feasibility of an extended-release product for a prodrug, feasibility of an extended-release product for a biopharmaceutics classification system class 4 compound and predicting the pharmacokinetics in humans based on a primate model and coupling the physiologically-based pharmacokinetic model with a pharmacodynamic model so that the clinical efficacy of the formulations could be predicted based on the simulated plasma concentrations. The use of physiologically based pharmacokinetic models in the development of extended release formulations is rapidly becoming an acceptable part of the knowledge management and design space components of a quality by design approach to product development. As the use of these in silico tools increase and examples become available through scientific presentations and literature, the inclusion of this approach will become a necessary part of the development process rather than the exception. PMID- 23035592 TI - RNAi-based therapies for Huntington's disease: delivery challenges and opportunities. AB - Huntington's disease (HD) is a polyglutamine neurodegenerative disease caused by a mutation in the HTT gene coding for the Huntingtin protein (HTT). Unfortunately, there is no cure for HD and there is also no known way to modify the disease progression. RNAi approaches offer the promise of a certain degree of control over the disease. However, there are several challenges in potential use of RNAi in the treatment of HD. This article will discuss the details of RNAi technology as applied to the treatment of HD, and novel approaches to overcome the drug delivery challenges. PMID- 23035593 TI - Functional RNA delivery targeted to dendritic cells by synthetic nanoparticles. AB - Dendritic cells (DCs) are essential to many aspects of immune defense development and regulation. They provide important targets for prophylactic and therapeutic delivery. While protein delivery has had considerable success, RNA delivery is still expanding. Delivering RNA molecules for RNAi has shown particular success and there are reports on successful delivery of mRNA. Central, therein, is the application of cationic entities. Following endocytosis of the delivery vehicle for the RNA, cationic entities should promote vesicular membrane perturbation, facilitating cytosolic release. The present review explains the diversity of DC function in immune response development and control. Promotion of delivered RNA cytosolic release is discussed, relating to immunoprophylactic and therapeutic potential, and DC endocytic machinery is reviewed, showing how DC endocytic pathways influence the handling of internalized material. The potential advantages for application of replicating RNA are presented and discussed, in consideration of their value and development in the near future. PMID- 23035594 TI - Systemic delivery of antihypertensive drugs via skin. AB - Hypertension is a chronic disease with one of the highest chances of causing death, and long-term treatment is required. The antihypertensive drugs used in the treatment are generally administered orally. The limitations of the oral route make transdermal delivery of drugs more attractive. The transdermal route offers numerous advantages including avoidance of systemic first-pass metabolism and high patient compliance. The transdermal therapeutic systems, popularly known as 'patches', deliver drugs across the skin with a constant release rate. However, skin is a unique membrane having excellent barrier properties. Either chemical enhancers or physical methods such as iontophoresis and electroporation have been used to provide effective plasma drug concentrations. This review article focuses on the approaches to enhance skin permeability of antihypertensive drugs for the optimization of transdermal therapeutic systems of these drugs and the research studies intended for the optimization of transdermal dosage forms of antihypertensive drugs are summarized. PMID- 23035595 TI - Emerging nanodelivery strategies of RNAi molecules for colon cancer therapy: preclinical developments. AB - Although local colonic delivery is achievable through several strategies, colon cancer is still considered one of the leading causes of death worldwide. Failure of chemotherapeutics to exhibit efficient anticancer activity might be attributed to the development of multidrug resistance (MDR) mechanisms including the overexpression of certain oncogenes such as MDRI/P-gp. One of the major reasons for the shortcoming of P-gp inhibitors in clinic is the nonspecific distribution of them to nontarget organs, which leads to reduced elimination and increased toxicity of its substrates including anticancer agents. Numerous studies have demonstrated the effectiveness ofgene-silencing approaches in reversing the P-gp mediated MDR. However, none have reached clinical trials yet. Several drug delivery systems have been investigated primarily to address P-gp and the observed improved anticancer efficacy suggests that nanomedicine provides new opportunities to overcome MDR in cancer. In this review, novel therapeutic strategies for colon cancer therapy will be discussed in the context of P-gp inhibition by low-molecular-weight agents and RNAi molecules. PMID- 23035596 TI - [Carbonology: pharmacochemical aspect and research prospects]. AB - The paper is devoted to the new direction of science - carbonology. Carbon is the base of organic compounds. Compounds of carbon with metals are known. The article gives a brief description of the three allotropic forms of carbon (soot, graphite, diamond), and various types of hybridization in organic structures, describes the role of biogenic carbon. At the end of the twentieth century new carbon nanostructures were discovered: fullerenes and carbon nanotubes. Scientists all over the world study physical, chemical, pharmacological and toxicological properties of the allotropes of carbon structures, which are promising for nanochemistry, nanopharmacology and nanotoxicology. The main characteristics of fullerenes are the high electrical conductivity, antiviral, antioxidant properties and possible use for targeted drug delivery. Carbon nanotubes have strong adsorption properties, high electrical conductivity, strength, are used for targeted drug delivery and the production of biosensors. In order to introduce carbon nanoparticles in the practical medicine it is necessary to intensify research to biosafety. PMID- 23035597 TI - [The preparation of pediatrics physicians in different countries of the world]. AB - The authors carried out the analysis of training system of doctors - pediatrists in the different countries of Europe and USA. It is shown, that there exist three models of the organization of rendering of medical care to the children: pediatric model (the doctor - pediatrist as a primary part of rendering of medical care of children), system of the general practice (the doctor - pediatrist carries out functions of the adviser) and the combined system which is based on the listed above models. Pointed that the system of the general practice is inherent in the countries with a high level of incomes on one inhabitant of the country. PMID- 23035598 TI - [The revised Gell and Coombs classification: a new reading of old truths in the context of immunodeficiencies theory]. AB - The publication covers the world-known Gell and Coombs classification of immunopathological reactions, last revised, in the context of immunodeficiencies theory. A great attention is paid to the description of protective immune reactions, allergic and autoimmune complications, being developed according to one or another mechanism, defined in the classification. The strong and weak points of the classification were marked and the promising trends to carry out further scientific enquiry were emphasized. Primary immunodeficiencies were considered in detail as natural models of immunopathological complications. The problems of immunodiagnosis and immunotherapy were discussed. PMID- 23035599 TI - [Obstructive sleep apnea: connection with cardiovascular diseases and basic methods of diagnostics]. AB - These literatures are analyses about reasons, pathogenesis, and clinical displays obstructive sleep apnea. Mechanisms over of connection are brought sleep obstructive apnea with development of hypertensive, of cardiac arrhythmias, development of metabolic syndrome, obesity, to pulmonary hypertension, write ventricular insufficiency. PMID- 23035600 TI - [Diagnostics, prognosis factors, and treatment of malignant lymphoproliferative disease, Hodgkin Disease]. AB - Data are presented about modern histomorphological, cytological, radiological methods of diagnostics of malignant lymphoproliferative diseases (illness of Hodgkin). Principles and methods of treatment are presented are charts of polychimiotherapy their quality and amount, sequence of realization of radial therapy. Onkomarker being most perspective and studied presently is described, factors of prognosis at non-Hodgkin's malignant lymphadenomas, illness of Hodgkin, - galectin-1, galectin-3. PMID- 23035601 TI - [Effect of combined treatment with dopamine receptor agonists and antagonists of aldosterone on the performance of daily blood pressure monitoring in patients with hypertension and concomitant obesity]. AB - In hypertensive patients with concomitant obesity observed decrease in activity of dopaminergic system in conjunction with increased activity of the renin angiotensin-aldosterone system. Identified changes point to the advisability of appointing this group of patients the dopamine receptor agonist - bromocriptine KV and antagonist of aldosterone - veroshpiron. As a result of treatment was an increase in dopamine levels in the urine, a decrease of aldosterone in the blood, normalization of the daily blood pressure monitoring. PMID- 23035602 TI - [Angiographic evaluation of coronary vessels in patients with diabetes mellitus type 2 and myocardial infarction]. AB - High risk of vascular complications in diabetes foundation gave the American Heart Association ranked diabetes to diseases of the cardiovascular system. More than 60% of patients with type 2 diabetes life expectancy will be reduced by the development of their coronary artery disease, diabetes was an independent factor that increases the risk of myocardial infarction (2-3 times), stroke (more than 2 times) independently of other known risk factors for cardiovascular disease, and acute coronary events are characterized by the extremely serious nature against the background of pronounced coronary atherosclerosis. In the present study, a comparative assessment of the frequency of coronary vessels of different severity in patients with myocardial infarction in the presence of diabetes and without. Status of the coronary vessels were studied by means of selective coronary angiography. The study found that in patients with myocardial infarction in combination with type 2 diabetes is much more frequent multivessel disease and coronary delay the passage of contrast material than patients with MI without diabetes. These features and characteristics of coronary lesions in patients with diabetes and myocardial infarction may explain why more severe myocardial infarction with frequent development of coronary events in these patients. After analyzing the data obtained, it can be assumed relationship progression of vascular lesions with concomitant coronary glycemic decompensation. PMID- 23035603 TI - [The new algorithm for disease management of patients with epilepsy based on genetic research]. AB - We have developed and proposed a new algorithm for treating patients with epilepsy, which takes into account the genetic criteria for the effectiveness of AEDs and provides an opportunity to significantly reduce the time drug-resistance definition, which in turn reduces the time progression epileptohenesis. Therefore, the use of alternative treatments for epilepsy, it is possible before the occurrence of irreversible changes in the patient's central nervous system. Therefore, treatment for this algorithm accelerates the choice of adequate treatment tactics in a particular patient, which promotes safety in society as active and healthy citizens. PMID- 23035604 TI - [Effect of atoxil and triglobulin on cytokine balance and level of C-reactive protein upon treatment of children with serious forms of bacterial infections]. AB - 81 children with severe forms of the bacterial anginas passing on endotoxinemia of intestinal origin were examined. Use of preparations atoxil and triglobulin in a complex therapy was accompanied by normalization of cytokine activity and level of C-reactive protein on the background of reduction of concentration endotoxin in blood serum. PMID- 23035605 TI - [Correction of altered serotonin exchange in adolescents with functional disorders of digestive system]. AB - With the purpose of search the ways of improvement treatment of functional pathologies of the system of digestion an author is studied the concentration and the role of serotonin in 180 adolescents. Got results of serotonin receptors 5HT1 agonists were used for patients with paroxysms of abdominal pain mainly at neurocirculatory disfunction and migraine. PMID- 23035606 TI - [The pneumoperitoneum course forecasting and surgery tactic in the group of patients with acute and chronic cholecystitis and concomitant pathology of cardiovascular system]. AB - The share of elderly and senile patients with acute cholecystitis concomitant cardiovascular pathology whom the laparoscopic cholecystectomy has been provided is increased. The heightened intraabdominal pressure has negative influence at the cardiovascular system, so the alternative ways for treatment of this group of patients are used in clinic. We propose the pneumoperitoneum model using the pneumatic belt which is fixed at the abdomen in preoperative period in patients with an acute and chronic cholecystitis. This model is useful to forecast cardiovascular disorders during future laparoscopic cholecystectomy. The arterial pressure level, pulse score and ECG are monitored during the test (90 min). Myocardial ischemia appearance seems that the risk of laparoscopic cholecystectomy with pneumoperitoneum is high. The alternative method of surgery in such group of patients (no pneumoperitoneum is applied) is laparoscopic assisted cholecystectomya from miniaccess. This method allows to reducing frequency of intra- and postoperative complications connected with pneumoperitoneum negative influence at the patients with concomitant pathology of cardiovascular system. PMID- 23035607 TI - [Physical development and anthropometric parameters of Kharkiv adolescents]. AB - To improve the quality of evaluation of abnormal anthropological status through a detailed analysis of physical development and setting standards for the Slavic population of the region's children conducted population-based study involving 582 school children using cluster sampling method for selecting a level of accuracy of 95 %. Through the detailed anthropometry it was revealed that physical development of Kharkov region adolescents mainly harmonious and corresponds to median values for the WHO charts. Percentage of accelerated adolescents significantly greater than delayed ones. Prevalence of overweight and obesity it's about (15,00 +/- 2,96) % of the total population. Differences in the body composition are recorded reliably after 14 years. Weight gain in boys develops mainly stepwise at the expense of muscle mass with a physiological abdominal fat tissue predisposition, and in the girls both from muscle and fat mass with the advantage of fat with its gynoid predisposition. According to our data, waist to hip ratio reflects gender dependence of the fat predisposition and the waist to height ratio the abdominal one. The results can be used as a preliminary standard for further studies. PMID- 23035608 TI - [Influence of immunotropic preparation cycloferon and phytopreparations of Cynara scolimus L. on blood cytokines profile of the patients with chronic viral hepatitis C in medical rehabilitation period]. AB - The effect of the immunotropic drug cycloferon and herbal medicine resources on the basis of Cynara scolimus L. on the blood cytokine profile in the patients with chronic viral hepatitis C (CVHC) in medical rehabilitation (MR) period. Established that prior to MR period in the patients with CVHC was noted significantly increased levels of proinflammatory cytokines (CK) at the blood serum, and the level of antiinflammatory CK changed significantly. The use of cycloferon and herbal medicine resources on the basis of Cynara scolimus L. in the MR complex provided to normalize the studied CK concentration in the serum of the patients with CVHC. PMID- 23035609 TI - [Differential approach to the diagnosis of acute appendicitis and acute gynecological pathology in pregnant women]. AB - This article discusses the differential diagnosis of acute appendicitis and acute gynecological pathology in different terms of the gestation. PMID- 23035610 TI - [Lymphangioleiomyomatosis of lungs and spontaneous pneumochylothorax]. AB - Lymphangioleiomyomatosis occupies a special place among rare systemic diseases of lungs, which are manifested by respiratory failure and the gradual development of pulmonary heart. Manifestations of the pleural cavity in the form of pneumothorax and pleural effusion syndrome are characteristic for the disease. In order to verify the process, the authors recommend a study of pleural punctate with Sudan III for detection of lymph and a CT-scanning after removal of the contents of the pleural cavity. "Cell" pattern of lungs in combination with chylothorax confirm the diagnosis of lymphangioleiomyomatosis. In particularly complex cases, in their opinion, the lung and pleura biopsy is required. PMID- 23035611 TI - [Effect of Korargin on reactivity of isolation aorta of adult and old irradiated rats]. AB - Introduction to the diet of adult (7-8 months) and old (24-26 months) male rats for 30 days after a single R-irradiation at a dose of 5 Gy of preparation "Korargin" (whose active ingredients are L-arginine, contributing to the prevention of endothelial dysfunction, and inosine) in old irradiated rats significantly increased the relaxation of isolated segments of thoracic aorta by the action of acetylcholine, sodium nitroprusside and insulin. In adults irradiated animals this effect was not observed. Vasoconstriction response of isolated segments of thoracic aorta to norepinephrine was decreased in isolated segments of thoracic aorta by adults and old irradiated rats compared with controls, and application of korargin had no significant effect. Thus, in old irradiated rats, in contrast to adult irradiated animals, the use of korargin increased of vascular sensitiveness to act of endothelial-dependent and endothelial-nondependent vazodilatators, helped to preserve of endothelial function and increase the capacity of vazodilatator potential. PMID- 23035613 TI - [The mobile medical clinic: a role of mobile physician crews in the provision of health care for rural populations]. AB - Medical mobile clinics (MMK) have several advantages: autonomous functioning, rapid reacting, mobility and universality, availability and also possibility of providing of medicare even in the most difficult of access and remote districts. For 2 the movable medical brigade of MMK is do more than 30 departures in 25 districts of six areas of Ukraine (Chernovithky, Nicolajevsky, Zhitomirsky and other regions), more than 6000 ultrasonic studies are undertaken, is carried out on nosologies with providing of consultative help narrow specialists. High efficiency of echography is confirmed as the first instrumental method of research at the inspection of wide layers of villagers resident in remote settlements. For a population development of pharm services appeared a comfortable help in the points of work of departure brigade of medicare, and also programs of humanitarian help. PMID- 23035612 TI - [Spermatogenic function under the influence of heavy metal salts and its correction by preparation Tivortin]. AB - Entrance of threshold concentrations of copper, zinc, iron, manganese, lead, chromium into the body of sexually mature male rats leads to secretory malfunction of the testicles, which manifests by a decrease of sperm concentration in the ejaculate, a decrease of percentage of motile gametes, an increase in the proportion of morphologically abnormal sperm forms. The evidence of disorders in spermatogram's parameters is directly depends on the duration of the influence of combination of heavy metal salts. The application of the drug Tivortin against intoxication of heavy metal salts decrease the adverse movement of quantitative and qualitative parameters of rat's spermatogramms, so far as Tivortin improves blood circulation, stimulates cell proliferation and cell differentiation, inhibits oxidative apoptosis. These explain beneficial effects of the drug on the growth and maturation of germ cells in case of the influence heavy metal salts combination on organ and the whole body. PMID- 23035614 TI - [Structure of leucosis prevalence in the Republic of Karakalpakstan]. AB - The WHO recommends performance of the evaluation of the measurement of prevalence of the main forms of leucosis in the region as the primary step of the development of the National Program of the struggle with leukemia. During the period from 2000 to 2010 in the Republic of Karakalpakstan there were registered 252 cases (3,9 %) cases of leucosis. Of them 141 (49,5 %) were males, and 111 (38,9 %) - females at the age from 15 to 70 years. In the structure of leucosis prevalence in the population of the Republic of Karakalpakstan there were prevailed chronic myeloleucosis (CML) (31,9 %) and acute lymphoblast leucosis (ALL) (22,5 %). The men (mean age - 35,80 years +/- 1,34 years) were ill more frequent, on the average, 1,3 times than women (mean age - 40,00 years +/- 1,45 years). Chronic lympholeucosis (CLL) and acute lymphoblast leucosis (ALL) is diagnosed predominantly among rural inhabitants, while AML and CML (24,2 %) are rather registered among the urban inhabitants. In the Republic of Karakalpakstan the chance of development of ALL (30,2 % SD 2,33 {95 % DI 1,18-4,58}; P = 0,02) and AML (21,9 % SD 7,47 {95 % DI 2,23-25,0}; P = 0,0004) in the young age was 2 and 6,1 times higher, respectively, than in the adult age, but the content of CML increased 2,3 times. PMID- 23035615 TI - [Health conditions and physical development of soldiers during enrollment in the Armed Forces of Ukraine and military service in 2001-2010]. AB - Fitness of soldiers in military reserve for military service at the stage in the Armed Forces of Ukraine has been studied in the article. It has been established that the growing number of soldiers in military reserve with changes in health and physical condition indicates insufficient level of their health which has a negative impact on their capability and gradually on their fitness for military service. Priorities of changes in organization of the process of completion by human resources of the soldiers' military reserve in the Armed Forces of Ukraine during their transition towards professional army have been defined, to include optimization of criteria of fitness for military service. PMID- 23035616 TI - [Medicine in symbols and emblems]. AB - Medical emblems and symbols of medicine are considered in a lecture. PMID- 23035617 TI - First online measurements of sulfuric acid gas in modern heavy-duty diesel engine exhaust: implications for nanoparticle formation. AB - To mitigate the diesel particle pollution problem, diesel vehicles are fitted with modern exhaust after-treatment systems (ATS), which efficiently remove engine-generated primary particles (soot and ash) and gaseous hydrocarbons. Unfortunately, ATS can promote formation of low-vapor-pressure gases, which may undergo nucleation and condensation leading to formation of nucleation particles (NUP). The chemical nature and formation mechanism of these particles are only poorly explored. Using a novel mass spectrometric method, online measurements of low-vapor-pressure gases were performed for exhaust of a modern heavy-duty diesel engine operated with modern ATS and combusting low and ultralow sulfur fuels and also biofuel. It was observed that the gaseous sulfuric acid (GSA) concentration varied strongly, although engine operation was stable. However, the exhaust GSA was observed to be affected by fuel sulfur level, exhaust after treatment, and driving conditions. Significant GSA concentrations were measured also when biofuel was used, indicating that GSA can be originated also from lubricant oil sulfur. Furthermore, accompanying NUP measurements and NUP model simulations were performed. We found that the exhaust GSA promotes NUP formation, but also organic (acidic) precursor gases can have a role. The model results indicate that that the measured GSA concentration alone is not high enough to grow the particles to the detected sizes. PMID- 23035618 TI - High-performance solution-processed solar cells and ambipolar behavior in organic field-effect transistors with thienyl-BODIPY scaffoldings. AB - Green-absorbing dipyrromethene dyes engineered from bis-vinyl-thienyl modules are planar molecules, exhibiting strong absorption in the 713-724 nm range and displaying comparable electron and hole mobilities in thin films (maximum value 1 * 10(-3) cm(2)/(V.s)). Bulk heterojunction solar cells assembled with these dyes and a fullerene derivative (PC(61)BM) at a low ratio give a power conversion efficiency as high as 4.7%, with short-circuit current values of 14.2 mA/cm(2), open-circuit voltage of 0.7 V, and a broad external quantum efficiency ranging from 350 to 920 nm with a maximum value of 60%. PMID- 23035619 TI - Red cell distribution width predicts new-onset atrial fibrillation after coronary artery bypass grafting. AB - INTRODUCTION: Red cell distribution width (RDW) has been associated with poor outcomes in patients with cardiovascular diseases. However, little is known about the role of RDW in prediction of new-onset atrial fibrillation (AF) after coronary artery bypass grafting (CABG). We aimed to investigate the relation between the RDW and postoperative AF in patients undergoing CABG. METHODS: A total of 132 patients undergoing nonemergency CABG were included in the study. Patients with previous atrial arrhythmia or requiring concomitant valve surgery were excluded. We retrospectively analyzed 132 consecutive patients (mean age, 60.55 +/- 9.5 years; 99 male and 33 female). The RDW level was determined preoperatively and on postoperative Day 1. RESULTS: Preoperative RDW levels were significantly higher in patients who developed AF than in those who did not (13.9 +/- 1.4 vs. 13.3 +/- 1.2, p = 0.03). There was not any correlation between postoperative RDW levels and AF. Using a cutpoint of 13.45, the preoperative level correlated with the incidence of AF with a sensitivity of 61% and specificity of 60%. CONCLUSION: Preoperative RDW level predicts new-onset AF after CABG in patients without histories of AF. PMID- 23035620 TI - RE: "Mn-porphyrins as novel molecular MRI contrast agents" by Mouraviev et al. AB - The article entitled, "Mn-porphyrins as novel molecular MRI contrast agents" by Mouraviev et al., published online ahead of print on November 3, 2011 (DOI: 10.1089/end.2011.0133), in its unedited, uncorrected format, is being officially withdrawn from Journal of Endourology. This early version of the manuscript was not in its final form. A further revision has since submitted for re-review and has been accepted for publication. It is currently published in its Instant Online format (the raw, unedited manuscript) and carries a DOI of 10.1089/end.2012.0171. It will be included in the November 2012 issue of Journal of Endourology. PMID- 23035623 TI - Acute urinary retention increases the risk of complications after transurethral resection of the prostate: a population-based study. AB - Study Type--Prognosis (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Higher mortality and morbidity rates in men presenting with AUR have been reported in previous studies. This study has comprehensive comparisons of post-TURP complications between patients with and without AUR. Furthermore, it shows that AUR is associated with increased risk of complications after TURP. OBJECTIVE: * To assess the association between a history of acute urinary retention (AUR) and complications after transurethral resection of prostate (TURP). PATIENTS AND METHODS: * We conducted a retrospective, national, population-based study using Taiwan's National Health Insurance Research Database. * We included men > 50 years old, diagnosed with benign prostatic hyperplasia (BPH) and divided these into two groups: an AUR(+) group--those with AUR who underwent TURP between 2002 and 2004; and an AUR(-) group--those without AUR who underwent TURP between those dates. * Prostate cancer, Parkinsonism and multiple sclerosis were exclusion criteria. * Postoperative complications, e.g. re-catheterization, haematuria or urinary tract infection (UTI), were compared using crude odds ratios (ORs), 95% confidence intervals (CIs), and Student's t-test. * A chi-squared test was used for potential confounding factors: preoperative UTI and anticoagulant use. * Univariate and multivariate analysis on medical expenses were conducted. RESULTS: * The AUR(+) group contained 3305 men; the AUR(-) group contained 1062. * Re catheterization (13.8%), septicaemia (1.1%) and shock (0.3%) were found only in the AUR(+) group. * The AUR(+) group had more UTIs (18.9% vs. 15.6%, OR: 1.26, 95% CI: 1.05-1.52), more lower urinary tract symptoms (22.8% vs. 16.9%, OR: 1.45, 95% CI: 1.21-1.73), fewer blood transfusions (3.2% vs. 1.5%, OR: 2.19, 95% CI: 1.29-3.72) and higher medical expenses. * There were no significant differences in haematuria, lower urinary tract stricture, or re-surgical intervention of the prostate and second-line antibiotic use. CONCLUSION: * Patients in Taiwan with BPH with AUR who were treated by TURP were associated with a higher risk of complications, longer hospital stay and more comorbidities than those without AUR and a preoperative warning is warranted for these patients. PMID- 23035624 TI - Fitness and metabolic syndrome in obese fatty liver children. AB - BACKGROUND: Metabolic Syndrome (MS) is highly prevalent among obese children with fatty liver. However, it is well-known that there is a lower prevalence of MS in individuals with higher cardiorespiratory fitness (CRF). AIM: To analyse the association between CRF with features of the MS in obese children that present fat liver indicators, namely abnormal alanine aminotransferase (ALT) values. METHODS: A total of 79 obese students (40 girls), 10-11 year-olds ( +/- 0.60), with abnormal serum ALT from Porto public schools comprised the sample. Measurements included CRF (20-metre Shuttle Run Test), Metabolic Risk Factors (MRF), according to MS International Diabetes Federation criteria, ALT values (Cholestech LDX((r)) analyser) and maturational stage (Tanner criteria). Logistic regression analysis was used to determine the influence of CRF on MRF adjusted for sex, maturation, and BMI. RESULTS: The logistic regression showed that, despite being classified as being obese and presenting abnormal levels of ALT, those classified as fit were less likely to have MS than their unfit counterparts (OR = 0.52; p <= 0.05). CONCLUSION: Obese-fit children with abnormal ALT values have a significant reduction in the likelihood to be classified as having MS, even after adjustments for gender, maturation and BMI, Thus, CRF might be an important factor for tackling fatty liver among obese. PMID- 23035625 TI - Cost-effectiveness of denosumab in the treatment of postmenopausal osteoporosis in Canada. AB - OBJECTIVE: Denosumab is a novel biologic agent approved in Canada for treatment of post-menopausal osteoporosis (PMO) in women at high risk for fracture or who have failed or are intolerant to other osteoporosis therapies. This study estimated cost-effectiveness of denosumab vs usual care from the perspective of the Ontario public payer. METHODS: A previously published PMO Markov cohort model was adapted for Canada to estimate cost-effectiveness of denosumab. The primary analysis included women with demographic characteristics similar to those from the pivotal phase III denosumab PMO trial (FREEDOM; age 72 years, femoral neck BMD T-score -2.16 SD, vertebral fracture prevalence 23.6%). Three additional scenario sub-groups were examined including women: (1) at high fracture risk, defined in FREEDOM as having at least two of three risk factors (age 70+; T-score <= -3.0 SD at lumbar spine, total hip, or femoral neck; prevalent vertebral fracture); (2) age 75+; and (3) intolerant or contraindicated to oral bisphosphonates (BPs). Analyses were conducted over a lifetime horizon comparing denosumab to usual care ('no therapy', alendronate, risedronate, or raloxifene [sub-group 3 only]). The analysis considered treatment-specific persistence and post-discontinuation residual efficacy, as well as treatment-specific adverse events. Both deterministic and probabilistic sensitivity analyses were conducted. RESULTS: The multi-therapy comparisons resulted in incremental cost-effectiveness ratios for denosumab vs alendronate of $60,266 (2010 CDN$) (primary analysis) and $27,287 per quality-adjusted life year gained for scenario sub-group 1. Denosumab dominated all therapies in the remaining scenarios. LIMITATIONS: Key limitations include a lack of long-term, real-world, Canadian data on persistence with denosumab as well as an absence of head-to-head clinical data, leaving one to rely on meta-analyses based on trials comparing treatment to placebo. CONCLUSIONS: Denosumab may be cost-effective compared to oral PMO treatments for women at high risk of fractures and those who are intolerant and/or contraindicated to oral BPs. PMID- 23035626 TI - The direct and indirect costs of long bone fractures in a working age US population. AB - OBJECTIVE: Information regarding the burden of fractures is limited, especially among working age patients. The objective of this study was to evaluate the direct and indirect costs associated with long bone fractures in a working age population using real-world claims data. METHODS: This was a claims-based retrospective analysis, comparing adult patients in the 6 months before and 6 months after a long bone fracture between 1/1/2001 and 12/31/2008 using the MarketScan Research Databases. Outcomes included direct medical costs and utilization, as well as work absenteeism and short term disability, which was available for a sub-set of the patients. Observed and adjusted incremental costs (i.e., the difference in costs before and after a fracture) were evaluated and reported in 2008 US$. RESULTS: A total of 208,094 patients with at least one fracture were included in the study. Six, mutually exclusive fracture cohorts were evaluated: tibia shaft (n = 49,839), radius (n = 97,585), hip (n = 11,585), femur (n = 6788), humerus (n = 29,884), and those with multiple long bone fractures (n = 12,413). Average unadjusted direct costs in the 6-months before a long bone fracture ranged from $3291 (radius) to $12,923 (hip). The average incremental direct cost increase in the 6-months following a fracture ranged from $5707 (radius) to $39,041 (multiple fractures). Incremental absenteeism costs ranged from $950 (radius) to $2600 (multiple fractures), while incremental short term disability costs ranged from $2050 (radius) to $4600 (multiple fractures). CONCLUSIONS: The results of this study indicate that long bone fractures are costly, both in terms of direct medical costs and lost productivity. Workplace absences and short-term disability represent a significant component of the burden of long bone fractures. These results may not be generalizable to all patients with fractures in the US, and do not reflect the burden of undiagnosed or sub-clinical fractures. PMID- 23035627 TI - Cost analysis of the treatments for patients with advanced Parkinson's disease: SCOPE study. AB - OBJECTIVE: To perform a comparative long-term analysis of the associated healthcare costs for the therapeutic options in advanced Parkinson's Disease (PD): deep brain stimulation (DBS), continuous duodenal levodopa-carbidopa infusion (CDLCI), and continuous subcutaneous apomorphine infusion (CSAI). METHODS: Resource use associated with the pre-treatment period, procedure, and follow-up was assessed for the three therapies from the perspective of the Spanish national healthcare system. Resources consumption was measured with a Healthcare Resources Questionnaire (at nine advanced PD centres). Unit costs (Euro-Spain 2010) were applied to measure resource use to obtain the average total cost for each therapy over 5 years. RESULTS: Mean cumulative 5-year cost per patient was significantly lower with DBS (?88,014) vs CSAI (?141,393) and CDLCI (?233,986) (p < 0.0001). DBS was associated with the lowest cumulative costs from year 2, with a yearly average cost of ?17,603 vs ?46,797 for CDLCI (p = 0.001) and ?28,279 for CSAI (p = 0.008). For every patient treated annually with CDLCI, two could be treated with DBS (or ?29,194 could be saved) and for every patient treated with CSAI, ?10,676 could be saved with DBS. The initial DBS investment (32.2% of the total 5-year costs) was offset by decreases in anti Parkinsonian drugs and follow-up costs. CDLCI and CSAI required constant drug use (i.e., levodopa and carbidopa for CDLCI, apomorphine for CSAI), representing ~95% of their total 5-year cost. LIMITATIONS: All costs were based on a questionnaire, not on actual clinical data. The study is not a cost-effectiveness analysis as there is a lack of comparable outcomes data. An expert panel was used due to the complexity and variability in the treatment of advanced PD. The sample size was relatively small. CONCLUSIONS: Overall, DBS requires less use of health resources than CDLCI or CSAI in advanced PD patients, mostly pharmacological. The initial DBS investment was offset at year 2 by reductions in the ongoing consumption of anti-Parkinsonian medication. For every patient treated annually with CDLCI or CSAI, substantial cost savings could be made with DBS. PMID- 23035628 TI - Low body mass index is associated with a positive response during a head-up tilt test. AB - BACKGROUND: To describe the association between body mass index (BMI) and a positive response during a head-up tilt test (HUT) in patients referred for an investigation of syncope. METHODS: Observational study of patients referred for the diagnostic evaluation of syncope. Patients were divided into four groups according to their BMI: <18.5 kg/m(2), 18.5-24.9 kg/m(2), 25-29.9 kg/m(2), and > 30 kg/m(2). RESULTS: A total of 419 patients were evaluated. The mean age was 43 +/- 22 years, and 62% were female. The prevalence of a positive tilt test was different between groups when stratified by BMI (P = 0.01), with a higher proportion of patients with positive tests among those with BMI <18.5 kg/m(2) compared with other groups (P = 0.05). Multivariate analysis also showed that underweight patients had a 3.9 times higher risk for a positive HUT response (P = 0.01); additionally, the use of contraceptive drugs was associated with a protective effect during HUT (odds ratio: 0.35, confidence interval: 0.19-0.45, P = 0.001). CONCLUSION: In our sample, changes in BMI are associated with a positive response for HUT, and oral contraceptives seemed to protect against this response. Further studies are needed with larger numbers of patients to corroborate this finding. PMID- 23035629 TI - Synthesis, protonation, and reduction of ruthenium-peroxo complexes with pendent nitrogen bases. AB - Cyclopentadienyl and pentamethylcyclopentadienyl ruthenium(II) complexes have been synthesized with cyclic (RPCH(2)NR'CH(2))(2) ligands, with the goal of using these [Cp(R'')Ru(P(R)(2)N(R')(2))](+) complexes for catalytic O(2) reduction to H(2)O (R = t-butyl, phenyl; R' = benzyl, phenyl; R" = methyl, H). In each compound, the Ru is coordinated to the two phosphines, positioning the amines of the ligand in the second coordination sphere where they may act as proton relays to a bound dioxygen ligand. The phosphine, amine, and cyclopentadienyl substituents have been systematically varied in order to understand the effects of each of these parameters on the properties of the complexes. These Cp(R")Ru(P(R)(2)N(R')(2))(+) complexes react with O(2) to form eta(2)-peroxo complexes, which have been characterized by NMR, IR, and X-ray crystallography. The peak reduction potentials of the O(2) ligated complexes have been shown by cyclic voltammetry to vary as much as 0.1 V upon varying the phosphine and amine. In the presence of acid, protonation of these complexes occurs at the pendent amine, forming a hydrogen bond between the protonated amine and the bound O(2). The ruthenium-peroxo complexes decompose upon reduction, precluding catalytic O(2) reduction. The irreversible reduction potentials of the protonated O(2) complexes depend on the basicity of the pendent amine, giving insight into the role of the proton relay in facilitating reduction. PMID- 23035630 TI - Pathogen variation and urea influence selection and success of Streptomyces mixtures in biological control. AB - Success in biological control of plant diseases remains inconsistent in the field. A collection of well-characterized Streptomyces antagonists (n = 19 isolates) was tested for their capacities to inhibit pathogenic Streptomyces scabies (n = 15 isolates). There was significant variation among antagonists in ability to inhibit pathogen isolates and among pathogens in their susceptibility to inhibition. Only one antagonist could inhibit all pathogens, and antagonist pathogen interactions were highly specific, highlighting the limitations of single-strain inoculum in biological control. However, the collection of pathogens could be inhibited by several combinations of antagonists, suggesting the potential for successful antagonist mixtures. Urea generally increased effectiveness of antagonists at inhibiting pathogens in vitro (increased mean inhibition zones) but its specific effects varied among antagonist-pathogen combinations. In greenhouse trials, urea enhanced the effectiveness of antagonist mixtures relative to individual antagonists in controlling potato scab. Although antagonist mixtures were frequently antagonistic in the absence of urea, all n= 2 and n = 3 antagonist-isolate combinations were synergistic in the presence of urea. This work provides insights into the efficacy of single- versus multiple strain inocula in biological control and on the potential for nutrients to influence mixture success. PMID- 23035631 TI - Heat treatment eliminates 'Candidatus Liberibacter asiaticus' from infected citrus trees under controlled conditions. AB - Huanglongbing (HLB) is one of the most destructive diseases of citrus worldwide. The three known causal agents of HLB are species of alpha-proteobacteria: 'Candidatus Liberibacter asiaticus', 'Ca. L. africanus', and 'Ca. L. americanus'. Previous studies have found distinct variations in temperature sensitivity and tolerance among these species. Here, we describe the use of controlled heat treatments to cure HLB caused by 'Ca. L. asiaticus', the most prevalent and heat tolerant species. Using temperature-controlled growth chambers, we evaluated the time duration and temperature required to suppress or eliminate the 'Ca. L. asiaticus' bacterium in citrus, using various temperature treatments for time periods ranging from 2 days to 4 months. Results of quantitative polymerase chain reaction (qPCR) after treatment illustrate significant decreases in the 'Ca. L. asiaticus' bacterial titer, combined with healthy vigorous growth by all surviving trees. Repeated qPCR testing confirmed that previously infected, heat treated plants showed no detectable levels of 'Ca. L. asiaticus', while untreated control plants remained highly infected. Continuous thermal exposure to 40 to 42 degrees C for a minimum of 48 h was sufficient to significantly reduce titer or eliminate 'Ca. L. asiaticus' bacteria entirely in HLB-affected citrus seedlings. This method may be useful for the control of 'Ca. Liberibacter'-infected plants in nursery and greenhouse settings. PMID- 23035632 TI - Lipid profiles in wheat cultivars resistant and susceptible to tan spot and the effect of disease on the profiles. AB - Lipid profiles in wheat leaves and the effects of tan spot on the profiles were quantified by mass spectrometry. Inoculation with Pyrenophora tritici-repentis significantly reduced the amount of leaf lipids, including the major plastidic lipids monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG), which together accounted for 89% of the mass spectral signal of detected lipids in wheat leaves. Levels of these lipids in susceptible cultivars dropped much more quickly during infection than those in resistant cultivars. Furthermore, cultivars resistant or susceptible to tan spot displayed different lipid profiles; leaves of resistant cultivars had more MGDG and DGDG than susceptible ones, even in noninoculated plants. Lipid compositional data from leaves of 20 noninoculated winter wheat cultivars were regressed against an index of disease susceptibility and fitted with a linear model. This analysis demonstrated a significant relationship between resistance and levels of plastidic galactolipids and indicated that cultivars with high resistance to tan spot uniformly had more MGDG and DGDG than cultivars with high susceptibility. These findings suggest that lipid composition of wheat leaves may be a determining factor in the resistance response of cultivars to tan spot. PMID- 23035633 TI - Walkability parameters, active transportation and objective physical activity: moderating and mediating effects of motor vehicle ownership in a cross-sectional study. AB - BACKGROUND: Neighborhood walkability has been associated with physical activity in several studies. However, as environmental correlates of physical activity may be context specific, walkability parameters need to be investigated separately in various countries and contexts. Furthermore, the mechanisms by which walkability affects physical activity have been less investigated. Based on previous research, we hypothesized that vehicle ownership is a potential mediator. We investigated the associations between walkability parameters and physical activity, and the mediating and moderating effects of vehicle ownership on these associations in a large sample of Swedish adults. METHODS: Residential density, street connectivity and land use mix were assessed within polygon-based network buffers (using Geographic Information Systems) for 2,178 men and women. Time spent in moderate to vigorous physical activity was assessed by accelerometers, and walking and cycling for transportation were assessed by the International Physical Activity Questionnaire. Associations were examined by linear regression and adjusted for socio-demographic characteristics. The product of coefficients approach was used to investigate the mediating effect of vehicle ownership. RESULTS: Residential density and land use mix, but not street connectivity, were significantly associated with time spent in moderate to vigorous physical activity and walking for transportation. Cycling for transportation was not associated with any of the walkability parameters. Vehicle ownership mediated a significant proportion of the association between the walkability parameters and physical activity outcomes. For residential density, vehicle ownership mediated 25% of the association with moderate to vigorous physical activity and 20% of the association with the amount of walking for transportation. For land use mix, the corresponding proportions were 34% and 14%. Vehicle ownership did not moderate any of the associations between the walkability parameters and physical activity outcomes. CONCLUSIONS: Residential density and land use mix were associated with time spent in moderate to vigorous physical activity and walking for transportation. Vehicle ownership was a mediator but not a moderator of these associations. The present findings may be useful for policy makers and city planners when designing neighborhoods that promote physical activity. PMID- 23035634 TI - Effects of flavone derivatives on antigen-stimulated degranulation in RBL-2H3 cells. AB - Mast cells are primarily responsible for IgE-mediated allergic responses. The activation level of mast cells is reflected in their degree of degranulation. This can in turn be determined by measuring the amount of beta-hexosaminidase release, a key parameter in degranulation. In this study, 40 flavone derivatives, including flavone, 14 methoxyflavones, 13 hydroxyflavones, and 12 hydroxymethoxyflavones, were evaluated for their inhibition of degranulation in rat basophilic leukemia RBL-2H3 cells. 3',7-Dihydroxyflavone inhibited degranulation (IC(50) = 13.56 MUM), which was comparable to PP2 (3-(4 chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) used as a control. In addition, we report quantitative relationships between the structural properties of flavones and their inhibitory effects on degranulation. PMID- 23035635 TI - Bone marrow involvement as initial presentation of CD8 cytotoxic peripheral T cell lymphoma with CD20 coexpression and relatively indolent clinical course. PMID- 23035636 TI - Radial probe endobronchial ultrasound: factors influencing visualization yield of peripheral pulmonary lesions. AB - BACKGROUND AND OBJECTIVE: Endobronchial ultrasound (EBUS) has improved the diagnostic yield of transbronchial biopsy of peripheral pulmonary lesions (PPL). While EBUS diagnostic yield has been the focus of the majority of publications, few have investigated factors associated with EBUS visualization yield. This study evaluated the factors predicting visibility of PPL using EBUS-guided bronchoscopy. METHODS: We performed a retrospective analysis of 196 consecutive patients who underwent investigation with radial EBUS. Size and distance of the lesion from the hilum and pleura measured on computed tomography scans were correlated with malignancy status, gender and EBUS visualization yields. Final diagnosis was obtained from pathology. RESULTS: A definitive diagnosis was established for 109 PPL (56%) using radial EBUS. Visualized lesion by EBUS probe had a higher diagnostic yield (65%) than EBUS-invisible lesions (20%; P = 0.0001). In multivariate analysis, lesion size, final diagnosis and distance from hilum to lesion were all found to significantly affect EBUS visualization yield. Lesions of >= 20 mm had a significantly greater visualization yield (85%) than lesions of <20 mm (63%; P = 0.0022). Malignant lesions had a higher visualization rate (85%) than benign lesions (66%; P value = 0.0025). Distance of hilum <= 50 mm to PPL was found to have a significantly higher visualization yield (91%) than lesions located >50 mm from the hilum. (66%; P = 0.0001). CONCLUSIONS: Lesion size, malignancy status and distance from hilum to lesion are significant predictors of EBUS visualization yield. Clinicians should review these factors in patients to guide choice of optimal investigation and diagnosis of PPL. PMID- 23035637 TI - Respiratory and olfactory turbinal size in canid and arctoid carnivorans. AB - Within the nasal cavity of mammals is a complex scaffold of paper-thin bones that function in respiration and olfaction. Known as turbinals, the bones greatly enlarge the surface area available for conditioning inspired air, reducing water loss, and improving olfaction. Given their functional significance, the relative development of turbinal bones might be expected to differ among species with distinct olfactory, thermoregulatory and/or water conservation requirements. Here we explore the surface area of olfactory and respiratory turbinals relative to latitude and diet in terrestrial Caniformia, a group that includes the canid and arctoid carnivorans (mustelids, ursids, procyonids, mephitids, ailurids). Using high-resolution computed tomography x-ray scans, we estimated respiratory and olfactory turbinal surface area and nasal chamber volume from three-dimensional virtual models of skulls. Across the Caniformia, respiratory surface area scaled isometrically with estimates of body size and there was no significant association with climate, as estimated by latitude. Nevertheless, one-on-one comparisons of sister taxa suggest that arctic species may have expanded respiratory turbinals. Olfactory surface area scaled isometrically among arctoids, but showed positive allometry in canids, reflecting the fact that larger canids, all of which are carnivorous, had relatively greater olfactory surface areas. In addition, among the arctoids, large carnivorous species such as the polar bear (Ursus maritimus) and wolverine (Gulo gulo) also displayed enlarged olfactory turbinals. More omnivorous caniform species that feed on substantial quantities of non-vertebrate foods had less expansive olfactory turbinals. Because large carnivorous species hunt widely dispersed prey, an expanded olfactory turbinal surface area may improve a carnivore's ability to detect prey over great distances using olfactory cues. PMID- 23035638 TI - Determinants of chymotrypsin C cleavage specificity in the calcium-binding loop of human cationic trypsinogen. AB - The pancreatic serine protease chymotrypsin C (CTRC) cleaves the Leu81-Glu82 peptide bond in the calcium-binding loop of human cationic trypsinogen and thereby promotes its degradation. This serves as a protective mechanism against ectopic trypsinogen activation in the pancreas. In the present study, we demonstrate that cleavage of the Leu81-Glu82 peptide bond by CTRC is highly specific, and other human pancreatic chymotrypsins (CTRB1, CTRB2 and CTRL1) and elastases (ELA2A, ELA3A and ELA3B) do not catalyze this reaction. To elucidate the mechanistic basis for CTRC specificity, we surveyed the primary (P1) cleavage preference of these pancreatic proteases on peptide substrates. We found that CTRC cleaved after a P1 Leu with at least tenfold higher catalytic efficiency than other enzymes tested. To assess extended sub-site interactions, we introduced Ala mutations into human cationic trypsinogen at the P3, P1' P3' and P4' amino acid positions, where P1-P1' corresponds to Leu81-Glu82. Interestingly, CTRC-mediated cleavage was stimulated threefold by mutation E82A and unaffected by mutations E79A and N84A, but all three mutations compromised specificity and resulted in increased cleavage by ELA2A. Mutation E85A decreased CTRC cleavage by twofold. Remarkably, other chymotrypsins and elastases did not cleave human cationic trypsinogen even with the L81F or L81A mutations, which introduced favorable P1 residues for these enzymes. We conclude that specific cleavage of the Leu81-Glu82 peptide bond in human cationic trypsinogen by CTRC is primarily determined by its distinctively high activity on leucyl peptide bonds, with the P1' Glu82, P3' Asn84 and P4' Glu85 residues serving as additional specificity determinants. PMID- 23035639 TI - The downside of broiler vaccination. PMID- 23035640 TI - The role of energetic cost in the age-related slowing of gait speed. AB - OBJECTIVES: To determine whether slow gait represents a compensatory strategy to reduce the energetic cost of walking with age. DESIGN: Cross-sectional analysis. SETTING: Community-dwelling volunteers from the Baltimore Longitudinal Study of Aging (BLSA). PARTICIPANTS: Four hundred twenty community-dwelling persons aged 32 to 96 (mean 68.1 +/- 12.5) who underwent a physical examination, physical function testing, and energy expenditure assessment. MEASUREMENTS: Energy expenditure per minute (mL/kg/min) and per meter (mL/kg/m) during 2.5 minutes of overground walking at customary speed and usual gait speed over 6 m (m/s) were examined. General linear regression models were used to assess the relationship between customary walking energy expenditure and usual gait speed, adjusted for potential confounders including smoking, medical diagnoses, walking-related pain, and balance difficulty. RESULTS: Usual gait speed was slower with increasing age after age 65. Energy expenditure per minute during customary walking averaged 13.0 +/- 2.8 mL/kg/min and was independent of age (rho < 0.01, P = .88). In contrast, energy expenditure per meter walked was progressively higher after age 65 (rho = 0.35, P < .001) and heightened after age 80 (r = 0.57, P < .001), mirroring the observed pattern of usual gait speed. This relationship remained significant after adjusting for multiple impairments and comorbidities. CONCLUSION: These observations support the hypothesis that slower gait at older ages may reflect a compensatory action to offset the greater energetic cost of walking associated with aging and chronic conditions. Future studies should evaluate the specific mechanisms that contribute to this phenomenon as novel targets for clinical intervention. PMID- 23035641 TI - Development of a manualized protocol of massage therapy for clinical trials in osteoarthritis. AB - BACKGROUND: Clinical trial design of manual therapies may be especially challenging as techniques are often individualized and practitioner-dependent. This paper describes our methods in creating a standardized Swedish massage protocol tailored to subjects with osteoarthritis of the knee while respectful of the individualized nature of massage therapy, as well as implementation of this protocol in two randomized clinical trials. METHODS: The manualization process involved a collaborative process between methodologic and clinical experts, with the explicit goals of creating a reproducible semi-structured protocol for massage therapy, while allowing some latitude for therapists' clinical judgment and maintaining consistency with a prior pilot study. RESULTS: The manualized protocol addressed identical specified body regions with distinct 30- and 60-min protocols, using standard Swedish strokes. Each protocol specifies the time allocated to each body region. The manualized 30- and 60-min protocols were implemented in a dual-site 24-week randomized dose-finding trial in patients with osteoarthritis of the knee, and is currently being implemented in a three-site 52 week efficacy trial of manualized Swedish massage therapy. In the dose-finding study, therapists adhered to the protocols and significant treatment effects were demonstrated. CONCLUSIONS: The massage protocol was manualized, using standard techniques, and made flexible for individual practitioner and subject needs. The protocol has been applied in two randomized clinical trials. This manualized Swedish massage protocol has real-world utility and can be readily utilized both in the research and clinical settings. TRIAL REGISTRATION: Clinicaltrials.gov NCT00970008 (18 August 2009). PMID- 23035642 TI - Comparative genomic analysis of human infective Trypanosoma cruzi lineages with the bat-restricted subspecies T. cruzi marinkellei. AB - BACKGROUND: Trypanosoma cruzi marinkellei is a bat-associated parasite of the subgenus Schizotrypanum and it is regarded as a T. cruzi subspecies. Here we report a draft genome sequence of T. c. marinkellei and comparison with T. c. cruzi. Our aims were to identify unique sequences and genomic features, which may relate to their distinct niches. RESULTS: The T. c. marinkellei genome was found to be ~11% smaller than that of the human-derived parasite T. c. cruzi Sylvio X10. The genome size difference was attributed to copy number variation of coding and non-coding sequences. The sequence divergence in coding regions was ~7.5% between T. c. marinkellei and T. c. cruzi Sylvio X10. A unique acetyltransferase gene was identified in T. c. marinkellei, representing an example of a horizontal gene transfer from eukaryote to eukaryote. Six of eight examined gene families were expanded in T. c. cruzi Sylvio X10. The DGF gene family was expanded in T. c. marinkellei. T. c. cruzi Sylvio X10 contained ~1.5 fold more sequences related to VIPER and L1Tc elements. Experimental infections of mammalian cell lines indicated that T. c. marinkellei has the capacity to invade non-bat cells and undergo intracellular replication. CONCLUSIONS: Several unique sequences were identified in the comparison, including a potential subspecies-specific gene acquisition in T. c. marinkellei. The identified differences reflect the distinct evolutionary trajectories of these parasites and represent targets for functional investigation. PMID- 23035645 TI - Synthesis and evaluation of (99m)Tc chelate-conjugated bevacizumab. AB - Vascular endothelial growth factor (VEGF) is one of the classic factors involved in tumor-induced angiognesis in several solid tumors. Bevacizumab, a monoclonal antibody against VEGF, can be used as an imaging tool in preclinical studies. The aim of this study was to radiolabel Bevacizumab with (99m)Tc and to evaluate in vivo its imaging properties in an adenocarcinoma animal model. For this purpose, Bevacizumab was derivatized with Suc-HYNIC as a bifunctional coupling agent. A mixture of Tricine/SnCl(2).2H(2)O was added to Bevacizumab-HYNIC and radiolabeled with (99m)TcO(4)(-). The radiochemical stability of the radiolabeled antibody was assessed. Biodistribution and scintigraphy imaging were performed in normal CD1 female mice and in spontaneous adenocarcinoma tumor bearing CD1 mice (n = 5). We demonstrated that 99mTc-HYNIC-Bevacizumab was stable. In vivo biodistribution studies revealed that tumor uptake of (99m)Tc-HYNIC-Bevacizumab was 1.37 +/- 0.51% and 5.33 +/- 2.13% at 4 and 24 h postinjection, respectively. Scintigraphy image studies showed tumor selective uptake of (99m)Tc-HYNIC-Bevacizumab in the tumor-bearing mice. We conclude that (99m)Tc-HYNIC-Bevacizumb has the potential to be used as a tracer for tumor imaging in preclinical studies. PMID- 23035646 TI - Stroke after cardiac surgery--hemispheric distribution and survival. AB - OBJECTIVES: Stroke following cardiac surgery may occur either in association with surgery (early) or occur postoperatively (delayed). The hemispheric distribution of lesions may provide information about embolic routes, which was analyzed here. DESIGN: In 10,809 patients undergoing cardiac surgery, early (n = 223) and delayed stroke (n = 116) were explored. Symptoms and computed tomography findings were evaluated to categorize hemispheric distributions. This was compared with pre- and intra-operative characteristics and survival, using logistic regression and Kaplan-Meier statistics. RESULTS: Early stroke had preponderance for the right rather than the left hemisphere (P = 0.009), whereas delayed stroke had a uniform distribution. Several intraoperative variables predicted the development of bilateral stroke compared with its unilateral counterpart. At multivariable analysis, the use of tranexamic acid was associated with bilateral stroke (P = 0.017), but was also associated with right rather than left-hemispheric stroke (P = 0.001). Bilateral lesions dramatically impaired survival versus those with unilateral lesions (P < 0.001). There was no survival difference between left and right-hemispheric stroke. CONCLUSIONS: When stroke, after cardiac surgery, is subdivided into early and delayed forms, it becomes evident that early, but not delayed stroke, demonstrates a hemispheric side difference. The preponderance for right-hemispheric lesions may indicate embolic mechanisms routed via the brachiocephalic trunk. PMID- 23035644 TI - Patterns and socioeconomic influences of tobacco exposure in tobacco cultivating rural areas of Yunnan Province, China. AB - BACKGROUND: This study describes the patterns and socioeconomic influences of tobacco use among adults in tobacco-cultivating regions of rural southwest China. METHODS: A cross-sectional survey was conducted in 8681 adults aged >=18 years in rural areas of Yunnan Province, China from 2010 to 2011. A standardized questionnaire was administered to obtain data about participants' demographic characteristics, individual socioeconomic status, ethnicity, self-reported smoking habits, and exposure to secondhand smoke (SHS). The socioeconomic predictors of current smoking, nicotine addiction, and SHS exposure were analyzed using multivariate logistic regression. RESULTS: The prevalence rates of tobacco use were much higher in men compared with women (current smoking 68.5% vs. 1.3%; and nicotine dependence 85.2% vs. 72.7%). However, the rate of SHS exposure was higher in women compared with men (76.6% vs. 70.5%). Tobacco farmers had higher prevalence rates of current smoking, nicotine dependence, and SHS exposure compared with participants not engaged in tobacco farming (P<0.01). Most tobacco users (84.5%) reported initiating smoking during adolescence. A total of 81.1% of smokers smoked in public places, and 77.6% smoked in workplaces. Individuals belonging to an ethnic minority had a lower probability of SHS exposure and nicotine dependence. Individual educational level was found to be inversely associated with the prevalence of current smoking, exposure to SHS, and nicotine dependence. Higher annual household income was associated with a greater risk of nicotine dependence. CONCLUSIONS: This study suggests that tobacco control efforts in rural southwest China must be tailored to address tobacco-cultivating status and socioeconomic factors. PMID- 23035643 TI - Drosophila S2 cells secrete wingless on exosome-like vesicles but the wingless gradient forms independently of exosomes. AB - Wingless acts as a morphogen in Drosophila wing discs, where it specifies cell fates and controls growth several cell diameters away from its site of expression. Thus, despite being acylated and membrane associated, Wingless spreads in the extracellular space. Recent studies have focussed on identifying the route that Wingless follows in the secretory pathway and determining how it is packaged for release. We have found that, in medium conditioned by Wingless expressing Drosophila S2 cells, Wingless is present on exosome-like vesicles and that this fraction activates signal transduction. Proteomic analysis shows that Wingless-containing exosome-like structures contain many Drosophila proteins that are homologous to mammalian exosome proteins. In addition, Evi, a multipass transmembrane protein, is also present on exosome-like vesicles. Using these exosome markers and a cell-based RNAi assay, we found that the small GTPase Rab11 contributes significantly to exosome production. This finding allows us to conclude from in vivo Rab11 knockdown experiments, that exosomes are unlikely to contribute to Wingless secretion and gradient formation in wing discs. Consistent with this conclusion, extracellularly tagged Evi expressed from a Bacterial Artificial Chromosome is not released from imaginal disc Wingless-expressing cells. PMID- 23035647 TI - The assessment and interpretation of Demirjian, Goldstein and Tanner's dental maturity. AB - BACKGROUND: A frequently reported advancement in dental maturity compared with the 50(th) percentile of Demirjian, Goldstein and Tanner (1973, Hum Biol 45:211 27) has been interpreted as a population difference. AIM: To review the assessment and interpretation of Demirjian et al.'s dental maturity. SUBJECTS AND METHODS: Dental maturity of boys from published reports was compared as maturity curves and difference to the 50(th) percentile in terms of chronological age and score. Dental maturity, as well as maturity of individual teeth, was compared in the fastest and slowest maturing groups of boys from the Chaillet database. RESULTS: Maturity curves from published reports by age category were broadly similar and differences occurred at the steepest part of the curve. These reduced when expressed as score rather than age. Many studies report a higher than expected score for chronological age and the database contained more than expected children with scores>97(th) percentile. Revised scores for chronological age from this database were calculated (4072 males, 3958 females, aged 2.1-17.9). CONCLUSION: Most published reports were similar to the database smoothed maturity curve. This method of dental maturity is designed to assess maturity for a single child and is unsuitable to compare groups. PMID- 23035648 TI - The National Institutes of Health criteria for classification and scoring of chronic graft versus host disease: long-term follow-up of a single center series. AB - We assessed the retrospective applicability and prognostic value of the National Institutes of Health (NIH) classification of chronic graft versus host disease (cGVHD) in 159 consecutive patients after allogeneic hematopoietic stem cell transplant (HSCT). Seventy-four patients (46.5%) were affected by late-acute GVHD (n = 19; 25.7%), classic cGVHD (n = 44; 59.4%) and overlap syndrome (n = 11; 14.9%). Overall, patients with NIH-defined cGVHD (i.e. classic cGVHD and overlap syndrome) had better 10-year overall survival (OS) as compared to patients without GVHD (76.9% vs. 47.4%, p = 0.0002) or with late-acute GVHD (47.4%, p = 0.001). Relapse mortality (RM) was lower in patients with NIH-defined cGVHD than in patients without GVHD (14.5% vs. 38.7%, p = 0.001), but comparable to that of late-acute type (19.4%, p = 0.31). Non-relapse mortality (NRM) was lower in patients with NIH-defined cGVHD as compared to late-acute GVHD (10.0% vs. 41.1%, p = 0.0005), as well as patients without GVHD (22.2%, p = 0.045). At multivariate analysis, NIH-defined cGVHD remained independently predictive for lower RM, but not for NRM. Thus, the new NIH classification identifies two subtypes of GVHD (late-acute and chronic) with different long-term outcomes and impact on RM and NRM. PMID- 23035650 TI - The semantic specificity of gestures when verbal communication is not possible: the case of emergency evacuation. AB - The aim of the present study was to examine the comprehension of gesture in a situation in which the communicator cannot (or can only with difficulty) use verbal communication. Based on theoretical considerations, we expected to obtain higher semantic comprehension for emblems (gestures with a direct verbal definition or translation that is well known by all members of a group, or culture) compared to illustrators (gestures regarded as spontaneous and idiosyncratic and that do not have a conventional definition). Based on the extant literature, we predicted higher semantic specificity associated with arbitrarily coded and iconically coded emblems compared to intrinsically coded illustrators. Using a scenario of emergency evacuation, we tested the difference in semantic specificity between different categories of gestures. 138 participants saw 10 videos each illustrating a gesture performed by a firefighter. They were requested to imagine themselves in a dangerous situation and to report the meaning associated with each gesture. The results showed that intrinsically coded illustrators were more successfully understood than arbitrarily coded emblems, probably because the meaning of intrinsically coded illustrators is immediately comprehensible without recourse to symbolic interpretation. Furthermore, there was no significant difference between the comprehension of iconically coded emblems and that of both arbitrarily coded emblems and intrinsically coded illustrators. It seems that the difference between the latter two types of gestures was supported by their difference in semantic specificity, although in a direction opposite to that predicted. These results are in line with those of Hadar and Pinchas-Zamir (2004), which showed that iconic gestures have higher semantic specificity than conventional gestures. PMID- 23035651 TI - Thoracic injuries sustained by severely injured front-seat passengers and drivers: injury patterns and their relationship to crash characteristics. AB - Thoracic injuries are common in vehicle crashes, but only a few studies thus far have analysed the relationship between injury characteristics and collision details and discussed the possible implications for future vehicle design and prevention. In this study, the crash details were prospectively collected at the scene of injury between 2004 and 2009 for severely injured patients. The collected data included the type of collision, angle of impact and change of velocity on impact as well as injury characteristics and patient demographics, including abbreviated injury scale (AIS) and injury severity score (ISS).There were 5998 accidents involving 8830 patients over this five-year period; 31 met the inclusion criteria (23 males and eight females). The mean ISS was 37 +/- 12.68, the mean AIS Thorax was 4.0. Lung contusions were found in 90% of the patients, pneumothoraces in 58% and rib fractures in 81%. There was a significant relationship between accident deceleration speed (DeltaV), AIS Thorax (p = 0.02) and the incidence of pneumothoraces (p = 0.046). The analysis showed a high overall incidence of thoracic injuries in car passengers. Future improvements in automobile safety and design should seek to reduce the incidence of thoracic injuries by uniform vehicle deformation and further implementation of side airbags. PMID- 23035652 TI - Analysis method of epigenetic DNA methylation to dynamically investigate the functional activity of transcription factors in gene expression. AB - BACKGROUND: DNA methylation is a fundamental component of epigenetic modification, which is intimately involved in the regulation of gene expression. One important DNA methylation pathway reduces the abilities of transcription factors to bind to gene promoter regions. Although many experiments have been designed to measure genome-wide DNA methylation levels at high resolution, the meaning of these different DNA methylation levels on transcription factor binding abilities remains poorly understood. We have, therefore, developed a method to quantitatively explore the extent to which DNA methylation levels can significantly reduce or even abolish the binding of certain transcription factors, resulting in reduced or non-expression of flanking genes. This method allows transcription factors that are functionally active in gene expression to be investigated. RESULTS: The method is based on a general model that depicts the relationship between DNA methylation and transcription factor binding ability based on intrinsic component properties, and the model parameters can be optimized through relative analysis of recognized transcription factor binding status and gene expression profiling. With fixed models, transcription factors functionally active in the regulation of gene expression and affected by epigenetic DNA methylation can be identified and subsequently confirmed. The method identified eleven apparently functionally active transcriptional factors in SH-SY5Y neuroblastoma cells. CONCLUSIONS: Compared with gene regulatory elements, epigenetic modifications are able to change to dynamically respond to signals from physical, biological and social environments. Our proposed method is therefore designed to provide a dynamic assessment to investigate functionally active transcription factors. With the information deduced from our method, we can predict transcription factor binding status in promoter regions to further investigate how a particular gene is regulated by a specific group of transcription factors organized in a particular pattern. This will be helpful in the diagnosis and development of treatment for numerous diseases, including cancer. Although the method only investigates DNA methylation, it has the potential to be applied to more epigenetic factors, such as histone modification. PMID- 23035653 TI - Generation of porcine-induced pluripotent stem cells by using OCT4 and KLF4 porcine factors. AB - Induced pluripotent stem cells (iPSCs) can be artificially reprogrammed from somatic cells by overexpression of exogenous transcription factors. The pig has increasingly become an important large animal model for preclinical tests and studies of human diseases; thus, the generation of porcine iPSCs will facilitate research into the efficacy and safety of stem cell therapy. A current major problem facing the generation of porcine iPSCs is the failure to silence exogenous transgenes. We hypothesized that this problem can be resolved by reducing the number of transcriptional factors used for porcine iPSCs induction. Here, we report the successful generation of porcine iPSCs using the porcine factors Oct4 and Klf4 in combination with specific small molecules. In comparison with high oxygen conditions (20%), the efficiency of porcine iPSC generation was higher under low oxygen conditions (5%). Porcine iPSCs exhibited a normal karyotype and morphology, like mouse embryonic stem cells (ESCs), and could proliferate in the absence of basic fibroblast growth factor (bFGF) and in the presence of human leukemia inhibitory factor (hLIF) and mouse embryonic fibroblast feeder cells. These iPSCs also expressed ESC-like markers (Oct4, Nanog, Klf4, c-Myc, Bmp4, bFgf). Importantly, the porcine iPSCs showed pluripotency, as evidenced by differentiation into three germ layers in vitro following embryoid body formation, as well as by efficiently forming teratomas containing three germ layers in immunodeficient mice. Thus, pluripotent porcine iPSCs can be generated from somatic stem cells by using only two porcine transcription factors in combination with small molecules. These attempts represent the first step toward generating truly pluripotent porcine iPSCs with fewer exogenous genes and less integration. PMID- 23035654 TI - Induced pluripotent stem cells: progress and future perspectives in the stem cell world. AB - Pluripotent stem cells (PSCs) have the potential to differentiate into many cell types and therefore can be a valuable source for cell therapy. Embryonic stem cells (ESCs), which are derived from the inner cell mass (ICM) of the blastocyst, are representative of PSCs. However, use of these cells has some limitations, especially ethical restrictions and immune response. As a result, researchers have been looking for other cell sources or strategies to overcome these limitations. One kind of cellular reprogramming is the process of guiding mature cells into a state of gene expression similar to PSCs. It has been demonstrated that somatic cells can be reprogrammed by various methods, including somatic cell nuclear transfer (SCNT) and cell fusion with ESCs or treatment with their extracts. This implies that some factors in oocytes and ESCs are able to initiate the reprogramming process. Accordingly, induced pluripotent stem cells (iPSCs) have been derived from somatic cells by ectopic expression of some transcription factors. This discovery has resulted in raising several important questions about the mechanisms by which these factors influence the reprogramming and epigenetic status of the cells. iPSCs hold great promise for regenerative medicine, developmental biology, and drug discovery because they circumvent problems associated with both ethical issues and immunological rejection. Here we review the experiments involved in the discovery of iPSCs, important factors in their reprogramming, and their future perspectives in cell therapy. PMID- 23035655 TI - Fat free mass explains the relationship between stunting and energy expenditure in urban Mexican Maya children. AB - BACKGROUND: Childhood stunting has been associated with an increased risk of obesity in adulthood, but the causes are unclear. This study hypothesizes that stunting significantly reduces both resting and activity energy expenditure. AIM: To assess and describe energy expenditure of low socio-economic Maya children and to determine whether stunting is independently related to energy expenditure after controlling for lean mass. SUBJECTS AND METHODS: Thirty-three urban Maya children, 17 boys, aged 7-9 years, living in Merida, Mexico, were measured for height, weight and bioelectrical impedance analysis (BIA). Body composition was estimated from BIA. Energy expenditure was measured for one week using the Actiheart (combined heart rate and accelerometer). RESULTS: Stunting (height-for age below the 5(th) percentile of NHANES III based references) affected 35% of these physically active children. Using multiple linear regression analysis, greater lean body mass predicted higher resting and activity energy expenditure. Stature was not a significant predictor of resting energy expenditure. A lower height-for-age z-score, but not stunting as a categorical variable, significantly predicted lower activity energy expenditure. CONCLUSION: The hypothesis that stunting reduces total energy expenditure (resting + active) in children is not supported. Rather, children with shorter stature and less lean body mass have lower total energy expenditure. Complex interactions between body size, body composition, and metabolic activity appear to elevate the risk for later life obesity in these Maya children. PMID- 23035656 TI - Dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (DPACE) is an effective salvage regimen for multiple myeloma refractory to novel agents. PMID- 23035657 TI - Thorough QT studies and indirect causes of QTc changes. PMID- 23035658 TI - Editorial comment: Acute urinary retention increases the risk of complications after transurethral resection of the prostate: a population-based study. PMID- 23035659 TI - Involvement of gangliosides in the process of Cbp/PAG phosphorylation by Lyn in developing cerebellar growth cones. AB - The association of gangliosides with specific proteins in the central nervous system was examined by coimmunoprecipitation with an anti-ganglioside antibody. The monoclonal antibody to the ganglioside GD3 (R24) immunoprecipitated the Csk (C-terminal src kinase)-binding protein (Cbp). Sucrose density gradient analysis showed that Cbp of rat cerebellum was detected in detergent-resistant membrane (DRM) raft fractions. R24 treatment of the rat primary cerebellar cultures induced Lyn activation and tyrosine phosphorylation of Cbp. Treatment with anti ganglioside GD1b antibody also induced tyrosine phosphorylation. Furthermore, over-expressions of Lyn and Cbp in Chinese hamster ovary (CHO) cells resulted in tyrosine 314 phosphorylation of Cbp, which indicates that Cbp is a substrate for Lyn. Immunoblotting analysis showed that the active form of Lyn and the Tyr314 phosphorylated form of Cbp were highly accumulated in the DRM raft fraction prepared from the developing cerebellum compared with the DRM raft fraction of the adult one. In addition, Lyn and the Tyr314-phosphorylated Cbp were highly concentrated in the growth cone fraction prepared from the developing cerebellum. Immunoelectron microscopy showed that Cbp and GAP-43, a growth cone marker, are localized in the same vesicles of the growth cone fraction. These results suggest that Cbp functionally associates with gangliosides on growth cone rafts in developing cerebella. PMID- 23035661 TI - Reducing analytical variation between point-of-care and laboratory HbA1c testing. AB - BACKGROUND: Point-of-care (POC) HbA1c testing allows for timely treatment changes, improved glycemic control, and patient and provider satisfaction. Substantial variation between POC and laboratory HbA1c results has been reported. At our university hospital diabetes clinic, we observed significant negative bias in HbA1c with the DCA Vantage (Siemens Healthcare Diagnostics, Tarrytown, NY, USA) compared with the Tosoh G8 HPLC laboratory analyzer (Tosoh Bioscience, San Francisco, CA, USA). This led us to systematically analyze the bias with the goal of recalibrating the DCA to minimize bias. METHODS: We analyzed 45 patient samples, with HbA1c ranging between 5% and 10.8%, concurrently on two DCA analyzers and on the Tosoh G8 machine. The bias for each sample was the difference between the value on the DCA and the Tosoh G8 analyzer. Based on regression equations derived from the data, a correction factor for each DCA analyzer was calculated. The analyzers were recalibrated and retested for bias. RESULTS: At baseline, the mean bias (range) was -0.5229 (+0.1 to -1.3) for Analyzer 1 and -0.5348 (0.0 to -1.6) for Analyzer 2. After recalibration, the mean bias (range) was 0.000 (+0.6 to -0.6) and 0.0003 (+0.5 to -0.5) for Analyzers 1 and 2, respectively, and the systematic negative bias seen prior to the calibration was almost eliminated. CONCLUSIONS: We recommend periodic recalibration of POC analyzers to eliminate systematic unidirectional bias and to harmonize results between the POC and central laboratory analyzers within a healthcare system. Calibration may need to be repeated with any change in the reagent lot. PMID- 23035660 TI - Congenital hypothyroidism mutations affect common folding and trafficking in the alpha/beta-hydrolase fold proteins. AB - The alpha/beta-hydrolase fold superfamily of proteins is composed of structurally related members that, despite great diversity in their catalytic, recognition, adhesion and chaperone functions, share a common fold governed by homologous residues and conserved disulfide bridges. Non-synonymous single nucleotide polymorphisms within the alpha/beta-hydrolase fold domain in various family members have been found for congenital endocrine, metabolic and nervous system disorders. By examining the amino acid sequence from the various proteins, mutations were found to be prevalent in conserved residues within the alpha/beta hydrolase fold of the homologous proteins. This is the case for the thyroglobulin mutations linked to congenital hypothyroidism. To address whether correct folding of the common domain is required for protein export, we inserted the thyroglobulin mutations at homologous positions in two correlated but simpler alpha/beta-hydrolase fold proteins known to be exported to the cell surface: neuroligin3 and acetylcholinesterase. Here we show that these mutations in the cholinesterase homologous region alter the folding properties of the alpha/beta hydrolase fold domain, which are reflected in defects in protein trafficking, folding and function, and ultimately result in retention of the partially processed proteins in the endoplasmic reticulum. Accordingly, mutations at conserved residues may be transferred amongst homologous proteins to produce common processing defects despite disparate functions, protein complexity and tissue-specific expression of the homologous proteins. More importantly, a similar assembly of the alpha/beta-hydrolase fold domain tertiary structure among homologous members of the superfamily is required for correct trafficking of the proteins to their final destination. PMID- 23035662 TI - Transport of nanoparticles in cystic fibrosis sputum and bacterial biofilms by single-particle tracking microscopy. AB - AIM: The aim of this study was to evaluate the effect of the surface functionalization of model nanoparticles on their mobility in bacterial biofilms and cystic fibrosis sputum. MATERIALS & METHODS: With single-particle tracking microscopy, the mobility of 0.1- and 0.2-um fluorescent polyethylene glycol (PEG) modified, carboxylate- and N,N-dimethylethylenediamine-modified polystyrene nanospheres were evaluated in fresh cystic fibrosis sputum, as well as Burkholderia multivorans and Pseudomonas aeruginosa biofilms. RESULTS: PEGylation increased the mobility of the particles in sputum and biofilms, while the charged nanospheres were strongly immobilized. However, the transport of the PEGylated nanoparticles was lower in sputum compared with biofilms. Furthermore, the particle transport showed heterogeneity in samples originating from different patients. CONCLUSION: This study's data suggest that for future nanocarrier design it will be essential to combine PEGylation with a targeting moiety to ensure sufficient mobility in mucus and a better accumulation of the nanoparticles in the biofilm. PMID- 23035664 TI - A multilevel memory based on proton-doped polyazomethine with an excellent uniformity in resistive switching. AB - The uniformity of operating parameters in organic nonvolatile memory devices is very important to avoid false programming and error readout problems. In the present work, we fabricated an organic resistive-switching memory based on protonic-acid-doped polyazomethine (PA-TsOH), which demonstrates an excellent operative uniformity and multilevel storage capability. The deliberate tuning of the resistance states can be attributed to the electric-field-controlled molecular doping of the imine-containing polymers. PMID- 23035663 TI - Changes in specialized blood vessels in lymph nodes and their role in cancer metastasis. AB - BACKGROUND: High endothelial venules (HEV) have been recognized to play a role in metastasis by its changes seen in the cancer microenvironment of lymph nodes (LN) and solid cancers. Squamous cell carcinoma (SCC) of the tongue is a prevalent tumor of the head and neck region with high propensity for LN metastasis. The extent of LN metastasis is the most reliable adverse prognostic factor. Primary tumors can induce vasculature reorganization within sentinel LN before the arrival of tumor cells and HEV represents these remodelled vessels. This study aims to evaluate the cancer induced vascular changes in regional lymph nodes (LN) of patients by studying the morphological and functional alterations of HEV and its correlation with clinical outcome and pathological features. METHODS: This study was based on 65 patients with SCC tongue who underwent primary surgical treatment including neck dissection. The patients were categorized into 2 groups based on the presence of malignancy in their cervical lymph nodes. A review of the patients' pathological and clinical data was performed from a prospective database. Immunohistochemical staining of the tissue blocks for HEV and high power-field image analysis were performed and analyzed with correlation to the patients' clinical and pathological features. RESULTS: The total number of HEV was found to be significantly associated to disease-free interval. There was a similar association comparing the HEV parameters to overall survival. The density of abnormal HEV was significantly higher in patients with established metastases in their lymph nodes and HEV was shown to be a better prognosis factor than conventional tumor staging. The HEV morphological metamorphosis demonstrates a spectrum that correlates well with disease progression and clinical outcome. CONCLUSIONS: The results suggest that the HEV displays a spectrum of morphological changes in the presence of cancer and LN metastasis, and that HEV is possibly involved in the process of cancer metastasis. We revealed the relationship of HEV and their metamorphosis in pre-metastatic and metastatic environments in regional lymph nodes of tongue cancer patients in relation to clinical outcomes. The significant observation of modified dilated HEV containing red blood cells in lymph nodal basin of a cancer suggests the shifting of its function from one primarily of immune response to that of a blood carrying vessel. It also demonstrated potential prognostic value. More studies are needed to elucidate its potential role in cancer immunotherapy and as a potential novel therapeutic approach to preventing metastasis by manipulating the remodelling processes of HEV. PMID- 23035665 TI - Novel word integration in the mental lexicon: evidence from unmasked and masked semantic priming. AB - We sought to establish whether novel words can become integrated into existing semantic networks by teaching participants new meaningful words and then using these new words as primes in two semantic priming experiments, in which participants carried out a lexical decision task to familiar words. Importantly, at no point in training did the novel words co-occur with the familiar words that served as targets in the primed lexical decision task, allowing us to evaluate semantic priming in the absence of direct association. We found that familiar words were primed by the newly related novel words, both when the novel word prime was unmasked (experiment 1) and when it was masked (experiment 2), suggesting that the new words had been integrated into semantic memory. Furthermore, this integration was strongest after a 1-week delay and was independent of explicit recall of the novel word meanings: Forgetting of meanings did not attenuate priming. We argue that even after brief training, newly learned words become an integrated part of the adult mental lexicon rather than being episodically represented separately from the lexicon. PMID- 23035667 TI - Chewing ability and tooth loss: association with cognitive impairment in an elderly population study. AB - OBJECTIVES: To determine whether there is an association between tooth loss, chewing ability, and cognitive function in a general elderly population. DESIGN: Data from the Panel Study of Living Conditions of the Oldest Old in 2002 were analyzed. Stepwise logistic regression analyses were used to examine the relationship between cognitive function and tooth loss and chewing ability. PARTICIPANTS: Five hundred fifty-seven persons who were nationally representative of the Swedish population aged 77 and older. MEASUREMENTS: Cognitive function was measured using the abridged version of the Mini-Mental State Examination. Information on dental status and chewing difficulty was obtained according to self-assessment. RESULTS: Persons with multiple tooth loss and persons with difficulty chewing hard food had significantly higher odds of cognitive impairment. When adjusted for sex, age, and education, the odds of cognitive impairment were not significantly different between persons with natural teeth and with multiple tooth loss, but the odds of impairment remained significantly higher for persons with chewing difficulty even when adjusted for sex, age, education, depression, and mental illness. CONCLUSION: Sex, age, education, and certain illnesses do not explain the association between cognition and chewing ability. Whether elderly persons chew with natural teeth or prostheses may not contribute significantly to cognitive impairment as long as they have no chewing difficulty. The results add to the evidence of the association between chewing ability and cognitive impairment in elderly persons. PMID- 23035666 TI - Cluster randomized controlled trial of a peer support program for people with diabetes: study protocol for the Australasian Peers for Progress study. AB - BACKGROUND: Well managed diabetes requires active self-management in order to ensure optimal glycaemic control and appropriate use of available clinical services and other supports. Peer supporters can assist people with their daily diabetes self-management activities, provide emotional and social support, assist and encourage clinical care and be available when needed. METHODS: A national database of Australians diagnosed with type 2 diabetes is being used to invite people in pre-determined locations to participate in community-based peer support groups. Peer supporters are self-identified from these communities. All consenting participants receive diabetes self-management education and education manual prior to randomization by community to a peer support intervention or usual care. This multi-faceted intervention comprises four interconnected components for delivering support to the participants. (1) Trained supporters lead 12 monthly group meetings. Participants are assisted to set goals to improve diabetes self-management, discuss with and encourage each other to strengthen linkages with local clinical services (including allied health services) as well as provide social and emotional support. (2) Support through regular supporter participant or participant-participant contact, between monthly sessions, is also promoted in order to maintain motivation and encourage self-improvement and confidence in diabetes self-management. (3) Participants receive a workbook containing diabetes information, resources and community support services, key diabetes management behaviors and monthly goal setting activity sheets. (4) Finally, a password protected website contains further resources for the participants. Supporters are mentored and assisted throughout the intervention by other supporters and the research team through attendance at a weekly teleconference. Data, including a self-administered lifestyle survey, anthropometric and biomedical measures are collected on all participants at baseline, 6 and 12 months. The primary outcome is change in cardiovascular disease risk using the UKPDS risk equation. Secondary outcomes include biomedical, quality of life, psychosocial functioning, and other lifestyle measures. An economic evaluation will determine whether the program is cost effective. DISCUSSION: This manuscript presents the protocol for a cluster randomized controlled trial of group-based peer support for people with type 2 diabetes in a community setting. Results from this trial will contribute evidence about the effectiveness of peer support in achieving effective self-management of diabetes. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR); ACTRN12609000469213. PMID- 23035668 TI - Chest computed tomography predicts microbiological burden and symptoms in pulmonary Mycobacterium xenopi. AB - BACKGROUND AND OBJECTIVE: The development of computed tomography (CT) findings usually precedes the diagnosis of pulmonary nontuberculous mycobacterial infection. The utility of specific CT scan features, although often available long before respiratory sample cultures, is not fully understood. We sought to assess associations among CT features, symptoms and microbiological disease criteria in pulmonary Mycobacterium xenopi isolation. METHODS: We reviewed 70 consecutive immunocompetent patients with pulmonary M. xenopi isolation and classified them according to the American Thoracic Society (ATS) diagnostic criteria for disease. 'Definite disease' patients (n = 16) met modified ATS criteria. 'Possible disease' patients (n = 10) met microbiological criteria, had abnormal CT scans, but data regarding symptoms were unavailable. 'No disease' patients (n = 44) had only one positive sputum culture, or were asymptomatic or had no relevant CT findings. Two radiologists, without knowledge of the clinical or microbiological information, independently reviewed the scans. RESULTS: The mean (standard deviation) age of all patients was 63 (16) years, and 39% were women. Patients with 'definite disease' usually had nodules (88%) and cavities (63%), but less often bronchiectasis (50%) and tree-in-bud (50%). Patients with 'possible' or 'no disease', respectively, had nodules (100% or 80%), bronchiectasis (40% or 18%) or tree-in-bud (40% or 11%). Cavitation (P <= 0.0001) and nodules >= 5 mm (P = 0.0002) were associated with fulfilled microbiological criteria for disease. Bronchiectasis (P = 0.02) and nodules <5 mm (P = 0.002) were associated with symptoms of infection. CONCLUSIONS: Among immunocompetent patients with pulmonary M. xenopi isolation, cavitation and large nodules predict fulfilling microbiological disease criteria, while bronchiectasis and small nodules predict symptoms. PMID- 23035670 TI - Influence of age and changes over time on erectile dysfunction: results from two large cross-sectional surveys 11 years apart. AB - OBJECTIVE: The aim was to explore how erectile dysfunction (ED) correlates with increasing age and a number of demographic, physical and lifestyle factors. MATERIAL AND METHODS: A questionnaire was sent to a random sample (10,458) of men living in Gothenburg, Sweden, in 1992. The men were from the age cohorts 45, 50, 55 years, etc., up to the age of 85 or older. An analogous survey was sent to a random sample (10,845) of men of age cohorts 46, 51, 56 years, etc., in 2003. The prevalence of ED from the different age cohorts assessed on the two specific occasions 11 years apart was compared with a number of factors. RESULTS: The response rates were 74.2% in 1992 and 68.7% in 2003. Within each survey the rate of ED increased with age at the same time as sexual activity decreased. This was paralleled by an increase in concomitant morbidity, intake of medications and alcohol consumption. The proportion of smokers and body mass index (BMI) decreased and the frequency of physical exercise increased until the age cohorts 70-71 years (1992) and 80-81 years (2003). Comparing the surveys, there was increased ED and decreased sexual activity over time despite an increase in exercise and decrease in smoking. In a multivariate analysis age, living alone, concomitant medication and smoking were the factors that significantly affected the risk of reporting ED. CONCLUSION: Despite a seemingly healthier lifestyle in 2003 compared with 1992, the rate of ED increased in the population, highlighting the importance of assessing lifestyle factors when examining ED patients. PMID- 23035671 TI - Thirty years of cardiac collaboration at Epworth. PMID- 23035669 TI - Physical activity as an aid to smoking cessation during pregnancy (LEAP) trial: study protocol for a randomized controlled trial. AB - BACKGROUND: Many women try to stop smoking in pregnancy but fail. One difficulty is that there is insufficient evidence that medications for smoking cessation are effective and safe in pregnancy and thus many women prefer to avoid these. Physical activity (PA) interventions may assist cessation; however, trials examining these interventions have been too small to detect or exclude plausible beneficial effects. The London Exercise And Pregnant smokers (LEAP) trial is investigating whether a PA intervention is effective and cost-effective when used for smoking cessation by pregnant women, and will be the largest study of its kind to date. METHODS/DESIGN: The LEAP study is a pragmatic, multi-center, two arm, randomized, controlled trial that will target pregnant women who smoke at least one cigarette a day (and at least five cigarettes a day before pregnancy), and are between 10 and 24 weeks pregnant. Eligible patients are individually randomized to either usual care (that is, behavioral support for smoking cessation) or usual care plus a intervention (entailing supervised exercise on a treadmill plus PA consultations). The primary outcome of the trial is self reported and biochemically validated continuous abstinence from smoking between a specified quit date and the end of pregnancy. The secondary outcomes, measured at 1 and 4 weeks after the quit date, and at the end of pregnancy and 6 months after childbirth, are PA levels, depression, self-confidence, and cigarette withdrawal symptoms. Smoking status will also be self-reported at 6 months after childbirth. In addition, perinatal measures will be collected, including antenatal complications, duration of labor, mode of delivery, and birth and placental weight. Outcomes will be analyzed on an intention-to-treat basis, and logistic regression models used to compare treatment effects on the primary outcome. DISCUSSION: This trial will assess whether a PA intervention is effective when used for smoking cessation during pregnancy. TRIAL REGISTRATION: ISRCTN48600346. PMID- 23035675 TI - Clinical-scientific notes. PMID- 23035676 TI - Total arterial coronary artery bypass grafting in patients with diabetes: an 8 year experience. AB - OBJECTIVE: Coronary artery bypass grafting using arterial conduits may improve survival and minimise harvest site complications. However, in diabetes, the outcomes of coronary artery bypass grafting performed exclusively using arterial conduits are uncertain. We reviewed our experience with this approach. METHODS: From 1996 to 2008, 400 patients with diabetes (managed with oral hypoglycaemics, insulin or both) underwent primary isolated coronary artery bypass grafting for triple vessel coronary disease. In 246 (61.5%), total arterial revascularisation was achieved using single or bilateral internal thoracic arteries supplemented by one or more radial arteries (arterial group), while in the remaining 154 (38.5%), at least one venous conduit was used (mixed conduits group: mean 1.5 veins per patient). Propensity-score matching was used to adjust for bias. RESULTS: Total arterial revascularisation patients were more likely to be younger (arterial: 63 +/- 10 years vs mixed: 67 +/- 10 years, P < 0.0001), of elective priority (85% vs 75%, P = 0.018) and less likely to have moderate-severe left ventricular dysfunction (23% vs 36%, P = 0.024). Use of bilateral internal thoracic arteries was similar between groups (16% vs 11%, P = 0.19). There was a comparable in hospital mortality (1.9% vs 2.0%, P > 0.99) and major morbidities, except the arterial group who experienced less stroke (0.4% vs 3.2% vs P = 0.04) and harvest site infections (0.4% vs 4%, P = 0.016). Mean follow was 7.8 +/- 3.7 years. Estimated survival at 12-year survival in the arterial group was 80% +/- 3.2% vs 54% +/- 5.5% (P < 0.0001). Subsequently, 103 propensity-score-matched patient pairs were created between the two groups. After matching, in-hospital mortality (1% vs 2%, P > 0.99) and major morbidities were similar, as was an estimated 12 year survival (69% +/- 6.1% vs 59% +/- 6.5%, P > 0.99). CONCLUSIONS: The use of veins to supplement arterial conduits did not deleteriously affect survival. However, the significant number of patients receiving arterial grafts in both groups may have masked any potential difference. Greater numbers and longer follow-up will reveal the potential of this approach. PMID- 23035677 TI - Towards appreciating appropriate clinical responses to highly sensitive cardiac troponin assays. AB - Cardiac troponins (cTn) are structural components of the contractile apparatus of the cardiomyocyte and the recommended biochemical markers for diagnosing myocardial infarction. Although the diagnostic performance of both cTnT and cTnI as biochemical markers are quite similar, it is the analytical sensitivities of these assays that have been found to create the difference. High-sensitivity cTn assays, which are capable of measuring cTn levels 10-folds lower than conventional fourth generation assays, are results of continuous effort to develop more sensitive and accurate tests to detect cardiac injury. While the improvement in the sensitivity of these assays promises improvement in many aspects of patient care, such as earlier myocardial infarction diagnosis and cardiac disease risk assessment, shortcoming of these assays must be considered. Very low measurable levels of cardiac damage biochemical markers can deliver occult yet possible decisive message. Better understanding of the pros and cons of these assays will pledge an appropriate clinical reaction to highly sensitive results. PMID- 23035678 TI - Coronary computed tomography angiography: a new wave of cardiac imaging. AB - Coronary computed tomography angiography (CTA) is becoming a popular non-invasive imaging modality for coronary arteries. It has high sensitivity and specificity in the evaluation of coronary artery disease (CAD). Due to its high negative predictive value, the main clinical role of coronary CTA is in the exclusion of significant CAD in the low to intermediate pretest probability patients. In the emergency department, coronary CTA helps to fast-track the triage of acute chest pain patients. One of the major coronary CTA's limitations is its false positive findings in the presence of heavily calcified lesions. With the advance of CT technology, the radiation dose of coronary CTA has been reduced significantly. At present, coronary CTA is still not indicated for screening asymptomatic patients. PMID- 23035679 TI - Comprehensive echocardiographic diagnosis of right heart enlargement in association with partial anomalous pulmonary venous drainage in three adult women. AB - Partial anomalous pulmonary venous drainage is a rare congenital anomaly which can lead to right heart enlargement. It may present in isolation or more commonly in association with other congenital cardiac anomalies. We present three different cases of partial anomalous pulmonary venous drainage in adults. The importance of identifying partial anomalous venous drainage as the cause of otherwise unexplained right heart enlargement is illustrated by these cases. PMID- 23035680 TI - Non-invasive ventilation in critical care. AB - Non-invasive ventilation refers to a number of respiratory support strategies commonly used in critical care settings. This paper describes the principles of non-invasive ventilation, the practicalities of its use and the evidence for its use in a number of common acute conditions. PMID- 23035681 TI - Embolism as a mechanism of cerebral infarction. AB - In the last half century, cerebral embolism from proximal sources other than the heart has been better understood thanks to technological advances that have become routine in stroke investigation. PMID- 23035682 TI - Percutaneous coronary intervention or prehospital thrombolysis? What is the preferred treatment in S-T elevation myocardial infarction? AB - There is no situation in medicine where outcome is so utterly dependent on time than in the treatment of patients with S-T elevation myocardial infarction. This life-threatening situation accounts for 30% of acute coronary syndromes. Prompt myocardial reperfusion saves lives, but health services need to be thoroughly organised to achieve this outcome. Unfortunately, a minority of patients in Australia present within 2 h of symptom onset and most patients receive reperfusion 3-4 h after. So health professionals begin at a disadvantage. A novel approach to this problem has been to give thrombolysis at first contact with the patient, before admission to hospital. A French study has assessed this practice against the gold standard treatment for S-T elevation myocardial infarction with some very interesting results. The implications of this study now challenge well entrenched guidelines for the management of patients with this condition. PMID- 23035683 TI - Sugar restriction: the evidence for a drug-free intervention to reduce cardiovascular disease risk. AB - BACKGROUND/AIM: Uncertainty exists about what dietary component is most likely to cause coronary heart disease. Over the last thirty years, attention has focused on saturated fat and salt as guilty parties. More recently, evidence suggests that excess sugar intake is more likely than either traditional factor to lead to atherosclerotic disease. Some researchers have also speculated that sugar is addictive, in a similar manner to caffeine and established drugs of abuse. METHODS: Here we review the epidemiological, biochemical and psychological evidence that implicates excess sugar intake as an important cause of ill-health. RESULTS: We found relatively consistent evidence of association between markers of sugar intake and risk factors for cardiovascular disease, or the disease itself. This evidence contrasted with rather weaker evidence which linked either saturated fat or salt with cardiovascular disease endpoints. We also found some evidence of a sugar addiction syndrome. CONCLUSION: We suggest that advice to restrict sugar intake should be a routine part of clinical care, particularly when patients are being counselled about cardiovascular risk. PMID- 23035684 TI - Current state of the performance of percutaneous coronary intervention in centres without on-site cardiac surgery. AB - Before the routine use of coronary stents, potential complications of percutaneous coronary interventions required the presence of backup cardiac surgery on-site. Advances in pharmacotherapy and interventional techniques, particularly in the last decade, have significantly decreased the rates of complications requiring emergency cardiac surgery, from approximately 4% to 6% in the balloon angioplasty era to as low as 0.3% to 0.6% in the contemporary era of routine intracoronary stent implantation. An early invasive approach has been shown to improve outcomes among patients with non-ST elevation acute coronary syndromes (NSTEACS), particularly in those at the highest risk, emphasising the importance of early access to revascularisation premises in such patients. Patients with ST-segment elevation myocardial infarction require immediate and sustained recanalisation of the culprit vessel to obtain rapid reperfusion of the threatened myocardium, in order to reduce infarct size and improve outcomes. Primary percutaneous coronary intervention at hospitals without on-site cardiac surgery improves clinical outcomes and reduces length of stay when compared with fibrinolytic therapy. It also significantly reduces door-to-balloon times when compared with transfer for percutaneous coronary interventions at hospitals with on-site surgery. It has been published that risk-adjusted mortality rates for patients undergoing percutaneous coronary interventions in centres without on site surgical backup are comparable with those of percutaneous coronary intervention facilities that have cardiac surgery on-site, regardless of whether percutaneous coronary intervention was performed as primary therapy for ST segment elevation myocardial infarction or in a non-primary setting. To achieve these results however, an adequate percutaneous coronary intervention programme is required, including proper hospital infrastructure and appropriately trained interventional cardiologists. PMID- 23035685 TI - The 'Epworth-China connection'. AB - Interventional cardiologists from China first arrived at the Epworth Hospital in Melbourne for training in percutaneous transluminal coronary angioplasty in 1988. Percutaneous transluminal coronary angioplasty was initially performed in China in 1981 in Xian. In those days, angioplasty balloons and catheters that were brought into China mainly by foreign experts were used repeatedly until they were broken. Dr. Antonio Colombo was invited to visit Beijing, China, in 1998 to demonstrate coronary stenting at the Chaoyang Hospital. By 2010, more than 300,000 cases of percutaneous coronary interventions (PCIs) had been performed throughout China. If the current rate of PCIs per population in the West was to be applied in China, more than 4 million PCIs should have been performed annually. PMID- 23035686 TI - Perspectives in ablation of arrhythmias in children and patients with congenital heart disease. AB - Although most arrhythmias in children have a benign outcome, recurrent arrhythmic events have a significant impact on quality of life. Electrophysiology studies with ablation have good short-term success and an acceptably low complication rate. The long-term outlook for this patient group is incompletely defined, however. Factors that require special consideration in children include the need to limit the size, depth and number of lesions, and the radiation exposure incurred during fluoroscopy-guided catheters manipulation. The use of cryoablation seems promising in limiting lesion size. Three-dimensional (3D) mapping systems clearly have been shown to reduce the radiation dose. In congenital heart disease, these advances in technology have helped to further our understanding of the mechanisms underlying arrhythmias. It is anticipated that earlier intervention and newer operative techniques will reduce the incidence of postoperative arrhythmias in the future. For those patients who still develop tachyarrythmias after cardiac surgery, the use of three-dimensional systems and other new technologies permits more efficient intervention in the electrophysiology laboratory. PMID- 23035687 TI - Interventional cardiology audit report for 2011. AB - In 2011 there were 658 percutaneous coronary intervention cases performed with more than 60% of the patients presenting to the hospital as an acute coronary syndrome. Most procedures consisted of balloon dilatation followed by stent deployment, and 93% of these stents were drug-eluting stents. Procedural success was achieved in 93.3% of cases and an overall major adverse cardiac events rate of 3.6%. This includes a mortality rate of (0.5%). In addition, there were 25 Core Valve procedures carried out. This is more than twice the amount of patients who had a transcatheter aortic valve implantation in 2010, reflecting the changing direction of the management of structural heart disease. PMID- 23035688 TI - Epworth HealthCare cardiac surgery audit report 2011. AB - 2011 is the first year Epworth has contributed to Australian and New Zealand Society of Cardiac and Thoracic Surgeons cardiac surgery database. There is now a 30-day follow-up data for all cardiac surgical patients as well as benchmarking of our results with 19 public hospitals and 6 private hospitals contributing data to the Australian and New Zealand Society of Cardiac and Thoracic Surgeons. This is an extension of the John Fuller Melbourne University database that has compiled cardiac surgery data for the last 30 years. PMID- 23035689 TI - Syntheses and electronic properties of rhodium(III) complexes bearing a redox active ligand. AB - A series of rhodium(III) complexes of the redox-active ligand, H(L = bis(4-methyl 2-(1H-pyrazol-1-yl)phenyl)amido), was prepared, and the electronic properties were studied. Thus, heating an ethanol solution of commercial RhCl(3).3H(2)O with H(L) results in the precipitation of insoluble [H(L)]RhCl(3), 1. The reaction of a methanol suspension of [H(L)]RhCl(3) with NEt(4)OH causes ligand deprotonation and affords nearly quantitative yields of the soluble, deep-green, title compound (NEt(4))[(L)RhCl(3)].H(2)O, 2.H(2)O. Complex 2.H(2)O reacts readily with excess pyridine, triethylphosphine, or pyrazine (pyz) to eliminate NEt(4)Cl and give charge-neutral complexes trans-(L)RhCl(2)(py), trans-3, trans-(L)RhCl(2)(PEt(3)), trans-4, or trans-(L)RhCl(2)(pyz), trans-5, where the incoming Lewis base is trans- to the amido nitrogen of the meridionally coordinating ligand. Heating solutions of complexes trans-3 or trans-4 above about 100 degrees C causes isomerization to the appropriate cis-3 or cis-4. Isomerization of trans-5 occurs at a much lower temperature due to pyrazine dissociation. Cis-3 and cis-5 could be reconverted to their respective trans- isomers in solution at 35 degrees C by visible light irradiation. Complexes [(L)Rh(py)(2)Cl](PF(6)), 6, [(L)Rh(PPh(3))(py)Cl](PF(6)), 7, [(L)Rh(PEt(3))(2)Cl](PF(6)), 8, and [(L)RhCl(bipy)](OTf = triflate), 9, were prepared from 2.H(2)O by using thallium(I) salts as halide abstraction agents and excess Lewis base. It was not possible to prepare dicationic complexes with three unidentate pyridyl or triethylphosphine ligands; however, the reaction between 2, thallium(I) triflate, and the tridentate 4'-(4-methylphenyl)-2,2':6',2"-terpyridine (ttpy) afforded a high yield of [(L)Rh(ttpy)](OTf)(2), 10. The solid state structures of nine new complexes were obtained. The electrochemistry of the various derivatives in CH(2)Cl(2) showed a ligand-based oxidation wave whose potential depended mainly on the charge of the complex, and to a lesser extent on the nature and the geometry of the other supporting ligands. Thus, the oxidation wave for 2 with an anionic complex was found at +0.27 V versus Ag/AgCl in CH(2)Cl(2), while those waves for the charge-neutral complexes 3-5 were found between +0.38 to +0.59 V, where the cis- isomers were about 100 mV more stable toward oxidation than the trans- isomers. The oxidation waves for 6-9 with monocationic complexes occurred in the range +0.74 to 0.81 V while that for 10 with a dicationic complex occurred at +0.91 V. Chemical oxidation of trans-3, cis-3, and 8 afforded crystals of the singly oxidized complexes, [trans-(L)RhCl(2)(py)](SbCl(6)), cis [(L)RhCl(2)(py)](SbCl(4)).2CH(2)Cl(2), and [(L)Rh(PEt(3))(2)Cl](SbCl(6))(2), respectively. Comparisons of structural and spectroscopic features combined with the results of density functional theory (DFT) calculations between nonoxidized and oxidized forms of the complexes are indicative of the ligand-centered radicals in the oxidized derivatives. PMID- 23035690 TI - Airborne particulate matter and innate immunity activation. PMID- 23035692 TI - Interim positron emission tomography and clinical outcome in patients with early stage Hodgkin lymphoma treated with combined modality therapy. AB - The aim of the study was to investigate whether interim positron emission tomography (iPET) is prognostic in a cohort of patients with early stage Hodgkin lymphoma (HL) homogeneously treated with 3-4 cycles of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) followed by 30 Gy involved field radiotherapy. Eighty patients were selected (stage I-IIA HL, availability of iPET, minimum follow-up of 12 months), and after central review, 70 were judged negative (iPET-: 87.5%) and 10 positive (iPET+: 12.5%). The two groups were then analyzed for response, progression-free survival (PFS) and overall survival (OS). Only one out of 70 iPET- patients relapsed, with 69 in continuous complete remission (CCR). All 10 iPET + patients achieved a complete response and maintained persistent CCR at follow-up. The 3-year PFS and OS were, respectively, 97% and 98.4% for iPET- and 100% and 100% for iPET+ (p = 0.63). iPET positivity does not seem to be a significant prognostic factor, and change in therapeutic strategy on the basis of iPET does not appear currently advisable outside clinical trials. PMID- 23035691 TI - Analysis of the Lactobacillus casei supragenome and its influence in species evolution and lifestyle adaptation. AB - BACKGROUND: The broad ecological distribution of L. casei makes it an insightful subject for research on genome evolution and lifestyle adaptation. To explore evolutionary mechanisms that determine genomic diversity of L. casei, we performed comparative analysis of 17 L. casei genomes representing strains collected from dairy, plant, and human sources. RESULTS: Differences in L. casei genome inventory revealed an open pan-genome comprised of 1,715 core and 4,220 accessory genes. Extrapolation of pan-genome data indicates L. casei has a supragenome approximately 3.2 times larger than the average genome of individual strains. Evidence suggests horizontal gene transfer from other bacterial species, particularly lactobacilli, has been important in adaptation of L. casei to new habitats and lifestyles, but evolution of dairy niche specialists also appears to involve gene decay. CONCLUSIONS: Genome diversity in L. casei has evolved through gene acquisition and decay. Acquisition of foreign genomic islands likely confers a fitness benefit in specific habitats, notably plant-associated niches. Loss of unnecessary ancestral traits in strains collected from bacterial-ripened cheeses supports the hypothesis that gene decay contributes to enhanced fitness in that niche. This study gives the first evidence for a L. casei supragenome and provides valuable insights into mechanisms for genome evolution and lifestyle adaptation of this ecologically flexible and industrially important lactic acid bacterium. Additionally, our data confirm the Distributed Genome Hypothesis extends to non-pathogenic, ecologically flexible species like L. casei. PMID- 23035693 TI - Quality of life in raloxifene-treated Japanese women with postmenopausal osteoporosis: a prospective, postmarketing observational study. AB - OBJECTIVE: To assess changes in quality of life (QOL) and pain in raloxifene treated Japanese women with postmenopausal osteoporosis. RESEARCH DESIGN AND METHODS: This prospective, postmarketing observational study was conducted at 60 Japanese hospitals from September 2007 to February 2009 and included Japanese women with postmenopausal osteoporosis who were new to standard treatment with raloxifene (60 mg/day). Primary outcome measures (QOL and pain) were assessed using the Short Form-8 (SF-8), European Quality of Life Instrument (EQ-5D), osteoporosis-specific Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), a visual analogue scale (VAS-pain), and a pain frequency survey. Assessments were performed at baseline and 8 (except JOQOL) and 24 weeks after first administration of raloxifene. Adverse drug reactions were recorded. Japan Pharmaceutical Information Center registration number: JapicCTI-070465. RESULTS: A total of 506 participants, mean (+/-standard deviation [SD]) age = 70.7 +/- 8.7 years, completed >=1 follow-up assessment and were included in the analyses. All QOL scores increased from baseline during follow-up. All SF-8 domain scores increased significantly from baseline after 8 and 24 weeks (P < 0.001). Mean (+/ SD) EQ-5D scores increased significantly from baseline (0.70 +/- 0.17) by 0.05 +/ 0.15 after 8 weeks and 0.07 +/- 0.17 after 24 weeks (P < 0.001). The mean (+/ SD) total JOQOL score increased significantly from baseline (66.8 +/- 16.5) by 3.8 +/- 11.3 after 24 weeks (P < 0.001). The percentage of participants with a >=20 mm reduction in VAS-pain was 32.6% (120/368) and 39.5% (115/291) after 8 and 24 weeks, respectively. The frequency of pain reported by participants decreased after 8 and 24 weeks. Forty adverse drug reactions were reported by 34 participants. LIMITATIONS: Limitations include the lack of a control group, the possibility of the changes being due to the natural disease course, and potential selection bias. CONCLUSIONS: Our findings suggest that standard treatment with raloxifene improves QOL and relieves pain in Japanese women with postmenopausal osteoporosis in a real-world clinical setting. PMID- 23035694 TI - Conformational and dynamic changes at the interface contribute to ligand binding by ubiquitin. AB - Ubiquitin interacts with numerous domains and motifs in its lifetime that vary in structure but bind the same hydrophobic patch. To identify the structural features of ubiquitin that make it an exceptional protein-protein interaction partner, we have studied the interaction of ubiquitin with the signal transducing adaptor molecule-1 ubiquitin interacting motif (UIM) using nuclear magnetic resonance. Our studies bring to light the role of the inherent backbone flexibility of ubiquitin in its interactions with a large array of binding partners, revealed from the changes in C(alpha) chemical shifts, backbone dynamics, and hydrogen bond lengths upon UIM binding. The crystal structures of ubiquitin complexes lend further support to our findings, underscoring the importance of the unique and flexible hydrogen bond network within ubiquitin and simultaneously providing insights into the nature of the slow motions. Taken together, our studies provide an in-depth view of the molecular changes associated with ligand recognition by ubiquitin. PMID- 23035696 TI - Principal component analysis based pre-cystectomy model to predict pathological stage in patients with clinical organ-confined bladder cancer. AB - OBJECTIVE: To develop a model that integrates the clinical and pathological information prior to radical cystectomy to increase the accuracy of current clinical stage in prediction of pathological stage in patients with bladder cancer (BC) using a modelling approach called principal component analysis (PCA). PATIENTS AND METHODS: In a single-centre retrospective study, demographic and clinicopathological information of 1186 patients with clinically organ-confined (OC) BC was reviewed. Putative predictors of post-cystectomy pathological stage were identified using a stepwise logistic regression model. Patients were randomly divided into training data set (two-thirds of the study population, 790 patients) and test data set (one-third of the study population, 396 patients). The PCA method was used to develop the model in the training data set and the cut off point (PCA score) to differentiate pathological OC disease from extravesical disease was determined. The model was then applied to the test data set without recalculation. RESULTS: In all, 685 patients (57.7%) had pathological OC disease. Age, clinical stage, number of intravesical treatments, lymphovascular invasion, multiplicity of tumours, hydronephrosis and palpable mass were incorporated into the PCA model as predictors of pathological stage. The sensitivity and specificity of the PCA model in the test data set were 62.8% (95% CI 55.6%-68.1%) and 68.9% (95% CI 60.8%-76.0%), respectively. The positive and negative predictive values were 75.8% (95% CI 69.0%-81.6%) and 51.5% (95% CI 44.4%-58.5%), respectively. CONCLUSIONS: The pre-cystectomy PCA model improved the ability to differentiate OC disease from extravesical BC and especially decreased the under staging rate. The pre-cystectomy PCA model represented a user-friendly staging aid without the need for sophisticated statistical interpretation. PMID- 23035695 TI - 1alpha,25-Dihydroxyvitamin D3-liganded vitamin D receptor increases expression and transport activity of P-glycoprotein in isolated rat brain capillaries and human and rat brain microvessel endothelial cells. AB - Induction of the multidrug resistance protein 1 (MDR1)/P-glycoprotein (P-gp) by the vitamin D receptor (VDR) was investigated in isolated rat brain capillaries and rat (RBE4) and human (hCMEC/D3) brain microvessel endothelial cell lines. Incubation of isolated rat brain capillaries with 10 nM of the VDR ligand, 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] for 4 h increased P-gp protein expression fourfold. Incubation with 1,25(OH)(2)D(3) for 4 or 24 h increased P-gp transport activity (specific luminal accumulation of NBD-CSA, the fluorescent P gp substrate) by 25-30%. In RBE4 cells, Mdr1b mRNA was induced in a concentration dependent manner by exposure to 1,25(OH)(2)D(3). Concomitantly, P-gp protein expression increased 2.5-fold and was accompanied by a 20-35% reduction in cellular accumulation of the P-gp substrates, rhodamine 6G (R6G), and HiLyte Fluor 488-labeled human amyloid beta 1-42 (hAbeta(42)). In hCMEC/D3 cells, a 3 day exposure to 100 nM 1,25(OH)(2)D(3) increased MDR1 mRNA expression (40%) and P gp protein (threefold); cellular accumulation of R6G and hAbeta(42) was reduced by 30%. Thus, VDR activation up-regulates Mdr1/MDR1 and P-gp protein in isolated rat brain capillaries and rodent and human brain microvascular endothelia, implicating a role for VDR in increasing the brain clearance of P-gp substrates, including hAbeta(42), a plaque-forming precursor in Alzheimer's disease. PMID- 23035697 TI - Therapeutic options for Acinetobacter baumannii infections: an update. AB - INTRODUCTION: Although the clinical importance of Acinetobacter pittii and Acinetobacter nosocomialis has increased in the nosocomial setting in the last decade, infections caused by Acinetobacter baumannii still have the highest clinical relevance. The most important features of this latter species are the ability to persist in the hospital environment and the multi-drug, extended-drug or pandrug resistance they may present which compromises the treatment of infections caused by this microorganism. AREAS COVERED: In the present review, the authors describe the molecular bases of the acquisition of resistant mechanisms as well as different current and potential future strategies to treat infections caused by multi-drug resistant A. baumannii. EXPERT OPINION: With the increase in resistance to carbapenems, colistin has been extensively used, however some data suggest that the doses recommended are insufficient before a steady state is reached, suggesting that the administration of a loading dose on initiation of treatment may be beneficial. Combinations of antibacterial agents such as impenem plus sulbactam or imipenem plus colistin have been successfully used to treat VAP. Nonetheless, future alternatives for treating A. baumannii infections should be explored. PMID- 23035698 TI - Your words are my words: effects of acting together on encoding. AB - Social influences on action and memory are well established. However, it is unknown how acting together affects the incidental encoding of information. The present study asked whether coactors encode information that is relevant to a partner's task, but irrelevant to their own task. In Experiment 1, participants performed a categorization task alone and together, followed by a surprise free recall test where they were asked to recall items from the categorization task. Recall was better not only for items that participants had responded to themselves, but also for items that their coactor had responded to, than for items that had not required a response. The same results were found in Experiment 2, even though financial incentives motivated participants to only encode words they had responded to themselves. Together, the findings suggest that performing tasks together can modulate how information relevant to coactors is processed. Shared task representations may act as a vehicle for establishing shared memories. PMID- 23035699 TI - Effect of different blood glucose target levels on the incidence of hypoglycemia during insulin therapy in the intensive care unit. AB - BACKGROUND: Prior to 2003, the target blood glucose level at our institute was <200 mg/dL. This target was reassessed in 2004 and again in 2006 based on reports showing decreased mortality in patients with target glucose levels between 80 and 110 mg/dL and results from subsequent randomized controlled trials. The aim of the present study was to determine the incidence of hypoglycemia due to IIT. The primary endpoint of the study was the incidence of hypoglycemia, with secondary outcomes of morbidity and mortality in three different periods. METHODS: A total of 2038 patients admitted to the intensive care unit (ICU) were divided into three groups with different target blood glucose levels: Group H, <200 mg/dL; Group M, <150 mg/dL; and Group L, <120 mg/dL. The incidence of hypoglycemia and patient outcomes in the three groups were compared. RESULTS: The incidence of serious hypoglycemia (<40 mg/dL) in Groups H, M and L was 3.5%, 4.0%, and 5.4%, respectively; the incidence of moderate hypoglycemia (<60 mg/dL) was 9.4%, 11.7%, and 21.0% (P < 0.01), respectively. There were no significant differences among the groups in terms of days connected to the ventilator, length of ICU stay and ICU mortalities. CONCLUSIONS: The incidence of moderate hypoglycemia (<60 mg/dL) was significantly increased during the period when the target blood glucose level was <120 mg/dL. Changes in target blood glucose levels did not affect patient mortality. PMID- 23035700 TI - Human growth and chronic disease: a memorial to Jim Tanner. AB - CONTEXT: Memorial to Jim Tanner. OBJECTIVE: To examine the links between early growth and chronic disease in later life. METHODS: Literature review. RESULTS: There is now a developmental model for the origins of chronic disease in which the causes to be identified are linked to normal variations in feto-placental, infant and childhood growth and development. These variations lead to variations in the supply of nutrients to the baby that permanently alters gene expression, a process known as 'programming'. CONCLUSIONS: Variations in the processes of development programme the function of a few key systems that are linked to chronic disease-the immune system, anti-oxidant defences, inflammatory responses, the number and quality of stem cells, neuro-endocrine settings and the balance of the autonomic nervous system. There is not a separate cause for each different disease. Which chronic disease originates during development may depend more on timing than on qualitative differences in exposures to external influences. PMID- 23035701 TI - Efficacy of phosphatidic acid ingestion on lean body mass, muscle thickness and strength gains in resistance-trained men. AB - BACKGROUND: Phosphatidic acid (PA) has been reported to activate the mammalian target of rapamycin (mTOR) signaling pathway and is thought to enhance the anabolic effects of resistance training. The purpose of this pilot study was to examine if oral phosphatidic acid administration can enhance strength, muscle thickness and lean tissue accruement during an 8-week resistance training program. METHODS: Sixteen resistance-trained men were randomly assigned to a group that either consumed 750 mg of PA (n = 7, 23.1 +/- 4.4 y; 176.7 +/- 6.7 cm; 86.5 +/- 21.2 kg) or a placebo (PL, n = 9, 22.5 +/- 2.0 y; 179.8 +/- 5.4 cm; 89.4 +/- 13.6 kg) group. During each testing session subjects were assessed for strength (one repetition maximum [1-RM] bench press and squat) and body composition. Muscle thickness and pennation angle were also measured in the vastus lateralis of the subject's dominant leg. RESULTS: Subjects ingesting PA demonstrated a 12.7% increase in squat strength and a 2.6% increase in LBM, while subjects consuming PL showed a 9.3% improvement in squat strength and a 0.1% change in LBM. Although parametric analysis was unable to demonstrate significant differences, magnitude based inferences indicated that the Delta change in 1-RM squat showed a likely benefit from PA on increasing lower body strength and a very likely benefit for increasing lean body mass (LBM). CONCLUSIONS: Results of this study suggest that a combination of a daily 750 mg PA ingestion, combined with a 4-day per week resistance training program for 8-weeks appears to have a likely benefit on strength improvement, and a very likely benefit on lean tissue accruement in young, resistance trained individuals. PMID- 23035703 TI - Impact of atrial fibrillation termination on clinical outcome after ablation in relation to the duration of persistent atrial fibrillation. AB - BACKGROUND: Whether procedural termination of persistent atrial fibrillation (AF) is necessary for optimal clinical efficacy still remains controversial. We sought to characterize the patients with persistent AF in whom procedural AF termination impacted an improved clinical outcome after ablation. METHODS: We retrospectively assessed 132 patients (61.0 +/- 9.3 years, 114 males) undergoing catheter ablation of persistent AF (duration 3 years, median). A stepwise ablation approach including pulmonary vein isolation and atrial substrate ablation targeting complex fractionated and high-frequency electrograms was performed with desired endpoint of AF termination. RESULTS: Overall, 90 patients (68%) were free from recurrent arrhythmias at 20 +/- 11 months of follow-up after one or two procedures. The left atrial diameter and continuous AF duration according to medical history were associated with the outcome (P = 0.002 and P< 0.001, respectively). In multivariate Cox regression analysis, the continuous AF duration was the only independent predictor of recurrent arrhythmias (hazard ratio 1.17, 95% confidence interval 1.10-1.23, P < 0.001). In patients with AF duration of >= 3 years, the clinical success was comparable regardless of whether AF termination was achieved or not (log-rank, P = 0.27). In the remaining patients with AF duration of <3 years, procedural AF termination was associated with a higher arrhythmia-free rate than when AF was sustained after ablation (log rank, P = 0.023). CONCLUSION: Extensive ablation to terminate AF might not be warranted in patients with a longer AF duration. On the contrary, procedural AF termination could be associated with maintenance of sinus rhythm in patients with a shorter AF duration with a less proarrhythmic substrate. (PACE 2012;35:1436 1443). PMID- 23035702 TI - Patterns of multimorbidity in elderly veterans. AB - OBJECTIVES: To determine patterns of co-occurring diseases in older adults and the extent to which these patterns vary between the young-old and the old-old. DESIGN: Observational study. SETTING: Department of Veterans Affairs. PARTICIPANTS: Veterans aged 65 years and older (1.9 million male, mean age 76 +/- 7; 39,000 female, mean age 77 +/- 8) with two or more visits to Department of Veterans Affairs (VA) or Medicare settings in 2007 and 2008. MEASUREMENTS: The presence of 23 common conditions was assessed using hospital discharge diagnoses and outpatient encounter diagnoses from the VA and Medicare. RESULTS: The mean number of chronic conditions (out of 23 possible) was 5.5 +/- 2.6 for men and 5.1 +/- 2.6 for women. The prevalence of most conditions increased with advancing age, although diabetes mellitus and hyperlipidemia were 11% to 13% less prevalent in men and women aged 85 and older than in those aged 65 to 74 (P < .001 for each). In men, the most common three-way combination of conditions was hypertension, hyperlipidemia, and coronary heart disease, which together were present in 37% of men. For women, the most common combination was hypertension, hyperlipidemia, and arthritis, which co-occurred in 25% of women. Reflecting their high population prevalence, hypertension and hyperlipidemia were both present in 9 of the 15 most common three-way disease combinations in men and in 11 of the 15 most common combinations in women. The prevalence of many disease combinations varied substantially between young-old and old-old adults. CONCLUSIONS: Specific combinations of diseases are highly prevalent in older adults and inform the development of guidelines that account for the simultaneous presence of multiple chronic conditions. PMID- 23035704 TI - Influence of asthma definition on the asthma-obesity relationship. AB - BACKGROUND: Epidemiological studies suggest an association between obesity and asthma in adults and children. Asthma diagnosis criteria are different among studies. The aim of this study was to test the influence of asthma definition on the asthma-obesity relationship. METHODS: In a cross-sectional analysis of 1922 men and women, subjects completed a translated questionnaire from the European Community Respiratory Health Survey and underwent spirometry and a bronchial challenge test. Weight, height and waist circumference were measured. Multiple logistic regression analysis was carried out to assess the association of variables related to obesity and asthma. Asthma was defined either by the presence of symptoms with bronchial hyperresponsiveness (BHR) or by a self-report of a physician-made diagnosis. The following variables were separately tested for associations with asthma: socioeconomic characteristics, schooling, physical activity, smoking status, anthropometry and spirometry. RESULTS: No association was detected between asthma confirmed by BHR and obesity indicators, odds ratio (OR) = 1.08 (95% confidence interval: 0.69 - 1.68) for obesity assessed by body mass index >= 30 kg/m2; OR = 1.02 (0.74 - 1.40) for obesity assessed by abnormal waist-to-height ratio; and, OR = 0.96 (0.69 - 1.33) for abnormal waist circumference. On the contrary, a previous diagnosis of asthma was associated with obesity, OR = 1.48 (1.01 - 2.16) for body mass index >= 30 kg/m2; OR = 1.48 (1.13 - 1.93) for abnormal waist-to-height ratio; and, OR = 1.32 (1.00 - 1.75) for abnormal waist circumference. Female gender, schooling >= 12 years and smoking were associated with BHR-confirmed asthma. Physically inactive subjects were associated with a previous diagnosis of asthma. CONCLUSIONS: Our findings indicate that the relationship between asthma and obesity in epidemiological studies depends on the definition adopted. Certain components of asthma, for instance, symptoms may be more prone to the obesity influence than other ones, like bronchial hyperresponsiveness. PMID- 23035705 TI - Empirically defined patterns of executive function deficits in schizophrenia and their relation to everyday functioning: a person-centered approach. AB - Executive function (EF) deficits in schizophrenia (SZ) are well documented, although much less is known about patterns of EF deficits and their association to differential impairments in everyday functioning. The present study empirically defined SZ groups based on measures of various EF abilities and then compared these EF groups on everyday action errors. Participants (n = 45) completed various subtests from the Delis-Kaplan Executive Function System (D KEFS) and the Naturalistic Action Test (NAT), a performance-based measure of everyday action that yields scores reflecting total errors and a range of different error types (e.g., omission, perseveration). Results of a latent class analysis revealed three distinct EF groups, characterized by (a) multiple EF deficits, (b) relatively spared EF, and (c) perseverative responding. Follow-up analyses revealed that the classes differed significantly on NAT total errors, total commission errors, and total perseveration errors; the two classes with EF impairment performed comparably on the NAT but performed worse than the class with relatively spared EF. In sum, people with SZ demonstrate variable patterns of EF deficits, and distinct aspects of these EF deficit patterns (i.e., poor mental control abilities) may be associated with everyday functioning capabilities. PMID- 23035706 TI - Molecular mechanism of fertilization in the pig. AB - At fertilization, the sperm triggers resumption from the arrest, extrusion of the second polar body and pronuclear formation, the events of which are collectively acknowledged as 'oocyte activation'. In all species up to date, oocyte activation requires a fertilization-associated increase in the intracellular concentration of calcium. Especially in mammals, the signal of intracellular calcium rise at fertilization consists of periodical rises, which are also referred to as calcium oscillations. Our recent results suggest that these calcium oscillations have an important role in not only oocyte activation but also development of mammals. Pigs are animals of great agricultural value and ones in which assisted reproductive techniques, including somatic cell nuclear transfer, to produce gene modified pigs. Although reconstructed embryos require artificial activation stimuli which mimic fertilization-associated increase of intracellular calcium in the oocytes, it has been known that the developmental ability of the oocytes after artificial activation is low and the regimen seems to be required for improvement. Recently we focused on two molecules, phospholipase C zeta and inositol 1,4,5-triphosphate receptor which have important roles in regulation of calcium oscillations during fertilization in mammals, including pigs. In this review, we will discuss the present status and future perspective of molecular mechanisms during fertilization in pigs. PMID- 23035707 TI - Assessment of pregnancy-associated glycoprotein (PAG) concentrations in swamp buffalo samples from fetal and maternal origins by using interspecies antisera. AB - Pregnancy-associated glycoproteins (PAG) constitute a large family of glycoproteins found in the outer placental epithelial cell layer of the placenta in Eutherian species. In ruminants, they are noted to be structurally closely related among the different species. This study was designed to determine PAG concentrations in maternal and fetal plasma, allantoic and amniotic fluids in buffalo species. Antisera (AS) generated in rabbits against distinct PAG molecules were used in three radioimmunoassay (RIA)-PAG systems: RIA-1 (antiserum raised against bovine PAG67kDa; AS#497), RIA-2 (antiserum raised against caprine PAG55 + 62 kDa; AS#706) or RIA-3 (antiserum raised against buffalo PAG; AS#859). Samples were collected at a slaughterhouse (n = 67). PAG concentrations determined by RIA-2 gave significantly higher results in both allantoic and amniotic fluids (12.7 +/- 2.1 ng/mL and 24.0 +/- 7.3 ng/mL, respectively). Regarding maternal and fetal plasma, PAG concentrations obtained by RIA-2 (21.8 +/- 2.4 ng/mL and 20.2 +/- 2.5 ng/mL, respectively) and RIA-3 (25.0 +/- 2.2 ng/mL and 21.9 +/- 3.2 ng/mL, respectively) were higher than those obtained by RIA-1 (15.5 +/- 1.4 ng/mL and 16.1 +/- 1.8 ng/mL, respectively). The correlation among the three systems was very high. The study clearly reveals the ability of different PAG-RIA systems to measure PAG concentration in swamp buffalo samples. PMID- 23035708 TI - Improvement and validation of the method to determine neutral detergent fiber in feed. AB - To improve the performance of the analytical method for neutral detergent fiber in feed with heat-stable alpha-amylase treatment (aNDFom), the process of adding heat-stable alpha-amylase, as well as other analytical conditions, were examined. In this new process, the starch in the samples was removed by adding amylase to neutral detergent (ND) solution twice, just after the start of heating and immediately after refluxing. We also examined the effects of the use of sodium sulfite, and drying and ashing conditions for aNDFom analysis by this modified amylase addition method. A collaborative study to validate this new method was carried out with 15 laboratories. These laboratories analyzed two samples, alfalfa pellet and dairy mixed feed, with blind duplicates. Ten laboratories used a conventional apparatus and five used a Fibertec((r)) type apparatus. There were no significant differences in aNDFom values between these two refluxing apparatuses. The aNDFom values in alfalfa pellet and dairy mixed feed were 388 g/kg and 145 g/kg, the coefficients of variation for the repeatability and reproducibility (CV(r) and CV(R) ) were 1.3% and 2.9%, and the HorRat values were 0.8 and 1.1, respectively. This new method was validated with 5.8% uncertainty (k = 2) from the collaborative study. PMID- 23035709 TI - Use of bean husk as an easily digestible fiber source for activating the fibrolytic rumen bacterium Fibrobacter succinogenes and rice straw digestion. AB - A series of in sacco and in vitro studies were carried out to evaluate bean husks for activation of fibrolytic rumen bacteria and rice straw digestion. First, lablab bean husk, chickpea husk and rice straw were suspended in the rumen of sheep to analyze the bacterial consortium developed on each fiber source. Known members of fiber-associating bacteria were found on both lablab bean husk and rice straw, but some of these bacteria were lacking on chickpea husk. Second, a pure culture study was carried out using six strains of Fibrobacter succinogenes. Both husks stimulated the growth of all tested strains, including a strain that did not grow on rice straw. The strain OS128 that showed the highest growth on rice straw displayed even higher growth on lablab bean husk without a time lag. Finally, two-step incubations were carried out to determine whether prior incubation of rumen fluid with husks stimulates subsequent rice straw digestion. Higher digestibility of rice straw was recorded in the second-round incubation following the first incubation with bean husks. These results suggest that the tested bean husks improve the digestion of rice straw by activating fibrolytic F. succinogenes and other associated bacteria. PMID- 23035710 TI - Production of bacteriocin by Leuconostoc mesenteroides 406 isolated from Mongolian fermented mare's milk, airag. AB - The purification and characterization of a bacteriocin produced by Leuconostoc mesenteroides strain 406 that was isolated from traditional Mongolian fermented mare's milk, airag, were carried out. Leuconostoc mesenteroides strain 406 was identified on the basis of its morphological and biochemical characteristics and carbohydrate fermentation profile and by API 50 CH kit and 16S ribosomal DNA analyses. The neutral-pH cell-free supernatant of this bacterium inhibited the growth of several lactic acid bacteria and food spoilage and pathogenic organisms, including Listeria monocytogenes and Clostridium botulinum. The bacteriocin was heat-stable and not sensitive to acid and alkaline conditions, but was sensitive to several proteolytic enzymes such as pepsin, pronase E, proteinase K, trypsin, and alpha-chymotrypsin, but not catalase. Optimum bacteriocin production (4000 activity units/mL) was achieved when the strain was cultured at 25 degrees C for 24-36 h in Man Rogosa Sharpe medium. The bacteriocin was partially purified by ammonium sulfate precipitation (80% saturation), dialysis (cut-off MW: 1000), and gel filtration chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the bacteriocin had a molecular weight of approximately 3.3 kDa. To our knowledge, this is the first report of the isolation of a bacteriocin-producing Leuconostoc strain from airag. An application to fermented milks would be desired. PMID- 23035711 TI - Time-coordinated prevalence of extracellular HGF, FGF2 and TGF-beta3 in crush injured skeletal muscle. AB - Successful regeneration and remodeling of neuromuscular junctions are critical for restoring functional capacities and properties of skeletal muscle after damage, and axon-guidance molecules may be involved in the signaling that regulates such restoration. Recently, we found that early-differentiated satellite cells up-regulate a secreted neural chemorepellent Sema3A upon in vivo muscle-crush injury. The study also revealed that Sema3A expression is up regulated in primary satellite-cell cultures in response to hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2) and is prevented by transforming growth factor (TGF)-beta2, 3. In order to verify the physiological significance of this regulation in vitro, the present study was designed to estimate the time-course of extracellular HGF, FGF2 and TGF-beta3 concentrations after crush-injury of Gastrocnemius muscle in the rat lower hind-limb, using a combination of a non-homogenization/non-spin extraction of extracellular wound fluids and enhanced chemiluminescence-Western blotting analyses. Results clearly demonstrated that active HGF and FGF2 are prevalent in 2-8 days post-crush, whereas active TGF-beta3 increases after 12 days, providing a better understanding of the time-coordinated levels of HGF, FGF2 and TGF-beta3 that drive regulation of Sema3A expression during regenerative intramuscular moto neuritogenesis. PMID- 23035712 TI - Leiomyomata of the genitourinary tract: a case series from the "rare urological neoplasm" registry. AB - OBJECTIVE: Leiomyomata are benign neoplasms that are rarely encountered in the genitourinary tract outside the uterus. Pathological confirmation is always needed for definitive diagnosis, in order to rule out malignancies such as leiomyosarcoma. In cases of small leiomyomata, a surveillance strategy can be suggested, although the preferred approach is complete resection. Prognosis seems to be excellent, but available data are based on few, inconsistent series, as is often the case with rare neoplasms. This article presents long-term follow-up data from the most heterogeneous series, in terms of anatomical location, currently available. MATERIAL AND METHODS: The present series of 33 genitourinary leiomyomata was retrieved after joining the "rare urogenital neoplasm" registry of two Italian regions. Two pathologists jointly reviewed all pathological slides and confirmed the diagnosis of leiomyoma. RESULTS: Sixteen cases were localized to the scrotum, eight to the bladder, five to the kidney, two to the prostate, one to the urethra and one to the penis. Mean patient age was 58.4 (range 32-80) years. Mean follow-up was 15.5 (range 2-20) years. CONCLUSIONS: In this highly heterogeneous series, the disease showed excellent long-term recurrence- and progression-free interval. The accuracy of pathological diagnosis, along with the indolent long-term course, make the role of active surveillance amenable for asymptomatic cases, particularly where surgery may result in overtreatment. PMID- 23035713 TI - Endocarditis prophylaxis and congenital heart defects in the Norwegian Public Dental Service. AB - AIMS: The aims of this study are (i) to assess how dental health workers of the Public Dental Service, PDS, carry out endocarditis prophylaxis related to dental treatment for children and adolescents with congenital heart defects (CHD) and to identify factors influencing their appropriate use of guidelines and (ii) to assess how dental health workers perceive any characteristics of patients with CHD. METHODS: This cross-sectional study was based on self-administered questionnaires mailed to all dentists and hygienists in the PDS in three Norwegian counties. RESULTS: The response rates among dentists (n = 130) and dental hygienists (n = 54) were, respectively, 63% and 68%. The findings revealed an over-prescription of endocarditis antibiotics to patients with CHD. Most of the background variables investigated did not influence the responders' prescription decision for appropriate use of the current guidelines on the topic. The only significant factor was whether or not the respondent considered that the endocarditis prophylaxis guidelines were consistent and easy to follow. Compared with healthy children, dental healthcare workers felt less confident when providing dental treatment to children with CHD. CONCLUSION: There is room for improved education about children with CHD in dentistry and dental education. PMID- 23035714 TI - Prescribing of potentially inappropriate medications among the elderly population in an ambulatory care setting in a Saudi military hospital: trend and cost. AB - AIM: To explore the prevalence of potentially inappropriate medication (PIM) use in the elderly, to identify the trends and the patterns of prescribing such medication, and to calculate the associated direct medication cost of such practice in a Saudi hospital. METHODS: This was a retrospective cross-sectional study of patients who were aged 65 years or older on at least one PIM. The source of our data was outpatient pharmacy prescription records at Riyadh Military Hospital (RMH) for 2002, 2003 and 2004. Beers' explicit criteria for PIM was used to identify these medications. RESULTS: A total of 20521 PIM were identified. The prevalence of PIM for 2002, 2003 and 2004 was 2.5%, 2.3% and 2.1%, respectively. A total of 43.6% of the patients had filled a prescription of one PIM, 18% filled two PIM and 38.4% filled three or more PIM. Digoxin accounted for 23.7% of these PIM. The most commonly prescribed medications were cardiovascular medications at 26.7%. The total direct cost that was associated with inappropriate prescribing was 518314 Saudi Riyals (US$138217) during the study period. CONCLUSION: PIM prescribing in RMH was less compared with what was published in the literature in other countries. It was unclear whether these results reflect the level of elderly healthcare services provided to RMH patients or because of underreporting. Drug utilization review programs, medical education, recruiting physicians and clinical pharmacists who are specialized in geriatrics, finding safer medications or integration of computer software to detect such medications during prescriptions entry can improve the medical services provided to the elderly. PMID- 23035715 TI - Quantification of carbon nanomaterials in vivo. AB - A diverse array of carbon nanomaterials (NMs), including fullerene, carbon nanotubes (CNTs), graphene, nanodiamonds, and carbon nanoparticles, have been discovered and widely applied in a variety of industries. Carbon NMs have been detected in the environment and have a strong possibility of entering the human body. The safety of carbon NMs has thus become a serious concern in academia and society. To achieve strict biosafety assessments, researchers need to fully understand the effects and fates of NMs in the human body, including information about absorption, distribution, metabolism, excretion, and toxicity (ADME/T). To acquire the ADME data, researchers must quantify NMs, but carbon NMs are very difficult to quantify in vivo. The carbon background in a typical biological system is high, particularly compared with the much lower concentration of carbon NMs. Moreover, carbon NMs lack a specific detection signal. Therefore, isotopic labeling, with its high sensitivity and specificity, is the first choice to quantify carbon NMs in vivo. Previously, researchers have used many isotopes, including 13C, 14C, 125I, 131I, 3H, 64Cu, 111In, 86Y, 99mTc, and 67Ga, to label carbon NMs. We used these isotopic labeling methods to study the ADME of carbon NMs via different exposure pathways in animal models. Except for the metabolism of carbon NMs, which has seldom been investigated, significant amounts of data have been reported on the in vivo absorption, distribution, excretion, and toxicity of carbon NMs, which have revealed characteristic behaviors of carbon NMs, such as reticuloendothelial system (RES) capture. However, the complexity of the biological systems and diverse preparation and functionalization of the same carbon NMs have led to inconsistent results across different studies. Therefore, the data obtained so far have not provided a compatible and systematic profile of biosafety. Further efforts are needed to address these problems. In this Account, we review the in vivo quantification methods of carbon NMs, focusing on isotopic labeling and tracing methods, and summarize the related labeling, purification, bio-sampling, and detection of carbon NMs. We also address the advantages, applicable situations, and limits of various labeling and tracing methods and propose guidelines for choosing suitable labeling methods. A collective analysis of the ADME information on various carbon NMs in vivo would provide general principles for understanding the fate of carbon NMs and the effects of chemical functionalization and aggregation of carbon NMs on their ADME/T in vivo and their implications in nanotoxicology and biosafety evaluations. PMID- 23035716 TI - Design and synthesis of inhibitors of Plasmodium falciparum N myristoyltransferase, a promising target for antimalarial drug discovery. AB - Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in Plasmodium falciparum , the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development. PMID- 23035717 TI - Determining similarity in histological images using graph-theoretic description and matching methods for content-based image retrieval in medical diagnostics. AB - BACKGROUND: Computer-based analysis of digitalized histological images has been gaining increasing attention, due to their extensive use in research and routine practice. The article aims to contribute towards the description and retrieval of histological images by employing a structural method using graphs. Due to their expressive ability, graphs are considered as a powerful and versatile representation formalism and have obtained a growing consideration especially by the image processing and computer vision community. METHODS: The article describes a novel method for determining similarity between histological images through graph-theoretic description and matching, for the purpose of content based retrieval. A higher order (region-based) graph-based representation of breast biopsy images has been attained and a tree-search based inexact graph matching technique has been employed that facilitates the automatic retrieval of images structurally similar to a given image from large databases. RESULTS: The results obtained and evaluation performed demonstrate the effectiveness and superiority of graph-based image retrieval over a common histogram-based technique. The employed graph matching complexity has been reduced compared to the state-of-the-art optimal inexact matching methods by applying a pre-requisite criterion for matching of nodes and a sophisticated design of the estimation function, especially the prognosis function. CONCLUSION: The proposed method is suitable for the retrieval of similar histological images, as suggested by the experimental and evaluation results obtained in the study. It is intended for the use in Content Based Image Retrieval (CBIR)-requiring applications in the areas of medical diagnostics and research, and can also be generalized for retrieval of different types of complex images. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1224798882787923. PMID- 23035718 TI - Expression of Shigella flexneri gluQ-rs gene is linked to dksA and controlled by a transcriptional terminator. AB - BACKGROUND: Glutamyl queuosine-tRNA(Asp) synthetase (GluQ-RS) is a paralog of the catalytic domain of glutamyl-tRNA synthetase and catalyzes the formation of glutamyl-queuosine on the wobble position of tRNA(Asp). Here we analyze the transcription of its gene in Shigella flexneri, where it is found downstream of dksA, which encodes a transcriptional regulator involved in stress responses. RESULTS: The genomic organization, dksA-gluQ-rs, is conserved in more than 40 bacterial species. RT-PCR assays show co-transcription of both genes without a significant change in transcript levels during growth of S. flexneri. However, mRNA levels of the intergenic region changed during growth, increasing at stationary phase, indicating an additional level of control over the expression of gluQ-rs gene. Transcriptional fusions with lacZ as a reporter gene only produced beta-galactosidase activity when the constructs included the dksA promoter, indicating that gluQ-rs do not have a separate promoter. Using bioinformatics, we identified a putative transcriptional terminator between dksA and gluQ-rs. Deletion or alteration of the predicted terminator resulted in increased expression of the lacZ reporter compared with cells containing the wild type terminator sequence. Analysis of the phenotype of a gluQ-rs mutant suggested that it may play a role in some stress responses, since growth of the mutant was impaired in the presence of osmolytes. CONCLUSIONS: The results presented here, show that the expression of gluQ-rs depends on the dksA promoter, and strongly suggest the presence and the functionality of a transcriptional terminator regulating its expression. Also, the results indicate a link between glutamyl queuosine synthesis and stress response in Shigella flexneri. PMID- 23035719 TI - Very distal apical prostate tumours: identification on multiparametric MRI at 3 Tesla. AB - What's known on the subject? and What does the study add? MRI has been shown to improve prostate cancer detection rates. Pinto et al. (J Urol 2011; 86: 1281-5) reported their outcomes on 101 patients with low, moderate or high suspicion lesions on multiparametric MRI that were subsequently targeted via an MRI/ultrasound fusion biopsy platform. The prostate cancer detection rates were 27%, 66% and 89% respectively. Sciarra et al. (Clin Cancer Res 2010; 16: 1875-83) performed a prospective trial in 180 patients with prior negative biopsy and persistent PSA elevation. Patients were randomized to either MRI targeted biopsy followed by random 12-core TRUS biopsy vs random TRUS guided biopsy alone. Prostate cancer detection in the MRI targeted group was 45.5% vs 24.4% in the random group. Although MRI has been shown to improve prostate cancer detection rates, there has not previously been any work looking at the ability of MRI to detect prostate cancer localized to the very distal apex of the prostate. This is an important topic in that it might lead clinicians to counsel their patients in treatment decisions if it is felt that a treatment might not treat this section of the prostate well, e.g. high intensity focused ultrasound therapy that might spare the distal apex. OBJECTIVE: * To describe an undescribed 'very distal' apical prostate cancer on multiparametric MRI (mpMRI) since apical prostate cancer can be difficult to detect in transrectal ultrasound guided biopsy and might therefore be missed in treatment decisions such as high intensity focused ultrasound or surgical therapy. PATIENTS AND METHODS: * From January 2011 to December 2012 a total of 210 consecutive patients underwent 3 T mpMRI with endorectal coil followed by our previously described MRI/ultrasound image fused and directed TRUS biopsies. * Patients also underwent 12-core TRUS sextant biopsies. * The inclusion criteria required at least one distal apical prostate lesion visualized on mpMRI and targeted for biopsy. RESULTS: * A total of 38 men (median age 62 years, median PSA 7.68 ng/dL) were identified as having distal apical prostate cancer on mpMRI. * Thirteen patients (34%) had a prior diagnosis of cancer and were on active surveillance protocols while 25 (66%) did not. Of those patients, 21 (55%) had undergone a median of two prior negative biopsies. * Twenty-two patients (58%) were positive on biopsy for prostate cancer. On breakdown of patients who were positive, 17 (77%) were positive on TRUS random biopsies and 21 (95%) were positive on MRI targeted biopsies with the majority of patients having multifocal disease. * At the distal apical lesions of interest, 80% were positive on MRI targeted biopsy. In addition 33% of these patients were upgraded based on MRI targeted biopsy at the distal lesion. CONCLUSIONS: * Very distal apical prostate cancer can be accurately detected and sampled with mpMRI and subsequent MRI/ultrasound fusion biopsy. * This may aid clinicians and patients in decision making for therapeutic modalities. PMID- 23035720 TI - Comparison of health-related quality of life of children during maintenance therapy with acute lymphoblastic leukemia versus siblings and healthy children in India. AB - Data on quality of life (QOL) specifically in maintenance therapy of acute lymphoblastic leukemia (ALL) are minimal. This study was done to assess various items listed in domains of QOL (physical, emotional, social and school health domains) of children with ALL during maintenance therapy, and compare the same with those of their siblings and other healthy children. Forty children on maintenance therapy of ALL, 40 siblings and 40 healthy children were assessed for QOL by child self-report using PedsQL 4.0 Generic Core in the local language. Means were computed and compared for each domain with one-way analysis of variance (ANOVA), wherein higher values reflected better QOL. Overall QOL of children with ALL in maintenance therapy (77.16 +/- 10.98) was significantly poorer than that of siblings (93.56 +/- 4.41) and healthy children (93.02 +/- 3.76) (p < 0.001), but their abilities of self-care, household work, exercise, attentiveness, memory and homework were unaffected. There was significantly higher absenteeism due to sickness and hospital visits, and increased emotional problems (fear, anger, sleeping problems) among children with ALL. In the social health domain, children with ALL reported difficulty in maintaining friendships and competing. QOL of siblings was as good as that of healthy children in physical, social and school health domains, but they had increased emotional problems such as anger and sadness. Healthy children reported significantly higher future worries and bullying than children with ALL and siblings. This study validated that the QOL of children with ALL during maintenance therapy was significantly poorer than that of siblings and healthy children. The study identified various items in each domain of QOL that were affected in these children, and thus would assist in guiding healthcare professionals to focus on these specific items so as to improve their overall QOL. PMID- 23035721 TI - Hot flush symptom-free days with bazedoxifene/conjugated estrogens in postmenopausal women. AB - OBJECTIVE: The aim of this study was to examine the number of hot flush symptom free days in symptomatic postmenopausal women treated with bazedoxifene/conjugated estrogens (BZA/CE). METHODS: In this 12-week, randomized, double-blind, placebo-controlled, phase-3 study, 322 postmenopausal women aged 40 65 years with an intact uterus who had >= seven moderate-to-severe daily hot flushes (or >= 50 per week) were randomized to BZA 20 mg/CE 0.45 or 0.625 mg or placebo. Subjects recorded the incidence and severity of hot flushes on daily diary cards. In this secondary analysis, the number of days per week without hot flushes from baseline to week 12 was determined. The percentage of women who experienced no hot flushes at week 12 was also evaluated. RESULTS: From baseline to week 12, the number of days per week without moderate-to-severe hot flushes or without any hot flushes steadily increased for women treated with BZA 20 mg/CE 0.45 or 0.625 mg versus placebo. In addition, the rate of increase in days per week without any hot flushes was significantly greater with either BZA/CE dose than with placebo (p < 0.0001). Compared with placebo, the percentage of women who experienced no moderate-to-severe hot flushes or no severe hot flushes at week 12 was greater with BZA 20 mg/CE 0.45 mg (p < 0.01 and p < 0.05, respectively) and BZA 20 mg/CE 0.625 mg (p < 0.001 for both). CONCLUSIONS: BZA/CE increased the number of hot flush symptom-free days and the proportion of women without hot flushes over 12 weeks of therapy. PMID- 23035724 TI - Livestock agroterrorism: the deliberate introduction of a highly infectious animal pathogen. AB - Agroterrorism refers to attacks with any of a variety of biological or chemical agents against commercial crops or livestock populations, either as targets in their own right or as vehicles to attack humans. An agroterrorism incident would generally involve bioterrorism, and potential agents include pathogens such as viruses, bacteria, or fungi. Within the context of agroterrorism, livestock agroterrorism is described as the intentional introduction of an animal-borne infectious disease with the goal of spreading fear, producing economic losses, and/or threatening social stability. Causing human illness or human casualties is another potential goal of livestock agroterrorism. Livestock agroterrorism is considered to be attractive to terrorists because biological agents that affect livestock or poultry are more readily available and more difficult to monitor than are agents that infect humans. In addition, a terrorist attack on animal husbandry may have huge economic consequences with no human casualties. Therefore, a biological attack that targets the animal husbandry sector should be regarded as both a "high-consequence" event and a grave national security risk. This review addresses the use of biological weapons that may be used to target livestock or poultry rather than agricultural inputs or equipment. It first defines livestock agroterrorism. Then, the common priority disease agents that may be used to target livestock or poultry in an agroterrorist attack and that are attractive to terrorists are outlined. PMID- 23035722 TI - Inhibition of melanoma development in the Nras((Q61K)) ::Ink4a(-/-) mouse model by the small molecule BI-69A11. AB - To date, there are no effective therapies for tumors bearing NRAS mutations, which are present in 15-20% of human melanomas. Here we extend our earlier studies where we demonstrated that the small molecule BI-69A11 inhibits the growth of melanoma cell lines. Gene expression analysis revealed the induction of interferon- and cell death-related genes that were associated with responsiveness of melanoma cell lines to BI-69A11. Strikingly, the administration of BI-69A11 inhibited melanoma development in genetically modified mice bearing an inducible form of activated Nras and a deletion of the Ink4a gene (Nras((Q61K)) ::Ink4a(-/ ) ). Biweekly administration of BI-69A11 starting at 10 weeks or as late as 24 weeks after the induction of mutant Nras expression inhibited melanoma development (100 and 36%, respectively). BI-69A11 treatment did not inhibit the development of histiocytic sarcomas, which constitute about 50% of the tumors in this model. BI-69A11-resistant Nras((Q61K)) ::Ink4a(-/-) tumors exhibited increased CD45 expression, reflective of immune cell infiltration and upregulation of gene networks associated with the cytoskeleton, DNA damage response, and small molecule transport. The ability to attenuate the development of NRAS mutant melanomas supports further development of BI-69A11 for clinical assessment. PMID- 23035725 TI - Molecular characterization of Salmonella Enteritidis: comparison of an optimized multi-locus variable-number of tandem repeat analysis (MLVA) and pulsed-field gel electrophoresis. AB - Salmonella Enteritidis (SE) is a genetically homogenous serovar, which makes optimal subtype discrimination crucial for epidemiological research. This study describes the development and evaluation of an optimized multiple-locus variable number tandem-repeat assay (MLVA) for characterization of SE. The typeability and discriminatory power of this MLVA was determined on a selected collection of 60 SE isolates and compared with pulsed-field gel electrophoresis (PFGE) using restriction enzymes XbaI, NotI, or SfiI. In addition, the estimated Wallace coefficient (W) was calculated to assess the congruence of the typing methods. Selection of epidemiologically unrelated isolates and more related isolates (originating from layer farms) was also based on the given phage type (PT). When targeting six loci, MLVA generated 16 profiles, while PFGE produced 10, 9, and 16 pulsotypes using XbaI, NotI, and SfiI, respectively, for the entire strain collection. For the epidemiologically unrelated isolates, MLVA had the highest discriminatory power and showed good discrimination between isolates from different layer farms and among isolates from the same layer farm. MLVA performed together with PT showed higher discriminatory power compared to PFGE using one restriction enzyme together with PT. Results showed that combining PT with the optimized MLVA presented here provides a rapid typing tool with good discriminatory power for characterizing SE isolates of various origins and isolates originating from the same layer farm. PMID- 23035726 TI - Effect of x-ray treatments on pathogenic bacteria, inherent microbiota, color, and texture on parsley leaves. AB - This work is a part of systematic studies of the effect of X-ray treatments on fresh produce. The main objective of this investigation was to study the effects of X-ray treatments in reducing the concentration of artificially inoculated Escherichia coli O157:H7, Listeria monocytogenes, Salmonella enterica, and Shigella flexneri, and inherent microbiota on parsley leaves. The secondary objective was to study the effects of X-ray treatments on color and texture parameters on treated parsley leaves. The Dip-inoculated method was used to inoculate parsley leaves with a mixture of two or three strains of each tested organism at 10(8) to 10(9) colony-forming unit (CFU)/mL; the inoculated parsley leaves were then air-dried and followed by treatment with different doses of X ray (0, 0.1, 0.5, 1.0, and 1.5 kGy) at 22 degrees C and 55-60% relative humidity. Surviving bacterial populations on parsley leaves were evaluated using a nonselective medium (tryptic soy agar) with a selective medium overlay for each bacterium: E. coli O157:H7 (CT-SMAC agar), L. monocytogenes (MOA), and S. enterica and S. flexneri (XLD). Approximately 5.8, 3.1, 5.7, and 5.2 log CFU reductions of E. coli O157:H7, L. monocytogenes, S. enterica, and Shigella flexneri were achieved by treatment with 1.0 kGy X-ray, respectively. Furthermore, the populations of E. coli O157:H7, L. monocytogenes, S. enterica, and Shigella flexneri were reduced to less than the detectable limit (1.0 log CFU/g) by treatment with 1.5 kGy X-ray. Treatment with 1.5 kGy X-ray significantly reduced the initial inherent microbiota on parsley leaves, and inherent levels were significantly (p < 0.05) lower than the control sample throughout refrigerated storage for 30 days. No significant differences (p > 0.05) in color or texture of control and treated samples with 0.1-1.5 X-ray were observed. The results of investigation indicated that X-ray is an effective technology to eliminate E. coli O157:H7, L. monocytogenes, S. enterica, and Shigella flexneri, and to extend the shelf life of parsley leaves. PMID- 23035727 TI - Risk analysis of human anisakidosis through the consumption of the blue whiting, Micromesistius poutassou, sold at Spanish supermarkets. AB - European legislation directed at the catering industry concerning the prevention of anisakidosis proposes efficient measures to avoid human infestation, but this legislation does not directly address the consumer at the household level. Assessing the anisakidosis risk for consumers who buy fresh fish at supermarkets in Spain, 284 blue whiting, Micromesistius poutassou, specimens, originating from two fishing zones and seasons of capture, sold at five nationwide Spanish supermarket chains, were examined to identify the presence of anisakid species and analyze their prevalence and abundance in viscera and flesh. The potential influence of intrinsic (length and weight) and extrinsic (origin, season, and days after catch) factors was statistically analyzed. The only two species detected were Anisakis simplex complex and Hysterothylacium sp. Total anisakid prevalence was 55.6%, with A. simplex being more prevalent (53.9%) and abundant (3.9 helminths/fish), and also carrying the biggest risk for consumers. Origin (Atlantic and Mediterranean) and season (spring and autumn) were the most influential factors among those considered. Results suggest that specimens originating from the Atlantic, of greater weight and length, and caught in spring pose the highest transmission risk of anisakidosis. Moreover, the days passed between the catch and consumption should be considered as a risk factor. Thus, in addition to the recommendation of freezing fish at -20 degrees C for at least 24 h (in case the fish is consumed raw or poorly cooked), new and easy-to-follow recommendations are being proposed to avoid anisakidosis at home, which emphasize the importance of the information provided on fish crate labels. PMID- 23035728 TI - Older adults with biliary tract cancer: treatment and prognosis. AB - OBJECTIVES: To compare survival in older (>=65) and younger (<65) individuals with biliary tract cancer (BTC) and to determine whether treatment efficacy varies according to age. DESIGN: Retrospective cohort study and nested case control study. SETTING: Tertiary referral center in Korea. PARTICIPANTS: Five hundred thirty-one individuals diagnosed with BTC from 2003 to 2011. MEASUREMENTS: Demographic and clinical characteristics of 326 older (>=65) and 205 younger (<65) individuals with BTC were compared. Differences in survival were also assessed after matching according to propensity score. RESULTS: There were no significant differences in sex, symptoms and signs, tumor histology, stage, or surgery between the two groups, but older participants had more comorbidities and poorer performance status and underwent less chemotherapy and radiotherapy (P < .05). Survival of the two groups was compared. After adjustment for baseline characteristics using the propensity score method, survival was still comparable (P = .72). When survival of older participants in the treatment group (TG, those who underwent surgery, chemotherapy, or radiotherapy) was compared with that of those in the supportive care group (SCG, those who received only supportive care), those in the TG had a longer survival time than those in the SCG (P < .001). This result was confirmed in the propensity analysis (including individuals undergoing surgery, P < .001; excluding individuals undergoing surgery, P < .001). In the multivariable Cox analysis, surgical resection and chemotherapy were significantly associated with longer survival, and advanced tumor stage, lower baseline serum albumin level, and greater comorbidity were found to significantly predict poor survival. Age was not associated with survival in individuals with BTC (P = .33). CONCLUSION: Older age was not associated with poor survival in BTC, and treated individuals had longer survival in the older BTC population. Therefore, treatment should not be restricted on the basis of age. PMID- 23035729 TI - Effects of acute exercise on the diameter of the spermatic vein, and duration of reflux in patients with varicocele. AB - OBJECTIVE: The aim of this study was to investigate the effects of acute exercise on the diameter of the spermatic vein, and on the duration of reflux in patients with varicocele. MATERIAL AND METHODS: The study included 38 patients with complaints of infertility and scrotal pain between 2009 and 2010. The diagnoses were made by physical examination and colour Doppler ultrasound, with both performed before and after exercise tests. RESULTS: The mean age of the participants was 25.7 +/- 4.9 years. During the first examination, the grades of the varicoceles detected were as follows: grade I, n = 7; II, n = 10; and III, n = 21. The diameters of veins in patients with grades I, II and III varicocele were 2.1 mm, 2.9 mm and 4.2 mm, respectively, before exercise, whereas they were 2.6 mm, 3.2 mm and 4.3 mm, respectively, after exercise. In patients with grade I varicoceles, compared with pre-exercise values, the diameter of the left spermatic vein and duration of reflux measured during Valsalva manoeuvres were increased significantly after exercise (p = 0.042 and p = 0.034, respectively); similar results were obtained for the patients with grade II varicoceles (p = 0.007 and p = 0.008, respectively). However, the minimal relative increase in cases with grade III varicoceles was not statistically significant (p > 0.05). CONCLUSIONS: This study demonstrates that acute exercise increases the spermatic vein diameter and reflux time in patients with varicoceles. These outcomes demonstrate that acute exercise may be an aggravating factor for varicocele, as seen in chronic exercise. PMID- 23035731 TI - Filling gaps in asymmetric hydrogenation methods for acyclic stereocontrol: application to chirons for polyketide-derived natural products. AB - The large volume of research studying hydrogenation catalysis might suggest that stereoselective hydrogenation of alkenes is a solved problem, but we believe the most important parts of asymmetric hydrogenation methodology remain unmastered. The most popular chiral catalysts, Rh- and Ir-diphosphine complexes, do not hydrogenate the largest categories of prochiral alkenes, hindered tri- and tetra substituted ones, at useful rates unless the substrate has a "classical" coordinating functional group (CFG), for example, amides or homoallylic alcohols, to anchor the substrate to the metal. Therefore, while many methods are available for the asymmetric hydrogenation of alkenes with appropriate CFGs, synthetic chemistry would benefit from chiral hydrogenations of substrates with functional groups that typically do not coordinate in Rh- and Ir-diphosphine complexes. In this Account, we demonstrate the application of chiral analogues of Crabtree's catalyst to asymmetric hydrogenations of coordinating unfunctionalized, trisubstituted alkenes. Crabtree's catalyst, a complex of iridium with 1,5 cyclooctadiene, tris-cyclohexylphosphine, and pyridine, differs from Rh- and Ir diphosphine complexes, which we broadly refer to as "chiral analogues of Wilkinson's catalyst." Crabtree's catalyst analogues hydrogenate substrates that do not contain functionalities generally recognized as CFGs, and we propose reasons for this chemistry based on the catalytic mechanisms. Thus, chiral analogues of Crabtree's catalyst facilitate many hydrogenations that would not be possible using Rh- or Ir-diphosphine complexes. Directed hydrogenations have been used in acyclic stereocontrol for decades, but the realization that these catalysts can be used for acyclic stereocontrol without the types of directing groups that are necessary for other hydrogenations significantly broadens the scope of hydrogenations for this purpose. Recently, we have prepared chirons for polyketide-derived natural products using an N,carbene-Ir complex (1). This approach has led to catalytic syntheses of several important chirons to facilitate preparations of these ubiquitous natural products. PMID- 23035730 TI - What determines patient preferences for treating low risk basal cell carcinoma when comparing surgery vs imiquimod? A discrete choice experiment survey from the SINS trial. AB - BACKGROUND: The SINS trial (Controlled Clinical Trials ISRCTN48755084; Eudract No. 2004-004506-24) is a randomised controlled trial evaluating long term success of excisional surgery vs. imiquimod 5% cream for low risk nodular and superficial basal cell carcinoma (BCC). The trial included a discrete choice experiment questionnaire to explore patient preferences of a cream versus surgery for the treatment of their skin cancer. METHODS: The self-completed questionnaire was administered at baseline to 183 participants, measuring patients' strength of preferences when choosing either alternative 'surgery' or 'imiquimod cream' instead of a fixed 'current situation' option (of surgical excision as standard practice in UK). The treatments were described according to: cost, chance of complete clearance, side effects and appearance. Participants had to choose between various scenarios. Analysis was performed using a mixed logit model, which took into account the impact of previous BCC treatment and sample preference variability. RESULTS: The analysis showed that respondents preferred 'imiquimod cream' to their 'current situation' or 'surgery', regardless of previous experience of BCC symptoms and treatment. Respondents were more likely to be worried about their cosmetic outcomes and side effects they might experience over and above their chance of clearance and cost. Those with no experience of surgery (compared with experience) valued more the choice of 'imiquimod cream' (L1013 vs L781). All treatment characteristics were significant determinants of treatment choice, and there was significant variability in the population preferences for all of them. CONCLUSIONS: Patients with BCC valued more 'imiquimod cream' than alternative 'surgery' options, and all treatment characteristics were important for their choice of care. Understanding how people with a BCC value alternative interventions may better inform the development of health care interventions. PMID- 23035732 TI - Reactivity of borylenes toward ethyne, ethene, and methane. AB - The electronic and geometric structure of various substituted borylenes BR (where R = H, F, Cl, Br, CH(3), Ph, NH(2), NHMe, and NMe(2)) in their lowest singlet and triplet electronic states was investigated by computational means using hybrid density functional (B3LYP) and second-order Moller-Plesset perturbation theories combined with 6-311+G** and cc-pVTZ basis sets. The reactivity of singlet borylenes towards prototypical saturated and unsaturated hydrocarbons was examined by the MP2 method in conjugation with the cc-pVTZ basis set and also by coupled cluster [CCSD(T)] computations in combination with the aug-cc-pVTZ basis set. To study the energetics and the mechanism of the addition reaction of borylenes to unsaturated CC bonds, ethyne and ethene are chosen as model compounds. The insertion reaction of borylene into a C-H bond of methane was also investigated. The addition reactions of borylenes to multiple C-C bonds are strongly exothermic. In case of the BH molecule the reactions proceed without barrier and are the most exothermic. For the insertion reaction of borylenes into methane, two approaches could be identified. Again, the smallest reaction barriers and highest reaction energies were computed for the BH insertion, while the highest barriers and the smallest exothermicities were obtained for the BF molecule. On the basis of frontier molecular orbital energies, barrier heights, reaction energies, and transition state geometries BH is the most electrophilic borylene, followed by BPh, while aminoborylenes and BF are the most nucleophilic ones among the investigated derivatives. Accordingly, reactions of BH have the smallest barriers (if there is one at all) and the largest reaction energies, while the reactions of BF have the highest barriers and the smallest reaction energies. PMID- 23035733 TI - Role of surface composition in morphological evolution of GaAs nano-dots with low energy ion irradiation. AB - The surface chemistry of GaAs (100) with 50-keV Ar+ ion beam irradiation at off normal incidence has been investigated in order to elucidate the surface nano structuring mechanism(s). Core level and valence band studies of the surface composition were carried out as a function of fluences, which varied from 1 * 1017 to 7 * 1017 ions/cm2. Core-level spectra of samples analyzed by X-ray photoelectron spectroscopy confirmed the Ga enrichment of the surface resulting in bigger sized nano-dots. Formation of such nano-dots is attributed to be due to the interplay between preferential sputtering and surface diffusion processes. Valence band measurement shows that the shift in the Fermi edge is higher for Ga- rich, bigger sized nano-dots due to the partial oxide formation of Ga. 'One dimensional power spectral density' extracted from atomic force micrographs also confirms the significant role of surface diffusion in observed nano-structuring. PMID- 23035734 TI - Signal transduction pathway analysis in desmoid-type fibromatosis: transforming growth factor-beta, COX2 and sex steroid receptors. AB - Despite reports of sex steroid receptor and COX2 expression in desmoid-type fibromatosis, responses to single agent therapy with anti-estrogens and non steroidal anti-inflammatory drugs are unpredictable. Perhaps combination pharmacotherapy might be more effective in desmoid tumors that co-express these targets. Clearly, further understanding of the signaling pathways deregulated in desmoid tumors is essential for the development of targeted molecular therapy. Transforming growth factor-beta (TGFbeta) and bone morphogenetic proteins (BMP) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGFbeta superfamily in fibromatosis. A tissue microarray representing 27 desmoid tumors was constructed; 14 samples of healing scar and six samples of normal fibrous tissue were included for comparison. Expression of selected receptors and activated downstream transcription factors of TGFbeta family signaling pathways, beta-catenin, sex steroid hormone receptors and COX2 were assessed using immunohistochemistry; patterns of co-expression were explored via correlational statistical analyses. In addition to beta-catenin, immunoreactivity for phosphorylated SMAD2/3 (indicative of active TGFbeta signaling) and COX2 was significantly increased in desmoid tumors compared with healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD1/5/8 were detected in only a minority of cases. Transforming growth factor-beta receptor type 1 and androgen receptor were expressed in both desmoid tumors and scar, but not in fibrous tissue. Estrogen receptor-beta was present in all cases studied. Transforming growth factor-beta signaling appears to be activated in desmoid-type fibromatosis and phosphorylated SMAD2/3 and COX2 immunoreactivity might be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor-beta and COX2 co-expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX2 inhibitors should be considered. PMID- 23035735 TI - Fluoroscopic and electrical assessment of a series of defibrillation leads: prevalence of externalized conductors. AB - INTRODUCTION: Insulation defects with externalized conductors have been reported in the St. Jude Riata((r)) family of defibrillation leads (St. Jude Medical, Sylmar, CA, USA). The objective of the Northern Ireland Riata((r)) lead screening program was to identify insulation defects and externalized conductors by systematic fluoroscopic and electrical assessment in a prospectively defined cohort of patients. We sought to estimate the prevalence, identify risk factors, and determine the natural history of this abnormality. METHODS: All patients with a Riata((r)) lead under follow-up at the Royal Victoria Hospital were invited for fluoroscopic imaging and implantable cardioverter-defibrillator lead parameter checks. Fluoroscopic images were read independently by two cardiologists and the presence of externalized conductors was classified as positive, negative, or borderline. RESULTS: One hundred and sixty-five of 212 patients with a Riata lead were evaluated by fluoroscopy and lead parameter measurements. The mean duration after implantation was 3.98+/-1.43 years. After screening 25 (15%) patients were classified as positive, 137 (83%) negative, and three (1.8%) borderline. Time since implantation (P = 0.001), presence of a single coil lead (P = 0.042), and patient age (P = 0.034) were significantly associated with externalized conductors. The observed rate of externalized conductors was 26.9% for 8-French and 4.7% for 7-French leads. No leads that were identified prospectively with externalized conductors had electrical abnormalities. Seven of 25 (28%) patients had a defective lead extracted by the end of this screening period. CONCLUSION: A significant proportion (15%) of patients with a Riata lead had an insulation breach 4 years after implantation. High-resolution fluoroscopic imaging in at least two orthogonal views is required to identify this abnormality. PMID- 23035737 TI - Selection criteria for internships in clinical neuropsychology. AB - Criteria used in the evaluation and selection of applicants for clinical neuropsychology internships were identified by a survey of programs that met guidelines for specialty training. The number of internships that offer training with specialization in clinical neuropsychology has more than doubled during the past 10 years. Supervising neuropsychologists from 75 programs replied to the survey, yielding a 72.8% response rate. Clinical experience in neuropsychological assessment, specialization in clinical neuropsychology during graduate education, personal interview, and letters of recommendation were reported to be the most salient selection criteria. Practica that provide experience with flexible or functional systems assessment approaches at university-affiliated or VA (U.S. Department of Veterans Affairs) medical centers and doctoral curricula that follow International Neuropsychological Society/Division 40 course guidelines, with teaching and supervision provided by neuropsychologists, were preferred prerequisites to internship. These results are consistent with selection criteria reported over a decade ago and indicate continued endorsement of the vertically integrated model of education and training outlined by the Houston Conference on Specialty Education and Training in Clinical Neuropsychology. PMID- 23035736 TI - Proteomic and bioinformatic profile of primary human oral epithelial cells. AB - Wounding of the oral mucosa occurs frequently in a highly septic environment. Remarkably, these wounds heal quickly and the oral cavity, for the most part, remains healthy. Deciphering the normal human oral epithelial cell (NHOEC) proteome is critical for understanding the mechanism(s) of protection elicited when the mucosal barrier is intact, as well as when it is breached. Combining 2D gel electrophoresis with shotgun proteomics resulted in identification of 1662 NHOEC proteins. Proteome annotations were performed based on protein classes, molecular functions, disease association and membership in canonical and metabolic signaling pathways. Comparing the NHOEC proteome with a database of innate immunity-relevant interactions (InnateDB) identified 64 common proteins associated with innate immunity. Comparison with published salivary proteomes revealed that 738/1662 NHOEC proteins were common, suggesting that significant numbers of salivary proteins are of epithelial origin. Gene ontology analysis showed similarities in the distributions of NHOEC and saliva proteomes with regard to biological processes, and molecular functions. We also assessed the interindividual variability of the NHOEC proteome and observed it to be comparable with other primary cells. The baseline proteome described in this study should serve as a resource for proteome studies of the oral mucosa, especially in relation to disease processes. PMID- 23035738 TI - Protective role of lycopene against Aroclor 1254-induced changes on GLUT4 in the skeletal muscles of adult male rat. AB - Aroclor 1254 is the commercial mixture of highly toxic environmental pollutant, polychlorinated biphenyls (PCBs). Being immensely durable, it is extensively used and widely distributed. Studies show that Aroclor 1254 causes a variety of adverse health effects through free radical generation. The present investigation was designed to check the effect of Aroclor 1254 on the glucose transporter protein, GLUT4, which plays a key role in glucose homeostasis. The protective role of lycopene against the adverse effect of Aroclor 1254 was also tested. Group 1 rats received corn oil as vehicle and served as control. Groups 2, 3, and 4 were administered with Aroclor 1254 [2 mg kg(-1) body weight (b.w.) day(-1)] intraperitoneally for 30 days. Groups 3 and 4 received lycopene (2 and 4 mg kg( 1) b.w. day(-1), respectively) orally in addition to Aroclor 1254. After 30 days, animals were euthanized and the skeletal muscles were dissected to determine the following parameters: GLUT4 messenger RNA (mRNA), GLUT4 protein (both plasma membrane and cytosolic fractions), and (14)C-2-deoxyglucose uptake. Though there was no change in GLUT4 mRNA and fasting plasma glucose levels, Aroclor 1254 significantly decreased the GLUT4 protein level in both the subcellular fractions of the gracilis and triceps muscles. Most important, (14)C-2-deoxyglucose uptake showed a significant decrease in Aroclor 1254 alone treated rats, and Aroclor 1254 plus 4 mg lycopene supplementation treatment maintained the same at par with control. Thus, Aroclor 1254 has adverse effects on GLUT4 translocation and (14)C 2-deoxyglucose uptake, and lycopene administered along with Aroclor 1254 has a protective role over it. PMID- 23035740 TI - Electron beam manipulation of nanoparticles. AB - We report on electron beam manipulation and simultaneous transmission electron microscopy imaging of gold nanoparticle movements in an environmental cell. Nanoparticles are trapped with the beam and move dynamically toward the location with higher electron density. Their global movements follow the beam positions. Analysis on the trajectories of nanoparticle movements inside the beam reveals a trapping force in the piconewton range at the electron density gradient of 10(3) 10(4) (e.nm(-2).s(-1)).nm(-1). Multiple nanoparticles can also be trapped with the beam. By rapidly converging the beam, we further can "collect" nanoparticles on the membrane surface and assemble them into a cluster. PMID- 23035739 TI - Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis. AB - BACKGROUND: Pain and impaired mobility because of osteoarthritis (OA) is common in dogs and humans. Efficacy studies of analgesic drug treatment of dogs with naturally occurring OA may be challenging, as a caregiver placebo effect is typically evident. However, little is known about effect sizes of common outcome measures in canine clinical trials evaluating treatment of OA pain. Forty-nine client-owned dogs with hip OA were enrolled in a randomized, double-blinded placebo-controlled prospective trial. After a 1 week baseline period, dogs were randomly assigned to a treatment (ABT-116 - transient receptor potential vanilloid 1 (TRPV1) antagonist, Carprofen - non-steroidal anti-inflammatory drug (NSAID), Tramadol - synthetic opiate, or Placebo) for 2 weeks. Outcome-measures included physical examination parameters, owner questionnaire, activity monitoring, gait analysis, and use of rescue medication. RESULTS: Acute hyperthermia developed after ABT-116 treatment (P < 0.001). Treatment with carprofen (P <= 0.01) and tramadol (P <= 0.001) led to improved mobility assessed by owner questionnaire. Nighttime activity was increased after ABT-116 treatment (P = 0.01). Kinetic gait analysis did not reveal significant treatment effects. Use of rescue treatment decreased with treatment in the ABT-116 and Carprofen groups (P < 0.001). Questionnaire score and activity count at the end of treatment were correlated with age, clinical severity at trial entry, and outcome measure baseline status (SR >= +/-0.40, P <= 0.005). Placebo treatment effects were evident with all variables studied. CONCLUSION: Treatment of hip OA in client-owned dogs is associated with a placebo effect for all variables that are commonly used for efficacy studies of analgesic drugs. This likely reflects caregiver bias or the phenomenon of regression to the mean. In the present study, outcome measures with significant effects also varied between groups, highlighting the value of using multiple outcome measures, as well as an a priori analysis of effect size associated with each measure. Effect size data from the present study could be used to inform design of future trials studying analgesic treatment of canine OA. Our results suggest that analgesic treatment with ABT-116 is not as effective as carprofen or tramadol for treatment of hip arthritis pain in client-owned dogs. PMID- 23035741 TI - Citronellol reduces orofacial nociceptive behaviour in mice - evidence of involvement of retrosplenial cortex and periaqueductal grey areas. AB - Citronellol (CT) is a monoterpenoid alcohol present in the essential oil of many medicinal plants, such as Cymbopogon citratus. We evaluated the antinociceptive effects of CT on orofacial nociception in mice and investigated the central pathway involved in the effect. Male Swiss mice were pretreated with CT (25, 50 and 100 mg/kg, i.p.), morphine (5 mg/kg, i.p.) or vehicle (saline + tween 80 0.2%). Thirty minutes after the treatment, we injected formalin (20 MUl, 2%), capsaicin (20 MUl, 2.5 MUg) or glutamate (40 MUl, 25 MUM) into the right limb. For the action in the CNS, ninety minutes after the treatment, the animals were perfused, the brains collected, crioprotected, cut in a criostate and submitted in an immunofluorescence protocol for Fos protein. CT produced significant (p < 0.01) antinociceptive effect, in all doses, in the formalin, capsaicin and glutamate tests. The immunofluorescence showed that the CT activated significantly (p < 0.05) the olfactory bulb, the piriform cortex, the retrosplenial cortex and the periaqueductal grey of the CNS. Together, our results provide first-time evidence that this monoterpene attenuates orofacial pain at least, in part, through an activation of CNS areas, mainly retrosplenial cortex and periaqueductal grey. PMID- 23035743 TI - Minor effects of green tea catechin supplementation on cardiovascular risk markers in active older people: a randomized controlled trial. AB - AIM: Although previous studies have shown that consumption of green tea catechins (GTC) and walking might prevent development of cardiovascular disease (CVD), the effects of GTC supplementation on CVD risk in active older people are unknown. METHODS: A total of 52 older adults (male/female 20/32, mean age 69.1 +/- 5.9 years) participating in a pedometer-based walking program were randomly assigned to a GTC group with an intake of 630.9 mg GTC daily (n=26) or a control group (n=26) for 14 weeks. Cardiovascular risk markers were measured before and after this trial. RESULTS: In the GTC group, values of the following markers were significantly reduced (P<0.05) from the beginning to the end of the trial: waist circumference (from 84.2 +/- 8.4 to 82.2 +/- 8.5 cm), hip circumference (from 95.1 +/- 6.9 to 92.2 +/- 6.3 cm), total cholesterol (from 233.0 +/- 46.3 to 218.8 +/- 42.3 mg/dL), low-density lipoprotein cholesterol (from 130.4 +/- 36.2 to 119.1 +/- 33.4 mg/dL) and low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (from 2.0 +/- 1.7 to 1.7 +/- 0.5); only hip circumference (from 95.6 +/- 8.1 to 94.1 +/- 7.6 cm) was significantly reduced (P<0.05) in the control group. No significant between-group differences were found for any parameter measured. CONCLUSIONS: Although GTC might reduce cholesterol levels, the present randomized control trial suggests that GTC supplementation in active older participants did not significantly affect cardiovascular risk markers. Future studies should identify more effective combinations of GTC supplementation and physical activity. PMID- 23035744 TI - Structures of human acetylcholinesterase in complex with pharmacologically important ligands. AB - Human acetylcholinesterase (AChE) is a significant target for therapeutic drugs. Here we present high resolution crystal structures of human AChE, alone and in complexes with drug ligands; donepezil, an Alzheimer's disease drug, binds differently to human AChE than it does to Torpedo AChE. These crystals of human AChE provide a more accurate platform for further drug development than previously available. PMID- 23035745 TI - Rapid detection of DNMT3A R882 codon mutations allows early identification of poor risk patients with acute myeloid leukemia. PMID- 23035748 TI - Nonblurred regions show priority for gaze direction over spatial blur. AB - The human eye continuously forms images of our 3D environment using a finite and dynamically changing depth of focus. Since different objects in our environment reside at different depth planes, the resulting retinal images consist of both focused and spatially blurred objects concurrently. Here, we wanted to measure what effect such a mixed visual diet may have on the pattern of eye movements. For that, we have constructed composite stimuli, each containing an intact photograph and several progressively blurred versions of it, all arranged in a 3 * 3 square array and presented simultaneously as a single image. We have measured eye movements for 7 such composite stimuli as well as for their corresponding root mean square (RMS) contrast-equated versions to control for any potential contrast variations as a result of the blurring. We have found that when observers are presented with such arrays of blurred and nonblurred images they fixate significantly more frequently on the stimulus regions that had little or no blur at all (p < .001). A similar pattern of fixations was found for the RMS contrast-equated versions of the stimuli indicating that the observed distributions of fixations is not simply the result of variations in image contrasts due to spatial blurring. Further analysis revealed that, during each 5 second presentation, the image regions containing little or no spatial blur were fixated first while other regions with larger amounts of blur were fixated later, if fixated at all. The results contribute to the increasing list of stimulus parameters that affect patterns of eye movements during scene perception. PMID- 23035747 TI - Randomized and prospective trial comparing tract creation using plasma vaporization with balloon dilatation in percutaneous nephrolithotomy. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Use of balloon dilatation leads to less blood transfusion rates than metallic dilators. Plasma vaporization leads to less blood loss than balloon dilatation in this study. The study evaluates a novel technique for the creation of a nephrostomy tract for PCNL. Compared with other techniques, plasma vaporization is a safer procedure that causes lesser blood loss, requires a shorter hospital stay, causes less radiation exposure, and enables easier nephrostomy tract creation for PCNL. OBJECTIVE: To evaluate the efficacy and safety of plasma vaporization for tract creation in percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: In this randomized prospective trial we enrolled 65 patients and assigned each to one of two groups: 33 patients were randomly scheduled to undergo plasma vaporization and 32 were scheduled to undergo balloon dilatation for tract creation. A bipolar resectoscope mounted with a plasma vaporization button electrode or a traditional balloon dilator were used to create the nephrostomy tract. RESULTS: The mean blood loss, mean length of hospital stay and mean operating time, stone-free rates and postoperative complications in the two groups were compared using the t test or chi-squared test (Fisher's exact test). The plasma vaporization group had a significantly lower mean (SD) decrease in haematocrit level (3.5 [2.8]% vs 6.6 [3.3]%; P = 0.02) and a shorter mean (SD) hospital stay (2.6 [1.2] days vs 5.3 [3.4] days; P = 0.0). There were no significant differences in the operating time, stone-free rate or cases of postoperative fever between the two groups. CONCLUSION: The plasma vaporization technique is safe, leads to less blood loss than the other techniques, and is a simple solution for creating the nephrostomy tract for PCNL. PMID- 23035749 TI - Dosage regimen of antenatal steroids prior to preterm delivery and effects on maternal and neonatal outcomes. AB - OBJECTIVE: The objective of this study was to compare the effects of two betamethasone dosage regimens on selected parameters in mothers and on the status of the preterm newborn. METHODS: The analysis included 121 patients who gave birth by gestational week 35 and within 7 days after the completion of a full course of steroid treatment (24 mg). The study group consisted of 45 patients receiving six 4-mg doses of betamethasone every 8 h. The control group consisted of 76 patients receiving two 12-mg doses of betamethasone separated by 24 h. RESULTS: After treatment, a significant increase in the leukocyte count was observed in the control group. Significant reductions in the erythrocyte counts, hemoglobin levels and hematocrit after treatment were also found in the control group. The post-natal status of newborns did not differ significantly between groups. The betamethasone dosage regimen used did not affect the incidence of moderate and severe respiratory disorders, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy (ROP), infection, hyperbilirubinemia or anemia in neonates. Mild respiratory disorders were slightly more common in the study group. CONCLUSION: A reduction in the single steroid dose administered to patients at risk of premature birth may reduce maternal side-effects. PMID- 23035746 TI - The Thai Phase III HIV Type 1 Vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120. AB - The Thai Phase III clinical trial (RV144) showed modest efficacy in preventing HIV-1 acquisition. Plasma collected from HIV-1-uninfected trial participants completing all injections with ALVAC-HIV (vCP1521) prime and AIDSVAX B/E boost were tested for antibody responses against HIV-1 gp120 envelope (Env). Peptide microarray analysis from six HIV-1 subtypes and group M consensus showed that vaccination induced antibody responses to the second variable (V2) loop of gp120 of multiple subtypes. We further evaluated V2 responses by ELISA and surface plasmon resonance using cyclic (Cyc) and linear V2 loop peptides. Thirty-one of 32 vaccine recipients tested (97%) had antibody responses against Cyc V2 at 2 weeks postimmunization with a reciprocal geometric mean titer (GMT) of 1100 (range: 200-3200). The frequency of detecting plasma V2 antibodies declined to 19% at 28 weeks post-last injection (GMT: 110, range: 100-200). Antibody responses targeted the mid-region of the V2 loop that contains conserved epitopes and has the amino acid sequence KQKVHALFYKLDIVPI (HXB2 Numbering sequence 169 184). Valine at position 172 was critical for antibody binding. The frequency of V3 responses at 2 weeks postimmunization was modest (18/32, 56%) with a GMT of 185 (range: 100-800). In contrast, naturally infected HIV-1 individuals had a lower frequency of antibody responses to V2 (10/20, 50%; p=0.003) and a higher frequency of responses to V3 (19/20, 95%), with GMTs of 400 (range: 100-3200) and 3570 (range: 200-12,800), respectively. RV144 vaccination induced antibodies that targeted a region of the V2 loop that contains conserved epitopes. Early HIV-1 transmission events involve V2 loop interactions, raising the possibility that anti-V2 antibodies in RV144 may have contributed to viral inhibition. PMID- 23035750 TI - The quality of the outdoor environment influences childrens health -- a cross sectional study of preschools. AB - AIM: To test how the quality of the outdoor environment of child day care centres (DCCs) influences children's health. METHODS: The environment was assessed using the Outdoor Play Environmental Categories (OPEC) tool, time spent outdoors and physical activity as measured by pedometer. 172/253 (68%) of children aged 3.0 5.9 from nine DCCs participated in Southern Sweden. Health data collected were body mass index, waist circumference, saliva cortisol, length of night sleep during study, and symptoms and well-being which were scored (1-week diary - 121 parent responders). Also, parent-rated well-being and health of their child were scored (questionnaire, 132 parent responders). MANOVA, ANOVA and principal component analyses were performed to identify impacts of the outdoor environment on health. RESULTS: High-quality outdoor environment at DCCs is associated with several health aspects in children such as leaner body, longer night sleep, better well-being and higher mid-morning saliva cortisol levels. CONCLUSION: The quality of the outdoor environment at DCCs influenced the health and well-being of preschool children and should be given more attention among health care professionals and community planners. PMID- 23035752 TI - Increased inflammatory biomarkers in early pregnancy is associated with the development of pre-eclampsia in patients with periodontitis: a case control study. AB - AIM(S): To explore the relationship between biomarkers of systemic inflammation in plasma and gingival crevicular fluid in early pregnancy and the subsequent development of pre-eclampsia in patients with periodontitis. MATERIALS AND METHODS: A case-control study was performed. From a cohort composed of 126 pregnant women, 43 normotensive healthy pregnant women were randomly selected, and 11 cases of preeclampsia were identified. Plasmatic and gingival crevicular fluid (GCF) samples were collected in early pregnancy (11-14 wk gestation). The levels of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) were measured in the plasma and GCF samples, whereas the level of C-reactive protein (CRP) was measured in plasma samples. Biomarkers were determined by ELISA assays. The data were analysed using descriptive statistics, and the association between variables was estimated through logistic regression models. RESULTS: There was observed an association between pre-eclampsia and plasmatic levels of CRP (OR: 1.07; p = 0.003). Additionally, pre-eclampsia also was associated with IL-6 levels in GCF samples in early pregnancy (OR: 1.05; p = 0.039). A multiple logistic regression model suggests that increased levels of IL-6 in GCF (OR = 1.06; p = 0.02; CI 95% 1.007-1.117) in early pregnancy increase the risk of developing pre-eclampsia. CONCLUSION(S): Pregnant women with periodontitis who later development pre-eclampsia, shows increased levels of IL-6 in GCF and CRP in plasma during early pregnancy. Periodontal disease could contribute to systemic inflammation in early pregnancy via a local increase of IL-6 and the systemic elevation of CRP. Therefore, both inflammatory markers could be involved in the relationship between periodontal disease and pre-eclampsia. PMID- 23035751 TI - Insights into the molecular mechanism of RGL2-mediated inhibition of seed germination in Arabidopsis thaliana. AB - BACKGROUND: Seed germination is of immense significance for agriculture and has been studied for centuries. Yet, our understanding of the molecular mechanisms underlying regulation of dormancy and germination is still in its infancy. Gibberellins are the key phytohormones that promote germination, and the DELLA protein RGL2 is the main signalling intermediate involved in this response. Germination is completely inhibited if functional RGL2 is overexpressed and/or stabilized; however, the molecular mechanisms of RGL2 function are still largely unknown. We therefore attempted to shed light onto some of the genetic events downstream of RGL2. RESULTS: Gene ontology of the transcriptome differentially regulated by RGL2, as well as extensive cross-comparison with other available microarray data indicates that RGL2-mediated inhibition of germination causes seeds to enter a state of dormancy. RGL2 also appears to differentially regulate a number of transcription factors, many of which are known to be involved in light- or phytohormone-mediated aspects of germination. A promoter analysis of differentially expressed genes identified an enrichment of several motifs that can be bound by specific transcription factors, for example GAMYB, ARF1, or Dof type zinc fingers. We show that Dof-binding motifs indeed play a role in RGL2 mediated transcription. Using Chromatin Immunoprecipitation (ChIP), we show that RGL2 directly downregulates at least one cell wall modifying enzyme, which is predicted to constrain cell growth thereby leading to inhibition of seed germination. CONCLUSIONS: Our results reveal that RGL2 controls various aspects of germination. Through the repression of cell wall modifying enzymes, cell growth is directly constrained to inhibit germination. Furthermore, RGL2 likely interacts with various types of proteins to regulate transcription, and differentially regulates several transcription factors. Collectively, our data indicate that gibberellins, acting via RGL2, control several aspects of seed germination. PMID- 23035753 TI - HMMC-1, a human monoclonal antibody to fucosylated core 1 O-glycan, suppresses growth of uterine endometrial cancer cells. AB - HMMC-1 is a human monoclonal antibody that reacts with a fucosylated and extended core 1 O-glycan, Fucalpha1-2Galbeta1-4GlcNAcbeta1-3Galbeta1-3GalNAc-Ser/Thr, as an epitope. In the present study, we examined the effects of HMMC-1 on cell proliferation of two human uterine endometrial cancer cell lines, HEC8 and HEC9, to investigate the role of glycoproteins bearing the HMMC-1 epitope in cancer progression. HEC9 cells expressed high levels of the HMMC-1 epitope, but HMMC-1 reactivity was hardly detected in HEC8 cells. In a mouse model of lymph node metastasis using orthotopic implantation, HEC8 and HEC9 showed low (10%) and high (80%) metastatic potency, respectively. Growth of HEC9, but not HEC8, was remarkably inhibited by addition of HMMC-1 to the culture medium. Cell cycle analysis and expression analysis showed that HMMC-1 treatment increased the G(1) phase population of HEC9 cells and induced cyclin-dependent kinase inhibitors p16 and p21. Two glycoproteins, 97 and 137 kDa, with a strong reactivity to HMMC-1 were purified, and the 97-kDa glycoprotein was identified as CD166, an immunoglobulin superfamily cell adhesion molecule assumed to be involved in cancer metastasis. CD166 gene-silencing dramatically reduced HMMC-1 epitope expression and growth in HEC9 cells, indicating that CD166 is the primary glycoprotein presenting the HMMC-1 epitope in HEC9 cells. Collectively, HMMC-1 might arrest the cell cycle in the G(1) phase by binding to O-glycans on the CD166 expressed in HEC9 cells, raising the possibility that HMMC-1 extensively inhibits invasive growth of HMMC-1 epitope-positive uterine endometrial cancer cells by targeting the cancer-associated form of CD166. PMID- 23035754 TI - Quantitative assessment of preloaded 4-alkoxybenzyl alcohol resins for solid phase peptide syntheses by 1D and 2D HR-MAS NMR. AB - The quality of preloaded Wang resins is very important for the success of solid phase peptide syntheses (SPPS). A critical factor is the capping of remaining hydroxyl groups after loading with the first amino acid, since these free alcohols lead to truncated sequences during the following SPPS steps. Because the detection of hydroxyl groups by color tests is difficult and unreliable, the capping efficiency is often controlled by time-consuming peptide test syntheses. Here, we describe a two-dimensional, high resolution magic angle spinning NMR method for the quantitative determination of remaining 4-alkoxybenzyl alcohols in Fmoc-Xaa-Wang resins with a detection limit of 1 mol-%. The NMR method was validated with samples of known ratios between Fmoc-Ala-Wang and 4 alkoxybenzylalcohol resin. Application to a set of preloaded Fmoc-Ala- and Fmoc Thr(tBu)-Wang test resins demonstrated that the full range of essential amino acids can be quantified without further spectrometer calibration. Compared to established test synthesis protocols, the NMR method represents not only advantages in terms of time and cost savings but also eliminates all inaccuracies due to further sample treatment like SPPS and cleavage from the resin. PMID- 23035756 TI - Combination of real-time elastography and urine prostate cancer gene 3 (PCA3) detects more than 97% of significant prostate cancers. AB - OBJECTIVE: The prostate cancer gene 3 (PCA3) score in urine is a promising biomarker for prostate cancer. Real-time elastography (RTE) is a well-documented ultrasound modality. The objective of this study was to evaluate the ability to detect significant cancer foci in the prostate with these methods alone and in combination. MATERIAL AND METHODS: From September 2009 to September 2010, 40 patients planned for radical prostatectomy underwent a PCA3 urine test and RTE before operation. A Hitachi EUB-8500 with prostate end-fire transrectal probe was used. The PCA3 score was evaluated with a standard cut-off value of 35. RTE was evaluated in correlation with whole-mount section pathology. Three patients fulfilled the criteria for insignificant prostate cancer and were excluded from the study. RESULTS: The PCA3 score was increased in 26 patients (70%). RTE identified at least one tumour in 33 out of 37 patients (89%). RTE detected the largest tumour in 27 out of 37 patients (73%). More than one cancer was present in 29 patients and RTE identified more than one tumour in 13 of these. The RTE was false positive in four patients. The PCA3 score was increased in three out of four false-negative RTE patients. By combining both methods, 36 out of 37 patients (97%) with significant prostate cancer were detected. CONCLUSIONS: The combination of PCA3 score and RTE detected 97% of significant prostate cancers. The combinative use of RTE and PCA3 will be further investigated in an unselected series of men with suspected prostate cancer. PMID- 23035755 TI - Probing sequence-specific DNA flexibility in a-tracts and pyrimidine-purine steps by nuclear magnetic resonance (13)C relaxation and molecular dynamics simulations. AB - Sequence-specific DNA flexibility plays a key role in a variety of cellular interactions that are critical for gene packaging, expression, and regulation, yet few studies have experimentally explored the sequence dependence of DNA dynamics that occur on biologically relevant time scales. Here, we use nuclear magnetic resonance (NMR) carbon spin relaxation combined with molecular dynamics (MD) simulations to examine the picosecond to nanosecond dynamics in a variety of dinucleotide steps as well as in varying length homopolymeric A(n).T(n) repeats (A(n)-tracts, where n = 2, 4, or 6) that exhibit unusual structural and mechanical properties. We extend the NMR spin relaxation time scale sensitivity deeper into the nanosecond regime by using glycerol and a longer DNA duplex to slow overall tumbling. Our studies reveal a structurally unique A-tract core (for n > 3) that is uniformly rigid, flanked by junction steps that show increasing sugar flexibility with A-tract length. High sugar mobility is observed at pyrimidine residues at the A-tract junctions, which is encoded at the dinucleotide level (CA, TG, and CG steps) and increases with A-tract length. The MD simulations reproduce many of these trends, particularly the overall rigidity of A-tract base and sugar sites, and suggest that the sugar-backbone dynamics could involve transitions in sugar pucker and phosphate backbone BI <-> BII equilibria. Our results reinforce an emerging view that sequence-specific DNA flexibility can be imprinted in dynamics occurring deep within the nanosecond time regime that is difficult to characterize experimentally at the atomic level. Such large-amplitude sequence-dependent backbone fluctuations might flag the genome for specific DNA recognition. PMID- 23035757 TI - Personalized medicine in multiple sclerosis: hope or reality? AB - Personalized treatment is highly desirable in multiple sclerosis because it is an immensely heterogeneous disease. This heterogeneity is seen in both the disease course and the treatment responses. Currently, a combination of clinical features and imaging parameters in magnetic resonance imaging is used to classify active and non-active patients and treatment responders and non-responders. Although this classification works on a group level, individual patients often behave differently from the group. Therefore additional biomarkers are needed to provide better indicators for prognosis and treatment response. Basic and clinical research have discovered different promising targets. It is now essential to verify the utility and accuracy of these markers in large, prospectively sampled patient cohorts. PMID- 23035759 TI - Validity issues in Atkins death cases. AB - Justice Scalia warned in his dissent in ATKINS v. VIRGINIA, 536 U.S. 304, 122S.Ct. 2242 (2002) that the problem of feigned mental retardation would complicate the findings in cases involving the death penalty in low IQ individuals. Validity measurement in low IQ individuals has been criticized, largely with questions concerning specificity of performance validity tests (PVTs; Salekin & Doane, 2009, Applied Neuropsychology, 16, 105). In this article, our purpose is to examine the false positive rates of specific PVTs in low IQ individuals, particularly with reference to a Symptom Validity Scale previously developed for low functioning individuals (Chafetz, Abrahams, & Kohlmaier, 2007, Archives of Clinical Neuropsychology, 22, 1). The findings show that the PVTs analyzed have few false positives in a low IQ range of 60-75 when these individuals are well motivated to perform highly on testing, which allows these PVTs to be used in high stakes cases to provide evidence concerning malingering. Principles of dealing with performance validity in low functioning individuals are discussed with reference to the issues in capital cases. A practical summary guide is supplied. PMID- 23035758 TI - Adherence to mediterranean diet and decline in walking speed over 8 years in community-dwelling older adults. AB - OBJECTIVES: To determine the association between Mediterranean diet (MedDiet) score and 20-m walking speed over 8 years. DESIGN: Health, Aging and Body Composition Study (Health ABC) beginning in 1997/98. SETTING: Community. PARTICIPANTS: Two thousand two hundred twenty-five well-functioning individuals aged 70 and older. MEASUREMENTS: Walking speed was assessed in relation to low, medium, and high adherence to the MedDiet (0-2, 3-5, 6-9 points, respectively). RESULTS: Individuals in the highest MedDiet adherence group were more likely to be male; less likely to smoke; and more likely to have lower body mass index, higher energy intake, and greater physical activity (P < .05). Usual and rapid 20 m walking speed were highest in the high MedDiet adherence group than in the other groups (high, 1.19 +/- 0.19 m/s; medium, 1.16 +/- 0.21 m/s; low, 1.15 +/- 0.19 m/s, P = .02, for usual speed; high, 1.65 +/-0.30 m/s; medium, 1.59 +/- 0.32 m/s; low, 1.55 +/- 0.30 m/s, P = .001, for rapid speed). Over 8 years, usual and rapid 20-m walking speed declined in all MedDiet adherence groups. Higher MedDiet adherence was an independent predictor of less decline in usual 20-m walking speed (P = .049) in generalized estimating equations adjusted for age, race, sex, site, education, smoking, physical activity, energy intake, health status, depression and cognitive score. The effect decreased after adding total body fat percentage to the model (P = .13). Similar results were observed for MedDiet adherence and rapid 20-m walking speed; the association remained significant after adjustment for total body fat percentage (P = .01). The interaction between time and MedDiet adherence was not significant in any of the models. CONCLUSION: Walking speed over 8 years was faster in those with higher MedDiet adherence at baseline. The differences remained significant over 8 years, suggesting a long term effect of diet on mobility performance with aging. PMID- 23035760 TI - Effectiveness and efficiency of a practice accreditation program on cardiovascular risk management in primary care: study protocol of a clustered randomized trial. AB - BACKGROUND: Cardiovascular risk management is largely provided in primary healthcare, but not all patients with established cardiovascular diseases receive preventive treatment as recommended. Accreditation of healthcare organizations has been introduced across the world with a range of aims, including the improvement of clinical processes and outcomes. The Dutch College of General Practitioners has launched a program for accreditation of primary care practices, which focuses on chronic illness care. This study aims to determine the effectiveness and efficiency of a practice accreditation program, focusing on patients with established cardiovascular diseases. METHODS/DESIGN: We have planned a two-arm cluster randomized trial with a block design. Seventy primary care practices will be recruited from those who volunteer to participate in the practice accreditation program. Primary care practices will be the unit of randomization. A computer list of random numbers will be generated by an independent statistician. The intervention group (n = 35 practices) will be instructed to focus improvement on cardiovascular risk management. The control group will be instructed to focus improvement on other domains in the first year of the program. Baseline and follow-up measurements at 12 months after receiving the accreditation certificate are based on a standardized version of the audit in the practice accreditation program. Primary outcomes include controlled blood pressure, serum cholesterol, and prescription of recommended preventive medication. Secondary outcomes are 15 process indicators and two outcome indicators of cardiovascular risk management, self-reported achievement of improvement goals and perceived unintended consequences. The intention to treat analysis is statistically powered to detect a difference of 10% on primary outcomes. The economic evaluation aims to determine the efficiency of the program and investigates the relationship between costs, performance indicators, and accreditation. DISCUSSION: It is important to gain more information about the effectiveness and efficiency of the practice accreditation program to assess if participation is worthwhile regarding the quality of cardiovascular risk management. The results of this study will help to develop the practice accreditation program for primary care practices. PMID- 23035761 TI - Use of hyperlinks in electronic test result communication: a survey study in general practice. AB - BACKGROUND: Information is essential in healthcare. Recording, handling and sharing healthcare information is important in order to ensure high quality of delivered healthcare. Information and communication technology (ICT) may be a valuable tool for handling these challenges. One way of enhancing the exchange of information could be to establish a link between patient-specific and general information sent to the general practitioner (GP). The aim of the present paper is to study GPs' use of a hyperlink inserted into electronic test result communication. METHODS: We inserted a hyperlink into the electronic test result communication sent to the patients' GPs who participated in a regional, systematic breast cancer screening program. The hyperlink target was a web-site with information on the breast cancer screening program and breast cancer in general. Different strategies were used to increase the GPs' use of this hyperlink. The outcome measure was the GPs' self-reported use of the link. Data were collected by means of a one-page paper-based questionnaire. RESULTS: The response rate was 73% (n=242). In total, 108 (45%) of the GPs reported to have used the link. In all, 22% (n=53) of the GPs used the web-address from a paper letter and 37% (n=89) used the hyperlink in the electronic test result communication (Delta = 15%[95%confidence int erval(CI) = 8 - 22%P < 0.001]). We found no statistically significant associations between use of the web address/hyperlink and the GP's gender, age, or attitude towards mammography screening. CONCLUSIONS: The results suggest that hyperlinks in electronic test result communication could be a feasible strategy for combining and sharing different types of healthcare information. PMID- 23035763 TI - Increasing collaboration in NOK 2012, the XXXX Nordic Congress of Ophthalmology. PMID- 23035764 TI - Comparison of macular pigment in patients with age-related macular degeneration and healthy control subjects - a study using spectral fundus reflectance. AB - PURPOSE: Previous studies have reported an age-dependent decline of macular pigment optical density (MPOD) as well as a relative lack of MPOD in age-related macular degeneration (AMD). Results are, however, strongly dependent on the technique used. In this study, we investigated the age dependence of MPOD using spectral fundus reflectance. In addition, we hypothesized that patients with AMD have a reduced MPOD as compared to healthy controls. METHODS: A total of 85 healthy subjects and 96 patients with AMD were included in this study. The healthy control subjects showed a wide range of ages (mean, 51.6 years; range, 21 79years). Patients with AMD were significantly older (mean, 71.2 years; range, 50 89 years). Spectral fundus reflectance of the fovea was measured in a 2.3 degrees detection field with a custom built fundus reflectometer. Calculation of MPOD was based on a previously published fundus reflectance model. RESULTS: Patients with AMD showed a reduced MPOD (0.35 +/- 0.12) as compared to the healthy control group (0.39 +/- 0.12, p = 0.013 between groups). No age dependence of MPOD (r = 0.14, p = 0.19) was found in the healthy control group. In the AMD group, however, MPOD declined with age (r = -0.24, p = 0.019). CONCLUSIONS: This study indicates that MPOD is reduced in patients with AMD. In addition, the data of this study indicate that MPOD is age dependent in AMD patients, but not in healthy controls. Taken together with data indicating that lutein supplementation increases MPOD, this provides a rationale for supplementation of the macular pigments in patients with AMD, although long-term clinical outcome data are lacking. PMID- 23035765 TI - Toward efficient optical trapping of sub-10-nm particles with coaxial plasmonic apertures. AB - Optical trapping using focused laser beams has emerged as a powerful tool in the biological and physical sciences. However, scaling this technique to nanosized objects remains challenging due to the diffraction limit of light and the high power levels required for nanoscale trapping. In this paper, we propose plasmonic coaxial apertures as low-power optical traps for nanosized specimens. The illumination of a coaxial aperture with a linearly polarized plane wave generates a dual optical trapping potential well. We theoretically show that this potential can stably trap dielectric particles smaller than 10 nm in diameter while keeping the trapping power level below 20 mW. By tapering the thickness of the coaxial dielectric channel, trapping can be extended to sub-2-nm particles. The proposed structures may enable optical trapping and manipulation of dielectric particles ranging from single proteins to small molecules with sizes previously inaccessible. PMID- 23035766 TI - Describing the clinical reasoning process: application of a model of enablement to a pediatric case. AB - BACKGROUND AND PURPOSE: Clinical reasoning is a core tenet of physical therapy practice leading to optimal patient care. The purpose of this case was to describe the outcomes, subjective experience, and reflective clinical reasoning process for a child with cerebral palsy using the International Classification of Functioning, Disability, and Health (ICF) model. CASE DESCRIPTION: Application of the ICF framework to a 9-year-old boy with spastic triplegic cerebral palsy was utilized to capture the interwoven factors present in this case. Interventions in the pool occurred twice weekly for 1 h over a 10-week period. OUTCOMES: Immediately post and 4 months post-intervention, the child made functional and meaningful gains. The family unit also developed an enjoyment of exercising together. Each individual family member described psychological, emotional, or physical health improvements. DISCUSSION: Reflection using the ICF model as a framework to discuss clinical reasoning can highlight important factors contributing to effective patient management. PMID- 23035768 TI - Correlation between the 8-repetition maximum test and isokinetic dynamometry in the measurement of muscle strength of the knee extensors: A concurrent validity study. AB - The 8-repetition maximum test has the potential to be a feasible, cost-effective method of measuring muscle strength for clinicians. The purpose of this study was to investigate the concurrent validity of the 8-repetition maximum test in the measurement of muscle strength by comparing the 8-repetition maximum test to the gold standard of isokinetic dynamometry. Thirty participants (15 males and 15 females, mean age = 23.2 years [standard deviation = 1.0]) underwent 8-repetition maximum testing and isokinetic dynamometry testing of the knee extensors (at 60, 120, and 240 degrees per second) on two separate sessions with 2-3 days between each mode of testing. Linear regression was used to assess the validity by comparing the findings between 8-repetition maximum testing and isokinetic dynamometry testing. Significant correlations were found between the 8-repetition maximum and isokinetic dynamometry peak torque at each testing velocity (r = 0.71-0.85). The highest correlations were between the 8-repetition maximum and isokinetic dynamometry peak torques at 60 (r = 0.85) and 120 (r = 0.85) degrees per second. The findings of this study provide supportive evidence for the use of 8-repetition maximum testing as a valid, alternative method for measuring muscle strength. PMID- 23035767 TI - Preoperative education addressing postoperative pain in total joint arthroplasty: review of content and educational delivery methods. AB - OBJECTIVE: Evaluate content and educational delivery methods of preoperative education in total joint arthroplasties of the hip and knee (THA and TKA) addressing postoperative pain. DATA SOURCES: Systematic searches conducted on Biomed Central, BMJ.com, CINAHL, the Cochrane Library, NLM Central Gateway, OVID, ProQuest (Digital Dissertations), PsycInfo, PubMed/Medline, ScienceDirect, and Web of Science. Secondary searching (pearling) was undertaken. DATA EXTRACTION: Data were extracted utilizing the participants, interventions, comparisons, and outcomes approach. STUDY SELECTION: All randomized controlled trials (RCTs) evaluating the effect of preoperative education on postoperative pain in THA and TKA surgery were considered for inclusion. LIMITATIONS: Studies published in English; published within the last 20 years and patients over the age of 18. No limitations were set on specific outcome measures of pain. DATA SYNTHESIS: This review included 13 RCTs involving a total of 1,017 subjects who underwent THA or TKA. Educational delivery methods comprised verbal one-on-one or group education sessions, delivered within 4 weeks of surgery lasting an average of 30 minutes, and accompanied by other written materials. The educational content centered on descriptions of preoperative preparation, hospital stay, surgical procedure, immediate/intermediate experiences, expectations following surgery, rehabilitation, encouragement/reassurance, and answering common question associated with the surgical experience. CONCLUSIONS: Preoperative education centered on a biomedical model of anatomy and pathoanatomy as well as procedural information has limited effect in reducing postoperative pain after THA and TKA surgeries. Preoperative educational sessions that aim to increase patient knowledge of pain science may be more effective in managing postoperative pain. PMID- 23035769 TI - Screening for gestational diabetes in the 21st century: a population-based cohort study in Israel. AB - Studies indicate that gestational diabetes mellitus (GDM) prevalence is increasing worldwide. We aimed to examine secular trends in GDM prevalence and screening practices over the last decade in Israel, and to identify changes in GDM risk factors. METHODS: We collected data on all 367,247 pregnant women who were screened for GDM between 2000 and 2010 in Israel's second largest healthcare organization. Multivariable logistic regression analysis was used to identify risk factors for GDM. RESULTS: GDM prevalence increased by 12%, from 3.8% in 2000 to 4.3% in 2010 and was accompanied by a 37% rise in the proportion screened directly by 100-gram oral glucose tolerance test without a prior 50-gram glucose challenge test (from 6.5% to 8.9%). During the study period there was an on-going increment in the proportion of pregnant women with one or more GDM risk factor, such as older age, low socioeconomic level, history of polycystic ovary syndrome or in vitro fertilization, which was all significantly (p < 0.05) associated with the risk of GDM. CONCLUSIONS: The increasing risk of GDM in Israel can be explained by both rising prevalence of women with established risk factors, as well as shifting screening practices. PMID- 23035770 TI - An ectopic ureter of a duplicated system presenting as a pelvic collection following laparoscopic radical prostatectomy. AB - Radical prostatectomy remains the gold-standard surgical treatment for clinically localized prostate cancer. Contrast imaging of the upper urinary tract is not part of the routine work-up of the patient before radical prostatectomy. This may lead to rare, albeit serious complications when anatomical anomalies are present. This article reports a case of delayed anastomotic leakage following radical prostatectomy due to an unrecognized duplex system on the left side and inclusion of the ureteric orifice draining the upper moiety in the anastomosis, which caused failure of healing and persistent leakage. PMID- 23035771 TI - Correlation between upstream human activities and riverine antibiotic resistance genes. AB - Antimicrobial resistance remains a serious and growing human health challenge. The water environment may represent a key dissemination pathway of resistance elements to and from humans. However, quantitative relationships between landscape features and antibiotic resistance genes (ARGs) have not previously been identified. The objective of this study was to examine correlations between ARGs and putative upstream anthropogenic sources in the watershed. sul1 (sulfonamide) and tet(W) (tetracycline) were measured using quantitative polymerase chain reaction in bed and suspended sediment within the South Platte River Basin, which originates from a pristine region in the Rocky Mountains and runs through a gradient of human activities. A geospatial database was constructed to delineate surface water pathways from animal feeding operations, wastewater treatment plants, and fish hatchery and rearing units to river monitoring points. General linear regression models were compared. Riverine sul1 correlated with upstream capacities of animal feeding operations (R(2) = 0.35, p < 0.001) and wastewater treatment plants (R(2) = 0.34, p < 0.001). Weighting for the inverse distances from animal feeding operations along transport pathways strengthened the observed correlations (R(2) = 0.60-0.64, p < 0.001), suggesting the importance of these pathways in ARG dissemination. Correlations were upheld across the four sampling events during the year, and averaging sul1 measurements in bed and suspended sediments over all events yielded the strongest correlation (R(2) = 0.92, p < 0.001). Conversely, a significant relationship with landscape features was not evident for tet(W), which, in contrast to sul1, is broadly distributed in the pristine region and also relatively more prevalent in animal feeding operation lagoons. The findings highlight the need to focus attention on quantifying the contribution of water pathways to the antibiotic resistance disease burden in humans and offer insight into potential strategies to control the spread of ARGs. PMID- 23035772 TI - Indiacens A and B: prenyl indoles from the myxobacterium Sandaracinus amylolyticus. AB - The gliding bacterium Sandaracinus amylolyticus, strain NOSO-4T, was recently characterized as the first representative of a new myxobacterial genus. A screening of the culture broth for antibiotically active metabolites followed by isolation and characterization revealed two unique 3-formylindol derivatives, indiacen A (1) and its chloro derivative indiacen B (2). Both are active against Gram-positive and Gram-negative bacteria as well as the fungus Mucor hiemalis. The biosynthetic origin of the isoprene-like side chain in 1 and 2 was studied by in vivo feeding experiments with 13C-labeled precursors. PMID- 23035773 TI - ECG criteria for accurate localization of left anterolateral and posterolateral accessory pathways. AB - BACKGround : Left lateral accessory pathway (AP) location along the mitral annulus (MA) can influence ablation strategy, including choice of a transseptal or retrograde aortic approach and the use of deflectable sheaths and/or bidirectional catheters. We aimed to develop electrocardiographic (ECG) criteria to accurately localize a left lateral AP, hypothesizing that the relationship of QRS amplitudes in limb leads II and III could be used to differentiate left anterolateral (LAL) from left posterolateral (LPL) AP locations. METHODS: The ECGs from patients who underwent ablation of a left-sided AP between 2001 and 2008 were evaluated for the relationship of QRS amplitudes in limb leads II and III. A LAL-AP was defined by successful ablation between 12 and 3 o'clock on the MA, as seen in left anterior oblique (LAO) fluoroscopic projection. A LPL-AP was defined by successful ablation between 3 and 6 o'clock in the LAO projection. RESULTS: In 249 consecutive patients undergoing AP ablation, 23 met the prespecified inclusion criteria: manifest preexcitation due to single AP, ablated successfully in a LAL or LPL location. The ratio of dominant QRS amplitude in lead II to lead III was >= 1 in 10/11 patients with LAL-AP, compared with 3/12 patients with a LPL-AP (P = 0.002). Using these criteria, two blinded reviewers predicted a LAL or LPL location with 87% accuracy and 100% interobserver agreement. CONCLUSIONS: We report new ECG criteria that can be used to accurately predict the anterior and posterior location of a left lateral AP. Such localization may facilitate procedural planning. PMID- 23035774 TI - "Symptom-based insulin adjustment for glucose normalization" (SIGN) algorithm: a pilot study. AB - BACKGROUND: Lack of self-monitoring of blood glucose (SMBG) records in actual practice settings continues to create therapeutic challenges for clinicians, especially in adjusting insulin therapy. In order to overcome this clinical obstacle, a "Symptom-based Insulin adjustment for Glucose Normalization" (SIGN) algorithm was developed to guide clinicians in caring for patients with uncontrolled type 2 diabetes who have few to no SMBG records. This study examined the clinical outcome and safety of the SIGN algorithm. SUBJECTS AND METHODS: Glycated hemoglobin (HbA1c), insulin usage, and insulin-related adverse effects of a total of 114 patients with uncontrolled type 2 diabetes who refused to use SMBG or performed SMBG once a day for less than three times per week were studied 3 months prior to the implementation of the algorithm and prospectively at every 3-month interval for a total of 6 months after the algorithm implementation. Patients with type 1 diabetes, nonadherence to diabetes medications, or who were not on insulin therapy at any time during the study period were excluded from this study. RESULTS: Mean HbA1c improved by 0.29% at 3 months (P = 0.015) and 0.41% at 6 months (P = 0.006) after algorithm implementation. A slight increase in HbA1c was observed when the algorithm was not implemented. There were no major hypoglycemic episodes. The number of minor hypoglycemic episodes was minimal with the majority of the cases due to irregular meal habits. CONCLUSIONS: The SIGN algorithm appeared to offer a viable and safe approach when managing uncontrolled patients with type 2 diabetes who have few to no SMBG records. PMID- 23035775 TI - Mobile phone-based pattern recognition and data analysis for patients with type 1 diabetes. AB - BACKGROUND: Persons with type 1 diabetes who use electronic self-help tools, most commonly blood glucose meters, record a large amount of data about their personal condition. Mobile phones are powerful and ubiquitous computers that have a potential for data analysis, and the purpose of this study is to explore how self gathered data can help users improve their blood glucose management. SUBJECTS AND METHODS: Thirty patients with insulin-regulated type 1 diabetes were equipped with a mobile phone application for 3-6 months, recording blood glucose, insulin, dietary information, physical activity, and disease symptoms. The data were analyzed in terms of usage of the different modules and which data processing and visualization tools could be constructed to support the use of these data. RESULTS: Eighteen patients (denoted "adopters") recorded complete data for over 80 consecutive days, up to 247 days. Among those who withdrew or did not use the application extensively, the most common reasons given were outdated or difficult to-use phone. Data analysis using period finding and scale-space trends was found to yield significant patterns for most adopters. Pattern recognition methods to predict low or high blood glucose were found to be performing poorly. CONCLUSIONS: Minimally intrusive mobile applications enable users with type 1 diabetes to record data that can provide data-driven feedback to the user, potentially providing relevant insight into their disease. PMID- 23035777 TI - Immediate effects of physical therapy on gait disturbance and frontal assessment battery in Parkinson's disease. AB - AIM: To examine whether the Frontal Assessment Battery is associated with the immediate effects of physical therapy on gait disturbance in patients with Parkinson's disease. METHODS: A total of 18 patients with idiopathic Parkinson's disease (Hoehn and Yahr stage range 3-4) who were able to ambulate independently and who were not demented were included. Patients were divided into two groups on the basis of Frontal Assessment Battery scores: the high score group (score >= 13, n=11) and the low score group (score <= 12, n=7). A 3-D motion analysis system was used to acquire gait parameter data before and after a 30-min physical therapy program. Stride length, step length, cadence, walking velocity, single support time and double support time were measured. The range of motion of the hip, knee and ankle joint, and maximal trunk displacement on the horizontal plane were measured. RESULTS: In the high-score group, significant improvement was observed in walking velocity, stride length and step length, and in the range of motion of the hip and knee joint. Maximal trunk displacement decreased significantly. In contrast, no significant improvement was observed in the low score group. Multivariate logistic regression analysis showed that Frontal Assessment Battery scores were a predictor of improvement in the range of motion of bilateral hip and knee joints, and maximal trunk displacement. CONCLUSIONS: We showed that the subtests of motor learning of the Frontal Assessment Battery might be associated with the immediate effects of physical therapy on gait disturbance in Parkinson's disease. PMID- 23035776 TI - Identification of defensin-encoding genes of Picea glauca: characterization of PgD5, a conserved spruce defensin with strong antifungal activity. AB - BACKGROUND: Plant defensins represent a major innate immune protein superfamily that displays strong inhibitory effects on filamentous fungi. The total number of plant defensins in a conifer species is unknown since there are no sequenced conifer genomes published, however the genomes of several angiosperm species provide an insight on the diversity of plant defensins. Here we report the identification of five new defensin-encoding genes from the Picea glauca genome and the characterization of two of their gene products, named PgD5 and endopiceasin. RESULTS: Screening of a P. glauca EST database with sequences of known plant defensins identified four genes with homology to the known P. glauca defensin PgD1, which were designated PgD2-5. Whereas in the mature PgD2-4 only 7 9 amino acids differed from PgD1, PgD5 had only 64% sequence identity. PgD5 was amplified from P. glauca genomic DNA by PCR. It codes for a precursor of 77-amino acid that is fully conserved within the Picea genus and has similarity to plant defensins. Recombinant PgD5, produced in Escherichia coli, had a molecular mass of 5.721 kDa, as determined by mass spectrometry. The PgD5 peptide exhibited strong antifungal activity against several phytopathogens without any effect on the morphology of the treated fungal hyphae, but strongly inhibited hyphal elongation. A SYTOX uptake assay suggested that the inhibitory activity of PgD5 could be associated with altering the permeability of the fungal membranes. Another completely unrelated defensin gene was identified in the EST library and named endopiceasin. Its gene codes for a 6-cysteine peptide that shares high similarity with the fungal defensin plectasin. CONCLUSIONS: Screening of a P. glauca EST database resulted in the identification of five new defensin-encoding genes. PgD5 codes for a plant defensin that displays non-morphogenic antifungal activity against the phytopathogens tested, probably by altering membrane permeability. PgD5 has potential for application in the plant biotechnology sector. Endopiceasin appears to derive from an endo- or epiphytic fungal strain rather than from the plant itself. PMID- 23035778 TI - Metabolic engineering of novel lignin in biomass crops. AB - Lignin, a phenolic polymer in the secondary wall, is the major cause of lignocellulosic biomass recalcitrance to efficient industrial processing. From an applications perspective, it is desirable that second-generation bioenergy crops have lignin that is readily degraded by chemical pretreatments but still fulfill its biological role in plants. Because plants can tolerate large variations in lignin composition, often without apparent adverse effects, substitution of some fraction of the traditional monolignols by alternative monomers through genetic engineering is a promising strategy to tailor lignin in bioenergy crops. However, successful engineering of lignin incorporating alternative monomers requires knowledge about phenolic metabolism in plants and about the coupling properties of these alternative monomers. Here, we review the current knowledge about lignin biosynthesis and the pathways towards the main phenolic classes. In addition, the minimal requirements are defined for molecules that, upon incorporation into the lignin polymer, make the latter more susceptible to biomass pretreatment. Numerous metabolites made by plants meet these requirements, and several have already been tested as monolignol substitutes in biomimetic systems. Finally, the status of detection and identification of compounds by phenolic profiling is discussed, as phenolic profiling serves in pathway elucidation and for the detection of incorporation of alternative lignin monomers. PMID- 23035779 TI - Biomimetic wet adhesion of viscoelastic liquid films anchored on micropatterned elastic substrates. AB - Inspired by the natural adhesives in the toe pads of arthropods and some other animals, we explore the effectiveness and peel failure of a thin viscoelastic liquid film anchored on a micropatterned elastic surface. In particular, we focus on the role of the substrate pattern in adhesion energy of the liquid layer and in allowing its clean separation without cohesive failure. Peel tests on the microfabricated wet adhesives showed two distinct modes of adhesive (interfacial) and cohesive (liquid bulk) failures depending on the pattern dimensions. The adhesion energy of a viscoelastic liquid layer on an optimized micropatterned elastic substrate is ~3.5 times higher than that of a control flat bilayer and ~26 times higher than that of a viscoelastic film on a rigid substrate. Adhesive liquid layers anchored by narrow microchannels undergo clean, reversible adhesive failure rather than the cohesive failure seen on flat substrates. An increase in the channel width engenders cohesive failure in which droplets of the wet adhesive remain on the peeled surface. PMID- 23035780 TI - Can inspiratory muscle training increase survival in early-affected amyotrophic lateral sclerosis patients? PMID- 23035781 TI - Efficacy and safety of once-daily tadalafil in men with erectile dysfunction who reported no successful intercourse attempts at baseline. AB - INTRODUCTION: Tadalafil is efficacious and well tolerated for erectile dysfunction (ED), but effects in men with "complete ED" are unclear. AIM: To investigate effects of once-daily tadalafil in men with no successful intercourse attempts at baseline. METHODS: Through a post hoc, pooled-data analysis of four randomized, double-blind trials on the effects of tadalafil 2.5 or 5 mg (vs. placebo) in men with ED, we evaluated efficacy and safety in subjects with 0 "yes" responses to Sexual Encounter Profile question 3 (SEP3) during an initial 4 week treatment-free run-in period. MAIN OUTCOME MEASURES: Changes from baseline in the SEP diary and the International Index of Erectile Function-erectile function (IIEF-EF) domain were subjected to analysis of covariance models. RESULTS: Five hundred ninety-five subjects with no successful attempts at baseline were included in the analysis. The mean (+/- standard deviation) age was 58.2 +/- 10.7 years; and most subjects had ED for >= 1 year (95.0%). ED was severe in 61.5% and moderate in 26.4%. Approximately 45% had diabetes mellitus or hypertension. After 12 weeks, the mean per-patient SEP3 percentage increased from 0% to 32.4% with tadalafil 2.5 mg and to 46.4% with tadalafil 5 mg (each P < 0.001 vs. placebo). Corresponding data for successful penetration (SEP2) were increases from 21.1% to 48.2% with tadalafil 2.5 mg and from 24.4% to 66.2% with 5 mg (each P < 0.001 vs. placebo). Mean IIEF-EF increased from 9.7 to 15.7 with tadalafil 2.5 mg and from 10.7 to 19.2 with 5 mg (each P < 0.001 vs. placebo). Tadalafil also significantly improved the intercourse-satisfaction and overall satisfaction domains (vs. placebo). Both doses of tadalafil were generally well tolerated, with adverse event rates similar to placebo. CONCLUSIONS: The posttreatment intercourse success rate was 32% and 46% for tadalafil 2.5 mg and 5 mg, respectively, in men with no successful intercourse attempts at baseline. PMID- 23035782 TI - Introduction to special section on "measures of anxiety and stress: a contemporary update and review". PMID- 23035784 TI - Effect of embryonic and maternal genotype on embryo and foetal survival in rabbit. AB - The aim of this work was to study the influence of embryonic and maternal genotype of two lines of rabbits selected by growth rate (line R) and litter size at weaning (line A) on prenatal survival. Embryos were recovered at 48 h of gestation from R and A donors (39 and 35 does, respectively) and reciprocally transferred to the oviducts of recipient does to the R (n = 15) and A (n = 14) lines. Each recipient doe received six embryos from line R into one oviduct and six embryos from line A into the other. Recipient does were examined by laparoscopy to determine implantation rate on day 14 and slaughtered on day 25 of gestation to determine the number of live foetuses and the weight of foetuses and placentas. No differences were found between lines in fertilization rate and stage of embryo development at 48 h post-insemination. Implantation rate was affected by both the embryonic and maternal genotype. While embryos from donor line A had the highest implantation rate (0.78 +/- 0.032 vs 0.65 +/- 0.036 for line R), recipient line R had a better implantation rate (0.78 +/- 0.033 vs 0.64 +/- 0.036 for line A). Foetal survival was affected by the embryonic genotype. Embryos from donor line A had a higher foetal survival rate than embryos from donor line R (0.65 +/- 0.036 vs 0.53 +/- 0.038, respectively) but lower foetal and placenta weights. In conclusion, while embryonic genotype influenced both implantation and foetal survival rate, R embryos had the lowest rates, maternal genotype affected the implantation rate and R recipients may show a greater uterine receptivity during implantation period. Moreover, it must be observed that foetal and placenta weights were significantly affected by embryonic genotype and heavier for R line. PMID- 23035785 TI - 1-methylthio-D-xylulose 5-phosphate methylsulfurylase: a novel route to 1-deoxy-D xylulose 5-phosphate in Rhodospirillum rubrum. AB - Rhodospirillum rubrum produces 5-methylthioadenosine (MTA) from S adenosylmethionine in polyamine biosynthesis; however, R. rubrum lacks the classical methionine salvage pathway. Instead, MTA is converted to 5-methylthio-d ribose 1-phosphate (MTR 1-P) and adenine; MTR 1-P is isomerized to 1-methylthio-d xylulose 5-phosphate (MTXu 5-P) and reductively dethiomethylated to 1-deoxy-d xylulose 5-phosphate (DXP), an intermediate in the nonmevalonate isoprenoid pathway [Erb, T. J., et al. (2012) Nat. Chem. Biol., in press]. Dethiomethylation, a novel route to DXP, is catalyzed by MTXu 5-P methylsulfurylase. An active site Cys displaces the enolate of DXP from MTXu 5-P, generating a methyl disulfide intermediate. PMID- 23035786 TI - Clinicopathological significance of MAML2 gene split in mucoepidermoid carcinoma. AB - CRTC1-MAML2 and CRTC3-MAML2 fusions have been associated with favorable clinicopathological features of mucoepidermoid carcinomas. However, the significance of the MAML2 gene split has not been fully clarified. In the present study, 95 mucoepidermoid carcinomas (paraffin-embedded materials) were analyzed for CRTC1-MAML2 and CRTC3-MAML2 fusions by RT-PCR and for the MAML2 gene split by FISH. Quantitative RT-PCR for the CRTC1-MAML2 transcript was performed in selected cases. MLL gene involvement, which has been reported in some leukemia cases, was examined by FISH in fusion partner-unknown cases. CRTC1-MAML2 and CRTC3-MAML2 fusions were detected in 37 and 6 cases, respectively. The MAML2 gene split was detected in 62 cases, which included all CRTC1/3-MAML2 fusion-positive cases. The level of CRTC1-MAML2 transcript expression was highly variable, and its clinicopathological impact was unclear. The MLL gene split was not detected. Mucoepidermoid carcinomas negative for CRTC1/3-MAML2 and positive for the MAML2 gene split (n = 19) showed favorable clinicopathological tumor features similar to those positive for CRTC1/3-MAML2 fusions. Compared with negative cases (n = 33), mucoepidermoid carcinomas positive for the MAML2 split (n = 62) were associated with lower patient age, a mild female predilection, a smaller tumor size, less frequent nodal metastasis, a lower clinical stage, a lower histological grade, and longer overall and disease-free survival. The MAML2 gene split emerged as an independent prognostic factor for both overall and disease free survival in multivariate prognostic analysis. The presence of the MAML2 gene split defines a distinct mucoepidermoid carcinoma subset that is associated clinicopathologically with favorable tumor features. PMID- 23035787 TI - Principal component analysis based pre-cystectomy model to predict pathological stage in patients with clinical organ-confined bladder cancer. PMID- 23035788 TI - Cryptococcosis, lymphoproliferative disorders and modern day chemotherapy regimens. PMID- 23035789 TI - On mechanisms of reactive metabolite formation from drugs. AB - Idiosyncratic adverse drug reactions (IADRs) cause a broad range of clinically severe conditions of which drug induced liver injury (DILI) in particular is one of the most frequent causes of safety-related drug withdrawals. The underlying cause is almost invariably formation of reactive metabolites (RM) which by attacking macromolecules induc eorgan injuries. Attempts are being made in the pharmaceutical industry to lower the risk of selecting unfit compounds as clinical candidates. Approaches vary but do not seem to be overly successful at the initial design/synthesis stage. We review here the most frequent categories of mechanisms for RM formation and propose that many cases of RMs encountered within early ADME screening can be foreseen by applying chemical and metabolic knowledge. We also mention a web tool, SpotRM, which can be used for efficient look-up and learning about drugs that have recognized IADRs likely caused by RM formation. PMID- 23035790 TI - Occupational therapists' experiences in integrating a new intervention in collaboration with a researcher. AB - OBJECTIVE: The aim of this study was to describe occupational therapists' expectations and experiences of integrating a new intervention programme within an RCT pilot study, in collaboration with a researcher. METHODS: Six occupational therapists participated in a five-day training course (during a one-month period) including lectures, reading articles, and discussions. The data were collected through interviews and written reflections, analysed by a qualitative constant comparative approach. RESULTS: The findings displayed a process of change, primarily in the participants' way of integrating research in their clinical practice. Three main categories were identified as: hope of taking part in a research project, confirmation of anchoring, and experience of scepticism. These categories constituted the core category "The occupational therapist's process of integrating research in a clinical context with the prerequisite being a dialogue and a sharing of responsibility and authority between researcher and occupational therapist". A tentative model was formulated which described how the various categories were related to one another as well as how change occurred over time in the context in which the study was carried out. CONCLUSIONS: One conclusion is the importance of providing opportunities for creating dialogues among researcher and practitioners to narrowing the gap between research and "everyday practice of occupational therapy". PMID- 23035791 TI - Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1. AB - BACKGROUND: To examine the natural growth dynamics of internal plexiform neurofibromas (PNs) in patients with neurofibromatosis 1 (NF1). METHODS: Two hundred and one NF1 patients underwent whole body MRI (WBMRI). Tumour burden was estimated volumetrically. Non-parametric Spearman's rho correlation coefficients were used to analyse the relationship of growth rate to tumour volume and age. Chi-squared and Mann-Whitney U tests were used for analysing the association of tumour occurrence with sex or age. Chi-squared tests were used to analyse the association of tumour growth with age group. RESULTS: Seventy-one of 171 patients with serial WBMRI exams had internal PNs (median follow up 2.2 years [1.1 to 4.9 years]). Median whole body tumour volume was 86.4 mL [5.2 to 5878.5 mL]) with a median growth rate of 3.7%/year (-13.4 to 111%/year) that correlated with larger whole body tumour volume (P<0.001) and lower age (P=0.004). No new PNs developed in 273.0 patient-years among patients without tumours. Rate of new tumour development among patients with PNs was 0.6%/year (95% confidence interval 0.02 to 3.4%). Twenty-seven (13.5%) tumours increased significantly and were more frequent among children (P<0.001). Growth rate of tumours was inversely correlated with age (Spearman's rho=-0.330, P<0.001). Seventy-one (35.5%) tumours had smaller volumes on follow up (median -3.4%/year [-0.07% to -35.9%/year]). CONCLUSION: Children with NF1 and internal PNs are at risk for tumour growth. Most PNs grow slowly or not at all, and some decrease in size. New tumours are infrequent in NF1 patients with PNs and unlikely in patients without PNs. PMID- 23035792 TI - Use of amphoteric rinsing solution for treatment of ocular tissues exposed to nitrogen mustard. AB - PURPOSE: Ocular exposure to mustard agents may cause severe and prolonged injury to the anterior segment tissues. Effective decontamination of the external eye surface after exposure is of paramount importance. The purpose of the present study was to assess the effectiveness of Diphoterine rinsing solution (DRS) in reducing ocular damage after exposure to nitrogen mustard (NM) and to compare it with normal saline solution. METHODS: One eye of 16 New Zealand albino rabbits was exposed to 2% NM. Immediate thorough irrigation was performed with either 500 ml of DRS (treated group) or with 500 ml of normal saline (control group). The magnitude of ocular injury and response to treatment were assessed by examiners masked to the treatment assignment during 22 days following the exposure. RESULTS: Immediate ocular irrigation with DRS was more effective compared with saline in reducing corneal, iris and anterior chamber injury. In the DRS-treated group, the corneal opacity and corneal neovascularization were less severe, and development of iris atrophy was delayed. Intraocular pressure (mmHg) was better maintained when compared to the control group (day 7 24.3 versus 14.8, p = 0.003; day 12 28 versus 15, p = 0.003; day 22 33.5 versus 21.8, p = 0.014, respectively). Systemic oxidative stress associated with exposure to NM was significantly higher in the saline-treated group than in DRS-treated group (p < 0.011). CONCLUSIONS: The findings of this study indicate the effectiveness of DRS in reducing of NM-induced ocular injuries. Its use should be considered as an immediate treatment modality following exposure to mustard agents to reduce potential ocular injury. PMID- 23035794 TI - A novel endoscopic treatment for ureteric remnant hemorrhage post laparoscopic radical nephrectomy. AB - Laparoscopic radical nephrectomy is commonly used to treat renal masses. Given the ubiquitous presence of this technique, rare complications are becoming more commonplace. It is thus essential that practicing urologists be aware of all possible complications as well as the novel management approaches that exist. This report presents a situation in which a patient developed rapid-onset, postoperative gross hematuria. This complication is rare and multiple sources of bleeding must be considered. In the situation reported here, the ureteric remnant was the cause of the unremitting gross hematuria. While others have described surgical exploration as the primary treatment, the authors were successful in using a minimally invasive endoscopic approach with fulguration and instillation of a fibrin sealant. Indeed, they propose that the endoscopic approach described herein may be considered first line in cases of unremitting gross hematuria originating from the ureteric remnant. PMID- 23035793 TI - Evaluation of age-related changes in translocator protein (TSPO) in human brain using (11)C-[R]-PK11195 PET. AB - BACKGROUND: We studied the distribution and expression of translocator protein in the human brain using (11)C-[R]-PK-11195 positron emission tomography (PK11195 PET) and evaluated age-related changes. METHODS: A dynamic PK11195 PET scan was performed in 15 normal healthy adults (mean age: 29 +/-8.5 years (range: 20 to 49); 7 males) and 10 children (mean age: 8.8 +/-5.2 years (range: 1.2 to 17); 5 males), who were studied for potential neuroinflammation but showed no focally increased PK11195 binding. The PET images were evaluated by calculating standard uptake values and regional binding potential, based on a simplified reference region model, as well as with a voxel-wise analysis using statistical parametric mapping. RESULTS: PK11195 uptake in the brain is relatively low, compared with the subcortical structures, and symmetrical. The overall pattern of PK11195 distribution in the brain does not change with age. PK11195 uptake was lowest in the frontal-parietal-temporal cortex and highest in the pituitary gland, midbrain, thalamus, basal ganglia, occipital cortex, hippocampus and cerebellum, in descending order. White matter showed negligible PK11195 uptake. Overall, brain PK11195 uptake increased with age, with midbrain and thalamus showing relatively higher increases with age compared with other brain regions. CONCLUSIONS: The brain shows low PK11195 uptake, which is lower in the cortex and cerebellum compared with subcortical structures, suggesting a low level of translocator protein expression. There is no hemispheric asymmetry in PK11195 uptake and the overall pattern of PK11195 distribution in the brain does not change with age. However, brain PK11195 uptake increases with age, with the thalamus and midbrain showing relatively higher increases compared with other brain regions. This increase in uptake suggests an age-related increase in translocator protein expression or the number of cells expressing these receptors or both. PMID- 23035795 TI - Biodegradation of chlorobenzene and nitrobenzene at interfaces between sediment and water. AB - Plumes of contaminated groundwater often pass through an oxic/anoxic interface when they discharge into surface water bodies. We tested the hypothesis that contaminants recalcitrant under anaerobic conditions but degradable under aerobic conditions can be biodegraded at the interface resulting in the protection of the overlying water. Flow-through columns containing sediment and water were used to evaluate degradation of synthetic organic compounds at the thin organic layer at the sediment/water interface. Sediment samples collected from several sites contaminated with nitrobenzene (NB) or chlorobenzene (CB) were tested for their biodegradation capacities in the columns. The biodegradation capacities of sediment in the columns were 2-4.2 g CB.m(-2).d(-1) and 6.5 g NB.m(2).d(-1). Bacteria able to carry out rapid and complete biodegradation of CB or NB were detected in the sediments prior to the experiments, which suggested the presence of an active microbial community at the contaminated sites. The results revealed robust biodegradation of toxic compounds migrating across the sediment/water interface and indicate that the biodegradation capacities were sufficient to eliminate transport of the contaminants to the overlying water in the field. PMID- 23035796 TI - Urine dipstick analysis for identification of runners susceptible to acute kidney injury following an ultramarathon. AB - This study examined whether urine dipstick testing might be useful to predict the development of acute kidney injury after an ultramarathon. Participants in the 2011 161-km Western States Endurance Run underwent post-race blood and urine dipstick analyses. Of the 310 race finishers, post-race urine dipstick testing was completed on 152 (49%) and post-race blood also was obtained from 150 of those runners. Based on "injury" and "risk" criteria for acute kidney injury of blood creatinine 2.0 and 1.5 times estimated baseline, respectively, 4% met the criteria for injury and an additional 29-30% met the criteria for risk of injury. Those meeting the injury criteria had higher creatine kinase concentrations (P < 0.001) than those not meeting the criteria. Urine dipstick tests that read positive for at least 1+ protein, 3+ blood, and specific gravity >= 1.025 predicted those meeting the injury criteria with sensitivity of 1.00 (95% confidence interval [CI] 0.54-1.00), specificity of 0.76 (95% CI 0.69-0.83), positive predictive value of 0.15 (95% CI 0.06-0.30), negative predictive value of 1.00 (95% CI 0.97-1.00), and likelihood ratio for a positive test of 4.2. We conclude that urine dipstick testing was successfully able to identify those individuals meeting injury criteria for acute kidney injury with excellent sensitivity and specificity. PMID- 23035797 TI - Ten-nanometer dense hole arrays generated by nanoparticle lithography. AB - Large area dense hole arrays with a feature size of ~10 nm were generated using self-assembled monolayers of nanoparticles as etch masks. To fabricate the hole arrays, monolayers of nanoparticles were irradiated by electron beam to turn surfactants into amorphous carbon, treated by acid to remove the nanoparticle cores, and then etched by CF(4) to deepen the holes. Evaporated gold films preferentially diffuse into the holes to generate gold nanoparticle arrays. However no obvious diffusion into holes was observed for a sputtered iron platinum film. PMID- 23035798 TI - Mirror syndrome in a Chinese hospital: diverse causes and maternal fetal features. AB - OBJECTIVE: To investigate the clinical characteristics of mirror syndrome. METHODS: Retrospective analysis of cases with mirror syndrome. Data of clinical manifestations, laboratory examinations, placental morphology, treatment and prognosis of these patients were obtained and studied. RESULTS: Five cases satisfying the inclusion criteria for mirror syndrome were identified from our hospital database. The incidence of the condition was 0.0154% in China. Mirror syndrome was associated with Rhesus isoimmunization, intrauterine parvovirus B19 infection, fetal neuroblastoma, fetal heart malformation and unknown cause respectively. Fetal symptoms were multi-hydrocele and fetal heart failure complicating fetal hydrops. All of the cases manifested maternal hydrops and hemodilution, the other most common symptoms included hypertension, proteinuria, hypoalbuminemia, anemia, thrombocytopenia and elevated uric acid levels. Fetal outcomes in this study were poor with a perinatal mortality rate of 100%. Placentomegaly was observed in most cases and placental morphology showed villous edema, increased intervillous fibrin deposition and one rare case of fetal adrenal neuroblastoma. Resolution of maternal symptoms was noted within 3-30 days after delivery. CONCLUSION: Mirror syndrome is associated with a substantially increased risk of fetal death and severe maternal complications. Early diagnosis of this condition during pregnancy is crucial for providing proper treatments and achieving better clinical outcomes. PMID- 23035800 TI - Cyanide-selective electrode based on Zn(II) tetraphenylporphyrin as ionophore. AB - Receptors that exhibit high selectivity are essential for potentiometric cyanide sensors. Therefore, CN- binding to metallotetraphenylporphyrins with different metal centers (i.e., Co(II), Co(III), Zn(II), Ni(II), Cu(II), and Fe(III)) was investigated. All these metalloporphyrins were found to function as neutral ionophores. Co(III) and Fe(III) tetraphenylporphyrins with their positive charges seemed likely to bind up to two axial CN- ligands, but only the Co(III) porphyrin was found to strongly bind a second CN- ligand. The electrode membranes doped with Zn(II) tetraphenylporphyrin provided the highest selectivity over chloride (logK(CN-,Cl-)(pot) = -3.71, as opposed to -0.36 for an ionophore-free ISE) and were optimized by adjusting the site-to-ionophore ratio to achieve the highest CN selectivity, with special consideration of interfering ions present in gold mining applications. The Zn(II) tetraphenylporphyrin-based CN(-)-selective electrodes exhibited the best discrimination of OH-; no pH effect was observed even at pH 11 (logK(CN-,OH-)(pot) = -3.42). The response slopes and unbiased selectivities of the ionophore-free and the ionophore-based electrodes with 25 mol % and 71 mol % cationic sites relative to ionophore showed that the Zn(II) tetraphenylporphyrin forms a 1:1 complex with the target ion CN- and 2:1 and 1:1 complexes with the interfering ions OH- and S(2-), respectively. The CN- binding constant was 2.3 * 10(6) (mol/kg)(-1), which is slightly bigger but of the same order of magnitude as for binding of Zn(II) tetraphenylporphyrin to CN- in dichloroethane. PMID- 23035799 TI - Personal attributes that influence the adequate management of hypertension and dyslipidemia in patients with type 2 diabetes. Results from the DIAB-CORE Cooperation. AB - BACKGROUND: Hypertension and dyslipidemia are often insufficiently controlled in persons with type 2 diabetes (T2D) in Germany. In the current study we evaluated individual characteristics that are assumed to influence the adequate treatment and control of hypertension and dyslipidemia and aimed to identify the patient group with the most urgent need for improved health care. METHODS: The analysis was based on the DIAB-CORE project in which cross-sectional data from five regional population-based studies and one nationwide German study, conducted between 1997 and 2006, were pooled. We compared the frequencies of socio-economic and lifestyle factors along with comorbidities in hypertensive participants with or without the blood pressure target of<140/90 mmHg. Similar studies were also performed in participants with dyslipidemia with and without the target of total cholesterol/HDL cholesterol ratio<5. Furthermore, we compared participants who received antihypertensive/lipid lowering treatment with those who were untreated. Univariable and multivariable logistic regression models were used to assess the odds of potentially influential factors. RESULTS: We included 1287 participants with T2D of whom n=1048 had hypertension and n=636 had dyslipidemia. Uncontrolled blood pressure was associated with male sex, low body mass index (BMI), no history of myocardial infarction (MI) and study site. Uncontrolled blood lipid levels were associated with male sex, no history of MI and study site. The odds of receiving no pharmacotherapy for hypertension were significantly greater in men, younger participants, those with BMI<30 kg/m(2) and those without previous MI or stroke. Participants with dyslipidemia received lipid lowering medication less frequently if they were male and had not previously had an MI. The more recent studies HNR and CARLA had the greatest numbers of well controlled and treated participants. CONCLUSION: In the DIAB-CORE study, the patient group with the greatest odds of uncontrolled co-morbidities and no pharmacotherapy was more likely comprised of younger men with low BMI and no history of cardiovascular disease. PMID- 23035801 TI - Clinical and electrophysiologic variability in amyotrophic lateral sclerosis within a kindred harboring the C9ORF72 repeat expansion. AB - Our objective was to characterize the motor neuron disease features within a large c9FTD/ALS kindred. We analyzed clinical, electrophysiologic and neuropathologic data in a c9FTD/ALS kindred of Scandinavian ancestry. Results showed that of six family members affected, three had only ALS, two had FTD and one had FTD and ALS. Each patient with motor neuron disease had a different clinical presentation: one patient had only bulbar symptoms, one had bulbar and limb involvement, one had limb symptoms, and one had primarily upper motor neuron disease. Later in the course of disease, all ALS patients developed bulbar involvement and died from respiratory causes. Survival was uniformly short (two to five years). Electrophysiologic studies recorded progressive lower motor neuron dysfunction except in the patient with predominantly upper motor neuron features. In conclusion, this kindred demonstrates that the presentation of ALS within c9FTD/ALS families may vary considerably and electrophysiologic findings reflect this heterogeneity. PMID- 23035803 TI - Multimodal management of colorectal liver metastases and the effect on regeneration and outcome after liver resection. AB - Management of colorectal liver metastases (CRLM) has dramatically changed during the last decade and has now become more multimodal and aggressive, including the use of downstaging chemotherapy, portal vein embolization to increase the function of the liver remnant or both in combination. Radiofrequency ablation is also an option in CRLM, potentially combined with surgical resection. Results are quite convincing concerning the safety of liver resection also when performed following neoadjuvant chemotherapy. Sparing liver parenchyma in patients with bilobar liver metastatic disease subjected to liver resection may be possible without endangering surgical radicality. Sparing liver parenchyma when using neoadjuvant chemotherapy, a chemotherapy-free period of 6 weeks or more seems to positively affect liver regeneration. There is still the possibility to reresect recurrent liver lesions, though there seems to be a tendency toward fewer reresections following the use of adjuvant chemotherapy. PMID- 23035802 TI - Transcriptome variation along bud development in grapevine (Vitis vinifera L.). AB - BACKGROUND: Vegetative buds provide plants in temperate environments the possibility for growth and reproduction when environmental conditions are favorable. In grapevine, crucial developmental events take place within buds during two growing seasons in consecutive years. The first season, the shoot apical meristem within the bud differentiates all the basic elements of the shoot including flowering transition in lateral primordia and development of inflorescence primordia. These events practically end with bud dormancy. The second season, buds resume shoot growth associated to flower formation and development. Gene expression has been previously monitored at specific stages of bud development but has never been followed along the two growing seasons. RESULTS: Gene expression changes were analyzed along the bud annual cycle at eight different time points. Principal Components Analysis (PCA) revealed that the main factors explaining the global gene expression differences were the processes of bud dormancy and active growth as well as stress responses. Accordingly, non dormant buds showed an enrichment in functional categories typical of actively proliferating and growing cells together with the over abundance of transcripts belonging to stress response pathways. Differential expression analyses performed between consecutive time points indicated that major transcriptional changes were associated to para/endodormancy, endo/ecodormancy and ecodormancy/bud break transitions. Transcripts encoding key regulators of reproductive development were grouped in three major expression clusters corresponding to: (i) transcripts associated to flowering induction, (ii) transcripts associated to flower meristem specification and initiation and (iii) transcripts putatively involved in dormancy. Within this cluster, a MADS box gene (VvFLC2) and other transcripts with similar expression patterns could participate in dormancy regulation. CONCLUSIONS: This work provides a global view of major transcriptional changes taking place along bud development in grapevine, highlighting those molecular and biological functions involved in the main events of bud development. As reported in other woody species, the results suggest that genes regulating flowering could also be involved in dormancy regulatory pathways in grapevine. PMID- 23035804 TI - Assessment of iodine nutrition in populations: past, present, and future. AB - Iodine status has been historically assessed by palpation of the thyroid and reported as goiter rates. Goiter is a functional biomarker that can be applied to both individuals and populations, but it is subjective. Iodine status is now assessed using an objective biomarker of exposure, i.e., urinary iodine concentrations (UICs) in spot samples and comparison of the median UIC to UIC cut offs to categorize population status. This has improved standardization, but inappropriate use of the crude proportion of UICs below the cut-off level of 100 ug/L to estimate the number of iodine-deficient children has led to an overestimation of the prevalence of iodine deficiency. In this review, a new approach is proposed in which UIC data are extrapolated to iodine intakes, adjusted for intraindividual variation, and then interpreted using the estimated average requirement cut-point model. This may allow national programs to define the prevalence of iodine deficiency in the population and to quantify the necessary increase in iodine intakes to ensure sufficiency. In addition, thyroglobulin can be measured on dried blood spots to provide an additional sensitive functional biomarker of iodine status. PMID- 23035806 TI - Influences of micronutrient and omega-3 fatty acid supplementation on cognition, learning, and behavior: methodological considerations and implications for children and adolescents in developed societies. AB - The purpose of this review is to outline the current evidence regarding the effects of micronutrient and omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on the cognition, learning, and behavior of children and adolescents living in developed societies. Existing evidence suggests that children and adolescents in developed countries may perform better on tests of nonverbal intelligence and on behavioral measures after receiving vitamin and mineral supplements with or without n-3 PUFA supplementation compared with those receiving placebo, regardless of age and supplementation formula. The strongest effects were observed in trials that lasted over 3 months and in subgroups of children with low socioeconomic status, symptoms of attention deficit hyperactivity disorder, and/or learning disabilities. Future studies should focus on children and adolescents who have a low socioeconomic status or are likely to be suffering nutritional deficiencies to determine the impact of vitamin and mineral supplements with or without n-3 PUFA supplementation on their cognitive and behavioral functioning. These studies should ideally include blood sample analyses to help determine if nutritional status influences the response to supplementation and whether changes in blood status account for effects on cognition and behavior. PMID- 23035805 TI - Does food marketing need to make us fat? A review and solutions. AB - Food marketing is often singled out as the leading cause of the obesity epidemic. The present review examines current food marketing practices to determine how exactly they may be influencing food intake, and how food marketers could meet their business objectives while helping people eat healthier. Particular attention is paid to the insights provided by recently published studies in the areas of marketing and consumer research, and those insights are integrated with findings from studies in nutrition and related disciplines. The review begins with an examination of the multiple ways in which 1) food pricing strategies and 2) marketing communication (including branding and food claims) bias food consumption. It then describes the effects of newer and less conspicuous marketing actions, focusing on 3) packaging (including the effects of package design and package-based claims) and 4) the eating environment (including the availability, salience, and convenience of food). Throughout, this review underscores the promising opportunities that food manufacturers and retailers have to make profitable "win-win" adjustments to help consumers eat better. PMID- 23035807 TI - Update on perilipin polymorphisms and obesity. AB - Perilipin proteins were discovered in the adipocyte, where they regulate lipid storage and lipolysis. Animal knockout models provided initial evidence of the critical role of perilipin 1, the most abundant of the adipocyte proteins, in energy and glucose metabolism. During a decade of study, genetic variation in perilipin 1 has been consistently but not invariably associated with body weight and obesity-related complications. Related phenotypes such as postprandial lipid metabolism and aerobic fitness are also modulated by perilipin 1 genotype, consistent with earlier metabolic studies. Investigations of gene-diet interactions, together with gene expression studies, have yielded increased understanding, but important questions about causal variants and mechanisms remain. The newest work examines perilipin 4, an adipocyte regulator of triglyceride synthesis and packaging. The novel discovery that a perilipin 4 variant creates a binding site for regulation of the perilipin gene (PLIN) by microRNA suggests intriguing new possibilities for additional mechanistic investigations of other perilipin proteins. PMID- 23035809 TI - Outcome of laparoscopic versus open hepatectomy for colorectal liver metastases. AB - BACKGROUND: Liver resection provides one of the best oncological outcomes for liver metastases in patients with colorectal cancer. However, long-term results concerning laparoscopic resection versus open hepatectomy for stage IV colon cancer are still limited. The aim of this study is to compare the survival outcome of laparoscopic liver resection with open liver resection for colorectal metastases. METHOD: Between October 2002 and September 2011, a total of 1697 patients underwent liver resection for liver tumour and 60 patients underwent pure laparoscopic liver resection. Twenty patients had laparoscopic resection for colorectal liver metastases. Case-matched control patients who received open liver resection were included for comparison. The immediate operative outcomes and survival outcomes including operation morbidity were compared. RESULTS: Twenty patients underwent laparoscopic resection of liver metastases. Forty patients who had open hepatectomy for colorectal metastases were selected as case control. Comparing the laparoscopic group with the open resection group, the median operating time was 180 min versus 210 min P = 0.059, the median blood loss was 200 versus 310 mL (P = 0.043). Hospital stay was 4.5 versus 7 days (P = 0.021), disease-free survival was 9.8 versus 10.9 months (P = 0.299), and the median survival was 69.4 versus 42.1 months (P = 0.235). CONCLUSIONS: Laparoscopic liver resection is a safe and effective treatment for liver metastases in patients with colorectal cancer. It is associated with less blood loss and shorter hospital stay when compared with open surgery. Long-term survival is comparable to the conventional open approach. PMID- 23035810 TI - Report of findings in a DSM-5 field trial for hypersexual disorder. AB - INTRODUCTION: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for hypersexual disorder (HD) have been proposed to capture symptoms reported by patients seeking help for out-of-control sexual behavior. The proposed criteria created by the DSM-5 Work Group on Sexual and Gender Identity Disorders require evaluation in a formal field trial. AIM: This DSM-5 Field Trial was designed to assess the reliability and validity of the criteria for HD in a sample of patients seeking treatment for hypersexual behavior, a general psychiatric condition, or a substance-related disorder. METHOD: Patients (N = 207) were assessed for psychopathology and HD by blinded raters to determine inter-rater reliability of the HD criteria and following a 2 week interval by a third rater to evaluate the stability of the HD criteria over time. Patients also completed a number of self-report measures to assess the validity of the HD criteria. MAIN OUTCOME MEASURES: HD and psychopathology were measured by structured diagnostic interviews, the Hypersexual Behavior Inventory, Sexual Compulsivity Scale, and Hypersexual Behavior Consequences Scale. Emotional dysregulation and stress proneness were measured by facets on the NEO Personality Inventory-Revised. RESULTS: Inter-rater reliability was high and the HD criteria showed good stability over time. Sensitivity and specificity indices showed that the criteria for HD accurately reflected the presenting problem among patients. The diagnostic criteria for HD showed good validity with theoretically related measures of hypersexuality, impulsivity, emotional dysregulation, and stress proneness, as well as good internal consistency. Patients assessed for HD also reported a vast array of consequences for hypersexual behavior that were significantly greater than those diagnosed with a general psychiatric condition or substance-related disorder. CONCLUSIONS: The HD criteria proposed by the DSM-5 Work Group on Sexual and Gender Identity Disorders appear to demonstrate high reliability and validity when applied to patients in a clinical setting among a group of raters with modest training on assessing HD. PMID- 23035811 TI - Is walking faster or walking farther more important to persons with chronic stroke? AB - PURPOSE: The purposes of this mixed-methods study were to (1) investigate whether walking faster or walking farther was more important for getting "out and about" to persons with chronic stroke and (2) explore explanations for walking preferences. METHOD: A convenience sample of 77 adults with chronic stroke completed questionnaires and walking outcomes in one visit. Participants were asked whether walking faster or farther was more important to them for getting "out and about", and differences between response groups (faster vs. farther) were evaluated. Participants also described their preference for walking faster or farther. Qualitative responses were analyzed using content analysis. RESULTS: The majority of participants (76%; n = 58) reported walking farther was more important, while 18% (n = 14) reported walking faster was more important. Statistically significant differences were not found between response groups for any variable. Primary themes identified from participant preferences for walking faster included: (1) faster speed equals better walking ability and (2) getting places faster/quicker. Primary themes from preferences for walking farther included: (1) engaging in activity and participation within home and community; (2) walking farther at a slower pace; and (3) fatigue with walking. CONCLUSIONS: Individual preferences for walking faster versus walking farther by persons with chronic stroke should be considered by clinicians when making decisions for rehabilitation. IMPLICATIONS FOR REHABILITATION: * Individual preferences for walking faster versus walking farther by patients with chronic stroke should be considered by rehabilitation clinicians when making decisions about examination and intervention. * The majority of participants with chronic stroke in this study indicated the importance of walking farther in order to better engage in activities both at home and away from home. * Interventions that focus on improving endurance and energy conservation may need to be used for persons with chronic stroke who want to walk father in order to maximize their potential for walking longer distances. PMID- 23035812 TI - Flow cytometric identification of Mamiellales clade II in the Southern Atlantic Ocean. AB - Flow cytometric sorting, based on cellular optical properties and macromolecule content, has been successfully employed to taxonomically affiliate bacterioplankton. However, this approach has not been much used for eukaryotic plankton. To redress this imbalance, we identified a conspicuous group of red autofluorescent picoplankton in surface waters of the South Atlantic Ocean. Using catalysed reporter deposition fluorescence in situ hybridization, virtually, all cells sorted from that group were affiliated with the Mamiellales clade II (84 +/ 4%, division Chlorophyta) with a size of 1.6 +/- 0.03 MUm. Based on electron microscopy, the Mamiellales clade II-sorted cells have a simple morphology with apparently no scales, flagella or surface features. Their latitudinal distribution resembled the distribution of Synechococcus with very low concentrations in the surface waters of the Southern subtropical gyre (0.6-1.6 * 10(3) cells mL(-1)) and increased concentrations in the Southern temperate waters 8.3 * 10(3) cells mL(-1). Identification of the flow cytometric group as Mamiellales clade II allowed us to characterize the morphology of these enigmatic uncultured picoplanktonic cells by electron microscopy and to determine their apparent preference for temperate rather than subtropical oceanic photic waters. PMID- 23035813 TI - Domain swapping of the heme and N-terminal alpha-helix in Hydrogenobacter thermophilus cytochrome c(552) dimer. AB - Oxidized horse cytochrome c (cyt c) has been shown to oligomerize by domain swapping its C-terminal helix successively. We show that the structural and thermodynamic properties of dimeric Hydrogenobacter thermophilus (HT) cytochrome c(552) (cyt c(552)) and dimeric horse cyt c are different, although both proteins belong to the cyt c superfamily. Optical absorption and circular dichroism spectra of oxidized dimeric HT cyt c(552) were identical to the corresponding spectra of its monomer. Dimeric HT cyt c(552) exhibited a domain-swapped structure, where the N-terminal alpha-helix together with the heme was exchanged between protomers. Since a relatively strong H-bond network was formed at the loop around the heme-coordinating Met, the C-terminal alpha-helix did not dissociate from the rest of the protein in dimeric HT cyt c(552). The packing of the amino acid residues important for thermostability in monomeric HT cyt c(552) were maintained in its dimer, and thus, dimeric HT cyt c(552) exhibited high thermostability. Although the midpoint redox potential shifted from 240 +/- 2 to 213 +/- 2 mV by dimerization, it was maintained relatively high. Ethanol has been shown to decrease both the activation enthalpy and activation entropy for the dissociation of the dimer to monomers from 140 +/- 9 to 110 +/- 5 kcal/mol and 310 +/- 30 to 270 +/- 20 cal/(mol.K), respectively. Enthalpy change for the dissociation of the dimer to monomers was positive (14 +/- 2 kcal/mol per protomer unit). These results give new insights into factors governing the swapping region and thermodynamic properties of domain swapping. PMID- 23035814 TI - Design, synthesis, and anti-tobacco mosaic virus (TMV) activity of phenanthroindolizidines and their analogues. AB - On the basis of our previous structure-activity relationship (SAR) and antiviral mechanism studies, a series of phenanthroindolizidines and their analogues 3-20 were designed, targeting tobacco mosaic virus (TMV) RNA, synthesized, and systematically evaluated for their antiviral activity against TMV. The bioassay results showed that most of these compounds displayed good anti-TMV activity, and some of them exhibited higher antiviral activity than that of commercial Ningnanmycin (perhaps the most successful registered antiplant viral agent). Especially, (S)-deoxytylophorinine (5) with excellent anti-TMV activity (inactivation activity, 59.8%/500 MUg mL(-1) and 40.3%/100 MUg mL(-1); curative activity, 65.1%/500 MUg mL(-1) and 43.7%/100 MUg mL(-1); and protection activity, 70.2%/500 MUg mL(-1) and 51.3%/100 MUg mL(-1)) emerged as a potential inhibitor of the plant virus. Compound 20 exhibited a strong in vivo protection effect against TMV at 100 MUg mL(-1), which indicated that phenanthroindolizidine analogues with a seven-membered D ring have a new and interesting structural scaffold and have great potential for further development as tobacco protection agents. PMID- 23035815 TI - High grade prostatic intraepithelial neoplasia does not display loss of heterozygosity at the mutation locus in BRCA2 mutation carriers with aggressive prostate cancer. AB - What's known on the subject? and What does the study add? The risk of developing aggressive prostate cancer is increased for men carrying a pathogenic germline mutation in BRCA2. An earlier study by the Kathleen Cuningham Consortium for Research into Familial Breast Cancer showed that BRCA2 mutation carriers displayed a loss of heterozygosity (LOH) within their prostate cancer tissue in the majority of cases, thus implying that the prostate cancer in these men occurred as a result of LOH for BRCA2. High grade prostatic intraepithelial neoplasia (HGPIN) has been considered a precursor to prostate adenocarcinoma in some, but not all, cases of prostate adenocarcinoma. The study found that there was no LOH for BRCA2 in HGPIN. From this small cohort of BRCA2-positive men, we suggest HGPIN is not necessarily a precursor to their prostate cancer development. The presence of HGPIN in a TRUS biopsy in these men at risk of high risk disease is not an indication for prostatectomy. OBJECTIVES: * To determine if high grade prostatic intraepithelial neoplasia (HGPIN), which is considered a precursor to the development of prostate adenocarcinoma, displays the same genetic hallmarks as adenocarcinoma. * To identify, using molecular genetic techniques, if HGPIN is a precursor of tumour development and progression in men carrying a pathogenic germline mutation in BRCA2. PATIENTS AND METHODS: * Ten participants from the Kathleen Cuningham Consortium for Research into Familial Breast Cancer cohort of high-risk breast cancer families were identified, with (i) a diagnosis of aggressive prostate cancer and presence of HGPIN, (ii) a pathogenic BRCA2 mutation, and (iii) access to archival prostate tissue specimens. * Loss of heterozygosity (LOH) at the BRCA2 gene was examined using mutation-specific PCR and sequencing of DNA from laser microdissected HGPIN. RESULTS: * Within this cohort of 10 pathogenic BRCA2 carriers, no patient displayed LOH at the mutation locus within HGPIN, irrespective of whether or not corresponding adenocarcinoma DNA displayed LOH. CONCLUSIONS: * Although HGPIN is considered a precursor to cancer, as no LOH was observed, this assay does not provide a genetic marker that may be considered a positive predictor of tumorigenesis in BRCA2 carriers. * In this group of high-risk men, early screening via prostate-specific antigen testing, rectal examination and prostate biopsy may be prudent to permit the detection and the optimum clinical management of prostate cancer. PMID- 23035816 TI - Evaluation of von Willebrand factor during pregnancy, lactation and oestrous cycle in bitches affected and unaffected by von Willebrand disease. AB - Plasmatic concentrations of von Willebrand Factor (vWF) increase during pregnancy in humans and dogs; however the mechanism of such increase is still not well defined. The aims of this study were: (i) to evaluate changes in vWF concentration during pregnancy and during the subsequent oestrous cycle in bitches affected and unaffected by von Willebrand Disease (vWD); (ii) to correlate the vWF levels and cortisol levels in both groups. Seven vWD affected (GI) and nine unaffected (GII) bitches were used. The animals were assessed during pregnancy, parturition, lactation and non-gestational oestrous cycle in 11 moments (Pregnancy 1, Pregnancy 2, Parturition, Lactation 1, Lactation 2, Lactation 3, Anestrus, Proestrus, Oestrus, Diestrus 1, and Diestrus 2). The following tests were performed; measurement of von Willebrand factor antigen (vWF:Ag), albumin and cortisol. In both groups, vWF concentration remained stable during the non-gestational oestrous cycle, but increased during pregnancy, with the highest value observed at parturition. Increases of 70% and 124% in vWF were seen in GI and GII, respectively, compared to anestrus. No correlation was found between vWF and cortisol. Values of vWF:Ag changed during pregnancy, with a peak at parturition, both in vWD affected and unaffected animals. Values of vWF were not altered in the different phases of the oestrous cycle following pregnancy in both groups. Evaluation of vWF during pregnancy can cause false negative results for vWD, but assessment can be performed at any point in the oestrous cycle of non-pregnant bitches. PMID- 23035817 TI - Metal release and speciation changes during wet aging of coal fly ashes. AB - Introduction of coal fly ash into aquatic systems poses a potential environmental hazard because of its heavy metal content. Here we investigate the relationship between solid phase transformations, fluid composition, and metal release and speciation during prolonged wet aging of a class C and class F coal fly ash. The class C ash causes rapid alkalinization of water that is neutralized over time by CO(2) uptake from air and calcite precipitation. The resulting aqueous metal concentrations are below regulatory limits with the exception of Cr; solubility constraints suggest this is released as chromate. Limited As release is accompanied by no change in solid-phase speciation, but up to 35% of the Zn in the ash dissolves and reprecipitates in secondary phases. Similar processes inhibit Ba and Cu release. In contrast, the class F ash causes rapid acidification of water and initially releases substantial quantities of As, Se, Cr, Cu, Zn, and Ba. Arsenic concentrations decline during aging because of adsorption to the iron oxide-rich ash; this is aided by As(III) oxidation. Precipitation processes lower Ba and Cr concentrations during aging. Se, Cu, and Zn concentrations remain elevated during wet aging and solid-phase Zn speciation is not affected by ash-water reactions. Total metal contents were poor predictors of metal release, which is predominantly controlled by metal speciation and the effects of ash-water reactions on fluid pH. While contact with atmospheric gases has little effect on class F ash, carbonation of class C ash inhibits metal release and neutralizes the alkalinity produced by the ash. PMID- 23035818 TI - Fluoroquinolone prophylaxis: worth the cost? PMID- 23035820 TI - Prevalence of Salmonella spp. in cane toads (Bufo marinus) from Grenada, West Indies, and their antimicrobial susceptibility. AB - Cloacal swabs and caecal contents sampled from 58 cane toads (Bufo marinus) in St George's parish, Grenada, during a 7-month period in 2011 were examined by an enrichment and selective culture method for presence of Salmonella spp. Twenty four (41%) toads were positive for Salmonella spp. of which eight were Salmonella enterica serovar Javiana, and eight were S. enterica serovar Rubislaw. The other serovars were as follows: Montevideo, 6; Arechavaleta, 1; and serovar: IV:43:-:-, 1. The high frequency of isolation of serovar Javiana, an emerging human pathogen associated with several outbreaks in the recent years in the eastern United States, suggests a possible role for cane toads in transmission of this serovar. Although S. Rubislaw has been isolated from lizards, bats and cases of some human infections, there is no report of its carriage by cane toads, and in such high frequency. The rate of carriage of S. Montevideo, a cause for human foodborne outbreaks around the world was also over 10% in the 58 toads sampled in this study. The antimicrobial drug susceptibility tests against amoxicillin-clavulanic acid, ampicillin, cefotaxime, ceftazidime, ciprofloxacin, enrofloxacin, gentamicin, imipenem, nalidixic acid, streptomycin, tetracycline and trimethoprim sulfamethoxazole showed that drug resistance is minimal and is of little concern. Antimicrobial resistance was limited to ampicillin and amoxicillin-clavulanic acid in one isolate of S. Javiana and one isolate of S. Rubislaw. This is the first report of isolation and antimicrobial susceptibilities of various Salmonella serovars not identified previously in cane toads in Grenada, West Indies. PMID- 23035821 TI - Hydrogen peroxide route to Sn-doped titania photocatalysts. AB - BACKGROUND: The work aims at improving photocatalytic activity of titania under Vis light irradiation using modification by Sn ions and an original, simple synthesis method. Tin-doped titania catalysts were prepared by thermal hydrolysis of aqueous solutions of titanium peroxo-complexes in the presence of SnCl4 or SnCl2 using an original, proprietary "one pot" synthesis not employing organic solvents, metallo-organic precursors, autoclave aging nor post-synthesis calcination. The products were characterized in details by powder diffraction, XPS, UV-vis, IR, and Raman spectroscopies, electron microscopy and surface area and porosity measurements RESULTS: The presence of tin in synthesis mixtures favors the formation of rutile and brookite at the expense of anatase, decreases the particle size of all formed titania polymorphs, and extends light absorption of titania to visible light region >400 nm by both red shift of the absorption edge and introduction of new chromophores. The photocatalytic activity of titania under UV irradiation and >400 nm light was tested by decomposition kinetics of Orange II dye in aqueous solution CONCLUSIONS: Doping by Sn improves titania photoactivity under UV light and affords considerable photoactivity under >400 nm light due to increased specific surface area and a phase heterogeneity of the Sn doped titania powders. PMID- 23035819 TI - Macrophages and their relevance in Human Immunodeficiency Virus Type I infection. AB - Macrophages are important target cells for the Human Immunodeficiency Virus Type I (HIV-1) in vivo. Several studies have assessed the molecular biology of the virus in this cell type, and a number of differences towards HIV-1 infection of CD4+ T cells have been described. There is a broad consensus that macrophages resist HIV-1 infection much better than CD4+ T cells. Among other reasons, this is due to the presence of the recently identified host cell restriction factor SamHD1, which is strongly expressed in cells of the myeloid lineage. Furthermore, macrophages produce and release relatively low amounts of infectious HIV-1 and are less sensitive to viral cytotoxicity in comparison to CD4+ T cells. Nevertheless, macrophages play a crucial role in the different phases of HIV-1 infection. In this review, we summarize and discuss the significance of macrophages for HIV-1 transmission, the acute and chronic phases of HIV-1 infection, the development of acquired immunodeficiency syndrome (AIDS) and HIV associated diseases, including neurocognitive disorders. We propose that interaction of HIV-1 with macrophages is crucial during all stages of HIV-1 infection. Thus, long-term successful treatment of HIV-1 infected individuals requires potent strategies to prevent HIV-1 from entering and persisting in these cells. PMID- 23035822 TI - Acute and subacute toxicity of novel biogenic selenium nanoparticles in mice. AB - CONTEXT: In the present investigation, acute and subacute toxicity of the biogenic Se nanoparticles (Se NPs) has been reported. OBJECTIVE: To characterize the Se NPs produced by a bacterium species and to evaluate their toxicity and impact on clinical chemistry and hematological parameters of NMRI mice. MATERIALS AND METHODS: The Se NPs were prepared by Bacillus sp. MSh-1 in a culture medium containing SeO(2) (1.26 mM) and their physiochemical properties investigated using TEM, XRD and FT-IR. The LD(50) of Se NPs and SeO(2) were determined and the subacute toxicity evaluated by orally administration of 0, 2.5, 5, 10 and 20 mg kg(-1) of Se NPs to male mice for 14 consecutive days. Parameters of blood cells, AST, ALT, ALP, creatinine, BUN, cholesterol, bilirubin, triglyceride and CPK were experimentally measured. RESULTS: The XRD and TEM analyses showed that the spherical NPs were amorphous, in the size range of 80-220 nm. The toxicological evaluation showed that the LD(50) values of SeO(2) and Se NPs were 7.3 and 198.1 mg kg(-1), respectively. No biochemical changes were observed from the administration of 2.5, 5 and 10 mg kg(-1) of Se NPs, but a dose of 20 mg kg(-1) was accompanied with signs of toxicity including lower body weight and changes in clinical chemistry and hematological parameters. CONCLUSION: The biogenic Se NPs were less toxic than synthetic Se NPs and much less (26-fold) toxic than the SeO(2), which demonstrates the important role of Bacillus sp. MSh-1 in conversion of a highly toxic Se compound to the less toxic Se NPs. PMID- 23035823 TI - The severity of hypoxic changes and oxidative DNA damage in the placenta of early onset preeclamptic women and fetal growth restriction. AB - OBJECTIVE: To investigate the relation between the severity of hypoxic changes and oxidative DNA damage in the placenta of early and late-onset preeclampic women and fetal growth restriction (FGR), serum parameters of oxidative stress, placental hypoxic change, and oxidative DNA damage were determined. METHODS: We examined 10 participants with uncomplicated pregnancies, 13 with early-onset and 12 with late-onset preeclampsia. Maternal and umbilical plasma derivatives of reactive oxygen metabolites (d-ROMs) were measured as markers of oxygen free radicals. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for 8-hydroxy-2' deoxyguanosine (8-OHdG), redox factor-1 (ref-1), and hypoxia-induced factor 1alpha (HIF-1alpha), which are markers of oxidative DNA damage, repair functions, and hypoxia status, respectively. RESULTS: 8-OHdG was higher in both preeclamptic groups, but significantly higher in the early-onset preeclamptic group. Ref-1 was higher in the late-onset preeclamptic group. HIF-1alpha was higher in both preeclamptic groups, with a tendency towards a higher in the early-onset preeclamptic group. CONCLUSIONS: Our findings indicate that the severity of hypoxic changes and oxidative DNA damage are greater in the placenta of women with early-onset preeclampsia, and that the prolonged preeclamptic conditions may reduce placental blood flow, ultimately leading to FGR. PMID- 23035825 TI - Safe and correct use of peripheral intravenous devices. AB - BACKGROUND: A peripheral intravenous device (PIVD) provides venous access for the administration of medications, blood products and fluids. They can be associated with a risk of infection and other complications, which have prompted the development of evidence-based guidelines for their use at the Royal Adelaide Hospital (RAH). A previous audit performed at the RAH found unsatisfactory compliance with these guidelines across a group of wards. The Burns Unit performed poorly compared with other wards, but the reasons for this were not explored. METHODS: A repeat audit was performed for all PIVDs in the Burns Unit over a 3-week period and compliance with the PIVD safety guidelines was assessed. Factors influencing compliance were investigated and the evidence behind the guidelines was reviewed. RESULTS: Overall compliance with the seven safety criteria was 71%. Poorest compliance was for documentation of insertion date, which has implications for scheduling PIVD replacement. CONCLUSION: The guidelines are largely evidence-based; however, not all of them are feasible for all patients within a hospital. The Burns Unit had an overall compliance rate of 71%. Auditing of individual wards is not effective in assessing those wards' compliance with the guidelines as many PIVDs are inserted in other locations in the hospital. For compliance to improve, other areas of the hospital where PIVDs are inserted need to be targeted. PMID- 23035824 TI - Re-annotation of the CAZy genes of Trichoderma reesei and transcription in the presence of lignocellulosic substrates. AB - BACKGROUND: Trichoderma reesei is a soft rot Ascomycota fungus utilised for industrial production of secreted enzymes, especially lignocellulose degrading enzymes. About 30 carbohydrate active enzymes (CAZymes) of T. reesei have been biochemically characterised. Genome sequencing has revealed a large number of novel candidates for CAZymes, thus increasing the potential for identification of enzymes with novel activities and properties. Plenty of data exists on the carbon source dependent regulation of the characterised hydrolytic genes. However, information on the expression of the novel CAZyme genes, especially on complex biomass material, is very limited. RESULTS: In this study, the CAZyme gene content of the T. reesei genome was updated and the annotations of the genes refined using both computational and manual approaches. Phylogenetic analysis was done to assist the annotation and to identify functionally diversified CAZymes. The analyses identified 201 glycoside hydrolase genes, 22 carbohydrate esterase genes and five polysaccharide lyase genes. Updated or novel functional predictions were assigned to 44 genes, and the phylogenetic analysis indicated further functional diversification within enzyme families or groups of enzymes. GH3 beta-glucosidases, GH27 alpha-galactosidases and GH18 chitinases were especially functionally diverse. The expression of the lignocellulose degrading enzyme system of T. reesei was studied by cultivating the fungus in the presence of different inducing substrates and by subjecting the cultures to transcriptional profiling. The substrates included both defined and complex lignocellulose related materials, such as pretreated bagasse, wheat straw, spruce, xylan, Avicel cellulose and sophorose. The analysis revealed co-regulated groups of CAZyme genes, such as genes induced in all the conditions studied and also genes induced preferentially by a certain set of substrates. CONCLUSIONS: In this study, the CAZyme content of the T. reesei genome was updated, the discrepancies between the different genome versions and published literature were removed and the annotation of many of the genes was refined. Expression analysis of the genes gave information on the enzyme activities potentially induced by the presence of the different substrates. Comparison of the expression profiles of the CAZyme genes under the different conditions identified co-regulated groups of genes, suggesting common regulatory mechanisms for the gene groups. PMID- 23035826 TI - Recent advances in the comprehension and the management of perioperative systemic host response during cardiopulmonary bypass. AB - Cardiac surgery with cardiopulmonary induces a systemic inflammatory response (SIRS). SIRS is broadly defined as an inflammatory state of the whole body without a proven source of infection. Many pre and postoperative variables have been defined that have a negative impact on SIRS. Although many strategies have been developed, targeting given biomarkers very few of these proved to be effective in a clinical setting. In order to better understand why this happened a new approach for defining SIRS was proposed. This review describes this new concept and the recent patents involved. PMID- 23035827 TI - Review of the fibrinolytic system: comparison of different antifibrinolytics used during cardiopulmonary bypass. AB - Antifibrinolytic agents are often used in different clinical situations, especially in cardiac surgery. During several years, aprotinin was the drug of choice because more than antifibrinolytic properties, aprotinin offers a direct effect on kallikrein and inflammatory pathways. In 2008, The Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) initiated a discussion about real risks associated with aprotinin administration. Tranexamic acid and epsilon aminocaproic acid appear to be interesting alternatives in our daily practice. The exact mechanism of action, the pharmacokinetic parameters, the efficacy, and the safety profile need to be clarified for lysine analogs. In this review, the different antifibrinolytics will be described with a special interest into the route of work, and recent patents. Current studies about the pharmacokinetic and the pharmacodynamic profile will be described, and finally the benefit-to-risk balance in patients undergoing cardiac surgery with cardiopulmonary bypass will be discussed. PMID- 23035828 TI - Routine use of corticosteroids to prevent inflammation response in cardiac surgery. AB - Cardiac surgery, especially if it involves cardiopulmonary bypass, is associated with a severe systemic inflammatory response. It is characterized by complement activation and initiation of coagulation, fibrinolysis and kallikrein cascades. Consecutive activation of immunoregulatory cells results in an extensive release of pro- and anti-inflammatory cytokines. This inflammatory storm is related to organ dysfunction or failure and correlates with postoperative morbidity. In order to attenuate this deleterious inflammatory response in the perioperative period alternative surgical techniques, novel extracorporeal circulation devices and immunomodulatory pharmacological strategies are in focus of contemporary research. Since decades corticosteroids have been used and studied in patients undergoing cardiac surgery. Although it could be shown that glucocorticoids seem to change the pro-inflammatory cytokine profile in a favourable manner, it still remains controversial if this effect translates into a better clinical outcome. Several clinical trials have proclaimed an association between this inflammatory response and the incidence of major complications i.e, myocardial infarction and pulmonary complications, but until now they have failed to show conclusive results. This article describes the different types and recommended dose schemes of corticosteroids in the perioperative period of cardiac surgery along with the discussion of few patents. It will comment on potential side effects and review the effect on the postoperative outcome. PMID- 23035829 TI - Editorial: management of perioperative systemic inflammation during cardiopulmonary bypass: we need a multimodal approach. PMID- 23035830 TI - Bioactive oligostilbenoids from Shorea maxwelliana King and their chemotaxonomic significance. AB - Phytochemical investigation on the stem bark of Shorea maxwelliana yielded five oligostilbenoids identified as alpha-viniferin (1), maximol A (2), vaticanol A (3), suffruticosol A (4) and vaticanol G (5). Chemotaxonomy of isolated compounds was discussed briefly. Major compounds were tested for neurotoxic and cytotoxic activities. Neurotoxicity for all tested compounds did not pose any toxic effect against cultured cell (cell viability range +/-100-94%). Compounds 2-5 possessed active cyctotoxic activity against HL60 cell line with IC50 values range of 2.7 78 ug mL(-1). PMID- 23035831 TI - Explaining emigration intentions and behaviour in the Netherlands, 2005-10. AB - We examined the emigration intentions of native-born Dutch residents and their subsequent emigration behaviour from 2005 to 2010. Data were collected from two surveys on emigration intentions, one conducted locally and one nationally. A number of novel results stand out. First, intentions were good predictors of future emigration: 34 per cent of those who had stated an intention to emigrate actually emigrated within the 5-year follow-up period. Second, the personality of potential migrants and their discontent with the quality of the public domain in the Netherlands (e.g., crowded space and inadequate access to unspoilt nature, pollution, crime level, mentality of people) were the strongest contributors to the motivation to move abroad. Third, the main difference between movers and those who stated intentions to emigrate but had not (yet) followed through was their state of health: healthy people were more likely to follow through with their migration intentions than those in poorer health. PMID- 23035832 TI - Effects of mechanical properties of thermoplastic materials on the initial force of thermoplastic appliances. AB - OBJECTIVE: To measure the forces delivered by thermoplastic appliances made from three materials and investigate effects of mechanical properties, material thickness, and amount of activation on orthodontic forces. MATERIALS AND METHODS: Three thermoplastic materials, Duran (Scheu Dental), Erkodur (Erkodent Erich Kopp GmbH), and Hardcast (Scheu Dental), with two different thicknesses were selected. Values of elastic modulus and hardness were obtained from nanoindentation measurements at 28 degrees C. A custom-fabricated system with a force sensor was employed to obtain measurements of in vitro force delivered by the thermoplastic appliances for 0.5-mm and 1.0-mm activation for bodily tooth movement. Experimental results were subjected to several statistical analyses. RESULTS: Hardcast had significantly lower elastic modulus and hardness than Duran and Erkodur, whose properties were not significantly different. Appliances fabricated from thicker material (0.75 mm or 0.8 mm) always produced significantly greater force than those fabricated from thinner material (0.4 mm or 0.5 mm). Appliances with 1.0-mm activation produced significantly lower force than those with 0.5-mm activation, except for 0.4-mm thick Hardcast appliances. A strong correlation was found between mechanical properties of the thermoplastic materials and force produced by the appliances. CONCLUSIONS: Orthodontic forces delivered by thermoplastic appliances depend on the material, thickness, and amount of activation. Mechanical properties of the polymers obtained by nanoindentation testing are predictive of force delivery by these appliances. PMID- 23035833 TI - Speciation of inorganic- and methyl-mercury in biological matrixes by electrochemical vapor generation from an L-cysteine modified graphite electrode with atomic fluorescence spectrometry detection. AB - A novel nonchromatographic speciation technique for ultratrace inorganic mercury (Hg(2+)) and methylmercury (CH(3)Hg(+)) in biological materials is developed and validated by electrolytic vapor generation (EVG) coupled with atomic fluorescence spectrometry (AFS). The studies show that CH(3)Hg(+) and Hg(2+) can be converted to Hg vapor efficiently on an l-cysteine modified graphite cathode, which has never been reported before. We observe that only Hg(2+) can be converted efficiently to Hg vapor at low current mode (0.2 A). While at high current mode (2.2 A), both CH(3)Hg(+) and Hg(2+) can be reduced efficiently. As a result, we successfully establish an exact and sensitive method based on the current control to detect mercury speciation for the first time. The factors of electrolytic conditions have been optimized, and the potential mechanism is discussed. Under the optimal conditions, the detection limits (3s) of Hg(2+) and CH(3)Hg(+) in aqueous solutions are 0.098 and 0.073 MUg L(-1), respectively. The relative standard deviations for 6 replicate determinations of 2 MUg L(-1) Hg are determined as 3.2% and 4.7% for Hg(2+) and CH(3)Hg(+). The accuracy of the method is verified through the analysis of certified reference materials (CRM, NRC-DORM 2), and the proposed method has been applied satisfactorily to the determination of mercury speciation in several seafood samples by calibration curve mode. PMID- 23035834 TI - Feasibility of a nursing rehabilitation guideline for patients with stroke: evaluating the use by nurses. AB - PURPOSE: To determine the feasibility of the Clinical Nursing Rehabilitation Stroke-guideline (CNRS-guideline) in the care of stroke patients in terms of the experiences, views and attitudes of nurses towards the guideline and their adoption of the guideline and how often the recommendations were used. METHOD: A four phase cross sectional design was used. Demographic data were collected from nurses (n=30) and patients (n=105). After each test phase the nurses received questionnaires about their experiences of the guideline including questions about their attitude towards the guideline and adoption of the guideline. Also, how often the recommendations were used was registered. RESULTS: The nurses' general impression of the recommendations scored a median of 6.0. A majority of the nurses indicated that the aims of the guideline were clear, that it provided new insights into stroke care. Among the challenges experienced were lack of knowledge and skills and organizational difficulties. Half of the nurses adopted the guideline and the nurses' attitude towards the guideline scored a median of 6.0. CONCLUSION: The guideline provides nurses with an important means for evidence based care for patients with stroke. The guideline was feasible for nurses to use but various challenges need ongoing attention when planning implementation. IMPLICATIONS FOR REHABILITATION: * The CNRGS-guideline was found to be feasible for nurses to use in the daily care of patients with stroke, but various challenges, need an ongoing attention. * The CNRGS-guideline is an important step in the stimulation of quality improvement and efficiency and may result in better outcome and satisfaction of patients with stroke. * The CNRGS guideline provides nurses with an important means to provide evidence based care for patients with stroke. PMID- 23035835 TI - Ultrastrong optical binding of metallic nanoparticles. AB - We demonstrate nanometer precision manipulation of multiple nanoparticles at room temperature. This is achieved using the optical binding force, which has been assumed to be weak compared to the optical gradient and scattering forces. We show that trapping by the optical binding force can be over 20 times stronger than by the gradient force and leads to ultrastable, rigid configurations of multiple nanoparticles free in solution - a realization of "optical matter." In addition, we demonstrate a novel trapping scheme where even smaller nanoparticles are trapped between larger "anchor" particles. Optical binding opens the door for the observation of collective phenomena of nanoparticles and the design of new materials and devices made from optical matter. PMID- 23035836 TI - Cardiac structure and function in relation to cardiovascular risk factors in Chinese. AB - BACKGROUND: Cardiac structure and function are well-studied in Western countries. However, epidemiological data is still scarce in China. METHODS: Our study was conducted in the framework of cardiovascular health examinations for the current and retired employees of a factory and their family members. According to the American Society of Echocardiography recommendations, we performed echocardiography to evaluate cardiac structure and function, including left atrial volume, left ventricular hypertrophy and diastolic dysfunction. RESULTS: The 843 participants (43.0 years) included 288 (34.2%) women, and 191 (22.7%) hypertensive patients, of whom 82 (42.9%) took antihypertensive drugs. The prevalence of left atrial enlargement, left ventricular hypertrophy and concentric remodeling was 2.4%, 5.0% and 12.7%, respectively. The prevalence of mild and moderate-to-severe left ventricular diastolic dysfunction was 14.2% and 3.3%, respectively. The prevalence of these cardiac abnormalities significantly (P <= 0.002) increased with age, except for the moderate-to-severe left ventricular diastolic dysfunction. After adjustment for age, gender, body height and body weight, left atrial enlargement was associated with plasma glucose (P = 0.009), and left ventricular hypertrophy and diastolic dysfunction were significantly associated with systolic and diastolic blood pressure (P <= 0.03), respectively. CONCLUSIONS: The prevalence of cardiac structural and functional abnormalities increased with age in this Chinese population. Current drinking and plasma glucose had an impact on left atrial enlargement, whereas systolic and diastolic blood pressures were major correlates for left ventricular hypertrophy and diastolic dysfunction, respectively. PMID- 23035838 TI - Synthesis of tubuphenylalanines via Ireland-Claisen rearrangement. AB - The Ireland-Claisen rearrangement is the central step in the synthesis of tubuphenylalanine, a key building block of the highly antitumor-active tubulysins. The rearrangement of substituted beta-amino acid allyl esters, in combination with subsequent decarboxylation and oxidative cleavage of the double bond, allows the highly stereoselective introduction of substituents into the alpha-position of the resulting gamma-amino acids. PMID- 23035837 TI - Is a multispecies probiotic mixture effective in constipation during pregnancy? 'A pilot study'. AB - BACKGROUND: Constipation during pregnancy is a common problem. Nowadays only few effective interventions are published preventing or treating constipation during pregnancy. However, their use is limited due to side-effects. This uncontrolled intervention study was performed to determine if a mixture of probiotics in the treatment of constipation during pregnancy is effective. METHODS: Women aged >= 18 years with functional constipation were included at the Obstetrical outpatient clinic and midwife practices. Patients received during four weeks a daily dose of Ecologic(r)Relief (Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Bifidobacterium longum W108, Lactobacillus casei W79, Lactobacillus plantarum W62 and Lactobacillus rhamnosus W71 (total 4*109 CFU)). For all analyses, the non parametric paired Wilcoxon test was used. Primary outcome measure was change in defecation frequency. Secondary outcome measures were stool consistency, sensation of incomplete evacuation, sensation of anorectal obstruction, manual manoeuvres to facilitate defecation, abdominal pain, adverse effects, presence of reflux episodes and intake of Bisacodyl. RESULTS: 20 women were included. Defecation frequency significantly increased from 3.1 at baseline to 6.7 in week four (p < 0.01). Compared to baseline, a significant decrease in 1) sensation of anorectal obstruction from 90.0% to 45.0% (p < 0.01), 2) sensation of incomplete evacuation from 90.0% to 40.0% (p < 0.01), 3) straining during defecation from 100% to 65% (p = 0.01), 4) episodes of abdominal pain from 60% to 20% (p = 0.01) and 5) the presence of reflux episodes from 60% to 20% in week four (p = 0.01) was found. Other secondary outcomes did not decrease significantly. No side effects were reported. CONCLUSIONS: Ecologic(r)Relief is effective in the treatment of constipation during pregnancy. A randomised placebo controlled trial is required to confirm these data. PMID- 23035839 TI - PilT2 enhances the speed of gonococcal type IV pilus retraction and of twitching motility. AB - Type IV pilus (T4P) dynamics is important for various bacterial functions including host cell interaction, surface motility, and horizontal gene transfer. T4P retract rapidly by depolymerization, generating large mechanical force. The gene that encodes the pilus retraction ATPase PilT has multiple paralogues, whose number varies between different bacterial species, but their role in regulating physical parameters of T4P dynamics remains unclear. Here, we address this question in the human pathogen Neisseria gonorrhoeae, which possesses two pilT paralogues, namely pilT2 and pilU. We show that the speed of twitching motility is strongly reduced in a pilT2 deletion mutant, while directional persistence time and sensitivity of speed to oxygen are unaffected. Using laser tweezers, we found that the speed of single T4P retraction was reduced by a factor of ~ 2 in a pilT2 deletion strain, whereas pilU deletion showed a minor effect. The maximum force and the probability for switching from retraction to elongation under application of high force were not significantly affected. We conclude that the physical parameters of T4P are fine-tuned through PilT2. PMID- 23035840 TI - Factors associated with successful decrease and discontinuation of antegrade continence enemas (ACE) in children with defecation disorders: a study evaluating the effect of ACE on colon motility. AB - BACKGROUND: Antegrade continence enemas (ACE) have been used in the treatment of defecation disorders in children; little is known on their effect on colon motility and the utility of the colon manometry (CM) predicting long-term ACE outcomes. METHODS: Retrospective review of children with constipation undergoing CM before and after ACE to evaluate CM changes and their utility on predicting ACE outcome. KEY RESULTS: A total of 40 patients (mean age 8.8 SD 3 years and 53% female patients) were included; 39 of 40 responded to the ACE. Of these 39, 14 (36%) were dependent and 25 (64%) had decreased it (11 of those or 28% discontinued it). On repeat CM we found a significant increase in the fasting (P < 0.01) and postprandial (P = 0.03) motility index, number of bisacodyl-induced high amplitude propagating contractions (HAPCs) (P = 0.03), and total HAPCs (P = 0.02). Gastrocolonic response to a meal, propagation and normalization of HAPCs improved in 28%, 58%, and 33%, respectively, with CM normalizing in 33% of patients. The baseline CM did not predict ACE outcome. The presence of normal HAPCs on the repeat CM was associated with ACE decrease. Progression and normalization of HAPCs (P = 0.01 and 0.02, respectively) and CM normalization (P = 0.01) on repeat CM were individually associated with ACE decrease. No CM change was associated with ACE discontinuation. Multivariate analysis showed that older age and HAPC normalization on CM predict ACE decrease and older age is the only predictor for ACE discontinuation. CONCLUSIONS & INFERENCES: Colon motility improves after ACE and the changes on the repeat CM may assist in predicting ACE outcome. PMID- 23035841 TI - The gammaretroviral p12 protein has multiple domains that function during the early stages of replication. AB - BACKGROUND: The Moloney murine leukaemia virus (Mo-MLV) gag gene encodes three main structural proteins, matrix, capsid and nucleocapsid and a protein called p12. In addition to its role during the late stages of infection, p12 has an essential, but undefined, function during early post-entry events. As these stages of retroviral infection remain poorly understood, we set out to investigate the function of p12. RESULTS: Examination of the infectivity of Mo MLV virus-like particles containing a mixture of wild type and mutant p12 revealed that the N- and C-terminal regions of p12 are sequentially acting domains, both required for p12 function, and that the N-terminal activity precedes the C-terminal activity in the viral life cycle. By creating a panel of p12 mutants in other gammaretroviruses, we showed that these domains are conserved in this retroviral genus. We also undertook a detailed mutational analysis of each domain, identifying residues essential for function. These data show that different regions of the N-terminal domain are necessary for infectivity in different gammaretroviruses, in stark contrast to the C-terminal domain where the same region is essential for all viruses. Moreover, chimeras between the p12 proteins of Mo-MLV and gibbon ape leukaemia virus revealed that the C-terminal domains are interchangeable whereas the N-terminal domains are not. Finally, we identified potential functions for each domain. We observed that particles with defects in the N-terminus of p12 were unable to abrogate restriction factors, implying that their cores were impaired. We further showed that defects in the C-terminal domain of p12 could be overcome by introducing a chromatin binding motif into the protein. CONCLUSIONS: Based on these data, we propose a model for p12 function where the N-terminus of p12 interacts with, and stabilizes, the viral core, allowing the C-terminus of p12 to tether the preintegration complex to host chromatin during mitosis, facilitating integration. PMID- 23035842 TI - Will intra-specific differences in transpiration efficiency in wheat be maintained in a high CO2 world? A FACE study. AB - This study evaluates whether the target breeding trait of superior leaf level transpiration efficiency is still appropriate under increasing carbon dioxide levels of a future climate using a semi-arid cropping system as a model. Specifically, we investigated whether physiological traits governing leaf level transpiration efficiency, such as net assimilation rates (A(net)), stomatal conductance (g(s)) or stomatal sensitivity were affected differently between two Triticum aestivum L. cultivars differing in transpiration efficiency (cv. Drysdale, superior; cv. Hartog, low). Plants were grown under Free Air Carbon dioxide Enrichment (FACE, approximately 550 umol mol-1 or ambient CO2 concentrations (approximately 390 umol mol-1). Mean A(net) (approximately 15% increase) and gs (approximately 25% decrease) were less affected by elevated [CO2] than previously found in FACE-grown wheat (approximately 25% increase and approximately 32% decrease, respectively), potentially reflecting growth in a dry land cropping system. In contrast to previous FACE studies, analyses of the Ball et al. model revealed an elevated [CO2] effect on the slope of the linear regression by 12% indicating a decrease in stomatal sensitivity to the combination of [CO2], photosynthesis rate and humidity. Differences between cultivars indicated greater transpiration efficiency for Drysdale with growth under elevated [CO2] potentially increasing the response of this trait. This knowledge adds valuable information for crop germplasm improvement for future climates. PMID- 23035844 TI - Effects of Aloe vera supplementation in subjects with prediabetes/metabolic syndrome. AB - BACKGROUND: Metabolic syndrome affects 1 in 3 U.S. adults. The primary target of treatment of patients with metabolic syndrome is therapeutic lifestyle change. Numerous animal trials have reported positive effects of Aloe vera in in vivo models of diabetes, but there is a paucity of controlled clinical trials in patients with prediabetes. Thus, the objective of this pilot study was to examine the effect of aloe compared to placebo on fasting blood glucose, lipid profile, and oxidative stress in subjects with prediabetes/metabolic syndrome. METHODS: This was a double-blind, placebo-controlled Institutional Review Board (IRB) approved pilot study of two aloe products (UP780 and AC952) in patients with prediabetes over an 8-week period. A total of 45 subjects with impaired fasting glucose or impaired glucose tolerance and having two other features of metabolic syndrome were recruited (n=15/group). Parameters of glycemia [fasting glucose, insulin, homeostasis model assessment (HOMA), glycosylated hemoglobin (HbA1c), fructosamine, and oral glucose tolerance test (OGTT)] and oxidative stress (urinary F2-isoprostanes) were measured along with lipid profile and high sensitivity C-reactive protein (hsCRP) levels before and after supplementation. RESULTS: There were no significant baseline differences between groups. Compared to placebo, only the AC952 Aloe vera inner leaf gel powder resulted in significant reduction in total and low-density lipoprotein cholesterol (LDL-C) levels, glucose, and fructosamine. In the UP780 Aloe vera inner leaf gel powder standardized with 2% aloesin group, there were significant reductions in HbA1c, fructosamine, fasting glucose, insulin, and HOMA. Only the UP780 aloe group had a significant reduction in the F2-isoprostanes compared to placebo. CONCLUSIONS: Standardized aloe preparations offer an attractive adjunctive strategy to revert the impaired fasting glucose and impaired glucose tolerance observed in conditions of prediabetes/metabolic syndrome. PMID- 23035843 TI - Pathogenesis of and strategies for preventing Edwardsiella tarda infection in fish. AB - Edwardsiella tarda is one of the serious fish pathogens, infecting both cultured and wild fish species. Research on edwardsiellosis has revealed that E. tarda has a broad host range and geographic distribution, and contains important virulence factors that enhance bacterial survival and pathogenesis in hosts. Although recent progress in edwardsiellosis research has enabled the development of numerous, highly effective vaccine candidates, these efforts have not been translated into a commercialized vaccine. The present review aims to provide an overview of the identification, pathology, diagnosis and virulence factors of E. tarda in fish, and describe recent strategies for developing vaccines against edwardsiellosis. The hope is that this presentation will be useful not only from the standpoint of understanding the pathogenesis of E. tarda, but also from the perspective of facilitating the development of effective vaccines. PMID- 23035845 TI - Nuclear reprogramming and induced pluripotent stem cells: a review for surgeons. AB - Induced pluripotent stem cells (iPSCs) are generated from somatic cells by the exogenous expression of defined transcription factors. iPSCs share the defining features of embryonic stem cells (ESCs) in that they are able to self-renew indefinitely and maintain the potential to develop into all cell types of the body. These cells have key advantages over ESCs in that they are autologous to the donor cells and can be generated from individuals at any age. iPSCs also circumvent ethical and political issues surrounding the destruction of embryos that is necessary in the isolation of ESCs. This review briefly describes the advent of iPSC technology and the concepts of nuclear reprogramming, and discusses the potential application of this powerful biological tool in both surgical research and regenerative medicine. PMID- 23035846 TI - Interdomain communication modulates the tRNA-dependent pre-transfer editing of leucyl-tRNA synthetase. AB - EcLeuRS [Escherichia coli LeuRS (leucyl-tRNA synthetase)] has evolved both tRNA dependent pre- and post-transfer editing capabilities to ensure catalytic specificity. Both editing functions rely on the entry of the tRNA CCA tail into the editing domain of the LeuRS enzyme, which, according to X-ray crystal structural studies, leads to a dynamic disordered orientation of the interface between the synthetic and editing domains. The results of the present study show that this tRNA-triggered conformational rearrangement leads to interdomain communication between the editing and synthetic domains through their interface, and this communication mechanism modulates the activity of tRNA-dependent pre transfer editing. Furthermore, tRNA-dependent editing reaction inhibits misactivating non-cognate amino acids from the synthetic active site. These results also suggested a novel quality control mechanism of EcLeuRS which is achieved through the co-ordination between the synthetic and editing domains. PMID- 23035847 TI - Counting bacteria using functionalized gold nanoparticles as the light-scattering reporter. AB - A simple and rapid bacterial counting method was developed based on dark-field light-scattering imaging of bacteria and gold nanoparticle (AuNP) reporter simultaneously. Commercially available DH5alpha E. coli strain was used as the model bacterium to demonstrate the feasibility of the proposed method. With antibody-conjugated AuNPs, the simple sample treatment and target E. coli strain recognition can be finished within 15-30 min, with a detection limit of 2 6 * 10(4) colony forming unit per milliliter (CFU/mL). By using 90 nm AuNPs as the light-scattering signal reporter, the bacterial recognition and counting can be easily performed with low-cost instrumentation such as an entry-level dark field microscope setup and a common tungsten lamp as the light source. An automatic image analysis algorithm was also developed to facilitate robust and fast bacterial counting. The preliminary results of water, milk, and fruit juice sample analysis showed that this simple, fast, and cost-effective method can be easily adopted for routine bacterial detection. PMID- 23035848 TI - Randomized and prospective trial comparing tract creation using plasma vaporization with balloon dilatation in percutaneous nephrolithotomy. PMID- 23035849 TI - The significance of early accumulation of nanomolar concentrations of NO as an inducer of denitrification. AB - Denitrifying bacteria have variable ability to perform efficient and balanced denitrification during oxygen depletion. NO is often assumed to exert a positive feedback in the transcription of denitrification genes, because NO-dependent activators have been identified. The regulatory network of denitrification is complex, however, and the significance of NO signalling needs to be studied in vivo. We utilized acetylene-catalysed NO oxidation to scavenge NO produced by batch cultures of denitrifying bacteria during transition from oxic to anoxic respiration, to explore the effects on the kinetics of NO, N(2) O and N(2) production. The results demonstrated that nanomolar concentrations of NO accumulating prior to complete depletion of oxygen exert a significant positive feedback on the initiation of denitrification in Paracoccus denitrificans. The early NO signal appeared essential to minimize the transient accumulation of NO during the subsequent anoxic phase for Agrobacterium tumefaciens, but not for P. denitrificans and Pseudomonas aureofaciens. In summary, the results indicate that the early accumulation of nanomolar concentrations of NO has a significant, but strain-dependent effect on the expression of denitrification. PMID- 23035850 TI - Toll-like receptors and viral immunity. PMID- 23035851 TI - Interleukin-29 suppresses hepatitis A and C viral internal ribosomal entry site mediated translation. AB - Our aim was to investigate the effects of interferons (IFNs)-lambda (interleukin 29 [IL-29], IL-28A, and IL-28B) on hepatitis C virus (HCV) and hepatitis A virus (HAV) internal ribosomal entry site (IRES)-mediated translation. The effects of these IFNs on HCV/HAV translation from HAV/HCV IRES were investigated using bicistronic reporter constructs. We transfected HCV/HAV IRES constructs into these IFN-expressing cell lines. IL-29 showed stronger inhibition of their IRES mediated translation. Combining IL-29 with IFN-alpha or amantadine resulted in stronger inhibition of HAV IRES activity. Our findings demonstrated a novel antiviral effect of IFNs-lambda against HAV and HCV through the suppression of IRES-mediated translation. PMID- 23035853 TI - Immunization with multiple vaccine modalities induce strong HIV-specific cellular and humoral immune responses. AB - Heterologous priming and boosting with antigens expressed by DNA, viral vectors, or as proteins, are experimental strategies to induce strong immune responses against infectious diseases and cancer. In a preclinical study we compared the ability of recombinant modified vaccinia Ankara encoding HIV antigens (MVA-CMDR), and/or recombinant gp140C (rgp140C), to boost responses induced by a multigene/multisubtype HIV DNA vaccine delivered by electroporation (EP). Homologous DNA immunizations augmented by EP stimulated strong cellular immune responses. Still stronger cellular immune responses were observed after DNA priming and MVA-CMDR boosting, which was superior to all other immunization schedules tested in terms of antigen-specific IFN-gamma, IL-2, and bifunctional IFN-gamma and IL-2 responses. For HIV Env-specific antibody responses, mice receiving repeated rgp140C immunizations, and mice boosted with rgp140C, elicited the highest binding titers and the highest numbers of antibody-secreting B cells. When considering both cellular and humoral immune responses, a combination of DNA, MVA-CMDR, and rgp140C immunizations induced the overall most potent immune responses and the highest avidity of HIV Env-specific antibodies. These data emphasize the importance of including multiple vaccine modalities that can stimulate both T and B cells, and thus elicit strong and balanced immune responses. The present HIV vaccine combination holds promise for further evaluation in clinical trials. PMID- 23035852 TI - Chemokine binding protein vCCI attenuates vaccinia virus without affecting the cellular response elicited by immunization with a recombinant vaccinia vector carrying the HPV16 E7 gene. AB - Viral CC chemokine inhibitor (vCCI) of the clone P13 vaccinia virus (VACV) strain PRAHA lacks eight amino acids in the signal peptide sequence. To study the influence of vCCI on virus biology, a virus with the vCCI gene coding for a prolonged signal sequence was prepared. We found that secreted vCCI attenuated the virus in vivo, and that it correlated with decreased levels of RANTES, eotaxin, TARC, and MDC in the blood in comparison with the parental virus. We determined the influence of vCCI on the CTL response against VACV E3((140-148)) (VGPSNSPTF) and HPV16 E7((49-57)) (RAHYNIVTF) H-2D(b)-restricted epitopes. The examination of the specific CTL response elicited by immunization with the recombinant VACV-expressing tumor-associated HPV16 E7 antigen by IFN-gamma ELISPOT showed that the immunogenicity of the recombinant VACV-producing secretory vCCI was similar to that of the parent virus or deletion mutant in the C23L/B29R locus. Immunization with the secretory vCCI-producing recombinant virus has a lower therapeutic anti-tumor effect against TC-1 tumors. Viral CCI downregulated the E7-specific response induced by gene gun immunization with the DNA vaccines pBSC-SigE7 LAMP and pBSC-vCCI. We also observed that the immune response against vCCI elicited by the DNA vaccine did not affect the multiplication of VACV in vivo. PMID- 23035854 TI - Subcutaneous mastectomy in female-to-male transsexuals: a retrospective cohort analysis of 202 patients. AB - INTRODUCTION: Subcutaneous mastectomy is the first surgical procedure to be completed by female to male transsexuals after appropriate mental health and endocrine therapy. Objectives of subcutaneous mastectomy in this group are to masculinize the chest by the removal of breast tissue and skin excess, reduction and proper positioning of the nipple-areola complex, obliteration of the infra mammary fold, and ideally with a minimal of chest wall scars. In this study, the largest series of subcutaneous mastectomies in female-to-male transsexuals to date is presented. AIMS: Our aim was to determine relations between surgical technique, risk factors, complications, reoperations and secondary corrections in female-to-male transsexuals. METHODS: We performed a retrospective survey study on 404 mastectomies in 202 female-to-male transsexuals during the period of 2000 2011. MAIN OUTCOME MEASURES: Primary outcomes for this study were complication rate, acute reoperations, secondary corrections, surgical time, and length of hospital stay in relation to the surgical technique used. RESULTS: The average age of these patients at time of the intervention was 31 years (+/-10) with an average BMI of 25 kg/m(2) (+/-4). The chosen technique depended strongly on breast volume, which, in turn, was strongly related to BMI and age. The number of acute reoperations and secondary corrections depended on the surgical technique. The total rate of acute complications was 5.0%. This percentage was highest in surgeries without skin resection (10.5%). To improve overall aesthetic results, the following secondary corrections were performed: nipple and/or areola corrections (8.9%), scar revisions (12.6%), and chest contouring (17.8%). CONCLUSION: This study shows a correlation between the surgical technique, complication rate, and length of hospital stay. In general, the larger the breast, the larger the scars that remain after the operation. On the other hand, the smaller the scars resulting from the operation, the higher the risk of hematoma. PMID- 23035855 TI - Effects of total flavonoids from Dracocephalum moldavica on the proliferation, migration, and adhesion molecule expression of rat vascular smooth muscle cells induced by TNF-alpha. AB - CONTEXT: Dracocephalum moldavica Linn (Labiatae) is one of the ethnomedicinal drugs of Uygur in Xinjiang, China. This herb is mainly used in treating cardiovascular diseases, such as atherosclerosis. However, the mechanism of pharmacological activity of D. moldavica has been poorly studied. OBJECTIVE: To explore the pharmacological mechanism of D. moldavica in treating atherosclerosis by investigating the effects of total flavonoids from the aerial portion of D. moldavica on rat vascular smooth muscle cells (VSMCs). MATERIALS AND METHODS: The proliferation and migration of VSMCs were evaluated via a 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and transwell chamber experiment, respectively. The expression of proliferating cell nuclear antigen (PCNA), nuclear factor kappaB p65 (NF-kappaB p65), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) of VSMCs was determined using immunohistochemistry staining and quantitative real-time PCR (qRT-PCR). RESULTS: Total flavonoids (IC(50) = 145.63 MUg/mL) significantly inhibited tumor necrosis factor-alpha (TNF-alpha) induced VSMC proliferation at concentrations of 25, 50, and 100 MUg/mL. Treatment with 50 and 100 MUg/mL of total flavonoids also significantly inhibited TNF-alpha-induced VSMC migration, whereas 25 MUg/mL of total flavonoids did not elicit any significant inhibitory effect. In addition, the effects of total flavonoids on inflammatory molecule expression of cells were tested by immunohistochemistry staining, showing that TNF-alpha-induced expression of PCNA, NF-kappaB p65, ICAM-1, and VCAM-1 in VSMCs was dose-dependently suppressed by total flavonoids. Furthermore, qRT-PCR data confirmed the inhibition of mRNA expressions of these inflammatory molecules. DISCUSSION AND CONCLUSION: These data suggest that total flavonoids from D. moldavica exhibit anti-inflammatory activities, which is probably one of the underlying mechanisms of D. moldavica for clinical treatment of atherosclerosis. PMID- 23035857 TI - Personality traits, quality of life and perceived health in adolescents with congenital heart disease. AB - This study investigated how the big five personality traits were related to quality of life and perceived health in adolescents with congenital heart disease (CHD). Adolescents with CHD were selected from the database of paediatric and congenital cardiology of the University Hospitals Leuven. A total of 366 adolescents (15-20 years) participated; 364 were matched on sex and age with community controls. Adolescents' personality was assessed using the quick big five, quality of life was measured using a linear analogue scale and several domains of perceived health were assessed using the paediatric quality of life inventory. Adolescents with CHD displayed similar big five levels as controls, except for a lower score on extraversion. Whereas disease-specific domains of perceived health were mainly related to emotional stability, several traits contributed to patients' quality of life and generic perceived health. Hence, the present findings demonstrate that the Big Five is a valuable framework for examining linkages between personality and disease adaptation in chronic disease populations. Moreover, these findings underscore the importance of examining patients' personality to shed light on their daily functioning. Future research should explore potential mechanisms detailing how personality influences disease adaptation over time in these patients. PMID- 23035858 TI - Leaving a spinal unit and returning to the wider community: an interpretative phenomenological analysis. AB - PURPOSE: The study investigated the experience of community (re)integration from the perspective of people with spinal cord injury (SCI) within 12 months of discharge from a specialist spinal injuries unit in New Zealand (NZ). METHOD: Nine participants were interviewed. The verbatim transcripts were analysed using Interpretive Phenomenological Analysis (IPA). RESULTS: Three main themes were: Leaving, Not Coping with a Capital C, and Power and Control. Leaving related to the process of planning for, and discharge from the spinal unit. Not Coping with a Capital C incorporated the coping and adjustment to life following a SCI, including the role of hope. Power and Control denoted the alteration in balance of power and control following SCI which was evident both in the rehabilitation facility and within the wider community setting. CONCLUSIONS: The results indicated that the spinal unit may not adequately equip the recovering person with SCI for life in the real world. Individuals with SCI returning to the community remained hopeful of recovery of function and or cure; this focus, particularly on physical rehabilitation, potentially reduced their availability for other forms of community reintegration such as work and leisure activities. PMID- 23035859 TI - Particle deposition in airways of chronic respiratory patients exposed to an urban aerosol. AB - Urban atmospheres in modern cities carry characteristic mixtures of particulate pollution which are potentially aggravating for chronic respiratory patients (CRP). Although air quality surveys can be detailed, the obtained information is not always useful to evaluate human health effects. This paper presents a novel approach to estimate particle deposition rates in airways of CRP, based on real air pollution data. By combining computational fluid dynamics with physical chemical characteristics of particulate pollution, deposition rates are estimated for particles of different toxicological relevance, that is, minerals, iron oxides, sea salts, ammonium salts, and carbonaceous particles. Also, it enables some qualitative evaluation of the spatial, temporal, and patient specific effects on the particle dose upon exposure to the urban atmosphere. Results show how heavy traffic conditions increases the deposition of anthropogenic particles in the trachea and lungs of respiratory patients (here, +0.28 and +1.5 MUg.h(-1), respectively). In addition, local and synoptic meteorological conditions were found to have a strong effect on the overall dose. However, the pathology and age of the patient was found to be more crucial, with highest deposition rates for toxic particles in adults with a mild anomaly, followed by mild asthmatic children and adults with severe respiratory dysfunctions (7, 5, and 3 MUg.h(-1), respectively). PMID- 23035860 TI - Non-invasive prenatal screening of fetal Down syndrome by maternal plasma DNA sequencing in twin pregnancies. AB - Non-invasive prenatal screening for fetal Down syndrome (NIFTY) by maternal plasma sequencing was performed in 12 subjects with twin pregnancies, including 11 with normal fetuses and 1 with discordant fetal Trisomy 21. For every sample, it was processed, sequenced and reported as soon as it was collected as other clinical samples for singleton pregnancies. The NIFTY test was negative in the 11 pregnancies carried normal fetuses, and was positive (high risk) in the case with discordant fetal Trisomy 21. The sensitivity and specificity were both 100%. This small case series suggested the NIFTY as a screening test for fetal Trisomy 21 is feasible in twin pregnancies. PMID- 23035861 TI - Social and emotional difficulties in children with ADHD and the impact on school attendance and healthcare utilization. AB - BACKGROUND: The objective of this study was to examine the impact of co-occurring social and emotional difficulties on missed school days and healthcare utilization among children with attention deficit/hyperactivity disorder (ADHD). METHODS: Data were from the 2007 U.S. National Health Interview Survey (NHIS) and were based on parental proxy responses to questions in the Sample Child Core, which includes questions on demographics, health, healthcare treatment, and social and emotional status as measured by questions about depression, anxiety, and phobias, as well as items from the brief version of the Strength and Difficulties Questionnaire (SDQ). Logistic regression was used to assess the association between co-occurring social and emotional difficulties with missed school days and healthcare utilization, adjusting for demographics. RESULTS: Of the 5896 children aged 6-17 years in the 2007 NHIS, 432 (7.3%) had ADHD, based on parental report. Children with ADHD and comorbid depression, anxiety, or phobias had significantly greater odds of experiencing > 2 weeks of missed school days, >= 6 visits to a healthcare provider (HCP), and >= 2 visits to the ER, compared with ADHD children without those comorbidities (OR range: 2.1 to 10.4). Significantly greater odds of missed school days, HCP visits, and ER visits were also experienced by children with ADHD who were worried, unhappy/depressed, or having emotional difficulties as assessed by the SDQ, compared with ADHD children without those difficulties (OR range: 2.2 to 4.4). CONCLUSIONS: In children with ADHD, the presence of social and emotional problems resulted in greater odds of missed school days and healthcare utilization. These findings should be viewed in light of the limited nature of the parent-report measures used to assess social and emotional problems. PMID- 23035862 TI - Organocatalytic asymmetric anti-selective Michael reactions of aldehydes and the sequential reduction/lactonization/Pauson-Khand reaction for the enantioselective synthesis of highly functionalized hydropentalenes. AB - A new method has been developed for the enantioselective synthesis of highly functionalized hydropentalenes bearing up to four stereogenic centers with high stereoselectivity (up to 99% ee). This process combines an enantioselective organocatalytic anti-selective Michael addition with a highly efficient one-pot reduction/lactonization/Pauson-Khand reaction sequence. The structures and absolute configurations of the products were confirmed by X-ray analysis. PMID- 23035863 TI - Synbiotics, probiotics or prebiotics in infant formula for full term infants: a systematic review. AB - BACKGROUND: Synbiotics, probiotics or prebiotics are being added to infant formula to promote growth and development in infants. Previous reviews (2007 to 2011) on term infants given probiotics or prebiotics focused on prevention of allergic disease and food hypersensitivity. This review focused on growth and clinical outcomes in term infants fed only infant formula containing synbiotics, probiotics or prebiotics. METHODS: Cochrane methodology was followed using randomized controlled trials (RCTs) which compared term infant formula containing probiotics, prebiotics or synbiotics to conventional infant formula with / without placebo among healthy full term infants. The mean difference (MD) and corresponding 95% confidence intervals (CI) were reported for continuous outcomes, risk ratio (RR) and corresponding 95% CI for dichotomous outcomes. Where appropriate, meta-analysis was performed; heterogeneity was explored using subgroup and sensitivity analyses. If studies were too diverse a narrative synthesis was provided. RESULTS: Three synbiotic studies (N = 475), 10 probiotics studies (N = 933) and 12 prebiotics studies (N = 1563) were included. Synbiotics failed to significantly increase growth in boys and girls. Use of synbiotics increased stool frequency, had no impact on stool consistency, colic, spitting up / regurgitation, crying, restlessness or vomiting. Probiotics in formula also failed to have any significant effect on growth, stool frequency or consistency. Probiotics did not lower the incidence of diarrhoea, colic, spitting up / regurgitation, crying, restlessness or vomiting. Prebiotics in formula did increase weight gain but had no impact on length or head circumference gain. Prebiotics increased stool frequency but had no impact on stool consistency, the incidence of colic, spitting up / regurgitation, crying, restlessness or vomiting. There was no impact of prebiotics on the volume of formula tolerated, infections and gastrointestinal microflora. The quality of evidence was compromised by imprecision, inconsistency of results, use of different study preparations and publication bias. AUTHORS' CONCLUSIONS: There is not enough evidence to state that supplementation of term infant formula with synbiotics, probiotics or prebiotics does result in improved growth or clinical outcomes in term infants. There is no data available to establish if synbiotics are superior to probiotics or prebiotics. PMID- 23035864 TI - Predictive factors for pacemaker requirement after transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has been established as a treatment option for inoperable patients with symptomatic aortic valve stenosis. However, patients suffer frequently from conduction disturbances after TAVI. METHODS: Baseline, procedural as well as surface and intracardiac ECG parameters were evaluated for patients treated with TAVI and a comparison between patients requiring pacemaker with those not suffering from relevant conduction disorders were done. RESULTS: TAVI was successfully in all patients (n=45). Baseline surface and intracardiac ECG recording revealed longer PQ (197.1+/-51.2 msec versus 154.1+/-32.1 msec; p<0.001), longer AH (153.6+/-43.4 msec versus 116.1+/-31.2 msec; p<0.001) and HV interval (81.7+/-17.8 msec versus 56.8+/-8.5 msec; p<0.001) in patients with need for a pacemaker (n=23) versus control group (n=22); furthermore, 7-day follow-up analysis showed a higher prevalence of new left bundle branch block (LBBB) (87.0% versus 31.9%; p<0.001). Multivariate analysis revealed that only new LBBB, QRS duration >120 msec and a PQ interval >200 msec immediately (within 60 minutes) after implantation of the aortic valve were predictors for high-grade (type II second-degree and third-degree) AV block. Other clinical parameters as well as baseline electrocardiographic parameters had no impact on critical conduction delay. CONCLUSION: Cardiac conduction disturbances are common after TAVI. The need for pacing after TAVI is predictable by surface ECG evaluation immediately (within 60 minutes) after the procedure. PMID- 23035865 TI - Metabolic syndrome and population attributable risk among HIV/AIDS patients: comparison between NCEP-ATPIII, IDF and AHA/NHLBI definitions. AB - BACKGROUND: Metabolic Syndrome (MetS) is based on the same individual components, but has received several amendments to the original definition. In this study, we verified the prevalence of metabolic syndrome according to different criteria, and the impact of each component on the diagnostic. METHODS: This cross-sectional study enrolled HIV infected patients from a HIV/AIDS reference Center in southern Brazil. Metabolic syndrome was identified according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP-ATPIII), the International Diabetes Federation (IDF) and the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) criteria, and using a standardized questionnaire and blood testing. RESULTS: A sample of 1240, out of 1295, HIV-infected patients was enrolled. Males were on average older, more educated, and had shorter time since the HIV diagnosis. The population attributable risk (PAR) for waist circumference explained 80% of the prevalence among men and women (AHA/NHLBI criteria). Triglycerides had the highest impact on prevalence of metabolic syndrome according to all criteria, independently of age, skin color and HAART use, among men. CONCLUSIONS: In this large sample of HIV infected patients, the overall prevalence of metabolic syndrome, under either classification, was noticeable and the AHA/NHLBI definition accounted for the highest prevalence. PMID- 23035866 TI - LuxU connects quorum sensing to biofilm formation in Vibrio fischeri. AB - Biofilm formation by Vibrio fischeri is a complex process involving multiple regulators, including the sensor kinase (SK) RscS and the response regulator (RR) SypG, which control the symbiosis polysaccharide (syp) locus. To identify other regulators of biofilm formation in V. fischeri, we screened a transposon library for mutants defective in wrinkled colony formation. We identified LuxQ as a positive regulator of syp-dependent biofilm formation. LuxQ is a member of the Lux phosphorelay and is predicted to control bioluminescence in concert with the SK AinR, the phosphotransferase LuxU and the RR LuxO. Of these, LuxU was the only other regulator that exerted a substantial impact on biofilm formation. We propose a model in which the Lux pathway branches at LuxU to control both bioluminescence and biofilm formation. Furthermore, our evidence suggests that LuxU functions to regulate syp transcription, likely by controlling SypG activity. Finally, we found that, in contrast to its predicted function, the SK AinR has little impact on bioluminescence under our conditions. Thus, this study reveals a novel connection between the Lux and Syp pathways in V. fischeri, and furthers our understanding of how the Lux pathway regulates bioluminescence in this organism. PMID- 23035867 TI - The effect of changes in intraocular pressure on the risk of primary open-angle glaucoma in patients with ocular hypertension: an application of latent class analysis. AB - BACKGROUND: Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. While lowering intraocular pressure (IOP) has been proven to be effective in delaying or preventing the onset of POAG in many large-scale prospective studies, one of the recent hot topics in glaucoma research is the effect of IOP fluctuation (IOP lability) on the risk of developing POAG in treated and untreated subjects. METHOD: In this paper, we analyzed data from the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) for subjects who had at least 2 IOP measurements after randomization prior to POAG diagnosis. We assessed the interrelationships among the baseline covariates, the changes of post randomization IOP over time, and the risk of developing POAG, using a latent class analysis (LCA) which allows us to identify distinct patterns (latent classes) of IOP trajectories. RESULT: The IOP change in OHTS was best described by 6 latent classes differentiated primarily by the mean IOP levels during follow up. Subjects with high post-randomization mean IOP level and/or large variability were more likely to develop POAG. Five baseline factors were found to be significantly predictive of the IOP classification in OHTS: treatment assignment, baseline IOP, gender, race, and history of hypertension. In separate analyses of EGPS, LCA identified different patterns of IOP change from those in OHTS, but confirmed that subjects with high mean level and large variability were at high risk to develop POAG. CONCLUSION: LCA provides a useful tool to assess the impact of post-randomization IOP level and fluctuation on the risk of developing POAG in patients with ocular hypertension. The incorporation of post-randomization IOP can improve the overall predictive ability of the original model that included only baseline risk factors. PMID- 23035868 TI - Listening to placebo in clinical trials for female sexual dysfunction. AB - INTRODUCTION: Placebo responses are substantial in many clinical trials of treatments for female sexual dysfunctions (FSDs). Recent studies from other fields suggest a need to reconceptualize placebo response and to design future trials accordingly. AIM: The aims of this review are to (i) summarize current conceptualizations of placebo response in the literature; (ii) identify potential mechanisms of placebo response that are relevant to the study of FSD; and (iii) provide recommendations for incorporating this knowledge into design of future trials. METHODS: Narrative review of literature relevant to the topic of placebo response and FSD. MAIN OUTCOME MEASURES: Possible predictors and mechanisms of placebo response in women with FSD are described based on the synthesis of empirical findings in studies of placebo. RESULTS: Placebo response is a complex phenomenon that represents cognitive, behavioral, motivational, and possibly relational mediating factors. Instructions given to trial participants, behavioral changes required to participate in a trial, changes in partner behavior, and interactions with study staff may influence participants' expectations of benefit and therefore their responses to placebo treatment. Side effects may enhance placebo response within active treatment arms. At present, it is unclear to what extent to which specific factors affect outcomes of clinical trials in FSD. CONCLUSIONS: Procedural and methodological factors are likely to contribute to placebo response in trials for FSD, though additional research is needed to clarify these effects. Study designs should be reevaluated to avoid unnecessary creation or exaggeration of placebo responses and to draw appropriate conclusions from trial results. PMID- 23035870 TI - A wide spectral range photoacoustic aerosol absorption spectrometer. AB - A photoacoustic spectrometer for the measurement of aerosol absorption spectra, based on the excitation of a pulsed nanosecond optical parametrical oscillator (OPO), will be introduced. This spectrometer is working at ambient pressure and can be used to detect and characterize different classes of aerosols. The spectrometer features a spectral range of 410 to 2500 nm and a sensitivity of 2.5 * 10(-7) m(-1) at 550 nm. A full characterization of the system in the visible spectral range is demonstrated, and the potential of the system for near IR measurement is discussed. In the example of different kinds of soot particles, the performance of the spectrometer was assessed. As we demonstrate, it is possible to determine a specific optical absorption per particle by a combination of the new spectrometer with an aerosol particle counter. PMID- 23035871 TI - Cytosolic [Ca2+] regulation of InsP3-evoked puffs. AB - InsP3-mediated puffs are fundamental building blocks of cellular Ca2+ signalling, and arise through the concerted opening of clustered InsP3Rs (InsP3 receptors) co ordinated via Ca2+-induced Ca2+ release. Although the Ca2+ dependency of InsP3Rs has been extensively studied at the single channel level, little is known as to how changes in basal cytosolic [Ca2+] would alter the dynamics of InsP3-evoked Ca2+ signals in intact cells. To explore this question, we expressed Ca2+ permeable channels (nicotinic acetylcholine receptors) in the plasma membrane of voltage-clamped Xenopus oocytes to regulate cytosolic [Ca2+] by changing the electrochemical gradient for extracellular Ca2+ entry, and imaged Ca2+ liberation evoked by photolysis of caged InsP3. Elevation of basal cytosolic [Ca2+] strongly increased the amplitude and shortened the latency of global Ca2+ waves. In oocytes loaded with EGTA to localize Ca2+ signals, the number of sites at which puffs were observed and the frequency and latency of puffs were strongly dependent on cytosolic [Ca2+], whereas puff amplitudes were only weakly affected. The results of the present study indicate that basal cytosolic [Ca2+] strongly affects the triggering of puffs, but has less of an effect on puffs once they have been initiated. PMID- 23035872 TI - Molecular cloning, characterization and comparison of bile salt hydrolases from Lactobacillus johnsonii PF01. AB - AIMS: To clone, characterize and compare the bile salt hydrolase (BSH) genes of Lactobacillus johnsonii PF01. METHODS AND RESULTS: The BSH genes were amplified by polymerase chain reaction (PCR) using specific oligonucleotide primers, and the products were inserted into the pET21b expression vector. Escherichia coli BLR (DE3) cells were transformed with pET21b vectors containing the BSH genes and induced using 0.1 mmol l(-1) isopropylthiolgalactopyranoside. The overexpressed BSH enzymes were purified using a nickel-nitrilotriacetic acid (Ni(2+) -NTA) agarose column and their activities characterized. BSH A hydrolysed tauro conjugated bile salts optimally at pH 5.0 and 55 degrees C, whereas BSH C hydrolysed glyco-conjugated bile salts optimally at pH 5.0 and 70 degrees C. The enzymes had no preferential activities towards a specific cholyl moiety. CONCLUSIONS: BSH enzymes vary in their substrate specificities and characteristics to broaden its activity. Despite the lack of conservation in their putative substrate-binding sites, these remain functional through motif conservation. SIGNIFICANCE AND IMPACT OF THE STUDY: This is to our knowledge the first report of isolation of BSH enzymes from a single strain, showing hydrolase activity towards either glyco-conjugated or tauro-conjugated bile salts. Future structural homology studies and site-directed mutagenesis of sites associated with substrate specificity may elucidate specificities of BSH enzymes. PMID- 23035873 TI - Use of recombinant activated factor VII in Jehovah's Witness patients with critical bleeding. AB - INTRODUCTION: The Australian and New Zealand Haemostasis Registry (ANZHR) included patients who received off-licence recombinant activated factor VII (rFVIIa) for critical bleeding from 2000 to 2009. Approximately 1.3% of the ANZHR patients were Jehovah's Witnesses (JWs). We compared them with the non-JW patients in the registry. METHODS: Patient characteristics (e.g. gender, context of bleeding), factors influencing rFVIIa use (e.g. body temperature and pH) and outcomes (e.g. bleeding response (stopped/attenuated or unchanged) to rFVIIa, mortality) were compared between JW and non-JW patients using Fisher's exact chi square tests and Kruskal-Wallis tests. RESULTS: A total of 42 JW and 3134 non-JW patients were included in the analysis. Approximately 99% (n = 3098) of non-JWs received blood products compared with only 30% (n = 13) of JWs (P < 0.01). The distribution of gender and contexts of critical bleeding in the two groups was significantly different. Approximately 17% of the non-JW patients were hypothermic (T < 35 degrees C) and about 19% were acidotic (pH < 7.2) at the time of initial rFVIIa administration. Conversely, none of the JWs were hypothermic and only one was acidotic. The proportion of positive responders to rFVIIa (stopped/attenuated bleeding following rFVIIa use) was similar in both groups (75% non-JWs, 74% JWs; P = 1.0). Approximately 28% of non-JW and 17% of JW patients were deceased by day 28 following rFVIIa use (P = 0.16). DISCUSSION: Several factors were observed to be significantly different between JW and non-JW patients, yet the proportions of responders to rFVIIa were similar in both groups. The actual factors influencing response to rFVIIa are yet to be determined. PMID- 23035874 TI - BCL10GFP fusion protein as a substrate for analysis of determinants required for mucosa-associated lymphoid tissue 1 (MALT1)-mediated cleavage. AB - BACKGROUND: MALT1 belongs to a family of paracaspase and modulates NF-kappaB signaling pathways through its scaffolding function and proteolytic activity. MALT1 cleaves protein substrates after a positively charged Arginine residue. BCL10, a 233 amino acids polypeptide, is identified as one of the MALT1 proteolytic substrates. MALT1 cleaves BCL10 at the C-terminal end of Arg228. A mere 5 amino acids difference between the substrate and the proteolytic product made it difficult to tell whether the cleavage event took place by using a simple western blot analysis. Here, BCL10GFP was constructed and utilized to examine the specificity and domain determinants for MALT1 cleavage in cells. METHODS: Various BCL10GFP constructs were transfected into HEK293T cell with MALT1 construct by using calcium phosphate-DNA precipitation method. Lysates of transfectants were resolved by SDS/PAGE and analyzed by western blot analysis. RESULTS: BCL10GFP was proteolytically processed by MALT1 as BCL10. The integrity of caspase recruitment domain (CARD) and MALT1-interacting domain on BCL10 were required for MALT1 proteolytic activity. Besides the invariant P1 cleavage site Arg228, P4 Leu225 played a role in defining BCL10 as a good substrate for MALT1. CONCLUSIONS: We offered a way of monitoring the catalytic activity of MALT1 in HEK293T cells using BCL10GFP as a substrate. BCL10GFP can be utilized as a convenient tool for studying the determinants for efficient MALT1 cleavage in HEK293T cells. PMID- 23035875 TI - Interhemispheric transfer time in sportsmen. AB - The authors' aim was to compare interhemispheric transfer time between 2 groups: highly skilled sportsmen and control subjects. Left- and right-handed individuals were included in the study. The Poffenberger paradigm was used to measure the crossed-uncrossed difference, representing the time to transfer information from one hemisphere to the other. No difference in laterality was found, but the results revealed a greater crossed-uncrossed difference in the skilled sportsmen than in the controls. The authors suggest that this may be due to more highly developed within-hemisphere integration of inputs and outputs, at the expense of cross-hemisphere integration. PMID- 23035876 TI - [Ln(BH4)2(THF)2] (Ln = Eu, Yb)--a highly luminescent material. Synthesis, properties, reactivity, and NMR studies. AB - The divalent lanthanide borohydrides [Ln(BH(4))(2)(THF)(2)] (Ln = Eu, Yb) have been prepared in a straightforward approach. The europium compound shows blue luminescence in the solid state, having a quantum yield of 75%. Nonradiative deactivation of C-H and B-H oscillator groups could be excluded in the perdeuterated complex [Eu(BD(4))(2)(d(8)-THF)(2)], which showed a quantum yield of 93%. The monocationic species [Ln(BH(4))(THF)(5)][BPh(4)] and the bis(phosphinimino)methanides [{(Me(3)SiNPPh(2))(2)CH}Ln(BH(4))(THF)(2)] have been prepared from [Ln(BH(4))(2)(THF)(2)]. They show significantly lower or no luminescence. Using the diamagnetic compound [{(Me(3)SiNPPh(2))(2)CH}Yb(BH(4))(THF)(2)], we performed a 2D (31)P/(171)Yb HMQC experiment. PMID- 23035877 TI - Clean intermittent catheterization and urinary tract infection: review and guide for future research. AB - What's known on the subject? and What does the study add? Clean intermittent catheterization (CIC) is considered the method of choice for bladder emptying when neurological or non-neurological causes make normal voiding impossible or incomplete. The outcome is overall good, also in the long-term. There is neither one best technique nor one best material, as both depend greatly on patients' individual anatomic, social and economic possibilities. The most frequent complication is urinary tract infection (UTI). Studies differ in the definition criteria for UTI, methods for evaluation, CIC techniques, frequency of urine analysis, prophylaxis and patients studied. The study provides a literature review and shows that most studies do not have a high level of evidence. There are various risk factors for UTI and phenotyping them helps to assess prognosis by considering what can happen if treatment is not initiated. The study concludes, that the role of biofilms in CIC deserves more attention and that diagnosis should be made on urine sample obtained with catheterization, because symptoms are often less reliable. It also concludes that treatment in those who catheterize for a long time is only necessary for symptomatic infections. The study identifies the following areas for further research: prevention of UTI in patients performing CIC; the use of special catheter types; and the role of frequency of catheterization, prophylactic antibiotics and preservation of natural defence mechanisms in the lower urinary tract. OBJECTIVE: * To review the factors related to urinary tract infection (UTI), the most prevalent complication in patients who perform clean intermittent catheterization (CIC). METHODS: * We conducted a literature search then a group discussion to gather relevant information on aspects of UTI to guide future research and to help provide clearer recommendations for the prevention of UTI in patients performing CIC. RESULTS: * UTI is a major complication of CIC, the incidence of which varies widely in the literature owing to differences in methodology and definitions. * Phenotyping the risk factors for UTI helps to assess prognosis by considering what can happen if treatment is not initiated. The role of biofilms in CIC deserves more attention. * Diagnosis is made using the urine sample obtained by catheterization. Because of neurological or other deficiencies in patients performing CIC, symptoms are less reliable. Thorough evaluation for the source of signs and symptoms should be made before attributing them to UTI. * There have been many different proposals for the prevention of UTI in patients performing CIC, but most need more research. The role of the type of catheter is unclear but further exploration of special catheter types might be worthwhile. * Treatment in those who perform CIC for a long time is best reserved for symptomatic infections. CONCLUSIONS: * Several mechanisms are relevant in UTI related to CIC. * As UTI is prevalent, more research into its prevention is needed. PMID- 23035878 TI - Evidence of global-scale As, Mo, Sb, and Tl atmospheric pollution in the antarctic snow. AB - We report the first comprehensive and reliable time series for As, Mo, Sb, and Tl in the snowpack from Dome Fuji in the central East Antarctic Plateau. Our results show significant enrichment of these elements due to either anthropogenic activities or large volcanic eruptions during the past 50 years. With respect to the values reported from 1960 to 1964, we observed the maximum increases in crustal enrichment factors (EFs) for As (a factor of ~15), Mo (~4), Sb (~4), and Tl (~2) during the period between the 1970s and 1990s, reflecting the global dispersion of anthropogenic pollutants of these elements, even to the most remote areas on Earth. Such enrichments are likely related to emissions of trace elements from nonferrous metal smelting and fossil fuel combustion processes in South America, especially in Chile. A drastic decrease in the As concentration and its EF values was observed after the year 2000 in response to the introduction of environmental regulations in the 1990s to reduce As emissions from the copper industry, primarily in Chile. The observed decrease suggests that governmental regulations for pollution control are effective in reducing air pollution at both the regional and global level. PMID- 23035879 TI - Gender differential on characteristics and outcome of leprosy patients admitted to a long-term care rural hospital in South-Eastern Ethiopia. AB - INTRODUCTION: In previous studies, women are less aware of causation and symptoms of leprosy and have less access to health care coverage than men, thus contributing to their delay in seeking for treatment. We assess the gender differences in leprosy cases admitted to a rural referral hospital in Ethiopia for 7 and a half years. METHODS: Retrospective data of the leprosy patients admitted to referral hospital were collected using leprosy admission registry books from September 2002 to January 2010. Variables were entered in an Excel 97 database. RESULTS: During the period of study, 839 patients with leprosy were admitted; 541 (64.5%) were male, and 298 (35.6%) female. Fifteen per cent of female patients, and 7.3% of male patients were paucibacillary leprosy cases while 84.8% of female patients and 92.7% of males were multibacillary leprosy cases (p<0.001). Female leprosy patients were younger than male ones (median: 36 versus 44 years) (p<0.001). In the multivariate analysis, age (odds ratio [OR]: 0.97; 95% confidence interval [CI]: 0.96-0.98; p<0.001), admission for cardiovascular diseases (OR: 7.6, 95% CI: 1.9-29.3; p=0.004), admission for gastroenteritis (OR: 14.0; 95% CI: 1.7-117; p=0.02), admission from out patients clinic (OR: 2.04; 95% CI: 1.1-4.01; p=0.02), and mortality as final outcome (OR: 3.1, 95% CI: 1.2-8.0; p=0.02) were independently associated with female gender. CONCLUSIONS: Female patients with leprosy admitted to hospital were younger, had a different profile of admission and a higher mortality rate than male ones. PMID- 23035880 TI - Detection and characterization of Histoplasma capsulatum in a German badger (Meles meles) by ITS sequencing and multilocus sequencing analysis. AB - A wild badger (Meles meles) with a severe nodular dermatitis was presented for post mortem examination. Numerous cutaneous granulomas with superficial ulceration were present especially on head, dorsum, and forearms were found at necropsy. Histopathological examination of the skin revealed a severe granulomatous dermatitis with abundant intralesional round to spherical yeast like cells, 2-5 MUm in diameter, altogether consistent with the clinical appearance of histoplasmosis farciminosi. The structures stained positively with Grocott's methenamine silver and Periodic acid-Schiff stains, but attempts to isolate the etiologic agent at 25 and 37 degrees C failed. DNA was directly extracted from tissue samples and the ribosomal genes ITS1-5.8S-ITS2 were partially sequenced. This revealed 99% identity to sequences from Ajellomyces capsulatus, the teleomorph of Histoplasma capsulatum, which was derived from a human case in Japan, as well as from horses from Egypt and Poland. Phylogenetic multi-locus sequence analysis demonstrated that the fungus in our case belonged to the Eurasian clade which contains members of former varieties H. capsulatum var. capsulatum, H. capsulatum var. farciminosum. This is the first study of molecular and phylogenetic aspects of H. capsulatum, as well as evidence for histoplasmosis farciminosi in a badger, further illuminating the role of this rare pathogen in Central Europe. PMID- 23035881 TI - Decompressive hemicraniectomy following malignant middle cerebral artery infarctions: a mixed methods exploration of carer experience and level of burden. AB - PURPOSE: This study explores the experiences and sense of burden of family carers of survivors of malignant middle cerebral artery infarctions who had undergone decompressive hemicraniectomy. To date, there have been no studies examining carer outcomes among this unique population. This study, taken alongside an already published study of survivor outcomes, provides a more holistic picture with regard to sequelae within the sample. METHOD: Six family carers completed the Sense of Competence Questionnaire and the Hospital Anxiety and Depression Scale. These results were compared with existing normative data. Carers also consented to a semi-structured interview. Interview data were examined using thematic content analysis. Consistent with the mixed methods design, quantitative and qualitative findings were integrated for further analysis. RESULTS: While carers experienced many losses, their overall sense of burden was not outside 'Average' limits, nor did they experience clinically significant symptoms of depression. All carers identified methods of coping with the demands of caregiving. These included intrapersonal, interpersonal and practical strategies. All carers apart from one were able to identify areas of post-traumatic growth. CONCLUSION: Carers will benefit from information, support and care. In addition, problem solving skills are essential in managing the myriad difficulties that arise in the aftermath of stroke. PMID- 23035883 TI - Activity participation and cognitive aging from age 50 to 80 in the glostrup 1914 cohort. AB - OBJECTIVES: To examine the cognitively protective effect of leisure and physical activities while accounting for prior cognitive ability, a rarely considered confounder of the previously reported associations between activity and cognitive aging. DESIGN: Longitudinal cohort study. SETTING: Glostrup, Denmark. PARTICIPANTS: Community-dwelling sample of adults recruited into the Glostrup 1914 Cohort (baseline N = 802). All were born in 1914 and were assessed at ages 50, 60, 70, and 80. New participants were recruited during the study to counter attrition. MEASUREMENTS: On each occasion, cognitive ability was assessed using four tests, which defined a general cognitive ability score. Self-reported participation in leisure and physical activities was also collected. In general, physical activity was summarized on a 3- or 4-point scale, and leisure activity as none versus some (ages 50 and 60) or according to participation in a list of common activities (age 70). The effect of activity-leisure and physical-on the level of cognitive ability and cognitive change over time from age 60 to 80 was examined in growth curve models. RESULTS: Greater activity (leisure or physical) was consistently associated with a higher level of cognitive ability. Adjusting for baseline cognitive ability (age 50) attenuated these associations, suggesting that associations between activity and cognition reported in old age are largely a consequence of preserved differentiation. A small but significant association remained between greater physical activity at age 60 or 70 and less cognitive decline. CONCLUSION: The association between more-frequent leisure activity and less cognitive decline mainly reflects the positive cross-sectional association between activity and cognition, although the link that remains between greater physical activity and a more-successful cognitive aging trajectory is of particular relevance to those who are developing interventions. PMID- 23035884 TI - Prediction of preeclampsia: liver function tests during the first 20 gestational weeks. AB - OBJECTIVE: To examine whether plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) during the first 20 weeks of pregnancy can predict preeclampsia in the second half of pregnancy. METHODS: The study population included 150,10 registered births. Receiver operating characteristic (ROC) curve analysis was used to describe the relationship between different values of AST and ALT during the first 20 weeks of pregnancy in the prediction of preeclampsia. RESULTS: Using ROC curve analyses, elevated ALT levels were significantly associated with both mild preeclampsia (p < 0.001) and severe preeclampsia (p = 0.032). However, an ALT level of 50 IU/L had a sensitivity of only 3.3% (despite a specificity of 97%) in the prediction of severe preeclampsia. While no significant association was noted between AST levels and mild preeclampsia (p = 0.669), elevated levels of AST during this period were significantly associated with severe preeclampsia (p = 0.027). However, AST of 50I U/L had a sensitivity of only 2.0% (despite a specificity of 98%) in the prediction of severe preeclampsia. CONCLUSIONS: Higher levels of the liver enzymes AST and ALT during the first 20 weeks of pregnancy are associated with higher risk for the development of severe preeclampsia in the second half of the pregnancy. Nevertheless, there is no clinical cutoff value that can be practically used for the prediction of preeclampsia. PMID- 23035882 TI - PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. AB - BACKGROUND: Many methodologies have been used in research to identify the "intrinsic" subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E) and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC) markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions. METHODS: We used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER), progesterone receptor (PR), and Her2/neu (HER2) protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH). Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and "intrinsic" subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments. RESULTS: ESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC) >= 0.9). Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B) subtypes (92%), but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74%) and Luminal A tumors were less likely to have high proliferation (11% vs 77%). Seventy-seven percent (30/39) of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57%) and HER2-E (30%) subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as shown in a multivariate analysis. CONCLUSIONS: The standard immunohistochemical panel for breast cancer (ER, PR, and HER2) does not adequately identify the PAM50 gene expression subtypes. Although there is high agreement between biomarker scoring by protein immunohistochemistry and gene expression, the gene expression determinations for ESR1 and ERBB2 status was more prognostic. PMID- 23035886 TI - Dietary and supplemental folate and the risk of left- and right-sided colorectal cancer. AB - Epidemiological evidence suggests that folate may lower the risk of colorectal cancer (CRC) although studies have been inconsistent and some have indicated differences in the effects of naturally occurring dietary folate and the synthetic form of this vitamin, folic acid. Most studies to date have considered CRC as a single disease; however, cancers that develop on the left and right sides of the colorectum display important phenotypic differences, suggesting they may also have different risk factors. A population-based case-control study was conducted in Western Australia to examine the relationship between intake of both natural dietary folate and supplements containing folic acid and the risk of left and right-sided CRC. Data were available for 850 cases (575 left-sided and 275 right-sided) and 958 controls. Odds ratios were calculated using multinomial logistic regression models. There was no association between natural dietary folate intake and risk of either left-or right-sided CRC. Supplement use similarly had no significant effect on right-sided CRC. However, long-term supplement users (4+ yr) were at lower risk of left-sided CRC than those who had not taken supplements (OR = 0.65, 95% CI, 0.50-0.86) and there was a significant trend in risk reduction as duration of use increased (P < 0.01). PMID- 23035887 TI - The disappearance of the "revolving door" patient in Scottish general practice: successful policies. AB - BACKGROUND: We describe the health of "revolving door" patients in general practice in Scotland, estimate changes in their number over the timescale of the study, and explore reasons for changes, particularly related to NHS and government policy. METHODS: A mixed methods predominantly qualitative study, using a grounded theory approach, set in Scottish general practice. Semi structured interviews were conducted with professional key informants, 6 Practitioner Services staff who administer the GP registration system and 6 GPs with managerial or clinical experience of working with "revolving door" patients. Descriptive statistical analysis and qualitative analysis of patient removal episodes linked with routine hospital admissions, outpatient appointments, drug misuse treatment episodes and deaths were carried out with cohorts of "revolving door" patients identified from 1999 to 2005 in Scotland. RESULTS: A "revolving door" patient is removed 4 or more times from GP lists in 7 years. Patients had complex health issues including substance misuse, psychiatric and physical health problems and were at high risk of dying. There was a dramatic reduction in the number of "revolving door" patients during the course of the study. CONCLUSIONS: "Revolving door" patients in general practice had significant health problems. Their numbers have reduced dramatically since 2004 and this probably resulted from improved drug treatment services, pressure from professional bodies to reduce patient removals and the positive ethical regulatory and financial climate of the 2004 GMS GP contract. This is a positive development for the NHS. PMID- 23035885 TI - Synthesis, characterization, and paclitaxel release from a biodegradable, elastomeric, poly(ester urethane)urea bearing phosphorylcholine groups for reduced thrombogenicity. AB - Biodegradable polymers with high elasticity, low thrombogenicity, and drug loading capacity continue to be pursued for vascular engineering applications, including vascular grafts and stents. A biodegradable elastomeric polyurethane was designed as a candidate material for use as a drug-eluting stent coating, such that it was nonthrombogenic and could provide antiproliferative drug release to inhibit smooth muscle cell proliferation. A phosphorylcholine containing poly(ester urethane) urea (PEUU-PC) was synthesized by grafting aminated phosphorylcholine onto backbone carboxyl groups of a polyurethane (PEUU-COOH) synthesized from a soft segment blend of polycaprolactone and dimethylolpropionic acid, a hard segment of diisocyanatobutane and a putrescine chain extender. Poly(ester urethane) urea (PEUU) from a soft segment of polycaprolactone alone was employed as a control material. All of the synthesized polyurethanes showed high distensibility (>600%) and tensile strengths in the 20-35 MPa range. PEUU-PC experienced greater degradation than PEUU or PEUU-COOH in either a saline or lipase enzyme solution. PEUU-PC also exhibited markedly inhibited ovine blood platelet deposition compared with PEUU-COOH and PEUU. Paclitaxel loaded in all of the polymers during solvent casting continued to release for 5 d after a burst release in a 10% ethanol/PBS solution, which was utilized to increase the solubility of the releasate. Rat smooth muscle cell proliferation was significantly inhibited in 1 wk cell culture when releasate from the paclitaxel loaded films was present. Based on these results, the synthesized PEUU-PC has promising functionality for use as a nonthrombogenic, drug eluting coating on metallic vascular stents and grafts. PMID- 23035888 TI - Histone acetylation mediates epigenetic regulation of transcriptional reprogramming in insects during metamorphosis, wounding and infection. AB - BACKGROUND: Gene expression in eukaryotes is regulated by histone acetylation/deacetylation, an epigenetic process mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) whose opposing activities are tightly regulated. The acetylation of histones by HATs increases DNA accessibility and promotes gene expression, whereas the removal of acetyl groups by HDACs has the opposite effect. RESULTS: We explored the role of HDACs and HATs in epigenetic reprogramming during metamorphosis, wounding and infection in the lepidopteran model host Galleria mellonella. We measured the expression of genes encoding components of HATs and HDACs to monitor the transcriptional activity of each enzyme complex and found that both enzymes were upregulated during pupation. Specific HAT inhibitors were able to postpone pupation and to reduce insect survival following wounding, whereas HDAC inhibitors accelerated pupation and increased survival. The administration of HDAC inhibitors modulated the expression of effector genes with key roles in tissue remodeling (matrix metalloproteinase), the regulation of sepsis (inhibitor of metalloproteinases from insects) and host defense (antimicrobial peptides), and simultaneously induced HAT activity, suggesting that histone acetylation is regulated by a feedback mechanism. We also discovered that both the entomopathogenic fungus Metarhizium anisopliae and the human bacterial pathogen Listeria monocytogenes can delay metamorphosis in G. mellonella by skewing the HDAC/HAT balance. CONCLUSIONS: Our study provides for the first evidence that pathogenic bacteria can interfere with the regulation of HDACs and HATs in insects which appear to manipulate host immunity and development. We conclude that histone acetylation/deacetylation in insects mediates transcriptional reprogramming during metamorphosis and in response to wounding and infection. PMID- 23035889 TI - Repeated immobilization stress induces catecholamine production in rat mesenteric adipocytes. AB - Catecholamines (CATs), the major regulator of lipolysis in adipose tissue, are produced mainly by the sympathoadrenal system. However, recent studies report endogenous CAT production in adipocytes themselves. This study investigated the effects of single and repeated (7-14 times) immobilization (IMO) stress on CAT production in various fat depots of the rat. Single IMO quickly induced a rise of norepinephrine (NE) and epinephrine (EPI) concentration in mesenteric and brown adipose depots. Adaptive response to repeated IMO included robust increases of NE and EPI levels in mesenteric and subcutaneous adipose tissue. These changes likely reflect the activation of sympathetic nervous system in fat depots by IMO. However, this process was also paralleled by an increase in tyrosine hydroxylase gene expression in mesenteric fat, suggesting regulation of endogenous CAT production in adipose tissue cells. Detailed time-course analysis (time course 10, 30, and 120 min) clearly showed that repeated stress led to increased CAT biosynthesis in isolated mesenteric adipocytes resulting in gradual accumulation of intracellular EPI during IMO exposure. Comparable changes were also found in stromal/vascular fractions, with more pronounced effects of single than repeated IMO. The potential physiological importance of these findings is accentuated by parallel increase in expression of vesicular monoamine transporter 1, indicating a need for CAT storage in adipocyte vesicles. Taken together, we show that CAT production occurs in adipose tissue and may be activated by stress directly in adipocytes. PMID- 23035890 TI - Meta-analysis: adherence to colorectal cancer screening and the detection rate for advanced neoplasia, according to the type of screening test. AB - BACKGROUND: A variety of tests have been proposed for colorectal cancer (CRC), giving rise to uncertainty regarding the optimal approach. The efficacy and effectiveness of different tests are related to both screened participation and the detection rate. AIM: To perform a meta-analysis on adherence and detection rates of CRC screening tests. METHODS: Relevant publications were identified by MEDLINE/EMBASE and other databases for the period 1999-2012. A previous systematic review was used for the period before 1966-1999. RCTs and controlled studies including a direct comparison of the uptake rates among different options for CRC screening were included. Adherence and detection rates for advanced neoplasia and cancer were extracted. Risk for bias was ascertained according to CONSORT guidelines. Forrest plots were produced based on random-effect models. RESULTS: Fourteen studies provided data on 197 910 subjects. Endoscopic strategies were associated with a lower participation (RR: 0.67, 95% CI: 0.56, 0.80) rate, but a higher detection rate of advanced neoplasia (RR: 3.21, 95% CI: 2.38, 4.32) compared with faecal tests. FIT was superior to g-FOBT with regard to both adherence (RR: 1.16, 95% CI 1.03, 1.30) and detection of advanced neoplasia (RR: 2.28, 95% CI 1.68, 3.10) and cancer (RR: 1.96, 95% CI: 1.2, 3.2). CONCLUSION: The superior accuracy of endoscopy compared with faecal tests minimised any impact of the participation rate in determining the detection rate of advanced neoplasia in a screening setting. PMID- 23035891 TI - Patch testing with 2.0% (0.60 mg/cm 2) formaldehyde instead of 1.0% (0.30 mg/cm 2) detects significantly more contact allergy. AB - BACKGROUND: The currently used patch test concentration for formaldehyde is 1.0% (wt/vol) in water. However, clinical experience and previous studies suggest that 1.0% might be insufficient for detecting an optimized number of clinically relevant cases of contact allergy to formaldehyde. OBJECTIVES: To validate earlier patch test results for comparison of 1% (wt/vol) and 2% (wt/vol) formaldehyde in water, and to investigate co-reactivity with quaternium-15. MATERIALS AND METHODS: In 12 dermatology clinics, 3591 patients were routinely patch tested simultaneously with 2.0% (wt/vol) (0.60 mg/cm(2)) and 1.0% (wt/vol) (0.30 mg/cm(2)) formaldehyde. Micropipettes were used for delivering the exact dosage of the allergen. RESULTS: Significantly more patients reacted to 2.0% formaldehyde than to 1.0% (3.4% versus 1.8%, p < 0.001). Overall, there were no sex differences between those reacting positively to 2.0% and 1.0%. Of 25 quaternium-15-positive patients, 4 (0.1%) reacted positively without reacting to formaldehyde. CONCLUSION: On the basis of the results of this multicentre study, as well as of previous studies, it can be suggested that 2.0% (wt/vol) in water formaldehyde should be used in routine patch testing in the baseline series. PMID- 23035892 TI - The prodomain of the Bordetella two-partner secretion pathway protein FhaB remains intracellular yet affects the conformation of the mature C-terminal domain. AB - Two-partner secretion (TPS) systems use beta-barrel proteins of the Omp85-TpsB superfamily to transport large exoproteins across the outer membranes of Gram negative bacteria. The Bordetella FHA/FhaC proteins are prototypical of TPS systems in which the exoprotein contains a large C-terminal prodomain that is removed during translocation. Although it is known that the FhaB prodomain is required for FHA function in vivo, its role in FHA maturation has remained mysterious. We show here that the FhaB prodomain is required for the extracellularly located mature C-terminal domain (MCD) of FHA to achieve its proper conformation. We show that the C-terminus of the prodomain is retained intracellularly and that sequences within the N-terminus of the prodomain are required for this intracellular localization. We also identify sequences at the C terminus of the MCD that are required for release of mature FHA from the cell surface. Our data support a model in which the intracellularly located prodomain affects the final conformation of the extracellularly located MCD. We hypothesize that maturation triggers cleavage and degradation of the prodomain. PMID- 23035894 TI - Syn-selective Kobayashi aldol reaction using the E,E-vinylketene silyl N,O acetal. AB - The Kobayashi aldol reaction is one of the most powerful methods to synthesize the polyketide skeleton and has been applied to the total synthesis of natural products. This methodology has been used to construct anti-aldol products, and only a few precedents on the syn-selective Kobayashi aldol reaction are known. A syn-selective Kobayashi aldol reaction by using the E,E-vinylketene silyl N,O acetal and an excess amount of Lewis acid is presented. PMID- 23035893 TI - Protective effect of the aqueous extract from the root of Platycodon grandiflorum on cholestasis-induced hepatic injury in mice. AB - CONTEXT: The root of Platycodon grandiflorum (Jacq.) A. DC. (Campanulaceae) has been widely studied for its hepatoprotective effects against various hepatotoxicants. OBJECTIVE: The present study evaluated the protective effect of the standardized aqueous extract of P. grandiflorum (BC703) on cholestasis induced hepatic injury in mice. MATERIALS AND METHODS: BC703 is a standardized aqueous extract of P. grandiflorum in reference to platycodin D (at least 0.8%). The mice were allocated into five groups as follows: Sham-operated, bile duct ligation (BDL) alone, and BDL with BC703 (1, 5, and 10 mg/kg BW) treated group. BC703 was given for 3 consecutive days before BDL operation. The animals were sacrificed by CO2 anesthesia post-24 h of BDL operations. RESULTS AND DISCUSSION: Serum alanine aminotransferase and serum aspartate aminotransferase increased to 395.2 +/- 90.0 and 266.0 +/- 45.6 Unit/L in the BDL alone group and decreased with BC703 in a dose-dependent manner. Especially the 10 mg/kg of BC703-treated mice showed a 77% decrease of serum alanine aminotransferase and 56% of aspartate aminotransferase as compared with BDL alone. Decreased antioxidant enzyme levels in BDL alone group were elevated in BC703-treated groups ranging from 7 to 29% for glutathione and from 13 to 25% for superoxide dismutase. BC703 treatment also attenuated malondialdehyde (from 3 to 32%) and nitric oxide levels (from 32 to 50%) as compared with BDL alone. Histopathological studies further confirmed the hepatoprotective effect of BC703 in BDL-induced cholestesis. CONCLUSION: BC703 could attenuate liver injury by BDL in mice, and test results indicate that BC703 might be useful in cholestatic liver injury. PMID- 23035895 TI - New insights in mechanisms of bacterial inactivation by carvacrol. AB - AIMS: To study the mechanism of bacterial inactivation by carvacrol and the influence of genetic and environmental factors in its antimicrobial activity. METHODS AND RESULTS: In general, bacterial inactivation by carvacrol was higher in the Gram-positive Listeria monocytogenes than in the Gram-negative Escherichia coli and at acidic pH. At pH 4.0, 25 MUl l(-1) of carvacrol for 5 h inactivated 1 and more than 5 log(10) cycles of E. coli and L. monocytogenes populations, respectively. Genetic and environmental factors also influenced cell resistance to carvacrol: rpoS and sigB deletion decreased carvacrol resistance in E. coli and L. monocytogenes, respectively; a heat shock induced a phenomenon of cross protection to carvacrol treatments. Repair of sublethal injuries in cell envelopes suggested that carvacrol targets lipid fractions and proteins of these structures. This result was corroborated by attenuated total reflectance infrared microspectroscopy analysis. CONCLUSIONS: This study shows critical genetic and environmental factors, such as rpoS or sigB and heat shocks, and reveals new microbial structures involved in the mechanism of bacterial inactivation by carvacrol. SIGNIFICANCE AND IMPACT OF THE STUDY: A better understanding of the mechanisms of microbial inactivation is of great relevance to design more appropriate carvacrol treatments with high antimicrobial effects. PMID- 23035896 TI - A pilot study of HIV/STI risk among men having sex with men using erectile dysfunction medications: challenges and opportunities for sexual medicine physicians. AB - INTRODUCTION: A growing literature suggests relationships between erectile dysfunction medications (EDM) and riskier sexual behavior among men who have sex with men (MSM). Questions remain concerning EDM use and related HIV/sexually transmitted infections (STI) risk among older MSM, particularly those 40 years and over, for whom EDM may be medically warranted. AIM: This exploratory pilot study explores the relationship between EDM and risky sexual behavior in a convenience sample of MSM using EDM and attending historic sex-on-premises venues. METHODS: We examined anonymous surveys from 139 MSM. Bivariate relationships were examined. We then fit a multiple logistic regression model to determine predictors of engaging in unprotected anal intercourse (UAI) at last EDM, using variables identified as being significantly related to UAI in the bivariate analyses. Potential predictors entered the model in a stepwise fashion. MAIN OUTCOME MEASURES: The primary outcome measure was engaging in UAI at last EDM use. RESULTS: MSM participating in the study ranged from 27 to 77 years and averaged 52.0 years (standard deviation = 10.73 years). These participants were primarily older MSM; fewer were younger MSM (12.12%), under age 40. Participants reporting UAI at last EDM use (N = 41) were significantly younger (P < 0.01). Men visiting bars within the last 6 months reported less UAI (P < 0.01). Both variables were independent predictors of UAI in the logistic regression model (P < 0.01). CONCLUSIONS: Similar to reports from younger MSM, our findings suggest older MSM using EDM and reporting UAI are also recreational drug users. We include recommendations for urologists and other sexual medicine physicians treating MSM who may be at elevated risk for HIV/STI infection because of joint EDM and club drug use. PMID- 23035897 TI - The habitable zone and extreme planetary orbits. AB - The habitable zone for a given star describes the range of circumstellar distances from the star within which a planet could have liquid water on its surface, which depends upon the stellar properties. Here we describe the development of the habitable zone concept, its application to our own solar system, and its subsequent application to exoplanetary systems. We further apply this to planets in extreme eccentric orbits and show how they may still retain life-bearing properties depending upon the percentage of the total orbit which is spent within the habitable zone. Key Words: Extrasolar planets-Habitable zone Astrobiology. PMID- 23035898 TI - Selected ion flow tube-MS analysis of headspace vapor from gastric content for the diagnosis of gastro-esophageal cancer. AB - Gastric content is a complex biofluid within the human stomach which has an important role in digestive processes. It is believed that gastric content may be a contributory factor in the development of upper gastro-intestinal diseases. In this work, selected ion flow tube mass spectrometry (SIFT-MS) has been applied to the quantification of volatile organic compounds (VOCs) in the headspace vapor of gastric content samples, which were retrieved from three groups of patients, including those with gastro-esophageal cancer, noncancer diseases of the upper gastro-intestinal tract, and a healthy cohort. Twelve VOCs have been investigated in this study; the following 7 VOCs, acetone, formaldehyde, acetaldehyde, hexanoic acid, hydrogen sulphide, hydrogen cyanide, and methyl phenol, were found to be significantly different between cancer and healthy groups by the Mann Whitney U test. Receiver operating characteristics (ROC) analysis was applied for the combined VOCs of acetaldehyde, formaldehyde, hydrogen sulphide, and methyl phenol to discriminate cancer patients from healthy controls. The area under the curve (AUC) was 0.9. This result raises the prospect that a VOC profile rather than a single biomarker may be preferable in the molecular-orientated diagnosis of gastro-oseophageal cancer, and this warrants further investigation to assess its potential application as a new diagnostic test. PMID- 23035899 TI - Improving promiscuous mammalian cell entry by the baculovirus Autographa californica multiple nuclear polyhedrosis virus. AB - The insect baculovirus AcMNPV (Autographa californica multiple nuclear polyhedrosis virus) enters many mammalian cell lines, prompting its application as a general eukaryotic gene delivery agent, but the basis of entry is poorly understood. For adherent mammalian cells, we show that entry is favoured by low pH and by increasing the available cell-surface area through a transient release from the substratum. Low pH also stimulated baculovirus entry into mammalian cells grown in suspension which, optimally, could reach 90% of the transduced population. The basic loop, residues 268-281, of the viral surface glycoprotein gp64 was required for entry and a tetra mutant with increasing basicity increased entry into a range of mammalian cells. The same mutant failed to plaque in Sf9 cells, instead showing individual cell entry and minimal cell-to-cell spread, consistent with an altered fusion phenotype. Viruses grown in different insect cells showed different mammalian cell entry efficiencies, suggesting that additional factors also govern entry. PMID- 23035901 TI - Cost-effective framework for basic surgical skills training. AB - BACKGROUND: The importance of basic surgical skills is entirely agreed among surgical educators. However, restricted by ethical issues, finance etc, the basic surgical skills training is increasingly challenged. Increasing cost gives an impetus to the development of cost-effective training models to meet the trainees' acquisition of basic surgical skills. In this situation, a cost effective training framework was formed in our department and introduced here. METHODS: Each five students were assigned to a 'training unit'. The training was implemented weekly for 18 weeks. The framework consisted of an early, a transitional, an integrative stage and a surgical skills competition. Corresponding training modules were selected and assembled scientifically at each stage. The modules comprised campus intranet databases, sponge benchtop, nonliving animal tissue, local dissection specimens and simulating reality operations. The training outcomes used direct observation of procedural skills as an assessment tool. The training data of 50 trainees who were randomly selected in each year from 2006 to 2011 year, were retrospectively analysed. RESULTS: An excellent and good rate of the surgical skills is from 82 to 88%, but there is no significant difference among 6 years (P > 0.05). The skills scores of the contestants are markedly higher than those of non-contestants (P < 0.05). The average training cost per trainee is about $21.85-34.08. CONCLUSION: The present training framework is reliable, feasible, repeatable and cost-effective. The skills competition can promote to improve the surgical skills level of trainees. PMID- 23035900 TI - Zerumbone suppresses IKKalpha, Akt, and FOXO1 activation, resulting in apoptosis of GBM 8401 cells. AB - BACKGROUND: Zerumbone, a sesquiterpene compound isolated from subtropical ginger, Zingiber zerumbet Smith, has been documented to exert antitumoral and anti- inflammatory activities. In this study, we demonstrate that zerumbone induces apoptosis in human glioblastoma multiforme (GBM8401) cells and investigate the apoptotic mechanism. METHODS: We added a caspase inhibitor and transfected wild type (WT) IKK and Akt into GBM 8401 cells, and measured cell viability and apoptosis by MTT assay and flow cytometry. By western blotting, we evaluated activation of caspase-3, dephosphorylation of IKK, Akt, FOXO1 with time, and change of IKK, Akt, and FOXO1 phosphorylation after transfection of WT IKK and Akt. RESULTS: Zerumbone (10~50 MUM) induced death of GBM8401 cells in a dose dependent manner. Flow cytometry studies showed that zerumbone increased the percentage of apoptotic GBM cells. Zerumbone also caused caspase-3 activation and poly (ADP-ribose) polymerase (PARP) production. N-benzyloxycarbonyl -Val-Ala-Asp- fluoromethylketone (zVAD-fmk), a broad-spectrum caspase inhibitor, hindered zerumbone-induced cell death. Transfection of GBM 8401 cells with WT IKKalpha inhibited zerumbone-induced apoptosis, and zerumbone significantly decreased IKKalpha phosphorylation levels in a time-dependent manner. Similarly, transfection of GBM8401 cells with Akt suppressed zerumbone-induced apoptosis, and zerumbone also diminished Akt phosphorylation levels remarkably and time dependently. Moreover, transfection of GBM8401 cells with WT IKKalpha reduced the zerumbone-induced decrease in Akt and FOXO1 phosphorylation. However, transfection with WT Akt decreased FOXO1, but not IKKalpha, phosphorylation. CONCLUSION: The results suggest that inactivation of IKKalpha, followed by Akt and FOXO1 phosphorylation and caspase-3 activation, contributes to zerumbone induced GBM cell apoptosis. PMID- 23035902 TI - Tracking temporal trend breaks of anthropogenic change in Mussel Watch (MW) databases. AB - The potential for structural changes in time trend concentrations of mercury (Hg), lead (Pb), cadmium (Cd), zinc (Zn), and copper (Cu) in the Mediterranean mussel, Mytilus galloprovincialis, was examined in Mussel Watch (MW) databases of metal pollution at eighteen coastal stations over a decadal period, from 1992 to 2007. Simultaneously, by using two statistical methods representing both the classical hypothesis-testing and the Bayesian approaches, we found single and multiple trend breaks for Hg (28% of the stations), Cd (17%), and Pb (11%) within trends in connection with anthropogenic and subtle natural environmental changes. Also called change point problems, if not accounted for, these could bias time trend investigations and interpretations. We calculated trend rate differences of 39% and switches up to 1 order of magnitude from classical linear trend assessments. We discuss sampling, analytical, and environmental (both natural and anthropogenic) sources of data set variabilities, showing that, in practice, the overall 16-year analytical performance could be as elevated as the yearly sampling reproducibility. We demonstrate that environmental time trend interpretations benefit from undertaking prior structural change analysis. After decades of MW marine chemical pollution assessments these have proven extremely useful, although the occurrence of trend breaks directly affects the long-term marine environmental monitoring strategies. Our results suggest a broader concept to design monitoring programs in agreement with rapid global anthropogenic and environmental changes. PMID- 23035903 TI - The impact of acepromazine on the efficacy of crystalloid, dextran or ephedrine treatment in hypotensive dogs under isoflurane anesthesia. AB - OBJECTIVE: To determine the impact of acepromazine on the cardiovascular responses to three treatments for hypotension in dogs during deep isoflurane anesthesia. STUDY DESIGN: Prospective blinded randomized cross-over experimental design. ANIMALS: Six adult (2.5 +/- 0.5 year old) healthy mixed breed dogs (24.2 +/- 7.6 kg). METHODS: Anesthesia was induced with propofol (4-6 mg kg(-1) , IV) and maintained with isoflurane. Each dog received six treatments separated by at least 5 days. Once instrumented, dogs randomly received acepromazine (0.05 mg kg( 1) ) (Ace) or saline (equal volume) (Sal) IV and end-tidal isoflurane (E'Iso) was adjusted to achieve hypotension, defined as a mean blood pressure between 45 and 50 mmHg. Dogs randomly received dextran (D) (7 mL kg(-1) ) or lactated Ringer's (LR) (20 mL kg(-1) ) over 14 minutes, or ephedrine (Eph) (0.1 mg kg(-1) followed by 10 MUg kg(-1) minute(-1) ) throughout the study. Measurements were taken at baseline, 5, 10, 15, 20, 30, and 40 minutes. Data were analyzed with a Latin Square in two factors (Ace/Sal and treatment) for repeated measures, with further comparisons if appropriate (p < 0.05). RESULTS: E'Iso producing hypotension was significantly less following Ace (2.07 +/- 0.23%) than Sal (2.43 +/- 0.23%). No improvement in cardiac output (CO) was observed with D or LR. LR initially intensified hypotension with a significant reduction in SVR, while D caused a minor improvement in ABP. Eph produced a significant increase in ABP, CO, hemoglobin, oxygen content and delivery. Pre-treatment with Ace minimized ABP improvements with all treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Acepromazine (0.05 mg kg(-1) IV) enhanced the hypotensive effect of isoflurane, although it maintained CO. Administration of LR significantly worsens ABP initially by further vasodilation. D caused minimal improvement in ABP. At the infusion studied, Eph effectively countered the cardiovascular depression produced by deep isoflurane anesthesia, but extremes in ABP associated with initial vasoconstriction prevent our recommendation at this dose. PMID- 23035904 TI - Effect of yohimbine on detomidine induced changes in behavior, cardiac and blood parameters in the horse. AB - OBJECTIVE: To describe selected pharmacodynamic effects of detomidine and yohimbine when administered alone and in sequence. STUDY DESIGN: Randomized crossover design. ANIMALS: Nine healthy adult horses aged 9 +/- 4 years and weighing 561 +/- 56 kg. METHODS: Three dose regimens were employed in the current study. 1) 0.03 mg kg(-1) detomidine IV, 2) 0.2 mg kg(-1) yohimbine IV and 3) 0.03 mg kg(-1) detomidine IV followed 15 minutes later by 0.2 mg kg(-1) yohimbine IV. Each horse received all three treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for detomidine and yohimbine concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume and plasma proteins were monitored. RESULTS: Yohimbine rapidly reversed the sedative effects of detomidine in the horse. Additionally, yohimbine effectively returned heart rate and the percent of atrio-ventricular conduction disturbances to pre-detomidine values when administered 15 minutes post-detomidine administration. Plasma glucose was significantly increased following detomidine administration. The detomidine induced hyperglycemia was effectively reduced by yohimbine administration. Effects on packed cell volume and plasma proteins were variable. CONCLUSIONS AND CLINICAL RELEVANCE: Intravenous administration of yohimbine effectively reversed detomidine induced sedation, bradycardia, atrio-ventricular heart block and hyperglycemia. PMID- 23035905 TI - Mesenchymal stem cells restore CCl4-induced liver injury by an antioxidative process. AB - We have investigated BM (bone marrow)-derived MSCs (mesenchymal stem cells) for the treatment of liver injury. It was hypothesized that MSC-mediated resolution of liver injury could occur through an antioxidative process. After being injected with CCl4 (carbon tetrachloride), mice were injected with syngenic BM derived MSCs or normal saline. Oxidative stress activity of the MSCs was determined by the analysis of ROS (reactive oxygen species) and SOD (superoxide dismutase) activity. In addition, cytoprotective genes of the liver tissue were assessed by real-time PCR and ARE (antioxidant-response element) reporter assay. Up-regulated ROS of CCl4-treated liver cells was attenuated by co-culturing with MSCs. Suppression of SOD by adding an SOD inhibitor decreased the effect of MSCs on injured liver cells. MSCs significantly increased SOD activity and inhibited ROS production in the injured liver. The gene expression levels of Hmox-1 (haem oxygenase-1), BI-1 (Bax inhibitor-1), HGF (hepatocyte growth factor), GST (glutathione transferase) and Nrf2 (nuclear factor-erythoid 2 p45 subunit-related factor 20), attenuated by CCl4, were increased up to basal levels after MSC transplantation. In addition, MSCs induced an ARE, shown by luciferase activity, which represented a cytoprotective response in the injured liver. Evidence of a new cytoprotective effect is shown in which MSCs promote an antioxidant response and supports the potential of using MSC transplantation as an effective treatment modality for liver disease. PMID- 23035906 TI - Endocytic uptake and intracellular trafficking of bis-MPA-based hyperbranched copolymer micelles in breast cancer cells. AB - Dendrimers and their less well-defined cousins, hyperbranched polymers, are widely investigated as scaffold materials in tissue engineering, as drug delivery agents, and in diagnostic imaging applications. Despite the large interest of using these unique materials as polymer-based nanoparticles in biomedical applications, a clear understanding of the cellular uptake and transport of these polyester-based nanoparticles is still lacking. The objective of this study is to evaluate the cellular uptake profiles and intracellular trafficking of polymer micelles built from the hyperbranched polyester Boltorn, fitted with poly(ethylene glycol) and fluorescent groups in MDA-MB468 breast cancer cells. Results show that the uptake of these nanoparticles correlated positively to both time and concentration, and that the uptake of the nanoparticles was energy dependent. These polyesterbased nanoparticles appear to translocate across cells via clathrin- and macropinocytosis-mediated endocytosis. Observations of the intracellular trafficking of the nanoparticles indicate that particles could be released from early endosomes after being internalized, and the particles exhibit perinuclear localization. The uptake behavior of the nanoparticles was further evaluated in a range of cell lines. These results allow the generation of the knowledge base required to design polyester-based nanocarriers that can be used efficiently and specifically for drug delivery applications and imaging applications. PMID- 23035907 TI - Effects of a pulsed light-induced stress on Enterococcus faecalis. AB - AIMS: Pulsed light (PL) technology is a surface decontamination process that can be used on food, packaging or water. PL efficiency may be limited by its low degree of penetration or because of a shadow effect. In these cases, surviving bacteria will be able to perceive PL as a stress. Such a stress was mimicked using low transmitted energy conditions, and its effects were investigated on the highly environmental adaptable bacterium Enterococcus faecalis V583. METHODS AND RESULTS: In these laboratory conditions, a complete decontamination of the artificially inoculated medium was performed using energy doses as low as 1.8 J cm(-2) , while a treatment of 0.5, 1 and 1.2 J cm(-2) led to a 2.2, 6 and 7 log(10) CFU ml(-1) reduction in the initial bacterial population, respectively. Application of a 0.5 J cm(-2) pretreatment allowed the bacteria to resist more efficiently a 1.2 J cm(-2) subsequent PL dose. This 0.5 J cm(-2) treatment increased the bacterial mutation frequency and affected the abundance of 19 proteins as revealed by a global proteome analysis. CONCLUSIONS: Enterococcus faecalis is able to adapt to a PL treatment, providing a molecular response to low-energy PL dose, leading to enhanced resistance to a subsequent treatment and increasing the mutation frequency. SIGNIFICANCE AND IMPACT OF THE STUDY: This study gives further insights on Ent. faecalis capacities to adapt and to resist to stress. PMID- 23035908 TI - Evaluation of recurrent hyphema after trabeculectomy with ultrabiomicroscopy 50 80 MHz: a case report. AB - BACKGROUND: Hyphema is a complication that can occur after glaucoma filtering surgery. Biomicroscopic examination of the anterior segment is commonly used to diagnose it and gonioscopy may provide a useful support to find the source of the haemorrhage. Unfortunately, when the blood hides the structure of the anterior segment the gonioscopic examination fails. In this case we performed ultrabiomiscroscopy with 50-80 MHz probes to overcome the limits of gonioscopy. The use of this technique to study the anterior segment of the eye has previously been reported in literature, but we illustrates its importance for performing a correct diagnosis in a specific case of hyphema. CASE PRESENTATION: We report a case of a sixty-year-old caucasian male with recurrent hyphema in the left eye. The episodes of hyphema were four in two years and the patient came to the hospital for the first time in the last occasion. The past episodes were managed with topical corticosteroids and mydriatic drops. He referred surgical trabeculectomy in both eyes 5 years before the first symptoms and no specific eye trauma before the first episode. The examination of the anterior segment revealed a 2 mm hyphema in the left eye due to blood leakage through the superior iridectomy. Gonioscopy could not identify the source of the haemorrhage. B-scan ultrasound and ultrabiomiscroscopy, with 50-80 MHz probes, were performed. Ultrabiomiscroscopy, mainly with the probe of 80 MHz, provided images of high resolution of the structures of the anterior segment and it allowed the visualization of an abnormal vessel at the inner margin of the trabeculectomy opening, probably responsible of the recurrent hyphema. CONCLUSION: Ultrabiomicroscopy proved to be a useful diagnostic technique for identifying the cause of the recurrent hyphema when other examination techniques are not applicable. PMID- 23035909 TI - Herba Cistanches stimulates cellular glutathione redox cycling by reactive oxygen species generated from mitochondrial respiration in H9c2 cardiomyocytes. AB - CONTEXT: Earlier findings demonstrated that pretreatment of Herba Cistanches [the dried whole plant of Cistanche deserticola Y.C. Ma (Orobanchaceae)], a "Yang invigorating" Chinese tonic herb, stimulated the ATP-generation capacity (ATP-GC) in mitochondria isolated from rat heart ex vivo. The enhancement of mitochondrial ATP-GC by Herba Cistanches was associated with induction of glutathione antioxidant status and protection against ischemia/reperfusion (I/R) injury in rat hearts. OBJECTIVES: This study investigated the relationship between enhancements in mitochondrial ATP-GC and glutathione antioxidant status in H9c2 cardiomyocytes using a semipurified fraction of Herba Cistanches (HCF1). MATERIALS AND METHODS: HCF1 (10-300 ng/mL) was tested for its effects on mitochondrial ATP generation, glutathione antioxidant status and protection against oxidant injury in H9c2 cardiomyocytes and rat hearts. RESULTS AND DISCUSSION: HCF1 at 30 ng/mL increased mitochondrial ATP-GC and ADP-stimulated state 3 respiration (by 50 and 100%, respectively) in H9c2 cardiomyocytes. The stimulation of mitochondrial respiration was associated with the induction of mitochondrial uncoupling (27%) and enhancement of cellular glutathione redox cycling as well as protection against hypoxia/reoxygenation (hypox/reoxy)-induced apoptosis (by 60%). While HCF1 treatment increased reactive oxygen species generation from mitochondrial respiration in H9c2 cardiomyocytes, pretreatment with antioxidants (DMTU) abrogated the HCF1-induced cellular responses and the associated cytoprotective effect. HCF1 pretreatment (1.14 and 3.41 mg/kg * 14) also protected against myocardial I/R injury in rats (by 13 and 32%), presumably mediated by the induction of glutathione antioxidant response. CONCLUSION: The long-term intake of HCF1 may offer a prospect for the prevention of ischemic heart disease. PMID- 23035910 TI - Regioselective synthesis of pyrazole triflones based on triflyl alkyne cycloadditions. AB - The regioselective synthesis of pyrazole triflones has been achieved by 1,3 dipolar cycloaddition of triflyl alkynes and hydrazonoyl chloride in the presence of Hunig's base. Pyrazolo[5,1-a]isoquinoline triflones were also regioselectively synthesized for the first time via tandem 1,3-dipolar cycloaddition/oxidative aromatization between triflyl alkynes and C,N-cyclic azomethine imines. PMID- 23035911 TI - The combined effects of storage temperature and packaging type on the sensory and chemical properties of chardonnay. AB - Californian Chardonnay was stored in five different wine-packaging configurations at three different temperatures for a period of 3 months to study the combined packaging and temperature effects on the sensory and chemical properties of the wines. A trained descriptive panel evaluated aroma, taste, mouthfeel, and color attributes, and the sensory results were correlated to physical and chemical measurements including volatile compounds, SO(2), titratable and volatile acidity, oxygen consumption, and wine color, using partial least squares regression. In general, increased storage temperatures induced the largest changes in the wines; however, significant packaging--temperature effects were found for some attributes as well. Particularly wines stored in bag-in-boxes at 40 degrees C showed significant increases in oxidized and vinegar aromas and yellow color. Volatile esters also decreased in these wines, while increased levels of compounds generally associated with age- or heat-affected wine were found including 1,1,6-trimethyl-1,2-dihydronaphthalene and furfuryl ether, consistent with previously reported chemical aging reactions. In summary, storing unoaked Chardonnay in different packages significantly changes the sensory and chemical properties depending on the storage temperature. After a storage period of 3 months, bottle storage with various closures (natural cork, synthetic cork, and screw cap) changed the wine in a different way than bag-in-box storage. PMID- 23035912 TI - Chlorogenic acid and maize ear rot resistance: a dynamic study investigating Fusarium graminearum development, deoxynivalenol production, and phenolic acid accumulation. AB - Fusarium graminearum is the causal agent of Gibberella ear rot and produces trichothecene mycotoxins. Basic questions remain unanswered regarding the kernel stages associated with trichothecene biosynthesis and the kernel metabolites potentially involved in the regulation of trichothecene production in planta. In a two-year field study, F. graminearum growth, trichothecene accumulation, and phenolic acid composition were monitored in developing maize kernels of a susceptible and a moderately resistant variety using quantitative polymerase chain reaction and liquid chromatography coupled with photodiode array or mass spectrometry detection. Infection started as early as the blister stage and proceeded slowly until the dough stage. Then, a peak of trichothecene accumulation occurred and infection progressed exponentially until the final harvest time. Both F. graminearum growth and trichothecene production were drastically reduced in the moderately resistant variety. We found that chlorogenic acid is more abundant in the moderately resistant variety, with levels spiking in the earliest kernel stages induced by Fusarium infection. This is the first report that precisely describes the kernel stage associated with the initiation of trichothecene production and provides in planta evidence that chlorogenic acid may play a role in maize resistance to Gibberella ear rot and trichothecene accumulation. PMID- 23035913 TI - Aphid protein effectors promote aphid colonization in a plant species-specific manner. AB - Microbial pathogens and pests produce effectors to modulate host processes. Aphids are phloem-feeding insects, which introduce effectors via saliva into plant cells. However, it is not known if aphid effectors have adapted to modulate processes in specific plant species. Myzus persicae is a polyphagous insect that colonizes Arabidopsis thaliana and Nicotiana benthamiana, while the pea aphid Acyrthosiphon pisum specializes on colonizing plant species of the family Fabaceae. We found that M. persicae reproduction increased on transgenic Arabidopsis, producing the M. persicae effectors C002, PIntO1 (Mp1), and PIntO2 (Mp2), whereas reproduction of M. persicae did not increase on Arabidopsis producing the A. pisum orthologs of these three proteins. Plant-mediated RNA interference experiments showed that c002- and PIntO2-silenced M. persicae produce less progeny on Arabidopsis and N. benthamiana than nonsilenced aphids. Orthologs of c002, PIntO1, and PIntO2 were identified in multiple aphid species with dissimilar plant host ranges. We revealed high nonsynonymous versus synonymous nucleotide substitution rates within the effector orthologs, indicating that the effectors are fast evolving. Application of maximum likelihood methods identified specific sites with high probabilities of being under positive selection in PIntO1, whereas those of C002 and PIntO2 may be located in alignment gaps. In support of the latter, a M. persicae c002 mutant without the NDNQGEE repeat region, which overlaps with an alignment gap in C002, does not promote M. persicae colonization on Arabidopsis. Taken together, these results provide evidence that aphid effectors are under positive selection to promote aphid colonization on specific plant species. PMID- 23035914 TI - Identification and characterization of in planta-expressed secreted effector proteins from Magnaporthe oryzae that induce cell death in rice. AB - Interactions between rice and Magnaporthe oryzae involve the recognition of cellular components and the exchange of complex molecular signals from both partners. How these interactions occur in rice cells is still elusive. We employed robust-long serial analysis of gene expression, massively parallel signature sequencing, and sequencing by synthesis to examine transcriptome profiles of infected rice leaves. A total of 6,413 in planta-expressed fungal genes, including 851 genes encoding predicted effector proteins, were identified. We used a protoplast transient expression system to assess 42 of the predicted effector proteins for the ability to induce plant cell death. Ectopic expression assays identified five novel effectors that induced host cell death only when they contained the signal peptide for secretion to the extracellular space. Four of them induced cell death in Nicotiana benthamiana. Although the five effectors are highly diverse in their sequences, the physiological basis of cell death induced by each was similar. This study demonstrates that our integrative genomic approach is effective for the identification of in planta-expressed cell death inducing effectors from M. oryzae that may play an important role facilitating colonization and fungal growth during infection. PMID- 23035915 TI - Toward understanding the role of aphid effectors in plant infestation. AB - In recent years, immense progress has been made toward understanding the functions of effectors from a range of plant pathogens, such as oomycetes, fungi, bacteria, and nematodes. Like plant pathogens, aphids form close associations with host plants, featuring signal exchange between the two organisms. While feeding and probing, aphids deliver effector proteins mixed with saliva directly into the host-stylet interface. With the increasing availability of aphid genome and transcriptome sequence data, aphid effector biology is emerging as a new and exciting area of research. In this review, we provide an overview of recent advances in the aphid effector biology field and highlight some of the current questions. PMID- 23035916 TI - Spatial and orientation control of cylindrical nanostructures in ABA triblock copolymer thin films by raster solvent vapor annealing. AB - We present a spatially resolved approach for the solvent vapor annealing (SVA) of block copolymer thin films that permits the facile and relatively rapid manipulation of nanoscale ordering and nanostructure orientation. In our method, a localized (point) SVA zone is created through the use of a vapor delivery nozzle. This point annealing zone can be rastered across the thin film using a motorized stage to control the local nanoscale structure and orientation in a cylinder-forming ABA triblock copolymer thin film. At moderate rastering speeds (~100 MUm/s) (i.e., relatively modest annealing time at a given point), the film displayed ordered cylindrical nanostructures with the cylinders oriented parallel to the substrate surface. As the rastering speed was decreased (~10 MUm/s), the morphology transformed into a surface nanostructure indicative of cylinders oriented perpendicular to the substrate surface. These perpendicular cylinder orientations also were created by rastering multiple times over the same region, and this effect was found when rastering in either retrace (overlapping) or crossed-path (orthogonal) geometries. Similar trends in nanostructure orientation and ordering were obtained from various nozzle diameters by accounting for differences in solvent flux and annealing time, illustrating the universality of this approach. Finally, we note that our "stylus-based" raster solvent vapor annealing technique allows a given point to be solvent annealed approximately 2 orders of magnitude faster than conventional "bell jar" solvent vapor annealing. PMID- 23035917 TI - Effect of coexisting chronic obstructive pulmonary disease and cognitive impairment on health outcomes in older adults. AB - OBJECTIVES: To determine the extent to which the co-occurrence of chronic obstructive pulmonary disease (COPD) and cognitive impairment affect adverse health outcomes in older adults. DESIGN: Multicenter longitudinal cohort study. SETTING: California, Pennsylvania, Maryland, and North Carolina. PARTICIPANTS: Three thousand ninety-three community-dwelling adults aged 65 and older from the Cardiovascular Health Study. Four hundred thirty-one had chronic obstructive pulmonary disease (COPD) at study baseline. MEASUREMENTS: Follow-up began at the second CHS visit and continued for 3 years. Spirometric criteria for airflow limitation served to establish COPD using the Lambda-Mu-Sigma method, which accounts for age-related changes in lung function. Cognitive impairment was evaluated using the modified Mini-Mental State Examination and claims data. Outcomes were respiratory-related and all-cause hospitalizations and death. RESULTS: Participants with coexisting COPD and cognitive impairment had the highest rates of respiratory-related (adjusted hazard ratio (aHR) = 4.10, 95% confidence interval (CI) = 1.86-9.05) and all-cause hospitalizations (aHR = 1.34, 95% CI = 1.00-1.80) and death (aHR = 2.29, 95% CI = 1.18-4.45). In particular, individuals with both conditions had a 48% higher rate of all-cause hospitalizations (adjusted synergy index (aSI) = 1.48, 95% CI = 0.19-11.31) and a rate of death nearly three times as high (aSI = 2.74, 95% CI = 0.43-17.32) as the sum of risks for each respective outcome associated with having COPD or cognitive impairment alone. Nevertheless, tests for interaction were not statistically significant for the presence of synergism between the two conditions contributing to each of the outcomes. Therefore, it cannot be concluded that the combined effect of COPD and cognitive impairment is greater than additive. CONCLUSION: Coexisting COPD and cognitive impairment have an additive effect on respiratory related and all-cause hospitalizations and death. Optimizing outcomes in older adults with COPD and cognitive impairment will require that how to improve concurrent management of both conditions be determined. PMID- 23035918 TI - Chemistry, technology, and nutraceutical functions of cumin (Cuminum cyminum L): an overview. AB - Cumin is a seed spice belonging to the family umbelliferae. Cumin and value added products from cumin are used in food flavoring and perfumery. Cumin contains volatile oil (3-4%), cuminaldehyde, the major active principle, which is present to an extent of 45-50%. Cumin and value added products from cumin, viz., cumin oil and oleoresin are exported. Cumin powder forms the main component of many spice mixes and curry powders. Cuminaldehyde is an important phytochemical and possesses many health benefits. Alcohol and water extract of cumin are reported to possess many nutraceutical properties like antiallergic, antioxidant, anti platelet aggregation, and hypoglycemic. Cumin and value added products from cumin can be a good source of nutraceuticals with many biological activities. Incorporation of cumin into food products will have the benefits of a flavorant and nutraceutical at the same time. In the present review, the chemistry, processing, and biological activities of cumin and its components are discussed. PMID- 23035919 TI - Antibiotic-resistant bacteria: a challenge for the food industry. AB - Antibiotic-resistant bacteria were first described in the 1940s, but whereas new antibiotics were being discovered at a steady rate, the consequences of this phenomenon were slow to be appreciated. At present, the paucity of new antimicrobials coming into the market has led to the problem of antibiotic resistance fast escalating into a global health crisis. Although the selective pressure exerted by the use of antibiotics (particularly overuse or misuse) has been deemed the major factor in the emergence of bacterial resistance to these antimicrobials, concerns about the role of the food industry have been growing in recent years and have been raised at both national and international levels. The selective pressure exerted by the use of antibiotics (primary production) and biocides (e.g., disinfectants, food and feed preservatives, or decontaminants) is the main driving force behind the selection and spread of antimicrobial resistance throughout the food chain. Genetically modified (GM) crops with antibiotic resistance marker genes, microorganisms added intentionally to the food chain (probiotic or technological) with potentially transferable antimicrobial resistance genes, and food processing technologies used at sub lethal doses (e.g., alternative non-thermal treatments) are also issues for concern. This paper presents the main trends in antibiotic resistance and antibiotic development in recent decades, as well as their economic and health consequences, current knowledge concerning the generation, dissemination, and mechanisms of antibacterial resistance, progress to date on the possible routes for emergence of resistance throughout the food chain and the role of foods as a vehicle for antibiotic-resistant bacteria. The main approaches to prevention and control of the development, selection, and spread of antibacterial resistance in the food industry are also addressed. PMID- 23035920 TI - Impact of diet on breast cancer risk: a review of experimental and observational studies. AB - Breast cancer, which presents the highest global incidence of all female cancers, is caused by the interaction of genetic and environmental factors. Among the latter, diet has attracted considerable attention, as it is a modifiable risk factor and thus offers an opportunity to design preventive strategies. Nevertheless, only alcohol consumption has been unequivocally related to increased breast cancer risk. Despite the failure of observational studies in human populations to clearly define the nature of the relationship between specific nutrient exposures and breast cancer risk, in vivo and in vitro studies strongly suggest its existence. Moreover, studies at the molecular level have identified the putative action mechanism by which the nutritional constituents of specific foodstuffs may exert protective or enhancing effects with respect to breast cancer risk. The inadequate experimental design of some observational studies, or the occurrence of measurement errors and/or recall bias during data collection, or insufficient follow-up and subject characterization, may underlie these controversies. By improving the methods used to study the relationship between diet and breast cancer risk, and by applying new technologies linked to novel approaches such as "nutrigenomics," it might be possible to derive effective recommendations for breast cancer prevention and thus improve anti cancer treatment. PMID- 23035921 TI - Bioaccessibility of nutrients and micronutrients from dispersed food systems: impact of the multiscale bulk and interfacial structures. AB - Many food systems are dispersed systems, that is, they possess at least two immiscible phases. This is generally due to the coexistence of domains with different physicochemical properties separated by many interfaces which control the apparent thermodynamic equilibrium. This feature was and is still largely studied to design pharmaceutical delivery systems. In food science, the recent intensification of in vitro digestion tests to complement the in vivo ones holds promises in the identification of the key parameters controlling the bioaccessibility of nutrients and micronutrients. In this review, we present the developments of in vitro digestion tests for dispersed food systems (mainly emulsions, dispersions and gels). We especially highlight the evidences detailing the roles of the constituting multiscale structures. In a perspective section, we show the potential of structured interfaces to allow controlled bioaccessibility. PMID- 23035922 TI - Inhibition of immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion by injected leptin in rats. AB - Leptin, originally identified as an anti-obesity hormone, also has an important role in the regulation of mood and emotion. The present study was designed to monitor effects of injected leptin on immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion in rats. Exposure to 2 h immobilization stress decreased food intake and body weight in saline-injected animals. Animals exposed to open field, elevated plus maze, and light-dark transition tests the day following immobilization exhibited anxiety-like behavior. Leptin injected at doses of 0.1 and 0.5 mg/kg also decreased food intake and body weight in unstressed animals and elicited anxiolytic effects at dose of 0.5 mg/kg, monitored on the following day. Immobilization-induced decreases in food intake, body weight, as well as stress-induced behavioral deficits in the open field, elevated plus maze, and light-dark transition test were reversed by exogenous leptin in a dose-dependent (0.1-0.5 mg/kg) manner. Acute exposure to 2 h immobilization produced a fourfold rise in plasma levels of corticosterone. Animals injected with leptin at a dose of 0.1 mg/kg, but not at dose of 0.5 mg/kg, exhibited a marginal increase in plasma corticosterone. Immobilization-induced increases of plasma corticosterone were reversed by leptin injected at doses of 0.1 or 0.5 mg/kg. The data suggest that exogenous leptin can reduce stress perception, resulting in an inhibition of stress effects on the activity of hypothalamic-pituitary-adrenal axis and behavior. The reported pharmacological effects of leptin represent an innovative approach for the treatment of stress-related disorders. PMID- 23035923 TI - The use of daily aspirin, nutritional supplements and alternative medications among Amish and non-Amish living in Ohio Appalachia. AB - The purpose of this study was to assess daily aspirin and supplement use among Amish and non-Amish adults living in Ohio Appalachia to understand their potential contribution to lower cancer incidence rates among the Amish. A cross sectional study was conducted with random samples of 134 Amish adults and 154 non Amish adults. Face-to-face interviews about cancer-related behaviors included questions regarding aspirin and supplement use. Amish compared to non-Amish adults reported 1) taking significantly (P < 0.05) more supplements [mean number of daily products by Amish males (3.5 +/- 3.7) and females (5.2 +/- 4.3) vs. non Amish males (1.4 +/- 1.3) and females (3.0 +/- 3.2)]; 2) taking significantly (P < 0.05) more vitamins, minerals, fiber supplements (females only), and enzymes (females only); 3) taking significantly (P < 0.01) more herbal supplements (approximately 55% and 71% of Amish males and females vs. 17% and 23% of non Amish males and females, respectively); and 4) taking significantly (P < 0.05) less aspirin on a regular basis. Aspirin and supplement use among Amish and non Amish adults show significant differences characteristic of their social and cultural norms. Future studies that clarify the impact of aspirin and supplement use among the Amish and their impacts upon the risk of certain cancers and other disease processes are warranted. PMID- 23035924 TI - Renal function is impaired in small for gestational age premature infants. AB - OBJECTIVES: Small for gestational age (SGA) premature infants are at increased risk for complications. We aimed to evaluate if SGA infants are at higher risk for presenting renal insufficiency in the newborn period compared to appropriate for gestational age (AGA) premature infants. METHODS: We conducted a retrospective case-control study of infants <= 34 weeks gestation. Markers of renal function based upon the Acute Kidney Injury Network were compared between both groups. RESULTS: Twenty SGA infants were compared to twenty AGA infants matching in sex and gestational age. SGA infants had higher serum creatinine on day of life (DOL) 1 (p = 0.014) and DOL 3 (p = 0.05) and a higher overall maximum creatinine concentration (p = 0.013). They were also more likely to have an increase in serum creatinine more than 0.3 mg/dL in a 48-h period (OR: 7.8, p = 0.008) and increase in serum creatinine more than 50% in a 48-h period (OR: 12.4, p = 0.002). Urine output (mL/kg/h) was significantly less in the SGA group on DOL 3 (p = 0.002) and DOL 7 (p = 0.017). CONCLUSIONS: SGA infants are at increased risk for renal insufficiency during the neonatal period, thereby implying the need for special considerations in their fluid and medication management. PMID- 23035925 TI - Load emphasizes muscle effort minimization during selection of arm movement direction. AB - BACKGROUND: Directional preferences during center-out horizontal shoulder-elbow movements were previously established for both the dominant and non-dominant arm with the use of a free-stroke drawing task that required random selection of movement directions. While the preferred directions were mirror-symmetrical in both arms, they were attributed to a tendency specific for the dominant arm to simplify control of interaction torque by actively accelerating one joint and producing largely passive motion at the other joint. No conclusive evidence has been obtained in support of muscle effort minimization as a contributing factor to the directional preferences. Here, we tested whether distal load changes directional preferences, making the influence of muscle effort minimization on the selection of movement direction more apparent. METHODS: The free-stroke drawing task was performed by the dominant and non-dominant arm with no load and with 0.454 kg load at the wrist. Motion of each arm was limited to rotation of the shoulder and elbow in the horizontal plane. Directional histograms of strokes produced by the fingertip were calculated to assess directional preferences in each arm and load condition. Possible causes for directional preferences were further investigated by studying optimization across directions of a number of cost functions. RESULTS: Preferences in both arms to move in the diagonal directions were revealed. The previously suggested tendency to actively accelerate one joint and produce passive motion at the other joint was supported in both arms and load conditions. However, the load increased the tendency to produce strokes in the transverse diagonal directions (perpendicular to the forearm orientation) in both arms. Increases in required muscle effort caused by the load suggested that the higher frequency of movements in the transverse directions represented increased influence of muscle effort minimization on the selection of movement direction. This interpretation was supported by cost function optimization results. CONCLUSIONS: While without load, the contribution of muscle effort minimization was minor, and therefore, not apparent, the load revealed this contribution by enhancing it. Unlike control of interaction torque, the revealed tendency to minimize muscle effort was independent of arm dominance. PMID- 23035926 TI - The 20-year public health impact and direct cost of testosterone deficiency in U.S. men. AB - INTRODUCTION: Testosterone deficiency (TD) imposes a substantial public health burden in the U.S. We modeled the costs associated with TD-related sequelae including cardiovascular disease (CVD), diabetes mellitus (DM), and osteoporosis related fractures (ORFs). AIM: To quantify the incremental cost burden imposed by TD's cardiometabolic sequelae. METHOD: Incidence, prevalence, and mortality of these conditions were collected for men ages 45-74 from six national databases and large cross-sectional studies. Relative risk (RR) rates were determined for these sequelae in patients with T < 300 ng/dL. The prevalence of TD was determined for this cohort of men. MAIN OUTCOME MEASURES: Adjusted incidence and prevalence were determined. Annual costs for the three TD-related sequelae were inflated at a real rate of 3% for 20 years. RESULTS: Actual and adjusted (normalized for T deficiency) rates of CVD, DM, and ORFs in U.S. men aged 45-74 assuming a TD prevalence of 13.4% were calculated. We determined that, over a 20 year period, T deficiency is projected to be involved in the development of approximately 1.3 million new cases of CVD, 1.1 million new cases of DM, and over 600,000 ORFs. In year 1, the attributed cost burden of these diseases was approximately $8.4 billion. Over the entire 20-year period, T deficiency may be directly responsible for approximately $190-$525 billion in inflation-adjusted U.S. health care expenditures. CONCLUSION: TD may be a significant contributor to adverse public health. Further study is needed to definitively describe the whether TD is a modifiable risk factor for CVD, DM, and ORFs. This may represent an opportunity for nationwide public health initiatives aimed at preventive care. PMID- 23035927 TI - Controlling pH-regulated bionanoparticles translocation through nanopores with polyelectrolyte brushes. AB - A novel polyelectrolyte (PE)-modified nanopore, comprising a solid-state nanopore functionalized by a nonregulated PE brush layer connecting two large reservoirs, is proposed to regulate the electrokinetic translocation of a soft nanoparticle (NP), comprising a rigid core covered by a pH-regulated, zwitterionic, soft layer, through it. The type of NP considered mimics bionanoparticles such as proteins and biomolecules. We find that a significant enrichment of H(+) occurs near the inlet of a charged solid-state nanopore, appreciably reducing the charge density of the NP as it approaches there, thereby lowering the NP translocation velocity and making it harder to thread the nanopore. This difficulty can be resolved by the proposed PE-modified nanopore, which raises effectively both the capture rate and the capture velocity of the soft NP and simultaneously reduces its translocation velocity through the nanopore so that both the sensing efficiency and the resolution are enhanced. The results gathered provide a conceptual framework for the interpretation of relevant experimental data and for the design of nanopore-based devices used in single biomolecules sensing and DNA sequencing. PMID- 23035928 TI - Cardiovascular risk management in patients with coronary heart disease in primary care: variation across countries and practices. An observational study based on quality indicators. AB - BACKGROUND: Primary care has an important role in cardiovascular risk management (CVRM) and a minimum size of scale of primary care practices may be needed for efficient delivery of CVRM . We examined CVRM in patients with coronary heart disease (CHD) in primary care and explored the impact of practice size. METHODS: In an observational study in 8 countries we sampled CHD patients in primary care practices and collected data from electronic patient records. Practice samples were stratified according to practice size and urbanisation; patients were selected using coded diagnoses when available. CVRM was measured on the basis of internationally validated quality indicators. In the analyses practice size was defined in terms of number of patients registered of visiting the practice. We performed multilevel regression analyses controlling for patient age and sex. RESULTS: We included 181 practices (63% of the number targeted). Two countries included a convenience sample of practices. Data from 2960 CHD patients were available. Some countries used methods supplemental to coded diagnoses or other inclusion methods introducing potential inclusion bias. We found substantial variation on all CVRM indicators across practices and countries. We computed aggregated practice scores as percentage of patients with a positive outcome. Rates of risk factor recording varied from 55% for physical activity as the mean practice score across all practices (sd 32%) to 94% (sd 10%) for blood pressure. Rates for reaching treatment targets for systolic blood pressure, diastolic blood pressure and LDL cholesterol were 46% (sd 21%), 86% (sd 12%) and 48% (sd 22%) respectively. Rates for providing recommended cholesterol lowering and antiplatelet drugs were around 80%, and 70% received influenza vaccination. Practice size was not associated to indicator scores with one exception: in Slovenia larger practices performed better. Variation was more related to differences between practices than between countries. CONCLUSIONS: CVRM measured by quality indicators showed wide variation within and between countries and possibly leaves room for improvement in all countries involved. Few associations of performance scores with practice size were found. PMID- 23035929 TI - DMET-analyzer: automatic analysis of Affymetrix DMET data. AB - BACKGROUND: Clinical Bioinformatics is currently growing and is based on the integration of clinical and omics data aiming at the development of personalized medicine. Thus the introduction of novel technologies able to investigate the relationship among clinical states and biological machineries may help the development of this field. For instance the Affymetrix DMET platform (drug metabolism enzymes and transporters) is able to study the relationship among the variation of the genome of patients and drug metabolism, detecting SNPs (Single Nucleotide Polymorphism) on genes related to drug metabolism. This may allow for instance to find genetic variants in patients which present different drug responses, in pharmacogenomics and clinical studies. Despite this, there is currently a lack in the development of open-source algorithms and tools for the analysis of DMET data. Existing software tools for DMET data generally allow only the preprocessing of binary data (e.g. the DMET-Console provided by Affymetrix) and simple data analysis operations, but do not allow to test the association of the presence of SNPs with the response to drugs. RESULTS: We developed DMET Analyzer a tool for the automatic association analysis among the variation of the patient genomes and the clinical conditions of patients, i.e. the different response to drugs. The proposed system allows: (i) to automatize the workflow of analysis of DMET-SNP data avoiding the use of multiple tools; (ii) the automatic annotation of DMET-SNP data and the search in existing databases of SNPs (e.g. dbSNP), (iii) the association of SNP with pathway through the search in PharmaGKB, a major knowledge base for pharmacogenomic studies. DMET-Analyzer has a simple graphical user interface that allows users (doctors/biologists) to upload and analyse DMET files produced by Affymetrix DMET-Console in an interactive way. The effectiveness and easy use of DMET Analyzer is demonstrated through different case studies regarding the analysis of clinical datasets produced in the University Hospital of Catanzaro, Italy. CONCLUSION: DMET Analyzer is a novel tool able to automatically analyse data produced by the DMET platform in case-control association studies. Using such tool user may avoid wasting time in the manual execution of multiple statistical tests avoiding possible errors and reducing the amount of time needed for a whole experiment. Moreover annotations and the direct link to external databases may increase the biological knowledge extracted. The system is freely available for academic purposes at: https://sourceforge.net/projects/dmetanalyzer/files/ PMID- 23035930 TI - Revisions of the Fish Invasiveness Screening Kit (FISK) for its application in warmer climatic zones, with particular reference to peninsular Florida. AB - The initial version (v1) of the Fish Invasiveness Scoring Kit (FISK) was adapted from the Weed Risk Assessment of Pheloung, Williams, and Halloy to assess the potential invasiveness of nonnative freshwater fishes in the United Kingdom. Published applications of FISK v1 have been primarily in temperate-zone countries (Belgium, Belarus, and Japan), so the specificity of this screening tool to that climatic zone was not noted until attempts were made to apply it in peninsular Florida. To remedy this shortcoming, the questions and guidance notes of FISK v1 were reviewed and revised to improve clarity and extend its applicability to broader climatic regions, resulting in changes to 36 of the 49 questions. In addition, upgrades were made to the software architecture of FISK to improve overall computational speed as well as graphical user interface flexibility and friendliness. We demonstrate the process of screening a fish species using FISK v2 in a realistic management scenario by assessing the Barcoo grunter Scortum barcoo (Terapontidae), a species whose management concerns are related to its potential use for aquaponics in Florida. The FISK v2 screening of Barcoo grunter placed the species into the lower range of medium risk (score = 5), suggesting it is a permissible species for use in Florida under current nonnative species regulations. Screening of the Barcoo grunter illustrates the usefulness of FISK v2 as a proactive tool serving to inform risk management decisions, but the low level of confidence associated with the assessment highlighted a dearth of critical information on this species. PMID- 23035932 TI - Abstracts of the 37th European Congress of Cytopathology. September 30-October 3, 2012. Dubrovnik-Cavtat, Croatia. PMID- 23035931 TI - Contribution of phage-derived genomic islands to the virulence of facultative bacterial pathogens. AB - Facultative pathogens have extremely dynamic pan-genomes, to a large extent derived from bacteriophages and other mobile elements. We developed a simple approach to identify phage-derived genomic islands and apply it to show that pathogens from diverse bacterial genera are significantly enriched in clustered phage-derived genes compared with related benign strains. These findings show that genome expansion by integration of prophages containing virulence factors is a major route of evolution of facultative bacterial pathogens. PMID- 23035933 TI - What are the most important factors for work participation in the young disabled? An expert view. AB - PURPOSE: To define the most important factors for the work participation of the young disabled according to experts. METHOD: A Delphi study was conducted with internet questionnaires. Health-related, personal and environmental factors known from literature were presented to insurance physicians and labour experts. The experts assessed whether a factor was important for the work participation of the young disabled. New factors added by the experts in the first round were assessed in the second round. Factors assessed as important by at least 80% of the experts were input for the last round, in which the experts chose the ten most important factors. RESULTS: Participation included 156 experts in the first round and 91 experts in the last round. They selected 44 of 92 factors as important. Severity of limitations, type of limitations and motivation were placed by more than 55% of the experts on their top-ten list to be assessed in a plan to help the young disabled participate in work. CONCLUSION: Severity and type of limitations and motivation are considered to be the most important factors for the work participation of the young disabled and should be included in a participation plan. PMID- 23035934 TI - Sensitization of Candida albicans biofilms to various antifungal drugs by cyclosporine A. AB - BACKGROUND: Biofilms formed by Candida albicans are resistant towards most of the available antifungal drugs. Therefore, infections associated with Candida biofilms are considered as a threat to immunocompromised patients. Combinatorial drug therapy may be a good strategy to combat C. albicans biofilms. METHODS: Combinations of five antifungal drugs- fluconazole (FLC), voriconazole (VOR), caspofungin (CSP), amphotericin B (AmB) and nystatin (NYT) with cyclosporine A (CSA) were tested in vitro against planktonic and biofilm growth of C. albicans. Standard broth micro dilution method was used to study planktonic growth, while biofilms were studied in an in vitro biofilm model. A chequerboard format was used to determine fractional inhibitory concentration indices (FICI) of combination effects. Biofilm growth was analyzed using XTT-metabolic assay. RESULTS: MICs of various antifungal drugs for planktonic growth of C. albicans were lowered in combination with CSA by 2 to 16 fold. Activity against biofilm development with FIC indices of 0.26, 0.28, 0.31 and 0.25 indicated synergistic interactions between FLC-CSA, VOR-CSA, CSP-CSA and AmB-CSA, respectively. Increase in efficacy of the drugs FLC, VOR and CSP against mature biofilms after addition of 62.5 MUg/ml of CSA was evident with FIC indices 0.06, 0.14 and 0.37, respectively. CONCLUSIONS: The combinations with CSA resulted in increased susceptibility of biofilms to antifungal drugs. Combination of antifungal drugs with CSA would be an effective prophylactic and therapeutic strategy against biofilm associated C. albicans infections. PMID- 23035935 TI - Coronary venous retention-a feature in heart failure as evidenced by mean of cardiac computed tomography. AB - BACKGROUND: Whether the functional status of the heart can influence the coronary venous system itself has not yet been examined. In order to answer this question, we used multislice computed tomography (CT) imaging. PURPOSE: To answer the question of whether the heart failure (HF) is associated with significant anatomical changes in the coronary venous system? METHODS: In 136 (aged 56.6 +/- 11.5) patients, a 64-slice CT was performed. Patients were divided into three groups according their ejection fraction. In each case, nine 3D volume rendering reconstructions, using a 2-mm layer with electrocardiographic-gating, were created at 0% to 90% R-R intervals (step 10%). The visualization of coronary veins (CVs) was graded independently by two experts trained in multislice computed tomography on a 0-5 point scale (0-not visible/lack of vein; 5-smoothly bordered vascular structure). RESULTS: The average number of visible CVs per case was 3.44 in the HF group and 2.72 in patients with a normal ejection fraction (P = 0.0246). The statistical correlation between a reduction in ejection fraction and the increase in the number of veins was found (r =-0.2446, P < 0.05). For two of seven common variants of the coronary venous system at least two target veins (posterolateral and lateral) for cardiac resynchronization were presented. CONCLUSIONS: The statistically higher number of veins in patients with heart failure may suggest an association between a failing heart and cardiac venous retention. PMID- 23035936 TI - Association of catechol-o-methyltransferase polymorphism (Val108/158Met) with Parkinson's disease: a meta-analysis. AB - Parkinson's disease (PD) is a common neurodegenerative disease, the risk factors of which are gaining more attentions. Among all these risk factors, catechol-o methyltransferase (COMT) has been widely studied, and believed to be associated with PD. However, the relationship between COMT polymorphism and PD has not been confirmed hitherto. Therefore, a meta-analysis was performed to evaluate the effect of COMT polymorphism on PD patients. A total of 24 study subjects comprising 3,807 patients with PD and 3,942 unrelated healthy controls were recruited in this meta-analysis. Heterogeneity testing and sensitivity analysis were conducted with Review Manager 5.0 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Stata software (StataCorp, College Station, TX), together with publication bias by funnel plot method and modified Egger's linear regression test. No evidences of publication bias and heterogeneity were detected. In the 24 studies, the estimated odds ratios (OR) in PD patients are 0.98 for the Met allele (95% confidence interval [0.92, 1.05]) under a fixed-effects model. The authors also conducted a stratified analysis according to geographic region among Europe, Asia, and North America, the ORs for the Met allele are 0.92, 1.02, and 1.10, respectively. According to the results of the meta-analysis, a conclusion could be drawn that polymorphism of Val108/158Met are not associated with the risk of PD. However, more convincing studies are warranted to have a solid conclusion supported. PMID- 23035937 TI - Speciation of Zn in blast furnace sludge from former sedimentation ponds using synchrotron X-ray diffraction, fluorescence, and absorption spectroscopy. AB - Blast furnace sludge (BFS), an industrial waste generated in pig iron production, typically contains high contents of iron and various trace metals of environmental concern, including Zn, Pb, and Cd. The chemical speciation of these metals in BFS is largely unknown. Here, we used a combination of synchrotron X ray diffraction, micro-X-ray fluorescence, and X-ray absorption spectroscopy at the Zn K-edge for solid-phase Zn speciation in 12 BFS samples collected on a former BFS sedimentation pond site. Additionally, one fresh BFS was analyzed for comparison. We identified five major types of Zn species in the BFS, which occurred in variable amounts: (1) Zn in the octahedral sheets of phyllosilicates, (2) Zn sulfide minerals (ZnS, sphalerite, or wurtzite), (3) Zn in a KZn ferrocyanide phase (K(2)Zn(3)[Fe(CN)(6)](2).9H(2)O), (4) hydrozincite (Zn(5)(OH)(6)(CO(3))(2)), and (5) tetrahedrally coordinated adsorbed Zn. The minerals franklinite (ZnFe(2)O(4)) and smithsonite (ZnCO(3)) were not detected, and zincite (ZnO) was detected only in traces. The contents of ZnS were positively correlated with the total S contents of the BFS. Similarly, the abundance of the KZn-ferrocyanide phase was closely correlated with the total CN contents, with the stoichiometry suggesting this as the main cyanide phase. This study provides the first quantitative Zn speciation in BFS deposits, which is of great relevance for environmental risk assessment, the development of new methods for recovering Zn and Fe from BFS, and potential applications of BFS as sorbent materials in wastewater treatment. PMID- 23035938 TI - Serious diarrhea with weight loss caused by Capillaria philippinensis acquired in China: a case report. AB - BACKGROUND: Diarrhea caused by Capillaria philippinensis (C. philippinensis) has not been reported in any areas with the exception of Taiwan province in China. We herein report the misdiagnosis and subsequent management of a patient with diarrhea caused by C. philippinensis. CASE PRESENTATION: A 33-year-old woman from the outskirts of Danzhou city, Hainan province, China, had an 11-month history of chronic diarrhea with abdominal pain, edema, hypoalbuminemia, and severe weight loss. The patient was misdiagnosed at an outpatient clinic and one hospital. She was finally correctly diagnosed with C. philippinensis by stool examination. The patient was given a 30-days course of albendazole (400 mg/day) and had an uneventful and stable recovery. CONCLUSION: Doctors cannot lose sight of patients' dietary histories, must query stool examination results, and need to expand their knowledge of certain nonlocal and global diseases, especially those described in new case reports. Some diagnostic examinations must be performed repeatedly. Hainan province may be the epidemic focus of C. philippinensis. PMID- 23035939 TI - Optimizing blood pressure control in hypertension: the need to use ABPM. AB - Hypertension is the most prevalent, treatable cause of cardiovascular (CV) disease. Patients with hypertension and one or more comorbidities increasingly form a significant part of the primary care practitioner's caseload. The emphasis on intensive blood pressure (BP) lowering has softened, encouraging any degree of BP lowering, since any fall in BP is beneficial for reducing CV risk. Consistency of BP control during long-term therapy (i.e. low visit-to-visit variability) and decreasing BP variability over 24-h may be as, if not more, important than degree of BP lowering per se. Fluctuations in BP between visits as well as within a 24-h period have been associated with increased CV risk. Ambulatory BP monitoring (ABPM) is a crucial element of the clinician's armamentarium not only for assessing the "true" BP load and fluctuations under real-life conditions but for identification of various abnormal BP patterns that may require attention, including white- coat hypertension, masked hypertension, non-dipping and the morning BP surge. ABPM provides accurate assessment of treatment effectiveness over 24-h and may lead to better tailoring of therapy. This article reviews the benefits of ABPM and discusses the importance of selecting long-acting antihypertensive agents for optimizing BP control. PMID- 23035941 TI - Novel route of tannic acid biotransformation and their effect on major biopolymer synthesis in Azotobacter sp. SSB81. AB - AIMS: To examine tannic acid (TA) utilization capacity by nitrogen-fixing bacteria, Azotobacter sp. SSB81, and identify the intermediate products during biotransformation. Another aim of this work is to investigate the effects of TA on major biopolymers like extracellular polysaccharide (EPS) and polyhydroxybutyrate (PHB) synthesis. METHODS AND RESULTS: Tannic acid utilization and tolerance capacity of the strain was determined according to CLSI method. Intermediate products were identified using high-performance liquid chromatography, LC-MS/MS and (1) H NMR analysis. Intermediates were quantified by multiple reactions monitoring using LC-MS/MS. The strain was able to tolerate a high level of TA and utilized through enzymatic system. Growth of Azotobacter in TA-supplemented medium was characterized by an extended lag phase and decreased growth rate. Presence of TA catalytic enzymes as tannase, polyphenol oxidase (PPO) and phenol decarboxylase was confirmed in cell lysate using their specific substrates. PPO activity was more prominent in TA-supplemented mineral medium after 48 h of growth when gallic to ellagic acid (EA) reversible reaction was remarkable. Phase contrast and scanning electron microscopic analysis revealed elongated and irregular size of Azotobacter cells in response to TA. (1) H NMR analysis indicated that TA was transformed into gallic acid (GA), EA and pyrogallol. Biopolymer (EPS and PHB) production was decreased several folds in the presence of TA compared with cells grown in only glucose medium. CONCLUSIONS: This is the first evidence on the biotransformation of TA by Azotobacter and also elevated level of EA production from gallotannins. Azotobacter has developed the mechanism to utilize TA for their carbon and energy source. SIGNIFICANCE AND IMPACT OF THE STUDY: The widespread occurrence and exploitation of Azotobacter sp. strain SSB81 in agricultural and forest soil have an additional advantage to utilize the soil-accumulated TA and detoxifies the allelopathic effect of constant accumulated TA in soil. PMID- 23035942 TI - Oxidative stability of (-)-epigallocatechin gallate in the presence of thiols. AB - Polyphenols are attractive ingredients due to their purported health benefits, but their addition to foods is limited by their chemical instability, as they are rapidly oxidized under many conditions. This oxidation not only compromises the potential biological activity of the phenolic compound, but can also affect the chemical stability of the surrounding food matrix. Polyphenols bearing catechol or gallate groups, when oxidized to their benzoquinone forms, are strong electrophiles capable of reacting with nucleophilic thiols via 1,4-Michael addition reactions. These reactions are known to proceed in foods during processing and storage, and can profoundly affect the quality and biological efficacy of polyphenols when they are added as functional food ingredients. The stability of (-)-epigallocatechin gallate (EGCG) in the presence of three thiol containing species [cysteine (Cys), glutathione (GSH), 3-mercaptohexan-1-ol (3SH)] was followed under both neutral and acidic conditions. Both Cys and GSH increased the rate of EGCG oxidation at pH 4. At pH 7, only Cys was found to increase the rate of EGCG oxidation. On the basis of these results, the reactivity of thiols toward EGCG follows the trend: Cys > GSH > 3SH, which is consistent with observed thiol-quinone adduct formation rates. Contrary to the results observed for Cys and GSH, 3SH was observed to inhibit EGCG oxidation. PMID- 23035943 TI - Resveratrol analog 4-[2-(3,5-dimethoxyphenyl)vinyl]pyridine reduces differentiation of the 3T3-L1 adipocyte. AB - CONTEXT: Resveratrol (3,5,4'-trihydroxystilbene) is a phytoalexin synthesized by plants, most notably grapes, against microbial invasion or ultraviolet stimulation, and is known to exert antioxidant, anticancer, and antiobesity effects. OBJECTIVE: This study was conducted to find resveratrol derivatives with higher anti-obesity activity compared to resveratrol and to verify their mechanism of action. MATERIALS AND METHODS: The inhibitory effect of resveratrol and its derivatives on adipocyte differentiation in 3T3-L1 cells was studied using Oil Red O staining, and the effects on the intracellular expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) were measured via Western blot analysis. RESULTS: A derivative of resveratrol, 4-[2-(3,5 dimethoxyphenyl)vinyl]pyridine (DPVP), exerted inhibitory effects against 3T3-L1 adipocyte differentiation (IC(50) = 13.5 uM) and FAS expression. Notably, it displayed higher activity at concentrations lower than 25 uM compared to resveratrol. DISCUSSION AND CONCLUSION: DPVP is considered to have greater potential as an anti-obesity substance, as it exhibits excellent activity at low concentrations compared to resveratrol. PMID- 23035944 TI - Cytogenetic characterization reveals differences in nuclear organization of cystic cells among Brazilian species of Triatoma (Heteroptera, Reduviidae). AB - Cytogenetic studies in triatomines have described the occurrence of holokinetic chromosomes, heterochromatin distribution and the location of rDNA (ribosomal DNA) sites, but few aspects of nuclear organization in this group have been discussed. We have focused on ultrastructural and cytogenetic features and differences in cystic cells of seminiferous tubules between five species of Triatoma. Cystic cells showed evidence of polyploidy events and heterochromatic blocks appeared predominantly in the central region of the nuclei. Cytogenetic analyses showed that there was variation in chromocenter number between species, and that the central regions were AT-rich [DAPI+ (4',6-diamidino-2 phenylindole+)], whereas the periphery was CG-rich (CMA+). Another characteristic was the distribution of 45S rDNA, which differed according to the chromosomal location of this sequence. In all we have compared aspects of nuclear organization, polyploidy, heterochromatin, rDNA site distribution and methylation levels, as well as the relationships between five species of Triatoma from a cystic cell perspective. PMID- 23035946 TI - Increased incidence of metabolic syndrome in older men with high normotension. AB - INTRODUCTION: Hypertension and prehypertension are correlated with future cardiovascular disease (CVD) and diabetes. Whether these harmful effects of the blood pressure (BP) could be found in normotensive is of interest. METHODS: In this cross-sectional study, totally 2388 normotensive older men aged 65-80 years undergoing routine health examinations were enrolled. To eliminate the influence of age on BP, subjects were initially grouped in each age stratum. Then in each age-stratum, subjects were further grouped into low, middle and high-tertile systolic BP (SBP) subgroups. Finally, all the low-tertile subgroups in each age stratum were gathered to form Group-1. Similarly, Group-2 (middle-tertile) and Group-3 (high-tertile) were also created. Metabolic syndrome (MetS) was regarded as having risks for future CVD and diabetes. RESULTS: Age, waist circumstance (WC), fasting plasma glucose (FPG) and log triglyceride (TG) were independently and significantly correlated with SBP by multiple linear regression analysis. On the other hand, logistic regression showed that Group-3 had significant higher odds ratios (ORs) for having abnormal WC, FPG and TG. In addition, Group-3 presented a 1.55-fold OR (p < 0.001) for having MetS than Group-1. CONCLUSIONS: In normotensive older men, the risk for having MetS was significantly associated with higher SBP. Primary prevention of hypertension should be stressed. PMID- 23035945 TI - Prevalence and factors associated with condom use among Chinese monogamous female patients with sexually transmitted infection in Hong Kong. AB - INTRODUCTION: Monogamous female sexually transmitted infection (STI) patients are at high risk of recurrent STI, but there is no study investigating their risk behaviors. AIM: We investigated the prevalence of male condom use and associated factors among monogamous STI female patients. MAIN OUTCOME MEASURES: Independent variables included socio-demographic characteristics, STI history, nature of relationship, and cognitions (Health Belief Model). Dependent variables included the use of male condoms in the past two months and intention to use male condoms consistently in the future 6 months. METHODS: A cross-sectional survey using a structured questionnaire was conducted among STI female patients with only one male sex partner in the last 12 months and attended a major government STI clinic in Hong Kong. RESULTS: Among the 538 participants, 25.1% used condoms consistently (every time) during sex in the past 2 months, while 35.2% intended to do so in the next 6 months. A multiple stepwise logistic regression model identified three statistically significant factors associated with lower likelihoods of consistent condom use in the past 2 months: type of sole sex partner (cohabitant vs. husband: OR = 0.29, 95% CI = 0.12 to 0.70; regular boyfriend vs. husband: OR = 0.52, 95% CI = 0.30 to 0.91), being financially dependent (OR = 0.45, 95% CI = 0.27 to 0.75), and partner's dislike of condom use (OR = 0.23, 95% CI = 0.15 to 0.39). In a similar model, the same three factors were found to be significantly associated with the intention to use condoms consistently in the next 6 months. The low prevalence of intention to use condoms consistently in the future suggested that our study population might be victimized again. The impact of financially dependent relationships and men's dislike of using condoms on condom use may operate through imbalanced gender power. CONCLUSIONS: Interventions are greatly warranted and should increase risk awareness and empower this vulnerable population. PMID- 23035947 TI - Facially selective Cu-catalyzed carbozincation of cyclopropenes using arylzinc reagents formed by sequential I/Mg/Zn exchange. AB - Described is a Cu-catalyzed directed carbozincation of cyclopropenes with organozinc reagents prepared by I/Mg/Zn exchange. This protocol broadens the scope with respect to functional group tolerance and enables use of aryl iodide precursors, rather than purified diorganozinc precursors. Critical to diastereoselectivity of the carbozincation step is the removal of magnesium halide salts after transmetalation with ZnCl(2). PMID- 23035948 TI - A traveller presenting with severe melioidosis complicated by a pericardial effusion: a case report. AB - BACKGROUND: Burkholderia pseudomallei, the etiologic agent of melioidosis, is endemic to tropic regions, mainly in Southeast Asia and northern Australia. Melioidosis occurs only sporadically in travellers returning from disease-endemic areas. Severe clinical disease is seen mostly in patients with alteration of immune status. In particular, pericardial effusion occurs in 1-3% of patients with melioidosis, confined to endemic regions. To our best knowledge, this is the first reported case of melioidosis in a traveller complicated by a hemodynamically significant pericardial effusion without predisposing disease. CASE PRESENTATION: A 44-year-old Caucasian man developed pneumonia, with bilateral pleural effusions and complicated by a hemodynamically significant pericardial effusion, soon after his return from Thailand to Switzerland. Cultures from different specimens including blood cultures turned out negative. Diagnosis was only accomplished by isolation of Burkholderia pseudomallei from the pericardial aspirate, thus finally enabling the adequate antibiotic treatment. CONCLUSIONS: Melioidosis is a great mimicker and physicians in non endemic countries should be aware of its varied manifestations. In particular, melioidosis should be considered in differential diagnosis of pericardial effusion in travellers , even without risk factors predisposing to severe disease. PMID- 23035949 TI - DHA effect on chemotherapy-induced body weight loss: an exploratory study in a rodent model of mammary tumors. AB - Body weight loss during the course of cancer disease has been associated with poor prognosis. Beside cancer-associated cachexia, weight loss can also result from chemotherapy. This work explored whether a model of mammary tumors in female Sprague Dawley rats could be appropriate to study the effect of doxorubicin on body weight, described weight change in this model, and assessed the effect of DHA on weight during chemotherapy. After tumor induction, rats were randomly assigned to a control or a DHA-enriched diet, and treated with doxorubicin or placebo twice a week for 2.5 wk (n = 6 in each group). Body weight, food intake, and tumor growth were monitored. Neither the induction of tumors nor their initial development impaired body weight gain. No reduction in food intake was observed. Tumor growth was similar between groups from day 1 to day 11. Although doxorubicin induced body weight loss from day 4 compared to placebo (P< 0.01) in rats fed the control diet, it did not induce body weight loss in rats fed the DHA enriched diet (P = 0.02), indicating that DHA had a protective effect. These results indicate that doxorubicin can induce body weight loss in this model and that a DHA-enriched diet can prevent this effect. PMID- 23035950 TI - Improved nonlinearity-transparency-thermal stability trade-off with spirobifluorene-bridged donor-pi-acceptor chromophores. AB - A series of novel 9,9'-spirobifluorene-bridged donor-pi-acceptor chromophores containing triarylamine moieties were easily synthesized starting from the readily available reagent 4,4'-dimethylbiphenyl. These chromophores were found to combine excellent transparency in the visible region, high thermal stabilities, and large optical nonlinearity. PMID- 23035952 TI - Improving interunit transitions of care between emergency physicians and hospital medicine physicians: a conceptual approach. AB - Patient care transitions across specialties involve more complexity than those within the same specialty, yet the unique social and technical features remain underexplored. Further, little consensus exists among researchers and practitioners about strategies to improve interspecialty communication. This concept article addresses these gaps by focusing on the hand-off process between emergency and hospital medicine physicians. Sensitivity to cultural and operational differences and a common set of expectations pertaining to hand-off content will more effectively prepare the next provider to act safely and efficiently when caring for the patient. Through a consensus decision-making process of experienced and published authorities in health care transitions, including physicians in both specialties as well as in communication studies, the authors propose content and style principles clinicians may use to improve transition communication. With representation from both community and academic settings, similarities and differences between emergency medicine and internal medicine are highlighted to heighten appreciation of the values, attitudes, and goals of each specialty, particularly pertaining to communication. The authors also examine different communication media, social and cultural behaviors, and tools that practitioners use to share patient care information. Quality measures are proposed within the structure, process, and outcome framework for institutions seeking to evaluate and monitor improvement strategies in hand-off performance. Validation studies to determine if these suggested improvements in transition communication will result in improved patient outcomes will be necessary. By exploring the dynamics of transition communication between specialties and suggesting best practices, the authors hope to strengthen hand off skills and contribute to improved continuity of care. PMID- 23035951 TI - Upper extremity rehabilitation of stroke: facilitation of corticospinal excitability using virtual mirror paradigm. AB - BACKGROUND: Several experimental studies in stroke patients suggest that mirror therapy and various virtual reality programs facilitate motor rehabilitation. However, the underlying mechanisms for these therapeutic effects have not been previously described. OBJECTIVES: We attempted to delineate the changes in corticospinal excitability when individuals were asked to exercise their upper extremity using a real mirror and virtual mirror. Moreover, we attempted to delineate the role of visual modulation within the virtual environment that affected corticospinal excitability in healthy subjects and stroke patients. METHODS: A total of 18 healthy subjects and 18 hemiplegic patients were enrolled into the study. Motor evoked potential (MEP)s from transcranial magnetic stimulation were recorded in the flexor carpi radialis of the non-dominant or affected upper extremity using three different conditions: (A) relaxation; (B) real mirror; and (C) virtual mirror. Moreover, we compared the MEPs from the virtual mirror paradigm using continuous visual feedback or intermittent visual feedback. RESULTS: The rates of amplitude increment and latency decrement of MEPs in both groups were higher during the virtual mirror task than during the real mirror. In healthy subjects and stroke patients, the virtual mirror task with intermittent visual feedback significantly facilitated corticospinal excitability of MEPs compared with continuous visual feedback. CONCLUSION: Corticospinal excitability was facilitated to a greater extent in the virtual mirror paradigm than in the real mirror and in intermittent visual feedback than in the continuous visual feedback, in both groups. This provides neurophysiological evidence supporting the application of the virtual mirror paradigm using various visual modulation technologies to upper extremity rehabilitation in stroke patients. PMID- 23035953 TI - ppGpp controlled by the Gac/Rsm regulatory pathway sustains biocontrol activity in Pseudomonas fluorescens CHA0. AB - In Pseudomonas fluorescens CHA0 and other fluorescent pseudomonads, the Gac/Rsm signal transduction pathway is instrumental for secondary metabolism and biocontrol of root pathogens via the expression of regulatory small RNAs (sRNAs). Furthermore, in strain CHA0, an imbalance in the Krebs cycle can affect the strain's ability to produce extracellular secondary metabolites, including biocontrol factors. Here, we report the metabolome of wild-type CHA0, a gacA negative mutant, which has lost Gac/Rsm activities, and a retS-negative mutant, which shows strongly enhanced Gac/Rsm-dependent activities. Capillary electrophoresis-based metabolomic profiling revealed that the gacA and retS mutations had opposite effects on the intracellular levels of a number of central metabolites, suggesting that the Gac/Rsm pathway regulates not only secondary metabolism but also primary metabolism in strain CHA0. Among the regulated metabolites identified, the alarmone guanosine tetraphosphate (ppGpp) was characterized in detail by the construction of relA (for ppGpp synthase) and spoT (for ppGpp synthase/hydrolase) deletion mutants. In a relA spoT double mutant, ppGpp synthesis was completely abolished, the expression of Rsm sRNAs was attenuated, and physiological functions such as antibiotic production, root colonization, and plant protection were markedly diminished. Thus, ppGpp appears to be essential for sustaining epiphytic fitness and biocontrol activity of strain CHA0. PMID- 23035954 TI - The pathogenic white-rot fungus Heterobasidion parviporum responds to spruce xylem defense by enhanced production of oxalic acid. AB - Pathogen challenge of tree sapwood induces the formation of reaction zones with antimicrobial properties such as elevated pH and cation content. Many fungi lower substrate pH by secreting oxalic acid, its conjugate base oxalate being a reductant as well as a chelating agent for cations. To examine the role of oxalic acid in pathogenicity of white-rot fungi, we conducted spatial quantification of oxalate, transcript levels of related fungal genes, and element concentrations in heartwood of Norway spruce challenged naturally by Heterobasidion parviporum. In the pathogen-compromised reaction zone, upregulation of an oxaloacetase gene generating oxalic acid coincided with oxalate and cation accumulation and presence of calcium oxalate crystals. The colonized inner heartwood showed trace amounts of oxalate. Moreover, fungal exposure to the reaction zone under laboratory conditions induced oxaloacetase and oxalate accumulation, whereas heartwood induced a decarboxylase gene involved in degradation of oxalate. The excess level of cations in defense xylem inactivates pathogen-secreted oxalate through precipitation and, presumably, only after cation neutralization can oxalic acid participate in lignocellulose degradation. This necessitates enhanced production of oxalic acid by H. parviporum. This study is the first to determine the true influence of white-rot fungi on oxalate crystal formation in tree xylem. PMID- 23035940 TI - Modeling and simulation of ion channels. PMID- 23035955 TI - Effects of cysteine on the pharmacokinetics of tamoxifen in rats with protein calorie malnutrition. AB - Protein-calorie malnutrition (PCM) could occur frequently in cancer patients and alter the pharmacokinetics of drugs. Also cysteine shows anti-oxidative effect and changes the activities of drug metabolizing enzyme and/or transporters. Herein, we investigated the effects of cysteine on the pharmacokinetics of tamoxifen in rats with protein-calorie malnutrition (PCM). The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of tamoxifen were assessed using control, CC (control with cysteine), PCM, PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of tamoxifen were further investigated through in vitro transport studies using rat intestine. The AUCs of intravenous tamoxifen in PCM rats were significantly greater than control rats due to the decrease in the hepatic metabolism via CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels by oral cysteine supplement. The AUC of oral tamoxifen in PCM rats was significantly smaller than in control rats mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of tamoxifen probably via intestinal P-gp inhibition. The present study demonstrated that PCM state and/or oral cysteine supplement had a profound impact on the pharmacokinetics of tamoxifen in rats. If the present rat data are extrapolated to humans, the alterations in tamoxifen absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM and/or oral cysteine supplement. PMID- 23035956 TI - Usefulness of the noncontact mapping system to elucidate the conduction property for the treatment of common atrial flutter. AB - BACKGROUND: The functional role of the cavotricuspid isthmus (CTI) for common atrial flutter (cAFL) remains to be elucidated. In the present study, we examined whether the EnSite system (St. Jude Medical, St. Paul, MN, USA), a noncontact mapping system, is useful to evaluate the conduction properties of CTI to minimize radiofrequency (RF) ablation applications for cAFL. METHODS: We enrolled 22 consecutive patients with cAFL (64.1 +/- 9.5 years old, M/F 21/1) treated with the EnSite system and examined the conduction properties during cAFL and during atrial pacing. In addition, the effectiveness of the system was evaluated in comparison with the conventional ablation group (67 +/- 8.9 years old, n = 15, M/F 13/2). RESULT: In 11 out of the 22 patients, CTI block line was achieved by fewer RF applications on a presumed single activation pathway which the EnSite system showed (point ablation [PA] group), and the remaining 11 patients needed additional linear ablation (additional ablation [AA] group). The number of RF applications in the PA group was significantly smaller than that in the conventional group. During the lower lateral right atrial pacing at a cycle length of 600 ms, the CV of the CTI in the PA group was smaller compared to that in the AA group (1.36 +/- 0.61 vs 2.17 +/- 0.66 m/s, P < 0.05), although the CV during cAFL (averaged cycle length 245 +/- 34 ms) was not different in both groups. CONCLUSIONS: These results indicate that targeting the presumed single line identified by EnSite could be an optional therapy for cAFL RF ablation, and diverse conduction properties in CTI are related to the success rate of this procedure. (PACE 2012;35:1464-1471). PMID- 23035957 TI - Risk-informed regulation and safety management of nuclear power plants--on the prevention of severe accidents. AB - There are four operating nuclear power plant (NPP) units in Finland. The Teollisuuden Voima (TVO) power company has two 840 MWe BWR units supplied by Asea Atom at the Olkiluoto site. The Fortum corporation (formerly IVO) has two 500 MWe VVER 440/213 units at the Loviisa site. In addition, a 1600 MWe European Pressurized Water Reactor supplied by AREVA NP (formerly the Framatome ANP- Siemens AG Consortium) is under construction at the Olkiluoto site. Recently, the Finnish Parliament ratified the government Decision in Principle that the utilities' applications to build two new NPP units are in line with the total good of the society. The Finnish utilities, Fenno power company, and TVO company are in progress of qualifying the type of the new nuclear builds. In Finland, risk-informed applications are formally integrated in the regulatory process of NPPs that are already in the early design phase and these are to run through the construction and operation phases all through the entire plant service time. A plant-specific full-scope probabilistic risk assessment (PRA) is required for each NPP. PRAs shall cover internal events, area events (fires, floods), and external events such as harsh weather conditions and seismic events in all operating modes. Special attention is devoted to the use of various risk-informed PRA applications in the licensing of Olkiluoto 3 NPP. PMID- 23035958 TI - A case report of Citrobacter koseri bacteraemia after transfusion of contaminated red cells. AB - BACKGROUND: Citrobacter koseri has not been associated to infection caused by blood component transfusions. CASE REPORT: A 46-year-old female patient presented sudden chills, dyspnoea, and tachycardia during a transfusion from a unit of packed red blood cells. Citrobacter koseri was isolated in the two sample collected from the patient and from the content of the packed red blood cells. RESULTS: We report a case of bacteraemia due to a transfusion of contaminated red blood cells. CONCLUSION: C. koseri should be taken into account in bacteraemias caused by transfusion of blood components. PMID- 23035959 TI - Evolutionary dynamics of rRNA gene clusters in cichlid fish. AB - BACKGROUND: Among multigene families, ribosomal RNA (rRNA) genes are the most frequently studied and have been explored as cytogenetic markers to study the evolutionary history of karyotypes among animals and plants. In this report, we applied cytogenetic and genomic methods to investigate the organization of rRNA genes among cichlid fishes. Cichlids are a group of fishes that are of increasing scientific interest due to their rapid and convergent adaptive radiation, which has led to extensive ecological diversity. RESULTS: The present paper reports the cytogenetic mapping of the 5S rRNA genes from 18 South American, 22 African and one Asian species and the 18S rRNA genes from 3 African species. The data obtained were comparatively analyzed with previously published information related to the mapping of rRNA genes in cichlids. The number of 5S rRNA clusters per diploid genome ranged from 2 to 15, with the most common pattern being the presence of 2 chromosomes bearing a 5S rDNA cluster. Regarding 18S rDNA mapping, the number of sites ranged from 2 to 6, with the most common pattern being the presence of 2 sites per diploid genome. Furthermore, searching the Oreochromis niloticus genome database led to the identification of a total of 59 copies of 5S rRNA and 38 copies of 18S rRNA genes that were distributed in several genomic scaffolds. The rRNA genes were frequently flanked by transposable elements (TEs) and spread throughout the genome, complementing the FISH analysis that detect only clustered copies of rRNA genes. CONCLUSIONS: The organization of rRNA gene clusters seems to reflect their intense and particular evolutionary pathway and not the evolutionary history of the associated taxa. The possible role of TEs as one source of rRNA gene movement, that could generates the spreading of ribosomal clusters/copies, is discussed. The present paper reinforces the notion that the integration of cytogenetic data and genomic analysis provides a more complete picture for understanding the organization of repeated sequences in the genome. PMID- 23035961 TI - Novel lithium-containing honeycomb structures. AB - Rock-salt-based honeycomb structures containing Te(VI) and Sb(V) with innumerable prospects of properties and applications were realized in the two new series of mixed-metal oxides of lithium, Li(8)M(2)Te(2)O(12) (M(II) = Co, Ni, Cu, Zn) and Li(8)M(2)Sb(2)O(12) (M(III) = Cr, Fe, Al, Ga). The structures of Li(8)Co(2)Te(2)O(12) and Li(8)Cu(2)Te(2)O(12) were determined by single-crystal X ray diffraction for the first time, and mixed-occupancy Li/M was identified. PMID- 23035960 TI - Aetiological agents of cerebrospinal meningitis: a retrospective study from a teaching hospital in Ghana. AB - BACKGROUND: Meningitis is an important cause of morbidity and mortality in low resource settings. In sub-Saharan Africa, the meningitis belt has been characterized by particularly high and seasonal incidences of bacterial meningitis extending throughout life. Despite the progress being made in treating the condition, the mortality rates continue to be high, ranging between 2% and 30% globally. In Ghana, the mortality rate of meningitis has been estimated to range from 36% to 50%. However little information is available on the pathogens contributing to meningitis and their antimicrobial susceptibilities. Updated information is essential to adjust the recommendations for empirical treatment or prevention of meningitis which could have immense implications for local and global health. METHODS: We retrospectively reviewed laboratory records of all patients suspected of bacterial meningitis who underwent a lumbar puncture from January 1, 2008 to December 31, 2010. Data were retrieved from laboratory record books and double entered into a Microsoft((r)) excel spreadsheet. RESULTS: Records of 4,955 cerebrospinal fluid samples were analysed. Of these, 163 (3.3%, 95%CI: 2.8% to 3.8%) were confirmed meningitis and 106 (2.1%, 95%CI: 1.7% to 2.6%) were probable meningitis cases. Confirmed meningitis cases were made up of 117 (71.8%) culture positive bacteria, 19 (11.7%) culture positive Cryptococcus neoformans and 27(16.6%) Gram positive bacteria with negative culture. The most prevalent bacteria was Streptococcus pneumoniae 91 (77.7%), followed by E.coli 4 (3.4%), Salmonella species 4 (3.4%), Neisseria meningitidis 3 (2.5%), Pseudomonas species 3(2.5%) and others. Pneumococcal isolates susceptibility to penicillin, chloramphenicol and ceftriaxone were 98.9% (95%CI: 94.0% to 100.0%), 83.0% (95%CI: 73.4% to 90.1%) and 100.0% (95%CI: 95.8% to 100.0%) respectively. CONCLUSION: Streptococcus pneumoniae is an important cause of meningitis among all age groups and its susceptibility to penicillin and ceftriaxone still remains very high. Ghanaians of all ages and possibly other developing countries in the meningitis belt could benefit from the use of the pneumococcal vaccine. Other bacterial and fungal pathogens should also be considered in the management of patients presenting with meningitis. PMID- 23035962 TI - Self-help treatment for insomnia symptoms associated with chronic conditions in older adults: a randomized controlled trial. AB - OBJECTIVES: To evaluate the effectiveness of a self-help cognitive behavioral intervention in improving sleep quality in older adults reporting insomnia symptoms associated with chronic disease. DESIGN: A pragmatic two-arm randomized controlled trial comparing supported self-help with treatment as usual (TAU). SETTING: Primary care. PARTICIPANTS: One hundred ninety-three self-referred individuals aged 55 to 87 with long-term conditions and chronic insomnia symptoms (as defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). INTERVENTION: Self-help participants received six consecutive booklets, at weekly intervals, providing structured advice on important components of cognitive behavioral therapy for insomnia (CBT-I, including self-monitoring, sleep restriction, stimulus control procedures, and cognitive strategies), plus access to a telephone helpline. Control group participants received a single sheet of advice detailing standard sleep hygiene measures. MEASUREMENTS: The primary outcome was sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes were the Insomnia Severity Index (ISI), the subjective sleep efficiency index, and the Fatigue Severity Scale. RESULTS: In the self-help group, sleep outcomes showed significant improvements after treatment (PSQI, P < .001; ISI, P < .001; sleep efficiency, P < .001) and at 3-month (PSQI, P = .002; ISI, P = .006; sleep efficiency, P = .001) and 6-month (PSQI, P = .003; ISI, P = .003; sleep efficiency, P = .001) follow-up. Effect sizes were moderate (range of adjusted Cohen d = 0.51-0.75). Treatment had no effect on levels of daytime fatigue. Most treated participants (73%) said they would recommend the self-help program to others. CONCLUSION: Self-help CBT-I offers a practical first-line response to individual reporting insomnia symptoms associated with chronic disease in primary care settings. In these individuals, symptoms of daytime fatigue may be more closely associated with disease processes than with sleep quality. PMID- 23035963 TI - Microsatellites grant more stable flanking genes. AB - BACKGROUND: Microsatellites, or simple sequence repeats (SSRs), are DNA sequences that include tandem copies of specific sequences no longer than six bases. SSRs are ubiquitous in all genomes and highly mutable. PRESENTATION OF THE HYPOTHESIS: Results from previous studies suggest that flanking regions of SSR are exhibit high stability in a wide range of organisms. We hypothesized that the SSRs ability to discard weak DNA polymerases could be responsible for this unusual stability. . When the weak polymerases are being decayed over SSRs, the flanking sequences would have higher opportunity to be replicated by more stable DNA polymerases. We present evidence of the molecular basis of our hypothesis. TESTING THE HYPOTHESIS: The hypothesis could be tested by examining the activity of DNA polymerase during and after a number of PCRs. The PCR reactions should be run with the same SSR locus possessing differences in the SSR length. The hypothesis could also be tested by comparing the mutational rate of a transferred gene between two transformations. The first one has a naked T-DNA (transferred DNA), while the second one has the same T-DNA flanked with two SSRs. IMPLICATIONS OF THE HYPOTHESIS: In any transformation experiment, flanking the T-DNA fragment with SSR sequences would result in more stably transferred genes. This process would decrease the unpredictable risks that may occur because of the mutational pressure on this foreign segment. PMID- 23035964 TI - Gadolinium MRI contrast agents based on triazine dendrimers: relaxivity and in vivo pharmacokinetics. AB - Four gadolinium (Gd)-based macromolecular contrast agents, G3-(Gd-DOTA)(24), G5 (Gd-DOTA)(96), G3-(Gd-DTPA)(24), and G5-(Gd-DTPA)(96), were prepared that varied in the size of dendrimer (generation three and five), the type of chelate group (DTPA or DOTA), and the theoretical number of metalated chelates (24 and 96). Synthesis relied on a dichlorotriazine derivatized with a DOTA or DTPA ligand that was incorporated into the dendrimer and ultimately metalated with Gd ions. Paramagnetic characteristics and in vivo pharmacokinetics of all four contrast agents were investigated. The DOTA-containing agents, G3-(Gd-DOTA)(24) and G5-(Gd DOTA)(96), demonstrated exceptionally high r1 relaxivity values at off-peak magnetic fields. Additionally, G5-(Gd-DOTA)(96) showed increased r1 relaxivity in serum compared to that in PBS, which was consistent with in vivo images. While G3 (Gd-DOTA)(24) and G3-(Gd-DTPA)(24) were rapidly excreted into the urine, G5-(Gd DOTA)(96) and G5-(Gd-DTPA)(96) did not clear as quickly through the kidneys. Molecular simulation of the DOTA-containing dendrimers suggests that a majority of the metalated ligands are accessible to water. These triazine dendrimer-based MRI contrast agents exhibit several promising features such as high in vivo r1 relaxivity, desirable pharmacokinetics, and well-defined structure. PMID- 23035965 TI - Reduced functional connectivity of prefrontal regions and amygdala within affect and working memory networks in pediatric bipolar disorder. AB - This study examined whether adolescents with pediatric bipolar disorder (PBD) have abnormal regional functional connectivity in distributed brain networks during an affective working memory task. Adolescents with PBD (n=41) and healthy controls (HC; n=16) performed a two-back functional magnetic resonance imaging working memory task with blocks of either angry or neutral faces. Independent component analysis methodology identified two temporally independent and functionally connected brain networks that showed differential functional connectivity in PBD and HC. Within a network for "affect evaluation and regulation," PBD showed decreased functional connectivity relative to HC in regions involved in emotion processing such as the right amygdala, and in emotion regulation regions such as the right ventrolateral prefrontal cortex (VLPFC), while functional connectivity was increased in emotion evaluation regions such as the bilateral medial PFC. Furthermore, in an "Affective Working Memory Network," PBD exhibited greater connectivity relative to HC in left dorsolateral PFC (DLPFC), caudate, and right VLPFC; and simultaneously reduced connectivity in emotion processing regions, such as the right amygdala, bilateral temporal regions, and the junction of DLPFC/VLPFC, which interfaces affective and cognitive processes. Dysfunction in network engagement in PBD patients illustrates that they are expending greater effort in face emotion evaluation, while being less able to engage affect regulation regions. PMID- 23035967 TI - Base-mediated carboxylation of unprotected indole derivatives with carbon dioxide. AB - A simple and straightforward method for the preparation of indole-3-carboxylic acids was discovered through the direct carboxylation of indoles with atmospheric pressure of carbon dioxide (CO(2)) under basic conditions. The key for the reaction was found to be the use of a large excess of LiO(t)Bu as a base to suppress the undesired decarboxylation side reaction. PMID- 23035966 TI - A multimineral natural product from red marine algae reduces colon polyp formation in C57BL/6 mice. AB - The goal of this study was to determine if a multimineral natural product derived from red marine algae could reduce colon polyp formation in mice on a high-fat diet. C57BL/6 mice were maintained for up to 18 mo either on a high-fat "Western style" diet or on a low-fat diet (AIN 76A), with or without the multimineral supplement. To summarize, colon polyps were detected in 22 of 70 mice (31%) on the high-fat diet but in only 2 of 70 mice (3%) receiving the mineral supplemented high-fat diet (P < 0.0001). Colon polyps were detected in 16 of 70 mice (23%) in the low-fat group; not significantly different from high-fat group but significantly higher than the high-fat-supplemented group (P = 0.0006). This was in spite of the fact that the calcium level in the low-fat diet was comparable to the level of calcium in the high-fat diet containing the multimineral-product. Supplementation of the low-fat diet reduced the incidence to 8 of 70 mice (11% incidence). Taken together, these findings demonstrate that a multimineral natural product can protect mice on a high-fat diet against adenomatous polyp formation in the colon. These data suggest that increased calcium alone is insufficient to explain the lower incidence of colon polyps. PMID- 23035969 TI - Two unconventional risk factors for major adverse cardiovascular events in subjects with sexual dysfunction: low education and reported partner's hypoactive sexual desire in comparison with conventional risk factors. AB - INTRODUCTION: The classification of subjects as low or high cardiovascular (CV) risk is usually performed by risk engines, based upon multivariate prediction algorithms. However, their accuracy in predicting major adverse CV events (MACEs) is lower in high-risk populations as they take into account only conventional risk factors. AIM: To evaluate the accuracy of Progetto Cuore risk engine in predicting MACE in subjects with erectile dysfunction (ED) and to test the role of unconventional CV risk factors, specifically identified for ED. METHODS: A consecutive series of 1,233 men (mean age 53.33 +/- 9.08 years) attending our outpatient clinic for sexual dysfunction was longitudinally studied for a mean period of 4.4 +/- 2.6 years. MAIN OUTCOME MEASURE: Several clinical, biochemical, and instrumental parameters were evaluated. Subjects were classified as high or low risk, according to previously reported ED-specific risk factors. RESULTS: In the overall population, Progetto Cuore-predicted population survival was not significantly different from the observed one (P = 0.545). Accordingly, receiver operating characteristic (ROC) analysis shows that Progetto Cuore has an accuracy of 0.697 +/- 0.037 (P < 0.001) in predicting MACE. Considering subjects at high risk according to ED-specific risk factors, the observed incidence of MACE was significantly higher than the expected for both low educated and patients reporting partner's hypoactive sexual desire (HSD, both <0.05), but not for other described factors. The area under ROC curves of Progetto Cuore for MACE in subjects with low education and reported partner's HSD were 0.659 +/- 0.053 (P = 0.008) and 0.550 +/- 0.076 (P = 0.570), respectively. CONCLUSION: Overall, Progetto Cuore is a proper instrument for evaluating CV risk in ED subjects. However, in ED, other factors such as low education and partner's HSD concur to risk profile. At variance with low education, Progetto Cuore is not accurate enough to predict MACE in subjects with partner's HSD, suggesting that the latter effect is not mediated by conventional risk factors included in the algorithm. PMID- 23035968 TI - The independence of deficits in position sense and visually guided reaching following stroke. AB - BACKGROUND: Several studies have found correlations between proprioception and visuomotor function during stroke recovery, however two more recent studies have found no correlation. Unfortunately, most of the studies to date have been conducted with clinical assessments of sensation that are observer-based and have poor reliability. We have recently developed new tests to assess position sense and motor function using robotic technology. The present study was conducted to reassess the relationship between position sense and upper limb movement following stroke. METHODS: We assessed position sense and motor performance of 100 inpatient stroke rehabilitation subjects and 231 non-disabled controls. All subjects completed quantitative assessments of position sense (arm-position matching task) and motor performance (visually-guided reaching task) using the KINARM robotic device. Subjects also completed clinical assessments including handedness, vision, Purdue Pegboard, Chedoke-McMaster Stroke Assessment Impairment Inventory and Functional Independence Measure (FIM). Neuroimaging documented lesion localization. Fisher's exact probability tests were used to determine the relationship between performances on the arm-position matching and visually-guided reaching task. Pearson's correlations were conducted to determine the relationship between robotically measured parameters and clinical assessments. RESULTS: Performance by individual subjects on the matching and reaching tasks was statistically independent (Fisher's test, P<0.01). However, performance on the matching and reaching tasks both exhibited relationships with abilities in daily activities as measured by the FIM. Performance on the reaching task also displayed strong relationships with other clinical measures of motor impairment. CONCLUSIONS: Our data support the concept that position sense deficits are functionally relevant and point to the importance of assessing proprioceptive and motor impairments independently when planning treatment strategies. PMID- 23035970 TI - Factors associated with high levels of patient satisfaction with pain management. AB - OBJECTIVES: The objective was to determine, among emergency department (ED) patients, the factors associated with a high level of satisfaction with pain management. METHODS: This was a prospective cohort study in a single ED. Consecutive adult patients, with triage pain scores of >=4 (numerical rating scale=0 to 10), were enrolled. Variables examined included demographics, presenting complaint, pain scores, nurse-initiated analgesia, analgesia administered, time to first analgesia, specific pain communication, and whether "adequate analgesia" was provided (defined as a decrease in pain score to <4 and a decrease from the triage pain score of >=2). The level of patient satisfaction with their pain management (six-point scale: very unsatisfied to very satisfied) was determined by a blinded investigator 48 hours post discharge. Logistic regression analyses were undertaken. RESULTS: Data were complete for 476 patients: mean (+/-standard deviation [SD]) age was 43.6 (+/-17.2) years, and 237 were males (49.8%, 95% confidence interval [CI]=45.2% to 54.4%). A total of 190 (39.9%, 95% CI=35.5% to 44.5%) patients were "very satisfied" with their pain management, and 207 (43.5%, 95% CI=39.0% to 48.1%) patients received adequate analgesia. Three variables were associated with the patient being very satisfied: the provision of adequate analgesia (odds ratio [OR]=7.8, 95% CI=4.9 to 12.4), specific pain communication (OR=2.3, 95% CI=1.3 to 4.1), and oral opioid administration (OR=2.0, 95% CI=1.1 to 3.4). Notably, the provision of nurse initiated analgesia to 211 patients (44.3%, 95% CI=39.8% to 48.9%) and the short time to analgesia (median=11.5 minutes; interquartile range [IQR]=2.0 to 85.8 minutes) were not associated with being very satisfied. CONCLUSIONS: The receipt of adequate analgesia (as defined) is highly associated with patient satisfaction. This variable may serve as a clinically relevant and achievable target in the pursuit of best-practice pain management. PMID- 23035971 TI - Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems. AB - BACKGROUND: Deletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication. METHODS: We analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization. RESULTS: We have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted. CONCLUSIONS: We report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications. PMID- 23035972 TI - Neuroprotective effects of luteolin against apoptosis induced by 6 hydroxydopamine on rat pheochromocytoma PC12 cells. AB - CONTEXT: Apoptotic neuronal cell death plays an important role in Parkinson's disease (PD), a progressive neurodegenerative disorder. Luteolin, a flavonoid, has been shown to possess various pharmacological properties including strong antioxidant capacity. OBJECTIVE: This study investigated the neuroprotective effect of luteolin against cytotoxicity induced by 6-hydroxy-dopamine (6-OHDA) (250 uM) in rat pheochromocytoma (PC12) cell line. MATERIALS AND METHODS: The neuroprotective effect of luteolin against 6-OHDA-induced cytotoxicity in PC12 was evaluated by using cell viability test, nuclear staining and flow cytometry. In addition, the apoptotic role of luteolin was unveiled by monitoring mRNA expression of proapoptotic and anti-apoptotic genes. RESULTS: Pretreatment with luteolin (3.13, 6.25, 12.5, 25 or 50 uM) could markedly attenuate 6-OHDA-induced PC12 cell viability loss in a concentration-dependent manner. Cell morphologic analysis and nuclear staining assays showed that luteolin (3.13, 12.5 or 50 uM) protected the cells from 6-OHDA-induced damage. As shown in the flow cytometry assay, the increased apoptotic rate induced by 6-OHDA could be significantly (p < 0.001) suppressed by luteolin (12.5 or 50 uM) pretreatment. The protection of luteolin (50 uM) against 6-OHDA-induced cell damage was shown to be through suppressing the over-expression of Bax gene (p < 0.01), inhibiting the reduction of Bcl-2 gene expression (p < 0.05) and markedly depressing the enhanced Bax/Bcl 2 ratio. Luteolin also downregulated the gene expression level of p53. DISCUSSION AND CONCLUSION: Luteolin has protective effects against 6-OHDA-induced cell apoptosis and might be a potential nutritional supplement which could be used to prevent neurodegenerative diseases such as PD. PMID- 23035973 TI - Methyltrioxorhenium-catalyzed epoxidation of homoallylic alcohols with hydrogen peroxide. AB - Homoallylic alcohols were efficiently converted to the corresponding 3,4-epoxy alcohols in excellent yields by methyltrioxorhenium (MTO)-catalyzed epoxidation with aqueous hydrogen peroxide as the terminal oxidant and 3-methylpyrazole (10 mol %) as an additive. The epoxidations of homoallylic alcohols proceeded under organic solvent-free conditions faster than those in dichloromethane. PMID- 23035974 TI - Factors affecting precipitation of vancomycin and ceftazidime on intravitreal injection. AB - PURPOSE: The aim of this study was to investigate the factors that affect the precipitation of vancomycin and ceftazidime which are currently used in intravitreal injections for infectious endophthalmitis. METHODS: The minimum concentration required for precipitation of the 2 antibiotics was estimated by 2 fold dilution. In addition, the amount of the precipitate that formed was measured at 4, 3, 2, and 1 mL volumes, temperatures (37 degrees C or 4 degrees C), and in different medias (balanced salt solution plus and normal saline). RESULTS: When 2-fold serial dilutions of vancomycin and ceftazidime were mixed, precipitates started forming at a concentration of 12.5 mg/mL for ceftazidime and 10 mg/mL for vancomycin. The precipitation of vancomycin and ceftazidime increased at lower temperatures (4 degrees C) and lower media volumes (1 mL). However, using a micropipette with a complete mixed media and an antibiotic (vancomycin or ceftazidime) prevented the formation of a precipitate when the other antibiotic was added. CONCLUSION: The formation of a precipitate associated with intravitreal injections was correlated with the diffusion rate of the antibiotics in the media. Precipitation increased at lower temperatures, lower media volumes, and at higher antibiotic concentrations. PMID- 23035976 TI - Technological properties and probiotic potential of Enterococcus faecium strains isolated from cow milk. AB - AIM: To identify enterococci from the fermentation of milk for the production of nono, an African fermented dairy product, to determine the technological properties for suitability as starter cultures and safety as probiotics. METHODS AND RESULTS: Enterococcus faecium CM4 and Enterococcus faecium 2CM1 were isolated from raw cow's milk. The strains were phenotypically and genotypically identified. Technological properties, safety investigations, in vitro adherence properties and antimicrobial characteristics were carried out. Strong acidification and tolerance to bile salts were recorded. The strains were bile salts hydrolytic positive and no haemolysis. There was no resistance to clinically relevant antibiotics. The strains exhibited adherence to human collagen type IV, human fibrinogen and fibronectin. The bacteriocins were active against Bacillus cereus DSM 2301, Bacillus subtilis ATCC 6633, Micrococcus luteus and Listeria monocytogenes. Bacteriocins were stable at pH 4-9 and on treatment with lipase, catalase, alpha-amylase and pepsin, while their activity was lost on treatment with other proteases. The bacteriocins produced were heat stable at 100 degrees C for 10 min. The bacteriocin produced by the strains was identified as enterocin A. CONCLUSIONS: The E. faecium strains in this study exhibited probiotic activity, and the safety investigations indicate their suitability as good candidates for a starter culture fermentation process. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of bacteriocin-producing E. faecium strains as starter cultures in fermented foods is beneficial but, however, their safety investigations as probiotics must be greatly emphasized. PMID- 23035975 TI - Lentivirus vector-mediated knockdown of erythropoietin-producing hepatocellular carcinoma receptors B4 inhibits laser-induced choroidal neovascularization. AB - PURPOSE: To evaluate the efficacy of erythropoietin-producing hepatocellular carcinoma receptors B4 (EphB4) knockdown on the development of laser-induced choroidal neovascularization (CNV) in vivo. METHODS: We constructed recombinant lentiviral vectors (Lv) Lv-shRNA-EphB4 to specifically knock down the expression of EphB4. The mRNA and protein expression of EphB4 was investigated by real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot. CNV was induced by laser photocoagulation in C57BL/6 mice. The mice were then randomly assigned to be intravitreally injected with phosphate-buffered saline (PBS), Lv-shRNA-EphB4 recombinant lentivirus, or an unrelated shRNA recombinant lentivirus (pFU LV-shRNA-NC). An uninjected group was used as the control. Fundus fluorescein angiography (FFA), histologic analysis, and choroidal flat mounts analysis were applied to evaluate the inhibition of CNV after an intravitreal injection. RESULTS: Transfection of Lv-shRNA-EphB4 led to the knockdown of EphB4, and EphB4 mRNA was down-regulated by about 80%. FFA and histologic analysis revealed that the leakage areas and the mean thickness of CNV were much smaller in the Lv-shRNA-EphB4 group than in the PBS-treated, pFU Lv-shRNA-NC group and the non-injection group. Choroidal flat mounts showed significantly less leakage and smaller leakage areas in the Lv-shRNA-EphB4 group than those in other groups. CONCLUSION: Knocking down the expression of EphB4 exerts an inhibitory effect on CNV in vivo. It may provide a potential strategy for the treatment of CNV. PMID- 23035977 TI - Adsorption of poly(vinylformamide-co-vinylamine) polymers (PVFA-co-PVAm) on copper. AB - The adsorption of poly(vinylformamide) (PVFA) and its derivative statistical copolymer poly(vinyl-formamide-co-vinylamine) (PVFA-co-PVAm) on metallic copper and copper oxide particles as well as planar copper surfaces was studied as a function of the degree of hydrolysis of PVFA, the pH, and the polymer concentration in solution. The chemical composition and molecular structure of the PVFA-co-PVAm layers were investigated by surface-sensitive spectroscopic methods such as XPS, DRIFT spectroscopy, and ellipsometry. The findings allowed us to explain the adsorption mechanisms and the forces driving the PVFA-co-PVAm adsorption. It was shown that PVFA-co-PVAm layers thicker than 30 nm are able to protect the planar copper surface against corrosive attack. PMID- 23035978 TI - Effects of particle size and coating on nanoscale Ag and TiO2 exposure in zebrafish (Danio rerio) embryos. AB - Manufactured metal (oxide) nanoparticles are entering the aquatic environment with little understanding on their potential health impacts for exposed organisms. Adopting an integrative approach, we investigated effects of particle size and coating on biological responses for two of the most commonly used metal (oxide) nanoscale particles, silver (Ag) and titanium dioxide (TiO2) in zebrafish embryos. Titanium dioxide nanoparticles (nominally, 4 nm, 10 nm, 30 nm and 134 nm) had little or no toxicity on the endpoints measured. Ag both in nano form (10 nm and 35 nm) and its larger counterpart (600-1600 nm) induced dose-dependent lethality and morphological defects, occurring predominantly during gastrula stage. Of the silver material tested 10 nm nanoparticles appeared to be the most toxic. Coating Ag nanoparticles with citrate or fulvic acid decreased toxicity significantly. In situ hybridisation analysis identified the yolk syncytial layer (YSL) as a target tissue for Ag-nano toxicity where there was a significant induction of the heavy metal stress response gene, metallothionein 2 (Mt2) at sub lethal exposures. Coherent Anti-stroke Raman Scattering (CARS) microscopy provided no evidence for silver particles crossing the chorionic membrane in exposed embryos. Collectively, our data suggest that silver ions play a major role in the toxicity of Ag nanoparticles. PMID- 23035979 TI - Lens and retina regeneration: new perspectives from model organisms. AB - Comparative studies of lens and retina regeneration have been conducted within a wide variety of animals over the last 100 years. Although amphibians, fish, birds and mammals have all been noted to possess lens- or retina-regenerative properties at specific developmental stages, lens or retina regeneration in adult animals is limited to lower vertebrates. The present review covers the newest perspectives on lens and retina regeneration from these different model organisms with a focus on future trends in regeneration research. PMID- 23035980 TI - Structure-function relationships in calpains. AB - Calpains are a family of complex multi-domain intracellular enzymes that share a calcium-dependent cysteine protease core. These are not degradative enzymes, but instead carry out limited cleavage of target proteins in response to calcium signalling. Selective cutting of cytoskeletal proteins to facilitate cell migration is one such function. The two most abundant and extensively studied members of this family in mammals, calpains 1 and 2, are heterodimers of an isoform-specific 80 kDa large subunit and a common 28 kDa small subunit. Structures of calpain-2, both Ca2+-free and bound to calpastatin in the activated Ca2+-bound state, have provided a wealth of information about the enzyme's structure-function relationships and activation. The main association between the subunits is the pairing of their C-terminal penta-EF-hand domains through extensive intimate hydrophobic contacts. A lesser contact is made between the N terminal anchor helix of the large subunit and the penta-EF-hand domain of the small subunit. Up to ten Ca2+ ions are co-operatively bound during activation. The anchor helix is released and individual domains change their positions relative to each other to properly align the active site. Because calpains 1 and 2 require ~30 and ~350 MUM Ca2+ ions for half-maximal activation respectively, it has long been argued that autoproteolysis, subunit dissociation, post translational modifications or auxiliary proteins are needed to activate the enzymes in the cell, where Ca2+ levels are in the nanomolar range. In the absence of robust support for these mechanisms, it is possible that under normal conditions calpains are transiently activated by high Ca2+ concentrations in the microenvironment of a Ca2+ influx, and then return to an inactive state ready for reactivation. PMID- 23035981 TI - Promoter-associated small double-stranded RNA interacts with heterogeneous nuclear ribonucleoprotein A2/B1 to induce transcriptional activation. AB - Several recent reports have demonstrated that small activating dsRNA [double stranded RNA; saRNA (small activating dsRNA)] complementary to promoter regions can up-regulate gene expression in mammalian cells, a phenomenon termed RNAa (RNA activation). However, the mechanism of RNAa remains obscure with regard to what is the target molecule for promoter-targeted saRNA and what are the proteins involved in this process. p21Waf1/Cip1 (p21) [CDKN1A (cyclin-dependent kinase inhibitor 1A)], an important tumour suppressor gene, is among the genes that can be activated by RNAa in tumour cells. In the present study, we provide direct evidence that p21 promoter-targeted saRNA interact with its intended target on the p21 promoter to activate p21 expression. This process is associated with recruitment of RNA polymerase II and AGO2 (argonaute 2) protein to the saRNA target site. Additionally, we found that several hnRNPs (heterogeneous nuclear ribonucleoproteins) (A1, A2/B1 and C1/C2) are associated with saRNA. Further studies show that hnRNPA2/B1 interacts with the saRNA in vivo and in vitro and is required for RNAa activity. These findings indicate that RNAa results from specific targeting of promoters and reveals additional mechanistic details of RNAa. PMID- 23035982 TI - Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score. AB - OBJECTIVES: Previous studies in HIV-infected populations have yielded conflicting results on the effect of antiretroviral therapy (ART) on cognition. Our objective was to investigate the effect of several years of ART with stable central nervous system penetration effectiveness (CPE) score on neuropsychological performance in HIV-infected individuals. METHODS: We analysed a clinical cohort of HIV-infected patients who initiated ART between June 2003 and December 2006 and maintained stable CPE scores. Patients were evaluated with a short neuropsychological battery. Using linear regression, we examined the relationship between results of cognitive tests and CPE scores in all patients. RESULTS: Patients were divided into three similarly sized groups (CPE <= 1, CPE between 1.5 and 2.5, and CPE >= 2.5). We found that ART with high CPE scores was associated with poorer executive performances in HIV-1-infected patients. CONCLUSION: These results suggest that cognitive performance in treated HIV-infected patients could be influenced by ART. PMID- 23035983 TI - Electrocardiographic algorithms to localize the origins of idiopathic ventricular arrhythmias. PMID- 23035984 TI - Terrorism risks and cost-benefit analysis of aviation security. AB - We evaluate, for the U.S. case, the costs and benefits of three security measures designed to reduce the likelihood of a direct replication of the 9/11 terrorist attacks. To do so, we assess risk reduction, losses, and security costs in the context of the full set of security layers. The three measures evaluated are installed physical secondary barriers (IPSB) to restrict access to the hardened cockpit door during door transitions, the Federal Air Marshal Service (FAMS), and the Federal Flight Deck Officer (FFDO) Program. In the process, we examine an alternate policy measure: doubling the budget of the FFDO program to $44 million per year, installing IPSBs in all U.S. aircraft at a cost of $13.5 million per year, and reducing funding for FAMS by 75% to $300 million per year. A break-even cost-benefit analysis then finds the minimum probability of an otherwise successful attack required for the benefit of each security measures to equal its cost. We find that the IPSB is costeffective if the annual attack probability of an otherwise successful attack exceeds 0.5% or one attack every 200 years. The FFDO program is costeffective if the annual attack probability exceeds 2%. On the other hand, more than two otherwise successful attacks per year are required for FAMS to be costeffective. A policy that includes IPSBs, an increased budget for FFDOs, and a reduced budget for FAMS may be a viable policy alternative, potentially saving hundreds of millions of dollars per year with consequences for security that are, at most, negligible. PMID- 23035986 TI - Iodide-mediated control of rhodium epitaxial growth on well-defined noble metal nanocrystals: synthesis, characterization, and structure-dependent catalytic properties. AB - Metal nanocrystals (NCs) comprising rhodium are heterogeneous catalysts for CO oxidation, NO reduction, hydrogenations, electro-oxidations, and hydroformylation reactions. It has been demonstrated that control of structure at the nanoscale can enhance the performance of a heterogeneous metal catalyst, such as Rh, but molecular-level control of NCs comprising this metal is less studied compared to gold, silver, platinum, and palladium. We report an iodide-mediated epitaxial overgrowth of Rh by using the surfaces of well-defined foreign metal crystals as substrates to direct the Rh surface structures. The epigrowth can be accomplished on different sizes, morphologies, and identities of metal substrates. The surface structures of the resulting bimetallic NCs were studied using electron microscopy, and their distinct catalytic behaviors were examined in CO stripping and the electro-oxidation of formic acid. Iodide was found to play a crucial role in the overgrowth mechanism. With the addition of iodide, the Rh epigrowth can even be achieved on gold substrates despite the rather large lattice mismatch of ~7%. Hollow Rh nanostructures have also been generated by selective etching of the core substrates. The new role of iodide in the overgrowth and the high level of control for Rh could hold the key to future nanoscale control of this important metal's architecture for use in heterogeneous catalysis. PMID- 23035987 TI - Ion association in AlCl3 aqueous solutions from constrained first-principles molecular dynamics. AB - The Car-Parrinello-based molecular dynamics (CPMD) method was used to investigate the ion-pairing behavior between Cl(-) and Al(3+) ions in an aqueous AlCl(3) solution containing 63 water molecules. A series of constrained simulations was carried out at 300 K for up to 16 ps each, with the internuclear separation (r(Al Cl)) between the Al(3+) ion and one of the Cl(-) ions held constant. The calculated potential of mean force (PMF) of the Al(3+)-Cl(-) ion pair shows a global minimum at r(Al-Cl) = 2.3 A corresponding to a contact ion pair (CIP). Two local minima assigned to solvent-separated ion pairs (SSIPs) are identified at r(Al-Cl) = 4.4 and 6.0 A. The positions of the free energy minima coincide with the hydration-shell intervals of the Al(3+) cation, suggesting that the Cl(-) ion is inclined to reside in regions with low concentrations of water molecules, that is, between the first and second hydration shells of Al(3+) and between the second shell and the bulk. A detailed analysis of the solvent structure around the Al(3+) and Cl(-) ions as a function of r(Al-Cl) is presented. The results are compared to structural data from X-ray measurements and unconstrained CPMD simulations of single Al(3+) and Cl(-) ions and AlCl(3) solutions. The dipole moments of the water molecules in the first and second hydration shells of Al(3+) and in the bulk region and those of Cl(-) ions were calculated as a function of r(Al-Cl). Major changes in the electronic structure of the system were found to result from the removal of Cl(-) from the first hydration shell of the Al(3+) cation. Finally, two unconstrained CPMD simulations of aqueous AlCl(3) solutions corresponding to CIP and SSIP configurations were performed (17 ps, 300 K). Only minor structural changes were observed in these systems, confirming their stability. PMID- 23035985 TI - Quinone-induced activation of Keap1/Nrf2 signaling by aspirin prodrugs masquerading as nitric oxide. AB - The promising therapeutic potential of the NO-donating hybrid aspirin prodrugs (NO-ASA) includes induction of chemopreventive mechanisms and has been reported in almost 100 publications. One example, NCX-4040 (pNO-ASA), is bioactivated by esterase to a quinone methide (QM) electrophile. In cell cultures, pNO-ASA and QM donating X-ASA prodrugs that cannot release NO rapidly depleted intracellular GSH and caused DNA damage; however, induction of Nrf2 signaling elicited cellular defense mechanisms including upregulation of NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase (GCL). In HepG2 cells, the "NO-specific" 4,5 diaminofluorescein reporter, DAF-DA, responded to NO-ASA and X-ASA, with QM induced oxidative stress masquerading as NO. LC-MS/MS analysis demonstrated efficient alkylation of Cys residues of proteins including glutathione-S transferase-P1 (GST-P1) and Kelch-like ECH-associated protein 1 (Keap1). Evidence was obtained for alkylation of Keap1 Cys residues associated with Nrf2 translocation to the nucleus, nuclear translocation of Nrf2, activation of antioxidant response element (ARE), and upregulation of cytoprotective target genes. At least in cell culture, pNO-ASA acts as a QM donor, bioactivated by cellular esterase activity to release salicylates, NO(3)(-), and an electrophilic QM. Finally, two novel aspirin prodrugs were synthesized, both potent activators of ARE, designed to release only the QM and salicylates on bioactivation. Current interest in electrophilic drugs acting via Nrf2 signaling suggests that QM donating hybrid drugs can be designed as informative chemical probes in drug discovery. PMID- 23035988 TI - Age-related differences in microstructure, density and biomechanics of vertebral cancellous bone of Chinese males. AB - The conventional lumbar separation was performed by removing soft tissue, subsidiary structures and leaving only the vertebral body. The vertebral body was cut into two halves along the median sagittal plane, keeping the upper and lower end plates of each half, which were subsequently used for biomechanical, morphological and density experiments. From the age of 20-29 to 30-39 years, both the horizontal trabecular thickness (Tb.Th) and vertical Tb.Th decreased; the horizontal and vertical Tb.Sp increased; the plate-like trabecular Tb.Th decreased; the apparent density and volume ratio decreased; and the elastic modulus and the ultimate stress decreased; with all changes being statistically significant (p < 0.01). Similar trends were obtained from ages 40-49 to 50-59, although the changes were not significant (p > 0.05), except for the reduction in ultimate stress (p < 0.05). With aging, the collagen cross-linking capacity declined; the thicknesses of the collagen fibrils were variable, ranging from almost the same to loose, sparse or disordered thickness; and the finer collagen fibrils between the thick filaments were disorganized. In males aged from 20 to 59 years old, the horizontal and vertical Tb.Th and the plate-like Tb.Th of the vertebral body decreased, while the horizontal and vertical Tb.Sp increased. Additionally, the density, elastic modulus and the ultimate stress of the cancellous bone decreased with age. Thus, the associated changes of bone microstructure, density and biomechanics with age may lead to an increased risk of osteoporosis and fracture. PMID- 23035989 TI - Molecular junctions of self-assembled monolayers with conducting polymer contacts. AB - We present a method to fabricate individually addressable junctions of self assembled monolayers (SAMs) that builds on previous studies which have shown that soft conductive polymer top contacts virtually eliminate shorts through the SAMs. We demonstrate devices with nanoscale lateral dimensions, representing an order of magnitude reduction in device area, with high yield and relatively low device to-device variation, improving several features of previous soft contact devices. The devices are formed in pores in an inorganic dielectric layer with features defined by e-beam lithography and dry etching. We replace the aqueous PEDOT:PSS conductive polymer used in prior devices with Aedotron P, a low-viscosity, amphiphilic polymer, allowing incorporation of self-assembled monolayers with either hydrophobic or hydrophilic termination with the same junction geometry and materials. We demonstrate the adaptability of this new design by presenting transport measurements on SAMs composed of alkanethiols with methyl, thiol, carboxyl, and azide terminations. We establish that the observed room-temperature tunnel barrier is primarily a function of monolayer thickness, independent of the terminal group's hydrophilicity. Finally, we investigate the temperature dependence of transport and show that the low-temperature behavior is based on the energy distribution of sites from which carriers can tunnel between the polymer and gold contacts, as described by a model of variable-range hopping transport in a disordered conductor. PMID- 23035990 TI - Role of laparoscopy in non-trauma emergency pediatric surgery: a 5-year, single center experience a retrospective descriptive study with literature review. AB - BACKGROUND: Although laparoscopy is rapidly becoming the abdominal surgical modality of choice in adults, there are obstacles to its use in children. We analyzed our experience with pediatric laparoscopic surgery over the past 5 years, with particular emphasis on emergency procedures. FINDINGS: We retrospectively evaluated the records of patients aged <14 years who had undergone laparoscopic procedures for non-trauma emergency conditions at our institution from January 2006 to December 2010. The clinical parameters evaluated included operation time, total length of hospital stay, and postoperative complications.During the 5-year study period, 482 laparoscopic procedures were performed on patients aged <14 years, comprising 300 emergency and 182 elective operations. The majority of procedures were laparoscopic appendectomies, with most of the others being resections of ovarian cysts or Meckel's diverticulae, or adhesiolyses. We observed an improvement in outcomes over the 5-year period, as shown by shorter operation times and shorter postoperative hospital stays. The numbers of laparoscopic procedures performed increased over time. CONCLUSIONS: Pediatric laparoscopic surgery for emergency conditions provides excellent results, including better exposure and cosmetic outcomes than laparotomy. At our institution, the numbers and types of laparoscopic procedures performed have increased over time, and the outcomes of laparoscopic procedures have improved. PMID- 23035991 TI - (68)Ga small peptide imaging: comparison of NOTA and PCTA. AB - In this study, a bifunctional version of the chelate PCTA was compared to the analogous NOTA derivative for peptide conjugation, (68)Ga radiolabeling, and small peptide imaging. Both p-SCN-Bn-PCTA and p-SCN-Bn-NOTA were conjugated to cyclo-RGDyK. The resulting conjugates, PCTA-RGD and NOTA-RGD, retained their affinity for the peptide target, the alpha(v)beta(3) receptor. Both PCTA-RGD and NOTA-RGD could be radiolabeled with (68)Ga in >95% radiochemical yield (RCY) at room temperature within 5 min. For PCTA-RGD, higher effective specific activities, up to 55 MBq/nmol, could be achieved in 95% RCY with gentle heating at 40 degrees C. The (68)Ga-radiolabeled conjugates were >90% stable in serum and in the presence of excess apo-transferrin over 4 h; (68)Ga-PCTA-RGD did have slightly lower stability than (68)Ga-NOTA-RGD, 93 +/- 2% compared to 98 +/- 1%, at the 4 h time point. Finally, the tumor and nontarget organ uptake and clearance of (68)Ga-radiolabeled PCTA-RGD and NOTA-RGD was compared in mice bearing HT-29 colorectal tumor xenografts. Activity cleared quickly from the blood and muscle tissue with >90% and >70% of the initial activity cleared within the first 40 min, respectively. The majority of activity was observed in the kidney, liver, and tumor tissue. The observed tumor uptake was specific with up to 75% of the tumor uptake blocked when the mice were preinjected with 160 nmol (100 MUg) of unlabeled peptide. Uptake observed in the blocked tumors was not significantly different than the background activity observed in muscle tissue. The only significant difference between the two (68)Ga-radiolabeled bioconjugates in vivo was the kidney uptake. (68)Ga-radiolabeled PCTA-RGD had significantly lower (p < 0.05) kidney uptake (1.1 +/- 0.5%) at 2 h postinjection compared to (68)Ga-radiolabeled NOTA-RGD (2.7 +/- 1.3%). Overall, (68)Ga-radiolabeled PCTA RGD and NOTA-RGD performed similarly, but the lower kidney uptake for (68)Ga radiolabeled PCTA-RGD may be advantageous in some imaging applications. PMID- 23035992 TI - Assessment of blood administration competencies using objective structured clinical examination. AB - BACKGROUND: In order to minimise the risk of blood transfusion errors, all healthcare professionals who participate in the transfusion process are required to be assessed as competent. New and innovative methods of training and competency assessment are required to improve the training process. AIM/OBJECTIVE: The aim of this study was to explore the use of objective structured clinical examination (OSCE) in the assessment of competencies for blood administration. DESIGN: A mixed-methods approach was employed using structured observations of simulated practice through a three station OSCE to assess three stages of the blood transfusion process: (i) communication; (ii) documentation and (iii) identification of patients and blood products. Nurses and midwives were assessed using a 28-item checklist that was rated on a 5-point Bondy scale. After the OSCE, a questionnaire was given to participants to evaluate their attitudes. SETTING AND PARTICIPANTS: Eighty four midwives and nurses from 10 different clinical areas in a District General Hospital in London. RESULTS: Inter-rater reliability between assessors was high (>0.8). Overall assessors scored participants highest on aseptic technique (97%) and lowest for positive patient identification (81%). Participants felt that the OSCE was a useful intervention and could contribute to improving the competences of staff in blood transfusion safety. CONCLUSION: A simulation OSCE is valid and reliable for competency asessment in blood administration. The checklist is simple to complete and can be used to identify weaknesses and evaluate learning needs of staff in blood administration. PMID- 23035993 TI - Assessing a method to limit influence of standardized tests on clerkship grades. AB - BACKGROUND: Grading committees give excessive weight to standardized-examination scores. PURPOSE: Understanding that biases are often ingrained in grading processes, we sought to assess the influence of a structured grading policy in limiting this effect. METHODS: All 7 clerkship grading committees derived students' clinical scores while blinded to examination scores. Scores were combined to yield a final rank order, which was used to derive grade cutoffs. Logit regression was performed to assess the contribution of clinical and examination scores to final grades. Results were compared to a similar analysis where committees were not blinded to examination scores. RESULTS: In contrast to prior findings, grading committees consistently assigned greater weight to clinical-performance scores in assigning final grades when blinded to examination scores. CONCLUSIONS: Grading committees may be unaware of the extent to which they discount clinical assessments when they are at odds with the results of standardized examinations. This can be addressed with a procedure that blinds grading committees to examination scores. PMID- 23035994 TI - What does a good lifestyle mean to you? Perspectives of 4th-year U.S. medical students with military service obligations in 2009. AB - BACKGROUND: A specialties' lifestyle is known to be important for specialty selection, but how medical students define this concept is unknown. PURPOSE: The aim of this article is to determine how 4th-year medical students perceive lifestyle of specialties. METHODS: All 4th-year U.S. medical students graduating in 2009 with a military service obligation were invited to participate in an electronic survey. Responses to an open-ended question, "When someone says 'That specialty has a good lifestyle,' what does that mean to you?" were classified into themes by a consensus of the authors and then compared to the students' selected specialty. RESULTS: Response rate for the questionnaire was 46% (369 of 797). Four themes describing lifestyle emerged: "schedule control" (67% of students), "off time" (53%), "financial aspects" (48%), and "work life" (26%). CONCLUSIONS: Medical students' definition of a "good lifestyle" includes four themes, which should be used in future research of the lifestyle factor of specialty selection. PMID- 23035995 TI - Associations between medical student log data and clerkship learning outcomes. AB - BACKGROUND: Largely due to regulatory requirements, medical students increasingly document patient encounters in logs. Prior studies demonstrated value in achieving course objectives but not regarding objective learning outcomes. PURPOSE: The purpose of this article is to assess the associations between students' log data and clerkship outcomes. METHODS: We assessed ambulatory, internal medicine-pediatrics clerkship logs. Students recorded patients' diagnoses, preceptor's teaching content and performing histories and physicals (H&P). We examined associations between log data and National Board of Medical Examiners Subject Exams (NBME), Objective Structured Clinical Exams (OSCE), and clinical evaluations. RESULTS: All 272 students completed logs (M diagnoses = 146.5, SD = 24.9). In univariate analysis number of diagnoses, preceptors' teaching patient management and performing H&P independently correlated with OSCE scores (r = .13-.24, p < .05). NBME scores correlated with diagnoses, performing H&P independently (r = .13-.18, p < .05). Teaching patient management, diagnoses, performing H&P independently were associated with clinical evaluations (all ps < .05). Regressions demonstrated that performing physicals independently was associated with NBME and OSCE scores (p < .05, R (2) = .03 and .05, respectively). Teaching disease management and pediatric diagnoses were associated with clinical evaluations (p < .05) in medicine and pediatrics, respectively. CONCLUSIONS: Aspects of teaching, increased clinical involvement, and student autonomy were associated with clerkship performance. PMID- 23035996 TI - An evaluation of cost and appropriateness of care as recommended by candidates on a national clinical skills examination. AB - BACKGROUND: The National Board of Osteopathic Medical Examiners administers the COMLEX-USA Level 2-PE, an assessment of clinical skills of osteopathic medical students. This evaluation includes developing a patient care plan. PURPOSE: Based on one simulated case, we investigated the appropriateness and cost of care and quantified their relationship to performance. METHODS: Four hundred sixty-seven postencounter notes were coded for appropriateness using expert physician judgments and for cost of care using Centers for Medicare and Medicaid Services data. Various outcome measures were correlated with physician scores. RESULTS: In this case, candidates recommended an average of 5.6 interventions with an average cost of $227 and appropriateness rating of 2.4 on a 1 (indicated) to 4 (potentially dangerous) scale. Total cost and inappropriateness of actions were negatively correlated with candidate scores (r = -.208, p < .0001 and r = -.318, p < .0001, respectively). CONCLUSIONS: Results from this investigation provide some evidence to support the validity of physician note ratings of patient care plans and demonstrate the need to include these principles in medical education. PMID- 23035997 TI - Mindfulness as a predictor of positive reappraisal and burnout in standardized patients. AB - BACKGROUND: Standardized patients (SPs) portray emotionally intense roles that can have unintended deleterious effects including burnout. PURPOSE: This study explored SP characteristics that could serve as protective factors against these adverse effects. The literature suggests that positive reappraisal and mindfulness are protective factors, with positive reappraisal mediating the relationship between mindfulness and burnout. METHODS: Seventy-six SPs completed an instrument measuring burnout, positive reappraisal, and mindfulness. Multiple regression was performed to test the hypothesized mediator model. RESULTS: The results revealed that mindfulness and positive reappraisal explained a meaningful portion of SP burnout variance (R (2) = .31 p < .01). Germane to the mediator model, all correlations were significant: mindfulness and positive reappraisal (a) r = .668; positive reappraisal and burnout (b) r = -.527; and mindfulness and burnout (c) r = -.496, p < 01. When positive reappraisal and mindfulness were included in the model, the previously significant relationship c was no longer statistically significant. The combination of these three relationships supports a mediator model. CONCLUSIONS: Education to enhance mindfulness and positive reappraisal offers a way to offset the adverse effects of portraying intense emotional patient experiences. PMID- 23035998 TI - Language use in the informed consent discussion for emergency procedures. AB - BACKGROUND: The field of health literacy has closely examined the readability of written health materials to optimize patient comprehension. Few studies have examined spoken communication in a way that is comparable to analyses of written communication. PURPOSE: The study objective was to characterize the structural elements of residents' spoken words while obtaining informed consent. METHODS: Twenty-six resident physicians participated in a simulated informed consent discussion with a standardized patient. Audio recordings of the discussions were transcribed and analyzed to assess grammar statistics for evaluating language complexity (e.g., reading grade level). Transcripts and time values were used to assess structural characteristics of the dialogue (e.g., interactivity). RESULTS: Discussions were characterized by physician verbal dominance. The discussions were interactive but showed significant differences between the physician and patient speech patterns for all language complexity metrics. CONCLUSIONS: In this study, physicians spoke significantly more and used more complex language than the patients. PMID- 23035999 TI - An educational intervention to increase internists' confidence with and provision of preventive services to adolescents and young adults. AB - BACKGROUND: Internal medicine (IM) physicians report inadequate preparation to care for adolescents and young adults. PURPOSE: The aim is to (a) improve IM residents' comfort and confidence caring for adolescents/young adults and (b) increase the percentage of adolescent/young adult patients receiving preventive healthcare. METHODS: Fifty-two PGY1 IM residents were assigned to treatment or control groups. Residents in the treatment group interviewed and received feedback from adolescent instructors. We developed a survey to measure residents' comfort and confidence caring for adolescents/young adults and evaluated their adherence to screening guidelines for patients ages 16 to 26. RESULTS: Significantly more residents in the intervention group felt confident identifying sexually transmitted infections (STIs) and substance abuse and treating STIs, substance abuse, and depression compared to residents in the control group. Residents in the intervention group were no more likely to screen adolescents/young adults for Chlamydia, HIV, alcohol misuse, or depression in the 6 months following the intervention. CONCLUSIONS: An educational intervention utilizing adolescent instructors improves resident confidence but does not increase adherence to screening guidelines. PMID- 23036000 TI - Evaluation of a firearm injury prevention web-based curriculum. AB - BACKGROUND: Firearm injury prevention training is lacking in pediatric residency programs. DESCRIPTION: This study aimed to evaluate a web-based curriculum teaching residents how to provide injury prevention anticipatory guidance, emphasizing firearm injury prevention. Ninety-two residents participated and completed pretesting. Residents in the intervention group completed the curriculum, posttesting, and 6-month follow-up testing. Residents in the nonintervention group completed 6-month follow-up testing. Pre- and posttest comparisons between and within each group were made. EVALUATION: Baseline knowledge of the participants was high, and no significant change in knowledge was shown in either group. Changes in attitude were noted regarding physician role in providing firearm injury anticipatory guidance in the intervention group, which persisted at 6 months. Participants completing the curriculum showed significant improvement for all self-efficacy questions in the immediate and 6 month follow-up testing. CONCLUSIONS: Participants reported changes in attitudes and in confidence in their ability to provide firearm injury prevention counseling after completion of a web-based curriculum. PMID- 23036001 TI - The quality of life of medical students studying in New Zealand: a comparison with nonmedical students and a general population reference group. AB - BACKGROUND: Quality of life is an essential component of learning and has strong links with the practice and study of medicine. There is burgeoning evidence in the research literature to suggest that medical students are experiencing health related problems such as anxiety, depression, and burnout. PURPOSE: The aim of the study was to investigate medical students' perceptions concerning their quality of life. METHODS: Two hundred seventy-four medical students studying in their early clinical years (response rate = 80%) participated in the present study. Medical students were asked to fill in the abbreviated version of the World Health Organization Quality of Life questionnaire to elicit information about their quality of life perceptions in relation to their physical health, psychological health, social relationships, and environment. Subsequently, their responses were compared with two nonmedical students groups studying at a different university in the same city and an Australian general population norm. The findings were compared using independent group's t tests, confidence intervals, and Cohen's d. RESULTS: The main finding of the study indicated that medical students had similar quality of life perceptions to nonmedical students except in relation to the environment domain. Furthermore, the medical student group scored lower than the general population reference group on the physical health, psychological health, and environment quality of life domains. CONCLUSIONS: The results suggest that all university students are expressing concerns related to quality of life, and thus their health might be at risk. The findings in this study provided no evidence to support the notion that medical students experience lower levels of quality of life compared to other university students. When compared to the general population, all student groups examined in this study appeared to be experiencing lower levels of quality of life. This has implications for pastoral support, educationalists, student support personnel, and the university system. PMID- 23036002 TI - Local development of MCQ tests for evidence-based medicine and clinical decision making can be successful. AB - BACKGROUND: Guidelines for the design of multiple-choice item (MCQ) tests of evidence-based medicine (EBM) and clinical decision making (CDM) have not been published. PURPOSE AND METHODS: We describe a strategy to develop an EBM/CDM MCQ test database guided by educational theory and used psychometric analyses, including reliability, validity, and item analyses, to judge the strategy's success. RESULTS: The internal consistency reliability of tests derived from the database was in the good-to-excellent range (0.74-0.95) and test-retest reliability was fair (0.51). One test discriminated across three levels of EBM/CDM learners (discriminant validity). Tests also predictively correlated with other medical school assessments according to theory (convergent and discriminant validity). The items were infrequently misclassified, had statistics close to historical standards, and were acceptable after no more than one round of revisions. CONCLUSIONS: Our strategy for developing an EBM/CDM MCQ database was successful and tests derived from it can be flexibly sampled to assess different EBM/CDM knowledge domains and three levels of EBM/CDM learners. Assuming the availability of similar resources to support its application, this strategy should be replicable at other settings. PMID- 23036003 TI - The responsible use of online social networking: who should mentor medical students. AB - BACKGROUND: As medical students become more active in online social networking (OSN), there are increasing concerns regarding violations of patient privacy and a lack of professionalism. PURPOSE: Students need to be mentored, but who is best suited to the task? We hypothesized that residents are closer to students in usage and attitudes toward online communication than are faculty. If so, they would be more credible as mentors. METHODS: We surveyed faculty (N = 16), 1st year residents (N = 120), and 3rd-year medical students (N = 130) to compare attitudes about OSN and the online usage patterns. RESULTS: We found residents to be more like students in usage patterns of personal electronic media and in their choice of the mentoring techniques that should be used. CONCLUSION: Residents say they were not prepared to mentor students without additional guidance but were more confident than faculty members that they had the knowledge to do so. PMID- 23036004 TI - Improving clinical teaching in China: initial report of a multihospital pilot faculty development effort. AB - BACKGROUND: The study's purpose was to investigate whether or not a US-based faculty development program could be successfully used to improve the teaching skills of Chinese medical faculty. DESCRIPTION: The program, based on the Stanford Faculty Development Program (SFDP) model, was presented to 28 faculty teachers affiliated with Zhejiang University School of Medicine, Hangzhou, China. Outcomes included the attendees' satisfaction of the seminars and their ratings of self-reported teaching ability using a previously studied retrospective pre post questionnaire. Paired mean scores of the retrospective pre-test were statistically compared to the means of the retrospective post-test for all respondents. EVALUATION: Twenty-eight teachers completed the survey. The seminars were rated highly and summative ratings of both global teaching performance and use of specific teaching behaviors were significantly improved between the retrospective pre- and post-test scores. CONCLUSION: We were able to demonstrate a positive effect of a Western-based faculty development course on the teaching skills of Chinese clinical medical teachers. PMID- 23036005 TI - Developing a national collaborative of medical educators who lead clinical skills courses. AB - BACKGROUND: The majority of US medical schools now have pre-clerkship clinical skills (PCCS) courses. Course directors for these often logistically complicated courses may be in different medical specialties and, historically, have had few formal opportunities for communication and collaboration with their counterparts at other institutions. As such, we hypothesized that leaders of PCCS courses would benefit from a national network. SUMMARY: In this paper, we outline the methodology used to form a national collaborative from grass roots interest. Over three years, a self-identified eleven-person task force with national representation has created an organization for PCCS course directors from US medical schools called Directors Of Clinical Skills courses (DOCS) that meets annually. CONCLUSIONS: Through iterative presentations at regional and national medical education meetings, we have produced an inventory of educational issues for those developing, administering, and evaluating PCCS courses. Further development of this nascent organization is ongoing. Our process is generalizable. PMID- 23036009 TI - Lack of association between four SNPs in the SLC22A3-LPAL2-LPA gene cluster and coronary artery disease in a Chinese Han population: a case control study. AB - BACKGROUND: Lipoprotein (a) (Lp [a]) is known being correlated with coronary artery disease (CAD). The SLC22A3-LPAL2-LPA gene cluster, relating with modulating the level of plasma Lp (a), has recently been reported to be associated with CAD in Caucasians. The purpose of this study was to verify whether this finding can be expanded to the Chinese Han population. METHODS AND RESULTS: Using a Chinese Han sample, which consisted of 1012 well-characterized CAD patients and 889 healthy controls, we tested the associations of four SNPs (rs2048327, rs3127599, rs7767084 and rs10755578) in the SLC22A3-LPAL2-LPA gene cluster, and their inferred haplotypes with the risk of CAD. Allelic, genotypic and haplotype association analyses all showed that the gene cluster was not associated with CAD in this Chinese Han sample. CONCLUSIONS: We for the first time explored the association of the four SNPs in the SLC22A3-LPAL2-LPA gene cluster with CAD in a large Chinese Han sample. Nevertheless, this study did not reveal any significant evidence of this gene cluster to increase the risk of CAD in this population. PMID- 23036010 TI - Visualizing the third dimension in virtual training environments for neurologically impaired persons: beneficial or disruptive? AB - BACKGROUND: Many contemporary systems for neurorehabilitation utilize 3D virtual environments (VEs) that allow for training patients' hand or arm movements. In the current paper we comparatively test the effectiveness of two characteristics of VEs in rehabilitation training when utilizing a 3D haptic interaction device: Stereo Visualization (monoscopic vs stereoscopic image presentation) and Graphic Environment (2.5D vs 3D). METHOD: An experimental study was conducted using a factorial within-subjects design. Patients (10 MS, 8 CVA) completed three tasks, each including a specific arm-movement along one of three directional axes (left right, up-down and forward-backward). RESULTS: The use of stereoscopy within a virtual training environment for neurorehabilitation of CVA and MS patients is most beneficial when the task itself requires movement in depth. Further, the 2.5D environment yields the highest efficiency and accuracy in terms of patients' movements. These findings were, however, dependent on participants' stereoscopic ability. CONCLUSION: Despite the performance benefits of stereoscopy, our findings illustrate the non-triviality of choices of using stereoscopy, and the type of graphic environment implemented. These choices should be made with the task and target group, and even the individual patient in mind. PMID- 23036011 TI - Shared ancestral susceptibility to colorectal cancer and other nutrition related diseases. AB - BACKGROUND: The majority of non-syndromic colorectal cancers (CRCs) can be described as a complex disease. A two-stage case-control study on CRC susceptibility was conducted to assess the influence of the ancestral alleles in the polymorphisms previously associated with nutrition-related complex diseases. METHODS: In stage I, 28 single nucleotide polymorphisms (SNPs) were genotyped in a hospital-based Czech population (1025 CRC cases, 787 controls) using an allele specific PCR-based genotyping system (KASPar((r))). In stage II, replication was carried out for the five SNPs with the lowest p values. The replication set consisted of 1798 CRC cases and 1810 controls from a population-based German study (DACHS). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between genotypes and CRC risk were estimated using logistic regression. To identify signatures of selection, Fay-Wu's H and Integrated Haplotype Score (iHS) were estimated. RESULTS: In the Czech population, carriers of the ancestral alleles of AGT rs699 and CYP3A7 rs10211 showed an increased risk of CRC (OR 1.26 and 1.38, respectively; two-sided p<=0.05), whereas carriers of the ancestral allele of ENPP1 rs1044498 had a decreased risk (OR 0.79; p<=0.05). For rs1044498, the strongest association was detected in the Czech male subpopulation (OR 0.61; p=0.0015). The associations were not replicated in the German population. Signatures of selection were found for all three analyzed genes. CONCLUSIONS: Our study showed evidence of association for the ancestral alleles of polymorphisms in AGT and CYP3A7 and for the derived allele of a polymorphism in ENPP1 with an increased risk of CRC in Czechs, but not in Germans. The ancestral alleles of these SNPs have previously been associated with nutrition-related diseases hypertension (AGT and CYP3A7) and insulin resistance (ENPP1). Future studies may shed light on the complex genetic and environmental interactions between different types of nutrition-related diseases. PMID- 23036012 TI - Annotated genetic linkage maps of Pinus pinaster Ait. from a Central Spain population using microsatellite and gene based markers. AB - BACKGROUND: Pinus pinaster Ait. is a major resin producing species in Spain. Genetic linkage mapping can facilitate marker-assisted selection (MAS) through the identification of Quantitative Trait Loci and selection of allelic variants of interest in breeding populations. In this study, we report annotated genetic linkage maps for two individuals (C14 and C15) belonging to a breeding program aiming to increase resin production. We use different types of DNA markers, including last-generation molecular markers. RESULTS: We obtained 13 and 14 linkage groups for C14 and C15 maps, respectively. A total of 211 and 215 markers were positioned on each map and estimated genome length was between 1,870 and 2,166 cM respectively, which represents near 65% of genome coverage. Comparative mapping with previously developed genetic linkage maps for P. pinaster based on about 60 common markers enabled aligning linkage groups to this reference map. The comparison of our annotated linkage maps and linkage maps reporting QTL information revealed 11 annotated SNPs in candidate genes that co-localized with previously reported QTLs for wood properties and water use efficiency. CONCLUSIONS: This study provides genetic linkage maps from a Spanish population that shows high levels of genetic divergence with French populations from which segregating progenies have been previously mapped. These genetic maps will be of interest to construct a reliable consensus linkage map for the species. The importance of developing functional genetic linkage maps is highlighted, especially when working with breeding populations for its future application in MAS for traits of interest. PMID- 23036013 TI - Predictors of parent satisfaction in pediatric laceration repair. AB - OBJECTIVES: Patient and parent satisfaction are important measures of quality of care. Data are lacking regarding satisfaction with emergency procedures, including laceration repair. The objective was to define the elements of care that are important to parents during a pediatric laceration repair and to determine the predictors of excellent parent satisfaction. METHODS: This was a cross-sectional observational study of a convenience sample of patients younger than 18 years of age presenting for laceration repair to an urban tertiary care children's hospital emergency department (ED). At the end of the ED visit, parents completed a survey developed for this study assessing ratings of their experience and their perception of how their child experienced the repair. Exploratory factor analysis was used to derive the factors comprising parents' perception of the laceration repair process. A separate factor analysis was performed for the 0- to 4-years age subgroup. Multivariate logistic regression was used to determine which of these factors predicted excellent parent satisfaction with the visit, and also satisfaction with the procedure itself, adjusting for sociodemographic factors. RESULTS: A total of 408 parents returned completed surveys (response rate=76%). Factor analysis revealed that three factors provided a summary of the 16 survey items. They were labeled "provider performance,""anxiety and pain," and "cosmetic appearance," based on factor loading patterns. Provider performance was the only predictor of satisfaction with the visit (adjusted odds ratio [OR]=11.6; 95% confidence interval [CI]=6.2 to 21.6). Provider performance (adjusted OR=4.7; 95% CI=3.1 to 7.2) and cosmetic appearance (adjusted OR 2.7; 95% CI=1.7 to 4.2) predicted satisfaction with the procedure. Anxiety and pain did not predict either outcome. CONCLUSIONS: Provider performance, which comprises the elements of physician communication, caring attitude, confidence, and hygiene, is the strongest predictor of excellent parent satisfaction for pediatric patients with ED visits for laceration repair. PMID- 23036014 TI - Application of the VALUE communication principles in ACTIVE hospice team meetings. AB - BACKGROUND: The ACTIVE (Assessing Caregivers for Team Intervention through Video Encounters) intervention uses technology to enable family caregivers to participate in hospice interdisciplinary team (IDT) meetings from geographically remote locations. Previous research has suggested that effective communication is critical to the success of these meetings. The purpose of this study was to explore communication in ACTIVE IDT meetings involving family caregivers and to assess the degree to which hospice teams use specific communication principles (summarized in the mnemonic VALUE: value, acknowledge, listen, understand, and elicit), which have been supported in previous research in intensive care settings. METHODS: Researchers analyzed team-family communication during 84 video and/or audio-recorded care plan discussions that took place during ACTIVE team meetings, using a template approach to text analysis to determine the extent and quality of VALUE principles. The total content analyzed was 9 hours, 28 minutes in length. RESULTS: Hospice clinicians routinely employed the VALUE communication principles in communication during ACTIVE IDT meetings with family caregivers, but the quality of this communication was frequently rated moderate or poor. The majority of such communication was task-focused. Less often, communication centered on emotional concerns and efforts to gain a more holistic understanding of patients and families. CONCLUSIONS: This analysis suggests an opportunity for improving support for family members during ACTIVE IDT meetings. Members of hospice IDTs should remain aware of the opportunity for additional attention to the emotional realities of the hospice experience for family caregivers and could improve support for family caregivers during IDT meetings by ensuring that messages used to exemplify VALUE principles during team-family communication are of a high quality. PMID- 23036015 TI - "It takes two to tango": the relational domain in a cohort of subjects with erectile dysfunction (ED). AB - INTRODUCTION: The relational domain of erectile dysfunction (ED) is difficult to investigate in a clinical setting. We developed and validated SIEDY, a 13-item structured interview, that evaluates, besides the organic (Scale 1) and intra psychic (Scale 3) domains, also the relational one (Scale 2). We previously established a pathological threshold for SIEDY Scale 1 and 3. AIM: The aim of this study is to identify a pathological threshold of SIEDY Scale 2. METHOD: A nonselected, consecutive series of 2,992 subjects with ED was retrospectively evaluated. In a first consecutive series of 844 patients (Sample A, studied without systematically applying a psychometric test: Middlesex Hospital Questionnaire), a pathological threshold of SIEDY Scale 2 score was identified through receiver operating characteristic, using, as surrogate marker of impaired couple relationship, at least a positive answer to two standard questions on conflict within the couple and on the presence of extramarital affairs. MAIN OUTCOME MEASURE: Sensitivity and specificity, along with possible associations with biological and psychological correlates were verified in a further sample of 2,148 patients (Sample B). RESULTS: In Sample A, a threshold of Scale 2 score >=2 predicts couple impairment with a sensitivity of 53% and specificity of 66% and an overall accuracy of 62.0 +/- 2.2% (P < 0.0001). When this threshold was verified in sample B, Scale 2 score >=2 was associated with a higher risk of anxiety and depressive symptoms, higher prevalence of psychopathology, and higher Scale 3 scoring, even after adjusting for confounders. In the same sample, a Scale 2 score >=2 was associated with a reduced intimacy during sexual intercourse and overall worse sexual functioning. CONCLUSIONS: Until now, no instrument is available to quantify the marital domain of ED. The validation of a threshold of SIEDY Scale 2 score (>=2) represents an easy tool for the identification of ED patients with a relevant marital impairment. PMID- 23036016 TI - Impaired translation of spatial representation in young onset Alzheimer's disease patients. AB - BACKGROUND: Many early-stage Alzheimer's disease (AD) patients suffer from spatial navigational impairment even in familiar environments. Growing evidence shows that the retrosplenial cortex (RSC) is more damaged in young-onset AD patients (YOAD, onset age before 65) than in late-onset AD (LOAD) in the early stage of AD. Impaired translation between egocentric and allocentric representations of the environment, as a cause for spatial navigational impairment, usually occurs in people with lesions in the RSC. OBJECTIVE: To test translational ability between spatial representations in early-stage YOAD and LOAD patients. METHODS: Tests deemed sensitive to translation of spatial representations were used to evaluate 29 AD (14 YOAD, 15 LOAD) and 27 cognitively healthy controls (14 younger NC and 13 older NC). RESULTS: Younger NC outperformed YOAD in the tests of translation of spatial representations in spite of their equal basic visuoperceptual abilities and distance estimation. No such difference existed between LOAD and older NC. CONCLUSION: The translation of egocentric-allocentric representation ability, as a principal function of RSC, does not deteriorate equally in early-stage AD patients of different onset age. That early-stage YOAD show more deviations in translation of their spatial representation ability deserves our attention because it may endanger their daily activities. PMID- 23036017 TI - Pathogenesis of Abeta oligomers in synaptic failure. AB - The soluble Abeta oligomers in brain are highly correlated with memory related synaptic dysfunctions in Alzheimer's disease (AD). However, more recent studies implicate the involvement of Abeta dimers and trimers in memory related AD pathology. Apparently, Abeta oligomers can bind with cellular prion protein at the membrane receptors, forming annular amyloid pores and membrane ion channels to induce aberrant spine cytoskeletal changes. Hence synapse targeting of Abeta oligomers involves activation of many receptors such as N-Methyl-D-aspartate (NMDA), alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), nicotinic acetylcholine (nAChRs), p75 neurotrophin (p75NTR) following aberrant clustering of metabotropic glutamate receptors (mGluR5) leading to neuronal loss and LTP failure. In particular, NMDA and AMPA receptor activation by soluble amyloid oligomers involves calcium mediated mitochondrial dysfunction, decreased Ca((2+))/calmodulin-dependent protein kinase II (CaMKII) levels at the synapses accompanying dramatic loss of synaptic proteins such as postsynaptic density-95 (PSD-95), dynamin-1 and synaptophysin. This kind of receptor-Abeta oligomer interaction might eventually affect the neuronal membrane integrity by altering dielectric barrier, various synaptic proteins, spine morphology and density and P/Q calcium currents that might provoke a cascade of events leading to neuronal loss and memory failure. In this review, we try to explain in detail the various possible mechanisms that connect Abeta oligomers with synapse damage and memory failure. PMID- 23036018 TI - Mortality and treatment costs have a great impact on the cost-effectiveness of disease modifying treatment in Alzheimer's disease--a simulation study. AB - BACKGROUND: The societal costs of Alzheimer's Disease (AD) are enormous and pose a great challenge for the health and social care in any society. It is of vital importance to develop and identify cost effective treatment. The aim of the study was to present a hypothetical economic model of Disease Modifying Treatment (DMT) in AD. METHODS: A 20 year Markov cohort model of DMT was constructed, based on Swedish care conditions. States and progression were defined according to the Mini Mental State Examination (MMSE). Epidemiological studies of incidence of dementia, prevalence and costs of Mild Cognitive Impairment (MCI) and AD as well as conversion studies of MCI and demographic statistics were used as inputs in the model. RESULTS: Total costs were 113,797 million SEK for patients treated with DMT vs 88,562 million SEK for untreated patients. The corresponding gained QALYs were 529,945 and 450,307 respectively, giving an incremental cost effectiveness ratio of 293,002 SEK/QALY in the base option. Survival in the model was 8.72 years with DMT and 7.77 years for untreated. With an assumed Willingness to pay (WTP) of 600,000 SEK (about 86,200 US$ and 62,000 ) per gained QALY, the model indicated cost effectiveness with DMT. The sensitivity analysis implied no cost savings with DMT, but most options indicated cost effectiveness vs. the chosen WTP. CONCLUSION: The main reasons for the higher costs with DMT were the costs of DMT itself and the prolonged survival with DMT. Even if costs increase with DMT, the model indicates cost effectiveness. PMID- 23036019 TI - Asymmetric dimethylarginine: a possible link between vascular disease and dementia. AB - There is good epidemiological evidence that vascular disease predisposes to cognitive decline and dementia. The impact of vascular disease on dementia is likely to increase further because of the poor diagnosis and management of vascular risk factors, the increase in life expectancy, and the improved survival following major cardiovascular events, e.g. acute stroke. It is estimated that the adequate management of vascular risk factors, with pharmacological and/or nonpharmacological interventions, might result in a 50% reduction in the forecasted dementia prevalence. The exact mechanisms by which vascular risk factors and vascular disease adversely affect brain function remain unclear, but it is hypothesized that endothelial dysfunction plays an important role. Reduced synthesis and availability of endothelial nitric oxide (NO) may contribute to the development of dementia by at least two mechanisms: (1) favoring the onset and progression of atherosclerosis, vasoconstriction, and impaired cerebral blood flow regulation; and (2) reduced neuroprotection.Several studies have shown that asymmetric dimethylarginine (ADMA), an endogenous methylated form of the amino acid L-arginine, inhibits NO synthesis and favors oxidative stress and vascular damage. Unlike NO, ADMA concentrations are relatively stable and can be accurately measured in plasma. There is good evidence that higher plasma ADMA concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups. ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. This review discusses the biological role of ADMA, its potential contribution to the onset and progression of dementia through vascular disease and atherosclerosis, the available evidence linking ADMA with cognitive impairment and dementia, and the strategies to characterize the predictive role of ADMA in cognitive impairment in epidemiological studies. Therapeutic implications and suggestions for future research directions are also discussed. PMID- 23036020 TI - Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid beta deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer's disease. AB - The remarkable potentiality of bone marrow-derived mesenchymal stem cells (BM MSCs) after transplantation to models of neurological disease and injury has been described. We have previously published data confirming the influence of BM-MSCs on beta-amyloid (Abeta) deposition in an Alzheimer's disease (AD) mouse model. However, therapeutic approaches in neurological diseases such as AD, including those for BM-MSCs, are increasingly centered on the potential for prophylactic therapy in pro-dromal states where the underlying cause of the disease is apparent but functional deficits are not. In order to investigate whether BM-MSCs could have a beneficial effect in high-risk pre-dementia AD individuals, we treated young AD mice, at an age at which they display neuropathological, but not cognitive features of AD. Following a single intra-cerebral injection of BM-MSCs, interestingly, we found a significant decrease in the cerebral Abeta deposition compared with controls treated with PBS that was sustained up to 2 months post injection. Expression of dynamin 1 and Synapsin 1, key pre-synaptic proteins associated with synaptic transmission, which are typically decreased in brains of AD patients, were considerably enhanced in the brains of AD mice treated with BM MSCs and this response was sustained beyond 2 months. These data demonstrate that BM-MSCs produce an acute reduction in Abeta deposits and facilitate changes in key proteins required for synaptic transmission. These findings suggest that BM MSC transplantation warrants further investigation as a potential therapy for early intervention in pro-dromal AD. PMID- 23036021 TI - Pro-inflammatory cytokines IL-1beta and TNF-alpha are not associated with blood homocysteine concentration in Alzheimer's disease. AB - Increased concentrations of pro-inflammatory blood cytokines and plasma homocysteine (Hcy) are frequently reported in Alzheimer's disease (AD). Hcy appears to have immunomodulating and pro-inflammatory activities. Further, emerging evidence from animal and non-AD human studies implicates Hcy in potentiating the activities of pro-inflammatory cytokines; Hcy toxicity may also, in part, be mediated by these cytokines. As little is known about the potential relationship between these inflammatory markers specific to AD, the aim of this study was to assess potential impact of Hcy on the widely reported increases in cytokine concentrations in AD. Blood concentrations of two pro-inflammatory cytokines, IL-1beta and TNF-alpha, along with Hcy were assessed in 40 AD patients and 30 cognitively intact controls. Mean blood concentrations of IL-1beta and TNF alpha differed significantly between the AD and control groups (p=0.001 and p<0.001 resp). This difference survived adjustment for age and gender on logistic regression. Hcy was significantly correlated with age only in the patient (rs=0.38, p=0.02) but not the control group. There was no significant correlation between IL-1beta and Hcy, and between TNF-alpha, and Hcy in either the AD or the control group. Hence, our AD data did not replicate results obtained from animal and non-AD human studies which have linked pro-inflammatory cytokines concentrations to Hcy. A different inflammatory focus may exist in AD which may be influenced at least in a significant part by non-vascular pathogenesis. However, these results indirectly support the notion that the observed mild hyperhocysteinemia in AD may be due to non-inflammatory factors. PMID- 23036022 TI - Valproic acid attenuates neuronal loss in the brain of APP/PS1 double transgenic Alzheimer's disease mice model. AB - Alzheimer's disease (AD) is characterized by senile plaques (SP) of extracellular amyloid beta peptides(Abeta), neurofibrillary tangles (NFT) of intracellular hyper-phosphorylated tau and widespread loss of neurons. Apoptosis is the main reason of neuronal loss. It is proved that Abeta triggers apoptotic cell death via the activation of caspase-dependent and - independent cell death effectors, respectively. Valproic acid (VPA) is a widely used mood stabilizer and antiepileptic drug. Our previous study showed that VPA treatment significantly reduced SP formation and improved memory deficits in transgenic AD model mice. The present study intended to explore the protective effect of VPA on neuronal loss in transgenic AD model mice and the possible mechanisms involved. Histological and ultra-structural analysis showed that VPA partially decreased the swollen mitochondria and neurophil and promoted neurite outgrowth in AD mice model. Meanwhile, VPA greatly rescued the neuronal loss in the brain of AD mice. TUNEL staining showed that VPA significantly reduced the number of apoptotic cells. Western blot analysis revealed that VPA notably down-regulated the expression of Caspase-3, Caspase-9 and Caspase-12, reduced the level of cytochrome C and Bax. The expression of the antiapoptotic protein Bcl-2 was increased after VPA treatment. Flow cytometry revealed that VPA significantly decreased intracellular level of Ca(2+) and elevated mitochondrial membrane potential. Altogether, these results indicate that VPA protected AD mice via suppression of upstream factors of apoptosis, namely inhibition of both mitochondrial and endoplasmic reticulum pathway of apoptosis. PMID- 23036024 TI - Hypoglycemia induces tau hyperphosphorylation. AB - Cerebral hypoglycemia/hypometabolism is associated with Alzheimer's disease (AD) and is routinely used to assist clinical diagnosis of AD by brain imaging. However, whether cerebral hypoglycemia/hypometabolism contributes to the development of AD or is a response of reduced neuronal activity remains unclear. To investigate the causal relationship, we cultured the differentiated N2a neuroblastoma cells in glucose/pyruvate-deficient media (GDM). Shortly after the N2a cells cultured in the GDM, the mitochondria membrane potential was reduced and the AMP-activated-proteinkinase (AMPK), an energy sensor, was activated. Treatment of GDM not only increased the levels of tau phosphorylation at Ser(262) and Ser(396), but also increased the levels of active forms of GSK3alpha and GSK3beta, two known kinases for tau phosphorylation, of the N2a cells. The levels of activated Akt, a mediator downstream to AMPK and upstream to GSK3alpha/beta, were reduced by the GDM treatment. The effect of hypoglycemia was further examined in vivo by intracerebroventricular (icv) injection of streptozotocin (STZ) to the Wistar rats. STZ selectively injuries glucose transporter type 2 bearing cells which are primarily astrocytes in the rat brain, hence, interrupts glucose transportation from blood vessel to neuron. STZicv injection induced energy crisis in the brain regions surrounding the ventricles, as indicated by higher pAMPK levels in the hippocampus, but not cortex far away from the ventricles. STZ-icv treatment increased the levels of phosphorylated tau and activated GSK3beta, but decreased the levels of activated Akt in the hippocampus. The hippocampus-dependent spatial learning and memory was impaired by the STZ-icv treatment. In conclusion, our works suggest that hypoglycemia enhances the AMPK Akt-GSK3 pathway and leads to tau hyperphosphorylation. PMID- 23036023 TI - BACE1 levels by APOE genotype in non-demented and Alzheimer's post-mortem brains. AB - The APOE genotype is a known susceptibility factor for Alzheimer's disease (AD). It is apparent that the presence of the APOE epsilon40 allele increases the risk for developing AD, lowers the age of onset in AD, and may influence the pathological burden seen in AD. In this study, we asked whether BACE1 levels differ by APOE genotype in the AD and non-demented (ND) brain. We isolated mid frontal cortex (MFC) and mid-temporal cortex (MTC) from post-mortem ND and AD subjects that were APOE epsilon3/3, epsilon3/4, epsilon4/4 carriers. All AD subjects met NINDS-ADRDA and NIA-Reagan criteria for a diagnosis of AD. The MFC and MTC were homogenized and the lysates underwent ELISA and Western blotting for BACE1. The ELISA revealed that total BACE1 levels were lower in the MFC of AD compared to ND subjects. Furthermore, in APOE epsilon4 carriers BACE1 levels were lower than epsilon3/3 carriers in the ND frontal cortex. No difference in BACE1 levels was observed in AD MFC and in ND and AD MTC tissues. The ELISA results were confirmed by Western blotting. Our data suggest that brain BACEl levels may be influenced by the apolipoprotein E genotype before the onset of AD, providing an alternative explanation for the lower amyloid beta 42 levels in CSF in ND and AD subjects. PMID- 23036025 TI - Benefit of 13-desmethyl spirolide C treatment in triple transgenic mouse model of Alzheimer disease: beta-amyloid and neuronal markers improvement. AB - Spirolides are marine toxins that are not currently in the routine monitoring assays. Nicotinic receptors seem to be the target of these compounds making them a promising pharmacological tool for related diseases as dementias as previously shown in vitro. In the present work, the bioavailability of 13-desMethyl spirolide C (13-desMeC) in the brain and in vivo effects were tested. Bioavailability was studied by ultra-performance liquid chromatography-mass spectrometry and its effect over Alzheimer hallmarks was studied by Proton magnetic resonance spectroscopy (H-MRS) and western blot. Only 2 minutes after its intraperitoneal injection it is found in brain and remains detectable even 24 hours post administration. Based on previous works that showed beneficial effects in an in vitro model of Alzheimer's disease (AD), we studied the effect in the same mice, 3xTg-AD, in vivo. We found that 13-desMeC (11.9 ug/kg, i.p.) induced positive effects on AD markers with an increase in N-acetyl aspartate (NAA) levels. These results were supported by an increase in synaptophysin levels and also a decrease in the intracellular amyloid beta levels in the hippocampus of treated 3xTg- AD versus non treated mice remarking the positive effects of this molecule in a well known model of AD. These data indicate for the first time that 13-desMeC cross the blood brain barrier and shows in vivo beneficial effects against AD after administration of low intraperitoneal doses of this marine toxin. This toxin may inspire a novel medical treatment of age-related diseases. PMID- 23036026 TI - Metal-score as a potential non-invasive diagnostic test for Alzheimer's disease. AB - The link between biometals and Alzheimer's disease (AD) has been investigated with a focus on local metal accumulations. In this work, we have looked at systemic metal changes and computed a score (M-score) based on metal disarrangements to discriminate patients with AD from patients with vascular dementia (VaD) and from controls. We measured serum levels of iron, copper, ceruloplasmin, transferrin, and total antioxidant capacity (TAS), performed Apolipoprotein E (APOE) genotyping and calculated non-ceruloplasmin copper ('free' copper') levels, transferrin saturation, total iron binding capacity, and ceruloplasmin-transferrin ratio (Cp/Tf) in 93 patients with AD, 45 patients with VaD, and 48 controls. All subjects underwent biochemical, neuroimaging and cognitive evaluations. Significant differences were observed among the tested groups for the levels of copper, free copper, peroxides, and TAS and for the Cp/Tf with disparity in couple comparison. On this basis we created the M-score as linear combination of biometal variables and APOE genotype. Besides its ability to discriminate AD patients vs. controls (ROC AUC=90%), M-score was able to distinguish AD vs. VaD (ROC AUC=79%). Moreover, we calculated the sensitivity and the specificity for M-score and for the other significant variables: M-score reached the highest sensitivity without a relevant loss in terms of specificity. When we compared M-score with APOE genotype and Medial Temporal Atrophy score, it resulted statistically better than these diagnostic markers. In conclusion, we confirm the link between biometals and AD and suggest its potential as diagnostic tool. Further studies may elucidate its potential role as reliable diagnostic test. PMID- 23036027 TI - A prospective analysis of the preoperative assessment of duodenal involvement in gallbladder cancer. AB - BACKGROUND: Duodenal involvement occurs frequently in gallbladder cancer (GBC) as a result of the proximity of the duodenum to the gallbladder. METHODS: The study group included 74 GBC patients assessed between August 2009 and March 2011 in whom computed tomography (CT) of the abdomen indicated suspicion for duodenal involvement. RESULTS: Of 172 patients with resectable GBC, 74 (43.0%) had suspected duodenal involvement on imaging. Of these, 51 (68.9%) had suspected duodenal involvement on upper gastrointestinal endoscopy (UGIE). Symptoms of gastric outlet obstruction (GOO) were present in only 14 (18.9%) patients. Thirteen (17.6%) patients underwent staging laparoscopy alone. Of the 61 patients who underwent laparotomy, 31 (50.8%) were found to have actual duodenal involvement. The positive predictive value (PPV) of CT of the abdomen for duodenal involvement was 50.8% (31 of 61 patients). The addition of UGIE increased the PPV to 65.9% (27 of 41 patients). In the subgroup with evidence of duodenal mural thickening or mucosal irregularity on CT of the abdomen (n= 9) or duodenal mucosal infiltration on UGIE (n= 14), the PPV increased to 100%. A total of 33 (44.6%) patients underwent curative resection. The resectability rate was significantly lower in patients with symptoms of GOO [two of 14 (14.3%) vs. 31 of 60 (51.7%); P= 0.010], CT findings of duodenal mural thickening or mucosal irregularity compared with only loss of the fat plane [two of 12 (16.7%) vs. 31 of 62 (50.0%); P= 0.032], and UGIE evidence of duodenal infiltration compared with extrinsic compression or normal endoscopic findings [three of 16 (18.8%) vs. 18 of 35 (51.4%) and 12 of 23 (52.2%), respectively; P= 0.027 and P= 0.036, respectively]. CONCLUSIONS: Overall, CT of the abdomen demonstrated a PPV of 50.8% in detecting duodenal involvement, which increased to 65.9% with the addition of UGIE. The combined presence of GOO symptoms, CT findings of duodenal mural thickening and mucosal irregularity, and UGIE findings of infiltration of the duodenal mucosa significantly decreases resectability but does not preclude resection. PMID- 23036028 TI - Role of pain medications, consultants, and other services in improved pain control of elderly adults with cancer in geriatric evaluation and management units. AB - OBJECTIVES: To determine whether pain medication use and inpatient consultations and services were associated with significantly better pain control. DESIGN: Secondary data analysis from a randomized two-by-two factorial trial. Hospitalized, frail individuals aged 65 and older were randomized to receive care in a geriatric inpatient unit, a geriatric outpatient clinic, both, or neither. SETTING: Eleven Veterans Affairs Medical Centers. PARTICIPANTS: Ninety-nine individuals with a diagnosis of cancer, excluding nonmelanoma skin cancer; 44 received geriatric evaluation and management unit (GEMU) care and 55 usual care. MEASUREMENTS: Pain medications were measured at baseline and discharge; consultations and other services were quantified for the entire admission. RESULTS: Participants receiving GEMU care had a significantly higher number of consultations than those in usual care. Participants in GEMU care received psychiatry, endocrinology, and psychology consultations 12.7% (P = .004), 9.1% (P = .04), and 21.8% (P = .05) times more, respectively, and occupational and physical therapy 27.3% (P = .004) and 18.2% (P = .04) more, respectively. There were no significant differences in pain medication use between intervention and usual care. CONCLUSION: Significantly greater use of psychology, psychiatry, physical and occupational therapy in the GEMU participants may have improved the effectiveness of pain management in individuals in inpatient GEMUs. Although analgesic use was not significantly different between the GEMU and usual care groups, small sample size may have limited the ability to detect these differences. PMID- 23036029 TI - Effect of sterilization on solute transport performances of super high-flux dialyzers. AB - The effect of sterilization was quantitatively evaluated for modern super high flux dialyzers in terms of solute transport performances for autoclave sterilization (AC), gamma ray sterilization (G-ray), combination of these two and no sterilization (NS) as reference. A commercial polysulfone dialyzer (Kawasumi Laboratory Co., Tokyo, Japan) was chosen for investigation with six different sterilization processes, i.e., sterilization with AC one time and two times, that with G-ray using either no additives or an additive, that with AC one time followed by G-ray using no additive and that with NS. In vitro dialysis and ultrafiltration experiments were performed with aqueous test solution as pseudo blood, varying Q(B) , Q(D) , and Q(F) . Creatinine (MW113), vitamin B(12) (MW1355), and alpha-chymotrypsin (MW25000) were chosen as test solutes for dialysis experiments. Clearances (C(L) ) calculated from dialysis experiments and the sieving coefficient for albumin (MW66000) from ultrafiltration experiments were compared among six models. A dialyzer with NS showed much lower clearances for all three solutes than those with sterile. Therefore, the sterilization increases the solute transfer performances. Although no significant changes in clearances for creatinine and vitamin B(12) were found among five sterile models, much higher clearances for alpha-chymotrypsin were found in AC sterile models. Then, the effect of sterilization may become greater with the increase of molecular weight of solutes. According to the results of the sieving coefficient for albumin, AC may have enlarged the pore size of the membrane that could increase clearances for large solutes without changing those for relatively small solutes. The sterilization increases the solute clearance even in so-called super high-flux dialyzers and the effect of sterilization may be greater in larger solutes. PMID- 23036030 TI - Physiologic volume of phosphorus during hemodialysis: predictions from a pseudo one-compartment model. AB - The kinetics of plasma phosphorus concentrations during hemodialysis (HD) are complex and cannot be described by conventional one- or two-compartment kinetic models. It has recently been shown by others that the physiologic (or apparent distribution) volume for phosphorus (Vr-P) increases with increasing treatment time and shows a large variation among patients treated by thrice weekly and daily HD. Here, we describe the dependence of Vr-P on treatment time and predialysis plasma phosphorus concentration as predicted by a novel pseudo one compartment model. The kinetics of plasma phosphorus during conventional and six times per week daily HD were simulated as a function of treatment time per session for various dialyzer phosphate clearances and patient-specific phosphorus mobilization clearances (K(M)). Vr-P normalized to extracellular volume from these simulations were reported and compared with previously published empirical findings. Simulated results were relatively independent of dialyzer phosphate clearance and treatment frequency. In contrast, Vr-P was strongly dependent on treatment time per session; the increase in Vr-P with treatment time was larger for higher values of K(M). Vr-P was inversely dependent on predialysis plasma phosphorus concentration. There was significant variation among predicted Vr-P values, depending largely on the value of K(M). We conclude that a pseudo one compartment model can describe the empirical dependence of the physiologic volume of phosphorus on treatment time and predialysis plasma phosphorus concentration. Further, the variation in physiologic volume of phosphorus among HD patients is largely due to differences in patient-specific phosphorus mobilization clearance. PMID- 23036031 TI - Association between antimicrobial locks for hemodialysis central venous catheters and antibiotic resistance. AB - Antimicrobial locks (AMLs) are effective in preventing catheter-associated bloodstream infections (CABSI) in hemodialysis (HD) patients, but may increase antibiotic resistance. In our center, gentamicin-heparin locks have been used for all HD central venous catheters since July 1, 2004. We previously reported a significant reduction in CABSI rates, but a short-term trend to increased gentamicin resistance among coagulase-negative staphylococci (CNS). We present a further 3-year follow-up study of bacterial resistance in our dialysis center. We examined the susceptibility of bacterial isolates from CABSI from July 1, 2006 to July 31, 2009, restricting analyses to CNS, gram-negative bacilli, and Staphylococcus aureus. We compared the frequency of gentamicin resistance in these isolates between four groups: CABSI in HD patients, non-CABSI in HD patients, peritonitis in peritoneal dialysis (PD) patients, and bloodstream infection in the non-end-stage kidney failure general population. For CNS isolates, the frequency of gentamicin resistance was similar between the CABSI and PD peritonitis groups, but higher in both groups than the general population. The pattern was similar for S. aureus although the differences were of borderline statistical significance. The frequency of gentamicin resistance among gram negative bacilli isolates did not differ between groups. Gentamicin resistance was more common than expected in CNS and possibly S. aureus isolates from CABSI, although this resistance may be part of a generally higher frequency of antibiotic resistance in the dialysis population, rather than a direct result of AML use. AMLs remain a valuable clinical tool although surveillance is needed to ensure that benefits continue to outweigh risks. PMID- 23036032 TI - Bioimpedance analysis and cardiovascular status in pediatric patients on chronic hemodialysis. AB - Bioimpedance analysis (BIA) is reported to be useful in assessing dry weight (DW) in patients on hemodialysis (HD), but its exact role has never been clearly defined. We reviewed our experience of using the BIA measure of reactance (Xc) in pediatric patients on chronic HD. Our approach is currently based on identifying a range of patient-specific Xc values at which a child can be considered at DW according to a multidisciplinary assessment. Values lower than the patient specific limit suggests the need for a reduction in DW, whereas values higher than the limit suggest that DW should be increased. The accuracy of our approach was retrospectively assessed by analyzing the left ventricular mass index (LVMI) and the incidence of pulmonary edema (PE) in two groups: The first consisted of 13 patients (median age 15.6 years) on dialysis in 2007, before the introduction of the BIA-based approach; the second included 18 patients (median 14.8 years) on dialysis in 2011. In 2007, three children experienced four episodes of PE, whereas no PE occurred in 2011. The median LVMI was 56.8 g/m(2.7) in 2007, and 44.5 g/m(2.7) in 2011 (P < 0.05). The percentage of patients with LV hypertrophy (LVMI>38.5 g/m(2.7)) was 92.3% in 2007 and 61.1% in 2011 (P < 0.05). There were no between-group differences in terms of blood pressure, antihypertensive medications, percentage of symptomatic sessions, or biochemistry. In conclusion, a simple approach based on BIA may be useful in assessing DW in pediatric patients on HD, and thus improve their cardiovascular status. PMID- 23036033 TI - Home hemodialysis: a successful option for obese and bariatric people with end stage kidney disease. AB - The increasing prevalence of obesity in developed countries is reflected in the chronic kidney disease, dialysis, and transplant populations. The added risk factor of obesity increases the risk of vascular events, inflammation, insulin resistance, blood pressure, dyslipidemia, and mortality risk. Nephrology center policies may exclude obese people from transplantation programs resulting in many years of dialysis. The case of a 215-kg Australian male who has successfully dialyzed at home for more than 8 years will be used to illustrate the important considerations and clinical support that these people require for successful home dialysis treatment. The aim of this paper is to report on a program that has successfully trained 23 obese (body mass index >30) people who commenced on home hemodialysis between 2001 and 2009. Body weight ranged between 94.0 and 215 kg (mean 126, SD 26.19) and body mass index ranged between 34.9 and 71 (mean 43.38, SD 9.99) at the start of home training. During the 8.5 years of follow-up, average time on home dialysis was 43.7 months. Home hemodialysis is a feasible treatment for obese people to facilitate longer and more frequent dialysis, resulting in improved hemodynamic stability and improved quality of life. For obese people with end-stage kidney disease, home hemodialysis has shown to be cost-effective and can result in greater treatment efficacy than in-center hospital dialysis. PMID- 23036034 TI - De novo HBV infection in a Mayo Clinic hemodialysis population: economic impact of reduced HBV testing and a call for changes in current US CDC guidelines on HBV testing protocols. AB - Hemodialysis (HD) exposes end-stage renal disease patients to significantly higher risks for Hepatitis B Virus (HBV) infection, a major public health scourge. Therefore, current US CDC guidelines, last revised in 2001, call for monthly HbsAg tests. The charge to Medicare per HbsAg test is $100. In an economic analysis, we hypothesized that in the new environment of Medicare Fee Bundling, this is unwise and wasteful if de novo HBV infection rate among HD patients is <1%. We determined de novo HBV infection rate among a Mayo Clinic HD cohort, July 2000-July 2010. A retrospective analysis of all relevant medical records of the cohort was completed to identify de novo HBV infection. Nine hundred sixty-five HD patients were analyzed. One case of de novo HBV infection was identified in a 54-year old known IV drug user, a previous Hepatitis C carrier. This translates to a de novo HBV case incidence rate of 0.1%. De novo HBV infection among HD patients in the US, 2000-2010, is only 0.1%. In the early 1970s, rates were as high as 30%. We recommend 3-monthly HbsAg testing, but to continue current monthly testing for IV drug users and other high-risk groups. Huge cost savings would result, without any compromise of quality outcomes. With over 500,000 HD patients, this represents a mind-boggling $40 billion savings in Medicare charges over 10 years. The US CDC should revise these outdated guidelines, last revised in 2001, to fall in line with current clinical realities on the ground. PMID- 23036035 TI - Predictors of suboptimal and crash initiation of dialysis at two tertiary care centers. AB - Many end-stage renal disease patients do not have an optimal start to dialysis. Many patients have suboptimal initiation, while others "crash" start on dialysis without prior care from a nephrologist. We examined factors associated with suboptimal or crash starts. We conducted a retrospective cohort study of 377 incident dialysis patients at two tertiary care centers from January 2006 to April 2011. Logistic regression was used to identify factors associated with suboptimal and crash starts to dialysis. Out of 377 patients, 102 (27%) had optimal starts, 221 (59%) had suboptimal starts, and 54 (14%) had crash starts. Three hundred thirty-four patients (89%) began with hemodialysis, while 11% started with peritoneal dialysis. Factors independently associated with a suboptimal start as opposed to an optimal start included nephrology care more than 12 months prior to initiation of dialysis (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.12-0.58), Charlson Comorbidity Index (OR, 1.25 per 1 point; 95% CI, 1.09-1.43), and age (OR, 1.02 per 1 year; 95% CI, 1.00-1.04). In comparison, diabetic nephropathy (OR, 0.25; 95% CI, 0.12-0.54), a history of pulmonary edema within 6 months prior to initiation of dialysis (OR, 3.70; 95% CI, 1.77-7.75), and a diagnosis of chronic obstructive lung disease (OR, 0.07; 95% CI, 0.01-0.52) were independently associated with a crash start. There was a low incidence of optimal dialysis starts in our tertiary care dialysis population. Our study highlights that suboptimal and crash start patients are distinct populations. Modifying factors that predict nonoptimal dialysis starts will need to consider these distinctions. PMID- 23036036 TI - Bath salt intoxication causing acute kidney injury requiring hemodialysis. AB - Traditional bath salts contain a combination of inorganic salts like Epsom salts, table salt, baking soda, sodium metaphosphate, and borax that have cleansing properties. Since 2010, there have been rising concerns about a new type of substance abuse in the name of "bath salts." They are beta-ketone amphetamine analogs and are derivates of cathinone, a naturally occurring amphetamine analog found in the "khat" plant (Catha edulis). Effects reported with intake included increased energy, empathy, openness, and increased libido. Serious adverse effects reported with intoxication included cardiac, psychiatric, and neurological signs and symptoms. Not much is known about the toxicology and metabolism of these compounds. They inhibit monoamine reuptake (dopamine, nor epinephrine, etc.) and act as central nervous system stimulants with high additive and abuse potential because of their clinical and biochemical similarities to effects from use of cocaine, amphetamine, and 3,4-methylenedioxy N-methylamphetamine. Deaths associated with use of these compounds have also been reported. We report a case of acute kidney injury associated with the use of "bath salt" pills that improved with hemodialysis. PMID- 23036037 TI - Piperacillin-induced thrombocytopenia reversed by high-flux hemodialysis in an uremic patient. AB - Drug-induced thrombocytopenia in an infected patient often is overlooked. We present a 74-year-old uremic female with continuous renal replacement therapy developed severe thrombocytopenia during the treatment course of piperacillin/tazobactam. Platelet counts recovered rapidly after discontinuing piperacillin/tazobactam and receiving high-flux hemodialysis. The George criteria indicates piperacillin/tazobactam as the probable cause of thrombocytopenia in this patient. Immediate withdrawal of the causative drug is important for drug induced thrombocytopenia. Prompt high-flux hemodialysis may be an adjunctive management for uremic patients. PMID- 23036038 TI - Isolated pleural effusion as a presentation of high cardiac output heart failure in a hemodialysis patient. AB - Congestive heart failure is a well-recognized complication of hemodialysis arteriovenous fistula. Symptoms of dyspnea are usually associated with signs of congestive heart failure including pulmonary edema, pleural effusions, lower extremity edema, and liver enlargement, to name a few. We present a case of a gentleman with end-stage renal disease on chronic hemodialysis, which developed acute bilateral transudative pleural effusions in the absence of other signs of systemic venous congestion, associated with pulmonary venous congestion. We also discuss the pathogenesis and role of hemodialysis in management of this patient. PMID- 23036039 TI - Decompensated high-output congestive heart failure in a patient with AVF and the role of right heart catheterization: a case study. AB - A 70-year-old Caucasian male presented 8 months postcadaveric renal transplant with slowly progressive shortness of breath, abdominal distention, and cough for a duration of a few days. Thorough evaluation found him to have severe pulmonary hypertension (PH) on echocardiogram with decompensated high-output congestive heart failure. A right heart catheterization was done, which confirmed elevated right-sided pressures and high cardiac output. The mean pulmonary artery pressure, on a Swan-Ganz catheter, improved from 37 to 30 mmHg on partial manual occlusion of his still functioning hemodialysis arteriovenous fistula. Subsequently, the patient underwent ligation of the fistula and this led to gradual improvement in his symptoms. Follow-up right heart catheterization and echocardiogram showed marked improvement and normalization of right heart pressures. We recommend that patients with arteriovenous fistula should undergo close monitoring for development of early signs and symptoms of congestive heart failure and screening for PH by echocardiography post-kidney transplant. Right heart catheterization should be considered if screening is positive. Risk and benefit of fistula closure should be weighed in face of reduced survival from PH in dialysis patients and closure should be considered in post-transplant patients. PMID- 23036040 TI - Stable silaimines with three- and four-coordinate silicon atoms. AB - The reactions of silylenes with organic azides are quite diverse, depending on the substituents of the silylene center and on the nature of the azide employed. Elusive silaimine with three-coordinate silicon atom L(1)SiN(2,6-Triip(2) C(6)H(3)) (5) {L(1) = CH[(C?CH(2))(CMe)(2,6-iPr(2)C(6)H(3)N)(2)] and Triip = 2,4,6-triisopropylphenyl} was synthesized by treatment of the silylene L(1)Si (1) with a sterically demanding 2,6-bis(2,4,6-triisopropylphenyl)phenyl azide (2,6 Triip(2)C(6)H(3)N(3)). The reaction of Lewis base-stabilized dichlorosilylene L(2)SiCl(2) (2) {L(2) = 1,3-bis(2,6-iPr(2)C(6)H(3))imidazol-2-ylidene} with Ph(3)SiN(3) afforded four-coordinate silaimine L(2)(Cl(2))SiNSiPh(3) (6). Treatment of 2,6-Triip(2)C(6)H(3)N(3) with L(3)SiCl (3) (L(3) = PhC(NtBu)(2)) yielded silaimine L(3)(Cl)SiN(2,6-Triip(2)-C(6)H(3)) (7) possessing a four coordinate silicon atom. The reactions of L(3)SiN(SiMe(3))(2) (4) with adamantyl and trimethylsilyl azide furnished silaimine compounds with a four-coordinate silicon atom L(3)(N(Ad)SiMe(3))SiN(SiMe(3)) (8) (Ad = adamantyl) and L(3)(N(SiMe(3))(2))SiN(SiMe(3)) (9). Compound 8 was formed by migration of one of the SiMe(3) groups. Compounds 5-9 are stable under inert atmosphere and were characterized by elemental analysis, NMR spectroscopy, and single-crystal X-ray studies. PMID- 23036041 TI - Mirror writing: a tachistoscopic study of a woman suffering from migraine when writing with the right hand. AB - An experimental study was conducted with a young woman who had suddenly developed mirror writing in the right hand, which she used for writing. She was not cured for eight years. The patient was ambidextrous and had no medical complaints except for migraine with perceptual and sensory abnormalities, and an enlarged cavity of the septum pellucidum. A previous study using functional magnetic resonance imaging (fMRI), conducted when she imagined letters and wrote letters in the air with either hand, indicated that both her cerebral hemispheres were active. In the present study three experiments were conducted using a tachistoscope to explore the stage in the cognitive process when directional errors emerged. In the experiments, after independently being presented with Attneave's meaningless figures or letters to each hemisphere, participants were requested to do the following: (a) verbally respond whether the orientation of two consecutively shown figures were the same or different and the letters were standard or reversed; (b) distinguish the orientations with right and left hand movements other than by writing (by pushing a button); and (c) reproduce the stimuli (drawing) immediately after the presentation. Results showed a higher rate of incorrect directions only when drawings were reproduced by the right hand. Results also indicated that the woman's inaccurate judgment in direction emerged only when in writing and not at the perceptual level, or when responding with hand movements other than writing. Her migraine was cured after five years following the experiment. The mirror writing was cured 2-3 months later. PMID- 23036042 TI - Formulation development of albumin based theragnostic nanoparticles as a potential delivery system for tumor targeting. AB - BACKGROUND: Generally, chemotherapeutic drugs attack on both normal and tumor cells non-specifically causing life threatening side effects, necessitating targeted drug delivery to tumors. PURPOSE: The purpose of this study is to formulate albumin-based nanoparticles for tumor targeted drug delivery and noninvasive diagnosis. METHODS: Albumin based nanoparticles (NPs) were developed as a potential tumor theragnostic agent by entrapping an anti cancer drug, doxorubicin and a near infrared dye, indocyanine green. Theragnostic nanoparticles were prepared using a well established coacervation/nanoprecipitation method followed by lyophilization. The formulation was optimized by varying process parameters using full factorial design of experiments. Release of dye and drug from NPs and physical state of the drug in NPs was studied using DSC. The NPs were injected into tumor bearing mice intravenously and imaged using a bio-imager. RESULTS: The optimized nanoparticle formulation had a particle size of 125.0 +/- 1.8 nm, poly dispersity index of 0.180 +/- 0.057 and zeta potential of -32.7 +/- 0.9 mV. The release of dye and drug from the nanoparticles was determined to be quasi-fickian diffusion mediated. Differential scanning calorimetry (DSC) studies revealed the stability of drug in the NP. The in-vivo studies showed enhanced accumulation of the dye loaded NPs at the tumor site than the dye solution, thus allowing noninvasive tumor monitoring. CONCLUSION: These results project the newly proposed and evaluated nanoparticle formulation as a potential tumor targeting and imaging delivery system. PMID- 23036043 TI - Reversible photodynamic chloride-selective sensor based on photochromic spiropyran. AB - We report here for the first time on a reversible photodynamic bulk optode sensor based on the photoswitching of a spiropyran derivative (Sp). The photoswitching of Sp induces a large basicity increase in the polymeric phase, which triggers the extraction of Cl(-) and H(+). Cl(-) is stabilized by a lipophilic chloride selective ionophore inside the membrane, while H(+) binds with the open form of Sp and induces a spectral change, hence providing the sensor signal. The system was studied with spectroscopic and electrochemical methods. PMID- 23036044 TI - Speed bumps and the disabled community. PMID- 23036046 TI - Targeting the blind spot of polycationic nanocarrier-based siRNA delivery. AB - Polycationic nanocarriers attract increasing attention to the field of siRNA delivery. We investigated the self-assembly of siRNA vs pDNA with polycations, which are broadly used for nonviral gene and siRNA delivery. Although polyethyleneimine (PEI) was routinely adopted as siRNA carrier based on its efficacy in delivering pDNA, it has not been investigated yet why PEI efficiently delivers pDNA to cells but is controversially discussed in terms of efficacy for siRNA delivery. We are the first to investigate the self-assembly of PEI/siRNA vs PEI/pDNA and the steps of complexation and aggregation through different levels of hierarchy on the atomic and molecular scale with the novel synergistic use of molecular modeling, molecular dynamics simulation, isothermal titration calorimetry, and other characterization techniques. We are also the fist to elucidate atomic interactions, size, shape, stoichiometry, and association dynamics for polyplexes containing siRNA vs pDNA. Our investigation highlights differences in the hierarchical mechanism of formation of related polycation siRNA and polycation-pDNA complexes. The results of fluorescence quenching assays indicated a biphasic behavior of siRNA binding with polycations where molecular reorganization of the siRNA within the polycations occurred at lower N/P ratios (nitrogen/phosphorus). Our results, for the first time, emphasize a biphasic behavior in siRNA complexation and the importance of low N/P ratios, which allow for excellent siRNA delivery efficiency. Our investigation highlights the formulation of siRNA complexes from a thermodynamic point of view and opens new perspectives to advance the rational design of new siRNA delivery systems. PMID- 23036045 TI - Ageing and long-term CD4 cell count trends in HIV-positive patients with 5 years or more combination antiretroviral therapy experience. AB - OBJECTIVES: The aim of this study was to describe the long-term changes in CD4 cell counts beyond 5 years of combination antiretroviral therapy (cART). If natural ageing leads to a long-term decline in the immune system via low-grade chronic immune activation/inflammation, then one might expect to see a greater or earlier decline in CD4 counts in older HIV-positive patients with increasing duration of cART. METHODS: Retrospective and prospective data were examined from long-term virologically stable HIV-positive adults from the Australian HIV Observational Database. We estimated mean CD4 cell count changes following the completion of 5 years of cART using linear mixed models. RESULTS: A total of 37 916 CD4 measurements were observed for 892 patients over a combined total of 9753 patient-years. Older patients (> 50 years old) at cART initiation had estimated mean (95% confidence interval) changes in CD4 counts by year-5 CD4 count strata (< 500, 500-750 and > 750 cells/MUL) of 14 (7 to 21), 3 (-5 to 11) and -6 (-17 to 4) cells/MUL/year. Of the CD4 cell count rates of change estimated, none were indicative of long-term declines in CD4 cell counts. CONCLUSIONS: Our results suggest that duration of cART and increasing age do not result in decreasing mean changes in CD4 cell counts for long-term virologically suppressed patients, indicating that the level of immune recovery achieved during the first 5 years of treatment is sustained through long-term cART. PMID- 23036048 TI - Is it dormant pulmonary vein conduction? PMID- 23036047 TI - Effect of flaxseed supplementation and exercise training on lipid profile, oxidative stress and inflammation in rats with myocardial ischemia. AB - BACKGROUND: Flaxseed has recently gained attention in the area of cardiovascular disease primarily because of its rich contents of alpha-linolenic acid (ALA), lignans, and fiber. Although the benefits of exercise on any single risk factor are unquestionable, the effect of exercise on overall cardiovascular risk, when combined with other lifestyle modifications such as proper nutrition, can be dramatic.This study was carried out to evaluate the protective role of flaxseed and exercise on cardiac markers, lipids profile and inflammatory markers in isoproterenol (ISO)-induced myocardial ischemia in rats. METHODS: The research was conducted on 40 male albino rats, divided into 4 groups (n=10): group I served as control, group II has acute myocardial ischemia induced by isoproterenol, groups III and IV have acute myocardial ischemia induced by isoproterenol pretreated with flaxseed supplementation orally for 6 weeks, additionally group IV practiced muscular exercise through swimming. RESULTS: Alterations of lipid profile, cardiac and inflammatory markers (Il-1beta, PTX 3 and TNF- alpha) were observed in myocardial ischemia group. Flaxseed supplementation combined with exercise training showed significant increase of HDL and PON 1, on the other hand cardiac troponin, Il- 1beta and TNF- alpha levels significantly decreased as compared to myocardial ischemic group. Receiver Operating Characteristics (ROC) analysis of cTnI, PTX 3, Il-1beta and TNF- alpha revealed a satisfactory level of sensitivity and specificity. CONCLUSION: Regular exercise enhances the improvement in plasma lipoprotein levels and cardiovascular protection that results from flaxseed supplementation by mitigating the pathophysiology of atherosclerosis. Elevation of HDL, the antioxidant PON 1 and the cardioprotective marker PTX 3 emphasizes the protective effects of flaxseed and muscular exercise mutually against the harmful effects of acute myocardial ischemia. PMID- 23036049 TI - Toward attenuating the impact of arm positions on electromyography pattern recognition based motion classification in transradial amputees. AB - BACKGROUND: Electromyography (EMG) pattern-recognition based control strategies for multifunctional myoelectric prosthesis systems have been studied commonly in a controlled laboratory setting. Before these myoelectric prosthesis systems are clinically viable, it will be necessary to assess the effect of some disparities between the ideal laboratory setting and practical use on the control performance. One important obstacle is the impact of arm position variation that causes the changes of EMG pattern when performing identical motions in different arm positions. This study aimed to investigate the impacts of arm position variation on EMG pattern-recognition based motion classification in upper-limb amputees and the solutions for reducing these impacts. METHODS: With five unilateral transradial (TR) amputees, the EMG signals and tri-axial accelerometer mechanomyography (ACC-MMG) signals were simultaneously collected from both amputated and intact arms when performing six classes of arm and hand movements in each of five arm positions that were considered in the study. The effect of the arm position changes was estimated in terms of motion classification error and compared between amputated and intact arms. Then the performance of three proposed methods in attenuating the impact of arm positions was evaluated. RESULTS: With EMG signals, the average intra-position and inter-position classification errors across all five arm positions and five subjects were around 7.3% and 29.9% from amputated arms, respectively, about 1.0% and 10% low in comparison with those from intact arms. While ACC-MMG signals could yield a similar intra-position classification error (9.9%) as EMG, they had much higher inter-position classification error with an average value of 81.1% over the arm positions and the subjects. When the EMG data from all five arm positions were involved in the training set, the average classification error reached a value of around 10.8% for amputated arms. Using a two-stage cascade classifier, the average classification error was around 9.0% over all five arm positions. Reducing ACC-MMG channels from 8 to 2 only increased the average position classification error across all five arm positions from 0.7% to 1.0% in amputated arms. CONCLUSIONS: The performance of EMG pattern-recognition based method in classifying movements strongly depends on arm positions. This dependency is a little stronger in intact arm than in amputated arm, which suggests that the investigations associated with practical use of a myoelectric prosthesis should use the limb amputees as subjects instead of using able-body subjects. The two stage cascade classifier mode with ACC-MMG for limb position identification and EMG for limb motion classification may be a promising way to reduce the effect of limb position variation on classification performance. PMID- 23036050 TI - Glycodelin A is a prognostic marker to predict poor outcome in advanced stage ovarian cancer patients. AB - BACKGROUND: Glycodelin is a cell surface glycoprotein offering a unique gender specific carbohydrate configuration. Sialylated carbohydrate structures, which are unusual for mammals, characterize Glycodelin isolated from amniotic fluid (Glycodelin A, GdA). Glycodelin in general exerts multiple, partly opposing functions ranging from immunosuppression to cell differentiation. As these markedly influence tumorigenesis, this study aimed to clarify whether expression of different Glycodelin isoforms is related to clinicopathological characteristics and prognosis of ovarian cancer patients. Further the use of Glycodelin as a serum marker in benign and malignant ovarian diseases was evaluated. METHODS: Ovarian cancer specimens (n = 152) were stained for Glycodelin with carbohydrate and peptide specific antibodies. Associations between Glycodelin expression and histological grading, FIGO stage as well as patient's prognosis were examined. Glycodelin was correlated to expression of gonadotropin receptors and mucin-1, which are discussed as ovarian cancer tissue markers. In addition, Glycodelin serum concentrations were analyzed in patients suffering from benign (n = 73) or malignant (n = 38) ovarian neoplasias. RESULTS: Glycodelin A was found to be an independent prognostic marker for poor prognosis in advanced ovarian cancer patients. GdA staining correlated with gonadotropin receptor (FSHR and LHCGR) and with hCG expression. Gd expression showed a positive correlation with a tumour-associated epitope of mucin 1 (TA-MUC1). Further, compared to ovarian cancer, serum Gd was increased in patients with benign ovarian tumors. CONCLUSION: Glycodelin A might be related to tumor aggressiveness and poor clinical outcome in advanced epithelial ovarian cancer. Glycodelin serum levels found in patients suffering from benign ovarian tumors, might contribute to a more global attenuation during progression of these precursor lesions. PMID- 23036051 TI - Pharmacological and toxicological evaluation of Urtica dioica. AB - CONTEXT: Medicinal plants are a largely unexplored source of drug repository. Urtica dioica L. (Urticaceae) is used in traditional medicine to treat diverse conditions. OBJECTIVE: The present study describes the antidiabetic, antiinflammatory, antibacterial activity, and toxicological studies of Urtica dioica. MATERIALS AND METHODS: U. dioica leaves were subjected to solvent extraction with hexane, chloroform, ethyl acetate, methanol, and aqueous, respectively, and screened for antidiabetic (300 mg/kg bw by glucose tolerance test; GTT), antiinflammatory (200 mg/kg bw by rat paw edema assay) and antibacterial activities [by disc-diffusion and minimum inhibitory concentration (MIC) assays]. Toxicological studies were carried on Artemia salina and Wistar rats; phytochemical analyses were carried out, using chromatographic and spectroscopic techniques. RESULTS: The aqueous extract of U. dioica (AEUD) significantly (p < 0.001; 67.92%) reduced the blood glucose level during GTT in Wistar rats with an effective dose of 300 mg/kg bw in dose-dependent studies. High-performance liquid chromatography with photodiode-array detection (HPLC-DAD) analysis showed the presence of hydroxycinnamic acid derivatives and flavonoids in AEUD. Hexane Fraction-2 (HF2) exhibited both antiinflammatory activity (48.83% after 3 h), comparable to that of indomethacin (53.48%), and potent antibacterial activity with MIC values ranging from 31.25-250 ug/mL against all the tested strains. Gas chromatography-mass spectrometry (GC-MS) analysis showed fatty acid esters and terpenes as the major constituents of HF2. Toxicity tests showed higher safety margin of all the solvent extracts with LC(50) > 1000 MUg/mL each on A. salina. DISCUSSION AND CONCLUSION: Our results showed that the U. dioica leaves are an interesting source of bioactive compounds, justifying their use in folk medicine, to treat various diseases. PMID- 23036053 TI - The complexities of hydrolytic enzymes from the termite digestive system. AB - The main challenge in second generation bioethanol production is the efficient breakdown of cellulose to sugar monomers (hydrolysis). Due to the recalcitrant character of cellulose, feedstock pretreatment and adapted hydrolysis steps are needed to obtain fermentable sugar monomers. The conventional industrial production process of second-generation bioethanol from biomass comprises several steps: thermochemical pretreatment, enzymatic hydrolysis and sugar fermentation. This process is undergoing continuous optimization in order to increase the bioethanol yield and reduce the economic cost. Therefore, the discovery of new enzymes with high lignocellulytic activity or new strategies is extremely important. In nature, wood-feeding termites have developed a sophisticated and efficient cellulose degrading system in terms of the rate and extent of cellulose hydrolysis and exploitation. This system, which represents a model for digestive symbiosis has attracted the attention of biofuel researchers. This review describes the termite digestive system, gut symbionts, termite enzyme resources, in vitro studies of isolated enzymes and lignin degradation in termites. PMID- 23036052 TI - Monocytes and the 38kDa-antigen of mycobacterium tuberculosis modulate natural killer cell activity and their cytolysis directed against ovarian cancer cell lines. AB - BACKGROUND: Despite strong efforts to improve clinical outcome of ovarian cancer patients by conventional and targeted immuno-based therapies, the prognosis of advanced ovarian cancer is still poor. Natural killer (NK) cells mediate antibody dependent cellular cytotoxicity (ADCC), release immunostimulatory cytokines and thus function as potent anti-tumour effector cells. However, tumour cells developed mechanisms to escape from an effective immune response. So highly immunogenic substances, like the 38 kDa-preparation of M. tuberculosis, PstS-1, are explored for their potential to enhance cancer-targeted immune responses. In this study we examined the modulation of different NK cell functions by accessory monocytes and PstS-1. We focussed on NK cell activation as well as natural and antibody-dependent cellular cytotoxicity directed against epidermal-growth-factor receptor (EGFR)-positive ovarian cancer cell lines. METHODS: Activation, cytokine release and cytotoxicity of NK cells stimulated by monocytes and PstS-1 were determined by FACS-analysis, ELISA, Bioplex assay and quantitative polymerase chain reaction (qPCR). Transwell assays were used to discriminate cell-cell contact-dependent from contact-independent mechanisms. Five ovarian cancer cell lines (A2780, IGROV-1, OVCAR-3, OVCAR-4 and SKOV-3) with different EGFR expression were used as target cells for natural and antibody-dependent cellular cytotoxicity assays. Cetuximab (anti-EGFR-antibody) was used for ADCC studies. RESULTS: Our data show that monocytes effectively enhance activation as well natural and antibody-dependent cytolytic activity of NK cells. PstS-1 directly stimulated monocytes and further activated monocyte-NK-co-cultures. However, PstS 1 did not directly influence purified NK cells and did also not affect natural and antibody-dependent cellular cytotoxicity directed against EGFR-positive ovarian cancer cells, even in presence of monocytes. Direct cell-cell contact between NK cells and monocytes was required for NK activation, while released cytokines seemed to play a minor role. CONCLUSIONS: Our data suggest that monocytes enhance natural and antibody-dependent cytotoxic activity of NK cells in a cell-cell contact dependent manner. The TLR-agonist PstS-1 provides additional monocyte activation and induces NK activation markers, while NK cytotoxicity remains unaffected. We conclude that monocytes provide accessory function for ADCC exerted by NK during antibody-based cancer immunotherapy directed against EGFR-positive ovarian cancer cells. PMID- 23036054 TI - Targeting the estrogen receptor using steroid-therapeutic drug conjugates (hybrids). AB - The estrogen receptor (ER) is a potentially useful biological target for diagnosis and therapy in hormonally responsive human breast cancer. This protein is often overexpressed both on the membrane and on the nuclear compartment of breast cancer cells and therefore provides a mechanism for targeted drug delivery. Over the past 30 years, many research groups have attempted to exploit the high affinity and receptor selectivity of steroidal estrogens to deliver cytotoxic agents that by themselves lack selectivity. In this review, we describe the strategies and methods employed by those investigators in their efforts to develop steroid-drug conjugates with the goals of enhanced antiproliferative activity and ER-selectivity. In particular, the choices of steroid scaffolds and sites for drug conjugation have evolved as the understanding of role of ER in cell function has expanded. Present knowledge of the mechanism of action for estrogens and antiestrogens helps explain the failure of most efforts to achieve their stated objectives. The review culminates in the description of our program, which has produced the first conjugate that clearly has achieved those goals and provides an approach for developing new agents for future clinical use. PMID- 23036055 TI - Dual stimuli-responsive polymeric hollow nanogels designed as carriers for intracellular triggered drug release. AB - Dual stimuli-responsive hollow nanogel spheres serving as an efficient intracellular drug delivery platform were obtained from the spontaneous coassociation of two graft copolymers into the vesicle architecture in aqueous phase. Both copolymers comprise acrylic acid (AAc) and 2-methacryloylethyl acrylate (MEA) units as the backbone and either poly(N-isopropylacrylamide) (PNIPAAm) alone or both PNIPAAm and monomethoxypoly(ethylene glycol) (mPEG) chain segments as the grafts. The assemblies were then subjected to covalent stabilization within vesicle walls with ester-containing cross-links by radical polymerization of MEA moieties, thereby leading to hollow nanogel particles. Taking the advantage of retaining a low quantity of payload within polymer layer enclosed aqueous chambers through the entire loading process, doxorubicin (DOX) in the external bulk phase can be effectively transported into the gel membrane and bound therein via electrostatic interactions with ionized AAc residues and hydrogen-bond pairings with PNIPAAm grafts at pH 7.4. With the environmental pH being reduced (e.g., from 7.4 to 5.0) at 37 degrees C, the extensive disruption of AAc/DOX complexes due to the reduced ionization of AAc residues within the gel layer and the pronounced shrinkage of nanogels enable the rapid release of DOX species from drug-loaded hollow nanogels. By contrast, the drug liberation at 4 degrees C was severally restricted, particularly at pH 7.4 at which the DOX molecules remain strongly bound with ionized AAc residues and PNIPAAm grafts. The in vitro characterizations suggest that the DOX-loaded hollow nanogel particles after being internalized by HeLa cells via endocytosis can rapidly release the payload within acidic endosomes or lysosomes. This will then lead to significant drug accumulation in nuclei (within 1 h) and a cytotoxic effect comparable to free drug. This work demonstrates that the novel DOX-loaded hollow nanogel particles show great promise of therapeutic efficacy for potential anticancer treatment. PMID- 23036057 TI - Guidelines for using electronic and social media: the regulatory perspective. AB - Social media can be a very effective way of communicating in nursing, but guidelines for appropriate use by healthcare providers are essential. This article briefly introduces the phenomenon of social media and introduces three actual scenarios where nurses unintentionally violated appropriate use of social media in healthcare. The scenarios are discussed related to social media, career, concerns, and nursing regulation. Incorporating these and other examples with data from board of nursing cases, the nature of complaints against nurses is explored as well as common myths and misunderstandings about using social media platforms. Guidelines for appropriate use by nurses and available resources to inform policy are highlighted. Next steps in social media in nursing should include development of organizational level policies and educational programs on the use of social media. PMID- 23036056 TI - Increasing parity is associated with cumulative effects on memory. AB - BACKGROUND: The purpose of this investigation was to determine if reproductive experience is associated with cumulative effects on human memory performance during pregnancy and if these effects persist into the postpartum period. METHODS: Verbal recall memory performance was assessed in 254 women four times during pregnancy and at 3 months postpartum. The relation between parity and memory function was evaluated with hierarchical linear modeling and analysis of covariance (ANCOVA). RESULTS: The data indicate that the previously documented adverse effects of pregnancy on memory performance are compounded with successive pregnancies. During gestation and postpartum, multiparity was associated with poorer memory function, and these effects did not appear to be due to differences in maternal demographics, depressive symptoms, or sleep quality. CONCLUSIONS: Animal models demonstrate that the effects of reproduction on brain structure and function are both cumulative and enduring. However, little is known about the influence of reproductive experience on the human female brain. These findings provide evidence that in humans, reproduction is associated with striking and perhaps persisting changes in cognitive function. PMID- 23036058 TI - Social media use in nursing education. AB - As technological advances continue to expand connectivity and communication, the number of patients and nurses engaging in social media increases. Nurses play a significant role in identification, interpretation, and transmission of knowledge and information within healthcare. Social media is a platform that can assist nursing faculty in helping students to gain greater understanding of and/or skills in professional communication; health policy; patient privacy and ethics; and writing competencies. Although there are barriers to integration of social media within nursing education, there are quality resources available to assist faculty to integrate social media as a viable pedagogical method. This article discusses the background and significance of social media tools as pedagogy, and provides a brief review of literature. To assist nurse educators who may be using or considering social media tools, the article offers selected examples of sound and pedagogically functional use in course and program applications; consideration of privacy concerns and advantages and disadvantages; and tips for success. PMID- 23036059 TI - Communication technology and social media: opportunities and implications for healthcare systems. AB - Electronic patient education and communications, such as email, text messaging, and social media, are on the rise in healthcare today. This article explores potential uses of technology to seek solutions in healthcare for such challenges as modifying behaviors related to chronic conditions, improving efficiency, and decreasing costs. A brief discussion highlights the role of technologies in healthcare informatics and considers two theoretical bases for technology implementation. Discussion focuses more extensively on the ability and advantages of electronic communication technology, such as e-mail, social media, text messaging, and electronic health records, to enhance patient-provider e communications in nursing today. Effectiveness of e-communication in healthcare is explored, including recent and emerging applications designed to improve patient-provider connections and review of current evidence supporting positive outcomes. The conclusion addresses the vision of nurses' place in the vanguard of these developments. PMID- 23036060 TI - Health tweets: an exploration of health promotion on twitter. AB - Twitter(r) is a popular microblogging site that allows users to disseminate information in 140 characters of text or less. A review of literature indicated that, to date, there has been little inquiry into the health based discussions conceptualized and enacted within and among Twitter users. Methods for this qualitative study included a directed content analysis, guided by the Public Health Agency of Canada's Determinant of Health (DOH) framework was completed to explore health based discussions on Twitter. A 24-hour cross-section of tweets (N=2400) containing the word or hashtag 'health' were collected for analysis. Findings revealed predominant themes of health services, personal health practices, and education. Many of the tweeted messages reflected existing political and social issues publicized within the global mass media. This study also considered the evolving dynamic behind the conceptualization of health and how it is co-constructed through news media, advertising, and social network technologies. Discussion of the emerging themes and implications for practice are presented. PMID- 23036061 TI - A decade of published evidence for psychiatric and mental health nursing interventions. AB - Current psychiatric nursing practice remains grounded in tradition, unsystematic trial and error, and authority. Although some of the wisdom that has been passed down over time is questionable, it continues to influence nursing practice today. This state-of-the-evidence review examined features of intervention studies published between January 2006 and December 2010 in five psychiatric nursing journals; it compared findings with those from a previous study of comparable literature published between 2000 and 2005. The analysis included studies that evaluated strategies, procedures, or practices that promote mental health or prevent mental illness. Of the 553 data-based articles, 71% tested interventions; 54% were conducted in the United States. Intervention studies reflected psychological (38%) social (17%), and biological (1%) dimensions of the biopsychosocial model. Some studies involved two dimensions and 17% included all three dimensions. Studies involved nurses, students, or staff (15%), mentally ill (50%), or mentally healthy persons (35%) ranging in age from childhood through older adulthood. The 10 year review showed continuing progress toward increased dissemination compared to earlier years; less focus on nurses, students, and staff; an increase in international studies; and greater emphasis on holistic interventions. In this article, the authors note a need for more randomized, controlled trials and studies to compare effectiveness across interventions. PMID- 23036062 TI - Advancing nursing practice through social media: a global perspective. AB - Social media has been used globally as a key vehicle for communication. As members of an innovative profession, many nurses have embraced social media and are actively utilizing its potential to enhance practice and improve health. The ubiquity of the Internet provides social media with the potential to improve both access to health information and services and equity in health care. Thus there are a number of successful nurse-led initiatives. However, the open and democratising nature of social media creates a number of potential risks, both individual and organisational. This article considers the use of social media within nursing from a global perspective, including discussion of policy and guidance documents. The impact of social media on both healthcare consumers and nurses is reviewed, followed by discussion of selected risks associated with social media. To help nurses make the most of social media tools and avoid potential pitfalls, the article conclusion suggests implications appropriate for global level practice based on available published guidance. PMID- 23036063 TI - Responsibility of a frontline manager regarding staff bullying. AB - Canadian frontline nursing managers are observing an increase in the reporting of workplace bullying as more nurses become aware of their employers' legal obligations to provide employees with a respectful workplace, per the Canada Human Rights Code, Canada Labor Code, and Canada Occupational Health and Safety Regulations. One problem with this reporting is that the victim's reports of bullying may become overshadowed by the bully's reports of victim incompetence, resulting in the victim experiencing further victimization. Bullies may report the victim (target) as inept, deficient in knowledge, or lacking ability. Fear of re-victimization plays a significant role in the victim's failure to report workplace bullying. It is important that managers focus on the bullying and not on the perceived character flaws described by the bully. The author begins by describing workplace bullying and reviewing the workplace bullying literature. She then presents and discusses a composite case study. To assist managers in discouraging bullying she shares supports for addressing bullying, specifically workplace policies, collective agreements, human resources departments, mediation, alternative dispute resolution, and arbitration, and concludes by reminding frontline managers of their important role in identifying bullying and understanding the victim's fears of further victimization. PMID- 23036064 TI - Ethics: creating a culture of ethical watchfulness. PMID- 23036065 TI - Legislative: nursing distance learning programs and state board of nursing authorizations. PMID- 23036067 TI - The observation of bleeding complications in haemato-oncological patients: stringent watching, relevant reporting. AB - BACKGROUND: The reported percentage of haemato-oncological patients experiencing bleeding complications is highly variable, ranging from 5 to 70%, posing a major problem for comparison of clinical platelet transfusion trials using bleeding complications as a primary endpoint. In a pilot study we assessed the impact of the design of scoring of bleeding on the percentage of patients with WHO grade 2 or higher bleeding grades. STUDY DESIGN AND METHODS: We performed a prospective, observational study using a rigorous bleeding observation system in thrombocytopenic patients with haemato-oncological disorders. Endpoints of the study were the percentage of patients and days with bleeding WHO grade >= 2 comparing designs in which skin bleeding represent a continuation of a previous bleed or a new bleed. RESULTS: In four participating hospitals 64 patients suffering 870 evaluable thrombocytopenic days (platelet count < 80 * 10(9) L(-1)) were included. At least one episode of bleeding grade >= 2 occurred in 36 patients (56%). Most grade 2 bleeding complications occurred mucocutaneously. The percentage of days with bleeding of grade >= 2 was 16% but decreases to 8% when only newly developed skin bleeding was included. CONCLUSION: Rigorous daily observation results in a bleeding incidence that is comparable to recent reportings applying the same method. The results of this study show that censoring for stable skin bleeding has a profound effect on bleeding incidence per day. The clinical relevance of rigorous or clinically judged bleeding scores as an endpoint remains to be defined. PMID- 23036066 TI - Bacterial translational regulations: high diversity between all mRNAs and major role in gene expression. AB - BACKGROUND: In bacteria, the weak correlations at the genome scale between mRNA and protein levels suggest that not all mRNAs are translated with the same efficiency. To experimentally explore mRNA translational level regulation at the systemic level, the detailed translational status (translatome) of all mRNAs was measured in the model bacterium Lactococcus lactis in exponential phase growth. RESULTS: Results demonstrated that only part of the entire population of each mRNA species was engaged in translation. For transcripts involved in translation, the polysome size reached a maximum of 18 ribosomes. The fraction of mRNA engaged in translation (ribosome occupancy) and ribosome density were not constant for all genes. This high degree of variability was analyzed by bioinformatics and statistical modeling in order to identify general rules of translational regulation. For most of the genes, the ribosome density was lower than the maximum value revealing major control of translation by initiation. Gene function was a major translational regulatory determinant. Both ribosome occupancy and ribosome density were particularly high for transcriptional regulators, demonstrating the positive role of translational regulation in the coordination of transcriptional networks. mRNA stability was a negative regulatory factor of ribosome occupancy and ribosome density, suggesting antagonistic regulation of translation and mRNA stability. Furthermore, ribosome occupancy was identified as a key component of intracellular protein levels underlining the importance of translational regulation. CONCLUSIONS: We have determined, for the first time in a bacterium, the detailed translational status for all mRNAs present in the cell. We have demonstrated experimentally the high diversity of translational states allowing individual gene differentiation and the importance of translation-level regulation in the complex process linking gene expression to protein synthesis. PMID- 23036068 TI - Is increased libido an atypical symptom of bipolar depression? An interesting case. AB - INTRODUCTION: Decreased libido is recognized as one of the vegetative symptoms of depression. Increased libido has not been acknowledged as one of its symptoms, neither has it been reported, particularly in depressed bipolar patients. AIM: We hereby report a case of atypical presentation of increased sexual function in a patient in depressed phase of bipolar II thereby querying the fact, whether increased libido is actually an unrecognized atypical symptom of bipolar depression. METHODS: A 48-year-old male presented with mood swings whereby his sexual function was increased during his depressive phase. Antidepressant, mood stabilizer, and antipsychotic medication were administered. Electroconvulsive therapy (ECT) was offered for augmentation therapy. MAIN OUTCOME MEASURES: When sexual dysfunction is not identified, there is a risk of misdiagnosis and mismanagement. RESULTS: Patient did not attain full remission with medication. Compliance with medication was an issue, most probably due to the sexual side effects. The patient refused ECT. CONCLUSION: This case highlights atypical presentation of high libido in a patient in the depressive phase of bipolar II disorder. The uncommon presentation of a common illness posed a diagnostic challenge and complicated the subsequent management. It was concluded that increased sexual function deserves further consideration as a symptom of bipolar depression. PMID- 23036069 TI - Temporal orbicularis oculi island pedicle flap for periorbital reconstruction. PMID- 23036070 TI - Resection or transplant-listing for solitary hepatitis C-associated hepatocellular carcinoma: an intention-to-treat analysis. AB - OBJECTIVES: The relative roles of liver resection (LR) and liver transplantation (LT) in the treatment of a solitary hepatocellular carcinoma (HCC) remain unclear. This study was conducted to provide a retrospective intention-to-treat comparison of these two curative therapies. METHODS: Records maintained at the study centre for all patients treated with LR or listed for LT for hepatitis C associated HCC between January 2002 and December 2007 were reviewed. Inclusion criteria required: (i) an initial diagnosis of a solitary HCC lesion measuring <= 5 cm, and (ii) Child-Pugh class A or B cirrhosis. The primary endpoint analysed was intention-to-treat survival. RESULTS: A total of 75 patients were listed for transplant (LT-listed group) and 56 were resected (LR group). Of the 75 LT-listed patients, 23 (30.7%) were never transplanted because they were either removed from the waiting list (n = 13) or died (n = 10). Intention-to-treat median survival was superior in the LR group compared with the LT-listed group (61.8 months vs. 30.6 months), but the difference did not reach significance. Five-year recurrence was higher in the LR group than in the 52 LT patients (71.5% vs. 30.5%; P < 0.001). CONCLUSIONS: In the context of limited donor organ availability, partial hepatectomy represents an efficacious primary approach in properly selected patients with hepatitis C-associated HCC. PMID- 23036071 TI - The usefulness of amyloid imaging in predicting the clinical outcome after two years in subjects with mild cognitive impairment. AB - BACKGROUND: Mild cognitive impairment (MCI) is a syndrome heterogeneous with regards to etiology and prognosis. Amyloid imaging enables to visualize a hallmark pathology of Alzheimer's disease (AD). Therefore we aimed to assess the usefulness of [(11)C]PiB PET for predicting clinical outcome of MCI patients after an interval of 2 years. METHODS: In 28 MCI participants with a global CDR rating at baseline of 0.5 a baseline examination including clinical assessments and [(11)C]PiB PET imaging and a clinical follow-up examination after a planned interval of 24 months were performed. Predictive values and accuracy of amyloid positive and negative scans for conversion to dementia of any type and to dementia due to AD were calculated and compared to neuropsychological tests and ApoE genotyping. RESULTS: Of 17 MCI patients who were amyloid-positive at baseline converted 9 to dementia all of the AD type. 3 of the 11 amyloid-negative MCI subjects converted to dementia but none to dementia due to AD. PPV, NPV and accuracy (to dementia: 0.53, 0.73 and 0.61; to AD: 0.53, 1.00 and 0.70) was comparable to neuropsychological tests and superior to ApoE genotyping. CONCLUSION: All MCI subjects who converted to dementia due to AD were amyloid positive. However, only 50% of these MCI due to AD, intermediate likelihood, patients developed manifest dementia due to AD after 24 months limiting the usefulness of [(11)C]PiB PET for individual prediction of clinical outcome. PMID- 23036072 TI - Associations of serum 25-hydroxyvitamin D with circulating PTH, phosphate and calcium in patients with primary hyperparathyroidism. AB - BACKGROUND: Despite NIH clinical recommendations, many clinicians are reluctant to replace vitamin D in patients with hypercalcaemia with primary hyperparathyroidism (PHP) due to concerns over aggravating hypercalcaemia. Furthermore, the optimum level of vitamin D replacement in PHP remains unclear. METHODS: We performed a large retrospective study to determine whether a relationship exists between serum 25-hydroxyvitamin D levels, calcium and other important biochemical markers in patients with PHP. Serum, plasma and urinary biochemical measurements were collected from 251 patients with hypercalcaemia diagnosed with PHP. RESULTS: When examining overall mean circulating levels during clinical follow-up, serum 25-hydroxyvitamin D correlated highly significantly with plasma parathyroid hormone (PTH) (r = -0.23, P = 0.0003) and serum phosphate (r = 0.16, P = 0.0119). No significant relationship was observed between serum calcium and 25-hydroxyvitamin D (r = 0.002, P = 0.98). Mean plasma PTH during clinical follow-up was 51% lower in patients with serum 25 hydroxyvitamin D > 60 nm when compared with patients who had 25-hydroxyvitamin D < 20 nm (P < 0.01). CONCLUSIONS: Patients with PHP who have 25-hydroxyvitamin D levels > 60 nm have significantly reduced PTH hypersecretion when compared with patients with deficient vitamin D levels, without exhibiting worse hypercalcaemia. PMID- 23036073 TI - Musical memory in a patient with severe anterograde amnesia. AB - The ability to play a musical instrument represents a unique procedural skill that can be remarkably resilient to disruptions in declarative memory. For example, musicians with severe anterograde amnesia have demonstrated preserved ability to play musical instruments. However, the question of whether amnesic musicians can learn how to play new musical material despite severe memory impairment has not been thoroughly investigated. We capitalized on a rare opportunity to address this question. Patient S.Z., an amateur musician (tenor saxophone), has extensive bilateral damage to his medial temporal lobes following herpes simplex encephalitis, resulting in a severe anterograde amnesia. We tested S.Z.'s capacity to learn new unfamiliar songs by sight-reading following three months of biweekly practices. Performances were recorded and were then evaluated by a professional saxophonist. S.Z. demonstrated significant improvement in his ability to read and play new music, despite his inability to recognize any of the songs at a declarative level. The results suggest that it is possible to learn certain aspects of new music without the assistance of declarative memory. PMID- 23036074 TI - The feasibility of rapid baseline objective physical activity measurement in a natural experimental study of a commuting population. AB - BACKGROUND: Studies of the effects of environmental interventions on physical activity should include valid measures of physical activity before and after the intervention. Baseline data collection can be difficult when the timetable for introduction of an intervention is outside researchers' control. This paper reports and reflects on the practical issues, challenges and results of rapid baseline objective physical activity measurement using accelerometers distributed by post in a natural experimental study. METHODS: A sample of working adults enrolling for the Commuting and Health in Cambridge study and expressing willingness to wear an activity monitor was selected to undertake baseline accelerometer assessment. Each selected participant received a study pack by post containing the core study questionnaire and an accelerometer to wear for seven consecutive days, and was asked to return their accelerometer and completed questionnaire in person or by post using the prepaid special delivery envelope provided. If a pack was not returned within two weeks of issue, a reminder was sent to the participant. Each participant received up to five reminders by various methods including letter, email, telephone and letter sent by recorded delivery. RESULTS: 95% of participants registering for the study were willing in principle to undertake accelerometer assessment. Using a pool of 221 accelerometers, we achieved a total of 714 issues of accelerometers to participants during a six month period. 116 (16%) participants declined to use the accelerometer after receiving it. Three accelerometers failed, 45 (6% of 714) were lost and many were returned with insufficient data recorded, resulted in 109 (15%) participants re-wearing their accelerometer for a second week of measurement. 550 (77%) participants completed data collection, 478 (87% of 550) to the required standard. A total of 694 reminders were issued to retrieve unreturned accelerometers. More than 90% of accelerometers were retrieved after a maximum of two reminders. CONCLUSIONS: It is feasible to use accelerometers to collect baseline objective physical activity data by post from a large number of participants in a limited time period. However, a substantial pool of devices is required and researchers need to be prepared to make significant efforts to recover some of the devices. PMID- 23036075 TI - Oral colon-specific therapeutic approaches toward treatment of inflammatory bowel disease. AB - INTRODUCTION: Inflammatory bowel disease (IBD) is a chronic relapsing idiopathic disease. In clinical terms, most patients require lifelong medication associated with possible unpleasant adverse effects. Oral colon-specific drug delivery systems are designed to deliver therapeutic drugs to the inflamed colon to target pathophysiological manifestations of IBD. The aim is to maintain the drug with proper concentration in the inflamed colon, to enhance drug residence time and to minimize drug absorption by healthy tissues. AREAS COVERED: This review addresses the main barriers for colon-specific drug delivery from organism, tissue and cell levels, respectively. It also summarizes novel colon-specific therapeutic strategies using microparticles and nanoparticles. EXPERT OPINION: Oral colon specific drug delivery represents a possible approach toward efficient treatment of IBD. As the environment of the gastrointestinal tract is harsh and intricate, this approach requires that drug carriers can respond to specific environmental factors of the inflamed colon, permitting stimulus-responsive release of loaded drugs to specific cells or even into specific organelles within cells. PMID- 23036076 TI - Cross-cultural adaptation and validation of the Brazilian Portuguese version of the pain catastrophizing scale. AB - OBJECTIVE: Catastrophizing is a maladaptive response to pain and is one of the factors that contribute to the chronicity of some pain syndromes. The Pain Catastrophizing Scale (PCS) assists both treatment planning and outcome assessment. Its use is limited in Portuguese-speaking countries because of the lack of a validated translated version. We conducted the validation of the Brazilian Portuguese (BP)-PCS and explored its psychometric properties. This study reports the internal consistency, factor structure, and its capability to discriminate pain reported by patients with specific chronic pain conditions. METHODS: Three hundred eighty-four patients, 317 women (82.55%), aged 18-79 years with chronic nonmalignant pain attending an outpatient multidisciplinary pain center participated in this cross-sectional study. The instruments were the BP PCS, pain intensity, pain interference in functional capacity, and a sociodemographic questionnaire. One subsample with chronic tensional headache (CTH) according to the criteria of the International Headache Society (N = 19), and another with a diagnosis of fibromyalgia according to the American College of Rheumatology criteria (N = 50) were selected to assess the discriminative properties of BP-PCS. RESULTS: We observed good internal consistency (Cronbach's alpha values of 0.91 for the total BP-PCS, and 0.93 [helplessness], 0.88 [magnification], and 0.86 [rumination] for the respective subdomains). The item total correlation coefficients ranged from 0.91 to 0.94. Confirmatory factor analysis (CFA) supported the three factors structure, with the comparative fit index = 0.98, root mean square error of approximation = 0.09, and normed fit index = 0.98. Significant correlations were found for pain intensity, pain interference, and patient's mood (correlation coefficients ranged from 0.48 to 0.66, P < 0.01). No significant gender difference was observed for BP-PCS scores. When comparing scores of BP-PCS scale and subscales between the selected control group (patients with pain scores on visual analog scale equal or lower than 40 mm in the most part of the day in the last 6 months) and patients with fibromyalgia or CTH, we observed lower scores for the former group. CONCLUSION: Our findings support the validity and reliability of the BP-PCS. The scale showed satisfactory psychometric properties. CFA provides support for the three-factor structure reported in previous studies. This factor structure presented good discriminative properties to identify catastrophizers who present with mild chronic pain, fibromyalgia, and CTH. The BP-PCS is a valuable tool for use in scientific studies and in the clinical setting in patients with chronic pain in Brazilian Portuguese-speaking countries. PMID- 23036077 TI - Expanding yttrium bis(trimethylsilylamide) chemistry through the reaction chemistry of (N2)2-, (N2)3-, and (NO)2- complexes. AB - The reaction chemistry of the side-on bound (N(2))(2-), (N(2))(3-), and (NO)(2-) complexes of the [(R(2)N)(2)Y](+) cation (R = SiMe(3)), namely, [(R(2)N)(2)(THF)Y](2)(MU-eta(2):eta(2)-N(2)), 1, [(R(2)N)(2)(THF)Y](2)(MU eta(2):eta(2)-N(2))K, 2, and [(R(2)N)(2)(THF)Y](2)(MU-eta(2):eta(2)-NO), 3, with oxidizing agents has been explored to search for other (E(2))(n-), (E = N, O), species that can be stabilized by this cation. This has led to the first examples for the [(R(2)N)(2)Y](+) cation of two fundamental classes of [(monoanion)(2)Ln](+) rare earth systems (Ln = Sc, Y, lanthanides), namely, oxide complexes and the tetraphenylborate salt. In addition, an unusually high yield reaction with dioxygen was found to give a peroxide complex that completes the (N(2))(2-), (NO)(2-), (O(2))(2-) series with 1 and 3. Specifically, the (MU-O)(2 ) oxide-bridged bimetallic complex, [(R(2)N)(2)(THF)Y}(2)(MU-O), 4, is obtained as a byproduct from reactions of either the (N(2))(2-) complex, 1, or the (N(2))(3-) complex, 2, with NO, while the oxide formed from 2 with N(2)O is a polymeric species incorporating potassium, {[(R(2)N)(2)Y](2)(MU-O)(2)K(2)(MU C(7)H(8))}(n), 5. Reaction of 1 with 1 atm of O(2) generates the (O(2))(2-) bridging side-on peroxide [(R(2)N)(2)(THF)Y](2)(MU-eta(2):eta(2)-O(2)), 6. The O O bond in 6 is cleaved by KC(8) to provide an alternative synthetic route to 5. Attempts to oxidize the (NO)(2-) complex, 3, with AgBPh(4) led to the isolation of the tetraphenylborate complex, [(R(2)N)(2)Y(THF)(3)][BPh(4)], 7, that was also synthesized from 1 and AgBPh(4). Oxidation of the (N(2))(2-) complex, 1, with the radical trap (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, TEMPO, generates the (TEMPO)(-) anion complex, (R(2)N)(2)(THF)Y(eta(2)-ONC(5)H(6)Me(4)), 8. PMID- 23036078 TI - The limit for chronic myeloid leukemia relapse after allogeneic hematopoietic stem cell transplant moves ever forward: when can you safely talk about healing? PMID- 23036079 TI - Postacute rehabilitation care for hip fracture: who gets the most care? AB - OBJECTIVES: To determine the extent to which demographic and geographic disparities exist in postacute rehabilitation care (PARC) use after hip fracture. DESIGN: Cross-sectional analysis of 2 years (2005-06) of population-based hospital discharge data. SETTING: All short-term acute care hospitals in four demographically and geographically diverse states (AZ, FL, NJ, WI). PARTICIPANTS: Individuals aged 65 and older (mean 82.9) admitted to the hospital with a hip fracture who survived their inpatient stay (N = 64,065). The sample was 75.1% female and 91.5% white, 5.8% Hispanic, and 2.7% black. MEASUREMENTS: Whether the participant received institutional PARC; for participants who did not receive institutional care, whether they received home health (HH) care; and for participants who received institutional care, whether they received skilled nursing facility (SNF) or inpatient rehabilitation facility (IRF) care. Multilevel logistic regression analyses were conducted to identify demographic and geographic disparities in PARC use. RESULTS: Considering PARC on a continuum from more to fewer hours of care per day (IRF->SNF->HH->no HH), minorities and individuals of lower socioeconomic status (SES) generally received a lower volume of care. Individuals on Medicaid or who were uninsured were less likely to receive institutional care (odds ratio (OR) = 0.23, 95% confidence interval (CI) = 0.18-0.30) and to receive HH (OR = 0.46, 95% CI = 0.30-0.70) and more likely to receive SNF than IRF care (OR = 2.03, 95% CI = 1.36-3.05). Hispanics were less likely to receive institutional care (OR = 0.70, 95% CI = 0.62-0.79), and Hispanics (OR = 1.31) and blacks (OR = 1.49) were more likely to receive SNF than IRF care. There were also geographic differences in PARC. CONCLUSION: Several demographic and geographic disparities in PARC use were identified. Future research should confirm these findings and further elucidate factors that contribute to the observed disparities. PMID- 23036080 TI - Microenvironment and tumor progression of melanoma: new therapeutic prospectives. AB - Malignant melanoma is a very representative disease in terms of tumor progression processes. During its evolution, a series of events takes place; among these, the cells' 'out-of-control' growth and loss of homeostasis play crucial roles in the genesis of the tumor itself and its subsequent progression. These events involve several molecular mechanisms associated with both melanocyte transformation and changes to/in the surrounding microenvironment. In particular, interactions between transformed cells and between these cells and the local extracellular matrix (ECM) play key roles in melanoma progression. A description of main ECM molecules involved in melanoma tumor progression, of different cell types present in the tumor microenvironment, and the interactions between all these elements, will be discussed in this review. Taking a broad view of the activity of these cells, molecules, and systems and mechanisms that allow for interference with their expression/function could be useful for designing potential combinations of specific target therapies and immunotherapies that could be more efficient approaches against malignant melanoma. PMID- 23036081 TI - Analysis of a native whitefly transcriptome and its sequence divergence with two invasive whitefly species. AB - BACKGROUND: Genomic divergence between invasive and native species may provide insight into the molecular basis underlying specific characteristics that drive the invasion and displacement of closely related species. In this study, we sequenced the transcriptome of an indigenous species, Asia II 3, of the Bemisia tabaci complex and compared its genetic divergence with the transcriptomes of two invasive whiteflies species, Middle East Asia Minor 1 (MEAM1) and Mediterranean (MED), respectively. RESULTS: More than 16 million reads of 74 base pairs in length were obtained for the Asia II 3 species using the Illumina sequencing platform. These reads were assembled into 52,535 distinct sequences (mean size: 466 bp) and 16,596 sequences were annotated with an E-value above 10-5. Protein family comparisons revealed obvious diversification among the transcriptomes of these species suggesting species-specific adaptations during whitefly evolution. On the contrary, substantial conservation of the whitefly transcriptomes was also evident, despite their differences. The overall divergence of coding sequences between the orthologous gene pairs of Asia II 3 and MEAM1 is 1.73%, which is comparable to the average divergence of Asia II 3 and MED transcriptomes (1.84%) and much higher than that of MEAM1 and MED (0.83%). This is consistent with the previous phylogenetic analyses and crossing experiments suggesting these are distinct species. We also identified hundreds of highly diverged genes and compiled sequence identify data into gene functional groups and found the most divergent gene classes are Cytochrome P450, Glutathione metabolism and Oxidative phosphorylation. These results strongly suggest that the divergence of genes related to metabolism might be the driving force of the MEAM1 and Asia II 3 differentiation. We also analyzed single nucleotide polymorphisms within the orthologous gene pairs of indigenous and invasive whiteflies which are helpful for the investigation of association between allelic and phenotypes. CONCLUSIONS: Our data present the most comprehensive sequences for the indigenous whitefly species Asia II 3. The extensive comparisons of Asia II 3, MEAM1 and MED transcriptomes will serve as an invaluable resource for revealing the genetic basis of whitefly invasion and the molecular mechanisms underlying their biological differences. PMID- 23036082 TI - The susceptibility of five African Anopheles species to Anabaena PCC 7120 expressing Bacillus thuringiensis subsp. israelensis mosquitocidal cry genes. AB - BACKGROUND: Malaria, one of the leading causes of death in Africa, is transmitted by the bite of an infected female Anopheles mosquito. Problems associated with the development of resistance to chemical insecticides and concerns about the non target effects and persistence of chemical insecticides have prompted the development of environmentally friendly mosquito control agents. The aim of this study was to evaluate the larvicidal activity of a genetically engineered cyanobacterium, Anabaena PCC 7120#11, against five African Anopheles species in laboratory bioassays. FINDINGS: There were significant differences in the susceptibility of the anopheline species to PCC 7120#11. The ranking of the larvicidal activity of PCC 7120#11 against species in the An. gambiae complex was: An. merus T CD14 SNP on the outcome from critical conditions. We monitored 524 critically ill patients from South Brazilian, daily from the ICU admission to their discharge from hospital, or death. Our results revealed that TLR2, TLR4 or TNF-alpha SNPs alone did not show a significant role in the outcome from critical illness. However, when we performed a combined analysis with the CD14 inheritance, we detected a significant higher survivor rate in -260TT CD14/-308GG TNF-alpha individuals (P = 0.037). In the adjusted analysis including the main clinical predictors to mortality, we observed that 260TT/-308GG double-genotype was a significant protective factor towards survival (P = 0.046). An increased probability for survival of -260TT/-308GG was also observed by 'pathway genetic load' analysis (unweighted: P = 0.041; weighted: P = 0.036). When we applied a hazard function analysis with the -260TT/-308GG variable as a discriminating factor, -260TT/-308GG patients group had, in fact, a higher survivor rate (P = 0.024). Connected to the beneficial effect of -260TT CD14, the -308GG TNF-alpha genotype was protective against the reported over expression of TNF-alpha caused by -308A rare allele. Results support the hypothesis that the interaction between -260C>T CD14 and -308G>A TNF-alpha functional SNPs may be synergistically influencing the outcome of critically ill patients. PMID- 23036098 TI - High throughput screening for drug discovery of autophagy modulators. AB - Autophagy is an evolutionally conserved process in cells for cleaning abnormal proteins and organelles in a lysosome dependent manner. Growing studies have shown that defects or induced autophagy contributes to many diseases including aging, neurodegeneration, pathogen infection, and cancer. However, the precise involvement of autophagy in health and disease remains controversial because the theories are built on limited assays and chemical modulators, indicating that the role of autophagy in diseases may require further verification. Many food and drug administration (FDA) approved drugs modulate autophagy signaling, suggesting that modulation of autophagy with pharmacological agonists or antagonists provides a potential therapy for autophagy-related diseases. This suggestion raises an attractive issue on drug discovery for exploring chemical modulators of autophagy. High throughput screening (HTS) is becoming a powerful tool for drug discovery that may accelerate screening specific autophagy modulators to clarify the role of autophagy in diseases. Herein, this review lays out current autophagy assays to specifically measure autophagy components such as LC3 (mammalian homologue of yeast Atg8) and Atg4. These assays are feasible or successful for HTS with certain chemical libraries, which might be informative for this intensively growing field as research tools and hopefully developing new drugs for autophagy-related diseases. PMID- 23036099 TI - Preliminary, favorable experience with microperc in kidney and bladder stones. AB - PURPOSE: In this study, we report our initial experience using microperc for treatment of kidney stones and the implications of the microperc system in bladder stone management. PATIENTS AND METHODS: Microperc was performed with a 4.85F "all-seeing needle" in 11 patients with stone disease; 9 of the patients had kidney stones and 2 had bladder stones. Access to the renal collecting system was achieved under fluoroscopic control in eight patients, while ultrasonography was used in one. Fluoroscopy was not used in any of the patients with bladder stones for bladder access. RESULTS: The mean stone burden was 12.8 mm (range 7-18 mm). The stone locations were pelvis in three, upper calix in one, middle calix in two, and lower calix in three. The mean age for kidney stones was 20.8 years (range 3-47 years). Single access was sufficient in all cases. In two patients, although the procedure was progressing without complication, conversion to miniperc was needed because of operator-related system errors. There were no intraoperative complications. The stone-free rate in the postoperative first month was 85%. CONCLUSION: The least invasive microperc with an optical puncture system appears to be a safe and effective treatment modality in patients with different kinds of stone disease with respect to various features. Although the initial cases were patients with single stones of less than 20 mm, the combined use of this system with other minimally invasive treatment modalities for the management of larger stones is promising. PMID- 23036100 TI - Arylated versus cyclometalated platinum(II) polypyridines: photoluminescence from Pt(4'-R-trpy)Ph+ systems (R = NMe2, N-pyrrolidinyl, or 1-pyrenyl). AB - Many platinum(II) polypyridine complexes are good luminophores, an enigmatic exception being Pt(trpy)Ph(+), where trpy denotes 2,2':6',2"-terpyridine. A new analysis suggests the complex is nonemissive due to (3)SBLCT (sigma-bond-to ligand charge transfer) character in the lowest energy excited state. Bases for two distinct strategies for inducing emission from aryl derivatives become clear. The standard approach of incorporating a phenyl group into a (N(/?)N(/?)C) cyclometalating ligand relies in part on the rigidity of the ligand framework. An alternative strategy, which involves expanding the chromophore and altering the orbital parentage of the emitting state, is capable of suppressing radiationless decay even further. Indeed, the Pt(4'-pyren-1-yl-trpy)Ph(+) system emits from a low-lying (3)pi-pi*(pyrene) excited state that has a lifetime of 45 MUs in fluid solution. PMID- 23036101 TI - Earlier reperfusion in patients with ST-elevation myocardial infarction by use of helicopter. AB - BACKGROUND: In patients with ST-elevation myocardial infarction (STEMI) reperfusion therapy should be initiated as soon as possible. This study evaluated whether use of a helicopter for transportation of patients is associated with earlier initiation of reperfusion therapy. MATERIAL AND METHODS: A prospective study was conducted, including patients with STEMI and symptom duration less than 12 hours, who had primary percutaneous coronary intervention (PPCI) performed at Aarhus University Hospital in Skejby. Patients with a health care system delay (time from emergency call to first coronary intervention) of more than 360 minutes were excluded. The study period ran from 1.1.2011 until 31.12.2011. A Western Denmark Helicopter Emergency Medical Service (HEMS) project was initiated 1.6.2011 for transportation of patients with time-critical illnesses, including STEMI. RESULTS: The study population comprised 398 patients, of whom 376 were transported by ambulance Emergency Medical Service (EMS) and 22 by HEMS. Field triage directly to the PCI-center was used in 338 of patients. The median system delay was 94 minutes among those field-triaged, and 168 minutes among those initially admitted to a local hospital. Patients transported by EMS and field triaged were stratified into four groups according to transport distance from the scene of event to the PCI-center: <=25 km., 26-50 km., 51-75 km. and > 75 km. For these groups, the median system delay was 78, 89, 99, and 141 minutes. Among patients transported by HEMS and field-triaged the estimated median transport distance by ground transportation was 115 km, and the observed system delay was 107 minutes. Based on second order polynomial regression, it was estimated that patients with a transport distance of >60 km to the PCI-center may benefit from helicopter transportation, and that transportation by helicopter is associated with a system delay of less than 120 minutes even at a transport distance up to 150 km. CONCLUSION: The present study indicates that use of a helicopter should be considered for field-triage of patients with STEMI to the PCI-center in case of long transportation. Such a strategy may ensure that patients living up to 150 km. from the PCI-center can be treated within 120 minutes of emergency call. PMID- 23036102 TI - Editorial note: in appreciation. PMID- 23036103 TI - Map-following skills in left and right brain-damaged patients with and without hemineglect. AB - Map-following tasks require a "semantic interpretation" of the map, which could be affected by left brain damage, and "superimposition of the map upon the space," which could be compromised by right lesions and particularly by the presence of hemineglect. Participants followed a pathway depicted on a map of a real environment. The pathway included four left and four right turns. A legend explained the meaning of each symbol that appeared on the map. Our results showed no deficits in left brain-damaged patients, but poor performance in right brain damaged patients affected by hemineglect. This deficit can be ascribed to their impaired egocentric frame of reference, but we cannot exclude a prevalent role of the right hemisphere in their use of the allocentric information on the map despite the presence of hemineglect. Indeed, three right brain-damaged patients without hemineglect showed a specific deficit in performing the task. We discuss the results in light of the possible impairment of the parietomedial temporal pathway, which supports spatial navigation and could be responsible for the patients' deficit. PMID- 23036106 TI - Assessment of undergraduate clinical reasoning in geriatric medicine: application of a script concordance test. AB - A challenging aspect of geriatric practice is that it often requires decision making under conditions of uncertainty. The Script Concordance Test (SCT) is an assessment tool designed to measure clinical data interpretation, an important element of clinical reasoning under uncertainty. The purpose of this study was to develop and analyze the validity of results of an SCT administered to undergraduate students in geriatric medicine. An SCT consisting of 13 cases and 104 items covering a spectrum of common geriatric problems was designed and administered to 41 undergraduate medical students at a medical school in Sao Paulo, Brazil. A reference panel of 21 practicing geriatricians contributed to the test's score key. The responses were analyzed, and the psychometric properties of the tool were investigated. The test's internal consistency and discriminative capacity to distinguish students from experienced geriatricians supported construct validity. The Cronbach alpha for the test was 0.84, and mean scores for the experts were found to be significantly higher than those of the students (80.0 and 70.7, respectively; P < .001). This study demonstrated robust evidence of reliability and validity of an SCT developed for use in geriatric medicine for assessing clinical reasoning skills under conditions of uncertainty in undergraduate medical students. These findings will be of interest to those involved in assessing clinical competence in geriatrics and will have important potential application in medical school examinations. PMID- 23036105 TI - Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes. AB - INTRODUCTION: Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome. METHODS: Stat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models. RESULTS: Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naive, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome. CONCLUSIONS: Loss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials. PMID- 23036108 TI - Driving unidirectional molecular rotary motors with visible light by intra- and intermolecular energy transfer from palladium porphyrin. AB - Driving molecular rotary motors using visible light (530-550 nm) instead of UV light was achieved using palladium tetraphenylporphyrin as a triplet sensitizer. Visible light driven rotation was confirmed by UV/vis absorption, circular dichroism and (1)H NMR spectroscopy and the rotation was confirmed to be unidirectional and with similar photostationary states, despite proceeding via a triplet instead of a singlet excited state of the molecular motor. Energy transfer proceeds in both inter- and intramolecular fashion from the triplet state of the porphyrin to the motor. Stern Volmer plots show that the rate of intermolecular quenching of the porphyrin excited state by the molecular motor is diffusion-controlled. PMID- 23036107 TI - Microarray gene expression profiles from mature gonad tissues of Atlantic bluefin tuna, Thunnus thynnus in the Gulf of Mexico. AB - BACKGROUND: Bluefin tunas are highly prized pelagic fish species representing a significant economic resource to fisheries throughout the world. Atlantic bluefin tuna (Thunnus thynnus) populations have significantly declined due to overexploitation. As a consequence of their value and population decline, T. thynnus has been the focus of considerable research effort concerning many aspects of their life history. However, in-depth understanding of T. thynnus reproductive biology is still lacking. Knowledge of reproductive physiology is a very important tool for determining effective fisheries and aquaculture management. Transcriptome techniques are proving powerful and provide novel insights into physiological processes. Construction of a microarray from T. thynnus ESTs sourced from reproductive tissues has provided an ideal platform to study the reproductive physiology of bluefin tunas. The aim of this investigation was to compare transcription profiles from the ovaries and testes of mature T. thynnus to establish sex specific variations underlying their reproductive physiology. RESULTS: Male and females T. thynnus gonad tissues were collected from the wild and histologically staged. Sub-samples of sexually mature tissues were also measured for their mRNA differential expression among the sexes using the custom microarray design BFT 4X44K. A total of 7068 ESTs were assessed for differential expression of which 1273 ESTs were significantly different (p<0.05) with >2 fold change in expression according to sex. Differential expression for 13 of these ESTs was validated with quantitative PCR. These include genes involved in egg envelope formation, hydration, and lipid transport/accumulation more highly expressed in ovaries compared with testis, while genes involved in meiosis, sperm motility and lipid metabolism were more highly expressed in testis compared with ovaries. CONCLUSIONS: This investigation has furthered our knowledge of bluefin tunas reproductive biology by using a contemporary transcriptome approach. Gene expression profiles in T. thynnus sexually mature testes and ovaries were characterized with reference to gametogenesis and potential alternative functions. This report is the first application of microarray technology for bluefin tunas and demonstrates the efficacy by which this technique may be used for further characterization of specific biological aspects for this valuable teleost fish. PMID- 23036109 TI - Left ventricular systolic dyssynchrony in patients with isolated symptomatic myocardial bridge. AB - OBJECTIVES: The impact of myocardial bridge (MB) on left ventricular (LV) systolic synchrony is insufficiently understood. DESIGN: Thirty-five subjects with isolated mid-left, anterior, descending artery (LAD) MB, preserved LV ejection fraction (LVEF > 50%), and otherwise, normal coronary angiogram were identified from 3607 patients who underwent diagnostic coronary angiography and were evaluated by tissue Doppler imaging and real-time three-dimensional echocardiography (RT3DE). Control subjects consisted of 26 age and sex-matched coronary angiographically "normal" subjects. RESULTS: MB patients were characterized by reduced, early, diastolic strain rate in LAD-supplied apical segments (lateral and anterior), with prevalence of LV systolic dyssynchrony of 25.7% (9/35). MB patients were further classified by the medians of MB stenosis and length. For MB stenosis < 52.5%, Class I: length < 17 mm (n = 7), Class II: length >= 17 mm (n = 10); for stenosis >= 52.5%, Class III: length < 17 mm (n = 10), Class IV: length >= 17 mm (n = 8). Binary Logistic regression model revealed that higher MB lesion classification (odds ratio: 4.944, 95%CI 1.174-20.82, P < 0.05) and hypertension (odds ratio: 15.32, 95%CI: 1.252-187.6, P < 0.05) are statistically associated with LV systolic dyssynchrony, which was independent of LV mass. CONCLUSIONS: MB in the mid LAD is associated with myocardial dyssynchrony. Hypertensive individuals and those with more severe bridging (determined by length and stenosis) tend to have an increased incidence of dyssynchrony. PMID- 23036111 TI - Natural products as sources of new fungicides (I): synthesis and antifungal activity of acetophenone derivatives against phytopathogenic fungi. AB - Several series of 45 acetophenone derivatives bearing various alkyl or benzyl substituents were conveniently synthesized and their structures characterized by (1)H and (13)C NMR spectroscopy, HRMS and single-crystal X-ray analysis. Their in vitro antifungal activities against a panel of phytopathogenic fungi were evaluated by mycelial growth rate assay. Of them, 12 derivatives (e.g., 3a-c, 4c and 4e) exhibited more potent antifungal effects on some phytopathogens than a commercial fungicide hymexazol as positive control. In particular, compound 3b with IC50 values of 10-19 MUg/mL was found to be the most active in this series and might be a potential lead structure for further optimization. The preliminary structure-activity relationship (SAR) studies of a series of acetophenones are also discussed. PMID- 23036110 TI - Frontiers of parasitology research in the People's Republic of China: infection, diagnosis, protection and surveillance. AB - Control and eventual elimination of human parasitic diseases in the People's Republic of China (P.R. China) requires novel approaches, particularly in the areas of diagnostics, mathematical modelling, monitoring, evaluation, surveillance and public health response. A comprehensive effort, involving the collaboration of 188 scientists (>85% from P.R. China) from 48 different institutions and universities (80% from P.R. China), covers this collection of 29 articles published in Parasites & Vectors. The research mainly stems from a research project entitled "Surveillance and diagnostic tools for major parasitic diseases in P.R. China" (grant no. 2008ZX10004-011) and highlights the frontiers of research in parasitology. The majority of articles in this thematic series deals with the most important parasitic diseases in P.R. China, emphasizing Schistosoma japonicum, Plasmodium vivax and Clonorchis sinensis plus some parasites of emerging importance such as Angiostrongylus cantonensis. Significant achievements have been made through the collaborative research programme in the following three fields: (i) development of strategies for the national control programme; (ii) updating the surveillance data of parasitic infections both in human and animals; and (iii) improvement of existing, and development of novel, diagnostic tools to detect parasitic infections. The progress is considerable and warrants broad validation efforts. Combined with the development of improved tools for diagnosis and surveillance, integrated and multi-pronged control strategies should now pave the way for elimination of parasitic diseases in P.R. China. Experiences and lessons learned can stimulate control and elimination efforts of parasitic diseases in other parts of the world. PMID- 23036112 TI - Multiple shocks following ICD implantation. PMID- 23036113 TI - Autoimmune pulmonary alveolar proteinosis: treatment options in year 2013. AB - Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of a periodic acid Schiff (PAS)-positive eosinophilic material in the distal airways. For decades, the standard treatment of PAP has been whole lung lavage (WLL), where large quantities of saline are instilled into the lungs to remove the proteinaceous material. However, not all patients respond to this treatment. Thus, new treatment modalities, such as subcutaneous or inhaled granulocyte macrophage colony-stimulating factor (GM-CSF), and the CD20 antibody rituximab and plasmapheresis, have been investigated. Based on the current literature, a stepwise treatment plan is suggested starting with WLL, continuing to inhaled GM-CSF, and then to rituximab if the former treatment regimes are unsuccessful. PMID- 23036115 TI - Succinate dehydrogenase assembly factor 2 is needed for assembly and activity of mitochondrial complex II and for normal root elongation in Arabidopsis. AB - Mitochondria complex II (succinate dehydrogenase, SDH) plays a central role in respiratory metabolism as a component of both the electron transport chain and the tricarboxylic acid cycle. We report the identification of an SDH assembly factor by analysis of T-DNA insertions in At5g51040, a protein with unknown function that was identified by mass spectrometry analysis as a low abundance mitochondrial protein. This gene is co-expressed with a number of genes encoding mitochondrial proteins, including SDH1-1, and has low partial sequence similarity to human SDHAF2, a protein required for flavin-adenine dinucleotide (FAD) insertion into SDH. In contrast to observations of other SDH deficient lines in Arabidopsis, the sdhaf2 line did not affect photosynthetic rate or stomatal conductance, but instead showed inhibition of primary root elongation with early lateral root emergence, presumably due to the low SDH activity caused by the reduced abundance of SDHAF2. Both roots and leaves showed succinate accumulation but different responses in the abundance of other organic acids and amino acids assayed. Isolated mitochondria showed lowered SDH1 protein abundance, lowered maximal SDH activity and less protein-bound flavin-adenine dinucleotide (FAD) at the molecular mass of SDH1 in the gel separation. The short root phenotype and SDH function of sdhaf2 was fully complemented by transformation with SDHAF2. Application of the SDH inhibitor, malonate, phenocopied the sdhaf2 root architecture in WT. Whole root respiratory assays showed no difference between WT and sdhaf2, but micro-respirometry of the tips of roots clearly showed low oxygen consumption in sdhaf2 which could explain a metabolic deficit responsible for root tip growth. PMID- 23036116 TI - Electrical behavior of Langmuir-Blodgett networks of sorted metallic and semiconducting single-walled carbon nanotubes. AB - Langmuir-Blodgett deposition has been used to form thin film networks of both metallic and semiconducting single-walled carbon nanotubes. These have been investigated to understand their physical, optical, and morphological properties. The electrical conductivities over the temperature range 80-350 K and across electrode gaps of 220 nm and 2 mm have been explored. In the case of semiconducting tubes, the results suggest that Poole-Frenkel conduction is the dominant electrical process at temperatures below 150 K and electric fields of greater than 1 MV m(-1). Metallic nanotube networks exhibit a decrease in resistance with a reduction in temperature. This can be approximated by a linear relationship, giving a temperature coefficient of resistance of 10(-3) K(-1). PMID- 23036114 TI - Role of multidetector computed tomography in the diagnosis and management of patients attending the rapid access chest pain clinic, The Scottish computed tomography of the heart (SCOT-HEART) trial: study protocol for randomized controlled trial. AB - BACKGROUND: Rapid access chest pain clinics have facilitated the early diagnosis and treatment of patients with coronary heart disease and angina. Despite this important service provision, coronary heart disease continues to be under diagnosed and many patients are left untreated and at risk. Recent advances in imaging technology have now led to the widespread use of noninvasive computed tomography, which can be used to measure coronary artery calcium scores and perform coronary angiography in one examination. However, this technology has not been robustly evaluated in its application to the clinic. METHODS/DESIGN: The SCOT-HEART study is an open parallel group prospective multicentre randomized controlled trial of 4,138 patients attending the rapid access chest pain clinic for evaluation of suspected cardiac chest pain. Following clinical consultation, participants will be approached and randomized 1:1 to receive standard care or standard care plus >=64-multidetector computed tomography coronary angiography and coronary calcium score. Randomization will be conducted using a web-based system to ensure allocation concealment and will incorporate minimization. The primary endpoint of the study will be the proportion of patients diagnosed with angina pectoris secondary to coronary heart disease at 6 weeks. Secondary endpoints will include the assessment of subsequent symptoms, diagnosis, investigation and treatment. In addition, long-term health outcomes, safety endpoints, such as radiation dose, and health economic endpoints will be assessed. Assuming a clinic rate of 27.0% for the diagnosis of angina pectoris due to coronary heart disease, we will need to recruit 2,069 patients per group to detect an absolute increase of 4.0% in the rate of diagnosis at 80% power and a two-sided P value of 0.05. The SCOT-HEART study is currently recruiting participants and expects to report in 2014. DISCUSSION: This is the first study to look at the implementation of computed tomography in the patient care pathway that is outcome focused. This study will have major implications for the management of patients with cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01149590. PMID- 23036117 TI - Retraction: Prospects and applications of nanobiotechnology: a medical perspective. AB - This article [1] is retracted as it contains large amount of text that has been duplicated from other articles previously published. We apologize to all affected parties for the inconvenience caused. PMID- 23036118 TI - Molecularly targeted therapies in head and neck cancers. AB - Head and neck cancers (HNC) are 6th most common malignancies according to the incidence rate. Over 85% of tumors of this region are epithelial tumors, especially squamous cell carcinomas (head and neck squamous cell carcinomas - HNSCC). Surgery, chemotherapy and radiotherapy are still the standard for the treatment of HNC. Despite the great development of the various methods of treatment, survival of patients have not improved significantly over the last 30 years, with the overall, 5-year survival not exceeding 50%. Progress in understanding the biology of cancer leads to personalization of therapy and introduction of drugs with molecular mechanism of action to everyday practice. At present, the effectiveness of monoclonal antibodies against EGFR in the treatment of HNSCC has already been proven. Cetuximab in combination with radiotherapy was found to be effective in patients with advanced and locally advanced HNSCC. There are also some promising results of phase III trials with zalutumumab and panitumumab. Initial efficacy of sorafenib (an inhibitor of the intracellular domain of VEGFR, PDGFR and c-Kit) and afatinib (an irreversible inhibitor of pan HER tyrosine kinase) have been demonstrated. Great hopes for the future are linked with the potential use of STAT3, EGFRvIII, abnormal proteins K-ras, H-ras and PTEN as well as proteasome as a target for therapy. PMID- 23036119 TI - [Vocal fold paralysis in the Medical University of Warsaw's Ambulatory of Phoniatry in years 2000-2011]. AB - INTRODUCTION: Vocal fold paralysis it is an important problem in Phoniatrics' Ambulatory. There are a lot of difficulties in estimation a precise incidence of vocal fold paralysis in the population. As many as 50% of cases with paralysis might present nonspecific symptoms. AIM OF THE STUDY: The aim of the research it was to determine a vocal fold paralysis' epidemiology and etiology in material of the Medical University of Warsaw's Ambulatory of Phoniatry. MATERIAL AND METHODS: Authors present a group of 593 patients with vocal cord paralysis who were diagnosed and treated in The Ambulatory of Phoniatry from 2000 to 2011. The paralysis was observed in 439 women and in 154 men. In 488 patients paralysis was unilateral and in 105 - bilateral. RESULTS: In the study, surgery was responsible for most vocal fold paralysis (79.0%). In 357 patients, paralysis was caused by thyroid surgery. Other surgical causes of the paralysis there were: endarterectomy, thoracic surgery and skull base surgery. Of the total group, 1.2% of cases were diagnosed after intubation. In the review, in another 19.8% cases, paralysis was caused by thoracic, neck or brain tumors, by traumas and in 21 patients there was no obvious reason (idiopathic cases). CONCLUSIONS: Etiology of vocal fold paralysis seems to be affected by a character of institutions or hospitals who make a study and by geographic location. The most common etiology of vocal cord paralysis is iatrogenic. PMID- 23036120 TI - [The influence of high frequency hearing loss on the distortion product otoacoustic emissions in tinnitus subjects with normal hearing threshold (0,25-8 kHz)]. AB - AIM OF THE STUDY: To evaluate the influence of high frequency hearing loss (> 8000 Hz) on distortion product otoacoustic emissions registered in the frequency range from 0,5 to 8 kHz. MATERIAL AND METHODS: 280 ears with tinnitus and normal hearing (0.25-8 kHz) divided into 3 groups depending on the degree of high frequency hearing loss: group A--hearing threshold up to 20 dB for 10, 12.5, 14 and 16 kHz (68 ears); group B--hearing threshold 25-40 dB HL for at least one of four EHfs (93 ears); group C--hearing threshold above 40 dB HL for at least one of four EHFs (119 ears). For each group mean audiogram and DP-gram were obtained and statistical analysis was used for comparison across these groups. RESULTS: Mean DPOAE values in group C were significantly lower in comparison with group A for the frequency range 2-8 kHz, and in comparison with group B were significantly lower for the frequency range 4-8 kHz. CONCLUSIONS: High frequency hearing loss (above 8 kHz) has a relevant influence on distortion product otoacoustic emissions registered at frequencies below 8 kHz in tinnitus patients. The greater is hearing loss above 8 kHz, the lower is DPOAE value below 8 kHz. PMID- 23036121 TI - [Causes and indwelling times of multiple voice prosthesis replacements in patients after total laryngectomy--analysis of 184 replacements in 42 patients]. AB - INTRODUCTION: Implantation of the indwelling voice prosthesis has become the preferred method of voice rehabilitation after total laryngectomy. Frequent prosthesis dysfunction remains the major problem. AIM: Analysis of the indwelling time and indications for multiple voice prosthesis replacements. METHODS: Forty two patients after total laryngectomy due to laryngeal cancer (6 women and 36 men, mean age 62.1 +/- 6.7 years) were included. 184 voice prosthesis replacements were analyzed (1271 patient-months). RESULTS: Mean time between replacements was 260 +/- 150 days. The indwelling time decreased from 267 days to the first replacement to 100-160 days at eighth and subsequent exchanges (p < 0.01). Most frequent indications for replacement were leakage of fluids through the prosthesis, phonation problems caused by mucosal overgrowth around the prosthesis, inaccurate sizing, deformation, and spontaneous extrusion. The lifetime of voice prostheses was positively correlated with patients' age. Mycological culture of the smear taken from tracheoesophageal fistula at first replacement was positive in 34/41 cases, at the second in 29/31 cases, the third in 29/31, and at the fourth and subsequent replacements in all specimens. Most patients indicated the following factors as possible causes of a shortened lifetime of the prosthesis: use of alcohol and coffee (34% of responders), inappropriate dietary habits (sweets and tough foodstuff - 17%), cleaning of voice prosthesis discordant with the recommendations of the manufacturer (14%). CONCLUSIONS: Although our results confirm common indications for voice prosthesis replacement we also showed that the time between exchanges is gradually getting shorter. This observation could have implications for the current reimbursement practices. PMID- 23036122 TI - [The usage of modern physioterapeutic methods of rehabilitation in treatment of chosen kinds of dysphonia]. AB - Voice quality disorders--dysphonias are the significant problem from therapeutic, social and economic point of view. The routine therapy does not always bring spectacular effects. The important role play the innovative methods supporting therapy of voice quality disorders. PURPOSE: The aim of the study is to assess the effects of vibratory therapy of the larynx (Medical VR) in patients with hyperfunctional dysphonia and stimulating currents in phonatory exercises (VocaStim-Master) in paralytic dysphonia based on the analysis of parameters of objective assessment of voice quality. MATERIAL AND METHODS: Forty patients with hyperfunctional dysphonia treated routinely were included in the study. 20 patients apart from the routine therapy were additionally treated using the vibratory therapy of regions of the larynx (Medical VR, CyberBioMed LLC). In group of 40 patients with paralytic dysphonia, in 20 patients the adjuvant therapy by stimulating currents in phonatory exercises (VocaStim-Master, Physiomed) was used. The results of treatment and adjuvant therapy in hyperfunctional and paralytic dysphonia were analyzed based on: MPT, parameters of stroboscopic and acoustic evaluation (F(0), Jitter, Shimmer, NHR) and narrow band spectrography. RESULTS AND CONCLUSIONS: : The analysis of the results indicated the usefulness of used parameters of objective assessment of voice quality taking into consideration the diagnostic and therapeutic aspect in hyperfunctional and paralytic dysphonia. Adjuvant vibratory therapy of the larynx in hyperfunctional dysphonia and stimulating currents in phonatory exercises in paralytic dysphonia improved the effectiveness of the therapy, what was confirmed by the analysis of parameters of objective assessment of voice quality. PMID- 23036123 TI - [The evaluation of the efficiency of kinesitherapy in the patients with mixed type vertigo]. AB - INTRODUCTION: The aim of this work was to evaluate the efficiency of kinesitherapy in the patients with mixed-type vertigo. MATERIAL AND METHODS: The study was conducted on a randomized group of 35 patients, 21 women and 14 men aged 24-75 years (mean age 42.5 years), who were treated at the Department of Otolaryngology and Laryngological Oncology Medical University Teaching Hospital in Lodz for mixed-type vertigo. The inclusion criteria were an interview, physical and otorhinolaryngological examinations, laboratory investigations, complete audiological and otoneurological examinations, including BERA and VNG, USG examination of the blood vessels to the cranium, and CT of the cervical spine. Each patient underwent an individually selected set of habituation exercises, corrective exercises for posture and its orientation in space through 2 months. The efficiency of the implemented therapy was evaluated after two weeks, one month and two months with the use of the complete videonystagmographic test and Silvoniemi's criteria. RESULTS: The mean excitability of the labyrinths was 25.38 degrees/s before rehabilitation and 22.26 degrees/s after rehabilitation, absolute directional preponderance was 7.62 degrees/s and 1.92 degrees/s respectively, relative directional preponderance was 31.36 degrees/s and 12.57 degrees/s, and unilateral deficit 32.12 degrees/s and 14.34 degrees/s. The subjective evaluation of the vertigo intensification based on the 5 stages of Silvoniemi's scale indicates that the mean point-based evaluation reported by the patients at the beginning of the therapy was 3.85 points, whereas after the therapy was 2.91 points after two weeks, 2.35 points after one month, and 1.2 points after two months. CONCLUSIONS: Kinesitherapy is an alternative and very effective method for treating mixed-type vertigo. PMID- 23036124 TI - [Device for graphic visualization of pressure course in the opening of sphincter of oesophagus mouth in patients after total laryngectomy]. AB - INTRODUCTION: Oesophageal speech were described for the first time by Gutzmann in 1909. The diagnostic method based upon checking the pressure causing opening of oesophagus mouth was developed by Seeman and Van Den Bergh. In the initial stage, the method was meant to determine the level, to which the patient can master oesophageal speech. In the course of further investigations, an additional element of diagnostics was noted, which enabled early detection of recurrence of the neoplastic process in the oesopagus mouth area. MATERIAL AND METHODS: The material includes 96 patients treated in 2008-2010 at the Department of Otolaryngology, Medical University in Katowice. All patients were classified on the basis of CT of the larynx and the result of histopathological examination to the total laryngectomy. All the patients were subjected to examination by device to visualize the process of opening pressure of the sphincter of the esophagus paragraph. RESULTS: During two years of observation in 28 cases (29%), oesophageal pressure was open his mouth more than 80 mmHg. When performed CT of the neck and histopathology examination recurrence of laryngeal cancer was confirmed in 23 cases (82%). CONCLUSION: This device is used to determine the best method of voice and speech rehabilitation in patients after total laryngectomy and early diagnosis of laryngeal and/or hypopharynx cancer recurrence. PMID- 23036125 TI - [Skull base defects in the middle and posterior cranial fossa with unchanged mucous lining middle ear spaces]. AB - BACKGROUND: Skull bone defects in the region of middle ear are usually observed in the cases of chronic otitis media. Such loses can also be congenital, posttraumatic, iatrogenic or due to hyperplasia. They can potentially lead to development of otogenic intracranial complications. AIM: We present the patients who were not observed during otosurgery to have any pathological changes to the mucous of the middle ear and were diagnosed as having bone defects in the middle and/or posterior cranial fossa. We discuss also methods of reconstruction during otosurgery. MATERIAL AND METHODS: The prospective analysis involves the patients operated on middle ear in the Department of Otolaryngology at the Jagiellonian University of Krakow in the years 2007-2011. 495 first-time otosurgeries were performed in this period of time. RESULTS: Skull bone defects were diagnosed in 46 patients who had undergone surgery and 25% of these patients had no changes to the middle ear mucous. This points to congenital etiology of the defects. In this group the most common cause for otosurgery was chronic otitis media (10 patients). In 1 patient, bone defect occurred along with otosclerosis. In patients with congenital skull bone defects otogenic intracranial complications were described in 4 cases. CONCLUSIONS: Nearly 80% of skull bone defects remain asymptomatic; they are revealed incidentally during the surgery of the middle ear. The above observations emphasize the significant role of preoperative imaging diagnostics. The methods of bone defects reconstruction using the fascia, strengthened with the pedicle muscle flap where larger defects occurred, as well as with either bone lamella or cartilage in particular cases, proved successful. PMID- 23036127 TI - Ossifying fibroma-cementoma of jaw. Differences in histopathological nomenclature. AB - Ossifying fibroma (cementoma) is a tumor of mesenchymal origin which represents about 1% of odontogenic tumors. It is commonly found in patients under 25, more often so in women. As its growth is slow and painless, it is usually accidentally detected by dental radiological examination. The aim of our study was to present the histopathological dilemma concerning the naming of a rare odontogenic tumor of the jaw. The authors present a rare jaw tumor, a benign ossifying fibroma, in the maxilla of a 12-year-old girl treated surgically, and they discuss the difficulty in making a definitive histopathological diagnosis. The clinical and histological criteria for identifying this type of tumor are still uncertain, as the most common sites, that is the tooth-bearing areas of the mandible, are very rare in the maxilla. The differentiation from the central fibro-osseous lesions in the maxilla bones is discussed. The final diagnosis of ossifying fibroma was based on the WHO classification. A literature search reveals a fundamental flaw in defining a unified classification for this type of change. As there is no clear diagnostic criterion, few repeatable diagnoses can be found. Although individual researchers tend to use their own means of classification in their routine work, the WHO classification should be applied. PMID- 23036126 TI - [Cost effectiveness of a free forearm flap in reconstruction of the oral cavity and pharynx--the donor site complications]. AB - PURPOSE: Evaluation of the donor site efficiency in patients after reconstructive surgery with use of free forearm flap. All patients were treated for oral cavity and larynx cancer. MATERIALS AND METHODS: a group of 21 patients (16 men and 5 women) treated in 2007-2011. The retrospective analysis was conducted on the anamnesis, operating protocols, physical examination and a questionnaire, there was completed by patients during a routine ENT follow up examination. The PRWE (Patient Rated Wrist Evaluation) subjective questionnaire was used to estimate the rate of pain severity and wrist mobility. RESULTS: In 59% of patients the wrist was healed primary, in 36% of patients by granulation. In all patients the wound was healed satisfactory in follow up examination, but 60% of patients revealed extensive scars formation. 62% of patients showed no local pain at rest, while in 38% of them worsening of symptoms was noticed--average 0.5/10 (median 1.0). Pain was more intense in patients who did basic motor activity of hands approximately 1/10 and lifting weights averaging 2.1/10. Dysfunction of the wrist was at the level of the average value of 4.2/50. CONCLUSIONS: Surgical reconstruction with a use of the free forearm flap is associated with the formation of extensive wrist scars. The risk of local complications is low while preserving the qualification protocol, postoperative care and proper surgical management. Reconstructive surgery based on the free forearm flaps gives satisfactory functional results of the donor site. However, it requires surgical experience and practical knowledge of anatomy. PMID- 23036128 TI - [Postoperative vertigo caused by too long stapes prosthesis--radiological diagnostics]. AB - The aim of the study was to describe the value of High Resolution Computed Tomography (HRCT) with MPR and VR reconstruction of the temporal bone in patients with persistent vertigo after stapedotomy. High Resolution Computed Tomography with MPR and VR reconstruction of the temporal bone in the axial and coronal planes with 0.625 - mm slice thickness were performed in 2 patients with persistent vertigo after stapedotomy. Persistent vertigo were observed in 2 patients suffered from otosclerosis several months after stapedotomy. High Resolution Computed Tomography with MPR and VR reconstruction of the temporal bone showed in both cases too long stapes prosthesis. On the base of HRCT results restapedotomy and length reduction of stapes prosthesis were done. The vertigo was resolved in all the cases with revision surgery. HRCT with MPR and VR reconstruction can diagnosed the possible cause of persistent vertigo in patients after stapedotomy. PMID- 23036129 TI - [Iatrogenic internal carotid artery pseudoaneurysm as a complication of myryngotomy in 6-years-old boy]. AB - The aberrant internal carotid artery (ICA) is a rare congenital vascular anomaly. Misdiagnosed may result in life threatening complications during middle ear surgery. Authors present a case of a 6-year old boy in whom ventilation tube insertion was complicated by ICA pseudo-aneurysm formation. Symptoms, diagnosis and management of ICA pseudo-aneurysm are discussed. PMID- 23036130 TI - Active and inactive forms of matrix metalloproteinases 2 and 9 in cutaneous melanoma. AB - BACKGROUND: Cutaneous melanoma is the most aggressive type of skin cancer, with high implications on the morbidity and mortality of patients. Matrix metalloproteinases (MMP) 2 and 9 have been involved in melanoma progression because they degrade important components of the basement membrane. We studied the relationship between the levels of active and inactive MMP 2, MMP 9, and clinicopathological parameters. MATERIALS AND METHODS: Expression of both active and latent forms of MMP 2 and MMP 9 was evaluated by zymography in 21 melanoma tissue samples and 19 benign melanocytic nevi samples. RESULTS: In the melanoma group, inactive MMP 2 was detected in 100% of samples and active MMP 2 in 95%. Inactive MMP 9 was detected in 85% of samples and active MMP 9 in 38%. In the nevi group, 78.9% of samples expressed inactive MMP 2, 5.26% active MMP 2, 21% inactive MMP 9, and 0% active MMP 9. Both forms of MMP 2 and MMP 9 were found to be correlated with skin tumor malignancy. Expression of active and latent MMP 9 was higher in tumors >2 mm thick (P = 0.03, P = 0.014). A correlation was also found between positive lymph node metastasis, inactive MMP 9, and active MMP 9 expression (r = 0.59 P < 0.01, r = 0.668, P < 0.01). The amount of active and latent form of MMP 2 did not have an impact on lymph node metastasis. CONCLUSIONS: Our study demonstrates that active and latent MMP 2 and MMP 9 correlate with melanoma, and both forms of MMP 9 correlate with positive lymph node metastasis. PMID- 23036132 TI - Tuning and maximizing the single-molecule surface-enhanced Raman scattering from DNA-tethered nanodumbbells. AB - We extensively study the relationships between single-molecule surface-enhanced Raman scattering (SMSERS) intensity, enhancement factor (EF) distribution over many particles, interparticle distance, particle size/shape/composition and excitation laser wavelength using the single-particle AFM-correlated Raman measurement method and theoretical calculations. Two different single-DNA tethered Au-Ag core-shell nanodumbbell (GSND) designs with an engineerable nanogap were used in this study: the GSND-I with various interparticle nanogaps from ~4.8 nm to <1 nm or with no gap and the GSND-II with the fixed interparticle gap size and varying particle size from a 23-30 nm pair to a 50-60 nm pair. From the GSND-I, we learned that synthesizing a <1 nm gap is a key to obtain strong SMSERS signals with a narrow EF value distribution. Importantly, in the case of the GSND-I with <1 nm interparticle gap, an EF value of as high as 5.9 * 10(13) (average value = 1.8 * 10(13)) was obtained and the EF values of analyzed particles were narrowly distributed between 1.9 * 10(12) and 5.9 * 10(13). In the case of the GSND-II probes, a combination of >50 nm Au cores and 514.5 nm laser wavelength that matches well with Ag shell generated stronger SMSERS signals with a more narrow EF distribution than <50 nm Au cores with 514.5 nm laser or the GSND-II structures with 632.8 nm laser. Our results show the usefulness and flexibility of these GSND structures in studying and obtaining SMSERS structures with a narrow distribution of high EF values and that the GSNDs with < 1 nm are promising SERS probes with highly sensitive and quantitative detection capability when optimally designed. PMID- 23036131 TI - Caries treatment in a dental practice-based research network: movement toward stated evidence-based treatment. AB - OBJECTIVES: Practice-based research networks (PBRNs) provide a venue to foster evidence-based care. We tested the hypothesis that a higher level of participation in a dental PBRN is associated with greater stated change toward evidence-based practice. METHODS: A total of 565 dental PBRN practitioner investigators completed a baseline questionnaire entitled 'Assessment of Caries Diagnosis and Treatment'; 405 of these also completed a follow-up questionnaire about treatment of caries and existing restorations. Certain questions (six treatment scenarios) were repeated at follow-up a mean (SD) of 36.0 (3.8) months later. A total of 224 were 'full participants' (enrolled in clinical studies and attended at least one network meeting); 181 were 'partial participants' (did not meet 'full' criteria). RESULTS: From 10% to 62% of practitioners were 'surgically invasive' at baseline, depending on the clinical scenario. Stated treatment approach was significantly less invasive at follow-up for four of six items. Change was greater among full participants and those with a more-invasive approach at baseline, with an overall pattern of movement away from the extremes. CONCLUSIONS: These results are consistent with a preliminary conclusion that network participation fostered movement of scientific evidence into routine practice. PBRNs may foster movement of evidence into everyday practice as practitioners become engaged in the scientific process. PMID- 23036133 TI - Robust DNA-functionalized core/shell quantum dots with fluorescent emission spanning from UV-vis to near-IR and compatible with DNA-directed self-assembly. AB - The assembly and isolation of DNA oligonucleotide-functionalized gold nanoparticles (AuNPs) has become a well-developed technology that is based on the strong bonding interactions between gold and thiolated DNA. However, achieving DNA-functionalized semiconductor quantum dots (QDs) that are robust enough to withstand precipitation at high temperature and ionic strength through simple attachment of modified DNA to the QD surface remains a challenge. We report the synthesis of stable core/shell (1-20 monolayers) QD-DNA conjugates in which the end of the phosphorothiolated oligonucleotide (5-10 nucleotides) is "embedded" within the shell of the QD. These reliable QD-DNA conjugates exhibit excellent chemical and photonic stability, colloidal stability over a wide pH range (4-12) and at high salt concentrations (>100 mM Na(+) or Mg(2+)), bright fluorescence emission with quantum yields of up to 70%, and broad spectral tunability with emission ranging from the UV to the NIR (360-800 nm). PMID- 23036135 TI - Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis associated delirium. AB - INTRODUCTION: Sepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis. METHODS: Cerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2. RESULTS: 30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 +/ 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035). CONCLUSIONS: AR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD. TRIAL REGISTRATION: clinicalTrials.gov ID NCT01029080. PMID- 23036136 TI - Australasian respiratory and emergency physicians do not use the pneumonia severity index in community-acquired pneumonia. AB - BACKGROUND AND OBJECTIVE: The value of community-acquired pneumonia (CAP) severity scoring tools is almost exclusively reliant upon regular and accurate application in clinical practice. Until recently, the Australasian Therapeutic Guidelines has recommended the use of the Pneumonia Severity Index (PSI) in spite of poor user-friendliness. METHODS: Electronic and postal survey of respiratory and emergency medicine physician and specialist registrar members of the Royal Australasian College was undertaken to assess the use of the PSI and the accuracy of its application to hypothetical clinical CAP scenarios. The confusion, urea, respiratory rate, blood pressure, age 65 or older (CURB-65) score was also assessed as a simpler alternative. RESULTS: Five hundred thirty-six (228 respiratory, 308 emergency) responses were received. Only 12% of respiratory and 35% of emergency physicians reported using the PSI always or frequently. The majority were unable to accurately approximate PSI scores, with significantly fewer respiratory than emergency physicians recording accurate severity classes (11.8% vs 21%, OR 0.50, 95% CI: 0.37-0.68, P < 0.0001). In contrast, significantly more respiratory physicians were able to accurately calculate the CURB-65 score (20.4% vs 15%, OR 1.45, 95% CI: 1.10-1.91, P = 0.006). CONCLUSIONS: Australasian specialist physicians primarily responsible for the acute management of CAP report infrequent use of the PSI and are unable to accurately apply its use to hypothetical scenarios. Furthermore, respiratory and emergency physicians contrasted distinctly in their use and application of the two commonest severity scoring systems--the recent recommendation of two further alternative scoring tools by Australian guidelines may add to this confusion. A simple, coordinated approach to pneumonia severity assessment across specialties in Australasia is needed. PMID- 23036134 TI - Anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence. AB - BACKGROUND: Anticholinergic medications and onabotulinumtoxinA are used to treat urgency urinary incontinence, but data directly comparing the two types of therapy are needed. METHODS: We performed a double-blind, double-placebo controlled, randomized trial involving women with idiopathic urgency urinary incontinence who had five or more episodes of urgency urinary incontinence per 3 day period, as recorded in a diary. For a 6-month period, participants were randomly assigned to daily oral anticholinergic medication (solifenacin, 5 mg initially, with possible escalation to 10 mg and, if necessary, subsequent switch to trospium XR, 60 mg) plus one intradetrusor injection of saline or one intradetrusor injection of 100 U of onabotulinumtoxinA plus daily oral placebo. The primary outcome was the reduction from baseline in mean episodes of urgency urinary incontinence per day over the 6-month period, as recorded in 3-day diaries submitted monthly. Secondary outcomes included complete resolution of urgency urinary incontinence, quality of life, use of catheters, and adverse events. RESULTS: Of 249 women who underwent randomization, 247 were treated, and 241 had data available for the primary outcome analyses. The mean reduction in episodes of urgency urinary incontinence per day over the course of 6 months, from a baseline average of 5.0 per day, was 3.4 in the anticholinergic group and 3.3 in the onabotulinumtoxinA group (P=0.81). Complete resolution of urgency urinary incontinence was reported by 13% and 27% of the women, respectively (P=0.003). Quality of life improved in both groups, without significant between group differences. The anticholinergic group had a higher rate of dry mouth (46% vs. 31%, P=0.02) but lower rates of catheter use at 2 months (0% vs. 5%, P=0.01) and urinary tract infections (13% vs. 33%, P<0.001). CONCLUSIONS: Oral anticholinergic therapy and onabotulinumtoxinA by injection were associated with similar reductions in the frequency of daily episodes of urgency urinary incontinence. The group receiving onabotulinumtoxinA was less likely to have dry mouth and more likely to have complete resolution of urgency urinary incontinence but had higher rates of transient urinary retention and urinary tract infections. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health; ClinicalTrials.gov number, NCT01166438.). PMID- 23036137 TI - Hereditary and environmental epidemiology of sarcomas. PMID- 23036138 TI - Reducing the stigma of herpes simplex virus infection: lessons from an online video contest. AB - BACKGROUND: Herpes simplex virus (HSV) is one of the most common sexually transmisible infections worldwide. HSV-associated stigma negatively impacts emotional and sexual health, suggesting a need for novel approaches to reducing stigma. The aims of this study were to describe the range of destigmatising strategies used by the public in brief online videos, and to describe videos that were successful or unsuccessful in creating a destigmatising message. METHODS: A thematic content analysis was performed on 103 publicly produced YouTube videos designed to destigmatise HSV infection for an Australian online contest. RESULTS: Five destigmatising strategies were identified: providing information, normalising through familiarity, promoting disclosure, negating a negative perception and expressing moral indignation. Most videos employed multiple strategies. Regarding the degree of destigmatisation achieved, videos were coded as unsuccessful, successful, mixed or neutral. Unsuccessful and successful videos often employed the same strategies, but differed in their ability to balance positive and negative messages about HSV and to manage affective content. Some videos were successful despite not providing information about HSV. Mixed videos were appreciated differently in different contexts, and the use of humour was especially problematic. Neutral videos tended to exclusively provide information while avoiding affective content. CONCLUSIONS: Efforts to reduce HSV-associated stigma may be unsuccessful and may even perpetuate stigma. Special attention must be paid to balance and to affective content, specifically humour, when attempting to convey a destigmatising message. Doing so may help reduce the role stigma plays as a barrier to appropriate care for patients with HSV infection. PMID- 23036139 TI - Effect of naturopathic and nutritional supplement treatment on tumor response, control, and recurrence in patients with prostate cancer treated with radiation therapy. AB - OBJECTIVES: Use of naturopathic and nutritional supplements (NNS) with antioxidant activity is controversial in patients receiving radiation therapy. The effects of concomitant use of NNS with antioxidant activity during radiation therapy for prostate cancer were investigated in terms of clinical tumor responsiveness, kinetics, and durability. MATERIALS AND METHODS: A retrospective investigation was done of 134 patients treated with curative intent for limited stage prostate cancer by radiation therapy. Patients self-selected to receive NNS as part of their treatment and maintenance during an extended post-treatment interval of at least 2 years. The outcome measures were the following: prostate specific antigen (PSA) nadir; >=24 months post-treatment PSA; time to reach nadir; and time to last follow-up were compared across +NNS and -NNS. RESULTS: Sixty-nine (69) patients elected to receive NNS while 65 did not. Seventy-seven (77) (+NNS 39, -NNS 38) patients received hormone therapy while 57 (+NNS 30, -NNS 27) did not. In the nonhormone cohort, median pretreatment PSA, nadir, post treatment PSA, time to reach nadir, and time to follow-up were 5.5 ng/mL, 0.56 ng/mL, 0.61 ng/mL, 25 months, and 39.7 months for the -NNS group and 5.1 ng/mL, 0.32 ng/mL, 0.44 ng/mL, 27 months, and 50.1 months for the +NNS group, respectively (p>0.05 for all). Similarly, no significant differences were observed between +NNS and -NNS in the hormone-receiving cohort. CONCLUSIONS: The clinical tumor response to radiation therapy in patients with limited-stage prostate cancer is not inhibited by concomitant NNS based on the magnitude of the PSA response, the velocity of the PSA nadir, and the duration of PSA normalization. PMID- 23036140 TI - Effect of risk adjustment method on comparisons of health care utilization between complementary and alternative medicine users and nonusers. AB - OBJECTIVES: Complementary and alternative medicine (CAM) providers are becoming more integrated into the United States health care system. Because patients self select CAM use, risk adjustment is needed to make the groups more comparable when analyzing utilization. This study examined how the choice of risk adjustment method affects assessment of CAM use on overall health care utilization. DESIGN AND SUBJECTS: Insurance claims data for 2000-2003 from Washington State, which mandates coverage of CAM providers, were analyzed. Three (3) risk adjustment methods were compared in patients with musculoskeletal conditions: Adjusted Clinical Groups (ACG), Diagnostic Cost Groups (DCG), and the Charlson Index. Relative Value Units (RVUs) were used as a proxy for expenditures. Two (2) sets of median regression models were created: prospective, which used risk adjustments from the previous year to predict RVU in the subsequent year, and concurrent, which used risk adjustment measures to predict RVU in the same year. RESULTS: The sample included 92,474 claimants. Prospective models showed little difference in the effect of CAM use on RVU among the three risk adjustment methods, and all models had low predictive power (R(2) <=0.05). In the concurrent models, coefficients were similar in direction and magnitude for all risk adjustment methods, but in some models the predicted effect of CAM use on RVU differed by as much as double between methods. Results of DCG and ACG models were similar and were stronger than Charlson models. CONCLUSIONS: Choice of risk adjustment method may have a modest effect on the outcome of interest. PMID- 23036141 TI - Marching home, again: spine casualties, combat exposure, and the long wars. PMID- 23036142 TI - Military contributions to spine care. PMID- 23036143 TI - A history of military spine surgery. PMID- 23036144 TI - Commentary: penetrating neck injury: George Orwell is "Struck by Lighting". PMID- 23036145 TI - Commentary: the veteran: "a need to talk but no one wanted to hear about it". PMID- 23036146 TI - Commentary: battle injuries: Jessica Lynch sets the record straight. PMID- 23036147 TI - Large caliber ballistic fragment within the spinal canal. PMID- 23036148 TI - Implementing wavelet inverse-transform processor with surface acoustic wave device. AB - The objective of this research was to investigate the implementation schemes of the wavelet inverse-transform processor using surface acoustic wave (SAW) device, the length function of defining the electrodes, and the possibility of solving the load resistance and the internal resistance for the wavelet inverse-transform processor using SAW device. In this paper, we investigate the implementation schemes of the wavelet inverse-transform processor using SAW device. In the implementation scheme that the input interdigital transducer (IDT) and output IDT stand in a line, because the electrode-overlap envelope of the input IDT is identical with the one of the output IDT (i.e. the two transducers are identical), the product of the input IDT's frequency response and the output IDT's frequency response can be implemented, so that the wavelet inverse transform processor can be fabricated. X-112(0)Y LiTaO(3) is used as a substrate material to fabricate the wavelet inverse-transform processor. The size of the wavelet inverse-transform processor using this implementation scheme is small, so its cost is low. First, according to the envelope function of the wavelet function, the length function of the electrodes is defined, then, the lengths of the electrodes can be calculated from the length function of the electrodes, finally, the input IDT and output IDT can be designed according to the lengths and widths for the electrodes. In this paper, we also present the load resistance and the internal resistance as the two problems of the wavelet inverse-transform processor using SAW devices. The solutions to these problems are achieved in this study. When the amplifiers are subjected to the input end and output end for the wavelet inverse-transform processor, they can eliminate the influence of the load resistance and the internal resistance on the output voltage of the wavelet inverse-transform processor using SAW device. PMID- 23036149 TI - A multi-faceted tailored strategy to implement an electronic clinical decision support system for pressure ulcer prevention in nursing homes: a two-armed randomized controlled trial. AB - BACKGROUND: Frail older people admitted to nursing homes are at risk of a range of adverse outcomes, including pressure ulcers. Clinical decision support systems are believed to have the potential to improve care and to change the behaviour of healthcare professionals. OBJECTIVES: To determine whether a multi-faceted tailored strategy to implement an electronic clinical decision support system for pressure ulcer prevention improves adherence to recommendations for pressure ulcer prevention in nursing homes. DESIGN: Two-armed randomized controlled trial in a nursing home setting in Belgium. The trial consisted of a 16-week implementation intervention between February and June 2010, including one baseline, four intermediate, and one post-testing measurement. Primary outcome was the adherence to guideline-based care recommendations (in terms of allocating adequate pressure ulcer prevention in residents at risk). Secondary outcomes were the change in resident outcomes (pressure ulcer prevalence) and intermediate outcomes (knowledge and attitudes of healthcare professionals). SETTING: Random sample of 11 wards (6 experimental; 5 control) in a convenience sample of 4 nursing homes in Belgium. PARTICIPANTS: In total, 464 nursing home residents and 118 healthcare professionals participated. METHODS: The experimental arm was involved in a multi-faceted tailored implementation intervention of a clinical decision support system, including interactive education, reminders, monitoring, feedback and leadership. The control arm received a hard-copy of the pressure ulcer prevention protocol, supported by standardized 30 min group lecture. RESULTS: Patients in the intervention arm were significantly more likely to receive fully adequate pressure ulcer prevention when seated in a chair (F=16.4, P=0.003). No significant improvement was observed on pressure ulcer prevalence and knowledge of the professionals. While baseline attitude scores were comparable between both groups [exp. 74.3% vs. contr. 74.5% (P=0.92)], the mean score after the intervention was 83.5% in the experimental group vs. 72.1% in the control group (F=15.12, P<0.001). CONCLUSION: The intervention was only partially successful to improve the primary outcome. Attitudes improved significantly while the knowledge of the healthcare workers remained unsatisfactorily low. Further research should focus on the underlying reasons for these findings. PMID- 23036150 TI - Label-free enrichment of avian Leucocytozoon using flow cytometric sorting. AB - The group of haemosporidian parasites is of general interest to basic and applied science, since several species infect mammals, leading to malaria and associated disease symptoms. Although the great majority of haemosporidian parasites appear in bird hosts, as in the case of Leucocytozoon buteonis, there is little genomic information about genetic aspects of their co-evolution with hosts. Consequently, there is a high need for parasite-enrichment strategies enabling further analyses of the genomes, namely without exposure to DNA-intercalating dyes. Here, we used flow cytometry without an additional labelling step to enrich L. buteonis from infected buzzard blood. A specific, defined area of two-dimensional scattergramms was sorted and the fraction was further analysed. The successful enrichment of L. buteonis in the sorted fraction was demonstrated by Giemsa-staining and qPCR revealing a clear increase of parasite-specific genes, while host-specific genes were significantly decreased. This is the first report describing a labelling free enrichment approach of L. buteonis from infected buzzard blood. The enrichment of parasites presented here is free of nucleic acid-intercalating dyes which may interfere with fluorescence-based methods or subsequent sequencing approaches. PMID- 23036151 TI - Prediction of preeclampsia and fetal growth restriction using placental protein 13. PMID- 23036152 TI - SAR, cardiac myocytes protection activity and 3D-QSAR studies of salubrinal and its potent derivatives. AB - Salubrinal is a selective inhibitor of endoplasmic reticulum (ER) stress and affords remarkable protection to cardiomyocytes. By studying the structure activity relationship (SAR) of salubrinal, it was found that modification of the quinoline ring terminus and thiourea unit could confer the compound PP1-24 with markedly enhanced cardioprotective activity (EC50 <= 0.3 MUM) that is 50-fold more potent than salubrinal. Comparative molecular field analysis (CoMFA) was performed using the obtained biological data and resulted in a statistically significant CoMFA model with high predictive power (q2 = 0.741, r2 = 0.991). PMID- 23036154 TI - Prognostic significance of solitary lymph node metastasis in patients with squamous cell carcinoma of middle thoracic esophagus. AB - BACKGROUND: The aim of this study is to compare clinical outcomes between patients with solitary lymph node metastasis and node-negative (N0) patients in squamous cell carcinoma of the middle thoracic esophagus. METHODS: A series of 135 patients with squamous cell carcinoma of the middle thoracic esophagus were retrospectively investigated. There were 33 patients with solitary lymph node metastasis and 102 N0 patients. Skip metastasis in 33 patients with solitary lymph node metastasis was defined according to three criteria: Japanese Society for Esophageal Disease (JSED), American Joint Commission on Cancer (AJCC), and the anatomical compartment. RESULTS: In 33 patients with solitary lymph node metastasis, skip metastasis was shown in 13, 23, and 8 patients according JSED, AJCC and anatomical compartment respectively. The 5-year survival rates for N0 patients and patients with solitary lymph node metastasis were 58% and 32% respectively (P =0.008). Multivariate analysis revealed that skip metastasis was not an independent prognostic factor. CONCLUSIONS: For patients with middle thoracic esophageal squamous cell carcinoma, solitary lymph node metastasis has a negative impact on survival compared with N0 disease; skip metastasis, however, is comparable to N0 diseases in predicting prognosis. PMID- 23036153 TI - The population structure of Glossina fuscipes fuscipes in the Lake Victoria basin in Uganda: implications for vector control. AB - BACKGROUND: Glossina fuscipes fuscipes is the primary vector of trypanosomiasis in humans and livestock in Uganda. The Lake Victoria basin has been targeted for tsetse eradication using a rolling carpet initiative, from west to east, with four operational blocks (3 in Uganda and 1 in Kenya), under a Pan-African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC). We screened tsetse flies from the three Ugandan PATTEC blocks for genetic diversity at 15 microsatellite loci from continental and offshore populations to provide empirical data to support this initiative. METHODS: We collected tsetse samples from 11 sites across the Lake Victoria basin in Uganda. We performed genetic analyses on 409 of the collected tsetse flies and added data collected for 278 individuals in a previous study. The flies were screened across 15 microsatellite loci and the resulting data were used to assess the temporal stability of populations, to analyze patterns of genetic exchange and structuring, to estimate dispersal rates and evaluate the sex bias in dispersal, as well as to estimate demographic parameters (NE and NC). RESULTS: We found that tsetse populations in this region were stable over 4-16 generations and belong to 4 genetic clusters. Two genetic clusters (1 and 2) corresponded approximately to PATTEC blocks 1 and 2, while the other two (3 and 4) fell within PATTEC block 3. Island populations grouped into the same genetic clusters as neighboring mainland sites, suggesting presence of gene flow between these sites. There was no evidence of the stretch of water separating islands from the mainland forming a significant barrier to dispersal. Dispersal rates ranged from 2.5 km per generation in cluster 1 to 14 km per generation in clusters 3 and 4. We found evidence of male-biased dispersal. Few breeders are successfully dispersing over large distances. Effective population size estimates were low (33-310 individuals), while census size estimates ranged from 1200 (cluster 1) to 4100 (clusters 3 and 4). We present here a novel technique that adapts an existing census size estimation method to sampling without replacement, the scheme used in sampling tsetse flies. CONCLUSION: Our study suggests that different control strategies should be implemented for the three PATTEC blocks and that, given the high potential for re-invasion from island sites, mainland and offshore sites in each block should be targeted at the same time. PMID- 23036155 TI - Impact of age on epidermal growth factor receptor mutation in lung cancer. AB - Aging is one of the best, but rarely referred, risk factors for various types of cancer including lung cancer, because age could be a surrogate for accumulation of genetic events in cancers. Smoking inversely associates with the presence of epidermal growth factor receptor (EGFR) mutation in lung cancer, but its strong confounding with age and sex makes it difficult to evaluate sole impact of age. To clarify an impact of age on EGFR mutation, we conducted a cross-sectional study based on data of 1262 lung cancer patients. The associations between EGFR mutation and age, considering sex, smoking and histology, were evaluated using logistic regression models. In multivariate analysis, we found a significant increase of EGFR mutation prevalence by increase of age (p-trend=0.0004). Consistent trend was observed among never-smoking females (p-trend=0.011) and never-smoking males also showed similar trend although not significant. These were consistently observed when we limit the subject to those with adenocarcinoma. In conclusion, age independently associates with EGFR mutation among lung cancer. Positive association between EGFR mutation and age among never smokers regardless of sex might indicate that EGFR mutation occurs cumulatively by unidentified internal/external factors other than smoking. PMID- 23036156 TI - Formation of self-assembled organosilicon-functionalized quinquethiophene monolayers by fast processing techniques. AB - Different techniques for a relatively fast self-assembled monolayer film formation such as Langmuir-Blodgett (LB), spin-coating, and dip-coating methods have been compared using chloro[11-(5''''-ethyl-2,2':5',2":5''',2''':5''',2'''' quinquethiophene-5-yl)undecyl]dimethylsilane as a reactive precursor. It was shown that both spin-coating and LB techniques are very promising methods for preparation of highly ordered monolayer films of organosilicon-functionalized quinquethiophene with vertical orientation of oligothiophene fragments, while dip coating gives only partial coverage. Optimal conditions for complete filling out the substrate surface by the quinquethiophene-containing monolayer by spin coating and LB methods have been found. Grazing incidence X-ray diffraction measurements confirmed formation of in-plane crystalline order within the monolayer film. Changes in the layer structure were established by X-ray reflectivity and grazing incidence X-ray diffraction methods. PMID- 23036157 TI - In vivo extraction of Arabidopsis cell turgor pressure using nanoindentation in conjunction with finite element modeling. AB - Turgor pressure in plant cells is involved in many important processes. Stable and normal turgor pressure is required for healthy growth of a plant, and changes in turgor pressure are indicative of changes taking place within the plant tissue. The ability to quantify the turgor pressure of plant cells in vivo would provide opportunities to understand better the process of pressure regulation within plants, especially when plant stress is considered, and to understand the role of turgor pressure in cellular signaling. Current experimental methods do not separate the influence of the turgor pressure from the effects associated with deformation of the cell wall when estimates of turgor pressure are made. In this paper, nanoindentation measurements are combined with finite element simulations to determine the turgor pressure of cells in vivo while explicitly separating the cell-wall properties from the turgor pressure effects. Quasi static cyclic tests with variable depth form the basis of the measurements, while relaxation tests at low depth are used to determine the viscoelastic material properties of the cell wall. Turgor pressure is quantified using measurements on Arabidopsis thaliana under three pressure states (control, turgid and plasmolyzed) and at various stages of plant development. These measurements are performed on cells in vivo without causing damage to the cells, such that pressure changes may be studied for a variety of conditions to provide new insights into the biological response to plant stress conditions. PMID- 23036158 TI - The combined effects of the 5- HTTLPR and HTR1A rs6295 polymorphisms modulate decision making in schizophrenia patients. AB - Decision making ability has been reported to be impaired in schizophrenia patients, but no research has examined the genetic bases of this impairment. This study investigated how decision making was affected by the genetic variants in the serotonin transporter gene (triallelic 5- HTTLPR) and serotonin receptor 1A gene (rs6295) and their interaction in 465 schizophrenia patients and 448 healthy controls. The Iowa Gambling Task (IGT) was used to evaluate decision making under ambiguity (the first 40 trials) and decision making under risk (the last 60 trials). Results showed that, among the patients, the main effects of 5- HTTLPR (F(2) (,16) = 6.54, P = 0.002) and HTR1A rs6295 (F(2) (,16) = 3.87, P = 0.021) polymorphisms and their interaction effect (F(4) (,16) = 3.32, P = 0.005) were significant for the first 40 trials, with the GG genotype of HTR1A rs6295, the L'L' genotype of 5- HTTLPR and the GG-L'L' combination showing poorer IGT performance than their counterparts. Results for the healthy controls showed a similar pattern but did not reach statistical significance. No significant effects were found for the last 60 trials. These results are discussed in terms of their implications for our understanding of the genetic mechanisms of decision making in schizophrenia patients as well as healthy adults. PMID- 23036159 TI - Supercritical fluid technology: a promising approach in pharmaceutical research. AB - Supercritical fluids possess the unique properties of behaving like liquids and gases, above their critical point. Supercritical fluid technology has recently emerged as a green and novel technique for various processes such as solubility enhancement of poorly soluble drugs, plasticization of polymers, surface modification, nanosizing and nanocrystal modification, and chromatographic extraction. Research interest in this area has been fuelled because of the numerous advantages that the technology offers over the conventional methods. This work aims to review the merits, demerits, and various processes such as rapid expansion of supercritical solutions (RESS), particles from gas saturated solutions (PGSS), gas antisolvent process (GAS), supercritical antisolvent process (SAS) and polymerization induced phase separation (PIPS), that have enabled this technology to considerably raise the interest of researchers over the past two decades. An insight has been given into the numerous applications of this technology in pharmaceutical industry and the future challenges which must be appropriately dealt with to make it effective on a commercial scale. PMID- 23036160 TI - First-generation autologous chondrocyte implantation in patients with cartilage defects of the knee: 7 to 14 years' clinical and magnetic resonance imaging follow-up evaluation. AB - PURPOSE: The purpose of this study was to evaluate the overall long-term improvement of autologous chondrocyte implantation (ACI) treatment in terms of patient satisfaction, clinical assessment, and magnetic resonance imaging (MRI) evaluation. Furthermore, we aimed to assess the impact of independent variables on clinical outcomes and patient satisfaction. METHODS: We evaluated 23 patients (mean age, 30.5 +/- 8.2 years) with full-thickness chondral lesions of the distal femur who underwent first-generation ACI with periosteum between 1997 and 2004. The Lysholm score, Tegner activity score, subjective International Knee Documentation Committee score, numeric rating scale score, and Short Form 36 score were used for clinical assessment preoperatively, at 1 year postoperatively, and at 7 to 14 years (mean, 9.9 years) after surgery. MRI was performed to evaluate the cartilage preoperatively and at final follow-up, by use of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. RESULTS: ACI resulted in a substantial improvement in all clinical outcome parameters, even as much as 14 years after implantation, although a small deterioration was noticed between intermediate and final evaluations in some outcome parameters. Of the patients, 73.1% stated that they would undergo the operation again. Younger patients with a shorter duration of preoperative symptoms and smaller defect sizes benefited most. MRI findings confirmed complete defect filling in 52.3% of the patients at final follow-up. CONCLUSIONS: Our long term results confirm that first-generation ACI is an effective treatment for large full-thickness chondral and osteochondral lesions of the knee joint. Younger patients with a shorter duration of preoperative symptoms and smaller defect size benefited most in our study. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23036161 TI - Cartilage on the move: cartilage lineage tracing during tadpole metamorphosis. AB - The reorganization of cranial cartilages during tadpole metamorphosis is a set of complex processes. The fates of larval cartilage-forming cells (chondrocytes) and sources of adult chondrocytes are largely unknown. Individual larval cranial cartilages may either degenerate or remodel, while many adult cartilages appear to form de novo during metamorphosis. Determining the extent to which adult chondrocytes/cartilages are derived from larval chondrocytes during metamorphosis requires new techniques in chondrocyte lineage tracing. We have developed two transgenic systems to label cartilage cells throughout the body with fluorescent proteins. One system strongly labels early tadpole cartilages only. The other system inducibly labels forming cartilages at any developmental stage. We examined cartilages of the skull (viscero- and neurocranium), and identified larval cartilages that either resorb or remodel into adult cartilages. Our data show that the adult otic capsules, tecti anterius and posterius, hyale, and portions of Meckel's cartilage are derived from larval chondrocytes. Our data also suggest that most adult cartilages form de novo, though we cannot rule out the potential for extreme larval chondrocyte proliferation or de- and re differentiation, which could dilute our fluorescent protein signal. The transgenic lineage tracing strategies developed here are the first examples of inducible, skeleton-specific, lineage tracing in Xenopus. PMID- 23036162 TI - Angiopoietin-1 variant reduces LPS-induced microvascular dysfunction in a murine model of sepsis. AB - INTRODUCTION: Severe sepsis is characterised by intravascular or extravascular infection with microbial agents, systemic inflammation and microcirculatory dysfunction, leading to tissue damage, organ failure and death. The growth factor angiopoietin (Ang-1) has therapeutic potential but recombinant Ang-1 tends to aggregate and has a short half-life in vivo. This study aimed to investigate the acute effects of the more stable Ang-1 variant matrilin-1-angiopoietin-1 (MAT.Ang 1) on the function of the microcirculation in an experimental model of sepsis, and whether any protection by MAT-Ang-1 was associated with modulation of inflammatory cytokines, angiogenic factors or the endothelial nitric oxide synthase (eNOS)-Akt and vascular endothelial (VE)-cadherin pathways. METHODS: Aluminium window chambers were implanted into the dorsal skinfold of male C3H/HeN mice (7 to 10 weeks old) to expose the striated muscle microcirculation. Endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (LPS, 1 mg/kg at 0 and 19 hours). MAT.Ang-1 was administered intravenously 20 hours after the onset of sepsis. Microcirculatory function was evaluated by intravital microscopy and Doppler fluximetry. RESULTS: Endotoxemia resulted in macromolecular leak, which was ameliorated by MAT.Ang-1 post-treatment. LPS induced a dramatic reduction in tissue perfusion, which was improved by MAT.Ang 1. Proteome profiler array analysis of skeletal muscle also demonstrated increased inflammatory and reduced angiogenic factors during endotoxemia. MAT.Ang 1 post-treatment reduced the level of IL-1beta but did not significantly induce the expression of angiogenic factors. MAT.Ang-1 alone did not induce leak or increase angiogenic factors but did reduce vascular endothelial growth factor expression in controls. CONCLUSION: Administration of MAT.Ang-1 after the onset of sepsis protects the microcirculation from endotoxemia-induced vascular dysfunction through reducing inflammation but without pro-angiogenic actions, thus representing a novel, potential pharmacotherapeutic agent for the treatment of sepsis. PMID- 23036163 TI - Gingival crevicular fluid levels of matrix metalloproteinases cross-sectionally related to periodontitis and metabolic syndrome in community Koreans. AB - BACKGROUND: Metabolic syndrome (MetS) may be associated with periodontitis. This study aimed to investigate whether the existence of periodontitis and MetS is cross-sectionally associated with matrix metalloproteinase (MMP) in gingival crevicular fluid (GCF) among community Koreans. MATERIALS AND METHODS: Medical and periodontal parameters were evaluated by physicians and dentists in 314 subjects (199 healthy, 58 only periodontitis, 34 only MetS and 23 both). The community periodontal index was used to assess periodontitis. MMP-8, 9, 13 were determined by enzyme-linked immunosorbent assay. Age, gender, monthly household income, smoking and drinking were interviewed as confounders. Analysis of covariance (ANCOVA) was applied. Gender-stratified analyses were applied. RESULTS: After controlling for various confounders, MMP-8, MMP-9 and MMP-13 in GCF were significantly associated with periodontitis in both genders and MMP-9, MMP-13 were associated with MetS in women. MMP-8, MMP-9 and MMP-13 showed association with periodontitis-MetS coexistence non-synergistically in both genders. MMP-9 was synergistically associated with periodontitis-MetS coexistence in women. CONCLUSION: Our results suggest that MMP-8, MMP-9, MMP-13 in GCF were independently related to coexistence of periodontitis and MetS. MMP-9 and MMP-13 could be an appropriate common indicator of periodontitis and MetS in women. Further studies might guarantee that MMPs in GCF could screen periodontitis and MetS. PMID- 23036164 TI - The epidemiology of sarcoma. AB - Sarcomas account for over 20% of all pediatric solid malignant cancers and less than 1% of all adult solid malignant cancers. The vast majority of diagnosed sarcomas will be soft tissue sarcomas, while malignant bone tumors make up just over 10% of sarcomas. The risks for sarcoma are not well-understood. We evaluated the existing literature on the epidemiology and etiology of sarcoma. Risks for sarcoma development can be divided into environmental exposures, genetic susceptibility, and an interaction between the two. HIV-positive individuals are at an increased risk for Kaposi's sarcoma, even though HHV8 is the causative virus. Radiation exposure from radiotherapy has been strongly associated with secondary sarcoma development in certain cancer patients. In fact, the risk of malignant bone tumors increases as the cumulative dose of radiation to the bone increases (p for trend <0.001). A recent meta-analysis reported that children with a history of hernias have a greater risk of developing Ewing's sarcoma (adjusted OR 3.2, 95% CI 1.9, 5.7). Bone development during pubertal growth spurts has been associated with osteosarcoma development. Occupational factors such as job type, industry, and exposures to chemicals such as herbicides and chlorophenols have been suggested as risk factors for sarcomas. A case-control study found a significant increase in soft tissue sarcoma risk among gardeners (adjusted OR 4.1, 95% CI 1.00, 14.00), but not among those strictly involved in farming. A European-based study reported an increased risk in bone tumors among blacksmiths, toolmakers, or machine-tool operators (adjusted OR 2.14, 95% CI 1.08, 4.26). Maternal and paternal characteristics such as occupation, age, smoking status, and health conditions experienced during pregnancy also have been suggested as sarcoma risk factors and would be important to assess in future studies. The limited studies we identified demonstrate significant relationships with sarcoma risk, but many of these results now require further validation on larger populations. Furthermore, little is known about the biologic mechanisms behind each epidemiologic association assessed in the literature. Future molecular epidemiology studies may increase our understanding of the genetic versus environmental contributions to tumorigenesis in this often deadly cancer in children and adults. PMID- 23036165 TI - Assessing and combining repeated prognosis of physicians and temporal models in the intensive care. AB - OBJECTIVE: Recently, we devised a method to develop prognostic models incorporating patterns of sequential organ failure to predict the eventual hospital mortality at each day of intensive care unit (ICU) stay. In this study, we investigate using a real world setting how these models perform compared to physicians, who are exposed to additional information than the models. METHODS: We developed prognostic models for days 2-7 of ICU stay by data-driven discovery of patterns of sequential qualitative organ failure (SOFA) scores and embedding the patterns as binary variables in three types of logistic regression models. Type A models include the severity of illness score at admission (SAPS-II) and the SOFA patterns. Type B models add to these covariates the mean, max and delta (increments) of SOFA scores. Type C models include, in addition, the mean, max and delta in expert opinion (i.e. the physicians' prediction of mortality). RESULTS: Physicians had a statistically significantly better discriminative ability compared to the models without subjective information (AUC range over days: 0.78-0.79 vs. 0.71-0.74) and comparable accuracy (Brier score range: 0.15 0.18 vs. 0.16-0.18). However when we combined both sources of predictions, in Type C models, we arrived at a significantly superior discrimination as well as accuracy than the objective and subjective models alone (AUC range: 0.80-0.83; Brier score range: 0.13-0.16). CONCLUSION: The models and the physicians draw on complementary information that can be best harnessed by combining both prediction sources. Extensive external validation and impact studies are imperative to further investigate the ability of the combined model. PMID- 23036166 TI - Pyogenic granuloma of the large intestine: case report and review of reported cases in the adult. AB - Pyogenic granuloma (PG) is a polypoid lobular capillary hemangioma rarely described in the large bowel. We describe the case of a 72-year-old man with recent weight loss, anemia, and change in bowel habit. A 3cm*2cm polypoid lesion in the right flexure of the colon was observed and treated with extended right hemicolectomy. A review of the English-language literature on PG of the large bowel in adults yielded eight previously reported cases. The age of the patients ranged from 26 to 80 years with a mean of 54.8 years. The lesions were all solitary, except one case of multiple lesions in the colon. Another case was associated with satellite lesions. Seven cases were located in the colon and two in the rectum. The mean maximum diameter of the lesions was 1.6cm (range 0.5 3cm). Colorectal bleeding was the most common clinical symptom. Due to its unusual appearance, PG can be misdiagnosed and mistreated as colon carcinoma with extensive surgery. Polypectomy or endoscopy mucosal resection is the optimal treatment. In large or deep lesions, a surgical excision may be necessary. Pathologists should be familiar with this condition so as to avoid overdiagnosis as a malignant vascular tumor. PMID- 23036167 TI - The influence of target population on nonculture-based detection of markers of Neisseria gonorrhoeae antimicrobial resistance. AB - BACKGROUND: With treatment options for gonorrhoea (Neisseria gonorrhoeae) diminishing, strengthening antimicrobial resistance (AMR) surveillance is paramount. METHODS: In this study, we investigated polymerase chain reaction (PCR) based methods, in parallel with N. gonorrhoeae multi-antigen sequence typing (NG-MAST), for direct detection of four N. gonorrhoeae chromosomal mechanisms associated with emerging resistance to extended spectrum cephalosporins using noncultured samples: an adenine deletion in the mtrR promoter, a mosaic penicillin-binding protein (PBP) 2, an A501V PBP2 mutation, and alterations at positions 120 and 121 of the porB protein. The PCR assays were validated using a panel of characterised N. gonorrhoeae isolates (n=107) and commensal Neisseria (n=100) species. These PCR assays with NG-MAST were then applied to noncultured clinical specimens from distinct populations in Australia with differing levels of N. gonorrhoeae AMR: the Northern Territory (NT), where resistance has a low population prevalence, and Queensland (Qld), with higher AMR prevalence. RESULTS: The real-time PCR assays proved highly sensitive and specific. When applied to the noncultured samples, only 1 out of 50 (2%) samples from NT harboured a resistant mechanism, whereas the Qld samples (n=129) collected over different periods showed progressive acquisition of resistant mechanisms, and these were associated with specific NG-MAST types, including Type 225. CONCLUSIONS: The results suggest that our PCR-based methods could be used to rapidly pinpoint incursion of resistant strains into previously unaffected populations. Likewise, our results show that for molecular AMR surveillance, the population being investigated is as important as the genetic mechanisms being targeted. PMID- 23036168 TI - Outcomes of spinal fusion following autologous stem cell transplantation. AB - Patients who have undergone myeloablative chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) for conditions such as multiple myeloma, Hodgkin's disease, and primary amyloidosis may be at higher risk for failure of spinal fusion. As HSCT care and outcomes continue to improve, it is increasingly likely that neurosurgeons will encounter patients post-HSCT who require spinal procedures. To our knowledge there are no published data on fusion outcomes in this unique patient population. We report three patients who underwent spinal fusion following an autologous HSCT. Spinal surgery was performed, on average, 4.5 years after autologous HSCT. No patients were on immunosuppressant chemotherapy at the time of the procedure, although one patient was being treated with rituximab for disease progression peri-operatively. Average radiographic confirmation of fusion was 37 months and all patients ultimately demonstrated fusion, although not without incident. Our results suggest that spinal fusion can occur in patients who have previously undergone myeloablative chemotherapy followed by autologous HSCT. PMID- 23036169 TI - Clinical characteristics and surgical outcomes of patients with interdural epidermoid cyst of the cavernous sinus. AB - Interdural epidermoid cysts of the cavernous sinus originate within the lateral dural wall of the cavernous sinus. Few data are available on the diagnosis and treatment of these tumors. In this study, four patients with interdural epidermoid cyst of the cavernous sinus are reported and data from six patients reported in the English literature are summarized. Trigeminal nerve dysfunction, ophthalmoplegia, and headache were the common symptoms and signs. MRI was the primary diagnostic tool. Contrast enhanced MRI showed slight or strong rim enhancement in six of the 10 patients. All patients were treated by surgical resection using frontotemporal or pterional craniotomy via the intradural or interdural approach. Total removal was achieved in three of the four patients, and four of 10 patients in the whole series. Postoperative neurological function improved in all patients. During follow-up, there were three known clinical recurrences in the total group, but no recurrence in the four patients treated at Qilu Hospital of Shandong University. The findings suggest that aggressive surgical management is associated with good results and with low complication and recurrence rates, but radical resection at the risk of impairing the cranial nerves is not recommended. PMID- 23036170 TI - Fluorescence-guided surgery for glioblastoma multiforme using high-dose fluorescein sodium with excitation and barrier filters. AB - We have developed a technique of fluorescence-guided surgery using high-dose fluorescein sodium (20mg/kg) with excitation and barrier filters for glioblastoma multiforme surgery. This technique was used in 10 patients, with surgery proceeding as expected in all patients. There were no complications or permanent side effects. This method uses filters to help distinguish between the usually invisible tumor and the brain surface, as well as allowing a detailed assessment of the positional relationships with tumor vessels and the surrounding normal vessels. As sufficient yellow staining was present even without filters, delicate microsurgery was also possible under a normal white-light microscope. Both environments could be used as necessary during surgery according to the requirements of resection, thereby improving the reliability and safety of surgery. PMID- 23036171 TI - A comparison of immunomodulation therapies in mechanically ventilated patients with Guillain Barre syndrome. AB - A comparison of the effectiveness of immunomodulatory therapies in patients with Guillain Barre syndrome (GBS) who require mechanical ventilation (MV) is important for patient treatment and cost. We aimed to compare the effectiveness of three modes of intervention on the outcome of patients with GBS receiving MV: intravenous immunoglobulin (IVIgG); small volume plasmapheresis (SVP) and large volume plasmapheresis (LVP). Patients with GBS satisfying National Institute of Neurological and Communicative Disorders and Stroke 1990 criteria and requiring MV between 1997 between 2007 were analyzed. The primary outcome parameters evaluated were mortality, duration of MV, hospital stay and Hughes scale at discharge from hospital. Of the 173 (Male: Female, 118:55) patients who required MV during the study, 106 patients received single modality treatment (IVIgG 31, LVP 45, SVP 30) based on availability, affordability and feasibility. Patients receiving IVIgG had a higher incidence of severe weakness and bulbar involvement. The mean duration of MV (p=0.61), total hospital stay (p=0.44) and Hughes scale at discharge (p=0.31) did not differ among the three groups. Complications were similar in the three treatment groups except for hypoalbuminemia and anemia, which were more common in patients in the LVP group. In conclusion, the outcome of patients treated with these three immunomodulatory treatment modalities did not vary. The beneficial effects of SVP in our study warrant further randomized control trials especially in resource-constrained settings. PMID- 23036172 TI - The rs42524 COL1A2 polymorphism is associated with primary intracerebral hemorrhage in a Chinese population. AB - Hypertensive arteriosclerosis and amyloid angiopathy account for 78-88% of primary cerebral hemorrhages, and collagen plays a critical role in the pathology of these hemorrhages. The COL1A2 gene on chromosome 7q22.1 has been shown to be associated with intracranial aneurysms. In our study, 393 Han Chinese patients with primary intracerebral hemorrhage (mean age 58.49 +/- 9.49 years) and 486 controls (mean age 59.22 +/- 8.79 years) underwent genotyping for the rs42524 polymorphism of COL1A2 using polymerase chain reaction-based restriction analysis. Differences in genotypic and allelic frequencies between the cases and controls were evaluated using the chi(2) test. The association between the rs42524 polymorphism and primary intracerebral hemorrhage was also tested using logistic regression analysis with adjustment for risk factors. We found that there was a significant difference between patients with primary intracerebral hemorrhage and control subjects with respect to genotype distribution (chi(2)=16.33, P<0.001) and allelic frequencies (chi(2)=15.01; P<0.001; odds ratio 2.261; 95% confidence interval 1.482-3.451) for the rs42524 polymorphism of COL1A2. Adjustment for risk factors did not change our conclusions. We conclude that the COL1A2 rs42524 polymorphism could be a genetic risk factor for primary intracerebral hemorrhage among Han Chinese. PMID- 23036173 TI - Lamotrigine in epilepsy, pregnancy and psychiatry--a drug for all seasons? AB - Lamotrigine has been demonstrated to be effective as both an antiepileptic drug and a mood stabiliser. For epilepsy it is less efficacious than valproate in primary generalised epilepsy, but it is comparable to some traditional drugs in partial epilepsy. In psychiatry it has significant advantages over other mood stabilisers for the treatment and prevention of depressive phases of bipolar illness, but not for the treatment of mania. It has a more benign adverse effect profile than older antiepileptic agents and is not a proven teratogen. Risk of adverse reactions is reduced by commencing treatment at a markedly reduced dose that is gradually increased. PMID- 23036174 TI - The neuroprotective effect of diazoxide is mediated by mitochondrial ATP dependent potassium channels in a rat model of acute subdural hematoma. AB - Acute subdural hematoma (ASDH) results in neuronal death due to mitochondrial dysfunction and a subsequent cascade of apoptotic and necrotic events. We previously demonstrated that mitochondrial ATP-dependent potassium (mitoK(ATP)) channels have a major role in cerebral ischemic preconditioning in vivo and in vitro. However, the role of the mitoK(ATP) channel has not been investigated in the context of ASDH. Thus, the purpose of this study was to determine whether the mitoK(ATP) channel mediates neuroprotection in a rat model of ASDH. Male Wistar rats were subjected to subdural infusion of 400 MUL autologous venous blood. The rats were assigned to four experimental groups pretreated intraventricularly 15 minutes before ASDH with (1) vehicle (n=10); (2) the mitoK(ATP) channel agonist diazoxide (n=9); (3) diazoxide plus the selective mitoK(ATP) channel antagonist 5 hydroxydecanoate (5-HD) (n=6); or (4) 5-HD alone (n=6). Infarct volume was assessed at 4 days after ASDH. Brain edema formation was also measured. Pretreatment with diazoxide significantly reduced infarct volume and brain edema formation after ASDH. However, the effects of diazoxide were abolished by co treatment with 5-HD. 5-HD alone increased infarct volume. These data suggest that the mitoK(ATP) channel is an important mediator of the neuroprotective effects of cerebral preconditioning in a rat model of ASDH. PMID- 23036175 TI - Assessment of oxidative stress biomarkers in exhaled breath condensate and blood of Thoroughbred foals. AB - This study reports preliminary data on systemic and local biomarkers of oxidative stress (OS) in Thoroughbred foals. Blood and exhaled breath condensate (EBC) were sampled from 13 foals on two farms. Values of reactive oxygen metabolites (d ROMs), biological antioxidant potential (BAP), antioxidant barrier (OXY-ads), thiol antioxidant barrier (SHp) and advanced oxidation protein products (AOPPs) were determined in blood, while EBC samples were assayed for hydrogen peroxide (H(2)O(2)) levels. Systemic and local OS biomarkers did not differ between farms and gender. Increased oxidative stress index (OSI) values in a foal recovering from pneumonia and elevated H(2)O(2) in EBC coupled with low SHp and elevated AOPPs in the blood of a foal with overt upper respiratory tract disease suggested that the OS markers measured in this study may relate to the respiratory health status of foals. PMID- 23036176 TI - Review of diagnostic plaque reduction neutralization tests for flavivirus infection. AB - Flavivirus infections (including Japanese encephalitis, West Nile encephalitis and dengue fever/severe dengue) present a worldwide public health problem. Recent climate change may affect the geographical distribution of the arthropod vectors for these viruses and so the risk of flavivirus epidemics may increase. Many methods have been developed for the serological diagnosis of flavivirus infections, such as haemagglutination inhibition assay, enzyme-linked immunosorbent assay, and immunofluorescence in staining. However, the specificity of these assays varies. The plaque reduction neutralizing test (PRNT) using live viruses is currently the 'gold standard' for the differential serodiagnosis of flaviviruses. The specificity of results obtained with PRNT is better than that for other protocols and many laboratories apply the PRNT protocol to the differential serodiagnosis of flaviviruses. Here, recent refinements to the PRNT protocols with genetically modified recombinant viruses or reporter-harbouring virus-like particles are reviewed. Further, the problems associated with the differential serodiagnosis of flaviviruses using PRNT are discussed. PMID- 23036177 TI - Multiple RT-PCR markers for the detection of circulating tumour cells of metastatic canine mammary tumours. AB - In humans, detection of circulating tumour cells (CTCs) using nucleic acid-based methods such as reverse transcription polymerase chain reaction (RT-PCR) has proven to be of prognostic relevance. However, similar procedures are still lacking in veterinary oncology. To assess the correlation of CTC markers with the metastatic potential of canine mammary tumours, 120 peripheral blood samples from bitches with mammary carcinomas with (group 1) and without (group 2) histological evidence of vascular invasion and/or presence of lymph node metastases and mammary adenomas (group 3) were analyzed. Blood samples were collected in EDTA tubes and RNA was extracted within 48 h. Subsequently, the samples were tested by RT-PCR for a panel of seven CTC mRNA markers. CRYAB was the most sensitive single marker with a sensitivity of 35% and also the most specific marker with a specificity of 100% to detect group 1 blood samples. A multimarker assay combining four genes enhanced the sensitivity up to 77.5%, but decreased the specificity to 80%. CRYAB appeared to be highly specific but only moderately sensitive at detecting blood samples from dogs with metastatic tumours and detection significantly correlated with vascular invasion of primary mammary tumours. However, a multimarker assay of four genes significantly enhanced the sensitivity of the assay and is therefore preferable for CTC detection. PMID- 23036178 TI - Breach effect over mitten patterns mimicking focal spike-waves in a patient with psychogenic nonepileptic seizures. PMID- 23036180 TI - Which ultrasonographic measure has the upper hand in ulnar neuropathy at the elbow? AB - OBJECTIVE: To compare the diagnostic accuracy of ultrasonographic ulnar nerve diameter, cross-sectional area (CSA) and swelling ratio measurement in ulnar neuropathy at the elbow (UNE). METHODS: Ultrasonographic diameter, CSA, and swelling ratio measurements were compared with a reference standard including clinical examination, electrophysiological studies, and follow-up in a prospective cohort of patients. All patients in whom a diagnosis of UNE was considered were eligible for the study. Reference values for ultrasonography were obtained in 73 healthy volunteers. RESULTS: Of 191 patients, 137 had UNE or probable UNE, while 54 had another condition and these were analysed as patient controls. Patients with UNE had a larger ulnar nerve diameter, CSA and swelling ratio than healthy controls and patient controls (p < 0.01). The diagnostic accuracies of these different measurements were comparable with a specificity of 78-87%, a positive predictive value of 87-90%, a sensitivity of 42-61% and negative predictive value of 37-44%. ROC-analysis for these measurements showed an area under the curve of 0.75-0.77. CONCLUSION: Ultrasonographic measurements of ulnar nerve diameter, CSA and swelling ratio have comparable diagnostic value, which was lower than reported previously. SIGNIFICANCE: Ultrasonographic ulnar nerve diameter, CSA and swelling ratio measurements are equally useful in diagnosing UNE. PMID- 23036179 TI - EEG during pedaling: evidence for cortical control of locomotor tasks. AB - OBJECTIVE: This study characterized the brain electrical activity during pedaling, a locomotor-like task, in humans. We postulated that phasic brain activity would be associated with active pedaling, consistent with a cortical role in locomotor tasks. METHODS: Sixty four channels of electroencephalogram (EEG) and 10 channels of electromyogram (EMG) data were recorded from 10 neurologically-intact volunteers while they performed active and passive (no effort) pedaling on a custom-designed stationary bicycle. Ensemble averaged waveforms, 2 dimensional topographic maps and amplitude of the beta (13-35 Hz) frequency band were analyzed and compared between active and passive trials. RESULTS: The peak-to-peak amplitude (peak positive-peak negative) of the EEG waveform recorded at the Cz electrode was higher in the passive than the active trials (p < 0.01). beta-band oscillations in electrodes overlying the leg representation area of the cortex were significantly desynchronized during active compared to the passive pedaling (p < 0.01). A significant negative correlation was observed between the average EEG waveform for active trials and the composite EMG (summated EMG from both limbs for each muscle) of the rectus femoris (r = 0.77, p < 0.01) the medial hamstrings (r = -0.85, p < 0.01) and the tibialis anterior (r = -0.70, p < 0.01) muscles. CONCLUSIONS: These results demonstrated that substantial sensorimotor processing occurs in the brain during pedaling in humans. Further, cortical activity seemed to be greatest during recruitment of the muscles critical for transitioning the legs from flexion to extension and vice versa. SIGNIFICANCE: This is the first study demonstrating the feasibility of EEG recording during pedaling, and owing to similarities between pedaling and bipedal walking, may provide valuable insight into brain activity during locomotion in humans. PMID- 23036181 TI - Low rate repetitive nerve stimulation in Lambert-Eaton myasthenic syndrome: peculiar characteristics of decremental pattern from a single-centre experience. PMID- 23036182 TI - Developmental sex-specific change in auditory-vocal integration: ERP evidence in children. AB - OBJECTIVE: The present event-related potential (ERP) study examined the developmental mechanisms of auditory-vocal integration in normally developing children. Neurophysiological responses to altered auditory feedback were recorded to determine whether they are affected by age and sex. METHOD: Forty-two children were pairwise matched for sex and were divided into a group of younger (10 12years) and a group of older (13-15years) children. Twenty healthy young adults (20-25years) also participated in the experiment. ERPs were recorded from the participants who heard their voice pitch feedback unexpectedly shifted -50, -100, or -200 cents during sustained vocalization. RESULTS: P1 amplitudes became smaller as subjects increased in age from childhood to adulthood, and males produced larger N1 amplitudes than females. An age-related decrease in the P1-N1 latencies was also found: latencies were shorter in young adults than in school children. A complex age-by-sex interaction was found for the P2 component, where an age-related increase in P2 amplitudes existed only in girls, and boys produced longer P2 latencies than girls but only in the older children. CONCLUSIONS: These findings demonstrate that neurophysiological responses to pitch errors in voice auditory feedback depend on age and sex in normally developing children. SIGNIFICANCE: The present study provides evidence that there is a sex-specific development of the neural mechanisms involved in auditory-vocal integration. PMID- 23036183 TI - Thermal application modulates orofacial somatosensory perception in healthy men and women. AB - OBJECTIVE: To test if orofacial somatosensory perception can be modulated by experimental thermal application in healthy human. METHODS: Twelve men and twelve age-matched women participated. In each session thermal application with 10, 42 or 32 degrees C (cooling, warming, control) was applied to the skin over the right masseter using a thermode. Quantitative sensory testing was performed at the skin over the right (testing side) and left (contralateral side) masseter before, during, after the thermal application. RESULTS: During the cooling, mechanical detection threshold (MDT), mechanical pain threshold (MPT) and pressure pain threshold (PPT) were increased, and mechanical pain sensitivity was decreased at testing side compared with baseline (P<0.005). The MPT and PPT at the contralateral side were also increased (P<0.004). During the warming and control, the MDT was increased at the testing side compared with baseline (P=0.002). The somatosensory sensitivity was decreased during cooling compared to warming and control (P<0.05). No gender differences were found. CONCLUSIONS: This study shows an ipsilateral decrease of cutaneous sensation or pain sensitivity during cooling without gender differences. In addition, hypoalgesia on the contralateral side suggests a central mode of action. SIGNIFICANCE: The results support clinical experiences that cooling may alleviates pain both locally and generally. PMID- 23036184 TI - The influence of host ecology and biogeography on the helminth species richness of freshwater fishes in Mexico. AB - Freshwater fish helminths, the most well known Mexican vertebrate parasites, include approximately 260 species (platyhelminthes, acanthocephalans, nematodes, and hirudineans). The distribution patterns of adult helminth diversity (throughout parasite and host groups and hydrological regions) are described and the effects of host traits and environmental and geographical factors on diversity are evaluated. Adult helminths include 160 species, parasitizing 149 fish species of 23 families distributed in 21 regions. Nematoda was the most species-rich (>50 species). Cichlidae harboured rich helminth assemblages, with widespread parasites. By contrast, Atherinopsidae and Goodeidae showed relatively poor helminth assemblages, including specific parasites with narrow distribution. Helminth richness in southeastern Mexico was higher than northern or central regions. Non-parametric richness estimators were used to avoid confusion in comparisons with unequal sampling efforts. Bootstrap values, the method with the best performance, indicated that estimated richness shows the same distribution pattern that observed richness. Non-phylogenetic and phylogenetic analyses were used to determine the role of different factors in the parasite diversification. The distribution range was the most important richness predictor (widespread fishes harbour richer parasite assemblages), although interactions between this variable and others such as trophic level, latitude, habitat temperature and precipitation are also important. Likewise, biogeographical factors can also affect parasite diversity. PMID- 23036185 TI - Multimodality endoscopic treatment of pancreatic duct disruption with stenting and pseudocyst drainage: how efficacious is it? AB - BACKGROUND: Few studies have described the role of multimodality therapy and the complexity of endoscopic management of pancreatic duct disruption. Our study aim was to analyse and confirm factors associated with the resolution of pancreatic duct disruption. METHODS: Over 6 years, retrospective data on patients with pancreatic duct disruption managed endoscopically were retrieved. Success was defined as resolution of the pancreatic duct disruption at 12 months. Logistic regression analysis was performed to determine factors associated with resolution. RESULTS: 113 patients (78 male) with a mean age 51.3 year were included. Resolution of the pancreatic duct leak occurred in 80 cases (70.2%). 72 cases received transpapillary pancreatic duct stents, with 51 demonstrating resolution of pancreatic duct leak (71%) cystenterostomy was performed in 68 patients with 51 resolved (75%). In partial duct disruptions, pancreatic duct stenting combined with endoscopic drainage of fluid collections resulted in an increased rate of resolution (80%) compared to complete disruptions treated in a similar manner (57%). In complete pancreatic ductal disruptions, transpapillary pancreatic duct stenting had no additional benefit (9/17, 52.9%) compared to cystenterostomy or percutaneous drainage alone (24/34, 70.6%; P=0.61). CONCLUSION: Pancreatic duct disruptions require multimodality treatment, addressing not only the integrity of the pancreatic duct but also any fluid collections associated. Partial ductal disruption should be managed by a bridging stent. PMID- 23036187 TI - Neurometabolic and genetic diseases: a question of screening? PMID- 23036186 TI - A new approach to facilitate diagnosis of nonalcoholic fatty liver disease through a galactose single point method in rats with fatty liver. AB - BACKGROUND: Liver biopsy reliably diagnoses nonalcoholic fatty liver disease, but its invasiveness and inter- and intra-observer errors limit its usefulness in monitoring. AIMS: Use a galactose single point method or combined biochemical parameters to improve assessments of nonalcoholic fatty liver disease in a rat model. METHODS: Three nonalcoholic fatty liver disease severities were generated in 50 rats: a control group (n=18) on a standard diet, and 2 study groups on a choline-deficient diet (n=18), with and without treatment with silymarin (n=14). At weeks 4, 8, and 18, a galactose solution (0.5 g/kg/body weight) was rapidly injected intravenously. Sixty minutes later, internal artery blood was taken for biochemical analyses, including galactose. The livers were then removed for haematoxylin-eosin staining and to measure the hepatic lipid content. RESULTS: Alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, albumin, and total protein were each significantly correlated with nonalcoholic fatty liver disease severity. Regarding logistic regression, galactose single point method and total protein were significantly predictive. The optimal alanine aminotransferase cutoff point for nonalcoholic fatty liver disease prediction from the receiver-operating characteristic curve had 72.4% sensitivity and 52.4% specificity; galactose single point method alone had 82.8% and 72.4%, whereas galactose single point method+total protein showed 82.8% and 81.0%. CONCLUSIONS: Both galactose single point method and galactose single point method+total protein had greater diagnostic sensitivity and specificity for nonalcoholic fatty liver disease than traditional biochemical tests. PMID- 23036190 TI - Carcinoma cuniculatum: not a verrucous carcinoma. AB - BACKGROUND: Carcinoma cuniculatum and verrucous carcinoma are both very well differentiated forms of squamous carcinoma and thus difficult to separate histologically from pseudocarcinomatous hyperplasia. The diagnosis of each often requires clinical-pathologic correlation. METHODS: We reviewed the literature on cases reported as carcinoma cuniculatum and compared these to the cases originally reported by Aird et al. In addition, we report an additional case of this entity that we encountered in our practice. RESULTS: In reviewing the literature it is evident that most authors consider carcinoma cuniculatum and verrucous carcinoma to be synonymous even though Aird's original two cases had no verrucous features. The lack of a clear conceptual distinction between these two entities may cause diagnostic confusion. CONCLUSION: The purpose of this report is to record a case of carcinoma cuniculatum which the authors believe to be similar to those reported by Aird et al., to emphasize the differences between carcinoma cuniculatum and verrucous carcinoma, and to explain how the lack of a clear conceptual distinction between these two tumors can lead to further delay in an already difficult diagnosis. PMID- 23036191 TI - Avian Plasmodium lineages found in spot surveys of mosquitoes from 2007 to 2010 at Sakata wetland, Japan: do dominant lineages persist for multiple years? AB - The ecology and geographical distribution of disease vectors are major determinants of spatial and temporal variations in the transmission dynamics of vector-borne pathogens. However, there are limited studies on the ecology of vectors that contribute to the natural transmission of most vector-borne pathogens. Avian Plasmodium parasites are multihost mosquito-borne pathogens transmitted by multiple mosquito species, which might regulate the diversity and persistence of these parasites. From 2007 to 2010, we conducted entomological surveys at Sakata wetland in central Japan, to investigate temporal variation in mosquito occurrence and prevalence of avian Plasmodium lineages in the mosquito populations. A polymerase chain reaction (PCR)-based method was used to detect Plasmodium parasites and identify the blood sources of mosquitoes. Culex inatomii and C. pipiens pallens represented 60.0% and 34.8% of 11 mosquito species collected, respectively. Our results showed that the two dominant mosquito species most likely serve as principal vectors of avian Plasmodium parasites during June, which coincides with the breeding season of bird species nesting in the wetland reed beds. Fourteen animal species were identified as blood sources of mosquitoes, with the oriental reed warbler (Acrocephalus orientalis) being the commonest blood source. Although there was significant temporal variation in the occurrence of mosquitoes and prevalence of Plasmodium lineages in the mosquitoes, the dominant Plasmodium lineages shared by the two dominant mosquito species were consistently found at the same time during transmission seasons. Because vector competence cannot be confirmed solely by PCR approaches, experimental demonstration is required to provide definitive evidence of transmission suggested in this study. PMID- 23036192 TI - Sarcomas in hereditary retinoblastoma. AB - Children diagnosed with the hereditary form of retinoblastoma (Rb), a rare eye cancer caused by a germline mutation in the RB1 tumor suppressor gene, have excellent survival, but face an increased risk of bone and soft tissue sarcomas. This predisposition to sarcomas has been attributed to genetic susceptibility due to inactivation of the RB1 gene as well as past radiotherapy for Rb. The majority of bone and soft tissue sarcomas among hereditary Rb survivors occur in the head, within the radiation field, but they also occur outside the radiation field. Sarcomas account for almost half of the second primary cancers in hereditary Rb survivors, but they are very rare following non-hereditary Rb. Sarcomas among hereditary Rb survivors arise at ages similar to the pattern of occurrence in the general population. There has been a trend over the past two decades to replace radiotherapy with chemotherapy and other focal therapies (laser or cryosurgery), and most recently, chemosurgery in order to reduce the incidence of sarcomas and other second cancers in Rb survivors. Given the excellent survival of most Rb patients treated in the past, it is important for survivors, their families and health care providers to be aware of the heightened risk for sarcomas in hereditary patients. PMID- 23036193 TI - Identification of sepsis subtypes in critically ill adults using gene expression profiling. AB - INTRODUCTION: Sepsis is a syndromic illness that has traditionally been defined by a set of broad, highly sensitive clinical parameters. As a result, numerous distinct pathophysiologic states may meet diagnostic criteria for sepsis, leading to syndrome heterogeneity. The existence of biologically distinct sepsis subtypes may in part explain the lack of actionable evidence from clinical trials of sepsis therapies. We used microarray-based gene expression data from adult patients with sepsis in order to identify molecularly distinct sepsis subtypes. METHODS: We used partitioning around medoids (PAM) and hierarchical clustering of gene expression profiles from neutrophils taken from a cohort of septic patients in order to identify distinct subtypes. Using the medoids learned from this cohort, we then clustered a second independent cohort of septic patients, and used the resulting class labels to evaluate differences in clinical parameters, as well as the expression of relevant pharmacogenes. RESULTS: We identified two sepsis subtypes based on gene expression patterns. Subtype 1 was characterized by increased expression of genes involved in inflammatory and Toll receptor mediated signaling pathways, as well as a higher prevalence of severe sepsis. There were differences between subtypes in the expression of pharmacogenes related to hydrocortisone, vasopressin, norepinephrine, and drotrecogin alpha. CONCLUSIONS: Sepsis subtypes can be identified based on different gene expression patterns. These patterns may generate hypotheses about the underlying pathophysiology of sepsis and suggest new ways of classifying septic patients both in clinical practice, and in the design of clinical trials. PMID- 23036194 TI - Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate. AB - T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF-SEA treated with 15MUg, mean tumor weight: 1.128g versus 0.252g, difference=0.876g). CD4(+) and CD8(+) T cells driven by VEGF-SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF-SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers. PMID- 23036195 TI - Histone modification-mediated Lhx2 gene expression. AB - Lhx2, a member of LIM homeobox transcription factors, plays a key role in central nervous system (CNS) and embryonic tissue development. However, molecular mechanism of Lhx2 gene regulation remains largely unknown. Here, we identified and characterized a regulatory region of Lhx2 gene which mediates responses to two different signals such as inhibition of HDAC3 and stimulation by E2F1. In particular, the promoter region of -229 to -126 was responsible not only for basal expression but also for a inhibitor of histone deacetylase, trichostatin A (TSA)-mediated activation of Lhx2 gene. Intriguingly, transcription factor E2F1 also activates Lhx2 gene via direct binding to the same -229 to -126 region. Based on these observations, we could have demonstrated that E2F1 is necessary for TSA-mediated activation of Lhx2 gene and acetylation of histone 3 is involved in this event. This study provides evidence that the histone modification and E2F1 binding are integral parts of the mechanism for Lhx2 gene expression. PMID- 23036196 TI - Modification of the inflammatory mediator LRRFIP2 by the ubiquitin-like protein FAT10 inhibits its activity during cellular response to LPS. AB - FAT10 is a ubiquitin-like protein made of two tandem, head-to-tail, ubiquitin domains. It is known to covalently modify proteins in a mechanism similar, though not identical, to that of other ubiquitin-like proteins. The lack of known physiological substrates covalently conjugated by the protein made it difficult to unravel its biological functions. Here we identify two proteins that are covalently modified by FAT10, the inflammatory mediator LRRFIP2 and the endoplasmic reticulum membrane protein LULL1. LRRFIP2 is involved in NF-kappaB activation following stimulation of TLR4. It is recruited along with MYD88 to the cytosolic tail of the receptor, and by that mediates activation of the downstream signaling cascade. We show that FATylation of LRRFIP2 occurs on two distinct sites, each being modified by a single FAT10 moiety. Furthermore, the second modification is regulated by the first one. Importantly, FATylation of LRRFIP2 interferes with its recruitment to the membrane by translocating it to the cellular insoluble fraction, thus inhibiting NF-kappaB activation. PMID- 23036197 TI - Recombinant proteins incorporating short non-native extensions may display increased aggregation propensity as detected by high resolution NMR spectroscopy. AB - The use of a recombinant protein to investigate the function of the native molecule requires that the former be obtained with the same amino acid sequence as the template. However, in many cases few additional residues are artificially introduced for cloning or purification purposes, possibly resulting in altered physico-chemical properties that may escape routine characterization. For example, increased aggregation propensity without visible protein precipitation is hardly detected by most analytical techniques but its investigation may be of great importance for optimizing the yield of recombinant protein production in biotechnological and structural biology applications. In this work we show that bile acid binding proteins incorporating the common C-terminal LeuValProArg extension display different hydrodynamic properties from those of the corresponding molecules without such additional amino acids. The proteins were produced enriched in nitrogen-15 for analysis via heteronuclear NMR spectroscopy. Residue-specific spin relaxation rates were measured and related to rotational tumbling time and molecular size. While the native-like recombinant proteins show spin-relaxation rates in agreement with those expected for monomeric globular proteins of their mass, our data indicate the presence of larger adducts for samples of proteins with very short amino acid extensions. The used approach is proposed as a further screening method for the quality assessment of biotechnological protein products. PMID- 23036198 TI - The tomato SlWRKY gene plays an important role in the regulation of defense responses in tobacco. AB - WRKY-type transcription factors are involved in multiple aspects of plant growth, development and stress responses. SlWRKY, a cDNA clone encoding a polypeptide of 552 amino acids and exhibiting the structural features of group I of WRKY protein family, was isolated from tomato (Solanum lycopersicum L. cv Zhongshu No. 4) using the homologous cloning method. Semi-quantitative RT-PCR analysis indicated that SlWRKY was up-regulated by salt and drought treatment in tomato seedlings. To investigate the biological roles of SlWRKY, we generated transgenic tobaccos overexpressing the SlWRKY and analyzed their responses to salt and drought stresses. Transgenic tobacco plants exhibited more vigorous growth than wild-type plants and display high tolerance to salt and drought stresses. In order to minimize oxidative damage, the activities of antioxidant enzymes were increased but EC and the MDA content were decreased in the transgenic tobacco leaves. Furthermore, it was observed that the SlWRKY proteins regulate the downstream genes and increased the expression of defense-related PR1 and PR2 genes. These results demonstrate that, SlWRKY plays an important role in responding to abiotic stress. PMID- 23036199 TI - Adrenaline promotes cell proliferation and increases chemoresistance in colon cancer HT29 cells through induction of miR-155. AB - Recently, catecholamines have been described as being involved in the regulation of cancer genesis and progression. Here, we reported that adrenaline increased the cell proliferation and decreased the cisplatin induced apoptosis in HT29 cells. Further study found that adrenaline increased miR-155 expression in an NFkappaB dependent manner. HT29 cells overexpressing miR-155 had a higher cell growth rate and more resistance to cisplatin induced apoptosis. In contrast, HT29 cells overexpressing miR-155 inhibitor displayed decreased cell proliferation and sensitivity to cisplatin induced cell death. In summary, our study here revealed that adrenaline-NFkappaB-miR-155 pathway at least partially contributes to the psychological stress induced proliferation and chemoresistance in HT29 cells, shedding light on increasing the therapeutic strategies of cancer chemotherapy. PMID- 23036200 TI - Rmi1 functions in S phase-mediated cohesion establishment via a pathway involving the Ctf18-RFC complex and Mrc1. AB - Saccharomyces cerevisiae RecQ helicase (Sgs1) combines with DNA topoisomerase III (Top3) and RecQ-mediated genome instability 1 (Rmi1) to form an evolutionarily conserved complex that is required for processing homologous recombination intermediates and restarting collapsed replication forks. It was previously reported that Rmi1 contributes to sister chromatid cohesion; however, the underlying molecular mechanism has been unclear. In the present study, Rmi1 was found to be enriched at the region close to an early-firing replication origin when replication forks were arrested near their origins in the presence of hydroxyurea. Genetic analyses revealed that Rmi1 promoted sister chromatid cohesion in a process that was distinct from both the cohesion establishment pathway involving Ctf4, Csm3, and Chl1 and the pathway involving the acetylation of Smc3. On the other hand, Rmi1 seemed to function in a pathway involving the Ctf18-RFC complex and Mrc1, which were previously predicted to regulate leading strand DNA replication. PMID- 23036201 TI - CD36 is required for myoblast fusion during myogenic differentiation. AB - Recently, CD36 has been found to be involved in the cytokine-induced fusion of macrophage. Myoblast fusion to form multinucleated myotubes is required for myogenesis and muscle regeneration. Because a search of gene expression database revealed the attenuation of CD36 expression in the muscles of muscular dystrophy patients, the possibility that CD36 could be required for myoblast fusion was investigated. CD36 expression was markedly up-regulated during myoblast differentiation and localized in multinucleated myotubes. Knockdown of endogenous CD36 significantly decreased the expression of myogenic markers as well as myotube formation. These results support the notion that CD36 plays an important role in cell fusion during myogenic differentiation. Our finding will aid the elucidation of the common mechanism governing cell-to-cell fusion in various fusion models. PMID- 23036202 TI - Green tea inhibits cycolooxygenase-2 in non-small cell lung cancer cells through the induction of Annexin-1. AB - Elevated cyclooygenase-2 (COX-2) expression is frequently observed in human non small cell lung cancer (NSCLC) and associated with poor prognosis, indicating critical involvement of the inflammatory pathway in lung carcinogenesis. Recently, we found that green tea extract (GTE) induced Annexin-1 (ANX1) in the lung adenocarcinoma A549 cells. ANX1 is a glucocorticoid-inducible 37kDa protein involved in a wide range biological function and is an important anti inflammatory mediator. The present study further examines the interplay between the expressions and production of ANX1, COX-2, phospholipase A(2) (cPLA(2)) and prostaglandin E(2) (PGE(2)) following the treatment of NSCLC cell lines with GTE. We found that GTE induced ANX1 and inhibited COX-2 expression in lung cancer A549, H157 and H460 cell lines. Addition of pro-inflammatory cytokine IL-1beta diminished GTE-induced ANX1. Silence of ANX1 in cells abrogates the inhibitory activity on COX-2, indicating that the anti-inflammatory activity of GTE is mediated at least partially by the up-regulation of ANX1. However, differential pattern of inhibitory effects of ANX1 on cPLA(2) expression was observed among various cell types, suggesting that the anti-inflammatory activity mediated by ANX1 is cell type specific. Our study may provide a new mechanism of GTE on the prevention of lung cancer and other diseases related to inflammation. PMID- 23036203 TI - Neighborhood disadvantage and adult alcohol outcomes: differential risk by race and gender. AB - OBJECTIVE: We examined whether relationships of neighborhood disadvantage with drinker status, heavy drinking, alcohol-related consequences, and dependence differed by race and/or gender. We hypothesized that neighborhood disadvantage would be negatively associated with drinker status but positively associated with heavy and problem drinking, with more pronounced relationships among African American and Hispanic men than other groups. METHOD: Data consisted of nationally representative, randomly selected, cross-sectional samples of White, African American, and Hispanic adults (N = 13,864, of which 52% were female; with 7,493 drinkers, of which 48% were female) from the 2000 and 2005 National Alcohol Surveys merged with 2000 Census data. Analyses included logistic and linear regression using weights to adjust for sampling and nonresponse. RESULTS: Hypotheses were partly supported. Bivariate relationships were in the expected direction. Multivariate main effect models showed that neighborhood disadvantage was significantly associated with increased abstinence and marginally associated with increased negative consequences experienced by drinkers, but race/ethnicity and gender modified these associations. Disadvantage was significantly associated with increased abstinence for all groups except African American and Hispanic men. Among drinkers, disadvantage was significantly negatively associated with heavy drinking by Whites but significantly positively associated with heavy drinking by African Americans. Disadvantage also was associated with elevated alcohol-related consequences for White women and African American men. CONCLUSIONS: The findings have implications for the development of targeted interventions to reduce the unequal impacts of neighborhood disadvantage on alcohol outcomes. Future research should examine the contribution of multiple types of disadvantage to heavy drinking and alcohol problems. PMID- 23036204 TI - Barriers to effective tobacco-dependence treatment for the very poor. AB - OBJECTIVE: People who live in poverty have a high prevalence of smoking, are less likely to engage in evidence-based treatment, and find it harder to quit. Their beliefs about smoking and quitting can serve as barriers to quitting. Little is known about the smoking and quitting beliefs of the very poor (about U.S. $15,000 or less annual family income) because they tend not to be included in research. This study sought to assess beliefs about smoking and quitting by the very poor in relation to past quitting behavior and intention to quit in the future. METHOD: A survey was administered in person to residents in randomly selected addresses in two very impoverished Milwaukee, WI, ZIP codes during the day to ensure the inclusion of the very poor. RESULTS: Six hundred fifty-four people completed the survey, a response rate of 78.3%. Sixty-eight percent reported annual household incomes of less than $15,000 compared with 30.8% in the community as a whole and 13.0% of households nationally. Self-reported smoking prevalence was 42.1%. Specific beliefs about smoking and quitting were related to past quit attempts and intentions to quit in the future. Both race and income predicted beliefs and quitting-related variables independently and jointly. CONCLUSIONS: Continued tobacco-control progress requires addressing specific populations with known high tobacco use. One of these populations is those with low income. Efforts to engage them in treatment will have to address specific beliefs about smoking and quitting. PMID- 23036205 TI - Are social network correlates of heavy drinking similar among black homeless youth and white homeless youth? AB - OBJECTIVE: Understanding factors associated with heavy drinking among homeless youth is important for prevention efforts. Social networks are associated with drinking among homeless youth, and studies have called for attention to racial differences in networks that may affect drinking behavior. This study investigates differences in network characteristics by the racial background of homeless youth, and associations of network characteristics with heavy drinking. (Heavy drinking was defined as having five or more drinks of alcohol in a row within a couple of hours on at least one day within the past 30 days.) METHOD: A probability sample of 235 Black and White homeless youths ages 13-24 were interviewed in Los Angeles County. We used chi-square or one-way analysis of variance tests to examine network differences by race and logistic regressions to identify network correlates of heavy drinking among Black and White homeless youth. RESULTS: The networks of Black youth included significantly more relatives and students who attend school regularly, whereas the networks of White youth were more likely to include homeless persons, relatives who drink to intoxication, and peers who drink to intoxication. Having peers who drink heavily was significantly associated with heavy drinking only among White youth. For all homeless youth, having more students in the network who regularly attend school was associated with less risk of heavy drinking. CONCLUSIONS: This study is the first to our knowledge to investigate racial differences in network characteristics and associations of network characteristics with heavy drinking among homeless youth. White homeless youth may benefit from interventions that reduce their ties with peers who drink. Enhancing ties to school-involved peers may be a promising intervention focus for both Black and White homeless youth. PMID- 23036206 TI - Social influences on the clustering of underage risky drinking and its consequences in communities. AB - OBJECTIVE: The purpose of this research was to examine whether the clustering of underage risky drinking and its consequences within communities might arise from shared perceptions regarding underage drinking as well as the social context of drinking. METHOD: The Enforcing Underage Drinking Laws Randomized Community Trial provided data from repeated cross-sectional samples of 5,017 current drinkers (2,619 male) ages 14-20 years from 68 communities surveyed in 2004, 2006, and 2007. Alternating logistic regressions were used to estimate the influence of social factors on the clustering of getting drunk, heavy episodic drinking, nonviolent consequences, and driving after drinking or riding with a drinking driver. RESULTS: The clustering of getting drunk, heavy episodic drinking, and nonviolent consequences was no longer statistically significant after adjustment for drinking with friends and drinking with parents. Parents providing alcohol explained the clustering of heavy episodic drinking and nonviolent consequences, whereas drinking with other underage drinkers and friends providing alcohol explained the clustering of nonviolent consequences. Drinking with friends or other underage drinkers and friends providing alcohol increased the risk of these behaviors, whereas drinking with parents and parents providing alcohol were protective. Perceptions regarding peer drinking, community norms, consequences for drinking, and drinking at a party did not influence clustering. CONCLUSIONS: These findings suggest that interventions to reduce underage risky drinking in communities should focus on the differential effects of the social context in which drinking occurs. PMID- 23036207 TI - Systematic review: effect of alcohol intake on adherence to outpatient medication regimens for chronic diseases. AB - OBJECTIVE: Nonadherence to medications can lead to adverse health outcomes. Alcohol consumption has been shown to be associated with nonadherence to antiretroviral medications, but this relationship has not been examined at different drinking levels or with other chronic disease medications. We conducted a narrative synthesis of the association of alcohol consumption with nonadherence to medications for four chronic diseases. METHOD: We searched MEDLINE, PsycINFO, Cochrane Library, and Web of Science for relevant studies published through 2009. To be included in this analysis, studies had to be quantitative; have a sample size of 50 or greater; and examine the effect of alcohol consumption on medication adherence for diabetes, hypertension, depression, or HIV/AIDS. Study characteristics and results were abstracted according to pre-specified criteria, and study quality was assessed. Study heterogeneity prevented a systematic synthesis. RESULTS: Sixty eligible studies addressed medication adherence for HIV in 47 (78%), diabetes in 6 (10%), hypertension in 2 (3%), both diabetes and hypertension in 1 (2%), depression in 2 (3%), and all medications in 2 (3%). Mean number of subjects was 245 (range: 57-61,511). Effect sizes for the association of alcohol use with nonadherence varied (0.76-4.76). Six of the seven highest quality studies reported significant effect sizes (p < .05), ranging from 1.43 to 3.6. Most (67%) studies reporting multivariate analyses, but only half of non-HIV medicine studies, reported significant associations. CONCLUSIONS: Most studies reported negative effects of alcohol consumption on adherence, but evidence among non-HIV studies was less consistent. These data suggest the relevance of addressing alcohol use in improving antiretroviral adherence and a need for further rigorous study in non-HIV chronic diseases. PMID- 23036208 TI - Costs of alcohol screening and brief intervention in medical settings: a review of the literature. AB - OBJECTIVE: This article summarizes the literature on the implementation costs of alcohol screening and brief intervention (SBI) in medical settings. METHOD: Electronic databases were searched using SBI- and cost-related terms. Methodological approaches and cost estimates were abstracted from each study and categorized based on the cost methodology. Costs were updated to 2009 U.S. dollars. To determine a summary cost measure, we excluded outliers and computed the median of the remaining cost estimates. RESULTS: Seventeen studies with cost estimates were identified for further study. Costs ranged from $0.51 to $601.50 per screen and from $3.41 to $243.01 per brief intervention (BI). Cost estimates were lower when an activity-based cost methodology was used, in primary care settings, and when the provider was not a doctor. The median summary cost of a screen is approximately $4, and the median summary cost of a BI is approximately $48. CONCLUSIONS: Screening cost estimates had more variation than BI cost estimates. Provider type and service delivery time drive the cost variation. Interpretation of cost differences was limited by insufficient reporting of the cost methodology. Cost estimates presented here are similar in size to the Healthcare Common Procedure Coding System and Current Procedural Terminology reimbursement amounts, suggesting that insurance-based service reimbursement may be sufficient to sustain alcohol SBI in practice. PMID- 23036209 TI - Greater elevation in risk for nicotine dependence per pack of cigarettes smoked among those with an anxiety disorder. AB - OBJECTIVE: Recent work shows that the time from the initial use of nicotine, cannabis, and alcohol to the onset of dependence on these substances is shorter ("telescoped") in anxiety-disordered individuals. Previously, we hypothesized that telescoping may result from a shared neurobiology underlying both anxiety disorders and dependence. This hypothesis implies that telescoping occurs because individuals with an anxiety disorder transition to dependence with less overall drug exposure ("dependence susceptibility"). To investigate this further, we examined an estimate of the amount smoked (rather than the time transpired) from smoking initiation milestones to the onset of nicotine dependence in those with and without an anxiety disorder. METHOD: We used the subset of respondents in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Wave 1 who reported having smoked at least 100 cigarettes (N = 18,013). All data were based on face-to-face interviews. RESULTS: Individuals with any anxiety disorder transitioned to nicotine dependence after smoking fewer total cigarettes than did individuals with no anxiety disorder. Furthermore, those with more than one anxiety disorder transitioned to nicotine dependence after smoking fewer cigarettes than did those with one anxiety disorder only. Several potentially confounding covariates were controlled for in these analyses. CONCLUSIONS: Dependence susceptibility is a novel concept with the potential to inform theoretical accounts of and prevention strategies for substance dependence among those with an anxiety disorder. In addition to nicotine, our theory and past data suggest that dependence susceptibility for other addictive substances (e.g., alcohol) also would be found among those with an anxiety disorder. PMID- 23036210 TI - Low sensitivity to alcohol: relations with hangover occurrence and susceptibility in an ecological momentary assessment investigation. AB - OBJECTIVE: The current investigation tested whether low sensitivity to alcohol, as measured by the Self-Rating of the Effects of Alcohol (SRE) form, is associated with hangover occurrence or resistance, two potentially important predictors of later problematic drinking outcomes. METHOD: Drinkers who reported using alcohol at least four times in the past month (N = 402) completed the SRE at baseline and used ecological momentary assessment methods with an electronic diary to record drinking behaviors and related experiences over 21 days. Each morning, the diary assessed prior-night drinking behaviors and the presence of current hangover. RESULTS: After adjustments for sex, body weight, age, and smoking status, higher SRE scores (indicating lower alcohol sensitivity) predicted hangover occurrence on postdrinking mornings (odds ratio [OR] = 1.24 per interquartile range [IQR], p = .003). However, when the number of drinks consumed in the drinking episode was covaried, SRE scores were negatively associated with hangover (OR = 0.67 per IQR, p <.001). An interaction between SRE scores and the number of drinks consumed indicated that low-sensitivity drinkers tend to be differentially resistant to hangover at a given number of drinks. Higher SRE scores were associated with consuming more drinks on average (generalized estimating equations coefficient = 2.20 per IQR, p <.001). CONCLUSIONS: Individuals lower in alcohol sensitivity appear to be more resistant to hangovers per unit of alcohol. However, they are also more likely to engage in excessive drinking, and this may account for their increased odds of experiencing hangover during an arbitrary monitoring period. Heavy consumption, hangover resistance, and hangover frequency may each be manifestations of low sensitivity to alcohol, an established risk factor for alcohol use disorder. PMID- 23036211 TI - Establishment of an immunodeficient alcohol mouse model to study the effects of alcohol on human cells in vivo. AB - OBJECTIVE: The effects of alcohol (ethanol) are well documented and contribute to significant health problems and financial burden on the health care system. Several mouse models have been described that facilitate studies of the effects of alcohol on the mouse immune system. Our goal was to establish a chronic alcohol mouse model using the immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This severely immunodeficient model has previously been shown to allow efficient engraftment of human hematopoietic repopulating cells and cancer cells, thereby facilitating diverse studies on human hematopoiesis, immune cell function, and oncogenesis in vivo. METHOD: NSG mice were provided ethanol in their drinking water as the only available fluid, starting at 5% weight/volume (w/v) and subsequently were increased to 10%, 15%, and 20% w/v. Mice were then maintained at 20% w/v, a level that models chronic alcohol use in humans. Alcohol consumption and weight were monitored. RESULTS: NSG mice readily consumed alcohol throughout the study and showed no adverse effects. No significant difference between group mean weights was identified the day before increasing the ethanol dose or at the end of 5 weeks at 20% w/v (p > .28). While the mice were maintained at 20% w/v ethanol, the mean daily ethanol intake was 27.2 g/kg of body weight, 32% of caloric intake. CONCLUSIONS: Here we have established a chronic alcohol mouse model using the powerful immunodeficient NSG mouse. This model should allow for novel studies on the effects of alcohol on engrafted human cells, including studies on the effects of alcohol on hematopoiesis, immunity, and cancer. PMID- 23036213 TI - Prevalence of psychoactive substances in dutch and belgian traffic. AB - OBJECTIVE: The purpose of this study was to compare the prevalence of psychoactive substances in general traffic in The Netherlands and Belgium. METHOD: Randomly selected car drivers and drivers of small vans in six police regions in The Netherlands and five police regions in Belgium were included between January 2007 and August 2009. Blood and oral fluid samples were analyzed for 23 substances, including ethanol (alcohol), by means of ultra performance liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry analysis. Samples were weighted according to the distribution of traffic over eight 6-hour periods. Substance groups were categorized in five mutually exclusive classes: single alcohol use, single illicit drug use, single medicinal drugs use, multiple drug use (including drugs from two or more separate substance groups but excluding alcohol), and drug use (either single or multiple) in combination with alcohol. RESULTS: In total, 7,771 drivers (4,822 in The Netherlands and 2,949 in Belgium) were included in the study. In Belgium, the prevalence of single alcohol (6.4%) and single medicinal drugs (3.0%) was much higher than in The Netherlands (2.2% and 0.6%, respectively), whereas the single illicit drugs were more common in Dutch traffic (2.2%) than in Belgian traffic (0.6%). Compared with the estimated prevalence of psychoactive substances in the general driving public in Europe, the prevalence in Belgium (10.7%) was greater than the European average (7.4%), and the prevalence in The Netherlands was below the European average (5.5%). CONCLUSIONS: The observed prevalence of psychoactive substances varies largely between The Netherlands and Belgium. Probable reasons for the differences are the higher level of alcohol enforcement in The Netherlands and nonresponse bias in the Belgian study (for illicit drugs in particular). Furthermore, cultural differences and variances in prescription policy could also be influential. PMID- 23036212 TI - Sex differences in prevalence and comorbidity of alcohol and drug use disorders: results from wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVE: The present study examined sex differences in lifetime Axis I and II psychiatric comorbidity of DSM-IV alcohol use disorders (AUDs) and drug use disorders (DUDs) among general population U.S. adults. METHOD: Using data from Waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions, Wave 2 lifetime prevalences of each disorder comorbid with alcohol abuse, alcohol dependence, drug abuse, and drug dependence were compared between men and women. Sex-specific associations of alcohol, any drug, and cannabis- and cocaine-specific abuse and dependence with each comorbid disorder were examined using logistic regression, first with adjustment for sociodemographic variables and then with additional adjustment for all other psychiatric disorders. RESULTS: Prevalences of most comorbid disorders differed significantly by sex among respondents with each AUD and DUD. However, after adjustment for sociodemographic characteristics and additional co-occurring psychiatric diagnoses, there were few sex differences in unique comorbid associations of specific AUDs and DUDs with specific psychiatric disorders. CONCLUSIONS: Rates of psychiatric disorders comorbid with AUDs and DUDs indicate large burdens of morbidity in both sexes, highlighting the need for careful assessment and appropriate treatment of both substance use and mental health disorders. The unique comorbid associations with AUDs and DUDs identified in this study further indicate the need for prospective etiological research to characterize these associations, their underlying mechanisms, and the possible sex specificity of those mechanisms. PMID- 23036214 TI - Social comparison as a moderator of the association between perceived norms and alcohol use and negative consequences among college students. AB - OBJECTIVE: The present study aimed to extend previous research examining the relationships among perceived drinking norms, alcohol use, and related negative consequences by examining the moderating influence of social comparison orientation. METHOD: A sample of 481 college students (44% male) completed a Web based survey that assessed perceptions of drinking behavior, social comparison orientation, and alcohol use. RESULTS: The results suggested that social comparison orientation moderated the norm-behavior relationship such that the association between perceived drinking norms and alcohol-related negative consequences was stronger for those higher in social comparison. Results also showed that there was no moderation effect for alcohol consumption as the dependent variable. CONCLUSIONS: The findings of the present study are potentially important when developing efficacious alcohol prevention and intervention programs at colleges and universities and in considering more complex models of social influences on drinking. PMID- 23036215 TI - Permissive norms and young adults' alcohol and marijuana use: the role of online communities. AB - OBJECTIVE: Young adults are increasingly interacting with their peer groups online through social networking sites. These online interactions may reinforce or escalate alcohol and other drug (AOD) use as a result of more frequent and continuous exposure to AOD promotive norms; however, the influence of young adults' virtual networks on AOD use remains untested. The purpose of this study was to examine the association between the presence of AOD use content in online social networking, perceived norms (online norms regarding AOD use and anticipated regret with AOD use postings), and alcohol and marijuana use in a sample of 18- to 24-year-olds. METHOD: Using an adapted web version of respondent driven sampling (webRDS), we recruited a sample of 18- to 24-year-olds (N = 3,448) in the United States. Using multivariate regression, we explored the relationship between past-30-day alcohol and marijuana use, online norms regarding AOD use, peer substance use, and online and offline peer support. RESULTS: Alcohol use was associated with more alcohol content online. Anticipated regret and online peer support were associated with less alcohol use. Anticipated regret was negatively associated with marijuana use. Peer AOD use was positively associated with both alcohol and marijuana use. CONCLUSIONS: Peers play an important role in young adult alcohol and marijuana use, whether online or in person. Our findings highlight the importance of promoting online network-based AOD prevention programs for young adults in the United States. PMID- 23036216 TI - Correcting exaggerated marijuana use norms among college abstainers: a preliminary test of a preventive intervention. AB - OBJECTIVE: College students have high rates of marijuana initiation and use, and they report exaggerated perceptions of peers' use. Computerized norm-correcting intervention programs have been developed, but minimal efficacy research has been conducted, especially with regard to preventing the onset of marijuana use. The purpose of this pilot study was to evaluate the efficacy of the Marijuana eCHECKUP TO GO (e-TOKE) for Universities & Colleges program in (a) correcting descriptive norms, (b) correcting injunctive norms, and (c) preventing initiation of marijuana use in a group of college-age abstainers. METHOD: Participants were 245 college students (73% female) recruited from psychology courses for course credit who reported no marijuana use in the past month at baseline. Participants were randomized to receive the e-TOKE program or assessment only. All participants reported on marijuana use, descriptive norms, and injunctive norms 1 month later. RESULTS: Participants receiving the e-TOKE program estimated lower descriptive norms than the control group (p < .01), and fewer believed friends disapproved of their choice to abstain (p < .05). However, rates of use/initiation did not differ between the two conditions (p = .18). CONCLUSIONS: The current study provides preliminary evidence for the utility of the e-TOKE program in correcting abstainers' misperceptions about others' marijuana use as well as making them perceive less disapproval for their abstention. However, more research with longer follow-ups is necessary to determine if changes in norms affect initiation rates over time. PMID- 23036218 TI - Hepatic safety of injectable extended-release naltrexone in patients with chronic hepatitis C and HIV infection. AB - OBJECTIVE: Naltrexone (Revia, Vivitrol) is recognized as having the potential for hepatotoxicity. We evaluated the safety of intramuscular extended-release naltrexone (XR-NTX) in a cohort of patients with a high prevalence of chronic hepatitis C virus (HC V) and HIV infection undergoing treatment for opioid dependence. METHOD: A total of 250 (88% male) opioid-dependent patients were randomized to receive monthly injections of XR-NTX 380 mg or placebo. Of the 250 subjects, 222 (88.8%) had a history of HCV; 42% were positive for HIV. Liver chemistry tests for aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, gamma-glutamyl aminotransferase (GGT), alkaline phosphatase, serum albumin, and total protein were obtained at the screening visit, at baseline, and monthly for up to 6 months. RESULTS: In a longitudinal analysis, the frequency of elevations in AST, ALT, and GGT greater than three times the upper limit of normal (ULN) was not statistically different in patients treated with XR-NTX compared with placebo (p = .71). Most of the elevations greater than three times the ULN occurred in patients with chronic HCV infection. In patients who had a treatment-emergent elevation in AST or ALT greater than three times the ULN, the aminotransferases improved and returned toward baseline in those patients with available follow-up data. No specific symptoms were associated with any of the elevations in ALT, AST, or GGT. The frequency of elevations in AST and ALT during treatment in patients with HIV infection was not significantly different compared with that in patients without HIV infection. CONCLUSIONS: XR-NTX can be used safely in eligible patients with opioid dependence, including those with underlying mild to moderate chronic HCV and/or HIV infections. PMID- 23036217 TI - Alcohol use disorders and perceived drinking norms: ethnic differences in Israeli adults. AB - OBJECTIVE: Individuals' perceptions of drinking acceptability in their society (perceived injunctive drinking norms) are widely assumed to explain ethnic group differences in drinking and alcohol use disorders (AUDs), but this has never been formally tested. Immigrants to Israel from the former Soviet Union (FSU) are more likely to drink and report AUD symptoms than other Israelis. We tested perceived drinking norms as a mediator of differences between FSU immigrants and other Israelis in drinking and AUDs. METHOD: Adult household residents (N = 1,349) selected from the Israeli population register were assessed with a structured interview measuring drinking, AUD symptoms, and perceived drinking norms. Regression analyses were used to produce odds ratios (OR) and risk ratios (RR) and 95% confidence intervals (CI) to test differences between FSU immigrants and other Israelis on binary and graded outcomes. Mediation of FSU effects by perceived drinking norms was tested with bootstrapping procedures. RESULTS: FSU immigrants were more likely than other Israelis to be current drinkers (OR = 2.39, CI [1.61, 3.55]), have higher maximum number of drinks per day (RR = 1.88, CI [1.64, 2.16]), have any AUD (OR = 1.75, CI [1.16, 2.64]), score higher on a continuous measure of AUD (RR = 1.44, CI [1.12, 1.84]), and perceive more permissive drinking norms (p < .0001). For all four drinking variables, the FSU group effect was at least partially mediated by perceived drinking norms. CONCLUSIONS: This is the first demonstration that drinking norms mediate ethnic differences in AUDs. This work contributes to understanding ethnic group differences in drinking and AUDs, potentially informing etiologic research and public policy aimed at reducing alcohol-related harm. PMID- 23036219 TI - Inverse association between triglycerides-to-HDL-cholesterol ratio and alcohol drinking in middle-aged Japanese men. AB - OBJECTIVE: Triglycerides-to-high-density-lipoprotein (HDL)-cholesterol ratio (TG/HDL-C ratio) has been proposed to be a useful predictor of cardiovascular disease. Habitual alcohol drinking causes elevation of triglycerides and HDL cholesterol levels. The purpose of this study was to determine how the TG/HDL-C ratio is influenced by alcohol intake. METHOD: Subjects were 21,572 Japanese men (age range: 35-60 years) who were divided into non-, light (<22 g ethanol/day), heavy (>=22 but <44 g ethanol/day), and very heavy (>=44 g ethanol/day) drinkers. The relationship between alcohol intake and TG/HDL-C ratio was investigated by using analysis of covariance and logistic regression analysis. RESULTS: Log transformed TG/HDL-C ratio was significantly lower in light, heavy, and very heavy drinkers than in nondrinkers and was lowest in light drinkers. Odds ratios for high TG/HDL-C ratios in light and heavy drinkers versus nondrinkers were significantly lower than a reference level of 1.00 (light drinkers: 0.63, 95% CI [0.57, 0.71],p < .01); heavy drinkers: 0.75, 95% CI [0.69, 0.81],p < .01]). Odds ratios for high waist-to-height ratio of subjects with versus subjects without high TG/HDL-C ratios were significantly higher than the reference level in non-, light, heavy, and very heavy drinkers and were significantly lower in heavy and very heavy drinkers than in nondrinkers (nondrinkers: 3.84 [3.42,4.31]; light drinkers: 3.65 [2.97,4.48]; heavy drinkers: 3.17 [2.84, 3.54],p < .05 compared with nondrinkers; very heavy drinkers: 2.61 [2.29, 2.97],p < .01 compared with nondrinkers). CONCLUSIONS: Alcohol drinking is inversely associated with TG/ HDL C ratio and confounds the relationship between TG/HDL-C ratio and obesity. PMID- 23036220 TI - Not all those who wander are lost: examining the impact of sojourner adjustment and drinking motives on alcohol consequences experienced by Americans studying in foreign countries. AB - OBJECTIVE: American students studying in foreign countries represent a unique group at risk for increased and problematic drinking. Examination of risk and protective factors for negative alcohol-related consequences can lead to the development of efficacious preventive interventions for reducing high-risk drinking while abroad. The present study examined the relationship between sojourner adjustment (i.e., the sociocultural and psychological adjustment of short-term residents in foreign environments), drinking motives, and alcohol related consequences. METHOD: Participants were 248 college students (81% women) who recently completed study-abroad trips and completed online surveys about their drinking motives and behavior, alcohol-related consequences, and sojourner adjustment. RESULTS: In general, positive sojourner adjustment (i.e., social interaction with host nationals, language development and use, and host culture identification) was protective against negative consequences, whereas negative sojourner adjustment (i.e., social interaction with co-nationals and homesickness/feeling out of place) was associated with increased reporting of consequences. Unexpectedly, the positive sojourner adjustment factor of cultural understanding and participation was associated with greater alcohol-related consequences. Social motives for drinking also predicted consequences. Drinking motives moderated several of the relationships between sojourner adjustment and consequences. CONCLUSIONS: Interest in and adoption of the host country culture may protect against problematic alcohol use; however, this may vary based on students' reasons for drinking. These findings support the need for further examination of sojourner adjustment in college students abroad and indicate potential areas for development of preventive interventions. PMID- 23036221 TI - Ultrastructural and molecular studies of Microgemma carolinus n. sp. (Microsporidia), a parasite of the fish Trachinotus carolinus (Carangidae) in Southern Brazil. AB - A new species of Microsporidia Microgemma carolinus n. sp. found in the marine teleost Trachinotus carolinus collected in Florianopolis, Brazil was described based on light, ultrastructural and phylogenetic studies. This parasite developed in the liver forming whitish xenomas that contained different developmental stages with monokaryotic nuclei. The periphery of the xenoma presented some vacuolization and possessed several small projections in the membrane. The mature spores, measuring 3.8 +/- 0.4 MUm in length and 2.4 +/- 0.4 MUm in width, were slightly pyriform to ellipsoidal and had rounded ends. The polaroplast was bipartite and the isofilar polar filament was coiled with 8 - 9 turns in a single or double row at the posterior end of the spore. The nucleus was voluminous and in a central position, measuring ~0.9 MUm in diameter. A large posterior vacuole appeared as a pale area, occupying about a third of the spore length. The SSU rRNA gene was sequenced and analysed using maximum parsimony, maximum likelihood and neighbour-joining methods. This study allowed us to conclude that this was a new species of the genus Microgemma, being the first description of this genus from among South America fauna. PMID- 23036222 TI - Effects of linking a soil-water-balance model with a groundwater-flow model. AB - A previously published regional groundwater-flow model in north-central Nebraska was sequentially linked with the recently developed soil-water-balance (SWB) model to analyze effects to groundwater-flow model parameters and calibration results. The linked models provided a more detailed spatial and temporal distribution of simulated recharge based on hydrologic processes, improvement of simulated groundwater-level changes and base flows at specific sites in agricultural areas, and a physically based assessment of the relative magnitude of recharge for grassland, nonirrigated cropland, and irrigated cropland areas. Root-mean-squared (RMS) differences between the simulated and estimated or measured target values for the previously published model and linked models were relatively similar and did not improve for all types of calibration targets. However, without any adjustment to the SWB-generated recharge, the RMS difference between simulated and estimated base-flow target values for the groundwater-flow model was slightly smaller than for the previously published model, possibly indicating that the volume of recharge simulated by the SWB code was closer to actual hydrogeologic conditions than the previously published model provided. Groundwater-level and base-flow hydrographs showed that temporal patterns of simulated groundwater levels and base flows were more accurate for the linked models than for the previously published model at several sites, particularly in agricultural areas. PMID- 23036224 TI - Cancer nanomedicines: so many papers and so few drugs! AB - This review identifies a timeline to nanomedicine anticancer drug approval using the business model of inventors, innovators and imitators. By evaluating the publication record of nanomedicine cancer therapeutics we identified a trend of very few publications prior to FDA approval. We first enumerated the publications related to cancer involving polymers, liposomes or monoclonal antibodies and determined the number of citations per publication as well as the number of published clinical trials among the publications. Combining these data with the development of specific nanomedicines, we are able to identify an invention phase consisting of seminal papers in basic science necessary for the development of a specific nanomedicine. The innovation phase includes the first report, the development and the clinical trials involving that nanomedicine. Finally, the imitation phase begins after approval when others ride the wave of success by using the same formulation for new drugs or using the same drug to validate other nanomedicines. We then focused our analysis on nanomedicines containing camptothecin derivatives, which are not yet approved including two polymers considered innovations and one liposomal formulation in the imitation phase. The conclusion that may be drawn from the analysis of the camptothecins is that approved drugs reformulated in polymeric and liposomal cancer nanomedicines have a more difficult time navigating through the approval process than the parent molecule. This is probably due to the fact that for most currently approved drugs, reformulating them in a nanocarrier provides a small increase in performance that large pharmaceutical companies do not consider being worth the time, effort and expense of development. It also appears that drug carriers have a more difficult path through the clinic than monoclonal antibodies. The added complexity of nanocarriers also deters their use to deliver new molecular entities. Thus, the new drug candidates that might be most improved by drug delivery in nanocarriers are not formulated in this fashion. PMID- 23036225 TI - Liposomal drug delivery systems: from concept to clinical applications. AB - The first closed bilayer phospholipid systems, called liposomes, were described in 1965 and soon were proposed as drug delivery systems. The pioneering work of countless liposome researchers over almost 5 decades led to the development of important technical advances such as remote drug loading, extrusion for homogeneous size, long-circulating (PEGylated) liposomes, triggered release liposomes, liposomes containing nucleic acid polymers, ligand-targeted liposomes and liposomes containing combinations of drugs. These advances have led to numerous clinical trials in such diverse areas as the delivery of anti-cancer, anti-fungal and antibiotic drugs, the delivery of gene medicines, and the delivery of anesthetics and anti-inflammatory drugs. A number of liposomes (lipidic nanoparticles) are on the market, and many more are in the pipeline. Lipidic nanoparticles are the first nanomedicine delivery system to make the transition from concept to clinical application, and they are now an established technology platform with considerable clinical acceptance. We can look forward to many more clinical products in the future. PMID- 23036226 TI - n-3 fatty acid-enriched parenteral nutrition regimens in elective surgical and ICU patients: a meta-analysis. AB - INTRODUCTION: Previous studies and a meta-analysis in surgical patients indicate that supplementing parenteral nutrition regimens with n-3 polyunsaturated fatty acids (PUFAs), in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is associated with improved laboratory and clinical outcomes in the setting of hyper-inflammatory conditions. Refined or synthetic fish oils are commonly used as a source of EPA and DHA. The objective of the present meta analysis was to evaluate n-3 PUFA-enriched parenteral nutrition regimens in elective surgical and intensive care unit (ICU) patients. METHODS: Medline was searched for randomized controlled trials comparing n-3 PUFA-enriched lipid emulsions with standard non-enriched lipid emulsions (i.e. soybean oil, MCT/LCT or olive/soybean oil emulsions) in surgical and ICU patients receiving parenteral nutrition. Extracted data were pooled by means of both random and fixed effects models, and subgroup analyses were carried forward to compare findings in ICU versus non-ICU patients. RESULTS: A total of 23 studies (n = 1502 patients: n = 762 admitted to the ICU) were included. No statistically significant difference in mortality rate was found between patients receiving n-3 PUFA-enriched lipid emulsions and those receiving standard lipid emulsions (RR = 0.89; 0.59, 1.33), possibly reflecting a relatively low underlying mortality risk. However, n-3 PUFA enriched emulsions are associated with a statistically and clinically significant reduction in the infection rate (RR = 0.61; 0.45, 0.84) and the lengths of stay, both in the ICU (-1.92; -3.27, -0.58) and in hospital overall (-3.29; -5.13, 1.45). Other beneficial effects included reduced markers of inflammation, improved lung gas exchange, liver function, antioxidant status and fatty acid composition of plasma phospholipids, and a trend towards less impairment of kidney function. CONCLUSIONS: These results confirm and extend previous findings, indicating that n-3 PUFAs-enriched parenteral nutrition regimens are safe and effective in reducing the infection rate and hospital/ICU stay in surgical and ICU patients. PMID- 23036227 TI - Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. AB - The discovery of underlying molecular genetic abnormalities in gastrointestinal stromal tumors (GISTs) such as activating mutations in the tyrosine kinase genes, KIT and platelet derived growth factor receptor-alpha (PDGFRA), has led to remarkable clinical advances in treatment. Small molecule inhibitors such as imatinib and sunitinib are known to inhibit the aberrantly activated KIT and PDGFRA receptor signaling and can lead to excellent clinical outcomes for patients with GIST. Though the majority of GISTs appear to arise sporadically, a number of families with high frequencies of GISTs have been reported and germline mutations have been identified. This review will highlight the various inherited mutations associated with familial GIST syndromes and describe how an improved understanding of these genetic syndromes has important clinical implications for future understanding of this heterogeneous disease. PMID- 23036228 TI - LDL-apheresis dramatically improves generalized calciphylaxis in a patient undergoing hemodialysis. AB - We present the first documented case of generalized calciphylaxis that dramatically improved after low-density lipoprotein-apheresis (LA) in a patient undergoing long-term hemodialysis. Calciphylaxis was diagnosed by skin biopsy and was manifest as painful ulcers on the right leg, left buttock, and glans penis. Skin perfusion pressure (SPP), which has recently been used as an indicator of impaired capillary perfusion in distal lesions of the lower extremities, was markedly reduced. The ulcers continued to worsen despite general wound care, correction of levels of calcium * phosphate product, hyperbaric oxygen therapy, and use of bisphosphonate, antiplatelet therapy, and vasodilators. Because LA is known to exert favorable effects on peripheral arterial disease through improved hemorheology, anti-inflammatory action, vasodilation, and angiogenesis, we introduced LA to produce the same effects on calciphylaxis. LA dramatically increased SPP and promoted ulcer healing, demonstrating that LA can be a useful treatment option for calciphylaxis. PMID- 23036229 TI - Predictive factors associated with change rates of LV hypertrophy and renal dysfunction in CKD patients. AB - BACKGROUND: This longitudinal study is the first report on the factors associated with change rates of the estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) using echocardiography in chronic kidney disease (CKD) patients. METHODS: Measurements of biochemical and physical values, and LVMI evaluated by echocardiography were performed twice (baseline and follow-up period) in pre-dialysis CKD patients. Blood and urine samples were collected at the time of the echocardiographic study. RESULTS: The change rates of hemoglobin (Hb) and transferrin saturation (TSAT: (serum iron/total iron binding capacity)) were identified as independent risk factors for changes in eGFR by multivariate regression analysis. In the LVMI improvement group, the change rate of systolic blood pressure (sBP) was identified as an independent factor for change in LVMI. In the LVMI worsening group, the change rates of sBP, proteinuria and Hb were identified as independent risk factors for changes in LVMI. CONCLUSIONS: It appears that treatment of renal and iron deficiency anemia might prevent progression of renal dysfunction. To prevent LV hypertrophy in CKD patients, renal anemia, hypertension and proteinuria should be treated. PMID- 23036230 TI - First reported case of collagenofibrotic glomerulopathy with a full-house pattern of immune deposits. AB - Collagenofibrotic glomerulopathy is a very rare glomerular disease characterized by the deposition of Type III collagen fibrils within the subendothelial and mesangial areas, and by elevated serum levels of pro-collagen Type III peptide. We reported here an elderly patient representing the first case of collagenofibrotic glomerulopathy with a "full-house" pattern of glomerular immunoglobulin and complement deposits by immunofluorescence. A 79-year-old Japanese woman was admitted to our hospital for clinical examinations of leg edema. A renal biopsy specimen showed a remarkable enlargement of the glomerular tufts due to the deposition of periodic acid-Schiff- and Masson's trichrome positive material. All three immunoglobulins, complements, and light chains were detected in the subendothelial space and capillary walls of the glomeruli. Electron microscopy of tannic acid staining showed spiraled and frayed fibers in the subendothelial areas, which were positive for Type III collagen staining. Serum levels of pro-collagen Type III peptide were increased. Therefore, even in cases where the renal biopsy sample displays a "full-house" immunofluorescence pattern of glomerulopathy, as in systemic lupus erythematosus, we may not always rule out the diagnosis of collagenofibrotic glomerulopathy. PMID- 23036231 TI - Malignant peripheral nerve sheath tumours in inherited disease. AB - BACKGROUND: Malignant peripheral nerve sheath tumours (MPNST) are rare tumours known to occur at high frequency in neurofibromatosis 1 (NF1), but may also occur in other cancer prone syndromes. METHODS: The North West Regional Genetic Register covers a population of 4.1 million and was interrogated for incidence of MPNST in 12 cancer prone syndromes. Age, incidence and survival curves were generated for NF1. RESULTS: Fifty two of 1254 NF1 patients developed MPNST, with MPNST also occurring in 2/181 cases of schwannomatosis and 2/895 NF2 patients. Three cases were also noted in TP53 mutation carriers. However, there were no cases amongst 5727BRCA1/2 carriers and first degree relatives, 2029 members from Lynch syndrome families, nor amongst 447 Familial Adenomatous Polyposis, 202 Gorlin syndrome, nor 87 vHL cases. CONCLUSION: MPNST is associated with schwannomatosis and TP53 mutations and is confirmed at high frequency in NF1. It appears to be only increased in NF2 amongst those that have been irradiated. The lifetime risk of MPNST in NF1 is between 9-13%. PMID- 23036232 TI - Freeze core sampling to validate time-lapse resistivity monitoring of the hyporheic zone. AB - A freeze core sampler was used to characterize hyporheic zone storage during a stream tracer test. The pore water from the frozen core showed tracer lingered in the hyporheic zone after the tracer had returned to background concentration in collocated well samples. These results confirmed evidence of lingering subsurface tracer seen in time-lapse electrical resistivity tomographs. The pore water exhibited brine exclusion (ion concentrations in ice lower than source water) in a sediment matrix, despite the fast freezing time. Although freeze core sampling provided qualitative evidence of lingering tracer, it proved difficult to quantify tracer concentration because the amount of brine exclusion during freezing could not be accurately determined. Nonetheless, the additional evidence for lingering tracer supports using time-lapse resistivity to detect regions of low fluid mobility within the hyporheic zone that can act as chemically reactive zones of importance in stream health. PMID- 23036233 TI - Identification and characterization of a cDNA clone-encoding antigen of Eimeria acervulina. AB - Eimeria spp. are the causative agents of coccidiosis, a major disease affecting the poultry industry. So far, only a few antigen genes of E. acervulina have been reported. In this study, a clone, named as cSZ-JN2, was identified from a cDNA expression library prepared from E. acervulina sporozoite stage with the ability to stimulate the chicken immune response. The sequence analysis showed that the open reading fragment (ORF) of cSZ-JN2 was 153 bp in size and encoded a predicted protein of 50 amino acids of Mr 5.3 kDa. BLASTN search revealed that cSZ-JN2 had no significant homology with the known genes of E. acervulina or any other organism (GenBank). The recombinant cSZ-JN2 antigen expressed in E. coli was recognized strongly by serum from chickens experimentally infected with E. acervulina. Immunofluorescence analysis using antibody against recombinant cSZ JN2 indicated that this protein was expressed in sporozoite and merozoite developmental stages. Animal challenge experiments demonstrated that the recombinant protein of cSZ-JN2 and DNA vaccine carrying cSZ-JN2 could significantly increase the average body weight gains, decrease the mean lesion scores and the oocyst outputs of the immunized chickens and presented anti coccidial indices of more than 165. All the above results suggested that the cSZ JN2 was a novel E. acervulina antigen and could be an effective candidate for the development of a new vaccine against E. acervulina infection. PMID- 23036234 TI - Reversal of Vitamin K Antagonist (VKA) effect in patients with severe bleeding: a French multicenter observational study (Optiplex) assessing the use of Prothrombin Complex Concentrate (PCC) in current clinical practice. AB - INTRODUCTION: Prothrombin Complex Concentrate (PCC) is a key treatment in the management of bleeding related to Vitamin K antagonists (VKA). This study aimed to evaluate prospectively PCC use in patients with VKA-related bleeding in view of the French guidelines published in 2008. METHODS: All consecutive patients with VKA-related bleeding treated with a 4-factor PCC (Octaplex(r)) were selected in 33 French hospitals. Collected data included demographics, site and severity of bleeding, modalities of PCC administration, International Normalized Ratio (INR) values before and after PCC administration, outcomes and survival rate 15 days after infusion. RESULTS: Of 825 patients who received PCC between August 2008 and December 2010, 646 had severe bleeding. The main haemorrhage sites were intracranial (43.7%) and abdominal (24.3%). Mean INR before PCC was 4.4 +/- 1.9; INR was unavailable in 12.5% of patients. The proportions of patients who received a PCC dose according to guidelines were 15.8% in patients with initial INR 2-2.5, 41.5% in patients with INR 2.5-3, 40.8% in patients with INR 3-3.5, 26.9% in patients with INR > 3.5, and 63.5% of patients with unknown INR. Vitamin K was administered in 84.7% of patients. The infused dose of PCC did not vary with initial INR; the mean dose was 25.3 +/- 9.8 IU/Kg. Rates of controlled bleeding and target INR achievement were similar, regardless of whether or not patients were receiving PCC doses as per the guidelines. No differences in INR after PCC treatment were observed, regardless of whether or not vitamin K was administered. INR was first monitored after a mean time frame of 4.5 +/- 5.6 hours post PCC. The overall survival rate at 15 days after PCC infusion was 75.4% (65.1% in patients with intracranial haemorrhage). A better prognosis was observed in patients reaching the target INR. CONCLUSIONS: Severe bleeding related to VKA needs to be better managed, particularly regarding the PCC infused dose, INR monitoring and administration of vitamin K. A dose of 25 IU/kg PCC appears to be efficacious in achieving a target INR of 1.5. Further studies are required to assess whether adjusting PCC dose and/or better management of INR would improve outcomes. PMID- 23036235 TI - Sarcoma risk after radiation exposure. AB - Sarcomas were one of the first solid cancers to be linked to ionizing radiation exposure. We reviewed the current evidence on this relationship, focusing particularly on the studies that had individual estimates of radiation doses. There is clear evidence of an increased risk of both bone and soft tissue sarcomas after high-dose fractionated radiation exposure (10 + Gy) in childhood, and the risk increases approximately linearly in dose, at least up to 40 Gy. There are few studies available of sarcoma after radiotherapy in adulthood for cancer, but data from cancer registries and studies of treatment for benign conditions confirm that the risk of sarcoma is also increased in this age-group after fractionated high-dose exposure. New findings from the long-term follow-up of the Japanese atomic bomb survivors suggest, for the first time, that sarcomas can be induced by acute lower-doses of radiation (<5 Gy) at any age, and the magnitude of the risk is similar to that observed for other solid cancers. While there is evidence that individuals with certain rare familial genetic syndromes predisposing to sarcoma, particularly Nijmegen Breakage Syndrome, are particularly sensitive to the effects of high dose radiation, it is unclear whether this is also true in very low-dose settings (<0.1 Gy). The effects of common low-penetrance alleles on radiosensitivity in the general population have not been well-characterized. Some evidence suggests that it may be possible to identify radiation-induced sarcomas by a distinct molecular signature, but this work needs to be replicated in several dose settings, and the potential role of chemotherapy and tumor heterogeneity needs to be examined in more detail. In summary, radiation exposure remains one of the few established risk factors for both bone and soft tissue sarcomas. Similar to many other cancers children have the highest risks of developing a radiation-related sarcoma. Efforts to limit unnecessary high-dose radiation exposure, particularly in children, therefore remain important given the high fatality rates associated with this disease. PMID- 23036236 TI - The effect of groundwater allocation on economic welfare loss. AB - Water scarcity has become a constraint for regional economic development in many cities and regions. Water rationing serves as one instrument to constrain water consumption to persuade users to save water and to moderate their consumption. When the supply of water is unable to satisfy demand, a loss of welfare for the water users will usually occur. This paper conducts an empirical case study on a Chicago suburban county, McHenry County, to evaluate effective water allocation strategies under possible water scarcity scenarios, by specifically taking into consideration of the economic welfare loss under water rationing. It points out the inefficiency of equal rationing and tests a more effective optimal rationing regime which could significantly lower the overall welfare loss for McHenry County. Instead of a conventional watershed-based approach that would provide little advantage for an area that mostly relies on groundwater, this study adopts regional planning/political boundaries as its spatial analytical units. The outcomes suggest that municipality-level water resources management models, powered under economic welfare objective functions, are both possible and practical. The planning strategy drawn under such optimization models suggests a variety of promising approaches to manage groundwater resources at county scales. PMID- 23036237 TI - Use of contraindicated drugs in patients with chronic liver disease: a therapeutic dilemma. AB - OBJECTIVE: To investigate the prevalence of prescribing of contraindicated drugs or those requiring caution, in hospital inpatients with chronic liver disease. METHODS: The medical records and drug charts of adult hospitalized patients, consecutively admitted with clinical documentation and biochemical evidence of chronic liver disease, were studied retrospectively. Comparison was made between the prescription details for each drug and the recommendations for use in patients with liver disease under the approved product information, which indicates drugs that could be hepatotoxic and those that could have markedly altered pharmacokinetics or pharmacodynamics in chronic liver disease. RESULTS: 49 eligible patients with both clinical documentation and confirmatory biochemical evidence of chronic liver disease were identified. Of these, 15 had received at least 1 contraindicated medication during hospitalization, with diazepam being the most common. 31 patients had received at least 1 drug which requires precaution in liver disease, with propranolol being the most common. CONCLUSION: The use of contraindicated drugs or those requiring caution, occurred frequently in hospital patients with chronic liver disease. This could reflect the somewhat limited evidence base and the perhaps overly cautious nature of the official product information. PMID- 23036238 TI - The use of TNF-inhibitors in ankylosing spondylitis in Austria from 2007 to 2009 a retrospective analysis. AB - OBJECTIVE: The introduction of anti- tumor necrosis factor-alpha agents (TNF inhibitors) offered new dimensions in symptom relief and alteration of disease progression for patients with Ankylosing Spondylitis (AS). In 2007, Infliximab, Etanercept and Adalimumab were approved for AS in Austria. Drug reimbursement data of 2007 were retrieved to evaluate frequency of prescription, preferred substance and data on switching therapies. METHODS: Data from eight health insurance funds covering 5.4 million insured people, which corresponds to 64% of the population, was analyzed by linking two databases, combining data on therapy of individual patients and their diagnosis. For those patients on TNF-inhibitors in 2007 reimbursement data from 2008 and 2009 were obtained, respectively. RESULTS: A total of 694 patients with AS on TNF inhibitors in 2007 were identified for data analysis. Yearly costs for TNF-inhibitors were highest for Adalimumab (14,399 ? per patient) followed by Infliximab (11,685 ? per patient) and Etanercept (10,184 ? per patient). In first-time TNF-inhibitor prescriptions, Adalimumab was prescribed most often, with a tendency towards prescription of Adalimumab and Etanercept in the younger and Infliximab in the older population. In the first year of prescription, 12% of patients already switched from the initially prescribed drug to another substance with those started on Etanercept showing the lowest switching rate. One-year drug survival in our data was highest for Etanercept with 83% still on the drug after 1 year, followed by Infliximab and then Adalimumab, while two-year drug survival was also highest for Etanercept (58%), followed by Adalimumab and then Infliximab. CONCLUSIONS: Patients with Ankylosing Spondylitis starting on TNF-inhibiting therapy in Austria in 2007 were treated most often with Adalimumab, while Etanercept showed the lowest switching rate and the longest 1- and 2-year drug survival. PMID- 23036240 TI - Alteration in mononuclear cell subpopulations in dogs immunized with gentamicin attenuated Leishmania infantum. AB - The impact of immunization with gentamicin-attenuated Leishmania infantum (H line) on the immunophenotypic profile of popliteal lymph node (PLN) and peripheral blood mononuclear cells (PBMCs) of dogs was assessed by flow cytometry and immunohistochemistry. Compared with the dogs infected with L. infantum wild type (Group WT), there was a significantly higher percentage of CD4+, CD44+ T cells and CD14+, MHC-II+ cells and a lower percentage of CD4+ CD25+ regulatory T cells in PLN of the immunized dogs with L. infantum H-line (Group H). The percentage of CD4+ and CD8+ T cells in PBMCs of immunized dogs was higher than that in dogs of Group WT. The CD4:CD8 ratio in PLN of dogs of Group H was significantly higher than that in dogs of Group WT. A significantly higher percentage of CD21+ B cells and a lower percentage of CD79b+ cells were found in PLN of the immunized dogs compared with dogs of Group WT. Immunohistochemical investigation showed no parasites in the PLN of immunized dogs whereas there were parasites in the PLN of 60% of dogs infected with L. infantum WT. In this study, the immunophenotypic profile of mononuclear cells of the immunized dogs correlates with cellular immunity. PMID- 23036239 TI - Hypertonic saline reduces lipopolysaccharide-induced mouse brain edema through inhibiting aquaporin 4 expression. AB - INTRODUCTION: Three percent sodium chloride (NaCl) treatment has been shown to reduce brain edema and inhibited brain aquaporin 4 (AQP4) expression in bacterial meningitis induced by Escherichia coli. Lipopolysaccharide (LPS) is the main pathogenic component of E. coli. We aimed to explore the effect of 3% NaCl in mouse brain edema induced by LPS, as well as to elucidate the potential mechanisms of action. METHODS: Three percent NaCl was used to treat cerebral edema induced by LPS in mice in vivo. Brain water content, IL-1beta, TNFalpha, immunoglobulin G (IgG), AQP4 mRNA and protein were measured in brain tissues. IL 1beta, 3% NaCl and calphostin C (a specific inhibitor of protein kinase C) were used to treat the primary astrocytes in vitro. AQP4 mRNA and protein were measured in astrocytes. Differences in various groups were determined by one-way analysis of variance. RESULTS: Three percent NaCl attenuated the increase of brain water content, IL-1beta, TNFalpha, IgG, AQP4 mRNA and protein in brain tissues induced by LPS. Three percent NaCl inhibited the increase of AQP4 mRNA and protein in astrocytes induced by IL-1beta in vitro. Calphostin C blocked the decrease of AQP4 mRNA and protein in astrocytes induced by 3% NaCl in vitro. CONCLUSIONS: Osmotherapy with 3% NaCl ameliorated LPS-induced cerebral edema in vivo. In addition to its osmotic force, 3% NaCl exerted anti-edema effects possibly through down-regulating the expression of proinflammatory cytokines (IL 1beta and TNFalpha) and inhibiting the expression of AQP4 induced by proinflammatory cytokines. Three percent NaCl attenuated the expression of AQP4 through activation of protein kinase C in astrocytes. PMID- 23036241 TI - Pediatric pharmacokinetics: human development and drug disposition. AB - Human development is described by the various anatomic and physiologic changes that occur as the single-celled zygote matures into an adult human being. Concomitant with bodily maturation are changes in the complex interactions between pharmacologic agents and the biologic matrix that is the human body. Profound changes in the manner by which drugs traverse the body during development can have significant implications in drug efficacy and toxicity. Although not a replacement for well-conducted, pediatric, pharmacokinetic studies, an understanding of developmental biology and the mechanisms for drug disposition invariably assists the pediatric clinician with the judicious use of medications in children. PMID- 23036243 TI - Metabolomics in the developing human being. AB - Metabolomics is based on the detailed analysis of metabolites and represents a unique chemical fingerprint of an organism. This approach allows assessing the dynamic behavior of biologic systems with multiple network interactions among individual components. The field of metabolic profiling has rapidly developed over the last decade, with successful applications in various research areas including toxicology, disease diagnosis and classification, pharmacology, and nutrition. This article provides a comprehensive account of existing data in the literature from animal and clinical studies on the use of metabolomics for improved understanding of medical conditions affecting the neonate and the developing human being. PMID- 23036244 TI - Emerging biomarkers of intrauterine neonatal and pediatric exposures to xenobiotics. AB - Biomarkers are an important tool for clinicians to detect long-term exposure to a multitude of compounds, including drugs of abuse, alcohol, and environmental toxicants. Using hair and meconium as matrices for biomarker testing provides a longer window of detection than that of blood or urine, providing clinically relevant information on prenatal exposures. The use of biomarkers can aid clinicians in early diagnosis and implementing appropriate interventions. The increasing burden of environmental toxicants has warranted the development of biomarkers for specific compounds, which could decrease exposure in humans. PMID- 23036242 TI - Pediatric pharmacogenomics: a systematic assessment of ontogeny and genetic variation to guide the design of statin studies in children. AB - The dose-exposure-response relationship for drugs may differ in pediatric patients compared with adults. Many clinical studies have established drug dose exposure relationships across the pediatric age spectrum; however, genetic variation was seldom included. This article applies a systematic approach to determine the relative contribution of development and genetic variation on drug disposition and response using HMG-CoA reductase inhibitors as a model. Application of the approach drives the collection of information relevant to understanding the potential contribution of ontogeny and genetic variation to statin dose-exposure-response in children, and identifies important knowledge deficits to be addressed through the design of future studies. PMID- 23036245 TI - New ways to detect adverse drug reactions in pediatrics. AB - Adverse drug reactions (ADRs) complicate at least 5% of all courses of therapy for children. Dealing with an ADR requires a stepwise approach in appreciation of the possibility of an ADR, assessment of whether the adverse event in question is drug-related, assessment of causality, assistance in treating the symptoms of the ADR, and dealing with the aftermath of the event. Several new developments likely will improve the ability to assess, evaluate, treat, and prevent ADRs in children. These developments include tools to evaluate causality, laboratory tests to diagnose ADRs, pharmacogenomic approaches to prevent ADRs, and new insights into treating serious ADRs. PMID- 23036246 TI - Pharmacotherapy of pediatric HIV infection. AB - The delivery of safe and effective antiretroviral therapy to children and adolescents is crucial to save the lives of millions of children worldwide. The immunologic response to human immunodeficiency infection is closely related to a child's development and creates age-specific parameters for the evaluation of therapeutic response to antiretroviral therapy. Similarly, the development and maturation of organ systems involved in drug absorption, distribution, metabolism, and elimination determines significant changes in the pharmacokinetics of antiretroviral drugs throughout childhood. The authors review the evolution in treatment of pediatric HIV from infancy through adolescence. PMID- 23036247 TI - How to optimize the evaluation and use of antibiotics in neonates. AB - The optimal evaluation and use of antibacterial agents that are very frequently prescribed in neonates during various situations such as early- and late-onset invasive infections depend on adapted dose selection, based on population pharmacokinetic/pharmacodynamic modeling and simulation, using approved surrogate biomarkers as pharmacodynamic end points. Data on efficacy can be extrapolated from adult and pediatric data because of comparable mechanistic action of antibiotics in neonates, children, and adults. However, evaluation of efficacy and toxicity in the neonate should always be discussed with regulatory agencies and are highly recommended when feasible. PMID- 23036248 TI - Pharmacotherapy for pulmonary hypertension. AB - Pulmonary arterial hypertension is a serious disease with significant morbidity and mortality. Although it can occur idiopathically, it is more commonly associated with other cardiac or lung diseases. While most of the available therapies have been tested in adult populations and most therapies in children remain off-label, new reports and randomized trials are emerging that inform the treatment of pediatric populations. This review discusses currently available therapies for pediatric pulmonary hypertension, their biological rationales, and evidence for their clinical effectiveness. PMID- 23036250 TI - Update on pain assessment in sick neonates and infants. AB - This article describes developments in pain assessment in critically ill neonates and infants during the last 5 to 6 years. Pain assessment instruments show a redundancy of items and a lack of profound psychometric background. Although most research focuses primarily on acute pain, in clinical practice there is also the challenge of assessing prolonged and/or persisting pain. The effectiveness of pain assessment is still a matter of debate and has recently been challenged as a primary end point in analgesia-related trials. Integration of observation of behavior with reliable and specific neurobiology-based parameters remains a challenge. PMID- 23036249 TI - Pharmacologic management of the opioid neonatal abstinence syndrome. AB - Opioid use in pregnant women has increased over the last decade. Following birth, infants with in utero exposure demonstrate signs and symptoms of withdrawal known as the neonatal abstinence syndrome (NAS). Infants express a spectrum of disease, with most requiring the administration of pharmacologic therapy to ensure proper growth and development. Treatment often involves prolonged hospitalization. There is a general lack of high-quality clinical trial data to guide optimal therapy, and significant heterogeneity in treatment approaches. Emerging trends in the treatment of infants with NAS include the use of sublingual buprenorphine, transition to outpatient therapy, and pharmacogenetic risk stratification. PMID- 23036253 TI - Neonatal and pediatric clinical pharmacology. PMID- 23036252 TI - Ethical issues in neonatal and pediatric clinical trials. AB - Children have been identified as uniquely vulnerable clinical research subjects since the early 1970s. This article reviews the historical underpinnings of this designation, the current regulatory framework for pediatric and neonatal research, and common problems in pediatric research oversight. It also presents 3 areas of pediatric and neonatal research (genomic screening, healthy children donating stem cells, and therapeutic hypothermia for neonates with hypoxic ischemic encephalopathy) that highlight contemporary challenges in pediatric research ethics, including balancing risk and benefit, informed consent and assent, and clinical equipoise. PMID- 23036254 TI - [Use of multidetector computed tomography for locating the site of gastrointestinal tract perforations]. AB - INTRODUCTION: The purpose of this study was to evaluate the accuracy of multidetector computed tomography (MDCT) for locating the site of gastrointestinal tract perforations and to determine the most predictive signs in this diagnosis. MATERIAL AND METHODS: A total of 98 patients with pneumoperitoneum on MDCT were retrospectively analysed. Two experienced radiologists reviewed the presence or absence of direct signs (extravasation of oral contrast, focal defect in the bowel wall, focal defect with multiplanar reformations images) and indirect signs (free air in supramesocolic, inframesocolic, supramesocolic and inframesocolic compartments, concentration of extraluminal air bubbles adjacent to the bowel wall, extraluminal fluid, segmental bowel-wall thickening, perivisceral fat stranding, abscess) to identify the site of the perforation. The Kappa index was evaluated between radiologists to determine the site of perforation and for each predictive sign, as well as Kappa index between the site of perforation detected with MDCT and the site proven at surgery. The frequency, sensitivity, specificity and positive and negative predictive value (PPV and NPV, respectively) were calculated. RESULTS: The perforation site was identified correctly in 80.4% of cases. Kappa index between radiologists to identify the site was excellent (0.919), varying between 0.5-1.0 for each radiological sign. The most frequent site of perforation at surgery (33.7%) and in MDCT (40.82%) was the sigmoid colon/rectum. Concentration of extraluminal air bubbles adjacent to the bowel wall was the most sensitive (91%) sign and "segmental bowel-wall thickening" had the highest PPV (90%). CONCLUSION: MDCT is useful for locating the site of GI perforation, with a high sensitivity (80%) and an excellent agreement between radiologists. PMID- 23036251 TI - The impact of extracorporeal life support and hypothermia on drug disposition in critically ill infants and children. AB - Extracorporeal membrane oxygenation (ECMO) support is an established lifesaving therapy for potentially reversible respiratory or cardiac failure. In 10% of all pediatric patients receiving ECMO, ECMO therapy is initiated during or after cardiopulmonary resuscitation. Therapeutic hypothermia is frequently used in children after cardiac arrest, despite the lack of randomized controlled trials that show its efficacy. Hypothermia is frequently used in children and neonates during cardiopulmonary bypass (CPB). By combining data from pharmacokinetic studies in children on ECMO and CPB and during hypothermia, this review elucidates the possible effects of hypothermia during ECMO on drug disposition. PMID- 23036255 TI - [Radiation proctitis and chronic and refractory bleeding. Experience with 4% formaldehyde]. AB - INTRODUCTION: Bleeding is a common complication of proctitis secondary to radiotherapy of pelvic tumours. Between 5 and 10% may become severe and refractory to topical and endoscopic treatment. Experience with the application of 4% formaldehyde is presented. PATIENTS AND METHOD: A retrospective and descriptive study was performed on a patient cohort with severe radiation proctitis admitted to the Hospital Universitario Donostia between January 2003 and September 2009. All patients were diagnosed by colonoscopy and admitted due to the severity of their treatment. Both 4% formaldehyde and the gauze technique were used, as well as using enemas, in cases refractory to topical and endoscopic treatment with argon. The technique was performed in theatre with regional anaesthetic. Clinical and endoscopic follow up was carried out. RESULTS: The study included 25 males (73.5%) and 9 women (26.5%), with a mean age of 69 years (32-80) who had rectal bleeding due to radiation proctitis and required admission. All treatments failed in 6 (28.5%) patients, and 4% formaldehyde was used, with a complete response to the bleeding in all 6 patients, with 3 cases requiring one session, and the 3 others 2 sessions. The gauze technique was used in 4 patients and another 2 were given a formaldehyde enema due to the presence of stenosis. Pain appeared as the main complication in 2 (33.3%) patients. The median follow up was 60 months (interquartile range 26 to 67 months). CONCLUSIONS: The use of 4% formaldehyde in bleeding due to radiation proctitis is an effective, easy to reproduce technique, with a low morbidity. PMID- 23036256 TI - [Sublingual schwannoma]. PMID- 23036257 TI - Intestinal obstruction caused by recurrent phytobezoar: resolved with non surgical treatment with cellulase. PMID- 23036259 TI - Biphasic alveolosquamoid renal carcinoma: a histomorphological, immunohistochemical, molecular genetic, and ultrastructural study of a distinctive morphologic variant of renal cell carcinoma. AB - Only a few cases of sarcomatoid renal cell carcinomas (RCCs) with squamous differentiation have been published. We present 2 RCCs exhibiting a hitherto not reported biphasic neoplastic cell population exhibiting a predominantly alveolar architecture where squamoid differentiation was identified in one of the neoplastic cell populations. None of the tumors showed chromophobe features or any evidence of sarcomatoid transformation. The tumors arose in 2 adult patients and were characterized by routine histology, immunohistochemistry, ultrastructure, array comparative genomic hybridization, confirmatory fluorescent in situ hybridization, and loss of heterozygosity analysis. Tumors measured 3 and 4 cm and were located within the renal parenchyma and had no pelvicalyceal connection. Both tumors were composed of a distinctly dual-cell population. The larger tumor cells displayed squamoid features and formed round well-demarcated solid alveolated islands that, in large parts, were surrounded by a smaller neoplastic cell component. The squamoid cells were immunoreactive for cytokeratins (CKs) (AE1-AE3, Cam 5.2, CK5/6, CK7, and CK20), epithelial membrane antigen, racemase/AMACR, and carboanhydrase IX (in 1 case focally). The small cell population was positive for CK7, epithelial membrane antigen, and racemase/AMACR, whereas CK20, AE1-3, and carboanhydrase IX were negative. CD10 was focally positive in the large squamoid cells in 1 case. Cathepsin K, E cadherin, and CD117 displayed focal positivity in 1 case. Vimentin, RCC marker, parvalbumin, S100 protein, S100 A1, p63, p53, CDX2, uroplakin III, HMB45, TFE3, WT1, synaptophysin, chromogranin A, thyroglobulin, and TTF1 were negative. The proliferative activity (Ki-67) was low (1%) in the small cell component in both cases, whereas the large neoplastic tumor cells displayed a significantly higher proliferation (20%-35%). Ultrastructurally, desmosomes and tonofilaments were identified in the large tumor cells, confirming squamoid differentiation in a subset of tumor cells. Array comparative genomic hybridization of 1 analyzable case (confirmed with fluorescent in situ hybridization and loss of heterozygosity analysis) revealed partial or complete losses of chromosomes 2, 5, 6, 9, 12, 15, 16, 17, 18 and 22, (including biallelic loss of CDKN2A locus) and partial gains of chromosomes 1, 5, 11, 12 and 13. Follow-up at 6 years showed no recurrence or metastasis in 1 patient. The other (male) patients had a subcutaneous metastasis at presentation, but during a 1-year follow-up no evidence of recurrence or further metastatic events have been documented. Our data indicate that biphasic alveolosquamoid renal carcinoma is a unique and distinctive tumor. The large squamoid and small tumor cells have overlapping but still distinctive immunohistochemical patterns of protein expression. Multiple chromosomal aberrations were identified, some of them located in regions with known tumor suppressor genes and oncogenes. PMID- 23036260 TI - Gastrointestinal stromal tumor of the ampulla of Vater with osteoclastic giant cells, osteoid-like matrix deposition, and aneurysmal bone cyst-like features. AB - Gastrointestinal stromal tumors are a heterogeneous group with a wide spectrum of histologic features. We describe the first case of 61-year-old woman who presented gastrointestinal stromal tumors of the ampulla of Vater with osteoclast like giant cells surrounding osteoid-like material and aneurismal bone cyst-like areas. The phenotype was supported by light microscopy and corroborated by immunohistochemistry analysis. Because of the presence of osteoid-like and aneurismal bone cyst-like components, it is first necessary to make differential diagnosis with other entities such as metastatic osteosarcoma. Our case shows another form of differentiation that has not previously been reported. PMID- 23036261 TI - Plasmablastic lymphoma in pediatric patients: clinicopathologic study of three cases. AB - Plasmablastic lymphoma (PBL) is an aggressive high grade non-Hodgkin lymphoma which occurs predominantly in adult patients who are concomitantly afflicted with HIV infection. In contrast to several reports and studies of PBL in adult patients, PBL has very rarely been reported in pediatric patients. This article hereby provides collaborative clinicopathologic information of de novo PBL diagnosed in 3 pediatric patients with concomitant HIV infection. Cognizance of this rare tumor in the pediatric population coupled with antiretroviral therapy and prompt initiation of multimodality treatment may, in the future, facilitate improved outcome in pediatric patients with PBL. PMID- 23036262 TI - Mood and the menstrual cycle: a review of prospective data studies. AB - BACKGROUND: The human menstrual cycle (MC) has historically been the focus of myth and misinformation, leading to ideas that constrain women's activities. OBJECTIVES: We wished to examine one pervasive idea, that the MC is a cause of negative mood, by studying the scientific literature as a whole. We briefly reviewed the history of the idea of premenstrual syndrome and undertook a systematic review of quality studies. METHODS: We searched PubMed, PsycINFO, and article bibliographies for published studies using non-help-seeking samples with daily mood data collected prospectively for a minimum of 1 complete MC. We critiqued their methodologies and tabulated the key findings. RESULTS: Of 47 English language studies identified, 18 (38.3%) found no association of mood with any MC phase; 18 found an association of negative mood in the premenstrual phase combined with another MC phase; and only 7 (14.9%) found an association of negative mood and the premenstrual phase. Finally, the remaining 4 studies (8.5%) showed an association between negative mood and a non-premenstrual phase. Considering the only 41 adequately powered studies, the same phase links were reported by 36.6%, 41.5%, and 13.5% of studies, respectively. Their diversity of methods (sampling, instruments, and cycle phase definitions) precluded a meta analysis. CONCLUSIONS: Taken together, these studies failed to provide clear evidence in support of the existence of a specific premenstrual negative mood syndrome in the general population. This puzzlingly widespread belief needs challenging, as it perpetuates negative concepts linking female reproduction with negative emotionality. PMID- 23036263 TI - Women and heart disease: shifting the paradigm in the 21st century. PMID- 23036265 TI - Long-term use of pramipexole in the management of restless legs syndrome. AB - OBJECTIVE: Few studies have examined the long-term use of dopamine agonists for restless legs syndrome (RLS). We report a cohort study of 50 patients initially prescribed pramipexole between 1998 and 2002. The objective was to determine duration of treatment, long-term efficacy, development of side effects and augmentation over an extended period. METHODS: We performed a long-term analysis on a previously reported group of patients initially followed for a mean of 27.2 months. Data were collected using retrospective chart reviews, written surveys and systematic telephone interviews. RESULTS: Pramipexole was used for a mean of 8 years (range 0.6-12 years). Nine (18%) discontinued pramipexole because of poor efficacy (four), impulse control disorders (ICD) (two), augmentation (one) and resolved symptoms (two). Pramipexole was reported completely effective in 40% (compared to 67% at the end of the initial study), partially effective in 58% and ineffective in 2%. The median daily dose increased from 0.38 mg after initial stabilization to 1.0mg at the end of the study. As many as 74% of patients experienced side effects. A total of 56% reported daytime sleepiness including 10% reporting sleep attacks while driving and 10% developed ICDs. Augmentation developed in 42% of patients, after a mean of 16.5 months, and no later than 4.1 years after commencing treatment. A total of 28% needed additional non dopaminergic medications. CONCLUSION: The efficacy of pramipexole dropped with time, with increase in dose and addition of other agents, although the majority of patients remained on the drug. Problems included the development of augmentation within the first 4 years of therapy and side effects such as sleepiness increasing with time and the development of ICDs. The study highlights the need for further research into alternative non-dopaminergic treatments for RLS. PMID- 23036264 TI - Effect of continuous positive airway pressure on day/night rhythm of prothrombotic markers in obstructive sleep apnea. AB - OBJECTIVE: Obstructive sleep apnea (OSA) has been associated with an increased risk of atherothrombotic events. A prothrombotic state might partially explain this link. This study investigated OSA patients' day/night rhythm of several prothrombotic markers and their potential changes with therapeutic continuous positive airway pressure (CPAP). METHODS: The study included 51 OSA patients [apnea hypopnea index (AHI) ?10] and 24 non-OSA controls (AHI<10). Of the 51 OSA patients, 25 were randomized to CPAP and 26 to placebo-CPAP. Twelve blood samples were collected over a 24h period to measure prothrombotic markers. For the apneic patients these samples were collected before treatment and after 3weeks of treatment with either CPAP or placebo-CPAP. Day/night variation in prothrombotic markers was examined using a cosinor analysis. RESULTS: Compared with controls, OSA patients showed lower mesor (mean) and amplitude (difference between maximum and minimum activity) of D-dimer. In unadjusted (but not in adjusted) analysis, patients showed higher mesor of plasminogen activator inhibitor-1 (p<0.05 in all cases). No significant group differences were seen in mesor and amplitude for either soluble tissue factor or von Willebrand factor, or the acrophase (time of the peak) and periodic pattern for any prothrombotic markers. There were no significant differences in changes of periodic pattern and in day/night rhythm parameters of prothrombotic markers pre- to post-treatment between the CPAP and placebo condition. CONCLUSIONS: There may be altered day/night rhythm of some prothrombotic markers in OSA patients compared with controls. CPAP treatment for 3weeks did not affect day/night rhythm of prothrombotic markers in OSA patients differently from placebo-CPAP. PMID- 23036266 TI - Application of the Cambridge-Hopkins diagnostic questionnaire for investigating restless legs syndrome in patients with chronic renal failure. PMID- 23036267 TI - Mazindol in narcolepsy and idiopathic and symptomatic hypersomnia refractory to stimulants: a long-term chart review. AB - OBJECTIVE: Mazindol is a tricyclic, anorectic, non-amphetamine stimulant used in narcolepsy and obesity since 1970. This study aimed to evaluate the long-term benefit/risk ratio in drug-resistant hypersomniacs and cataplexy sufferers. METHODS: By retrospective analysis of the patients' files in the hospitals of Paris-Salpetriere (n=91), Montpellier (n=40) and Lyon (n=8), the benefit (Epworth Sleepiness Score (ESS), cataplexy frequency, authorization renewal) and tolerance (side-effects, vital signs, electrocardiogram and cardiac echography) of mazindol were assessed. RESULTS: The 139 patients (45% men) aged 36+/-15years (range: 9 74) suffered narcolepsy (n=94, 66% with cataplexy), idiopathic (n=37) and symptomatic hypersomnia (n=8) refractory to modafinil, methylphenidate and sodium oxybate. Under mazindol (3.4+/-1.3mg/day, 1-6mg) for an average of 30months, the ESS decreased from 17.7+/-3.5 to 12.8+/-5.1, with an average fall of -4.6+/-4.7 (p<0.0001) and the frequency of cataplexy fell from 4.6+/-3.1 to 2+/-2.8 episodes per week. The cataplexy was eliminated in 14.5% of patients, improved in 27.5%, and unchanged in 29% (missing data in 29%). The treatment was maintained long term in 83 (60%) patients, and stopped because of a lack of efficacy (22%) and/or secondary effects (9%). There was no pulmonary hypertension in the 45 patients who underwent a cardiac echography. The most common adverse effects were dry mouth (13%), palpitations (10%, including one with ventricular hyperexcitability), anorexia (6%), nervousness (6%) and headaches (6%). CONCLUSION: Mazindol has a long-term, favorable benefit/risk ratio in 60% of drug resistant hypersomniacs, including a clear benefit on cataplexy. PMID- 23036269 TI - Comparative in vitro antimicrobial susceptibility and synergistic activity of antimicrobial combinations against Helicobacter pylori isolates in Taiwan. AB - BACKGROUND: Antimicrobial resistance is a major determinant of Helicobacter pylori treatment failures. We conducted a population-based survey to monitor changing antimicrobial susceptibility of H. pylori isolates in Taiwan, with a focus on combinatorial effects of synergism and the influence of acidity. METHODS: H. pylori isolates from endoscopic specimens taken from patients enrolled at two medical centers were obtained between January 2008 and December 2009. Minimum inhibitory concentrations (MICs) were determined by agar dilution and Etest methods. Agar media of varying pH (pH 7.3, 6.0, or 5.0) were used to assess whether acidity influences the bactericidal effects of the agents tested. Time-kill assays were used to assess for synergism between different drug combinations. RESULTS: A total of 176 non-duplicate H. pylori isolates from endoscopic specimens were tested. The following MIC90 (mg/L) (susceptible) results were obtained at neutral pH 7.3: amoxicillin, 0.25 (100%); tetracycline, 0.5 (100%); metronidazole, 32 (67.6%); clarithromycin, 0.25 (90.3%); ciprofloxacin, 1 (92.0%); gemifloxacin, 0.5 (94.9%); levofloxacin, 1 (93.2%); and moxifloxacin, 1 (91.5%). A decrease in pH from 6.0 to 5.0 significantly decreased the antimicrobial activity of levofloxacin and moxifloxacin against H. pylori. For clarithromycin-susceptible isolates, levofloxacin combined with clarithromycin provided both synergistic and bactericidal effects. For clarithromycin-resistant isolates with amoxicillin hypersusceptibility (MIC <0.01 mg/L), levofloxacin with amoxicillin or minocycline had at best additive effect but no bactericidal effects. CONCLUSION: Amoxicillin, tetracycline, clarithromycin, and fluoroquinolones, but not metronidazole, showed good in vitro anti-H. pylori activity (>90% susceptible). Synergism was only observed for clarithromycin-susceptible isolates. Acidity adversely influenced the antimicrobial activity of levofloxacin against H. pylori. PMID- 23036268 TI - The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis. AB - INTRODUCTION: X-linked adrenoleukodystrophy (X-ALD) is a complex disorder with variable expressivity that affects the nervous, adrenocortical and male reproductive systems. Although ABCD1 mutations are known to provide the genetic basis for X-ALD, its pathogenesis is not fully elucidated. While elevated very long chain fatty acid (VLCFA) levels in blood and reduced VLCFA catabolic activity in cultured fibroblasts are biomarkers used to identify ABCD1 mutation carriers, the roles peroxisomal lipid metabolism play in disease etiology are unknown. METHODS: Primary skin fibroblasts from two male patients with the childhood cerebral form of the disease (CCALD) caused by ABCD1 frameshift or missense mutations and three healthy donors were transduced with retroviral vectors expressing the OCT4, SOX2, KLF4 and c-MYC factors. Candidate induced pluripotent stem cells (iPSCs) were subject to global gene expression, DNA methylation, DNA copy number variation, and genotyping analysis and tested for pluripotency through in vitro differentiation and teratoma formation. Saturated VLCFA (sVLCFA) and plasmalogen levels in primary fibroblasts and iPSCs from healthy donors as well as CCALD patients were determined through mass spectroscopy. RESULTS: Skin fibroblasts from CCALD patients and healthy donors were reprogrammed into validated iPSCs. Unlike fibroblasts, CCALD patient iPSCs show differentially expressed genes (DEGs) relevant to both peroxisome abundance and neuroinflammation. Also, in contrast to fibroblasts, iPSCs from patients showed no significant difference in sVLCFA levels relative to those from controls. In all cell types, the plasmalogen levels tested did not correlate with ABCD1 mutation status. CONCLUSION: Normal ABCD1 gene function is not required for reprogramming skin fibroblasts into iPSCs or maintaining pluripotency. Relative to DEGs found in fibroblasts, DEGs uncovered in comparisons of CCALD patient and control iPSCs are more consistent with major hypotheses regarding disease pathogenesis. These DEGs were independent of differences in sVLCFA levels, which did not vary according to ABCD1 mutation status. The highlighted genes provide new leads for pathogenic mechanisms that can be explored in animal models and human tissue specimens. We suggest that these iPSC resources will have applications that include assisting efforts to identify genetic and environmental modifiers and screening for therapeutic interventions tailored towards affected cell populations and patient genotypes. PMID- 23036270 TI - Impact of molecular diagnosis on treating Mendelian susceptibility to mycobacterial diseases. AB - BACKGROUND/OBJECTIVE: The IL-12-IFN-gamma axis is critical for immune defense against mycobacterial infections. Inherited mutations that affect normal activation of this self-amplifying cytokine reaction lead to increased chances of mycobacterial infections, known as Mendelian susceptibility to mycobacterial diseases (MSMD). Delayed diagnosis and difficulty in identifying pathogenic mycobacteria hinder proper treatment of patients, so the aim of this study was to facilitate the diagnosis of mycobacterial infections in MSMD patients using an oligonucleotide array method. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from three MSMD patients in the same family. A series of immunologic studies, including testing for cytokine secretion after leukocyte stimulation, cell-surface marker analysis, and cDNA sequencing, were then performed. An oligonucleotide array was used to rapidly identify pathogens. RESULTS: Cytokine secretion testing showed normal IFN-gamma secretion after IL-12 stimulation but low IL-12 secretion after IFN-gamma stimulation, which indicates a defect in the IFN-gamma receptor or its intracellular signaling. Cell-surface receptor analysis showed IFN-gamma receptor 1 overexpression, suggesting an autosomal dominant IFN-gamma receptor 1 deficiency. cDNA sequencing identified the IFNGR1 818del4 mutation in three members of the family with known MSMD, and an oligonucleotide array identified Mycobacterium tuberculosis complex and Mycobacterium abscessus as pathogens. CONCLUSIONS: Patients with suspected MSMD should undergo molecular diagnosis of the primary immunodeficiency. Oligonucleotide array methods may be a tool for rapid identification of pathogens and for guiding antimicrobial treatment in immunodeficient patients. PMID- 23036271 TI - The role of CD14 gene promoter polymorphism in tuberculosis susceptibility. AB - BACKGROUND: CD14 is expressed principally by cells of monocyte/macrophage lineage and plays a pivotal role in the innate immunity to intracellular infections. Recent research findings have revealed an association between the CD14 gene promoter polymorphism and several major infectious diseases. OBJECTIVE: The aim of the present study was to investigate the association between the CD14-159C/T polymorphism and tuberculosis in a Turkish population. METHODS: For this purpose, 88 consecutive patients with tuberculosis (63 pulmonary, 25 extrapulmonary) and 116 control subjects were enrolled into a prospective study. We determined CD14 159 genotypes by polymerase chain reaction - restriction fragment length polymorphism analysis and also measured serum concentrations of soluble CD14 (sCD14) by using a quantitative sandwich enzyme immunoassay technique. RESULTS: There was no significant difference in terms of genotype distribution between patients with tuberculosis (CC 18.2%, CT 48.9%, TT 33.0%) and controls (CC 12.9%, CT 50.9%, TT 36.2%) or between patients with pulmonary and extrapulmonary tuberculosis. Serum levels of sCD14 were significantly increased in patients with active tuberculosis compared to those with inactive tuberculosis and healthy controls (p<0.001). However, levels of sCD14 were not associated with any genotypes of CD14-159. CONCLUSION: The genotyping findings of the present study do not support a role for the CD14-159C/T polymorphism in the development of tuberculosis, at least in the geographical region of central Anatolia. Significantly elevated serum sCD14 levels in patients with active disease reflect the importance of the mononuclear phagocytic system activation in tuberculosis. PMID- 23036273 TI - Role of stereotaxically injected IgG from db/db mice in the phosphorylation of the microtubule-associated protein tau in hippocampus. AB - People with type 2 diabetes (T2DM) mellitus are high risk for dementia and Alzheimer's disease (AD) via several plausible pathways. However, the underlying mechanisms have been still unclear, and the relation of immune injury to the pathogenesis of T2DM-related AD is not yet completely understood. Our present study aimed to elucidate the possible role of immunoglobulin IgG in the immune process of AD associated with T2DM in db/db mice. Hippocampi of 20 db/db mice and 20 C57BL/6 mice were subjected to immunohistochemistry and immunofluorescence assays. The phosphorylation of tau, glycogen synthase kinase (GSK)-3beta and AKT activity was examined by Western blot analysis. IgG purified from the sera of IgG deposit-positive db/db mice was stereotaxically injected into the hippocampi of another 12 db/db mice and 12 C57BL/6 mice. The phosphorylation of tau, Abeta, GSK 3beta and AKT activity was analyzed. Compared with the C57BL/6 control, 13 of the 20 db/db mice exhibited high levels of IgG deposits in the hippocampus. Treatment with IgG triggered tau hyperphosphorylations and Abeta deposition, which are likely major factors in AD. Meanwhile, IgG inhibited AKT phosphorylation and promoted GSK-3beta activity. The IgG deposits observed in some db/db mice were possibly related to the impairment of T2DM-related AD development. Some autoimmune processes may be involved in AD in type 2 diabetes mellitus development at the level of the hippocampus. PMID- 23036272 TI - Genetically engineered mouse models and human osteosarcoma. AB - Osteosarcoma is the most common form of bone cancer. Pivotal insight into the genes involved in human osteosarcoma has been provided by the study of rare familial cancer predisposition syndromes. Three kindreds stand out as predisposing to the development of osteosarcoma: Li-Fraumeni syndrome, familial retinoblastoma and RecQ helicase disorders, which include Rothmund-Thomson Syndrome in particular. These disorders have highlighted the important roles of P53 and RB respectively, in the development of osteosarcoma. The association of OS with RECQL4 mutations is apparent but the relevance of this to OS is uncertain as mutations in RECQL4 are not found in sporadic OS. Application of the knowledge or mutations of P53 and RB in familial and sporadic OS has enabled the development of tractable, highly penetrant murine models of OS. These models share many of the cardinal features associated with human osteosarcoma including, importantly, a high incidence of spontaneous metastasis. The recent development of these models has been a significant advance for efforts to improve our understanding of the genetics of human OS and, more critically, to provide a high throughput genetically modifiable platform for preclinical evaluation of new therapeutics. PMID- 23036274 TI - Behavioral and ERP evidence of word and pseudoword superiority effects in 7- and 11-year-olds. AB - In groups of 7-year-olds and 11-year-olds, event-related potentials (ERPs) were recorded to briefly presented, masked letter strings that included real word (DARK/PARK), pronounceable pseudoword (DARL/PARL), unpronounceable nonword (RDKA/RPKA), and letter-in-xs (DXXX, PXXX) stimuli in a variant of the Reicher Wheeler paradigm. Behaviorally, participants decided which of two letters occurred at a given position in each string (here, forced-choice alternatives D and P). Both groups showed evidence of behavioral word (more accurate choices for letters in words than in baseline nonwords or letter-in-xs) and pseudoword (more accurate choices for letters in pseudowords than in baseline nonwords or letter in-xs) superiority effects. Electrophysiologically, 11-year-olds evidenced superiority effects on P150 and N400 peak amplitude, while 7-year-olds showed effects only on N400 amplitude. These findings suggest that the mechanisms underlying the observed behavioral superiority effects may be lexical in younger children but both sublexical and lexical in older children. These results are consistent with a lengthy developmental time course for automatic sublexical orthographic specialization, extending beyond the age of 11. PMID- 23036276 TI - Abnormal myelinogenesis in the central nervous system of the VF mutant rat with recoverable tremor. AB - The vacuole formation (VF) rat is an autosomal recessive myelin mutant characterized by generalized tremor and vacuole formation within the myelin of the central nervous system (CNS). The tremor is prominent between 4 and 8 weeks of age but thereafter gradually improves. The present study, aimed at producing a detailed description of how the principal lesions evolve, revealed that the VF rat has abnormal vacuoles in the periaxonal space in the spinal cord and that these vacuoles decreased concurrently with the loss of tremor. However, a degree of hypomyelination persisted throughout the CNS after the resolution of periaxonal vacuoles. In situ hybridization for proteolipid protein (PLP) demonstrated that the number of small, round PLP-positive oligodendrocytes increased in the spinal cord of VF rats between 10 and 20 weeks of age, suggesting a disruption of oligodendrocytes' maturation. Activated astrocytes and microglia were also found in the VF rats from 4 weeks of age. Our results indicate that the causative genetic defect of the VF rat is likely to be involved in the formation and maintenance of the CNS myelin. PMID- 23036275 TI - The effect of long-term ovariectomy on midbrain stress systems in free ranging macaques. AB - Communication between the serotonin system and the CRF system plays a pivotal role in the mediation of stress and stress reactivity. CRF appears to be inhibitory of serotonin neurotransmission through the CRF receptor type 1 (CRF R1). Serotonin neurons also detect the urocortins, which are thought to be anxiolytic. Components of the CRF system in the serotonergic dorsal raphe region were examined in macaques that were ovary-intact or ovariectomized for 3 years living in a relatively natural environment. Female Japanese macaques (Macaca fuscata) were ovariectomized or tubal-ligated (n=5/group) and returned to their natal troop for 3 years. Quantitation of (1) CRF innervation of the serotonergic dorsal raphe, (2) CRF-Receptor type 1 (CRF-R1) in the dorsal raphe, (3) Urocortin 1 (UCN1) cells near the Edinger-Westfal nucleus and (4) UCN1 axons, was obtained with immunocytochemical staining and image analysis. There was no statistical difference in CRF axonal staining in the dorsal raphe, or in UCN1 axonal staining near the dorsal raphe. However, the average number of detectable UCN1 postive cells was significantly lower in the Ovx group than in the Intact group (p=0.003). Average CRF-R1 positive pixel number and positive cell number were significantly higher in the Ovx group than in the Intact group (p=0.005 and 0.02, respectivly). The higher expression of CRF-R1 and lower expression of UCN1 in the Ovx group indicates they may be more vulnerable to stress. The greater expression of CRF-R1 could cause a greater inhibition of serotonin upon a stress-induced increase in CRF as well. PMID- 23036277 TI - A randomised controlled trial to evaluate both the role and the optimal fractionation of radiotherapy in the conservative management of early breast cancer. AB - AIMS: Postoperative radiotherapy is routinely used in early breast cancer employing either 50 Gy in 25 daily fractions (long course) or 40 Gy in 15 daily fractions (short course). The role of radiotherapy and shorter fractionation regimens require validation. MATERIALS AND METHODS: Patients with clinical stage I and II disease were randomised to receive immediate radiotherapy or delayed salvage treatment (no radiotherapy). Patients receiving radiotherapy were further randomised between long (50 Gy in 25 daily fractions) or short (40 Gy in 15 daily fractions) regimens. The primary outcome measure was time to first locoregional relapse. Reported results are at a median follow-up of 16.9 years (interquartile range 15.4-18.8). RESULTS: In total, 707 women were recruited between 1985 and 1992: median age 59 years (range 28-80), 68% postmenopausal, median tumour size 2.0 cm (range 0.12-8.0); 271 patients have relapsed: 110 radiotherapy, 161 no radiotherapy. The site of first relapse was locoregional158 (64%) and distant 87 (36%). There was an estimated 24% reduction in the risk of any competing event (local relapse, distant relapse or death) with radiotherapy (hazard ratio = 0.76; 95% confidence interval 0.65, 0.88). The benefit of radiotherapy treatment for all competing event types was statistically significant (X(Wald)(2) = 36.04, P < 0.001). Immediate radiotherapy reduced the risk of locoregional relapse by 62% (hazard ratio = 0.38; 95% confidence interval 0.27, 0.53), consistent across prognostic subgroups. No differences were seen between either radiotherapy fractionation schedules. CONCLUSIONS: This study confirmed better locoregional control for patients with early breast cancer receiving radiotherapy. A radiotherapy schedule of 40 Gy in 15 daily fractions is an efficient and effective regimen that is at least as good as the international conventional regimen of 50 Gy in 25 daily fractions. PMID- 23036278 TI - Silver nanoparticle-alginate composite beads for point-of-use drinking water disinfection. AB - Silver nanoparticles (AgNPs)-alginate composite beads were synthesized using three different approaches as filler materials of packed columns for simultaneous filtration-disinfection as an alternative portable water treatment process. The prepared composite beads were packed into a column through which Escherichia coli containing water was filtered to evaluate the disinfection efficacy. Excellent disinfection performance (no detectable viable colony) was achieved with a hydraulic retention time (HRT) as short as 1 min (the shortest tested) with the SGR (Simultaneous-Gelation-Reduction) and AR (Adsorption-Reduction) beads that were prepared using in situ reduction of Ag(+). Comparatively, the SGR beads released significantly less Ag(+)/AgNPs than the AR beads did within the same HRT. From the results of this study it was identified that SGR may be the best choice among all three different synthesis approaches in that the SGR beads can achieve satisfactory bactericidal performance with a relatively low material consumption rate. PMID- 23036279 TI - Risk of bleeding on triple antithrombotic therapy after percutaneous coronary intervention/stenting: a systematic review and meta-analysis. AB - BACKGROUND: There are no reported randomized controlled trials of triple antithrombotic therapy (TT; aspirin plus a thienopyridine plus vitamin K antagonist) vs dual antiplatelet therapy (DAPT; aspirin plus a thienopyridine) among patients undergoing percutaneous coronary intervention with stenting (PCI S). A systematic review and meta-analysis was undertaken to assess the risk of bleeding among patients receiving TT after PCI-S. METHODS: Electronic databases were searched for studies reporting bleeding among patients receiving TT after PCI-S. Of the 4108 articles screened, 18 met study inclusion criteria and underwent detailed data extraction: of these, 6 reported in-hospital outcomes, 14 reported 30-day outcomes, and 9 reported 6-month outcomes. At each time point, pooled estimates of bleeding with TT were ascertained and where possible summary odds ratios (ORs) for comparative risks vs DAPT were calculated. RESULTS: The pooled estimate of major bleeding rate with TT post PCI-S was 2.38% by 30 days postprocedure (95% confidence interval [CI], 0.98-3.77%) and 4.55% by 6 months postdischarge (95% CI, 0.56-8.53%). At 30 days and 6 months the rates of major bleeding with TT were significantly higher than those observed with DAPT: OR, 2.38 at 30 days (95% CI, 1.05-5.38) and OR, 2.87 at 6 months (95% CI, 1.47-5.62). CONCLUSIONS: This systematic review and meta-analysis of reports of triple therapy with a vitamin K antagonist, aspirin, and clopidogrel after PCI-S provides precise and valid bleeding risk data. Based on existing observational studies the rates of major and any bleeding associated with TT are clinically important and significantly greater than those reported with DAPT. PMID- 23036280 TI - Personalized cardiovascular medicine: status in 2012. AB - Personalized medicine is the tailoring of the diagnosis, prevention, and treatment to the characteristics of each individual patient. In this review, we provide a status report on genetic variants that influence therapy with antiplatelet agents, warfarin, and statins. Resistance to clopidogrel, an antiplatelet therapy, has been shown to be present in 25% to 30% of Caucasians and an even higher percentage in Asians. Part of this resistance is because of the CYP2C19*2 allele. Administering clopidogrel on the basis of previous genetic testing remains controversial. A recent breakthrough in point-of-care genetic testing for clopidogrel might be significant, not only for genetic testing for clopidogrel, but for the whole of personalized medicine. Genetic testing for aspirin resistance is not yet recommended because of incomplete genetic data. Studies to determine the value of genetic testing before the administration of warfarin are ongoing. Testing for SLCO1B1 allele for individuals with muscle cramps who are taking statins could be very helpful but is not yet recommended as routine. Pharmacogenetics has the potential to customize therapy and move away from the current model of 1 drug fits all. PMID- 23036281 TI - ERP index of the morphological family size effect during word recognition. AB - The purpose of this study was to examine whether the N400 is affected by the semantic richness of associated neighboring word members or by the density of the orthographic syllable neighborhood. Another purpose of this study was to investigate the source of the different LPC in respect to the semantic richness. To do so, the density of the syllable neighborhood and the size of the morphological family of a word were orthogonally manipulated. ERPs from 24 participants were collected during a go/no-go semantic categorization task. The results showed that the N400 effect was mainly influenced by the density of the syllable neighborhood rather than by the morphological family size. The results also showed that words with a larger morphological family size generate significantly larger LPC than words with a smaller morphological family size. The present study did not support the assumption that the main source of the N400 effect is the semantic richness of the associated neighbors. The present results suggest that the N400 is more sensitive to the density of the syllable neighborhood and LPC is sensitive to the density of the semantic neighborhood reflected by the morphological family size. PMID- 23036282 TI - The neural basis of autobiographical memory deficits in transient epileptic amnesia. AB - Transient epileptic amnesia (TEA) is a recently recognized form of temporal lobe epilepsy which is often associated with persistent interictal impairment of autobiographical memory. We used fMRI to investigate the neural basis of this deficit. Eleven patients with TEA, who had no significant deficits on standard tests of anterograde memory, and 17 age and IQ matched healthy controls retrieved memories from across the lifespan. Both groups engaged the autobiographical memory network, but activation in patients was less extensive than in controls. Direct comparison revealed hypoactivation of regions in the right hemisphere. Specifically, patients showed reduced activation of the posterior parahippocampal gyrus (pPHG), especially for mid-life and recent memories, with decreased engagement of the right temporoparietal junction and the cerebellum. In addition, we found reduced effective connectivity in patients between the right pPHG and the right middle temporal gyrus. Our results are consistent with other evidence that TEA is a syndrome of medial temporal lobe epilepsy and indicate that it affects the function and connectivity of regions within the autobiographical memory network. PMID- 23036283 TI - Analgesic effects mediated by neuronal nicotinic acetylcholine receptor agonists: correlation with desensitization of alpha4beta2* receptors. AB - Nicotinic alpha4beta2* agonists are known to be effective in a variety of preclinical pain models, but the underlying mechanisms of analgesic action are not well-understood. In the present study, we characterized activation and desensitization properties for a set of seventeen novel alpha4beta2*-selective agonists that display druggable physical and pharmacokinetic attributes, and correlated the in vitro pharmacology results to efficacies observed in a mouse formalin model of analgesia. ABT-894 and Sazetidine-A, two compounds known to be effective in the formalin assay, were included for comparison. The set of compounds displayed a range of activities at human (alpha4beta2)(2)beta2 (HS alpha4beta2), (alpha4beta2)(2)alpha5 (alpha4beta2alpha5) and (alpha4beta2)(2)alpha4 (LS-alpha4beta2) receptors. We report the novel finding that desensitization of alpha4beta2* receptors may drive part of the antinociceptive outcome. Our molecular modeling approaches revealed that when receptor desensitization rather than activation activitiesat alpha4beta2* receptors are considered, there is a better correlation between analgesia scores and combined in vitro properties. Our results suggest that although all three alpha4beta2 subtypes assessed are involved, it is desensitization of alpha4beta2alpha5 receptors that plays a more prominent role in the antinociceptive action of nicotinic compounds. For modulation of Phase I responses, correlations are significantly improved from an r(2) value of 0.53 to 0.67 and 0.66 when HS- and LS-alpha4beta2 DC(50) values are considered, respectively. More profoundly, considering the DC(50) at alpha4beta2alpha5 takes the r(2) from 0.53 to 0.70. For Phase II analgesia scores, adding HS- or LS alpha4beta2 desensitization potencies did not improve the correlations significantly. Considering the alpha4beta2alpha5 DC(50) value significantly increased the r(2) from 0.70 to 0.79 for Phase II, and strongly suggested a more prominent role for alpha4beta2alpha5 nAChRs in the modulation of pain in the formalin assay. The present studies demonstrate that compounds which are more potent at desensitization of alpha4beta2* receptors display better analgesia scores in the formalin test. Consideration of desensitization propertiesat alpha4beta2* receptors, especially at alpha4beta2alpha5, in multiple linear regression analyses significantly improves correlations with efficacies of analgesia. Thus, alpha4beta2* nicotinic acetylcholine receptor desensitization may contribute to efficacy in the mediation of pain, and represent a mechanism for analgesic effects mediated by nicotinic agonists. PMID- 23036284 TI - An analysis of consumer demand for fruits in Sri Lanka. 1981-2010. AB - Micronutrient deficiency has become a serious health concern in many countries and Sri Lanka is no exception. Inclusion of vegetables and fruits, which are rich in micronutrients, in the diet is considered as one of the most cost effective measures to alleviate such deficiencies. The purpose of this paper is to analyze consumer demand for fruits in Sri Lanka. The specific objectives are to: (i) describe the patterns of fruit consumption across various households groups (ii) document the changes that have taken place in the local fruit supply for meeting the changes in demand, and (iii) to estimate price and income effects of changes in fruit consumption during 1981-2010. The study was conducted using secondary data which were extracted from government publications. The analysis shows that banana, papaw, mangoes and pineapple are the major fruits consumed and the consumption levels of such fruits have been rising over the years. The urban households and the households in high-income deciles are found to be allocating a relatively higher proportion of their food expenditure on fruits. The country is self sufficient in most of the fruits and only a small portion is traded. The results of econometric estimations reveal large income effects and relatively small price effects. A larger role for income based interventions as opposed to price based interventions to improve fruit consumption in Sri Lanka is evident from the results. PMID- 23036286 TI - Environmental determinants of Ixodes ricinus ticks and the incidence of Borrelia burgdorferi sensu lato, the agent of Lyme borreliosis, in Scotland. AB - Lyme borreliosis (LB) is the most common arthropod-borne disease of humans in the Northern hemisphere. In Europe, the causative agent, Borrelia burgdorferi sensu lato complex, is principally vectored by Ixodes ricinus ticks. The aim of this study was to identify environmental factors influencing questing I. ricinus nymph abundance and B. burgdorferi s.l. infection in questing nymphs using a large scale survey across Scotland. Ticks, host dung and vegetation were surveyed at 25 woodland sites, and climatic variables from a Geographical Information System (GIS) were extracted for each site. A total of 2397 10 m2 transect surveys were conducted and 13 250 I. ricinus nymphs counted. Questing nymphs were assayed for B. burgdorferi s.l. and the average infection prevalence was 5.6% (range 0.8 13.9%). More questing nymphs and higher incidence of B. burgdorferi s.l. infection were found in areas with higher deer abundance and in mixed/deciduous compared to coniferous forests, as well as weaker correlations with season, altitude, rainfall and ground vegetation. No correlation was found between nymph abundance and infection prevalence within the ranges encountered. An understanding of the environmental conditions associated with tick abundance and pathogen prevalence may be used to reduce risk of exposure and to predict future pathogen prevalence and distributions under environmental changes. PMID- 23036285 TI - Contribution of evening macronutrient intake to total caloric intake and body mass index. AB - The goal of this study was to evaluate the relationship between sleep timing and macronutrient intake as an approach towards better understanding of how sleep and eating affect weight regulation. Fifty-two volunteers (25 women) completed 7 days of wrist actigraphy and food logs. "Average sleepers" (56%) were defined as having a midpoint of sleep <5:30 am and "late sleepers" (44%) were defined as having a midpoint of sleep >= 5:30 am. Data were analyzed using t-tests, correlations and regression. Late sleepers consumed a greater amount of protein fat and carbohydrates in the evening (defined as after 8:00 pm) but less fat in the 4 h before sleep. Total protein, protein, carbohydrate, and fat consumed after 8:00 pm, protein consumed within 4h of sleep as well as the percentage of fat consumed after 8:00 were associated with higher BMI. The amount of protein and carbohydrates consumed within 4h of sleep and the amount and percentage of carbohydrate and fat consumed after 8:00 pm were associated with greater total calories. In multivariate analyses controlling for age, gender, sleep timing and duration, protein consumed 4 h before sleep was associated with BMI; carbohydrates consumed after 8 pm, protein and carbohydrates consumed 4h before sleep were associated with higher total calories. Results indicate that evening intake of macronutrients and intake before sleep are not synonymous, particularly among late sleepers. Eating in the evening or before sleep may predispose individuals to weight gain through higher total calories. PMID- 23036287 TI - Applications of biomaterials in plastic surgery. AB - The expansion of the application of biomaterials in plastic surgery has led to the increased availability of commercial products in recent years. This overview discusses soft tissue fillers, bioengineered skins, acellular dermal matrices, biomaterials for craniofacial surgery, and peripheral nerve repair. We summarize indications, properties, uses, types, advantages and disadvantages of some of the currently available products from each category. Finally, the current state of development in drug delivery system is also briefly summarized. PMID- 23036288 TI - Surgical treatment of congenital lymphedema. AB - Lymphedema is a pathologic condition that results from a disturbance of the lymphatic system, with localized fluid retention and tissue swelling. Primary lymphedema is a congenital disorder, caused by a malformation of lymph vessels or nodes. Major progress has been achieved in the radiologic diagnosis of patients affected by lymphedema. The ideal treatment of the affected limb should restore function and cosmetic appearance. Surgical treatment is an alternative method of controlling chronic lymphedema. Free lymph nodes autologous transplantation is a new approach for lymphatic reconstruction in hypoplastic forms of primary lymphedema. The transferred nodes pump extracellular liquid out of the affected limb and contain germinative cells that improve immune function. PMID- 23036289 TI - Microlymphatic surgery for the treatment of iatrogenic lymphedema. AB - Lymphedema is a chronic and progressive condition that occurs after cancer treatment. Autologous lymph node transplant, or microsurgical vascularized lymph node transfer (ALNT), is a surgical treatment option that brings vascularized vascular endothelial growth factor-C-producing tissue into the operated field to promote lymphangiogenesis and bridge the distal obstructed lymphatic system with the proximal lymphatic system. Operative techniques for upper- and lower extremity ALNT are described with 3 donor lymph node flaps (inguinal, thoracic, cervical). Surgical technique is described for the combination of ALNT with abdominal flaps and nonabdominal flaps. Imaging showing restoration of lymphatic drainage after ALNT is shown. PMID- 23036290 TI - Tissue restructuring by energy-based surgical tools. AB - Energy-based noninvasive surgical tools can be used for ablative bio-stimulation (eg, collagen production) or tissue restructuring functions (eg, tightening or lifting) and are the subject of this review. The authors present the various methods and tools for noninvasive cosmetic surgery (ultrasound, radiofrequency, cryolipolysis, and lasers) and present the clinical outcomes of each. They summarize techniques and methods and their indications, physical parameters and tissue target, and consistency. PMID- 23036291 TI - Early clinical experience with the 1440-nm wavelength internal pulsed laser in facial rejuvenation: two-year follow-up. AB - This article reports on the early experience with the 1440-nm wavelength, using a specially designed side-firing fiber, in a four-step approach, primarily to the lower third of the midface and neck. The author presents the clinical protocol, procedure steps, outcomes, and adverse events of use of the laser. Outcomes are described at 3 months, 6 months, and 18 months. PMID- 23036292 TI - Robot-assisted plastic surgery. AB - Robot assisted surgery is a technology that is being used frequently among multiple surgical specialties; robot assisted microsurgery (RAMS) and transoral robotic surgery (TORS) are applications relevant to plastic surgery that are being studied and clinically utilized. Advantages of RAMS include elimination of tremor and the ability to provide enhanced exposure. TORS facilitates oropharyngeal tumor excision and reconstruction without mandibular splitting. This article investigates current and potential uses of the surgical robot in plastic surgery as well as obstacles to its application. PMID- 23036293 TI - Impact of reconstructive transplantation on the future of plastic and reconstructive surgery. AB - This article summarizes the current knowledge on the new developing field of reconstructive transplantation. A brief outline of vascularized composite allografts (VCA) such as human hand, face, larynx, and abdominal wall transplants is provided. The clinical applications and indications for these new reconstructive transplantation procedures are outlined. The advantages, disadvantages, and complications and concerns surrounding clinical VCA are discussed. Finally, the impact of reconstructive transplantation on the future of plastic and reconstructive surgery is presented. PMID- 23036294 TI - Surgical advances in burn and reconstructive plastic surgery: new and emerging technologies. AB - This article introduces and discusses several biophysical and cellular modalities that are being tested or used in clinical practice to optimize wound bed preparation, effect soft tissue coverage, and improve the quality of the inevitable and resultant scar. Among these promising technologies is the use of electrical stimulation to mimic a physiologic current of injury in an effort to accelerate re-epithelialization and the wound healing process. Over the past several years an on-site individualized regenerative medicine kit has become commercially available (ReCell, Avita Medical), utilizing well-established laboratory techniques of cell separation without the need for cell cultivation in an effort to expand and promote wound coverage and end result. PMID- 23036295 TI - New concepts and technologies in reconstructive hand surgery. AB - Complex traumatic injuries and degenerative conditions of the hand continue to lead to significant impairment and disability. From technical innovations to regenerative concepts, this article presents the latest advances in the dynamic field of hand surgery in which worldwide efforts are made around the globe to repair, regenerate, or restore each composite tissue forming the hand. The systematic method by which finger replantation is performed, from bony fixation to skin closure, provides a platform for discussion of the newest innovations available to reconstructive hand surgeons. PMID- 23036296 TI - Adipocyte-derived stem and regenerative cells in facial rejuvenation. AB - The identification of regenerative cells in adult human fat has invigorated the field of facial fat grafting. This article reviews traditional and cell-enriched fat grafting methods and the use of fat to create or refine aesthetic results. The rationale and potential applications of adipocyte-derived stem and regenerative cells in facial surgery are also described. The reader is presented with surgical techniques for harvesting and delivering fat grafts to optimize engraftment. Mesotherapy and related applications currently under investigation are also discussed. PMID- 23036297 TI - Impact of advances in breast cancer management on reconstructive and aesthetic breast surgery. AB - An overview of advances and controversies in the management of breast cancer and their impact on plastic breast surgery is presented, including prophylactic mastectomy for women at high risk of breast cancer, size and location of the primary tumor and feasibility of breast-conserving surgery and oncoplastic approach, the management of the axilla, postmastectomy radiation and chemotherapy, emerging breast reconstructive techniques and cancer risk, and oncological follow-up and imaging of the reconstructed breast. This material should help plastic surgeons to understand multiple specialty considerations regarding breast cancer and provide comprehensive surgical care and interventions in aesthetic and reconstructive settings. PMID- 23036298 TI - Advances in autologous breast reconstruction with pedicled perforator flaps. AB - This article presents an overview of pedicled perforator flaps available in breast surgery. The indications, classification, surgical anatomy, and techniques for safe flap elevation are described. Clinical outcomes and complications are discussed, and illustrative case examples are presented. PMID- 23036299 TI - Microsurgical advances in extremity salvage. AB - The main goal of reconstructive microsurgery must be an optimal functional and esthetic reconstruction meeting the individual trauma site requirements with minimal donor site morbidity. The authors discuss new microsurgical options for extremity salvage: indications for reconstruction versus amputation, timing of free tissue transfer, reconstruction of soft tissue and bone, and functional muscle transfer. They discuss indications and contraindications for these procedures, along with emphasizing the important points of each. PMID- 23036300 TI - The latissimus dorsi detrusor myoplasty for functional treatment of bladder acontractility. AB - Patients with bladder acontractility caused by lower motor neuron lesion are generally dependent on lifelong clean intermittent catheterization with all of its inherent risks. The functional neurovascular transfer of the latissimus dorsi muscle to the pelvis allows the restoration of voluntary voiding. This article describes the operative technique, indications, preoperative considerations, and postoperative care. The literature is reviewed and the latissimus detrusor myoplasty is compared with other functional muscle transfers to restore voluntary micturition. PMID- 23036301 TI - Competency versus performance in plastic surgery: navigating through new technologies and medical devices. AB - The purpose of this article is to examine how plastic surgeons learn to use novel technology in their practices. In addition, a critical evaluation of current teaching methods as they relate to surgeon competence in these new technologies is discussed. PMID- 23036302 TI - Are we witnessing the emergence of a superspecialty? PMID- 23036303 TI - Blood levels of copeptin on admission predict outcomes in out-of-hospital cardiac arrest survivors treated with therapeutic hypothermia. AB - INTRODUCTION: Prognostic stratification of cardiac arrest survivors is essential for the selection of the most appropriate therapeutic strategy. However, accurate early outcome predictions for this patient population remain challenging. At present, there is a lack of data examining the prognostic value of C-terminal provasopressin (copeptin) in cardiac arrest survivors. METHODS: A group of 40 out of-hospital cardiac arrest survivors who were treated with endovascular hypothermia was analyzed. Copeptin levels were measured in blood samples taken at admission using a commercially available immunoassay. Neurological outcome was assessed at 30 days post admission according to the Cerebral Performance Category (CPC): CPC 1, no neurological deficit; CPC 2, mild to moderate dysfunction; CPC 3, severe dysfunction; CPC 4, coma; and CPC 5, death. RESULTS: Copeptin levels were significantly lower in patients with CPC 1 compared with CPC 2 or CPC 3 to CPC 5 (74.3 +/- 14.4 pmol/l, 219.8 +/- 33.9 pmol/l and 302.7 +/- 52.1 pmol/l, respectively; P < 0.0001). Using an optimal cutoff value <= 217.9 pmol/l calculated from the receiver operating characteristic curve (area under curve = 0.801, 95% confidence interval = 0.644 to 0.910; P = 0.0001), the sensitivity of predicting survival with good neurological outcome was 78.6% and the specificity was 75.0%. Multiple logistic regression analysis revealed that a copeptin level > 217.9 pmol/l was an independent predictor of severe neurological dysfunction or death, with an adjusted odds ratio of 27.00 (95% confidence interval = 2.27 to 321.68; P = 0.009). CONCLUSION: The present study found that copeptin levels have a significant prognostic value at the time of hospital admission, and are a promising diagnostic tool for predicting outcomes in out-of-hospital cardiac arrest survivors. PMID- 23036304 TI - Potential of monitoring nuclides with the epiphyte Tillandsia usneoides: Uptake and localization of 133Cs. AB - Epiphytic Tillandsia plants are efficient air pollution biomonitors and traditionally used to monitor atmospheric heavy metal pollution, but rarely nuclides monitoring. Here we evaluated the potential of Tillandsia usneoides for monitoring (133)Cs and investigated if Cs was trapped by the plant external surface structures. The results showed that T. usneoides was able to survive relatively high Cs stress. With the increase of Cs solution concentration, the total of Cs in plants increased significantly, which suggests that the plants could accumulate Cs quickly and effectively. Therefore, T. usneoides has considerable potential for monitoring Cs polluted environments. In addition, scanning electron microscopy (SEM) and energy dispersive spectrometer (EDS) analysis showed that Cs was detected in each type of cells in foliar trichomes, and the ratio of Cs in the internal disc cell was higher than that in ring cell and wing cell, which indicates that the mechanism of adsorption Cs in Tillandsia has an active component. PMID- 23036305 TI - Effects of salinity on the toxicity of ionic silver and Ag-PVP nanoparticles to Tisbe battagliai and Ceramium tenuicorne. AB - The toxic effects of polyvinylpyrrolidone (PVP) coated silver nanoparticles (Ag NP(PVP)) and ionic Ag, to Tisbe battagliai (Tb) and Ceramium tenuicorne (Ct) were investigated and the usefulness of standardised marine guidelines for ENP risk assessment were assessed. The toxicity of Ag-NP(PVP) [CtEC(50)=26.6MUg/L, TbEC(50)=7.9MUg/L] and Ag(+) [CtEC(50)=2312.2MUg/L, Tb EC(50)=90.9MUg/L] to both test species differed, with the silver ENPs being more toxic. In contrast to Ag(+) the toxicity of Ag-NP(PVP) increased significantly with increasing salinity, however, after thorough characterisation it was not possible to correlate the behaviour of the particles with an increase in toxicity and salinity. The results suggest that the observed toxicity is being elicited by the free ionic silver complexing in solution and also from an unknown potential particle related effect. PMID- 23036306 TI - Experimental model of tooth movement in mice: a standardized protocol for studying bone remodeling under compression and tensile strains. AB - During orthodontic tooth movement (OTM), alveolar bone is resorbed by osteoclasts in compression sites (CS) and is deposited by osteoblasts in tension sites (TS). The aim of this study was to develop a standardized OTM protocol in mice and to investigate the expression of bone resorption and deposition markers in CS and TS. An orthodontic appliance was placed in C57BL6/J mice. To define the ideal orthodontic force, the molars of the mice were subjected to forces of 0.1N, 0.25 N, 0.35 N and 0.5 N. The expression of mediators that are involved in bone remodeling at CS and TS was analyzed using a Real-Time PCR. The data revealed that a force of 0.35 N promoted optimal OTM and osteoclast recruitment without root resorption. The levels of TNF-alpha, RANKL, MMP13 and OPG were all altered in CS and TS. Whereas TNF-alpha and Cathepsin K exhibited elevated levels in CS, RUNX2 and OCN levels were higher in TS. Our results suggest that 0.35 N is the ideal force for OTM in mice and has no side effects. Moreover, the expression of bone remodeling markers differed between the compression and the tension areas, potentially explaining the distinct cellular migration and differentiation patterns in each of these sites. PMID- 23036307 TI - A lattice-based approach to model distraction osteogenesis. AB - Distraction osteogenesis is a well-known technique in which new bone tissue is created when a distraction displacement is applied through an external frame. This orthopedic process is nowadays focus of intense research, both experimentally and numerically, as there are still many aspects not well understood. The aim of this study is to simulate bone distraction by means of a combined discrete-continuum approach based on a lattice formulation. Existing computational models simulate the main processes of distraction osteogenesis from a continuum perspective, considering as state variables the population of cells and tissue distributions. Results of the continuum and lattice-based approaches are similar with respect to the global evolution of the different cells but rather different in terms of the type of ossification process. Differences in the size of the soft interzone in the gap have also been found. In addition, the discrete-continuum formulation allows including a more realistic approach of the migration/proliferation process with a discrete random walk model instead of the Fick's law used in continuum approaches. Also, blood vessel growth can be simulated explicitly in this model with the inclusion of the endothelial cells. Further study is needed to provide additional insights to understand coupled phenomena at different scales in the cell-tissue interactions. However this work provides a first preliminary step for improving multiscale models. PMID- 23036308 TI - Systematic nonlinear relations between joint mechanics and the neural reflex response with changes in stretch amplitude at the wrist. AB - The effects on both joint mechanics and the neural stretch reflex of changes in amplitude of stretch ranging from within the region of short range stiffness up to 3% of resting muscle length were quantified. The level of activation of the primary agonist was held constant but there was a small but systematic increase in activation of the other flexor and extensor muscles as stretch amplitude increased. The patterns of change with stretch amplitude in both the joint mechanics and stretch reflex properties were non-linear but systematic and were well described by power relationships that accounted for high proportions of variance. With an increase in stretch amplitude, joint stiffness, viscosity, damping ratio and natural frequency decreased. In parallel with these mechanical changes, the neural reflex coherence increased and the phase advance and gain decreased. Multiple regression analyses partitioned the variation in the joint mechanics that was attributable to the various factors and it was found that the variation of the mechanics was almost entirely attributable to the variation of the neural reflex gain, which accounted for 93% of the changes in the stiffness, viscosity and natural frequency and 82% of the changes in the damping ratio. It is concluded that joint mechanics are significantly affected by changes in the neural reflex gain. PMID- 23036309 TI - A novel heterozygous deletion-insertion mutation in the desmin gene causes complete atrioventricular block and mild myopathy. AB - Defects in the desmin gene have been identified in patients with cardiac and skeletal myopathy characterized by sarcoplasmic accumulation of desmin-positive deposits and electron dense granulofilamentous aggregates. We describe a desminopathy family with unusual clinical features of complete atrioventricular block and mild myopathy. The atrioventricular block can be found in each of the affected members sparing of the detectable cardiac structural abnormalities through echocardiogram. A novel heterozygous deletion-insertion mutation (c.1045 1063 del/G ins), deleting 7 amino acid (Met349-Arg355) and inserting 1 amino acid (Gly349) in a highly conserved alpha-helical 2B domain of desmin, has been identified. The results of this study indicate that atrioventricular conduction block without cardiac structural abnormalities may be an intrinsic feature of disease associated with specific desmin mutation. Furthermore atrioventricular conduction block may be an exclusive clinical manifestation and a major cause of disability and death in some patients with desmiopathy. PMID- 23036310 TI - Cavernous angiomas in chronic epilepsy associated with focal cortical dysplasia. AB - Both cavernous angiomas and focal cortical dysplasia (FCD) are well recognized causes of pharmacoresistant epilepsy. Anecdotal cases of FCD adjacent to cavernous angiomas have been documented in the literature. This study systematically reviews a series of cavernous angiomas in epilepsy patients, looking for evidence of coexistent FCD. 146 patients were diagnosed with cavernous angiomas on resection specimens from January 1989 to May 2011; 18 cases also had epilepsy and had ample tissue excised to assess for FCD. FCD was classified according to criteria outlined by Palmini et al. [12]. Patients included 10 females (55.6%); the mean age of study patients was 38.5 years (range 21 - 51 years) at the time of resection. All patients had a history of epilepsy (median 11 years) prior to surgery. 17 cavernomas were located in the temporal lobe and 1 in the occipital lobe. Adjacent FCD was identified in 13 out of the 18 cases (72.2%): Type Ia (n = 8; 61.5%), Type Ib (n = 4; 30.8%), and Type IIa (n = 1; 7.7%). After resection, a majority of the patients experienced resolution of their epilepsy (n = 14; 77.8%). Of the 4 patients that did not experience seizure resolution, 2 had evidence of adjacent FCD (Type Ia = 1, Type Ib = 1) and 2 did not. FCD is frequently present in association with cavernous angiomas in patients with chronic epilepsy. The type of FCD seen adjacent to these lesions varies, but most are Palmini et al. Type I. Resection of the cavernous angiomas and adjacent FCD often results in a resolution of the epilepsy. PMID- 23036311 TI - Acetylcholinesterases of blood-feeding flies and ticks. AB - Acetylcholinesterase (AChE) is the biochemical target of organophosphate (OP) and carbamate pesticides for invertebrates, vertebrate nerve agents, and AChE inhibitors used to reduce effects of Alzheimer's disease. Organophosphate pesticides (OPs) are widely used to control blood-feeding arthropods, including biting flies and ticks. However, resistance to OPs in pests affecting animal and human health has compromised control efficacy. OP resistance often results from mutations producing an OP-insensitive AChE. Our studies have demonstrated production of OP-insensitive AChEs in biting flies and ticks. Complementary DNA (cDNA) sequences encoding AChEs were obtained for the horn fly, stable fly, sand fly, and the southern cattle tick. The availability of cDNA sequences enables the identification of mutations, expression and characterization of recombinant proteins, gene silencing for functional studies, as well as in vitro screening of novel inhibitors. The southern cattle tick expresses at least three different genes encoding AChE in their synganglion, i.e. brain. Gene amplification for each of the three known cattle tick AChE genes and expression of multiple alleles for each gene may reduce fitness cost associated with OP-resistance. AChE hydrolyzes the neurotransmitter, acetylcholine, but may have additional roles in physiology and development. The three cattle tick AChEs possess significantly different biochemical properties, and are expressed in neural and non-neural tissues, which suggest separation of structure and function. The remarkable complexity of AChEs in ticks suggested by combining genomic data from Ixodes scapularis with our genetic and biochemical data from Rhipicephalus microplus is suggestive of previously unknown gene duplication and diversification. Comparative studies between invertebrate and vertebrate AChEs could enhance our understanding of structure-activity relationships. Research with ticks as a model system offers the opportunity to elucidate structure-activity relationships for AChE that are important for advances in targeted pest control, as well as potential applications for medicine and biosecurity. PMID- 23036312 TI - Finding a wider horizon: experiences of being a next-of-kin of a person suffering from colorectal cancer as told after having participated in a psychoeducational program. AB - AIM: The aim of this study was twofold: first, to describe the experience of being the next-of-kin of a person suffering from colorectal cancer (CRC), and second, to describe how a psychoeducational program (PEP) might contribute to the next-of-kin's life experience. Psychosocial interventions for next-of-kin to cancer patients are effective in improving quality of life issues, although there are conflicting results in previous studies. Most studies have evaluated the effects of PEP for mixed cancer groups but there is little knowledge about how next-of-kin to a person treated for CRC describe their experience of life and their experience of participating in a PEP. METHODS: The study used a qualitative descriptive design. Individual, open-ended interviews with each of the 18 next-of kin, of persons receiving treatment for CRC, who participated in a PEP. Data were analyzed using content analysis. RESULTS: Based on the experiences described by the next-of-kin to a person treated for CRC, the subtheme; Facing a personal challenge was developed. From their described experiences of participating in a PEP, the subtheme Obtaining New Insights and Perspectives emerged. One main theme was finally identified; Finding a Wider Horizon. The study illuminates the importance of integrating the next-of-kin/family in the colorectal cancer care. CONCLUSION: The findings from this study can be used to plan future interventions for next-of-kin to patients with CRC as it offers possibilities to understand the next-of-kin's situation and experience from participating in a PEP. PMID- 23036313 TI - [Primary trimethylaminuria or fish odour syndrome: early diagnosis from primary care]. PMID- 23036314 TI - Microarray analysis of differentially expressed genes engaged in fruit development between Prunus mume and Prunus armeniaca. AB - Microarray analysis is a technique that can be employed to provide expression profiles of single genes and new insights to elucidate the biological mechanisms responsible for fruit development. To evaluate expression of genes mostly engaged in fruit development between Prunus mume and Prunus armeniaca, we first identified differentially expressed transcripts along the entire fruit life cycle by using microarrays spotted with 10,641 ESTs collected from P. mume and other Prunus EST sequences. A total of 1418 ESTs were selected after quality control of microarray spots and analysis for differential gene expression patterns during fruit development of P. mume and P. Armeniaca. From these, 707 up-regulated and 711 down-regulated genes showing more than two-fold differences in expression level were annotated by GO based on biological processes, molecular functions and cellular components. These differentially expressed genes were found to be involved in several important pathways of carbohydrate, galactose, and starch and sucrose metabolism as well as in biosynthesis of other secondary metabolites via KEGG. This could provide detailed information on the fruit quality differences during development and ripening of these two species. With the results obtained, we provide a practical database for comprehensive understanding of molecular events during fruit development and also lay a theoretical foundation for the cloning of genes regulating in a series of important rate-limiting enzymes involved in vital metabolic pathways during fruit development. PMID- 23036315 TI - [Menopause and bone]. AB - Osteoporosis is a diffuse disease of the skeleton characterized by a decrease and a change in bone microarchitecture, which causes excessive fragility of the bone exposing them to increased risk of fracture. It represents a major public health issue, with 200 million people suffering from this disease in the world. The therapeutic goal is to maintain bone mineral density while avoiding the risk of falling. PMID- 23036316 TI - Inconsistent genetic structure among members of a multitrophic system: did bruchid parasitoids (Horismenus spp.) escape the effects of bean domestication? AB - Anthropogenic range expansion and cultural practices have modified the distribution, abundance and genetic diversity of domesticated organisms, thereby altering multitrophic assemblages through space and time. The putative Mesoamerican domestication centre of the common bean, Phaseolus vulgaris L., in Mexico allows investigating the effects of plant domestication on the genetic structure of members of a multitrophic system. The aim of this study was to compare the evolutionary history of Horismenus parasitoids (Hymenoptera: Eulophidae) to those of their bruchid beetle hosts (Coleoptera: Bruchidae) and their domesticated host plant (P. vulgaris), in the context of traditional agriculture in Mexico. We analyzed the population genetic structure of four Horismenus species in Mexico using mitochondrial COI haplotype data. The two most abundant parasitoid species were Horismenus depressus and Horismenus missouriensis. Horismenus missouriensis were infected by Wolbachia endosymbionts and had little to no population differentiation (F(ST) = 0.06). We suspect the mitochondrial history of H. missouriensis to be blurred by Wolbachia, because differentiation among infected vs. non-infected individuals exists (F(ST) = 0.11). Populations of H. depressus were found to be highly differentiated (F(ST) = 0.34), but the genetic structuring could not be explained by tested spatial components. We then compared the genetic structure observed in this parasitoid species to previously published studies on bruchid beetles and their host plants. Despite extensive human-mediated migration and likely population homogenization of its two Acanthoscelides bruchid beetle hosts, H. depressus populations are structured like its host plant, by a recent dispersal from a diverse ancestral gene pool. Distinct evolutionary dynamics may explain inconsistent patterns among trophic levels. Parasitoids likely migrate from wild bean populations and are poorly adapted to bean storage conditions similar to their bruchid beetle hosts. Integrating several trophic levels to the study of evolutionary history has proven to be fruitful in detecting different ecological responses to human mediated disturbances and host parasite interactions. PMID- 23036317 TI - Commentary on an article by C.-E. Thelu et al.: "poor results of the Optetrak(TM) cemented posterior stabilized knee prosthesis after a mean 25-month follow-up: analysis of 110 prostheses". PMID- 23036318 TI - Mouse models of sarcomas: critical tools in our understanding of the pathobiology. AB - Sarcomas are neoplastic malignancies that typically arise in tissues of mesenchymal origin. The identification of novel molecular mechanisms leading to sarcoma formation and the establishment of new therapies has been hampered by several critical factors. First, this type of cancer is rarely observed in the clinic with fewer than 15,000 newly cases diagnosed each year in the United States. Another complicating factor is that sarcomas are extremely heterogeneous as they arise in a multitude of tissues from many different cell lineages (e.g. bone (osteosarcoma), fat (liposarcoma), and muscle (myosarcoma)). The scarcity of clinical samples coupled with its inherent heterogeneity creates a challenging experimental environment for clinicians and scientists. Faced with these challenges, there has been extremely limited advancement in treatment options available to patients as compared to other cancers. In order to glean insight into the pathobiology of sarcomas, scientists are now using in vivo mouse models whose genomes have been specifically tailored to carry gene deletions, gene amplifications, and point mutations commonly observed in human sarcomas. The use of these model organisms has been successful in increasing our knowledge and understanding of how alterations in relevant oncogenic, tumor suppressive, and signaling pathways directly impact sarcomagenesis. It is the goal of many in the biological community that the use of these mouse models will serve as powerful in vivo tools to further our understanding of sarcomagenesis and potentially identify new therapeutic strategies. PMID- 23036319 TI - Love is not thanked. PMID- 23036321 TI - Degradation of 3,3'-iminobis-propanenitrile in aqueous solution by Fe(0)/GAC micro-electrolysis system. AB - The degradation of 3,3'-iminobis-propanenitrile was investigated using the Fe(0)/GAC micro-electrolysis system. Effects of influent pH value, Fe(0)/GAC ratio and granular activated carbon (GAC) adsorption on the removal efficiency of the pollutant were studied in the Fe(0)/GAC micro-electrolysis system. The degradation of 3,3'-iminobis-propanenitrile was affected by influent pH, and a decrease of the influent pH values from 8.0 to 4.0 led to the increase of degradation efficiency. Granular activated carbon was added as cathode to form macroscopic galvanic cells between Fe(0) and GAC and enhance the current efficiency of the Fe(0)/GAC micro-electrolysis system. The GAC could only adsorb the pollutant and provide buffer capacity for the Fe(0)/GAC micro-electrolysis system, and the macroscopic galvanic cells of the Fe(0)/GAC micro-electrolysis system played a leading role in degradation of 3,3'-iminobis-propanenitrile. With the analysis of the degradation products with GC-MS, possible reaction pathway for the degradation of 3,3'-iminobis-propanenitrile by the Fe(0)/GAC micro electrolysis system was suggested. PMID- 23036322 TI - Biological nitrogen and carbon removal in a gravity flow biomass concentrator reactor for municipal sewage treatment. AB - A novel membrane system, the Biomass Concentrator Reactor (BCR), was evaluated as an alternative technology for the treatment of municipal wastewater. Because the BCR is equipped with a membrane whose average poresize is 20 MUm (18-28 MUm), the reactor requires low-pressure differential to operate (gravity). The effectiveness of this system was evaluated for the removal of carbon and nitrogen using two identical BCRs, identified as conventional and hybrid, that were operated in parallel. The conventional reactor was operated under full aerobic conditions (i.e., organic carbon and ammonia oxidation), while the hybrid reactor incorporated an anoxic zone for nitrate reduction as well as an aerobic zone for organic carbon and ammonia oxidation. Both reactors were fed synthetic wastewater at a flow rate of 71 L d(-1), which resulted in a hydraulic retention time of 9 h. In the case of the hybrid reactor, the recycle flow from the aerobic zone to the anoxic zone was twice the feed flow rate. Reactor performance was evaluated under two solids retention times (6 and 15 d). Under these conditions, the BCRs achieved nearly 100% mixed liquor solids separation with a hydraulic head differential of less than 2.5 cm. The COD removal efficiency was over 90%. Essentially complete nitrification was achieved in both systems, and nitrogen removal in the hybrid reactor was close to the expected value (67%). PMID- 23036320 TI - Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish. AB - The teleost swim bladder is assumed a homolog of the tetrapod lung. Both swim bladder and lung are developmental targets of persistent aryl hydrocarbon receptor (AHR(2)) agonists; in zebrafish (Danio rerio) the swim bladder fails to inflate with exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB126). The mechanism for this effect is unknown, but studies have suggested roles of cytochrome P450 1 (CYP1) and cyclooxygenase 2 (Cox-2) in some Ahr-mediated developmental effects in zebrafish. We determined relationships between swim bladder inflation and CYP1 and Cox-2 mRNA expression in PCB126-exposed zebrafish embryos. We also examined effects on beta-catenin dependent transcription, histological effects, and Ahr2 dependence of the effect of PCB126 on swim bladder using morpholinos targeting ahr2. One-day-old embryos were exposed to waterborne PCB126 or carrier (DMSO) for 24h and then held in clean water until day 4, a normal time for swim bladder inflation. The effects of PCB126 were concentration-dependent with EC(50) values of 1.4 to 2.0 nM for induction of the CYP1s, 3.7 and 5.1 nM (or higher) for cox 2a and cox-2b induction, and 2.5 nM for inhibition of swim bladder inflation. Histological defects included a compaction of the developing bladder. Ahr2 morpholino treatment rescued the effect of PCB126 (5 nM) on swim bladder inflation and blocked induction of CYP1A, cox-2a, and cox-2b. With 2nM PCB126 approximately 30% of eleutheroembryos(3) failed to inflate the swim bladder, but there was no difference in CYP1 or cox-2 mRNA expression between those embryos and embryos showing inflated swim bladder. Our results indicate that PCB126 blocks swim bladder inflation via an Ahr2-mediated mechanism. This mechanism seems independent of CYP1 or cox-2 mRNA induction but may involve abnormal development of swim bladder cells. PMID- 23036323 TI - Could triplet-sensitised transformation of phenolic compounds represent a source of fulvic-like substances in natural waters? AB - Here we show that fluorescent compounds that could be classified as "M-like" (marine-like) fulvic acids are formed upon phototransformation of phenol by a triplet sensitiser (anthraquinone-2-sulphonate, AQ2S). The relevant process most likely involves phenol oxidation to phenoxyl radical by triplet AQ2S, followed by dimerisation of phenoxyl radicals into phenoxyphenols and dihydroxybiphenyls. It might be the first step of an oligomerization process that bears resemblance with the expected formation pathways of humic-like substances (HULIS) in the atmosphere. Such a process could account for the formation in surface waters of compounds having similar fluorescence properties as "M-like" fulvic acids. Presently it is thought that such species are formed upon photo-fragmentation of larger humic and fulvic acids ("top-down" pathway), and we propose that an opposite, "bottom-up" pathway could also be operational. PMID- 23036324 TI - Evaluation of insect CAP2b analogs with either an (E)-alkene, trans- or a (Z) alkene, cis-Pro isostere identifies the Pro orientation for antidiuretic activity in the stink bug. AB - The CAP2b neuropeptide family plays an important role in the regulation of the processes of diuresis and/or antidiuresis in a variety of insects. While Manse CAP2b (pELYAFPRV-NH2) and native CAP2bs elicit diuretic activity in a number of species of flies, native CAP2b sequences have been shown to elicit antidiuretic activity in the kissing bug Rhodnius prolixus and the green stink bug Acrosternum hilare, the latter being an important pest of cotton and soybean in the southern United States. Analogs of CAP2b containing either a (Z)-alkene, cis-Pro or an (E) alkene, trans-Pro isosteric component were synthesized and evaluated in an in vitro stink bug diuretic assay, which involved measurement of fluid secretion by Malpighian tubules isolated from A. hilare. The conformationally constrained trans-Pro analog demonstrated statistically significant antidiuretic activity, whereas the cis-Pro analog failed to elicit activity. The results are consistent with the adoption of a trans orientation for the Pro in CAP2b neuropeptides during interaction with receptors associated with the antidiuretic process in the stink bug. In addition, the results are further consistent with a theory of ligand-receptor coevolution between the CAP2b and pyrokinin/PBAN neuropeptide classes, both members of the '-PRXamide' superfamily. This work further identifies a scaffold with which to design mimetic CAP2b analogs as potential leads in the development of environmentally favorable pest management agents capable of disrupting CAP2b-regulated diuretic/antidiuretic functions. PMID- 23036325 TI - Gene expression analysis of normal and colorectal cancer tissue samples from fresh frozen and matched formalin-fixed, paraffin-embedded (FFPE) specimens after manual and automated RNA isolation. AB - Although RNA isolation is a routine process in gene expression analysis studies, the applicability of most widely available formalin-fixed, paraffin-embedded (FFPE) samples is still limited compared to fresh frozen tissue samples due to the lower quality of the isolated RNA. Recently, novel automated isolation methods were developed in order to reduce manual sample handling and increase RNA quality and quantity. Here we present a comparison of the performance of fresh frozen and matched FFPE tissue samples obtained from the same surgically removed colonic specimens (10 normal, 10 CRC) in RT-PCR experiments. RNA isolations were performed with the automated MagNA Pure 96 Cellular RNA Large Volume Kit (Roche) compared to the manual RNeasy FFPE Mini Kit (Qiagen). Gene expression analysis of a colorectal cancer-specific marker set (with 7 genes: COL12A1, CXCL1, CXCL2, GREM1, IL1B, IL8, SLC7A5) was performed with array real-time PCR using Transcriptor First Strand cDNA Synthesis Kit (Roche) and RealTime ready assays on LightCycler(r) 480 System (Roche). On the basis of the gene expression of the analyzed markers, fresh frozen tumorous and normal samples could be distinguished with 100% sensitivity and 100% specificity after both isolation methods. The FFPE samples could be distinguished by similarly high specificity and sensitivity with the MagNA Pure 96 isolated samples (sensitivity: 90,0%; specificity: 90,0%) and the samples isolated with manual Qiagen method (sensitivity: 85,0%; specificity: 70,0%). According to these results, FFPE samples isolated by automated methods can serve as valuable source for retrospective gene expression studies in the field of biomarker discovery and development. PMID- 23036326 TI - Gene expression analysis of both mRNA and miRNA on the same TaqMan(r) Array Card: development of a pancreatic tumor tissue classification methodology. PMID- 23036327 TI - Integrated expression profiling of multiple RNA species by real-time PCR. AB - MicroRNAs (miRNAs) are endogenous, non-coding RNAs comprising approximately 21-23 nucleotides that regulate gene expression by binding to and targeting messenger RNA (mRNA) for translational repression or degradation. miRNAs have been shown to regulate cellular processes including proliferation, differentiation, and development and to play an important role in immune system function. The expression of miRNAs is misregulated in numerous diseases, including cancers of immunological origin. To better understand the role of miRNA in T-cell activation, we used a real-time PCR-based system to analyze changes in miRNA expression following activation of Jurkat T-cells with the inducing agents Phorbol Myristyl Acetate (PMA) and Ionomycin (CI) and detected several miRNAs that showed differential regulation following treatment. Using this system, miRNAs and their mRNA targets, along with other non-coding RNAs, can be simultaneously detected and quantified using SYBR(r) Green real time-PCR, enabling comprehensive, genome-wide expression profiles of multiple RNA species. PMID- 23036328 TI - A genome wide RNA interference screening method to identify host factors that modulate influenza A virus replication. AB - The use of genome wide RNA interference (RNAi) screens to investigate host-virals interactions has revealed unexpected connections that have improved our understanding of viral pathogenesis and cell biology. This work describes the use of an RNAi screening method employing an immunofluorescence image-based strategy and influenza A virus. We find this approach to be readily implemented, scalable and amenable to the direct evaluation of a variety of viral lifecycles. PMID- 23036329 TI - Assessing sample and miRNA profile quality in serum and plasma or other biofluids. AB - MicroRNAs (miRNAs) constitute a class of small cellular RNAs (typically 21-23nt) that function as post-transcriptional regulators of gene expression. Current estimates indicate that more than one third of the cellular transcriptome is regulated by miRNAs, although they are relatively few in number (less than 2000 human miRNAs). The high relative stability of miRNA in common clinical tissues and biofluids (e.g. plasma, serum, urine, saliva, etc.) and the ability of miRNA expression profiles to accurately classify discrete tissue types and disease states have positioned miRNA quantification as a promising new tool for a wide range of diagnostic applications. Furthermore miRNAs have been shown to be rapidly released from tissues into the circulation with the development of pathology. To facilitate discovery and clinical development of miRNA-based biomarkers, we developed a genome-wide Locked Nucleic Acid (LNATM)-based miRNA qPCR platform with unparalleled sensitivity and robustness. The platform allows high-throughput profiling of miRNAs from important clinical sources without the need for pre-amplification. Using this system, we have profiled thousands of biofluid samples including blood derived plasma and serum. An extensive quality control (QC) system has been implemented in order to secure technical excellence and reveal any unwanted bias coming from pre-analytical or analytical variables. We present our approaches to sample and RNA QC as well as data QC and normalization. Specifically we have developed normal reference ranges for circulating miRNAs in serum and plasma as well as a hemolysis indicator based on microRNA expression. PMID- 23036330 TI - Droplet DigitalTM PCR quantitation of HER2 expression in FFPE breast cancer samples. AB - The human epidermal growth factor receptor 2 (HER2, also known as erbB2) gene is involved in signal transduction for cell growth and differentiation. It is a cell surface receptor tyrosine kinase and a proto-oncogene. Overexpression of HER2 is of clinical relevance in breast cancer due to its prognostic value correlating elevated expression with worsening clinical outcome. At the same time, HER2 assessment is also of importance because successful anti-tumor treatment with Herceptin(r) is strongly correlated with HER2 overexpression in the tumor (approximately 30% of all breast tumors overexpress HER2). In a comprehensive national study, Wolff et al. [1] state that "Approximately 20% of current HER2 testing may be inaccurate" which underscores the importance of developing more accurate methods to determine HER2 status. Droplet DigitalTM PCR (ddPCRTM) has the potential to improve upon HER2 measurements due to its ability to quantitate DNA and RNA targets with high precision and accuracy. Here we present a study which investigates whether ddPCR can be used to assess HER2 transcript levels in formalin-fixed paraffin embedded (FFPE) human breast tumors and whether these ddPCR measurements agree with prior assessments of these same samples by pathologists using immunohistochemistry (IHC) and in some cases fluorescence in situ hybridization (FISH). We also determined the copy number of HER2 in these samples as compared to the CEP17 reference gene. RESULTS: Clinical FFPE samples were successfully studied using ddPCR and compared to results from standard FISH and IHC methodology. The results demonstrate that ddPCR can rank order the samples in complete agreement with the current standard methods and that ddPCR has the added benefit of providing quantitative results, rather than relying on the expert skill of a seasoned pathologist for determination. PMID- 23036331 TI - Detecting and visualizing gene fusions. AB - In recent years, gene fusions have gained significant recognition as biomarkers. They can assist treatment decisions, are seldom found in normal tissue and are detectable through Next-generation sequencing (NGS) of the transcriptome (RNA seq). To transform the data provided by the sequencer into robust gene fusion detection several analysis steps are needed. Usually the first step is to map the sequenced transcript fragments (RNA-seq) to a reference genome. One standard application of this approach is to estimate expression and detect variants within known genes, e.g. SNPs and indels. In case of gene fusions, however, completely novel gene structures have to be detected. Here, we describe the detection of such gene fusion events based on our comprehensive transcript annotation (ElDorado). To demonstrate the utility of our approach, we extract gene fusion candidates from eight breast cancer cell lines, which we compare to experimentally verified gene fusions. We discuss several gene fusion events, like BCAS3-BCAS4 that was only detected in the breast cancer cell line MCF7. As supporting evidence we show that gene fusions occur more frequently in copy number enriched regions (CNV analysis). In addition, we present the Transcriptome Viewer (TViewer) a tool that allows to interactively visualize gene fusions. Finally, we support detected gene fusions through literature mining based annotations and network analyses. In conclusion, we present a platform that allows detecting gene fusions and supporting them through literature knowledge as well as rich visualization capabilities. This enables scientists to better understand molecular processes, biological functions and disease associations, which will ultimately lead to better biomedical knowledge for the development of biomarkers for diagnostics and therapies. PMID- 23036332 TI - Synthesis and antifungal activity of diverse C-2 pyridinyl and pyridinylvinyl substituted quinolines. AB - Diverse 2-pyridinyl quinolines 6-12 and 2-pyridinilvinyl quinolines 13-17 were prepared using a straightforward synthesis based on the BiCl(3)-catalyzed multicomponent imino Diels-Alder (imino DA) reaction or a novel tandem imino DA/catalytic tetrahydroquinoline ring oxidation/Perkin condensation sequential process. All members of the series showed activities against dermatophytes and some of them possessed a broad spectrum of action. 2-(Pyridin-4-yl)quinoline 9 and 2-(2-pyridin-4-yl)vinyl)quinoline 16 showed the best MIC(80) and MIC(50) against the clinically important fungi Candida albicans and non-albicans Candida species. In turn, 6-ethyl-2-(pyridin-2-yl)quinoline 6 showed the best properties against standardized as well as clinical strains of Cryptococcus neoformans. PMID- 23036333 TI - Development and characterization of endocannabinoid hydrolases FAAH and MAGL inhibitors bearing a benzotriazol-1-yl carboxamide scaffold. AB - A series of (1H-benzo[d][1,2,3]triazol-1-yl)(4-benzylpiperazin-1-yl)methanones and of (1H-benzo[d][1,2,3]triazol-1-yl)(4-phenylpiperazin-1-yl)methanones has been prepared and tested on human fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In the benzylpiperazinyl series, compound 29 (ML30) exhibited an IC(50) value of 0.54 nM on MAGL, combined with a 1000-fold selectivity versus FAAH, while compounds 11 and 16 acted as potent dual FAAH-MAGL inhibitors (IC(50)<10 nM). In the phenylpiperazinyl series, compounds 37, 38, 42, and 43 displayed IC(50) values against MAGL in the nanomolar range, whilst being between one and two orders of magnitude less potent on the FAAH, while compounds 31 and 32 were potent FAAH inhibitors (IC(50)<20 nM) and over 12-fold selective versus MAGL. The key structural determinants driving the structure-activity relationships were explored by the minimization of the inhibitors inside the active site of both enzymes. PMID- 23036334 TI - Carbonic anhydrase IX in malignant pleural mesotheliomas: a potential target for anti-cancer therapy. AB - Malignant mesothelioma is a neoplasm deriving from mesothelial cells, which line the body cavities. The most common type is malignant pleural mesothelioma (MPM), which is a locally aggressive malignancy with poor prognosis. To improve both the clinical diagnostics and treatment it is necessary to identify novel molecular targets which are characteristic for MPM. Although carbonic anhydrase (CA) enzymes have been linked to pH regulation and spread of cancer cells, they have not been thoroughly studied in MPM specimens. We investigated by immunohistochemistry the expression of CA isozymes II, VII, IX, and XII in a series of 27 histological MPM tumor samples. CA IX was absent in the normal lung alveolar cells, whereas it was abundantly expressed in the normal pleural mesothelium and malignant mesothelioma cells. CA VII also showed weak or moderate reactions in several cases of mesotheliomas. Neither high expression of CA VII nor CA IX did correlate significantly with the survival of the patients. The very high expression of CA IX in MPM suggests that it could represent a novel molecular target for cancer research applications. PMID- 23036335 TI - Homo- and heterodimeric Smac mimetics/IAP inhibitors as in vivo-active pro apoptotic agents. Part I: Synthesis. AB - Novel pro-apoptotic, homo- and heterodimeric Smac mimetics/IAPs inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold were prepared from monomeric structures connected through a head-head (8), tail-tail (9) or head-tail (10) linker. The selection of appropriate decorating functions for the scaffolds, and of rigid and flexible linkers connecting them, is described. The synthesis, purification and analytical characterization of each prepared dimer 8-10 is thoroughly described. PMID- 23036336 TI - Family history of alcohol dependence modulates functional neurophysiology in mood/anxiety disorders. AB - BACKGROUND: A family history (FH) of alcohol dependence (AD) not only increases the risk for AD, but is also associated with an increased risk for mood and anxiety disorders. However, it is unknown how a FH of AD affects neural substrates in patients with mood and anxiety disorders. In this study we examined the effects of an alcoholic FH on cognitive and emotional functions in these patients using functional magnetic resonance imaging (fMRI). Method In a sample of non-alcoholic patients with depressive and/or anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA) neuroimaging study, patients with a first-degree FH of AD (FH + ; n = 31) were compared with patients without a FH (FH-; n = 77) on performance and brain activation during visuospatial planning and emotional word encoding. Results were compared with those of healthy controls (HCs) without a FH of AD (n = 31). RESULTS: FH+ patients performed slower during planning with increasing task load, coupled with stronger blood oxygen level-dependent responses in dorsal prefrontal areas compared with FH- patients and HCs. FH was not associated with performance differences during word encoding, but right insula activation during positive word encoding was present in FH+ patients, comparable with HCs, but absent in FH- patients. CONCLUSIONS: This study demonstrates subtle impairments during planning in FH+ compared with FH- patients and HCs, whereas activation during mood-incongruent stimuli in FH+ patients was similar to HCs but not FH- patients, suggesting that the presence of a FH of AD is a useful marker for the neurophysiological profile in mood/anxiety disorders and possible predictor for treatment success. PMID- 23036337 TI - Japanese regulatory system for approval of off-label drug use: evaluation of safety and effectiveness in literature-based applications. AB - BACKGROUND: Although approved elsewhere, many drug indications remain unapproved in Japan. Many of these unapproved indications are off-label, which, despite strong supporting evidence, are not covered by the Japanese health insurance system. To address this situation, the Ministry of Health, Labour and Welfare of Japan announced in 1999 that, under certain conditions, it would approve a new supplement for a drug indication without clinical trials. This approval scheme involved application evaluation using literature-based evidence; however, the type of indications and the kind of evidence used in practical applications remain to be clarified. OBJECTIVE: This commentary sought to investigate the factors that contribute to the approval of individual applications through an analysis of review reports and to assess the outcome of efforts to facilitate the approval of off-label drugs by this approval system that has been used for over a decade in Japan. METHODS: Data from 80 approvals granted under this scheme were obtained from the official review reports of the Japanese regulatory agency. The following criteria were selected for the analysis of individual applications: review time, therapeutic class, application category under Japanese regulations, international approval status, postapproval monitoring plan, and variety and quantity of literature evidence. The literature used as a source of evidence was categorized into 4 types: (I) standard textbooks, (II) standard guidelines, (III) reviews, and (IV) application dossier submitted to the foreign regulatory authorities. RESULTS: The number of approvals and applications per year showed no consistent trend. The median (SD) review time was 16.4 (9.0) months, which was not affected by the international approval status or the literature evidence. This approval scheme was applied to not only a new indication (56 applications [70%]) or dosage (9 [11%]) but also a new route of administration (13 [16%]). Of the 80 applications, 46 (58%) had been approved in the United States, the United Kingdom, or both; 11 (14%), in other countries; and 23 (29%), in no country. For 2 approvals, the review reports were not released; the other 78 were based on either standard textbooks or guidelines, while 67 (84%) were based on both. The variety and quantity of literature evidence provided in the application showed no consistent trend with respect to international approval status. CONCLUSIONS: Prior approval by foreign authorities, although important, did not appear to be essential for approval in Japan. However, substantiating safety and effectiveness of agents by means of standard textbooks or guidelines was used consistently to obtain approval for off-label use. PMID- 23036338 TI - Vismodegib and the hedgehog pathway: a new treatment for basal cell carcinoma. AB - BACKGROUND: Vismodegib is an oral inhibitor of the Hedgehog pathway approved by the US Food and Drug Administration. It is the first systemic treatment for patients with locally advanced or metastatic basal cell carcinoma that is not amenable to surgery and radiation. This is the first drug to use the Hedgehog pathway to inhibit the proliferation of tumors and is also implicated in the development of other cancers such as medulloblastoma. OBJECTIVE: The goal of this review was to summarize the development, pharmacology, efficacy, and safety of vismodegib. METHODS: Relevant English-language literature was identified and then evaluated based on results from database searches of MEDLINE and EMBASE from 1975 to June 19, 2012. The terms searched included, but were not limited to, vismodegib, Erivedge, GDC-0449, basal cell carcinoma, and 2-chloro-N-[4-chloro-3 (pyridin-2-yl)phenyl]-4-(methylsulfonyl)benzamide. Additional literature was identified by assessing the reference lists of previously identified articles and through abstracts presented by the American Society of Clinical Oncology. RESULTS: A total of 70 full text citations were identified although two national conference proceedings were then excluded. An additional 10 published abstracts were also identified. A Phase II, nonrandomized, multicenter, international study demonstrated a 30.3% objective response rate in metastatic basal cell carcinoma and a 42.9% objective response rate in locally advanced basal cell carcinoma. The adverse effect profile for vismodegib is similar to other identified Hedgehog pathway inhibitors; muscle cramps (71.7%), alopecia (63.8%), and dysgeusia (55.1%) were the most common adverse effects seen in trials. A Phase II, randomized, placebo-controlled trial in Gorlin syndrome patients with basal cell carcinoma concluded that vismodegib was significantly better than placebo at reducing new basal cell carcinoma lesions (P < 0.001) and at decreasing the sum of the longest diameter of existing lesions (P = 0.003). CONCLUSIONS: For patients with unresectable basal cell carcinoma or where resection would be cosmetically disadvantageous, vismodegib is an effective therapy with good response rates. At this time, the data are too limited to determine overall survival. The Hedgehog pathway is a newly identified area in which mutations or dysregulation can occur, leading to the development and progression of tumors. Studies continue to look at other cancers with involvement of the Hedgehog pathway. PMID- 23036339 TI - New models and predictions for Brownian coagulation of non-interacting spheres. AB - The classical steady-state Smoluchowski model for Brownian coagulation is evaluated using Brownian Dynamics Simulations (BDS) as a benchmark. The predictions of this approach compare favorably with the results of BDS only in the dilute limit, that is, for volume fractions of phi<=5*10(-4). From the solution of the more general unsteady-state diffusion equation, a new model for coagulation is developed. The resulting coagulation rate constant is time dependent and approaches the steady-state limit only at large times. Moreover, in contrast to the Smoluchowski model, this rate constant depends on the particle size, with the transient effects becoming more significant at larger sizes. The predictions of the unsteady-state model agree well with the BDS results up to volume fractions of about phi=0.1, at which the aggregation half-time predicted by the Smoluchowski model is five times that of the BDS. A new procedure to extract the aggregation rate constant from simulation results based on this model is presented. The choice of the rate constant kernel used in the population balance equations for complete aggregation is also evaluated. Extension of the new model to a variable rate constant kernel leads to increased accuracy of the predictions, especially for phi<=5*10(-3). This size-dependence of the rate constant kernel affects particularly the predictions for initially polydisperse sphere systems. In addition, the model is extended to account in a novel way for both short-range viscous two-particle interactions and long-range many-particle Hydrodynamic Interactions (HI). Predictions including HI agree best with the BDS results. The new models presented here offer accurate and computationally less intensive predictions of the coagulation dynamics while also accounting for hydrodynamic coupling. PMID- 23036340 TI - A reusable naphthalimide-functionalized magnetic fluorescent nanosensor for the simultaneous determination and removal of trace Hg2+ in aqueous solution. AB - On the basis of high selective and sensitive interaction of 1,8-naphthalimide with Hg(2+) and the formation of stable neutral imide-Hg-imide complexes, we designed and synthesized a novel magnetic fluorescent sensor (S1) employed Fe(3)O(4) magnetic nanoparticles and 1,8-naphthalimide fluorescent sensor. Under optimum conditions, S1 exhibits the high selectivity toward Hg(2+) over other metal ions, with the detection limit of 1.03*10(-8)M. We demonstrated that a reliable fluorescence response of S1 toward Hg(2+) over a broad pH range (pH=5.0 9.0) could be reused at least four cycles. The maximum sorption capacity of S1 was about 5.6 mg g(-1). In addition, the removal of Hg(2+) in water was achieved by the aggregation-induced sedimentation (AIS) strategy. Moreover, the suspended magnetic nanoparticles could be removed by external magnetic field, and the secondary pollution was avoided. The above-mentioned results indicate that this approach may serve as a foundation of the preparation of the multifunctional magnetic fluorescent sensor for simple, rapid, and simultaneous determination and removal of trace Hg(2+) and other pollutants in environmental samples. PMID- 23036341 TI - Re: Multicentre survey of radiologically inserted gastrostomy feeding tube (RIG) in the UK. A reply. PMID- 23036342 TI - Tyrosinemia Type III detected via neonatal screening: management and outcome. AB - Tyrosinemia Type III is caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), an enzyme involved in the catabolic pathway of tyrosine. To our knowledge, only a few patients presenting with this disease have been described in the literature, and the clinical phenotype remains variable and unclear. We report the case of a boy with tyrosinemia Type III detected using neonatal screening, who is homozygous for the splice donor mutation IVS11+1G>A in intron 11 of the HPD gene. At the age of 30 months, the boy's outcome under mild protein restriction was characterized by normal growth and psychomotor development. PMID- 23036344 TI - Words of wisdom. Re: Psychoaffective differences between sexually functional and dysfunctional men in response to a sexual experience. PMID- 23036343 TI - Regeneration of the elbow joint in the developing chick embryo recapitulates development. AB - Synovial joints are among the most important structures that give us complex motor abilities as humans. Degenerative joint diseases, such as arthritis, cause loss of normal joint functioning and affect over 40 million people in the USA and approximately 350 million people worldwide. Therapies based on regenerative medicine hold the promise of effectively repairing or replacing damaged joints permanently. Here, for the first time, we introduce a model for synovial joint regeneration utilizing the chick embryo. In this model, a block of tissue that contains the prospective elbow is excised, leaving a window with strips of anterior and posterior tissue intact (window excision, WE). In contrast, we also slice out the same area containing the elbow and the distal piece of the limb is pinned back onto the stump (slice excision, SE). Interestingly, when the elbow is removed via WE, regeneration of the joint takes place, whereas the elbow joint does not regenerate following SE. In order to investigate whether the regeneration response recapitulates the developmental program of forming joints, we used GDF-5 and Autotaxin (Atx) as joint tissue specific markers, and Sox-9 and Col-9 as cartilage markers for in situ hybridization on sections at different time points after WE and SE surgeries. Re-expression of GDF-5 and Atx is observed in the WE samples by 60h after surgery. In contrast, the majority of the samples that underwent SE surgery did not express GDF-5 and Atx. Also, in SE fusion of cartilage elements takes place and the joint interzone does not form. This is indicated by continuous Col-9 expression in SE limbs, whereas Col-9 is downregulated at the joint interzone in the regenerating WE samples. This order and pattern of gene expression observed in regenerates is similar to the development of a joint suggesting that regeneration recapitulates development at the molecular level. This model defines some of the conditions required for inducing joint regeneration in an otherwise nonregenerating environment. This knowledge can be useful for designing new therapeutic approaches for joint loss or for conditions affecting joint integrity in humans. PMID- 23036345 TI - Words of wisdom. Re: Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. PMID- 23036346 TI - Words of wisdom. Re: Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. PMID- 23036347 TI - Words of wisdom. Re: Adverse effects of robotic-assisted laparoscopic versus open retropubic radical prostatectomy among a nationwide random sample of Medicare-age men. PMID- 23036348 TI - Words of wisdom. Re: Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. PMID- 23036349 TI - Words of wisdom. Re: Prevalence of kidney stones in the United States. PMID- 23036350 TI - In search of new targets for retinal neuroprotection: is there a role for autophagy? AB - Autophagy is a highly conserved catabolic pathway in which proteins and organelles are engulfed by vacuoles that are targeted to lysosomes for degradation. Defects in the autophagic machinery have been described in several neurodegenerative diseases uncovering the tight dependency of neuronal survival on the efficiency of the autophagic process. Despite the large amount of literature investigating autophagy in a number of pathological conditions our knowledge of its role in glaucoma neurodegeneration is just beginning. However, recent experimental data revealing that autophagy modulation occurs in retinal ganglion cells (RGCs) under glaucoma-related stressing conditions support the hypothesis that dysfunctional autophagy might underlie the process leading to RGC death. Although our understanding of the role of autophagy in glaucoma is still developing, there is the possibility that neuroprotection may be achieved by modulating autophagy. This would be a promising approach as it could lead to the much-sought development of alternative therapeutic strategies to prevent visual loss in glaucoma. PMID- 23036351 TI - Fetal development and variations in the cartilages surrounding the human external acoustic meatus. AB - In contrast to the osseus part that develops from the tympanic ring of the squamous part of the temporal bone after birth, there is little information on fetal development of the cartilages surrounding the human external acoustic meatus. Using routine histology and immunohistochemistry, we examine sections of 22 fetuses (CRL 100-270mm) to study the development of these cartilages. Early external ear cartilages are composed of three groups: (1) a ring-like cartilage at the putative tragus on the anterior side of the meatus, (2) two or three bar like cartilages along the inferior wall of the meatus, and (3) a plate-like cartilage in a skin fold for the putative helix on the posterior side. In contrast to the first and second pharyngeal arch cartilages, all the external ear cartilages express glial fibrillary acidic protein. Notably, the bar-like cartilages along the meatus are connected with a fascia-like structure to the second pharyngeal arch cartilage. Later, with considerable individual variation, new cartilage bars extend from the inferior cartilages to the superior side of the meatus. Thus, via an intermediate stage showing a chain of triangular elastic cartilages, a chain of bar-like cartilages on the inferior side appears to change into a complex of H-shaped cartilages. Numerous ceruminous glands are seen in the thick subcutaneous tissue overlying the cartilaginous part of the meatus. However, they do not insert into the cartilage. The external ear cartilages develop much earlier than, and independently of, the osseus part. PMID- 23036352 TI - Reporting heterogeneity in self-assessed health among elderly Europeans. AB - INTRODUCTION: Self-assessed health (SAH) is a frequently used measure of individuals' health status. It is also prone to reporting heterogeneity. To control for reporting heterogeneity objective measures of true health need to be included in an analysis. The topic becomes even more complex for cross-country comparisons, as many key variables tend to vary strongly across countries, influenced by cultural and institutional differences. This study aims at exploring the key drivers for reporting heterogeneity in SAH in an international context. To this end, country specific effects are accounted for and the objective health measure is concretized, distinguishing effects of mental and physical health conditions. METHODS: We use panel data from the SHARE-project which provides a rich dataset on the elderly European population. To obtain distinct indicators for physical and mental health conditions two indices are constructed. Finally, to identify potential reporting heterogeneity in SAH a generalized ordered probit model is estimated. RESULTS: We find evidence that in addition to health behaviour, health care utilization, mental and physical health condition as well as country characteristics affect reporting behaviour. We conclude that observed and unobserved heterogeneity play an important role when analysing SAH and have to be taken into account. PMID- 23036353 TI - A novel CB2 agonist, COR167, potently protects rat brain cortical slices against OGD and reperfusion injury. AB - Cannabinoid CB2 receptor activation has been shown to have many pharmacological but not psychotropic effects. The aim of this study was to investigate the potential protection of brain tissues afforded by the novel substituted 4 quinolone-3-carboxylic acid derivative COR167, a selective CB2 agonist, toward ischemia and reperfusion-induced injury, as well as the mechanism of this potential effect. Rat brain cortical slices subjected to oxygen and glucose deprivation (OGD) followed by re-oxygenation were used. Cell damage was quantified by measuring at the end of the reperfusion phase the release into the artificial cerebrospinal fluid (ACSF) of lactate dehydrogenase (LDH), glutamate, IL-6 and TNF-alpha and by evaluating in tissue the lipid-peroxides (thiobarbituric acid-reactive substances, TBARS), the free, reduced glutathione content (GSH) and the water gain (TWG), taken as an index of cell swelling. COR167 (10nM or 100 nM), added to ACSF during the entire reperfusion phase, markedly reduced LDH and glutamate release, as well as TWG. Lower (0.1-1 nM) or higher concentrations (1,000 nM) were ineffective, suggesting thereby an hormetic behavior. COR167 at 10nM concentration markedly reverted in tissues TBARS increase and GSH decrease, while reducing IL-6 and TNF-alpha release into ACSF. COR167 effects on glutamate and LDH release were abrogated by the selective CB2 inverse-agonists COR170 (1 nM) and AM630 (1MUM) but not by the CB1 antagonist AM251 (1 MUM). COR170 as well as AM630 per se were able to revert TWG. The CB2 receptor agonist COR167 potently protected rat brain cortical slices against OGD and reperfusion injury, partly through CB2 receptors activation. PMID- 23036354 TI - Epigenetics makes its mark on women-specific cancers--an opportunity to redefine oncological approaches? AB - Over the past decade it has become clear that cancer is an epigenetic and a genetic disease. While we have begun to understand the impact of variations in the DNA sequence on cancer development, it is only more recently that we have appreciated the significant contribution of the epigenome to carcinogenesis and cancer biology. Twin studies demonstrate that genetics makes little contribution to the development of women-specific cancers and that the 'epigenome,' the interphase between genome and environment, is likely to confer the largest component of risk. Epigenetic factors can therefore act as surrogate markers of disease risk that could potentially facilitate tailored treatment and refine preventive measures. This review focuses attention on DNA methylation-a core epigenetic mechanism that can be readily detected in body fluids and has the potential to substantially reform cancer screening and treatment. PMID- 23036355 TI - Visual outcome and complications after posterior iris-claw aphakic intraocular lens implantation. AB - PURPOSE: To evaluate the indications, visual outcomes, and complication rate after implantation of a posterior chamber iris-claw aphakic intraocular lens (IOL). SETTING: Department of Ophthalmology, University Medicine Charite Berlin, Berlin, Germany. DESIGN: Retrospective case series. METHODS: Eyes without adequate capsule support had posterior chamber iris-claw aphakic IOL implantation (Verisyse/Artisan) between 2005 and 2010. RESULTS: The study comprised 137 eyes (126 patients). The mean follow-up was 5 months (range 1 to 48 months). The IOLs were inserted during primary lens surgery in 10 eyes (7.3%), during an IOL exchange procedure for dislocated posterior chamber IOLs in 95 eyes (69.4%), and as a secondary procedure in 32 aphakic eyes (23.3%). The final mean corrected distance visual acuity (CDVA) (0.38 +/- 0.31 [SD] logMAR) was significantly better than preoperatively (0.65 +/- 0.58 logMAR) (P < .05). In 128 eyes (93.4%), postoperative refractive errors were within +/-2.00 diopters (D) of emmetropia. Complications included slight temporary pupil ovalization in 34 eyes (24.8%), cystoid macular edema in 12 eyes (8.7%), hyphema in 3 eyes (2.1%), early postoperative hypotony in 7 eyes (5.1%) and elevated intraocular pressure in 6 eyes (4.3%), chronic uveitis in 1 eye (0.7%), toxic anterior segment syndrome in 1 eye (0.7%), and endophthalmitis in 1 eye (0.7%). Iris-claw IOL disenclavation occurred in 12 eyes (8.7%); all IOLs could be easily repositioned. CONCLUSION: The retropupillary iris-claw IOL provided good visual outcomes with a favorable complication rate and can be used for a wide range of indications in eyes without adequate capsule support. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23036356 TI - Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a Northern California eye department. AB - PURPOSE: To evaluate post-cataract-surgery endophthalmitis rates in relation to changing practice patterns in antibiotic administration. SETTING: Kaiser Permanente, Diablo Service Area, California. DESIGN: Ecological time-trend study. METHODS: During 2007 through 2011, 3 time periods were identified based on increasing adoption of intracameral injections after phacoemulsification cataract surgery. In 2007, patients primarily received postoperative antibiotic drops without intracameral injection. During 2008 and 2009, in addition to the surgeons' usual postoperative topical drop regimen, patients received intracameral cefuroxime unless contraindicated by allergy or posterior capsule rupture (PCR). During 2010 and 2011, all patients received an intracameral injection of cefuroxime, moxifloxacin, or vancomycin while topical antibiotics were used according to surgeon preference. The rates of postoperative endophthalmitis during these 3 periods were calculated. Also evaluated separately were consecutive patients without PCR from a subgroup of 3 surgeons who used intracameral injection alone without perioperative topical antibiotics. RESULTS: Nineteen cases of endophthalmitis occurred in 16,264 cataract surgeries. The respective rates per 1000 during the 3 time periods (2007, 2008 and 2009, 2010 and 2011) were as follows: 3.13 (95% confidence interval [CI], 1.43-5.93); 1.43 (95% CI, 0.66-2.72); 0.14 (95% CI, 0-0.78). One case of endophthalmitis was observed in 2038 patients without PCR who received intracameral injection only without topical antibiotics (rate per 1000: 0.49; 95% CI, 0.01-2.73). CONCLUSIONS: The adoption of intracameral antibiotic injection coincided with a decline in the rate of postoperative endophthalmitis, and a low infection rate was observed with intracameral injection alone. PMID- 23036357 TI - Utilization of a calmodulin lysine methyltransferase co-expression system for the generation of a combinatorial library of post-translationally modified proteins. AB - By successfully incorporating sequence diversity into proteins, combinatorial libraries have been a staple technology used in protein engineering, directed evolution, and synthetic biology for generating proteins with novel specificities and activities. However, these approaches mostly overlook the incorporations of post-translational modifications, which nature extensively uses for modulating protein activities in vivo. As an initial step of incorporating post translational modifications into combinatorial libraries, we present a bacterial co-expression system, utilizing a recently characterized calmodulin methyltransferase (CaM KMT), to trimethylate a combinatorial library of the calmodulin central linker region. We show that this system is robust, with the successful over-expression and post-translational modification performed in Escherichia coli. Furthermore we show that trimethylation differentially affected the conformational dynamics of the protein upon the binding of calcium, and the thermal stability of the apoprotein. Collectively, these data support that when applied to an appropriately designed protein library scaffold, CaM KMT is able to produce a post-translationally modified library of protein sequences, thus providing a powerful tool for future protein library designs and constructions. PMID- 23036358 TI - Cell-free expression of human glucosamine 6-phosphate N-acetyltransferase (HsGNA1) for inhibitor screening. AB - Glucosamine 6-phosphate N-acetyltransferase (GNA1; EC 2.3.1.4) is required for the de novo synthesis of N-acetyl-d-glucosamine-6-phosphate (GlcNAc-6P), which is an essential precursor in Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) biosynthesis pathway. Therefore, GNA1 is indispensable for the viability of organisms. Here, a novel cell-free expression strategy was developed to efficiently produce large amounts of human GNA1(HsGNA1) and HsGNA1-sGFP for throughput inhibitor screening. The binding site of inhibitor glucose-6-phosphate (G6P) to hGNA was identified by simulated annealing. Subtle differences to the binding site of Aspergillius GNA1(AfGNA1) can be harnessed for inhibitor design. HsGNA1 may be also useful as an antimicrobial and chemotherapeutic target against cancer. Additionally HsGNA1 inhibitors/modulators can possibly be administered with other drugs in the next generation of personalized medicine. PMID- 23036359 TI - Expression and purification of two Family GH31 alpha-glucosidases from Bacteroides thetaiotaomicron. AB - Microorganisms in the human gut outnumber human cells by a factor of 10. These microbes have been shown to have relevance to the human immune, nutrition and metabolic systems. A dominant symbiont of this environment is Bacteroides thetaiotaomicron which is characterized as being involved in degrading non digestible plant polysaccharides. This organism's genome is highly enriched in genes predicted to be involved in the hydrolysis of various glycans. Presented here is a comparative functional analysis of two alpha-glucosidases (designated BT_0339 and BT_3299), Family 31 Glycoside Hydrolases from B. thetaiotaomicron. The purpose of this research is to explore the contributions these enzymes may have to human nutrition and specifically starch digestion. Expression of both alpha-glucosidases in pET-29a expression vector resulted in high levels of expressed protein in the soluble fraction. Two-step purification allowed for the isolation of the enzymes of interest in significant yield and fractions were observed to be homogenous. Both enzymes demonstrated activity on maltose, isomaltose and malto-oligosaccharide substrates and low level of activity on lactose and sucrose. Enzymatic kinetics revealed these enzymes both preferentially cleave the alpha1-6 linkage in comparison to the expected alpha1-4 and specifically favor maltose-derived substrates of longer length. The flexible hydrolytic capabilities of BT_0339 and BT_3299 reveal the ability of this bacterium to maintain its dominant position in its environment by utilizing an array of substrates. Specifically, these enzymes demonstrate an important aspect of this organism's contribution to starch digestion in the distal gut and the overall energy intake of humans. PMID- 23036360 TI - Nutritional quality of foods and beverages on child-care centre menus in Mexico. AB - OBJECTIVE: The purpose of the present study was to assess the nutritional quality of foods and beverages listed on menus serving children in government-sponsored child-care centres throughout Mexico. DESIGN: For this cross-sectional menu assessment, we compared (i) food groups and portion sizes of foods and beverages on the menus with MyPlate recommendations and (ii) macronutrients, sugar and fibre with Daily Reference Intake standards. SETTING: Menus reflected foods and beverages served to children attending one of 142 government-sponsored child-care centres throughout Mexico. SUBJECTS: There were fifty-four distinct menus for children aged 4-6 months, 7-9 months, 10-12 months, 13-23 months, 24-47 months and 48-72 months. RESULTS: Menus included a variety of foods meeting minimum MyPlate recommendations for each food category except whole grains for children aged 48-72 months. Menus listed excessive amounts of high-energy beverages, including full-fat milk, fruit juice and sugar-sweetened beverages for children of all ages. The mean daily energy content of menu items yielded an average of 2?76 MJ for infants, 4.77 MJ for children aged 13-23 months, 5.36 MJ for children aged 24-47 months and 5.87 MJ for children aged 48-72 months. Foods and beverages on menus provided sufficient grams of carbohydrate and fat, but excessive protein. CONCLUSIONS: Menus provided a variety of foods but excessive energy. Whole grains were limited, and high-energy beverages were prevalent. Both may be appropriate targets for nutrition intervention. Future studies should move beyond menus and assess what children actually consume in child care. PMID- 23036361 TI - Iron overload, measured as serum ferritin, increases brain damage induced by focal ischemia and early reperfusion. AB - High levels of iron, measured as serum ferritin, are associated to a worse outcome after stroke. However, it is not known whether ischemic damage might increase ferritin levels as an acute phase protein or whether iron overload affects stroke outcome. The objectives are to study the effect of stroke on serum ferritin and the contribution of iron overload to ischemic damage. Swiss mice were fed with a standard diet or with a diet supplemented with 2.5% carbonyl iron to produce iron overload. Mice were submitted to permanent (by ligature and by in situ thromboembolic models) or transient focal ischemia (by ligature for 1 or 3h). Treatment with iron diet produced an increase in the basal levels of ferritin in all the groups. However, serum ferritin did not change after ischemia. Animals submitted to permanent ischemia had the same infarct volume in the groups studied. However, in mice submitted to transient ischemia followed by early (1h) but not late reperfusion (3h), iron overload increased ischemic damage and haemorrhagic transformation. Iron worsens ischemic damage induced by transient ischemia and early reperfusion. In addition, ferritin is a good indicator of body iron levels but not an acute phase protein after ischemia. PMID- 23036362 TI - A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia. AB - Lanthionines are novel neurotrophic and neuroprotective small molecules that show promise for the treatment of neurodegenerative diseases. In particular, a recently developed, cell permeable lanthionine derivative known as LKE (lanthionine ketimine 5-ethyl ester) promotes neurite growth at low nanomolar concentrations. LKE also has neuroprotective, anti-apoptotic, and anti inflammatory properties. Its therapeutic potential in cerebral ischemia and its mechanisms of neurotrophic action remain to be fully elucidated. Here, we hypothesize that the neuroprotective actions of LKE could result from induction or modulation of CRMP2. We found that treating primary cultured mouse neurons with LKE provided significant protection against t-butyl hydroperoxide-induced neuronal death possibly through CRMP2 upregulation. Similarly, in vivo studies showed that LKE pre and/or post-treatment protects mice against permanent distal middle cerebral artery occlusion (p-MCAO) as evidenced by lower stroke lesions and improved functional outcomes in terms of rotarod, grip strength and neurologic deficit scores in treated groups. Protein expression levels of CRMP2 were higher in brain cortices of LKE pretreated mice, suggesting that LKE's neuroprotective activity may be CRMP2 dependent. Lower activity of cleaved PARP-1 and higher activity of SIRT-1 was also observed in LKE treated group suggesting its anti-apoptotic properties. Our results suggest that LKE has potential as a therapeutic intervention in cerebral ischemia and that part of its protective mechanism may be attributed to CRMP2 mediated action and PARP-1/SIRT-1 modulation. PMID- 23036363 TI - Dynamic informed consent processes vital for treatment with antidepressants. AB - Advances in technology and transparency have greatly accelerated the ability of clinicians to remain current with regards to being informed and informing patients about the risk/benefit ratio when considering antidepressant medication. In spite of this, the current climate of pharmaceutical industry influence on medical practice does much to hinder informed consent processes. Recent findings of previously unknown and potentially dangerous adverse effects of the second- and third-generation classes of antidepressants underscore the importance of enhancing the practice of informed consent. After considering the concept of informed consent as it has evolved over time, the authors summarize some of the newer side effects associated with second- and third-generation antidepressants and then move on to describe impediments in the way of achieving adequate informed consent at the clinical encounter. Among these impediments, the authors discuss the impact of industry influence, cognitive bias in decision-making, and time constraints. These obstacles and the notion that modern antidepressants are not as safe as once thought offer an opportunity to revisit the process of informed consent. A dynamic concept of informed consent is proposed with the acknowledgement that a mere listing of side effects or pro forma approach to informed consent is inadequate, and that a mindful and ongoing dialog with patients in which clinicians are responsive to patients' evolving needs as new information becomes available will more likely result in patient empowerment and a strengthening of the therapeutic alliance, thereby allowing patient and doctor to shoulder the burden of uncertainty together and leading to more optimal treatment outcomes. PMID- 23036364 TI - Exposing conflict of interest in psychiatry: does transparency matter? AB - BACKGROUND: No one has been more effective than U.S. Senator Charles Grassley in promoting transparency in medicine. His investigations into undisclosed physician industry ties culminated in the Physician Payments Sunshine Act (PPSA), which will make drug and device companies' payments to physicians a matter of public record. Yet it is unclear whether PPSA will resolve the problems that Grassley's campaign for it revealed. METHODS AND FINDINGS: We analyzed five signal cases, all involving psychiatrists, that Grassley presented to the U.S. Senate as examples of why PPSA was needed. We sought to determine the impact of the information Grassley brought to light on the physicians who failed to report their industry ties and on the medical institutions responsible for overseeing their conduct. Despite the clarity of the violations and the powerful actors and institutions involved, the consequences of exposure were slow to materialize and limited in their impact. CONCLUSIONS: Our findings demonstrate both the need for transparency and its limitations. The medical profession and the government should use the PPSA data to verify disclosures, but they must also implement stronger conflict of interest policies to help ensure that physicians' industry ties, however transparent, do not compromise scientific integrity or patient care. PMID- 23036365 TI - Ubiquitin drug discovery and diagnostics. PMID- 23036366 TI - Increased expression of apoptosis-related protein 3 is highly associated with tumorigenesis and progression of cervical squamous cell carcinoma. AB - The apoptosis-related protein 3 (APR3) gene was first cloned from HL-60 cells treated with all-trans-retinoic acid and was thought to be related to tumor cell apoptosis or differentiation. In this study, we sought to investigate its expression profile in cervical squamous cell carcinoma (SCC) and preneoplastic lesions to determine whether APR3 is involved in the malignant progression of SCC. The purified partial recombinant APR3 proteins were used to immunize rabbits for raising antibodies, and the specificity of the polyclonal anti-APR3 antibody was determined by enzyme-linked immunosorbent assay and Western blot. Sections were assessed for APR3 expression by immunohistochemistry in archived tissues from human normal cervix samples (n = 20), cervical intraepithelial neoplasia (n = 19), and invasive SCC (n = 52). Specific cytoplasmic immunostaining was evaluated for overall intensity and uniformity to derive a combined histoscore. The results of enzyme-linked immunosorbent assay and Western blot indicated that anti-APR3 antibody can serve as a good tool for research. The immunohistochemical analysis demonstrated an increased expression of APR3 in SCC relative to normal cervix epithelium and cervical intraepithelial neoplasia (P < .05). Strikingly, APR3 expression level was significantly higher in nonkeratinizing SCCs compared with keratinizing SCCs (P < .05) and higher in carcinomas with lymph node metastasis compared with cases without lymph node metastasis (P < .05). This study demonstrates that APR3 expression is increased significantly with malignant progression of human cervical SCC, and thus, it may serve as a potential biomarker to predict prognosis of cervical SCC. PMID- 23036367 TI - Papillary thyroid carcinoma with hobnail features: histopathologic criteria to predict aggressive behavior. AB - Recent reports indicate that papillary thyroid carcinoma with hobnail features, also designated as micropapillary variant of papillary thyroid carcinoma, is a rare but very aggressive variant of papillary thyroid carcinoma. We examined the histopathologic and immunohistochemical features of 24 cases of papillary thyroid carcinoma with hobnail/micropapillary component to determine the prognostic significance of the amount of hobnail/micropapillary features in these tumors. The patients included 18 women and 6 men. Ages ranged from 28 to 78 years (mean, 57 years). Tumor size ranged from 1 to 5.8 cm (mean, 3 cm). The average follow-up time was 106 months (range, 4-274 months). Twelve cases (50%) of papillary thyroid carcinoma showed more than 30% hobnail/micropapillary features, and all but 3 cases were associated with an aggressive behavior. During the follow-up, 6 of these patients died of disease after a mean of 44.8 months, and 3 patients remained alive with extensive disease after a mean follow-up of 32.3 months. Metastases to lymph nodes or distant organs showed a hobnail pattern of growth similar to the primary tumor. The remaining 3 patients with prominent hobnail/micropapillary features were alive with no evidence of disease after a mean follow-up of 125.3 months. The other 12 papillary thyroid carcinoma cases (50%) showed less than 30% hobnail/micropapillary features. Nine of these patients were alive without disease after a mean of 162 months, and 1 patient died of sepsis, which was not related to thyroid tumor after 155 months. Two patients in this group died of disease after 21 and 163 months, respectively. These findings confirm earlier observations that papillary thyroid carcinoma with hobnail/micropapillary features is an aggressive variant of papillary thyroid carcinoma. Tumors with more than 30% hobnail/micropapillary features were often very aggressive, although 2 patients with tumors with 10% hobnail/micropapillary features also had poor outcomes. PMID- 23036369 TI - Image analysis of microscopic crack patterns applied to thermal fatigue heat checking of high temperature tool steels. AB - Surface cracking or heat-checking is investigated at a microscopic scale on a hot work tool steel (X38CrMoV5) tested under thermal fatigue. Thermal fatigue tests are periodically interrupted to observe the surface of the specimens by scanning electron microscopy (SEM). A non destructive and semi-automatic method is developed to assess and evaluate the two-dimensional crack pattern initiated on the oxide scale layer formed on the specimen surface. The crack pattern is characterized by image analysis in terms of density, morphological and topological features. This technique allows to determine the number of cycles to initiate the microscopic heat-checking and to follow its evolution. PMID- 23036368 TI - Immunohistochemical analysis of cancer stem cell markers in invasive breast carcinoma and associated ductal carcinoma in situ: relationships with markers of tumor hypoxia and microvascularity. AB - We performed immunohistochemical analysis of 3 cancer stem cell-related markers (CD44(+)/CD24(-/low), aldehyde dehydrogenase [ALDH]-1, CD133) in 94 invasive ductal carcinomas and assessed relationships with markers of hypoxia (carbonic anhydrase IX [CAIX]), tumor microvessel density (CD31), and clinicopathologic variables. Overall, 10% of tumors were CD44(+)/CD24(-/low), 13% were ALDH-1(+), 25% were CD133(+), 35% were immunonegative, and 1 tumor was immunopositive for all 3 markers. Associated ductal carcinoma in situ (DCIS) was present in 48% of tumors. Marker immunopositivity was detected in DCIS in 13% (CD44(+)/CD24( /low)), 7% (ALDH-1(+)), and 32% (CD133(+)) of these tumors and was more likely present in DCIS when also detected in the invasive compartment (P = .03, P = .001, and P = .009, respectively). CD44(+)/CD24(-/low) cells were more common in progesterone receptor-negative tumors (P < .01), and ALDH-1(+) cells were more common in estrogen receptor-negative tumors (P < .01). CD133(+) cells were more common in patients younger than 50 years (P < .05) and in high grade (P < .01), localized (P < .05), and estrogen receptor-negative (P < .001), progesterone receptor-negative (P = .02), and triple-negative breast cancers (P < .001). CD44(+)/CD24(-/low) (P = .06) and CD133(+) (P = .02) tumor cells were more common in CAIX(+) versus CAIX(-) tumors, whereas ALDH-1(+) tumors had a higher mean microvessel density than did ALDH-1(-) tumors (P = .002). No significant relationships were observed between the markers studied and survival for 5 years. Our study demonstrated the presence of cancer stem cell marker-positive tumor cells in DCIS as well as invasive breast cancer and showed that CD44(+)/CD24( /low) and CD133(+) cells were more frequently observed in hypoxic regions of tumor, whereas ALDH-1(+) cells more commonly colocalized to tumors with high microvessel density. PMID- 23036370 TI - Antennal sensilla of female Encarsia guadeloupae Viggiani (Hymenoptera: Aphelinidae), a nymphal parasitoid of the spiraling whitefly Aleurodicus dispersus (Hemiptera: Aleyrodidae). AB - Encarsia guadeloupae Viggiani (Hymenoptera: Aphelinidae) is a minute, obligate endoparasitoid against the spiraling whitefly Aleurodicus dispersus nymph. The external morphology and distribution of the antennal sensilla of female E. guadeloupae were observed by scanning electron microscopy. Antennae of female E. guadeloupae were geniculate in shape, which consist of scape with a radicula, pedicel, and flagellum. Eight morphological sensilla types were recorded in the females: nonporous sensilla chaetica (CH-NP) and nonporous sensilla trichodea (ST NP); uniporous sensilla chaetica (CH-UP) and uniporous sensilla trichodea (ST-UP) with a tip pore, basiconic capitate peg sensilla with numerous pores open at the bottom of the grooves; multiporous sensilla placoid (MSP) with the multiporous cuticular structure; uniporous rod-like sensilla (RO-UP) with robust grooved surfaces and the tremendous apical hole; nonporous finger-like sensilla (FI-NP) with abundant pimples at the bulgy, mortar-shaped short stalk. In order to further explore the host location mechanisms and courtship behavior of E. guadeloupae, the possible roles of the antennal sensilla of this species were discussed. PMID- 23036372 TI - Systematic review of hepatocellular carcinoma mortality rates among hepatitis B virus-infected renal transplant recipients, with supplemental analyses of liver failure and all-cause mortality. AB - OBJECTIVES: The purpose of this review was to compare the mortality rates for hepatocellular carcinoma (HCC) among hepatitis B surface antigen (HBsAg) seropositive renal transplant (RT) patients versus HBsAg-seropositive persons of the general population. METHODS: A comprehensive search was performed to identify cohort studies of HBsAg-seropositive RT patients with at least 4 years of follow up. Data were analyzed as outlined below. HCC was a rare event in regions of low and intermediate seroprevalence of HBsAg. Subsequently, studies from low and intermediate seroprevalence areas were analyzed separately from those of high seroprevalence areas. RESULTS: Thirty-one retrospective studies that followed 1277 seropositive RT patients were identified for inclusion. The studies were pooled and compared to four different general population studies that included 12558 seropositive persons using Poisson methods. The mortality rate of HCC was increased in low and intermediate seroprevalence areas (RR 7.67, 95% confidence interval (CI) 3.93-15.0; RR 9.92, 95% CI 5.38-18.3). In high seroprevalence areas, the mortality rate of HCC was increased compared to one population study, but not another (RR 2.76, 95% CI 1.64-4.63; RR 1.02, 95% CI 0.61-1.69). CONCLUSIONS: Mortality due to HCC was increased in low and intermediate seroprevalence areas, but the evidence was inconclusive for high seroprevalence areas. PMID- 23036371 TI - Predicting the accuracy of facial affect recognition: the interaction of child maltreatment and intellectual functioning. AB - Previous research demonstrates that both child maltreatment and intellectual performance contribute uniquely to the accurate identification of facial affect by children and adolescents. The purpose of this study was to extend this research by examining whether child maltreatment affects the accuracy of facial recognition differently at varying levels of intellectual functioning. A sample of maltreated (n=50) and nonmaltreated (n=56) adolescent females, 14 to 19 years of age, was recruited to participate in this study. Participants completed demographic and study-related questionnaires and interviews to control for potential psychological and psychiatric confounds such as symptoms of posttraumatic stress disorder, negative affect, and difficulties in emotion regulation. Participants also completed an experimental paradigm that recorded responses to facial affect displays starting in a neutral expression and changing into a full expression of one of six emotions: happiness, sadness, anger, disgust, fear, or surprise. Hierarchical multiple regression assessed the incremental advantage of evaluating the interaction between child maltreatment and intellectual functioning. Results indicated that the interaction term accounted for a significant amount of additional variance in the accurate identification of facial affect after controlling for relevant covariates and main effects. Specifically, maltreated females with lower levels of intellectual functioning were least accurate in identifying facial affect displays, whereas those with higher levels of intellectual functioning performed as well as nonmaltreated females. These results suggest that maltreatment and intellectual functioning interact to predict the recognition of facial affect, with potential long-term consequences for the interpersonal functioning of maltreated females. PMID- 23036373 TI - Effects of serotonergic terminal lesion in the amygdala on conditioned fear and innate fear in rats. AB - The amygdala and the medial prefrontal cortex (mPFC) are crucial brain structures for anxiety, and it is speculated that the serotonergic neural system in these structures has an important role in regulating anxiety. In our previous study, we indicated that local injections of selective serotonin reuptake inhibitor into the amygdala attenuated anxiety-related behaviors in conditioned fear in rats. In the present study, we investigated the effects of serotonergic terminal lesions in the amygdala and in mPFC induced by local injection of 5,7-dihydroxytryptamine (5,7-DHT), on anxiety-related behaviors in conditioned fear and the elevated plus maze test in rats. A 5,7-DHT lesion in the amygdala attenuated memory-dependent fear assessed by conditioned fear, but enhanced memory-independent fear assessed by the elevated plus-maze test. These results suggest that the role of the amygdalar serotonergic system in fear is different between memory-dependent and independent fear and, in particular, it is paradoxical that an amygdalar serotonergic lesion exerts a similar effect on memory-dependent fear to SSRI. Moreover, a serotonergic lesion in the amygdala enhanced the retrieval of extinction memory in conditioned fear; however, a serotonergic lesion in mPFC did not bring about any behavioral changes. PMID- 23036374 TI - 2'-Benzoyloxycinnamaldehyde inhibits nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells via regulation of AP-1 pathway. AB - Cinnamaldehyde, an active compound of cinnamon, has been reported to exert various biological functions such as anti-inflammatory and anti-tumor activities. Previously, we showed that 2'-hydroxycinnamaldehyde (HCA) has an inhibitory effect on nitric oxide (NO) production through the inhibition of NF-kappaB signaling. In an effort to find a more effective anti-atherosclerotic agent, here we evaluated the anti-inflammatory effect of 2'-benzoyloxycinnamaldehyde (BCA) in RAW 264.7 murine macrophage cells. We showed that BCA more effectively inhibited NO production than HCA with less cytotoxicity. We also demonstrated that BCA inhibited the lipopolysaccharide (LPS)-induced expression of iNOS in a concentration-dependent manner. Signal transduction studies showed that BCA significantly inhibited the phosphorylation of SAPK/JNK and AP-1-dependent reporter gene activity. LPS-induced expression levels of JunB, c-Jun and c-Fos were also decreased by BCA treatment. Moreover, the LPS-induced DNA binding activity of AP-1 was markedly inhibited by BCA. The direct injection of BCA into mice inhibited the LPS-induced increase in plasma nitrite levels, confirming the anti-inflammatory effect of BCA in vivo. Overall, these observations suggest that BCA has the potential for use as an anti-atherosclerotic agent. PMID- 23036375 TI - The possible role of HSPs on Behcet's disease: a bioinformatic approach. AB - Current evidence lends increasing support to immunoinflammatory mechanisms as one of the prime pathogenic processes involved in the development and progression of Behcet's disease (BD). It has been observed that most human beings have cellular and humoral reactions against microbial heat shock proteins (HSPs). The observation that eukaryotic and prokaryotic HSPs have high sequence similarity promoted the hypothesis that HSPs might be potential candidates for molecular mimicry and could act as potentially dangerous autoantigens. In this study, using bioinformatics tools, we examined the hypothesis that HSPs (evolutionarily conserved proteins), which are present in pathogenic and commensal organisms and their hosts, provide the stimulus that initiates BD in susceptible individuals. In this regards, the nucleotide and amino acid sequences of the human HSP 60 kDa and bacterial HSP 60 kDa deposited in the NCBI and PDB databases were subjected to analysis using bioinformatics tools, including The CLC Sequence Viewer and MEGA softwares. These data showed that the sequence homology between bacterial and self HSPs (leading to cross-reactivity and molecular mimicry phenomenon) may be associated with the development of the disease; and suggesting that microbial HSPs, which cross-react with host tissues and elicit significant immune responses are possible pathogenetic agents involved in the development and progression of BD. PMID- 23036376 TI - Powered two-wheelers within the traffic system. AB - The world of powered two-wheelers has changed dramatically in recent decades, along with a steady increase in the number and diversity of the fleet and uses. This evolution has led to some benefits in terms of mobility, but also some drawbacks in terms of safety. The problems involved are neither simple nor monolithic and there is a lack of knowledge about their different facets and backgrounds that require research work both in terms of risk exposure, accidents factors and impact severity. This special issue of Accident Analysis and Prevention regroups 30 papers devoted to an improvement in this knowledge, exploring the different aspects involved in the safety of powered two-wheelers by complementary methods. PMID- 23036377 TI - Risk factors for injury accidents among moped and motorcycle riders. AB - OBJECTIVE: To study and quantify the effect of factors related to the riders of powered two-wheelers on the risk of injury accident involvement. METHODOLOGY: Based on national data held by the police from 1996 to 2005, we conducted a case control study with responsibility for the accident as the event of interest. We estimated the odds ratios for accident responsibility. Making the hypothesis that the non-responsible riders in the study are representative of all the riders on the road, we thus identified risk factors for being responsible for injury accidents. The studied factors are age, gender, helmet wearing, alcohol consumption, validity of the subject's driving licence and for how long it has been held, the trip purpose and the presence of a passenger on the vehicle. Moped and motorcycle riders are analyzed separately, adjusting for the main characteristics of the accident. RESULTS: For both moped and motorcycle riders, being male, not wearing a helmet, exceeding the legal limit for alcohol and travelling for leisure purposes increased the risk of accident involvement. The youngest and oldest users had a greater risk of accident involvement. The largest risk factor was alcohol, and we identified a dose-effect relationship between alcohol consumption and accident risk, with an estimated odds ratio of over 10 for motorcycle and moped riders with a BAC of 2 g/l or over. Among motorcycle users, riders without a licence had twice the risk of being involved in an accident than those holding a valid licence. However, the number of years the rider had held a licence reduced the risk of accident involvement. One difference between moped and motorcycle riders involved the presence of a passenger on the vehicle: while carrying a passenger increased the risk of being responsible for the accident among moped riders, it protected against this risk among motorcycle riders. CONCLUSION: This analysis of responsibility has identified the major factors contributing to excess risk of injury accidents, some of which could be targeted by prevention programmes. PMID- 23036378 TI - Analysis of factors that increase motorcycle rider risk compared to car driver risk. AB - As in other parts of the Western world, there is concern in New Zealand about increasing popularity of motorcycles because of potential increases in road trauma. This study sought to identify important factors associated with increased risk for motorcyclists to inform potential policy approaches to reduce motorcyclist injury, such as changes to motorcyclist licensing, training and education. Using data extracted from a register of all New Zealand licensed motor vehicles that were matched to crash data, statistical models were fitted to examine patterns of motorcycle risk in comparison with small cars. These showed generally elevated risks for motorcyclists compared to cars, but particularly elevated risks for motorcycle owners aged in their 20s or who lived in more urbanised settings. In crashes, motorcyclists have little protection from injury, putting the motorcyclist at high risk of injury. When comparing new motorcycles with new cars, the odds of fatal or serious injury to a motorcycle rider involved in an injury crash were almost eight times the odds for a car driver. PMID- 23036379 TI - Validity of using linked hospital and police traffic crash records to analyse motorcycle injury crash characteristics. AB - Linking hospital discharge and police traffic crash records has been used to provide information on causes and outcomes for hospitalised traffic crash cases. Motorcyclists are particularly vulnerable to injury in a traffic crash, but no published linkage studies have reported in detail on this road user group. The present study examined motorcycle traffic crash injury cases in New Zealand in 2000-2004 by probabilistically linking national hospital discharge records with police traffic crash reports. Injury cases had to have spent at least one night in hospital before being discharged and were defined as serious or moderate based on their International Classification of Disease Injury Severity Scores (ICISS). Despite a robust linkage process, only 46% of cases could be linked to a police record; 60% of the serious injuries and 41% of the moderate. The low linkage was most likely due to under-reporting of crashes to or by the police. While moderate injury cases were expected to be under-reported, the level of under-reporting of cases with serious threat-to-life injuries is concerning. To assess whether the linked dataset could provide valid information on the crash circumstances and injury outcomes of hospitalised motorcycle crash cases, the characteristics of the linked and unlinked hospital discharge cases were compared using chi-square tests and multivariate logistic regression. Serious injury cases were less likely to be linked if only one vehicle was involved, or the injured riders and passengers were younger than 20 years or spent less than one week in hospital. For moderate injury cases, there were also differences in linkage by injured body region and crash month. While these discrepancies need to taken into consideration when interpreting results, the linked hospital-police dataset has the potential to provide insights into motorcycle crash circumstances and outcomes not otherwise obtainable. PMID- 23036380 TI - Traffic safety analysis of powered two-wheelers (PTWs) in Slovenia. AB - Due to the 2006 European research report on powered two-wheelers (PTWs) riders' traffic safety, Slovenia represents the highest risk for PTW riders in the European Union. Namely, in Slovenia we have the largest number of PTW riders' deaths per billion travelled kilometers in 2006. Since then the traffic safety situation in the field of PTW riders in Slovenia has been improving and we will discuss that phenomenon in the present paper. The paper identifies and analyzes the causes that led to such a critical situation. Further, the evaluation of activities that were carried out to improve the road safety for powered two wheeler riders in Slovenia in the last past years are discussed. In conclusion a selection of measures and actions is presented that already has been and also should be carried out in the future. PMID- 23036381 TI - Severity of motorcycle crashes in Calgary. AB - Motorcycle riders would be more vulnerable in the event of a crash because of their lack of protection which would often result in them suffering more severe injuries than car drivers. This paper estimated three crash severity models to identify factors that contributed to increasing the severity of motorcycle involved crashes in the Canadian City of Calgary. We found that results from the ordered logit model, heterogeneous choice model and partially constrained generalized ordered logit model produced estimates that were very similar which attested to their robustness. Injury severity tended to increase in neighborhoods with loops and lollipops types of streets or involved right-angle and left-turn across-path crashes, a truck, unsafe speed or alcohol use but tended to decrease if the crash occurred in parking lots or during winter, involved a van or male rider, or a rider following-too-closely to the vehicle in front. PMID- 23036382 TI - Traffic safety among motorcyclists in Norway: a study of subgroups and risk factors. AB - Although it is widely recognized that motorcyclists have a particularly high accident risk, our knowledge of the mechanisms producing this accident risk is incomplete. The aims of the present paper are to identify subgroups of motorcyclists with a particularly high accident risk and to identify the relevant risk factors at work. The study presented in this paper relies both on a questionnaire (N=3356) relating rider characteristics, behaviors and accident risk, and analyses of fatal motorcycle accidents (ca. 100) from 2005 to 2008 in Norway. The results reveal that riders of racing replica bikes (sport bikes), and riders younger than 19 years, including especially youths (16-17 years) riding light motorcycles (<=125 cm(3)), are subgroups of Norwegian motorcyclists with particularly high accident risks. Analysis of fatal motorcycle accidents reveals that about half of the fatal accidents involve sport bikes. Nearly all fatal accidents with sport bikes involved excessive speed. The combination of low age, low experience, risky behavior and "unsafe" attitudes seems to be a particular potent risk factor for Norwegian motorcyclists. PMID- 23036383 TI - Analysis of powered two-wheeler crashes in Italy by classification trees and rules discovery. AB - Aim of the study was the analysis of powered two-wheeler (PTW) crashes in Italy in order to detect interdependence as well as dissimilarities among crash characteristics and provide insights for the development of safety improvement strategies focused on PTWs. At this aim, data mining techniques were used to analyze the data relative to the 254,575 crashes involving PTWs occurred in Italy in the period 2006-2008. Classification trees analysis and rules discovery were performed. Tree-based methods are non-linear and non-parametric data mining tools for supervised classification and regression problems. They do not require a priori probabilistic knowledge about the phenomena under studying and consider conditional interactions among input data. Rules discovery is the identification of sets of items (i.e., crash patterns) that occur together in a given event (i.e., a crash in our study) more often than they would if they were independent of each other. Thus, the method can detect interdependence among crash characteristics. Due to the large number of patterns considered, both methods suffer from an extreme risk of finding patterns that appear due to chance alone. To overcome this problem, in our study we randomly split the sample data in two data sets and used well-established statistical practices to evaluate the statistical significance of the results. Both the classification trees and the rules discovery were effective in providing meaningful insights about PTW crash characteristics and their interdependencies. Even though in several cases different crash characteristics were highlighted, the results of the two the analysis methods were never contradictory. Furthermore, most of the findings of this study were consistent with the results of previous studies which used different analytical techniques, such as probabilistic models of crash injury severity. Basing on the analysis results, engineering countermeasures and policy initiatives to reduce PTW injuries and fatalities were singled out. The simultaneous use of classification trees and association discovery must not, however, be seen as an attempt to supplant other techniques, but as a complementary method which can be integrated into other safety analyses. PMID- 23036384 TI - Motorcyclists' speed and "looked-but-failed-to-see" accidents. AB - Previous research on motorcycle crashes has shown the frequency and severity of accidents in which a non-priority road user failed to give way to an approaching motorcyclist without seeing him/her, even though the road user had looked in the approaching motorcycle's direction and the motorcycle was visible. These accidents are usually called "looked-but-failed-to-see" (LBFS) accidents. This article deals with the effects that the motorcyclist's speed has in these accidents. It is based on the in-depth study and precise kinematic reconstruction of 44 accident cases involving a motorcyclist and another road user, all occurring in intersections. The results show that, in urban environments, the initial speeds of motorcyclists involved in "looked-but-failed-to-see" accidents are significantly higher than in other accidents at intersections. In rural environments, the difference in speed between LBFS accidents and other accidents is not significant, but further investigations would be necessary to draw any conclusions. These results suggest that speed management, through road design or by other means, could contribute to preventing "looked-but-failed-to-see" motorcycle accidents, at least in urban environments. PMID- 23036386 TI - Risk and threat factors in prior representations of driving situations among powered two-wheeler riders and car drivers. AB - Our research objective is to contribute to gaining a better understanding of the difficulties inherent to managing interactions between power two-wheeler riders and car drivers. 132 power two-wheeler riders and 94 car drivers have been asked what they perceive as being riskiest in driving situations for the representatives of their generic reference group. From all the answers produced, only those which provide information on risk factors related to the other and the occurrence of interferences due to the dynamic situation have been retained and analysed. The results provide a partial explanation of the difficulties related to the two types of users' taking each other into account. On the one hand, the frequency with which the other is mentioned as a source of risk is linked to the concept of conspicuity. This interpretation is related to the relative frequency of the interactions and the difference of real and perceived vulnerability between the users. On the other hand, the specific risk factors attributed to the other illustrates a mutual misunderstanding or ignorance of the driving situation's determinants. These include various practices among users which can be related to the physical and dynamic characteristics of their vehicle and their level of familiarity with other users. The potential road safety consequences of prior representations of risk factors among users are presented and suggestions for improving road user safety are proposed. PMID- 23036385 TI - Are car daytime running lights detrimental to motorcycle conspicuity? AB - For a long time, motorcycles were the only vehicles with daytime running lights (DRLs), but this conspicuity advantage has been questioned due to the rapidly increasing introduction of DRLs on cars as well. The present experiment was designed to assess effects of car DRLs on motorcycle perception in a situation that specifically brought attentional conspicuity to bear. Photographs representing complex urban traffic scenes were displayed briefly (250 ms) to 24 participants who had to detect vulnerable road users (motorcyclists, cyclists, pedestrians) appearing at different locations and distances. Car DRLs hampered motorcycle perception compared to conditions where car lights were not on, especially when the motorcycle was at a greater distance from the observer and when it was located in the central part of the visual scene. Car DRLs also hampered the perception of cyclists and pedestrians. Although the globally positive safety effect of car DRLs is generally acknowledged, our study suggests that more attention should be paid to motorcyclists and other vulnerable road users when introducing car DRLs. Several means of improving motorcycle conspicuity in car DRL environments are discussed. PMID- 23036387 TI - Public attitudes towards motorcyclists' safety: a qualitative study from the United Kingdom. AB - The aim of the reported research was to examine the perceptions of road user safety amongst different road users and examine the link between attitudes, empathy and skill in motorcycle safety behaviour. Motorcyclists were perceived by the study participants, members of the public at four different locations at the UK (including motorcyclists and non-motorcyclists), as a group be at a high risk of accidents on the road. This was due to perceived behavioural characteristics of motorcyclists--who were viewed as 'thrill seekers'--as well as observed behaviours on the road. This, coupled with the physical vulnerability and excessive speeds, meant that motorbike driving was considered by the study participants as the least safe form of road use. There was broad agreement that motorcycling was dangerous as a whole, but not all motorcyclists were necessarily risky riders. The issue of 'competitive space' emerged between car drivers and motorcyclists in particular and it was suggested that there was a lack of mutual awareness and considerations between the two groups. Generally, greatest empathy comes from drivers who are motorcyclists themselves. Engineering, education, enforcement interventions were investigated. These were aimed at two main areas: normalising safer driving behaviours for motorcyclists and increasing awareness of bikes for motorists--particularly in relation to reducing speed limits at urban junctions. Finally, the idea of risk mapping and reduced speed limits on rural roads was seen as potentially effective--particularly as certain motorcyclists highlighted that they changed their riding behaviours by increasing speed and taking greater risks on these roads. PMID- 23036388 TI - Powered two-wheelers road accidents and their risk perception in dense urban areas: case of Paris. AB - For a few years, the use of powered two-wheelers has taken off in Paris. It then became critical for the City of Paris to understand both the mechanisms leading to traffic accidents involving at least one powered two-wheelers user and the perception of their risk when riding in dense urban areas. In so doing, two studies were carried out along similar lines so that their results could be compared. The first study focused on the perception of situations where accidents are most likely to occur. The second one was an analysis of police reports of accidents involving at least one powered two-wheelers and the drawing-up of prototypical accident scenarios. Comparing the results of the two studies revealed a gap between perceived and objective risks of these users. In fact, they rather fear the situations during which a car driver is changing lanes, while accidents involving them occur more often when a car driver turns (right, left or U). Knowledge of this dissonance in terms of awareness of road risks for powered two-wheelers and equally, other road users, will give the City of Paris food for thought. The promising results of this study have encouraged the City of Paris to extend it to other types of users, such as cyclists or elderly pedestrians. PMID- 23036389 TI - Motorcycle accidents, rider behaviour, and psychological models. AB - The aims of the present study were to: (a) investigate the factor structure of the Motorcycle Rider Behaviour Questionnaire (MRBQ) [Elliott, M.A., Baughan, B.J., Sexton, B.F., 2007. Errors and violations in relation to motorcyclists' crash risk. Accident Analysis and Prevention 39, 491-499] in among Turkish riders, and (b) study the relationships between different types of rider behaviour and motorcyclists' active and passive accidents and offences, and (c) investigate the usefulness of the Theory of Planned Behaviour (TPB), Health Belief Model (HBM), and Locus of Control (T-LOC) in explaining rider behaviours. MRBQ was administered to a sample of motorcyclists (N=451). Principal components analysis yielded a 5-factor solution including traffic errors, control errors, speed violations, performance of stunts, and use of safety equipment. Annual mileage was related to higher number of active and passive accidents and offences whereas age was related to lower number of active and passive accidents. Stunts were the main predictors of active accidents and offences. Speeding violations predicted offences. Stunts and speeding violations were associated with the fate factor of the T-LOC, and with attitudes, subjective norms, and intention components of TPB, and cues to action and perceived severity components of the HBM. Use of safety equipment was related to the high level of perceived behavioural control and intention components of the TPB, the low score of perceived barriers component of the HBM, and the low fate factor of the T-LOC. While traffic errors were associated with the high score of perceived barriers and cues to action component of the HBM, control errors were related to the high score of vehicle and environment factor of the T-LOC. PMID- 23036390 TI - Understanding the factors influencing safe and unsafe motorcycle rider intentions. AB - The increasing popularity of motorcycles in Australia is a significant concern as motorcycle riders represent 15% of all road fatalities and an even greater proportion of serious injuries. This study assessed the psychosocial factors influencing motorcycle riders' intentions to perform both safe and risky riding behaviours. Using an extended theory of planned behaviour (TPB), motorcycle riders (n=229) from Queensland, Australia were surveyed to assess their riding attitudes, subjective norm (general and specific), perceived behavioural control (PBC), group norm, self-identity, sensation seeking, and aggression, as well as their intentions, in relation to three safe (e.g., handle my motorcycle skilfully) and three risky (e.g., bend road rules to get through traffic) riding behaviours. Although there was variability in the predictors of intention across the behaviours, results revealed that safer rider intentions were most consistently predicted by PBC, while riskier intentions were predicted by attitudes and sensation seeking. The TPB was able to explain a greater proportion of the variance for intentions to perform risky behaviours. Overall, this study has provided insight into the complexity of factors contributing to rider intentions and suggests that different practical strategies need to be adopted to facilitate safer and reduce risky rider decisions. PMID- 23036391 TI - Identifying the psychological determinants of risky riding: an application of an extended Theory of Planned Behaviour. AB - The Theory of Planned Behaviour (TPB) plus moral norms, anticipated regret, past behaviour, self-identity and perceived susceptibility was applied to predicting motorcyclists' intention to ride above the speed limit and ride at inappropriate speeds. Past behaviour, control beliefs, attitudes, moral norm, normative beliefs, age and self-identity explained 60% of the variance in motorcyclists' intention to exceed the speed limit on motorways (N=1381). A total of 62% of the variance in motorcyclists' intention to really go for it on rural roads was accounted for, with past behaviour, attitudes, control beliefs, age, normative beliefs, anticipated regret, self-identity, behavioural beliefs and training status being significant (N=1116). Finally, attitudes, past behaviour, control beliefs, moral norm, anticipated regret, behavioural beliefs, normative beliefs, engine size and self-identity explained 57% of the variance in motorcyclists' intention to ride faster than felt safe in order to keep up with the group (N=1940). The belief-based measures also successfully differentiated between those who intended to speed and those who did not. Theoretical and practical implications of the findings are discussed. PMID- 23036392 TI - Towards a conceptual model of motorcyclists' Risk Awareness: a comparative study of riding experience effect on hazard detection and situational criticality assessment. AB - This research investigates risk awareness abilities among different populations of motorcyclists. Risk awareness is defined here as an extension of the Situational Awareness theory applied to critical driving situations. This study is more particularly focused on two main cognitive abilities supporting risk awareness: hazard detection, corresponding to riders' skill to perceive critical event occurring in the road environment and to identify it as a threat, and situational criticality assessment, corresponding to a subjective assessment of the accident risk. From this theoretical framework, the aim is to compare motorcyclists' performances in risk awareness according to their experience in motorcycling. Four populations of motorcyclists are investigated: Professional (Policemen), Experienced riders, Novices, and Beginners. Method implemented is based of a set of 25 video sequences of driving situations presenting a risk of collision. Participants' task was firstly to stop the video film if they detect a hazard. Then, at the end of each sequence, they have also to assess the criticality of the driving situation as a whole, with a Likert scale (from 0 to 100% of criticality). Results obtained show that cognitive abilities in both (i) hazard detection and (ii) situational criticality assessment depend of the riding experience, and are learnt from two different timing. On one side, Professional and Experienced riders obtained better results than Novices and Beginners for hazard perception (i.e. shortest reaction time). In terms of situational criticality assessment, Beginners underestimate the situational risk and seem overconfident in their abilities to manage the situational risk, against Novices, Professional and Experienced riders, who have better competences in criticality assessment. From these empirical results, a conceptual model of motorcyclists' Risk Awareness is proposed. PMID- 23036393 TI - Beyond general behavioral theories: structural discrepancy in young motorcyclist's risky driving behavior and its policy implications. AB - While many studies examine the mean score differences of psychological determinants between heterogeneous driver groups, this study reveals a structural discrepancy in a causal behavioral framework. Using young motorcyclists (ages 18 28) as subjects, this study investigates the various roles of key influential factors in determining risky driving behavior. Multi-group analysis of structural equation modeling shows that age and gender are two factors that can effectively distinguish heterogeneous driver groups exhibiting different decision-making mechanisms in shaping their risky driving behaviors. When encountering undesirable traffic conditions, road rage can immediately increase male motorcyclists' intentions to engage in risky driving behaviors; on the other hand, young female motorcyclists further calculate their perceived risk to determine whether to engage in risky driving behaviors. This result shows that there is a significant link between risk perception and traffic condition awareness for experienced drivers (ages 25-28), but not for younger drivers (ages 18-24). This finding shows that while well-developed theories such as planned behavior and risk homeostasis provide general frameworks to explain risky driving behavior, heterogeneous driver groups may exhibit structural discrepancies that reflect their various decision-making mechanisms. This suggests that, in addition to mean differences, understanding structural discrepancies among heterogeneous groups could help researchers identify effective intervention strategies. PMID- 23036394 TI - The intention and willingness to pay moving violation citations among Taiwan motorcyclists. AB - This study uses three-level scenario design and Spike model constructs to investigate the risk premium Taiwan motorcycle operators are willing to pay for moving violations. The primary focus of the investigation is on four types of moving violations including speeding, running red lights, right turn on red violations, and drunk driving. In the model, these four types of violations influence the willingness to pay a risk premium. The results show that, in addition to increasing enforcement, raising the level of fines is one of the most effective methods to influence levels of compliance. Estimated results through the Spike model show that speeders will accept a risk premium of NT$740 (US$1=NT$30), while motorcycle operators who run red lights will accept a risk premium of NT$1100, motorcycle operators who turn right on red will accept a risk premium of NT$367, and motorcyclists who drive drunk will accept a risk premium of NT$18,540. This indicates that current fines in Taiwan could be raised. PMID- 23036395 TI - The red-light running behavior of electric bike riders and cyclists at urban intersections in China: an observational study. AB - Electric bikes and regular bicycles play an important role in the urban transportation system of China. Red-light running is a type of highly dangerous behavior of two-wheeled riders. The main purpose of this study was to investigate the rate, associated factors, and behavior characteristics of two-wheelers' red light running in China. A field observational study was conducted using two synchronized video cameras at three signalized intersections in Beijing. A total of 451 two-wheelers facing a red light (222 e-bike riders and 229 cyclists) were observed and analyzed. The results showed that 56% of the two-wheelers crossed the intersection against a red light. Age was found to be a significant variable for predicting red-light runners, with the young and middle-aged riders being more likely than the old ones to run against a red light. The logistic regression analysis also indicated that the probability of a rider running a red light was higher when she or he was alone, when there were fewer riders waiting, and when there were riders already crossing on red. Further analysis of crossing behavior revealed that the majority of red-light running occurred in the early and late stages of a red-light cycle. Two-wheelers' crossing behavior was categorized into three distinct types: law-obeying (44%), risk-taking (31%) and opportunistic (25%). Males were more likely to act in a risk-taking manner than females, and so were the young and middle-aged riders than the old ones. These findings provide valuable insights in understanding two-wheelers' red-light running behaviors, and their implications in improving road safety were discussed. PMID- 23036396 TI - A dynamic analysis of motorcycle ownership and usage: a panel data modeling approach. AB - This study aims to develop motorcycle ownership and usage models with consideration of the state dependence and heterogeneity effects based on a large scale questionnaire panel survey on vehicle owners. To account for the independence among alternatives and heterogeneity among individuals, the modeling structure of motorcycle ownership adopts disaggregate choice models considering the multinomial, nested, and mixed logit formulations. Three types of panel data regression models--ordinary, fixed, and random effects--are developed and compared for motorcycle usage. The estimation results show that motorcycle ownership in the previous year does exercise a significantly positive effect on the number of motorcycles owned by households in the current year, suggesting that the state dependence effect does exist in motorcycle ownership decisions. In addition, the fixed effects model is the preferred specification for modeling motorcycle usage, indicating strong evidence for existence of heterogeneity. Among various management strategies evaluated under different scenarios, increasing gas prices and parking fees will lead to larger reductions in total kilometers traveled. PMID- 23036397 TI - The kinematic features of motorcycles in congested urban networks. AB - The aim of this paper is to compare the kinematic features of motorcycles with those of passenger cars in urban traffic. The hypothesis that motorcycles' capability to swerve in urban traffic contributes to their seemingly assertive behaviour is examined. Data for this study were collected in afternoon peak hours at Central London using video recorders. Detailed information on the trajectories of 2109 vehicles (including 477 motorcycles and 1293 passenger cars) was extracted from the video images and the observable kinematic features were analysed. In addition, a model describing the longitudinal following behaviour of motorcycles was employed to analyse the impacts of motorcycles' swerving behaviour. The model was calibrated using Markov Chain Monte Carlo (MCMC) numerical methods. The observable kinematic features show that in comparison to passenger cars, motorcycles have shorter safety gaps, higher speeds and severer acceleration and deceleration rates reflecting their generally much higher power to weight ratios and usage of available braking power. However, the data also support the hypothesis that motorcyclists maintain a considerable safety margin as they have the ability to avoid a collision by swerving away. PMID- 23036398 TI - Analysis of the stability of PTW riders in autonomous braking scenarios. AB - While fatalities of car occupants in the EU decreased remarkably over the last decade, Powered Two Wheelers (PTWs) fatalities still increase following the increase of PTW ownership. Autonomous braking systems have been implemented in several types of vehicles and are presently addressed by research in the field of PTWs. A major concern in this context is the rider stability. Experiments with volunteers were performed in order to find out whether autonomous braking for PTWs will produce a greater instability of the rider in comparison to manual braking. The PTW's braking conditions were simulated in a laboratory with a motorcycle mock-up mounted on a sled, which was accelerated with an average of 0.35 g. The motion of the rider was captured in autonomous braking scenarios with and without pre-warning as well as in manual braking scenarios. No significant differences between the scenarios were found with respect to maximum forward displacement of the volunteer's torso and head (p<0.05). By performing clustering analysis on two kinematic parameters, two different strategies of the volunteers were identified. They were not related to the braking scenarios. A relation of the clusters with the initial posture represented by the elbow angle was revealed (p<0.05). It is concluded that autonomous braking at low deceleration will not cause significant instabilities of the rider in comparison to manual braking in idealized laboratory conditions. Based on this, further research into the development and implementation of autonomous braking systems for PTWs, e.g. by extensive riding tests, seems valuable. PMID- 23036399 TI - Injuries among powered two-wheeler users in eight European countries: a descriptive analysis of hospital discharge data. AB - Powered two-wheelers (PTWs--mopeds, motorcycles, and scooters) remain the most dangerous form of travel on today's roads. This study used hospital discharge data from eight European countries to examine the frequencies and patterns of injury among PTW users (age>=14 years), the predicted incidence of the loss of functional ability, and the mechanisms of the head injuries observed (all in light of increased helmet use). Of 977,557 injured patients discharged in 2004, 12,994 were identified as having been injured in PTW collisions. Lower extremity injuries accounted for 26% (25.6-26.7, 95% C.I.) of the total injuries, followed by upper extremity injuries (20.7%: 20.3-21.2), traumatic brain injuries (TBI) (18.5%: 18-19), and thoracic injuries (8.2%: 7.8-8.5). Approximately 80% of the lower extremity injury cases were expected to exhibit some functional disability one year following discharge (predicted Functional Capacity Index, pFCI AIS98<100), compared to 47% of the upper extremity injury cases and 24% of the TBI cases. Although it occurred less frequently, patients that were expected to experience some functional limitation from TBI were predicted to fair worse on average (lose more functional ability) than patients expected to have functional limitations from extremity injuries. Cerebral concussion was the most common head injury observed (occurring in 56% of head injury cases), with most concussion cases (78%) exhibiting no other head injury. Among the AIS3+ head injuries that could be mapped to an injury mechanism, 48% of these were associated with a translational-impact mechanism, and 37% were associated with a rotational mechanism. The observation of high rates of expected long-term disability suggests that future efforts aim to mitigate lower and upper extremity injuries among PTW users. Likewise, the high rates of concussion and head injuries associated with a rotational mechanism provide goals for the next phase of PTW user head protection. PMID- 23036400 TI - Motorcycle-related spinal injury: crash characteristics. AB - This study presents an analysis of crash characteristics of motorcyclists who sustained spinal injuries in motorcycle crashes. The aim of the study is to identify the salient crash characteristics that would help explain spinal injury risks for motorcyclists. Data were retrospectively collected from police case reports that were archived at MIROS from year 2005 to 2007. The data were categorized into two subcategories; the first group was motorcycle crashes with spinal injury (case) and the second group was motorcycle crashes without spinal injury (control). A total of 363 motorcyclists with spinal injury and 873 motorcyclists without spinal injury were identified and analyzed. Descriptive analysis and multivariate analysis were performed in order to determine the odds of each characteristic in contributing to spinal injury. Single vehicle crash, collision with fixed objects and crash configuration were found to have significant influence on motorcyclists in sustaining spinal injury (p<0.05). Although relatively few than other impact configurations, the rear-end impacted motorcyclist shows the highest risk of spinal injury. Helmets have helped to reduce head injury but they did not seem to offer corresponding protection for the spine in the study. With a growing number of young motorcyclists, further efforts are needed to find effective measures to help reduce the crash incidents and severity of spinal injury. In sum, the study provides some insights on some vital crash characteristics associated with spinal injury that can be further investigated to determine the appropriate counter-measures and prevention strategies to reduce spinal injury. PMID- 23036401 TI - Motorcycle-related injuries in the United Arab Emirates. AB - OBJECTIVES: To study the anatomical distribution, severity, outcome, and age by nationality of hospitalized motorcycle-related injured patients in Al-Ain, United Arab Emirates so as to improve preventive measures. METHODS: All motorcycle riders involved in a road traffic collision and admitted to Al-Ain Hospital for more than 24 h or who died in hospital after arrival were studied. Patient data were retrieved from Al-Ain Hospital Trauma Registry. Data had been prospectively collected during four and half years (March 2003-October 2007). Demography of patients, Glasgow Coma Scale (GCS), Injury Severity Score (ISS), Hospital stay, mortality, nationality, time, day of week, and month of occurrence were analyzed. RESULTS: There were 95 patients (93 males). Mean (SD) age was 29.8 (11.5) years. 35% were United Arab Emirates (UAE) nationals. Upper limbs were most frequently involved (54%) followed by lower limbs (48%), head (41%), and face (30%). On arrival at hospital, median (range) ISS was 4.5 (1-36) and median (range) GCS was 15 (3-15). Mean (range) hospital stay was 8.8 (1-79) days. 14 patients (15%) were admitted to the Intensive Care Unit. In-hospital mortality was 6%. UAE national victims were significantly younger and had more abdominal injuries than expatriates, who had lower limb injuries. CONCLUSIONS: The most common mechanism of motorcycle crashes was hitting a moving vehicle. Young UAE national motorcyclists are at a higher risk of being injured compared with non UAE nationals. This may be due to risk-taking behavior of young motorcyclists who are mainly riding for leisure. Extremities were the most common injured body region. Severe head injury was the main cause of death. This signifies the need for effective application of motorcycle helmet law in the UAE along with other preventive measures that might include increasing the licensing age. PMID- 23036402 TI - Does wearing helmets reduce motorcycle-related death? A global evaluation. AB - BACKGROUND: The high risk of injury and death of motorcycle riders is a major global health problem. This study aimed to evaluate the effect of helmet wearing on motorcycle riders' death rates on a global level. METHODS: Data for motorcycle riders were collected from 70 countries. These data included motorcycle-related death rates per 100,000 population, helmet non-usage percentage, Gross National Income per capita (GNI), number of registered motorized 2-3 wheelers, the effectiveness of law enforcement in each country, and whether there was standards for helmets use or not. Correlations between studied variables were done using Pearson correlation. Multiple linear regression models were used to define factors affecting motorcycle-related death rates. RESULTS: The correlation between motorcycle-related death rate and helmet non-usage, was almost significant (p=0.056, r=0.28). Helmet non-usage percentage was significantly correlated with GNI (p<0.0001, r=-0.61) and effectiveness of the law (p<0.0001, r=-0.73). A multiple linear regression model which was highly significant (adjusted R-squared=0.3, F=6.69, p<0.001) has shown that helmet non-usage percentage (p=0.003), motorcycle per person ratio (p=0.01) and the presence of helmet standards (p=0.05) were positively associated with motorcycle-related death rates. A simple linear regression model between helmet usage and road traffic death rate has shown that for each 10% increase in helmet usage, one life per 1,000,000 inhabitants can be saved per year. CONCLUSION: Helmet non-usage percentage was the most significant factor affecting motorcyclists' death rate. Wearing a motorcycle helmet reduces the risk of death from a motorcycle crash. Enforcement of motorcycle helmet laws should be effectively supported by motorcycle safety programs. PMID- 23036403 TI - Injury typology of fatal motorcycle collisions with roadside barriers in Australia and New Zealand. AB - Motorcyclists contribute significantly to road trauma around the world through the high incidence of serious injuries and fatalities. The role of roadside safety barriers in such trauma is an area of growing concern amongst motorcyclists, road authorities and road safety researchers and advocates. This paper presents a case series analysis of motorcyclists that were fatally injured following a collision with a roadside barrier during the period 2001-2006 in Australia and New Zealand. Injury profiles and severities are detailed, and associations with crash characteristics are investigated. It is shown that the thorax region had the highest incidence of injury and the highest incidence of maximum injury in fatal motorcycle-barrier crashes, followed by the head region. This is in contrast to fatal motorcycle crashes in all single- and multi-vehicle crash modes, where head injury predominates. The injury profiles of motorcyclists that slid into barriers and those that collided with barriers in the upright posture were similar. However, those that slid in were more likely to receive thorax and pelvis injuries. PMID- 23036404 TI - More mad and more wise. AB - It is clearly important that clinicians have appropriate assessment and management pathways when working in clinical settings where illnesses associated with cognitive impairment may impair both mobility and safety, such as memory clinics and medical services dealing with older people. However, in wider terms, particularly in terms of an understanding of the impact of cognitive function on the whole population of older drivers, it is critical that debate on cognitive function and driving is adequately informed by the sciences of gerontology and public health, embraces a broad definition of cognitive function which recognizes both the gains and losses of ageing, recognizes the barriers and disruptive influences which may skew scientific debate, and frames such a discourse in terms of an appropriate balance between mobility and safety. PMID- 23036405 TI - Crash risk factors related to individuals sustaining and drivers following traumatic brain injuries. AB - OBJECTIVE: Some crashes result in drivers experiencing (or sustaining) a traumatic brain injury (TBI) while other crashes involve drivers that have already experienced a TBI. The objective of this study is to examine the factors that influence these two TBI crash groups. METHODS: Data from the Iowa Department of Public Health's Brain Injury Registry and Department of Transportation's crash records were linked together and used in logistic regression models to predict the likelihood of a driver sustaining a TBI in a crash and those who drive after a TBI. RESULTS: Between 2001 and 2006, there were 2382 crashes in which an individual sustained a TBI. As expected, a higher likelihood of sustaining a TBI was observed for motorcycle drivers who did not wear a helmet and in crashes that resulted in total or disabling vehicle damage. Focusing specifically on the post TBI drivers (and not occupants), 1583 were involved in crashes. These post-TBI drivers were less likely to wear seatbelts or have passengers in the vehicle at the time of the crash, and were more likely to crash at night. Post-TBI drivers were also involved in significantly more multiple crashes (about 14%) when compared to drivers who have not experienced a TBI (about 10%) during the study period. When controlling for gender, date of injury, and severity of TBI (using Glasgow Coma Scale), individuals that sustained a TBI when they were younger were more likely to be involved in multiple crashes. CONCLUSIONS: Different factors influence the crash likelihood for those that sustain a TBI in a crash and those that crash following a TBI. In general, post-TBI drivers have a higher occurrence of multiple crashes and this should be further explored to guide driver rehabilitation, evaluation, and training. PMID- 23036406 TI - Validity of the Occupational Therapy-Drive Home Maze Test for right and left handed test takers. AB - The Occupational Therapy-Drive Home Maze Test (OT-DHMT) is part of the OT-DORA Battery used in licensing recommendations for older and/or functionally impaired drivers. Previously published research has been conducted to investigate the predictive validity, inter-rater reliability and establish norms for this timed test with normal and cognitively impaired drivers. Anecdotal evidence from this research indicated there could be a bias against right-handers (dextrals) who may need to lift their hand to view the maze, thus increasing the time taken. Therefore this study investigated the validity of the OT-DHMT when administered to left and right handed individuals. The OT-DHMT was individually administered to a new sample of 144 healthy drivers aged 18-69 years. From this, 34 participant pairs were matched for age and gender, according to their dexterity. The results show that there were no significant differences in time taken when completing the maze test, for participants who complete the test with either writing hand t(33)=1.59, p=0.12 (95%CI: -0.63 to 5.08). While further testing is required with samples from different cultures and with more participants aged 30 69 and 70 years and over to extend generalizability of these findings, the results suggest the OT-DHMT is suitable to be administered and scored using the methods published as part of the OT-DORA Battery. PMID- 23036407 TI - The Addenbrooke's Cognitive Examination Revised as a potential screening test for elderly drivers. AB - Considerable research has shown that neuropsychological tests are predictive of real-world driving ability. The Mini-Mental State Examination (MMSE) is a brief cognitive test that has been commonly used in the assessment of older drivers. However, this test has inherent problems that limit its validity to evaluate cognitive abilities related to driving and to screen for driving impairments in non-demented people. Therefore, it is useful to test new screening instruments that may predict potential unsafe drivers who require an in-depth neuropsychological assessment in a specialised centre. To date, the utility of the Addenbrooke's Cognitive Examination Revised (ACE-R) as an indicator of driving ability has not been established. In the current study, fifty older drivers (mean age=73.1 years) who were referred for a psychological assessment, the protocol of which included the ACE-R, underwent an on-road driving test. Using linear discriminant analyses, the results highlighted the higher classification accuracy of the ACE-R compared to the MMSE score, particularly for detecting unsafe drivers. Measures of visuospatial and executive functions, which are not incorporated in the MMSE score, had an incremental value in the prediction of driving ability. This emerging brief cognitive test may warrant additional study for use in the fitness to drive assessment of older adults. PMID- 23036408 TI - MMSE as a predictor of on-road driving performance in community dwelling older drivers. AB - Screening tools such as the MMSE have been used extensively in driving research studies to determine mild cognitive impairment or dementia. While some studies have shown the MMSE to correlate with driving performance, few studies have shown the predictive validity of the MMSE in determining on-road performance. In a sample of 168 community dwelling older adults, including 20 with Parkinson's disease (PD), the primary objective was to determine the validity of the MMSE to predict pass/fail outcomes of an on-road driving test using receiver operating characteristics curves. The area under the curve (AUC), an index of discriminability, for the total sample was .654, 95% CI=0.536-0.772, p=.009. Meanwhile, the AUC for the PD group was 0.791, 95% CI=0.587-0.996, p=.036. The total sample showed statistically significant yet poor predictive validity. However, the PD group showed statistically significant and good predictive validity of the MMSE to predict pass/fail outcomes on the road test, but caution is warranted as the confidence intervals are wide (due to small sample) and the positive and negative predictive values are less than desirable due to the associated error. The findings show that using the current cut-off point of <=24 on the MMSE is not adequately sensitive to predict on-road performance in both community dwelling older drivers and in drivers with PD. This study offers strong evidence to support the current best practice of not using the MMSE in isolation to predict on-road performance. PMID- 23036409 TI - Age and inconsistency in driving performance. AB - Research in cognitive neuropsychology suggests that investigation of the within person variability, or inconsistency, of cognitive performance may provide valuable insights into ageing mental processes. It is rare though, for this interest in intraindividual variability to extend to everyday activities. As this may provide important information about driving behaviour, we therefore assessed age differences in driving inconsistency in younger (n=24, M age=21.29 years) and older (n=21, M age=71.24 years) persons who drove in residential, urban and motorway conditions in a fully immersive driving simulator. In measures of headway (maintaining a safe distance to a preceding vehicle) and lateral lane position, older drivers exhibited significantly greater performance inconsistency, and this was particularly marked in the faster motorway condition. Older drivers also recorded greater perceived mental demands associated with driving, and greater within-person variability across a range of cognitive measures. The findings suggest that age-related deficits in attentional and executive control may affect the consistency of driving performance in older persons. Discussion considers interventions to introduce in-vehicle systems to help maintain attention in older drivers, and to intervene when safety-critical boundaries are exceeded. PMID- 23036410 TI - Investigating driving behaviour of older drivers with mild cognitive impairment using a portable driving simulator. AB - While there is a large body of research indicating that individuals with moderate to severe dementia are unfit to drive, relatively little is known about the driving performance of older drivers with mild cognitive impairment (MCI). The aim of the current study was to examine the driving performance of older drivers with MCI on approach to intersections, and to investigate how their healthy counterparts perform on the same driving tasks using a portable driving simulator. Fourteen drivers with MCI and 14 age-matched healthy older drivers (aged 65-87 years) completed a 10-min simulator drive in an urban environment. The simulator drive consisted of stop-sign controlled and signal-controlled intersections. Drivers were required to stop at the stop-sign controlled intersections and to decide whether or not to proceed through a critical light change at the signal-controlled intersections. The specific performance measures included; approach speed, number of brake applications on approach to the intersection (either excessive or minimal), failure to comply with stop signs, and slower braking response times on approach to a critical light change. MCI patients in our sample performed more poorly than controls across a number of variables. However, because the trends failed to reach statistical significance it will be important to replicate the study using a larger sample to qualify whether the results can be generalised to the broader population. PMID- 23036411 TI - The influence of cognitive impairment with no dementia on driving restriction and cessation in older adults. AB - Cognitively impaired older adults may be at increased risk of unsafe driving. Individuals with insight into their own impairments may minimize their risk by restricting or stopping driving. The purpose of this study was to examine the influence of cognitive impairment on driving status and driving habits and intentions. Participants were classified as cognitively impaired, no dementia single (CIND-single), CIND-multiple, or not cognitively impaired (NCI) and compared on their self-reported driving status, habits, and intentions to restrict or quit driving in the future. The groups differed significantly in driving status, but not in whether they restricted their driving or reduced their driving frequency. CIND-multiple group also had significantly higher intention to restrict/stop driving than the NCI group. Reasons for restricting and quitting driving were varied and many individuals reported multiple reasons, both external and internal, for their driving habits and intentions. Regardless of cognitive status, none of the current drivers were seriously thinking of restricting or quitting driving in the next 6 months. It will be important to determine, in future research, how driving practices change over time and what factors influence decisions to restrict or stop driving for people with cognitive impairment. PMID- 23036412 TI - Cognitive problems, self-rated changes in driving skills, driving-related discomfort and self-regulation of driving in old drivers. AB - Ageing in general is associated with functional decline that may have an adverse effect on driving. Nevertheless, older drivers have been found to show good judgement and to self-regulate their driving, which may enable them to continue driving safely despite functional decline. The process of the self-monitoring of driving ability and the awareness of functional decline, and its association with the self-regulation of driving is, however, not fully understood. The aim of the present study was to examine the perceived changes in driving skills, the discomfort experienced in driving, and the self-regulation of driving as measured by the avoidance of certain driving situations by older drivers with different levels of self-rated cognitive problems. Eight hundred and forty Danish drivers aged 75-95 completed a structured telephone interview. The results showed that the recognition of cognitive problems was associated with an experience of improvement in higher level driving skills but also of a decline in lower level driving skills. Moreover, cognitive problems recognised by drivers were associated with discomfort in, and avoidance of, driving situations. Finally, a linear relationship between discomfort in driving and avoidance was found and this tended to be stronger for drivers recognising cognitive problems. The results indicate that older drivers who recognise problems with cognitive functions display good self-assessment of changes in their driving skills. In addition, the results suggest that driving-related discomfort is an important factor affecting the self-regulation of driving. Finally, the findings indicate that driving-related discomfort functions as an indirect self-monitoring of driving ability and may contribute to the safe driving performance of Danish older drivers. PMID- 23036413 TI - Driving behaviors in early stage dementia: a study using in-vehicle technology. AB - According to the Alzheimer's Association (2011), (1) in 8 people age 65 and older, and about one-half of people age 85 and older, have Alzheimer's disease in the United States (US). There is evidence that drivers with Alzheimer's disease and related dementias are at an increased risk for unsafe driving. Recent advances in sensor, computer, and telecommunication technologies provide a method for automatically collecting detailed, objective information about the driving performance of drivers, including those with early stage dementia. The objective of this project was to use in-vehicle technology to describe a set of driving behaviors that may be common in individuals with early stage dementia (i.e., a diagnosis of memory loss) and compare these behaviors to a group of drivers without cognitive impairment. Seventeen drivers with a diagnosis of early stage dementia, who had completed a comprehensive driving assessment and were cleared to drive, participated in the study. Participants had their vehicles instrumented with a suite of sensors and a data acquisition system, and drove 1-2 months as they would under normal circumstances. Data from the in-vehicle instrumentation were reduced and analyzed, using a set of algorithms/heuristics developed by the research team. Data from the early stage dementia group were compared to similar data from an existing dataset of 26 older drivers without dementia. The early stage dementia group was found to have significantly restricted driving space relative to the comparison group. At the same time, the early stage dementia group (which had been previously cleared by an occupational therapist as safe to drive) drove as safely as the comparison group. Few safety-related behavioral errors were found for either group. Wayfinding problems were rare among both groups, but the early stage dementia group was significantly more likely to get lost. PMID- 23036414 TI - Grandparents and child passenger safety. AB - PURPOSE: This study compares child passenger safety (CPS) practices of grandparents versus parents and determines grandparents' opinions on car safety seats (CSS), barriers to use, and ways to transport grandchildren safely. METHODS: Observational surveys were conducted on a convenience sample of drivers transporting children younger than sixteen years at 25 locations by certified child passenger safety technicians observing children in motor vehicles and recorded use of child passenger restraints. The drivers were surveyed on their knowledge, attitudes, beliefs, and practices regarding CPS. Data from drivers identifying themselves as grandparents were analyzed; also, three grandparent focus groups provided opinions on CPS practices. RESULTS: During the study 1758 parents transporting 2713 children and 284 grandparents transporting 391 grandchildren were included. While most drivers were restrained and used child occupant restraints, almost 25% of parents and grandparents chose the incorrect seat to transport the child, and greater than 68% had at least one harness error. Grandparents were more likely to have looser lower anchor straps or seat belts and have children younger than thirteen years in the front seat. The focus group grandparents had a favorable attitude toward CSS. Grandparents acknowledged the need for CSS but opined that CSS were difficult to use. Physical barriers included arthritis, back pain, mobility, decreased strength, and vision problems. CONCLUSIONS: Grandparents and parents were equally likely to use CSS and choose correct seats. Compared to parents, grandparents were more likely to travel with their grandchildren with CSS installed with looser harnesses or an installed CSS with looser seat belt or lower anchors. Additionally, grandparents were more likely to have a child younger than thirteen years in the front seat. The use of community resources such as permanent fitting stations could help grandparents improve a grandchild's travel safety. PMID- 23036415 TI - The effects of congestion charging on road traffic casualties: a causal analysis using difference-in-difference estimation. AB - This paper aims to identify the impacts of the London congestion charge on road casualties within the central London charging zone. It develops a full difference in-difference (DID) model that is integrated with generalized linear models, such as Poisson and Negative Binomial regression models. Covariates are included in the model to adjust for factors that violate the parallel trend assumption, which is critical in the DID model. The lower Bayesian Information Criterion value suggests that the full difference-in-difference model performs well in evaluating the relationship between road accidents and the London congestion charge as well as other socio-economic factors. After adjusting for a time trend and regional effects, the results show that the introduction of the London congestion charge has a significant influence on the incidence of road casualties. The congestion charge reduces the total number of car accidents, but is associated with an increase in two wheeled vehicle accidents. PMID- 23036416 TI - Obesity is associated with the future risk of heavy truck crashes among newly recruited commercial drivers. AB - This study estimates the dose-response relationship between body mass index (BMI) and crash risk in operators of heavy commercial motor vehicles. Intake data were collected during the first two weeks of instruction from 744 new truck drivers training for their commercial driver's licenses at a school operated by the cooperating trucking firm. Drivers were then followed prospectively on the job using the firm's operational data for two years, or until employment separation, whichever came first. Multivariate Poisson regression and Cox proportional hazards models were used to estimate the relationship between crash risk and BMI, controlling for demographic characteristics and for variations in the exposure to risks on the road. Results from the Poisson regression, which used cumulative miles driven as an exposure control, indicated that compared to normal BMI (18.5=30] and 75 nonobese (BMI <30) women. RESULTS: Suppression of ovulation during the luteal phase was dose dependent, with the highest dose (AG200-15) preventing progesterone increases in all women (cycles 2-3). In the follicular phase, the lowest-dose patch had the highest rate of increased progesterone in nonobese subjects. Progesterone levels >=3.0 ng/mL in the follicular phase were more common in obese than nonobese women. CONCLUSIONS: AG200-15 suppresses ovulation in obese and nonobese women. All three patches found increased progesterone in the follicular phase, albeit more in obese versus nonobese women. PMID- 23036479 TI - Isolation anterooms: important components of airborne infection control. PMID- 23036480 TI - Computer keyboard covers impregnated with a novel antimicrobial polymer significantly reduce microbial contamination. AB - BACKGROUND: Contaminated computer keyboards have been acknowledged as a potential source for bacterial transmission between health care providers and patients. Biosafe HM 4100 is an antimicrobial polymer that can be incorporated into the polyurethane material used to make keyboard covers. This study aimed to determine whether plastic keyboard covers containing HM 4100 effectively minimize the survival of bacterial species commonly present on health care environmental surfaces. METHODS: Polyurethane material that contained 0.5% HM 4100, 1% HM 4100, and 1% HM 4100 with spray coating of 1% HM 4100 were tested. In 2 separate experiments, the surfaces of test materials were inoculated with suspensions of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VREF), Escherichia coli, or Pseudomonas aeruginosa. Viability was assessed on the materials at 0, 10, 30, 60, 120, and 240 minutes after inoculation. RESULTS: Maximum reductions in viability were observed for all 4 organisms at the longest tested time period on each test material. Mean reductions on the 0.5% HM 4100 material at 240 minutes were 99.99% for E coli, 97.8% for MRSA, 95.0% for VREF, and 92.1% for P aeruginosa. Mean reductions on the 1% HM 4100 at 120 minutes were 99.9% for VREF, 99.9% for MRSA, 99.9% for P aeruginosa, and 99.5% for E coli. Mean reductions on the 1% HM 4100 plus spray coating at 30 minutes were 99.9% for E coli, 99.8% for VREF, 98.8% for P aeruginosa, and 97.2% for MRSA. CONCLUSIONS: Incorporation of the HM 4100 antimicrobial polymer into polyurethane keyboard material may reduce the hand carriage of bacteria between health care providers and patients. PMID- 23036481 TI - Compliance of nursing students with infection prevention precautions: effectiveness of a teaching program. AB - BACKGROUND: In Jordan's nursing schools, infection prevention precautions are not taught in special courses. Instead, most nursing schools include the topic as a 1 hour lecture within the clinical courses, which is believed to be insufficient. This study aimed to test the effectiveness of a nursing infection prevention educational program presented to nursing students before graduation, to promote their knowledge of infection prevention precautions. METHODS: A true experimental design was used to examine the effects of the infection prevention educational program on students' educational knowledge. This study involved a random assignment of subjects to experimental and control groups, and administration of the pretest and the posttest to all subjects in both groups separately. RESULTS: Participants in the experimental group demonstrated significantly better knowledge (t = 19.15; df = 95; P = .000) and attitude scores (t = 2.29; df = 46; P = .04) than participants in the control group after particpating in the infection prevention educational program. However, compliance scores were not significantly differernt between the 2 groups (t = 1.92; df = 95; P = .067); indeed, compliance was found to be significant within the experimental group (t = 10.65; df = 46; P = .000). CONCLUSIONS: It is important that nursing students be competent in infection prevention precautions; however, there may be deficits in their education in this area. The nursing curriculum should include additional emphasis on practice as a means to help translate theory into clinical behavior. PMID- 23036482 TI - Patterns of altered neurobehavior in preterm infants within the neonatal intensive care unit. AB - OBJECTIVE: To investigate differences in neurobehavior between preterm infants at term and full-term infants, changes in neurobehavior between 34 weeks postmenstrual age (PMA) and term equivalent in the preterm infant, and the relationship of neurobehavior to perinatal exposures. STUDY DESIGN: In this prospective cohort study, 75 infants were tested at 34 weeks PMA and again at term using the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Infants underwent magnetic resonance imaging at term equivalent. Regression was used to investigate differences in the scale's domains of function across time and in relation to perinatal exposures. RESULTS: At term equivalent, preterm infants exhibited altered behavior compared with full-term infants, with poorer orientation (P < .001), lower tolerance of handling (P < .001), lower self regulation (P < .001), poorer reflexes (P < .001), more stress (P < .001), hypertonicity (P < .001), hypotonia (P < .001), and more excitability (P = .007). Preterm infants from 34 weeks PMA to term equivalent, demonstrated changes in motor functions with declining quality of movement (P = .006), increasing hypertonia (P < .001), decreasing hypotonia (P = .001), and changes in behavior with increasing arousal (P < .001), increasing excitability (P < .001), and decreasing lethargy (P < .001). Cerebral injury was associated with more excitability (P = .002). However, no associations were detected between any of the perinatal exposures and developmental change from 34 weeks PMA to term equivalent. CONCLUSION: Preterm infants have altered neurobehavior in a broad number of domains at term equivalent. Cerebral injury alters neurobehavior but does not appear to impair early neurobehavioral changes. Important neurobehavioral changes occur before term, and this provides an opportunity for interventions in the neonatal intensive care unit. PMID- 23036483 TI - Predictors for asthma at age 7 years for low-income children enrolled in the Childhood Asthma Prevention Study. AB - OBJECTIVE: To identify the predictive factors of early childhood wheezing in children of low socioeconomic status. STUDY DESIGN: The Childhood Asthma Prevention Study enrolled 177 low-income children (9-24 months old) with frequent wheezing. At age 7 years, presence of asthma was assessed through caregiver reports of physician diagnosis of asthma (CRPDA) and corroborated by assessment of bronchial hyperresponsiveness (BHR). Lung function, inflammatory markers, and asthma symptom severity were compared for children with +/-CRPDA, +/-BHR, and asthma. Baseline predictors for CRPDA, BHR, and asthma at 7 years of age were examined. RESULTS: Maternal symptom report strongly differentiated children with +CRPDA (49%) despite comparable airflow measurements (P < .0001), and spirometric lung function measurements were different for +BHR (65%) versus -BHR (P < .005). Univariate analyses revealed different baseline predictors of +CRPDA and +BHR for children at age 7 years. Higher levels of maternal psychological resources were associated with +CRPDA, but not +BHR. Only 39% of children with a history of frequent wheezing met the conservative definition of asthma at age 7 years, with the following significant predictors found: low birth weight, baseline symptom severity, and maternal psychological resources. CONCLUSIONS: This low-income, multi-ethnic group of wheezing infants represents a unique population of children with distinct characteristics and risks for persistent asthma. Determination of asthma status at 7 years of age required objective measurement of BHR in addition to CRPDA. The association of maternal psychological resources with +CRPDA may represent a previously unrecognized factor in the determination of asthma status among low-income groups. PMID- 23036484 TI - Maternal residential atrazine exposure and risk for choanal atresia and stenosis in offspring. AB - OBJECTIVE: To assess the relationship between estimated residential maternal exposure to atrazine during pregnancy and the risk for choanal atresia or stenosis in offspring. STUDY DESIGN: Data for 280 nonsyndromic cases and randomly selected, population-based controls delivered between 1999 and 2008 were obtained from the Texas Birth Defects Registry. County-level estimates of atrazine levels obtained from the US Geological Survey were assigned to cases and controls based on maternal county of residence at delivery. Unconditional logistic regression was used to assess the relationship between maternal residential atrazine exposure and the risk for choanal atresia or stenosis in offspring. RESULTS: Compared with offspring of mothers with low levels of estimated residential atrazine exposure, those with high levels had nearly a 2-fold increase in risk for choanal atresia or stenosis (aOR, 1.79; 95% CI, 1.17-2.74). A significant linear trend was also observed with increasing levels of atrazine exposure (adjusted P = .002). CONCLUSION: A link between maternal exposure to endocrine disruptors, such as atrazine, and the risk of choanal atresia is plausible based on previous findings. Our results lend further support to this hypothesis. PMID- 23036485 TI - Tianeptine exerts neuroprotective effects in the brain tissue of rats exposed to the chronic stress model. AB - Animal models of chronic stress represent valuable tools by which to investigate the behavioral, endocrine and neurobiological changes underlying stress-related psychopathologies, such as major depression, and the efficacy of antidepressant therapies. The present study was aimed at investigating the neurochemical effects of the antidepressant tianeptine in rats exposed to the chronic stress model. To this aim, rats were subjected to 40days of chronic unpredictable stressful stimuli, after which the animals received saline or tianeptine (15mg/kg) once a day for 7days. Additionally, IL-6, IL-1, TNF-alpha levels and oxidative stress parameters were assessed in the prefrontal cortex (PFC), hippocampus (HPC), amygdala (AMY) and nucleus accumbens (NAc) in all of the experimental groups studied. The results indicated that chronic mild stress and tianeptine did not exercise any effects on cytokines in all of the structures studied; in the PFC and AMY thiobarbituric acid reactive substances (TBARS) levels were decreased in control rats treated with tianeptine in the HPC; superoxide dismutase (SOD) activity was found to have decreased in stressed rats treated with saline in the PFC, HPC, AMY and NAc, and tianeptine reversed this effect; catalase (CAT) activity was found to have decreased in the PFC, HPC and NAc of stressed rats treated with saline, but was shown to have increased in stressed rats treated with tianeptine, and tianeptine also reversed the decreases in CAT activity in stressed rats treated with saline, suggesting that tianeptine exerted antioxidant activity. In conclusion, the present findings open new vistas on the pharmacological activity of tianeptine, in particular, concerning its ability to attenuate oxidative stress. PMID- 23036486 TI - Interferon gamma Assays in the Diagnosis of Tuberculosis Infection in Psoriasis Patients Who Are Candidates for Biologic Therapies. AB - Although there is no doubt that biologic agents are an effective alternative for the treatment of moderate and severe psoriasis, anti-tumor necrosis factor alpha therapy has been associated with reactivation of latent tuberculosis infection. Tuberculin skin testing (TST) is used to diagnose tuberculosis infection but it has low specificity in patients who have received the Mycobacterium bovis BCG vaccine and low sensitivity in patients with altered cell-mediated immunity. In vitro assays based on the detection of interferon gamma released by T cells stimulated by specific Mycobacterium tuberculosis antigens have emerged as an option for the diagnosis of tuberculosis infection. The results to date show that they are a viable alternative to TST thanks to their higher specificity and sensitivity. Furthermore, these assays are also proving to have high negative predictive value, meaning that we might be able to use them without TST in the short to medium term. PMID- 23036487 TI - Ovarian reserve testing before and after laparoscopic tubal bipolar electrodesiccation and transection. AB - OBJECTIVE: To find out whether tubal sterilization leads to loss of ovarian reserve, we assessed the hormonal and ultrasonographic parameters of ovarian reserve in women who underwent laparoscopic tubal sterilization by bipolar electrodesiccation and transection. STUDY DESIGN: In this preliminary study, laparoscopic tubal sterilization was performed on 49 healthy women who had voluntarily requested elective surgical sterilization. Among the current ovarian reserve indicators, in the early proliferative phases, preoperative (baseline) and postoperative (third month) serum follicle-stimulating hormone (FSH), estradiol (E2), and anti-Mullerian hormone (AMH) levels, ovarian volume, and antral follicle counts (AFCs) were determined. Analysis of these hormonal and ultrasonographic parameters of ovarian reserve preoperatively and postoperatively was the main outcome measure. RESULTS: Preoperative and third-month postoperative FSH, LH, E2, and AMH levels did not reveal statistically significant differences (p=0.101, p=0.180, p=0.254, and p=0.079; respectively). The ultrasonographic indicators of ovarian reserve did not change in terms of total ovarian volume and total AFC (p=0.793 and p=0.098, respectively). CONCLUSIONS: Short-term follow-up study results revealed a slight but non-significant change in the current ovarian reserve markers, especially in the AMH levels. PMID- 23036489 TI - Knockdown of Hop downregulates RhoC expression, and decreases pseudopodia formation and migration in cancer cell lines. AB - The Hsp90/Hsp70 organising protein (Hop) is a co-chaperone that mediates the interaction of Hsp90 and Hsp70 molecular chaperones during assembly of Hsp90 complexes in cells. Formation of Hsp90 complexes is a key intermediate step in the maturation and homeostasis of oncoproteins and several hormone receptors. In this paper, we demonstrate that knockdown of Hop decreased migration of Hs578T and MDA-MB-231 breast cancer cells. Hop was identified in isolated pseudopodia fractions; it colocalised with actin in lamellipodia, and co-sedimented with purified actin in vitro. Knockdown of Hop caused a decrease in the level of RhoC GTPase, and significantly inhibited pseudopodia formation in Hs578T cells. Our data suggest that Hop regulates directional cell migration by multiple unknown mechanisms. PMID- 23036488 TI - Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment. AB - We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches. PMID- 23036490 TI - A comparison of symptoms and drug use between patients with methamphetamine associated psychoses and patients diagnosed with schizophrenia in two acute psychiatric wards. AB - Psychosis induced by the use of amphetamine or methamphetamine leads to dramatic symptoms and frequent readmissions and poses diagnostic challenges. Earlier studies have often relied on history taking and/or urine samples to reveal drug use. The aim of this study was to compare the psychotic symptoms of two groups: (1) acutely admitted patients who tested positive for methamphetamines and were diagnosed with drug-induced or methamphetamine-induced psychoses and (2) acutely admitted patients who tested negative for methamphetamines and were diagnosed with schizophrenia. Blood and urine samples were used. In addition, we investigated whether the severity of symptoms, in those who tested positive, was related to the blood concentration of methamphetamine. Of 285 patients who volunteered blood and/or urine samples within 48h of admission, 37 (13%) had recently taken methamphetamine. Positive psychotic symptoms between the two groups were compared by PANSS using the positive subscale. The results showed no differences in positive psychotic symptoms between the two groups. The severity of positive psychotic symptoms in patients with three different levels of urine/blood methamphetamine concentrations, were compared. We found no clinically or statistically significant relationship between blood methamphetamine levels and severity of psychotic symptoms. PMID- 23036491 TI - Executive functioning deficits and childhood trauma in juvenile violent offenders in China. AB - A large body of evidence indicates that violent offenders have executive functioning deficits. However, previous studies have not considered childhood trauma, which is likely to influence the executive functioning of violent offenders. The aim of the present study was to compare the difference of executive functioning among juvenile violent offenders, with non-violent offenders and normal controls, and then to analyse whether executive functioning was affected independently of childhood trauma. In addition to using a battery of tests assessing executive functioning including the Intra/Extradimensional Shift Test(IED), the Stockings of Cambridge Test (SOC), and the Spatial Working Memory Test (SWM) from the Cambridge Automated Neuropsychological Testing Battery (CANTAB), the short form of the Chinese Revision of the Wechsler Adult Intelligence Scale (WAIS-RC) and Childhood Trauma Questionnaire-28 item Short Form (CTQ) were also used among 107 violent offenders, 107 non-violent offenders and 107 normal controls. Our results showed that both offender groups obtained significantly lower estimated Intelligence Quotient (IQ) scores and experienced more childhood trauma than did normal controls. Violent offenders showed impaired executive functioning on tasks of attention set-shifting, working memory and planning. Finally, spatial working memory (SWM) deficits, particularly SWM strategy scores, may be associated with childhood trauma. PMID- 23036492 TI - Lack of genetic association of the HLA-DQA1(*)0501 variant with schizophrenia in a Chinese population. PMID- 23036493 TI - The long-term effects of birth by caesarean section: the case for a randomised controlled trial. AB - Birth by caesarean section is rising rapidly around the world and is associated with a range of adverse short and long-term outcomes in offspring. The latter include features of the metabolic syndrome, type-1 diabetes, and asthma. Though there are several plausible candidate biological mechanisms, evidence of a causal relationship between mode of delivery and long-term outcomes remains lacking. Here we review the evidence to date, and examine ways in which future studies might advance understanding. We conclude that a randomised controlled trial of mode of delivery for the healthy term, cephalic pregnancy, is neither unethical nor unfeasible and should be seriously considered as the optimum means of addressing a question of great relevance to public health. PMID- 23036494 TI - A multilocus molecular phylogeny of boxfishes (Aracanidae, Ostraciidae; Tetraodontiformes). AB - Boxfishes (superfamily Ostracioidea, order Tetraodontiformes) are comprised of 37 species within the families Aracanidae (13 sp.) and Ostracidae (24 sp.). These species are characterized by several dramatic reductive trends in their axial and appendicular skeleton, and by the presence of a carapace formed by enlarged and thickened scale plates. While strong support exists for the monophyly of both families, interspecific relationships remain unclear as no species-level molecular phylogeny currently exists for either of these two clades, and the only hypotheses of relationships are based on morphological studies that were mostly restricted to generic-level relationships. Here we present the results of a new phylogenetic study of a dataset composed of 9 loci for 26 species of boxfishes using both likelihood and Bayesian methods. Our topology strongly supports the monophyly of both groups, and additionally provides strongly supported resolution for the vast majority of species-level interrelationships. Based on this new phylogeny, we suggest changing the taxonomic status of the species Lactoria fornasini to Tetrasomus fornasini, and Rhynchostracion nasus to Ostracion nasus. Using a Bayesian approach to divergence time estimation we inferred a Paleocene origin of the Ostracioidea, with an estimated origin of the reef-associated ostraciids spanning the Eocene and Oligocene, and a Miocene/Pliocene origin of the aracanids. PMID- 23036495 TI - Comparison of APSIM and DNDC simulations of nitrogen transformations and N2O emissions. AB - Various models have been developed to better understand nitrogen (N) cycling in soils, which is governed by a complex interaction of physical, chemical and biological factors. Two process-based models, the Agricultural Production Systems sIMulator (APSIM) and DeNitrification DeComposition (DNDC), were used to simulate nitrification, denitrification and nitrous oxide (N2O) emissions from soils following N input from either fertiliser or excreta deposition. The effect of environmental conditions on N transformations as simulated by the two different models was compared. Temperature had a larger effect in APSIM on nitrification, whereas in DNDC, water content produced a larger response. In contrast, simulated denitrification showed a larger response to temperature and also organic carbon content in DNDC. And while denitrification in DNDC is triggered by rainfall >=5mm/h, in APSIM, the driving factor is soil water content, with a trigger point at water content at field capacity. The two models also showed different responses to N load, with nearly linearly increasing N2O emission rates with N load simulated by DNDC, and a lower rate by APSIM. Increasing rainfall intensity decreased APSIM-simulated N2O emissions but increased those simulated by DNDC. PMID- 23036496 TI - Production and immunogenicity of chimeric virus-like particles containing porcine reproductive and respiratory syndrome virus GP5 protein. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) poses a severe threat in swine industry and causes heavy economic losses worldwide. Currently, the available vaccines are the inactivated and attenuated virus vaccines, but the use of PRRSV in their production raises the issue of safety. We developed a chimeric virus-like particles (VLPs) vaccine candidate for PRRSV protection. The chimeric VLPs was composed of M1 protein from H1N1 influenza virus and a fusion protein, denoted as NA/GP5, containing the cytoplasmic and transmembrane domains of H1N1 virus NA protein and PRRSV GP5 protein. Vaccination of BALB/c mice with 10 MUg of chimeirc VLPs by intramuscular immunization stimulated antibody responses to GP5 protein, and induced cellular immune response. The data suggested that the chimeric VLP vaccine candidate may provide a new strategy for further development of vaccines against PRRSV infection. PMID- 23036497 TI - The end of the Australia antigen? An ecological study of the impact of universal newborn hepatitis B vaccination two decades on. AB - BACKGROUND: A universal newborn hepatitis B (HBV) vaccination program was introduced in the Northern Territory of Australia in 1990, followed by a school based catch-up program. We evaluated the prevalence of hepatitis B infection in birthing women up to 20 years after vaccination and compared this to women born before the programs commenced. METHODS: A cohort of birthing mothers was defined from Northern Territory public hospital birth records between 2005 and 2010 and linked to laboratory confirmed notifications of chronic HBV, based principally on a record of hepatitis B surface antigen detection. Prevalence of HBV was compared between women born before or after implementation of the newborn and catch-up vaccination programs. FINDINGS: Among 10797 birthing mothers, 138 (1.3%) linked to a chronic HBV record. HBV prevalence was substantially higher in Aboriginal women compared to non-Indigenous women (2.4% versus 0.04%; p<0.001). Among 5678 Aboriginal women, those eligible for catch-up and newborn HBV vaccination programs had a significantly lower HBV prevalence than older women born prior to the programs: HBV prevalence respectively 2.2% versus 3.5%, (OR 0.61, 95%CI 0.43 0.88) and 0.8% versus 3.5% (OR 0.21, 95%CI 0.11-0.43). This represents a risk reduction of respectively 40% and 80% compared to unvaccinated women. INTERPRETATION: The progressively greater reduction in the prevalence of chronic HBV in adult Aboriginal women co-inciding with eligibility for catch-up and newborn vaccination programs is consistent with a significant impact from both programs. The use of data derived from antenatal screening to track ongoing vaccine impact is applicable to a range of settings globally. PMID- 23036498 TI - Immune response after one or two doses of pandemic influenza A (H1N1) monovalent, AS03-adjuvanted vaccine in HIV infected adults. AB - INTRODUCTION: Continued research is needed to evaluate and improve the immunogenicity of influenza vaccines in HIV infected patients. We aimed to determine the antibody responses after one or two doses of the AS03-adjuvanted pandemic influenza A (H1N1) vaccine in HIV infected patients. METHOD: Following the influenza season 2009/2010, 219 HIV infected patients were included and divided into three groups depending on whether they received none (n=60), one (n=31) or two (n=128) doses of pandemic influenza A (H1N1) vaccine. At inclusion, antibody titers for all patients were analyzed and compared to pre-pandemic antibody titers analyzed from serum samples in a local storage facility. RESULTS: 4-9 months after a single immunization, we found a seroprotection rate of 77.4% and seroconversion rate of 67.7%. After two immunizations the rates increased significantly to seroprotection rate of 97.7% and seroconversion rate of 86.7%. CONCLUSION: A single dose of AS03-adjuvanted pandemic influenza A (H1N1) vaccine created an adequate immune response in HIV infected patients lasting as long as 4 9 months. Two doses improved the immunogenicity further. PMID- 23036499 TI - Intramuscular DNA immunization with in vivo electroporation induces antigen specific cellular and humoral immune responses in both systemic and gut-mucosal compartments. AB - Mucosal delivery of antigens induces antigen-specific immune responses in both systemic and mucosal compartments, and is an attractive approach for preventing initial infection with mucosal pathogens. It has been shown that the intramuscular (i.m.) immunization of plasmid DNA by in vivo electroporation (DNA e.p.) induces both cellular and humoral immune responses in the airway-mucosal compartment as well as in the systemic compartment, implying there is a mechanism that bridges between the systemic and mucosal immune responses. An important question is whether the i.m. DNA e.p.-immunization alone can induce antigen specific immune responses in the gut-mucosal compartment. Here, we investigated the induction of antigen-specific CD8(+) T cells and antibodies in both systemic and gut-mucosal compartments following i.m. DNA e.p.-immunization to mice. Surprisingly, the i.m. DNA e.p.-immunization induced the antigen-specific CD8(+) T cells and antigen-specific antibodies in the gut-mucosal as well as the systemic compartment. These results suggest that the i.m. DNA e.p.-immunization should be considered as an effective vaccine strategy for the prevention of gut mucosal infectious diseases. PMID- 23036500 TI - Relevance of O-acetyl and phosphoglycerol groups for the antigenicity of Streptococcus pneumoniae serotype 18C capsular polysaccharide. AB - Capsular polysaccharides are important virulence factors of Streptococcus pneumoniae. The polysaccharide has been used as a component of vaccines against pneumococcal diseases either as plain polysaccharide or better conjugated to a protein. The last one is the vaccine of choice to target child protection. The immune responses depend on several polysaccharide physicochemical properties that can be affected during either purification or modification in the case of conjugate vaccines. In serotype 18C, the repeating unit has a complex structure having a branched pentasaccharide with two apparently labile subtituents: glycerol-phosphate and O-acetyl group. The loss of these groups may potentially reduce the ability of the 18C polysaccharide to induce the desired immune response. Therefore, the relationship of both groups with the antigenicity and immunogenicity of 18C capsular polysaccharide is explored. It is shown that glycerol-phosphate must be preserved for conserving adequate antigenicity of the 18C capsular polysaccharide. At the same time, it was proved that O-acetyl groups do not play any role for the antigenicity and immunogenicity. PMID- 23036501 TI - Efficacy of Hyalomma scupense (Hd86) antigen against Hyalomma excavatum and H. scupense tick infestations in cattle. AB - The Rhipicephalus microplus recombinant Bm86-based tick vaccines have shown their efficacy for the control of several Hyalomma cattle ticks genera, namely H. dromedarii and H. anatolicum. However, H. scupense species, the most important tick in North Africa has never been studied. Vaccination trials using either a recombinant Bm86-based vaccine or a recombinant Hd86-based vaccine (the Bm86 ortholog in H. scupense) were conducted in cattle against immature and adult H. scupense ticks and adult H. excavatum ticks. The results showed a 59.19% reduction in the number of scupense nymphs engorging on Hd86 vaccinated cattle. However, cattle vaccination with Bm86 or Hd86 did not have an effect on H. scupense or H. excavatum adult ticks infestations. These results showed that Hd86 vaccines are selectively effective against H. scupense immature instars and emphasize on an integrated anti-tick vaccine control in North Africa. PMID- 23036502 TI - New DIVA vaccine for the protection of poultry against H5 highly pathogenic avian influenza viruses irrespective of the N-subtype. AB - Most human cases of highly pathogenic H5N1 avian influenza virus (HPAIV) infection are the result of direct contact with infected poultry. Therefore, infection of poultry should be prevented to avoid human exposure. One method to combat HPAIV outbreaks relies on depopulation. An alternative or supplementary method is the use of DIVA (discriminating infected from vaccinated animals) vaccines to prevent infection of animals on holdings surrounding an outbreak. Discrimination between infected and vaccinated animals is often based on the 'heterologous neuraminidase' strategy. This implies that a suitable vaccine can only be selected when the N-subtype of the outbreak strain is known. Thus, at least two vaccines with different N-subtypes must be available, allowing a switch of vaccine in the event that one of them matches the outbreak strain. However, such vaccines cannot be used preventively in situations in which the N-subtype of the outbreak strain is unknown. In order to circumvent these drawbacks we generated a recombinant influenza virus containing the HA gene of a contemporary H5N1 HPAIV strain in combination with the NA gene of a human type B influenza virus. An inactivated vaccine based on this virus protected chickens against clinical disease, and completely prevented virus shedding after H5N1 HPAIV challenge infection. Serological analyses confirmed that the vaccine complied with the DIVA principle. Since NA of type B does not occur in avian influenza strains, this vaccine is suitable as a DIVA vaccine against any H5 HPAIV, and may be used preventively without compromising the DIVA principle. PMID- 23036504 TI - Public vs private administration of rural health insurance schemes: a comparative study in Zhejiang of China. AB - Since 2003, China has experimented in some of the country's counties with the private administration of the New Cooperative Medical Scheme (NCMS), a publicly subsidized health insurance scheme for rural populations. Our study compared the effectiveness and efficiency of private vs public administration in four counties in one of China's most affluent provinces in the initial stage of the NCMS's implementation. The study was undertaken in Ningbo city of Zhejiang province. Out of 10 counties in Ningbo, two counties with private administration for the NCMS (Beilun and Ninghai) were compared with two others counties with public administration (Zhenhai and Fenghua), using the following indicators: (1) proportion of enrollees who were compensated for inpatient care; (2) average reimbursement-expense ratio per episode of inpatient care; (3) overall administration cost; (4) enrollee satisfaction. Data from 2004 to 2006 were collected from the local health authorities, hospitals and the contracted insurance companies, supplemented by a randomized household questionnaire survey covering 176 households and 479 household members. In our sample counties, private administration of the NCMS neither reduced transaction costs, nor improved the benefits of enrollees. Enrollees covered by the publicly administered NCMS were more likely to be satisfied with the insurance scheme than those covered by the privately administered NCMS. Experience in the selected counties suggests that private administration of the NCMS did not deliver the hoped-for results. We conclude that caution needs to be exercised in extending private administration of the NCMS. PMID- 23036503 TI - Multivalent fusion protein vaccine for lymphatic filariasis. AB - Lymphatic filariasis affects approximately 3% of the whole world population. Mass drug administration is currently the major control strategy to eradicate this infection from endemic regions by year 2020. Combination drug treatments are highly efficient in controlling the infection. However, there are no effective vaccines available for human or animal lymphatic filariasis despite the identification of several subunit vaccines. Lymphatic filariasis parasites are multicellular organisms and potentially use multiple mechanisms to survive in the host. Therefore, there is a need to combine two or more vaccine candidate antigens to achieve the desired effect. In this study we combined three well characterized vaccine antigens of Brugia malayi, heat shock protein 12.6 (HSP12.6), Abundant Larval transcript-2 (ALT-2) and tetraspanin large extra cellular loop (TSP-LEL) as a multivalent fusion vaccine. Putative immune individuals carry circulating antibodies against all three antigens. Depletion of these antigen specific antibodies from the sera samples removed the ability of the sera to participate in the killing of B. malayi L3 in an antibody dependent cellular cytotoxicity (ADCC) mechanism. Vaccination trials in mice with a bivalent [HSP12.6+ALT-2 (HA), HSP12.6+TSP-LEL (HT) or TSP-LEL+ALT-2 (TA)] or trivalent [HSP12.6+ALT-2+TSP-LEL (HAT)] vaccines using DNA, protein or heterologous prime boost regimen showed that trivalent HAT vaccine either as protein alone or as heterologous prime boost vaccine could confer significant protection (95%) against B. malayi L3 challenge. Immune correlates of protection suggest a Th1/Th2 bias. These finding suggests that the trivalent HAT fusion protein is a promising prophylactic vaccine against lymphatic filariasis infection in human. PMID- 23036505 TI - A new paradigm for understanding gamma-aminobutyric acid cell pathology in schizophrenia? PMID- 23036506 TI - On a quest for the elusive schizophrenia biomarker. PMID- 23036507 TI - Maternal inflammatory bowel disease has short and long-term effects on the health of their offspring: a multicenter study in Israel. AB - BACKGROUND: There are concerns about the effect of inflammatory bowel diseases (IBD) on fertility, pregnancy and pregnancy outcomes, but no long-term data on the health of offspring born to IBD mothers. The aims were to assess the short- and long-term effects of maternal IBD on the morbidity and development of their offspring. METHODS: Female IBD patients and controls completed questionnaires on their pregnancy outcome, and their offspring's short- and long-term health and development. RESULTS: IBD and control mothers (159 and 175, respectively) were recruited. Medical data of 412 IBD and 417 control offspring were recorded. IBD mothers had significantly more singleton pregnancies, their offspring's birth weight was significantly lower, and they breastfed significantly less compared to controls (P=0.028, 0.007, and <0.0001, respectively). There were significantly more congenital anomalies (mainly limb deformities) among the IBD offspring (P<0.035). Offspring born post-maternal IBD diagnosis, compared to pre-diagnosis, tended to have more neurodevelopmental problems (e.g., gross motor delay, P=0.03). IBD was significantly more prevalent in the offspring of IBD mothers, while allergies and atopic dermatitis were more frequent in offspring of control mothers. More offspring of IBD mothers taking medications during pregnancy were born preterm and had lower birth weights compared to offspring of IBD mothers not taking medications during pregnancy. Children of mothers taking steroids had the lowest birth weights, compared to those of IBD mothers taking 5ASAs or immunomodulators. CONCLUSIONS: Maternal IBD affects pregnancy and the offspring's immediate and long-term morbidity, specifically, congenital anomalies and neurodevelopmental problems. PMID- 23036508 TI - Smoking and Crohn's disease: active modification of an independent risk factor (education alone is not enough). AB - INTRODUCTION: Smoking can induce the onset of Crohn's disease in genetically susceptible patients and may accelerate progression and disease severity. There is a paucity of information as to patient knowledge of the impact of smoking on disease progression. The aim of this study was to assess patient awareness, initiate smoking cessation therapy and monitor the effectiveness of an active smoking cessation programme in patients with Crohn's disease. METHODS: All patients with a diagnosis of Crohn's disease over a ten year period were identified from a prospectively managed database. Details of smoking history and patient knowledge of the link between Crohn's disease and smoking were collected through a telephone questionnaire. Current smokers who wished to quit were enrolled in a smoking cessation programme and followed prospectively for 12 months. RESULTS: 340 patients were identified with 281 eligible for inclusion. 181 patients agreed to a telephone survey (64.4% patient uptake). Smokers had an increased incidence of surgical intervention (OR 2.2; CI 1.02, 4.78 P=0.043). Awareness of the link between smoking and Crohn's disease was highest in the current smoking cohort and lowest in the non-smoking cohort (CS:NS; 79.5%:43% p<0.001). 29% of patients with a smoking history had previously been offered smoking cessation therapy. 77% of current smokers opted for smoking cessation therapy. At 6 months 53% of these patients remained smoke free and 37% at 12 months. CONCLUSION: In patients with Crohn's disease, information alone is ineffective at achieving smoking cessation. Good cessation rates are achievable if information is supported by active smoking cessation therapy. PMID- 23036509 TI - Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells. AB - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a familiar fatal progressive degenerative disorder characterized by cognitive decline, and recurrent stroke in young adults. Pathological features include a dramatic reduction of brain vascular smooth muscle cells and severe arteriopathy with the presence of granular osmophilic material in the arterial walls. Here we have investigated the cellular and mitochondrial function in vascular smooth muscle cell lines (VSMCs) established from CADASIL mutation carriers (R133C) and healthy controls. We found significantly lower proliferation rates in CADASIL VSMC as compared to VSMC from controls. Cultured CADASIL VSMCs were not more vulnerable than control cells to a number of toxic substances. Morphological studies showed reduced mitochondrial connectivity and increased number of mitochondria in CADASIL VSMCs. Transmission electron microscopy analysis demonstrated increased irregular and abnormal mitochondria in CADASIL VSMCs. Measurements of mitochondrial membrane potential (Deltapsi(m)) showed a lower percentage of fully functional mitochondria in CADASIL VSMCs. For a number of genes previously reported to be changed in CADASIL VSMCs, immunoblotting analysis demonstrated a significantly reduced SOD1 expression. These findings suggest that alteration of proliferation and mitochondrial function in CADASIL VSMCs might have an effect on vital cellular functions important for CADASIL pathology. PMID- 23036510 TI - Direct molecular identification of Trypanosoma cruzi discrete typing units in domestic and peridomestic Triatoma infestans and Triatoma sordida from the Argentine Chaco. AB - We assessed the distribution of Trypanosoma cruzi Discrete Typing Units (DTUs) in domestic and peridomestic Triatoma infestans and Triatoma sordida specimens collected in a well-defined rural area in Pampa del Indio, northeastern Argentina. Microscopically-positive bugs were randomly selected with a multi level sampling design, and DTUs were identified using direct PCR strategies. TcVI predominated in 61% of 69 T. infestans and in 56% of 9 T. sordida. TcV was the secondary DTU in T. infestans (16%) and was found in 1 T. sordida specimen (11%). Three T. sordida (33%) were found infected with TcI, a DTU also identified in local Didelphis albiventris opossums. Mixed DTU infections occurred rarely (5%) and were detected both directly from the bugs' rectal ampoule and parasite cultures. The identified DTUs and bug collection sites of T. infestans were significantly associated. Bugs infected with TcV were almost exclusively captured in domiciles whereas those with TcVI were found similarly in domiciles and peridomiciles. All mixed infections occurred in domiciles. TcV-infected bugs fed more often on humans than on dogs, whereas TcVI-infected bugs showed the reverse pattern. T. sordida is a probable sylvatic vector of TcI linked to D. albiventris, and could represent a secondary vector of TcVI and TcV in the domestic/peridomestic cycle. PMID- 23036511 TI - The meaning of a "hippo" response on the Montreal Cognitive Assessment in Parkinson's disease. PMID- 23036512 TI - THAP1 mutations in a Greek primary blepharospasm series. PMID- 23036514 TI - Autoimmunity: insights from human genomics. PMID- 23036513 TI - Local circuit inhibition in the cerebral cortex as the source of gain control and untuned suppression. AB - Theoretical considerations have led to the concept that the cerebral cortex is operating in a balanced state in which synaptic excitation is approximately balanced by synaptic inhibition from the local cortical circuit. This paper is about the functional consequences of the balanced state in sensory cortex. One consequence is gain control: there is experimental evidence and theoretical support for the idea that local circuit inhibition acts as a local automatic gain control throughout the cortex. Second, inhibition increases cortical feature selectivity: many studies of different sensory cortical areas have reported that suppressive mechanisms contribute to feature selectivity. Synaptic inhibition from the local microcircuit should be untuned (or broadly tuned) for stimulus features because of the microarchitecture of the cortical microcircuit. Untuned inhibition probably is the source of Untuned Suppression that enhances feature selectivity. We studied inhibition's function in our experiments, guided by a neuronal network model, on orientation selectivity in the primary visual cortex, V1, of the Macaque monkey. Our results revealed that Untuned Suppression, generated by local circuit inhibition, is crucial for the generation of highly orientation-selective cells in V1 cortex. PMID- 23036515 TI - Radical gastrectomy with para-aortic lymphadenectomy for carcinoma? The controversy continues. Commentary on Risk factors for metastasis to para-aortic lymph nodes in gastric cancer: a single institution study in China. Journal of Surgical Research. PMID- 23036516 TI - Early laparotomy wound failure as the mechanism for incisional hernia formation. AB - BACKGROUND: Incisional hernia is the most common complication of abdominal surgery leading to reoperation. In the United States, 200,000 incisional hernia repairs are performed annually, often with significant morbidity. Obesity is increasing the risk of laparotomy wound failure. METHODS: We used a validated animal model of incisional hernia formation. We intentionally induced laparotomy wound failure in otherwise normal adult, male Sprague-Dawley rats. Radio-opaque, metal surgical clips served as markers for the use of x-ray images to follow the progress of laparotomy wound failure. We confirmed radiographic findings of the time course for mechanical laparotomy wound failure by necropsy. RESULTS: Noninvasive radiographic imaging predicts early laparotomy wound failure and incisional hernia formation. We confirmed both transverse and craniocaudad migration of radio-opaque markers at necropsy after 28 d that was uniformly associated with the clinical development of incisional hernias. CONCLUSIONS: Early laparotomy wound failure is a primary mechanism for incisional hernia formation. A noninvasive radiographic method for studying laparotomy wound healing may help design clinical trials to prevent and treat this common general surgical complication. PMID- 23036517 TI - Functional relationship between high mobility group A1 (HMGA1) protein and insulin-like growth factor-binding protein 3 (IGFBP-3) in human chondrocytes. AB - INTRODUCTION: Insulin-like growth factor I (IGF-I) regulates articular cartilage homeostasis. During osteoarthritis (OA), the anabolic responses of chondrocytes to IGF-I are likely to be prevented by the enhanced production of IGF-binding proteins (IGFBPs), especially IGFBP-3. The aim of this study is to evaluate whether the architectural transcription factor high mobility group A1 (HMGA1) influences IGFBP-3 overexpression in vitro, in cultured chondrocytic cell lines, and ex vivo, in human osteoarthritic cartilage compared to healthy human cartilage controls. METHODS: Quantitative real-time reverse transcription-PCR (qRT-PCR) was performed to assess the relative transcript levels of HMGA1 and IGFBP-3 in vitro, in the human chondrocytic cell lines T/C-28a4 and C-28/I2. An electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and transient transfection assays were performed to investigate the HMGA1-IGFBP-3 gene interaction. Samples of articular cartilage were harvested from osteoarthritic patients and controls and analyzed by qRT-PCR for HMGA1 and IGFBP 3 mRNA levels. RESULTS: A parallelism between HMGA1 protein levels and IGFBP-3 gene expression has been observed in T/C-28a4 and C-28/I2 cells. The interaction of HMGA1 with the IGFBP-3 gene promoter has been demonstrated by EMSA and ChIP. In transient transfections, IGFBP-3 promoter activity increased in cells overexpressing HMGA1 and decreased in cells pretreated with siRNA detected against HMGA1. IGFBP-3 mRNA expression was higher in cartilage from patients with OA, where the increased expression of IGFBP-3 closely paralleled the increased expression of HMGA1 mRNA. CONCLUSIONS: Our observations indicate that increased HMGA1 expression in human chondrocytes is associated with increased expression of IGFBP-3. It is tempting to speculate that, through the regulation of IGFBP3 expression, HMGA1 may act as a pathogenetic factor for OA. PMID- 23036518 TI - Intravesical botulinum type-A toxin (Dysport(r)) in the treatment of idiopathic detrusor overactivity in children. AB - OBJECTIVE: Botulinum type-A toxin is increasingly used for refractory idiopathic detrusor overactivity (IDO) in children. We reviewed our experience and sought to ascertain the influence of dose and functional bladder capacity on outcome. PATIENTS AND METHODS: Thirty patients, aged 6-16 years, with urodynamically proven IDO, had intravesical injections of 400-500 iu of Dysport((r)). Outcome was assessed clinically at least 5 months after the injection. RESULTS: Data were available for 27 patients. Urinary frequency was improved in 10; nocturia was improved in 7. Urgency resolved in 10 patients and urge incontinence in 12 (44%). Complications reported were UTI (7), urinary retention (1) and bladder pain (1). The dose of Dysport((r)) used was not significantly higher (14 iu/kg v 13 iu/kg) in patients dry at follow up than in those who remained wet (p = 0.45). Functional bladder capacity was not significantly different in patients dry after treatment (p = 0.82). CONCLUSION: This retrospective study demonstrates similar response to a single treatment with intravesical Botulinum type-A toxin to previous series. We did not demonstrate a correlation between dose or functional bladder capacity and resolution of incontinence. A multi-centre study is required to further investigate this promising treatment. PMID- 23036520 TI - University students' pursuit of healthy behaviors may influence sexual risk reduction strategies. PMID- 23036519 TI - Understanding ethnic and nativity-related differences in low cardiovascular risk status among Mexican-Americans and non-Hispanic Whites. AB - OBJECTIVE: Recent guidelines highlight the importance of improving cardiovascular health in the general population in addition to disease prevention among high risk individuals. We investigated factors associated with ethnic and nativity related differences in the prevalence of low cardiovascular risk (optimal levels of all major cardiovascular risk factors). METHODS: We used logistic regression to estimate differences in likelihood of being low risk (not currently smoking; no diabetes; untreated total cholesterol <200mg/dL; untreated blood pressure <120/<80; and body mass index <25 kg/m(2)) among 8693 foreign- and U.S.-born Mexican-American and non-Hispanic White 2003-2008 U.S. National Health and Nutrition Examination Survey participants before and after adjustment for socioeconomic, lifestyle, and acculturation-related factors. RESULTS: Foreign born Mexican-Americans were more likely to be low risk than non-Hispanic Whites after adjustment for all covariates (Odds Ratio [OR]: 1.53; 95% Confidence Interval [CI]: 1.00, 2.34). In contrast, U.S.-born Mexican-Americans were less likely to be low risk compared to Whites (OR: 0.60; 95% CI: 0.43, 0.84). Differences between foreign-born and U.S.-born Mexican-Americans were largely attenuated after adjustment for acculturation indicators. CONCLUSIONS: Our findings support the healthy migrant hypothesis and suggest that acculturation related factors may be important drivers of ethnic and nativity-related differences in low cardiovascular risk. PMID- 23036521 TI - Human contamination by environmental chemical pollutants: can we assess it more properly? PMID- 23036522 TI - Insular networks for emotional processing and social cognition: comparison of two case reports with either cortical or subcortical involvement. AB - INTRODUCTION: The processing of the emotion of disgust is attributed to the insular cortex (IC), which is also responsible for social emotions and higher cognitive functions. We distinguish the role of the IC from its connections in regard to these functions through the assessment of emotions and social cognition in a double case report. These subjects were very rare cases that included a focal IC lesion and a subcortical focal stroke affecting the connections of the IC with frontotemporal areas. MATERIALS & METHODS: Both patients and a sample of 10 matched controls underwent neuropsychological and affective screening questionnaires, a battery of multimodal basic emotion recognition tests, an emotional inference disambiguation task using social contextual clues, an empathy task and a theory of mind task. RESULTS: The insular lesion (IL) patient showed no impairments in emotion recognition and social emotions and presented with a pattern of delayed reaction times (RTs) in a subset of both groups of tasks. The subcortical lesion (SL) patient was impaired in multimodal aversive emotion recognition, including disgust, and exhibited delayed RTs and a heterogeneous pattern of impairments in subtasks of empathy and in the contextual inference of emotions. CONCLUSIONS: Our results suggest that IC related networks, and not the IC itself, are related to negative emotional processing and social emotions. We discuss these results with respect to theoretical approaches of insular involvement in emotional and social processing and propose that IC connectivity with frontotemporal and subcortical regions might be relevant for contextual emotional processing and social cognition. PMID- 23036523 TI - Comment on Brazdil (2012) "unveiling the mystery of deja-vu: the structural anatomy of deja-vu". PMID- 23036524 TI - Behavioral responses to partial-gravity conditions in rats. AB - The effects of microgravity or hypergravity on living organisms have been studied extensively; however, thus far no studies have addressed the effects of "partial gravity", that is, the low-gravity levels between the unit gravity (1G) on Earth and zero gravity (0 G) in space. The purpose of the present study was to examine behavioral responses in rats under partial-gravity conditions. Rat behavior was monitored by video cameras during parabolic flights. The flight trajectory was customized in order to generate graded levels of partial gravity. Gravity dependent behavior patterns were observed in rats. In the conditions of 0.4 G through 0.2G, rats showed startle and crouching. Hindlimb stretching emerged at 0.15 G and was more frequently observed toward 0.01 G. Different thresholds may exist for emotional and balance/posture-related behaviors. PMID- 23036525 TI - Neuraxial modulation for ventricular arrhythmias: a new hope. PMID- 23036526 TI - Sympathoadrenal imbalance and beta-blockers revisited. PMID- 23036527 TI - Placing pacing leads into the cavity of the left ventricle using a snare catheter: innovating a tabooed procedure. PMID- 23036528 TI - Expression of tlr4, md2 and cd14 in equine blood leukocytes during endotoxin infusion and in intestinal tissues from healthy horses. AB - The expression of tlr4, md2 and cd14 was studied in equine blood leukocytes and in intestinal samples using real time PCR. The stability of three commonly used reference genes, glyceraldehyde-3P-dehydrogenase (GAPDH), hypoxantine ribosyltransferase (HPRT) and succinate dehydrogenase complex subunit A (SDHA), was evaluated using qbase(PLUS). The equine peripheral blood mononuclear cells (eqPBMC) examined were either stimulated in vitro with Phorbol 12-myristate 13 acetate (PMA) and ionomycin or with the CpG oligodeoxynuclotide 2216 (CpG-ODN 2216) or obtained from horses before, during and after infusion of endotoxin. Intestinal tissue from healthy horses was sampled at ileum, right dorsal colon and rectum. Ranking of the three reference genes used for normalisation identified the combination HPRT/SDHA as most suitable both when determined ex vivo in leukocytes obtained from experimentally induced endotoxaemia and in eqPBMC activated in vitro while HPRT/GAPDH were most appropriate for the intestinal samples. The relative amounts of mRNA for TLR4 and MD-2 increased threefold during in vitro activation of the cells with CpG-ODN 2216 but was decreased in cultures stimulated with PMA/ionomycin. A transient elevation in the transcription of tlr4 and md2 was also evident for equine blood leukocytes following endotoxaemia. The levels of mRNA for CD14 on the other hand remained unaffected both during the induction of endotoxaemia and in the in vitro stimulated PBMCs. A low steady expression of TLR4, MD-2 and CD14 mRNA was demonstrated for the intestinal samples with no variation between the intestinal segments analysed. Thus, the foundation for real time PCR based levels of analysis of mRNA for all three components in the equine LPS receptor complex in different intestinal segments was set, making it possible to carry out future expression studies on clinical material. PMID- 23036529 TI - Soft tissue mechanotransduction in wound healing and fibrosis. AB - Recent evidence suggests that mechanical forces can significantly impact the biologic response to injury. Integrated mechanical and chemical signaling networks have been discovered that enable physical cues to regulate disease processes such as pathologic scar formation. Distinct molecular mechanisms control how tensional forces influence wound healing and fibrosis. Conceptual frameworks to understand cutaneous repair have expanded beyond traditional cell cytokine models to include dynamic interactions driven by mechanical force and the extracellular matrix. Strategies to manipulate these biomechanical signaling networks have tremendous therapeutic potential to reduce scar formation and promote skin regeneration. PMID- 23036530 TI - Capturing epidermal stemness for regenerative medicine. AB - The skin is privileged because several skin-derived stem cells (epithelial stem cells from epidermis and its appendages, mesenchymal stem cells from dermis and subcutis, melanocyte stem cells) can be efficiently captured for therapeutic use. Main indications remain the permanent coverage of extensive third degree burns and healing of chronic cutaneous wounds, but recent advances in gene therapy technology open the door to the treatment of disabling inherited skin diseases with genetically corrected keratinocyte stem cells. Therapeutic skin stem cells that were initially cultured in research or hospital laboratories must be produced according strict regulatory guidelines, which ensure patients and medical teams that the medicinal cell products are safe, of constant quality and manufactured according to state-of-the art technology. Nonetheless, it does not warrant clinical efficacy and permanent engraftment of autologous stem cells remains variable. There are many challenges ahead to improve efficacy among which to keep telomere-dependent senescence and telomere-independent senescence (clonal conversion) to a minimum in cell culture and to understand the cellular and molecular mechanisms implicated in engraftment. Finally, medicinal stem cells are expansive to produce and reimbursement of costs by health insurances is a major concern in many countries. PMID- 23036531 TI - Mechanisms of action of microdeformational wound therapy. AB - Microdeformational Wound Therapy (MDWT) is a class of medical devices that have revolutionized the treatment of complex wounds over the last 20 years. These devices, are a subset of Negative Pressure Wound Therapy (NPWT), in which there is a highly porous interface material placed between the wound and a semi occlussive dressing and connected to suction. The porous interface material acts to deform the wound on a micro scale promoting cellular proliferation. These devices appear to significantly improve the speed of healing in many wounds, facilitate granulation tissue formation and reduce the complexity of subsequent reconstructive operations. The mechanisms through which such effects are obtained are beginning to be better understood through basic research and clinical trials. Further work in this field is likely to yield devices that are designed to treat specific wound types. PMID- 23036533 TI - The assessment of thrombotic risk using a predictive model in metastatic cancer patients undergoing first-line therapy. PMID- 23036534 TI - Peripheral expression of LACK-mRNA induced by intranasal vaccination with PCI-NEO LACK defines the protection duration against murine visceral leishmaniasis. AB - LACK (Leishmania analogue of the receptor kinase C) is a conserved protein in the protozoan of the genus Leishmania, which is associated with the immunopathogenesis and susceptibility of BALB/c mice to Leishmania major infection. We previously demonstrated that intranasal immunization with a plasmid DNA encoding the p36/LACK leishmanial antigen (pCI-neo-LACK) followed by challenge 7 days after a booster dose effectively protects BALB/c mice against both cutaneous and visceral leishmaniasis. In the present study, the correlation between systemic mRNA expression after nasal DNA uptake, and the duration of protective immunity was addressed. LACK mRNA transcripts were detected in the spleen, brain, cervical lymph nodes and popliteal lymph nodes as early as 7 days, lasting 3 months after vaccination with pCI-neo-LACK. The kinetics of transcript expression correlated with enhanced cutaneous hypersensitivity against parasite antigens. Leishmania chagasi infection at 7 days or 3 months, but not 6 months after vaccination resulted in significantly lower parasite loads as compared with non-vaccinated controls. Protection also correlated with enhanced spleen cell responsiveness to parasite antigens leading to increased IFN- gamma and IL-4 and decreased IL-10 production. Together, these data demonstrate that the protection conferred by the intranasal DNA vaccine lasts at least 3 months and is associated with expression of vaccine mRNA in peripheral organs. PMID- 23036532 TI - Differential regulation of fibrinogen gamma chain splice isoforms by interleukin 6. AB - INTRODUCTION: Fibrinogen is a major structural protein in blood clots, and is also a well-known acute phase reactant. The gamma chain gene of fibrinogen has two alternative splice variants, gammaA and gamma' chains. gamma' fibrinogen constitutes about 7% of total fibrinogen. Total fibrinogen levels and gamma' fibrinogen levels have been associated with cardiovascular disease, but the mechanisms regulating the production of the two isoforms are unknown. Several inflammatory cytokines are known to influence the production of total fibrinogen, but the role of cytokines in the production of gamma' fibrinogen has not been examined. However, epidemiologic studies have shown an association between gamma' fibrinogen levels and inflammatory markers in humans. MATERIALS AND METHODS: The expression of gamma' fibrinogen and total fibrinogen by HepG2 liver cells was quantitated after treatment with interleukin-1beta, transforming growth factor beta, tumor necrosis factor-alpha, and interleukin-6. RESULTS: Interleukin-1beta, transforming growth factor-beta, and tumor necrosis factor-alpha, known down regulators of total fibrinogen synthesis, also downregulate gamma' fibrinogen synthesis in HepG2 cells. However, interleukin-6 differentially up-regulates the production of total and gamma' fibrinogen, leading to a 3.6-fold increase in gammaA mRNA, but an 8.3-fold increase in gamma' mRNA. CONCLUSIONS: These findings indicate that gamma' fibrinogen is disproportionately up-regulated by inflammatory responses induced by interleukin-6. PMID- 23036535 TI - The new oral anticoagulants and stroke. PMID- 23036536 TI - A million neurons can be wrong. PMID- 23036537 TI - The changing face of amblyopia. PMID- 23036538 TI - A comparison of hand- and foot-activated surgical tools in simulated ophthalmic surgery. PMID- 23036539 TI - New concepts concerning the neural mechanisms of amblyopia and their clinical implications. AB - Amblyopia is a visual impairment secondary to abnormal visual experience (e.g., strabismus, anisometropia, form deprivation) during early childhood that cannot be corrected immediately by glasses alone. It is the most common cause of monocular blindness globally. Patching remains the mainstay of treatment, but it is not always successful and there are also compliance and recurrence issues. Because amblyopia is a neural disorder that results from abnormal stimulation of the brain during the critical periods of visual development, it is essential to understand the neural mechanisms of amblyopia in order to devise better treatment strategies. In this review, I examine our current understanding of the neural mechanisms that underlie the characteristic deficits associated with amblyopia. I then examine modern neuroimaging findings that show how amblyopia affects various brain regions and how it disrupts the interactions among these brain regions. Following this, I review current concepts of brain plasticity and their implications for novel therapeutic strategies, including perceptual learning and binocular therapy, that may be beneficial for both children and adults with amblyopia. PMID- 23036540 TI - Twitter as a tool for ophthalmologists. AB - Twitter is a social media web site created in 2006 that allows users to post Tweets, which are text-based messages containing up to 140 characters. It has grown exponentially in popularity; now more than 340 million Tweets are sent daily, and there are more than 140 million users. Twitter has become an important tool in medicine in a variety of contexts, allowing medical journals to engage their audiences, conference attendees to interact with one another in real time, and physicians to have the opportunity to interact with politicians, organizations, and the media in a manner that can be freely observed. There are also tremendous research opportunities since Twitter contains a database of public opinion that can be mined by keywords and hashtags. This article serves as an introduction to Twitter and surveys the peer-reviewed literature concerning its various uses and original studies. Opportunities for use in ophthalmology are outlined, and a recommended list of ophthalmology feeds on Twitter is presented. Overall, Twitter is an underutilized resource in ophthalmology and has the potential to enhance professional collegiality, advocacy, and scientific research. PMID- 23036541 TI - A comparison of hand- and foot-activated surgical tools in simulated ophthalmic surgery. AB - OBJECTIVE: To compare the performance characteristics of hand-activated surgical tools with those of foot-activated surgical tools using a virtual-reality simulator of intraocular surgery. DESIGN: Prospective, unmasked, interventional cohort study. PARTICIPANTS: Eighteen ophthalmology residents at the University of Toronto. METHODS: The EYESi ophthalmic surgery simulator was used for the study. The surgical tool evaluated was a simulation of intraocular forceps activated by either a handpiece or a foot pedal. Each resident completed 2 modules-a dexterity module and a capsulorrhexis/cataract module. Each module was completed 4 times, alternating between the hand-activated forceps and the foot-activated forceps. An overall score was calculated for each task on the basis of the efficiency and accuracy of completion of the task, with 100 representing a perfect score. Overall scores were compared between hand and foot control for both modules. RESULTS: For the dexterity module, there was no significant difference in the overall scores between the 2 groups (91 +/- 6 and 93 +/- 6 for the foot- and hand activated forceps groups, respectively; p > 0.05, t test). For the capsulorrhexis module, overall scores were also similar for both groups, the scores being 50 +/- 21 and 53 +/- 16 for the foot- and hand-activated forceps groups, respectively (p > 0.05, t test). An exit survey of the study's participants revealed that subjects did not have a preference for the hand or foot modality of the forceps tool, with 10 preferring the hand-activated forceps tool and 8 preferring the foot-activated tool. CONCLUSIONS: During simulated intraocular surgery, foot- and hand-activated surgical tools appear to have similar performance characteristics and are equally well received by residents. PMID- 23036542 TI - An improved surgical method to correct conjunctivochalasis: conjunctival semiperitomy based on corneal limbus with subconjunctival cauterization. AB - OBJECTIVE: To introduce an improved surgical method to correct conjunctivochalasis. DESIGN: Retrospective study. PARTICIPANTS: We studied 28 eyes in 28 patients. METHODS: First, conjunctival semiperitomy based on the corneal limbus was performed. Next, the subconjunctival tissues received 2 lines (12 to 18 spots) of gentle cauterization using a cautery to adhere the conjunctiva to underlying sclera. The grade of conjunctivochalasis, Schirmer test (St), and tear breakup time (BUT) were recorded under a slit-lamp, and the severity of patients' symptoms were assessed by using the Ocular Surface Disease Index (OSDI) questionnaires. The values before surgery and 3 months after surgery were collected and then compared. RESULTS: The conjunctivochalasis gradings were as follows: preoperatively, there were 0 eyes in grade 0 and grade 1; 13 (46.43%) eyes in grade 2; and 15 (53.57%) eyes in grade 3. Postoperatively, there were 26 (92.86%) eyes in grade 0; 2 (7.14%) eyes in grade 1; and 0 eyes in grades 2 and 3. Preoperatively, the St, BUT, and OSDI were 8.49 +/- 4.42 mm, 7.74 +/- 2.72 seconds, and 40.64 +/- 10.30, respectively; postoperatively, they were 13.22 +/- 4.26 mm, 12.06 +/- 2.48 seconds, and 10.50 +/- 3.87, respectively. There was a significant difference (p < 0.05) between pre- and postoperative patients in conjunctivochalasis grade, St, BUT and OSDI. CONCLUSIONS: Conjunctival semiperitomy combined with gentle subconjunctival cauterization is a better therapy for conjunctivochalasis because it both resects the redundant conjunctiva and reestablishes the anatomic tight adhesion between the conjunctiva and the underlying sclera along the corneal limbus. PMID- 23036543 TI - Effects of pterygium surgery on front and back corneal astigmatism. AB - OBJECTIVE: To evaluate changes in front and back corneal astigmatism after pterygium surgery using the Scheimpflug imaging of Pentacam. DESIGN: Prospective interventional case series. PARTICIPANTS: We studied 96 eyes with primary pterygium that underwent surgery. METHODS: Preoperatively and at 1, 3, and 6 months after surgery, Pentacam (Oculus, Wetzlar, Germany) was used to measure astigmatism at the front and back corneal surfaces. Surgically induced astigmatism (SIA) on the front corneal surface was also calculated, using vector analysis. RESULTS: Of the eyes, 73 completed 6-month postoperative follow-up without developing pterygium recurrence. Front corneal astigmatism decreased from 3.97 +/- 4.49 D preoperatively to 1.23 +/- 1.88 D at 1 month (p < 0.001). Back corneal astigmatism decreased, but nonsignificantly, from 0.35 +/- 0.39 D preoperatively to 0.32 +/- 0.2 D at 1 month (p = 0.49). However, although back astigmatism was with-the-rule in 43.8% of patients and against-the-rule in 24.6% of patients preoperatively, these changed to 87.7% and 4.1%, respectively, at 1 month (p = 0.02). Refractive cylinder (52 eyes) reduced from 2.62 +/- 2.22 D preoperatively to 1.06 +/- 1.57 D at 1 month (p = 0.05). There was no significant change in any parameter after 1 month throughout the 6 months after surgery. SIA was 3.51 +/- 2.66 D at 1 month postoperatively, which showed significant correlation with age, preoperative astigmatism, and pterygium length and area, but there was no correlation with gender, pterygium width, preoperative spherical power, or surgical technique. Moreover, higher grades of pterygium morphology had higher SIA postoperatively (p = 0.05). CONCLUSIONS: Pterygium surgery was associated with significant changes in front and back corneal surfaces. Eyes with more advanced pterygia achieved higher SIA. PMID- 23036544 TI - The ocular surface in the Behcet's disease patient. AB - OBJECTIVE: Evaluation of the morphological changes in conjunctival surface epithelial cells with impression cytology in Behcet's disease patients. PATIENTS: A total of 89 eyes of 89 subjects were included. These consisted of 56 patients with inactive Behcet's disease (group 1) and a control group of 33 age- and sex matched subjects (group 2). METHODS: Schirmer-I and break-up time (BUT) tests were used to evaluate the tear film of the subjects. Impression cytology was used to evaluate morphological changes of the conjunctival surface epithelial cells. The results of the 2 groups were compared. RESULTS: The mean Schirmer-I test result was 8.59 +/- 4.83 in group 1 and 14.52 +/- 6.38 in group 2. There was a statistically significant difference between the 2 groups for this test (p = 0.001). The mean BUT test value was 10.05 +/- 3.26 in group 1 and 13.64 +/- 4.28 in group 2. There was a statistically significant difference between the 2 groups for this test (p = 0.001). The mean impression cytology score was 1.65 +/- 0.90 in group 1 and 1.39 +/- 0.96 in group 2. There was no statistically significant difference between the 2 groups when the cytology grade score was compared (p = 0.227). We found no statistically significant difference for age, gender, disease duration, systemic drug use, Schirmer-I, BUT, and impression cytology degrees between the Behcet's disease patients with and without ocular involvement (p > 0.05). CONCLUSIONS: We found that there was a statistically significant difference between Behcet's disease patients and normal subjects regarding the ocular film layer, but no difference regarding conjunctival surface epithelial morphology. PMID- 23036545 TI - Understanding macular holes that develop after repair of retinal detachment. AB - OBJECTIVE: To present the characteristics and outcomes of macular holes (MHs) that arise in eyes that have been treated for retinal detachment (RD). DESIGN: Retrospective, interventional, consecutive case series. PARTICIPANTS: We studied 18 eyes that developed a MH following RD repair. METHODS: We report the demographic and clinical characteristics, MH closure rates, and best corrected visual acuity (BCVA) following MH repair. RESULTS: We detected 18 full-thickness MHs in 985 eyes. In 14 of 18, the original RD involved the macula, and in 16 of 18, the BCVA was 20/200 or worse. Of the RDs, 8 of 18 required multiple procedures to achieve reattachment. Post-RD BCVA was 20/200 or worse in 15 of 18 patients. The median time to MH diagnosis after RD repair was 1 month (range, 2 days to 53 months), and from MH diagnosis to MH repair, the median time was 1.75 months (range, 3 weeks to 8 months). Of 16 eyes (89%) that underwent surgical repair of the MH, 14 achieved MH closure, 1 requiring multiple pars plana vitrectomy, and 11 saw at least 1 Snellen line of improvement (median, 1; range, 1 to 6); 2 lost vision (1 and 2 Snellen lines, respectively); and 3 remained unchanged at a median follow-up of 3 months (range, 1 month to 25 months). Of the 18 patients, 6 had at least 20/80 BCVA at last follow-up. CONCLUSIONS: MHs following RDs (incidence 1.9%) are likely to be macula-off RDs requiring multiple interventions for RD repair. Post-MH-repair closure rates are similar to the rates for idiopathic MHs. BCVA outcomes are moderate and are dependent on impairment post-RD repair. The findings suggest other pathogenic mechanisms besides vitreofoveal traction may be leading to these MHs. PMID- 23036546 TI - Long-term evolution of idiopathic lamellar macular holes and macular pseudoholes. AB - OBJECTIVE: To analyze the natural evolution of idiopathic lamellar macular holes (LMH) and macular pseudoholes (MPH) in the long term, based on optical coherence tomography (OCT) configuration and on best corrected visual acuity (BCVA) evolution. DESIGN: A prospective, longitudinal study. PARTICIPANTS: We prospectively analyzed 108 eyes (67 left eyes and 41 right eyes) of 99 patients (55 female and 44 male) whose eyes had been diagnosed as having an MPH or an LMH on OCT examination. METHODS: The following variables were assessed: BCVA; lens status; and hole size (diameter, residual foveal thickness, and perifoveal thickness) at baseline and at final examination. RESULTS: The mean follow-up period was 31.07 +/- 18.77 (12 to 84) months. The mean BCVA (logMAR) in the total group at baseline was 0.31 +/- 0.25, and at final examination it was 0.22 +/- 0.21 (p = 0.200). Moreover, we did not observe statistically significant differences regarding diameter, residual foveal thickness, or perifoveal thickness (p = 0.325). CONCLUSIONS: Most idiopathic LMH and MPH do not progress anatomically and do not contribute to a significant diminution in visual acuity during the follow-up period. PMID- 23036547 TI - Pre- versus post-dilation changes in intraocular pressure: their clinical significance. AB - OBJECTIVE: To measure the difference in intraocular pressure (IOP) before and following pharmacologic mydriasis with a cycloplegic-mydriatic combination agent in normal subjects using the Goldmann applanation tonometer. DESIGN: A prospective, university hospital-based, nonrandomized interventional case series. METHODS: We recruited 67 normal subjects without glaucoma. Data were collected on the patients' IOPs before and 45 minutes after pharmacologic mydriasis in both eyes using the Goldmann applanation tonometer. Central corneal thickness and additional parameters were measured to further confirm the absence of glaucoma and to study the correlation between IOP fluctuations and these characteristics. RESULTS: The IOP was measured in 127 eyes. The mean difference between pre- and post-dilation time points was 1.1 +/- 2.5 mm Hg in the right eye and 0.7 +/- 2.3 mm Hg in the left eye. Post-dilation, the maximum deviation was a change of 6 mm Hg.; 35% of patients had a post-dilation variation of >2 mm Hg (clinically significant). Of these, 31.1% of changes were IOP increases, and 68.9% of changes were IOP decreases after dilation. Central corneal thickness and other parameters showed no correlation with IOP changes. CONCLUSIONS: The use of pharmacologic mydriasis prior to IOP measurement affected the reliability of IOP measurements taken post-dilation in our group of patients. Thus, we believe that the stringent measurement of IOP prior to dilation is the responsible method of measuring and following IOP in every single patient. PMID- 23036548 TI - Clinical features of 8 cases of orbital sparganosis in southern China. AB - OBJECTIVE: To describe clinicoradiologic characteristics of orbital sparganosis. DESIGN: Retrospective case series. PARTICIPANTS: We studied 8 patients diagnosed with orbital sparganosis at Zhongshan Ophthalmic Center between 1999 and 2011. METHODS: A thorough review of clinical and imaging manifestations. RESULTS: The primary clinical manifestations were redness and edema of the eyelids and conjunctivas (100%); proptosis (mild in 87.5% of cases and severe in 12.5%); subconjunctival yellow-white granulomatous lesions (75.0%); and migratory hyperemic masses of the eyelid or conjunctiva (50.0%). Of the patients, 6 had diffuse orbital or nodular masses on computed tomography imaging, 2 had the "tunnel sign" on magnetic resonance imaging, and 1 had subconjunctival tubular lesions on ultrasound biomicroscopy imaging. CONCLUSIONS: Subconjunctival yellow white granulomatous lesions, migratory hyperemic masses, and the tunnel sign on magnetic resonance imaging are characteristic clues to preoperative diagnosis of orbital sparganosis. PMID- 23036549 TI - Re: Effects of posterior capsular opacification on the evaluation of retinal nerve fiber layer as measured by Stratus optical coherence tomography. 47(2). PMID- 23036551 TI - Long-term ranibizumab treatment for choroidal neovascularization secondary to serpiginous choroiditis. PMID- 23036552 TI - Spontaneous resolution of vitreomacular traction syndrome with persistent vitreofoveal adhesion observed on spectral-domain optical coherence tomography. PMID- 23036553 TI - Central visual disturbance associated with transient disruption of photoreceptor inner-outer segment junction. PMID- 23036554 TI - Bilateral colobomas with avascular peripheral retina: case report. PMID- 23036555 TI - Acute anterior uveitis following zoledronic acid infusion for osteoporosis. PMID- 23036556 TI - Bloody tears from lacrimal sac rhinosporidiosis. PMID- 23036557 TI - Epidermal growth factor receptor exists in the early stage of proliferative vitreoretinopathy. PMID- 23036558 TI - Isolated postganglionic Horner syndrome: some lessons learned. PMID- 23036559 TI - Topical fresh frozen plasma and heparin treatment of ligneous conjunctivitis in a Canadian hospital setting. PMID- 23036560 TI - Idiopathic recurrent subconjunctival hemorrhage. PMID- 23036561 TI - Medial rectus rhabdomyosarcoma presenting as an esotropia with limited abduction. PMID- 23036562 TI - Clinically evident chloroquine toxicity undetected by multifocal electroretinogram. PMID- 23036563 TI - Acute lymphoblastic leukemia presenting as bilateral serous macular detachment and lacrimal gland enlargement. PMID- 23036564 TI - Optomotor and immunohistochemical changes in the juvenile S334ter rat. AB - The aim of this study was to examine the temporal relationship between behaviorally measured visual thresholds, photoreceptor degeneration and dysfunction, synaptic and neuronal morphology changes in the retina in the S334ter line 4 rat. Specifically, we examined the optokinetic tracking (OKT) behavior in S334ter rats daily and found that OKT thresholds reflected normal values at eye opening but quickly reduced to a non-response level by postnatal day (P) 22. By contrast, the scotopic electroretinogram (ERG) showed a much slower degeneration, with substantial scotopic function remaining after P90 as previously demonstrated for this line of rats. Photopic b-wave amplitudes revealed functional levels between 70 and 100% of normal between P30 and P90. Histological evidence demonstrated that photoreceptor degeneration occurred over many months, with an outer nuclear layer (ONL) roughly half the thickness of a normal age-matched control at P90. Immunohistochemical analysis revealed a number of changes in retinal morphology in the Tg S334ter line 4 rat that occur at or before P40 including: elevated levels of rod opsin expression in the ONL, cone photoreceptor morphology changes, glial cell activation, inner retinal neuron sprouting, and microglial cell activation. Many of these changes were evident at P30 and in some cases as early as eye opening (P15). Thus, the morphological changes occurred in concert with or before the very rapid loss of the behavioral (OKT) responses, and significantly before the loss of photoreceptors and photoreceptor function. PMID- 23036565 TI - Diagnostic work-up of an elderly patient with unilateral head and neck pain. A case report. AB - Headache patients frequently contact physiotherapists and manual therapists. In case of elderly patients with unilateral headache, neck and facial pain clinical practice guidelines recommend further referral for medical investigation to exclude red flags. The present patient was seen in a multidisciplinary headache clinic. He was referred by the neurologist (headache specialist) for physiotherapeutic assessment after screening for red flags, including giant cell arteritis (GCA). After first assessment, GCA was considered unlikely, since the sedimentation rate, as a marker for inflammation, was only slightly elevated. The purpose of the referral was to exclude cervicogenic headache (CEH) and to explore physical treatment as a therapeutic option. Physiotherapeutic assessment consisted of a history taking on CEH signs (Sjaastad criteria, 1998), followed by cervical spine assessment including tests for neck mobility, joint pain, and endurance of the short neck flexors. The patient's history revealed no specific signs of CEH and cervical spine assessment was negative. In consultation with the neurologist, the diagnosis of CEH was abandoned. Since palpation of the temporal artery proved to be painful, laboratory examination and biopsy of the temporal artery were thereafter performed, this time revealing GCA. Appropriate treatment (high dose steroids) was initiated promptly, with a good clinical evolution. The presented case shows the potential of a multidisciplinary collaboration in the clinical diagnostic work-up of patients with head and neck pain. PMID- 23036566 TI - Pseudoexfoliation syndrome and the long-term incidence of cataract and cataract surgery: the blue mountains eye study. AB - PURPOSE: To assess whether the pseudoexfoliation syndrome (PXS) is associated with the long-term incidence of cataract or cataract surgery. DESIGN: Population based cohort study. METHODS: The Blue Mountains Eye Study examined 3654 persons 49 years of age and older at baseline; 2564 were re-examined after 5 or 10 years, or both. PXS was recorded at the baseline eye examination by an ophthalmologist. Masked graders assessed lens photographs using the Wisconsin Cataract Grading System. Generalized estimating equation regression models were used to examine the association between PXS and cataract by eye. RESULTS: Eyes with PXS had a significantly greater prevalence of cortical cataract (P=.02) and nuclear cataract (P < .0001) than eyes without PXS. The association between PXS and cortical cataract, however, did not persist after further adjustment for age, gender, smoking, diabetes, steroid use, myopia, socioeconomic status, and open angle glaucoma (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.53 to 1.46), whereas the association between PXS and nuclear cataract persisted after adjustment for the above confounders (OR, 1.90; 95% CI, 1.04 to 3.48). In addition, significant associations were found between the presence of PXS at baseline and the 10-year incidence of either nuclear cataract (P < .0001) or cataract surgery (P < .0001). These associations persisted after adjustment for the potential confounders listed above (OR, 3.25; 95% CI, 1.38 to 7.65; and OR, 4.09; 95% CI, 2.25 to 7.44; respectively). No significant cross-sectional or longitudinal associations were found between PXS and posterior subcapsular cataract. CONCLUSIONS: Long-term follow-up data from this population-based older cohort suggest that the presence of PXS is associated with an increased risk of nuclear cataract and cataract surgery. PMID- 23036567 TI - Macular edema following cataract surgery in eyes with previous 23-gauge vitrectomy and peeling of the internal limiting membrane. AB - PURPOSE: To investigate intraretinal changes after successful cataract surgery in patients with previous pars plana vitrectomy (PPV) and indocyanine green-assisted peeling of epiretinal membrane and internal limiting membrane (ILM). DESIGN: Prospective nonrandomized controlled clinical study. METHODS: Twenty eyes of 20 patients with cataract with previous 23-gauge PPV and ILM peeling (PPV group) and 15 consecutive eyes with senile cataract with a healthy macula (control group) were included. Best-corrected visual acuity (BCVA), spectral-domain optical coherence tomography (OCT), infrared fundus imaging, and biomicroscopy were performed at baseline and at week 1, month 1, and month 3 after cataract surgery. OCT raster scans were further analyzed regarding the central millimeter thickness (CMMT), area of retinal thickening size on the topographic map, and changes in retinal structural morphology. RESULTS: The baseline mean visual acuity in the PPV group was 0.3 +/- 0.18 Snellen lines, which improved significantly to 0.85 +/ 0.18 (P < .05) 3 months after cataract surgery. CMMT was 393 (+/- 44) MUm at baseline and increased to 408 (+/- 47) MUm at month 3 (P < .05). One patient was not seen at the final visit, so data of 19 patients was used. In the PPV group, 8 of 19 patients (42%) developed an increase in CMMT more than 35 MUm 1 month after cataract surgery; 5 of these 8 patients (26%) developed macular edema with cyst formation. Three months after surgery, the area of retinal thickening was significantly larger in most patients compared with baseline values. No cystoid macular edema was observed in the control group. CONCLUSIONS: This study provides evidence that patients with previous PPV and membrane and ILM peeling often develop macular edema after successful cataract surgery. PMID- 23036568 TI - Quality of image of grating target placed in model eye and observed through toric intraocular lenses. AB - PURPOSE: To evaluate the quality of an image of a grating target placed in a model eye and viewed through implanted toric intraocular lenses (IOLs). DESIGN: Laboratory investigation. METHODS: Toric IOLs, SN6AT5 with a cylinder power of 3.0 diopters (3.0 D, Alcon), ST6AT9 (6.0 D, Alcon), 311T5 (3.0 D, HOYA), or 311T9 (6.0 D, HOYA), were placed in a fluid-filled model eye. A United States Air Force test target was placed internally on the posterior surface of the model eye. A flat contact lens or a wide-angle contact lens was placed on the cornea. The contrast and length of the grating targets perpendicular (vertical) or parallel (horizontal) to the flat meridian of the toric IOL were compared with those obtained through aspheric IOLs. RESULTS: The contrast of the targets viewed through the flat contact lens and toric IOLs in the vertical direction was significantly lower than that viewed through the aspheric IOL at 16 cycle/mm (SN6AT9, P=.002; SN6AT5, P=.028; 311T9, P=.002; 311T5, P =.011) but not with the wide-angle viewing lens at 16, 32, and 64 cycle/mm. The vertical length of the target with a flat contact lens was longer and the horizontal length was shorter than that through the aspheric IOL by 1% to 3% with the SN6AT5 and 311T5 IOLs and by 3% to 5% with the SN6AT9 and 311T9 IOLs. However, the vertical and horizontal lengths were not significantly different through the wide-viewing lens. CONCLUSION: Toric IOLs affect the contrast of a grating target viewed through a flat contact lens but not through a wide-angle viewing lens. The wide-angle viewing system is not influenced by cylindrical aberrations. PMID- 23036569 TI - The relationship between axial length and choroidal thickness in eyes with high myopia. AB - PURPOSE: To investigate the choroidal thickness in highly myopic eyes with no history of choroidal neovascularization or ocular surgery, and to correlate it with axial length, age, and spherical equivalent. DESIGN: Retrospective, comparative, noninterventional case series. METHODS: A total of 120 eyes of 83 patients with high myopia (spherical equivalent >=-6 diopters or axial length >=26 mm) and 96 eyes of 62 healthy patients were studied in a clinical setting. Eyes with prior vitreoretinal surgery or laser or anti-vascular endothelial growth factor therapy were excluded. Eyes were imaged using optical coherence tomography employing a 6-mm line, reference position "Choroid," and image averaging 50. Choroidal thickness was manually measured from the posterior edge of the retinal pigment epithelium to the choroid-scleral junction at 500-MUm intervals up to 2500 MUm nasal and temporal to the fovea. Statistical analysis was performed. RESULTS: The high myopia group mean age was 54.4 +/- 18.2 years (range, 18-99) and mean axial length was 29.17 +/- 2.44 mm (range, 26.00-35.63). Mean macular choroidal thickness was 115.5 +/- 85.3 MUm (range, 6.9-436.0). The choroid was thickest temporally (134 MUm), then subfoveally (130 MUm), and was thinnest in the nasal area (68 MUm). This pattern differed markedly from the control eyes. In the high myopia group, axial length had the best correlation with choroidal thickness (r = -0.740; P < .001). Choroidal thickness decreased 25.9 +/- 2.1 MUm for each additional millimeter. CONCLUSIONS: Axial length is especially associated with choroidal thickness in high myopia. Choroidal thickness profile in highly myopic patients differs from that in emmetropic patients. PMID- 23036571 TI - Increasing prevalence and severity of conjunctivochalasis with aging detected by anterior segment optical coherence tomography. AB - PURPOSE: To evaluate the impact of aging on conjunctivochalasis in an objective manner using anterior segment optical coherence tomography. DESIGN: Prospective clinical trial. METHODS: Sixty eyes of 30 healthy volunteers (15 men, 15 women; age range, 24-75 years) without any ophthalmic diseases were recruited for the study. Subjects were organized into 3 sex-matched groups, each including 10 subjects according to their ages: 20-39 years (Group 1), 40-59 years (Group 2), 60-75 years (Group 3). Cross-sectional area of conjunctivochalasis was measured at 3 locations (temporal, central, and nasal) using Fourier-domain optical coherence tomography. Tear meniscus height was also measured in all images where a typical triangular-shaped tear meniscus was obtained. RESULTS: In terms of the cross-sectional area of conjunctivochalasis, there were statistically significant differences among 3 groups at temporal and nasal locations (P < .001). At the central location, whereas there were no subjects in Groups 1 and 2, solely 3 eyes revealed conjunctivochalasis in Group 3. The severity of conjunctivochalasis affecting the temporal and nasal bulbar conjunctiva was strongly correlated with age (eta(2) = 0.81, P < .001 and eta(2) = 0.78, P < .001). Lower central tear meniscus height was compared among the groups and a significant increase with age was observed (P < .001). CONCLUSION: Fourier-domain optical coherence tomography provides an objective and quantitative approach for assessing the stages of conjunctivochalasis. The current study objectively confirms that conjunctivochalasis can be observed even in younger, healthy eyes; its severity increases with age; and it may alter tear distribution along the lower lid. PMID- 23036572 TI - Laser clearance of drusen deposit in patients with autosomal dominant drusen (p.Arg345Trp in EFEMP1). AB - PURPOSE: To assess whether laser treatment to the retinal pigment epithelium anterior to drusen in eyes of patients with EFEMP1-related maculopathy affects visual acuity, deposit volume, and retinal sensitivity. DESIGN: Prospective, interventional case series. METHODS: In 11 patients with autosomal dominant drusen and confirmed disease-causing EFEMP1 mutation, the worse-seeing eye was treated with Argon green laser (10 to 15 laser spots; 200-MUm spot size, 0.1 second duration, 80 to 120 mW). Patients were examined before treatment as well as 1, 3, 6, and 12 months after the procedure. Clinical assessment included visual acuity, fundus-controlled perimetry, spectral-domain optical coherence tomography, and autofluorescence imaging. Custom-made software allowed for coregistration of fundus-controlled perimetry and spectral-domain optical coherence tomography data sets. The main outcome measures were change in visual acuity, retinal sensitivity, and drusen volume. RESULTS: The untreated eyes lost an average of 0.8 letters, whereas the treated eyes gained an average of 4.9 letters. For fundus-controlled perimetry, locus-by-locus differences in sensitivity were calculated between pretreatment and posttreatment assessments; subsequently, the overall difference in the treated and untreated eye was compared. Five patients showed significant improvement in retinal sensitivity, 5 patients showed no change, and 1 patient showed significant deterioration. An increase in mean drusen thickness was observed in the untreated eyes, but not in the treated eyes (P = .0322). The thickness of the drusen correlated with retinal sensitivity (rho = -0.49; P < .0001). Safety was demonstrated and no adverse events were observed. CONCLUSIONS: Low-energy laser treatment is safe and may be effective in the treatment of autosomal dominant drusen. Further evaluation with long-term assessment is required to confirm the benefits. PMID- 23036570 TI - Retinal nerve fiber layer atrophy is associated with visual field loss over time in glaucoma suspect and glaucomatous eyes. AB - PURPOSE: To compare prospectively detection of progressive retinal nerve fiber layer thickness (RNFL) atrophy identified using time-domain optical coherence tomography with visual field progression using standard automated perimetry in glaucoma suspect and preperimetric glaucoma patients or perimetric glaucoma patients. DESIGN: Prospective, longitudinal clinical trial. METHODS: Eligible eyes with 2 years or more of follow-up underwent time-domain optical coherence tomography and standard automated perimetry every 6 months. The occurrence of visual field progression was defined as the first follow-up visit reaching a significant (P < .05) negative visual field index slope over time. RNFL progression or improvement was defined as a significant negative or positive slope over time, respectively. Specificity was defined as the number of eyes with neither progression nor improvement, divided by the number of eyes without progression. Cox proportional hazard ratios were calculated using univariate and multivariate models with RNFL loss as a time-dependent covariate. RESULTS: Three hundred ten glaucoma suspect and preperimetric glaucoma eyes and 177 perimetric glaucoma eyes were included. Eighty-nine eyes showed visual field progression and 101 eyes showed RNFL progression. The average time to detect visual field progression in those 89 eyes was 35 +/- 13 months, and the average time to detect RNFL progression in those 101 eyes was 36 +/- 13 months. In multivariate Cox models, average and superior RNFL losses were associated with subsequent visual field index loss in the entire cohort (every 10-MUm loss; hazard ratio, 1.38; P = .03; hazard ratio, 1.20; P = .01; respectively). Among the entire cohort of 487 eyes, 42 had significant visual field index improvement and 55 had significant RNFL improvement (specificity, 91.4% and 88.7%, respectively). CONCLUSIONS: Structural progression is associated with functional progression in glaucoma suspect and glaucomatous eyes. Average and superior RNFL thickness may predict subsequent standard automated perimetry loss. PMID- 23036573 TI - Surgical outcomes in childhood uveitic glaucoma. AB - PURPOSE: To evaluate surgical outcomes and to describe a strategy for pediatric uveitic glaucoma. DESIGN: Retrospective case series. METHODS: The clinical practice of a single surgeon identified 36 patients with juvenile uveitic glaucoma (diagnosed before 18 years of age) who underwent 1 or more intraocular pressure (IOP)-lowering surgical procedures. The first eye operated on was included in the analysis. The main indication for success was IOP of less than 21 mm Hg with controlled inflammation, without further IOP-lowering surgery or devastating complication. RESULTS: Patients with uveitic glaucoma associated with juvenile idiopathic arthritis (n = 20), idiopathic uveitis (n = 9), other (n = 6) were included. Mean age +/- standard deviation at initial glaucoma surgery was 11.1 +/- 4.4 years with a follow-up of 5.6 +/- 4.8 years (range, 0.2 to 16.4 years). Goniotomy was the initial surgical procedure in 31 (86%) eyes. Fifteen eyes did not require further IOP-lowering surgery. Sixteen eyes had additional IOP-lowering surgery: second goniotomy (n = 9), glaucoma drainage device (n = 6), and trabeculectomy (n = 1). By Kaplan-Meier survival analysis, the first versus the first or second goniotomy were successful at 10 years in 48% (95% confidence interval, 28% to 65%) versus 69% (95% confidence interval, 47% to 84%). Goniotomy failure was noncorrelative with phakic status or presence of preoperative synechiae. Five eyes (14%) had initial glaucoma drainage device implantation because of closed angles. Visual acuity was similar between initial and final examinations (0.37 +/- 0.48 logarithm of the minimal angle of resolution units [Snellen 20/47] vs 0.28 +/- 0.34 logarithm of the minimal angle of resolution units [Snellen 20/38]). IOP was reduced (33.0 +/- 8.0 mm Hg vs 12.6 +/- 4.5 mm Hg; P < .0001), as was number of glaucoma medications (3.2 +/- 1.1 vs 1.2 +/- 1.3; P < .0001). Eyes undergoing cataract removal after successful glaucoma surgery maintained IOP control. Glaucoma was controlled and vision was preserved in 33 (92%) eyes. CONCLUSIONS: Refractory juvenile uveitic glaucoma was managed successfully by goniosurgery and glaucoma drainage device implantation. Cataract removal can be accomplished successfully, provided IOP and uveitis are well controlled before surgery. PMID- 23036574 TI - Coping with asthma: is the physician able to identify patient's behaviour? AB - INTRODUCTION: The strategies patients use to manage their asthma (coping) have been found to be associated with clinical and patient-reported outcomes. OBJECTIVES: The aim of this large cross-sectional survey is to assess the use of coping methods employed by patients with asthma and to explore the ability of general practitioners (GPs) to correctly identify these strategies. METHODS: A modified Coping Orientations to Problem Experienced Questionnaire was completed by patients with asthma and their physicians. RESULTS: The survey was completed by 3089 GPs (69% male; mean age 55 +/- 6) and by 6264 patients (52% male; mean age 45 + 14). Active strategies were reported as the predominant method of coping by 51-59% of patients, whilst passive/avoidant techniques accounted for 12-28%. GPs believed the active coping methods were employed primarily by 35-45% of patients and the passive/avoidant methods by 8-26%. Physicians were able to identify the specific strategy used by a patient in 34%-64% of cases. The ability to identify the use of active strategies rather than the passive/avoidant was significantly higher (T test 8,250, p < 0.0001). Coefficient of concordance between GPs' and patients' answers was fair. CONCLUSIONS: These results revealed the extent of maladaptive coping strategies used by patients and the tendency for physicians to underestimate these. These observations may well represent two obstacles in improving asthma clinical outcomes. PMID- 23036575 TI - Vitamin A supplementation ameliorates obesity-associated retinal degeneration in WNIN/Ob rats. AB - OBJECTIVE: Obesity is associated with various health afflictions, including ocular complications such as diabetic retinopathy, high intraocular pressure, cataracts, and macular degeneration. We previously reported progressive retinal degeneration after the onset of obesity in the spontaneously obese rat (WNIN/Ob) model. In the present study, we investigated vitamin A supplementation to ameliorate obesity-associated retinal degeneration in the WNIN/Ob rat. METHODS: Five-month-old male WNIN/Ob obese (O) and lean (L) control rats were fed with vitamin A 2.6 mg (L/O-I), 26 mg (L/O-II), 52 mg (L/O-III), and 129 mg (L/O-IV) per kilogram of diet as retinyl palmitate for 4 mo 2 wk. Retinal morphology and retinal gene expression were assessed by histologic, immunohistochemical, and real-time polymerase chain reaction methods. RESULTS: Supplementation of vitamin A at 26 or 52 mg significantly modulated the expression of retinal genes in the O but not in the L phenotype. Vitamin A supplementation significantly upregulated the expression of genes, such as rhodopsin, rod arrestin, phosphodiesterase, transducins, and fatty acid elongase-4, that were otherwise downregulated in O rat retina. The expression of glial fibrillary acidic protein was downregulated by vitamin A feeding in O rat retina. The immunohistochemical and histologic findings corroborated the gene expression data. The effects were significant at a 26- or 52-mg dose of vitamin A. CONCLUSION: Vitamin A supplementation alleviated obesity-associated retinal degeneration in the WNIN/Ob rat. PMID- 23036576 TI - Utility of choline positron emission tomography/computed tomography for lymph node involvement identification in intermediate- to high-risk prostate cancer: a systematic literature review and meta-analysis. AB - CONTEXT: Determination of tumour involvement of regional lymph nodes in patients with prostate cancer (PCa) is of key importance for the proper planning of treatment. OBJECTIVES: To provide a critical overview of published reports and to perform a meta-analysis about the diagnostic performance of 18F-choline and 11C choline positron emission tomography (PET) or PET/computed tomography (CT) in the lymph node staging of PCa. EVIDENCE ACQUISITION: A Medline, Web of Knowledge, and Google Scholar search was carried out to select English-language articles published before January 2012 that discussed the diagnostic performance of choline PET to individualise lymph node disease at initial staging in PCa patients. Articles were included only if absolute numbers of true-positive, true negative, false-positive, and false-negative test results were available or derivable from the text and focused on lymph node metastases. Reviews, clinical reports, and editorial articles were excluded. All complete studies were reviewed; thus qualitative and quantitative analyses were performed. EVIDENCE SYNTHESIS: From the year 2000 to January 2012, we found 18 complete articles that critically evaluated the role of choline PET and PCa at initial staging. The meta analysis was carried out and consisted of 10 selected studies with a total of 441 patients. The meta-analysis provided the following results: pooled sensitivity 49.2% (95% confidence interval [CI], 39.9-58.4) and pooled specificity 95% (95% CI, 92-97.1). The area under the curve was 0.9446 (p<0.05). The heterogeneity ranged between 22.7% and 78.4%. The diagnostic odds ratio was 18.999 (95% CI, 7.109-50.773). CONCLUSIONS: Choline PET and PET/CT provide low sensitivity in the detection of lymph node metastases prior to surgery in PCa patients. A high specificity has been reported from the overall studies. Studies carried out on a larger scale with a homogeneous patient population together with the evaluation of cost effectiveness are warranted. PMID- 23036578 TI - Re: Roman Mayr, Matthias May, Thomas Martini, et al. Comorbidity and performance indices as predictors of cancer-independent mortality but not of cancer-specific mortality after radical cystectomy for urothelial carcinoma of the bladder. Eur Urol 2012;62:662-70. PMID- 23036577 TI - Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma. AB - BACKGROUND: Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown. OBJECTIVE: To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC. DESIGN, SETTING, AND PARTICIPANTS: Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]). RESULTS AND LIMITATIONS: PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events. CONCLUSIONS: Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted. PMID- 23036579 TI - Water-soluble andrographolide sulfonate exerts anti-sepsis action in mice through down-regulating p38 MAPK, STAT3 and NF-kappaB pathways. AB - Andrographolide is a prescribed drug used for preventing and treating the common cold, influenza, viral infections or allergies. However, its poor water solubility enormously limits its bioavailability. In the present study, we aimed at examining and comparing the effect of andrographolide sulfonate (trade name: Xi-Yan-Ping Injection), a water-soluble form made from andrographolide through sulfonating reaction, on the treatment of murine sepsis model induced by lipopolysaccharide (LPS). Pretreatment with andrographolide sulfonate significantly decreased the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and transaminase activities in serum, attenuated liver and lung damage, and improved the survival of mice with experimental sepsis. Andrographolide sulfonate also remarkably reduced the expression levels of TNF-alpha, IL-1beta, IL-6 and inducible nitric oxide synthase in the injured liver from septic mice. Moreover, andrographolide sulfonate time-dependently suppressed the activation of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase (ERK1/2) or c-Jun NH(2)-terminal kinase (JNK). Furthermore, pretreatment with andrographolide sulfonate markedly inhibited the activation of p65 subunit of nuclear factor-kappaB (NF-kappaB) as well as signal transducers and activators of transcription 3 (STAT3) in the injured liver from mice with endotoxic shock. Notably, andrographolide sulfonate showed a much stronger alleviation of LPS-induced sepsis in mice compared with andrographolide. Taken together, these results reveal that andrographolide sulfonate ameliorates sepsis in mice through suppressing p38 MAPK, STAT3 and NF kappaB pathways and suggest that andrographolide sulfonate has an advantage of andrographolide for the treatment of endotoxin shock. PMID- 23036580 TI - Reproductive mode and life cycle of the ash dieback pathogen Hymenoscyphus pseudoalbidus. AB - Ash dieback caused by the fungal pathogen Hymenoscyphus pseudoalbidus is currently ravaging in Europe, killing Fraxinus excelsior and Fraxinus angustifolia trees of all age classes. The aim of this work was to elucidate aspects of the reproduction biology of this fungal pathogen and its cryptic, non pathogenic sister species Hymenoscyphus albidus. The mating type (MAT) locus of both species was identified, partly sequenced and characterized. Whereas a heterothallic MAT organization was detected in H. pseudoalbidus, H. albidus was shown to be structurally homothallic. The molecular MAT determination of H. pseudoalbidus was confirmed by crossing experiments on sterile ash petioles. Crossings of strains exhibiting alternate MAT idiomorphs produced fertile apothecia whereas crosses of strains with identical MAT idiomorphs were never successful. Offspring genotyping with microsatellites (MSs) and the MAT marker confirmed that both parental strains were involved in apothecia formation. In addition, polymorphic MS were shown to follow Mendelian inheritance. However, for yet unknown reasons the MAT ratio of progenies of one successful cross revealed a significant segregation distortion. Based on the MAT sequences of H. pseudoalbidus a multiplex PCR was developed, allowing for a quick and reliable MAT determination. The PCR was applied to screen the MAT ratio of two H. pseudoalbidus populations derived from the country of the disease outbreak in Poland and two populations from the disease periphery in Switzerland. None of the screened populations showed a significant deviation from the 1:1 ratio, expected under random mating. Therefore, an initial clonal distribution through asexually produced conidiospores as observed for other fungal pathogens holds not true for H. pseudoalbidus. Instead, our data is highly supportive for a distribution through ascospores. Leaf petioles collected in the field were thoroughly analyzed for the number of different colonizing strains and their mating behavior. Up to eight different H. pseudoalbidus genotypes were found on a single petiole. Cross fertilizations of strains on the same petiole and fertilizations of unknown strains from outside were found, indicating that fertilization is mediated by spermatia. The presented study complements our understanding of the life cycle of this highly destructive pathogen. The possibility to perform sexual crosses in the lab provides ample opportunities for further genetic studies of H. pseudoalbidus and related species in the future. PMID- 23036581 TI - Effects of latrunculin B on the actin cytoskeleton and hyphal growth in Phytophthora infestans. AB - The actin cytoskeleton is conserved in all eukaryotes, but its functions vary among different organisms. In oomycetes, the function of the actin cytoskeleton has received relatively little attention. We have performed a bioinformatics study and show that oomycete actin genes fall within a distinct clade that is divergent from plant, fungal and vertebrate actin genes. To obtain a better understanding of the functions of the actin cytoskeleton in hyphal growth of oomycetes, we studied the actin organization in Phytophthora infestans hyphae and the consequences of treatment with the actin depolymerising drug latrunculin B (latB). This revealed that latB treatment causes a concentration dependent inhibition of colony expansion and aberrant hyphal growth. The most obvious aberrations observed upon treatment with 0.1 MUM latB were increased hyphal branching and irregular tube diameters whereas at higher concentrations latB (0.5 and 1 MUM) tips of expanding hyphae changed into balloon-like shapes. This aberrant growth correlated with changes in the organization of the actin cytoskeleton. In untreated hyphae, staining with fluorescently tagged phalloidin revealed two populations of actin filaments: long, axially oriented actin filament cables and cortical actin filament plaques. Two hyphal subtypes were recognized, one containing only plaques and the other containing both cables and plaques. In the latter, some hyphae had an apical zone without actin filament plaques. Upon latB treatment, the proportion of hyphae without actin filament cables increased and there were more hyphae with a short apical zone without actin filament plaques. In general, actin filament plaques were more resilient against actin depolymerisation than actin filament cables. Besides disturbing hyphal growth and actin organization, actin depolymerisation also affected the positioning of nuclei. In the presence of latB, the distance between nuclei and the hyphal tip decreased, suggesting that the actin cytoskeleton plays a role in preventing the movement of nuclei towards the hyphal tip. PMID- 23036582 TI - CD133(+)/CD44(+)/Oct4(+)/Nestin(+) stem-like cells isolated from Panc-1 cell line may contribute to multi-resistance and metastasis of pancreatic cancer. AB - Pancreatic cancer is an aggressive malignant disease. Owing to the lack of early symptoms, accompanied by extensive metastasis and high resistance to chemotherapy, pancreatic adenocarcinoma becomes the fourth leading cause of cancer-related deaths. In this study, we identified a subpopulation of cells isolated from the Panc-1 cell line and named pancreatic cancer stem-like cells. These Panc-1 stem-like cells expressed high levels of CD133/CD44/Oct4/Nestin. Compared to Panc-1 cells, Panc-1 stem-like cells were resistant to gemcitabine and expressed high levels of MDR1; furthermore, Panc-1 stem-like cells have high anti-apoptotic, but weak proliferative potential. These results indicated that Panc-1 stem-like cells, as a novel group, may be a potential major cause of pancreatic cancer multidrug resistance and extensive metastasis. PMID- 23036583 TI - C9ORF72 repeat expansions not detected in a group of patients with schizophrenia. AB - A hexanucleotide repeat expansion in C9ORF72 was recently found to cause some cases of frontotemporal lobar degeneration, frontotemporal dementia (FTD) amyotrophic lateral sclerosis, and amyotrophic lateral sclerosis. Patients with frontotemporal lobar degeneration with the C9ORF72 repeat expansion are more likely than those without to present with psychosis. In this study, we screened DNA samples from 192 unrelated subjects with schizophrenia for the C9ORF72 repeat expansion. None of the subjects with schizophrenia had the pathogenic expansion. C9ORF72 repeat expansions either do not cause schizophrenia, or do so rarely (less than 1% of cases). PMID- 23036584 TI - Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease. AB - Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35 2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the epsilon4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p >= 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the epsilon4 allele of apolipoprotein E genotype, and geographic region. PMID- 23036585 TI - Exploratory analysis of seven Alzheimer's disease genes: disease progression. AB - The relationships between genome wide association study-identified and replicated genetic variants associated with Alzheimer's disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. Seven hundred and one AD patients with at least 3 different cognitive evaluations and genotypic information for APOE and 6 genome wide association study-significant single-nucleotide polymorphisms were selected for this study. Mean differences in Global Deterioration Score and Mini Mental State Examination (MMSE) were evaluated using nonparametric tests, general linear model and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor, memantine, or both. Relationships between therapeutic protocols, genetic markers, and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared with GG carriers at the end of the follow-up (MMSE mean difference = -0.57; 95% confidence interval, -1.145 to 0.009; p = 0.047). This observation remained unaltered after covariate adjustments although it did not achieve predefined multiple testing significance threshold. The PICALM single-nucleotide polymorphism also displayed a significant effect protecting against rapid progression during pharmacogenetic assays although its observed effect displayed heterogeneity among AD therapeutic protocols (p = 0.039). None of the studied genetic markers were convincingly linked to AD progression or drug response. However, by using different statistical approaches, the PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes. PMID- 23036586 TI - Increased working memory-related brain activity in middle-aged women with cognitive complaints. AB - Individuals who report subjective cognitive complaints but perform normally on neuropsychological tests might be at increased risk for pathological cognitive aging. The current study examined the effects of the presence of subjective cognitive complaints on functional brain activity during a working memory task in a sample of middle-aged postmenopausal women. Twenty-three postmenopausal women aged 50-60 completed a cognitive complaint battery of questionnaires. Using 20% of items endorsed as the threshold, 12 women were categorized as cognitive complainers (CC) and 11 were noncomplainers (NC). All subjects then took part in a functional magnetic resonance imaging scanning session during which they completed a visual-verbal N-back test of working memory. Results showed no difference in working memory performance between CC and NC groups. However, the CC group showed greater activation relative to the NC group in a broad network involved in working memory including the middle frontal gyrus (Brodmann area [BA] 9 and 10), the precuneus (BA 7), and the cingulate gyrus (BA 24 and 32). The CC group recruited additional regions of the working memory network compared with the NC group as the working memory load and difficulty of the task increased. This study showed brain activation differences during working memory performance in a middle-aged group of postmenopausal women with subjective cognitive complaints but without objective cognitive deficit. These findings suggest that subjective cognitive complaints in postmenopausal women might be associated with increased cortical activity during effort-demanding cognitive tasks. PMID- 23036587 TI - Forensic medical examination of adolescent and adult victims of sexual violence. AB - The acute care and examination of a victim of sexual violence must be carried out by a competent forensic examiner in a setting appropriate for crisis intervention, forensic evidence collection, and medical follow up. The aim of forensic evidence and biological material collection is to document an alleged physical or sexual contact between individuals and to corroborate the victim's and the assailant's history. This is why the forensic examiner is expected to be objective and in possession of specialised technical and scientific skills. These skills are addressed and recommendations are made on how to carry out a forensic examination. This includes medical and assault history, top-to-toe examination, biological material collection, and documenting injuries while obtaining the chain of custody. Yet, consensus on time limitations for forensic evidence collection is lacking. Available forensic evidence has been shown to benefit prosecution. To meet the legal system's needs, an interpretation of the findings in a written legal report is mandatory. PMID- 23036588 TI - Assembly of Bacillus subtilis FtsA: effects of pH, ionic strength and nucleotides on FtsA assembly. AB - In this work, the assembly of purified Bacillus subtilis FtsA was analyzed by several complimentary techniques. FtsA assembled to form filaments and bundles and the polymers disassembled upon dilution. FtsA assembled more efficiently at pH 6.0 as compared to that at pH 7.0 or 8.0 and high salt inhibited the assembly of FtsA. FtsA was found to hydrolyze ATP in vitro; however, neither ATP nor ADP influenced the assembly kinetics of FtsA. Though FtsA is a homologue of actin, cytochalasin D did not inhibit the assembly of FtsA. Interestingly, a hydrophobic molecule, 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid, inhibited the assembly of FtsA. PMID- 23036589 TI - Evidence for the binding affinity of daunomycin to HMGB1 protein in chromatin and in solution. AB - In this study the interaction of daunomycin with HMGB1 nonhistone chromatin protein in the chromatin context using hydroxyapatite (HAP) column chromatography and free in solution was investigated employing fluorescence, circular dichroism spectroscopy and thermal denaturation techniques. The results demonstrate that HMGB1 fraction eluted from HAP column contained the most amount of daunomycin. Upon addition of daunomycin to HMGB1 solution, fluorescence emission intensity was dependent on the drug concentration used whereas the ellipticity in CD spectra was decreased at both 205 and 220 nm extremes implying that quenching of the drug with the HMGB1 chromospheres alters secondary structure of the protein. Although daunomycin slightly increased the melting point of HMGB1, but exhibited a significant hyperchromicity at low concentrations and hypochromicity at higher concentrations of daunomycin. The results suggest that daunomycin binds to HMGB1 protein which may influence its interaction with DNA in nucleosomes and other cellular processes. PMID- 23036590 TI - Evaluation of polyurethane based on cellulose derivative-ketoprofen biosystem for implant biomedical devices. AB - A polyether-urethane based on polytetrahydrofuran containing hydroxypropyl cellulose for biomedical applications was tested for its biocompatibility. Ketoprofen was incorporated (3% and 6%) in the polyurethane matrix as an anti inflammatory drug. Dynamic vapour sorption method was employed for testing the water sorption/desorption behaviour of these materials with the determination of the surface isotherms, surface parameters and the kinetic curves of sorption/desorption processes. Cytotoxicity testing in vitro for quantifying cell proliferation was employed, and the results evidence noncytotoxicity for the studied polyurethane-drug systems. In vivo biocompatibility study was performed on 200 g weight male rats. It was found that after implantation of the polyether urethane samples a reduced acute inflammation occurred, especially for polyurethane samples with added ketoprofen. PMID- 23036591 TI - Dendritic cells provide a potential link between smoking and inflammation in rheumatoid arthritis. AB - INTRODUCTION: Smoking increases the risk of developing rheumatoid arthritis (RA) and affects the severity of established RA. Smoking can impact on Th17 lymphocyte differentiation and function through activation of the aryl hydrocarbon receptor (AHR), a process with implications for the pathogenic mechanisms in RA that involve the cytokine, interleukin (IL)-17A. The objective of this study was to establish any effect of smoking on the inflammatory tissue lesions of rheumatoid arthritis via the AHR and IL-17A. METHODS: Twenty synovial and eighteen subcutaneous nodule tissue samples from 31 patients with RA were studied. Patient smoking status at the time of tissue collection was established. Expression of AHR, CYP1A1, AHRR, IL6, IL17A, IL17F, IL22, IL23, IL23R, IFNG, TBX21, IDO1 and FOXP3 genes were assessed in tissues and cultured cells using real-time PCR. Two colour immunofluorescence was used to co-localise AHR and CYP1A1 protein in synovial tissues. The response of monocytes and monocyte-derived dendritic cells (mo-DCs) to the AHR agonist, benzo(a)pyrene (BaP) was compared in vitro. RESULTS: AHR gene expression was demonstrated in rheumatoid synovial tissues and nodules with significantly greater expression in synovia. Expression was not influenced by smoking in either tissue. Evidence of AHR activation, indicated by CYP1A1 and AHRR gene expression, was found only in synovia from patients who smoked. However, IL17A gene expression was lower in synovia from smokers. TBX21 and FOXP3 expression was not affected by smoking. Within the synovial tissues of smokers the principal cell type with evidence of AHR activation was a subset of synovial DCs. This observation was consistent with the sensitivity of human mo-DCs to BaP stimulation demonstrated in vitro. Exposure to BaP affected mo-DC function as demonstrated by decreased IL6 expression induced by PolyI:C, without affecting indoleamine 2,3 dioxygenase (IDO)1 expression. CONCLUSION: Our findings show that one effect of smoking on inflamed rheumatoid synovial tissue involves activation of the AHR pathway. A subset of synovial DCs is important in the response to cigarette smoke. The potential for smoking to affect DC behaviour in joint tissues has relevance to both early and late phases of RA pathogenesis and warrants further investigation. PMID- 23036592 TI - A peptide prime-DNA boost immunization protocol provides significant benefits as a new generation Abeta42 DNA vaccine for Alzheimer disease. AB - Immunotherapy has the potential to provide a possible treatment therapy to prevent or delay Alzheimer disease. In a clinical trial (AN1792) in which patients received this immunotherapy and received active Abeta1-42 peptide immunizations, treatment was stopped when 6% of patients showed signs of meningoencephalitis. Follow up on these patients led to the conclusion that the antibody response was beneficial in removing Abeta1-42 from brain but an accompanying inflammatory Th1 T cell response was harmful. As a safe alternative treatment targeting the same self protein, Abeta1-42, in brain, we and others are working on a DNA Abeta1-42 immunization protocol as the immune response to DNA immunizations differs in many aspects from immunizations with peptide antigens. Because the immune response to DNA vaccination has different kinetics and has a significantly lower antibody production, we evaluated two different prime boost regimens, Abeta1-42 DNA prime/Abeta1-42 peptide boost and Abeta1-42 peptide prime/Abeta1-42 DNA boost for their effectiveness in antibody production and possible side effects due to inflammatory T cell responses. While both boost regimes significantly enhanced the specific antibody production with comparable antibody concentrations, the absence of the Abeta1-42 T cell response (no proliferation and no cytokine production) is consistent with our previous findings using this DNA Abeta1-42 trimer immunization and greatly enhances the safety aspect for possible clinical use. PMID- 23036593 TI - A previously undescribed ostreid herpes virus 1 (OsHV-1) genotype detected in the pacific oyster, Crassostrea gigas, in Ireland. AB - Significant mortalities of the Pacific oyster, Crassostrea gigas, have been reported worldwide since the 1950s. The impact these re-occurring mortality events have had on the C. gigas industry has highlighted the necessity to determine the factors that may be causing these mortalities. This study investigated the possible role of ostreid herpes virus (OsHV-1) in C. gigas mortalities over 2 successive summers at 2 study areas in Ireland. A single sample of adult C. gigas, which had been experiencing mortalities at one of the sites was screened. Successive cohorts of C. gigas spat obtained from a hatchery outside Ireland was relayed to both sites in 2003 and in 2004. Spat were screened each year prior to relaying. Samples were collected every 2 weeks and mortality counts were recorded and observed at both sites. Polymerase chain reaction (PCR) analysis and subsequent sequencing indicated that a previously undocumented variant genotype of OsHV-1 was present in the single cohort of adult C. gigas and in seed and juveniles at both sites, in both years. Analysis suggests that the Irish OsHV-1 MUvar variant genotype is closely related to OsHV-1 MUvar, first described in France in 2008. PMID- 23036594 TI - Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. AB - BACKGROUND: Glutathione-dependent catalysis is a metabolic adaptation to chemical challenges encountered by all life forms. In the course of evolution, nature optimized numerous mechanisms to use glutathione as the most versatile nucleophile for the conversion of a plethora of sulfur-, oxygen- or carbon containing electrophilic substances. SCOPE OF REVIEW: This comprehensive review summarizes fundamental principles of glutathione catalysis and compares the structures and mechanisms of glutathione-dependent enzymes, including glutathione reductase, glutaredoxins, glutathione peroxidases, peroxiredoxins, glyoxalases 1 and 2, glutathione transferases and MAPEG. Moreover, open mechanistic questions, evolutionary aspects and the physiological relevance of glutathione catalysis are discussed for each enzyme family. MAJOR CONCLUSIONS: It is surprising how little is known about many glutathione-dependent enzymes, how often reaction geometries and acid-base catalysts are neglected, and how many mechanistic puzzles remain unsolved despite almost a century of research. On the one hand, several enzyme families with non-related protein folds recognize the glutathione moiety of their substrates. On the other hand, the thioredoxin fold is often used for glutathione catalysis. Ancient as well as recent structural changes of this fold did not only significantly alter the reaction mechanism, but also resulted in completely different protein functions. GENERAL SIGNIFICANCE: Glutathione-dependent enzymes are excellent study objects for structure-function relationships and molecular evolution. Notably, in times of systems biology, the outcome of models on glutathione metabolism and redox regulation is more than questionable as long as fundamental enzyme properties are neither studied nor understood. Furthermore, several of the presented mechanisms could have implications for drug development. This article is part of a Special Issue entitled Cellular functions of glutathione. PMID- 23036595 TI - Entrapment of human flavin-containing monooxygenase 3 in the presence of gold nanoparticles: TEM, FTIR and electrocatalysis. AB - BACKGROUND: Nanosized particles of gold are widely used as advanced materials for enzyme catalysis investigations. In some bioanalytical methods these nanoparticles can be exploited to increase the sensitivity by enhancing electron transfer to the biological component i.e. redox enzymes such as drug metabolizing enzymes. METHODS: In this work, we describe the characterization of human flavin containing monooxygenase 3 (hFMO3) in a nanoelectrode system based on AuNPs stabilized with didodecyldimethylammonium bromide (DDAB) on glassy carbon electrodes. Once confirmed by FTIR spectroscopy that in the presence of DDAB AuNPs the structural integrity of hFMO3 is preserved, the influence of AuNPs on the electrochemistry of the enzyme was studied by cyclic voltammetry and square wave voltammetry. RESULTS: Our results show that AuNPs improve the electrochemical performance of hFMO3 on glassy carbon electrodes by enhancing the electron transfer rate and the current signal-to-noise ratio. Moreover, the electrocatalytic activity of hFMO3-DDAB-AuNP electrodes which was investigated in the presence of two well known substrates, benzydamine and sulindac sulfide, resulted in K(M) values of 52MUM and 27MUM, with V(max) of 8nmolmin(-1)mg(-1) and 4nmolmin(-1)mg(-1), respectively, which are in agreement with data obtained with the microsomal enzyme. CONCLUSIONS: The immobilization of hFMO3 protein in DDAB stabilized AuNP electrodes improves the bioelectrochemical performance of this important phase I drug metabolizing enzyme. GENERAL SIGNIFICANCE: This bio analytical method can be considered as a promising advance in the development of new techniques suitable for the screening of novel hFMO3 metabolized pharmaceuticals. PMID- 23036596 TI - Health profiles of adolescents in foster care. AB - The purpose of this paper is to describe health profiles of adolescents in foster care. The Child Health and Illness Profile-Adolescent Edition clustered adolescents in foster care into 13 mutually exclusive health profiles using dimensions of satisfaction with health, risks, resilience, and discomfort. Health profiles were further characterized into four health status rankings from best to worst health status. Many reported best health status (39%); nearly equal numbers (30.6%) had profiles indicating poor or worst health status, particularly girls and those with high risk behaviors, aggression, sexual abuse, or suicidality. It is valuable to identify health characteristics of the most vulnerable subgroups of foster youth to tailor specific interventions. PMID- 23036597 TI - Impact of music therapy interventions (listening, composition, Orff-based) on the physiological and psychosocial behaviors of hospitalized children: a feasibility study. AB - The purpose of this study was to compare three music therapy strategies (music listening, music composition, and Orff-based active engagement) on physiological (heart rate, blood pressure, oxygen saturation, and pain) and psychosocial (anxiety) behaviors of hospitalized children (N=32, 17 females,15 males, ranging in age from 6 to 17). This study was designed and facilitated cooperatively by pediatric nurses and music therapists. Results indicated no clinically significant changes in heart rate, blood pressure, or oxygen saturation (p>.05). Pain and anxiety both decreased significantly (p=.01) but not differentiated among conditions. Videotape analysis determined level of engagement in coping related behaviors. PMID- 23036598 TI - Bedside reporting and SBAR: improving patient communication and satisfaction. PMID- 23036600 TI - Regeneration of the damaged central nervous system through reprogramming technology: basic concepts and potential application for cell replacement therapy. AB - Neural stem cell (NSC) transplantation provides a new approach for the repair of damage to the central nervous system (CNS), including that resulting from cerebral infarction and spinal cord injury (SCI). In the past, there were no reputable means of converting non-neural somatic cells into neural cells. This status was overturned by the establishment of induced pluripotent stem (iPS) cells, which have pluripotency akin to that of embryonic stem (ES) cells and can differentiate into most cells of the three germ layers. If differentiated somatic cells could be reprogrammed into iPS cells, and if these iPS cells could be induced to differentiate once again, it would be theoretically possible to obtain a large number of neural cells. However, this is not yet feasible due to the limitations of existing stem cell technology. Induction of neural cells from iPS cells is currently hindered by two distinct problems: 1) the preparation of specific types of targeted neural cells requires extensive cell culture, and 2) tumors are likely to form due to the presence of residual undifferentiated cells following transplantation of the induced cells. By contrast, direct induction methods permit the generation of target cells from somatic cells without the transitional iPS cell stage. This review outlines the present-day status of research surrounding the direct induction of NSCs from somatic cells, as well as the perspectives for the future clinical application of this technique for cell replacement therapy following CNS injury. PMID- 23036601 TI - The Mammotome biopsy system is an effective treatment strategy for breast abscess. AB - BACKGROUND: Although most breast abscesses can be treated with the current first line treatment of antibiotics by needle aspiration, the therapeutic duration is lengthy and recurrences often occur. Therefore, we aimed to investigate the clinical efficacy of the Mammotome biopsy system (Johnson & Johnson Corp., New Brunswick, NJ) in a cohort of patients with breast abscesses. METHODS: Forty lactating and 30 nonlactating breast abscess patients with unfavorable outcomes with antibiotic treatment and/or needle aspiration failure were recruited and treated with the Mammotome biopsy system. RESULTS: Skin inflammation of all patients disappeared within 6 days with no recurrence. The clinical outcomes in patients with an abscess size <= 3.5 cm was significantly better than those with an abscess size >3.5 cm (P = .025). CONCLUSIONS: The Mammotome biopsy system, an effective treatment strategy that is minimally invasive and less damaging, in combination with appropriate antibiotic therapy can be used safely as the first line approach to breast abscess management. PMID- 23036602 TI - Clinicopathologic study of node-negative advanced gastric cancer and analysis of factors predicting its recurrence and prognosis. AB - BACKGROUND: This study aimed to reveal the predictors for the recurrence pattern of gastric cancer (GC) and analyze the prognostic factors in node-negative advanced (T2 to T4) GC after curative resection. METHODS: Between 1994 and 2006, 448 patients with node-negative advanced GC undergoing radical resection were enrolled in this study. Clinicopathologic factors affecting the recurrence pattern and prognosis for GC were analyzed. RESULTS: Location, size, tumor invasion depth, and perineural invasion were associated with tumor recurrence and outcome. T4 status was a predictor for locoregional recurrence and peritoneal seeding, and a large tumor size and the presence of perineural invasion predicted hematogenous spread. Patients with only locoregional recurrence had better survival than those with peritoneal seeding or hematogenous spread. CONCLUSIONS: In node-negative advanced GC, the prognostic factor differed significantly between locoregional recurrence/peritoneal seeding and hematogenous metastasis. Survival rates were higher in patients with locoregional recurrence alone than in patients with other recurrence patterns. PMID- 23036599 TI - Stem cells and modeling of autism spectrum disorders. AB - Human neurons, generated from reprogrammed somatic cells isolated from live patients, bring a new perspective on the understanding of Autism Spectrum Disorders (ASD). The new technology can nicely complement other models for basic research and the development of therapeutic compounds aiming to revert or ameliorate the condition. Here, we discuss recent advances on the use of stem cells and other models to study ASDs, as well as their limitations, implications and future perspectives. PMID- 23036603 TI - Assessment of mitotic rate reporting in melanoma. AB - BACKGROUND: In patients with cutaneous melanoma, mitotic rate (MR) historically has been reported as the number of mitoses per high-power field (hpf) or per 10 hpf. The most recent revision of the American Joint Committee on Cancer melanoma staging system now incorporates MR and specifies that MR should be reported as mitoses per mm(2), with a conversion factor of 1 mm(2) equaling 4 hpf. However, because many pathologists continue to report MR in hpf units, we sought to compare the 2 conventions for reporting MR; this is important now that MR is used for staging and prognostic information. METHODS: A retrospective analysis was performed of a database that combined patients from a large multicenter study and our single-institution melanoma database. All patients with pathology reports that included MR were included. For patients with MR reported in hpf units, MR was converted to mitoses per 10 hpf. Statistical analysis was performed to test differences in Breslow thickness (BT), ulceration, sentinel lymph node (SLN) status, and overall survival (OS) (log-rank test) between the mitoses per mm(2) group versus the mitoses per 10-hpf group. RESULTS: A total of 1,148 patients were identified; of these, 759 were reported as per mm(2) and 389 were reported in hpf units. When patients were subdivided into categories of MR of 0, 1, or more than 1, there was no statistically significant difference in mean or median BT, ulceration, or SLN positivity within categories between patients with MR per mm(2) versus patients with MR reported per 10 hpf. There was also no difference in OS between groups. Subdividing into smaller categories of MR of 0, 1, 2, 3, 4, 5, or more than 5 did not yield different results. CONCLUSIONS: Although the American Joint Committee on Cancer staging system reports a conversion factor for MR of 1 mm(2) equals 4 hpf, no clinically meaningful differences in predictors of prognosis (BT, ulceration, SLN positivity) or OS were seen between groups when a conversion factor of 1 mm(2) equaling 10 hpf was used. Therefore, for practical purposes, MR reported per 10 hpf approximates MR per mm(2). PMID- 23036604 TI - Clostridium difficile-associated infection: a disease of varying severity. AB - Clostridium difficile-associated infection (CDI) can have varying severity from asymptomatic carriage to fulminant colitis. Its incidence and virulence in North America are increasing. The increase in virulence is associated with emergence of the highly toxigenic North American pulsed field gel electrophoresis-1 strain. The major risk factor for CDI is exposure to antibiotics. Another major risk factor is hospitalization. The spectrum of CDI ranges from asymptomatic carriers to fulminant disease. Although asymptomatic carriers require no treatment, fulminant disease carries a substantial mortality regardless of management strategy. PMID- 23036605 TI - Predicting outcome of patients with chest wall injury. AB - BACKGROUND: Rib fractures occur in 10% of injured patients, are associated with morbidity and mortality, and frequently necessitate intensive care unit (ICU) care. A scoring system that identifies the risk for respiratory failure early in the evaluation process may allow early intervention to improve outcomes. The aim of this study was to test the hypothesis that a scoring system based on initial clinical findings can identify patients with rib fractures at greatest risk for morbidity and mortality. METHODS: A simple scoring system to stratify risk was developed and applied to patients through a retrospective trauma registry review. Points were assigned as follows: age < 45 years = 1 point, age 45 to 65 years = 2 points, age > 65 years = 3 points; <3 fractures = 1 point, 3 to 5 fractures = 2 points, >5 fractures = 3 points; no pulmonary contusion = 0 points, mild pulmonary contusion = 1 point, severe pulmonary contusion = 2 points, bilateral pulmonary contusion = 3 points; and bilateral rib fracture absent = 0 points, bilateral rib fracture absent present = 2 points. A review of trauma registry patients with rib fractures (June 2008 to February 2010) at a state-designated level 1 trauma center was performed. Data reviewed included age, number of fractures, bilateral injury, presence of pulmonary contusion, classification of the contusion, length of hospital stay, mechanical ventilation, ICU admission, and length of stay. The scoring system was retrospectively applied to 649 patients to determine validity. RESULTS: A score <= 7 indicated lower mortality (24 of 579 [4.2%]) compared with patients with scores > 7 (10 of 70 [14.3%]) (Fisher's 2-sided P = .0018). Patients with scores <= 6 were less likely to be admitted to an ICU (29.7%) compared with those with scores >= 7 (56.7%) (P < .0001). Patients with total scores < 7 were less likely to require intubation (20.6%) compared with those with scores >= 7 (40.0%) (P < .0001). Patients with scores <= 4 had shorter lengths of stay (36.0% <5 days) compared with those who had scores > 4 (59.7%) (P < .0001). CONCLUSIONS: A simple scoring system predicts the likelihood that patients will require mechanical ventilation and prolonged courses of care. A score of 7 or 8 predicted increased risk for mortality, admission to the ICU, and intubation. A score > 5 predicted a longer length of stay and a longer period of ventilation. This scoring system may assist in the earlier implementation of treatment strategies such epidural anesthesia, ventilation, and operative fixation of fractures. PMID- 23036606 TI - Is early extraction really the silver bullet to avoid nerve injury in lower third molar removal? PMID- 23036607 TI - Rat neural stem cell proliferation and differentiation are durably altered by the in utero polyunsaturated fatty acid supply. AB - We isolated neural stem cells/neural progenitors (NSC) from 1-day-old rat pups born to mothers fed diets that were deficient or supplemented with n-3 polyunsaturated fatty acids (PUFAs) and compared their proliferation and differentiation in vitro. The cells isolated from the n-3PUFA-deficient pups consistently proliferated more slowly than cells that were isolated from n-3PUFA supplemented pups, despite the fact that both were cultured under the same conditions. The differences in the proliferation rates were evaluated up until 40 days of culture and were highly significant. When the cells were allowed to differentiate, the deficient cells exhibited a higher degree of neuronal maturation in response to the addition of PUFAs in the medium, as demonstrated by an increase in neurite length, whereas the neurons derived from the supplemented pups showed no change. This result was consistent, regardless of the age of the culture. The properties of the NSC were durably modified throughout the length of the culture, although the membrane phospholipid compositions were similar. We examined the differential expression of selected mRNAs and micro RNAs. We found significant differences in the gene expression of proliferating and differentiating cells, and a group of genes involved in neurogenesis was specifically modified by n-3 PUFA treatment. We conclude that n-3 PUFA levels in the maternal diet can induce persistent modifications of the proliferation and differentiation of NSCs and of their transcriptome. Therefore, the n-3 supply received in utero may condition on a long-term basis cell renewal in the brain. PMID- 23036609 TI - (+)RNA viruses rewire cellular pathways to build replication organelles. AB - Positive-strand RNA [(+)RNA] viruses show a significant degree of conservation of their mechanisms of replication. The universal requirement of (+)RNA viruses for cellular membranes for genome replication, and the formation of membranous replication organelles with similar architecture, suggest that they target essential control mechanisms of membrane metabolism conserved among eukaryotes. Recently, significant progress has been made in understanding the role of key host factors and pathways that are hijacked for the development of replication organelles. In addition, electron tomography studies have shed new light on their ultrastructure. Collectively, these studies reveal an unexpected complexity of the spatial organization of the replication membranes and suggest that (+)RNA viruses actively change cellular membrane composition to build their replication organelles. PMID- 23036608 TI - Missing links? - The connection between replication and movement of plant RNA viruses. AB - Plant virus infection spreads from cell-to-cell within the host with the aid of viral movement proteins (MPs) that transport infectious genomes through intercellular pores called plasmodesmata (PD). MPs are able to accomplish RNA trafficking independent of virus infection. However, although dispensable for replication, they often associate with or assist in the formation of viral replication complexes. Quantitative analyses of genetic bottlenecks during infection, as well as considerations of transport specificity, suggest that intricate links between replication and movement may facilitate efficient delivery of plant viruses through PD during early infection, at a stage when viral genomes are still rare. PMID- 23036610 TI - Emeritus, old age, William Osler and William Dock. PMID- 23036611 TI - Perceived stress, behavior, and body mass index among adults participating in a worksite obesity prevention program, Seattle, 2005-2007. AB - INTRODUCTION: Stress in numerous contexts may affect the risk for obesity through biobehavioral processes. Acute stress has been associated with diet and physical activity in some studies; the relationship between everyday stress and such behavior is not clear. The objective of this study was to examine associations between perceived stress, dietary behavior, physical activity, eating awareness, self-efficacy, and body mass index (BMI) among healthy working adults. Secondary objectives were to explore whether eating awareness modified the relationship between perceived stress and dietary behavior and perceived stress and BMI. METHODS: Promoting Activity and Changes in Eating (PACE) was a group-randomized worksite intervention to prevent weight gain in the Seattle metropolitan area from 2005 through 2007. A subset of 621 participants at 33 worksites provided complete information on perceived stress at baseline. Linear mixed models evaluated cross-sectional associations. RESULTS: The mean (standard deviation [SD]) Perceived Stress Scale-10 score among all participants was 12.7 (6.4), and the mean (SD) BMI was 29.2 kg/m2 (6.3 kg/m2). Higher levels of perceived stress were associated with lower levels of eating awareness, physical activity, and walking. Among participants who had low levels of eating awareness, higher levels of perceived stress were associated with fewer servings of fruit and vegetables and greater consumption of fast food meals. CONCLUSION: Dietary and physical activity behaviors of workers may be associated with average levels of perceived stress. Longitudinal studies are needed, however, to support inclusion of stress management or mindfulness techniques in workplace obesity prevention efforts. PMID- 23036612 TI - Effect of personal characteristics on individual support for indoor smoke-free air laws, Indiana, 2008. AB - INTRODUCTION: Policy makers should understand the attitudes and beliefs of their constituents regarding smoke-free air legislation. The purpose of this study was to evaluate the effect of selected personal characteristics on attitudes and beliefs about secondhand smoke in Indiana and on support for smoke-free air laws. METHODS: Data were obtained from the 2008 Indiana Adult Tobacco Survey of 2,140 adults and included 11 sociodemographic variables. Chi-square and multiple logistic regression analyses were used to test for significant associations between sociodemographic characteristics and support for statewide or community smoke-free air legislation. RESULTS: Most respondents (72.3%) indicated that they supported laws making work places smoke-free. After adjusting for the effects of the other variables, 3 were found to be significant predictors of support: being a never or former smoker, being female, and being aware of the health hazards of secondhand smoke. Age, race/ethnicity, income, urban or rural county of residence, employment status, and having children in the household were not significant when adjusting for the other characteristics. CONCLUSION: Most Indiana residents support smoke-free air legislation for workplaces. The support was constant among most groups across the state, suggesting policy makers would have the backing of their constituents to pass such legislation. The results of this study suggest that efforts to gain support for smoke-free air laws should focus on men, people unaware of the health hazards from secondhand smoke, and smokers and former smokers. PMID- 23036613 TI - Characterization of novel nitrite-based nitric oxide generating delivery systems for topical dermal application. AB - Topical application of nitric oxide (NO) has been shown to exert beneficial effects in the therapy of chronic wounds, impaired microcirculation, and skin infections. Nitrite acidified by ascorbic acid has been widely used in many studies as NO-donor system, unfortunately with inflammatory and toxic effects on the treated skin due to unregulated excessive NO generation, low pH and possible toxic side products. Here we describe an essentially modified nitrite based NO generating system that avoid the mentioned unwanted side effects on human skin by using a pH-stable acetate/acetic acid buffer with a skin neutral pH of 5.5 and sodium ascorbate. In order to overcome the shortcoming of lower NO yields due to the higher pH-value and low nitrite concentrations, we have determined additionally the influence of copper ions. To investigate the influence of different NO release and penetration kinetics on NO-induced toxicity, we have developed a fibroblast assay using cell culture plates with gas permeable bottoms. The results show clearly that the donor system can achieve a sustained NO generation without generating high peaks. Furthermore, the presence of Cu(2+) ions enhances manifold NO generation of pH/ascorbate-induced nitrite decomposition, a mechanism comprising the reduction of Cu(2+) ions to Cu(1+) by ascorbate. Finally, we have found that apart from the NO dose the NO release kinetics had a significant influence of cell toxicity. Thus, application of comparable NO amounts within a time interval of 600s led to the development of variable cell toxicities, which predominantly depended on the NO concentration values generated in the first 200s. In summary, we here describe a novel nitrite based NO-donor system that can provide well defined NO concentrations at skin neutral pH-values for side effect poor topical dermal application, i.e. in the therapy of chronic wounds and impaired microcirculation. PMID- 23036614 TI - 'Autoimmune epilepsy' or exasperated search for the etiology of seizures of unknown origin? PMID- 23036615 TI - Curcumin reduces cisplatin-induced neurotoxicity in NGF-differentiated PC12 cells. AB - The potential neuroprotective benefits of curcumin against cisplatin neurotoxicity were investigated. Curcumin is a polyphenol derived from the rhizome of Curcuma longa whose pharmacological effects include antioxidant, anti inflammatory and anti-cancer properties. Cisplatin is a potent chemotherapeutic drug with activity against a wide variety of tumors, although it has notorious side effects. Cisplatin neurotoxicity is clinically evident in patients that have undergone a full course of chemotherapy and develop a peripheral neuropathy that may affect the treatment regimen and the patient's qualify of life. In this study, we examined whether curcumin can protect against cisplatin neurite outgrowth inhibition in PC12 cells, which is an indicator of the protective potential against neuropathy. We also investigated whether curcumin affects cisplatin effectiveness by analyzing the modulation of p53 gene expression and its effect on cisplatin cytotoxicity in HepG2 tumor cells. Non-cytotoxic concentrations of curcumin reduced in vitro neurotoxicity of cisplatin in PC12 cells. The treatment of PC12 cells with cisplatin (10MUg/mL) significantly reduced neurite outgrowth. The tested concentration of curcumin (1.0 and 10MUg/mL) did not result in neurite toxicity but nevertheless diminished cisplatin-induced inhibition of neurite outgrowth by up to 50% (p<0.05). Our results indicate that curcumin does not compromise cisplatin's anticancer activity. Curcumin neither suppressed p53 mRNA transcription nor protected tumor cells against cisplatin cytotoxicity. These results indicate that curcumin may reduce cisplatin-induced neurotoxicity, and clinical studies should potentially be considered. PMID- 23036616 TI - Invasion of lesion territory by regenerating fibers after spinal cord injury in adult macaque monkeys. AB - In adult macaque monkeys subjected to an incomplete spinal cord injury (SCI), corticospinal (CS) fibers are rarely observed to grow in the lesion territory. This situation is little affected by the application of an anti-Nogo-A antibody which otherwise fosters the growth of CS fibers rostrally and caudally to the lesion. However, when using the Sternberger monoclonal-incorporated antibody 32 (SMI-32), a marker detecting a non-phosphorylated neurofilament epitope, numerous SMI-32-positive (+) fibers were observed in the spinal lesion territory of 18 adult macaque monkeys; eight of these animals had received a control antibody infusion intrathecally for 1 month after the injury, five animals an anti-Nogo-A antibody, and five animals received an anti-Nogo-A antibody together with brain derived neurotrophic factor (BDNF). These fibers occupied the whole dorso-ventral axis of the lesion site with a tendency to accumulate on the ventral side, and their trajectories were erratic. Most of these fibers (about 87%) were larger than 1.3 MUm and densely SMI-32 (+) stained. In the undamaged spinal tissue, motoneurons form the only large population of SMI-32 (+) neurons which are densely stained and have large diameter axons. These data therefore suggest that a sizeable proportion of the fibers seen in the lesion territory originate from motoneurons, although fibers of other origins could also contribute. Neither the presence of the antibody neutralizing Nogo-A alone, nor the presence of the antibody neutralizing Nogo-A combined with BDNF influenced the number or the length of the SMI-32 (+) fibers in the spinal lesion area. In summary, our data show that after a spinal cord lesion in adult monkeys, the lesion site is colonized by fibers, a large portion of which presumably originate from motoneurons. PMID- 23036617 TI - A pubertal immune challenge alters the antidepressant-like effects of chronic estradiol treatment in inbred and outbred adult female mice. AB - Puberty is a period characterized by brain reorganization that contributes to the development of neural and behavioral responses to gonadal steroids. A single injection of the bacterial endotoxin, lipopolysaccharide (LPS), during the pubertal period decreases sexual receptivity in response to ovarian hormones in adulthood. Because chronic estradiol treatment alleviates depression-like symptoms in ovariectomized adult mice, we investigated the effect of pubertal LPS treatment on estradiol's antidepressant effects. We hypothesized that pubertal LPS treatment would decrease the antidepressant-like effect of estradiol in adult ovariectomized female mice, as it decreases other behavioral responses to ovarian hormones. As expected, chronic estradiol treatment decreased depression-like behavior, as measured by the duration of immobility, in saline-treated mice from two different strains, as well as in mice treated with LPS in adulthood. In contrast, in mice treated pubertally with LPS, estradiol strikingly increased the duration of immobility. No difference in body weight and in locomotion was found among the groups, suggesting that the differences in depression-like behavior were not due to differences in body weight or locomotor activity between LPS treated and control mice. These results suggest that exposure to an immune challenge during the pubertal period alters the responsiveness of depression-like behavior to estradiol. PMID- 23036618 TI - Pregnancy or stress decrease complexity of CA3 pyramidal neurons in the hippocampus of adult female rats. AB - Pregnancy is a time of distinct neural, physiological and behavioral plasticity in the female. It is also a time when a growing number of women are vulnerable to stress and experience stress-related diseases, such as depression and anxiety. However, the impact of stress during gestation on the neurobiology of the mother has yet to be determined, particularly with regard to changes in the hippocampus; a brain area that plays an important role in stress-related diseases. Therefore, the aim of the present study was to understand how stress and reproductive state may alter dendritic morphology of CA1 and CA3 pyramidal neurons in the hippocampus. To do this, adult age-matched pregnant and virgin female Wistar rats were divided into two conditions: (1) control and (2) stress. Females in the stress condition were restrained for 1h/day for the last 2 weeks of gestation and at matched time-points in virgin females. Females were sacrificed the day after the last restraint session and brains were processed for Golgi impregnation. Dendritic length and number of branch points were quantified for apical and basal regions of CA1 and CA3 pyramidal neurons. Results show that regardless of reproductive state, stressed females had significantly shorter apical dendrites and fewer apical branch points in CA3 pyramidal cells. In addition, pregnant females, regardless of stress exposure, had less complex CA3 pyramidal neurons, as measured by Sholl analysis. No differences between conditions were seen in morphology of CA1 pyramidal neurons. This work shows that both repeated restraint stress and pregnancy affect dendritic morphology by decreasing complexity of CA3, but not CA1, neurons in the hippocampus. PMID- 23036619 TI - The posterior hypothalamus exerts opposing effects on nociception via the A7 catecholamine cell group in rats. AB - Stimulation of the posterior hypothalamic area (PH) produces antinociception in rats and humans, but the precise mechanisms are unknown. The PH forms anatomical connections with the parabrachial area, which contains the pontine A7 catecholamine cell group, a group of spinally projecting noradrenergic neurons known to produce antinociception in the dorsal horn. The aim of the present study was to determine whether PH-induced antinociception is mediated in part through connections with the A7 cell group in female Sprague-Dawley rats, as measured by the tail flick and foot withdrawal latency. Stimulation of the PH with the cholinergic agonist carbachol (125 nmol) produced antinociception that was blocked by pretreatment with atropine sulfate. Intrathecal injection of the alpha(2)-adrenoceptor antagonist yohimbine reversed PH-induced antinociception, but the alpha(1)-adrenoceptor antagonist WB4101 facilitated antinociception. Intrathecal injection of normal saline had no effect. In a separate experiment, cobalt chloride, which reversibly arrests synaptic activity, was microinjected into the A7 cell group and blocked PH-induced antinociception. These findings provide evidence that the PH modulates nociception in part through connections with the A7 catecholamine cell group through opposing effects. Antinociception occurs from actions at alpha(2)-adrenoceptors in the dorsal horn, while concurrent hyperalgesia occurs from actions of norepinephrine at alpha(1) adrenoceptors. This hyperalgesic response likely attenuates antinociception from PH stimulation. PMID- 23036620 TI - Progesterone, brain-derived neurotrophic factor and neuroprotection. AB - While the effects of progesterone in the CNS, like those of estrogen, have generally been considered within the context of reproductive function, growing evidence supports its importance in regulating non-reproductive functions including cognition and affect. In addition, progesterone has well-described protective effects against numerous insults in a variety of cell models, animal models and in humans. While ongoing research in several laboratories continues to shed light on the mechanism(s) by which progesterone and its related progestins exert their effects in the CNS, our understanding is still incomplete. Among the key mediators of progesterone's beneficial effects is the family of growth factors called neurotrophins. Here, we review the mechanisms by which progesterone regulates one important member of the neurotrophin family, brain derived neurotrophic factor (BDNF), and provides support for its pivotal role in the protective program elicited by progesterone in the brain. PMID- 23036621 TI - Temporal regularity determines the impact of electrical stimulation on tactile reactivity and response to capsaicin in spinally transected rats. AB - Nociceptive plasticity and central sensitization within the spinal cord depend on neurobiological mechanisms implicated in learning and memory in higher neural systems, suggesting that the factors that impact brain-mediated learning and memory could modulate how stimulation affects spinal systems. One such factor is temporal regularity (predictability). The present paper shows that intermittent hindleg shock has opposing effects in spinally transected rats depending upon whether shock is presented in a regular or irregular (variable) manner. Variable intermittent legshock (900 shocks) enhanced mechanical reactivity to von Frey stimuli (hyperreactivity), whereas 900 fixed-spaced legshocks produced hyporeactivity. The impact of fixed-spaced shock depended upon the duration of exposure; a brief exposure (36 shocks) induced hyperreactivity whereas an extended exposure (900 shocks) produced hyporeactivity. The enhanced reactivity observed after variable shock was most evident 60-180 min after treatment. Fixed and variable intermittent stimulation applied to the sciatic nerve, or the tail, yielded a similar pattern of results. Stimulation had no effect on thermal reactivity. Exposure to fixed-spaced shock, but not variable shock, attenuated the enhanced mechanical reactivity (EMR) produced by treatment with hindpaw capsaicin. The effect of fixed-spaced stimulation lasted 24h. Treatment with fixed-spaced shock also attenuated the maintenance of capsaicin-induced EMR. The results show that variable intermittent shock enhances mechanical reactivity, while an extended exposure to fixed-spaced shock has the opposite effect on mechanical reactivity and attenuates capsaicin-induced EMR. PMID- 23036623 TI - Evaluation of autonomic reserves in cardiac surgery patients. AB - OBJECTIVE: Autonomic nervous system dysfunction is a well-recognized but rarely evaluated risk factor for patients undergoing cardiac surgery. By measuring autonomic reserves in patients scheduled for cardiac surgery, the authors aimed to identify those with autonomic dysfunction and to evaluate their risk of perioperative complications. DESIGN: This was a prospective, observational study. SETTING: The study was conducted in a single academic center. PARTICIPANTS: Sixty seven patients completed the study. INTERVENTIONS: Autonomic reserves were evaluated using analysis of heart rate variability (HRV) and blood pressure variability (BPV) after a Valsalva maneuver. MEASUREMENTS AND MAIN RESULTS: The patients were divided into 2 groups depending on their response to the autonomic challenge, a group with autonomic reserves (AR, n = 38) and a group with negligible autonomic reserves (NAR, n = 29). The groups were compared for baseline psychologic distress, demographic and medical profiles, autonomic response to morphine premedication and the induction of anesthesia, hemodynamic instability, the occurrence of decreases in cerebral oxygen saturation, and postoperative complications. Patients in the NAR group had significantly higher psychologic distress scores (p < 0.001), a higher baseline parasympathetic tone (p = 0.003), were unable to increase parasympathetic tone with morphine premedication, had more severe hypotension at the induction of anesthesia (p < 0.001), more episodes of decreases in cerebral saturation (p = 0.0485), and a higher overall complication rate (p = 0.0388) independent of other variables studied. CONCLUSIONS: Patients with diminished autonomic reserves can be identified before cardiac surgery using analysis of HRV and BPV of the response to the Valsalva maneuver, and some evidence suggests that they may be at increased risk of perioperative complications. PMID- 23036624 TI - Pulmonary hypertension in patients undergoing cardiac surgery: pathophysiology, perioperative management, and outcomes. PMID- 23036625 TI - Bivalirudin versus heparin as an anticoagulant during extracorporeal membrane oxygenation: a case-control study. AB - OBJECTIVE: Heparin-based anticoagulation for patients undergoing extracorporeal membrane oxygenation has many limitations, including a high risk of heparin induced thrombocytopenia. However, little experience with other anticoagulants in these patients has been described. The aim of this study was to compare bivalirudin-based anticoagulation with heparin-based protocols in a population of patients treated with venovenous or venoarterial extracorporeal membrane oxygenation. DESIGN: In this case-control study, 10 patients received bivalirudin (cases) and 10 heparin (controls). The target activated partial thromboplastin time (aPTT) was 45 to 60 seconds. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: aPTT variations >20% of the previous value were much more frequent in patients treated with heparin than in patients receiving bivalirudin (52 v 24, p < 0.001). The number of corrections of the anticoagulant dose was higher in the heparin group compared with the bivalirudin group (58 v 51), although it did not reach statistical significance. Bleeding, thromboembolic complications, extracorporeal membrane oxygenation (ECMO) support duration, mortality, and the number of episodes of aPTT >80 seconds were not different between the 2 groups. A further analysis was performed in the bivalirudin group according to the presence of acute renal failure requiring continuous venovenous hemofiltration. The median bivalirudin dose in patients with or without hemofiltration was 0.041 (0.028 0.05) mg/kg/h and 0.028 (0-0.041) mg/kg/h, respectively (p = 0.2). CONCLUSIONS: Bivalirudin-based anticoagulation may represent a new method of anticoagulation for reducing thromboembolic and bleeding complications, which still jeopardize the application of extracorporeal membrane oxygenation. Moreover, bivalirudin is free from the risk of heparin-induced thrombocytopenia. Higher doses of bivalirudin may be needed in patients undergoing hemofiltration. PMID- 23036626 TI - Anesthesia for transfemoral aortic valve replacement in North America and Europe. AB - OBJECTIVE: The purpose of this study was to determine how the anesthestic approach to transcatheter aortic valve replacement (TAVR) differs in North America and Europe. DESIGN: The study was a nonrandomized survey of 82 institutions in North America and Europe performing TAVR procedures. SETTING: This was an international multi-institutional survey of medical centers performing TAVR in North America and Europe. PARTICIPANTS: Anesthesiologists. INTERVENTIONS: Participant anesthesiologists from 82 institutions contacted were asked by telephone and e-mail to describe their anesthetic approach to TAVRs. MEASUREMENTS AND MAIN RESULTS: The major finding of interest was if general anesthesia or sedation was used for TAVR cases. CONCLUSIONS: General anesthesia is the predominant practice in North America and only 5% use sedation for TAVR cases, whereas sedation is more common in Europe. PMID- 23036627 TI - Reversibility of intrathoracic lipotoxicity in obesity after bariatric surgery: use of magnetic resonance imaging. PMID- 23036622 TI - Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression. AB - Dendritic spines provide a compartment for assembly and functional organization of synaptic machinery that plays a fundamental role in neuronal communication and neuroplasticity. Studies in humans as well as in animal models have demonstrated abnormal spine architecture in several psychiatric disorders, including depression and other stress-related illnesses. The negative impact of stress on the density and organization of spines is thought to contribute to the behavioral deficits caused by stress exposure. Moreover, there is now evidence that medication-induced recovery involves changes in synaptic plasticity and dendrite morphology, including increased expression of pre- and postsynaptic plasticity related proteins, as well as the density and function of axo-spinous synapses. Here we review the evidence from brain imaging and postmortem studies demonstrating that depression is accompanied by structural and functional alterations of cortical and limbic brain regions, including the prefrontal cortex, hippocampus and amygdala. In addition, we present more direct evidence from basic research studies that exposure to stress alters spine morphology, function and plasticity and that antidepressants, particularly new rapid acting agents, reverse these effects. Elucidation of the signaling pathways and molecular mechanisms that control spine synapse assembly and plasticity will contribute to a better understanding of the pathophysiology of depression and development of novel, more effective therapeutic agents. PMID- 23036628 TI - Severe multivessel coronary vasospasm presenting as acute ST-segment elevation myocardial infarction. PMID- 23036629 TI - Accurate echocardiographic assessment of left atrial appendage ostium and peri device flow in device closure. PMID- 23036632 TI - New oral anticoagulants: good but not good enough! PMID- 23036633 TI - The use of 18F-FDG-PET/CT in the diagnostic workup of CIED infections: another perspective. PMID- 23036634 TI - Clinical utility of 18F-FDG positron emission tomography and computed tomography in patients with suspected cardiovascular implantable electronic device infection. PMID- 23036636 TI - Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. AB - OBJECTIVES: The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. BACKGROUND: A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. METHODS AND RESULTS: Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, the Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC 2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiography recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. CONCLUSIONS: This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavors of applying definitions to other transcatheter valve therapies (for example, mitral valve repair). PMID- 23036637 TI - Intracardiac and intravenous leiomyomatosis. PMID- 23036640 TI - [Chronic constrictive pericarditis: new imaging features]. AB - We report on a patient hospitalized in cardiology department to explore dyspnea and right ventricular failure evoking constrictive pericarditis. This case is of great interest to review conventional and new imaging features used for the diagnosis of constrictive pericarditis versus restrictive cardiomyopathy. PMID- 23036641 TI - The importance of the aggregation of ticks on small mammal hosts for the establishment and persistence of tick-borne pathogens: an investigation using the R(0) model. AB - Aggregation of parasites amongst hosts is important for the epidemiology of vector-borne diseases because hosts that support the majority of the vector population are responsible for the majority of pathogen transmission. Ixodes ricinus ticks transmit numerous pathogens of medical importance including Borrelia burgdorferi s.l. and tick-borne encephalitis virus. One transmission route involved is 'co-feeding transmission', where larvae become infected via feeding alongside infected nymphs. The aggregation of ticks on hosts leads to an increase in the number of larvae feeding alongside nymphs, increasing the transmission potential via this route. The basic reproduction number, R 0, can be used to identify whether a pathogen will become established if introduced. In the current study we use previously published tick, and pathogen, specific data to parameterize an R 0 model to investigate how the degree of aggregation of ticks on hosts affects pathogen persistence. The coincident aggregated distribution permitted the establishment of tick-borne encephalitis virus but did not influence whether B. burgdorferi s.l. became established. The relationship between the k-exponent of the negative binomial distribution and R 0 was also defined. Therefore, the degree of aggregation of ticks on small mammal hosts has important implications for the risk to human health in a given area. PMID- 23036642 TI - Impaired skeletal muscle microcirculation in systemic sclerosis. AB - INTRODUCTION: Muscle symptoms in systemic sclerosis (SSc) may originate from altered skeletal muscle microcirculation, which can be investigated by means of blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI). METHODS: After ethics committee approval and written consent, 11 consecutive SSc patients (5 men, mean age 52.6 years, mean SSc disease duration 5.4 years) and 12 healthy volunteers (4 men, mean age 45.1 years) were included. Subjects with peripheral arterial occlusive disease were excluded. BOLD MRI was performed on calf muscles during cuff-induced ischemia and reactive hyperemia, using a 3-T whole-body scanner (Verio, Siemens, Erlangen, Germany) and fat-suppressed single short multi-echo echo planar imaging (EPI) with four different effective echo times. Muscle BOLD signal time courses were obtained for gastrocnemius and soleus muscles: minimal hemoglobin oxygen saturation (T2*min) and maximal T2* values (T2*max), time to T2* peak (TTP), and slopes of oxygen normalization after T2* peaking. RESULTS: The vast majority of SSc patients lacked skeletal muscle atrophy, weakness or serum creatine kinase elevation. Nevertheless, more intense oxygen desaturation during ischemia was observed in calf muscles of SSc patients (mean T2*min -15.0%), compared with controls (-9.1%, P = 0.02). SSc patients also had impaired oxygenation during hyperemia (median T2*max 9.2% vs. 20.1%, respectively, P = 0.007). The slope of muscle oxygen normalization was significantly less steep and prolonged (TTP) in SSc patients (P<0.001 for both). Similar differences were found at a separate analysis of gastrocnemius and soleus muscles, with most pronounced impairment in the gastrocnemius. CONCLUSIONS: BOLD MRI demonstrates a significant impairment of skeletal muscle microcirculation in SSc. PMID- 23036643 TI - Stimulation of Escherichia coli DNA damage inducible DNA helicase DinG by the single-stranded DNA binding protein SSB. AB - Escherichia coli DNA damage inducible protein DinG is a superfamily II DNA helicase and is closely related to human DNA helicase XPD. Here, we report that E. coli single-stranded DNA binding protein (SSB) is able to form a stable protein complex with DinG and to stimulate the DinG DNA helicase activity. An SSB mutant that retains the single-stranded DNA binding activity but fails to form a protein complex with DinG becomes a potent inhibitor for the DinG DNA helicase, suggesting that E. coli wild-type SSB stimulates the DinG DNA helicase via specific protein-protein interaction. PMID- 23036646 TI - Influence of daily alcohol consumption on serum adiponectin levels in men. AB - BACKGROUND: The risk of cardiovascular diseases is lower among moderate alcohol drinkers than among both nondrinkers and heavy drinkers. However, factors that can account for the U-shaped or J-shaped relationship between daily alcohol consumption and incident cardiovascular diseases remain obscure. PURPOSE: The present cross-sectional study investigated the relationship between alcohol consumption and serum adiponectin levels. METHOD: Total adiponectin was measured in 527 males participating in health check-up programs (age range 40-86 years, mean 60.5 years). Based on questionnaire responses, alcohol intake was categorized into three groups: none or occasional (A1); <50 g/day and >=3 days/week (A2); and >=50 g/day and >=3 days/week (A3). RESULTS: No significant differences in adiponectin levels were observed among the three alcohol consumption groups of subjects without the metabolic syndrome (MetS). In subjects with the MetS, the adiponectin level was significantly higher in the A2 (moderate drinker) group than in both the A1 and A3 groups. MetS subjects in group A2 had higher HDL-C levels than those in A1, but levels in group A3 were not significantly different from those in group A2. CONCLUSION: An increased adiponectin level in moderate alcohol drinkers who have MetS may contribute to the U-shaped relationship between alcohol consumption and risk of cardiovascular events, in addition to the involvement of HDL-C. PMID- 23036645 TI - Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: Liver ultrasound data from the National Health and Nutrition Examination Survey. AB - OBJECTIVE: Experimental and observational studies suggest a role for uric acid in non-alcoholic fatty liver disease (NAFLD). We examined the association between serum uric acid levels and NAFLD in a large population-based study from the United States. MATERIALS/METHODS: A cross-sectional analysis of 10,732 nondiabetic adults who participated in the National Health and Nutrition Examination Survey 1988-1994. Sex specific uric acid quartiles were defined: <=5.2, 5.3-6.0, 6.1-6.9, and >6.9mg/dL for men and <=3.7, 3.8-4.5, 4.6-5.3, and >5.3mg/dL for women. NAFLD presence and severity were defined by ultrasonographic detection of steatosis in the absence of other liver diseases. We modeled the probability that more severe NAFLD would be associated with the highest quartiles of uric acid. RESULTS: Compared to the 1st quartile, the odds ratio for NAFLD was 1.79 (95% C.I. 1.49-2.15, p<0.001) and 3.14 (95% C.I. 2.63-3.75, p<0.001) for the 3rd and 4th quartiles, respectively. After adjusting for demographics, hypertension, waist circumference, triglycerides, high-density lipoprotein cholesterol, homeostasis model assessment-estimated insulin resistance, estimated glomerular filtration rate, and aspartate aminotransferase, uric acid (4th quartile) was significantly associated with NAFLD (odds ratio 1.43; 95% C.I. 1.16 1.76, p<0.001). Positive parameter estimates suggest increasing uric acid is associated with greater severity of NAFLD. CONCLUSIONS: Elevated uric acid level is independently associated with ultrasound-diagnosed NAFLD in a nationally representative sample of United States nondiabetic adults. Increasing uric acid is associated with increasing severity of NAFLD on ultrasonography. These findings warrant further studies on the role of uric acid in NAFLD. PMID- 23036644 TI - Near-cognate suppression of amber, opal and quadruplet codons competes with aminoacyl-tRNAPyl for genetic code expansion. AB - Over 300 amino acids are found in proteins in nature, yet typically only 20 are genetically encoded. Reassigning stop codons and use of quadruplet codons emerged as the main avenues for genetically encoding non-canonical amino acids (NCAAs). Canonical aminoacyl-tRNAs with near-cognate anticodons also read these codons to some extent. This background suppression leads to 'statistical protein' that contains some natural amino acid(s) at a site intended for NCAA. We characterize near-cognate suppression of amber, opal and a quadruplet codon in common Escherichia coli laboratory strains and find that the PylRS/tRNA(Pyl) orthogonal pair cannot completely outcompete contamination by natural amino acids. PMID- 23036648 TI - Why small-scale cannabis growers stay small: five mechanisms that prevent small scale growers from going large scale. AB - BACKGROUND: Over the past 15-20 years, domestic cultivation of cannabis has been established in a number of European countries. New techniques have made such cultivation easier; however, the bulk of growers remain small-scale. In this study, we explore the factors that prevent small-scale growers from increasing their production. METHODS: The study is based on 1 year of ethnographic fieldwork and qualitative interviews conducted with 45 Norwegian cannabis growers, 10 of whom were growing on a large-scale and 35 on a small-scale. RESULTS: The study identifies five mechanisms that prevent small-scale indoor growers from going large-scale. First, large-scale operations involve a number of people, large sums of money, a high work-load and a high risk of detection, and thus demand a higher level of organizational skills than for small growing operations. Second, financial assets are needed to start a large 'grow-site'. Housing rent, electricity, equipment and nutrients are expensive. Third, to be able to sell large quantities of cannabis, growers need access to an illegal distribution network and knowledge of how to act according to black market norms and structures. Fourth, large-scale operations require advanced horticultural skills to maximize yield and quality, which demands greater skills and knowledge than does small-scale cultivation. Fifth, small-scale growers are often embedded in the 'cannabis culture', which emphasizes anti-commercialism, anti-violence and ecological and community values. Hence, starting up large-scale production will imply having to renegotiate or abandon these values. CONCLUSION: Going from small to large-scale cannabis production is a demanding task-ideologically, technically, economically and personally. The many obstacles that small-scale growers face and the lack of interest and motivation for going large-scale suggest that the risk of a 'slippery slope' from small-scale to large-scale growing is limited. Possible political implications of the findings are discussed. PMID- 23036649 TI - Prevalence and correlates of prescription drug misuse among socially active young adults. AB - BACKGROUND: Prescription drug misuse represents an emerging global drug trend. Data indicate that young adults are misusing prescription drugs at high rates. As such, continued surveillance of the patterns of prescription drug misuse among young adults is critical, particularly for those engaged in social scenes known to accommodate drug use. METHODS: Prevalence and correlates of lifetime and recent prescription drug misuse among urban young adults recruited at nightlife venues using time-space sampling are assessed via prevalence estimates and logistic regression analyses. RESULTS: In a diverse sample of 1207 young adults, 44.1% reported lifetime prescription drug misuse, and 20.3% reported misuse during the past three months. Stimulants were the most common class of drug respondents misused within the past six months (16.7%), followed by pain killers (16.5%) and sedatives (14.5%). While no gender or sexual orientation differences in misuse prevalence existed, Black youth reported the lowest prevalence of misuse. In multivariate analyses, increased age was associated with lower odds of recent misuse, females report lower odds of recent use, and Black, Asian, and Latino individuals had lower odds of recent misuse than Whites. These odds varied by prescription drug type. Negative binomial regression analyses indicate that, among prescription drug misusers, women misuse prescription drugs less frequently. Younger individuals more frequently misuse stimulants and older individuals more frequently misuse sedatives. Racial variation existed with frequency of use across classes. CONCLUSIONS: This study illustrates the need for health promotion efforts targeting prescription drug misuse among young adults who are highly socially active. Future research should focus on motivations for and factors associated with prescription drug misuse within youth cultures. Further research may provide a fuller sense of how to reduce the impact of prescription drug misuse for nations whose prescription drug problem lags behind that of the U.S. PMID- 23036650 TI - An urgent need to scale-up injecting drug harm reduction services in Tanzania: prevalence of blood-borne viruses among drug users in Temeke District, Dar-es Salaam, 2011. AB - BACKGROUND: Injecting drug use (IDU) is a growing concern in Tanzania compounded by reports of high-risk injecting and sexual risk behaviours among people who inject drugs (PWID). These behaviours have implications for transmission of blood borne viruses, including HIV and hepatitis C (HCV). METHODS: We recruited 267 PWID (87% male) from Temeke District, Dar-es-Salaam through snowball and targeted sampling. A behavioural survey was administered alongside repeated rapid HIV and HCV antibody testing. HIV and HCV prevalence estimates with 95% confidence intervals (CIs) were calculated. RESULTS: Among PWID, 34.8% (95%CI 29.1-40.9) tested HIV positive (29.9% of males and 66.7% of females); 27.7% (95%CI 22.0 34.0) tested HCV antibody positive. Almost all (97%) participants were aware of HIV and 34% of HCV. 45% of male and 64% of female PWID reported a previous HIV test; only five (2%) PWID reported a previous HCV test. Of HIV and HCV positive tests, 73% and 99%, respectively, represented newly diagnosed infections. CONCLUSION: High prevalence of HIV and HCV were detected in this population of PWID. Rapid scale-up of targeted primary prevention and testing and treatment services for PWID in Tanzania is needed to prevent further transmission and consequent morbidities. PMID- 23036651 TI - Socio-demographic factors, health risks and harms associated with early initiation of injection among people who inject drugs in Tallinn, Estonia: evidence from cross-sectional surveys. AB - AIM: To explore socio-demographic factors, health risks and harms associated with early initiation of injecting (before age 16) among injecting drug users (IDUs) in Tallinn, Estonia. METHODS: IDUs were recruited using respondent driven sampling methods for two cross-sectional interviewer-administered surveys (in 2007 and 2009). Bivariate and multivariate logistic regression analysis was used to identify factors associated with early initiation versus later initiation. RESULTS: A total of 672 current IDUs reported the age when they started to inject drugs; the mean was 18 years, and about a quarter of the sample (n = 156) reported early initiation into injecting drugs. Factors significantly associated in multivariate analysis with early initiation were being female, having a lower educational level, being unemployed, shorter time between first drug use and injecting, high-risk injecting (sharing syringes and paraphernalia, injecting more than once a day), involvement in syringe exchange attendance and getting syringes from outreach workers, and two-fold higher risk of HIV seropositivity. CONCLUSIONS: Our results document significant adverse health consequences (including higher risk behaviour and HIV seropositivity) associated with early initiation into drug injecting and emphasize the need for comprehensive prevention programs and early intervention efforts targeting youth at risk. Our findings suggest that interventions designed to delay the age of starting drug use, including injecting drug use, can contribute to reducing risk behaviour and HIV prevalence among IDUs. PMID- 23036652 TI - Drug policy coordination: identifying and assessing dimensions of coordination. AB - BACKGROUND: Coordination has been recognised as a critical ingredient for successful drug policy governance. Yet what coordination means and how we assess the processes, outputs and outcomes of drug policy coordination is seldom defined. In this article we explore the utility of internationally recognised principles of good governance for examining aspects of drug policy coordination. We describe the development of an assessment tool, and pilot it in one context that has been both praised and criticised for its approach to drug policy coordination: Australia. METHODS: Eight good governance principles of the United Nations Economic and Social Commission for Asia and the Pacific (which specify the need for policy processes to be participatory, responsive, equitable etc.), were adapted to drug policy coordination. A pilot survey was created to enable assessment of their perceived importance and perceived application and administered to 36 stakeholders from peak Australian advisory bodies. RESULTS: The instrument was shown to have high internal reliability and high face validity. Application to the Australian context suggested that the eight principles differed in importance, and that the most important principles were 'accountability' and 'participation'. Application also revealed perceived strengths and weaknesses in coordination, most notably, an apparent need to increase 'accountability' for stakeholder actions. CONCLUSION: The instrument requires further assessment of reliability and validity. Yet, at least within the Australian context, it starts to unpack normative statements about coordination to show perceptions of what coordination is, areas where improvement may be warranted and the degree of contestation amongst different players. Further application of the good governance lens within this and other contexts will progress the assessment of a fundamental yet neglected policy process and foster a more nuanced consideration of the possibilities for coordination in the drug policy "soup". PMID- 23036653 TI - Thresholds in a low-threshold setting: an empirical study of barriers in a centre for people with drug problems and mental health disorders. AB - BACKGROUND: Some services for drug users with mental health disorders can be characterised as low-threshold services. These aim at making help easily accessible for people who are not able to request help from services at higher levels. In this study we examine what kind of thresholds are experienced by clients at a low-threshold centre. METHODS: Ethnographic field work, including participant observation, individual interviews and focus group interviews with clients and staff in a low-threshold centre for the most vulnerable drug users in Oslo were employed. RESULTS: Our analyses agree with other studies in showing that the following three thresholds are significant, also in services for drug users with mental health disorders: the registration threshold, the competence threshold and the threshold of effectiveness. In addition to these, we suggest that a fourth threshold is of importance for this group: the threshold of trust. In the low-threshold centre we studied, we observed that for the clients, crossing the threshold of trust seemed to be an essential precondition for subsequently being able to cross the other thresholds in order to receive the help they need. We suggest that focus on the four thresholds can improve our understanding of clients' access to services. We also suggest that processes of recovery may be improved if increased attention is given to the barriers that clients experience. CONCLUSION: The threshold of trust seems to be particularly important for people suffering from drug problems and mental health disorders. The results have implications both for practice and policy because if taken seriously into consideration, more clients could access the services they need. Services for this group may be improved by focusing on the fourth threshold: trust. PMID- 23036654 TI - Towards revision of the UN drug control conventions: harnessing like-mindedness. AB - BACKGROUND: Almost all nations are currently parties to the UN international drug control conventions of 1961, 1971 and 1988; treaties that taken together form what can be usefully called the global drug prohibition regime. Despite interpretative tensions around some national policy approaches that deviate from punitive prohibition, the inherent flexibility within the conventions permit members of the regime some policy space at the national level. Should they wish to do so, however, states already pushing at the limits of the regime would only be able to expand such national policy space via an alteration in their relationship to the UN drug control conventions and the prohibitive norm at the regime's core. METHOD: The article applies an international relations approach, including examples from the UN system in general and other issue areas in particular, to explore how the formation and operation of a group, or groups, of like-minded nations may offer a route towards some form of substantive treaty revision. RESULTS: Although common in other areas of international concern, the varied nature of dissatisfaction with the prohibitive ethos of the regime combines with the character of drug policy to generate specific dilemmas for the like-minded group (LMG) approach. Nonetheless, within the current policy environment it is plausible to foresee the construction of groupings around a number of themes: traditional and religious drug use, cannabis regulation, technical issues relating to inconsistencies within the conventions and UN system wide coherence. These potential groups provide the basis for a number of possible scenarios for treaty revision and highlight essential commonalities of approach that should be considered whatever the route towards reform. CONCLUSION: The increasingly obvious weaknesses within, tensions around and negative consequences of the regime in its current form make a recalibration of the UN drug control conventions via an LMG approach an enterprise worthy of time and effort. PMID- 23036655 TI - Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children. AB - The objective of the study was to evaluate etiology, clinical characteristics and outcome in children with epilepsia partialis continua (EPC). The investigation included 51 children with EPC aged 0.2-18 years treated in the period 1993-2009. The median period from the onset of underlying disorder to EPC was 6 months (0-72 months). EPC was caused by different pathologies: inflammatory and immune mediated (52%), metabolic (13.7%), structural brain abnormalities (11.8%), cryptogenic (7.8%), vascular (5.9%), dual (5.9%), postoperative (2%). Median duration of EPC was 15 days (1-200 days). EPC involved more frequently the right side of the body comparing to the left one. The outcome was assessed at the end of the follow up period (mean 6.5 years, ranged 0.2-16 years). Unchanged neurological status was observed in 10 (19.6%) children, neurological consequences in 33 (64.7%) children and lethal outcome in 8 (15.7%) children. The most frequent etiology in our cohort was inflammatory and immune-mediated disease of central nerve system including Rasmussen's encephalitis. The duration of EPC was prolonged, most frequently involving the right upper limb. The outcome of EPC in children was unfavorable. PMID- 23036657 TI - Repositioning of proximally mislocated biliary metallic stent using rat-tooth forceps. PMID- 23036658 TI - Somatosensory input and oromandibular dystonia. PMID- 23036659 TI - A disabling cervical compressive myelopathy with normal JOA score. PMID- 23036660 TI - The neurolinguistic approach to awake surgery reviewed. AB - OBJECTIVES: Intraoperative direct electrical stimulation (DES) is increasingly used in patients operated on for tumours in critical language areas. Although a positive impact of DES on postoperative linguistic outcome is generally advocated, the literature is only scantily documented with information about the linguistic methods applied in awake surgery. This article critically reviews the neurolinguistic procedures currently used in awake studies. METHODS: Based on an extensive review of the literature, an overview is given of the language mapping techniques applied in brain tumour surgery. Studies investigating linguistic testing and outcome in awake surgery were analysed. Information about the timing of the assessment(s), the linguistic tasks, the linguistic stimuli and the indication for awake surgery was also discussed. RESULTS: Intraoperative DES remains the 'gold standard' for language mapping, but pre- and postoperative non invasive mapping methods are important adjuncts. In the pre- and postoperative phase, standardised linguistic test batteries are generally used to assess language function. In the intraoperative phase, only naming and number counting are commonly applied. Most often no detailed information about the linguistic stimuli is provided and no standardised protocols measuring different linguistic levels have been described. CONCLUSIONS: Awake surgery with DES is a useful tool for preserving linguistic functions in patients undergoing surgery in critical brain regions. However, no studies exist that apply a well-balanced and standardised linguistic protocol to reliably identify the critical language zones. The availability of a standardised linguistic protocol might substantially increase intraoperative comfort and might improve outcome and quality of life. PMID- 23036661 TI - Evoked potential mapping of the rostral region by frameless navigation system in Mexican hairless pig. AB - There is an increasing need for a pig model for use in functional brain studies, but a system for determining precise stereotactic coordinates has yet to be developed. Thus, we devised a frameless navigation system for stereotactic positioning, and measured coordinates for the rostral region and the primary somatosensory cortex in the pig brain. Raw coordinates for somatic evoked potential recordings were obtained by passive optical tracking. The location was registered to a computed tomographic image in reference to four stable skull landmarks: the upper margin of each auditory meatus, the external occipital protuberance, and the point where the interfrontal suture crosses a line drawn between the two supraorbital foramina ("IF" point). The cortical position with the greatest response in evoked potential was mapped -51.0 +/- 4.67 mm rostro caudally, 9.1 +/- 1.19 mm medio-laterally, and -8.8 +/- 0.48 mm dorso-ventrally (means +/- SD; n=3) to the IF point. These results show that frameless registration is useful for coordinate-based evoked-potential mapping of the rostral region of the Mexican hairless pig. PMID- 23036662 TI - Effect of a pre-freezing treatment with cholesterol-loaded cyclodextrins on boar sperm longevity, capacitation dynamics, ability to adhere to porcine oviductal epithelial cells in vitro and DNA fragmentation dynamics. AB - The aim of this work was to examine how a pre-freezing treatment with cholesterol loaded cyclodextrins (CLC) affects boar sperm longevity, capacitation dynamics, ability to bind to a porcine telomerase-immortalised oviductal epithelial cell line (TERT-OPEC) in vitro and DNA integrity dynamics after freeze-thawing. Although the samples treated with CLC exhibited lower sperm quality than the control samples (P<0.05) immediately after thawing, these differences disappeared (P>0.05) after long-term incubation (26h at 37 or 16 degrees C). Additionally, the CLC-treated spermatozoa underwent similar capacitation and DNA fragmentation dynamics as the control spermatozoa (P>0.05). However, CLC-treated spermatozoa were better able to bind to TERT-OPEC in vitro (P<0.0001). In conclusion, the pre freezing treatment of boar spermatozoa with CLC enhanced the ability of the spermatozoa to bind to TERT-OPEC in vitro, which could have an effect on the establishment of the sperm reservoir in the ampullary--isthmic junction in vivo. Additionally, frozen-thawed spermatozoa can be stored at 16 degrees C for at least 6h without a significant observable decline in sperm quality, which could be beneficial for the transport of thawed diluted doses of spermatozoa from the laboratory to the farm. PMID- 23036663 TI - Importance and relevance of pulmonary symptoms among patients receiving second- and third-line treatment for advanced non-small-cell lung cancer: support for the content validity of the 4-item Pulmonary Symptom Index. AB - BACKGROUND: In advanced non-small-cell lung cancer (NSCLC), reducing symptoms can be a meaningful treatment outcome. This study characterizes the pulmonary symptoms of patients receiving second- and third-line systemic therapies for NSCLC and assesses the content validity of the 4-item Pulmonary Symptom Index (PSI) of the Functional Assessment of Cancer Therapy-Lung (FACT-L). METHODS: Twenty patients with advanced NSCLC undergoing second- and third-line treatment ("qualitative sample") completed semistructured interviews regarding their NSCLC symptoms and the importance of pulmonary symptoms. Results were mapped to the PSI. In addition, existing PSI data from 912 patients with cancer ("validation sample") was analyzed to evaluate the scalability of the 4 PSI items. RESULTS: In the qualitative sample, mean age was 62 years (range 30-79 years); 80% had nonsquamous histologic type, and 25% had comorbid chronic obstructive pulmonary disease (COPD). A core set of pulmonary symptoms emerged in the data-shortness of breath, cough, and chest tightness. These mapped to 3 PSI items. A quarter of the patients reported an absence of pulmonary symptoms, which supports the inclusion of the final PSI item, "breathing is easy." In the validation sample, for the shortness of breath/breathing ease item pair, weighted kappa representing chance adjusted agreement ranged from 0.39 to 0.54 and percent agreement from 44% to 49% (both considered moderate), supporting a distinct contribution of each item. CONCLUSION: The PSI captures the most important and relevant symptoms reported by patients with NSCLC receiving second- and third-line treatment. Our results suggest that the PSI may provide a clinically useful method to measure patient benefit from lung cancer therapies. PMID- 23036664 TI - A new gene superfamily of pathogen-response (repat) genes in Lepidoptera: classification and expression analysis. AB - Repat (REsponse to PAThogens) genes were first identified in the midgut of Spodoptera exigua (Lepidoptera: Noctuidae) in response to Bacillus thuringiensis and baculovirus exposure. Since then, additional repat gene homologs have been identified in different studies. In this study the comprehensive larval transcriptome from S. exigua was analyzed for the presence of novel repat-homolog sequences. These analyses revealed the presence of at least 46 repat genes in S. exigua, establishing a new gene superfamily in this species. Phylogenetic analysis and studies of conserved motifs in these hypothetical proteins have allowed their classification in two main classes, alphaREPAT and betaREPAT. Studies on the transcriptional response of repat genes have shown that alphaREPAT and betaREPAT differ in their sequence but also in the pattern of regulation. The alphaREPAT were mainly regulated in response to the Cry1Ca toxin from B. thuringiensis but not to the increase in the midgut microbiota load. In contrast, betaREPAT were neither responding to Cry1Ca toxin nor to midgut microbiota. Differential expression between midgut stem cells and the whole midgut tissue was studied for the different repat genes revealing changes in the gene expression distribution between midgut stem cells and midgut tissue in response to midgut microbiota. This high diversity found in their sequence and in their expression profile suggests that REPAT proteins may be involved in multiple processes that could be of relevance for the understanding of the insect gut physiology. PMID- 23036665 TI - Visual cue learning and odometry in guiding the search behavior of desert ants, Melophorus bagoti, in artificial channels. AB - Terrestrial panoramic cues, path integration and search behavior are the main navigational strategies used by ants to locate food and find their way back to the nest. Searching becomes important when the other navigational cues are either not available or cannot provide sufficient information to pinpoint the goal. When searching in one-dimensional channels Melophorus bagoti ants exhibit a systematic drift in the starting-point-to-goal direction as they turn back and forth, sometimes past the goal location (Narendra et al., 2008). Here we show that this drift in channels is not a stereotypical part of the search behavior in these ants. It rather depends on the conditions of training. In experiments in which the nest entrance is located not at the end but at the side of the channel, forward drift is not always part of the nest search. Experiments on food searches showed that with the food source at the end of the channel, ants performed a linear drift in the starting-point-to-food direction. With food at the side of the channel, they showed a less pronounced drift toward the food source. In this constrained environment, especially with the goal at the end of the channel, ants seem to learn a routine such as 'run along the channel', and mix this routine with their usual strategy of turning back and forth in search. PMID- 23036666 TI - Specializations of birds that attend army ant raids: an ecological approach to cognitive and behavioral studies. AB - Tropical birds forage at army ant raids on several continents. Obligate foraging at army ant raids evolved several times in the Neotropical true antbird family (Thamnophilidae), and recent evidence suggests a diversity of bird species from other families specialize to varying degrees on army ant exploitation. Army ant raids offer access to high prey densities, but the ant colonies are mobile and widely spaced. Successful army ant exploitation requires solving a complex foraging problem because army ant raids are unpredictable in space and time. Birds can counteract the challenges posed by the ants by using strategies that raise their chances of detecting army ant raids, and birds can use additional strategies to track army ant colonies they have located. Some features of army ant biology, such as their conspicuous swarms and columns, above-ground activity, and regular cycles of behavior, provide opportunities for birds to increase their effectiveness at exploiting raids. Changes in sensory, cognitive and behavioral systems may all contribute to specialized army ant exploitation in a bird population. The combination of specializations that are employed may vary independently among bird species and populations. The degree of army ant exploitation by birds varies geographically with latitude and elevation, and with historical patterns such as centers of distribution of obligate thamnophilid antbirds. We predict the set of specializations a given bird population exhibits will depend on local ecology, as well as phylogenetic history. Comparative approaches that focus on these patterns may indicate ecological and evolutionary factors that have shaped the costs and benefits of this foraging strategy. The development of army ant exploitation in individual birds is poorly understood, and individual expression of these specializations may depend on a combination of genetic adaptation with cognitive plasticity, possibly including social and experiential learning. Future studies that measure developmental changes and quantify individual differences in army ant exploitation are needed to establish the mechanisms underlying this behavior. PMID- 23036667 TI - The pursuit of ideal cardiovascular health: an individual and societal challenge. PMID- 23036668 TI - Integrating value assessment into discussions about the price of cancer drugs. PMID- 23036669 TI - The high cost of cancer drugs and what we can do about it. PMID- 23036670 TI - Ideal cardiovascular health and mortality: Aerobics Center Longitudinal Study. AB - OBJECTIVE: To analyze the relationship of ideal cardiovascular health to disease specific death. PATIENTS AND METHODS: We used data from the Aerobics Center Longitudinal Study from October 9, 1987, to March 3, 1999, to estimate the prevalence of ideal cardiovascular health in 11,993 individuals (24.3% women) and to examine its relationship with deaths from all causes, cardiovascular disease (CVD), and cancer. RESULTS: During a mean follow-up of 11.6 years, 305 deaths occurred: 70 (23.0%) from CVD and 127 (41.6%) from cancer. In the entire cohort, only 29 individuals (0.2%) had 7 ideal metrics. After adjusting for age, sex, examination year, alcohol intake, and parental history of CVD, risk of death due to CVD was 55% lower in those participants who met 3 or 4 ideal metrics (hazard ratio, 0.45; 95% confidence interval, 0.27-0.77) and 63% lower in those with 5 to 7 ideal metrics (hazard ratio, 0.37; 95% confidence interval, 0.15-0.95), compared with those who met 0 to 2 ideal metrics. Although not significant, there was also a trend toward lower risk of death due to all causes across incremental numbers of ideal metrics. No association was observed for deaths due to cancer. CONCLUSION: The prevalence of ideal cardiovascular health was extremely low in a middle-aged cohort of men and women recruited between 1987 and 1999. The American Heart Association construct reflects well the subsequent risk of CVD, as reflected by graded CVD mortality in relation to the number of ideal metrics. PMID- 23036671 TI - Chronic medical conditions as risk factors for herpes zoster. AB - OBJECTIVE: To determine the degree to which chronic conditions might contribute to the unexplained burden of herpes zoster. METHODS: We conducted a case-control study using MarketScan data from January 1, 2007, through December 31, 2007, to investigate chronic conditions as risk factors for herpes zoster among persons 20 to 64 years old. Cases were enrollees with a herpes zoster diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification codes 053.xx), and controls were those without a herpes zoster diagnosis, matched by age groups and insurance plan. We selected 10 chronic conditions based on their prevalence in the general population. We calculated the attributable fraction and created a comorbidity composite score by summing the significant coefficient of regression of chronic conditions. We used logistic regression to evaluate the associations between herpes zoster and chronic conditions. RESULTS: We identified a total of 59,173 cases and 616,177 controls for the analysis. Risk of herpes zoster was significant for 8 of the 10 study conditions (odds ratios, 1.06-1.52). Herpes zoster risk also increased as a function of comorbidity composite score. The attributable fractions for these 8 significant conditions ranged from 0.24% to 2.89%. CONCLUSION: The risk of herpes zoster may be increased in people with chronic conditions. However, this risk may not contribute substantially to the burden of herpes zoster in the population. The causes for most cases of herpes zoster remain unknown. PMID- 23036672 TI - Melanoma brain metastases and vemurafenib: need for further investigation. AB - Brain metastases are a major cause of morbidity and mortality in patients with advanced melanoma. With the development of targeted agents for the treatment of metastatic melanoma, a great deal of interest has focused on whether selective BRAF inhibitors may play a role in the treatment of brain metastases in lieu of or in addition to surgery and/or radiation therapy. However, relatively little is known about the intracranial effectiveness of vemurafenib, the only US Food and Drug Administration-approved selective BRAF V600E inhibitor, because patients with brain metastases have historically been excluded from vemurafenib clinical trials. We describe 3 patients with BRAF V600E mutation metastatic melanoma in whom treatment with vemurafenib resulted in prompt extracranial disease response but progression of metastatic disease in the brain. Further, we discuss possible mechanisms responsible for the suboptimal central nervous system response observed in these patients and alternative therapies for patients with melanoma metastatic to the brain. PMID- 23036674 TI - 66-year-old woman with painless jaundice. PMID- 23036673 TI - Melanoma in immunosuppressed patients. AB - The immunogenic characteristics of malignant melanoma are intriguing. To date, multiple studies exist regarding the immunogenicity of melanoma. In this article, we summarize data in the literature on the role of immunosuppression in melanoma and discuss several immunocompromised patient populations in detail. A comprehensive PubMed search was conducted with no date limitation. The following search terms were used: melanoma in combination with immunosuppression, immunocompromised, genetics, antigen processing, UV radiation, organ transplantation, organ transplant recipients, lymphoproliferative disease, lymphoma, CLL, NHL, radiation, and HIV/AIDS. Although no formal criteria were used for inclusion of studies, most pertinent studies on the topic were reviewed, with the exception of smaller case reports and case series. The included studies were generally large (>= 1000 patients in organ transplant recipient studies; >= 500 patients in lymphoma studies), with a focus on institutional experiences, or population-based national or international epidemiologic studies. Melanoma induced immunosuppression, the role of UV radiation in melanoma development, and the epidemiology, clinical course, and prognosis of melanoma in immunocompromised patients are highlighted. Organ transplant recipients, patients with lymphoproliferative disorders, patients with iatrogenic immunosuppression, and patients with human immunodeficiency virus infection/AIDS are also highlighted. Recommendations are proposed for the care and monitoring of immunosuppressed patients with melanoma. With better understanding of the molecular microenvironment and clinical course of melanoma in immunosuppressed patients, novel therapies could be developed and outcomes potentially affected in these patients. PMID- 23036675 TI - Polyclonal immunoglobulin free light chain and chronic inflammation. PMID- 23036676 TI - Changes in serum prostate-specific antigen levels. PMID- 23036678 TI - Levamisole toxicity. PMID- 23036681 TI - Benzodiazepine oncogenesis as mediated via diminished restorative sleep effected sympathoadrenal activation. PMID- 23036683 TI - Sidney Altman--Nobel laureate for work with RNA. PMID- 23036685 TI - Pulmonary Kaposi sarcoma in AIDS. PMID- 23036687 TI - Can we better understand the known variations in coronary arterial anatomy? AB - Coronary arterial anatomy is remarkably diverse. Identification of surgical risk factors, however, requires description in a uniform fashion. Such description mandates that account be given of both aortic sinusal origin and variability in aortopulmonary relationships. Currently, however, it is rare to find all this information provided either in clinical reports or published reviews. In this review, therefore, we summarize why both these features are important, emphasizing the marriage of convenience between the aortic root position within the cardiac base and the arrangement of the epicardial coronary arteries. The inductive approach accounts for all potential variations. PMID- 23036686 TI - Analysis of the arrhythmogenic substrate in human heart failure. AB - BACKGROUND: The mechanism of sudden cardiac death in patients with heart failure (HF) is uncertain. Both electrical instability and structural remodelling could be factors that lead to fatal arrhythmias. We sought to analyse the expression of the sodium (SCN5A) and potassium (KCND3) channels as well as the fibrosis content in the ventricles of human HF and of non-diseased hearts under different post mortem intervals. METHODS AND RESULTS: We analysed normal human hearts as controls [n=20 for the right ventricle (RV) and n=13 for the left ventricle (LV)] and human hearts from HF patients, which were obtained at the time of cardiac transplantation, as cases (n=48 for RV and n=34 for LV). Transcription of the SCN5A (probes SCN5A E4-5, E11-12, and E28) and KCND3 channels and of COLLAGEN I and III were assayed by real-time polymerase chain reaction. In addition, paraffin sections were used to analyse the percentage of collagen deposition in both cases and controls. KCND3 mRNA expression in the LV was lower in the cases than in controls (P<.001). Higher levels of SCN5A mRNA were found in the HF samples when analysed with probe SCN5A E4-5 (P<.05). SCN5A expression was lower in the controls with longer post-mortem interval (n=4) than in the controls with a shorter post- mortem interval (n=16, P<.01). KCND3 mRNA levels were also different between the two control groups (P<.05). Collagen deposition was higher in the LV tissues of the cases when compared to controls (P<.001), and it was higher in the LV from HF patients than in the RV (P<.05). Furthermore, collagen deposition was higher in the LV samples from patients with implanted cardiac defibrillator (ICD) therapy than in the LV of patients with no ICD therapy (P<.05). CONCLUSIONS: These data indicate that ionic and structural remodelling could be pathophysiological mechanisms of cardiac arrhythmias in HF patients. PMID- 23036688 TI - Using social network analysis to examine collaborative relationships among PhD and DNP students and faculty in a research-intensive university school of nursing. AB - The nursing profession has seen a dramatic rise in the number of schools offering both DNP and PhD nursing programs. Information is limited on the impact of this parallel approach in doctoral education on the quality and scope of scholarly interactions or institutional culture.The authors studied collaboration characteristics across the DNP and PhD programs of a research-intensive university school of nursing, before and after programmatic enhancements. An IRB approved online survey was delivered to faculty and students of both programs at baseline and one year after curricular changes. Response rates were 70% and 74%, respectively. The responses were analyzed by using social network analysis and descriptive statistics to characterize the number and strength of connections between and within student groups, and between students and faculty. At baseline, the flow of communication was centralized primarily through faculty. At Time 2, density of links between students increased and network centralization decreased, suggesting more distributed communication. This nonlinear quantitative approach may be a useful addition to the evaluation strategies for doctoral education initiatives. PMID- 23036689 TI - Scholarly nursing practice from the perspectives of early-career nurses. AB - Although clinical scholarship is an espoused professional ideal, how nurses develop and maintain a scholarly approach to nursing practice throughout different stages of their careers is not well understood. This qualitative study describes early-career nurses' accounts of pursuing professional practice as a scholarly endeavor. Semi-structured interviews were conducted with 18 early career nurses purposively sampled from an ANCC Magnet-designated tertiary-care facility. The data were analyzed using content analysis. Findings center on four major themes. I Need Skills First and My Practice Evolves explain how early career nurses conceptualized their practice in its initial stage. I Think I Know What It Looks Like and I Am Not There Yet reflect their assessment of how their current practice level in comparison with their understanding of scholarly nursing practice. Nursing needs requires a new scholarly practice development paradigm for a multistage career beginning with a concerted focus on the critical first stage of practice. PMID- 23036690 TI - Perinatal and pediatric issues in palliative and end-of-life care from the 2011 Summit on the Science of Compassion. AB - More than 25,000 infants and children die in US hospitals annually; 86% occur in the NICU or PICU. Parents see the child's pain and suffering and, near the point of death, must decide whether to resuscitate, limit medical treatment, and/or withdraw life support. Immediately after the death, parents must decide whether to see and/or hold the infant/child, donate organs, agree to an autopsy, make funeral arrangements, and somehow maintain functioning. Few children and their families receive pediatric palliative care services, especially those from minority groups. Barriers to these programs include lack of services, difficulty identifying the dying point, discomfort in withholding or withdrawing treatments, communication problems, conflicts in care among providers and between parents and providers, and differences in cultural beliefs about end-of-life care. The 2011 NIH Summit on the Science of Compassion provided recommendations in family involvement, end-of-life care, communication, health care delivery, and transdisciplinary participation. PMID- 23036691 TI - Health care transition for adolescents with special healthcare needs: where is nursing? AB - The population of adolescents with special healthcare needs (ASHCN) surviving into adulthood has increased dramatically over the past two decades. Approximately, nine of every 10 children diagnosed with a chronic condition are expected to reach adulthood. Experts estimate nearly 750,000 ASHCN enter into adulthood each year. Advances in medical treatments, new technologies and scientific discoveries have all contributed to the increases in ASHCN life expectancies. As a result, new demands for services have emerged to address their clear needs for long-term services and supports. Foremost among the ASHCN service needs are healthcare transition services. Healthcare transition is recognized as a needed area of practice to facilitate ASHCN transfer of care from pediatric to adult healthcare and to support the acquisition of the developmental competencies needed to successfully transition to adulthood. Yet, few evidence-based and exemplary models of care exist. Healthcare transition research is in the early stages of development. The medical community has provided the leadership with the development of healthcare transition policy, practice, and research. As a result, policymaking, practice issues, and research have a prominent medically related focus. In contrast, the influence of nursing as it pertains to these areas of professional practice is limited. Opportunities exist for pediatric and child health nursing leaders to provide direction for greater involvement in this emerging and growing field of specialty practice. PMID- 23036692 TI - TLR4-mediated IL-12 production enhances IFN-gamma and IL-1beta production, which inhibits TGF-beta production and promotes antibody-induced joint inflammation. AB - INTRODUCTION: Toll-like receptor (TLR)4 promotes joint inflammation in mice. Despite that several studies report a functional link between TLR4 and interleukin-(IL-)1beta in arthritis, TLR4-mediated regulation of the complicated cytokine network in arthritis is poorly understood. To address this, we investigated the mechanisms by which TLR4 regulates the cytokine network in antibody-induced arthritis. METHODS: To induce arthritis, we injected mice with K/BxN serum. TLR4-mediated pathogenesis in antibody-induced arthritis was explored by measuring joint inflammation, cytokine levels and histological alteration. RESULTS: Compared to wild type (WT) mice, TLR4-/- mice showed attenuated arthritis and low interferon (IFN)-gamma, IL-12p35 and IL-1beta transcript levels in the joints, but high transforming growth factor (TGF)-beta expression. Injection of lipopolysaccharide (LPS) enhanced arthritis and exaggerated joint cytokine alterations in WT, but not TLR4-/- or IL-12p35-/- mice. Moreover, STAT4 phosphorylation in joint cells and intracellular IL-12p35 expression in macrophages, mast cells and Gr-1+ cells were detected in WT mice with arthritis and enhanced by LPS injection. Therefore, IL-12p35 appears to act downstream of TLR4 in antibody-induced arthritis. TLR4-mediated IL-12 production enhanced IFN-gamma and IL-1beta production via T-bet and pro-IL-1beta production. Recombinant IL-12, IFN-gamma and IL-1beta administration restored arthritis, but reduced joint TGF-beta levels in TLR4-/- mice. Moreover, a TGF-beta blockade restored arthritis in TLR4-/- mice. Adoptive transfer of TLR4-deficient macrophages and mast cells minimally altered joint inflammation and cytokine levels in macrophage- and mast cell-depleted WT mice, respectively, whereas transfer of WT macrophages or mast cells restored joint inflammation and cytokine expression. Gr-1+ cell-depleted splenocytes partially restored arthritis in TLR4 /- mice. CONCLUSION: TLR4-mediated IL-12 production by joint macrophages, mast cells and Gr-1+ cells enhances IFN-gamma and IL-1beta production, which suppresses TGF-beta production, thereby promoting antibody-induced arthritis. PMID- 23036693 TI - Identification of a new species of digenean Notocotylus malhamensis n. sp. (Digenea: Notocotylidae) from the bank vole (Myodes glareolus) and the field vole (Microtus agrestis). AB - Notocotylus malhamensis n. sp. is described from the caecum of the bank vole (Myodes glareolus) and the field vole (Microtus agrestis) from Malham Tarn Nature Reserve in North Yorkshire, UK. In total, 581 specimens were collected from rodents trapped at a wetland site (Tarn Fen) between July 2010 and October 2011 with a prevalence of 66.7% and mean intensity of 94.6 in the bank vole and 50% prevalence and a mean intensity of 4.3 in the field vole. This species appears to be most closely related to other previously described Notocotylus species infecting rodents in Europe but differs principally by the metraterm to cirrus sac ratio (1:1.5-1:1.2) in combination with a densely spinulated cirrus, simple caeca and a greater number of ventral glands in the lateral rows (14-17). The use of molecular differentiation was of limited use in this study due to a paucity of relevant information in the DNA sequence databases. However, the complete ITS1 5.8S rDNA-ITS2 and partial 28S gene sequences have been generated to provide a definitive tool for identification of this species in future studies. As far as we know this is the first report of a notocotylid infection in M. glareolus in the UK. PMID- 23036694 TI - Effects of intravenous diazepam on high-frequency oscillations in EEGs with CSWS. AB - High-frequency oscillations (HFOs) associated with continuous spike-waves during slow-wave sleep (CSWS) are speculated to be linked to the disturbance of higher brain function. We intended to investigate the generative mechanisms of HFOs in CSWS by clarifying the effects of intravenous injection (IV) of diazepam (DZP), an agonist for the gamma-aminobutyric acid A (GABAA) receptor in the GABAergic interneuron system, in patients who had previously been treated with IV DZP. The subjects were three patients with epilepsy with CSWS. For each patient, EEG data before and after IV DZP were separated into consecutive 5-min sections. Time frequency power spectral analysis was performed on the spikes of each section, and peak-power and frequency of detected high-frequency spectral spots were compared before and after IV DZP. Spectral spots with peak-frequencies at 85.9 121.1Hz in the ripple band were revealed in all three patients. Although the amplitudes of the spikes largely returned to the baseline levels 20-25min after IV DZP, the recovery of the peak-power levels of HFOs lagged behind that of the spike amplitudes, and the power levels of HFOs were lower than the baseline data within 25min after the injection of DZP. No consistent changes were found regarding the spectral frequencies of HFOs. The dissociation of the effect of IV DZP in terms of recovery when comparing spike-amplitudes and the power of HFOs may correspond to an already suggested difference in the pathophysiological mechanisms that generate the spikes and HFOs. PMID- 23036695 TI - [Risk of thromboembolic phenomena in patients with inflammatory bowel disease]. AB - INTRODUCTION: Inflammatory bowel disease (IBD) is an independent risk factor for thromboembolic phenomena (TEP). We evaluated the prevalence and the possible risk factors associated with developing TEP in patients with IBD in our center. MATERIAL AND METHODS: Data were retrospectively collected from January 1995 to December 2011 from 23 patients. A total of 61% were diagnosed with Crohn's disease (CD) and 39% with ulcerative colitis (UC) according to routine criteria. RESULTS: When the Montreal classification was used, 58% of the patients with CD had an inflammatory pattern (B1), 25% a stenosing pattern (B2) and 17% a fistulizing pattern (B3). Half the patients had ileocolic involvement (L3), one third had colonic involvement (L2) and the remainder had ileal involvement (L1). Among patients with UC according to the Montreal classification, 78% had extensive colitis (E3), 11% had left colonic involvement (E2) and 11% had proctocolitis (E1). During the event, almost half the patients with UC had severe inflammatory activity (S3; 44%), 33% had mild-moderate activity (S1: 22%, S2: 11%) and only 22% were in remission (S0). Overall, at the time of the TEP, 48% of the patients had mild-moderate activity and 22% had severe activity. Likewise, 44% were hospitalized at the time of the event. In UC, an increase in the prevalence of TEP was found in admitted patients (66%). None of the patients had a family history of TEP, two patients (9%) had associated thrombophilia and 26% were active smokers. There were no TEP during pregnancy. Only one patient was taking contraceptive pills when the event occurred. The most frequent forms of TEP were deep vein thrombosis of the legs (55%) followed by pulmonary thromboembolism (25%). CONCLUSIONS: TEP are relatively frequent in patients with IBD, with a strong impact on morbidity and mortality. In our series, risk factors for these events were more extensive involvement (any of the groups) and severe inflammatory activity. No significant association between classical risk factors such as the use of contraceptives, pregnancy, coagulation disorders or smoking and the risk of TEP were found. PMID- 23036696 TI - Acquired genomic copy number changes in CML patients with the Philadelphia chromosome (Ph+). AB - Chronic myeloid leukemia (CML) is characterized by the BCR-ABL1 fusion gene; this fusion gene is usually a consequence of the Philadelphia (Ph(+)) chromosome, which results from the t(9;22)(q34;q11.2). Patients newly diagnosed with CML are routinely treated with tyrosine kinase inhibitors; however, the clinical course of the disease can vary, and this variance may be associated with genetic heterogeneity. Array comparative genomic hybridization (CGH) technology is a powerful tool for identifying subtle genomic segmental alterations, which can result from either losses or gains of chromosomal material. These changes may reveal the presence of genes that play important roles in disease initiation or progression or in treatment outcomes. To investigate whether subtle somatic copy number changes (CNCs) are commonly present in CML patients, a pilot study of 19 patients with the Ph(+) chromosome, but who were negative for common secondary chromosomal anomalies [+der(22), +8, i(17q), and +19], was conducted using a high density whole genomic oligonucleotide array CGH analysis. Four of the 19 cases had somatic segmental CNCs, including the loss of 9q34, 15q25.3, and 15q13 and a gain of 7p21.1-p15.3. The findings demonstrate that subtle genomic changes are relatively common in CML patients with a Ph(+) chromosome and that the clinical significance of these findings, especially the newly discovered regions, must be determined in large patient population studies. PMID- 23036697 TI - Heterozygous loss of NF2 is an early molecular alteration in well-differentiated papillary mesothelioma of the peritoneum. AB - Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare disease, and many cases are either benign neoplasms or low-graded malignancies; however, a few cases show rapid progressive clinical courses. No effective therapy has yet been established for WDPMP, and the molecular basis of WDPMP tumorigenesis has never been reported. This study shows the malignant transformation of WDPMP in a Japanese female patient, who was alive for 54 months after the initial diagnosis by a laparoscopic biopsy. A molecular analysis of single nucleotide polymorphisms (SNPs), which were located in the neurofibromatosis type 2 (NF2) gene, a tumor suppressor gene assigned to chromosome 22q12.3, revealed the loss of heterozygosity (LOH) of the NF2 gene. Furthermore, SNP analyses determined that LOH was observed in the IL17RA (22q11.1), CHECK2 (22q12.1), and SHANK3 (22q13.3) genes, thus suggesting that NF2 loss occurred through 22q deletions or monosomy 22. The LOH of the NF2 gene was observed in an early stage of WDPMP, thus indicating that LOH of the NF2 gene is an early molecular alteration, and NF2 loss is a molecular mechanism associated not only with malignant pleural mesothelioma, but also with WDPMP. PMID- 23036698 TI - Hepatic steatosis, carotid plaques and achieving MDA in psoriatic arthritis patients starting TNF-alpha blockers treatment: a prospective study. AB - INTRODUCTION: We prospectively evaluated whether hepatic steatosis (HS) and the presence of carotid plaques (CPs) impacts on achieving minimal disease activity (MDA) in psoriatic arthritis (PsA) patients starting tumor necrosis factor (TNF) alpha blockers treatment. METHODS: Before starting treatment with TNF-alpha blockers, consecutive PsA subjects with an active disease were evaluated for the presence of the metabolic syndrome (MetS), HS and CPs. The incidence of MDA was evaluated 12 and 24 months later. RESULTS: Among 270 PsA subjects, 91 (33.7%) exhibited the MetS, 58 (21.5%) CPs and 76 (28.1%) HS. At the 12-month follow-up, 98 (36.3%) individuals achieved MDA. Compared with those who did, a higher prevalence of the MetS, HS and CPs was found in subjects who did not achieve the MDA (P always < 0.001). After adjusting for the MetS and for all the other demographic/clinical characteristics analyzed, the presence of HS and CPs at baseline independently predicted the risk of not achieving MDA (Hazard Ratio: 1.91, 95% confidence interval (CI): 1.04 to 3.38, P = 0.035 and Hazard Ratio: 3.21, 95%CI: 1.64 to 6.29, P = 0.001, respectively). Separate Kaplan-Meier survival models confirmed this (Log-Rank: 12.894, P < 0.001 and Log-Rank: 12.849, P < 0.001, respectively). Compared with those without, progressively increasing Hazard Ratios of not achieving MDA were found in those with HS, CPs or HS + CPs at baseline. Moreover, the presence of HS and/or CPs predicted the risk of relapse during the additional 12-month follow-up (Hazard Ratio: 2.85, 95%CI: 1.27 to 6.37, P = 0.011 and Hazard Ratio: 3.17, 95%CI: 1.57 to 6.41, P = 0.001 respectively). CONCLUSIONS: HS and/or CPs at baseline are negative predictors of achieving and maintaining MDA. PMID- 23036699 TI - DRD1 rs4532 polymorphism: a potential pharmacogenomic marker for treatment response to antipsychotic drugs. AB - We investigated the association of dopamine receptor D1 gene (DRD1) rs4532 polymorphism with antipsychotic treatment response in schizophrenia. We have analyzed 124 patients with schizophrenia, consisting of 59 treatment resistant (TR) and 65 non-TR. We found an association between G-allele and TR schizophrenia (p=0.001; adjusted OR=2.71). Setting the common AA-genotype as reference, the GG homozygous presented a five-fold risk compared to AA-homozygous (p=0.010; OR=5.56) with an intermediate result for AG-genotype (p=0.030; adjusted OR=2.64). The DRD1 rs4532 polymorphism showed a dose-response gradient with increased risk for treatment resistance and may be a potential pharmacogenetic marker for antipsychotic drug treatment response. PMID- 23036700 TI - Nanoparticle-specific changes in Arabidopsis thaliana gene expression after exposure to ZnO, TiO2, and fullerene soot. AB - The effect of exposure to 100 mg/L zinc oxide (nZnO), fullerene soot (FS) or titanium dioxide (nTiO(2)) nanoparticles on gene expression in Arabidopsis thaliana roots was studied using microarrays. After 7d, nZnO, FS, or nTiO(2) exposure resulted in 660 up- and 826 down-regulated genes, 232 up- and 189 down regulated genes, and 80 up- and 74 down-regulated genes, respectively (expression difference>2-fold; p[t test]<0.05). The genes induced by nZnO and FS include mainly ontology groups annotated as stress responsive, including both abiotic (oxidative, salt, water deprivation) and biotic (wounding and defense to pathogens) stimuli. The down-regulated genes upon nZnO exposure were involved in cell organization and biogenesis, including translation, nucleosome assembly and microtubule based process. FS largely repressed the transcription of genes involved in electron transport and energy pathways. Only mild changes in gene expression were observed upon nTiO(2) exposure, which resulted in up- and down regulation of genes involved mainly in responses to biotic and abiotic stimuli. The data clearly indicate that the mechanisms of phytotoxicity are highly nanoparticle dependent despite of a limited overlap in gene expression response. PMID- 23036701 TI - Magnetic composites based on metallic nickel and molybdenum carbide: a potential material for pollutants removal. AB - New magnetic composites based on metallic nickel and molybdenum carbide, Ni/Mo(2)C, have been produced via catalytic chemical vapor deposition from ethanol. Scanning electron microscopy, thermal analysis, Raman spectroscopy and X ray diffraction studies suggest that the CVD process occurs in a single step. This process involves the reduction of NiMo oxides at different temperatures (700, 800 and 900 degrees C) with catalytic deposition of carbon from ethanol producing molybdenum carbide on Ni surface. In the absence of molybdenum the formation of Ni/C was observed. The magnetic molybdenum carbide was successfully used as pollutants removal by adsorption of sulfur and nitrogen compounds from liquid fuels and model dyes such as methylene blue and indigo carmine. The dibenzothiofene adsorption process over Ni/Mo(2)C reached approximately 20 mg g( 1), notably higher than other materials described in the literature and also removed almost all methylene blue dye. The great advantage of these carbide composites is that they may be easily recovered magnetically and reused. PMID- 23036702 TI - Competitive adsorption of Reactive Orange 16 and Reactive Brilliant Blue R on polyaniline/bacterial extracellular polysaccharides composite--a novel eco friendly polymer. AB - The performance of polyaniline/extracellular polymeric substances (Pn/EPS) composite as an adsorbent to remove the anionic reactive dyes, Reactive Brilliant Blue R (RBBR) and Reactive Orange 16 (RO), was investigated in single and binary systems. The pH(pzc) of Pn/EPS composite was calculated as 3.7 through potentiometric mass titration method. Electrostatic interaction between the dye anion and the nitrogen present in the polymer was identified as a major mechanism in adsorption process. Single component isotherms followed the Langmuir model with the maximum adsorption capacity of 0.5775 mmol g(-1) for RBBR and 0.4748 mmol g(-1) for RO. In binary system, both the reactive dye anions compete with each other and resulted in lower uptake. Binary adsorption data were interpreted well by the Sheindorf-Rehbun-Sheintuch equation as compared to extended Langmuir model with constant interaction factor. Kinetic analysis of single solute followed pseudo-first order model. Thermodynamic studies computed that RBBR and RO adsorption was endothermic, spontaneous, and feasible process. PMID- 23036703 TI - An integrated computational and experimental study for overproducing fatty acids in Escherichia coli. AB - Increasing demands for petroleum have stimulated sustainable ways to produce chemicals and biofuels. Specifically, fatty acids of varying chain lengths (C6 C16) naturally synthesized in many organisms are promising starting points for the catalytic production of industrial chemicals and diesel-like biofuels. However, bio-production of fatty acids from plants and other microbial production hosts relies heavily on manipulating tightly regulated fatty acid biosynthetic pathways. In addition, precursors for fatty acids are used along other central metabolic pathways for the production of amino acids and biomass, which further complicates the engineering of microbial hosts for higher yields. Here, we demonstrate an iterative metabolic engineering effort that integrates computationally driven predictions and metabolic flux analysis techniques to meet this challenge. The OptForce procedure was used for suggesting and prioritizing genetic manipulations that overproduce fatty acids of different chain lengths from C6 to C16 starting with wild-type E. coli. We identified some common but mostly chain-specific genetic interventions alluding to the possibility of fine tuning overproduction for specific fatty acid chain lengths. In accordance with the OptForce prioritization of interventions, fabZ and acyl-ACP thioesterase were upregulated and fadD was deleted to arrive at a strain that produces 1.70 g/L and 0.14 g fatty acid/g glucose (~39% maximum theoretical yield) of C14-16 fatty acids in minimal M9 medium. These results highlight the benefit of using computational strain design and flux analysis tools in the design of recombinant strains of E. coli to produce free fatty acids. PMID- 23036705 TI - Molecular and functional evolution of human DHRS2 and DHRS4 duplicated genes. AB - Human DHRS2 and DHRS4 genes code for similar NADP-dependent short-chain carbonyl reductase enzymes having different substrate specificity. Human DHRS2 and DHRS4 enzymes share several common sequence motives including residues responsible for coenzyme binding as well as for the intimate catalytic oxido-reductase mechanism, while their substrate-binding sequences have very low similarity. We found that DHRS2 and DHRS4 genes are syntenic outparalogues originated from a duplication of the DHRS4 gene that took place before the formation of the mammalian clade. DHRS2 gene evolved more rapidly and underwent positive selection on more sites than the DHRS4 gene. DHRS2 sites under positive selection were mainly located on the enzyme active site thus showing that substrate specificity drove the divergence from the DHRS4 enzyme. Rapid divergent evolution brought the human DHRS2 enzyme to have subcellular localization, synthesis regulation and specialized cellular functions very different from those of the human DHRS4 enzyme. PMID- 23036704 TI - A novel big protein TPRBK possessing 25 units of TPR motif is essential for the progress of mitosis and cytokinesis. AB - Through the comprehensive analysis of the genomic DNA sequence of human chromosome 22, we identified a novel gene of 702 kb encoding a big protein of 2481 amino acid residues, and named it as TPRBK (TPR containing big gene cloned at Keio). A novel protein TPRBK possesses 25 units of the TPR motif, which has been known to associate with a diverse range of biological functions. Orthologous genes of human TPRBK were found widely in animal species, from insecta to mammal, but not found in plants, fungi and nematoda. Northern blotting and RT-PCR analyses revealed that TPRBK gene is expressed ubiquitously in the human and mouse fetal tissues and various cell lines of human, monkey and mouse. Immunofluorescent staining of the synchronized monkey COS-7 cells with several relevant antibodies indicated that TPRBK changes its subcellular localization during the cell cycle: at interphase TPRBK locates on the centrosomes, during mitosis it translocates from spindle poles to mitotic spindles then to spindle midzone, and through a period of cytokinesis it stays on the midbody. Co immunoprecipitation assay and immunofluorescent staining with adequate antibodies revealed that TPRBK binds to Aurora B, and those proteins together translocate throughout mitosis and cytokinesis. Treatments of cells with two drugs (Blebbistatin and Y-27632), that are known to inhibit the contractility of actin myosin, disturbed the proper intracellular localization of TPRBK. Moreover, the knockdown of TPRBK expression by small interfering RNA (siRNA) suppressed the bundling of spindle midzone microtubules and disrupted the midbody formation, arresting the cells at G(2)+M phase. These observations indicated that a novel big protein TPRBK is essential for the formation and integrity of the midbody, hence we postulated that TPRBK plays a critical role in the progress of mitosis and cytokinesis during mammalian cell cycle. PMID- 23036706 TI - 5-aza-CdR induces the demethylation of Syk promoter in nasopharyngeal carcinoma cell. AB - The present study employed 5-aza-2'-deoxycytidine (5-aza-CdR) to treat nasopharyngeal carcinoma cell line CNE-1, CNE-2 and non-cancerous human nasopharyngeal epithelial cell line NP-69 to understand the effects on spleen tyrosine kinase (Syk) gene promoter methylation. The results showed that the methylation level of Syk gene is negatively associated with the differentiation level of the cell lines, and the 5-aza-CdR treatment decreased the methylation level in nasopharyngeal carcinoma cell lines. Additionally, the drug sensitivity of low-differentiated cell line was significantly higher than the high differentiated cell line. In conclusion, the Syk gene promoter methylation reflects the cell differentiation status, and 5-aza-CdR treatment could induce the demethylation of Syk gene promoter. PMID- 23036708 TI - Association of MTHFR and PPARgamma2 gene polymorphisms in relation to type 2 diabetes mellitus cases among north Indian population. AB - BACKGROUND: Type 2 diabetes mellitus is a multifactorial and polygenic disease, which is considered as a major life threatening problem all over the world. There has been a worldwide effort in the identification of susceptibility genes for type 2 diabetes mellitus and its complications. At present, adequate data is not available dealing with MTHFR (rs1801133) and PPARgamma2 (rs1801282) gene polymorphisms and its association with type 2 diabetes mellitus cases among north Indian populations. Thus, we conceived the need for further studies to investigate MTHFR and PPARgamma2 gene polymorphisms and their susceptibility to type 2 diabetes mellitus in north Indian population. MATERIALS AND METHODS: In this study, a total 175 subjects including 87 type 2 diabetes mellitus cases and 88 controls were enrolled. MTHFR and PPARgamma2 gene polymorphisms in the cases and controls were evaluated by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). RESULTS: The MTHFR gene CC, CT, TT genotype frequencies obtained were 40%, 43%, and 17% in type 2 diabetes mellitus cases and 56%, 29%, and 15% in healthy controls respectively. The OR for CC was 0.54 (95%CI 0.29-0.98, P=0.041, chi(2)=4.18, power=0.98), for CT 1.76 (95%CI 0.94-3.30, P=0.07, chi(2)=3.2, power=0.96), and for TT 1.2 (95%CI 0.53-2.70, P=0.66, chi(2)=0.198, power=0.76). The PPARgamma2 gene GG CG, CC genotype frequencies obtained were 28%, 41%, and 31% in cases and 40%, 39%, and 21% in healthy controls respectively. OR for GG was 0.58 (95%CI 0.30-1.09, P=0.08, chi(2)=2.9, power=0.96), for CG 1.12 (95%CI 0.61-2.05, P=0.71, chi(2)=0.137, power=0.778), and for CC 1.63 (95%CI 0.82-3.23, P=0.156, chi(2)=2.01, power=0.92). CONCLUSION: It might be recommended that MTHFR CC genotype seems to be a good marker for the early identification of population at risk of type 2 diabetes mellitus. While we have detected significant difference in allelic frequencies of PPARgamma2 C (Proline) and G (Alanine), but at genotypic level significant difference was not detected in this case-control study. Further study with larger groups may be required to validate the study. PMID- 23036707 TI - Comparative profiling of miRNA expression of lung adenocarcinoma cells in two dimensional and three-dimensional cultures. AB - Three-dimensional organotypic culture using reconstituted basement membrane matrix (rBM 3-D) is an invaluable tool to characterize morphogenesis of epithelial cells and to elucidate the tumor-modulating actions of extracellular matrix. microRNAs (miRNA) are a novel class of tumor modulating genes. A substantial amount of investigation of miRNAs in cancer is carried out using monolayer 2-D culture on plastic substratum, which lacks a consideration of the matrix-mediated regulation of miRNAs. In the current study we compared the expression of miRNAs in rBM 3-D and 2-D cultures of two lung adenocarcinoma cell lines. Our findings revealed a profound difference in miRNA profiles between 2-D and rBM 3-D cultures of lung adenocarcinoma cells. The rBM 3-D culture-specific miRNA profile was highlighted with higher expression of the tumor suppressive miRNAs (i.e., miR-200 family) and lower expression of the oncogenic miRNAs (i.e., miR-17-92 cluster and miR-21) than that of 2-D culture. Moreover, the expression pattern of miR-17, miR-21, and miR-200a in rBM 3-D culture correlated with the expression of their targets and acinar morphogenesis, a differentiation behavior of lung epithelial cells in rBM 3-D culture. Over-expression of miR-21 suppressed its target PTEN and disrupted acinar morphogenesis. In summary, we provide the first miRNA profile of lung adenocarcinoma cells in rBM 3-D culture with respect to acinar morphogenesis. These results indicate that rBM 3-D culture is essential to a comprehensive understanding of the miRNA biology in lung epithelial cells pertinent to lung adenocarcinoma. PMID- 23036709 TI - Effect of protein-tyrosine phosphatase 4A3 by small interfering RNA on the proliferation of lung cancer. AB - Previous studies on PTP4A3 mainly focused on tumor metastasis due to the close relationship between the overexpression of lung cancer and metastasis. However, the role of PTP4A3 in the proliferation of tumor still has remained unclear. To investigate the role of PTP4A3 in cell growth of lung cancer, we constructed PTP4A3-siRNA expressing lentivirus and infected human lung cancer H1299 cells, and then examined the inhibitory effect of PTP4A3 in vitro. The levels of PTP4A3 mRNA and protein in H1299 cells decreased after PTP4A3-siRNA lentivirus infection. The growth and colony formation of the infected cells were also inhibited, indicating that PTP4A3 gene is closely associated with the proliferation of H1299 cells. In addition, after PTP4A3 specific siRNA lentivirus infection, it was notable that whilst H1299 cells in G1 phase apparently reduced, both of H1299 cells in G2/M phase and the cell apoptosis increased significantly. This finding indicated the close relationship between PTP4A3 gene and apoptosis in the H1299 cells. These results come to their conclusion that PTP4A3 plays an important role in the growth of lung cancer cells. PTP4A3 may be considered as a valuable target for anti-tumor therapeutic strategies. PMID- 23036710 TI - Gene expression profiles displayed by peripheral blood mononuclear cells from patients with type 2 diabetes mellitus focusing on biological processes implicated on the pathogenesis of the disease. AB - Patients with type 2 diabetes mellitus (T2DM) exhibit insulin resistance associated with obesity and inflammatory response, besides an increased level of oxidative DNA damage as a consequence of the hyperglycemic condition and the generation of reactive oxygen species (ROS). In order to provide information on the mechanisms involved in the pathophysiology of T2DM, we analyzed the transcriptional expression patterns exhibited by peripheral blood mononuclear cells (PBMCs) from patients with T2DM compared to non-diabetic subjects, by investigating several biological processes: inflammatory and immune responses, responses to oxidative stress and hypoxia, fatty acid processing, and DNA repair. PBMCs were obtained from 20 T2DM patients and eight non-diabetic subjects. Total RNA was hybridized to Agilent whole human genome 4*44K one-color oligo microarray. Microarray data were analyzed using the GeneSpring GX 11.0 software (Agilent). We used BRB-ArrayTools software (gene set analysis - GSA) to investigate significant gene sets and the Genomica tool to study a possible influence of clinical features on gene expression profiles. We showed that PBMCs from T2DM patients presented significant changes in gene expression, exhibiting 1320 differentially expressed genes compared to the control group. A great number of genes were involved in biological processes implicated in the pathogenesis of T2DM. Among the genes with high fold-change values, the up-regulated ones were associated with fatty acid metabolism and protection against lipid-induced oxidative stress, while the down-regulated ones were implicated in the suppression of pro-inflammatory cytokines production and DNA repair. Moreover, we identified two significant signaling pathways: adipocytokine, related to insulin resistance; and ceramide, related to oxidative stress and induction of apoptosis. In addition, expression profiles were not influenced by patient features, such as age, gender, obesity, pre/post-menopause age, neuropathy, glycemia, and HbA(1c) percentage. Hence, by studying expression profiles of PBMCs, we provided quantitative and qualitative differences and similarities between T2DM patients and non-diabetic individuals, contributing with new perspectives for a better understanding of the disease. PMID- 23036711 TI - Mitochondrial DNA as effective molecular markers for the genetic variation and phylogeny of the family Osteoglossidae. AB - The present study examined the genetic variation of the family Osteoglossidae from different geographical locations based on the mitochondrial NADH dehydrogenase subunit 2 (ND2) and ATPase subunit 6 (ATPase6) genes; we then re constructed the phylogenetic relationships using the two sequences in combination. The results showed that the partial sequences of mitochondrial ND2 and ATPase6 of the family Osteoglossidae were 813 bp and 669 bp, respectively. A total of 42 species-specific nucleotide positions of the family Osteoglossidae were found to be useful for molecular identification. The sequence variation showed greater differences (8.3%~28.1% for the combined sequences, 8.3%~26.7% for the ND2 gene, and 9.3%~28.7% for the ATPase6 gene) among the different species of Osteoglossidae, and there was a significant association between the genetic difference and geographical location. Phylogenetic analyses using neighbor joining, Bayesian inference, and maximum parsimony (MP) methods based on the combined sequences of the two genes were able to distinguish the different species and were in agreement with the existing taxonomy based on morphological characters and in association with the geographical distribution among seven species of the family Osteoglossidae. PMID- 23036712 TI - Single nucleotide polymorphisms in genes that are common targets of luteotropin and luteolysin in primate corpus luteum: computational exploration. AB - Luteal insufficiency affects fertility and hence study of mechanisms that regulate corpus luteum (CL) function is of prime importance to overcome infertility problems. Exploration of human genome sequence has helped to study the frequency of single nucleotide polymorphisms (SNPs). Clinical benefits of screening SNPs in infertility are being recognized well in recent times. Examining SNPs in genes associated with maintenance and regression of CL may help to understand unexplained luteal insufficiency and related infertility. Publicly available microarray gene expression databases reveal the global gene expression patterns in primate CL during the different functional state. We intend to explore computationally the deleterious SNPs of human genes reported to be common targets of luteolysin and luteotropin in primate CL. Different computational algorithms were used to dissect out the functional significance of SNPs in the luteinizing hormone sensitive genes. The results raise the possibility that screening for SNPs might be integrated to evaluate luteal insufficiency associated with human female infertility for future studies. PMID- 23036713 TI - PPARgamma2 Pro12Ala polymorphism is associated with improved lipoprotein lipase functioning in adipose tissue of insulin resistant obese women. AB - Lipoprotein lipase (LPL) plays a pivotal role in lipid metabolism, contributes to metabolic disorders related to insulin action and body weight regulation, and is influenced by inflammation. The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)gamma2 gene seems to influence LPL functioning, but its role in obesity and insulin resistance status, which usually coexist in the clinical setting, has not been explored. Our aim was to analyze the association of obesity and insulin resistance with adipose LPL activity and expression, and the influence of the PPARgamma2 Pro12Ala polymorphism. A cross sectional study was conducted in 58 reproductive-age women who underwent elective abdominal surgery. Free-fatty acids, glucose, insulin, and selected adipokines were measured in fasting blood samples. DNA was isolated and the polymorphism genotyped. Biopsies of abdominal subcutaneous adipose tissue obtained during surgery were used to determine enzymatic LPL activity and expression; and expression of selected cytokines. Overweight/obese women presented lower LPL activity (P=0.022) and higher circulating TNF-alpha (P=0.020) than controls. Insulin resistant women also showed borderline lower LPL activity than non resistant (P=0.052), but adiposity and inflammatory molecules were comparable. Nevertheless, LPL activity was higher in Pro12Ala carriers than in non-carriers after adjusting for obesity, insulin resistance and inflammation. Likewise, adipose LPL expression was increased in carriers while expression of cytokines was decreased. Our data suggest that insulin resistance is associated with low adipose LPL activity independently of obesity, but the PPARgamma2 Pro12Ala polymorphism seems to protect the LPL functioning of obese insulin resistant women, likely through regulating inflammation in adipose tissue. PMID- 23036714 TI - Relevance of fluoroquinolone use in a French teaching hospital. AB - OBJECTIVE: The objective of our study was to assess the good use of fluoroquinolone (FQ) in a French teaching hospital by a two round relevance review before and after proposal for better use of FQ prescriptions. PATIENTS AND METHODS: The relevance of FQ prescription according to regional guidelines was assessed using a standard card filled out retrospectively by physicians in the 3 previous months, in volunteer hospital wards. Then, two experts checked the relevance of prescriptions according to the regional antibiotherapy guidelines, a book called "Antibioguide", and determined a therapeutic index of adequacy for each card. The first survey (R1) took place in January 2008. The second survey (R2) took place in June 2009 to evaluate the impact of corrective measures, adopted at a meeting of the regional antibiotics commission in January 2009. RESULTS: Physicians in 18 wards completed 475 cards in R1 and physicians in 16 wards completed 263 in R2. The inappropriateness of FQ indication was significantly improved by 57% (P<0.001) between the two rounds and the rate of adequate cards was 33% in R1 and 55% in R2, giving an improvement of 66% (P<0.001). CONCLUSIONS: The improvement of FQ prescriptions and observance of guidelines demonstrate the importance of assessing the state of things before introducing corrective actions. "Antibioguide" was updated at the end of this study. PMID- 23036715 TI - RAG-dependent and independent adaptive systems: towards an understanding of sepsis and autoimmunity. PMID- 23036716 TI - Key molecules in the differentiation and commitment program of T helper 17 (Th17) cells up-to-date. AB - The mechanisms underlying autoimmunity and cancer remain elusive. However, perpendicular evidence has been evolved in the past decade that T helper (Th)17 cells and their related molecules are implicated in initiation and induction of various disease settings including both diseases. Meanwhile, extensive research on Th17 cells elucidated various molecules including cytokines and transcription factors as well as signaling pathways involved in the differentiation, maturation, survival and ultimate commitment of Th17 cells. In the current review, we revise the mechanistic underpinnings delivered by recent research on these molecules in the Th17 differentiation/commitment concert. We emphasize on those molecules proposed as targets for attaining potential therapies of various autoimmune disorders and cancer, aiming both at dampening the dark-side of Th17 repertoire and simultaneously potentiating its benefits in the roster of the antimicrobial response. PMID- 23036717 TI - The effect of the in vitro supplementation of exogenous long-chain fatty acids on bovine sperm cell function. AB - This study aimed to investigate the effects of long-chain fatty acids (alpha linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), linoleic acid (LA), oleic acid (OA) and palmitic acid (PA)) at concentrations of 10-100 uM, on extended bull spermatozoa stored in vitro for up to 7 days. Progressive linear motion (PLM), viability (Experiments 1-3), ability to penetrate artificial mucus (Experiment 1), reactive oxygen species (ROS; Experiment 2) and superoxide production (Experiment 3) were assessed. Spermatozoa maintained the ability to penetrate artificial mucus up to Day 4, irrespective of treatment. In Experiments 2 and 3, DHA and EPA had detrimental effects on PLM and viability. PA preserved PLM and viability at levels greater than the control (P<0.05), whilst keeping ROS levels to a minimum, particularly on Days 1 and 3 (P<0.01) when ROS generation peaked in other treatments. In contrast, superoxide production peaked on Day 0 (Experiment 3) and declined thereafter with no significant effect of fatty acid. This study supports the notion that superoxide dominates on Day 0, whereas its breakdown products, hydrogen peroxide and the hydroxyl radical as assessed by CM-H2DCFDA, contribute to ROS generation on subsequent days. PMID- 23036718 TI - Sarcoptic mange and cheetah conservation in Masai Mara (Kenya): epidemiological study in a wildlife/livestock system. AB - The sanitary control of threatened wild animals is of pivotal interest for their conservation. This task, however, is highly complex in wildlife/livestock systems. In this paper we report findings from a 2-year cross-sectional study of the epidemiology and attempted control of a Sarcoptes mite infestation in the threatened cheetah population in Masai Mara (Kenya), and discuss its interaction with sympatric wild (lion, wildebeest and Thomson's gazelle) and domestic (dog, cattle and sheep) animals. Sarcoptes scabiei was isolated from cheetahs, Thomson's gazelles, wildebeests, lions, cattle, goats and dogs; Psoroptes ovis, on the other hand, was only isolated from sheep. The prevalence study revealed 12.77% infection rates in cheetahs, 4.7% in dogs, 0.8% in Thomson's gazelles, 0.8% in sheep, 0.09% in cattle, and 0.09% in goats, while it opportunistically affected lions and wildebeest. Our study revealed that prevalence of Sarcoptes mite in cheetah population was not associated with the studied geographical blocks, animal sex or the presence of affected domestic animals. Cheetah infection with S. scabiei was associated with the climatic conditions (dry more than wet season) and the balancing between the total number of Thomson's gazelles and the prevalence of infected individuals. Apparently the high prevalence of mangy gazelles has a negative effect on cheetah; this negative effect was reduced when the number of healthy gazelles was increased. Treatment with injectable ivermectin of the clinically affected wild and domestic animals during the first year of this study was associated with much lower incidence of sarcoptic mange during the second year. PMID- 23036720 TI - A comparative study of two composts as filter media for the removal of gaseous reduced sulfur compounds (RSCs) by biofiltration: application at industrial scale. AB - This work presents the use of two composts as filter media for the treatment by biofiltration of odors emitted during the aerobic composting of a mixture containing sewage sludge and yard waste. The chemical analysis of the waste gas showed that the malodorous compounds at trace level were the reduced sulfur compounds (RSCs) which were dimethyl sulfide (Me(2)S), methanethiol (MeSH) and hydrogen sulfide (H(2)S). Laboratory tests for biofiltration treatment of RSCs were performed in order to compare the properties of two filter media, consisted of a mature compost with yard waste (YW) and a mixture of mature compost with sewage sludge and yard waste (SS/YW). The maximum elimination capacity (EC) values obtained with the YW mature compost as packing material were 12.5 mg m( 3)h(-1) for H(2)S, 7.9 mg m(-3)h(-1) for MeSH and 34 mg m(-3)h(-1) for Me(2)S, and the removal efficiency decreased in the order of: H(2)S>MeSH>Me(2)S. Moreover, the YW compost filter medium had a better behavior than the filter medium based on SS/YW in terms of acclimation of the microbial communities and moisture content. According to these results, a YW mature compost as packing material for an industrial biofilter were designed and this industrial biofilter was found effective under specified conditions (without inoculation and addition of water). The results showed that the maximum EC value of RSCs was 935 mg m( 3)h(-1) (100% removal efficiency, RE) for an inlet loads (IL) between 0 and 1000 mg m(-3)h(-1). Thus, YW compost medium was proven efficient for biofiltration of RSCs both at laboratory and industrial scale. PMID- 23036721 TI - Investigation of the performance of trackpoint and touchpads with varied right and left buttons function locations. AB - This study investigates the relationships of the following 5 factors with commonly-used task patterns: 4 (2 existing and 2 newly-designed) built-in cursor input devices of notebook PCs, usage experiences, genders, sensitivity of cursor movements, and 5 tasks of input applications (including click, drag-drop, click select, select-drag-drop, and type-select-click). This experiment reveals that there are significant differences among these factors in the operating times and/or error rates of particular tasks. Although somewhat influenced by the task patterns, the results show that the touchpad with the cursor-tracking pad located on the bottom-center and the right and left buttons on the bottom-left beneath the keyboard, which avoids ulnar and radial deviation and hindrance of text-entry pointer-manipulation switching, leads to higher performance and preference, while the trackpoint leads to lower performance and preference. In addition, the touchpads with sensitivity values of 10 and 12 for cursor movement are preferred over those with the value of 8. PMID- 23036719 TI - A functional architecture of the human brain: emerging insights from the science of emotion. AB - The 'faculty psychology' approach to the mind, which attempts to explain mental function in terms of categories that reflect modular 'faculties', such as emotions, cognitions, and perceptions, has dominated research into the mind and its physical correlates. In this paper, we argue that brain organization does not respect the commonsense categories belonging to the faculty psychology approach. We review recent research from the science of emotion demonstrating that the human brain contains broadly distributed functional networks that can each be re described as basic psychological operations that interact to produce a range of mental states, including, but not limited to, anger, sadness, fear, disgust, and so on. When compared to the faculty psychology approach, this 'constructionist' approach provides an alternative functional architecture to guide the design and interpretation of experiments in cognitive neuroscience. PMID- 23036722 TI - Characterization of chlorinated valepotriates from Valeriana jatamansi. AB - HPLC-PDA-MS and TLC analysis were used to look for minor cytotoxic chlorinated valepotriates from whole plants of Valeriana jatamansi (syn. Valeriana wallichii DC.). This resulted in isolation of 15 chlorinated valepotriates, designated as chlorovaltrates A-O, together with six known analogues, (1S,3R,5R,7S,8S,9S)-3,8 epoxy-1,5-dihydroxyvalechlorine, volvaltrate B, chlorovaltrate, rupesin B, (1S,3R,5R,7S,8S,9S)-3,8-epoxy-1-O-ethyl-5-hydroxyvalechlorine, and (1R,3R,5R,7S,8S,9S)-3,8-epoxy-1-O-ethyl-5-hydroxyvalechlorine. Their structures were elucidated by spectroscopic methods including homo- and heteronuclear two dimensional NMR experiments. Chlorovaltrates K-N, chlorovaltrate and rupesin B showed moderate cytotoxicity against lung adenocarcinoma (A 549), metastatic prostate cancer (PC-3M), colon cancer (HCT-8) and hepatoma (Bel 7402) cell lines with IC50 values of 0.89-9.76 MUM. PMID- 23036723 TI - Identification of a novel mutation in CYP17A1 gene. AB - 17alpha-hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive genetic disease that is characterized by low-renin hypertension, hypokalemia, and abnormal development of the genitalia. Mutations in the CYP17A1 gene account for this disease. We aim to investigate the CYP17A1 mutation and analyze its possible influence on phenotype in a Chinese patient with 17OHD. Steroid hormones were assayed. The 8 exons of the CYP17A1 gene were amplified and directly sequenced. Wild-type and mutant CYP17A1 cDNA were cloned into pcDNA3.1 expression vectors and transfected into 293T cells. Finally, 17-hydroxylase and 17,20-lyase activity were detected by using progesterone and 17-hydroxypregnenolone as the substrates. A novel missense mutation c.716 G>A located in exon 4 that changed the amino acid from arginine to glutamine (R239Q) was discovered in the patient. Steric model analysis of CYP17A1 showed that R239Q changed the local structure and the electrostatic potential. Functional study indicated that the R239Q mutant caused the complete loss of both 17alpha-hydroxylase and 17,20-lyase activities. Our study expanded the CYP17A1 mutation spectrum. With a functional study, we confirmed that the novel mutation caused the complete loss of both 17alpha hydroxylase and 17,20-lyase activities. PMID- 23036724 TI - MALDI-TOF MS analysis of human and animal Brachyspira species and benefits of database extension. AB - Spirochaetes belonging to the genus Brachyspira are anaerobic bacteria that colonize the large intestine of humans and animals, mainly pigs. The main species are namely, B. hyodysenteriae, the etiological agent of swine dysentery, B. pilosicoli, a zoonotic agent causing colonic spirochaetosis both in humans and different animal species, B. aalborgi, exclusively infecting humans causing colonic spirochaetosis, B. intermedia, a potential animal pathogen, B. innocens and B. murdochii, generally commensal of pigs, and B. alvinipulli, found in egg laying hens with diarrhea. In this study, for the first time, MALDI-TOF MS was applied on Brachyspira strains of human and animal origins, supplementing the existing database, limited to the species B. murdochii only, with spirochaetal protein profiles and demonstrating its usefulness in the rapid, cheap and reliable identification of Brachyspira strains at the species level, overcoming the problems previously encountered in the identification of these spirochaetes when using biochemical and genetic-based methods. Moreover, a dendrogram based on protein profiles of the different spirochaetal species was generated reflecting their host spectrum, showing in the same branch the only two species able to infect humans (B. aalborgi and B. pilosicoli) and in the other branch the spirochaetes infecting exclusively animals. PMID- 23036726 TI - Tips and traps in spinal cord pathology. AB - While reviewing major pathological conditions, the radiologist must learn to adapt his technique to the indication and look for multifocal lesions. In conditions involving malformation, transdural cord herniation and diastematomyelia may be discovered late. In vascular diseases, a dural arteriovenous fistula with perimedullary venous drainage is the most common vascular malformation and a source of diagnostic error. On discovering a medullary cavity, the radiologist needs to know when to discount focal distensions of the ependymal canal and how to detect tumoral syringomyelia. In the case of a tumour, he should know the characteristics of common tumours such as astrocytomas, ependymomas, haemangioblastomas and cavernomas. In inflammatory diseases, he should know when a brain examination is required. When faced with images appearing to show a tumour, he should consider the possibility of pseudotumours and in particular of granulomatoses. PMID- 23036725 TI - Chaperone-mediated acetylation of histones by Rtt109 identified by quantitative proteomics. AB - Rtt109 is a fungal-specific histone acetyltransferase (HAT) that associates with either Vps75 or Asf1 to acetylate histone H3. Recent biochemical and structural studies suggest that site-specific acetylation of H3 by Rtt109 is dictated by the binding chaperone where Rtt109-Asf1 acetylates K56, while Rtt109-Vps75 acetylates K9 and K27. To gain further insights into the roles of Vps75 and Asf1 in directing site-specific acetylation of H3, we used quantitative proteomics to profile the global and site-specific changes in H3 and H4 during in vitro acetylation assays with Rtt109 and its chaperones. Our analyses showed that Rtt109-Vps75 preferentially acetylates H3 K9 and K23, the former residue being the major acetylation site. At high enzyme-to-substrate ratio, Rtt109 also acetylated K14, K18, K27 and to a lower extent K56 of histone H3. Importantly, this study revealed that in contrast to Rtt109-Vps75, Rtt109-Asf1 displayed a far greater site-specificity, with K56 being the primary site of acetylation. For the first time, we also report the acetylation of histone H4 K12 by Rtt109-Vps75, whereas Rtt109-Asf1 showed no detectable activity toward H4. This article is part of a Special Issue entitled: From protein structures to clinical applications. PMID- 23036727 TI - Single- and dual-source chest CT protocols: Levels of radiation dose in routine clinical practice. AB - PURPOSE: To establish the radiation dose level for single- and dual-source thoracic CT scans in daily practice. MATERIALS AND METHODS: The dose levels delivered during 634 consecutive examinations over a period of 2 months were recorded. The CT scans were performed using: (a) a standard protocol (single source, single energy [group 1]: n=266; dual source, single energy [group 2]: n=276; (b) with prospective ECG synchronisation [group 3]: n=13; or (c) with dual energy [group 4]: n=79. All the acquisitions included kilovoltage selection depending on the weight and automatic milliamperage modulation. RESULTS: The mean DLP of the standard protocols was 97.12 mGycm (group 2; BMI=23.1kg/m(2)) and 211.1 mGycm (group 1; BMI=27.3kg/m(2)), the choice of protocol depending on the diameter of the thorax relative to the diameter of the field of the second source, and therefore on the patient's morphotype. When imaging included examination of the proximal and middle coronary arteries (group 3), the mean DLP was 105.5 mGycm. Morphological and functional imaging (group 4) was obtained with a mean DLP of 404.3 mGycm. CONCLUSION: Depending on the objective of the protocol, the mean DLP varied from 97.12 to 404.3 mGycm. PMID- 23036729 TI - [Clinical practice guideline on the management of patients with dyspepsia. Update 2012]. AB - The aim of the Clinical Practice Guideline (CPG) on the Management of Patients with Dyspepsia is to generate recommendations on the optimal approach to dyspepsia in the primary care and specialized outpatient setting. The main objective of this CPG is to help to optimize the diagnostic process, identifying patients with a low risk of a serious organic disease (mainly tumoral), who could be safely managed without the need for invasive diagnostic tests and/or referral to a specialist. The importance of this aim lies in the need to accurately diagnose patients with esophagogastric cancer and correctly treat peptic ulcer while, at the same time, reduce negative endoscopies in order to appropriately use the available healthcare resources. This CPG reviews the initial strategies that can be used in patients with uninvestigated dyspepsia and evaluates the possible decision to begin empirical therapy or to investigate the existence of a lesion that could explain the symptoms. This CPG also discusses functional dyspepsia, which encompasses all patients with dyspepsia with no demonstrable cause on endoscopy. Recommendations for the diagnosis and treatment of peptic ulcer and Helicobacter pylori infection are also made. To classify the scientific evidence and strengthen the recommendations, the GRADE (Grading of Recommendations Assessment, Development and Evaluation Working Group) system has been used (http://www.gradeworkinggroup.org/). PMID- 23036730 TI - Skeletal muscle fatty acids shift from oxidation to storage upon dexamethasone treatment in chickens. AB - The effect of an exogenous glucocorticoid on the lipid metabolism and fatty acid pattern of skeletal muscle in broiler chickens (Gallus gallus domesticus) was investigated in vivo and in vitro. Male Arbor Acres chickens were subjected to dexamethasone (DEX) treatment for 3days. We found that DEX retarded body growth, facilitated lipid accumulation in adipose and skeletal muscle tissues, and elevated the thigh monounsaturated fatty acids (MUFA) to saturated fatty acids (SFA) ratio at fasted state. DEX-treated chickens exhibited increased stearoyl CoA desaturase-1 (SCD1) activity and decreased carnitine palmitoyltransferase-1 (CPT1) activity in the thigh muscle under fasting conditions and in primary cultured myoblasts. Phosphorylation of AMP-activated protein kinase alpha at Thr172 did not occur in vivo but was increased in vitro by DEX. In cells exposed to DEX, fatty acid transport protein-1 mRNA expression and fatty acid storage were enhanced while fatty acid oxidation was repressed. In conclusion, in oxidative muscle of fasted chickens, DEX stimulated uptake of myocellular fatty acids which was stored with the modified MUFA to SFA ratio in a process that maybe involved SCD1 activation. The altered fatty acid composition together with the inactivation of CPT1 showed an increased tendency towards fatty acid accumulation as opposed to oxidation. These findings provide important insight concerning the influence of glucocorticoids on lipid metabolism. PMID- 23036731 TI - Kisspeptin and seasonal control of reproduction in male European sea bass (Dicentrarchus labrax). AB - In the present study, we developed and validated real-time quantitative RT-PCR assays for a suite of genes involved in the brain-pituitary gonadal axis in fish including kisspeptin genes and its receptor (Kiss1, kiss2, kissr4) and gonadotropin-releasing hormone genes (sbGnRH, sGnRH, cGnRHII) in the brain, and gonadotropin genes (fshbeta and lhbeta) in the pituitary. Sex steroid profiles (T and 11-KT) and gonadal development were also studied over a full annual reproductive cycle in adult male sea bass. The cDNA partial sequence of sea bass kissr4 encoding 185 amino acids showed a high degree of conservation with other fish kissr4 subtype. Results clearly showed a seasonal profile for Kiss1, kiss2 and kissr4 mRNAs. Kissr4, fshbeta and lhbeta levels increased gradually and peaked during spermatogenesis (January) while Kiss1, kiss2, cGnRH-II as well as steroids showed peaks during early spawning (March). No significant seasonal changes were observed for sbGnRH and sGnRH expression. These results support the possible involvement of the kiss genes and their receptor (kissr4) in the seasonal control sea bass reproduction. However, a lack of correlation between kiss genes and sbGnRH expression and the mismatch between kisspeptin and the onset of gonadotropin surge contrast with previous findings. PMID- 23036732 TI - Divergent responsiveness of the dentary and vertebral bone to a selective estrogen-receptor modulator (SERM) in the teleost Sparus auratus. AB - In teleosts the regulation of skeletal homeostasis and turnover by estrogen is poorly understood. For this reason raloxifene, a selective estrogen-receptor modulator (SERM), was administered to sea bream (Sparus auratus) and its effect on plasma calcium balance and transcript expression in dentary (dermal bone) and vertebra (perichondral bone) was studied. The concentration of total calcium or phosphorus in plasma was unchanged by raloxifene treatment for 6days. The activity of alkaline phosphatase (ALP) in dentary bone of raloxifene treated fish was significantly (p<0.05) higher than control fish but it was not changed in vertebral bone. Transcripts for estrogen receptor (ER) alpha were in very low abundance in the sea bream dentary and vertebra and were unchanged by raloxifene treatment. In contrast, raloxifene caused significant (p<0.05) up-regulation of the duplicate ERbeta transcripts in the dentary but did not affect specific transcripts for osteoclast (TRAP), osteoblast (ALP, Runx2, osteonectin) or cartilage (IGF1, CILP2, FN1a). In the vertebra ERbetab was not changed by raloxifene but ERbetaa was significantly (p<0.05) down-regulated as was the skeletal specific transcripts, TRAP, ALP, CILP2, FN1a. In summary, ERbetas regulate estrogen sensitivity of the skeleton in sea bream, which responds in a non uniform manner. In common with mammals raloxifene appears to have an anti resorptive role (in sea bream vertebra), but also an osteoblast stimulatory role, inducing ALP activity in the dentary of sea bream. Overall, the results indicate bone specific responsiveness to raloxifene in the sea bream. Further work will be required to understand the basis of bone responsiveness and the role of E(2) and ERs in teleost bone homeostasis. PMID- 23036733 TI - Alteration of immune function endpoints and differential expression of estrogen receptor isoforms in leukocytes from 17beta-estradiol exposed rainbow trout (Oncorhynchus mykiss). AB - While the endocrine system is known to modulate immune function in vertebrates, the role of 17beta-estradiol (E2) in cellular immune function of teleosts is poorly understood. The cellular and molecular responses of juvenile rainbow trout (Oncorhynchus mykiss) to E2 treatment were evaluated by exposing fish to 0.47+/ 0.02MUg/L E2 (mean+/-SEM) for either 2 or 7d, with a subsequent 14d recovery period. After 2 and 7d of exposure to E2, hematocrit was significantly lower than in control fish. Lipopolysaccharide-induced lymphocyte proliferation was elevated on day 2 and concanavalin A-induced lymphocyte proliferation was reduced following 7d of E2 exposure. Four estrogen receptor (ER) transcripts were identified in purified trout head kidney leukocytes (HKL) and peripheral blood leukocytes (PBL). While the mRNA abundance of ERbeta1 and ERbeta2 was unaffected by treatment, ERalpha1 was up-regulated in HKL and PBL following 7d of E2 exposure. ERalpha2 was up-regulated in HKL after 7d of E2 exposure, but down regulated in PBL after 2 and 7d of treatment. All parameters that were altered during the E2 exposure period returned to baseline levels following the recovery period. This study reports the presence of the full repertoire of ERs in purified HKL for the first time, and demonstrates that ERalpha transcript abundance in leukocytes can be regulated by waterborne E2 exposure. It also demonstrated that physiologically-relevant concentrations of E2 can modulate several immune functions in salmonids, which may have widespread implications for xenoestrogen associated immunotoxicity in feral fish populations inhabiting contaminated aquatic environments. PMID- 23036734 TI - Molecular events during the induction of neurodegeneration and memory loss in estrogen-deficient rats. AB - This study aims to delineate the relationship among estrogen deficiency, neurodegeneration, and cognitive impairment of ovariectomized rats. Female Sprague-Dawley rats were ovariectomized and euthanized after 1-4 month periods (M(0)-M(4) groups). Blood samples were collected for the determination of serum levels of 17beta-estradiol (E(2)), luteinizing hormone (LH), and follicle stimulating hormone (FSH). Five consecutive days before the euthanization, cognitive performance of the rats was examined by Morris water maze test. After euthanization, the hippocampus was collected, and expression of the genes associated with amyloid plaques (App, Adam10 and Bace1) and neurofibrillary tangles (Tau4 and Tau3) were examined by real-time PCR. Serum E(2) levels were declined following 2 weeks of ovariectomy. Conversely, serum FSH and LH levels were profoundly increased by 2 weeks of ovariectomy for approximately 4 and 22 times, respectively. Cognitive impairments, indicated by the longer latency and distance, were observed only in the M(3) and M(4) groups. The Tau4 mRNA levels were significantly increased as early as 1 month after ovariectomy (in the M(1) group; P<0.05), and tended to be increased further with the advancing time. Similarly, the Tau3 mRNA levels were increased by ovariectomy, but with the highest level in the M(1) group, and decreased thereafter. The mRNA levels of App, Adam10 and Bace1 were increased by ovariectomy, but significant differences were observed only in the M(4) group. These results indicate that estrogen deficiency can induce a sequence of events that results in the production of neurofibrillary tangles, amyloid deposition, and spatial memory deficit in rats. PMID- 23036735 TI - Inverse urinary corticosterone and testosterone metabolite responses to different durations of restraint in the cane toad (Rhinella marina). AB - Non-invasive measurement of urinary corticosterone and testosterone metabolites in amphibians provides opportunities for endocrine studies of responses to physiological and psychological stressors. Typically, corticosterone metabolite concentrations increase in frog urine within 1-2h of a mild capture and handling stress protocol. However, no study has investigated the effect of duration of manual restraint on the changes in corticosterone and reproductive hormones in amphibians. We quantified urinary corticosterone and testosterone metabolite responses for 8h following various durations of manual restraint (control, 5, 15 or 30min) in adult male cane toads (Rhinella marina) under controlled laboratory conditions. All toads had a corticosterone stress response over 8h to our standard capture and handling stressor. The mean corticosterone stress response was significantly higher after 15 or 30min restraint in comparison to the control (no restraint) or to 5min restraint. Manual restraint for 5, 15 or 30min caused a significant reduction in urinary testosterone concentrations over 8h. We also provide a novel method of quantifying plasticity in corticosterone stress responses in amphibians with respect to restraint duration using the concept of a "reaction norm". The reaction norm, which was calculated as slope of the regression line of integrated corticosterone response against restraint duration, was 9.69 (pg corticosterone/MUg creatinineh)/min for male toads. In summary, corticosterone and testosterone responses to restraint are affected by restraint duration in male toads. Glucocorticoid reaction norms can be applied to study the change in physiological stress hormonal response with respect to restraint duration in other amphibian species. PMID- 23036736 TI - Differential regulation of gonadotropin receptors (fshr and lhcgr) by epidermal growth factor (EGF) in the zebrafish ovary. AB - Epidermal growth factor (egf) is expressed in the zebrafish oocyte whereas its receptor EGF receptor (egfr) is expressed in the somatic follicle layer, strongly suggesting a role for Egf in the intrafollicular paracrine communication that mediates an oocyte-to-follicle cell signaling pathway. However, the exact function of Egf in the follicle remains largely unknown. The present study aimed to explore the possible role of Egf in regulating gonadotropin receptors (fshr and lhcgr) in cultured zebrafish follicle cells. EGF down-regulated lhcgr expression dose-dependently in a biphasic manner with significant effect observed at 1.5 and 24 h. The effect was mediated via Egfr on the follicle cells. On the contrary, EGF also tended to decrease fshr expression at 1.5 h but it appeared to up-regulate fshr at 24 h. The EGF suppression of lhcgr expression was functionally relevant as pre-exposure to EGF reduced the follicle cell responsiveness to LH/hCG. We have recently reported that estradiol (E2) strongly stimulated lhcgr expression in the zebrafish ovary. In the current study, we further demonstrated that EGF and other EGF family members, heparin-binding EGF like growth factor (HBEGF), transforming growth factor alpha (TGFalpha) and betacellulin (BTC), all reduced basal and E2-induced lhcgr expression. This study provides evidence for a potential paracrine role of Egf and its related peptides in the zebrafish follicle. The oocyte-derived EGF family ligands may actively control the process of follicle growth and maturation by differentially controlling the expression of fshr and lhcgr in the follicle cells in a paracrine manner. PMID- 23036737 TI - Effects of sex and scotorefractory state on obesity induced by photostimulation and serum leptin in Siberian hamsters (Phodopus sungorus). AB - The rising prevalence of obesity is associated with an increasing incidence of heart disease, diabetes and other health risks. In addition, severe cases of obesity are associated with an even greater risk of morbidity and mortality. Therefore, animal models of morbid obesity are required to better elucidate the underlying mechanisms. Our investigations in the Siberian hamster (Phodopus sungorus) suggest that pronounced obesity can be reliably induced in this species without relying on genetic manipulation or overly fatty and palatable foods. In a prior study on reproductive aging in female Siberian hamsters, we incidentally observed marked obesity in a group of hamsters that were exposed to a particular photoperiodic regime. In short day (SD) lengths, Siberian hamsters inhibit their reproductive physiology and reduce food intake and body mass. However, hamsters become refractory to SD after 15-20weeks and revert to the long day (LD) phenotype. In the previous study, refractory animals appeared to be particularly sensitive to photostimulation (transfer to LD), in terms of increasing body mass. To test the hypothesis that refractoriness to SD predisposes hamsters to severe obesity, we photostimulated females and males in different states of SD responsiveness (inhibited or refractory). We determined that photostimulation during the SD-refractory state is particularly effective in inducing pronounced obesity and high serum leptin concentration in female hamsters. We propose that this experimental framework is a useful model to investigate the factors and signals that create a predisposition to excessive food intake and body mass, without having to rely on genetic or dietary manipulations. PMID- 23036738 TI - Non-invasive assessment of stress in captive numbats, Myrmecobius fasciatus (Mammalia: Marsupialia), using faecal cortisol measurement. AB - Annual patterns of faecal cortisol metabolite (FCM) secretion were examined in six captive numbats (Myrmecobius fasciatus). The use of enzyme-immunoassay for the measurement of FCM in the numbat faeces was validated using an adrenocorticotropic hormone (ACTH) challenge and the resultant FCM measurements represent the first description of adrenal endocrinology in this species. Total overall, baseline and peak FCM mean concentrations varied according to individual, but not gender. For males, mean baseline and overall FCM secretion was higher in spring in summer (compared to winter and autumn) and was elevated during the breeding season. For females, mean baseline FCM secretion did not differ by season or breeding season, but mean overall FCM secretion was elevated during the breeding season. Thus, male (but not female) numbats display an annual change in FCM secretion that is strongly linked to their seasonal pattern of reproduction. Significant FCM elevations (n=178) were observed in response to 20 different stressors, with these stressors being allocated to one of six categories: ANIM, ENVIRO, HAND, HEALTH, MAN and UNK. The mean proportion of positive responses to each category varied according to category, season and breeding season, but did not vary by individual or gender. ANIM and HEALTH stressors elicited a higher response rate than all other categories and an increase in the number of ANIM, ENVIRO, and HEALTH stressors were observed during the breeding season. Although there were multiple stressors within the captive environment that the numbats reacted to, this did not translate into a welfare issue. PMID- 23036739 TI - Expression of AP-2alpha, AP-2gamma and ESDN in primary melanomas: correlation with histopathological features and potential prognostic value. PMID- 23036740 TI - Connective tissue sheath of hair follicle is a major source of dermal type I procollagen in human scalp. PMID- 23036741 TI - The contribution of human small intestine to chlorpyrifos biotransformation. AB - Despite the oral intake is the major route of exposure to chlorpyrifos for the general population, few data are available on human intestine biotransformation. In this study the contribution of chlorpyrifos (CPF) metabolism in human small intestine was investigated in microsomes from duodenum (HDM) and ileum/jejunum (HS2M) from 11 individual donors. Samples were characterized for testosterone hydroxylated metabolite formation and CYP content quantification by means of Western blotting. The two methods gave consistent results, evidencing the presence of CY3A4 and its-related activity in 10/11 samples, among which one showed also the presence of CYP2C9. Analogously, although with high interindividual variability (about 10 fold), CPF bioactivation to chlorpyrifos oxon (CPFO) was observed in 10/11 HDM: intrinsic clearance highest value was 0.75 pmolCPFO/(mgproteinminMUM). Detoxication to 3,5,6-trichloropyrin-2-ol formation was negligible. The comparison between HDM and HS2M indicates that most CPF bioactivation was confined in the duodenum, declining toward the distal ileum. Results suggest that following oral exposure, the small intestine CPF bioactivation, although much lower when compared to the total hepatic metabolism, could play a role in the pre-systemic CPF clearance, with CPFO transported into the lumen by the efflux P-glycoprotein and further metabolized by esterases. PMID- 23036742 TI - Phycocyanin may suppress D-galactose-induced human lens epithelial cell apoptosis through mitochondrial and unfolded protein response pathways. AB - Apoptosis of lens epithelial cell (LEC) plays an important role in cataract formation, and its prevention may be one of the therapeutic strategies in treating cataract. This study used human lens epithelial cell (hLEC) line SRA01/04 to investigate the protective effect and mechanism of phycocyanin on glactose-induced apoptosis in hLEC. hLECs were cultured in D/F(12)-10% FBS medium containing 125mM d-galactose with or without phycocyanin. Cell viability was assessed by methylthiazol tetrazolium (MTT) assay. Cell apoptosis was elevated with Wright-Giemsa staining, AO/EB double staining, and DNA fragmentation assay. Mitochondrial apoptosis-associated molecules and unfolded protein response associated molecules from cultured SRA01/04 cells were quantified using protein blot analysis. The results demonstrated that phycocyanin suppressed SRA01/04 cells' morphologic changes and apoptosis induced by d-galactose, inhibited the expression and activation of caspase 3, alternated the Bax/Bcl-2 ratio, and down regulated the level of p53, GRP78, and CHOP in d-galactose-treated SRA01/04 cells. These results suggest that phycocyanin might suppress d-galactose-induced hLEC apoptosis through two pathways: mitochondrial pathway, involving p53 and Bcl 2 family protein expression, and unfolded protein response pathway, involving GRP78 and CHOP expression. PMID- 23036743 TI - 'Herpes present' reported in a routine cervical cytology and how to deal with it. AB - In spite of advances in processing and interpreting liquid based cervical cytology, the reliability of diagnosing genital herpes from cervical cytology specimens is disputed. This letter highlights the issues when 'herpes present' is reported in routine smears taken from asymptomatic women. PMID- 23036744 TI - The asthma disease activity score: a discriminating, responsive measure predicts future asthma attacks. AB - BACKGROUND: Classifying asthma severity or activity has evolved, but there are no published weighted composite measures of asthma disease activity that account for the relative importance of the many individual clinical variables that are widely used. OBJECTIVES: We sought to develop a weighted and responsive measure of asthma disease activity. METHODS: Discriminant and multiple regression analyses based on 2 previously conducted clinical trials were used to develop the Asthma Disease Activity Score (ADAS-6). RESULTS: The ADAS-6 demonstrated content validity because its components assess different manifestations of asthma: FEV(1) (percent predicted), Asthma Quality of Life Questionnaire-Symptom domain, rescue beta-agonist use, nocturnal awakenings, peak expiratory flow diurnal variability, and rescue beta-agonist use diurnal variability. The ADAS-6 demonstrated cross sectional and longitudinal validity. It was discriminating: it distinguished levels of disease activity and response to different treatment intensities (P < .0001). Similar results were obtained with an independent clinical trial. The ADAS-6 was highly responsive to treatment effects, with a standardized effect size exceeding that of other widely used outcome measures. Using ADAS-6 as the primary end point in the montelukast pivotal trials would have significantly reduced the sample size needed to detect a comparable change in outcome. Furthermore, increments in the ADAS-6 predicted the risk of future asthma attacks. A simplified Asthma Disease Activity Score 4-variable version (ADAS-4) demonstrated similar measurement properties. CONCLUSIONS: The ADAS-6 and ADAS-4 are novel, weighted, and responsive measures of asthma disease activity. Use of these measures in clinical trials might better separate treatment effects, predict future asthma attacks, and substantially reduce sample size. PMID- 23036747 TI - Distinct TLR-mediated pathways regulate house dust mite-induced allergic disease in the upper and lower airways. AB - BACKGROUND: Allergic rhinitis (AR) and asthma are 2 entities of allergic airway diseases that frequently occur together, which is referred to as united airways. In contrast to this general concept, we hypothesized that innate immunity of the upper and lower airways is respectively distinctive, because the immunologic conditions of the nasal and lung mucosa as well as the functions of the immune cells within their epithelia are different. OBJECTIVE: We wanted to identify distinctive mechanisms of innate immunity in the nose and lung mucosa, which are responsible for house dust mite (HDM)-induced AR and allergic asthma (AA), respectively. METHODS: We constructed a mouse model of AR or AA induced by sensitization and consequent provocation with HDM extracts. RESULTS: HDM-derived beta-glucans, rather than LPS, were proven to be essential to activating innate immunity in the nasal mucosa and triggering AR, which depended on Toll-like receptor 2 (TLR2), but not on TLR4; however, the LPS/TLR4 signaling axis, rather than beta-glucans/TLR2, was critical to HDM-induced AA. These differences were attributed to the specific role of beta-glucans and LPS in inducing the surface expression of TLR2 and TLR4 and their translocation to lipid rafts in nasal and bronchial epithelial cells, respectively. We also showed that dual oxidase 2 generated reactive oxygen species mediate both beta-glucan-induced TLR2 activation and LPS-induced TLR4 activation. CONCLUSIONS: We describe a novel finding of distinctive innate immunity of the nose and lungs, respectively, which trigger AR and AA, by showing the critical role of HDM-induced TLR activation via dual oxidase 2-mediated reactive oxygen species. PMID- 23036745 TI - Warts and all: human papillomavirus in primary immunodeficiencies. AB - Infection with human papillomavirus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and dedicator of cytokinesis 8 (DOCK8) are typically associated with extensive HPV infections, whereas several other primary immune defects result in severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them. PMID- 23036746 TI - Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand. AB - BACKGROUND: Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in T(H)2 priming and polarization. OBJECTIVES: We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection. METHODS: Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12. RESULTS: OX40L was expressed mainly on CD11c(+)MHC class II (MHCII)(+)CD11b(+) DCs but not CD103(+) DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection. CONCLUSIONS: In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and T(H)2 polarization, accounting for the enhanced response on reinfection. PMID- 23036749 TI - [Genotyping of clinical isolates of Aspergillus flavus and its relationship with environmental isolates of an oncohematological center]. AB - BACKGROUND: During 4 months, and while conducting an environmental sampling of air, 2 cases of aspergillosis by Aspergillus flavus (A. flavus) were diagnosed at an oncohematological center in Buenos Aires, Argentina. AIMS: The aim of this study was to know the variability and the genetic relationship between the clinical and environmental isolates, obtained in the oncohematological center. METHODS: Two genotyping techniques of different discriminatory power (RAPD and AFLP) were used. A genetic similarity matrix was calculated using Jaccard method and was the basis for the construction of a dendrogram by UPGMA. The level of genetic variability was assessed by measuring the percentage of polymorphic loci, number of effective allele, expected heterocygozity and association index test (I(A)). RESULTS: The dendrogram reveals that the A. flavus isolates recovered from the patients were not genetically related to those gotten from the rooms occupied by the patients. The environmental isolates had higher values of genetic diversity than the clinical isolates. The I(A) estimated for all the isolates suggest that recombination events occurred. CONCLUSIONS: Patients 1 and 2 were not infected with isolates from the nosocomial environment. Clinical and environmental isolates of A. flavus showed high genetic variability among them. PMID- 23036748 TI - Physiological and molecular characterization of Phytophthora infestans isolates from the Central Colombian Andean Region. AB - BACKGROUND: Late blight, caused by Phytophthora infestans, is one of the most devastating diseases found in potato and tomato crops worldwide. In Colombia it also attacks other important crops: cape gooseberry and tree tomato. The knowledge of the pathogen population is determinant to effectively design control strategies. AIMS: To determine the physiological and molecular characteristics of a set of Colombian P. infestans isolates. METHODS: Strains isolated from Cundinamarca and Boyaca were examined for the level of resistance to mefenoxam and cymoxanil. Virulence was tested for all strains and crosses between A1 mating type, from different hosts, and the Colombian A2 mating type were tested for the production and viability of oospores in different substrates. Additionally, the molecular diversity of the avirulence gene Avr3a, the beta-tubulin gene, and two single copy genes showing RxLR motif, was assessed. RESULTS: We found all levels of mefenoxam sensitivity, with 48% of the strains resistant. A high diversity of races was detected and the population was genetically clonal. Colombian strains had the possibility of sexual reproduction. CONCLUSIONS: These results will help in optimizing the use of fungicides and deployment of resistance as control strategies and will contribute to broader studies on diversity of this pathogen. PMID- 23036751 TI - Wisdom in our history. PMID- 23036750 TI - Simple diffusion-constrained immunoassay for p24 protein with the sensitivity of nucleic acid amplification for detecting acute HIV infection. AB - Nucleic acid amplification techniques have become the mainstay for ultimate sensitivity for detecting low levels of virus, including human immunodeficiency virus (HIV). As a sophisticated technology with relative expensive reagents and instrumentation, adoption of nucleic acid testing (NAT) can be cost inhibited in settings in which access to extreme sensitivity could be clinically advantageous for detection of acute infection. A simple low cost digital immunoassay was developed for the p24 capsid protein of HIV based on trapping enzyme-labeled immunocomplexes in high-density arrays of femtoliter microwells and constraining the diffusion of the enzyme-substrate reaction. The digital immunoassay was evaluated for analytical sensitivity for HIV capsid protein p24, and compared with commercially available NAT methods and immunoassays for p24, including 4th generation antibody/antigen combo assays, for early detection of HIV in infected individuals. The digital immunoassay was found to exhibit 2000-3000-fold greater analytical sensitivity than conventional immunoassays reactive for p24, and comparable sensitivity to NAT methods. Assaying serial samples from 10 HIV infected individuals, the digital immunoassay detected acute HIV infection as early as NAT methods, and 7-10 days earlier than conventional immunoassays. Comparison of assay results between the digital immunoassay and a quantitative NAT method from HIV infected serum exhibited a linear correlation R(2)>0.99. The data indicate that by constraining diffusion of the signal generation step of a simple sandwich immunoassay and enabling the digital counting of immunocomplexes, dramatic improvements in sensitivity to virus can be obtained to match the sensitivity of NAT at a fraction of the cost. PMID- 23036752 TI - Are we really ready for patient-centered care? PMID- 23036754 TI - Molding the future of advanced practice nursing. 1995. PMID- 23036755 TI - Commentary on: Molding the future of advanced practice nursing. PMID- 23036756 TI - Faculty practice: what do the data show? Findings from the NONPF Faculty Practice Survey. 2002. PMID- 23036757 TI - Nursing research and graduate education. 1975. PMID- 23036758 TI - Commentary on: Nursing research and graduate education. PMID- 23036759 TI - New rules for the game: interdisciplinary education for health professionals. 1995. PMID- 23036760 TI - Commentary on: New rules for the game: interdisciplinary education for health professionals. PMID- 23036761 TI - The interaction between theory and research. 1977. PMID- 23036762 TI - Commentary on: The interaction between theory and research. PMID- 23036763 TI - A nursing informatics research agenda for 2008-18: contextual influences and key components. 2008. PMID- 23036764 TI - Commentary on: A nursing informatics research agenda for 2008-18: contextual influences and key components. PMID- 23036765 TI - Should there be a National Institute for Nursing? 1984. PMID- 23036766 TI - Meta-analysis and public policy: opportunity for nursing impact. 1996. PMID- 23036767 TI - Commentary on: Meta-analysis and public policy: opportunity for nursing impact. PMID- 23036768 TI - The public's stake in health insurance. 1958. PMID- 23036769 TI - Stevens-Johnson syndrome induced by levetiracetam. PMID- 23036770 TI - Bioengineered olfactory sensory neuron-based biosensor for specific odorant detection. AB - It is highly desirable to obtain functional cells with specific olfactory receptors (ORs) for the development of cell-based biosensors towards odorant detection. In this study, we explored the feasibility of bioengineered primary olfactory sensory neurons (OSNs) as sensing elements of biomimetic olfactory based biosensors, in which light addressable potentiometric sensor (LAPS) was used to monitor bioengineered OSNs membrane potential responses to odorant molecules. An olfactory receptor of C. elegances, ODR-10, as a model receptor, was expressed on the plasma membrane of OSNs by transient transfection. The response profile of bioengineered OSNs to odorant molecules was investigated by analyzing extracellular potential firings features in frequency and time domains. The results indicated that bioengineered OSNs can specifically respond to diacetyl, the natural ligand of ODR-10. In addition, bioengineered OSNs showed different temporal firing patterns in responding to different concentrations of diacetyl. All the results demonstrate that bioengineered OSNs are useful and promising to serve as novel sensing elements of biosensors for specific odorant molecule detection. It is suggested that bioengineering techniques could provide novel approaches for preparing sensitive elements as well as promoting the development of practical applicable olfactory-based biosensors. PMID- 23036771 TI - Highly sensitive and selective detection of cancer cell with a label-free electrochemical cytosensor. AB - Electrochemical methods have attracted considerable attention for developing cytosensing system since they can decrease the cost and time requirement for cell detection with simple instrumentation. Herein, a label-free electrochemical cytosensor with surface-confined ferrocene as signal indicator was developed for highly sensitive and selective detection of cancer cell. With layer-by-layer (LBL) self-assembly technique, positively charged poly(ethylene imine) functionalized with ferrocene (Fc-PEI) and negatively charged single-wall carbon nanotubes (SWNTs) were alternately assembled on 3-mercaptopropionic acid (MPA) modified gold substrate. Folic acid (FA) was covalently bonded onto SWNTs surface to specifically recognize cancer cells according to the high affinity of FA for folate receptor (FR) on cellular surface. The developed cytosensor presented high sensitivity and selectivity for the detection of human cervical carcinoma (HeLa) cell. By using fast-response differential pulse voltammetry (DPV) method, a wide detection range from 10 to 10(6) cells/mL with a detection limit as low as 10 cells/mL was reached even in the presence of a large amount of non-cancerous cells. PMID- 23036772 TI - Growth of coral-like PtAu-MnO2 binary nanocomposites on free-standing graphene paper for flexible nonenzymatic glucose sensors. AB - The growing demand for compact point-of-care medical devices and portable instruments for on-site environmental sampling has stimulated intense research on flexible sensors that can be miniaturized and function under considerable physical deformation. We report a new type of flexible electrochemical biosensors based on free-standing graphene paper carrying binary nanocomposites of PtAu alloy and MnO(2). The coral-like PtAu-MnO(2) nanocomposites are grown on the substrate through one-step template-free electrodeposition, leading to an intimate contact between the PtAu alloy and MnO(2) matrix. The flexible electrode exhibits a unique set of structural and electrochemical properties such as better uniformity, larger active surface areas, and faster electron transfer in comparison with the control electrode prepared by tandem growth of MnO(2) network and PtAu alloy in two steps. In nonenzymatic amperometric glucose detection, the PtAu-MnO(2) binary nanostructure-decorated graphene paper has shown greatly enhanced sensing performance such as wide liner range (0.1 mM to 30.0 mM), high sensitivity (58.54 MUA cm(-2) mM(-1)), low detection limit (0.02 mM, S/N=3), satisfactory selectivity, excellent reproducibility and stability, and tolerability to mechanical stress. The strategy of co-growth of metal and metal oxides on freestanding carbon substrates opens new possibility to develop high performance flexible electrochemical sensors. PMID- 23036773 TI - Carbohydrate immobilized on a dendrimer-coated colloidal gold surface for fabrication of a lectin-sensing device based on localized surface plasmon resonance spectroscopy. AB - Carbohydrate-mediated functions in biological systems have generated considerable interest in recent years. We have developed a device bearing immobilized carbohydrates on a colloidal gold surface and applied this device to the detection of carbohydrate-binding molecules by using localized surface plasmon resonance (LSPR) spectroscopy. The sensing device was constructed by using cyanuric chloride as an amine-linker between an amino residue of a polyamidoamine (PAMAM) dendrimer-coated colloidal gold surface and the amino residue of a 12 aminododecyl glycoside. After optimizing the construction of the device, we characterized its LSPR-based sensing capability. Binding specificity with lectins and linear range responses were obtained with the device. Our LSPR-based sensing device thus provides a label-free, low-cost detection method for use as a laboratory research tool or in medical glycan arrays. PMID- 23036774 TI - Total lesion glycolysis: a possible new prognostic parameter in oral cavity squamous cell carcinoma. AB - OBJECTIVES: We sought to determine potential prognostic value of total lesion glycolysis (TLG) calculated from combined positron emission tomography/computed tomography (PET/CT) in patients with oral cavity squamous cell carcinoma (OSCC). MATERIALS AND METHODS: We prospectively studied 126 patients with OSCC who underwent PET/CT before definitive treatment by radical surgery. The metabolic tumor volume (MTV) was calculated for the primary tumor according to an absolute standardized uptake value (SUV) of 3. TLG was calculated as MTV * the average SUV. The nodal SUVmax was also recorded. The median value of SUVmax and TLG were used to divide the patients into two categories (high and low). Patients were followed up until death or for at least 24 months from their surgery. Disease free (DFS) and disease-specific survivals (DSS) were the main outcome measures. RESULTS: The median TLG of the primary tumor ((T)TLG) was 71.4, and the median nodal SUVmax ((N)SUV) was 7.5. Patients with high (T)TLG (>= median) had a 2-year DFS of 52% whereas the DFS was 74% for those with a low (T)TLG (P=0.007); the 2 year-DSS rates were 53% vs. 84%, respectively (P<0.001). Similarly, patients with high (N)SUVmax (>= median) had a 2-year DFS of 42% vs. 70% for patients with a low (N)SUVmax (P=0.001); the 2-year-DSS rates were 39% vs. 78%, respectively (P<0.001). In multivariate analyses, (T)TLG, (N)SUVmax, and pathological nodal status were independent prognostic factors for the 2-year DSS. A 3-point prognostic scoring system was formulated based on the presence or absence of the independent factors. Patients with positive neck nodes, high (N)SUVmax, and high (T)TLG (score 3) had a 32-fold higher risk of cancer death compared with those lacking such risk factors (2-year-DSS=26% vs. 97%, P<0.001). CONCLUSION: Primary tumor TLG is an independent prognostic factor for cancer control and survival in patients with OSCC. A prognostic scoring system that includes primary tumor TLG, nodal SUVmax, and pathological neck status may be useful for risk stratification in this group of patients. PMID- 23036775 TI - Sentinel node identification in laryngeal cancer: Feasible in primary cancer with previously untreated neck. AB - OBJECTIVES: With the current diagnostic techniques a considerable percentage of occult lymph node metastases are missed in the clinically negative (cN0) neck. Therefore, in patients with laryngeal cancer and cN0 neck a total laryngectomy is usually combined with elective neck dissection. Based on the risk of occult lymph node metastases the decision whether to perform a neck dissection or not is difficult. In recurrent laryngeal cancer or second primary tumors previous treatment possibly influences lymphatics and metastatic behavior. In this pilot study we investigated the feasibility of sentinel node (SN) identification and potential accuracy of sentinel node biopsy (SNB) in laryngeal cancer patients undergoing total laryngectomy with elective neck dissection. PATIENTS AND METHODS: Patients with cN0 laryngeal cancer were included. During surgery 40MBq (99m)Technetium labeled Nanocolloid was endoscopically injected around the tumor. Lymphoscintigraphy was not performed. We identified the sentinel node (SN) ex vivo in the neck dissection specimen with a gammaprobe. Histopathological examination of the neck dissection specimen served as reference test. RESULTS: We included 19 patients, 13 patients with untreated necks and six with prior neck treatment. SN identification was successful in 68.4% (13/19) of patients, and significantly higher in patients with untreated necks (92.3% versus 16.7%, p<0.01). Four of 13 (30.7%) patients would potentially be upstaged by SNB. Sensitivity and negative predictive value would have been 80.0% and 87.5%, respectively. CONCLUSION: With the current methodology, SN identification in laryngeal cancer patients undergoing total laryngectomy is feasible in patients with untreated necks. Further studies are needed to determine the exact accuracy of SNB in total laryngectomy patients. PMID- 23036776 TI - Costs of allergic diseases from birth to two years in Finland. AB - OBJECTIVES: Costing studies are needed to identify the resources used for treatment and inform payers of the costs incurred. The objectives were to determine the costs of diagnosing and treating atopic dermatitis, food allergy and asthma, and to compare the share of costs to society and to the family during the first two years of life. STUDY DESIGN: The data were obtained from an ongoing mother-infant nutrition study. The sample comprised 60 infants who developed allergic disease by the age of 24 months and 56 healthy infants with no allergic disease. METHODS: The costs included diagnosis and treatment of the allergy, disability allowances, travel expenses and time spent by parents. RESULTS: The median costs per infant were ?275 (range 94-1306) for atopic dermatitis, ?1408 (163-5408) for asthma, ?3182 (628-11195) for food allergy, and ?10 (0-619) for the healthy infants due to the suspicion of allergic disease. The highest costs in atopic dermatitis were caused by primary care visits, topical treatments, travel costs and parents' time, and those for food allergy by hospital out patient care, infant formulae for cow's milk allergy, disability allowances and travel costs. The families paid 43% of the costs arising from atopic dermatitis, 13.6% of those from food allergy and 16.5% of those from asthma. CONCLUSIONS: Cow's milk allergy emerged as the most expensive allergic disease, especially for the society, and concurrent asthma in particular further increased the costs. PMID- 23036777 TI - Why do community health workers volunteer? A qualitative study in Kenya. AB - OBJECTIVES: Globally, there is a dire shortage of healthcare workers, but the situation is particularly bad in low- and middle-income countries. To address this, task shifting of clinical work to lower-level staff, including volunteer health workers, has been used. Whilst there are examples worldwide of such an approach working, the sustainability of programmes based on a volunteer workforce is less certain. In addition, little is known about the factors that motivate such volunteers. This study sought to ascertain these motivational drivers. STUDY DESIGN: Qualitative study using focus group discussions. METHODS: Qualitative study of volunteer community health workers (CHWs) in a rural district of Western Kenya. Twenty-three CHWs were sampled purposively, and took part in six focus group discussions. Thematic analysis was performed on the transcribed discussions. RESULTS: A variety of factors were identified as important drivers of motivation. These included financial as well as non-financial drivers, such as personal recognition, personal development and working conditions. CONCLUSIONS: There are serious unanswered questions regarding the viability of healthcare programmes founded on a workforce reliant on volunteer CHWs. This study revealed the importance of some form of reward, be it financial or otherwise, in order to retain and maintain the engagement and motivation of volunteer CHWs in these settings. PMID- 23036778 TI - [Transition from pediatric to adult care: a challenge]. AB - There are an increasing number of adolescents with chronic illness requiring specific health care. This renders the need of their transition to adult-oriented care. Some studies have evaluated health outcomes following transition programs in order to prevent poor health outcome and to improve quality of life. These transition need to be implemented early in adolescence with organized multidimensional process. This is important to consider not only medical issue but also the psychosocial and educational needs in order to improve both long term outcome and future personal plans. PMID- 23036779 TI - [Vertebral sarcoidosis. Spontaneous favorable outcome: A case report and literature review]. AB - INTRODUCTION: The prevalence of vertebral sarcoidosis is highly variable (1 to 36% of reported case series). Because of limited clinical expression, its frequency is probably underestimated. Its proper management is not clearly defined. CASE REPORT: A 42-year-old woman who had a past medical history of cutaneous and pulmonary sarcoidosis presented with low back pain that was refractory to usual medical treatment. A diagnosis of vertebral localisation of sarcoidosis was considered on the history of proven sarcoidosis, radiological features, and the absence of evidence of an alternative diagnosis. In the absence of other clinical or biological evidence of active sarcoidosis, a simple follow up was planned. MRI control at 1 year showed the resolution of vertebral sarcoidosis lesions. CONCLUSION: Spontaneous regression is a possible outcome of vertebral sarcoidosis. Initiation of a specific treatment should be discussed in the absence of other visceral involvement. PMID- 23036780 TI - [Lymphomatoid granulomatosis]. AB - Lymphomatoid granulomatosis, described in 1972 by Liebow, is a rare, Epstein-Barr virus (EBV)-associated lymphoproliferative disorder, involving the lung, and often the skin or the central nervous system. It could have a systemic course making its diagnosis difficult. Controversy still remains about precise taxonomy and lymphomatoid granulomatosis is classified as a lymphoma, whose severity extends from indolent forms to aggressive large B cell lymphomas. Histology is essential and shows characteristically an inflammatory angiocentric infiltrate, composed with polymorphous mononucleated cells containing a varying number of large atypical CD20-positive B-lymphocytes within a background of numerous small reactive CD3-positive T-lymphocytes, often associated with necrosis. In situ hybridization often shows EBV RNA within atypical B-cells. Atypical large B lymphocytes proportion and to a lesser degree EBV-positive B-lymphocytes proportion allow to classify the disease (grade I to III) and have a prognostic value. An aggressive form of B lymphoma occurs in 7 to 47% of cases during lymphomatoid granulomatosis course. Moreover, grade III diseases share numerous characteristics of lymphoma and often require chemotherapy. Several conditions mimic lymphomatoid granulomatosis, and include various hematologic malignancies (large B-cells lymphomas, T/NK lymphomas, post-immunodepression lymphoproliferative disorders) or granulomatosis with polyangiitis. The objective of this article is to review the clinical, radiological, histological and therapeutic characteristics of this rare disorder. PMID- 23036781 TI - [Post-traumatic stress disorder: Clinical aspects and pharmacological approach]. AB - All medical specialities are interested in the clinical aspects of psychological trauma. Due to psychopathological determinants which structure the trauma, although pathognomonic of posttraumatic stress disorder, flashbacks are rarely highlighted by the psychotraumatised patient in their contact with the health care system. Contact with the medical profession is expressed by somatic symptoms or psychiatric comorbidities. Addictive and suicidal problems, as well as somatisations and physical pain, are more traditional methods of contact with the health care system. In relation to the evolution of investigative techniques, modern wars have highlighted other dissociative and psychotic dimensions of the psycho- and craniatraumatic repercussions. These different clinical forms of posttraumatic stress disorder can receive a specific pharmacological treatment according to the predominant impairment of the incriminated monoaminergic neuromodulatory system. PMID- 23036782 TI - Disturbed grey matter coupling in schizophrenia. AB - In schizophrenia, grey matter deficits have been shown for many regions throughout the brain. These regions do not operate in isolation. Rather, they form a structural network of interconnected grey matter regions. To examine the mutual dependence of brain regions, this study investigated interregional coupling in lobar and regional grey matter volumes obtained from 146 schizophrenia patients and 122 healthy comparison subjects. Compared to healthy controls, schizophrenia patients showed both decreased (e.g. between left frontal and bilateral subcortical, p<=0.005) and increased (e.g. between left temporal and bilateral subcortical, p<=0.001) coupling between lobar grey matter volumes. On a regional scale, decreased coupling was most pronounced between fronto parietal cortical regions and subcortical structures, and between frontal and occipital regions. In addition, an increased association was found among frontal and limbic regions, and for temporo-occipital connexions. Consistent with dysconnectivity theories of schizophrenia, impaired grey matter coupling may be reflective of reduced integrity of the brain's network. Furthermore, as cross sectional volumetric coupling is indicative of maturational coupling, aberrant grey matter coupling may be a marker of neurodevelopmental abnormalities in schizophrenia. PMID- 23036783 TI - Court-based participatory research: collaborating with the justice system to enhance sexual health services for vulnerable women in the United States. AB - BACKGROUND: Although jail screening programs have an important role in the diagnosis and treatment of sexually transmissible infections (STI) and HIV among incarcerated individuals, many arrestees are not screened before release. Justice involved women are at particularly high risk for these conditions because of individual risk behaviour as well as other network-level risk factors. Court based programs could provide a critical bridge between these women, STI risk counselling and health services. This formative study explored the features of a program that would encourage STI testing among court-involved women. Further, we describe how community-based participatory research principles were adapted for use in a court setting and the resulting justice-public health partnership. METHODS: Using semistructured interviews and focus group discussions, we explored issues related to health-seeking behaviours, perceived gaps in services for high risk women and the components of a court-based screening program. RESULTS: Six focus groups were conducted with women with a history of commercial sex work and staff from the court, as well as local organisations providing HIV and social support services for high-risk women. Community-based participatory research (CBPR) principles facilitated development of relevant research questions and equitable processes, and assisted partners to consider individual and sociostructural sources of health disparities. DISCUSSION: Although not every principle was applicable in a court setting, the CBPR framework was helpful for building cohesion and support for the project. We provide a description of how CBPR principles were operationalised, describe the key lessons learned and discuss the implications for CBPR projects in a community court. PMID- 23036784 TI - Testosterone increases repertoire size in an open-ended learner: an experimental study using adult male European starlings (Sturnus vulgaris). AB - Song in songbirds is a learned secondary sexual behavior, first acquired during a sensitive phase of juvenile development, which is affected by hormones such as testosterone (T). While the latter has received much attention, the potential involvement of T in the adult repertoire changes observed in a number of species is much less understood. Yet, this may prove essential to understand the role of song as a sexually selected trait. We therefore performed a T-implantation experiment during the non-breeding season (when T is basal), using adult male European starlings (Sturnus vulgaris), a songbird species in which song repertoire size (and composition) changes seasonally and increases with age. Repertoire size increased rapidly in T-males, but not in control males, indicating a role for T in repertoire size changes. This increase resulted from a lower proportion of dropped song types in T-males than in control males, while the proportion of added song types did not differ between both groups. Interestingly, the observed repertoire turnover (adding and removing song types from the repertoire) in both groups, suggests that elevated plasma T levels were not essential for changes in repertoire composition (contrary to repertoire size). Finally, T-males (but not control males) significantly increased their song rate, while neither group showed a significant change in their song bout length and phrase repetition rate. Taken together, our results suggest a role for T in adult song learning and provide new insights into the information content of repertoire size and song bout length as sexually selected traits. PMID- 23036786 TI - The optimal dose reduction level using iterative reconstruction with prospective ECG-triggered coronary CTA using 256-slice MDCT. AB - AIM: To assess the image quality (IQ) of an iterative reconstruction (IR) technique (iDose(4)) from prospective electrocardiography (ECG)-triggered coronary computed tomography angiography (coronary CTA) on a 256-slice multi detector CT (MDCT) scanner and determine the optimal dose reduction using IR that can provide IQ comparable to filtered back projection (FBP). METHOD AND MATERIALS: 110 consecutive patients (69 men, 41 women; age: 54 +/- 10 years) underwent coronary CTA on a 256-slice MDCT (Brilliance iCT, Philips Healthcare). The control group (Group A, n=21) were scanned using the conventional tube output (120 kVp, 210 mAs) and reconstructed using FBP. The other 4 groups were scanned with the same kVp but successively reduced tube output as follows: B[n=15]: 125 mAs; C[n=22]: 105 mAs; D[n=36]: 84 mAs: E[n=16]: 65 mAs) and reconstructed using IR levels of L3 (Group B), L4 (Group C) and L5 (Groups D and E), to compensate for the noise increase. All images were reconstructed using the same kernel (XCB). Two radiologists graded IQ in a blinded fashion on a 4-point scale (4 - excellent, 3 - good, 2 - fair and 1 - poor). Quantitative measurements of CT values, image noise and contrast-to-noise (CNR) were measured in each group. A receiver-operating characteristic (ROC) analysis was performed to determine a radiation reduction threshold up to which excellent IQ was maintained. RESULTS: There were no significant differences in objective noise, SNR and CNR values among Groups A, B, C, D, and E (P=0.14, 0.09, 0.17, respectively). There were no significant differences in the scores of the subjective IQ between Group A, and Groups B, C, D, E (P=0.23-0.97). Significant differences in image sharpness and study acceptability were observed between groups A and E (P<0.05). Using the criterion of excellent IQ (score 4), the ROC curve of dose levels and IQ acceptability established a reduction of 60% of tube output (Group D) as optimum cutoff point (AUC: 0.72, 95% CI: 0.59-0.86). Group D (84 mAs with L5) provided equivalent subjective image ranking (with lumen sharpness taken into account) and objective IQ measurements (noise: 36.5 +/- 10.7; SNR: 13.6 +/- 4.9; CNR: 16.28 +/ 5.4) compared with FBP images in Group A (noise: 35.5 +/- 9.4; SNR: 12.4 +/- 2.5; CNR: 15.4 +/- 3.2) (P=0.14, 0.09, 0.17, respectively). The effective dose (ED) of Group D was 63% lower than that of Group A (1.2 +/- 0.1 mSv versus 3.2 +/ 0.6 mSv). CONCLUSION: Iterative reconstruction techniques can provide 63% ED reduction in prospectively-triggered coronary CTA using 256-slice MDCT while maintaining excellent image quality. PMID- 23036785 TI - Impact of inpatient diabetes management, education, and improved discharge transition on glycemic control 12 months after discharge. AB - AIM: To determine whether inpatient diabetes management and education with improved transition to outpatient care (IDMET) improves glycemic control after hospital discharge in patients with uncontrolled type 2 diabetes (T2DM). METHODS: Adult inpatients with T2DM and HbA1c > 7.5% (58 mmol/mol) admitted for reasons other than diabetes to an academic medical center were randomly assigned to either IDMET or usual care (UC). Linear mixed models estimated treatment dependent differences in the change in HbA1c (measured at 3, 6, and 12 months) from baseline to 1-year follow-up. RESULTS: Thirty-one subjects had mean age 55 +/- 12.6 years, with mean HbA1c of 9.7 +/- 1.6% (82 +/- 18 mmol/mol). Mean inpatient glucose was lower in the IDMET than in the UC group (176 +/- 66 versus 195 +/- 74 mg/dl [9.7 versus 10.8 mmol/l], P = 0.001). In the year after discharge, the average HbA1c reduction was greater in the IDMET group compared with the UC group by 0.6% (SE 0.5%, [7 (SE 5)mmol/mol], P = 0.3). Among patients newly discharged on insulin, the average HbA1c reduction was greater in the in the IDMET group than in the UC group by 2.4% (SE 1.0%, [25 (SE 11)mmol/mol], P = 0.04). CONCLUSIONS: Inpatient diabetes management (IDMET) substantially improved glycemic control 1 year after discharge in patients newly discharged on insulin; patients previously treated with insulin did not benefit. PMID- 23036787 TI - Uncoupling protein 1 dependent reactive oxygen species production by thymus mitochondria. AB - We have previously shown that uncoupling protein 1 is present in thymus and has a role in T-cell development. As reactive oxygen species have been implicated in T cell development, we set out to determine whether uncoupling protein 1 had the potential to regulate reactive oxygen species production in mitochondria isolated from thymus. This was achieved by inhibiting proton leak through uncoupling protein 1 using the purine nucleotide GDP and through ablation of uncoupling protein 1, measuring the amplex red sensitive reactive oxygen species production by mitochondria. In this work we demonstrate, for the first time, that uncoupling protein 1 has the potential to regulate reactive oxygen species production in thymus mitochondria. We also show that reverse electron transport is possible in thymus mitochondria respiring on succinate and glycerol-3-phosphate. The implications of this regulatory role for uncoupling protein 1 are discussed in the context of thymus function. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. PMID- 23036788 TI - Insulin resistance and mitochondrial function in skeletal muscle. AB - The mechanism(s) behind the decreased ability of insulin to facilitate glucose uptake in insulin sensitive tissues as seen in type 2 diabetes is not resolved. With the rapidly increasing prevalence of this disease world-wide, and the many complications that follow the disease, large resources are used in the attempt to resolve the mechanisms of insulin resistance. In this context, a dysfunction of mitochondria in the skeletal muscle has been suggested to play a pivotal role. It has been postulated that a decrease in the content of mitochondria in the skeletal muscle can explain the insulin resistance. Complementary to this also specific defects of components in the respiratory chain in the mitochondria have been suggested to play a role in insulin resistance. A key element in these mechanistic suggestions is inability to handle substrate fluxes and subsequently an accumulation of ectopic intramyocellular lipids, interfering with insulin signaling. In this review we will present the prevailing view-points and argue for the unlikelihood of this scenario being instrumental in human insulin resistance. This article is part of a Directed Issue entitled: Bioenergetic dysfunction. PMID- 23036789 TI - Virus-induced changes in mitochondrial bioenergetics as potential targets for therapy. AB - Infectious diseases such as those caused by virus, account for a vast proportion of deaths worldwide. Re-emerging aspects of host-virus interactions in recent literature include the vital role played by host metabolism on viral replication and the pro-active participation of mitochondria in this process. Different viruses use distinctive strategies to modulate mitochondrial bioenergetics and enhance viral replication. As a result, energy yielding metabolic pathways are programmed to provide both energy and biosynthetic resources to drive viral protein synthesis and produce infectious particles. Therefore, metabolic antagonists may prove important not only to outline efficient therapy strategies but also to shed light on the pathogenesis of viral infections. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. PMID- 23036790 TI - Nurse Jackie and the politics of care. AB - This essay considers Nurse Jackie, one of several recent television shows, including HawthoRNe, and Mercy, that features a nurse as the main character. All 3 shows premiered in 2009 and challenged nursing's longstanding invisibility and misrepresentation on television. Although the plots of each show corrected problematic aspects of nursing's usual media representation, only Nurse Jackie remains on the air. In this paper, I analyze why Nurse Jackie succeeded where the other 2 shows did not, considering the representational politics of care on television and in the national context where health care remains a significant concern. PMID- 23036791 TI - A film producer focuses on issues of social justice and nurses: an interview with Richard Harding. Interviewed by Kathleen McHugh. AB - This case study of Richard Harding, a producer currently making a film about the Benghazi Six, includes an introductory biography, an interview with the producer, and a brief conclusion. Harding's commitments to both filmmaking and social justice issues led him to The Benghazi Six and the injustices suffered by these Bulgarian nurses, who were persecuted and imprisoned in Libya for 9 years on false charges of infecting Libyan children with HIV. The film production ran alongside of and aided international efforts to free the nurses and one physician from Libya. PMID- 23036792 TI - The representation of nurses in 1950s melodrama: a cross-cultural approach. AB - Melodrama is identified as one of the most prolific cinematic genres in terms of the representation of nurses. Its contribution to the overall media depiction of the professional category has therefore been significant. This paper explores melodramatic portrayals of nurses with a specific focus on cinema of the 1950s, the golden age of Western melodrama, and concentrates on two representative case studies: Anna (ITA, 1951), and The Nun's Story (USA, 1959). These films enable a fruitful comparison, sharing several narrative elements, featuring religious nurses as protagonists, and yet eventually conferring on the nursing vocation different values. Such similar nurses' images are examined through a multidisciplinary approach, spanning feminist film theory, gender and cultural studies, cultural history and the social history of nursing. Among the goals of this study is to consider whether different national origins--in these films, Italy and America--have also been influential in the depiction of the respective nurse-character. PMID- 23036793 TI - A review of images of nurses and smoking on the World Wide Web. AB - With the advent of the World Wide Web, historic images previously having limited distributions are now widely available. As tobacco use has evolved, so have images of nurses related to smoking. Using a systematic search, the purpose of this article is to describe types of images of nurses and smoking available on the World Wide Web. Approximately 10,000 images of nurses and smoking published over the past century were identified through search engines and digital archives. Seven major themes were identified: nurses smoking, cigarette advertisements, helping patients smoke, "naughty" nurse, teaching women to smoke, smoking in and outside of health care facilities, and antitobacco images. The use of nursing images to market cigarettes was known but the extent of the use of these images has not been reported previously. Digital archives can be used to explore the past, provide a perspective for understanding the present, and suggest directions for the future in confronting negative images of nursing. PMID- 23036794 TI - Nurses and doctors in prime time series: the dynamics of depicting professional power. AB - This essay sketches a comparison of 1960s' television portrayals with those of the present to show that a limited and incomplete portrayal of nurses has been an enduring feature of prime-time medical television programs. They have depicted physicians then and now as captains of the medical ship and nurses then and now their ancillary and ill-defined helpers. As the comparison makes clear, part of nurses' lack of clear power in TV medical scenarios has to do with the explicit and implicit clout exercised by physicians' organizations to present doctor images effectively. That clout contrasts with nursing organizations' lack of attempts or ability (it's hard to gauge which) to influence network television's most prominent representations of their roles and the environments in which they work. PMID- 23036795 TI - Making a difference from the inside out. AB - Nursing leaders, researchers, and activists have called for change in mass media depictions of nurses since the 1980s, but some nurses are not sure they should make any effort. This article offers a focused look at the trajectories of 2 individuals: Theresa Brown, a clinical nurse and author who writes for the New York Times, and Larry Deutchman, the Executive Vice President of Marketing and Industry Relations at Entertainment Industries Council, Inc. Both Brown and Deutchman were motivated to acquire skills and to take risks to think creatively, and/or to collaborate with other professionals in media to benefit nursing and health. Analysis of their paths offers ideas for action, growth, learning, and collaboration for nurses in relation to the ways that nursing is represented in written and visual media. PMID- 23036796 TI - Erythema multiforme major following treatment with infliximab. AB - BACKGROUND: The growth in the use of anti-tumor necrosis factor alpha (TNF-alpha) agents for treatment of inflammatory conditions has led to increased recognition of the side effects associated with this class of drugs. CASE DESCRIPTION: We report a case of a patient who developed erythema multiforme (EM) major with characteristic oral and cutaneous lesions following treatment with the anti-TNF alpha medication infliximab therapy for Crohn's disease (CD). CLINICAL IMPLICATIONS: To our knowledge, this is the first reported case of infliximab induced EM secondary to the treatment of CD. It is important for dental clinicians evaluating patients using anti-TNF-alpha agents to be aware of this possible complication. PMID- 23036797 TI - Intravenous bisphosphonate-related osteonecrosis of the jaw: long-term follow-up of 109 patients. AB - OBJECTIVE: We report long-term follow-up of patients with intravenous bisphosphonate-related osteonecrosis of the jaw (BRONJ). STUDY DESIGN: Medical and dental histories, including type and duration of bisphosphonate treatment and comorbidities, were analyzed and compared with clinical course of 109 patients with BRONJ at Memorial Sloan-Kettering Cancer Center Dental Service. RESULTS: Median onset of BRONJ in months was 21 (zoledronic acid), 30 (pamidronate), and 36 (pamidronate plus zoledronic acid), with a significant difference between the pamidronate plus zoledronic acid and zoledronic acid groups (P = .01; Kruskal Wallis). The median number of doses for BRONJ onset was significantly less with zoledronic acid (n = 18) than pamidronte plus zoledronic acid (n = 36; P = .001), but not pamidronate alone (n = 29). An association between diabetes (P = .05), decayed-missing-filled teeth (P = .02), and smoking (P = .03) and progression of BRONJ was identified through chi(2) test. CONCLUSIONS: This long-term follow-up of BRONJ cases enhances the literature and contributes to the knowledge of BRONJ clinical course. PMID- 23036798 TI - Patients appearing to dental professionals with orofacial pain arising from intracranial tumors: a literature review. AB - BACKGROUND: A small proportion of patients with orofacial pain appearing to dentists and dental specialists will have intracranial tumors as the underlying cause. These patients may undergo unnecessary dental interventions before the correct diagnosis is made. METHOD: A search of the literature using the PubMed database was performed to identify case reports of this occurrence. Cases were analyzed for common characteristics or presenting features that may aid dentists in identifying patients with intracranial tumors. RESULTS: Twenty-eight cases were identified. Features consistent with the diagnoses of trigeminal neuralgia, persistent idiopathic facial pain, and temporomandibular disorders were the most common presentations. Fifty-nine percent of patients presented with sensory or motor function loss at their initial diagnosis. CLINICAL IMPLICATIONS: Patients who present with symptoms that extend beyond the typical presentation of these entities are at highest risk for intracranial tumors and should be further evaluated. PMID- 23036799 TI - Dermatomyositis: a contemporary review for oral health care providers. AB - Dermatomyositis (DM) is an autoimmune muscle disorder characterized by skin rashes and progressive muscle weakness. This disease is a subset of the idiopathic inflammatory myopathies (IIM) and affects both children and adults. Increased incidence of malignancy has been observed in adult DM, making early diagnosis, treatment, and monitoring crucial. In the past, limitations of these diagnostic criteria and classifications often made it difficult to identify the disease in the early stages. However, in recent years a new understanding of the pathogenesis and clinical features of DM has developed, which enables clinicians to distinguish DM from other autoimmune disorders and other subsets of IIM. Many signs and symptoms of DM involve the orofacial regions. This paper reviews and updates the disease process, orofacial manifestations, and dental considerations for patients with DM. Understanding new knowledge of DM helps oral health care providers coordinate care for patients with this disease. PMID- 23036800 TI - Metal-induced streak artifact reduction using iterative reconstruction algorithms in x-ray computed tomography image of the dentoalveolar region. AB - OBJECTIVE: The objective of this study was to reduce metal-induced streak artifact on oral and maxillofacial x-ray computed tomography (CT) images by developing the fast statistical image reconstruction system using iterative reconstruction algorithms. STUDY DESIGN: Adjacent CT images often depict similar anatomical structures in thin slices. So, first, images were reconstructed using the same projection data of an artifact-free image. Second, images were processed by the successive iterative restoration method where projection data were generated from reconstructed image in sequence. Besides the maximum likelihood expectation maximization algorithm, the ordered subset-expectation maximization algorithm (OS-EM) was examined. Also, small region of interest (ROI) setting and reverse processing were applied for improving performance. RESULTS: Both algorithms reduced artifacts instead of slightly decreasing gray levels. The OS EM and small ROI reduced the processing duration without apparent detriments. Sequential and reverse processing did not show apparent effects. CONCLUSIONS: Two alternatives in iterative reconstruction methods were effective for artifact reduction. The OS-EM algorithm and small ROI setting improved the performance. PMID- 23036801 TI - Somatostatin antagonist potentiates haloperidol-induced catalepsy in the aged rat. AB - Extrapyramidal motor signs are the major features of Parkinson's disease (PD). It is unclear whether there is a link between these signs and such PD-associated factors as aging and somatostatin deficiency. In this study, the intensity of haloperidol-induced catalepsy was examined in young and aged rats with decreased brain somatostatinergic activity. Catalepsy was measured using the bar test. The inhibition of the brain somatostatin activity was simulated by i.c.v. administration of a somatostatin antagonist, cyclosomatostatin. The drug potentiated the haloperidol-induced catalepsy in aged but not young rats. This action of cyclosomatostatin was inhibited by a somatostatin receptor agonist, octreotide. The results suggest that aging and somatostatin deficiency may be of pathogenic relevance for extrapyramidal signs in PD. PMID- 23036802 TI - Progestin-induced heart and neural crest derivatives expressed transcript 2 is associated with fibulin-1 expression in human endometrial stromal cells. AB - OBJECTIVE: To investigate whether heart and neural crest derivatives expressed transcript 2 (HAND2) regulates fibulin-1 (FBLN1) expression during decidualization of human endometrial stromal cells (ESCs). DESIGN: In vitro experiment. SETTING: Research laboratory. PATIENT(S): Twenty-four patients undergoing hysterectomy for benign reasons. INTERVENTION(S): ESCs were cultured with various progestins (medroxyprogesterone acetate [MPA], norethisterone, levonorgestrel, dienogest, and P), E(2), dexamethasone, and/or 8-bromoadenosine 3', 5'-cyclic monophosphate (8-Br-cAMP). HAND2 and FBLN1 were silenced by small interfering RNA technology. MAIN OUTCOME MEASURE(S): HAND2 and FBLN1 expression levels were assessed by real-time polymerase chain reaction and Western blot analysis. RESULT(S): MPA or E(2) + MPA increased HAND2 mRNA levels in ESCs in a time- and dose-dependent manner, and this stimulatory effect was blocked by RU 486 (P receptor antagonist). HAND2 was increased by E(2) + MPA earlier than FBLN1. Simultaneous MPA and 8-Br-cAMP treatment synergistically enhanced HAND2 mRNA levels. P and all the progestins significantly increased HAND2 mRNA levels, whereas E(2), 8-Br-cAMP, or dexamethasone alone had no effect. Silencing of HAND2 expression significantly reduced FBLN1 expression, whereas FBLN1 silencing had no effect on HAND2 expression. CONCLUSION(S): These results suggest that progestin induced HAND2 contributes to FBLN1 expression in human ESCs. PMID- 23036803 TI - Predicting fertility with antimullerian hormone: is a cutoff value adequate? PMID- 23036804 TI - The levels of hepatocyte growth factor in serum and follicular fluid and the expression of c-Met in granulosa cells in patients with polycystic ovary syndrome. AB - OBJECTIVE: To evaluate the levels of hepatocyte growth factor (HGF) in follicular fluid (FF) and the expression of c-Met in granulosa cells (GCs) with respect to the quality of the oocyte and embryo both in patients with polycystic ovary syndrome (PCOS) and in the normal ovary during controlled ovarian hyperstimulation cycles. DESIGN: Prospective controlled study. SETTING: University hospital. PATIENT(S): Fifty-nine women undergoing IVF treatment (of whom 21 had PCOS and 38 were in the control group). INTERVENTION(S): A total of 168 FF samples were collected at the time of oocyte retrieval. The HGF levels were measured by ELISA, and the mRNA expression of c-Met in GCs was detected by real-time polymerase chain reaction. MAIN OUTCOME MEASURE(S): The predictive values of HGF levels in serum and FF and the mRNA expression of c-Met in GCs for successful fertilization and oocyte-embryo quality. RESULT(S): The levels of HGF in serum and FF and the c-Met expression in GCs were similar between the PCOS and control groups. Granulosa cells of fertilized oocytes (2PN) had a significantly higher level of c-Met expression than that in oocytes that failed to fertilize. The mean HGF level in FF was significantly higher in the grade 1 embryos than in the grades 2-4 embryos. CONCLUSION(S): This study suggests that HGF/c-Met signaling may be a crucial determinant of fertilization success. PMID- 23036805 TI - Proteomic analysis of seminal plasma in adolescents with and without varicocele. AB - OBJECTIVE: To compare proteomic profiles of seminal plasma from adolescents with varicocele and changes in semen quality with the plasma from adolescents with varicocele without seminal changes and from adolescents without varicocele. DESIGN: Observational study. SETTING: Patients in an academic research environment. PATIENT(S): Adolescents without varicocele (control group), adolescents with varicocele and normal semen quality (VNS group), adolescents with varicocele and abnormal semen quality (VAS group). INTERVENTION(S): Two semen collections at 1-week interval. Protein separation by two-dimensional protein electrophoresis, analysis by gel densitometry, and identification by mass spectrometry. MAIN OUTCOME MEASURE(S): Overexpressed proteins in each group, observed by increased densitometric signal in gels, and exclusively identified proteins in each group. RESULT(S): No differences were observed among the three groups regarding clinical parameters. In semen analysis, the VAS group presented lower sperm concentration, motility, and morphology compared with the VNS and control groups. Forty-seven protein spots of interest were submitted to mass spectrometry identification. Apoptosis regulation proteins were overexpressed in the VAS group, whereas spermatogenesis proteins were overexpressed in the VNS group. Controls presented proteins related to homeostasis. CONCLUSION(S): Changes in the proteomic profile of adolescents with varicocele and normal semen parameters (VNS group) indicate that normal semen analysis may not reflect alterations in proteins in seminal plasma. Implementation of proteomics will help characterize proteins identified in seminal plasma and will facilitate detection of new proteins associated with spermatogenesis and sperm function. PMID- 23036806 TI - A mathematical model of intestinal oedema formation. AB - Intestinal oedema is a medical condition referring to the build-up of excess fluid in the interstitial spaces of the intestinal wall tissue. Intestinal oedema is known to produce a decrease in intestinal transit caused by a decrease in smooth muscle contractility, which can lead to numerous medical problems for the patient. Interstitial volume regulation has thus far been modelled with ordinary differential equations, or with a partial differential equation system where volume changes depend only on the current pressure and not on updated tissue stress. In this work, we present a computational, partial differential equation model of intestinal oedema formation that overcomes the limitations of past work to present a comprehensive model of the phenomenon. This model includes mass and momentum balance equations which give a time evolution of the interstitial pressure, intestinal volume changes and stress. The model also accounts for the spatially varying mechanical properties of the intestinal tissue and the inhomogeneous distribution of fluid-leaking capillaries that create oedema. The intestinal wall is modelled as a multi-layered, deforming, poroelastic medium, and the system of equations is solved using a discontinuous Galerkin method. To validate the model, simulation results are compared with results from four experimental scenarios. A sensitivity analysis is also provided. The model is able to capture the final submucosal interstitial pressure and total fluid volume change for all four experimental cases, and provide further insight into the distribution of these quantities across the intestinal wall. PMID- 23036807 TI - Entamoeba dispar strains: analysis of polymorphism in Tunisian isolates. AB - The ability to detect intra-species polymorphism in Entamoeba histolytica and Entamoeba dispar is an important tool for studying geographic distribution and transmission mechanisms. E. dispar and E. histolytica share the same mechanism for transmission among human hosts, and so after differentiation between these species. We studied the intra-species variation and distribution of E. dispar strains obtained from cyst passers, specifically from African students and Tunisian food handlers. We analyzed the polymorphic region of the chitinase protein gene in 13 individuals infected with E. dispar, of which 9 were from Tunisia and 4 from other African countries. We identified 7 different chitinase patterns in Tunisians while the 4 isolates from other countries each had a distinct pattern. Two of the patterns we found have been reported in studies from Mexico and India, possibly indicating worldwide spread of certain strains. PMID- 23036808 TI - Immunodetection of coproantigens for the diagnosis of amphistomosis in naturally infected Indian Water Buffalo, Bubalus bubalis. AB - The infection of gastrointestinal helminths in livestock is routinely diagnosed by microscopical examination of faecal samples for the presence of ova/eggs but this approach becomes ineffective for the seasonally egg producing trematodes. Therefore, an alternative approach to detect the coproantigens of liver and rumen amphistomes, Gigantocotyle explanatum and Gastrothylax crumenifer respectively, infecting Indian water buffalo Bubalus bubalis, was undertaken using ELISA, immunodot and countercurrent immunoelectrophoresis (CCIEP). The hyperimmune polyclonal antisera were separately raised in rabbits against excretory/secretory (ES) antigens of both the flukes under study. An overall 70% buffalo faecal samples were tested positive for G. crumenifer and 75% for G. explanatum in Aligarh region. The ELISA results reflected higher infection intensity among individual buffaloes that was also observed at necropsy. Using the respective homologous hyperimmune antiserum, 55% buffaloes tested positive for G. crumenifer and 65% positive for G. explanatum in immunodot assay. Further, the faecal samples with high absorbance values in ELISA and strong immunodot reaction tested positive in CCIEP. The analysis of CCIEP result revealed two and one precipitin bands in G. crumenifer and G. explanatum respectively, indicating prominent antigenic differences in the coproantigens of these two parasites. Taken together, it is suggested that polyclonal antibodies could be conveniently used for the detection of coproantigens by ELISA and immunodot methods, particularly during the non-egg producing phase of the seasonally regulated reproductive cycle of the rumen amphistome G. crumenifer. It is concluded that the coproantigen detection is a good alternative over conventional method for the diagnosis of amphistomosis in livestock; however, further studies are required on a larger sample size of field buffaloes to augment the reproducibility of the present results. PMID- 23036809 TI - Effect of a derived herbal recipe from an ancient Chinese formula, Danggui Buxue Tang, on ovariectomized rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Radix Astragali (root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, RA), Radix Angelicae sinensis (root of Angelica sinensis (Oliv.) Diels, RAS) and Folium Epimedii (leaves of Epimedium brevicomum Maxim., FE) are three of the extensively applied herbal remedies among traditional Chinese medicines for gynecological disorders and osteoporosis. A derivative herbal recipe-RRF, composed of the three medicines with a weight ratio of 5:1:5, is derived from a famous Chinese herbal formula-Danggui Buxue Tang (DBT). RRF has shown noteworthy protective effect in ovariectomized rats, which might represent a promising candidate for the treatment of perimenopausal disorders. The aim of this study was to investigate the herbal recipe RRF for its efficacy on perimenopausal disorders and the underlying mechanisms via ovariectomy (OVX) models. MATERIALS AND METHODS: An experimental model of OVX female rats was applied. Vehicle (Sham and OVX group), RRF (564, 282 and 141 mg/kg/d) and conjugated equine estrogens (CEE, 0.1mg/kg/d, reference drug) were all administrated orally once daily for 16 weeks post operation. After the treatment, radioimmunoassay for estradiol (E(2)), lutenizing hormone (LH), follicle stimulating hormone (FSH) and beta-endorphin (beta--EP), neurotransmitter determination by high-performance liquid chromatography with electrochemical detector (HPLC-ECD) for norepinephrine (NE), dopamine (DA), 5 hydroxytryptamine (5-HT) and 5-HIAA (5-hydroxyindoleacetic acid), bone mineral density (BMD) assay as well as lipid peroxidation assessment, were carried out to probe into the effectiveness of RRF. RESULTS: (1) RRF treatment enhanced E(2) synthese while diminished the elevated serum FSH and LH levels; in terms of neurotransmitter, beta-EP syntheses rallied whereas the hypothalamic NE, DA and 5 HT release experienced varying mitigation in OVX female rats. (2) Repeated administration of RRF was able to attenuate osteoporosis by elevating the BMD levels of total body, and arrest the bone trabeculae degradation. (3) RRF exposure decreased serum levels of constituent MDA and increased endogenous SOD activity. CONCLUSIONS: Results of the current studies revealed that RRF was capable of acting at multiple targets which presumably underlay its potential protective effect in OVX rats mimicking symptoms as observed in perimenopausal women. Hence, RRF might represent a promising candidate in the treatment of perimenopausal disorders in midlife women. PMID- 23036810 TI - Characterization and immunostimulating effects on murine peritoneal macrophages of oligosaccharide isolated from Panax ginseng C.A. Meyer. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C.A. Meyer has been the most precious and renowned Chinese herb used in Asian countries for the treatment of various medical disorders. AIM OF THE STUDY: The aim of this work was to investigate the activation effect on murine peritoneal macrophages of oligosaccharide from the roots of P. ginseng. MATERIALS AND METHODS: In this work, the water-extracted oligosaccharide of P. ginseng was (WGOS) isolated and purified from the roots of P. ginseng by hot water extraction, ultrafiltration and gel-permeation chromatography. The monosaccharide composition and degree of polymerization (DP) of WGOS were determined by a combination of acid hydrolysis, high performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis. Phagocytosis of macrophages was measured by uptake of the neutral red by macrophages, nitric oxide (NO) was determined by the Griess method, inducible NO synthase (iNOS) activity was determined by colorimetric method using a reagent kit, and tumor necrosis factor-alpha (TNF-alpha) was analyzed by enzyme linked immunosorbent assay (ELISA). The reactive species detection kit was used to measure the reactive oxygen species (ROS) level. RESULTS: WGOS was composed of glucose and the DP was ranging from 2 to 14. Immunological tests showed that treatment of WGOS significantly increased phagocytosis of macrophages, and promoted NO, TNF-alpha and ROS production. Furthermore, WGOS dose-dependently stimulated NO formation through the up-regulation of iNOS activity. CONCLUSIONS: Taken together, WGOS possessed high immunopotentiating activity and could be developed as a novel immnunostimulant. PMID- 23036811 TI - Antiallergic effect of Trigonella foenum-graecum L. extracts on allergic skin inflammation induced by trimellitic anhydride in BALB/c mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fenugreek (Trigonella foenum-graecum L.) has a wide variety of therapeutic properties for allergic and inflammatory diseases and is used as a traditional functional food, but its antiallergenic mechanism in these diseases is yet to be clearly elucidated. AIM: In the present study, we investigated the antiallergic activity of fenugreek extract using trimellitic anhydride (TMA)-induced contact hypersensitivity (CHS) mice in vivo and ovalbumin (OVA)-immunized BALB/c mice ex vivo as represented model of T-helper (Th) 2 induced allergy. MATERIALS AND METHODS: BALB/c mice were administered 250 mg/kg body weight (BW) of fenugreek extract for 7 days after sensitization and challenge treatment with 2-5% TMA. Ear thickness were noted, and the infiltration of eosinophils and mast cells was investigated by hematoxylin and eosin (H&E) and toluidine blue (TB) staining. The supernatants from homogenized ear and splenocytes were used for cytokine determination using ELISA. In addition, splenocytes from OVA-immunized BALB/c mice were treated with fenugreek extract ex vivo. The levels of cytokines present in the supernatants were determined by ELISA. The mRNA expression of T-box transcription factor 21 gene (T-bet), GATA binding protein 3 (GATA-3), interferon (IFN)-gamma, and interleukin (IL)-4 were evaluated by real-time RT-PCR. RESULTS: Fenugreek extract was found to reduce ear thickness as well as the infiltration of eosinophils and mast cells. In homogenized ear, the production of IL-4, IL-5, IL-13, and IL-1beta was suppressed. To determine the mechanism by which fenugreek extract inhibits allergic skin inflammation, detailed studies were conducted revealing that fenugreek extract prevented differentiation into Th2 cells in the splenocytes of OVA-induced allergic mice, resulting from suppressing the secretion of IL-4 and mRNA expression of GATA-3, an IL-4 transcription factor. In earlier phase, these extracts enhanced the secretion of IFN-gamma, the mRNA expression of T-bet, an IFN-gamma transcription factor, and the number of IFN-gamma-producing CD4(+) T cells. CONCLUSIONS: These results indicate that fenugreek extract cures Th2 induced allergic skin inflammation by enhancing Th1 differentiation. These data suggest that fenugreek extracts may prove to be an useful therapeutic agent on allergic inflammatory diseases as traditional use as well as Th2-mediated allergic response. PMID- 23036812 TI - Anti-hyperglycemic effects and mechanism of traditional Chinese medicine Huanglian Wan in streptozocin-induced diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Huanglian Wan (HLW) is a prescription of traditional Chinese medicine (TCM), which has been used to treat diabetes mellitus for thousands of years in China. In this study we provide experimental evidence for the clinical use of HLW in the treatment of diabetes mellitus. MATERIALS AND METHODS: HLW extract was prepared and the main components (namely berberine and catalpol) contained in the extract were assayed with high performance liquid chromatography (HPLC), and diabetic model rats were induced by intraperitoneal injection of streptozotocin (STZ). After grouped randomly, diabetic rats were administered low or high dose of HLW extract, acarbose and vehicle for 33 days, respectively. Body weight, food intake, urine volume, urine sugars, fasting plasma glucose and fasting plasma insulin were monitored to evaluate its antidiabetic effects in diabetic rats. Intestinal mucosa homogenate was prepared and the activities of intestinal disaccharidases were assayed. Moreover, oral sucrose tolerance test (OSTT) was performed and the inhibitory effect of HLW extract on the maltase and sucrase in vitro was evaluated. RESULTS: After the treatment of HLW extract, the body weight and the fasting plasma insulin level were found to be increased while food intake, urine volume, urine sugars and fasting plasma were decreased. OSTT showed that HLW extract could lower the postprandial plasma glucose level of diabetic rats. Furthermore, HLW extract could inhibit the activities of sucrase and maltase in vitro. CONCLUSIONS: According to our present findings, the TCM prescription HLW possessed potent anti-hyperglycemic effect on STZ-induced diabetic rats. And HLW extract exerted anti-hyperglycemic effect partly via inhibiting the increased activities of intestinal disaccharidases and elevating the level of plasma insulin in diabetic rats induced by streptozotocin. PMID- 23036813 TI - Study to establish the role of JAK2 and SMAD1/5/8 pathways in the inhibition of hepcidin by polysaccharides from Angelica sinensis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Angelica sinensis polysaccharide (ASP) is one of the major active ingredients in Angelica sinensis (Oliv.) Diels. This traditional Chinese medicine has been used for thousands of years for treating gynecological diseases. AIM OF THE STUDY: Previous studies have suggested that ASP from the roots of Angelica sinensis (Oliv.) Diels suppresses hepcidin expression, but the underlying molecular mechanisms are not known. The present study was designed to establish the role of the janus-kinases 2 (JAK2) and son of mothers against decapentaplegic 1/5/8 (SMAD1/5/8) pathways in the inhibition of hepcidin by polysaccharides from Angelica sinensis in normal rats. MATERIALS AND METHODS: ASP was administered orally (0.3, 0.6 and 1.2g/kg body weight) to male Sprague-Dawley rats every day for 20 days. Intraperitoneal injections of recombinant human erythropoietin (rhEPO; 800 and 2000U/kg body weight) were given to the positive control group every day for 3 days. After administration, hepcidin levels, blood parameters, serum iron status and non-heme iron concentrations in the liver were examined. Western blot analyses were used to investigate the expression of five relevant signaling proteins in the liver. RESULTS: RhEPO injection significantly stimulated erythropoiesis and expression of the serum transferrin receptor (sTfR), and decreased serum iron status and non-heme iron concentrations in the liver. However, blood parameters barely changed in the ASP groups. sTfR, serum iron, and liver iron levels altered only in the ASP high-dose group (1.2g/kg body weight). rhEPO and ASP significantly reduced hepcidin expression by inhibiting the expression of phospho-SMAD1/5/8 and JAK2 in the liver, but not through transmembrane protease serine 6 (TMPRSS6) and extracellular signal-regulated kinase 1/2 (ERK1/2). CONCLUSIONS: These data suggested that ASP can interrupt the JAK2 and SMAD1/5/8 pathways, which eventually results in lower expression of hepcidin. PMID- 23036814 TI - Ethanolic extract and water-soluble polysaccharide from Chaenomeles speciosa fruit modulate lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophage cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chaenomeles speciosa fruits have been widely used in traditional Chinese medicine for treatment of diseases related to inflammatory reaction. This study aims to identify anti-inflammatory and immunomodulatory components of Chaenomeles speciosa fruit and unravel their potential mechanisms. MATERIALS AND METHODS: Ethanolic extract and its n-hexane, chloroform, ethyl acetate and n-butanol fractions, as well as water-soluble polysaccharide, were prepared from dry fruits of Chaenomeles speciosa. The mouse macrophage-like RAW264.7 cells were induced by lipopolysaccharide (LPS) and used as an inflammatory cell model. Production of nitric oxide in the cells was determined by the Griess assay, and cell viability was tested by the MTT method. Cellular apoptosis was evaluated by fluorescence-activated cell sorting. Relative quantification of inflammation-related genes was analyzed by real-time PCR. RESULTS: LPS-induced production of nitric oxide in RAW264.7 cells was significantly inhibited by the ethyl acetate fraction (EAF) at 200-800MUg/ml, while Chaenomeles speciosa polysaccharide (CPS) promoted nitric oxide production at 250-750MUg/ml either alone or in an additive fashion with LPS. Both EAF and CPS did not provoke noticeable cytotoxicity and apoptosis at the above effective concentrations. EAF significantly reduced LPS-induced upshift of iNOS mRNA level but showed no significant effect on the induction of IFN-gamma and G-CSF, while CPS reduced the gene induction of TNF-alpha, IFN-gamma and G-CSF by LPS. CONCLUSIONS: EAF was able to inhibit nitric oxide production by reducing LPS induced upshift of iNOS mRNA level. CPS was an activator of nitric oxide production through cytokines such as TNF-alpha, IFN-gamma and G-CSF. These results demonstrate the therapeutic effects of both ethanolic and aqueous extracts of Chaenomeles speciosa fruit, a traditional edible medicine used in health maintenance and disease treatment. PMID- 23036816 TI - [Technicians and ultrasound. Response to the letter by Dr. Catala]. PMID- 23036817 TI - [Vascular tumors in the joints]. PMID- 23036819 TI - Frontiers and challenges of biophysical methods: from computational biology to X ray free electron laser. PMID- 23036818 TI - Heterosubtypic protection against influenza A induced by adenylate cyclase toxoids delivering conserved HA2 subunit of hemagglutinin. AB - The protective efficacy of currently available influenza vaccines is restricted to vaccine strains and their close antigenic variants. A new strategy to obtain cross-protection against influenza is based on conserved antigens of influenza A viruses (IAV), which are able to elicit a protective immune response. Here we describe a vaccination approach involving the conserved stem part of hemagglutinin, the HA2 subunit, shared by different HA subtypes of IAV. To increase its immunogenicity, a novel strategy of antigen delivery to antigen presenting cells (APCs) has been used. The HA2 segment (residues 23-185) was inserted into a genetically detoxified adenylate cyclase toxoid (CyaA-E5) which specifically targets and penetrates CD11b-expressing dendritic cells. The CyaA-E5 HA2 toxoid induced HA2(93-102), HA2(96-104) and HA2(170-178)-specific and Th1 polarized T-cell responses, and also elicited strong broadly cross-reactive HA2 specific antibody response. BALB/c mice immunized with three doses of purified CyaA-E5-HA2 without any adjuvant recovered from influenza infection 2days earlier than the control mock-immunized mice. More importantly, immunized mice were protected against a lethal challenge with 2LD(50) dose of a homologous virus (H3 subtype), as well as against the infection with a heterologous (H7 subtype) influenza A virus. This is the first report on heterosubtypic protection against influenza A infection mediated by an HA2-based vaccine that can induce both humoral and cellular immune responses without the need of adjuvant. PMID- 23036820 TI - What are the prospects of slowing the progression of Alzheimer's disease? PMID- 23036821 TI - Cellular programs for arbuscular mycorrhizal symbiosis. AB - In arbuscular mycorrhizal (AM) symbiosis, AM fungi colonize root cortical cells to obtain carbon from the plant, while assisting the plant with the acquisition of mineral nutrients from the soil. Within the root cells, the fungal hyphae inhabit membrane-bound compartments that the plant establishes to accommodate the fungal symbiont. Recent data provide new insights into the events associated with development of the symbiosis including signaling for the formation of a cellular apparatus that guides hyphal growth through the cell. Plant genes that play key roles in a cellular program for the accommodation of microbial symbionts have been identified. In the inner cortical cells, tightly regulated changes in gene expression accompanied by a transient reorientation of secretion, enables the cell to build and populate the periarbuscular membrane with its unique complement of transporter proteins. Similarities between the cellular events for development of the periarbuscular membrane and cell plate formation are emerging. PMID- 23036822 TI - How many hours are enough? Accelerometer wear time may provide bias in daily activity estimates. AB - BACKGROUND: There is little consensus on how many hours of accelerometer wear time is needed to reflect a usual day. This study identifies the bias in daily physical activity (PA) estimates caused by accelerometer wear time. METHODS: 124 adults (age = 41 +/- 11 years; BMI = 27 +/- 7 kg.m-2) contributed approximately 1,200 days accelerometer wear time. Five 40 day samples were randomly selected with 10, 11, 12, 13, and 14 h.d-1 of wear time. Four semisimulation data sets (10, 11, 12, 13 h.d-1) were created from the reference 14 h.d-1 data set to assess Absolute Percent Error (APE). Repeated-measures ANOVAs compared min.d-1 between 10, 11, 12, 13 h.d-1 and the reference 14 h.d-1 for inactivity (<100 cts.min-1), light (100-1951 cts.min-1), moderate (1952-5724 cts.min-1), and vigorous (>=5725 cts.min-1) PA. RESULTS: APE ranged from 5.6%-41.6% (10 h.d-1 = 28.2%-41.6%; 11 h.d-1 = 20.3%-36.0%; 12 h.d-1 = 13.5%-14.3%; 13 h.d-1 = 5.6% 7.8%). Min.d-1 differences were observed for inactivity, light, and moderate PA between 10, 11, 12, and 13 h.d-1 and the reference (P < .05). CONCLUSIONS: This suggests a minimum accelerometer wear time of 13 h.d-1 is needed to provide a valid measure of daily PA when 14 h.d-1 is used as a reference. PMID- 23036823 TI - FDG PET/CT findings of thyrotoxicosis induced thymic hyperplasia associated to interferon. PMID- 23036824 TI - Superoxide production during ischemia-reperfusion in the perfused rat heart: a comparison of two methods of measurement. AB - Reactive oxygen species (ROS) have been implicated in many aspects of tissue/cellular metabolic signaling and pathology, including cardioprotection against ischemia-reperfusion damage. Recent reports of enhanced ROS production under global or simulated ischemia in intact heart or isolated cardiomyocytes, respectively, and its decrease again upon reperfusion are paradoxical. Mechanisms for increasing ROS production with decreasing reactant (oxygen) concentration remain elusive, making it important to critically evaluate the experimental methods used to measure ROS production. In the present paper superoxide production in isolated perfused rat hearts was monitored by lucigenin chemiluminescence or dihydroethidine (DHE) oxidation product fluorescence in parallel with redox state of flavin and cytochrome oxidase. Lucigenin luminescence decreased in ischemia and increased again upon reperfusion, transiently reaching values eightfold the control value coincidently with an overshoot of mitochondrial oxygen concentration. Hypoxic perfusion decreased lucigenin chemiluminescence in spite of coronary flow increase, whereas change in lucigenin concentration in the perfusate had negligible effect. In contrast to lucigenin luminescence, the fluorescence of the DHE oxidation product increased continuously during a 30-min global ischemia and decreased precipitously upon reperfusion, this change is coincident with absorption changes of the oxygen binding protein myoglobin. The time course of DHE oxidation product fluorescence during ischemia and reperfusion was similar to that of the mitochondrial membrane potential probe safranin as shown in perfused heart previously [Ylitalo KV, Ala Rami A, Liimatta EV, Peuhkurinen KJ, Hassinen IE. J Mol Cell Cardiol 2000;32:1223 38]. In solution under high oxygen partial pressure DHE was mainly oxidized to a product, whose fluorescence, absorbance and mass spectra were similar to ethidium, and this product behaved like a mitochondrial membrane potential probe in isolated mitochondria. As a membrane permeable cation it accumulates into the mitochondria when the membrane potential is high (high intramitochondrial concentration quenches fluorescence) and then is released (increased fluorescence) during hypoxia/ischemia. Upon reperfusion it is re-accumulated in the mitochondria as the membrane potential recovers. The non-specific oxidation of DHE makes this dye less suitable for superoxide detection in experiments on isolated perfused hearts that necessitate high oxygen partial pressure in the perfusate. The time course of lucigenin luminescence during ischemia/reperfusion is consistent with decreased ROS production during ischemia/hypoxia, while the oxygen concentration is decreased, followed by an overshoot when the heart tissue is reperfused and the oxygen pressures return to normal or above normal. PMID- 23036825 TI - Comparison of the MGIT TBc immunochromatographic assay with the Accuprobe Gen Probe TB assay for identification of Mycobacterium tuberculosis complex: results from a low-burden tuberculosis setting. AB - We compared the BD MPT64 TBc Antigen assay with the Gen-Probe TB assay for identifying Mycobacterium tuberculosis (MTB) from liquid culture vials. The BD TBc Antigen assay was more sensitive than and as specific as the Gen-Probe TB assay, making it a useful alternative for the rapid detection of MTB. PMID- 23036826 TI - The interaction between dopamine transporter function, gender differences, and possible laterality in depression. AB - The Dopamine Transporter (DAT) can reflect the general state of striatal dopamine activity. This current study examined the role of DAT in depressed patients before and after bupropion treatment. Twenty-three patients with major depression were treated with bupropion for 8 weeks. Before and after the treatment, they and 20 normal subjects received the radioligand (99m)Tc-TRODAT-1 single photon emission tomography scan (SPECT). Subjects were assessed with the Hamilton Depression Rating Scale. All DAT images were spatially normalized to an averaged brain template, and the specific binding ratios of the striatum, caudate, and putamen were calculated according the formulae of: [region counts] / [occipital counts] - 1. Depressed patients had greater DAT availability on both sides of the striatum. DAT binding was significantly decreased in the striatum after bupropion treatment. Women had higher initial and final DAT binding in the right and left caudate when compared to depressed men. DAT binding decreased in all areas of the brain in women after successful antidepressant treatment, but only in the right caudate of men. Depressed patients had a greater availability of DAT; it was decreased after bupropion treatment.Women seemed to have more DAT availability. PMID- 23036827 TI - The road to curative surgery in gastric cancer treatment: a different path in the elderly? AB - BACKGROUND: The aim of this study was to evaluate the possibility of a different path to achieve curative surgery in patients older than age 70 years and affected by resectable gastric cancer. STUDY DESIGN: This is a multicentric retrospective study based on an analysis of 1,465 patients with gastric adenocarcinoma who underwent surgery with curative intent. Patients were divided into 2 age groups (younger than 70 years vs older than 70 years) and were evaluated with respect to postoperative morbidity and mortality and survival. RESULTS: Postoperative morbidity and mortality in elderly and nonelderly groups were 24.8% vs 20.6% and 2.6% vs 3.7%, respectively (p = NS). In the elderly group, multivisceral resection was independently associated with surgical complications (hazard ratio [HR] = 1.988; 95% CI, 1.124-3.516; p = 0.018), total gastrectomy with medical complications (HR = 2.007; 95% CI, 1.165-3.459; p = 0.012), and higher postoperative mortality (HR = 4.319; 95% CI, 1.571-11.873; p = 0.005); D1 lymph node dissection was predictive of a lower postoperative mortality rate (HR = 0.219; 95% CI, 0.080-0.603; p = 0.003). Five-year overall survival rates differed significantly in young and elderly patients (58.9% vs 38.9%; p < 0.001), and 5 year cancer-specific survival did not show any significant difference. CONCLUSIONS: Age should not be considered as a factor in the selection of treatment for gastric cancer patients. Curative surgery can be performed as safely in elderly patients as in younger patients, with comparable postoperative results and long-term survival rates, although the life expectancy of elderly patients is shorter. PMID- 23036828 TI - Hazard regression models of early mortality in trauma centers. AB - BACKGROUND: Factors affecting early hospital deaths after trauma can be different from factors affecting later hospital deaths, and the distribution of short and long prehospital times can vary among hospitals. Hazard regression (HR) models might therefore be more useful than logistic regression (LR) models for analysis of trauma mortality, especially when treatment effects at different time points are of interest. STUDY DESIGN: We obtained data for trauma center patients from the 2008-2009 National Trauma Data Bank. Patients were included if they had complete data for prehospital times, hospital times, survival outcomes, age, vital signs, and severity scores. Patients were excluded if pulseless on admission, transferred in or out, or had an Injury Severity Score <9. Using covariates proposed for the Trauma Quality Improvement Program and an indicator for each hospital, we compared LR models predicting survival at 8 hours after injury with HR models with survival censored at 8 hours. Hazard regression models were then modified to allow time-varying hospital effects. RESULTS: A total of 85,327 patients in 161 hospitals met inclusion criteria. Crude hazards peaked initially and then declined steadily. When hazard ratios were assumed constant in HR models, they were similar to odds ratios in LR models associating increased mortality with increased age, firearm mechanism, increased severity, more deranged physiology, and estimated hospital-specific effects. However, when hospital effects were allowed to vary by time, HR models demonstrated that hospital outliers were not the same at different times after injury. CONCLUSIONS: Hazard regression models with time-varying hazard ratios reveal inconsistencies in treatment effects, data quality, and/or timing of early death among trauma centers. Hazard regression models are generally more flexible than LR models, can be adapted for censored data, and potentially offer a better tool for analysis of factors affecting early death after injury. PMID- 23036829 TI - Adapting clinical guidelines to take account of multimorbidity. PMID- 23036830 TI - Labour will halt sell off of NHS to private sector if elected, Burnham says. PMID- 23036831 TI - Craniofacial development: current concepts in the molecular basis of Treacher Collins syndrome. AB - The human face and skull are an elegant example of the anatomical sophistication that results from the interplay between the molecular cascades and the tissue interactions that are necessary for the proper development of the craniofacial complex. When it fails to develop normally the consequences can have life-long implications for the biological, psychological, and aesthetic wellbeing of an affected person. Among the many syndromes that affect the region, understanding of the biology that underlies Treacher Collins syndrome has advanced in the last decade, particularly concerning the causative TCOF1 gene that encodes TREACLE protein, a serine/alanine-rich nucleolar phosphoprotein with an essential function during ribosome biogenesis in cranial neural crest cells. Abnormal growth and differentiation of these cells affect much of the craniofacial skeleton. PMID- 23036832 TI - Re.: Towards a classification system for complex craniofacial fractures: how close are we to developing a satisfactory scale? PMID- 23036833 TI - Marking the skin for oral surgical procedures: improving the WHO checklist. AB - We present a system for marking the skin during oral surgical operations. This system identifies teeth to be extracted or exposed under general anaesthesia. Removal of the wrong tooth can cause appreciable morbidity and leaves the surgeon and organisation liable for litigation and scrutiny by regulatory bodies. A recent review of claims to the NHS litigation authority between 1995 and 2010 showed that in the field of oral and maxillofacial surgery, dentoalveolar surgery resulted in the largest number of claims for negligence, of which removal of the wrong tooth was one of the most common. In 2010/2011 the National Reporting and Learning System (NRLS) of the National Patient Safety Agency (NPSA) were notified of 20 incidents when the wrong tooth had been extracted, which accounted for 5% of all incidents reported. We have therefore developed a robust marking system for oral surgical procedures in our hospital, which improves on the World Health Organisation (WHO) checklist. We have audited patients' perceptions and the clinical application of our marking system, and have shown that the system is welcomed by patients, and is simple and effective for clinicians to use. PMID- 23036834 TI - Free groin flap in hemifacial volume reconstruction. AB - Use of the free groin flap, one of the first microvascular free flaps described, has been neglected recently because it has a short pedicle and varies anatomically. However, we have found its anatomical features and type of tissue ideal for volumetric enhancement in severe hemifacial asymmetry. We present a retrospective review of a consecutive series of 14 patients who had hemifacial augmentation with a free groin flap (mean age at operation 17 years, range 10-42) since 2001, and discuss the surgical technique. The most common cause of asymmetry was hemifacial microsomia (n=6). Anatomical variation of the vessels in the groin did not cause problems. Arterial anastomosis was to the facial artery in 13 patients; 12 patients had simultaneous hard tissue procedures. No flaps failed. The free groin flap is a useful adjunct in the management of hemifacial deficits in volume when free fat grafts will not provide enough bulk. Although the operation can take longer than non-vascularised grafts, little tissue is lost so long-term results may be more predictable. We have found the anatomy fairly consistent and the short pedicle caused no problems. PMID- 23036835 TI - Influence of formalin fixation on the implant stability quotient and mechanical characteristics of bone. AB - The implant stability quotient (ISQ) has been widely evaluated in clinical studies and animal experiments. However, accurate measurement is often difficult in animal models. In such cases, measurement of ISQ in bone is needed after formalin fixation. However, it is not yet clear how such fixation influences the measurement. The purpose of this study was to investigate the influence of formalin fixation on ISQ and the mechanical characteristics of bone. Fourteen tibias were harvested from rabbits; the samples from the left (length 60mm, control group) were soaked in saline and the samples from the right (length 60mm, fixation group) were fixed in 10% neutral-buffered formalin at 4 degrees C for 4h. Three-point bending tests were done at 5mm/min to measure the maximum load and total absorbed energy. Twelve titanium implants (Branemark System((r)) Mk-III TiUnite, Nobel Biocare, Sweden) were placed into the edentulous molar site of the mandibles of 2 dogs and the ISQ was measured by Osstell((r)) (control group) 3 months later. The implants involved in the bone block were then fixed for 4h (fixation group) and the ISQ measured. The maximum load values did not differ significantly between the control and fixation groups. Total absorbed energy was significantly higher in the control group than in the fixation group. ISQ did not differ significantly between the groups. These results suggest that formalin fixation of bone might affect some of the mechanical characteristics of bone, but not its ISQ. PMID- 23036837 TI - Optimization of the masking molecule for active-site-protected immobilization of Taq DNA polymerase and its application. AB - The method of oriented and activity-preserved immobilization of biologically active proteins based on concepts of active-site masking and kinetic control was further developed in this study. Minimal requirements for the masking DNA molecule were found to be a 5'overhang of 5-7 nucleotides and a double-stranded region of 11-13 bp to retain approximately 70% of the enzyme activity. The amplification range of protected immobilized (PIM) Taq DNA polymerase was over 1.2 kb. These data suggest that PIM Taq DNA polymerase can be used for various commercial applications. PMID- 23036836 TI - Interpreting genomic data via entropic dissection. AB - Since the emergence of high-throughput genome sequencing platforms and more recently the next-generation platforms, the genome databases are growing at an astronomical rate. Tremendous efforts have been invested in recent years in understanding intriguing complexities beneath the vast ocean of genomic data. This is apparent in the spurt of computational methods for interpreting these data in the past few years. Genomic data interpretation is notoriously difficult, partly owing to the inherent heterogeneities appearing at different scales. Methods developed to interpret these data often suffer from their inability to adequately measure the underlying heterogeneities and thus lead to confounding results. Here, we present an information entropy-based approach that unravels the distinctive patterns underlying genomic data efficiently and thus is applicable in addressing a variety of biological problems. We show the robustness and consistency of the proposed methodology in addressing three different biological problems of significance--identification of alien DNAs in bacterial genomes, detection of structural variants in cancer cell lines and alignment-free genome comparison. PMID- 23036839 TI - Future-of-nursing report: the impact on emergency nursing. PMID- 23036840 TI - Elemental analysis by NMR. AB - We explore the possibility for elemental analysis by NMR. To keep the efficiency of the signal acquisition common for all spin species, we propose to fix the frequency and vary the magnetic field to cover the isotopes involved in a sample. We introduce constant-frequency receptivity for quantitative elemental analysis in the frequency-fixed NMR experiment. Field-variable NMR experiments are demonstrated using a cryogen-free superconducting magnet. In addition to elemental analysis in liquid solution, solid-state NMR under magic-angle spinning is also described. PMID- 23036838 TI - Adverse effects of analgesics commonly used by older adults with osteoarthritis: focus on non-opioid and opioid analgesics. AB - BACKGROUND: Osteoarthritis (OA) is the most common cause of disability in older adults, and although analgesic use can be helpful, it can also result in adverse drug events. OBJECTIVE: To review the recent literature to describe potential adverse drug events associated with analgesics commonly used by older adults with OA. METHODS: To identify articles for this review, a systematic search of the English-language literature from January 2001 to June 2012 was conducted using PubMed, MEDLINE, EBSCO, and the Cochrane Database of Systematic Reviews for publications related to the medical management of OA. Search terms used were "analgesics," "acetaminophen," "nonsteroidal anti-inflammatory drugs" (NSAIDs), "opioids," "pharmacokinetics," "pharmacodynamics," and "adverse drug events." The search was restricted to those articles that concerned humans aged >=65 years. A manual search of the reference lists from identified articles and the authors' article files, book chapters, and recent reviews was conducted to identify additional articles. From these, the authors identified those studies that examined analgesic use in older adults. RESULTS: There are limited data to suggest that non-frail elders are more likely than their younger counterparts to develop acetaminophen-induced hepatotoxicity. However, decreased hepatic phase II metabolism in frail elders may result in increased risk of hepatotoxicity. It is now well established that older adults are at higher risk of NSAID-induced gastrointestinal toxicity and renal insufficiency. Insofar as opioids, the data that suggest an increased risk of falls, fractures, or delirium need to be tempered by the potential risk of inadequately treating severe chronic OA-related pain. CONCLUSIONS: Acetaminophen is the mainstay frontline analgesic for treating OA-related pain in older adults. NSAIDs should be limited to short-term use only, and for moderate to severe OA-related pain, opioids may be preferable in individuals without substance abuse or dependence issues. PMID- 23036841 TI - A 6-month follow-up after constraint-induced movement therapy with and without transfer package for patients with hemiparesis after stroke: a pilot quasi randomized controlled trial. AB - OBJECTIVE: To investigate the long-term effects of the 'transfer package' in constraint-induced movement therapy, which is an optional protocol to facilitate actual use of the trained affected arm in activities of daily living. DESIGN: A pilot quasi-randomized controlled trial with a blinded single assessor with six month follow-up. SETTING: Hospitalized care at university hospital. SUBJECTS: Twenty-one post-stroke patients were quasi-randomized to either a group with transfer package during constraint-induced movement therapy or a control group (without transfer package). INTERVENTIONS: The transfer package group received 4.5 hours of intensive task training and 0.5 hours of transfer package whereas the control group received 5.0 hours of intensive task training per day during 10 consecutive weekdays. MAIN MEASURES: Arm function was measured with Fugl-Meyer Assessment and Amount of Use score of Motor Activity Log. RESULTS: Twenty-three patients were quasi-randomized, but data from two patients were missing from the long-term follow-up. Both groups showed increase in arm function postintervention. However, at six months' follow-up only the transfer package group showed consistent increase in arm function (with transfer package group versus control group; Fugl-Meyer Assessment, mean (+/- SD) from 48.6 +/- 7.8 (preintervention) to 55.7 +/- 4.5 (postintervention) and 59.0 +/- 3.6 (six months postintervention) versus from 49.1 +/- 5.5 to 52.8 +/- 6.0 and 53.3 +/- 4.9, P= 0.003; Amount of Use scale of Motor Activity Log, mean from 1.3 +/- 0.55 (preintervention) to 2.12 +/- 0.55 (postintervention) and 2.79 +/- 0.98 (six months postintervention) versus from 1.18 +/- 0.70 to 1.61 +/- 0.54 and 1.65 +/- 0.68, P= 0.002). CONCLUSIONS: Our results confirmed the long-term effects of the transfer package in constraint-induced movement therapy. PMID- 23036842 TI - Effectiveness of different exercises and stretching physiotherapy on pain and movement in patellofemoral pain syndrome: a randomized controlled trial. AB - OBJECTIVE: To compare the effectiveness of proprioceptive neuromuscular facilitation combined with exercise, classic stretching physiotherapy intervention, and educational intervention at improving patient function and pain in patients with patellofemoral pain syndrome. DESIGN: Randomized, controlled, blind trial over four months. SETTING: Urban population, Spain. PARTICIPANTS: Patients undergoing primary care for retropatellar pain. INTERVENTION: Subjects were allocated on three different treatment options: a proprioceptive neuromuscular facilitation and aerobic exercise group, a classic stretching group, and a control treatment were applied over four months under the supervision of a physiotherapist. MAIN OUTCOME: Knee Society Score, pain reported (Visual analogue scale) and knee range of motion. Assessments were completed at baseline and after four months. RESULTS: 74 patients were enrolled in the study and distributed between groups. Both the proprioceptive neuromuscular facilitation and classic stretching group showed significant changes in all variables after four months intervention (p < 0.001). The difference in mean Kujala knee score changes between groups (classic stretching group vs. proprioceptive neuromuscular facilitation group vs. control group) at four months was -24.05 (95% confidence interval (CI) -30.19, -17.90), p <= 0.001; vs. -39.03 (95% confidence interval (CI) -42.5, -35.5), p <= 0.001; vs. -0.238 (95% confidence interval (CI) -1.2, 0.726), p = 0.621, respectively. CONCLUSIONS: A proprioceptive neuromuscular facilitation intervention protocol combined with aerobic exercise showed a better outcome than a classic stretching protocol after four months. PMID- 23036843 TI - High frequency electro-acupuncture enhances striatum DAT and D1 receptor expression, but decreases D2 receptor level in 6-OHDA lesioned rats. AB - The direct effects of electro-acupuncture (EA) on the dopaminergic neurotransmitter system in Parkinson's disease (PD) patients remain elusive. In the present study, 0, 2 or 100Hz EA was applied to acupoints Sanyinjiao (SP6), Yanglingquan (GB34) and Zusanli (ST36) in a rat model unilaterally lesioned by 6 hydroxydopamine. Rotational behavior tests were performed and the animals were then decapitated. Levels of striatal dopamine (DA), dopamine transporter, and D1- and D2-like DA receptors were subsequently evaluated. EA at 100 Hz was shown to significantly enhance survival of dopaminergic neurons in the substantia nigra (52.10 +/- 11.41% of the level on the non-lesioned rats vs. 21.22 +/- 5.52% in the non-EA group, P<0.05) and reduce motor deficits (207.80 +/- 31.14 vs. 476.11 +/- 68.80 turns/30 min, P<0.05), whereas it only slightly restored the 6 hydroxydopamine-induced loss of striatal DA (P>0.05 vs. the non-EA group). There was a 253.78% increase in dopamine transporter protein expression in the striatum in the 100 Hz EA group (P<0.05 vs. the non-EA group). Moreover, high frequency EA induced increases in striatal D1-like receptor mRNA and protein levels of 81.88% and 62.62%, respectively (P<0.001 and P<0.05 vs. the non-EA group). However, the D2-like DA receptor up-regulation observed in the non-EA group was suppressed in high frequency group (P>0.05 vs. the sham operation group). These findings suggest that high-frequency EA might work by acting on presynaptic dopamine transporter and postsynaptic dopamine receptors simultaneously to achieve a therapeutic effect in PD patients and models. This might shed some light on the mechanism by which EA affects the DA neurotransmitter system. PMID- 23036844 TI - Early postnatal experience and DRD2 genotype affect dopamine receptor expression in the rat ventral striatum. AB - Dopamine systems can be altered by experiences such as early life adversity. The intensity of these effects seems to vary as a function of interactions between genetic and environmental influences. In a series of experiments we have investigated the effects of genetic variants and early life adversity on several biobehavioral outcomes. Here we investigated the presence of single nucleotide polymorphisms (SNPs) in the gene coding for dopamine D2 receptors (DRD2) and the interaction between these variants with early life adversity on the expression of D2 receptors in the striatum. Time-mated pregnant female rats underwent restraint stress (gestational days 10-21) or were left undisturbed. Following parturition rat pups were maternally reared (MR) or artificially reared (AR). Subsequent to adult behavioral testing, rats were genotyped and their brains were processed (autoradiography) for D2 receptor expression. We found three variants in the DRD2 gene and these variants interacted with early adversity to affect D2 receptor expression in the nucleus accumbens. Specifically, artificially reared rats with AG DRD2 variant showed significantly higher D2 expression compared to mother reared rats with the AG DRD2 variant as well as the artificially reared rats with a GG DRD2 variant. These findings show that adult D2 expression is significantly influenced by the interaction of DRD2 SNPs and early developmental factors. These finding may explain why there are significant individual differences in the impact of early life adversity on dopamine-dependent processes and disorder vulnerabilities. PMID- 23036845 TI - The effect of a honey based gel and silver sulphadiazine on bacterial infections of in vitro burn wounds. AB - Bacterial contamination remains a constant threat in burn wound care. Topical treatments to combat contaminations have good bactericidal effects but can have detrimental effects for the healing process. Treatments with for example silver can increase healing times. Honey based products can be a good alternative as it is antibacterial and patient-friendly. We evaluated the bactericidal and cytotoxic effects of a honey based gel and silver sulphadiazine in a human burn wound model with Pseudomonas aeruginosa. After adding 10(5)colony forming units of P. aeruginosa, topical treatments were applied on the burn wound models. After 2, 12, 24, 28 and 70 h, bacteria were dislodged and counted by plating dilutions. Cytotoxic effects were evaluated histologically in samples of burn wound models treated topically for 3 weeks, without bacteria. L-Mesitran Soft significantly reduced the bacterial load (5-log reduction) up to 24h but did not completely eliminate bacteria from the burn wounds. After Flammazine((r)) treatment, only a few colony forming units were observed at all time points. In contrast, re epithelialization was significantly reduced after application of Flammazine((r)) compared to L-Mesitran Soft or control. This in vitro model of burn wound infection can be used to evaluate topical treatments. L-Mesitran Soft is a good alternative for treating burn wounds but the slightly lower bactericidal activity in the burn wound model warrants a higher frequency of application. PMID- 23036846 TI - Effects of glycine supplementation on myocardial damage and cardiac function after severe burn. AB - BACKGROUND: Glycine has been shown to participate in protection from hypoxia/reoxygenation injury. However, the cardioprotective effect of glycine after burn remains unclear. This study aimed to explore the protective effect of glycine on myocardial damage in severely burned rats. METHODS: Seventy-two Wistar rats were randomly divided into three groups: normal controls (C), burned controls (B), and glycine-treated (G). Groups B and G were given a 30% total body surface area full-thickness burn. Group G was administered 1.5 g/(kg d) glycine and group B was given the same dose of alanine via intragastric administration for 3d. Serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), and blood lactate, as well as myocardial ATP and glutathione (GSH) content, were measured. Cardiac contractile function and histopathological changes were analyzed at 12, 24, 48, and 72 hours. RESULTS: Serum CK, LDH, AST, and blood lactate increased, while myocardial ATP and GSH content decreased in both burned groups. Compared with group B, the levels of CK, LDH, and AST significantly decreased, whereas blood lactate as well as myocardial ATP and GSH content increased in group G. Moreover, cardiac contractile function inhibition and myocardial histopathological damage in group G significantly decreased compared with group B. CONCLUSION: Myocardial histological structure and function were damaged significantly after burn. Glycine is beneficial to myocardial preservation by improving cardiomyocyte energy metabolism and increasing ATP and GSH abundance. PMID- 23036847 TI - Diagnostic accuracy and value of magnetic resonance imaging (MRI) in planning exenterative pelvic surgery for advanced colorectal cancer. AB - PURPOSE: To assess the diagnostic accuracy of magnetic resonance imaging (MRI) in detecting colorectal tumour invasion according to seven intrapelvic compartments for planning exenterative pelvic surgery. METHOD: Sixty-three consecutive patients underwent preoperative MRI planning for exenterative surgery, defined as operative excision beyond conventional mesenteric planes for locally advanced (n=23) and recurrent (n=41) pelvic colorectal cancer. The institutional research committee approved of the study and waived the need for a consent form as the images were retrospectively assessed. Two radiologists reported tumour invasion for each of seven anatomic surgical resection compartments, blinded to histopathology and the intraoperative findings. Sensitivity, specificity and predictive values were calculated for the seven intrapelvic compartments. Cox regression analysis was used to calculate the risk of death and recurrence. Overall interobserver agreement was assessed using Cohen's Kappa coefficient (k). RESULTS: The sensitivity of MRI was >=93.3% in all but the lateral compartment where it was 89.3%. Specificity for the posterior (82.2%) and anterior compartments below the peritoneal reflection (86.4%) was lower compared to the other compartments. Agreement between the two radiologists was found to be good or very good for all compartments (k>0.72). An MRI diagnosis of tumour invasion in the anterior compartment above the peritoneal reflection was associated with a poorer survival (p=0.012). CONCLUSION: MRI is accurate in predicting the extent of colorectal tumour within the pelvis and therefore can be used to determine the type of surgery required for curative resection. It should always be used to stage patients with advanced colorectal pelvic cancer. PMID- 23036848 TI - Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours. AB - BACKGROUND: Brain tumours cause the highest mortality and morbidity rate of all childhood tumour groups and new methods are required to improve clinical management. (1)H magnetic resonance spectroscopy (MRS) allows non-invasive concentration measurements of small molecules present in tumour tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to investigate whether MRS detectable molecules can predict the survival of paediatric brain tumour patients. PATIENTS AND METHODS: Short echo time (30ms) single voxel (1)H MRS was performed on children attending Birmingham Children's Hospital with a suspected brain tumour and 115 patients were included in the survival analysis. Patients were followed-up for a median period of 35 months and Cox-Regression was used to establish the prognostic value of individual MRS detectable molecules. A multivariate model of survival was also investigated to improve prognostic power. RESULTS: Lipids and scyllo-inositol predicted poor survival whilst glutamine and N-acetyl aspartate predicted improved survival (p<0.05). A multivariate model of survival based on three MRS biomarkers predicted survival with a similar accuracy to histologic grading (p<5e-5). A negative correlation between lipids and glutamine was found, suggesting a functional link between these molecules. CONCLUSIONS: MRS detectable biomolecules have been identified that predict survival of paediatric brain tumour patients across a range of tumour types. The evaluation of these biomarkers in large prospective studies of specific tumour types should be undertaken. The correlation between lipids and glutamine provides new insight into paediatric brain tumour metabolism that may present novel targets for therapy. PMID- 23036849 TI - Accurate classification of childhood brain tumours by in vivo 1H MRS - a multi centre study. AB - AIMS: To evaluate the accuracy of single-voxel Magnetic Resonance Spectroscopy ((1)H MRS) as a non-invasive diagnostic aid for paediatric brain tumours in a multi-national study. Our hypotheses are (1) that automated classification based on (1)H MRS provides an accurate non-invasive diagnosis in multi-centre datasets and (2) using a protocol which increases the metabolite information improves the diagnostic accuracy. METHODS: Seventy-eight patients under 16 years old with histologically proven brain tumours from 10 international centres were investigated. Discrimination of 29 medulloblastomas, 11 ependymomas and 38 pilocytic astrocytomas (PILOAs) was evaluated. Single-voxel MRS was undertaken prior to diagnosis (1.5 T Point-Resolved Spectroscopy (PRESS), Proton Brain Exam (PROBE) or Stimulated Echo Acquisition Mode (STEAM), echo time (TE) 20-32 ms and 135-136 ms). MRS data were processed using two strategies, determination of metabolite concentrations using TARQUIN software and automatic feature extraction with Peak Integration (PI). Linear Discriminant Analysis (LDA) was applied to this data to produce diagnostic classifiers. An evaluation of the diagnostic accuracy was performed based on resampling to measure the Balanced Accuracy Rate (BAR). RESULTS: The accuracy of the diagnostic classifiers for discriminating the three tumour types was found to be high (BAR 0.98) when a combination of TE was used. The combination of both TEs significantly improved the classification performance (p<0.01, Tukey's test) compared with the use of one TE alone. Other tumour types were classified accurately as glial or primitive neuroectodermal (BAR 1.00). CONCLUSION: (1)H MRS has excellent accuracy for the non-invasive diagnosis of common childhood brain tumours particularly if the metabolite information is maximised and should become part of routine clinical assessment for these children. PMID- 23036850 TI - A discordant histological risk classification in preoperative and operative biopsy in endometrial cancer is reflected in metastatic risk and prognosis. AB - INTRODUCTION: In endometrial cancer, tissue for histological evaluation is obtained preoperatively (endometrial biopsy) and operatively (hysterectomy specimen). We investigated if a discordant risk classification based on preoperative and operative biopsy is reflected in metastatic risk and prognosis. PATIENTS AND METHODS: One thousand three hundred and seventy-four patients were prospectively included in a multicentre setting (Molecular Markers for Treatment of Endometrial Cancer (MoMaTEC) study). Preoperative and operative specimens were classified as high risk if non-endometrioid histology or endometrioid grade 3; otherwise low risk. Disease specific survival differences were calculated by means of Kaplan-Meier and Cox proportional hazard models. RESULTS: Discordant risk was found in 207 (16%) cases. Lymph node metastases were detected in 7% and 23% of patients with concordant low and high risk respectively versus 14% and 20% in the discordant groups (p<0.001). Five-year disease specific survival in the discordant groups proved intermediate (75-80%) to concordant low (94%) or high (58%) risk. Both operative and preoperative biopsy high-risk results have independent prognostic impact on disease specific survival with adjusted hazard ratios of 2.4 (95% confidence interval (95% CI) 1.5-3.9) and 2.1 (95% CI 1.3-3.2) respectively by Cox analysis. CONCLUSIONS: Discordant risk in preoperative biopsy and hysterectomy identifies an intermediate group with respect to disease spread and prognosis. Preoperative biopsy results remain important also with the hysterectomy histology available. PMID- 23036851 TI - Treatment factors rather than genetic variation determine metabolic syndrome in childhood cancer survivors. AB - BACKGROUND: Genetic variation that regulates insulin resistance, blood pressure and adiposity in the normal population might determine differential vulnerability for metabolic syndrome after treatment for childhood cancer. OBJECTIVE: To evaluate the contribution of candidate single nucleotide polymorphisms (SNPs) relevant for metabolic syndrome in our single centre cohort of adult long-term childhood cancer survivors. METHODS: In this retrospective study 532 survivors were analysed. Median age at diagnosis was 5.7 years (range 0.0-17.8 years), median follow-up time was 17.9 years (range 5.0-48.8) and median age at follow-up was 25.6 years (range 18.0-50.8). JAZF1 gene rs864745, THADA gene rs7578597, IRS1 gene rs2943641, TFAP2B gene rs987237, MSRA gene rs7826222, ATP2B1 gene rs2681472 and rs2681492 were genotyped. The association of genotypes with total cholesterol levels, blood pressure, body mass index, waist circumference and frequency of diabetes were assessed. RESULTS: Metabolic syndrome was more frequent in cranially (23.3%, P=0.002) and abdominally (23.4%, P=0.009) irradiated survivors as compared with non-irradiated survivors (10.0%). Association of allelic variants in rs2681472 and rs2681492 with hypertension, rs987237 and rs7826222 with waist circumference and rs864745, rs7578597 and rs2943641 with diabetes were not significant. None of the SNPs was associated with the metabolic syndrome. Adjusting for age, sex, follow-up time, cranial irradiation and abdominal irradiation did not change these results. CONCLUSIONS: Treatment factors and not genetic variation determine hypertension, waist circumference, diabetes and metabolic syndrome in adult long-term survivors of childhood cancer. PMID- 23036852 TI - Synseed technology-a complete synthesis. AB - Progress in biotechnological research over the last two decades has provided greater scope for the improvement of crops, forest trees and other important plant species. Plant propagation using synthetic seeds has opened new vistas in the field of agriculture. Synseed technology is a highly promising tool for the management of transgenic and seedless plant species, polyploid plants with elite traits and plant lines that are difficult to propagate through conventional propagation methods. Delivery of synseeds also alleviates issues like undertaking several passages for scaling up in vitro cultures as well as acclimatization to ex vitro conditions. Optimization of synchronized propagule development followed by automation of the whole process (sorting, harvesting, encapsulation and conversion) can enhance the pace of synseed production. Cryopreservation of encapsulated germplasm has now been increasingly used as an ex vitro conservation tool with the possible minimization of adverse effects of cryoprotectants and post-preservation damages. Through synseed technology, germplasm exchange between countries could be accelerated as a result of reduced plant quarantine requirements because of the aseptic condition of the plant material. PMID- 23036853 TI - Dioxin suppresses benzo[a]pyrene-induced mutations and DNA adduct formation through cytochrome P450 1A1 induction and (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10 epoxide inactivation in human hepatoma cells. AB - Benzo[a]pyrene (BaP) is metabolically activated by cytochrome P450 enzymes, and forms DNA adduct leading to mutations. Cytochrome P450 1A1 plays a central role in this activation step, and this enzyme is strongly induced by chemical agents that bind to the aryl hydrocarbon receptor (AhR), which is also known as a dioxin receptor. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand has not been shown to form any DNA adduct, but has a possibility to aggravate the toxicity of precarcinogenic polycyclic hydrocarbons through the induction of metabolic enzymes. We treated human hepatoma cells (HepG2) with TCDD, and subsequently exposed them to BaP to elucidate the synergistic effects on mutations. Surprisingly, mutant frequency induced by BaP at the hypoxanthine guanine phosphribosyltransferase (HPRT) locus was decreased by pretreatment with TCDD. In correlation with decrease in the mutant frequencies, BaP-DNA adduct formation was also decreased by TCDD pretreatment. This suppressive effect of TCDD was more potent when the cells were exposed to (+/-)-anti-benzo[a]pyrene-7,8 diol-9,10-epoxide (BPDE), a reactive metabolic intermediate of BaP. Among the enzymes catalyzing BaP oxidation and conjugation, cytochrome P450 1A1, 1A2, 3A4 and UDP-glucuronosyltransferase 1A1 mRNAs were induced by the exposure to TCDD. In cytochrome P450 1A1-deficient murine cells and cytochrome P450 1A1-uninducible human cells, TCDD could not suppress BPDE-DNA adduct formation. Further experiments using "Tet-On" cytochrome P450 1A1-overexpressing cells and a recombinant cytochrome P450 1A1 enzyme demonstrated that this is the key enzyme involved in the biotransformation of BaP, that is, both production and inactivation of BPDE. We conclude that TCDD-induced cytochrome P450 catalyzes the metabolism of BPDE to as yet-unidentified products that are not apparently DNA reactive, thereby reducing mutations in hepatoma cells. PMID- 23036854 TI - BTK: an open-source toolkit for fetal brain MR image processing. AB - Studies about brain maturation aim at providing a better understanding of brain development and links between brain changes and cognitive development. Such studies are of great interest for diagnosis help and clinical course of development and treatment of illnesses. However, the processing of fetal brain MR images remains complicated which limits the translation from the research to the clinical domain. In this article, we describe an open-source image processing toolkit dedicated to these images. In this toolkit various tools are included such as: denoising, image reconstruction, super-resolution and tractography. The BTK resource program (distributed under CeCILL-B license) is developed in C++ and relies on common medical imaging libraries such as Insight Toolkit (ITK), Visualization Toolkit (VTK) and Open Multi-Processing (OpenMP). PMID- 23036855 TI - TreeVis: a MATLAB-based tool for tree visualization. AB - Network-based analyses of high-dimensional biological data often produce results in the form of tree structures. Generating easily interpretable layouts to visualize these tree structures is a non-trivial task. We present a new visualization algorithm to generate two-dimensional layouts for complex tree structures. Implementations in both MATLAB and R are provided. PMID- 23036857 TI - Crystal structure of the filamin N-terminal region reveals a hinge between the actin binding and first repeat domains. AB - The filamin proteins cross-link F-actin and interact with protein partners to integrate both extracellular and intracellular signalling events with the cytoskeleton and to provide mechanoprotection and sensing to cells. The filamins are large, flexible, multi-domain homodimers with the interactions between domains important for protein function. The crystal structure of the N-terminal region of filamin B, containing the actin binding domain (ABD) and the first filamin repeat (FR1) domain, reveals an extended two-domain conformation with no interaction between the ABD and FR1 other than the connecting linker region. The two FLNB347 structures in the crystallographic asymmetric unit exhibit differing relative domain orientations providing the first high-resolution structural characterisation of a filamin inter-domain conformational change. The structure reveals a new hinge in the linker region between ABD and FR1 that is ideally positioned to orient the ABD for actin binding and adds to the previously described hinge regions, hinge 1 (between repeats 15 and 16) and hinge 2 (repeats 23 and 24), providing an additional mechanism by which filamin can exhibit inter domain flexibility. The extended structure, with the absence of interactions between the domains, implies that any conformational rearrangements required for actin binding by the ABD, as observed for homologous proteins, can freely occur without being influenced by FR1. The ABD retains its previously observed compact conformation. FR1 exhibits a filamin immunoglobulin-like domain fold with a closed C-D beta-strand groove, in contrast to filamin repeats that bind protein partners with this region of the domain surface. PMID- 23036856 TI - Exercise adherence, cardiopulmonary fitness and anthropometric changes improve exercise self-efficacy and health-related quality of life. AB - BACKGROUND: Regular exercise increases exercise self-efficacy and health-related quality of life (HRQOL); however, the mechanisms are unknown. We examined the associations of exercise adherence and physiological improvements with changes in exercise self-efficacy and HRQOL. METHODS: Middle-aged adults (N = 202) were randomized to 12 months aerobic exercise (360 minutes/week) or control. Weight, waist circumference, percent body fat, cardiopulmonary fitness, HRQOL (SF-36), and exercise self-efficacy were assessed at baseline and 12 months. Adherence was measured in minutes/day from activity logs. RESULTS: Exercise adherence was associated with reduced bodily pain, improved general health and vitality, and reduced role-emotional scores (P(trend) <= 0.05). Increased fitness was associated with improved physical functioning, bodily pain and general health scores (P(trend) <= 0.04). Reduced weight and percent body fat were associated with improved physical functioning, general health, and bodily pain scores (P(trend) < 0.05). Decreased waist circumference was associated with improved bodily pain and general health but with reduced role-emotional scores (P(trend) <= 0.05). High exercise adherence, increased cardiopulmonary fitness and reduced weight, waist circumference and percent body fat were associated with increased exercise self-efficacy (P(trend) < 0.02). CONCLUSIONS: Monitoring adherence and tailoring exercise programs to induce changes in cardiopulmonary fitness and body composition may lead to greater improvements in HRQOL and self-efficacy that could promote exercise maintenance. PMID- 23036858 TI - Bacterial and plant ketol-acid reductoisomerases have different mechanisms of induced fit during the catalytic cycle. AB - Ketol-acid reductoisomerase (KARI) is the second enzyme in the branched-chain amino acid biosynthesis pathway, which is found in plants, fungi and bacteria but not in animals. This difference in metabolism between animals and microorganisms makes KARI an attractive target for the development of antimicrobial agents. Herein we report the crystal structure of Escherichia coli KARI in complex with Mg(2+) and NADPH at 2.3A resolution. Ultracentrifugation studies confirm that the enzyme exists as a tetramer in solution, and isothermal titration calorimetry shows that the binding of Mg(2+) increases structural disorder while the binding of NADPH increases the structural rigidity of the enzyme. Comparison of the structure of the E. coli KARI-Mg(2+)-NADPH complex with that of enzyme in the absence of cofactors shows that the binding of Mg(2+) and NADPH opens the interface between the N- and C-domains, thereby allowing access for the substrates to bind: the existence of only a small opening between the domains in the crystal structure of the unliganded enzyme signifies restricted access to the active site. This observation contrasts with that in the plant enzyme, where the N-domain can rotate freely with respect to the C-domain until the binding of Mg(2+) and/or NADPH stabilizes the relative positions of these domains. Support is thereby provided for the idea that plant and bacterial KARIs have evolved different mechanisms of induced fit to prepare the active site for catalysis. PMID- 23036860 TI - Impaired folding of the mitochondrial small TIM chaperones induces clearance by the i-AAA protease. AB - The intermembrane space of mitochondria contains a dedicated chaperone network the small translocase of the inner membrane (TIM) family-for the sorting of hydrophobic precursors. All small TIMs are defined by the presence of a twin CX(3)C motif and the monomeric proteins are stabilized by two intramolecular disulfide bonds formed between the cysteines of these motifs. The conserved cysteine residues within small TIM members have also been shown to participate in early biogenesis events, with the most N-terminal cysteine residue important for import and retention within the intermembrane space via the receptor and disulfide oxidase, Mia40. In this study, we have analyzed the in vivo consequences of improper folding of small TIM chaperones by generating site specific cysteine mutants and assessed the fate of the incompletely oxidized proteins within mitochondria. We show that no individual cysteine residue is required for the function of Tim9 or Tim10 in yeast and that defective assembly of the small TIMs induces their proteolytic clearance from mitochondria. We delineate a clearance mechanism for the mutant proteins and their unassembled wild-type partner protein by the mitochondrial ATP-dependent protease, Yme1 (yeast mitochondrial escape 1). PMID- 23036859 TI - Unfolding of the C-terminal domain of the J-protein Zuo1 releases autoinhibition and activates Pdr1-dependent transcription. AB - The C-terminal 69 residues of the J-protein Zuo1 are sufficient to activate Pdr1, a transcription factor involved in both pleiotropic drug resistance and growth control. Little is understood about the pathway of activation by this primarily ribosome associated Hsp40 co-chaperone. Here, we report that only the C-terminal 13 residues of Zuo1 are required for activation of Pdr1, with hydrophobic residues being critical for activity. Two-hybrid interaction experiments suggest that the interaction between this 13-residue Zuo1 peptide and Pdr1 is direct, analogous to the activation of Pdr1 by xenobiotics. However, simply dissociation of Zuo1 from the ribosome is not sufficient for induction of Pdr1 transcriptional activity, as the C-terminal 86 residues of Zuo1 fold into an autoinhibitory left handed four-helix bundle. Hydrophobic residues critical for interaction with Pdr1 are sequestered within the structure of this C-terminal domain (CTD), necessitating unfolding for activation. Thus, although expression of the CTD does not result in activation, alterations that destabilize the structure cause induction of pleiotropic drug resistance. These destabilizing alterations also result in dissociation of the full-length protein from the ribosome. Thus, our results are consistent with an activation pathway in which unfolding of Zuo1's C terminal helical bundle domain results in ribosome dissociation followed by activation of Pdr1 via a direct interaction. PMID- 23036861 TI - Making space for criminalistics: Hans Gross and fin-de-siecle CSI. AB - This article explores the articulation of a novel forensic object-the 'crime scene'-and its corresponding expert-the investigating officer. Through a detailed engagement with the work of the late nineteenth-century Austrian jurist and criminalist Hans Gross, it analyses the dynamic and reflexive nature of this model of 'CSI', emphasising the material, physical, psychological and instrumental means through which the crime scene as a delineated space, and its investigator as a disciplined agent operating within it, jointly came into being. It has a further, historiographic, aim: to move away from the commonplace emphasis in histories of forensics on fin-de-siecle criminology and toward its comparatively under-explored contemporary, criminalistics. In so doing, it opens up new ways of thinking about the crime scene as a defining feature of our present-day forensic culture that recognise its historical contingency and the complex processes at work in its creation and development. PMID- 23036862 TI - Just truth? Carefully applying history, philosophy and sociology of science to the forensic use of CCTV images. AB - Using as a case study the forensic comparison of images for purposes of identification, this essay considers how the history, philosophy and sociology of science might help courts to improve their responses to scientific and technical forms of expert opinion evidence in ways that are more consistent with legal system goals and values. It places an emphasis on the need for more sophisticated models of science and expertise that are capable of helping judges to identify sufficiently reliable types of expert evidence and to reflexively incorporate the weakness of trial safeguards and personnel into their admissibility decision making. PMID- 23036863 TI - Influence of surface conditioning on bonding to polyetheretherketon (PEEK). AB - OBJECTIVE: The purpose of the study was the evaluation of the bond strength of a provisional resin to a polyetheretherketon (PEEK) using different surface treatments and conditioning methods. METHODS: PEEK disks were polished with 600grit rotating silicon carbide papers. Plexiglas tubes were filled and bonded with a provisional resin (Luxatemp Fluorescence) to the PEEK disks which were air abraded either with 110MUm alumina particles (Rocatec Pre) and conditioned with the primers Ecusit Composite Repair, Luxatemp Glaze & Bond or Clearfil Ceramic Primer or they were tribochemically silica-coated (Rocatec Plus) and silanated with Espe Sil or Clearfil Ceramic Primer. Air-abraded PEEK disks without priming served as control. Subgroups of 8 specimens each were stored in distilled water at 37 degrees C either for 3 days without thermal cycling (TC) or for 150 days with additional 37,500 thermal cycles between 5 and 55 degrees C (dwell time 30s). Following storage tensile bond strength (TBS) was tested at a crosshead speed of 2mm/min in a universal testing machine. Statistical analysis was conducted with Kruskal-Wallis test followed by Wilcoxon rank sum test adjusted by Bonferroni-Holm. RESULTS: After 3 days TBS ranged from 0 to 15.0MPa. After artificial aging over 150 days TBS ranged from 0 to 12.9MPa. Using air-abrasion and priming with Luxatemp Glaze & Bond resulted in significantly higher TBS than all other methods, which was also durable over time. CONCLUSION: The use of the methylmethacrylate containing primer Luxatemp Glaze & Bond after air-abrasion of PEEK surfaces can be recommended clinically as promising bonding method to PEEK. PMID- 23036864 TI - Role of estrogen receptor-alpha (ESR1) and the type 1 insulin-like growth factor receptor (IGFR1) in estradiol-stimulated proliferation of cultured bovine satellite cells. AB - Although the exact mechanism(s) by which estradiol (E(2)) enhances muscle growth in a number of species, including humans and cattle, is not known, E(2) treatment has been shown to stimulate proliferation of cultured bovine satellite cells (BSCs). This is particularly significant because satellite cells are the source of nuclei needed to support postnatal muscle fiber hypertrophy and are thus crucial in determining the rate and extent of muscle growth. The objective of this study was to assess the role of estrogen receptor-alpha (ESR1) and the type 1 insulin-like growth factor receptor (IGFR1) in E(2)-stimulated proliferation of cultured BSCs. To accomplish this, we have used small interfering RNA (siRNA) to silence expression of ESR1 or IGFR1 and assessed the effects on E(2)-stimulated proliferation in BSC cultures. In BSCs treated with nonspecific siRNA, E(2) significantly (P < 0.05) stimulates proliferation under conditions in which neither IGF-1 nor IGF-2 expression is increased; however, treatment of ESR1- or IGFR1-silenced cells with E(2) does not significantly stimulate proliferation. These results indicate that both ESR1 and IGFR1 are required for E(2) to stimulate proliferation in BSC cultures. The fact that this occurs under culture conditions in which neither IGF-1 nor IGF-2 mRNA expression is increased strongly suggests that E(2) activates IGFR1 via a mechanism that does not involve increased IGF-1 or IGF-2 binding to the receptor. PMID- 23036865 TI - [Pedunculated giant pharyngoepiglottic lipoma in the airway]. PMID- 23036867 TI - Identifying with a process of change: a qualitative assessment of the components included in a smoking cessation intervention at antenatal clinics in South Africa. AB - INTRODUCTION: previous research has suggested that pregnant women prefer a person centred approach for smoking cessation interventions. However few studies have illustrated the mechanism through which such an approach has an influence on quitting or reduction rates among pregnant women in resource poor settings. PURPOSE: to explore the role of different components included in a smoking cessation intervention delivered to disadvantaged pregnant women with high smoking rates attending public health antenatal clinics in South Africa. METHODS: a qualitative design consisting of focus-group discussion with women exposed to the intervention was used. Women were purposively selected from four antenatal clinics and one tertiary hospital to represent different experiences of the intervention. Focus group discussions with four groups of smokers and four groups of quitters were conducted and a total of 41 women were interviewed. Data were analysed using content analysis. MAIN FINDINGS: the main theme describing the intervention effect that emerged from the interviews was, 'Making identification with change possible'. The categories 'An impulse for change', 'An achievable recipe', 'A physical reminder' and 'A compassionate companion' further described how each intervention component was perceived by women and how it contributed to behaviour change. CONCLUSIONS: behaviour change interventions that are directly informed by the target population with regards to its design, content and delivery offer great opportunities for positive behaviour change. Women positively evaluated all the components employed in this intervention but rated the social support they received from peer-counsellors as the overriding aspect of the intervention. PMID- 23036866 TI - [The usefulness of ultrasound-guided pectoral nerve block for postoperative pain control in reconstructive breast surgery]. PMID- 23036868 TI - Reproductive health services in Malawi: an evaluation of a quality improvement intervention-reply to paper YMIDW-D-11-00257. PMID- 23036869 TI - Methionine sulfoxide reductase A attenuates heme oxygenase-1 induction through inhibition of Nrf2 activation. AB - Methionine sulfoxide reductase A (MsrA) functions as a protein repair enzyme by catalyzing the stereospecific reduction of methionine-S-sulfoxide to methionine. We previously identified that MsrA deficiency inhibits normal cell growth via activation of the p53-p21 pathway. In this study, we report a critical role of MsrA in expression of heme oxygenase-1 (HO-1), a highly inducible enzyme that has an anti-proliferative effect mediated by up-regulation of p21. Down-regulation of MsrA induced HO-1 expression in mammalian cells with increased p21 levels, but MsrA overexpression did not affect HO-1 expression. MsrA depletion activated Nrf2 by increasing its expression and nuclear translocation. Nrf2 activation was associated with increased reactive oxygen species production. MsrA overexpression in MsrA-depleted cells led to the reduction of increased HO-1 expression, and suppressed nuclear accumulation of Nrf2. Taken together, the data suggest that MsrA attenuates HO-1 induction by inhibiting Nrf2 activation. PMID- 23036870 TI - 1,4-Diamino-2-butanone, a putrescine analogue, promotes redox imbalance in Trypanosoma cruzi and mammalian cells. AB - The putrescine analogue 1,4-diamino-2-butanone (DAB) is highly toxic to various microorganisms, including Trypanosoma cruzi. Similar to other alpha-aminocarbonyl metabolites, DAB exhibits pro-oxidant properties. DAB undergoes metal-catalyzed oxidation yielding H(2)O(2), NH(4)(+) ion, and a highly toxic alpha-oxoaldehyde. In vitro, DAB decreases mammalian cell viability associated with changes in redox balance. Here, we aim to clarify the DAB pro-oxidant effects on trypomastigotes and on intracellular T. cruzi amastigotes. DAB (0.05-5 mM) exposure in trypomastigotes, the infective stage of T. cruzi, leads to a decline in parasite viability (IC(50)c.a. 0.2 mM DAB; 4 h incubation), changes in morphology, thiol redox imbalance, and increased TcSOD activity. Medium supplementation with catalase (2.5 MUM) protects trypomastigotes against DAB toxicity, while host cell invasion by trypomastigotes is hampered by DAB. Additionally, intracellular amastigotes are susceptible to DAB toxicity. Furthermore, pre-treatment with 100 500 MUM buthionine sulfoximine (BSO) of LLC-MK2 potentiates DAB cytotoxicity, whereas 5 mM N-acetyl-cysteine (NAC) protects cells from oxidative stress. Together, these data support the hypothesis that redox imbalance contributes to DAB cytotoxicity in both T. cruzi and mammalian host cells. PMID- 23036871 TI - Discrete sliding mode control for robust tracking of higher order delay time systems with experimental application. AB - In this paper, a discrete time sliding mode controller (DSMC) is proposed for higher order plus delay time (HOPDT) processes. A sliding mode surface is selected as a function of system states and error and the tuning parameters of sliding mode controller are determined using dominant pole placement strategy. The condition for the existence of stable sliding mode is obtained by using Lyapunov function. The proposed method is applicable to HOPDT processes with oscillatory and integrating behavior, open loop instability or non-minimum phase characteristics and works satisfactory under the effect of parametric uncertainty. The method does not require reduced order model and provides simple way to design the controllers. The simulation and experimentation results show that the proposed method ensures desired tracking dynamics. PMID- 23036872 TI - Interaction of disciplines. PMID- 23036873 TI - Effectiveness of two manipulative therapies in sacroiliac joint syndrome- thoughts for research and clinical applications. PMID- 23036874 TI - Why reservations remain: a critical reflection about the systematic review and meta-analysis "Osteopathic manipulative treatment for low back pain" by Licciardone et al. AB - In 2005 John Licciardone, Angela Brimhall, and Linda King published a systematic review and meta-analysis of randomized controlled trials with the title: Osteopathic manipulative treatment for low back pain. The conclusions of systematic review and meta-analysis depend highly on the right search strategy, the quality of the included studies (internal validity), and the error-free, unbiased and transparent evaluation of the review. As illustrated by the following article Licciardone's review includes elements that could lead to biased results. It is concluded that Licciardone et al. focused too much on the statistical significance, and overlooked that the problem of the review lay not in the calculations but in the quality and compilation of the studies. PMID- 23036875 TI - The immediate effects of sigmoid colon manipulation on pressure pain thresholds in the lumbar spine. AB - Visceral manual therapy is increasingly used by UK osteopaths and manual therapists, but there is a paucity of research investigating its underlying mechanisms, and in particular in relation to hypoalgesia. The aim of this study was to investigate the immediate effects of osteopathic visceral mobilisation on pressure pain thresholds. A single-blinded, randomised, within subjects, repeated measures design was conducted on 15 asymptomatic subjects. Pressure pain thresholds were measured at the L1 paraspinal musculature and 1st dorsal interossei before and after osteopathic visceral mobilisation of the sigmoid colon. The results demonstrated a statistically significant improvement in pressure pain thresholds immediately after the intervention (P<0.001). This effect was not observed to be systemic, affecting only the L1 paraspinal musculature. This novel study provides new experimental evidence that visceral manual therapy can produce immediate hypoalgesia in somatic structures segmentally related to the organ being mobilised, in asymptomatic subjects. PMID- 23036876 TI - Ottawa Panel evidence-based clinical practice guidelines on therapeutic massage for low back pain. AB - OBJECTIVE: To update evidence-based clinical practice guidelines (EBCPG) on massage therapy compared to control or other treatment for adults (>18 years) suffering from acute, sub-acute and chronic low back pain (LBP). METHODS: A literature search was performed for relevant articles between January 1, 1948 and December 31, 2010. Eligibility criteria were then applied focussing on participants, interventions, controls, and outcomes, as well as methodological quality. Recommendations based on this evidence were then assigned a grade (A, B, C, C+, D, D+, D-) based on their strength. RESULTS: A total of 100 recommendations were formulated from 11 eligible articles, including 37 positive recommendations (25 grade A and 12 grade C+) and 63 neutral recommendations (49 grade C, 12 grade D, and 2 grade D+). DISCUSSION: These guidelines indicate that massage therapy is effective at providing pain relief and improving functional status. CONCLUSION: The Ottawa Panel was able to demonstrate that massage interventions are effective to provide short term improvement of sub-acute and chronic LBP symptoms and decreasing disability at immediate post treatment and short term relief when massage therapy is combined with therapeutic exercise and education. PMID- 23036877 TI - Medical exercise therapy, and not arthroscopic surgery, resulted in decreased depression and anxiety in patients with degenerative meniscus injury. AB - The purpose of this pilot study was to compare the effectiveness of conservative therapy involving medical exercise therapy (MET) versus arthroscopic surgery in patients with knee pain, with MRI-verified degenerative meniscus. The patients were randomly assigned either to MET (n = 9) or to arthroscopic surgery (n = 8). Patients receiving MET had 3 treatments a week for 3 months, a total of 36 treatments. The arthroscopy consisted of meniscectomy with no structured conservative therapy after surgery. Assessment of pain, function, anxiety and depression were performed at inclusion and after 3 months. At the end of treatment, which was 3 months after inclusion, there were no statistical differences between the two groups regarding pain and function. However, anxiety and depression were significantly reduced in the MET group compared with the patients receiving arthroscopic surgery. Bearing in mind the low number of included patients in this pilot study, arthroscopy was found to be no better than MET regarding knee pain and overall daily function. The results from this pilot study are similar to other clinical studies, thereby demonstrating that conservative therapy is just as effective as surgery. PMID- 23036878 TI - Applied kinesiology: distinctions in its definition and interpretation. AB - Modification of the motor system in assessing and treating as well as understanding one of the causes of musculoskeletal dysfunctions is a topic of growing importance in healthcare. Applied kinesiology (AK) addresses this interest in that it is a system which attempts to evaluate numerous aspects of health (structural, chemical, and mental) by the manual testing of muscles combined with other standard methods of diagnosis. It leads to a variety of conservative, non-invasive treatments which involve joint manipulations or mobilizations, myofascial therapies, cranial techniques, meridian and acupuncture skills, clinical nutrition and dietary management, counseling skills, evaluating environmental irritants, and various reflex techniques. The effectiveness of these ancillary treatments is believed to be consistent with the expanded construct validity of the manual muscle test (MMT), as described, although this assertion has primarily been tested in outcome studies. AK and its adjunctive procedures (challenge and therapy localization) are highlighted in this review providing details of its implementation as prescribed by an International College of Applied Kinesiology's Board of Examiners, cited for its scholarly and scientific activities. Because these procedures are believed to identify specific articular, soft tissue, biochemical, or emotional issues underlying muscle function, the applicability of this diagnostic method for all clinicians treating muscle imbalance disorders is described. As of yet, MMT efficacy in therapy localization and challenge techniques has not been established in published, peer reviewed research. A variety of challenges likewise remain for professional AK to establish itself as an emerging science, with numerous gaps in the literature and testable hypotheses enumerated. Of particular concern are a multiplicity of derivatives of AK that have been described in the literature, which should be greeted with caution in light of the fact that they lack one or more of the essential attributes of AK as described in this report. The validity of these studies which have been critical of applied kinesiology appears in many instances to be no greater than several of the randomized controlled trials, cohort studies, case control studies, and case studies found in this communication to support various aspects of applied kinesiology. PMID- 23036880 TI - Fascia science and clinical applications: editorial. PMID- 23036879 TI - The effect of fatigue and velocity on the relative timing of hamstring activation in relation to quadriceps. AB - Inter-muscular coordination has an important role in proper function and prevention of injuries in the knee joint. The purpose of this study was to characterize the effect of velocity and fatigue on the relative activation onset of hamstring to quadriceps muscles during knee extension. Thirty one healthy and non-athletic volunteers (24 women, 7 men) were recruited for the study. The onset time of vastus medialis, vastus lateralis, rectus femoris, medial and lateral hamstring were measured during maximum voluntary extension of the knee joint at velocities of 45 degrees /s, 150 degrees /s & 300 degrees /s before and after fatigue and the mean delay onset of all pairs of H-Q were measured. A two-way repeated measures ANOVA test was used to compare across the mean delayed onset of hamstring related to quadriceps muscles at various velocities. Hamstring muscle showed a delayed activation related to quadriceps and increasing the velocity of shortening has a prominent effect on the inter-muscular coordination with early activation of hamstring related to quadriceps muscles (F = 6.7, p < 0.002 for Biceps-rectus femoris, F = 6.31, p < 0.003 for semitendinosus-rectus femoris, F = 6.26, p < 0.003 for biceps-vastus lateralis, F = 5.98, p < 0.004 for semitendinosus-vastus lateralis, F = 3.19, p < 0.04 for biceps-vastus medialis and F = 3.2, p < 0.04 for semitendinosus-vastus medialis). This could predispose these muscles to over strain and possible injuries. The main effect of fatigue condition and its interaction with velocity however, showed statistically nonsignificant result. PMID- 23036881 TI - What is 'fascia'? A review of different nomenclatures. AB - There are many different definitions of fascia. Here the three most common nomenclatures are compared, including that of the Federative International Committee on Anatomical Terminology (1998), the definition included in the latest British edition of Gray's Anatomy (2008) and the newer and more comprehensive terminology suggested at the last international Fascia Research Congress (2012). This review covers which tissues are included and excluded in each of these nomenclatures. The advantages and disadvantages of each terminology system are suggested and related to different fields of application, ranging from histology, tissue repair, to muscular force transmission and proprioception. Interdisciplinary communication involving professionals of different fields is also discussed. PMID- 23036882 TI - Selected fascial aspects of osteopathic practice. AB - Fascia is a connective tissue organised as a three-dimensional network that surrounds, supports, suspends, protects, connects and divides muscular, skeletal and visceral components of the body. Studies suggest that fascia reorganises itself along the lines of tension imposed or expressed in the body, and in ways that may cause repercussions to fascial restriction that are body-wide. This may potentially create stress on any structures enveloped by fascia itself, with consequent mechanical and physiological effects. From an osteopathic perspective, fascial techniques aim to release such tensions, decrease pain and restore function. The proposed mechanism for fascial techniques is based on various studies that have looked at the plastic, viscoelastic and piezoelectric properties of connective tissue. This review explores some of the features described above, together with evidence supporting the therapeutic efficacy of fascial manipulation, offering a selected overview of the fascial component in osteopathic assessment and treatment. PMID- 23036883 TI - Phylontogenic progressions or infant development--sit to crawl. PMID- 23036884 TI - Pattern recognition: the miracle of foresight, with the benefit of hindsight. AB - One of the central skills integral to effective Bodywork and Movement Therapies is pattern recognition. The ability to be able identify key patterns of data and piece them together using skill, knowledge, intuition and reasoning is what can separate great results from mediocre results. One such pattern that has been observed by movement therapists over the last century, infant developmental progressions, are highlighted and contextualized below in the light of evolution. PMID- 23036885 TI - Conservative care of sports hernias within soccer players: a case series. AB - OBJECTIVE: To detail the progress of 2 high-level soccer players and 1 recreational soccer player with chronic groin pain that was exacerbated by participation in sports and relieved by rest. The patients under went a conservative treatment plan featuring manual therapy, therapeutic modalities, and plyometric training. CLINICAL FEATURES: The most important examination findings were palpable tenderness over the internal oblique fascia and anterior pubic tubercle, pain with resisted hip adduction, and pain with a resisted abdominal curl-up. Conventional treatment aimed at decreasing healing time of the injury through manual therapy, including soft tissue and modality techniques; rehabilitative exercises, focusing on the pelvic muscles; and plyometric training, aiming at sport specific functional improvement. INTERVENTION: The conservative treatment approach utilized in this case series involved manual therapy, 1-2 times a week for 6-8 weeks, consisting of soft tissue, laser, microcurrent, and acupuncture; rehabilitative exercise and plyometric training, 3 times a week for 8 weeks, to help improve strength, coordination, and correct pelvic muscle imbalances. Outcome measures included visual analog scale scores and resisted muscle testing. SUMMARY: Three soccer players, of varying levels of ability, presenting with a suspected sports hernia (chronic groin pain exacerbated by sports and relieved by rest) were relieved of their pain after 8 weeks of conservative care featuring manual therapy, rehabilitative exercises, and plyometric training. PMID- 23036886 TI - Changes in gait and balance parameters in elderly subjects attending an 8-week supervised Pilates programme. AB - Falls in the elderly have important clinical and economic costs and interventions that may reduce the risk of such problems are potentially important. Although evidence exists for a range of exercise interventions, few have looked at a Pilates-based intervention in a supervised community-based setting and none have specifically measured gait parameters as an outcome. This observational study investigated gait parameters including inter-stride variability (ISV) and postural sway in a group (n = 9) of elderly (age range, 60-76) subjects attending a weekly Pilates class over eight weeks. The results suggest that significant improvement in walking speed (0.14 m/s (95% CI: 0.06-0.21)), step cycle (0.07 m (95% CI: 0.01-0.14)) and length (0.10 m (95% CI: 0.05-0.15)) and a composite ambulation index (6.5% (95% CI: 1.85-11.26)) were seen post the intervention, while coefficients of variation decreased around 15%. In addition both anterior posterior sway decreased along with a improvement in a fall risk index (FRI). Inter-stride variability on the other hand did not change. The results of this study suggest that a short Pilates program may have the potential to improve gait and sway parameters, including those associated with fall risk. PMID- 23036887 TI - Hip mobility training. PMID- 23036888 TI - Subclavian steal syndrome presenting as recurrent pulmonary oedema associated with acute left ventricular diastolic dysfunction. AB - Subclavian steal syndrome typically presents as angina in patients with internal mammary artery grafts. Atypical clinical presentations have been rarely described. We report an unusual case of subclavian steal syndrome presenting as pulmonary oedema with acute left ventricular diastolic dysfunction and preserved ejection fraction in a patient with internal mammary artery graft and severe stenosis of the proximal left subclavian artery. After successful angioplasty and stenting of subclavian artery, the patient remained asymptomatic for six months, but then experienced acute diastolic dysfunction and recurrent pulmonary oedema associated with critical subclavian in-stent restenosis with stent deformation. This report points out that, in patients with internal mammary-to-LAD grafts, subclavian steal syndrome may present as acute left ventricular diastolic dysfunction and pulmonary oedema even in the presence of normal ejection fraction. PMID- 23036889 TI - Fluorescent ligand-directed co-localization of the parathyroid hormone 1 receptor with the brush-border scaffold complex of the proximal tubule reveals hormone dependent changes in ezrin immunoreactivity consistent with inactivation. AB - Through binding to parathyroid hormone (PTH), PTH1R interacts with kidney specific scaffold proteins, including the sodium hydrogen exchanger regulatory factors 1 and 2 (NHERFs), and ezrin. To facilitate in vivo localization, tetramethylrhodamine-labeled PTH (PTH-TMR) was used as a fluorescent probe. In mice, PTH-TMR localizes to luminal surfaces of tubular S1 segments that overlap PTH1R immunostaining, but does not directly overlap with megalin-specific antibodies. PTH-TMR staining directly overlaps with Npt2a in nascent, endocytic vesicles, marking the location of transporter regulation. PKA substrate antibodies display marked staining increases in segments labeled with PTH-TMR, demonstrating a functional effect. In the presence of secondary hyperparathyroidism, PTH-TMR staining is markedly reduced and shifts to co localizing with megalin. At 15min post-injection, PTH-TMR-labeled vesicles do not co-localize with either NHERF or ezrin, suggesting PTH1R dissociation from the scaffold complex. At the 5min time point, PTH-TMR stains the base of microvilli where it localizes with both NHERF2 and ezrin, and only partially with NHERF1. Strikingly, the bulk of ezrin protein becomes undetectable with the polyclonal, CS3145 antibody, revealing a PTH-induced conformational change in the scaffold. A second ezrin antibody (3C12) is capable of detecting the altered ezrin protein. The CS3145 antibody only binds to the active form of ezrin and fails to recognize the inactive form, while the 3C12 reagent can detect either active or inactive ezrin. Here we show that the PTH1R is part of the ezrin scaffold complex and that acute actions of PTH suggest a rapid inactivation of ezrin in a spatially defined manner. PMID- 23036890 TI - Neuroglobin involvement in respiratory chain function and retinal ganglion cell integrity. AB - Neuroglobin is a member of the globin superfamily expressed in vertebrate brain and retina. The protein is thought to be involved in neuronal protection from hypoxia or oxidative stress and could represent a key element of Alzheimer disease pathogenesis. Our aim was to determine whether neuroglobin could be directly associated with mitochondrial metabolism and integrity. We identified three different forms of neuroglobin in the retina, varying in their apparent molecular masses; all forms are abundant in mitochondrial fractions. This indicates that a significant fraction of the protein localizes within the organelle either in the matrix or in the matrix side of the inner membrane. Since neuroglobin was especially abundant in the ganglion cell layer, we transduced retinal ganglion cells with an anti-neuroglobin short hairpin RNA using in vivo electroporation. Neuroglobin knockdown leads to reduced activities of respiratory chain complexes I and III, degeneration of retinal ganglion cells, and impairment of visual function. The deleterious effect on cell survival was confirmed in primary retinal ganglion cells subjected to inhibition of neuroglobin expression. Hence, neuroglobin should be considered as a novel mitochondrial protein involved in respiratory chain function which is essential for retinal ganglion cell integrity. PMID- 23036891 TI - Anemia in a 17-year-old Hispanic girl. PMID- 23036892 TI - An unusual case of fulminant heart failure. PMID- 23036893 TI - Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the in vivo predictive value. AB - With the ultimate aim of increasing the utility of in vitro assays for toxicological risk assessment, a method was developed to calculate in vivo estrogenic potencies from in vitro estrogenic potencies of compounds by taking into account systemic availability. In vitro estrogenic potencies of three model compounds (bisphenol A, genistein, and 4-nonylphenol) relative to ethinylestradiol (EE2), determined with the estrogen receptor alpha (ERalpha) transcriptional activation assay using hER-HeLa-9903 cells, were taken from literature and used to calculate the EE2 equivalent (EE2EQ) effect doses in the predominantly ERalpha-dependent rat uterotrophic assay. Compound-specific differences in hepatic clearance relative to the reference compound EE2 were determined in vitro to examine whether in vivo estrogenic potencies reported in literature could be more accurately estimated. The EE2EQ doses allowed to predict in vivo uterotrophic responses within a factor of 6-25 and the inclusion of the hepatic clearance further improved the prediction with a factor 1.6-2.1 for especially genistein and bisphenol A. Yet, the model compounds still were less potent in vivo than predicted based on their EE2 equivalent estrogenic potency and hepatic clearance. For further improvement of the in vitro to in vivo predictive value of in vitro assays, the relevance of other kinetic characteristics should be studied, including binding to carrier proteins, oral bioavailability and the formation of estrogenic metabolites. PMID- 23036894 TI - The relations of suicidal ideation and attempts with physical activity among Korean adolescents. AB - PURPOSE: Suicide is the leading cause of death among Korean adolescents. This study investigates the cross- sectional relations of physical activity with suicidal ideation and attempts in adolescents, simultaneously considering previously reported risk factors of suicide such as depression, stress, and body image. METHODS: This study used the 2007 Korea Youth Risk Behavior Web-based Survey (KYRBWS). Four hundred middle schools and 400 high schools in Korea were monitored, and 74,698 students completed the questionnaire. Logistic regression analysis was conducted to investigate the relationship between physical activity and suicidal ideation and attempts, progressively adjusting for body image, depression and stress. RESULTS: After controlling for body image, stress, and depression, the significant relationship between physical activity and suicidal ideation disappeared, and the only remaining relationship was a positive relationship between frequent vigorous physical activity and suicide attempts. No sex differences were found after adjusting for all the variables. CONCLUSION: Unlike the general expectation that physical activity protects adolescents from suicidal behaviors, the results from this study suggest that physical activity does not have protective effect. Korean adolescents who perform frequent vigorous physical activities are more likely to attempt suicide. PMID- 23036895 TI - Failure rates of metal-on-metal hip resurfacings: analysis of data from the National Joint Registry for England and Wales. AB - BACKGROUND: Implant survival after conventional total hip replacement (THR) is often poor in younger patients, so alternatives such as hip resurfacing, with various sizes to fit over the femoral head, have been explored. We assessed the survival of different sizes of metal-on-metal resurfacing in men and women, and compared this survival with those for conventional stemmed THRs. METHODS: We analysed the National Joint Registry for England and Wales (NJR) for primary THRs undertaken between 2003 and 2011. Our analysis involved multivariable flexible parametric survival models to estimate the covariate-adjusted cumulative incidence of revision adjusting for the competing risk of death. FINDINGS: The registry included 434,560 primary THRs, of which 31,932 were resurfacings. In women, resurfacing resulted in worse implant survival than did conventional THR irrespective of head size. Predicted 5-year revision rates in 55-year-old women were 8.3% (95% CI 7.2-9.7) with a 42 mm resurfacing head, 6.1% (5.3-7.0) with a 46 mm resurfacing head, and 1.5% (0.8-2.6) with a 28 mm cemented metal-on polyethylene stemmed THR. In men with smaller femoral heads, resurfacing resulted in poor implant survival. Predicted 5-year revision rates in 55-year-old men were 4.1% (3.3-4.9) with a 46 mm resurfacing head, 2.6% (2.2-3.1) with a 54 mm resurfacing head, and 1.9% (1.5-2.4) with a 28 mm cemented metal-on-polyethylene stemmed THR. Of male resurfacing patients, only 23% (5085 of 22076) had head sizes of 54 mm or above. INTERPRETATION: Hip resurfacing only resulted in similar implant survivorship to other surgical options in men with large femoral heads, and inferior implant survivorship in other patients, particularly women. We recommend that resurfacing is not undertaken in women and that preoperative measurement is used to assess suitability in men. Before further new implant technology is introduced we need to learn the lessons from resurfacing and metal on-metal bearings. FUNDING: National Joint Registry for England and Wales. PMID- 23036896 TI - Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. AB - BACKGROUND: The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial showed that apixaban is better than warfarin at prevention of stroke or systemic embolism, causes less bleeding, and results in lower mortality. We assessed in this trial's participants how results differed according to patients' CHADS(2), CHA(2)DS(2)VASc, and HAS-BLED scores, used to predict the risk of stroke and bleeding. METHODS: ARISTOTLE was a double blind, randomised trial that enrolled 18,201 patients with atrial fibrillation in 39 countries. Patients were randomly assigned apixaban 5 mg twice daily (n=9120) or warfarin (target international normalised ratio 2.0-3.0; n=9081). The primary endpoint was stroke or systemic embolism. The primary safety outcome was major bleeding. We calculated CHADS(2), CHA(2)DS(2)VASc, and HAS-BLED scores of patients at randomisation. Efficacy analyses were by intention to treat, and safety analyses were of the population who received the study drug. ARISTOTLE is registered with ClinicalTrials.gov, number NCT00412984. FINDINGS: Apixaban significantly reduced stroke or systemic embolism with no evidence of a differential effect by risk of stroke (CHADS(2) 1, 2, or >=3, p for interaction=0.4457; or CHA(2)DS(2)VASc 1, 2, or >=3, p for interaction=0.1210) or bleeding (HAS-BLED 0-1, 2, or >=3, p for interaction=0.9422). Patients who received apixaban had lower rates of major bleeding than did those who received warfarin, with no difference across all score categories (CHADS(2), p for interaction=0.4018; CHA(2)DS(2)VASc, p for interaction=0.2059; HAS-BLED, p for interaction=0.7127). The relative risk reduction in intracranial bleeding tended to be greater in patients with HAS-BLED scores of 3 or higher (hazard ratio [HR] 0.22, 95% CI 0.10-0.48) than in those with HAS-BLED scores of 0-1 (HR 0.66, 0.39 1.12; p for interaction=0.0604). INTERPRETATION: Because apixaban has benefits over warfarin that are consistent across patient risk of stroke and bleeding as assessed by the CHADS2, CHA2DS2VASc, and HAS-BLED scores, these scores might be less relevant when used to tailor apixaban treatment to individual patients than they are for warfarin. Further improvement in risk stratification for both stroke and bleeding is needed, particularly for patients with atrial fibrillation at low risk for these events. FUNDING: Bristol-Myers Squibb and Pfizer. PMID- 23036897 TI - Apixaban in atrial fibrillation: does predicted risk matter? PMID- 23036898 TI - Hip resurfacing: a complex challenge for device regulation. PMID- 23036900 TI - Is there a role for proximal tubular cells in regulating dendritic cell maturation and function in renal disease? PMID- 23036899 TI - Transgenic expression of interferon-gamma in mouse stomach leads to inflammation, metaplasia, and dysplasia. AB - Gastric adenocarcinoma is one of the leading causes of cancer mortality worldwide. It arises through a stepwise process that includes prominent inflammation with expression of interferon-gamma (IFN-gamma) and multiple other pro-inflammatory cytokines. We engineered mice expressing IFN-gamma under the control of the stomach-specific H(+)/K(+) ATPase beta promoter to test the potential role of this cytokine in gastric tumorigenesis. Stomachs of H/K-IFN gamma transgenic mice exhibited inflammation, expansion of myofibroblasts, loss of parietal and chief cells, spasmolytic polypeptide expressing metaplasia, and dysplasia. Proliferation was elevated in undifferentiated and metaplastic epithelial cells in H/K-IFN-gamma transgenic mice, and there was increased apoptosis. H/K-IFN-gamma mice had elevated levels of mRNA for IFN-gamma target genes and the pro-inflammatory cytokines IL-6, IL-1beta, and tumor necrosis factor-alpha. Intracellular mediators of IFN-gamma and IL-6 signaling, pSTAT1 and pSTAT3, respectively, were detected in multiple cell types within stomach. H/K IFN-gamma mice developed dysplasia as early as 3 months of age, and 4 of 39 mice over 1 year of age developed antral polyps or tumors, including one adenoma and one adenocarcinoma, which expressed high levels of nuclear beta-catenin. Our data identified IFN-gamma as a pivotal secreted factor that orchestrates complex changes in inflammatory, epithelial, and mesenchymal cell populations to drive pre-neoplastic progression in stomach; however, additional alterations appear to be required for malignant conversion. PMID- 23036901 TI - The role of T cells in the pathogenesis of primary hypertension. AB - Accumulating evidence indicates that T cells play an important role in the pathogenesis of hypertension. Here we review the investigations that have shown that T cells are infiltrating the kidney in hypertension. Interstitial accumulation of immune cells is associated with increments in oxidative stress and renal angiotensin II activity that result in the impairment in pressure natriuresis. The severity of salt-sensitive hypertension is directly correlated with the intensity of immune cell infiltration in the kidney. Reducing the renal infiltration of T cells prevents or ameliorates hypertension and the induction of tubulointerstitial inflammation results in salt-sensitive hypertension. The potential participation of autoimmune mechanisms in the renal infiltration of immune competent cells is discussed. PMID- 23036902 TI - Variations in the first steps of photosynthesis for the diatom Cyclotella meneghiniana grown under different light conditions. AB - In this work we have applied picosecond and steady-state fluorescence measurements to study excitation energy transfer and trapping in intact Cyclotella meneghiniana diatom cells grown at different light intensities. Different excitation and detection wavelengths were used to discriminate between Photosystem I and II (PSI and PSII) kinetics and to study excitation energy transfer from the outer antenna to the core of PSI and PSII. It is found that the light-harvesting fucoxanthin chlorophyll proteins (FCPs) transfer their excitation energy predominantly to PSII. It is also observed that the PSII antenna is slightly richer in red-absorbing fucoxanthin than the FCPs associated with PSI. The average excitation trapping time in PSI is around 75 ps whereas this time is around 450 ps for PSII in cells grown in 20 MUmol of photons per m(2) per s. The latter time decreases to 425 ps for 50 MUmol of photons and 360 ps for 140 MUmol of photons. It is concluded that cells grown under higher photon flux densities have a smaller antenna size than the ones grown in low light. At the same time, the increase of growth light intensity leads to a decrease of the relative amount of PSI. This effect is accompanied by a substantial increase in the amount of chlorophyll a that is not active in excitation energy transfer and most probably attached to inactivated/disassembled PSII units. PMID- 23036903 TI - Proximal femoral fractures: issues and challenges. PMID- 23036904 TI - Emotion-on-a-chip (EOC): evolution of biochip technology to measure human emotion using body fluids. AB - Recent developments in nano/micro technology have made it possible to construct small-scale sensing chips for the analysis of biological markers such as nucleic acids, proteins, small molecules, and cells. Although biochip technology for the diagnosis of severe physiological diseases (e.g., cancer, diabetes, and cardiovascular disease) has been extensively studied, biochips for the monitoring of human emotions such as stress, fear, depression, and sorrow have not yet been introduced, and the development of such a biochip is in its infancy. Emotion science (or affective engineering) is a rapidly expanding engineering/scientific discipline that has a major impact on human society. The growing interest in the integration of emotion science and engineering is a result of the recent trend of merging various academic fields. In this paper we discuss the potential importance of biochip technology in which human emotion can be precisely measured in real time using body fluids such as blood, saliva, urine, or sweat. We call these biochips emotion-on-a-chip (EOC). The EOC system consists of four parts: (1) collection of body fluids, (2) separation of emotional markers, (3) detection of optical or electrical signals, and (4) display of results. These techniques provide new opportunities to precisely investigate human emotion. Future developments in EOC techniques will combine social and natural sciences to expand their scope of study. PMID- 23036905 TI - Computer assisted minimally invasive surgery: is medical computer vision the answer to improving laparosurgery? AB - Minimally Invasive Surgery (MIS) is one of the most effective methods of modern surgical intervention that has considerable advantages compared with open surgery, including reduced trauma, pain, and post-operative recovery time. MIS has improved substantially over the years, chiefly due to new hardware innovations, including HD cameras and flexible head endoscopes. However, MIS continues to be hindered by several problems. In addition to hardware innovation, Computer Vision (CV) has been proposed as a way to overcome some of its current limitations. However, the research literature lacks a coherent picture of how the limitations can be best overcome by hardware, CV or a combination of the two. In this paper we focus on laparoscopic MIS, and list these limitations into 5 clear categories. We detail the effectiveness of hardware and CV solutions with respect to each limitation, from which we base the following hypothesis: CV is both complementary and necessary to hardware development, to overcome all 5 limitations in laparoscopy. Our paper is of value to laparoscopy surgeons, by conveying what is expected to be achieved in computer-aided laparoscopy over the next decade. It is also of value to medical CV researchers, by clarifying which problems are best solved with CV, in light of the hardware developments likely to occur over the next decade. PMID- 23036906 TI - Dried blood spot analysis of an iron chelator--deferasirox and its potential application to therapeutic drug monitoring. AB - Deferasirox is an iron chelating agent for the treatment of transfusional iron over load in patients with chronic anemia. These anemic patients require close monitoring of the deferasirox exposures for ensuring its therapeutic efficacy. Dried blood spot (DBS) sampling methodology has the advantages of low volume of blood withdrawal and ease of transportation and storage over liquid blood methods. A LC-MS/MS based analytical method was developed using reversed phase column with gradient elution program and quantitated in MRM mode. Linearity range for the liquid blood was 1-1000 ng/mL and for DBS was 5-5000 ng/mL under similar mass spectrometry conditions. The method was validated with respective (M-H)(-) ions, m/z 372->118 for deferasirox and m/z 410->348 for fluvastatin (internal standard). The validated method was applied for the analysis of DBS samples from a rat pharmacokinetic study and results were compared against liquid blood samples from the same animal. The mean C(max) from DBS sample (1121 ng/mL) was comparable to mean C(max) found in blood samples (1015 ng/mL) at 2h after oral dose of deferasirox. All the other calculated pharmacokinetic parameters were quite comparable for both liquid blood and DBS samples. PMID- 23036907 TI - LC-MS analysis of glycopeptides of recombinant monoclonal antibodies by a rapid digestion procedure. AB - N-glycan analysis of recombinant monoclonal antibodies (mAbs) usually requires the removal of oligosaccharides by PNGase F followed by 2-AB labeling, normal phase high performance liquid chromatography (NP-HPLC) separation and fluorescence detection. Alternatively antibodies can be completely digested by trypsin to generate glycopeptides for analysis by liquid chromatography-mass spectrometry (LC-MS). Here, we report the development of a rapid digestion procedure to generate glycopeptides for quantitative LC-MS analysis. Recombinant monoclonal antibodies were digested using a combination of Lys-C and trypsin at 37 degrees C for 15 min. The glycan profiles from this rapid digestion procedure are in good agreement with those from LC-MS analysis of glycopeptides from completely digested antibodies and those from NP-HPLC analysis of 2-AB labeled PNGase F released oligosaccharides. This rapid digestion procedure was applied to the comparison of oligosaccharides of two different antibodies. Glycopeptides from the two antibodies were differentially labeled with stable isotopes and analyzed simultaneously after a 1:1 mixing. The combination of the rapid digestion procedure and differential stable isotope labeling significantly reduced the turnaround time. PMID- 23036908 TI - Effect of NaCl on the conformational stability of the thermophilic gamma glutamyltranspeptidase from Geobacillus thermodenitrificans: Implication for globular protein halotolerance. AB - The transpeptidation activity of gamma-glutamyltranspeptidase from Geobacillus thermodenitrificans (GthGT) is negligible and the enzyme is highly thermostable. Here we have examined the effect of concentrated NaCl solutions on structure, stability, dynamics and enzymatic activity of GthGT. The protein exhibited hydrolytic activity over a broad range of NaCl concentrations. Even at 4.0M NaCl, GthGT retained more than 90% of the initial activity and showed unaltered fluorescence emission, secondary structure and acrylamide quenching on tryptophan fluorescence. Furthermore, at 2.8M and 4.0M NaCl the temperature-induced unfolding profiles are dramatically changed with large (>20 degrees C) positive shifts in the denaturation temperature. These features make GthGT an ideal system to be used in industrial processes that require high temperatures and high-salt environments. A general explanation of the NaCl effect by means of a statistical thermodynamic model is also provided, together with an analysis of residue distribution between protein surface and interior in 15 non-redundant families of halophilic and non-halophilic proteins. The results are in line with a comparative sequence and structural analysis between halophilic and non halophilic gamma-glutamyltranspeptidases which revealed that a major role in halotolerance should be played by solvent exposed negatively charged residues. PMID- 23036909 TI - Long term effect of MnO2 powder addition on nitrogen removal by anammox process. AB - This study examined long-term effect of MnO(2) powder (average diameter of 4-7 MUm) on nitrogen removal in anammox process. Two lab-scale up-flow anammox reactors were operated for 380 days, one with and one without MnO(2) powder addition. During the period when only substrate concentrations varied, the maximum nitrogen removal rate in the reactor with MnO(2) addition reached 920.9 g N/m(3)/d. This value was 2-folds higher than that (464.6 g-N/m(3)/d) of the reactor without MnO(2) addition. The crude enzyme activities of the anammox biomass from the two reactors was measured as 0.531+/-0.019 and 0.298+/-0.007 MUmol cytochrome c reduced/mg protein/min, respectively. Transmission electron microscopy observation demonstrated more undefined particles existing inside anammox bacterial cell in the reactor with MnO(2) powder addition. Furthermore, filament-like structures inside anammoxosome were observed, which formed a net like structure with particles as the connecting nodes. The experiment results demonstrated that MnO(2) improved nitrogen removal performance of anammox process. PMID- 23036910 TI - Growth and spectral characterization of ethylene diamine tetra acetic acid (EDTA) doped zinc sulphate hepta hydrate - a semi organic NLO material. AB - Semi-organic non-linear optical single crystals of ethylene diamine tetra acetic acid (EDTA) doped zinc sulphate hepta hydrate crystals were grown by slow evaporation solution growth technique, at room temperature, using de-ionized water as solvent. The modes of vibrations of different molecular groups present in the grown crystal were identified by FT-IR technique. The optical absorbance/transmittance was recorded in the wavelength range of 190-1100 nm. Thermal properties of the grown crystal were studied by thermo gravimetric analysis and differential thermal analysis. The melting point of the grown crystal was estimated by differential scanning calorimetric analysis. The inclusion of the dopant (EDTA) was confirmed by colorimetric estimation method. The second harmonic generation efficiency is about 30% of potassium dihydrogen orthophosphate. PMID- 23036911 TI - Measuring stakeholder participation in evaluation: an empirical validation of the Participatory Evaluation Measurement Instrument (PEMI). AB - BACKGROUND: Stakeholder participation is an important trend in the field of program evaluation. Although a few measurement instruments have been proposed, they either have not been empirically validated or do not cover the full content of the concept. OBJECTIVES: This study consists of a first empirical validation of a measurement instrument that fully covers the content of participation, namely the Participatory Evaluation Measurement Instrument (PEMI). It specifically examines (1) the intercoder reliability of scores derived by two research assistants on published evaluation cases; (2) the convergence between the scores of coders and those of key respondents (i.e., authors); and (3) the convergence between the authors' scores on the PEMI and the Evaluation Involvement Scale (EIS). SAMPLE: A purposive sample of 40 cases drawn from the evaluation literature was used to assess reliability. One author per case in this sample was then invited to participate in a survey; 25 fully usable questionnaires were received. MEASURES: Stakeholder participation was measured on nominal and ordinal scales. Cohen's kappa, the intraclass correlation coefficient, and Spearman's rho were used to assess reliability and convergence. RESULTS: Reliability results ranged from fair to excellent. Convergence between coders' and authors' scores ranged from poor to good. Scores derived from the PEMI and the EIS were moderately associated. CONCLUSIONS: Evidence from this study is strong in the case of intercoder reliability and ranges from weak to strong in the case of convergent validation. Globally, this suggests that the PEMI can produce scores that are both reliable and valid. PMID- 23036912 TI - Design of a basic system of indicators for monitoring and evaluating Spanish Cooperation's Culture and Development Strategy. AB - OBJECTIVE: This article describes the process implemented in order to define and build up a Basic Monitoring and Evaluation System for Spanish Cooperation's Culture and Development Strategy (CD-S). RESEARCH DESIGN: Delphi techniques were used to assess a wide catalogue of indicators for each of the strategic areas included in the CD-S. Afterward, those indicators considered most suitable for monitoring and evaluating purposes were selected based on the assessments provided by a panel of experts. RESULTS: As a consequence, the resulting system, made up by a total of 80 indicators, was designed to be a practical, manageable, and targeted tool for its potential users, who include managers and technical officers who map out strategy together with stakeholders involved in its implementation, and specifically with staff at cultural centers abroad and in technical aid offices. PMID- 23036913 TI - Governability framework for the evaluation and implementation of complex public health functions. AB - BACKGROUND: The dominant theoretical basis of our public health practice originates from a positivist or reductionist paradigm. It fails to take into account the complexity emerging out of public health's multiple influences originating from biological and social worlds. A deeper understanding of the interaction of elements that characterize the implementation of public health functions will enhance our ability to generate evidence and learn further. OBJECTIVE: The "interactive governance theory" by Jan Kooiman introduced here offers an analytical framework that uses the concept of "governability." It is a measure of how governable a particular social system is that takes care of a public function. Assessment is facilitated by breaking down and describing the social system into constituent parts and by exploring the properties, qualities, and the way in which they interact with each other. Further, by deliberating a complex public health function such as immunization services in the context of developing countries, we explore the application of the interactive governance theory and governability. CONCLUSION: The theory offers new insights into how interactive and holistic approaches can be integrated into public health practice. The advantage of the concept of "governability" is that it enables us to explore why some governance systems deliver what they are expected to, while others do not. This might help us to identify areas where governance can be improved. PMID- 23036914 TI - Preferring the fittest mates: an analytically tractable model. AB - We develop an analytically tractable model of female preference for fit mates. Our population-genetic model allows to trace the dynamics at both the individual and the population level. The preference for fit mates links ecological adaptation and mating success is individually advantageous and causes polymorphic subpopulations. This polymorphism is a strong and stable clustering in genotype and phenotype space. The alleles coding for the mating preference spread rapidly through the population, thereby increasing the selection pressure between different habitats. The resulting polymorphism exceeds the expected selection migration equilibrium by several orders of magnitude. The evolution of preference for fit mates can, thus, act as the trigger for parapatric speciation because it initiates prezygotic isolation and divergence. PMID- 23036915 TI - Neural field theory of plasticity in the cerebral cortex. AB - A generalized timing-dependent plasticity rule is incorporated into a recent neural field theory to explore synaptic plasticity in the cerebral cortex, with both excitatory and inhibitory populations included. Analysis in the time and frequency domains reveals that cortical network behavior gives rise to a saddle node bifurcation and resonant frequencies, including a gamma-band resonance. These system resonances constrain cortical synaptic dynamics and divide it into four classes, which depend on the type of synaptic plasticity window. Depending on the dynamical class, synaptic strengths can either have a stable fixed point, or can diverge in the absence of a separate saturation mechanism. Parameter exploration shows that time-asymmetric plasticity windows, which are signatures of spike-timing dependent plasticity, enable the richest variety of synaptic dynamics to occur. In particular, we predict a zone in parameter space which may allow brains to attain the marginal stability phenomena observed experimentally, although additional regulatory mechanisms may be required to maintain these parameters. PMID- 23036916 TI - The peaks and geometry of fitness landscapes. AB - Fitness landscapes are central in the theory of adaptation. Recent work compares global and local properties of fitness landscapes. It has been shown that multi peaked fitness landscapes have a local property called reciprocal sign epistasis interactions. The converse is not true. We show that no condition phrased in terms of reciprocal sign epistasis interactions only, implies multiple peaks. We give a sufficient condition for multiple peaks phrased in terms of two-way interactions. This result is surprising since it has been claimed that no sufficient local condition for multiple peaks exist. We show that our result cannot be generalized to sufficient conditions for three or more peaks. Our proof depends on fitness graphs, where nodes represent genotypes and where arrows point toward more fit genotypes. We also use fitness graphs in order to give a new brief proof of the equivalent characterizations of fitness landscapes lacking genetic constraints on accessible mutational trajectories. We compare a recent geometric classification of fitness landscape based on triangulations of polytopes with qualitative aspects of gene interactions. One observation is that fitness graphs provide information that are not contained in the geometric classification. We argue that a qualitative perspective may help relating theory of fitness landscapes and empirical observations. PMID- 23036918 TI - Overuse of antibiotics in pets must be tackled to reduce resistance, conference hears. PMID- 23036917 TI - Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: prospective cohort study. AB - OBJECTIVE: To validate the use of the Wells clinical decision rule combined with a point of care D-dimer test to safely exclude pulmonary embolism in primary care. DESIGN: Prospective cohort study. SETTING: Primary care across three different regions of the Netherlands (Amsterdam, Maastricht, and Utrecht). PARTICIPANTS: 598 adults with suspected pulmonary embolism in primary care. INTERVENTIONS: Doctors scored patients according to the seven variables of the Wells rule and carried out a qualitative point of care D-dimer test. All patients were referred to secondary care and diagnosed according to local protocols. Pulmonary embolism was confirmed or refuted on the basis of a composite reference standard, including spiral computed tomography and three months' follow-up. MAIN OUTCOME MEASURES: Diagnostic accuracy (sensitivity and specificity), proportion of patients at low risk (efficiency), number of missed patients with pulmonary embolism in low risk category (false negative rate), and the presence of symptomatic venous thromboembolism, based on the composite reference standard, including events during the follow-up period of three months. RESULTS: Pulmonary embolism was present in 73 patients (prevalence 12.2%). On the basis of a threshold Wells score of <= 4 and a negative qualitative D-dimer test result, 272 of 598 patients were classified as low risk (efficiency 45.5%). Four cases of pulmonary embolism were observed in these 272 patients (false negative rate 1.5%, 95% confidence interval 0.4% to 3.7%). The sensitivity and specificity of this combined diagnostic approach was 94.5% (86.6% to 98.5%) and 51.0% (46.7% to 55.4%), respectively. CONCLUSION: A Wells score of <= 4 combined with a negative qualitative D-dimer test result can safely and efficiently exclude pulmonary embolism in primary care. PMID- 23036919 TI - Government abandons plans to use payments to prevent private providers selecting simplest cases. PMID- 23036921 TI - Amoxicillin prophylaxis in oral surgery. AB - INTRODUCTION: Postoperative infection is the most common postsurgical oral complication but no double-blind, randomized, placebo-controlled trial has been made yet to assess amoxicillin prophylaxis for oral surgery. The aim of this pilot study was to assess the effectiveness of prophylactic amoxicillin 3g per os versus placebo in the prevention of postoperative oral infections. METHODS AND MATERIALS: A 5-year, multicentric, randomized, double-blind clinical trial was made on healthy patients undergoing complex oral surgery. Final analysis was by intention to treat. RESULTS: The 286 patients were randomly assigned to the amoxicillin or placebo group. After a mean follow-up of two weeks, 11 patients in the control group and three patients in the amoxicillin prophylaxis group developed a postoperative infection (P=0.001 in unilateral test). The hazard ratio was 0.27 [95% CI: 0.07-0.94]. CONCLUSION: Amoxicillin prophylaxis seems to be effective in preventing postoperative infection in complex oral surgery, especially when mandibular third molars and multiple avulsions are involved. PMID- 23036920 TI - Concurrent group treatment for hepatitis C: implementation and outcomes in a methadone maintenance treatment program. AB - Chronic hepatitis C virus (HCV) infection is highly prevalent among current and former drug users. However, the minority of patients enrolled in drug treatment programs have initiated HCV treatment. New models are needed to overcome barriers to care. In this retrospective study, we describe the implementation and outcomes of 42 patients treated in a concurrent group treatment (CGT) program. Patients participated in weekly provider-led group treatment sessions which included review of side effects; discussion of adherence and side effect management; administration of interferon injections; brief physical examination; and ended with brief meditation. Of the first 27 patients who initiated CGT, 42% achieved a sustained viral response. In addition, 87% (13/15) of genotype-1 infected patients treated with direct acting antiviral agent achieved an undetectable viral load at 24 weeks. The CGT model may be effective in overcoming barriers to treatment and improving adherence and outcomes among patients enrolled in drug treatment programs. PMID- 23036922 TI - Peripubertal viral-like challenge and social isolation mediate overlapping but distinct effects on behaviour and brain interferon regulatory factor 7 expression in the adult Wistar rat. AB - A range of adverse, early life environmental influences such as viral infection and social deprivation are thought to increase risk of psychiatric illness later in life. Here, we used peripheral administration of the viral infection mimic polyriboinosinic-polyribocytidylic acid (polyI:C) to compare the consequences of peripubertal infection and isolation rearing. Isolation rearing induced deficits in sensorimotor gating and recognition memory while no changes in social interaction or spatial learning were observed. PolyI:C injection during the peripubertal period markedly increased expression of interferon-stimulated genes (Ifit2, Prkr, Mx2 and Irf7) in the hippocampal dentate gyrus demonstrating that peripheral administration of the viral mimic in the adolescent animal does have direct effects in the brain. Peripubertal infection mimicry induced a similar but later emerging behavioural deficit in prepulse inhibition implying the existence of a peripubertal window of opportunity for viral-mediated cytokine increases to impact brain development and function. PolyI:C treatment also impaired novel object recognition but did not alter spatial reference memory or social interaction. Combining the polyI:C challenge with social isolation did not exacerbate the behavioural deficits seen with isolation rearing alone. Using Irf7 as a marker, peripubertal viral infection mimicry, isolation rearing and a combination of both were all seen to produce a long-lasting molecular imprint on the interferon-associated signalling pathway in the principal neuron population of the hippocampal dentate gyrus. The data suggest that the sensitivity of brain structure and function to disruption by viral infection extends into the peripubertal period. Moreover, augmented interferon signalling in hippocampus may represent a common molecular imprint of environmental insults associated with neuropsychiatric illnesses like schizophrenia. PMID- 23036923 TI - Genetically programmed superparamagnetic behavior of mammalian cells. AB - Although magnetic fields and paramagnetic inorganic materials were abundant on planet earth during the entire evolution of living species the interaction of organisms with these physical forces remains a little-understood phenomenon. Interestingly, rather than being genetically encoded, organisms seem to accumulate and take advantage of inorganic nanoparticles to sense or react to magnetic fields. Using a synthetic biology-inspired approach we have genetically programmed mammalian cells to show superparamagnetic behavior. The combination of ectopic production of the human ferritin heavy chain 1 (hFTH1), engineering the cells for expression of an iron importer, the divalent metal ion transferase 1 (DMT1) and the design of an iron-loading culture medium to maximize cellular iron uptake enabled efficient iron mineralization in intracellular ferritin particles and conferred superparamagnetic behavior to the entire cell. When captured by a magnetic field the superparamagnetic cells reached attraction velocities of up to 30 MUm/s and could be efficiently separated from complex cell mixtures using standard magnetic cell separation equipment. Technology that enables magnetic separation of genetically programmed superparamagnetic cells in the absence of inorganic particles could foster novel opportunities in diagnostics and cell based therapies. PMID- 23036924 TI - Antimicrobial activity and composition profile of grape (Vitis vinifera) pomace extracts obtained by supercritical fluids. AB - The possibility of increasing the aggregated value of the huge amount of residues generated by wineries around the world foment studies using the grape pomace - the residue from the wine production, composed by seed, skin and stems - to obtain functional ingredients. Nowadays, consumers in general prefer natural and safe products mainly for food and cosmetic fields, where the supercritical fluid extraction is of great importance due to the purity of the extracts provided. Therefore, the objective of this work is to evaluate the global extraction yield, the antimicrobial activity and the composition profile of Merlot and Syrah grape pomace extracts obtained by supercritical CO2 (SC-CO2) and CO2 added with co solvent at pressures up to 300 bar and temperatures of 50 and 60 degrees C. The results were compared with the ones obtained by Soxhlet and by ultrasound assisted leaching extraction methods. The main components from the extracts, identified by HPLC, were gallic acid, p-OH-benzoic acid, vanillic acid and epicatechin. The antibacterial and antifungal activities of the extracts were evaluated using four strains of bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa) and three fungi strains (Candida albicans, Candida parapsilosis, Candida krusei). Despite lower extraction yield results, the supercritical fluid extracts presented the highest antimicrobial effectiveness compared to the other grape pomace extracts due to the presence of antimicrobial active compounds. Syrah extracts were less efficient against the microorganisms tested and Merlot extracts were more active against Gram-positive bacteria. PMID- 23036925 TI - Construction and characterization of nitrate and nitrite respiring Pseudomonas putida KT2440 strains for anoxic biotechnical applications. AB - Pseudomonas putida KT2440 is frequently used in biotechnical research and applications due to its metabolic versatility and organic solvent resistance. A major drawback for a broad application is the inability of the bacterium to survive and grow under anoxic conditions, which prohibits the production of oxygen-sensitive proteins and metabolites. To develop a P. putida strain, which is able to survive under anoxic conditions, the enzymatic systems of anaerobic nitrate and nitrite respiration were introduced into KT2440. For this purpose, two cosmids encoding all structural, maturation and regulatory genes for P. aeruginosa nitrate reductase (pNAR) and nitrite- and nitric oxide reductase (pNIR NOR) were stably maintained in P. putida KT2440. Transcriptome analyses revealed expression of the encoded nar, nir and nor operons and accessory genes under anoxic conditions. The produced enzyme systems efficiently reduced nitrate or nitrite, respectively, sustaining anaerobic life of recombinant KT2440. Interestingly, anaerobic life of P. putida induced genes involved in arginine fermentation and genes encoding a putative copper stress resistance operon. PMID- 23036926 TI - Flux balance analysis of mixed microbial cultures: application to the production of polyhydroxyalkanoates from complex mixtures of volatile fatty acids. AB - Fermented agro-industrial wastes are potential low cost substrates for polyhydroxyalkanoates (PHA) production by mixed microbial cultures (MMC). The use of complex substrates has however profound implications in the PHA metabolism. In this paper we investigate PHA accumulation using a lumped metabolic model that describes PHA storage from arbitrary mixtures of volatile fatty acids (VFA). Experiments were conducted using synthetic and complex VFA mixtures obtained from the fermentation of sugar cane molasses. Metabolic flux analysis (MFA) and flux balance analysis (FBA) were performed at different stages of culture enrichment in order to investigate the effect of VFA composition and time of enrichment in PHA storage efficiency. Substrate uptake and PHA storage fluxes increased over enrichment time by 70% and 73%, respectively. MFA calculations show that higher PHA storage fluxes are associated to an increase in the uptake of VFA with even number of carbon atoms and a more effective synthesis of hydroxyvalerate (HV) precursors from VFA with odd number of carbons. Furthermore, FBA shows that the key metabolic objective of a MMC subjected to the feast and famine regimen is the minimization of the tricarboxylic acid cycle fluxes. The PHA flux and biopolymer composition (hydroxybutyrate (HB): HV) could be accurately predicted in several independent experiments. PMID- 23036927 TI - Production and characterization of a novel human recombinant alpha-1-antitrypsin in PER.C6 cells. AB - Alpha-1-antitrypsin (A1PI) is a proteinase inhibitor of the serpin superfamily and circulates in plasma at about 1-2 g/L. A1PI deficiency in humans often results in organ damage, particularly to the lungs and liver. Current augmentation therapies rely entirely on A1PI isolated from human plasma, thus prompting an evaluation of alternate sources. We have co-expressed recombinant A1PI and alpha-2,3-sialyltransferase in the human cell line, PER.C6. The requirement for sialyltransferase overexpression in PER.C6 and the essential contribution of sialic acid glycan capping on pdA1PI and recA1PI to prevent rapid A1PI plasma elimination is shown. Using assays to predict high levels of A1PI production and sialylation, stably transfected PER.C6 cells were screened through two rounds of cell cloning to ensure monoclonality. Fed-batch culturing was used to evaluate recA1PI production and cell line characteristics, identifying subclones expressing over 2.5 g/L recA1PI. Cell stability was assessed over 50 generations, verifying subclone stability during continuous culture. Finally, data are presented showing that recA1PI and pdA1PI are equivalent in their ability to block elastase activity in functional cell-based assays and their pharmacokinetic properties. These data show that recombinant human A1PI recovered from PER.C6 cells offers a reliable source of functionally active A1PI for augmentation therapies and, potentially, other diseases. PMID- 23036928 TI - Kidney protection and regeneration following acute injury: progress through stem cell therapy. AB - Acute kidney injury (AKI) is a common clinical entity with high morbidity and mortality rates and ever increasing medical costs. A large number of patients who are hospitalized with morbidities such as diabetes, vascular disease, or chronic kidney disease are at high risk to develop AKI due to ischemic and nephrotoxic insults. The pathophysiology of ischemic and toxic forms of AKI is complex and includes tubular and vascular cell damage and inflammation. Given the seriousness of this essentially therapy-resistant complication, treatment beyond supportive measures and renal replacement therapy is urgently needed. Recent stem cell research has shown promising results, and cell therapy-based interventions are advancing into clinical trials. An example is our phase 1 clinical trial (NCT00733876) in which cardiac surgery patients at high risk of postoperative AKI were treated safely with allogeneic mesenchymal stem cells. Together with the introduction of biomarkers for an earlier and specific AKI diagnosis, currently tested stem cell-based therapies are expected to provide an entirely new class of diagnostic and therapeutic tools. PMID- 23036929 TI - Outcomes of extended-hours hemodialysis performed predominantly at home. AB - BACKGROUND: Recent evidence suggests that increased frequency and/or duration of dialysis are associated with improved outcomes. We aimed to describe the outcomes associated with patients starting extended-hours hemodialysis and assess for risk factors for these outcomes. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients were from 6 Australian centers offering extended-hours hemodialysis. Cases were patients who started treatment for 24 hours per week or longer at any time. OUTCOMES: All-cause mortality, technique failure (withdrawal from extended hours hemodialysis therapy), and access-related events. MEASUREMENTS: Baseline patient characteristics (sex, primary cause of end-stage kidney disease, age, ethnicity, diabetes, and cannulation technique), presence of a vascular access related event, and dialysis frequency. RESULTS: 286 patients receiving extended hours hemodialysis were identified, most of whom performed home (96%) or nocturnal (77%) hemodialysis. Most patients performed alternate-daily dialysis (52%). Patient survival rates using an intention-to-treat approach at 1, 3, and 5 years were 98%, 92%, and 83%, respectively. Of 24 deaths overall, cardiac death (n = 7) and sepsis (n = 5) were the leading causes. Technique survival rates at 1, 3, and 5 years were 90%, 77%, and 68%, respectively. Access event-free rates at the same times were 80%, 68%, and 61%, respectively. Access events significantly predicted death (HR, 2.85; 95% CI, 1.14-7.15) and technique failure (HR, 3.76; 95% CI, 1.93-7.35). Patients with glomerulonephritis had a reduced risk of technique failure (HR, 0.31; 95% CI, 0.14-0.69). Higher dialysis frequency was associated with elevated risk of developing an access event (HR per dialysis session, 1.56; 95% CI, 1.03-2.36). LIMITATIONS: Selection bias, lack of a comparator group. CONCLUSIONS: Extended-hours hemodialysis is associated with excellent survival rates and is an effective treatment option for a select group of patients. The major treatment-associated adverse events were related to complications of vascular access, particularly infection. The risk of developing vascular access complications may be increased in extended-hours hemodialysis, which may negatively affect long-term outcomes. PMID- 23036930 TI - Hydrophilic interaction/weak cation-exchange mixed-mode chromatography for chitooligosaccharides separation. AB - A hydrophilic interaction/weak cation-exchange (HILIC/WCX) mixed-mode chromatography was developed for separation of chitooligosaccharides (COS) using a weak cation-exchange column. For better understanding of the retention characteristics of the column, organic solvent content effect was investigated. WCX mode, HILIC mode, and mixed-mode could be performed on this column according to investigating results. COS were separated on the column in mixed-mode. The usage of volatile buffer salt made it favorable for evaporative light-scattering detector (ELSD). Mild elution conditions were economical and environment-friendly relative to other conditions used in early reports. This method may offer a possibility for large-scale COS preparation. PMID- 23036931 TI - Structural analysis of the lipoteichoic acids isolated from bovine mastitis Streptococcus uberis 233, Streptococcus dysgalactiae 2023 and Streptococcus agalactiae 0250. AB - Lipoteichoic acid (LTA) is an amphiphilic polycondensate located in the cell envelope of Gram-positive bacteria. In this study, LTAs were isolated from the three bovine mastitis species Streptococcus uberis 233, Streptococcus dysgalactiae 2023, and Streptococcus agalactiae 0250. Structural investigations of these LTAs were performed applying 1D and 2D nuclear magnetic resonance experiments as well as chemical analyses and mass spectrometry. Compositional analysis revealed the presence of glycerol (Gro), Glc, alanine (Ala), and 16:0, 16:1, 18:0, 18:1. The LTAs of the three Streptococcus strains possessed the same structure, that is, a lipid anchor comprised of alpha-Glcp-(1->2)-alpha-Glcp-(1 >3)-1,2-diacyl-sn-Gro and the hydrophilic backbone consisting of poly(sn-Gro-1 phosphate) randomly substituted at O-2 of Gro by d-Ala. PMID- 23036932 TI - gamma-Hemolysin oligomeric structure and effect of its formation on supported lipid bilayers: an AFM investigation. AB - gamma-Hemolysins are bicomponent beta-barrel pore forming toxins produced by Staphylococcus aureus as water-soluble monomers, which assemble into oligomeric pores on the surface of lipid bilayers. Here, after investigating the oligomeric structure of gamma-hemolysins on supported lipid bilayers (SLBs) by atomic force microscopy (AFM), we studied the effect produced by this toxin on the structure of SLBs. We found that oligomeric structures with different number of monomers can assemble on the lipid bilayer being the octameric form the stablest one. Moreover, in this membrane model we found that gamma-hemolysins can form clusters of oligomers inducing a curvature in the lipid bilayer, which could probably enhance the aggressiveness of these toxins at high concentrations. PMID- 23036933 TI - Lipid peroxidation and water penetration in lipid bilayers: a W-band EPR study. AB - Lipid peroxidation plays a key role in the alteration of cell membrane's properties. Here we used as model systems multilamellar vesicles (MLVs) made of the first two products in the oxidative cascade of linoleoyl lecithin, namely 1 palmitoyl-2-(13-hydroperoxy-9,11-octadecanedienoyl)-lecithin (HpPLPC) and 1 palmitoyl-2-(13-hydroxy-9,11-octadecanedienoyl)-lecithin (OHPLPC), exhibiting a hydroperoxide or a hydroxy group at position 13, respectively. The two oxidized lipids were used either pure or in a 1:1 molar ratio mixture with untreated 1 palmitoyl-2-linoleoyl-lecithin (PLPC). The model membranes were doped with spin labeled lipids to study bilayer alterations by electron paramagnetic resonance (EPR) spectroscopy. Two different spin-labeled lipids were used, bearing the doxyl ring at position (n) 5 or 16: gamma-palmitoyl-beta-(n-doxylstearoyl) lecithin (n-DSPPC) and n-doxylstearic acid (n-DSA). Small changes in the acyl chain order in the sub-polar region and at the methyl-terminal induced by lipid peroxidation were detected by X-band EPR. Concomitantly, the polarity and proticity of the membrane bilayer in those regions were investigated at W band in frozen samples. Analysis of the g(xx) and A(zz) parameters revealed that OHPLPC, but mostly HpPLPC, induced a measurable increase in polarity and H-bonding propensity in the central region of the bilayer. Molecular dynamics simulation performed on 16-DSA in the PLPC-HpPLPC bilayer revealed that water molecules are statistically favored with respect to the hydroperoxide groups to interact with the nitroxide at the methyl-terminal, confirming that the H-bonds experimentally observed are due to increased water penetration in the bilayer. The EPR and MD data on model membranes demonstrate that cell membrane damage by oxidative stress cause alteration of water penetration in the bilayer. PMID- 23036934 TI - Relationship of thyroid-stimulating hormone levels to development of dyslipidemia and determination of an ideal cut-off point to start replacement therapy. AB - BACKGROUND AND OBJECTIVE: There are studies showing a strong association between thyroid dysfunction and increased cardiovascular risk due to lipid profile changes. The purpose of this study was to assess the degree of association and predictive power of thyroid-stimulating hormone (TSH) levels in relation to lipid profile changes, identifying the TSH cut-off point beyond which lipid changes occur. PATIENTS AND METHODS: A cross-sectional, retrospective study in Quito (Ecuador) conducted from January 2004 to December 2008 on patients first attending the endocrinology department. RESULTS: A total of 278 histories were analyzed, and a 36.3% prevalence of subclinical hypothyroidism was found. No association was found between sex and cholesterol or between sex and low density lipoprotein (LDL). However, associations were found between sex and dyslipidemia, sex and body mass index (BMI), and sex and TSH. Linear regression analysis between LDL and TSH, cholesterol and TSH, and BMI and TSH showed significant associations in all cases, with Pearson R2 coefficients of 0.80, 0.81, and 0.85 respectively. CONCLUSIONS: TSH levels show a statistically significant association to total cholesterol and LDL levels, but are not a good clinical predictor in this process. A cut-off point beyond which replacement therapy should be started to prevent occurrence of dyslipidemia cannot therefore be established. PMID- 23036935 TI - [Dissociated cholestasis: an uncommon complication of thioamide therapy]. PMID- 23036936 TI - New prospects for drug treatment in Cushing disease. AB - Hypercortisolism induced by Cushing disease causes high morbidity and mortality. The treatment of choice is pituitary surgery, but it often fails to achieve cure, and other treatment modalities (radiotherapy, bilateral adrenalectomy) may therefore be required. If these treatments are not effective or while waiting for their results, hypercortisolism should be controlled with drugs. The classical drug treatments are those that act by inhibiting cortisol secretion by the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate). The preliminary results of a new drug (LCI699) which is a potent enzyme inhibitor of cortisol secretion have been reported. A clinical trial of the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, has just been published. The drugs deserving more attention today are those with a direct action on the tumor by inhibiting ACTH secretion: somatostatin analogues (pasireotide), dopamine agonists (cabergoline), PPAR-gamma, and retinoic acid. A special review is made of the available clinical trials with pasireotide and cabergoline. PMID- 23036937 TI - Supramolecular structure and spectral studies on mixed-ligand complexes derived from beta-diketone with azodye rhodanine derivatives. AB - A novel method to synthesize some mononuclear ternary palladium(II) complexes of the general formula [Pd(L(n))L] (where LH=diketone=acetylacetone, HL(n)=azorhodanine) has been synthesize. The structure of the new mononuclear ternary palladium(II) complexes was characterized using elemental analysis, spectral (electronic, infrared and (1)H &(13)C NMR) studies, magnetic susceptibility measurements and thermal studies. The IR showed that the ligands (HL(n) & LH) act as monobasic bidentate through the azodye nitrogen, oxygen keto moiety and two enolato oxygen atoms. The molar conductivities show that all the complexes are non-electrolytes. Bidentate chelating nature of beta-diketone and azorhodanine anions in the complexes was characterized by (electronic, infrared and (1)H &(13)C NMR) spectra. Square planar geometry around palladium has been assigned in all complexes. Various ligand and nephelouxetic parameter have been calculated for the complexes. The thermal decomposition for complexes was studied. PMID- 23036938 TI - A theoretical DFT study on the structural parameters and azide-tetrazole equilibrium in substituted azidothiazole systems. AB - Azido-tetrazole equilibrium is sensitive to: substitution, solvent, temperature and phase. In this work, the effects of the type and position of substitution on the thiazole ring of azidothiazoles on its structural parameters and on the azido tetrazole equilibrium have been theoretically investigated using the density functional procedures at the B3LYP/6-311G(**) level of theory. This study includes the investigation of the equilibrium geometry, the transformation of the trans-conformer to the cis one then the ring closure to the tetrazole isomer. The transition states of the two steps were located, confirmed and the structural parameters were calculated. In all the steps of calculations, geometry optimization was considered. The results obtained indicate that substitution by: NO(2) and -CN group shifts the equilibrium to the azide side and in some cases the tetrazole isomer is not obtained. On the other hand, substitution by: -NH(2) and -OH groups shifts the equilibrium to the tetrazole side and in some cases the azide isomer is not obtained and if formed changes spontaneously to the tetrazole isomer. The decisive parameters which determine the position of the equilibrium are: charge density on atoms N3 and N8, rearrangement of bond length and bond angles during the process of cyclization and variation of dipole moment as a result of cyclization. Results of this work indicate that substitution on C5 is more efficient than substitution on C4 of the thiazole ring. PMID- 23036939 TI - Field effect transistors and photodetectors based on nanocrystalline graphene derived from electron beam induced carbonaceous patterns. AB - We describe a transfer-free method for the fabrication of nanocrystalline graphene (nc-graphene) on SiO(2) substrates directly from patterned carbonaceous deposits. The deposits were produced from the residual hydrocarbons present in the vacuum chamber without any external source by using an electron beam induced carbonaceous deposition (EBICD) process. Thermal treatment under vacuum conditions in the presence of Ni catalyst transformed the EBIC deposit into nc graphene patterns, confirmed using Raman and TEM analysis. The nc-graphene patterns have been employed as an active p-type channel material in a field effect transistor (FET) which showed a hole mobility of ~90 cm(2) V(-1) s(-1). The nc-graphene also proved to be suitable material for IR detection. PMID- 23036940 TI - Relationship of weekly activity minutes to metabolic syndrome in prediabetes: the healthy living partnerships to prevent diabetes. AB - BACKGROUND: Physical inactivity contributes to metabolic syndrome (MetS) in overweight/obesity. However, little is known about this relationship in prediabetes. METHODS: The study purpose is to examine relationships between physical activity (PA) and MetS in prediabetes. The Healthy Living Partnerships to Prevent Diabetes tested a community translation of the Diabetes Prevention Program (DPP). Three hundred one overweight/obese prediabetics provided walking minutes/week (WM) and total activity minutes/week (AM) via the International Physical Activity Questionnaire. MetS was at least 3 of waist (men >= 102 cm, women >= 88 cm), triglycerides (>=150 mg.dl), blood pressure (>=130.85 mm Hg), glucose (>=100 mg.dl), and HDL (men < 40 mg.dl, women < 50 mg.dl). RESULTS: The sample was 57.5% female, 26.7% nonwhite/Hispanic, 57.9 +/- 9.5 years and had a body mass index (BMI) 32.7 +/- 4 kg.m2. Sixty percent had MetS. Eighteen percent with MetS reported at least 150 AM compared with 29.8% of those without MetS. The odds of MetS was lower with greater AM (P(trend) = .041) and WM (P(trend) = .024). Odds of MetS with 0 WM were 2.08 (P = .046) and with no AM were 2.78 (P = .009) times those meeting goal. One hour additional WM led to 15 times lower MetS odds. CONCLUSIONS: Meeting PA goals reduced MetS odds in this sample, which supported PA for prediabetes to prevent MetS. PMID- 23036941 TI - Impact of carboxymethyl cellulose (CMC) and microcrystalline cellulose (MCC) on functional characteristics of emulsified sausages. AB - Inclusion of fibers, such as carboxymethyl cellulose (CMC) and microcrystalline cellulose (MCC), at the expense of fat or protein in meat batters could be used to produce healthier sausages while lowering production costs. To study the impact of CMC/MCC on structural/functional characteristics of emulsified sausages, standard-fat Lyoner-style sausages were formulated with CMC/MCC at concentrations of 0.3-2.0%. Methods of analysis included rheology, water binding capacity (WBC), texture measurements, and Confocal Laser Scanning Microscopy (CLSM). WBC, texture measurements, and rheology all indicated that addition of CMC (>0.7%) led to destabilization of the batter, which upon heating could no longer be converted into a coherent protein network, a fact that was also revealed in CLSM images. In contrast, MCC was highly compatible with the matrix and improved firmness (1405-1651N/100g) with increasing concentration compared to control (1381N/100g) while keeping WBC (4.6-5.9%) with <2% MCC at the level of the control (4.8%). Results were discussed in terms of molecular interactions of meat proteins with celluloses. PMID- 23036942 TI - Analysis of raw hams using SELDI-TOF-MS to predict the final quality of dry-cured hams. AB - The relationship between protein profiles of Gluteus medius (GM) muscles of raw hams obtained from 4 pure breed pigs (Duroc, Large White, Landrace, and Pietrain) with the final quality of the Semimembranosus and Biceps femoris muscles of dry cured hams was investigated. As expected, Duroc hams showed higher levels of marbling and intramuscular fat content than the other breeds. Pietrain hams were the leanest and most conformed, and presented the lowest salt content in dry cured hams. Even if differences in the quality traits (colour, water activity, texture, composition, intramuscular fat, and marbling) of dry-cured hams were observed among the studied breeds, only small differences in the sensory attributes were detected. Surface-enhanced laser desorption/ionisation time-of flight mass spectrometry (SELDI-TOF-MS) was used to obtain the soluble protein profiles of GM muscles. Some associations between protein peaks obtained with SELDI-TOF-MS and quality traits, mainly colour (b*) and texture (F(0), Y(2), Y(90)) were observed. Candidate protein markers for the quality of processed dry cured hams were identified. PMID- 23036943 TI - Consumer perception of boar meat as affected by labelling information, malodorous compounds and sensitivity to androstenone. AB - This study aimed to assess the influence of two label conditions on the acceptance of boar meat. A central location test was conducted with 145 consumers each assessing 4 pieces of pork loin. Samples varied with respect to two factors: actual meat type (boar vs. standard pork) and label information (young boar meat vs. pork). Androstenone and skatole levels in the tested boar meat ranged from 0.51 to 2.72 MUg/g and 0.01 to 0.23 MUg/g melted fat, respectively. Consumers' sensitivity to and appreciation of androstenone and skatole odour was determined through a smell experiment. The acceptance of taste, tenderness, juiciness, and overall liking was neither influenced by the label information nor by the meat type. Twenty-seven % of all participants were classified as insensitive to androstenone odour, whereas 52% perceived it as positive and 21% as negative. Consumers who disliked the androstenone odour indicated a higher disliking of boar meat. PMID- 23036944 TI - Inflammatory cell response to calcium phosphate biomaterial particles: an overview. AB - Bone is a metabolically active and highly organized tissue consisting of a mineral phase of hydroxyapatite (HA) and amorphous calcium phosphate (CaP) crystals deposited in an organic matrix. One objective of bone tissue engineering is to mimic the chemical and structural properties of this complex tissue. CaP ceramics, such as sintered HA and beta-tricalcium phosphate, are widely used as bone substitutes or prosthesis coatings because of their osteoconductive properties. These ceramic interactions with tissues induce a cell response that can be different according to the composition of the material. In this review, we discuss inflammatory cell responses to CaP materials to provide a comprehensive overview of mechanisms governing the integration or loosening of implants, which remains a major concern in tissue engineering. A focus on the effects of the functionalization of CaP biomaterials highlights potential ways to increase tissue integration and limit rejection processes. PMID- 23036946 TI - Advanced functional polymers for medicine: multifunctional biomaterials. PMID- 23036945 TI - On the biomechanical role of glycosaminoglycans in the aortic heart valve leaflet. AB - While the role of collagen and elastin fibrous components in heart valve valvular biomechanics has been extensively investigated, the biomechanical role of the glycosaminoglycan (GAG) gelatinous-like material phase remains unclear. In the present study, we investigated the biomechanical role of GAGs in porcine aortic valve (AV) leaflets under tension utilizing enzymatic removal. Tissue specimens were removed from the belly region of porcine AVs and subsequently treated with either an enzyme solution for GAG removal or a control (buffer with no enzyme) solution. A dual stress level test methodology was used to determine the effects at low and high (physiological) stress levels. In addition, planar biaxial tests were conducted both on-axis (i.e. aligned to the circumferential and radial axes) and at 45 degrees off-axis to induce maximum shear, to explore the effects of augmented fiber rotations on the fiber-fiber interactions. Changes in hysteresis were used as the primary metric of GAG functional assessment. A simulation of the low-force experimental setup was also conducted to clarify the internal stress system and provide viscoelastic model parameters for this loading range. Results indicated that under planar tension the removal of GAGs had no measureable affect extensional mechanical properties (either on- or 45 degrees off-axis), including peak stretch, hysteresis and creep. Interestingly, in the low-force range, hysteresis was markedly reduced, from 35.96+/-2.65% in control group to 25.00+/ 1.64% (p<0.001) as a result of GAG removal. Collectively, these results suggest that GAGs do not play a direct role in modulating the time-dependent tensile properties of valvular tissues. Rather, they appear to be strongly connected with fiber-fiber and fiber-matrix interactions at low force levels. Thus, we speculate that GAGs may be important in providing a damping mechanism to reduce leaflet flutter when the leaflet is not under high tensile stress. PMID- 23036947 TI - Gene delivery of PEI incorporating with functional block copolymer via non covalent assembly strategy. AB - A novel functional diblock polymer P(PEGMA-b-MAH) is prepared and incorporated to improve the gene delivery efficiency of poly(ethyleneimine) PEI via non-covalent assembly strategy. First, P(PEGMA-b-MAH) is prepared from l methacrylamidohistidine methyl ester (MAH) by reversible addition fragmentation chain transfer polymerization, with poly[poly(ethylene glycol) methyl ether methacrylate] (P(PEGMA)) as the macroinitiator. Then P(PEGMA-b-MAH) is assembled with plasmid DNA (pDNA) and PEI (M(w)=10kDa) to form PEI/P(PEGMA-b-MAH)/pDNA ternary complexes. The agarose gel retardation assay shows that the presence of P(PEGMA-b-MAH) does not interfere with DNA condensation by the PEI. Dynamic light scattering tests show that PEI/P(PEGMA-b-MAH)/pDNA ternary complexes have excellent serum stability. In vitro transfection indicates that, compared to the P(PEGMA-b-MAH) free PEI-25k/pDNA binary complexes, PEI-10k/P(PEGMA-b-MAH)/pDNA ternary complexes have lower cytotoxicity and higher gene transfection efficiency, especially under serum conditions. The ternary complexes proposed here can inspire a new strategy for the development of gene and drug delivery vectors. PMID- 23036948 TI - Evaluation of strengthening mechanisms in calcite single crystals from mollusk shells. AB - Biogenic single-crystal calcite is often reported to be harder and tougher than geologic calcite in the form of Iceland spar. However, the mechanistic origins of the superior mechanical properties of the biogenic materials are still debated. We investigate the hardness and modulus of biogenic calcite from the prismatic layer of the mollusk Atrina rigida compared with a pure geologic calcite, Iceland spar. On the {001} face, biogenic calcite is found to be 50-70% harder than geologic calcite. This range is due to the fact that changes in azimuthal angle of the indenter tip lead to a hardness variation of ~20% in A. rigida but only ~7% in Iceland spar. The higher hardness and increased anisotropy of biogenic calcite could be accounted for by hardening mechanisms based on hindered dislocation motion rather than crack deflection. PMID- 23036949 TI - Spatial and temporal evaluation of cell attachment to printed polycaprolactone microfibres. AB - Surface topography plays a crucial role in influencing cellular responses and has therefore been utilized in the development of numerous implantable devices. Whilst numerous studies have either investigated cell attachment or migration post-attachment, few have looked at the early-stages of this process temporally. The aim of this study was to evaluate the use of time-lapse microscopy to study the behaviour of fibroblasts cultured with polycaprolactone microfibres and to assess spatially and temporally the cell-structure interaction over a 24h period. Ordered polymeric structures were printed (predetermined) onto glass substrates using an electrohydrodynamic direct write process to produce fine (3-5 MUm wide) structures. Fibroblast attachment and migration were characterized as a function of distance perpendicular from structures (~17.3, 34.6 and 51.9 MUm). The use of time-lapse microscopy revealed a gradual decrease in cell attachment as the distance from the microfibres was increased. The technique also revealed that some cells were attaching and detaching from the microfibre multiple times. Our findings demonstrate that time-lapse microscopy is a useful technique for evaluating early-stage cell-biomaterial interaction that is capable of recording important events that might otherwise be overlooked. PMID- 23036950 TI - Injectable and biodegradable thermosensitive hydrogels loaded with PHBHHx nanoparticles for the sustained and controlled release of insulin. AB - Biodegradable PHBHHx (poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)) nanoparticles containing insulin phospholipid complex were loaded in chitosan based thermosensitive hydrogels for long-term sustained and controlled delivery of insulin. The injectable hydrogels, prepared by adding beta-glycerophosphate disodium salt (GP) solution to chitosan (CS) solution under stirring, showed a rapid solution-to-gel transition at 37 degrees C, a porous structure and a comparative degradation and swelling rate in vitro. In the in vitro release studies, only 19.11% of total insulin was released from the nanoparticle-loaded hydrogel (NP-CS/GP) within 31 days. However, 96.41% of total insulin was released from the free insulin-loaded hydrogel (INS-CS/GP) within 16 days. Most importantly, the hypoglycemic effect of NP-CS/GP following subcutaneous injection in diabetic rats lasted for >5 days, much longer than the effect caused by INS CS/GP or other long-acting insulin formulations. The pharmacological availability of NP-CS/GP relative to INS-CS/GP was 379.85%, indicating that the bioavailability of insulin was significantly enhanced by NP-CS/GP gels. Therefore, biodegradable and thermosensitive NP-CS/GP gels have great potential for use in novel ultralong-acting insulin injections. In addition, the NP-loaded hydrogel system also paves the way for long-term delivery of other proteins and peptides. PMID- 23036952 TI - Synthesis and biological evaluation of new phenothiazine derivatives bearing a pyrazole unit as protein farnesyltransferase inhibitors. AB - A new family of protein farnesyltransferase inhibitors, based on a phenothiazine scaffold, was designed and synthesized. The biological evaluation of these products showed that compounds 28 and 30 were the most active, with protein farnesyltransferase inhibition potencies in the low micromolar range. Compounds were also evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. Indenopyrazole 30 exhibited the most potent in vitro cytostatic activity inhibiting the growth of HCT-116, LOX IMVI and SK-MEL-5 cell lines. PMID- 23036951 TI - Controlling fibrous capsule formation through long-term down-regulation of collagen type I (COL1A1) expression by nanofiber-mediated siRNA gene silencing. AB - The foreign body reaction often interferes with the long-term functionality and performance of implanted biomedical devices through fibrous capsule formation. While many implant modification techniques have been adopted in attempts to control fibrous encapsulation, the outcomes remained sub-optimal. Nanofiber scaffold-mediated RNA interference may serve as an alternative approach through the localized and sustained delivery of siRNA at implant sites. In this study, we investigated the efficacy of siRNA-poly(caprolactone-co-ethylethylene phosphate) nanofibers in controlling fibrous capsule formation through the down-regulation of collagen type I (COL1A1) in vitro and in vivo. By encapsulating complexes of COL1A1 siRNA with a transfection reagent (Transit TKO) or the cell penetrating peptides CADY or MPG within the nanofibers (550-650 nm in diameter), a sustained release of siRNA was obtained for at least 28 days (loading efficiency ~60-67%). Scaffold-mediated transfection significantly enhanced cellular uptake of oligonucleotides and prolonged in vitro gene silencing duration by at least 2-3 times as compared to conventional bolus delivery of siRNA (14 days vs. 5-7 days by bolus delivery). In vivo subcutaneous implantation of siRNA scaffolds revealed a significant decrease in fibrous capsule thickness at weeks 2 and 4 as compared to plain nanofibers (p<0.05). Taken together, the results demonstrated the efficacy of scaffold-mediated siRNA gene-silencing in providing effective long term control of fibrous capsule formation. PMID- 23036953 TI - Novel 3-substituted-1-aryl-5-phenyl-6-anilinopyrazolo[3,4-d]pyrimidin-4-ones: docking, synthesis and pharmacological evaluation as a potential anti inflammatory agents. AB - Novel 3-substituted-1-aryl-5-phenyl-6-anilino-pyrazolo[3,4-d]pyrimidin-4-ones of pharmacological significance were synthesized by the reaction of ethyl-(5-amino-3 methylthio-1-aryl-5-phenyl-2H-pyrazole)-4-carboxylates 3a-c with S-methyl diphenyl thiourea independently to produce 1-aryl-3-thiomethyl-5-phenyl pyrazolo[3,4-d]pyrimidines 4a-c in DMF with catalytic amount of K(2)CO(3), which on further treatment with different aromatic amines independently under same reaction conditions generated for compounds 5a-l. The compounds were screened for the anti-inflammatory activity and evaluated for ulcerogenic potential. The compounds 5i exhibited superior anti-inflammatory activity in comparison with diclofenac sodium and comparable activity with celecoxib at a dose of 25mg/kg. The other compounds 4c, 5c, 5f and 5l were found as active with inhibition of edema in the range of 35-39 after 3 h of administration of test compounds. The ulcerogenic potential of active compounds was observed to be quite lesser as compared to standard. COX-2 docking score of the active compound 5i was found to be better than standard celecoxib. PMID- 23036954 TI - Design, synthesis, and structure-activity-relationship of phenyl imidazoles as potent Smoothened antagonists. AB - Through scaffold morphing of a known Smoothened antagonist Antag691, a series of novel phenyl imidazole derivatives were developed. Structure-activity relationship studies and lead optimization led to the discovery of potent, selective and orally bioavailable Smoothened antagonist 19 that is suitable for in vivo studies. PMID- 23036955 TI - N,N-Dimethyl-[9-(arylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amines as novel, potent and selective 5-HT6 receptor antagonists. AB - The design, synthesis and SAR of novel tetrahydrocarbazole derivatives having 5 HT(6) receptor antagonist activity is presented. The racemic compound 15e was found to possess desirable pharmacokinetic properties, adequate brain penetration and activity in animal models of cognition. PMID- 23036956 TI - Design, synthesis and anticancer activity of 1-acyl-3-amino-1,4,5,6 tetrahydropyrrolo[3,4-c]pyrazole derivatives. AB - A series of novel 1-acyl-3-amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives were designed and synthesized. These derivatives were initially evaluated for their in vitro anticancer activity against human colon carcinoma HCT-116 cell line, and compounds 11a, b were chosen for further evaluation their in vitro activity against other five human cancer cell lines. These results indicate that most of the target compounds have considerable in vitro anticancer activity. The most active compound 11a was found to be 4- to 28-fold more potent than (R)-roscovitine against six human cancer cell lines. In addition, compound 11a was assessed for its activity against 12 kinases, and then evaluated for its interaction mode by docking experiments with cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3beta (GSK3beta). PMID- 23036957 TI - Synthesis and SAR of geminal substitutions at the C5' carbosugar position of pyrimidine-derived HCV inhibitors. AB - The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species. PMID- 23036958 TI - Abnormal temporal lobe white matter as a biomarker for genetic risk of bipolar disorder. AB - BACKGROUND: Brain white matter (WM) abnormalities have been hypothesized to play an important role in the neurobiology of bipolar disorder (BD). The nature of these abnormalities is not well-characterized, however, and it is unknown whether they occur after disease onset or represent potential markers of genetic risk. METHODS: We examined WM integrity (assessed via fractional anisotropy [FA]) with diffusion tensor imaging in patients with BD (n=26), unaffected siblings of patients with BD (n=15), and healthy volunteers (n=27) to identify WM biomarkers of genetic risk. RESULTS: The FA differed significantly (p<.05; corrected) among the three groups within the right temporal WM. Unaffected siblings had FA values that were intermediate to and significantly different from those of healthy volunteers and patients with BD (healthy control subjects>unaffected siblings>BD). Moreover, FA values in this region correlated negatively and significantly with trait impulsivity in unaffected siblings. Probabilistic tractography indicated that the regional abnormality lies along the inferior fronto-occipital fasciculus, a large intrahemispheric association pathway. CONCLUSIONS: Our results suggest that lower WM integrity in the right temporal lobe might be a biomarker for genetic risk of BD. It is conceivable that the attenuated nature of these WM abnormalities present in unaffected siblings allows for some preservation of adaptive emotional regulation, whereas more pronounced alterations observed in patients is related to the marked emotional dysregulation characteristic of BD. PMID- 23036959 TI - Molecular networks of DYX1C1 gene show connection to neuronal migration genes and cytoskeletal proteins. AB - BACKGROUND: The dyslexia susceptibility 1 candidate 1 (DYX1C1) gene has recently been associated with dyslexia and reading scores in several population samples. The DYX1C1 has also been shown to affect neuronal migration and modulate estrogen receptor signaling. METHODS: We have analyzed the molecular networks of DYX1C1 by gene expression and protein interaction profiling in a human neuroblastoma cell line. RESULTS: We find that DYX1C1 can modulate the expression of nervous system development and neuronal migration genes such as RELN and associate with a number of cytoskeletal proteins. We also show by live cell imaging that DYX1C1 regulates cell migration of the human neuroblastoma cell line dependent on its tetratricopeptide repeat and DYX1 protein domains. The DYX1 domain is a novel highly conserved domain identified in this study by multiple sequence alignment of DYX1C1 proteins recovered from a wide range of eukaryotic species. CONCLUSIONS: Our results contribute to the hypothesis that dyslexia has a developmental neurobiological basis by linking DYX1C1 with many genes involved in neuronal migration disorders. PMID- 23036960 TI - Contrasting effects of pretraining, posttraining, and pretesting infusions of corticotropin-releasing factor into the lateral amygdala: attenuation of fear memory formation but facilitation of its expression. AB - BACKGROUND: The lateral nucleus of the amygdala (LA) is a crucial part of the neural circuitry underlying the formation and storage of memories established through fear conditioning. To investigate corticotropin-releasing factor (CRF) contributions to fear memory in LA, the present experiments tested the effects of intra-LA infusions on the formation and expression of memory after Pavlovian fear conditioning. METHODS: In experiment 1, CRF was infused bilaterally into LA of rats 1 hour before fear conditioning training. Two days later, rats were tested for conditioned stimulus (CS)-elicited freezing behavior in a distinct context. In experiment 2, rats were infused with CRF in LA immediately after auditory fear conditioning and then tested 2 days later. In experiment 3, rats were fear conditioned and then 2 days later infused with CRF in LA 1 hour before fear memory testing to assess effects on the expression of fear memory. Finally, we repeated the pretraining and pretesting experiments with the central nucleus of the amygdala infusions. RESULTS: Rats given either pretraining or posttraining CRF infusions in LA showed dose-dependent suppression of CS-elicited freezing in the fear memory test session. In contrast, rats given pretesting CRF showed facilitation of CS-elicited freezing. Corticotropin-releasing factor infusions into the central nucleus of the amygdala had no effect when given before-training or testing. CONCLUSIONS: Corticotropin-releasing factor infusions into LA impair the consolidation of memory for fear conditioning but enhance the expression of pre-established fear memories. These findings may have important implications for understanding mechanisms underlying contributions of CRF to fear-related disorders. PMID- 23036962 TI - PEG modified BaGdF5:Yb/Er nanoprobes for multi-modal upconversion fluorescent, in vivo X-ray computed tomography and biomagnetic imaging. AB - Herein, a multi-functional nanoprobe of polyethylene glycol (PEG) modified BaGdF5:Yb/Er upconversion nanoparticles (UCNPs) for tri-modal bioimaging of fluorescence, computed X-ray tomography (CT), and magnetic application is demonstrated for the first time. The PEG-modified BaGdF5:Yb/Er UCNPs with optimal small size were synthesized by a facile one-pot hydrothermal method. The as designed single-phase nanoprobe presents near-infrared to visible upconversion emissions in UC fluorescent bioimaging of HeLa cell. Importantly, we have demonstrated in vivo CT images with enhanced signals of spleen of a mouse for 2 h, indicating the UCNPs can be successfully used as CT contrast agent for improving the detection of splenic diseases. In addition, these UCNPs also exhibit excellent intrinsic paramagnetic property which can be also for magnetic imaging. Therefore, our results indicate that a tri-modal nanoprobe served as fluorescent/CT/magnetic bioimaging can be realized using the PEG-modified BaGdF5:Yb/Er UCNPs with very low cytotoxicity and long circulation time, which would be very useful in a variety of biomedical application fields. PMID- 23036961 TI - A silk-based scaffold platform with tunable architecture for engineering critically-sized tissue constructs. AB - In the field of tissue engineering and regenerative medicine there is significant unmet need for critically-sized, fully degradable biomaterial scaffold systems with tunable properties for optimizing tissue formation in vitro and tissue regeneration in vivo. To address this need, we have developed a silk-based scaffold platform that has tunable material properties, including localized and bioactive functionalization, degradation rate, and mechanical properties and that provides arrays of linear hollow channels for delivery of oxygen and nutrients throughout the scaffold bulk. The scaffolds can be assembled with dimensions that range from millimeters to centimeters, addressing the need for a critically-sized platform for tissue formation. We demonstrate that the hollow channel arrays support localized and confluent endothelialization. This new platform offers a unique and versatile tool for engineering 'tailored' scaffolds for a range of tissue engineering and regenerative medicine needs. PMID- 23036963 TI - Collagen-based layer-by-layer coating on electrospun polymer scaffolds. AB - Preparation of microfibre constructs of collagen by electrospinning has been problematic due to the instability of collagen in volatile solvents, such as 1,1,1,3,3,3-hexafluoro-2-propanol, so that electrospinning leads to a substantial amount of gelatin fibres. In the present study we have demonstrated the production of collagen-based microfibre constructs by use of a layer-by-layer coating process onto a preformed synthetic polymer microfibre base. Soluble native collagen, which has a basic isoelectric point, has been used with modified triple-helical collagens that have acidic isoelectric points. These modified collagens have been prepared as deamidated, succinylated, maleylated and citraconylated derivatives. Together, the acidic and basic collagens have successfully coated polyacrylonitrile and poly(DL-lactide-co-glycolide) fibres, as shown by spectroscopy and microscopy. These coatings allow good cell attachment and spreading on the fibres. The native, triple helical form of the collagen has been confirmed through use of a conformation dependent monoclonal antibody. PMID- 23036964 TI - Treatment of postpartum hemorrhage with misoprostol. PMID- 23036965 TI - A trade-off between feedback-based learning and episodic memory for feedback events: evidence from Parkinson's disease. AB - Parkinson's disease (PD) is characterized by a loss of dopaminergic projections to the striatum, leading to both motor and cognitive impairments. The cognitive impairments are relatively selective and include deficits in incremental learning from trial-by-trial feedback, while other forms of learning, such as hippocampal dependent episodic memory, remain intact. Interestingly, it has been suggested that the striatum and the hippocampus compete during learning, leading to the intriguing prediction that the striatal disruption in PD could lead to enhanced performance on tasks that depend on the hippocampus. We tested this prediction by simultaneously assessing incremental learning and episodic memory for trial unique feedback events, within a single task, in patients with PD. Further, in order to modulate the engagement of the striatum versus the hippocampus, we manipulated the timing of feedback during learning, building on prior results showing that delaying feedback by a few seconds shifts learning to depend on the hippocampus instead of the striatum. We found that Parkinson's patients were impaired at learning from immediate feedback, but had enhanced episodic memory for those immediate feedback events. Thus, our results provide evidence for concurrent impaired and enhanced learning and memory functions within the same group of patients from a single task. PMID- 23036967 TI - Evaluation of disintegration properties of orally rapidly disintegrating tablets using a novel disintegration tester. AB - This report describes a new disintegration tester that can determine not only the disintegration time of orally rapidly disintegrating tablets (ODT), but also the disintegration behavior and mechanism. Using the tester, the disintegration properties of the tablets prepared in a previous study were examined. The purpose of this study is to confirm the utility of the tester as an instrument for evaluating the disintegration properties of ODT and determine relations among time, behavior and mechanism of the disintegration. Results demonstrated that in vitro disintegration time in the tester is similar to that in the commercial disintegration tester for ODT and is highly correlated with oral disintegration time. Observations of disintegration process revealed that a difference in disintegration behavior between tablets compressed at 50-75 MPa and 100 MPa; the disintegration behavior of the tablets were designated immediate disintegrating type and gradual disintegrating type, respectively. The dynamic swelling profile and water absorption profile indicated that the disintegration mechanism of the tablets involved wicking action induced by swelling of the disintegrant; the disintegration time was closely related to the initial rates of swelling and water absorption. Furthermore, the mechanism of water absorption of tablets compressed at 50-75 MPa and 100 MPa shows anomalous diffusion and case-II transport, respectively. The shift in this mechanism is consistent with differences in disintegration time and behavior between the tablets. These findings suggest that information on disintegration properties obtained by our tester is useful for understanding of disintegration phenomena of ODT. PMID- 23036966 TI - Minor withanolides of Physalis longifolia: structure and cytotoxicity. AB - In our recent publication on bioactive guided isolation of compounds from Physalis longifolia (Solanaceae) novel anti-proliferative agents withalongolides A (4) and B (5), and their highly cytotoxic analogues, withalongolide A 4,19,27 triacetate (4a) and withalongolide B 4,19-diacetate (5a) were elucidated. In this study, the two lead compounds (4, 5) were re-isolated in gram quantities for the purpose of further analogue preparation and in vivo testing that would continue to probe structure-activity relationships. During this process, two additional withanolides, named withalongolides O (1) and P (2), were elucidated. Their structures were determined by spectroscopic techniques with 1 being subsequently confirmed by X-ray crystallographic analysis. Utilizing a MTS [3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium] viability assay, withalongolide O (1) and its 4,7-diaceatate (1a), both containing the functionalities of Delta(2)-1-oxo- in A ring, a 5beta,6beta epoxy in B ring, and a lactone ring in the nine-carbon side chain, exhibited potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal lung fibroblast (MRC 5) cells with IC(50) values in the range between 0.15 and 2.95 uM. In addition, the previously reported alpha orientation of 7-acetate group in acnistins C and D should be revised to the beta orientation on the basis of NMR data comparison. PMID- 23036968 TI - A strontium-90 sequestrant for first-aid treatment of radiation emergency. AB - In this study, hydrophilic porous polymer beads with phosphonic acid groups (PGMA EGDMA-TTA-MP) were synthesized, and assessed as a radioactive strontium-90 sequestrant for the treatment of the radiation emergency. Strontium ions were rapidly absorbed into the blood from the gastrointestinal (GI) tract after oral administration to rats, and distributed to the target organ, i.e., bones. Over 40% of the administered strontium was absorbed into the blood, while the remainder was discharged in the feces within 48 h after the administration. When the PGMA-EGDMA-TTA-MP beads were administered to rats subsequent to the strontium solution, the strontium had accumulated less in the femur. Consequently, the oral administration of the PGMA-EGDMA-TTA-MP beads was effective in suppressing the absorption of strontium from the GI tract. PMID- 23036969 TI - Triterpene saponins from the pericarps of Akebia trifoliata. AB - Eleven new triterpene saponin components (1-11) were isolated from the MeOH extract of pericarp of Akebia trifoliata (THUNB.) KOIDZ. Each of their structures was determined using NMR techniques and mass spectrometry. PMID- 23036970 TI - New cardenolides from the seeds of Adonis aestivalis. AB - Chemical investigation of the seeds of Adonis aestivalis has led to the isolation of a new cardenolide (3beta,5alpha,14beta,17beta-tetrahydroxycard-20,22-enolide) (1), two new glycosides (2, 3) of 1, and a new strophanthidin hexaglycoside (4), together with a known compound, strophanthidin 3-O-beta-D-glucopyranoside (5). The structures of 1-4 were determined by 1D- and 2D-NMR spectroscopic analysis and the results of hydrolytic cleavage. The isolated compounds (1-5) were examined for their cytotoxic activity against neoplastic HSC-2, HSC-3, HSC-4, and HL-60 cells, as well as HGF, HPLF, and HPC normal cell lines. Compounds 2, 4, and 5 were found to display selective cytotoxicity toward malignant tumor cell lines. Although the morphological observations of HL-60 and HSC-2 cell deaths by 2, 4, and 5 revealed changes characteristic of apoptosis, neither DNA degradation nor activation of caspase-3 was observed. Our findings demonstrated that 2, 4, and 5 may trigger caspase-3-independent apoptotic cell death in HL-60 and HSC-2 cells. PMID- 23036971 TI - Two new nortriterpenoid glycosides and a new phenylpropanoid glycoside from the bulbs of Scilla scilloides. AB - Two new norlanostane-type triterpenoid glycosides and a new phenylpropanoid glycoside were isolated from the bulbs of Scilla scilloides DRUCE (Liliaceae), along with two known alkaloids. Their chemical structures were determined on the basis of spectroscopic data as well as chemical evidence. PMID- 23036972 TI - Effects of food intake on the mucoadhesive and gastroretentive properties of submicron-sized chitosan-coated liposomes. AB - The gastrointestinal transition of mucoadhesive drug carriers may be affected by food intake, since food changes the physiological conditions of the gastrointestinal tract, and the food content itself is a physical obstruction for the drug carriers. Here we investigated the effects of food intake on the gastrointestinal transition and mucoadhesive function of submicron-sized chitosan coated liposomes (ssCS-Lip). The stomach and small intestine were removed after oral administration of ssCS-Lip and non-coated liposomes (ssLip) containing fluorescent dye to fasted or fed rats, and retentive properties were quantitatively confirmed by measuring the amount of dye in each part of the gastrointestinal tract. Both types of liposome were retained in the stomach at approx. 40% in the fed rats at 1 h after oral administration, whereas transitions in the intestine were reduced compared to the fasted rats. However, the transition of ssCS-Lip in intestine was prolonged compared to ssLip even, in the fed state. The mucoadhesive behavior of ssCS-Lip was evaluated by confocal laser scanning microscopy. The ssCS-Lip tended to penetrate into the mucosal part of the intestine, and in addition, ssCS-Lip was detected in the basolateral side in both conditions, and therefore the mucopenetrative function was confirmed in the fed condition. Based on these results, we confirmed that ssCS-Lip shows a predominant gastrointestinal transition and mucopenetration, even after food intake. PMID- 23036973 TI - Tinospinosides D, E, and tinospin E, further clerodane diterpenoids from Tinospora sagittata. AB - Chemical investigation on the roots of Tinospora sagittata resulted in the isolation of three novel cis-clerodane diterpenoids, tinospinosides D, E, and tinospin E, together with two known compounds, columbin and columbin glucoside, and their structures were determined by extensive spectroscopic analyses, chemical reactions and computer-assisted calculations. The inhibitory activity of the isolated compounds and their chemical derivatives on nitric oxide production in lipopolysaccharide and interferon-gamma activited J774.1 macrophage-like cells was also evaluated. PMID- 23036974 TI - A new method for the protection of carboxylic acids with a triisopropylsiloxymethyl group. AB - An effective method for the protection of carboxylic acids with a triisopropylsiloxymethyl (TIPSOCH(2)) group is described. The reactions of various carboxylic acids with C(12)H(25)SCH(2)OTIPS in the presence of CuBr(2), Et(3)N, and molecular sieves 4A afford the corresponding triisopropylsiloxymethyl esters in good yields. PMID- 23036975 TI - Synthesis and biological activities of 1alpha,4alpha,25- and 1alpha,4beta,25 trihydroxyvitamin D(3) and their metabolism by human CYP24A1 and UDP glucuronosyltransferase. AB - A previous report has demonstrated the existence of a C4-hydroxylated vitamin D(2) metabolite in serum of rats treated with pharmacological doses of vitamin D(2). However, the biological significance and metabolic fate of this metabolite have not been described. To explore its potential biological activities, we therefore synthesized 1alpha,4alpha,25-trihydroxyvitamin D(3) and its diastereoisomer, 1alpha,4beta,25-trihydroxyvitamin D(3), using Trost Pd-mediated coupling reaction, and studied their vitamin D receptor (VDR) binding affinity, osteocalcin promoter transactivation activity, and their further metabolism by human CYP24A1 as well as by human liver microsomal fraction based on CYP- and UDP glucuronosyltransferases (UGTs)-reactions. PMID- 23036976 TI - Reinvestigation of structures of robustasides B and C, and isolation of (E)-2,5 dihydroxycinnamic acid esters of arbutin and glucose from the leaves of Grevillea robusta. AB - From the leaves of Grevillea robusta, compounds whose NMR data were superimposable on those of robustasides B and C were isolated along with two new compounds, (E)-2,5-dihydroxycinnamic acid esters of arbutin and D-glucose, and two known compounds, robustaside A and (E)-2,5-dihydroxycinnamic acid. The structures of robustasides B and C were not arbutin caffeates, being revised to arbutin (E)-2,5-dihydroxycinnamic acid esters. PMID- 23036977 TI - Endograft salvage of hemodialysis accesses threatened by pseudoaneurysms. AB - OBJECTIVE: Currently, no formal practice guidelines exist regarding the use of endografts to exclude hemodialysis access pseudoaneurysms and prolong access lifespan in dialysis patients. We evaluated the efficacy of percutaneous endograft placement for exclusion of hemodialysis access pseudoaneurysms. METHODS: Between July 2005 and October 2009, 32 patients were prospectively evaluated. Twenty-four patients were actively enrolled in the study based upon clinical and ultrasonographic evaluation of their hemodialysis accesses. Self expanding covered endografts were placed percutaneously to exclude access pseudoaneurysms. Patients were evaluated at 2 and 6 months to assess for graft patency, access or outflow stenosis, endoleak, or stent graft migration. RESULTS: No procedural complications resulted from these interventions. An average of 1.8 endografts was placed per patient, with patients requiring between 1 and 3 endografts to exclude pseudoaneurysms. Primary-assisted patency was 83% at completed 2-month follow-up and 54% at 6-month follow-up. At 12 months, primary assisted patency was 50%. Eleven patients left the study before 6-month follow up: five (21%) required explantation secondary to infection between 1 and 4 months; three (13%) were lost to follow-up; two (8%) died of unrelated causes; and 1 requested explantation citing pain from the "stent poking the vein." Mean time to explantation secondary to infection was 2.4 months. Mean duration of patency was 17.6 months with a range from 0 to 76 months. Mean duration of patency for patients who completed 6-month follow-up was 28.7 months. The longest duration of patency is 6 years 4 months, after stent fracture and subsequent placement of a new stent at 6 years 2 months. One other incident of stent fracture occurred at 36 months. Dialysis patterns were not interrupted in either patient. CONCLUSIONS: The long-term results demonstrate that endograft salvage of failing hemodialysis accesses is a viable and safe alternative to open surgical revision that excludes pseudoaneurysms while maintaining uninterrupted access patency. A larger sample size and longer follow-up are needed to support the study data. PMID- 23036979 TI - Circle of life: the fascinating aspects of reproduction. PMID- 23036980 TI - Flare phenomenon following gefitinib treatment of lung adenocarcinoma with bone metastasis. AB - The skeleton is the most common site for distant metastasis in patients with cancer. To detect bone metastasis and evaluate the efficacy of treatment, we usually use bone scintigraphy and check serum alkaline phosphatase (ALP). However, such evaluation is sometimes difficult due to flare phenomenon. A 61 year-old male was referred to our department with a suspected diagnosis of lung cancer. Following thorough examinations, he was diagnosed with primary lung cancer (adenocarcinoma, Stage IV) and found to have a mutation in the epidermal growth factor receptor gene at exon 21 (L858R). After initiating treatment with oral gefitinib, ALP increased and peaked at 3,592 U/L by 3 weeks and decreased thereafter. At 4 weeks following treatment initiation, bone scintigraphy revealed a marked increase in abnormal accumulation of (99m)Tc-polyphosphate, but the primary tumor and metastases in regions other than the bone were reduced. At 9 weeks after treatment initiation, abnormal accumulations was improved in bone scintigraphy, and computed tomography revealed osteoblastic changes consistent with the accumulated lesion observed by bone scintigraphy. After initiating cancer treatment for bone metastasis, it is not uncommon to observe transient asynchronous accumulation in bone scintigraphy or transient increases in ALP in patients who ultimately respond to the treatment. These changes are called flare phenomenon, and documented in patients with prostate cancer or breast cancer receiving treatment. When determining the efficacy of treatments that target carcinomas with bone metastases, it is important to note that flare phenomenon is often indistinguishable from disease progression indicators. PMID- 23036978 TI - Lysophosphatidic acid induces increased BACE1 expression and Abeta formation. AB - The abnormal production and accumulation of beta-amyloid peptide (Abeta), which is produced from amyloid precursor protein (APP) by the sequential actions of beta-secretase and gamma-secretase, are thought to be the initial causative events in the development of Alzheimer's disease (AD). Accumulating evidence suggests that vascular factors play an important role in the pathogenesis of AD. Specifically, studies have suggested that one vascular factor in particular, oxidized low density lipoprotein (oxLDL), may play an important role in regulating Abeta formation in AD. However, the mechanism by which oxLDL modulates Abeta formation remains elusive. In this study, we report several new findings that provide biochemical evidence suggesting that the cardiovascular risk factor oxLDL may contribute to Alzheimer's disease by increasing Abeta production. First, we found that lysophosphatidic acid (LPA), the most bioactive component of oxLDL induces increased production of Abeta. Second, our data strongly indicate that LPA induces increased Abeta production via upregulating beta-secretase expression. Third, our data strongly support the notion that different isoforms of protein kinase C (PKC) may play different roles in regulating APP processing. Specifically, most PKC members, such as PKCalpha, PKCbeta, and PKCepsilon, are implicated in regulating alpha-secretase-mediated APP processing; however, PKCdelta, a member of the novel PKC subfamily, is involved in LPA-induced upregulation of beta-secretase expression and Abeta production. These findings may contribute to a better understanding of the mechanisms by which the cardiovascular risk factor oxLDL is involved in Alzheimer's disease. PMID- 23036981 TI - Testing for the recurrent HOXB13 G84E germline mutation in men with clinical indications for prostate biopsy. AB - PURPOSE: The G84E variant of HOXB13 was recently found to be associated with a significantly increased risk of prostate cancer in a case control study. We estimated the prevalence of this mutation in a clinical population of men at risk for prostate cancer who were scheduled to undergo prostate biopsy. MATERIALS AND METHODS: We prospectively collected clinical information and DNA samples from men who underwent diagnostic prostate biopsy between June 2005 and October 2011. We genotyped samples for HOXB13 G84E using the MassARRAY(r) system. We determined the prevalence of the G84E variant in the overall cohort, among patients with a positive family history and among men age 55 years or younger. RESULTS: A total of 1,175 subjects underwent biopsy, of whom 948 had a DNA sample for analysis. The G84E variant was detected in 4 patients (prevalence 0.42%, 95% CI 0.12-1.08), of whom 3 had prostate cancer on biopsy. None of 301 patients with a positive family history (prevalence 0.00%, 95% CI 0.00-1.22) and 1 of 226 patients age 55 years or younger tested positive (prevalence 0.44%, 95% CI 0.01-2.44). CONCLUSIONS: The HOXB13 G84E variant is rare in this cohort, even among those with a positive family history. Our findings question the utility of testing for this variant among unselected men presenting for a diagnostic prostate biopsy. PMID- 23036982 TI - Evaluation of factors influencing the natural history of nocturia in elderly subjects: results of the Fujiwara-kyo Study. AB - PURPOSE: We evaluated the natural history of nocturia and determined factors influencing the incidence or remission of nocturia. MATERIALS AND METHODS: Study subjects were 4,427 volunteers 65 years old or older who participated in the Fujiwara-kyo Study. The nocturia prevalence was assessed at baseline and 1 year later. Nocturia incidence and remission rates were calculated and factors influencing these results were evaluated based on characteristics, including gender, age, body mass index, HbA1c, creatinine clearance, life style, comorbidities, depressive status, metabolic syndrome and voiding symptoms. Independent factors were determined by multivariate analysis. RESULTS: Of the 4,427 subjects 3,685 provided complete replies to self-administered questionnaires at baseline and 1 year later. The prevalence of nocturia at baseline and 1 year later was 47.0% and 50.3%, and nocturia incidence and remission rates were 20.0% and 15.4%, respectively. Male gender, high body mass index, voiding symptom deterioration and new onset overactive bladder were independent factors associated with the nocturia incidence. Male gender, sum of the voiding symptoms, age and new onset overactive bladder were independent negative factors associated with nocturia remission. CONCLUSIONS: The prevalence of nocturia worsened with time, although nocturia in older subjects progressed dynamically. Male gender, age, body mass index, sum of voiding symptoms, voiding symptom deterioration and new onset overactive bladder influence the natural history of nocturia. PMID- 23036983 TI - Association between organic dietary choice during pregnancy and hypospadias in offspring: a study of mothers of 306 boys operated on for hypospadias. AB - PURPOSE: The etiology of hypospadias is poorly understood. Exposure to pesticides has been considered a risk factor, although findings are inconsistent. Diet constitutes a significant exposure route for pesticides, and pesticide residues are more frequently reported in conventional than organic food products. We examined the association between organic dietary choice during pregnancy and presence of hypospadias in the offspring. MATERIALS AND METHODS: Mothers of 306 boys operated on for hypospadias were frequency matched for geography and child birth year to 306 mothers of healthy boys in a case-control study. Telephone interviews were conducted regarding demographic and lifestyle factors, including intake and organic choice of selected food items (milk, dairy products, egg, fruit, vegetables and meat). Logistic regression models were constructed for dietary variables, and odds ratios were calculated controlling for maternal age, body mass index and alcohol consumption. RESULTS: Overall organic choice of food items during pregnancy was not associated with hypospadias in the offspring. However, frequent current consumption of high fat dairy products (milk, butter) while rarely or never choosing the organic alternative to these products during pregnancy was associated with increased odds of hypospadias (adjusted OR 2.18, 95% CI 1.09-4.36). CONCLUSIONS: This large case-control study of boys operated on for hypospadias suggests an association between hypospadias in the offspring and the mother not choosing the organic alternative, and having a high current intake of nonorganic butter and cheese. This finding could be due to chemical contamination of high fat dairy products. However, general lifestyle and health behavior related to choosing organic alternatives may also explain the finding. PMID- 23036984 TI - p53 Immunohistochemistry expression in Wilms tumor: a prognostic tool in the detection of tumor aggressiveness. AB - PURPOSE: We studied whether immunohistochemical expression of p53 in Wilms tumors correlates with tumor aggressiveness. We also examined whether preoperative chemotherapy results in any alteration of p53 expression. MATERIALS AND METHODS: A total of 18 patients underwent preoperative chemotherapy and 30 underwent immediate surgery for Wilms tumor. All children were younger than 10 years and had histologically confirmed disease. Patients with a bilateral tumor or a syndrome related to Wilms tumor were excluded. All pathology slides were uniformly stained for p53 protein, and p53 staining density and intensity were scored. The p53 scoring was then compared to the clinical behavior of the Wilms tumor, ie unfavorable tumor staging, and survival and recurrence rates. RESULTS: In the direct surgery and the preoperatively treated groups p53 positivity correlated with unfavorable Wilms tumor staging (p = 0.007). In addition, a positive p53 correlation predicted poorer survival (p = 0.017). Interestingly patients who underwent preoperative chemotherapy had an increased intensity of p53 staining compared to the direct surgery group (p <0.001). CONCLUSIONS: This study provides preliminary evidence that a higher score for immunohistochemical p53 expression correlates with unfavorable Wilms tumor staging and predicts poorer survival. This test could become a useful addition to the current histopathological analysis of Wilms tumor. PMID- 23036985 TI - Use of cardiocerebral resuscitation or AHA/ERC 2005 Guidelines is associated with improved survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. AB - OBJECTIVE: To determine whether the use of cardiocerebral resuscitation (CCR) or AHA/ERC 2005 Resuscitation Guidelines improved patient outcomes from out-of hospital cardiac arrest (OHCA) compared to older guidelines. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, Web of Science and the Cochrane Library databases. We also hand-searched study references and consulted experts. STUDY SELECTION: Design: randomised controlled trials and observational studies. POPULATION: OHCA patients, age >17 years. COMPARATORS: 'Control' protocol versus 'Study' protocol. 'Control' protocol defined as AHA/ERC 2000 Guidelines for cardiopulmonary resuscitation (CPR). 'Study' protocol defined as AHA/ERC 2005 Guidelines for CPR, or a CCR protocol. OUTCOME: Survival to hospital discharge. QUALITY: High-quality or medium-quality studies, as measured by the Newcastle Ottawa Scale using predefined categories. RESULTS: Twelve observational studies met inclusion criteria. All the three studies using CCR demonstrated significantly improved survival compared to use of AHA 2000 Guidelines, as did five of the nine studies using AHA/ERC 2005 Guidelines. Pooled data demonstrate that use of a CCR protocol has an unadjusted OR of 2.26 (95% CI 1.64 to 3.12) for survival to hospital discharge among all cardiac arrest patients. Among witnessed ventricular fibrillation/ventricular tachycardia (VF/VT) patients, CCR increased survival by an OR of 2.98 (95% CI 1.92 to 4.62). Studies using AHA/ERC 2005 Guidelines showed an overall trend towards increased survival, but significant heterogeneity existed among these studies. CONCLUSIONS: We demonstrate an association with improved survival from OHCA when CCR protocols or AHA/ERC 2005 Guidelines are compared to use of older guidelines. In the subgroup of patients with witnessed VF/VT, there was a threefold increase in OHCA survival when CCR was used. CCR appears to be a promising resuscitation protocol for Emergency Medical Services providers in increasing survival from OHCA. Future research will need to be conducted to directly compare AHA/ERC 2010 Guidelines with the CCR approach. PMID- 23036986 TI - Evidence for risk of cardiomyopathy with hydroxychloroquine. PMID- 23036988 TI - The debate about the funding of Herceptin: a case study of 'countervailing powers'. AB - In December 2008 the newly elected Prime Minister of New Zealand bypassed the agency that negotiates with manufacturers about the cost of medicines and agreed to fund Herceptin for women with early stage breast cancer for a twelve months course of treatment. This paper describes the unfolding of this decision and seeks to explain it in terms of the theory of countervailing powers, which has recently been applied to understand the rapid growth of medicines and the governance of the pharmaceutical industry. We explore the role of various actors in this debate about Herceptin funding, drawing on documentary analysis based on a systematic search of journals, websites and media databases. The case of Herceptin both confirms and questions the propositions of countervailing powers theory. On the one hand the manufacturers of the drug proved to be highly influential in their attempts to get Herceptin funded and were generally supported by consumer groups. On the other hand some scientists and regulators attempted to challenge the power of the manufacturers, with the regulators not showing signs of corporate bias as one might expect. Groups did not, as has been proposed, exert power monolithically, with several groups exhibiting opposing factions. The media, ignored in this literature, are considered as a potential countervailing force in the debate. In the end the government bypassed the recommendation of its regulators, thereby undermining the latter's efforts to act as a countervailing power. PMID- 23036990 TI - Effective plasmid DNA and small interfering RNA delivery to diseased human brain microvascular endothelial cells. AB - Expression of exogenous DNA or small interfering RNA (siRNA) in vitro is significantly affected by the particular delivery system utilized. In this study, we evaluated the transfection efficiency of plasmid DNA and siRNA into human brain microvascular endothelial cells (HBMEC) and meningioma cells, which constitute the blood-cerebrospinal fluid barrier, a target of meningitis-causing pathogens. Chemical transfection methods and various lipofection reagents including LipofectaminTM, FuGeneTM, or jetPRIME(r), as well as physical transfection methods and electroporation techniques were applied. To monitor the transfection efficiencies, HBMEC and meningioma cells were transfected with the reporter plasmid pTagGFP2-actin vector, and efficiency of transfection was estimated by fluorescence microscopy and flow cytometry. We established protocols based on electroporation using Cell Line Nucleofector(r) Kit V with the Amaxa(r) Nucleofector(r) II system from Lonza and the Neon(r) Transfection system from Invitrogen resulting in up to 41 and 82% green fluorescent protein-positive HBMEC, respectively. Optimal transfection solutions, pulse programs and length were evaluated. We furthermore demonstrated that lipofection is an efficient method to transfect meningioma cells with a transfection efficiency of about 81%. Finally, we applied the successful electroporation protocols to deliver synthetic siRNA to HBMEC and analyzed the role of the actin-binding protein cortactin in Neisseria meningitidis pathogenesis. PMID- 23036991 TI - Reduction of graphene damages during the fabrication of InGaN/GaN light emitting diodes with graphene electrodes. AB - Although graphene looks attractive to replace indium tin oxide (ITO) in optoelectronic devices, the luminous efficiency of light emitting diodes (LEDs) with graphene transparent conducting electrodes has been limited by degradation in graphene taking place during device fabrication. In this study, it was found that the quality of graphene after the device fabrication was a critical factor affecting the performance of GaN-based LEDs. In this paper, the qualities of graphene after two different device fabrication processes were evaluated by Raman spectroscopy and atomic force microscopy. It was found that graphene was severely damaged and split into submicrometer-scale islands bounded by less conducting boundaries when graphene was transferred onto LED structures prior to the GaN etching process for p-contact formation. On the other hand, when graphene was transferred after the GaN etch and p-contact metallization, graphene remained intact and the resulting InGaN/GaN LEDs showed electrical and optical properties that were very close to those of LEDs with 200 nm thick ITO films. The forward voltages and light output powers of LEDs were 3.03 V and 9.36 mW at an injection current of 20 mA, respectively. PMID- 23036987 TI - NC-mediated nucleolar localization of retroviral gag proteins. AB - The assembly and release of retrovirus particles from the cell membrane is directed by the Gag polyprotein. The Gag protein of Rous sarcoma virus (RSV) traffics through the nucleus prior to plasma membrane localization. We previously reported that nuclear localization of RSV Gag is linked to efficient packaging of viral genomic RNA, however the intranuclear activities of RSV Gag are not well understood. To gain insight into the properties of the RSV Gag protein within the nucleus, we examined the subnuclear localization and dynamic trafficking of RSV Gag. Restriction of RSV Gag to the nucleus by mutating its nuclear export signal (NES) in the p10 domain or interfering with CRM1-mediated nuclear export of Gag by leptomycin B (LMB) treatment led to the accumulation of Gag in nucleoli and discrete nucleoplasmic foci. Retention of RSV Gag in nucleoli was reduced with cis-expression of the 5' untranslated RU5 region of the viral RNA genome, suggesting the psi (Psi) packaging signal may alter the subnuclear localization of Gag. Fluorescence recovery after photobleaching (FRAP) demonstrated that the nucleolar fraction of Gag was highly mobile, indicating that there was rapid exchange with Gag proteins in the nucleoplasm. RSV Gag is targeted to nucleoli by a nucleolar localization signal (NoLS) in the NC domain, and similarly, the human immunodeficiency virus type 1 (HIV-1) NC protein also contains an NoLS consisting of basic residues. Interestingly, co-expression of HIV-1 NC or Rev with HIV-1 Gag resulted in accumulation of Gag in nucleoli. Moreover, a subpopulation of HIV-1 Gag was detected in the nucleoli of HeLa cells stably expressing the entire HIV-1 genome in a Rev-dependent fashion. These findings suggest that the RSV and HIV-1 Gag proteins undergo nucleolar trafficking in the setting of viral infection. PMID- 23036992 TI - Two new de novo interstitial duplications covering 2p14-p22.1: clinical and molecular analysis. AB - We provide a detailed clinical and molecular analysis of 2 patients with de novo interstitial duplications at 2p14-p16.1 and 2p16.1-p22.1. The 10.13-Mb duplication of chromosome 2p14-p16.1 was identified in a 9-year-old boy with mental retardation, behavioral problems (hyperactivity, hyperphagia, and subsequent vomiting), recurrent respiratory tract infections, macrocephaly, epilepsy, and dysmorphic features. The 17.49-Mb duplication of 2p16.1-p22.1 was found in a 17-year-old girl with moderate mental retardation, behavioral and emotional problems, anxiety, and facial dysmorphic features. Very few cases of de novo interstitial duplication of 2p14-p22.1 are reported in the literature, with the great majority of them lacking a detailed molecular analysis. The abnormal phenotype of these cases is caused by mechanisms such as the overdose of a duplicated gene (or genes), the disruption of a gene or its regulatory sequence by the breakpoints of duplication, or by an excess of genetic material which may disorganize chromatin conformation affecting distant gene expression. The clinical and molecular analysis of these 2 rare de novo interstitial duplications provides useful information which is extremely valuable for clinical evaluation at the prenatal and postnatal level and for the molecular understanding of the underlying mechanisms of human diseases. PMID- 23036994 TI - Immunosuppressive properties of regulatory T cells generated by incubation of peripheral blood mononuclear cells with supernatants of human RPE cells. AB - PURPOSE: To determine whether supernatants of human retinal pigment epithelium (RPE) cells can convert CD4+ T cells into regulatory T cells (Tregs) under Treg induction conditions in vitro and in vivo. METHODS: Peripheral blood mononuclear cells were cocultured with supernatants from TGFbeta2-pretreated human RPE lines on anti-CD3-coated plates. Cells were then separated with a CD4+CD25+ Treg isolation kit and cultured with supernatants from RPE, anti-CD3/CD28 antibodies, high-dose IL-2, and TGFbeta2. By flow cytometry sorting, CD25+CD45RA- Tregs were separated. Expressions of CD25(high), Foxp3, CD152, and TNFRSF 18 on Tregs were analyzed by flow cytometry. Cytokine production by Tregs was measured by ELISA. Proliferation of target T cells was assessed by [3H]thymidine incorporation or CFSE incorporation. In addition, mouse RPE-induced Tregs were used for the in vitro assay and in vivo experimental autoimmune uveitis (EAU) models. RESULTS: Human RPE-induced Tregs expressed higher levels of the Treg markers CD25(high), Foxp3, CD152, and TNFRSF 18. In addition, RPE-induced Tregs included significant numbers of CD4+CD25(high)Foxp3(high)CD45RA- active effector Tregs that significantly suppressed the activation of Th1/Th17 cell lines, indicating that they have immunosuppressive properties. Furthermore, CD4+CD25(low)Foxp3(low)CD45RA- nonsuppressing cytokine-secreting T cells were removed from the in vitro-manipulated Treg population. Administration of mouse RPE-induced Tregs significantly suppressed ocular inflammation in mice with EAU. In addition, the Tregs suppressed retinal antigen-specific T cells in vitro. CONCLUSIONS: It is hoped that through the data provided in this study that Tregs might become useful as individualized therapeutic agents for ocular autoimmune diseases. PMID- 23036993 TI - Exercise training with weight loss and either a high- or low-glycemic index diet reduces metabolic syndrome severity in older adults. AB - BACKGROUND: The efficacy of combining carbohydrate quality with exercise on metabolic syndrome risk is unclear. Thus, we determined the effects of exercise training with a low (LoGIx)- or high (HiGIx)-glycemic index diet on the severity of the metabolic syndrome (Z-score). METHODS: Twenty-one adults (66.2+/-1.1 years; BMI=35.3+/-0.9 kg/m2) with the metabolic syndrome were randomized to 12 weeks of exercise (60 min/day for 5 days/week at about 85% HRmax) and provided a LoGIx (n=11) or HiGIx (n=10) diet. Z-scores were determined from: blood pressure, triglycerides (TGs), high-density lipoproteins (HDLs), fasting plasma glucose (FPG), and waist circumference (WC) before and after the intervention. Body composition, aerobic fitness, insulin resistance, and nonesterfied fatty acid (NEFA) suppression were also assessed. RESULTS: LoGIx and HiGIx diets decreased body mass and insulin resistance and increased aerobic fitness comparably (p<0.05). LoGIx and HiGIx diets decreased the Z-score similarly as each intervention decreased blood pressure, TGs, FPG and WC (p<0.05). The HiGIx diet tended to suppress NEFA during insulin stimulation compared with the LoGIx diet (p=0.06). CONCLUSIONS: Our findings highlight that exercise with weight loss reduces the severity of the metabolic syndrome whether individuals were randomized to a HiGIx or a LoGIx diet. PMID- 23036995 TI - Correlation of endothelin-1 concentration in aqueous humor with intraocular pressure in primary open angle and pseudoexfoliation glaucoma. AB - PURPOSE: Endothelin-1 (ET-1) has been found in elevated concentrations in the aqueous humor of glaucoma patients. Indirect evidence from animal studies suggests that ET-1 might directly influence intraocular pressure (IOP). The aim of this study was to determine whether ET-1 concentrations in aqueous humor of cataract and glaucoma patients correlate with IOP. METHODS: Aqueous humor and blood samples from patients with either cataract (control, n = 38), primary open angle glaucoma (POAG, n = 35), or pseudoexfoliation glaucoma (PEXG, n = 21), without other ocular or systemic disease, were collected during routine cataract surgery or trabeculectomy. ET-1 concentration was determined by an ET-1 ELISA kit. IOP was measured preoperatively by standard Goldmann applanation tonometry. All statistical analysis was performed using commercial predictive analytics software. RESULTS: Both IOP and ET-1 concentration in aqueous humor were significantly increased in POAG (23.4 +/- 6.8 mm Hg, 5.9 +/- 2.9 pg/mL) and PEXG (24.3 +/- 8.8 mm Hg, 7.7 +/- 2.1 pg/mL) compared with control (15.0 +/- 2.9 mm Hg, 4.3 +/- 2.4 pg/mL). No difference was detected for plasma ET-1 concentrations. IOP and ET-1 in the aqueous humor were significantly correlated (R = 0.394, R2 = 0.155, P < 0.001), although no correlation was found between IOP and ET-1 in blood plasma or between ET-1 in aqueous humor and ET-1 in plasma. CONCLUSIONS: In this study, a small but highly significant correlation between IOP and the ET-1 concentration in the aqueous humor was found. Although no causative relationship can be deduced from this, ocular ET-1 effects on IOP control may merit further investigation. PMID- 23036996 TI - The diabetic ocular environment facilitates the development of endogenous bacterial endophthalmitis. AB - PURPOSE: We tested the hypothesis that changes in the diabetic ocular environment facilitate the development of endogenous bacterial endophthalmitis (EBE). METHODS: C57BL/6J mice were rendered diabetic with streptozotocin (STZ) for 1, 3, or 5 months' duration. Diabetic and age-matched nondiabetic mice were tail vein injected with 10(8) CFU of Klebsiella pneumoniae, a common cause of EBE in diabetics. After either 2 or 4 days postinfection, the EBE incidence was assessed by electroretinography, histology, bacterial counts, and myeloperoxidase ELISAs. Blood-retinal barrier (BRB) permeability in uninfected diabetic mice also was determined. RESULTS: No cases of EBE were observed among the 1-month diabetic group. Extending the time from diabetes induction to 3 months resulted in a 23.8% EBE incidence after 2 days, and a 22% incidence after 4 days. The incidence of EBE increased to 27% in the 5-month diabetic group. Infected eyes had an average 8.01 * 10(2) and 6.19 * 10(4) CFU/eye for the 3- and 5-month diabetic groups, respectively. There was no significant difference in BRB permeability between control and 1-month uninfected diabetic mice. However, 3- and 5-month diabetic mice had significantly greater BRB permeability than control mice. These results suggested that increasing the time from STZ diabetes induction to 3 and 5 months resulted in an ocular environment more conducive to the development of EBE. CONCLUSIONS: These results demonstrated a correlation between an increase in BRB permeability and an increase in EBE incidence, supporting the hypothesis that diabetic ocular changes contribute to the development of EBE. PMID- 23036998 TI - Pupillometric evaluation of the dynamics of the pupillary response to a brief light stimulus in healthy subjects. AB - PURPOSE: To investigate the correlation between measurements of amplitude (A) and peak velocity (V) of constriction in the pupil light reflex of normal subjects, and to determine the effects of stimulus intensity, pupil size, and age on this relationship. METHODS: The pupil response to a variable intensity 1.0 second light stimulus presented under open-loop conditions (Maxwellian optics) was measured using infrared video techniques in 43 healthy subjects aged 20 to 75 years old. RESULTS: In response to the "standard-intensity" light stimulus, mean measurements of A and V were 1.92 mm (SD 0.39) and 5.65 mm/s (SD 1.17), respectively. Over a 4.0 log unit range of stimulus intensities measurements of A and V were seen to co-vary with the data being best fit by the equation V=0.86+2.65A (linear regression coefficient, R = 0.919, P < 0.001). In each subject the regression plot was used to normalize the velocity estimates for A = 1.0 mm; these normalized velocity estimates showed no significant correlation with the starting size of the pupil or the age of the subject. CONCLUSIONS: There is a strong linear correlation between amplitude and peak velocity of constriction for the pupil light reflex in normal subjects. This relationship is unaffected by the stimulus intensity, size of the pupil, or age of the subject. Clinicians and researchers must keep this interdependence in mind when drawing inferences from the observed (or measured) speed of the pupillary constriction to light. PMID- 23036997 TI - Effects of VIP on corneal reconstitution and homeostasis following Pseudomonas aeruginosa induced keratitis. AB - PURPOSE: Studies from our laboratory have demonstrated that vasoactive intestinal peptide (VIP) directly converts the normally susceptible C57BL/6J (B6) mouse to resistant after ocular infection through modulation of the inflammatory response. This study examines mechanisms by which VIP influences the healing phase following infection--specifically reconstitution of the extracellular matrix (ECM). METHODS: B6 mice received daily intraperitoneal (IP) injections of VIP, while control mice were similarly injected with sterile phosphate buffered saline (PBS). Real-time RT-PCR, ELISA, and immunofluorescent staining were used to assess the effects of VIP treatment on ECM molecule expression after Pseudomonas aeruginosa-induced keratitis. We also compared the effect of VIP treatment on lipopolysaccharide (LPS)-stimulated B6- and BALB/c-derived fibroblasts. RESULTS: In vivo analyses revealed that VIP treatment of P. aeruginosa-infected B6 corneas led to a significant increase in ECM molecules associated with healing/homeostasis, while those associated with ECM degradation were significantly down-regulated when compared to wild-type (WT) controls. In vitro studies revealed that VIP treatment of lipopolysaccharide-stimulated fibroblasts derived from susceptible B6 and resistant BALB/c mice expressed distinct differences in ECM molecule expression, whereby the latter expressed higher levels of ECM molecules aimed at reconstitution. Furthermore, differential expression of VIP receptor-1/VIP receptor-2 (VIPR1/VIPR2) was observed between B6 and BALB/c after VIP treatment of LPS-stimulated fibroblasts. CONCLUSIONS: VIP treatment functions to enhance ECM reconstitution, which appears to be carried out in large part by fibroblasts via VIPR2. Overall, the data from this study suggest that VIP not only regulates disease pathogenesis, but also functions to restore integrity of the corneal stroma. PMID- 23036999 TI - Lectin from Agaricus bisporus inhibited S phase cell population and Akt phosphorylation in human RPE cells. AB - PURPOSE: Lectin from the edible mushroom Agaricus bisporus (ABL) was found to inhibit cell proliferation of some ocular and cancer cell lines. To elucidate how ABL inhibited RPE cell proliferation, we investigated the changes in cell cycle distribution and cell proliferation-related signaling pathways after ABL treatment. METHODS: Primary human RPE cells were isolated and grown in DMEM/F12 with or without the ABL (20 or 90 MUg/mL) for 3 days. Analysis of cell cycle was performed by flow cytometry. Phosphorylation status of Erk, Jnk, p38, and Akt as well as p53 expression levels were investigated by Western blotting. The role of phosphorylated-Akt in RPE cell proliferation was further evaluated using LY294002. RESULTS: After ABL treatment (90 MUg/mL), the amount of cells present in the S phase was found to be reduced. These changes were not apparent in cells treated with 20 MUg/mL ABL. In addition, Erk and Akt were found to be hyperphosphorylated and hypophosphorylated, respectively. The expression levels of phosphorylated-Jnk, phosphorylated-p38, and p53 were not altered when compared with those of the control cells. When RPE cells were treated with LY294002 and deprived from phosphorylated-Akt expression, cell proliferation rate was reduced. Reduction in the amount of cells present in S phase was also observed. CONCLUSIONS: Our results showed that ABL hypophosphorylated Akt and this observation is in line with the fact that ABL attenuates cell proliferation. As the level of p53 was not significantly altered by ABL, this indicated that ABL arrested cell cycle progression was independent of p53 activation. PMID- 23037001 TI - Irreversible electroporation in porcine liver: short- and long-term effect on the hepatic veins and adjacent tissue by CT with pathological correlation. AB - OBJECTIVE: The objective of the study was to determine the short- and long-term effects of irreversible electroporation (IRE) on the hepatic veins and the perivascular tissue through serial computed tomography (CT) with pathological correlation. MATERIALS AND METHODS: Multiple IRE lesions were created percutaneously by ultrasound guidance in livers of 11 Yorkshire pigs using a prototype IRE generator. Paired electrodes were used. Three pigs were killed at the same day; 2 pigs, at 2 days; 2 pigs, at 2 weeks; 2 pigs, at 4 weeks; and 2 pigs, at 8 weeks. Contrast-enhanced CT was performed in all pigs initially and thereafter at selected intervals. Pathological sections were performed for correlation. Initial CT scans were analyzed for lesions for degree of circumferential contact (< 25%, 26%-50%, 51%-75%, and 76%-100%) to the hepatic veins for analysis of any contour deformity. The hepatic veins were also analyzed for any thrombus and for any narrowing. Those lesions with follow-up scans were also analyzed for changes over time. RESULTS: Twenty-three lesions showed contiguity to the hepatic veins between 3 to 9 mm in size at the initial CT. No contour deformity due to perivascular tissue sparing is detected for any lesion. There was no thrombus detected in any vessel at any time point. Vessel narrowing was seen in 9 of 23 veins on the initial CT, all less than 50% in diameter and all with lesion contact of greater than 25% in circumference, but 2 of 3 veins with follow-up scans showed return-to-normal caliber. No late narrowing of any hepatic vein was seen on the long-term follow-up. CONCLUSION: Irreversible electroporation creates uniform tissue ablation around the hepatic veins without perivascular tissue sparing. Vessel narrowing may occur acutely but without long term sequela. PMID- 23037000 TI - Quantifying physical activity in physical education via pedometry: a further analysis of steps/min guidelines. AB - BACKGROUND: The validity of common pedometer steps/min guidelines for 1st-12th grade physical education physical activity (PA) recommendations (ie, 33% and 50% PA) was investigated. METHODS: Data sets from previous research, where physical education PA was quantified via pedometry, were combined. Participants (1st-12th grade, N = 1152) with concurrent steps/min and observed %PA scores were included. Data were analyzed using correlation, regression, and receiver-operator characteristic (ROC) statistics. Alpha was set at .05. RESULTS: Overall, by gender and school level group (ie, 1st-6th, 7th-12th) PA outcome measures were strongly correlated and significant (r = .85-.92). Steps/min2, lesson time3, stature4, and BMI5 were significant predictors (r12.345=.91) of %PA1. Steps/min accounted for 85.4% of the variance for %PA; however, the other predictors only accounted for an additional 0.5%. ROC analyses indicated that steps/min was an excellent discriminator (AUC >= .90) of %PA guideline achievement. Steps/min values of 60.6 and 82.2 were the most accurate cut points overall for the 33% and 50% PA guidelines, respectively. Steps/min cut points for gender and school level demonstrated agreement with the overall steps/min cut points. CONCLUSIONS: These findings support the contention that common steps/min guidelines can be applied in the surveillance of physical education PA. PMID- 23037002 TI - A microfluidic device with removable packaging for the real time visualisation of intracellular effects of nanosecond electrical pulses on adherent cells. AB - The biological mechanisms induced by the application of nanosecond pulsed electric fields (nsPEFs: high electrical field amplitude during very short duration) on cells remain partly misunderstood. In this context, there is an increasing need for tools that allow the delivering of such pulses with the possibility to monitor their effects in real-time. Thanks to miniaturization and technology capabilities, microtechnologies offer great potential to address this issue. We report here the design and fabrication of a microfluidic device optimized for the delivery of ultra short (10 ns) and intense (up to 280 kV cm( 1)) electrical pulses on adherent cells, and the real time monitoring of their intracellular effects. Ultra short electric field pulses (nsPEFs or nanopulses) affect both the cell membrane and the intracellular organelles of the cells. In particular, intracellular release of calcium from the endoplasmic reticulum was detected in real time using the device, after exposure of adherent cells to these nsPEFs. The high intensity and spatial homogeneity of the electric field could be achieved in the device thanks to the miniaturization and the use of thick (25 MUm) electroplated electrodes, disposed on a quartz substrate whose transparency allowed real time monitoring of the nsPEFs effects. The proposed biochip is compatible with cell culture glass slides that can be placed on the chip after separate culture of several days prior to exposure. This device allows the easy exposure of almost any kind of attached cells and the monitoring in real time while exposed to nsPEFs, opening large possibilities for potential use of the developed biochips. PMID- 23037003 TI - Circadian clock- and PIF4-controlled plant growth: a coincidence mechanism directly integrates a hormone signaling network into the photoperiodic control of plant architectures in Arabidopsis thaliana. AB - The plant circadian clock generates rhythms with a period close to 24 h, and it controls a wide variety of physiological and developmental events, enabling plants to adapt to ever-changing environmental light conditions. In Arabidopsis thaliana, the clock regulates the diurnal and photoperiodic plant growth including the elongation of hypocotyls and petioles in a time-of-day-specific and short-day (SD)-specific manner. In this mechanism, the clock-regulated PHYTOCHROME-INTERACTING FACTOR 4 gene encoding a basic helix-loop-helix transcription factor, together with phytochromes (mainly phyB), plays crucial roles. This diurnal and photoperiodic control of plant growth is best explained by the accumulation of the PIF4 protein at the end of the night-time specifically under SDs, due to coincidence between the internal (circadian rhythm) and external (photoperiod) cues. In this model, however, the PIF4-controlled downstream factors are not fully identified, although it has been generally proposed that the auxin-mediated signal transduction is crucially implicated. Here, we identified a set of hormone-associated genes as the specific PIF4 targets implicated in the photoperiodic control of plant growth. They include not only auxin-associated genes (GH3.5, IAA19 and IAA29), but also genes associated with other growth-regulating hormones such as brassinosteroids (BR6ox2), gibberellic acids (GAI), ethylene (ACS8) and cytokinin (CKX5). The dawn- and SD specific expression profiles of these genes are modified in a set of phyB and clock mutants, both of which compromise the coincidence mechanism. The results of this study suggest that the circadian clock orchestrates a variety of hormone signaling pathways to regulate the photoperiod-dependent morphogenesis in A. thaliana. PMID- 23037004 TI - A circadian clock- and PIF4-mediated double coincidence mechanism is implicated in the thermosensitive photoperiodic control of plant architectures in Arabidopsis thaliana. AB - In Arabidopsis thaliana, the circadian clock regulates diurnal and photoperiodic plant growth including the elongation of hypocotyls in a time-of-day-specific and short-day (SD)-specific manner. The clock-controlled PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) encoding a basic helix-loop-helix (bHLH) transcription factor plays crucial roles in this regulation. PIF4 is transcribed precociously at the end of the night in SDs, under which conditions the protein product is stably accumulated, while PIF4 is expressed exclusively during the daytime in long days (LDs), under which conditions the protein product is degraded by light-activated phytochrome B. The dawn- and SD-specific elongation of hypocotyls is best explained by the coincident accumulation of the active PIF4 protein during the night-time before dawn specifically in SDs. However, this coincidence model was challenged with the recent finding that the elongation of hypocotyls is markedly promoted at high growth temperature (i.e. 28 degrees C) even under LDs in a PIF4 dependent manner. Here, we reconciled these apparently conflicting facts by showing that the transcription of PIF4 occurs precociously at the end of the night-time at 28 degrees C in LDs, similarly to in SDs. Both the events resulted in the same consequence, i.e. that a set of PIF4 target genes (ATHB2, GH3.5, IAA19, IAA29, BRox2, GAI, ACS8 and CKX5) was induced accordingly in a time-of-day specific manner. Taken together, we propose an extended double coincidence mechanism, by which the two environmental cues (i.e. photoperiods and temperatures), both of which vary on a season to season basis, are integrated into the same clock- and PIF4-mediated output pathway and regulate a hormone signaling network to fit plant architectures properly to domestic habitats. PMID- 23037005 TI - Impact of pH on activity of trimethoprim, fosfomycin, amikacin, colistin and ertapenem in human urine. AB - OBJECTIVE: Although major impairment of activity at lower pH values has been reported for fluoroquinolones, acidification is a widely recommended practice for the prophylaxis and treatment of uncomplicated urinary tract infections (UTIs). Until now, there is little evidence for the influence of pH on the activity on other antimicrobial classes in urine. METHODS: Bacterial growth curves of Staphylococcus aureus (ATCC 29213), Klebsiella oxytoca (ATCC 700324), Proteus mirabilis (ATCC 14153), Escherichia coli (ATCC 25922) and Enterococcus faecalis (ATCC 29212) were performed in Mueller-Hinton broth and in pooled human urine with a pH of between 5.0 and 8.0. Bacterial killing of trimethoprim, fosfomycin, amikacin, colistin and ertapenem against the five strains (where appropriate) was determined consecutively at concentrations equal to the MIC. RESULTS: While no difference in the bacterial growth of E. coli, S. aureus, P. mirabilis and K. oxytoca was observed at different pH values, bacterial growth of E. faecalis was significantly reduced at low pH. Acidification to pH 5 impaired the antimicrobial activity of all investigated antibiotics, i.e. the net effect of bacterial growth and killing resulted in increased colony-forming units/ml at the end of the experiment. CONCLUSION: The present in vitro findings indicate that acidification of urine during the treatment of UTIs should be carefully considered. While growth curves of one strain supports the concept of therapeutic or prophylactic acidification during UTIs, the most common pathogen, E. coli, was not affected by low pH. Independent of the investigated strain or antibiotic, pH values below 6 lead to a reduction of antimicrobial activity. PMID- 23037006 TI - Implantable continuous Doppler monitoring device for detection of hepatic artery thrombosis after liver transplantation. AB - BACKGROUND: Early hepatic artery thrombosis (eHAT) after liver transplantation occurs in 3% of adults and 8% of children and often results in retransplantation. eHAT is initially asymptomatic and arterial patency is monitored with percutaneous Doppler ultrasound screening (pDUS). The aim of the study is to analyze the diagnostic accuracy of "continuous" Doppler registration (CONDOR) using an implantable miniature Doppler. METHODS: This prospective observational study was conducted in 102 liver transplant recipients. Hepatic arterial signal is checked by CONDOR at least six times per day for the first 10 days after transplantation with comparison of diagnostic accuracy of CONDOR versus pDUS. RESULTS: Extra investigations were performed after 48 (11%) regular pDUS where arterial patency was questioned: 32 extra pDUS, 14 computed tomography (CT) angiographies, and 2 reoperations. CT scan confirmed eHAT in 4 cases. In 10 cases of pDUS-suspected eHAT, where subsequent CT showed an open artery, the CONDOR signal was clearly pulsatile. In 2 of 4 patients with five eHATs, a weak arterial signal was inadvertently interpreted as an open artery (sensitivity of 60%). The accuracy for detection of eHAT increased from 93% (pDUS) to 99% (CONDOR). Using CONDOR, additional CT angiographies may be prevented in 10% of cases. CONCLUSION: CONDOR is a useful adjunct to pDUS because it reduces the false-positive rate of pDUS. Further development of the technique and analysis of the signal generated by CONDOR are needed to improve the sensitivity before CONDOR can replace pDUS as a reliable screening method for detection of eHAT. PMID- 23037007 TI - Impact of tacrolimus-sirolimus maintenance immunosuppression on proteinuria and kidney function in pancreas transplant alone recipients. AB - BACKGROUND: Nephrotoxicity is a major complication with immunosuppression regimens used in transplantation. Calcineurin inhibitor-sparing or reduction regimens using sirolimus (SRL) have shown variable success in kidney transplantation. There is limited data on the role of SRL on native kidney function in pancreas transplantation. METHODS: All patients undergoing pancreas transplantation from 2003 to 2010 were enrolled in this study (n=65). Patient demographic characteristics were identified and divided into two groups: those receiving tacrolimus (Tac) in combination with mycophenolate mofetil (MMF) and those maintained on a regimen of Tac and SRL with or without MMF. The slopes for estimated glomerular filtration rate (eGFR), serum creatinine level (sCr), and proteinuria changes over time were assessed between groups. Urine protein and creatinine ratio (uPr/uCr) was used to assess proteinuria. RESULTS: There was no difference in baseline demographic characteristics. Patients were followed for a median of 3 years. Baseline sCr and eGFR were similar between groups. Differences in uPr/uCr and rate of change in sCr and eGFR were not significant between the groups overall or for any specific time. There was worsening of sCr, eGFR, and uPr/uCr within the groups over the period of study. There were no significant differences when groups were split by age or gender or when the SRL group was split further based on MMF inclusion. CONCLUSIONS: Our study findings suggest that using a Tac-SRL regimen in patients with pancreas alone transplantation is a safe approach and may not lead to worsening proteinuria and kidney function when compared with regimens using Tac with MMF. PMID- 23037008 TI - The pathophysiology of endothelin in complications after solid organ transplantation: a potential novel therapeutic role for endothelin receptor antagonists. AB - Although short-term allograft survival after solid organ transplantation has improved during the past two decades, improvement in long-term graft survival has been less pronounced. Common complications after transplantation include chronic allograft rejection, nephrotoxicity from calcineurin inhibitors (CNIs), and systemic hypertension, which all impact posttransplantation morbidity and mortality. Endothelin (ET)-1, a potent endogenous vasoconstrictor, inducer of fibrosis, and vascular smooth muscle cell proliferation, may play a key role in both the development of CNI-induced nephrotoxicity and endothelial vasculopathy in chronic allograft rejection. ET-1 levels increase after isograft implantation, and ET-1 plays a key role in CNI-induced renal vasoconstriction, sodium retention, and hypertension. Preclinical studies have demonstrated that endothelin receptor antagonists (ERAs) can reduce or prevent CNI-induced hypertension after renal transplantation. In addition, ERAs can ameliorate CNI induced renal vasoconstriction and improve proteinuria and preserve renal function in animal models of renal transplantation. ET-1 may also play a significant role in cardiac allograft vasculopathy, and in animal models, ERAs improve pulmonary function and ischemic-reperfusion injury in lung transplantation and hepatic function and structure in liver transplantation. Emerging pharmacokinetic data suggest that the selective ERA ambrisentan may be used safely in conjunction with the most commonly used immunosuppressive agents tacrolimus and mycophenolate, albeit with appropriate dose adjustment. The weight of available evidence pointing toward a potential beneficial role of ERAs in ameliorating common complications after solid organ transplantation must be balanced with potential toxicities of ERAs but suggests that a randomized clinical trial of ERAs in transplant patients is warranted. PMID- 23037009 TI - Slow magnetic relaxation in a 4,2-ribbon like Fe(III)2Co(II) heterobimetallic chain. AB - The reaction of Co(NO(3))(2).6H(2)O and 3-benzoylpyridine with the low-spin iron(III) complex, H[Fe(III)(phen)(CN)(4)], in methanol gives rise to a cyanide bridged heterobimetallic chain [{Fe(III)(phen)(CN)(4)}(2)Co(II)(3-bpe)(2)] (1) that exhibits intrachain ferromagnetic coupling and slow double magnetic relaxation. PMID- 23037010 TI - A new cyclic tetrapeptide from the jellyfish-derived fungus Phoma sp. AB - A new cyclic tetrapeptide (1), along with known congeners (2, 3), was isolated from the fungus Phoma sp. derived from the giant jellyfish Nemopilema nomurai. The absolute configuration of 1 was determined using the modified Mosher's method and Marfey's method. Compound 1 displayed a weak suppressive effect on the production of nitric oxide (NO) in murine macrophage cells (RAW264.7) without notable cytotoxicity. PMID- 23037011 TI - Excess electron transfer dynamics in DNA hairpins conjugated with N,N dimethylaminopyrene as a photosensitizing electron donor. AB - Excess electron transfer dynamics in DNA hairpins was investigated by femtosecond laser flash photolysis of a donor-DNA-acceptor system using N,N dimethylaminopyrene and diphenylacetylene as an electron donor and acceptor, respectively. It was revealed that the excess electron hopping rate between T's is faster than that of the hole. PMID- 23037012 TI - Axonal transport and mitochondrial dysfunction in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia. It is characterized by pathological hallmarks such as extracellular deposits of amyloid plaques as well as intracellular neurofibrillary tangles and a progressive loss of neurons. Additional early pathological features of AD also include a decline in synapse number, axonal dystrophies, mitochondrial hypometabolism and increased oxidative stress. It is assumed that the aggregates of amyloid-beta and tau are not the major pathogenic players in AD, but that nonaggregated oligomeric forms of amyloid-beta and specific phosphorylated forms of tau cause neurodegeneration. It is tempting to speculate that oligomeric amyloid-beta and phosphorylated tau might trigger mitochondrial dysfunction associated with oxidative stress as well as dysfunctions of axonal transport, leading to the loss of spines and neurodegeneration. Here, we summarize the actual data supporting this hypothesis and provide a model how these different mechanisms might be intertwined with each other. PMID- 23037013 TI - High-throughput optical coherence tomography at 800 nm. AB - We report high-throughput optical coherence tomography (OCT) that offers 1,000 times higher axial scan rate than conventional OCT in the 800 nm spectral range. This is made possible by employing photonic time-stretch for chirping a pulse train and transforming it into a passive swept source. We demonstrate a record high axial scan rate of 90.9 MHz. To show the utility of our method, we also demonstrate real-time observation of laser ablation dynamics. Our high-throughput OCT is expected to be useful for industrial applications where the speed of conventional OCT falls short. PMID- 23037014 TI - Distributed gain in plasmonic reflectors and its use for terahertz generation. AB - Semiconductor plasmons have potential for terahertz generation. Because practical device formats may be quasi-optical, we studied theoretically distributed plasmonic reflectors that comprise multiple interfaces between cascaded two dimensional electron channels. Employing a mode-matching technique, we show that transmission through and reflection from a single interface depend on the magnitude and direction of a dc current flowing in the channels. As a result, plasmons can be amplified at an interface, and the cumulative effect of multiple interfaces increases the total gain, leading to plasmonic reflection coefficients exceeding unity. Reversing the current direction in a distributed reflector, however, has the opposite effect of plasmonic deamplification. Consequently, we propose structurally asymmetric resonators comprising two different distributed reflectors and predict that they are capable of terahertz oscillations at low threshold currents. PMID- 23037015 TI - Quasi-nonvolatile storage in Ru-doped Bi12SiO20 crystals by two-wavelength holography. AB - Prolonged read-out process of a hologram recorded at near infrared with simultaneous green light exposure is measured in Ru-doped Bi12SiO20 crystal. The experimental results are confirmed by numerical simulations, suggesting two different traps involved in the space-charge transport mechanism. In addition, quasi-permanent holographic recording of image with fast updating speed by using two-wavelength recording is demonstrated. PMID- 23037016 TI - Sputtered ZnO-SiO2 nanocomposite light-emitting diodes with flat-top nanosecond laser treatment. AB - Sputtered ZnO-SiO2 nanocomposite light-emitting diodes (LEDs) were treated using a flat-top nanosecond laser (FTNL) under room temperature. The intensity of the 376 nm electroluminescence (EL) emission of ZnO-SiO2 nanocomposite LEDs at a current of 9 mA with FTNL treatment was approximately 1.4 times greater than LEDs without FTNL treatment. Furthermore, the FTNL-treated LEDs indicated a narrower full width at half maximum of the 376 nm EL emission than those of LEDs without FTNL treatment. Thus, FTNL treatment of ZnO-SiO2 nanocomposite LEDs could induce the recrystallization of distributed ZnO nanoclusters and reduce the defects in ZnO-SiO2 nanocomposite layers. PMID- 23037017 TI - A fiber optic probe design to measure depth-limited optical properties in-vivo with low-coherence enhanced backscattering (LEBS) spectroscopy. AB - Low-coherence enhanced backscattering (LEBS) spectroscopy is an angular resolved backscattering technique that is sensitive to sub-diffusion light transport length scales in which information about scattering phase function is preserved. Our group has shown the ability to measure the spatial backscattering impulse response function along with depth-selective optical properties in tissue ex-vivo using LEBS. Here we report the design and implementation of a lens-free fiber optic LEBS probe capable of providing depth-limited measurements of the reduced scattering coefficient in-vivo. Experimental measurements combined with Monte Carlo simulation of scattering phantoms consisting of polystyrene microspheres in water are used to validate the performance of the probe. Additionally, depth limited capabilities are demonstrated using Monte Carlo modeling and experimental measurements from a two-layered phantom. PMID- 23037018 TI - Coherence holography by achromatic 3-D field correlation of generic thermal light with an imaging Sagnac shearing interferometer. AB - We propose a new technique for achromatic 3-D field correlation that makes use of the characteristics of both axial and lateral magnifications of imaging through a common-path Sagnac shearing interferometer. With this technique, we experimentally demonstrate, for the first time to our knowledge, 3-D image reconstruction of coherence holography with generic thermal light. By virtue of the achromatic axial shearing implemented by the difference in axial magnifications in imaging, the technique enables coherence holography to reconstruct a 3-D object with an axial depth beyond the short coherence length of the thermal light. PMID- 23037019 TI - Compact MEMS external cavity tunable laser with ultra-narrow linewidth for coherent detection. AB - A compact and ultra-narrow linewidth tunable laser with an external cavity based on a simple single-axis-MEMS mirror is presented in this paper. We discuss the simulation of this tunable laser using a two-step hybrid analysis method to obtain an optimal design of the device. A wide wavelength tuning range about 40 nm in C-band with a narrow linewidth of less than 50 kHz and wavelength accuracy of +/- 1 GHz over the entire tuning range can be achieved experimentally. We also conduct several experiments under different conditions to test the tunable laser. This device shows an excellent performance in both single-carrier polarization multiplexed quadrature phase-shift keying (PM-QPSK) and multi-carrier orthogonal frequency division multiplexing (OFDM) coherent systems. PMID- 23037020 TI - Phase transition in crowd synchrony of delay-coupled multilayer laser networks. AB - An analogy between crowd synchrony and multi-layer neural network architectures is proposed. It indicates that many non-identical dynamical elements (oscillators) communicating indirectly via a few mediators (hubs) can synchronize when the number of delayed couplings to the hubs or the strength of the couplings is large enough. This phenomenon is modeled using a system of semiconductor lasers optically delay-coupled in either a fully connected or a diluted manner to a fixed number of non-identical central hub lasers. A universal phase transition to crowd synchrony with hysteresis is observed, where the time to achieve synchronization diverges near the critical coupling independent of the number of hubs. PMID- 23037021 TI - Shifting of surface plasmon resonance due to electromagnetic coupling between graphene and Au nanoparticles. AB - Shifting of the surface plasmon resonance wavelength induced by the variation of the thickness of insulating spacer between single layer graphene and Au nanoparticles is studied. The system demonstrates a blue-shift of 29 nm as the thickness of the spacer layer increases from 0 to 15 nm. This is due to the electromagnetic coupling between the localized surface plasmons excited in the nanoparticles and the graphene film. The strength of the coupling decays exponentially with a decay length of d/R = 0.36, where d is the spacer layer thickness and R is the diameter of the Au nanoparticles. The result agrees qualitatively well with the plasmon ruler equation. Interestingly, a further increment of the spacer layer thickness induces a red-shift of 17 nm in the resonance wavelength and the shift saturates when the thickness of the spacer layer increases above 20 nm. PMID- 23037022 TI - Dynamic three-dimensional tracking of single fluorescent nanoparticles deep inside living tissue. AB - Three-dimensional (3D) spatial information can be encoded in two-dimensional images of fluorescent nanoparticles by astigmatic imaging. We combined this method with light sheet microscopy for high contrast single particle imaging up to 200 um deep within living tissue and real-time image analysis to determine 3D particle localizations with nanometer precision and millisecond temporal resolution. Axial information was instantly directed to the sample stage to keep a moving particle within the focal plane in an active feedback loop. We demonstrated 3D tracking of nanoparticles at an unprecedented depth throughout large cell nuclei over several thousand frames and a range of more than 10 um in each spatial dimension, while simultaneously acquiring optically sectioned wide field images. We conclude that this 3D particle tracking technique employing light sheet microscopy presents a valuable extension to the nanoscopy toolbox. PMID- 23037023 TI - Strong correlations between incoherent vortices. AB - We establish a correlation rule of which the value of the topological charge obtained in intensity correlation between two coherence vortices is such that this value is bounded by the topological charge of each coherence vortex. The original phase information is scrambled in each speckle pattern and unveiled using numerical intensity correlation. According to this rule, it is also possible to obtain a coherence vortex stable, an integer vortex, even when each incoherent vortex beam is instable, non-integer vortex. PMID- 23037024 TI - Wavefront reconstruction by modal decomposition. AB - We propose a new method to determine the wavefront of a laser beam based on modal decomposition by computer-generated holograms. The hologram is encoded with a transmission function suitable for measuring the amplitudes and phases of the modes in real-time. This yields the complete information about the optical field, from which the Poynting vector and the wavefront are deduced. Two different wavefront reconstruction options are outlined: reconstruction from the phase for scalar beams, and reconstruction from the Poynting vector for inhomogeneously polarized beams. Results are compared to Shack-Hartmann measurements that serve as a reference and are shown to reproduce the wavefront and phase with very high fidelity. PMID- 23037025 TI - Integrated hybrid Si/InGaAs 50 Gb/s DQPSK receiver. AB - A monolithic 25 Gbaud DQPSK receiver based on delay interferometers and balanced detection has been designed and fabricated on the hybrid Si/InGaAs platform. The integrated 30 um long InGaAs p-i-n photodetectors have a responsivity of 0.64 A/W at 1550 nm and a 3dB bandwidth higher than 25 GHz. The delay interferometer shows a delay time of 39.2 ps and an extinction ratio higher than 20 dB. The demodulation of a 25 Gb/s DPSK signal by a single branch of the receiver demonstrates its correct working principle. PMID- 23037026 TI - Amplified all-optical polarization phase modulator assisted by a local surface plasmon in Au-hybrid CdSe quantum dots. AB - We propose an amplified all-optical polarization phase modulator assisted by a local surface plasmon in Au-hybrid CdSe quantum dots. When the local surface plasmon of a spherical Au quantum dot is in resonance with the exciton energy level of a CdSe quantum dot, a significant enhancement of the linear and nonlinear refractive index is found in both the real and imaginary terms via the interaction with the dipole field of the local surface plasmon. Given a gating pulse intensity, an elliptical polarization induced by the phase retardation is described in terms of elliptical and rotational angles. In the case that a larger excitation than the bleaching intensity is applied, the signal light can be amplified due to the presence of gain in the CdSe quantum dot. This enables a longer propagation of the signal light relative to the metal loss, resulting in more feasible polarization modulation. PMID- 23037027 TI - Selectable-wavelength low-coherence digital holography with chromatic phase shifter. AB - We propose a new digital holography method using an ultra-broadband light source and a chromatic phase-shifter. The chromatic phase-shifter gives different frequency shifts for respective spectral frequencies so that the spectrum of the light reflected from the object can be measured to reveal the spectral property of the object, and arbitrary selection of signals in the temporal frequency domain enables single- and multi-wavelength measurements with wide dynamic range. A theoretical analysis, computer simulations, and optical experiments were performed to verify the advantages of the proposed method. PMID- 23037028 TI - Crosstalk reduction in auto-stereoscopic projection 3D display system. AB - In auto-stereoscopic multi-views 3D display systems, the crosstalk and low resolution become problems for taking a clear depth image with the sufficient motion parallax. To solve these problems, we propose the projection-type auto stereoscopic multi-view 3D display system, in which the hybrid optical system with the lenticular-parallax barrier and multi projectors. Condensing width of the projected unit-pixel image within the lenslet by hybrid optics is the core concept in this proposal. As the result, the point crosstalk is improved 53% and resolution is increased up to 5 times. PMID- 23037029 TI - Low-temperature THz time domain waveguide spectrometer with butt-coupled emitter and detector crystal. AB - A compact high-resolution THz time-domain waveguide spectrometer that is operated inside a cryostat is demonstrated. A THz photo-Dember emitter and a ZnTe electro optic detection crystal are directly attached to a parallel copper-plate waveguide. This allows the THz beam to be excited and detected entirely inside the cryostat, obviating the need for THz-transparent windows or external THz mirrors. Since no external bias for the emitter is required, no electric feed through into the cryostat is necessary. Using asynchronous optical sampling, high resolution THz spectra are obtained in the frequency range from 0.2 to 2.0 THz. The THz emission from the photo-Dember emitter and the absorption spectrum of 1,2 dicyanobenzene film are measured as a function of temperature. An absorption peak around 750 GHz of 1,2-dicyanobenzene displays a blue shift with increasing temperature. PMID- 23037030 TI - Two-dimensional plasma current and optimized terahertz generation in two-color photoionization. AB - Two-dimensional (2-D) transverse photocurrent generation is studied and applied to control and optimize terahertz energy and polarization in two-color, laser produced air filaments. A full control of terahertz output is demonstrated and explained in the context of 2-D photocurrent model. PMID- 23037031 TI - Edges in CNC polishing: from mirror-segments towards semiconductors, paper 1: edges on processing the global surface. AB - Segment-edges for extremely large telescopes are critical for observations requiring high contrast and SNR, e.g. detecting exo-planets. In parallel, industrial requirements for edge-control are emerging in several applications. This paper reports on a new approach, where edges are controlled throughout polishing of the entire surface of a part, which has been pre-machined to its final external dimensions. The method deploys compliant bonnets delivering influence functions of variable diameter, complemented by small pitch tools sized to accommodate aspheric mis-fit. We describe results on witness hexagons in preparation for full size prototype segments for the European Extremely Large Telescope, and comment on wider applications of the technology. PMID- 23037032 TI - A hollow beam supercontinuum generation by the supermode superposition in a GeO2 doped triangular-core photonic crystal fiber. AB - A GeO2 doped triangular-core photonic-crystal fiber (PCF) is designed and fabricated to allow the generation of a hollow beam through a nonlinear-optical transformation by femtosecond pulses at 1040 nm from a high power Yb-doped PCF laser oscillator. The hollow beam supercontinuum is obtained at far field by adjusting incident light polarization to excite the high order supermode, behaving as a mode convertor. The supercontinuum ranging from 540 to 1540 nm is achieved with an average power of 1.04 W. PMID- 23037034 TI - Marked performance improvement of 256 QAM transmission using a digital back propagation method. AB - We demonstrate substantial performance improvements in 256 QAM transmission in terms of both data rate and distance that we realized by using a digital back propagation (DBP) method. 160 Gbit/s-160 km and 64 Gbit/s-560 km transmissions were successfully achieved with a polarization-multiplexed 256 QAM signal, in which the symbol rate and transmission distance were greatly increased by compensating for the interplay between dispersion and nonlinearity, which is responsible for the transmission impairment especially for a higher symbol rate and longer distance. PMID- 23037033 TI - Algorithm for reconstructing wide space-bandwidth information in parallel two step phase-shifting digital holography. AB - We propose an image-reconstruction algorithm of parallel phase-shifting digital holography (PPSDH) which is a technique of single-shot phase-shifting interferometry. In the conventional algorithms in PPSDH, the residual 0th-order diffraction wave and the conjugate images cannot be removed completely and a part of space-bandwidth information is discarded. The proposed algorithm can remove these residual images by modifying the calculation of phase-shifting interferometry and by using Fourier transform technique, respectively. Then, several types of complex amplitudes are derived from a recorded hologram according to the directions in which the neighboring pixels used for carrying out the spatial phase-shifting interferometry are aligned. Several distributions are Fourier-transformed and wide space-bandwidth information of the object wave is obtained by selecting the spectrum among the Fourier-transformed images in each region of the spatial frequency domain and synthesizing a Fourier-transformed image from the spectrum. PMID- 23037035 TI - Reconstruction of objects above and below the objective focal plane with dimensional fidelity by FINCH fluorescence microscopy. AB - Fresnel Incoherent Correlation Holography (FINCH) can faithfully reproduce objects above and below the optical plane of focus. However, as in optical imaging, the transverse magnification and optimal reconstruction depth changes based on the longitudinal distance of objects from the focal plane of the input lens with the exception that objects above and below the focal plane are in focus with FINCH and out of focus by standard optical imaging. We have analyzed these effects both theoretically and experimentally for two configurations of a FINCH fluorescence microscopy system. This information has been used to reconstruct a test planar object placed above or below the optical plane of focus with high dimensional and image fidelity. Because FINCH is inherently a super-resolving system, this advance makes it possible to create super-resolved 3D images from FINCH holograms. PMID- 23037036 TI - Linear and nonlinear propagation of optical Nyquist pulses in fibers. AB - We present an analytical and numerical description of optical Nyquist pulse propagation in optical fibers in the presence of dispersion and nonlinearity. An optical Nyquist pulse has a profile given by the sinc-like impulse response of a Nyquist filter, which has periodic zero-crossing points at every symbol interval. This property makes it possible to interleave bits to an ultrahigh symbol rate with no intersymbol interference in spite of the strong overlap between adjacent pulses. We analyze how this periodic zero-crossing property is maintained or affected by the fiber dispersion and nonlinearity, and show that it is better maintained against nonlinearity in the presence of normal dispersion. PMID- 23037037 TI - Imbalanced initial populations between dark and bright states in semiconductor quantum dots. AB - We present the observation and analysis of long-lived exciton in individual InAs quantum dots (QDs). The general model considering the interplay between dark and bright states reveals the two key factors responsible for the long decay time: the shortened spin-flip time at elevated temperature and the imbalanced initial populations between the dark and bright states. The later one plays a key role in the unusual phenomena and leads to the possibility of spin-dependent relaxation process in QDs. PMID- 23037038 TI - Complementary apodized grating waveguides for tunable optical delay lines. AB - A novel class of high-speed and tunable integrated photonic delay lines that compromise between loss and size is proposed. The devices consist of two cascaded apodized grating waveguides and with complementary (positively and negatively modulated) refractive index profiles for dispersion compensation. It is shown that the compact tunable delay lines are low-loss and offer long true-time delays and tuning ranges and high operation bit rates. PMID- 23037039 TI - Profile measurement of transparent inclined surface with transmitted differential interference contrast shearing interferometer. AB - A quantitative phase shifting differential interference contrast (PS-DIC) shearing interferometer is adopted to measure the profile of transparent specimen with inclined surface. The effects of the incline angle on DIC measurement accuracy were studied. The optical model of the test system was constructed and the measurement of surface with various incline angles ranging from 5 degrees to 60 degrees was simulated. The experiments validate the simulation model and show the feasibility of profile reconstruction of inclined structure. It is interested to find that even with an inclined angle of 15 degrees , unwrapping technique is required to make the measurement more accurate. In addition, the measurement can be further improved by taking into account the effects of the change in shear distance on the optical path difference. This study provides useful information that should be considered for complex geometry measurement with quantitative DIC technique. PMID- 23037040 TI - Demonstration of a curved sidewall grating demultiplexer on silicon. AB - We experimentally demonstrate a new type of waveguide multiplexer device designed for silicon photonics, with a crosstalk level as low as -35 dB and an operational wavelength range of 300 nm. A compact device footprint of only 100 * 160 um2 offers an excellent potential for integration with other silicon nanophotonic circuits. PMID- 23037041 TI - Stepwise fabrication of arbitrary fiber optic tapers. AB - This work reports a modified flame-brush technique to fabricate fiber tapers with arbitrary waist profiles. The flame-brush approach is used to produce small step reductions in the fiber diameter, or step-tapers, with a constant speed flame brush sweep, while the fiber is uniformly stretched. Arbitrary waist profiles in tapers are fabricated by approximating the taper diameter function to any monotonic function of the fiber length while combining a superposition of step tapers. This method to produce the arbitrary profiles is described and a set of tapers with dissimilar transition regions are fabricated for its validation. PMID- 23037042 TI - Raman fiber laser harmonically mode-locked by exploiting the intermodal beating of CW multimode pump source. AB - We report here the first demonstration of a harmonic mode-locked Raman fiber laser using the intermodal beating of a continuous-wave (CW) multiple longitudinal-mode pump laser. By matching the Raman-cavity round-trip frequency with the intermodal-beating one of a 1064 nm CW pump source, harmonic mode locking in phosphosilicate Raman fiber laser is stably initiated at the first order Stokes of 1239.5 nm, and generates rectangular-shape nanosecond pulses with the pulse energy up to 4.25 nJ. Using the new type of mode-locking, the harmonic order can be discretely tuned from 78 th- to 693 rd-order, and the cavity supermode is suppressed up to 51.1 dB with the signal-to-noise ratio of more than 65 dB. PMID- 23037043 TI - Photonic crystal-based all-optical on-chip sensor. AB - In this paper we demonstrate a sensor based on a two-dimensional photonic crystal cavity structure. Design, theoretical simulations, fabrication and experiments are shown to illustrate the working principle of this device. Sensitivity of our sensor is determined by observing the shift of resonant wavelength of the photonic crystal cavity as a function of the refractive index variation of the analyte. By experimentally infiltrating solutions of water and ethanol through an elastomeric micro-fluidic channel, we have confirmed that our all-optical sensor achieves a sensitivity of 460 nm/RIU. PMID- 23037044 TI - Fiber nonlinearity compensation for OFDM super-channels using optical phase conjugation. AB - We experimentally demonstrate that mid-link optical phase conjugation (OPC) effectively compensates fiber nonlinearity in coherent optical OFDM super channels. The OPC was produced by pump * subcarrier degenerate four-wave-mixing in a 1-km highly nonlinear fiber. The nonlinear threshold for the 10 * 80-km 604.7-Gb/s 16-QAM test system was increased by 4.8 dB. The performance at the optimum power was only improved by 0.2 dB because the OPC module produces a 1.6 dB penalty for the back-to-back system. FWM theory shows that the 'noise' processes of OPC modules utilizing chi3 nonlinearities could be reduced by increasing the pump power, which will improve back-to-back performance with the OPC module. PMID- 23037045 TI - Resonant metamaterials for contrast enhancement in optical lithography. AB - The transmission through ultra-thin metal films is noticeable and thus limits their potential for the formation of lithographic masks. By sub-wavelength patterning of a metal film with a post structure, a resonant metamaterial is formed, which can effectively suppress the transmission. Measurements as well as calculations identify the width of the metal islands as a critical geometrical feature. Hence, the extraordinarily low transmission effect can be explained by the resonant response of single scatterers known as Localized Surface Plasmon Resonances (LSPR). A potential application of this suppressed transmission effect to thin metal masks in optical lithography is experimentally investigated. PMID- 23037046 TI - Improved signal model for confocal sensors accounting for object depending artifacts. AB - The conventional signal model of confocal sensors is well established and has proven to be exceptionally robust especially when measuring rough surfaces. Its physical derivation however is explicitly based on plane surfaces or point like objects, respectively. Here we show experimental results of a confocal point sensor measurement of a surface standard. The results illustrate the rise of severe artifacts when measuring curved surfaces. On this basis, we present a systematic extension of the conventional signal model that is proven to be capable of qualitatively explaining these artifacts. PMID- 23037047 TI - Regrowth-free high-gain InGaAsP/InP active-passive platform via ion implantation. AB - We demonstrate a regrowth-free material platform to create monolithic InGaAsP/InP photonic integrated circuits (PICs) with high-gain active and low-loss passive sections via a PL detuning of >135 nm. We show 2.5 um wide by 400 um long semiconductor optical amplifiers with >40 dB/mm gain at 1570 nm, and passive waveguide losses <2.3 dB/mm. The bandgap in the passive section is detuned using low-energy 190 keV channelized phosphorous implantation and subsequent rapid thermal annealing to achieve impurity-induced quantum well intermixing (QWI). The PL wavelengths in the active and passive sections are 1553 and 1417 nm, respectively. Lasing wavelengths for 500 um Fabry-Perot lasers are 1567 and 1453 nm, respectively. PMID- 23037048 TI - Photophysics of single silicon vacancy centers in diamond: implications for single photon emission. AB - Single silicon vacancy (SiV) color centers in diamond have recently shown the ability for high brightness, narrow bandwidth, room temperature single photon emission. This work develops a model describing the three level population dynamics of single SiV centers in diamond nanocrystals on iridium surfaces including an intensity dependent de-shelving process. Furthermore, we investigate the brightness and photostability of single centers and find maximum single photon rates of 6.2 Mcps under continuous excitation. We investigate the collection efficiency of the fluorescence and estimate quantum efficiencies of the SiV centers. PMID- 23037049 TI - Analytic description of Airy-type beams when truncated by finite apertures. AB - In this paper, we have developed an analytic method for describing Airy-type beams truncated by finite apertures. This new approach is based on suitable superposition of exponentially decaying Airy beams. Regarding both theoretical and numerical aspects, the results here shown are interesting because they have been quickly evaluated through a simple analytic solution, whose propagation characteristics agree with those already published in literature through the use of numerical methods. To demonstrate the method's potentiality three different truncated beams have been analyzed: ideal Airy, Airy-Gauss and Airy-Exponential. PMID- 23037050 TI - Focussing over the edge: adaptive subsurface laser fabrication up to the sample face. AB - Direct laser writing is widely used for fabrication of subsurface, three dimensional structures in transparent media. However, the accessible volume is limited by distortion of the focussed beam at the sample edge. We determine the aberrated focal intensity distribution for light focused close to the edge of the substrate. Aberrations are modelled by dividing the pupil into two regions, each corresponding to light passing through the top and side facets. Aberration correction is demonstrated experimentally using a liquid crystal spatial light modulator for femtosecond microfabrication in fused silica. This technique allows controlled subsurface fabrication right up to the edge of the substrate. This can benefit a wide range of applications using direct laser writing, including the manufacture of waveguides and photonic crystals. PMID- 23037052 TI - Ultraviolet single-frequency coupled optofluidic ring resonator dye laser. AB - Ultraviolet single-frequency lasing is realized in a coupled optofluidic ring resonator (COFRR) dye laser that consists of a thin-walled capillary microfluidic ring resonator and a cylindrical resonator. The whispering gallery modes (WGMs) in each resonator couple to each other and generate single-frequency laser emission. Single-frequency lasing occurs at 386.75 nm with a pump threshold of 5.9 MUJ/mm. The side-mode-suppression ratio (SMSR) is about 20 dB. Moreover, the laser emits mainly in two directions, and each of them has a divergence of only 10.5 degrees . PMID- 23037051 TI - High phase noise tolerant pilot-tone-aided DP-QPSK optical communication systems. AB - In this paper we experimentally demonstrate a novel, high phase-noise tolerant, optical dual polarization (DP) quadrature phase-shift keying (QPSK) communication system based on pilot-tone-aided phase noise cancellation (PNC) algorithm. Vertical cavity surface emitting lasers (VCSELs) with approximate 300 MHz linewidth are used as transmitters and local oscillators for coherent detection of optical DP-QPSK signals. The proposed system, with central wavelength at 1540.68 nm, operates at 40 Gb/s over 80 km single mode fiber (SMF) as part of a passive optical network (PON). The deployment of pilot-tone-aided PNC algorithm guarantees a bit error rate (BER) performance below the forward error correction (FEC) threshold. Moreover, we also evaluate a novel digital signal processing (DSP) algorithm for adaptive pilot tone detection. PMID- 23037053 TI - Half-joule output optical-parametric oscillation by using 10-mm-thick periodically poled Mg-doped congruent LiNbO3. AB - We present a next generation of large-aperture periodically poled Mg-doped LiNbO3 (PPMgLN) device with 10-mm thickness. Efficient optical parametric oscillation with 540 mJ output energy at 709 mJ pumping by 1.064 um laser in 10 nanoseconds operation could be demonstrated using the 10-mm-thick PPMgLN with an inversion period of 32.2 um at total conversion efficiency > 76%. We also confirmed that degradation effect of conversion-efficiency distribution by wedged-inversion structures, which is inevitable in current poling condition of the large-aperture PPMgLN, can be ignored in high-intensity operation. PMID- 23037054 TI - Frequency-domain optical probing of coherent spins in nanocrystal quantum dots. AB - Spin-photon interactions such as the Faraday effect provide techniques for measuring coherent spin dynamics in semiconductors. In contrast to typical ultrafast pulsed laser techniques, which measure spin dynamics in the time domain with an intense, spectrally broad probe pulse, we demonstrate a frequency-domain spin-photon resonance effect using modulated continuous-wave lasers which enables measurement of GHz-scale coherent spin dynamics in semiconductors with minimal spectral linewidth. This technique permits high-resolution spectroscopic measurements not possible with ultrafast methods. We have employed this effect to observe coherent spin dynamics in CdSe nanocrystals using standard diode lasers. By fitting the results to the expected model, we extract electron g-factors, and spin coherence and dephasing times in agreement with time-domain measurements. PMID- 23037055 TI - Fabrication tolerant polarization splitter and rotator based on a tapered directional coupler. AB - A polarization splitter and rotator (PSR) based on a tapered directional coupler with relaxed fabrication tolerance is proposed and demonstrated on the silicon-on insulator platform. The device is simply constructed by parallel-coupling a narrow silicon waveguide with a linearly tapered wider waveguide. Compared to previously reported PSRs based on a normal directional coupler, which suffer from stringent requirements on the accuracy of the narrow waveguide width, the introduced tapered structure of the wide waveguide can be used to compensate the fabrication errors of the narrow waveguide. In addition, only a single step of exposure and etching is needed for the fabrication of the device. Similar high conversion efficiencies are experimentally demonstrated for a narrow waveguide width deviation of 14 nm with large tolerance to the coupler length. PMID- 23037056 TI - Vulnerability of CMOS image sensors in Megajoule Class Laser harsh environment. AB - CMOS image sensors (CIS) are promising candidates as part of optical imagers for the plasma diagnostics devoted to the study of fusion by inertial confinement. However, the harsh radiative environment of Megajoule Class Lasers threatens the performances of these optical sensors. In this paper, the vulnerability of CIS to the transient and mixed pulsed radiation environment associated with such facilities is investigated during an experiment at the OMEGA facility at the Laboratory for Laser Energetics (LLE), Rochester, NY, USA. The transient and permanent effects of the 14 MeV neutron pulse on CIS are presented. The behavior of the tested CIS shows that active pixel sensors (APS) exhibit a better hardness to this harsh environment than a CCD. A first order extrapolation of the reported results to the higher level of radiation expected for Megajoule Class Laser facilities (Laser Megajoule in France or National Ignition Facility in the USA) shows that temporarily saturated pixels due to transient neutron-induced single event effects will be the major issue for the development of radiation-tolerant plasma diagnostic instruments whereas the permanent degradation of the CIS related to displacement damage or total ionizing dose effects could be reduced by applying well known mitigation techniques. PMID- 23037057 TI - Modal theory of slow light enhanced third-order nonlinear effects in photonic crystal waveguides. AB - In this paper, we derive the couple-mode equations for third-order nonlinear effects in photonic crystal waveguides by employing the modal theory. These nonlinear interactions include self-phase modulation, cross-phase modulation and degenerate four-wave mixing. The equations similar to that in nonlinear fiber optics could be expanded and applied for third-order nonlinear processes in other periodic waveguides. Based on the equations, we systematically analyze the group velocity dispersion, optical propagation loss, effective interaction area, slow light enhanced factor and phase mismatch for a slow light engineered silicon photonic crystal waveguide. Considering the two-photon and free-carrier absorptions, the wavelength conversion efficiencies in two low-dispersion regions are numerically simulated by utilizing finite difference method. Finally, we investigate the influence of slow light enhanced multiple four-wave-mixing process on the conversion efficiency. PMID- 23037058 TI - Determination of optimal converting point of color temperature conversion complied with ANSI C78. 377 for indoor solid-state lighting and display applications. AB - In recent years, displays and lighting require color temperature (CT) conversion function because observers have different preferences. This paper proposes effective methods to determine the optimal converting point of CT conversion for display and lighting application. For display application, the concepts of center of gravity and isotemperature line are applied to determine the optimal converting point. The maximal enhancement of luminance between the optimal and average is 18%. For lighting application, this paper proposes two methods to determine the optimal converting point in the CT quadrangle which complies with ANSI C78. 377. The enhancement of luminance in two CT modes (5700K and 6500K) are 14.2% and 23.6%, respectively. PMID- 23037059 TI - Optical 16-QAM-52-OFDM transmission at 4 Gbit/s by directly modulating a coherently injection-locked colorless laser diode. AB - Coherently injection-locked and directly modulated weak-resonant-cavity laser diode (WRC-FPLD) for back-to-back optical 16-quadrature-amplitude-modulation (QAM) and 52-subcarrier orthogonal frequency division multiplexing (OFDM) transmission with maximum bit rate up to 4 Gbit/s at carrier frequency of 2.5 GHz is demonstrated. The WRC-FPLD transmitter source is a specific design with very weak-resonant longitudinal modes to preserve its broadband gain spectral characteristics for serving as a colorless WDM-PON transmitter. Under coherent injection-locking, the relative-intensity noise (RIN) of the injection-locked WRC FPLD can be suppressed to ?105 dBc/Hz and the error vector magnitude of the received optical OFDM data is greatly reduced with the amplitude error suppressed down 5.5%. Such a coherently injection-locked single-mode WRC-FPLD can perform both the back-to-back and the 25-km-SMF 16-QAM-52-OFDM transmissions with a symbol rate of 20-MSa/s in each OFDM subcarrier. After coherent injection locking, the BER of the back-to-back transmitted 16-QAM-52-OFDM data is reduced to 2.5 * 10(-5) at receiving power of ?10 dBm. After propagating along a 25-km long SMF, a receiving power sensitivity of ?7.5 dBm is required to obtain a lowest BER of 2.5 * 10(-5), and a power penalty of 2.7 dB is observed when comparing with the back-to-back transmission. PMID- 23037060 TI - Modified Roberts-Langenbeck test for measuring thickness and refractive index variation of silicon wafers. AB - We describe a method to simultaneously measure thickness variation and refractive index homogeneity of 300 mm diameter silicon wafers using a wavelength-shifting Fizeau interferometer operating at 1550 nm. Only three measurements are required, corresponding to three different cavity configurations. A customized phase shifting algorithm is used to suppress several high order harmonics and minimize intensity sampling errors. The new method was tested with both silicon and fused silica wafers and measurement results proved to be highly repeatable. The reliability of the method was further verified by comparing the measured thickness variation of a 150 mm diameter wafer to a measurement of the wafer flatness after bonding the wafer to an optical flat. PMID- 23037062 TI - Estimation of broadband emissivity (8-12 um) from ASTER data by using RM-NN. AB - Land surface window emissivity is a key parameter for estimating the longwave radiative budget. The combined radiative transfer model (RM) with neural network (NN) algorithm is utilized to directly estimate the window (8-12 um) emissivity from the brightness temperature of the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) with 90 m spatial resolution. Although the estimation accuracy is very high when the broadband emissivity is estimated from AST05 (ASTER Standard Data Product) by using regression method, the accuracy of AST05 is about +/- 0.015 for 86 spectra which is determined by the atmosphere correction for ASTER 1B data. The MODTRAN 4 is used to simulate the process of radiance transfer, and the broadband emissivity is directly estimated from the brightness temperature of ASTER 1B data at satellite. The comparison analysis indicates that the RM-NN is more competent to estimate broadband emissivity than other method when the brightness temperatures of band 11, 12, 13, 14 are made as input nodes of dynamic neural network. The estimation average accuracy is about 0.009, and the estimation results are not sensitive to instrument noise. The RM NN is applied to extract broadband emissivity from an image of ASTER 1B data in China, and the comparison against a classification based multiple bands with 15 m spatial resolution shows that the estimation results from RM-NN are very good. PMID- 23037061 TI - 170 GHz Uni-Traveling Carrier Photodiodes for InP-based photonic integrated circuits. AB - We demonstrate the capability of fabricating extremely high-bandwidth Uni Traveling Carrier Photodiodes (UTC-PDs) using techniques that are suitable for active-passive monolithic integration with Multiple Quantum Well (MQW)-based photonic devices. The devices achieved a responsivity of 0.27 A/W, a 3-dB bandwidth of 170 GHz, and an output power of -9 dBm at 200 GHz. We anticipate that this work will deliver Photonic Integrated Circuits with extremely high bandwidth for optical communications and millimetre-wave applications. PMID- 23037063 TI - A complex-weighted, decision-aided, maximum-likelihood carrier phase and frequency-offset estimation algorithm for coherent optical detection. AB - We present a symbol-by-symbol coherent optical receiver, which employs a novel, complex-weighted, decision-aided, maximum-likelihood (CW-DA-ML) carrier phase and frequency offset estimator. The CW-DA-ML carrier estimator uses a CW transversal filter to generate a carrier reference phasor, and the filter weights are automatically adapted on-line by linear regression on the observed signals. A complete modulo-R reduced frequency offset estimation (FOE) range of +/- R/2 is achieved, independent of modulation format, where R is the symbol rate. Carrier phase and frequency tracking is achieved rapidly. The acquisition speed of frequency offset in quaternary phase-shift keying (4-PSK) signals is more than 5 times faster than that of differential FOE. A constant penalty of approximately 1 dB at bit-error rate of 10(-4) is demonstrated for all frequency offsets in 4-PSK signals with laser-linewidth-symbol-duration product of 8 * 10(-5). PMID- 23037064 TI - Low-jitter single flux quantum signal readout from superconducting single photon detector. AB - We developed a single-flux-quantum (SFQ) readout technology for superconducting single-photon detectors (SSPDs) to achieve low-jitter signal readout. By optimizing circuit parameters of the SFQ readout circuit, the input current sensitivity was improved below 10 MUA, which is smaller than a typical critical current of SSPD. The experiment using a pulse-pattern generator as an input pulse source revealed that the measured jitter of the SFQ readout circuit is well below the system jitter of our measurement setup for the input current level above 15 MUA. The measured jitter of the SSPD connected to the SFQ readout circuit was 37 ps full width at half maximum (FWHM) for an SSPD bias current of around 18 MUA, which is a significant improvement on 67 ps FWHM jitter observed in conventional readout without an SFQ readout circuit. PMID- 23037065 TI - Submillisecond-response and scattering-free infrared liquid crystal phase modulators. AB - We demonstrate a submillisecond-response and scattering-free infrared phase modulator using a polymer network liquid crystal (PNLC). The required voltage for achieving 2pi phase change at lambda = 1.06 um is 70V (or 5.8 V/MUm) and the measured response time is ~200 us at 25 degrees C and 30 us at 70 degrees C. Opposite to our conventional understanding, a high viscosity LC helps to achieve small domain size during polymerization process, which in turn reduces the response time and light scattering. We use Rayleigh-Gans-Debye scattering model to analyze the voltage-on state transmission spectra. When the domain size is comparable to the wavelength, the model fits with experimental results well. But when the domain size is smaller than the wavelength, the simple Rayleigh model works well. PMID- 23037066 TI - A frontal projection-type three-dimensional display. AB - In a typical auto-stereoscopic three-dimensional display, the parallax barrier or lenticular lens is located in front of the display device. However, in a projection-type auto-stereoscopic display, such optical components make it difficult to display elemental images on the screen or to reconstruct a three dimensional image, even though a projection-type display has many advantages. Therefore, it is necessary to use a rear projection technique in a projection type auto-stereoscopic display, despite the fact that this is an inefficient use of space. We propose here a frontal projection-type auto-stereoscopic display by using a polarizer and a quarter-wave retarding film. Since the proposed method uses a frontal projection scheme and passive polarizing components, it has the advantage of being both space saving and cost effective. This is the first report that describes a frontal projection-type auto-stereoscopic display based on a parallax barrier and integral imaging by using a projector. Experimental results that support the proposed method are provided. PMID- 23037067 TI - Extending nodal aberration theory to include mount-induced aberrations with application to freeform surfaces. AB - This paper introduces the path forward for the integration of freeform optical surfaces, particularly those related to phi-polynomial surfaces, including Zernike polynomial surfaces, with nodal aberration theory. With this formalism, the performance of an optical system throughout the field of view can be anticipated analytically accounting for figure error, mount-induced errors, and misalignment. Previously, only misalignments had been described by nodal aberration theory, with the exception of one special case for figure error. As an example of these new results, three point mounting error that results in a Zernike trefoil deformation is studied for the secondary mirror of a two mirror and three mirror telescope. It is demonstrated that for the case of trefoil deformation applied to a surface not at the stop, there is the anticipated field constant contribution to elliptical coma (also called trefoil) as well as a newly identified field dependent contribution to astigmatism: field linear, field conjugate astigmatism. The magnitude of this astigmatic contribution varies linearly with the field of view; however, it has a unique variation in orientation with field that is described mathematically by a concept that is unique to nodal aberration theory known as the field conjugate vector. PMID- 23037068 TI - Multicore fiber with integrated fiber Bragg gratings for background-free Raman sensing. AB - In the last years a variety of fiber optic Raman probes emerged, which are only partly suited for in vivo applications. The in vivo capability is often limited by the bulkiness of the probes. The size is associated with the required filtering of the probes, which is necessary due to Raman scattering inside the fibers. We employed in-line fiber Bragg gratings (FBG) as notch filter for the collection path and integrated them in a novel type of Raman probe. Multicore singlemode fibers (MCSMF) were designed and drawn integrating 19 singlemode cores to achieve better collection efficiency. A Raman probe was assembled with one excitation fiber and six MCSMF with inscribed FBGs as collection fibers. The probe was characterized regarding Raman background suppression, collection efficiency, and distance dependence. First Raman measurements on brain tissue are presented. PMID- 23037069 TI - Characterization of a high coherence, Brillouin microcavity laser on silicon. AB - Recently, a high efficiency, narrow-linewidth, chip-based stimulated Brillouin laser (SBL) was demonstrated using an ultra-high-Q, silica-on-silicon resonator. In this work, this novel laser is more fully characterized. The Schawlow Townes linewidth formula for Brillouin laser operation is derived and compared to linewidth data, and the fitting is used to measure the mechanical thermal quanta contribution to the Brillouin laser linewidth. A study of laser mode pulling by the Brillouin optical gain spectrum is also presented, and high-order, cascaded operation of the SBL is demonstrated. Potential application of these devices to microwave sources and phase-coherent communication is discussed. PMID- 23037070 TI - Imprints of the molecular-orbital geometry on the high-harmonic ellipticity. AB - The influence of the orbital symmetry on the ellipticity of the high-order harmonics is investigated. It is found that the ellipticity maps have distinct shapes for the molecular orbitals with different symmetry. Our analysis shows that the feature of the harmonic ellipticity map is essentially determined by the nodal structure of the nonsymmetric orbital. The results indicate that the molecular-orbital geometry is imprinted on the ellipticity of the high-order harmonics, which invites the use of ellipticity measurements as a probe of the orbital structure for polar molecules. PMID- 23037071 TI - Cladding-pumped erbium-doped multicore fiber amplifier. AB - A cladding pumped multicore erbium-doped fiber amplifier for simultaneous amplification of 6 channels is demonstrated. Peak gain over 32 dB has been obtained at a wavelength of 1560 nm and the bandwidth measured at 20-dB gain was about 35 nm. Numerical modeling of cladding pumped multicore erbium-doped amplifier was also performed to study the properties of the amplifier. The results of experiment and simulation are found to be in good agreement. PMID- 23037072 TI - Revealing the multi-electron effects in sequential double ionization using classical simulations. AB - We theoretically investigated sequential double ionization (SDI) of Ar by the nearly circularly polarized laser pulses with a fully correlated classical ensemble model. The ion momentum distributions of our numerical results at various laser intensities and pulse durations agree well with the experimental results. The experimentally observed multi-electron effects embodied in the joint momentum spectrum of the two electrons is also reproduced by our correlated classical calculations. Interestingly, our calculations show that the angular distribution of the first photoelectron from the trajectories which eventually suffer SDI differs from the distribution of the photoelectrons from above threshold ionization trajectories. This observation provides additional evidence of multi-electron effects in strong field SDI. PMID- 23037073 TI - Study on spontaneous emission in complex multilayered plasmonic system via surface integral equation approach with layered medium Green's function. AB - A rigorous surface integral equation approach is proposed to study the spontaneous emission of a quantum emitter embedded in a multilayered plasmonic structure with the presence of arbitrarily shaped metallic nanoscatterers. With the aid of the Fermi's golden rule, the spontaneous emission of the emitter can be calculated from the local density of states, which can be further expressed by the imaginary part of the dyadic Green's function of the whole electromagnetic system. To obtain this Green's function numerically, a surface integral equation is established taking into account the scattering from the metallic nanoscatterers. Particularly, the modeling of the planar multilayered structure is simplified by applying the layered medium Green's function to reduce the computational domain and hence the memory requirement. Regarding the evaluation of Sommerfeld integrals in the layered medium Green's function, the discrete complex image method is adopted to accelerate the evaluation process. This work offers an accurate and efficient simulation tool for analyzing complex multilayered plasmonic system, which is commonly encountered in the design of optical elements and devices. PMID- 23037074 TI - Generation of ultra-wideband triplet pulses based on four-wave mixing and phase to-intensity modulation conversion. AB - We propose and demonstrate a novel scheme to generate ultra-wideband (UWB) triplet pulses based on four-wave mixing and phase-to-intensity modulation conversion. First a phase-modulated Gaussian doublet pulse is generated by four wave mixing in a highly nonlinear fiber. Then an UWB triplet pulse is generated by generating the first-order derivative of the phase-modulated Gaussian doublet pulse using an optical filter serving as a frequency discriminator. By locating the optical signal at the linear slope of the optical filter, the phase modulated Gaussian doublet pulse is converted to an intensity-modulated UWB triplet pulse which well satisfies the Federal Communications Commission spectral mask requirements, even in the extremely power-restricted global positioning system band. PMID- 23037075 TI - Non-paraxial TM01 and TE01 from Laguerre-Gauss angular spectrum. AB - We demonstrate that a Laguerre-Gauss spectrum of plane waves distribution optimize the variance of the spectrum-bandwidth product. In the space domain, the axial Ez (TM01) and the azimuthal Ephi (TE01) have also a Laguerre-Gauss profile that describes correctly some experimental published and calculated results in the focal plane. PMID- 23037076 TI - Semi-guiding high-aspect-ratio core (SHARC) fiber amplifiers with ultra-large core area for single-mode kW operation in a compact coilable package. AB - A new class of optical fiber, the SHARC fiber, is analyzed in a high-power fiber amplifier geometry using the gain-filtering properties of confined-gain dopants. The high-aspect-ratio (~30:1) rectangular core allows mode-area scaling well beyond 10,000 MUm2, which is critical to high-pulse-energy or narrow-linewidth high-power fiber amplifiers. While SHARC fibers offer modally dependent edge loss at the wide "semi-guiding" edge of the waveguide, the inclusion of gain filtering adds further modal discrimination arising from the variation of the spatial overlap of the gain with the various modes. Both methods are geometric in form, such that the combination provides nearly unlimited scalability in mode area. Simulations show that for kW-class fiber amplifiers, only the fundamental mode experiences net gain (15 dB), resulting in outstanding beam quality. Further, misalignment of the seed beam due to offset, magnification, and tilt are shown to result in a small (few percent) efficiency penalty while maintaining kW-level output with 99% of the power in the fundamental mode for all cases. PMID- 23037077 TI - Dual-frequency laser Doppler velocimeter for speckle noise reduction and coherence enhancement. AB - We study the characteristics of a dual-frequency laser Doppler velocimeter (DF LDV) based on an optically injected semiconductor laser. The laser operated in a period-one (P1) dynamical state with two optical frequencies separated by 11.25 GHz is used as the dual-frequency light source. With a microwave beat signal carried by the light, the DF-LDV possesses both the advantages of good directionality, high intensity, and high spatial resolution from the light and low speckle noise and good coherence from the microwave, respectively. By phase locking the two frequency components with a microwave signal, the coherence of the dual-frequency light source can be further improved and the detection range can be much extended. In this paper, velocity resolutions of the DF-LDV with different amounts of speckle noise and at different detection ranges are experimentally measured and analyzed. Compared with the conventional single frequency LDV (SF-LDV), the velocity resolution of the DF-LDV is improved by 8 * 10(3) times from 2.5 m/s to 0.31 mm/s for a target with a longitudinal velocity vz = 4 cm/s, a transverse velocity vt = 5 m/s, and at a detection range of 108 m. PMID- 23037078 TI - Optical characteristics of silicon nanowires grown from tin catalyst layers on silicon coated glass. AB - The optical characteristics of silicon nanowires grown on Si layers on glass have been modeled using the FDTD (Finite Difference Time Domain) technique and compared with experimental results. The wires were grown by the VLS (vapour liquid-solid) method using Sn catalyst layers and exhibit a conical shape. The resulting measured and modeled absorption, reflectance and transmittance spectra have been investigated as a function of the thickness of the underlying Si layer and the initial catalyst layer, the latter having a strong influence on wire density. High levels of absorption (>90% in the visible wavelength range) and good agreement between the modeling and experiment have been observed when the nanowires have a relatively high density of ~4 wires/um2. The experimental and modeled results diverge for samples with a lower density of wire growth. The results are discussed along with some implications for solar cell fabrication. PMID- 23037079 TI - Excellent color rendering indexes of multi-package white LEDs. AB - This study introduces multi-package white light-emitting diodes (LEDs) system with the ability to realize high luminous efficacy and an excellent color rendering index (CRI, R a) using the R B,M A B,M G B,M C B (R B,M A B,M G B,M denoted as a long-pass dichroic filter (LPDF)-capped, monochromatic red, amber and green phosphor converted-LED (pc-LED) pumped by a blue LED chip, and C B denoted as a cyan and blue mixed pc-LED pumped by a blue LED) system. The luminous efficacy and color rendering index (CRI) of multi-package white LED systems are compared while changing the concentration of the cyan phosphor used in the paste of a cyan-blue LED package and the driving current of individual LEDs in multi-package white LEDs at correlated color temperatures (CCTs) ranging from 6,500 K (cold white) to 2,700 K (warm white) using a set of eight CCTs as specified by the American National Standards Institute (ANSI) standard number C78.377-2008. A R B,M A B,M G B,M C B white LED system provides high luminous efficacy (>= 96 lm/W) and a color rendering index (>= 91) encompassing the complete CCT range. We also compare the optical properties of the R B,M A B,M G B,M C B system with those of the R B,M A B,M G B,M B and RAGB (red, amber, green, and blue semiconductor-type narrow-spectrum-band LEDs) systems. It can be expected that the cyan color added to a blue LED in multi-package white LEDs based on LPDF-capped, phosphor-converted monochromatic LEDs will meet the needs of the high-quality, highly efficient, full-color white LED lighting market in the near future. PMID- 23037080 TI - Single-shot femtosecond-pulsed phase-shifting digital holography. AB - Parallel phase-shifting digital holography is capable of three-dimensional measurement of a dynamically moving object with a single-shot recording. In this letter, we demonstrated a parallel phase-shifting digital holography using a single femtosecond light pulse whose central wavelength and temporal duration were 800 nm and 96 fs, respectively. As an object, we set spark discharge in atmospheric pressure air induced by applying a high voltage to between two electrodes. The instantaneous change in phase caused by the spark discharge was clearly reconstructed. The reconstructed phase image shows the change of refractive index of air was -3.7 * 10(-4). PMID- 23037081 TI - Cascadable excitability in microrings. AB - To emulate a spiking neuron, a photonic component needs to be excitable. In this paper, we theoretically simulate and experimentally demonstrate cascadable excitability near a self-pulsation regime in high-Q-factor silicon-on-insulator microrings. For the theoretical study we use Coupled Mode Theory. While neglecting the fast energy and phase dynamics of the cavity light, we can still preserve the most important microring dynamics, by only keeping the temperature difference with the surroundings and the amount of free carriers as dynamical variables of the system. Therefore we can analyse the microring dynamics in a 2D phase portrait. For some wavelengths, when changing the input power, the microring undergoes a subcritical Andronov-Hopf bifurcation at the self-pulsation onset. As a consequence the system shows class II excitability. Experimental single ring excitability and self-pulsation behaviour follows the theoretic predictions. Moreover, simulations and experiments show that this excitation mechanism is cascadable. PMID- 23037082 TI - Highly sensitive biosensor based on UV-imprinted layered polymeric-inorganic composite waveguides. AB - An evanescent field sensor utilizing layered polymeric-inorganic composite waveguide configuration was developed in this work. The composite waveguide structure consists of a UV-imprint patterned polymer inverted rib waveguide with a Ta2O5 thin film sputter-deposited on top of the low refractive index polymer layers. The results suggest that the polymer based sensor can achieve a detection limit of 3 * 10(-7) RIU for refractive index sensing and corresponding limit of about 100 fg/mm2 for molecular adsorption detection. Besides enhancing the sensitivity significantly, the inorganic coating on the polymer layer was found to block water absorption effectively into the waveguide resulting in a stabilized sensor operation. The ability to use the developed sensor in specific molecular detection was confirmed by investigating antibody - antigen binding reactions. The results of this work demonstrate that high performance sensing capability can be obtained with the developed composite waveguide sensor. PMID- 23037083 TI - Volume flow calculations on gas leaks imaged with infrared gas-correlation. AB - Two methods for volume flow calculation from images of methane leakages to the atmosphere are presented. The images contain calibrated gas concentration * path length pixel information, and are processed with a block matching method and a theoretical velocity field method. Results from known methane flow in two laboratory setups and one unknown real leakage from a gas processing plant are compared with the image processing methods. The methods are generic and can be implemented in common infrared systems for gas visualization. This work provides a new tool for estimating and reporting volume flow emissions from gas processing plants to the authorities. PMID- 23037084 TI - Switching energy limits of waveguide-coupled graphene-on-graphene optical modulators. AB - The fundamental switching energy limitations for waveguide coupled graphene-on graphene optical modulators are described. The minimum energy is calculated under the constraints of fixed insertion loss and extinction ratio. Analytical relations for the switching energy both for realistic structures and in the quantum capacitance limit are derived and compared with numerical simulations. The results show that sub-femtojoule per bit switching energies and peak-to-peak voltages less than 0.1 V are achievable in graphene-on-graphene optical modulators using the constraint of 3 dB extinction ratio and 3 dB insertion loss. The quantum-capacitance limited switching energy for a single TE-mode modulator geometry is found to be < 0.5 fJ/bit at lambda = 1.55 MUm, and the dependences of the minimum energy on the waveguide geometry, wavelength, and graphene location are investigated. The low switching energy is a result of the very strong optical absorption in graphene, and the extremely-small operating voltages needed as the device approaches the quantum capacitance regime. PMID- 23037085 TI - Plasmonic mode converter for controlling optical impedance and nanoscale light matter interaction. AB - To enable multiple functions of plasmonic nanocircuits, it is of key importance to control the propagation properties and the modal distribution of the guided optical modes such that their impedance matches to that of nearby quantum systems and desired light-matter interaction can be achieved. Here, we present efficient mode converters for manipulating guided modes on a plasmonic two-wire transmission line. The mode conversion is achieved through varying the path length, wire cross section and the surrounding index of refraction. Instead of pure optical interference, strong near-field coupling of surface plasmons results in great momentum splitting and modal profile variation. We theoretically demonstrate control over nanoantenna radiation and discuss the possibility to enhance nanoscale light-matter interaction. The proposed converter may find applications in surface plasmon amplification, index sensing and enhanced nanoscale spectroscopy. PMID- 23037086 TI - Design of a compact mode and polarization converter in three-dimensional photonic crystals. AB - A mode and polarization converter is proposed and optimized for 3D photonic integrated circuits based on photonic crystals (PhCs). The device converts the index-guided TE mode of a W1 solid-core (SC) waveguide to the band-gap-guided TM mode of a W1 hollow-core (HC) waveguide in 3D PhCs, and vice versa. The conversion is achieved based on contra-directional mode coupling. For a 25 MUm long device, simulations show that the power conversion efficiency is over 98% across a wavelength range of 16 nm centered at 1550 nm, whereas the reflection remains below -20 dB. The polarization extinction ratio of the conversion is in principle infinitely high because both W1 waveguides operate in the single-mode regimes in this wavelength range. PMID- 23037087 TI - 10-Gb/s direct modulation of polymer-based tunable external cavity lasers. AB - We demonstrate a directly-modulated 10-Gb/s tunable external cavity laser (ECL) fabricated by using a polymer Bragg reflector and a high-speed superluminescent diode (SLD). The tuning range and output power of this ECL are measured to be >11 nm and 2.6 mW (@ 100 mA), respectively. We directly modulate this laser at 10 Gb/s and transmit the modulated signal over 20 km of standard single-mode fiber. The power penalty is measured to be <2.8 dB at the bit-error rate (BER) of 10( 10). PMID- 23037088 TI - Boosting the directivity of optical antennas with magnetic and electric dipolar resonant particles. AB - Dielectric particles supporting both magnetic and electric Mie resonances are shown to be able to either reflect or collect the light emitted by a single photon source. An analytical model accurately predicts the scattering behavior of a single dielectric particle electromagnetically coupled to the electric dipole transition moment of a quantum emitter. We derive near field extensions of the Kerker conditions in order to determine the conditions that strongly reduce scattering in either the forward or backward directions. This concept is then employed to design a lossless dielectric collector element whose directivity is boosted by the coherent scattering of both electric and magnetic dipoles. PMID- 23037089 TI - Diode pumped laser operation and spectroscopy of Pr3+:LaF3. AB - We report on the first results of diode pumped laser operation of Pr3+:LaF3 in a quasi continuous wave (qcw) mode with average output powers of up to 80.0 mW (~ 161.3 mW qcw) and a maximum slope efficiency of 37% at 719.8 nm. Furthermore it was possible to operate the laser at 537.1 nm and 635.4 nm and to tune the emission wavelength from 609 nm to 623 nm. The pump source was an InGaN laser diode with a maximum output power of 1 W at a central emission wavelength of 442 nm. PMID- 23037090 TI - On the optimum signal constellation design for high-speed optical transport networks. AB - In this paper, we first describe an optimum signal constellation design algorithm, which is optimum in MMSE-sense, called MMSE-OSCD, for channel capacity achieving source distribution. Secondly, we introduce a feedback channel capacity inspired optimum signal constellation design (FCC-OSCD) to further improve the performance of MMSE-OSCD, inspired by the fact that feedback channel capacity is higher than that of systems without feedback. The constellations obtained by FCC OSCD are, however, OSNR dependent. The optimization is jointly performed together with regular quasi-cyclic low-density parity-check (LDPC) code design. Such obtained coded-modulation scheme, in combination with polarization-multiplexing, is suitable as both 400 Gb/s and multi-Tb/s optical transport enabling technology. Using large girth LDPC code, we demonstrate by Monte Carlo simulations that a 32-ary signal constellation, obtained by FCC-OSCD, outperforms previously proposed optimized 32-ary CIPQ signal constellation by 0.8 dB at BER of 10(-7). On the other hand, the LDPC-coded 16-ary FCC-OSCD outperforms 16-QAM by 1.15 dB at the same BER. PMID- 23037091 TI - Optimal wavelength-space crossbar switches for supercomputer optical interconnects. AB - We propose a most economical design of the Optical Shared MemOry Supercomputer Interconnect System (OSMOSIS) all-optical, wavelength-space crossbar switch fabric. It is shown, by analysis and simulation, that the total number of on-off gates required for the proposed N * N switch fabric can scale asymptotically as N ln N if the number of input/output ports N can be factored into a product of small primes. This is of the same order of magnitude as Shannon's lower bound for switch complexity, according to which the minimum number of two-state switches required for the construction of a N * N permutation switch is log2 (N!). PMID- 23037092 TI - Hierarchical Bayesian estimation improves depth accuracy and spatial resolution of diffuse optical tomography. AB - High-density diffuse optical tomography (HD-DOT) is an emerging technique for visualizing the internal state of biological tissues. The large number of overlapping measurement channels due to the use of high-density probe arrays permits the reconstruction of the internal optical properties, even with a reflectance-only measurement. However, accurate three-dimensional reconstruction is still a challenging problem. First, the exponentially decaying sensitivity causes a systematic depth-localization error. Second, the nature of diffusive light makes the image blurred. In this paper, we propose a three-dimensional reconstruction method that overcomes these two problems by introducing sensitivity-normalized regularization and sparsity into the hierarchical Bayesian method. Phantom experiments were performed to validate the proposed method under three conditions of probe interval: 26 mm, 18.4 mm, and 13 mm. We found that two absorbers with distances shorter than the probe interval could be discriminated under the high-density conditions of 18.4-mm and 13-mm intervals. This discrimination ability was possible even if the depths of the two absorbers were different from each other. These results show the high spatial resolution of the proposed method in both depth and horizontal directions. PMID- 23037093 TI - Dynamics of transient absorption in bulk DKDP crystals following laser energy deposition. AB - The transient changes in the optical properties of bulk DKDP material arising from its exposure to high temperatures and pressures associated with localized laser energy deposition are investigated. Two methods for initiation of laser induced breakdown are used, intrinsic, involving relatively large energy deposition brought about by focusing of the laser beam to high intensities, and extrinsic, arising from more localized deposition due to the presence of pre existing absorbing damage initiating defects. Each method leads to a very different volume of material being affected, which provides for different material thermal relaxation times to help better understand the processes involved. PMID- 23037094 TI - Continuous wavelet transform for non-stationary vibration detection with phase OTDR. AB - We propose the continuous wavelet transform for non-stationary vibration measurement by distributed vibration sensor based on phase optical time-domain reflectometry (OTDR). The continuous wavelet transform approach can give simultaneously the frequency and time information of the vibration event. Frequency evolution is obtained by the wavelet ridge detection method from the scalogram of the continuous wavelet transform. In addition, a novel signal processing algorithm based on the global wavelet spectrum is used to determine the location of vibration. Distributed vibration measurements of 500 Hz and 500 Hz to 1 kHz sweep events over 20 cm fiber length are demonstrated using a single mode fiber. PMID- 23037095 TI - Optimum selection of input polarization states in determining the sample Mueller matrix: a dual photoelastic polarimeter approach. AB - Dual photoelastic modulator polarimeter systems are widely used for the measurement of light beam polarization, most often described by Stokes vectors, that carry information about an interrogated sample. The sample polarization properties can be described more thoroughly through its Mueller matrix, which can be derived from judiciously chosen input polarization Stokes vectors and correspondingly measured output Stokes vectors. However, several sources of error complicate the construction of a Mueller matrix from the measured Stokes vectors. Here we present a general formalism to examine these sources of error and their effects on the derived Mueller matrix, and identify the optimal input polarization states to minimize their effects in a dual photoelastic modulator polarimeter configuration. The input Stokes vector states leading to the most robust Mueller matrix determination are shown to form Platonic solids in the Poincare sphere space; we also identify the optimal 3D orientation of these solids for error minimization. PMID- 23037096 TI - A simple optical model to estimate diffuse attenuation coefficient of photosynthetically active radiation in an extremely turbid lake from surface reflectance. AB - Accurate estimation of the diffuse attenuation coefficient is critical for our understanding and modelling of key physical, chemical, and biological processes in water bodies. For extremely turbid, shallow, Lake Taihu in China, we synchronously monitored the diffuse attenuation coefficient of photosynthetically active radiation (Kd(PAR)) and the remote sensing reflectance at 134 sites. Kd(PAR)) varied greatly among different sites from 1.62 to 14.68 m(-1) with a mean value of 5.62 +/- 2.99 m(-1). A simple optical model from near-infrared remote sensing reflectance of MODIS channels 2 (859 nm) and 15 (748 nm) was calibrated, and validated, to estimate Kd(PAR). With the simple optical model, the root mean square error and mean relative error were 0.95 m(-1) and 17.0% respectively at 748 nm, and 0.98 m(-1) and 17.6% at 859 nm, based on an independent validation data set. Our results showed a good precision of estimation for Kd(PAR) using the new simple optical model, contrasting with the poor estimations derived from existing empirical and semi-analytical models developed in clear, open ocean waters or slightly turbid coastal waters. Although at 748 nm the model had slightly higher precision than at 859 nm, the spatial resolution at 859 nm was four times that at 748 nm. Therefore, we propose a new model based on the MODIS-derived normalized water-leaving radiances at a wavelength of 859 nm, for accurate retrieval of Kd(PAR) in extremely turbid, shallow lakes with Kd(PAR) larger than 1.5 m(-1). PMID- 23037097 TI - Measuring higher-order modes in a low-loss, hollow-core, photonic-bandgap fiber. AB - We perform detailed measurements of the higher-order-mode content of a low-loss, hollow-core, photonic-bandgap fiber. Mode content is characterized using Spatially and Spectrally resolved (S2) imaging, revealing a variety of phenomena. Discrete mode scattering to core-guided modes are measured at small relative group-delays. At large group delays a continuum of surface modes and core-guided modes can be observed. The LP11 mode is observed to split into four different group delays with different orientations, with the relative orientations preserved as the mode propagates through the fiber. Cutback measurements allow for quantification of the loss of different individual modes. The behavior of the modes in the low loss region of the fiber is compared to that in a high loss region of the fiber. Finally, a new measurement technique is introduced, the sliding-window Fourier transform of high-resolution transmission spectra of hollow-core fibers, which displays the dependence of HOM content on both wavelength and group delay. This measurement is used to illustrate the HOM content as function of coil diameter. PMID- 23037098 TI - Second-order nonlinear silicon-organic hybrid waveguides. AB - We describe a concept for second-order nonlinear optical processes in silicon photonics. A silicon-organic hybrid (SOH) double slot waveguide is dispersion engineered for mode phase-matching (MPM). The proposed waveguide enables highly efficient nonlinear processes in the mid-IR range. With a cladding nonlinearity of chi(2) = 230 pm/V and 20 dBm pump power at a CW wavelength of 1550 nm, we predict a gain of 14.7 dB/cm for a 3100 nm signal. The suggested structure enables for the first time efficient second-order nonlinear optical mixing in silicon photonics with standard technology. PMID- 23037099 TI - Angiography of the retina and the choroid with phase-resolved OCT using interval optimized backstitched B-scans. AB - In conventional phase-resolved OCT blood flow is detected from phase changes between successive A-scans. Especially in high-speed OCT systems this results in a short evaluation time interval. This method is therefore often unable to visualize complete vascular networks since low flow velocities cause insufficient phase changes. This problem was solved by comparing B-scans instead of successive A-scans to enlarge the time interval. In this paper a detailed phase-noise analysis of our OCT system is presented in order to calculate the optimal time intervals for visualization of the vasculature of the human retina and choroid. High-resolution images of the vasculature of a healthy volunteer taken with various time intervals are presented to confirm this analysis. The imaging was performed with a backstitched B-scan in which pairs of small repeated B-scans are stitched together to independently control the time interval and the imaged lateral field size. A time interval of >= 2.5 ms was found effective to image the retinal vasculature down to the capillary level. The higher flow velocities of the choroid allowed a time interval of 0.64 ms to reveal its dense vasculature. Finally we analyzed depth-resolved histograms of volumetric phase-difference data to assess changes in amount of blood flow with depth. This analysis indicated different flow regimes in the retina and the choroid. PMID- 23037100 TI - Novel hybrid plasmonic waveguide consisting of two identical dielectric nanowires symmetrically placed on each side of a thin metal film. AB - It is well-known that, a dielectric cylinder on a metal surface offers the advantage of not yielding singular field, which would effectively reduce the propagation loss as opposed to a rectangle-shaped waveguide on a metal surface. In this article, a novel hybrid plasmonic waveguide consisting of two identical dielectric nanowires symmetrically placed on each side of a thin metal film is presented. With the strong interaction between the dielectric cylindrical waveguide mode and long-range surface plasmon polaritons (LRSPP) mode of a thin metal film, deep-subwavelength mode confinement can be achieved. Compared with the hybrid plasmonic mode guided in only one dielectric nanowire above a metal film, a much larger propagation length as well as improved figure of merit (FoM) can be simultaneously realized. A typical propagation length is 434 MUm, and optical field is confined into an ultra-small area of approximately 0.0096 MUm at 1.55 MUm. This structure could enable various applications such as nanophotonic waveguides, high-quality nanolasers, and optical trapping and transportation of nanoparticles and biomolecules. PMID- 23037101 TI - A semiconductor laser with monolithically integrated dynamic polarization control. AB - We report the first demonstration of a semiconductor laser monolithically integrated with an active polarization controller, which consists of a polarization mode converter followed by an active, differential phase shifter. High speed modulation of the device output polarization is demonstrated via current injection to the phase shifter section. PMID- 23037102 TI - Sub-wavelength GaN-based membrane high contrast grating reflectors. AB - The GaN-based membrane high contrast grating (HCG) reflectors have been fabricated and investigated. The structural parameters including grating periods, grating height, filling factors and air-gap height were calculated to realize high reflectivity spectra with broad bandwidth by the rigorous coupled-wave analysis and finite-difference time-domain method. Based on the optimized simulation results, the GaN-based membrane HCGs were fabricated by e-beam lithography and focused-ion beam process. The fabricated GaN-based membrane HCG reflectors revealed high reflectivity at 460 nm band with large stopband width of 60 nm in the TE polarization measured by using the micro-reflectivity spectrometer. The experimental results also showed a good agreement with simulated ones. We believe this study will be helpful for development of the GaN based novel light emitting devices in the blue or UV region. PMID- 23037103 TI - Integrated Tm:fiber MOPA with polarized output and narrow linewidth with 100 W average power. AB - We report on a Tm:fiber master oscillator power amplifier (MOPA) system producing 109 W CW output power, with >15 dB polarization extinction ratio, sub-nm spectral linewidth, and M2 <1.25. The system consists of polarization maintaining (PM) fiber and PM-fiber components including tapered fiber bundle pump combiners, a single-mode to large mode area mode field adapter, and a fiber-coupled isolator. The laser components ultimately determine the system architecture and the limits of laser performance, particularly considering the immature and rapidly developing state of fiber components in the 2 MUm wavelength regime. PMID- 23037104 TI - Direct fabrication of silicon photonic devices on a flexible platform and its application for strain sensing. AB - We demonstrate a process to fabricate silicon photonic devices directly on a plastic film which is both flexible and transparent. This process allows the integration of complex structures on plastic films without the need of transferring from another substrate. Waveguides, grating couplers, and microring resonators are fabricated and optically characterized. An optical strain sensor is shown as an application using 5 um-radius microring resonators on the flexible substrate. When strain is applied, resonance wavelength shifts of the microring resonators are observed. Contributions of different effects are analyzed and evaluated. Finally, we measure the influence of residual strain and confirm the material undergoes elastic deformation within the applied strain range. PMID- 23037105 TI - Broadband and wide-angle distributed Bragg reflectors based on amorphous germanium films by glancing angle deposition. AB - We fabricated the distributed Bragg reflectors (DBRs) with amorphous germanium (a Ge) films consisted of the same materials at a center wavelength (lambdac) of 1.33 MUm by the glancing angle deposition. Their optical reflectance properties were investigated in the infrared wavelength region of 1-1.9 MUm at incident light angles (theta inc) of 8-70 degrees , together with the theoretical analysis using a rigorous coupled-wave analysis simulation. The two alternating a-Ge films at the incident vapor flux angles of 0 and 75 degrees were formed as the high and low refractive index materials, respectively. The a-Ge DBR with only 5 periods exhibited a normalized stop bandwidth (?lambda/lambda c) of ~24.1%, maintaining high reflectance (R) values of > 99%. Even at a high theta inc of 70 degrees , the ?lambda/lambda c was ~21.9%, maintaining R values of > 85%. The a Ge DBR with good uniformity was obtained over the area of a 2 inch Si wafer. The calculated reflectance results showed a similar tendency to the measured data. PMID- 23037106 TI - Confocal light sheet microscopy: micron-scale neuroanatomy of the entire mouse brain. AB - Elucidating the neural pathways that underlie brain function is one of the greatest challenges in neuroscience. Light sheet based microscopy is a cutting edge method to map cerebral circuitry through optical sectioning of cleared mouse brains. However, the image contrast provided by this method is not sufficient to resolve and reconstruct the entire neuronal network. Here we combined the advantages of light sheet illumination and confocal slit detection to increase the image contrast in real time, with a frame rate of 10 Hz. In fact, in confocal light sheet microscopy (CLSM), the out-of-focus and scattered light is filtered out before detection, without multiple acquisitions or any post-processing of the acquired data. The background rejection capabilities of CLSM were validated in cleared mouse brains by comparison with a structured illumination approach. We show that CLSM allows reconstructing macroscopic brain volumes with sub-cellular resolution. We obtained a comprehensive map of Purkinje cells in the cerebellum of L7-GFP transgenic mice. Further, we were able to trace neuronal projections across brain of thy1-GFP-M transgenic mice. The whole-brain high-resolution fluorescence imaging assured by CLSM may represent a powerful tool to navigate the brain through neuronal pathways. Although this work is focused on brain imaging, the macro-scale high-resolution tomographies affordable with CLSM are ideally suited to explore, at micron-scale resolution, the anatomy of different specimens like murine organs, embryos or flies. PMID- 23037107 TI - All-dielectric optical nanoantennas. AB - We study in detail a novel type of optical nanoantennas made of high-permittivity low-loss dielectric particles. In addition to the electric resonances, the dielectric particles exhibit very strong magnetic resonances at the nanoscale, that can be employed in the Yagi-Uda geometry for creating highly efficient optical nanoantennas. By comparing plasmonic and dielectric nanoantennas, we demonstrate that all-dielectric nanoantennas may exhibit better radiation efficiency also allowing more compact design. PMID- 23037108 TI - Enhancement of imaging depth of two-photon microscopy using pinholes: analytical simulation and experiments. AB - Achieving a greater imaging depth with two-photon fluorescence microscopy (TPFM) is mainly limited by out-of-focus fluorescence generated from both ballistic and scattered light excitation. We report on an improved signal-to-noise ratio (SNR) in a highly scattering medium as demonstrated by analytical simulation and experiments for TPFM. Our technique is based on out-of-focus rejection using a confocal pinhole. We improved the SNR by introducing the pinhole in the collection beam path. Using the radiative transfer theory and the ray-optics approach, we analyzed the effects of different sizes of pinholes on the generation of the fluorescent signal in the TPFM system. The analytical simulation was evaluated by comparing its results with the experimental results in a scattering medium. In a combined confocal pinhole and two-photon microscopy system, the imaging depth limit of approximately 5 scattering mean free paths (MFP) was found to have improved to 6.2 MFP. PMID- 23037109 TI - Test of spectral emission and absorption characteristics of active optical fibers by direct side pumping. AB - Emission and absorption are two main properties of active optical fibers that are important for fiber amplifiers and lasers. We propose a direct side pumping scheme for non-deconstructive evaluation of active optical fibers. This scheme enables a simple in situ test of both emission and absorption characteristics without cutting fiber and produces good accuracy with very low pumping background. A commercial Er-doped fiber and a home-made Bi/Er co-doped optical fiber have been tested to demonstrate that the scheme is a useful alternative technique for characterizing active optical fiber or waveguides. PMID- 23037110 TI - Power scaling of a directly diode-laser-pumped Ti:sapphire laser. AB - Improvements in the output power of a directly GaN diode-laser-pumped Ti:Al2O3 laser are achieved by using double-sided pumping. In continuous wave operation, an output power of 159 mW is reported. A tuning range of over 125 nm with output powers in excess of 100 mW is achieved. Pulses of 111 fs duration and an average power of 101 mW are demonstrated by mode locking the laser with a saturable Bragg reflector. Pumping with GaN diode lasers at wavelengths around 450 nm induces an additional parasitic crystal loss of about 1% per resonator roundtrip that is not observed at the conventional green pump wavelengths. PMID- 23037111 TI - Asymmetric light propagation in chirped photonic crystal waveguides. AB - We report numerical and experimental investigations of asymmetric light propagation in a newly designed photonic structure that is formed by creating a chirped photonic crystal (PC) waveguide. The use of a non-symmetric distribution of unit cells of PC ensures the obtaining of asymmetric light propagation. Properly designing the spatial modulation of a PC waveguide inherently modifies the band structure. That in turn induces asymmetry for the light's followed path. The investigation of the transmission characteristics of this structure reveals optical diode like transmission behavior. The amount of power collected at the output of the waveguide centerline is different for the forward and backward propagation directions in the designed configuration. The advantageous properties of the proposed approach are the linear optic concept, compact configuration and compatibility with the integrated photonics. These features are expected to hold great potential for implementing practical optical rectifier-type devices. PMID- 23037112 TI - Indirectly pumped 3.7 THz InGaAs/InAlAs quantum-cascade lasers grown by metal organic vapor-phase epitaxy. AB - Device-performances of 3.7 THz indirect-pumping quantum-cascade lasers are demonstrated in an InGaAs/InAlAs material system grown by metal-organic vapor phase epitaxy. The lasers show a low threshold-current-density of ~420 A/cm2 and a peak output power of ~8 mW at 7 K, no sign of parasitic currents with recourse to well-designed coupled-well injectors in the indirect pump scheme, and a maximum operating temperature of Tmax ~100 K. The observed roll-over of output intensities in current ranges below maximum currents and limitation of Tmax are discussed with a model for electron-gas heating in injectors. Possible ways toward elevation of Tmax are suggested. PMID- 23037113 TI - Efficient light coupling into in-plane semiconductor nanomembrane photonic devices utilizing a sub-wavelength grating coupler. AB - We report a subwavelength grating (SWG) coupler for coupling light efficiently into in-plane semiconductor nanomembrane photonic devices for the first time. The SWG coupler consists of a periodic array of rectangular trenches fabricated on a silicon nanomembrane (SiNM) transferred onto a glass substrate. At a wavelength of 1555.56 nm, the coupling efficiency of the fabricated 10 um wide, 17.1 um long SWG is 39.17% (-4.07 dB), with 1 dB and 3 dB bandwidths of 29 nm and 57 nm, respectively. Peak efficiency varies by 0.26 dB when measuring 5 fabricated grating pairs. Coupling efficiency can further be improved with an improved SiNM transfer process. Such high efficiency couplers allow for the successful realization of a plethora of hybrid photonic devices utilizing nanomembrane technology. PMID- 23037114 TI - Experimental demonstration of record high 19.125 Gb/s real-time end-to-end dual band optical OFDM transmission over 25 km SMF in a simple EML-based IMDD system. AB - Record high 19.125 Gb/s real-time end-to-end dual-band optical OFDM (OOFDM) transmission is experimentally demonstrated, for the first time, in a simple electro-absorption modulated laser (EML)-based 25 km standard SMF system using intensity modulation and direct detection (IMDD). Adaptively modulated baseband (0-2GHz) and passband (6.125 +/- 2GHz) OFDM RF sub-bands, supporting line rates of 10 Gb/s and 9.125 Gb/s respectively, are independently generated and detected with FPGA-based DSP clocked at only 100 MHz and DACs/ADCs operating at sampling speeds as low as 4GS/s. The two OFDM sub-bands are electrically frequency division-multiplexed (FDM) for intensity modulation of a single optical carrier by an EML. To maximize and balance the signal transmission performance of each sub-band, on-line adaptive features and on-line performance monitoring is fully exploited to optimize key OOFDM transceiver and system parameters, which includes subcarrier characteristics within each individual OFDM sub-band, total and relative sub-band power as well as EML operating conditions. The achieved 19.125 Gb/s over 25 km SMF OOFDM transmission system has an optical power budget of 13.5 dB, and shows almost identical bit error rate (BER) performances for both the baseband and passband signals. In addition, experimental investigations also indicate that the maximum achievable transmission capacity of the present system is mainly determined by the EML frequency chirp-enhanced chromatic dispersion effect, and the passband BER performance is not affected by the two sub-band induced intermixing effect, which, however, gives a 1.2dB optical power penalty to the baseband signal transmission. PMID- 23037115 TI - Exponentiated Weibull distribution family under aperture averaging Gaussian beam waves: comment. AB - Recently, an exponentiated Weibull distribution model was presented for describing the effects of aperture averaging on scintillation of Gaussian beams propagating through atmospheric turbulence. The model uses three parameters that are derived from physical quantities so that in principle the model could be used to predict optical link performance. After reviewing this model, however, we find several inconsistencies that render it unusable for this purpose under any scintillation conditions. PMID- 23037117 TI - Highly range-resolved ammonia detection using near-field picosecond differential absorption lidar. AB - Ammonia detection is highly relevant for combustion in boilers and furnaces since NH3 is able to suppress nitric oxide levels by catalytic as well as non-catalytic reduction. The mixing of ammonia with flue gases is an important parameter to obtain efficient non-catalytic reduction. In this paper picosecond DIAL was used for range-resolved, single ended, NH3 detection, utilizing a tunable picosecond laser source. The absorption spectrum of the A(nu2 = 1) <- X(nu2 = 0) band was recorded and 212.2 and 214.5 nm was selected as the on- and off-resonance wavelength, respectively. One-dimensional concentration profiles with various NH3 concentration distributions are presented. The detection limit was found to be 40 ppm with a spatial resolution of 16 cm. PMID- 23037118 TI - Surface plasmon-enhanced lasing in dye-doped cholesteric liquid crystals. AB - This study shows the results of a photonic band-edge laser using dye-doped cholesteric liquid crystals (CLCs) combined with silver (Ag) nanoparticles. When the Ag nanoparticle surface plasmon resonance wavelength matched the excitation source wavelength, the large optical fields provided by surface plasmons increased the fluorescence of dye molecules by enhancing the molecular excitation rate, achieving a low lasing threshold and high pumping efficiency. PMID- 23037119 TI - Chromatically-corrected, high-efficiency, multi-colour, multi-plane 3D imaging. AB - It is shown that grisms, a grating and prism combination, are a simple way to achieve chromatic control in 3D multi-plane imaging. A pair of grisms, whose separation can be varied, provide a collimated beam with a tuneable chromatic shear from a collimated polychromatic input. This simple control permits the correction of chromatic smearing in 3D imaging using off-axis Fresnel zone plates and improved control of the axial profile of a focussed spot in multi-photon experiments. PMID- 23037120 TI - Simultaneous generation and Brillouin amplification of a dark hollow beam with a liquid-core optical fiber. AB - We propose and demonstrate a new method to generate a dark hollow beam (DHB) and amplify it simultaneously by a liquid-core optical fiber (LCOF) filled with CS2. A DHB with an adjustable dark spot size (DSS) is simply obtained by changing the incident angle of the laser beam. Based on non-collinear Brillouin amplification, a weak DHB can be amplified with high gain. The amplification factor of 10(6) is achieved for a DHB of 4pJ. This DHB should have promising applications in many fields due to its compact structure, low cost, wide adjustment range of the DSS, and wide operating wavelength. PMID- 23037121 TI - Perfect transmission through Anderson localized systems mediated by a cluster of localized modes. AB - In a strongly scattering medium where Anderson localization takes place, constructive interference of local non-propagating waves dominate over the incoherent addition of propagating waves. This results in the disappearance of propagating waves within the medium, which significantly attenuates energy transmission. In this numerical study performed in the optical regime, we systematically found resonance modes, called eigenchannels, of a 2-D Anderson localized system that allow for the near-perfect energy transmission. We observed that the internal field distribution of these eigenchannels exhibit dense clustering of localized modes. This strongly suggests that the clustered resonance modes facilitate long-range energy flow of local waves. Our study explicitly elucidates the interplay between wave localization and transmission enhancement in the Anderson localization regime. PMID- 23037122 TI - flatFLIM: enhancing the dynamic range of frequency domain FLIM. AB - Fluorescence Lifetime Imaging Microscopy (FLIM) is a quantitative technique to probe the nanoenvironment of fluorescent molecules. It is the most robust way to quantify Forster Resonance Energy Transfer (FRET) as it allows reliable differentiation between concentration changes and quenching. In this way, molecular interactions can be imaged in single living cells. The most common wide field implementation is homodyne Frequency Domain (FD) FLIM, which determines the fluorescence lifetime by measuring the phase and modulation changes of the fluorescence in each pixel upon excitation with a light source modulated at a high frequency. The fluorescence lifetimes are derived from a stack of images acquired at different phase shifts between excitation and detection. In this work we describe a simple method to enhance the dynamic range of FD-FLIM based on precompensating the expected fluorescence modulation by varying the laser power through the phase stack. We show theoretically and experimentally that most of the dynamic range of the camera can be recovered to quantify cells with different intensities. This improvement can be added to any FD-FLIM setup with minimal modifications, enhancing the throughput of information content. PMID- 23037123 TI - All-reflective, highly accurate polarization rotator for high-power short-pulse laser systems. AB - We present the setup of a polarization rotating device and its adaption for high power short-pulse laser systems. Compared to conventional halfwave plates, the all-reflective principle using three zero-phase shift mirrors provides a higher accuracy and a higher damage threshold. Since plan-parallel plates, e.g. these halfwave plates, generate postpulses, which could lead to the generation of prepulses during the subsequent laser chain, the presented device avoids parasitic pulses and is therefore the preferable alternative for high-contrast applications. Moreover the device is easily scalable for large beam diameters and its spectral reflectivity can be adjusted by an appropriate mirror coating to be well suited for ultra-short laser pulses. PMID- 23037124 TI - Enhancement of ultraviolet detecting by coupling the photoconductive behavior of GaN nanowires and p-n junction. AB - The giant improvement of ultraviolet response behavior of a conventional GaN p-n film structured detector by the incorporation of slanted GaN nanowires is reported. The GaN nanowires/p-n film structure shows great photoresponse performance, exhibiting a short response time <0.1 s and a high sensitivity, being stable and reproducible with an on/off current contrast ratio as high as 1800 at zero bias under 365 nm ultraviolet light irradiation. Via carefully analyzing the experiment result and the band diagram of the device, the enhancement can be predominantly attributed to the photogenerated electrons in the slanted GaN nanowires. PMID- 23037125 TI - Atmospheric correction of satellite ocean color imagery using the ultraviolet wavelength for highly turbid waters. AB - Instead of the conventionally atmospheric correction algorithms using the near infrared and shortwave infrared wavelengths, an alternative practical atmospheric correction algorithm using the ultraviolet wavelength for turbid waters (named UV AC) is proposed for satellite ocean color imagery in the paper. The principle of the algorithm is based on the fact that the water-leaving radiance at ultraviolet wavelengths can be neglected as compared with that at the visible light wavelengths or even near-infrared wavelengths in most cases of highly turbid waters due to the strong absorption by detritus and colored dissolved organic matter. The UV-AC algorithm uses the ultraviolet band to estimate the aerosol scattering radiance empirically, and it does not need any assumption of the water's optical properties. Validations by both of the simulated data and in situ data show that the algorithm is appropriate for the retrieval of the water leaving radiance in turbid waters. The UV-AC algorithm can be used for all the current satellite ocean color sensors, and it is especially useful for those ocean color sensors lacking the shortwave infrared bands. Moreover, the algorithm can be used for any turbid waters with negligible water-leaving radiance at ultraviolet wavelength. Based on our work, we recommend the future satellite ocean color remote sensors setting the ultraviolet band to perform the atmospheric correction in turbid waters. PMID- 23037126 TI - Polarization studies for backscattering of RBC suspensions based on Mueller matrix decomposition. AB - Tissue polarimetry has demonstrated its great potential in biomedical field presently. In this study, the polarization characteristics of red blood cell (RBC) suspensions in a back-detection geometry have been investigated with experimental measurements and Monte Carlo (MC) simulation based on Mueller matrix decomposition. It is revealed that the simulated dependence of degree of polarization (DOP) and diattenuation on the distance away from incident point is qualitatively consistent with experimental result. DOP and diattenuation decay with increasing radial distance except in the region adjacent to the incident point. Further analysis shows that the number of scattering events and the scattering angle simultaneously influence the trends of DOP and diattenuation curves in the central region. PMID- 23037127 TI - Terahertz substance imaging by waveform shaping. AB - Terahertz pulse shaping technique is used to adaptively design terahertz waveforms of enhanced spectral correlation to particular materials among a given set of materials. In a proof-of-principle experiment performed with a two dimensional image target consisted of meta-materials of distinctive resonance frequencies, the as-designed waveforms are used to demonstrate terahertz substance imaging. It is hoped that this material-specific terahertz waveforms may enable single- or few-shot terahertz material classification when being used in conjunction with terahertz power measurement. PMID- 23037128 TI - Enhanced optomechanical interaction in coupled microresonators. AB - We investigate the optomechanical interaction in two coupled microresonators. Compared to the single resonator optomechanical system where the input light is required to detune from the cavity resonance to generate two asymmetrical sidebands and thus large mechanical damping/amplification, the coupled resonator system can allow both the input light and its frequency sideband to be on resonance. In this configuration, we find that the optomechanical interaction can be enhanced and optically induced energy transfer between different mechanical oscillators is possible. PMID- 23037129 TI - Distinct clinical features of two patients that progressed from the early phase of chronic pancreatitis to the advanced phase. AB - Chronic pancreatitis (CP) has been considered an intractable inflammatory disease that is progressive and irreversible after definite structural changes appear in the pancreas. The Japanese diagnostic criteria for CP were revised in 2009. One of the reasons for this revision was to define a diagnostic criterion for the early phase of CP (early CP) to improve a patient's clinical outcome, because the disease progression might be reversed in this phase by a therapeutic intervention. However, the clinical features and outcome of early CP remain largely unknown, and the diagnostic reliability of early CP needs to be verified. Here, we show two patients who met the diagnostic criteria of early CP and then progressed to the advanced, late phase of CP (definite CP). A 64-year-old man with recurrent acute pancreatitis was diagnosed as early CP and later progressed to definite CP with multiple pancreatic calcifications at the age of 69. The etiology of CP in this patient was thought to be idiopathic. The other patient was a 57-year-old man with alcohol abuse (ethanol consumption>120 g/day). He was diagnosed as early CP and then rapidly progressed to definite CP without any acute attack. He could not remain abstinent after the diagnosis of early CP. In the present report, we retrospectively demonstrated distinct clinical features of the two patients, both of whom were diagnosed as early CP first and then progressed to definite CP. Thus, our findings support the disease concept of early CP and also suggest the validity of the revised Japanese criteria for the diagnosis of early CP. PMID- 23037130 TI - Stigmatization of patients with epilepsy: a review of the current problem and assessment of the perceived stigma in Bulgarian patients. AB - No study of stigmatization in patients with epilepsy has thus far been conducted in Bulgaria. Our aim was to assess the perceived stigma of Bulgarian patients with refractory epilepsy (RE) and the factors associated with stigmatization. A study based on questionnaires and a purposeful interview on clinical and social factors were conducted in 94 patients with RE and 70 patients with pharmacosensitive epilepsy (PSE). Stigmatization was found in 43.62% of the participants with RE and in 5.71% of those with PSE. Stigmatization was associated with depression and mental status impairment. In conclusion, stigmatization in Bulgarian patients with RE was confirmed. Stigmatization was frequently severe, especially in cases with concomitant personality and behavioral impairment and depression. The study participants explained the existence of stigmatization as being due to fear of seizures and due to inadequate education on the special features of the disease or on administering first aid during seizures. PMID- 23037131 TI - The effect of dorsal hippocampal administration of nicotinic and muscarinic cholinergic ligands on pentylenetetrazol-induced generalized seizures in rats. AB - In the present study, the effects of intrahippocampal injections of cholinergic ligands on pentylenetetrazol (PTZ)-induced seizures were investigated in rats. The rats were assigned to 1 of the following 9 groups: saline, nicotine (0.5 or 1 MUg), atropine (0.25 or 1 MUg), oxotremorine-M (0.1 or 1 MUg), or mecamylamine (2 or 8 MUg). Cholinergic ligands were administered via intrahippocampal infusion 30 min before seizure induction (intraperitoneal injection of 80 mg/kg PTZ). Results show that antagonists caused nonsignificant increases in the latency of tonic clonic seizures, significant decreases in the duration of tonic-clonic seizures, significant decreases in the latency of death, and increases in mortality rate. Agonists led to increases in the duration of tonic-clonic seizures, decreases in the latency of death, and decreases in mortality rate. These results provide compelling evidence that cholinergic ligands show modulatory effects on a PTZ model of acute seizure in the rat hippocampus. PMID- 23037132 TI - Superior therapeutic efficacy of adrenocorticotrophic hormone (ACTH) in infantile spasms: emerging evidence. PMID- 23037133 TI - The Auger effect in biology and medicine. PMID- 23037134 TI - Sodium-iodide symporter positive cells after intracellular uptake of (99m)Tc versus alpha-emitter 211At. Reduction of clonogenic survival and characterization of DNA damage. AB - PURPOSE: We evaluated the DNA damaging potential of Auger electrons emitted in the decay of (99m)Tc compared to alpha-particles of 211At. MATERIAL AND METHODS: The impact of (99m)Tc and 211At was monitored in a NIS-expressing rat thyroid cell model PCCl3 with varying, yet defined intra- and extracellular radionuclide distribution (using +/- perchlorate). The radiotoxicity of (99m)Tc and 211At was studied by the comet assay under neutral and alkaline conditions and colony formation. RESULTS: In the presence of perchlorate, the radioactivity yielding 37% cellular survival, A37, was estimated to be (0.27 +/- 0.02) MBq/ml and (450 +/- 30) MBq/ml for 211At and (99m)Tc, respectively. In absence of perchlorate, cellular radiotracer uptake was similar for both radionuclides (2.2%, 2.7%), yet the A37 was reduced by 82% for the alpha-emitter and by 95% for (99m)Tc. Cellular dose increased by a factor of 5 (211At) and 38 (99mTc). Comet assays revealed an increased DNA damage after intracellular uptake of both radiotracers. CONCLUSIONS: The data indicate damage to the cell to occur from absorbed dose without recognizable contribution from intracellular heterogeneity of radionuclide distribution. Comet assay under alkaline and neutral conditions did not reveal any shift to more complex DNA damage after radionuclide uptake. Cellular uptake of (99m)Tc and 211At increased cellular dose and reduced clonogenic survival. PMID- 23037135 TI - Comments on 'principles of research' by Jerome Cornfield. PMID- 23037136 TI - Comment on paper by J. Cornfield. PMID- 23037137 TI - Comment on 'principles of research' by Jerome Cornfield. PMID- 23037138 TI - Cornfield, risk relativism, and research synthesis. PMID- 23037139 TI - Potential updates to Cornfield's 1959 'principles of research'. PMID- 23037140 TI - A voice from the past, lessons for today. PMID- 23037141 TI - Colonization of Caenorhabditis elegans by Bacillus nematocida B16, a bacterial opportunistic pathogen. AB - BACKGROUND: Soil-dwelling Bacillus nematocida B16 can kill Caenorhabditis elegans via a Trojan horse-like mechanism. However, colonization is a key problem that must be solved during the infection process. AIMS: To study the molecular mechanism involved in the colonization of B. nematocida B16 against the host C. elegans. METHODS: GFP-expressing strain B16g was constructed and its nematocidal activity was assayed. 'Feeding transfer' experiments were carried out separately using of B16 and B16g strains to explore the colonization mode of the bacteria. Fluorescence microscopy was used to observe the interactions between fluorescent signal and the quantity of bacteria in the intestine. A mariner-based transposon called TnYLB-1 was also applied in the random mutagenesis of B16 to screen the mutants with impaired colonization of nematode worms and identify potential localization-related genes. RESULTS AND CONCLUSION: A small inoculum of the bacteria resulted in its proliferation in the C. elegans intestine. The fluorescence signal was enhanced with increasing bacterial density in the intestine. Several candidate genes with possibly important roles in colonization were found. These results provide a solid foundation for further elucidation of the infection process at the molecular level and enrichment of our knowledge of bacterial pathogenesis. PMID- 23037142 TI - Fertility preservation in cancer patients. Review of the French speaking part of Switzerland and recommendations for different situations. AB - Due to constant progress in oncology, survival rates of patients (children and adults) with cancer are increasing. Consequently, the reproductive future of young cancer patients needs to be addressed carefully. Fertility preservation techniques are available and issues such as the time available for fertility treatments, patients' age, presence of a partner and patients' personal wishes have to be considered. In Switzerland, a first therapeutic network (Reseau Romand de Cancer et Fertilite), was created in the French speaking part of Switzerland in 2006. Since 2010, a global Swiss network (FertiSave) has been created. The goal of these networks is to maximise the safety and efficacy of fertility preservation options offered to cancer patients without compromising their oncological prognosis. Patients' needs have to be identified, the therapeutic options evaluated rapidly and the optimal treatment promptly implemented in these urgent situations. This article reviews the fertility preservation options currently available and makes recommendations for different specific cancer situations, consistent with the latest scientific evidence and in general agreement with international recommendations. PMID- 23037143 TI - Turn-on fluorescence sensor based on single-walled-carbon-nanohorn-peptide complex for the detection of thrombin. AB - Proteases play a central role in several widespread diseases. Thus, there is a great need for the fast and sensitive detection of various proteolytic enzymes. Herein, we have developed a carbon nanotube (CNT)-based protease biosensing platform that uses peptides as a fluorescence probe for the first time. Single walled carbon nanohorns (SWCNHs) and thrombin were used to demonstrate this detection strategy. SWCNHs can adsorb a fluorescein-based dye (FAM)-labeled peptide (FAM-pep) and quench the fluorescence of FAM. In contrast, thrombin can cleave FAM-pep on SWCNHs and recover the fluorescence of FAM, which allows the sensitive detection of thrombin. This biosensor has a high sensitivity and selectivity toward thrombin, with a detection limit of 100 pM. PMID- 23037144 TI - Paroxysmal exercise-induced dyskinesia of the hands. PMID- 23037145 TI - Association of genes on chromosome 6, GRIK2 , TMEM217 and TMEM63B (linked to MRPL14 ) with diabetic retinopathy. AB - PURPOSE: Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM). The susceptibility genes responsible for increasing the risk for DR in type 2 diabetes (T2D) were sought in this study. METHODS: A case control study was carried out, comprising 749 unrelated T2D individuals with (n = 174) and without (n = 575) DR. Genotypic distributions of single nucleotide polymorphisms (SNPs) were determined for subjects with and without DR. RESULTS: Eight chromosome 6 SNPs, having the most significant differences, were delineated: rs10499298, rs10499299, rs17827966, rs1224329, rs1150790, rs713050, rs2518344 and rs487083; all were associated with genes TMEM217, MRPL14 and GRIK2. After adjusting for the duration of DM and levels of hemoglobin A(1c), the TT genotype of rs713050, and the AG + AA genotypes of rs2518344 and rs10499298, differed significantly between those with and without DR. Haplotype analysis revealed haplotype C-A-C, residing in rs10499299, rs10499298 and rs17827966, to have significant linkage disequilibrium. CONCLUSIONS: We identified new loci on chromosome 6 associated to DR; all loci showed high levels of linkage disequilibrium. PMID- 23037146 TI - Effect of foot orthoses as treatment for plantar fasciitis or heel pain. AB - CLINICAL SCENARIO: Plantar fasciitis is a debilitating and painful problem present in the general population. It most often presents with moderate to severe pain in the proximal inferior heel region and is most commonly associated with repeated trauma to the plantar fascia. Plantar fasciitis, itself, is an injury at the site of attachment at the medial tubercle of the calcaneus, often due to excessive and repetitive traction. Plantar fasciitis is the most common cause of heel pain and is estimated to affect 2 million people in the United States alone. FOCUSED CLINICAL QUESTION: For adults suffering from plantar fasciitis, are foot orthoses a viable treatment option to reduce pain? PMID- 23037148 TI - How does a newly born mouse get to the nipple? Odor substrates eliciting first nipple grasping and sucking responses. AB - It is a mammalian female strategy to emit odor cues and signals that direct their inexperienced newborns to the nipple, and optimize their initial sucking success and, hence, viability. Here, natural odorous substrates that contribute to nipple grasping were investigated in mice, a species that has not been much scrutinized on this topic. The response of pups toward the nipples of lactating females (LF) versus nonlactating females (NLF) were first assessed right after watched birth, before and after the first suckling experience, and at 1 day old, after more extended suckling experience. It appeared that only nipples of LF induced grasping at these early ages, leading to take NLF as the baseline setting to present various odor substrates sampled from LF, viz. amniotic fluid, murine milk, LF saliva, pup saliva, LF urine, and an odorless control stimulus (water). Results indicate that: (1) only amniotic fluid and fresh milk induced nipple grasping before the first suckling experience; (2) LF saliva started inducing grasping after the first suckling experience; (3) pup saliva released grasping after 24-36 hr of suckling experience; finally (4) neither LF urine, nor water induced any nipple grasping. In conclusion, the activity of amniotic fluid and murine milk on neonatal pup behavior before any postnatal suckling experience suggests that either prenatal learning and/or predisposed olfactory mechanisms do operate, while the behavioral activation due to maternal and infantile salivas clearly depends on postnatal exposure. PMID- 23037149 TI - Foreword. PMID- 23037147 TI - Protective effect of extract from Rumex aquaticus herba on ethanol-induced gastric damage in rats. AB - BACKGROUND/AIMS: In this study, we investigated the gastroprotective effect of extract including quercetin-3-O-beta-D-glucuronopyranoside (EIQ) from Rumex aquaticus herba against the ethanol-induced gastric damage in rats. METHODS: The rats were divided into eight groups composed of a non-ethanol group, only EIQ (10 mg/kg) group, groups with absolute ethanol after pretreatment with various doses of EIQ (1, 3 and 10 mg/kg), rebamipide (10 mg/kg), stillen (40 mg/kg) and a control receiving only absolute ethanol. Ethanol-induced gastric lesions, lipid peroxidation, neutrophil infiltration and glutathione level were measured. Superoxide dismutase (SOD) and catalase activity were assessed by an assay kit. Protein expression of SOD, catalase or hemoxygenase-1 (HO-1) was assessed by western blotting analysis. RESULTS AND CONCLUSION: In the absolute ethanol treated group, gastric lesion and malondialdehyde levels were significantly increased with enhanced myeloperoxidase activity. Administration of EIQ 1 h prior to ethanol treatment significantly inhibited the formation of gastric lesions and the elevation of the malondialdehyde levels with myeloperoxidase activity. In addition, pretreatment with EIQ significantly increased the level of glutathione, and elevated the activity and protein expression of radical scavenging enzymes, such as SOD, catalase and HO-1. EIQ may exert anti-inflammatory and anti oxidative effects against ethanol-induced gastric injury through the reduction of lipid peroxidation, myeloperoxidase activity and free radicals. PMID- 23037150 TI - Recent progress in carbohydrate biosynthesis and function in relation to tumor biology. AB - Recent development in carbohydrate markers and functions are described. Identification of carbohydrate epitope for cancer-specific antibody is introduced. This novel approach involves the key glycosyltransferases that synthesize tumor-associated carbohydrate-antigens and elucidate the biosynthetic pathways. This is the true determination of carbohydrate ligands and glycan array is secondary to determine the epitope. Tumor suppressor activity of carbohydrate is described. Cell surface carbohydrate, which expressed in normal cells is diminished on cancer cells, function as a tumor suppressor. Glycans attached to alpha-dystroglycan function as laminin-binding glycans. In cancer cells, oncogene downregulates laminin-binding glycans and they do not bind to laminin in extracellular matrix, making cells to mobile. Thus, laminin-binding glycans function to suppress the cell mobility, thereby suppressing tumor formation in normal cells. This article summarizes the recent progress in the regulation of carbohydrate function in cancer cells. Since the review is short and not comprehensive, other several important topics may be missing. PMID- 23037151 TI - Carbohydrate mimetic peptides as research reagent and therapeutic. AB - Although numerous carbohydrates play significant roles in mammalian cells, development of carbohydrate-based reagents and therapeutics are hampered by the technical difficulty of chemically synthesizing complex carbohydrate structures. Use of carbohydrate mimetic peptides circumvents this difficulty, as short peptide can be easily synthesized and modified. We as well as others identified carbohydrate mimetic peptides by screening peptide displaying phage library using anti-carbohydrate antibodies and lectins. This review introduces our experiences with I-peptide that was used for identification of new carbohydrate binding receptor expressed in the lung endothelial cells, and those with IF7 peptide that can be used as a therapeutic against malignant tumors. PMID- 23037152 TI - Tumor defense systems using O-glycans. AB - During the process of hematogenous tumor metastasis, tumor cells that dissociated from the primary site enter the blood vessels and are exposed to innate immune systems in host blood circulation. In the innate immune systems, natural killer (NK) cells play a major role in rejecting tumors and suppressing metastasis. To establish metastasis, tumor cells therefore need to defend themselves against tumor rejection by NK cells. It has been recently discovered that some tumor cells develop defense systems against NK cell attack using certain types of cell surface carbohydrates. The types of carbohydrates attached to cell-surface glycoproteins through serine or threonine residues contain a branch consisting of beta-1,6-linkage of N-acetylglucosamine and N-acetylgalactosamine and are designated as core2 O-glycans. Tumor cells expressing core2 O-glycans evade NK cell-mediated tumor rejection, thereby surviving longer in host circulation and acquiring high-metastatic phenotypes. This review explains two types of tumor defense systems against NK cell immunity using core2 O-glycans. PMID- 23037154 TI - An approach to glycobiology from glycolipidomics: ganglioside molecular scanning in the brains of patients with Alzheimer's disease by TLC-blot/matrix assisted laser desorption/ionization-time of flight MS. AB - We have established a new approach to glyco- and lipidomics using a thin layer chromatography (TLC)-Blot/matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MS) system. This new approach consists of a combination of a method for transferring lipids separated on a TLC-plate to a poly-vinylidene difluoride (PVDF) membrane and direct mass spectrometric analysis of the individual lipids on the membrane by ion trap-type MALDI-TOF MS. This technology was applied to the analysis of individual lipids from the human brain. Then, based on the results of this analysis, ganglioside molecular species in neural diseases were analyzed. The levels of gangliosides GD1b and GT1b were lower in the hippocampal gray matter of patients with Alzheimer's disease than in the hippocampal gray matter of patients with Parkinson's disease or the control patients. The molecular scanning of individual ganglioside molecular species showed a significant reduction of d20 : 1/C18 : 0 ceramide-containing gangliosides in patients with Alzheimer's disease. These findings suggest that Alzheimer's disease is a kind of ganglioside metabolic disease affecting the hippocampal area. A new approach to glycobiology by the TLC-Blot/MALDI-TOF MS system is proposed. PMID- 23037153 TI - Roles of the gel-forming MUC2 mucin and its O-glycosylation in the protection against colitis and colorectal cancer. AB - MUC2 is the major gel-forming colonic mucin that forms the two mucus layers. Recent studies using gene-targeted mice have revealed the physiological functions of Muc2, the mouse counterpart of human MUC2, and its O-glycosylation in the colon. Muc2-deficient mice spontaneously developed colitis and colorectal cancer. As for the O-glycosylation of Muc2, conditional core 1-derived O-glycan-deficient mice in the intestines exhibited a breached inner mucus layer and spontaneously developed colitis. Similarly, core 3-derived O-glycan-deficient mice exhibited an increased susceptibility to colitis and colorectal cancer, suggesting that both core 1- and core 3-derived O-glycans on Muc2 are required for colonic protection. Mice deficient in core 2-branched O-glycans synthesized after the formation of core 1 O-glycans also exhibited increased experimental colitis. Furthermore, our recent studies using gene-targeted mice deficient in N-acetylglucosamine-6-O sulfotransferase (GlcNAc6ST)-2 revealed that sulfation of the core 2-branched O glycans of the colonic mucins by GlcNAc6ST-2 is required for the protection against experimental colitis. Taken together, these findings demonstrate the critical roles of the MUC2 mucin and its various O-glycans in the protection against colitis and colorectal cancer. Consistently, various alterations in the expression of mucins and their O-glycosylation have been noted in clinical samples of colorectal cancer. This review focuses on the roles of the MUC2 core protein and its O-glycosylation in health and disease. PMID- 23037155 TI - Erythroid recovery affects tacrolimus levels after engraftment during stem cell transplantation. AB - Tacrolimus is commonly used in stem-cell transplants (SCT) for prophylaxis of graft-versus-host disease and is continuously administered throughout transplantation. The dose of tacrolimus is frequently decreased to maintain a desired concentration during the recovery of hemocytes after engraftment. If parameters which affect tacrolimus clearance are identified, it is of clinical use to estimate concentrations and aid dosing. The objective of this study was to identify which hematologic parameters affect tacrolimus clearance. Seventeen consecutive Japanese patients with hematological malignancies who received allogeneic SCT between March 2004 and January 2007 were enrolled in this study. Their steady-state concentrations were routinely measured and standardized as the concentration/dose (C/D) ratio ((ng/mL)/(mg/kg/d)). Multivariate analysis was performed to identify which hemocyte parameters affected the C/D ratio. Of the 13 patients, gradual dose reduction was required to combat elevated tacrolimus concentrations. The mean post-engraftment C/D ratio was higher than the pre engraftment C/D ratio in each patient. The mean C/D ratio for all patients after engraftment was 1.56-fold higher (p=0.00004, range: 1.04-3.03) than that before engraftment. The variation ratio was calculated by dividing the C/D ratio by that on the engraftment day. Multivariate analysis revealed that the reticulocyte (RET) level (*10(3) count/uL) was the sole parameter influencing this ratio, and both parameters were expressed as: Variation ratio=0.004*RET+1.0. RET recovery of patients could influence the C/D ratio and tacrolimus clearance was affected by recipient original red blood cells, but not that of transfused red blood cells. PMID- 23037156 TI - Possible pathway of Na(+) flux into mitochondria in ischemic heart. AB - Previous studies showed that myocardial Na(+) overload during ischemia directly induced mitochondrial damage. The pathway for Na(+) flux into mitochondria remains unclear. We examined possible routes for Na(+) flux into mitochondria in the ischemic heart. Isolated perfused rat hearts were subjected to 15- to 35-min ischemia followed by 60-min reperfusion and then Na(+) content and respiratory function in mitochondria of the ischemic heart were determined. The mitochondrial Na(+) content of the ischemic heart was ischemic duration-dependently increased, associated with a reduction in mitochondrial respiratory function. To mimic induction of mitochondrial Na(+) overload in vitro, isolated mitochondria were incubated with 6.25 to 50 mM NaCl or sodium lactate, a metabolite of anaerobic glycolysis, in the presence and absence of a mitochondrial Na(+)/Ca(2+) exchanger inhibitor CGP37157 and a monocarboxylate transporter (MCT) inhibitor alpha-cyano 4-hydroxy cinnamic acid (CHCA). Incubation of mitochondria with NaCl or sodium lactate increased the mitochondrial Na(+) concentration. This increase in mitochondrial Na(+) was partially attenuated by the presence of either inhibitor. Combined treatment of mitochondria with both inhibitors attenuated sodium lactate induced increase in Na(+) content to a greater degree than that treated with either agent. These results suggest that mitochondrial Na(+)/Ca(2+) exchanger and MCT inhibitor-sensitive Na(+) transporter are possible pathways for the mitochondrial Na(+) overload in the ischemic myocardium. PMID- 23037157 TI - Effects of macelignan isolated from Myristica fragrans (Nutmeg) on expression of matrix metalloproteinase-1 and type I procollagen in UVB-irradiated human skin fibroblasts. AB - Exposure to ultraviolet (UV) light causes premature skin aging that is associated with upregulated matrix metalloproteinases (MMPs) and decreased collagen synthesis. Macelignan, a natural lignan compound isolated from Myristica fragrans HOUTT. (nutmeg), has been reported to possess antioxidant and antiinflammatory activities. This study assessed the effects of macelignan on photoaging and investigated its mechanisms of action in UV-irradiated human skin fibroblasts (Hs68) by reverse transcription-polymerase chain reaction, Western blot analysis, 2',7'-dichlorofluorescein diacetate assay, and enzyme-linked immunosorbent assay. Our results show that macelignan attenuated UV-induced MMP-1 expression by suppressing phosphorylation of mitogen-activated protein kinases (MAPKs) induced by reactive oxygen species. Macelignan also increased type I procollagen expression and secretion through transforming growth factor beta (TGF-beta)/Smad signaling. These findings indicate that macelignan regulates the expression of MMP-1 and type I procollagen in UV-irradiated human skin fibroblasts by modulating MAPK and TGF-beta/Smad signaling, suggesting its potential as an efficacious antiphotoaging agent. PMID- 23037158 TI - Rhein inhibits integrin-linked kinase expression and regulates matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio in high glucose induced epithelial-mesenchymal transition of renal tubular cell. AB - Studies have found overexpressed integrin-linked kinase (ILK) and disturbed matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) ratio in diabetic nephropathy epithelial-mesenchymal transition (EMT). However, the underlying mechanisms of EMT and the inhibiting effect of rhein need further understanding. The aim of this study was to investigate the possible regulating effects of ILK towards MMP-9/TIMP-1 ratio in EMT and the inhibiting effect of rhein. The characteristic epithelial marker and mesenchymal marker of EMT were examined by cytoimmunostaining, real-time reverse transcription polymerase chain reaction (real-time RT-PCR) and Western blot. To observe the EMT inhibiting effects of rhein, specific ILK-small interfering RNA (ILK-siRNA) was used as a positive control. The results showed that in high glucose conditions, overexpression of ILK and an abnormal changing of MMP-9/TIMP-1 ratio occurred; ILK inhibition by siRNA could adjust MMP-9/TIMP-1 ratio to near normal. Meanwhile, rhein inhibited the overexpressing ILK and inhibits high glucose induced EMT; the effect was similar to that of ILK-siRNA. The decreased expression of ILK regulated by rhein contributed to the adjustment of the MMP 9/TIMP-1 ratio. Our data indicates that rhein inhibits high glucose-induced-EMT partially through the inhibition of ILK expression and regulates the MMP-9/TIMP-1 ratio in HK-2 cells. This mechanism may be associated with rhein's effect of ILK suppression. PMID- 23037159 TI - A versatile transfection assay system to evaluate the biological effects of diverse industrial chemicals. AB - Gene expression processes are now recognized as important targets of the toxic effects exerted by industrial chemicals. The transient transfection assay is a powerful tool to evaluate such effects. Thus, we developed a versatile assay system by constructing a basic reporter plasmid in which the regulatory DNA sequence to be studied can easily be substituted. To verify the performance of this system, reporter plasmids carrying any of the three distinct regulatory sequences, estrogen responsive element (ERE), glucocorticoid responsive element (GRE) and xenobiotic responsive element (XRE) were constructed. After transfection of human cells, these plasmids successfully expressed the relevant reporter genes in response to specific inducers, beta-estradiol, dexamethasone and 3-methylcholanthrene, respectively. Several industrial chemicals were assayed using these reporter plasmids, and the ability of p-dimethylaminoazobenzene to elevate GRE- and XRE-mediated transcription was detected. alpha-Naphthylamine and o-tolidine were also observed to increase the XRE-mediated response. The transfection assay system established here will be useful to evaluate the effects of a wide variety of industrial chemicals. PMID- 23037160 TI - A rat model of early sepsis: relationships between gentamicin pharmacokinetics and systemic and renal effects of bacterial lipopolysaccharide combined with interleukin-2. AB - A rat model of early sepsis induced by lipopolysaccharide (LPS) combined with interleukin-2 (IL-2) was developed. The primary aim was to assess the pharmacokinetics of gentamicin and sepsis-induced pathophysiological changes. Moreover, the effects on the glomerular filtration rate and tubular function were studied in septic and control rats. First, an intravenous (i.v.) bolus of LPSIL-2 (1 mg/kg-Pseudomonas aeruginosa, 15 ug/kg IL-2) or saline (controls, C) was administred. The Wistar rats were treated 30 min after LPSIL-2 with gentamicin as a 3 mg/kg i.v. bolus followed 10 min later by an i.v. 170-min infusion (GE, 0.09 mg/kg.min(-1)). The monitoring of vital functions, biochemistry and GE concentrations was performed. Creatinine clearance was 2-3 times lower and fractional urea excretion was 3-4 times less in septic rats as compared to controls(p<0.05), although urine flow was comparable. Capillary leakage caused a 55% elevation in the volume of distribution (V(c)) in the LPSIL+GE group vs. C+GE (p<0.05). The renal CL(ge) was less (2.2+/-0.59 vs. 3.8+/-0.53 mL/min.kg(-1), p<0.05), while the total CL(ge) was comparable (5.9+/-1.5 vs. 6.7+/-1.1 mL/min.kg(-1); p=0.30). In the LPSIL+GE group relative to C+GE, the half-life (t(1/2)) was 79% higher (p<0.05) and GE concentrations detected at the end of the study in the plasma and kidney were elevated 2.5-fold (p=0.09) and 2.2-fold (p<0.05), respectively. The model reproduced several consequences of early sepsis like in patients such as capillary leak, a decreased glomerular filtration rate (GFR) and the changes in pharmacokinetics of GE (increased values of V(c) and t(1/2) and a drop in renal CL(ge) proportional to that of CL(cr)). Nonrenal routes which, for the most part, compensate the reduced renal CL(ge) in septic rats deserve further study. PMID- 23037161 TI - Menthosomes, novel ultradeformable vesicles for transdermal drug delivery: optimization and characterization. AB - Menthosomes, novel deformable carriers for the enhancement of transdermal delivery are introduced in this study. Meloxicam (MX)-loaded menthosomes were formulated, and their physicochemical characteristics and skin permeability were evaluated. A two-factor spherical and second-order composite experimental design was used to prepare the formulation of the menthosomes. Ten formulations of menthosomes composed of a phospholipid as the lipid bilayer carrier, cholesterol (Chol) as a stabilizer and cetylpyridinium chloride (CPC) and L-menthol as penetration enhancers were prepared. The amounts of Chol and CPC were selected as causal factors. Physicochemical characteristics (particle size, size distribution, zeta potential, elasticity and drug content) and an in vitro skin permeation study of meloxicam-loaded menthosomes were evaluated. The concentrations of MX that permeated the skin at 2-12 h and the flux were selected as response variables. The optimal formulation was estimated using a nonlinear response-surface method incorporating thin-plate spline interpolation. The experimental values were very close to the values predicted by the computer programs in this study. A Bayesian network analysis was applied to gain a mechanistic understanding of the relationships between causal factors and response variables. PMID- 23037162 TI - Effects of Kampo medicines on MDR-1-mediated multidrug resistance in human hepatocellular carcinoma HuH-7/PTX cells. AB - Paclitaxel-resistant HuH-7 (HuH-7/PTX) cells were established by one-week exposure of HuH-7 cells to paclitaxel to analyze the effects of Kampo medicines on MDR-1-mediated multidrug resistance. HuH-7/PTX cells expressed high levels of MDR-1 and efficiently exported calcein-acetoxymethylester (calcein-AM), which is a substrate of MDR-1, suggesting that HuH-7/PTX cells resist paclitaxel by overexpressing MDR-1. We assessed the effects of 26 kinds of Kampo medicine on MDR-1 by calcein-AM efflux assay using HuH-7/PTX cells, and the results revealed that takushato and goreisan are potential inhibitors of drug efflux by MDR-1. Additionally, the sensitivity of HuH-7/PTX cells to paclitaxel was increased in combination with these Kampo medicines, indicating that takushato and goreisan overcame paclitaxel resistance in the cells by suppressing drug export by MDR-1. We further clarified that Alismatis Rhizoma contained in both takushato and goreisan reversed paclitaxel resistance by preventing drug efflux by MDR-1 without affecting the expression levels of MDR-1. Moreover, the principal components of Alismatis Rhizoma, Alisol A, Alisol B, and Alisol B acetate, were found to increase the sensitivity to paclitaxel in HuH-7/PTX by inhibiting drug export by MDR-1 without affecting the expression levels of MDR-1. These results suggested that the reversal effects of takushato and goreisan on paclitaxel resistance are derived from these principal components in Alismatis Rhizoma. Accordingly, Kampo medicines containing Alismatis Rhizoma such as takushato and goreisan may be useful as MDR-1 inhibitors. PMID- 23037163 TI - Anti-Pseudomonas aeruginosa compound, 1,2,3,4-tetrahydro-1,3,5-triazine derivative, exerts its action by primarily targeting MreB. AB - In order to find new anti-Pseudomonas agents, we carried out whole-cell based P. aeruginosa growth assay, and identified 1,2,3,4-tetrahydro-1,3,5-triazine (Compound A). This compound showed anti-Pseudomonas activity against wild as well as pumpless strain equally at a same concentration. Also, this compound was structurally very similar to A22, which is known to inhibit the bacterial actin like protein MreB. By the analysis of resistant strains, the primary target of this compound in P. aeruginosa was definitely confirmed to be MreB. In addition, these compounds showed a bacteriostatic effect, and induced the morphology changes in P. aeruginosa from rod shape to sphere shape, which leads to be clinically favorable in terms of susceptibility to phagocytosis and release of endotoxin. These results display that Compound A is a very attractive compound which shows anti-P. aeruginosa activity based on inhibition of MreB without being affected by efflux pumps, and could provide a new step toward development of new promising anti-Pseudomonas agents, MreB inhibitors. PMID- 23037164 TI - Levels of mercury and organohalogen compounds in the muscle and liver of kidako moray eels (Gymnothorax kidako) caught off the southern region of Japan. AB - We analyzed the levels of total mercury (T-Hg), methylmercury (M-Hg) and Cd in the muscle and liver of kidako moray eels (Gymnothorax kidako) of different body lengths caught off Kochi Prefecture in southern Japan. Furthermore, we analyzed the levels of organohalogen compounds such as polychlorinated biphenyls (PCBs), p,p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), trans-nonachlor and 2,3,3',4,4',5,5'-heptachloro-1'-methyl-1-2'-bipyrrole (Q1) and stable isotope ratios of carbon (delta(13)C) and nitrogen (delta(15)N) in the muscle of eels. The concentrations of T-Hg and M-Hg in the muscle (edible part) were 0.31+/-0.08 ug/wet g and 0.25+/-0.06 ug/wet g (n=26), respectively, and those in large eels exceeded the Japanese legislated levels of T-Hg (0.4 ug/wet g) and M-Hg (0.3 ug/wet g) in fish and shellfish, respectively. The T-Hg and M-Hg concentrations in the liver were markedly higher than those in the muscle, respectively. The ratios of M-Hg to T-Hg in the muscle and liver were about 80 and 60%, respectively, and those ratios tended to decrease with increased body length. The Cd concentrations in the liver tended to increase proportionally with body length, while that in the muscle was trace (around or below 0.03 ug/wet g). The concentrations of PCBs, p,p'-DDE, trans-nonachlor in the muscle tended to increase proportionally with body length, while that of Q1 did not. The delta(13)C and delta(15)N values in the kidako moray eel were markedly higher than those in offshore habit predators reported elsewhere, which may reflect the inshore habitat of this eels. PMID- 23037165 TI - Leishmanicidal activity of two naphthoquinones against Leishmania donovani. AB - Here we studied ability of two naphthoquinones to inhibit Leishmania growth (2,3 dichloro-5,8-dihydroxy-1,4-naphthoquinone (TR 001) and 2,3-dibromo-1,4 naphthoquinone (TR 002). TR 001 was more efficient than TR 002 in inducing killing of promastigotes and intracellular amastigotes. These values compare well to those obtained with the standard first-line antileishmanial agent sodium stibogluconate (SSG). TR 001 also induced significantly more nitric oxide (NO) production than TR 002 or SSG. Taken together, these data show that TR 001 and TR 002 could be promising new drugs for treatment of visceral leishmaniasis. PMID- 23037166 TI - Tetrandrine prevents bone loss in sciatic-neurectomized mice and inhibits receptor activator of nuclear factor kappaB ligand-induced osteoclast differentiation. AB - One of the mediators of osteoclast differentiation is receptor activator of nuclear factor kappaB ligand (RANKL), which is produced by osteoblasts. Binding of RANKL to its receptor, RANK, activates several signaling pathways, including those involving mitogen-activated protein kinases (MAPKs), nuclear factor kappaB (NF-kappaB), nuclear factor of activated T cells c1 (NFATc1) and Ca(2+) calcineurin. In the present study, we found that tetrandrine, a bisbenzylisoquinoline alkaloid extracted from the root of Stephania tetrandra S. MOORE, significantly ameliorated the decrease of bone mass in sciatic neurectomized osteoporosis model mice. It appears that tetrandrine acts directly on osteoclast precursors, since tetrandrine inhibited osteoclast differentiation not only in mouse bone marrow cells, but also in monocultures of murine macrophage RAW 264.7 cells without osteoblasts. Tetrandrine suppressed RANKL induced amplification of NFATc1, a master regulator of osteoclast differentiation. However, it did not affect other signaling molecules such as MAPKs and NF-kappaB. These results suggest that tetrandrine is a candidate for the treatment of bone-destructive diseases, or at least a suitable lead compound for further development. PMID- 23037167 TI - Involvement of neuropeptide Y signaling in the antidepressant-like effect and hippocampal cell proliferation induced by kososan, a Kampo medicine, in the stress-induced depression-like model mice. AB - Neuropeptide Y (NPY) and Orexin-A (OX-A), well-known neuropeptides associated with feeding and arousal, show antidepressant-like properties via hippocampal cell proliferation. Previous studies have revealed that kososan, a Kampo (Japanese herbal) medicine, has an antidepressant-like effect in behavioral animal models of depression; the mechanisms underlying this effect may involve the orexinergic system and subsequent upregulation of hippocampal cell proliferation. However, the roles of NPY in kososan's antidepressant-like effect remain unclear. Here we investigated whether the regulation of the NPY system could play crucial roles in this effect in the stress-induced depression-like model mice. The antidepressant-like effect of kososan administered orally (1.0 g/kg) for 28 d was abolished by a continuous intracerebroventricular injection of BIBO3304, a neuropeptide Y1 receptor antagonist, for 7 d. Likewise, BIBO3304 injection blocked the kososan-induced increases in hippocampal cell proliferation and cluster formation of neural progenitor cells. On the other hand, BIBO3304 injection did not affect kososan-induced increases in hypothalamic OX-A-producing cells or in serum OX-A levels. These results suggest that the control of the NPY system in the brain plays an essential role in kososan's antidepressant-like effect and facilitates hippocampal cell proliferation, both of which could be attributed, at least in part, to the control of the NPY system subsequent to the control of the OX-A system. PMID- 23037168 TI - Possible involvement of hypothalamic nucleobindin-2 in hyperphagic feeding in Tsumura Suzuki obese diabetes mice. AB - The aim of this study was to clarify the hypothalamic neuropeptides that are associated with hyperphagic feeding in Tsumura Suzuki Obese Diabetes (TSOD) mice, a model of type 2 diabetes with polygenic abnormalities. TSOD mice showed an increase in body weight and hyperleptinemia from 1 month of age and hyperphagic feeding, hyperglycemia, hyperlipidemia and hyperinsulinemia from 3 to 12 months of age compared with age-matched non-diabetic control Tsumura Suzuki Non Obesity (TSNO) mice. The mRNA level of nucleobindin-2 (NUCB2), the precursor of the anorexigenic neuropeptide nesfatin-1, was significantly decreased in the hypothalamus of TSOD mice compared with that in TSNO mice from 3 to 12 months of age. The protein level of NUCB2 was significantly decreased in the hypothalamus of TSOD mice compared with that in TSNO mice at 3 months of age. The mRNA levels of galanin, melanin-concentrating hormone, neuropeptide Y, and pro opiomelanocortin were significantly changed in the hypothalamus in TSOD mice at several time points. Another model of type 2 diabetes, db/db mice, which is a mutant mouse that lacks a functional leptin receptor, showed hyperphagic feeding but no change in hypothalamic NUCB2 mRNA compared with non-diabetic control db/+ mice. The results suggest that the disrupted control of hypothalamic NUCB2 mediated signaling may contribute to hyperphagic feeding in TSOD mice. In addition, the mechanism for the development of hyperphagic feeding in TSOD mice is different than that in db/db mice. PMID- 23037169 TI - Combination therapy with taurine, epigallocatechin gallate and genistein for protection against hepatic fibrosis induced by alcohol in rats. AB - This study was to investigate the possibility of enhancing the anti-fibrotic effect by using a combination therapy with taurine, epigallocatechin gallate and genistein in a rat liver fibrosis model induced by alcohol, and to explore its underlying mechanism. Hepatic fibrosis was induced by intragastric administration with various amount of alcohol (5.0-9.5 g/kg) within 24 weeks in rats. The model group received alcohol only, and treatment groups received the corresponding drugs plus alcohol respectively, while the normal control group received an equal volume of saline. The antifibrotic effects of combination therapy were assessed directly by hepatic histology, and indirectly by measurement of serum biochemical markers, the fibrosis markers and related key cytokines/proteins. The results showed that combination therapy could significantly improve the liver function, as indicated by decreasing levels of alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyltransferase, interleukin-6 and tumor necrosis factor-alpha. Moreover, combination therapy could effectively suppress the serum levels of fibrosis markers and hepatic hydroxyproline content, inhibit collagen deposition and reduce the pathological tissue damage. Research on mechanism showed that combination therapy was able to markedly reduce lipid peroxidation and recruit the anti-oxidative defense system, and inhibit the expression of B-cell lymphoma 2, alpha-smooth muscle actin, transforming growth factor beta(1) and small mothers against decapentaplegic homolog 3 proteins. Our results showed that combination therapy is effective in attenuating hepatic injury and fibrosis in the alcohol-induced rat model. The improved efficacy of the combination therapy with its good safety profile could represent a new protective approach for liver fibrosis. PMID- 23037170 TI - Anti-arthritic effect of eugenol on collagen-induced arthritis experimental model. AB - This study was designed to test the efficacy of eugenol, a compound obtained from the essential oil of cloves (Syzygium aromaticum) in collagen-induced arthritis (CIA), a well characterized murine model of rheumatoid arthritis. Macroscopic clinical evidence of CIA manifests first as periarticular erythema and edema in the hind paws. Treatment with eugenol starting at the onset of arthritis (day 25) ameliorated these clinical signs of CIA. Furthermore, eugenol inhibited mononuclear cell infiltration into the knee joints of arthritic mice and also lowered the levels of cytokines (tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and tumor growth factor (TGF)-beta) within the ankle joints. Eugenol treatment did not affect the in vitro cell viability as assessed using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Therefore, eugenol ameliorates experimental arthritis and could be useful as a beneficial supplement in treating human arthritis. PMID- 23037171 TI - Quantitation and human monocyte cytotoxicity of the polymerization agent 1 hydroxycyclohexyl phenyl ketone (Irgacure 184) from three brands of aqueous injection solution. AB - In this study, levels of the photoinitiator 1-hydroxycyclohexyl phenyl ketone (1 HCHPK) in aqueous injection solutions were analyzed by GC-MS. In our previous studies, photoinitiators such as 2-methyl-4'-(methylthio)-2 morpholinopropiophenone (MTMP) were detected in intravenous (i.v.) injection bag solution, and they were found to be cytotoxic to human monocytes. Therefore, we hypothesized that 1-HCHPK might display similarly cytotoxicity. The purpose of this study was to quantitate the amount of contaminants from plastic containers such as those used for peripheral parenteral nutrition and to determine the cytotoxicity of such extracts on human monocytes. The sample extraction procedure for GC-MS analysis involved a liquid-phase extraction. The solvent was evaporated under a stream of nitrogen at 50 degrees C to yield a residue, which was dissolved in n-hexane and injected into a GC-MS. Normal human peripheral blood mononuclear cells (PBMC), isolated from the buffy coat by centrifugation, were suspended in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated fetal calf serum. In the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay, cells (1*10(4)) were treated with 1-HCHPK for 24 h or 48 h at 37 degrees C. From the GC-MS analysis, 6.13-8.32 ug/mL of 1-HCHPK was found in 20 mL vials of water for injection solution. In the MTT assay, 1-HCHPK decreased cell viability for both the 24 h and 48 h incubation periods. In conclusion, our findings suggest that 1-HCHPK could promote adverse events in patients. Future studies will clarify the possible health risks of photoinitiator accumulation in human cells. PMID- 23037172 TI - Screening system of blocking agents of the receptor for advanced glycation endproducts in cells using fluorescence. AB - Activation of the receptor for advanced glycation endproducts (RAGE) triggers cellular responses implicated in the pathogenesis of diabetic complications; blockade of RAGE has been shown to inhibit the development of diabetic complications. To develop a screening system to identify novel disruptors of advanced glycation endproducts (AGE)-RAGE binding, we used an AGE-RAGE binding system in RAGE-overexpressing cells; test compounds were screened using this system. To construct human RAGE-overexpressing cells, mouse mesangial cells (MMCs) were stably transfected with the pcDNA-human RAGE (hRAGE) vector and selected under 1 mg/mL gentamicin (G418). RAGE expression in hRAGE-overexpressing MMCs was analyzed by Western blotting with specific RAGE antibody. To identify novel disruptors of AGE-RAGE binding, 50 single compounds and AGE-bovine serum albumin (BSA)-Alexa 488 (AGE-BSA labeled with Alexa 488) were treated to the hRAGE-overexpressing MMCs. Nonbinding AGE-BSA-Alexa 488 was washed and fluorescence measured by microtiter plate reader (excitation wavelength, 485 nm; emission wavelength, 528 nm). In hRAGE-overexpressing cells, only treatment with AGE-BSA-Alexa 488 significantly increased fluorescence intensity in a dose dependent manner. Of 50 compounds tested, genistein disrupted AGE-RAGE binding in a dose-dependent manner. This AGE-RAGE binding system using AGE-BSA-Alexa 488 in hRAGE-overexpressing cells was suitable for screening of agents that disrupt AGE hRAGE binding. PMID- 23037173 TI - The cyanine Dye NK-4 improves scopolamine-induced memory impairments in mice. AB - The aim of this study is to evaluate the effects of NK-4, a kind of cyanine dye, on cholinergic memory deficits in mice. We examined whether NK-4 could reverse scopolamine-induced amnesia in mice since NK-4 displays a potent and selective inhibitory effect on acetylcholinesterase (AChE) in vitro. Intraperitoneal administration of NK-4 significantly reversed scopolamine-induced cognitive impairments in mice in the Y maze and the passive avoidance tests, and NK-4 also improved spatial learning ability in the Morris water maze test. Despite NK-4 displaying remarkable AChE inhibitory activity in vitro, we could not detect a significant reduction of AChE activity in brain homogenates of NK-4-treated mice. Although the mechanism through which NK-4 reverses cognitive impairments in scopolamine-treated mice remains unclear, these data suggest that NK-4 may have potential as a therapeutic agent for the treatment of dementia. PMID- 23037174 TI - Naringenin inhibits the aggregation of expanded polyglutamine tract-containing protein through the induction of endoplasmic reticulum chaperone GRP78. AB - Polyglutamine (polyQ) diseases are inherited neurodegenerative diseases characterized by the aggregation of proteins containing expanded polyQ tract. Recently, we have shown that GRP78, the endoplasmic reticulum (ER) chaperone, was significantly decreased in the cells expressing enhanced green fluorescent protein with a pathological-length polyQ tract (EGFP-polyQ97), but not with a non pathological-length polyQ tract (EGFP-polyQ24), and the expression levels of GRP78 were inversely related to the aggregation of EGFP-polyQ97. In this study, we performed the screening for compounds that modulate the GRP78 expression in herbal medicines, and found that naringenin, one of the major constitutions of Kanzo (Glycyrrhizae Radix), induced the expression of GRP78 in several mammalian cells. Furthermore, naringenin suppressed the protein aggregation caused by EGFP polyQ97 in mammalian cells. These findings suggested that naringenin seemed to be a new inducer of GRP78 in mammalian cells, and may be a potential therapeutic agent for diseases caused by ER stress such as polyQ diseases. PMID- 23037175 TI - Application of matrix-assisted laser desorption ionization-time of flight mass spectrometry for discrimination of laboratory-derived antibiotic-resistant bacteria. AB - The ability of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) to discriminate laboratory-derived antibiotic resistant bacterial strains of known genetic origin was examined. A computer based cluster analysis of spectral data successfully discriminated the majority of single- as well as multiple-antibiotic-resistant Escherichia coli strains examined. Cluster analysis of Staphylococcus aureus strains with different levels of novobiocin resistance showed that as the degree of resistance increased similarity to the wild-type strain decreased. These results demonstrate that MALDI-TOF MS is capable of discriminating antibiotic-resistant bacterial strains and may have potential for differentiating bacterial strains with varying degrees of antibiotic-resistance. PMID- 23037176 TI - Quality requirements for genomic DNA preparations and storage conditions for a high-density oligonucleotide microarray. AB - High-density oligonucleotide microarrays are widely used in genome-wide association studies. The purpose of this study was to assess the influence of various factors during the preparation of DNA on genotype calling for the Affymetrix high-density oligonucleotide microarray 250K GeneChip. DNA was extracted from peripheral whole blood by solution-based and silica-membrane-based methods. Blood was stored at 4 degrees C or 25 degrees C for 4 or 24 h, followed by DNA extraction. To examine the effects of freeze-thaw cycles, blood and DNA were also subjected to 5 and 10 or 20 of freeze-thaw cycles, respectively. The suitability of variously DNA preparations for the array was assessed by the call rate resulting from genotyping. All DNA samples showed mean call rates of more than 0.99, which passed the quality criteria for genotyping (greater than 0.95). The results indicated that the solution-based method and the silica-membrane based DNA extraction method could provide DNA of sufficient quality for genotyping. In addition, DNA quality suitable for high-density oligonucleotide microarrays is not strongly dependent on the preparation conditions under standard procedures. PMID- 23037177 TI - Effects of sulfaphenazole after collagenase-induced experimental intracerebral hemorrhage in rats. AB - Treatment of intracerebral hemorrhage is often pointless, although considerable effort has been devoted to developing treatments for ischemic stroke. The purpose of this study was to determine the influence of drugs in improving neurological outcomes with pharmaceutical therapy after intracerebral hemorrhage. The free radical hypothesis for intracerebral hemorrhage is based on the cytotoxicity triggered by blood components and its degradation products, such as heme and iron as a potent pro-oxidant atom. Sulfaphenazole (SPZ) has a different mechanism such as reactive oxygen species scavenging, in addition to the inhibition of superoxide production by cytochrome P450. The present study investigated the properties of SPZ in collagenase-induced intracerebral hemorrhage rat brain damage. The results show that systemic SPZ treatment after intracerebral hemorrhage reduces striatal dysfunction, the elevation of lipid peroxidation, and brain edema in the rat. These results suggest that SPZ is a potentially effective therapeutic approach for intracerebral hemorrhage as the effect of SPZ was initiated for either 1 h or 3 d post-intracerebral hemorrhage. PMID- 23037178 TI - Predictors of 1-year mortality at hospital admission for acute exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AE COPD) are related to high mortality, especially in hospitalized patients. Predictors for severe outcomes are still not sufficiently defined. OBJECTIVES: To assess the mortality rate and identify potential determinants of mortality in a cohort of patients hospitalized for AE-COPD. METHODS: A retrospective, observational cohort study including all consecutive patients admitted between January 1, 2009, and April 1, 2010, for AE-COPD. Potential predictors were assessed at initial presentation at the emergency room. The primary outcome was mortality during 1-year follow-up. Univariate and multivariate time-to-event analyses using Cox proportional hazard models were employed for statistical analysis. RESULTS: A total of 260 patients were enrolled in this study. Mean age was 70.5 +/- 10.8 years, 50.0% were male and 63.4% had severe COPD. The in hospital mortality rate was 5.8% and the 1-year mortality rate was 27.7%. Independent risk factors for mortality were age [hazard ratio (HR) = 1.04; 95% confidence interval (CI) = 1.01-1.07], male sex (HR = 2.00; 95% CI = 1.15-3.48), prior hospitalization for AE-COPD in the last 2 years (HR = 2.56; 95% CI = 1.52 4.30), prior recorded congestive heart failure (HR = 1.75; 95% CI = 1.03-2.97), PaCO2 >=6.0 kPa (HR = 2.90; 95% CI = 1.65-5.09) and urea >=8.0 mmol/l (HR = 2.38; 95% CI = 1.42-3.99) at admission. CONCLUSIONS: Age, male sex, prior hospitalization for AE-COPD in the last 2 years, prior recorded congestive heart failure, hypercapnia and elevated levels of urea at hospital admission are independent predictors of mortality within the first year after admission. PMID- 23037179 TI - Age-based seizure threshold determination. AB - OBJECTIVE: The intent was to improve seizure threshold titration by decreasing stimuli number. METHOD: An age-based method of titration for initial seizure threshold bilateral electroconvulsive therapy was constructed and used in 15 women and 9 men aged 35 to 80 years. Titration steps were one eighth, one fourth, three eighths, one half, five eighths, three fourths, 1, and 1.2 times age, expressed as "% Energy." RESULTS: Male thresholds were a significantly (P < 0.05, t(22) = 2.18) higher percentage of age (61.9%; SD, 32.6%) than female thresholds (41.2%; SD, 15.2%). Four women (27%) and 4 men (44%) showed seizure thresholds more than 50% of age. On average, women received 3.2 stimuli and men received 4.4 stimuli. No patient seized at one-eighth age. All patients who seized at one fourth age were women and younger than 65 years. CONCLUSIONS: For women younger than 65 years, these data suggest that titration starting at one-fourth age should require 1.8 stimuli on average. For older women, starting at three-eighths age should average 1.8 stimuli. For men, starting at three-eighths age should require 2.4 stimuli, but with steps at three fourths, 1, and 1.25 age titration should average 1.8 stimuli. Age-based dosing should succeed in women younger than 65 years at one-half age and older than 65 years at five-eighths age. For men, dosing at one-half age should succeed among one half and is a reasonable initial titration dose. PMID- 23037180 TI - Association between dietary patterns and insulin resistance in Mexican children and adolescents. AB - BACKGROUND/OBJECTIVE: Insulin resistance (IR) is a metabolic disorder that is increasing worldwide and has been associated with several negative health outcomes. The aim of this study was to evaluate the relationship between different dietary patterns and IR among Mexican children and adolescents. METHODS: We performed a cross-sectional analysis on baseline data from Mexican children and adolescents aged 7-18 years participating in the Health Workers Cohort Study. We included 916 children and adolescents of both sexes. Fasting serum glucose and insulin levels were determined by standardized methods. We defined IR using the homeostasis model assessment (HOMA) as >=3.5. Factor analysis was used to identify dietary patterns. The associations of interest, those between IR and dietary patterns, were analyzed with multiple logistic regression models. RESULTS: IR prevalence was 20.3% among girls and boys aged 7 18 years, for whom the prevalence of overweight and obesity was 29.7%. We identified 3 major dietary patterns in this group: 'Western', 'prudent' and 'high protein/fat'. For the purposes of this analysis we compared the upper versus the lower quintile of each dietary pattern. Independently of other covariates, participants in the highest quintile of the Western pattern had 92% greater odds of IR (OR 1.92, 95% CI: 1.08-3.43) compared with those in the lowest quintile. CONCLUSIONS: These findings support the hypothesis that high carbohydrate diets like our Western dietary pattern may increase IR in young people. This result emphasizes the importance of preventive nutrition interventions geared toward Mexican children and adolescents. PMID- 23037181 TI - The second seminar for Magnetic Resonance Imaging in the Republic of Macedonia. AB - The Second International Seminar for Magnetic Resonance Imaging in the Republic of Macedonia, held in Ohrid in June 2011, attracted over 150 MR professionals from nine countries. The seminar consisted of educational lectures on the basics of magnetic resonance, followed by scientific presentations from the leading MR researchers from the Balkans. PMID- 23037182 TI - Current density imaging during tissue electroporation. AB - Delivery of externally applied electric pulses on the target tissue during electroporation increases membrane permeability and induces electric currents in the tissue. To optimize electroporation parameters, the current density and with it associated electric field distributions can be monitored by means of current density imaging (CDI) and magnetic resonance electric impedance tomography (MREIT). PMID- 23037183 TI - Improving spatiotemporal characterization of cognitive processes with data-driven EEG-fMRI analysis. AB - To fully understand the cognitive processes occurring in the human brain, high resolution in both spatial and temporal information is needed. Most neuroimaging approaches, however, only possess high accuracy in one of these two domains. Therefore, the multimodal analysis of brain activity is becoming more and more popular among the research community. One of these approaches concerns the integration of simultaneously acquired electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) data. This combination poses a series of challenges, ranging from recovering data quality to the fusion of two types of data of a completely different nature. In this work, several of these challenges will be addressed, and an overview of different integration approaches is provided. PMID- 23037184 TI - The use of a combination of different MR methods to study swelling of hydrophilic xanthan matrix tablets at different pHs. AB - Modified-release matrix tablets have been extensively used by the pharmaceutical industry as one of the most successful oral drug-delivery systems. The key element in drug release from hydrophilic matrix tablets is the gel layer that regulates the penetration of water and controls drug dissolution and diffusion. Magnetic resonance imaging (MRI) is a powerful, non-invasive technique that can help improve our understanding of the gel layer formed on swellable, polymer matrix tablets, as well as the layer's properties and its influence on the drug release. The aim was to investigate the effects of pH and ionic strength on swelling and to study the influence of structural changes in xanthan gel on drug release. For this purpose a combination of different MRI methods for accurate determination of penetration, swelling and erosion fronts was used. The position of the penetration and swelling fronts were the same, independently of the different xanthan gel structures formed under different conditions of pH and ionic strength. The position of the erosion front, on the other hand, is strongly dependent on pH and ionic strength, as reflected in different thicknesses of the gel layers. PMID- 23037185 TI - Software platform for visualization and evaluation of Carpal Tunnel Syndrome. AB - Carpal tunnel syndrome (CTS) is one of the most common peripheral neuropathies due to the compression of the median nerve. Improvements in magnetic resonance imaging have allowed visualization of the anatomy of the carpal tunnel and the possibility of assessing eventual abnormalities associated with CTS. This work presents a software platform for interactive visualization and enhanced evaluation of the carpal tunnel syndrome (CTS), based on MRI. The software platform provides a fully scalable real-time 3D reconstruction of the tendons and the median nerve, allowing multiplanar reformatting, realistic visualization of the integrity of myelin sheath, and colour enhancement, without the use of contrast agents. The software platform is based on a methodology which provides metrics and measurement tools for different parameters, including median nerve location, size and flattening, but also nerve adjacency and local deformation shape measures. The proposed methodology was experimentally evaluated. The group of 60 persons (half of whom were patients with CTS) were involved in the evaluation process, conducted by a radiologist with more than 15 years of experience in the field, who was blinded to the clinical information of the patients. The results of this study showed that the developed software and the MR imaging of the carpal tunnel structures can be used as a valuable tool for CTS evaluation and detection, and it can also help in planning of surgery or revealing the CTS etiology. PMID- 23037186 TI - Counting and language. AB - Number words could be considered as a part of general verbal lexicon, although clinical and scientific data suggest that there are specific brain areas that are involved in specific aspects of number and language processing. In this fMRI study we examine the brain response to two number words generation tasks that should be closely related to the process of language generation: counting forward and counting backward. Our results imply that both investigated tasks strongly rely on brain structures usually related to language generation processes with a distinct activation of the prefronatal area for both counting tasks. Furthermore, we found differences in brain response among the investigated tasks regarding activation in the posterior part of the superior temporal gyrus and parietal cortex for the task of counting backward. Those findings suggest that the tasks of counting rely on established language-related brain areas with specific differences depending on cognitive content of the specified task. PMID- 23037187 TI - Neuroimaging and neuroethics: imaging the ethics in neuroscience. AB - This paper outlines the topics that are on the intersection of neuroethics and neuroimaging domain. MATERIALS AND METHODS: An extensive search through Medline bibliographic database was performed for a period of 12 years (1997-2009), using a combination of 3 keywords ("ethics", "neuroethics", "neuroimaging"). The search returned 119 indexed articles, of which 102 were found relevant. The articles were classified in two main categories tackling ethical challenges in basic research (55 papers) and applied clinical research and practice (39 papers). RESULTS AND CONCLUSIONS: For each of the categories, the majority of articles came under one of the following topics--the neural basis of emotion, reasoning and personality (30 papers) and ethics of neuroimaging in disorders of consciousness (15 papers). The appointed topics stand at the very intersection of the neuroethics and neuroimaging domain, evidencing their strong interdependent relationship. Furthermore, the number of topics and corresponding articles has been steadily increasing over the years (minimal in 1997, maximal in 2009). These data are in good acconcordance with other scientific findings. Also, they correspond to the period of progress in the investigated disciplines, giving rise to the fact that future advances in neuroethics are in strong correlation to the advances of neuroimaging technologies. PMID- 23037188 TI - The role of MR spectroscopy in neurooncology. AB - Magnetic resonance spectroscopy (MRS) is a diagnostic tool that provides information related to brain's metabolic activity. Literature data suggest that elevation of the ratio between the choline and creatine (the Cho/Cr ratio), the reduction of the ratio between n-acetyl-aspartate acid and creatine (the NAA/Cr ratio), increase of the ratio between myo-inositol and creatine (the MI/Cr ratio), and the presence of lipids and lactate are useful diagnostic markers in grading tumors as well as in the prediction of tumor malignancy potential. Two additional important roles of MRS are differentiation between recurrent tumor and radiation necrosis and evaluation of peritumoral region. PMID- 23037189 TI - Magnetic resonance microscopy in biomedical research. AB - Magnetic resonance (MR) microscopy is a special modality of MRI with an emphasis on high spatial resolution. While its main principle is identical to conventional clinical MRI, there are several differences between the two that are mainly associated with a use of stronger magnets and gradients. MR microscopy has numerous interesting applications in material and bio sciences in which high spatial resolution is demanded and long experiment times are allowed. PMID- 23037190 TI - Magnetic resonance imaging safety: principles and guidelines. AB - This paper provides an overview of the published literature regarding magnetic resonance imaging (MRI) safety. It gives basic information about the electromagnetic fields that are generated during the MRI diagnostic procedure, followed by a description of the biological effects of those fields on humans. It concludes with a discussion of the safety issues related to MRI use in clinical practice, highlighting the existing MRI standards and guidelines. PMID- 23037191 TI - Large-scale fabrication of a continuous gold network for use as a transparent conductive electrode in photo-electronic devices. AB - Large-scale periodic gold network electrodes were fabricated using the developed and versatile nanosphere lithography technique. The fabrication processes, structural characterizations and network formation mechanism were described in detail. An enhanced optical transmission peak was observed from the transmission spectrum, which could be assigned to the extraordinary transmission mediated commonly by (a) localized surface plasmon resonance (LSPR) and (b) surface plasmon polaritons. The effects of film thickness, sphere diameter (periodicity) and reactive ion etching time on their optical and electrical properties were also investigated. By controlling these three independent variables, we could tune the SPR peak position and their light transmission distributions flexibly. Our large-scale continuous gold network can serve as a transparent conductive electrode, while possessing the role of a surface plasmonic resonance component can make it very attractive for potential photo-electric device applications in a range from plasmon-enhanced broadband photovoltaics to SPR-based chemo- and biosensors. PMID- 23037192 TI - The utility of FDG-PET in the diagnosis of thymic epithelial tumors. AB - In this article, seven studies evaluating the utility of FDG-PET in the diagnosis of thymic epithelial tumors were reviewed and the results of an investigation conducted in Tokushima University Hospital are reported. FDG accumulation of low risk thymoma is low, and FDG accumulation of thymic carcinoma is high. High-risk thymoma exhibits various degrees of accumulation and a definite conclusion has not yet been reached; however, overall, the higher the histological grade, the higher the FDG accumulation becomes, suggesting that this is correlated to staging. Our data also support the previous reports. FDG-PET may indicate lymph node metastasis and distant metastasis, which are sometimes difficult to detect using other modalities. When lymph node metastasis and/or distant metastasis are suspected in addition to thymic lesions, FDG-PET/CT, which allows for searching of the entire body at once, is useful. FDG-PET/CT is effective for estimating histopathological malignancy and staging in the diagnosis of thymic epithelial tumors and can be an important imaging test with high relevance to the prognosis of a patient. PMID- 23037193 TI - The safety and usefulness of the single incision, transabdominal pre-peritoneal (TAPP) laparoscopic technique for inguinal hernia. AB - BACKGROUND: The safety and usefulness of the SILS-TAPP (transabdominal pre peritoneal) procedure remain unclear. The aim of this study was to clarify the safety and usefulness of the SILS-TAPP procedure compared with standard laparoscopic TAPP and TEPP (totally extra-peritoneal pre-peritoneal) procedures. PATIENTS AND METHODS: 85 patients underwent laparoscopic inguinal hernia repairs (TEPP, 30 patients; TAPP, 20 patients; SILS-TAPP, 35 patients) from 2007 to 2011. The operative outcomes of the three groups were compared. RESULTS: There was no difference in the patients' characteristics among the three groups. The TEPP Group had a longer operation time. One patient in the SILS-TAPP group had an intraoperative complication. One patient in the TAPP group had a postoperative complication, and one patient had ileus and one had an umbilical hernia in the SILS-TAPP group. The postoperative hospital stay was not significantly different among the three groups. There were no recurrences in the TEPP group, 1 case of recurrence (5.0%) in the TAPP group, and 1 case (2.9%) in the SILS-TAPP group. CONCLUSIONS: The present findings show that the SILS-TAPP repair is safe and feasible for the repair of adult inguinal hernia. PMID- 23037194 TI - Histological characteristics of incidentally-found growing meningiomas. AB - OBJECT: With the wider use of CT and MRI, many meningiomas are discovered as incidental findings during diagnostic work-up for unrelated symptoms. The majority shows no or minimal growth. The purpose of this study was to distinguish pathological features of incidentally-found growing meningiomas by comparing incidentally-found with symptomatic meningiomas. METHODS: One hundred and thirty two consecutive non-recurrent surgically-treated meningiomas treated between 2005 and 2007 were divided into three categories: 19 incidentally-found growing meningiomas (IG), 50 incidentally-found meningiomas (I), and 63 symptomatic (S) meningiomas. The average follow-up period for the IG meningiomas was 3.7 years. Six out of 19 patients of the IG meningiomas became symptomatic during observation. RESULTS: There is a significant difference of the incidence of WHO grades I, II, and III between all three groups (p=0.035). The incidence of WHO grades II and III in groups IG, I, and S were 26%, 2%, and 10%, respectively. We compare MIB-1 staining index between three groups: an average was 3.8% in IG, 1.3% in I, and 2.4% in S meningiomas. CONCLUSIONS: Incidentally-found meningiomas need careful follow-up. One fourth of the meningiomas that showed signs of growing belonged to the atypical or malignant grade. PMID- 23037195 TI - Effects of indole-3-carbinol and phenethyl isothiocyanate on bile and pancreatic juice excretion in rats. AB - Bile and pancreatic juice contain a number of parameters for cancer chemoprevention. Indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC), which are hydrolytic products of brassica plants, have been established to be anti-cancer agents. Here, we developed a method for the continuous and selective sampling of bile and pancreatic juice, and the effects of I3C and PEITC on bile and pancreatic excretion and gamma-glutamyl transpeptidase (gamma-GTP) activity in the samples were investigated. Male Fisher 344 rats (eight weeks of age) were challenged intragastrically with I3C (150 mg/kg) or PEITC (160 mg/kg) for five days. Twenty-four hours after the final administration, cannulation was undertaken into the rats' bile and pancreatic ducts, and the bile and pancreatic juice were separately collected for 48 h. In this rat model, bile was stably excreted, and the bile and pancreatic excretion of the control rats was 21.9 +/- 1.4 ml/48 h and 12.8 +/- 1.7 ml/48 h, respectively. Bile excretion for the first 24 h significantly increased in the I3C- or PEITC-treated rats compared with the control rats. In the case of pancreatic juice, excretion during the first 24 h significantly increased in the PEITC-treated rats. In bile, gamma-GTP activity was significantly increased for the first 24 h in the I3C- and PEITC-treated rats, but no difference was observed in the pancreatic juice. Increases of bile excretion and gamma-GTP activity in bile might be a factor involved in the anti cancer effect of I3C and PEITC. Our rat model described here is a useful tool for the study of cancer chemoprevention. PMID- 23037196 TI - Basal metabolic rate and body composition of elite Japanese male athletes. AB - The estimated energy requirement is important for adequate nutritional management in athletes. The energy requirement can be estimated from the basal metabolic rate (BMR). However, there is little data regarding the BMR of Japanese athletes. This study measured the BMR and body composition of 81 elite Japanese male athletes in different sports categories: endurance (E), strength, power and sprint (S) and ball game (B). The factors influencing the BMR were also investigated. The BMR and body composition were measured by indirect calorimetry and an air-displacement plentysmograph device (the BOD POD), respectively. The BMR per lean body mass (LBM) differed significantly among the three groups. The BMR was significantly correlated with the body weight (BW) and LBM in all groups. A multiple-regression analysis showed that the LBM was the most powerful predictor in the E and S groups, whereas the BW was the most powerful predictor in the B group. The BW appears to become an important predictor as the BW of athletes increases. Additionally, height was the second explanatory variable in the S and B groups, thus suggesting that height needs to be considered for the BMR in these groups. Therefore, the BMR in elite athletes needs to be estimated according to their body composition. PMID- 23037197 TI - Bicuspid aortic valve endocarditis complicated by perivalvular abscess. AB - A 37-year-old man presenting with fever and chest pain was admitted to our hospital. Electrocardiogram showed sinus tachycardia and complete left bundle branch block. Transthoracic echocardiogram showed infective endocarditis in the bicuspid aortic valve, complicated by multiple hyperechoic vegetations and severe aortic regurgitation. Blood cultures were negative and intravenous empiric antibiotic therapy was begun. However, fever lasted for 7 days and follow-up echocardiography revealed a newly emerged perivalvular abscess. The patient eventually underwent an urgent aortic root replacement that confirmed the echocardiographic findings. Our case report emphasizes that all patients with suspected aortic valve endocarditis should undergo early and follow-up echocardiographic studies. PMID- 23037198 TI - Recurring facial low-grade fibromyxoid sarcoma in an elderly patient: a case report. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare type of sarcoma that is characterized by benign-appearing histologic features but a paradoxically aggressive clinical course. These tumors generally occur in young to middle-aged adults, sometimes in children, but rarely in high-aged adults. LGFMS typically affects the deep soft tissues of the trunk or lower extremities; however, it is rarely seen in the face. We here describe a case of LGFMS on the right forehead of an 84-year-old woman. After resection with a 1-cm skin margin, recurrence occurred at 15 months postoperatively. Additional wide excision was subsequently performed with a 2-cm skin margin. Recurrence and metastasis have not been observed for 1 year after the second excision. A wide surgical margin should be considered in cases of LGFMS. PMID- 23037199 TI - Hepatic screlosed hemangioma which was misdiagnosed as metastasis of gastric cancer: report of a case. AB - A screlosed hemangioma of the liver is rare among hepatic tumors. A 75 years old male was referred to our hospital for gastric cancer and a hepatic tumor. The histological finding of gastric cancer was revealed to be well differentiated adenocarcinoma. The liver tumor was 1.1*1.0 cm in size and located in segment 8 of the liver. Computed tomography (CT) showed it to be a tumor with ring enhancement. Magnetic resonance imaging (MRI) showed the tumor to have a low signal on T1-weighted and slightly high signal on T2-weighted images. Level of hemoglobin was 7.8 g/dl. It was thought to be persistent bleeding from gastric cancer. With diagnosis of liver metastasis from gastric cancer, chemotherapy is recommended. However, to control the bleeding from gastric cancer, we performed distal gastrectomy and wedge resection of liver (S8). The histological examination of the liver tumor revealed to be a hepatic sclerosed hemangioma with hyalinized tissue and collagen fibers. We report herein a case of the rare tumor which was misdiagnosed as a liver metastasis of gastric cancer. PMID- 23037200 TI - Trigonal cavernous malformation with intraventricular hemorrhage: a case report and literature review. AB - We reported a case of trigonal cavernous malformation (CM) with intraventricular hemorrhage. This 67-year-old woman experienced sudden onset of loss of consciousness and her Glasgow Coma Scale (GCS) was 5 points (E1V1M3) on admission. CT scan demonstrated intraventricular hemorrhage and acute hydrocephalus. Angiography did not demonstrate any vascular abnormality. Ventricular drainage was performed for acute hydrocephalus and the postoperative course was good. CT showed a hyperdense lesion in the left trigone, which was contrast-enhanced on T1-weighted MR. Removal of CM was performed via the left middle temporal sulcus. We conducted a Pub Med search for trigonal CM and found 17 cases. Herein we discuss the symptoms, CT and MR findings and treatment. PMID- 23037201 TI - High serum levels of both carcinoembryonic antigen and carbohydrate antigen 19-9 in a patient with sigmoid colon cancer without metastasis. AB - Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9 are well known as the most common tumor markers of colon cancer, and levels are used not only for preoperative assessment of extent and outcome of cancer, but also postoperative monitoring of recurrence. We encountered a patient with sigmoid colon cancer showing abnormally high serum levels of CEA (311.1 ng/ml) and CA19-9 (5731.2 U/ml) preoperatively. We could not detect any metastases on computed tomography (CT) or (18)F-fluorodeoxyglucose positron emission tomography/CT. Sigmoidectomy and lymph node dissection were performed. Pathological analysis revealed well-differentiated tubular adenocarcinoma of the sigmoid colon with cancer cells infiltrating to the subserosa, but no lymph node metastases. As of postoperative day 60, serum levels of CEA and CA19-9 were 3.4 ng/ml and 9.2 U/ml, respectively, without any further anti-tumor treatment. This represents a rare case of sigmoid colon cancer with high levels of tumor markers in sera that improved following sigmoidectomy without further anti-cancer treatment. PMID- 23037202 TI - Usefulness of transcatheter arterial embolization prior to excision of hypervascular musculoskeletal tumors. AB - The objective of this study was to evaluate the usefulness of transcatheter arterial embolization prior to surgical excision of musculoskeletal tumors. We reviewed the records of nine patients (3 females and 6 males) who received arterial embolization prior to excision of musculoskeletal tumors in our hospital from December 2009 to April 2010. We evaluated tumor region, size, histopathology, feeding artery, embolic material, and blood loss during surgery. We compared the actual amount of intraoperative bleeding with arterial embolization to estimated amounts of bleeding without embolization predicted by three orthopedic surgeons. Arterial embolization was performed on the same day or within 5 days before surgery. Operations were performed as planned in all patients without serious complications. The amount of intraoperative bleeding was 35-4200 mL and there was significantly less bleeding with arterial embolization compared with the estimated amounts (p<0.01). Our results show that arterial embolization prior to resection of hypervascular musculoskeletal tumors reduces the amount of bleeding during surgery and contributes to patient safety. PMID- 23037203 TI - Fluorescence from atmospheric aerosols observed with a multi-channel lidar spectrometer. AB - A lidar for measuring fluorescence from atmospheric aerosols was constructed with a third harmonic Nd:YAG laser, a 1-m diameter telescope, and a 32-channel time resolved photon-counting spectrometer system. Fluorescence spectrum and vertical distribution of fluorescent aerosols in the lower atmosphere were observed during the nighttime with excitation at 355 nm. Relatively strong broad fluorescence was observed from Asian dust and air-pollution aerosols transported from urban and industrial areas. Rough estimates of the fluorescence efficiency were given for these aerosols. The intensity of the total fluorescence over the spectral range from 420 to 510 nm was comparable to that of nitrogen vibrational Raman scattering. That indicates the possibility of making a compact Raman-Mie fluorescence lidar for aerosol monitoring. PMID- 23037204 TI - Co-polymer clad design for high performance athermal photonic circuits. AB - Ubiquitous, low power consumption and high bandwidth density communication will require passive athermal optical filters for WDM transceivers in Si-CMOS architecture. Two silicon-polymer composite structures, deposited using initiated chemical vapor deposition (iCVD), poly(perfluorodecyl acrylate) (pPFDA) and poly(perfluorodecyl acrylate-co-divinyl benzene) p(PFDA-co-DVB), are analyzed as candidates for thermal compensation. The addition of DVB to a fluorinated acrylate backbone reduces the C-F bond density, increases the density in the copolymer and thereby increases refractive index. The addition of DVB also increases the volume expansion coefficient of the copolymer, resulting in an increased thermo-optic (TO) coefficient for the copolymer system. The increased index and TO coefficient of the co-polymer gives improved bend loss, footprint and FSR performance for athermal silicon photonic circuits. PMID- 23037205 TI - Optical forces on submicron particles induced by full Poincare beams. AB - In this paper, we have considered the optical forces acting on submicron particles induced by arbitrary-order full Poincare (FP) beams. Different from the traditional scalar beams, the optical forces of the FP beams include three contributions: the scattering, gradient, and curl forces. The last contribution is due to both the vectorial properties of the FP beams' polarization and the rotating phase structure of the FP beams. We analytically derive all components of the optical forces of the FP beams acting on Rayleigh particles. The numerical results show that the optical curl force is very significant to the absorbing Rayleigh particles, and it has the same order with the scattering force. The total vortex force fields and their trapping effects of different order FP beams on the absorbing dielectric and metallic Rayleigh particles are discussed in detail. Our results may stimulate further investigations on the trapping effect of various vector-vortex beams on submicron or nanometer sized objects. PMID- 23037206 TI - Imaging nanoscale features with plasmon-coupled leakage radiation far-field superlenses. AB - Optical images from nano-scale features were obtained by collection of leakage radiation coupled to surface plasmon polaritons excited by near-field fluorescence. Plasmonic crystals with spatial periods as small as 190 nm and non periodic features separated by 80 nm, corresponding to ~lambda/7, were clearly visible in the real plane images using this far-field technique. We show that the leaked light from the investigated samples carries detailed information to the far-field which is not present in the images obtained with conventional optical microscopy. PMID- 23037207 TI - Accurate modal gain control in a multimode erbium doped fiber amplifier incorporating ring doping and a simple LP01 pump configuration. AB - We experimentally validate a numerical model to study multimode erbium-doped fiber amplifiers (MM-EDFAs). Using this model, we demonstrate the improved performance achievable in a step index MM-EDFA incorporating a localized erbium doped ring and its potential for Space Division Multiplexed (SDM) transmission. Using a pure LP01 pump beam, which greatly simplifies amplifier construction, accurate modal gain control can be achieved by carefully tuning the thickness of the ring-doped layer in the active fiber and the pump power. In particular, by optimizing the erbium-ring-doped structure and the length of active fiber used, over 20dB gain for both LP01 and LP11 signals with a maximum gain difference of around 2 dB across the C band are predicted for a pure LP01 pump beam delivering 250 mW power at 980 nm. PMID- 23037208 TI - Impact of sub-pixel variations on ocean color remote sensing products. AB - Passive remote sensing of the Earth system has used spatial resolutions ranging from meters to kilometers. It is thus necessary to understand how data products with different spatial resolutions can be compared with each other, and how sub pixel variations may affect data comparison. This is particularly important for ocean color remote sensing where the measured signal (water-leaving radiance or remote sensing reflectance) is a non-linear function of sub-surface constituents. As a result, products at low resolution are not necessarily arithmetic or geometric means of those at higher resolution. Here, we developed analytical expressions to link ocean color properties derived from high- and low-resolution data, and the proof-of-concept is further demonstrated with both simple examples and measurements of MERIS full-resolution (FR) and reduced resolution (RR). These results suggest that current global chlorophyll concentration is likely underestimated due to the coarse spatial resolutions. Application of the expressions will facilitate cross-sensor comparisons and may also reduce uncertainties. PMID- 23037209 TI - Mode-locking of a terahertz laser by direct phase synchronization. AB - A novel scheme to achieve mode-locking of a multimode laser is demonstrated. Traditional methods to produce ultrashort laser pulses are based on modulating the cavity gain or losses at the cavity roundtrip frequency, favoring the pulsed emission. Here, we rather directly act on the phases of the modes, resulting in constructive interference for the appropriated phase relationship. This was performed on a terahertz quantum cascade laser by multimode injection seeding with an external terahertz pulse, resulting in phase mode-locked terahertz laser pulses of 9 ps duration, characterized unambiguously in the time domain. PMID- 23037210 TI - Method of compensating for pixel migration in volume holographic optical disc (VHOD). AB - Volume holographic optical disc (VHOD) technology is simpler than the angular multiplexing holographic system. However, disc rotation usually causes pixel migration, thus reducing signal quality. This study proposes a special geometrical arrangement to counteract pixel migration. Using paraxial approximation analysis, an optimal geometrical distance ratio, K, is calculated to compensate for pixel migration and improve image quality during disc rotation. The results of approximation analysis are confirmed by both simulation and experimental results. PMID- 23037211 TI - Accurate target-plane focal-spot characterization in high-energy laser systems using phase retrieval. AB - Target-plane intensities on the short-pulse beamlines of OMEGA EP, a petawatt class laser, are characterized on-shot using the focal-spot diagnostic (FSD), an indirect wavefront-based measurement. Phase-retrieval methods are employed using on-shot and offline camera-based far-field measurements to improve the wavefront measurements and yield more-accurate, repeatable focal-spot predictions. Incorporation of these techniques has improved the mean cross-correlation between the FSD predictions and direct far-field fluence measurements in the target chamber from 0.78 to 0.94. PMID- 23037212 TI - 6-micron interaction length electro-optic modulation based on lithium niobate photonic crystal cavity. AB - We report on electro-optic modulation using a Lithium Niobate (LN) Photonic Crystal (PC) cavity structure. The compact device (6 MUm in length) consists of a 2D photonic crystal cavity made on an Annealed Proton Exchange (APE) LN waveguide with vertical deposited electrodes. Experimental results show a tunability of 0.6 nm/V. This compact design opens a way towards micro and nano-scale tunable photonic devices with low driving electrical power. PMID- 23037213 TI - High-power room-temperature continuous-wave mid-infrared interband cascade lasers. AB - We demonstrate cw output powers >290 mW into a nearly diffraction-limited (M2 ~2.2) output beam from an interband cascade laser operating at lambda = 3.6-3.7 MUm at room temperature. The interband cascade laser was designed for nearly equal electron and hole populations in the active region with heavy electron injector doping, and was processed into narrow ridges mounted epitaxial side down on a copper heat sink. A 15.7-MUm-wide, 4-mm-long ridge with the back facet coated for high reflection (HR) and an anti-reflection-coated front facet produced 253 mW of cw output power at T = 25 degrees C into a beam with M2 ~2.7. Furthermore, corrugating the sidewalls of the ridge leads to a 20% improvement in the brightness. A 15.7-MUm-wide, 0.5-mm-long ridge with an HR-coated back facet and an uncoated front facet exhibited a maximum cw wall-plug efficiency of nearly 15% at room temperature. PMID- 23037214 TI - Dispersionless slow light in MIM waveguide based on a plasmonic analogue of electromagnetically induced transparency. AB - We have proposed a metal-insulator-metal (MIM) waveguide system, which exhibits a significant slow-light effect, based on a plasmonic analogue of electromagnetically induced transparency (EIT). By appropriately adjusting the distance between the two stubs of a unit cell, a flat band corresponding to nearly constant group index over a broad bandwidth of 8.6 THz can be achieved. The analytical results show that the group velocity dispersion (GVD) parameter can reach zero and normalized delay-bandwidth product (NDBP) is more than 0.522. Finite-Difference Time-Domain (FDTD) simulations show that the incident pulse can be slowed down without distortion owing to the low dispersion. The proposed compact configuration can avoid the distortion of signal pulse, and thus may find potential applications in plasmonic slow-light systems, especially optical buffers. PMID- 23037215 TI - Modeling and correction of distorted two-dimensional Fourier transform spectra from pixelated pulse shaping devices. AB - Two-dimensional Fourier transform spectra of a three level model system are simulated using a non-perturbative density matrix formalism. The electric field distortions resultant from using pixelated pulse shaping devices to produce phase locked pulse pairs are modeled and the effects on the recovered spectra are examined. To minimize spectral distortions, a temporal filtering scheme is employed which eliminates contributions from spurious sample polarizations. PMID- 23037216 TI - Under the hood of satellite empirical chlorophyll a algorithms: revealing the dependencies of maximum band ratio algorithms on inherent optical properties. AB - Empirically-based satellite estimates of chlorophyll a [Chl] (e.g. OC3) are an important indicator of phytoplankton biomass. To correctly interpret [Chl] variability, estimates must be accurate and sources of algorithm errors known. While the underlying assumptions of band ratio algorithms such as OC3 have been tacitly hypothesized (i.e. CDOM and phytoplankton absorption covary), the influence of component absorption and scattering on the shape of the algorithm and estimated [Chl] error has yet to be explicitly revealed. We utilized the NOMAD bio-optical data set to examine variations between satellite estimated [Chl] and in situ values. We partitioned the variability into (a) signal contamination and (b) natural phytoplankton variability (variability in chlorophyll-specific phytoplankton absorption). Not surprisingly, the OC3 best fit curve resulted from a balance between these two different sources of variation confirming the bias by detrital absorption on global scale. Unlike previous descriptions of empirical [Chl] algorithms, our study (a) quantified the mean detrital:phytoplankton absorption as ~1:1in the global NOMAD data set, and (b) removed detrital (CDOM + non-algal particle) absorption in radiative transfer models directly showing that the scale of the remaining variability in the band ratio algorithm was dominated by phytoplankton absorption cross section. PMID- 23037217 TI - Size-selective detection in integrated optical interferometric biosensors. AB - We present a new size-selective detection method for integrated optical interferometric biosensors that can strongly enhance their performance. We demonstrate that by launching multiple wavelengths into a Young interferometer waveguide sensor it is feasible to derive refractive index changes from different regions above the waveguide surface, enabling one to distinguish between bound particles (e.g. proteins, viruses, bacteria) based on their differences in size and simultaneously eliminating interference from bulk refractive index changes. Therefore it is anticipated that this new method will be ideally suited for the detection of viruses in complex media. Numerical calculations are used to optimize sensor design and the detection method. Furthermore the specific case of virus detection is analyzed theoretically showing a minimum detectable virus mass coverage of 4 * 10(2) fg/mm(2) < (typically corresponding to 5 * 10(1) particles/ml). PMID- 23037218 TI - Long-period grating and its cascaded counterpart in photonic crystal fiber for gas phase measurement. AB - Regular and cascaded long period gratings (LPG, C-LPG) of periods ranging from 460 to 590 MUm were inscribed in an endlessly single mode photonic crystal fiber (PCF) using CO(2) laser for sensing measurements of helium, argon and acetylene. High index sensitivities in excess of 1700 nm/RIU were achieved in both grating schemes with a period of 460 MUm. The sharp interference fringes in the transmission spectrum of C-PCF-LPG afforded not only greatly enhanced sensing resolution, but also accuracy when the phase-shift of the fringe pattern is determined through spectral processing. Comparative numerical and experimental studies indicated LP(01) to LP(03) mode coupling as the principal coupling step for both PCF-LPG and C-PCF-LPG with emergence of multi-mode coupling at shorter grating periods or longer resonance wavelengths. PMID- 23037219 TI - Fast calculation of computer-generated holograms based on 3-D Fourier spectrum for omnidirectional diffraction from a 3-D voxel-based object. AB - We have derived the basic spectral relation between a 3-D object and its 2-D diffracted wavefront by interpreting the diffraction calculation in the 3-D Fourier domain. Information on the 3-D object, which is inherent in the diffracted wavefront, becomes clear by using this relation. After the derivation, a method for obtaining the Fourier spectrum that is required to synthesize a hologram with a realistic sampling number for visible light is described. Finally, to verify the validity and the practicality of the above-mentioned spectral relation, fast calculation of a series of wavefronts radially diffracted from a 3-D voxel-based object is demonstrated. PMID- 23037220 TI - Harmonic-seeded remote laser emissions in N2-Ar, N2-Xe and N2-Ne mixtures: a comparative study. AB - We report on the investigation on harmonic-seeded remote laser emissions at 391 nm wavelength from strong-field ionized nitrogen molecules in three different gas mixtures, i.e., N2-Ar, N2-Xe and N2-Ne. We observed a decrease in the remote laser intensity in the N2-Xe mixture because of the decreased clamped intensity in the filament; whereas in the N2-Ne mixture, the remote laser intensity slightly increases because of the increased clamped intensity within the filament. Remarkably, although the clamped intensity in the filament remains nearly unchanged in the N2-Ar mixture because of the similar ionization potentials of N2 and Ar, a significant enhancement of the lasing emission is realized in the N2-Ar mixture. The enhancement is attributed to the stronger third harmonic seed, and longer gain medium due to the extended filament. PMID- 23037221 TI - Analysis of light scattering from surface roughness in hollow-core photonic bandgap fibers. AB - We present a theoretical method for analyzing radiation loss from surface roughness scattering in hollow-core photonic bandgap fibers (HC-PBGFs). We treat the scattering process as induced dipole radiation and combine statistical information about surface roughness, mode field distribution and fibre geometry to accurately describe the far-field scattering distribution and loss in fibers with an arbitrary cross-sectional distribution of air holes of any shape. The predicted angular scattering distribution, total scattering loss and the loss wavelength dependence are all shown to agree well with reported experimental data. Our method yields a simpler result than that obtained by more complex approaches and is to the best of our knowledge the first successful attempt to accurately describe roughness scattering in HC-PBGFs. PMID- 23037222 TI - Observation of dual-wavelength dissipative solitons in a figure-eight erbium doped fiber laser. AB - We report on the generation of dual-wavelength dissipative solitons (DSs) in a passively mode-locked figure-eight fiber laser operating in the net-normal dispersion regime. DSs with central wavelengths of 1572 and 1587 nm can be achieved simultaneously or respectively. The dual-wavelength DSs, traveling at different round-trip time, exhibit double-rectangular spectral profile. The intensities of two mode-locked spectra decrease or increase simultaneously after passing through a polarization beam splitter, indicating that the dual-wavelength DSs almost share the same polarization state. Experimental results demonstrated that dual-wavelength mode locking strongly depends on birefringence-induced filtering effect. PMID- 23037223 TI - Adaptive optics enables 3D STED microscopy in aberrating specimens. AB - Stimulated emission depletion (STED) microscopy allows fluorescence far-field imaging with diffraction-unlimited resolution. Unfortunately, extending this technique to three-dimensional (3D) imaging of thick specimens has been inhibited by sample-induced aberrations. Here we present the first implementation of adaptive optics in STED microscopy to allow 3D super-resolution imaging in strongly aberrated imaging conditions, such as those introduced by thick biological tissue. PMID- 23037224 TI - Alignment-free, all-spliced fiber laser source for CARS microscopy based on four wave-mixing. AB - An environmentally-stable low-repetition rate fiber oscillator is developed to produce narrow-bandwidth pulses with several tens of picoseconds duration. Based on this oscillator an alignment-free all-fiber laser for multi-photon microscopy is realized using in-fiber frequency conversion based on four-wave-mixing. Both pump and Stokes pulses for coherent anti-Stokes Raman scattering (CARS) microscopy are readily available from one fiber end, intrinsically overlapped in space and time, which drastically simplifies the experimental handling for the user. The complete laser setup is mounted on a home-built laser scanning microscope with small footprint. High-quality multimodal microscope images of biological tissue are presented probing the CH-stretching resonance of lipids at an anti-Stokes Raman-shift of 2845 cm(-1) and second-harmonic generation of collagen. Due to its simplicity, compactness, maintenance-free operation, and ease-of-use the presented low-cost laser is an ideal source for bio-medical applications outside laser laboratories and in particular inside clinics. PMID- 23037225 TI - A new bound on excess frequency noise in second harmonic generation in PPKTP at the 10-19 level. AB - We report a bound on the relative frequency fluctuations in nonlinear second harmonic generation. A 1,064 nm Nd:YAG laser is used to read out the phase of a Mach-Zehnder interferometer while PPKTP, a nonlinear crystal, is placed in each arm to generate second harmonic light. By comparing the arm length difference of the Mach Zehnder as read out by the fundamental 1064 nm light, and its second harmonic at 532 nm, we can bound the excess frequency noise introduced in the harmonic generation process. We report an amplitude spectral density of frequency noise with total RMS frequency deviation of 3 mHz and a minimum value of 20 MUHz/Hz1/2 over 250 seconds with a measurement bandwidth of 128 Hz, corresponding to an Allan deviation of 10-19 at 20 seconds. PMID- 23037226 TI - Narrowband terahertz emitters using metamaterial films. AB - In this article we report on metamaterial-based narrowband thermal terahertz (THz) emitters with a bandwidth of about 1 THz. Single band emitters designed to radiate in the 4 to 8 THz range were found to emit as high as 36 W/m(2) when operated at 400 degrees C. Emission into two well-separated THz bands was also demonstrated by using metamaterial structures featuring more complex unit cells. Imaging of heated emitters using a microbolometer camera fitted with THz optics clearly showed the expected higher emissivity from the metamaterial structure compared to low-emissivity of the surrounding aluminum. PMID- 23037227 TI - Probing coherence in microcavity frequency combs via optical pulse shaping. AB - Recent investigations of microcavity frequency combs based on cascaded four-wave mixing have revealed a link between the evolution of the optical spectrum and the observed temporal coherence. Here we study a silicon nitride microresonator for which the initial four-wave mixing sidebands are spaced by multiple free spectral ranges (FSRs) from the pump. Additional lines then fill in to yield a comb with single FSR spacing, resulting in partial coherence. By using a pulse shaper to select and manipulate the phase of various subsets of spectral lines, we are able to probe the structure of the coherence within the partially coherent comb. Our data demonstrate strong variation in the degree of mutual coherence between different groups of lines and provide support for a simple model of partially coherent comb formation. PMID- 23037228 TI - Single-frequency ytterbium doped photonic bandgap fiber amplifier at 1178 nm. AB - 1178 nm single-frequency amplification by Yb doped photonic bandgap fiber has been demonstrated. 24.6 W output power and 12 dB gain were obtained without parasitic lasing and also stimulated Brillouin scattering. 1.8 dB suppression of Brillouin gain by an acoustic antiguiding effect has been found in the Yb doped photonic bandgap fiber. PMID- 23037229 TI - Fast super-resolution using an adaptive Wiener filter with robustness to local motion. AB - We present a new adaptive Wiener filter (AWF) super-resolution (SR) algorithm that employs a global background motion model but is also robust to limited local motion. The AWF relies on registration to populate a common high resolution (HR) grid with samples from several frames. A weighted sum of local samples is then used to perform nonuniform interpolation and image restoration simultaneously. To achieve accurate subpixel registration, we employ a global background motion model with relatively few parameters that can be estimated accurately. However, local motion may be present that includes moving objects, motion parallax, or other deviations from the background motion model. In our proposed robust approach, pixels from frames other than the reference that are inconsistent with the background motion model are detected and excluded from populating the HR grid. Here we propose and compare several local motion detection algorithms. We also propose a modified multiscale background registration method that incorporates pixel selection at each scale to minimize the impact of local motion. We demonstrate the efficacy of the new robust SR methods using several datasets, including airborne infrared data with moving vehicles and a ground resolution pattern for objective resolution analysis. PMID- 23037230 TI - Electroluminescent devices with function of electro-optic shutter. AB - The polymer-dispersed liquid crystal (PDLC) was used as a dielectric layer of electroluminescent (EL) device to provide multi-function of electroluminescence and electro-optic shutter. A 50 MUm-thick PDLC layer was formed between a transparent electrode and a ZnS:Cu phosphor layer. The electro-optic properties of the EL device were not distorted by the introduction of the PDLC layer. The extraction efficiency of luminescence was improved by more than 14% by PDLC layer. The transmittance of the PDLC was also founded not to be degraded significantly by excitation frequency. Therefore, the electroluminescence of the device was ignited by excitation frequency at a given voltage for full transparency of the PDLC. This device has great potential for applications in transparent displays with the function of a privacy window. PMID- 23037231 TI - Halting the fuse discharge propagation using optical fiber microwires. AB - We report and analyze the halting of the fuse effect propagation in optical fiber microwires. The increase of the mode field diameter in the tapered region decreases the optical intensity resulting in the extinction of the fuse effect. This fiber element presents a low insertion loss and can be introduced in the optical network in order to protect the active equipment from the damage caused by the fuse effect. PMID- 23037232 TI - REAM intensity modulator-enabled 10Gb/s colorless upstream transmission of real time optical OFDM signals in a single-fiber-based bidirectional PON architecture. AB - Reflective electro-absorption modulation-intensity modulators (REAM-IMs) are utilized, for the first time, to experimentally demonstrate colorless ONUs in single-fiber-based, bidirectional, intensity-modulation and direct-detection (IMDD), optical OFDM PONs (OOFDM-PONs) incorporating 25 km SSMFs and OLT-side seeded CW optical signals. The colorlessness of the REAM-IMs is characterized, based on which optimum REAM-IM operating conditions are identified. In the aforementioned PON architecture, 10Gb/s colorless upstream transmissions of end to-end real-time OOFDM signals are successfully achieved for various wavelengths within the entire C-band. Over such a wavelength window, corresponding minimum received optical powers at the FEC limit vary in a range as small as <0.5 dB. In addition, experimental measurements also indicate that Rayleigh backscattering imposes a 2.8 dB optical power penalty on the 10 Gb/s over 25 km upstream OOFDM signal transmission. Furthermore, making use of on-line adaptive bit and power loading, a linear trade-off between aggregated signal line rate and optical power budget is observed, which shows that, for the present PON system, a 10% reduction in signal line rate can improve the optical power budget by 2.6 dB. PMID- 23037233 TI - Brillouin gain spectrum dependence on large strain in perfluorinated graded-index polymer optical fiber. AB - We investigate the dependence of Brillouin gain spectra on large strain of > 20% in a perfluorinated graded-index polymer optical fiber, and prove, for the first time, that the dependence of Brillouin frequency shift (BFS) is highly non monotonic. We predict that temperature sensors even with zero strain sensitivity can be implemented by use of this non-monotonic nature. Meanwhile, the Stokes power decreases rapidly when the applied strain is > ~10%. This behavior seems to originate from the propagation loss dependence on large strain. By exploiting the Stokes power dependence, we can probably solve the problem of how to identify the applied strain, when the identification is difficult only by BFS because of its non-monotonic nature. PMID- 23037234 TI - Indirect doping of microstructures fabricated by two-photon polymerization with gold nanoparticles. AB - Nanoplasmonics and metamaterials sciences are rapidly growing due to their contributions to photonic devices fabrication with applications ranging from biomedicine to photovoltaic cells. Noble metal nanoparticles incorporated into polymer matrix have great potential for such applications due to their distinctive optical properties. However, methods to indirectly incorporate metal nanoparticles into polymeric microstructures are still on demand. Here we report on the fabrication of two-photon polymerized microstructures doped with gold nanoparticles through an indirect doping process, so they do not interfere in the two-photon polymerization (2PP) process. Such microstructures present a strong emission, arising from gold nanoparticles fluorescence. The microstructures produced are potential candidates for nanoplasmonics and metamaterials devices applications and the nanoparticles production method can be applied in many samples, heated simultaneously, opening the possibility for large scale processes. PMID- 23037235 TI - Low-loss optical waveguides and Y-branch splitters in lithium niobate fabricated by MeV oxygen ions with low dose. AB - Single-mode optical waveguides in LiNbO(3) substrate with loss as low as 0.17dB/cm were fabricated by a multi-energy low-dose ion implantation technology and cumulative annealing treatment. A waveguide Y-Branch splitter was demonstrated. Index profile in waveguide is described based on the ion implantation-induced damage profile, and propagation property in waveguide is simulated. Simulation results show a good consistence with the measured ones. PMID- 23037236 TI - Optical trapping using cascade conical refraction of light. AB - Cascade conical refraction occurs when a beam of light travels through two or more biaxial crystals arranged in series. The output beam can be altered by varying the relative azimuthal orientation of the two biaxial crystals. For two identical crystals, in general the output beam comprises a ring beam with a spot at its centre. The relative intensities of the spot and ring can be controlled by varying the azimuthal angle between the refracted cones formed in each crystal. We have used this beam arrangement to trap one microsphere within the central spot and a second microsphere on the ring. Using linearly polarized light, we can rotate the microsphere on the ring with respect to the central sphere. Finally, using a half wave-plate between the two crystals, we can create a unique beam profile that has two intensity peaks on the ring, and thereby trap two microspheres on diametrically opposite points on the ring and rotate them around the central sphere. Such a versatile optical trap should find application in optical trapping setups. PMID- 23037237 TI - Field induced dynamic waveguides based on potassium tantalate niobate crystals. AB - In this paper, a new type of optical waveguide based on potassium tantalate niobate (KTN) electro-optic crystal is presented. The guiding property of the optical waveguide can be quickly (on the order of nanosecond) tuned and controlled by the applied external electric field, which can be useful for many applications such as broadband ultrafast optical modulators, variable optical attenuators, and dynamic gain equalizers. PMID- 23037238 TI - 3D objects enlargement technique using an optical system and multiple SLMs for electronic holography. AB - One problem in electronic holography, which is caused by the display performance of spatial light modulators (SLM), is that the size of reconstructed 3D objects is small. Although methods for increasing the size using multiple SLMs have been considered, they typically had the problem that some parts of 3D objects were missing as a result of the gap between adjacent SLMs or 3D objects lost the vertical parallax. This paper proposes a method of resolving this problem by locating an optical system containing a lens array and other components in front of multiple SLMs. We used an optical system and 9 SLMs to construct a device equivalent to an SLM with approximately 74,600,000 pixels and used this to reconstruct 3D objects in both the horizontal and vertical parallax with an image size of 63 mm without losing any part of 3D objects. PMID- 23037239 TI - Three-dimensional clustered speckle fields: theory, simulations and experimental verification. AB - Clustered speckle patterns are a particular type of speckles that appear when a coherently illuminated diffuser is imaged through a multiple aperture pupil mask attached to a lens. The cluster formation is the result of the complex speckle modulations of the multiple interferences produced by the apertures. In this paper, a three-dimensional analytical approach to simulate cluster speckles everywhere after the lens is presented. This approach has the possibility of including multiple aperture masks at the lens and at the diffuser, in contrast to previous works which were also limited to the description of the patterns only at the image plane. This model contributes to the development of tailor made speckle patterns that can be used in diverse optical applications, including those lying in the focus region. The approach is validated under different conditions by comparing experimental results with simulations on a statistical basis. Some aspects of possible uses of these clusters are briefly revised, such as optical trapping, manipulation and metrology. PMID- 23037240 TI - Static compressive tracking. AB - This paper presents the Static Computational Optical Undersampled Tracker (SCOUT), an architecture for compressive motion tracking systems. The architecture uses compressive sensing techniques to track moving targets at significantly higher resolution than the detector array, allowing for low cost, low weight design and a significant reduction in data storage and bandwidth requirements. Using two amplitude masks and a standard focal plane array, the system captures many projections simultaneously, avoiding the need for time sequential measurements of a single scene. Scenes with few moving targets on static backgrounds have frame differences that can be reconstructed using sparse signal reconstruction techniques in order to track moving targets. Simulations demonstrate theoretical performance and help to inform the choice of design parameters. We use the coherence parameter of the system matrix as an efficient predictor of reconstruction error to avoid performing computationally intensive reconstructions over the entire design space. An experimental SCOUT system demonstrates excellent reconstruction performance with 16X compression tracking movers on scenes with zero and nonzero backgrounds. PMID- 23037241 TI - High thermal stability of high indium content InGaN films grown by pulsed laser deposition. AB - Thermal stability on the structural and optical properties of high indium content InGaN films grown using pulsed laser deposition (PLD) was investigated through long-duration and high-temperature annealing. X-ray diffraction and cathode- luminescence measurements of the 33% indium InGaN revealed no differences in the line-shape and peak position even after annealing at 800 degrees C for 95 min; similar structural stability was found for the 60% samples after annealing for 75 min. The higher thermal stability is attributed to nanoscale InN domains with different orientations create mixed-polarity InGaN/InN interfaces, resulting in higher activation energies at interfaces and increasing the thermal stability of the material. Furthermore, the InGaN films were subjected to metalorganic chemical vapor deposition treatment to regrow a GaN layer; results are promising for the development of high thermal stability InGaN films using the PLD technique. PMID- 23037242 TI - 50-Gb/s silicon quadrature phase-shift keying modulator. AB - We report the first successful demonstration of quadrature phase-shift keying (QPSK) modulation using two nested silicon Mach-Zehnder modulators. 50-Gb/s QPSK signal is generated with only 2.7-dB optical signal-to-noise ratio penalties from the theoretical limit at a bit-error ratio of 10(-3). This result validates that silicon photonics could be a viable and powerful platform of photonic integrated circuits in coherent optical communications. PMID- 23037243 TI - Voigt Airy surface magneto plasmons. AB - We present a basic theory on Airy surface magneto plasmons (SMPs) at the interface between a dielectric layer and a metal layer (or a doped semiconductor layer) under an external static magnetic field in the Voigt configuration. It is shown that, in the paraxial approximation, the Airy SMPs can propagate along the surface without violating the nondiffracting characteristics, while the ballistic trajectory of the Airy SMPs can be tuned by the applied magnetic field. In addition, the self-deflection-tuning property of the Airy SMPs depends on the direction of the external magnetic field applied, owing to the nonreciprocal effect. PMID- 23037244 TI - A theoretical study of transient stimulated Brillouin scattering in optical fibers seeded with phase-modulated light. AB - Beam combining of phase-modulated kilowatt fiber amplifiers has generated considerable interest recently. We describe in the time domain how stimulated Brillouin scattering (SBS) is generated in an optical fiber under phase-modulated laser conditions, and we analyze different phase modulation techniques. The temporal and spatial evolutions of the acoustic phonon, laser, and Stokes fields are determined by solving the coupled three-wave interaction system. Numerical accuracy is verified through agreement with the analytical solution for the un modulated case and through the standard photon conservation relation for counter propagating optical fields. As a test for a modulated laser, a sinusoidal phase modulation is examined for a broad range of modulation amplitudes and frequencies. We show that, at high modulation frequencies, our simulations agree with the analytical results obtained from decomposing the optical power into its frequency components. At low modulation frequencies, there is a significant departure due to the appreciable cross talk among the laser and Stokes sidebands. We also examine SBS suppression for a white noise source and show significant departures for short fibers from analytically derived formulas. Finally, SBS suppression through the application of pseudo-random bit sequence modulation is examined for various patterns. It is shown that for a fiber length of 9 m the patterns at or near n=7 provide the best mitigation of SBS with suppression factors approaching 17 dB at a modulation frequency of 5 GHz. PMID- 23037245 TI - High quality factor 1-D Er3+-activated dielectric microcavity fabricated by RF sputtering. AB - Rare earth-activated 1-D photonic crystals were fabricated by RF-sputtering technique. The cavity is constituted by an Er3+-doped SiO2 active layer inserted between two Bragg reflectors consisting of ten pairs of SiO2/TiO2 layers. Scanning electron microscopy is employed to put in evidence the quality of the sample, the homogeneities of the layers thickness and the good adhesion among them. Near infrared transmittance and variable angle reflectance spectra confirm the presence of a stop band from 1500 nm to 2000 nm with a cavity resonance centered at 1749 nm at 0 degrees and a quality factor of 890. The influence of the cavity on the 4I13/2 -->4I15/2 emission band of Er3+ ion is also demonstrated. PMID- 23037246 TI - Design and demonstration of ultra-fast W-band photonic transmitter-mixer and detectors for 25 Gbits/sec error-free wireless linking. AB - A 25 Gbits/s error-free on-off-keying (OOK) wireless link between an ultra high speed W-band photonic transmitter-mixer (PTM) and a fast W-band envelope detector is demonstrated. At the transmission end, the high-speed PTM is developed with an active near-ballistic uni-traveling carrier photodiode (NBUTC-PD) integrated with broadband front-end circuitry via the flip-chip bonding technique. Compared to our previous work, the wireless data rate is significantly increased through the improvement on the bandwidth of the front-end circuitry together with the reduction of the intermediate-frequency (IF) driving voltage of the active NBUTC PD. The demonstrated PTM has a record-wide IF modulation (DC-25 GHz) and optical to-electrical fractional bandwidths (68-128 GHz, ~67%). At the receiver end, the demodulation is realized with an ultra-fast W-band envelope detector built with a zero-bias Schottky barrier diode with a record wide video bandwidth (37 GHz) and excellent sensitivity. The demonstrated PTM is expected to find applications in multi-gigabit short-range wireless communication. PMID- 23037247 TI - Design for broadband on-chip isolator using Stimulated Brillouin Scattering in dispersion-engineered chalcogenide waveguides. AB - We propose a scheme for on-chip isolation in chalcogenide (As2S3) rib waveguides, in which Stimulated Brillouin Scattering is used to induce non-reciprocal mode conversion within a multi-moded waveguide. The design exploits the idea that a chalcogenide rib buried in a silica matrix acts as waveguide for both light and sound, and can also be designed to be multi-moded for both optical and acoustic waves. The enhanced opto-acoustic coupling allows significant isolation (> 20 dB) within a chip-scale (cm-long) device (< 10 cm). We also show that the bandwidth of this device can be dramatically increased by tuning the dispersion of the waveguide to match the group velocity between optical modes: we find that 20 dB isolation can be extended over a bandwidth of 25 nm. PMID- 23037248 TI - Efficient holoscopy image reconstruction. AB - Holoscopy is a tomographic imaging technique that combines digital holography and Fourier-domain optical coherence tomography (OCT) to gain tomograms with diffraction limited resolution and uniform sensitivity over several Rayleigh lengths. The lateral image information is calculated from the spatial interference pattern formed by light scattered from the sample and a reference beam. The depth information is obtained from the spectral dependence of the recorded digital holograms. Numerous digital holograms are acquired at different wavelengths and then reconstructed for a common plane in the sample. Afterwards standard Fourier-domain OCT signal processing achieves depth discrimination. Here we describe and demonstrate an optimized data reconstruction algorithm for holoscopy which is related to the inverse scattering reconstruction of wavelength scanned full-field optical coherence tomography data. Instead of calculating a regularized pseudoinverse of the forward operator, the recorded optical fields are propagated back into the sample volume. In one processing step the high frequency components of the scattering potential are reconstructed on a non equidistant grid in three-dimensional spatial frequency space. A Fourier transform yields an OCT equivalent image of the object structure. In contrast to the original holoscopy reconstruction with backpropagation and Fourier transform with respect to the wavenumber, the required processing time does neither depend on the confocal parameter nor on the depth of the volume. For an imaging NA of 0.14, the processing time was decreased by a factor of 15, at higher NA the gain in reconstruction speed may reach two orders of magnitude. PMID- 23037249 TI - Photoluminescence and photoresponse from InSb/InAs-based quantum dot structures. AB - InSb-based quantum dots grown by metal-organic vapor-phase epitaxy (MOVPE) on InAs substrates are studied for use as the active material in interband photon detectors. Long-wavelength infrared (LWIR) photoluminescence is demonstrated with peak emission at 8.5 um and photoresponse, interpreted to originate from type-II interband transitions in a p-i-n photodiode, was measured up to 6 um, both at 80 K. The possibilities and benefits of operation in the LWIR range (8-12 um) are discussed and the results suggest that InSb-based quantum dot structures can be suitable candidates for photon detection in the LWIR regime. PMID- 23037250 TI - Aluminum oxide nanostructure-based substrates for fluorescence enhancement. AB - A new fluorescence enhancement technical platform based on anodic aluminum oxide (AAO) nanostructure substrate is reported for the first time. Several fluorophores have been examined on the AAO nanostructure substrates. Systematic experiments found that the enhancement factor can be up to two orders of magnitude compared to the fluorescence signals on a glass substrate, indicating its great potential for ultrasensitive fluorescence detection. Given the simple and cost-effective fabrication process of lithographically patterned AAO nanostructure, this type of AAO nanostructure platform has great potential applications, especially its integration with microdevices and microfluidic devices for fluorescence-based biological analysis. PMID- 23037251 TI - Optimized plasmonic nanostructures for improved sensing activities. AB - The paper outlines the optimization of plasmonic nanostructures in order to improve their sensing properties such as their sensitivity and their ease of manipulation. The key point in this study is the optimization of the localized surface plasmon resonance (LSPR) properties essential to the sensor characteristics, and more especially for surface-enhanced Raman scattering (SERS). Two aspects were considered in order to optimize the sensing performance: apolar plasmonic nanostructures for non polarization dependent detection and improvements of SERS sensitivity by using a molecular adhesion layer between gold nanostructures and glass. Both issues could be generalized to all plasmon resonance-based sensing applications. PMID- 23037252 TI - Comparison of IPDA lidar receiver sensitivity for coherent detection and for direct detection using sine-wave and pulsed modulation. AB - We use theoretical models to compare the receiver signal to noise ratio (SNR) vs. average rate of detected signal photons for an integrated path differential absorption (IPDA) lidar using coherent detection with continuous wave (CW) lasers and direct detection with sine-wave and pulse modulations. The results show the coherent IPDA lidar has high receiver gain and narrow bandwidth to overcome the effects of detector circuit noise and background light, but the actual receiver performance can be limited by the coherent mixing efficiency, speckle and other factors. For direct detection, using sine-wave modulation allows the use of a low peak power laser transmitter and synchronous detection. The pulse modulation technique requires higher laser peak powers but is more efficient than sine-wave modulation in terms of average detected signal photon rate required to achieve a given receiver SNR. We also conducted experiments for the direct detection cases and the results agreed well with theory. PMID- 23037253 TI - An optical leaky wave antenna with Si perturbations inside a resonator for enhanced optical control of the radiation. AB - We investigate the directive radiation at 1550 nm from an optical leaky wave antenna (OLWA) with semiconductor perturbations made of silicon (Si). We study the radiation pattern dependence on the physical dimensions, number of perturbations and carrier densities in these semiconductor perturbations through optical excitations at a visible wavelength, 625 nm. In this detailed theoretical study we show the correlation between the pump power absorbed in the perturbations, the signal guided in the waveguide and the radiation through leakage. To overcome the limited control of the radiation intensity through excess carrier generation in Si, we present a new design with the OLWA integrated with a Fabry-Perot resonator (FPR). We provide analytical and numerical studies of the enhanced radiation performance of the OLWA antenna inside the FPR, and derive closed-form formulas accounting for LW reflection at the edges of the FPR. A discussion on the constructive and destructive radiation by the direct and reflected leaky waves in the FPR resonator is provided. Results shown in this paper exhibit 3 dB variation of the radiation and pave the way for further optimization and theoretical developments. PMID- 23037254 TI - A surface plasmon resonance spectrometer using a super-period metal nanohole array. AB - We investigate the surface plasmon resonance in super-period nanohole arrays and demonstrate a surface plasmon resonance spectrometer using a super-period metal nanohole array device. Super-period nanohole arrays are patterned metal nanohole array gratings. In a super-period nanohole array, there is a small subwavelength nanohole period that supports local surface plasmon resonance, and also a large grating period that diffracts surface plasmon radiations to non-zeroth order diffractions. With the super-period metal nanohole array, surface plasmon resonance can be measured in the first order diffraction in addition to be traditionally measured in the zeroth order transmission. The resonance peak wavelength measured in the first order diffraction is slightly blue-shifted from the resonance wavelength measured in the zeroth order transmission. PMID- 23037255 TI - Wavelength conversion of 544-Gbit/s dual-carrier PDM-16QAM signal based on the co polarized dual-pump scheme. AB - Due to its relative low baud rate as well as simple and cost-efficient implementation, dual-carrier polarization-division-multiplexing 16-ary quadrature amplitude modulation (PDM-16QAM) is a promising candidate for the next generation optical systems and networks at 400Gb/s per channel. The co-polarized dual-pump scheme, based on four-wave mixing (FWM) in a 1-km high nonlinear fiber (HNLF), can realize the all-optical wavelength conversion (AOWC) of the dual-carrier PDM 16QAM signal with spectral non-inversion and polarization insensitivity. We first experimentally demonstrated AOWC of the 544-Gbit/s dual-carrier PDM-16QAM signal based on the co-polarized dual-pump scheme. We investigated the conversion efficiency (CE) and optical signal-to-noise ratio (OSNR) of the converted signal at different pump spacing and pump power. We measured that the OSNR penalty is 0.6 dB due to AOWC when the bit-error ratio (BER) and pump spacing is 2 x 10-2 and 200 GHz, respectively. PMID- 23037256 TI - Optimal Mueller matrix estimation in the presence of Poisson shot noise. AB - We address the optimization of Mueller polarimeters in the presence of additive Gaussian noise and signal-dependent shot noise, which are two dominant types of noise in most imaging systems. We propose polarimeter architectures in which the noise variances on each coefficient of the Mueller matrix are equalized and independent of the observed matrices. PMID- 23037257 TI - High quality factor and high confinement silicon resonators using etchless process. AB - We demonstrate high quality factor and high confinement in a silicon ring resonator fabricated by a thermal oxidation process. We fabricated a 50 MUm bending radius racetrack resonator, with a 5 MUm coupling region. We achieved an intrinsic quality factor of 760,000 for the fundamental TM mode, which corresponds to a propagation loss of 0.9 dB/cm. Both the fundamental TE and TM modes are highly confined in the waveguide, with effective indices of 3.0 for the TE mode and 2.9 for the TM mode. PMID- 23037258 TI - Broadband isolated attosecond pulse with high spatiotemporal quality in pre excited medium by multi-cycle two-color fields. AB - We propose a scheme that combines multi-cycle two-color pump pulses and pre excited medium to simultaneously control the ionization and acceleration steps of electron wave packet. Intense two-plateau supercontinua are observed at microscopic level, which support isolated attosecond pulse with tunable central wavelength. We further investigate the propagation effects and find that the macroscopic response is mainly associated with the initial population of the excited state. Large initial population can distort the pump field and weaken the phase-matching of the supercontinua due to the high density of free electrons. On the contrary, small initial population of 3% can generate well phase-matched supercontinua, and an efficient isolated attosecond pulse with gaussian-like spatial distribution is directly achieved. The divergence angle of the generated pulse is less than 0.2 mrad, which indicates its beam quality is good. This pulse benefits for some potential applications of ultrafast measurements with high spatiotemporal resolutions. PMID- 23037259 TI - Frequency comb generation by CW laser injection into a quantum-dot mode-locked laser. AB - We report on frequency comb generation at 1.5 MUm by injection of a CW laser in a hybridly mode-locked InAs/InP two-section quantum-dot laser (HMLQDL). The generated comb has > 60 modes spaced by ~ 4.5 GHz and a -20 dBc width of > 100 GHz (23 modes) at > 30 dB signal to background ratio. Comb generation was observed with the CW laser (red) detuned more than 20 nm outside the HMLQDL spectrum, spanning a large part of the gain spectrum of the quantum dot material. It is shown that the generated comb is fully coherent with the injected CW laser and RF frequency used to drive the hybrid mode-locking. This method of comb generation is of interest for the creation of small and robust frequency combs for use in optical frequency metrology, high-frequency (> 100 GHz) RF generation and telecommunication applications. PMID- 23037260 TI - High-Q UV whispering gallery mode resonators made of angle-cut BBO crystals. AB - We report an investigation on angle-cut beta barium borate (BBO) whispering gallery mode (WGM) resonators operating in the ultra violet (UV) wavelength range. A quality (Q) factor of 1.5 * 10(8) has been demonstrated at 370 nm. New upper bounds for the absorption coefficients of BBO are obtained from the Q factor measurements. Moreover, polarization rotations of WGMs in the angle-cut birefringent resonators are observed and investigated. To the best of our knowledge, this is not only the first reported demonstration of an angle-cut WGM resonator but also the first reported high Q WGM resonator in the UV region. PMID- 23037261 TI - Spectroscopy on a single trapped 137Ba+ ion for nuclear magnetic octupole moment determination. AB - We present precision measurements of the hyperfine intervals in the 5D3/2 manifold of a single trapped Barium ion, 137Ba+. Measurements of the hyperfine intervals are made between mF = 0 sublevels over a range of magnetic fields allowing us to interpolate to the zero field values with an accuracy below a few Hz, an improvement on previous measurements by three orders of magnitude. Our results, in conjunction with theoretical calculations, provide a 30-fold reduction in the uncertainty of the magnetic dipole (A) and electric quadrupole (B) hyperfine constants. In addition, we obtain the magnetic octupole constant (C) with an accuracy below 0.1Hz. This gives a subsequent determination of the nuclear magnetic octupole moment, Omega, with an uncertainty of 1% limited almost completely by the accuracy of theoretical calculations. This constitutes the first observation of the octupole moment in 137Ba+ and the most accurately determined octupole moment to date. PMID- 23037262 TI - Fast three-dimensional imaging of gold nanoparticles in living cells with photothermal optical lock-in Optical Coherence Microscopy. AB - We introduce photothermal optical lock-in Optical Coherence Microscopy (poli OCM), a volumetric imaging technique, which combines the depth sectioning of OCM with the high sensitivity of photothermal microscopy while maintaining the fast acquisition speed inherent to OCM. We report on the detection of single 40 nm gold particles with a 0.5 MUm lateral and 2 MUm axial resolution over a 50 MUm depth of field and the three-dimensional localization of gold colloids within living cells. In combination with intrinsic sample contrast measured with dark field OCM, poli-OCM offers a versatile platform for functional cell imaging. PMID- 23037263 TI - Phase and amplitude characteristics of a phase-sensitive amplifier operating in gain saturation. AB - We investigate a non-degenerate phase-sensitive amplifier (PSA) operating in gain saturation experimentally and numerically using the three-wave model. The phase dependent gain and phase-to-phase transfer functions are obtained for different levels of saturation with good agreement between experimental and numerical data when higher-order FWM is small. Moreover, we identify an operating point where the PSA is found to be able to significantly reduce both phase- and amplitude noise simultaneously. PMID- 23037264 TI - A self-coherent receiver for detection of PolMUX coherent signals. AB - A self-coherent receiver capable of demultiplexing PolMUX-signals without an external polarization controller is presented. Training sequences are introduced to estimate the polarization rotation, and a decision feedback recursive algorithm mitigates the random walk of the recovered field. The concept is tested for a PolMUX-DQPSK modulation format where one polarization carries a normal DQPSK signal while the other polarization is encoded as a progressive phase-shift DQPSK signal. An experimental demonstration of the scheme for a 112 Gbit/s PolMUX DQPSK signal is presented. PMID- 23037265 TI - Cladding mode coupling in highly localized fiber Bragg gratings II: complete vectorial analysis. AB - Highly localized fiber Bragg gratings can be inscribed point-by-point with focused ultrashort pulses. The transverse localization of the resonant grating causes strong coupling to cladding modes of high azimuthal and radial order. In this paper, we show how the reflected cladding modes can be fully analyzed, taking their vectorial nature, orientation and degeneracies into account. The observed modes' polarization and intensity distributions are directly tied to the dispersive properties and show abrupt transitions in nature, strongly correlated with changes in the coupling strengths. PMID- 23037266 TI - Surface and thickness measurement of a transparent film using wavelength scanning interferometry. AB - A wavelength scanning interferometer for measuring the surface and thickness of a transparent film has been studied. A halogen light source combined with an acousto-optic tuneable filter is used to generate a sequence of filtered light in a Linnik interferometer, which leads to a sequence of interferograms captured by a CCD camera. When a transparent thin film is measured, the reflection signals from both the top and bottom surfaces of the film will interfere with the reference signal. At the same time, the multiple reflection signals between the two film surfaces will also interfere with each other. Effective separation of the interference signals from each other is the key to achieving a successful measurement. By performing a frequency-domain analysis, these interference signals can be separated. An optimized Fourier transform method is used in the analysis. Measurements of the top and bottom surface finishes of the film, as well as the film thickness map, have been achieved. The film needs to be more than 3 um in optical path length, and must transparent with no absorption of light. The film's refractive index needs to be known as a function of wavelength. In this paper, the theoretical analysis and simulation study of wavelength scanning interferometry for transparent film measurement is discussed. Experiments on thin film layers of Parylene N coated on a glass slide surface are studied and analyzed. Comparison study results with other contact and non-contact methods are also presented. PMID- 23037267 TI - Analysis of fine-mode aerosol retrieval capabilities by different passive remote sensing instrument designs. AB - Remote sensing of aerosol optical properties is difficult, but multi-angle, multi spectral, polarimetric instruments have the potential to retrieve sufficient information about aerosols that they can be used to improve global climate models. However, the complexity of these instruments means that it is difficult to intuitively understand the relationship between instrument design and retrieval success. We apply a Bayesian statistical technique that relates instrument characteristics to the information contained in an observation. Using realistic simulations of fine size mode dominated spherical aerosols, we investigate three instrument designs. Two of these represent instruments currently in orbit: the Multiangle Imaging SpectroRadiometer (MISR) and the POLarization and Directionality of the Earths Reflectances (POLDER). The third is the Aerosol Polarimetry Sensor (APS), which failed to reach orbit during recent launch, but represents a viable design for future instruments. The results show fundamental differences between the three, and offer suggestions for future instrument design and the optimal retrieval strategy for current instruments. Generally, our results agree with previous validation efforts of POLDER and airborne prototypes of APS, but show that the MISR aerosol optical thickness uncertainty characterization is possibly underestimated. PMID- 23037268 TI - Detailed simulation of structural color generation inspired by the Morpho butterfly. AB - The brilliancy and variety of structural colors found in nature has become a major scientific topic in recent years. Rapid-prototyping processes enable the fabrication of according structures, but the technical exploitation requires a profound understanding of structural features and material properties regarding the generation of reflected color. This paper presents an extensive simulation of the reflectance spectra of a simplified 2D Morpho butterfly wing model by utilizing the finite-difference time-domain method. The structural parameters are optimized for reflection in a given spectral range. A comparison to simpler models, such as a plane dielectric layer stack, provides an understanding of the origin of the reflection behavior. We find that the wavelength of the reflection maximum is mainly set by the lateral dimensions of the structures. Furthermore small variations of the vertical dimensions leave the spectral position of the reflectance wavelength unchanged, potentially reducing grating effects. PMID- 23037269 TI - Polarization suppression of the nonresonant background in femtosecond coherent anti-Stokes Raman scattering for flame thermometry at 5 kHz. AB - Coherent anti-Stokes Raman scattering (CARS) spectra are acquired at 5 kHz in steady and unsteady flames while suppressing the nonresonant background by polarization techniques. Broadband femtosecond (fs) pump and Stokes pulses efficiently excite many Raman transitions in diatomic nitrogen which subsequently interfere and decay. Single-laser-shot measurements are performed as the decay of the Raman coherence is mapped to the frequency of the CARS signal by a chirped probe pulse (CPP). As temperature increases, more Raman transitions contribute to the Raman coherence which leads to faster decay of the Raman coherence. Experimental fs CARS spectra are compared to a theoretical model to extract temperature measurements. The effects of probe time delay and temperature on nonresonant background suppressed CPP fs CARS spectra are examined. By suppressing the nonresonant background the evolution of the Raman coherence near zero probe time delay is more clearly revealed. The structure of the CPP fs CARS spectra with and without nonresonant background suppression is compared. The utility of polarization suppression of the nonresonant background for CPP fs CARS measurements is discussed. PMID- 23037270 TI - Subwavelength ripples adjustment based on electron dynamics control by using shaped ultrafast laser pulse trains. AB - This study reveals that the periods, ablation areas and orientations of periodic surface structures (ripples) in fused silica can be adjusted by using designed femtosecond (fs) laser pulse trains to control transient localized electron dynamics and corresponding material properties. By increasing the pulse delays from 0 to 100 fs, the ripple periods are changed from ~550 nm to ~255 nm and the orientation is rotated by 90 degrees . The nearwavelength/subwavelength ripple periods are close to the fundamental/second-harmonic wavelengths in fused silica respectively. The subsequent subpulse of the train significantly impacts free electron distributions generated by the previous subpulse(s), which might influence the formation mechanism of ripples and the surface morphology. PMID- 23037271 TI - A reconstruction method for cone-beam differential x-ray phase-contrast computed tomography. AB - Most existing differential phase-contrast computed tomography (DPC-CT) approaches are based on three kinds of scanning geometries, described by parallel-beam, fan beam and cone-beam. Due to the potential of compact imaging systems with magnified spatial resolution, cone-beam DPC-CT has attracted significant interest. In this paper, we report a reconstruction method based on a back projection filtration (BPF) algorithm for cone-beam DPC-CT. Due to the differential nature of phase contrast projections, the algorithm restrains from differentiation of the projection data prior to back-projection, unlike BPF algorithms commonly used for absorption-based CT data. This work comprises a numerical study of the algorithm and its experimental verification using a dataset measured with a three-grating interferometer and a micro-focus x-ray tube source. Moreover, the numerical simulation and experimental results demonstrate that the proposed method can deal with several classes of truncated cone-beam datasets. We believe that this feature is of particular interest for future medical cone-beam phase-contrast CT imaging applications. PMID- 23037272 TI - Silicon based plasmonic coupler. AB - Plasmonics is a field in which the light matter interaction can be controlled at the nanoscale by patterning the material surface to achieve enhanced optical effects. Realisation of micron sized silicon based plasmonic devices will require efficient coupling of light from an optical fibre grating coupler into silicon compatible plasmonic waveguides. In this paper we have investigated a silicon based plasmonic coupler with a very short taper length, which confines and focuses light from a broad input fibre opening into a plasmonic waveguide at the apex of the structure. A simple transfer matrix model was also developed to analyse the transmission performance of the coupler with respect to its key physical parameters. The proposed plasmonic coupler was optimised with respect to its different structural parameters using finite element simulations. A maximum coupling efficiency of 72% for light coupling from a 6.2 MUm wide input opening into a 20 nm slit width was predicted. The simulated result also predicted an insertion loss of ~ 2.0 dB for light coupling into a 300 nm single mode SOI waveguide from a plasmonic structure with a 10.4 MUm input opening width and a taper length of only 3.15 MUm. Furthermore, the application of the optimised plasmonic coupler as a splitter was investigated, in which the structure simultaneously splits and couples light with a predicted coupling efficiency of ~ 37 % (or a total coupling efficiency of 73%) from a 6.22 MUm input opening into two 50 nm wide plasmonic waveguides. PMID- 23037273 TI - Particulate optical scattering coefficients along an Atlantic Meridional Transect. AB - The particulate optical backscattering coefficient (bbp) is a fundamental optical property that allows monitoring of marine suspended particles both in situ and from space. Backscattering measurements in the open ocean are still scarce, however, especially in oligotrophic regions. Consequently, uncertainties remain in bbp parameterizations as well as in satellite estimates of bbp. In an effort to reduce these uncertainties, we present and analyze a dataset collected in surface waters during the 19th Atlantic Meridional Transect. Results show that the relationship between particulate beam-attenuation coefficient (cp) and chlorophyll-a concentration was consistent with published bio-optical models. In contrast, the particulate backscattering per unit of chlorophyll-a and per unit of cp were higher than in previous studies employing the same sampling methodology. These anomalies could be due to a bias smaller than the current uncertainties in bbp. If that was the case, then the AMT19 dataset would confirm that bbp:cp is remarkably constant over the surface open ocean. A second-order decoupling between bbp and cp was, however, evident in the spectral slopes of these coefficients, as well as during diel cycles. Overall, these results emphasize the current difficulties in obtaining accurate bbp measurements in the oligotrophic ocean and suggest that, to first order, bbp and cp are coupled in the surface open ocean, but they are also affected by other geographical and temporal variations. PMID- 23037274 TI - Significant infrared lateral photovoltaic effect in Mn-doped ZnO diluted magnetic semiconducting film. AB - Mn-doped ZnO has attracted considerable attention as an important kind of diluted magnetic semiconductors (DMSs). Here we report a new finding of lateral photovoltaic effect (LPE) in Mn-doped ZnO thin film based on DMS/SiO2/Si structure. Remarkably the induced LPE laser can be extended to infrared region in Mn-doped ZnO film. Besides we studied the dependence of the lateral photovoltage (LPV) position sensitivity on the laser wavelength and optical power by modulating the two factors and give a complete theoretical analysis. The LPE observation adds a significant new functionality to this DMS material and suggests Mn-doped ZnO a potential candidate for versatile devices. PMID- 23037275 TI - Robust optimization of adiabatic tapers for coupling to slow-light photonic crystal waveguides. AB - We investigate the design of taper structures for coupling to slow-light modes of various photonic-crystal waveguides while taking into account parameter uncertainties inherent in practical fabrication. Our short-length (11 periods) robust tapers designed for ? = 1.55?m and a slow-light group velocity of c/34 have a total loss of < 20 dB even in the presence of nanometer-scale surface roughness, which outperform the corresponding non-robust designs by an order of magnitude. We discover a posteriori that the robust designs have smooth profiles that can be parameterized by a few-term (intrinsically smooth) sine series which helps the optimization to further boost the performance slightly. We ground these numerical results in an analytical foundation by deriving the scaling relationships between taper length, taper smoothness, and group velocity with the help of an exact equivalence with Fourier analysis. PMID- 23037276 TI - Polarization memory of white luminescence of Ag nanoclusters dispersed in glass host. AB - A mechanism for white luminescence of Ag nanoclusters dispersed in oxyfluoride glass host has been revealed by studying a temperature dependence of its polarization memory. The spectral dependence of the polarization memory indicates the presence of a variety of Ag nanoclusters, particularly emitting in the blue, green and red. Temperature activated intercluster energy transfer has been found responsible for white luminescence. The means for increasing luminescence quantum yield have been suggested. This efficient white luminescence may be used in highly demanded devices, such as luminescent lamps, displays, color phosphors for LEDs, photovoltaic devices based on down shifting of solar spectrum. PMID- 23037277 TI - Vector analysis of bending waveguides by using a modified finite-difference method in a local cylindrical coordinate system. AB - A vector mode solver for bending waveguides by using a modified finite-difference (FD) method is developed in a local cylindrical coordinate system, where the perfectly matched layer absorbing boundary conditions are incorporated. Utilizing Taylor series expansion technique and continuity condition of the longitudinal field components, a standard matrix eigenvalue equation without the averaged index approximation approach for dealing with the discrete points neighboring the dielectric interfaces is obtained. Complex effective indexes and field distributions of leaky modes for a typical rib bending waveguide and a silicon wire bend are presented, and solutions accord well with those from the film mode matching method, which shows the validity and utility of the established method. PMID- 23037278 TI - Study of hybrid driven micromirrors for 3-D variable optical attenuator applications. AB - Aluminium-coated micromirrors driven by electrothermal and electromagnetic actuations have been demonstrated for 3-D variable optical attenuation applications. Three types of attenuation schemes based on electrothermal, electromagnetic and hybrid, i.e. combination of electrothermal and electromagnetic, actuations have been developed. In addition, two different designs have been fabricated and characterized to investigate the effects of the variations made to both the actuators on the optical attenuation performances of the micromirror. Our unique design of using both ET and EM actuators simultaneously to achieve attenuation is the first demonstration of such hybrid driven CMOS compatible MEMS VOA device. PMID- 23037279 TI - Generation and transmission of 85.4 Gb/s real-time 16QAM coherent optical OFDM signals over 400 km SSMF with preamble-less reception. AB - This paper presents a real-time, coherent optical OFDM transmitter based on a field programmable gate array implementation. The transmitter uses 16QAM mapping and runs at 28 GSa/s achieving a data rate of 85.4 Gb/s on a single polarization. A cyclic prefix of 25% of the symbol duration is added enabling dispersion tolerant transmission over up to 400 km of SSMF. This is the first transmission experiment performed with a real-time OFDM transmitter running at data rates higher than 40 Gb/s. A key aspect of the paper is the introduction of a novel method for OFDM symbol synchronization without relying on training symbols. Unlike conventional preamble-based synchronization methods which perform cross correlations at regular time intervals and let the system run freely in between, the proposed method performs synchronization in a continuous manner ensuring correct symbol alignment at all times. PMID- 23037280 TI - Study of optical Tamm states based on the phase properties of one-dimensional photonic crystals. AB - We demonstrate the physical mechanism of optical Tamm states using the phase properties of the photonic crystals. Based on such mechanism, we propose an efficient way that can precisely produce optical Tamm states at specific frequencies. Moreover, we show that dielectric photonic crystals and single negative materials can be effectively connected through their reflection phase. Two kinds of one-dimensional dielectric photonic crystals with different single negative characteristics are designed and repeated alternately to construct a superlattice structure. The band structures and the transmission spectra of this superlattice show that multiple optical Tamm states arise and these Tamm states are coupled with each other to form transmission bands. A special zero-effective phase gap can also be observed in such superlattice. PMID- 23037281 TI - High peak-power stretcher-free femtosecond fiber amplifier using passive spatio temporal coherent combining. AB - We report on the passive coherent combining of up to 8 temporally and spatially separated ultrashort pulses amplified in a stretcher-free ytterbium-doped fiber system. An initial femtosecond pulse is split into 4 temporal replicas using divided-pulse amplification, and subsequently divided in two counter-propagating beams in a Sagnac interferometer containing a fiber amplifier. The spatio temporal distribution of the peak-power inside the amplifier allows the generation of record 3.1 uJ and 50 fs pulses at 1 MHz of repetition rate with 52 MW of peak-power from a stretcher-free fiber amplifier and without additional nonlinear post-compression stages. PMID- 23037282 TI - Experimental observations of channel reciprocity in single-mode free-space optical links. AB - This article describes observations made during a recent series of single-mode lasercom experiments in which high-rate data transmission was demonstrated between a small aircraft and a ground station separated by distances up to 80 km. A significant result of the subsequent data analysis was the discovery of near unity correlations between the signal fluctuations observed by power monitors at the two ends of the link. This evidence of reciprocity is presented, along with the description of a preliminary concept for utilizing this channel state information to improve link performance. PMID- 23037283 TI - Real-time capture and reconstruction system with multiple GPUs for a 3D live scene by a generation from 4K IP images to 8K holograms. AB - We developed a real-time capture and reconstruction system for three-dimensional (3D) live scenes. In previous research, we used integral photography (IP) to capture 3D images and then generated holograms from the IP images to implement a real-time reconstruction system. In this paper, we use a 4K (3,840 * 2,160) camera to capture IP images and 8K (7,680 * 4,320) liquid crystal display (LCD) panels for the reconstruction of holograms. We investigate two methods for enlarging the 4K images that were captured by integral photography to 8K images. One of the methods increases the number of pixels of each elemental image. The other increases the number of elemental images. In addition, we developed a personal computer (PC) cluster system with graphics processing units (GPUs) for the enlargement of IP images and the generation of holograms from the IP images using fast Fourier transform (FFT). We used the Compute Unified Device Architecture (CUDA) as the development environment for the GPUs. The Fast Fourier transform is performed using the CUFFT (CUDA FFT) library. As a result, we developed an integrated system for performing all processing from the capture to the reconstruction of 3D images by using these components and successfully used this system to reconstruct a 3D live scene at 12 frames per second. PMID- 23037284 TI - Tunable luminescence Y3Al5O12:0.06Ce3+, xMn2+ phosphors with different charge compensators for warm white light emitting diodes. AB - Y3Al5O12:0.06Ce3+, xMn2+ (YAG:0.06Ce,xMn) phosphors have been synthesized and the effect of different charge compensators on the color adjustment has been investigated for the first time. The luminescence properties of Mn2+ singly doped and co-doped with Ce3+ into YAG host have been discussed. It is observed that in singly doped sample, Mn2+ ions not only occupy two kinds of Al3+ sites to generate a yellow and a deep red emission bands, but also occupy Y3+ sites to obtain a green emission band in YAG host. Considering Mn2+ substitution for Al3+, quadrivalence ions including Zr4+, Ge4+ and Si4+ ions are introduced to balance the charge difference. The results show that Si4+ as charge compensator exhibits the best tunable effect on controlling the Mn2+ emissions in YAG:0.06Ce, xMn. In Si4+-Mn2+ co-doped samples, the emission color can be tuned from greenish-yellow to red with increasing the content of Mn2+. The Commission International de L'Eclairage (CIE) chromaticity coordinates are also investigated. PMID- 23037285 TI - Angle determination and scattering suppression in polarization-enhanced two dimensional infrared spectroscopy in the pump-probe geometry. AB - The signal to noise in two-dimensional spectra recorded in the pump-probe geometry can be significantly improved with a quasi-crossed polarizer configuration, often employed in linear dichroism measurements. Here we examine this method in detail and demonstrate how to analyse and interpret the amplified signals. The angle between transition dipole moments can be determined with better accuracy than in conventional anisotropy measurements, and the method can be used to selectively suppress individual peaks and to efficiently remove scattering contributions. We present spectra of the coupled CO-stretch modes of a Ruthenium-carbonyl complex in DMSO for experimental illustration. PMID- 23037286 TI - Profile estimation for Pt submicron wire on rough Si substrate from experimental data. AB - An efficient forward scattering model is constructed for penetrable 2D submicron particles on rough substrates. The scattering and the particle-surface interaction are modeled using discrete sources with complex images. The substrate micro-roughness is described by a heuristic surface transfer function. The forward model is applied in the numerical estimation of the profile of a platinum (Pt) submicron wire on rough silicon (Si) substrate, based on experimental Bidirectional Reflectance Distribution Function (BRDF) data. PMID- 23037287 TI - Hardy's nonlocality proof using twisted photons. AB - Hardy's nonlocality proof is considered as "the best version of Bell's theorem". We report an experimental implementation of this by measuring the orbital angular momentum (OAM) of entangled twisted photon pairs. Two advantages arise from using twisted photons. First, the limited OAM spectrum generated by parametric down conversion provides a natural set of OAM non-maximally entangled states with selective degrees of entanglement. Second, the measurement of any non-trivial superposition of OAM states can be conveniently done with spatial light modulators. We measure states that are defined on asymmetric OAM Bloch spheres and show results which are incompatible with local realism. PMID- 23037288 TI - Tapered optical fiber sensor based on localized surface plasmon resonance. AB - A tapered fiber localized surface plasmon resonance (LSPR) sensor is demonstrated for refractive index sensing and label-free biochemical detection. The sensing strategy relies on the interrogation of the transmission intensity change due to the evanescent field absorption of immobilized gold nanoparticles on the tapered fiber surface. The refractive index resolution based on the interrogation of transmission intensity change is calculated to be 3.2*10-5 RIU. The feasibility of DNP-functionalized tapered fiber LSPR sensor in monitoring anti-DNP antibody with different concentrations spiked in buffer is examined. Results suggest that the compact sensor can perform qualitative and quantitative biochemical detection in real-time and thus has potential to be used in biomolecular sensing applications. PMID- 23037289 TI - Comparative study of total absorption of light by two-dimensional channel and hole array gratings. AB - A detailed study of light absorption by silver gratings having two-dimensional periodicity is presented for structures constructed either of channels or of holes with subwavelength dimensions. Rigorous numerical modelling shows a systematic difference between the two structures: hole (cavity) gratings can strongly absorb light provided the cavity is sufficiently deep, when compared to the wavelength, whereas very thin channel gratings can induce total absorption. A detailed analysis is given in the limit when the period tends towards zero, and an explanation of the differences in behavior is presented using the properties of effective optical index of the metamaterial layer that substitutes the periodical structure in the limit when the period tend to zero. PMID- 23037290 TI - Generation of arbitrary spatially variant polarization beams with a trapezoid Sagnac interferometer. AB - We present a flexible approach to generate arbitrary vector beams with a trapezoid Sagnac interferometer. With the interferometer, the different orders of two orthogonally polarized beams from computer-generated holograms coincide with each other in Fourier spectrum domain, and coaxially combine into the vector beams. This approach provides convenient way to experimentally study the properties of vector beams with complex polarization. PMID- 23037291 TI - Ultralow-loss polycrystalline silicon waveguides and high uniformity 1x12 MMI fanout for 3D photonic integration. AB - We have investigated the feasibility of multimode polysilicon waveguides to demonstrate the suitability of polysilicon as a candidate for multilayer photonic applications. Solid Phase Crystallization (SPC) with a maximum temperature of 1000 degrees C is used to create polysilicon on thermally grown SiO2. We then measure the propagation losses for various waveguide widths on both polysilicon and crystalline silicon platforms. We find that as the width increases for polysilicon waveguides, the propagation loss decreases similar to crystalline silicon waveguides. At a waveguide width of 10 um, polysilicon and crystalline silicon waveguides have propagation losses of 0.56 dB/cm and 0.31 dB/cm, respectively, indicating there is little bulk absorption from the polysilicon and is the lowest propagation loss for polysilicon demonstrated to date. In addition, the first 1x12 polysilicon MMI is demonstrated with a low insertion loss of -1.29dB and a high uniformity of 1.07 dB. These results vindicate the use of polysilicon waveguides of varying widths in photonic integrated circuits. PMID- 23037292 TI - Fiber-optic waveguide coupled surface plasmon resonance sensor. AB - A novel approach to give an excellent tunability and self-referencing capability was presented by applying a concept of waveguide coupled surface plasmon resonance mode to a fiber-optic sensor. The presence of dielectric waveguide sandwiched between two metal layers made it possible to precisely tune the resonance wavelength in a broad range from visible to infrared region and to generate multiple modes which may be selectively used for suitable applications. Our approach also verified the potential capability of self-referencing based on a remarkable difference in sensitivity between the plasmonic and waveguide modes excited by p- and s-polarized lights, respectively, without using an additional reference channel. Experimental measurement carried out on sucrose solutions with varying concentration demonstrated the feasibility of our approach. PMID- 23037293 TI - Output characteristics of high power cryogenic Yb:YAG TRAM laser oscillator. AB - We analyzed the output power characteristics of a cryogenically cooled Yb:YAG total-reflection active-mirror (TRAM) laser oscillator including the temperature dependence of the emission cross section and the reabsorption loss of the Yb:YAG TRAM. A CW multi-transverse mode oscillation of a 9.8 at.% doped 0.6 mm thick Yb:YAG ceramic TRAM was investigated for various pump spot sizes and compared with theoretical results. The Yb:YAG temperatures were inferred from the ratio between fluorescence intensities at 1022 nm and 1027 nm which varied significantly with temperature below 200 K. Output power calculations using evaluated temperatures were in good agreement with the experimental data measured between 77 and 200 K, and the output power suppression due to the temperature rise observed above ~140 K. To the best of our knowledge, this is the first evaluation of output power for a cryogenically cooled Yb:YAG TRAM laser. PMID- 23037294 TI - Intermodal coupling of supermodes in a twin-core photonic crystal fiber and its application as a pressure sensor. AB - In this paper, we experimentally demonstrated the fabrication and hydrostatic pressure characteristics of a twin-core photonic crystal fiber (TC-PCF). Mode couplings in the TC-PCF for x- and y-polarizations were analyzed simultaneously using group effective index of guiding modes. The output spectrum of the TC-PCF was modulated due to the combined couplings of the two polarizations. To the best of our knowledge, it is the first time to measure hydrostatic pressure through the dual-polarization mode coupling in a TC-PCF. The measured sensitivity of the pressure sensor was -21 pm/MPa. The length of the TC-PCF used for pressure measurement was 20 cm, which is much shorter than pressure sensor based on PM PCF, and does not require any external polarizing components, meaning that it is a good candidate for compact pressure sensor. PMID- 23037295 TI - Widely tunable, efficient on-chip single photon sources at telecommunication wavelengths. AB - We demonstrate tunable on-chip single photon sources using the Stark tuning of single quantum dot (QD) excitonic transitions in short photonic crystal waveguides (PhC WGs). The emission of single QDs can be tuned in real-time by 9 nm with an applied bias voltage less than 2V. Due to a reshaped density of optical modes in the PhC WG, a large coupling efficiency beta >= 65%to the waveguide mode is maintained across a wavelength range of 5 nm. When the QD is resonant with the Fabry-Perot mode of the PhC WG, a strong enhancement of spontaneous emission is observed leading to a maximum coupling efficiency beta = 88%. These results represent an important step towards the scalable integration of single photon sources in quantum photonic integrated circuits. PMID- 23037296 TI - A mode-matching analysis of dielectric-filled resonant cavities coupled to terahertz parallel-plate waveguides. AB - We use the mode-matching technique to study parallel-plate waveguide resonant cavities that are filled with a dielectric. We apply the generalized scattering matrix theory to calculate the power transmission through the waveguide-cavities. We compare the analytical results to experimental data to confirm the validity of this approach. PMID- 23037297 TI - Effects of non-lasing band in two-dimensional photonic-crystal lasers clarified using omnidirectional band structure. AB - We investigated the effects of non-lasing bands on the beam patterns in photonic crystal lasers by evaluating the omnidirectional band structure both experimentally and theoretically. We found that a new, weak dual-streak pattern is occasionally generated around the main lobe of the output beam because of scattering of the lasing beam in the non-lasing bands despite a wavenumber mismatch. This result indicates that we can design the high-quality devices without such a noise pattern. In addition, this evaluation method is expected to be useful for developing various high-functionality PC lasers. PMID- 23037298 TI - Lineshapes in two-color polarization spectroscopy for cesium. AB - We present a theoretical study of lineshape in polarization spectroscopy for the 6S1/2-6P3/2-7S1/2 transition line in cesium atoms. A circularly polarized pump beam is tuned either to the lower or the upper transition line, while a linearly polarized probe beam is tuned to the other transition line. The polarization rotation of the probe beam is accurately calculated using a semi-classical density-matrix formalism taking into account all relaxation processes. PMID- 23037299 TI - Hotspot-aware fast source and mask optimization. AB - Source mask optimization (SMO) is a useful technique for printing the integrated circuit (IC) on a wafer with increasingly smaller feature size. However, complex SMO algorithms generally lead to undesirably long runtime resulting from an optimization of largely identical regions over the whole mask pattern. In this work, a weighted SMO scheme incorporating both an awareness of the hotspots and robustness against process variations is proposed. We show how optimal solutions are reached with fewer iterations by applying various degrees of correction in the corresponding regions. The proposed method includes identifying the hotspots and combining a weight matrix to the cost function for adjustment and control. Simulation results are compared with the mask optimization (under a fixed source) and conventional SMO to illustrate the performance improvement in terms of pattern fidelity, convergence rate and process window size. PMID- 23037300 TI - Scanned light sheet microscopy with confocal slit detection. AB - In light sheet fluorescence microscopy optical sectioning is achieved by illuminating the sample orthogonally to the detection pathway with a thin, focused sheet of light. However, light scattering within the sample often deteriorates the optical sectioning effect. Here, we demonstrate that contrast and degree of confocality can greatly be increased by combining scanned light sheet fluorescence excitation and confocal slit detection. A high frame rate was achieved by using the "rolling shutter" of a scientific CMOS camera as a slit detector. Synchronizing the "rolling shutter" with the scanned illumination beam results in confocal line detection. Acquiring image data with selective plane illumination minimizes photo-damage while simultaneously enhancing contrast, optical sectioning and signal-to-noise ratio. Thus the imaging principle presented here merges the benefits of scanned light sheet microscopy and line scanning confocal imaging. PMID- 23037301 TI - Thin film MoS2 nanocrystal based ultraviolet photodetector. AB - We report on the development of UV range photodetector based on molybdenum disulfide nanocrystals (MoS2-NCs). The inorganic MoS2-NCs are produced by pulsed laser ablation technique in deionized water and the colloidal MoS2-NCs are characterized by transmission electron microscopy, Raman spectroscopy, X-ray diffraction and UV/VIS absorption measurements. The photoresponse studies indicate that the fabricated MoS2-NCs photodetector (MoS2-NCs PD) operates well within 300-400 nm UV range, with diminishing response at visible wavelengths, due to the MoS2-NCs absorption characteristics. The structural and the optical properties of laser generated MoS2-NCs suggest promising applications in the field of photonics and optoelectronics. PMID- 23037302 TI - Quantification of collagen fiber organization using three-dimensional Fourier transform-second-harmonic generation imaging. AB - We present three-dimensional Fourier transform-second-harmonic generation (3D FT SHG) imaging, a generalization of the previously reported two-dimensional FT-SHG, to quantify collagen fiber organization from 3D image stacks of biological tissues. The current implementation calculates 3D preferred orientation of a region of interest, and classifies regions of interest based on orientation anisotropy and average voxel intensity. Presented are some example applications of the technique which reveal the layered structure of collagen fibers in porcine sclera, and estimates the cut angle of porcine tendon tissues. This technique shows promising potential for studying biological tissues that contain fibrillar structures in 3D. PMID- 23037304 TI - Probabilistic assessment of fatigue initiation data on highly crosslinked ultrahigh molecular weight polyethylenes. AB - Ultrahigh molecular weight polyethylenes (UHMWPE) showing wear resistance, oxidative stability and good mechanical performance go on being a relevant research area in biomaterials for total joint replacements, where fatigue happens to be a recurrent damage mode that needs to be investigated. While crack propagation lifetime has been extensively studied, fatigue initiation data are scarcely offered in the literature, often due to the higher costs implied in the experimental programs. Moreover, their analysis is not always suitable to obtain reliable guidance. Different deterministic and probabilistic methods, generally resting on empirical bases have been previously used to analyze the fatigue initiation data. In this work, the probabilistic Weibull regression model of Castillo et al., based on both physical and statistical conditions, such as weakest link principle and the necessary compatibility between life-time and stress range distributions, is applied for the first time in the assessment of fatigue results of polymers, particularly to highly crosslinked UHMWPEs (HXLPEs). Accordingly, different published experimental data corresponding to HXLPE stabilized by thermal treatments and with alpha-tocopherol (vitamin E) are re analyzed. Additional data are incorporated to assess the influence of notched HXLPE on fatigue performance. New conclusions are drawn from this revision. PMID- 23037303 TI - Molecular detection of nontuberculous mycobacteria: advantages and limits of a broad-range sequencing approach. AB - The isolation of nontuberculous mycobacteria (NTM) from clinical specimens has become very common in recent years. Such organisms are typically environmental and occasionally pathogenic for humans and animals. Standard diagnosis of mycobacterial infections relies on direct examination and culture. However, molecular tools are now available which allow quicker and more accurate diagnosis. Detection of NTM can be performed directly from clinical samples, although identification is mostly carried out after isolation. Sequencing of genomic targets (such as 16S rRNA, ITS, rpoB or hsp65) allows accurate and rapid identification, but has some technical limitations. A brief summary of the molecular methods available for NTM identification and a discussion of the problems associated with the use of sequencing analysis together with a description of available algorithms for NTM identification are the major objectives of this review. PMID- 23037305 TI - Development of allocentric spatial memory abilities in children from 18 months to 5 years of age. AB - Episodic memories for autobiographical events that happen in unique spatiotemporal contexts are central to defining who we are. Yet, before 2 years of age, children are unable to form or store episodic memories for recall later in life, a phenomenon known as infantile amnesia. Here, we studied the development of allocentric spatial memory, a fundamental component of episodic memory, in two versions of a real-world memory task requiring 18 month- to 5-year old children to search for rewards hidden beneath cups distributed in an open field arena. Whereas children 25-42-months-old were not capable of discriminating three reward locations among 18 possible locations in absence of local cues marking these locations, children older than 43 months found the reward locations reliably. These results support previous findings suggesting that allocentric spatial memory, if present, is only rudimentary in children under 3.5 years of age. However, when tested with only one reward location among four possible locations, children 25-39-months-old found the reward reliably in absence of local cues, whereas 18-23-month-olds did not. Our findings thus show that the ability to form a basic allocentric representation of the environment is present by 2 years of age, and its emergence coincides temporally with the offset of infantile amnesia. However, the ability of children to distinguish and remember closely related spatial locations improves from 2 to 3.5 years of age, a developmental period marked by persistent deficits in long-term episodic memory known as childhood amnesia. These findings support the hypothesis that the differential maturation of distinct hippocampal circuits contributes to the emergence of specific memory processes during early childhood. PMID- 23037306 TI - Antitumor, antibiotic and antileishmanial properties of the Pyranonaphthoquinone Psychorubrin from Mitracarpus frigidus. AB - The bioactivity guided fractionation of the dichloromethane extract of Mitracarpus frigidus afforded the pyranonaphthoquinone psychorubrin. This compound, hitherto unknown in the genus Mitracarpus, had its biological activity evaluated against one panel of bacteria and two fungi, three tumor cell lines (HL60, Jurkat and MCF-7) and four Leishmania species. Its identity was confirmed unambiguously by (1)H, (13)C, (1)H-COSY, IR and UV-Vis spectroscopy and mass spectrometry. Psychorubrin displayed a very promising antitumor with IC(50) of 4.5, 5.6 and 1.1 uM for HL60, Jurkat and MCF-7 cell lines, respectively. Antimicrobial activity, mainly against Cryptococcus neoformans (MIC of 87.3 uM) was observed. A pronounced antileishmanial potential was also verified with IC(50) varying from 1.7 to 2.7 uM for the Leishmania species tested. This is the first report of the presence of pyranonapthoquinones in the Mitracarpus genus, which may serve as a chemotaxonomical marker. PMID- 23037307 TI - Study of the Cu, Mn, Pb and Zn dynamics in soil, plants and bee pollen from the region of Teresina (PI), Brazil. AB - The purpose of this study is to characterize native bee plants regarding their capacity to extract and accumulate trace elements from the soil and its consequences to the sanity of the produced pollen. The trace elements Cu, Mn, Pb and Zn were analyzed in soil, plants and bee pollen from Teresina region (PI), Brazil, by flame atomic absorption spectrophotometer. Considering the studied plant species, Cu and Pb metals presented in the highest levels in the roots of B. platypetala with 47.35 and 32.71 MUg.mL(-1) and H. suaveolens with 39.69 and 17.06 MUg.mL(-1), respectively, while in the aerial parts Mn and Zn metals presented the highest levels in S. verticillata with 199.18 and 85.73 MUg.mL(-1). In the pollen, the levels of Cu, Mn, Pb and Zn vary from 5.44 to 11.75 MUg.mL( 1); 34.31 to 85.75 MUg.mL(-1); 13.98 to 18.19 MUg.mL(-1) and 50.19 to 90.35 MUg.mL(-1), respectively. These results indicate that in the apicultural pasture the translocation (from soil to pollen) of Mn and Zn was more effective than in case of Cu and Pb, therefore, the bee pollen can be used as food supplement without causing risks to human health. PMID- 23037308 TI - Using multiplex single-base extension typing to screen for mutants defective in RNA editing. AB - RNA editing is an RNA maturation process that changes the nucleotide present at particular positions (editing sites) in specific RNAs; in plant organelles, the most common nucleotide change is from cytidine (C) to uridine (U). In a mutant suspected of affecting RNA editing, all known editing sites have to be analyzed. Therefore, to screen a population of mutants, all individuals must be analyzed at every editing site. We describe a multiplex single-nucleotide polymorphism (SNP) typing procedure to economically screen a mutant individual or population for differences at hundreds of nucleotide positions in RNA or DNA. By using this protocol, we have previously identified mutants defective in RNA editing in a randomly mutated population of Arabidopsis thaliana. The procedure requires 2-3 weeks to identify the individual plant in the mutant population. The time required to locate the mutated gene is between 3 and 24 months in Arabidopsis. Although this procedure has been developed to study RNA editing in plants, it could also be used to investigate other RNA modification processes. It could also be adapted to investigate RNA editing in other organisms. PMID- 23037309 TI - One-step (18)F-labeling of peptides for positron emission tomography imaging using the SiFA methodology. AB - Here we present a procedure to label peptides with the positron-emitting radioisotope fluorine-18 ((18)F) using the silicon-fluoride acceptor (SiFA) labeling methodology. Positron emission tomography (PET) has gained high importance in noninvasive imaging of various diseases over the past decades, and thus new specific imaging probes for PET imaging, especially those labeled with (18)F, because of the advantageous properties of this nuclide, are highly sought after. N-terminally SiFA-modified peptides can be labeled with (18)F(-) in one step at room temperature (20-25 degrees C) or below without forming side products, thereby producing satisfactory radiochemical yields of 46 +/- 1.5% (n = 10). The degree of chemoselectivity of the (18)F-introduction, which is based on simple isotopic exchange, allows for a facile cartridge-based purification fully devoid of HPLC implementation, thereby yielding peptides with specific activities between 44.4 and 62.9 GBq MUmol(-1) (1,200-1,700 Ci mmol(-1)) within 25 min. PMID- 23037310 TI - Synthesis of [(18)F]SiFB: a prosthetic group for direct protein radiolabeling for application in positron emission tomography. AB - N-Succinimidyl 3-(di-tert-butyl[(18)F]fluorosilyl)benzoate ([(18)F]SiFB) is a highly reactive prosthetic group for radiolabeling of proteins for use in positron emission tomography (PET). It is similar to N-succinimidyl-4 [(18)F]fluorobenzoate ([(18)F]SFB), the 'gold-standard' prosthetic group for protein (18)F-labeling, but can be synthesized using a much shorter and technically easier procedure. A recently reported simple procedure to obtain anhydrous (18)F- by avoiding time-consuming azeotropic drying is applied with a slight modification to prevent basic hydrolysis of the active N hydroxysuccinimide (NHS) ester moiety of [(18)F]SiFB. The labeling of [(18)F]SiFB is performed by a fast (18)F-(19)F isotopic exchange (IE) reaction at room temperature (20-25 degrees C) within 30 min. [(18)F]SiFB is purified using a C18 cartridge instead of HPLC, further decreasing the overall time required for protein labeling. High specific activities > 18.5 GBq MUmol(-1) (> 500 Ci mmol( 1)) can be obtained. Finally, incubation of [(18)F]SiFB with the desired protein in an aqueous solution at pH 9, followed by HPLC purification, provides the final solution of the labeled protein ready for in vivo applications. PMID- 23037311 TI - Protein labeling with the labeling precursor [(18)F]SiFA-SH for positron emission tomography. AB - Proteins previously derivatized with the cross-coupling reagent sulfo-SMCC (4-(N maleimidomethyl)cyclohexane-1-carboxylic acid 3-sulfo-N-hydroxy-succinimide ester sodium salt) can be easily labeled in high radiochemical yields with the silicon fluoride acceptor (SiFA) reagent [(18)F]SiFA-SH, obtained via isotopic exchange, by thiol-maleimide coupling chemistry (n = 10). The specific activity of SiFA-SH obtained in a one-step labeling reaction was > 18.5 GBq MUmol(-1) (> 500 Ci mmol( 1)). The number of SiFA building blocks per protein molecule is defined by the previously introduced number of maleimide groups, which can be determined by a simple and convenient Ellman's assay. Not more than two maleimide groups are introduced using sulfo-SMCC, thereby keeping the modification of the protein low and preserving its biological activity. PMID- 23037312 TI - Complete testis-epididymis nonfusion anomaly: a typical association with cryptorchid testis. AB - INTRODUCTION: Fusion anomalies of the testis and epididymis are associated with cryptorchidism. We present an analysis of the fusion anomalies of the epididymis in cryptorchid boys. PATIENTS AND METHODS: We performed a retrospective review of patients presenting with undescended testes between 1986 and 1993. Patients were stratified among four groups based on the degree of testis-epididymis nonfusion. RESULTS: A total of 880 testes were eligible for review, of which 93% (815/880) had normal fusion, 3.6% (32/880) had epididymal head nonfusion, 2% (19/880) had epididymal tail nonfusion, and 1.6% (14/880) had complete nonfusion. Increasing degree of nonfusion was associated with higher perioperative testes position. Head and tail nonfusion were observed together with a contralateral descended testis, but less frequently than in bilateral undescended testes (p = 3.89 * E 10). Complete nonfusion was not observed in the contralateral descended testes in unilateral cryptorchid boys. CONCLUSIONS: Different degrees of fusion anomalies of the epididymis are associated with unilateral and bilateral undescended testis, indicating that nonfusion anomalies interact with epididymal-testicular descent because of impaired epididymal function. PMID- 23037313 TI - The value of balance-assessment measurements in identifying and monitoring acute postural instability among concussed athletes. AB - CLINICAL SCENARIO: Sport-related concussions are a significant health issue due to the high incidence of concussions sustained each sports season. Current approaches to the evaluation of acutely concussed athletes include the use of balance assessments to identify and monitor underlying postural instability arising from concussion. Balance assessment has been recommended as a primary measurement tool for monitoring recovery and for making return-to-play decisions. Balance impairments have been shown to occur in the initial postconcussion period (ie, 1-10 d). Numerous clinical and laboratory measures have been used in the assessment of balance immediately after concussion, and clinicians are faced with deciding which measures to use. FOCUSED CLINICAL QUESTION: How do clinical or field-based balance-assessment tools compare to laboratory-based balance measures in identifying deficits in postural stability among acutely concussed athletes? PMID- 23037314 TI - Pituitary surgery: experience from a large network in Central Switzerland. AB - PRINCIPLES: During the past years our group built a care network for patients with pituitary tumours with referrals from the midlands and the central part of Switzerland, comprising about 1.6 million inhabitants. The purpose of this retrospective observational study with longitudinal data is to review the experience of pituitary surgery and the operative outcome within this Swiss-wide largest network. METHODS: A total of 182 patients operated at the Neurosurgical Department of the Kantonsspital Aarau 2005-2010 were included in this study. The follow-up was 3.6+/-1.6 years. RESULTS: The following lesions were found: non functioning adenoma (n = 114; 63%); macroprolactinoma (n = 18; 10%); microprolactinoma (n = 11; 6%); acromegaly (n = 11; 6%), Cushing's disease (n = 7; 4%); Rathke's cleft cyst (RCC; n = 9; 5%); others (n = 12; 7%). Intraoperative MRI (iMRI) was used in 115 (63%) patients. Preoperatively, hypopituitarism was found in 105 (58%) patients. Postoperative recovery of defunct axes was detected in 48%. Visual field and visual acuity deficits due to optic pathway compression by tumour were detected in 48% and 41% of the patients, respectively. Postoperative recovery of visual function was seen in 89%. The increase of total resection rate by iMRI was statistically significant (p = 0.0007). Recurrent tumour growth was seen in 5 (3%) patients during follow-up. CONCLUSIONS: Transsphenoidal surgery is the primary treatment for most sellar lesions. The use of iMRI may lead to higher gross total resection rates. In Switzerland close cooperation between specialised centres is a very positive experience both to support operative case loads and to optimise patient follow-up. PMID- 23037315 TI - A critical review of classification of organisations in relation to the voluntary implementation of environmental management systems. AB - The need and ability of an organisation to manage and control its impact on the environment has been hotly debated in recent times. However, the uptake of certificated environmental management systems (EMS), specifically BS EN ISO 14001 (ISO 14001) (British Standards Institution, 2004), is becoming more prevalent, even though evidence of the individual benefits is less clear. Furthermore, reports are often limited and anecdotal in their discussion of the true barriers that organisations experience during the certification and management of their EMS. Presently organisations are commonly classified simply according to size and the barriers they experience when implementing an EMS successfully. This system of classification is not sufficient to understand the multifaceted environments within which modern organisations operate. This paper reviews existing classification methodologies relevant to environmental management so as to determine whether opportunities exist for their practical application in this sector. It begins with an introduction to EMS and existing discussions regarding implementation is provided before a more detailed consideration of organisational size, the integration and development of environmental management within an organisation, then cladistics and quality management systems (QMS) are reviewed as potential opportunities for classification. This shows that whilst numerous methods are available, none function beyond the theoretical, or that the classes provided restrain the description of the complex tasks. Central to differences faced by organisations are insights to the true hurdles that each experience when implementing an EMS. It is shown here how the manipulation of techniques from the more mature field of Energy Management may offer a direction for the development of robust classes. A valuable outcome is that these methods produce classifications that are fit for purpose to better support organisations through the implementation and management of their EMS. PMID- 23037316 TI - A sustainable approach to controlling oil spills. AB - As a result of the huge economic and environmental destruction from oil spills, studies have been directed at improving and deploying natural sorbents which are not only the least expensive but also the safest means of spill control. This research reviews the limitations and environmental impact of existing cleanup methods. It also justifies the need for concerted research effort on oil spill control using natural and sustainable technology concepts. The article proposes future guidelines for the development of a sustainable cleanup technology. Finally, guidelines for the development of a new technology for the Middle East are proposed, which is the use of an abundant resource--date palm fibers--for such techniques. PMID- 23037317 TI - Thermal stimulation of primary sensory neurons in the rat hind paw: effect of morphine on ERK1/2 phosphorylation, TRPV1 and TRPA1 channel expression. AB - Temperature-sensitive transient receptor potential (TRP) channels or 'thermo-TRP' were stimulated on rat sensory afferents, and the effects on the phosphorylation of ERK1/2, on the regulation of TRPV1 and TRPA1, as well as the pharmacological modulation by the opioid analgesic morphine were investigated. The thermal stimuli were applied to the rat hind paw by immersion into either hot or cold water. Phospho-ERK1/2 (p-ERK1/2) was measured by fluorescence immunohistochemistry in the lumbar dorsal root ganglion (DRG) neurons. TRP channel mRNA expression was measured by RT-PCR in the innervating DRGs, and the protein content of TRPV1 and TRPA1 was determined by Western blot in the DRGs and in the sciatic nerve. The thermal stimuli led to a time-dependent increase in the number of DRG cells displaying cytoplasmic and nuclear staining for p-ERK1/2. Morphine partly prevented this increase in ERK1/2 phosphorylation, exerting its effect mainly on the nuclear staining. The mRNA expression for TRPV1 and TRPA1 in the DRG did not change within 24 h following the thermal stimuli. However, the protein content of both TRPV1 and TRPA1 was regulated by the thermal stimulation and by morphine. In the DRGs and in the sciatic nerve, heat or cold stimuli per se tended to decrease TRP protein levels, whereas with morphine pretreatment protein levels were raised. The present findings shed new light on the time dependent reactions of primary sensory neurons towards irritant thermal stimuli to the skin and on their opioid modulation. PMID- 23037318 TI - Liver function tests in patients with acute heart failure. AB - INTRODUCTION: Acute heart failure (AHF) is associated with multiorgan dysfunction, which may unfavorably affect prognosis. OBJECTIVES: We investigated the prevalence, clinical determinants, and prognostic consequences of abnormal liver function tests (LFTs) in population with AHF. PATIENTS AND METHODS: We conducted a retrospective analysis of patients with AHF, in whom the following LFTs were performed on admission: serum bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), and albumin. Abnormal LFTs were defined as the elevation above the upper normal limit of bilirubin, AST, and ALT, or reduction below the lower normal limit of albumin. RESULTS: The study involved 189 patients (age, 68 +/-11 years; men, 68%; de novo AHF, 25%). On admission, abnormal LFTs were observed in 46% of the patients for AST, 31% for ALT, 33% for bilirubin, and 44% for albumin. Only 29% of the patients had all LFTs within the normal ranges. The following variables were independently related to abnormal LFTs: high hemoglobin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels for AST; high hemoglobin, bilirubin, and NT-proBNP levels for ALT; high hemoglobin, low sodium levels, and dilated right ventricle for bilirubin; and high NT-proBNP levels for albumin (all P <0.05). In 21 patients, hemodynamic monitoring was performed, which revealed that among LFTs only elevated bilirubin independently correlated with higher right atrial pressure (P <0.005). In a univariate Cox model, among LFTs, low albumin and markedly elevated AST and ALT (>3 times above the upper normal limit) were associated with increased mortality during 180-day follow-up. CONCLUSIONS: Abnormal LFTs are common in patients with AHF and may have prognostic relevance. Among them, only elevated bilirubin was correlated with impaired hemodynamic parameters. PMID- 23037319 TI - Theoretical illumination of water-inserted structures of the CaMn4O5 cluster in the S2 and S3 states of oxygen-evolving complex of photosystem II: full geometry optimizations by B3LYP hybrid density functional. AB - Full geometry optimizations of several inorganic model clusters, CaMn(4)O(4)XYZ(H(2)O)(2) (X, Y, Z = H(2)O, OH(-) or O(2-)), by the use of the B3LYP hybrid density functional theory (DFT) have been performed to illuminate plausible molecular structures of the catalytic site for water oxidation in the S(0), S(1), S(2) and S(3) states of the Kok cycle for the oxygen-evolving complex (OEC) of photosystem II (PSII). Optimized geometries obtained by the energy gradient method have revealed the degree of symmetry breaking of the unstable three-center Mn(a)-X-Mn(d) bond in CaMn(4)O(4)XYZ(H(2)O)(2). The right-elongated (R) Mn(a)-X...Mn(d) and left-elongated (L) Mn(a)...X-Mn(d) structures appear to occupy local minima on a double-well potential for several key intermediates in these states. The effects of insertion of one extra water molecule to the vacant coordination site, Mn(d) (Mn(a)), for R (L) structures have also been examined in detail. The greater stability of the L-type structure over the R-type has been concluded for key intermediates in the S(2) and S(3) states. Implications of the present DFT structures are discussed in relation to previous DFT and related results, together with recent X-ray diffraction results for model compounds of cubane-like OEC cluster of PSII. PMID- 23037320 TI - Effectiveness of low-dose prolonged infusion of tissue plasminogen activator in a nonagenarian patient with acute pulmonary embolism and main pulmonary artery thrombus. AB - Acute pulmonary embolism is an important emergency disease which frequently results in life-threatening complication. Systemic fibrinolysis is recommended as standard, first-line therapy in patients with massive pulmonary embolism. In the case described in this report, a 95-year-old woman was treated with low-dose prolonged infusion of tissue plasminogen activator for acute pulmonary embolism and mobile thrombus in the main pulmonary artery and right pulmonary artery. On the basis of echocardiographic findings, acute thrombolysis with low-dose prolonged infusion of tissue plasminogen activator was performed resulting in hemodynamic stabilization of the patient and complete resolution of the pulmonary artery thrombus. PMID- 23037321 TI - Occurrence of thrombosis in congenital thrombocytopenic disorders: a critical annotation of the literature. AB - Patients with a low platelet count are prone to bleeding. The occurrence of a thrombotic event in congenital thrombocytopenic patients is rare and puzzling. At least nine patients with Glanzmann thrombasthenia have been reported to have had a thrombotic event, eight venous and one arterial (intracardiac, in the left ventricle). On the contrary, three patients with Bernard-Soulier syndrome have been shown to have had arterial thrombosis (myocardial infarction) but no venous thrombosis. Finally, seven patients with the familiar macrothrombocytopenia due to alterations of the MYH9 gene have been reported to have had thrombosis (five myocardial infractions, one ischemic stroke, one deep vein thrombosis and one portal vein thrombosis). The significance of these findings is discussed with particular emphasis on the discrepancy between venous and arterial thrombosis seen in patients with Glanzmann thrombasthenia and Bernard-Soulier syndrome. PMID- 23037322 TI - High-density cholesterol and apolipoprotein AI as modifiers of plasma fibrin clot properties in apparently healthy individuals. AB - Low high-density lipoprotein cholesterol (HDL-C) increases cardiovascular risk, whereas its high levels protect against atherosclerosis via multiple beneficial effects. Dense and poorly lysable fibrin clot formation is observed in cardiovascular disease. We sought to investigate whether HDL-C and its major component apolipoprotein A (Apo A)-I affect fibrin clot properties. In 136 apparently healthy individuals (99 men, 37 women, aged 49-69 years) we determined plasma fibrin clot permeability (Ks coefficient) and lysis time (t50%) together with Apo A-I and lipoprotein (a) [Lp(a)] levels. The median HDL-C level was 1.33 mmol/l (range from 0.77 to 2.19 mmol/l). HDL-C was positively associated with Apo A-I (r = 0.62, P < 0.00001). HDL-C and Apo A-I were positively correlated with Ks (r = 0.52, P < 0.00001 and r = 0.44, P < 0.00001, respectively) and inversely with t50% (r = -0.44, P < 0.00001 and r = -0.35, P = 0.00003, respectively). No such associations were seen for other lipid variables. Ks and t50% were associated with Lp(a) (r = -0.42, P < 0.00001 and r = 0.42, P < 0.00001, respectively) and fibrinogen (r = -0.31, P = 0.00024 and r = 0.39, P < 0.00001, respectively). Individuals with HDL-C at least 1.4 mmol/l (n = 54) had 19% higher Ks (P = 0.00016) and 17% shorter t50% (P = 0.0012) than the remainder. After adjustment for age, fibrinogen, and Lp(a), HDL-C was the independent predictor of Ks (beta = 0.7, P < 0.00001) and t50% (beta = -0.62, P < 0.00001). This study shows that elevated HDL-C levels are associated with improved fibrin clot permeability and lysis, indicating a novel antithrombotic mechanism underlying the postulated beneficial effects of therapy targeted at HDL-C. PMID- 23037323 TI - Rho-kinase pathway. PMID- 23037324 TI - Multifaceted approach to analyzing the pathogenesis of cardiovascular disease. AB - Heart failure is a common clinical feature of advanced cardiovascular disease that carries a high mortality risk. This review focuses on my journey seeking to understand the pathogenesis of heart failure and on how to translate experimental findings into the clinic. PMID- 23037325 TI - Relationship between effective arterial elastance, total vascular resistance, and augmentation index at the ascending aorta and left ventricular diastolic function in older women. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is frequently observed in older women. Increased arterial stiffness in this population may be a cause of HFpEF. METHODS AND RESULTS: In 75 patients who underwent cardiac catheterization and who had no significant coronary artery stenosis or left ventricular (LV) wall motion abnormalities, the LV relaxation time constant (Tp) was calculated. The LVEF was obtained from left ventriculography, and plasma brain natriuretic peptide (BNP) level was measured. From the pressure waveforms at the ascending aorta, the augmentation index (AIx) was calculated. Effective arterial elastance (Ea) and total vascular resistance (TVR) were also determined. No significant differences were found between genders for age, heart rate, central blood pressure, or LVEF. Ea, TVR, AIx, and BNP level were significantly greater in women than in men, but only AIx was significantly correlated with Tp (r=0.25, P=0.04) and BNP level (r=0.33, P=0.005). CONCLUSIONS: The arterial system is stiffer in women than in men of the same age. Among the parameters of arterial stiffness, only AIx is related to abnormal LV relaxation and increased BNP level. Elevated AIx is a factor that causes LV diastolic dysfunction and may be associated with the development of HFpEF in this gender. PMID- 23037326 TI - Bevacizumab diminishes experimental autoimmune encephalomyelitis by inhibiting spinal cord angiogenesis and reducing peripheral T-cell responses. AB - Angiogenesis in the animal model of multiple sclerosis experimental autoimmune encephalomyelitis (EAE) is regulated by vascular endothelial growth factor (VEGF) and angiopoietin-2. We determined whether VEGF blockade with the anti-VEGF monoclonal antibody bevacizumab could inhibit angiogenesis and affect peripheral pathogenic immune responses in EAE. Mice treated with bevacizumab from the time of onset of clinical signs showed reduced clinical and pathologic scores. Bevacizumab suppressed angiogenesis and reduced angiopoietin-2 expression at Day 21 but had no effect on VEGF upregulation at Day 14. Messenger RNA levels for the angiogenesis-related protein CD105 were increased at Day 14. Bevacizumab reduced vascular permeability in the spinal cord at Day 14 and Day 21. In peripheral lymph nodes, it induced retention of CD4-positive T cells and inhibited T-cell proliferation. It also reduced mononuclear cell infiltration into spinal cord and the relative proportion of T cells. Isolated lymphoid cells showed reduced secretion of the T-helper 17 (Th-17) cell cytokine interleukin 17 and the Th-1 cytokine interferon-gamma. When bevacizumab was added to naive T cells or to antigen-stimulated T cells from mice with untreated EAE in vitro, it had no effect on proliferation or the secretion of interleukin 17 or interferon-gamma. These data indicate that bevacizumab ameliorates vascular and T-cell responses during EAE, but its effects on T cells may be indirect, possibly by suppressing angiogenesis. PMID- 23037327 TI - Peripheral autonomic neuropathy: diagnostic contribution of skin biopsy. AB - Skin biopsy has gained widespread use for the diagnosis of somatic small-fiber neuropathy, but it also provides information on sympathetic fiber morphology. We aimed to ascertain the diagnostic accuracy of skin biopsy in disclosing sympathetic nerve abnormalities in patients with autonomic neuropathy. Peripheral nerve fiber autonomic involvement was confirmed by routine autonomic laboratory test abnormalities. Punch skin biopsies were taken from the thigh and lower leg of 28 patients with various types of autonomic neuropathy for quantitative evaluation of skin autonomic innervation. Results were compared with scores obtained from 32 age-matched healthy controls and 25 patients with somatic neuropathy. The autonomic cutoff score was calculated using the receiver operating characteristic curve analysis. Skin biopsy disclosed a significant autonomic innervation decrease in autonomic neuropathy patients versus controls and somatic neuropathy patients. Autonomic innervation density was abnormal in 96% of patients in the lower leg and in 79% of patients in the thigh. The abnormal findings disclosed by routine autonomic tests ranged from 48% to 82%. These data indicate the high sensitivity and specificity of skin biopsy in detecting sympathetic abnormalities; this method should be useful for the diagnosis of autonomic neuropathy, together with currently available routine autonomic testing. PMID- 23037328 TI - Fluorescence quenching amplification in silica nanosensors for Au3+. AB - In this study silica nanoparticles (SiNPs) were covalently modified by the fluorescence ligand 2-((7-oxo-7H- furo [3, 2-g] chromen-9-yl) oxy)-N-(3 (triethoxysilyl) propyl) acetamide (CTPA) and provided an optical sensor allowing highly sensitive and selective detection for Au(3+). The probe exhibited a dynamic response range for Au(3+) from 5.0 * 10(-7) to 1.0 * 10(-4) M, with a detection limit of 2.3 * 10(-8) M. Other alkali, earth alkali and transition metal ions, even those that exist in high concentration, had no significant interference with Au(3+) determination. PMID- 23037329 TI - Prospective, nonrandomized controlled trials to compare the effect of a silk like fabric to standard hospital linens on the rate of hospital-acquired pressure ulcers. AB - Hospital bedding and gowns influence skin moisture, temperature, friction, and shear, which in turn may affect the development of pressure ulcers. To evaluate the effect of a new silk-like synthetic fabric on the incidence of pressure ulcers in an acute care setting, two consecutive 6-month clinical trials were conducted among 307 consecutively admitted patients in a Medical Renal Unit (August 2008 and March 2010) and in 275 patients admitted to a Surgical Intensive Care Unit (ICU) (September 2009 to March 2010). During the first 8 weeks, all patients used standard hospital bed linens, reusable underpads, and gowns. During the second 8 weeks, all admitted patients used the intervention linens (a silk like fabric) followed by another 8 weeks of control (standard linen) use. Demographic variables and the prevalence of pressure ulcers on admission were statistically similar for control and intervention groups in both study populations with the exception of gender in the Renal Unit study (13% higher proportion of men in intervention group). Average Braden Scores were also similar and low (<18) in all study patients. Upon admission to the Medical Renal Unit, 21 of 154 patients (13.6%) in the control and 26 of 153 patients (17.0%) in the intervention group had a pressure ulcer. The incidence of new ulcers was 12.3% in the control and 4.6% in the intervention group (P = 0.01); average length of stay was 5.97 days (sigma = 4.0) for control and 5.31 days (sigma = 3.8) for intervention patients (P = 0.07). In the Surgical ICU group, 18 of 199 patients in the control (9.1%) and four of 76 patients in the intervention group (5.3%) were admitted with a pressure ulcer; the incidence of new pressure ulcers was 7.5 % in the control and 0% in the intervention group (P = 0.01). Average length of stay was 4.5 days and 4.33 days in the control and intervention groups, respectively (P = 0.33). The significant differences between the control and intervention group in the rate of pressure ulcer development suggests that the type of linens used affect pressure ulcer risk and that this silk-like synthetic fabric technology may help reduce the incidence of pressure ulcers in high-risk patients. Controlled clinical studies in other patient populations are warranted. PMID- 23037330 TI - The effect of a wound care solution containing polyhexanide and betaine on bacterial counts: results of an in vitro study . AB - Polyhexanide and betaine topical solution is used in the management of infected wounds as a cleaning agent. An in vitro study was conducted to examine the antimicrobial effects of a solution containing 0.1% of the antimicrobial agent polyhexanide and 0.1% of the surfactant betaine. Three batches of each product were tested, and culture results of 13 microorganisms were evaluated after 7, 14, and 28 days using USP <51> methodology. Growth reduction was identical at each day following exposure to the solution in all micro-organisms except Aspergillus brasiliensis. A range of 5.3-log to 5.8-log reduction was seen for the following micro-organisms: Staphylococcus epidermidis, Pseudomonas aeruginosa, Serratia marcescens, Candida albicans, S. aureus, vancomycin-resistant Enterococcus faecalis, Proteus mirabilis, Escherichia coli, methicillin-resistant S. aureus, Acinetobacter baumannii, Enterobacter cloacae, and E. faecalis. For A. brasiliensis, reductions were 2.1-log, 2.3-log and 2.8-log at 7, 14, and 28 days, respectively. The results of this study indicate a 4+ log inhibition of activity in 12 of 13 micro-organisms exposed to the solution. Research to elucidate the potential clinical effects of these observations is needed. PMID- 23037331 TI - An e-learning program to prevent pressure ulcers in adults with spinal cord injury: a pre- and post- pilot test among rehabilitation patients following discharge to home. AB - Pressure ulcers (PrUs) are the most common medical complication following spinal cord injury (SCI), as well as costly and potentially life-threatening. Every individual with SCI is at life-long risk for developing PrUs, yet many lack access to readily available, understandable, and effective PrU prevention strategies and practices. To address barriers to adequate PrU prevention education, an interactive e-learning program to educate adults with SCI about PrU prevention and management was developed and previously pilot-tested among inpatients. This recent pilot study was conducted to evaluate the feasibility of using the learning portion of the program by adults with SCI following discharge to home among 15 outpatients with SCI. Fourteen patients (nine men, five women, median age 37 years) completed the program intervention and pre- and follow-up questionnaires. The median score for pre-program knowledge and skin care management practice was 96 (possible score: 0 to 120; range 70-100). Post-program use median score was 107 (range 97-114). The greatest improvement was in the responses to knowledge and practice questions about skin checks and preventing skin problems (P <0.005). In terms of their experiences and perceptions, the program was well received by the study participants. Further evaluation involving large samples is necessary to confirm these findings and ascertain the effect of this e-learning program on PrU incidence. Internet interventions that are proven effective hold tremendous potential for bringing prevention education to groups who would otherwise not receive it. PMID- 23037332 TI - Trunk and lower limb fat mass evaluated by dual-energy X-ray absorptiometry in a 20- to 80-year-old healthy Italian population. AB - BACKGROUND AND AIMS: Global fat mass distribution seems to correlate with different levels of cardio-metabolic risk; centrally distributed fat carries a high risk of cardiovascular disease, while lower limb adiposity may have a protective effect against insulin resistance. Reference data regarding body composition have already been published for the Italian population; the aim of this study was to add reference values for trunk and lower limb fat mass, and their ratio (TLR), developing percentile distributions for age brackets between 20 and 80 years. METHODS: A retrospective analysis of a multicenter, cross sectional study was conducted and 1,570 healthy Italian adults (1,241 females and 329 males) were selected. The regional fat mass, measured by dual-energy X-ray absorptiometry total body scan, was analyzed and the TLR was calculated. RESULTS: In both genders we observed higher trunk fat mass values in older subjects against a smaller difference in BMI values. The leg fat mass was higher in old men, while it was similar in women at different ages. The TLR values in older subjects doubled those of younger subjects in both genders (62% in males and 71% in females). CONCLUSIONS: The identified ranges for trunk, leg fat mass, and TLR may be used as reference values to describe the global fat mass distribution in healthy individuals and to identify states of altered body fat distribution. PMID- 23037333 TI - Multi-channel multi-carrier generation using multi-wavelength frequency shifting recirculating loop. AB - We propose and experimentally demonstrate a novel scheme to generate optical frequency-locked multi-channel multi-carriers (MCMC), using a recirculating frequency shifter (RFS) loop based on multi-wavelength frequency shifting single side band (MWFS-SSB) modulation. In this scheme, optical subcarriers with multiple wavelengths can be generated each round. Furthermore, the generated MCMC are frequency- and phase-locked within each channel, and therefore can be effectively used for WDM superchannel. Dual-wavelength frequency shifting SSB modulation is carried out with dual-wavelength optical seed source in our experimental demonstration. Using this scheme, we successfully generate dual channel multi-carriers, and one channel has 28 subcarriers while the other has 29 ones with 25-GHz subcarrier spacing. We also experimentally demonstrate that this kind of source can be used to carry 50-Gb/s optical polarization-division multiplexing quadrature phase shift keying (PDM-QPSK) signal. PMID- 23037334 TI - Ultra-compact, high-Q silicon microdisk reflectors. AB - We demonstrate wavelength-selective reflectors based on silicon microdisk resonators integrated with compact Y-branch splitters, using a CMOS-photonics technology. A high quality factor (Q) of ~ 88,000 was measured in the reflection spectrum for a 2.5-MUm-radius device with a small footprint of 6 * 17 MUm(2) and a wide free-spectral range (FSR) of over 41 nm. As the radius is reduced to 1.5 MUm, corresponding to a device footprint of 4 * 15 MUm(2), the spectrum shows an ultra-wide FSR of over 71 nm with the compromise of having a reduced Q of ~ 4000. The coupling between a microdisk and a waveguide is numerically investigated. We further propose a multichannel sensing system using cascaded microdisk reflectors. PMID- 23037335 TI - Dynamic response of modulators based on cascaded-ring-resonator. AB - We investigated the dynamic response of a cascaded-ring-resonator-loaded Mach Zehnder modulator (CRR-MZM), in which a number of cascaded ring resonators (RRs) are loaded in the interferometer as phase modulators. The analytical form is derived for the small-signal response of CRR-MZM using temporal-coupled-mode (TCM) theory, and its validity is confirmed by numerical calculations. It is revealed that the bandwidth of the CRR-MZM is maximized by setting proper delays in driving signals between neighboring RRs; the optimized delay is twice the photon lifetime of each RR. The calculated performances of CRR-MZMs are compared with those of standard modulators based on a single-ring-resonator (SRR) without interferometer, in terms of the modulation depth and bandwidth. For a given degree of the refractive index change in a waveguide, CRR-MZM can provide a larger modulation depth than a SRR-type modulator in frequency ranges exceeding 25 GHz. PMID- 23037336 TI - Comparison of emission characteristics between the CdZnO/ZnO quantum wells on ZnO and GaN templates. AB - CdZnO/ZnO quantum well (QW) samples are grown on GaN and ZnO templates with plasma-assisted molecular beam epitaxy under different conditions of substrate temperature, Cd effusion cell temperature, and O(2) flow rate for emission characteristics comparison. It is found that the Cd incorporation on the ZnO template is generally lower, when compared with that on the GaN template, such that the O(2) flow rate needs to be reduced for stoichiometric CdZnO/ZnO QW growth on the ZnO template. Besides the wurtzite (wt) CdZnO structure, the rock salt (rs) CdZnO structure exists in the CdZnO well layers when the total Cd content is high. The rs structure may dominate over the wt structure in photoluminescence intensity when the total Cd content is high. In either group of samples on the GaN and ZnO templates, the emission efficiency first increases and then decreases with increasing total Cd content. The low emission efficiency at low (high) Cd content is attributed to the weaker quantum confinement (the poorer crystal quality) of the QWs. The emission efficiencies of the QW samples on the GaN template are generally higher than those on the ZnO template. The carrier localization behavior in a CdZnO/ZnO QW, grown on either GaN or ZnO template, is significantly weaker than that in an InGaN/GaN QW. The strength of the quantum confined Stark effect generally increases with increasing Cd content in either group of samples on the GaN and ZnO templates. PMID- 23037337 TI - Characterizations of realized metal-insulator-silicon-insulator-metal waveguides and nanochannel fabrication via insulator removal. AB - We investigate experimentally metal-insulator-silicon-insulator-metal (MISIM) waveguides that are fabricated by using fully standard CMOS technology. They are hybrid plasmonic waveguides, and they have a feature that their insulator is replaceable with functional material. We explain a fabrication process for them and discuss fabrication results based on 8-inch silicon-on-insulator wafers. We measured the propagation characteristics of the MISIM waveguides that were actually fabricated to be connected to Si photonic waveguides through symmetric and asymmetric couplers. When incident light from an optical source has transverse electric (TE) polarization and its wavelength is 1318 or 1554 nm, their propagation losses are between 0.2 and 0.3 dB/MUm. Excess losses due to the symmetric couplers are around 0.5 dB, which are smaller than those due to the asymmetric couplers. Additional measurement results indicate that the MISIM waveguide supports a TE-polarized hybrid plasmonic mode. Finally, we explain a process of removing the insulator without affecting the remaining MISIM structure to fabricate ~30-nm-wide nanochannels which may be filled with functional material. PMID- 23037338 TI - Huge local field enhancement in perfect plasmonic absorbers. AB - In this work we theoretically reveal the huge local field enhancement in a so called perfect plasmonic absorber. We study the power absorption of light in a planar grid modelled as an effective sheet with zero optical thickness. The key prerequisite of the total absorption is the simultaneous presence of both resonant electric and magnetic modes in the structure. We show that the needed level of the magnetic mode is achievable using the effect of substrate-induced bianisotropy. On the microscopic level this bianisotropy is a factor which results in the huge local field enhancement at the same wavelength where the maximal absorption holds. PMID- 23037339 TI - Terahertz vector beam generation using segmented nonlinear optical crystals with threefold rotational symmetry. AB - We propose and demonstrate a simple method for cylindrical vector beam generation in the terahertz frequency region using optical rectification in segmented nonlinear crystals with threefold rotational symmetry. We used segmented GaP(111) plates to generate the terahertz cylindrical vector beam, and obtained clear evidence of the beam generation with a terahertz camera. By this method, a broadband terahertz cylindrical vector beam can be generated, and the radial and azimuth modes can be easily switched. We also report on the direct observation of the longitudinal electric field components at the focal point using a terahertz time-domain spectroscopy technique. PMID- 23037340 TI - Anisotropic coupled diffusion filter and binarization for the electronic speckle pattern interferometry fringes. AB - In this paper novel approaches based on anisotropic coupled diffusion equations are presented to do filter and binarization for ESPI fringes. An advantageous characteristic associated with the proposed technique is that diffusion takes place mainly along the direction of the edge. Therefore, the proposed anisotropic coupled diffusion filter method can avoid blur of the fringe edge and protect the useful information of the fringe patterns. The anisotropic coupled diffusion binarization, which can repair the image boundary anisotropically, is able to avoid the redundant burr. More important, it can be directly applied to the noisy ESPI fringe patterns without much preprocessing, which is a significant advance in fringe analysis for ESPI. The effective of the proposed methods are tested by means of the computer-simulated and experimentally obtained fringe patterns, respectively. PMID- 23037341 TI - Narrowband multispectral filter set for visible band. AB - We design, fabricate and characterise a narrowband Fabry-Perot multispectral filter set for the visible range (400-750 nm) that is suitable for integration onto complementary-metal oxide-semiconductor image sensors. We reduce the fabrication steps by fixing the physical cavity length and altering the effective optical length instead. Using electron-beam lithography, a sub-wavelength hole array is patterned in a silicon nitride cavity layer, backfilled with poly(methyl methacrylate), and bounded by aluminium mirrors to create 23 filters with full width half-maximums of 22-46 nm. Additionally, for colourmetric reproduction applications, using as few as 10 filters gives a colour difference (CIEDE2000) of 0.072, better than trichromatic filters. PMID- 23037342 TI - Terahertz confocal microscopy with a quantum cascade laser source. AB - We report on the implementation of a confocal microscopy system based on a 2.9 THz quantum cascade laser source. Lateral and axial resolutions better than 70 MUm and 400 MUm, respectively, are achieved, with a large contrast enhancement compared to the non-confocal arrangement. The capability of resolving overlapping objects lying on different longitudinal planes is also clearly demonstrated. PMID- 23037343 TI - Continuous real-time correction and averaging for frequency comb interferometry. AB - Interferograms from a dual-comb spectrometer are continuously corrected and averaged in real-time. The algorithm is implemented on a field-programmable gate array (FPGA) development board. The chosen approach and the algorithm are described. Measurements with high signal-to-noise ratio, resolution and bandwidth are shown to demonstrate the accuracy of the optical referencing and the processing algorithm with 24 hours of averaging time, reaching a signal to noise ratio of 10,750,000 (>21 bits) in the interferogram and 316,000 in the spectrum at 100 MHz resolution. An interferogram where signal dominates the noise over the full delay range imposed by the 100 MHz repetition rate is reported for the first time. PMID- 23037344 TI - Enhancement of cascaded four-wave mixing via optical feedback. AB - A scheme is proposed to enhance the cascaded four-wave mixing (CFWM) generation, by introducing an optical feedback to the input port. Experimental and numerical results show that more efficient CFWM generation can be obtained by the scheme. The number of CFWM products is increased, as well as the powers of most CFWM products are improved. PMID- 23037345 TI - Towards the control of highly sensitive Fabry-Perot strain sensor based on hollow core ring photonic crystal fiber. AB - A high sensitivity Fabry-Perot (FP) strain sensor based on hollow-core ring photonic crystal fiber was investigated. A low-finesse FP cavity was fabricated by splicing a section of hollow-core ring photonic crystal fiber between two standard single mode fibers. The geometry presents a low cross section area of silica enabling to achieve high strain sensitivity. Strain measurements were performed by considering the FP cavity length in a range of 1000 MUm. The total length of the strain gauge at which strain was applied was also studied for a range of 900 mm. The FP cavity length variation highly influenced the strain sensitivity, and for a length of 13 MUm a sensitivity of 15.4 pm/MUepsilon was attained. Relatively to the strain gauge length, its dependence to strain sensitivity is low. Finally, the FP cavity presented residual temperature sensitivity (~0.81 pm/ degrees C). PMID- 23037346 TI - Lens-less surface second harmonic imaging. AB - Lens-less surface second harmonic generation imaging (SSHGI) is used to image an SHG active molecule, (S)-(+)-1,1'-bi-2-naphthol (SBN), incorporated into a lipid bilayer patterned with the 1951 United States Air Force resolution test target. Data show the coherent plane-wave nature of SHG allows direct imaging without the aid of a lens system. Lens-less SSHGI readily resolves line-widths as small as 223 MUm at an object-image distance of 7.6 cm and line-widths of 397 MUm at distances as far as 30 cm. Lens-less SSHGI simplifies the detection method, raises photon collection efficiency, and expands the field-of-view. These advantages allow greater throughput and make lens-less SSHGI a potentially valuable detection method for biosensors and medical diagnostics. PMID- 23037348 TI - Entangled photon generation using four-wave mixing in azimuthally symmetric microresonators. AB - A novel quantum mechanical formulation of the bi-photon wavefunction and spectra resulting from four-wave mixing is developed for azimuthally symmetric systems. Numerical calculations are performed verifying the use of the angular group velocity and angular group velocity dispersion in such systems, as opposed their commonly used linear counterparts. The dispersion profile and bi-photon spectra of two illustrative examples are given, emphasizing the physical origin of the effects leading to the conditions for angular momentum and energy conservation. A scheme is proposed in which widely spaced narrowband entangled photons may be produced through a four-wave mixing process in a chip-scale ring resonator. The entangled photon pairs are found to conserve energy and momentum in the four-wave mixing interaction, even though both photon modes lie in spectral regions of steep angular group velocity dispersion. PMID- 23037347 TI - Ultra-small single-negative electric metamaterials for electromagnetic coupling reduction of microstrip antenna array. AB - We report initially the design, fabrication and measurement of using waveguided electric metamaterials (MTM) in the design of closely-spaced microtrip antenna arrays with mutual coupling reduction. The complementary spiral ring resonators (CSRs) which exhibit single negative resonant permittivity around 3.5GHz are used as the basic electric MTM element. For verification, two CSRs with two and three concentric rings are considered, respectively. By properly arranging these well engineered waveguided MTMs between two H-plane coupled patch antennas, both numerical and measured results indicate that more than 8.4 dB mutual coupling reduction is obtained. The mechanism has been studied from a physical insight. The electric MTM element is electrically small, enabling the resultant antenna array to exhibit a small separation (lambdao/8 at the operating wavelength) and thus a high directivity. The proposed strategy opens an avenue to new types of antenna with super performances and can be generalized for other electric resonators. PMID- 23037349 TI - High-energy, ceramic-disk Yb:LuAG laser amplifier. AB - We report the first short-pulse amplification results to several hundred millijoule energies in ceramic Yb:LuAG. We have demonstrated ns-pulse output from a diode-pumped Yb:LuAG amplifier at a maximum energy of 580 mJ and a peak optical to-optical efficiency of 28% at 550 mJ. In cavity dumped operation of a nanosecond oscillator we obtained 1 mJ at up to 100 Hz repetition rate. A gain bandwidth of 5.4 nm was achieved at room temperature by measuring the small signal single-pass gain. Furthermore, we compared our results with Yb:YAG within the same amplifier system. PMID- 23037350 TI - Bi-functional photonic structure in the Papilio nireus (Papilionidae): modeling by scattering-matrix optical simulations. AB - Scales of the Papilio nireus combine fluorophores confined in a natural photonic structure. By means of numerical simulations based on the scattering-matrix formalism, we reveal the bi-functional optical role of this peculiar architecture. Two aspects are considered: the absorption of an incident light flux and the emission of another luminous flux. First, results highlight a light trapping effect and a light absorption increase in the ultraviolet, visible and near infrared ranges. Then, results highlight an enhanced fluorescence occurring in the spatial as well as in the frequency domain. This observation could be of great interest to design new optical devices. PMID- 23037351 TI - Flexible coupling of high-Q goblet resonators for formation of tunable photonic molecules. AB - We report on a method for a highly flexible arrangement of polymeric high-Q whispering gallery mode resonators. Parallel on-chip fabricated goblet resonators are detached from the substrate by bonding a gold wire to the field-free center of their polymeric cavity. This enables the precise control of the resonator's spatial position. The modal spectrum of the detached resonator reveals preservation of its high optical quality. Manipulation of the resonators' position allows for designing coupled resonators geometries and tuning the coupling properties dynamically after batch fabrication. The properties of the modal spectrum evidence the successful optical coupling. PMID- 23037352 TI - Modified Maxwell fish-eye approach for efficient coupler design by graded photonic crystals. AB - We present a novel design of two dimensional graded index medium that provides coupling of light with high coupling efficiency between two planar dielectric waveguides of different widths (15.46 MUm vs. 2.21 MUm). Poor light coupling performance of butt-coupler can be mitigated by implementing tapered coupler at the expense of long coupler section. In order to reduce coupling losses, a new coupling device approach based on graded index (GRIN) concept is proposed. The refractive index distribution is in the form of modified version of the Maxwell fish-eye lens. The inhomogeneous refractive index distribution is approximated by photonic crystals (PCs) such that the positions of each PC rods are appropriately arranged. Strong electric field focusing ability of the designed GRIN PC medium provides relatively high coupling efficiency that is around 90%. Spectral region corresponding to coupling efficiency over 75% has a bandwidth of Deltaomega = 18.56% (284 nm). Finally, we discuss the durability of the proposed coupler against the lateral displacement and angular misalignment of output waveguides. PMID- 23037353 TI - Direct comparison of a Ca+ single-ion clock against a Sr lattice clock to verify the absolute frequency measurement. AB - Optical frequency comparison of the (40)Ca(+) clock transition nu(Ca)((2)S(1/2 )(2D(5/2), 729 nm) against the (87)Sr optical lattice clock transition nu(Sr) ((1)S(0)-(3)P(0), 698 nm) has resulted in a frequency ratio nu(Ca) / nu(Sr) = 0.957 631 202 358 049 9(2 3). The rapid nature of optical comparison allowed the statistical uncertainty of frequency ratio nu(Ca) / nu(Sr) to reach 1 * 10(-15) in 1000s and yielded a value consistent with that calculated from separate absolute frequency measurements of nu(Ca) using the International Atomic Time (TAI) link. The total uncertainty of the frequency ratio using optical comparison (free from microwave link uncertainties) is smaller than that obtained using absolute frequency measurement, demonstrating the advantage of optical frequency evaluation. We note that the absolute frequency of (40)Ca(+) we measure deviates from other published values by more than three times our measurement uncertainty. PMID- 23037354 TI - 250-MHz synchronously pumped optical parametric oscillator at 2.25-2.6 MUm and 4.1-4.9 MUm. AB - A compact and versatile femtosecond mid-IR source is presented, based on an optical parametric oscillator (OPO) synchronously pumped by a commercial 250-MHz Er:fiber laser. The mid-IR spectrum can be tuned in the range 2.25-2.6 MUm (signal) and 4.1-4.9 MUm (idler), with average power from 20 to 60 mW. At 2.5 MUm a minimum pulse duration of 110 fs and a power of 40 mW have been obtained. Active stabilization of the OPO cavity length has been achieved in the whole tuning range. PMID- 23037355 TI - Development of a scalable image formation pipeline for multiscale gigapixel photography. AB - We report on the image formation pipeline developed to efficiently form gigapixel scale imagery generated by the AWARE-2 multiscale camera. The AWARE-2 camera consists of 98 "microcameras" imaging through a shared spherical objective, covering a 120 degrees x 50 degrees field of view with approximately 40 microradian instantaneous field of view (the angular extent of a pixel). The pipeline is scalable, capable of producing imagery ranging in scope from "live" one megapixel views to full resolution gigapixel images. Architectural choices that enable trivially parallelizable algorithms for rapid image formation and on the-fly microcamera alignment compensation are discussed. PMID- 23037356 TI - Quantitative imaging of the optical near field. AB - When exposing small particles on a substrate to a light plane wave, the scattered optical near field is spatially modulated and highly complex. We show, for the particular case of dielectric microspheres, that it is possible to image these optical near-field distributions in a quantitative way. By placing a single microsphere on a thin film of the photosensitive phase change material Ge(2)Sb(5)Te(5) and exposing it to a single short laser pulse, the spatial intensity modulation of the near field is imprinted into the film as a pattern of different material phases. The resulting patterns are investigated by using optical as well as high-resolution scanning electron microscopy. Quantitative information on the local optical near field at each location is obtained by calibrating the material response to pulsed laser irradiation. We discuss the influence of polarization and angle of incidence of the laser beam as well as particle size on the field distribution. The experimental results are in good quantitative agreement with a model based on a rigorous solution of Maxwell's equations. Our results have potential application to near-field optical lithography and experimental determination of near fields in complex nanostructures. PMID- 23037357 TI - Characterization of passive optical components with ultra-fast speed and high resolution based on DD-OFDM. AB - The passive optical components with very fine structures in wavelength domain are very sensitive to the mechanical vibrations or thermal fluctuations. If the measurement speed is lower than the temperature and mechanical fluctuation, we cannot measure the dynamic characteristics of the optical components. In this paper, we propose and demonstrate a novel method with ultra-fast measurement speed and high-resolution based on optical channel estimation using direct detected orthogonal frequency division multiplexing (DD-OFDM) signal, which can be used to measure the dynamic characteristics and fine structure of the passive optical components. In experiment, by using fast Fourier transform (FFT) and a low-cost electro-absorption modulated laser (EML), we can achieve the transfer function characteristics with 3.9 MHz resolution. Compared with the optical channel estimation using coherent OFDM signal reported before, the proposed measurement technique is cost-effective. PMID- 23037358 TI - A close to unity and all-solar-spectrum absorption by ion-sputtering induced Si nanocone arrays. AB - Si nanocone arrays are formed on Si(100) by Ar(+) ion sputtering combined with metal ion co-deposition. The aspect ratio of Si cone is found to increases steadily with increasing sample temperature, but decreases slowly with increasing ion dose. Furthermore, the height and base diameter of Si cone increase monotonously with increasing dose at a constant temperature. The absorptivity increases in general with increasing aspect ratio and height. A close to unity and all-solar-spectrum absorption by the nanostructured Si is finally achieved, with the absorbance for lambda = 350 to 1100 nm being higher than 96%, and that for lambda = 1100 to 2000 nm higher than 92%. Photocurrents for different Si samples are also investigated. PMID- 23037359 TI - Investigation of laser-induced damage by various initiators on the subsurface of fused silica. AB - We develop a model that describes the effect of size distribution of nanoabsorbers on the subsurface of fused silica on laser-damage probability. Using Mie theory and heat equation, we obtain the correlation between the critical fluence and particle radius. Considering a power law distribution of nanoabsorbers, the curves of laser-damage probability are calculated based on experimental results of contents of contaminations and a fit parameter of size distribution of nanoabsorbers. This paper presents the influence of various potential candidates, jointly, on laser-induced damage. PMID- 23037360 TI - Object reconstruction in block-based compressive imaging. AB - A block-based compressive imaging (BCI) system using sequential architecture is presented in this paper. Feature measurements are collected using the principal component analysis (PCA) projection. The linear Wiener operator and a nonlinear method based on the Field-of-Expert (FoE) prior model are used for object reconstruction. Experimental results are given to demonstrate the superior reconstruction performance of the FoE-based method over the Wiener operator. In addition, the effects of system parameters, such as the object block size, the number of features per block, and the noise level to the BCI reconstruction performance are discussed with different kinds of objects. Then an optimal block size is defined and studied for BCI. PMID- 23037361 TI - Simultaneous temperature, mixture fraction and velocity imaging in turbulent flows using thermographic phosphor tracer particles. AB - This paper presents an optical diagnostic technique based on seeded thermographic phosphor particles, which allows the simultaneous two-dimensional measurement of gas temperature, velocity and mixture fraction in turbulent flows. The particle Mie scattering signal is recorded to determine the velocity using a conventional PIV approach and the phosphorescence emission is detected to determine the tracer temperature using a two-color method. Theoretical models presented in this work show that the temperature of small tracer particles matches the gas temperature. In addition, by seeding phosphorescent particles to one stream and non luminescent particles to the other stream, the mixture fraction can also be determined using the phosphorescence emission intensity after conditioning for temperature. The experimental technique is described in detail and a suitable phosphor is identified based on spectroscopic investigations. The joint diagnostics are demonstrated by simultaneously measuring temperature, velocity and mixture fraction in a turbulent jet heated up to 700 K. Correlated single shots are presented with a precision of 2 to 5% and an accuracy of 2%. PMID- 23037362 TI - High efficiency laser action of 1% at. Yb3+:2O3 ceramic. AB - We report the spectroscopic characteristics and the laser performances of a low doped 1% at. Yb:Sc(2)O(3) ceramic sample. Under end- pumping at 933 nm and 968 nm in quasi-CW mode, at 1040.5 nm the laser delivers a maximum output power of 4.3 W and 1.77 W, respectively with a corresponding slope efficiency of 74% and 80%, which are, to the best of our knowledge, the highest value reported in literature for ceramics. We explored the tuning range of the sample, which spans from 1005 nm to 1050.5 nm, and finally we characterized the low losses tunable cavity at 1032 nm. PMID- 23037363 TI - Double-deformable-mirror adaptive optics system for laser beam cleanup using blind optimization. AB - An optimization-based correction method is developed to control simultaneously two deformable mirrors in a wavefront-sensor-less adaptive beam cleanup system, where the wave-front aberrations could not be compensated by a single deformable mirror. Stochastic parallel gradient decent algorithm is chosen as the optimization algorithm. In this control method, different aberrations are assigned to each deformable mirror according to their different correction quality. The method is proved to be effective by numerical simulations as well as experiments. Experimental results showed that the area containing 84% energy of the laser beam in the far-field can reach 3.0 times diffraction limited. PMID- 23037364 TI - Comparison of principal component analysis and biochemical component analysis in Raman spectroscopy for the discrimination of apoptosis and necrosis in K562 leukemia cells. AB - Raman spectroscopy has been explored as a promising label-free technique in discriminating apoptosis and necrosis induced cell death in leukemia cells. In addition to Principal component analysis (PCA) as commonly employed in Raman data analysis, another less commonly used but powerful method is Biochemical Component Analysis (BCA). In BCA, a Raman spectrum is decomposed into the contributions from several known basic biochemical components, such as proteins, lipid, nucleic acids and glycogen groups etc. The differences in terms of classification accuracy and interpretability of resulting data between these two methods in Raman spectroscopy have not been systematically investigated to our knowledge. In this study, we utilized both methods to analyze the Raman spectra measured from live cells, apoptotic and necrotic leukemia cells. The comparison indicates that two methods yield comparable accuracy in sample classification when the numbers of basic components are equal. The changes in the contributions of biochemical components in BCA can be interpreted by cell biology principles in apoptosis and necrosis. In contrast, the contributions of most principle components in PCA are difficult to interpret except the first one. The capability of BCA to unveil fine biochemical changes in cell spectra and excellent accuracy in classification can impel the broad application of Raman spectroscopy in biological research. PMID- 23037365 TI - Orders of magnitude enhancement of mode splitting by plasmonic intracavity resonance. AB - we report on significant mode splitting in plasmonic resonators induced by intracavity resonance. In contrast to traditional dielectric resonators where only picometer range of splitting was achieved, splitting over several hundred nanometers can be obtained without using ultrahigh quality resonators. We show that by appropriately choosing the coupling length, minute reflection is sufficient to establish intracavity resonance, which effectively lifts the degeneracy of the counterpropagating modes in the resonator. The mode splitting provides two self-referenced channels enabling simultaneous monitoring of the position and the polarizability of nano-scatterers in the resonator. PMID- 23037366 TI - Continuous-wave InAs/GaAs quantum-dot laser diodes monolithically grown on Si substrate with low threshold current densities. AB - We report the first room-temperature continuous-wave operation of III-V quantum dot laser diodes monolithically grown on a Si substrate. Long-wavelength InAs/GaAs quantum-dot structures were fabricated on Ge-on-Si substrates. Room temperature lasing at a wavelength of 1.28 MUm has been achieved with threshold current densities of 163 A/cm(2) and 64.3 A/cm(2) under continuous-wave and pulsed conditions for ridge-waveguide lasers with as cleaved facets, respectively. The value of 64.3 A/cm(2) represents the lowest room-temperature threshold current density for any kind of laser on Si to date. PMID- 23037367 TI - Understanding the fiber tip thermal runaway present in 3 um fluoride glass fiber lasers. AB - When the tip of a fluoride glass fiber is exposed to ambient air, water vapor reacts with the glass constituents, increasing the OH contaminants at the surface. These OH impurities then diffuse inside the glass according to Fick's laws. Laser radiation at around 3 um is strongly absorbed by the OH contaminants, causing local heating of the fiber tip resulting in an increase of the diffusion process which ultimately leads to fiber tip destruction. We accurately model this phenomenon by combining the diffusion theory with a basic thermal equation. Experimental measurements are in agreement with the model predictions for a good range of operating conditions. PMID- 23037368 TI - Digitally enhanced homodyne interferometry. AB - We present two variations of a novel interferometry technique capable of simultaneously measuring multiple targets with high sensitivity. The technique performs a homodyne phase measurement by application of a four point phase shifting algorithm, with pseudo-random switching between points to allow multiplexed measurement based upon propagation delay alone. By multiplexing measurements and shifting complexity into signal processing, both variants realise significant complexity reductions over comparable methods. The first variant performs a typical coherent detection with a dedicated reference field and achieves a displacement noise floor 0.8 pm/?Hz above 50 Hz. The second allows for removal of the dedicated reference, resulting in further simplifications and improved low frequency performance with a 1 pm/?Hz noise floor measured down to 20 Hz. These results represent the most sensitive measurement performed using this style of interferometry whilst simultaneously reducing the electro-optic footprint. PMID- 23037369 TI - The effect of silicon loss and fabrication tolerance on spectral properties of porous silicon Fabry-Perot cavities in sensing applications. AB - In this paper, we investigate the effect of non-uniformities (enlargement of current passage, non-equal surface current densities, etc.) in axial as well as transverse directions of a porous silicon Fabry-Perot (FP) cavity as well as loss nature of bulk silicon on spectral properties of this cavity, even that cavity is created with an anisotropic etching process. Without correct and comprehensive characterization of such cavities by incorporating these non-uniformities and inherent lossy nature of a cavity, detection and identification of biological and chemical molecules by that cavity may yield unpredictable and misleading results. From our simulations, we note the following two key points. First, effects of the refractive index and the thickness of microcavity region of a lossless or lossy FP cavity on resonance wavelength is more prevailing than those of first and last layers. Second, the effect of some small loss inside the FP cavity is not detectable by the measurement of resonance wavelength whereas the same influence is noticeable by the measurement of reflectivity. We carried out some measurements from two different regions on the fabricated cavities to validate our simulation results. From a practical point of view in correct detection and/or identification of lossy biological or chemical vapor by FP cavities, we conclude that not only the measurement of resonance wavelength as well as its shift but also the reflectivity value at the resonance wavelength or some specific wavelengths should be utilized. PMID- 23037370 TI - High speed GeSi electro-absorption modulator at 1550 nm wavelength on SOI waveguide. AB - We demonstrate a high speed GeSi electro-absorption (EA) modulator monolithically integrated on 3 um silicon-on-insulator (SOI) waveguide. The demonstrated device has a compact active region of 1.0 * 55 MUm(2), an insertion loss of 5 dB and an extinction ratio of 6 dB at wavelength of 1550 nm. The modulator has a broad operating wavelength range of 35 nm and a 3 dB bandwidth of 40.7 GHz at 2.8 V reverse bias. This compact and energy efficient modulator is a key building block for optical interconnection applications. PMID- 23037371 TI - Compact slit-based couplers for metal-dielectric-metal plasmonic waveguides. AB - We introduce compact wavelength-scale slit-based structures for coupling free space light into metal-dielectric-metal (MDM) subwave-length plasmonic waveguides. We first show that for a single slit structure the coupling efficiency is limited by a trade-off between the light power coupled into the slit, and the transmission of the slit-MDM waveguide junction. We next consider a two-section slit structure, and show that for such a structure the upper slit section enhances the coupling of the incident light into the lower slit section. The optimized two-section slit structure results in ~ 2.3 times enhancement of the coupling into the MDM plasmonic waveguide compared to the optimized single slit structure. We finally consider a symmetric double-slit structure, and show that for such a structure the surface plasmons excited at the metal-air interfaces are partially coupled into the slits. Thus, the coupling of the incident light into the slits is greatly enhanced, and the optimized double-slit structure results in ~ 3.3 times coupling enhancement compared to the optimized single-slit structure. In all cases the coupler response is broadband. PMID- 23037372 TI - A novel method of diffraction imaging flow cytometry for sizing microspheres. AB - We report a novel method of diffraction imaging flow cytometry to measure and analyze size distribution of microspheres. An automated and robust image processing software based on the short-time-Fourier-transform algorithm has been developed to analyze the characteristic and spatially varying oscillations of side scatters recorded as a diffraction image. Our results demonstrate that the new method allows accurate and rapid determination of single microspheres' diameters ranging from 1 to 100 MUm. The capacity for analysis of light scattering by two-sphere aggregates has been demonstrated but analytical tools for characterization of aggregates by multiple microspheres remain to be developed. PMID- 23037373 TI - Digital deformation model for fisheye image rectification. AB - Fisheye lens can provide a wide view over 180 degrees . It then has prominence advantages in three dimensional reconstruction and machine vision applications. However, the serious deformation in the image limits fisheye lens's usage. To overcome this obstacle, a new rectification method named DDM (Digital Deformation Model) is developed based on two dimensional perspective transformation. DDM is a type of digital grid representation of the deformation of each pixel on CCD chip which is built by interpolating the difference between the actual image coordinate and pseudo-ideal coordinate of each mark on a control panel. This method obtains the pseudo-ideal coordinate according to two dimensional perspective transformation by setting four mark's deformations on image. The main advantages are that this method does not rely on the optical principle of fisheye lens and has relatively less computation. In applications, equivalent pinhole images can be obtained after correcting fisheye lens images using DDM. PMID- 23037374 TI - Dynamic light scattering optical coherence tomography. AB - We introduce an integration of dynamic light scattering (DLS) and optical coherence tomography (OCT) for high-resolution 3D imaging of heterogeneous diffusion and flow. DLS analyzes fluctuations in light scattered by particles to measure diffusion or flow of the particles, and OCT uses coherence gating to collect light only scattered from a small volume for high-resolution structural imaging. Therefore, the integration of DLS and OCT enables high-resolution 3D imaging of diffusion and flow. We derived a theory under the assumption that static and moving particles are mixed within the OCT resolution volume and the moving particles can exhibit either diffusive or translational motion. Based on this theory, we developed a fitting algorithm to estimate dynamic parameters including the axial and transverse velocities and the diffusion coefficient. We validated DLS-OCT measurements of diffusion and flow through numerical simulations and phantom experiments. As an example application, we performed DLS OCT imaging of the living animal brain, resulting in 3D maps of the absolute and axial velocities, the diffusion coefficient, and the coefficient of determination. PMID- 23037375 TI - Reflectionless grating couplers for Silicon-on-Insulator photonic integrated circuits. AB - We propose a novel grating coupler design which is inherently reflectionless by focusing the reflected light away from the entrance waveguide. The design rules for this reflectionless grating coupler are explained and the grating coupler design is investigated by means of 3D FDTD simulations for the case of a Silicon on-Insulator based platform. PMID- 23037376 TI - Gigabit NRZ, CAP and optical OFDM systems over POF links using LEDs. AB - Simulations have been performed to compare the system capacity and power dissipation of NRZ, CAP-64 and 64-QAM-OFDM systems over FEC enhanced POF links using LEDs, for both unidirectional and bidirectional transmission. It is shown that CAP-64 outperforms NRZ and 64-QAM-OFDM in terms of system capacity and supports a record high 3.5 Gb/s bidirectional and 2.1 Gb/s unidirectional transmissions over 50 m POF. The CAP-64 transceiver consumes similar power compared with NRZ whilst the 64-QAM-OFDM transceiver consumes about twice as much. PMID- 23037377 TI - Polarization properties of surface plasmon enhanced photoluminescence from a single Ag nanowire. AB - Metallic nanowires are of great research interest due to their applications in surface plasmon polariton coupling of light. The efficiency is much dependent on the polarization of the light due to the phase matching requirement in the light surface plasmon polariton coupling. By scanning confocal microscope, the photoluminescence from a single Ag nanowire was demonstrated strongly dependent on the excitation laser polarization, showing good consistency with the theoretical simulation. Meanwhile strong avalanche photoluminescence from a single Ag nanowire was observed when the excitation laser was polarized along the long axis of the Ag nanowire. The photoluminescence emission exhibited a polarization-sensitive spatial distribution. This may stimulate promising applications in designing polarization-controllable nanoscale plasmonic devices. PMID- 23037379 TI - Laser-written waveguides in KTP for broadband Type II second harmonic generation. AB - Femto-second laser writing was used to fabricate waveguides in a z-cut KTP sample with losses below 0.8 dB/cm. They were used for efficient, broad bandwidth, Type II birefringent second harmonic generation to the green. The temperature and wavelength bandwidth were, 28 C ? cm and 0.85 nm ? cm, respectively. PMID- 23037378 TI - Serpentine low loss trapezoidal silica waveguides on silicon. AB - We report the fabrication and characterization of straight and serpentine low loss trapezoidal silica waveguides integrated on a silicon substrate. The waveguide channel was defined using a dual photo-lithography and buffered HF etching and isolated from the silicon substrate using an isotropic silicon etchant. The waveguide is air-clad and thus has a core-cladding effective index contrast of approximately 25%. Measured at 658, 980 and 1550 nm, the propagation loss was found to be 0.69, 0.59, and 0.41 dB/cm respectively, with a critical bending radius less than 375 MUm. The waveguide's polarization behavior was investigated both theoretically and experimentally. Additionally, the output power shows a linear response with input power up to 200 mW. PMID- 23037381 TI - Enhanced photoluminescence and electroluminescence of multilayer GeSi islands on Si001 substrates by phosphorus-doping. AB - Ge/Si heterojunction light emitting diodes with 20-bilayers undoped or phosphorus in situ doped GeSi islands were fabricated on n(+)(-)Si(001) substrates by ultrahigh vacuum chemical vapor deposition (UHV-CVD). Enhanced room temperature photoluminescence (PL) and electroluminescence (EL) around 1.5 MUm were observed from the devices with phosphorus-doped GeSi islands. Theoretical calculations indicated that the emission is from the radiative recombination in GeSi islands. The intensity enhancement of PL and EL is attributed to the sufficient supply of electrons in active layer for radiative recombination. PMID- 23037380 TI - Electro-optofluidics: achieving dynamic control on-chip. AB - A vital element in integrated optofluidics is dynamic tuning and precise control of photonic devices, especially when employing electronic techniques which are challenging to utilize in an aqueous environment. We overcome this challenge by introducing a new platform in which the photonic device is controlled using electro-optical phase tuning. The phase tuning is generated by the thermo-optic effect using an on-chip electric microheater located outside the fluidic channel, and is transmitted to the optofluidic device through optical waveguides. The microheater is compact, high-speed (> 18 kHz), and consumes low power (~mW). We demonstrate dynamic optical trapping control of nanoparticles by an optofluidic resonator. This novel electro-optofluidic platform allows the realization of high throughput optofluidic devices with switching, tuning, and reconfiguration capability, and promises new directions in optofluidics. PMID- 23037382 TI - Reducing the effect of pixel crosstalk in phase only spatial light modulators. AB - A method for compensating for pixel crosstalk in liquid crystal based spatial light modulators is presented. By modifying a commonly used hologram generating algorithm to account for pixel crosstalk, the intensity errors in obtained diffraction spot intensities are significantly reduced. We also introduce a novel method for characterizing the pixel crosstalk in phase-only spatial light modulators, providing input for the hologram generating algorithm. The methods are experimentally evaluated and an improvement of the spot uniformity by more than 100% is demonstrated for an SLM with large pixel crosstalk. PMID- 23037383 TI - Remote detection of buried land-mines and IEDs using LWIR polarimetric imaging. AB - We report results of an ongoing study designed to assess the ability for enhanced detection of recently buried land-mines and/or improvised explosive devices (IED) devices using passive long-wave infrared (LWIR) polarimetric imaging. Polarimetric results are presented for a series of field tests conducted at various locations and soil types. Well-calibrated Stokes images, S0, S1, S2, and the degree-of-linear-polarization (DoLP) are recorded for different line-of-sight (LOS) slant paths at varying distances. Results span a three-year time period in which three different LWIR polarimetric camera systems are used. All three polarimetric imaging platforms used a spinning-achromatic-retarder (SAR) design capable of achieving high polarimetric frame rates and good radiometric throughput without the loss of spatial resolution inherent in other optical designs. Receiver-operating-characteristic (ROC) analysis and a standardized contrast parameter are used to compare detectability between conventional LWIR thermal and polarimetric imagery. Results suggest improved detectability, regardless of geographic location or soil type. PMID- 23037384 TI - Full-range spectral domain Jones matrix optical coherence tomography using a single spectral camera. AB - Jones matrix optical coherence tomography can fully characterize depth-resolved polarization properties in tissue. In this report, we described a simple single camera based implementation of full-range spectral domain Jones matrix optical coherence tomography. The Jones matrix reconstruction algorithm was described in detail and system calibration was demonstrated with comprehensive examples. In addition to the conventional structural image, the images of retardance, optical axis and relative attenuation can be obtained from the measured Jones matrix image. Both in vitro and in vivo image examples were presented to demonstrate the polarization imaging ability of the system. PMID- 23037385 TI - Giant transverse optical forces in nanoscale slot waveguides of hyperbolic metamaterials. AB - Here we demonstrate that giant transverse optical forces can be generated in nanoscale slot waveguides of hyperbolic metamaterials, with more than two orders of magnitude stronger compared to the force created in conventional silicon slot waveguides, due to the nanoscale optical field enhancement and the extreme optical energy compression within the air slot region. Both numerical simulation and analytical treatment are carried out to study the dependence of the optical forces on the waveguide geometries and the metamaterial permittivity tensors, including the attractive optical forces for the symmetric modes and the repulsive optical forces for the anti-symmetric modes. The significantly enhanced transverse optical forces result from the strong optical mode coupling strength between two metamaterial waveguides, which can be explained with an explicit relation derived from the coupled mode theory. Moreover, the calculation on realistic metal-dielectric multilayer structures indicates that the predicted giant optical forces are achievable in experiments, which will open the door for various optomechanical applications in nanoscale, such as optical nanoelectromechanical systems, optical sensors and actuators. PMID- 23037386 TI - Phase shifting technique for extended inline holographic microscopy with a pinhole array. AB - Digital inline holographic microscopy using a pinhole for sample illumination allows lensless imaging. To overcome restrictions of the sample size and density in the setup additional reference waves are generated by extending the single pinhole to a regular 2D pinhole array illumination. A technique is presented that uses phase shifting between the pinhole waves. Multiple foci with stable phase differences and a phase error (rms) of 0.027 rad generate pinhole waves which illuminate an undiluted, dense blood smear sample. Amplitude and phase images of the blood sample were successfully reconstructed. PMID- 23037387 TI - ZnCdSe/ZnCdMgSe quantum well infrared photodetector. AB - We report the design, fabrication and characterization of a II-VI Zn(0.51)Cd(0.49)Se / Zn0.45(Cd)0.42(Mg)(0.13)Se-based quantum well infrared photodetector (QWIP) with a bound to quasi-bound transition centered at 8.7 um. The good growth quality of the epitaxial layers was verified by x-ray diffraction measurements. Absorption and photocurrent measurements yield results consistent with conventional III-V QWIPs. Photocurrent measurements reveal an exponential decrease with temperature. In addition, we also observe more than 4 orders of magnitude increase in photocurrent with applied bias. By compensating the drop in temperature performance with an increase in applied bias, we achieve an operating temperature of up to 140K and a responsivity of 1-10 uA/W. PMID- 23037388 TI - Characteristics of electro-refractive modulating based on Graphene-Oxide-Silicon waveguide. AB - Graphene has attracted a high level of research interest because of its outstanding electronic transport properties and optical properties. Based on the Kubo formalism and the Maxwell equations, it's demonstrated that the optical conductivity of graphene can be controlled through the applied voltage. And we find that the graphene-oxide-silicon (GOS) based waveguide can be made into either the electro-absorptive or electron-refractive modulators. Using graphene as the active medium, we present a new electro-refractive Mach-Zender interferometer based on the GOS structure. This new GOS-based electron-refractive modulation mechanism can enable novel architectures for on-chip optical communications. PMID- 23037389 TI - Loss compensation in metamaterials through embedding of active transistor based negative differential resistance circuits. AB - Dielectric and ohmic losses in metamaterials are known to limit their practical use. In this paper, an all-electronic approach for loss compensation in metamaterials is presented. Each unit cell of the meta-material is embedded with a cross-coupled transistor pair based negative differential resistance circuit to cancel these losses. Design, simulation and experimental results for Split Ring Resonator (SRR) metamaterials with and without loss compensation are presented. Results indicate that the quality factor (Q) of the SRR improves by over 400% at 1.6 GHz, showing the effectiveness of the approach. The proposed technique is scalable over a broad frequency range and is limited only by the maximum operating frequency of transistors, which is reaching terahertz in today's semiconductor technologies. PMID- 23037390 TI - Transfer of arbitrary quantum emitter states to near-field photon superpositions in nanocavities. AB - We present a method to analyze the suitability of particular photonic cavity designs for information exchange between arbitrary superposition states of a quantum emitter and the near-field photonic cavity mode. As an illustrative example, we consider whether quantum dot emitters embedded in "L3" and "H1" photonic crystal cavities are able to transfer a spin superposition state to a confined photonic superposition state for use in quantum information transfer. Using an established dyadic Green's function (DGF) analysis, we describe methods to calculate coupling to arbitrary quantum emitter positions and orientations using the modified local density of states (LDOS) calculated using numerical finite-difference time-domain (FDTD) simulations. We find that while superposition states are not supported in L3 cavities, the double degeneracy of the H1 cavities supports superposition states of the two orthogonal modes that may be described as states on a Poincare-like sphere. Methods are developed to comprehensively analyze the confined superposition state generated from an arbitrary emitter position and emitter dipole orientation. PMID- 23037391 TI - Sampled Fiber Bragg Grating spectral synthesis. AB - In this paper, a technique to estimate the deformation profile of a Sampled Fiber Bragg Grating (SFBG) is proposed and experimentally verified. From the SFBG intensity reflection spectrum, any arbitrary longitudinal axis deformation profile applied to a SFBG is estimated. The synthesis algorithm combines a custom defined error metric to compare the measured and the synthetic spectra and the Particle Swarm Optimization technique to get the deformation profile. Using controlled deformation profiles, the proposed method has been successfully checked by means of simulated and experimental tests. The results obtained under different controlled cases show a remarkable repetitiveness (< 50 MUepsilon) and good spatial accuracy (< 1 mm). PMID- 23037392 TI - High average power picosecond pulse generation from a thulium-doped all-fiber MOPA system. AB - We report a stable highly-integrated high power picosecond thulium-doped all fiber MOPA system without using conventional chirped pulse amplification technique. The master oscillator was passively mode-locked by a SESAM to generate average power of 15 mW at a fundamental repetition rate of 103 MHz in a short linear cavity, and a uniform narrow bandwidth FBG is employed to stabilize the passively mode-locked laser operation. Two-stage double-clad thulium-doped all fiber amplifiers were used directly to boost average power to 20.7 W. The laser center wavelength was 1962.8 nm and the pulse width was 18 ps. The single pulse energy and peak-power after the amplication were 200 nJ and 11.2 kW respectively. To the best of our knowledge, this is the highest average power ever reported for a picosecond thulium-doped all-fiber MOPA system. PMID- 23037393 TI - Passively Q-switched Nd:Sc0.2Y0.8SiO5 dual-wavelength laser with the orthogonally polarized output. AB - We have demonstrated a laser-diode pumped continuous-wave (CW) and passively Q switched laser with a Nd:Sc(0.2)Y(0.8)SiO(5) (Nd:SYSO) crystal for the first time. In the CW operation, the laser was found to oscillate in tri-wavelength regime at 1074.8 nm, 1076.6 nm and 1078.2 nm, respectively. The maximum CW output power of 1.96 W was obtained, giving an optical-to-optical conversion efficiency of 35% and a slope efficiency of 39%. Using either Cr(4+):YAG or V(3+):YAG crystal as saturable absorber, stable passively Q-switched laser was obtained at dual-wavelength of 1074.8 nm and 1078.2 nm with orthogonal-polarization. The maximum average output power, pulse repetition rate, and shortest pulse width were 1.03 W, 50 kHz, and 24 ns, respectively. The passively Q-switched dual wavelength laser could be potentially used as a source for generation of terahertz radiation. PMID- 23037394 TI - Numerical twin image suppression by nonlinear segmentation mask in digital holography. AB - The in-line holography has obvious advantages especially in wider spatial bandwidth over the off-axis holography. However, a direct current(DC)-noise and an unwanted twin image should be separated or eliminated in the in-line holography for a high quality reconstruction. An approach for suppressing the twin image is proposed by separating the real and twin image regions in the digital holography. Specifically, the initial region of real and twin images is obtained by a blind separation matrix, and the segmentation mask to suppress the twin image is calculated by nonlinear quantization from the segmented image. For the performance evaluation, the proposed method is compared with the existing approaches including the overlapping block variance and manual-based schemes. Experimental results showed that the proposed method has a better performance at the overlapped region of the real and twin images. Additionally, the proposed method causes less loss of real image than the overlapping block variance-based scheme. Therefore, we believe that the proposed scheme can be a useful tool for high quality reconstruction in the in-line holography. PMID- 23037395 TI - Compact and fast photonic crystal silicon optical modulators. AB - We demonstrate the first sub-100 MUm silicon Mach-Zehnder modulators (MZMs) that operate at >10 Gb/s, by exploiting low-dispersion slow-light in lattice-shifted photonic crystal waveguides (LSPCWs). We use two LSPCW-MZM structures, one with LSPCWs in both arms of the MZM, and the other with an LSPCW in only one of the arms. Using the first structure we demonstrate 10 Gb/s operation with a operating bandwidth of 12.5 nm, in a device with a phase-shifter length of only 50 MUm. Using the second structure, owing to a larger group index as well as lower spectral noise, we demonstrate 40 Gb/s operation with a phase-shifter length of only 90 MUm, which is more than an order-of-magnitude shorter than most 40 Gb/s MZMs. PMID- 23037396 TI - Asymmetries in the momentum distributions of electrons stripped by a XUV chirped pulse in the presence of a laser field. AB - The ionization of hydrogen by a chirped XUV pulse in the presence of a few cycle infrared laser pulse has been investigated. The electron momentum distribution has been obtained by treating the interaction of the atom with the XUV radiation at the first order of the time-dependent perturbation theory and describing the emitted electron through the Coulomb-Volkov wavefunction. The results of the calculations agree with the ones found by solving numerically the time-dependent Schrodinger equation. It has been found that depending on the delay between the pulses the combined effect of the XUV chirp and of the steering action on the infrared field brings about asymmetries in the electron momentum distribution. These asymmetries may give information on both the chirp and the XUV pulse duration. PMID- 23037397 TI - Pulse shortening of gain switched single mode semiconductor lasers using a variable delay interferometer. AB - We propose a pulse shaping and shortening technique for pulses generated from gain switched single mode semiconductor lasers, based on a Mach Zehnder interferometer with variable delay. The spectral and temporal characteristics of the pulses obtained with the proposed technique are investigated with numerical simulations. Experiments are performed with a Distributed Feedback laser and a Vertical Cavity Surface Emitting Laser, emitting at 1.5 um, obtaining pulse duration reduction of 25-30%. The main asset of the proposed technique is that it can be applied to different devices and pulses, taking advantage of the flexibility of the gain switching technique. PMID- 23037398 TI - Structural factors impacting carrier transport and electroluminescence from Si nanocluster-sensitized Er ions. AB - We present an analysis of factors influencing carrier transport and electroluminescence (EL) at 1.5 um from erbium-doped silicon-rich silica (SiOx) layers. The effects of both the active layer thickness and the Si-excess content on the electrical excitation of erbium are studied. We demonstrate that when the thickness is decreased from a few hundred to tens of nanometers the conductivity is greatly enhanced. Carrier transport is well described in all cases by a Poole Frenkel mechanism, while the thickness-dependent current density suggests an evolution of both density and distribution of trapping states induced by Si nanoinclusions. We ascribe this observation to stress-induced effects prevailing in thin films, which inhibit the agglomeration of Si atoms, resulting in a high density of sub-nm Si inclusions that induce traps much shallower than those generated by Si nanoclusters (Si-ncs) formed in thicker films. There is no direct correlation between high conductivity and optimized EL intensity at 1.5 um. Our results suggest that the main excitation mechanism governing the EL signal is impact excitation, which gradually becomes more efficient as film thickness increases, thanks to the increased segregation of Si-ncs, which in turn allows more efficient injection of hot electrons into the oxide matrix. Optimization of the EL signal is thus found to be a compromise between conductivity and both number and degree of segregation of Si-ncs, all of which are governed by a combination of excess Si content and sample thickness. This material study has strong implications for many electrically-driven devices using Si-ncs or Si excess mediated EL. PMID- 23037399 TI - Square-wave oscillations in semiconductor ring lasers with delayed optical feedback. AB - We analyze experimentally and theoretically the effects of delayed optical cross feedback in semiconductor ring lasers. We show that under appropriate conditions, feeding of only one directional mode back into the counter-propagating mode leads to square-wave oscillations. In this regime, the laser switches regularly between the two counter-propagating modes with a period close to twice the roundtrip time in the external feedback loop. We find that these oscillations are robust and appear for a wide range of parameters as long as a small asymmetry in the linear coupling between both modes is present. We show that by increasing the feedback strength or the injection current, the square-wave oscillations gradually disappear. Due to noise, mode-hopping between stable lasing in one directional mode and square wave oscillations is observed in this transition region. PMID- 23037400 TI - Multimode fiber laser for simultaneous measurement of strain and temperature based on beat frequency demodulation. AB - A multimode fiber laser sensor system for simultaneous measurement of strain and temperature is proposed and demonstrated. Because of the long cavity and birefringence, longitudinal mode beat frequency and polarization mode beat frequency are achieved in the beat frequency signals of the multimode fiber laser. The strain and temperature can be obtained by monitoring both of them for their different strain and temperature responses. The experimental measurement errors are within +/- 16.2 MUepsilon and +/- 1.9 degrees C. The usage of only one fiber laser and one demodulation system makes the system simple, cost effective and portable. PMID- 23037401 TI - System evaluation of economic 16/32chs 1.25Gbps WDM-PON with self-seeded RSOA. AB - We investigate a novel WDM-PON system by using self-seeded Reflective Semiconductor Optical Amplifier (RSOA) both in downstream and upstream. The transmission performance is evaluated and reported for the first time and meets carrier level requirements. PMID- 23037402 TI - Fabrication and characterization of suspended SiO2 ridge optical waveguides and the devices. AB - Novel suspended SiO(2) ridge optical waveguides on silicon are fabricated and characterized. The present suspended SiO(2) ridge optical waveguide has a SiO(2) ridge core surrounded by air. The propagation loss and the bend loss measured are about 0.385dB/cm and 0.037dB/90 degrees respectively for the fabricated 1 MUm wide waveguides with a bending radius of 100 MUm when operating at the wavelength of 1550 nm. With the present suspended SiO(2) optical waveguides, a small racetrack resonator with a radius of 100 MUm is also demonstrated and the measured Q-factor is about 3160. PMID- 23037403 TI - Theory of SNAP devices: basic equations and comparison with the experiment. AB - A SNAP (Surface Nanoscale Axial Photonics) device consists of an optical fiber with introduced nanoscale effective radius variation, which is coupled to transverse input/output waveguides. The input waveguides excite whispering gallery modes circulating near the fiber surface and slowly propagating along the fiber axis. In this paper, the theory of SNAP devices is developed and applied to the analysis of transmission amplitudes of simplest SNAP models exhibiting a variety of asymmetric Fano resonances and also to the experimental characterization of a SNAP bottle microresonator and to a chain of 10 coupled microresonators. Excellent agreement between the theory and the experiment is demonstrated. PMID- 23037404 TI - Angular bandpass filters based on dielectric resonant waveguide gratings. AB - We report on a novel concept for transmissive optical elements based on resonant waveguide gratings (RWGs), which enables the realization of direction selective filters. Hereby, the broadband reflectivity of an RWG for nearly normal incidence angles is combined with high diffractive efficiency in transmission for a specific angle of incidence. Silicon is used as material with high refractive index and good compatibility with semiconductor fabrication. By adjusting the grating parameters different transmission angles and angular widths of the transmission range are feasible. First experimental results of the introduced filters provide a high transmission up to 63% at an incidence angle of 45 degrees with a full width at half maximum of 20 degrees . PMID- 23037405 TI - Hybrid lasing in an ultra-long ring fiber laser. AB - In this paper, we reported the realization of an ultra-long ring fiber laser (RFL) with hybrid emission related to both random lasing and cavity resonance. Compared with a linear random fiber laser (LRFL), the Rayleigh scattering (RS) inducting distributed feedback effect and the cavity inducting resonance effect exist simultaneously in the laser, which reduces the lasing threshold considerably and provides a hybrid way to form random lasing (RL). The laser output can be purely modeless RL when pump power is high enough. It is also discovered that the laser is insensitive to temperature variation and mechanical disturbance, this is unique and quite different from conventional RFLs which are environmentally unstable due to existence of the cavity modes. PMID- 23037406 TI - Broadband NIR luminescence from a new bismuth doped Ba2B5O9Cl crystal: evidence for the Bi0 model. AB - A new type of bismuth doped Ba(2)B(5)O(9)Cl crystal is reported to exhibit broadband near infrared (NIR) photoluminescence at room temperature, which has been identified here originating from elementary bismuth atom. Rietveld refining, static and dynamic spectroscopic properties reveal two types of Bi(0) centers in the doped compound due to the successful substitution for two different nine coordinated barium lattice sites. These centers can be created only in a reducing condition, and when treated in air and N(2)/H(2) flow in turn, they can be removed and restored reversely. As the dwelling time is prolonged in N(2)/H(2) at high temperature, conversion from Bi(2+) to Bi(0), as reflected by changes of their relative emission intensities, is witnessed in the crystal of Ba(2)B(5)O(9)Cl:Bi. The lifetime of the NIR luminescence was observed in a magnitude of ~30 MUs, rather different from bismuth doped either glasses or crystals reported previously. PMID- 23037407 TI - Diffractive optical element embedded in silver-doped nanocomposite glass. AB - A diffractive optical element is fabricated with relative ease in a glass containing spherical silver nanoparticles 30 to 40 nm in diameter and embedded in a surface layer of thickness ~10 MUm. The nanocomposite was sandwiched between a mesh metallic electrode with a lattice constant 2 MUm, facing the nanoparticle containing layer and acting as an anode, and a flat metal electrode as cathode. Applying moderate direct current electric potentials of 0.4 kV and 0.6 kV at an elevated temperature of 200 degrees C for 30 minutes across the nanocomposites led to the formation of a periodic array of embedded structures of metallic nanoparticles. The current-time dynamics of the structuring processes, optical analyses of the structured nanocomposites and diffraction pattern of one such fabricated element are presented. PMID- 23037408 TI - Optimal tracking of a Brownian particle. AB - Optical tracking of a fluorescent particle in solution faces fundamental constraints due to Brownian motion, diffraction, and photon shot noise. Background photons and imperfect tracking apparatus further degrade tracking precision. Here we use a model of particle motion to combine information from multiple time-points to improve the localization precision. We derive successive approximations that enable real-time particle tracking with well controlled tradeoffs between precision and computational cost. We present the theory in the context of feedback electrokinetic trapping, though the results apply to optical tracking of any particle subject to diffusion and drift. We use numerical simulations and experimental data to validate the algorithms' performance. PMID- 23037409 TI - Performance enhancement of sub-nanosecond diode-pumped passively Q-switched Yb:YAG microchip laser with diamond surface cooling. AB - We experimentally confirm that diamond surface cooling can significantly enhance the output performance of a sub-nanosecond diode-end-pumped passively Q-switched Yb:YAG laser. It is found that the pulse energy obtained with diamond cooling is approximately 1.5 times greater than that obtained without diamond cooling, where a Cr(4+):YAG absorber with the initial transmission of 84% is employed. Furthermore, the standard deviation of the pulse amplitude peak-to-peak fluctuation is found to be approximately 3 times lower than that measured without diamond cooling. Under a pump power of 3.9 W, the passively Q-switched Yb:YAG laser can generate a pulse train of 3.3 kHz repetition rate with a pulse energy of 287 MUJ and with a pulse width of 650 ps. PMID- 23037410 TI - Amorphous silicon nanowires combining high nonlinearity, FOM and optical stability. AB - We demonstrate optically stable amorphous silicon nanowires with both high nonlinear figure of merit (FOM) of ~5 and high nonlinearity Re(gamma) = 1200W( 1)m(-1). We observe no degradation in these parameters over the entire course of our experiments including systematic study under operation at 2 W coupled peak power (i.e. ~2GW/cm(2)) over timescales of at least an hour. PMID- 23037411 TI - Magnetic interaction in all silicon waveguide spherical coupler device. AB - The magnetic field component of light in dielectric materials generally plays a negligible role at optical frequency values. However, it is a key component of metal based metamaterials. Here we report on the dominant role of the magnetic interaction in a dielectric spherical silicon nanocavity coupled to a silicon waveguide. The analytical method, as well as the finite difference time domain (FDTD) simulation, show a three dimensional (3D) magnetic trap effect when the magnetic like Mie resonances of the nanocavity are excited. PMID- 23037412 TI - Enhanced coherent terahertz Smith-Purcell superradiation excited by two electron beams. AB - This paper presents the studies on the enhanced coherent THz Smith-Purcell superradiation excited by two pre-bunched electron beams that pass through the 1 D sub-wavelength holes array. The Smith-Purcell superradiation has been clearly observed. The radiation emitting out from the system has the radiation angle matching the 2nd harmonic frequency component of the pre-bunched electron beams. The results show that the two electron beams can be coupled with each other through the holes array so that the intensity of the radiated field has been enhanced about twice higher than that excited by one electron beam. Consequently superradiation at the frequency of 0.62 THz can be generated with 20A/cm(2) current density of electron beam based on above mechanism. The advantages of low injection current density and 2nd harmonic radiation promise the potential applications in the development of electron-beam driven THz sources. PMID- 23037413 TI - Depth-filtered digital holography. AB - We introduce depth-filtered digital holography (DFDH) as a method for quantitative tomographic phase imaging of buried layers in multilayer samples. The procedure is based on the acquisition of multiple holograms for different wavelengths. Analyzing the intensity over wavelength pixel wise and using an inverse Fourier transform leads to a depth-profile of the multilayered sample. Applying a windowed Fourier transform with a narrow window, we choose a depth-of interest (DOI) which is used to synthesize filtered interference patterns that just contain information of this limited depth. We use the angular spectrum method to introduce an additional spatial filtering and to reconstruct the corresponding holograms. After a short theoretical framework we show experimental proof-of-principle results for the method. PMID- 23037414 TI - A new design of light illumination scheme for deep tissue photoacoustic imaging. AB - A new light illumination scheme to increase imaging depth in photoacoustic (PA) imaging was designed and evaluated by in silico simulations and tested by in vitro experiments. A relatively large portion of the light energy shining into the body of a human reflects off the skin surfaces. Collecting the reflected light and redirecting it onto skin surfaces will increase the effective input energy, resulting in an increase of light penetration depth for the same light source. Its performance in PA imaging was evaluated using a finite element (FE) based numerical simulation model composed of four modules. In the in vitro experiments with the light catcher, PA image of multiple targets at different locations exhibited an enhancement both in uniformity and in depth of the light illumination. PMID- 23037415 TI - Sidelobes in the response of arrayed waveguide gratings caused by polarization rotation. AB - Earlier it was observed that polarization rotation in an AWG built from birefringent waveguides can result in sidelobes in its response. This effect was measured in a polarization sensitive AWG with an orthogonal layout. Now we investigate through detailed simulation whether this effect also exists in polarization desensitised AWGs. It is shown that a dispersion compensated AWG does not suffer from a polarization sidelobe. Alternatively, the AWG can be designed to minimize polarization rotation to suppress the sidelobe. PMID- 23037416 TI - Environmentally stable all-PM all-fiber giant chirp oscillator. AB - We report on an environmentally stable giant chirp oscillator operating at 1030 nm. Thanks to the use of a nonlinear amplifying loop mirror as the mode-locker, we are able to extract pulse energies in excess of 10 nJ from a robust all-PM cavity with no free-space elements. Extensive numerical simulations reveal that the output oscillator energy and duration can simply be up-scaled through the lengthening of the cavity with suitably positioned single-mode fiber. Experimentally, using different cavity lengths we have achieved environmentally stable mode-locking at 10, 3.7 and 1.7 MHz with corresponding pulse energies of 2.3, 10 and 16 nJ. In all cases external grating-pair compression below 400 fs has been demonstrated. PMID- 23037417 TI - Particle-wave duality in quantum tunneling of a bright soliton. AB - One of the most fundamental difference between classical and quantum mechanics is observed in the particle tunneling through a localized potential: the former predicts a discontinuous transmission coefficient (T) as a function in incident velocity between one (complete penetration) and zero (complete reflection); while in the latter T always changes smoothly with a wave nature. Here we report a systematic study of the quantum tunneling property for a bright soliton, which behaves as a classical particle (wave) in the limit of small (large) incident velocity. In the intermediate regime, the classical and quantum properties are combined via a finite (but not full) discontinuity in the tunneling transmission coefficient. We demonstrate that the formation of a localized bound state is essential to describe such inelastic collisions, showing a nontrivial nonlinear effect on the quantum transportation of a bright soliton. PMID- 23037418 TI - Comparative assessment of freeform polynomials as optical surface descriptions. AB - Slow-servo single-point diamond turning as well as advances in computer controlled small lap polishing enables the fabrication of freeform optics, or more specifically, optical surfaces for imaging applications that are not rotationally symmetric. Various forms of polynomials for describing freeform optical surfaces exist in optical design and to support fabrication. A popular method is to add orthogonal polynomials onto a conic section. In this paper, recently introduced gradient-orthogonal polynomials are investigated in a comparative manner with the widely known Zernike polynomials. In order to achieve numerical robustness when higher-order polynomials are required to describe freeform surfaces, recurrence relations are a key enabler. Results in this paper establish the equivalence of both polynomial sets in accurately describing freeform surfaces under stringent conditions. Quantifying the accuracy of these two freeform surface descriptions is a critical step in the future application of these tools in both advanced optical system design and optical fabrication. PMID- 23037419 TI - Stochastic logic gate that exploits noise and polarization bistability in an optically injected VCSEL. AB - We study numerically the dynamics of a vertical-cavity surface-emitting laser (VCSEL) with optical injection and show that the interplay of polarization bistability and noise yields a reliable logic output to two logic inputs. Specifically, by encoding the logic inputs in the strength of the light injected into the suppressed polarization mode of the VCSEL (the so-called 'orthogonal' injection), and by decoding the output logic response from the polarization state of the emitted light, we demonstrate an all-optical stochastic logic gate that exploits the ubiquitous presence of noise. It gives the correct logic output response for as short as 5 ns bit times when the dimensionless spontaneous emission coefficient, beta(sp), is within the range 10(-4)-10(-1). Considering that typical values of beta(sp) in semiconductor lasers are in the range 10(-5) 10(-4), the VCSEL-based logic gate can be implemented with nowadays commercially available VCSELs, exploiting either their intrinsic noise, or external and background noise sources. PMID- 23037420 TI - Polarization scramblers with plasmonic meander-type metamaterials. AB - Due to plasmonic excitations, metallic meander structures exhibit an extraordinarily high transmission within a well-defined pass band. Within this frequency range, they behave like almost ideal linear polarizers, can induce large phase retardation between s- and p-polarized light and show a high polarization conversion efficiency. Due to these properties, meander structures can interact very effectively with polarized light. In this report, we suggest a novel polarization scrambler design using spatially distributed metallic meander structures with random angular orientations. The whole device has an optical response averaged over all pixel orientations within the incident beam diameter. We characterize the depolarizing properties of the suggested polarization scrambler with the Mueller matrix and investigate both single layer and stacked meander structures at different frequencies. The presented polarization scrambler can be flexibly designed to work at any wavelength in the visible range with a bandwidth of up to 100 THz. With our preliminary design, we achieve depolarization rates larger than 50% for arbitrarily polarized monochromatic and narrow-band light. Circularly polarized light could be depolarized by up to 95% at 600 THz. PMID- 23037421 TI - Three-dimensional optoacoustic tomography at video rate. AB - Using optoacoustic excitation, a complete volumetric tomographic data sets from the imaged object can in principle be generated with a single interrogating laser pulse. Thus, optoacoustic imaging intrinsically has the potential for fast three dimensional imaging. We have developed a system capable of acquiring volumetric optoacoustic data in real time and showcase in this work the undocumented capacity to generate high resolution three-dimensional optoacoustic images at a rate of 10 Hz, currently mainly limited by the pulse repetition rate of the excitation laser. PMID- 23037422 TI - Digital confocal microscope. AB - We demonstrate experimentally a scanning confocal microscopy technique based on digital holography. The method relies on digital holographic recording of the scanned spot. The data collected in this way contains all the necessary information to digitally produce three-dimensional images. Several methods to treat the data are presented. Examples of reflection and transmission images of epithelial cells and mouse brain tissue are shown. PMID- 23037423 TI - Fully-tunable microwave photonic filter with complex coefficients using tunable delay lines based on frequency-time conversions. AB - A fully electrically tunable microwave photonic filter is realized by the implementation of delay lines based on frequency-time conversion. The frequency response and free spectral range (FSR) of the filter can be engineered by a simple electrical tuning of the delay lines. The method has the capability of being integrated on a silicon photonic platform. In the experiment, a 2-tap tunable microwave photonic filter with a 3-dB bandwidth of 2.55 GHz, a FSR of 4.016 GHz, a FSR maximum tuning range from -354 MHz to 354 MHz and a full FSR translation range is achieved. PMID- 23037424 TI - Self-aligned silicon fins in metallic slits as a platform for planar wavelength selective nanoscale resonant photodetectors. AB - We propose and demonstrate a novel nanoscale resonant metal-semiconductor-metal (MSM) photodetector structure based on silicon fins self-aligned to metallic slits. This geometry allows the center wavelength of the photodetector's spectral response to be controlled by the silicon fin width, allowing multiple detectors, each sensitive to a different wavelength, to be fabricated in a single-step process. In addition, the detectors are highly efficient with simulations showing ~67% of the light (lambda = 800 nm) incident on the silicon fin being absorbed in a region of thickness ~170 nm whereas the absorption length at the same wavelength is ~10 um. This approach is promising for the development of multispectral imaging sensors and low-capacitance photodetectors for short-range optical interconnects. PMID- 23037425 TI - Ultrahigh-Q photonic crystal nanocavities in wide optical telecommunication bands. AB - We have studied the feasibility of extending the operating wavelength range of high-Q silicon nanocavities above and below the 1.55 MUm wavelength band, while maintaining Q factors of more than one million. We have succeeded in developing such nanocavities in the optical telecommunication bands from 1.27 MUm to 1.50 MUm. Very high Q values of more than two million were obtained even for the 1.30 MUm band. The Q values increase proportionally to the resonant wavelength because the scattering loss decreases. We have also analyzed the influence of absorption due to surface water. We conclude that high-Q nanocavities are feasible for an even wider wavelength region including parts of the mid-infrared. PMID- 23037426 TI - Quasi-phase-matching for third harmonic generation in noble gases employing ultrasound. AB - We study a novel method of quasi-phase-matching for third harmonic generation in a gas cell using the periodic modulation of the gas pressure and thus of the third order nonlinear coefficient in the axial direction created by an ultrasound wave. Using a comprehensive numerical model we describe the quasi-phase matched third harmonic generation of UV (at 266 nm) and VUV pulses (at 133 nm) by using pump pulses at 800 nm and 400 nm, respectively, with pulse energy in the range from 3 mJ to 1 J. In addition, using chirped pump pulses, the generation of sub 20-fs VUV pulses without the necessity for an external chirp compensation is predicted. PMID- 23037427 TI - First-principles method for high-Q photonic crystal cavity mode calculations. AB - We present a first-principles method to compute radiation properties of ultra high quality factor photonic crystal cavities. Our Frequency-domain Approach for Radiation (FAR) can compute the far-field radiation pattern and quality factor of cavity modes ~ 100 times more rapidly than conventional finite-difference time domain calculations. We explain how the radiation pattern depends on the perturbation used to create the cavity and on the Bloch modes of the photonic crystal. PMID- 23037428 TI - A new method for obtaining transparent electrodes. AB - In this article, we propose a simple scheme to make a metallic film on a semi infinite substrate optically transparent, thus obtaining a completely transparent electrode in a desired frequency range. By placing a composite layer consisting of dielectric and metallic stripes on top of the metallic one, we found that the back-scattering from the metallic film can be almost perfectly canceled by the composite layer under certain conditions, leading to transparency of the whole structure. We performed proof-of-concept experiments in the terahertz domain to verify our theoretical predictions, using carefully designed metamaterials to mimic plasmonic metals in optical regime. Experiments are in excellent agreement with full-wave simulations. PMID- 23037429 TI - All-optical reservoir computing. AB - Reservoir Computing is a novel computing paradigm that uses a nonlinear recurrent dynamical system to carry out information processing. Recent electronic and optoelectronic Reservoir Computers based on an architecture with a single nonlinear node and a delay loop have shown performance on standardized tasks comparable to state-of-the-art digital implementations. Here we report an all optical implementation of a Reservoir Computer, made of off-the-shelf components for optical telecommunications. It uses the saturation of a semiconductor optical amplifier as nonlinearity. The present work shows that, within the Reservoir Computing paradigm, all-optical computing with state-of-the-art performance is possible. PMID- 23037430 TI - Three-dimensional retinal and choroidal capillary imaging by power Doppler optical coherence angiography with adaptive optics. AB - Retinal and choroidal vascular imaging is a key to the better understanding and diagnosis of eye diseases. To achieve comprehensive three-dimensional capillary imaging, we used an enhanced vascular imaging technique, so called adaptive optics optical coherence angiography (AO-OCA). AO-OCA enables in vivo high resolution and high-contrast micro-vascular imaging by detecting Doppler frequency shifts. Using this technique, the retinal and choroidal vasculatures of healthy subjects were imaged. The results show that both intensity and Doppler power images have sufficient contrast to discriminate almost all vasculatures from the static tissue. However, the choriocapillaris, pre-arterioles, and post venules in the Sattler layer were more contrasted by the Doppler technique. In conclusion, AO-OCA enables three-dimensional capillary imaging, and is especially useful for the detection of the choriocapillaris and choroidal capillary network. PMID- 23037431 TI - Optical fiber Fabry-Perot interferometer cavity fabricated by femtosecond laser micromachining and fusion splicing for refractive index sensing. AB - We demonstrate a fiber in-line Fabry-Perot interferometer cavity sensor for refractive index measurement. The interferometer cavity is formed by drilling a micro-hole at the cleaved fiber end facet, followed by fusion splicing. A micro channel is inscribed by femtosecond laser micromachining to vertically cross the cavity to allow liquid to flow in. The refractive index sensitivity obtained is ~994 nm/RIU (refractive index unit). Such a device is simple in configuration, easy for fabrication and reliable in operation due to extremely low temperature cross sensitivity of ~4.8 * 10(-6) RIU/ degrees C. PMID- 23037432 TI - A general design algorithm for low optical loss adiabatic connections in waveguides. AB - Single-mode waveguide designs frequently support higher order transverse modes, usually as a consequence of process limitations such as lithography. In these systems, it is important to minimize coupling to higher-order modes so that the system nonetheless behaves single mode. We propose a variational approach to design adiabatic waveguide connections with minimal intermodal coupling. An application of this algorithm in designing the "S-bend" of a whispering-gallery spiral waveguide is demonstrated with approximately 0.05 dB insertion loss. Compared to other approaches, our algorithm requires less fabrication resolution and is able to minimize the transition loss over a broadband spectrum. The method can be applied to a wide range of turns and connections and has the advantage of handling connections with arbitrary boundary conditions. PMID- 23037433 TI - The light filtering and guiding properties of high finesse phase resonant compound gratings. AB - Phase resonances in compound gratings are studied in the frequency and time domains, with the gratings having two dissimilar grooves within the unit cell that each support waveguide cavity modes that couple. Described in this work are the dependence of the phase resonances' Q on the degree of difference between the grooves in the unit cell, their optical properties, a closed-form expression describing their dispersion, their excitation, and the extraction of energy from the phase resonances into free space and into a waveguide. Application to optical filters and corrugated surface antennas are discussed. PMID- 23037434 TI - Two-out-of-two color matching based visual cryptography schemes. AB - Visual cryptography which consists in sharing a secret message between transparencies has been extended to color prints. In this paper, we propose a new visual cryptography scheme based on color matching. The stacked printed media reveal a uniformly colored message decoded by the human visual system. In contrast with the previous color visual cryptography schemes, the proposed one enables to share images without pixel expansion and to detect a forgery as the color of the message is kept secret. In order to correctly print the colors on the media and to increase the security of the scheme, we use spectral models developed for color reproduction describing printed colors from an optical point of view. PMID- 23037435 TI - Imaging velocities of a vibrating object by stroboscopic sideband holography. AB - We propose here to combine sideband holography with stroboscopic illumination synchronized with the vibration of an object. By sweeping the optical frequency of the reference beam such a way the holographic detection is tuned on the successive sideband harmonic ranks, we are able to image the instantaneous velocities of the object. Since the stroboscopic illumination is made with an electronic device, the method is compatible with fast (up to several MHz) vibration motions. The method is demonstrated with a vibrating clarinet reed excited sinusoidally at 2 kHz, and a stroboscopic illumination with cyclic ratio 0.15. Harmonic rank up to n = +/- 100 are detected, and a movie of the instantaneous velocities is reported. PMID- 23037436 TI - Wavelength tunable infrared light source based on semiconductor-integrated liquid crystal filter. AB - This work proposes an electrically tunable infrared light source based on a new compact structure, i.e., an AlGaInAs semiconductor multiple quantum well (MQW) integrated with a liquid crystal Fabry-Perot filter. The AlGaInAs MQW is used as a luminance layer that emits broadband light. By sandwiching the AlGaInAs and LC material with two conducting mirrors, the active light source with an optical filter can be tuned with a wide wavelength range. The filter filled with nematic liquid crystal enables continuous tuning of emission along the extraordinary mode and provides a 58 nm tuning range with a bias of 14 V. The simulation results of wavelength and tunability are consistent with the experimental results. Cholesteric liquid crystal with a planar texture is also used to examine the properties of the tunable light source. Under an electric field, all the helical liquid crystal molecules tend to be aligned parallel to the field. The variation of the refractive index is normal to the substrate surface, and the polarization independent tuning range is 41 nm. The wide tuning range and the polarization properties observed when NLC and CLC are respectively incorporated into the AlGaInAs based Fabry-Perot cavity suggest that this integration scheme has potential for applying to optical communication system. PMID- 23037437 TI - None pilot-tones and training sequence assisted OFDM technology based on multiple differential amplitude phase shift keying. AB - This paper proposes a novel none pilot-assisted orthogonal frequency division multiplexing (OFDM) technology based on multi-differential amplitude phase shift keying (mDAPSK) for optical OFDM system. It doesn't require any bandwidth consuming pilot tones or training sequence for channel estimation due to the differential detection during demodulation. In the experiment, a 41.31 Gb/s 64DAPSK-OFDM signal without pilot tones is successfully transmitted over 160-km single mode fiber (SMF). The performance comparison between multi-quadrature amplitude modulation (mQAM) and mDAPSK is also given in the experiment, and the results indicate a prospect of this technology in optical OFDM system. PMID- 23037438 TI - The role of phase coherence in seeded supercontinuum generation. AB - The noise properties of a supercontinuum can be controlled by modulating the pump with a seed pulse. In this paper, we numerically investigate the influence of seeding with a partially phase coherent weak pulse or continuous wave. We demonstrate that the noise properties of the generated supercontinuum are highly sensitive to the degree of phase noise of the seed and that a nearly coherent seed pulse is needed to achieve a coherent pulse break-up and low noise supercontinuum. The specific maximum allowable linewidth of the seed laser is found to decrease with increasing pump power. PMID- 23037439 TI - Temporal synchronization and spectral combining of pulses from fiber lasers Q switched by independent MEMS micro-mirrors. AB - We present what we believe to be the first demonstration of spectral combining of multiple fiber lasers Q-switched by independent micro-electro-mechanical system (MEMS). By correlating the actuation of the individual MEMS devices, the associated Q-switched lasers can be operated in either synchronous or asynchronous modes in such a way that their overall combined output may result in high energy emission pulses or in laser emission with higher pulse repetition rate. In a proof-of-principle experiment, we demonstrate the combination of four individual Q-switched lasers (each of them operating at 20 kHz repetition rate) leading to a final laser system generating pulses with a repetition rate of 80 kHz. PMID- 23037440 TI - Method to map individual electromagnetic field components inside a photonic crystal. AB - We present a method to map the absolute electromagnetic field strength inside photonic crystals. We apply the method to map the dominant electric field component Ez of a two-dimensional photonic crystal slab at microwave frequencies. The slab is placed between two mirrors to select Bloch standing waves and a subwavelength spherical scatterer is scanned inside the resulting resonator. The resonant Bloch frequencies shift depending on the electric field at the position of the scatterer. To map the electric field component Ez we measure the frequency shift in the reflection and transmission spectrum of the slab versus the scatterer position. Very good agreement is found between measurements and calculations without any adjustable parameters. PMID- 23037441 TI - Terahertz beam steering using interference of femtosecond optical pulses. AB - A terahertz (THz) beam steering method is demonstrated by applying the characteristic of grating lobe (GL) radiation from a linear array antenna and the interference of femtosecond optical pulses. A photoconductive device is illuminated by two femtosecond laser beams combined at an angle of less than 0.5 degrees . Considering the interference pattern as a THz point source array, THz GL radiation is generated through the superposition of radiation emitted from all point sources and steered by varying the interval of the interference pattern. The THz beam direction could be changed by 20 degrees at 0.93THz by varying the relative incidence angle of the pump beams by 0.033 degrees . PMID- 23037442 TI - Photo-chemical study and optical properties of microtips self- written on vertical laser diodes using NIR photo-polymerization. AB - Near infra-red (NIR) self-guided photo-polymerization is investigated in the context of micro-optics photo-fabrication on VCSELs (Vertical-Cavity Surface Emitting Lasers). We present the optimized process we have developed to allow for a collective fabrication on III-V devices wafers under real-time optical monitoring. The influence of photo-chemical parameters on final micro-elements dimensions is studied for two types of single mode 760 nm VCSELs. The difference of the resulting tip shape between the two lasers is due to the strong differences of their emissions, as they are nicely reproduced by the computed near-field profiles. The tip shapes are also compared to those produced by the light emitted by an optical fiber and differences with VCSEL tips are discussed. Also the VCSEL characteristics with fabricated tips are discussed and found in good agreement with optical modeling. PMID- 23037443 TI - A fully integrated high-Q Whispering-Gallery Wedge Resonator. AB - Microresonator devices which possess ultra-high quality factors are essential for fundamental investigations and applications. Microsphere and microtoroid resonators support remarkably high Q's at optical frequencies, while planarity constrains preclude their integration into functional lightwave circuits. Conventional semiconductor processing can also be used to realize ultra-high-Q's with planar wedge-resonators. Still, their full integration with side-coupled dielectric waveguides remains an issue. Here we show the full monolithic integration of a wedge-resonator/waveguide vertically-coupled system on a silicon chip. In this approach the cavity and the waveguide lay in different planes. This permits to realize the shallow-angle wedge while the waveguide remains intact, allowing therefore to engineer a coupling of arbitrary strength between these two. The precise size-control and the robustness against post-processing operation due to its monolithic integration makes this system a prominent platform for industrial-scale integration of ultra-high-Q devices into planar lightwave chips. PMID- 23037444 TI - Effects of plasmonic coupling and electrical current on persistent photoconductivity of single-layer graphene on pristine and silver-nanoparticle coated SiO2/Si. AB - Effects and mechanisms of conductivity variation of chemically vapor deposited single-layer graphene covering silver nanoparticles on SiO(2)/Si are reported based on blue-light (405 nm) induced plasmonic coupling and electrical current induced annealing and desorption of surface adsorbates. With 1V applied voltage, photoconductivity is positive except a brief negative period when the graphene is first illuminated by light. At 10 mV applied voltage, negative photoconductivity persists for hours. In comparison, negative photoconductivity of graphene on pristine SiO(2)/Si persists for tens of hours. When the applied voltage is increased to 1V, it takes tens of hours of light illumination to change to positive photoconductivity. PMID- 23037446 TI - Instability of higher-order optical vortices analyzed with a multi-pinhole interferometer. AB - Higher-order optical vortices are inherently unstable in the sense that they tend to split up in a series of vortices with unity charge. We demonstrate this vortex splitting phenomenon in beams produced with holograms and spatial light modulators and discuss its generic and practically unavoidable nature. To analyze the splitting phenomena in detail, we use a multi-pinhole interferometer to map the combined amplitude and phase profile of the optical field. This technique, which is based on the analysis of the far-field interference pattern observed behind an opaque screen perforated with multiple pinholes, turns out to be very robust and can among others be used to study very 'dark' regions of electromagnetic fields. Furthermore, the vortex splitting provides an ultra sensitive measurement method of unwanted scattering from holograms and other phase-changing optical elements. PMID- 23037445 TI - Gain-assisted hybrid-superlens hyperlens for nano imaging. AB - We propose an innovative active imaging device named gain-assisted hybrid superlens hyperlens and examine its resolving power theoretically. This semi cylindrical device consists of a core of semi-cylindrical super-lens and a half cylindrical outer shell of hyperlens. Both the superlens and hyperlens parts of the device are appropriately designed multi-layered metal-dielectric structures having indefinite eigenvalues of dielectric tensors. The dielectric layers of the hyperlens are doped with Coumarin, which play the role of gain medium. The gain medium is analyzed thoroughly using a generic four-level system model, and the permittivity of the gain medium is extracted from this analysis for simulating the imaging characteristics of the device. According to our simulation at wavelength of 365 nm, an excellent resolution power much better than the diffraction limit value can be achieved. PMID- 23037447 TI - Effects of fullerene derivatives on bioluminescence and application for protease detection. AB - The effects of two C(60) derivatives: C(60)[C(COOH)(2)](3) and C(60)(NH(2))(x)(OH)(y), have been investigated on the bioluminescence of humanized Gaussia luciferase (hGluc) for the first time. Utilizing the dual properties of carboxyl C(60) with luminescence quenching and free radicals scavenging, a novel BRET system was constructed for protease detection with high sensitivity. PMID- 23037448 TI - Head position and expressed emotion of adolescents with schizophrenia and their caregivers compared to non-patient controls. AB - BACKGROUND: Family interactions with schizophrenia patients and caregivers rated as high expressed emotion (EE) are characterized by increased negative non-verbal behaviour. Head position is one important component of non-verbal behaviour and has not been examined in relation to EE before. The aim of this pilot study was to investigate the influence of caregivers' EE on the head position of adolescents with schizophrenia and their caregivers. SAMPLING AND METHODS: 15 adolescent schizophrenia patients and 17 non-patient adolescents were videotaped during a 10-min problem-solving task with their caregiver. The head position was coded by the Berner System of Non-Verbal Behaviour. The caregivers' EE level (high EE vs. low EE) was measured by the Five-Minute Speech Sample. RESULTS: Adolescent patients and non-patients showed a higher frequency of averted head positions towards high EE caregivers compared to low EE caregivers (beta = 47.85, t = 2.41, p = 0.023). They displayed longer mean times of averting towards high EE caregivers compared to low EE caregivers (beta = -1.78, t = -2.51, p = 0.018). An indirect approach was shown more frequently by adolescent patients towards low EE compared to high EE caregivers (beta = 39.99, t = 2.31, p = 0.028). In contrast, non-patient adolescents showed a more indirect approach towards high EE caregivers compared to low EE caregivers. Caregivers of schizophrenia patients had head positions with a straight ahead lowered approach for a longer time compared to caregivers of non-patients (beta = -29.75, t = -2.51, p = 0.018). Within the patient and non-patient groups, low EE caregivers showed longer total times of positions with a straight ahead lowered approach than high EE caregivers. CONCLUSIONS: High EE communication may be characterized by a higher ratio of averting head position in adolescents, which is especially pronounced in adolescents with schizophrenia. Low EE communication seems to be better adjusted by a more indirect approach being shown by the adolescent and straight ahead lowered head positions by the caregiver, especially when the adolescent suffers from schizophrenia. PMID- 23037449 TI - Tumorigenesis: Pushing pancreatic cancer to take off. PMID- 23037450 TI - Epigenetics: Melanoma insights written in the DNA. PMID- 23037451 TI - DNA damage: The enemy within. PMID- 23037452 TI - Tumorigenesis: Megaphone MYC. PMID- 23037453 TI - The diagnostic value of measuring pressure pain perception in patients with diabetes mellitus. AB - QUESTION UNDER STUDY: Repetitive skin trauma and reduced pressure pain sensation are necessary components of plantar ulcer risk in patients with diabetic neuropathy. The diagnostic value of measuring pressure nociception to detect ulcer risk is, however, unknown. Instead, measuring the vibration perception threshold (VPT) by 64 Hz graduated Rydel-Seiffer tuning fork has become standard clinical practice to screen for neuropathy and ulcer proneness. We therefore set up a diagnostic case-control study to compare the VPT, the cutaneous pressure pain perception threshold (CPPPT) and the deep pressure pain perception threshold (DPPPT) at the foot sole in diabetic patients with and without past or present painless plantar ulcer. METHODS: A total of 68 patients were studied, 34 with active or previous plantar ulcer. VPT was measured by Rydel-Seiffer tuning fork at the 1st metatarsal head (<=4/8 grade indicating clinical neuropathy). CPPPT was measured at a toe skinfold by calibrated monofilaments. DPPPT was measured by Algometer II((r)) over musculus hallucis longus and over a metatarsophalangeal joint. RESULTS: The sensitivity and specificity to identify patients with present or past foot ulcer were as follows: 0.82 and 0.88 (VPT cut-off 1/8); 0.97 and 0.62(VPT cut-off 4/8); 0.93 and 0.77 (CPPPT cut-off 513 mN); 0.76 and 0.58 (DPPPT muscle, cut-off 545 kPa); 0.82 and 0.79 (DPPPT joint, cut-off 760 kPa). CONCLUSION: Pressure algometry was not superior to measuring VPT for distinguishing between patients with and without painless plantar ulcers; VPT <=1/8 was more efficient than <=4/8 grade in identifying ulcer patients. PMID- 23037454 TI - Cranial dermal sinus: presentation, complications and management. AB - OBJECTIVE: Cranial dermal sinus is a very rare anomaly mostly found in the midline occipital area, presenting with diverse clinical features from asymptomatic dermal sinus to symptomatic situations including meningitis, dermoid tumor or abscess. METHODS: Medical records of 18 patients with 19 cranial dermal sinuses operated at the Children's Hospital Medical Center in Tehran from 1999 to 2011 were retrospectively studied. Their presentations, accompanying anomalies, radiological and surgical findings were evaluated. RESULTS: Patients were aged 1 month to 6 years and were followed for 2-12 years. Most sinuses were located in the midline occipital region. Infection was the most common reason for referral (50%) followed by skin dimple (33.3%). Creamy white discharge was found in 50% of patients. Posterior fossa abscess, hydrocephalus and meningitis were observed in 38.9, 38.9 and 22.2% of children, respectively. All sinus tracts with associated dermoid tumors or abscesses were removed en bloc to decrease the risk of recurrence. CONCLUSION: The sinus tracts are a portal of entry for pathogens which result in serious complications of meningitis or abscess. In this series, 67% of children presented with serious symptoms; therefore, we recommend prophylactic surgery in all cranial dermal sinuses. The exact time of surgery is not obvious as the natural course of the disease is unknown. If any symptom is observed surgery should be done as soon as possible. For asymptomatic sinuses identified by the pediatrician during a regular visit prophylactic surgery is recommended as soon as the child can tolerate operation. PMID- 23037455 TI - The usefulness of double-balloon enteroscopy in gastrointestinal stromal tumors of the small bowel with obscure gastrointestinal bleeding. AB - OBJECTIVE: Gastrointestinal stromal tumors (GISTs) are the most frequently occurring mesenchymal tumors of the GI tract. Double-balloon enteroscopy (DBE) and capsule endoscopy (CE) promise the detection and accurate diagnosis of small bowel diseases in patients with obscure GI bleeding (OGIB). The aim of the present study was to analyze the clinical characteristics of small bowel GISTs and the usefulness of DBE, CE and computed tomography (CT). METHODS: Among 705 cases with OGIB examined between December 2003 and January 2011, 12 (1.7%) cases of small bowel GIST were identified. We analyzed endoscopic appearance, tumor size and location, detection rate by DBE, CE and CT and clinical course in each of these cases. RESULTS: Of the 12 patients with GIST, eight were men. The mean patient age was 53.6 years. The presenting symptoms in most patients included tarry stools and/or anemia. Six patients required blood transfusions. The detection rates of DBE, CE and CT were 92%, 60% and 67%, respectively. All cases, except for one incomplete study, were identified using DBE; however, one case was not diagnosed as a tumor because of the presence of extramural growth. A pathological diagnosis of GIST was obtained using biopsies during DBE in three (45%) of seven cases. Lower detection rates were found in cases with intramural and extramural growth, larger tumors (>=35 mm) detected by CE and intraluminal growth and smaller tumors (<35 mm) detected by CT. CONCLUSION: DBE or a combination of CE and CT are thus considered to be useful for detecting small bowel GISTs. PMID- 23037456 TI - Histopathology of the tissue adhering to the multiple tine expandable electrodes used for radiofrequency ablation of hepatocellular carcinoma predicts local recurrence. AB - OBJECTIVE: To assess the ability to predict the local recurrence of hepatocellular carcinoma by analyzing tissues adhering to the radiofrequency ablation probe after complete ablation. METHODS: From May 2002 to March 2011, tissue specimens adhering to the radiofrequency ablation probe from 284 radiofrequency ablation sessions performed for hepatocellular carcinomas <=3 cm in size were analyzed. The specimens were classified as either viable tumor tissue or complete necrosis, and the local recurrence rates were calculated using the Kaplan-Meier method. RESULTS: From the tumors <=3 cm in size, viable tissue was present in 6 (2.1%) of 284 specimens, and the local recurrence rates after 1 and 2 years of follow-up were 6.7% and 11.2%, respectively. Local recurrence developed significantly earlier in the viable tissue group. The recurrence rate was not significantly different based on whether transcatheter arterial chemoembolization was performed. CONCLUSION: The histopathology of the tissue adhering to the radiofrequency ablation probes used for hepatocellular carcinoma treatment can predict local recurrence. Additional aggressive treatment for patients with viable tissue can therefore improve the overall survival. PMID- 23037457 TI - Insulation defects in Riata implantable cardioverter-defibrillator leads. AB - BACKGROUND: The structures composing implantable cardioverter-defibrillator (ICD) leads have become more complicated and thinner with technological advances. Silicon insulation defects with and without clinically manifested electrical abnormalities have been reported in Riata leads (St. Jude Medical). OBJECTIVE: The aim of this study was to assess the incidence and clinical implications of insulation defects in Riata leads implanted at our hospital. METHODS: The subjects included 10 consecutive patients who received 8-French Riata ICD leads with dual-coil conductors (model 1580 or 1581) between 2006 and 2010 at our hospital. Operative records, chest X-rays and interrogation data were reviewed. RESULTS: In all cases, Atlas+ (St. Jude Medical) was used as an ICD generator and the Riata leads were implanted transvenously and fixed to the right ventricular apex. During a mean follow-up period of 52+/-9 (36-70) months, chest X-rays revealed insulation defects in Riata leads and conductor wires projecting from the bodies of the Riata leads in two of 10 (20%) patients. One of the patients received inappropriate ICD therapies due to T-wave oversensing based on attenuation of R waves and augmentation of T waves 41 months after implantation. In the other patient, an insulation defect without any clinically manifested electrical troubles was detected 50 months after implantation. CONCLUSION: Riata leads have a high incidence of insulation defects, which may be occasionally accompanied by inappropriate ICD discharges. For patients with Riata leads, careful observation of any changes in the lead-electrical measurements and a routine chest X-ray follow-up are necessary. PMID- 23037458 TI - Retrospective comparison of midterm clinical and angiographic outcomes after the implantation of paclitaxel- and sirolimus-eluting stents for de novo coronary complex lesions in nonrandomized Japanese patients. AB - OBJECTIVE: We retrospectively analyzed the midterm clinical and angiographic outcomes after the implantation of paclitaxel- (PES, TAXUS Express) and sirolimus (SES, Cypher Bx Velocity) eluting stents in Japanese patients with complex coronary lesions. METHODS: From August 2004 to May 2009, 1,335 nonrandomized de novo native complex coronary lesions treated with either a PES (357 cases) or SES were included. The inclusion criteria for patients with complex lesions were those with diabetes, those undergoing hemodialysis, and those with a low ejection fraction, as well as subjects who had lesions with severe calcification, ostiums of the right coronary and left circumflex arteries, and who underwent the side branch bifurcation 2-stent technique. The subjects were evaluated for consistent predictors of cardiac events, binary restenosis and target lesion vascularization of the SES. The composite primary endpoint percentage (900-day cardiac death, nonfatal recurrent myocardial infarction, and definite stent thrombosis) after PES placement was 0.6%, which was not significantly different from that after SES placement (0.12%; p=0.290). The incidence of the secondary endpoint (binary restenosis; stenosis >50% of the diameter at the secondary angiographic examination performed within 550 days after the procedure) after PES placement (15.0%) was also not significantly different than that after SES placement (13.3%; p=0.498). There was no relationship between PES placement and binary restenosis upon angiographic follow-up of 989 lesions (odds ratio of 1.14; 95% confidence interval, 0.73-1.77; p=0.57). CONCLUSION: For de novo native complex coronary stenosis, the midterm safety and efficacy of PES placement was statistically equivalent to that of SES placement in a clinical setting in Japan. PMID- 23037459 TI - Risk for future diabetes among individuals with high-normal glycemia at 40 years of age. AB - OBJECTIVE: The present study investigated the risk for future diabetes among individuals with high-normal glycemia (fasting plasma glucose (FPG) of 100-109 mg/dL) in an early middle-aged population. METHODS: We retrospectively observed a workplace cohort all aged 40 and followed the incidence of diabetes according to the FPG levels at baseline. A total of 901 non-diabetic males were included in the analysis. The 10-year cumulative incidence of diabetes was calculated. The hazard ratios of developing diabetes were calculated using a Cox proportional hazards regression. RESULTS: The proportions of those with high-normal glycemia and impaired fasting glucose (IFG) (FPG of 110-125 mg/dL) at baseline were 21.5% and 4.7%. The 10-year cumulative incidence of diabetes was 14.7% and 48.9%, respectively, in these individuals. After adjustment for possible confounders, the hazard ratios of developing diabetes among individuals with high-normal glycemia and IFG were 5.2 (95% CI=2.4-11.2) and 21.3 (95% CI=9.2-49.5) relative to those with an FPG of <90 mg/dL. CONCLUSION: High-normal glycemia is a risk for future diabetes even in the relatively young and healthy workplace population. Although the relative risk is much higher in those with IFG, the absolute number of incident diabetes developing from those with high-normal glycemia seems to be considerable given the prevalence of this condition. PMID- 23037460 TI - N-acetylcysteine for the prevention of contrast-induced nephropathy in the emergency department. AB - OBJECTIVE: To evaluate the use of N-acetylcysteine (NAC), a potent antioxidant, to prevent contrast-induced nephropathy (CIN). METHODS: We prospectively studied 209 patients (106 in the NAC group and 103 in the control group) who received contrast-enhanced computed tomography (CECT) in the emergency department (ED). The NAC group received intravenous NAC (600 mg) before CECT imaging to prevent CIN. Both the NAC and control groups were treated using a standardized hydration strategy, where clinically feasible. RESULTS: The patients' mean age was 79.6+/ 9.8 years. The prevalence of hypertension, diabetes, and chronic kidney disease (CKD) were 63.2%, 27.3%, and 21.5%, respectively. The baseline clinical characteristics were similar between the two groups except for their body weight (p=0.011), amount of contrast material administered (p=0.049) and prevalence of CKD (p=0.002). The incidence of CIN was 7.5% in the NAC group and 14.6% in the control group. The adjusted odds ratio was 0.305 (95% confidence interval: 0.097 to 0.960, p=0.042). All-cause mortality was 7.5% in the NAC group and 12.6% in the control group, which was not significantly different. Temporary hemodialysis was required in 0% of subjects in the NAC group and 1.0% in the control group, which was not a statistically significant difference. CONCLUSION: A single dose of NAC before CECT imaging can prevent CIN in an ED setting. However, it does not improve the mortality rate or the need for dialysis. PMID- 23037461 TI - Serum immunoglobulin G is a marker for the risk of opportunistic infection in steroid-dependent severe asthmatic patients. AB - BACKGROUND: Approximately 10% of asthmatic patients are refractory to inhaled corticosteroids and therefore need long-term oral corticosteroid therapy, which is associated with a risk of opportunistic infections due to immunosuppression. OBJECTIVE: To ascertain the applicability of serum Immunoglobulin G (IgG) as a marker for predicting the risk of opportunistic infections in patients undergoing oral corticosteroid therapy. METHODS: Three thousand asthmatics were screened, and 14 patients who had been administered daily oral corticosteroids for more than two years were enrolled. The patients enrolled were maintained under observation with ordinary check-ups and treatments for one year. After the observation period, the patients were divided into two groups according to the presence (OPI) or absence (non-OPI) of opportunistic infections during the period. The differences in the clinical parameters between the groups were investigated. RESULTS: There were no statistically significant differences in age, forced expiratory volume in 1 second (FEV(1)), smoking status or serum albumin between the groups. The serum IgG level of the OPI group was significantly lower than that of the non-OPI group (567.2+/-151.1 mg/dL vs. 931.6+/-198.8 mg/dL, p<0.01). The average total dose of corticosteroids administered during the one year period was higher in the OPI group (2,633+/ 554.2 mg) than that in the Non-OPI group (1,793+/-466.2 mg) (p<0.05). There was a significant correlation between the serum IgG and total dose of corticosteroids administered during the one-year period (r = -0.75, p<0.01). The area under the receiver operating characteristic curve regarding the serum IgG and incidence of opportunistic infections was 0.97, which suggests that the serum IgG level has a high accuracy for predicting the risk of opportunistic infections. CONCLUSION: The serum IgG was therefore found to be a useful marker for predicting the risk of opportunistic infections in steroid-dependent asthmatics. PMID- 23037462 TI - Survival of Japanese patients with pulmonary arterial hypertension after the introduction of endothelin receptor antagonists and/or phosphodiesterase type-5 inhibitors. AB - OBJECTIVE: Although endothelin receptor antagonists (ERAs) and phosphodiesterase type 5 (PDE5) inhibitors have become the most commonly used treatments for pulmonary arterial hypertension (PAH) since their introduction in 2005, it remains unknown whether these medications play a significant role in the survival of Japanese patients with PAH. METHODS: The cardiac catheterization and survival data of 103 PAH patients were retrospectively reviewed. A comparison of survival benefits with regard to the type of PAH was completed in PAH patients diagnosed between 2005 and 2012 and those diagnosed between 1983 and 2004 and in patients undergoing treatment with ERAs and/or PDE5 inhibitors and those being treated with conventional therapy and/or oral beraprost. Although pulmonary vascular resistance (PVR) at baseline differed, the more recent group showed better survival rates compared with those observed in the early group (5-year survival: 70.1% vs. 44.8) (p<0.05). In addition, the survival of PAH patients treated with ERAs and/or PDE5 inhibitors was superior to that of the patients treated without these medications (5- and 8-year survival: 77.8% and 66.7% vs. 39.0% and 37.0%, respectively) (p<0.05), especially in patient with idiopathic and heritable PAH. CONCLUSION: Superior survival rates are observed in patients with idiopathic and heritable PAH after introduction of ERAs and PDE5 inhibitors, and the use of these drugs provides benefits for survival. PMID- 23037463 TI - Intrathoracic administration of OK-432 elevates the serum procalcitonin levels. AB - OBJECTIVE: The intrathoracic administration of OK-432, a lyophilized preparation of the heat- and penicillin-treated Su-strain of type 3, group A Streptococcus pyogenes, is performed in Japan for pleurodesis of malignant pleural effusion or pneumothorax. Persistent fever is often observed after pleurodesis. To elucidate whether procalcitonin (PCT) is useful for distinguishing between the side effects of OK-432 and infection, we measured the serum PCT levels before and after pleurodesis. METHODS: We performed a prospective study of 12 patients with refractory pleural effusion or pneumothorax who required pleurodesis using OK-432 between August 2011 and February 2012. The serum PCT and C-reactive protein (CRP) levels were measured on days 1 and 3. RESULTS: Of the 12 patients, five had pneumothorax and seven had uncontrolled pleural effusion with carcinomatous pleurisy. The median serum levels of PCT and CRP increased from 0.055 to 1.59 ng/mL (p=0.0022) and from 1.52 to 16.82 mg/dL (p=0.0022), respectively. The fevers subsided without antibiotic administration. CONCLUSION: The serum PCT level may not be useful for distinguishing fever caused by side effects of OK-432 from that caused by bacterial infection. The intrathoracic administration of OK 432 increased the serum levels of both PCT and CRP in the absence of any bacterial infection. PMID- 23037464 TI - A case series of Bacillus cereus septicemia in patients with hematological disease. AB - OBJECTIVE: Bacillus cereus (B. cereus) septicemia is a cause of life-threatening infection in patients with hematologic diseases. However, preventing a fatal prognosis in patients with B. cereus infection has not yet been achieved due to insufficient clinical investigations. To discover more optimal treatment strategies, we analyzed B. cereus septicemia in patients with hematologic diseases. METHODS: At our institution, we observed 13 cases of B. cereus septicemia in 12 patients with hematologic diseases between January 2001 and September 2010. The susceptibility of B. cereus strains to antibiotics was also analyzed. RESULTS: Of 12 patients, four died of B. cereus septicemia. In this study, the delayed administration of appropriate antibiotics (starting >24 hours after presentation), the presence of liver dysfunction and evidence of central nervous system (CNS) involvement tended to result in a fatal prognosis. All of the bacterial strains were found to be susceptible to vancomycin and quinolones (such as ciprofloxacin and levofloxacin), whereas many strains were resistant to clindamycin (76.9%) and imipenem (30.8%). In seven of 10 patients, central venous (CV) catheter tips were removed and routinely cultured. Catheter tip cultures were positive for B. cereus in three of seven patients. CONCLUSION: Although not specific to B. cereus bacteremia, patients who died of B. cereus tended to present with CNS symptoms and/or liver dysfunction. Our clinical data suggested that carbapenem and clindamycin are no longer appropriate choices for treating B. cereus. In addition, B. cereus septicemia was found to frequently originate from CV catheters. Constant attention must be paid to update assessments of antibiotic susceptibility and careful management must be applied to CV catheters in patients with hematologic diseases. PMID- 23037465 TI - Toxic megacolon associated with cytomegalovirus infection in a patient with steroid-naive ulcerative colitis. AB - Most cases of cytomegalovirus (CMV) colitis in patients with inflammatory bowel disease (IBD) occur in those treated with immunosuppressants and/or corticosteroids. We herein present the case of a 57-year-old man with toxic megacolon associated with CMV colitis in corticosteroid-naive ulcerative colitis (UC). To date, there have been only eight previous case reports of CMV colitis in steroid-naive UC. We discuss the need to consider CMV colitis when making a differential diagnosis of patients with refractory UC who are not receiving corticosteroid treatment. PMID- 23037466 TI - Regression of Hodgkin lymphoma in response to antiviral therapy for hepatitis C virus infection. AB - Links between hepatitis C virus (HCV) infection and several non-Hodgkin lymphomas have been suggested by epidemiological studies. We herein report the first documented case of a patient with HCV-associated Hodgkin lymphoma who showed a marked regression following interferon-based antiviral therapy. This unique case extends the spectrum of HCV-associated malignant lymphomas, confirms the efficacy of antiviral therapy for this rare extrahepatic manifestation and provides valuable clues for achieving a better understanding of lymphomagenesis in HCV. PMID- 23037467 TI - Dilatation of the bile and pancreatic ducts due to compression by an unruptured abdominal aortic aneurysm (AAA): a case ameliorated by an endovascular stent grafting. AB - An 88-year-old woman was referred to our hospital due to abdominal discomfort. Imaging modalities showed an abdominal aortic aneurysm (AAA) compressing the duodenum, the distal common bile duct and the head of the pancreas concurrent with distension of the proximal bile and main pancreatic ducts in the body and tail of the pancreas. After admission, the patient underwent endovascular stent grafting to treat the AAA. The size of the aneurysm decreased and the dilatation of the bile and pancreatic ducts became less prominent. AAA should therefore be considered as a possible diagnosis in patients with findings of dilatation of the bile ducts in the absence of stones or tumors in the pancreaticobiliary system. This is the first reported case of a patient treated for both AAA and dilatation of the bile and pancreatic ducts with endovascular stent grafting via the femoral artery. PMID- 23037468 TI - Hepatic nodules associated with an inferior mesentric arteriovenous malformation. AB - Splanchnic arteriovenous malformation (AVM) is a rare condition in which patients present with portal hypertension, which thus causes bleeding varices and ascites. However, to our knowledge, hepatic nodules associated with splanchnic AVM have not yet been described. We herein first report the case of a 78-year-old man with inferior mesenteric AVM presenting with portal hypertension and multiple hepatic nodules dominantly supplied by the portal vein. This unique case not only extends the spectrum of hepatic nodules resulting from abnormal hepatic circulation, but also provides clues for better understanding the etiology of hepatic nodules. PMID- 23037469 TI - Acute myocardial infarction with a left main trunk lesion and documented lambda like J waves. AB - We herein describe a case of a myocardial infarction, in which Lambda-like J waves were documented. The patient was referred to our hospital due to ventricular fibrillation. The twelve-lead electrocardiogram (ECG) on admission showed prominent J waves in the lateral and precordial leads. Coronary angiography revealed 99% stenosis with a delay in the left anterior descending artery, 75% stenosis in the left main trunk, and possible ischemia in the conus branch. Our report addresses the possibility that ischemic J waves can be used as an important marker for lethal arrhythmias in patients with acute myocardial infarction. PMID- 23037470 TI - Rapid amelioration of hyperglycemia facilitated by dasatinib in a chronic myeloid leukemia patient with type 2 diabetes mellitus. AB - Tyrosine kinase inhibitors (TKIs) have been shown to affect glucose metabolism in patients with chronic myeloid leukemia (CML); however, their precise mechanism of action remains unknown. We herein report the case of a 57-year-old diabetic CML patient who was resistant to imatinib and initially required 20 units of insulin daily to control his blood glucose levels. After the initiation of dasatinib, the patient's insulin requirements declined rapidly and insulin treatment was discontinued within two weeks. Meanwhile, the fasting C-peptide immunoreactivity increased two-fold, suggesting that dasatinib facilitated the recovery of insulin production. Dasatinib may therefore be beneficial for diabetic CML patients, especially those who require insulin treatment. PMID- 23037471 TI - Pulmonary tumor thrombotic microangiopathy diagnosed antemortem and treated with combination chemotherapy. AB - A 29-year-old man developed a persistent dry cough. Chest high-resolution computed tomography (HRCT) revealed centrilobular ultrafine granular shadows scattered in all lung fields. A lung biopsy with video-assisted thoracoscopic surgery revealed findings compatible with pulmonary tumor thrombotic microangiopathy (PTTM). However, the primary tumor was not identified. Combination chemotherapy with S-1 and cisplatin decreased his cough and improved the chest HRCT findings. The illness, however, gradually became difficult to control. He eventually developed pulmonary hypertension and died. Typically, an antemortem diagnosis of PTTM cannot be made. In this case, the diagnosis of PTTM and combination chemotherapy improved the chest HRCT findings, respiratory symptoms, and prognosis. PMID- 23037472 TI - The long-term survival of a patient with adenosquamous lung carcinoma harboring EGFR-activating mutations who was treated with gefitinib. AB - A 56-year-old woman diagnosed with squamous cell lung carcinoma after a transbronchoscopic examination underwent left upper lobectomy, which revealed a pathological diagnosis of adenosquamous carcinoma containing moderately differentiated squamous cell carcinoma and bronchioloalveolar carcinoma. The epidermal growth factor receptor (EGFR) exon 19 delE746-A750 mutation was detected in deoxyribonucleic acid (DNA) isolated from specimens of both components using microdissection. Treatment with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in a long-term tumor response lasting three years. Adenosquamous carcinoma is difficult to diagnose using transbronchoscopic procedures. Therefore, the examination of EGFR mutation status is important in order to determine the appropriate treatment, even in patients with non adenocarcinoma. PMID- 23037473 TI - Sarcoidosis complicated with major pulmonary artery obstruction and stenosis. AB - A 34-year-old woman with bilateral pulmonary infiltrates was diagnosed with sarcoidosis. She refused corticosteroid treatment despite a worsening of the pulmonary infiltrate, and thereafter developed dyspnea following hemoptysis 6 years later. The upper lobe branches of the pulmonary artery were obstructed and the left main pulmonary artery was narrowed by mediastinal soft tissue, thus complications of granulomatous mediastinitis and fibrosing mediastinitis were suspected. The mediastinal soft tissue regressed, following the administration of corticosteroids, whereas the vascular obstruction and narrowing remained unchanged. Although the obstruction or stenosis of major pulmonary vessels is rare in sarcoidosis, such potential developments should be considered when mediastinal soft tissue appears in follow-up examinations. PMID- 23037474 TI - Attainment of a stringent complete response in multiple myeloma with thalidomide monotherapy. AB - Treatment of patients with multiple myeloma (MM) has drastically changed with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, but treatment outcome of elderly patients has remained dismal mainly due to toxicities. We report an 82-year-old MM patient attaining stringent complete response (sCR) at 12 months with a daily dose of 100 mg of thalidomide monotherapy. She remains on thalidomide monotherapy and presently maintains a normalized serum free light chain ratio at 18 months. This is the first case of MM achieving sCR with thalidomide monotherapy, and shows that single-agent thalidomide can be effective and concomitant use of dexamethasone may not be necessary in frail elderly patients. PMID- 23037475 TI - Cyclosporine A and reduced-intensity conditioning allogeneic stem cell transplantation for relapsed angioimmunoblastic T cell lymphoma with hemophagocytic syndrome. AB - No standard therapeutic approaches have so far been established for the treatment of relapsed angioimmunoblastic T-cell lymphoma (AITL), a subtype of non-Hodgkin lymphoma. This case report describes an AITL patient who relapsed with hemophagocytic syndrome (HPS) two months after receiving high-dose chemotherapy (HDCT) supported by autologous peripheral blood stem cell transplantation (PBSCT). The patient was successfully treated with cyclosporine A (CsA) and subsequent allogeneic PBSCT with reduced intensity conditioning regimen (RIST). RIST may deserve consideration for treatment of AITL patients with severe complications such as HPS. Additionally, CsA could be a less-toxic therapeutic option for pre-RIST induction therapy against AITL. PMID- 23037476 TI - Central neurogenic hyperventilation in anti-NMDA receptor encephalitis. AB - Central neurogenic hyperventilation (CNH) is a rare condition that is generally associated with infiltrative tumors of the brainstem. Respiratory dysfunction, particularly central hypoventilation, is common in anti-N-methyl D-aspartate (NMDA) receptor encephalitis. CNH, to the best of our knowledge, has not been described previously in this disease. A 24-year-old woman was diagnosed with anti NMDA receptor encephalitis secondary to ovarian teratoma. In addition to the typical symptoms of the disease, recurrent CNH episodes were observed during the course of the illness, which subsided with midazolam and propofol infusion. Supportive and disease-specific treatments, including oopherectomy, plasmapheresis and intravenous immunoglobulin, provided excellent recovery. These observations suggest that NMDA receptors may play a role in the pathophysiology of CNH. PMID- 23037477 TI - Alternating skew deviation due to hemorrhage in the cerebellar vermis. AB - A 76-year-old Japanese woman with essential hypertension and diabetes mellitus abruptly presented with nausea, dizziness, an occipital headache, truncal ataxia, gaze-evoked nystagmus and alternating skew deviation (ASD) with abducting eye hypertropia. Cranial computed tomography demonstrated hemorrhage in the cerebellar vermis and its vicinity. These symptoms gradually resolved within three weeks. This is the first reported case of ASD secondary to cerebellar hemorrhage without hydrocephalus. The vertical misalignment of the eyes during the right-sided gaze was consistently larger than during the left-sided gaze. We speculated that bilateral and asymmetrical damage to the utricular pathway due to the bilateral involvement of the nodulus and uvula might have caused the ASD. PMID- 23037478 TI - A headache misunderstood for a grief reaction: an unusual cerebral venous thrombosis presentation. AB - This is a report of a 24-year-old woman who presented to the emergency department (ED) at Imam Hossein Hospital in Tehran, Iran with a one-week history of headache and agitation following her father's death. Before presenting to our ED, a diagnosis of conversion reaction was suggested by three physicians in different outpatient clinics. Cerebral venous thrombosis (CVT) was confirmed in this case on the basis of brain magnetic resonance imaging (MRI) and magnetic resonance venography (MRV). In this report, current knowledge regarding cerebral venous thrombosis and its related clinical features are discussed. PMID- 23037479 TI - Angioedema of the periorbital region that developed during treatment with etanercept in a case of refractory adult-onset Still's disease. AB - A 78-year-old Japanese man with adult-onset Still's disease that was refractory to conventional treatment, such as prednisolone (PSL) concomitant with methotrexate (MTX). Etanercept (50 mg/week) was added to PSL (12.5 mg/day) and MTX (12 mg/week). His manifestation improved dramatically, nonetheless massive edema of the periorbital region developed by the fourth injection, which kept his palpebral fissure completely closed. There was also a marked injection site reaction to etanercept. A diagnosis of angioedema due to etanercept was thus made, and the drug was discontinued. His angioedema began to ameliorate soon after antihistamines were introduced without any critical involvement, such as laryngeal obstruction. PMID- 23037480 TI - Adult-onset acute rheumatic fever. AB - A 62-year-old man was hospitalized for acute rheumatic fever. He had previously suffered from rheumatic fever at 15 years of age. The rheumatic fever was complicated by carditis, which caused valve disease that required surgical treatment. The incidence of rheumatic fever has decreased in most developed countries with improvements in sanitary conditions. The low incidence of this disease makes a timely and accurate diagnosis difficult. Due to the fact that both the first occurrence and recurrence of acute rheumatic fever can occur in the elderly and adults, this potential disease should not be overlooked when making a differential diagnosis. PMID- 23037481 TI - Successful treatment of a previously healthy woman with Pseudomonas aeruginosa community-acquired pneumonia with plasmapheresis. AB - A previously healthy 39-year-old woman with severe chest pain presented at our hospital. She was diagnosed with bacterial pneumonia by chest X-ray and computed tomography. Despite adequate antimicrobial treatment, she had to undergo intubation for respiratory distress and was treated with mechanical ventilation 42 hours after admission. However, her condition improved markedly after plasmapheresis. Bacterial culture specimens from the sputum, blood, and pleural fluid were positive for Pseudomonas aeruginosa (P. aeruginosa). Pseudomonas aeruginosa community-acquired pneumonia (CAP) in previously healthy individuals is very rare, rapidly progressive, and often fatal. This is the first report of the successful treatment of this life-threatening pneumonia with plasmapheresis. PMID- 23037482 TI - Successful treatment of a patient with sepsis and liver abscess caused by Edwardsiella tarda. AB - Edwardsiella tarda is a bacterium that is associated with both an asymptomatic oral carrier state and self-limiting diarrhoeal illness in humans. We herein report a case of sepsis and liver abscess caused by E. tarda and review the patients with E. tarda sepsis who presented at our hospital. An 85-year-old woman developed enterocolitis and sepsis caused by E. tarda. She was administered intensive care and thus was able to soon show a good recovery, however, she subsequently developed a liver abscess. During a complicated course, she continued to be treated with antibiotics and after a successful course was discharged on the 44th day after admission. PMID- 23037483 TI - Long-term survival in metastatic malignant melanoma: ipilimumab followed by vemurafenib in a patient with brain metastasis. AB - A 46-year-old man was diagnosed with brain metastasis after a two-year history of melanoma. Paliative radiotherapy was administered followed by dacarbazine, temozolamide, ipilimumab, stereotactic radiosurgery, ipilimumab reinduction and finally vemurafenib, to which the patient showed objective responses. The patient received vemurafenib for four months and died after progresive disease. Long-term follow-ups after surgery have been reported in the literature. However, in patients with unresectable metastases, outcomes are mostly detrimental. The present patient survived for 40 months after brain metastasis. The unusually long survival observed in the present case indicates the sequential effectiveness of radiotherapy, chemotherapy, ipilimumab, stereotactic radiosurgery and vemurafenib. PMID- 23037484 TI - Immunopathological analysis of Erdheim-Chester disease with massive ascites. AB - We treated a 77-year-old woman with pleural and pericardial effusion and ascites. Initially, collagen vascular disease was suspected due to the presence of anti centromere antibodies and suspected complication of pulmonary arterial hypertension. However, soft-tissue abnormalities surrounding the bilateral kidneys detected on computed tomography (CT) and symmetrical lesions of the long bones detected on bone scintigraphy made us consider a diagnosis of Erdheim Chester disease (ECD), which is a rare form of histiocytosis. We immunochemically analyzed the cells derived from the ascites in detail and confirmed the diagnosis. Immunocytochemical analyses may therefore help to achieve a better understanding of the pathogenesis of this rare disease. PMID- 23037485 TI - Mycotic pseudoaneurysm of the femoral artery in a patient with psoriasis. AB - Mycotic aneurysms of the common femoral artery are rare and usually occur in intravenous drug abusers who use the femoral vessels for injection. We herein describe a case of mycotic aneurysm of the common femoral artery caused by methicillin-sensitive Staphylococcus aureus seeding of an atherosclerotic plaque in which the bacteria possibly originated from psoriatic skin lesions. A 67-year old Caucasian man was admitted to the hospital after experiencing chest pain for two days. He was known to have psoriasis and coronary artery disease with a history of coronary artery bypass grafting surgery three years earlier. He was found to have methicillin-sensitive Staphylococcus aureus bacteremia and later developed a mycotic aneurysm of the femoral artery opposite to the site of catheterization access. Mycotic aneurysms are rare clinical conditions associated with significant morbidity and mortality. In patients with psoriasis, a high prevalence of Staphylococcus aureus colonization of the skin makes possible bacterial seeding of existing atherosclerotic plaques. Therefore, the risk of mycotic pseudoaneurysm formation in these patients should be considered. PMID- 23037486 TI - Infective endocarditis in a patient with incomplete Shone's anomaly. PMID- 23037487 TI - Elephantiasic pretibial myxedema. PMID- 23037488 TI - Asymptomatic congenital lobar emphysema in a young adult. PMID- 23037489 TI - Laryngeal tuberculosis: a diagnosis that should be remembered. PMID- 23037490 TI - Drug-induced camptocormia: a lesson regarding vascular Parkinsonism. PMID- 23037491 TI - Osteomalacia as a complication of ileal neobladder. PMID- 23037492 TI - Going for the gold. PMID- 23037494 TI - Evolution of axillary nodal staging in breast cancer: clinical implications of the ACOSOG Z0011 trial. AB - BACKGROUND: Management of the axilla in breast cancer patients has evolved from routine axillary lymph node dissection (ALND) for all patients to a highly selective approach based on the assessment of the sentinel lymph nodes (SLNs) as well as tumor and patient characteristics. Although ALND continues to have an important role in staging and regional control for many breast cancer patients, recent trial results question the need for routine ALND in patients who have positive SLNs. METHODS: Not all axillary disease becomes clinically detectable or relevant with respect to recurrence and survival. Therefore, recent trends indicate that many surgeons have omitted ALND in subgroups of patients, particularly those with clinically node-negative, SLN-positive, early-stage breast cancer undergoing breast-conserving therapy with postoperative irradiation. This review explores trends in axillary management, focusing primarily on the clinical implications of the results from the American College of Surgeons Oncology Group (ACOSOG) Z0011 randomized controlled trial. RESULTS: According to the results of the ACOSOG Z0011 trial, the use of SLN dissection alone did not result in inferior survival compared with ALND in patients with limited SLN disease treated with breast-conserving therapy. This subgroup of women was spared the morbidity associated with ALND. However, several points of debate, including the smaller than anticipated sample size, the older study population, and the length of follow-up, suggest caution when applying these findings to all women with breast cancer. CONCLUSIONS: Although the findings of ACOSOG Z0011 are impressive, in clinical practice they are applicable to a limited number of women with breast cancer: those with T1-2 primary tumors with clinically negative axilla and 1 to 2 positive SLNs undergoing breast-conserving surgery and adjuvant whole-breast irradiation. The next generation of clinical trials may answer some of the remaining questions regarding how best to manage the axilla in additional subsets of patients undergoing treatment of breast cancer. PMID- 23037495 TI - Axillary staging prior to neoadjuvant chemotherapy: the roles of sentinel lymph node biopsy and axillary ultrasonography. AB - BACKGROUND: Clinical evaluation of the axilla is an area of controversy in current breast cancer research and management. Evidence of axillary metastasis on biopsy affects all modalities of cancer therapeutics and is central to breast cancer staging. Neoadjuvant chemotherapy is standard therapy for patients with locally advanced breast cancer and considered for patients with early-stage breast cancer. METHODS: This article discusses axillary ultrasonography for axillary staging relative to neoadjuvant chemotherapy, reviews advances in sentinel lymph node (SLN) biopsy techniques, and explores an integrated approach to axillary staging. Techniques for staging the axilla after a breast cancer diagnosis relative to the use of neoadjuvant chemotherapy are also discussed. RESULTS: There is increasing support in the literature for routine axillary ultrasonography and percutaneous biopsy in the evaluation of regional nodal metastasis for breast cancer. SLN biopsy and axillary node dissection continue to be the standards for definitive staging. CONCLUSIONS: Axillary ultrasonography (with or without biopsy) and SLN biopsy are safe and feasible options for breast cancer staging and may facilitate treatment decisions for surgery, chemotherapy, and radiation therapy. Multidisciplinary review may also significantly influence treatment and timing of staging and therapy. An integrated approach to diagnosis and treatment is beneficial for both patients and providers. PMID- 23037496 TI - The changing face of mastectomy: an oncologic and cosmetic perspective. AB - BACKGROUND: The history of surgical treatment of breast cancer is rich with contributions from many surgeons over the centuries. Among the recent advances in technique is the nipple-sparing mastectomy, which reflects the emerging focus on cosmetic outcomes. METHODS: We took a backward glance at the literature illustrating the evolution of surgical management of breast cancer, culminating with nipple-sparing mastectomy. The growing clinical data with nipple-sparing mastectomy are explored. RESULTS: The demand for nipple-sparing mastectomy has been steadily increasing at many institutions. Based on the clinical data reported, nipple-sparing mastectomy is an oncologically safe procedure for selected women who have or are at high risk for breast cancer. CONCLUSIONS: For women facing mastectomy and their surgeons, the optimal aesthetic result centers on preservation of the nipple. However, nipple-sparing mastectomy is technically challenging, with long-term safety not yet confirmed. Evidence-based data are needed to document local tumor recurrence, distant metastasis, cosmetic outcomes, patient satisfaction, and procedural complications. PMID- 23037493 TI - Genetic risk assessments in individuals at high risk for inherited breast cancer in the breast oncology care setting. AB - BACKGROUND: It has become increasingly common to consider BRCA mutation status when determining optimal cancer risk management and treatment options in order to improve patient outcomes. Knowledge about the risk for hereditary cancer at or as close as possible to the time of diagnosis allows patients access to the most risk reduction options available. METHODS: This paper illustrates the role of genetic risk assessment for hereditary breast cancer, using hereditary breast and ovarian cancer (HBOC) syndrome as a model due to germline mutations in the BRCA1 and BRCA2. Specifically, the value of genetic counseling and testing for HBOC across the cancer prevention and control continuum is outlined as it pertains to breast cancer. RESULTS: In recognition of the importance of risk assessment for hereditary breast cancer, leading health professional organizations have developed specific guidelines and recommendations to providers for identification of women at increased risk for carrying a BRCA mutation. CONCLUSIONS: Institutional efforts specific to genetic counseling and testing have resulted in the implementation of a model driven by physician recommendation as a referral system for high-risk breast cancer patients. Establishing an infrastructure to support research, education, and outreach initiatives focused on BRCA genetic counseling and testing will provide information that can improve the delivery of cancer genetics services. PMID- 23037497 TI - Accelerated partial breast irradiation: a review and description of an early North American surgical experience with the intrabeam delivery system. AB - BACKGROUND: Targeted intraoperative radiation therapy (IORT) as an alternative to whole breast irradiation (WBI) has been described for patients with early-stage breast cancer. The randomized phase III TARGiT trial demonstrated similar recurrence rates to WBI and a lower overall toxicity profile on short-term follow up. We report on our early North American surgical experience using the Intrabeam radiotherapy delivery system and review the current literature. METHODS: Prospectively gathered estrogen receptor-positive, clinically node-negative patients with invasive breast cancer < 3 cm receiving IORT using the Intrabeam system were reviewed. IORT-related effects and early postoperative outcome were assessed. A literature review was also performed. RESULTS: Forty-two patients (median age 71 years) underwent lumpectomy, sentinel lymph node (SLN) biopsy, and concurrent IORT from January 2011 to July 2011. Ninety-one percent of patients had invasive ductal histology with a median tumor size of 1.0 cm. This review highlights the patient selection criteria, describes commercially available accelerated partial breast irradiation (APBI) treatment options, and discusses outcomes for the variety of APBI techniques currently utilized in clinical practice as well as an institutional review of our early surgical experience using the Intrabeam radiotherapy delivery system. CONCLUSIONS: While a variety of APBI techniques are currently available for clinical use, our early North American operative experience with IORT shows it is well tolerated with low morbidity. Delivery of IORT adds moderate operative time and may require creating subcutaneous tissue fl aps. The addition of WBI may be necessary in situations for positive residual margins or microscopic nodal disease in patients who do not undergo additional surgery. PMID- 23037498 TI - Lessons learned from the bevacizumab experience. AB - BACKGROUND: Bevacizumab is an important agent in the oncologic armamentarium, with activity in a broad spectrum of solid tumors. It has been approved in the management of metastatic colorectal cancer, non-small cell lung cancer, renal cancers, and recurrent glioblastoma multiforme. METHODS: We reviewed the published literature and briefing documents of the US Food and Drug Administration that provided the data leading to approval or change in approval status. RESULTS: Bevacizumab initially received accelerated approval for the treatment of advanced breast cancer. However, lack of confirmatory data from additional clinical trials resulted in the loss of that indication. Both the expected and unexpected toxicities reported from clinical trials using bevacizumab have helped us to understand the drug's mechanism of action and to identify who are most likely to benefit from this important agent. CONCLUSIONS: The side effects of treatment may provide important information about drug mechanism and efficacy. Bevacizumab is clearly an important agent in oncology and is likely to become more significant once a clinical or pathological marker to predict its efficacy has been identified. PMID- 23037499 TI - Menopausal symptoms in young survivors of breast cancer: a growing problem without an ideal solution. AB - BACKGROUND: New breast cancers occur in 25% to 30% of women < 50 years of age. These young women undergo ablative surgery, chemotherapy, or hormonal/targeted treatment. These treatments have resulted in increased survival but at the expense of early menopause, marked by distressing vasomotor symptoms, sexual dysfunction, decreased metabolism, and musculoskeletal and cardiovascular effects. METHODS: A comprehensive literature search was performed using PubMed. This article reviews the evidence-based approaches to the treatment of these distressing symptoms in young breast cancer survivors. RESULTS: Menopausal symptoms in young patients are typically more severe due to the abrupt and rapid decrease in estrogen, and chemotherapy and hormones worsen these symptoms. Evidence supporting the efficacy of most complementary therapies is scarce. Behavioral modification and yoga may be helpful in mild cases of vasomotor symptoms, whereas newer antidepressants are promising in moderate to severe cases, and stellate ganglion block may be used in refractory cases. Local vaginal moisturizers, and in refractory cases low-dose estrogen creams, may ameliorate most urogenital symptoms. Bisphosphonates, vitamin D, and calcium can treat osteoporosis, and weight-bearing exercises decrease bone mineral density loss and help to control weight. Smoking cessation, exercise, and dietary modifications should be recommended to all young patients to decrease cardiac morbidity. At present, there is insufficient evidence to support any natural agent as a viable alternative to hormone replacement therapy to treat these symptoms. CONCLUSIONS: No single agent can ameliorate vasomotor, cardiac, skeletal, and sexual concerns of young breast cancer survivors coping with menopausal symptoms. Quality-of-life research involving premenopausal breast cancer survivors is lacking. Further study is needed to identify safe and effective treatments for menopausal symptoms and to confirm their long-term safety in young breast cancer survivors. PMID- 23037500 TI - Moderate correlations of in vitro versus in vivo pharmacokinetics questioning the need of early microsomal stability testing. AB - BACKGROUND/AIMS: Putative in vitro-in vivo correlations of pharmacokinetic (PK) parameters are regarded as a prerequisite to filter hits derived from high throughput screening (HTS) approaches for subsequent murine in vivo PK studies. METHODS: In this study, we assessed stabilities in rat and human microsomes of 121 compounds from an early, academic drug discovery programme targeting the (pro)renin receptor and correlated the respective data with single-dose, in vivo PK parameters of 22 hits administered intravenously in rats. RESULTS: After transformation of in vitro half-lives to predicted in vivo hepatic clearances, r(2) regarding in vitro-in vivo clearance correlations were 0.31 and 0.27 for the rat and human species, respectively. CONCLUSIONS: Our data concerning structurally diverse real-world compounds indicate that microsomal stability testing is not a tool to triage early compounds for in vivo PK testing. PMID- 23037501 TI - An integrated allele-specific polymerase chain reaction-microarray chip for multiplex single nucleotide polymorphism typing. AB - An integrated allele-specific polymerase chain reaction (AS PCR) and microarray chip has been developed for multiplex single nucleotide polymorphism (SNP) typing on a portable genetic analyzer instrumentation. We applied the integrated PCR microarray system for on-site Hanwoo (Korean indigenous beef cattle) identification. Eleven sets of primers were designed, among which ten sets of primers targeted ten SNP loci to discriminate Hanwoo from the imported beef cattle and one primer set was used as a positive PCR control. The AS PCR for multiplex SNP typing was conducted on a glass-based microchip consisting of four layers: a microchannel plate for microfluidic control, a Pt-electrode plate for a resistance temperature detector (RTD), a poly(dimethylsiloxane) (PDMS) membrane and a manifold glass for micropump and microvalve function. The resultant AS PCR products were mixed with a hybridization buffer in a micromixer channel through the micropumping operation, and then the microarray assay was performed in the downstream process. Eleven duplicate probes were spotted in a glass slide, which was connected at the end of the micromixer channel unit. When the mixed solution was injected into the disposable microarray chip, pneumatically actuated micropumping was executed to speed up the hybridization process by inducing the convective flow. The fluorescence signals on each spot were monitored by a miniaturized fluorescence scanner, and the Hanwoo was verified by detecting the number of fluorescent spots with three or fewer among eleven. An integrated portable PCR-microarray genetic analysis microsystem was first demonstrated for rapid, accurate, and on-site multiplex SNP typing to differentiate animal species. PMID- 23037502 TI - Kinetics of the electrocardiographic changes after permanent coronary occlusion in rats: Relationship with infarct size. AB - The electrocardiogram (ECG) has been a useful tool to identify ischemia in humans and laboratory animals. Previous ECG studies showed that presence of pathological Q waves in lead DI in rats submitted to ligature of the left coronary artery (LCA) is a good predictor of successful myocardial infarction (MI). This study aimed to determine the sensitivity and the specificity of these ECG findings to predict successful MI. Male Wistar rats were submitted to surgical ligature of the LCA (N=86) or sham-operation (SO, N=16). ECG was recorded under halothane/ether anesthesia before surgery and 1, 3, 5, 7, and 15 days later. MI was determined by the presence of a transmural fibrous scar. Sixty-nine rats survived and 60 showed fibrous scar indicating a successful production of MI (18 and 42 animals were analyzed 1 or 15 days after MI, respectively). Twenty-four hours after, Q amplitude was linearly related to infarct size (r=-0.778; P<0.01), but not 15 days after (r=-0.416; P>0.05). In 53 out of 60 rats with transmural scar, Q wave in lead DI was identified in the ECG. Absence of Q wave occurred in 7 animals. The sensitivity was 88% (CI(95)=83-93%). Nine animals submitted to coronary ligature did not show infarct scar. One of these animals, however, showed Q wave in DI, indicating a specificity of 77% (CI(95)=65-104%). In conclusion, ECG can be used as a reliable tool to identify MI and can be used to predict the infarct size as earlier as 1 day after LCA ligation in rats. PMID- 23037503 TI - Inhibition of tumor promotion by parthenolide: epigenetic modulation of p21. AB - The promotion stage in the multistep process of epidermal tumorigenesis is NF-kB dependent, epigenetically regulated, and reversible, thus, a suitable target for chemoprevention. We investigated whether the NF-kB inhibitor, parthenolide, currently in cancer clinical trials, attenuates tumor promotion by modulating the epigenetically regulated NF-kB target genes, p21 and cyclin D1. Parthenolide selectively inhibited the growth of neoplastic keratinocytes while sparing normal ones. Specifically, in JB6P+ cells, a model of tumor promotion, noncytotoxic parthenolide concentrations abrogated tumor promoter-induced cell proliferation and anchorage-independent growth. Furthermore, parthenolide decreased tumor promoter-induced NF-kB activity, increased p21, and decreased cyclin D1 expression. In parthenolide-treated cells, p21 transcription correlated with relaxed chromatin and p65/NF-kB binding at the p21 promoter. However, cyclin D1 transcription correlated more with p65/NF-kB binding than with chromatin structure at the cyclin D1 promoter. Epigenetic regulation by parthenolide seemed specific, as parthenolide did not alter global histone acetylation and methylation and histone deacetylase activity. Because p21 expression by parthenolide was sustained, we used p21-siRNA and p21 -/- cancer cells and showed that the loss of p21 is cytoprotective against parthenolide. Low parthenolide concentrations (0.25 mg/kg) inhibited tumor growth of promoted JB6P+ cells in xenograft immunocompromised mice using two different chemoprevention protocols. Tissue microarray of mouse tumors showed that parthenolide decreased scores of the cell proliferation marker Ki67 and p65/NF-kB, whereas it increased p21 expression. These results show that low doses of parthenolide inhibit tumor promotion and epigenetically modulate p21 expression, highlighting the potential role of this drug as a chemopreventive agent and in epigenetic cancer therapy. PMID- 23037504 TI - Ozone exposure response for U.S. soybean cultivars: linear reductions in photosynthetic potential, biomass, and yield. AB - Current background ozone (O(3)) concentrations over the northern hemisphere's midlatitudes are high enough to damage crops and are projected to increase. Soybean (Glycine max) is particularly sensitive to O(3); therefore, establishing an O(3) exposure threshold for damage is critical to understanding the current and future impact of this pollutant. This study aims to determine the exposure response of soybean to elevated tropospheric O(3) by measuring the agronomic, biochemical, and physiological responses of seven soybean genotypes to nine O(3) concentrations (38-120 nL L(-1)) within a fully open-air agricultural field location across 2 years. All genotypes responded similarly, with season-long exposure to O(3) causing a linear increase in antioxidant capacity while reducing leaf area, light absorption, specific leaf mass, primary metabolites, seed yield, and harvest index. Across two seasons with different temperature and rainfall patterns, there was a robust linear yield decrease of 37 to 39 kg ha(-1) per nL L(-1) cumulative O(3) exposure over 40 nL L(-1). The existence of immediate effects of O(3) on photosynthesis, stomatal conductance, and photosynthetic transcript abundance before and after the initiation and termination of O(3) fumigation were concurrently assessed, and there was no evidence to support an instantaneous photosynthetic response. The ability of the soybean canopy to intercept radiation, the efficiency of photosynthesis, and the harvest index were all negatively impacted by O(3), suggesting that there are multiple targets for improving soybean responses to this damaging air pollutant. PMID- 23037505 TI - Disruption of abscisic acid signaling constitutively activates Arabidopsis resistance to the necrotrophic fungus Plectosphaerella cucumerina. AB - Plant resistance to necrotrophic fungi is regulated by a complex set of signaling pathways that includes those mediated by the hormones salicylic acid (SA), ethylene (ET), jasmonic acid (JA), and abscisic acid (ABA). The role of ABA in plant resistance remains controversial, as positive and negative regulatory functions have been described depending on the plant-pathogen interaction analyzed. Here, we show that ABA signaling negatively regulates Arabidopsis (Arabidopsis thaliana) resistance to the necrotrophic fungus Plectosphaerella cucumerina. Arabidopsis plants impaired in ABA biosynthesis, such as the aba1-6 mutant, or in ABA signaling, like the quadruple pyr/pyl mutant (pyr1pyl1pyl2pyl4), were more resistant to P. cucumerina than wild-type plants. In contrast, the hab1-1abi1-2abi2-2 mutant impaired in three phosphatases that negatively regulate ABA signaling displayed an enhanced susceptibility phenotype to this fungus. Comparative transcriptomic analyses of aba1-6 and wild-type plants revealed that the ABA pathway negatively regulates defense genes, many of which are controlled by the SA, JA, or ET pathway. In line with these data, we found that aba1-6 resistance to P. cucumerina was partially compromised when the SA, JA, or ET pathway was disrupted in this mutant. Additionally, in the aba1-6 plants, some genes encoding cell wall-related proteins were misregulated. Fourier transform infrared spectroscopy and biochemical analyses of cell walls from aba1 6 and wild-type plants revealed significant differences in their Fourier transform infrared spectratypes and uronic acid and cellulose contents. All these data suggest that ABA signaling has a complex function in Arabidopsis basal resistance, negatively regulating SA/JA/ET-mediated resistance to necrotrophic fungi. PMID- 23037506 TI - Long-term acclimation of the cyanobacterium Synechocystis sp. PCC 6803 to high light is accompanied by an enhanced production of chlorophyll that is preferentially channeled to trimeric photosystem I. AB - Cyanobacteria acclimate to high-light conditions by adjusting photosystem stoichiometry through a decrease of photosystem I (PSI) abundance in thylakoid membranes. As PSI complexes bind the majority of chlorophyll (Chl) in cyanobacterial cells, it is accepted that the mechanism controlling PSI level/synthesis is tightly associated with the Chl biosynthetic pathway. However, how Chl is distributed to photosystems under different light conditions remains unknown. Using radioactive labeling by (35)S and by (14)C combined with native/two-dimensional electrophoresis, we assessed the synthesis and accumulation of photosynthetic complexes in parallel with the synthesis of Chl in Synechocystis sp. PCC 6803 cells acclimated to different light intensities. Although cells acclimated to higher irradiances (150 and 300 MUE m(-2)s(-1)) exhibited markedly reduced PSI content when compared with cells grown at lower irradiances (10 and 40 MUE m(-2) s(-1)), they grew much faster and synthesized significantly more Chl, as well as both photosystems. Interestingly, even under high irradiance, almost all labeled de novo Chl was localized in the trimeric PSI, whereas only a weak Chl labeling in photosystem II (PSII) was accompanied by the intensive (35)S protein labeling, which was much stronger than in PSI. These results suggest that PSII subunits are mostly synthesized using recycled Chl molecules previously released during PSII repair-driven protein degradation. In contrast, most of the fresh Chl is utilized for synthesis of PSI complexes likely to maintain a constant level of PSI during cell proliferation. PMID- 23037507 TI - The cell wall of the Arabidopsis pollen tube--spatial distribution, recycling, and network formation of polysaccharides. AB - The pollen tube is a cellular protuberance formed by the pollen grain, or male gametophyte, in flowering plants. Its principal metabolic activity is the synthesis and assembly of cell wall material, which must be precisely coordinated to sustain the characteristic rapid growth rate and to ensure geometrically correct and efficient cellular morphogenesis. Unlike other model species, the cell wall of the Arabidopsis (Arabidopsis thaliana) pollen tube has not been described in detail. We used immunohistochemistry and quantitative image analysis to provide a detailed profile of the spatial distribution of the major cell wall polymers composing the Arabidopsis pollen tube cell wall. Comparison with predictions made by a mechanical model for pollen tube growth revealed the importance of pectin deesterification in determining the cell diameter. Scanning electron microscopy demonstrated that cellulose microfibrils are oriented in near longitudinal orientation in the Arabidopsis pollen tube cell wall, consistent with a linear arrangement of cellulose synthase CESA6 in the plasma membrane. The cellulose label was also found inside cytoplasmic vesicles and might originate from an early activation of cellulose synthases prior to their insertion into the plasma membrane or from recycling of short cellulose polymers by endocytosis. A series of strategic enzymatic treatments also suggests that pectins, cellulose, and callose are highly cross linked to each other. PMID- 23037508 TI - A carbon monoxide gas sensor using oxygen plasma modified carbon nanotubes. AB - Carbon monoxide (CO) is a highly toxic gas that can be commonly found in many places. However, it is not easily detected by human olfaction due to its colorless and odorless nature. Therefore, highly sensitive sensors need to be developed for this purpose. Carbon nanotubes (CNTs) have an immense potential in gas sensing. However, CNT-based gas sensors for sensing CO are seldom reported due to the lack of reactivity between CO and CNTs. In this work, O(2) plasma modified CNT was used to fabricate a CNT gas sensor. The plasma treated CNTs showed selectively towards CO, with the capability of sensing low concentrations of CO (5 ppm) at room temperature, while the pristine CNTs showed no response. UV spectra and oxygen reduction reaction provided evidence that the difference in sensing property was due to the elimination of metallic CNTs and enhancement of the oxygen reduction property. PMID- 23037509 TI - Religiosity as a protective factor in suicidal behavior: a case-control study. AB - The impact of religiosity in suicidal behavior was evaluated in Brazil through a case-control study in which 110 subjects who had attempted suicide through the use of toxic substances were compared with 114 control subjects with no history of suicide attempts. Religiosity was measured in three aspects: organizational religious activities (ORAs), nonorganizational religious activities (NORAs), and intrinsic religiosity (IR). Multivariate logistic regression was used to evaluate the impact of religiosity on suicide attempts, controlling for sociodemographic variables, impulsivity, and mental illness. Religiosity, in its three dimensions, was shown to be an important protective factor against suicide attempts, even after controlling for relevant risk factors associated with suicidal behavior: ORA: odds ratio (OR), 0.63 (95% confidence interval [CI], 0.45-0.89); NORA: OR, 0.56 (95% CI, 0.42-0.75); and IR: OR, 0.59 (95% CI, 0.49-0.70). These data have important implications for understanding religiosity factors that might protect against suicide. PMID- 23037510 TI - The association between trauma and chronic medical conditions in individuals with severe mental illness. AB - Based on the concept of allostatic load, this study proposed and evaluated a model for the relationship between childhood trauma, chronic medical conditions, and intervening variables affecting this relationship in individuals with severe mental illness. Childhood trauma, adult trauma, major depressive disorder symptoms, posttraumatic stress disorder symptoms, health risk factors, and chronic medical conditions were retrospectively assessed using a cross-sectional survey design in a sample of 117 individuals with severe mental illness receiving public mental health services. Path analyses produced a good-fitting model, with significant pathways from childhood to adult trauma and from adult trauma to chronic medical conditions. Multisample path analyses revealed the equivalence of the model across sex. The results support a model for the relationship between childhood and adult trauma and chronic medical conditions, which highlights the pathophysiological toll of cumulative trauma experienced across the life span and the pressing need to prevent retraumatization in this population. PMID- 23037511 TI - Probiotic mechanisms of action. AB - Probiotics are live microorganisms that provide health benefits to the host when ingested in adequate amounts. The strains most frequently used as probiotics include lactic acid bacteria and bifidobacteria. Probiotics have demonstrated significant potential as therapeutic options for a variety of diseases, but the mechanisms responsible for these effects have not been fully elucidated yet. Several important mechanisms underlying the antagonistic effects of probiotics on various microorganisms include the following: modification of the gut microbiota, competitive adherence to the mucosa and epithelium, strengthening of the gut epithelial barrier and modulation of the immune system to convey an advantage to the host. Accumulating evidence demonstrates that probiotics communicate with the host by pattern recognition receptors, such as toll-like receptors and nucleotide binding oligomerization domain-containing protein-like receptors, which modulate key signaling pathways, such as nuclear factor-KB and mitogen-activated protein kinase, to enhance or suppress activation and influence downstream pathways. This recognition is crucial for eliciting measured antimicrobial responses with minimal inflammatory tissue damage. A clear understanding of these mechanisms will allow for appropriate probiotic strain selection for specific applications and may uncover novel probiotic functions. The goal of this systematic review was to explore probiotic modes of action focusing on how gut microbes influence the host. PMID- 23037512 TI - Asymmetric cross-coupling of aryl triflates to the benzylic position of benzylamines. PMID- 23037513 TI - Acutely ill patients in internal medicine departments want treatment for undiagnosed, symptomatic skin conditions. AB - OBJECTIVE: Concomitant skin conditions may be neglected in internal medicine patients due to lack of knowledge or resources. Thus, we investigated the prevalence of undiagnosed skin conditions in this population. METHODS: 200 patients in a university medical center's internal medicine division were examined clinically for dermatoses and quality of life in a prospective, 2-month, single-center study. RESULTS: All patients had several dermatological problems (mean per patient: 13; range: 3-25). There was no relationship between the patient's main medical problem and the number or nature of dermatological conditions. Most patients (84%) requested treatment for their skin condition during hospitalization, especially for xerosis (76%), warts (69%), seborrheic eczema (67%) and onychorrhexis (53%) but not for asymptomatic dermatoses. The impairment in skin-related quality of life was mild but significant, with a mean +/- SD Dermatology Life Quality Index of 3 +/- 4 (p < 0.001), and global quality of life impairment was severe (p < 0.001). CONCLUSIONS: Inpatients suffered from many different, mostly age-related, skin conditions that remained undiagnosed. When prompted, however, patients requested treatment, particularly for symptomatic dermatological conditions such as xerosis, revealing an unmet need that needs to be addressed by qualified evaluation and care. PMID- 23037514 TI - Development of a neurotechnological system for relieving phantom limb pain using transverse intrafascicular electrodes (TIME). AB - Phantom limb pain (PLP) is a chronic condition that develops in the majority of amputees. The underlying mechanisms are not completely understood, and thus, no treatment is fully effective. Based on recent studies, we hypothesize that electrical stimulation of afferent nerves might alleviate PLP by giving sensory input to the patient if nerve fibers can be activated selectively. The critical component in this scheme is the implantable electrode structure. We present a review of a novel electrode concept to distribute highly selective electrode contacts over the complete cross section of a peripheral nerve to create a distributed activation of small nerve fiber ensembles at the fascicular level, the transverse intrafascicular multichannel nerve electrode (TIME). The acute and chronic implantations in a small animal model exhibited a good surface and structural biocompatibility as well as excellent selectivity. Implantation studies on large animal models that are closer to human nerve size and anatomical complexity have also been conducted. They proved implant stability and the ability to selectively activate nerve fascicles in a limited proximity to the implant. These encouraging results have opened the way forward for human clinical trials in amputees to investigate the effect of selective electrical stimulation on PLP. PMID- 23037515 TI - Improved software on the Sysmex XE-5000 BF mode for counting leukocytes in cerebrospinal fluid. PMID- 23037516 TI - Laboratory diagnostics of myocardial infarction--troponins and beyond. AB - In the case of suspected acute coronary syndrome and myocardial infarction positive diagnosis or exclusion strongly depend on the use of biomarkers and in particular cardiac troponins (cTn). Especially in the early phase of myocardial infarction the sensitivity of cTn assays has been unsatisfactory. This has led to the investigation of many other potential markers for the early diagnosis of myocardial infarction. In addition, several traditional markers have been advocated, e.g., myoglobin, as these were considered to be more sensitive than cTn. With the advent of high-sensitive (hs) cTn assays the value and practical use of the alternative or additional markers has to be reassessed. According to the currently available data, no single marker is superior to hs-cTn for the diagnosis of acute myocardial infarction. In particular, the notion of superior sensitivity of myoglobin compared to cTn no longer holds true. There are two protein markers, heart-type fatty acid binding protein and copeptin, and plasma free fatty acids that may increase the diagnostic value and specifically the negative predictive value when determined on admission in combination with hs cTn. However, the incremental gain, if any, is small. Further data are needed to determine, whether these markers can in fact improve diagnosis and if they are superior to the recommended use of the relative or absolute change of hs-cTn after 3 h. PMID- 23037517 TI - Critical review of laboratory investigations in clinical practice guidelines: proposals for the description of investigation. AB - BACKGROUND: Correct information provided by guidelines may reduce laboratory test related errors during the pre-analytical, analytical and post-analytical phase and increase the quality of laboratory results. METHODS: Twelve clinical practice guidelines were reviewed regarding inclusion of important laboratory investigations. Based on the results and the authors' experience, two checklists were developed: one comprehensive list including topics that authors of guidelines may consider and one consisting of minimal standards that should be covered for all laboratory tests recommended in clinical practice guidelines. The number of topics addressed by the guidelines was related to involvement of laboratory medicine specialists in the guideline development process. RESULTS: The comprehensive list suggests 33 pre- analytical, 37 analytical and 10 post analytical items. The mean percentage of topics dealt with by the guidelines was 33% (median 30%, range 17%-55%) and inclusion of a laboratory medicine specialist in the guideline committee significantly increased the number of topics addressed. Information about patient status, biological and analytical interferences and sample handling were scarce in most guidelines even if the inclusion of a laboratory medicine specialist in the development process seemingly led to increased focus on, e.g., sample type, sample handling and analytical variation. Examples underlining the importance of including laboratory items are given. CONCLUSIONS: Inclusion of laboratory medicine specialist in the guideline development process may increase the focus on important laboratory related items even if this information is usually limited. Two checklists are suggested to help guideline developers to cover all important topics related to laboratory testing. PMID- 23037518 TI - Absence of coronary calcification with normal endothelial function: a unique entity for preemptive medical care. PMID- 23037519 TI - Can combined assessment of baroreflex sensitivity and iodine-123 metaiodobenzylguanidine imaging be used for risk stratification of patients with type 2 diabetes mellitus? PMID- 23037520 TI - Do plasma levels of brain natriuretic peptide (BNP) and N-terminal proBNP (NT proBNP) increase in diastolic dysfunction as well as in systolic dysfunction? PMID- 23037521 TI - Serial changes in glucose-loaded 18F-fluoro-2-deoxyglucose positron emission tomography, 99mTc-tetrofosmin and 123I-beta-methyl-p-iodophenyl-penta-decanoic acid myocardial single-photon emission computed tomography images in patients with anterior acute myocardial infarction. AB - BACKGROUND: (18)F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) is assumed to be the most useful method for evaluating the viability of the myocardium. However, there are few reports regarding serial changes in (18)F-FDG PET images of acute myocardial infarction (AMI). We evaluated serial changes in glucose-loaded (18)F-FDG-PET, (123)I-beta-methyl-p-iodophenyl-penta-decanoic acid (BMIPP) single-photon emission computed tomography (SPECT) and (99m)Tc Tetrofosmin (TF) gated SPECT images in patients with AMI. METHODS AND RESULTS: We enrolled 7 consecutive patients with first anterior AMI who successfully underwent percutaneous coronary intervention (PCI). (18)F-FDG-PET images were obtained in the acute, subacute, chronic, mid-term and long-term phases. (123)I BMIPP and (99m)Tc-TF SPECT images were obtained in the subacute, chronic, mid term and long-term phases. We determined the total defect score (TDS) for each image. The TDS of the glucose-loaded (18)F-FDG-PET, (123)I-BMIPP and( 99m)Tc-TF SPECT images indicated significant serial decrease (P<0.001). Comparing these images, the TDS of the glucose-loaded (18)F-FDG-PET images was larger than that of the (123)I-BMIPP and (99m)Tc-TF SPECT images, and the TDS indicated (18)F-FDG PET>(123)I-BMIPP>(99m)Tc-TF in all phases. CONCLUSIONS: The defect areas of glucose-loaded (18)F-FDG-PET images were significantly larger than those of (123)I-BMIPP and( 99m)Tc-TF SPECT images during 9 months follow-up of patients with successful PCI for anterior AMI. Additionally, the impairment of glucose metabolism was prolonged. PMID- 23037522 TI - Safety and efficacy of a bolus injection of landiolol hydrochloride as a premedication for multidetector-row computed tomography coronary angiography. AB - BACKGROUND: We evaluated the safety and efficacy of a bolus injection of landiolol hydrochloride, an ultrashort-acting beta1-selective antagonist, as an additional treatment after premedication with an oral beta-blocker to reduce heart rate prior to multidetector-row computed tomography (MDCT) coronary angiography (CAG). METHODS AND RESULTS: A total of 458 patients who underwent MDCT CAG were retrospectively enrolled. Image quality and hemodynamic parameters were compared in patients before and after approval of landiolol hydrochloride. If heart rate reduction was insufficient after premedication with an oral beta blocker, a bolus injection of landiolol hydrochloride (n=66) or other drugs (n=30) was used. The percentage of evaluable images per segment in patients after approval of landiolol (99.3%) was greater than that in patients before approval of landiolol (97.4%, P<0.01). Heart rates before scanning in patients receiving landiolol hydrochloride were similar to those receiving other drugs. Heart rate was significantly reduced approximately 5 min after injection of landiolol hydrochloride and increased shortly. No decrease in systolic blood pressure or other adverse effects was observed. CONCLUSIONS: Bolus injection of landiolol hydrochloride sufficiently reduced heart rate without significantly reducing systolic blood pressure and produced a high percentage of evaluable images, suggesting that bolus injection of landiolol hydrochloride as an additional pretreatment is feasible in MDCT CAG. PMID- 23037523 TI - Combined front and back diffraction gratings for broad band light trapping in thin film solar cell. AB - In this paper, we present the integration of combined front and back 1D and 2D diffraction gratings with different periods, within thin film photovoltaic solar cells based on crystalline silicon layers. The grating structures have been designed considering both the need for incident light absorption enhancement and the technological feasibility. Long wavelength absorption is increased thanks to the long period (750 nm) back grating, while the incident light reflection is reduced by using a short period (250 nm) front grating. The simulated short circuit current in a solar cell combining a front and a back grating structures with a 1.2 um thick c-Si layer, together with the back electrode and TCO layers, is increased up to 30.3 mA/cm2, compared to 18.4 mA/cm2 for a reference stack, as simulated using the AM1.5G solar spectrum intensity distribution from 300 nm to 1100 nm, and under normal incidence. PMID- 23037524 TI - Kind of broad-band photonic valve and its application to silicon solar cells. AB - We investigate the dual optical behaviour of a photonic grating interface presenting a more or less important index contrast, showing either efficient broadband reflectivity, either high transmittance within the same spectral window, depending on the direction of the incident light. This behaviour is reminiscent of a diode one and could find interesting applications. A typical example is given for thin crystalline silicon solar cells where the rear side is directly nano-textured to trap light without metal reflector (bifacial device), well compatible with an integration in a photovoltaic module. PMID- 23037525 TI - Conditions for admittance-matched tunneling through symmetric metal-dielectric stacks. AB - We used the theory of potential transmittance to derive a general expression for reflection-less tunneling through a periodic stack with a dielectric-metal dielectric unit cell. For normal-incidence from air, the theory shows that only a specific (and typically impractically large) dielectric index can enable a perfect admittance match. For off-normal incidence of TE-polarized light, an admittance match is possible at a specific angle that depends on the index of the ambient and dielectric media and the thickness and index of the metal. For TM polarized light, admittance matching is possible within the evanescent-wave range (i.e. for tunneling mediated by surface plasmons). The results provide insight for research on transparent metals and superlenses. PMID- 23037526 TI - Broadband absorption enhancement in a-Si:H thin-film solar cells sandwiched by pyramidal nanostructured arrays. AB - A new thin-film solar cell structure with a broadband absorption enhancement is proposed. The active a-Si:H film is sandwiched by two periodic pyramidal structured layers. The upper dielectric pyramidal layer acts as matching impedance by gradual change of the effective refractive index to enhance the absorption of the active layer in the short wavelength range. The lower metallic pyramidal layer traps light by the excitation of Fabry-Perot (FP) resonance, waveguide (WG) resonance and surface plasmon (SP) mode to enhance the absorption in the long wavelength range. With the cooperation of the two functional layers, a broadband absorption enhancement is realized. The structure parameters are designed by the cavity resonance theory, which shows that the results are accordant with the finite-difference time-domain (FDTD) simulation. By optimizing, the absorption of the sandwich structure is enhanced up to 48% under AM1.5G illumination in the 350-900 nm wavelength range compared to that of bare thin-film solar cells. PMID- 23037527 TI - Cup-shaped copper heat spreader in multi-chip high-power LEDs application. AB - In this study, cup-shaped copper sheets were developed to improve heat dispassion for high-power light emitting diodes (LEDs) array module (3 * 3, 4 * 4, and 5 * 5) using an electroplating technique. The cup-shaped copper sheets were directly contacted with sapphire to enhance the heat dissipation of the chip itself. The lateral emitting light extraction and heat dissipation of high-power LEDs were enhanced and efficient. The surface temperature was not only decreasing but also uniform for each LED chip with the cup-shaped copper heat spreader adoption. The high thermal transmitting performance of cup-shaped copper heat spreader allows thermal resistance reducing 0.7, 0.6, and 0.7 K/W of 3 * 3, 4 * 4, and 5 * 5 LED array module, respectively. In addition, the light output power was increased of 14, 13, and 12% with 3 * 3, 4 * 4, and 5 * 5 LEDs array module using cup-shaped copper sheet at high current injection. High heat dissipation performance and light extraction were obtained by cup-shaped copper sheet with copper bulk and silver mirror. PMID- 23037528 TI - Design of high efficiency organic solar cell with light trapping. AB - We have designed a high efficiency organic solar cell with light trapping structure on transference cylindrical substrate. An electrical and optical simulation of the light trapping structure has been performed on the basis of finite element and transfer matrix formalism methods. Absorption spectrum, internal quantum efficiency, external quantum efficiency, maximum power output and efficiency of the organic solar cell are simulated and presented in terms of three variables: the height, diameter of the glass substrate and the thickness of the organic active layer. The efficiency of the proposed organic solar cell with light trapping structure is enhanced by a factor of 2 than the similar structure on the flat plain glass substrate. The optimum organic active layer thickness to achieve the highest efficiency is shifted from 65 to 20 nm. Finally, we have investigated the effect of light incident angle on the performance of the proposed cell structure. PMID- 23037529 TI - Nonimaging optics in luminescent solar concentration. AB - Light trapped within luminescent solar concentrators (LSCs) is naturally limited in angular extent by the total internal reflection critical angle, thetacrit, and hence the principles of nonimaging optics can be leveraged to increase LSC concentration ratio by appropriately reshaping the edges. Here, we use rigorous ray-tracing simulations to explore the potential of this concept for realistic LSCs with compound parabolic concentrator (CPC)-tapered edges and show that, when applied to a single edge, the concentration ratio is increased by 23% while maintaining >90% of the original LSC optical efficiency. Importantly, we find that CPC-tapering all of the edges enables a significantly greater intensity enhancement up to 35% at >90% of the original optical efficiency, effectively enabling two-dimensional concentration through a cooperative, ray-recycling effect in which rays rejected by one CPC are accepted by another. These results open up a significant opportunity to improve LSC performance at virtually no added manufacturing cost by incorporating nonimaging optics into their design. PMID- 23037530 TI - Light extraction efficiency of GaN-based LED with pyramid texture by using ray path analysis. AB - We study three different gallium-nitride (GaN) based light emitting diode (LED) cases based on the different locations of the pyramid textures. In case 1, the pyramid texture is located on the sapphire top surface, in case 2, the pyramid texture is locate on the P-GaN top surface, while in case 3, the pyramid texture is located on both the sapphire and P-GaN top surfaces. We study the relationship between the light extraction efficiency (LEE) and angle of slant of the pyramid texture. The optimization of total LEE was highest for case 3 among the three cases. Moreover, the seven escape paths along which most of the escaped photon flux propagated were selected in a simulation of the LEDs. The seven escape paths were used to estimate the slant angle for the optimization of LEE and to precisely analyze the photon escape path. PMID- 23037531 TI - Prospects of near-field plasmonic absorption enhancement in semiconductor materials using embedded Ag nanoparticles. AB - Metal nanoparticles are efficient antennas for light. If embedded in a semiconductor material, they can enhance light absorption in the semiconductor, due to the strong plasmonic near-field coupling. We use numerical simulations to calculate the absorption enhancement in the semiconductor using Ag nanoparticles with diameters in the range 5-60 nm for crystalline Si, amorphous Si, a polymer blend, and Fe2O3. We study single Ag particles in a 100*100*100 nm semiconductor volume, as well as periodic arrays with 100 nm pitch. We find that in all cases Ohmic dissipation in the metal is a major absorption factor. In crystalline Si, while Ag nanoparticles cause a 5-fold enhancement of the absorbance in the weakly absorbing near-bandgap spectral range, Ohmic losses in the metal dominate the absorption. We conclude crystalline Si cannot be sensitized with Ag nanoparticles in a practical way. Similar results are found for Fe2O3. The absorbance in the polymer blend can be enhanced by up to 100% using Ag nanoparticles, at the expense of strong additional absorption by Ohmic losses. Amorphous Si cannot be sensitized with Ag nanoparticles due to the mismatch between the plasmon resonance and the bandgap of a-Si. By using sensitization with Ag nanoparticles the thickness of some semiconductor materials can be reduced while keeping the same absorbance, which has benefits for materials with short carrier diffusion lengths. Scattering mechanisms by plasmonic nanoparticles that are beneficial for enhanced light trapping in solar cells are not considered in this paper. PMID- 23037532 TI - Increased efficiency of luminescent solar concentrators after application of organic wavelength selective mirrors. AB - Organic wavelength-selective mirrors are used to reduce the loss of emitted photons through the surface of a luminescent solar concentrator (LSC). A theoretical calculation suggests that application of a 400 nm broad reflector on top of an LSC containing BASF Lumogen Red 305 as a luminophore can reflect 91% of all surface emitted photons back into the device. Used in this way, such broad reflectors could increase the edge-emission efficiency of the LSC by up to 66%. Similarly, 175 nm broad reflectors could increase efficiency up to 45%. Measurements demonstrate more limited effectiveness and dependency on the peak absorbance of the LSC. At higher absorbance, the increased number of internal re absorption events reduces the effectiveness of the reflectors, leading to a maximum increase in LSC efficiency of ~5% for an LSC with a peak absorbance of 1. Reducing re-absorption by reducing dye concentration or the coverage of the luminophore coating results in an increase in LSC efficiency of up to 30% and 27%, respectively. PMID- 23037533 TI - Solution-processed Li-Al layered-double-hydroxide platelet structures for high efficiency InGaN light emitting diodes. AB - High-oriented Li-Al layered double hydroxide (LDH) films were grown on an InGaN light-emitting diode (LED) structures by immersing in an aqueous alkaline Al(3+)- and Li+-containing solution. The stand upward and adjacent Li-Al LDH platelet structure was formed on the LED structure as a textured film to increase the light extraction efficiency. The light output power of the LED structure with the Li-Al LDH platelet structure had a 31% enhancement compared with a conventional LED structure at 20 mA. The reverse leakage currents, at -5V, were measured at 2.3 * 10(-8) A and -1.0 * 10(-10)A for the LED structures without and with the LDH film that indicated the Li-Al LDH film had the insulated property acted a passivation layer that had potential to replace the conventional SiO2 and Si3N4 passivation layers. The Li-Al LDH layer had the textured platelet structure and the insulated property covering whole the LED surface that has potential for high efficiency InGaN LED applications. PMID- 23037534 TI - Mn-doped GaN as photoelectrodes for the photoelectrolysis of water under visible light. AB - Hydrogen generation through direct photoelectrolysis of water was studied using photoelectrochemical (PEC) cells made of Mn-doped GaN photoelectrodes. In addition to its absorption of the ultraviolet spectrum, Mn-doped GaN photoelectrodes could absorb photons in the visible spectrum. The photocurrents measured from PEC cells made of Mn-doped GaN were at least one order higher than those measured from PEC cells made of undoped GaN-working electrodes. Under the visible light illumination and a bias voltage below 1.2 V, the Mn-doped GaN photoelectrodes could drive the water splitting reaction for hydrogen generation. However, hydrogen generation could not be achieved under the same condition wherein undoped GaN photoelectrodes were used. According to the results of the spectral responses and transmission spectra obtained from the experimental photoelectrodes, the enhanced photocurrent in the Mn-doped GaN photoelectrodes, compared with the undoped GaN photoelectrodes, was attributable to the Mn-related intermediate band within the band gap of GaN that resulted in further photon absorption. PMID- 23037535 TI - Spectral optimization of the color temperature tunable white light-emitting diode (LED) cluster consisting of direct-emission blue and red LEDs and a diphosphor conversion LED. AB - The correlated color temperature (CCT) tunable white-light LED cluster, which consists of direct-emission blue and red LEDs as well as phosphor-conversion (PC) LEDs packaged by combining green and orange phosphors with a blue LED die, has been obtained by nonlinear program for maximizing luminous efficacy (LE) of radiation (LER) under conditions of both color rendering index (CRI) and special CRI of R9 for strong red above 90 at CCTs of 2700 K to 6500 K. The optimal peak wavelengths of blue LED, red LED, blue LED die, green and orange phosphors are 465 nm, 628 nm, 452 nm, 530 nm and 586 nm, respectively. The real CCT tunable PC/red/blue LED cluster with CRIs of 90~96, R9s of 90~96, CQSs of 89~94, LERs of 303~358 lm/W, and LEs of 105~119 lm/W has been realized at CCTs of 2722 K to 6464 K. The deviation of the peak wavelength should be less than +/- 5 nm for blue LED die, +/- 1 nm for red LED, and +/- 2 nm for blue LED to achieve the PC/R/B LED cluster with high optical performance. PMID- 23037536 TI - Simultaneous broadband light trapping and fill factor enhancement in crystalline silicon solar cells induced by Ag nanoparticles and nanoshells. AB - Crystalline silicon solar cells are predominant and occupying more than 89% of the global solar photovoltaic market. Despite the boom of the innovative solar technologies, few can provide a low-cost radical solution to dramatically boost the efficiency of crystalline silicon solar cells, which has reached plateau in the past ten years. Here, we present a novel strategy to simultaneously achieve dramatic enhancement in the short-circuit current and the fill factor through the integration of Ag plasmonic nanoparticles and nanoshells on the antireflection coating and the screen-printed fingers of monocrystalline silicon solar cells, respectively, by a single step and scalable modified electroless displacement method. As a consequence, up to 35.2% enhancement in the energy conversion efficiency has been achieved due to the plasmonic broadband light trapping and the significant reduction in the series resistance. More importantly, this method can further increase the efficiency of the best performing textured solar cells from 18.3% to 19.2%, producing the highest efficiency cells exceeding the state of-the-art efficiency of the standard screen-printed solar cells. The dual functions of the Ag nanostructures, reported for the first time here, present a clear contrast to the previous works, where plasmonic nanostructures were integrated into solar cells to achieve the short-circuit current enhancement predominately. Our method offers a facile, cost-effective and scalable pathway for metallic nanostructures to be used to dramatically boost the overall efficiency of the optically thick crystalline silicon solar cells. PMID- 23037537 TI - Negative thermal quenching of photoluminescence in zinc oxide nanowire core/graphene-shell complexes. AB - Graphene is an atomic thin two-dimensional semimetal whereas ZnO is a direct wide band gap semiconductor with a strong light-emitting ability. In this paper, we report on photoluminescence (PL) of ZnO-nanowires (NWs)-core/Graphene-shell heterostructures, which shows a negative thermal quenching (NTQ) behavior both for the near band-edge and deep level emission. The abnormal PL behavior was understood through the charging and discharging processes between ZnO NWs and graphene. The NTQ properties are most possibly induced by the unique rapidly increasing density of states of graphene as a function of Fermi level, which promises a higher quantum tunneling probability between graphene and ZnO at a raised temperature. PMID- 23037538 TI - Conformally direct imprinted inorganic surface corrugation for light extraction enhancement of light emitting diodes. AB - We describe the fabrication of corrugated inorganic oxide surface via direct single step conformal nanoimprinting to achieve enhanced light extraction in light emitting diodes (LEDs). Nanoscale zinc oxide (ZnO) and indium tin oxide (ITO) corrugated layer were created on a nonplanar GaN LED surface including metal electrode using ultraviolet (UV) assisted conformal nanoimprinting and subsequent inductively coupled plasma reactive ion etching (ICP-RIE) treatment. The total output powers of the surface corrugated LEDs increased by 45.6% for the patterned sapphire substrate LED and 41.9% for the flat c-plane substrate LED without any degradation of the electrical characteristics. The role of the nanoscale corrugations on the light extraction efficiency enhancement was examined using 3-dimensional finite-difference time-domain (FDTD) analysis. It was found that light scattering by subwavelength scale surface corrugation plays important role to redirect the trapped light into radiative modes. This straightforward inorganic oxide imprint method with inherent flexibility provides an efficient way to generate nanoscale surface textures for the production of high power LEDs and optoelectronic devices. PMID- 23037539 TI - Near-infrared luminescence and energy transfer studies of LaOBr:Nd3+/Yb3+. AB - LaOBr:Nd(3+)/Yb(3+) has been prepared via a high temperature solid-state method, and near-infrared (NIR) quantum cutting (QC) luminescence in this system has been demonstrated. NIR luminescence of LaOBr:Nd(3+)/Yb(3+) has been investigated by excitation, emission spectra and lifetime measurements, respectively. After absorption of a single 363 nm photon, down-conversion (DC) occurs from the Nd(3+) 4G(9/2) level via the cross-relaxation process Nd(3+) (4G(9/2)->4F(3/2)), Yb(3+) (2F(7/2)->2F(5/2)), followed by a second energy transfer step from Nd(3+) (4F(3/2)level) to Yb(3+) (2F(5/2)level), leading to the emission of two IR photons from Yb(3+), which is a promising avenue to boost the efficiency of solar cells with a twofold increase in the photon number. PMID- 23037540 TI - Plasmonic nanograting design for inverted polymer solar cells. AB - Plasmonic nanostructures for effective light trapping in a variety of photovoltaics have been actively studied. Metallic nanograting structures are one of promising architectures. In this study, we investigated numerically absorption enhancement mechanisms in inverted polymer photovoltaics with one dimensional Ag nanograting in backcontact. An optical spacer layer of TiO2, which also may act as an electron transport layer, was introduced between nanograting pillars. Using a finite-difference-time domain method and performing a modal analysis, we explored correlations between absorption enhancements and dimensional parameters of nanograting such as period as well as height and width. The optimal design of nanograting for effective light trapping especially near optical band gap of an active layer was discussed, and 23% of absorption enhancement in a random polarization was demonstrated numerically with the optimally designed nanograting. In addition, the beneficial role of the optical spacer in plasmonic light trapping was also discussed. PMID- 23037541 TI - Analysis and optimization of surface plasmon-enhanced organic solar cells with a metallic crossed grating electrode. AB - We perform a systematic analysis of enhanced short-circuit current density (J(sc) in organic solar cells (OSCs) where one metallic electrode is optically thick and the other consists of a two-dimensional metallic crossed grating. By examining a model device representative of such surface plasmon (SP)-enhanced OSCs by the Fourier modal and finite-element methods for electromagnetic and exciton diffusion calculations, respectively, we provide general guidelines to maximize J(sc) of the SP-enhanced OSCs. Based on this study, we optimize the performance of a small-molecule OSC employing a copper phthalocyanine-fullerene donor acceptor pair, demonstrating that the optimized SP-enhanced device has J(sc) that is 75 % larger than that of the optimized device with an ITO-based conventional structure. PMID- 23037542 TI - Theoretical performance of multi-junction solar cells combining III-V and Si materials. AB - A route to improving the overall efficiency of multi-junction solar cells employing conventional III-V and Si photovoltaic junctions is presented here. A simulation model was developed to consider the performance of several multi junction solar cell structures in various multi-terminal configurations. For series connected, 2-terminal triple-junction solar cells, incorporating an AlGaAs top junction, a GaAs middle junction and either a Si or InGaAs bottom junction, it was found that the configuration with a Si bottom junction yielded a marginally higher one sun efficiency of 41.5% versus 41.3% for an InGaAs bottom junction. A significant efficiency gain of 1.8% over the two-terminal device can be achieved by providing an additional terminal to the Si bottom junction in a 3 junction mechanically stacked configuration. It is shown that the optimum performance can be achieved by employing a four-junction series-connected mechanically stacked device incorporating a Si subcell between top AlGaAs/GaAs and bottom In0.53Ga0.47As cells. PMID- 23037543 TI - Analysis of light extraction efficiency enhancement for thin-film-flip-chip InGaN quantum wells light-emitting diodes with GaN micro-domes. AB - The enhancement of light extraction efficiency for thin-film flip-chip (TFFC) InGaN quantum wells (QWs) light-emitting diodes (LEDs) with GaN micro-domes on n GaN layer was studied. The light extraction efficiency of TFFC InGaN QWs LEDs with GaN micro-domes were calculated and compared to that of the conventional TFFC InGaN QWs LEDs with flat surface. The three dimensional finite difference time domain (3D-FDTD) method was used to calculate the light extraction efficiency for the InGaN QWs LEDs emitting at 460nm and 550 nm, respectively. The effects of the GaN micro-dome feature size and the p-GaN layer thickness on the light extraction efficiency were studied systematically. Studies indicate that the p-GaN layer thickness is critical for optimizing the TFFC LED light extraction efficiency. Significant enhancement of the light extraction efficiency (2.5-2.7 times for lambda(peak) = 460nm and 2.7-2.8 times for lambda(peak) = 550nm) is achievable from TFFC InGaN QWs LEDs with optimized GaN micro-dome diameter and height. PMID- 23037544 TI - The tradeoff between plasmonic enhancement and optical loss in silicon nanowire solar cells integrated in a metal back reflector. AB - We perform a systematic numerical study to characterize the tradeoff between the plasmonic enhancement and optical loss in periodically aligned, silicon nanowire (SiNW) arrays integrated with a silver back reflector (Ag BR). Optimizing the embedded depth of the wire bottoms into a silver reflector achieved a highly efficient SiNW solar cell. Compared to the SiNW solar cell employing a flat back reflector, the embedded depth of ~20 nm resulted in the relative increase of ~5% in ultimate solar cell efficiency. PMID- 23037545 TI - Selective imine formation from alcohols and amines catalyzed by polymer incarcerated gold/palladium alloy nanoparticles with molecular oxygen as an oxidant. AB - Carbon black stabilized, polymer incarcerated gold/palladium alloy nanoparticles (PICB-Au/Pd) act as an efficient, reusable heterogeneous catalyst for imine synthesis from alcohols and amines through a tandem oxidative process using molecular oxygen as the terminal oxidant. PMID- 23037546 TI - Serum levels of LIGHT in MS. AB - BACKGROUND: Recently, a polymorphism in the LIGHT gene was shown to increase the risk of multiple sclerosis (MS) in a genome-wide association study (GWAS). OBJECTIVE: Our aim was to investigate if serum levels of LIGHT were affected by this polymorphism and by the disease itself. METHODS: Serum levels of LIGHT were investigated in four cohorts; 1) MS (n = 159) and controls (n = 160) in relation to rs1077667 genotype; 2) MS at relapse (n = 30) vs. healthy controls (n = 26); 3) MS (n = 27) vs. other neurological disease (OND, n = 33); and 4) MS patients before and after one year of treatment with natalizumab (n = 30). RESULTS: Carriers of the GG genotype had the lowest serum levels of LIGHT (p=0.02). Serum levels of LIGHT were increased in MS at relapse in two separate cohorts: vs. healthy controls (p=0.00005) and vs. remission (p=0.00006), other neurological disease (OND) (p=0.002) and OND with signs of inflammation (iOND; p=0.00005). Furthermore, serum levels of LIGHT were decreased by natalizumab treatment (p=0.001). CONCLUSION: Soluble LIGHT is an inhibitor of T-cell activation and GG carriers of rs1077667, with the highest risk for MS, had the lowest serum levels. The increased levels of LIGHT at times of increased MS activity suggest that soluble LIGHT is protective and may act to limit inflammation. PMID- 23037547 TI - Effects of Wii exercises on balance in people with multiple sclerosis. PMID- 23037548 TI - Long-term treatment risks in multiple sclerosis: risk knowledge and risk perception in a large cohort of mitoxantrone-treated patients. AB - BACKGROUND: Balancing treatment benefits and risks is part of a shared decision making process before initiating any treatment in multiple sclerosis (MS). Patients understand, appreciate and profit from evidence-based patient information (EBPI). While these processes are well known, long-term risk awareness and risk processing of patients has not been studied. Mitoxantrone treatment in MS is associated with long-term major potential harms - leukaemia (LK) and cardiotoxicity (CT). The risk knowledge and perception among patients currently or previously treated with mitoxantrone is unknown. OBJECTIVES: The objective of this article is to conduct a retrospective cohort study in greater Hamburg, Germany, to estimate risk awareness and perception in MS patients treated with mitoxantrone. METHODS: MS patients with at least one dose of mitoxantrone between 1991 and 2010 from six major MS centres in greater Hamburg received a questionnaire assessing risk awareness and perception as well as a written EBPI about mitoxantrone-associated LK and CT. RESULTS: Fifty-one per cent in the cohort of n = 575 patients returned the questionnaire. Forty per cent correctly estimated the risk of LK (CT 16%); 56% underestimated the risk (CT 82%). Reading the information increased the accuracy of LK risk estimation, and patients did not report an increase of worries. The EBPI was appreciated and recommended by 85%. CONCLUSION: Risk awareness of mitoxantrone-treated patients is insufficient, but can be increased by EBPI without increasing worries. Continued patient information during and after treatment should be implemented in management algorithms. PMID- 23037549 TI - Reply to Guidi et al. 'Effects of balance-specific Wii exercises on balance in persons with multiple sclerosis'. PMID- 23037550 TI - Analysis of prognostic factors associated with longitudinally extensive transverse myelitis. AB - OBJECTIVE: The aim of this study is to report the clinical profile and outcome of longitudinally extensive transverse myelitis (LETM). METHODS: We prospectively studied adult patients who presented with LETM from January 2008 to December 2011. Information on demographic, clinical course, magnetic resonance imaging (MRI) and outcome was collected. HLA-DRB1 genotype was compared with those of 225 normal controls and patients with MS (228) and neuromyelitis optica (NMO) (22). RESULTS: In total, 23 patients (16 female) with a median age of 44.5 years (range: 20-77 years) were included. Most (74%) had moderate-severe disability at nadir (48% non-ambulatory), normal/non-multiple sclerosis (MS) brain MRI (96%) and a median MRI cord lesion of 5 vertebral segments (range: 3-19). Laboratory analysis showed cerebrospinal fluid pleocytosis (45%), NMO-IgG (9%), antinuclear antibodies (70%), and genotype HLA-DRB1*13 (57%). The frequency of DRB1*13 genotype was higher compared with controls (p=0.002), MS (p=0.001) and NMO (p=0.003) patients. After a median follow-up of 32 months, one patient converted to MS, two had relapsing LETM with NMO-IgG, and 20 remained as idiopathic with recurrences in four (20%). Twelve (52%) patients recovered with minimal disability (Expanded Disability Status Scale (EDSS) <=2.5) and three (13%) remained wheelchair dependent. Disability at nadir was associated with the final outcome and extension of the spinal cord lesion with risk of recurrence. Recurrence was not associated with worse outcome. CONCLUSIONS: Inflammatory LETM is mostly idiopathic with a good outcome. It includes a relatively homogenous group of patients with an overrepresentation of the HLA-DRB1*13 genotype. EDSS at nadir is a predictor of the final outcome and extension of the myelitis of the recurrence risk. PMID- 23037551 TI - ADvanced IMage Algebra (ADIMA): a novel method for depicting multiple sclerosis lesion heterogeneity, as demonstrated by quantitative MRI. AB - BACKGROUND: There are modest correlations between multiple sclerosis (MS) disability and white matter lesion (WML) volumes, as measured by T2-weighted (T2w) magnetic resonance imaging (MRI) scans (T2-WML). This may partly reflect pathological heterogeneity in WMLs, which is not apparent on T2w scans. OBJECTIVE: To determine if ADvanced IMage Algebra (ADIMA), a novel MRI post processing method, can reveal WML heterogeneity from proton-density weighted (PDw) and T2w images. METHODS: We obtained conventional PDw and T2w images from 10 patients with relapsing-remitting MS (RRMS) and ADIMA images were calculated from these. We classified all WML into bright (ADIMA-b) and dark (ADIMA-d) sub regions, which were segmented. We obtained conventional T2-WML and T1-WML volumes for comparison, as well as the following quantitative magnetic resonance parameters: magnetisation transfer ratio (MTR), T1 and T2. Also, we assessed the reproducibility of the segmentation for ADIMA-b, ADIMA-d and T2-WML. RESULTS: Our study's ADIMA-derived volumes correlated with conventional lesion volumes (p < 0.05). ADIMA-b exhibited higher T1 and T2, and lower MTR than the T2-WML (p < 0.001). Despite the similarity in T1 values between ADIMA-b and T1-WML, these regions were only partly overlapping with each other. ADIMA-d exhibited quantitative characteristics similar to T2-WML; however, they were only partly overlapping. Mean intra- and inter-observer coefficients of variation for ADIMA b, ADIMA-d and T2-WML volumes were all < 6 % and < 10 %, respectively. CONCLUSION: ADIMA enabled the simple classification of WML into two groups having different quantitative magnetic resonance properties, which can be reproducibly distinguished. PMID- 23037552 TI - Three types of human CpG motifs differentially modulate and augment immunogenicity of nonviral and viral replicon DNA vaccines as built-in adjuvants. AB - NakedDNA vaccines given by intramuscular injection are efficient in mouse models, but they require improvement for human use. As the immunogenicity of DNA vaccines depends, to a large extent, on the presence of CpG motifs as built-in adjuvants, we addressed this issue by inserting three types of human CpG motifs (A-type, B type, and C-type) into the backbone of nonviral DNA and viral DNA replicon vectors with distinct immunostimulatory activities on human PBMCs. The adjuvant effects of CpG modifications in DNA vaccines expressing three types of antigens (beta-Gal, AHc, or PA4) were then characterized in mice and found to significantly enhance antigen-specific humoral and cell-mediated immune responses. The three types of CpG motifs also differentially affected and modulated immune responses and protective potency against botulinum neurotoxin serotype A and Bacillus anthracis A16R challenge. Taken together, these results demonstrate that insertion of human CpG motifs can differentially modulate the immunogenicity of nonviral DNA vaccines as well as viral DNA replicon vaccines. Our study provides not only a better understanding of the in vivo activities of CpG motif adjuvants but implications for the rational design of such motifs as built-in adjuvants for DNA vectors targeting specific antigens. PMID- 23037553 TI - FluBreaks: early epidemic detection from Google flu trends. AB - BACKGROUND: The Google Flu Trends service was launched in 2008 to track changes in the volume of online search queries related to flu-like symptoms. Over the last few years, the trend data produced by this service has shown a consistent relationship with the actual number of flu reports collected by the US Centers for Disease Control and Prevention (CDC), often identifying increases in flu cases weeks in advance of CDC records. However, contrary to popular belief, Google Flu Trends is not an early epidemic detection system. Instead, it is designed as a baseline indicator of the trend, or changes, in the number of disease cases. OBJECTIVE: To evaluate whether these trends can be used as a basis for an early warning system for epidemics. METHODS: We present the first detailed algorithmic analysis of how Google Flu Trends can be used as a basis for building a fully automated system for early warning of epidemics in advance of methods used by the CDC. Based on our work, we present a novel early epidemic detection system, called FluBreaks (dritte.org/flubreaks), based on Google Flu Trends data. We compared the accuracy and practicality of three types of algorithms: normal distribution algorithms, Poisson distribution algorithms, and negative binomial distribution algorithms. We explored the relative merits of these methods, and related our findings to changes in Internet penetration and population size for the regions in Google Flu Trends providing data. RESULTS: Across our performance metrics of percentage true-positives (RTP), percentage false-positives (RFP), percentage overlap (OT), and percentage early alarms (EA), Poisson- and negative binomial-based algorithms performed better in all except RFP. Poisson-based algorithms had average values of 99%, 28%, 71%, and 76% for RTP, RFP, OT, and EA, respectively, whereas negative binomial-based algorithms had average values of 97.8%, 17.8%, 60%, and 55% for RTP, RFP, OT, and EA, respectively. Moreover, the EA was also affected by the region's population size. Regions with larger populations (regions 4 and 6) had higher values of EA than region 10 (which had the smallest population) for negative binomial- and Poisson-based algorithms. The difference was 12.5% and 13.5% on average in negative binomial- and Poisson-based algorithms, respectively. CONCLUSIONS: We present the first detailed comparative analysis of popular early epidemic detection algorithms on Google Flu Trends data. We note that realizing this opportunity requires moving beyond the cumulative sum and historical limits method-based normal distribution approaches, traditionally employed by the CDC, to negative binomial- and Poisson-based algorithms to deal with potentially noisy search query data from regions with varying population and Internet penetrations. Based on our work, we have developed FluBreaks, an early warning system for flu epidemics using Google Flu Trends. PMID- 23037554 TI - Tumour immunology: chromosome overload. PMID- 23037555 TI - Innate immunity: inflammasome triggered by cell swelling. PMID- 23037556 TI - Surgical treatment for secondary dystonia. AB - Surgical therapy for the secondary dystonias is generally perceived to be less effective than for primary disease. However, a number of case reports and small open series have recently appeared describing quite favorable outcomes following surgery for some nonprimary dystonias. We discuss surgical treatment options for this group of diverse conditions, including tardive dystonia, dystonic cerebral palsy, and certain heredodegenerative diseases in which deep brain stimulation and ablative lesions of the posteroventral pallidum have been shown to be effective. Other types of secondary dystonia respond less well to pallidal surgery, particularly when anatomical lesions of the basal ganglia are prominent on preoperative imaging. For these conditions, central baclofen delivery and botulinum toxin denervation may be considered. With optimal medical and surgical care, some patients with secondary dystonia have achieved reductions in disability and pain that approach those documented for primary dystonia. PMID- 23037557 TI - Cryptosporidium spp. in drinking water. Samples from rural sites in Switzerland. AB - In most rural areas and small communities in Switzerland the drinking water is supplied to the consumers after a minimum or even no treatment at all. However, it is just in these areas where drinking water from sources of agricultural activities can be contaminated by liquid manure and faeces of pasturing animals. The Swiss drinking water regulations are limited to the monitoring of E. coli, Enterococcus spp. and total plate counts only. Hence, resistant pathogens, as for example Cryptosporidium spp., remain unnoticed. During a drinking water survey, which lasted from June 2003 to December 2004, water samples were collected from 3 selected rural sites in Switzerland. The drinking water was investigated for Cryptosporidium spp., E. coli, Enterococcus spp., Clostridium perfringens and other parameters. In all samples oocysts of Cryptosporidium spp. were detected at elevated concentrations of up to 0.18 oocysts/l. Between 28% and 75% of the oocysts were found to be vital by the excystation method. Sampled oocysts collected from the three sites were subjected to genotyping and in one case the isolate was found to belong to the genotype of C. parvum. No evidence for increased incidents of diarrhoea in the past years was noted by local authorities. PMID- 23037558 TI - Expression of Concern: Kiel et al. Efficacy of a hip protector to prevent hip fracture in nursing home residents: the HIP PRO randomized controlled trial. JAMA. 2007;298(4):413-422. PMID- 23037559 TI - Diffusion/perfusion MR imaging of the liver: practice, challenges, and future. AB - Diffusion-weighted (DWI) magnetic resonance (MR) imaging is useful in diagnosing various pathologic conditions in the liver, such as malignant tumors or hepatic fibrosis, and is now part of routine MR imaging protocols for the liver following the development of a parallel encoding technique that has markedly improved image quality. DWI is not very sensitive for detecting hepatocellular carcinomas (HCC) and is useless for characterizing border-line hepatocellular nodules in cirrhosis, but it complements gadolinium-enhanced MR imaging in detecting regional tumor recurrence or intrahepatic metastases of HCC following treatment. DWI is more useful for detecting hepatic metastasis, because histopathologic architecture of metastases does not resemble that of liver tissue and T(2) relaxation time of hepatic metasitasis is fairly longer than that of liver parenchyma. DWI is also useful for detecting moderate and advanced hepatic fibrosis. In cirrhosis, however, decreased blood flow in fibrotic liver is thought to lower apparent diffusion coefficient of the liver. For MR perfusion analysis, a dual-input one-compartment model is used to correlate various hepatic blood flow parameters that represent hepatic arterial/portal blood flow or fraction, mean transit time, and distribution volume with the severity of cirrhosis and portal hypertension. Conventional multisectional imaging and perfusion study can be combined using a 3-dimensional sequence with high temporal resolution, but spatial resolution is not sufficiently high to diagnose tiny hepatic lesions. The advent of liver-specific contrast agents, such as gadoxetic acid, may spur the development of a new analysis model that incorporates extracellular perfusion and hepatocyte function. PMID- 23037560 TI - MR characterization of focal nodular hyperplasia: gadoxetic acid versus superparamagnetic iron oxide imaging. AB - PURPOSE: We evaluated the diagnostic efficacy of gadoxetic acid- and superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance (MR) imaging for focal nodular hyperplasia (FNH). MATERIALS AND METHODS: We retrospectively evaluated 11 patients with 11 FNHs. Both gadoxetic acid- and SPIO-enhanced MR imaging were performed. A 3-dimensional (3D) volumetric interpolated breath-hold examination was used with the gadoxetic acid dynamic study. SPIO-enhanced MR imaging included T2- and T2*-weighted images. We quantitatively and qualitatively compared lesion-specific enhancement of both contrast media. RESULTS: The mean signal-to-noise (S/N) ratio of the FNH lesions differed significantly on pre- and postenhanced imaging of each contrast medium (P<0.05); mean contrast-to-noise (C/N) ratio did not (P>0.05). All observers described all lesions as hyperintense in the arterial phase on gadoxetic acid-enhanced MR imaging and observed the presence of central scar, fibrous septa, and rim most clearly in gadoxetic acid enhanced hepatobiliary phase images. CONCLUSION: Gadoxetic acid-enhanced MR imaging was more useful than SPIO-enhanced MR imaging in characterizing FNH. PMID- 23037561 TI - Visualization of ovarian tumors using 3T MR imaging: diagnostic effectiveness and difficulties. AB - PURPOSE: We evaluated the diagnostic effectiveness of magnetic resonance (MR) imaging at 3 tesla to visualize ovarian tumors and problems associated with its use. MATERIALS AND METHODS: From the records of 423 consecutive women who underwent pelvic MR imaging using a 3T system from April 2009 to June 2010, we analyzed 50 continuous cases of ovarian tumors proved by histopathology. We evaluated visualization of these tumors for image quality and artifacts using 5 point scales. For qualitative assessment, we scored overall image quality (1, poor, to 5, excellent), degree of conviction regarding the diagnosis (1, undiagnosable, to 5, diagnosable with high certainty), and 4 representative artifacts (penetrating, chemical shift, motion, and susceptibility artifact) (1, severe, to 5, little degradation). We also retrospectively reviewed the diagnostic features of the ovarian tumors and preoperative diagnostic accuracy. For quantitative assessment, we determined tumor size and ADC value. RESULTS: Overall quality score was scored 4.9+/-0.5, and conviction regarding diagnosis was 4.9+/-0.3. Artifacts caused little degradation in most cases: penetrating, 4.8+/-0.5; chemical shift, 4.3+/-0.5; motion, 4.6+/-0.6; and susceptibility, 3.8+/-0.9. Preoperative diagnostic accuracy was 92% (sensitivity 94.7%, specificity 90.3%). Mean tumor diameter was 88.3+/-61 mm. The mean ADC value was 1.04+/-0.3 in malignant tumors and 1.15+/-0.5 (*10-6 mm2/s) in benign tumors. CONCLUSION: The quality of ovarian tumor images obtained with a 3T MR imaging system is adequate for diagnosis, with only slight degradation from penetrating or susceptibility artifacts. PMID- 23037562 TI - Diffusion fractional anisotropy-based transformation in skeletal muscle caused by pressure. AB - PURPOSE: We used diffusion tensor imaging (DTI) to evaluate anisotropic changes in skeletal muscle cells under external pressure. MATERIALS AND METHODS: In 6 healthy volunteers, we compared DTI of the tibialis anterior (TA) and soleus (SOL) muscles under pressure. We performed imaging using a 1.5-tesla magnetic resonance (MR) scanner and diffusion-weighted stimulated-echo echo-planar pulse sequences optimized for skeletal muscle. We calculated diffusion tensor eigenvalues (lambda), apparent diffusion coefficients, and fractional anisotropy (FA) values in a series of axially acquired DTI and compared them between the pressurized and nonpressurized lower limbs. We also measured a cross-sectional area of skeletal muscle. RESULTS: We observed clear differences in FA and lambda3 between pressurized muscles and the nonpressurized muscles we used as controls. The mean control FAs were 0.36+/-0.02 (TA) and 0.30+/-0.02 (SOL). The mean control lambda3s were 0.74+/-0.02 s/mm2 (TA) and 0.85+/-0.03 s/mm2 (SOL). FA values in the pressurized (200 mmHg) limbs increased to 0.39+/-0.02 (TA) and 0.35+/-0.04 (SOL) compared with those values in the nonpressurized controls. lambda3 values in the pressurized (200 mmHg) limbs decreased to 0.68+/-0.05 s/mm2 (TA) and 0.77+/-0.06 s/mm2 (SOL) compared with those in controls. Moreover, the mean value of cross-sectional area of skeletal muscle (control) was 907.3+/-140.1 mm2 (TA) and 1522+/-201.0 mm2 (SOL). The cross-sectional area in the pressurized (200 mmHg) limbs decreased to 590.3+/-68.1 mm2 (TA) and 1131+/-112.6 mm2 (SOL) compared with those in controls. One-way analysis of variance (ANOVA) and post hoc Tukey-Kramer tests showed significant differences. CONCLUSION: Anisotropy changed markedly on pressurizing the lower limb based on the correlation of the cross-sectional area and lambda3 suggested marked changed in anisotropy following application of pressure to the lower limb. If compression of the cross-sectional area is assumed to represent compression of the cell, change in lambda3 reflected the change in the size of muscle cells. PMID- 23037563 TI - Diffusion- and T2-weighted MR imaging of the liver: effect of intravenous administration of gadoxetic acid disodium. AB - PURPOSE: We evaluated the effect of intravenous administration of gadoxetic acid disodium to hepatic lesions and liver parenchyma on T2-weighted (T2WI) and diffusion-weighted imaging (DWI). MATERIALS AND METHODS: One hundred and one consecutive patients with 259 hepatic lesions underwent T2WI and DWI (b-values of 500 and 1000 s/mm2) before and after gadoxetic acid administration. We compared the ratio of signal intensity (SIR) of the liver parenchyma and hepatic lesions, the ratio of contrast intensity of the lesion to the liver (CIR), the apparent diffusion coefficients (ADCs) of the liver and lesions, and lesion detectability between pre- and post-contrast images. RESULTS: SIRs, CIRs, and ADC of focal hepatic lesions were comparable on pre- and post-contrast images, and lesion detectability did not differ significantly between pre- and post-contrast T2WI and DWI. The SIRs of the liver parenchyma were significantly lower on post contrast DWI (1.4+/-0.68 [b=500 s/mm2] and 1.71+/-0.67 [b=1000 s/mm2]) than pre contrast images (1.89+/-0.68 [b=500 s/mm2] and 2.26+/-0.78 [b=1000 s/mm2]) (P<0.001). ADCs of the liver parenchyma were also significantly decreased on post contrast DWI (0.77+/-0.32 mm2/s) than pre-contrast images (0.64+/-0.33 mm2/s) (P=0.001). CONCLUSION: T2WI and DWI after administration of gadoxetic acid are feasible and do not compromise the SIR, CIR, and ADC of focal hepatic lesions. However, the signal intensity of DWI and ADC value of the liver parenchyma were decreased on gadoxetic acid-enhanced hepatocyte phase images. PMID- 23037564 TI - Experimental demonstration of the proportionality of the RF reception field to a complex conjugate of B1-. AB - We demonstrated that the radiofrequency (RF) reception field is proportional to B1-* straightforwardly in magnetic resonance (MR) imaging experiments at 4.7 T. We compared maps of the reception field and the B1- of a saline phantom in magnitude and phase. First, we measured the image using an adiabatic spin echo (ASE) sequence with homogeneous excitation. That image corresponds to a map of the reception field. Next, we rotated the RF coil with the sample 180 degrees around the vertical axis to measure the map of the transmission field that corresponded to B1- in the original configuration. The magnitude of the distribution fields of the reception field and B1- maps was almost identical. Examining the phases of the ASE images in the original and inverted configurations, we observed almost the same distribution in both phase maps, which indicated the proportionality of the reception field to B1-*. PMID- 23037565 TI - Spinal subdural hematoma mimicking epidural lipomatosis. AB - We report a case of spinal subdural hematoma in the lumbar spine of a 75-year-old woman. Magnetic resonance imaging showed lesions of homogeneous high intensity in the spinal canal on both T1- and T2-weighted images, findings closely resembling those for epidural lipomatosis. Identification of 2-layered signal intensity surrounding the cauda equina on axial images is the key for accurate diagnosis. PMID- 23037566 TI - MR imaging of polypoid endometriosis of the ovary. AB - We report a case of polypoid endometriosis of the ovary and correlate magnetic resonance (MR) and pathological findings. The endometriosis appeared as multiple polypoid areas along the wall of the ovarian cystic lesion with hyperintensity on T2-weighted images and slight hyperintensity on diffusion-weighted images. However, the polypoid areas did not yield low apparent diffusion coefficient (ADC) values on ADC map images. These MR findings were similar to the signal intensity of the uterine endometrium, reflecting the presence of abundant endometrial glands. PMID- 23037567 TI - Clinical value of 3D T2*-weighted imaging with multi-echo acquisition: comparison with conventional 2D T2*-weighted imaging and 3D phase-sensitive MR imaging. AB - Susceptibility-weighted angiography (SWAN) is a state-of-the-art 3-dimensional (3D) T2*-weighted imaging (T2*WI) technique with multiple echo acquisitions, but its clinical utility remains to be determined. We compared the utility of susceptibility-weighting sequences among SWAN, 3D phase-sensitive magnetic resonance (MR) imaging (PSI), and conventional 2-dimensional (2D) T2*WI in routine clinical practice. Our results indicate that SWAN can achieve susceptibility weighting more effectively than conventional 2D T2*WI and as effectively as PSI and requires a much shorter scan time than PSI. PMID- 23037568 TI - Imaging of Meniere's disease after intravenous administration of single-dose gadodiamide: utility of subtraction images with different inversion time. AB - For the separate visualization of endolymph, perilymph, and bone on a single image after intravenous injection of single-dose gadodiamide, we fused gray-scale inverted positive endolymph (PEI) with native positive perilymph (PPI) images, that is, we subtracted PEI from PPI. Subtraction significantly improved the contrast noise ratio between endolymph and perilymph and the subjective visibility score for endolymphatic space. The 24 patients with the suspect of Meniere's disease were included. PMID- 23037569 TI - The effects of 17beta-oestradiol on increased alpha(1)-adrenergic vascular reactivity induced by prolonged ovarian hormone deprivation: the role of voltage dependent L-type Ca channels. AB - The present study investigated the hypothesis that the duration of ovarian hormone deprivation before reintroduction of oestrogen affects the role of oestrogen as a mediator of the contractile function of alpha(1)-adrenergic receptors. Rats underwent ovariectomy (OVX) or were sham-operated, and the OVX rats were treated with vehicle (corn oil) or 17beta-oestradiol (E(2)) for 5 days either 10, 28 or 60 days after OVX. The OVX increased phenylephrine- and Ca(2+) induced contractions. Interestingly, the phenylephrine-induced contractions were increased at each of the three time points, whereas the Ca(2+)-induced contractions were only increased in the 60-day group. E(2) had biphasic effects on phenylephrine- and Ca(2+)-induced contractility. Indeed, E(2) increased contractions in the 10-day group and diminished contractions in the other groups (the increased contractions were avoided by verapamil). These results indicate that E(2) controls alpha(1)-adrenergic receptor-mediated contractility through effects on L-type Ca(2+) channels in a way that depends on the timing in which the treatment with E(2) is initiated. PMID- 23037571 TI - Flexible parametric joint modelling of longitudinal and survival data. AB - The joint modelling of longitudinal and survival data is a highly active area of biostatistical research. The submodel for the longitudinal biomarker usually takes the form of a linear mixed effects model. We describe a flexible parametric approach for the survival submodel that models the log baseline cumulative hazard using restricted cubic splines. This approach overcomes limitations of standard parametric choices for the survival submodel, which can lack the flexibility to effectively capture the shape of the underlying hazard function. Numerical integration techniques, such as Gauss-Hermite quadrature, are usually required to evaluate both the cumulative hazard and the overall joint likelihood; however, by using a flexible parametric model, the cumulative hazard has an analytically tractable form, providing considerable computational benefits. We conduct an extensive simulation study to assess the proposed model, comparing it with a B spline formulation, illustrating insensitivity of parameter estimates to the baseline cumulative hazard function specification. Furthermore, we compare non adaptive and fully adaptive quadrature, showing the superiority of adaptive quadrature in evaluating the joint likelihood. We also describe a useful technique to simulate survival times from complex baseline hazard functions and illustrate the methods using an example data set investigating the association between longitudinal prothrombin index and survival of patients with liver cirrhosis, showing greater flexibility and improved stability with fewer parameters under the proposed model compared with the B-spline approach. We provide user-friendly Stata software. PMID- 23037572 TI - The plakotenins: biomimetic Diels-Alder reactions, total synthesis, structural investigations, and chemical biology. AB - The total synthesis of plakotenin, a cytotoxic marine natural product, using a biomimetic Diels-Alder reaction is described in detail. Two approaches were used, whereby the Diels-Alder reaction occurs at different stages of the synthesis. Homo- and nor-plakotenin, related natural products, were also prepared, as well as iso-plakotenin, a diastereoisomer of plakotenin. The syntheses prove the relative and absolute stereochemistry of the latter. The chemical biology of the plakotenins was investigated on selected compounds. PMID- 23037573 TI - Sinus pericranii: a scalp mass in a 6-month-old boy. AB - 'Sinus pericranii' is an abnormal communication between the extracranial veins and the dural venous sinuses (usually the superior sagittal and the transverse sinuses). It is a rare childhood abnormality. We report a case of a 6-month-old boy presenting with a scalp swelling in the left parietal region. Ultrasound with color Doppler and MRI showed a dilated epicranial vein that communicated with the superior sagittal sinus. This anomalous venous connection is known as sinus pericranii. We describe the imaging findings, associated abnormalities and management of this rare vascular abnormality. PMID- 23037570 TI - Learning the molecular mechanisms of the reprogramming factors: let's start from microRNAs. AB - Induced reprogramming of somatic cells has had a great impact on stem cell research, and the reprogramming technologies have evolved from four transgenic factors (Oct4, Sox2, Klf4, and c-Myc; OSKM) to just a few microRNAs (mainly miR 290/302 seed family). Despite these advances, the molecular events occurring during various stages of reprogramming remain largely unknown. Here, we concisely review current knowledge of miRNA regulation from the initiation phase of OSKM induced reprogramming, through the transitional stage, to final maturation. At the start of reprogramming, the microRNAs miR-21, miR-29a, let-7a, and miR-34 act as guards to secure the somatic identity and genomic integrity of the cell of origin. As reprogramming proceeds, miR-155, miR-10b, miR-205, and miR-429 modulate the epithelial-mesenchymal/mesenchymal-epithelial transition (EMT/MET), which is a critical step towards transformed pluripotent status. Finally, the pluripotency regulatory network is secured in the iPSCs and fine-tuned by a group of miRNAs belonging to the miR-290/302 seed family. Among the four reprogramming factors, c-Myc plays the dominant role in regulating the miRNAs under reprogramming-specific conditions. Accumulating evidence suggests that the reprogramming efficiency can be improved by either blocking barrier miRNAs or introducing helper miRNAs. Intriguingly, induced pluripotency can be obtained by introducing a single miR-302 cluster, although the supportive molecular mechanism is still lacking. In the near future, we may be able to realize the broad potential of miRNAs in the stem cell field, such as altering cell identities with high efficiency through the transient introduction of tissue-specific miRNAs. PMID- 23037574 TI - Rational design of ferromagnetic coupled diphenoxocarboxylate triply bridged dinuclear nickel(II) complexes: orbital countercomplementarity of the bridging ligands. AB - Four new dinuclear complexes [Ni(MU-L)(MU-OAc)Ni(H2O)2]NO3 (1), Ni(MU-L)(MU OBz)Ni(H2O)(MeOH)]NO3.3MeOH (2), [Ni(MU-L)(MU-9-An)Ni(H2O)(MeOH)]NO3 (3) and [Ni(MU-L)(MU-OAc)Ni(H2O)(N3)].CH3OH (4) have been prepared from the compartmental ligand N,N',N''-trimethyl-N,N''-bis(2-hydroxy-3-methoxy-5 methylbenzyl)diethylenetriamine (H2L) and different carboxylate ligands (OBz = benzoate and 9-An = 9-anthracenecarboxylate), and then magnetically and structurally characterized. The X-ray structures of these complexes reveal that the Ni2+ ions are bridged by two phenoxo groups belonging to the L2- ligand and one syn-syn carboxylate group, giving rise to diphenoxocarboxylate triply bridged dinuclear nickel(II) complexes. The syn-syn carboxylate bridging group folds the structure with hinge angles (beta) in the range 32-36 degrees . The folding of the structure takes place with a concomitant decrease of the O-Ni-O bridging angle (theta) and an increase of the shift carbon atom directly linked to the phenoxo oxygen atom with respect to the Ni-Ni-O plane in the bridging region (tau angle). All the complexes exhibit ferromagnetic interactions between the slightly distorted octahedral Ni2+ ions. A comparative analysis of the magneto-structural data for 1-4 and other diphenoxocarboxylate bridged complexes clearly show that not only the theta angle, but also the tau and beta angles play a significant role in determining the sign and magnitude of the magnetic exchange coupling in these complexes. The ferromagnetic behaviour observed for 1-4 has been justified on the basis of their relatively low theta and high beta and tau values, all of them decreasing the antiferromagnetic contribution in complexes 1-4, as well as the countercomplementarity effects between the diphenoxo and carboxylate bridging ligands. DFT theoretical calculations unequivocally demonstrate that the countercomplementarity mechanism is operative in compounds 1-4. PMID- 23037575 TI - Azide photochemistry for facile modification of graphitic surfaces: preparation of DNA-coated carbon nanotubes for biosensing. AB - A facile, two-step method for chemically attaching single-stranded DNA to graphitic surfaces, represented here by carbon nanotubes, is reported. In the first step, an azide-containing compound, N-5-azido-nitrobenzoyloxy succinimide (ANB-NOS), is used to form photo-adducts on the graphitic surfaces in a solid state photochemical reaction, resulting in active ester groups being oriented for the subsequent reactions. In the second step, pre-synthesized DNA strands bearing a terminal amine group are coupled in an aqueous solution with the active esters on the photo-adducts. The versatility of the method is demonstrated by attaching pre-synthesized DNA to surfaces of carbon nanotubes in two platforms-as vertically-aligned multi-walled carbon nanotubes on a solid support and as tangled single-walled carbon nanotubes in mats. The reaction products at various stages were characterized by x-ray photoelectron spectroscopy. Two different assays were used to check that the DNA strands attached to the carbon nanotubes were able to bind their partner strands with complementary base sequences. The first assay, using partner DNA strands tethered to gold nanoparticles, enabled the sites of DNA attachment to the carbon nanotubes to be identified in TEM images. The second assay, using radioactively labelled partner DNA strands, quantified the density of functional DNA strands attached to the carbon nanotubes. The diversity of potential applications for these DNA-modified carbon nanotube platforms is exemplified here by the successful use of a DNA-modified single-walled carbon-nanotube mat as an electrode for the specific detection of metal ions. PMID- 23037576 TI - [Unusual presentation of rib malformation]. AB - Rib malformation and anatomical variations are not well known and are still often underdiagnosed. Usually, rib malformations are fortuitously discovered. We describe here the case of a girl, 4 years and 4 months old, who presented at the emergency unit for fever and an anterior tumefaction of the ribcage, without any other symptoms. She was eupneic with a normal pulmonary auscultation and viral tonsillitis with a negative streptococcus test. The thoracic tumefaction was parasternal, painless, and fixed and measured approximately 2.5 * 2cm. Ultrasound findings consisted of a duplicated and hypoechogenic hypertrophy of the sterno costal cartilage of the 4th left rib. Magnetic resonance imaging (MRI) confirmed the diagnosis of chondral bifidity of the sterno-costal junction of the 4th left rib. Fever, due to the viral tonsillitis, disappeared after 4 days. Rib malformations are rare, often anterior, unilateral, and preferentially located on the 3rd or the 4th rib. The main malformative rib lesions are bifid ribs, rib spurs, and widened ribs. Very rarely, they can be associated with Gorlin-Goltz syndrome or with other malformations such as VATER complex. The main differential diagnoses of these rib malformations are traumatic, tumoral, and infectious etiologies. In case of tumoral diseases, the topography of the lesion focuses the etiologic diagnosis: whereas an anterior and cartilaginous lesion is always benign, a lateral or posterior lesion can be an Ewing sarcoma. Rib malformation investigation consists in meticulous questioning, a complete clinical examination looking for any associated anomaly, completed by basic imaging explorations such as plain thoracic radiography focused on the ribcage and ultrasound. Finally, complementary computerized tomography or preferably MRI, depending on the anatomic location of the lesion, confirms the final diagnosis, as presented in our case report, and removes any uncertainty. PMID- 23037577 TI - [Acute pancreatitis: an unusual manifestation of scorpion envenomation]. PMID- 23037578 TI - [Late onset Ondine syndrome: literature review on a case report]. AB - Ondine syndrome is the central congenital hypoventilation syndrome (CCHS) caused by the mutation of the PHOX2B gene. In late onset cases, the symptomatology often appears after an acute event (infection, general anesthesia, drug intake), increasing hypoventilation. We report a case of late onset Ondine curse in a 9 year-old girl. The diagnosis was made based on a hypercapnic coma complicating a respiratory infection caused by Mycoplasma pneumoniae and was confirmed by genetic testing. In the patient's history we found symptoms that had not been noted (e.g., enuresis, morning headache, adynamia), attesting to chronic hypoventilation. Through this observation, we review the literature on CCHS, notably late onset cases, which are rare and insidious, emphasizing the pre existing hypoventilation symptoms in this child. This case underlines the need for all practitioners not to trivialize these symptoms so as to decrease the current delay in diagnosis for late onset CCHS and to introduce optimal care as soon as possible. PMID- 23037579 TI - [Response to Dr. Maisonneuve's letter]. PMID- 23037580 TI - [Leprosy with an unusual course]. AB - In developed countries, Hansen disease, or leprosy, is a rare and little-known disease. Over the last few years, its prevalence in New Caledonia has remained stable (0.35 per 10,000 inhabitants). We report the case of an 11-year-old child who presented lepromatous leprosy complicated by a type 2 reaction. Despite appropriate treatment, the course was unusual with fever lasting a few weeks associated with asthenia, weight loss, and biological perturbations such as inflammatory syndrome, anemia, and hyperferritinemia. After a brief review of Hansen disease and its complications, we discuss the different hypotheses that can explain the clinical and biological progression of our patient (hemolytic anemia secondary to dapsone, type 2 reaction, and aspects of hemophagocytic syndrome) and describe therapeutic management, which led to a good outcome. PMID- 23037581 TI - [Osteoid osteoma in children: 5 cases treated with electrocoagulation]. AB - Osteoid osteoma is a benign bone tumor. Its diagnosis is often delayed despite typical symptoms: severe pain mainly situated on the lower limbs and characteristically worse at night. Once diagnosed, an antalgic treatment by aspirin is well known to be very effective in relieving pain. Osteoid osteoma will resolve spontaneously. If symptoms persist despite the use of aspirin, surgery can be performed to remove the tumor. Percutaneous electrocoagulation can be performed instead of surgical resection as a less invasive procedure. The success rate of surgery and percutaneous electrocoagulation is comparable. We reviewed the cases of 5 patients who were hospitalized in our institution for percutaneous electrocoagulation of an osteoid osteoma. We compared them to the literature. PMID- 23037582 TI - [Technical aspects and relevance of physical activity assessment in children and adolescents in free-living conditions]. AB - Physical activity accounts for 25-30 % of total daily energy expenditure. Total energy expenditure varies according to the physical activity, which can be voluntarily modulated. Assessment of physical activity is therefore an important factor in the promotion of health and in several childhood and adolescent pathological situations. Questionnaires are widely used for assessing physical activity patterns in youth because of their low cost and ease of use, but they systematically overestimate physical activity. Heart rate monitoring requires individual calibration in the laboratory and a number of factors other than physical activity can affect heart rate (i.e., stress, temperature, etc.). Pedometers are objective devices but give only information on the number of steps and do not assess physical activity patterns. Accelerometers seem the best compromise between feasibility and validity in the assessment of physical activity in children in free-living conditions because this is an objective and accurate method whose cost is low. The choice of the type of device depends on the objectives of the clinician or researcher. PMID- 23037583 TI - [Cerebellar ataxia: a rare revelation of Fahr syndrome]. PMID- 23037584 TI - [Megakaryoblastic acute leukemia: bone and joint manifestations in a 7-month-old child]. AB - Acute megakaryoblastic leukemia accounts for approximately 3-10% of acute myeloid leukemia in children. Its diagnosis may be difficult because of associated myelofibrosis. We report the case of a 7-month-old child who presented hepatomegaly with bicytopenia. She also developed bone and joint pain with recurrent aseptic arthritis. We suggested the diagnosis of megakaryoblastic leukemia early but multiple bone marrow investigations had been processed without positive results because of sampling problems and lack of abnormal cells in the morphological, phenotypic, and cytogenetic examinations. We had a variety of indirect evidence for our assumption: the x-ray showing periosteal new bone, lytic lesions and metaphyseal bands, bone marrow aspirate smears with micromegakaryocytes, and bone marrow biopsy suggesting myelofibrosis. This was very suggestive of leukemia but we could not prove it and we finally found megakaryoblasts on bone marrow aspirate smears after more than 2 months of investigation and initiated a course of corticosteroids. PMID- 23037585 TI - [Scabies: a common infection in children]. PMID- 23037587 TI - Gene mutations associated with anomalies of human gonad formation. AB - Here, we discuss recent progress on our understanding of the genetic anomalies that impact directly on the specification and development of the somatic cell compartment of the human gonad. Several new genes and pathways have been identified in the last 5 years associated with human disorders of sex development (DSD). New methods and analytical approaches, including comparative genomic hybridization and next-generation sequencing technologies, are beginning to provide deeper insights into the complexities and alterations of the genetic architecture that are associated with human DSD. The challenges as well as the research opportunities for the future are highlighted as efforts are made to bridge the gap between an increasing quantity of genetic information and the underlying biology. PMID- 23037586 TI - [Usefulness of topical cidofovir treatment for recalcitrant molluscum contagiosum in immunocompromised children]. AB - Molluscum contagiosum (MC) is common and often numerous and recalcitrant in immunocompromised children. The response to available treatments is frequently unsatisfactory. Cidofovir is a nucleoside analog of the deoxycytidine antiviral drug approved for the intravenous treatment of cytomegalovirus retinitis in AIDS patients. We report four cases of children, 5-8 years old, who developed extensive MC in the context of chemotherapy for acute lymphoid leukemia and who were treated with a cream containing cidofovir 1%. In all patients, the lesions began to regress within 2 to 4 months. For three patients, complete regression was observed in 7 to 9 months, and the children remained clear of recurrence. For one patient, partial regression was obtained after 17 months of treatment. No side effects have been observed. Treatment of MC in immunocompromised children is difficult because the usual treatments are inappropriate. Successful use of either topically or intralesionally administered cidofovir in several virally induced cutaneous diseases has been demonstrated and recently documented in the treatment of MC in immunocompromised adults. Conversely, its use in children is not documented. Although intravenous use of cidofovir may lead to severe adverse effects, one single case of a systemic side effect has been reported after topical use at a greater concentration, but no changes in laboratory data were observed. Topical cidofovir offers an effective and well-tolerated therapeutic alternative option for the treatment of MC in immunosuppressed children. PMID- 23037588 TI - Stabilization of ArSiH4(-) and SiH6(2-) anions in diruthenium Si-H sigma complexes. AB - Hydridosilicate anions ([ArSiH(4)](-) and [SiH(6)](2-)) were stabilized as ligands in diruthenium Si-H sigma-complexes [{(PhBP(Ph(3))Ru}(2)(MU-Cl)(MU eta(3),eta(3)-H(4)SiAr)] (Ar = 2-MeOC(6)H(4), Mes, Ph) and [{(PhBP(Ph)(3))Ru}(2)(MU-eta(4),eta(4)-H(6)Si)] (see picture). These complexes were formed under mild conditions and characterized by single-crystal X-ray diffraction (see picture), NMR and IR spectroscopy, and computational techniques. PMID- 23037589 TI - Activation of aryl hydrocarbon receptor mediates indoxyl sulfate-induced monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells. AB - BACKGROUND: Indoxyl sulfate (IS) is a uremic toxin that causes renal injury, but little is known about its adverse effects on the cardiovascular system. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor that mediates adaptive and toxic responses in cells. Recent studies identified IS as an endogenous agonist for AhR, as well as other tryptophan metabolites. The aim of the study was to investigate whether IS activates AhR, with subsequent inflammatory responses contributing to the development of atherogenesis, in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: We demonstrated that IS stimulates the expression of AhR target genes, including cytochromes P450 1A1 and 1B1 mRNA, in a time-dependent manner, as well as translocation of AhR into the nucleus from the cytoplasm, indicating AhR activation. IS-stimulated AhR activation was accompanied by an increase in oxidative stress, proven by enhanced NADPH oxidase 4 expression and dihydroethidium staining. Additionally, AhR inhibitors abolished the IS-induced increase in monocyte chemoattractant protein 1 (MCP-1) expression in a dose-dependent manner. Taken together, these results suggest that IS activates AhR as an endogenous agonist and induces MCP-1 expression through reactive oxygen species production in HUVECs. CONCLUSIONS: Our findings give a novel understanding of the physiological effect of IS on the cardiovascular system and indicate possibilities for preventing cardiorenal syndrome by regulating serum IS levels. PMID- 23037590 TI - Protection and functionalisation of silver as an optical sensing platform for highly sensitive SPR based analysis. AB - Silver thin films are well known as the most sensitive material for surface plasmon resonance (SPR) based analysis. However, the use of silver for this purpose is limited by three main issues, namely poor adhesion to plastic substrates, chemical instability in both air and aqueous environments and hence the difficulty in functionalizing the silver coated substrate for immobilizing biomolecular ligands by conventional liquid phase methods. In this work, we have successfully addressed these problems using gas-phase coating processes. We demonstrate highly adherent sputter-deposited silver coatings on low cost polymer substrates using a sputter-deposited thin gold adhesion layer. The problems of chemical instability and functionalisation have been addressed by using the gas phase process of plasma enhanced chemical vapour deposition (PECVD) to deposit thin films with a base SiO(x)C(y)H(z) layer (using tetraethyl orthosilicate precursor) functionalised with carboxylic acid (from sequential deposition with acrylic acid precursor). The resultant coating serves as a protective layer against degradation of the optical properties of silver under long term storage and use in ambient conditions. The reactive carboxyl functionality is used for the covalent immobilization of biomolecules. The successful stabilisation and functionalization of silver films on plastic sensor chips is demonstrated by mouse IgG immunoassays. The expected superior performance of the silver thin films over gold thin films for SPR analysis is demonstrated. PMID- 23037591 TI - Enzyme-regulated unmodified gold nanoparticle aggregation: a label free colorimetric assay for rapid and sensitive detection of adenosine deaminase activity and inhibition. AB - Based on enzyme-regulated unmodified gold nanoparticle aggregation, a visual and homogeneous assay of adenosine deaminase (ADA) activity without any other coupling enzymes, aptamers or additional modifications has been developed. The present strategy is simple, cost-effective, high throughput, selective and sensitive for ADA with a detection limit of 0.8227 U L(-1). PMID- 23037592 TI - Context is everything: activators can also repress. AB - Maintenance of genome integrity, cell division and gene expression have all been shown to be regulated by the condensation of DNA into heterochromatin. In a study published in this issue, Bulut-Karslioglu et al. reveal a new heterochromatin function for transcription factors in a mammalian system. They show that instead of activating gene expression, in the context of heterochromatic repeats, specific transcription factors are necessary for the maintenance of transcriptional repression and heterochromatin. PMID- 23037593 TI - Two-step insertion at the SecY translocon. AB - SecY and Sec61 translocons mediate the orderly insertion of transmembrane segments into the lipid bilayer during membrane-protein biogenesis. Reporting in this issue, Ismail et al. now use a SecM-based molecular force sensor to show that the translocon exerts a pulling force on the nascent chain that is capable of mechanical action at two distinct stages of the insertion process. PMID- 23037594 TI - Solving the mystery of procollagen chain selectivity. AB - The recently solved crystal structure of the procollagen C propeptide reveals the basis for chain selectivity as well as an unexpected asymmetry to this homotrimeric molecule. In addition, mapping disease-causing mutations to the structure demonstrates clear correlation between severity of disease and mutation location. PMID- 23037595 TI - Making the cut: intramembrane cleavage by a rhomboid protease promotes ERAD. AB - Endoplasmic reticulum-associated degradation (ERAD) is a cellular protein quality control process that disposes of proteasomal substrates from the early secretory pathway. Recent work shows that the endoplasmic reticulum-resident rhomboid protease RHBDL4 facilitates ERAD by recognizing and cleaving integral membrane substrates. The work indicates that intramembrane proteolysis may have a general role in the extraction of misfolded membrane proteins from the endoplasmic reticulum. PMID- 23037600 TI - [Neurological features of decision-making deficit: Korinai syndrome in Parkinson disease and fearlessness in dementia]. AB - For patients with Parkinson disease, falls are generally attributed to postural instability. However, closer examination often shows that parkinsonian patients tend to keep falling at the same spot in their home on performing the same actions such as standing up from a chair, starting to walk, or turning at the corner and hitting the same part of the head. Each time the patients fall, their treating physicians explain the reasons for falling and tell them how to avoid falls in daily life. In spite of the repeated advice given by physicians, these patients fall in the same manner and location. When physicians question them regarding the reason for repeating the same risky actions that they had been asked to avoid, the patients answer that they clearly remembered their physician's advice but had thought that they would be able to successfully accomplish the risky actions at that time. Thus, it seems that this type of fall is partly caused by decision-making deficit. Negative-reward motor learning is known to be defective in parkinsonian patients who are being treated with dopamine agonists and are liable to indulge in risky behavior and tend to be involved in pathological gambling. The behavioral abnormalities that are caused by defective decision making and are common to pathological gambling and repeated falling in parkinsonian patients could be termed as "Korinai syndrome, " which means "syndrome involving the inability to learn by experience." In contrast, patients with dementia often show loss of fear reaction, which may result in the life-threatening inability to perceive crises. The present author performed a series of studies just after the Great East Japan Earthquake in March 2011; these studies were based on the behavior of patients with dementia during this large earthquake. The results showed that both intellectually normal elderly people and patients with mild dementia had shown evident fear reactions and could remember their own fearful experience, whereas patients with moderate or severe dementia had not shown any fear reactions during the earthquake and had remained calm in spite of the highly confused behavior of their caregivers. Moreover, those who had remained calm without showing any fear reaction also did not show any trace of memory of the recently experienced large earthquake. PMID- 23037601 TI - [Emotional functions of the insula]. AB - This paper reviews theories and research pertaining to emotional functions of the insula--a cortical area that is located deep in the lateral sulcus and has been included in the limbic lobe because of its intimate connections with the cingulate, amygdala, and orbitofrontal cortex. The insula is known to contain the primary gustatory cortex across mammalian species, and thus, earlier studies have focused on its special role in disgust, which is an emotion closely associated with the sensation of bad taste. In recent years, more emphasis has been placed on the insular contribution to conscious experience of emotion in general. Emotional experience has been known to depend on both the perception of bodily reactions to emotion-provoking objects and the cognitive appraisal of contexts. The insula is theoretically suited for representing such emotional experience because it receives interoceptive inputs from the whole body, and its connections with the prefrontal regions can provide contextual information. In fact, many studies have shown that the activation of the insula, particularly its anterior part, covaries with subjective feelings, which reflect not only physical stimulus intensity but also cognitive factors such as prediction. Such insular activation seems to work as a so-called "as if" somatic marker that inclines us to approach or avoid the stimulus; in addictive disorders, insular activation is proposed to be the neural basis for intense urges. In addition, the insula also represents "simulated" emotional experience, including empathy with others, which may play an important role in social learning. Thus, further investigations into the emotional functions of the insula would help elucidate the still unknown role of conscious experience in regulating cognitive processes and behavior. PMID- 23037602 TI - [Emotion, amygdala, and autonomic nervous system]. AB - Emotion refers to the dynamic changes of feeling accompanied by the alteration of physical and visceral activities. Autonomic nervous system (sympathetic and parasympathetic) regulates the visceral activities. Therefore, monitoring and analyzing autonomic nervous activity help understand the emotional changes. To this end, the survey of the expression of immediate early genes (IEGs), such as c Fos in the brain and target organs, and the viral transneuronal labeling method using the pseudorabies virus (PRV) have enabled the visualization of the neurocircuitry of emotion. By comparing c-Fos expression and data from PRV or other neuroanatomical labeling techniques, the central sites that regulate emotional stress-induced autonomic activation can be deduced. Such regions have been identified in the limbic system (e. g., the extended amygdaloid complex; lateral septum; and infralimbic, insular, and ventromedial temporal cortical regions), as well as in several hypothalamic and brainstem nuclei. The amygdala is structurally diverse and comprises several subnuclei, which play a role in emotional process via projections from the cortex and a variety of subcortical structures. All amygdaloid subnuclei receive psychological information from other limbic systems, while the lateral and central subnuclei receive peripheral and sensory information. Output to the hypothalamus and peripheral sympathetic system mainly originates from the medial amygdala. As estrogen receptor alpha, estrogen receptor beta, and androgen receptor are expressed in the medial amygdala, sex steroids may modulate the autonomic nervous activities. PMID- 23037603 TI - [Orbitofrontal cortex and morality]. AB - Research on the neural substrates of morality is a recently emerging field in neuroscience. The anatomical structures implicated to play a role in morality include the frontal lobe, temporal lobe, cingulate gyrus, amygdala, hippocampus, and basal ganglia. In particular, the orbitofrontal or ventromedial prefrontal areas are thought to be involved in decision-making, and damage to these areas is likely to cause decision-making deficits and/or problems in impulsive control, which may lead to antisocial and less moral behaviors. In this article, we focus on case presentation and theory development with regard to moral judgment. First, we discuss notable cases and syndromes developing after orbitofrontal/ventromedial prefrontal damage, such as the famous cases of Gage and EVR, cases of childhood orbitofrontal damage, forced collectionism, squalor syndrome, and hypermoral syndrome. We then review the proposed theories and neuropsychological mechanisms underlying decision-making deficits following orbitofrontal/ventromedial prefrontal damage, including the somatic-marker hypothesis, reversal learning, preference judgment, theory of mind, and moral dilemma. PMID- 23037604 TI - [Towards more efficient clinical trials for multiple system atrophy in Japan]. AB - Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterized by various combinations of autonomic dysfunction, cerebellar symptoms, parkinsonism, and pyramidal signs. Although MSA is known as a sporadic disease, multiplex families with MSA suggest a genetic predisposition to MSA. The advanced genome research using high-throughput sequencing technology will enable identification of MSA-related genes. Disease-modifying therapy for MSA is expected to be available in the near future. In 2003, the Japan MSA research consortium (JAMSAC) was established to understand the natural history of MSA, which could be the basis for designing clinical trials, and to elucidate the molecular pathogenetic mechanisms of MSA. In Japan, MSA with predominant cerebellar ataxia (MSA-C) is more frequent than that MSA with predominant parkinsonism (MSA-P); this is in contrast to the previous reports from Europe and North America. JAMSAC has conducted a prospective study on the natural history of MSA by using the established consensus criteria for MSA and the unified multiple system atrophy rating scale (UMSARS). Determining the optimum endpoint, sample size, and duration of trial is essential for designing efficient clinical trials. In addition, more sensitive diagnostic criteria are needed to recruit MSA patients in the earlier phase of the condition. Sample size estimation from a longitudinal study suggested the need for sensitive outcome measures, other than UMSARS. Although the knowledge on MSA has increased in the past several decades, biomarkers for this disease are not yet available. The establishment of more sensitive diagnostic criteria and the development of biomarkers are required to conduct more efficient clinical trials for MSA. PMID- 23037605 TI - [Diagnostic imaging of high-grade astrocytoma: heterogeneity of clinical manifestation, image characteristics, and histopathological findings]. AB - Recent developments in diagnostic radiology, which have enabled accurate differential diagnoses of brain tumors, have been well described in the last three decades. MR and PET imaging can also provide information to predict histological grades and prognoses that might influence treatment strategies. However, high-grade astrocytomas consist of many different subtypes that are associated with different imaging and histological characteristics. Hemorrhage and necrosis results in a variety of imaging features, and infiltrative tumor growth entrapping normal neurons may cause different clinical manifestations. We reviewed patients with high-grade astrocytomas that showed various imaging characteristics, with special emphasis on initial symptoms and histological features. Clinicopathological characteristics of astrocytomas were also compared with other malignant tumors. Neurological deficits were not notable in patients with grade 3-4 astrocytomas when they showed infiltrative tumor growth, while brain metastases with compact cellular proliferation caused more neurological symptoms. Infiltrative tumors did not show any enhancing masses on MR imaging, but these tumors may show intratumor heterogeneity. Seizures were reported to be more frequent in low-grade glioma and in secondary glioblastoma. Tumor heterogeneity was also reported in molecular genetic profile, and investigators identified some subsets of astrocytomas. They investigated IHD1/2 mutation, EGFR amplification, TP53 mutation, Ki-67 index, etc. In summary, high-grade astrocytomas are not homogenous groups of tumors, and this is associated with the heterogeneity of clinical manifestation, image characteristics, and histopathological findings. Molecular studies may explain the tumor heterogeneity in the near future. PMID- 23037606 TI - [Review of the new treatment guideline for major depressive disorder by the Japanese Society of Mood Disorders]. AB - The Japanese Society of Mood Disorders (JSMD) published the "Treatment Guideline II: Major Depressive Disorder, 2012 Ver. 1" on July 26, 2012. This guideline (GL) is the first one published by an academic society in Japan. Presently in Japan, many people have depressive symptoms, and the socioeconomic loss (suicide, absence from work, etc.) induced by this condition cannot be overlooked. Although the Japanese society, including mass media and psychiatrists, has attempted to solve this public problem, a solution has not been found. JSMD regarded diagnosis and psychiatric management of depression, among other factors, as the key to solving this problem. For example, patients who meet the DSM-IV major depressive disorder (MDD) criteria still have numerous subtypes, and they often have other psychiatric comorbidities that a diagnosis of MDD alone cannot detect. Although the process for differential diagnosis and treatment planning is indispensable, its methodology has not been necessarily shared even among psychiatrists until today. In this GL, considering the research evidence and its limitations, JSMD suggests necessary steps for appropriate information intake, diagnosis, therapeutic alliance formation, psychoeducation, and treatment modality choice in every phase (acute and continuation/maintenance). This GL also considers pharmaco , psycho-, and electroconvulsive therapy for major depressive subtypes (mild, moderate/severe, and psychotic). Simultaneously, psychiatrists are required to be alert to the risk from diffuse and multiple prescription of benzodiazepine receptor agonists (dependence, deterioration of sleep apnea, cognitive decline, paradoxical reaction, etc.), especially barbiturates. This GL will be revised on the basis of public comments, including criticism. In the future, treatment GLs for comorbid patients, return-to-work cases, primary care physicians, psychiatric residents, and patients with depressions other than MDD (subthreshold depression, dysthymic disorder, and adaptation disorder) may be needed. PMID- 23037607 TI - [Clinical efficacy of the novel antiepileptic agent levetiracetam: evaluation in patients with localization-related epilepsy]. AB - In this retrospective study, we evaluated the safety and efficacy of levetiracetam (LEV) as an antiepileptic drug by using data in our hospital database from October 2010, when LEV became available in Japan, through August 2011. Data from patients aged 16 years or more (n=132) with localization-related epilepsy (n=112) and generalized epilepsy (n=19) were reviewed. Among patients with localization-related epilepsy, 53.6% showed a greater than 50% reduction in seizure frequency compared with the pretreatment baseline, and 28.6% of them became seizure free during the treatment period. Adverse events were reported in 27.3% of patients and caused discontinuation of LEV in 10.6%. The most frequent adverse events were somnolence (14.4%), irritability or aggressiveness (6.1%), and depression (4.5%). However, most of the adverse events were of mild to moderate severity. More than 80% of patients continued LEV treatment. The frequency of adverse events and discontinuation rate after LEV treatment were not associated with the starting dose (1,000 mg/day or less). LEV was well tolerated and efficacious as an adjunctive therapy for localization-related epilepsy. PMID- 23037608 TI - [Ischemic stroke induced by a left atrial myxoma]. AB - We reported a case of ischemic stroke induced by a left atrial myxoma. A 76-year old man was found unconscious and transferred to the emergency ward in our hospital. He experienced consciousness disturbance, motor dominant aphasia, and severe right hemiparesis. His neurological and radiological findings indicated that he had ischemic stroke and was eligible to undergo intravenous thrombolysis. Alteplase was administrated 155 min after the onset of stroke. Intracerebral hemorrhage was not seen 24h after thrombolysis. A tumor in the left atrium was detected on transthoracic echocardiography, and this finding suggested that the tumor was a myxoma. Although cardiac surgery was scheduled, hemorrhagic transformation was found on day 11, which made us postpone the surgery. After the hemorrhage was disappeared, the tumor was resected by open-heart surgery and it was confirmed to be a myxoma. Neither his neurological symptom nor intracerebral hemorrhage was not deteriorated after the operation. Thrombolytic treatment seemed a safe option for ischemic stroke caused by left atrial myxoma. However, we should carefully monitor the extent of anticoagulation therapy because hemorrhagic transformation might alter the timing of surgery for tumor resection. PMID- 23037609 TI - [A 74-year-old man with progressive parkinsonism and dysphasia of seven years duration]. PMID- 23037610 TI - Anticoagulant treatment: the end of the old agents? AB - New oral anticoagulants used as single target inhibitors of coagulation enzymes have been developed and tested in extensive trial programmes. Results of most of these trials showed non-inferior and/or superior efficacy and safety compared to standard treatment with LMWH or VKA. These results led to registration of these agents for the prophylaxis or treatment of thrombosis, as well as stroke prophylaxis in atrial fibrillation. In addition to good efficacy and safety these agents are more convenient in their use and promise advantages in quality of life. Caution is needed, though, since drug-interactions, interferences with coagulation tests and risk of accumulation in case of renal failure should always be taken into consideration when planning a treatment. In the present current opinion review these advantages and disadvantages are discussed and expressed options are analysed. PMID- 23037611 TI - Do the noncaffeine ingredients of energy drinks affect metabolic responses to heavy exercise? AB - Energy drinks (EDs) such as Red Bull (RB) are marketed to enhance metabolism. Secondary ingredients of EDs (e.g., taurine) have been purported to improve time trial performance; however, little research exists on how such secondary ingredients affect aerobic metabolism during heavy exercise. The purpose of this study was to investigate the effect of the secondary ingredients of RB on aerobic metabolism during and subsequent to heavy exercise. In double-blind, counterbalanced, and crossover fashion, 8 recreationally trained individuals completed a graded exercise test to determine the gas exchange threshold (GET). Subjects returned on 2 separate occasions and ingested either a 245 ml serving of RB or a control (CTRL) drink with the equivalent caffeine before engaging in two 10-minute constant-load cycling bouts, at an intensity equivalent to GET, with 3 minutes of rest between bouts. Accumulated liters of O2 (10 minutes) were higher for the first bout (17.1 +/- 3.5 L) vs. the second bout (16.7 +/- 3.5 L) but did not differ between drinks. Similarly, excess postexercise oxygen consumption was higher after the initial bout (RB mean, 2.6 +/- 0.85 L; CTRL mean, 2.9 +/- 0.90 L) vs. the second bout (RB mean, 1.5 +/- 0.85 L; CTRL mean, 1.9 +/- 0.87 L) but did not differ between drinks. No differences occurred between drinks for measures of heart rate or rating of perceived exertion. These results indicate that the secondary ingredients contained in a single serving of RB do not augment aerobic metabolism during or subsequent to heavy exercise. PMID- 23037612 TI - Maximal and ventilatory thresholds of oxygen uptake and rating of perceived exertion responses to water aerobic exercises. AB - This study aimed to compare the V[Combining Dot Above]O2max and first and second ventilatory threshold (1stVT and 2ndVT) V[Combining Dot Above]O2 values and rating of perceived exertion (RPE) responses of treadmill running (TR) with those of 3 water aerobic exercises: stationary running (SR), jumping jack (JJ), and forward kick (FK). Nine women (22.89 +/- 1.81 years, 1.66 +/- 0.07 m, 58.46 +/- 4.19 kg) performed 1 maximal test session for each of the 4 exercise protocols in a randomized order to determine the V[Combining Dot Above]O2max and V[Combining Dot Above]O2 values and RPE responses corresponding with the 1stVT and 2ndVT. V[Combining Dot Above]O2 values were also expressed as a percentage of V[Combining Dot Above]O2max (%V[Combining Dot Above]O2max). A repeated measures analysis of variance and Bonferroni's post hoc test were used, with alpha = 0.05 denoting statistical significance. The analyses showed that the V[Combining Dot Above]O2 responses were significantly higher for TR than for the other exercises at all effort intensities (V[Combining Dot Above]O2max: p < 0.001; 1stVT and 2ndVT V[Combining Dot Above]O2: p < 0.001), followed by intermediate responses for SR and FK and lower responses for JJ. However, no significant differences between exercises for values of %V[Combining Dot Above]O2max (1stVT: p = 0.099; 2ndVT: p = 0.131) and RPE (1stVT: p = 0.275; 2ndVT: p = 0.477) were found at submaximal intensities, indicating that it is possible to achieve and maintain the same training intensity with these exercises during a typical water fitness lesson. Moreover, the RPE values obtained for the 1stVT and 2ndVT can make the prescription of intensity for these water exercises for young women more simple and practical. PMID- 23037613 TI - The potential influence of perception of achievement on performance in volitional time-to-exhaustion cycle ergometer trials. AB - The purpose of this short communication was to report the findings of an investigation of the potential influence of spontaneous goal setting on subjects undertaking maximal fitness testing. Subjects were asked to complete a single incremental volitional time-to-exhaustion cycle ergometer trial. The final minute of the trial, after the last increase in increment in resistance, was broken down into six 10-second intervals and a frequency count made of how many subjects stopped within each interval. A chi-square test was used to determine that there was a significant difference between the expected and the observed frequencies (p < 0.05), with 45% of subjects stopping in the first interval (0-10 seconds) and 0% within the last interval (51-60 seconds). Reflections of the subjects revealed that those who were close to exhaustion but near to reaching the next increment of resistance were more likely to "push on." However, despite having been told to keep going as long as they could, subjects upon reaching that increment stopped almost immediately as they believed they could not manage to reach the next increment. This suggests a potential psychological element related to goal achievement that influences performance in incremental volitional time-to exhaustion cycle ergometer trials. Practically, this means that the information participants have available on which to base goals (level of increment, time, etc.) needs to be minimized to prevent spontaneous goal setting. PMID- 23037614 TI - Relationship between tests of physical qualities and physical match performance in elite rugby league players. AB - Previous investigators have reported significant relationships between tests of physical qualities and physical match performance in high-intensity, intermittent team sport (e.g., soccer) players. Although rugby league requires competitors to perform high-intensity running, unlike most other high-intensity intermittent team sports, the physical demands are significantly increased through the large amounts of tackling, wrestling, and grappling that players are required to perform during match play. This study investigated the relationship between tests of physical qualities and match performance in professional rugby league players and determined whether running capacities were associated with the collision and repeated high-intensity effort demands of match play. Thirty-eight elite rugby league players (mean +/- SD, age, 23.1 +/- 2.7 years) performed tests of repeated sprint ability (12 * 20-m sprints on a 20-second cycle), prolonged high-intensity intermittent running ability (8 * 12-second shuttle sprints on a 48-second cycle), and estimated maximal aerobic power (VO2max) (multistage fitness test). Global positioning system data were collected during 16 professional rugby league matches. Players with better, prolonged, high-intensity intermittent running ability covered greater total distance and greater distance in high-speed running during match play. However, inconsistent relationships were found between tests of running abilities and other match performance variables, with prolonged high intensity running ability (negative), VO2max (positive), and repeated-sprint ability (no relationship) differentially associated with the total number of collisions and repeated high-intensity effort bouts performed in competition. These findings demonstrate the importance of prolonged high-intensity running ability to the match running performance of elite rugby league players but also highlight the need for game-specific conditioning to prepare players for the high intensity collision and repeated-effort demands of the game. PMID- 23037615 TI - Activity and recovery cycles of National Rugby League matches involving higher and lower ranked teams. AB - This study investigated the influence of ladder position on ball-in-play and recovery periods in elite National Rugby League (NRL) competitive matches. Video recordings of 192 NRL matches and 18 NRL finals matches played over 2 competitive seasons were coded for activity and recovery cycles. Time when the ball was continuously in play was considered activity, whereas any stoppages during the match (e.g., for scrums, penalties, line drop outs, tries, and video referee decisions) were considered recovery. In comparison to matches involving lower standard teams, there was a greater proportion (effect size [ES] = 0.37-0.67) of long duration (>91 seconds) and a smaller proportion (ES = 0.49-0.68) of short duration (<45 seconds) ball-in-play periods when Top 4 teams were competing against other Top 4 teams. No meaningful differences were found between teams of different ladder positions for the proportion of short (ES = 0.04-0.16) and long (ES = 0.06-0.28) recovery periods. In comparison to fixture matches involving the top 4 teams, finals matches had a smaller proportion (ES = 0.56) of long duration activity periods, and a greater proportion (ES = 0.54) of short duration activity periods. Only small differences were found between finals matches and matches involving the Top 4 teams for the proportion of short (ES = 0.42) and long (ES = 0.41) recovery periods. These findings suggest that the competitive advantage of the best NRL teams is closely linked to their ability to maintain a higher playing intensity than less successful teams. Furthermore, long ball-in-play periods in high-standard fixture matches (i.e., involving the top 4 teams) ensure that players are adequately prepared for the ball-in-play demands of finals matches. PMID- 23037616 TI - Influence of the opposing team on the physical demands of elite rugby league match play. AB - This study investigated the influence of playing standard, and winning and losing on the physical demands of elite rugby league match play. Twenty-two elite rugby league players participated in this study. Global positioning system data were collected during 16 rugby league matches. Players covered significantly greater (p <= 0.05) absolute and relative distance at high speeds when playing against Bottom 4 teams than when competing against Top 4 teams. The total distance per minute of match play and relative distance at low speeds were greater when matches were won. In addition, a greater absolute and relative number of maximal accelerations and repeated high-intensity effort bouts were performed when players were competing in winning teams than in losing teams. The mean and maximum number of efforts in a repeated high-intensity effort bout was also higher in winning teams, although the recovery between efforts was shorter in losing teams. Moderate (7-17 points) and large (>=18 points) winning margins were associated with greater relative distances covered and distances covered at low speeds than small winning margins. No meaningful differences were found in the physical demands between small, moderate, and large losing margins. The results of this study demonstrate that the physical demands of rugby league are greater when winning than losing, and when competing against lower ranked teams. Furthermore, larger winning margins are associated with greater physical demands than small and moderate winning margins, with these physical demands, in turn, greater than losing margins of any magnitude. These findings suggest that the competitive advantage of successful elite rugby league teams is closely linked to their ability to maintain a higher playing intensity than their less successful counterparts. PMID- 23037617 TI - Effect of concurrent training, flexible nonlinear periodization, and maximal effort cycling on strength and power. AB - Although there is considerable research on concurrent training, none has integrated flexible nonlinear periodization and maximal-effort cycling in the same design. The purpose of this investigation was to test outcome measures of strength and power using a pretest-posttest randomized groups design. A strength and endurance (SE) group was compared with a strength, endurance, and maximal effort cycling (SEC) group. Both groups used a flexible nonlinear periodization design. Thirteen male and 7 female students (mean +/- SD: age, 22.5 +/- 4.1 years; height, 173.5 +/- 12.4 cm; weight, 79.4 +/- 20.2 kg; strength training experience, 2.4 +/- 2.2 years) participated in this study. Groups were not matched for age, height, weight, strength training experience, or sex, but were randomly assigned to an SE (n = 10) or SEC (n = 10) group. All training was completed within 45 minutes, twice per week (Monday and Wednesday), over 12 consecutive weeks. Both groups were assigned 6.75 total hours of aerobic conditioning, and 13.5 hours of free weight and machine exercises totaling 3,188 repetitions ranging from 5 to 20 repetition maximums. The SEC group performed 2 cycling intervals per workout ranging from 10 to 45 seconds. Pretest and posttest measures included chest press and standing broad jump. Analysis of variance showed that there were no significant differences between the SE and SEC groups on measures of chest press or standing broad jump performance (p, not significant). Paired sample t-tests (p = 0.05) showed significant improvement in strength and power in all groups (pretest to posttest), except for SE jump performance (p, not significant). In conclusion, adding maximal-effort cycling does not provide additional strength or power benefits to a concurrent flexible nonlinear training program. However, an exercise professional can take confidence that a concurrent flexible nonlinear training program can increase strength and power in healthy individuals. PMID- 23037618 TI - Effect of training status on reliability of one repetition maximum testing in women. AB - In untrained adults, multiple trials of maximal strength testing are necessary to obtain reliable measures. Training status may positively influence test-retest reliability and increase testing efficiency. The purpose of this study was to evaluate the effect of training status on differences between trials of 1 repetition maximum (1RM) measurement in women. Before (untrained women [UTW]) and after (trained women [TRW]) an 8-week resistance training program, 10 women (45.6 +/- 1.4 years; body mass index 28.7 +/- 1.6 kg.m) completed 3 trials of 1RM chest and leg press with at least 24 hours rest between trials. In UTW, differences between chest press trials were nonsignificant (trials 1-2: 2.36 +/- 1.39 kg, p = 0.37; trials 2-3: 0.82 +/- 0.77 kg, p = 0.95; trials 1-3: 3.18 +/- 0.16 kg, p = 0.07), although a significant difference between leg press trials 1-3 was observed (trials 1-2: 6.55 +/- 3.31 kg, p = 0.25; trials 2-3: 2.52 +/- 1.1 kg, p = 0.15; trials 1-3: 9.07 +/- 2.83 kg, p = 0.04). In TRW, differences between all 1RM trials were nonsignificant for both the chest press (trials 1-2: -0.65 +/- 2.11 kg, p = 1.0; trials 2-3: 1.62 +/- 0.69 kg, p = 0.15; trials 1-3: 0.96 +/- 2.07 kg, p = 1.0) and leg press (trials 1-2: -1.51 +/- 2.13 kg, p = 1.0; trials 2 3: 3.53 +/- 3.0 kg, p = 0.82; trials 1-3: 2.01 +/- 3.87 kg, p = 1.0). Our results suggest that training status has a positive influence on the efficiency of maximal strength measurement. For trained middle-aged women, a single trial of 1RM chest or leg press may be sufficient to obtain an accurate and reliable measure of maximal strength. PMID- 23037619 TI - Uphill racewalking at iso-efficiency speed. AB - The aim of this study was to investigate the effects of gradients (0, 2, and 7%) on biomechanical parameters during racewalking (RW) at iso-efficiency speed (IES). During the experiment, 12 high-level athletes performed at IES on different slopes. The parameters studied were surface muscular activity (EMG) of 5 muscles of the leg using Muscle Lab (Boscosystem); kinematic parameters were collected using a high-speed camera (210 Hz) analyzed with Dartfish 5.5 Pro; and heart rate (HR) was monitored with a Cardio Polar. The results showed step length (SL), step frequency (SF), and internal work (WINT) decreased with increased treadmill gradient: SL = ([0-2% = 3.48%, p = 0.158], [0-7% = 12.17%, p < 0.001]); SF = ([0-2% = 2.38%, p = 0.173], [0-7% = 6.07%, p < 0.01]); WINT = ([0-2% = 8.34%, p < 0.001], [0-7% = 22.81%, p < 0.0001]). Conversely, contact time (CT) and HR increased less significantly with the increased gradients: CT = ([0-2% = 2.46%, p = 0.198], [0-7% = 6.56%, p < 0.01]); HR = ([0-2% = 0.62%, p = 0.652], [0 7% = 3.25%, p < 0.05]). The knee angle (KE) increased, whereas ankle angle (AK) and hip angle (HP) decreased with the increased gradients: AK = ([0-2% = 1.69%, p < 0.001], [0-7% = 1.13%, p < 0.01]); HP = ([0-2% = 0.22%, p < 0.03], [0-7% = 0.16%, p = 0.456]); KE = ([0-2% = 1.01%, p < 0.001], [0-7% = 1.60%, p < 0.001]). Electromyography (EMG) significantly decreased with the increased gradients in the: tibialis anterior ([0-2% = 22.49%, p < 0.0001], [0-7% = 41.18%, p < 0.0001]) and rectus femoris ([0-2% = 15.35%, p < 0.0001], [0-7% = 29.13%, p< 0.0001]). In contrast, EMG activity was significantly increased in the vastus lateralis ([0-2% = 22.95%, p < 0.0001], [0-7% = 31.15%, p < 0.0001]), gastrocnemius medialis ([0 2% = 21.40%, p < 0.001], [0-7% = 48.37%, p < 0.0001]), and biceps femoris ([0-2% = 190.78%, p < 0.0001], [0-7% = 201.37%, p < 0.0001]). The results indicate that increasing the gradient to 2% did not elicit an increased HR in racewalkers; however, at a 7% gradient, greater muscle activity was required. PMID- 23037620 TI - Effects of intensity and duration in aerobic high-intensity interval training in highly trained junior cross-country skiers. AB - The purpose of this study was to test whether a long duration of aerobic high intensity interval training is more effective than shorter intervals at a higher intensity in highly trained endurance athletes. The sample comprised of 12 male and 9 female, national-level, junior cross-country skiers (age, 17.5 +/- 0.4 years, maximal oxygen uptake (V[Combining Dot Above]O2max): 67.4 +/- 7.7 ml min kg), who performed 8-week baseline and 8-week intervention training periods on dry land. During the intervention period, a short-interval group (SIG, n = 7) added 2 weekly sessions with short duration intervals (2- to 4-minute bouts, total duration of 15-20 minutes), a long-interval group (LIG; n = 7) added 2 weekly sessions with long duration intervals (5- to 10-minute bouts, total duration of 40-45 minutes). The interval sessions were performed with the athletes' maximal sustainable intensity. A control group (CG; n = 7) added 2 weekly sessions with low-intensity endurance training at 65-74% of maximal heart rate. Before and after the intervention period, the skiers were tested for time trial performance on 12-km roller-ski skating and 7-km hill run. V[Combining Dot Above]O2max and oxygen uptake at the ventilatory threshold (V[Combining Dot Above]O2VT) were measured during treadmill running. After the intervention training period, the LIG-improved 12-km roller ski, 7-km hill run, V[Combining Dot Above]O2max, and V[Combining Dot Above]O2VT by 6.8 +/- 4.0%, 4.8 +/- 2.6%, 3.7 +/- 1.6%, and 5.8 +/- 3.3%, respectively, from pre- to posttesting, and improved both performance tests and V[Combining Dot Above]O2VT when compared with the SIG and the CG (all p < 0.05). The SIG improved V[Combining Dot Above]O2max by 3.5 +/- 3.2% from pre- to posttesting (p < 0.05), whereas the CG remained unchanged. As hypothesized, a long duration of aerobic high-intensity interval training improved endurance performance and oxygen uptake at the ventilatory threshold more than shorter intervals at a higher intensity. PMID- 23037621 TI - Victoria Symptom Validity Test performance in children and adolescents with neurological disorders. AB - It is becoming increasingly more important to study, use, and promote the utility of measures that are designed to detect non-compliance with testing (i.e., poor effort, symptom non-validity, response bias) as part of neuropsychological assessments with children and adolescents. Several measures have evidence for use in pediatrics, but there is a paucity of published support for the Victoria Symptom Validity Test (VSVT) in this population. The purpose of this study was to examine the performance on the VSVT in a sample of pediatric patients with known neurological disorders. The sample consisted of 100 consecutively referred children and adolescents between the ages of 6 and 19 years (mean = 14.0, SD = 3.1) with various neurological diagnoses. On the VSVT total items, 95% of the sample had performance in the "valid" range, with 5% being deemed "questionable" and 0% deemed "invalid". On easy items, 97% were "valid", 2% were "questionable", and 1% was "invalid." For difficult items, 84% were "valid," 16% were "questionable," and 0% was "invalid." For those patients given two effort measures (i.e., VSVT and Test of Memory Malingering; n = 65), none was identified as having poor test-taking compliance on both measures. VSVT scores were significantly correlated with age, intelligence, processing speed, and functional ratings of daily abilities (attention, executive functioning, and adaptive functioning), but not objective performance on the measure of sustained attention, verbal memory, or visual memory. The VSVT has potential to be used in neuropsychological assessments with pediatric patients. PMID- 23037622 TI - Celebrating but not confusing the 25th anniversary of deep brain stimulation. PMID- 23037623 TI - Hypocholesterolemia in patients with polycythemia vera. AB - Polycythemia vera (PV) is characterized by low serum total cholesterol despite its association with vascular events such as myocardial and cerebral infarction. Serum cholesterol level has not been used as a diagnostic criterion for PV since the 2008 revision of the WHO classification. Therefore, we revisited the relationship between serum lipid profile, including total cholesterol level, and erythrocytosis. The medical records of 34 erythrocytosis patients (hemoglobin : men, > 18.5 g/dL ; women, > 16.5 g/dL) collected between August 2005 and December 2011 were reviewed for age, gender, and lipid profiles. The diagnoses of PV and non-PV erythrocytosis were confirmed and the in vitro efflux of cholesterol into plasma in whole blood examined. The serum levels of total cholesterol, low density-lipoprotein cholesterol (LDL-Ch), and apolipoproteins A1 and B were lower in PV than in non-PV patients. The in vitro release of cholesterol into the plasma was greater in PV patients than in non-PV and non-polycythemic subjects. Serum total cholesterol, LDL-Ch, and apolipoproteins A1 and B levels are lower in patients with PV than in those with non-PV erythrocytosis. The hypocholesterolemia associated with PV may be attributable to the sequestration of circulating cholesterol into the increased number of erythrocytes. PMID- 23037624 TI - Germinal center B-cell-like versus non-germinal center B-cell-like as important prognostic factor for localized nodal DLBCL. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. Although many investigations have been performed on the prognostic factors of DLBCL, no reports have focused on localized nodal DLBCL. We examined the prognostic significance of 39 Japanese patients with localized nodal DLBCL with special reference to the germinal center B-cell-like (GCB) versus non germinal center B-cell-like (NGCB) types. The median age was 65 years with 23 males and 16 females. Using Hans algorithm of immunohistochemistry, 18 patients (46%) exhibited GCB type and 21 (54%) exhibited NGCB type. Twenty-nine patients (74%) presented with disease in the neck (neck group) and 10 (26%) had disease in non-neck regions (non-neck group). Comparing Hans, Choi, and Muris algorithms, patients with GCB type showed statistically significant progression-free survival (PFS) only with Hans algorithm (P = 0.022, P = 0.100, and P = 0.130, respectively). Patient survival analyses revealed that GCB-type patients by Hans algorithm had a better PFS (P = 0.012), and neck-group patients had better PFS and overall survival (OS) (P = 0.018 and P = 0.012, respectively). Univariate analysis revealed that only neck vs. non-neck exhibited a significant difference in terms of OS (P = 0.026). Multivariate analysis revealed that GCB type by Hans algorithm and neck vs. non-neck were significantly different in terms of PFS (P = 0.025 and P = 0.033, respectively). Therefore, the subclassifications of GCB type vs. NGCB type and neck vs. non-neck are important predictive prognostic factors in localized nodal DLBCL. PMID- 23037625 TI - Three cases of aggressive natural killer cell leukemia with a lethal hemorrhagic complication. AB - Aggressive natural killer cell leukemia (ANKL) is a rare malignant disease of NK cells that has a median survival of less than 2 months and a strong association with the Epstein-Barr virus. Herein, we report three Japanese cases of the disease. A 21-year male patient, a 31-year female patient, and a 76-year female patient presented with high fever, lymphadenopathy, hepatosplenomegaly, and severe liver damage. All three cases had granular lymphocytes in both peripheral blood and bone marrow. The phenotype of these cells was CD2(+)CD3(-)CD56(+)HLA DR(+). All cases had a high copy number of serum Epstein-Barr virus DNA in the peripheral blood and were diagnosed with ANKL. Case 1 and Case 2 were treated with chemotherapy, but suffered from gross intestinal bleeding or massive bleeding in the cerebellum, resulting in death. Although not treated with chemotherapy, Case 3 also suffered gross bleeding from an atypical duodenal ulcer and died from hemorrhagic shock 15 days after admission. There have been no previous reports of such acute lethal hemorrhagic complications with ANKL. The present cases suggest that patients with ANKL need a sufficient supply of coagulation factors, and that chemotherapy for this disease should be carefully designed with promising agents. [J Clin Exp Hematopathol 52(2) : 101-106, 2012]. PMID- 23037626 TI - Leukemic manifestation of blastic plasmacytoid dendritic cell neoplasm lacking skin lesion : a borderline case between acute monocytic leukemia. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with a poor prognosis. We encountered a unique case of BPDCN that was leukemic at presentation without skin lesion and expressed CD33 antigen. A 74 year-old man was admitted because of dyspnea. Physically, hepatosplenomegaly, but not skin lesions and superficial lymph node swelling, was noted. The white blood count was 33.6 * 10(9)/L with 19% giant abnormal cells. These cells were positive for CD4, CD86, CD123 (bright), BDCA-2, and HLA-DR, but negative for CD1a, CD3, CD11b, CD11c, CD13, CD14, CD19, CD64, and CD68. From these findings, a diagnosis of BPDCN was made. In terms of unusual expression, these tumor cells were positive for CD33 but negative for CD56. The karyotype was 47, XY, t(6;8) (p21;q24), + r. We performed combination chemotherapy (Ara-C + VP-16 + MIT), which resulted in a marked reduction of tumor cells and improvement of the dyspnea. On day 16, however, he died of sepsis due to Bacillus cereus. The clinical picture of this patient is unusual and may provide new information on the clinicopathology of BPDCN. PMID- 23037627 TI - Double-hit lymphoma with a feature of follicular lymphoma concurrent with clonally related B lymphoblastic leukemia : a preference of transformation for the bone marrow. AB - We describe a 65-year-old woman with follicular lymphoma (FL), grade 1, stage IV, which occurred concurrently with B lymphoblastic leukemia/lymphoma. Through the evaluation of FL, the cells that were morphologically suspected of having undergone transformation were found in the bone marrow, and flow cytometric and cytogenetic analyses detected the transformed population that suggested concomitant t(8;22) with typical t(14;18) FL cells. Repeated analyses of the lymph nodes demonstrated the typical morphological, phenotypic, and cytogenetic features of FL. The patient received several multiagent chemotherapy regimens, but the disease gradually became resistant, and the patient died of leukemic progression. In B-cell malignancies, cases involving both BCL2 and MYC translocations simultaneously, so-called "double-hit leukemia/lymphoma (DHL)", have occasionally been reported. Patients with this type of translocation have a very poor clinical outcome, and no standard therapy has been established. In our case, FL was supposed to have transformed into B lymphoblastic leukemia via Burkitt's lymphoma-like phase. Our case is unique in that the transformed DHL cells, derived from clonally related FL cells, showed ongoing transformation from Burkitt-like feature to B lymphoblastic leukemia exclusively in the bone marrow, which suggests that the bone marrow may provide a preferable milieu for malignant transformation. Similar cases should be accumulated and analyzed carefully. PMID- 23037628 TI - Rapidly progressing fatal adult multi-organ Langerhans cell histiocytosis complicated with fatty liver disease. AB - Langerhans cell histiocytosis (LCH) is a clonal neoplasm that shows diverse clinical manifestations and courses of disease progression. The etiology and pathophysiology of LCH remain uncertain. We describe the clinical course of a 23 year-old Japanese woman with multi-system LCH, who showed rapid progression after steroid reduction and developed multi-organ failure. Liver biopsy showed LCH infiltration with fatty degeneration. She was treated with cytarabine, vincristine, and prednisolone according to the Japan LCH study group 02 protocol, without any clinical improvement. Low expression of Ki67 and bcl-2 failed to explain the rapid clinical course. Panhypopituitarism and hypothalamic dysfunction may have caused nonalcoholic fatty liver disease and liver failure. This case indicates that some multi-system LCH patients with hypopituitarism and hypothalamic dysfunction show very rapid progression and are difficult to treat. PMID- 23037629 TI - Flow cytometric analysis of kappa and lambda light chain expression in endoscopic biopsy specimens before the diagnosis of B-cell lymphoma. AB - Forty-eight patients with gastrointestinal (GI) tract B-cell lymphoma (BCL) were analyzed retrospectively. The diagnosis was based on the histological examination of specimens obtained by endoscopic biopsy. Before the diagnosis was made, single color flow cytometry was performed to analyze the expression of light chains and B-cell antigens including CD10 in the specimens. Restricted light chain (RLC) expression, a marker of B-cell clonality, was defined as kappa and lambda ratios of either more than 3.0 or less than 0.5. The specimens from 30 patients (62.5%) showed RLC expression. No RLC expression or RLC expression not examined was divided into two groups : those showing CD10 positivity in more than 20% of cells (4 patients, 8.3%) and those showing no positivity (14 patients, 29.2%). The cell number analyzed in the latter group was significantly smaller than that in the other two groups. Abnormal karyotypes were found in the specimens from 8 patients (16.7%). These results indicate that the flow cytometric analysis of endoscopic biopsy specimens is useful when BCL is suspected if an adequate number of cells are obtained. PMID- 23037630 TI - CD20-positive and CD4/CD8-double-negative peripheral T-cell lymphoma of spleen complicated with severe disseminated intravascular coagulation and enteropathy. AB - A 71-year-old woman presented with massive splenomegaly. Open splenectomy was performed, and the diagnosis of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), was made, with a characteristic immunophenotype of CD3(+), CD4(-), CD8(-), T-cell receptor (TCR)alphabeta(+), and TCRgammadelta(-). After splenectomy, she suffered abrupt exacerbation of the lymphoma with disseminated intravascular coagulation and enteropathy. Although chemotherapy was started, her medical condition did not improve and she died a week later. Postmortem reevaluation of the pathological specimen confirmed her diagnosis as CD20(+) PTCL NOS. Although it is a rare disease entity, CD20(+) T-cell lymphoma can demonstrate aggressive clinical behavior. PMID- 23037631 TI - Orbital inflammatory lesion as an initial manifestation of systemic nasal type NK/T-cell lymphoma. PMID- 23037632 TI - Presence of immunoglobulin heavy chain rearrangement in so-called IgG4-related plasma cell granuloma of the eyelid. PMID- 23037633 TI - Disappearance of both the BCR/ABL1 fusion gene and the JAK2V617F mutation with dasatinib therapy in a patient with imatinib-resistant chronic myelogenous leukemia. PMID- 23037634 TI - Severe neurological symptoms in a patient with advanced renal cell carcinoma treated with sunitinib. AB - Neurological symptoms are uncommon in patients administered sunitinib therapy; however, a few cases of dramatic neurotoxicity attributable to the development of reversible posterior leukoencephalopathy syndrome have been reported. Here, we report a case of a 71-year old woman with severe neurological symptoms occurring during sunitinib therapy for metastatic renal cell carcinoma. The clinical symptoms were typical for reversible posterior leukoencephalopathy syndrome, but there were no accompanying neuroimaging abnormalities. A Naranjo probability score of 3 indicates the adverse drug reaction was possible, but we discuss other potential causes of this event. PMID- 23037635 TI - Strategies for engineered negligible senescence. AB - In this viewpoint, we describe the strategies for engineered negligible senescence (SENS) concept--a simple and appealing model for the design of therapeutic interventions able to meaningfully and persistently reverse the deleterious effects of aging. We go on to outline how current or foreseeable biotechnologies could feasibly be employed to repair every currently identified category of pathogenic damage that accumulates over a human lifespan. Then, briefly, we explain why this goal is not only ethically sound, but can in fact be considered to verge on an ethical obligation. Finally, we review recent progress in some key areas of the SENS platform, including proof-of-concept research sponsored by the SENS Foundation, a charity based in California. PMID- 23037636 TI - Solitary cholesteatoma of the parietal bone. PMID- 23037637 TI - pH-responsive size-tunable self-assembled DNA dendrimers. AB - Putting the DNA in dendrimers: a strategy to swiftly prepare DNA dendrimers based solely on DNA self-assembly is presented. This technique produces highly pure DNA dendrimers with an excellent yield of high generation dendrimers. The incorporation of molecular motors (i-motifs) into the DNA dendrimers allows for a change in size (up to 30%) in response to changing pH values. PMID- 23037638 TI - HPLC determination of the major active flavonoids and GC-MS analysis of volatile components of Dysphania graveolens (Amaranthaceae). AB - INTRODUCTION: Dysphania graveolens is used mainly in Mexican traditional medicine against gastrointestinal ailments. Previous investigations revealed that its flavonoids are important active principles; however, there is not a reliable and accurate analytical method for determining these compounds in the crude drug or preparations of the plant. In addition, its volatile chemical composition remains unknown. OBJECTIVE: The main goals were to develop a validated HPLC method for quantifying the active flavonoids (pinostrobin (1), pinocembrin (2) and chrysin (3)) of D. graveolens and to establish its volatile composition. METHODOLOGY: Separation was carried out on a Licrospher100 RP18 column with a linear gradient acetonitrile 0.1% formic acid and aqueous 0.1% formic acid. Accuracy was determined by spiking the crude drug with the standards, the recoveries were between 99% and 101%. A systematic description of the volatile components of D. graveolens was assessed via GC-MS using headspace solid-phase microextraction (HS SPME) and hydrodistillation extraction methods. RESULTS: The developed HPLC method represented a powerful technique for the quality control of D. graveolens allowing the quantification of the three active flavonoids. For each compound a linear response was evaluated within the range of 0.5-2.0 mg/mL for pinostrobin (1), 0.25-1.25 mg/mL for pinocembrin (2) and 0.05-0.5 mg/mL for chrysin (3). According to SPME the major components in D. graveolens were p-cymene (84.85%) and eucalyptol (11.26%). On the other hand, the essential oil had eucalyptol (42.89%) and p-cymene (16.51%) and did not contain ascaridol. Thus the most relevant volatile components in the species were monoterpenoids. PMID- 23037639 TI - Microplasma-based synthesis of vertically aligned metal oxide nanostructures. AB - Vertically aligned metal oxide nanostructures (e.g., wires, needles, pillars and trees) of CuO, PdO and NiO were synthesized on several substrates (e.g., Si and ITO (indium tin oxide)) using a high-pressure (~Torr) microplasma-based growth technique. Organometallic precursors were dissociated in the hollow cathode region of a supersonic plasma jet creating a directed flux of metal species (e.g., atoms, metastables, etc) which react with an oxygen background to form crystalline metal oxide films having a variety of nanomorphologies. Spiral-like growth fronts were seen in some cases for CuO, suggesting that nanowire growth may involve screw dislocations. Large area, nanowire films >1 cm(2) with good adhesion and electrical connection to ITO substrates were deposited by raster scanning a single jet. Details of the microplasma operation, the dynamics of the growth process and the resulting materials are discussed. PMID- 23037640 TI - The clock drawing task: common errors and functional neuroanatomy. PMID- 23037641 TI - The functional neuroanatomy of decision-making. AB - Decision-making is a complex executive function that draws on past experience, present goals, and anticipation of outcome, and which is influenced by prevailing and predicted emotional tone and cultural context. Functional imaging investigations and focal lesion studies identify the orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices as critical to decision-making. The authors review the connections of these prefrontal regions with the neocortex, limbic system, basal ganglia, and cerebellum, highlight current ideas regarding the cognitive processes of decision-making that these networks subserve, and present a novel integrated neuroanatomical model for decision making. Finally, clinical relevance of this circuitry is illustrated through a discussion of frontotemporal dementia, traumatic brain injury, and sociopathy. PMID- 23037642 TI - Psychotic disorder due to traumatic brain injury: analysis of case studies in the literature. AB - The present study utilized methodology from a previous descriptive study that analyzed case studies of psychotic disorder due to traumatic brain injury (PD TBI) reported in psychiatry and neurology journals. The purpose was to replicate findings from the PD-TBI literature and to elucidate a pattern of characteristics that would differentiate PD-TBI from schizophrenia. The findings supported both objectives. PD-TBI data were highly consistent with previous studies: PD-TBI differed from schizophrenia in showing more focal frontal and temporal abnormalities on neurological studies and a lower rate of negative symptoms. The authors discuss implications of these findings for conceptualizing psychosis as a neurobiological syndrome. PMID- 23037643 TI - Agomelatine in depressive disorders: its novel mechanisms of action. AB - Disruptions in sleep and sleep-wake cycle regulation have been identified as one of the main causes for the pathophysiology of depressive disorders. The search has been on for the identification of an ideal antidepressant that could improve both sleep disturbances and depressive symptomatology. Melatonin, the major hormone of the pineal gland, has been shown to improve sleep and is involved in the regulation of the sleep-wake cycle. Identification of high concentrations of MT1 and MT2 melatonergic receptors in the suprachiasmatic nucleus of the anterior hypothalamus, the structure concerned with regulation of circadian rhythms and sleep-wake cycles, has led to the development of melatonergic agonists with greater potency and longer durations of action. Agomelatine is one such melatonergic agonist that acts specifically on MT1/MT2 melatonergic receptors and at the same time exhibits 5-HT2C antagonism, a property that is utilized by current antidepressants that are in clinical use. Agomelatine has been shown to be effective in a number of animal models of depression. Clinical studies undertaken on patients with major depression, bipolar disorders, seasonal affective disorder, and generalized anxiety disorder have all shown that agomelatine is also very effective in ameliorating depressive symptoms and manifesting early onset of action with a good tolerability and safety profile. It improved sleep efficiency and also resynchronized the disrupted circadian rhythms. Hence, the melatonergic modulation by agomelatine is suggested as one of the mechanisms for its antidepressant effect. Agomelatine's action on dendritic neurogenesis in animal models of depression is also identified as yet another action. PMID- 23037644 TI - Diffusion tensor imaging atlas-based analyses in major depression after mild traumatic brain injury. AB - There are currently no known early neuroanatomical markers predictive of the development of major depression or depressive symptoms after mild traumatic brain injury (mTBI). The authors conducted a 1-year longitudinal pilot study to determine whether diffusion tensor imaging (DTI) measures collected within 1 month of mTBI could predict incident depression. Of the 14 subjects who met study inclusion criteria, 4 (28.6%) developed major depression over the follow-up period. Compared with the nondepressed group, those who developed depression had white-matter abnormalities in the fronto-temporal regions measured by DTI. These preliminary results highlight the need for additional studies, including studies using a larger sample and appropriate controls. PMID- 23037645 TI - Associations between bilateral subthalamic nucleus deep brain stimulation (STN DBS) and anxiety in Parkinson's disease patients: a controlled study. AB - The authors explored the associations between subthalamic nucleus deep brain stimulation (STN-DBS) and anxiety in Parkinson's disease (PD) patients. Recent research suggests that anxiety may be one of the earliest manifestations of PD; however, the lack of a dopamine-medication control group is a major limitation of these studies. Authors paired a group of 31 bilateral STN-DBS PD patients (STN DBS group) with 31 dopamine-medicated PD patients (Medication-control group) and used various psychological assessment scales for group evaluations. These were completed 1 month preoperatively, and 3 weeks, 5 weeks, 2 months, 4 months, 7 months, and 13 months postoperatively. As compared with the Medication group, the STN-DBS group improved in motor functioning and general status after 1 week Stimulator Power-On; State-Anxiety improved significantly at 1 week and 1 month after Stimulator Power-On, but was not significant at the subsequent time-points. Anxiety scores remained stable before 3rd-month Stimulator Power-On, but got worse after that time. In the STN-DBS group, S-AI was positively related to motor symptoms and life quality preoperatively and 4 months postoperatively, but, in the Medication group, this correlation existed throughout the study. PD-related anxiety decreased in STN-DBS patients because of the improvement in motor function for a short time; however, as the voltages and pulse-widths grew higher with time, the PD-related anxiety became worse. PMID- 23037646 TI - Are selective serotonin reuptake inhibitors associated with greater apathy in Parkinson's disease? AB - Apathy is a common neuropsychiatric feature of Parkinson's disease (PD), but little is known of relationships between apathy and specific medications in PD. Following a retrospective database and chart review of 181 Parkinson's patients, relationships between Apathy Scale scores and use of psychotropic and antiparkinsonian medications were examined with multiple regression. Controlling for age, sex, education, and depression, the use of selective serotonin reuptake inhibitors (SSRIs), but not other antidepressants, was associated with greater apathy. Use of monoamine oxidase B inhibitors was associated with less apathy. Longitudinal studies are needed to evaluate a potential SSRI-induced apathy syndrome in PD. PMID- 23037647 TI - Elevated neurobehavioral symptoms are associated with everyday functioning problems in chronic methamphetamine users. AB - Chronic methamphetamine (MA) use is commonly associated with neural injury and neurocognitive deficits. The authors examined the nature and correlates of self reported neurobehavioral symptoms (e.g., apathy, disinhibition, and executive dysfunction) in 73 individuals with histories of MA dependence (MA+) and 85 comparison participants with comparable demographics and risk histories. MA+ individuals endorsed significantly more severe neurobehavioral symptoms on the Frontal Systems Behavioral Scale, especially those of disinhibition and executive dysfunction. Elevations in neurobehavioral symptoms were independent of common comorbidities, including hepatitis C infection, attention-deficit/hyperactivity disorder (ADHD), mood disorders, and other substance-use factors. Notably, the severity of neurobehavioral symptoms was uniquely associated with self-reported decrements in instrumental activities of daily living in the MA-dependent sample. Findings indicate that chronic MA users may experience elevated neurobehavioral symptoms of disinhibition and executive dysfunction, potentially increasing their risk of functional declines. PMID- 23037648 TI - The role of HIV infection, cognition, and depression in risky decision-making. AB - The authors examined the impact of HIV, cognitive dysfunction, and depression on decision-making. HIV+ (N=100) and HIV- (N=26) participants were administered a comprehensive neuropsychological battery, a modified version of the Iowa Gambling Task, and a measure of depressive symptoms. HIV+ participants demonstrated more difficulties in learning the gambling task than did HIV- participants. Executive functioning and depression emerged as strong predictors of gambling task performance. Depression partially mediated the relationship between executive functioning and gambling performance. Our findings suggest that HIV infection, executive dysfunction, and depression place individuals at risk for poor decision making. PMID- 23037649 TI - Duloxetine versus citalopram and sertraline in the treatment of poststroke depression, anxiety, and fatigue. AB - The authors sought to determine the relative efficacy and tolerability of duloxetine versus citalopram and sertraline in the treatment of poststroke depression (PSD), anxiety, and fatigue. A group of 60 patients with PSD were assigned to receive duloxetine, citalopram, or sertraline and were assessed over a 3-month period for depression, anxiety, and fatigue. Improvement of depression and anxiety, but not fatigue, was observed in all study groups. Duloxetine was well tolerated and significantly more effective than citalopram and sertraline for the treatment of anxiety symptoms in PSD patients. None of the antidepressants used was effective for reducing symptoms of fatigue. PMID- 23037650 TI - Effects of sleep deprivation on nocturnal cytokine concentrations in depressed patients and healthy control subjects. AB - Previous studies have reported alterations of cytokine and cytokine-receptor concentrations in psychiatric patient populations, including patients with major depressive disorder (MDD). However, study results are conflicting, and possible causes for these abnormalities are unknown. Since sleep deprivation may induce a rapid improvement of mood in depressed patients, the authors investigated the impact of total sleep deprivation (TSD) for one night, and subsequent recovery sleep, on nocturnal concentrations of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1RA), and soluble IL-2 receptor (sIL-2R) in 15 unmedicated patients with MDD and 16 healthy volunteers. Whereas IL-6 levels normalized again during the recovery night in depressed patients, they were still elevated in control subjects. Serum levels of IL-1RA were higher in depressed patients than in controls, but were not affected by TSD. During recovery sleep, IL-1RA levels increased as compared with the preceding TSD night only in controls. Responders (N=8) differed from nonresponders (N=7) to TSD with regard to IL-1RA, which increased significantly during TSD in responders only. Sleep deprivation therefore seems to significantly affect cytokine levels in both depressed patients and healthy subjects, but does so in different ways. Sleep disturbances in depressed patients could account for the increased levels of cytokines found in these patients in several previous studies. The interaction between antidepressant effects of TSD and alterations of cytokines warrants further investigation. PMID- 23037651 TI - Case reports of Rasmussen's syndrome and literature review. AB - Rasmussen's encephalitis (RE) is a chronic inflammatory disease of unknown origin that usually affects one hemisphere of the brain. Serial electroencephalographic (EEG) and magnetic resonance imaging (MRI) associated with magnetic resonance angiography (MRA) features specific for RE are rarely reported. By assessing the progression of RE revealed through EEG, MRI/MRA, and treatment results, the authors determined that RE is a focal epileptic syndrome characterized by chronic and progressive partial epileptic seizures, with specific changes in EEG and MRI/MRA findings. PMID- 23037653 TI - Environment multiple-layer map, inspired from hippocampal function. PMID- 23037652 TI - Hyperammonemia associated with valproic acid use in elderly psychiatric patients. AB - Valproic acid (VPA) is associated with hyperammonemia; however, little is known about this phenomenon in the geriatric psychiatric population. Of 12 such patients prescribed VPA, 83.3% had elevated ammonia. This occurred in the absence of elevated liver enzymes, and there was no association of VPA serum-level to hyperammonemia. PMID- 23037654 TI - Olfactory reference syndrome: an unusual delusion in a patient with Parkinson's disease. PMID- 23037655 TI - Venlafaxine causing akathisia: a case report. PMID- 23037656 TI - Insomnia and risk of falling in older adults. PMID- 23037657 TI - Possible association between Alice in Wonderland syndrome and influenza A infection. PMID- 23037658 TI - Combination therapy of zonisamide with aripiprazole on ECT- and benzodiazepine resistant periodic catatonia. PMID- 23037659 TI - Introducing a new method for early diagnosis of Parkinson's disease. PMID- 23037660 TI - Decreased expression of CCL3 in monocytes and CCR5 in lymphocytes from frontotemporal dementia as compared with Alzheimer's disease patients. PMID- 23037661 TI - Increased anterior cingulate regional homogeneity after duloxetine therapy in first-episode, drug-naive, major depressive disorder with panic disorder patients: a case series. PMID- 23037662 TI - Naloxone successfully counters life-threatening toxicity of benzodiazepine in a patient in methadone-maintenance treatment. PMID- 23037663 TI - Paliperidone as an alternative for risperidone in a case of schizophrenia with retrograde ejaculation. PMID- 23037664 TI - An unusual presentation of dhat syndrome. PMID- 23037665 TI - We are all zombies anyway: aggression in Cotard's syndrome. PMID- 23037666 TI - Possible paliperidone-induced neuroleptic malignant syndrome: a case report. PMID- 23037667 TI - Increases in amplitude of low-frequency fluctuations in left fronto-parietal area after duloxetine therapy in first-episode, drug-naive, major depressive disorder with panic disorder patients. PMID- 23037668 TI - Acute Pisa syndrome after administration of a single dose of donepezil. PMID- 23037669 TI - Donepezil-induced mania. PMID- 23037670 TI - Capgras delusion in paranoid schizophrenia complicated by vascular dementia. PMID- 23037671 TI - Hypofrontality with positive anti-NMDA receptor antibodies. PMID- 23037672 TI - A case of Pisa syndrome during sertraline and quetiapine treatment. PMID- 23037673 TI - Catatonic schizophrenia with cavum septum pellucidum. PMID- 23037674 TI - Catatonia: a rare presenting symptom of Wilson's disease. PMID- 23037675 TI - Psychiatric comorbidity in arousal disorders: chicken or egg? PMID- 23037676 TI - Metoclopramide-induced tardive respiratory dyskinesia. PMID- 23037677 TI - Low-dose aripiprazole in the treatment of SSRI-induced bruxism. PMID- 23037678 TI - Charles Bonnet syndrome responding to amisulpride. PMID- 23037679 TI - Myoclonus induced by haloperidol in the intensive care unit. PMID- 23037680 TI - Antecollis, lingual dystonia, and mutism secondary to risperidone. PMID- 23037681 TI - Probable aripiprazole-induced tardive writer's cramp. PMID- 23037682 TI - The use of dexmedetomidine in alcohol withdrawal. PMID- 23037684 TI - Proposing a new management for freezing of gait in Parkinson's disease. PMID- 23037683 TI - Venlafaxine augmentation with lithium leading to serotonin syndrome. PMID- 23037685 TI - Aripiprazole monotherapy-related gray-matter growth in a patient with first episode drug-naive non-psychotic major depressive disorder. PMID- 23037686 TI - New variant Creutzfeldt-Jacob disease presenting with catatonia: a rare presentation. PMID- 23037687 TI - A rare case of schizophrenia with tongue rupturation and comorbid analgesic drug abuse. PMID- 23037688 TI - Tissue specific delivery of estrone-conjugated siRNAs. AB - An estrone phosphoramidite, synthesized in a single step, was directly incorporated at the 5' ends of small interfering RNAs (siRNAs). The resulting estrone-conjugated siRNAs readily pass through cellular membranes and down regulate the target protein, and show specific distributions in vivo. PMID- 23037689 TI - Superazaporphyrins: meso-pentaazapentaphyrins and one of their low-symmetry derivatives. AB - Supersized: Three pentaazapentaphyrin derivatives, that is, the superazaporphyrins (SAzPs), as well as a superphthalocyanine (SPc) and a mixed low-symmetry derivative have been prepared and characterized. Decaaryl SAzPs have a distorted (4n+2) pi structure and show the Q bands at about lambda=840-880 nm. These compounds are relatively air stable. PMID- 23037690 TI - Cobalt(II) fluorophosphate frameworks. AB - Nine new cobalt fluorophosphates frameworks have been synthesised hydrothermally in a fluoride-rich medium, through the use of CoF(3) and HPF(6) as reactants in combination with Group I/II metal hydroxides and organic cations as templating species. Products have been structurally characterised using single crystal X-ray diffraction. Reaction in fluoride-rich conditions produces chain, layer and three dimensional framework structures containing new and unusual structural features based on the linking of PO(3)F, PO(2)(OH,F)(2) and Co(O,F)(n) polyhedra (n = 5-6) including MU(2), MU(3) and MU(4) bridging fluoride. Structures exhibiting inter layer spaces and channels frequently have these lined by terminal fluoride anions of the PO(3)F, PO(2)(OH,F)(2) and Co(O,F)(n) polyhedra. PMID- 23037692 TI - [Importance of the studies on the drug actions to the mitochondria for the future drug development]. PMID- 23037691 TI - A goodness-of-fit test for the proportional odds regression model. AB - We examine goodness-of-fit tests for the proportional odds logistic regression model-the most commonly used regression model for an ordinal response variable. We derive a test statistic based on the Hosmer-Lemeshow test for binary logistic regression. Using a simulation study, we investigate the distribution and power properties of this test and compare these with those of three other goodness-of fit tests. The new test has lower power than the existing tests; however, it was able to detect a greater number of the different types of lack of fit considered in this study. Moreover, the test allows for the results to be summarized in a contingency table of observed and estimated frequencies, which is a useful supplementary tool to assess model fit. We illustrate the ability of the tests to detect lack of fit using a study of aftercare decisions for psychiatrically hospitalized adolescents. The test proposed in this paper is similar to a recently developed goodness-of-fit test for multinomial logistic regression. A unified approach for testing goodness of fit is now available for binary, multinomial, and ordinal logistic regression models. PMID- 23037693 TI - [Mitochondria as targets of chemotherapy]. AB - Living organisms have developed a wide variety of energy metabolism to survive within the specialized environments. There is a remarkable diversity in mitochondrial electron transport system, which might be potential targets for chemotherapy. Atovaquone, clinically used to treat malaria and pneumocystis pneumonia, is a specific inhibitor of Qo site in the cytochrome bc(1) complex of Plasmodium falciparum and Pneumocystis jirovecii. Phytopathogenic fungus, Ascochyta viciae produces two antibiotics, ascochlorin and ascofuranone. Ascochlorin specifically binds to inhibit the electron transport of both Qi and Qo sites in cytochrome bc(1) complex. Besides the unique respiratory inhibition, further investigation is in progress to elucidate the effects on cancer cells. On the other hand, ascofuranone specifically inhibits cyanide-insensitive trypanosome alternative oxidase, which is a sole terminal oxidase in the mitochondrion of Trypanosoma brucei, causative of African trypanosomiasis. In vivo study suggests that ascofuranone is a promising candidate for chemotherapeutic agents to treat African trypanosomiasis. PMID- 23037694 TI - [The mechanisms of the release of cytochrome C from mitochondria revealed by proteomics analysis]. AB - Mitochondrial permeability transition (PT) is the phenomenon in which the mitochondrial inner membrane becomes permeable to various solutes and ions. When PT is induced by Ca(2+), cytochrome c is released from mitochondria into the cytosol where it then triggers subsequent steps of programmed cell death, apoptosis. Thus, the proteins that regulate PT and cytochrome c release could become druggable targets for various diseases. However, the mechanisms of PT and the release of cytochrome c have not yet been revealed. We previously showed that valinomycin, a potassium selective ionophore, also caused release of cytochrome c from mitochondria without inducing PT. This result indicates that cytochrome c could be released from mitochondria with or without induction of PT. In this study, to understand the difference of effects of valinomycin and Ca(2+) on mitochondria, we examined what protein species are released from valinomycin- and Ca(2+)-treated mitochondria by LC-MS/MS. As a result, only the proteins located in the intermembrane space were found to be released from valinomycin-treated mitochondria, while those in both the intermembrane space and in the matrix were released from Ca(2+)-treated mitochondria. Furthermore, the protein releases by each reagent occurred not selectively but in a concentration-dependent manner. Based on these results, the permeabilization effects of Ca(2+) and valinomycin on the inner and outer mitochondrial membranes are discussed. PMID- 23037695 TI - [Function of DJ-1 in mitochondria]. AB - Parkinson's disease is a degenerative disorder of the central nervous system caused by selective dopamine-generating cell death, and oxidative stress and mitochondrial dysfunction are thought to be responsible for the onset of Parkinson's disease. While most cases of Parkinson's disease are idiopathic, 5 10% of cases are attributed to genetic factors. DJ-1 was first identified as an activated ras-dependent oncogene and later found to be a causative gene for a familial form of Parkinson's disease, PARK7. We and others found that DJ-1 plays roles in transcriptional regulation and anti-oxidative stress function, and loss of its function is thought to affect the onset of Parkinson's disease. DJ-1 is mainly located in the cytoplasma and nucleus and partially in mitochondria. When mice or mouse cells were treated with bisphenol A, an endocrine disruptor and inducer of reactive oxygen species, DJ-1 was translocated into mitochondria to maintain mitochondrial complex I activity. We also found that DJ-1 directly bound to and was co-localized with NDUFA4 and ND1, nuclear and mitochondrial DNA encoding subunits of mitochondrial complex I, respectively, and that these associations were enhanced by oxidative stress. Furthermore, complex I activity was reduced in two types of DJ-1-knockdown NIH3T3 and HEK293 cells. These findings suggest that DJ-1 is an integral mitochondrial protein and maintains mitochondrial complex I activity to regulate mitochondrial homeostasis. PMID- 23037696 TI - [Targeting mitochondria: innovation from mitochondrial drug delivery system (DDS) to mitochondrial medicine]. AB - Mitochondrial dysfunction has been implicated in a variety of human diseases, including cancer and neurodegenerative disorders. Effective medical therapies for such diseases will ultimately require the targeted delivery of therapeutic agents to mitochondria. This will likely be achieved through innovations in the areas of the nanotechnology of intracellular trafficking. Mitochondrial delivery systems for a variety of cargoes have been repored to date. However, only a limited number of approaches are available for delivering macromolecules directly to mitochondria. We previously reported on the construction of a MITO-Porter, a liposome-based carrier that introduces macromolecular cargos into mitochondria via membrane fusion. Using the green fluorescence protein as a model macromolecule in conjunction with analysis by confocal laser scanning microscopy, we were able to confirm the mitochondrial delivery of a macromolecule by the MITO Porter. Moreover, we reported that the Dual Function MITO-Porter (DF-MITO-Porter) could efficiently deliver cargo to mitochondria, through endosomal and mitochondrial membranes via step-wise membrane fusion. Here, We will present our findings on the development of our mitochondrial drug delivery system, and discuss our attempts regarding mitochondrial gene delivery and therapy. Finally, We will discuss the potential use of mitochondrial drug delivery systems in mitochondrial medicine. PMID- 23037697 TI - [Development and application of high-sensitive determination methods for bio related compounds]. AB - This review summarizes the results that were obtained by the author at School of Pharmaceutical Sciences and Graduate School of Biomedical Sciences, Nagasaki University with many co-authors as a memoir upon the author's retirement. The author has studied the development and application of sensitive determination methods for bio-related compounds mainly using fluorescence and/or chemiluminescence as the detection tool in instrumental analysis. As the most interesting bio-related compounds, the author mainly selected drugs of abuse and determined their presence in biological samples such as hair and urine. Also, the author focused on the development of new analytical reagents such as fluorescent and chemiluminescent reagents. Some of these were very useful and became commercially available. I hope that the developed methods would be useful and helpful in the pharmaceutical and forensic science fields. PMID- 23037698 TI - [Development of versatile oxidation systems based on the design of oxoammonium salts]. AB - Organic nitroxyl radical catalysts have recently attracted great attention because they realize efficient alcohol oxidation under mild and environmentally benign conditions. A representative of this class is 2,2,6,6 tetramethylpiperidine 1-oxyl (TEMPO). We have also developed 2-azaadamantane N oxyls (AZADOs) as highly efficient oxidation catalysts. These nitroxyl radicals are generally oxidized by a cooxidant to generate oxoammonium salts, which are active species for alcohol oxidation. In the oxidation systems presented in this paper, we focus on the differences between these two species in terms of oxidation state and counter anion. Herein, the effects of a counter anion of an oxoammonium species on its reaction selectivity are shown. On the basis of the control of the counter anion, we have developed catalytic oxidative rearrangement of tertiary allylic alcohols to beta-substituted alpha,beta-unsaturated carbonyl compounds. Moreover, we have developed novel useful oxidation systems utilizing a catalytic oxoammonium salt; namely, a one-pot oxidation of primary alcohols to carboxylic acids and an aerobic alcohol oxidation. PMID- 23037699 TI - [Signaling factors in a variety of cells derived from mesenchymal stem cells]. AB - L-Glutamate (Glu) and gamma-aminobutyric acid (GABA) has been thought to be an excitatory/inhibitory amino acid neurotransmitter in the mammalian central nervous system (CNS). Limited information is available in the literature with regard to an extracellular transmitter role of Glu and GABA in peripheral neuronal and non-neuronal tissues, whereas recent molecular biological analyses including ours give rise to a novel function for Glu and GABA as an autocrine and/or paracrine factor in a variety of cells derived from mesenchymal stem cells, in addition to other peripheral tissues including pancreas, adrenal, and pituitary glands. Emerging evidence suggests that Glu and GABA could play a dual role in mechanisms underlying maintenance of cellular homeostasis as a neurotransmitter in the CNS and as an extracellular signal mediator in peripheral autocrine and/or paracrine tissues. In this review, therefore, we summarized the possible signaling by Glu and GABA as an extracellular signal mediator in mechanisms underlying maintenance of cellular homeostasis in mesenchymal stem cells, osteoblasts and chondrocytes. PMID- 23037700 TI - [Development of radiopharmaceuticals for diagnosis and therapy of metastatic bone cancer]. AB - Rhemium-186-1-hydroxyethylidene-1,1-diphosphonate ((186)Re-HEDP) has been used for the palliation of metastatic bone pain. However, delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of (186)Re-HEDP. We designed, synthesized and evaluated a stable (186)Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl] carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) ((186)Re MAG3-HBP). The stability of (186)Re-MAG3-HBP and (186)Re-HEDP in phosphate buffer were compared. No measurable decomposition of (186)Re-MAG3-HBP occurred, while only approximately 30% of (186)Re-HEDP remained intact 24 hours post-incubation. In biodistribution experiments, the radioactivity level of (186)Re-MAG3-HBP in bone was significantly higher than that of (186)Re-HEDP. Blood clearance of (186)Re-MAG3-HBP was faster than that of (186)Re-HEDP. In addition, the gastric accumulation of (186)Re-MAG3-HBP radioactivity was lower. To evaluate the therapeutic effects of (186)Re-MAG3-HBP, an animal model of bone metastasis was prepared. In the rats treated with (186)Re-HEDP, tumor growth was comparable to that in untreated rats. In contrast, when (186)Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Bone pain was attenuated by treatment with (186)Re-MAG3-HBP or (186)Re-HEDP, but (186)Re-MAG3-HBP tended to be more effective. These results indicate that (186)Re-MAG3-HBP could be useful as a therapeutic agent of metastatic bone pain. Moreover, based on the similar concept, we designed, synthesized, and evaluated a (99m)Tc-6-hydrazinopyridine-3 carboxylic acid-conjugated bisphosphonate ((99m)Tc-HYNIC-HBP) as a bone scintigraphic agent. (99m)Tc-HYNIC-HBP gave higher levels of radioactivity in bone than (99m)Tc-HMDP. There was no significant difference in clearance from blood between (99m)Tc-HYNIC-HBP and (99m)Tc-HMDP. Consequently, (99m)Tc-HYNIC-HBP showed a higher bone-to-blood ratio than (99m)Tc-HMDP. The findings indicate that (99m)Tc-HYNIC-HBP holds great potential for bone scintigraphy. PMID- 23037701 TI - [Positron emission tomography (PET) imaging of small interfering RNA (siRNA) delivery in drug development]. AB - Pharmacokinetic studies of nanoparticles have provided significant information by which advanced delivery systems have been designed. On the other hand, pharmacokinetics of RNA interference (RNAi) effectors such as small interfering RNA (siRNA) is poorly understood. We have synthesized [(18)F]-labeled siRNA for a pharmacokinetic study using positron emission tomography (PET). PET is a noninvasive bioimaging modality applicable to a microdosing study that is designed to evaluate pharmacokinetics of drug candidates in human at an early stage of drug development. We have demonstrated that the resulting PET images clearly show the biodistribution of siRNA in mice. Naked [(18)F]-siRNA accumulates in the bladder immediately after intravenous administration due to rapid degradation. [(18)F]-siRNA formulated in cationic liposomes rapidly accumulates in the lungs due to positive surface charge of the cationic liposomes. [(18)F]-siRNA formulated in PEGylated liposomes shows long circulation in the bloodstream. Thus, the biodistribution of [(18)F]-siRNA is reflected by the characteristics of each liposomal biodistribution. Importantly, it has been demonstrated that accumulation of siRNA in tumors is able to be evaluated using [(18)F]-siRNA/PET. In addition, [(18)F]-siRNA/PET is also found to be useful to evaluate the effect of chemical modification of siRNA on its biodistribution. Cholesterol-conjugated [(18)F]-siRNA shows long half-life in the bloodstream and accumulates in the liver compared with naked [(18)F]-siRNA. Our findings indicate that the pharmacokinetic PET study of siRNA provides important insights into the development of RNAi medicine. PMID- 23037702 TI - [Nature of cancer explored from the perspective of the functional evolution of proto-oncogenes]. AB - The products of proto-oncogene play critical roles in the development or maintenance of multicellular societies in animals via strict regulatory systems. When these regulatory systems are disrupted, proto-oncogenes can become oncogenes, and thereby induce cell transformation and carcinogenesis. To understand the molecular basis for development of the regulatory system of proto oncogenes during evolution, we screened for ancestral proto-oncogenes from the unicellular choanoflagellate Monosiga ovata (M. ovata) by monitoring their transforming ability in mammalian cells; consequently, we isolated a Pak gene ortholog, which encodes a serine/threonine kinase as a 'primitive oncogene'. We also cloned Pak orthologs from fungi and the multicellular sponge Ephydatia fluviatilis, and compared their regulatory features with that of M. ovata Pak (MoPak). MoPak is constitutively active and induces cell transformation in mammalian cells. In contrast, Pak orthologs from multicellular animals are strictly regulated. Analyses of Pak mutants revealed that structural alterations in the auto-inhibitory domain (AID) are responsible for the enhanced kinase activity and the oncogenic activity of MoPak. Furthermore, we show that Rho family GTPases-mediated regulatory system of Pak kinase is conserved throughout the evolution from unicellular to multicellular animals, but the MoPak is more sensitive to the Rho family GTPases-mediated activation than multicellular Pak. These results show that maturation of AID function was required for the development of the strict regulatory system of the Pak proto-oncogene, and support the potential link between the development of the regulatory system of proto-oncogenes and the evolution of multicellularity. Further analysis of oncogenic functions of proto-oncogene orthologs in the unicellular genes would provide some insights into the mechanisms of the destruction of multicellular society in cancer. PMID- 23037703 TI - [The development of appropriate dosage of anti-bacterial and anti-fungal agents based on pharmacokinetics and pharmacodynamics]. AB - An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum concentration for the treatment of methicillin resistant Staphylococcus aureus (MRSA). The mean trough concentrations were 13.2 mg/L for patients with eradication of MRSA. I showed that the administration of >=36 mg/kg during the first 3 days was effective in promptly obtaining a trough concentration target of >=13 mg/L for the initial treatment of MRSA infections. The major adverse effect associated with linezolid treatment is reversible myelosuppression, primarily thrombocytopenia. I demonstrated that the incidence of linezolid-induced thrombocytopenia was higher among patients with renal failure than in patients with normal renal function. A statistically significant (p<0.01) and strong correlation (r=0.933) was observed between linezolid and creatinine clearance. A negative correlation (r=-0.567) was also shown between linezolid clearance and blood urea nitrogen. Voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity. Logistic regression analysis revealed that the therapeutic range for the voriconazole trough concentration should be 2-4 mg/L. Nonlinear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9 mg/kg/day for CYP2C19 wild type and 4.4-6.5 mg/kg/day for the non-wild type in patients. Anaemia and thrombocytopenia are major side effects of liposomal amphotericin B. I demonstrated that the doses of liposomal amphotericin B estimated to cause side effects of a low red blood cell count, anaemia and thrombocytopenia with 50% probability are 4.0, 3.3 and 3.0 mg/kg/day, respectively. PMID- 23037704 TI - [Adaptation of peer evaluation to small group discussion (SGD) and its validity for summative evaluation]. AB - We adopted peer evaluation (mutual evaluation between students) for small group discussion (SGD) among first graders. The peer evaluation criteria were 5 grade scales for 5 fields: "preparation," "remark," "listening," "activeness," and "role." A comparison with tutor evaluation clarified the validity of peer evaluation for summative evaluation. Although the average of peer evaluation (4.2 (4.0-4.4)) was higher than that of tutor evaluation (3.8 (3.7-4.1)) (p=0.0601, Mann-Whitney U test), the value of the correlation coefficient between peer evaluation and summative evaluation of SGD (average 0.35 (0.12-0.54)) was almost the same as that of the coefficient between tutor evaluation and summative evaluation of SGD (average 0.36 (0.24-0.42)) (p=0.6761, Mann-Whitney U test). Principal component analysis showed that the tutor could not evaluate "remark" and "listening" independently, while students evaluate "listening" independently from other evaluation criteria. The combination of peer and tutor evaluation may be multilateral evaluation for SGD. The questionnaire about peer evaluation for students showed that they recognized the value of peer evaluation and favorably accepted its use. PMID- 23037705 TI - [An attempt to degradation of anticancer drug and odor in the medical environment by photocatalyst]. AB - Currently, there is a need to reduce the occupational exposure of health care workers to anticancer drugs. Environmental contamination by anticancer drugs and subsequent exposure of health care workers are associated with vaporization of anticancer drugs. Furthermore, carcinomatous unpleasant odor is an additional problem to vaporized anticancer drugs in the field of clinical cancer therapy. We attempted to degrade vaporized anticancer drug and unpleasant odor using a photocatalyst. Cyclophosphamide or unpleasant odors (ammonia, formaldehyde, isovaleric acid, and butyric acid) were vaporized by heating in a closed chamber. Plates of photocatalyst coated with titanium dioxide were placed into the chamber and irradiated by light source. Vaporized cyclophosphamide in the chamber was recovered by bubbling the internal air through acetone and derivatized by trifluoroacetic anhydride for analysis by gas chromatographic-mass spectrometric assay. Vaporized odors were determined using a gas-detector tube, which changed color depending on the concentration. Following activation of the photocatalyst by a light source, the residual amounts of anticancer drug and unpleasant odor components were significantly decreased compared with when the photocatalyst was not activated without a light source. These results indicate that the photocatalysts can accelerate the degradation of vaporized anticancer drugs and odor components. Air-cleaning equipment using a photocatalyst is expected to be useful in improving the QOL of cancer patients experiencing carcinomatous unpleasant odor, and in reducing occupational exposure of health care workers to anticancer drugs. PMID- 23037706 TI - [Examination of analytical method for triphenyltin (TPT) and tributyltin (TBT) to revise the official methods based on "Act on the Control of Household Products Containing Harmful Substances"]. AB - The use of triphenyltin (TPT) and tributyltin (TBT) in some household products is banned by "Act on the Control of Household Products Containing Harmful Substances" in Japan. To revise the official analytical method, the method for detecting these organotin compounds was examined in six laboratories using a textile product, water-based adhesive, oil-based paint, which contained known amounts of TPT and TBT (0.1, 1.0, 10 MUg/g). TPT and TBT were measured by GC-MS after ethyl-derivation with sodium tetraethylborate. The TBT recoveries in the samples were 70-120%. The TPT recoveries in the water-based adhesive samples were 80-110%, while its concentrations in the textile product and oil-based paint samples decreased because of dephenylation during storage. However, the precision of the method examined was satisfactory because most coefficients of variation for TPT and TBT in the samples were less than 10%. Furthermore, the revised method was able to detect concentrations lower than the officially regulated value. However, the sample matrix and the condition of analytical instrument might affect the estimated TPT and TBT concentrations. Therefore, the revised method may not be suitable for quantitative tests; rather, it can be employed to judge the acceptable levels of these organotin compounds by comparing the values of control sample containing regulated amounts of TPT and TBT with those for an unknown sample, with deuterated TPT and TBT as surrogate substances. It is desirable that TPT in textile and oil-based paint samples are analyzed immediately after the samples obtained because of the decomposition of TPT. PMID- 23037707 TI - One-step synthesis of 1-halo-1,3-butadienes via ruthenium-catalysed hydrohalogenative dimerisation of alkynes. AB - An efficient, novel and direct access to 1-halo-1,3-butadienes is developed. This stereoselective ruthenium-catalysed reaction proceeds under mild conditions via the head-to-head oxidative coupling of two alkynes and a concomitant hydrohalogenation. PMID- 23037709 TI - Rapid and highly selective dipchecking for cyanide ions in aqueous media. AB - This article reports a simple dipping method for the detection of cyanide ions in water and biological samples, such as blood, using chitosan-gold nanoparticle (CH Au NP) composite films prepared using CH-Au NP colloids. Here, gold nanoparticles were generated by heating (to ~80 degrees C) a solution of chitosan and gold chloride, where chitosan plays the dual role of reducing and stabilizing agent. The well-known chemistry of leaching of gold by cyanide is exploited here to detect cyanide ions. The CH-Au films showed the localized surface plasmon resonance (LSPR) absorption, similar to the CH-Au colloidal solution, at 534 nm. Gold nanoparticles (Au NPs) in the films are found to be dissolved quantitatively, causing a proportional decrease in intensity of the LSPR peak. Color change was observable by the naked eye above a concentration of 2 mg L(-1) of CN(-) in solution. We found a good correlation between the reduction in intensity of the absorption peak at 534 nm and concentrations of CN(-) ions as low as 0.06 mg L(-1). Most of the previously reported methods for cyanide detection involve tedious chemistry, demand the use of sophisticated instruments and still are not suitable for on-site cyanide monitoring. Our reported approach is rapid, eco-friendly, low cost, easy to use, and highly selective for cyanide detection in aqueous solution. We feel that this simple, low cost, novel and portable method is suitable particularly for third world countries, where more sophisticated aids are not so common. PMID- 23037710 TI - Expert opinion: should coronary CT angiography be used as a screening test? PMID- 23037711 TI - Monogenic diabetes mellitus due to defects in insulin secretion. AB - Monogenic forms of diabetes mellitus cover a heterogeneous group of diabetes which are uniformly caused by a single gene mutation and are characterised by impaired insulin secretion of the pancreatic beta cell. It is estimated that they account for up to 5% of all cases of diabetes mellitus, which are often not diagnosed or are misclassified as type 1 or 2 diabetes. However, accurate diagnosis is important because of the special implications for treatment, prognosis and family risk. The knowledge of typical clinical features such as mode of inheritance, age at diagnosis and impaired insulin secretion, as well as genetic testing establishes the diagnosis of MODY, mitochondrial diabetes and neonatal diabetes. PMID- 23037712 TI - Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients. AB - BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial. PMID- 23037713 TI - The FOXM1-PLK1 axis is commonly upregulated in oesophageal adenocarcinoma. AB - BACKGROUND: The transcription factor FOXM1 is an important regulator of the cell cycle through controlling periodic gene expression during the G2 and M phases. One key target for FOXM1 is the gene encoding the protein kinase PLK1 and PLK1 itself acts in a positive feedback loop to phosphorylate and activate FOXM1. Both FOXM1 and PLK1 have been shown to be overexpressed in a variety of different tumour types. METHODS: We have used a combination of RT-PCR, western blotting, tissue microarrays and metadata analysis of microarray data to study whether the FOXM1-PLK1 regulatory axis is upregulated and operational in oesophageal adenocarcinoma. RESULTS: FOXM1 and PLK1 are expressed in oesophageal adenocarcinoma-derived cell lines and demonstrate cross-regulatory interactions. Importantly, we also demonstrate the concomitant overexpression of FOXM1 and PLK1 in a large proportion of oesophageal adenocarcinoma samples. This co-association was extended to the additional FOXM1 target genes CCNB1, AURKB and CKS1. In a cohort of patients who subsequently underwent surgery, the expression of several FOXM1 target genes was prognostic for overall survival. CONCLUSIONS: FOXM1 and its target gene PLK1 are commonly overexpressed in oesophageal adenocarcinomas and this association can be extended to other FOXM1 target genes, providing potentially important biomarkers for predicting post-surgery disease survival. PMID- 23037714 TI - International multicentre study examining selection criteria for active surveillance in men undergoing radical prostatectomy. AB - BACKGROUND: The controversies concerning possible overtreatment of prostate cancer, highlighted by debate over PSA screening, have highlighted active surveillance (AS) as an alternative management option for appropriate men. Regional differences in the underlying prevalence of PSA testing may alter the pre-test probability for high-risk disease, which can potentially interfere with the performance of selection criteria for AS. In a multicentre study from three different countries, we examine men who were initially suitable for AS according to the Toronto and Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, that underwent radical prostatectomy (RP) in regards to:1.the proportion of pathological reclassification(Gleason score >=7, >=pT3 disease),2.predictors of high-risk disease,3.create a predictive model to assist with selection of men suitable for AS. METHODS: From three centres in the United Kingdom, Canada and Australia, data on men who underwent RP were retrospectively reviewed (n=2329). Multivariable logistic regression was performed to identify predictors of high-risk disease. A nomogram was generated by logistic regression analysis, and performance characterised by receiver operating characteristic curves. RESULTS: For men suitable for AS according to the Toronto (n=800) and PRIAS (410) criteria, the rates for upgrading were 50.6, 42.7%, and upstaging 17.6, 12.4%, respectively. Significant predictors of high-risk disease were:*Toronto criteria: increasing age, cT2 disease, centre of diagnosis and number of positive cores.*PRIAS criteria: increasing PSA and cT2 disease.Cambridge had a high pT3a rate (26 vs 12%). To assist selection of men in the United Kingdom for AS, from the Cambridge data, we generated a nomogram predicting high-risk features in patients who meet the Toronto criteria (AUC of 0.72). CONCLUSION: The proportion of pathological reclassification in our cohort was higher than previously reported. Care must be used when applying the AS criteria generated from one population to another. With more stringent selection criteria, there is less reclassification but also fewer men who may benefit from AS. PMID- 23037715 TI - Ligand-independent activation of EphA2 by arachidonic acid induces metastasis like behaviour in prostate cancer cells. AB - BACKGROUND: High intake of omega-6 polyunsaturated fatty acids (PUFA) has been associated with clinical progression in prostate cancer (CaP). This study investigates the signalling mechanism by which the omega-6 PUFA arachidonic acid (AA) induces prostatic cellular migration to bone marrow stroma. METHODS: Western blot analysis of the PC-3, PC3-GFP, DU 145 and LNCaP cells or their lipid raft (LR) components post AA stimulation was conducted in association with assays for adhesion and invasion through the bone marrow endothelial monolayers. RESULTS: Arachidonic acid increased transendothelial migration of PC3-GFP cells (adhesion 37%+/-0.08, P=0.0124; transmigration 270%+/-0.145, P=0.0008). Akt, Src and focal adhesion kinase (FAK) pathways were induced by AA and integrally involved in transendothelial migration. LR were critical in AA uptake and induced Akt activity. Ephrin receptor A2 (EphA2), localised in LR, is expressed in DU 145 and PC-3 cells. Arachidonic acid induced a rapid increase of EphA2 Akt dependent/ligand-independent activation, while knockdown of the EphrinA1 ligand decreased AA induced transendothelial migration, with an associated decrease in Src and FAK activity. Arachidonic acid activated Akt in EphA2(-) LNCaP cells but failed to induce BMEC transendothelial invasion. CONCLUSION: Arachidonic acid induced stimulation of EphA2 in vitro is associated fundamentally with CaP epithelial migration across the endothelial barrier. PMID- 23037717 TI - Cost and logistics of alternative roll-out options for implementing human papillomavirus testing as a triage in cervical screening: results of the sentinel sites study. AB - BACKGROUND: Previous studies have indicated that human papillomavirus (HPV) testing as a triage for managing equivocal cytology is cost-effective. The aim of this study was to assess the costs of alternative roll-out options. METHODS: Detailed cost estimates were collected from six laboratories where HPV triage had been implemented. Costs were assessed for the two different service delivery models that were implemented; a 'hub and spoke model' of central HPV testing in a microbiology laboratory with separate cytology laboratories, and an 'integrated model' where HPV testing was conducted within the cytology laboratory. RESULTS: Comparison of alternative delivery models indicated that setting up HPV processing within existing cytology laboratory, i.e., an 'integrated cytology/HPV laboratory' generated savings in staff time amounting to between L2.54 and 4.86 per sample processed. Running full HPV testing batches was also an important consideration. For full batches to be run on a twice weekly basis requires having no more than two laboratories per Strategic Health Authority. CONCLUSIONS: To be cost-efficient, and to meet turn-around times, HPV testing needs to be conducted at integrated cytology/HPV testing centres with sufficient throughput to run full batches of HPV tests. PMID- 23037716 TI - Paclitaxel and CYC3, an aurora kinase A inhibitor, synergise in pancreatic cancer cells but not bone marrow precursor cells. AB - BACKGROUND: Amplification of aurora kinase A (AK-A) overrides the mitotic spindle assembly checkpoint, inducing resistance to taxanes. RNA interference targeting AK-A in human pancreatic cancer cell lines enhanced taxane chemosensitivity. In this study, a novel AK-A inhibitor, CYC3, was investigated in pancreatic cancer cell lines, in combination with paclitaxel. METHODS: Western blot, flow cytometry and immunostaining were used to investigate the specificity of CYC3. Sulforhodamine B staining, time-lapse microscopy and colony-formation assays were employed to evaluate the cytotoxic effect of CYC3 and paclitaxel. Human colony forming unit of granulocyte and macrophage (CFU-GM) cells were used to compare the effect in tumour and normal tissue. RESULTS: CYC3 was shown to be a specific AK-A inhibitor. Three nanomolar paclitaxel (growth inhibition 50% (GI(50)) 3 nM in PANC-1, 5.1 nM in MIA PaCa-2) in combination with 1 MUM CYC3 (GI(50) 1.1 MUM in MIA PaCa2 and 2 MUM in PANC-1) was synergistic in inhibiting pancreatic cell growth and causing mitotic arrest, achieving similar effects to 10-fold higher concentrations of paclitaxel (30 nM). In CFU-GM cells, the effect of the combination was simply additive, displaying significantly less myelotoxicity compared with high concentrations of paclitaxel (30 nM; 60-70% vs 100% inhibition). CONCLUSION: The combination of lower doses of paclitaxel and CYC3 merits further investigation with the potential for an improved therapeutic index in vivo. PMID- 23037719 TI - The beta-2 agonist debate: is there still a problem? AB - PURPOSE OF REVIEW: To present an evidence-based review of the US Food and Drug Administration (FDA) recommendations for long-acting beta agonist (LABA) use in asthma. RECENT FINDINGS: The FDA recommendation contraindicating the use of LABAs without a concomitant asthma-controller medication such as an inhaled corticosteroid (ICS) is supported, with the caveat that concomitant use of an asthma-controller medication applies only to ICS therapy and not other asthma controller medications (such as leukotriene receptor antagonist therapy or theophylline). The recommendation that LABA therapy be stopped once asthma control is achieved is restrictive. Although downtitration of therapy should be considered in patients with asthma, who are well controlled, other options such as reducing the dose of ICS may be preferable to stopping LABA therapy. In patients who are at risk of unstable asthma or severe exacerbations, maintaining the ICS/LABA therapy without downtitration may be required. The recommendation against LABA use in patients whose asthma is adequately controlled with a low or medium dose ICS is supported. The recommendation that fixed-dose combination ICS/LABA products should be the only form in which LABAs are prescribed in adolescents and paediatric patients should be extended to all asthma patients. SUMMARY: The current beta agonist debate focuses on the optimal management approaches for the use of LABA therapy to both minimize risk and maximize clinical efficacy. PMID- 23037718 TI - Changing views on intergenerational ties. AB - Ties to parents or grown children may be the most important social relationships in an adult's life. Research examining intergenerational relationships has focused on three broader topics: (a) the strength of emotional bonds, (b) exchanges of social support, and (c) the effects of the relationship on individual well-being. This review considers some of the major theoretical developments in the field including solidarity and intergenerational ambivalence theory as well as the newly developed multidimensional model of support. We also consider weaknesses in the research and theories to date and provide suggestions for future research. PMID- 23037720 TI - [Differential diagnosis between aplastic anemia and hypoplastic myelodysplastic syndromes: from the viewpoint of pediatrics]. PMID- 23037721 TI - [Differential diagnosis between aplastic anemia and myelodysplastic syndromes: from the viewpoint of internal medicine]. PMID- 23037722 TI - [Disease stage-adapted treatment strategy for aplastic anemia]. PMID- 23037723 TI - [Risk-stratified treatment strategy for myelodysplastic syndromes]. PMID- 23037724 TI - [Pathophysiology and management of paroxysmal nocturnal hemoglobinuria]. PMID- 23037725 TI - [Treatment strategy for adult acute lymphoblastic leukemia]. PMID- 23037726 TI - [Treatment strategy for childhood acute lymphoblastic leukemia]. PMID- 23037727 TI - [Molecular pathophysiology and diagnosis of acute myeloid leukemia]. PMID- 23037728 TI - [Current treatment of acute myeloid leukemia]. PMID- 23037729 TI - [Standard therapy for chronic myelogenous leukemia]. PMID- 23037730 TI - [Chronic myelogenous leukemia: management of treatment-related adverse events]. PMID- 23037731 TI - [Molecular pathophysiology and treatment overview of PV, ET and PMF]. PMID- 23037732 TI - [JAK2 inhibitors in the treatment of myeloproliferative neoplasms]. PMID- 23037733 TI - [Pathological diagnosis of Hodgkin lymphoma]. PMID- 23037734 TI - [Standard therapy and research questions in Hodgkin lymphoma]. PMID- 23037735 TI - [Standard therapy and research questions in follicular lymphoma]. PMID- 23037736 TI - [Standard therapy and research questions in diffuse large B-cell lymphoma]. PMID- 23037737 TI - [Molecular and cytogenetic heterogeneity of diffuse large B-cell lymphoma]. PMID- 23037738 TI - [Recent progress in research on pathophysiology and therapy for NK/T-cell lymphoma]. PMID- 23037739 TI - [Development of novel therapeutic agents for adult T-cell leukemia-lymphoma]. PMID- 23037740 TI - [Standard therapy for multiple myeloma]. PMID- 23037741 TI - [Complications and their management in multiple myeloma patients: bone disease, renal impairment and peripheral neuropathy]. PMID- 23037742 TI - [Trends in development of novel therapeutic agents for multiple myeloma]. PMID- 23037743 TI - [Heparin-induced thrombocytopenia: HIT]. PMID- 23037744 TI - [Diagnosis and treatment of disseminated intravascular coagulation]. PMID- 23037745 TI - [Environment of evacuation facility and deep vein thrombosis in the Great East Japan Earthquake]. PMID- 23037746 TI - [Overview of current treatment for hemophilia: needs of tailor-made treatment]. PMID- 23037747 TI - [Pitfalls in management of infectious complications after hematopoietic cell transplantation]. PMID- 23037748 TI - [Histopathological diagnosis of the complications after hematopoietic stem cell transplantation]. PMID- 23037749 TI - [Immunotherapy for hematological neoplasms]. PMID- 23037750 TI - [Trends in development of molecular targeted therapy for hematological neoplasms]. PMID- 23037751 TI - [Transfusion-related acute lung injury: TRALI]. PMID- 23037752 TI - [Severe infections associated with hematological diseases]. PMID- 23037753 TI - [Management for reactivation of hepatitis B virus following systemic chemotherapy]. PMID- 23037754 TI - [Regulatory aspect of regenerative medicine/cell therapy: focused on non-clinical studies]. PMID- 23037755 TI - [How to read scientific papers on clinical studies: focused on statistics]. PMID- 23037756 TI - [History and perspectives of leukemia stem cell research]. PMID- 23037757 TI - [Hematopoietic stem cell niche]. PMID- 23037758 TI - [Progress in xenotransplantation model for human hematopoietic stem cell assay]. PMID- 23037759 TI - [Development and differentiation systems of lymphocyte]. PMID- 23037760 TI - [Telomere dysfunction in cancer progression]. PMID- 23037761 TI - [Newly discovered roles for basophils in allergy and protective immunity: a neglected minority gains new respect]. PMID- 23037762 TI - [Hematological diseases and induced pluripotent stem (iPS) cells]. PMID- 23037763 TI - [Genetic diagnosis and treatment for primary immunodeficiency]. PMID- 23037764 TI - [Epstein-Barr virus and hematological neoplasms]. PMID- 23037765 TI - [Long-term effects of low dose radiation exposure on health]. PMID- 23037766 TI - A switchable two-photon membrane tracer capable of imaging membrane-associated protein tyrosine phosphatase activities. AB - When I look into your cells: a two-photon dye (Flu7) was developed, which strongly fluoresces only upon selective binding to the plasma membrane of mammalian cells. Upon addition of a UV- and phosphatase-controlled quencher (Q12), the system exhibits ON/OFF/ON fluorescence switching and can be used to image membrane-associated receptor-like protein tyrosine phosphatase (RPTP) activity. PMID- 23037767 TI - Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer. AB - PURPOSE: In a substantial population of non-small cell lung cancer (NSCLC), expression and activation of EGF receptor (EGFR) have been reported and is regarded as a novel molecular target. A growing body of evidence has shown the signaling crosstalk between EGFR and integrins in cellular migration and invasion. NEDD9 is an integrin signaling adaptor protein composed of multiple domains serving as substrate for a variety of tyrosine kinases. In the present study, we aimed at elucidating a role of NEDD9 in the signaling crosstalk between EGFR and integrins. EXPERIMENTAL DESIGN: Using NSCLC cell lines, we conducted immunoblotting and cellular migration/invasion assay in vitro. Next, we analyzed metastasis assays in vivo by the use of xenograft transplantation model. Finally, we retrospectively evaluated clinical samples and records of patients with NSCLCs. RESULTS: We showed that tyrosine phosphorylation of NEDD9 was reduced by the inhibition of EGFR in NSCLC cell lines. Overexpression of constitutively active EGFR caused tyrosine phosphorylation of NEDD9 in the absence of integrin stimulation. By gene transfer and gene knockdown, we showed that NEDD9 plays a pivotal role in cell migration and invasion of those cells in vitro. Furthermore, overexpression of NEDD9 promoted lung metastasis of an NSCLC cell line in NOD/Shi scid, IL-2Rgamma(null) mice (NOG) mice. Finally, univariate and multivariate Cox model analysis of NSCLC clinical specimens revealed a strong correlation between NEDD9 expression and recurrence-free survival as well as overall survival. CONCLUSION: Our data thus suggest that NEDD9 is a promising biomarker for the prognosis of NSCLCs and its expression can promote NSCLC metastasis. PMID- 23037768 TI - Efficacy and anticarcinogenic activity of ribavirin combination therapy for hepatitis C virus-related compensated cirrhosis. AB - OBJECTIVE: Anticarcinogenic activity of ribavirin combination therapy for hepatitis C virus (HCV)-related compensated cirrhosis is still unclear. METHODS: In study 1, in 157 consecutive patients with HCV-related compensated cirrhosis, treatment efficacy with interferon plus ribavirin therapy was evaluated for 48 weeks of HCV genotype 1b (HCV-1b) or 24 weeks of HCV-2a/2b. In study 2, in 185 consecutive patients with HCV-related compensated cirrhosis, who showed no sustained virological response following the first course of interferon monotherapy, hepatocarcinogenesis rates were evaluated according to the additional treatment, and they were classified into three groups: no treatment, interferon monotherapy, and ribavirin combination therapy. RESULTS: In study 1, in HCV-1b, rates of sustained virological response and sustained biochemical response were 21 and 56%, respectively. In HCV-2a/2b, rates of sustained virological response and sustained biochemical response were 70 and 78%, respectively. In HCV-1b, sustained biochemical response rates were significantly higher than those of sustained virological response. In study 2, the hepatocarcinogenesis rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy and no treatment, respectively. CONCLUSION: Ribavirin combination therapy for HCV-related compensated cirrhosis reduces the risk of hepatocarcinogenesis in comparison with interferon monotherapy, and higher rates of sustained biochemical response might be associated with lower hepatocarcinogenesis rates. PMID- 23037769 TI - Inversion of axial chirality in coordinated bis-beta-diketonato ligands. AB - Mononuclear and dinuclear ruthenium(III) complexes with bis-beta-diketonato ligands (denoted by [Ru(acac)(2)(L-LH)] and [Ru(acac)(2)(L-L)Ru(acac)(2)], respectively) were synthesized, where acac, L-LH(-) and L-L(2-) denote acetylacetonato, monoprotonated and unprotonated bis-beta-diketonato ligands, respectively. The following three ligands were used as the bis-beta-diketonato ligand (L-L(2-)): 1,2-diacetyl-1,2-dibenzoylethanato (denoted by dabe(2-)), 1,2 diacetyl-1,2-bis(3-methylbutanoyl)ethanato (baet(2-)) and 1,2-diacetyl-1,2 dipropanoylethanato (dpe(2-)). For the mononuclear and the meso-type dinuclear complexes, a pair of diastereomeric species were identified as Delta- (or Lambda ) [Ru(acac)(2)(R- or S-L-LH)] and [Delta-Ru(acac)(2)(R- or S-L-L)Lambda Ru(acac)(2)], respectively. The possibility of thermal inversion in coordinated L LH(-) (mononuclear) or L-L(2-) (dinuclear) was pursued by monitoring the changes in the electronic circular dichroism or the (1)H NMR spectra. No inversion occurred for the dinuclear complexes, when their chloroform solutions were kept at 50 degrees C for ca. 100 h. In contrast, some of the mononuclear complexes underwent the inversion of axial chirality to give an equilibrium mixture under the same conditions. The reaction followed the first-order rate law and the overall first-order rate constants (k) of [Ru(acac)(2)(L-LH)] were determined to be k = 0.13, 0.0048 and less than 0.001 h(-1) for L-LH(-) = dabeH(-), baetH(-) and dpeH(-), respectively. The results suggest that the main factor determining the barrier height of the internal rotation is not the steric but the electronic properties of the carbon-carbon bond connecting the two beta-diketonato moieties. PMID- 23037770 TI - Dynamic behaviors of memristor-based recurrent neural networks with time-varying delays. AB - The paper introduces a general class of memristor-based recurrent neural networks with time-varying delays. Conditions on the nondivergence and global attractivity are established by using local inhibition, respectively. Moreover, exponential convergence of the networks is studied by using local invariant sets. The analysis in the paper employs results from the theory of differential equations with discontinuous right-hand sides as introduced by Filippov. The obtained results extend some previous works on conventional recurrent neural networks. PMID- 23037771 TI - Complete stability of cellular neural networks with unbounded time-varying delays. AB - In this paper, we are concerned with the delayed cellular neural networks (DCNNs) in the case that the time-varying delays are unbounded. Under some conditions, it shows that the DCNNs can exhibit 3(n) equilibrium points. Then, we track the dynamics of u(t)(t>0) in two cases with respect to different types of subset regions in which u(0) is located. It concludes that every solution trajectory u(t) would converge to one of the equilibrium points despite the time-varying delays, that is, the delayed cellular neural networks are completely stable. The method is novel and the results obtained extend the existing ones. In addition, two illustrative examples are presented to verify the effectiveness of our results. PMID- 23037772 TI - Generalized locality preserving Maxi-Min Margin Machine. AB - Research on large margin classifiers from the "local" and "global" view has become an active topic in machine learning and pattern recognition. Inspired from the typical local and global learning machine Maxi-Min Margin Machine (M4) and the idea of the Locality Preserving Projections (LPP), we propose a novel large margin classifier, the Generalized Locality Preserving Maxi-Min Margin Machine (GLPM), where the within-class matrices are constructed using the labeled training points in a supervised way, and then used to build the classifier. The within-class matrices of GLPM preserve the intra-class manifold in the training sets, as well as the covariance matrices which indicate the global projection direction in the M4 model. Moreover, the connections among GLPM, M4 and LFDA are theoretically analyzed, and we show that GLPM can be considered as a generalized M4 machine. The GLPM is also more robust since it requires no assumption on data distribution while Gaussian data distribution is assumed in the M4 machine. Experiments on data sets from the machine learning repository demonstrate its advantage over M4 in both local and global learning performance. PMID- 23037773 TI - Output feedback direct adaptive neural network control for uncertain SISO nonlinear systems using a fuzzy estimator of the control error. AB - A direct adaptive control algorithm, based on neural networks (NN) is presented for a class of single input single output (SISO) nonlinear systems. The proposed controller is implemented without a priori knowledge of the nonlinear systems; and only the output of the system is considered available for measurement. Contrary to the approaches available in the literature, in the proposed controller, the updating signal used in the adaptive laws is an estimate of the control error, which is directly related to the NN weights instead of the tracking error. A fuzzy inference system (FIS) is introduced to get an estimate of the control error. Without any additional control term to the NN adaptive controller, all the signals involved in the closed loop are proven to be exponentially bounded and hence the stability of the system. Simulation results demonstrate the effectiveness of the proposed approach. PMID- 23037774 TI - Balanced echo state networks. AB - This paper investigates the interaction between the driving output feedback and the internal reservoir dynamics in echo state networks (ESNs). The interplay is studied experimentally on the multiple superimposed oscillators (MSOs) benchmark. The experimental data reveals a dual effect of the output feedback strength on the network dynamics: it drives the dynamic reservoir but it can also block suitable reservoir dynamics. Moreover, the data shows that the reservoir size crucially co-determines the likelihood of generating an effective ESN. We show that dependent on the complexity of the MSO dynamics somewhat smaller networks can yield better performance. Optimizing the output feedback weight range and the network size is thus crucial for generating an effective ESN. With proper parameter choices, we show that it is possible to generate ESNs that approximate MSOs with several orders of magnitude smaller errors than those previously reported. We conclude that there appears to be still much more potential in ESNs than previously thought and sketch-out some promising future research directions. PMID- 23037775 TI - Correlation of fronto-central phase coupling with sensorimotor rhythm modulation. AB - We investigated neurophysiologic correlates of individual differences in the modulation of sensorimotor rhythms (SMRs) in the human electroencephalography (EEG) during motor imagery. The ability of modulating SMRs to different motor imageries was correlated with the strength of alpha phase synchronization across frontal and central sensorimotor areas. The results suggest that fronto-central coupling may elucidate individual variations in SMR modulation that is essential for using SMR-based brain-computer interfaces. PMID- 23037776 TI - Hopf bifurcation stability in Hopfield neural networks. AB - In this paper we consider a simple discrete Hopfield neural network model and analyze local stability using the associated characteristic model. In order to study the dynamic behavior of the quasi-periodic orbit, the Hopf bifurcation must be determined. For the case of two neurons, we find one necessary condition that yields the Hopf bifurcation. In addition, we determine the stability and direction of the Hopf bifurcation by applying normal form theory and the center manifold theorem. An example is given and a numerical simulation is performed to illustrate the results. We analyze the influence of bias weights on the stability of the quasi-periodic orbit and study the phase-locking phenomena for certain experimental results with Arnold Tongues in a particular weight configuration. PMID- 23037777 TI - The impact of the United Nations Convention on Biological Diversity on natural products research. AB - The discovery and development of novel, biologically active agents from natural sources, whether they be drugs, agrochemicals or other bioactive entities, involve a high level of interdisciplinary as well as international collaboration. Such collaboration, particularly at the international level, requires the careful negotiation of collaborative agreements protecting the rights of all parties, with special attention being paid to the rights of host (source) country governments, communities and scientific organizations. While many biodiversity rich source countries currently might not have the necessary resources for in country drug discovery and advanced development, they provide valuable opportunities for collaboration in this endeavor with research organizations from more high-income nations. This chapter discusses the experiences of the US National Cancer Institute and the US government-sponsored International Cooperative Biodiversity Groups program in the establishment of international agreements in the context of the Convention of Biological Diversity's objectives of promoting fair and equitable collaboration with multiple parties in many countries, and includes some specific lessons of value in developing such collaborations. PMID- 23037778 TI - Sandwich-like Cu(1.94)S-ZnS-Cu(1.94)S nanoheterostructure: structure, formation mechanism and localized surface plasmon resonance behavior. AB - In this communication, a thermolysis route is developed to synthesize novel Cu(1.94)S-ZnS-Cu(1.94)S nanoheterostructures with interesting sandwich-like architectures, taking Cu(1.94)S nanoplates as precursors. Evidently, the trimeric nanostructure is formed by a three-stage process, which includes the Zn-oleate induced assembling of Cu(1.94)S nanoplate couples, the heteronucleation and growth of a ZnS layer between two Cu(1.94)S plates dominated by interfacial diffusion, and the catalyst assisted axial growth of ZnS nanorod following the solution-liquid-solid mechanism. With epitaxial growth of ZnS nanocrystal between two Cu(1.94)S nanoplates, the localized surface plasmon resonance frequency of Cu(1.94)S shifts from 1875 to 1323 nm, indicating that this new material is potentially applicable as a light absorbing agent in laser photothermal therapy. The reported growth mechanism may provide new strategies for designing and fabricating various technologically important polymeric nanoheterostructures. PMID- 23037779 TI - Overexpression of interleukin 2 receptor, thymidine kinase and immunoglobulin associated alpha-1 messenger RNA in a clinical case of enzootic bovine leukosis. AB - A 49-month-old Holstein cow with anorexia, tachypnea, enlarged peripheral lymph nodes, and difficulty standing up was suspected of bovine leukosis. Hematological examination revealed lymphocytosis with the presence of neoplastic cells. Increased total lactate dehydrogenase (LDH) activity, isozymes of LDH-2 and LDH-3 activities and thymidine kinase activity were observed. Cytological findings of fine needle aspiration of subiliac lymph nodes indicated lymphosarcoma. Histopathology and antibody analysis confirmed the diagnosis of enzootic bovine leukosis, a B-cell bovine lymphoma caused by bovine leukemia virus. Gene expressions known as biomarkers of hematopoietic neoplasia in human were also examined in the present case. Increased messenger RNA expression of interleukin 2 receptor, thymidine kinase, and immunoglobulin-associated alpha-1 was observed in the case animal. PMID- 23037780 TI - Comparison of commercial enzyme-linked immunosorbent assay kits with agar gel precipitation and hemagglutination-inhibition tests for detecting antibodies to avian influenza viruses. AB - We evaluated the utility of 5 commercial enzyme-linked immunosorbent assay (ELISA) kits for detecting antibodies to avian influenza viruses. The sensitivities and specificities of the ELISA kits were compared with those of the agar gel precipitation (AGP) and hemagglutination-inhibition (HI) tests. The results suggest that some ELISA kits might not be suitable for monitoring during the early stages of avian influenza virus infections. Therefore, ELISA kits should only be used in conjunction with a profound knowledge about monitoring of avian influenza. PMID- 23037782 TI - New approach towards mini dental implants and small-diameter implants: an option for long-term prostheses. AB - BACKGROUND. Mini dental implants (MDI) and small diameter implants (SDI) have been extensively used as temporary or orthodontic anchorage; however there have been studies that proved their availability as a mean for long term prosthodontics. Our aim was to review the indications, advantages of MDI and SDI, and their long-term survival. METHODS. Computerized searches were conducted for clinical studies between year 2000 and 2011 that involved either implants with 3.3 mm diameter or less, used in prosthodontics; or provided a follow up of MDI or SDI duration of at least 4 months following implant placement including survival rate data. All studies about implants used in orthodontics were excluded. The range of available MDI and SDI has been found in cataloges of the companies: 3M ESPE IMTEC, Bicon Dental, Zimmer, Implant Direct, Intra lock, Hiossen, Simpler Implant, KAT Implants, OCO Biomedical, American Dental Implant. RESULTS. 41 studies meeting the above criteria were selected, 22 out of them reviewed survival rates of MDI and SDI. The follow up duration varried from 4 months to 8 years with survival rates between 91.17 and 100%. Nevertheless, the companies showed a big variety of MDI and SDI provided in the market for long term prostheses. CONCLUSIONS. Implants with small diameters can be used successfully in a variety of clinical situations. Less surgical time, less postoperative pain, ability of direct loading after surgery with no harm to bone and cost effectiveness are the advantages. The reduced surface implants require correct treatment planning so that the loading force would not cause bone loss or implant failure. MDI and SDI show high survival rates, but special cautions for bone quality and good oral hygiene should be maintained. PMID- 23037783 TI - The influence of simvastatin in rats mandible and femur bone mass under Freund's adjuvant arthritis. AB - OBJECTIVES. Complete Freund's Adjuvant (CFA)-induced arthritis in rats has been used widely as a model of rodent arthropathy and polyarthritis followed by osteoporosis, decreased bone formation and increased bone formation. Osteoporosis is characterized by rapid reduce of bone mass affecting more than 100 million people worldwide. Periodontitis a chronic inflammatory, of multifactorian origin disease has been associated with general osteoporosis. Protective bone-specific anabolic and antiresorptive effects of HMG-CoA reductase inhibitors have also been evaluated in normal and osteoporotic bone. AIM. The aim of the study was to investigate mandible and femur bone density in Freund's adjuvant induced arthritis rats under the influence of simvastatin. METHODS. Three groups (A, B, C) of 7 Wistar male rats each aged 3 months, (292+/-48.38 g) were used. A control. Group B and C subjected experimental arthritis via complete Freund's adjuvant injected in right paw. Group C was treated with simvastatin 0.5 mg/kg/daily po 14 days. Femur, mandible were isolated and sizes parameters, biochemical serum findings and BMD were estimated. RESULTS. CFA established by paw diameter, adrenals and spleen weight increase and thymus weight decrease, while biochemical serum findings were also affected. Reduced femur, mandible weight and general bone mass parameters BMD evaluated via DEXA occurred and restored under simvastatin treatment. CONCLUSIONS. CFA induced mandible and femur injuries are repaired by ssimvatatin treatment that could be therapeutically useful. PMID- 23037784 TI - An alternative technique using a gutta percha points and blue methylene to excision of congenital fistula of lower lip in patient with Van der Woude syndrome. AB - Van der Woude syndrome is a rare disorder of craniofacial development, characterized by the triad (congenital lip fistula, cleft lip and/or cleft palate). Discomfort caused by spontaneous or induced drainage of saliva/mucus when pressure is applied or during a meal as well as poor aesthetics match is one of the main complaints of patients with congenital lip fistula. This paper aims to describe an alternative technique for excision of the congenital fistula of lower lip in patient with Van der Woude syndrome, using gutta percha points and methylene blue for better identify the the fullest extent of the fistula. This approach aims to facilitate a dissection of fistula tissues providing better preservation of the tissues around the fistula, faster healing and better aesthetics lip of the patient. PMID- 23037785 TI - Mandibular midline supernumerary tooth associated with agenesis of permanent central incisors: a diagnostic conundrum. AB - Concomitant hypo-hyperdontia is a rare mixed numeric anomalous condition. The presence of this condition in the same area of dental arch and specifically in the mandibular anterior region is reported very infrequently. This case report presents a case of 20 years old male with congenitally missing permanent mandibular central incisors in conjunction with a mandibular midline supernumerary tooth. Only 3 cases have been documented in English literature till date. The article focuses on the review of mandibular mesiodens and the clarity regarding the usage of the terminology "mesiodens". PMID- 23037786 TI - Fabrication of heterogeneous exposed core-shell catalyst array using the space specificity of an embodied micelle and their application to a high performance photocatalyst. AB - We report a new recipe to synthesize heterogeneous catalyst arrays using the space specificity of an embodied micelle. Also, SEM, AFM, STEM, and TXRF analyses prove that these catalysts are of exposed core-shell types. Furthermore, their structures were found to allow the design of a high performance photocatalyst for water splitting. PMID- 23037798 TI - Structural models used in real-time biosurveillance outbreak detection and outbreak curve isolation from noisy background morbidity levels. AB - OBJECTIVE: We discuss the use of structural models for the analysis of biosurveillance related data. METHODS AND RESULTS: Using a combination of real and simulated data, we have constructed a data set that represents a plausible time series resulting from surveillance of a large scale bioterrorist anthrax attack in Miami. We discuss the performance of anomaly detection with structural models for these data using receiver operating characteristic (ROC) and activity monitoring operating characteristic (AMOC) analysis. In addition, we show that these techniques provide a method for predicting the level of the outbreak valid for approximately 2 weeks, post-alarm. CONCLUSIONS: Structural models provide an effective tool for the analysis of biosurveillance data, in particular for time series with noisy, non-stationary background and missing data. PMID- 23037799 TI - Scientific research in the age of omics: the good, the bad, and the sloppy. AB - It has been claimed that most research findings are false, and it is known that large-scale studies involving omics data are especially prone to errors in design, execution, and analysis. The situation is alarming because taxpayer dollars fund a substantial amount of biomedical research, and because the publication of a research article that is later determined to be flawed can erode the credibility of an entire field, resulting in a severe and negative impact for years to come. Here, we urge the development of an online, open-access, postpublication, peer review system that will increase the accountability of scientists for the quality of their research and the ability of readers to distinguish good from sloppy science. PMID- 23037800 TI - A unified inference procedure for a class of measures to assess improvement in risk prediction systems with survival data. AB - Risk prediction procedures can be quite useful for the patient's treatment selection, prevention strategy, or disease management in evidence-based medicine. Often, potentially important new predictors are available in addition to the conventional markers. The question is how to quantify the improvement from the new markers for prediction of the patient's risk in order to aid cost-benefit decisions. The standard method, using the area under the receiver operating characteristic curve, to measure the added value may not be sensitive enough to capture incremental improvements from the new markers. Recently, some novel alternatives to area under the receiver operating characteristic curve, such as integrated discrimination improvement and net reclassification improvement, were proposed. In this paper, we consider a class of measures for evaluating the incremental values of new markers, which includes the preceding two as special cases. We present a unified procedure for making inferences about measures in the class with censored event time data. The large sample properties of our procedures are theoretically justified. We illustrate the new proposal with data from a cancer study to evaluate a new gene score for prediction of the patient's survival. PMID- 23037801 TI - Induced self-assembly of a tetrathiafulvalene-based open-shell dyad through intramolecular electron transfer. AB - An organic switch: An open-shell dyad, consisting of an electron acceptor perchlorotriphenylmethyl radical unit linked to an electron pi-donor tetrathiafulvalene unit through a vinylene pi-bridge, was synthesized (see picture). The self-assembly of the dyad in solution induced by its intramolecular electron transfer was studied. PMID- 23037802 TI - Bare gold nanoparticles as facile and sensitive colorimetric probe for melamine detection. AB - In this study, we demonstrate a more sensitive colorimetric assay for the detection of melamine based on the strong attraction between exocyclic amine groups of melamine and surface-bound AuCl(4)(-)/AuCl(2)(-) ions on bare gold nanoparticles prepared by the borohydride reduction method. This method is rather simple without further modification of gold nanoparticles and complicated pretreatment of samples. The detection limit of the method is 2.0 * 10(-7) g L( 1) for melamine in infant formula, which is much lower (about 1000-fold) than that of using citrate-capped GNPs as a colorimetric probe. The proposed scheme could be a good alternative means for on-site and real-time screening of melamine adulterant in infant formula without costly instruments. PMID- 23037803 TI - Assessment of in vivo behavior of polymer tube nerve grafts simultaneously with the peripheral nerve regeneration process using scanning electron microscopy technique. AB - In this study, scanning electron microscopy (SEM) has been applied for instantaneous assessment of processes occurring at the site of regenerating nerve. The technique proved to be especially useful when an artificial implant should have been observed but have not yet been extensively investigated before for assessment of nerve tissue. For in vivo studies, evaluation of implant's morphology and its neuroregenerative properties is of great importance when new prototype is developed. However, the usually applied histological techniques require separate and differently prepared samples, and therefore, the results are never a 100% comparable. In our research, we found SEM as a technique providing detailed data both on an implant behavior and the nerve regeneration process inside the implant. Observations were carried out during 12-week period on rat sciatic nerve injury model reconstructed with nerve autografts and different tube nerve grafts. Samples were analyzed with haematoxylin-eosin (HE), immunocytochemical staining for neurofillament and S-100 protein, SEM, TEM, and the results were compared. SEM studies enabled to obtain characteristic pictures of the regeneration process similarly to TEM and histological studies. Schwann cell transformation and communication as well as axonal outgrowth were identified, newly created and matured axons could be recognized. Concurrent analysis of biomaterial changes in the implant (degradation, collapsing of the tube wall, migration of alginate gel) was possible. This study provides the groundwork for further use of the described technique in the nerve regeneration studies. PMID- 23037804 TI - A cyber-physical management system for delivering and monitoring surgical instruments in the OR. AB - BACKGROUND: The standard practice in the operating room (OR) is having a surgical technician deliver surgical instruments to the surgeon quickly and inexpensively, as required. This human "in the loop" system may result in mistakes (eg, missing information, ambiguity of instructions, and delays). OBJECTIVE: Errors can be reduced or eliminated by integrating information technology (IT) and cybernetics into the OR. Gesture and voice automatic acquisition, processing, and interpretation allow interaction with these new systems without disturbing the normal flow of surgery. METHODS: This article describes the development of a cyber-physical management system (CPS), including a robotic scrub nurse, to support surgeons by passing surgical instruments during surgery as required and recording counts of surgical instruments into a personal health record (PHR). The robot used responds to hand signals and voice messages detected through sophisticated computer vision and data mining techniques. RESULTS: The CPS was tested during a mock surgery in the OR. The in situ experiment showed that the robot recognized hand gestures reliably (with an accuracy of 97%), it can retrieve instruments as close as 25 mm, and the total delivery time was less than 3 s on average. CONCLUSIONS: This online health tool allows the exchange of clinical and surgical information to electronic medical record-based and PHR based applications among different hospitals, regardless of the style viewer. The CPS has the potential to be adopted in the OR to handle surgical instruments and track them in a safe and accurate manner, releasing the human scrub tech from these tasks. PMID- 23037805 TI - [Case report: Free combined osteo-tendo-cutaneous flap from the medial femoral condyle for coverage of skin, tendon and bone defect on the back of the foot]. AB - For the first time we present the case of a microsurgical reconstruction with an osteo-tendo-cutaneous free flap harvested from the medial femoral condyle for the coverage of a bone-tendon-soft tissue defect of the foot. PMID- 23037806 TI - Mechanisms of action underlying the immunotherapeutic activity of Allovectin in advanced melanoma. AB - Allovectin (velimogene aliplasmid) is a cancer immunotherapeutic currently completing a pivotal phase 3 study for metastatic melanoma. Consisting of a bicistronic plasmid encoding both major histocompatibility complex (MHC) class I heavy and light chains (HLA-B7 and beta2-microglobulin, respectively) formulated with a cationic lipid-based system, it is designed for direct intratumoral administration. Following injection into a single lesion, the product is intended to induce anti-tumor immune responses against both treated and distal lesions. Both the plasmid and lipid components of Allovectin contribute to the biological activity of the drug product, and its therapeutic activity is hypothesized to derive from multiple mechanisms of actions (MOAs). These include the induction of both cytotoxic T-cell and innate immune responses directed against allogeneic as well as tumor-derived targets, consequences of both an increased MHC class I expression on tumor cells and the induction of a localized immune/inflammatory response. In this paper, we review Allovectin's proposed MOAs, placing their contributions in the context of anti-tumor immunity and highlighting both preclinical and clinical supporting data. PMID- 23037807 TI - Tissue inhibitor of metalloproteinases-3 transfer suppresses malignant behaviors of colorectal cancer cells. AB - Colorectal carcinoma is one of the most frequent cancer diseases. For patients with this type of cancer, liver metastases are the main cause of death. Therefore, new therapeutic approaches are urgently needed to improve the outcomes. We found that both mRNA and protein levels of tissue inhibitor of metalloproteinase-3 (TIMP3) were decreased significantly in colorectal cancer tissue when compared with normal mucosa, suggesting that decrease of TIMP3 expression was correlated with malignant behavior of colorectal cancer. We evaluated the power of TIMP3, a new potent multiple functional molecule, as a biotheropeutic tool to treat cancer. Adenovirus-mediated TIMP3 transduction in CT26 colon cancer model demonstrated multiple effects to arrest cancer cell growth and induced massive apoptosis. Also, adenovirally transferred TIMP3 reduced adhesion, migration and invasion behaviors of CT26 cells in vitro. In vivo data showed that TIMP3 suppressed in vivo tumor growth and that liver metastasis was significantly reduced by TIMP3 transduction. This is the first systematic preclinical study to show that TIMP3 may be a potential molecular tool for colon cancer biological therapy. PMID- 23037808 TI - A steep radioiodine dose response scalable to humans in sodium-iodide symporter (NIS)-mediated radiovirotherapy for prostate cancer. AB - The sodium-iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. We have extended the use of NIS-mediated radioiodine therapy to prostate cancer. We have developed a prostate tumor specific conditionally replicating adenovirus that expresses hNIS (Ad5PB_RSV-NIS). For radiovirotherapy to be effective in humans, the radioiodine dose administered in the pre-clinical animal model should scale to the range of acceptable doses in humans. We performed (131)I dose-response experiments aiming to determine the dose required in mice to achieve efficient radiovirotherapy. Efficacy was determined by measuring tumor growth and survival times. We observed that individual tumors display disparate growth rates that preclude averaging within a treatment modality indicating heterogeneity of growth rate. We further show that a statistic and stochastic approach must be used when comparing the effect of an anti-cancer therapy on a cohort of tumors. Radiovirotherapy improves therapeutic value over virotherapy alone by slowing the rate of tumor growth in a more substantial manner leading to an increase in survival time. We also show that the radioiodine doses needed to achieve this increase scaled well within the current doses used for treatment of thyroid cancer in humans. PMID- 23037810 TI - Decidua mesenchymal stem cells migrated toward mammary tumors in vitro and in vivo affecting tumor growth and tumor development. AB - Mesenchymal stem cells (MSCs) have affinity to tumor sites where they home, affecting their biology and growth. Previously, we have isolated mesenchymal cells from the decidua of the human placenta named as decidua-derived MSCs (DMSCs). The aims of the present study were to investigate the migration capacity of DMSCs in vitro, and in vivo in a preclinical model of mammary tumors induced by N-nitroso-N-methylurea (NMU). Additionally, we assessed the safety of DMSC administration in vivo and their effect on tumor growth. In vitro studies showed that DMSCs significantly migrate toward both, healthy human breast tissue and breast adenocarcinoma. Nevertheless, the effect on DMSC migration was significantly higher in the presence of tumor tissue. DMSCs also significantly migrated in vitro in the presence of NMU-mammary tumor homogenate when compared with control media alone. In vivo studies showed both migration and engraftment of DMSCs into NMU-induced tumors. Interestingly, DMSCs showed an inhibitory effect on the growth of primary tumors and in the development of new tumors. DMSCs did not affect the growth of secondary tumors, although secondary tumors appeared 2 weeks later, and the number of secondary tumors was lower in the DMSC treated rats as compared with vehicle-treated rats. To our knowledge, this is the first report showing placental MSCs effect on tumor growth. In conclusion, DMSCs could serve as a therapeutic agent themselves and as a cellular vehicle of anticancer drugs. PMID- 23037809 TI - Synthetic DNA immunogen encoding hepatitis B core antigen drives immune response in liver. AB - The prevalence of hepatitis B virus (HBV) infection in Asia and sub-Sahara Africa is alarming. With quarter of a billion people chronically infected worldwide and at risk of developing liver cancer, the need for a prophylactic or therapeutic vaccination approach that can effectively induce protective responses against the different genotypes of HBV is more important than ever. Such a strategy will require both the induction of a strong antigen-specific immune response and the subsequent deployment of immune response towards the liver. Here, we assessed the ability of a synthetic DNA vaccine encoding a recombinant consensus plasmid from genotype A through E of the HBV core antigen (HBcAg), to drive immunity in the liver. Intramuscular vaccination induced both strong antigen-specific T cell and high titer antibody responses systematically and in the liver. Furthermore, immunized mice showed strong cytotoxic responses that eliminate adoptively transferred HBV-coated target cells. Importantly, vaccine-induced immune responses provided protection from HBcAg plasmid-based liver transfection in a hydrodynamic liver transfection model. These data provide important insight into the generation of peripheral immune responses that are recruited to the liver-an approach that can be beneficial in the search for vaccines or immune-therapies to liver disease. PMID- 23037812 TI - East versus West: organic contaminant differences in brown pelican (Pelecanus occidentalis) eggs from South Carolina, USA and the Gulf of California, Mexico. AB - Brown pelicans (Pelecanus occidentalis) were listed as endangered in the United States in 1970, largely due to reproductive failure and mortality caused by organochlorine contaminants, such as DDT. The southeast population, P.o. carolinensis, was delisted in 1985, while the west coast population, P.o. californicus, was not delisted until 2009. As fish-eating coastal seabirds, brown pelicans may serve as a biomonitors. Organic contaminants were examined in brown pelican eggs collected from the Gulf of California in 2004 and South Carolina in 2005 using gas chromatography/mass spectrometry (GC/MS). Contaminants were compared using all individual data as well as statistically pooled samples to provide similar sample sizes with little difference in results. Principal components analysis separated the Gulf of California brown pelican eggs from the South Carolina eggs based on contaminant patterns. The South Carolina population had significantly (P<0.05) higher levels of polychlorinated biphenyls (PCBs), chlordanes, dieldrin and mirex, while the Gulf of California eggs had higher levels of dichlorodiphenyltrichloroethanes (DDTs) and hexachlorocyclohexanes (HCHs). With the exception of dieldrin and brominated diphenyl ether (BDE) 47, this pattern was observed for mussel and oyster tissues from these regions, indicating the need for further study into the differences between east and west coast brown pelican populations and ecosystem contamination patterns. PMID- 23037811 TI - F2A sequence linking MGMT(P140K) and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells. AB - Chemoprotection of haematopoietic stem cells (HSCs) by gene therapeutic transfer of drug-resistance genes represents the encouraging approach to prevent myelosuppression, which is one of the most severe side effects in tumor therapy. Thus, we cloned and evaluated six different bicistronic lentiviral SIN vectors encoding two transgenes, MGMT(P140K) (an O(6)-benzylguanine-resistant mutant of methylguanine-DNA methyltransferase) and MDR1 (multidrug resistance 1), using various linker sequences (IRESEMCV, IRESFMDV and 2A-element of FMDV (F2A)). Expression of both transgenes in HL-60 and in K562 cells was assayed by quantitative real-time PCR. Combination therapy with ACNU plus paclitaxel in HL 60 cells and with carmustin (BCNU) plus doxorubicin in K562 cells resulted in the most significant survival advantage of cells transduced with the lentiviral vector HR'SIN-MGMT(P140K)-F2A-MDR1 compared with untransduced cells. In human HSCs, overexpression of both transgenes by this vector also caused significantly increased survival and enrichment of transduced cells after treatment with BCNU plus doxorubicin or temozolomide plus paclitaxel. In summary, we could show significant chemoprotection by overexpression of MDR1 and MGMT(P140K) with a lentiviral vector using the F2A linker element in two different haematopoietic cell lines and in human primary HSCs with various combination regimens. Consequently, we are convinced that these in vitro investigations will help to improve combination chemotherapy regimens by reducing myelotoxic side effects and increasing the therapeutic efficiency. PMID- 23037813 TI - Is it better to remove pharmaceuticals in decentralized or conventional wastewater treatment plants? A life cycle assessment comparison. AB - After ingestion, pharmaceuticals are excreted unchanged or metabolized. They subsequently arrive in conventional wastewater treatment plants and are then released into the environment, often without undergoing any degradation. Conventional treatment plants can be upgraded with post treatment, alternatively the removal of pharmaceuticals could be achieved directly at point sources. In the European project PILLS, several solutions for decentralized treatment of pharmaceuticals at hospitals were investigated at both pilot plant and full scale, and were then compared to conventional and upgraded centralized treatment plants using Life Cycle Assessment (LCA). Within the scope of the study, pharmaceuticals were found to have a comparatively minor environmental impact. As a consequence, an additional post treatment does not provide significant benefits. In the comparison of post treatment technologies, ozonation and activated carbon performed better than UV. These results suffer however from high uncertainties due to the assessment models of the toxicity of pharmaceuticals in LCA. Our results should therefore be interpreted with caution. LCA is a holistic approach and does not cover effects or issues on a local level, which may be highly relevant. We should therefore apply the precautionary ALARA principle (As Low As Reasonably Achievable) and not conclude that the effect of pharmaceuticals is negligible in the environment. PMID- 23037814 TI - Microcatheter looping technique for coil embolization of complex configuration middle cerebral artery aneurysms. AB - BACKGROUND: Protection techniques using stents or microcatheters allow treatment of aneurysms with complex configurations by coil embolization. However, the application of these techniques is occasionally limited in wide-neck middle cerebral artery (MCA) aneurysms with acute angularity of the efferent branch vessel. OBJECTIVE: We describe a looping technique for passage of a microcatheter and microwire into the acutely angled efferent branch vessel without navigating the system through the aneurysm lumen. METHODS: To select the acutely angulated branch, a looped microcatheter was advanced near the orifice of the distal acutely angled branch vessel, followed by microwire passage through the looped microcatheter into the efferent vessel. The microcatheter loop was straightened after the microwire had been sufficiently advanced. The microcatheter was then navigated into the distal branch vessel over the advanced microwire. RESULTS: A total of 36 wide-neck MCA aneurysms were successfully treated using this looping method. This technique was used to pass the microcatheter for stent protection in 13 patients and for microcatheter protection in 23. The method was most commonly used for aneurysms located at the M1 trunk (n = 21), followed by the MCA bifurcation (n = 15). Complete or near-complete endosaccular occlusion was achieved in 31 aneurysms. There were no complications related to looping the microcatheter. CONCLUSION: This microcatheter looping technique facilitates safe entry into the distal branch during coil embolization of wide-neck MCA aneurysms incorporating the origins of acutely angulated branches. PMID- 23037816 TI - Higher complications and no improvement in mortality in the ACGME resident duty hour restriction era: an analysis of more than 107000 neurosurgical trauma patients in the nationwide inpatient sample database. PMID- 23037815 TI - Efficacy and safety of Oberlin's procedure in the treatment of brachial plexus birth palsy. AB - BACKGROUND: In brachial plexus injuries, when there are no available roots to use as a source for graft reconstruction, nerve transfers emerge as an elective technique. For this purpose, transfer of an ulnar nerve fascicle to the biceps motor branch (Oberlin's procedure) is often used. Despite the high rate of good to excellent results in adults, this technique is seldom used in children. OBJECTIVE: To evaluate the efficacy and safety of Oberlin's procedure in the surgical treatment of brachial plexus birth palsy. METHODS: Striving to restore elbow flexion, we performed Oberlin's procedure in 17 infants with brachial plexus birth palsy. After follow-up of at least 19 months, primary outcomes were the strength of elbow flexion (modified British Medical Research Council scale), hand function measured using Al-Qattan's scale, and comparative x-rays of both hands to detect altered growth. RESULTS: Good to excellent results related to biceps contraction were obtained in 14 patients (82.3%) (3/MRC3, 11/MRC4). The preoperative Al-Qattan scale score for the hand was maintained at final follow up. Comparing the treated and normal limb, no difference was observed in hand development by x-ray. CONCLUSION: Oberlin's procedure is an effective and safe option for the surgical treatment of upper brachial plexus birth palsy. PMID- 23037817 TI - Poor cognitive outcome in shunt-responsive idiopathic normal pressure hydrocephalus. AB - BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce. OBJECTIVE: To elucidate the long-term cognitive condition of shunt responsive iNPH patients. METHODS: The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years. RESULTS: At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidence interval [CI] 1.9-175), male sex (OR 3.29; 95% CI 1.11-9.73), age (OR 1.17 year; 95% CI 1.07-1.28), and follow-up time (OR 1.20 year; 95% CI 1.02-1.40) predicted dementia. Interestingly, 8 (5%) iNPH patients had dementia without any signs of other neurodegenerative diseases in clinical, neuroradiological, or brain biopsy evaluation. These patients initially presented a full triad of symptoms, with gait disturbance being the most frequent initial symptom followed by deterioration in cognition. CONCLUSION: The novel findings were (a) a significant risk of dementia in iNPH initially responsive to cerebrospinal fluid shunt, (b) cognitive impairment most commonly due to iNPH related dementia followed by concurrent degenerative brain disease, and (c) a subgroup with dementia related to iNPH without comorbidities. PMID- 23037818 TI - Flat-panel fluoroscopy O-arm-guided percutaneous radiofrequency cordotomy: a new technique for the treatment of unilateral cancer pain. AB - BACKGROUND: Percutaneous radiofrequency cordotomy (PRFC) involves controlled ablation of the anterolateral quadrant of the spinal cord, thereby relieving pain. Evolving from a morbid open surgery, the procedure has been modernized through the application of physiological target confirmation, well-regulated thermal ablation, and improved intraoperative imaging. OBJECTIVE: To evaluate the utility in PRFC of a new high-resolution, portable flat-panel fluoroscopic imaging technology, the O-arm Imaging System. The O-arm allows traditional 2 dimensional fluoroscopy in addition to axial and 3-dimensional reconstructed computed tomography imaging. METHODS: PRFC was performed using the O-arm Imaging System in 6 patients with unilateral cancer pain. RESULTS: Patients experienced 90% to 100% initial pain relief, with 50% to 100% sustained pain relief at the time of death at 2 to 12 months. There were no complications. CONCLUSION: Portable flat-panel fluoroscopy allows high-resolution, readily updated computed tomography and fluoroscopic image guidance during PRFC. Use of this new technology may assist neurosurgeons in providing an important analgesic intervention at centers possessing the imaging technology. PMID- 23037820 TI - Biomechanical comparison of posterior lumbar interbody fusion and transforaminal lumbar interbody fusion by finite element analysis. AB - BACKGROUND: The transforaminal lumbar interbody fusion (TLIF) procedure may reduce many of the risks and limitations associated with posterior lumbar interbody fusion (PLIF). However, little is known about the biomechanical difference between PLIF and TLIF. OBJECTIVE: To determine the biomechanical difference between PLIF and TLIF by finite-element analysis. METHODS: Three validated finite-element models of L3-5 lumbar segment were created (intact model, PLIF model, and TLIF model). To analyze the biomechanics of these models, flexion, extension, rotation, and lateral bending moments of 7.5 N-m with a compressive preload of 400 N were imposed on the superior surfaces of the L3 vertebral body. RESULTS: The range of motion at the L4-5 level of the PLIF and TLIF models decreased for all loading cases, compared with the intact model. Differences in the range of motion between PLIF and TLIF were not significant at less than 1 degree for all loading cases. The stress of the cage was found to be high in the PLIF model at the cage-endplate interface under all loading conditions. The stress exerted on the pedicle screw was greater in TLIF than PLIF. Particularly in flexion loading, the stress experienced by the pedicle screw in the TLIF model was 70.7% greater than that in the PLIF model. CONCLUSION: The TLIF procedure increases the approximate biomechanical stability and reduces stress at the cage-endplate interface, except for a slight increase in screw stress. Clinically, the TLIF procedure may reduce many of the risks and limitations associated with PLIF and offer a useful alternative to the PLIF procedure. PMID- 23037822 TI - Carotid cave microsurgical anatomy. PMID- 23037821 TI - Retrograde third ventriculocisternostomy from the posterior fossa. AB - BACKGROUND: Postoperative hydrocephalus is common in patients after resection of a posterior fossa tumor, with as many as 25% of patients requiring permanent cerebrospinal fluid diversion in the form of ventricular shunting or ventriculocisternostomy in some series. Prophylactic ventriculocisternostomy has been described with success in this patient population to prevent postoperative hydrocephalus. OBJECTIVE: To define the technique of microsurgical retrograde third ventriculostomy from the posterior fossa. METHODS: The operative technique is described and a single patient with 4-year follow-up is reported. RESULTS: We describe the case of a 32-year-old woman who presented with a large cerebellopontine angle epidermoid tumor. She underwent a simultaneous lesion resection and third ventriculocisternostomy by accessing the interpeduncular cistern via a suboccipital posterior fossa approach and then making an incision through the tuber cinereum to access the third ventricle under direct vision. CONCLUSION: Retrograde third ventriculostomy may be useful in the surgical treatment of patients already undergoing operations for large posterior fossa lesions who have a high likelihood of requiring permanent cerebrospinal fluid diversion and in whom exposure of the interpeduncular cistern is available. PMID- 23037823 TI - Validation in humans for the Brown-Roberts-Wells and Cosman-Roberts-Wells stereotactic frames. PMID- 23037824 TI - Silent or Subclinical Corticotroph Pituitary Macroadenoma Transforming Into Cushing Disease: 11-Year Follow-up. PMID- 23037825 TI - Optimal target of deep brain stimulation for essential tremor. PMID- 23037826 TI - In reply. PMID- 23037827 TI - In reply. PMID- 23037828 TI - Contemporary surgical management of vestibular schwannomas: analysis of complications and lessons learned over the past decade. AB - BACKGROUND: Despite advanced microsurgical techniques, more refined instrumentation, and expert team management, there is still a significant incidence of complications in vestibular schwannoma surgery. OBJECTIVE: To analyze complications from the microsurgical treatment of vestibular schwannoma by an expert surgical team and to propose strategies for minimizing such complications. METHODS: Surgical outcomes and complications were evaluated in a consecutive series of 410 unilateral vestibular schwannomas treated from 2000 to 2009. Clinical status and complications were assessed postoperatively (within 7 days) and at the time of follow-up (range, 1-116 months; mean, 32.7 months). RESULTS: Follow-up data were available for 357 of the 410 patients (87.1%). Microsurgical tumor resection was performed through a retrosigmoid approach in 70.7% of cases. Thirty-three patients (8%) had intrameatal tumors and 204 (49.8%) had tumors that were <20 mm. Gross total resection was performed in 306 patients (74.6%). Hearing preservation surgery was attempted in 170 patients with tumors <20 mm, and good hearing was preserved in 74.1%. The main neurological complication was facial palsy (House-Brackmann grade III-VI), observed in 14% of patients (56 cases) postoperatively; however, 59% of them improved during the follow-up period. Other neurological complications were disequilibrium in 6.3%, facial numbness in 2.2%, and lower cranial nerve deficit in 0.5%. Nonneurological complications included cerebrospinal fluid leaks in 7.6%, wound infection in 2.2%, and meningitis in 1.7%. CONCLUSION: Many of these complications are avoidable through further refinement of operative technique, and strategies for avoiding complications are proposed. PMID- 23037829 TI - A gaze beyond the surface: acknowledging the little we know about radiographic parameters for evaluation of lumbar spinal stenosis. PMID- 23037830 TI - Do octogenarians benefit from coronary artery bypass surgery: a question with a rapidly changing answer? AB - PURPOSE OF REVIEW: Octogenarians represent the fastest-growing segment of the population. Over 40% manifest cardiovascular disease, frequently in an advanced state requiring surgical revascularization. Increased mortality, morbidity, and expense in this high-risk group, with decreased longevity, present a growing challenge to our healthcare system. RECENT FINDINGS: Results of coronary artery bypass graft (CABG) surgery in octogenarians show a consistent pattern of improvement over time, with documented long-term survival and quality of life that rivals the age-matched population. Comparison with alternative therapies appears to be favorable. Clearer understanding of costs will provide a more rational context for treatment decisions. Increasing interest in the specific issues regarding frailty will help to guide the most appropriate patient selection. SUMMARY: Although it is clear that CABG surgery in octogenarians can be accomplished with increasingly good results, future research will need to focus on what specific surgical strategies are most appropriate for this elderly cohort; how the collaborative 'Heart Team' approach can be most effectively applied to determination of the most appropriate therapeutic course for these complex, frequently high-risk patients; what strategies can be applied to best manage and possibly reverse patient frailty; and what economic models most meaningfully inform clinical and public policy decision-making. PMID- 23037831 TI - Addition of platinum and silver nanoparticles to toughen dental porcelain. AB - Several studies have investigated toughening porcelain that is layered over a frame or a core. The introduction of residual compressive stress to the surface of porcelain has been shown to be effective to strengthen it. In the present study, nanoparticles of precious metals of silver and platinum (rather than non precious metals) were used to evaluate if they could increase the fracture resistance of porcelain. The addition of silver and platinum nanoparticles was found to improve the mechanical properties of porcelain since it increased both the Young's modulus and the fracture toughness of commercial porcelain. PMID- 23037832 TI - Optimizing the concentration of 2,4,6-trimethylbenzoyldiphenylphosphine oxide initiator in composite resins in relation to monomer conversion. AB - The aim of this study was to optimize the concentration of 2,4,6 trimethylbenzoyldiphenylphosphine oxide (Lucirin(r) TPO) in unfilled and filled composite resins in relation to the degree of conversion (DC). Increasing concentrations of Lucirin(r) TPO between 0.05-4.97 wt% were added to equimolar mixtures of Bis-GMA/TEGDMA. Filled resins contained 75 wt% fillers. Standardized samples were cured using a polywave LED light-curing unit (bluephase(r) G2, Ivoclar Vivadent). Increased initiator concentrations increased logarithmically the DC of unfilled and filled resins. The DC of unfilled resins was in the range of 73-91% at the top and 63-81% at the bottom surfaces and that of filled resins was in the range of 53-81% at the top and 47-70% at the bottom surfaces. The DC in unfilled and filled resins reached a plateau at 1.08 wt% and 1.50 wt% Lucirin(r) TPO, respectively. Fillers significantly reduced conversion but had no effect on the logarithmic relationship between initiator concentration and the DC. PMID- 23037833 TI - Properties of experimental titanium cast investment mixing with water reducing agent solution. AB - This study aimed to develop a dental investment for titanium casting. ZrO(2) and Al(2)O(3) were selected as refractory materials to prepare three investments (Codes: A-C) according to the quantity of Zr. Al(2)O(3) cement was used as a binder at a ratio of 15%, they were mixed with special mixing liquid. B1 was used as a control mixed with water. Fundamental examinations were statistically evaluated. A casting test was performed with investment B. Fluidities, setting times, and green strengths showed no remarkable differences; however, they were significantly different from those of B1. Expansion values for A, B, C, and B1 at 850 degrees C were 1.03%+/-0.08%, 1.96%+/-0.17%, 4.35%+/-0.23%, and 1.50%+/ 0.28%, respectively. Castings were covered by only small amounts of mold materials. The hardness test showed no significant differences between castings from B and the ones from commercial investments. The experimental special mixing liquid effectively reduced the water/powder ratio and improved the strength and thermal expansion. PMID- 23037834 TI - Surface hardness of different restorative materials after long-term immersion in sports and energy drinks. AB - The purpose of this study was to evaluate the effect of sports and energy drinks on the surface hardness of different restorative materials over a 6-month period. Forty-two disk-shaped specimens were prepared for each of the four restorative materials tested: Compoglass F, Filtek Z250, Filtek Supreme, and Premise. Specimens were immersed for 2 min daily, up to 6 months, in six storage solutions (n=7 per material for each solution): distilled water, Powerade, Gatorade, X-IR, Burn, and Red Bull. Surface hardness was measured at baseline, after 1 week, 1 month, and 6 months. Data were analyzed statistically using repeated measures ANOVA followed by the Bonferroni test for multiple comparisons (alpha=0.05). Surface hardness of the restorative materials was significantly affected by both immersion solution and immersion period (p<0.001). All tested solutions induced significant reduction in surface hardness of the restorative materials over a 6 month immersion period. PMID- 23037835 TI - Creep of experimental short fiber-reinforced composite resin. AB - The purpose of this study was to investigate the reinforcing effect of short E glass fiber fillers oriented in different directions on composite resin under static and dynamic loading. Experimental short fiber-reinforced composite resin (FC) was prepared by mixing 22.5 wt% of short E-glass fibers, 22.5 wt% of resin, and 55 wt% of silane-treated silica fillers. Three groups of specimens (n=5) were tested: FC with isotropic fiber orientation, FC with anisotropic fiber orientation, and particulate-filled composite resin (PFC) as a control. Time dependent creep and recovery were recorded. ANOVA revealed that after secondary curing in a vacuum oven and after storage in dry condition for 30 days, FC with isotropic fiber orientation (1.73%) exhibited significantly lower static creep value (p<0.05) than PFC (2.54%). For the different curing methods and storage conditions evaluated in this study, FC achieved acceptable static and dynamic creep values when compared to PFC. PMID- 23037836 TI - Preparation and characterization of fluorinated porcine hydroxyapatite. AB - Simple chemical and thermal treatments were applied to prepare fluorinated porcine hydroxyapatite (FPHA). Morphology of FPHA was observed using SEM. Physiochemical characteristics, namely crystalline phase, chemical composition, functional groups, and binding energy of fluorine were investigated using XRD, EDX, FTIR, and XPS respectively. Concentration of free fluoride ion released from FPHA in HCl solution (pH 3.0-4.0) was detected using a fluoride ion concentration meter. SEM, XPS, XRD, and FTIR results confirmed the fluorination of porcine hydroxyapatite (PHA). Significant crystal morphological difference was observed between PHA and FPHA. Concentration of free fluoride ion released from FPHA increased with rising concentration of immersion solution and length of immersion period. Fluoride was successfully incorporated into PHA by chemical and thermal processes in this study. Fluoride incorporation rate into PHA was a strong function of the fluorine concentration in the immersion solution. PMID- 23037837 TI - Influence of air-abrasion and subsequent heat treatment on bonding between zirconia framework material and indirect composites. AB - The purpose of this study was to evaluate the influence of air-abrasion and subsequent heat treatment on the shear bond strength of the bond between indirect composites and a zirconia material. Four surface preparations were employed; ground flat, then heated to regenerate the crystal phase (C); air-abraded with alumina for 10 s (S10), for 20 s (S20), and air-abraded for 10 s and heated (H). Disks were primed with Alloy Primer and bonded either with Estenia or with Gradia composite. XRD analysis suggested that the monoclinic zirconia content was increased by air-abrasion, and decreased by heating. The surface roughness of S10, S20 and H disks was similar. Nevertheless, H groups showed lower bond strengths than the S10 and S20 groups both before and after thermal cycling. Although alumina air-abrasion considerably enhanced bonding between zirconia and indirect composites, subsequent heat treatment had a negative effect on the durability of bond strength. PMID- 23037838 TI - Influence of powdered dentin on the shear bond strength of dentin bonding systems. AB - This study evaluated the effect of different amounts of dentin powder (DP) mixed in Clearfil SE Bond (CSB) or Single Bond (SB) on adhesion to dentin. Human third molars (n=96) were sectioned to expose the mid-coronal dentin and divided into eight experimental groups (n=12 per group), namely, Group 1: CSB, Group 2: CSB+1.5 mg DP, Group 3: CSB+3 mg DP, Group 4: CSB+4.5 mg DP, Group 5: SB, Group 6: SB+1.5 mg DP, Group 7: SB+3 mg DP, and Group 8: SB+4.5 mg DP. Filtek Z250 composite was bonded onto dentin, and all specimens were subjected to shear bond strength test at a crosshead speed of 1 mm/min. Highest bond strength was obtained in Groups 1, 2, and 3 (15.1, 13.5, and 16.4 MPa respectively; p>0.05) and the lowest in Groups 6, 7, and 8 (5.5, 5.6, 4 MPa; p>0.05). DP addition, regardless of amount, adversely affected the bond strength of SB. Bond strength of CSB was not affected when 1.5 or 3 mg of DP was added. PMID- 23037839 TI - Shear bond strength between autopolymerizing acrylic resin and Co-Cr alloy using different primers. AB - This study aimed to examine the shear bond strength between cobalt chromium alloy and autopolymerizing acrylic resin using experimental primers containing 5, 10, and 15 wt% of 4-methacryloxyethyl trimellitic anhydride or 1, 2, and 3 wt% of 3 methacryloxypropyl-trimethoxysilane comparison to 5 commercial primers (ML primers, Alloy primer, Metal/Zirconia primer, Monobond S, and Monobond plus). Sixty alloy specimens were sandblasted and treated with each primer before bonded with an acrylic resin. The control group was not primed. The shear bond strengths were tested and statistically compared. Specimens treated with commercial primers significantly increased the shear bond strength of acrylic resin to cobalt chromium alloy (p<0.05). The highest shear bond strength was found in the Alloy primer group. Among experimental group, using 10 wt% of 4-methacryloxyethyl trimellitic anhydride -or 2 wt% of 3-methacryloxypropyltrimethoxysilane enhanced highest shear bond strength. The experimental and commercial primers in this study all improved bonding of acrylic resin to cobalt chromium alloy. PMID- 23037840 TI - A novel glass ionomer cement containing MgCO(3 )apatite induced the increased proliferation and differentiation of human pulp cells in vitro. AB - This study aimed to investigate the in vitro biological response of human dental pulp cells to glass ionomer cement (GIC, Fuji IX GP((r))) containing 2.5% magnesium carbonate apatite (MgCO(3)Ap). MgCO(3)Ap was synthesized by wet method and characterized using FT-IR, XPS, and SEM. Fuji IX GP((r)) served as a control. Test and control cements were prepared by encapsulated mixing the powder with Fuji IX-liquid (P/L=3.6:1). Eluates from cements extracted by 1 mL culture medium were collected at day 1, 7 and 14, and used for WST-1 proliferation assay. For ALPase activity, cells were maintained with cements in transwells, harvested and enzyme activity was measured at day 1, 4, 7, 14, and 21. We found a higher cell proliferation and increased ALPase activity by pulp cells in the test group compared to the control. This suggests the potential of GIC containing this novel biological apatite as a restorative material for pulp-dentin regeneration. PMID- 23037841 TI - Shear and micro-shear bond strengths of four self-etching adhesives measured immediately and 24 hours after application. AB - This study measured the immediate and 24 h shear (SBS) and micro-shear bond strengths (MSBS) to dentin of four self-etching adhesives. A resin composite was bonded using each adhesive to the area of 5-mm diameter for SBS test or 0.75-mm diameter for MSBS test of flat bovine dentin. The bond strengths of all adhesives at 10 min were lower than at 24 h for both tests. The mean SBS (MPa, 10 min, 24 h) were similar in ranking order at both time periods that is: Clearfil SE Bond (21.2, 25.3) >Clearfil TriS Bond (12.7, 19.5)=i Bond (11.7, 19.5)=G Bond (11.1, 16.6). For the MSBS test, G Bond provided equivalent mean bond strength (35.0) to Clearfil SE Bond (36.9) and higher than the other adhesives at 24 h [i Bond (26.3), Clearfil TriS Bond (28.5)]. In conclusion, the MSBS test was slightly more discriminating than the SBS test. PMID- 23037842 TI - Effects of a convenient silica-coating treatment on shear bond strengths of porcelain veneers on zirconia-based ceramics. AB - Porcelain veneering of zirconia is necessary, but chipping of the veneer may cause clinical problems. We investigated the effects of silica coating to improve the bond strength between porcelain veneers and zirconia-based ceramics. The ceramics tested were zirconia/alumina nanocomposites stabilized with ceria. Three surface treatments, grinding with a carborundum point (CA), sandblasting with alumina (SB), and Silano-Pen treatment (SP), were performed. Untreated specimens (NT) were examined as a control. The surface roughnesses and contact angles after treatment were measured. Shear bond tests were conducted, and the average strengths were calculated. EPMA was used for elemental identifications and surface observations. The bond strengths with SP were 20.00+/-3.43MPa and were significantly larger than that (15.35+/-3.12 MPa) of NT (p<0.05). However, differences among treated specimens were not significant. Moreover, SP gave superior wettability, and smoothness as good as NT. These data suggest that SP affects the bond strength between zirconia and a porcelain veneer. PMID- 23037843 TI - Development of surface coating material for discolored tooth equipped with bleaching effect. AB - It is attempted to augment a coating resin with a bleaching effect to provide both short- and long-term whitening effects. Base resin containing sodium percarbonate (SPC) effectively bleached bovine teeth discolored by the Maillard reaction. SPC did not reduce Vickers hardness, but hardness in the hybrid material increased. The shear bonding strength of SPC-containing resin was low. No inflammation was apparent in hamster cheek pouch mucosa when exposed to SPC resin covered with a layer of base resin. H(2)O(2) was released into buffer from this resin, but when placed onto tooth tissue with a protective layer of base resin, penetration of H(2)O(2) into the pulp chamber was undetectable. It is concluded that SPC resin equipped with a bleaching aid can be safely used as a coating material for discolored teeth. PMID- 23037844 TI - Change in surface properties of zirconia and initial attachment of osteoblastlike cells with hydrophilic treatment. AB - The objectives of this study were to characterize change in surface properties of tetragonal zirconia polycrystals (TZP) after hydrophilic treatment, and to determine the effect of such changes on initial attachment of osteoblast-like cells. Roughened surfaces were produced by alumina-blasting and acid-etching. Hydrophilic treatment comprised application of immediately after blasting and acid-etching (Blast/Etch), oxygen plasma (O2-Plasma), ultraviolet light (UV). Specimens stored in air were used as a control. The water contact angle was determined and surface analysis was performed using an X-ray photoelectron spectroscopy. Blast/Etch, O2-Plasma and UV specimens showed superhydrophilicity, and these hydrophilic treatments to TZP elicited a marked decrease in carbon content and an increase in hydroxyl groups. Hydrophilic treatments enhanced initial attachment of osteoblast-like cells and a change in cell morphologies. These results indicate that Blast/Etch, O2-Plasma, or UV treatment has potential in the creation and maintenance of superhydrophilic surfaces and enhancing initial attachment of osteoblast-like cells. PMID- 23037845 TI - Fabrication of porous titanium implants by three-dimensional printing and sintering at different temperatures. AB - This study evaluated the feasibility of using three-dimensional printing (3DP) to fabricate porous titanium implants. Titanium powder was blended with a water soluble binder material. Green, porous, titanium implants fabricated by 3DP were sintered under protective argon atmosphere at 1,200, 1,300, or 1,400 degrees C. Sintered implant prototypes had uniform shrinkage and no obvious shape distortion after sintering. Evaluation of their mechanical properties revealed that titanium prototypes sintered at different temperatures had elastic modulus of 5.9-34.8 GPa, porosity of 41.06-65.01%, hardness of 115.2-182.8 VHN, and compressive strength of 81.3-218.6 MPa. There were significant differences in each type of these data among the different sintering temperatures (p<0.01). Results of this study confirmed the feasibility of fabricating porous titanium implants by 3DP: pore size and pore interconnectivity were conducive to bone cell ingrowth for implant stabilization, and the mechanical properties matched well with those of the human bone. PMID- 23037846 TI - Effect of microbubbled water on the removal of a biofilm attached to orthodontic appliances--an in vitro study. AB - Orthodontic appliances often cause oral diseases such as dental caries and gingivitis due to the attachment of an oral biofilm. However, there are few reliable methods to remove the biofilm from the orthodontic appliances. The aim of this study was to investigate the effects of microbubbled water on the removal of biofilms made with Streptococcus mutans or Candida albicans on orthodontic appliances. The orthodontic appliances with biofilm were immersed with microbubbled water and the remaining biofilm on the appliances was detected and measured using a micro-plate reader and an absorbance meter. The microbubbled water had a sufficient effect on the removal of biofilm from orthodontic appliances. The effects of microbubbled water were significantly higher than those of tap water (S. mutans: p<0.05, C. albicans: p<0.01). The results of this study suggest that microbubbled water is effective in the removal of biofilm from the mouth of orthodontic patients. PMID- 23037847 TI - Toughening of CAD/CAM all-ceramic crowns by staining slurry. AB - The ability of staining slurries containing silver and/or potassium compounds to enhance the mechanical properties of a leucite-reinforced glass ceramic (IPS Empress CAD) was investigated by measuring the Vickers hardness, median crack length, toughness, and compressive residual stress of specimens. A staining slurry containing potassium ions was found to increase the toughness of IPS specimens more than a staining slurry containing only silver ions when applied prior to sintering. None of the staining slurries produced any color changes. Thus, the results obtained in this study demonstrate that staining slurries increase the Vickers hardness and the fracture toughness of the surface and subsurface regions of all-ceramic IPS blocks fabricated by a CAD/CAM system without sacrificing their aesthetics. PMID- 23037848 TI - Porosity of dental phosphate-bonded investments after setting and heating processes. AB - Porosities of set and burnout compacts of phosphate-bonded investments were determined. A gas pycnometer was used to measure the volumes, and hence the densities, of fine powders and porous compacts. Porosities of set and burnout compacts were then obtained from these data for as-received powders and dry set compacts by a numerical simulation method, subsequently leading on to the estimated compositions of conventional and rapid-heating investments used in this study. Excess water content in the hardening investment compact was evaluated as a function of setting time elapsed from the start of mixing. Porosities were about 24-32% for set compacts and 43% for burnout compacts, which well agreed with the numerically computed results. It was concluded that the functional composition of investment powder needed to achieve the optimal porosity as well as process parameters such as water-powder (W/P) ratio and keeping time of mixed investment casting slurry before heat treatment could be determined using the numerical simulation method developed in this study. PMID- 23037849 TI - In vitro osteoinduction of human mesenchymal stem cells in biomimetic surface modified titanium alloy implants. AB - Interaction between cells and implant surface is crucial for clinical success. This interaction and the associated surface treatment are essential for achieving a fast osseointegration process. Several studies of different topographical or chemical surface modifications have been proposed previously in literature. The Biomimetic Advanced Surface (BAS) topography is a combination of a shot blasting and anodizing procedure. Macroroughness, microporosity of titanium oxide and Calcium/Phosphate ion deposition is obtained. Human mesenchymal stem cells (hMCSs) response in vitro to this treatment has been evaluated. The results obtained show an improved adhesion capacity and a higher proliferation rate when hMSCs are cultured on treated surfaces. This biomimetic modification of the titanium surface induces the expression of osteblastic differentiation markers (RUNX2 and Osteopontin) in the absence of any externally provided differentiation factor. As a main conclusion, our biomimetic surface modification could lead to a substantial improvement in osteoinduction in titanium alloy implants. PMID- 23037850 TI - Effect of experimental acid/base conditioner on microtensile bond strength of 4 META/MMA-TBB resin to dentin after long-term water immersion. AB - An experimental conditioner (Exp), which was an aqueous solution of 10% ascorbic acid and 5% ferric chloride, was prepared in this study. This study evaluated the effect of Exp on the microtensile bond strength between a self-curing resin and dentin after long-term water immersion. Flat human dentin surfaces were sequentially pretreated with 40% phosphoric acid, 10% sodium hypochlorite, and Exp. Surface pretreatment with an aqueous solution of 10% citric and 3% ferric chloride (10-3) was used as a control. Composite resin rods were bonded to pretreated dentin surfaces using 4-META/MMA-TBB resin. Microtensile bond strengths were evaluated after water immersion at 24 h, 12 months, 24 months, and 36 months. At each immersion period, the bond strength of Exp was significantly higher than that of 10-3. After 36 months, Exp showed no significant decrease in microtensile bond strength, but 10-3 showed significant reductions. Pretreatment with experimental acid/base conditioner markedly improved the bonding durability of 4-META/MMA-TBB resin to human dentin when compared against the conventional 10 3 treatment. PMID- 23037851 TI - Electric toothbrushes induce electric current in fixed dental appliances by creating magnetic fields. AB - Magnetic fields can represent a health problem, especially low frequency electromagnetic fields sometimes induced by electric current in metallic objects worn or used in or on the body (as opposed to high frequency electromagnetic fields that produce heat). Electric toothbrushes are widely used because of their convenience, but the electric motors that power them may produce electromagnetic waves. In this study, we showed that electric toothbrushes generate low frequency (1-2000 Hz) magnetic fields and induce electric current in dental appliances (e. g. orthodontic and prosthetic appliances and dental implants). Current induced by electric toothbrushes might be dependent on the quantity and types of metals used, and the shape of the appliances. Furthermore, these induced currents in dental appliances could impact upon human oral health, producing pain and discomfort. PMID- 23037852 TI - Morinda citrifolia leaves enhance osteogenic differentiation and mineralization of human periodontal ligament cells. AB - This present study investigated the potential of Morinda citrifolia leaf aqueous extract to induce osteogenic differentiation and matrix mineralization of human periodontal ligament (hPDL) cells. Human periodontal ligament cells were cultured in complete medium, ascorbic acid with beta-glycerophosphate, or Morinda citrifolia leaf aqueous extract. Morinda citrifolia leaf aqueous extract significantly increased alkaline phosphatase activity compared to culturing in complete medium or ascorbic acid with beta-glycerophosphate. Matrixcontaining mineralized nodules were formed only when the cells were cultured in the presence of Morinda citrifolia leaf aqueous extract. These nodules showed positive alizarin red S staining and were rich in calcium and phosphorus according to energy dispersive X-ray analysis. In conclusion, Morinda citrifolia leaf extract promoted osteogenic differentiation and matrix mineralization in human periodontal ligament cells, a clear indication of the therapeutic potential of Morinda citrifolia leaves in bone and periodontal tissue regeneration. PMID- 23037853 TI - Effects of fibers on the color change and stability of resin composites after accelerated aging. AB - Composite resins were reinforced with glass and polyethylene fibers in this study, and the effect of fiber reinforcement on the color change of composite resins was investigated. After accelerated aging, the effect of fiber reinforcement on the color stability of composite resins was also examined. There were three experimental groups (n=12 disks per group): non-fiber-reinforced composite (non-FRC control), polyethylene fiber (Ribbond-THM)-reinforced composite, and glass fiber (everstick NET)-reinforced composite. According to the critical remarks of color change of National Bureau of Standarts (NSB), glass fiber-reinforced anterior composites showed trace color change and polyethylene fiber reinforced composites showed slight color change before accelerated aging. After accelerated aging, both control and fiber-reinforced composite groups showed noticeable color change. It was concluded that both the types of fiber reinforcement and composite resin influenced the color change of fiber-reinforced composite resins. PMID- 23037854 TI - The color stability of silorane- and methacrylate-based resin composites. AB - The purpose of this study were to evaluate the discoloration of a silorane-based resin and two methacrylated-based resin composites upon exposure to different staining solutions coffee, red wine, porcine liver esterase and distilled water for 7 days. The colors of all specimens before and after storage in the solutions were measured by a spectrophotometer based on CIE Lab system, and the color differences thereby calculated. Data were statistically analyzed by ANOVA and Scheffe's test. For coffee and red wine, the mean color change in silorane-based resin was significantly lower than that in methacylate-based resin composites (p<0.05). For porcine liver esterase and distilled water, there was no significant difference in the mean values of color change between silorane- and methacrylate-based resin composites (p>0.05). In conclusion, the silorane-based resin composites exhibited better color stability (less DeltaE) after exposure to the colored staining solutions. PMID- 23037855 TI - An infant with heart failure due to ventricular dyssynchrony and refractory tachycardia caused by a right anterolateral accessory pathway. AB - Wolff-Parkinson-White syndrome is associated with heart failure (HF) mainly via tachycardia. Several case report series have suggested dyssynchrony due to an accessory pathway as a possible cause of HF even in the absence of tachyarrhythmias. The role of cardiac resynchronization in the suppression of anterograde conduction of accessory pathways by catheter ablation or pharmacotherapy in such patients remains unclear, especially in the pediatric population. We describe an infant case with HF due to ventricular dyssynchrony and refractory tachycardia caused by a right anterolateral accessory pathway. Cardiac resynchronization either by catheter ablation or amiodarone appears to be of value in such cases. PMID- 23037856 TI - Direct Pd-catalyzed cross-coupling of functionalized organoaluminum reagents. AB - A handsome couple: Through the use of the simple Pd catalyst [Pd(tmpp)(2)Cl(2)] (tmpp = tris(2,4,6-trimethoxyphenyl)phosphine) and THF/DMF as solvent, various aryl-, heteroaryl-, benzyl- and alkylaluminum reagents can be readily cross coupled with aryl or heteroaryl iodides, bromides, and nonaflates, and in special cases even with chlorides and triflates. This cross-coupling tolerates free NH(2) groups, aldehydes, ketones, esters, and nitro functions. PMID- 23037857 TI - Expression of Notch receptor and its target gene Hes-1 in bone marrow CD34+ cells from patients with psoriasis. AB - Psoriasis is an autoimmune disease mediated mainly by dysfunctional peripheral blood T cells. Both CD4+/CD8+ T cells and CD4+CD25+ regulatory T cells derived from psoriatic CD34+ bone marrow cells in vitro have been found to be functionally similar to those psoriatic circulating and lesional T cells. Notch signaling participates in diverse cell fate decisions during T cell development and has been reported to influence the proliferation of hematopoietic stem cells and the differentiation of T cells. The purpose of this study was to investigate the expression levels of Notch receptor 1, 2 and its target gene Hes-1 in CD34+ cells from patients with psoriasis. The total RNA and protein of CD34+ cells were extracted, and the mRNA as well as protein expression of Notch1, Notch2 and Hes-1 were investigated using real-time PCR and Western blot assays. We found that the mRNA and protein expression levels of Notch1 and Hes-1 in psoriasis patients were higher compared to normal controls, while the Notch2 mRNA and protein expression levels in psoriasis patients were similar to those of normal controls. The elevated Notch1 and Hes-1 expression levels in psoriatic CD34+ cells might be one reason for the immune disorders which are mainly mediated by T cells. PMID- 23037858 TI - Accessing carboxylesterase diversity from termite hindgut symbionts through metagenomics. AB - A shotgun metagenomic library was constructed from termite hindgut symbionts and subsequently screened for esterase activities. A total of 68 recombinant clones conferring esterolytic phenotypes were identified, of which the 14 most active were subcloned and sequenced. The nucleotide lengths of the esterase-encoding open reading frames (ORFs) ranged from 783 to 2,592 bp and encoded proteins with predicted molecular masses of between 28.8 and 97.5 kDa. The highest identity scores in the GenBank database, from a global amino acid alignment ranged from 39 to 83%. The identified ORFs revealed the presence of the G-X-S-X-D, G-D-S-X, and S-X-X-K sequence motifs that have been reported to harbour a catalytic serine residue in other previously reported esterase primary structures. Five of the ORFs (EstT5, EstT7, EstT9, EstT10, and EstT12) could not be classified into any of the original eight esterase families. One of the ORFs (EstT9) showed a unique primary structure consisting of an amidohydrolase-esterase fusion. Six of the 14 esterase-encoding genes were recombinantly expressed in Escherichia coli and the purified enzymes exhibited temperature optima of between 40-50 degrees C. Substrate-profiling studies revealed that the characterised enzymes were 'true' carboxylesterases based on their preferences for short to medium chain length p nitrophenyl ester substrates. This study has demonstrated a successful application of a metagenomic approach in accessing novel esterase-encoding genes from the gut of termites that could otherwise have been missed by classical culture enrichment approaches. PMID- 23037859 TI - High resolution imaging of superficial mosaicity in single crystals using grazing incidence fast atom diffraction. AB - A new table top technique is used to simultaneously analyze the local morphology of crystalline surfaces as well as the misalignment of large scale domains at the topmost surface layer. The approach is based on fast atom diffraction at grazing incidence (GIFAD); the diffraction pattern yields the structural characteristics and the topology of the surface electronic density with atomic resolution. If superficial mosaicity is present, diffraction patterns arising from each mosaic domain can be distinguished, providing high sensitivity to the properties of each of the domains. Taking NaCl(001) as an example, we observe a discrete tilt angle distribution of the mosaic domains following an arithmetic progression with a 0.025 degrees +/- 0.005 degrees difference; a twist mosaic angle of 0.09 degrees +/- 0.01 degrees is also observed. PMID- 23037860 TI - Fighting outbreaks with bacterial genomics: case review and workflow proposal. AB - BACKGROUND: Disease outbreak investigation is a key aspect of public health. Whole-genome sequencing of bacterial pathogen based on new generation high throughput sequencing technologies has facilitated outbreak investigations recently. Whilst the approach has become more affordable and accessible to research and clinical laboratories, a system for adequate and efficient analyses of genome data in the context of bacterial outbreak investigations is missing. METHODS: We performed a literature review of timely genomic investigations performed during the course of bacterial outbreaks that are based on new generation sequencing technologies. Currently available bioinformatics tools for genomic analyses are also reviewed here. RESULTS: Genomic investigations in early stages of bacterial outbreaks have shown to provide timely information on evolutionary origin, transmission route, pathogenic potential, and resistance information of the outbreak strains and allow development of strain-specific typing methods. A systematic genomic analytical workflow is proposed here for the first time to facilitate efficient extraction of epidemiologically useful information from genome data of bacterial pathogens in future bacterial outbreak investigations. CONCLUSION: With the continuous reduction of genome sequencing cost and development of user-friendly analytical tools, it is expected that high throughput genome sequencing will be applied routinely for timely genomic analysis in bacterial outbreaks in the near future. PMID- 23037861 TI - Factors associated with supracricoid laryngectomy functional outcomes. AB - BACKGROUND: Supracricoid partial laryngectomy (SCPL) is an option for laryngeal cancer resection that preserves laryngeal function; however, little information exists regarding factors that are associated with functional outcomes. METHODS: A medical chart review was performed on patients that underwent SCPL at our institution between 2006 and 2011. Data were collected on surgical, voice, and swallowing outcomes. RESULTS: Eighteen patients were identified. Thirteen underwent cricohyoidoepiglottopexy (CHEP) and 5 had a cricohyoidopexy (CHP). Mean follow-up was 737 days. On average, decannulation occurred at 27.4 days and feeding tube removal at 87.9 days postoperatively. Sixty-seven percent of patients tolerated an unrestricted diet at follow-up. Increased age and a CHP procedure were associated with negative outcomes. Age may be a proxy for more extensive disease and prior treatments. CONCLUSION: Patients who undergo an SCPL require extensive rehabilitation after surgery. Those who have undergone multiple cancer interventions and have more extensive surgery may be at risk for poorer outcomes. PMID- 23037862 TI - Use of a polyol liquid collection medium to obtain ultrasmall magnetic nanoparticles by laser pyrolysis. AB - The present work addresses the main bottleneck in the synthesis of magnetic nanoparticles by laser pyrolysis. Since the introduction of laser pyrolysis for the production of nanoparticles nearly three decades ago, this method has been repeatedly presented as a highly promising alternative, on account of two main characteristics: (i) its flexibility, since nanoparticles can be formed from a wide variety of precursors in both gas and liquid phase, and (ii) its continuous nature, avoiding the intrinsic variability of batch processing. However, the results reported to date invariably show considerable aggregation of the obtained nanoparticles, which strongly limits their application in most fields. In this work, we have been able to circumvent this problem by collecting the particles in a polyol liquid medium. This method prevents the formation of aggregates and renders a uniform distribution of well dispersed ultrasmall nanoparticles (<4 nm) in a water-compatible solvent. We consider that the effectiveness of this novel collection method for the production of well-dispersed magnetic nanoparticles will be of high interest to a wide range of scientists working in the nanoparticle synthesis field and may enable new applications wherever there is a strict requirement for non-agglomerated nanoparticles. PMID- 23037863 TI - Water-soluble, redox-active organometallic calcium chelators. AB - This paper describes a new series of organometallic water-soluble chelators combining a redox moiety (ferrocene) and a selective Ca2+ chelator (BAPTA) separated by an ethynyl bridge. We report the synthesis and characterization of organometallic derivatives of the BAPTA chelator featuring one (2a) and two ferrocenyl (2b) moieties. Single crystal X-ray structural analysis on these chelators revealed unexpected conformations for the ferrocenyl substituent with respect to the phenyl ring of the BAPTA unit. DFT calculations on a model system of the ferrocenyl-ethynyl-BAPTA molecule were carried out to evaluate the energy separation between the two limiting conformations observed experimentally in the solid state, and to check the effective electronic communication between the binding pocket and the redox probe. The binding affinity of 2a-b for Ca2+, as probed by UV-Vis and cyclic voltammetry, revealed distinct behaviors in the presence of a metal ion depending on whether BAPTA is substituted by one or two ferrocenyl groups. PMID- 23037864 TI - A PCR based survey of Babesia ovata in cattle from various Asian, African and South American countries. AB - Babesia ovata is a tick-transmitted hemoprotozoan parasite that infects cattle. In our study, bovine blood samples (n=2,034) were collected from 10 different countries (Brazil, China, Ghana, Japan, Mongolia, the Philippines, South Africa, Sri Lanka, Thailand and Vietnam) and DNA extracted. The DNA samples were screened using an established and specific polymerase chain reaction (PCR) assay targeting the Apical membrane antigen 1 (AMA-1) gene. Parasite DNA was detected among samples collected from Japan, Mongolia and Thailand. Sequence analyses confirmed that the PCR assay detected only B. ovata AMA-1, and that amplicons from different geographical locations were conserved. Our findings highlight the importance of designing adequate strategies to control B. ovata infection in Japan, Mongolia, and Thailand. PMID- 23037865 TI - Can simple clinical tests predict walking ability after prosthetic rehabilitation? AB - OBJECTIVE: To investigate whether simple clinical measures can predict walking ability after lower limb prosthetic rehabilitation. DESIGN: Prospective observational study. SUBJECTS: Ninety five adults who were assessed as suitable for lower limb prosthetic rehabilitation by the multidisciplinary team. METHODS: Information regarding baseline clinical factors (amputation details, comorbidities, physical ability, mood and cognitive ability) was collected prior to provision of the prosthesis. Backward step linear regression was used to identify factors predictive of performance on the Timed Up and Go test following rehabilitation. RESULTS: Seventy one participants were able to complete this walking test and were included in the final analysis. The backward step regression model had an adjusted R2 of 0.588 and comprised 6 factors: age (p = 0.002), gender (p = 0.027), level of amputation (p = 0.000), presence of contracture (p = 0.088), ability to stand on one leg (p = 0.062) and Trail Making Tests A + B (p = 0.047), a test of cognitive flexibility. Cause of amputation (dysvascular or non-dysvascular) was not an independent predictor of walking outcome. CONCLUSION: These results indicate that simple clinical assessments completed prior to prosthetic provision can be used to predict mobility outcome. These findings need to be validated in a larger population across other amputee rehabilitation services and if confirmed could easily be incorporated into routine clinical practice. PMID- 23037867 TI - A hematology consensus agreement on antifungal strategies for neutropenic patients with hematological malignancies and stem cell transplant recipients. Gruppo Italiano Malattie Ematologiche dell'Adulto, Gruppo Italiano Trapianto di Midollo Osseo, Associazione Italiana Ematologia ed Oncologia Pediatrica, Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and Sorveglianza Epidemiologica delle Infezioni Fungine nelle Emopatie Maligne. AB - In the attempt to establish key therapy definitions and provide shared approaches to invasive fungal diseases in neutropenic patients, trials of empiric, preeemptive and targeted antifungal therapy (EAT, PAT and TAT) were reviewed, and a Consensus Development Conference Project was convened. The Expert-Panel concurred that all antifungal treatments, including EAT, should always follow an adequate diagnostic strategy and that the standard definition of PAT may be misleading: being PAT guided by the results of a diagnostic work-up, it should better be termed diagnostic-driven antifungal therapy (DDAT). The Expert-Panel agreed that radiological findings alone are insufficient for the choice of a TAT and that the identification of the etiologic pathogen is needed. The Consensus Agreement proceeded identifying which clinical and microbiological findings were sufficient to start a DDAT and which were not. Finally, an algorithm to rationalize the choice of antifungal drugs on the basis of clinical manifestations, antifungal prophylaxis, instrumental and laboratory findings was drawn up. PMID- 23037866 TI - Stressful life events and cognitive decline in late life: moderation by education and age. The Cache County Study. AB - OBJECTIVE: Stressful life events (SLE) have been associated with increased dementia risk, but their association with cognitive decline has been inconsistent. In a longitudinal population-based study of older individuals, we examined the association between SLE and cognitive decline, and the role of potential effect modifiers. METHODS: A total of 2665 non-demented participants of the Cache County Memory Study completed an SLE questionnaire at Wave 2 and were revisited 4 and 7 years later. The events were represented via several scores: total number, subjective rating (negative, positive, and unexpected), and a weighted summary based on their impact. Cognition was assessed at each visit with the modified Mini-Mental State Exam. General linear models were used to examine the association between SLE scores and cognition. Effect modification by age, education, and APOE genotype was tested. RESULTS: Years of formal education (p = 0.006) modified the effect of number of SLE, and age (p = 0.009) modified the effect of negative SLE on the rate of cognitive decline. Faster decline was observed among those with fewer years of education experiencing more SLE and also among younger participants experiencing more negative SLE. There was no association between other indicators of SLE and cognitive decline. APOE genotype did not modify any of the aforementioned associations. CONCLUSIONS: The effects of SLE on cognition in late life are complex and vary by individual factors such as age and education. These results may explain some of the contradictory findings in the literature. PMID- 23037868 TI - Self-assembled nanostructures of optically active phthalocyanine derivatives. Effect of central metal ion on the morphology, dimension, and handedness. AB - Four optically active {(2,3,9,10,16,17,23,24-octa[(S)-2-methylbutoxy]} phthalocyanine derivatives with different central metal ions, namely (S) H2Pc(beta-OC5H11)8 (1), (S)-ZnPc(beta-OC5H11)8 (2), (S)-CuPc(beta-OC5H11)8 (3), and (S)-NiPc(beta-OC5H11)8 (4) have been synthesized and their self-assembly behaviors systematically investigated by electronic absorption and circular dichroism (CD) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) techniques, and X-ray photoelectron spectroscopy (XPS). Metal free phthalocyanine together with its zinc and copper congeners self-assembles into right-handed helical arrangements in a stack of phthalocyanine chromophores according to the CD spectroscopic result, while the nickel complex does so into the left-handed helical arrangements. These helical arrangements, acting as elemental primary structures, further pack in a hierarchical fashion into either highly ordered right-handed fibrous nanostructures with average 300 MUm length, 4.8 MUm width, and 4.4 MUm helical pitch for 1 and 300 MUm length, 2.4 MUm width, and 1.8 MUm helical pitch for 2 but left-handed fibrous nanostructures with average 4 MUm length, 0.48 MUm width, and 0.12 MUm helical pitch for 3 and 300 MUm length, 2 MUm width, and 1.2 MUm helical pitch for 4, clearly revealing the effect of central metal ion on the distance and relative orientation of neighboring phthalocyanine chromophores and in turn the supramolecular chirality, morphology, dimension, and handedness of the self-assembled nanostructures. The present result not only represents a unique phenomenon in the self-assembly of phthalocyanine compounds but more importantly denotes the transcription and amplification of molecular chirality to supramolecular helicity with different helical bias during the self-assembly processes without changing the chiral handles attached to the phthalocyanine chromophore. PMID- 23037869 TI - A novel quantum dot-laccase hybrid nanobiosensor for low level determination of dopamine. AB - This work reports a novel nanobiosensor based on a thioglycolic acid (TGA)-capped CdTe quantum dot-laccase (Lac) enzyme system for sensitive detection of dopamine (DA). The enzyme used catalyzes the oxidation of DA to dopamine-o-quinone (DOQ), which can selectively quench the strong luminescence of CdTe nanocrystals at neutral pH. The relationship between luminescence intensity of CdTe nanocrystals and DA concentration is nicely described by the Stern-Volmer equation. At an optimum pH of 7.4, the proposed sensor gives a linear calibration over a DA concentration range of 0.3 to 100 MUM, with a limit of detection of 0.16 MUM and a response time of 2 min. The relative standard deviation for seven replicate determinations of 6.0 MUM of DA was found to be 3.7%. The sensor was successfully applied to the determination of DA in a blood plasma sample and in a DA injection formulation. PMID- 23037871 TI - Vitamin D status in pediatric patients with a history of malignancy. AB - BACKGROUND: Multiple studies associate low vitamin D levels with cancer morbidity and mortality. However, few studies have measured vitamin D in pediatric patients with malignancy. Our aim was to assess vitamin D status in a large cohort of pediatric patients with cancer and to define risk factors for deficiency. METHODS: Circulating 25-hydroxyvitamin D (25OHD) levels were measured in 211 patients. Calcium intake and sun exposure habits were assessed in 142 patients (age 12.1 +/- 5.8 y; number of male patients, 69; mean time from diagnosis, 4.4 +/- 3.8 y). RESULTS: Daily calcium intake was 66.2 +/- 39.3% of the recommended daily allowance. Mean 25OHD levels were 20.6 +/- 7.9 ng/ml. Vitamin D deficiency (<15 ng/ml) was found in 24.6% of the patients and insufficiency (15-20 ng/ml) in 23.2%. Younger age and amount of sun exposure were associated with higher serum 25OHD. No association was found with calcium intake, disease type, gender, BMI SD score, years since diagnosis, or stem cell transplantation. The 25OHD levels during winter were significantly lower than the summer levels. CONCLUSION: The prevalence of vitamin D deficiency and insufficiency in pediatric patients with a history of malignancy was high, whereas calcium intake was low. These findings are concerning, given the risk for osteoporosis in this population and the possible role of vitamin D in the context of malignancy. PMID- 23037870 TI - CD117(+) amniotic fluid stem cells: state of the art and future perspectives. AB - Broadly multipotent stem cells can be isolated from amniotic fluid by selection for the expression of the membrane stem cell factor receptor c-Kit, a common marker for multipotential stem cells. They have clonogenic capability and can be directed into a wide range of cell types representing the three primary embryonic lineages. Amniotic fluid stem cells maintained for over 250 population doublings retained long telomeres and a normal karyotype. Clonal human lines verified by retroviral marking were induced to differentiate into cell types representing each embryonic germ layer, including cells of adipogenic, osteogenic, myogenic, endothelial, neuronal and hepatic lineages. AFS cells could be differentiate toward cardiomyogenic lineages, when co-cultured with neonatal cardiomyocytes, and have the potential to generate myogenic and hematopoietic lineages both in vitro and in vivo. Very recently first trimester AFS cells could be reprogrammed without any genetic manipulation opening new possibilities in the field of fetal/neonatal therapy and disease modeling. In this review we are aiming to summarize the knowledge on amniotic fluid stem cells and highlight the most promising results. PMID- 23037872 TI - Moderate tidal volumes and oxygen exposure during initiation of ventilation in preterm fetal sheep. AB - BACKGROUND: Preterm infants often receive mechanical ventilation and oxygen at birth. Exposure to large tidal volumes (V(T)s) at birth causes lung inflammation, and oxygen may amplify the injury. We hypothesized that normal V(T) ventilation at birth causes lung injury that is exacerbated by 95% oxygen. METHODS: The head and chest of anesthetized preterm fetal sheep (129 +/- 1 d gestation) were surgically exteriorized while maintaining the placental circulation. Fetuses were randomized to four groups with either V(T) ventilation to 6 ml/kg or continuous positive airway pressure of 5 cm H2O, and either 95%O2/5%CO2 or 95%N2/5%CO2. Age matched fetuses were used as controls. After a 15-min intervention, the fetal lamb was returned to the uterus for 1 h 45 min. RESULTS: In ventilated lambs, V(T) was 6.2 +/- 0.4 ml/kg at 15 min. Ventilation increased proinflammatory cytokines as compared with controls and lambs on continuous positive airway pressure, with recruitment of primarily monocytes to bronchoalveolar lavage fluid. Early response protein 1 was activated around the bronchioles in V(T) ventilated animals. The 15-min oxygen exposure did not change inflammatory mediators or other markers of lung and oxidative stress. CONCLUSION: A V(T) of 6 7 ml/kg at birth increased early markers of injury and lung inflammation. Brief exposure to 95% oxygen did not alter lung inflammation. PMID- 23037873 TI - The relationship between patterns of intermittent hypoxia and retinopathy of prematurity in preterm infants. AB - BACKGROUND: We have previously shown an increased incidence of intermittent hypoxemia (IH) events in preterm infants with severe retinopathy of prematurity (ROP). Animal models suggest that patterns of IH events may play a role in ROP severity as well. We hypothesize that specific IH event patterns are associated with ROP in preterm infants. METHODS: Variability in IH event duration, severity, and the time interval between IH events (<=80%, >=10 s, and <=3 min) along with the frequency spectrum of the oxygen saturation (SpO2) waveform were assessed. RESULTS: Severe ROP was associated with (i) an increased mean and SD of the duration of IH event (P < 0.005), (ii) more variability (histogram entropy) of the time interval between IH events (P < 0.005), (iii) a higher IH nadir (P < 0.05), (iv) a time interval between IH events of 1-20 min (P < 0.05), and (v) increased spectral power in the range of 0.002-0.008 Hz (P < 0.05), corresponding to SpO2 waveform oscillations of 2-8 min in duration. Spectral differences were detected as early as 14 d of life. CONCLUSION: Severe ROP was associated with more variable, longer, and less severe IH events. Identification of specific spectral components in the SpO2 waveform may assist in early identification of infants at risk for severe ROP. PMID- 23037874 TI - Functional outcome of very preterm-born and small-for-gestational-age children at school age. AB - BACKGROUND: Our aim was to determine functional outcome of very preterm-born and small-for-gestational-age (SGA) children as compared with matched controls at school age. METHODS: We included 28 very preterm SGA children (GA <32 wk, birth weight (BW) <10th percentile), born in 2000-2001. We also included 28 very preterm but appropriate-for-gestational-age (AGA) children, matched for GA, gender, and birth year, as controls. We assessed motor skills, intelligence quotient (IQ), attention, verbal memory, visual perception, visuomotor integration, executive functioning, and behavior of both sets of children at school age. RESULTS: The SGA children had a median GA of 29.7 wk and BW of 888 g, whereas the controls had a median GA of 29.4 wk and BW of 1,163 g. At 8.6 y, the median total IQ of the SGA children was 94 as compared with 95 in the controls (not significant). Performance IQ was significantly lower in SGA children (89 vs. 95, P = 0.043), whereas verbal IQ was not (95 vs. 95). Total motor skills (P = 0.048) and fine motor skills (P = 0.021) were worse in SGA children. Furthermore, SGA children scored lower on selective attention (P = 0.026) and visual perception (P = 0.025). Other scores did not differ significantly between groups. CONCLUSION: The differences we found between the groups were small. This suggests that the impaired functioning of very preterm-born SGA children is attributable to their having been born very preterm rather than to being SGA. PMID- 23037876 TI - Damage control orthopedics: current evidence. AB - PURPOSE OF REVIEW: There is still an ongoing debate whether damage control orthopedics (DCO) or other treatment strategies should be favored in the treatment of multiply injured patients. This review gives an overview of the current literature concerning this important question in the treatment of severely injured patients. RECENT FINDINGS: Several studies could show that DCO can reduce the inflammatory burden due to surgery (second hit). The only randomized study showed a benefit for borderline patients treated by DCO in comparison to early total care. Other studies showed advantages for early care treatment in similar patients. SUMMARY: In severely injured patients, DCO should be considered. On the other hand, there is still a lack of randomized studies for a more precise characterization of the patients who benefit from DCO treatment. PMID- 23037875 TI - Late administration of surfactant replacement therapy increases surfactant protein-B content: a randomized pilot study. AB - BACKGROUND: Surfactant dysfunction may contribute to the development of bronchopulmonary dysplasia (BPD) in persistently ventilated preterm infants. We conducted a multicenter randomized, blinded, pilot study to assess the safety and efficacy of late administration of doses of a surfactant protein-B (SP-B) containing surfactant (calfactant) in combination with prolonged inhaled nitric oxide (iNO) in infants <=1,000 g birth weight (BW). METHODS: We randomized 85 preterm infants ventilated at 7-14 d after birth to receive either late administration of surfactant (up to 5 doses) plus prolonged iNO or iNO alone. Large aggregate surfactant was isolated from daily tracheal aspirates (TAs) for measurement of SP-B content, total protein, and phospholipid (PL). RESULTS: Late administration of surfactant had minimal acute adverse effects. Clinical status as well as surfactant recovery and SP-B content in tracheal aspirate were transiently improved as compared to the controls; these effects waned after 1 d. The change in SP-B content with surfactant dosing was positively correlated with SP-B levels during treatment (r = 0.50, P = 0.02). CONCLUSION: Low SP-B values increased with calfactant administration, but the relationship of this response to SP-B levels suggests that degradation is a contributing mechanism for SP-B deficiency and surfactant dysfunction. We conclude that late therapy with surfactant in combination with iNO is safe and transiently increases surfactant SP-B content, possibly leading to improved short- and long-term respiratory outcomes. PMID- 23037877 TI - Burn injuries. AB - PURPOSE OF REVIEW: To summarize and highlight recent advances in the understanding and management of burn injuries. RECENT FINDINGS: The review focuses on topics which are of particular relevance for critical care practitioners involved in burn care: resuscitation, management of infection and sepsis, epidemiology and outcome, and organization and costs of burn care. SUMMARY: While being the mainstay of early survival in burn victims, various aspects of burn resuscitation are still contentious and highlighted in this review. In particular, several strategies to overcome the repeatedly observed 'fluid creep' in burn patients are discussed, including the use of computerized resuscitation algorithms and the administration of colloids. Sepsis and multiorgan failure have become the major causes of death in patients surviving the initial phase of burn shock. Various aspects of sepsis management are reviewed, amongst which diagnosis, antibiotic treatment and prophylaxis. Recent epidemiologic data allow to identify risk factors associated with mortality as these are potentially amenable to targeted prevention and therapy. Examples are acute kidney injury and sepsis. The overview is completed by recent findings on organization and costs of burn care, including the adherence to referral criteria and the main determinants of cost. PMID- 23037878 TI - Fluid overload in AKI: epiphenomenon or putative effect on mortality? AB - PURPOSE OF REVIEW: The incidence of acute kidney injury (AKI) is increasing dramatically, and despite advances in dialytic therapy and critical care, there has been little improvement in associated morbidity and mortality. Recently, several articles have suggested that fluid overload in patients with AKI is associated with an increased risk of death. RECENT FINDINGS: Observational studies have demonstrated an association between fluid overload and poor outcomes (including death) in patients with AKI; however, whether this association is causal or due to residual confounding is unknown. A recent study testing the impact of fluid overload and diuretics on outcomes in the context of a randomized controlled trial suggests that the beneficial impact of diuretics in those with AKI is mediated by reducing fluid overload. Finally, potential mechanisms by which fluid overload may contribute to death include failure to recognize AKI due to creatinine dilution, direct tissue edema leading to decreased renal perfusion, and an increased risk of other complications such as sepsis. SUMMARY: On the basis of the current literature, the relative contributions of the direct effects of fluid overload versus the association of fluid overload with other patient characteristics associated with adverse outcome (e.g. sepsis) remain unknown. Additional human studies, including randomized controlled trials, are warranted to further clarify these issues. PMID- 23037879 TI - General switch in regioselectivity in the Mukaiyama aldol reaction of silyloxyfuran with aldehydes in aqueous solvents. AB - An unexpected yet disciplined course of catalytic Mukaiyama-aldol reaction instead of the expected vinylogous Mukaiyama-aldol reaction has been observed for the reaction of silyloxyfuran with various aldehydes under Lewis acid catalytic control in water-containing solvents. PMID- 23037880 TI - Proton defect solvation and dynamics in aqueous acid and base. AB - Easy come, easy go: LEWIS, a new model of reactive and polarizable water that enables the simulation of a statistically reliable number of proton hopping events in aqueous acid and base at concentrations of practical interest, is used to evaluate proton transfer intermediates in aqueous acid and base (picture, left and right, respectively). PMID- 23037881 TI - Nano-TiO2/polyurethane composites for antibacterial and self-cleaning coatings. AB - Grafting from polymerization was used to synthesize nano-titania/polyurethane (nTiO(2)/polyurethane) composite coatings, where nTiO(2) was chemically attached to the backbone of the polyurethane polymer matrix with a bifunctional monomer, 2,2-bis(hydroxymethyl) propionic acid (DMPA). This bifunctional monomer can coordinate to nTiO(2) through an available -COOH group, with two available hydroxyl groups that can react with diisocyanate terminated pre-polyurethane through step-growth polymerization. The coordination reaction was monitored by FTIR and TGA, with the coordination reaction found to follow first order kinetics. After step-growth polymerization, the polyurethane nanocomposites were found to be stable on standing with excellent distribution of Ti in the polymer matrix without any significant agglomeration compared to simple physical mixtures of nTiO(2) in the polyurethane coatings. The functionalized nTiO(2)-polyurethane composite coatings showed excellent antibacterial activity against gram-negative bacteria Escherichia coli; 99% of E. coli were killed within less than one hour under solar irradiation. Self-cleaning was also demonstrated using stearic acid as a model for 'dirt'. PMID- 23037882 TI - Estimation of inhibitory effects of hemicellulosic wood hydrolysate inhibitors on PHA production by Burkholderia cepacia ATCC 17759 using response surface methodology. AB - Sugar maple hemicellulosic hydrolysate was utilized as a renewable feedstock for polyhydroxyalkanoates production by Burkholderia cepacia ATCC 17759. To estimate inhibitory effects of the hydrolysate, response surface methodology was utilized to analyze cell growth and PHA accumulation in the presence of multiple inhibitors. Mixture design was employed to study the correlation between the proportion of phenolics and total inhibition. The resultant models (R(2) as 92.42% and 93.14% for cell growth and PHA production, respectively) indicated syringic acid was the most inhibitory among three phenolics and synergistic inhibition was observed for the combinations of vanillin/syringic acid and vanillic acid/syringic acid. When furfural, levulinic acid, and acetate were also present during the fermentation, central composite design was employed. The regression model using 48 h cell growth as the response surface (R(2)=87.82%) showed acetate was the most inhibitory. Additionally, strong synergistic effects were observed for the combinations of acetate/phenolics and levulinic acid/furfural. PMID- 23037883 TI - Microaerophilic microenvironment at biocathode enhances electrogenesis with simultaneous synthesis of polyhydroxyalkanoates (PHA) in bioelectrochemical system (BES). AB - Microaerophilic microenvironment at biocathode was evaluated for electrogenesis along with the polyhydroxyalkanoates (PHA) accumulation in bio-electrochemical system (BES). The electrogenic activity (512 mV; 15.2 mW/m(2)) was extended for longer periods (144 h) which might be attributed to the lowering of losses due to the controlled microbial metabolism. Growth limiting stress at cathode due to lower oxygen levels and its effective utilization by the protons and electrons coming from anode, might have diverted the microbial metabolism towards PHA synthesis instead of oxidation. PHA accumulation (19% of dry cell weight (DCW)) was observed with higher hydroxy butyrate (HB) (89%) concentration at 48 th h in the cathodic biocatalyst and was re-utilized by the end of experiment. Bio electro kinetics studied through voltammetry and Tafel analysis further supported the observed electrogenesis in microaerophilic reduction microenvironment, in terms of redox catalytic currents, Tafel slopes, exchange current densities and polarization resistance. PMID- 23037884 TI - Erythroderma: a clinical and prognostic study. AB - BACKGROUND: Erythroderma is a rare skin disorder and studies on its causes and prognosis are rare in the literature. OBJECTIVES: We reviewed the clinical, laboratory and biopsy materials of 260 patients diagnosed with erythroderma who were treated in our department over an 11-year period. Patients were followed up to better understand the evolution of erythroderma. METHODS: This study was performed at our hospital between January 2001 and 2012 and included 260 patients with erythroderma. We recorded epidemio-clinical, biological and histological data, treatments and outcomes. Clinical-histological correlation was analyzed. Overall survival and relapse-free survival for a limited number of etiologies were described using Kaplan-Meier estimates. RESULTS: The mean age at onset in this study was 52.57 +/- 17.94 (SD) years (range 13-87), with a male-to-female ratio of 3:1. Acute onset was present in 15.38% of patients. Clinical findings were dominated by pruritus (87.69%), fever (40%), edema (37.69%), chills (31.15%), nail changes (29.62%), weakness (19.23%), lymphadenopathy (19.23%), weight loss (14.62%) and islands of normal skin (13.46%). Skin biopsies revealed the cause in 55.56% (65/117) of the patients. The most common causative factors were pre-existing dermatoses (70.77%), followed by idiopathic causes (14.23%), drug reactions (12.69%) and malignancies (2.31%). Among the pre-existing dermatoses, psoriasis was the most common etiology (143/260, 55%). In the drug induced group, carbamazepine was the most frequently implicated drug in our study (33.33%). Chinese traditional herbal medicines are among the causes of drug induced erythroderma as well. We also found that Langerhans cell histiocytosis, tongue cancer, hypereosinophilic syndrome, bullous pemphigoid and dermatomyositis could be causes of erythroderma. From our follow-up study, 39 (31.2%) of the 125 patients from whom information was available had relapsed. The patients with idiopathic erythroderma had a higher relapse rate. Of the 5 patients who died, 4 deaths were directly related to erythroderma. CONCLUSION: Most of the clinical features of erythroderma are unspecific with few cause-orienting clues. Although numerous laboratory values were abnormal, most findings were nondiagnostic and were related to the inflammatory process, except for skin biopsy. Our study had a high percentage of erythroderma secondary to pre-existing dermatoses and a low percentage of malignancy patients. Repeated evaluations, close follow-up and biopsy are recommended. PMID- 23037885 TI - Photonic engineering of hybrid metal-organic chromophores. AB - An aureate dye: Confined electromagnetic fields in DNA-templated gold nanoparticle dimers were tuned to engineer the fluorescence properties of organic dyes in water (see picture). Purified suspensions of hybrid metal-organic chromophores featured unprecedented photophysical properties, such as a short lifetime and low quantum yield but high brightness. PMID- 23037887 TI - Parent ratings of executive functioning in children with shunted hydrocephalus. AB - OBJECTIVES: The present study examined the executive functioning of a group of children with a history of communicating hydrocephalus and how their level of functioning was correlated with parent ratings of executive functioning. METHODS: The study examined the executive functioning of 39 shunted children with a history of hydrocephalus and 20 healthy peers. Additionally, parents of both groups of children completed the Behavior Rating Inventory of Executive Function (BRIEF) to assess the parents' perceptions of their children's executive functioning. Finally, the study investigated the relationship between the shunted hydrocephalus children's executive functioning and the parent ratings of their executive functioning. RESULTS: Overall, the children with a history of shunted hydrocephalus displayed more executive dysfunction than their healthy peers. These children were rated by their parents as having more executive dysfunction than their healthy peers and displaying working memory, initiation, mental flexibility and self-monitoring difficulties, which appear to increase with age among the shunted hydrocephalus group. While parent ratings as measured by the BRIEF indices did not correlate with all executive tasks within the shunted hydrocephalus group, the cognitive tests assessing mental flexibility may be sensitive to the problems noted by parents at home. CONCLUSIONS: The children with a history of shunted hydrocephalus displayed executive functioning deficits on formal examination. The parents of children with a history of shunted hydrocephalus report ongoing executive difficulties which may increase with age. PMID- 23037886 TI - Neuropathologic substrates of Parkinson disease dementia. AB - OBJECTIVE: A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD). METHODS: One hundred forty patients with a clinical diagnosis of PD and either normal cognition or onset of dementia 2 or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded. Autopsy records of genetic data and semiquantitative scores for the burden of neurofibrillary tangles, senile plaques, Lewy bodies (LBs), and Lewy neurites (LNs) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of comorbid Alzheimer disease (AD) were also examined. RESULTS: Niney-two PD patients developed dementia, and 48 remained cognitively normal. Severity of cortical LB (CLB)/LN pathology was positively associated with dementia (p < 0.001), with an odds ratio (OR) of 4.06 (95% confidence interval [CI], 1.87-8.81), as was apolipoprotein E4 (APOE4) genotype (p = 0.018; OR, 4.19; 95% CI, 1.28-13.75). A total of 28.6% of all PD cases had sufficient pathology for comorbid AD, of whom 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p = 0.001; OR, 1.12; 95% CI, 1.04-1.21), higher CLB/LN burden (p = 0.037; OR, 2.48; 95% CI, 1.06-5.82), and cerebral amyloid angiopathy severity (p = 0.032; OR, 4.16; 95% CI, 1.13-15.30). INTERPRETATION: CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target alpha-synuclein, tau, or amyloid beta could potentially improve cognitive performance in PD. PMID- 23037888 TI - Reaction energetics on long-range corrected density functional theory: Diels Alder reactions. AB - The possibility of quantitative reaction analysis on the orbital energies of long range corrected density functional theory (LC-DFT) is presented. First, we calculated the Diels-Alder reaction enthalpies that have been poorly given by conventional functionals including B3LYP functional. As a result, it is found that the long-range correction drastically improves the reaction enthalpies. The barrier height energies were also computed for these reactions. Consequently, we found that dispersion correlation correction is also crucial to give accurate barrier height energies. It is, therefore, concluded that both long-range exchange interactions and dispersion correlations are essentially required in conventional functionals to investigate Diels-Alder reactions quantitatively. After confirming that LC-DFT accurately reproduces the orbital energies of the reactant and product molecules of the Diels-Alder reactions, the global hardness responses, the halves of highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps, along the intrinsic reaction coordinates of two Diels-Alder reactions were computed. We noticed that LC-DFT results satisfy the maximum hardness rule for overall reaction paths while conventional functionals violate this rule on the reaction pathways. Furthermore, our results also show that the HOMO-LUMO gap variations are close to the reaction enthalpies for these Diels-Alder reactions. Based on these results, we foresee quantitative reaction analysis on the orbital energies. PMID- 23037889 TI - The effect of temperature and velocity on superlubricity. AB - We study the effects of temperature and sliding velocity on superlubricity in numerical simulations of the Frenkel-Kontorova model. We show that resonant excitations of the phonons in an incommensurate sliding body lead to an effective friction and to thermal equilibrium with energy distributed over the internal degrees of freedom. For finite temperature, the effective friction can be described well in terms of a viscous damping force, with a damping coefficient that emerges naturally from the microscopic dynamics. This damping coefficient is a non-monotonic function of the sliding velocity which peaks around resonant velocities and increases with temperature. At low velocities, it remains finite and nonzero, indicating the preservation of superlubricity in the zero-velocity limit. Finally, we propose experimental systems in which our results could be verified. PMID- 23037890 TI - Excess mortality risk after spinal cord injury is substantially increased with poor socioeconomic characteristics. PMID- 23037891 TI - November: a time for nurse practitioners, news, and needs. PMID- 23037892 TI - What are frail older people prepared to endure to achieve improved mobility following hip fracture? A Discrete Choice Experiment. AB - OBJECTIVE: To investigate the preferences of frail older people for individualised multidisciplinary rehabilitation to promote recovery from a hip fracture. DESIGN: Discrete Choice Experiment. SETTING: Acute and Rehabilitation Hospitals in Adelaide, South Australia. SUBJECTS: Eighty-seven patients with recent hip fracture (16 living in residential care facilities prior to fracture). METHODS: Patients providing informed consent (or consenting family carer proxies in cases where patients were unable to provide informed consent (n = 10)) participated in a face to face interview following surgery to repair a fractured hip to assess their preferences for different configurations of rehabilitation programs. RESULTS: Overall, participants expressed a strong preference for improvements in mobility and a willingness to participate in rehabilitation programs involving moderate pain and effort. However, negative preferences were observed for extremely painful interventions involving high levels of effort (2 h per day for 2 months). Subgroup analysis revealed consistently similar preferences according to place of residence (residential care vs community). CONCLUSIONS: Improvements in mobility are highly valued by frail older people recovering from hip fracture, including those living in residential care. Further research should be directed towards achieving greater equity in access to rehabilitation services for the wide spectrum of patients attending hospital with hip fractures. PMID- 23037893 TI - A historical perspective: infection from cadaveric dissection from the 18th to 20th centuries. AB - Today, the study of human anatomy utilizing the ultimate study guide, the cadaver, is relatively safe. In the past, however, human dissection was dangerous. Prior to the germ theory, antibiotics, and the use of gloves, cadavers were often life threatening to dissectors including both the teacher and the student. Medical students who graduated in the United States before 1880 were unlikely to practice antisepsis in the dissecting room. In the present article, we review human cadaveric dissection in Europe and the United States primarily from the 1700s to the early 1900s in regard to its potential for transmission of infection to the dissector. A brief account of the infectious hazards of human cadavers in general and those of cadavers used for dissection in particular is given. PMID- 23037894 TI - Increased time exposure to tenofovir is associated with a greater decrease in estimated glomerular filtration rate in HIV patients with kidney function of less than 60 ml/min/1.73 m2. AB - Tenofovir (TDF), atazanovir (ATAZ) and indinavir (IND) have been reported as possible risk factors for incident chronic kidney disease (CKD) in HIV-infected patients. We investigated the relationship between the duration of antiretroviral exposure and estimated glomerular filtration rate (eGFR) evolution in CKD patients. In a cohort of 1,750 HIV-infected patients, we identified 121 CKD patients with a mean follow-up of 44 +/- 35 months. The relationship between mean eGFR at baseline, eGFR slope and time exposure to antiretroviral treatment as well as confounding factors were investigated using a joint modeling procedure. Seventy (58%), 30 (25%) and 33 patients (27%), with a mean age of 50.3 +/- 11.7 years, mean eGFR at baseline of 53.0 +/- 0.8 (ml/min/1.73 m(2)) and eGFR slope of 0.46 +/- 0.07 ml/min/1.73 m(2)/year, were exposed to TDF, ATAZ and IND, respectively. In univariate analysis, hepatitis C virus infection, decreased nadir of log CD4 count, high blood pressure at baseline, angiotensin-converting enzyme inhibitor treatment and greater time exposure to TDF during follow-up were associated with a higher slope, whereas greater time exposure to IND was associated with a lower slope. In multivariate analysis, higher TDF time exposure was still significantly associated with eGFR decline, with a dose-effect relationship (slope +/- standard error of the mean: 1.1 +/- 0.1, 0.5 +/- 0.1, 0.07 +/- 0.08 and -0.87 +/- 0.06 ml/min/1.73 m(2)/year for no time exposure, <34, 34-67 and >=67%, respectively; trend test: p < 0.001), whereas the IND time exposure association was abolished. In HIV patients with CKD, a greater TDF time exposure was independently associated, in a graded manner, with a greater eGFR decline. PMID- 23037895 TI - A metastable He-O bond inside a ferroelectric molecular cavity: (HeO)(LiF)2. AB - Elemental helium is a prototypical noble gas and its atom sets the records for many physicochemical properties. With its two electrons in the closed 1s shell, He is the smallest, the least polarizable, the most difficult to ionize, the hardest (in Pearson's sense) and the most electronegative atom known. Helium gas is considered to be as close to an 'ideal gas' as possible and used as a standard of compressibility and pressure. As a consequence of its closed-shell electronic configuration, helium also exhibits chemical inertness: non-charged species which contain chemically bound helium have not been synthesized to date. Here we are able to predict, using quantum mechanical methods, a small neutral molecule, (HeO)(LiF)(2), which contains a helium atom chemically bound to oxygen. The molecule is planar with the polarized He(delta+)O(delta-) unit embedded anti parallel in-between two co-aligned LiF dipoles. We calculate its selected physicochemical properties as well as suggest possible decomposition and synthesis pathways. Successful preparation of neutral species, (HeO)(LiF)(2) or related molecules, would break down the paradigm of helium's inertness. PMID- 23037896 TI - Biological activity of ruthenium and osmium arene complexes with modified paullones in human cancer cells. AB - In an attempt to combine the ability of indolobenzazepines (paullones) to inhibit cyclin-dependent kinases (Cdks) and that of platinum-group metal ions to interact with proteins and DNA, ruthenium(II) and osmium(II) arene complexes with paullones were prepared, expecting synergies and an increase of solubility of paullones. Complexes with the general formula [M(II)Cl(eta(6)-p-cymene)L]Cl, where M=Ru (1, 3) or Os (2, 4), and L=L(1) (1, 2) or L(2) (3, 4), L(1)=N-(9-bromo 7,12-dihydroindolo[3,2-d][1]-benzazepin-6(5H)-yliden-N'-(2 hydroxybenzylidene)azine and L(2)=N-(9-bromo-7,12-dihydroindolo[3,2 d][1]benzazepin-6-yl)-N'-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl methylene]azinium chloride (L(2)(*)HCl), were now investigated regarding cytotoxicity and accumulation in cancer cells, impact on the cell cycle, capacity of inhibiting DNA synthesis and inducing apoptosis as well as their ability to inhibit Cdk activity. The MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide) assay yielded IC(50) values in the nanomolar to low micromolar range. In accordance with cytotoxicity data, the BrdU assay showed that 1 is the most and 4 the least effective of these compounds regarding inhibition of DNA synthesis. Effects on the cell cycle are minor, although concentration-dependent inhibition of Cdk2/cyclin E activity was observed in cell free experiments. Induction of apoptosis is most pronounced for complex 1, accompanied by a low fraction of necrotic cells, as observed by annexin V fluorescein isothiocyanate/propidium iodide staining and flow cytometric analysis. PMID- 23037897 TI - Simultaneous computed tomography-guided biopsy and radiofrequency ablation of solitary pulmonary malignancy in high-risk patients. AB - BACKGROUND: In recent years experience has been accumulated in percutaneous radiofrequency ablation (RFA) of lung malignancies in nonsurgical patients. OBJECTIVES: In this study, we retrospectively evaluated a simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions. METHODS: CT-guided transthoracic core needle biopsy of solitary pulmonary lesions suspicious for malignancy was performed and histology was proven based on immediate frozen sections. RFA probes were placed into the pulmonary tumors under CT guidance and the ablation was performed subsequently. The procedure-related morbidity was analyzed. Follow-up included a CT scan and pulmonary function parameters. RESULTS: A total of 33 CT guided biopsies and subsequent RFA within a single procedure were performed. Morbidity of CT-guided biopsy included pulmonary hemorrhage (24%) and a mild pneumothorax (12%) without need for further interventions. The RFA procedure was not aggravated by the previous biopsy. The rate of pneumothorax requiring chest tube following RFA was 21%. Local tumor control was achieved in 77% with a median follow-up of 12 months. The morbidity of the CT-guided biopsy had no statistical impact on the local recurrence rate. CONCLUSIONS: The simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions is a safe procedure. The potential of this combined approach is to avoid unnecessary therapies and to perform adequate therapies based on histology. Taking the local control rate into account, this approach should only be performed in those patients who are unable to undergo or who refuse surgery. PMID- 23037898 TI - Hydrogen bonding-driven rheological modulation of chemically reduced graphene oxide/poly(vinyl alcohol) suspensions and its application in electrospinning. AB - Rheology of graphene oxide (GO) and chemically reduced graphene oxide (RGO) nanosheets suspended in poly(vinyl alcohol) (PVA) solution were investigated by altering nanosheet loading and reduction time of RGO in a wide range. A small amount (0.5 wt%) of GO and RGO in the dilute regime of filler resulted in a threefold increase and a fourfold decrease in steady viscosity at 0.01 s(-1), respectively; increasing GO and RGO loadings in the semi-dilute regime of filler caused steady viscosity to increase to different degrees. Meanwhile, the steady viscosity of the suspension decreased gradually by more than one order of magnitude with increasing reduction time of RGO. By characterizing the microstructure in suspensions, the style and relative density of H-bonding between PVA chains and nanosheets were confirmed to account for the suspension rheology. Modulation of viscosity in a wide range via simply control of the loading and reduction time of RGO was hydrogen bonding-driven, which was successfully applied to electrospinning to prepare nanocomposite nanofibers. The addition of 1 wt% GO and RGO with respect to the polymer mass significantly improved PVA fibrous uniformity and fineness, and the spinnable concentration range of PVA was greatly broadened from (8.5-11.3 wt%) to (5-18 wt%). Meanwhile, the thermal stability of the nanofibers was also enhanced by GO or RGO addition. PMID- 23037899 TI - The role of cardiac fat in insulin resistance. AB - PURPOSE OF REVIEW: To evaluate the relationship between cardiac fat accumulation and insulin resistance. We discuss the current knowledge regarding the different techniques for measuring, in vivo in humans, cardiac fat deposition, the effects of systemic and myocardial insulin resistance and the clinical relevance of the relation between atherosclerosis and cardiac fat in conditions of insulin resistance. RECENT FINDINGS: In humans, fat accumulates mainly around the heart, as epicardial, perivascular and intrathoracic fat, but also inside the cardiomyocytes. All these cardiac fat depots have been shown to be markers of cardiac lipotoxicity, mitochondrial dysfunction, inflammation and local and systemic insulin resistance as well as of atherosclerosis and cardiac dysfunction. SUMMARY: Although cardiac fat is associated with impairment in heart metabolism and cardiac dysfunction, the interplay among cardiac fat accumulation, insulin resistance and cardiac dysfunction remains to be fully established. PMID- 23037900 TI - Adipose tissue oxygen tension: implications for chronic metabolic and inflammatory diseases. AB - PURPOSE OF REVIEW: The present review aims to address the role of adipose tissue oxygen partial pressure (PO2) in the metabolic and endocrine derangements in conditions characterized by insulin resistance. RECENT FINDINGS: The balance between adipose tissue oxygen supply and its metabolic rate seems to determine adipose tissue PO2. Studies in ob/ob and dietary-induced obese mice have provided evidence for adipose tissue hypoxia in obesity, which has been explained by insufficient adipose tissue angiogenesis during the massive and rapid weight gain in these animals. However, conflicting data have been reported in humans, showing both increased and decreased adipose tissue PO2 in obese compared with lean individuals. Both low and high adipose tissue PO2 may induce a proinflammatory phenotype in (pre)adipocytes, but most studies have been performed under rather extreme PO2 levels, not reflecting human adipose tissue physiology. Furthermore, adipose tissue PO2 may affect glucose and lipid metabolism as well as adipogenic differentiation, but many issues still need to be addressed. SUMMARY: Adipose tissue hypoxia has been demonstrated in animal models of obesity, but findings in humans are controversial and require further investigation. Although adipose tissue PO2 seems to be involved in metabolic and endocrine derangements in human adipose tissue, future studies should investigate how low and high adipose tissue PO2 within the human physiological range (3-11% O2) relates to adipose tissue blood flow and oxygen consumption, cellular metabolic responses, and the inflammatory phenotype. PMID- 23037901 TI - Artificial sweeteners: a place in the field of functional foods? Focus on obesity and related metabolic disorders. AB - PURPOSE OF REVIEW: Artificial sweeteners can be a helpful tool to reduce energy intake and body weight and thereby risk for diabetes and cardiovascular diseases (CVD). Considering the prevailing diabesity (obesity and diabetes) epidemic, this can, therefore, be an important alternative to natural, calorie-containing sweeteners. The purpose of this review is to summarize the current evidence on the effect of artificial sweeteners on body weight, appetite, and risk markers for diabetes and CVD in humans. RECENT FINDINGS: Short-term intervention studies have shown divergent results wrt appetite regulation, but overall artificial sweeteners cannot be claimed to affect hunger. Data from longer term intervention studies are scarce, but together they point toward a beneficial effect of artificial sweeteners on energy intake, body weight, liver fat, fasting and postprandial glycemia, insulinemia, and/or lipidemia compared with sugar. Epidemiological studies are not equivocal, but large cohort studies from the USA point toward decreased body weight and lower risk of type-2 diabetes and coronory heart diseases with increased intake of artificial sweeteners compared with sugar. SUMMARY: Artificial sweeteners, especially in beverages, can be a useful aid to maintain reduced energy intake and body weight and decrease risk of type-2 diabetes and CVD compared with sugars. However, confirmative long-term intervention trials are still needed. PMID- 23037902 TI - The role of essential fatty acids in the control of coronary heart disease. AB - PURPOSE OF REVIEW: Evidence from various research paradigms supports the cardiovascular benefits of a high intake of n-3 polyunsaturated fatty acids (PUFAs), especially the long-chain, marine-derived n-3 PUFA, eicosapentaenoic acids and docosahexaenoic acids. The effect of the plant-derived alpha-linolenic acid (ALA) is, however, not clear. Concerns about a high n-6 PUFA intake has been raised, because n-6 PUFA may weaken the effects of n-3 PUFA. RECENT FINDINGS: Most previous observational studies on the intake of PUFA and the risk of coronary heart disease (CHD) did not specify the replacement nutrient. A recent meta-analysis of cohort studies suggested that replacing saturated fatty acids with PUFA may lower the risk of CHD. On the other hand, recently published studies do not suggest that higher linoleic acid intake is associated to a lower risk of CHD or to give support for a negative association between ALA and CHD. Furthermore, recent studies do not suggest that the association between ALA and CHD is modified by linoleic acid. SUMMARY: Recent meta-analyses of cohort studies have reported a lower risk of CHD when PUFA replaces SFA in the diet. However, recent studies do not suggest that a higher linoleic acid intake is related to a lower risk of CHD. The effect of ALA on the risk of CHD is not clear. PMID- 23037903 TI - Prebiotics, probiotics and digestive health. AB - PURPOSE OF REVIEW: The human gastrointestinal lumen is inhabited by a wide variety of microbiota. Our understanding of the intestinal microbiota and its full consequences on gastrointestinal health is still evolving. However, it is well accepted that altered colonic flora drives the pathogenesis of many disorders and diseases as seen in antibiotic-associated diarrhea and Clostridium difficile infection. Recent works published in the area of probiotics are reviewed here. RECENT FINDINGS: Alterations in colonic microbiota, or dysbiosis, are now implicated in irritable bowel syndrome and inflammatory bowel diseases. Probiotics and prebiotics are evolving treatment options that are targeted at restoring nonpathogenic digestive flora. There has been great interest in the role of these therapies in treatment of many diseases including childhood diarrhea, antibiotic-associated diarrhea, Clostridium difficile infection, irritable bowel syndrome, and inflammatory bowel disease. SUMMARY: Trials of probiotics have been shown to be helpful in some of these, not in others, and more work is needed in others. We review recent work done in these areas. PMID- 23037904 TI - Brown adipose tissue and the regulation of nonshivering thermogenesis. AB - PURPOSE OF REVIEW: The recent rediscovery of functional cold activated brown adipose tissue (BAT) in adult humans fuelled an uprise in studies on this tissue. This review focuses on the contribution of human BAT to nonshivering thermogenesis and on factors other than cold that activate BAT. RECENT FINDINGS: Earlier studies revealed BAT activity using a glucose tracer for positron emission tomography/computed tomography (PET/CT) scanning. Several recent studies, using a mix of tracers and PET/CT dynamic scanning showed that human brown fat is metabolically active and related to the perfusion of the tissue. The actual contribution of BAT to nonshivering thermogenesis still needs to be explored.The last few years, several new factors that activate human BAT have been described. These studies also highlight the plasticity of brown and white adipose tissue. Some of these factors may have pharmacological significance. SUMMARY: New PET/CT studies provide information on oxidative human BAT metabolism in vivo. This new information in combination with the study on factors activating BAT are promising with respect to management of obesity and related disorders. PMID- 23037905 TI - Diverse physiological effects of long-chain saturated fatty acids: implications for cardiovascular disease. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss the metabolism of long-chain saturated fatty acids and the ensuing effects on an array of metabolic events. RECENT FINDINGS: Individual long-chain saturated fatty acids exhibit unique biological properties. Dietary saturated fat absorption varies depending on chain-length and the associated food matrix. The in-vivo metabolism of saturated fatty acids varies depending on the individual fatty acid and the nutritional state of the individual. A variety of fatty acid metabolites are formed, each with their own unique structure and properties that warrant further research. Replacing saturated fatty acids with unsaturated fatty acids improves the blood lipid profile and reduces cardiovascular disease risk, although the benefits depend on the specific saturated fatty acid(s) being replaced. SUMMARY: Acknowledging the complexity of saturated fatty acid metabolism and associated metabolic events is important when assessing their effects on cardiovascular disease risk. Investigating the biological effects of saturated fatty acids will advance our understanding of how they affect cardiovascular disease risk. PMID- 23037906 TI - Do we need to take calcium with vitamin D supplements to prevent falls, fractures, and death? AB - PURPOSE OF REVIEW: The 2011 report by the US Institute of Medicine (IOM) on dietary reference intakes for calcium and vitamin D is based on meta-analyses of randomized controlled trials (RCTs), which concluded that vitamin D supplements need to be taken with calcium supplements to prevent falls, fractures, and all cause mortality. This study reviews recent meta-analyses of RCTs of vitamin D supplementation to determine whether their conclusions are consistent with the meta-analyses underpinning the IOM report. RECENT FINDINGS: Since 2007 when the first IOM meta-analysis was published, up to May 2012, there have been nine meta analyses of RCTs of vitamin D supplements on risk of falls, 10 on fractures, and five on all-cause mortality. About half of these reported summary effects for both vitamin D combined with calcium supplements and also vitamin D alone. However, statistical testing of results from recent meta-analyses does not support the conclusions of the IOM meta-analyses. SUMMARY: The inconsistency in the conclusions from meta-analyses is due to limitations in the design of previous RCTs of vitamin D supplementation. Large RCTs, giving higher doses of vitamin D (without calcium), should provide a clear answer within several years as to whether vitamin D supplements are beneficial by themselves. PMID- 23037907 TI - Radiolabelled somatostatin analogue treatment in a case of carcinoid tumour with choroidal metastases. PMID- 23037908 TI - Enhanced depth imaging spectral-domain optical coherence tomography of a subtle choroidal metastasis. PMID- 23037909 TI - Characteristics of patients with a localized retinal nerve fiber layer defect and normal optic disc appearance. AB - PURPOSE: To investigate the characteristics of patients with a localized retinal nerve fiber layer (RNFL) defect and normal optic disc appearance compared with normal tension glaucoma (NTG) patients. METHODS: A total of 40 patients with an unchanged RNFL defect for more than 5 years and normal optic disc appearance, who were presumed as non-glaucomatous patients, were enrolled (group A). We recruited 40 age-matched patients with NTG (group B). On the RNFL photographs, we evaluated angles of RNFL defects. Angle alpha and beta were the angles made by the line 'L' from the center of the fovea to the disc center and the lines 'A' and 'B' from the disc center to the disc margin where the proximal and the distal border of the defect met, respectively. Angle theta was the angular width of the defect. Angle gamma was the angle made by lines 'L' and 'R', which divides angle theta into a 2 :1 ratio from line 'A' to line 'B'. We compared systemic diseases, baseline IOP, and location and angles of the RNFL defects between the two groups. RESULTS: Systemic diseases and superotemporal RNFL defects in group A were significantly greater than those in group B (P<0.001). Angle alpha was greater in group A, but angle beta, theta, and gamma were smaller in group A (P<0.05). CONCLUSION: If the patients with a superotemporal RNFL defect and normal optic disc appearance had systemic diseases and distal borders of the defects are closer to the macula, glaucoma is less likely. PMID- 23037910 TI - Adverse periocular reactions to five types of prostaglandin analogs. AB - PURPOSE: We investigated the appearance frequency of eyelid pigmentation and eyelash bristles after the use of five types of prostaglandin (PG) analogs. METHODS: This study included 250 eyes from 250 patients diagnosed with primary open-angle glaucoma or ocular hypertension who were treated with either latanoprost, travoprost, tafluprost, bimatoprost, or isopropyl unoprostone for >3 months in only one eye. Photographs of both eyes were obtained, and the images were assessed by three ophthalmologists who were masked to treatment type. The existence of eyelid pigmentation and eyelash bristles was judged, and images of the left and right eyes were compared. Subjective symptoms regarding the existence of eyelid pigmentation and eyelash bristles were investigated through a questionnaire. RESULTS: There was no significant difference between the five types of medications with regard to eyelid pigmentation (P=0.537). Use of isopropyl unoprostone resulted in a significantly lower incidence of eyelash bristles (P<0.0001). The questionnaire investigation showed that eyelid pigmentation and eyelash bristles were significantly more frequent with travoprost (42.0% and 42.0%, respectively) and bimatoprost (58.0% and 60.0%, respectively) than with other three medications (P<0.0001). CONCLUSION: The appearance frequency of eyelid pigmentation was similar among the five types of PG analogs studied, and eyelash bristles appeared less frequently with isopropyl unoprostone use. Patients are conscious of eyelash bristles; therefore, these adverse effects should be sufficiently explained to patients before PG administration. PMID- 23037911 TI - Choroidal new vessels in type 1 myotonic dystrophy-related macular dystrophy respond to anti-VEGF therapy. PMID- 23037912 TI - Bovine aortic arch: normal variant or a marker of aortopathy?. PMID- 23037914 TI - Coordination of a diphosphine-phosphine oxide to Au, Ag and Rh: when polyfunctionality rhymes with versatility. AB - Gold, silver and rhodium complexes of the diphosphine-phosphine oxide DPPO = {[o iPr(2)P-(C(6)H(4))](2)P(O)Ph} have been prepared and characterized. Thanks to its polyfunctional character, DPPO features versatile coordination properties. According to crystallographic data, only one phosphine moiety is engaged in coordination towards (AuCl) and [RhCl(nbd)]. However, NMR data indicate fluxional behavior in solution, as the result of the exchange between the free and coordinated phosphines around the metal. Chelating coordination via the two phosphine sites is observed towards (Au(+)) and (AgCl) with PMP bite angles varying from 122 degrees to 159 degrees . According to X-ray and theoretical analyses, the oxygen atom of the central phosphine oxide moiety points towards the metal but does not interact significantly with it. Tridentate coordination via the two phosphines as well as the oxygen atom of DPPO occurs with [Rh(CO)(+)], leading to an original PO(P)P pincer structure. PMID- 23037913 TI - Microwave-assisted synthesis of carbon nanodots through an eggshell membrane and their fluorescent application. AB - Carbon nanodots (C-Dots) as a new form of carbonaceous nanomaterials have aroused much interest and intensive research due to their inspiring properties. Compared to traditional semiconductor quantum dots, these newly emergent nanodots possess a number of advantageous characteristics, among which low-toxicity is particularly fascinating. More and more research into C-Dots have focused on synthesis methods and biology-related applications. Microwave-assisted approaches have attracted attention because microwave treatment can provide intensive and efficient energy, and as a consequence shorten the reaction time. In this article, we designed a "green", rapid, eco-friendly and waste-reused approach to synthesize fluorescent and water-soluble C-Dots from eggshell membrane (ESM) ashes according to a microwave-assisted process. ESM selected as the carbon source was a common protein-rich waste in daily life and can be obtained easily and cheaply. The C-Dots from our method showed the maximal fluorescence emission peak at 450 nm and the fluorescence quantum yield was about 14%. We further designed a sensitive probe for glutathione based on the fluorescence turn off and on of the C-Dots-Cu(2+) system, which showed a linear range of 0.5-80 MUmol L(-1) and detection limit of 0.48 MUmol L(-1). In general, the C-Dots prepared briefly and inexpensively from ESM revealed excellent fluorescent property with promising potential for applications such as sample detection and biotechnology. PMID- 23037915 TI - Back-scattering interferometry: an ultrasensitive method for the unperturbed detection of acetylcholinesterase-inhibitor interactions. AB - A series of inhibitors of acetylcholinesterase (AChE) have been screened by back scattering interferometry (BSI). Enzyme levels as low as 100 pM (22,000 molecules of AChE) can be detected. This method can be used to screen for mixed AChE inhibitors, agents that have shown high efficacy against Alzheimer's disease, by detecting dual-binding interactions. E = enzyme, I = inhibitor, S = substrate. PMID- 23037917 TI - 'Bovine' aortic arch - a marker for thoracic aortic disease. AB - OBJECTIVES: Very few studies have addressed the clinical significance of 'bovine' aortic arch (BA). We sought to determine whether BA is associated with thoracic aortic disease, including thoracic aortic aneurysm, aortic dissection, aortic rupture, and accelerated aortic growth rate. METHODS: We retrospectively reviewed CT and/or MRI scans of 612 patients with thoracic aortic disease and 844 patients without thoracic aortic disease to determine BA prevalence. In patients with thoracic aortic disease, we reviewed hospital records to determine growth rate, prevalence of dissection and rupture, and accuracy of radiology reports in citing BA. RESULTS: 26.3% of the patients with thoracic aortic disease had concomitant BA, compared to 16.4% of the patients without thoracic aortic disease (p < 0.001). There was no association between BA and prevalence of dissection or rupture (p = 0.38 and p = 0.56, respectively). The aortic expansion rate was 0.29 cm/year in the BA group and 0.09 cm/year in the non-BA group (p = 0.004). Radiology reports cited BA in only 16.1% of the affected patients. CONCLUSIONS: (1) BA is significantly more common in patients with thoracic aortic disease than in the general population. (2) Aortas expand more rapidly in the setting of BA. (3) Radiology reports often overlook BA. (4) BA should not be considered a 'normal' anatomic variant. PMID- 23037918 TI - Multiple variations of the arterial pattern in upper extremities: a case report and embryological pathogenesis. AB - During a routine dissection at the Department of Anatomy, Collegium Medicum, Jagiellonian University, one cadaver was found to have multiple variations of the arteries of the upper limbs. The variations pertained to the course of the brachial artery as well as to its distribution. An unusual formation of the superficial palmar arch was observed in both upper limbs. The anatomical peculiarities encountered included: in the left upper limb-the brachioradial artery, which formed the superficial palmar arch by turning to the palmar side of the hand and connecting with the ulnar artery and in the right upper limb-a subscapular-circumflex humeral-deep brachial trunk that correlated with a high division of the brachial artery (in the upper third of the biceps brachii muscle), a large anastomosis between the radial and the ulnar artery, the presence of a persistent median artery, and the unusual formation of the superficial palmar arch, which was created by the median, ulnar, and radial arteries. In this report, we will trace the path of the axillary artery and its branches in detail and emphasize its embryological significance. PMID- 23037919 TI - Francisella is sensitive to insect antimicrobial peptides. AB - Francisella tularensis causes the zoonotic disease tularemia. Arthropod vectors are important transmission routes for the disease, although it is not known how Francisella survives the efficient arthropod immune response. Here, we used Drosophila melanogaster as a model host for Francisella infections and investigated whether the bacteria are resistant to insect humoral immune responses, in particular to the antimicrobial peptides (AMPs) secreted into the insect hemolymph. Moreover, we asked to what extent such resistance might depend on lipopolysaccharide (LPS) structure and surface characteristics of the bacteria. We analyzed Francisella novicida mutant strains in genes, directly or indirectly involved in specific steps of LPS biosynthesis, for virulence in wild type and Relish(E20) immune-deficient flies, and tested selected mutants for sensitivity to AMPs in vitro. We demonstrate that Francisella is sensitive to specific fly AMPs, i.e. Attacin, Cecropin, Drosocin and Drosomycin. Furthermore, six bacterial genes, kpsF, manB, lpxF, slt, tolA and pal, were found to be required for resistance to Relish-dependent immune responses, illustrating the importance of structural details of Francisella lipid A and Kdo core for interactions with AMPs. Interestingly, a more negative surface charge and lack of O-antigen did not render mutant bacteria more sensitive to cationic AMPs and did not attenuate virulence in flies. PMID- 23037920 TI - Intramuscular perforator dissection with the hydrodissection technique. AB - BACKGROUND: Perforator flap breast reconstruction requires increased time for safe perforator dissection, especially the intramuscular course. We describe an adjunctive technique using hydrodissection to assist with the intramuscular perforator dissection. METHODS: Hydrodissection techniques were used for perforator dissection in 45 consecutive patients (64 flaps) undergoing deep inferior epigastric perforator (DIEP) flap breast reconstruction. These patients were compared with 39 patients (55 flaps) immediately prior to the use of this technique. The study time frame was between March 2008 and March 2010. Patient demographics, complications, and operative times were collected through an extensive chart review. RESULTS: There were no major differences in complications between groups; there were no flap losses encountered during this series, and fat necrosis rates were similar (9.4% with hydrodissection and 14.5% without, p = 0.41). Total operative time for bilateral reconstructions decreased by 59 minutes (p = 0.13) and 21 minutes (p = 0.57) for unilateral reconstructions with the utilization of hydrodissection, though this was not statistically significant. CONCLUSIONS: The use of hydrodissection to assist with intramuscular perforator vessel dissection is safe to perform, as there was no increase in complications. The procedures utilizing hydrodissection were faster, and surgeons using this technique found it easier to visualize the perforators and dissect through the intramuscular course. PMID- 23037921 TI - 44Sc-DOTA-BN[2-14]NH2 in comparison to 68Ga-DOTA-BN[2-14]NH2 in pre-clinical investigation. Is 44Sc a potential radionuclide for PET? AB - AIM: In the present study we demonstrate the in vitro and in vivo comparison of the (44)Sc and (68)Ga labeled DOTA-BN[2-14]NH(2). (44)Sc is a positron emitter with a half life of 3.92 h. Hence it could be used for PET imaging with ligands requiring longer observation time than in the case of (68)Ga. METHODS: The binding affinity of (nat)Sc-DOTA-BN[2-14]NH(2) and (nat)Ga-DOTA-BN[2-14]NH(2) to GRP receptors was studied in competition to [(125)I-Tyr(4)]-Bombesin in the human prostate cancer cell line PC-3. A preliminary biodistribution in normal rats was performed, while first microPET images were assessed in male Copenhagen rats bearing the androgen-independent Dunning R-3327-AT-1 prostate cancer tumor. RESULTS: The affinity to GRP receptors in the PC-3 cell line was higher for (nat)Ga-DOTA-BN[2-14]NH(2) (IC(50)(nM)=0.85 +/- 0.06) than that of (nat)Sc-DOTA BN[2-14]NH(2) (IC(50) (nM)=6.49 +/- 0.13). The internalization rate of (68)Ga labeled DOTA-BN[2-14]NH(2) was slower than that of (44)Sc, but their final internalization percents were comparable. (68)Ga-DOTA-BN[2-14]NH(2) was externalized faster than (44)Sc-DOTA-BN[2-14]NH(2). The biodistribution of (44)Sc DOTA-BN[2-14]NH(2) and (68)Ga-DOTA-BN[2-14]NH(2) in normal rats revealed a higher uptake in target organs and tissues of the first one while both excreted mainly through urinary tract. In microPET images both tracers were accumulated in the tumor with similar uptake patterns. CONCLUSIONS: Despite the differences in the receptor affinity both the (68)Ga- and the (44)Sc-labeled DOTA-BN[2-14]NH(2) tracers showed comparable distribution and similar time constants of uptake and elimination. Moreover no differences in tumor accumulation (neither in the overall uptake nor in the dynamics) were observed from the microPet imaging. From that perspective the use of either (44)Sc or (68)Ga for detecting tumors with GRP receptors is equivalent. PMID- 23037922 TI - Synthesis and characterization of radioisotope nanospheres containing two gamma emitters. AB - Silica-coated gold-silver alloy nanospheres prepared by Stober's method were irradiated in a nuclear reactor to prepare radioisotope nanospheres for use as radiotracers. The radioisotope nanospheres included two gamma nuclides: (i) Au 198, emitting major photons with 0.412 MeV and (ii) Ag-108, emitting photons with 0.434 and 0.633 MeV. The nanospheres shell and core diameters were 100-112 nm and 20-50 nm, respectively, depending on their preparation. The gamma-emitting nanospheres could be used as tracers in high-temperature petrochemical and refinery processes in which conventional organic radioactive labels will decompose. PMID- 23037923 TI - A study for improving detection efficiency of an HPGe detector based gamma spectrometer using Monte Carlo simulation and genetic algorithms. AB - This work aims at improving the detection efficiency of an HPGe detector based gamma spectrometer for measurements of environmental radioactivity sample. Application of a simple genetic algorithm and the Monte Carlo simulation computer code MCNP5 allows to search for optimal dimensions of the Marinelli beaker typed source geometry that maximizes the detector efficiency for a fixed configuration of the gamma spectrometer. The interested gamma energies are in the range of 255 1926 keV. Optimization calculation was repeated several times to deduce average dimensions of an optimal Marinelli beaker typed sample with a volume of 450 cm(3). Effects of gamma energy, sample chemical composition and sample density on the optimal dimensions were also investigated. Calculated results showed that the effects were negligible. A validated experiment with arrangements using an optimal beaker and three other ones was carried out to verify calculated results. It is shown that experimental and calculated results of the detector efficiency are in a good agreement. PMID- 23037924 TI - CaBe2Ge2 type phosphides REIr2P2 (RE = La-Nd, Sm) and arsenides REIr2As2 (RE = La Nd): synthesis, structure, and solid state NMR spectroscopy. AB - The phosphides REIr(2)P(2) (RE = La-Nd, Sm) and arsenides REIr(2)As(2) (RE = La Nd) were synthesized by a ceramic route via precursor compounds REIr(2) with phosphorus and arsenic, respectively. Well-shaped single crystals were obtained from lead and bismuth fluxes, respectively. The nine pnictides crystallize with the tetragonal CaBe(2)Ge(2) type structure, space group P4/nmm. The structures of CeIr(2)P(2), SmIr(2)P(2), LaIr(2)As(2) and CeIr(2)As(2) were refined from single crystal X-ray diffractometer data. The structures are composed of three dimensional [Ir(2)P(2)] and [Ir(2)As(2)] networks in which the rare earth atoms fill cavities of coordination number 16 (8 P + 8 Ir). The phosphorus and arsenic atoms have tetrahedral and square pyramidal iridium coordination. Temperature dependent magnetic susceptibility measurements show intermediate cerium valence for CeIr(2)P(2). The rare-earth and phosphorus local environments in LaIr(2)P(2) are characterized further by (139)La and (31)P single and double resonance solid state nuclear magnetic resonance (NMR) spectroscopy. Strong (31)P Knight shifts and extremely short spin-lattice relaxation times indicate that the bonding character of the phosphide species is strongly metallic. The two crystallographically distinct phosphorus sites are well-resolved in the (31)P magic-angle spinning (MAS) spectrum and also differ significantly with respect to their effective magnetic shielding anisotropies. Unambiguous site assignments are accomplished on the basis of homonuclear (31)P-(31)P magnetic dipole-dipole interactions, which can be measured in a site-resolved fashion in this compound using static (31)P spin echo decay spectroscopy. The highly symmetric La environment in LaIr(2)P(2) is characterized by a sharp (139)La MAS-NMR spectrum, revealing rather weak nuclear electric quadrupole coupling. Furthermore, a second local environment is detected, which is characterized by stronger quadrupolar coupling and similar dipolar coupling strength with (31)P as the regular site, according to (139)La{(31)P} rotational echo double resonance (REDOR) NMR results. On the basis of these data we attribute this site to a La species next to a phosphorus vacancy. From the signal area of this resonance we deduce a composition LaIr(2)P(1.90). PMID- 23037925 TI - Tailoring the physical properties of thin nanohole arrays grown on flat anodic aluminum oxide templates. AB - The introduction of voids in a magnetic thin-film alters the stray field distribution and enables the tailoring of the corresponding physical properties. Here we present a detailed study on thin magnetic nanohole arrays (NhAs) grown on top of hexagonally-ordered anodic aluminum oxide (AAO) substrates. We address the effect of AAO topography on the corresponding electrical and magneto-transport properties. Optimization of the AAO topography led to NhAs with improved resistance and magnetoresistance responses, while retaining their most important feature of enhanced coercivity. This opens new pathways for the growth of more complex structures on AAO substrates, a crucial aspect for their technological viability. PMID- 23037926 TI - Exocyst Sec10 is involved in basolateral protein translation and translocation in the endoplasmic reticulum. AB - BACKGROUND: Protein translation and translocation at the rough endoplasmic reticulum (RER) are the first steps in the secretory pathway. The translocon through which newly made proteins are translocated into or across the RER membrane consists of three main subunits: Sec61alpha, -beta, and -gamma. Sec61beta facilitates translocation, and we and others have shown that the highly conserved eight-protein exocyst complex interacts with Sec61beta. We have also shown that the exocyst is involved in basolateral, not apical, protein synthesis and delivery. Recently, however, exocyst involvement in apical protein delivery has been reported. Furthermore, we have shown that the exocyst is necessary for formation of primary cilia, organelles found on the apical surface. METHODS: GST pulldown was performed on lysate of renal tubule cells to investigate biochemical interactions. Cell-free assays consisting of cell-free extracts from rabbit reticulocytes, pancreatic endoplasmic reticulum (ER) microsomal membranes, transcripts of cDNA from apical and basolateral proteins, ATP/GTP, amino acids, and (35)S-methionine for protein detection were used to investigate the role of the exocyst in synthesis of polarized proteins. P(32)-orthophosphate and immunoprecipitation with antibody against Sec61beta was used to investigate Sec61beta phosphorylation in exocyst Sec10-overexpressing cells. RESULTS: Sec10 biochemically interacts with Sec61beta using GST pulldown. Using cell-free assays, there is enhanced exocyst recruitment to endoplasmic reticulum membranes following exocyst depletion and basolateral G protein of vesicular stomatitis virus protein translation, compared to apical hemagglutinin of influenza virus protein translation. Finally, Sec10 overexpression increases Sec61beta phosphorylation. CONCLUSION: These data confirm that the exocyst is preferentially involved in basolateral protein translation and translocation, and may well act through the phosphorylation of Sec61beta. PMID- 23037927 TI - Acute hemodynamic responses to supplemental oxygen and their prognostic implications in pulmonary hypertension. AB - BACKGROUND: Pulmonary hypertension (PH) of various causes leads to a poor prognosis. Pulmonary vasoreactivity testing during right heart catheterization (RHC) has prognostic and therapeutic consequences. OBJECTIVE: To characterize the acute hemodynamic response to short-term oxygen supplementation (SHOT) in adult PH patients and its impact on prognosis. METHODS: After a stable baseline period, 104 patients with PH [pulmonary arterial hypertension (PAH; n = 56), chronic thromboembolic (PH; n = 22) or respiratory diseases (PH; n = 26)], who were mainly therapy-naive (86.5%) (mean pO2 64.5 +/- 1.2 mm Hg), received a standardized SHOT during RHC and hemodynamic response was assessed for its prognostic potential. RESULTS: SHOT significantly reduced heart rate (HR: 78.9 +/ 1.5 to 74 +/- 1.5 beats/min), cardiac output (4 +/- 0.1 to 3.8 +/- 0.1 l/min), pulmonary arterial pressure (46.4 +/- 1.3 to 42.3 +/- 1.3 mm Hg) and pulmonary vascular resistance (10.1 +/- 0.5 to 9.6 +/- 0.5 Wood units; all p < 0.001) compared to baseline. The magnitude of this effect varied between the different PH groups. During a median follow-up of 25.1 months (range: 0.2-73.3 months), HR <72 beats/min in response to SHOT was associated with a better prognosis in patients with PH due to chronic thromboembolism to the lung and PH from chronic lung disease. CONCLUSIONS: SHOT leads to characteristic hemodynamic responses across different forms of PH. The preserved capability to acutely respond to SHOT with HR reduction is of prognostic significance in patients with non PAH PH. PMID- 23037929 TI - Evalution of Mulligan's technique for adhesive capsulitis of the shoulder. AB - OBJECTIVE: To evaluate Mulligan's technique for relieving pain and improving functional capacity of the shoulder in patients with adhesive capsulitis in the stiffness phase. DESIGN: Randomized controlled study. METHODS: A total of 40 subjects were randomly allocated into 2 groups: (i) group 1 (n = 20) were treated with hot pack, transcutaneous electrical nerve stimulation, and passive stretching exercises; (ii) group 2 (n = 20) were treated with hot pack, transcutaneous electrical nerve stimulation and Mulligan's technique. Mulligan's technique combines the sustained application of a manual "gliding" force to a joint, with the aim of repositioning bone positional faults while enabling concurrent physiological (osteo-kinematic) motion of the joint. All cases were evaluated using visual analogue scales for pain, passive and active range of motion, Constant score, Shoulder Disability Questionnaire, and patient and therapist satisfaction at baseline, after completion of treatment sessions and at the end of 3 months of follow-up. RESULTS: Marked improvement was noted in both groups after completion of treatment sessions and at the third month of follow-up compared with baseline. The improvements in outcome measures, namely pain, range of motion, shoulder scores, and patient and physiotherapist satisfaction, were significantly greater in subjects in group 2, who were treated with Mulligan's technique. CONCLUSION: Mulligan's technique and passive stretching exercises are both effective in reducing pain, and restoring range of motion and function. However, compared with stretching exercises, Mulligan's technique led to better improvements in terms of pain, range of motion, shoulder scores, and patient and physiotherapist satisfaction. PMID- 23037930 TI - Understanding properties of electrified interfaces as a prerequisite for label free DNA hybridization detection. AB - Label-free electrochemical detection of DNA hybridization with high selectivity and sensitivity is only achievable if the properties of DNA at an electrified interface are understood in depth. After a short summary of concepts of electrochemical DNA detection as well as initial attempts towards label-free DNA assays the review discusses the physico-chemical properties and differences between single-stranded and double-stranded DNA immobilized at electrode surfaces in the light of their persistence lengths, structural conformation, impact of the charge screening by ion condensation and the electric field generated upon polarization of the electrode. Electrochemical impedance spectroscopy as a tool for label-free elucidation of DNA hybridization is reviewed and the necessity for an in-depth understanding of the interfacial properties is highlighted. Our major aim is to demonstrate the advantageous application of specifically designed intercalating compounds for the design of label-free detection of DNA hybridization. PMID- 23037928 TI - Management of congenital adrenal hyperplasia in childhood. AB - PURPOSE OF REVIEW: Congenital adrenal hyperplasia (CAH) can present management challenges to the pediatric clinician. Glucocorticoid replacement remains the cornerstone of treatment; however, there are new formulations and delivery mechanisms being studied. Clinicians continue to discuss the optimal treatment of patients from the prenatal stage, through infancy to adulthood. As well, the role of genetics in the clinical care of patients with CAH, and screening for complications, remain topics of discussion. This review will highlight advances made in the past year, as they pertain to the management of pediatric patients with CAH. RECENT FINDINGS: This article covers recent studies pertaining to optimal medication regimens, including prenatal dexamethasone treatment; medication delivery; monitoring of hormonal control; and the role of genotyping and genetics in the management of children with CAH. SUMMARY: Much remains to be learned about the optimal management of children with CAH, including fludrocortisone replacement in simple-virilizing patients, frequency of specific monitoring strategies (e.g., electrolytes, bone age), catecholamine status, stress-dosing in nonclassical adrenal hyperplasia, and early screening for complications or metabolic sequelae. Further randomized and prospective studies are needed to address these issues. PMID- 23037931 TI - A modified guanosine phosphoramidite for click functionalization of RNA on the sugar edge. AB - A propargyl containing guanosine phosphoramidite was synthesized and incorporated into siRNA, enabling click-ligation with an azido fluorophore onto the nucleobase sugar edge. Duplex stability was not affected by labeling at this new site, which allowed deconvolution of the effects of label, structure and attachment site on RNAi activity. PMID- 23037932 TI - Duplications, deletions, and single-nucleotide variations: the complexity of genetic arithmetic. PMID- 23037933 TI - Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children. AB - PURPOSE: We provide background information/education for national recommendations to include initial newborn screening dried bloodspot serial numbers in electronic birth registrations. Mutual data linking would provide quality checks for each data source, determinations of percentages of newborns screened, and identification of locations where screening is lacking. METHODS: State newborn screening dried bloodspot programs were surveyed to determine the extent of newborn screening dried bloodspot and electronic birth registration linking and the states' level of interest in such linkages. These data were reviewed with federal and state policy makers and presented to the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children for national policy recommendations. RESULTS: Only 40% of state newborn screening dried bloodspot programs reported comparing births with screens. All states use serially numbered newborn screening dried bloodspot collection cards, and electronic birth registrations exist in almost all states. Newborn screening dried bloodspot serial number data fields currently exist in only 24% of state electronic birth registrations. CONCLUSION: The Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children recommends the universal use of the newborn screening dried bloodspot serial number in a standardized format as part of state birth registration; consideration of including the initial newborn screening dried bloodspot serial number as a required data field; and, once established, using these data linkages to monitor completeness of newborn screening and to validate demographic information in both systems. PMID- 23037934 TI - Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing. AB - PURPOSE: Mendelian phenotypes in humans vary from benign variants to lethal disorders. Embryonic lethal phenotypes that are similar to what has been known for a long time in mice have remained largely unknown because of the difficulty in arriving at a molecular diagnosis. The purpose of this study is to test whether next generation sequencing can reveal the underlying etiology of recurrent fetal loss. METHODS: We hypothesized that exome sequencing combined with autozygome analysis can reveal the underlying mutation in a family in which recurrent fetal loss was likely to be autosomal recessive in origin. RESULTS: A novel mutation in CHRNA1 was identified. This gene is known to cause multiple pterygium and fetal akinesia syndrome. CONCLUSION: This is the first report of exome sequencing to identify the cause of recurrent fetal loss and reveal the diagnosis of a lethal human phenotype. Our results should inspire a systematic examination of the extent of "unborn" Mendelian phenotypes in humans using next generation sequencing. PMID- 23037935 TI - Getting our priorities straight: a novel framework for stakeholder-informed prioritization of cancer genomics research. AB - PURPOSE: Prioritization of translational research on genomic tests is critically important given the rapid pace of innovation in genomics. The goal of this study was to evaluate a stakeholder-informed priority-setting framework in cancer genomics. METHODS: An external stakeholder advisory group including patients/consumers, payers, clinicians, and test developers used a modified Delphi approach to prioritize six candidate cancer genomic technologies during a 1-day meeting. Nine qualitative priority-setting criteria were considered. We used a directed, qualitative content-analysis approach to investigate the themes of the meeting discussion. RESULTS: Stakeholders primarily discussed six of the original nine criteria: clinical benefits, population health impacts, economic impacts, analytical and clinical validity, clinical trial implementation and feasibility, and market factors. Several new priority-setting criteria were identified from the workshop transcript, including "patient-reported outcomes," "clinical trial ethics," and "trial recruitment." The new criteria were incorporated with prespecified criteria to develop a novel priority-setting framework. CONCLUSION: This study highlights key criteria that stakeholders can consider when prioritizing comparative effectiveness research for cancer genomic applications. Applying an explicit priority-setting framework to inform investment in comparative effectiveness research can help to ensure that critical factors are weighed when deciding between many potential research questions and trial designs. PMID- 23037936 TI - Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations. AB - PURPOSE: Autosomal recessive congenital short bowel syndrome is caused by mutations in CLMP. No mutations were found in the affected males of a family with presumed X-linked congenital short bowel syndrome or in an isolated male patient. Our aim was to identify the disease-causing mutation in these patients. METHODS: We performed mutation analysis of the second exon of FLNA in the two surviving affected males of the presumed X-linked family and in the isolated patient. RESULTS: We identified a novel 2-base-pair deletion in the second exon of FLNA in all these male patients. The deletion is located between two nearby methionines at the N-terminus of filamin A. Previous studies showed that translation of FLNA occurs from both methionines, resulting in two isoforms of the protein. We hypothesized that the longer isoform is no longer translated due to the mutation and that this mutation is therefore not lethal for males in utero. CONCLUSION: Our findings emphasize that congenital short bowel syndrome can be the presenting symptom in male patients with mutations in FLNA. PMID- 23037937 TI - Study on the thermal reactions of [60]fullerene with amino acids and amino acid esters. AB - Thermal reactions of [60]fullerene with a series of amino acids and amino acid esters under aerobic and dark conditions have been investigated. Fulleropyrrolidines can be obtained from these reactions although an aldehyde is not added purposely. Possible reaction mechanisms involving uncommon C-N bond cleavages have been proposed to generate aldehydes, which then react with amino acids and amino acid esters to provide azomethine ylides, followed by 1,3-dipolar cycloaddition to [60]fullerene affording fulleropyrrolidines. Control experiments support our proposed mechanisms, and elucidate the innate nature of C-N bond cleavages of amino acids and amino acid esters. PMID- 23037938 TI - Mechanical drawing of gas sensors on paper. PMID- 23037939 TI - The effect of temperature on the autofluorescence of scattering and non scattering tissue. AB - BACKGROUND AND OBJECTIVES: With the increasing use of fluorescence in medical applications, a comprehensive understanding of the effect of temperature on tissue autofluorescence is essential. The purpose of this study is to explore the effect of temperature on the fluorescence of porcine cornea and rat skin and determine the relative contributions of irreversible changes in optical properties and in fluorescence yield. STUDY DESIGN/MATERIALS AND METHODS: Fluorescence, diffuse reflectance, and temperature measurements were acquired from excised porcine cornea and rat skin over a temperature range of 0-80 degrees C. A dual excitation system was used with a 337 nm pulsed nitrogen laser for the fluorescence and a white light source for the diffuse reflectance measurements. A thermal camera measured tissue temperature. Optical property changes were inferred from diffuse reflectance measurements. The reversibility of the change in fluorescence was examined by acquiring measurements while the tissue sample cooled from the highest induced temperature to room temperature. RESULTS: The fluorescence intensity decreased with increasing tissue temperature. This fluorescence change was reversible when the tissue was heated to a temperature of 45 degrees C, but irreversible when heated to a temperature of 80 degrees C. CONCLUSION: Auto-fluorescence intensity dependence on temperature appears to be a combination of temperature-induced optical property changes and reduced fluorescence quantum yield due to changes in collagen structure. Temperature-induced changes in measured fluorescence must be taken into consideration in applications where fluorescence is used to diagnose disease or guide therapy. PMID- 23037940 TI - Isotope-based analysis of modified tRNA nucleosides correlates modification density with translational efficiency. AB - Useful diversity: Quantification of modified tRNA nucleobases in different murine and porcine tissues reveals a tissue-specific overall modification content. The modification content correlates with rates of protein synthesis in vitro, suggesting a direct link between tRNA modification levels and tissue-specific translational efficiency. PMID- 23037941 TI - Cytogenetic study in a mutant of Triatoma infestans (Hemiptera: Reduviidae) carrying a spontaneous autosomal fusion and an extra chromosome. AB - Triatomainfestans (2n = 20 A + XY, male) is a blood-sucking bug and the most important vector of Chagas disease in the Southern Cone countries. A cytogenetic analysis of 14 individuals from the Argentine Gran Chaco has revealed the presence of a naturally heterozygous for an autosomal fusion. The fusion heterozygote (2n = 19 A + 1 extra chromosome + XY, male) presented an autosomal trivalent, 8 bivalents, the X and Y sex univalents, and a minute extra chromosome at meiosis I. The autosomal trivalent divided equationally at first anaphase. At metaphase II, cells had 8 autosomes, X and Y sex chromosomes, and an autosomal pseudo-trivalent composed by 3 different-sized chromatids. The orientation of this pseudo-trivalent led to a reductional segregation. The meiotic behaviour of this new chromosome complement was highly regular. The extra chromosome did not affect the segregation of autosomes and sex chromosomes during both meiotic divisions. We propose that the extra chromosome was originated as a product of an autosomal fusion, and it might become a B chromosome. Many authors suggest that karyotype evolution in Heteroptera has proceeded mainly by fusions and fragmentations. The fact that this rearrangement has been found in a natural population of T. infestans and that it shows a regular meiotic behaviour seems to support the suggested hypothesis. PMID- 23037942 TI - Characterization of contraction-induced IL-6 up-regulation using contractile C2C12 myotubes. AB - Muscle contractile activity functions as a potent stimulus for acute interleukin (IL)-6 expression in working skeletal muscles. Recently, we established an "in vitro contraction model" using highly-developed contractile C2C12 myotubes by applying electric pulse stimulation (EPS). Herein, we characterize the effects of EPS-evoked contraction on IL-6 expression in contractile C2C12 myotubes. Both secretion and mRNA expression of IL-6 were significantly up-regulated by EPS in a frequency-dependent manner in contracting myotubes during a 24-h period, and the response was blunted by cyclosporine A, a calcineurin inhibitor. Longer time (~12h) was required for the induction of IL-6 after the initiation of EPS as compared to that of other contraction-inducible CXC chemokines such as CXCL1/KC, which were induced in less than 3 hours. Furthermore, these acute inducible CXC chemokines exhibited no autocrine effect on IL-6 expression. Importantly, contraction-dependent IL-6 up-regulation was markedly suppressed in the presence of high levels of glucose along with increased glycogen accumulations. Experimental manipulation of intracellular glycogen contents by modulating available glucose or pyruvate during a certain EPS period further established the suppressive effect of glycogen accumulations on contraction-induced IL-6 up regulation, which appeared to be independent of calcineurin activity. We also document that EPS-evoked contractile activity improved insulin-responsiveness in terms of intracellular glycogen accumulations. Taken together, these data provide important insights into the regulation of IL-6 expression in response to contractile activity of muscle cells, which is difficult to examine using in vivo experimental techniques. Our present results thus expand the usefulness of our "in vitro contraction model". PMID- 23037943 TI - Evidence for coupling between exciton emissions and surface plasmon in Ni-coated ZnO nanowires. AB - We show that coating ZnO nanowires (NWs) with a transition metal, such as Ni, can increase the efficiency of light emission at room temperature. Based on detailed structural and optical studies, this enhancement is attributed to energy transfer between near-band-edge emission in ZnO and surface plasmons in the Ni film which leads to an increased rate of the spontaneous emission. It is also shown that the Ni coating leads to an enhanced non-radiative recombination via surface states, which becomes increasingly important at low measurement temperatures and in annealed ZnO/Ni NWs. PMID- 23037945 TI - Frontier and perspectives in molecule-based quantum magnets. PMID- 23037944 TI - Notes on the husbandry and long-term transportation of Bull ray (Pteromylaeus bovinus) and Dolphinfish (Coryphaena hippurus and Coryphaena equiselis). AB - Bull rays (Pteromylaeus bovinus) and Dolphinfish (Coryphaena hippurus and Coryphaena equiselis) were collected in Olhao (south of Portugal). These animals hosted multiple parasites, namely Caligus spp., and underwent a variety of treatments to remove them. Of all treatments tested, hydrogen peroxide showed the best results, although only concentrations above 100 ppm were effective in parasite removal. These high concentrations, however, proved to be highly toxic for the fish and led to the loss of some animals, especially those which had been handled before treatment. A total of 14 Bull rays were transported to Bolougne Sur-Mer (France) by road and some animals were lost, which was attributed to excessive time in transit (>45 hr). In another transport, three Bull rays and 10 Dolphinfishes were moved to Stralsund (Germany) by road and air. The mechanical wounds suffered by one of the Bull rays during transport led to its death and, consequently, a deterioration of water quality in the tank containing two other conspecifics. This deterioration of water quality resulted in problems for the other two Bull rays, and one perished approximately 48 hr after arrival. The authors concluded that Dolphinfish can be transported with a low bioload for at least 27 hr, and Bull rays should not undergo transports longer than 35 hr. Special attention must be taken to injured animals, since this can lead to a decrease in water quality and consequently affect other animals in the same transport tank. PMID- 23037946 TI - Contribution of cells derived from the area pellucida to extraembryonic mesodermal cell lineages in heterospecific quail chick blastodermal chimeras. AB - The current study has two main objectives: first, to determine if cells derived from the area pellucida are able to populate extraembryonic membranes, and second, to determine if donor cells have the potential to differentiate to endothelial (EC) and hematopoietic cells (HC) in the yolk sac and allantois, the two extraembryonic membranes functioning as hematopoietic organs in the avian embryo. To this end, quail chick chimeras were constructed by transferring dissociated cells from the areae pellucidae of the stage X-XII (EG&K) quail embryo into the subgerminal cavity of the unincubated chick blastoderm. The distribution of quail cells in the allantois, yolk sac, amnion, and chorion of resulting putative chimeras was examined using quail cell-specific antibody against a perinuclear antigen (QCPN) after 6 days of incubation. The presence of EC, HC, and smooth muscle cells among the QCPN(+) donor cells was examined using QH-1, a quail-specific marker identifying HC and EC and an anti-alpha-smooth muscle actin antibody. Evidence gathered in the present study demonstrates that quail cells derived from the areae pellucidae are able to populate all of the extraembryonic membranes of resulting heterospecific quail chick chimeras and, most importantly, give rise to HC, EC, and smooth muscle cells, all of the three main mesodermal lineages derived from the posterior mesoderm both in the yolk sac and allantois. PMID- 23037947 TI - Characterization of physiological response and identification of associated genes under heat stress in rice seedlings. AB - Global warming, which is caused by greenhouse gas emissions, makes food crops more vulnerable to heat stress. Understanding the heat stress-related mechanisms in crops and classifying heat stress-related genes can increase our knowledge in heat-resistant molecular biology and propel developments in molecular design breeding, which can help rice cope with unfavorable temperatures. In this study, we carried out a physiological analysis of rice plants after heat stress. The results show a dramatic increase in malondialdehyde contents and SOD activities. We successfully isolated 11 heat-related rice genes with known function annotation through DNSH, which is an improved SSH method for screening long cDNA fragments. The reanalysis of microarray data from public database revealed that all these genes displayed various expression patterns after heat stress, drought, cold and salt. Quantitative real-time reverse transcription PCR was also performed to validate the expression of these genes after heat stress. The expressions in 10 genes were all significantly changed except for contig 77, which is a CBL-interacting protein kinase. Several reports have been published about the members of the same gene family. PMID- 23037948 TI - Influencing CYP enzymes to boost psychiatric treatment: a review on clinical evidence. AB - INTRODUCTION: Therapeutic drug monitoring to optimize blood plasma concentrations is advised for certain psychiatric drugs. The current standard is to change the dose based on the blood plasma concentration. We present an overview that blood plasma concentrations can also be influenced by adding co-medication based on pharmacokinetic knowledge. METHOD: We performed a systematic review in medical databases for pharmaco-enhancing strategies, and we present 2 cases on actively influencing CYP3A4 metabolism. RESULTS: 4 original studies were selected on strategies to influence CYP metabolism. 2 studies on influencing CYP2D6 metabolism, 2 studies on influencing CYP1A2 metabolism. In all studies an effect of this influence was present.Ample clinical evidence is present, but shows promising results. Pharmacokinetic knowledge can and should be used in clinical settings to optimize pharmacotherapy for vulnerable patients. Also the access to expensive medication can be increased by reduction of high dosage schemes. PMID- 23037949 TI - Lithium treatment of a bipolar patient with Wilson's disease: a case report. AB - We present the case of a male patient with a family history of both bipolar disorder (BD) and Wilson's disease (WD). Wilson's disease was diagnosed for this patient in 2008, at the age of 28 years, and shortly thereafter his bipolar illness began with depressive episodes. The patient has been treated with zinc sulphate for WD and with antidepressants for depression. In 2009, lithium was added, and in 2010 antidepressants were discontinued. During treatment with zinc sulphate, a gradual improvement of hepatic indices and a decrease of mandibulofacial dystonia was noted. In 2011, a hypomanic state occurred which subsided with an increase of the lithium dose. Since then, the patient has been mostly in a euthymic mood with subclinical hypomanic periods. We suggest that lithium may be a viable option for treating bipolar illness in patients with Wilson's disease. PMID- 23037951 TI - Towards chemically accurate simulation of molecule-surface reactions. AB - This perspective addresses four challenges facing theorists whose aim is to make quantitatively accurate predictions for reactions of molecules on metal surfaces, and suggests ways of meeting these challenges, focusing on dissociative chemisorption reactions of H(2), N(2), and CH(4). Addressing these challenges is ultimately of practical importance to a more accurate description of overall heterogeneously catalysed reactions, which play a role in the production of more than 90% of man-made chemicals. One challenge is to describe the interaction of a molecule with a metal surface with chemical accuracy, i.e., with errors in reaction barrier heights less than 1 kcal mol(-1). In this framework, the potential of a new implementation of specific reaction parameter density functional theory (SRP-DFT) will be discussed, with emphasis on applications to reaction of H(2) with metal surfaces. Two additional challenges are to come up with improved descriptions of the effects of phonons and electron-hole pairs on reaction of molecules like N(2) on metal surfaces. Phonons can be tackled using sudden approximations in quantum dynamics, and through Ab Initio Molecular Dynamics (AIMD) calculations using classical dynamics. To additionally achieve an accurate description of the effect of electron-hole pair excitation on dissociative chemisorption within a classical dynamics framework, it may be possible to combine AIMD with electronic friction. The fourth challenge we will consider is how to achieve an accurate quantum mechanical description of the dissociative chemisorption of a polyatomic molecule, like methane, on a metal surface. A method of potential interest is the Multi-Configuration Time-Dependent Hartree (MCTDH) method. PMID- 23037950 TI - Possible association of nicotinic acetylcholine receptor gene (CHRNA4 and CHRNB2) polymorphisms with nicotine dependence in Japanese males: an exploratory study. AB - INTRODUCTION: Smoking is a leading global cause of avoidable mortality. It has been reported that the nicotinic acetylcholine receptor (CHRNA4 and CHRNB2) genes might be associated with smoking behavior in several ethnic populations. However, no study between the 2 genes and nicotine dependence (ND) using a Japanese population has been reported. METHODS: We examined the association between ND and 5 single nucleotide polymorphisms (SNPs) within the CHRNA4 and 3 SNPs within the CHRNB2 using a well characterized sample of 558 Japanese healthy male workers with a relatively homogeneous background. The Fagerstrom test for nicotine dependence (FTND) was used to quantify the degree of ND. Additionally, we explored the effect of gene-gene interactions of the 2 genes on ND. RESULTS: We found CHRNB2 rs4845652 genotypes to be associated with FTND scores under an additive genetic model: rs4845652 T-allele carriers had lower ND levels (p=0.038; when adjusted for smoking duration: p=0.052). Furthermore, we demonstrated a possible gene-gene interaction of CHRNA4 and CHRNB2 on ND in a dose-dependent manner: those smokers with CHRNA4 rs1044397 GG or GA genotypes along with CHRNB2 rs4845652 CC genotype are likely to demonstrate higher ND scores. DISCUSSION: These findings suggest that CHRNB2 rs4845652 T-allele carriers may be associated with lower levels of ND, and that certain allelic combinations of CHRNA4 and CHRNB2 might be correlated with higher ND levels. This preliminary study has certain limitations (issues such as sample size/power and multiple testing) that need to be taken into account, and the present work thus has an experimental nature. PMID- 23037952 TI - Palladium electrodes for molecular tunnel junctions. AB - Gold has been the metal of choice for research on molecular tunneling junctions, but it is incompatible with complementary metal-oxide-semiconductor fabrication because it forms deep level traps in silicon. Palladium electrodes do not contaminate silicon, and also give higher tunnel current signals in the molecular tunnel junctions that we have studied. The result is cleaner signals in a recognition-tunneling junction that recognizes the four natural DNA bases as well as 5-methyl cytosine, with no spurious background signals. More than 75% of all the recorded signal peaks indicate the base correctly. PMID- 23037953 TI - Activating transcription factor 6 mediates oxidized LDL-induced cholesterol accumulation and apoptosis in macrophages by up-regulating CHOP expression. AB - AIM: This study was to explore whether activating transcription factor 6 (ATF6), an important sensor to endoplasmic reticulum (ER) stress, would mediate oxidized low-density lipoprotein (ox-LDL)- induced cholesterol accumulation and apoptosis in cultured macrophages and the underlying molecular mechanisms. METHODS: Intracellular lipid droplets and total cholesterol levels were assayed by oil red O staining and enzymatic colorimetry, respectively. Cell viability and apoptosis were determined using MTT assay and AnnexinV-FITC apoptosis detection kit, respectively. The nuclear translocation of ATF6 in cells was detected by immunofluorescence analysis. Protein and mRNA levels were examined by Western blot analysis and real time-PCR, respectively. ATF6 siRNA was transfected to RAW264.7 cells by lipofectamin. RESULTS: Exposure of cells to ox-LDL induced glucose-regulated protein 78 (GRP78). C/EBP homologous protein (CHOP), a key signaling component of ER stress-induced apoptosis, was up-regulated in ox-LDL treated cells. ATF6, a factor that positively regulates CHOP expression, was activated by ox-LDL in a concentration- and time- dependent manner. The role of the ATF6-mediated ER stress pathway was further confirmed through the siRNA mediated knockdown of ATF6, which attenuated ox-LDL-induced upregulation of CHOP, cholesterol accumulation and apoptosis in macrophages. In addition, the phosphorylation of double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK), another factor that positively regulates CHOP expression, was induced in the presence of ox-LDL, and PERK-specific siRNA also inhibited the ox-LDL-induced upregulation of CHOP and apoptosis in RAW264.7 cells. CONCLUSION: These results demonstrate that ER stress-related proteins, particularly ATF6 and its downstream molecule CHOP, are involved in ox-LDL induced cholesterol accumulation and apoptosis in macrophages. PMID- 23037954 TI - Value and level of galectin-3 in acute myocardial infarction patients undergoing primary percutaneous coronary intervention. AB - AIM: This study investigated the impact of the circulating galectin-3 level on the 30-day prognostic outcome in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: From May 2009 to March 2011, blood samples for assessment of the circulating galectin-3 level were collected from 196 consecutive STEMI patients treated by primary PCI and from 30 healthy volunteers. RESULTS: The galectin-3 level was determined using ELISA. Our results demonstrated that the circulating level of galectin-3 was significantly higher in STEMI patients than in healthy control subjects (p<0.001). As compared with patients with galectin-3 <7.67 ng/mL, patients with galectin-3 >=7.67 ng/mL were significantly older, had significantly lower left ventricular ejection fraction and significantly higher frequency of elevated white blood cell count, advanced Killip score (defined as >= score 3), congestive heart failure (defined as >= New York Heart Association Functional Class III), respiratory failure, unstable hemodynamics requiring a mechanical ventilator and intra-aortic balloon pump support, multiple vessel diseases and 30-day mortality (all p<0.04). Furthermore, multivariate analysis showed that elevated circulating level of galectin-3 was the strongest independent predictor of the combined 30-day major adverse clinical outcome (MACO) (defined as advanced CHF or 30-day mortality) (p<0.0001). CONCLUSION: A high circulating galectin-3 level may serve as a useful biomarker for predicting 30-day MACO in patients with STEMI undergoing primary PCI. PMID- 23037955 TI - Novel mutation in GJB4 gene (connexin 30.3) in a family with erythrokeratodermia variabilis. PMID- 23037956 TI - Asymmetric catalysis based on tropos ligands. AB - All enantiopure atropisomeric (atropos) ligands essentially require enantiomeric resolution or synthetic transformation from a chiral pool. In sharp contrast, the use of tropos (chirally flexible) ligands, which are highly modular, versatile, and easy to synthesize without enantiomeric resolution, has recently been the topic of much interest in asymmetric catalysis. Racemic catalysts bearing tropos ligands can be applied to asymmetric catalysis through enantiomeric discrimination by the addition of a chiral source, which preferentially transforms one catalyst enantiomer into a highly activated catalyst enantiomer. Additionally, racemic catalysts bearing tropos ligands can also be utilized as atropos enantiopure catalysts obtained via the control of chirality by a chiral source followed by the memory of chirality. In this feature article, our results on the asymmetric catalysis via the combination of various central metals and tropos ligands are summarized. PMID- 23037957 TI - Neuropsychological performance and conversion to Alzheimer's disease in early- compared to late-onset amnestic mild cognitive impairment: CREDOS study. AB - BACKGROUND: Amnestic mild cognitive impairment (aMCI) is regarded as a prodromal stage of Alzheimer's disease (AD). Given that patients with early-onset AD (EOAD) and with late-onset AD (LOAD) are known to have different clinical courses, symptoms and neuroimaging findings, early-onset (EOMCI) and late-onset aMCI (LOMCI) might be expected to have similar differences as EOAD versus LOAD. METHODS: Our study involving 425 patients with aMCI (124 EOMCI, 301 LOMCI), who were followed for around 1.5 years, and 958 normal control subjects (NC) investigated neuropsychological characteristics and prediction of progression to AD in patients with EOMCI versus LOMCI. Neuropsychological scores were compared between EOMCI, LOMCI and NC with analyses of covariance controlling age, gender, education and disease duration. The risk of AD conversion was evaluated by Cox proportional hazard analyses. RESULTS: The baseline neuropsychological performances were comparable between EOMCI and LOMCI. Visuospatial memory for EOMCI and verbal memory scores for LOMCI were significant predictors of AD conversion. CONCLUSION: Our study indicates that EOMCI with visuospatial memory impairment, which implies underlying right predominant pathology, and LOMCI with poor verbal memory, which suggests underlying left predominant pathology, are individual conditions at an increased risk of conversion to AD. PMID- 23037958 TI - Usefulness of the LCOPD, CAFS and CASIS scales in understanding the impact of COPD on patients. AB - BACKGROUND: The Living with COPD (LCOPD), COPD and Asthma Fatigue Scale (CAFS), and COPD and Asthma Sleep Impact Scale (CASIS) are instruments developed to assess the overall impact of chronic obstructive pulmonary disease (COPD) on daily life, fatigue, and sleep impairment, respectively. OBJECTIVES: To assess the usefulness of these instruments and to identify factors associated with the concepts they measure. METHOD: The questionnaires were administered to patients with moderate to severe COPD. Descriptive analyses of sociodemographic and clinical data were performed, and bivariate and multivariate analyses were used to identify factors associated with the overall impact of COPD on patients' lives, fatigue, and sleep impairment. RESULTS: A total of 408 patients was included (mostly males, 91.2%), with an average age of 68 years (SD = 9.3). Statistically significant differences were observed in the scores of the three questionnaires with regard to level of education, presence of chronic cough or expectoration, level of dyspnea, number of exacerbations, physical activity level, presence of depression and anxiety, and number of treatments indicated for COPD. The LCOPD and CAFS questionnaires also discriminated between different levels of airflow obstruction and, in the case of CAFS, age and gender. Linear regression showed that level of dyspnea, physical activity, and presence of anxiety were significantly related to the LCOPD, CAFS and CASIS scores. The presence of depression was significant in the LCOPD and CAFS questionnaires and chronic cough was significant in the CAFS questionnaire. CONCLUSIONS: The LCOPD, CAFS, and CASIS instruments are valid and useful in understanding the overall impact of COPD on daily life, fatigue, and sleep impairment in patients with moderate to severe COPD. PMID- 23037959 TI - Enhanced stability in rigid peptide-based porous materials. AB - Pepped up: Notwithstanding the intrinsic conformational flexibility of peptides, [Zn(Gly-Thr)(2)] behaves as a robust porous metal-organic framework thanks to the rigidity introduced by the use of Gly-Thr (see scheme). This rigidity arises from the sequence of amino acids in the dipeptide that locks its conformational flexibility in the framework. PMID- 23037961 TI - Subjective cognitive impairment. AB - PURPOSE OF REVIEW: To describe the recent (2011-2012) literature relevant to subjective cognitive impairment (SCI), focusing principally on studies of this symptom in older age groups. This is an issue of growing importance: although the symptom itself is controversial in older people because of variable associations with objective cognitive impairment, it remains one of the few presenting complaints which may identify people experiencing early cognitive decline. RECENT FINDINGS: Several neuroimaging studies confirm earlier reports of associations between SCI and underlying abnormalities whereas those between subjective and objective cognitive function remain heterogeneous. Several studies now highlight the fact that, regardless of underlying associations, SCI as a symptom is associated with significant concern but is something for which older people rarely seek help. SUMMARY: Neuroimaging findings suggest that older people may be more aware of underlying brain changes than was previously apparent or than can be detected using conventional neuropsychological assessments. However, not all of these brain changes are necessarily progressive or neurodegenerative. At least some attention should be paid to interventions for what is a common, often distressing, but underreported symptom. PMID- 23037960 TI - Identification and profiling of targeted oxidized linoleic acid metabolites in rat plasma by quadrupole time-of-flight mass spectrometry. AB - Linoleic acid (LA) and LA-esters are the precursors of LA hydroperoxides, which are readily converted to 9- and 13-hydroxy-octadecadienoic acid (HODE) and 9- and 13-oxo-octadecadienoic acid (oxo ODE) metabolites in vivo. These four oxidized LA metabolites (OXLAMs) have been implicated in a variety of pathological conditions. Therefore, their accurate measurement may provide mechanistic insights into disease pathogenesis. Here we present a novel quadrupole time-of flight mass spectrometry (Q-TOFMS) method for quantitation and identification of target OXLAMs in rat plasma. In this method, the esterified OXLAMs were base hydrolyzed and followed by liquid-liquid extraction. Quantitative analyses were based on one-point standard addition with isotope dilution. The Q-TOFMS data of target metabolites were acquired and multiple reaction monitoring extracted-ion chromatograms were generated post-acquisition with a 10 ppm extraction window. The limit of quantitation was 9.7-35.9 nmol/L depending on the metabolite. The method was reproducible with a coefficient of variation of <18.5%. Mean concentrations of target metabolites in rat plasma were 57.8, 123.2, 218.1 and 57.8 nmol/L for 9-HODE, 13-HODE, 9-oxoODE and 13-oxoODE, respectively. Plasma levels of total OXLAMs were 456.9 nmol/L, which correlated well with published concentrations obtained by gas chromatography/mass spectrometry (GC/MS). The concentrations were also obtained utilizing a standard addition curve approach. The calibration curves were linear with correlation coefficients of >0.991. Concentrations of 9-HODE, 13-HODE, 9-oxoODE and 13-oxoODE were 84.0, 138.6, 263.0 and 69.5 nmol/L, respectively, which were consistent with the results obtained from one-point standard addition. Target metabolites were simultaneously characterized based on the accurate Q-TOFMS data. This is the first study of secondary LA metabolites using Q-TOFMS. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23037963 TI - Quality of life in people living with dementia in nursing homes. AB - PURPOSE OF REVIEW: To describe the impact of living in a nursing home on quality of life (QoL) in people living with dementia. RECENT FINDINGS: People with dementia are likely to spend time in a nursing home, particularly in the late stage of the syndrome when declining functional and cognitive ability add to the burden of community care. Although it is commonly assumed that QoL decreases for people with dementia once they are placed into a nursing home, the reviewed studies suggest that self-ratings of QoL are significantly higher than staff and family ratings, several nonpharmacological interventions may increase QoL and further research is needed that focuses on the influence of care provision. SUMMARY: Dementia is associated with a reduced QoL that can be partly caused by environment, staff attitudes and limited relationships. Although people with dementia experience variations in QoL across the trajectory of the syndrome, there is evidence that they can communicate their preferences and have meaning in their lives when key factors related to QoL are addressed. Some of these key factors include meaningful time use through activities focused on their interests, social engagement, positive staff attitudes and an environment that allows connection with others. PMID- 23037962 TI - Neuroimaging in dementias. AB - PURPOSE OF REVIEW: To critically review data on the use of neuroimaging tools in the clinical diagnostic investigation of dementias. RECENT FINDINGS: For many years, the use of neuroimaging tools in the evaluation of dementias has been restricted to excluding neurosurgical lesions that may account for the cognitive decline. However, modern neuroimaging extends beyond this traditional role of excluding other conditions and has a key role in the clinical investigation of Alzheimer's disease and of other degenerative cortical dementias. MRI, PET with fluorodeoxyglucose, and single-photon emission computed tomography are topographic markers of neural damage and enable the identification of specific lesional patterns that characterize Alzheimer's disease and other cortical dementias. More recently, PET amyloid markers have enabled the in-vivo assessment of amyloid load, a key feature in the physiopathology of Alzheimer's disease. SUMMARY: The combined use of neuroimaging examinations with clinical, neuropsychological, and cerebrospinal fluid markers can improve the specificity of the diagnosis of Alzheimer's disease, even at early stages of the disease. In the following years, progress in research will provide standardized and validated imaging markers of Alzheimer's disease and other dementias, which may increase their application in clinical settings. PMID- 23037964 TI - Reinventing intention: 'self-harm' and the 'cry for help' in postwar Britain. AB - PURPOSE OF REVIEW: To sketch out how contemporary Anglophone literature on self damaging behaviour negotiates serious conceptual difficulties around intention, and to demonstrate (in the British context) how the large-scale emergence of this type of behaviour is made possible by new forms of psychological provision at district general hospitals. RECENT FINDINGS: In the past decade, there has been increasing public awareness of 'self-harm'. Despite the view that 'self-harm' has always existed, the British roots of the current 'epidemic' can be traced to changes in the organization of mental healthcare in the postwar period. These changes make possible new understandings of the story behind physical injuries, and allow these readings to be aggregated and projected onto a national, epidemic scale. SUMMARY: The increasing provision of psychiatric expertise in general hospitals makes possible new interpretations of self-injury - as psychosocial communication, or affect self-regulation - and creates the phenomenon of 'self harm' as we understand it today. PMID- 23037966 TI - Current world literature. PMID- 23037968 TI - Surgical anatomy of the radial nerve branches to triceps muscle. AB - The objectives of the study are to demonstrate the innervation patterns of the triceps muscles and the most suitable branch of the radial nerve for nerve transfer to restore the motor function of the deltoid muscle in patients with complete C5-C6 root injury. Seventy-nine arms (40 left arms and 39 right arms) from 46 embalmed cadavers (24 male and 22 female) were included in the study. The nerves to the triceps were dissected from the triceps muscles (long head, lateral head, and medial head). The lengths of the branches were measured from the main trunk. The distance from the inferior margin of the teres major muscle to the origin of the nerve to the long head, lateral head, and medial head of the triceps were recorded as well. The first branch was the nerve to the long head of the triceps in 79 arms (100%). The second branch was the nerve to the upper medial head in 30 arms (38%), nerve to the medial head in 8 arms (10.1%), nerve to the upper lateral head in 35 arms (44.3%) and nerve to the lateral head in 6 arms (7.6%). The patterns of branches to the triceps were classified according to our dissections. The nerve to the long head of the triceps was constant as the first branch of the nerve to the triceps branch of the radial nerve in the vicinity of the inferior margin of the teres major muscle. PMID- 23037965 TI - The treatment of alcohol and opioid dependence in pregnant women. AB - PURPOSE OF REVIEW: This article addresses the question of 'best treatment options', which clinicians face when treating pregnant women with alcohol and opioid dependence. RECENT FINDINGS: Studies show that alcohol consumption is associated with fetal abnormalities and long-term cognitive problems depending on the amount consumed, drinking pattern, and time of gestation. Screening and evaluation of specific interventions are important to reduce alcohol consumption during pregnancy and associated problems in infants. Opioid detoxification is only recommended beyond the first trimester and only in those pregnant women who refuse opioid maintenance therapy. Methadone is the most established treatment of pregnant opioid-dependent women, though recent results indicate some advantages of buprenorphine, slow-release oral methadone and diamorphine compared with methadone. SUMMARY: Benzodiazepines seem to be the most recommendable option for managing alcohol withdrawal, and psychosocial interventions succeed in reducing alcohol consumption or in maintaining abstinence in alcohol-dependent pregnant women. Regarding opioid dependence, current results suggest that factors like the health status of the mother, the need for additional medications (e.g. treatment for HIV), comorbid drug dependence, and concurrent drug use need to be considered in order to find the 'best opioid substitute'. PMID- 23037969 TI - Diastereoselective synthesis of substituted dihydropyrans via an oxonium-ene cyclization reaction. AB - Substituted dihydropyrans can be efficiently synthesized in good yields with excellent diastereoselectivity from the reaction of aldehydes or epoxides and ethyl 3-alkyl-3-hydroxy-5-methylhex-5-enoate via an oxonium-ene cyclization reaction catalyzed by trimethylsilyl trifluoromethanesulfonate (TMSOTf) under mild conditions. PMID- 23037970 TI - A facile fabrication of spherical and beanpod-like magnetic-fluorescent particles with targeting functionalities. AB - Magnetic-fluorescent particles with targeting functionalities were fabricated by a modified Stober method and two shapes (spherical and beanpod-like) were obtained by simply tuning the reaction temperature. The two multifunctional probes combined the useful functions of magnetism, fluorescence and FA (folic acid)-targeting recognition into one entity. The products were characterized by scanning electron microscopy, transmission electron microscopy, photoluminescence spectroscopy, confocal laser scanning microscopy, by a superconducting quantum interference device and by Fourier transform infrared spectroscopy. The experimental results show that the products possessed rapid magnetic response, relatively strong fluorescent signal, higher photostability and FA-targeting recognition as well as good water-dispersibility, suggesting that they would have potential medical applications in biolabeling and bioimaging. PMID- 23037971 TI - Elective high-frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. AB - BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease (CLD). A newer form of ventilation called high-frequency oscillatory ventilation (HFOV) has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine the effect of the elective use of HFOV as compared to conventional ventilation (CV) on the incidence of CLD, mortality and other complications associated with prematurity and assisted ventilation in preterm infants who are mechanically ventilated for respiratory distress syndrome (RDS). SEARCH METHODS: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross-references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in January 2009. SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who required assisted ventilation. Randomization and commencement of treatment needed to be as soon as possible after the start of CV and usually in the first 12 h of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. The standard effect measures are relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat to produce one outcome were calculated. For all measures of effect, 95% confidence intervals were used. In subgroup analyses the 99% CIs are also given for summary RRs in the text. Meta analysis was performed using a fixed effect model. Where heterogeneity was over 50%, the random effects RR is also given. MAIN RESULTS: Seventeen eligible studies of 3,652 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28-30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The effect of HFOV on CLD in survivors at term equivalent gestational age was inconsistent across studies and the reduction was of borderline significance overall. The effect was similar in trials with a high lung volume strategy for HFOV targeting at very low FiO(2) and trials with a high lung volume strategy with somewhat higher or unspecified target FiO(2). Subgroups of trials showed a significant reduction in CLD with HFOV when no surfactant was used, when piston oscillators were used for HFOV, when lung protective strategies for CV were not used, when randomization occurred at two to six hours of age, and when inspiratory:expiratory ratio of 1:2 was used for HFOV. In the meta-analysis of all trials, pulmonary air leaks occurred more frequently in the HFOV group. In some studies, short-term neurological morbidity with HFOV was found, but this effect was not statistically significant overall. The subgroup of two trials not using a high-volume strategy with HFOV found increased rates of grade 3 or 4 intraventricular hemorrhage and of periventricular leukomalacia. An adverse effect of HFOV on long-term neurodevelopment was found in one large trial but not in the five other trials that reported this outcome. The rate of retinopathy of prematurity is reduced overall in the HFOV group. PMID- 23037972 TI - Characterization and genome organization of a repetitive element associated with the nucleolus organizer region in Leporinus elongatus (Anostomidae: Characiformes). AB - Chromosome mapping and studies of the genomic organization of repetitive DNA sequences provide valuable insights that enhance our evolutionary and structural understanding of these sequences, as well as identifying chromosomal rearrangements and sex determination. This study investigated the occurrence and organization of repetitive DNA sequences in Leporinus elongatus using restriction enzyme digestion and the mapping of sequences by chromosomal fluorescence in situ hybridization (FISH). A 378-bp fragment with a 54.2% GC content was isolated after digestion with the SmaI restriction enzyme. BLASTN search found no similarity with previously described sequences, so this repetitive sequence was named LeSmaI. FISH experiments were conducted using L. elongatus and other Anostomidae species, i.e. L. macrocephalus, L. obtusidens, L. striatus, L. lacustris, L. friderici, Schizodon borellii, S. isognathus, and Abramites hypselonotus which detected signals that were unique to male and female L. elongatus individuals. Double-FISH using LeSmaI and 18S rDNA showed that LeSmaI was located in a nucleolus organizer region (NOR) in the male and female metaphases of L. elongatus. This report also discusses the role of repetitive DNA associated with NORs in the diversification of Anostomidae species karyotypes. PMID- 23037973 TI - Self-enhanced electrochemiluminescence of an iridium(III) complex: mechanistic insight. AB - Improved luminophore: The electrochemiluminescence (ECL) of an iridium complex self-enhanced up to 16 times is reported. Three excited states were observed in the emission spectra (see picture). The ECL efficiency of this complex is the highest reported for an iridium complex. PMID- 23037977 TI - Black tea: chemical analysis and stability. AB - Tea is the most popular flavored and functional drink worldwide. The nutritional value of tea is mostly from the tea polyphenols that are reported to possess a broad spectrum of biological activities, including anti-oxidant properties, reduction of various cancers, inhibition of inflammation, and protective effects against diabetes, hyperlipidemia and obesity. Tea polyphenols include catechins and gallic acid in green and white teas, and theaflavins and thearubigins as well as other catechin polymers in black and oolong teas. Accurate analysis of black tea polyphenols plays a significant role in the identification of black tea contents, quality control of commercial tea beverages and extracts, differentiation of various contents of theaflavins and catechins and correlations of black tea identity and quality with biological activity, and most importantly, the establishment of the relationship between quantitative tea polyphenol content and its efficacy in animal or human studies. Global research in tea polyphenols has generated much in vitro and in vivo data rationally correlating tea polyphenols with their preventive and therapeutic properties in human diseases such as cancer, and metabolic and cardiovascular diseases etc. Based on these scientific findings, numerous tea products have been developed including flavored tea drinks, tea-based functional drinks, tea extracts and concentrates, and dietary supplements and food ingredients, demonstrating the broad applications of tea and its extracts, particularly in the field of functional food. PMID- 23037978 TI - Preparation and complete (1) H and (13)C assignment of some pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane-8,11-dione (PCUD) derivatives. AB - The preparation of a number of alkyl and alkoxy derivatives of pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane-8,11-dione derivatives utilising a cheap, practical, low energy, 'green', single-pass continuous flow photochemical reactor is reported. Their (1)H and (13)C NMR spectra are fully assigned, revealing some general characteristics not previously reported for this class of compound, which should aid the assignment and prediction of the NMR spectra of PCUD derivatives. PMID- 23037979 TI - Photo-killing mechanism of 2-demethoxy-2,3-ethylenediamino hypocrellin B (EDAHB) to HeLa cells. AB - 2-Demethoxy-2,3-ethylenediamino hypocrellin B (EDAHB) is a diamino-substituted hypocrellin B (HB) with high absorption of red light and high quantum yield of both singlet oxygen ((1)O(2)) and superoxide anions (O(2)(-)). Here we reported the cellular uptake, subcellular location, and cytotoxicity of EDAHB, as well as EDAHB-mediated photodynamic therapy (PDT) efficiency, and cell apoptosis. Results showed that EDAHB accumulated in HeLa cells rapidly up to 1h, with a subsequent decrease in the rate of uptake. EDAHB distributed with well-defined spots throughout the cytoplasm of the cells. EDAHB showed a much higher photopotentiation factor than HB. The phototoxicity of EDAHB to HeLa cells occurred via a mitochondria/caspase apoptosis pathway. This study showed EDAHB to be a promising candidate of photosensitizer for anti-tumor PDT. PMID- 23037980 TI - Use of multiple imputation method to improve estimation of missing baseline serum creatinine in acute kidney injury research. AB - BACKGROUND AND OBJECTIVES: Baseline creatinine (BCr) is frequently missing in AKI studies. Common surrogate estimates can misclassify AKI and adversely affect the study of related outcomes. This study examined whether multiple imputation improved accuracy of estimating missing BCr beyond current recommendations to apply assumed estimated GFR (eGFR) of 75 ml/min per 1.73 m(2) (eGFR 75). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From 41,114 unique adult admissions (13,003 with and 28,111 without BCr data) at Vanderbilt University Hospital between 2006 and 2008, a propensity score model was developed to predict likelihood of missing BCr. Propensity scoring identified 6502 patients with highest likelihood of missing BCr among 13,003 patients with known BCr to simulate a "missing" data scenario while preserving actual reference BCr. Within this cohort (n=6502), the ability of various multiple-imputation approaches to estimate BCr and classify AKI were compared with that of eGFR 75. RESULTS: All multiple-imputation methods except the basic one more closely approximated actual BCr than did eGFR 75. Total AKI misclassification was lower with multiple imputation (full multiple imputation + serum creatinine) (9.0%) than with eGFR 75 (12.3%; P<0.001). Improvements in misclassification were greater in patients with impaired kidney function (full multiple imputation + serum creatinine) (15.3%) versus eGFR 75 (40.5%; P<0.001). Multiple imputation improved specificity and positive predictive value for detecting AKI at the expense of modestly decreasing sensitivity relative to eGFR 75. CONCLUSIONS: Multiple imputation can improve accuracy in estimating missing BCr and reduce misclassification of AKI beyond currently proposed methods. PMID- 23037982 TI - Recovery from AKI and short- and long-term outcomes after lung transplantation. AB - BACKGROUND AND OBJECTIVES: Patients with AKI after lung transplantation are at increased risk for CKD and death. Whether patients who completely recover from AKI have improved long-term outcome compared with patients who do not completely recover remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study retrospectively evaluated data on 657 patients who underwent lung transplantation from 1997 to 2009. Outcomes analyzed were the incidence of renal recovery after AKI and the association of this recovery with short- and long-term mortality. AKI was defined by an absolute increase in serum creatinine of >=0.3 mg/dl or a percent increase in serum creatinine of >=50% from baseline at any time during the first 2 weeks after transplantation. RESULTS: Four hundred twenty four (65%) patients experienced AKI in the first 2 weeks after transplantation. Of these patients, complete renal recovery occurred in 142 (33%) patients. The incidence of in-hospital complications was similar between patients who recovered renal function and patients without recovery. At 1 year, the cumulative incidence of CKD was 14% and 22% (P=0.10) and patient survival rate was 81% and 76% (P=0.20) in patients with complete recovery from AKI and patients without recovery, respectively. Patients with completely recovered AKI had similar risk adjusted long-term mortality compared with patients who did not recover (hazard ratio [95% confidence interval]=1.42 [1.15-2.05] versus 1.53 [1.01-2.00]). CONCLUSIONS: Patients who recover completely from early AKI after lung transplantation have a similar risk for CKD and long-term mortality compared with patients who do not recover. PMID- 23037981 TI - How to overcome barriers and establish a successful home HD program. AB - Home hemodialysis (HD) is an underused dialysis modality in the United States, even though it provides an efficient and probably cost-effective way to provide more frequent or longer dialysis. With the advent of newer home HD systems that are easier for patients to learn, use, and maintain, patient and provider interest in home HD is increasing. Although barriers for providers are similar to those for peritoneal dialysis, home HD requires more extensive patient training, nursing education, and infrastructure support in order to maintain a successful program. In addition, because many physicians and patients do not have experience with home HD, reluctance to start home HD programs is widespread. This in-depth review describes barriers to home HD, focusing on patients, individual physicians and practices, and dialysis facilities, and offers suggestions for how to overcome these barriers and establish a successful home HD program. PMID- 23037983 TI - An elderly patient with chronic hyponatremia. AB - Hyponatremia is the most common electrolyte disorder. With the aging of the population and the greater propensity of the elderly to develop hyponatremia, this electrolyte disorder is of increasing importance to the practicing nephrologist. In this Attending Rounds, an illustrative patient with hyponatremia is presented. The reasons for the increased incidence and prevalence of hyponatremia in the elderly are discussed, with emphasis on the effects of aging on urinary dilution, the frequently multifactorial nature of hyponatremia in this population, and the absence of a definite cause for inappropriate and persistent vasopressin release in many such patients. The rationale for treating the hyponatremia, even when apparently asymptomatic, is discussed, with attention to cognitive function, gait, and bone structure disturbances that increase the risk for fractures. The various available treatment approaches, including water restriction, demeclocycline, loop diuretics with NaCl supplementation, urea, and vasopressin antagonists are summarized, with emphasis on the efficacy and limitations of each of these therapies. PMID- 23037985 TI - Drug-associated thrombotic microangiopathies. AB - Thrombotic microangiopathy is a pathological process that results in thrombocytopenia, schistocytes, and organ ischemia. A wide variety of causes of thrombotic microangiopathy have been described, each associated with a different pathological stimulus and predisposition toward certain vascular territories. This review will summarize our understanding of key drugs that have been classically and newly associated with thrombotic microangiopathy as well as mention of treatment options focusing on the role of plasma exchange. PMID- 23037984 TI - The case for routine parathyroid hormone monitoring. AB - Parathyroid hormone (PTH) is a uremic toxin with multiple systemic effects including bone disorders (renal osteodystrophy), myopathy, neurologic abnormalities, anemia, pruritus, and cardiomyopathy. Hyperparathyroidism is common in CKD and results in significant morbidity and mortality if left untreated. Clinical practice guidelines from the Kidney Disease Improving Global Outcomes initiative broadened the optimal PTH range to >2 and <9 times the upper limit of normal for the assay measured. Furthermore, the guidelines recommend following trends in PTH to determine the appropriate therapy. These guidelines overcome issues with the assay variability and help clinicians make judgments when treating individual patients. They also require frequent measurement in order to determine trends and implement appropriate treatments. PMID- 23037986 TI - Localized and guided electroluminescence from roll printed organic nanofibres. AB - Here, we report localized, polarized and waveguided electroluminescence (EL) from well aligned organic nanofibres integrated via roll printing on transistor platforms. The localized emission is due to the application of an alternating current voltage to the transistor gate electrodes, which causes sequential injection of holes and electrons into the organic material with subsequent charge carrier recombination and light emission from a small area near the metal nanofibre interface. The polarization results from the mutually parallel ordering of the molecular constituents, in which the emitting dipole is oriented along the long molecular axis. Furthermore, their morphology enables the nanofibres to operate as optical waveguides and part of the generated light is therefore guided along the nanofibre and radiated at the nanofibre end. In addition to the 'standard' hexaphenylene nanofibres, we also demonstrate that this scheme can facilitate EL from a nanofibre made from a different type of molecule with altered spectral characteristics. The realization of an electrically biased organic nanoscale light-emitter demonstrates the ability to fabricate on-chip light sources with a tunable emission spectrum via synthesis of appropriate molecular building blocks. PMID- 23037987 TI - Exogenous activation of BMP-2 signaling overcomes TGFbeta-mediated inhibition of osteogenesis in Marfan embryonic stem cells and Marfan patient-specific induced pluripotent stem cells. AB - Marfan syndrome (MFS) is a hereditary disease caused by mutations in the gene encoding Fibrillin-1 (FBN1) and characterized by a number of skeletal abnormalities, aortic root dilatation, and sometimes ectopia lentis. Although the molecular pathogenesis of MFS was attributed initially to a structural weakness of the fibrillin-rich microfibrils within the extracellular matrix, more recent results have documented that many of the pathogenic abnormalities in MFS are the result of alterations in TGFbeta signaling. Mutations in FBN1 are therefore associated with increased activity and bioavailability of TGF-beta1, which is suspected to be the basis for phenotypical similarities of FBN1 mutations in MFS and mutations in the receptors for TGFbeta in Marfan syndrome-related diseases. We have previously demonstrated that unique skeletal phenotypes observed in human embryonic stem cells carrying the monogenic FBN1 mutation (MFS cells) are faithfully phenocopied by cells differentiated from induced pluripotent-stem cells (MFSiPS) derived independently from MFS patient fibroblasts. In this study, we aimed to determine further the biochemical features of transducing signaling(s) in MFS stem cells and MFSiPS cells highlighting a crosstalk between TGFbeta and BMP signaling. Our results revealed that enhanced activation of TGFbeta signaling observed in MFS cells decreased their endogenous BMP signaling. Moreover, exogenous BMP antagonized the enhanced TGFbeta signaling in both MFS stem cells and MFSiPS cells therefore, rescuing their ability to undergo osteogenic differentiation. This study advances our understanding of molecular mechanisms underlying the pathogenesis of bone loss/abnormal skeletogenesis in human diseases caused by mutations in FBN1. PMID- 23037988 TI - A dynamic library of porphyrinic true nanorings. AB - Behind the wheel: a 10 nm diameter nanoring, containing 24 porphyrin units, has been created by a Vernier-templating self-organization of hexa- or octadentate templating units and linear covalently linked porphyrin oligomers. Coordination of a bidentate ligand triggers a conversion of the molecular nanocylinder into a molecular nanoannulus to afford the dimeric species, which can adopt a water wheel structure. PMID- 23037989 TI - Application of inhomogeneous fluid solvation theory to model the distribution and thermodynamics of water molecules around biomolecules. AB - The structures of biomolecules and the strengths of association between them depend critically on interactions with water molecules. Thus, understanding these interactions is a prerequisite for understanding the structure and function of all biomolecules. Inhomogeneous fluid solvation theory provides a framework to derive thermodynamic properties of individual water molecules from a statistical mechanical analysis. In this work, two biomolecules are analysed to probe the distribution and thermodynamics of surrounding water molecules. The great majority of hydration sites are predicted to contribute favourably to the total free energy with respect to bulk water, though hydration sites close to non-polar regions of the solute do not contribute significantly. Analysis of a biomolecule with a positively and negatively charged functional group predicts that a charged species perturbs the free energy of water molecules to a distance of approximately 6.0 A. Interestingly, short simulations are found to provide converged predictions if samples are taken with sufficient frequency, a finding that has the potential to significantly reduce the required computational cost of such analysis. In addition, the predicted thermodynamic properties of hydration sites with the potential for direct hydrogen bonding interactions are found to disagree significantly for two different water models. This study provides important information on how inhomogeneous fluid solvation theory can be employed to understand the structures and intermolecular interactions of biomolecules. PMID- 23037990 TI - Strain state of GaN nanodisks in AlN nanowires studied by medium energy ion spectroscopy. AB - Medium energy ion spectroscopy experiments have been performed on an ensemble of nanowires deposited by molecular beam epitaxy on Si(111), taking advantage of their reduced in-plane mosaicity. In particular, the strain in nanometric GaN insertions embedded in AlN sections deposited on top of GaN nanowires has been determined. The measured strain is consistent with atomistic valence force field calculations. This opens the way for the structural study of a new range of discontinuous nanowire-based nanostructures by medium energy ion spectroscopy and to the determination of the strain profile of nanodisks in nanowires at the monolayer scale. PMID- 23037991 TI - Capsaicin for neuropathic pain: linking traditional medicine and molecular biology. AB - Capsaicin has long been used as a traditional medicine to treat pain and, recently, its mechanism of analgesic action has been discovered. This review article documents the clinical development of capsaicin to demonstrate that pharmacognosy still has a profound influence on modern-day drug development programs. Capsaicin is a highly selective agonist for the transient receptor potential channel vanilloid-receptor type 1 (TRPV1), which is expressed on central and peripheral terminals of nociceptive primary sensory neurons. Knockout studies have revealed the importance of TRPV1 as a molecular pain integrator and target for novel analgesic agents. Topical application of capsaicin at the peripheral terminal of TRPV1-expressing neurons superficially denervates the epidermis in humans in a highly selective manner and results in hypoalgesia. In three recent randomized controlled trials, a patch containing high-concentration capsaicin demonstrated meaningful efficacy and tolerability relative to a low concentration capsaicin control patch in patients with peripheral neuropathic pain. Data from clinical practice will determine if the high-concentration capsaicin patch is effective in real-world settings. PMID- 23037994 TI - Science fact versus SENS foreseeable. AB - Scientists in the various fields of aging share a common goal--the extension of healthy life. However, claiming that the only way to accomplish this is to treat the complications of aging rather than its causes requires more than declarations made by proponents of SENS--it requires empirical research based on the scientific method. As this paper illustrates, it will be difficult to prove that SENS interventions work because the primary result of interest, negligible senescence, is not an outcome variable in empirical tests of SENS. PMID- 23037995 TI - Quantitative determination of rupestonic acid in rat plasma by high-performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study. AB - A sensitive and specific high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method was developed and validated for determination of rupestonic acid in rat plasma. Protein precipitation method was used to extract rupestonic acid and the internal standard (IS) warfarin sodium from rats plasma. The chromatographic separation was performed on an Agela Venusil XBP Phenyl column with an isocratic mobile phase consisting of methanol-0.1% formic acid in water (40:60, v/v), pumped at 0.4 mL/min. Rupestonic acid and the internal standard (IS) warfarin sodium were detected at m/z 247.2 -> 203.1 and 307.1 -> 161.3 in positive ion and multiple reaction monitoring mode respectively. The standard curves were linear over the concentration range of 2.5-5000 ng/mL (r(2) > 0.99). The within-day and between day precision values for rupestonic acid at four concentrations were 4.7-5.7 and 4.4-8.7%, respectively. The method described herein was fully validated and successfully applied to the pharmacokinetic study after an intravenous administration of rupestonic acid in rats. PMID- 23037996 TI - Effects of repetitive exposure to pain and morphine treatment on the neonatal rat brain. AB - BACKGROUND: Untreated exposure to pain in preterm neonates might damage the vulnerable premature brain and alter development. Pain treatment is limited because analgesic agents may also have adverse neurodevelopmental consequences in newborns. OBJECTIVE: To study the effects of neonatal pain and morphine treatment on the developing brain in a neonatal rat model. METHODS: Newborn rats were randomly assigned to: treatment with formalin injections (group 1), saline injections (group 2) and controls receiving no injections (group 3). Treatment was given on postnatal days 1-3 (model A), 1-5 (model B) and 10-12 (model C). Brains were studied histologically and protein expression was evaluated (protein kinase C epsilon and doublecortin). Effects of preemptive morphine treatment were studied in the same models (models A+M and B+M). RESULTS: Formalin injections resulted in increased apoptotic scores in models A and B. Saline injections increased the number of degenerative cells only in model B. Morphine showed protective effects in formalin-treated animals of model A+M and saline-treated animals of model B+M only. In model C, no neurodegenerative effects were detected. The protein expression of doublecortin showed a pain-related upregulation in the thalamus region, whereas protein kinase C epsilon expression was upregulated in the cortex. CONCLUSIONS: Severe inflammatory pain and pain caused by repetitive injections in neonatal rats may cause major changes in the developing brain during the first week of life. Morphine may only protect the newborn brain against these changes in specific situations. PMID- 23037997 TI - Nephrotoxic effect of subchronic exposure to S-(1,2-dichlorovinyl)-L-cysteine in mice. AB - The effect of subchronic exposure of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), an active metabolite of trichloroethylene (TCE), was investigated in mice, as a part of mechanistic assessment of renal toxicity of TCE. To examine the subchronic effects of DCVC on kidney function, Balb/c male mice were administered DCVC orally and intraperitoneally once a week for 13 weeks at 1, 10 and 30 mg/kg (Main Study) and for 8 weeks at 30 mg/kg (PCR Study). At the terminal sacrifice, mice orally and intraperitoneally administered with 10 and 30 mg/kg showed significantly lower kidney weight and significantly higher blood urea nitrogen levels than the control group. Pathological examination revealed that a dose of 30 mg/kg delivered by both routes resulted in renal tubular degeneration characterized by tubular necrosis and interstitial fibrosis, and in degradation of the cortex. Degenerative changes were accompanied by the increased expression of tumor necrosis factor-alpha, interleukin-6 and cyclooxygenase-2 mRNAs in the kidney of mice treated with 30 mg/kg for 8 weeks. These pathohistological observations mostly corresponded to those in short-term toxicity studies on DCVC. DCVC might be a direct cause of renal toxicity, which is suggested from the aggravation in these symptoms with the dose increase. PMID- 23037998 TI - Ovariectomized mouse uterotrophic assay of 36 chemicals. AB - The concern over endocrine disruptors prompted international establishment of a strategic framework for the identification of the estrogenic compounds. OECD has launched the Conceptual Framework tool box containing various screening and testing methods including the uterotrophic assay. The (anti)estrogenicity of 36 chemicals suspected to be estrogen-receptor interactive by in silico and/or in vitro screening in the Extended Scheme for Endocrine Disruptor Screening and Testing of the Ministry of Health, Labour and Welfare, Japan, were monitored by the uterotrophic assay using C57BL/6J ovariectomized adult female mice after a 7 day exposure by oral gavage (po) and subcutaneous injection (sc). Ethynyl estradiol was used as reference for agonist and antagonist detection. In addition, Bisphenol A (sc) and Genistein (po) were tested for the comparison to rat assays. Among the 36, 2-[Bis(4-hydroxy-phenyl)methyl]benzylalcohol, 2,2',4,4' Tetrahydroxybenzophenone, 2,4-Dihydroxybenzophenone, 3,3',5-Triiodothyroacetic acid, New fuchsin and alpha-Naphtholbenzein, showed both estrogenic agonistic and antagonistic activities; first two showed U-shaped dose-response in antagonistic studies. N,N-Diphenyl-p-phenylenediamine, 2,2'-Dihydroxy-4,4' dimethoxybenzophenone, n-Butyl 4-hydroxybenzoate, and Reserpine were agonistic by sc. Benzo [a] pyrene, Benz [a] anthracene, Dibenz [a,h] anthracene, 2-(2H Benzotriazol-2-yl)-4,6-di(t-pentyl)phenol, Rosemarinic acid, meta-Thymol, 6 Gingerol, Colchicine, Malachite green base, Fenbuconazole, and Lead acetate were antagonistic. The rest, i.e. n-Heptyl 4-hydroxybenzoate, Tetrazolium violet, Pravastatin sodium salt, Physostigmine, salicylate (1:1), Nordihydroguaiaretic acid, o-Cresolphthalein, 1,3-Dinitrobenzene, C.I. Pigment orange, Tetrabromobis phenol-A, 2-Hydroxy-4-methoxybenzophenone, Ethylparaben, Propyl p hydroxybenzoate, Kaempferol, 2-(2-Benzotriazolyl)-p-cresol and Phenolphthalein were negative for both effects. Taking together with in silico/ in vitro screening, the result suggested that the ovariectomized mouse uterotrophic bioassay has sufficient performance comparable to rat for the screening of (anti)estrogenicity of various chemicals. PMID- 23037999 TI - A method for detecting covalent modification of sensor proteins associated with 1,4-naphthoquinone-induced activation of electrophilic signal transduction pathways. AB - While metabolic activation of naphthalene, yielding 1,2-naphthoquinone (1,2-NQ) and 1,4-NQ that can covalently bind to cellular proteins, has been recognized to be associated with its toxicity, the current consensus is that such electrophile mediated covalent modification of sensor proteins with thiolate ions is also involved in activation of cellular signal transduction pathways for cellular protection against reactive materials. In the present study, we developed an immunochemical assay to detect cellular proteins adducted by 1,4-NQ. Dot blot analysis indicated that the antibody prepared against 1,4-NQ recognized the naphthalene moiety with the para-dicarbonyl group, rather than with the ortho dicarbonyl group. Furthermore, little cross-reactivity of para-quinones with either a different number of aromatic rings (n = 1) or substituent groups was observed. With this specific antibody against 1,4-NQ, we identified nine target proteins of 1,4-NQ following exposure of human epithelial carcinoma cell line A431 to 1,4-NQ. Among them, heat shock protein 90 (HSP90) and HSP70 are of interest because covalent modification of these chaperones causes activation of heat shock factor-1, which plays a role in the cellular response against electrophiles such as 1,4-NQ. Thus, our method, which does not use radiolabeled compounds, would be applicable for exploring activation of electrophilic signal transduction pathways coupled to covalent modification of sensor proteins during exposure to naphthalene as well as 1,4-NQ. PMID- 23038000 TI - Effects of butane-2,3-dione thiosemicarbazone oxime on testicular damage induced by cadmium in mice. AB - Our group of studies investigated the action of butane-2,3-dione thiosemicarbazone oxime against the testicular damage caused by cadmium chloride (CdCl(2)) in mice. Mice received a single injection of CdCl(2 )(5 mg/kg, intraperitoneally) and, after thirty minutes, the oxime (10 mg/kg, subcutaneously) was administered. Twenty four hours after the last administration, the animals were killed by cervical dislocation and the testes and serum were removed for analysis. The parameters determined were delta aminolevulinate dehydratase (delta-ALA-D), myeloperoxidase (MPO), glutathione-S transferase (GST) and glutathione peroxidase (GPx) activities. The levels of thiobarbituric acid-reactive substances (TBARS), nonprotein thiols (NPSH), ascorbic acid, cadmium and testosterone were also determined. In addition, histological analysis and cytokines quantification (IL-1, IL-6, IL-10, TNF-alpha and IFN-gamma) were performed. Our results demonstrated that the oxime was effective in restoring the inhibition in delta-ALA-D activity induced by CdCl(2). The activation of MPO and increase in IL-1, IL-6, TNF-alpha and IFN-gamma levels induced by CdCl(2) were also reduced by oxime. IL-10, which was reduced by cadmium, was restored by oxime administration. In addition, the oxime was effective in restoring the increase in TBARS levels and the reduction on NPSH levels induced by CdCl(2). Our results demonstrated that oxime was effective in containing the histological alterations induced by CdCl(2). In addition, oxime was able to increase the testosterone levels, reduced by cadmium exposure. In conclusion, the oxime tested was effective in reducing the testicular damage induced by CdCl(2) in mice. The beneficial effects of this oxime are related to its antioxidant and anti-inflammatory action. PMID- 23038001 TI - Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients. AB - Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent. However, some patients encounter hepatotoxicity after repeated APAP dosing at therapeutic doses. In the present study, we focused on the nutritional state as one of the risk factors of APAP-induced chronic hepatotoxicity in humans and investigated the contribution of undernourishment to susceptibility to APAP induced chronic hepatotoxicity using an animal model mimicking undernourished patients. Rats were divided into 2 groups: the ad libitum fed (ALF) and the restricted fed (RF) rats and were assigned to 3 groups (n = 8/group) for each feeding condition. The animals were given APAP at 0, 300 and 500mg/kg for 99 days under each feeding condition. Plasma and urinary glutathione-related metabolites and liver function parameters were measured during the dosing period and hepatic glutathione levels were measured at the end of the dosing period. In the APAP-treated ALF rats hepatic glutathione levels were increased and hepatic function parameters were not changed, but in the APAP-treated RF rats hepatic glutathione levels were decreased at 500mg/kg and hepatic function parameters were increased at 300 and 500mg/kg. Moreover the urinary endogenous metabolite profile after long-term treatment with APAP in the ALF and RF rats was similar to that in human non-responders and responders to APAP-induced chronic hepatotoxicity, respectively. In conclusion, the RF rats were more sensitive to APAP-induced chronic hepatotoxicity than the ALF rats and were considered to be a useful model to estimate the contribution of the nutritional state of patients to APAP-induced chronic hepatotoxicity. PMID- 23038002 TI - Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models. AB - Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation that starts with steatosis and progresses to non-alcoholic steatohepatitis (NASH). Recently, the number of patients with such liver diseases has increased, but the understanding of the fundamental mechanisms and appropriate therapies are lacking. Tamoxifen (TAM) is a selective estrogen receptor modulator. We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries. However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed. We first found that the administration of TAM to mouse models of steatosis and NASH significantly decreased the plasma ALT and AST levels. The administration of TAM decreased the accumulated fat and inflammation in the livers in both mouse models. In addition, we observed decreased hepatic mRNA levels of triglyceride synthesis, acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2), proinflammatory cytokines, tumor necrosis factor (TNF) alpha, and chemokines, monocyte chemoattractant protein (MCP) -1. TAM increased the extracellular signal-regulated kinase (ERK) phosphorylation, which is related to the proliferation and regeneration of liver and to decreased DGAT2 gene expression. Furthermore, a decrease in eukaryotic translational initiation factor (eIF2alpha), which is involved in apoptosis, was observed in both models. These findings suggest that TAM treatment exerts a hepatoprotective effect against steatosis and NASH, presumably via up-regulation of the ERK pathways and attenuation of eIF2alpha activation. These pathways represent a potential therapeutic target for steatosis and NASH in drug development. PMID- 23038003 TI - Effective use of the Pig-a gene mutation assay for mutagenicity screening: measuring CD59-deficient red blood cells in rats treated with genotoxic chemicals. AB - The Pig-a gene mutation assay using perpherial blood erythrocytes is being investigated as a screening tool for assessing mutagenicity in vivo. In this study, we evaluated two distinct approaches for performing the Pig-a assay in rats. We used antibodies to CD45 or the erythroid marker HIS49 to identify red blood cells (RBCs), and then monitored the kinetics of Pig-a mutant frequency, as measured by the frequency of CD59-deficient RBCs, in rats treated with the genotoxic chemicals, N-ethyl-N-nitrosourea, cyclophosphamide, 4-nitroquinoline-1 oxide, and ethylmethanesulfonate. In some instances, micronucleus frequency also was measured in the same animals. Time- and dose-related increases in Pig-a mutant frequency were found in all the chemical-treated groups, except for the groups treated with cyclophosphamide, which was a potent inducer of micronuclei. The two different approaches we employed were comparable for measuring induced mutant frequencies, but our historical data showed that the mean background frequencies for the CD45/CD59 method and the HIS49/CD59 method were 12.7 * 10(-6) and 5.5 *10(-6), respectively. The relatively low, stable background mutant frequency associated with the HIS49/CD59 method indicates that it may have greater power for discriminating weak induced responses. These results suggest that the HIS49/CD59 method is a promising tool for measuring Pig-a mutant RBCs. In addition, differences in their manifestation kinetics and in their relative sensitivity for detecting different test compounds suggest that the combination of the Pig-a assay and the micronucleus assay may be effective in identifying in vivo genotoxicity. PMID- 23038004 TI - Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats. AB - Anaemia is a significant prognostic factor in cancer patients receiving anticancer drugs such as methotrexate (MTX). This study focuses on the effects of toxicological changes on the hematopoietic systems in male and female Wistar Hannover rats when MTX is orally administered at a dose of 0, 0.05, 0.15, or 0.45 mg/(kg.day) for a period of 28 days. Both male and female rats receiving 0.45 mg/kg MTX showed a decrease in the haemoglobin concentration (Hb), haematocrit, and erythrocyte count. Female rats showed a decrease in mean corpuscular volume (MCV) and an increase in cell mean Hb (CHCM) in total erythrocytes, including the mature erythrocytes. These results indicate that MTX causes the production of small, mature erythrocytes that contain a high concentration of Hb. MTX reduced the number of peripheral reticulocytes but produced the cells with a large size and a high concentration of Hb, as demonstrated by the reticulocyte MCV and CHCM as well as the content of haemoglobin per reticulocyte (CHr). Consistent with these findings, bone marrow haematopoiesis was impaired by MTX, as there was a reduction in erythroid count in rats of both sexes. The number of cells of the myeloid lineage reduced in female rats, followed by a reduction in the total leukocyte and neutrophil counts in peripheral blood. Thrombocytopenia was detected in a small population of rats. These results indicate that MTX induces hyperchromic microcytic anaemia and pancytopenia, and the use of MCV and CHCM in mature erythrocytes and reticulocytes, along with the CHr, gives a better understanding of the development and nature of anaemia. PMID- 23038005 TI - Enhanced liver tumor promotion but not liver initiation activity in rats subjected to combined administration of omeprazole and beta-naphthoflavone. AB - Omeprazole (OPZ) and beta-naphthoflavone (BNF) are cytochrome P450 (CYP)1A inducers and have liver tumor promoting effects. In this study, we investigated the co-promoting and co-initiating effects of OPZ and BNF in rats. In Experiment 1, male rats were subjected to partial hepatectomy (PH), and given oral doses of 138 or 276 mg/kg OPZ, 0.125% or 0.25% BNF or 138 mg/kg OPZ+0.125% BNF (n = 9~12) for 6 weeks after N-diethylnitrosamine (DEN) initiation. In Experiment 2, male rats were treated with oral doses of 138 or 276 mg/kg OPZ, 0.03% or 0.06% BNF or 138 mg/kg OPZ+0.03% BNF (n = 11~12) for 9 days starting 1 week before initiating treatment. As an initiating treatment, 2-Amino-3,4-dimethylimidazo[4,5 f]quinolone (MeIQx) was orally administered 12 hr after PH. The rats were fed a basal diet for 15 days, followed by a diet containing 0.015% 2 acetylaminofluorene for the next 10 days with a single oral dose of carbon tetrachloride. In Experiment 1, the number and area of glutathione S-transferase placental form-positive foci in the OPZ+BNF group were significantly higher than the average values of the High OPZ or the High BNF group. The expression of cyclooxygenase-2 (Cox-2) and COX-2 protein in the liver significantly increased in the OPZ+BNF group. In Experiment 2, liver initiation activity was not enhanced by the co-administration of OPZ+BNF. The results of our studies suggest that the co-administration of OPZ and BNF results in synergistic effects in the liver tumor promotion probably owing to increased COX-2 expression, but no modifying effect in the liver initiation activity of MeIQx in rats. PMID- 23038006 TI - Postnatal exposure to low-dose decabromodiphenyl ether adversely affects mouse testes by increasing thyrosine phosphorylation level of cortactin. AB - Decabromodiphenyl ether (decaBDE) is a brominated flame retardant used in many commercial products such as televisions, computers, and textiles. Recent reports indicate that decaBDE adversely affects male reproductive organs in mice, but the underlying molecular mechanisms remain unknown. We hypothesized that decaBDE affects mouse testes by altering the expression and phosphorylation level of cortactin (CTTN), an F-actin-binding protein that is similar to flutamide, and we performed western blot analyses on testicular samples from mice subcutaneously injected with decaBDE (0.025, 0.25, and 2.5 mg/kg body weight/day) on postnatal days 1 to 5. Mice treated with low-dose decaBDE (0.025 mg/kg) showed reduced testicular weight, sperm count, elongated spermatid and Sertoli cell numbers, as well as induced Tyr phosphorylation of CTTN and reduced the expression level of p60 Src tyrosine kinase (SRC). Further, 0.25 and 2.5 mg/kg decaBDE-exposed groups produced an decrease the expression level of CTTN. High-dose decaBDE (2.5 mg/kg) showed increased abnormal germ cells, as well as induced Ser phosphorylation of CTTN and activated extracellular signal-regulated kinase (ERK1/2); however, high dose decaBDE did not affect testicular weight and sperm count. These findings suggest that postnatal exposure to low-dose decaBDE inhibits mouse testicular development by increasing Tyr phosphorylation of CTTN, although different mechanisms may be involved depending on the dose of decaBDE. PMID- 23038007 TI - Hepatic gene expression analysis of 2-aminoanthracene exposed Fisher-344 rats reveal patterns indicative of liver carcinoma and type 2 diabetes. AB - The goal of the present study was to examine hepatic differential gene expression patterns in Fisher-344 rats in response to dietary 2-aminoanthracene (2AA) ingestion for 14 and 28 days. Twenty four post-weaning 3-4 week old F-344 male rats were exposed to 0 mgkg(-1)-diet (control), 50 mgkg(-1)-diet (low dose), 75 mgkg(-1)-diet (medium dose) and 100 mgkg(-1)-diet (high dose) 2AA for 14 and 28 days. This was followed by analysis of the liver for global gene expression changes. In both time points, the numbers of genes affected seem to correlate with the dose of 2AA. Sixteen mRNAs were differentially expressed in all treatment groups for the short-term exposure group. Similarly, 51 genes were commonly expressed in all 28-day exposure group. Almost all the genes seem to have higher expression relative to the controls. In contrast, cytochrome P450 family 4, subfamily a, polypeptide 8 (Cyp4a8), and monocyte to macrophage differentiation-associated (Mmd2) were down-regulated relative to controls. Differentially expressed mRNAs were further analyzed for associations via DAVID. GO categories show the effect of 2AA to be linked with genes responsible for carbohydrate utilization and transport, lipid metabolic processes, stress responses such as inflammation and apoptosis processes, immune system response, DNA damage response, cancer processes and circadian rhythm. The data from the current study identified altered hepatic gene expression profiles that may be associated with carcinoma, autoimmune response, and/or type 2 diabetes. Possible biomarkers due to 2AA toxicity in the liver for future study include Abcb1a, Nhej1, Adam8, Cdkn1a, Mgmt, and Nrcam. PMID- 23038008 TI - Nitrergic, glutamatergic and gabaergic systems in lithium toxicity. AB - We examined the role of nitrergic, glutamatergic and gamma-aminobutyric acid (GABA)-ergic systems in the mechanism(s) underlying lithium induced acute toxicity. With this aim, lithium (18 mEq/kg, i.p.) intoxicated rats were observed for 3 hr recording their clinical signs and death. Lithium exposure at the dose used produced central nervous system (CNS) depression. Pre-treatment of N(w)-nitro-L-arginine methyl ester (L-NAME) a nonselective nitric oxide synthase inhibitor (10 mg/kg, i.p.), 7-nitroindazole (7-NI) a selective neuronal nitric oxide synthase inhibitor (25 mg/kg, i.p.), nitric oxide precursor L-arginine (1,000 mg/kg, i.p.) and MK-801 a noncompetitive antagonist of N-methyl-D-aspartic acid class of glutamate receptors (0.5 mg/kg, i.p.) all increased CNS depression and mortality in lithium group however, no change was seen in GABA receptor agonist GABA (1,000 mg/kg, i.p.) or D-arginine (1,000 mg/kg, i.p.) a biologically inactive enantiomer of L-arginine pre-treated rats. Glutamic acid decarboxylase (GAD) enzyme activity was measured in hippocampus, cerebral cortex and cerebellum of the different groups of animals. GAD enzyme activity reduced in cerebral cortex but not altered in hippocampus or cerebellum by lithium as compared to the control (saline) group. We conclude that an interaction with nitrergic and glutamatergic systems may have a role in the acute toxicity of lithium in rats.The inhibition of glutamate metabolism may arise from this interaction and the involvement of GABA-ergic system should be further investigated in this toxicity. PMID- 23038009 TI - Female heterozygous (+/fa) Zucker rats as a novel leptin-related mammary carcinogenesis model. AB - The homozygous mutant fatty Zucker rat (fa/fa) is the prominent model for the research of obesity, one of the most well-known risk factor of postmenopausal mammary cancer. But the usage as a mammary gland carcinogenesis model is considered to be restricted due to the hypoplasia of mammary gland. In the present study, to find the validity of heterozygous mutant (+/fa) lean Zucker rats as a new leptin-related mammary carcinogenesis model, we examined whether the number of terminal end buds of mammary gland, the serum biochemistry, leptin concentration in serum and adipose tissue are changed in 7-week-old female +/+, +/fa and fa/fa rats, and whether these changes and leptin, TNF-alpha and VEGF mRNA expression in adipose tissue of +/+ and +/fa rats are influenced by 10% corn oil diet for 5 weeks. We confirmed that mild hyperleptinemia was more pronounced in 7-week-old +/fa as compared with wild type (+/+) and hypoplasia of mammary glands characterized by fewer numbers of terminal end buds in fa/fa was not observed in +/fa. With 10% corn oil diet, leptin mRNA expression in adipose tissue showed increasing tendency both in +/fa and +/+. Comparing with +/+, adipose tissue in +/fa treated with 10% corn oil diet was found to be significantly increased in the concentration of leptin protein and tended to be elevated expression of TNF-alpha mRNA. These results suggest that +/fa with 10% corn oil diet may be a useful model for investigation of the participation of leptin and TNF-alpha in mammary gland carcinogenesis. PMID- 23038010 TI - Participation of metal transporters in cadmium transport from mother rat to fetus. AB - The mechanism of cadmium transport from mother to fetus remains unclear. In this study, we examined the roles of the metal transporters DMT1, ZIP, and ZnT and the metal-binding protein metallothionein in the transport of Cd from mother to fetus in Cd-exposed rats. Cadmium (as CdCl(2)) was administered to female Wistar rats at doses of 0, 1, 2, or 5 mg Cd/kg/day via gastric tube daily for six consecutive days each week for 7 weeks. The concentration of Cd, Zn, and Cu in the uterus and the placenta were then determined. Uterine and placental expression of genes encoding iso-MTs (I, II, and III) and the metal transporters DMT1, ZIP8, ZIP14, ZnT1, ZnT2 and ZnT4 was determined using real-time PCR. The Cd concentration in the placenta and uterus increased with the Cd dose, while the concentration of Cu decreased. Cadmium accumulation in the uterus and placenta resulted in a increase in MT-II gene expression, suggesting that MT-II prevents Cd transport to the fetus by trapping Cd in the uterus and placenta. Expression of the genes encoding DMT1, ZIP14 and ZnT2 was upregulated in the placenta in a dose-dependent manner. Relatively high expression level of the ZnT4 gene than the other ZnT genes (ZnT1 and ZnT2) was observed in the uterus and the placenta. Our results suggest that in the placenta the metal transporters DMT1 and ZIP14 involved in the uptake of Cd into the cytosol. PMID- 23038011 TI - Increased production of reactive oxygen species by the vacuolar-type (H(+)) ATPase inhibitors bafilomycin A1 and concanamycin A in RAW 264 cells. AB - Treatment of the mouse leukemic cell line RAW 264 with bafilomycin A1 or concanamycin A, inhibitors of vacuolar-type (H(+))-ATPases (V-ATPases), significantly increased the production of reactive oxygen species (ROS) and decreased cell viability. These effects were significantly suppressed by the presence of N-acetyl cysteine (NAC), an ROS scavenger. si-RNA mediated knockdown of the gene for the c subunit of the V0 domain of V-ATPase also resulted in an increase in ROS production and a decrease in cell viability. These results suggest that decreased cellular V-ATPase activity decreases cell viability by increasing ROS production in RAW 264 cells. PMID- 23038012 TI - Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells. AB - The inhibitors of heat shock protein-90 (Hsp90), geldanamycin (GA) and 17 (allylamino)-17-desmethoxygeldanamycin, show various cellular effects including destabilization of Hsp90 clients and expression of other chaperones, etc. and modulate cytotoxicity depending on cell types and stimuli. In this study, we investigated the effects of Hsp90 inhibitors on survival of PC12 cells with and without cytotoxic stimuli including orthovanadate, Na(3)VO(4). Treatment with Hsp90 inhibitors at 2 uM for 16 hr did not cause cell detachment and leakage of lactate dehydrogenase, and at concentrations greater than 5 uM resulted in cytotoxicity. The inhibitors at 2 uM enhanced the cytotoxicity of 1 mM Na(3)VO(4), and did not protect PC12 cells at any concentrations against Na(3)VO(4). Next, the effects of Hsp90 inhibitors on the intracellular metabolism of ceramide and arachidonic acid (AA) were examined, since these processes also regulate cytotoxicity. In cells treated with 4-nitrobenzo-2-oxa-1,3-diazole (NBD) labeled C6-ceramide, Hsp90 inhibitors reduced the formation of NBD glucosylceramide and Na(3)VO(4)-induced formation of NBD-caproic acid, a counterpart of sphingosine, without affecting other metabolites including NBD sphingomyelin. GA treatment did not change the amounts of AA released in PC12 cells with and without Na(3)VO(4). In HeLa cells, however, GA treatment decreased the release of AA via cytosolic phospholipase A(2)alpha's activation probably because of dysfunctional Hsp90 clients. Our results suggest the possible involvement of ceramide metabolism, not AA release, in GA-induced cytotoxicity in PC12 cells. PMID- 23038013 TI - Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells. AB - An appropriate balance between lipophilicity and hydrophilicity is necessary for pharmaceuticals to achieve fine Absorption, Distribution, Metabolism and Excretion (ADME) properties including absorption and distribution, in particular. We have designed and proposed symmetrically branched oligoglycerols (BGL) as an alternative approach to improve the lipophilic-hydrophilic balance. We have previously shown that stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds are much improved by conjugation to BGL. Albeit these successful applications of BGL, little was known whether BGL could be used in safety. Thus we conducted evaluation of the cytotoxicity of a representative BGL, symmetrically branched glycerol trimer (BGL003) in the cultured cells to clarify its biological safeness. Here we demonstrate that water-solubility of an extremely hydrophobic agent, fenofibrate was more than 2,000-fold improved just by conjugated with BGL003. BGL003 did not exhibit any significant cytotoxicity in human hepatocarcinoma HepG2 cells. Thus BGL003 should be safe and suitable strategy to endow hydrophobic molecules with much hydrophilicity. PMID- 23038014 TI - Possible involvement of glutathione balance disruption in dihydropyrazine-induced cytotoxicity on human hepatoma HepG2 cells. AB - Dihydropyrazines (DHPs), formed by nonenzymatic glycation, are known to exert various effects in vitro and in vivo, such as generation of radical species, DNA strand breakage, enzyme inhibition, and inhibition of bacterial growth. However, their effects on mammalian cells remain elusive. To address this issue, we investigated the effects of a range of DHP concentrations on human hepatoma HepG2 cells using 2,3-dihydro-5,6-dimethylpyrazine (DHP-1), 2,3-dihydro-2,5,6 trimethylpyrazine (DHP-2), and 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3) as model compounds. All of the tested compounds exerted cytotoxic activity against HepG2 cells in the range of 10 uM-1 mM, and significantly so at the highest concentration. DHP-3 was the most effective drug, and it also caused a significant decrease in the ratio of intracellular reduced and oxidized glutathione (GSH/GSSG). In addition, the cytotoxic effect of DHP-3, but not DHP-1 and DHP-2, was enhanced by the inhibition of GSH biosynthesis using 100 uM l buthionine-(S,R)-sulfoximine (BSO). From these results, it is suggested that the mechanisms of cytotoxicity exerted by DHP-3 are distinct from those exerted DHP-1 and DHP-2. In addition, it is possible that the disruption of intracellular glutathione balance induced by DHP-3 is related to its effect on HepG2 cells. PMID- 23038015 TI - Social isolation stress induces hepatic hypertrophy in C57BL/6J mice. AB - We previously reported that social isolation stimulated a stress response leading to increasing plasma corticosterone level and disruption of the hepatic lipid metabolism-related pathway, without changing body and organ weights, in mice after 4 weeks of social isolation stress, compared with the grouped-housing control (5 mice/cage). In this study, we evaluated the effects of social isolation stress for an extended period on physiologic changes in male C57BL/6J mice. Plasma corticosterone was reduced after 13 weeks, indicating mice might adapt to social isolation stress. However, body and visceral fat weights were significantly increased in combination with hepatic hypertrophy, and significant decreases in levels of triglyceride and adiponectin in plasma were observed. In conclusion, it is tempting to speculate that mice exposed to social isolation stress for 13 continuous weeks could be at an increased risk of overweight with hepatic hypertrophy. Our results also imply that physiological changes, at least fatty acid metabolism, under stress exposure might be an important factor when evaluating the chronic effects of environmental chemicals. PMID- 23038016 TI - Reporter gene mutation in the livers of gpt delta mice treated with 5 (hydroxymethyl)-2-furfural, a contaminant of various foods. AB - A major product formed during the Maillard reaction is 5-(hydroxymethyl)-2 furfural (HMF), which is present in various foods and beverages such as honey and fruit juice. HMF was shown to be a hepatocarcinogen in female mice using long term bioassays. Although HMF is not a mutagen in conventional in vitro mutation assays, 5-sulfoxymethylfurfural (SMF), a reactive metabolite of HMF produced following sulfotransferase conjugation, does show mutagenicity. Thus, HMF-induced hepatocarcinogenesis likely involves genotoxic mechanisms. To clarify the mechanisms underlying HMF-induced hepatocarcinogenesis, female B6C3F(1) gpt delta mice were given HMF at carcinogenic doses (188 or 375 mg/kg b.w.) by gavage for 5 days per week for 4 weeks. This treatment produced no significant differences in mutant frequencies (MFs) of gpt and red/gam (Spi(-)) genes among the groups. These results suggest that genotoxicity does not contribute to HMF-induced hepatocarcinogenesis. Parameters related to cell proliferation, such as proliferation cell nuclear antigen-labeling index and Cyclin D1 and E1 mRNA expression, exhibited no significant changes in the livers of HMF-treated groups. In view of the lack of carcinogenicity in rats, HMF may be considered to be a weak carcinogen. These results help us to understand the underlying mechanisms of action of HMF carcinogenesis. PMID- 23038017 TI - Impact of cigarette smoke exposure on the expression of cardiac hypertrophic genes, cytochrome P450 enzymes, and oxidative stress markers in rats. AB - Various experimental and clinical studies strongly support a cigarette smoke heart disease association and suggest possible mechanisms, unfortunately, the involvement of genetic modulations remain unexplored. Thus, the main aim of the current study was to evaluate the effects of sub-chronic cigarette smoke exposure on the mRNA expression of cardiac hypertrophy genes, cytochrome P450 (CYP) enzymes, and the oxidative stress markers in heart rats. For this purpose, Wistar albino rats were exposed to increasing doses of passive cigarette smoke 2, 4, 8, and 24 cigarettes per day for 7 consecutive days. The mRNA expression of fifteen cardiac genes was determined using real-time polymerase chain reaction. Our results showed that the levels of hypertrophic genes; atrial natriuretic peptide, brain natriuretic peptide, and beta-myosin heavy chain were significantly induced, whereas the anti-hypertrophic gene alpha-myosin heavy chain was dramatically inhibited, in heart tissues of passive-smoke-exposed groups compared with normal-control groups. This was accompanied with a significant induction of CYP enzymes; CYP1A1, CYP2C11, CYP2E1, and CYP3A2, and the expression of oxidative stress genes, heme oxygenase 1, catalase, cyclooxygenase, and glutathione S Transferase. The ability of cigarette smoke to induce cardiac hypertrophic genes, CYPs enzymes, and oxidative stress, collectively explore the molecular mechanism of cigarette smoke-induced cardiac diseases and brings further investigative attention to the public health issue of the injurious effects of chronic passive smoke exposure. In conclusion, sub-chronic environmental tobacco smoke exposure increases the incidence of cardiovascular diseases through modulation of cardiac genes. PMID- 23038019 TI - Study on the coupling of acyclic esters with alkenes--the synthesis of 2-(2 hydroxyalkyl)cyclopropanols via cascade cyclization using allylsamarium bromide. AB - The radical cyclization between aliphatic acyclic esters and alkenes was achieved unprecedentedly in the presence of allylsamarium bromide with HMPA and H(2)O as additives. The cascade radical cyclization-ring-opening-anionic cyclization allowed facile and efficient access to 2-(2-hydroxyalkyl)cyclopropanols from readily available materials. PMID- 23038020 TI - The adapted classification of male pattern hair loss improves reliability. AB - BACKGROUND: The Hamilton-Norwood classification (HNC) is used to assess the severity of pattern hair loss (PHL). Conflicting associations between PHL and cardiovascular disease (CVD) have been reported from studies that used different methods to assess alopecia severity. No classification including the HNC has been validated for population studies. We aimed to simplify the HNC, produce the adapted HNC and test its reliability for use in population studies. METHODS: Identifying vertex alopecia as distinct allowed for a simpler alignment of alopecia figures where scores 4V and 5V in the adapted HNC replace IV and V in the original HNC. The two classifications were to be used by twelve of our staff (secretaries, nurses, dermatology trainees and dermatologists) to evaluate 16 men with PHL. Observer agreement was estimated using intraclass correlation coefficient (ICC) and a percentage method duplicated from the recent basic and specific (BASP) classification. RESULTS: The ICC improved with the adapted HNC when assessed by both the nurses/secretaries (from 0.47 to 0.61) and dermatology residents/consultants (from 0.68 to 0.76). Agreement using the BASP percentage method for dermatologists was 62-69% for the original and 93-100% for the adapted HNC. CONCLUSIONS: The adapted HNC increased reliability at various staff levels, making it suitable for epidemiological studies; its use in future studies could help elucidate the association between PHL and CVD. PMID- 23038021 TI - Short-term effects of polyphenol-rich black tea on blood pressure in men and women. AB - There is increasing evidence that black tea polyphenols contribute to vascular health. We have recently shown that regular ingestion of polyphenol-rich black tea over 6 months results in lower systolic and diastolic blood pressure. However, the time course of these effects remains unclear. Therefore, our objective was to determine if short-term effects of tea on blood pressure could contribute to longer-term benefits of regular tea consumption on blood pressure. Men and women (n = 111) were recruited to a randomised placebo-controlled double blind parallel designed trial. During a 4-week run-in, all participants consumed 3 cups per day of black tea. Participants then consumed 3 cups over 1 day of either powdered black tea solids containing 429 mg of polyphenols (tea), or a control product matched in flavour and caffeine content but containing no tea solids. The 24 h ambulatory blood pressure and heart rate was measured at the end of the 4-week run-in (baseline) and again during the 24 h intervention period. The 24 h day-time and night-time blood pressures were not significantly different between tea and control (P > 0.05). Baseline-adjusted net effects on mean 24 h ambulatory blood pressure for systolic and diastolic blood pressure were -0.2 mm Hg (95% CI, -1.5 to 1.0), P = 0.72, and 0.0 mm Hg (95% CI, -1.0 to 0.9), P = 0.95, respectively. Heart rate was significantly lower for tea compared to control during the night-time and early-morning periods (-2.0 (95% CI, -3.2, 0.8) bpm, and -1.9 (95% CI, -3.7, -0.2) bpm, respectively; P < 0.05 for both), but not during the day-time. These results suggest that the longer-term benefits of black tea on blood pressure are unlikely to be due to short-term changes. PMID- 23038023 TI - Postirradiation pseudosclerodermatous panniculitis: three new cases with additional histopathologic features supporting the radiotherapy etiology. AB - Postirradiation pseudosclerodermatous panniculitis is a rare panniculitic disorder induced by radiotherapy. Clinically, it consists of an indurate plaque localized on the irradiated area that may appear months or even years after radiotherapy was administered. Histopathologically, postirradiation pseudosclerodermatous panniculitis is characterized by a mostly lobular panniculitis without vasculitis, with lipophagic granuloma involving the fat lobules, a variable inflammatory infiltrate of lymphocytes and plasma cells and sclerotic thickening of the connective tissue septa of the subcutis. We report 3 additional cases of this rare variant of panniculitis, in which besides the panniculitis findings, dermal vessels showed sclerotic vessel walls and atypical bizarre fibroblasts with large pleomorphic and hyperchromatic nuclei were interstitially arranged between collagen bundles of the dermis. These dermal findings represent additional histopathologic features supporting the pathogenic role of the radiotherapy in the development of this rare variant of panniculitis. PMID- 23038024 TI - Deposits of amyloid (Beta-2 microglobulin type) in the tongue. PMID- 23038025 TI - Lobular panniculitis due to Borrelia burgdorferi infection mimicking subcutaneous panniculitis-like T-cell lymphoma. AB - The authors present an unusual case of lobular panniculitis caused by Borrelia burgdorferi senso latu infection in a 56-year-old man. It presented clinically as a solitary subcutaneous nodule. Histopathologically, the lesion resembled subcutaneous panniculitis-like T-cell lymphoma by manifesting atypically appearing lymphocytes with cytotoxic phenotype. B. burgdorferi etiology was proven by positive polymerase chain reaction and serology and positive response to antibiotics. PMID- 23038026 TI - Sodium iodide symporter (NIS)-mediated radiovirotherapy of hepatocellular cancer using a conditionally replicating adenovirus. AB - In this study, we determined the in vitro and in vivo efficacy of sodium iodide symporter (NIS) gene transfer and the therapeutic potential of oncolytic virotherapy combined with radioiodine therapy using a conditionally replicating oncolytic adenovirus. For this purpose, we used a replication-selective adenovirus in which the E1a gene is driven by the mouse alpha-fetoprotein (AFP) promoter and the human NIS gene is inserted in the E3 region (Ad5-E1/AFP-E3/NIS). Human hepatocellular carcinoma cells (HuH7) infected with Ad5-E1/AFP-E3/NIS concentrated radioiodine at a level that was sufficiently high for a therapeutic effect in vitro. In vivo experiments demonstrated that 3 days after intratumoral (i.t.) injection of Ad5-E1/AFP-E3/NIS HuH7 xenograft tumors accumulated approximately 25% ID g(-1) (percentage of the injected dose per gram tumor tissue) (123)I as shown by (123)I gamma camera imaging. A single i.t. injection of Ad5-E1/AFP-E3/NIS (virotherapy) resulted in a significant reduction of tumor growth and prolonged survival, as compared with injection of saline. Combination of oncolytic virotherapy with radioiodine treatment (radiovirotherapy) led to an additional reduction of tumor growth that resulted in markedly improved survival as compared with virotherapy alone. In conclusion, local in vivo NIS gene transfer using a replication-selective oncolytic adenovirus is able to induce a significant therapeutic effect, which can be enhanced by additional (131)I application. PMID- 23038028 TI - "The beginning of new era of corneal research" 17th Annual Meeting of the Kyoto Cornea Club December 2-3, 2011. PMID- 23038027 TI - 1,8-Naphthyridine-2,7-diamine: a potential universal reader of Watson-Crick base pairs for DNA sequencing by electron tunneling. AB - With the aid of Density Functional Theory (DFT), we designed 1,8-naphthyridine 2,7-diamine as a recognition molecule to read DNA base pairs for genomic sequencing by electron tunneling. NMR studies show that it can form stable triplets with both A : T and G : C base pairs through hydrogen bonding. Our results suggest that the naphthyridine molecule should be able to function as a universal base pair reader in a tunneling gap, generating distinguishable signatures under electrical bias for each of DNA base pairs. PMID- 23038029 TI - Natural helper cells and TH2-type innate immunity. AB - Natural helper (NH) cells are a newly identified innate lymphocyte population, which respond to a combination of interleukin (IL)-2 and IL-25 or IL-33 to produce large amounts of TH2 cytokines, most notably, IL-5 and IL-13. We identified NH cells in lymphoid clusters in adipose tissues, which we termed fat associated lymphoid clusters. IL-5 and IL-13 produced by activated NH cells induce eosinophilia and goblet cell hyperplasia, respectively, and play an important role in anti-helminth immunity and allergic diseases, such as asthma. In addition, NH cells produce TH2 cytokines constitutively in the absence of stimulation and support the self-renewal of B1 cells and IgA production by B cells. After our identification of NH cells, other groups have also reported novel TH2 cytokine-producing cells, such as nuocytes, and innate helper type 2 cells. There are similarities and differences between these newly identified cell populations and NH cells. Multipotent progenitor cell type 2 (MPP) cells can differentiate to other myeloid cells, making this a distinct cell type from the others. MPP cells, nuocytes, and innate helper type 2 cells respond to IL-25 alone in vivo, whereas NH cells do not respond to IL-25 without IL-2, although they respond strongly to IL-33. Localization of NH cells in fat-associated lymphoid clusters is an intriguing difference compared with the other cell types, which are found in the lymph node and/or spleen. This article summarizes current information regarding the emerging field of TH2-type innate lymphocytes. PMID- 23038030 TI - Effectiveness of topical infliximab in a mouse model of experimental dry eye. AB - PURPOSE: To investigate the efficacy of a topical anti-tumor necrosis factor alpha agent, infliximab, in a mouse model of experimental dry eye (EDE). METHODS: EDE was induced in C57BL/6 mice, with or without topical treatment consisting of balanced salt solution or 0.001%, 0.01%, or 0.1% infliximab solutions. Tear volume and corneal smoothness were measured on days 5 and 10 after treatment. Levels of interleukin (IL)-1beta, IL-6, IL-17, and interferon gamma (IFN-gamma) were measured in the conjunctiva using a multiplex immunobead assay 10 days after treatment. Periodic acid-Schiff staining, immunohistochemistry, and flow cytometry were also performed 10 days after treatment. RESULTS: Mice treated with 0.01% or 0.1% infliximab showed a significant improvement in tear volume and corneal smoothness compared with controls. The 0.01% and 0.1% infliximab-treated groups showed decreased levels of conjunctival IL-1beta, IL-6, IL-17, and interferon gamma and a decreased staining intensity of tumor necrosis factor alpha. The density of conjunctival goblet cells was higher, whereas the number of CD4*CXCR3* T cells was lower, in the 0.01% and 0.1% infliximab-treated groups compared with the EDE and balanced salt solution control groups. However, there was no significant difference in all parameters between the 0.001% infliximab treated group and control group. CONCLUSIONS: : Topical application of infliximab can improve tear production and ocular surface irregularity, decrease inflammatory cytokines and cells on the ocular surface, and increase conjunctival goblet cell density. These results suggest that topical infliximab eye drops at a concentration of 0.01% and 0.1% may be useful for the treatment of dry eye disease. PMID- 23038031 TI - The antiaging approach for the treatment of dry eye. AB - Dry eye is one of the most common eye disorders affecting millions of people. It causes ocular irritation or discomfort, and decreases functional vision, causing a dramatic deterioration in the quality of life. Although new treatments such as the P2Y2 agonist or cyclosporine eye drops have been developed and a certain level of patient satisfaction can now be obtained, no fundamental treatment has been developed. Currently, there is no therapy available to recover lacrimal function to its normal status. Recent progress in the understanding of aging has laid the foundations for a new way of thinking about intervention of the aging process. Because dry eye is accelerated by aging, a useful approach for the prevention or treatment of dry eye may be to interfere with the aging process. In the scientific community, there is a global consensus that calorie restriction can extend the life span of various kinds of animals, establishing an intervention to aging. Another important hypothesis believed to be involved in aging is the free radical theory. According to these theories, the aging process may be managed by controlling levels of calories or reactive oxygen species. In this review, these 2 important aging theories, calorie restriction and free radical aging, are examined, and we discuss how to apply these theories to the prevention and treatment of dry eye. PMID- 23038032 TI - Choice of artificial tear formulation for patients with dry eye: where do we start? AB - Dry eye is prevalent in many parts of the world. As a result, ophthalmologists and other health care professionals, such as optometrists and general practitioners, often help these patients manage their symptoms. The most common form of treatment for management of dry eye is over-the-counter tear lubricants. A number of tear lubricant formulations are available that vary by their mechanism of action. This article suggests simple guidelines on how lubricants can be selected for patients with mild to moderate dry eye. Side effects of lubricants, such as burning on instillation because of mismatches of eye drop with tear acidity, are also discussed. PMID- 23038033 TI - Gelatinous drop-like corneal dystrophy. AB - Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive disorder, clinically characterized by grayish corneal deposits of amyloid and by severely impaired visual acuity. Most patients require corneal transplantation. We identified the gene responsible for GDLD, tumor-associated calcium signal transducer 2 (TACSTD2), by positional cloning and detected 4 disease-causing mutations in Japanese patients with GDLD. During the positional cloning process, strong linkage disequilibrium was observed between GDLD and some markers in the critical region. More than 90% of GDLD patients possessed the same haplotype with a Q118X mutation in TACSTD2. This may be the result of a founder effect and reflects that most GDLD patients are Japanese. TACSTD2 deleterious mutations resulted in destabilized tight junction proteins, including claudins, ZO-1, and occludin. These findings may explain why the corneal epithelium barrier function is impaired in GDLD patients. PMID- 23038034 TI - Meibomitis-related keratoconjunctivitis: implications and clinical significance of meibomian gland inflammation. AB - Meibomian gland inflammation, "meibomitis," is associated with ocular surface inflammatory diseases. However, these diseases are poorly defined clinically, making effective treatment difficult. Herein, we propose a new disease subset, termed meibomitis-related keratoconjunctivitis (MRKC). The ocular surface features of MRKC include: meibomitis with redness and swelling of the eyelid margin and palpebral conjunctiva; superficial vascularization and granulomatous nodules in the cornea; and conjunctival hyperemia, similar or identical to that observed in phlyctenular keratitis. The characteristics of MRKC patients include a significantly higher prevalence in women, multiple history of chalazia, close association with meibomitis, the presence of specific human leukocyte antigen association, high Propionibacterium acnes detection rates in meibum culture, and the effectiveness of systemic antimicrobial therapy targeting P. acnes. MRKC may share many clinical features with ocular rosacea, especially during childhood. The clinical effectiveness of systemic antimicrobial agents in treating both diseases suggests the importance of focusing on the elimination of bacteria such as P. acnes. PMID- 23038035 TI - Quality of vision in eyes after selective lamellar keratoplasty. AB - With the increasing popularity of selective lamellar keratoplasty procedures, it is important to characterize the optical differences among penetrating keratoplasty (PK), deep anterior lamellar keratoplasty (DALK), and Descemet stripping automated endothelial keratoplasty (DSAEK). The impact of optical differences on the visual acuity (VA) in eyes after keratoplasty is significant. Quantitative evaluation of corneal higher-order aberrations (HOAs) of anterior and posterior surfaces using a rotating Scheimpflug-based corneal topographer, showed that eyes that undergo DSAEK have lower anterior corneal HOAs compared with eyes subjected to PK or DALK. In DSAEK, the anterior corneal surfaces are not replaced, which is in contrast to PK or DALK, where they are replaced. Through evaluation of corneal scatter with a densitometry program associated with the rotating Scheimpflug-based corneal topographer, 3 characteristic patterns of corneal scatter were found in eyes that had undergone keratoplasty. Investigation of the impact of corneal HOAs and corneal scatter on VA after keratoplasty showed that the VA was correlated significantly with corneal scatter. PMID- 23038036 TI - Metalloproteinases in corneal diseases: degradation and processing. AB - Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases with the potential to degrade all types of extracellular matrix. The ADAM (a disintegrin and metalloproteinase) family of peptidases was recently identified as cleaving the extracellular domain of transmembrane proteins. This was termed ectodomain shedding. We investigated the MMP expression in patients with corneal diseases and the potential role of ADAMs in corneal pathophysiology. We detected upregulation of the active form of MMP-2 and MMP-9 in the tear fluid from patients with corneal melting or recurrent corneal erosion. Using human corneal epithelial cells, we observed ADAM17-dependent ectodomain shedding of soluble tumor necrosis factor receptor 1 and soluble interleukin-6 (IL-6) receptor (sIL 6R). The production of sIL-6R was also induced by messenger RNA splicing in the human corneal epithelial cells. IL-6/sIL-6R-induced signal transducer and activator of transcription 3 phosphorylation was observed in cultured human corneal fibroblasts, suggesting that IL-6 trans-signaling induced inflammatory cellular signaling in the human corneal fibroblasts. We demonstrated that MMPs are significantly upregulated in collagen-destructive disorders of the cornea. Additionally, we observed that ectodomain shedding by ADAMs in corneal epithelial cells mediated the production of soluble cytokine receptors. Trans-signaling of IL-6 can induce an inflammatory response in corneal stroma, indicating the significance of IL-6 trans-signaling in ocular surface inflammation. Thus, MMPs and ADAMs play an important role in the pathophysiology of corneal diseases. PMID- 23038037 TI - Epistatic interactions associated with Stevens-Johnson syndrome. AB - Stevens-Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, often including the ocular surface, and sometimes progresses to toxic epidermal necrolysis (TEN). SJS/TEN may be initiated by certain types of medication coupled with possible infection; however, few susceptibility genes have been identified as indicators for risk prediction, except for certain human leukocyte antigen alleles, although several candidate susceptibility genes were identified by candidate gene and genome-wide approaches. As an alternative genetic model, gene-gene interactions between candidate genes were investigated using high-dimensional variable selection methods such as iterative sure independence screening. Linkage disequilibria around the toll-like receptor (TLR)3 and prostaglandin E receptor (PTGER)3 genes were also investigated using additional single nucleotide polymorphisms in an extended additional sample set. A murine experimental allergic conjunctivitis (EAC) model was used to examine the functional interactions. Iterative sure independence screening analyses of Japanese SJS/TEN patients with ocular surface complications revealed 2 interactions that exerted SJS/TEN susceptibility effects, which were locus pairs of TLR3-PTGER3 and HLA-A-IL1alpha. Furthermore, functional interactions between TLR3 and EP3 (the protein of PTGER3) were demonstrated using the EAC model. Identification of functional interactions between TLR3 and EP3 supports an epistatic interaction conferring an increased risk for SJS with ocular complications. PMID- 23038038 TI - A new mouse model of dry eye disease: oxidative stress affects functional decline in the lacrimal gland. AB - PURPOSE: Oxidative damage and inflammation are proposed to be involved in the age related functional decline of lacrimal glands. The molecular mechanism(s) of how oxidative stress affects the secretory function of lacrimal glands was investigated because this is currently unclear. METHODS: We used a novel mev-1 conditional transgenic mouse model (Tet-mev-1) with a modified tetracycline system. The mev-1 gene encodes the cytochrome b560 large subunit of succinate ubiquinone oxidoreductase in complex II of mitochondria. RESULTS: Expression of the mev-1 gene induced excessive oxidative stress associated with ocular surface epithelial damage and a decrease in aqueous secretory function. Tear volume in Tet-mev-1 mice was lower than in wild-type mice, and histopathological analyses showed the hallmarks of lacrimal gland inflammation by intense mononuclear leukocytic infiltration and fibrosis in the lacrimal gland of Tet-mev-1 mice. CONCLUSIONS: This new model provides evidence that mitochondria-induced oxidative damage in the lacrimal gland induces lacrimal dysfunction, resulting in dry eye disease. Our findings strongly suggest that oxidative stress can be a causative factor in the development of dry eye disease. PMID- 23038039 TI - The "replacement hypothesis": corneal stem cell origin epithelia are replaced by limbal stem cell origin epithelia in mouse cornea during maturation. AB - PURPOSE: Previous studies have shown that the stem cells of corneal epithelia are located at the limbal basal layer. Limbal stem cells are believed to be the source of corneal epithelial cell proliferation and differentiation. This study tested the replacement hypothesis, which suggests that corneal stem cell origin epithelia may be replaced by limbal stem cell origin epithelia after 2 weeks of age in mice. METHODS: The cytokeratin 12 expression pattern in the cornea was examined using K12 IRES-Cre and Cre reporter mice. RESULTS: Before 2 weeks of age, K12 expression in corneal epithelia showed a mosaic pattern. After 2 weeks of age, centripetal K12 IRES-Cre expression gradually elongated from the limbal area. Around 12 weeks of age, the mosaic expression pattern disappeared from the center of the cornea. Temporal and spatial observations of K12 IRES-Cre expression patterns suggested that the mosaic pattern cells proliferated and amassed at the same position from day 15.5 of the embryonic stage at the latest. CONCLUSIONS: Therefore, these cells were considered corneal stem cell origin epithelia. In contrast, centripetal pattern cell populations were considered limbal stem cell origin epithelia because they originated from the limbal area and moved to the center of the cornea. These observations suggest that corneal stem cell origin epithelia are replaced by limbal stem cell origin epithelia after 2 weeks of age in mice. PMID- 23038041 TI - Two Zn(II) metal-organic frameworks with coordinatively unsaturated metal sites: structures, adsorption, and catalysis. AB - Assembly of Zn(NO(3))(2) with the tripodal ligand H(3)TCPB (1,3,5-tri(4 carboxyphenoxy)benzene) affords two porous isoreticular metal-organic frameworks, [Zn(3)(TCPB)(2)?2DEF]?3DEF (1) and [Zn(3)(TCPB)(2)?2H(2)O]?2H(2)O?4DMF (2). Single-crystal X-ray diffraction analyses reveal that 1 crystallizes in the monoclinic space group P2(1)/c and possesses a 2D network containing 1D microporous opening channels with an effective size of 3.0*2.9 A(2), whereas 2 crystallizes in the trigonal space group P3c1 and also possesses a 2D network containing 1D channels, with an effective aperture of 4.0*4.0 A(2). TOPOS analysis reveals that both 1 and 2 have a (3,6)-connected network topology with the Schlafli symbol of (4(3)?6(12)) (4(3))(2). According to the variable temperature powder X-ray diffraction patterns, the solid phase of 1 can be converted into that of 2 during a temperature-induced dynamic structural transformation, thus indicating that the framework of 2 represents the most thermally stable polymorph. Desolvated 2 exhibits highly selective adsorption behaviors toward H(2)/N(2), CO(2)/N(2), and CO(2)/CH(4); furthermore, it displays size-selective catalytic activity towards carbonyl cyanosilylation and Henry (nitroaldol) reactions. PMID- 23038040 TI - Wound healing after keratorefractive surgery: review of biological and optical considerations. AB - The introduction of the excimer laser for keratorefractive surgery in the 1990 s permanently reshaped the treatment landscape for correcting refractive errors, such as myopia, hyperopia, and astigmatism. Until that point, these treatments had relied on less predictable techniques, such as radial keratotomy and automated lamellar keratectomy. In recent years, other new technologies, along with increased understanding of the basic science of refractive errors, higher order aberrations, biomechanics, and the biology of corneal wound healing, have allowed for a reduction in the surgical complications of keratorefractive surgery. Novel technologies, such as eye tracking, anterior segment imaging, the femtosecond laser, and asphericity-optimized and wavefront-guided custom laser in situ keratomileusis, have assisted refractive surgeons in achieving greater predictability of their laser vision correction procedures. Understanding the cascade of events involved in the corneal wound healing process and examination of how corneal wound healing influences corneal biomechanics and optics are crucial to improve the efficacy and safety of laser vision correction. PMID- 23038042 TI - Is dual morphology of rock-salt crystals possible with a single additive? The answer is yes, with barbituric acid. AB - Crystal face lift: barbituric acid is shown to be a new crystal-habit modifier for sodium chloride crystals. Two morphologies of salt crystals can be prepared separately with this new additive. It is of the few additives able to induce rhombic dodecahedron crystals for NaCl, and is required only a trace of amount, unlike other additives, such as glycine. PMID- 23038043 TI - Pharmacokinetics and safety of eszopiclone in healthy Chinese volunteers. AB - The main objective of this study was to investigate the pharmacokinetic characters of eszopiclone (CAS: 138729-47-2) after single and multiple-dose oral administration in healthy adult Chinese volunteers.In single-dose study, 12 subjects were given oral administrations of 1.5, 3 and 6 mg eszopiclone in an open-label, randomized, crossover fashion. In multiple-dose study, 8 subjects were given 3 mg eszopiclone once daily consecutively for 7 days. Blood samples were collected over 24 h and plasma eszopiclone were determined using a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay. The safety and tolerability of eszopiclone was evaluated by adverse events recording, physical examination, laboratory testing, vital signs, and 12-lead ECG findings.The main pharmacokinetic parameters of eszopiclone after single-dose administration were as follows: doses of 1.5, 3 and 6 mg; Cmax of 18.08+/-4.65, 38.29+/-15.41 and 76.38+/-23.34 ng/ml; Tmax of 0.94+/-0.39, 1.04+/-0.63 and 1.08+/-0.51 h; AUC0-24 of 110.90+/-23.06, 227.36+/-62.41 and 504.10+/-140.13 ng*h/ml; elimination half lives of 5.84+/-1.03, 5.53+/-1.91 and 6.17+/-1.23 h. After multiple-dose administration, the steady-state levels of eszopiclone were achieved by the 4th day, and the main pharmacokinetic parameters were Css_max at 33.43+/-5.63 ng/ml and AUCss (0-24) at 263.30+/-51.21 ng*h/ml. The most common adverse event was bitter or abnormal taste. All the adverse events were judged as mild to moderate and resolved without any medication.The pharmacokinetic character of eszopiclone is linear and dose-proportional over the range of 1.5-6 mg. The systemic exposure does not accumulate with once-daily administrations. Eszopiclone appears to have good safety and is well tolerated. PMID- 23038044 TI - Frequency, risk factors, prognosis, and genetic polymorphism of the cyclooxygenase-1 gene for aspirin resistance in elderly Chinese patients with cardiovascular disease. AB - BACKGROUND: Cardiovascular disease (CVD) is an important cause of mortality in elderly patients worldwide. Aspirin resistance has been well reported in CVD. OBJECTIVE: The frequency, risk factors, prognosis, and genetic polymorphism of the cyclooxygenase-1 (COX-1) gene for aspirin resistance have not been reported in elderly patients with CVD. We therefore undertook this study to evaluate these associations among elderly Chinese patients with CVD. METHODS: Four hundred thirty-one elderly Chinese patients with CVD receiving daily aspirin therapy (>=75 mg) over 1 month were enrolled. Platelet aggregation was measured by light transmission aggregometry (LTA) and thromboelastography platelet mapping assay (TEG) using arachidonic acid (AA) as a stimulus. The median follow-up was 1.8 years. RESULTS: After the median follow-up, aspirin-resistant patients were at an increased risk of the composite endpoint compared to nonresistant patients by LTAAA + TEGAA (23.7 vs. 9.2%, p = 0.025). Additionally, Cox proportional hazards regression modeling demonstrated that aspirin resistance and cerebrovascular disease were associated with major adverse long-term outcomes (HR for aspirin resistance = 2.31, 95% CI 1.11-4.81, p = 0.026). The variant G-allele of COX-1 rs1330344 (-1676 A/G) significantly increased the risk of aspirin resistance defined by LTAAA + TEGAA (OR = 1.82, 95% CI 1.13- 2.92, p = 0.01). CONCLUSIONS: Aspirin resistance, evaluated by LTAAA + TEGAA, is associated with an increased risk of adverse clinical events in elderly Chinese patients with CVD. The variant G-allele of COX-1 rs1330344 is significantly associated with aspirin resistance defined by LTAAA + TEGAA. PMID- 23038045 TI - Ustekinumab in the treatment of refractory chronic cutaneous lupus erythematosus: a case report. PMID- 23038046 TI - Quantifying capital goods for collection and transport of waste. AB - The capital goods for collection and transport of waste were quantified for different types of containers (plastic containers, cubes and steel containers) and an 18-tonnes compacting collection truck. The data were collected from producers and vendors of the bins and the truck. The service lifetime and the capacity of the goods were also assessed. Environmental impact assessment of the production of the capital goods revealed that, per tonne of waste handled, the truck had the largest contribution followed by the steel container. Large high density polyethylene (HDPE) containers had the lowest impact per tonne of waste handled. The impact of producing the capital goods for waste collection and transport cannot be neglected as the capital goods dominate (>85%) the categories human-toxicity (non-cancer and cancer), ecotoxicity, resource depletion and aquatic eutrophication, but also play a role (>13%) within the other impact categories when compared with the impacts from combustion of fuels for the collection and transport of the waste, when a transport distance of 25 km was assumed. PMID- 23038047 TI - Factors predicting the need for cerebrospinal fluid diversion following posterior fossa tumor surgery in children. AB - BACKGROUND: No consensus exists regarding the management of hydrocephalus in children with posterior fossa tumors before, during or after surgery. In the present study we analyze the factors that predispose to persistent hydrocephalus and the need for a postoperative cerebrospinal fluid (CSF) diversion procedure. METHODS: Pediatric patients who underwent surgery for posterior fossa tumors with hydrocephalus at our hospital were reviewed to evaluate the need for a postoperative CSF diversion procedure. Patients having undergone CSF diversion preoperatively were excluded from the study group. The case records of 84 patients were reviewed. The factors evaluated included age at diagnosis, duration of symptoms, severity of preoperative hydrocephalus, tumor size, tumor location, tumor histology, extent of tumor resection and postoperative complications that could be related to CSF circulation disorders. RESULTS: At the time of presentation, 80/84 (95.2%) patients had symptomatic hydrocephalus; 25/84 (29.8%) patients required a CSF diversion procedure in the postoperative period. Children presenting with symptom duration of less than 3 months had a significantly higher requirement for postoperative CSF diversion in comparison to those with longer symptomatology (p = 0.016). Evan's index and frontal and occipital horn ratio on preoperative imaging were found to correlate closely with the need for postoperative shunt (p = 0.001 and p < 0.001, respectively). The requirement for shunt was statistically higher in patients with midline tumors in comparison to laterally placed lesions (p = 0.04) and in children with medulloblastoma (p < 0.001) and ependymoma (p = 0.016) as the tumor subtypes. Children who underwent intraoperative external ventricular drainage (EVD) had a shunt insertion rate of 39.6% compared with 16.7% of those who did not have an EVD (p < 0.001). Patients with meningitis and pseudomeningocele in the postoperative period had a statistically significant higher risk of shunt requirement (p = 0.008 and p = 0.016, respectively). The mean age at diagnosis and the extent of tumor resection did not correlate with the need for CSF diversion. CONCLUSION: The fact that less than one-third of patients require a CSF diversion after posterior fossa tumor resection refutes the role of prophylactic endoscopic third ventriculostomy. Awareness regarding the factors that can predict persistent postoperative hydrocephalus is essential for the surgeon during patient counseling and surgical planning, and also in deciding the intensity of postoperative clinical and radiological monitoring. PMID- 23038048 TI - Hybrid scatter correction for CT imaging. AB - The purpose of this study was to develop and evaluate the hybrid scatter correction algorithm (HSC) for CT imaging. Therefore, two established ways to perform scatter correction, i.e. physical scatter correction based on Monte Carlo simulations and a convolution-based scatter correction algorithm, were combined in order to perform an object-dependent, fast and accurate scatter correction. Based on a reconstructed CT volume, patient-specific scatter intensity is estimated by a coarse Monte Carlo simulation that uses a reduced amount of simulated photons in order to reduce the simulation time. To further speed up the Monte Carlo scatter estimation, scatter intensities are simulated only for a fraction of all projections. In a second step, the high noise estimate of the scatter intensity is used to calibrate the open parameters in a convolution-based algorithm which is then used to correct measured intensities for scatter. Furthermore, the scatter-corrected intensities are used in order to reconstruct a scatter-corrected CT volume data set. To evaluate the scatter reduction potential of HSC, we conducted simulations in a clinical CT geometry and measurements with a flat detector CT system. In the simulation study, HSC-corrected images were compared to scatter-free reference images. For the measurements, no scatter-free reference image was available. Therefore, we used an image corrected with a low noise Monte Carlo simulation as a reference. The results show that the HSC can significantly reduce scatter artifacts. Compared to the reference images, the error due to scatter artifacts decreased from 100% for uncorrected images to a value below 20% for HSC-corrected images for both the clinical (simulated data) and the flat detector CT geometry (measurement). Compared to a low-noise Monte Carlo simulation, with the HSC the number of photon histories can be reduced by about a factor of 100 per projection without losing correction accuracy. Furthermore, it was sufficient to calibrate the parameters in the convolution model at an angular increment of about 20 degrees . The reduction of the simulated photon histories together with the reduced amount of simulated Monte Carlo scatter projections decreased the total runtime of the scatter correction by about two orders of magnitude for the cases investigated here when using the HSC instead of a low-noise Monte Carlo simulation for scatter correction. PMID- 23038049 TI - Substituent effects on photosensitized splitting of thymine cyclobutane dimer by an attached indole. AB - In chromophore-containing cyclobutane pyrimidine dimer (CPD) model systems, solvent effects on the splitting efficiency may depend on the length of the linker, the molecular conformation, and the oxidation potential of the donor. To further explore the relationship between chromophore structure and splitting efficiency, we prepared a series of substituted indole-T< >T model compounds 2 a 2 g and measured their splitting quantum yields in various solvents. Two reverse solvent effects were observed: an increase in splitting efficiency in solvents of lower polarity for models 2 a-2 d with an electron-donating group (EDG), and vice versa for models 2 e-2 g with an electron-withdrawing group (EWG). According to the Hammett equation, the negative value of the slope of the Hammett plot indicates that the indole moiety during the T< >T-splitting reaction loses negative charge, and the larger negative value implies that the repair reaction is more sensitive to substituent effects in low-polarity solvents. The EDGs of the models 2 a-2 d can delocalize the charge-separated state, and low-polarity solvents make it more stable, which leads to higher splitting efficiency in low polarity solvents. Conversely, the EWGs of models 2 e-2 g favor destabilization of the charge-separated state, and high-polarity solvents decrease the destabilization and hence lead to more efficient splitting in high-polarity solvents. PMID- 23038050 TI - Endohedral metallofullerene Sc3NC@C84: a theoretical prediction. AB - Very recently, two novel Sc(3)NC-based cluster fullerenes Sc(3)NC@C(80) (Wang et. al. J. Am. Chem. Soc. 2010, 132, 16362) and Sc(3)NC@C(78) (Wu et. al. J. Phys. Chem. C 2011, 115, 23755) were prepared and characterized, respectively. Inspired by these findings, the possibility of encapsulating Sc(3)NC cluster in the C(84) fullerene is performed using density functional theory (DFT). Firstly, the isolated pentagon rule (IPR) D(2d) (23) C(84) fullerene is employed to encase the Sc(3)NC cluster: four possible endohedral metallofullerene isomers a-d are designed. The large binding energies (ranging from 163.7 to 210.0 kcal mol(-1)) indicate that the planar quinary cluster Sc(3)NC can be stably encapsulated in the C(84) (isomer 23) cage. Further, we consider the incorporation of Sc(3)NC into the non-IPR C(s) (51365) C(84) cage leading to isomer e and show the high stability of isomer e, which has a larger binding energy, larger HOMO-LUMO gap, higher adiabatic (vertical) ionization potential, and lower adiabatic (vertical) electron affinity than the former four Sc(3)NC@C(84) (isomer 23). Significantly, the predicted binding energy (294.2 kcal mol(-1)) of isomer e is even larger than that (289.2 and 277.7 kcal mol(-1), respectively) of the synthesized Sc(3)NC@C(80) and Sc(3)NC@C(78,) suggesting a considerable possibility for experimental realization. The (13)C NMR chemical shifts and Raman spectra of this a new endofullerene have been explored to assist future experimental characterization. PMID- 23038052 TI - Voice risk factors in kindergarten teachers in Greece. AB - OBJECTIVE: The purpose of this study was to identify voice risk factors for female kindergarten teachers and nurses in Heraklion, Crete. PATIENTS AND METHODS: A questionnaire consisting of voice use and lifestyle activities was given to 200 kindergarten teachers in Heraklion, Crete, of which 151 were returned (75.5%). A group of 89 nurses served as the control group. Both groups also completed the Greek version of the Voice Handicap Index (VHI-G). RESULTS: Kindergarten teachers sing more often, speak loudly more often when they are at work and present with more infections of the upper respiratory tract compared to nurses. They talk less than 30 min per day on the phone, drink less alcohol and water and smoke less in comparison with nurses. The median VHI-G score for the kindergarten teachers was significantly higher than that for the nurses. CONCLUSION: The results suggest that there is a difference in the factors that may be responsible for the appearance of voice problems in kindergarten teachers and in nurses. For kindergarten teachers, the risk factors for voice disorders are primarily related to vocal load factors and for nurses appear to be lifestyle related more than voice use alone. PMID- 23038051 TI - A strategy for revealing the packing in semicrystalline pi-conjugated polymers: crystal structure of bulk poly-3-hexyl-thiophene (P3HT). AB - To tilt or not to tilt: The crystal structure for bulk P3HT (phase I) was determined by "multi-technique crystallography", which combines X-ray diffraction, solid-state NMR spectroscopy, and DFT calculations. The results showed that this semiconducting polymer crystallizes in the monoclinic space group P2(1)/c with nontilted pi-stacks at a distance of 3.9 A (see picture). PMID- 23038053 TI - Development of an analytical method for the determination of arsenic in urine by gas chromatography-mass spectrometry for biological monitoring of exposure to inorganic arsenic. AB - OBJECTIVES: The purpose of this study was to develop an analytical method for the simultaneous determination of inorganic arsenic [As(III) and As(V)] and monomethylarsonic acid (MMA) in urine by gas chromatography-mass spectrometry (GC MS) for the biological monitoring of exposure to inorganic arsenic. METHODS: Arsenic compounds (after reduction of arsenic to the trivalent state) were derivatized with 2,3-dimercapto-1-propanol and then analyzed using a GC-MS. The proposed method was validated according to the US Food and Drug Administration guidelines. The accuracy of the proposed method was confirmed by analyzing Standard Reference Material (SRM) 2669 (National Institute of Standards and Technology). RESULTS: Calibration curves showed linearity in the range 1-100 MUg/l for each of the arsenic species, with correlation coefficients of >0.999. For each of the arsenic species, the limits of detection and quantification were 0.2 MUg/l and 1 MUg/l, respectively. The recoveries were 96-100%, 99-102% and 99 112% for As(III), As(V) and MMA, respectively. Intraday accuracy and precision were 82.7-99.8% and 0.9-7.4%, respectively. Interday accuracy and precision were 81.3-100.0% and 0.8-9.9%, respectively. The analytical values of SRM 2669 obtained by the proposed method were sufficiently accurate. CONCLUSIONS: The proposed method overcame the disadvantages of high-performance liquid chromatography with inductively coupled plasma mass spectrometry. It was a robust, selective and cost-effective method suitable for routine analyses and could be useful for the biological monitoring of occupational exposure to inorganic arsenic. PMID- 23038054 TI - Lymph node involvement beyond peripancreatic region in pancreatic head cancers: when results belie expectations. AB - OBJECTIVES: Surgery remains the standard therapy for curative management of pancreatic duct adenocarcinoma (PDA) involving the head of pancreas. This study aimed to report our experience in PDA about the prognostic value of lymph node (LN) invasion (N+) at the root of the superior mesenteric artery (SMA) and in N2 subgroup. METHODS: From January 2005 to September 2009, 110 patients were included for pancreaticoduodenectomy or total pancreatectomy. RESULTS: Etiologies were PDA (n = 87) or ampullary carcinomas (n = 23). Sixty-five percent of patients were N+, with N1/N2/N3 location, respectively, 63.6%, 9.1%, and 2.7%. Forty-four percent had a LN identified intraoperatively at the origin of the SMA, of whom only 12% were N+. In multivariate analysis (whole series), complication grade greater than II, location of positive LN (N1 to N3) and vascular resection were associated with a poorer survival. In the exocrine PDA subgroup, only location of positive LN and vascular resection were associated with a poorer survival. N+ SMA was not statistically correlated with survival, recurrence, or disease-free survival. CONCLUSIONS: N+ at the origin of the SMA was not a significant prognostic factor for PDA and should no longer be considered as a formal contraindication for curative surgery. Conversely, N2 invasion remains an unfavorable prognostic. PMID- 23038055 TI - The presentation and clinical significance of sinonasal respiratory epithelial adenomatoid hamartoma (REAH). AB - BACKGROUND: Sinonasal respiratory epithelial adenomatoid hamartoma (REAH) is a benign glandular proliferation with ciliated epithelium. Little is known about REAH, with only a few published case reports appearing since its original description in 1995. Classically described as an isolated polypoid lesion arising from the nasal septum, more recent descriptions also suggest that REAH can occur among nasal polyps. We report the largest experience with REAH to date, and aim to better understand and characterize this unique entity. METHODS: In this case series, all cases of REAH diagnosed between 2006 and 2011 were reviewed. Clinical presentation, histologic and radiographic features, and operative findings were examined. RESULTS: There were 45 patients 19 females and 26 males, with a mean age of 55.9 years (range, 23-83). Most cases of REAH (33/45, 73%) were found in association with another pathologic process (sinonasal polyposis, adenoiditis, hereditary hemorrhagic telangiectasia [HHT], inverted papilloma [IP], or malignancy). Of these, REAH occurring among diffuse polyposis (79% of cases) represented the large majority. The average Harvard computed tomography (CT) stage for this cohort was 3.1. The other presentation of REAH (12/45, 27%) was an isolated sinonasal mass. In cases of isolated REAH, the majority of lesions (75%) were noted to be originating in the olfactory clefts. CONCLUSION: Isolated REAH, which may mimic a neoplasm, appears to be a different clinical entity than the more common form encountered in association with nasal polyps and inflammation. Further investigation into the etiology and clinical significance is needed. PMID- 23038056 TI - Yarrowia lipolytica. AB - The yeast Yarrowia lipolytica presents specific physiological, metabolic and genomic characteristics, which differentiate it from the model yeast Saccharomyces cerevisiae. These properties have led several research groups to use this yeast as a model for basic knowledge. Thanks to the development of advanced genetic tools and -omic approaches, significant progress has been achieved in the understanding of specific biological processes. This review, after a short presentation of this model yeast, will briefly highlight the different use of Y. lipolytica for basic knowledge and the advantages gained by exploiting this non-conventional yeast. Future perspectives in employing this yeast for basic knowledge in the field of RNA splicing and genome evolution, and for the study of lipid metabolism, are also discussed. PMID- 23038058 TI - 'a'-Position-mutated and G4-mutated hemagglutinin-neuraminidase proteins of Newcastle disease virus impair fusion and hemagglutinin-neuraminidase-fusion interaction by different mechanisms. AB - OBJECTIVES: To determine the effects of heptad repeat regions (HRs) and N-linked carbohydrate sites of the Newcastle disease virus hemagglutinin-neuraminidase (HN) protein on fusion of HN and fusion (F) proteins and HN-F interaction. METHODS: We mutated six 'a' residues in the HRs and four asparagines in N-linked carbohydrate sites to alanine in the HN protein. A vaccinia-T7 RNA polymerase expression system was used to express HN cDNAs in BHK-21 cells to determine the HN functions. Deglycosylation was treated with PGNase F digestion. The formation of HN-F protein complexes was determined by the coimmunoprecipitation assay. RESULTS: Each HR-mutated protein interfered with fusion and the HN-F interaction. The G4-mutated protein not only impaired fusion and HN-F interaction but also decreased activities in cell fusion promotion, hemadsorption and neuraminidase. CONCLUSIONS: It is assumed that two different mechanisms for mutations in these two regions are responsible for the decreased fusion promotion activity and the reduced ability of interaction with F protein. Mutations in the HRs impair fusion and HN-F interaction by altering the transmission of a signal from the globular domain to the F-specific region in the stalk, but the G4 mutation modulates fusion and HN-F interaction by the misfolding of some important structures. PMID- 23038057 TI - The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model. AB - BACKGROUND: No- and low-carbohydrate diets delay tumor growth compared to western diet (WD) in prostate cancer (PCa) xenograft studies. The effect of these diets in concert with androgen deprivation is unknown. METHODS: A total of 160 male SCID mice were injected with 1* 10(5) LAPC-4 human PCa cells. Of these, 150 mice were castrated and randomized to an ad libitum WD or fed via a paired-feeding protocol with a no-carbohydrate ketogenic diet (NCKD), 10% carbohydrate diet, or 20% carbohydrate diet. The remaining 10 mice were not castrated and were fed an ad libitum WD. The mice were sacrificed once volumes reached 1,000 mm3 and survival tested using the log-rank test. Serum from the median surviving 8 mice/group was assayed for insulin, IGF-1, and IGFBP-3. RESULTS: Body weights were roughly equal among groups. The 10 non-castrated mice experienced accelerated tumor growth. Among castrated mice, WD had the most rapid tumor growth; 20% carbohydrate diet the slowest (P = 0.046). Survival was not significantly different among the various carbohydrate restricted groups (P = 0.51). When pooled, there was a non-significant trend (P = 0.11) in improved survival among the carbohydrate restricted diets versus WD. No significant difference in serum insulin, IGF-1, and IGFBP-3 levels was noted among all groups at pre-randomization or at sacrifice. CONCLUSIONS: A 20% carbohydrate diet slowed tumor growth versus a WD. Though the benefit of carbohydrate restriction was somewhat less than in prior studies in non-castrate mice, these data still suggest diets achievable in humans may play a role in PCa management. PMID- 23038059 TI - Solid supramolecular architecture of a perylene diimide derivative for fluorescent enhancement. AB - A new p-phenylenevinylene-linked perylene diimide has been synthesized and self assembled for the formation of zero-dimensional molecular aggregate structures of nanospheres and vesicles through solvent tuning. The solid-state optical properties induced by a special wavelength laser were studied and the results indicated excellent fluorescent enhancement properties. The emission intensity of these aggregates increased with elongation of the laser irradiation time. Based on the analysis of variable-temperature (1)H NMR spectra, DFT calculations, and the single-crystal structure of the linkage group, a conformation-dependent fluorescent enhancement mechanism could be demonstrated. The mechanism is different from the fluorescent bleaching of normal solid-state fluorescent materials and offers potential applications in optical devices. PMID- 23038060 TI - Stretchable spin valves on elastomer membranes by predetermined periodic fracture and random wrinkling. AB - The first highly stretchable and sensitive spin valve sensor on elastomeric membranes are demonstrated. The sensor elements exhibit stable GMR behavior up to tensile strains of 29% in in situ stretching experiments and show no fatigue over 500 loading cycles. This remarkable stretchability is achieved by a predetermined periodic fracture mechanism that creates a meander-like pattern upon stretching. PMID- 23038061 TI - Silica supported ruthenium oxide nanoparticulates as efficient catalysts for water oxidation. AB - Pre-synthesized ruthenium dioxide nanoparticulates (RuO(2) NPs) with low level of aggregation were well dispersed in mesoporous silica SBA-15. As a catalyst for water oxidation, the supported RuO(2) NPs exhibit excellent catalytic activity and recyclability. The initial turnover frequency (TOF) is to date the highest among comparable RuO(2) catalysts. PMID- 23038062 TI - Surfactant protein A associated with respiratory distress syndrome in Korean preterm infants: evidence of ethnic difference. AB - BACKGROUND: Insufficiency of the pulmonary surfactant system is the primary cause of respiratory distress syndrome (RDS) in preterm infants. Genetic factors, including specific single-nucleotide polymorphisms in the genetic components of surfactant protein A (SP-A1 and SP-A2), affect protein structure and function, as well as risk of RDS. OBJECTIVE: We investigated the association between variations in SP-A genotypes and RDS within the genetically homogeneous Korean population. METHODS: We used TaqMan(r) real-time polymerase chain reaction technology to assess nine single-nucleotide polymorphisms of SP-A in 261 full term and 152 preterm infants. Among the preterm infants, 76 infants with RDS were matched with 76 control infants with respect to gestation, use of antenatal steroids and gender. RESULTS: The SP-A2 1A(0) variant and the homozygous 1A(0)/1A(0) genotype were associated with protection from RDS (OR 0.31, 95% CI 0.13-0.78). In addition, the 1A(1) carrier genotype (containing one copy of the 1A(1) variant) was associated with increased risk of RDS (OR 2.42, 95% CI 1.06 5.52). The significance of these results is that the association of patterns with RDS was opposite to the findings of previous research with Finnish and North American study populations. CONCLUSIONS: We have identified associations between specific variants of the SP-A genes and RDS risk in the Korean preterm study population. Our data strongly support SP-A as a candidate gene for susceptibility to RDS, and reveal the dissimilarity of the associated risk/protective genetic variants between different ethnic study populations. PMID- 23038063 TI - A transgenic zebrafish liver tumor model with inducible Myc expression reveals conserved Myc signatures with mammalian liver tumors. AB - Myc is a pleiotropic transcription factor that is involved in many cellular activities relevant to carcinogenesis, including hepatocarcinogenesis. The zebrafish has been increasingly used to model human diseases and it is particularly valuable in helping to identify common and conserved molecular mechanisms in vertebrates. Here we generated a liver tumor model in transgenic zebrafish by liver-specific expression of mouse Myc using a Tet-On system. Dosage dependent induction of Myc expression specifically in the liver was observed in our Myc transgenic zebrafish, TO(Myc), and the elevated Myc expression caused liver hyperplasia, which progressed to hepatocellular adenoma and carcinoma with prolonged induction. Next generation sequencing-based transcriptomic analyses indicated that ribosome proteins were overwhelmingly upregulated in the Myc induced liver tumors. Cross-species analyses showed that the zebrafish Myc model correlated well with Myc transgenic mouse models for liver cancers. The Myc induced zebrafish liver tumors also possessed molecular signatures highly similar to human those of hepatocellular carcinoma. Finally, we found that a small Myc target gene set of 16 genes could be used to identify liver tumors due to Myc upregulation. Thus, our zebrafish model demonstrated the conserved role of Myc in promoting hepatocarcinogenesis in all vertebrate species. PMID- 23038064 TI - Children with phenylketonuria treated early: basic audiological and electrophysiological evaluation. AB - OBJECTIVES: Individuals with phenylketonuria (PKU) can exhibit deficits in executive functions, intelligence, attention, visual-spatial processing abilities, and efficiency stemming presumably from deficient neurotransmitter synthesis, even when the disorder is diagnosed and treated early. Basic audiological and electrophysiological evaluations were used to examine the peripheral and central auditory pathways of children with early-treated PKU, who followed adequate versus inadequate diets. Results were compared with those of age-matched children without PKU. DESIGN: The control group included 35 children aged 5 to 16 years, and the experimental group included 25 children with classic PKU, all of whom were diagnosed and treated early. The experimental group comprised children of two subgroups, divided according to their dietary control, as follows: 8 children aged 6 to 13 years with adequate diets (group A); 17 children ages 6 to 15 years demonstrating inadequate diets (group B). All participants underwent auditory evaluations, including otoscopy, pure-tone and speech audiometry, immittance testing (tympanometry and assessment of contralateral stapedial reflex thresholds), and evaluations of auditory brainstem and middle latency responses. The demographic variables and audiological examination results were analyzed for all groups. Results among groups and subgroups were compared using analysis of variance with repeated measures to test statistical significance across factors and measures at the p = 0.05 level. RESULTS: Audiometric evaluation revealed results within normal limits for all groups, except for one child from the inadequate diet group, who showed a mild bilateral conductive hearing loss. Results of speech and immittance audiometry suggested the children in group B as having poorer average speech-discrimination scores and higher stapedial reflex thresholds at 4000 Hz. Auditory brainstem response results revealed longer average latencies for waves III and V and greater interaural differences for wave V in group B, although both groups A and B showed longer average latencies for the interpeak interval I-V, compared with the control group. Middle latency responses showed no significant differences in the latencies of the Na and Pa waves or the Na-Pa amplitude for the experimental group, but electrode or ear effects were present in 87.5% of group A and 58.8% of group B. CONCLUSIONS: Overall, differences observed tended to be small (by clinical diagnostic standards), yet suggest that children with PKU exhibit some effect of this disorder on the pontine auditory pathway, even when diagnosed/treated early and independent of the appropriateness of diet. It thus seems prudent to follow PKU children with auditory processing assessments to evaluate functional implications of these findings. PMID- 23038065 TI - Multicomponent synthesis of pyrroles from cyclopropanes: a one-pot palladium(0) catalyzed dehydrocarbonylation/dehydration. AB - Ring the changes: The cycloaddition of nitrones with 1-carboallyloxy-1 carbomethoxycyclopropanes yields tetrahydro-1,2-oxazines, which in turn undergo a Tsuji dehydrocarbonylation to give dihydro-1,2-oxazines (see scheme; dba = dibenzylideneacetone). Addition of base to this reaction mixture results in clean conversion to pyrroles. The result is a flexible three-component strategy for the synthesis of tetrasubstituted pyrroles. PMID- 23038066 TI - Challenge for overcoming high blood pressure: Nagoya statement 2012. PMID- 23038067 TI - Reliability and validity of a continuous pain registration procedure. AB - BACKGROUND: Conventional pain rating scales [i.e. visual analogue scales (VAS) or numerical rating scales (NRS)] only provide a summary for different levels of pain felt, while the duration of these levels is not accounted for. If pain can be rated continuously, the area under the curve (AUC) of varying pain intensity over time can be calculated, which integrates varying pain intensity with duration. The present study examined the reproducibility and validity of a continuous pain rating procedure. METHODS: Twenty-eight healthy volunteers participated. Pain was induced using constant current delivered to the non dominant forearm using bipolar electrodes. Pain was rated continuously on an electronic VAS monitored by a computer. For each participant, the level of current needed to achieve a weak, mild, slightly moderate and moderate level of pain was determined (part I). Next, participants were asked to rate the painfulness of six periods of electrical stimulation (part II). Unknown to the participants, they were presented with the four levels of current obtained in part I, where the level of current for mild and moderate pain was presented twice (in order to assess consistency). The order of presentation was randomized for all subjects. RESULTS: In general, participants produced reliable mean AUCs. In addition, the AUC of pain intensity over time could clearly discriminate between the four levels of pain used in the present study. DISCUSSION: A continuous pain registration procedure, using an AUC approach, may be a promising direction to explore. Results can be improved by allowing more training on the use of the electronic VAS. PMID- 23038068 TI - Fine control of nuclear confinement identifies a threshold deformation leading to lamina rupture and induction of specific genes. AB - The quest to understand how the mechanical and geometrical environment of cells impacts their behavior and fate has been a major force driving the recent development of new technologies in cell biology research. Despite rapid advances in this field, many challenges remain in order to bridge the gap between the classical and simple cell culture plate and the biological reality of actual tissue. In tissues, cells have their physical space constrained by neighboring cells and the extracellular matrix. Here, we propose a simple and versatile device to precisely and dynamically control this confinement parameter in cultured cells. We show that there is a precise threshold deformation above which the nuclear lamina breaks and reconstructs, whereas nuclear volume changes. We also show that different nuclear deformations correlate with the expression of specific sets of genes, including nuclear factors and classical mechanotransduction pathways. This versatile device thus enables the precise control of cell and nuclear deformation by confinement and the correlative study of the associated molecular events. PMID- 23038069 TI - Photochemical electrocyclic ring closure and leaving group expulsion from N-(9 oxothioxanthenyl)benzothiophene carboxamides. AB - N-(9-Oxothioxanthenyl)benzothiophene carboxamides bearing leaving groups (LG(-) = Cl(-), PhS(-), HS(-), PhCH(2)S(-)) at the C-3 position of the benzothiophene ring system photochemically cyclize with nearly quantitative release of the leaving group, LG(-). The LG(-) photoexpulsions can be conducted with 390 nm light or with a sunlamp. Solubility in 75% aqueous CH(3)CN is achieved by introducing a carboxylate group at the C-6 position of the benzothiophene ring. The carboxylate and methyl ester derivatives regiospecifically cyclize at the more hindered C-1 position of the thioxanthone ring. Otherwise, the photocyclization favors the C-3 position of the thioxanthone. Quantum yields for reaction are 0.01-0.04, depending on LG(-) basicity. Electronic structure calculations for the triplet excited state show that excitation transfer occurs from the thioxanthone to the benzothiophene ring. Subsequent cyclization in the triplet excited state is energetically favourable and initially generates the triplet excited state of the zwitterionic species. Expulsion of LG(-) is thought to occur once this species converts to the closed shell ground state. PMID- 23038070 TI - Dexamethasone intravitreal implant: an effective adjunctive treatment for recalcitrant noninfectious uveitis. AB - PURPOSE: To describe our experience in treating recalcitrant and severe cases of noninfectious posterior uveitis with the 0.7-mg dexamethasone intravitreal implant as adjunctive anti-inflammatory treatment. PROCEDURES: Retrospective study. Twelve patients (8 females; 4 males; 14 affected eyes, 15 implants) with severe recalcitrant uveitis were treated. Patients had an inadequate control of uveitis despite different immunosuppressants and periocular corticosteroid therapy. Primary outcome measures evaluated were: decrease in uveitis activity, improvement in visual acuity, reduction of macular thickness, and occurrence of adverse events. RESULTS: Uveitis activity decreased in all patients after the implant. The mean follow-up time from injection was 9 months. Best-corrected visual acuity improved from 20/80 to 20/40 at the end of follow-up. The mean retinal thickness improved from 496 to 226 um. Adverse events encountered were: 3 eyes with intraocular pressure elevation, 1 vitreous hemorrhage and 1 subconjunctival hemorrhage. Three patients reduced the daily systemic corticosteroid dosage after treatment. CONCLUSIONS: The 0.7-mg dexamethasone intravitreal implant appears to be a novel and promising adjunctive treatment for patients with severe posterior noninfectious uveitis recalcitrant to different immunosuppressive agents. PMID- 23038071 TI - Laboratory information management system: an example of international cooperation in Namibia. AB - The authors describe the project undertaken by the Istituto G. Caporale to provide a laboratory information management system (LIMS) to the Central Veterinary Laboratory (CVL) in Windhoek, Namibia. This robust laboratory management tool satisfies Namibia's information obligations under international quality standard ISO 17025:2005. The Laboratory Information Management System (LIMS) for Africa was designed to collect and manage all necessary information on samples, tests and test results. The system involves the entry of sample data on arrival, as required by Namibian sampling plans, the tracking of samples through the various sections of the CVL, the collection of test results, generation of test reports and monitoring of outbreaks through data interrogation functions, eliminating multiple registrations of the same data on paper records. It is a fundamental component of the Namibian veterinary information system. PMID- 23038072 TI - Multi-antigen print immunoassay for seroepidemiological surveillance of bovine tuberculosis on Indian cattle farms. AB - Bovine tuberculosis caused by Mycobacterium bovis is a zoonotic disease that is responsible for significant economic losses in many countries. The standard diagnostic method, the tuberculin test (TST) that is used in control programmes has serious shortcomings and, given the complex nature and the economic impact of the disease, a number of other diagnostic methods have been examined. The authors have attempted to characterise antibody response using the multi-antigen print immunoassay (MAPIA). A total of 511 serum samples were collected from farms in India on which bovine tuberculosis was prevalent and on farms with low incidence. These were tested using the MAPIA against a panel of five defined M. bovis recombinant antigens and two purified protein derivatives (bovine PPD and avian PPD) to study the seroprevalence of the disease on Indian cattle farms. Results indicated that the fusion protein of antigen CFP-10:MPB83 showed a positive response in 142 out of 298 serum samples from tuberculosis-prevalent farms, thereby indicating the serological dominance of the proteins post infection. The antigen selected could be used further in the development of a simple, rapid and accurate serological diagnostic test, paired with TST, for use in bovine tuberculosis control programmes. PMID- 23038073 TI - Prevalence and distribution of Vibrio parahaemolyticus in finfish from Cochin (south India). AB - Finfish samples obtained from four retail outlets in Cochin between June 2009 and June 2010 were investigated for the occurrence of Vibrio parahaemolyticus. A total of 182 samples were collected and suspect isolates were identified using standard biochemical tests and were further confirmed by a species-specific tlh gene. V. parahaemolyticus was detected in 45.1% of samples, with demersal fish being more affected than pelagic species. The bacterium was isolated more frequently from the skin and gills of pelagic fish, while the intestine yielded greater numbers of V. parahaemolyticus in demersal fish. The highest incidence of antibiotic resistance was recorded against ampicillin and streptomycin, followed by carbenicillin, cefpodoxime, cephalothin, colistin and amoxycillin; the lowest was against nalidixic acid, tetracycline, chloramphenicol and ciprofloxacin. Multiple drug resistance was prevalent among isolates. Although only a fraction of strains are pathogenic for humans, the time-temperature abuse in markets provides ample scope for these strains to multiply to dangerous levels. The multidrug resistant nature of the strains adds to the gravity of the problem. High V. parahaemolyticus incidence rates in market finfish samples from areas in and around Cochin clearly indicates that control measures should be adopted to reduce post-harvest contamination in seafood and time-temperature abuse in markets to diminish the risk of V. parahaemolyticus infection associated with seafood destined for human consumption. PMID- 23038074 TI - Assessment of antimicrobial drug residues in beef in Abuja, the Federal Capital Territory, Nigeria. AB - Drugs administered to food-producing animals close to the time of slaughter often result in prohibited antimicrobial residues in the animal tissues at slaughter. Evidence based on the Premi(r) test confirmed the occurrence of antimicrobial drug residues in 89.3% of kidney and urine samples from cattle slaughtered within Abuja town where the residents rely heavily on beef as a source of protein. The administration of antibiotics close to the time of slaughter by marketers/herd owners and transporters was found to be significantly (p<0.05) higher when compared with butchers and abattoir workers. The practice of administering antibiotics to animals close to the time of slaughter was believed to be profit motivated. The research suggests that awareness campaigns amongst the stakeholders, the enactment of appropriate laws for the control of antibiotic use and the empowerment of veterinary public health practitioners in food regulatory agencies as some of the strategies which may positively reduce the risk of antimicrobial drug residues in food animals in Nigeria. PMID- 23038075 TI - Epidemiological survey of Cryptosporidium spp. in companion and stray dogs in Kerman, Iran. AB - A cross-sectional survey was conducted to determine the prevalence of Cryptosporidium spp. infection in companion and stray dogs in Kerman, Iran. Faecal samples were randomly collected from 548 dogs (450 companion and 98 stray). Cryptosporidium oocysts were concentrated using the formalin ether sedimentation method according to the modified Ziehl-Neelsen staining technique. Cryptosporidium oocysts were identified in 2% (11/548) of samples. Faeces were classified according to the consistency as diarrhoeic (56/548) and non-diarrhoeic (492/548). Diarrhoea was recorded in 4 of the positive samples (7.14%). The prevalence of cryptosporidiosis was significantly higher in diarrhoeic dogs (7.14%) compared to the non-diarrhoeic dogs (1.4%) (p<0.05). There was no significant difference between the prevalence of Cryptosporidium spp. in stray dogs (4.08%) and companion dogs (1.55%). The age distribution of Cryptosporidium spp. in dogs below 1 year of age had a higher overall prevalence than dogs over 12 months of age (p<0.05). There was no significant difference in the prevalence between male (1.93%) and female (2.1%) dogs. The highest rate of infection was recorded during the autumn (3.9%) but this difference was not statistically significant (p>0.05). This study confirmed that dogs have a potential role in human cryptosporidiosis and faecal examination of dogs with persistent diarrhoea should be performed on a routine basis. PMID- 23038076 TI - Antibiotic-resistant commensal Escherichia coli in faecal droplets from bats and poultry in Nigeria. AB - The prevalence of antibiotic resistance and plasmid carriage among commensal faecal Escherichia coli isolates of bats, broilers and free-range chickens in Ile Ife, Osun State, Nigeria was studied. A total of 125 E. coli isolates were recovered from the fresh faecal samples of bats, broilers and free-range chickens on eosin methylene blue agar plates and characterised using standard biochemical tests. The susceptibility of the isolates to antibiotics was performed using the disk diffusion method. All isolates developed resistance to antibiotics to varying degrees; resistance to augumentin, amoxicillin and tetracycline was significantly higher (p<0.05), compared to the other antibiotics. The lowest resistance was recorded with ofloxacin, ciprofloxacin and pefloxacin in bats and free-range isolates. In general, resistance was higher (p<0.05) in broilers than in free-range isolates, but was comparable in bat isolates (p>0.05) with the exception of ciprofloxacin, pefloxacin gentamicin and ofloxacin. A total of 90% of the bat isolates developed multiple antibiotic resistance with 28 multiple antibiotic resistance patterns. The free-range chicken and broiler isolates displayed 10 and 38 multiple antibiotic resistance patterns, respectively. Resistance was mostly plasmid-mediated with molecular weights ranging between 0.91 kb and 40.42 kb. Antibiotic resistance and plasmid carriage among the commensal E. coli isolates studied was relatively high and may be implicated in zoonotic infections. PMID- 23038077 TI - Avian influenza virus infection in apparently healthy domestic birds in Sokoto, Nigeria. AB - The study was conducted among apparently healthy birds brought from different local government areas, neighbouring states and across international boundaries to the Sokoto central live bird market between October 2008 and March 2009. Tracheal and cloacal swabs were collected from 221 apparently healthy birds comprising 182 chickens, 3 turkeys, 11 guineafowl, 17 ducks and 8 pigeons. These samples were analysed using nested polymerase chain reaction (nPCR) to check for the presence of avian influenza virus. An overall prevalence of 1.4% (3 positive cases) was detected with two cases observed in chickens and one in a pigeon. The findings indicate the circulation of avian influenza in the study area. This raises concern for human and animal health due to zoonotic and economic implications of this virus. PMID- 23038078 TI - Haematological and biochemical alterations caused by epidural and intramuscular administration of xylazine hydrochloride in dromedary camels (Camelus dromedarius). AB - This study was conducted in 16 healthy immature dromedary camels weighing 120-150 kg to evaluate and compare the effects of epidural and intramuscular injections of xylazine administered at 0.1 mg/kg and 0.2 mg/kg. Haematological parameters included haemoglobin, packed cell volume, total erythrocyte count and total leukocyte count. Biochemical parameters included alkaline phosphates, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine and glucose. Parameters were measured at different intervals before (baseline) and after the administration of drugs. Our study showed that the effect of xylazine on haematological and biochemical parameters is dose-dependant and is also related to the route of administration. The low dose of xylazine administered using both intramuscular and epidural methods showed minimal effects, whereas high doses of the drug, especially when injected intramuscularly, caused greater changes in haematological and biochemical parameters. PMID- 23038079 TI - Absence of link between abortion and seropositivity of cystic hydatid disease in ewes and female goats in Turkey. AB - This study was conducted to test whether there is a statistically significant association between seropositivity to cystic echinococcosis and abortion in ewes and female goats from the Turkish provinces of Elazig (east Anatolia), Sanliurfa (south-east Anatolia) and Kayseri (Inner Anatolia) using the enzyme-linked immunosorbent assay (ELISA). A total of 20 of 133 sera (15.1%) from ewes and 5 of 101 sera (4.9%) from goats with a history of abortion gave seropositive results that were not significantly different (p>0.05) from these, 9.9% (10/101) were reported for ewes and 1.6% (2/122) for female goats without a history of abortion. Serological prevalence rates among those animals with a history of abortion were not significantly different from the control group. No positive association was established between seropositivity for cystic echinococcosis and abortion in ewes and female goats. PMID- 23038080 TI - Canine testicular tumours: a retrospective investigation in Abruzzo and Molise, Italy. AB - Canine testicular tumours frequently occur and share relevant features with their human counterparts, thus being a putative model in comparative oncology. The authors present data on canine testicular tumours submitted to the Istituto G. Caporale over the last 12 years. In total, 183 testicular neoplasms were diagnosed: 108 seminomas, 37 Sertoli cell tumours, 18 interstitial Leydig cell tumours, 10 mixed tumours, 9 other primary tumours and one metastatic neoplasm. A systematic and more detailed collection of data (signalling, history, clinical signs and follow-up) enables a better evaluation of clinical and biological features of animal tumours, as well as a clear assessment of the real impact, if any, of specific intrinsic and extrinsic risk factors. PMID- 23038081 TI - In memoriam: Stuart Kenneth Hargreaves, DVM, 1946-2012. The humanist veterinarian from Zimbabwe who was committed to the improvement of animal health in Africa. PMID- 23038082 TI - Experimental determination of the effective point of measurement and the displacement correction factor for cylindrical ionization chambers in a 6 MV photon beam. AB - The displacement effect of cylindrical ionization chambers is taken into account either by an effective point of measurement (EPOM) or, alternatively, by using a displacement correction factor. The dependence of these effects on water was examined as a function of the cavity radius for (60)Co gamma radiation in a previous paper. This paper describes results for high-energy photon beams using the same measurement technique. Additionally, the displacement correction factor was directly measured. Absorbed doses measured under reference conditions following the international protocol IAEA TRS-398 and the German protocol DIN 6800-2 agreed well between the chambers with different cavity radii within a standard uncertainty of 0.2%. However, there was a constant difference of 0.2% between both protocols. Similar to our observations made in (60)Co, absorbed doses measured with the different chambers at depths beyond the maximum showed deviations of up to 0.6% and 0.5% for IAEA TRS-398 and DIN 6800-2, respectively, and deviations of more than 1% were found for both protocols in the build-up and maximum region. We therefore propose modified formulas for the determination of the EPOM and the displacement correction factor. PMID- 23038083 TI - German Oldenburg Sentence Test for Children: a useful speech audiometry tool for hearing-impaired children at kindergarten and school age. AB - BACKGROUND/AIMS: In speech audiometry, sentence tests have the advantage of assessing more words within a given period of time than single-word tests do. Consequently, greater accuracy (steeper discrimination function) is achieved. The recently developed German Oldenburg Sentence Test for Children (OlKiSa) has been evaluated thus far for school-aged children in noise, and normative data for younger children in a quiet environment have been established. In this study, the focus is on its applicability in hearing-impaired children fitted with hearing aids or cochlear implants. METHODS: The use of the OlKiSa in a quiet environment in hearing-impaired children aged 4 years or older was evaluated. One hundred and nineteen hearing-impaired children aged between 4 and 10 years performed the OlKiSa in a quiet environment. Individual speech reception thresholds (SRT) were measured aided and unaided and the slopes of the discrimination functions were calculated. RESULTS: Independent of age, the mean slope of the discrimination function for SRT was about 7%/dB in both conditions, which is a high value of steepness for a speech audiometric test in a quiet environment. CONCLUSION: The OlKiSa in quiet is a reliable test procedure for hearing-impaired children aged 4 years and older. PMID- 23038085 TI - Relationship between infarct tissue characteristics and left ventricular remodeling in patients with versus without early revascularization for acute myocardial infarction as assessed with contrast-enhanced cardiovascular magnetic resonance imaging. AB - Left ventricular (LV) remodeling following myocardial infarction (MI) is the result of complex interactions between various factors, including presence or absence of early revascularization. The impact of early revascularization on the relationship between infarct tissue characteristics and LV remodeling is incompletely known. Therefore, we investigated in patients with versus without successful early revascularization for acute MI potential relations between infarct tissue characteristics and LV remodeling with contrast-enhanced (CE) cardiovascular magnetic resonance (CMR). Patients with versus without successful early revascularization underwent CE-CMR for tissue characterization and assessment of LV remodeling including end-diastolic and end-systolic volumes, LV ejection fraction, and wall motion score index (WMSI). CE-CMR images were analyzed for infarct tissue characteristics including core-, peri- and total infarct size, transmural extent, and regional scar scores. In early revascularized patients (n = 46), a larger area of infarct tissue correlated significantly with larger LV dimensions and a more reduced LV function (r = 0.39 0.68; all P <= 0.01). Multivariate analyses identified peri-infarct size as the best predictor of LV remodeling parameters (R(2 )= 0.44-0.62). In patients without successful early revascularization (n = 47), there was no correlation between infarct area and remodeling parameters; only peri-infarct size versus WMSI (r = 0.33; P = 0.03) and transmural extent versus LVEF (r = -0.27; P = 0.07) tended to be related. A correlation between infarct tissue characteristics and LV remodeling was found only in patients with early successful revascularization. Peri-infarct size was found to be the best determinant of LV remodeling. Our findings stress the importance of taking into account infarct tissue characteristics and success of revascularization when LV remodeling is studied. PMID- 23038084 TI - Maximal medical therapy for chronic rhinosinusitis: a survey of otolaryngology consultants in the United Kingdom. AB - BACKGROUND: The management of chronic rhinosinusitis is based on a trial of "maximal medical therapy" before surgery is considered. Ear-Nose-Throat (ENT) UK consultant members were surveyed to determine the role and variability of UK-wide practices. METHODS: A survey was posted to all ENT UK consultant members (n = 603). This assessed the frequency of prescription, duration, and type of oral antibiotics, steroids, and antihistamines for chronic rhinosinusitis. RESULTS: A total of 158 questionnaires (26.3%) were returned. Of these, 61% were primarily rhinologists. The use of decongestants, antifungals, and immunotherapy was generally limited. Oral antibiotics were often used, with clarithromycin of <5 weeks duration being the preferred choice. Sixty-one percent of consultants always prescribe a steroid spray, most commonly mometasone furoate (75%). CONCLUSION: Although most respondents use triple therapy of oral antibiotics, steroid nasal spray, and saline douching to some extent, "maximal medical therapy" for chronic rhinosinusitis seems to vary greatly among consultants and frequently does not reflect recent guidelines. PMID- 23038086 TI - Site of transmural late gadolinium enhancement on the cardiac MRI coincides with the ECG leads exhibiting terminal QRS distortion in patients with ST-elevation myocardial infarctions. AB - Large infarcts are associated with a terminal QRS-distortion in ST-elevation myocardial infarction (STEMI) patients. Late gadolinium enhancement (LGE) on the cardiac MRI (CMR) can depict an infarct distribution. However, less is known about the relationship between the LGE findings and QRS-distortion on admission, including the best ECG-lead location to reveal the QRS-distortion (DIS-lead) in STEMI patients. Fifty STEMI patients successfully treated with percutaneous coronary intervention were classified into two groups according to whether the QRS-distortion was positive (+) or negative (-). The LGE on a recent CMR was classified into 12 left ventricular segments (Basal-Middle-Apical * Anterior Septal-Inferior-Lateral). The coincidences between the segmental LGE scores and DIS-lead were investigated. All patients were divided into 23 QRS-distortion (+) and 27 QRS-distortion (-) groups. The total LGE score was significantly greater in the QRS-distortion (+) group (14.7 +/- 6.8 versus 9.6 +/- 6.2, P < 0.01). The highest LGE score in 96% of QRS-distortion (+) patients was 4, and a score 4 segment indicated a good selection of the DIS-lead (86.4%). QRS-distortion in the ECG on admission represents severe transmural infarction in the LGE using CMR, which represents large infarcts in STEMI patients. PMID- 23038087 TI - Prediction of inappropriate implantable cardioverter-defibrillator therapies through parameters obtained in a simple exercise stress test. AB - Although the clinical benefits of implantable cardioverter-defibrillators (ICDs) have been demonstrated, inappropriate therapies (IATs) cannot be completely avoided even with the most advanced devices. Recently, IATs are considered to decrease the ventricular function and prognosis of a patient. The aim of this study was to investigate the predictors of IAT with parameters during cardiopulmonary exercise stress test (CPX). Sixty consecutive ICD patients underwent symptom-limited CPX, and were divided into IAT (+) and IAT (-) groups. During and after CPX, ECG and hemodynamic parameters of systemic blood pressure, heart rate, and maximal O2 consumption (max VO2) were evaluated every minute. In selected patients, sympathetic and parasympathetic activities were evaluated with analyses of heart rate variability (HRV). No significant differences were observed in clinical background parameters. In the CPX parameters, only the maximal heart rate exhibited a significant difference between the IAT (+) group and the IAT (-) group (154.8 +/- 5.9 versus 137.9 +/- 4.2 beats per minute, P = 0.032), and LF/HF was higher during the recovery phase 4 minutes after peak exercise in the former group (4.5 +/- 1.0 versus 2.4 +/- 0.9, P = 0.021). In ICD patients, IAT can be predicted using simple parameters of increased sympathetic activity such as increased maximal heart rate and increased LF/HF ratio during and after the exercise stress test. PMID- 23038088 TI - Relation between connective tissue growth factor and cardiac sympathetic nerve activity in heart failure in DCM patients. AB - Cardiac fibrosis is an important process of myocardial remodeling. Connective tissue growth factor (CTGF) is a cytokine that plays a key role in the occurrence of progressive fibrosis and excessive scarring. CTGF levels are increased in the failing heart. In addition, sympathetic nerve activity is enhanced in the failing heart, and exacerbates heart failure. To clarify the relation between cardiac sympathetic nerve activity and CTGF, we studied 35 (M/F = 28/7 patients) aged 57 +/- 15 years with dilated cardiomyopathy (DCM). Cardiac sympathetic nerve activity was estimated from the total defect score (TDS) and from the H/M ratio and washout rate (WR) on I-123-MIBG imaging. Cardiac symptoms (NYHA class), exercise capacity (specific activity scale: SAS), brain natriuretic peptide (BNP), hemodynamics, and CTGF were assessed. There was a significant correlation between the CTGF and WR on I-123-MIBG (r = 0.45, P = 0.008). Also, a higher plasma CTGF level was associated with a lower SAS score (r = 0.51, P = 0.002), but not the TDS, H/M ratio, or BNP concentration. Moreover, a higher NYHA class and pulmonary artery wedge pressure were associated with a higher plasma CTGF level. The plasma CTGF level can be strongly related with cardiac sympathetic nerve activity in heart failure in DCM patients. PMID- 23038089 TI - Usefulness of high-sensitive cardiac troponin T for evaluating the activity of cardiac sarcoidosis. AB - Since early intervention using corticosteroids improves prognosis in some patients with cardiac sarcoidosis, early and accurate diagnosis of this clinical condition is important. However, it is still not easy to evaluate the activity of cardiac sarcoidosis in clinical practice. The aim of this study was to determine whether high-sensitive cardiac troponin T (hscTnT) is useful as an additional parameter to standard assessment in patients with cardiac sarcoidosis. Twelve patients who were diagnosed as having cardiac sarcoidosis at our institution were retrospectively studied. Evaluation of patients included clinical examinations, electrocardiography, echocardiography, 67-gallium-citrate (Ga) scintigraphy, 18F fluoro2-deoxyglucose positron emission tomography (18F-FDG PET) and laboratory data including hs-cTnT, angiotensin-converting enzyme (ACE), lysozyme and B-type natriuretic peptide (BNP). The activity of cardiac sarcoidosis was judged mainly by using 18F-FDG PET. Localized uptake of 18F-FDG, which was considered to be active cardiac sarcoidosis, was seen in 8 patients. Based on the findings of 18F FDG PET, hs-cTnT was considered to be a reliable parameter: sensitivity and specificity were 87.5% and 75.0%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) were 87.5% and 75.0%, respectively. On the other hand, these values in lysozyme and BNP markers were not as high as those in hs-cTnT. Although an ACE marker and Ga-67 scintigraphy showed specificity and PPV of 100%, both sensitivity and NPV were less than 50%. Furthermore, hs-cTnT levels decreased after steroid therapy in some patients. Hs cTnT seems to be a useful marker for evaluating the activity of cardiac sarcoidosis. PMID- 23038090 TI - Cardiac output response to exercise in chronic cardiac failure patients. AB - The purpose of this study was to investigate the precise pattern of stroke volume (SV) response during exercise in patients with chronic heart failure (CHF) compared with age-matched controls. Fourteen patients with CHF and 7 controls performed symptom-limited bicycle exercise testing with respiratory gas exchange measurement. Patients were classified into group A (n = 7) with peak VO2 >= 18.0 mL/kg/minute and group B (n = 7) with peak VO2 < 18.0 mL/kg/ minute. SV and cardiac output (CO) were continuously measured during exercise using a novel thoracic impedance method (Physioflow). CO and SV were lower in the group B patients than those in controls at peak exercise [CO: 11.3 +/- 1.0 (SE) versus 15.6 +/- 0.9 L/minute, P < 0.05, SV: 89 +/- 6 versus 110 +/- 6 mL, P < 0.05]. SV reached its peak levels during submaximal exercise and remained close to the peak value until peak exercise in 6 of 7 group B patients (86%). On the other hand, it progressively increased until peak exercise in 6 of 7 controls (86%) and 5 of 7 group A patients (71%). In all subjects, CO at peak exercise was more closely correlated with SV at peak exercise (r = 0.86, P < 0.001) than with peak heart rate (r = 0.69, P < 0.001). CHF patients with impaired exercise capacity had attenuated increment of CO during exercise, and SV reached its peak levels during submaximal exercise. PMID- 23038091 TI - Evaluation of left ventricular diastolic function according to new criteria and determinants in acromegaly. AB - Left ventricular diastolic dysfunction (LVDD) develops in the early stages of acromegaly. The purpose of this study was to identify LVDD analyzing by new echocardiograpic criteria as well as to evaluate determinants of the LVDD in acromegaly. This cross-sectional study examined 42 patients with acromegaly; 16 in active disease (AA) and 26 cured/ well controlled (CA), and compared them with 30 healthy controls (CG). Ventricular systolic and diastolic functions were studied by conventional and tissue Doppler imaging based on the E/Em ratio and myocardial performance index (MPI). Other clinical parameters possibly contributing to LVDD in acromegaly were also investigated. The prevalence of LV hypertrophy (33%) and LVDD (35.7%) were increased in acromegaly, however, there were no differences between the AA and CA groups. Acromegalic patients had higher LV volumes and LV mass, and septal E/Em ratio compared to CG, whereas LV ejection fraction and MPI were not different. The presence of acromegaly (r = 0.29, P = 0.013), diabetes mellitus (DM) (r = 0.41, P < 0.001), hypertension (r = 0.35, P = 0.002), and sleep apnea (r = 0.56, P = 0.003) were found to be correlated with LVDD, whereas duration and activity of acromegaly were not. In regression analysis, advanced age (OR: 8.53, P = 0.006) and DM (OR: 25.9, P = 0.007) were found to be independent risk factors for LVDD. The risk of LVDD according to new criteria increases in acromegaly. However, it seems to be related to the presence of DM and advanced age and is independent of disease duration and activity. PMID- 23038092 TI - High sensitivity C-reactive protein predicts nonresponders and cardiac deaths in severe heart failure patients after CRT implantation. AB - The purpose of this study was to determine whether high sensitivity C-reactive protein (hsCRP) before cardiac re-synchronization therapy (CRT) implantation was able to predict the response to CRT and cardiac deaths in severe heart failure patients. The study population consisted of 65 heart failure patients (46 males, mean age 65.0 +/- 11.8 years, NYHA class III/IV) with CRT implantation. Levels of hsCRP and B-type natriuretic peptide (BNP) were measured before CRT implantation. Left ventricular end-diastolic volume index (LVEDVI), left ventricular end systolic volume index (LVESVI), and left ventricular ejection fraction (LVEF) were assessed by echocardiography at the same time. At 6 months after device implantation follow-up, echocardiography was performed and reverse remodeling was defined as > 15% reduction in LVESV. Of the 61 patients (4 patients died within 6 months), 41 patients (67%) and 20 patients (33%) were classified as responders (group-R) and nonresponders (group-NR), respectively. Cardiac deaths occurred more frequently in group-NR than in group-R (29% versus 5%, P < 0.05). Hs-CRP level was significantly higher in group-NR than in group-R (P < 0.01). Multivariate logistic regression analysis showed an independent relationship between hsCRP and the incidence of nonresponders (odds ratio: 1.499, P = 0.011). Stepwise multivariate Cox proportional hazard analysis identified the hsCRP level as the strongest predictive factor for cardiac death (hazard ratio: 1.337, P = 0.001). Receiver operating characteristic (ROC) analysis revealed hsCRP levels of 3.0 mg/L as the cut-off value for cardiac mortality. The hsCRP level may provide a new insight into CRT implantation for severe heart failure by predicting responses to CRT and cardiac death. PMID- 23038094 TI - Comparison of analytical performance of two single-step measurement devices of B type natriuretic Peptide. AB - Rapid measurement of B-type natriuretic peptide (BNP) plays a practical role in the diagnosis of congestive heart failure. Analytical evaluation of a new small footprint immunochromatography reader of BNP (Rapidpia(r)) was performed and compared with the commercially available SHIONOSPOT(r) Reader as the index. The new BNP assay had a within-run coefficient of variation (CV) of 9.0% and a between-run CV of 2.1%. Correlations between whole blood and plasma samples and those with the index SHIONOSPOT(r) Reader were y = 0.93x + 0.88, R2 = 0.98 and y = 1.08x - 6.67, R2 = 0.93, respectively. Based on our findings, the two point-of care (POC) assays for BNP, Rapidpia(r) and SHIONOSPOT(r) Reader, showed comparable results. PMID- 23038093 TI - Long-term prognostic impact after acute kidney injury in patients with acute heart failure. AB - The relationship between the short-term prognosis of acute heart failure (AHF) and acute kidney injury (AKI) using the risk, injury, failure, and end stage (RIFLE) criteria has already been reported, however, the relationship between the long-term prognosis and AKI has not. We investigated the relationship between the long-term prognosis after discharge and AKI using the RIFLE criteria. Five hundred patients with AHF admitted to our intensive care unit were analyzed. Patients were assigned to a no AKI (n = 156), Class R (risk; n = 201), Class I (injury; n = 73), or Class F (failure; n = 70) using the most severe RIFLE classifications during hospitalization. We evaluated the relationships between the RIFLE classifications and any-cause death, and HF events including death and readmission for HF within 1 year. A multivariate logistic regression model found that Class I (P = 0.013, OR: 2.768; 95% CI: 1.236-6.199) and Class F (P < 0.001, OR: 7.920; 95% CI: 3.497-17.938) were independently associated with any-cause death, and Class F was associated with HF events (P = 0.001, OR: 3.486; 95% CI: 1.669-7.281). The Kaplan-Meier survival curves showed the prognosis, including death, to be significantly poorer in Class I than in no AKI and Class R, to be significantly poorer in Class F than in no AKI, Class R, and Class I, and the prognosis including HF events to be significantly poorer in Class F than in no AKI, Class R, and Class I. The presence of severe AKI (Class I and F) was independently associated with long-term mortality for AHF. PMID- 23038095 TI - Periodontal pathogen Aggregatibacter actinomycetemcomitans deteriorates pressure overload-induced myocardial hypertrophy in mice. AB - Although a relationship between periodontitis and myocardial hypertrophy has been reported, the precise mechanism has not been clarified. The purpose of this study was to investigate the association between periodontal infection and myocardial hypertrophy. Transverse aortic constriction (TAC) was performed. Mice were injected with Aggregatibacter actinomycetemcomitans (A.a.) (0.1 mL of 10(8) CFU/mL) in the infected group and PBS in the control group. Echocardiography, histopathology, and immunohistochemistry were performed. Echocardiography indicated that left ventricular fractional shortening had decreased in the infected group compared to the control group on day 28. Heart to body weight ratio increased in the infected group compared to the control group. Histopathologically, A.a.-infected mice showed markedly enhanced cardiac hypertrophy, fibrosis and arteriosclerosis 4 weeks after TAC operation. Immunohistochemistry revealed that expression of MMP-2 in the interstitial tissue was enhanced in the infected group. These results suggested that the periodontal pathogen caused a deterioration of pressure overload-induced myocardial hypertrophy through MMP activation. PMID- 23038097 TI - Retraction. Long-term survival after cardiac retransplantation: a single-center experience. PMID- 23038096 TI - Azelnidipine inhibits Msx2-dependent osteogenic differentiation and matrix mineralization of vascular smooth muscle cells. AB - Vascular calcification is an active and regulated process that is similar to bone formation. While calcium channel blockers (CCBs) have been shown to improve outcomes in atherosclerotic vascular disease, it remains unknown whether CCBs have an effect on the process of vascular calcification. Here we investigated whether CCBs inhibit osteogenic differentiation and matrix mineralization of vascular smooth muscle cells induced by Msx2, a key factor of vascular calcification. Human aortic smooth muscle cells (HASMCs) were transduced with adenovirus expressing MSX2 and were treated with 3 distinct CCBs. Azelnidipine, a dihydropyridine subclass of CCBs, significantly decreased alkaline phosphatase (ALP) activity of Msx2-overexpressed HASMCs, whereas verapamil and diltiazem had no effect. Furthermore, azelnidipine, but not verapamil and diltiazem, significantly decreased matrix mineralization of Msx2-overexpressing HASMCs. Azelnidipine significantly attenuated the induction of ALP gene expression by Msx2, a key transcription factor in osteogenesis, while it did not reduce enzymatic activity of ALP. Furthermore, azelnidipine inhibited the ability of Msx2 to activate the ALP gene, but had no effect on Notch-induced Msx2 expression. Given that L-type calcium channels are equally blocked by these CCBs, our results suggest that azelnidipine inhibits the Msx2-dependent process of vascular calcification by mechanisms other than inhibition of calcium channel activity. PMID- 23038098 TI - Production of p-xylene from biomass by catalytic fast pyrolysis using ZSM-5 catalysts with reduced pore openings. AB - Pores for thought: Chemical liquid deposition of silica onto ZSM-5 catalysts led to smaller pore openings that resulted in >90% selectivity for p-xylene over the other xylenes in the catalytic fast pyrolysis of furan and 2-methylfuran (see scheme). The p-xylene selectivity increased from 51% with gallium spray-dried ZSM 5 to 72% with a pore-mouth-modified catalyst in the pyrolysis of pine wood. PMID- 23038099 TI - Use of copper alloy for preventing transmission of methicillin-resistant Staphylococcus aureus contamination in the dermatology ward. AB - Metallic copper has been shown significantly to reduce methicillin-resistant Staphylococcus aureus (MRSA) contamination of the ambient surroundings of the beds of MRSA-carrying patients in dermatology wards. The aim of this study was to determine whether a bed sheet made of copper-coated film will reduce the spread of MRSA contamination in the environment of a heavily-colonized patient. The bacterial count was highest on the bed sheet. MRSA cell counts on the surface of the non-film-coated control sheet were high (6,600-11,000 colony forming units (cfu)), but those on the copper film were considerably lower (20-130 cfu). Use of metallic copper on the bed sheets of patients who are likely to be a source of MRSA contamination may help to prevent the spread of MRSA contamination in hospital wards. PMID- 23038100 TI - Surface orientation effects in crystalline-amorphous silicon interfaces. AB - In this paper we present the results of empirical potential and density functional theory (DFT) studies of models of interfaces between amorphous silicon (a-Si) or hydrogenated amorphous Si (a-Si:H) and crystalline Si (c-Si) on three unreconstructed silicon surfaces, namely (100), (110) and (111). In preparing models of a-Si on c-Si, melting simulations are run with classical molecular dynamics (MD) at 3000 K for 10 ps to melt part of the crystalline surface and the structure is quenched to 300 K using a quench rate of 6 * 10(12) K s(-1) and finally relaxed with DFT. Incorporating the optimum hydrogen content in a-Si to passivate undercoordinated Si, followed by DFT relaxation, produces hydrogenated amorphous silicon on crystalline surfaces, a-Si:H/c-Si. The (100) surface is the least stable crystalline surface and forms the thickest amorphous Si region, while the most stable (110) surface forms the smallest amorphous region. Calculated radial distribution functions (RDF) in the amorphous and crystalline layers are consistent with a-Si and c-Si and indicate a structural interface region one layer thick. The electronic density of states shows an evolution from c-Si to a-Si (or a-Si:H), with a larger electronic interface layer, suggesting that the electronic properties are more strongly perturbed by interface formation compared to the atomic structure. The computed optical absorption spectra show strong effects arising from the formation of different a-Si and a-Si:H regions in different Si surfaces. PMID- 23038101 TI - Control of circularly polarized luminescence by using open- and closed-type binaphthyl derivatives with the same axial chirality. AB - The solution-dispersed-state and polymer-dispersed-state circular dichroism (CD) and circularly polarized luminescence (CPL) properties of chiral binaphthyl fluorophores could be controlled by the choice of open- or closed-type substituents on the binaphthyl units and by the axial chirality of the binaphthyls. PMID- 23038102 TI - The effects of vagus nerve stimulation on pro- and anti-inflammatory cytokines in children with refractory epilepsy: an exploratory study. AB - OBJECTIVES: The vagus nerve has important immunological and anti-inflammatory actions that might be relevant to the beneficial effects of vagus nerve stimulation (VNS). Therefore, we conducted an exploratory study on VNS effects on cytokine levels in plasma and cerebrospinal fluid of children suffering from refractory epilepsy. Moreover, as predictors of the response are lacking, we also aimed to determine if cytokine changes predict the clinical response. METHODS: VNS was performed according to a randomized double-blind design: plasma levels were compared between patients who received 20 weeks of high output (therapeutic) (n = 21) or low output (active control) stimulation (n = 20). Thereupon, all patients received high output stimulation for another 19 weeks; levels during this period were compared to baseline. Interictal interleukin-1beta, interleukin 6, and interleukin-10 were determined by ELISA. RESULTS: No significant changes were found between high and low output groups and between the last 19 weeks of stimulation and baseline. Changes in interleukin-1beta correlated with improved IQ (tau = 0.42, p < 0.01). Lower baseline plasma levels of interleukin-6 were associated with more seizure frequency reduction [R(2) = 0.105 (1, 35), p = 0.050]. CONCLUSION: Interictal cytokine levels were not altered by VNS but baseline interleukin-6 predicted the clinical response. In the future, patient selection may be aided by determination of the cytokine profile of the patient. PMID- 23038104 TI - More author disclosure: solution or absolution? PMID- 23038105 TI - Climate change: how can epidemiology best inform policy? PMID- 23038103 TI - Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate Via MLL histone methylase complex. AB - BACKGROUND: Chromatin regulators ANCCA and EZH2 are overexpressed in prostate cancer and play crucial roles in androgen-stimulated and castration-refractory prostate tumor growth and survival. However, how their expression is regulated in the tumors and whether they play a role in prostate development remains unclear. METHODS: Prostate tissue from different developmental stages of mouse and human were examined by IHC, qRT-PCR and Western for expression of ANCCA, EZH2, and Ki 67. Animals were castrated and T-implanted for the expression response in normal prostate and tumors. siRNA knockdown and ChIP were performed for the mechanism of ANCCA regulation of EZH2. RESULTS: In contrast to their very low level expression in adult prostate, ANCCA and EZH2 are strongly expressed in the epithelium and mesenchyme of mouse and human UGS. Their expression becomes more restricted to epithelial cells during later development and displays a second peak during puberty, which correlates with the proliferative status of the epithelium. Importantly, their expression in normal prostate and tumors is strongly suppressed by castration and markedly induced by testosterone replacement. While androgen suppresses EZH2 in CRPC cells, in LNCaP cells, physiological concentrations of androgen stimulate expression of PRC2 genes (EZH2, SUZ12, and EED), which is mediated by androgen-induced ANCCA and involves E2F and histone H3K4me3 methylase MLL1 complex. CONCLUSION: EZH2 and ANCCA are androgen regulated and strongly expressed in early prostate morphogenesis and during puberty, suggesting their important role in prostate development. Regulation of EZH2 by ANCCA emphasizes bromodomain protein ANCCA as a potential therapeutic target against prostate cancer. PMID- 23038106 TI - Epidemiologic methods are useless: they can only give you answers. PMID- 23038107 TI - What, me worry? Chemicals and causality. PMID- 23038108 TI - Infant feeding and growth: can we answer the causal question? PMID- 23038109 TI - Social epidemiology: questionable answers and answerable questions. PMID- 23038110 TI - Time-series analyses of count data to estimate the burden of seasonal infectious diseases. PMID- 23038112 TI - Understanding counterfactual-based mediation analysis approaches and their differences. PMID- 23038113 TI - Dynamic aspects of exposure history-do they matter? PMID- 23038114 TI - Reclassify controls at your own risk. PMID- 23038115 TI - To Correct or Not to Correct-and How. PMID- 23038116 TI - Bridging the gap between knowledge and health: the epidemiologist as Accountable Health Advocate ("AHA!"). AB - Epidemiology occupies a unique role as a knowledge-generating scientific discipline with roots in the knowledge translation of public health practice. As our fund of incompletely-translated knowledge expands and as budgets for health research contract, epidemiology must rediscover and adapt its historical skill set in knowledge translation. The existing incentive structures of academic epidemiology - designed largely for knowledge generation - are ill-equipped to train and develop epidemiologists as knowledge translators. A useful heuristic is the epidemiologist as Accountable Health Advocate (AHA) who enables society to judge the value of research, develops new methods to translate existing knowledge into improved health, and actively engages with policymakers and society. Changes to incentive structures could include novel funding streams (and review), alternative publication practices, and parallel frameworks for professional advancement and promotion. PMID- 23038117 TI - The pursuit of universal health advocacy. PMID- 23038118 TI - What's an Epidemiologist to Do? PMID- 23038119 TI - The epidemiologist as Accountable Health Advocate ("AHA!"): a useful model for promoting health. PMID- 23038121 TI - Virus interference and estimates of influenza vaccine effectiveness from test negative studies. PMID- 23038122 TI - Comparing bounds for vaccine effects on infectiousness. PMID- 23038123 TI - Superwarfarin rodent poisons and hemorrhagic disease. PMID- 23038124 TI - Lasagna plots made in different (statistical) ovens. PMID- 23038125 TI - Comparing ratings of occupational physical activity. PMID- 23038126 TI - Does risk compensation undo the protection of ski helmet use? PMID- 23038127 TI - Estimation with vanishing baseline risk. PMID- 23038128 TI - Candidates at risk for postnatal outcomes. PMID- 23038130 TI - Current evidence for postoperative monitoring of microvascular free flaps: a systematic review. AB - BACKGROUND: Despite a plethora of monitoring techniques reported in the literature, only a small number of studies directly address clinical relevant end points, such as the flap salvage rate and false-positive rate. METHOD: We conducted a systematic review of current evidence regarding the postoperative monitoring of microvascular free-tissue transfer via extensive electronic and manual search and perusing databases, such as PubMed, Cochrane, American College of Physicians (ACP) Journal Club, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Excerpta Medica Database (EMBASE), and Ovid MEDLINE. The included literature (n = 184 publications) was critically appraised using March 2009 Oxford Centre for Evidence-Based Medicine definitions, focusing on the evidence for the efficacy of each technique in improving the flap salvage rate of compromised flaps. RESULT: There is a paucity of outcome-based studies, with only implanted Doppler probes, near-infrared spectroscopy, laser Doppler flowmetry, quantitative fluorimetry, and digital photography assessment using smartphones having been demonstrated in comparative studies to improve flap salvage rate. Currently, the implantable Doppler probe is the technique with the largest number of comparative studies and case series to demonstrate its effectiveness compared with clinical monitoring. CONCLUSIONS: Future studies need to evaluate the most promising monitoring techniques further with a focus on assessing clinically relevant outcomes, such as the flap salvage rate and the false-positive rate, and not simple clinical series reporting patient and physician satisfaction. PMID- 23038132 TI - Fellowship review: ReSurge International: the Jerome P. Webster fellowship. PMID- 23038133 TI - Humanitarian work: a trainee's perspective. PMID- 23038134 TI - Facing the World: the evolution of a craniofacial charity. PMID- 23038135 TI - The Regan fellowship: a window into international surgical care. PMID- 23038136 TI - A cost-effective and simple electronic solution to communication with patients with tracheostomy in a burns and intensive care setting. AB - INTRODUCTION AND AIMS: Ventilated patients in ITU (intensive treatment unit) tend to be challenging to communicate with, especially patients who are being weaned. These patients usually have tracheostomy in situ and use means such as writing or letter boards to communicate. The situation becomes complex in patient groups that have burn injuries with bulky dressings and restricted upper limb function. We demonstrate a low cost, easy to use, potentially disposable system that can display words on any television screen via patient input device for such patient groups. MATERIALS AND METHODS: The system consists of input device incorporated with Arduino microcontroller (an open-source electronics prototyping platform based on easy-to-use hardware and software intended for creating interactive environments) and 4 generously oversized control buttons. These are used to control the cursor movements (up, down, left, right) while a fifth has a "select" function. These are large enough to be pressed by an entire bandaged hand using gross upper limb movements only. A standard television is used to display menu containing the 26 letters of the alphabet and a flashing cursor. The patient selects the required letters/icon by moving the cursor and the words so created are displayed along the lower part of the screen for the carers to read. It is envisaged that anyone with basic craft skills should be able to construct this device. CONCLUSION: This device is a self-contained, cost-effective, simple, and open-source system that can be used effectively to bridge the communication gap with significant potential for patient care globally. PMID- 23038137 TI - Fellowship review: the Jerome P. Webster Fellowship. PMID- 23038138 TI - Constructing the philtral column in the secondary cleft lip deformity: utilizing the palmaris longus graft. AB - BACKGROUND: The philtrum and the Cupid's bow are the most prominent features of the upper lip and are crucial for normal appearance. Unfortunately, projection of the philtral column is a common deficiency of the repaired cleft lip. Although a multitude of methods for constructing the philtral dimple and ridge have been described, no single procedure has achieved complete satisfactory results. The authors describe their technique for construction of the philtral column using palmaris longus tendon. METHODS: Between 1998 and 2009, a retrospective study was performed for identifying patients with depression of the philtral scar following cleft lip repair. Pre- and postoperative photographs were taken with at least 6 months follow-up. Postoperative patient satisfaction and occurrence of complications are reported. RESULTS: In all, 17 patients who developed depression of the philtral ridge following cleft lip repair underwent philtral reconstruction utilizing palmaris longus tendon grafts by the senior author (H.K.K.). At the time of surgery, average age for 11 females and 6 males was 18.5 years. The follow-up period ranged from 6 to 126 months, with an average of 42.3 months. In the early postoperative period, 2 complications in the form of graft exposure occurred. However, both cases were successfully managed with preservation of the graft. All patients were satisfied with their long-term results, and none required further surgery. CONCLUSIONS: The use of palmaris longus tendon graft is an effective, reproducible, and safe method by which to construct the philtral column in the secondary cleft lip deformity. PMID- 23038139 TI - Fellowship review: interface reconstructive cosmetic surgery fellowship at leicester. PMID- 23038140 TI - The superficial fascia as a new plane of elevation for anterolateral thigh flaps. AB - The elevation plane for the anterolateral thigh perforator flap is either subfascial or suprafascial approach. But extensive debulking is frequently performed with possibilities of endangering viability. We hypothesized that by elevating the flap in the layer between the deep and the superficial fat, the superficial fascia, we will be able to achieve elevation of a thin and hemodynamically reliable flap without wasting human tissue. This approach was performed on 54 cases. The average weight was 68.1 kg, and average body mass index was 24.6 kg/m. Primary closure was performed on 18 cases and skin grafts on 36 cases. Evaluation for flap survival, contour of the flap, and donor site were performed. All 54 flaps were successfully elevated with at least one viable perforator with this approach. Total flap loss was noted in 1 case, resulting in a 98% survival rate. Secondary debulking was performed on 3 cases whose body mass index was >29. Regarding donor site, the primarily closed sites showed no complications, and the grafted skin over the deep fat leads to similar contour compared with the contralateral side. The study shows that this new plane can be used as a level of elevation while acting as a guide to promise adequate blood supply based on the subdermal plexus. PMID- 23038141 TI - Body contouring after bariatric surgery: how much is really being done? AB - The proportion of postbariatric surgery patients who undergo body contouring (BC) procedures is unknown. We designed a study to explore demographic features and patient education regarding BC in the bariatric surgery (BS) population. A survey was mailed to 1158 patients who underwent BS by 2 surgeons between 2003 and 2011. A total of 284 (24.5%) patients responded. Seventy-two patients (25.4%) reported discussing BC surgery with their bariatric surgeon perioperatively. Forty patients (14.1%) were referred for plastic surgery consultation. Thirty-three patients (11.6%) underwent BC procedures. The most frequent reasons cited for not undergoing BC were expense (29.2%) and lack of awareness regarding options (23.6%). Thirty-nine percent of respondents reported that they might have chosen differently, had they received more information. As a result of insufficient perioperative counseling, the majority of BS patients are unaware of the multitude of BC procedures available. Additional efforts toward improving patient (and surgeon) education regarding postbariatric BC options are warranted. PMID- 23038142 TI - Bed isolation in experimental flap studies in rats: a dispensable procedure. AB - Review of the literature regarding rodent experimental flap models reveals fundamental differences in applied surgical procedures. Although some authors isolate the flap from its wound bed, others do not. This study was planned to investigate to what extent the insertion of a silicone sheet affects physiological wound healing in experimental flap surgery. An extended epigastric adipocutaneous flap (6 * 10 cm) was raised in 16 male Lewis rats. In the control group (group C), flaps were immediately inset without any intervention. In the experimental group (group M), a silicone sheet barrier was placed between the flap and the wound bed. Mean flap survival area and flap perfusion were evaluated. Microvessel density was visualized by immunohistochemistry, and semiquantitative real-time polymerase chain reaction addressed differential gene expression. All animals were investigated on postoperative day 5. Flap survival area and flap perfusion were found to be similar. Immunohistochemistry, however, demonstrated a significantly increased number of CD31-positive small vessels in group C. The insertion of the silicone sheet barrier (group M) was accompanied by a significantly enhanced expression of proinflammatory genes and a suppression of proangiogenic genes. Our results show that although the silicone membrane has no influence on the surgical outcome in terms of flap survival and perfusion, it does lead to significant molecular alterations in pathways involved in physiological wound healing. These alterations are artificially induced by the foreign body material and conceal the true driving forces of the healing process. As the latter might include relevant therapeutic targets to ameliorate surgical results, we regard wound bed isolation as a dispensable procedure in the study of rodent flap models. PMID- 23038144 TI - Bacillary angiomatosis presenting as a pyogenic granuloma of the hand in an otherwise apparently healthy patient. AB - Bacillary angiomatosis is a rare opportunistic infection caused by the gram negative bacteria Bartonella. The infection is strongly related to human immunodeficiency virus (HIV) infection, and hence, the diagnosis is usually considered based on the fact that the patient is HIV positive. We report on a case of bacillary angiomatosis presenting as a pyogenic granuloma of the hand in an otherwise apparently healthy man. The report is aimed to increase the awareness of hand surgeons that this serious disease may be the first clinical manifestation of HIV infection. The case also demonstrates that once the correct diagnosis is made, medical treatment alone may be sufficient to cure massive recurrent lesions. PMID- 23038143 TI - LEC score: a judgment tool for indication of indocyanine green lymphography. AB - Indocyanine green (ICG) lymphography is becoming popular in evaluation of lymphedema. However, indication of ICG lymphography is yet to be cleared. To solve this problem, Latency-Edema-Compression (LEC) score, which could be calculated solely from history taking, was developed based on a linear disease progression model. In 62 limbs of 31 patients with secondary lower extremity lymphedema, LEC scores were calculated and compared with corresponding dermal backflow (DB) stage of ICG lymphography. The LEC scores statistically correlated well with the DB stages (r = 0.713, P < 0.001). The DB stages in limbs with LEC scores smaller than 3.7 (n = 32) were significantly lower than those in limbs with LEC scores of >=3.7 (n = 30) (1.3 +/- 0.5 vs. 2.8 +/- 0.7, P < 0.001). The LEC score can be used to determine whether further examination is necessary in outpatient assessment of new secondary lymphedema cases. PMID- 23038145 TI - Single-donor allogeneic platelet fibrin glue and osteoconductive scaffold in orbital floor fracture reconstruction. AB - BACKGROUND: Commonly used materials for orbital floor fracture reconstruction include autologous cranial bone graft and titanium mesh. We have evaluated here a biomaterial combining biphasic calcium phosphate (hydroxyapatite [HA]/beta tricalcium phosphate [TCP]) osteoconductive scaffold with single-donor allogeneic platelet fibrin glue. METHODS: The study was conducted on 10 consecutive patients with a follow-up of up to 4 years. Platelet fibrin glue was prepared by mixing equal volumes of single-donor platelet-rich plasma and cryoprecipitate with HA/beta-TCP followed by activation with human thrombin prepared by plasma activation. Postoperative evaluations included serial photographs, repeated physical examination, and 3-dimensional computed tomography scan performed 2 years after surgery. RESULTS: The fibrin-rich platelet biomaterial was easy to mold and to apply on the surgical site allowing the surgeon to sculpt accurately the bone defect, providing mechanical stability while avoiding spillage of the scaffold. No infection of the orbit or extrusion of HA/beta-TCP was observed. Ocular motility was normal, and no diplopia or enophthalmos of the injured orbit was noted. Coronal computed tomography scans of the reconstructed orbits revealed good restoration of the orbital floor defect in all 10 patients. CONCLUSIONS: The use of single-donor platelet fibrin glue combined with an osteoconductive scaffold offers a valuable alternative to autologous cranial bone graft or titanium mesh in the reconstruction of orbital floor bone defect. PMID- 23038146 TI - Medical student perceptions of the scope of plastic and reconstructive surgery. AB - BACKGROUND: The scope of plastic surgery is not well understood by people outside the field. Better educating medical students about plastic surgery may improve understanding of the field, establish appropriate referral patterns early on, and assist with career decision-making. The purpose of this study was to assess medical student understanding of plastic surgery and to analyze the impact of prior plastic surgery clinical exposure on this understanding. METHODS: An online survey consisting of 24 clinical scenarios was administered to medical students of the University of Utah. After indicating their level of training and whether they had prior clinical exposure to plastic surgery or other surgical subspecialties, students selected one or more appropriate surgical subspecialties to manage each scenario. RESULTS: Of 408 students, 230 (56.4%) responded to the survey. Prior clinical exposure to plastic surgery was reported by 15.8% to 29.4% of students (first to fourth year). Overall, 92% of students chose at least one acceptable surgical specialty for referral. Plastic surgery was selected by only 54% of students for all conditions, and this did not improve throughout medical school. Senior students (third and fourth years) with prior plastic surgery exposure chose plastic surgery more often than those without prior exposure (71% vs. 51%, P < 0.0001). Plastic surgery was chosen most frequently for rhinoplasty and breast reconstruction and less frequently for hand/peripheral nerve surgery and wound surgery. CONCLUSIONS: Improved medical student education about the scope of plastic surgery is needed, especially in the areas of hand/peripheral nerve surgery and general reconstructive surgery. PMID- 23038147 TI - Management of the ptotic or hypertrophic breast in immediate autologous breast reconstruction: a comparison between the wise and vertical reduction patterns for mastectomy. AB - BACKGROUND: The Wise pattern can be used in mastectomies to address the excess skin in the ptotic or hypertrophic breast; however, limitations include mastectomy flap necrosis (MFN) and poor shape. The vertical pattern can potentially reduce the amount of MFN with improved aesthetic results. This study compares the Wise and vertical mastectomy patterns in immediate, autologous breast reconstruction. METHODS: Thirty-three patients with grade 2 or 3 ptosis who elected to undergo immediate, autologous breast reconstruction were prospectively recruited into 2 nonrandomized cohorts. Of total, 17 patients (26 reconstructions) had Wise pattern and 16 (28 reconstructions) had vertical pattern. All patients were followed for MFN, time for wound healing, and postoperative complications. Patient and surgeon surveys rated the aesthetics of the reconstructions. RESULTS: The 2 groups did not differ in age, body mass index, smoking, or breast measurements. The Wise group had significantly larger areas of MFN, higher number of postoperative visits, and longer wound-healing periods, compared with the vertical group (P < 0.05). There was no difference in time to adjuvant therapy or additional procedures. Patient surveys rated both incisions with equal satisfaction, except for symmetry that rated better in the Wise group. Surgeon surveys showed better scores for the vertical incision. CONCLUSIONS: The Wise pattern is associated with significantly more MFN and prolonged wound care. Despite this complication, patients rate their breast reconstructions favorably, regardless of the type of incision. Both the Wise and vertical patterns can be safely used in skin-sparing mastectomies with immediate, autologous breast reconstruction with good aesthetic outcomes. The authors recommend the vertical pattern because of less MFN and surgeon-preferred aesthetics. PMID- 23038148 TI - Effects of platelet-rich plasma on proliferation and myofibroblastic differentiation in human dermal fibroblasts. AB - Platelet-rich plasma (PRP) is plasma that is produced from autologous blood, and its usefulness in plastic surgery and dermal wound healing has garnered attention in recent years. The aim of this study was to investigate the effects of PRP and platelet-poor plasma on the proliferation and differentiation of skin fibroblasts into myofibroblasts and on wound contraction using Western blotting, immunofluorescence staining, and collagen gels containing an embedded fibroblast model. PRP promotes proliferation of human dermal fibroblasts. PRP addition enhanced the expression of alpha-smooth muscle actin protein, a myofibroblast marker, as shown by immunofluorescence staining and Western blotting. PRP-treated groups demonstrated more marked contraction in the collagen gel model than the platelet-poor plasma and vehicle groups. PRP promotes proliferation, causes the differentiation of human dermal fibroblasts into myofibroblasts and promotes wound contraction, thus providing a potential therapeutic agent for skin wound healing. PMID- 23038149 TI - Autologous fat grafting in secondary breast reconstruction. PMID- 23038150 TI - Cognitive-behavioral therapy for schizophrenia: a critical evaluation of its theoretical framework from a clinical-phenomenological perspective. AB - BACKGROUND: Cognitive-behavioral therapy (CBT) has played an increasingly important role in psychotherapy for schizophrenia since the 1990s, but it has also encountered many theoretical and practical limitations. For example, methodologically rigorous meta-analyses have recently found only modest overall effect sizes of CBT treatment, and therefore questions have emerged about forwhat and for whom it actually works. METHOD: The focus of the present paper is to elucidate the theoretical assumptions underlying CBT for schizophrenia and to examine their consistency with abnormalities of experience and self-awareness frequently reported by schizophrenia patients and systematically studied in phenomenological psychopathology from the beginning of the 20th century. RESULTS: We argue that a strong theoretical emphasis on cognitive appraisals with only subsidiary attention devoted to affective and behavioral processes - as is characteristic of many forms of CBT - cannot satisfactorily account for the complex subjective experiences of schizophrenia patients. We further argue that certain theoretical strategies widely employed in CBT to explore and explain mental disorders, which involve atomization and, at times, a reification of mental phenomena, can be problematic and may result in a loss of explanatory potential. Finally, we provide a detailed account of how negative symptoms and delusions are conceptualized in CBT and consider the question of how these concepts fit the actual phenomenology of schizophrenia. CONCLUSION: We suggest that further advancement of CBT theory and practice can benefit from a dialogue with phenomenological psychiatry in the search for effective psychotherapeutic strategies for schizophrenia patients. PMID- 23038151 TI - Hydrogenated Li(4)Ti(5)O(12) nanowire arrays for high rate lithium ion batteries. AB - Self-supported Li(4) Ti(5) O(12) nanowire arrays with high conductivity architectures are designed and fabricated for application in a Li-ion battery. The Li(4) Ti(5) O(12) nanowire arrays grow directly on Ti foil by a facile solution-based method, further enhancing Li-ion storage properties by creating Ti(3+) sites through hydrogenation. This configuration ensures that every Li(4) Ti(5) O(12) nanowire participates in the fast electrochemical reaction, enabling remarkable rate performance and a long cycle life. PMID- 23038152 TI - Established and novel methods of interrogating two-dimensional cell migration. AB - The regulation of cell motility is central to living systems. Consequently, cell migration assays are some of the most frequently used in vitro assays. This article provides a comprehensive, detailed review of in vitro cell migration assays both currently in use and possible with existing technology. Emphasis is given to two-dimensional migration assays using densely organized cells such as the scratch assay. Assays are compared and categorized in an outline format according to their primary biological readout and physical parameters. The individual benefits of the various methods and quantification strategies are also discussed. This review provides an in-depth, structured overview of in vitro cell migration assays as a means of enabling the reader to make informed decisions among the growing number of options available for their specific cell migration application. PMID- 23038153 TI - Retinal ganglion cell topography and spatial resolving power in penguins. AB - Penguins are a group of flightless seabirds that exhibit numerous morphological, behavioral and ecological adaptations to their amphibious lifestyle, but little is known about the topographic organization of neurons in their retinas. In this study, we used retinal wholemounts and stereological methods to estimate the total number and topographic distribution of retinal ganglion cells in addition to an anatomical estimate of spatial resolving power in two species of penguins: the little penguin, Eudyptula minor, and the king penguin, Aptenodytes patagonicus. The total number of ganglion cells per retina was approximately 1,200,000 in the little penguin and 1,110,000 in the king penguin. The topographic distribution of retinal ganglion cells in both species revealed the presence of a prominent horizontal visual streak with steeper gradients in the little penguin. The little penguin retinas showed ganglion cell density peaks of 21,867 cells/mm2, affording spatial resolution in water of 17.07-17.46 cycles/degree (12.81-13.09 cycles/degree in air). In contrast, the king penguin showed a relatively lower peak density of ganglion cells of 14,222 cells/mm2, but -due to its larger eye--slightly higher spatial resolution in water of 20.40 cycles/degree (15.30 cycles/degree in air). In addition, we mapped the distribution of giant ganglion cells in both penguin species using Nissl-stained wholemounts. In both species, topographic mapping of this cell type revealed the presence of an area gigantocellularis with a concentric organization of isodensity contours showing a peak in the far temporal retina of approximately 70 cells/mm2 in the little penguin and 39 cells/mm2 in the king penguin. Giant ganglion cell densities gradually fall towards the outermost isodensity contours revealing the presence of a vertically organized streak. In the little penguin, we confirmed our cytological characterization of giant ganglion cells using immunohistochemistry for microtubule-associated protein 2. This suite of retinal specializations, which is also observed in the closely related procellariiform seabirds, affords the eyes of the little and king penguins panoramic surveillance of the horizon and motion detection in the frontal visual field. PMID- 23038154 TI - Selective RNA versus DNA G-quadruplex targeting by in situ click chemistry. AB - It all clicks into place: A potent telomere-targeting small molecule has been identified by using the copper-free 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks catalyzed by a non-Watson-Crick DNA secondary structure (see picture). This method rapidly identifies, otherwise unanticipated, potent small-molecule probes to selectively target a given RNA or DNA. PMID- 23038155 TI - [Endometriosis: the gynecologist's opinion]. AB - Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. Endometriosis affects 7-10% of women of reproductive age, 60% of women with pelvic pain, and up to 50% of women with infertility. Etiology and pathogenesis of the disease are still unclear, with the theory of retrograde menstruation, and possibly associated cofactors, as the most important. The definitive method to diagnose endometriosis is visualization at surgery, preferably at laparoscopy, with histology confirmation of disease. The revised classification of the American Society for Reproductive Medicine is used to stage the disease and determine the patient's prognosis. The treatment of the disease depends on the patient's age, associated symptoms, and disease stage. Medical or surgical therapy may be used in case of pain associated with endometriosis, whereas surgery is the mainstay of treatment in case of endometriosis-associated infertility. PMID- 23038156 TI - Transformation of an antimicrobial peptide into a plasma membrane-permeable, mitochondria-targeted peptide via the substitution of lysine with arginine. AB - Simple substitution of D-lysine with D-arginine in antimicrobial peptide (RLA) considerably improved its membrane permeability and increased mitochondrial accumulation. The potential use of RLA in preventing apoptotic cell death is also demonstrated through delivery of the Bcl-x(L) BH4 domain peptide. PMID- 23038157 TI - Granulocyte macrophage colony-stimulating factor in 66 patients with myeloid or lymphoid neoplasms and recipients of hematopoietic stem cell transplantation with invasive fungal disease. AB - BACKGROUND/AIMS: Adding granulocyte macrophage colony-stimulating factor (GM-CSF) may improve the response to antifungal therapy in immunosuppressed patients with invasive fungal disease (IFD). METHODS: We retrospectively assessed 66 patients in whom GM-CSF was given during antifungal therapy. RESULTS: Severe neutropenia (77%) and refractory/relapsed cancer (65%) were common in the group. Prior to GM CSF therapy, 15% of patients received high-dose corticosteroids for a median of 30 +/- 16 days [median cumulative dose (c.d.) 1,184 +/- 1,019 mg], and 9 received steroids during GM-CSF therapy for a median of 16 +/- 12 days (median c.d. 230 +/ 1,314 mg). Mild toxic effects were noted in 9% of patients; there were no cases of cardiopulmonary toxicity. All-cause deaths were observed in 68% of patients and 48% died of progressive IFD. High-dose corticosteroids prior to GM-CSF (OR 24; 95% CI 2.21-264.9; p <= 0.009), GM-CSF started in the intensive care unit (OR 10; 95% CI 1.66-63.8; p <= 0.01), concurrent granulocyte transfusions (OR 5; 95% CI 1.27-16.8; p <= 0.02) and proven/probable IFD (OR 4; 95% CI 1-16.2; p <= 0.05) predicted antifungal treatment failure. CONCLUSIONS: GM-CSF adjuvant therapy was tolerated without serous toxicity and antifungal treatment failure remained a challenge in patients treated with high-dose systemic corticosteroids. PMID- 23038158 TI - The APE1 Asp/Asp genotype and the combination of APE1 Asp/Asp and hOGG1-Cys variants are associated with increased p53 mutation in non-small cell lung cancer. AB - BACKGROUND: The hOGG1 Ser326Cys polymorphism is associated with lung cancer risk, but there are limited data regarding an association between the APE1 Asp148Glu polymorphism and lung cancer. Biological evidence shows that the hOGG1-Cys allele results in less DNA repair activity; however, this is not associated with p53 mutation in lung cancer. Therefore, we investigated whether an interaction between hOGG1 and APE1 is associated with the frequency of p53 mutation in lung cancer. METHODS: We studied 217 Taiwanese adults with primary lung cancer. DNA polymorphisms of hOGG1 and APE1 were determined by polymerase chain reaction (PCR)-based restriction fragment length polymorphism. Mutations in p53 exons 5-8 were detected by direct sequencing. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% CIs for the risk of p53 mutation associated with polymorphisms of hOGG1 and APE1 in lung cancer. RESULTS: As expected, no association between hOGG1 polymorphism and p53 mutation was observed in this population. However, a higher risk of p53 mutation was found in participants with the APE1 Asp/Asp genotype than in those with the APE1-Glu allele (OR, 2.15; 95% CI, 1.19-3.87; P = 0.011). The risk of p53 mutation was also higher in participants with APE1 Asp/Asp plus hOGG1-Cys than in those with APE1-Glu plus hOGG1 Ser/Ser (OR, 3.72; 95% CI, 1.33-10.40; P = 0.012). CONCLUSIONS: These results suggest that the APE1 Asp/Asp genotype and the combination of the APE1 Asp/Asp and hOGG1-Cys variants are associated with increased risk of p53 mutation in non-small cell lung cancer. PMID- 23038159 TI - Multiparametric functional nuclear magnetic resonance imaging shows alterations associated with plasmid electrotransfer in mouse skeletal muscle. AB - BACKGROUND: In vivo gene electrotransfer is frequently used in preclinical gene therapy. Many studies have attempted to optimize protocols efficiency at the same time as reducing muscle damage. Most of them have reported histological evidence of muscle degeneration and completion of regeneration within 15 days. The functional consequences have rarely been addressed, which may reflect the lack of appropriate techniques. Yet, it is important to characterize the changes induced by the procedure itself because it may interfere with therapy. We used multiparametric functional (mpf)-nuclear magnetic resonance (NMR) imaging to evaluate mice hindlimb muscle after electrotransfer of an empty plasmid. METHODS: NMR experiments were performed in a 4T Bruker magnet. Arterial spin labeling imaging of perfusion and blood oxygenation level dependent contrast and (31) P spectroscopy of phosphocreatine kinetics and pH were simultaneously acquired from the mice hindlimb during 2 min of electrically stimulated exercise and recovery. RESULTS: After 15 days, hindlimb cross-sectional area decreased by 10% compared to control mice. Specific force-time integral and end-exercise pH were identical in both groups, whereas oxidative capacities increased. Perfusion values doubled, and oxygenation significantly decreased. Histology revealed: (i) degeneration/regeneration; (ii) a decrease in type IIb fibers and an increase in type I and IIa fibers; and (iii) increased capillary density. CONCLUSIONS: In this model, loss in muscle mass was accompanied by important alterations of perfusion and bioenergetics. Fifteen days after electrotransfer, this was correlated with fiber type shift, capillary bed remodeling and degeneration/regeneration. mpf-NMR provides new insights into the functional consequences of standard electrotransfer and represents a powerful tool for optimization and longitudinal assessment of preclinical gene therapy protocols. PMID- 23038160 TI - Using ecological niche modelling to predict spatial and temporal distribution patterns in Chinese gibbons: lessons from the present and the past. AB - Ecological niche modelling (ENM) is used to predict species' tolerance to changing environmental conditions. Understanding changes in the spatial distribution of species across time is essential in order to develop effective conservation strategies. Here we map the past and present distribution of gibbons across China, a country experiencing extensive anthropogenic habitat destruction and ongoing biodiversity loss. The distribution of gibbons across three time intervals is described based on fossil, historical and modern-day data, and ENM, implemented using DIVA-GIS, is used to predict how modern-day gibbon distributions might respond to future climate change. Predictions based on modern day data alone fail to reveal patterns of environmental tolerance and geographical distribution shown by gibbons in the relatively recent historical period, emphasizing the need to incorporate past as well as present data in conservation analyses. PMID- 23038161 TI - Construction of self-cloning bottom-fermenting yeast with low vicinal diketone production by the homo-integration of ILV5. AB - The vicinal diketones (VDK), such as diacetyl and 2,3-pentandione, impart an unpleasant butter-like flavour to beer. Typically, these are required to be reduced below the flavour thresholds during the maturation (lagering) stages of the brewing process. To shorten beer maturation time, we constructed a self cloning, bottom-fermenting yeast with low VDK production by integrating ILV5, a gene encoding a protein that metabolizes alpha-acetolactate and alpha-aceto-alpha hydroxybutyrate (precursors of VDK). A DNA fragment containing Saccharomyces cerevisiae-type ILV5 was inserted upstream of S. cerevisiae-type ILV2 in bottom fermenting yeast to construct self-cloning strains with an increased copy number of ILV5. Via transformation, ILV2 was replaced with the sulfometuron methyl (SM) resistance gene SMR1B, which differs by a single nucleotide, to create SM resistant transformants. The wort fermentation test, using the SC-ILV5-homo inserted transformant, confirmed a consecutive reduction in VDK and a shortening period during which VDK was reduced to within the threshold. The concentrations of ethyl acetate, isoamyl acetate, isoamyl alcohol, 1-propanol, isobutyl alcohol and active isoamyl alcohol (flavour components) were not changed when compared with the parent strain. We successfully constructed self-cloning brewer's yeast in which SC-ILV5 was homo-inserted. Using the transformed yeast, the concentration of VDK in fermenting wort was reduced, whereas the concentrations of flavour components were not affected. This genetically stable, low VDK producing, self-cloning bottom-fermenting yeast would contribute to the shortening of beer maturation time without affecting important flavour components produced by brewer's yeast. PMID- 23038162 TI - Snomed CT implementation. Mapping guidelines facilitating reuse of data. AB - Clinical practice as well as research and quality-assurance benefit from unambiguous clinical information resulting from the use of a common terminology like the Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT). A common terminology is a necessity to enable consistent reuse of data, and supporting semantic interoperability. Managing use of terminology for large cross specialty Electronic Health Record systems (EHR systems) or just beyond the level of single EHR systems requires that mappings are kept consistent. The objective of this study is to provide a clear methodology for SNOMED CT mapping to enhance applicability of SNOMED CT despite incompleteness and redundancy. Such mapping guidelines are presented based on an in depth analysis of 14 different EHR templates retrieved from five Danish and Swedish EHR systems. Each mapping is assessed against defined quality criteria and mapping guidelines are specified. Future work will include guideline validation. PMID- 23038163 TI - Sparse imaging of cortical electrical current densities via wavelet transforms. AB - While the cerebral cortex in the human brain is of functional importance, functions defined on this structure are difficult to analyze spatially due to its highly convoluted irregular geometry. This study developed a novel L1-norm regularization method using a newly proposed multi-resolution face-based wavelet method to estimate cortical electrical activities in electroencephalography (EEG) and magnetoencephalography (MEG) inverse problems. The proposed wavelets were developed based on multi-resolution models built from irregular cortical surface meshes, which were realized in this study too. The multi-resolution wavelet analysis was used to seek sparse representation of cortical current densities in transformed domains, which was expected due to the compressibility of wavelets, and evaluated using Monte Carlo simulations. The EEG/MEG inverse problems were solved with the use of the novel L1-norm regularization method exploring the sparseness in the wavelet domain. The inverse solutions obtained from the new method using MEG data were evaluated by Monte Carlo simulations too. The present results indicated that cortical current densities could be efficiently compressed using the proposed face-based wavelet method, which exhibited better performance than the vertex-based wavelet method. In both simulations and auditory experimental data analysis, the proposed L1-norm regularization method showed better source detection accuracy and less estimation errors than other two classic methods, i.e. weighted minimum norm (wMNE) and cortical low-resolution electromagnetic tomography (cLORETA). This study suggests that the L1-norm regularization method with the use of face-based wavelets is a promising tool for studying functional activations of the human brain. PMID- 23038164 TI - Basal lamella relaxing incision improves endoscopic middle meatal access. AB - BACKGROUND: Lateralization of the middle turbinate is a commonly cited factor leading to failure of functional endoscopic sinus surgery (FESS). Inadequate medialization during FESS may require repeat intraoperative attempts, and may lead to destabilization and mucosal trauma. A novel technique is described that increases middle meatal area and provides more definitive medialization at the outset of FESS. METHODS: Twenty-nine middle turbinate medializations were prospectively evaluated in 18 consecutive patients undergoing primary ESS. Three intraoperative images of the middle meatus were obtained in the native position, after Freer medialization, and after basal lamella relaxing incision (BLRI). Measurements of middle meatal area were then calculated in a blinded and randomized fashion. RESULTS: Distances measured from the middle turbinate to the lateral nasal wall for each position ranged from 0 to 8 mm (median = 3.00 mm) for the native position, 0.5 to 10 mm (median = 5.00 mm) for standard Freer medialization, and 3 to 21 mm (median = 10.00 mm) for BLRI. Friedman's analysis of variance (ANOVA) showed that there was significant difference between the 3 measurements, and the post hoc Wilcoxon signed ranks tests showed that BLRI distance (median = 10; 95% confidence interval [CI], 7-11.2) was significantly larger than both standard Freer (median = 5; 95% CI, 4-6.2) and native (median = 3; 95% CI, 2-3) and that standard Freer was significantly larger than native (all p values <0.001). CONCLUSION: BLRI is a safe, controlled technique that provides significantly greater medialization of the middle turbinate compared to standard medialization techniques. BLRI significantly enhances the operative space within the middle meatus. PMID- 23038165 TI - [(NHC)Yb{N(SiMe3)2}2]-catalyzed cross-dehydrogenative coupling of silanes with amines. AB - Top cat: [(NHC)Yb{N(SiMe(3))(2)}(2)] adducts (NHC = N-heterocyclic carbene) are efficient catalysts for catalytic cross-dehydrogenative coupling of silanes with a range of primary and secondary amines to yield silylamines in high yields (82 100%) under mild reaction conditions. The catalytic activity and selectivity of the rare-earth-metal silylamides are modulated by altering the steric bulk of the NHC. PMID- 23038166 TI - Solitary nodule on the nose: a quiz. PMID- 23038167 TI - A primary care-based treatment programme improves postpartum depression at 12 months. PMID- 23038168 TI - Tuberculosis patients in South Africa have a high prevalence of psychological distress. PMID- 23038169 TI - Abstracts of the 28th Annual Meeting of the German Obesity Society. October 4-6, 2012, Stuttgart, Germany. PMID- 23038170 TI - Special Section. Syndrome-specific growth charts. PMID- 23038171 TI - Characterization and transcription of arsenic respiration and resistance genes during in situ uranium bioremediation. AB - The possibility of arsenic release and the potential role of Geobacter in arsenic biogeochemistry during in situ uranium bioremediation was investigated because increased availability of organic matter has been associated with substantial releases of arsenic in other subsurface environments. In a field experiment conducted at the Rifle, CO study site, groundwater arsenic concentrations increased when acetate was added. The number of transcripts from arrA, which codes for the alpha-subunit of dissimilatory As(V) reductase, and acr3, which codes for the arsenic pump protein Acr3, were determined with quantitative reverse transcription-PCR. Most of the arrA (>60%) and acr3-1 (>90%) sequences that were recovered were most similar to Geobacter species, while the majority of acr3-2 (>50%) sequences were most closely related to Rhodoferax ferrireducens. Analysis of transcript abundance demonstrated that transcription of acr3-1 by the subsurface Geobacter community was correlated with arsenic concentrations in the groundwater. In contrast, Geobacter arrA transcript numbers lagged behind the major arsenic release and remained high even after arsenic concentrations declined. This suggested that factors other than As(V) availability regulated the transcription of arrA in situ, even though the presence of As(V) increased the transcription of arrA in cultures of Geobacter lovleyi, which was capable of As(V) reduction. These results demonstrate that subsurface Geobacter species can tightly regulate their physiological response to changes in groundwater arsenic concentrations. The transcriptomic approach developed here should be useful for the study of a diversity of other environments in which Geobacter species are considered to have an important influence on arsenic biogeochemistry. PMID- 23038172 TI - Iron-reducing bacteria accumulate ferric oxyhydroxide nanoparticle aggregates that may support planktonic growth. AB - Iron-reducing bacteria (FeRB) play key roles in anaerobic metal and carbon cycling and carry out biogeochemical transformations that can be harnessed for environmental bioremediation. A subset of FeRB require direct contact with Fe(III)-bearing minerals for dissimilatory growth, yet these bacteria must move between mineral particles. Furthermore, they proliferate in planktonic consortia during biostimulation experiments. Thus, a key question is how such organisms can sustain growth under these conditions. Here we characterized planktonic microbial communities sampled from an aquifer in Rifle, Colorado, USA, close to the peak of iron reduction following in situ acetate amendment. Samples were cryo-plunged on site and subsequently examined using correlated two- and three-dimensional cryogenic transmission electron microscopy (cryo-TEM) and scanning transmission X ray microscopy (STXM). The outer membranes of most cells were decorated with aggregates up to 150 nm in diameter composed of ~3 nm wide amorphous, Fe-rich nanoparticles. Fluorescent in situ hybridization of lineage-specific probes applied to rRNA of cells subsequently imaged via cryo-TEM identified Geobacter spp., a well-studied group of FeRB. STXM results at the Fe L(2,3) absorption edges indicate that nanoparticle aggregates contain a variable mixture of Fe(II) Fe(III), and are generally enriched in Fe(III). Geobacter bemidjiensis cultivated anaerobically in the laboratory on acetate and hydrous ferric oxyhydroxides also accumulated mixed-valence nanoparticle aggregates. In field-collected samples, FeRB with a wide variety of morphologies were associated with nano-aggregates, indicating that cell surface Fe(III) accumulation may be a general mechanism by which FeRB can grow while in planktonic suspension. PMID- 23038173 TI - 'Sponge-specific' bacteria are widespread (but rare) in diverse marine environments. AB - Numerous studies have reported the existence of sponge-specific 16S ribosomal RNA (rRNA) gene sequence clusters, representing bacteria found in sponges but not detected in other environments, such as seawater. The advent of deep-sequencing technologies allows us to examine the rare microbial biosphere in order to establish whether these bacteria are truly sponge specific, or are more widely distributed but only at abundances below the detection limit of conventional molecular approaches. We screened >12 million publicly available 16S rRNA gene pyrotags derived from 649 seawater, sediment, hydrothermal vent and coral samples from temperate, tropical and polar regions. We detected 77 of the 173 previously described sponge-specific clusters in seawater or other non-sponge samples, albeit generally at extremely low abundances. Sequences representing the candidate phylum 'Poribacteria', previously thought to be largely restricted to sponges, were recovered from 46 (out of 411) seawater and 41 (out of 129) sediment samples. While the presence of an organism does not imply that it is active in situ, our results do suggest that many 'sponge-specific' bacteria occur more widely outside of sponge hosts than previously thought. PMID- 23038175 TI - The virocell concept and environmental microbiology. PMID- 23038174 TI - Gut microbiome composition is linked to whole grain-induced immunological improvements. AB - The involvement of the gut microbiota in metabolic disorders, and the ability of whole grains to affect both host metabolism and gut microbial ecology, suggest that some benefits of whole grains are mediated through their effects on the gut microbiome. Nutritional studies that assess the effect of whole grains on both the gut microbiome and human physiology are needed. We conducted a randomized cross-over trial with four-week treatments in which 28 healthy humans consumed a daily dose of 60 g of whole-grain barley (WGB), brown rice (BR), or an equal mixture of the two (BR+WGB), and characterized their impact on fecal microbial ecology and blood markers of inflammation, glucose and lipid metabolism. All treatments increased microbial diversity, the Firmicutes/Bacteroidetes ratio, and the abundance of the genus Blautia in fecal samples. The inclusion of WGB enriched the genera Roseburia, Bifidobacterium and Dialister, and the species Eubacterium rectale, Roseburia faecis and Roseburia intestinalis. Whole grains, and especially the BR+WGB treatment, reduced plasma interleukin-6 (IL-6) and peak postprandial glucose. Shifts in the abundance of Eubacterium rectale were associated with changes in the glucose and insulin postprandial response. Interestingly, subjects with greater improvements in IL-6 levels harbored significantly higher proportions of Dialister and lower abundance of Coriobacteriaceae. In conclusion, this study revealed that a short-term intake of whole grains induced compositional alterations of the gut microbiota that coincided with improvements in host physiological measures related to metabolic dysfunctions in humans. PMID- 23038176 TI - Accuracy of protist diversity assessments: morphology compared with cloning and direct pyrosequencing of 18S rRNA genes and ITS regions using the conspicuous tintinnid ciliates as a case study. AB - Deep-sequencing technologies are becoming nearly routine to describe microbial community composition in environmental samples. The 18S ribosomal DNA (rDNA) pyrosequencing has revealed a vast diversity of infrequent sequences, leading to the proposition of the existence of an extremely diverse microbial 'rare biosphere'. Although rare microbes no doubt exist, critical views suggest that many rare sequences may actually be artifacts. However, information about how diversity revealed by molecular methods relates to that revealed by classical morphology approaches is practically nonexistent. To address this issue, we used different approaches to assess the diversity of tintinnid ciliates, a species rich group in which species can be easily distinguished morphologically. We studied two Mediterranean marine samples with different patterns of tintinnid diversity. We estimated tintinnid diversity in these samples employing morphological observations and both classical cloning and sequencing and pyrosequencing of two different markers, the 18S rDNA and the internal transcribed spacer (ITS) regions, applying a variety of computational approaches currently used to analyze pyrosequence reads. We found that both molecular approaches were efficient in detecting the tintinnid species observed by microscopy and revealed similar phylogenetic structures of the tintinnid community at the species level. However, depending on the method used to analyze the pyrosequencing results, we observed discrepancies with the morphology-based assessments up to several orders of magnitude. In several cases, the inferred number of operational taxonomic units (OTUs) largely exceeded the total number of tintinnid cells in the samples. Such inflation of the OTU numbers corresponded to 'rare biosphere' taxa, composed largely of artifacts. Our results suggest that a careful and rigorous analysis of pyrosequencing data sets, including data denoising and sequence clustering with well-adjusted parameters, is necessary to accurately describe microbial biodiversity using this molecular approach. PMID- 23038179 TI - [To provide information on vulnerability]. PMID- 23038180 TI - [Mankind]. PMID- 23038177 TI - Viruses in the desert: a metagenomic survey of viral communities in four perennial ponds of the Mauritanian Sahara. AB - Here, we present the first metagenomic study of viral communities from four perennial ponds (gueltas) located in the central Sahara (Mauritania). Three of the four gueltas (Ilij, Molomhar and Hamdoun) are located at the source of three different wadis belonging to the same hydrologic basin, whereas the fourth (El Berbera) belongs to a different basin. Overall, sequences belonging to tailed bacteriophages were the most abundant in all four metagenomes although electron microscopy and sequencing confirmed the presence of other viral groups, such as large DNA viruses. We observed a decrease in the local viral biodiversity in El Berbera, a guelta with sustained human activities, compared with the pristine Ilij and Molomhar, and sequences related to viruses infecting crop pests were also detected as a probable consequence of the agricultural use of the soil. However, the structure of the El Berbera viral community shared the common global characteristics of the pristine gueltas, that is, it was dominated by Myoviridae and, more particularly, by virulent phages infecting photosynthetic cyanobacteria, such as Prochlorococcus and Synechococcus spp. In contrast, the Hamdoun viral community was characterized by a larger proportion of phages with the potential for a temperate lifestyle and by dominant species related to phages infecting heterotrophic bacteria commonly found in terrestrial environments. We hypothesized that the differences observed in the structural and functional composition of the Hamdoun viral community resulted from the critically low water level experienced by the guelta. PMID- 23038183 TI - [Spinal units and other units]. PMID- 23038184 TI - [Side effects of bisphosphonates]. PMID- 23038188 TI - [Systematic review on mercury exposure]. PMID- 23038189 TI - [A comparison of apples and pears]. PMID- 23038191 TI - [Anticonvulsants and drivers license--new guidelines should be revised]. PMID- 23038192 TI - [Leucocoria is retinoblastoma until the opposite is proven]. PMID- 23038193 TI - [New steroid card for adrenal insufficiency]. PMID- 23038194 TI - Patient knowledge of late effects of acute lymphoblastic leukaemia. AB - BACKGROUND: Over 80% of children with acute lymphatic leukaemia (ALL) survive, but many develop long-term effects after the therapy. The aim of the study was to reveal how much Norwegian adults treated for acute lymphatic leukaemia before the age of 16 know about the risk of long-term effects. MATERIAL AND METHOD: The participants (n = 139) were recruited from a cross-sectional study (ALLBARN) of adults treated for acute lymphatic leukaemia before the age of 16 in the period 1970-2002. Their knowledge of diagnosis, treatment and long-term effects was investigated in a semi-structured interview. RESULTS: A median number of 23 years after treatment for acute lymphatic leukaemia, 85 (61%) of the participants were unable to give examples of possible long-term effects of cancer treatment. Reduced fertility was known to 35 participants (25%), while few were aware of the risk of heart failure (n = 3) or secondary malignancy (n = 5). Those who were aware of long-term effects usually had personal experience of the problem. However, the participants had a sound knowledge of their own diagnosis and the therapy they had been submitted to. INTERPRETATION: Long-term survivors of acute lymphatic leukaemia in childhood and adolescence know little of the risk of long term effects. The dissemination of information about the potential consequences of the therapy should be improved. PMID- 23038195 TI - Chronic lymphocytic leukaemia in Norway--incidence and prognostic markers at diagnosis. AB - BACKGROUND: The clinical courses of chronic lymphocytic leukaemia (CLL) are very heterogeneous. Biological markers that provide good prognostic information at the time of diagnosis are available. The aim of the study was to determine the prevalence of these markers in a population-based material. MATERIAL AND METHOD: Biological markers were examined using standard laboratory methods after obtaining an informed consent statement from patients diagnosed with chronic lymphocytic leukaemia in the period 1.10.2007-31.12.2009. RESULTS: There were 388 new cases of chronic lymphocytic leukaemia during the study period, and 236 patients (61%) were included in the study. Of 222 patients, 178 (80%) were in Binet's stage A, 26 (12%) in stage B and 18 (8%) in stage C. The V(H) gene was mutated in 69% and unmutated in 31% of cases. Cytogenetic aberrations were found in 68%: del(13q14) in 48%, trisomy 12 in 13%, del(11q22) in 10% and del(17p13) in 7%. CD38-positive disease was found in 28% of the patients. The V(H) gene was mutated in 67% of the patients in Binet's stage A, and in the majority of these a mutated V(H) gene was associated with non-expression of CD38 and del(13q14). INTERPRETATION: At the time of diagnosis, most patients are asymptomatic and do not need treatment. The biological markers that indicate a favourable prognosis occur most frequently in this group. Markers that indicate a poor prognosis occur more frequently in the group that has symptoms at the time of diagnosis. PMID- 23038196 TI - Familial occurrence of chronic lymphocytic leukaemia in Norway. AB - BACKGROUND: The only known risk factor for chronic lymphocytic leukaemia (CLL) is occurrence of the disease in close relatives. The aim of this study was to determine the frequency of familial chronic lymphocytic leukaemia. MATERIAL AND METHOD: All patients with chronic lymphocytic leukaemia notified to the Cancer Registry in the period 1.10.2007-31.12.2009 were asked to report occurrences of malignant disease in siblings, parents, grandparents and children. The information about malignant haematological disease was verified with the Cancer Registry. RESULTS: We found malignant haematological disease in close relatives of 42 of the 236 included patients (18%). CLL and lymphoma were the most common diagnoses. On average, 16 family members were identified in each family. The relative risk of developing CLL was six times higher in those who had close relatives with the disease (16 of a total of 3,776 family members) than among those who did not have close relatives who were affected (76 cases among 107,223 family members of 38,159 control subjects). The increased risk of disease was also associated with other lymphoproliferative diseases. With patrilinear, but not matrilinear inheritance, we found a birth order effect, with affection of younger men in a group of siblings, while the eldest escaped. INTERPRETATION: Malignant haematological disease is common in the family members of patients with CLL. CLL is the most common disease, but there is extensive pleiotropy. PMID- 23038197 TI - [Immunosuppressive drugs and the development of skin cancer after organ transplantation]. AB - BACKGROUND: Patients with organ transplants have a significantly increased risk of skin cancer, especially squamous cell carcinoma, as a result of long-term treatment with immunosuppressive drugs. This paper provides a brief overview of the assumed underlying mechanisms. METHOD: The paper builds on relevant articles and studies identified in the course of many years of interest in immunopharmacology and skin cancer after organ transplantation. RESULTS: Reduced immunological tumour surveillance as a result of chronic immunosuppression has long been assumed to underlie the increased risk of skin cancer after organ transplants. Recent studies indicate that immunosuppressive drugs may also have specific carcinogenic effects. Aziatropine, which inhibits proliferation of lymphocytes, increases oxidative DNA damage caused by UV radiation. Ciclosporin and tacrolimus, which have an immunosuppressive effect by inhibiting calcineurin, promote malignant phenotypes in cell culture and tumour growth in mouse models. Calcineurin has proved to be necessary in order for p53 protein to have a protective effect against skin cancer. A relatively new class of immunosuppressive drugs, mTOR inhibitors, have antineoplastic properties and are associated with less risk of skin cancer. A number of randomised studies are currently in progress to see whether mTOR inhibitors can reduce the risk of skin cancer after organ transplantation. INTERPRETATION: Immunosuppressive drugs contribute to skin cancer after organ transplantation, either as a result of immunosuppression or through specific carcinogenic mechanisms. Immunosuppressive drugs with antineoplastic properties are now starting to be used. PMID- 23038198 TI - [Secondary dementia]. PMID- 23038199 TI - A young woman with upper gastrointestinal bleeding. PMID- 23038200 TI - Normal gastroscopy findings. PMID- 23038202 TI - Neuropsychiatry--emerging from the mist. PMID- 23038201 TI - Young girl with psychosis, cognitive failure and seizures. PMID- 23038203 TI - [Primary, first choice or first-line?]. PMID- 23038206 TI - Nanoparticles and peptides: a fruitful liaison for biomimetic catalysis. AB - Inspired by nature: self-assembled peptide nanoparticles have been designed that accelerate ester hydrolysis (see picture; Cbz=carbobenzyloxy, NP=p-NO(2)-C(6) H(4)). The concerted interplay of the multivalent surface with the catalytically active peptide and the substrate at the same time combines several aspects decisive for the catalyst's efficiency, a property characteristic of enzymes. PMID- 23038208 TI - Impulse control and related disorders in Parkinson's disease. AB - Impulse control disorders (ICDs), such as compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized complication of dopamine replacement therapy in Parkinson's disease (PD). Other impulsive compulsive behaviors have been linked to dopaminergic medications; these include punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), particularly at higher dosages; in contrast, DDS is primarily associated with shorter-acting, higher potency dopaminergic medications, such as apomorphine and levodopa. Risk factors for ICDs may include male sex; younger age; younger age at PD onset; a pre-PD history of ICD(s); personal or family history of substance abuse; bipolar disorder; gambling problems; and impulsive personality traits. The primary treatment of ICDs in PD is discontinuation of DA therapy. Not all patients can tolerate this, however, due to worsening motor symptoms and/or DA withdrawal syndrome (a severe, stereotyped drug withdrawal syndrome similar to that of other psychostimulants). While psychiatric medications are frequently used to treat ICDs in the general population, there is no empirical evidence to suggest that they are effective in PD. Given the paucity of treatment options and potentially serious consequences of ICDs in PD, it is critical for patients to be monitored closely for their development. As empirically validated treatments for ICDs emerge, it will also be important to examine their efficacy and tolerability in individuals with comorbid PD. PMID- 23038209 TI - Rapid decrease of plasma galectin-9 levels in patients with acute HIV infection after therapy. AB - Acute HIV-1 infection is often diagnosed as infectious mononucleosis and the symptoms resolve spontaneously after varying periods of time. After the infection of HIV-1 through the mucosa, the characteristic clinical symptoms and laboratory markers of acute HIV-1 infection appear in each patient through a complicated virus-host interaction. To understand the host responses, we measured two unique proinflammatory cytokines, galectin-9 (Gal-9) and osteopontin (OPN). A beta galactoside-binding mammalian lectin, Gal-9, reduces pro-inflammatory type-1 helper T (Th1) cells and Th17 cells and increases anti-inflammatory regulatory T cells. The plasma level of Gal-9 is known to be associated with HIV-1 viral load in chronic HIV-1 infection. On the contrary, osteopontin induces Th1/Th17 cells and promotes tissue inflammation. OPN is synthesized by variety of cells in the body, and dendritic cells are known to synthesize OPN in HIV-1 infected individuals. It was hypothesized that Gal-9 and/or OPN could be not only immune modulators but also novel biomarkers of acute HIV-1 infection. We experienced 3 patients with acute HIV-1 and measured the levels of Gal-9 and OPN periodically before and after antiretroviral treatment. The results showed that the plasma levels of Gal-9 were extremely elevated [more than 2,300 pg/ml (normal range < 46 pg/ml)] in all three acute HIV-1 infected individuals and decreased rapidly after treatment. The changes in the OPN levels were less marked. In conclusion, the plasma levels of Gal-9 may be predictive of a severe inflammation status during the acute phase of HIV-1 infection and could be a potential biomarker during acute infection. PMID- 23038210 TI - Deaths due to fires in the tent city set up after the 2011 earthquake in Van, Turkey. PMID- 23038211 TI - Comparing the interactions of DNA, polyamide (PNA) and polycarbamate nucleic acid (PCNA) oligomers with graphene oxide (GO). AB - The fluorescently labelled short octameric oligothymine sequences of DNA, PNA and PCNA were used in fluorescence quenching studies in conjunction with dispersed graphene oxide. The measurable restoration of their fluorescence by complementary oligodeoxyadenylate was compared. This is the first study aimed at replacing the natural DNA probes with synthetic DNA mimics that show excellent properties in terms of formation of very strong duplexes with cDNA in addition to their stability towards proteases and nucleases. PMID- 23038212 TI - Tuning efficiency of the 4-exo-trig cyclization by the electronic effect: ring closure of 3,3-difluoro-4-pentenyl carbon radicals and synthesis of a gem difluorocyclobutane nucleoside. AB - 4-exo-trig Cyclization reaction of a 4-pentenyl carbon radical containing the gem difluoromethylene moiety adjacent to a radical accepting alpha,beta-unsaturated ester was found to proceed efficiently to furnish a novel gem-difluorocyclobutane derivative. The cyclized product could be transformed into a gem difluoromethylene analogue of oxetanocin T. PMID- 23038213 TI - Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant prostate cancer. AB - BACKGROUND: Previous work showed that the NF-kappaB survival pathway is activated by docetaxel (D) and contributes to D resistance in prostate cancer. In this study we aimed to investigate the dynamics of the relationship between NF-kappaB and IL-6 in the shift from D-naive castration-resistant prostate cancer (CRPC) to D-resistance in patients and cell lines. METHODS: CRPC tumor samples were tested for NF-kappaB/p65 and IL-6 by immunohistochemistry. CRPC patients treated with D were also tested for serum IL-6 (ELISA). Two D-resistant cell lines, PC-3R and DU 145R, derived from the CRPC cells PC-3 and DU-145, respectively, were tested for NF-kappaB activation (EMSA), NF-kappaB-related genes expression (RT-PCR), NF kappaB inhibition (p65 siRNA) and IL-6 and IL-8 soluble levels (ELISA). RESULTS: In CRPC patients treated with D (n = 72), pre-treatment IL-6 level correlated with nuclear NF-kappaB/p65 tumor staining and response to D, and was an independent prognostic factor for overall survival. However, IL-6 level changes under treatment did not correlate with clinical outcome. In PC-3 and DU-145 parental CRPC cells, as well as in D-resistant counterparts, D treatment induced NF-kappaB activation. In fact, NF-kappaB inhibition was sufficient to re sensitize DU-145R cells to D. Despite enhanced NF-kappaB activity, IL-6 secretion in D-resistant cell lines was reduced and not induced by D treatment. The same occurred with IL-8 cytokine. CONCLUSIONS: These preclinical and clinical results support a role of NF-kappaB and IL-6 in the resistance to D in CRPC, and support the investigation of targeted therapies to enhance the antitumor activity of D in this patient population. PMID- 23038214 TI - Physiotherapy services provided outside of business hours in Australian hospitals: a national survey. AB - BACKGROUND AND PURPOSE: Physiotherapy services provided outside of business hours may improve patient and hospital outcomes, but there is limited understanding of what services are provided. This study described current services provided outside of business hours across Australian hospitals. METHODS: Design Descriptive, cross-sectional, Web-based survey. Participants A random sample of Australian hospitals from the public or private sector located in either metropolitan or rural/regional areas. RESULTS: A total of 112 completed surveys were submitted. The most common service outside of business hours was a Saturday service, provided by 61% of participating hospitals with a median (interquartile range [IQR]) of 1.0 hour (0.0 and 3.4) of physiotherapy per 30 beds. Sunday services were provided by 43% of hospitals, and services provided outside of business hours from Monday to Friday were provided by 14% of hospitals. More private hospitals provided some form of physiotherapy service outside of business hours (91%) than public hospitals (48%). More metropolitan hospitals provided some form of physiotherapy service outside of business hours (90%) than rural/regional hospitals (28%). Few of the hospitals providing sub-acute services had weekend physiotherapy (30%), but the majority of highly acute wards provided weekend physiotherapy (81%). Highly acute wards also provided more hours of service on a Saturday (median 8.1 hours per 30 beds, IQR 0.6-22.5) compared with acute wards (median 0.8 hours per 30 beds, IQR 0.0-2.8). CONCLUSION: There is limited availability of physiotherapy services in Australian hospitals outside of business hours. There are inequalities in physiotherapy services provided outside of business hours, with public, rural/regional and sub-acute facilities receiving fewer services outside of business hours than private, metropolitan and highly acute facilities. PMID- 23038217 TI - Prevalence of lipodystrophy in HIV-infected children in Tanzania on highly active antiretroviral therapy. AB - OBJECTIVE: Highly active antiretroviral therapy (HAART) has been associated with lipodystrophy (LD) in adults but data are more limited for children. The purpose of this study was to determine the prevalence of and risk factors for LD in Tanzanian children receiving HAART by clinical assessment and to compare the results with anthropometric data. DESIGN AND METHODS: A cross-sectional study was performed in a cohort of HIV-infected children aged 1-18 years receiving HAART in a single center in Moshi, Tanzania. Age, gender, past and current medication regimens and anthropometric measurements were recorded. A clinical scoring method was used to assess LD. Backward binary multivariate logistic regression was used to determine relationships between anthropometric measurements and the presence of clinical LD. RESULTS: Among 210 HIV-infected children, the prevalence of LD was 30% (95% confidence interval [CI]: 23.8-36.2) overall, 19% (95% CI: 13.7 24.3) for lipoatrophy only, 3.8% (95% CI: 1.2-6.4) for lipohypertrophy only and 7.1% (95% CI: 3.6-10.6) for the mixed type. Most cases were mild. Older age and use of stavudine increased the risk of LD. Overall, the study population was stunted but not underweight. In children with relatively lower weight-for-height (<1), only the mid-upper arm circumference was found to be associated with lipoatrophy, while nearly all anthropometric measurements were associated with lipoatrophy in the well-nourished (weight-for-height >=1) children. CONCLUSIONS: Our findings demonstrate that LD is a significant problem among Tanzanian HIV infected children receiving HAART. Anthropometric measurements predicted LD in well-nourished children but generally failed to do so in relatively wasted children. Our findings support current efforts to avoid stavudine use in children. PMID- 23038219 TI - Patterns of molecular motors that guide and sort filaments. AB - Molecular motors can be immobilized to transport filaments and loads that are attached to these filaments inside a nano-device. However, if motors are distributed uniformly over a flat surface, the motility is undirected, and the filaments move equally in all directions. For many applications it is important to control the direction in which the filaments move, and two strategies have been explored to achieve this: applying external forces and confining the filaments inside channels. In this article, we discuss a third strategy in which the topography of the sample remains flat, but the motors are distributed non uniformly over the surface. Systems of filaments and patterned molecular motors were simulated using a stochastic engine that included Brownian motion and filament bending elasticity. Using an evolutionary algorithm, patterns were optimized for their capacity to precisely control the paths of the filaments. We identified patterns of motors that could either direct the filaments in a particular direction, or separate short and long filaments. These functionalities already exceed what has been achieved with confinement. The patterns are composed of one or two types of motors positioned in lines or along arcs and should be easy to manufacture. Finally, these patterns can be easily combined into larger designs, allowing one to precisely control the motion of microscopic objects inside a device. PMID- 23038218 TI - From bench to clinic and back: skeletal stem cells and impaction bone grafting for regeneration of bone defects. AB - Tissue engineering offers enormous potential for bone regeneration. Despite extensive in vitro and in vivo work, few strategies translate into clinical practice. This paper describes the combination of skeletal stem cells (SSCs) and impaction bone grafting (IBG) for the treatment of patients with bone defects associated with avascular necrosis of the femoral head. SSCs and milled allograft were impacted into necrotic bone in the femoral heads of four patients. Three patients remained asymptomatic at 22-44 month follow-up, but one patient has required total hip replacement (both hips). This has allowed retrieval of the femoral heads, which were analysed structurally and functionally by MUCT, histology and mechanical testing. A central channel of impacted bone was found in the femoral heads, which displayed a mature trabecular micro-architecture. The impacted bone was denser than the surrounding trabecular bone, as strong in compression and with histological micro-architecture comparable to that of trabecular bone. Analysis of the retrieved femoral head samples has demonstrated that this tissue-engineering strategy regenerates bone that is both structurally and functionally analogous to normal trabecular bone. SSCs, together with IBG, have proved an effective treatment for avascular necrosis of the femoral head and offer significant potential for the broader spectrum of bone defects. PMID- 23038220 TI - Influence of erythropoietin on arterial stiffness and endothelial function in renal transplant recipients. AB - BACKGROUND/AIMS: Recent retrospective studies suggest an association of therapy with erythropoiesis-stimulating agents (ESAs) and increased mortality in renal transplant recipients (RTR). Large artery structure and function are significantly impaired in RTR which contributes to their high cardiovascular morbidity and could be altered by erythropoietin. We aimed to examine the influence of ESA therapy on large artery stiffness and endothelial function in RTR. METHODS: 63 RTR with chronic allograft dysfunction and renal anemia were randomized to a group receiving darbepoetin alfa (Dar) and a control group (Co). At baseline and after 8 months of treatment (cumulative Dar dose 11.1 ug/kg b.w.) brachial and common carotid artery distensibility coefficients, aortic pulse wave velocity, brachial artery flow-mediated and nitroglycerin-mediated vasodilation were measured as well as the following biomarkers of vascular function: vWF, sVCAM, sICAM, E-selectin, t-PA and PAI-1. RESULTS: 23 patients in the Dar group and 17 patients in the Co group were available for per-protocol analysis. Hemoglobin increased significantly from 10.9 to 12.6 g/dl after 8 months in the Dar group, whereas it remained stable at 11.3 g/dl in the Co group. Effects on large artery stiffness, endothelial function and biomarkers of vascular function did not differ significantly between the two groups. CONCLUSION: Therapy with Dar during 8 months did not significantly impact parameters of large artery stiffness and endothelial function in RTR. These data suggest that therapy with erythropoietin does not deteriorate arterial stiffness and endothelial function in RTR. PMID- 23038221 TI - Pediatric astroblastoma: a rare case with a review of the literature. AB - Astroblastoma is a rare glial tumor with uncertain histopathological origin and unpredictable clinical behavior. We present a case of an 11-year-old girl who presented with headache and blurring of vision for 2 months. A well-demarcated mass was found in the right frontoparietal lobe on a brain MRI. The patient was treated with total tumor resection followed by postoperative radiotherapy. Histologically, the features were suggestive of high-grade astroblastoma. The patient is alive and disease free 23 months after surgery. The characteristic radiological and histopathological features and treatment of this case are described with a literature review. PMID- 23038222 TI - Tri-G-quadruplex: controlled assembly of a G-quadruplex structure from three G rich strands. AB - In my (DNA) dreams: A tri-G-quadruplex was constructed from three strands (T1-T3) of DNA using duplex formation to guide the G-rich tracts into close proximity with the addition of Li(+) ions (see scheme). The defined G-quadruplex structure was formed upon addition of Na(+) ions and characterized by gel electrophoresis and spectroscopy. PMID- 23038223 TI - Obtaining accurate p values from a dense SNP linkage scan. AB - A major concern of resequencing studies is that the pathogenicity of most mutations is difficult to predict. To address this concern, linkage (i.e. co segregation) analysis is often used to exclude neutral mutations and to better predict pathogenicity among the candidate mutations that remain. However, when linkage disequilibrium (LD) is present in the population but ignored in the analysis, unlinked regions with high LD can inflate the type 1 error and thousands of neutral mutations may be mistakenly included in a follow-up resequencing study, which could dramatically reduce the power to identify causal variants. To illustrate the need for concern, we simulated data on a sparsely spaced panel of single nucleotide polymorphisms (average spacing 1.27 cM) using an LD pattern estimated from real data. In our simulations, we find that the type 1 error of the maximum LOD can be as high as 14%. Therefore, to control the type 1 error of linkage tests we created Haplodrop - a fast and flexible simulation program that generates the haplotypes of founders with LD and then 'drops' these haplotypes with recombination to all non-founders in the pedigree. Haplodrop can be used to control the type 1 error of any linkage test, agrees well with existing software, accommodates arbitrary pedigree structures, and scales easily to the whole genome. Moreover, by correctly excluding mutations that lie in unlinked regions with high LD, Haplodrop should aid significantly in reducing the multiple testing burden of follow-up resequencing studies. PMID- 23038224 TI - Diagnostic differences between pulmonary actinomycosis and lung adenocarcinoma. PMID- 23038225 TI - Mortality of patients with hematological malignancy after admission to the intensive care unit. AB - BACKGROUND: The admission of patients with malignancies to an intensive care unit (ICU) still remains a matter of substantial controversy. The identification of factors that potentially influence the patient outcome can help ICU professionals make appropriate decisions. PATIENTS AND METHODS: 90 adult patients with hematological malignancy (leukemia 47.8%, high-grade lymphoma 50%) admitted to the ICU were analyzed retrospectively in this single-center study considering numerous variables with regard to their influence on ICU and day-100 mortality. RESULTS: The median simplified acute physiology score (SAPS) II at ICU admission was 55 (ICU survivors 47 vs. 60.5 for non-survivors). The overall ICU mortality rate was 45.6%. With multivariate regression analysis, patients admitted with sepsis and acute respiratory failure had a significantly increased ICU mortality (sepsis odds ratio (OR) 9.12, 95% confidence interval (CI) 1.1- 99.7, p = 0.04; respiratory failure OR 13.72, 95% CI 1.39-136.15, p = 0.025). Additional factors associated with an increased mortality were: high doses of catecholamines (ICU: OR 7.37, p = 0.005; day 100: hazard ratio (HR) 2.96, p < 0.0001), renal replacement therapy (day 100: HR 1.93, p = 0.026), and high SAPS II (ICU: HR 1.05, p = 0.038; day 100: HR 1.2, p = 0.027). CONCLUSION: The decision for or against ICU admission of patients with hematological diseases should become increasingly independent of the underlying malignant disease. PMID- 23038226 TI - Loss of expression of the tumor suppressor CEACAM1 links different hereditary colorectal carcinoma subtypes to the genesis of sporadic colorectal carcinoma. AB - According to their carcinogenesis, colorectal cancer (CRC) subtypes show distinct molecular parameters. Hereditary non-polypous colorectal cancer (HNPCC) is the most common inherited CRC characterized by clinical criteria and confirmed microsatellite instability (MSI). Interestingly, a recently identified subtype, familial colorectal cancer type X (FCC-X), shows the same clinical criteria but microsatellite stability (MSS). CEACAM1 is a known tumor suppressor that regulates apoptosis in colon cells, and its loss is one of the most frequent events in early tumorigenesis of CRC. Therefore its loss may characterize precursor colon cells prior to neoplastic transformation. We analyzed tumor specimens of HNPCC and FCC-X patients in order to investigate whether there is a loss of CEACAM1 expression analogous to sporadic CRC and whether the expression of CEACAM1 would distinguish between these tumor entities. No differences in CEACAM1 expression were noted between HNPPC (n = 38) and FCC-X (n = 30) tumors. CEACAM1 was reduced in near-identical frequencies in 36/38 (95%) HNPCC and 29/30 (97%) FCC-X. This is the first report to demonstrate the loss of CEACAM1 expression in hereditary CRC. There was no difference between HNPCC and FCC-X. The frequency of expression loss was comparable to sporadic CRC, indicating that loss of CEACAM1 is an early event in colorectal tumorigenesis linking the genesis of sporadic and hereditary CRC. PMID- 23038227 TI - Arginase activity in patients with breast cancer: an analysis of plasma, tumors, and its relationship with the presence of the estrogen receptor. AB - BACKGROUND: Breast cancer is an important cause of cancerrelated death in women. In this pathological condition, arginase plays a role by providing ornithine as a substrate for the biosynthesis of polyamines which are important in tumor progression. The aim of this work was to determine the arginase activity in the plasma and tumors of patients with breast cancer; also, we investigated the relationship between this activity and the presence of the estrogen receptor. PATIENTS AND METHODS: We evaluated the plasma arginase activity levels in 80 women with breast cancer and 42 healthy control subjects. We also measured the arginase levels in 42 breast cancer biopsies and 42 control tissues. RESULTS: The mean activity of arginase in plasma was higher in breast cancer patients (0.78 nM/min/mg protein +/- 0.04; p = 0.001) than in healthy volunteers (0.53 nM/ min/mg protein +/- 0.04); however, this difference was indicative of patients in the advanced stages of the disease (n = 38, stage III; p < 0.0001). In addition, we did not find a relationship between the estrogen receptor and arginase activity. CONCLUSION: Our results show a higher arginase activity in the plasma of patients in the advanced stages of the disease, suggesting that arginase activity could serve as a possible biological marker of breast cancer progression. PMID- 23038228 TI - Paclitaxel plus doxorubicin chemotherapy as second-line therapy in patients with advanced urothelial carcinoma pretreated with platinum plus gemcitabine chemotherapy. AB - BACKGROUND: We retrospectively evaluated the efficacy and toxicity of paclitaxel plus doxorubicin as a second-line treatment in patients with urothelial carcinoma, who had not responded to a prior platinum plus gemcitabine combination. PATIENTS AND METHODS: All patients received intravenous infusions of paclitaxel (175 mg/m(2)/h) and doxorubicin (50 mg/m(2)/30 min) on day 1. Chemotherapy courses were repeated every 21 days. RESULTS: The median followup duration was 13.5 months (range 2.8-22.4 months). Complete and partial responses were observed in 2 (5.6%) and 10 (27.8%) patients, respectively. Median overall survival was 8.9 months (95% confidence interval (CI): 6.2-11.6). Median time to progression was 3.8 months (95% CI: 2.7-4.8). The most common hematologic toxicities were neutropenia (n = 21, 58.3%), thrombocytopenia (n = 10, 27.8%), and anemia (n = 9, 25%). The most common nonhematologic toxicities consisted of fatigue (n = 15, 41.7%), nausea/vomiting (n = 13, 36.1%), peripheral neuropathy (n = 11, 30.6%), and mucositis (n = 6, 16.7%). Dose reductions by 25-35% were performed in 6 (16.7%) patients because of grade 3/4 toxicity. Anthracycline related heart failure did not occur. CONCLUSION: 3-weekly courses of cyclic paclitaxel plus doxorubicin were found to be effective and tolerable in patients with urothelial carcinoma, who had not responded to prior platinum- and gemcitabine-based chemotherapy. PMID- 23038229 TI - Pathologic findings in breast reduction specimens: detection of occult premalignant and cancerous lesions. AB - BACKGROUND: As reduction mammaplasty has become one of the most popular reconstructive procedures, there is an increasing number of reports regarding histopathologic findings in breast tissue yielded by the procedure. PATIENTS AND METHODS: This study evaluates histopathologic findings in breast tissue removed during reduction mammaplasty procedures performed during a 40-month period (2008 2011), and includes 300 patients of which 258 underwent bilateral breast reduction (group B) and 42 unilateral reduction for symmetry to the contralateral reconstructed breast (group U). RESULTS: Occult carcinomas were detected in 4 (1.55%) group B patients and 1 (2.38%) group U patient. Atypical hyperplasia and intraductal papillomas were identified in 22 (8.6%) and 5 (11.9%) patients, respectively. Benign pathologic changes including typical mild ductal hyperplasia, fibrocystic disease, adenosis, fibroadenoma, and lobular atrophy were identified in 174 (67.44%) group B and 26 (61.9%) group U patients. CONCLUSION: Breast carcinomas are rarely detected in breast tissue yielded by reduction mammaplasty procedures due to routinely performed preoperative assessment including clinical examination and mammograms. Pathologic examination of specimens provides the clinician with a conclusive diagnosis allowing for possible prompt further management. PMID- 23038230 TI - Variations in normal serum alpha-fetoprotein (AFP) levels in patients with testicular cancer on surveillance. AB - BACKGROUND: The aim of this study was to assess fluctuations in normal serum alpha-fetoprotein (AFP) levels in patients with germ cell cancer. Marked variations occur after serum AFP levels normalize, creating anxiety among patients and physicians during surveillance. PATIENTS AND METHODS: We conducted a retrospective review of patients with germ cell tumors in clinical remission, who had normal AFP levels and were followed at our center from 1991 to 2009. 72 patients, with a median follow-up of 50 months, were identified. RESULTS: Of the 72 patients, 57 (79%) had a non-seminomatous germ cell histology, and 15 (21%) had seminomas. Seminomas were included as controls as serum AFP levels do not increase in this group. 68 patients underwent orchiectomy, and 50 patients received systemic chemotherapy. The majority of patients (93%) demonstrated fluctuations in serum AFP. There was no difference in the mean AFP values between patients with seminona (2.95 ng/ml) and those with non-seminomatous germ cell tumors (3.3 ng/ml) (standard deviation 1.01 ng/ml). CONCLUSION: Marked variations occur after serum AFP levels normalize in patients undergoing surveillance. Fluctuating AFP levels within normal limits did not result in relapse in our cohort of patients with extended follow-up. PMID- 23038231 TI - Intraperitoneal catumaxomab therapy in a cirrhotic patient with malignant ascites due to urethelial carcinoma: a case report. AB - BACKGROUND: Refractory malignant ascites is a common complication in tumor patients. To date, chemotherapy and paracentesis represent the most widely used methods to relieve the symptoms. Lately, intraperitoneal therapy with catumaxomab, a trifunctional hybrid antibody, has been introduced for the treatment of malignant ascites, and its utility has been demonstrated in patients with distinct abdominal malignancies. CASE REPORT: We report the first case of successful catumaxomab treatment of malignant ascites in a patient with advanced carcinoma of the urinary bladder and liver cirrhosis. Although at admission a large volume paracentesis was needed every other day, paracentesis was no longer necessary after catumaxomab therapy. CONCLUSION: Catumaxomab might represent a safe treatment option for malignant ascites in the course of metastatic urothelial carcinoma, also in the setting of liver cirrhosis. PMID- 23038232 TI - Conservative management of L-asparaginase-induced hypertriglyceridemia in an adult patient: a case report and review of the literature. AB - BACKGROUND: L-Asparaginase (L-Asp) may induce hypertriglyceridemia; however, this has been mainly observed among pediatric patients. Treatment for L-Asp-induced hypertriglyceridemia is not standardized, ranging from fasting and diet restriction to the invasive plasmapheresis procedure. CASE REPORT: We describe a 53-year-old male patient who presented with L-Asp-induced severe hypertriglyceridemia. He was receiving L-Asp as part of his chemotherapy regimen for natural killer T-cell lymphoma. After the 20th dose, his serum triglyceride level was 3,552 mg/dl, with a total cholesterol of 418 mg/dl. Despite the high triglyceride, the patient did not present with acute pancreatitis symptoms. Treatment comprising fasting, fenofibrate, and omega-3 fatty acids was initiated. Triglyceride levels dropped rapidly to 1,000 mg/dl within 2 days, and to 268 mg/dl after 10 days. The chemotherapy regimen was subsequently switched to exclude L-Asp. CONCLUSION: L-Asp-induced severe hypertriglyceridemia may occur in adults and may be conservatively managed with fasting, fibrates, and omega-3 fatty acids. Plasmapheresis or continuous insulin infusion may be used for symptomatic patients with high triglyceride levels. Lipidlowering agents should be continued for patients previously treated for hyperlipidemia. Regular monitoring of lipid levels for patients receiving L-Asp is important, especially for those with a prior history of dyslipidemia. Re-challenge with L-Asp can be undertaken on an individual basis. PMID- 23038233 TI - Toxic epidermal necrolysis related to Cisplatin and pemetrexed for metastatic non small cell lung cancer. AB - BACKGROUND: Toxic epidermal necrolysis (TEN) is an uncommon but life-threatening adverse drug reaction. Pemetrexed is a multitargeted antifolate. It was first used in combination with cisplatin as a front-line treatment for malignant pleural mesothelioma. The same combination is nowadays approved in the first-line setting for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). PATIENT AND METHODS: We report the case of a 50-year-old man treated for metastatic NSCLC. Within 5 days after administration of the second cycle of cisplatin and pemetrexed, he developed large blisters, which secondarily became hemorrhagic, and mucosal lesions. The characteristic clinical appearance, the histopathological findings, and the clinical course were decisive for the diagnosis of TEN. Treatment with systemic steroids and intravenous antibiotics as well as topical wound treatment led to resolution and improvement of his general condition. CONCLUSIONS: To the best of our knowledge, this is the third case of TEN due to pemetrexed in a patient with NSCLC. Clinicians should be aware of TEN as a rare but potentially fatal disorder requiring hospitalization and multidisciplinary management. PMID- 23038234 TI - Pulmonary actinomycosis mimicking metastasis from lung adenocarcinoma. AB - BACKGROUND: Pulmonary actinomycosis may create a diagnostic and therapeutic dilemma especially in cancer patients. CASE REPORT: A 64-year-old male patient presented with a productive cough, bloody sputum, and weight loss. Thoracic computed tomography (CT) showed a 5-cm mass in the upper lobe of the right lung, and a 2-cm mass in the lower lobe of the left lung. Bronchoscopic examination did not show any endobronchial lesions. CT-guided needle biopsy of the right pulmonary lesion showed lung adenocarcinoma. Wholebody positron emission tomography/CT revealed an increase in fluorodeoxyglucose accumulation in the upper lobe of the right lung, in the lower lobe of the left lung, and in the right hilar and paratracheal lymph nodes. Before chemotherapy was initiated, the patient had to be admitted to the hospital because of massive hemoptysis. Bronchoscopic examination indicated persistent bleeding in the left lower lobe bronchus. The patient underwent diagnostic left thoracotomy, and wedge resection of the lower lobe mass. The diagnosis was pulmonary actinomycosis, and the patient received oral amoxicillin. He underwent successful surgery for the primary disease following 6 cycles of chemotherapy. CONCLUSION: Oncologists should be aware of rare diseases that may affect management approaches in the treatment of cancer. PMID- 23038235 TI - The clinical usefulness of DNA aneuploidy in borderline ovarian tumours. PMID- 23038236 TI - Commentary. PMID- 23038237 TI - Primary intracranial leiomyosarcoma: review of the literature and presentation of a case. AB - BACKGROUND: Primary intracranial leiomyosarcoma (LMS) is a rare tumor of the central nervous system and therefore has only been reported sporadically. METHODS: The MEDLINE database was searched for relevant case reports and series published in English from 1969 to March 2012. These papers were reviewed to identify clinical and histopathological features, treatment modalities, and prognoses of patients with primary intracranial LMS. RESULTS: We reviewed 37 patients, including our patient, with primary intracranial LMS. Of these cases, 16 (43.2%) involved immunosuppression, 4 (10.8%) involved radiation-induced LMS, 3 (8.1%) cases involved a potential leiomyosarcomatous transformation of a brain lesion, and 7 (18.9%) cases, including the presented case, had no specific medical history. The treatment for these cases included resection (33/37, 89.2%), postoperative radiotherapy (20/37, 54.1%), and chemotherapy (7/37, 18.9%). CONCLUSIONS: The best method for the treatment of LMS could not be determined due to the limited number of cases that have been reported. However, optimized surgical resection, postoperative radiotherapy, and sarcoma-based chemotherapy may improve treatment outcomes. PMID- 23038238 TI - Women with viral STIs face dilemmas in negotiating condom use and would like direct safe sex advice from clinicians. PMID- 23038239 TI - MITK diffusion imaging. AB - BACKGROUND: Diffusion-MRI provides a unique window on brain anatomy and insights into aspects of tissue structure in living humans that could not be studied previously. There is a major effort in this rapidly evolving field of research to develop the algorithmic tools necessary to cope with the complexity of the datasets. OBJECTIVES: This work illustrates our strategy that encompasses the development of a modularized and open software tool for data processing, visualization and interactive exploration in diffusion imaging research and aims at reinforcing sustainable evaluation and progress in the field. METHODS: In this paper, the usability and capabilities of a new application and toolkit component of the Medical Imaging and Interaction Toolkit (MITK, www.mitk.org), MITK-DI, are demonstrated using in-vivo datasets. RESULTS: MITK-DI provides a comprehensive software framework for high-performance data processing, analysis and interactive data exploration, which is designed in a modular, extensible fashion (using CTK) and in adherence to widely accepted coding standards (e.g. ITK, VTK). MITK-DI is available both as an open source software development toolkit and as a ready-to use installable application. CONCLUSIONS: The open source release of the modular MITK-DI tools will increase verifiability and comparability within the research community and will also be an important step towards bringing many of the current techniques towards clinical application. PMID- 23038241 TI - Mobility decline in old age. AB - Mobility is important for community independence. With increasing age, underlying pathologies, genetic vulnerabilities, physiological and sensory impairments, and environmental barriers increase the risk for mobility decline. Understanding how mobility declines is paramount to finding ways to promote mobility in old age. PMID- 23038242 TI - Proprioceptive feedback and preferred patterns of human movement. AB - During cyclical tasks, humans often prefer stereotyped movement patterns. Although minimization of metabolic energy expenditure commonly is proposed as an underlying motor control goal, the mechanism by which humans choose their preferred movement pattern is not clear. We hypothesize that humans use proprioceptive feedback, which provides information about body mechanics in the identification of the preferred pattern of movement. PMID- 23038243 TI - Origin and development of muscle cramps. AB - Cramps are sudden, involuntary, painful muscle contractions. Their pathophysiology remains poorly understood. One hypothesis is that cramps result from changes in motor neuron excitability (central origin). Another hypothesis is that they result from spontaneous discharges of the motor nerves (peripheral origin). The central origin hypothesis has been supported by recent experimental findings, whose implications for understanding cramp contractions are discussed. PMID- 23038240 TI - Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, IFT27 and parvalbumin. AB - We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case-control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5 Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P = 4.69 * 10(-4)). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P = 1.42 * 10(-5)). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P = 8.89 * 10(-6)). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P = 3.43 * 10(-4)). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P = 1.76 * 10(-6)). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region. PMID- 23038244 TI - Exercise ventilatory limitation: the role of expiratory flow limitation. PMID- 23038245 TI - A bacterial pathogen co-opts host plasmin to resist killing by cathelicidin antimicrobial peptides. AB - The bacterial pathogen Group A Streptococcus (GAS) colonizes epithelial and mucosal surfaces and can cause a broad spectrum of human disease. Through the secreted plasminogen activator streptokinase (Ska), GAS activates human plasminogen into plasmin and binds it to the bacterial surface. The resulting surface plasmin protease activity has been proposed to play a role in disrupting tissue barriers, promoting invasive spread of the bacterium. We investigated whether this surface protease activity could aid the immune evasion role through degradation of the key innate antimicrobial peptide LL-37, the human cathelicidin. Cleavage products of plasmin-degraded LL-37 were analyzed by matrix assisted laser desorption ionization mass spectrometry. Ska-deficient GAS strains were generated by targeted allelic exchange mutagenesis and confirmed to lack surface plasmin activity after growth in human plasma or media supplemented with plasminogen and fibrinogen. Loss of surface plasmin activity left GAS unable to efficiently degrade LL-37 and increased bacterial susceptibility to killing by the antimicrobial peptide. When mice infected with GAS were simultaneously treated with the plasmin inhibitor aprotinin, a significant reduction in the size of necrotic skin lesions was observed. Together these data reveal a novel immune evasion strategy of the human pathogen: co-opting the activity of a host protease to evade peptide-based innate host defenses. PMID- 23038246 TI - beta-Catenin activates the HOXA10 and CDX4 genes in myeloid progenitor cells. AB - HoxA10 is a homeodomain transcription factor that is involved in maintenance of the myeloid progenitor population and implicated in myeloid leukemogenesis. Previously, we found that FGF2 and CDX4 are direct target genes of HoxA10 and that HOXA10 is a Cdx4 target gene. We also found that increased production of fibroblast growth factor 2 (Fgf2) by HoxA10-overexpressing myeloid progenitor cells results in activation of beta-catenin in an autocrine manner. In this study, we identify novel cis elements in the CDX4 and HOXA10 genes that are activated by beta-catenin in myeloid progenitor cells. We determine that beta catenin interacts with these cis elements, identifying both CDX4 and HOXA10 as beta-catenin target genes in this context. We demonstrate that HoxA10-induced CDX4 transcription is influenced by Fgf2-dependent beta-catenin activation. Similarly, Cdx4-induced HOXA10 transcription is influenced by beta-catenin in an Fgf2-dependent manner. Increased expression of a set of Hox proteins, including HoxA10, is associated with poor prognosis in acute myeloid leukemia. Cdx4 contributes to leukemogenesis in Hox-overexpressing acute myeloid leukemia, and increased beta-catenin activity is also associated with poor prognosis. The current studies identify a molecular mechanisms through which increased expression of HoxA10 increases Cdx4 expression by direct CDX4 activation and by Fgf2-induced beta-catenin activity. This results in Cdx4-induced HoxA10 expression, creating a positive feedback mechanism. PMID- 23038247 TI - Architectural arrangement of the small nuclear RNA (snRNA)-activating protein complex 190 subunit (SNAP190) on U1 snRNA gene promoter DNA. AB - Myb repeats ~52 amino acid residues in length were first characterized in the oncogenic Myb transcription factor, which contains three tandem Myb repeats in its DNA-binding domain. Proteins of this family normally contain either one, two, or three tandem Myb repeats that are involved in protein-DNA interactions. The small nuclear RNA (snRNA)-activating protein complex (SNAPc) is a heterotrimeric transcription factor that is required for expression of small nuclear RNA genes. This complex binds to an essential promoter element, the proximal sequence element, centered ~50 base pairs upstream of the transcription start site of snRNA genes. SNAP190, the largest subunit of SNAPc, uncharacteristically contains 4.5 tandem Myb repeats. Little is known about the arrangement of the Myb repeats in the SNAPc-DNA complex, and it has not been clear whether all 4.5 Myb repeats contact the DNA. By using a site-specific protein-DNA photo-cross-linking assay, we have now mapped specific nucleotides where each of the Myb repeats of Drosophila melanogaster SNAP190 interacts with a U1 snRNA gene proximal sequence element. The results reveal the topological arrangement of the 4.5 SNAP190 Myb repeats relative to the DNA and to each other when SNAP190 is bound to a U1 promoter as a subunit of SNAPc. PMID- 23038248 TI - Poly(ADP-ribose) contributes to an association between poly(ADP-ribose) polymerase-1 and xeroderma pigmentosum complementation group A in nucleotide excision repair. AB - Exposure to ultraviolet radiation (UVR) promotes the formation of UVR-induced, DNA helix distorting photolesions such as (6-4) pyrimidine-pyrimidone photoproducts and cyclobutane pyrimidine dimers. Effective repair of such lesions by the nucleotide excision repair (NER) pathway is required to prevent DNA mutations and chromosome aberrations. Poly(ADP-ribose) polymerase-1 (PARP-1) is a zinc finger protein with well documented involvement in base excision repair. PARP-1 is activated in response to DNA damage and catalyzes the formation of poly(ADP-ribose) subunits that assist in the assembly of DNA repair proteins at sites of damage. In this study, we present evidence for PARP-1 contributions to NER, extending the knowledge of PARP-1 function in DNA repair beyond the established role in base excision repair. Silencing the PARP-1 protein or inhibiting PARP activity leads to retention of UVR-induced photolesions. PARP activation following UVR exposure promotes association between PARP-1 and XPA, a central protein in NER. Administration of PARP inhibitors confirms that poly(ADP ribose) facilitates PARP-1 association with XPA in whole cell extracts, in isolated chromatin complexes, and in vitro. Furthermore, inhibition of PARP activity decreases UVR-stimulated XPA chromatin association, illustrating that these relationships occur in a meaningful context for NER. These results provide a mechanistic link for PARP activity in the repair of UVR-induced photoproducts. PMID- 23038249 TI - Novel activation of voltage-gated K(+) channels by sevoflurane. AB - BACKGROUND: Halogenated inhaled anesthetics modulate voltage-gated ion channels by unknown mechanisms. RESULTS: Biophysical analyses revealed novel activation of K(v) channels by the inhaled anesthetic sevoflurane. CONCLUSION: K(v) channel activation by sevoflurane results from the positive allosteric modulation of activation gating. SIGNIFICANCE: The unique activation of K(v) channels by sevoflurane demonstrates novel anesthetic specificity and offers new insights into allosteric modulation of channel gating. Voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, but the underlying molecular mechanisms are not understood. Alkanols and halogenated inhaled anesthetics such as halothane and isoflurane inhibit the archetypical voltage gated Kv3 channel homolog K-Shaw2 by stabilizing the resting/closed states. By contrast, sevoflurane, a more heavily fluorinated ether commonly used in general anesthesia, specifically activates K-Shaw2 currents at relevant concentrations (0.05-1 mM) in a rapid and reversible manner. The concentration dependence of this modulation is consistent with the presence of high and low affinity interactions (K(D) = 0.06 and 4 mM, respectively). Sevoflurane (<1 mM) induces a negative shift in the conductance-voltage relation and increases the maximum conductance. Furthermore, suggesting possible roles in general anesthesia, mammalian Kv1.2 and Kv1.5 channels display similar changes. Quantitative description of the observations by an economical allosteric model indicates that sevoflurane binding favors activation gating and eliminates an unstable inactivated state outside the activation pathway. This study casts light on the mechanism of the novel sevoflurane-dependent activation of Kv channels, which helps explain how closely related inhaled anesthetics achieve specific actions and suggests strategies to develop novel Kv channel activators. PMID- 23038250 TI - Glutamate-gated chloride channels. AB - Glutamate-gated chloride channels (GluCls) are found only in protostome invertebrate phyla but are closely related to mammalian glycine receptors. They have a number of roles in these animals, controlling locomotion and feeding and mediating sensory inputs into behavior. In nematodes and arthropods, they are targeted by the macrocyclic lactone family of anthelmintics and pesticides, making the GluCls of considerable medical and economic importance. Recently, the three-dimensional structure of a GluCl was solved, the first for any eukaryotic ligand-gated anion channel, revealing a macrocyclic lactone-binding site between the channel domains of adjacent subunits. This minireview will highlight some unique features of the GluCls and illustrate their contribution to our knowledge of the entire Cys loop ligand-gated ion channel superfamily. PMID- 23038251 TI - Production of selenoprotein P (Sepp1) by hepatocytes is central to selenium homeostasis. AB - BACKGROUND: Sepp1 transports selenium, but its complete role in selenium homeostasis is not known. RESULTS: Deletion of Sepp1 in hepatocytes increases liver selenium at the expense of other tissues and decreases whole-body selenium by increasing excretion. CONCLUSION: Sepp1 production by hepatocytes retains selenium in the organism and distributes it from the liver to peripheral tissues. SIGNIFICANCE: Sepp1 is central to selenium homeostasis. Sepp1 is a widely expressed extracellular protein that in humans and mice contains 10 selenocysteine residues in its primary structure. Extra-hepatic tissues take up plasma Sepp1 for its selenium via apolipoprotein E receptor-2 (apoER2)-mediated endocytosis. The role of Sepp1 in the transport of selenium from liver, a rich source of the element, to peripheral tissues was studied using mice with selective deletion of Sepp1 in hepatocytes (Sepp1(c/c)/alb-cre(+/-) mice). Deletion of Sepp1 in hepatocytes lowered plasma Sepp1 concentration to 10% of that in Sepp1(c/c) mice (controls) and increased urinary selenium excretion, decreasing whole-body and tissue selenium concentrations. Under selenium deficient conditions, Sepp1(c/c)/alb-cre(+/-) mice accumulated selenium in the liver at the expense of extra-hepatic tissues, severely worsening clinical manifestations of dietary selenium deficiency. These findings are consistent with there being competition for metabolically available hepatocyte selenium between the synthesis of selenoproteins and the synthesis of selenium excretory metabolites. In addition, selenium deficiency down-regulated the mRNA of the most abundant hepatic selenoprotein, glutathione peroxidase-1 (Gpx1), to 15% of the selenium-replete value, while reducing Sepp1 mRNA, the most abundant hepatic selenoprotein mRNA, only to 61%. This strongly suggests that Sepp1 synthesis is favored in the liver over Gpx1 synthesis when selenium supply is limited, directing hepatocyte selenium to peripheral tissues in selenium deficiency. We conclude that production of Sepp1 by hepatocytes is central to selenium homeostasis in the organism because it promotes retention of selenium in the body and effects selenium distribution from the liver to extra-hepatic tissues, especially under selenium-deficient conditions. PMID- 23038252 TI - The Bacillus subtilis chemoreceptor McpC senses multiple ligands using two discrete mechanisms. AB - Bacillus subtilis can perform chemotaxis toward all 20 L-amino acids normally found in proteins. Loss of a single chemoreceptor, McpC, was previously found to reduce chemotaxis to 19 of these amino acids. In this study, we investigated the amino acid-sensing mechanism of McpC. We show that McpC alone can support chemotaxis to 17 of these amino acids to varying degrees. Eleven amino acids were found to directly bind the amino-terminal sensing domain of McpC in vitro. Sequence analysis indicates that the McpC sensing domain exhibits a dual Per-Arnt Sim (PAS) domain structure. Using this structure as a guide, we were able to isolate mutants that suggest that four amino acids (arginine, glutamine, lysine, and methionine) are sensed by an indirect mechanism. We identified four candidate binding lipoproteins associated with amino acid transporters that may function in indirect sensing: ArtP, GlnH, MetQ, and YckB. ArtP was found to bind arginine and lysine; GlnH, glutamine; MetQ, methionine; and YckB, tryptophan. In addition, we found that ArtP, MetQ, and YckB bind the sensing domain of McpC, suggesting that the three participate in the indirect sensing of arginine, lysine, methionine, and possibly tryptophan as well. Taken together, these results further our understanding of amino acid chemotaxis in B. subtilis and gain insight into how a single chemoreceptor is able to sense many amino acids. PMID- 23038253 TI - Subunit-specific incorporation efficiency and kinetics in mitochondrial complex I homeostasis. AB - Studies employing native PAGE suggest that most nDNA-encoded CI subunits form subassemblies before assembling into holo-CI. In addition, in vitro evidence suggests that some subunits can directly exchange in holo-CI. Presently, data on the kinetics of these two incorporation modes for individual CI subunits during CI maintenance are sparse. Here, we used inducible HEK293 cell lines stably expressing AcGFP1-tagged CI subunits and quantified the amount of tagged subunit in mitoplasts and holo-CI by non-native and native PAGE, respectively, to determine their CI incorporation efficiency. Analysis of time courses of induction revealed three subunit-specific patterns. A first pattern, represented by NDUFS1, showed overlapping time courses, indicating that imported subunits predominantly incorporate into holo-CI. A second pattern, represented by NDUFV1, consisted of parallel time courses, which were, however, not quantitatively overlapping, suggesting that imported subunits incorporate at similar rates into holo-CI and CI assembly intermediates. The third pattern, represented by NDUFS3 and NDUFA2, revealed a delayed incorporation into holo-CI, suggesting their prior appearance in CI assembly intermediates and/or as free monomers. Our analysis showed the same maximum incorporation into holo-CI for NDUFV1, NDUFV2, NDUFS1, NDUFS3, NDUFS4, NDUFA2, and NDUFA12 with nearly complete loss of endogenous subunit at 24 h of induction, indicative of an equimolar stoichiometry and unexpectedly rapid turnover. In conclusion, the results presented demonstrate that newly formed nDNA-encoded CI subunits rapidly incorporate into holo-CI in a subunit-specific manner. PMID- 23038254 TI - A small multidrug resistance-like transporter involved in the arabinosylation of arabinogalactan and lipoarabinomannan in mycobacteria. AB - The biosynthesis of the major cell envelope glycoconjugates of Mycobacterium tuberculosis is topologically split across the plasma membrane, yet nothing is known of the transporters required for the translocation of lipid-linked sugar donors and oligosaccharide intermediates from the cytoplasmic to the periplasmic side of the membrane in mycobacteria. One of the mechanisms used by prokaryotes to translocate lipid-linked phosphate sugars across the plasma membrane relies on translocases that share resemblance with small multidrug resistance transporters. The presence of an small multidrug resistance-like gene, Rv3789, located immediately upstream from dprE1/dprE2 responsible for the formation of decaprenyl monophosphoryl-beta-D-arabinose (DPA) in the genome of M. tuberculosis led us to investigate its potential involvement in the formation of the major arabinosylated glycopolymers, lipoarabinomannan (LAM) and arabinogalactan (AG). Disruption of the ortholog of Rv3789 in Mycobacterium smegmatis resulted in a reduction of the arabinose content of both AG and LAM that accompanied the accumulation of DPA in the mutant cells. Interestingly, AG and LAM synthesis was restored in the mutant not only upon expression of Rv3789 but also upon that of the undecaprenyl phosphate aminoarabinose flippase arnE/F genes from Escherichia coli. A bacterial two-hybrid system further indicated that Rv3789 interacts in vivo with the galactosyltransferase that initiates the elongation of the galactan domain of AG. Biochemical and genetic evidence is thus consistent with Rv3789 belonging to an AG biosynthetic complex, where its role is to reorient DPA to the periplasm, allowing this arabinose donor to then be used in the buildup of the arabinan domains of AG and LAM. PMID- 23038255 TI - Introduction to thematic minireview series on celebrating the discovery of the cysteine loop ligand-gated ion channel superfamily. AB - The year 2012 marks the 25th anniversary of the discovery of the Cys loop ligand gated ion channel superfamily of neurotransmitter receptors. This minireview series celebrates this with a series of articles reviewing current information for each of the family members, nicotinic acetylcholine receptors, glycine receptors, GABA(A) receptors, serotonin-3 (5-HT(3)) receptors, and glutamate gated chloride ion channels of proteasome invertebrate phyla. PMID- 23038256 TI - Functional compensation between cholecystokinin-1 and -2 receptors in murine paraventricular nucleus neurons. AB - Cholecystokinin (CCK) and its receptor subtypes CCK-1 and -2 have diverse homeostatic functions. CCK-1 and -2 receptors share a common phosphatidylinositol signaling pathway, yet little is known regarding their possible functional coupling. We focused on CCK-mediated Ca(2+) signaling in parvocellular paraventricular nucleus (PVN) cells, which control satiety and other autonomic functions. Analysis of mouse hypothalamic slices demonstrated that the general CCK receptor agonist CCK-8s (10 nM) triggered Ca(2+) transients most significantly in the posterior subregion of the PVN (PaPo). This 10 nM CCK-8s induced response was absent in CCK-1 receptor knock-out (CCK1R(-/-)) slices, showing that the response is mediated by CCK-1 receptors. CCK-8s concentrations higher than 30 nM triggered a Ca(2+) rise similarly in wild-type and CCK1R(-/-) slices. The large CCK-8s (100 nM)-induced Ca(2+) responses in CCK1R(-/-) slices were blocked by a CCK-2 receptor antagonist (CI-988), whereas those in wild-type slices required a mixture of CI-988 and lorglumide (a CCK-1 receptor antagonist) for complete antagonism. Therefore, CCK-1 and -2 receptors may function synergistically in single PaPo neurons and deletion of CCK-1 receptors may facilitate CCK-2 receptor signaling. This hypothesis was supported by results of real-time RT-PCR, immunofluorescence double labeling and Western blotting assays, which indicated CCK-2 receptor overexpression in PaPo neurons of CCK1R(-/-) mice. Furthermore, behavioral studies showed that intraperitoneal injections of lorglumide up-regulated food accesses in wild-type but not in CCK1R(-/-) mice, whereas CI-988 injections up-regulated food accesses in CCK1R(-/-) but not in wild-type mice. Compensatory CCK signaling via CCK-2 receptors in CCK1R(-/-) mice shed light on currently controversial satiety-controlling mechanisms. PMID- 23038257 TI - The nicotinic acetylcholine receptor: the founding father of the pentameric ligand-gated ion channel superfamily. AB - A critical event in the history of biological chemistry was the chemical identification of the first neurotransmitter receptor, the nicotinic acetylcholine receptor. Disciplines as diverse as electrophysiology, pharmacology, and biochemistry joined together in a unified and rational manner with the common goal of successfully identifying the molecular device that converts a chemical signal into an electrical one in the nervous system. The nicotinic receptor has become the founding father of a broad family of pentameric membrane receptors, paving the way for their identification, including that of the GABA(A) receptors. PMID- 23038258 TI - Competition between anion binding and dimerization modulates Staphylococcus aureus phosphatidylinositol-specific phospholipase C enzymatic activity. AB - BACKGROUND: Bacterial phosphatidylinositol-specific phospholipase C targets PI and glycosylphosphatidylinositol-linked proteins of eukaryotic cells. RESULTS: Functional relevance of a homodimeric S. aureus PI-PLC crystal structure is supported by enzyme kinetics and mutagenesis. Nonsubstrate phosphatidylcholine increases activity by facilitating enzyme dimerization. CONCLUSION: Activating transient dimerization is antagonized by anions binding to a discrete site. SIGNIFICANCE: Interplay of protein oligomerization and anion binding controls enzyme activity. Staphylococcus aureus phosphatidylinositol-specific phospholipase C (PI-PLC) is a secreted virulence factor for this pathogenic bacterium. A novel crystal structure shows that this PI-PLC can form a dimer via helix B, a structural feature present in all secreted, bacterial PI-PLCs that is important for membrane binding. Despite the small size of this interface, it is critical for optimal enzyme activity. Kinetic evidence, increased enzyme specific activity with increasing enzyme concentration, supports a mechanism where the PI PLC dimerization is enhanced in membranes containing phosphatidylcholine (PC). Mutagenesis of key residues confirm that the zwitterionic phospholipid acts not by specific binding to the protein, but rather by reducing anionic lipid interactions with a cationic pocket on the surface of the S. aureus enzyme that stabilizes monomeric protein. Despite its structural and sequence similarity to PI-PLCs from other Gram-positive pathogenic bacteria, S. aureus PI-PLC appears to have a unique mechanism where enzyme activity is modulated by competition between binding of soluble anions or anionic lipids to the cationic sensor and transient dimerization on the membrane. PMID- 23038259 TI - Isocitrate dehydrogenase (IDH) mutations promote a reversible ZEB1/microRNA (miR) 200-dependent epithelial-mesenchymal transition (EMT). AB - Mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a variety of tumor types, resulting in production of the proposed oncometabolite, 2-hydroxyglutarate (2-HG). How mutant IDH and 2-HG alter signaling pathways to promote cancer, however, remains unclear. Additionally, there exist relatively few cell lines with IDH mutations. To examine the effect of endogenous IDH mutations and 2-HG, we created a panel of isogenic epithelial cell lines with either wild-type IDH1/2 or clinically relevant IDH1/2 mutations. Differences were noted in the ability of IDH mutations to cause robust 2-HG accumulation. IDH1/2 mutants that produce high levels of 2-HG cause an epithelial mesenchymal transition (EMT)-like phenotype, characterized by changes in EMT related gene expression and cellular morphology. 2-HG is sufficient to recapitulate aspects of this phenotype in the absence of an IDH mutation. In the cells types examined, mutant IDH-induced EMT is dependent on up-regulation of the transcription factor ZEB1 and down-regulation of the miR-200 family of microRNAs. Furthermore, sustained knockdown of IDH1 in IDH1 R132H mutant cells is sufficient to reverse many characteristics of EMT, demonstrating that continued expression of mutant IDH is required to maintain this phenotype. These results suggest mutant IDH proteins can reversibly deregulate discrete signaling pathways that contribute to tumorigenesis. PMID- 23038260 TI - Inhibitory glycine receptors: an update. AB - Strychnine-sensitive glycine receptors (GlyRs) mediate synaptic inhibition in the spinal cord, brainstem, and other regions of the mammalian central nervous system. In this minireview, we summarize our current view of the structure, ligand-binding sites, and chloride channel of these receptors and discuss recently emerging functions of distinct GlyR isoforms. GlyRs not only regulate the excitability of motor and afferent sensory neurons, including pain fibers, but also are involved in the processing of visual and auditory signals. Hence, GlyRs constitute promising targets for the development of therapeutically useful compounds. PMID- 23038261 TI - Rit-mediated stress resistance involves a p38-mitogen- and stress-activated protein kinase 1 (MSK1)-dependent cAMP response element-binding protein (CREB) activation cascade. AB - The cAMP response element (CRE)-binding protein (CREB) is a key regulatory factor of gene transcription, and plays an essential role in development of the central nervous system and for neuroprotection. Multiple signaling pathways have been shown to contribute to the regulation of CREB-dependent transcription, including both ERK and p38 mitogen-activated protein (MAP) kinases cascades. Recent studies have identified the Ras-related small G-protein, Rit, as a central regulator of a p38-MK2-HSP27 signaling cascade that functions as a critical survival mechanism for cells adapting to stress. Here, we examine the contribution of Rit-p38 signaling to the control of stress-dependent gene transcription. Using a pheochromocytoma cell model, we find that a novel Rit-p38-MSK1/2 pathway plays a critical role in stress-mediated CREB activation. RNAi-mediated Rit silencing, or inhibition of p38 or MSK1/2 kinases, was found to disrupt stress-mediated CREB dependent transcription, resulting in increased cell death. Furthermore, ectopic expression of active Rit stimulates CREB-Ser133 phosphorylation, induces expression of the anti-apoptotic Bcl-2 and Bcl(XL) proteins, and promotes cell survival. These data indicate that the Rit-p38-MSK1/2 signaling pathway may have an important role in the stress-dependent regulation of CREB-dependent gene expression. PMID- 23038262 TI - p21-activated kinase-1 signaling regulates transcription of tissue factor and tissue factor pathway inhibitor. AB - Tissue factor (TF) is a cell-surface glycoprotein responsible for initiating the coagulation cascade. Besides its role in homeostasis, studies have shown the implication of TF in embryonic development, cancer-related events, and inflammation via coagulation-dependent and -independent (signaling) mechanisms. Tissue factor pathway inhibitor (TFPI) plays an important role in regulating TF initiated blood coagulation. Therefore, transcriptional regulation of TF expression and its physiological inhibitor TFPI would allow us to understand the critical step that controls many different processes. From a gene profiling study aimed at identifying differentially regulated genes between wild-type (WT) and p21-activated kinase 1-null (PAK1-KO) mouse embryonic fibroblasts (MEFs), we found TF and TFPI are differentially expressed in the PAK1-KO MEFs in comparison with wild-type MEFs. Based on these findings, we further investigated in this study the transcriptional regulation of TF and TFPI by PAK1, a serine/threonine kinase. We found that the PAK1.c-Jun complex stimulates the transcription of TF and consequently its procoagulant activity. Moreover, PAK1 negatively regulates the expression of TFPI and additionally contributes to increased TF activity. For the first time, this study implicates PAK1 in coagulation processes, through its dual transcriptional regulation of TF and its inhibitor. PMID- 23038263 TI - Ciliary neurotrophic factor protects mice against streptozotocin-induced type 1 diabetes through SOCS3: the role of STAT1/STAT3 ratio in beta-cell death. AB - Type 1 diabetes is characterized by a loss of islet beta-cells. Ciliary neurotrophic factor (CNTF) protects pancreatic islets against cytokine-induced apoptosis. For this reason, we assessed whether CNTF protects mice against streptozotocin-induced diabetes (a model of type 1 diabetes) and the mechanism for this protection. WT and SOCS3 knockdown C57BL6 mice were treated for 5 days with citrate buffer or 0.1 mg/kg CNTF before receiving 80 mg/kg streptozotocin. Glycemia in non-fasted mice was measured weekly from days 0-28 after streptozotocin administration. Diabetes was defined as a blood glucose > 11.2 mmol/liter. Wild-type (WT) and SOCS3 knockdown MIN6 cells were cultured with CNTF, IL1beta, or both. CNTF reduced diabetes incidence and islet apoptosis in WT but not in SOCS3kd mice. Likewise, CNTF inhibited apoptosis in WT but not in SOCS3kd MIN6 cells. CNTF increased STAT3 phosphorylation in WT and SOCS3kd mice and MIN6 cells but reduced STAT1 phosphorylation only in WT mice, in contrast to streptozotocin and IL1beta. Moreover, CNTF reduced NFkappaB activation and required down-regulation of inducible NO synthase expression to exert its protective effects. In conclusion, CNTF protects mice against streptozotocin induced diabetes by increasing pancreatic islet survival, and this protection depends on SOCS3. In addition, SOCS3 expression and beta-cell fate are dependent on STAT1/STAT3 ratio. PMID- 23038264 TI - Nuclear receptors HNF4alpha and LRH-1 cooperate in regulating Cyp7a1 in vivo. AB - Fibroblast growth factor 19 (FGF19) is a postprandial enterokine induced by the nuclear bile acid receptor, FXR, in ileum. FGF19 inhibits bile acid synthesis in liver through transcriptional repression of cholesterol 7alpha-hydroxylase (CYP7A1) via a mechanism involving the nuclear receptor SHP. Here, in a series of loss-of-function studies, we show that the nuclear receptors HNF4alpha and LRH-1 have dual roles in regulating Cyp7a1 in vivo. First, they cooperate in maintaining basal Cyp7a1 expression. Second, they enable SHP binding to the Cyp7a1 promoter and facilitate FGF19-mediated repression of bile acid synthesis. HNF4alpha and LRH-1 promote active transcription histone marks on the Cyp7a1 promoter that are reversed by FGF19 in a SHP-dependent manner. These findings demonstrate that both HNF4alpha and LRH-1 are important regulators of Cyp7a1 transcription in vivo. PMID- 23038265 TI - An L-glucose catabolic pathway in Paracoccus species 43P. AB - BACKGROUND: L-Glucose, the enantiomer of D-glucose, was believed not to be utilized by any organisms. RESULTS: An L-glucose-utilizing bacterium was isolated, and its L-glucose catabolic pathway was identified genetically and enzymatically. CONCLUSION: L-Glucose was utilized via a novel pathway to pyruvate and D-glyceraldehyde 3-phosphate. SIGNIFICANCE: This might lead to an understanding of homochirality in sugar metabolism. An L-glucose-utilizing bacterium, Paracoccus sp. 43P, was isolated from soil by enrichment cultivation in a minimal medium containing L-glucose as the sole carbon source. In cell-free extracts from this bacterium, NAD(+)-dependent L-glucose dehydrogenase was detected as having sole activity toward L-glucose. This enzyme, LgdA, was purified, and the lgdA gene was found to be located in a cluster of putative inositol catabolic genes. LgdA showed similar dehydrogenase activity toward scyllo- and myo-inositols. L-Gluconate dehydrogenase activity was also detected in cell-free extracts, which represents the reaction product of LgdA activity toward L-glucose. Enzyme purification and gene cloning revealed that the corresponding gene resides in a nine-gene cluster, the lgn cluster, which may participate in aldonate incorporation and assimilation. Kinetic and reaction product analysis of each gene product in the cluster indicated that they sequentially metabolize L-gluconate to glycolytic intermediates, D-glyceraldehyde 3-phosphate, and pyruvate through reactions of C-5 epimerization by dehydrogenase/reductase, dehydration, phosphorylation, and aldolase reaction, using a pathway similar to L-galactonate catabolism in Escherichia coli. Gene disruption studies indicated that the identified genes are responsible for L glucose catabolism. PMID- 23038266 TI - The ubiquitin-associated (UBA) 1 domain of Schizosaccharomyces pombe Rhp23 is essential for the recognition of ubiquitin-proteasome system substrates both in vitro and in vivo. AB - The ubiquitin-proteasome system is essential for maintaining a functional cell. Not only does it remove incorrectly folded proteins, it also regulates protein levels to ensure their appropriate spatial and temporal distribution. Proteins marked for degradation by the addition of Lys(48)-linked ubiquitin (Ub) chains are recognized by shuttle factors and transported to the 26 S proteasome. One of these shuttle factors, Schizosaccharomyces pombe Rhp23, has an unusual domain architecture. It comprises an N-terminal ubiquitin-like domain that can recognize the proteasome followed by two ubiquitin-associated (UBA) domains, termed UBA1 and UBA2, which can bind Ub. This architecture is conserved up to humans, suggesting that both domains are important for Rhp23 function. Such an extent of conservation raises the question as to why, in contrast to all other shuttle proteins, does Rhp23 require two UBA domains? We performed in vitro Ub binding assays using domain swap chimeric proteins and mutated domains in isolation as well as in the context of the full-length protein to reveal that the Ub binding properties of the UBA domains are context-dependent. In vivo, the internal Rhp23 UBA1 domain provides sufficient Ub recognition for the protein to function without UBA2. PMID- 23038267 TI - Role of glutamate decarboxylase-like protein 1 (GADL1) in taurine biosynthesis. AB - This manuscript concerns the tissue-specific transcription of mouse and cattle glutamate decarboxylase-like protein 1 (GADL1) and the biochemical activities of human GADL1 recombinant protein. Bioinformatic analysis suggested that GADL1 appears late in evolution, only being found in reptiles, birds, and mammals. RT PCR determined that GADL1 mRNA is transcribed at high levels in mouse and cattle skeletal muscles and also in mouse kidneys. Substrate screening determined that GADL1, unlike its name implies, has no detectable GAD activity, but it is able to efficiently catalyze decarboxylation of aspartate, cysteine sulfinic acid, and cysteic acid to beta-alanine, hypotaurine, and taurine, respectively. Western blot analysis verified the presence of GADL1 in mouse muscles, kidneys, C2C12 myoblasts, and C2C12 myotubes. Incubation of the supernatant of fresh muscle or kidney extracts with cysteine sulfinic acid resulted in the detection of hypotaurine or taurine in the reaction mixtures, suggesting the possible involvement of GADL1 in taurine biosynthesis. However, when the tissue samples were incubated with aspartate, no beta-alanine production was observed. We proposed several possibilities that might explain the inactivation of ADC activity of GADL1 in tissue protein extracts. Although beta-alanine-producing activity was not detected in the supernatant of tissue protein extracts, its potential role in beta-alanine synthesis cannot be excluded. There are several inhibitors of the ADC activity of GADL1 identified. The discovery of GADL1 biochemical activities, in conjunction with its expression and activities in muscles and kidneys, provides some tangible insight toward establishing its physiological function(s). PMID- 23038268 TI - Dynein light chain 1 (LC8) association enhances microtubule stability and promotes microtubule bundling. AB - BACKGROUND: Dynein Light Chain 1 (LC8) has been shown to pull down tubulin subunits, suggesting that it interacts with microtubules. RESULTS: LC8 decorates microtubules in vitro and in Drosophila embryos, promotes microtubule assembly, and stabilizes microtubules both in vitro and in tissue-cultured cells. CONCLUSION: LC8 stabilizes microtubules. SIGNIFICANCE: Data provide the first evidence of a novel MAP-like function of LC8. Dynein light chain 1 (LC8), a highly conserved protein, is known to bind to a variety of different polypeptides. It functions as a dimer, which is inactivated through phosphorylation at the Ser-88 residue. A loss of LC8 function causes apoptosis in Drosophila embryos, and its overexpression induces malignant transformation of breast cancer cells. Here we show that LC8 binds to tubulin, promotes microtubule assembly, and induces the bundling of reconstituted microtubules in vitro. Furthermore, LC8 decorates microtubules both in Drosophila embryos and in HeLa cells, increases the microtubule stability, and promotes microtubule bundling in these cells. Microtubule stability influences a number of different cellular functions including mitosis and cell differentiation. The LC8 overexpression reduces the susceptibility of microtubules to cold and nocodazole-induced depolymerization in tissue-cultured cells and increases microtubule acetylation, suggesting that LC8 stabilizes microtubules. We also show that LC8 knockdown or transfection with inhibitory peptides destabilizes microtubules and inhibits bipolar spindle assembly in HeLa cells. In addition, LC8 knockdown leads to the mitotic block in HeLa cells. Furthermore, molecular docking analysis using the crystal structures of tubulin and LC8 dimer indicated that the latter may bind at alpha-beta tubulin junction in a protofilament at sites distinct from the kinesin and dynein binding sites. Together, we provide the first evidence of a novel microtubule-associated protein-like function of LC8 that could explain its reported roles in cellular metastasis and differentiation. PMID- 23038269 TI - Structure, function, and modulation of GABA(A) receptors. AB - The GABA(A) receptors are the major inhibitory neurotransmitter receptors in mammalian brain. Each isoform consists of five homologous or identical subunits surrounding a central chloride ion-selective channel gated by GABA. How many isoforms of the receptor exist is far from clear. GABA(A) receptors located in the postsynaptic membrane mediate neuronal inhibition that occurs in the millisecond time range; those located in the extrasynaptic membrane respond to ambient GABA and confer long-term inhibition. GABA(A) receptors are responsive to a wide variety of drugs, e.g. benzodiazepines, which are often used for their sedative/hypnotic and anxiolytic effects. PMID- 23038270 TI - Systems analysis of cancer cell heterogeneity in caspase-dependent apoptosis subsequent to mitochondrial outer membrane permeabilization. AB - Deregulation of apoptosis is a hallmark of carcinogenesis. We here combine live cell imaging and systems modeling to investigate caspase-dependent apoptosis execution subsequent to mitochondrial outer membrane permeabilization (MOMP) in several cancer cell lines. We demonstrate that, although most cell lines that underwent MOMP also showed robust and fast activation of executioner caspases and apoptosis, the colorectal cancer cell lines LoVo and HCT-116 Smac(-/-), similar to X-linked inhibitor of apoptosis protein (XIAP)-overexpressing HeLa (HeLa XIAP(Adv)) cells, only showed delayed and often no caspase activation, suggesting apoptosis impairment subsequent to MOMP. Employing APOPTO-CELL, a recently established model of apoptosis subsequent to MOMP, this impairment could be understood by studying the systemic interaction of five proteins that are present in the apoptosis pathway subsequent to MOMP. Using APOPTO-CELL as a tool to study detailed molecular mechanisms during apoptosis execution in individual cell lines, we demonstrate that caspase-9 was the most important regulator in DLD-1, HCT-116, and HeLa cells and identified additional cell line-specific co regulators. Developing and applying a computational workflow for parameter screening, systems modeling identified that apoptosis execution kinetics are more robust against changes in reaction kinetics in HCT-116 and HeLa than in DLD-1 cells. Our systems modeling study is the first to draw attention to the variability in cell specific protein levels and reaction rates and to the emergent effects of such variability on the efficiency of apoptosis execution and on apoptosis impairment subsequent to MOMP. PMID- 23038272 TI - Efficiency-improved organic solar cells based on plasticizer assisted soft embossed PEDOT:PSS layers. AB - Organic solar cells (OSCs) have attracted extensive attention as a promising approach for cost-effective photovoltaic devices. This study demonstrates a novel imprinting approach based on additional plasticizing, which is suited for thin polyethylenedioxythiophene:polystyrenesulphonate (PEDOT:PSS) layers. Such films are widely used as electron blocking and hole collecting intermediate layers in OSCs. Master molds with nano-scale channels are used for the temperature and pressure assisted imprinting routine and the shape of the imprinted structures is easily tunable via the plasticizer concentration. Depending on the surface topology of the PEDOT:PSS films structured poly(3-hexylthiophene) (P3HT):phenyl C(61)-butyric acid methyl ester (PCBM) bulk heterojunction solar cells have improved power conversion efficiencies in comparison to their planar references. This effect results from enhanced optical absorption due to the resulting textured aluminum electrode and improved charge carrier extraction at the artificially structured electrodes. In addition, OSCs based on low aspect ratio PEDOT:PSS imprints show increased relative performance under oblique light incidence. PMID- 23038271 TI - 5-HT(3) receptors. AB - 5-Hydroxytryptamine type 3 (5-HT(3)) receptors are cation-selective Cys loop receptors found in both the central and peripheral nervous systems. There are five 5-HT(3) receptor subunits (A-E), and all functional receptors require at least one A subunit. Regions from noncontiguous parts of the subunit sequence contribute to the agonist-binding site, and the roles of a range of amino acid residues that form the binding pocket have been identified. Drugs that selectively antagonize 5-HT(3) receptors (the "setrons") are the current gold standard for treatment of chemotherapy-induced and postoperative nausea and vomiting and have potential for the treatment of a range of other conditions. PMID- 23038273 TI - PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response. AB - PI3K, mTOR and NOTCH pathways are frequently dysregulated in T-cell acute lymphoblastic leukaemia (T-ALL). Blockade of PI3K and mTOR with the dual inhibitor PI-103 decreased proliferation in all 15 T-ALL cell lines tested, inducing cell death in three. Combined PI3K/mTOR/NOTCH inhibition (with a gamma secretase inhibitor (GSI)) led to enhanced cell-cycle arrest and to subsequent cell death in 7/11 remaining NOTCH mutant cell lines. Commitment to cell death occurred within 48-72 h and was maximal when PI3K, mTOR and NOTCH activities were inhibited. PI-103 addition led to upregulation of c-MYC, which was blocked by coincubation with a GSI, indicating that PI3K/mTOR inhibition resulted in activation of the NOTCH-MYC pathway. Microarray studies showed a global increase in NOTCH target gene expression upon PI3K/mTOR inhibition. NOTCH-MYC-induced resistance to PI3K/mTOR inhibition was supported by synergistic cell death induction by PI-103 and a small molecule c-MYC inhibitor, and by reduction of the cytotoxic effect of PI-103+GSI by c-MYC overexpression. These results show that drugs targeting PI3K/mTOR can upregulate NOTCH-MYC activity, have implications for the use of PI3K inhibitors for the treatment of other malignancies with activated NOTCH, and provide a rational basis for the use of drug combinations that target both the pathways. PMID- 23038274 TI - SIAH proteins: critical roles in leukemogenesis. AB - The delicate balance between the synthesis and the degradation of proteins ensures cellular homeostasis. Proteases act in an irreversible manner and therefore have to be strictly regulated. The ubiquitin-proteasome system (UPS) is a major pathway for the proteolytic degradation of cellular proteins. As dysregulation of the UPS is observed in most cancers including leukemia, the UPS is a valid target for therapeutic intervention strategies. Ubiquitin-ligases selectively bind substrates to target them for poly-ubiquitinylation and proteasomal degradation. Therefore, pharmacological modulation of these proteins could allow a specific level of control. Increasing evidence accumulates that ubiquitin-ligases termed mammalian seven in absentia homologs (SIAHs) are not only critical for the pathogenesis of solid tumors but also for leukemogenesis. However, the relevance and therapeutic potential of SIAH-dependent processes has not been fully elucidated. Here, we summarize functions of SIAH ubiquitin-ligases in leukemias, how they select leukemia-relevant substrates for proteasomal degradation, and how the expression and activity of SIAH1 and SIAH2 can be modulated in vivo. We also discuss that epigenetic drugs belonging to the group of histone deacetylase inhibitors induce SIAH-dependent proteasomal degradation to accelerate the turnover of leukemogenic proteins. In addition, our review highlights potential areas for future research on SIAH proteins. PMID- 23038276 TI - Calixarene-supported clusters: employment of complementary cluster ligands for the construction of a ferromagnetic [Mn5] cage. AB - A combination of complementary cluster ligands results in the formation of a new calixarene-supported ferromagnetic [Mn(5)] cage that displays the characteristic bonding modes of each support. PMID- 23038275 TI - SIRT1 enhances matrix metalloproteinase-2 expression and tumor cell invasion in prostate cancer cells. AB - BACKGROUND: Matrix metalloproteinase-2 (MMP2) has been shown to play an important role in cancer cell invasion and the expression of MMP2 is associated with the poor prognosis of prostate cancer; however, the mechanism of MMP2 expression is largely unknown. SIRT1 is a nicotinamide adenine dinucleotide-dependent histone deacetylase (class III HDAC) that has recently been shown to have implications in regulating cancer cell growth and apoptosis. The purpose of this study is to determine the role of SIRT1 in regulating MMP2 expression and tumor invasion in prostate cancer cells. METHODS: The interfering RNAi was used to knockdown SIRT1 from prostate cancer cells. Immunoblots, RT-PCR, zymographic assays, co immunoprecipitation, analysis and transwell assays were used to examine the effects of SIRT1 silencing on MMP2 expression and activity, on SIRT1 and MMP2 interaction, and on prostate cancer cell invasion. The immuno-histochemical assay was performed to study SIRT1 expression in prostate cancer tissues. RESULTS: We show that SIRT1 associates and deacetylates MMP2 and SIRT1 regulates MMP2 expression by controlling MMP2 protein stability through the proteosomal pathway. Thus, we demonstrated a novel mechanism in that MMP2 expression can be regulated at the posttranslational level by SIRT1. Furthermore, we determined that SIRT1 inhibition reduced prostate cancer cell invasion and SIRT1 is highly expressed in advanced prostate cancer tissues. CONCLUSIONS: SIRT1 is an important regulator of MMP2 expression, activity, and prostate cancer cell invasion. Overexpressed SIRT1 in advanced prostate cancer may play an important role in prostate cancer progression. PMID- 23038277 TI - Sinonasal epithelial cells synthesize active vitamin D, augmenting host innate immune function. AB - BACKGROUND: Vitamin D, long recognized for its role in bone metabolism and calcium homeostasis, has been increasingly shown to augment innate immunity. 1 alpha-Hydroxylase, the enzyme responsible for the synthesis of active vitamin D, has been shown to have extrarenal expression in multiple cell types, including airway epithelial cells. The purpose of this study is to explore whether sinonasal epithelial cells (SNECs) express 1-alpha-hydroxylase, allowing for the local production of active vitamin D, thereby augmenting innate immune function. METHODS: Human SNECs were grown in culture and stimulated by inactive vitamin D. Expression of 1-alpha-hydroxylase was measured by real-time polymerase chain reaction and immunocytochemistry. Active vitamin D production was measured by enzyme-linked immunosorbent assay (ELISA). The expression of cathelicidin, an antimicrobial peptide, was measured by real-time polymerase chain reaction and immunocytochemistry. RESULTS: SNECs constitutively express the enzyme 1-alpha hydroxylase resulting in active vitamin D production. SNECs exposed to inactive vitamin D had a significant 8-fold increase in cathelicidin expression when compared to controls. CONCLUSION: SNECs can generate active vitamin D, which significantly increases expression of the antimicrobial peptide cathelicidin. (c) 2013 ARS-AAOA, LLC. PMID- 23038280 TI - Urine as a source of stem cells. AB - Traditionally, clinicians and researchers have relied on a skin biopsy or blood extraction as relatively accessible supplies for in vitro cell expansion and biological studies. Perhaps surprisingly, limited attention has been given to a totally noninvasive source, urine, which eliminates the discomfort associated with other procedures. This may arise from the perception that urine is merely a body waste. Yet, the analysis of urine is a longstanding fundamental test for diagnostic purposes and nowadays there is growing interest in using urine for detecting biomarkers. In addition, recent work including ours reinforces the idea that urine contains a variety of viable cell types with relevant applications. In this review, we describe those cell types and their potential uses. PMID- 23038281 TI - THz wave propagation in two-dimensional metallic photonic crystal with mechanically tunable photonic-bands. AB - Transmission and dispersion relation of THz waves in two-dimensional photonic crystal (PC) composed of metal rods are studied by using finite-difference time domain simulation and THz time-domain spectroscopy measurement. The PC is embedded in a parallel metal plate waveguide with an air gap between the PC and one of the plates. The photonic-band-gap well-defined at small air gap narrows systematically with opening the air gap and disappears when the air gap is 2 ~ 3 times the rod height, where the two-dimensional nature of PC is destroyed. The mechanical tunability of photonic band structure would be useful in functional THz device. PMID- 23038282 TI - Compressive fluorescence microscopy using saliency-guided sparse reconstruction ensemble fusion. AB - Compressive fluorescence microscopy has been proposed as a promising approach for fast acquisitions at sub-Nyquist sampling rates. Given that signal-to-noise ratio (SNR) is very important in the design of fluorescence microscopy systems, a new saliency-guided sparse reconstruction ensemble fusion system has been proposed for improving SNR in compressive fluorescence microscopy. This system produces an ensemble of sparse reconstructions using adaptively optimized probability density functions derived based on underlying saliency rather than the common uniform random sampling approach. The ensemble of sparse reconstructions are then fused together via ensemble expectation merging. Experimental results using real fluorescence microscopy data sets show that significantly improved SNR can be achieved when compared to existing compressive fluorescence microscopy approaches, with SNR increases of 16-9 dB within the noise range of 1.5%-10% standard deviation at the same compression rate. PMID- 23038283 TI - Lens based adaptive optics scanning laser ophthalmoscope. AB - We present an alternative approach for an adaptive optics scanning laser ophthalmoscope (AO-SLO). In contrast to other commonly used AO-SLO instruments, the imaging optics consist of lenses. Images of the fovea region of 5 healthy volunteers are recorded. The system is capable to resolve human foveal cones in 3 out of 5 healthy volunteers. Additionally, we investigated the capability of the system to support larger scanning angles (up to 5 degrees ) on the retina. Finally, in order to demonstrate the performance of the instrument images of rod photoreceptors are presented. PMID- 23038284 TI - High speed, high power one-dimensional beam steering from a 6-element optical phased array. AB - Beam steering at high speed and high power is demonstrated from a 6-element optical phased array using coherent beam combining (CBC) techniques. The steering speed, defined as the inverse of the time to required to sweep the beam across the steering range, is 40 MHz and the total power is 396 mW. The measured central lobe FWHM width is 565 MUrad. High on-axis intensity is maintained periodically by phase-locking the array via a stochastic-parallel-gradient-descent (SPGD) algorithm. A master-oscillator-power-amplifier (MOPA) configuration is used where the amplifier array elements are semiconductor slab-coupled-optical-waveguide amplifiers (SCOWAs). The beam steering is achieved by LiNbO(3) phase modulators; the phase-locking occurs by current adjustment of the SCOWAs. The system can be readily scaled to GHz steering speed and multiwatt-class output. PMID- 23038285 TI - A construction guide to analytically generated meshes for the Fourier Modal Method. AB - The concepts of adaptive coordinates and adaptive spatial resolution significantly enhance the performance of Fourier Modal Method for the simulation of periodic photonic structures, especially metallo-dielectric systems. We present several approaches for constructing different types of analytical coordinate transformations that are applicable to a great variety of structures. In addition, we analyze these meshes with an emphasis on the resulting convergence characteristics. This allows us to formulate general guidelines for the choice of mesh type and mesh parameters. PMID- 23038286 TI - Optofluidic particle manipulation in a liquid-core/liquid-cladding waveguide. AB - This paper describes a method for particle manipulation in a liquid-core/liquid cladding optical waveguide system. Step-index and graded-index waveguides were modeled with consideration for, respectively, miscible and immiscible core and cladding fluids. The characteristic motions of four different particles with refractive indices of 1.59, 1.48, 1.37, and 1.22 were examined. The guided beam was assumed to be Gaussian in shape. Our results showed that high-refractive index particles converged at the center of the core fluid due to a positive gradient force, whereas low-refractive-index particles converged at the flow periphery. The nonlinearity of the particle motion increased as the flow velocity and the guided beam waist decreased and the laser power and the particle size increased. The initial beam waist of the guided beam in the graded-index waveguide did not significantly affect the characteristics of the particle motion due to the effects of diffusion. PMID- 23038287 TI - Electrically tunable electroluminescence from SiN(x)-based light-emitting devices. AB - Two obvious Gauss peaks are observed in SiN(x)-based light-emitting devices with silver nanoparticles deposited onto the luminous layer, both of which are blue shifted with the increase of injected current. The origin of these two peaks is discussed by means of the changes of their positions, relative intensities, and full width at half maximum. We attribute the blue-shift of both electroluminescence peaks to the improvement of carrier injection as carriers can be injected into higher energy levels along their corresponding band tails, which is also confirmed by the changes of the transport mechanism. PMID- 23038288 TI - Femtosecond pulses at 50-W average power from an Yb:YAG planar waveguide amplifier seeded by an Yb:KYW oscillator. AB - We report the demonstration of a high-power single-side-pumped Yb:YAG planar waveguide amplifier seeded by an Yb:KYW femtosecond laser. Five passes through the amplifier yielded 700-fs pulses with average powers of 50 W at 1030 nm. A numerical simulation of the amplifier implied values for the laser transition saturation intensity, the small-signal intensity gain coefficient and the gain bandwidth of 10.0 kW cm(-2), 1.6 cm(-1), and 3.7 nm respectively, and identified gain-narrowing as the dominant pulse-shaping mechanism. PMID- 23038289 TI - Experimental demonstration of the three phase shifted DFB semiconductor laser based on Reconstruction-Equivalent-Chirp technique. AB - A three phase shifted (3PS) distributed feedback (DFB) semiconductor laser based on Reconstruction-Equivalent-Chirp (REC) technique is experimentally demonstrated for the first time. The simulation results show that the performances of the equivalent 3PS DFB semiconductor laser are nearly the same as that of the true 3PS laser. However, it only changes the MUm-level sampling structures but the seed grating is uniform. So, its cost of fabrication is low. The measurement results exhibit its good single longitudinal mode (SLM) operation even at high bias current and surrounding temperature. PMID- 23038290 TI - Microchip Random Laser based on a disordered TiO2-nanomembranes arrangement. AB - We developed a new scheme for obtaining coherent random lasing based on a chip consisting of a polymer film doped with Rhodamine 6G, having as scatterers butterfly-like TiO(2) nanomembranes (TiO(2)-NM) supported on a glass substrate. The feedback mechanism for laser action is due to the multiple scattering of light by TiO(2)-NM rather than provided by localized variations of the refractive index in the polymer film. The above-threshold multiple spikes signature indicative of random laser emission with coherent feedback is confirmed. As nanomembranes are foreseen as new MEMS/NEMS building blocks, a new generation of combined active/passive photonic devices can be envisaged. PMID- 23038291 TI - 47-km 1.25-Gbps transmission using a self-seeded transmitter with a modulation averaging reflector. AB - We demonstrate an extended-cavity (1-km round trip) transmitter employing a reflective-semiconductor optical amplifier (RSOA) self-seeded by spectrally sliced passive modulation-averaging reflector. We show that using modulation averaging reflectors in self-seeded transmitters improves link margin, allows a wider range of bias conditions for the RSOA by removing the modulation in the seeding light and consequently allows operation with higher extinction ratios. We furthermore demonstrate 47 km transmission at 1.25 Gbps with a 16-channel fully passive remote node. This type of transmitter is suitable for application in colorless WDM-PON systems. PMID- 23038292 TI - Longitudinally-graded optical fibers. AB - Optical fibers have become ubiquitous tools for the creation, propagation, manipulation, and detection of light. However, while the intensity of light propagating through the fiber can increase or decrease along the length through amplification or attenuation, respectively, the properties of the fiber itself generally do not, thus removing an opportunity to further control the behavior of light and performance of fiber-based devices. Shown here are optical fibers that exhibit significant changes in their longitudinal optical properties, specifically a tailored longitudinal numerical aperture change of about 12% over less than 20 meters of length. This is about 1900 times greater than previously reported. The Brillouin gain coefficient was found to decrease by over 6 dB relative to a standard commercial single mode fiber. Next generation analogs are expected to exhibit more than a 10 dB reduction in SBS gain using larger, yet still reasonably manufacturable gradients over practical lengths. PMID- 23038293 TI - Integration of short gold nanoparticles chain on SOI waveguide toward compact integrated bio-sensors. AB - We demonstrate the integration of short metal nanoparticle chains (L ~700 nm) supporting localized surface plasmons in Silicon On Insulator (SOI) waveguides at telecom wavelengths. Nanoparticles are deposited on the waveguide top and excited through the evanescent field of the TE waveguide modes. Finite difference time domain calculations and waveguide transmission measurements reveal that almost all the TE mode energy can be transferred to nanoparticle chains at resonance. It is also shown that the transmission spectrum is very sensitive to the molecular environment of nanoparticles, thus opening the way towards ultra-compact sensors in guided plasmonics on SOI. An experimental demonstration is reported with octadecanthiol molecules for a detection volume as small as 0.26 attoliter. PMID- 23038294 TI - Flexible quantum private queries based on quantum key distribution. AB - By adding a parameter theta in M. Jakobi et al's protocol [Phys. Rev. A 83, 022301 (2011)], we present a flexible quantum-key-distribution-based protocol for quantum private queries. We show that, by adjusting the value of theta, the average number of the key bits Alice obtains can be located on any fixed value the users wanted for any database size. And the parameter k is generally smaller (even k = 1 can be achieved) when theta < pi/4, which implies lower complexity of both quantum and classical communications. Furthermore, the users can choose a smaller theta to get better database security, or a larger theta to obtain a lower probability with which Bob can correctly guess the address of Alice's query. PMID- 23038295 TI - Performance benchmarking of core optical networking paradigms. AB - The sustainability of Future Internet critically depends on networking paradigms able to provide optimum and balanced performance over an extended set of efficiency and Quality of Service (QoS) metrics. In this work we benchmark the most established networking modes through appropriate performance metrics for three network topologies. The results demonstrate that the static reservation of WDM channels, as used in IP/WDM schemes, is severely limiting scalability, since it cannot efficiently adapt to the dynamic traffic fluctuations that are frequently observed in today's networks. Optical Burst Switching (OBS) schemes do provide dynamic resource reservation but their performance is compromised due to high burst loss. It is shown that the CANON (Clustered Architecture for Nodes in an Optical Network) architecture exploiting statistical multiplexing over a large scale core optical network and efficient grooming at appropriate granularity levels could be a viable alternative to existing static as well as dynamic wavelength reservation schemes. Through extensive simulation results we quantify performance gains and we show that CANON demonstrates the highest efficiency achieving both targets for statistical multiplexing gains and QoS guarantees. PMID- 23038296 TI - Robust phase-shift-keying silicon photonic modulator. AB - Here we propose a robust silicon modulator that seamlessly generates phase shift keyed data. The modulator has very low insertion loss and is robust against electrical amplitude variations in the modulating signal; specifically a 50%-200% variation in modulating amplitude leads to only a pi/9 variation in output optical phase, corresponding to only +/- 10% variation in the differentially detected signal. This yields a ~2.5dB enhancement in SNR over OOK (on-off-keying) formats. PMID- 23038297 TI - Localized surface plasmon resonance with broadband ultralow reflectivity from metal nanoparticles on glass and silicon subwavelength structures. AB - Metal nanoparticles (NPs) are well known to increase the efficiency of photovoltaic devices by reducing reflection and increasing light trapping within device. However, metal NPs on top flat surface suffer from high reflectivity losses due to the backscattering of the NPs itself. In this paper, we experimentally demonstrate a novel structure that exhibits localized surface plasmon resonance (LSPR) along with broadband ultralow reflectivity over a wide range of wavelength. Experimental results show that by depositing Ag NPs and Au NPs onto glass subwavelength structures (SWS) the backscattering effect of NPs can be suppressed, and the reflections can be considerably reduced by up to 87.5% and 66.7% respectively, compared to NPs fabricated on a flat glass substrate. Broadband ultralow reflection (< 2%) is also observed in the case of Ag NPs and Au NPs fabricated on cone shaped SWS silicon substrate over a wavelength range from 200 nm to 800 nm. This broadband ultralow reflectivity of Ag NPs and Au NPs on silicon SWS structure leads to a substantial enhancement of average absorption by 66.53% and 66.94%, respectively, over a broad wavelength range (200-2000 nm). This allows light absorption by NPs on SWS silicon structure close to 100% over a wavelength range from 300 nm to 1000 nm. The mechanism responsible for the increased light absorption is also explained. PMID- 23038298 TI - Polarization spectroscopy and magnetically-induced dichroism of the potassium D2 lines. AB - We study modulation-free methods for producing sub-Doppler, dispersive line shapes for laser stabilization near the potassium D(2) transitions at 767 nm. Polarization spectroscopy is performed and a comparison is made between the use of a mirror or beam splitter for aligning the counter-propagating pump and probe beams. Conventional magnetically-induced dichroism is found to suffer from a small dispersion and large background offset. We therefore introduce a modified scheme, using two spatially separated pump-probe beam pairs. Finally we compare our results to methods using phase modulation and heterodyne detection. PMID- 23038299 TI - Direct laser writing for nanoporous liquid core laser sensors. AB - We report the fabrication of nanoporous liquid core lasers via direct laser writing based on two-photon absorption in combination with thiolene-chemistry. As gain medium Rhodamine 6G was embedded in the nanoporous polybutadiene matrix. The lasing devices with thresholds of 19 uJ/mm(2) were measured to have bulk refractive index sensitivities of 169 nm/RIU at a laser wavelength of 600 nm, demonstrating strongly increased overlap of the modes with the analyte in comparison to solid state evanescent wave sensors. PMID- 23038300 TI - Four-wave mixing in slow light photonic crystal waveguides with very high group index. AB - We report efficient four-wave mixing in dispersion engineered slow light silicon photonic crystal waveguides with a flat band group index of n(g) = 60. Using only 15 mW continuous wave coupled input power, we observe a conversion efficiency of 28 dB. This efficiency represents a 30 dB enhancement compared to a silicon nanowire of the same length. At higher powers, thermal redshifting due to linear absorption was found to detune the slow light regime preventing the expected improvement in efficiency. We then overcome this thermal limitation by using oxide-clad waveguides, which we demonstrate for group indices of ng = 30. Higher group indices may be achieved with oxide clad-waveguides, and we predict conversion efficiencies approaching -10 dB, which is equivalent to that already achieved in silicon nanowires but for a 50x shorter length. PMID- 23038301 TI - Spatial and temporal coherence properties of single free-electron laser pulses. AB - The experimental characterization of the spatial and temporal coherence properties of the free-electron laser in Hamburg (FLASH) at a wavelength of 8.0 nm is presented. Double pinhole diffraction patterns of single femtosecond pulses focused to a size of about 10*10 MUm(2) were measured. A transverse coherence length of 6.2 +/- 0.9 MUm in the horizontal and 8.7 +/- 1.0 MUm in the vertical direction was determined from the most coherent pulses. Using a split and delay unit the coherence time of the pulses produced in the same operation conditions of FLASH was measured to be 1.75 +/- 0.01 fs. From our experiment we estimated the degeneracy parameter of the FLASH beam to be on the order of 10(10) to 10(11), which exceeds the values of this parameter at any other source in the same energy range by many orders of magnitude. PMID- 23038302 TI - Distributed feedback laser diode integrated with distributed Bragg reflector for continuous-wave terahertz generation. AB - A widely tunable dual mode laser diode with a single cavity structure is demonstrated. This novel device consists of a distributed feedback (DFB) laser diode and distributed Bragg reflector (DBR). Micro-heaters are integrated on the top of each section for continuous and independent wavelength tuning of each mode. By using a single gain medium in the DFB section, an effective common optical cavity and common modes are realized. The laser diode shows a wide tunability of the optical beat frequency, from 0.48 THz to over 2.36 THz. Continuous wave THz radiation is also successfully generated with low-temperature grown InGaAs photomixers from 0.48 GHz to 1.5 THz. PMID- 23038303 TI - Design of highly absorbing metamaterials for infrared frequencies. AB - Simple designs for polarization independent, metamaterial absorbers at mid infrared wavelengths and over wide angle of incidence are evaluated computationally. One design consists of an array of circular metallic disks separated from a continuous metallic film by a dielectric film, and shows over 99.9% peak absorbance and a resonant bandwidth of about 0.2 MUm wavelengths. The effects of various geometric parameters are analyzed for this metamaterial. Another design consisting of an array of stacked metal-dielectric-metal disks is shown to have an absorbance of over 90% in a comparatively large band of over 1 MUm bandwidth, although with a lower peak absorbance of 97%. PMID- 23038304 TI - Embedded metallic focus grating for silicon nitride waveguide with enhanced coupling and directive radiation. AB - We design a compact embedded metallic elliptical focus grating coupler based on gold or silver that efficiently interconnects free space with silicon nitride waveguide at 632.8 nm wavelength. The 3D far-field radiation pattern for the proposed grating coupler shows much higher gain and directivity towards free space coupling than that of the etched grating coupler. Specifically the free space transmission efficiency achieves 65% for silver grating coupler. It can also further enhance the fluorescence signal detection for Cy-5 fluorophore by isolating peak diffraction angle for 10 degrees . The dense system integration capability shows the application potential for on-chip interfacing sub-wavelength light processing circuits and near-field fluorescent biosensors with far-field detection of superb radiation directivity and coupling efficiency. PMID- 23038305 TI - Fourier domain optical coherence tomography system with balance detection. AB - A Fourier domain optical coherence tomography system with two spectrometers in balance detection is assembled using each an InGaAs linear camera. Conditions and adjustments of spectrometer parameters are presented to ensure anti-phase channeled spectrum modulation across the two cameras for a majority of wavelengths within the optical source spectrum. By blocking the signal to one of the spectrometers, the setup was used to compare the conditions of operation of a single camera with that of a balanced configuration. Using multiple layer samples, balanced detection technique is compared with techniques applied to conventional single camera setups, based on sequential deduction of averaged spectra collected with different on/off settings for the sample or reference beams. In terms of reducing the autocorrelation terms and fixed pattern noise, it is concluded that balance detection performs better than single camera techniques, is more tolerant to movement, exhibits longer term stability and can operate dynamically in real time. The cameras used exhibit larger saturation power than the power threshold where excess photon noise exceeds shot noise. Therefore, conditions to adjust the two cameras to reduce the noise when used in a balanced configuration are presented. It is shown that balance detection can reduce the noise in real time operation, in comparison with single camera configurations. However, simple deduction of an average spectrum in single camera configurations delivers less noise than the balance detection. PMID- 23038306 TI - High-power narrow-bandwidth thulium fiber laser with an all-fiber cavity. AB - We report diode pumped high power 2-um Tm(3+) fiber lasers with an all-fiber configuration. The all-fiber configuration is completed by specially designed fiber Bragg gratings with similar structure parameters matched to the gain fiber. The maximum output power is 137 W with an optical-to-optical slope efficiency of 62% with respect to absorbed 793-nm pump power. The laser wavelength is stabilized at ~2019 nm with a spectral linewidth less than 3 nm across all output levels. To the best of our knowledge, this is the highest 2-um laser output from a single narrow bandwidth all-fiber laser system. PMID- 23038307 TI - Planar metamaterial based on hybridization for directive emission. AB - We present the first experimental demonstration of a high-directivity using a mu and epsilon near zero (MENZ) metamaterial. We use the hybridization principles to design a planar MENZ structure based on the fishnet unit cell. Resonant mode engineering achieves an effective permittivity and permeability that approaches zeros around 10.5 GHz simultaneously. We use this metamaterial as a superstrate of a microstrip patch antenna. We show that the directivity of the antenna is effectively enhanced compared to that of the patch antenna alone at the desired frequency. PMID- 23038308 TI - Multiband plasmonic absorber based on transverse phase resonances. AB - We demonstrate a multiband plasmonic absorber based on transverse phase resonances. We show that the modification of conventional metallic surfaces of T shape grooves can cause mode splitting of the plasmonic waveguide cavity modes due to lattice scattering and all the new resonant modes exhibit large absorbtivity greater than 90%. Some of the generated absorption peaks have wide angle characteristics. Furthermore, we find that the proposed structure is fairly insensitive to the alignment error between different layers. PMID- 23038309 TI - Low-frequency correlations (1/f(alpha) type) in paint application of metallic colors. AB - We examine trial-to-trial variability of color coordinates in automotive coatings containing effect pigments, which are considered a reference paradigm for engineering angle-dependent color effects. We report the existence of correlations that show 1/f - Fourier spectra at low frequencies in all color coordinates. The scaling exponent was lower at near-specular conditions for lightness variations, suggesting a contribution from the deposition of metal flakes in metallic colors. However, the exponent was lower near the specular for blue-yellow variations, suggesting a contribution from chemical pigments in solid colors. These results were independent of the illuminant spectra. The methods employed are useful in the evaluation of industrial color matching among assembly parts. PMID- 23038310 TI - Generation of vacuum-ultraviolet pulses with a Doppler-broadened gas utilizing high atomic coherence. AB - We carry out the theoretical study for the generation of vacuum-ultraviolet pulses with a Doppler-broadened gas utilizing high atomic coherence. It is essentially a difference-frequency generation scheme induced by the two-photon near-resonant pump and probe pulses, where the key point is to generate high atomic coherence between the ground and two-photon near-resonant states through a variant of stimulated Raman adiabatic passage with a time-dependent detuning. The advantage of our scheme is that the degree of coherence is sensitive to neither the exact amount and even sign of the detuning, nor the exact timing between the pump, auxiliary, and probe pulses. Hence our scheme is practically insensitive to Doppler broadening. As a specific example, we consider the generation of picosecond Lyman-alpha pulses with a Kr gas, and quantitatively study the influence of Doppler broadening as well as the intensity and incident timing of the picosecond probe pulse with respect to the pump pulse. The numerical results indicate that our scheme has a certain advantage over the conventional scheme which utilizes two-photon resonant excitation. PMID- 23038311 TI - Highly-dispersive electromagnetic induced transparency in planar symmetric metamaterials. AB - We propose, design and experimentally demonstrate highly-dispersive electromagnetically induced transparency (EIT) in planar symmetric metamaterials actively switched and controlled by angles of incidence. Full-wave simulation and measurement results show EIT phenomena, trapped-mode excitations and the associated local field enhancement of two symmetric metamaterials consisting of symmetrically split rings (SSR) and a fishscale (FS) metamaterial pattern, respectively, strongly depend on angles of incidence. The FS metamaterial shows much broader spectral splitting than the SSR metamaterial due to the surface current distribution variation. PMID- 23038312 TI - Are scaling laws of sub-optical wavelength electric field confinement in arrays of metal nanoparticles related to plasmonics or to geometry? AB - In this work, we describe finite element simulations of the plasmonic resonance (PLR) properties of a self-similar chain of plasmonic nanostructures. Using a broad range of conditions, we find strong numerical evidence that the electric field confinement behaves as (Xi/lambda)(PLR)[proporationality] EFE(-gamma), where EFE is the electric field enhancement, Xiis the linear size of the focusing length, and lambda is the wavelength of the resonant excitation. We find that the exponent gamma is close to 1, i.e. significantly lower than the 1.5 found for two dimensional nanodisks. This scaling law provides support for the hypothesis of a universal regime in which the sub-optical wavelength electric field confinement is controlled by the Euclidean dimensionality and is independent of nanoparticle size, metal nature, or embedding medium permittivity. PMID- 23038313 TI - Heterodyne detection using spectral line pairing for spectral phase encoding optical code division multiple access and dynamic dispersion compensation. AB - A novel coherent optical code-division multiple access (OCDMA) scheme is proposed that uses spectral line pairing to generate signals suitable for heterodyne decoding. Both signal and local reference are transmitted via a single optical fiber and a simple balanced receiver performs sourceless heterodyne detection, canceling speckle noise and multiple-access interference (MAI). To validate the idea, a 16 user fully loaded phase encoded system is simulated. Effects of fiber dispersion on system performance are studied as well. Both second and third order dispersion management is achieved by using a spectral phase encoder to adjust phase shifts of spectral components at the optical network unit (ONU). PMID- 23038314 TI - Spectral linewidth preservation in parametric frequency combs seeded by dual pumps. AB - We demonstrate new technique for generation of programmable-pitch, wideband frequency combs with low phase noise. The comb generation was achieved using cavity-less, multistage mixer driven by two tunable continuous-wave pump seeds. The approach relies on phase-correlated continuous-wave pumps in order to cancel spectral linewidth broadening inherent to parametric comb generation. Parametric combs with over 200-nm bandwidth were obtained and characterized with respect to phase noise scaling to demonstrate linewidth preservation over 100 generated tones. PMID- 23038315 TI - Generalized weighted crosstalk for DWDM systems with cascaded wavelength selective switches. AB - A generalized method for estimating transmission penalties from spectrally-shaped crosstalk in cascaded multi-port WSS networks is derived, including effects of ASE, signal filtering, and crosstalk filtering. The weighted crosstalk value is computed by multiplying the shaped interfering signal by the power spectral density of the primary signal. This value is used to predict OSNR penalties in networks with cascaded WSSs of arbitrary port count. Theoretical treatment is supported by extensive numerical simulations and experiments for a variety of network configurations. Examples are presented for 43 Gb/s DPSK and 120 Gb/s DP QPSK in cascaded ROADM networks with three distinct WSS types. PMID- 23038316 TI - Particle backscattering as a function of chlorophyll and phytoplankton size structure in the open-ocean. AB - Using an extensive database of in situ observations we present a model that estimates the particle backscattering coefficient as a function of the total chlorophyll concentration in the open-ocean (Case-1 waters). The parameters of the model include a constant background component and the chlorophyll-specific backscattering coefficients associated with small (<20 MUm) and large (>20 MUm) phytoplankton. The new model performed with similar accuracy when compared with a traditional power-law function, with the additional benefit of providing information on the role of phytoplankton size. The observed spectral-dependency (gamma) of model parameters was consistent with past observations, such that gamma associated with the small phytoplankton population was higher than that of large phytoplankton. Furthermore, gamma associated with the constant background component suggests this component is likely attributed to submicron particles. We envisage that the model would be useful for improving Case-1 ocean-colour models, assimilating light into multi-phytoplankton ecosystem models and improving estimates of phytoplankton size structure from remote sensing. PMID- 23038317 TI - Sharper fluorescent super-resolution spot generated by azimuthally polarized beam in STED microscopy. AB - A novel method is proposed for generating sharper fluorescent super-resolution spot by azimuthally polarized beam in stimulated emission depletion (STED) microscopy. The incoherent superposition of azimuthally polarized beam with five zone binary phase plate and the same beam with quadrant 0/piphase plate can yield a tightly focused doughnut spot surrounded completely and uniformly. And azimuthally polarized beam modulated by a vortex 0-2pi phase plate works as pump beam. Compared with known effective excitation spot yielded by circular polarized STED beam, the azimuthally polarized beam result is shaper, as well as energy saving, costing only ~50% of the energy cost by circular polarized beam. A STED beam of less intensity has the potential to reduce fluorescence photobleaching and photodamage in living cell imaging. In addition, the influence of Ez absence as well as FWHM of pump beam in the focal field is discussed. PMID- 23038318 TI - Photonic wire bonding: a novel concept for chip-scale interconnects. AB - Photonic integration requires a versatile packaging technology that enables low loss interconnects between photonic chips in three-dimensional configurations. In this paper we introduce the concept of photonic wire bonding, where polymer waveguides with three-dimensional freeform geometries are used to bridge the gap between nanophotonic circuits located on different chips. In a proof-of-principle experiment, we demonstrate the fabrication of single-mode photonic wire bonds (PWB) by direct-write two-photon lithography. First-generation prototypes allow for efficient broadband coupling with average insertion losses of only 1.6 dB in the C-band and can carry wavelength-division multiplexing signals with multi Tbit/s data rates. Photonic wire bonding is well suited for automated mass production, and we expect the technology to enable optical multi-chip systems with enhanced performance and flexibility. PMID- 23038319 TI - Tuning of a nonlinear THz emitter. AB - We numerically study a passive THz source based on difference frequency generation between modes sustained by cylindrical AlGaAs microcavities. We show that ring-like structures are advantageous in that they provide additional degrees of freedom for tuning the nonlinear process and for maximizing the nonlinear overlap integral and conversion efficiency. PMID- 23038320 TI - Nonparaxial and paraxial focusing of azimuthal-variant vector beams. AB - Based on the vectorial Rayleigh-Sommerfeld formulas under the weak nonparaxial approximation, we investigate the propagation behavior of a lowest-order Laguerre Gaussian beam with azimuthal-variant states of polarization. We present the analytical expressions for the radial, azimuthal, and longitudinal components of the electric field with an arbitrary integer topological charge m focused by a nonaperturing thin lens. We illustrate the three-dimensional optical intensities, energy flux distributions, beam waists, and focal shifts of the focused azimuthal variant vector beams under the nonparaxial and paraxial approximations. PMID- 23038321 TI - Long-distance fiber-optic point-sensing systems based on random fiber lasers. AB - We find that the random fiber laser (RFL) without point-reflectors is a temperature-insensitive distributed lasing system for the first time. Inspired by such thermal stability, we propose the novel concept of utilizing the RFL to achieve long-distance fiber-optic remote sensing, in which the RFL offers high fidelity and long-distance transmission for the sensing signal. Two 100 km fiber Bragg grating (FBG) point-sensing schemes based on RFLs are experimentally demonstrated using the first-order and the second-order random lasing, respectively, to verify the concept. Each sensing scheme can achieve >20 dB optical signal-to-noise ratio (OSNR) over 100 km distance. It is found that the second-order random lasing scheme has much better OSNR than that of the first order random lasing scheme due to enhanced lasing efficiency, by incorporating a 1455 nm FBG into the lasing cavity. PMID- 23038322 TI - High luminescent Li2CaSiO4:Eu2+ cyan phosphor film for wide color gamut field emission display. AB - Li(2)CaSiO(4):Eu(2+) cyan phosphor screen for enlarging the color gamut of field emission display has been prepared and characterized. The luminance of Li(2)CaSiO(4):Eu(2+) phosphor film can reach as high as about 12000 cd/m(2) under the conditions of V(a) = 7 kV and J(a) = 2.8 mA/cm(2). The cathodoluminescent spectrum, luminance, saturation current density and degradation property are compared with another cyan phosphor Mg(2)SnO(4):Ti(4+),Mn(2+). It is found that Li(2)CaSiO(4):Eu(2+) phosphor exhibits narrower emission band, higher luminance, higher saturation current density, higher resistance to electron bombardment, higher thermal stability and conductivity as well as purer color. Thus, Li(2)CaSiO(4):Eu(2+) has great potential in application in field emission display as well as light emitting diode. PMID- 23038323 TI - Statistical moments-based OSNR monitoring for coherent optical systems. AB - We present a novel statistical moments-based method for optical signal-to-noise ratio (OSNR) monitoring in polarization-multiplexed (pol-mux) coherent optical systems. This technique only requires the knowledge of the envelope of the equalized signal before phase correction, which can be achieved by using any two arbitrary statistical moments, and it is suitable for both constant and non constant modulus modulation formats. The proposed estimation method is experimentally demonstrated for 10-Gbaud pol-mux coherent systems using QPSK and 16-QAM. Additionally, numerical simulations are carried out to demonstrate 20 Gbaud systems using 16-QAM and 64-QAM. The results show that the OSNR can be estimated accurately over a wide range of values for QPSK, 16-QAM or 64-QAM systems up to 1920-km long and with up to 50-ps all-order polarization mode dispersion. By setting a proper reference value for calibration, the proposed algorithm also shows good tolerance when the received signal is not well compensated. PMID- 23038324 TI - Ultrastable heterodyne interferometer system using a CMOS modulated light camera. AB - A novel ultrastable widefield interferometer is presented. This uses a modulated light camera (MLC) to capture and stabilise the interferogram in the widefield heterodyne interferometer. This system eliminates the contribution of piston phase to the interferogram without the need for common path optics and results in a highly stable widefield interferometer. The MLC uses quadrature demodulation circuitry built into each pixel to demodulate the light signal and extract phase information using an electronic reference signal. In contrast to the work previously presented [Opt. Express 19, 24546 (2011)], the reference signal is derived from one of the pixels on board the MLC rather than an external source. This local reference signal tracks the instantaneous modulation frequency detected by the other pixels and eliminates the contribution of piston phase to the interferogram, substantially removing the contributions of unwanted vibrations and microphonics to the interferogram. Interferograms taken using the ultrastable system are presented with one of the interferometer mirrors moving at up to 85 mm s(-1) over a variety of frequencies from 18 Hz to 20 kHz (giving a variation in optical path length of 220 MUm, or 350 wavelengths at 62 Hz). This limit was the result of complex motion in the mirror mount rather than the stability limit of the system. The system is shown to be insensitive to pure piston phase variations equivalent to an object velocity of over 3 m s(-1). PMID- 23038325 TI - Highly efficient nanofocusing based on a T-shape micro-slit surrounded with multi slits. AB - Highly efficient plasmonic nanofocusing is proposed and demonstrated in a T-shape micro-slit surrounded by multi-slits. The nanofocusing phenomenon is achieved based on the multimode interference in the micro-slit, the constructive interference in the T-shape slit, and also the multiple-beam interference of the light radiated from the multi-slits and the transmitted light from the T-shape micro-slit. Because of the large illumination areas of the incident light on the wide slit aperture in the proposed structure, a large amount of light can pass through the wide slit. This leads to a highly efficient nanofocusing. Meanwhile, the wide slit means easy fabrication. In the experiment, the focusing phenomenon in the proposed structure was successfully demonstrated with a scanning near field optical microscopy (SNOM) technology. PMID- 23038326 TI - Localization-based super-resolution microscopy with an sCMOS camera part II: experimental methodology for comparing sCMOS with EMCCD cameras. AB - Nowadays, there is a hot debate among industry and academic researchers that whether the newly developed scientific-grade Complementary Metal Oxide Semiconductor (sCMOS) cameras could become the image sensors of choice in localization-based super-resolution microscopy. To help researchers find answers to this question, here we reported an experimental methodology for quantitatively comparing the performance of low-light cameras in single molecule detection (characterized via image SNR) and localization (via localization accuracy). We found that a newly launched sCMOS camera can present superior imaging performance than a popular Electron Multiplying Charge Coupled Device (EMCCD) camera in a signal range (15-12000 photon/pixel) more than enough for typical localization based super-resolution microscopy. PMID- 23038327 TI - Validation of MODIS-derived bidirectional reflectivity retrieval algorithm in mid infrared channel with field measurements. AB - This work addressed the validation of the MODIS-derived bidirectional reflectivity retrieval algorithm in mid-infrared (MIR) channel, proposed by Tang and Li [Int. J. Remote Sens. 29, 4907 (2008)], with ground-measured data, which were collected from a field campaign that took place in June 2004 at the ONERA (Office National d'Etudes et de Recherches Aerospatiales) center of Fauga-Mauzac, on the PIRRENE (Programme Interdisciplinaire de Recherche sur la Radiometrie en Environnement Exterieur) experiment site [Opt. Express 15, 12464 (2007)]. The leaving-surface spectral radiances measured by a BOMEM (MR250 Series) Fourier transform interferometer were used to calculate the ground brightness temperatures with the combination of the inversion of the Planck function and the spectral response functions of MODIS channels 22 and 23, and then to estimate the ground brightness temperature without the contribution of the solar direct beam and the bidirectional reflectivity by using Tang and Li's proposed algorithm. On the other hand, the simultaneously measured atmospheric profiles were used to obtain the atmospheric parameters and then to calculate the ground brightness temperature without the contribution of the solar direct beam, based on the atmospheric radiative transfer equation in the MIR region. Comparison of those two kinds of brightness temperature obtained by two different methods indicated that the Root Mean Square Error (RMSE) between the brightness temperatures estimated respectively using Tang and Li's algorithm and the atmospheric radiative transfer equation is 1.94 K. In addition, comparison of the hemispherical-directional reflectances derived by Tang and Li's algorithm with those obtained from the field measurements showed that the RMSE is 0.011, which indicates that Tang and Li's algorithm is feasible to retrieve the bidirectional reflectivity in MIR channel from MODIS data. PMID- 23038328 TI - FPGA implementation of a 32x32 autocorrelator array for analysis of fast image series. AB - With the evolving technology in CMOS integration, new classes of 2D-imaging detectors have recently become available. In particular, single photon avalanche diode (SPAD) arrays allow detection of single photons at high acquisition rates (>= 100 kfps), which is about two orders of magnitude higher than with currently available cameras. Here we demonstrate the use of a SPAD array for imaging fluorescence correlation spectroscopy (imFCS), a tool to create 2D maps of the dynamics of fluorescent molecules inside living cells. Time-dependent fluorescence fluctuations, due to fluorophores entering and leaving the observed pixels, are evaluated by means of autocorrelation analysis. The multi-tau correlation algorithm is an appropriate choice, as it does not rely on the full data set to be held in memory. Thus, this algorithm can be efficiently implemented in custom logic. We describe a new implementation for massively parallel multi-tau correlation hardware. Our current implementation can calculate 1024 correlation functions at a resolution of 10 MUs in real-time and therefore correlate real-time image streams from high speed single photon cameras with thousands of pixels. PMID- 23038329 TI - Optical mode solving for complex waveguides using a finite cloud method. AB - A meshless method for the solution of full vectorial optical mode fields has been applied to micro-structured optical waveguides. The Finite Cloud Method is used to approximate the solution using a point distribution and material definitions. Presented are two methods of defining material interfaces, one which implements a step index and a second which uses a graded index. Coupled field equations are used to solve for both transverse components of the magnetic field as well as the guided wavelength and effective index of refraction. Comparing results for a ridge waveguide, solid core, micro-structured and air core structures with commercial FEM solvers highlight the methods versatility, accuracy and efficiency. PMID- 23038330 TI - Spectrum-, pulsewidth-, and wavelength-switchable all-fiber mode-locked Yb laser with fiber based birefringent filter. AB - We examined methods of controlling the pulse duration, spectral width and wavelength of the output from an all-fiber Yb laser mode-locked by carbon nanotubes. It is shown that a segment of polarization maintaining (PM) fiber inserted into a standard single mode fiber based laser cavity can function as a spectral selective filter. Adjustment of the length of the PM fiber from 1 to 2 m led to a corresponding variation in the pulse duration from 2 to 3.8 ps, the spectral bandwidth of the laser output changes from 0.15 to 1.26 nm. Laser output wavelength detuning within up to 5 nm was demonstrated with a fixed length of the PM fiber by adjustment of the polarization controller. PMID- 23038331 TI - Wave-front analysis of personal eye protection. AB - Shack-Hartmann wave-front sensing has been successfully applied to many fields of optical testing including the human eye itself. We propose wave-front measurement for testing protective eye wear for production control and investigation of aberrations. Refractive power data is derived from the wave-front data and compared to a subjective measurement technique based on a focimeter. Additional image quality classification was performed with a multivariate model using objective parameters to resample a subjectively determined visual quality. Wave front measurement advances optical testing of protective eye wear and may be used for objective quality control. PMID- 23038332 TI - Partially coherent self-similar pulses in resonant linear absorbers. AB - We theoretically describe several classes of ultrashort partially coherent pulses that maintain their shape on propagation in coherent linear absorbers near optical resonance. PMID- 23038333 TI - 1st-Stokes and 2nd-Stokes dual-wavelength operation and mode-locking modulation in diode-side-pumped Nd:YAG/BaWO4 Raman laser. AB - 1st-Stokes and 2nd-Stokes dual-wavelength operation within a diode-side-pumped Q switched Nd:YAG/BaWO(4) intracavity Raman laser was realized. Using an output coupler of transmission of 3.9% at 1180 nm and transmission of 60.08% at 1325 nm, the maximum output power of 8.30 W and 2.84 W at a pulse repetition rate of 15 kHz for the 1st Stokes and the 2nd Stokes laser were obtained, respectively. The corresponding optical conversion efficiency from diode laser to the 1st Stokes and 2nd Stokes laser are 5.0% and 1.4%, respectively. With the pump power of 209 W and a pulse repetition rate of 15 kHz, the 1st Stokes and the 2nd Stokes pulse widths were 20.5 ns and 5.8 ns, respectively. The stable simultaneous Q-switching and mode locking of the 2nd Stokes laser without mode locking component was obtained at the pump power of about 29~82 W. The estimated mode-locked pulse width was approximately 31 ps at the pump power of 50 W and a pulse repetition rate of 15 kHz. PMID- 23038334 TI - Experimental study on the existence and properties of speckle phase vortices in the diffraction region near random surfaces. AB - We design an optical setup to extract phase vortices in which the interference intensity of reference light wave and speckle fields produced by random screens with different roughness values in the diffraction region near random screens is obtained. Random screens with different roughness are used as samples. Fourier transform is used to extract speckle phase vortices from the interference intensity, and the experimental results show that the phase vortices can be produced when the roughness of the screen is large enough, and they even may appear on the surface. The density of phase vortices would become larger with an increase of the distances in the diffraction region near the random screen. When the distance is certain, the density of phase vortices becomes larger with the increase of roughness. These results would be helpful for understanding the formation of phase vortices. PMID- 23038335 TI - LCoS nematic SLM characterization and modeling for diffraction efficiency optimization, zero and ghost orders suppression. AB - Pixilated spatial light modulators are efficient devices to shape the wavefront of a laser beam or to perform Fourier optical filtering. When conjugated with the back focal plane of a microscope objective, they allow an efficient redistribution of laser light energy. These intensity patterns are usually polluted by undesired spots so-called ghosts and zero-orders whose intensities depend on displayed patterns. In this work, we propose a model to account for these discrepancies and demonstrate the possibility to efficiently reduce the intensity of the zero-order up to 95%, the intensity of the ghost up to 96% and increase diffraction efficiency up to 44%. Our model suggests physical cross-talk between pixels and thus, filtering of addressed high spatial frequencies. The method implementation relies on simple preliminary characterization of the SLM and can be computed a priori with any phase profile. The performance of this method is demonstrated employing a Hamamatsu LCoS SLM X10468-02 with two-photon excitation of fluorescent Rhodamine layers. PMID- 23038336 TI - Extended adding-doubling method for fluorescent applications. AB - In this paper a fast, yet accurate method to estimate the spectral and angular distribution of the scattered radiation of a fluorescent material is described. The proposed method is an extension of the adding-doubling algorithm for non fluorescent samples. The method is validated by comparing the spectral and angular transmittance and reflectance characteristics obtained with the extended algorithm with the results obtained using Monte Carlo simulations. The agreement using both methods is within 2%. However, the adding-doubling method achieves a reduction of the calculation time by a factor of 400. Due to the short calculation time, the extended adding-doubling method is very useful when fluorescent layers have to be optimized in an iterative process. PMID- 23038337 TI - Single-mode GaN nanowire lasers. AB - We demonstrate stable, single-frequency output from single, as-fabricated GaN nanowire lasers operating far above lasing threshold. Each laser is a linear, double-facet GaN nanowire functioning as gain medium and optical resonator, fabricated by a top-down technique that exploits a tunable dry etch plus anisotropic wet etch for precise control of the nanowire dimensions and high material gain. A single-mode linewidth of ~0.12 nm and >18 dB side-mode suppression ratio are measured. Numerical simulations indicate that single-mode lasing arises from strong mode competition and narrow gain bandwidth. PMID- 23038338 TI - Spatiotemporal characterization of few-cycle laser pulses. AB - In this paper we apply a broadband fiber optic coupler interferometer to the measurement of few-cycle laser pulses. Sub-8-fs pulses delivered by an ultrafast oscillator were characterized spatiotemporally using STARFISH, which is based on spatially resolved spectral interferometry. The reference pulse was measured with the d-scan technique. The pulses were focused by an off-axis parabolic mirror and were characterized at different transverse planes along the focusing region. The evolution of the retrieved pulses is analyzed, exhibiting small variations in the temporal (and spectral) amplitude and phase during propagation. Finally, the peak irradiance evolution is estimated from the integration of the spatiotemporal intensity. PMID- 23038339 TI - Femtosecond laser writing of a flat-top interleaver via cascaded Mach-Zehnder interferometers. AB - A flat-top interleaver consisting of cascaded Mach-Zehnder interferometers (MZIs) was fabricated in bulk glass by femtosecond laser direct writing. Spectral contrast ratios of greater than 15 dB were demonstrated over a 30 nm bandwidth for 3 nm channel spacing. The observed spectral response agreed well with a standard transfer matrix model generated from responses of individual optical components, demonstrating the possibility for multi-component optical design as well as sufficient process accuracy and fabrication consistency for femtosecond laser writing of advanced optical circuits in three dimensions. PMID- 23038340 TI - Free-space propagation of guided optical vortices excited in an annular core fiber. AB - The analytical expression for the propagation of guided optical vortices through free space is derived and used to study the dynamic evolution of guided optical vortices after passing through the free space, and the dependence of guided optical vortices on the control parameters where the effect of propagation distance is stressed. It is shown that the motion, pair creation and annihilation of guided optical vortices may take place. In particular, the creation and annihilation of a pair of guided optical vortices do not take place by varying fiber length. PMID- 23038341 TI - Response of plasmonic resonant nanorods: an analytical approach to optical antennas. AB - An analytical model of the response of a free-electron gas within the nanorod to the incident electromagnetic wave is developed to investigate the optical antenna problem. Examining longitudinal oscillations of the free-electron gas along the antenna nanorod a simple formula for antenna resonance wavelengths proving a linear scaling is derived. Then the nanorod polarizability and scattered fields are evaluated. Particularly, the near-field amplitudes are expressed in a closed analytical form and the shift between near-field and far-field intensity peaks is deduced. PMID- 23038342 TI - Asynchronous optical sampling with arbitrary detuning between laser repetition rates. AB - A method of asynchronous optical sampling based on free-running lasers with no requirement on the repetition rates is presented. The method is based on the a posteriori determination of the delay between each pair of pulses. A resolution better than 400 fs over 13 ns total delay scan is demonstrated. In addition to the advantages of conventional asynchronous sampling techniques, this method allows a straightforward implementation on already-existing laser systems using a fiber-based setup and an appropriate acquisition procedure. PMID- 23038343 TI - Optical-domain subsampling for data efficient depth ranging in Fourier-domain optical coherence tomography. AB - Recent advances in optical coherence tomography (OCT) have led to higher-speed sources that support imaging over longer depth ranges. Limitations in the bandwidth of state-of-the-art acquisition electronics, however, prevent adoption of these advances into the clinical applications. Here, we introduce optical domain subsampling as a method for imaging at high-speeds and over extended depth ranges but with a lower acquisition bandwidth than that required using conventional approaches. Optically subsampled laser sources utilize a discrete set of wavelengths to alias fringe signals along an extended depth range into a bandwidth limited frequency window. By detecting the complex fringe signals and under the assumption of a depth-constrained signal, optical-domain subsampling enables recovery of the depth-resolved scattering signal without overlapping artifacts from this bandwidth-limited window. We highlight key principles behind optical-domain subsampled imaging, and demonstrate this principle experimentally using a polygon-filter based swept-source laser that includes an intra-cavity Fabry-Perot (FP) etalon. PMID- 23038344 TI - Polarization dependent light extraction of a GaN light emitting diode using dark field angle-resolved photoluminescence spectrometry. AB - In this paper, the polarization dependent optical properties of GaN surface relief grating are investigated using dark field angle-resolved photoluminescence (ARPL) spectrometer. The light extraction efficiency with the transverse electric (TE) and transverse magnetic (TM) pumping source represents a TE polarized dominated property. It is found that the TE and TM waveguide modes cannot be simultaneously coupled out, therefore light extraction is polarization dependent. The ARPL spectrum also reveals that the extraction efficiency is relatively high as the dispersion line of the waveguide mode is coincident with the folded free photon dispersion of the 1D GaN grating. PMID- 23038345 TI - Pump-to-Stokes relative intensity noise transfer and analytical modeling of mid infrared silicon Raman lasers. AB - An analytical model for mid-infrared (mid-IR) silicon Raman lasers (SRLs) is developed. The relative intensity noise (RIN) transfer from the pump to the Stokes in the lasers is also investigated. The analytical model can be used as a versatile and efficient tool for analysis, design and optimization of mid-IR SRLs. It is shown that conversion efficiency of 70% is attainable and the low frequency RIN transfer may be suppressed to below 1 dB by pumping low-loss waveguides at high intensities. PMID- 23038346 TI - Compact real-time birefringent imaging spectrometer. AB - The design and experimental demonstration of a snapshot hyperspectral imaging Fourier transform (SHIFT) spectrometer is presented. The sensor, which is based on a multiple-image FTS (MFTS), offers significant advantages over previous implementations using Michelson interferometers. Specifically, its use of birefringent interferometry creates a vibration insensitive and ultra-compact (15x15x10 mm(3)) common-path interferometer while offering rapid reconstruction rates through the graphics processing unit. The SHIFT spectrometer's theory and experimental prototype are described in detail. Included are reconstruction and spectral calibration procedures, followed by the spectrometer's validation using measurements of gas-discharge lamps. Lastly, outdoor measurements demonstrate the sensor's ability to resolve spectral signatures in typical outdoor lighting and environmental conditions. PMID- 23038347 TI - Noise reduction with low dose CT data based on a modified ROF model. AB - In order to reduce the radiation exposure caused by Computed Tomography (CT) scanning, low dose CT has gained much interest in research as well as in industry. One fundamental difficulty for low dose CT lies in its heavy noise pollution in the raw data which leads to quality deterioration for reconstructed images. In this paper, we propose a modified ROF model to denoise low dose CT measurement data in light of Poisson noise model. Experimental results indicate that the reconstructed CT images based on measurement data processed by our model are in better quality, compared to the original ROF model or bilateral filtering. PMID- 23038348 TI - Force-induced optical nonlinearity and Kerr-like coefficient in opto-mechanical ring resonators. AB - This paper demonstrates the optical nonlinearity in opto-mechanical ring resonators that consist of a bus waveguide and two ring resonators, which is induced by the optical gradient force and characterized by the Kerr-like coefficient. Each ring resonator has a free-hanging arc that is perpendicularly deformable by an optical gradient force and subsequently this deformation changes the effective refractive index (ERI) of the ring resonator. The change of the ERI induces optical nonlinearity into the system, which is described by an equivalent Kerr coefficient (Kerr-like coefficient). Based on the experimental results, the Kerr-like coefficient of the ring resonator system falls in the range from 7.64 * 10(-12) to 2.01 * 10(-10) m(2)W(-1), which is at least 6-order higher than the silicon's Kerr coefficient. The dramatically improved optical nonlinearity in the opto-mechanical ring resonators promises potential applications in low power optical signal processing, modulation and bio-sensing. PMID- 23038349 TI - Carrier density dependence of the nonlinear absorption of intense THz radiation in GaAs. AB - We study the carrier density dependence of nonlinear terahertz (THz) absorption due to field-induced intervalley scattering in photoexcited GaAs using the optical-pump/THz-probe technique. The intervalley scattering in GaAs is strongly dependent on the photo-carrier density. As the carrier density is increased from 1 * 10(17) to 4.7 * 10(17) cm(-3), the nonlinear absorption bleaching increases. However, if the carrier density is increased further above 4.7 * 10(17) cm(-3), the trend reverses and the bleaching is reduced. The initial increase in absorption bleaching is because, unlike low THz field, high THz field experiences intervalley scattering and nonparabolicity of the conduction band. On the other hand, a simple electron transport model shows that the reduction in intervalley scattering is mainly due to the increase in the electron-hole scattering rate with the increase in the carrier density. This increase in the electron-hole scattering rate limits the maximum kinetic energy attainable by the electrons and thus reduces the observed nonlinear absorption. PMID- 23038350 TI - Linear photonic technique for fixed and time varying RF phase shifts of radar signals. AB - A simple linear photonic technique is proposed to achieve fixed or time varying radio-frequency (RF) phase shifts which can be used in applications such as radar signal manipulation. The technique is based on fixing or tuning the wavelength of an RF modulated optical signal within the reflection band of a fiber Bragg grating (FBG) filter with a step group delay profile. The scheme is verified in a realistic simulation to achieve a Doppler shift in a pulsed CW signal return. PMID- 23038351 TI - Appropriate green phosphor of SrSi2O2N2:Eu2+,Mn2+ for AC LEDs. AB - An AC (alternating current) LED exhibited the advantages of a low drive current, low static electricity, lack of a need for a rectifier, and high extraction efficiency. The input operating voltage of an AC LED is around 80V, and its operating frequency is 120 Hz or less. When the voltage is converted, a time gap of 1/120 s (10 ms), called dead time, is generated. This time gap is closely related to the scintillation phenomenon. Therefore, AC LEDs that have a phosphor composition, whose half-life composition can compensate for dead time that is generated during the voltage conversion, are sought to solve the problem of scintillation. The object of this work is to provide a phosphor SrSi(2)O(2)N(2):Eu(2+),Mn(2+) for AC LEDs, in which the dead time that is generated during the voltage conversion is compensated for by the half-life of the phosphor. PMID- 23038352 TI - Periodic plasmonic nanoantennas in a piecewise homogeneous background. AB - Periodic rectangular gold nanomonopoles and nanodipoles in a piecewise inhomogeneous background, consisting of a silicon substrate and a dielectric (aqueous) cover, have been investigated extensively via 3D finite-difference time domain simulations. The transmittance, reflectance and absorptance response of the nanoantennas were studied as a function of their geometry (length, width, thickness, gap) and found to vary very strongly. The nanoantennas were found to resonate in a single surface plasmon mode supported by the corresponding rectangular cross-section nanowire waveguide, identified as the sa(b)(0) mode [Phys. Rev. B 63, 125417 (2001)]. We determine the propagation characteristics of this mode as a function of nanowire cross-section and wavelength, and we relate the modal results to the performance of the nanoantennas. An approximate expression resting on modal results is proposed for the resonant length of nanomonopoles, and a simple equivalent circuit, also resting on modal results, but involving transmission lines and a capacitor (modelling the gap) is proposed to determine the resonant wavelength of nanodipoles. The expression and the circuit yield results that are in good agreement with the full computations, and thus will prove useful in the design of nanoantennas. PMID- 23038353 TI - Role of apodization in optical parametric amplifiers based on aperiodic quasi phasematching gratings. AB - We experimentally demonstrate and analyze two different techniques for apodizing the nonlinear coupling in aperiodically poled MgO:LiNbO(3) (APPLN) used in an ultrabroadband optical parametric chirped pulse amplifier (OPCPA). With an adiabatic increase of the nonlinear coupling, a smooth gain spectrum and spectral phase is preserved during amplification in such media. The two approaches we explore are poling period apodization (PPA) and duty cycle apodization (DCA). For the first implementation of the apodized APPLN amplifier we use a constant chirp rate in the grating k-vector. The nonlinear coupling is apodized over 10% of the total length at each side of the APPLN chip. This allows us to achieve high intensity output pulses with clean temporal structure. PMID- 23038354 TI - Femtosecond laser induced rotated 3D self-organized nanograting in fused silica. AB - Formation of rotated 3D self-organized nanograting inside fused silica is demonstrated by using a femtosecond pulse laser. The difference of birefringence signal of non-reciprocal writing lines indicates that the excited pulses may possess a finite tilt of intensity front, which produces an electric field vector parallel to the incident direction to modulate the excited electron plasma. We suggest that the orientation of nanograting depends on the correlation between the polarization plane azimuth and the tilted intensity front based on previous investigations. The result provides an opportunity to control the rotation of self-organized nanograting in three-dimensional space. PMID- 23038355 TI - Structural microfiber long-period gratings. AB - We experimentally demonstrate a novel structural long-period grating by helically coiling one microfiber onto another with the relatively thicker diameter. Owing to the strong periodic modulation of the coiled microfiber to the evanescent field of the straight microfiber, a resonance transmission notch of ~16.2 dB can be induced for a compact device length of ~450 MUm only (4 helical periods). Moreover, the filtered light energy from the straight fiber can emerge again at the output of the coiled one, providing great flexibility in producing new device functions. The spectral response to external strain is investigated and wide wavelength tuning range of around 106 nm is discussed. PMID- 23038356 TI - Saturated excitation of fluorescence to quantify excitation enhancement in aperture antennas. AB - Fluorescence spectroscopy is widely used to probe the electromagnetic intensity amplification on optical antennas, yet measuring the excitation intensity amplification is a challenge, as the detected fluorescence signal is an intricate combination of excitation and emission. Here, we describe a novel approach to quantify the electromagnetic amplification in aperture antennas by taking advantage of the intrinsic non linear properties of the fluorescence process. Experimental measurements of the fundamental f and second harmonic 2f amplitudes of the fluorescence signal upon excitation modulation are used to quantify the electromagnetic intensity amplification with plasmonic aperture antennas. PMID- 23038357 TI - Focused ion beam engineered whispering gallery mode resonators with open cavity structure. AB - We report the realization of an open cavity whispering gallery mode optical resonator, in which the circulating light traverses a free space gap. We utilize focused ion beam microfabrication to precisely cut a 10 MUm wide notch into the perimeter of a crystalline disc. We have shown that this modified resonator structure supports high quality modes, and demonstrated qualify factor, Q ~/= 10(6), limited by the notch surface roughness due to the ion milling process. Furthermore, we investigated the spatial profile of the modes inside the open cavity with a microfabricated probe mechanism. This new type of resonator structure facilitates interaction of the cavity's optical field with mechanical resonators as well as individual atoms or molecules. PMID- 23038358 TI - Coherent femtosecond pulse combining of multiple parallel chirped pulse fiber amplifiers. AB - We report on femtosecond pulse combining with up to four parallel chirped-pulse fiber amplifier channels. Active phase locking is implemented using the LOCSET (Locking of Optical Coherence by Single-detector Electronic-frequency Tagging) single detector feedback technique, resulting in 96.4%, 94.0%, and 93.9% relative combining efficiency with two, three, and four channels respectively. Theoretical and experimental analysis of combining efficiency dependence on amplitude and phase noise shows convergence to a fixed value with increasing number of channels, indicating that multi-channel pulse combining with LOCSET feedback should be scalable to very large numbers of channels. PMID- 23038359 TI - A polarized low-coherence interferometry demodulation algorithm by recovering the absolute phase of a selected monochromatic frequency. AB - A demodulation algorithm based on absolute phase recovery of a selected monochromatic frequency is proposed for optical fiber Fabry-Perot pressure sensing system. The algorithm uses Fourier transform to get the relative phase and intercept of the unwrapped phase-frequency linear fit curve to identify its interference-order, which are then used to recover the absolute phase. A simplified mathematical model of the polarized low-coherence interference fringes was established to illustrate the principle of the proposed algorithm. Phase unwrapping and the selection of monochromatic frequency were discussed in detail. Pressure measurement experiment was carried out to verify the effectiveness of the proposed algorithm. Results showed that the demodulation precision by our algorithm could reach up to 0.15kPa, which has been improved by 13 times comparing with phase slope based algorithm. PMID- 23038360 TI - Short-wavelength upconversion emissions in Ho3+/Yb3+ codoped glass ceramic and the optical thermometry behavior. AB - Ho(3+)/Yb(3+) codoped glass ceramic was prepared by melt-quenching and subsequent thermal treatment. Under a 980 nm diode laser excitation, upconversion emissions from Ho(3+) ions centered at 540, 650, and 750 nm were greatly enhanced compared with those in the precursor glass. Especially, the short-wavelength upconversion emissions centered at 360, 385, 418, 445, and 485 nm were successfully obtained in the glass ceramic. An explanation for this phenomenon is given based on the fluorescence decay curve measurements. In addition, an optical temperature sensor based on the blue upconversion emissions from (5)F(2,3)/(3)K(8)->(5)I(8) and (5)F(1)/(5)G(6)->(5)I(8) transitions in Ho(3+)/Yb(3+) codoped glass ceramic has been developed. It was found that by using fluorescence intensity ratio technique, appreciable sensitivity for temperature measurement can be achieved by using the Ho(3+)/Yb(3+) codoped glass ceramic. This result makes the Ho(3+)/Yb(3+) codoped glass ceramic be a promising candidate for sensitive optical temperature sensor with high resolution and good accuracy. PMID- 23038361 TI - Electrically-controlled rapid femtosecond pulse duration switching and continuous picosecond pulse duration tuning in an ultrafast Cr4+:forsterite laser. AB - We demonstrate rapid switching between picosecond and femtosecond operational regimes in a Cr(4+):forsterite laser, using an electrically-contacted GaInNAs SESAM with saturable absorption characteristics controlled via the quantum confined Stark effect. Additionally, continuous picosecond pulse duration tuning by over a factor 3 is reported. PMID- 23038362 TI - High-speed receiver based on waveguide germanium photodetector wire-bonded to 90nm SOI CMOS amplifier. AB - The performance of a receiver based on a CMOS amplifier circuit designed with 90nm ground rules wire-bonded to a waveguide germanium photodetector is characterized at data rates up to 40Gbps. Both chips were fabricated through the IBM Silicon CMOS Integrated Nanophotonics process on specialty photonics-enabled SOI wafers. At the data rate of 28Gbps which is relevant to the new generation of optical interconnects, a sensitivity of -7.3dBm average optical power is demonstrated with 3.4pJ/bit power-efficiency and 0.6UI horizontal eye opening at a bit-error-rate of 10(-12). The receiver operates error-free (bit-error-rate < 10(-12)) up to 40Gbps with optimized power supply settings demonstrating an energy efficiency of 1.4pJ/bit and 4pJ/bit at data rates of 32Gbps and 40Gbps, respectively, with an average optical power of -0.8dBm. PMID- 23038363 TI - Route to strong localization of light: the role of disorder. AB - By employing Random Matrix Theory (RMT) and first-principle calculations, we investigated the behavior of Anderson localization in 1D, 2D and 3D systems characterized by a varying disorder. In particular, we considered random binary layer sequences in 1D and structurally disordered photonic crystals in two and three dimensions. We demonstrated the existence of a unique optimal degree of disorder that yields the strongest localization possible. In this regime, localized modes are constituted by defect states, which can show subwavelength confinement properties. These results suggest that disorder offers a new avenue for subwavelength light localization in purely dielectric media. PMID- 23038364 TI - Dissipative soliton acceleration in nonlinear optical lattices. AB - An effective mechanism for dissipative soliton acceleration in nonlinear optical lattices under the presence of linear gain and nonlinear loss is presented. The key idea for soliton acceleration consists of the dynamical reduction of the amplitude of the effective potential experienced by the soliton so that its kinetic energy eventually increases. This is possible through the dependence of the effective potential amplitude on the soliton mass, which can be varied due to the presence of gain and loss mechanisms. In contrast to the case where either the linear or the nonlinear refractive index is spatially modulated, we show that when both indices are modulated with the same period we can have soliton acceleration and mass increasing as well as stable soliton propagation with constant non-oscillating velocity. The acceleration mechanism is shown to be very robust for a wide range of configurations. PMID- 23038365 TI - Low-frequency phase measurement with high-frequency squeezing. AB - Squeezed-state enhanced audio-frequency signal measurement is crucial for some special applications, such as gravitational wave detection. But generation of squeezed state of light at such frequency is more difficult than that at megahertz-frequency. In this paper we propose an experimental scheme to measure low-frequency phase signal with high-frequency squeezing. To utilize the high frequency sidebands of the squeezed light, a two-frequency intense laser is applied in the interferometry instead of a single-frequency laser as usual. This technique is in the reach of modern quantum optics technology. PMID- 23038366 TI - High speed adaptive liquid microlens array. AB - Liquid microlenses are attractive for adaptive optics because they offer the potential for both high speed actuation and parallelization into large arrays. Yet, in conventional designs, resonances of the liquid and the complexity of driving mechanisms and/or the device architecture have hampered a successful integration of both aspects. Here we present an array of up to 100 microlenses with synchronous modulation of the focal length at frequencies beyond 1 kHz using electrowetting. Our novel concept combines pinned contact lines at the edge of each microlens with an electrowetting controlled regulation of the pressure that actuates all microlenses in parallel. This design enables the development of various shapes of microlenses. The design presented here has potential applications in rapid parallel optical switches, artificial compound eye and three dimensional imaging. PMID- 23038367 TI - DNA optical nanofibers: preparation and characterization. AB - We demonstrate the preparation and characterization of DNA optical nanofibers. The prepared DNA optical nanofibers with strong strength and high flexibility are tested. Coupled with silica fiber tapers, their optical characteristics including light transmission performance, group delay and chromatic dispersion are experimentally investigated. The visible and near infrared light waveguiding properties of the DNA optical nanofibers with and without R6G doping are also studied. It is expected that the DNA optical nanofibers may be potential for building the miniaturized biomedical photonic devices. PMID- 23038368 TI - Static hyperspectral imaging polarimeter for full linear Stokes parameters. AB - A compact, static hyperspectral imaging linear polarimeter (HILP) based on a Savart interferometer (SI) is conceptually described. It improves the existing SI by replacing front polarizer with two Wollaston prisms, and can simultaneously acquire four interferograms corresponding to four linearly polarized lights on a single CCD. The spectral dependence of linear Stokes parameters can be recovered with Fourier transformation. Since there is no rotating or moving parts, the system is relatively robust. The interference model of the HILP is proved. The performance of the system is demonstrated through a numerical simulation, and the methods for compensating the imperfection of the polarization elements are described. PMID- 23038369 TI - Analysis of a hollow core photonic bandgap fiber ring resonator based on micro optical structure. AB - The fiber ring resonator (FRR) is the key component of resonator fiber optic gyros (R-FOGs). The configuration of a novel hollow core photonic bandgap fiber (HC-PBF) ring resonator is proposed based on the usage of micro-optical structure. The normalized transfer function of such kind of FRR is derived, and the effects of different FRR parameters' on the resonant depth, resonant finesse and sensitivity limited by the shot noise of the detector are simulated. The laboratory sample of integrated HC-PBF ring resonator is fabricated and tested experimentally and the optimal scheme is proposed based on the acquired test data. The experimental setup and results verify the feasibility of the micro optical coupling structure used in the HC-PBF ring resonator and also support the integration and miniaturization of R-FOGs composed of HC-PBFs. PMID- 23038371 TI - All optical tunable storage of phase-shift-keyed data packets. AB - The requirements for higher data rates in optical communication systems lead to the use of more efficient modulation formats. In the networks the all optical synchronization and storage of these signals is still a major challenge in order to enable higher transmittable data rates and reduce the energy consumption. In this contribution we show for the first time, to the best of our knowledge, the tunable storage of phase modulated optical data packets with up to 60 pulse widths. This opens the way to the optical storage of data packets modulated with highly efficient modulation formats. PMID- 23038370 TI - Analytical light scattering and orbital angular momentum spectra of arbitrary Vogel spirals. AB - In this paper, we present a general analytical model for light scattering by arbitrary Vogel spiral arrays of circular apertures illuminated at normal incidence. This model suffices to unveil the fundamental mathematical structure of their complex Fraunhofer diffraction patterns and enables the engineering of optical beams carrying multiple values of orbital angular momentum (OAM). By performing analytical Fourier-Hankel decomposition of spiral arrays and far field patterns, we rigorously demonstrate the ability to encode specific numerical sequences onto the OAM values of diffracted optical beams. In particular, we show that these OAM values are determined by the rational approximations (i.e., the convergents) of the continued fraction expansions of the irrational angles utilized to generate Vogel spirals. These findings open novel and exciting opportunities for the manipulation of complex OAM spectra using dielectric and plasmonic aperiodic spiral arrays for a number of emerging engineering applications in singular optics, secure communication, optical cryptography, and optical sensing. PMID- 23038372 TI - Tunable GHz pulse repetition rate operation in high-power TEM(00)-mode Nd:YLF lasers at 1047 nm and 1053 nm with self mode locking. AB - We report on a high-power diode-pumped self-mode-locked Nd:YLF laser with the pulse repetition rate up to several GHz. A novel tactic is developed to efficiently select the output polarization state for achieving the stable TEM(00) mode self-mode-locked operations at 1053 nm and 1047 nm, respectively. At an incident pump power of 6.93 W and a pulse repetition rate of 2.717 GHz, output powers as high as 2.15 W and 1.35 W are generated for the sigma- and pi polarization, respectively. We experimentally find that decreasing the separation between the gain medium and the input mirror not only brings in the pulse shortening thanks to the enhanced effect of the spatial hole burning, but also effectively introduces the effect of the spectral filtering to lead the Nd:YLF laser to be in a second harmonic mode-locked status. Consequently, pulse durations as short as 8 ps and 8.5 ps are obtained at 1053 nm and 1047 nm with a pulse repetition rate of 5.434 GHz. PMID- 23038373 TI - Experimental verification of spoof surface plasmons in wire metamaterials. AB - In this paper, we experimentally demonstrate the excitation of spoof surface plasmon polaritons (SPPs) on a wire-medium metamaterial slab in the microwave region. The spoof SPPs are excited on the opposite side of the slab from the source, which is desirable for applications such as sensing devices. Using the prism coupling method, we verify the excitation of spoof SPPs by measuring the reflection spectrum and near-field enhancement. The excitation of spoof SPPs is also verified by using the grating coupling method, where we demonstrate transmission enhancement through the metamaterial slab by placing diffraction gratings on both sides of the slab. Numerical investigation shows that the enhanced transmission can be attributed to the dispersion relations of the spoof SPPs and the periodicity of the diffraction grating. These properties can be used to realize extraordinary transmission and directional beaming. PMID- 23038374 TI - An ultracompact multimode interference wavelength splitter employing asymmetrical multi-section structures. AB - By using the film mode matching method, a novel design for asymmetrical multi section 1.55/1.31 MUm wavelength splitter based on multimode interference has been proposed and simulated, which can be effectively applied to wavelength multiplexer, self-biased photodiode, and other optical devices. Compared with the conventional wavelength splitter design, the length of the novel structure has been reduced to at least 1/5, showing better performance. The presented structure is also adequate for splitting other wavelengths and more tolerable fabrications. PMID- 23038375 TI - Analysis of reflective Mach-Zehnder interferometry for electro-optic characterization of poled polymer films in multilayer structures. AB - We consider the Mach-Zehnder interferometer (MZI) method that specifically uses a poled organic thin film as one of the reflective mirrors in order to characterize the two independent electro-optic tensor elements r(13) and r(33). We discuss both a simple analysis based on a three-layer structure and a rigorous method including multiple reflection effects in a multilayer structure. In doing so, we find that the simple analysis of the reflective MZI method yields identical results to the reflection ellipsometric method (simple Teng-Man method), first introduced by Teng and Man as well as Shildkraut in 1990, when the ratio of r(13) to r(33) obtained from the MZI method is used in the analysis of the simple Teng Man method. Error introduced by ignoring the multilayer nature of the sample structures in the MZI method is discussed and corrections are given for previous expressions in the literature for the simple analysis. PMID- 23038376 TI - Wide cantilever stiffness range cavity optomechanical sensors for atomic force microscopy. AB - We report on progress in developing compact sensors for atomic force microscopy (AFM), in which the mechanical transducer is integrated with near-field optical readout on a single chip. The motion of a nanoscale, doubly clamped cantilever was transduced by an adjacent high quality factor silicon microdisk cavity. In particular, we show that displacement sensitivity on the order of 1 fm/(Hz)(1/2) can be achieved while the cantilever stiffness is varied over four orders of magnitude (~0.01 N/m to ~290 N/m). The ability to transduce both very soft and very stiff cantilevers extends the domain of applicability of this technique, potentially ranging from interrogation of microbiological samples (soft cantilevers) to imaging with high resolution (stiff cantilevers). Along with mechanical frequencies (> 250 kHz) that are much higher than those used in conventional AFM probes of similar stiffness, these results suggest that our cavity optomechanical sensors may have application in a wide variety of high bandwidth AFM measurements. PMID- 23038377 TI - Temperature compensated microfiber Bragg gratings. AB - In this paper, temperature compensated microfiber Bragg grating (mFBG) is realized by use of a liquid with a negative thermo-optic coefficient. The effects of grating elongation and the index change of silica glass are compensated by refractive index change of the liquid through evanescent-field interaction. A reduced thermal sensitivity of 0.67 pm/ degrees C is achieved, which is 1/15 in magnitude of the uncompensated counterparts. Further theoretical analysis demonstrates that temperature insensitivity can be obtained with different combinations of microfiber diameter and the refractive index/thermal optic coefficient of the employed liquid. The proposed method is promising due to the compactness and high flexibility of the device. PMID- 23038378 TI - Simultaneous X-ray fluorescence and ptychographic microscopy of Cyclotella meneghiniana. AB - Scanning X-ray fluorescence microscopy (XFM) is a particularly useful method for studying the spatial distribution of trace metals in biological samples. Here we demonstrate the utility of combining coherent diffractive imaging (CDI) with XFM for imaging biological samples to simultaneously produce high-resolution and high contrast transmission images and quantitative elemental maps. The reconstructed transmission function yields morphological details which contextualise the elemental maps. We report enhancement of the spatial resolution in both the transmission and fluorescence images beyond that of the X-ray optics. The freshwater diatom Cyclotella meneghiniana was imaged to demonstrate the benefits of combining these techniques that have complementary contrast mechanisms. PMID- 23038379 TI - Surface mesoscopic effects in finite metamaterials. AB - While the effective medium treatment of unbounded metamaterials appears to be well established and firmly proven, related phenomena in finite structures have not received sufficient attention. We report on mesoscopic effects associated with the boundaries of finite discrete metamaterial samples, which can invalidate an effective medium description. We show how to avoid such effects by proper choice of boundary configuration. As all metamaterial implementations are naturally finite, we are confident that our findings are crucial for future metamaterial research. PMID- 23038380 TI - Digital Fresnel holography beyond the Shannon limits. AB - This paper presents a detailed analysis of the influence of the pixel dimension in digitally-recorded holograms. The investigation is based on both theoretical and experimental viewpoints for recordings beyond the Shannon limits. After discussing the pixel paradox, the sinc amplitude modulation is experimentally demonstration. The experimental analysis is well correlated to the theoretical basics; in addition, the filling factor of the sensor can be estimated. The analysis of the phase changes of the object show that they can be obtained with a very good contrast and that they are only limited by the decorrelation noise, as when the Shannon conditions are fulfilled. PMID- 23038381 TI - Broad-spectral-range synchronized flat-top arrayed-waveguide grating applied in a 225-channel cascaded spectrometer. AB - We present a new synchronized design for flattening the passband of an arrayed waveguide grating (AWG) over a broad wavelength range of 90 nm. A wavelength insensitive 3-dB balanced coupler is designed to be used in duplicate in a Mach Zehnder interferometer (MZI); the phase deviation created by one of the balanced couplers is cancelled by flipping the other coupler around. This MZI is arranged in tandem with the AWG such that the output signal of the MZI is the input signal of the AWG. We demonstrate a 5-channel, 18-nm-spacing AWG with a 0.5-dB bandwidth of 12 nm over a 90-nm spectral range. A low-loss cascaded AWG system is demonstrated by using the MZI-synchronized flat-top AWG as a primary filter. PMID- 23038382 TI - Controllable optical analog to electromagnetically induced transparency in coupled high-Q microtoroid cavities. AB - We experimentally demonstrate an all-optical analog to electromagnetically induced transparency (EIT) on chip using coupled high-Q silica microtoroid cavities with Q-factors above 10(6). The transmission spectrum of the all-optical analog to EIT is precisely controlled by tuning the distance between the two microtoroids, as well as the detunings of the resonance frequencies of the two cavities. PMID- 23038383 TI - Waveguide-fed optical hybrid plasmonic patch nano-antenna. AB - We propose a novel optical hybrid plasmonic patch nano-antenna for operation at the standard telecommunication wavelength of 1550 nm. The nano-antenna is designed to be compatible with a hybrid plasmonic waveguide through matching of both the operational mode and the wave impedance. The antenna is designed to receive the optical signal from a planar waveguide and redirect the signal out of plane, and is therefore useful for inter- or intra-chip optical communications and sensing. The transmission line model in conjunction with surface plasmon theory is used to develop analytical formulas for design and analysis, and a 3 dimensional full-wave numerical method is used to validate the design. The proposed device provides a bandwidth of more than 15 THz, a gain of 5.6 dB, and an efficiency of 87%. Furthermore, by designing an 8 * 8 array of the proposed antenna, a directivity of 20 dBi and steering of the beam angle are achieved by controlling the relative phase shift between elements of the array. PMID- 23038384 TI - 45 Gb/s low complexity optical front-end for soft-decision LDPC decoders. AB - In this paper a low complexity and energy efficient 45 Gb/s soft-decision optical front-end to be used with soft-decision low-density parity-check (LDPC) decoders is demonstrated. The results show that the optical front-end exhibits a net coding gain of 7.06 and 9.62 dB for post forward error correction bit error rate of 10(-7) and 10(-12) for long block length LDPC(32768,26803) code. The performance over a hard decision front-end is 1.9 dB for this code. It is shown that the soft-decision circuit can also be used as a 2-bit flash type analog-to digital converter (ADC), in conjunction with equalization schemes. At bit rate of 15 Gb/s using RS(255,239), LDPC(672,336), (672, 504), (672, 588), and (1440, 1344) used with a 6-tap finite impulse response (FIR) equalizer will result in optical power savings of 3, 5, 7, 9.5 and 10.5 dB, respectively. The 2-bit flash ADC consumes only 2.71 W at 32 GSamples/s. At 45 GSamples/s the power consumption is estimated to be 4.95 W. PMID- 23038385 TI - Durability of stochastic antireflective structures--analyses on damage thresholds and adsorbate elimination. AB - We fabricated stochastic antireflective structures (ARS) and analyzed their stability against high power laser irradiation and high temperature annealing. For 8 ps pulse duration and 1030 nm wavelength we experimentally determined their laser induced damage threshold to 4.9 (+/-0.3) J/cm(2), which is nearly as high as bulk fused silica with 5.6 (+/-0.3) J/cm(2). A commercial layer stack reached 2.0 (+/-0.2) J/cm(2). An annealing process removed adsorbed organics, as shown by XPS measurements, and significantly increased the transmission of the ARS. Because of their monolithic build the ARS endure such high temperature treatments. For more sensitive samples an UV irradiation proved to be capable. It decreased the absorbed light and reinforced the transmission. PMID- 23038386 TI - Athermal silicon waveguides with bridged subwavelength gratings for TE and TM polarizations. AB - In this paper, athermal silicon waveguides using bridged subwavelength grating (BSWG) structures are proposed and investigated. The realization of temperature independent BSWG waveguides for both polarizations is demonstrated numerically and experimentally. SU-8 polymer is used as the cladding material to compensate for the positive thermo-optic (TO) coefficient (dn/dT) of silicon. We investigate the dependence of the effective TO coefficient of BSWG waveguides on both the bridge width and grating duty cycle. The BSWG waveguides have a width of 490 nm, a height of 260 nm, and a grating pitch of 250 nm. Athermal behavior is achieved for both the transverse-magnetic (TM) and the transverse-electric (TE) polarized light for a variety of bridge width and duty cycle combinations. Furthermore, the BSWGs can be designed to be athermal for both TE and TM polarization simultaneously. PMID- 23038387 TI - Compact x-ray microscope for the water window based on a high brightness laser plasma source. AB - We present a laser plasma based x-ray microscope for the water window employing a high-average power laser system for plasma generation. At 90 W laser power a brightness of 7.4 x 10(11) photons/(s x sr x MUm(2)) was measured for the nitrogen Lyalpha line emission at 2.478 nm. Using a multilayer condenser mirror with 0.3 % reflectivity 10(6) photons/(MUm(2) x s) were obtained in the object plane. Microscopy performed at a laser power of 60 W resolves 40 nm lines with an exposure time of 60 s. The exposure time can be further reduced to 20 s by the use of new multilayer condenser optics and operating the laser at its full power of 130 W. PMID- 23038388 TI - Perfect absorbers on curved surfaces and their potential applications. AB - Recently perfect metamaterial absorbers triggered some fascination since they permit the observation of an extreme interaction of light with a nanostructured thin film. For the first time we evaluate here the functionality of such perfect absorbers if they are applied on curved surfaces. We probe their optical response and discuss potential novel applications. Examples are the complete suppression of back-scattered light from the covered objects, rendering it cloaked in reflection, and their action as optical black holes. PMID- 23038389 TI - Analysis of optical properties of metal/insulator/metal plasmonic metawaveguide with serial periodic stub resonators. AB - The optical properties of the Au/Al(2)O(3)/Ag plasmonic metawaveguide with serial periodic stub resonators were numerically investigated. The refractive index of this design provides large value by using the ultra thin Al(2)O(3) layer. Therefore, the dispersion relation which has negative group velocity, which is similar to the case of photonic crystals, can be formed in the sub diffraction energy range. The calculation results show the dependences of the negative group velocity dispersion curves on the size of the unit cell and the stub resonators. In addition, effective material properties are presented. From these analyses, it is found that this type of design has the property to strongly modulate the propagating characteristics of light. PMID- 23038390 TI - Carrier-envelope frequency stabilization of a Ti:sapphire oscillator using different pump lasers. AB - We investigate the suitability of various commercially available pump lasers for operation with a carrier-envelope offset frequency stabilized Ti:sapphire oscillator. Although the tested pump lasers differ in their setup and properties (e.g., single vs. multi-mode), we find that they are all well-suited for the purpose. The residual rms phase noise (integrated between 20 Hz and 5 MHz) of the stabilized oscillator is found to be below 160 mrad with each pump laser, corresponding to less than 1/40 of an optical cycle. Differences in performance vary slightly. In particular, our results indicate that the latest generation of multi-mode pump lasers can be used for applications where precise phase control of the oscillator is strictly required. PMID- 23038391 TI - Distributed source model for the full-wave electromagnetic simulation of nonlinear terahertz generation. AB - The process of terahertz generation through optical rectification in a nonlinear crystal is modeled using discretized equivalent current sources. The equivalent terahertz sources are distributed in the active volume and computed based on a separately modeled near-infrared pump beam. This approach can be used to define an appropriate excitation for full-wave electromagnetic numerical simulations of the generated terahertz radiation. This enables predictive modeling of the near field interactions of the terahertz beam with micro-structured samples, e.g. in a near-field time-resolved microscopy system. The distributed source model is described in detail, and an implementation in a particular full-wave simulation tool is presented. The numerical results are then validated through a series of measurements on square apertures. The general principle can be applied to other nonlinear processes with possible implementation in any full-wave numerical electromagnetic solver. PMID- 23038392 TI - Real-time monitoring of the solution concentration variation during the crystallization process of protein-lysozyme by using digital holographic interferometry. AB - We report a real-time measurement method of the solution concentration variation during the growth of protein-lysozyme crystals based on digital holographic interferometry. A series of holograms containing the information of the solution concentration variation in the whole crystallization process is recorded by CCD. Based on the principle of double-exposure holographic interferometry and the relationship between the phase difference of the reconstructed object wave and the solution concentration, the solution concentration variation with time for arbitrary point in the solution can be obtained, and then the two-dimensional concentration distribution of the solution during crystallization process can also be figured out under the precondition which the refractive index is constant through the light propagation direction. The experimental results turns out that it is feasible to in situ, full-field and real-time monitor the crystal growth process by using this method. PMID- 23038393 TI - Continuous-wave, short-wavelength infrared mixer using dispersion-stabilized highly-nonlinear fiber. AB - A new type of highly nonlinear fiber (HNLF) was designed and fabricated. The new HNLF was engineered to reduce dispersion shift due to transverse fluctuations while maintaining the modal confinement superior to that of the conventional fibers. The new design strategy was validated by the measurements of the global and local dispersive characteristics under considerable core and index profile deformation induced by tensile stress, which indicated that the dispersive and phase matching characteristics of the fiber did not change even under the highest tensile stress. The characteristics effectively decoupled tension-based Brillouin suppression from phase-matching impairments in parametric mixers for the first time. The new HNLF was used to demonstrate the first coherence-preserving mixer operating in the short-wavelength infrared (SWIR) band. The SWIR mixer was driven by continuous-wave near-infrared (NIR) pump and did not require pump phase dithering to suppress Brillouin scattering. PMID- 23038394 TI - Compact fiber-pigtailed InGaAs photoconductive antenna module for terahertz-wave generation and detection. AB - We propose a compact fiber-pigtailed InGaAs photoconductive antenna (FPP) module having an effective heat-dissipation solution as well as a module volume of less than 0.7 cc. The heat-dissipation of the FPP modules when using a heat-conductive printed circuit board (PCB) and an aluminium nitride (AlN) submount, without any cooling systems, improve by 40% and 85%, respectively, when compared with a photoconductive antenna chip on a conventional PCB. The AlN submount is superior to those previously reported as a heat-dissipation solution. Terahertz time domain spectroscopy (THz-TDS) using the FPP module perfectly detects the absorption lines of water vapor in free space and an alpha-lactose sample. PMID- 23038395 TI - MZI optical isolator with Si-wire waveguides by surface-activated direct bonding. AB - We fabricate a Mach-Zehnder interferometer-based optical isolator using a silicon wire waveguide with magneto-optic garnet cladding using direct bonding techniques. Using Si-wire waveguides, the size of the device is greatly reduced from that of our previous device. We investigate surface-activated direct bonding with nitrogen plasma treatment, which shows better bonding results than oxygen plasma treatment. A large magneto-optic phase shift of 0.8pi and an optical isolation of 18 dB are obtained at a wavelength of 1322 nm. PMID- 23038396 TI - Twisted nematic liquid crystal polarization grating with the handedness conservation of a circularly polarized state. AB - We propose a liquid crystal (LC) polarization grating that conserves the polarization state of incident light, wherein the variation range of the twist angle is 2pi. The design scheme for theoretically 100% diffraction efficiency of the first-diffraction order is derived, and a prototype LC grating is evaluated. Under zero voltage, the fabricated LC grating exhibits high efficiency of the first-order diffraction, validating the proposed design scheme. The high efficiency of the second-order diffraction can also be achieved under a high voltage so that the LC director in the midplane is vertical to the substrate plane. The circular polarization sense of the second-order diffraction is identical to that of the incident light as in the case of the first-order diffraction. This grating functions as a beam deflector, steering the input beam in three different directions (zeroth-, first-, and second-order diffractions) by adjusting the applied voltage. PMID- 23038397 TI - Phase demodulation using adaptive windowed Fourier transform based on Hilbert Huang transform. AB - The phase demodulation method of adaptive windowed Fourier transform (AWFT) is proposed based on Hilbert-Huang transform (HHT). HHT is analyzed and performed on fringe pattern to obtain instantaneous frequencies firstly. These instantaneous frequencies are further analyzed based on the condition of AWFT to locate local stationary areas where the fundamental spectrum will not be interfered by high order spectrum. Within each local stationary area, the fundamental spectrum can be extracted accurately and adaptively by using AWFT with the background, which has been determined previously with the presented criterion during HHT, being eliminated to remove the zero-spectrum. This method is adaptive and unconstrained by any precondition for the measured phase. Experiments demonstrate its robustness and effectiveness for measuring the object with discontinuities or complex surface. PMID- 23038398 TI - Maximum precision closed-form solution for localizing diffraction-limited spots in noisy images. AB - Super-resolution techniques like PALM and STORM require accurate localization of single fluorophores detected using a CCD. Popular localization algorithms inefficiently assume each photon registered by a pixel can only come from an area in the specimen corresponding to that pixel (not from neighboring areas), before iteratively (slowly) fitting a Gaussian to pixel intensity; they fail with noisy images. We present an alternative; a probability distribution extending over many pixels is assigned to each photon, and independent distributions are joined to describe emitter location. We compare algorithms, and recommend which serves best under different conditions. At low signal-to-noise ratios, ours is 2-fold more precise than others, and 2 orders of magnitude faster; at high ratios, it closely approximates the maximum likelihood estimate. PMID- 23038399 TI - Optimization of broadband optical response of multilayer nanospheres. AB - We propose an optimization-based theoretical approach to tailor the optical response of silver/silica multilayer nanospheres over the visible spectrum. We show that the structure that provides the largest cross-section per volume/mass, averaged over a wide frequency range, is the silver coated silica sphere. We also show how properly chosen mixture of several species of different nanospheres can have an even larger minimal cross-section per volume/mass over the entire visible spectrum. PMID- 23038400 TI - Superbroad near to mid infrared luminescence from closo-deltahedral Bi5(3+) cluster in Bi5(GaCl4)3. AB - Closo-deltahedral Bi(5)(3+) cluster in Bi(5)(GaCl(4))(3), which can be synthesized in benzene by oxidizing bismuth metal either with BiCl(3) or GaCl(3), respectively, can absorb ultraviolet, visible and infrared lights, and luminesce superbroadly in near to mid infrared (NMIR) spectral range from 1 to 3MUm at room temperature. Slight geometry change of the cluster can lead to the redshift of emission peak. These observations may initialize the development of Bi-based NMIR light sources with superbroad emission spectrum, where Bi(5)(3+) or similar polycationic species act as activators. Disputable crystal structure of Bi(5)(GaCl(4))(3) was redefined by classic Rietveld refining analysis. Consistent with crystallographic data, excitation, emission, temporal decay and time resolved infrared emission spectra all reveal only one type of luminescent centers, viz. Bi(5)(3+), in the compound. And a new absorption of Bi(5)(3+) was found at ~1100nm. PMID- 23038401 TI - Radiation of a uniformly moving line charge in a zero-index metamaterial and other periodic media. AB - Radiation of electromagnetic waves by a uniformly moving charge is the subject of extensive research over the last several decades. Fascinating effects such as Vavilov-Cherenkov radiation, transition radiation and the Smith-Purcell effect were discovered and studied in depth. In this letter we study the radiation of a line charge moving with relativistic constant velocity within an average zero index metamaterial consisting of periodically alternating layers with negative and positive refractive index. We observe a strong radiation enhancement, ~3 orders of magnitude, for specific combinations of velocities and radiation frequencies. This surprising finding is attributed to a gigantic increase in the density of states at the positive/negative index boundary. Furthermore, we shed light on radiation effects of such a line charge propagating within the more "traditional" structure of periodically alternating layers consisting of positive and different refractive index with focus on frequencies satisfying the quarter wave stack and the half wave stack conditions. We show that the quarter-wave stack case results in emission propagating vertically to the line charge trajectory, while the half-wave-stack results in negligible radiation. All these findings were obtained using a computationally efficient and conceptually intuitive computation method, based on eigenmode expansion of specific frequency components. For validation purposes this method was compared with the finite difference-time-domain method. PMID- 23038402 TI - An RNA-deaminase conjugate selectively repairs point mutations. AB - Checking for mistakes: By conjugating a catalytic domain with a guide RNA, deamination activity can be harnessed to repair a specific codon on mRNA. This method can be used for the highly selective repair of point mutations in mRNA by site-selective editing. PMID- 23038403 TI - Delay discounting of reward and caudate nucleus volume in individuals with alpha synuclein gene duplication before and after the development of Parkinson's disease. AB - BACKGROUND/AIMS: alpha-Synuclein (SNCA) may be a key factor in dopaminergic neurotransmission, reward processing, and neurodegeneration in Parkinson's disease (PD). We investigated delay discounting of reward and caudate volume in SNCA gene duplication carriers before and after the development of PD. METHODS: Participants were 7 presymptomatic SNCA duplication carriers who later developed PD (follow-up period: 5.4 years) and 10 matched non-carrier controls. At the follow-up assessment, patients received levodopa (L-DOPA) therapy. Delay discounting of reward was assessed with the Kirby discounting questionnaire. We measured the volume of the caudate nucleus and cerebral cortex using structural MRI and FreeSurfer software. RESULTS: In the presymptomatic stage, carriers showed similar delay discounting and caudate volume to that of non-carrier controls. However, after the development of PD, we observed a significant elevation in delay discounting (impulsive decisions) and reduced caudate volume. There was no cortical atrophy. CONCLUSION: Impaired reward-related decision making and caudate volume loss are not detectable in the presymptomatic stage in SNCA duplication carriers. These behavioral and neuroanatomical alterations are observed after the development of clinical symptoms when there is extensive neurodegeneration. Study limitations include a small sample size as well as the potential confounding effect of general cognitive decline. PMID- 23038405 TI - Fluidic microchemomechanical integrated circuits processing chemical information. AB - Lab-on-a-chip (LOC) technology has blossomed into a major new technology fundamentally influencing the sciences of life and nature. From a systemic point of view however, microfluidics is still in its infancy. Here, we present the concept of a microfluidic central processing unit (CPU) which shows remarkable similarities to early electronic Von Neumann microprocessors. It combines both control and execution units and, moreover, the complete power supply on a single chip and introduces the decision-making ability regarding chemical information into fluidic integrated circuits (ICs). As a consequence of this system concept, the ICs process chemical information completely in a self-controlled manner and energetically self-sustaining. The ICs are fabricated by layer-by-layer deposition of several overlapping layers based on different intrinsically active polymers. As examples we present two microchips carrying out long-term monitoring of critical parameters by around-the-clock sampling. PMID- 23038404 TI - Prevalence of cardiovascular events in patients with autosomal dominant polycystic kidney disease. AB - BACKGROUND: This study evaluates the prevalence of cardiovascular events in autosomal dominant polycystic kidney disease (ADPKD) patients. METHODS: We distributed surveys to 1,439 subjects from our ADPKD research database. In total, 426 subjects completed and returned surveys; 7 of these were from children and were excluded from the study. RESULTS: The patients who responded were female (63.2%), nonHispanic (88.1%) and white (93.6%). The mean age of the total group was 53.2 +/- 13.7 years; 82.8% had a family history of ADPKD and 32.5% had reached end-stage renal disease (ESRD). With respect to cardiovascular risk factors, 86.6% were hypertensive with a mean age at diagnosis of 36.9 +/- 12.9 years and hypertension was significantly more prevalent in males. In addition, 19.6% of the subjects were obese, 20.8% were smokers, 8.7% had diabetes, 45.7% had high cholesterol and 17.8% were sedentary. The most prevalent self-reported cardiovascular events were arrhythmias (25.9%), evidence of peripheral vascular disease (16.5%), heart valve problems (14.4%), cardiac enlargement (9.5%), stroke or cerebral bleeding (7.5%), myocardial infarction (6%) and brain aneurysm (5.0%). The most commonly used antihypertensive medications were renin angiotensin inhibitors used by 75% of ADPKD patients. Older ADPKD patients and those at ESRD had a significantly higher incidence of cardiovascular events. CONCLUSION: These findings support the high prevalence of cardiovascular risk factors and events in ADPKD patients which contribute to a greater mortality risk. Due to the prevalence of cardiovascular risk factors in the ADPKD population, early diagnosis and clinical intervention are recommended. PMID- 23038406 TI - Narrative synthesis of health service accreditation literature. AB - AIMS: To systematically identify and synthesise health service accreditation literature. METHODS: A systematic identification and narrative synthesis of health service accreditation literature published prior to 2012 were conducted. The search identified 122 empirical studies that examined either the processes or impacts of accreditation programmes. Study components were recorded, including: dates of publication; research settings; levels of study evidence and quality using established rating frameworks; and key results. A content analysis was conducted to determine the frequency of key themes and subthemes examined in the literature and identify knowledge-gaps requiring research attention. RESULTS: The majority of studies (n=67) were published since 2006, occurred in the USA (n=60) and focused on acute care (n=79). Two thematic categories, that is, 'organisational impacts' and 'relationship to quality measures', were addressed 60 or more times in the literature. 'Financial impacts', 'consumer or patient satisfaction' and 'survey and surveyor issues' were each examined fewer than 15 times. The literature is limited in terms of the level of evidence and quality of studies, but highlights potential relationships among accreditation programmes, high quality organisational processes and safe clinical care. CONCLUSIONS: Due to the limitations of the literature, it is not prudent to make strong claims about the effectiveness of health service accreditation. Nonetheless, several critical issues and knowledge-gaps were identified that may help stimulate and inform discussion among healthcare stakeholders. Ongoing effort is required to build upon the accreditation evidence-base by using high quality experimental study designs to examine the processes, effectiveness and financial value of accreditation programmes and their critical components in different healthcare domains. PMID- 23038407 TI - Quality measures: bridging the cultural divide. PMID- 23038408 TI - Comparison of traditional trigger tool to data warehouse based screening for identifying hospital adverse events. AB - BACKGROUND: Research supports medical record review using screening triggers as the optimal method to detect hospital adverse events (AE), yet the method is labour-intensive. METHOD: This study compared a traditional trigger tool with an enterprise data warehouse (EDW) based screening method to detect AEs. We created 51 automated queries based on 33 traditional triggers from prior research, and then applied them to 250 randomly selected medical patients hospitalised between 1 September 2009 and 31 August 2010. Two physicians each abstracted records from half the patients using a traditional trigger tool and then performed targeted abstractions for patients with positive EDW queries in the complementary half of the sample. A third physician confirmed presence of AEs and assessed preventability and severity. RESULTS: Traditional trigger tool and EDW based screening identified 54 (22%) and 53 (21%) patients with one or more AE. Overall, 140 (56%) patients had one or more positive EDW screens (total 366 positive screens). Of the 137 AEs detected by at least one method, 86 (63%) were detected by a traditional trigger tool, 97 (71%) by EDW based screening and 46 (34%) by both methods. Of the 11 total preventable AEs, 6 (55%) were detected by traditional trigger tool, 7 (64%) by EDW based screening and 2 (18%) by both methods. Of the 43 total serious AEs, 28 (65%) were detected by traditional trigger tool, 29 (67%) by EDW based screening and 14 (33%) by both. CONCLUSIONS: We found relatively poor agreement between traditional trigger tool and EDW based screening with only approximately a third of all AEs detected by both methods. A combination of complementary methods is the optimal approach to detecting AEs among hospitalised patients. PMID- 23038409 TI - Quality improvement initiative: enhanced communication of newly identified, suspected GI malignancies with direct critical results messaging to surgical specialist. AB - PURPOSE: To improve timely evaluation and management of newly identified, suspected, gastrointestinal (GI) malignancies discovered on radiologic imaging at a safety-net hospital through direct critical results messaging to surgical specialists. MATERIALS AND METHODS: To address delays in evaluating patients for suspected GI malignancies identified on imaging, an enhanced workflow was created -electronically routed critical results messaging to the ordering provider was supplemented with parallel messaging to the surgical oncology clinic. Messaging data obtained for 10 months pre and post intervention were compared. Using chart reviews, time intervals were recorded to assess the impact on (1) being seen by a specialist, (2) completing a diagnostic workup and (3) initiating definitive management. RESULTS: Significant improvements were achieved: (1) patients seen by a specialist increased from 45.9% to 98.0% (p<0.001), with median time decreasing from 35 to 7 days (p<0.001); (2) patients completing a diagnostic workup increased from 77.1% to 93.9% (p<0.05), with median time decreasing from 44 to 18 days (p<0.001); (3) patients with initiation of definitive management increased from 72.1% to 89.8% (p<0.05), with median time decreasing from 62 to 35 days (p<0.05). Further study is needed to assess impact on fragmentation of care and financial implications. CONCLUSIONS: Direct critical results messaging from the radiologist to the surgical oncologist at a safety-net hospital significantly improves the time to complete a diagnostic workup and initiate definitive management with significantly more patients being seen by a relevant specialist. PMID- 23038410 TI - Personalised performance feedback reduces narcotic prescription errors in a NICU. AB - OBJECTIVE: Neonates are at high risk for significant morbidity and mortality from medication prescribing errors. Despite general awareness of these risks, mistakes continue to happen. Alerts in computerised physician order entry intended to help prescribers avoid errors have not been effective enough. This improvement project delivered feedback of prescribing errors to prescribers in the neonatal intensive care unit (NICU), and measured the impact on medication error frequency. METHODS: A front-line multidisciplinary team doing multiple Plan Do Study Act cycles developed a system to communicate prescribing errors directly to providers every 2 weeks in the NICU. The primary outcome measure was number of days between medication prescribing errors with particular focus on antibiotic and narcotic errors. RESULTS: A T-control chart showed that the number of days between narcotic prescribing errors rose from 3.94 to 22.63 days after the intervention, an 83% improvement. No effect in the number of days between antibiotic prescribing errors during the same period was found. CONCLUSIONS: An effective system to communicate mistakes can reduce some types of prescribing errors. PMID- 23038411 TI - The robustness of generalized estimating equations for association tests in extended family data. AB - Variance components analysis (VCA), the traditional method for handling correlations within families in genetic association studies, is computationally intensive for genome-wide analyses, and the computational burden of VCA increases with family size and the number of genetic markers. Alternative approaches that do not require the computation of familial correlations are preferable, provided that they do not inflate type I error or decrease power. We performed a simulation study to evaluate practical alternatives to VCA that use regression with generalized estimating equations (GEE) in extended family data. We compared the properties of linear regression with GEE applied to an entire extended family structure (GEE-EXT) and GEE applied to nuclear family structures split from these extended families (GEE-SPL) to variance components likelihood-based methods (FastAssoc). GEE-EXT was evaluated with and without robust variance estimators to estimate the standard errors. We observed similar average type I error rates from GEE-EXT and FastAssoc compared to GEE-SPL. Type I error rates for the GEE-EXT method with a robust variance estimator were marginally higher than the nominal rate when the minor allele frequency (MAF) was <0.1, but were close to the nominal rate when the MAF was >=0.2. All methods gave consistent effect estimates and had similar power. In summary, the GEE framework with the robust variance estimator, the computationally fastest and least data management-intensive approach, appears to work well in extended families and thus provides a reasonable alternative to full variance components approaches for extended pedigrees in a genome-wide association study setting. PMID- 23038413 TI - Electrospun fibre diameter, not alignment, affects mesenchymal stem cell differentiation into the tendon/ligament lineage. AB - Efforts to develop engineered tendons and ligaments have focused on the use of a biomaterial scaffold and a stem cell source. However, the ideal scaffold microenvironment to promote stem cell differentiation and development of organized extracellular matrix is unknown. Through electrospinning, fibre scaffolds can be designed with tailorable architectures to mimic the intended tissue. In this study, the effects of fibre diameter and orientation were examined by electrospinning thin mats, consisting of small (< 1 um), medium (1-2 um) or large (> 2 um) diameter fibres with either random or aligned fibre orientation. C3H10T1/2 model stem cells were cultured on the six different electrospun mats, as well as smooth spin-coated films, and the morphology, growth and expression of tendon/ligament genes were evaluated. The results demonstrated that fibre diameter affects cellular behaviour more significantly than fibre alignment. Initially, cell density was greater on the small fibre diameter mats, but similar cell densities were found on all mats after an additional week in culture. After 2 weeks, gene expression of collagen 1alpha1 and decorin was increased on all mats compared to films. Expression of the tendon/ligament transcription factor scleraxis was suppressed on all electrospun mats relative to spin-coated films, but expression on the large-diameter fibre mats was consistently greater than on the medium-diameter fibre mats. These results suggest that larger-diameter fibres (e.g. > 2 um) may be more suitable for in vitro development of a tendon/ligament tissue. PMID- 23038414 TI - Frustrated Lewis pair inspired carbon dioxide reduction by a ruthenium tris(aminophosphine) complex. AB - Frustrating ruthenium: the ruthenium complex 1 is shown to bind carbon dioxide or aldehyde in a manner similar to a frustrated Lewis pair. Compound 2 catalyzes the reduction of CO(2) in the presence of pinacolborane (HBpin), yielding MeOBpin and O(Bpin)(2) (Ru red, P orange, N green, O light red, C black). PMID- 23038412 TI - Thalamic noradrenaline in Parkinson's disease: deficits suggest role in motor and non-motor symptoms. AB - The thalamus occupies a pivotal position within the corticobasal ganglia-cortical circuits. In Parkinson's disease (PD), the thalamus exhibits pathological neuronal discharge patterns, foremost increased bursting and oscillatory activity, which are thought to perturb the faithful transfer of basal ganglia impulse flow to the cortex. Analogous abnormal thalamic discharge patterns develop in animals with experimentally reduced thalamic noradrenaline; conversely, added to thalamic neuronal preparations, noradrenaline exhibits marked antioscillatory and antibursting activity. Our study is based on this experimentally established link between noradrenaline and the quality of thalamic neuronal discharges. We analyzed 14 thalamic nuclei from all functionally relevant territories of 9 patients with PD and 8 controls, and measured noradrenaline with high-performance liquid chromatography with electrochemical detection. In PD, noradrenaline was profoundly reduced in all nuclei of the motor (pallidonigral and cerebellar) thalamus (ventroanterior: -86%, P = .0011; ventrolateral oral: -87%, P = .0010; ventrolateral caudal: -89%, P = .0014): Also, marked noradrenaline losses, ranging from 68% to 91% of controls, were found in other thalamic territories, including associative, limbic and intralaminar regions; the primary sensory regions were only mildly affected. The marked noradrenergic deafferentiation of the thalamus discloses a strategically located noradrenergic component in the overall pathophysiology of PD, suggesting a role in the complex mechanisms involved with the genesis of the motor and non motor symptoms. Our study thus significantly contributes to the knowledge of the extrastriatal nondopaminergic mechanisms of PD with direct relevance to treatment of this disorder. PMID- 23038415 TI - Comparison of plasma concentrations of levobupivacaine with and without epinephrine for transversus abdominis plane block. AB - BACKGROUND AND OBJECTIVES: The pharmacokinetics for levobupivacaine in transversus abdominis plane (TAP) blocks has not been previously reported. We aimed to determine the extent of the block and the effect on plasma concentrations of levobupivacaine with the addition of epinephrine. METHODS: We enrolled 11 healthy volunteers in this double-blind, 2-intervention, 2-period crossover study. The intervention periods were defined as a unilateral left TAP block with 20 mL of 0.25% levobupivacaine with (E) or without (no E) 5 MUg/mL epinephrine. Subjects were randomized to E, followed by no E or no E followed by E, with 2-week washout period. Sensory dermatomal anesthesia was recorded. Blood samples were obtained for the measurement of plasma levobupivacaine levels. RESULTS: The median cranial-to-caudal spread of sensory blockade for sharp touch was T9 (interquartile range [IQR], T7-T10) to L1 (IQR, T12-L1) with epinephrine and T9 (IQR, T8-T10) to T12 (IQR, T11-L1) without epinephrine (P > 0.05). The mean maximum arterial levobupivacaine concentrations with epinephrine were 0.36 (95% bootstrap confidence interval [95% CI], 0.30-0.42) MUg/mL and 0.63 (95% CI, 0.49-0.85) MUg/mL without epinephrine (P = 0.014, difference in means of 0.27 [95% CI, 0.12-0.46]). The mean maximal venous levobupivacaine concentration was 0.32 (95% CI, 0.28-0.39) MUg/mL and 0.49 (95% CI, 0.37-0.68) MUg/mL, with and without epinephrine, respectively (P = 0.006, difference in means of 0.17 [95% CI, 0.08-0.33]). The mean duration of the blockade was 10.2 hours (95% CI, 8.5 12.5 hours) with epinephrine and 10.3 hours (95% CI, 8.7-12.4 hours) without epinephrine (P = 1.000). CONCLUSIONS: Adding epinephrine to levobupivacaine reduces its peak plasma concentration after unilateral TAP blocks, with no remarkable effects on block characteristics or duration. PMID- 23038416 TI - A novel anisotropic fast marching method and its application to blood flow computation in phase-contrast MRI. AB - BACKGROUND: Phase-contrast MRI (PC MRI) can be used to assess blood flow dynamics noninvasively inside the human body. The acquired images can be reconstructed into flow vector fields. Traditionally, streamlines can be computed based on the vector fields to visualize flow patterns and particle trajectories. OBJECTIVES: The traditional methods may give a false impression of precision, as they do not consider the measurement uncertainty in the PC MRI images. In our prior work, we incorporated the uncertainty of the measurement into the computation of particle trajectories. METHODS: As a major part of the contribution, a novel numerical scheme for solving the anisotropic Fast Marching problem is presented. A computing time comparison to state-of-the-art methods is conducted on artificial tensor fields. A visual comparison of healthy to pathological blood flow patterns is given. RESULTS: The comparison shows that the novel anisotropic Fast Marching solver outperforms previous schemes in terms of computing time. The visual comparison of flow patterns directly visualizes large deviations of pathological flow from healthy flow. CONCLUSIONS: The novel anisotropic Fast Marching solver efficiently resolves even strongly anisotropic path costs. The visualization method enables the user to assess the uncertainty of particle trajectories derived from PC MRI images. PMID- 23038417 TI - Posthemorrhagic hydrocephalus in preterm neonates: socioeconomic characteristics in a single-institution experience. AB - Patients with posthemorrhagic hydrocephalus (PHH) from germinal matrix hemorrhage of prematurity often require numerous early interventions, as well as long-term follow-up care from pediatric neurosurgeons, which continues to place high demands on the existing workforce and pediatric health care system. There are established correlations between premature birth and low socioeconomic status. The aim of this study is to characterize the demographic profile and follow-up patterns in this subpopulation of surgically treated infants with PHH from prematurity. METHODS: A retrospective analysis of the electronic patient records for a single institution, from 2007 to 2010, was performed. All patients who underwent neurosurgical intervention for the treatment of PHH were selected for further analysis. Data elements available within the records included patient demographic features, inpatient treatments and procedures, inpatient mortality rates, length of stay, and postoperative follow-up at the institution. Socioeconomic status was assessed using the median household income for the patient's zip code, as reported in the United States Census for the year 2000. RESULTS: A total of 40 patients who underwent neurosurgical intervention for PHH at a single institution were identified. More patients were female (52.5%); the majority of patients were Black (57.5%). No patients were uninsured; most patients had public insurance (62.5%), and 65% were below the Maryland State median household income (USD 52,868). There were trends toward more frequent emergency room visits among those covered by public insurance and those below the state and national median house income, although differences were not statistically significant. CONCLUSIONS: Our data indicate that the majority of patients fall within lower household income brackets, are born into households earning less than the statewide median household income, and are covered by public insurance. In light of the socioeconomic profile of the patient population reported here, these data may prove to be useful in preventative strategies aimed toward prematurity, PHH, and the ongoing treatment of hydrocephalus by pediatric neurosurgeons and other pediatric subspecialists. PMID- 23038418 TI - Diffraction analysis of mesostructured mesoporous materials. AB - Ordered mesostructured mesoporous materials, combining nano-organization with atomic disorder, are both attractive and challenging objects of investigation by X-ray and neutron diffraction. The development of diffraction mesostructure analysis methods and their applications in studies on structural characterization, formation processes and physisorption phenomena in these advanced materials are summarized in this tutorial review. The focus here is on the techniques that allow extracting mesostructure parameters and peculiarities of density distribution in the materials from the Bragg reflection positions and intensities. The investigations of mesoporous silicates, their nonsilica replicas and composites are discussed including the combined use of diffraction with electron microscopy and physisorption. The small-angle scattering curve analysis, which is also an important methodology in the field, is out of the scope of this review. PMID- 23038419 TI - Survey on the management of early cervical cancer among members of the GCIG. AB - OBJECTIVE: To establish the different imaging and treatment options offered to patients with early cervical cancer by members of the Gynecologic Cancer Intergroup. METHODS: A questionnaire was developed and disseminated electronically to members of the Gynecologic Cancer Intergroup and was completed online. RESULTS: One hundred sixty-two members viewed the questionnaire; 88 members started it; however, only 64 members fully completed it. Most (89.9%) of respondents used the International Federation of Gynecology and Obstetrics classification system when staging cervical cancer, using adjuncts to clinical staging: 33 respondents (37.5%) advocated computed tomography, 61 respondents (69.3%) advocated magnetic resonance imaging, 26 respondents (29.6%) positron emission tomography-computed tomography, and 36 respondents (40.9%) advocated staging lymphadenectomy, with 69.4% (50) performing lymphadenectomies laparoscopically. The external iliac nodal group was the nodal group that was consistently part of the lymphadenectomy with other nodal groups variably removed depending on the stage. All centers offered fertility-conserving surgery in stage IA1 cervical cancer and most up to and including stage IB1 with no lymphovascular space invasion. The fertility-conserving procedures performed varied among respondents: 20.3% (15 respondents) abdominal radical trachelectomy, 47.35 (35 respondents) radical vaginal trachelectomy, 58.1% (43 respondents) trachelectomy, 97.3% (72 respondents) cone biopsy, and 67.6% (50 respondents) large loop excision of the transformation zone. When fertility conservation was not desired, there was variation in the surgical techniques offered. Chemotherapy was used to downstage tumors preoperatively in 16.4% (11) before fertility-conserving surgery and 50.8% (34) before radical surgery. CONCLUSIONS: There are wide variations in the use of preoperative imaging, when pelvic and para-aortic lymph nodes are removed, and as to which surgical procedure should be offered in the management of cervical cancer both when fertility conservation is and is not an issue. PMID- 23038421 TI - CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy. AB - Genetic and phenotypic heterogeneities are considerably high in adult-onset leukoencephalopathy, in which comprehensive mutational analyses of the candidate genes by conventional methods are too laborious. We applied exome sequencing to conduct a comprehensive mutational analysis of genes for autosomal dominant leukoencephalopathies. Genomic DNA samples from four patients of three families with autosomal dominantly inherited adult-onset leukodystrophy were subjected to exome sequencing. On the basis of the results, 21 patients with adult-onset sporadic leukodystrophy and one patient with pathologically proven HDLS were additionally screened for CSF1R mutations. Exome sequencing identified heterozygous CSF1R mutations (p.I794T and p.R777W) in two families. I794T has recently been reported as a causative mutation for hereditary diffuse leukoencephalopathy with spheroids (HDLS), and R777W is a novel mutation. Although mutational analysis of CSF1R in 21 sporadic cases revealed no mutations, another novel CSF1R mutation, p.C653Y, was identified in one patient with autopsy proven HDSL. These variants were located in the PTK domain where the causative mutations cluster. Functional prediction of the mutant CSF1R as well as cross species conservation of the affected amino acids supports the notion that these variants are pathogenic for HDLS. Exome sequencing is useful for a comprehensive mutational analysis of causative genes for hereditary leukoencephalopathies, and CSF1R should be considered a candidate gene for patients with autosomal dominant leukoencephalopathies. PMID- 23038422 TI - Pillar[n]arenes (n = 8-10) with two cavities: synthesis, structures and complexing properties. AB - Three pillar[n]arenes (n = 8-10) were synthesized. X-ray analysis demonstrated that, different from early reported small pillar[n]arenes (n = 5, 6), these larger macrocycles gave rise to two cavities. (1)H NMR and MS experiments revealed that pillar[9]arene complexed one n-octyltrimethyl ammonium in chloroform, while pillar[10]arene could complex two. PMID- 23038420 TI - Cognitive impairment in Parkinson's disease: the dual syndrome hypothesis. AB - Research into the heterogeneous nature of cognitive impairment documented in patients with Parkinson's disease (PD) has focused on disentangling deficits that vary between individuals, evolve and respond differentially to pharmacological treatments, and relate differentially to PD dementia (PDD). We summarise studies conducted in our laboratory over the last 2 decades, outlining the incremental development of our hypotheses, the starting point for which is our early work on executive deficits mirroring fronto-striatal dysfunction. We present subsequent findings linking these deficits to a model of dopaminergic function that conforms to an inverted curvilinear function. We review studies that investigated the range of dopamine-independent attentional and visuospatial memory deficits seen in PD, demonstrating that abnormalities in these domains more accurately predict PDD. We conclude with an exposition of the dual syndrome hypothesis, which distinguishes between dopaminergically mediated fronto-striatal executive impairments and a dementia syndrome with distinctive prodromal visuospatial deficits in which cholinergic treatments offer some clinical benefits. PMID- 23038427 TI - Liquid alloy printing of microfluidic stretchable electronics. AB - Recently, microfluidic stretchable electronics has attracted great interest from academia since conductive liquids allow for larger cross-sections when stretched and hence low resistance at longer lengths. However, as a serial process it has suffered from low throughput, and a parallel processing technology is needed for more complex systems and production at low costs. In this work, we demonstrate such a technology to implement microfluidic electronics by stencil printing of a liquid alloy onto a semi-cured polydimethylsiloxane (PDMS) substrate, assembly of rigid active components, encapsulation by pouring uncured PDMS on-top and subsequent curing. The printing showed resolution of 200 MUm and linear resistance increase of the liquid conductors when elongated up to 60%. No significant change of resistance was shown for a circuit with one LED after 1000 times of cycling between a 0% and an elongation of 60% every 2 s. A radio frequency identity (RFID) tag was demonstrated using the developed technology, showing that good performance could be maintained well into the radio frequency (RF) range. PMID- 23038428 TI - Oxidative geminal functionalization of organoboron compounds. AB - Excellent tolerance: Stable acylboronates equipped with N-methyliminodiacetyl (MIDA) boryl groups ([B]) were prepared by using a sequence of oxidative manipulations at the boron-bound carbon center (green in scheme). Chemoselective transformations of these acylated organoboron building blocks yielded a range of multifunctionalized boron derivatives and supplied access to valuable borylated heterocycles (see scheme). PMID- 23038429 TI - Gene therapies need new development models. PMID- 23038440 TI - Malaria plan under scrutiny. PMID- 23038441 TI - New cures sought from old drugs. PMID- 23038442 TI - The telescopes that came in from the cold. PMID- 23038443 TI - Foundation opens TB lab in Africa. PMID- 23038444 TI - SARS veterans tackle coronavirus. PMID- 23038445 TI - Misconduct is the main cause of life-sciences retractions. PMID- 23038446 TI - Plant science: The chestnut resurrection. PMID- 23038447 TI - Galaxy formation: The new Milky Way. PMID- 23038448 TI - Digital archives: Don't let copyright block data mining. PMID- 23038449 TI - Nobel success: What makes a great lab? PMID- 23038454 TI - Policy: Biodiversity needs a scientific approach. PMID- 23038455 TI - Nanotechnology: Change of heart on nanoparticle risks. PMID- 23038456 TI - Publishing: Reviews turn facts into understanding. PMID- 23038457 TI - Cold fusion: Fleischmann denied due credit. PMID- 23038458 TI - Renewable energy: European biodiesel can be sustainable. PMID- 23038459 TI - Climate science: The aerosol effect. PMID- 23038460 TI - Mucosal immunology: Infection induces friendly fire. PMID- 23038461 TI - Quantum physics: Cruise control for a qubit. PMID- 23038462 TI - Genomics: Resident risks. PMID- 23038463 TI - Astrophysics: Two black holes found in a star cluster. PMID- 23038465 TI - Immunology: Tolerating pregnancy. PMID- 23038466 TI - Two stellar-mass black holes in the globular cluster M22. AB - Hundreds of stellar-mass black holes probably form in a typical globular star cluster, with all but one predicted to be ejected through dynamical interactions. Some observational support for this idea is provided by the lack of X-ray emitting binary stars comprising one black hole and one other star ('black-hole/X ray binaries') in Milky Way globular clusters, even though many neutron-star/X ray binaries are known. Although a few black holes have been seen in globular clusters around other galaxies, the masses of these cannot be determined, and some may be intermediate-mass black holes that form through exotic mechanisms. Here we report the presence of two flat-spectrum radio sources in the Milky Way globular cluster M22, and we argue that these objects are black holes of stellar mass (each ~10-20 times more massive than the Sun) that are accreting matter. We find a high ratio of radio-to-X-ray flux for these black holes, consistent with the larger predicted masses of black holes in globular clusters compared to those outside. The identification of two black holes in one cluster shows that ejection of black holes is not as efficient as predicted by most models, and we argue that M22 may contain a total population of ~5-100 black holes. The large core radius of M22 could arise from heating produced by the black holes. PMID- 23038467 TI - Comet-like mineralogy of olivine crystals in an extrasolar proto-Kuiper belt. AB - Some planetary systems harbour debris disks containing planetesimals such as asteroids and comets. Collisions between such bodies produce small dust particles, the spectral features of which reveal their composition and, hence, that of their parent bodies. A measurement of the composition of olivine crystals (Mg(2-2x)Fe(2x)SiO(4)) has been done for the protoplanetary disk HD 100546 (refs 3, 4) and for olivine crystals in the warm inner parts of planetary systems. The latter compares well with the iron-rich olivine in asteroids (x ~ 0.29). In the cold outskirts of the beta Pictoris system, an analogue to the young Solar System, olivine crystals were detected but their composition remained undetermined, leaving unknown how the composition of the bulk of Solar System cometary olivine grains compares with that of extrasolar comets. Here we report the detection of the 69-micrometre-wavelength band of olivine crystals in the spectrum of beta Pictoris. Because the disk is optically thin, we can associate the crystals with an extrasolar proto-Kuiper belt a distance of 15-45 astronomical units from the star (one astronomical unit is the Sun-Earth distance), determine their magnesium-rich composition (x = 0.01 +/- 0.001) and show that they make up 3.6 +/- 1.0 per cent of the total dust mass. These values are strikingly similar to those for the dust emitted by the most primitive comets in the Solar System, even though beta Pictoris is more massive and more luminous and has a different planetary system architecture. PMID- 23038468 TI - Stabilizing Rabi oscillations in a superconducting qubit using quantum feedback. AB - The act of measurement bridges the quantum and classical worlds by projecting a superposition of possible states into a single (probabilistic) outcome. The timescale of this 'instantaneous' process can be stretched using weak measurements, such that it takes the form of a gradual random walk towards a final state. Remarkably, the interim measurement record is sufficient to continuously track and steer the quantum state using feedback. Here we implement quantum feedback control in a solid-state system, namely a superconducting quantum bit (qubit) coupled to a microwave cavity. A weak measurement of the qubit is implemented by probing the cavity with microwave photons, maintaining its average occupation at less than one photon. These photons are then directed to a high-bandwidth, quantum-noise-limited amplifier, which allows real-time monitoring of the state of the cavity (and, hence, that of the qubit) with high fidelity. We demonstrate quantum feedback control by inhibiting the decay of Rabi oscillations, allowing them to persist indefinitely. Such an ability permits the active suppression of decoherence and enables a method of quantum error correction based on weak continuous measurements. Other applications include quantum state stabilization, entanglement generation using measurement, state purification and adaptive measurements. PMID- 23038469 TI - Sulphate-climate coupling over the past 300,000 years in inland Antarctica. AB - Sulphate aerosols, particularly micrometre-sized particles of sulphate salt and sulphate-adhered dust, can act as cloud condensation nuclei, leading to increased solar scattering that cools Earth's climate. Evidence for such a coupling may lie in the sulphate record from polar ice cores, but previous analyses of melted ice core samples have provided only sulphate ion concentrations, which may be due to sulphuric acid. Here we present profiles of sulphate salt and sulphate-adhered dust fluxes over the past 300,000 years from the Dome Fuji ice core in inland Antarctica. Our results show a nearly constant flux of sulphate-adhered dust through glacial and interglacial periods despite the large increases in total dust flux during glacial maxima. The sulphate salt flux, however, correlates inversely with temperature, suggesting a climatic coupling between particulate sulphur and temperature. For example, the total sulphate salt flux during the Last Glacial Maximum averages 5.78 mg m(-2) yr(-1), which is almost twice the Holocene value. Although it is based on a modern analogue with considerable uncertainties when applied to the ice-core record, this analysis indicates that the glacial-to-interglacial decrease in sulphate would lessen the aerosol indirect effects on cloud lifetime and albedo, leading to an Antarctic warming of 0.1 to 5 kelvin. PMID- 23038470 TI - Natural and anthropogenic variations in methane sources during the past two millennia. AB - Methane is an important greenhouse gas that is emitted from multiple natural and anthropogenic sources. Atmospheric methane concentrations have varied on a number of timescales in the past, but what has caused these variations is not always well understood. The different sources and sinks of methane have specific isotopic signatures, and the isotopic composition of methane can therefore help to identify the environmental drivers of variations in atmospheric methane concentrations. Here we present high-resolution carbon isotope data (delta(13)C content) for methane from two ice cores from Greenland for the past two millennia. We find that the delta(13)C content underwent pronounced centennial scale variations between 100 BC and AD 1600. With the help of two-box model calculations, we show that the centennial-scale variations in isotope ratios can be attributed to changes in pyrogenic and biogenic sources. We find correlations between these source changes and both natural climate variability--such as the Medieval Climate Anomaly and the Little Ice Age--and changes in human population and land use, such as the decline of the Roman empire and the Han dynasty, and the population expansion during the medieval period. PMID- 23038471 TI - Dynamical similarity of geomagnetic field reversals. AB - No consensus has been reached so far on the properties of the geomagnetic field during reversals or on the main features that might reveal its dynamics. A main characteristic of the reversing field is a large decrease in the axial dipole and the dominant role of non-dipole components. Other features strongly depend on whether they are derived from sedimentary or volcanic records. Only thermal remanent magnetization of lava flows can capture faithful records of a rapidly varying non-dipole field, but, because of episodic volcanic activity, sequences of overlying flows yield incomplete records. Here we show that the ten most detailed volcanic records of reversals can be matched in a very satisfactory way, under the assumption of a common duration, revealing common dynamical characteristics. We infer that the reversal process has remained unchanged, with the same time constants and durations, at least since 180 million years ago. We propose that the reversing field is characterized by three successive phases: a precursory event, a 180 degrees polarity switch and a rebound. The first and third phases reflect the emergence of the non-dipole field with large-amplitude secular variation. They are rarely both recorded at the same site owing to the rapidly changing field geometry and last for less than 2,500 years. The actual transit between the two polarities does not last longer than 1,000 years and might therefore result from mechanisms other than those governing normal secular variation. Such changes are too brief to be accurately recorded by most sediments. PMID- 23038472 TI - A Silurian armoured aplacophoran and implications for molluscan phylogeny. AB - The Mollusca is one of the most diverse, important and well-studied invertebrate phyla; however, relationships among major molluscan taxa have long been a subject of controversy. In particular, the position of the shell-less vermiform Aplacophora and its relationship to the better-known Polyplacophora (chitons) have been problematic: Aplacophora has been treated as a paraphyletic or monophyletic group at the base of the Mollusca, proximate to other derived clades such as Cephalopoda, or as sister group to the Polyplacophora, forming the clade Aculifera. Resolution of this debate is required to allow the evolutionary origins of Mollusca to be reconstructed with confidence. Recent fossil finds support the Aculifera hypothesis, demonstrating that the Palaeozoic-era palaeoloricate 'chitons' included taxa combining certain polyplacophoran and aplacophoran characteristics. However, fossils combining an unambiguously aplacophoran-like body with chiton-like valves have remained elusive. Here we describe such a fossil, Kulindroplax perissokomos gen. et sp. nov., from the Herefordshire Lagerstatte (about 425 million years bp), a Silurian deposit preserving a marine biota in unusual three-dimensional detail. The specimen is reconstructed three-dimensionally through physical-optical tomography. Phylogenetic analysis indicates that this and many other palaeoloricate chitons are crown-group aplacophorans. PMID- 23038475 TI - A novel pseudo-dicentric variant of 16p11.2-q11.2 contains euchromatin from 16p11.2-p11.1 and resembles pathogenic duplications of proximal 16q. AB - An unusually large G-light band between 2 G-dark bands in the proximal long arm of chromosome 16 was found in a boy of 5 years of age ascertained with growth retardation, microcephaly, and dysmorphic features. Dual color bacterial artificial chromosome fluorescence in situ hybridization (BAC FISH) and oligonucleotide array comparative genomic hybridization (oaCGH) were used to show that these bands contained a euchromatic duplication of a minimum of 940 kb between base pairs 34,197,413-35,137,025 in 16p11.2-p11.1 as well as a duplication of the centromere and major 16qh/16p11.2 heterochromatic block, covering a minimum of 12.3 Mb. The same pseudo-dicentric chromosome was found in the father who has attention deficit hyperactivity disorder (ADHD). The euchromatic region is not known to be subject to imprinting and overlaps multiple large copy number variations (CNVs) in the Database of Genomic Variants as well as similar CNVs that are benign or of uncertain significance in the International Standards for Cytogenomic Arrays database. We conclude that this family has a novel pseudo-dicentric euchromatic variant of chromosome 16 that is unlikely to be the cause of the variable phenotype in father and son but needs to be distinguished from heterochromatic variants or pathogenic duplications of proximal 16q. PMID- 23038474 TI - Regulation of androgen receptor expression by Z-isochaihulactone mediated by the JNK signaling pathway and might be related to cytotoxicity in prostate cancer. AB - BACKGROUND: The androgen receptor (AR) is a main therapeutic target for treatment of prostate cancer (PCa). The natural compound isochaihulactone (K8), which has a chiral center ring and two racemic forms (E-K8 and Z-K8), has anti-tumor effects on multiple cancer types both in vitro and in vivo. Here, we determined which form of K8 contains significant tumor cytotoxicity and examined how this form regulates AR expression in PCa cells and xenografts. METHODS: We chose the androgen-dependent human PCa cell line LNCaP and the androgen-independent cell lines DU145 and PC-3 to study the anti-tumor potency and AR regulation mediated by Z-K8. We measured cell viability and used flow cytometry, RT-PCR, and Western blotting. Growth inhibition in vivo was evaluated with an LNCaP xenograft animal model. RESULTS: In LNCaP cells, Z-K8 significantly repressed cell proliferation, induced apoptosis, repressed AR mRNA and protein expression in a time-dependent manner, and induced JNK phosphorylation. Furthermore, treatment with a JNK inhibitor significantly abolished Z-K8-induced AR downregulation. Z-K8 did not significantly inhibit reporter gene expression of constructs containing the AR promoter when it contained a mutated Sp1 binding site. Z-K8 also showed anti tumor effects in the xenograft animal model. CONCLUSION: Z-K8 not only induced LNCaP apoptosis but also reduced AR expression. These results indicate that Z-K8 may be a potential anti-tumor drug for PCa therapy. PMID- 23038476 TI - Influence of body mass index on postoperative complications after rectal resection for carcinoma. AB - OBJECTIVES: The influence of obesity on postoperative complications after various surgical interventions remains controversial. The aim of this study was to evaluate the impact of overweight and obesity on the occurrence of postoperative complications for patients undergoing elective resection for rectal carcinoma. METHODS: We conducted a retrospective data analysis of 676 patients undergoing surgical treatment for rectal carcinoma. Depending on their body mass index (BMI), patients were grouped as follows: group I, patients up to BMI 24.9 kg/m; group II patients, with a BMI between 25 and 29.9 kg/m; and group III, all patients with a BMI >30 kg/m. Complications were classified as minor and major with regard to severity grades (1-5). Statistical analysis was performed to evaluate the difference in complication rates between the different BMI groups. RESULTS: A total of 444 patients were included for analysis. Overall, 300 (67.6%) of the 444 patients did not develop postoperative complications, 82 (18.4%) patients had minor complications (grade 1 + 2), and 56 patients (12.6%) had major (grade 3 + 4) complications. Six (1.4%) patients died (grade 5). The Fisher exact test indicated no statistically significant difference of complication rates between the different BMI groups (P = 0.3716). CONCLUSIONS: Compared with nonobese or normal-weight patients, obese patients do not have a statistically significant higher risk of developing postoperative complications after rectal resection for carcinoma. PMID- 23038477 TI - Evaluation and treatment of hepatitis C in patients with human immunodeficiency virus. AB - OBJECTIVES: The rate of treatment of hepatitis C virus (HCV) infection in human immunodeficiency virus-hepatitis C virus (HIV-HCV) co-infected patients remains historically low. We undertook a retrospective study to review our treatment rate and factors that have negatively influenced this rate. In those treated, we reviewed outcomes and compared results with prior studies. METHODS: A total of 233 patients infected with HIV and HCV were followed for 7 years in the infectious diseases (ID) clinic of East Carolina University. Proper follow-up evaluation was determined based on the presence of HCV polymerase chain reaction viral load and genotype testing. The number of patients treated, response to treatment, and reason for no treatment were determined by chart review. RESULTS: Of 233 patients with positive HCV serology, 48 were excluded due to undetectable HCV viral load. Of the remaining 185 patients, 142 (77%) were evaluated by testing for HCV viral load and genotype, but only 112 of those who were followed up in the clinic regularly were considered eligible for therapy. Fourteen of 112 (12.5%) of patients underwent treatment and only 1 in 14 (7%) attained sustained virological response (SVR). Of the patients tested, 96% had HCV genotype 1, and 81% were African American. CONCLUSIONS: The majority of our HIV-HCV co-infected patients received a proper HCV evaluation, but only 12.5% were offered therapy. Of those treated, only one patient achieved SVR. The higher proportion of genotype 1 and African American patient population are considered the main reasons for the low SVR. Low SVR rate, high rate of adverse effects, and the unique demography of our patient population have been the main reasons for the lower treatment rate. PMID- 23038478 TI - Occurrence of vitamin D deficiency in pediatric patients at high risk in West Virginia. AB - OBJECTIVES: Vitamin D deficiency is prevalent and is increasingly associated with the development of medical conditions both related and unrelated to bone metabolism. The purpose of this study was to examine vitamin D deficiency in patients of a pediatrics subspecialty practice. METHODS: The study consisted of a retrospective chart review of patients aged 2 to 18 years who were referred to the West Virginia University Physicians of Charleston pediatrics subspecialty group with a diagnosis of obesity, chronic kidney disease, diabetes, hypertension, or cystic fibrosis. All of the patients had 25-hydroxyvitamin D levels measured from 2007-2009. Seventy-six patients met inclusion criteria. RESULTS: A total of 23.7% of patients were vitamin D deficient (<= 20 ng/mL). Children with vitamin D deficiency were older and had higher rates of obesity than those with nondeficient vitamin D levels. The comorbidities of cystic fibrosis, diabetes, hypertension, and chronic kidney disease did not associate with vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency is common in children in West Virginia and is associated with increasing age and obesity. Vitamin D screening and supplementation should be considered in all children with chronic illness, particularly those who are overweight. PMID- 23038479 TI - Cancer in relation to socioeconomic status: stage at diagnosis in Texas, 2004 2008. AB - OBJECTIVES: To determine whether stage of cancer diagnosis was associated with the socioeconomic status (SES) of the census tract where the patient resides, and to assess whether this is modified by race, ethnicity, or urban/rural residence, other factors known to affect cancer diagnosis stage. METHODS: Using 2004-2008 data from the Texas Cancer Registry, we examined the distribution of stage at diagnosis in Texas residents for 15 cancer sites by the SES of the census tract of residence. Stage at diagnosis was categorized into the summary stage categories of early (in situ [preinvasive disease] and localized) and late stage (regional and distant spread). Age-adjusted odds ratios for late-stage versus early-stage cancer diagnosis in low versus high SES census tracts were evaluated by cancer site, race, ethnicity, and urban versus rural residence. RESULTS: For most cancer sites, late-stage cancer diagnosis increased with decreasing SES. These findings were consistent by cancer site, race, ethnicity, and in urban and rural areas of the state. CONCLUSIONS: For most cancer sites, particularly those likely to have patients diagnosed early by screening, late-stage cancer diagnosis is increased in Texas populations residing in lower SES census tracts compared with higher SES census tracts. PMID- 23038481 TI - Commentary on "Prevalence and impact of initial misclassification of pediatric type 1 diabetes mellitus". PMID- 23038480 TI - Prevalence and impact of initial misclassification of pediatric type 1 diabetes mellitus. AB - PURPOSE: To characterize rates of initial misclassification of type 1 diabetes mellitus as type 2/unspecified diabetes mellitus in a cohort of children/adolescents and to examine the impact of misclassification on the risk of diabetes-related complications. METHODS: An 11-year dataset (1996-2006) was analyzed. Inclusion criteria included age 17 years and younger, enrollees in South Carolina State Medicaid, and diagnosis of type 2/unspecified or type 1 diabetes mellitus for at least two visits, 15 days apart. Survival analysis was used to assess the association of "misclassification" with the incidence of diabetic ketoacidosis (DKA), and the cumulative incidence of neuropathy, nephropathy, and cardiovascular complications, after controlling for individual risk factors and comorbid conditions. RESULTS: A total of 1130 individuals meeting the inclusion criteria were studied for a median of 7 years. Of the 1130 individuals, 669 (59.2%) maintained a diagnosis of type 2/unspecified diabetes mellitus, 205 (18.1%) were consistently diagnosed as type 1 diabetes mellitus, and the remaining 256 individuals (22.7%) were misclassified. Insulin treatment was used in 100% of the type 1 diabetes mellitus group and 73% of the misclassified group. Compared with the type 2 diabetes mellitus group, being misclassified was associated with earlier development of DKA (adjusted hazard ratio [aHR] 5.08, 95% confidence interval [CI] 3.09-8.37), neuropathy (aHR 1.94, CI 1.31-2.88), and nephropathy (aHR 1.72, CI 1.19-2.50), whereas being consistently classified with type 1 diabetes mellitus was associated only with earlier development of DKA (aHR 4.96, CI 2.56-9.61). CONCLUSIONS: Proper categorization of pediatric diabetes can be challenging, especially with comorbid obesity. Failure to ascertain type 1 diabetes mellitus in a timely manner in a pediatric population may increase the risk of substandard care and diabetes related complications. PMID- 23038482 TI - Patients' satisfaction with dermatology residents. AB - OBJECTIVES: Patients' perception of quality is a critical primary outcome of medical care. Important downstream effects of perceived quality include a more trusting attitude toward the physician, more adherence to treatment, and better treatment outcomes. Patients' satisfaction issues are important to address during dermatology residency training. The aim of the study was to determine patients' satisfaction with dermatology residents and identify potential areas that could be targeted to improve satisfaction. METHODS: Dermatology residents informed patients about a survey on an online doctor rating/patients' satisfaction Web site (www.DrScore.com), provided the patients with cards with the Web site address, and requested that they complete the survey. Respondents provided an overall rating, open comments, and detailed information in seven core areas. The numerical ratings were on a scale from 0 (not at all satisfied) to 10 (extremely satisfied). Patients had the option of indicating aspects of care that could be improved. Descriptive statistics are reported. RESULTS: A total of 148 surveys were collected with a mean rating for the six residents of 9.7 out of 10, with a range of 9.4 to 10. The average during the early period was 9.7 out of 10, whereas the average during the late period was 9.8 out of 10. Fifty-two surveys (35%) indicated areas for improvement, with the most common issues related to staff, parking availability, waiting time, waiting area, and ability to obtain information. CONCLUSIONS: Patients were generally satisfied with the care provided by dermatology residents. Areas for improvement were identified, but these were largely areas over which residents do not have direct control. PMID- 23038483 TI - Comparison of Florida skin cancer screening rates with those in different US regions. AB - OBJECTIVES: Florida has the second highest incidence of melanoma in the United States, and more than 600 Floridians die from melanoma annually. Given the lack of population-based data on skin cancer screening among the different US geographic regions, we compared skin cancer screening rates among Floridians to those in the rest of the South, the Northeast, the Midwest, and the West. METHODS: We used data from the 2000 and 2005 National Health Interview Survey. Data were grouped according to whether participants reported ever receiving a skin cancer examination in their lifetime. Data were pooled, and analyses accounted for sample weights and design effects. Multivariable logistic regression analyses were performed with self-reported skin screening as the outcome of interest. RESULTS: Results showed that compared to the rest of the US, Floridians who were women 70 years old and older, reported being of "other" race, of non-Hispanic ethnicity, having a high school education, having health insurance, and employed in the service industry or unemployed, had significantly higher lifetime skin cancer screening rates than their subgroup counterparts residing in the other regions. Multivariable logistic regression showed that Floridians remained significantly more likely to have ever been screened for skin cancer compared to the other US regions after controlling for a variety of sociodemographic variables. CONCLUSIONS: Increasing melanoma detection remains a national cancer goal for the US, and future identification of underlying causal factors for higher screening rates in Florida could inform intervention strategies in the other US regions. PMID- 23038484 TI - Actual medical and pharmacy costs for bariatric surgery: 6-year follow-up. AB - OBJECTIVE: To determine the change in total medical expenditures, total pharmacy expenditures, and subcategories of medical and pharmacy expenditures in obese individuals following weight loss surgery (WLS), and to compare these costs with expenditures in obese individuals not receiving WLS. METHODS: Louisiana Office of Group Benefits (OGB), the state-managed health insurer, invited members to be evaluated for insurance-covered WLS. Of 951 obese members who provided written consent to begin the WLS screening process, 40 were selected for surgery. Medical and pharmaceutical claims cost data of the 911 patients who did not have surgery and the 39 individuals who completed surgery were compared over a 2-year presurgical and 6-year postsurgical period. RESULTS: Total nonpharmacy medical costs were lower for WLS patients compared with non-WLS patients beginning 4 years postsurgery and lasting through 6 years postsurgery. No differences were found between WLS and non-WLS patients in expenditures for most medical subcategories examined, including emergency department, physical and occupational therapy, office visits, and laboratory/pathology; whereas sleep facility and all remaining medical expenditures not represented by a subcategory were lower for WLS patients during some postsurgery years. Total pharmacy costs were lower for WLS participants at 2 and 3 years postsurgery, but these lower costs were not maintained; however, costs remained lower for antidiabetic agents, antihypertensive agents, and dyslipidemic agents through all 6 postsurgery years under study. CONCLUSIONS: The cost of WLS may begin to be recouped within the first 4 years postsurgery with continued effects 6 years postsurgery. PMID- 23038485 TI - Reasons military patients with primary care access leave an emergency department waiting room before seeing a provider. AB - OBJECTIVES: Our objective was to assess patients' understanding of emergency department (ED) wait times and why patients may leave the waiting room before seeing a provider. METHODS: Survey of patients in the ED waiting room of an urban tertiary care military hospital where civilian and military patients are treated. RESULTS: A total of 508/517 surveys (98%) were completed. Age ranges were 18 to 35 years (49%), 36 to 60 (31%), or older than 60 (20%). Education levels were high school (20%), some college (37%), or college graduate (39%). Of 503 respondents, 125 (25%) had left an ED waiting room before seeing a provider. The reasons included excessive wait times (91%) and family responsibilities (5%). Five hundred eight reported the factors that would motivate them to wait to see the physician (not leave without being seen [LWOBS]) were the severity of illness (64%), and if they received an update of wait times (26%); 82% (391/480) understood that severely ill patients were seen first. Patients attributed long wait times to doctors and nurses caring for other patients (292/583, 50%) and insufficient physician and nurse staffing (245, 42%). Of 802 responses for ideas to improve the wait, 34% said regular updates on estimated wait times, 21% said television shows or movies to view, 20% said books and magazines to read, and 11% said computers to access. CONCLUSIONS: Long wait times were the primary reason that patients left before seeing a provider, despite having ready access to care. Respondents attributed long wait times to patient volume and inadequate staffing. Regular updates on wait times and material for entertainment may improve the waiting experience and reduce LWOBS. PMID- 23038486 TI - Commentary on "Reasons military patients with primary care access leave an emergency department waiting room before seeing a provider". PMID- 23038487 TI - Expanding Medicaid managed care: the right choice for Texas? AB - We set out to determine whether expanding Medicaid managed care in Texas is the solution to the challenges faced by the state of meeting the healthcare needs of a rapidly growing Medicaid population while addressing its own fiscal limitations. We reviewed the Texas Medicaid program, the potential effects of federal healthcare reform, and the state political climate through the perspectives (advantages and disadvantages) of the primary stakeholders: patients, practitioners, hospitals, and insurers. Research was performed through online, federal and state regulatory, and legislative review. In addition, we reviewed government and peer-reviewed reports and articles pertaining to issues related to Medicaid populations, healthcare practitioners, and hospitals that serve them. Each primary stakeholder had potential advantages and disadvantages associated with the expansion of Medicaid managed care. We conclude that expanding Medicaid managed care, if done in a manner responsive to the needs of recipients, can meet enrollees' healthcare needs while controlling the state's costs. PMID- 23038489 TI - Commentary on "Evolving role of computed tomographic colonography in colon cancer screening and diagnosis". PMID- 23038488 TI - Evolving role of computed tomographic colonography in colon cancer screening and diagnosis. AB - Computed tomographic colonography (CTC) is a relatively new imaging modality for the examination of patients for colorectal polyps and cancer. It has been validated in its accuracy for the detection of colon cancer and larger polyps (more than likely premalignant). CTC, however, is not widely accepted as a primary screening modality in the United States at present by many third-party payers, including Medicare, and its exact role in screening is evolving. Moreover, there has been opposition to incorporating CTC as an accepted screening instrument, especially by gastroenterologists. Heretofore, optical colonoscopy has been the mainstay in this screening. We discuss these issues and the continuing controversies concerning CTC. PMID- 23038490 TI - Thrombolysis in acute pulmonary thromboembolism. AB - Acute pulmonary embolism (PE) is a common clinical condition with presentations that may vary from asymptomatic subsegmental emboli to massive vascular obstruction and shock with high risk of death. Identifying patients at highest risk for death is critical to select those who would benefit most from thrombolytic therapy. New and evolving clinical prediction models, serum tests, and imaging modalities are being used to improve our ability to identify potential thrombolytic candidates. We review the evolution of the present guidelines on the management of PE, specifically regarding the evolving role of thrombolytics; outcomes following thrombolytic therapy, including mortality, hemorrhage, hemodynamic improvement, and prevention of chronic thromboembolic pulmonary hypertension; and our strategy for risk stratification of pulmonary embolism. PMID- 23038491 TI - Extending the fundamental imaging-depth limit of multi-photon microscopy by imaging with photo-activatable fluorophores. AB - It is highly desirable to be able to optically probe biological activities deep inside live organisms. By employing a spatially confined excitation via a nonlinear transition, multiphoton fluorescence microscopy has become indispensable for imaging scattering samples. However, as the incident laser power drops exponentially with imaging depth due to scattering loss, the out-of focus fluorescence eventually overwhelms the in-focal signal. The resulting loss of imaging contrast defines a fundamental imaging-depth limit, which cannot be overcome by increasing excitation intensity. Herein we propose to significantly extend this depth limit by multiphoton activation and imaging (MPAI) of photo activatable fluorophores. The imaging contrast is drastically improved due to the created disparity of bright-dark quantum states in space. We demonstrate this new principle by both analytical theory and experiments on tissue phantoms labeled with synthetic caged fluorescein dye or genetically encodable photoactivatable GFP. PMID- 23038493 TI - Unidirectionally optical coupling from free space into silicon waveguide with wide flat-top angular efficiency. AB - A grating coupling scheme from free-space light into silicon waveguide with a remarkable property of wide flat-top angular efficiency is proposed and theoretically investigated. The coupling structure is composed of two cascaded gratings with a proper distance between their peak angular efficiencies. A quantitative semi-analytical theory based on coupled-mode models is developed for performance prediction and validated with the fully vectorial aperiodic Fourier modal method (a-FMM). With the theory, wide flat-top angular response is achieved and the conditions are pointed out. Proof-of-principle demonstrations show that the -1 dB angular width, a figure of merit to evaluate the flat-top performance, is broadened to almost 3 to 4 times, and meanwhile the -3 dB angular width, i.e., angular-full-width-half-maximum (AFWHM), is widened to nearly more than twice, compared with the reference gratings composed of the same number of periodic defects. We believe this work will find applications in biological or chemical sensing and novel optical devices. PMID- 23038492 TI - Light extraction enhancement of bulk GaN light-emitting diode with hemisphere cones-hybrid surface. AB - InGaN flip-chip light-emitting diodes on bulk GaN substrate (FS-FCLEDs) with hemisphere-cones-hybrid surface were fabricated using both dry etching with CsCl nanoislands as mask and chemical wet etching. Compared with the corresponding flat LEDs, the light output power of FS-FCLEDs with combined nanostructures shows an enhancement factor of 1.9 at 350mA injection current. Finite-difference time domain (FDTD) simulation results show that such enhancement of the output power is mainly attributed to the reduction of the total internal reflection and increase of the light scattering probability in the hemisphere-cones-hybrid surface, which is due to a combination effect of light diffraction at the nanocones edges, and light interference within the hemisphere and nanocones. PMID- 23038494 TI - Tubular oxide microcavity with high-index-contrast walls: Mie scattering theory and 3D confinement of resonant modes. AB - Tubular oxide optical microcavities with thin walls (< 100 nm) have been fabricated by releasing pre-stressed Y2O3/ZrO2 bi-layered nanomembranes. Optical characterization demonstrates strong whispering gallery modes with a high quality factor and fine structures in the visible range, which are due to their high index-contrast property (high refractive index in thin walls). Moreover, the strong axial light confinement observed in rolled-up circular nanomembranes well agrees with our theoretical calculation by using Mie scattering theory. Novel material design and superior optical resonant properties in such self-rolled micro-tubular cavities promise many potential applications e.g. in optofluidic sensing and lasing. PMID- 23038495 TI - Processing method of spectral measurement using F-P etalon and ICCD. AB - A processing method for the precise acquisition of 1D interference spectrum from the 2D Fabry-Perot(F-P) fringe pattern is proposed in the paper. Current methods can only measure the spectrum with full-pixel accuracy. The new method is capable to achieve the sub-pixel accuracy as well as reduce the noise by taking full advantage of the 2D image information and analyzing the statistical values of pixels in a comprehensive way. Experimental results show that the accuracy of the measured Brillouin shift and linewidth is around several MHzs, which is significantly improved compared to methods with full-pixel accuracy. PMID- 23038496 TI - Propagation dynamics of abruptly autofocusing Airy beams with optical vortices. AB - We investigated the propagation dynamics of the Circular Airy Beams (CAB) with optical vortices (OVs) by numerical calculation. Comparing to the common CAB, the maximum intensity of CAB with vortices can be increased greatly at the focal plane and its focal intensity profile is doughnut-shaped when an on-axis vortex is imposed. The case for an off-axis OV and multiple OVs have been investigated as well. We demonstrate that two opposite OVs will annihilate exactly at the focal plane, with the focal intensity is highly increased. PMID- 23038497 TI - Femtosecond laser-induced crystallization of amorphous Ga-Sb-Se films and coherent phonon dynamics. AB - Femtosecond laser-irradiation-induced phase change of new environment friendly Te free amorphous Ga-Sb-Se films is studied by coherent phonon spectroscopy. New coherent optical phonons (COP) occur when laser irradiation power reaches some threshold, implying laser-induced phase change taken place. Pump power dependence of COP dynamics reveals the phase change as crystallization and crystallization quality is comparable to one of annealing crystallization, showing application potential of Ga-Sb-Se films in optical phase change memory. The laser-irradiated crystallization of different component Ga-Sb-Se films is studied. It is found crystallization threshold power depends on Sb content, implying Sb-content control of the crystallization temperature of Ga-Sb-Se films. PMID- 23038498 TI - High-current-sensitivity all-fiber current sensor based on fiber loop architecture. AB - In this paper, we demonstrate a novel all-fiber current sensor using ordinary silica fiber. The sensor employs a fiber solenoid as a current sensor head, which improves the current sensitivity by allowing optical signals to traverse the sensor head repeatedly. Theory and experiment prove that the improvement in sensitivity increases periodically with the number of repetitions of optical signals circulating round the loop. PMID- 23038499 TI - Polarization effect on the two-photon absorption of a chiral compound. AB - In this report, we investigate the polarization effect (linear, elliptical and circular) on the two-photon absorption (2PA) properties of a chiral compound based in azoaromatic moieties using the femtosecond Z-scan technique with low repetition rate and low pulse energy. We observed a strong 2PA modulation between 800 nm and 960 nm as a function the polarization changes from linear through elliptical to circular. Such results were interpreted employing the sum-over essential states approach, which allowed us to model the 2PA circular-linear dichroism effect and to identifier the overlapping of the excited electronic states responsible by the 2PA allowed band. PMID- 23038501 TI - Dispersion-stabilized highly-nonlinear fiber for wideband parametric mixer synthesis. AB - Conventional highly-nonlinear fiber (HNLF) designs are optimized for high field confinement but are also inherently susceptible to dispersion fluctuations. The design compromise prevents fiber-optical parametric mixers from possessing high power efficiency and extended operating bandwidth simultaneously. Using a new fiber waveguide design, we have fabricated and tested a new class of HNLF that possesses a significantly lower level of dispersion fluctuations while maintaining a high level of field-confinement comparable to that in conventional HNLFs. The fiber was used to demonstrate an all-fiber parametric oscillator operating in short-wavelength infrared (SWIR) band with a watt-level pump, for the first time. PMID- 23038502 TI - Femtosecond laser inscribed cladding waveguides in Nd:YAG ceramics: fabrication, fluorescence imaging and laser performance. AB - We report on the fabrication of depressed cladding waveguide lasers in Nd:YAG (neodymium doped yttrium aluminum garnet, Nd:Y3Al5O12) ceramics microstructured by femtosecond laser pulses. Full control over the confined light spatial distribution is demonstrated by the fabrication of high contrast waveguides with hexagonal, circular and trapezoidal configurations. The confocal fluorescence measurements of the waveguides reveal that the original luminescence features of Nd3+ ions are well-preserved in the waveguide regions. Under optical pump at 808 nm, cladding waveguides showed continuous wave efficient laser oscillation. The maximum output power obtained at 1064.5 nm is ~181 mW with a slope efficiency as high as 44%, which suggests that the fabricated Nd:YAG ceramic waveguides are promising candidates for efficient integrated laser sources. PMID- 23038503 TI - Efficient continuous wave and passively mode-locked Tm-doped crystalline silicate laser. AB - An efficient continuous wave and passively mode-locked thulium-doped oxyorthosilicate Tm:LuYSiO5 laser is demonstrated. A maximum slope efficiency of 56.3% is obtained at 2057.4 nm in continuous wave operation regime. With an InGaAs quantum well SESAM, self-starting passively mode-locked Tm:LuYSiO5 laser is realized in the 1929 nm to 2065 nm spectral region. A maximum average output power of 130.2 mW with a pulse duration of 33.1 ps and a repetition rate of about 100 MHz is generated at 1984.1 nm. Pulses as short as 24.2 ps with an average output power of 100 mW are obtained with silicon prisms where used to manage the intracavity dispersion. The shortest pulse duration of about 19.6 ps is obtained with an average output power of 64.5 mW at 1944.3 nm. PMID- 23038504 TI - A waveguide-typed plasmonic mode converter. AB - Waveguide-typed plasmonic mode converters (WPMCs) at a wavelength of 1.55 MUm are presented. The WPMC is composed of an insulator-metal-insulator waveguide (IMI W), a 1st reversely tapered insulator-metal-insulator-metal-insulator waveguide (RT-IMIMI-W), an insulator-metal-insulator-metal-insulator waveguide (IMIMI-W), a 2nd RT-IMIMI-W with lateral silver mirrors (LSMs), and a metal-insulator-metal waveguide (MIM-W) in series. The mode sizes for the IMI-W, IMIMI-W, and MIM-W via the IMIMI-W with LSMs were not only calculated using a finite element method but were also experimentally measured. The input mode size of 10.3 MUm * 10.3 MUm from a polarization-maintaining single-mode fiber was squeezed to the mode size of ~2.9 MUm * 2.9 MUm in measurement by converting an s0 mode to an Sa0 mode via an Ss0 mode. The WPMC may be potentially useful for bridging micro- to nano plasmonic integrated circuits. PMID- 23038505 TI - Measurement of effective refractive-index differences in a few-mode fiber by axial fiber stretching. AB - A method for measuring the effective refractive-index differences in a few-mode fiber by applying axial fiber stretching is described. This method represents a straightforward technique for characterization of few-mode fibers. Interference between LP01 and LP11 and in some cases also between LP11 and LP21 are observed in a fiber designed for support of LP01 and LP11. The relative strength of the coupled modes depends on specific splicing characteristics, and in some cases only two modes are seen. The results agree well with theoretical predictions for the fiber under investigation. PMID- 23038506 TI - BER-adaptive flexible-format transmitter for elastic optical networks. AB - We propose a new optical transmitter which is capable of changing flexibly the modulation format of the optical signal. By using this transmitter, we can handle and assign various modulation formats: binary phase shift keying (BPSK), quadrature phase shift keying (QPSK), 8-ary quadrature amplitude modulation (8QAM), and 16QAM. The proposed transmitter is based on a combination of a dual drive Mach-Zehnder modulator (DD-MZM) and a dual-parallel MZM (DP-MZM) with electrical binary drive signals. DD-MZM is a key element to produce the 8QAM and 16QAM formats where each arm of DD-MZM is driven by independent binary data. This is because we can modulate the amplitude and phase of the optical signal by using a frequency chirp of the modulator when we adjust properly the amplitudes of the electrical drive signals. In addition, we show an algorithm by which the proposed transmitter can intelligently select the modulation format in accordance with the signal quality. PMID- 23038507 TI - 1.3-mW tunable and narrow-band continuous-wave light source at 191 nm. AB - We report on the realization of a continuous-wave light source based on nonlinear interaction in KBBF at a wavelength of 191 nm. More than 1.3 mW of deep ultraviolet power was generated in a mechanically robust setup pumped by an amplified grating stabilized diode laser. Mode hop-free tuning over 40 GHz at 191 nm could be demonstrated. PMID- 23038508 TI - Analysis of long-range surface plasmon polaritons in nonlinear plasmonic waveguides using pseudospectral method. AB - A full-vectorial pseudospectral method is reported for solving the mode characteristics of nonlinear dielectric and plasmonic waveguides. The coupled equations are formulated in terms of transverse magnetic-field components, and self-consistent solutions are obtained through an iterative procedure. The proposed scheme applies in a saturable medium with biaxial anisotropy of practical interest. The accuracy and efficiency of this scheme are demonstrated by solving the mode bistability of a nonlinear dielectric optical waveguide, analyzed by the well-known finite-element-method-based imaginary-distance beam propagation method. Furthermore, the relationship between geometry and input power is studied by analyzing the power dispersion curve of the long-range surface plasmon polariton modes of a nonlinear plasmonic waveguide. PMID- 23038509 TI - Polarization-sensitive cathodoluminescence Fourier microscopy. AB - Determining the emission polarization properties of sub-wavelength structures like optical nanoantennas, nanocavities and photonic crystals is important to understand their physical properties and to optimize their use in applications. Recently we have shown that angle-resolved cathodoluminescence imaging spectroscopy (ARCIS), which uses a 30 keV electron beam as an excitation source, is a useful technique to study the far-field properties of such structures. Here we extend the technique with polarization-sensitive angular detection. As proof of-principle, we experimentally probe the emission polarization properties of three orthogonal dipolar emitters of which the polarization is well-known and find excellent agreement between experiment and theory. We access these dipole orientations by exciting an unstructured gold surface and a ridge nanoantenna with an in-plane dipolar plasmon resonance. The light emission is collected with an aluminum half paraboloid mirror. We show how to take the effect of the paraboloid mirror on the emission polarization into account and how to predict the polarization-filtered pattern if the emission polarization is known. Furthermore, we calculate that by introducing a slit in the beam path the polarization contrast in cathodoluminescence spectroscopy can be strongly enhanced. Finally, we reconstruct the emission polarization from the experimental data and show that from these field patterns we can infer the orientation of the induced dipole moment. The ability to measure the emission polarization, in combination with the sensitivity to the local density of optical states, broad spectral range and high excitation resolution, can be employed to study photonic nanostructures in great detail. PMID- 23038510 TI - Detailed investigation of the impact of the fiber design parameters on the transverse Anderson localization of light in disordered optical fibers. AB - We recently reported the observation of transverse Anderson localization as the waveguiding mechanism in optical fibers with random transverse refractive index profiles [Opt. Lett. 37, 2304 (2012)]. Here, we explore the impact of the design parameters of the disordered fiber on the beam radius of the propagating transverse localized beam. We show that the optimum value of the fill-fraction of the disorder is 50% and a lower value results in a larger beam radius. We also explore the impact of the average size of the individual random features on the value of the localized beam radius and show how the boundary of the fiber can impact the observed localization radius. A larger refractive index contrast between the host medium and the disorder sites results in smaller value of the beam radius. PMID- 23038511 TI - GaN microwires as optical microcavities: whispering gallery modes Vs Fabry-Perot modes. AB - GaN microwires grown by metalorganic vapour phase epitaxy and with radii typically on the order of 1-5 micrometers exhibit a number of resonances in their photoluminescence spectra. These resonances include whispering gallery modes and transverse Fabry-Perot modes. A detailed spectroscopic study by polarization resolved microphotoluminescence, in combination with electron microscopy images, has enabled to differentiate both kinds of modes and determined their main spectral properties. Finally, the dispersion of the ordinary and extraordinary refractive indices of strain-free GaN in the visible-UV range has been obtained thanks to the numerical simulation of the observed modes. PMID- 23038512 TI - Interferometric detection of extensional modes of GaN nanorods array. AB - Femtosecond pump probe spectroscopy experiments were carried out to observe extensional modes of GaN nanorods. Different orders of extensional modes were generated and observed following the absorption of femtosecond light pulses. This observation confirms that with a diameter on the order of 100 nm, no mechanical change is expected compared to bulk GaN. We propose and demonstrate that the detection of these modes is achieved through the modulation of the Fabry-Perot cavity formed by the nanorod array. The extensional modes change the nanorods length and thus modify the reflectivity of the rod-array cavity. PMID- 23038513 TI - Efficient laser emission in Ho3+:LiLuF4 grown by micro-Pulling Down method. AB - We report a spectroscopic investigation and an efficient Ho:LiLuF4 laser in-band pumped at 1938 nm. This represents the first laser emission of a fluoride crystal grown by micro-Pulling Down method in the 2 MUm wavelength range. The Ho:LiLuF4 laser yielded a maximum output power of 7.1W with a slope efficiency of 41% and a threshold around 5W, at lasing wavelength of 2054.2 nm. PMID- 23038514 TI - Characterization of broadband few-cycle laser pulses with the d-scan technique. AB - We present an analysis and demonstration of few-cycle ultrashort laser pulse characterization using second-harmonic dispersion scans and numerical phase retrieval algorithms. The sensitivity and robustness of this technique with respect to noise, measurement bandwidth and complexity of the measured pulses is discussed through numerical examples and experimental results. Using this technique, we successfully demonstrate the characterization of few-cycle pulses with complex and structured spectra generated from a broadband ultrafast laser oscillator and a high-energy hollow fiber compressor. PMID- 23038515 TI - Integral imaging using a color filter pinhole array on a display panel. AB - We propose methods of enhancing pinhole-type integral imaging ray density, resolution, and expressible depth range using a color filter pinhole array on a liquid crystal display panel with a projection scheme. A color filter structure on a liquid crystal display panel acts as pinhole array in integral imaging with separation of color channels. In conventional pinhole-type integral imaging, the resolution, viewing angle, and ray density are limited by the pinhole interval, the width and thickness of the pinhole structure, and the gap between the display panel and the pinhole array. To overcome the limitation of the pinhole interval, we use a color filter pinhole array on a display panel and a projection-type integral imaging scheme. The use of a color filter pinhole array and the projection scheme can enlarge the region of one elemental image and improve the resolution and ray density remarkably. This paper presents the experimental results of the proposed method and a comparison with conventional methods. PMID- 23038516 TI - Spectral broadening caused by dynamic speckle in self-mixing velocimetry sensors. AB - Self-mixing laser sensors require few components and can be used to measure velocity. The self-mixing laser sensor consists of a laser emitting a beam focused onto a rough target that scatters the beam with some of the emission re entering the laser cavity. This 'self-mixing' causes measurable interferometric modulation of the laser output power that leads to a periodic Doppler signal spectrum with a peak at a frequency proportional to the velocity of the target. Scattering of the laser emission from a rough surface also leads to a speckle effect that modulates the Doppler signal causing broadening of the signal spectrum adding uncertainty to the velocity measurement. This article analyzes the speckle effect to provide an analytic equation to predict the spectral broadening of an acquired self-mixing signal and compares the predicted broadening to experimental results. To the best of our knowledge, the model proposed in this article is the first model that has successfully predicted speckle broadening in a self-mixing velocimetry sensor in a quantitative manner. It was found that the beam spot size on the target and the target speed affect the resulting spectral broadening caused by speckle. It was also found that the broadening is only weakly dependent on target angle. The experimental broadening was consistently greater than the theoretical speckle broadening due to other effects that also contribute to the total broadening. PMID- 23038517 TI - a-SiOx active photonic crystal resonator membrane fabricated by focused Ga+ ion beam. AB - We have fabricated thin erbium-doped amorphous silicon sub-oxide (a-SiOx) photonic crystal membrane using focused gallium ion beam (FIB). The photonic crystal is composed of a hexagonal lattice with a H1 defect supporting two quasi doubly degenerate second order dipole states. 2-D simulation was used for the design of the structure and full 3-D FDTD (Finite-Difference Time-Domain) numerical simulations were performed for a complete analysis of the structure. The simulation predicted a quality factor for the structure of Q = 350 with a spontaneous emission enhancement of 7. Micro photoluminescence measurements showed an integrated emission intensity enhancement of ~2 times with a Q = 130. We show that the discrepancy between simulation and measurement is due to the conical shape of the photonic crystal holes and the optical losses induced by FIB milling. PMID- 23038518 TI - Ultrafast-laser-induced backward stimulated Raman scattering for tracing atmospheric gases. AB - By combining tunable broadband pulse generation with the technique of nonlinear spectral compression we demonstrate a prototype scheme for highly selective detection of air molecules by backward stimulated Raman scattering. The experimental results allow to extrapolate the laser parameters required for standoff sensing based on the recently demonstrated backward atmospheric lasing. PMID- 23038519 TI - Pixelated high-index ring Bragg fibers. AB - A new type of Anti Resonant Reflecting Optical Waveguide (ARROW) fiber with a low refractive index contrast is reported. This waveguide is similar to a Bragg fiber for which the high index rings are replaced by discontinuous rings made of circular High Index Inclusions (HII). As compared to conventional Bragg fibers, such a new structure enables true Photonic BandGap (PBG) guidance and limits the number of cladding modes located within the high index regions, thus enhancing the guiding properties. A Mode Field Diameter (MFD) of 26 MUm is reported at a wavelength of 1400 nm. Single Mode (SM) behavior is also observed beyond 1400 nm for a 1 m-long fiber. PMID- 23038520 TI - High-energy, in-band pumped erbium doped fiber amplifiers. AB - We have demonstrated and compared high-energy, in-band pumped erbium doped fiber amplifiers operating at 1562.5 nm under both a core pumping scheme (CRS) and a cladding pumping scheme (CLS). The CRS/CLS sources generated smooth, single-peak pulses with maximum pulse energies of ~1.53/1.50 mJ, and corresponding pulse widths of ~176/182 ns respectively, with an M2 of ~1.6 in both cases. However, the conversion efficiency for the CLS was >1.5 times higher than the equivalent CRS variant operating at the same pulse energy due to the lower pump intensity in the CLS that mitigates the detrimental effects of ion concentration quenching. With a longer fiber length in a CLS implementation a pulse energy of ~2.6 mJ is demonstrated with a corresponding M2 of ~4.2. Using numerical simulations we explain that the saturation of pulse energy observed in our experiments is due to saturation of the pump absorption. PMID- 23038521 TI - Beaming photons with spin and orbital angular momentum via a dipole-coupled plasmonic spiral antenna. AB - We analytically and numerically study the emission properties of an electric dipole coupled to a plasmonic spiral structure with different pitch. As a transmitting antenna, the spiral structure couples the radiation from the electric dipole into circularly polarized emitted photons in the far field. The spin carried by the emitted photons is determined by the handedness of the spiral antenna. By increasing the spiral pitch in the unit of surface plasmon wavelength, these circularly polarized photons also gain orbital angular momentum with different topological charges. This phenomenon is attributed to the presence of a geometric phase arising from the interaction of light from point source with the anisotropic spiral structure. The circularly polarized vortex emission from such optically coupled spiral antenna also has high directivity, which may find important applications in quantum optical information, single molecule sensing, and integrated photonic circuits. PMID- 23038522 TI - Self-accelerating self-trapped nonlinear beams of Maxwell's equations. AB - We present shape-preserving self-accelerating beams of Maxwell's equations with optical nonlinearities. Such beams are exact solutions to Maxwell's equations with Kerr or saturable nonlinearity. The nonlinearity contributes to self trapping and causes backscattering. Those effects, together with diffraction effects, work to maintain shape-preserving acceleration of the beam on a circular trajectory. The backscattered beam is found to be a key issue in the dynamics of such highly non-paraxial nonlinear beams. To study that, we develop two new techniques: projection operator separating the forward and backward waves, and reverse simulation. Finally, we discuss the possibility that such beams would reflect themselves through the nonlinear effect, to complete a 'U' shaped trajectory. PMID- 23038523 TI - Photonic chip based tunable and reconfigurable narrowband microwave photonic filter using stimulated Brillouin scattering. AB - We report the first demonstration of a photonic chip based dynamically reconfigurable, widely tunable, narrow pass-band, high Q microwave photonic filter (MPF). We exploit stimulated Brillouin scattering (SBS) in a 6.5 cm long chalcogenide (As2S3) photonic chip to demonstrate a MPF that exhibited a high quality factor of ~520 and narrow bandwidth and was dynamically reconfigurable and widely tunable. It maintained a stable 3 dB bandwidth of 23 +/- 2MHz and amplitude of 20 +/- 2 dB over a large frequency tuning range of 2-12 GHz. By tailoring the pump spectrum, we reconfigured the 3 dB bandwidth of the MPF from ~20 MHz to ~40 MHz and tuned the shape factor from 3.5 to 2 resulting in a nearly flat-topped filter profile. This demonstration represents a significant advance in integrated microwave photonics with potential applications in on-chip microwave signal processing for RADAR and analogue communications. PMID- 23038524 TI - Multifocus color image fusion based on quaternion curvelet transform. AB - Multifocus color image fusion is an active research area in image processing, and many fusion algorithms have been developed. However, the existing techniques can hardly deal with the problem of image blur. This study present a novel fusion approach that integrates the quaternion with traditional curvelet transform to overcome the above disadvantage. The proposed method uses a multiresolution analysis procedure based on the quaternion curvelet transform. Experimental results show that the proposed method is promising, and it does significantly improve the fusion quality compared to the existing fusion methods. PMID- 23038525 TI - Performance of dimming control scheme in visible light communication system. AB - We investigate the performance of visible light communication (VLC) system with a pulse width modulation (PWM) dimming control scheme. Under this scheme, the communication quality in terms of number of transmitted bits and bit error rate (BER) of less than 10(-3) should be guaranteed. However, for on-off-keying (OOK) signal, the required data rate becomes 10 times as high as the original data rate when the duty cycle of dimming control signal is 0.1. To make the dimming control scheme easy to be implemented in VLC system, we propose the variable M-QAM OFDM VLC system, where M is adjusted according to the brightness of LED light in terms of duty cycle. The results show that with different duty cycles the required data rates are not higher than the original value and less LED lamp power is required to guarantee the communication quality, which makes the dimming control system that satisfies both communication and illumination requirements easy to be implemented and power-saving. PMID- 23038526 TI - Weak interference in the high-signal regime. AB - Weak amplification is a signal enhancement technique which is used to measure tiny changes that otherwise cannot be determined because of technical limitations. It is based on: a) the existence of a weak interaction which couples a property of a system (the system) with a separate degree of freedom (the pointer), and b) the measurement of an anomalously large mean value of the pointer state (weak mean value), after appropriate pre-and post-selection of the state of the system. Unfortunately, the weak amplification process is generally accompanied by severe losses of the detected signal, which limits its applicability. However, we will show here that since weak amplification is essentially the result of an interference phenomena, it should be possible to use the degree of interference (weak interference) to get relevant information about the physical system under study in a more general scenario, where the signal is not severely depleted (high-signal regime). PMID- 23038527 TI - High quality beaming and efficient free-space coupling in L3 photonic crystal active nanocavities. AB - We report on far-field measurements of L3 photonic crystal (PhC) cavities with high quality beaming. This is achieved by means of the so-called "band folding" technique, in which a modulation of the radius of specific holes surrounding the cavity is introduced. Far-field patterns are measured from photoluminescence of quantum wells embedded in the PhC. A very good agreement between experimental results and simulated radiation patterns has been found. Laser effect is demonstrated in the beaming cavity with a threshold comparable to the regular one. In addition, free-space input coupling to this cavity has been achieved. In order to fully analyze the coupling efficiency, we generalize the approach developed in S. Fan, et al., [J. Opt. Soc. Am. A 20, 569 (2003)], relaxing the hypothesis of mirror symmetry. The obtained coupling efficiencies are about 15% with quality factors (Q) exceeding 10(4). These results further validate the "folding" technique on L3 cavities for nanocavity realization with efficient free space coupling and high Q factors. PMID- 23038528 TI - Elastography of soft materials and tissues by holographic imaging of surface acoustic waves. AB - We use optical interferometry to capture coherent surface acoustic waves for elastographic imaging. An inverse method is employed to convert multi-frequency data into an elastic depth profile. Using this method, we image elastic properties over a 55 mm range with <5 mm resolution. For relevance to breast cancer detection, we employ a tissue phantom with a tumor-like inclusion. Holographic elastography is also shown to be well-behaved in ex vivo tissue, revealing the subsurface position of a bone. Because digital holography can assess waves over a wide surface area, this constitutes a flexible new platform for large volume and non-invasive elastography. PMID- 23038529 TI - Visualization of superluminal pulses inside a white light cavity using plane wave spatio temporal transfer functions. AB - In a white light cavity (WLC), the group velocity is superluminal over a finite bandwidth. For a WLC-based data buffering system we recently proposed, it is important to visualize the behavior of pulses inside such a cavity. The conventional plane wave transfer functions, valid only over space that is translationally invariant, cannot be used for the space inside WLC or any cavity, which is translationally variant. Here, we develop the plane wave spatio temporal transfer function (PWSTTF) method to solve this problem, and produce visual representations of a Gaussian input pulse incident on a WLC, for all times and positions. PMID- 23038530 TI - Real-time monitoring of single-photon detectors against eavesdropping in quantum key distribution systems. AB - By employing real-time monitoring of single-photon avalanche photodiodes we demonstrate how two types of practical eavesdropping strategies, the after-gate and time-shift attacks, may be detected. Both attacks are identified with the detectors operating without any special modifications, making this proposal well suited for real-world applications. The monitoring system is based on accumulating statistics of the times between consecutive detection events, and extracting the afterpulse and overall efficiency of the detectors in real-time using mathematical models fit to the measured data. We are able to directly observe changes in the afterpulse probabilities generated from the after-gate and faint after-gate attacks, as well as different timing signatures in the time shift attack. We also discuss the applicability of our scheme to other general blinding attacks. PMID- 23038531 TI - Spectroscopic study of transparency current in mid-infrared quantum cascade lasers. AB - We report measurements which give direct insight into the origins of the transparency current for lambda ~5 um In0.6Ga0.4As/In0.42Al0.58As quantum cascade lasers in the temperature range of 80-280 K. The transparency current values have been found from broadband transmission measurements through the laser waveguides under sub-threshold operating conditions. Two active region designs were compared. The active region of the first laser is based on double-LO-phonon relaxation approach, while the second device has only one lower level, without specially designed resonant LO-phonon assisted depopulation. It is shown that transparency current contributes more than 70% to the magnitude of threshold current at high temperatures for both designs. PMID- 23038532 TI - An integrated tunable interferometer controlled by liquid diffusion in polydimethylsiloxane. AB - We demonstrated an integrated tunable interferometer in Polydimethylsiloxane (PDMS). In contrast to most on-chip interferometers which require complex fabrication, our design is realized by conventional soft lithography fabrication. The optical path difference occurs during propagation across a fluid-fluid interface. The diffusion level of the two miscible liquids which is controlled by liquid flow rates provides tunability. Different ratio of two liquid flow rates result in the interference spectral shift. Interference peak numbers are varied with flow rate ratio of two liquids. Mutual diffusion between two liquids changes the profile of the refractive index across the fluidic channel. The two arms structure of our design provides convenience for sensing and detection in biology system. This device not only offers the convenience for microfluidic networks but also paves the way for sensing in chemical microreactors. PMID- 23038533 TI - Design of curved photonic cavities for a narrow-band widely tunable resonance ranging 200 nm. AB - We propose a type of photonic resonator with a tunable curved cavity that enables efficient tuning of the optical length of a resonant cavity made of a solid material; we call this a "tunable curved resonator" (TCR). Its integration with a "tunable curved waveguide" (TCWG) and their actuation by a MEMS (micro electromechanical systems) electrostatic comb actuator are also designed for integrated photonic circuits. With this kind of structure, a widely and continuously tunable narrow-band resonance ranging up to 200 nm is achieved with a MEMS actuation voltage less than 70 V. Its applications in widely tunable photonic filters and lasers are promising. PMID- 23038534 TI - Integrated head design using a nanobeak antenna for thermally assisted magnetic recording. AB - We propose a near-field optical transducer using a triangular antenna and a thin film structure (wing) to efficiently generate an optical near-field near a magnetic head. A finite-difference time-domain calculation showed that the near field was efficiently generated at the apex of the antenna when the dimensions of the wing were optimized for efficient delivery of the surface plasmon excited on the wing to the antenna. The calculated light utilization efficiency (ratio between the absorbed power in the recording medium and the input power) was 8%. The temperature distribution on the medium, magnetic field distribution, and magnetization pattern were calculated; the proposed recording head may be capable of an areal recording density of 2.5 Tb/in.(2). PMID- 23038535 TI - Auto-focusing and self-healing of Pearcey beams. AB - We present a new solution of the paraxial equation based on the Pearcey function, which is related to the Airy function and describes diffraction about a cusp caustic. The Pearcey beam displays properties similar not only to Airy beams but also Gaussian and Bessel beams. These properties include an inherent auto focusing effect, as well as form-invariance on propagation and self-healing. We describe the theory of propagating Pearcey beams and present experimental verification of their auto-focusing and self-healing behaviour. PMID- 23038536 TI - Microfocusing transfocator for 1D and 2D compound refractive lenses. AB - An x-ray transfocator design for the combined use of 1D and 2D compound refractive lenses is described. The device includes stacks of beryllium parabolic lenses with different radii of curvature and provides microfocused x-ray beams in the 4-20 keV photon energy range. The transfocator has been implemented at the P10 Coherence Beamline of the PETRA III synchrotron at DESY, Hamburg. Results of transfocator performance and applications for coherent x-ray scattering experiments are presented. PMID- 23038537 TI - Compact, low-loss and low-power 8*8 broadband silicon optical switch. AB - We demonstrated a 8*8 broadband optical switch on silicon for transverse electrical polarization using a switch-and-selector architecture. The switch has a footprint of only 8 mm * 8 mm, minimum on-chip loss of about 4 dB, and a port to-port insertion loss variation of only 0.8 dB near some spectral regions. The port-to-port isolation is above 30 dB over the entire 80-nm-wide spectral range or above 45 dB near the central 30 nm. We also demonstrated a switching power of less than 1.5 mW per element and a speed of 2 kHz, and estimated the upper bound of total power consumption to be less than 70 mW even without optimization of the default state of the individual switch elements. PMID- 23038538 TI - Ultrashort optical-vortex pulse generation in few-cycle regime. AB - We generated a 2.3-cycle, 5.9-fs, 56-MUJ ultrashort optical-vortex pulse (ranging from ~650 to ~950 nm) in few-cycle regime, by optical parametric amplification. It was performed even by using passive elements (a pair of prisms and chirped mirrors) for chirp compensation. Spectrally-resolved interferograms and intensity profiles showed that the obtained pulses have no spatial or topological-charge dispersion during the amplification process. To the best of our knowledge, it is the first generation of optical-vortex pulses in few-cycle regime. They can be powerful tools for ultrabroadband and/or ultrafast spectroscopy and experiments of high-intensity field physics. PMID- 23038539 TI - Control of Fano asymmetry in plasmon induced transparency and its application to plasmonic waveguide modulator. AB - In this paper, we derive a governing equation for spectral asymmetry in electromagnetically induced transparency (EIT). From the key parameters of asymmetry factor - namely dark mode quality factor Q(d), and frequency separation between bright and dark mode Deltaomega(bd) = (omega(b) - omega(d)) -, a logical pathway for the maximization of EIT asymmetry is identified. By taking the plasmonic metal-insulator-metal (MIM) waveguide as a platform, a plasmon-induced transparency (PIT) structure of tunable frequency separation Deltaomega(bd) and dark mode quality factor Q(d) is suggested and analyzed. Compared to previous works on MIM-based plasmon modulators, an order of increase in the performance Fig. (12dB contrast at ~60% throughput) was achieved from the highly asymmetric, narrowband PIT spectra. PMID- 23038540 TI - All-fiber normal-dispersion single-polarization passively mode-locked laser based on a 45 degrees -tilted fiber grating. AB - An all-fiber normal-dispersion Yb-doped fiber laser with 45 degrees -tilted fiber grating (TFG) is, to the best of our knowledge, experimentally demonstrated for the first time. Stable linearly-chirped pulses with the duration of 4 ps and the bandwidth of 9 nm can be directly generated from the laser cavity. By employing the 45 degrees TFG with the polarization-dependent loss of 33 dB, output pulses with high polarization extinction ratio of 26 dB are implemented in the experiment. Our result shows that the 45 degrees TFG can work effectively as a polarizer, which could be exploited to single-polarization all-fiber lasers. PMID- 23038541 TI - Single-mode plasmonic waveguiding properties of metal nanowires with dielectric substrates. AB - Single-mode plasmonic waveguiding properties of metal nanowires with dielectric substrates are investigated using a finite-element method. Au and Ag are selected as plasmonic materials for nanowire waveguides with diameters down to 5-nm-level. Typical dielectric materials with relatively low to high refractive indices, including magnesium fluoride (MgF2), silica (SiO2), indium tin oxide (ITO) and titanium dioxide (TiO2), are used as supporting substrates. Basic waveguiding properties, including propagation constants, power distributions, effective mode areas, propagation distances and losses are obtained at the typical plasmonic resonance wavelength of 660 nm. Compared to that of a freestanding nanowire, the mode area of a substrate-supported nanowire could be much smaller while maintaining an acceptable propagation length. For example, the mode area and propagation length of a 100-nm-diameter Ag nanowire with a MgF2 substrate are about 0.004 MUm2 and 3.4 MUm, respectively. The dependences of waveguiding properties on geometric and material parameters of the nanowire-substrate system are also provided. Our results may provide valuable references for waveguiding dielectric-supported metal nanowires for practical applications. PMID- 23038542 TI - Wideband optical sensing using pulse interferometry. AB - Advances in fabrication of high-finesse optical resonators hold promise for the development of miniaturized, ultra-sensitive, wide-band optical sensors, based on resonance-shift detection. Many potential applications are foreseen for such sensors, among them highly sensitive detection in ultrasound and optoacoustic imaging. Traditionally, sensor interrogation is performed by tuning a narrow linewidth laser to the resonance wavelength. Despite the ubiquity of this method, its use has been mostly limited to lab conditions due to its vulnerability to environmental factors and the difficulty of multiplexing - a key factor in imaging applications. In this paper, we develop a new optical-resonator interrogation scheme based on wideband pulse interferometry, potentially capable of achieving high stability against environmental conditions without compromising sensitivity. Additionally, the method can enable multiplexing several sensors. The unique properties of the pulse-interferometry interrogation approach are studied theoretically and experimentally. Methods for noise reduction in the proposed scheme are presented and experimentally demonstrated, while the overall performance is validated for broadband optical detection of ultrasonic fields. The achieved sensitivity is equivalent to the theoretical limit of a 6 MHz narrow line width laser, which is 40 times higher than what can be usually achieved by incoherent interferometry for the same optical resonator. PMID- 23038543 TI - Fast multiphoton microfabrication of freeform polymer microstructures by spatiotemporal focusing and patterned excitation. AB - One of the limits of conventional scanning multiphoton microfabrication is its low throughput due to point-by-point processing. In order to surpass this limit, a multiphoton microfabrication system based on spatiotemporal focusing and patterned excitation has been developed to quickly provide three-dimensional (3D) freeform polymer microstructures. 3D freeform polymer microstructures using Rose Bengal as the photoinitiator are created by sequentially stacking two-dimensional fabricating patterns. The size of each fabrication area can be larger than 300 * 170 MUm2 (full width at half maximum). Compared to conventional scanning multiphoton excitation and fixed mask pattern generation, this approach offers freeform microstructures and a greater than three-order increase in fabrication speed. Furthermore, the system is capable of optically sectioning the fabricated microstructures for providing 3D inspection. PMID- 23038544 TI - Slowing light down by low magnetic fields: pulse delay by transient spectral hole burning in ruby. AB - We report on the observation of slow light induced by transient spectral hole burning in a solid, that is based on excited-state population storage. Experiments were conducted in the R1-line (2E<-4A2 transition) of a 2.3 mm thick pink ruby (Al2O3:Cr(III) 130 ppm). Importantly, the pulse delay can be controlled by the application of a low external magnetic field B||c<=9 mT and delays of up to 11 ns with minimal pulse distortion are observed for ~55 ns Gaussian pulses. The delay corresponds to a group velocity value of ~c/1400. The experiment is very well modelled by linear spectral filter theory and the results indicate the possibility of using transient hole-burning based slow light experiments as a spectroscopic technique. PMID- 23038545 TI - High numerical aperture reflection mode coherent diffraction microscopy using off axis apertured illumination. AB - We extend coherent diffraction imaging (CDI) to a high numerical aperture reflection mode geometry for the first time. We derive a coordinate transform that allows us to rewrite the recorded far-field scatter pattern from a tilted object as a uniformly spaced Fourier transform. Using this approach, FFTs in standard iterative phase retrieval algorithms can be used to significantly speed up the image reconstruction times. Moreover, we avoid the isolated sample requirement by imaging a pinhole onto the specimen, in a technique termed apertured illumination CDI. By combining the new coordinate transformation with apertured illumination CDI, we demonstrate rapid high numerical aperture imaging of samples illuminated by visible laser light. Finally, we demonstrate future promise for this technique by using high harmonic beams for high numerical aperture reflection mode imaging. PMID- 23038546 TI - Deep subwavelength confinement and giant enhancement of light field by a plasmonic lens integrated with a metal-insulator-metal vertical nanocavity. AB - A metal-insulator-metal vertical nanocavity is proposed to be integrated at the center of a plasmonic lens. Utilizing cavity resonance effect, the light intensity at the center of the integrated plasmonic lens gets enhancement up to 5500 times compared to that without the cavity, and the light field is tightly confined into a spot as small as 6.0 * 10(-3)lambda(0)(2). The Purcell factor of the cavity reaches up to 1400, ensuring greatly enhanced light-matter interaction inside the cavity. Moreover, the proposed structure takes advantage of linearly polarized light excitation and easy fabrication. PMID- 23038547 TI - Design of ultra-sensitive biosensor applying surface plasmon resonance to a triangular resonator. AB - We propose an ultra-sensitive integrated photonic sensor structure using an InP based triangular resonator, in which a surface plasmon resonance (SPR) gold film is applied on a total internal reflection mirror. We have analyzed and optimized the triangular resonator sensor structure with an extremely small SPR mirror sensing area of 3.3 * 0.35 MUm2. Due to the large phase shift in the SPR mirror, a significantly enhanced sensitivity of 930 nm/RIU (refractive index unit) and the maximum peak shift of half free spectral range have been obtained at the SPR angle of 24.125 degrees with Au thickness of 33.4 nm for the change of the refractive index Deltan = 1x10(-3). This value is larger than the previous largest value in micro resonator-type biosensors. Moreover, the proposed triangular resonator sensor can be easily made in a micro structure with optical source integration. PMID- 23038548 TI - Dual-channel, single-photon upconversion detector at 1.3 MUm. AB - We demonstrate a two-channel, upconversion detector for counting 1300-nm wavelength photons. By using two pumps near 1550 nm, photons near 1300 nm are converted to two spectrally distinct channels near 710 nm using sum-frequency generation (SFG) in a periodically poled LiNbO3 (PPLN) waveguide. We used spectral-conversion engineering to design the phase-modulated PPLN waveguide for simultaneous quasi-phasematching of two SFG processes. The two channels exhibit 31% and 25% full-system photon detection efficiency, and very low dark count rates (650 and 550 counts per second at a peak external conversion efficiency of 70%) through filtering using a volume Bragg grating. We investigate applications of the dual-channel upconversion detector as a frequency-shifting beamsplitter, and as a time-to-frequency converter to enable higher-data-rate quantum communications. PMID- 23038549 TI - Scrambled coherent superposition for enhanced optical fiber communication in the nonlinear transmission regime. AB - Coherent superposition of light waves has long been used in various fields of science, and recent advances in digital coherent detection and space-division multiplexing have enabled the coherent superposition of information-carrying optical signals to achieve better communication fidelity on amplified-spontaneous noise limited communication links. However, fiber nonlinearity introduces highly correlated distortions on identical signals and diminishes the benefit of coherent superposition in nonlinear transmission regime. Here we experimentally demonstrate that through coordinated scrambling of signal constellations at the transmitter, together with appropriate unscrambling at the receiver, the full benefit of coherent superposition is retained in the nonlinear transmission regime of a space-diversity fiber link based on an innovatively engineered multi core fiber. This scrambled coherent superposition may provide the flexibility of trading communication capacity for performance in future optical fiber networks, and may open new possibilities in high-performance and secure optical communications. PMID- 23038550 TI - Reconstruction of hidden 3D shapes using diffuse reflections. AB - We analyze multi-bounce propagation of light in an unknown hidden volume and demonstrate that the reflected light contains sufficient information to recover the 3D structure of the hidden scene. We formulate the forward and inverse theory of secondary scattering using ideas from energy front propagation and tomography. We show that using Fresnel approximation greatly simplifies this problem and the inversion can be achieved via a backpropagation process. We study the invertibility, uniqueness and choices of space-time-angle dimensions using synthetic examples. We show that a 2D streak camera can be used to discover and reconstruct hidden geometry. Using a 1D high speed time of flight camera, we show that our method can be used recover 3D shapes of objects "around the corner". PMID- 23038551 TI - Angularly positioned LED-based spatial-temporal color separation system. AB - This study proposes a two-field driving scheme for field sequential color liquid crystal displays (LCDs) without color filters. The proposed scheme is based on angularly positioned color LEDs. In each field, the angular rays of two colors are collimated by a collimation lens, redirected by a light guide, and converged by a cylindrical-lens array to map into corresponding sub-pixel positions to efficiently display color images. The three main advantages of this approach are the elimination of dye color filters, high feasibility using conventional ultra precision machining processes, and a larger color gamut. PMID- 23038552 TI - Light controlling in transverse separation modulated photonic lattices. AB - We numerically study the propagation of Gaussian beams in four different types of transverse separation modulated photonic lattices. We find the modulation obeying hyperbolic secant or rectangular functions can act as optical potentials, and the light waves can be localized or recur in the regions between such two positive potentials, respectively. While the beams decay in the regions between such two negative potentials since these structures could not support localized modes. Our results provide new ways for light controlling and manipulation in photonic lattices. PMID- 23038553 TI - A digital x-ray tomosynthesis coupled near infrared spectral tomography system for dual-modality breast imaging. AB - A Near Infrared Spectral Tomography (NIRST) system has been developed and integrated into a commercial Digital Breast Tomosynthesis (DBT) scanner to allow structural and functional imaging of breast in vivo. The NIRST instrument uses an 8-wavelength continuous wave (CW) laser-based scanning source assembly and a 75 element silicon photodiode solid-state detector panel to produce dense spectral and spatial projection data from which spectrally constrained 3D tomographic images of tissue chromophores are produced. Integration of the optical imaging system into the DBT scanner allows direct co-registration of the optical and DBT images, while also facilitating the synergistic use of x-ray contrast as anatomical priors in optical image reconstruction. Currently, the total scan time for a combined NIRST-DBT exam is ~50s with data collection from 8 wavelengths in the optical scan requiring ~42s to complete. The system was tested in breast simulating phantoms constructed using intralipid and blood in an agarose matrix with a 3 cm x 2 cm cylindrical inclusion at 1 cm depth from the surface. Diffuse image reconstruction of total hemoglobin (HbT) concentration resulted in accurate recovery of the lateral size and position of the inclusion to within 6% and 8%, respectively. Use of DBT structural priors in the NIRST reconstruction process improved the quantitative accuracy of the HbT recovery, and led to linear changes in imaged versus actual contrast, underscoring the advantages of dual-modality optical imaging approaches. The quantitative accuracy of the system can be further improved with independent measurements of scattering properties through integration of frequency or time domain data. PMID- 23038554 TI - Exploration of the horizontally staggered light guides for high concentration CPV applications. AB - The material and processing costs are still the major drawbacks of the c-Si based photovoltaic (PV) technology. The wafer cost comprises up to 35-40% of the total module cost. New approaches and system designs are needed in order to reduce the share of the wafer cost in photovoltaic energy systems. Here we explore the horizontally staggered light guide solar optics for use in Concentrated Photovoltaic (CPV) applications. This optical system comprises a lens array system coupled to a horizontal light guide which directs the incoming light beam to its edge. We have designed and simulated this system using a commercial ray tracing software (Zemax). The system is more compact, thinner and more robust compared to the conventional CPV systems. Concentration levels as high as 1000x can easily be reached when the system is properly designed. With such a high concentration level, a good acceptance angle of + -1 degree is still be conserved. The analysis of the system reveals that the total optical efficiency of the system could be as high as %94.4 without any anti-reflection (AR) coating. Optical losses can be reduced by just accommodating a single layer AR coating on the initial lens array leading to a %96.5 optical efficiency. Thermal behavior of high concentration linear concentrator is also discussed and compared with a conventional point focus CPV system. PMID- 23038555 TI - Spectral-domain OCT with dual illumination and interlaced detection for simultaneous anterior segment and retina imaging. AB - We present Fourier-domain/spectral-domain optical coherence tomography (FD/SD OCT) using a single spectrometer with dual illumination and interlaced detection at 830 nm, which can provide anterior segment and retinal tomograms simultaneously. Two orthogonal polarization components were used so that both parallel and focused beams could simultaneously be made incident on the eye. This configuration with a polarization-separated sample arm enables us to acquire images from the anterior segment and retina effectively with minimum loss of sample information. In the detector arm, a single spectrometer is illuminated via an ultrafast optical switch for interlaced detection. A graphical user interface (GUI) was built to control the optical switch for imaging the anterior segment and retina either simultaneously or individually. In addition, we implemented an off-pivot complex conjugate removal technique to double the imaging depth for anterior segment imaging. The axial resolution of our FD/SD-OCT system was measured to be ~6.7 MUm in air, which corresponds to 4.9 MUm in tissue (n = 1.35). The sensitivity was approximately 90 dB for both anterior segment and retina imaging when the acquisition speed was 35,000 A-scans per second and the depth position was near 120 MUm from the zero-depth location. Finally, we demonstrated the feasibility of our system for simultaneous in vivo imaging of both the anterior segment and retina of a healthy human volunteer. PMID- 23038556 TI - Optical magnetic field enhancement through coupling magnetic plasmons to Tamm plasmons. AB - We report on a theoretical investigation of the coupling between magnetic plasmons (MPs) and Tamm plasmons (TPs) in a metal-dielectric Bragg reflector (DBR) containing a gold nanowire pair array embedded in the low refractive index layer closest to the metal film. Strong coupling between MPs and TPs is observed, manifested by large anticrossings in the dispersion diagram. It creates a narrow band hybridized MP mode with a Rabi-type splitting as large as 290 meV. Upon the excitation of this hybridized MP mode, a 2.5-fold enhancement of the magnetic field in the center of nanowire pairs is achieved as compared with the pure MP of the nanowire pairs embedded in a bare DBR structure (without the metal film). This result holds a promising potential application in magnetic nonlinearity and sensors. PMID- 23038557 TI - Analytic and experimental investigations on influence of harmonic generation on acousto-optical modulation. AB - In application, laser power is modulated prior to harmonic generation to a large part. Consequently modulation characteristics are influenced as a result of the non-linearity of harmonic generation. Within this paper, straight-forward approaches to calculate modulation key parameters (rise time, fall time, bandwidth and contrast ratio) of an acousto-optical modulator prior to harmonic generation stage are presented. The results will be compared to experimental data for third harmonic generation (THG) of a 1064 nm fs-laser which is power modulated by a TeO2-AOM prior to THG. In the latter case, rise time and fall time are significantly reduced to approximately 66% after THG both in experimental and analytical study. PMID- 23038558 TI - Characterization of bending loss in hollow flexible terahertz waveguides. AB - Attenuation characteristics of hollow, flexible, metal and metal/dielectric coated polycarbonate waveguides were investigated using an optically pumped far infrared (FIR) laser at 215 um. The bending loss of silver coated polycarbonate waveguides were measured as a function of various bending angles, bending radii, and bore diameters. Minimal propagation losses of 1.77, 0.96 dB/m were achieved by coupling the lowest loss TE11 mode into the silver or gold coated waveguide, and HE11 mode into the silver/polystyrene coated waveguides respectively. The maximal bending loss was found to be less than 1 dB/m for waveguides of 2 to 4.1 mm bore diameters, with a 6.4 cm bend radius, and up to 150 degrees bending angle. The investigation shows the preservation of single laser mode in smaller bore waveguides even at greater bending angles. PMID- 23038559 TI - Dual-mode temperature compensation technique for laser stabilization to a crystalline whispering gallery mode resonator. AB - Frequency stabilization of a diode laser locked to a whispering gallery mode (WGM) reference resonator made of a MgF2 single crystal is demonstrated. The strong thermal dependence of the difference frequency between two orthogonally polarized TE an TM modes (dual-mode frequency) of the optically anisotropic crystal material allows sensitive measurement of the resonator's temperature within the optical mode volume. This dual-mode signal was used as feedback for self-referenced temperature stabilization to nanokelvin precision, resulting in frequency stability of 0.3 MHz/h at 972 nm, which was measured by comparing with an independent ultrastable laser. PMID- 23038560 TI - Highly reliable Ag/Zn/Ag ohmic reflector for high-power GaN-based vertical light emitting diode. AB - We report the improved performance of InGaN/GaN-based light-emitting diodes (LEDs) through Ag reflectors combined with a Zn middle layer. It is shown that the Zn middle layer (5 nm thick) suppresses the agglomeration of Ag reflectors by forming ZnO and dissolving into Ag. The Ag/Zn/Ag contacts show a specific contact resistance of 6.2 * 10(-5) Omegacm(2) and reflectance of ~83% at a wavelength of 440 nm when annealed at 500 degrees C, which are much better than those of Ag only contacts. Blue LEDs fabricated with the 500 degrees C-annealed Ag/Zn/Ag reflectors show a forward voltage of 2.98 V at an injection current of 20 mA, which is lower than that (3.02 V) of LEDs with the annealed Ag only contacts. LEDs with the 500 degrees C-annealed Ag/Zn/Ag contacts exhibit 34% higher output power (at 20 mA) than LEDs with the annealed Ag only contacts. PMID- 23038561 TI - Spectrum to space transformed fast terahertz imaging. AB - We present an imaging technique in which the broadband frequency information of terahertz (THz) pulses is transformed into spatial resolution. Efficient blazed diffractive gratings spread the individual frequency components over a wide and defined spatial range and f-theta optics are employed to focus the individual components onto a one-dimensional image-line. Measuring the time domain waveform of the THz waves allows therefore for a direct reconstruction of spatial sample characteristics as the spatial domain information is encoded in the terahertz spectrum. We will demonstrate terahertz imaging on selected samples with an improvement in acquisition speed up to two orders of magnitude. PMID- 23038562 TI - Elliptical mirror based imaging with aperture angle greater than pi/2. AB - Elliptical mirror based imaging systems permit aperture angles greater than pi/2 to be realized. It is therefore possible to collect part or all of both the forward and backward diffractive fields emitted from single molecules. In this paper we derive rigorous formulae for the image intensity when the single molecule is modeled as a dipole emitter. It is found in theory that the point spread function can be 2.44 times narrower at full-width-half-maximum in the axial direction when using an elliptical mirror with the maximum aperture angle of 2pi/3 as compared with a parabolic mirror system with the aperture angle of pi/2 whereas the side lobe level is increased by only 0.21% when the dipole is oriented along Z axis. PMID- 23038563 TI - Anomalously-large photo-induced magnetic response of metallic nanocolloids in aqueous solution using a solar simulator. AB - We experimentally, analytically, and numerically demonstrate the nonlinear photo induced plasmon-assisted magnetic response that occurs with metallic nanoparticles in aqueous solution. We measure the scattered spectra from solutions of gold nanospheres (10(-7) fill factor) and observe appreciable changes when simultaneously applying DC magnetic fields and illuminating samples with light. The magnetic response is achieved using light from a solar simulator at unprecedented low illumination intensities (< 1W/cm(2)) and is sustained when the magnetic field is removed. Distinctly different behavior is observed depending on the circular-polarization handedness given a fixed magnetic field. Nanoparticle aggregation is more likely to occur when the circular-polarization trajectory opposes the solenoid current that produces the magnetic field. Using Mie's theoretical solution, we show how vortex orbital surface currents lead to an increased and anisotropic electrical conductivity, which shifts the scattered spectra in agreement with experimental results. The single-nanoparticle plasmon induced magnetization, which couples the scattered and incident electric fields, changes sign with orthogonal circular-polarization handedness. PMID- 23038564 TI - On-chip spectrometer with a circular-hole defect for optical sensing applications. AB - We propose an optical sensor by integrating a circular-hole defect with an etched diffraction grating spectrometer based on amorphous silicon photonic platforms. There are some superiorities of this device, such as high sensitivity (~10000 nm/RIU), and ability to deliver component analysis from the near-infrared spectrum by using the integrated spectrometer. As application example, the chip is used for distinguishing similar biodiesel types and accurately determining their concentrations in a diesel oil mixture. PMID- 23038565 TI - Hard X-ray imaging of bacterial cells: nano-diffraction and ptychographic reconstruction. AB - Ptychographic coherent X-ray diffractive imaging (PCDI) has been combined with nano-focus X-ray diffraction to study the structure and density distribution of unstained and unsliced bacterial cells, using a hard X-ray beam of 6.2keV photon energy, focused to about 90nm by a Fresnel zone plate lens. While PCDI provides images of the bacteria with quantitative contrast in real space with a resolution well below the beam size at the sample, spatially resolved small angle X-ray scattering using the same Fresnel zone plate (cellular nano-diffraction) provides structural information at highest resolution in reciprocal space up to 2nm(-1). We show how the real and reciprocal space approach can be used synergistically on the same sample and with the same setup. In addition, we present 3D hard X-ray imaging of unstained bacterial cells by a combination of ptychography and tomography. PMID- 23038566 TI - Electromechanical tuning of vertically-coupled photonic crystal nanobeams. AB - We present the design, the fabrication and the characterization of a tunable one dimensional (1D) photonic crystal cavity (PCC) etched on two vertically-coupled GaAs nanobeams. A novel fabrication method which prevents their adhesion under capillary forces is introduced. We discuss a design to increase the flexibility of the structure and we demonstrate a large reversible and controllable electromechanical wavelength tuning (> 15 nm) of the cavity modes. PMID- 23038567 TI - Theoretical research on terahertz air-breakdown coherent detection with the transient photocurrent model. AB - The physical mechanism for sensing broadband terahertz (THz) wave via using femtosecond (fs) laser induced gas plasma without any local accessory near the plasma, i.e. THz air breakdown coherent detection, is systemically investigated by utilizing the transient photocurrent model. Previous observed results, such as conversion from incoherent to coherent detection, can be numerically obtained. Further calculations and analysis show that it is through modification of the gas ionization process, and not acceleration of freed electrons or through a four wave-mixing (FWM) process, that the THz waveforms can be encoded into the detected second harmonic (SH) signals. PMID- 23038568 TI - Distributed parametric amplifier for RZ-DPSK signal transmission system. AB - We have experimentally demonstrated a single pump distributed parametric amplification (DPA) system for differential phase shift keying (DPSK) signal in a spool of dispersion-shifted fiber (DSF). The gain spectrum of single pump DPA is thoroughly investigated by both simulation and experiment, and a possible reference for optimal input pump power and fiber length relationship is provided to DPA based applications. Furthermore, DPSK format is compared with on-off keying (OOK) within DPA scheme. Eight WDM signal channels at 10-Gb/s are utilized, and approximately 0.5-dB power penalties at the bit-error rate (BER) of 10(-9) are achieved for return-to-zero DPSK (RZ-DPSK), comparing to larger than 1.5-dB with OOK format. In order to improve the system power efficiency, at the receiver, the pump is recycled by a photovoltaic cell and the converted energy can be used by potential low-power-consuming devices, i.e sensors or small-scale electronic circuits. Additionally, with suitable components, the whole DPA concept could be directly applied to the 1.3-MUm telecommunication window along the most commonly used single-mode fiber (SMF). PMID- 23038569 TI - InGaAsP-based uni-travelling carrier photodiode structure grown by solid source molecular beam epitaxy. AB - We report the first InGaAsP-based uni-travelling carrier photodiode structure grown by Solid Source Molecular Beam Epitaxy; the material contains layers of InGaAsP as thick as 300 nm and a 120 nm thick InGaAs absorber. Large area vertically illuminated test devices have been fabricated and characterised; the devices exhibited 0.1 A/W responsivity at 1550 nm, 12.5 GHz -3 dB bandwidth and 5.8 dBm output power at 10 GHz for a photocurrent of 4.8 mA. The use of Solid Source Molecular Beam Epitaxy enables the major issue associated with the unintentional diffusion of zinc in Metal Organic Vapour Phase Epitaxy to be overcome and gives the benefit of the superior control provided by MBE growth techniques without the costs and the risks of handling toxic gases of Gas Source Molecular Beam Epitaxy. PMID- 23038570 TI - Coherent control of high-order harmonic generation by phase jump pulses. AB - We theoretically investigate the high-order harmonic generation driven by laser pulses with a pi-phase jump. The cutoff of high-order harmonic spectrum extends dramatically due to the phase jump which enlarges the asymmetry of the laser field. We find that the intensity and the coherence of the continuum can be controlled by the jump time. By selecting proper frequency of the continuum spectrum, a sub-100-attosecond pulse can be generated without any phase compensation. PMID- 23038572 TI - Managing SRS competition in a miniature visible Nd:YVO4/BaWO4 Raman laser. AB - We demonstrate the operation of a compact and efficient continuous wave (CW) self Raman laser utilizing a Nd:YVO4 gain crystal and BaWO4 Raman crystal, generating yellow emission at 590 nm. We investigate the competition that occurs between Stokes lines in the Nd:YVO4 and BaWO4 crystals, and within the BaWO4 crystal itself. Through careful consideration of crystal length and orientation, we are able to suppress competition between Stokes lines, and generate pure yellow emission at 590 nm with output power of 194 mW for just 3.8 W pump power. PMID- 23038571 TI - Beaming circularly polarized photons from quantum dots coupled with plasmonic spiral antenna. AB - Coupling nanoscale emitters via optical antennas enables comprehensive control of photon emission in terms of intensity, directivity and polarization. In this work we report highly directional emission of circularly polarized photons from quantum dots coupled to a spiral optical antenna. The structural chirality of the spiral antenna imprints spin state to the emitted photons. Experimental results reveal that a circular polarization extinction ratio of 10 is obtainable. Furthermore, increasing the number of turns of the spiral gives rise to higher antenna gain and directivity, leading to higher field intensity and narrower angular width of emission pattern in the far field. For a five-turn Archimedes' spiral antenna, field intensity increase up to 70-fold simultaneously with antenna directivity of 11.7 dB has been measured in the experiment. The highly directional circularly polarized photon emission from such optically coupled spiral antenna may find important applications in single molecule sensing, quantum optics information processing and integrated photonic circuits as a nanoscale spin photon source. PMID- 23038574 TI - All-optical quantum random bit generation from intrinsically binary phase of parametric oscillators. AB - We demonstrate a novel all-optical quantum random number generator (RNG) based on above-threshold binary phase state selection in a degenerate optical parametric oscillator (OPO). Photodetection is not a part of the random process, and no post processing is required for the generated bit sequence. We show that the outcome is statistically random with 99% confidence, and verify that the randomness is due to the phase of initiating photons generated through spontaneous parametric down conversion of the pump, with negligible contribution of classical noise sources. With the use of micro- and nanoscale OPO resonators, this technique offers a promise for simple, robust, and high-speed on-chip all-optical quantum RNGs. PMID- 23038573 TI - Antiresonant ring output-coupled continuous-wave optical parametric oscillator. AB - We demonstrate the successful deployment of an antiresonant ring (ARR) interferometer for the attainment of optimum output coupling in a continuous-wave (cw) optical parametric oscillator (OPO). The cw OPO, configured as a singly resonant oscillator (SRO), is based on a 50-mm-long MgO:PPLN crystal and pumped by cw Ytterbium-fiber laser at 1064 nm, with the ARR interferometer integrated into one arm of the standing-wave cavity. By fine adjustment of the ARR transmission, a continuously variable signal output coupling from 0.8% to 7.3% has been achieved, providing optimum output coupling for signal and optimum power extraction for the idler, at different input pumping levels. The experimental results are compared with theoretical calculations for conventional output coupled cw SRO, and the study shows that by reducing the insertion loss of the ARR elements, the performance of the ARR-coupled cw SRO can be further enhanced. We also show that the use of the ARR does not lead to any degradation in the cw SRO output beam quality. The proof-of-principle demonstration confirms the effectiveness of the technique for continuous, in situ, and fine control of output coupling in cw OPOs to achieve maximum output power at any arbitrary pumping level above threshold. PMID- 23038575 TI - Optimal energy-splitting method for an open-loop liquid crystal adaptive optics system. AB - A waveband-splitting method is proposed for open-loop liquid crystal adaptive optics systems (LC AOSs). The proposed method extends the working waveband, splits energy flexibly, and improves detection capability. Simulated analysis is performed for a waveband in the range of 350 nm to 950 nm. The results show that the optimal energy split is 7:3 for the wavefront sensor (WFS) and for the imaging camera with the waveband split into 350 nm to 700 nm and 700 nm to 950 nm, respectively. A validation experiment is conducted by measuring the signal-to noise ratio (SNR) of the WFS and the imaging camera. The results indicate that for the waveband-splitting method, the SNR of WFS is approximately equal to that of the imaging camera with a variation in the intensity. On the other hand, the SNR of the WFS is significantly different from that of the imaging camera for the polarized beam splitter energy splitting scheme. Therefore, the waveband splitting method is more suitable for an open-loop LC AOS. An adaptive correction experiment is also performed on a 1.2-meter telescope. A star with a visual magnitude of 4.45 is observed and corrected and an angular resolution ability of 0.31" is achieved. A double star with a combined visual magnitude of 4.3 is observed as well, and its two components are resolved after correction. The results indicate that the proposed method can significantly improve the detection capability of an open-loop LC AOS. PMID- 23038576 TI - Optical parametric amplification of arbitrarily polarized light in periodically poled LiNbO3. AB - Optical parametric amplification (OPA) of arbitrarily polarized light is proposed in a multi-section periodically poled Lithium Niobate (PPLN). External electric field is applied on selected sections to induce the polarization rotation of involved lights, thus the quasi-phase matched optical parametric processes exhibit polarization insensitivity under suitable voltage. In addition to the amplified signal wave, an idler wave with the same polarization is generated simultaneously. As an example, a ~10 times OPA showing polarization independency is simulated. Applications of this technology are also discussed. PMID- 23038577 TI - Broadly tunable femtosecond Tm:Lu2O3 ceramic laser operating around 2070 nm. AB - Femtosecond mode locking of a Tm-doped Lu2O3 ceramic laser is reported. Transform limited pulses as short as 180 fs are generated at 2076 nm with an average output power of 400 mW and a pulse repetition frequency of 121.2 MHz. An output power up to 750 mW can be reached at the somewhat longer pulse duration of 382 fs. Femtosecond pulse generation is realized in the 2030-2100 nm spectral range. Passive mode locking was achieved using an ion-implanted InGaAsSb quantum-well based SESAM. PMID- 23038578 TI - Solitons in parity-time symmetric potentials with spatially modulated nonlocal nonlinearity. AB - We study the solitons in parity-time symmetric potential in the medium with spatially modulated nonlocal nonlinearity. It is found that the coefficient of the spatially modulated nonlinearity and the degree of the uniform nonlocality can profoundly affect the stability of solitons. There exist stable solitons in low-power region, and unstable solitons in high-power region. In the unstable cases, the solitons exhibit jump from the original site to the next one, and they can continue the motion into the other lattices. The region of the stable soliton can be expanded by increasing the coefficient of the modulated nonlocality. Finally, critical amplitude of the imaginary part of the linear PT lattices is obtained, above which solitons are unstable and decay immediately. PMID- 23038579 TI - Broadband parametric multicasting via four-mode phase-sensitive interaction. AB - Optical frequency multicasting with significantly enhanced signal-to-noise-ratio (SNR) is demonstrated over wide wavelength range. High-fidelity multicasting relies on a four-mode phase-sensitive (PS) parametric process. Four-mode seeding was used to drive dual-pump, multistage mixer and achieve high-efficiency frequency comb generation and signal replication assisted by field interference. New PS mixer was measured to possess near 12-dB of spectrally uniform optical SNR advantage over conventional, phase-insensitive (PI) parametric multicaster. In signal attenuation regime, PS operation was measured with better than 10dB over the entire mixer band, indicating highly controllable PS interference. The role of the new PS mixer in near-noiseless signal replication is elaborated. PMID- 23038580 TI - Spectral tuning of the phosphorescence from metalloporphyrins attached to gold nanorods. AB - The spectral shape of the phosphorescence emission of organometallic porphyrin molecules is shown to be altered when these chromophores are incorporated into hybrid nanostructures with gold nanorods. This result shows that triplet-singlet transitions, which are (at least partially) dipolar forbidden, can be modified by the dipolar resonances of gold nanoparticles. By choosing nanorods of increasing aspect ratios, it is possible to match the long axis plasmon resonance of the nanorods to a specific phosphorescence transition. Consequently, the emission colour of the hybrids can be tuned. PMID- 23038581 TI - Complex refractive index variation in proton-damaged diamond. AB - An accurate control of the optical properties of single crystal diamond during microfabrication processes such as ion implantation plays a crucial role in the engineering of integrated photonic devices. In this work we present a systematic study of the variation of both real and imaginary parts of the refractive index of single crystal diamond, when damaged with 2 and 3 MeV protons at low-medium fluences (range: 10(15) - 10(17) cm(-2)). After implanting in 125 * 125 MUm(2) areas with a scanning ion microbeam, the variation of optical pathlength of the implanted regions was measured with laser interferometric microscopy, while their optical transmission was studied using a spectrometric set-up with micrometric spatial resolution. On the basis of a model taking into account the strongly non uniform damage profile in the bulk sample, the variation of the complex refractive index as a function of damage density was evaluated. PMID- 23038582 TI - Terahertz spectroscopy of the reactive and radiative near-field zones of split ring resonator. AB - A terahertz microscope has been used to excite and observe the resonant modes of a single split ring resonator in the reactive and radiative near-field zones. The two lowest resonant modes of an isolated split ring resonator with their corresponding radiation patterns are reported; they showed good agreement to simulations. The passage from the reactive to radiative near-field zone is also discussed. Further, our result introduced a novel technique to perform terahertz time-domain spectroscopy of samples a few tens of micrometers in size by measuring the in-plane radiative near-field zone. PMID- 23038583 TI - Growth of well-arrayed ZnO nanorods on thinned silica fiber and application for humidity sensing. AB - Thinned silica fibers were fabricated by drawing conventional single mode silica fiber through flame heated method and well-arrayed ZnO nanorods were grown on the thinned silica fibers by a hydrothermal method. The structure enables efficient light coupling between the fiber and the nanorods. With the unique property of high surface to volume ratio of one-dimensional ZnO nanorods, light coupled to nanorods array enhances the optical interaction between the device and the ambient environment. Sensitive humidity sensor was demonstrated by launching laser into ZnO nanorod-covered fibers. Theoretical and experimental results are presented. PMID- 23038584 TI - 3.7 W fluoride glass Raman fiber laser operating at 2231 nm. AB - The first demonstration of a multi-watt continuous wave fluoride glass Raman fiber laser operating beyond 2.2 MUm is reported. A maximum output power of 3.7 W was obtained from a nested cavity setup with a laser slope efficiency of 15% with respect to the launched pump power. PMID- 23038585 TI - Low-noise RF-amplifier-free slab-coupled optical waveguide coupled optoelectronic oscillators: physics and operation. AB - We demonstrate a 10-GHz RF-amplifier-free slab-coupled optical waveguide coupled optoelectronic oscillator (SCOW-COEO) system operating with low phase-noise (< 115 dBc/Hz at 1 kHz offset) and large sidemode suppression (>70 dB measurement limited). The optical pulses generated by the SCOW-COEO exhibit 26.8-ps pulse width (post compression) with a corresponding spectral bandwidth of 0.25 nm (1.8X transform-limited). We also investigate the mechanisms that limit the performance of the COEO. Our measurements indicate that degradation in the quality factor (Q) of the optical cavity significantly impacts COEO phase-noise through increases in the optical amplifier relative intensity noise (RIN). PMID- 23038586 TI - Second harmonic generation at the probe tip for background-free near-field optical imaging. AB - Second harmonic generation (SHG) has been applied to reduce background signals in near-field optical imaging, but this technique is usually limited to samples with strong second-order nonlinear susceptibilities. To overcome this limitation, in this paper, we present a versatile background-free SHG configuration, where it utilizes the second-order nonlinear susceptibility of the probe which essentially functions as a near-field polarizer capable of filtering out the background signal component. In the theoretical analysis, we first model the probe-sample optical interactions at both the fundamental frequency and the second harmonic frequency by using the coupled dipole method. The theoretical model reveals that the proposed versatile background-free SHG configuration requires two conditions. The first condition is that the incident optical field must be s-polarized. The second condition is that the probe must be made of crystals from symmetry class 222, symmetry class 622, symmetry class 422, symmetry class 42m, symmetry class 43m or symmetry class 23. To demonstrate the effectiveness of the proposed versatile background-free SHG configuration, a probe made of deuterated potassium dideuterium phosphate (DKDP) crystal from symmetry class 42m is analyzed numerically. It is shown that when imaging samples with negligible second-order nonlinear susceptibilities, the proposed background-free SHG configuration improves the imaging contrast by more than one-order of magnitude as compared to all other imaging configurations. Moreover, we also investigate the dependence of its performance on other parameters, such as the probe-sample distance, the relative size between probe and sample, and the tilt angle of probe crystal. It is believed that the proposed configuration could be widely used to achieve high contrast near-field optical imaging. PMID- 23038587 TI - Time-evolution of electron density in plasma measured by high-order harmonic generation. AB - We propose a new method of measuring the electron density in plasma by high-order harmonic generation (HHG) of intense two-color femtosecond (fs) laser. As the 800 nm fundamental beam is introduced after its second harmonic generation (SHG) beam, the recovery of HHG by the fundamental pulses at a delay of ~40 ps indicates the decay time of the generated plasma. The electron-ion recombination rate and electron density decay are revealed by fitting the harmonic emission to the model that accounts for depletion of neutral atoms, phase mismatch and re absorption of HHG. PMID- 23038588 TI - Demonstration of an ultra-high frequency picosecond pulse generator using an SBS frequency comb and self phase-locking. AB - We propose a method to generate phase-locked pulses in the picosecond regime by using Stimulated Brillouin Scattering (SBS). The phase-locked comb is generated using only long length of fiber and a single frequency CW pump laser. We show that there is a phase relationship between multiple Stokes peaks in a cavity, which directly leads to pulsing without the need to add a mode-locking component. This generates highly coherent pulses in the order of ~10 ps. The repetition frequency, which is very stable is in the order of tens of GHz, is based on the SBS frequency shift and has a linear dependence with temperature (1 MHz/ degrees C). Such a laser could therefore be used in high-speed optical clocks and optical communication system. This system allows the pulses to be generated at any wavelength by simply changing the pump wavelength. PMID- 23038589 TI - Graphene oxide vs. reduced graphene oxide as saturable absorbers for Er-doped passively mode-locked fiber laser. AB - In this work we demonstrate comprehensive studies on graphene oxide (GO) and reduced graphene oxide (rGO) based saturable absorbers (SA) for mode-locking of Er-doped fiber lasers. The paper describes the fabrication process of both saturable absorbers and detailed comparison of their parameters. Our results show, that there is no significant difference in the laser performance between the investigated SA. Both provided stable, mode-locked operation with sub-400 fs soliton pulses and more than 9 nm optical bandwidth at 1560 nm center wavelength. It has been shown that GO might be successfully used as an efficient SA without the need of its reduction to rGO. Taking into account simpler manufacturing technology and the possibility of mass production, GO seems to be a good candidate as a cost-effective material for saturable absorbers for Er-doped fiber lasers. PMID- 23038590 TI - Single nanohole and photoluminescence: nanolocalized and wavelength tunable light source. AB - We are first to demonstrate a broadband, nanometer-scale, and background-free light source that is based on photoluminescence of a single nanohole in an Au film. We show that a nanohole with a diameter of as small as 20 nm in a 200-nm thick Au film can be used for this purpose. Further development of the localized source that involves the use of a photon-crystal microcavity with a Q-factor of 100 makes it possible to create a 30-fold enhanced, narrowband tunable light source and with a narrow directivity of the radiation. PMID- 23038591 TI - Giant tunable Faraday effect in a semiconductor magneto-plasma for broadband terahertz polarization optics. AB - We report on a giant Faraday effect in an electron plasma in n-InSb probed via polarization-resolved terahertz (THz) time-domain spectroscopy. Polarization rotation angles and ellipticities reach as large as pi/2 and 1, respectively, over a wide frequency range (0.3-2.5 THz) at magnetic fields of a few Tesla. The experimental results together with theoretical simulations show its promising ability to construct broadband and tunable THz polarization optics, such as a circular polarizer, half-wave plate, and polarization modulators. PMID- 23038592 TI - High-speed three-dimensional profilometry for multiple objects with complex shapes. AB - This paper describes an easy-to-implement three-dimensional (3-D) real-time shape measurement technique using our newly developed high-speed 3-D vision system. It employs only four projection fringes to realize full-field phase unwrapping in the presence of discontinuous or isolated objects. With our self-designed pattern generation hardware and a modified low-cost DLP projector, the four designed patterns can be generated and projected at a switching speed of 360 Hz. Using a properly synchronized high-speed camera, the high-speed fringe patterns distorted by measured objects can be acquired and processed in real-time. The resulting system can capture and display high-quality textured 3-D data at a speed of 120 frames per second, with the resolution of 640 * 480 points. The speed can be trebled if a camera with a higher frame rate is employed. We detail our shape measurement technique, including the four-pattern decoding algorithm as well as the hardware design. Some evaluation experiments have been carried out to demonstrate the validity and practicability of the proposed technique. PMID- 23038593 TI - Wide spectral bandwidth electro-absorption modulator using coupled micro-cavity with asymmetric tandem quantum well. AB - For reliable three dimensional (3D) imaging system, it is necessary for the optical shutter to have a wide spectral bandwidth operation and enhanced modulation depth. We propose an electro-absorption modulator (EAM) based on coupled Fabry-Perot cavities with micro-cavity (CCMC) which uses asymmetric tandem quantum wells (ATQWs) to obtain improved spectral bandwidth and enhanced modulation depth. Several modulator designs are investigated to obtain improved modulation performance such as wider spectral bandwidth and enhanced modulation depth. It was found that among all the studied modulator geometries, CCMC structure with ATQWs provides the widest spectral bandwidth of 9.6nm and high modulation depth in excess of 50% at -24V, which is good agreement with theoretical calculations. These results suggest that EAM has excellent potential as optical shutter for 3D imaging application. PMID- 23038594 TI - OSNR monitoring for QPSK and 16-QAM systems in presence of fiber nonlinearities for digital coherent receivers. AB - OSNR monitoring is indispensable for coherent systems to ensure robust, reliable network operation and potentially enable impairment-aware routing for future dynamic optical networks. In a long-haul transmission link with chromatic dispersion (CD) and fiber nonlinearity, it is difficult to distinguish between amplifier noise and fiber nonlinearity induced distortions from received signal distributions even after various transmission impairment compensation techniques, thus resulting in grossly inaccurate OSNR estimates. Based on the received signal distributions after carrier phase estimation (CPE), we propose to characterize the nonlinearity-induced amplitude noise correlation across neighboring symbols and incorporate such information into error vector magnitude (EVM) calculation to realize fiber nonlinearity-insensitive OSNR monitoring. For a transmission link up to 1600 km and signal launched power up to 2 dBm, experimental results for 112 Gb/s polarization-multiplexed quadrature phase-shift keying (PM-QPSK) demonstrate an OSNR monitoring range of 10-24 dB with a maximum estimation error below 1 dB. For 224 Gb/s PM-16-quadrature amplitude modulation (PM-16-QAM) systems, simulation results demonstrate an OSNR monitoring range of 18-28 dB with a maximum estimation error below 1 dB. Tolerance of the proposed OSNR monitoring technique to different pulse shapes, timing phase offsets, polarization dependent loss (PDL), polarization-mode dispersion (PMD) and WDM effects are also investigated through simulations. PMID- 23038595 TI - A hybrid fiber-optic photoluminescence measurement system and its application in InGaN/GaN light emitting diode epi-wafer morphology studies. AB - We report a fiber optic photoluminescence (PL) measurement system using a novel hybrid probe composed of a series of single mode fiber (SMF) and double-clad fiber (DCF) terminated with a coreless silica fiber (CSF) segment and glass micro lens formed on its cleaved-facet. The fiber probe provided a good guidance and focusing capability for the excitation photon with a focal length of 125 MUm and a beam diameter of 13.6 MUm. Utilizing a special DCF-to-DCF coupling scheme, the photoluminescence signals were efficiently collected and delivered to a photodetector with a low loss. Utilizing the proposed system, PL morphology was investigated over a 200 * 200 MUm(2) area for two types of InGaN/GaN blue light emitting diode (LED) epi-wafers grown on 1) an un-patterned sapphire substrate (UPSS), and 2) a patterned sapphire substrate (PSS). The uniformity in the relative PL intensity and the spectral uniformity in terms of the peak PL wavelength were experimentally compared and analyzed. PMID- 23038596 TI - Coupling of ultrathin tapered fibers with high-Q microsphere resonators at cryogenic temperatures and observation of phase-shift transition from undercoupling to overcoupling. AB - We cooled ultrathin tapered fibers to cryogenic temperatures and controllably coupled them with high-Q microsphere resonators at a wavelength close to the optical transition of diamond nitrogen vacancy centers. The 310-nm-diameter tapered fibers were stably nanopositioned close to the microspheres with a positioning stability of approximately 10 nm over a temperature range of 7-28 K. A cavity-induced phase shift was observed in this temperature range, demonstrating a discrete transition from undercoupling to overcoupling. PMID- 23038597 TI - Antireflective disordered subwavelength structure on GaAs using spin-coated Ag ink mask. AB - We present a simple, cost-effective, large scale fabrication technique for antireflective disordered subwavelength structures (d-SWSs) on GaAs substrate by Ag etch masks formed using spin-coated Ag ink and subsequent inductively coupled plasma (ICP) etching process. The antireflection characteristics of GaAs d-SWSs rely on their geometric profiles, which were controlled by adjusting the distribution of Ag etch masks via changing the concentration of Ag atoms and the sintering temperature of Ag ink as well as the ICP etching conditions. The fabricated GaAs d-SWSs drastically reduced the reflection loss compared to that of bulk GaAs (>30%) in the wavelength range of 300-870 nm. The most desirable GaAs d-SWSs for practical solar cell applications exhibited a solar-weighted reflectance (SWR) of 2.12%, which is much lower than that of bulk GaAs (38.6%), and its incident angle-dependent SWR was also investigated. PMID- 23038598 TI - Beam position controlling method for 3D optical system and its application in non planar ring resonators. AB - A novel theoretical beam position controlling method for 3D optical system has been proposed in this paper. Non-planar ring resonator, which is a typical 3D optical system, has been chosen as an example to show its application. To the best of our knowledge, the generalized ray matrices, augmented 5 * 5 ray matrices for paraxial dielectric interface transmission and paraxial optical-wedge transmission, and their detailed deducing process have been proposed in this paper for the first time. By utilizing the novel coordinate system for Gaussian beam reflection and the generalized ray matrix of paraxial optical-wedge transmission, the rules and some novel results of the optical-axis perturbations of non-planar ring resonators have been obtained. Wedge angle-induced mismatching errors of non-planar ring resonators have been found out and two experimental beam position controlling methods to effectively eliminate the wedge angle induced mismatching errors have been proposed. All those results have been confirmed by related alignment experiments and the experimental results have been described with diagrammatic representation. These findings are important to the beam control, cavity design, and cavity alignment of high precision non-planar ring laser gyroscopes. Those generalized ray matrices and their deducing methods are valuable for ray analysis of various kinds of paraxial optical-elements and resonators. This novel theoretical beam position controlling method for 3D optical system is valuable for the controlling of various kinds of 3D optical systems. PMID- 23038599 TI - Correlated electron dynamics in nonsequential double ionization of molecules by mid-infrared fields. AB - The electron dynamics in strong field nonsequential double ionization (NSDI) of nitrogen molecules by mid-infrared (MIR) laser pulses is investigated with the three-dimensional classical ensemble model. The numerical results show that in the MIR regime, the correlated behavior of the two electrons from NSDI is independent on the molecular alignment, contrary to the case in the near-infrared (NIR) regime where the electron correlations exhibit a strong alignment dependence. In consistent with the experimental results, our numerical results show that the longitudinal momentum spectrum of the doubly charged ion evolves from a wide single-hump structure at NIR regime into a double-hump structure when wavelength enters the MIR regime. This double-hump structure becomes more pronounced as the wavelength further increases. The responsible microscopic electron dynamics of NSDI at the MIR regime is explored by back analysis of the classical trajectories. PMID- 23038601 TI - Pilot-aided carrier phase recovery for M-QAM using superscalar parallelization based PLL. AB - In this paper, we present a carrier phase recovery (CPR) algorithm using a modified superscalar parallelization based phase locked loop (M-SSP-PLL) combined with a maximum-likelihood (ML) phase estimation. Compared to the original SSP PLL, M-SSP-PLL + ML reduces the required buffer size using a novel superscalar structure. In addition, by removing the differential coding/decoding and employing ML phase recovery it also improves the performance. In simulation, we show that the laser linewidth tolerance of M-SSP-PLL + ML is comparable to blind phase search (BPS) algorithm, which is known to be one of the best CPR algorithms in terms of performance for arbitrary QAM formats. In 28 Gbaud QPSK (112 Gb/s) and 16-QAM (224 Gb/s), and 7 Gbaud 64-QAM (84 Gb/s) experiments, it is also demonstrated that M-SSP-PLL + ML can increase the transmission distance by at least 12% compared to BPS for each of them. Finally, the computational complexity is discussed and a significant reduction is shown for our algorithm with respect to BPS. PMID- 23038600 TI - Amplifier-free slab-coupled optical waveguide optoelectronic oscillator systems. AB - We demonstrate a free-running 3-GHz slab-coupled optical waveguide (SCOW) optoelectronic oscillator (OEO) with low phase-noise (<-120 dBc/Hz at 1-kHz offset) and ultra-low sidemode spurs. These sidemodes are indistinguishable from noise on a spectrum analyzer measurement (>88 dB down from carrier). The SCOW-OEO uses high-power low-noise SCOW components in a single-loop cavity employing 1.5 km delay. The noise properties of our SCOW external-cavity laser (SCOWECL) and SCOW photodiode (SCOWPD) are characterized and shown to be suitable for generation of high spectral purity microwave tones. Through comparisons made with SCOW-OEO topologies employing amplification, we observe the sidemode levels to be degraded by any amplifiers (optical or RF) introduced within the OEO cavity. PMID- 23038603 TI - Pd-PEPPSI-IPent(Cl): a highly effective catalyst for the selective cross-coupling of secondary organozinc reagents. AB - No migration? No problem! A series of new N-heterocyclic carbene based Pd complexes has been created and evaluated in the Negishi cross-coupling of aryl and heteroaryl chlorides, bromides, and triflates with a variety of secondary alkylzinc reagents. The direct elimination product is nearly exclusively formed; in most examples there is no migratory insertion at all. PMID- 23038604 TI - The subspecialty of rhinology: a survey of otolaryngology chairmen. AB - BACKGROUND: The past decade has witnessed the emergence of rhinology as a distinct subspecialty within otolaryngology. A critical evaluation of this process is necessary to define the field and to determine the impact of subspecialization on residency education. METHODS: An Internet-based survey of otolaryngology residency chairmen was performed to query attitudes about the importance of various aspects of rhinologic education including didactics, presence of rhinology faculty, exposure to research, office-based rhinology, and various surgical procedures. A 7-point Likert scale was used to rate responses. RESULTS: A 30.2% response rate was noted for the chairmen survey. From the chairmen's perspective, overall high levels of importance were ascribed to rhinology education and surgical training in otolaryngology residency. Lower scores for importance were noted for basic science research, exposure to office based allergy care, and advanced surgical procedures. High scores were noted for the importance of fellowship training in the professional development of a resident interested in pursuing a career in rhinology. CONCLUSION: Overall high levels of importance were ascribed by the participating chairmen to the importance of rhinology education in residency. As the subspecialty of rhinology continues to develop, the role of the various educational, research and clinical activities will require continued evaluation. PMID- 23038606 TI - Polymer-assisted-deposition: a chemical solution route for a wide range of materials. AB - In this tutorial article, the recent development of polymer assisted deposition (PAD) for the growth of a wide range of materials, in particular in thin films, is reviewed. Specifically, we describe the unique chemistry and processes of PAD for the deposition of metals, metal-oxides, metal-nitrides, metal-carbides, and their derived composites. Many examples are given not only to illustrate the powerfulness of PAD for high quality coatings, but also to give readers an opportunity to evaluate this technique for specific applications. The challenging issues related to PAD, based on the authors' experience, are also discussed in this review article. PMID- 23038605 TI - Endothelial cells stimulate osteogenic differentiation of mesenchymal stem cells on calcium phosphate scaffolds. AB - The interaction of mesenchymal stem cells (MSCs) with endothelium in vivo is significant for regenerative processes in organisms. To design concepts for tissue engineering for bone regeneration based on this interaction, the osteogenic differentiation of human bone marrow-derived MSCs in a co-culture with human dermal microvascular endothelial cells (HDMECs) was studied. The experiments were focussed on the regulation of MSCs in a co-culture with HDMECs on different calcium phosphate scaffolds. Alkaline phosphatase (ALP) activity and mRNA expression of various osteogenic markers increased significantly when cells were co-cultured on materials with calcium phosphate scaffolds compared to tissue culture polystyrene or when MSCs were cultured alone. In addition, it was observed that the expression of osteopontin and osteocalcin was highly sensitive to the substrate for cell adhesion. Whereas these late osteogenic markers were down-regulated in co-cultures on polystyrene, they were up-regulated on calcium phosphate and moreover, were differentially expressed on the three calcium phosphate scaffolds tested. To enhance the osteogenic differentiation of MSCs in a co-culture, direct cell-cell interactions were required. Concerning molecular mechanisms in the interactions between both cell types, it was found that connexin 43 was expressed in contact sites and more apparently, endothelial cells grew over the MSCs, which facilitated direct cellular interactions mediated by various adhesion receptors. This study revealed significant findings for the design of implant materials suitable for regeneration of bone by stimulating the functional interaction of MSCs with endothelial cells. PMID- 23038607 TI - Influence of preoperative intravitreal bevacizumab on visual function in eyes with proliferative diabetic retinopathy. AB - PURPOSE: Although bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is effective in treating ocular neovascularization, there are some concerns about whether blocking VEGF might be harmful to retinal neurons. The purpose of this study was to evaluate the effects of preoperative intravitreal bevacizumab (IVB) on the visual function of eyes with proliferative diabetic retinopathy (PDR). METHODS: Thirty eyes of 23 patients (13 men and 10 women) with PDR who were treated at the Nagoya University Hospital from November 2006 to October 2009 were studied. All of the eyes were treated with 1.25 mg/0.05 ml of IVB 2-8 days before the vitrectomy. The protocol was approved by the Institutional Review Board of Nagoya University, and a written informed consent was obtained from each patient. All of the eyes had an active proliferative membrane with vitreous hemorrhage, but the fundus was visible. The mean age of the patients was 41.6 +/- 10 years (range, 27-59), and the mean follow-up period was 9.7 +/- 8.9 months (range, 1-24) after the vitrectomy. The visual acuity (VA) was measured, the visual fields were determined by Goldmann perimetery, and full-field electroretinograms (ERGs) were recorded before IVB, and before and after the vitrectomy. Fluorescein angiography was also performed before and after IVB. The area of the visual field was measured using a computer software (Scion Image). RESULTS: All eyes showed a regression of the new vessels and a reduction of fluorescent leakage from the new vessels after IVB. In addition, there was less bleeding during the removal of the proliferative membrane. The average VA was improved postoperatively from 20/250 to 20/70. However, there was no significant change in the amplitudes of the a- (from 261.4 to 259.2 uV) and b-waves (from 256.9 to 253.3 uV) of the ERGs, and there was no significant change in the visual field area after the surgery (from 8,322.5 to 7,496.3 degrees(2)). No significant ocular or systemic adverse events were observed. CONCLUSION: IVB-assisted vitrectomy led to an improvement of the VA in eyes with PDR without significant adverse events. There was no change in the visual fields and ERGs. Although only a small number of patients were studied, we conclude that IVB is most likely not harmful to retinal neurons if bevacizumab is washed out in less than 1 week. In addition, preoperative IVB made the surgery much easier by decreasing the activity of new vessels. PMID- 23038608 TI - Diagnosing and managing postherpetic neuralgia. AB - Postherpetic neuralgia (PHN) represents a potentially debilitating and often undertreated form of neuropathic pain that disproportionately affects vulnerable populations, including the elderly and the immunocompromised. Varicella zoster infection is almost universally prevalent, making prevention of acute herpes zoster (AHZ) infection and prompt diagnosis and aggressive management of PHN of critical importance. Despite the recent development of a herpes zoster vaccine, prevention of AHZ is not yet widespread or discussed in PHN treatment guidelines. Diagnosis of PHN requires consideration of recognized PHN signs and known risk factors, including advanced age, severe prodromal pain, severe rash, and AHZ location on the trigeminal dermatomes or brachial plexus. PHN pain is typically localized, unilateral and chronic, but may be constant, intermittent, spontaneous and/or evoked. PHN is likely to interfere with sleep and daily activities. First line therapies for PHN include tricyclic antidepressants, gabapentin and pregabalin, and the lidocaine 5 % patch. Second-line therapies include strong and weak opioids and topical capsaicin cream or 8 % patch. Tricyclic antidepressants, gabapentinoids and strong opioids are effective but are also associated with systemic adverse events that may limit their use in many patients, most notably those with significant medical comorbidities or advanced age. Of the topical therapies, the topical lidocaine 5 % patch has proven more effective than capsaicin cream or 8 % patch and has a more rapid onset of action than the other first-line therapies or capsaicin. Given the low systemic drug exposure, adverse events with topical therapies are generally limited to application-site reactions, which are typically mild and transient with lidocaine 5 % patch, but may involve treatment-limiting discomfort with capsaicin cream or 8 % patch. Based on available clinical data, clinicians should consider administering the herpes zoster vaccine to all patients aged 60 years and older. Clinicians treating patients with PHN may consider a trial of lidocaine 5 % patch monotherapy before resorting to a systemic therapy, or alternatively, may consider administering the lidocaine 5 % patch in combination with a tricyclic antidepressant or a gabapentinoid to provide more rapid analgesic response and lower the dose requirement of systemic therapies. PMID- 23038609 TI - Aflibercept for intravitreal injection: in neovascular age-related macular degeneration. AB - Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF) family members VEGF-A, VEGF-B and placental growth factor, thereby preventing these ligands from binding to, and activating, their cognate receptors. The efficacy of intravitreal aflibercept in the treatment of wet (neovascular) age-related macular degeneration has been compared with that of intravitreal ranibizumab, the current gold standard for this indication, in two pivotal phase III studies of virtually identical design (VIEW 1 and 2). In both trials, the recommended regimen of aflibercept [2 mg every second month (after three initial monthly doses)] was shown to be noninferior to the recommended regimen of ranibizumab (0.5 mg every month) in terms of the primary endpoint of the proportion of patients who maintained their vision after 1 year of treatment; similar results were seen when monthly dosing with aflibercept (0.5 or 2 mg) was compared with ranibizumab. Over a period of 96 weeks in the VIEW studies, patients receiving the recommended regimen of aflibercept during the first year followed by modified quarterly treatment during the second year had a similar visual acuity gain to those receiving the recommended regimen of ranibizumab during first year followed by modified quarterly treatment during the second year, but on average required five fewer injections. Aflibercept was generally well tolerated in the VIEW studies; the ocular and non-ocular adverse event profile of the drug was similar to that of ranibizumab. PMID- 23038610 TI - Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed): a guide to its use in older adults. AB - Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) (PCV13; Prevenar 13((r)); Prevnar 13((r))) is approved in adults aged >=50 years (focus of review) and in children aged 6 weeks to 5 years for protection against pneumococcal diseases caused by Streptococcus pneumoniae in numerous countries worldwide, including the US and those in the EU; specific indications may vary between individual countries. Polysaccharide conjugated vaccines such as PCV13 may have an immunological advantage over unconjugated vaccines [e.g. 23-valent pneumococcal polysaccharide vaccine (PPV23)], since immunization with conjugated vaccines results in the development of T-cell-dependent immune responses, whereas unconjugated vaccines do not lead to booster responses on revaccination. In clinical trials in adults aged >=50 years, PCV13 elicited a functional immune response and, overall, was shown to be noninferior to PPV23 for all 12 serotypes common to the two vaccines. Furthermore, PCV13 elicited significantly greater functional immune responses than PPV23 for the majority of serotypes common to both vaccines. PCV13 administered concomitantly with trivalent inactivated influenza vaccine generally produced antibody responses that were noninferior to those following sequential administration of the vaccines. The PCV13 vaccine was generally well tolerated in older adults participating in these trials. PMID- 23038611 TI - Bilateral subthalamic nucleus stimulation for generalized dystonia after bilateral pallidotomy. AB - BACKGROUND: Thalamotomies and pallidotomies were commonly performed before the deep brain stimulation (DBS) era. Although ablative procedures can lead to significant dystonia improvement, longer periods of analysis reveal disease progression and functional deterioration. Today, the same patients seek additional treatment possibilities. METHODS: Four patients with generalized dystonia who previously had undergone bilateral pallidotomy came to our service seeking additional treatment because of dystonic symptom progression. Bilateral subthalamic nucleus DBS (B-STN-DBS) was the treatment of choice. The patients were evaluated with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Dystonia Rating Scale (UDRS) before and 2 years after surgery. RESULTS: All patients showed significant functional improvement, averaging 65.3% in BFMDRS (P = .014) and 69.2% in UDRS (P = .025). CONCLUSIONS: These results suggest that B-STN-DBS may be an interesting treatment option for generalized dystonia, even for patients who have already undergone bilateral pallidotomy. PMID- 23038612 TI - Automatic joint alignment measurements in pre- and post-operative long leg standing radiographs. AB - OBJECTIVES: For diagnosis or treatment assessment of knee joint osteoarthritis it is required to measure bone morphometry from radiographic images. We propose a method for automatic measurement of joint alignment from pre-operative as well as post-operative radiographs. METHODS: In a two step approach we first detect and segment any implants or other artificial objects within the image. We exploit physical characteristics and avoid prior shape information to cope with the vast amount of implant types. Subsequently, we exploit the implant delineations to adapt the initialization and adaptation phase of a dedicated bone segmentation scheme using deformable template models. Implant and bone contours are fused to derive the final joint segmentation and thus the alignment measurements. RESULTS: We evaluated our method on clinical long leg radiographs and compared both the initialization rate, corresponding to the number of images successfully processed by the proposed algorithm, and the accuracy of the alignment measurement. Ground truth has been generated by an experienced orthopedic surgeon. For comparison a second reader reevaluated the measurements. Experiments on two sets of 70 and 120 digital radiographs show that 92% of the joints could be processed automatically and the derived measurements of the automatic method are comparable to a human reader for pre-operative as well as post-operative images with a typical error of 0.7 degrees and correlations of r = 0.82 to r = 0.99 with the ground truth. CONCLUSIONS: The proposed method allows deriving objective measures of joint alignment from clinical radiographs. Its accuracy and precision are on par with a human reader for all evaluated measurements. PMID- 23038616 TI - Palladium-catalyzed dehydrogenation/oxidative cross-coupling sequence of beta heteroatom-substituted ketones. AB - Concise and selective: the title one-pot sequence allows formation of the enone functionality and subsequent cross-coupling. The process provides access to highly functionalized cyclic enolones and enaminones from readily accessible beta heteroatom-substituted cyclic ketones. PMID- 23038613 TI - Positive correlation between PEDF expression levels and macrophage density in the human prostate. AB - BACKGROUND: In this study, we investigated the capacity of pigment epithelium derived factor (PEDF) to modulate the recruitment and the differentiation of monocytes/macrophages both in vitro and in human prostate. METHODS: Using Boyden chambers, we assessed PEDF effect on the migration of monocytes and chemically activated RAW 264.7 macrophages. Normal, prostatitis, and prostate cancer specimens were retrospectively selected and examined by immunohistochemistry for PEDF expression and infiltration of immune CD68 + macrophagic cells. PEDF expression and macrophage density were then correlated with each other and clinicopathological parameters. M1 and M2 differentiation markers were quantified by qRT-PCR, Western blotting, and ELISA. RESULTS: In chemotaxis, PEDF induced the migration of monocytes/macrophages. In immunohistochemistry, macrophages were markedly increased in prostatitis and malignant compared to normal tissues. PEDF was expressed at variable levels in the stroma and epithelium. PEDF mRNA was down regulated in both prostate cancer and prostatitis compared to normal tissues. In correlation studies, macrophage density and PEDF expression were respectively positively and negatively associated with prostate size. Most importantly, PEDF expression positively correlated with macrophage density. Finally, PEDF stimulated the expression of iNOS, IL12, and TNFalpha; and inhibited IL10 and arginase 1 in mouse and human macrophages confirming a M1-type differentiation. CONCLUSIONS: Our data demonstrate that PEDF acts directly on monocytes/macrophages by inducing their migration and differentiation into M1 type cells. These findings suggest a possible role of macrophages in PEDF anti tumor properties and may support further development of PEDF-based anti-cancer therapy. PMID- 23038615 TI - Inhibition of bladder cancer by broccoli isothiocyanates sulforaphane and erucin: characterization, metabolism, and interconversion. AB - SCOPE: Epidemiologic evidence suggests diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Our objectives are to investigate these observations and determine the role of isothiocyanates in primary or secondary bladder cancer prevention. METHODS AND RESULTS: We initially investigate the mechanisms whereby broccoli and broccoli sprout extracts and pure isothiocyanates inhibit normal, noninvasive (RT4), and invasive (J82, UMUC3) human urothelial cell viability. Sulforaphane (IC(50) = 5.66 +/- 1.2 MUM) and erucin (IC(50) = 8.79 +/- 1.3 MUM) are found to be the most potent inhibitors and normal cells are least sensitive. This observation is associated with downregulation of survivin, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/neu), G(2) /M cell cycle accumulation, and apoptosis. In a murine UMUC3 xenograft model, we fed semipurified diets containing 4% broccoli sprouts, or 2% broccoli sprout isothiocyanate extract; or gavaged pure sulforaphane or erucin (each at 295 MUmol/kg, similar to dietary exposure); and report tumor weight reduction of 42% (p = 0.02), 42% (p = 0.04), 33% (p = 0.04), and 58% (p < 0.0001), respectively. Sulforaphane and erucin metabolites are present in mouse plasma (micromolar range) and tumor tissue, with N-acetylcysteine conjugates as the most abundant. Interconversion of sulforaphane and erucin metabolites was observed. CONCLUSION: This work supports development of fully characterized, novel food products containing broccoli components for phase I/II human studies targeting bladder cancer prevention. PMID- 23038617 TI - Evidence-based recommendations for spine surgery. PMID- 23038619 TI - Biomechanical comparison of spinopelvic reconstruction techniques in the setting of total sacrectomy. AB - STUDY DESIGN: An in vitro biomechanical study. OBJECTIVE: To biomechanically test and evaluate 4 different methods of spinopelvic reconstruction techniques and determine the most biomechanically stable construct for stabilization of the spinopelvic junction after total sacrectomy. SUMMARY OF BACKGROUND DATA: Total sacrectomy is necessary to treat a sacral tumor when it involves the S1 vertebra. Instrumentation and reconstruction of the lumbar spine and pelvis are required after total sacrectomy and can be achieved by various reconstruction techniques. Currently, the preferred method of spinopelvic fixation is controversial. METHODS: Seven human cadaveric (L1-pelvis) specimens were evaluated in flexion extension, lateral bending, and axial rotation in a total sacrectomy model. Test constructs included (1) intact; (2) double-rod, double iliac screw (DDS); (3) single-rod, single iliac screw (SSS); (4) double iliac screw (DIS) fixation; and (5) modified Galveston technique (MGT). A load control protocol with 7.0 Nm moments applied at a rate of 1.5 degrees /s was used to establish range of motion values for each tested construct on a 6-df spine motion simulator. Data were analyzed and normalized to intact. RESULTS: All instrumented constructs offered significant stability in all loading conditions compared with the intact condition. Stability offered by different constructs in all loading conditions trended as follows: DDS>DIS>SSS>MGT. Overall, the DDS construct provided 55%, 43%, and 60% more stability than SSS, DIS, and MGT, respectively. This was significant in flexion-extension when compared with SSS and in all loading conditions when compared with MGT. CONCLUSION: In the setting of total sacrectomy, the double-rod double iliac screw method provided the most rigid fixation, followed by DIS fixation, single-rod single screw, and the MGT. In spinopelvic reconstruction, the use of double iliac screws is recommended compared with single iliac screw fixation techniques when treating unstable conditions caused by total sacrectomy. PMID- 23038620 TI - Cervical spine research society 39th annual meeting presidential address: the power of technology, December 9, 2011, Scottsdale, Arizona. PMID- 23038618 TI - A replication study for association of 5 single nucleotide polymorphisms with curve progression of adolescent idiopathic scoliosis in Japanese patients. AB - STUDY DESIGN: A genetic association study of single nucleotide polymorphisms (SNPs) previously reported to be associated with curve progression of adolescent idiopathic scoliosis (AIS). OBJECTIVE: To determine whether the association of 5 SNPs with curve progression reported in Chinese with AIS are replicated in Japanese patients with AIS. SUMMARY OF BACKGROUND DATA: AIS is a common spinal deformity and has a strong genetic predisposition. Predicting curve progression is important in clinical practice. The progression of AIS is reported to be associated with a number of genes. Associations with neurotrophin 3, G protein coupled estrogen receptor, and tissue inhibitor of metalloproteinase 2 have been reported in Han Chinese with AIS; however, there has been no replication study for them. METHODS: We recruited 2117 patients with AIS with a Cobb angle of 10 degrees or greater of scoliosis curves. They were grouped into progression and nonprogression groups according to their scoliosis curves. Patients whose scoliotic curves were 40 degrees or greater were included in the progression group, and those whose scoliotic curves were less than 30 degrees and had reached skeletal maturation in the nonprogression group. We evaluated the association of 5 SNPs (rs11063714 in neurotrophin 3, rs3808351, rs10269151, and rs4266553 in G protein-coupled estrogen receptor, and rs8179090 in tissue inhibitor of metalloproteinase 2 with curve progression by comparing risk allele frequencies between the 2 groups and the mean Cobb angle for each genotype. RESULTS: We evaluated the progression (N = 880) and nonprogression (N = 492) subjects, and their risk allele frequencies were not significantly different. The mean Cobb angle for each genotype also did not have statistical difference. We found no replication of the association on AIS curve progression in any of the SNPs. CONCLUSION: The associations of the 5 SNPs with progression of AIS curve are not definite. Large-scale association studies based on appropriate criteria for progression would be necessary to identify SNPs associated with the curve progression. PMID- 23038621 TI - Costs associated with treatment of chronic low back pain: an analysis of the UK General Practice Research Database. AB - STUDY DESIGN: Retrospective cohort study of health care costs associated with the treatment of chronic low back pain (CLBP) in the United Kingdom. OBJECTIVE: To assess 12-month health care costs associated with the treatment of CLBP, using the UK General Practice Research Database. SUMMARY OF BACKGROUND DATA: CLBP is a common health problem. METHODS: Data were obtained from the General Practice Research Database, a computerized database of UK primary care patient data. Patients with CLBP were identified for the study period (January 1, 2007, to December 31, 2009) using diagnostic records and pain relief prescriptions (n = 64,167), and 1:1 matched to patients without CLBP (n = 52,986) on the basis of age, sex, and general practitioner's practice. Index date was defined as the first date of CLBP record; the same index date was assigned to matched controls. Multivariate analyses were performed to compare resource use costs (2009 values) in the 12 months after the index date between patients with and without CLBP. A sensitivity analysis was carried out with a more stringent definition for the control group by excluding a broad range of pain conditions. RESULTS: Total health care costs for patients with CLBP were double those of the matched controls (L1074 vs. L516; P < 0.05). Of the cost difference, 58.8% was accounted for by general practitioner's consultations, 22.3% by referrals to secondary care, and the rest by pain relief medications. The sensitivity analysis revealed an even greater cost difference between the 2 groups (L1052 vs. L304; P < 0.05). Because of the use of a retrospective administrative claims database, this study is subject to selection bias between study cohorts, misidentification of comorbidities, and an inability to confirm adherence to therapy or assess indirect costs and costs of over-the-counter medications. CONCLUSION: Our findings confirm the substantial economic burden of CLBP, even with direct costs only. PMID- 23038622 TI - Validation of the Arabic version of the Quebec Back Pain Disability Scale. AB - STUDY DESIGN: Validity and reliability of a back pain questionnaire. OBJECTIVE: This study tested the psychometric properties of the Arabic version of the Quebec Back Pain Disability Scale (QDS). SUMMARY OF BACKGROUND DATA: QDS is a questionnaire widely used to evaluate the level of disability in patients with low back pain. The questionnaire has been translated into Arabic but not tested in an Arabic population. METHODS: A total of 148 patients with nonspecific low back pain were recruited in the Gaza Strip. Patients were asked to complete a questionnaire booklet containing the Arabic version of the QDS, the Oswestry Disability Index (ODI), the Numeric Pain Rating Scale (NPRS), and a Likert scale, which was repeated 1 week later. Weighted kappa was used to measure test-retest reliability and Cronbach alpha for internal consistency. For construct validity, the Arabic version of the QDS and the ODI were correlated with Spearman correlation coefficient. For concurrent validity, the QDS, ODI, and NPRS were compared. For face and content validity, a Likert scale was used to assess whether it was understandable and comprehensive. RESULTS: The QDS demonstrated good test-retest reliability kappa = 0.86-0.98 (P < 0.001). Correlation between the items was excellent Cronbach alpha = 0.92; item-total correlation was good = 0.84-0.86. A positive relationship was found between Arabic versions of QDS, ODI, and NPRS, indicating adequate construct validity (P = 0.69, P < 0.01). A positive relationship was found between Arabic versions of QDS and ODI (r = 0.67, P < 0.01) and the NPRS (r = 0.61, P < 0.01). Face validity and content validity were deemed to be reasonable. CONCLUSION: The study showed that the psychometric properties of the original QDS have been preserved when translated into Arabic and can be used to measure disability in Arabic societies. PMID- 23038623 TI - Click and pick: identification of sialoside analogues for siglec-based cell targeting. AB - Click 'n' chips: Azide and alkyne-bearing sialic acids (purple diamond; see picture) were subjected to high-throughput click chemistry to generate a library of sialic acid analogues. Microarray printing of the library and screening with the siglec family of sialic-acid-binding proteins, led to the identification of high-affinity ligands for siglec-9 and siglec-10. PMID- 23038624 TI - Prednisolone reduces the ability of serum to activate the IGF1 receptor in vitro without affecting circulating total or free IGF1. AB - OBJECTIVE: End-point bioassays based on thymidine or sulfate incorporation have demonstrated that glucocorticoid (GC) treatment inhibits serum IGF1 action, but the mechanism is unknown as serum IGF1 concentrations have been reported to either increase or remain unchanged. AIM: To investigate whether GC treatment affects the ability of serum to activate the IGF1 receptor (IGF1R) in vitro (i.e. bioactive IGF1), using a specific cell-based IGF1 kinase receptor activation assay. SUBJECTS AND METHODS: Twenty children with stable asthma (age 7.7-13.8 years) treated for 1 week with 5 mg prednisolone in a randomized, double-blind, placebo-controlled crossover study. Non-fasting serum samples were collected in the afternoon after each 7-day period and assayed for bioactive IGF1, free IGF1, total IGFs, IGF-binding proteins (IGFBPs), and insulin. RESULTS: Prednisolone treatment reduced IGF1 bioactivity by 12.6% from 2.22+/-0.18 to 1.94+/-0.15 MUg/l (P=0.01) compared with placebo. In contrast, no changes were observed for (MUg/l; placebo vs prednisolone) total IGF1 (215+/-27 vs 212+/-24), free IGF1 (1.50+/ 0.16 vs 1.43+/-0.17), total IGF2 (815+/-26 vs 800+/-31), IGFBP3 (3140+/-101 vs 3107+/-95), IGFBP2 (238+/-21 vs 220+/-19), IGFBP1 (32+/-6 vs 42+/-10), or IGFBP1 bound IGF1 (24+/-5 vs 26+/-7). Insulin remained unchanged as did IGFBP levels as estimated by western ligand blotting. Prednisolone had no direct effects on IGF1R phosphorylation. CONCLUSIONS: Our study gives evidence that GC treatment induces a circulating substance that is able to inhibit IGF1R activation in vitro without affecting circulating free or total IGF1. This may be one of the mechanisms by which GC inhibits IGF1 action in vivo. However, the nature of this circulating substance remains to be identified. PMID- 23038625 TI - Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. AB - OBJECTIVE: Most cases of familial isolated pituitary adenomas with mutated aryl hydrocarbon receptor-interacting protein (AIP:HGNC:358) gene develop somatotropinomas. They are characterised by an aggressive clinical phenotype including early age at diagnosis, large tumours and frequent invasiveness. There is little information on AIP gene mutations' prevalence in isolated somatotropinomas characterised by poor response to somatostatin analogue treatment. The aim of this study was to investigate the prevalence of AIP mutations in non-familial cases of somatotropinomas with poor response to conventional treatment. DESIGN AND METHODS: Fifty patients with acromegaly (22 males/28 females, age 51+/-18 years) and 60 controls were included in this study performed at eight University Hospitals in Spain. None had family history of pituitary adenomas or other endocrine tumors. All patients failed to respond to conventional treatment including surgery and somatostatin analogues. Some patients received adjuvant radiotherapy and most cases required pegvisomant (PEG) treatment for normalisation of IGF1. AIP analysis was performed in DNA extracted from peripheral leucocytes, using standardised PCR protocol in which the coding regions of exons 1, 2, 3, 4, 5 and 6 were amplified. Possible deletions/duplications were studied using multiplex ligation-dependent probe amplification. RESULTS: SEQUENCE CHANGES OF POTENTIAL DIFFERENT SIGNIFICANCE THAT COULD BE CONSIDERED AS MUTATIONS OR VARIATIONS OF UNKNOWN SIGNIFICANCE (VUS) OF THE AIP GENE WERE FOUND IN FOUR PATIENTS (8%). IN TWO CASES, TWO DIFFERENT MUTATIONS PREVIOUSLY DESCRIBED WERE FOUND: p.Arg9Gln and p.Phe269Phe. Two other VUS were also found: c.787+24C>T in intron 5 and c.100-18C>T in intron 1. Age at diagnosis ranged from 21 to 50 years old, and in all patients, the tumor was a macroadenoma depicting IGF1 normalisation under PEG treatment. CONCLUSIONS: AIP germline mutations show a low, but non-negligible, prevalence in non-familial acromegaly patients with tumors resistant to treatment with somatostatin analogues. PMID- 23038626 TI - Triple-layer reconstruction technique for large cribriform defects after endoscopic endonasal resection of anterior skull base tumors. AB - BACKGROUND: Endoscopic endonasal transcribriform (EET) resection of anterior skull base (ASB) tumors results in large defects that may extend the entirety of the cribriform plate. Endoscopic repair of these cribriform defects can often be challenging. We describe our reconstruction technique for large ASB defects after EET resection of ASB tumors. This triple-layer technique is comprised of autologous fascia lata, acellular dermal allograft, and a vascularized pedicled nasoseptal flap (PNSF). The technique is described and postoperative cerebrospinal fluid (CSF) leak rate is evaluated. METHODS: Retrospective review over a 2-year period identified 10 patients who underwent a purely EET approach for resection of ASB tumors. Patients who underwent combined cranionasal approaches and those treated for ASB encephaloceles were excluded from this study. After tumor resection, patients underwent triple-layer reconstruction using autologous fascia lata inlay, acellular dermal allograft inlay/overlay, followed by a PNSF to reconstruct the cribriform defect. No postoperative lumbar drainage was used. RESULTS: The average cribriform defect size was 9.1 (range, 5.0-13.8) cm(2) . All 10 patients underwent successful reconstruction with a postoperative CSF leak rate of 0% without the use of postoperative lumbar drainage. The mean follow-up period was 7.4 (range, 2-17) months. The mean age was 45.8 (range, 15-81) years with 30% of the patients being females. CONCLUSION: The triple-layer reconstruction technique is effective in reconstructing large ASB defects after endoscopic resection of the cribriform plate. We feel that the use of postoperative lumbar drainage is not necessary when using this repair technique. PMID- 23038627 TI - Caveolin 1 expression correlates with poor prognosis and focal adhesion kinase expression in gastric cancer. AB - OBJECTIVE: Caveolin 1 gene is known as a tumor promoter or suppressor, depending on the tumor type and/or tumor stage. We aimed to investigate the clinical significance of caveolin 1 protein (Cav1) expression in gastric cancer (GC). METHODS: Immunohistochemistry was performed on tissue array slides containing 405 GC specimens. The relationships between Cav1 expression and clinicopathological factors, prognosis, focal adhesion kinase expression, mucin phenotypes and p53 expression were analyzed. RESULTS: In non-neoplastic gastric mucosa, Cav1 was not expressed in the epithelial compartment. In GC, positive staining of Cav1 was shown in 22 (5.4%) of 405 cases and was significantly higher in the advanced GC group than in the early GC group (p = 0.037). Also, it was significantly associated with advanced pTNM stage (p = 0.027) and lymph node metastasis (p = 0.018). Moreover, survival analysis showed that Cav1 expression was an independent prognostic factor of poor survival (p = 0.028). In addition, the expression of Cav1 was positively correlated with that of focal adhesion kinase (p = 0.034). CONCLUSIONS: These results indicate that the expression of Cav1 is significantly correlated with cancer progression and poor prognosis in GC. Thus, Cav1 could supplement its protein expression for the diagnosis and treatment of GC. PMID- 23038628 TI - Evaluation of decellularized human umbilical vein (HUV) for vascular tissue engineering - comparison with endothelium-denuded HUV. AB - Human umbilical vessels have been recognized as a valuable and widely available resource for vascular tissue engineering. Whereas endothelium-denuded human umbilical veins (HUVs) have been successfully seeded with a patient-derived neoendothelium, decellularized vessels may have additional advantages, due to their lower antigenicity. The present study investigated the effects of three different decellularization procedures on the histological, mechanical and seeding properties of HUVs. Vessels were decellularized by detergent treatment (Triton X-100, sodium deoxycholate, IGEPAL-CA630), osmotic lysis (3 m NaCl, distilled water) and peroxyacetic acid treatment. In all cases, nuclease treatments were required to remove residual nucleic acids. Decellularization resulted in a partial loss of fibronectin and laminin staining in the subendothelial layer and affected the appearance of elastic fibres. In addition to removing residual nucleic acids, nuclease treatment weakened all stainings and substantially altered surface properties, as seen in scanning electron micrographs, indicating additional non-specific effects. Detergent treatment and osmotic lysis caused failure stresses to decrease significantly. Although conditioned medium prepared from decellularized HUV did not severely affect endothelial cell growth, cells seeded on decellularized HUV did not remain viable. This may be attributed to the partial removal of essential extracellular matrix components as well as to changes of surface properties. Therefore, decellularized HUVs appear to require additional modifications in order to support successful cell seeding. Replacing the vessels' endothelium may thus be a superior alternative to decellularization when creating tissue-engineered blood vessels with non-immunogenic luminal interfaces. PMID- 23038629 TI - Locus coeruleus neuron density and parkinsonism in older adults without Parkinson's disease. AB - Previous work has showed that nigral neuron density is related to the severity of parkinsonism proximate to death in older persons without a clinical diagnosis of Parkinson's disease (PD). We tested the hypothesis that neuron density in other brain stem aminergic nuclei is also related to the severity of parkinsonism. We studied brain autopsies from 125 deceased older adults without PD enrolled in the Memory and Aging Project, a clinicopathologic investigation. Parkinsonism was assessed with a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). We measured neuron density in the substantia nigra, ventral tegmental area, locus coeruleus, and dorsal raphe, along with postmortem indices of Lewy body disease, Alzheimer's disease and cerebrovascular pathologies. Mean age at death was 88.0 years, and global parkinsonism was 14.8 (SD, 9.50). In a series of regression models that controlled for demographics and neuron density in the substantia nigra, neuron density in the locus coeruleus (estimate, -0.261; SE, 0.117; P = .028) but not in the ventral tegmental area or dorsal raphe was associated with severity of global parkinsonism proximate to death. These findings were unchanged in models that controlled for postmortem interval, whole brain weight, and other common neuropathologies including Alzheimer's disease and Lewy body pathology and cerebrovascular vascular pathologies. In older adults without a clinical diagnosis of PD, neuron density in locus coeruleus nuclei is associated with the severity of parkinsonism and may contribute to late-life motor impairments. PMID- 23038630 TI - Maternal supplementation with an excess of different fat sources during pregnancy and lactation differentially affects feeding behavior in offspring: putative role of the leptin system. AB - SCOPE: This study investigates the lasting effects of maternal supplementation with different fat sources during pregnancy and lactation on feeding behavior and energy homeostasis of their offspring, and its relation to hypothetical effects in the development of main central structures involved in leptin signaling. METHODS AND RESULTS: Offspring of dams supplemented with olive oil, butter, or margarine during late pregnancy and lactation were fed with normal fat (NF) diet until 4-month-old, and then with NF or high fat (HF) diet until 6-month-old. Results showed that 21-day-old margarine group pups presented a higher cell number in the arcuate nucleus (ARC) (females) and higher hypothalamic ObRb/SOCS3 mRNA ratio (males). In adulthood, and under HF diet, they displayed a lower body weight (both genders) and body fat (males) than the butter group, a lower preference for fat food (both genders), and lower leptin levels than the olive oil (both genders) and butter (males) groups. CONCLUSIONS: Maternal supplementation with different fat sources during the perinatal period may affect the development of hypothalamic structures and hence predisposition to obesity. Margarine, compared with other fats, may program the offspring for increased leptin sensitivity and a lower preference for fat food, thus providing relative protection against body weight gain in adulthood, particularly under an obesogenic environment. PMID- 23038631 TI - Histopathologic detection of rejection in acute allograft pyelonephritis. PMID- 23038632 TI - Self-kidney transplantation in Takayasu arteritis. PMID- 23038633 TI - Normalized NEFA dynamics during an OGTT after islet transplantation. PMID- 23038634 TI - Donor morbidity including biliary complications in living-donor liver transplantation: a single center analysis of 283 cases. PMID- 23038636 TI - Dual-energy CT-based assessment of the trabecular bone in vertebrae. AB - BACKGROUND: Osteoporosis can cause severe fractures of bone structures. One important indicator for pathology is a lowered bone mineral density (BMD) - conventionally assessed by dual-energy X-ray absorptiometry (DXA). Dual-energy CT (DECT) - being an alternative that is increasingly used in the clinics - allows the computation of the spatial BMD distribution. OBJECTIVES: Using DECT, the trabecular bone of vertebrae is examined. Several analysis methods for revealing the bone density distribution as well as appropriate visualization methods for detecting regions of lowered BMD are needed for computer-assisted diagnosis (CAD) of osteoporosis. The hypothesis that DECT is better suited than DXA for the computation of local BMD is investigated. METHODS: Building on a model of the interaction of X-rays with bone tissue, novel methods for assessing the spatial structure of the trabecular bone are presented. CAD of DECT image data is facilitated by segmenting the regions of interest interactively and with an Active Shape Model, respectively. The barycentric space of fractional volumes is introduced as a novel means for analyzing bone constitution. For 29 cadaver specimens, DECT as well as DXA has been examined. BMD values derived from both modalities are compared to local force measurements. In addition, clinical data from two patients who underwent DECT scanning for a different reason is analyzed retrospectively. RESULTS: A novel automated delineation method for vertebrae has been successfully applied to DECT data sets. It is shown that localized BMD measurements based on DECT show a stronger linear correlation (R2 = 0.8242, linear regression) to local force measurements than density values derived from DXA (R2 = 0.4815). CONCLUSIONS: DECT based BMD assessment is a method to extend the usage of increasingly acquired DECT image data. The developed DECT based analysis methods in conjunction with the visualization provide more detailed information for both, the radiologist and the orthopedist, compared to standard DXA based analysis. PMID- 23038639 TI - Differential expression of VEGF ligands and receptors in prostate cancer. AB - BACKGROUND: Prostate cancer disseminates to regional lymph nodes, however the molecular mechanisms responsible for lymph node metastasis are poorly understood. The vascular endothelial growth factor (VEGF) ligand and receptor family have been implicated in the growth and spread of prostate cancer via activation of the blood vasculature and lymphatic systems. The purpose of this study was to comprehensively examine the expression pattern of VEGF ligands and receptors in the glandular epithelium, stroma, lymphatic vasculature and blood vessels in prostate cancer. METHODS: The localization of VEGF-A, VEGF-C, VEGF-D, VEGF receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 was examined in cancerous and adjacent benign prostate tissue from 52 subjects representing various grades of prostate cancer. RESULTS: Except for VEGFR-2, extensive staining was observed for all ligands and receptors in the prostate specimens. In epithelial cells, VEGF-A and VEGFR-1 expression was higher in tumor tissue compared to benign tissue. VEGF-D and VEGFR-3 expression was significantly higher in benign tissue compared to tumor in the stroma and the endothelium of lymphatic and blood vessels. In addition, the frequency of lymphatic vessels, but not blood vessels, was lower in tumor tissue compared with benign tissue. CONCLUSIONS: These results suggest that activation of VEGFR-1 by VEGF-A within the carcinoma, and activation of lymphatic endothelial cell VEGFR-3 by VEGF-D within the adjacent benign stroma may be important signaling mechanisms involved in the progression and subsequent metastatic spread of prostate cancer. Thus inhibition of these pathways may contribute to therapeutic strategies for the management of prostate cancer. PMID- 23038640 TI - C(3i)-symmetric octanuclear cadmium cages: double-anion-templated synthesis, formation mechanism, and properties. AB - A series of C(3i)-symmetric bicapped trigonal antiprismatic Cd(8) cages [2X@Cd(8)L(6)(H(2)O)(6)]?n Y?solvents (X = Cl(-), Y = NO(3)(-), n = 2: MOCC-4; X = Br(-), Y = NO(3)(-), n = 2: MOCC-5; X = NO(3)(-), Y = NO(3)(-), n = 2: MOCC-6; X = NO(3)(-), Y = BF(4)(-), n = 2: MOCC-7; X = NO(3)(-), Y = ClO(4)(-), n = 2: MOCC-8; X = CO(3)(2-), n = 0: MOCC-9), doubly anion templated by different anions, were solvothermally synthesized by means of a flexible ligand. Interestingly, the CO(3)(2-) template for MOCC-9 was generated in situ by two step decomposition of DMF solvent. For other MOCCs, spherical or trigonal monovalent anions could also play the role of template in their formation. The template abilities of these anions in the formation of the cages were experimentally studied and are discussed for the first time. Anion exchange of MOCC-8 was carried out and showed anion-size selectivity. All of the cage-like compounds emit strong luminescence at room temperature. PMID- 23038641 TI - Synthesis of a trigold monocation: an isolobal analogue of [H3]+. PMID- 23038642 TI - Staphylococcus aureus prevalence in allergic fungal rhinosinusitis vs other subsets of chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: The pathogenesis of allergic fungal rhinosinusitis (AFRS) is thought to represent an immunological reaction to fungal antigens. Recent studies have implicated superantigens and non-immunoglobulin E (IgE)-mediated mechanisms in the development of AFRS. The objective of this study is to assess the prevalence of Staphylococcus aureus in AFRS vs other subsets of chronic rhinosinusitis with polyps (CRSwNP, also termed non-AFRS). METHODS: A case series with retrospective review of 19 patients with AFRS and 21 patients with CRSwNP was performed at a tertiary referral center. The diagnosis of AFRS required the presence of defined criteria described by Bent and Kuhn. Bacterial cultures and fungal cultures were analyzed for each group. RESULTS: S. aureus was significantly more prevalent in the AFRS group compared with the non-AFRS group (63.2% vs 24.1%, p = 0.005). CONCLUSION: S. aureus has been implicated as a disease modifier in CRSwNP through superantigen-mediated mechanisms. This study demonstrates a higher prevalence of S. aureus in patients with AFRS vs patients with other subsets of CRSwNP (non AFRS). These results support a potential role for S. aureus in the pathogenesis of AFRS. PMID- 23038643 TI - Robust helix formation in a new family of oligoureas based on a constrained bicyclic building block. AB - BAC for more: a constrained bicyclic building block with urea linkages is an efficient combination for the formation of a highly rigid helical system. This type of bicyclic amino carbamoyl (BAC) foldamer was studied both in solution and in the solid state. A robust H-bond (dotted line) network was found between the carbonyl oxygen atoms (red) and the amino groups (dark blue) within the helix. PMID- 23038644 TI - Loss of S100A14 expression is associated with the progression of adenocarcinomas of the small intestine. AB - OBJECTIVES: Small intestinal adenocarcinoma (SIAC) is an exceedingly rare human malignant tumor, and its association with the S100A14 gene is not known yet. We aimed to investigate the clinicopathological correlations between S100A14 expression and SIAC. METHODS: Immunohistochemical analyses of S100A14, p21 and p53 were performed using tissue microarray analysis of 175 surgically resected SIACs. RESULTS: Of 175 SIACs, loss of S100A14 expression was observed in 128 cases (73.1%). Loss of S100A14 expression was associated with lymph node metastasis (p = 0.009) and advanced disease stage (p = 0.013), and was more frequently observed in distal than duodenal tumors (p = 0.043). The majority of SIACs lost p21 expression (93.7%), and significant loss of p21 expression was observed in cancers with high pT stages (pT(3) and pT(4); p = 0.011), lymph node metastasis (p = 0.029) and advanced cancer stage defined by the American Joint Committee on Cancer (p = 0.005). Overexpression of p53 was found in 23.4% of cases. Positive expression of p53 was associated with distally located SIACs (jejunum or ileum; p = 0.006). There was no association between the expression of S100A14 and p21 or p53. CONCLUSION: Loss of S100A14 in SIAC is common and is associated with higher metastatic potential and advanced clinical stage. PMID- 23038645 TI - The neurobiology and neural circuitry of cognitive changes in Parkinson's disease revealed by functional neuroimaging. AB - Patients with Parkinson's disease (PD) often develop a spectrum of cognitive symptoms that can evolve into dementia. Dopamine (DA) replacement medications, though improving motor symptoms, can exert both positive and negative effects on cognitive ability, depending on the severity of the disease and the specific skill being tested. By considering the behavioral and clinical aspects of disease and treatment-mediated changes in cognition alongside the pathophysiology of PD, an understanding of the factors that govern the heterogeneous expression of cognitive impairment in PD is beginning to emerge. Here, we review the neuroimaging studies revealing the neural correlates of cognitive changes after DA loss and DA replacement as well as those that may accompany the conversion from milder stages of cognitive impairment to frank dementia. PMID- 23038646 TI - Inhibition of starch digestion by the green tea polyphenol, (-)-epigallocatechin 3-gallate. AB - SCOPE: Green tea has been shown to ameliorate symptoms of metabolic syndrome in vivo. The effects could be due, in part, to modulation of postprandial blood glucose levels. METHODS AND RESULTS: We examined the effect of coadministration of (-)-epigallocatechin-3-gallate (EGCG, 100 mg/kg, i.g.) on blood glucose levels following oral administration of common corn starch (CCS), maltose, sucrose, or glucose to fasted CF-1 mice. We found that cotreatment with EGCG significantly reduced postprandial blood glucose levels after administration of CCS compared to control mice (50 and 20% reduction in peak blood glucose levels and blood glucose area under the curve, respectively). EGCG had no effect on postprandial blood glucose following administration of maltose or glucose, suggesting that EGCG may modulate amylase-mediated starch digestion. In vitro, EGCG noncompetitively inhibited pancreatic amylase activity by 34% at 20 MUM. No significant change was induced in the expression of two small intestinal glucose transporters (GLUT2 and SGLT1). CONCLUSIONS: Our results suggest that EGCG acutely reduces postprandial blood glucose levels in mice when coadministered with CCS and this may be due in part to inhibition of alpha-amylase. The relatively low effective dose of EGCG makes a compelling case for studies in human subjects. PMID- 23038647 TI - The effect of pulsed electromagnetic fields and dehydroepiandrosterone on viability and osteo-induction of human mesenchymal stem cells. AB - The hypothesis of this work was that human bone marrow-derived mesenchymal stem cells (MSCs) are regulated by pulsed electromagnetic fields (PEMFs) and by intracrine conversion of an adrenal prohormone to dihydrotestosterone. The effect of PEMF and dehydroepiandrosterone (DHEA) on viability and osteogenic differentiation of human MSCs and on the viability of osteoblastic SaOS-2 cells was evaluated. It was found that PEMF promoted the viability rate of both cell types, whereas DHEA decreased the viability rate in a concentration-dependent manner. PEMF did not have major effects on osteo-induction at this low seeding density level (3000 cells/cm(2) ). Instead, DHEA, after MSC-mediated and 5alpha reductase-dependent conversion to dihydrotestosterone, clearly promoted the osteo induction of MSCs induced with beta-glyserophosphate, ascorbate and dexamethasone. Alkaline phosphatase (ALP), SMAD1, RUNX2, osteopontin (OP) and osteocalcin (OC) RNA levels were increased and alizarin red S- and hydroxyapatite specific OsteoImage(TM) stainings disclosed a promoted mineralization process. In addition, DHEA increased OP and OC mRNA levels of non-induced MSCs. A sequential use of mitogenic PEMF early during the fracture healing, followed by later administration of DHEA with osteogenic differentiating effect, might be worth subjecting to a randomized clinical trial. PMID- 23038648 TI - A generic framework for modeling brain deformation as a constrained parametric optimization problem to aid non-diffeomorphic image registration in brain tumor imaging. AB - OBJECTIVES: In the present paper a novel computational framework for modeling tumor induced brain deformation as a biophysical prior for non-rigid image registration is described. More precisely, we aim at providing a generic building block for non-rigid image registration that can be used to resolve inherent irregularities in non-diffeomorphic registration problems that naturally arise in serial and cross-population brain tumor imaging studies due to the presence (or progression) of pathology. METHODS: The model for the description of brain cancer dynamics on a tissue level is based on an initial boundary value problem (IBVP). The IBVP follows the accepted assumption that the progression of primary brain tumors on a tissue level is governed by proliferation and migration of cancerous cells into surrounding healthy tissue. The model of tumor induced brain deformation is phrased as a parametric, constrained optimization problem. As a basis of comparison and to demonstrate generalizability additional soft constraints (penalties) are considered. A back-tracking line search is implemented in conjunction with a limited memory Broyden-Fletcher-Goldfarb-Shanno (LBFGS) method in order to handle the numerically delicate log-barrier strategy for confining volume change. RESULTS: Numerical experiments are performed to test the flexible control of the computed deformation patterns in terms of varying model parameters. The results are qualitatively and quantitatively related to patterns in patient individual magnetic resonance imaging data. CONCLUSIONS: Numerical experiments demonstrate the flexible control of the computed deformation patterns. This in turn strongly suggests that the model can be adapted to patient individual imaging patterns of brain tumors. Qualitative and quantitative comparison of the computed cancer profiles to patterns in medical imaging data of an exemplary patient demonstrates plausibility. The designed optimization problem is based on computational tools widely used in non-rigid image registration, which in turn makes the model generally applicable for integration into non-rigid image registration algorithms. PMID- 23038650 TI - A great time to invest in baby Boomer's hepatitis C! PMID- 23038649 TI - Enzymatic mineralization of gellan gum hydrogel for bone tissue-engineering applications and its enhancement by polydopamine. AB - Interest is growing in the use of hydrogels as bone tissue-engineering (TE) scaffolds due to advantages such as injectability and ease of incorporation of active substances such as enzymes. Hydrogels consisting of gellan gum (GG), an inexpensive calcium-crosslinkable polysaccharide, have been applied in cartilage TE. To improve GG suitability as a material for bone TE, alkaline phosphatase (ALP), an enzyme involved in mineralization of bone by cleaving phosphate from organic phosphate, was incorporated into GG hydrogels to induce mineralization with calcium phosphate (CaP). Incorporated ALP induced formation of apatite-like material on the submicron scale within GG gels, as shown by FTIR, SEM, EDS, XRD, ICP-OES, TGA and von Kossa staining. Increasing ALP concentration increased amounts of CaP as well as stiffness. Mineralized GG was able to withstand sterilization by autoclaving, although stiffness decreased. In addition, mineralizability and stiffness of GG was enhanced by the incorporation of polydopamine (PDA). Furthermore, mineralization of GG led to enhanced attachment and vitality of cells in vitro while cytocompatibility of the mineralized gels was comparable to one of the most commonly used bone substitute materials. The results proved that ALP-mediated enzymatic mineralization of GG could be enhanced by functionalization with PDA. PMID- 23038651 TI - The role of paracrine signals during liver regeneration. PMID- 23038652 TI - Nonalcoholic fatty liver disease (NAFLD): is it really a serious condition? PMID- 23038653 TI - Revealing non-covalent interactions in molecular crystals through their experimental electron densities. AB - Non-covalent interactions (NCI) define the rules underlying crystallisation, self assembly and drug-receptor docking processes. A novel NCI descriptor, based on the reduced electron density gradient (RDG), that enables easy visualisation of the zones of the electron density (ED) involved in either the supposedly attractive (dispersive, hydrogen bonding) or allegedly repulsive (steric) intermolecular interactions, was recently developed by Johnson et al. Here, it is applied for the first time to EDs derived from single-crystal X-ray diffraction data. A computer code handling both experimental and ab initio EDs in the RDG-NCI perspective was purposely written. Three cases spanning a wide range of NCI classes were analysed: 1) benzene, as the prototype of stacking and weak CH...pi interactions; 2) austdiol, a heavily functionalised fungal metabolite with a complex hydrogen-bonding network; 3) two polymorphs of the heteroatom-rich anti ulcer drug famotidine, with van der Waals and hydrogen-bond contacts between N- and S-containing groups. Even when applied to experimental EDs, the RDG index is a valuable NCI descriptor that can highlight their different nature and strength and provide results of comparable quality to ab initio approaches. Combining the RDG-NCI study with Bader's ED approach was a key step forward, as the RDG index can depict inherently delocalised interactions in terms of extended and flat RDG isosurfaces, in contrast to the bond path analysis, which is often bounded to a too localised and possibly discontinuous (yes/no) description. Conversely, the topological tool can provide quantitative insight into the simple, qualitative NCI picture offered by the RDG index. Hopefully, this study may pave the way to a deeper analysis of weak interactions in proteins using structural and ED information from experiment. PMID- 23038654 TI - A novel de novo pathogenic mutation in the CACNA1A gene. PMID- 23038655 TI - Double flap technique for reconstruction of anterior skull base defects after craniofacial tumor resection: technical note. AB - BACKGROUND: Successful reconstruction of large anterior skull base (ASB) defects after craniofacial resection of malignant skull base tumors is paramount for preventing cerebrospinal fluid (CSF) fistulas. The vascularized pedicled pericranial flap (PCF) has been the gold standard for repairing ASB defects after transbasal transcranial approaches. However, flap necrosis and delayed CSF leaks can occur after adjuvant radiation therapy. We describe a "double flap" reconstruction technique in which the PCF is augmented inferiorly by a secondary vascularized pedicled nasoseptal flap (NSF) that is harvested and rotated using an endoscopic endonasal approach. METHODS: This technique is illustrated in 2 patients who underwent a combined cranionasal (transbasal and endoscopic endonasal) approach for large sinonasal malignancies with significant intracranial extension (1 esthesioneuroblastoma, 1 sinonasal teratocarcinosarcoma). After tumor removal via a combined cranionasal approach, primary repair of the ASB dural defect was performed with a free patch graft. The ASB defect was then repaired using the double flap technique with a vascularized PCF from above and augmented with a vascularized NSF from below. RESULTS: Postoperatively, there were no complications of CSF leakage, meningitis, or tension pneumocephalus in both patients. After subsequent radiation therapy, the double flap repair remained intact at 2 years postoperatively in both patients. CONCLUSION: The double flap skull base reconstruction technique provides an additional barrier of vascularized tissue to prevent CSF leakage, meningitis, tension pneumocephalus, and postradiation necrosis. This technique is a viable option if a combined transcranial and transnasal endoscopic tumor resection is performed and postoperative radiation is anticipated. PMID- 23038656 TI - To establish the parameters of optimal nutrition do we need to consider psychological in addition to physiological parameters? AB - The criteria used to establish dietary reference values are discussed and it is suggested that the too often the "need" they aim to satisfy is at the best vaguely specified. The proposition is considered that if we aim to establish optimal nutrition we will gain from considering psychological in addition to physiological parameters. The brain is by a considerable extent the most complex and metabolically active organ in the body. As such it would be predicted that the first signs of minor subclinical deficiencies will be the disruption of the functioning of the brain. The output of the brain is the product of countless millions of biochemical processes, such that if enzyme activity is only a few percentage points less than maximum, a cumulative influence would result. A series of studies of micronutrient supplementation in well-designed trials were reviewed. In metaanalyses the cognitive functioning of children and the mood and memory of adults has been shown to respond to multivitamin/mineral supplementation. Given the concerns that have been expressed about the negative responses to high levels of micronutrients, the implications are discussed of the finding that psychological functioning may benefits from an intake greater than those currently recommended. PMID- 23038658 TI - Possible involvement of host defense mechanism in the suppression of rat acute reflux esophagitis by the particular histamine H2 receptor antagonist lafutidine. AB - AIMS: Gastroesophageal reflux disease is considered to be caused primarily by gastric juice refluxed into the esophagus. Here, we investigated the possible involvement of host defense mechanisms in the development of acute reflux esophagitis using lafutidine, a histamine H(2) receptor antagonist (H(2)RA) with proven gastric mucosal protective effects. METHODS AND RESULTS: The ligation of both the pylorus and the forestomach of SD rats under anesthesia caused hemorrhagic lesions in the esophageal mucosa at 6 h. Lesion formation was significantly inhibited by treatment with H(2)RAs, including the conventional H(2)RAs famotidine and cimetidine as well as lafutidine. The maximum suppressive abilities of these agents were similar to that of the proton pump inhibitor lansoprazole. Interestingly, unlike famotidine, lafutidine at low doses significantly suppressed esophagitis without inhibiting gastric acid secretion. Note that neither lafutidine nor famotidine inhibited hexosamine output in gastric juice samples obtained 3 h after ligation. Additionally, the protective effect of lafutidine, but not of famotidine, was partly attenuated by the denervation of capsaicin-sensitive afferent nerves with a large dose of capsaicin. CONCLUSION: The present results indicate that esophageal host-defense via capsaicin-sensitive afferent nerves may contribute to the therapeutic action of lafutidine. PMID- 23038657 TI - Characterization of new organic nitrate hybrid drugs covalently bound to valsartan and cilostazol. AB - BACKGROUND AND PURPOSE: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. With the present studies we synthesized and characterized new organic nitrate hybrid molecules. Compounds CLC-1265 (valsartan mononitrate) and CLC-1280 (valsartan dinitrate) are derivatives of the angiotensin receptor blocker valsartan, with CLC-1265 containing a single organic nitrate linker and CLC-1280 also containing a second, different linker. Compounds CLC-2000 (cilostazol mononitrate) and CLC 2100 (cilostazol dinitrate) are nitrate derivatives of the phosphodiesterase III inhibitor cilostazol. All compounds are designed as hybrid molecules, potentially combining the NO-donating properties of organic nitrates with the AT1-blocking activity of valsartan or the phosphodiesterase-III-inhibiting effect of cilostazol. EXPERIMENTAL APPROACH: The properties of new drugs were assessed by isometric tension recording, inhibition of platelet aggregation and formation of mitochondrial reactive oxygen and nitrogen species. KEY RESULTS: In this report, all new nitrate compounds are shown, in vitro, to induce vasodilation in the range of other, classical organic nitrates, without inducing oxidative stress or classical nitrate tolerance. In addition, the new hybrid nitrate molecules displayed superior antiaggregatory properties over classical mono- and dinitrates. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that organic nitrates can be successfully linked to existing therapeutic molecules to create a new class of molecular entities with a potential dual mechanism of action via combining the established pharmacological properties of valsartan or cilostazol with the vasodilating properties of organic nitrates. Future experimental studies have to demonstrate whether the combined action of these compounds translates to superior therapeutic effects. PMID- 23038659 TI - Capecitabine-induced hypertriglyceridemia and hyperglycemia: two cases. AB - Capecitabine has shown significant antitumor activity against anthracycline/taxane refractory breast cancer and advanced colorectal carcinoma. The main drug-related adverse effects are palmar-plantar erythrodysesthesia (hand foot syndrome), diarrhea and stomatitis. Dyslipidemia is a rare but important side effect of this drug. The mechanism of capecitabine-induced hypertriglyceridemia (CI-HTG) is unclear. It may be due to the decreased activities of lipoprotein lipase and hepatic triglyceride lipase. This report is associated with 2 patients who developed severe HTG when receiving capecitabine. Capecitabine was discountinued and antilipemic treatments were given and both cases are in follow-up with normal lipid levels. This report describes CI-HTG and possible pathogenetic mechanisms and the literature is reviewed. PMID- 23038660 TI - Effects of acetaldehyde on action potentials and Ca2+ currents in single atrial myocytes from the bullfrog. AB - AIM: The purpose of the present study was to examine the effects of acetaldehyde on the contractile force and membrane potentials and currents in the bullfrog heart. METHODS: Contractile force was recorded using right atrial tissues, and membrane potentials and currents were measured by using whole cell patch clamp methods in right atrial myocytes. RESULTS: Acetaldehyde at 500 umol/l and 1 mmol/l increased the contractile force significantly. Acetaldehyde at 300 and 500 umol/l increased the overshoot and the plateau of electrically induced action potentials in a concentration-dependent and reversible manner, while the resting membrane potential did not change. The duration of the action potential (APD(90)) measured at the 90% repolarization level was shortened. The L-type Ca(2+) current (I(Ca)) increased significantly when 300 and 500 umol/l were applied. The fast transient inward current, the inward rectifying potassium current and the outward delayed-rectifier potassium current were not changed following acetaldehyde application (500 umol/l or 1 mmol/l). CONCLUSION: These results suggest that acetaldehyde increased the I(Ca), thereby increased the contractile force, the overshoot and the plateau of action potentials. The shortening of APD(90) may be due to the acceleration of the current decay during the I(Ca) inactivation phase. PMID- 23038661 TI - Therapeutic potential of ASP3258, a selective phosphodiesterase 4 inhibitor, on chronic eosinophilic airway inflammation. AB - We investigated and compared the pharmacological effects of a PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8 naphthyridin-3-yl] propanoic acid), with those of roflumilast, the most clinically advanced PDE4 inhibitor known. ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC(50) values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3-6 times more potent than roflumilast. ASP3258 inhibited LPS induced TNF-alpha production and PHA-induced IL-5 production in human whole blood cells with respective IC(50) values of 110 and 100 nmol/l, both approximately 10 times less potent than roflumilast. Repeatedly administered ASP3258 and roflumilast both suppressed chronic airway eosinophilia induced by repeated exposure to ovalbumin in Brown Norway rats with respective ED(50) values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of ASP3258. Although PDE4 inhibitors induce emesis by mimicking the pharmacological action of an alpha(2)-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with alpha(2) - adrenoceptor agonist. PDE4 inhibitors are also known to induce vascular injury in rats. Although repeatedly administered ASP3258 (3 and 10 mg/kg) significantly increased plasma fibrinogen, a biomarker for toxicity, 1 mg/kg of ASP3258 did not. These results suggest that ASP3258 is an attractive PDE4 inhibitor for treating chronic eosinophilic airway inflammation due to asthma. PMID- 23038662 TI - Using smell to triage samples in point-of-care assays. AB - Smell of success: Reagent 1 provides the dual readouts of odor (ethanethiol) and fluorescence (derivative of 7-hydroxycoumarin) and can be used in down-selection assays based on smell and quantitative fluorescence assays of the samples that give a positive result. An important feature of 1 is the matched sensitivity of the two outputs. This reagent is designed for use in resource-limited settings and is demonstrated in assays that detect enzymes. PMID- 23038663 TI - Implantation of osteogenic differentiated donor mesenchymal stem cells causes recruitment of host cells. AB - The interaction between host and donor cells is believed to play an important role in osteogenesis. However, it is still unclear how donor osteogenic cells behave and interact with host cells in vivo. The purpose of this study was to track the interactions between transplanted osteogenic cells and host cells during osteogenesis. In vitro migration assay was carried out to investigate the ability of osteogenic differentiated human mesenchymal stem cells (O-hMSCs) to recruit MSCs. At the in vivo level, O-hMSCs were implanted subcutaneously or into skull defects in severe combined immunodeficient (SCID) mice. New bone formation was observed by micro-CT and histological procedures. In situ hybridization (ISH) against human Alu sequences was performed to distinguish donor osteogenic cells from host cells. In vitro migration assay revealed an increased migration potential of MSCs by co-culturing with O-hMSCs. In agreement with the results of in vitro studies, ISH against human Alu sequences showed that host mouse MSCs migrated in large numbers into the transplantation site in response to O-hMSCs. Interestingly, host cells recruited by O-hMSCs were the major cell populations in newly formed bone tissues, indicating that O-hMSCs can trigger and initiate osteogenesis when transplanted in orthotopic sites. The observations from this study demonstrated that in vitro induced O-hMSCs were able to attract host MSCs in vivo and were involved in osteogenesis together with host cells, which may be of importance for bone tissue-engineering applications. PMID- 23038664 TI - Interactions between proteins and carbon-based nanoparticles: exploring the origin of nanotoxicity at the molecular level. AB - The widespread application of nanomaterials has spurred an interest in the study of interactions between nanoparticles and proteins due to the biosafety concerns of these nanomaterials. In this review, a summary is presented of some of the recent studies on this important subject, especially on the interactions of proteins with carbon nanotubes (CNTs) and metallofullerenols. Two potential molecular mechanisms have been proposed for CNTs' inhibition of protein functions. The driving forces of CNTs' adsorption onto proteins are found to be mainly hydrophobic interactions and the so-called pi-pi stacking between CNTs' carbon rings and proteins' aromatic residues. However, there is also recent evidence showing that endohedral metallofullerenol Gd@C82 (OH)22 can be used to inhibit tumor growth, thus acting as a potential nanomedicine. These recent findings have provided a better understanding of nanotoxicity at the molecular level and also suggested therapeutic potential by using nanoparticles' cytotoxicity against cancer cells. PMID- 23038665 TI - Effects of autologous, cross-linked erythrocytes on isolated hypoperfused rabbit heart dynamics. AB - The present study was aimed at assessing the effects of either red blood cells (RBC) or RBC cross-linked with the bifunctional dimethyl suberimidate reagent (C RBC) on contractile force (CFo), heart rate (HR) and coronary flow (CF) of the isolated rabbit heart hypoperfused with RBC suspensions under 30 mm Hg constant pressure. RBC or C-RBC caused a rapid and marked reduction of CF, CFo and HR. In RBC-treated hearts, however, reperfusion with Tyrode solution partially restored the initial myocardial parameters, while in C-RBC-treated hearts a rapid impairment of diastolic relaxation with a subsequent, steady and increasing heart contracture was observed. Histological analysis showed that in C-RBC-perfused hearts either capillaries or precapillary arterioles were occluded by C-RBC in spite of extensive washings with Tyrode solution. These findings indicate that C RBC impair coronary circulation markedly and irreversibly. PMID- 23038666 TI - Adipose-derived stem cells induce vascular tube formation of outgrowth endothelial cells in a fibrin matrix. AB - Vascularization of engineered tissues is one of the current challenges in tissue engineering. Several strategies aim to generate a prevascularized scaffold which can be implanted at sites of injury or trauma. Endothelial cells derived from peripheral blood (outgrowth endothelial cells, OECs) display promising features for vascular tissue engineering, including their autologous nature, capacity for proliferation and ability to form mature vessels. In this study we investigated the ability of OECs to form vascular structures in co-culture with adipose derived stem cells (ASCs) in a fibrin matrix. Using microcarrier beads coated with OECs, we showed ingrowth of endothelial cells in the fibrin scaffold. Furthermore, co-cultures with ASCs induced vessel formation, as evidenced by immunostaining for CD31. The degradation of fibrin is at least in part mediated by expression of matrix metalloproteinase-14. Moreover, we showed OEC/ASC-induced vessel-like structure formation even in the absence of microcarrier beads, where increasing amounts of ASCs resulted in a denser tubular network. Our data add new insights into co-culture-induced vessel formation of outgrowth endothelial cells within a fibrin matrix in an autologous system. PMID- 23038668 TI - Simple photosystem II water oxidation centre analogues in visible light oxygen and H+ generation. AB - Calcium manganese oxide nanoparticles for application in water oxidation are synthesized by combination with a carboxylated biopolymer stabilizing agent to form very simple but effective analogues of the photosynthetic PSII oxygen evolving complex. The relative efficiency of these materials for production of O(2) and protons under visible light-promoted reactions is evaluated and prolonged reaction lifetimes are observed. PMID- 23038669 TI - Treatment of penetrating brain injury in a rat model using collagen scaffolds incorporating soluble Nogo receptor. AB - Injuries and diseases of the central nervous system (CNS) have the potential to cause permanent loss of brain parenchyma, with severe neurological consequences. Cavitary defects in the brain may afford the possibility of treatment with biomaterials that fill the lesion site while delivering therapeutic agents. This study examined the treatment of penetrating brain injury (PBI) in a rat model with collagen biomaterials and a soluble Nogo receptor (sNgR) molecule. sNgR was aimed at neutralizing myelin proteins that hinder axon regeneration by inducing growth cone collapse. Scaffolds containing sNgR were implanted in the brains of adult rats 1 week after injury and analysed 4 weeks or 8 weeks later. Histological analysis revealed that the scaffolds filled the lesion sites, remained intact with open pores and were infiltrated with cells and extracellular matrix. Immunohistochemical staining demonstrated the composition of the cellular infiltrate to include macrophages, astrocytes and vascular endothelial cells. Isolated regions of the scaffold borders showed integration with surrounding viable brain tissue that included neurons and oligodendrocytes. While axon regeneration was not detected in the scaffolds, the cellular infiltration and vascularization of the lesion site demonstrated a modification of the injury environment with implications for regenerative strategies. PMID- 23038670 TI - Synthesis and biological studies of pyrazolyl-diamine Pt(II) complexes containing polyaromatic DNA-binding groups. AB - New [PtCl(pz*NN)](n+) complexes anchored by pyrazolyl-diamine (pz*NN) ligands incorporating anthracenyl or acridine orange DNA-binding groups have been synthesized so as to obtain compounds that would display synergistic effects between platination and intercalation of DNA. Study of their interaction with supercoiled DNA indicated that the anthracenyl-containing complex L(2) Pt displays a covalent type of binding, whereas the acridine orange counterpart L(3) Pt shows a combination of intercalative and covalent binding modes with a strong contribution from the former. L(2) Pt showed a very strong cytotoxic effect on ovarian carcinoma cell lines A2780 and A2780cisR, which are, respectively, sensitive to and resistant to cisplatin. In these cell lines, L(2) Pt is nine to 27 times more cytotoxic than cisplatin. In the sensitive cell line, L(3) Pt showed a cytotoxic activity similar to that of cisplatin, but like L(2) Pt was able significantly to overcome cisplatin cross-resistance. Cell-uptake studies showed that L(2) Pt accumulates preferentially in the cytoplasm, whereas L(3) Pt reaches the cell nucleus more easily, as clearly visualized by time-lapse confocal imaging of live A2870 cells. Altogether, these findings seem to indicate that interaction with biological targets other than DNA might be involved in the mechanism of action of L(2) Pt because this compound, despite having a weaker ability to target the cell nucleus than L(3) Pt, as well as an inferior DNA affinity, is nevertheless more cytotoxic. Furthermore, ultrastructural studies of A2870 cells exposed to L(2) Pt and L(3) Pt revealed that these complexes induce different alterations in cell morphology, thus indicating the involvement of different modes of action in cell death. PMID- 23038671 TI - Roles of CUB and LDL receptor class A domain repeats of a transmembrane serine protease matriptase in its zymogen activation. AB - Matriptase is a type II transmembrane serine protease containing two complement proteases C1r/C1s-urchin embryonic growth factor-bone morphogenetic protein domains (CUB repeat) and four low-density lipoprotein receptor class A domains (LDLRA repeat). The single-chain zymogen of matriptase has been found to exhibit substantial protease activity, possibly causing its own activation (i.e. conversion to a disulfide-linked two-chain fully active form), although the activation seems to be mediated predominantly by two-chain molecules. Our aim was to assess the roles of CUB and LDLRA repeats in zymogen activation. Transient expression studies of soluble truncated constructs of recombinant matriptase in COS-1 cells showed that the CUB repeat had an inhibitory effect on zymogen activation, possibly because it facilitated the interaction of two-chain molecules with a matriptase inhibitor, hepatocyte growth factor activator inhibitor type-1. By contrast, the LDLRA repeat had a promoting effect on zymogen activation. The effect of the LDLRA repeat seems to reflect its ability to increase zymogen activity. The proteolytic activities were higher in pseudozymogen forms of recombinant matriptase containing the LDLRA repeat than in a pseudozymogen without the repeat. Our findings provide new insights into the roles of these non-catalytic domains in the generation of active matriptase. PMID- 23038672 TI - Post-weaning increases in the milk-fat globule EGF-factor VIII on fat globules in mouse milk and in the uptake of the fat globules by HC11 mammary epithelial cells. AB - Milk fat globules (MFGs) secreted by lactating mammary gland are unique lipid surrounded by a phospholipid bi-layer. We report here post-weaning changes in MFG EGF factor VIII (MFG-E8) and annexin V-accessible phosphatidyl-l-serine on the surface of MFGs. The MFG content in milk markedly decreased to about one-half within 2 days after forced weaning, despite a slight increase in milk protein content. Immunofluorescence-staining of MFGs using anti-MFG-E8 and annexin V indicated that MFG-E8 was present on some, but not all, MFGs before weaning, whereas most of MFGs were MFG-E8-positive and annexin V-negative after weaning. Free MFG-E8 with binding activity to phosphatidyl-l-serine was present abundantly in the post-weaning milk, and indeed exhibited binding to MFGs in pre-weaning milk. MFGs were taken up by HC11 mouse mammary epithelial cells in vitro, and those from post-weaning milk were remarkable for such cellular uptake. Moreover, the uptake of MFGs by the cells was inhibited by an anti-MFG-E8 antibody. Taken together, these findings suggest that MFG-E8 plays a critical role in regulation of MFG dynamics after weaning or during the suckling interval through the control of MFG-epithelial cell interaction in lactating mammary glands. PMID- 23038673 TI - Conferral of allostery to Thermus sp. GH5 methylglyoxal synthase by a single mutation. AB - There is huge number of oligomeric proteins that show allosteric behaviour as soon as their allosteric effector is provided. Thermus sp. GH5 methylglyoxal synthase is also a homohexameric protein, which displays cooperative behaviour when phosphate concentration increases. Previous studies on this enzyme have indicated that binding of phosphate leads to formation of specific interactions which makes the enzyme capable of displaying allosteric behaviour when its substrate is bound. In this study, it has been shown that a single mutation, independent of phosphate, provides the requirements for showing such cooperative behaviour. However, it is proposed that the allosteric mechanism triggered by phosphate is different from that applied by the mutation. These findings point towards the fact that allostery can be acquired, modulated or eliminated by any alteration in structure and/or dynamics of the proteins and all proteins are potentially capable of showing cooperative behaviour as soon as their prerequisites for this phenomenon are provided by the allosteric effector. PMID- 23038675 TI - Possible involvement of glycolipids in anticancer drug resistance of human ovarian serous carcinoma-derived cells. AB - Glycolipid and transporter protein gene expression in ovarian serous carcinoma derived 2008 cells, and their paclitaxel-resistant Px2 and cisplatin-resistant C13 forms was examined to confirm the previous finding, i.e., that it was characteristically altered in anticancer drug-resistant cells established on continuous cultivation of ovarian carcinoma-derived KF28 cells in the different anticancer drug-containing media. Although the concentrations of lipid constituents in 2008 cells were higher than those in KF28 cells, and the glycolipid compositions were different, the following glycolipids and genes were commonly altered in KF28- and 2008-derived resistant cells. Gb(3)Cer was increased in all resistant cells, irrespective of whether the resistance was to paclitaxel or cisplatin, and expression of the MDR1 gene and gangliosides was enhanced in paclitaxel-resistant cells, but gangliosides were absent in cisplatin resistant cells. In accord with the decreased amounts of gangliosides in cisplatin-resistant cells, the gene expression and specific activity of GM3 synthase were greatly decreased in cisplatin-resistant cells. Furthermore, paclitaxel- and cisplatin-resistant cells were converted to forms more sensitive to the respective anticancer drugs on cultivation with D-PDMP, an inhibitor of GlcCer synthase, and GM3, respectively, prior to the addition of anticancer drugs, indicating the possible involvement of glycolipids in anticancer drug resistance. PMID- 23038674 TI - Activation of the Wnt/beta-catenin pathway and tissue inhibitor of metalloprotease 1 during tertiary dentinogenesis. AB - Tertiary dentin is deposited inside teeth after various stimuli and serves as a major defensive wall to preserve pulp cells. However, the molecular mechanisms of the activation of quiescent odontoblasts, immature pulp cells and tertiary dentin formation are still unclear. Therefore, we performed a comprehensive gene expression analysis of pulp cells after cavity preparation of 9-week-old rat molars to clarify the critical molecules in tertiary dentinogenesis. As a result, mRNA expression of various molecules was up- or down-regulated. Notably, several members of the matrix metalloprotease family and their endogenous inhibitors were up-regulated after cavity preparation. In situ hybridization showed that tissue inhibitor of metalloprotease 1 (Timp1) was widely and continuously distributed in the pulp beneath the cavity in vivo. We also observed accumulation of beta catenin in the pulp cells beneath the cavity by fluorescence immunohistochemistry. Furthermore, Timp1 transcription was repressed by a dominant-negative TCF4 in immature undifferentiated mesenchymal cells, but not altered in mature odontoblast-like cells. These results indicate that cavity preparation may activate the Wnt/beta-catenin pathway and the Wnt/beta-catenin pathway and Timp1 may be correlatively involved in pulp repair. Timp1 might play crucial roles in reactivation of immature pulp cells for tertiary dentinogenesis. PMID- 23038676 TI - Site-specific modification of adeno-associated viruses via a genetically engineered aldehyde tag. AB - As a consequence of their well-defined nanostructure and intrinsic bioactive functionality, virus-based nanoparticles have shown promise for mediating gene delivery. Adeno-associated virus (AAV) nanoparticles, which possess an excellent safety profile and therapeutic potential, hold potential for use in human gene therapy. However, because of their native tropisms, the applicability of AAV nanoparticles is often limited to restricted ranges of cells or tissues. Thus, retargeting AAV particles to the desired cell populations has continued to be a major research focus in many gene therapy applications. In this study, a general strategy is reported for nanoparticle targeting. This involves the site-specific modification of AAV type 2 (AAV2) by genetically incorporating a short peptide, in this case an aldehyde tag, in the viral capsid. Such a tag can be exploited for site-specific attachment of targeting molecules and allows for further introduction of targeting antibodies or ligands. It is shown that this modification neither affects the level of infectious viral titer nor intracellular trafficking properties. Furthermore, the site-specific conjugation of targeting antibodies could significantly enhance viral transduction to those target cells that have otherwise exhibited very low permissiveness to AAV2 infection. This method also allows the functional incorporation of RGD peptides onto AAV2 for enhanced delivery with implications for cancer gene therapy. PMID- 23038677 TI - Targeted delivery of adipose-derived stem cells via acellular dermal matrix enhances wound repair in diabetic rats. AB - Cell-based therapeutic intervention has emerged as a new approach to accelerate wound closure. Adipose-derived stem cells (ASCs), as a fascinating cell source, have received much attention in tissue repair and regeneration. In this study we evaluated the potential of acellular dermal matrix (ADM) scaffold serving as a carrier for the delivery of ASCs and investigated its therapeutic effects on wound healing. First, ASCs were isolated and characterized for multidifferentiation potential. ASCs-ADM grafts were then prepared, and ADM scaffold was shown to support the in vitro growth and proliferation of ASCs. Next, we analysed paracrine factors in conditioned medium and found that ASCs-ADM grafts secreted various cytokines, including VEGF, HGF, TGFbeta and bFGF. Moreover, ASCs-ADM conditioned medium notably stimulated the migration and proliferation of fibroblasts. In vivo, we established an excisional wound model in diabetic rats which received phosphate-buffered saline (PBS), ADM or ASCs-ADM grafts, respectively. Our results demonstrated that implantation of ASCs-ADM significantly enhanced tissue regeneration and increased epithelialization, resulting in accelerated wound closure. Immunofluorescence analysis further indicated that capillary density was evidently increased in the ASCs-ADM group compared with the control or ADM group. In addition, western blot analysis showed that ASCs-ADM significantly increased the expression of angiogenic factors, which was consistent with in vitro data. Taken together, our results suggest that targeted delivery of ASCs via ADM scaffold accelerate diabetic wound healing through a paracrine mechanism, with enhanced granulation tissue formation and increased re-epithelialization and neovascularization. PMID- 23038678 TI - Phosphate glass fibres promote neurite outgrowth and early regeneration in a peripheral nerve injury model. AB - Three-dimensional (3D) scaffolds, which are bioactive and aid in neuronal guidance, are essential in the repair and regeneration of injured peripheral nerves. In this study, we used novel inorganic microfibres guided by phosphate glass (PG). PG fibres (PGfs) were aligned on compressed collagen that was rolled into a nerve conduit. In vitro tests confirmed that adult dorsal root ganglion (DRG) neurons showed active neurite outgrowth along the fibres, with a maximum number and length of neurites being significantly higher than those cultured on tissue culture plastic. In vivo experiments with nerve conduits that either contained PGfs (PGf/Col) or lacked them (Col) were conducted on transected sciatic nerves of rats for up to 12 weeks. One week after implantation, the PGf/Col group showed many axons extending along the scaffold, whereas the Col group showed none. Eight weeks after implantation, the PGf/Col group exhibited greater recovery of plantar muscle atrophy than the Col group. Electrophysiological studies revealed that some animals in the PGf/Col group at 6 and 7 weeks post-implantation (5.3% and 15.8%, respectively) showed compound muscle action potential. The Col group over the same period showed no response. Motor function also showed faster recovery in the PGf/Col group compared to the Col group up to 7 weeks. However, there was no significant difference in the number of axons, muscle atrophy or motor and sensory functions between the two groups at 12 weeks post-implantation. In summary, phosphate glass fibres can promote directional growth of axons in cases of peripheral nerve injury by acting as physical guides. PMID- 23038679 TI - Proteome changes in auricular lymph nodes and serum after dermal sensitization to toluene diisocyanate in mice. AB - Some reactive chemicals, such as diisocyanates, are capable of initiating an allergic response, which can lead to occupational asthma after a latency period. Clinical symptoms such as cough, wheezing, and dyspnea occur only late, making it difficult to intervene at an early stage. So far, most studies using proteomics in lung research have focused on comparisons of healthy versus diseased subjects. Here, using 2D-DIGE, we explored proteome changes in the local draining lymph nodes and serum of mice dermally sensitized once or twice with toluene-2,4 diisocyanate (TDI) before asthma is induced. In the lymph nodes, we found 38 and 58 differentially expressed proteins after one and two treatments, respectively, between TDI-treated and vehicle-treated mice. In serum, seven and 16 differentially expressed proteins were detected after one and two treatments, respectively. We identified 80-85% of the differentially expressed proteins by MS. Among them, lymphocyte-specific protein-1, coronin 1a, and hemopexin were verified by Western blotting or ELISA in an independent group of mice. This study revealed alterations in the proteomes early during sensitization in a mouse model before the onset of chemical-induced asthma. If validated in humans, these changes could lead to earlier diagnosis of TDI-exposed workers. PMID- 23038680 TI - Clinical review: Present and future prospects of male fertility preservation for children and adolescents. AB - CONTEXT: Rapid progress in fertility preservation strategies has led to the investigation of ways in which fertile gametes could be generated from cryopreserved immature testicular tissue. Childhood cancer patients remain the major group that can benefit from these techniques. Other potential candidates include patients undergoing gonadectomy and patients with Klinefelter's syndrome and cryptorchid testes. This review aims to present an overview of the current state of knowledge in experimental germ cell transplantation, testicular tissue transplantation, and germ cell culture as fertility preservation methods for males. METHODOLOGY: We included English articles published in PubMed as well as personal files with the focus on studies including human or nonhuman material. MAIN FINDINGS: Germ cell and testicular tissue transplantation demonstrate clinical options to mature germ cells from immature primate testicular tissue. The most promising approach involves autologous grafting of immature testicular tissue, whereas germ cell maturation in vitro provides the best strategies to overcome problems of cancer contamination in cryopreserved testicular tissue. Three-dimensional and organ culture systems offer the possibility to differentiate immature male germ cells up to the stage of elongated spermatids. Further characterization of early germ cell development in humans is needed to modify these systems for clinical use. PMID- 23038681 TI - Serum levels of 3-epi-25-OH-D3 during hypervitaminosis D in clinical practice. AB - CONTEXT: Intoxication from vitamin D supplements has been rarely reported, but nowadays, it occurs more frequently. The presence of the C-3 epimer of 25 hydroxyvitamin D(3) (3-epi-25-OH-D(3)) is highly prevalent in adults, although there is little information regarding its in vivo relevance, if any, especially under pathological conditions. OBJECTIVE: Our aim was to assess the presence of the 3-epi-25-OH-D(3) in serum samples displaying 25-OH-D(3) concentrations indicative of hypervitaminosis D. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE: A total of 58 samples displaying a wide range of concentrations of 25-OH D(3) (>64-439 ng/ml) by ultrafast liquid chromatography were consecutively recruited and reassessed for the presence of 3-epi-25-OH-D(3) using a second chromatographic system. Data from additional biochemical tests performed as part of the patient evaluation were also recorded. RESULTS: Mean relative contribution of 3-epi-25-OH-D(3) was less than 4%, and concentrations ranged from 2-28.6 ng/ml. Serum levels of the C3 epimer, but not the relative contribution, correlate with serum 25-OH-D(3). Overall, in subjects with 25-OH-D(3) concentrations indicative of hypervitaminosis D, the presence of the C-3 epimer and its levels were apparently unrelated to age, serum markers of renal and liver function, acute-phase reactants, and the presence of hypercalcemia. 3-Epi-25-OH D(3) did not correlate with PTH, but subjects displaying PTH suppression (<14 pg/ml) showed higher concentrations of 3-epi-25-OH-D(3). CONCLUSION: The relative contribution of 3-epi-25-D(3) was not significantly altered during hypervitaminosis D, although the absolute levels reached in serum may be biologically relevant. From a clinical viewpoint, although the small size of the group may affect the lack of relationships, the presence of 3-epi-25-OH-D(3) was apparently unrelated to serum markers of renal and liver function, acute-phase reactants, PTH, and the presence of hypercalcemia. PMID- 23038682 TI - Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy. AB - BACKGROUND: Optimal doses of i.v. glucocorticoids for Graves' orbitopathy (GO) are undefined. METHODS: We carried out a multicenter, randomized, double-blind trial to determine efficacy and safety of three doses of i.v. methylprednisolone in 159 patients with moderate to severe and active GO. Patients were randomized to receive a cumulative dose of 2.25, 4.98, or 7.47 g in 12 weekly infusions. Efficacy was evaluated objectively at 12 wk by blinded ophthalmologists and subjectively by blinded patients (using a GO specific quality of life questionnaire). Adverse events were recorded at each visit. RESULTS: Overall ophthalmic improvement was more common using 7.47 g (52%) than 4.98 g (35%; P = 0.03) or 2.25 g (28%; P = 0.01). Compared with lower doses, the high-dose regimen led to the most improvement in objective measurement of ocular motility and in the Clinical Activity Score. The Clinical Activity Score decreased in all groups and to the least extent with 2.25 g. Quality of life improved most in the 7.47-g group, although not reaching statistical significance. No significant differences occurred in exophthalmos, palpebral aperture, soft tissue changes, and subjective diplopia score. Dysthyroid optic neuropathy developed in several patients in all groups. Because of this, differences among the three groups were no longer apparent at the exploratory 24-wk visit. Major adverse events were slightly more frequent using the highest dose but occurred also using the lowest dose. Among patients whose GO improved at 12 wk, 33% in the 7.47-group, 21% in the 4.98 group, and 40% in the 2.25-group had relapsing orbitopathy after glucocorticoid withdrawal at the exploratory 24-wk visit. CONCLUSIONS: The 7.47-g dose provides short-term advantages over lower doses. However, this benefit is transient and associated with slightly greater toxicity. The use of a cumulative dose of 7.47 g of methylprednisolone provides short-term advantage over lower doses. This may suggest that an intermediate-dose regimen be used in most cases and the high-dose regimen be reserved to most severe cases of GO. PMID- 23038684 TI - Effect of polymer degree of conversion on Streptococcus mutans biofilms. AB - Biofilm-material interactions are increasingly recognized as critical to success of some materials/devices and failure of others. We use a model system of dental monomers, salivary pellicles, and oral biofilms to demonstrate for the first time that degree of conversion of cross-linked dimethacrylate polymers alters biofilm metabolic activity. This response is due primarily to leachable release (not surface chemistry) and is complex, with no changes in some biofilm measurements (i.e., biomass), and time- and leachable-dependent responses in others (i.e., metabolic activity). These results highlight the need for considering biofilm material interactions when designing/evaluating new materials. PMID- 23038683 TI - Evaluation of domestic and Yucatan swine nasal sinus anatomy as models for future sinonasal research of medications delivered by standard instruments used in functional endoscopic sinus surgery. AB - BACKGROUND: There is a need to find an animal model to study new medications to improve mucosal wound healing after functional endoscopic sinus surgery (FESS). Current literature suggests swine as a potential candidate. The lack of information correlating swine computer tomography (CT) and endoscopic sinonasal anatomy prompted us to investigate them in the domestic and Yucatan swine to determine their feasibility as models to test new medications and drug-embedded stents applied using FESS techniques. METHODS: Two domestic pig heads and 2 Yucatan pig heads were imaged using helical thin slice (1 mm) CT. Two rhinologists analyzed the images and performed endoscopy on the swine. Particular attention was given to accessing the frontal sinus and suturing stents to the nasal septum using standard endoscopic instruments. RESULTS: CT confirmed that swine sinonasal anatomy is largely similar to human, with all major sinuses present. The middle and inferior turbinates of swine arise from a single uniturbinate. The superior turbinates contain large concha bullosa. Unlike human, swine nasal septum is bone anteriorly and cartilage posteriorly. The frontal sinus ostia, regardless of head size, were consistently around 10 cm from the nasal aperture. On endoscopy, domestic swine frontal sinus ostia were easily accessible for topical medication deposition. Silastic splints can be sutured to the domestic swine septum through the posterior cartilaginous portion, allowing for studies involving medication-eluting material. The narrower nasal cavity of Yucatan pigs prohibited endoscopic maneuvers. CONCLUSION: Domestic swine, but not Yucatan, are a feasible model for future sinonasal research using standard FESS instruments. PMID- 23038685 TI - Clinical severity and epithelial endotypes in chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous disease defined by epithelial inflammation. The link between measures of traditional disease severity and markers of epithelial inflammation is poorly understood as prior research has focused on presence of polyps or degree of eosinophilia. The expression of 3 epithelial derived cytokines implicated in initiation of T-helper 2 (Th2) inflammation and an eosinophil chemoattractant were compared with clinical measures used in CRS. METHODS: Sinus mucosal samples from CRS patients undergoing sinus surgery were analyzed for interleukin-25 (IL-25), IL-33, thymic stromal lymphopoietin (TSLP), and eotaxin-3 messenger RNA (mRNA) expression by quantitative polymerase chain reaction (PCR). Tumor patients undergoing surgery transnasally with normal sinus mucosa were controls. Gene expression was compared with symptom, radiology, and endoscopy scores, serological markers, presence of reactive airways disease (RAD), and atopy. RESULTS: Thirty-seven patients (38% female, mean age 48 +/- 15 years), 12 CRS with nasal polyps (CRSwNP), 18 CRS without nasal polyps (CRSsNP), and 7 controls were recruited. CRSwNP phenotype predicted elevated IL-25, IL-33, and eotaxin-3 levels. Increased eotaxin-3 correlated with poorer computed tomography (CT) (p = 0.004) and endoscopic scores (p = 0.049). Increased IL-25 correlated with poorer CT scores (p = 0.012) and raised serum eosinophils (p = 0.006). No associations with RAD, atopy, and symptom measures were found. No associations for IL-33 and TSLP were found. CONCLUSION: Inflammatory mediators of the epithelium in CRS has some correlation with traditional measures of disease burden. Certain epithelial profiles may predict highly dysfunctional epithelial barriers and prospective evaluation of the clinical outcomes from interventions is required. Future endotyping of the epithelium in CRS may be able to provide prognostic information. PMID- 23038686 TI - DOG1 immunoreactivity in uterine leiomyosarcomas. AB - AIMS: DOG1 is a recently described marker of gastrointestinal stromal tumour (GIST) which is considered to be extremely sensitive and, among mesenchymal neoplasms, quite specific for this tumour type. Following the identification of DOG1 immunoreactivity in a uterine leiomyosarcoma, we wished to ascertain how prevalent DOG1 immunoreactivity was in this tumour type. METHODS: We stained a series of uterine leiomyosarcomas (n=26) with DOG1 and with CD117 (c-kit), another marker of GIST. Staining with both markers was classified as negative, focal (<50% tumour cells positive) or diffuse (>=50% tumour cells positive). RESULTS: DOG1 immunoreactivity was present in seven of 26 (27%) leiomyosarcomas. Staining was focal in five cases and diffuse in two. CD117 was positive in three of 26 (11.5%) cases, two focal and one diffuse. Two cases were positive with DOG1 and CD117. One of five uterine leiomyomas was focally positive with DOG1, and one extrauterine pelvic leiomyoma was diffusely positive with this marker. CONCLUSIONS: Since GISTs have rarely been described as primary uterine neoplasms, the presence of DOG1 immunoreactivity in a uterine leiomyosarcoma may result in diagnostic confusion, and a panel of markers is necessary for diagnosis. Uterine leiomyosarcomas should be added to the list of mesenchymal neoplasms which may be DOG1 positive. PMID- 23038687 TI - Pointers and pitfalls of mycophenolate-associated colitis. AB - AIMS: Mycophenolate-associated colitis has been previously reported to show patterns of colonic mucosal injury mimicking a host of conditions, including graft-versus-host disease, ischaemia and inflammatory bowel disease (IBD). The aim of this study is to characterise, semiquantitatively, pathological changes of mycophenolate mofetil (MMF) mucosal injury. METHODS: Seven transplant patients receiving MMF who underwent colonoscopic examination and biopsy were identified retrospectively over a 2-year period. Multiple histologic parameters, including architectural distortion, cryptitis, stromal active inflammation, individual damaged crypts (IDC) and crypt apoptotic figures were evaluated in the biopsies semiquantitatively. Where biopsy site was identified, the parameters were assessed separately in biopsies from right and left colon. RESULTS: All cases showed mixed patterns of mucosal injury. All seven cases showed focal architectural distortion (in 58% of fragments per case), focal cryptitis (mean 3.0 foci per case), increased crypt apoptosis (mean 26.5/100 crypts) and IDC (mean 3.0 foci). Focal changes resembling acute self-limited colitis were noted in three cases. Possible proximal accentuation of some changes was noted with right side biopsies tending to show greater crypt apoptotic activity and more foci of architectural distortion. Three cases showed dual pathology (two with cytomegalovirus (CMV) infection and one with IBD). CONCLUSIONS: Although a wide spectrum of changes may be seen in MMF-associated colitis, important microscopic clues include a mixed pattern of injury (typically a combination of crypt apoptosis, isolated crypt damage and architectural distortion), and possible proximal accentuation of pathologic changes. The need for clinical correlation and follow-up is emphasised by the occurrence of dual pathology in patients treated with MMF. PMID- 23038688 TI - Point of Care INR testing devices: performance of the Roche CoaguChek XS and XS Plus in the UK NEQAS BC external quality assessment programme for healthcare professionals: four years' experience. AB - BACKGROUND: Vitamin K antagonists have been used for many decades and have been traditionally monitored by the measurement of the International Normalised Ratio (INR) in the laboratory. Introduction of Point of Care (POC) testing devices to measure INR has resulted in many tests being undertaken in primary care. External Quality Assessment (EQA) of these POC devices is recommended to ensure accuracy and reliability of INR results outside a laboratory setting. AIM: To assess the quality of INR results for users of two POC devices (CoaguChek XS and CoaguChek XS Plus) over a four-year period. METHODS: Four surveys (two samples) were sent in each 12-month period. The median INR value of each sample was calculated and the percentage deviation from this median determined. Any results greater than 15% from the median were considered to be outside consensus which indicated a possible problem within the testing system. RESULTS: Variability of INR results in this UK National External Quality Assessment Scheme (NEQAS) programme was comparable to that in the UK NEQAS EQA programme for laboratory INR testing. Occurrence of persistent problems was lower in the POC programme than the laboratory programme. CONCLUSIONS: Utilisation of an EQA programme for POC devices in primary care is feasible and necessary. Our data suggest for those health professionals using EQA, the reliability and accuracy of INR testing matches the quality of laboratory testing. PMID- 23038689 TI - First case of spontaneous myospherulosis of the liver. PMID- 23038690 TI - Fluorescence in situ hybridisation analysis of bone marrow trephine biopsy specimens; an additional tool in the diagnostic armoury. AB - Fluorescence in situ hybridisation (FISH) analysis is now widely employed in the diagnosis and risk stratification of a wide range of malignant diseases. While this technique is used successfully with formalin-fixed paraffin-embedded (FFPE) sections from numerous tissue types, FISH analysis of FFPE tissue sections from trephine biopsy specimens has been less widely reported, possibly due to technical limitations relating to the decalcification protocols employed. During the last 4 years FISH analysis has been carried out successfully in 42 out of 55 (76%) consecutive trephine biopsy specimens received as part of the standard diagnostic service at our institution. Samples decalcified using EDTA-based protocols were analysed successfully in 31/31 cases (100%), whereas only 11/24 samples (46%) decalcified using formic acid-based protocols were successful. In our experience, FISH analysis of trephine biopsy specimens is a highly reproducible technique and a very useful adjunctive tool in the diagnostic armoury; however, its use in a standard diagnostic setting relies on the use of EDTA-based decalcification protocols. PMID- 23038691 TI - Troponin testing for syncope: what are we predicting and why? PMID- 23038692 TI - Paediatric out-of-hospital cardiac arrests in Melbourne, Australia: improved reporting by adding coronial data to a cardiac arrest registry. AB - AIM: We describe improved reporting of paediatric out-of-hospital cardiac arrest (OHCA) by adding coronial findings to a cardiac arrest registry. METHODS: Non traumatic OHCA occurring in paediatric patients aged less than 16 years were identified using the Victorian Ambulance Cardiac Arrest Registry and available coronial findings reviewed. RESULTS: Between the years 2001 and 2009, emergency medical services (EMS) attended 26 974 non-traumatic OHCA of which 390 (1.4%) occurred in children less than 16 years of age. We successfully linked 301 patients with the coronial registry; excluding patients discharged alive from hospital (n=22) and patients with terminal illness (n=16), this represents 86% of OHCA attended by the ambulance. Agreement between the paramedic cause of OHCA and the coronial cause of death was 66.5% (kappa 0.16) for presumed cardiac, 74.4% (kappa 0.43) for sudden infant death syndrome (SIDS), 81.1% (kappa 0.17) for respiratory, 92.7% (kappa 0.18) for neurological and 98.3% (kappa 0.27) for drug overdose precipitants to OHCA. Undiagnosed congenital heart disease was a rare cause of OHCA (n=3, 1%). Intentional injury was found on autopsy in 13 cases; six cases were clinically thought to be SIDS and two cases presumed cardiac. Co sleeping was found in 35 cases (39%) of SIDS. CONCLUSIONS: This study highlights the limitations associated with ascribing the cause of OHCA on the basis of clinical details. Improved reporting is possible by linkage with coronial data. Such robust data inform EMS service providers but also the wider healthcare system where preventive, diagnostic and treatment strategies can be maximised. PMID- 23038693 TI - Characteristics of femur fractures in ambulatory young children. AB - OBJECTIVES: To determine and identify the characteristics and circumstances of femur fractures in ambulatory young children. DESIGN AND SETTING: Retrospective review of 203 ambulatory children, between 1 and 5 years old, presenting with femur fractures to an urban paediatric hospital over a 10-year period. chi(2) And Student's t test were employed for statistical analysis. RESULTS: The mean age was 36.6 months, with 155 (76.2%) being male. The most frequent mechanism of injury was fall from a height (n=62, 30.5%). The highest number of injuries occurred in 2-3-year-olds. The most common history in 1-2-year-olds was stumbling on/over something causing a fall. For 4-5 year olds it was road traffic accidents. Other additional physical findings were infrequent (14.3%) and not suspicious of inflicted injury. Child protective services concluded three of the cases to be likely non-accidental, and four cases were inconclusive but requiring close follow-up. Of these seven children, six occurred in 1-2-year-olds. No distinguishing feature was noted in fracture type or location. CONCLUSIONS: Femur fractures can occur with low velocity injury whether from a short fall or twisting/stumbling injury in young healthy ambulatory children. PMID- 23038694 TI - Violence in the emergency department: a multicentre survey of nurses' perceptions in Nigeria. AB - BACKGROUND: Emergency department (ED) violence is common and widespread. ED staff receive both verbal and physical abuse, with ED nurses bearing the brunt of this violence. The violence is becoming increasingly common and lethal and many institutions are still improperly prepared to deal with it. METHODS: A questionnaire based survey of the perception of violence among nurses working in six tertiary hospitals' EDs across five states in Nigeria was conducted. RESULTS: 81 nurses were interviewed with a male to female ratio of 1:4. Most were right about the definition of violence. About 88.6% of respondents have witnessed ED violence while 65.0% had been direct victims before. Nurses followed by doctors were the usual victims. The acts were carried out mostly by visitors to the ED. Men were usually responsible for the violence, which usually occurred in the evenings. Weapons were not commonly utilised: only 15.8% of the nurses had been threatened with a weapon over a 1-year period. The main perceived reasons for violence were overcrowded emergency rooms, long waiting time and inadequate system of security. All the institutions were lacking in basic strategies for prevention. While most of the nurses were not satisfied with the EDs that were considered not safe, few would wish for redeployment to other departments/units. CONCLUSIONS: There is a need to make the EDs safer for all users. This can be achieved by a deliberate management policy of 'zero' tolerance to workplace violence, effective reporting systems, adequate security and staff training on prevention of violence. PMID- 23038695 TI - Pulmonary embolism rule-out criteria (PERC) in pulmonary embolism--revisited: a systematic review and meta-analysis. AB - OBJECTIVES: To perform a systematic review and meta-analysis including all the current studies to assess the accuracy of pulmonary embolism rule-out criteria (PERC) in ruling out pulmonary embolism (PE). METHODS: We conducted a comprehensive search of the major databases (Ovid Medline In-Process & Other Non Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid PsycInfo, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews and Scopus) and references of potentially eligible articles and conference proceedings of major emergency medicine organisations through May 2012. We included all original research studies conducted in emergency departments on diagnostic performance of PERC. Two reviewers independently identified the eligible studies and extracted data. Sensitivity, specificity and likelihood ratios were calculated using contingency tables. RESULTS: 12 studies including 13 cohorts (three retrospective, 10 prospective) were included, comprising of 14 844 patients from six countries. 12 cohorts were urban and one was rural. Pooled (95% CI) sensitivity, specificity, positive and negative likelihood ratio were 0.97 (0.96 to 0.98), 0.22 (0.22 to 0.23), 1.22 (1.16 to 1.29) and 0.17 (0.13 to 0.23), respectively. The pooled (95% CI) diagnostic OR was 7.4 (5.5-9.8). On meta-regression analysis, there was no significant difference between PE prevalence and PERC diagnostic performance (coefficient (SE) of -0.032 (0.022), p=0.173) or on relative diagnostic OR (0.97, 95% CI 0.92 to 1.02). Significant heterogeneity was observed in specificity (I(2)=97.4%) and positive likelihood ratio (I(2)=89.1%). CONCLUSIONS: Because of the high sensitivity and low negative likelihood ratio, PERC rule can be used confidently in clinically low probability population settings. PMID- 23038697 TI - Relationship between autoantibody clustering and clinical subsets in SLE: cluster and association analyses in Hong Kong Chinese. AB - OBJECTIVE: This study aims to identify the existence of, and relationship between autoantibody clusters and clinical subsets in Chinese SLE patients. METHODS: Data from 1928 SLE patients from Hong Kong were analysed. Using cluster analysis, patients were grouped by autoantibodies into clusters. The frequencies of various clinical manifestations were then compared between each cluster. Separate association analyses between individual autoantibodies and clinical manifestations as well as between clinical manifestations were also performed without any prior clustering. RESULTS: Three separate autoantibody clusters were identified, each with significantly different clinical manifestations. Cluster 1 was characterized by anti-dsDNA and the greatest prevalence of renal disorder but the lowest frequencies of other clinical manifestations. Cluster 2 was represented by the predominance of anti-Smith, anti-RNP and aPL, with greater prevalence of malar rash, oral ulcers, arthritis and serositis. Cluster 3 was characterized by anti-Ro and anti-La with greater prevalence of discoid rash, photosensitivity and haematological involvement. Individual association analysis also revealed similar findings. Patients of clusters 2 and 3 were more closely related, while cluster 1 was more distinct, associated with renal disorder only and negatively associated or not associated with other manifestations. CONCLUSION: We conclude that autoantibody clustering and clinical subsets exist in SLE patients of our locality. These clusters may be viewed as a bipolar spectrum of related autoantibody and clinical manifestations. At one end are patients with over-representation of anti-dsDNA and renal disorder, while at the other end are two distinct autoantibody clusters (anti-Sm/anti-RNP/aPL and anti Ro/anti-La) with overlapping of other clinical manifestations. PMID- 23038698 TI - Neonatal jaundice. PMID- 23038700 TI - Time trials predict the competitive performance capacity of junior cross-country skiers. AB - PURPOSE: This study investigated whether there is a correlation between time trial performance and competitive performance capacity of male and female junior cross-country skiers and sought to explain sex-specific competitive performance capacity through multiple-regression modeling. METHODS: The International Ski Federation's (FIS) junior ranking points for distance (FISdist) and sprint (FISsprint) competitions were used as performance parameters. A total of 38 elite junior (age 18.5 +/- 1.0 y) cross-country skiers (24 men and 14 women) completed 3 time-trial tests: a 3-km level-running time trial (TTRun), a 2-km moderate uphill (1.2 degrees slope) roller-skiing time trial using the double-poling technique (TTDP), and a 2-km uphill (2.8 degrees slope) roller-skiing time trial using the diagonal-stride technique (TTDiag). The correlations were investigated using Pearson correlation analysis, and regression models were created using multiple-linear-regression analysis. RESULTS: For men, FISsprint and FISdist were correlated with the times for TTRun, TTDP, and TTDiag (all P < .001). For women, FISsprint was correlated with the times for TTRun (P < .05), TTDP (P < .01), and TTDiag (P < .01), whereas FISdist was correlated only with the times for TTDP (P < .01) and TTDiag (P < .05). The models developed for FISdist and FISsprint explained 73.9-82.3% of the variance in the performance capacity of male junior cross-country skiers. No statistically valid regression model was found for the women. CONCLUSIONS: Running and roller-skiing time trials are useful tests for accurately predicting the performance capacity of junior cross-country skiers. PMID- 23038701 TI - Direct urine ammonium measurement: time to discard urine anion and osmolar gaps. AB - BACKGROUND: A failure of urine ammonium to increase during acidosis indicates impaired renal acidification, and the urinary ammonium concentration is therefore a useful investigation in determining the cause of a metabolic acidosis. However, urine ammonium measurements are not widely available in routine diagnostic laboratories. This has led to the use of urine anion or osmolar gaps, which are unsatisfactory as surrogates for urine ammonium measurement. METHODS: We evaluated the adaptation of two widely available automated plasma ammonium assays for measurement of urinary ammonium. RESULTS: Both assays showed good recovery and linearity in urine samples spiked with ammonium chloride, and acceptable precision. Urine ammonium concentrations estimated from urinary anion and osmolar gaps showed poor agreement with measured urine ammonium concentrations. CONCLUSIONS: Direct urine ammonium measurements are easily performed with modern autoanalysers by simple adaptation of routine plasma ammonium assays. The use of urine anion and osmolar gaps should be abandoned where direct measurement is available. PMID- 23038702 TI - A randomized controlled trial on the anti-inflammatory effects of curcumin in patients with chronic sulphur mustard-induced cutaneous complications. AB - BACKGROUND: Chronic cutaneous complications such as pruritus are among the very frequent complaints of sulphur mustard (SM)-exposed patients. The present trial investigated the impact of curcumin on serum inflammatory biomarkers and their association with pruritus severity and quality of life (QoL). METHODS: This was a randomized, double-blind trial among 96 male Iranian veterans (age 37-59 y) who were suffering from chronic SM-induced pruritic skin lesions. Patients were randomly assigned to curcumin (1 g/d, n = 46) or placebo (n = 50) for four weeks. Serum concentrations of interleukins 6 (IL-6) and 8 (IL-8) together with high sensitivity C-reactive protein (hs-CRP) and calcitonin gene-related peptide (CGRP) were measured at baseline and at the end of the trial. Assessment of pruritus severity was performed using the pruritus score and QoL using the Dermatology Life Quality Index (DLQI). RESULTS: Serum IL-8 and hs-CRP were significantly reduced in both groups but the magnitude of reduction was greater in the curcumin group (P < 0.001). Serum CGRP was only decreased in the curcumin group (P < 0.001). No significant change was observed in serum IL-6. There were significant correlations between CGRP and IL-6 changes (P = 0.011) and between DLQI and IL-8 changes (P = 0.026) in the curcumin group. In the curcumin group, changes in serum IL-8 concentrations were found as the significant predictor of DLQI scores (P = 0.026) but none of the independent variables could predict pruritus scores. CONCLUSIONS: Curcumin supplementation effectively mitigates inflammation in patients suffering from chronic SM-induced cutaneous complications. This anti-inflammatory effect might account for the observed pruritus alleviation and QoL improvement by this phytochemical. PMID- 23038703 TI - Effect of warm-up and precooling on pacing during a 15-km cycling time trial in the heat. AB - PURPOSE: The best way to apply precooling for endurance exercise in the heat is still unclear. The authors analyzed the effect of different preparation regimens on pacing during a 15-km cycling time trial in the heat. METHODS: Ten male subjects completed four 15-km time trials (30 degrees C), preceded by different preparation regimes: 10 min cycling (WARM-UP), 30 min scalp cooling of which 10 min was cycling (SC+WARM-UP), ice-slurry ingestion (ICE), and ice slurry ingestion + 30 min scalp cooling (SC+ICE). RESULTS: No differences were observed in finish time and mean power output, although power output was lower for WARM-UP than for SC+ICE during km 13-14 (17 +/- 16 and 19 +/- 14 W, respectively) and for ICE during km 13 (16 +/- 16 W). Rectal temperature at the start of the time trial was lower for both ICE conditions (~36.7 degrees C) than both WARMUP conditions (~37.1 degrees C) and remained lower during the first part of the trial. Skin temperature and thermal sensation were lower at the start for SC+ICE. CONCLUSIONS: The preparation regimen providing the lowest body-heat content and sensation of coolness at the start (SC+ICE) was most beneficial for pacing during the latter stages of the time trial, although overall performance did not differ. PMID- 23038704 TI - Performance analysis of a world-class sprinter during cycling grand tours. AB - This investigation describes the sprint performances of the highest internationally ranked professional male road sprint cyclist during the 2008-2011 Grand Tours. Sprint stages were classified as won, lost, or dropped from the front bunch before the sprint. Thirty-one stages were video-analyzed for average speed of the last km, sprint duration, position in the bunch, and number of teammates at 60, 30, and 15 s remaining. Race distance, total elevation gain (TEG), and average speed of 45 stages were determined. Head-to-head performances against the 2nd-5th most successful professional sprint cyclists were also reviewed. In the 52 Grand Tour sprint stages the subject started, he won 30 (58%), lost 15 (29%), was dropped in 6 (12%), and had 1 crash. Position in the bunch was closer to the front and the number of team members was significantly higher in won than in lost at 60, 30, and 15 s remaining (P < .05). The sprint duration was not different between won and lost (11.3 +/- 1.7 and 10.4 +/- 3.2 s). TEG was significantly higher in dropped (1089 +/- 465 m) than in won and lost (574 +/- 394 and 601 +/- 423 m, P < .05). The ability to finish the race with the front bunch was lower (77%) than that of other successful sprinters (89%). However, the subject was highly successful, winning over 60% of contested stages, while his competitors won less than 15%. This investigation explores methodology that can be used to describe important aspects of road sprint cycling and supports the concept that tactical aspects of sprinting can relate to performance outcomes. PMID- 23038705 TI - p53 antagonizes the unfolded protein response and inhibits ground glass hepatocyte development during endoplasmic reticulum stress. AB - The unfolded protein response (UPR) is triggered during stress of the endoplasmic reticulum (ER) and facilitates tissue homeostasis. Considering the role of p53 tumor suppressor gene in the interpretation of stress-inducing stimuli, in this study, we explored whether p53 modulates UPR. We found that p53 ablation resulted in a profound sensitivity to tunicamycin that was associated with liver dysfunction, ground glass hepatocyte (GGH) development and nuclear atypia/dysplasia. Binding immunoglobulin protein (BiP)/glucose-regulated protein 78 (GRP78) chaperone was readily detected in the cytoplasm of GGHs, confirming ER expansion. Tunicamycin administration induced BiP/GRP78 and GRP94 expression more potently in the p53-deficient mice than in controls and elevated phosphatidylcholine, the major lipid of ER, by a p53-dependent mechanism. Furthermore, alternative splicing of XBP1, the transcription factor that executes the UPR, was more efficient in cells which do not express p53. The cytoprotective effects of p53 were confirmed by cell viability studies, indicating that p53 deficiency conferred sensitivity against tunicamycin. Our findings show that p53 protects from the hepatotoxic effects of chronic ER stress. Stimulation of p53 activity when intense UPR is undesirable may possess therapeutic implications. PMID- 23038706 TI - Human periprostatic white adipose tissue is rich in stromal progenitor cells and a potential source of prostate tumor stroma. AB - A body of growing evidence now implicates white adipose tissue as a relevant source of stromal progenitor cells recruited to the tumor microenvironment to form supportive tumor stroma. While the role of periprostatic (PP) adipose tissue in prostate cancer progression has been barely appreciated, we sought to determine the progenitor cell population in PP adipose tissue and the association with prostate cancer. We isolated and characterized CD31(-)CD34(+)CD45(-)CD146(-) progenitor cells (adipose-derived stem cells [ASC]) in paired samples of PP and preperitoneal visceral adipose tissue from prostate tissue and peripheral blood mononuclear cells of prostate cancer and nodular prostatic hyperplasia patients. ASC were quantified by flow cytometry and confirmed through target gene expression. Here we show a significantly higher amount of ASC in PP than in visceral adipose tissue, independent of body mass index and prostatic disease. In the prostate, ASC are increased in cancer compared with prostatic nodular hyperplasia patients. Concordantly, adipsin gene (CFD) expression, which is known to be up-regulated in adipose stem cells, was overexpressed in PP adipose tissue, in the prostate of cancer patients and in prostate CD31(-)CD34(+)CD45(-)CD146(-) sorted cells. ASC were found at higher levels in the blood of prostate cancer patients simultaneously overweight/obese. Present findings indicate that PP adipose tissue is a reservoir of progenitor cells with the potential to migrate towards prostate tumors, although its clinical significance merits further evaluation. PMID- 23038707 TI - Objective habitual physical activity and estradiol levels in obese Latina adolescents. AB - BACKGROUND: Lifetime physical activity (PA) is associated with decreased breast cancer (BC) risk; reports suggest that PA during adolescence contributes strongly to this relationship. PA lowers production of sex hormones, specifically estradiol, or decreases insulin resistance (IR), thereby lowering risk. Overweight Latina adolescents are insulin resistant and exhibit low levels of PA, potentially increasing their future BC risk. METHODS: 37 obese Latina adolescents (15.7 +/- 1.1 yrs) provided measures of PA using accelerometry; plasma follicular phase estradiol, sex-hormone binding globulin, total and free testosterone, dehydroepiandrosterone-sulfate (DHEAS); IR using HOMA-IR; and body composition via DEXA. Partial correlations and stepwise linear regressions assessed cross sectional relationships between sex hormones, IR and PA. Body composition, and age were included a priori as covariates. RESULTS: Estradiol was negatively associated with accelerometer counts per minute (CPM; r = -0.4; P = .02), percent time spent in moderate PA (%MPA; r = -0.5; P = .006), and percent time in moderate or vigorous PA (%MVPA; r = -0.5; P = .007). DHEAS was positively associated with CPM (r = .4, P = .009), %MPA (r = .3, P = .04), and %MVPA (r = .3, P = .04). Other sex hormones and IR were not associated with PA measures. CONCLUSION: This study is the first to show that higher habitual PA was inversely associated with estradiol in obese adolescents. PMID- 23038708 TI - Does collaborative research enhance the integration of research, policy and practice? The case of the Dutch Health Broker Partnership. AB - OBJECTIVES: A gap between health services research and practice has been identified: research findings often do not find their way into practice. Our objective was to explore the potential of collaborative research to bridge this gap in one specific area, health promotion, and to determine factors that influence the development of theory-based practice and practice-based theory. METHODS: This was investigated in an exploratory single-case study. First, we designed an analytical framework for collaborative research. Next, we used this framework to analyse developments in the Dutch Health Broker Partnership, which involved researchers, policymakers and practitioners. Data consisted of transcripts of the meetings of the Partnership over an 18-month period, as well as interviews with its 13 members. RESULTS: The development of theory-based practice and practice-based theory failed to progress beyond the initial stages, although practitioners' actions did become more comprehensive and researchers' thinking became more influenced by practical limitations and local contexts. The heterogeneity of the Partnership facilitated as well as impeded the progress of these developments. CONCLUSIONS: Although collaborative research may serve as a tool to narrow the gap between research and practice, discussing the collaborative process and partner heterogeneity among the partners at the outset may be a necessary prerequisite to achieving the full potential of any partnership, which is limited by the ambivalent influence of partner heterogeneity. Collaborative research may, therefore, additionally benefit from continuous cross-domain orchestration and boundary work. PMID- 23038709 TI - The contribution of age and time-to-death on health care expenditure for out-of hospital services. AB - OBJECTIVES: Controversy persists over the relationships between health care expenditure, time-to-death and age, undermining attempts to generate convincing predictions for policy. This paper explores the relationships between time-to death (TTD), age and health care expenditure for Australian Medicare-funded, out of-hospital services in the last five years of life, assessing if the relationship varies across different types of out-of-hospital services. METHODS: Medicare Benefit Scheme claims for five years before death in Western Australia (1990-2004) pertaining to out-of-hospital primary care, specialist or diagnostic and therapeutic services were used to determine the total and mean per capita health care expenditure (HCE) according to age and TTD. Data were evaluated using univariate linear regression (age) and segmented time-trend regression analysis (time-to-death). RESULTS: Changes to out-of-hospital HCE in the last five years of life did not consistently show a positive association with changes in the number of decedents. Only primary care services demonstrated a linear relationship for HCE and age. For TTD, a linear relationship was observed for all three service types within each retrospective period. CONCLUSIONS: This study has identified significant differences in the relationship between age, TTD and out of-hospital HCE across service type, further highlighting potential shortcomings in methods that use single, all-service, all-cause models to predict future HCE. These results build on our previous study and suggest that such predictions should either use separate models, or models capable of accounting for the different relationships of HCE with TTD and age across types of services in order to predict future HCE more accurately. PMID- 23038710 TI - Risk factors and pregnancy outcomes in women with syphilis diagnosed using a molecular approach. AB - OBJECTIVES: To investigate the risk factors for infection and the outcome of pregnancy in women diagnosed with syphilis using a molecular approach. METHODS: Case-control study of pregnant women admitted to a maternity ward, with the cases classified as early or latent maternal syphilis, based on clinical-serological diagnoses. The DNA of total peripheral blood was used to detect the polA gene using nested PCR (nPCR). The case and control groups were divided into subgroups based on whether the birth was successful (infant survived) or had a lethal outcome (miscarriage, stillbirth or neonatal death). RESULTS: The frequency of maternal syphilis was 1% (237/25 600), considering both those that had live births (71.3%, 169/237) and those with a lethal outcome (28.7%, 68/237), with a higher detection rate being provided by the nPCR in women with early syphilis. The cases of nPCR(+) congenital syphilis were more frequent in the women with early syphilis, nPCR(+) mothers and those who did not have treatment during the prenatal. The risk of maternal syphilis was greater in women who had not received preventive counselling, initiated sexual activity at 16 years of age or younger, had multiple partners, used drugs, were from households with a low income and poor sanitation, and had a history of miscarriage. CONCLUSIONS: The risk factors for congenital syphilis are closely related to the health of the mother, reflecting the lack of adequate prenatal care. The high frequency of maternal syphilis was associated in particular to the socio-economic conditions of the mother and her sexual and reproductive health. PMID- 23038711 TI - How likely is environmental or patient cross-contamination of Chlamydia trachomatis DNA to lead to false positive results in patients attending our clinic? AB - OBJECTIVES: Environmental contamination with DNA from Chlamydia trachomatis (CT) has previously been found in Genitourinary Medicine (GUM) clinics. There are no known cases of cross-contamination of clinical samples and no known nosocomial infections. We investigated whether diagnostic samples could become contaminated from the environment by running dummy sample and carrying out a patient throughput analysis. A total of 29 748 patients attended clinics over a year. Of these, 2860 (9.6%) had a positive Chlamydia test result. METHOD: (1) A run of dummy samples (60 urine samples and 10 swabs) were processed as normal clinic specimens. (2) Patient-throughput analysis: Patient numbers attending the GUM clinic on a given day was categorised as low, moderate or high. chi(2) Tests were used to look for associations between categorical variables and Chlamydia test positivity. A Poisson regression model was fitted to look at the effect of the number of people in the clinic on the number of positive results in a given day. As some clinics were only run on certain days of the week, a sensitivity analysis was later performed with attendances at non-daily clinics removed. RESULTS: All dummy samples tested negative and we did not find evidence of an association between daily Chlamydia positivity and clinic attendance. CONCLUSIONS: It is unlikely that environmental or cross-contamination of CT has lead to significant numbers of false positive results. Laboratories check for possible cross contamination routinely. The extension of this simple routine practice to all clinical areas could provide quality assurance, improving confidence in the results in clinics. PMID- 23038712 TI - Caring for children of parents with frontotemporal degeneration: a report of the AFTD Task Force on Families With Children. AB - The Association for Frontotemporal Degeneration (AFTD) organized a 7-person Task Force on Families With Children to explore the concerns of families when a parent of young children or teens is diagnosed with FTD. This report summarizes the findings of the task force and highlights the need for additional attention to this topic. The task force conducted a review of related literature and existing resources and compiled issues identified by spouses/partners, teens, and adult children within an affected family. The project confirmed a significant lack of information and support for parents caring for a spouse with FTD and for their children. Recommendations include developing resources and strategies that promote comprehensive family support, including those that build resiliency in the well parent and the children, and strengthen the changing family unit. Avenues for additional research in this area of need in the FTD community are suggested. PMID- 23038713 TI - The Influence of Cognitive Status on Elder Food Choice and Meal Service Satisfaction. AB - BACKGROUND: This article describes the testing of a new nursing home food delivery system that empowers elders to choose the foods they want to eat and gives them an active voice in menu development. METHODS: Using a 2-group, repeated measures design, 61 elderly residents from 2 eastern Washington nursing homes were recruited to participate in a 6-month study. Outcome measures included food and meal service satisfaction, body weight, serum prealbumin, and food intake. RESULTS: Serum prealbumin levels and body weight increased post intervention for treatment group residents. Mini-Mental Status Examination (MMSE) scores were not associated with the changes in serum prealbumin, body weight, or food intake. DISCUSSION: The MMSE scores did not influence the resident's ability to actively participate in the rate the food process or choose the foods they liked and preferred to eat. Cognitive impaired older adults experienced weight gain similarly to higher functioning elderly individuals. PMID- 23038714 TI - Trends in percutaneous endoscopic gastrostomy placement in the elderly from 1993 to 2003. AB - OBJECTIVES: To investigate national trends in percutaneous endoscopic gastrostomy (PEG) tube placement for hospitalized elderly patients from 1993 to 2003. METHODS: Retrospective analysis of patients >= 65 years of age with PEG tube placement from 1993 to 2003 from the Nationwide Inpatient Sample (NIS) database was utilized to calculate PEG placement rates per 1000 people. RESULTS: Placement of PEG tube increased by 38% in elderly patients during the study period, from 2.71 procedures during hospitalization per 1000 people to 3.75 procedures during hospitalization per 1,000 people. Placement of PEG tube in patients with Alzheimer's dementia doubled (5%-10%) over the study period. CONCLUSION: Over a 10-year period, PEG tube use in hospitalized elderly patients increased significantly. More importantly, approximately 1 in 10 PEG tube placements occurred in patients with dementia. PMID- 23038715 TI - Association of Alzheimer's Disease With APOE and IL-1alpha Gene Polymorphisms. AB - Apolipoprotein E (ApoE) gene polymorphisms are thought to be the most important genetic risk factor in the pathogenesis of late onset and sporadic Alzheimer's disease (AD). Moreover, interleukin-1alpha (IL-1alpha) is found to be associated with the pathogenesis of AD. In this research, ?2, ?3, and ?4 polymorphisms of ApoE gene and C889T polymorphism of IL-1alpha gene were genotyped in patients with AD and controls. Genotyping was performed by real-time polymerase chain reaction. ?3/?3 and ?3/?4 genotype frequencies were significantly higher in control and case groups, respectively. While ?3 allele frequencies were significantly higher in the control group, ?2 and ?4 allele frequencies were significantly higher among the cases with AD. No difference was found between the groups according to C889T polymorphism of IL-1alpha. In conclusion, we demonstrated that there was a strong association between ApoE ?4 allele and AD, while there was no relation with IL-1alpha C889T polymorphisms for this study. PMID- 23038717 TI - Reducing ACSCs. PMID- 23038716 TI - Clinical correlates and diagnostic utility of osmophobia in migraine. AB - BACKGROUND: Osmophobia is an under-investigated associated symptom in migraine. OBJECTIVE: To evaluate the clinical correlates and diagnostic utility of osmophobia. METHODS: Adult patients with migraine (with or without aura), probable migraine (PM), tension-type headache (TTH), and cluster headache (CH) were recruited retrospectively from our headache registration system. Migraine patients with and without osmophobia were compared. The newly proposed criteria for migraine requiring at least two of photo-, phono-, or osmophobia instead of both photo- and phonophobia were validated. RESULTS: In total, 2883 patients were included: 1809 migraine, 792 PM, 138 TTH, and 144 CH. Osmophobia was more common in migraine (62.2%) than in PM (33.8%), TTH (14.5%), and CH (31.3%) (all p < 0.001). Migraine patients with osmophobia scored higher on the Hospital Anxiety and Depression Scale (HADS) than those without (15.6 +/- 7.6 vs. 13.3 +/- 7.8, p < 0.001). The concordance in headache diagnoses between ICHD-2 (International Classification of Headache Disorders, Second Edition) and the newly proposed criteria was "almost perfect" (kappa = 0.886, p < 0.001). Additionally, 16.9% of ICHD-2 PM patients were reclassified as migraine using the newly proposed criteria. CONCLUSIONS: Osmophobia was prevalent in migraineurs, and was associated with higher HADS scores. The newly proposed criteria appear comparable to the ICHD-2 criteria, and may increase the diagnostic yield for Asian migraineurs, among whom photophobia was less common. PMID- 23038718 TI - Environmental triggers of hospital admissions for school-age children with asthma in two British cities. AB - Research has reported seasonal peaks in asthma in school age asthmatic children. The study aimed to assess if hospital admissions could be predicted from the possible environmental triggers using data from two British cities: Aberdeen and Doncaster. However, there were no consistent patterns across the two cities with no clear evidence that hospital admissions could be predicted from environmental data. PMID- 23038720 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Is heat application as good as pain killers in dysmenorrhoea? AB - A short cut review was carried out to establish whether heat application was a comparable alternative to traditional painkillers in women with dysmenorrheal pain. Two randomized trials were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line was that heat application was an alternative to NSAIDs. PMID- 23038721 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: Can emergency physicians safely rule in or rule out paediatric intussusception in the emergency department using bedside ultrasound? AB - A short cut review was carried out to establish whether emergency physicians (EPs) could confirm or refute the diagnosis of intussusception with the help of bedside ultrasonography. Two observational studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line was that EPs operated ultrasound was specific enough to rule in children with intussusception but its role to rule out this diagnosis needed to be further explored. PMID- 23038722 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: In patients with heatstroke is whole-body ice-water immersion the best cooling method? AB - A short cut review was carried out to establish whether whole body ice immersion was an effective way of cooling in patients presenting with heat stroke. One systematic review and three studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line was that immersion in ice-water was the most effective modality of lowering core body temperature in exertional heatstroke and shivering and vasoconstriction concerns were unfounded. PMID- 23038725 TI - Social scent marks do not improve avoidance of parasites in foraging bumblebees. AB - Foraging is a result of innate and acquired mechanisms, and is optimized in order to increase fitness. During foraging, an animal faces many threats, such as predation and infection. The uptake of parasites and diseases while foraging is common and an individual should be adapted to detect and avoid such threats, using cues from either the abiotic environment or the parasite. Social animals possess an additional cue to detect such contaminated food sources: information provided by conspecifics. Bumblebees avoid contaminated flowers, but the cues used by the bees to distinguish contamination remain unknown. Under controlled laboratory conditions, we tested the use of scent marks derived from other foragers in choosing between a contaminated (by Crithidia bombi) and an uncontaminated flower. As a positive control we tested the bee's choice between two flowers, one scented with geraniol and containing a highly rewarding sugar solution, and the other not scented and containing a poorer reward. The bees mainly chose the uncontaminated and the rewarding scented flowers. Scent marks did not increase the efficiency of the bumblebees in choosing the better flower. The bees from both experiments behaved similarly, showing that the main and most relevant cue used to choose the uncontaminated flower is the odour from the parasite itself. The adaptation of bumblebees to avoid flowers contaminated by C. bombi arose from the long-term host-parasite interaction between these species. This strong adaptation results in an innate behaviour of bees and a detection and aversion of the odour of contaminated flower nectar. PMID- 23038723 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 4: Prognostic value of B-type natriuretic peptides (BNP and NT proBNP) in community-acquired pneumonia. AB - A short cut review was carried out to establish the prognostic value of B-type natriuretic peptides (BNP and NT-proBNP) in community acquired pneumonia (CAP). Three cohort studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line was that B-type natriuretic peptides have prognostic value in CAP but further prospective studies were needed to assess their application in clinical practice. PMID- 23038726 TI - Glucose uptake and metabolism by red blood cells from fish with different extracellular glucose levels. AB - The aim of the present study was to assess whether mechanisms of glucose trafficking by red blood cells (RBCs) relate to species-specific extracellular glucose levels. Atlantic cod (Gadus morhua), Atlantic salmon (Salmo salar), cunner (Tautogolabrus adspersus) and short-horned sculpin (Myoxocephalus scorpius) had plasma glucose levels of 4, 4.1, 1.95 and 0.73 mmol l(-1), respectively. Glucose uptake by isolated RBCs was measured by the initial incorporation of [6-(14)C]-glucose and steady-state glucose metabolism was determined by the production of (3)H(2)O from [2-(3)H]-glucose. Saturation kinetics of glucose uptake and inhibition of both glucose uptake and metabolism by cytochalasin B and phloretin revealed that Atlantic cod, cunner and sculpin RBCs all had a facilitated transport component to glucose trafficking. RBCs from Atlantic salmon showed a linear relationship between glucose uptake and extracellular glucose level, but exhibited clear inhibition of glucose metabolism by cytochalasin B and phloretin, suggesting a component of facilitated glucose transport that is more elusive to detect. The production of (3)H(2)O was linear for at least 6 h and as such presents a rigorous approach to measuring glycolytic rate. Steady-state rates of glucose metabolism were achieved at extracellular levels of approximately 1 mmol l(-1) glucose for RBCs from all species, showing that within-species normal extracellular glucose level is not a primary determinant of the basal level of glycolysis. At physiological levels of extracellular glucose, the ratio of initial glucose uptake to glucose metabolism was 1.5 to 4 for all RBCs, suggesting that there is scope to increase metabolic rate without alteration of the basal glucose uptake capacity. PMID- 23038727 TI - Low-O2 acclimation shifts the hypoxia avoidance behaviour of snapper (Pagrus auratus) with only subtle changes in aerobic and anaerobic function. AB - It was hypothesised that chronic hypoxia acclimation (preconditioning) would alter the behavioural low-O(2) avoidance strategy of fish as a result of both aerobic and anaerobic physiological adaptations. Avoidance and physiological responses of juvenile snapper (Pagrus auratus) were therefore investigated following a 6 week period of moderate hypoxia exposure (10.2-12.1 kPa P(O(2)), 21 +/- 1 degrees C) and compared with those of normoxic controls (P(O(2))=20-21 kPa, 21 +/- 1 degrees C). The critical oxygen pressure (P(crit)) limit of both groups was unchanged at ~7 kPa, as were standard, routine and maximum metabolic rates. However, hypoxia-acclimated fish showed increased tolerances to hypoxia in behavioural choice chambers by avoiding lower P(O(2)) levels (3.3 +/- 0.7 vs 5.3 +/- 1.1 kPa) without displaying greater perturbations of lactate or glucose. This behavioural change was associated with unexpected physiological adjustments. For example, a decrease in blood O(2) carrying capacity was observed after hypoxia acclimation. Also unexpected was an increase in whole-blood P(50) following acclimation to low O(2), perhaps facilitating Hb-O(2) off-loading to tissues. In addition, cardiac mitochondria measured in situ using permeabilised fibres showed improved O(2) uptake efficiencies. The proportion of the anaerobic enzyme lactate dehydrogenase, at least relative to the aerobic marker enzyme citrate synthase, also increased in heart and skeletal red muscle, indicating enhanced anaerobic potential, or in situ lactate metabolism, in these tissues. Overall, these data suggest that a prioritization of O(2) delivery and O(2) utilisation over O(2) uptake during long-term hypoxia may convey a significant survival benefit to snapper in terms of behavioural low-O(2) tolerance. PMID- 23038728 TI - Contribution of larval nutrition to adult reproduction in Drosophila melanogaster. AB - Within the complex life cycle of holometabolous insects, nutritional resources acquired during larval feeding are utilized by the pupa and the adult. The broad features of the transfer of larval resources to the pupae and the allocation of larval resources in the adult have been described by studies measuring and tracking macronutrients at different developmental stages. However, the mechanisms of resource transfer from the larva and the factors regulating the allocation of these resources in the adult between growth, reproduction and somatic maintenance are unknown. Drosophila melanogaster presents a tractable system in which to test cellular and tissue mechanisms of resource acquisition and allocation because of the detailed understanding of D. melanogaster development and the experimental tools to manipulate its tissues across developmental stages. In previous work, we demonstrated that the fat body of D. melanogaster larvae is important for survival of starvation stress in the young adult, and suggested that programmed cell death of the larval fat cells in the adult is important for allocation of resources for female reproduction. Here, we describe the temporal uptake of larval-derived carbon by the ovaries, and demonstrate the importance of larval fat-cell death in the maturation of the ovary and in fecundity. Larvae and adults were fed stable carbon isotopes to follow the acquisition of larval-derived carbon by the adult ovaries. We determined that over half of the nutrients acquired by the ovaries in 2-day-old adult females are dependent upon the death of the fat cells. Furthermore, when programmed cell death is inhibited in the larval fat cells, ovarian development was depressed and fecundity was reduced. PMID- 23038729 TI - Mechanics of snout expansion in suction-feeding seahorses: musculoskeletal force transmission. AB - Seahorses and other syngnathid fishes rely on a widening of the snout to create the buccal volume increase needed to suck prey into the mouth. This snout widening is caused by abduction of the suspensoria, the long and flat bones outlining the lateral sides of the mouth cavity. However, it remains unknown how seahorses can generate a forceful abduction of the suspensoria. To understand how force is transmitted to the suspensoria via the hyoid and the lower jaw, we performed mathematical simulations with models based on computerized tomography scans of Hippocampus reidi. Our results show that the hinge joint between the left and right hyoid bars, as observed in H. reidi, allows for an efficient force transmission to the suspensorium from a wide range of hyoid angles, including the extremely retracted hyoid orientations observed in vivo for syngnathids. Apart from the hyoid retraction force by the sternohyoideus-hypaxial muscles, force generated in the opposite direction on the hyoid by the mandibulohyoid ligament also has an important contribution to suspensorium abduction torque. Forces on the lower jaw contribute only approximately 10% of the total suspensorium torque. In particular, when dynamical aspects of hyoid retraction are included in the model, a steep increase is shown in suspensorium abduction torque at highly retracted hyoid positions, when the linkages to the lower jaw counteract further hyoid rotation in the sagittal plane. A delayed strain in these linkages allows syngnathids to postpone suction generation until the end of cranial rotation, a fundamental difference from non-syngnathiform fishes. PMID- 23038730 TI - Pharmacological assays reveal age-related changes in synaptic transmission at the Caenorhabditis elegans neuromuscular junction that are modified by reduced insulin signalling. AB - Frailty is a feature of neuromuscular ageing. Here we provide insight into the relative contribution of pre- and postsynaptic dysfunction to neuromuscular ageing using the nematode Caenorhabditis elegans. Assays of C. elegans motility highlight a precipitous decline during ageing. We describe a novel deployment of pharmacological assays of C. elegans neuromuscular function to resolve pre- and postsynaptic dysfunction that underpin this decreased motility during ageing. The cholinergic agonist levamisole and the cholinesterase inhibitor aldicarb elicited whole worm contraction and allowed a direct comparison of neuromuscular integrity, from 1 to 16 days old: measurements could be made from aged worms that were otherwise almost completely immobile. The rapidity and magnitude of the drug induced contraction provides a measure of neuromuscular signalling whilst the difference between levamisole and aldicarb highlights presynaptic effects. Presynaptic neuromuscular transmission increased between 1 and 5 days old in wild type but not in the insulin/IGF1 receptor mutant daf-2 (e1370). Intriguingly, there was no evidence of a role for insulin-dependent effects in older worms. Notably in 16-day-old worms, which were virtually devoid of spontaneous movement, the maximal contraction produced by both drugs was unchanged. Taken together the data support a maturation of presynaptic function and/or upstream elements during early ageing that is lost after genetic reduction of insulin signalling. Furthermore, this experimental approach has demonstrated a counterintuitive phenomenon: in aged worms neuromuscular strength is maintained despite the absence of motility. PMID- 23038731 TI - Inter-leg coordination in the control of walking speed in Drosophila. AB - Legged locomotion is the most common behavior of terrestrial animals and it is assumed to have become highly optimized during evolution. Quadrupeds, for instance, use distinct gaits that are optimal with regard to metabolic cost and have characteristic kinematic features and patterns of inter-leg coordination. In insects, the situation is not as clear. In general, insects are able to alter inter-leg coordination systematically with locomotion speed, producing a continuum of movement patterns. This notion, however, is based on the study of several insect species, which differ greatly in size and mass. Each of these species tends to walk at a rather narrow range of speeds. We have addressed these issues by examining four strains of Drosophila, which are similar in size and mass, but tend to walk at different speed ranges. Our data suggest that Drosophila controls its walking speed almost exclusively via step frequency. At high walking speeds, we invariably found tripod coordination patterns, the quality of which increased with speed as indicated by a simple measure of tripod coordination strength (TCS). At low speeds, we also observed tetrapod coordination and wave gait-like walking patterns. These findings not only suggest a systematic speed dependence of inter-leg movement patterns but also imply that inter-leg coordination is flexible. This was further supported by amputation experiments in which we examined walking behavior in animals after the removal of a hindleg. These animals show immediate adaptations in body posture, leg kinematics and inter-leg coordination, thereby maintaining their ability to walk. PMID- 23038732 TI - Behavior and survival of Mytilus congeners following episodes of elevated body temperature in air and seawater. AB - Coping with environmental stress may involve combinations of behavioral and physiological responses. We examined potential interactions between adult mussels' simple behavioral repertoire - opening/closing of the shell valves - and thermal stress physiology in common-gardened individuals of three Mytilus congeners found on the West Coast of North America: two native species (M. californianus and M. trossulus) and one invasive species from the Mediterranean (M. galloprovincialis). We first continuously monitored valve behavior over three consecutive days on which body temperatures were gradually increased, either in air or in seawater. A temperature threshold effect was evident between 25 and 33 degrees C in several behavioral measures. Mussels tended to spend much less time with the valves in a sealed position following exposure to 33 degrees C body temperature, especially when exposed in air. This behavior could not be explained by decreases in adductor muscle glycogen (stores of this metabolic fuel actually increased in some scenarios), impacts of forced valve sealing on long-term survival (none observed in a second experiment), or loss of contractile function in the adductor muscles (individuals exhibited as many or more valve adduction movements following elevated body temperature compared with controls). We hypothesize that this reduced propensity to seal the valves following thermal extremes represents avoidance of hypoxia-reoxygenation cycles and concomitant oxidative stress. We further conjecture that prolonged valve gaping following episodes of elevated body temperature may have important ecological consequences by affecting species interactions. We then examined survival over a 90 day period following exposure to elevated body temperature and/or emersion, observing ongoing mortality throughout this monitoring period. Survival varied significantly among species (M. trossulus had the lowest survival) and among experimental contexts (survival was lowest after experiencing elevated body temperature in seawater). Surprisingly, we observed no cumulative impact on survival of 3 days relative to 1 day of exposure to elevated body temperature. The delayed mortality and context-specific outcomes we observed have important implications for the design of future experiments and for interpretation of field distribution patterns of these species. Ultimately, variation in the catalog of physiological and behavioral capacities among closely related or sympatric species is likely to complicate prediction of the ecological consequences of global change and species invasions. PMID- 23038733 TI - miR-203b: a novel regulator of MyoD expression in tilapia skeletal muscle. AB - MyoD is one of the helix-loop-helix proteins regulating muscle-specific gene expression in tilapia. Tight regulation of the MyoD protein level is necessary for the precise regulation of skeletal muscle development. MicroRNAs (miRNAs) are a class of regulatory RNAs that post-transcriptionally regulate gene expression. An increasing amount of evidence has suggested that miRNAs play an important role in regulating skeletal muscle development. We reasoned that MyoD expression may be regulated by miRNAs. Predictions from bioinformatics have identified a putative miR-203b target site in the 3'-UTR of the MyoD gene. Interestingly, miR 203b expression is negatively correlated with MyoD expression, whereas miR-203b suppression leads to a significant increase in MyoD expression, thereby activating MyoD downstream genes. A 3'-UTR luciferase reporter assay further verifies the direct interaction between miR-203b and MyoD. Taken together, our results reveal a novel molecular mechanism in which miRNA participates in transcriptional circuits that regulate gene expression in tilapia skeletal muscle. PMID- 23038735 TI - Factors shaping the ontogeny of vocal signals in a wild parrot. AB - Parrots rely heavily on vocal signals to maintain their social and mobile lifestyles. We studied vocal ontogeny in nests of wild green-rumped parrotlets (Forpus passerinus) in Venezuela. We identified three successive phases of vocal signaling that corresponded closely to three independently derived phases of physiological development. For each ontogenetic phase, we characterized the relative importance of anatomical constraints, motor skills necessary for responding to specific contexts of the immediate environment, and the learning of signals that are necessary for adult forms of communication. We observed shifts in the relative importance of these three factors as individuals progressed from one stage to the next; there was no single fixed ratio of factors that applied across the entire ontogenetic sequence. The earliest vocalizations were short in duration, as predicted from physical constraints and under-developed motor control. Calls became longer and frequency modulated during intermediate nestling ages in line with motor skills required for competitive begging. In the week before fledging, calls drastically shortened in accordance with the flight constrained short durations of adult contact calls. The latter constraints were made evident by the demonstrated links between wing-assisted incline running, a widespread prelude to avian flight, just before the shift from long-duration begging calls to short-duration contact calls. At least in this species, the shifting emphases of factors at different ontogenetic stages precluded the morphing of intermediate-stage begging calls into adult contact calls; as shown previously, the latter are influenced by sample templates provided by parents. PMID- 23038734 TI - A conserved role for the 20S proteasome and Nrf2 transcription factor in oxidative stress adaptation in mammals, Caenorhabditis elegans and Drosophila melanogaster. AB - In mammalian cells, hydrogen peroxide (H(2)O(2))-induced adaptation to oxidative stress is strongly dependent on an Nrf2 transcription factor-mediated increase in the 20S proteasome. Here, we report that both Caenorhabditis elegans nematode worms and Drosophila melanogaster fruit flies are also capable of adapting to oxidative stress with H(2)O(2) pre-treatment. As in mammalian cells, this adaptive response in worms and flies involves an increase in proteolytic activity and increased expression of the 20S proteasome, but not of the 26S proteasome. We also found that the increase in 20S proteasome expression in both worms and flies, as in mammalian cells, is important for the adaptive response, and that it is mediated by the SKN-1 and CNC-C orthologs of the mammalian Nrf2 transcription factor, respectively. These studies demonstrate that stress mechanisms operative in cell culture also apply in disparate intact organisms across a wide biological diversity. PMID- 23038736 TI - Intracapsular algae provide fixed carbon to developing embryos of the salamander Ambystoma maculatum. AB - Each spring, North American spotted salamander (Ambystoma maculatum) females each lay hundreds of eggs in shallow pools of water. Eggs are surrounded by jelly layers and are deposited as large gelatinous masses. Following deposition, masses are penetrated by a mutualistic green alga, Oophila amblystomatis, which enters individual egg capsules, proliferates and aggregates near the salamander embryo, providing oxygen that enhances development. We examined the effects of population density of intracapsular O. amblystomatis on A. maculatum embryos and show that larger algal populations promote faster embryonic growth and development. Also, we show that carbon fixed by O. amblystomatis is transferred to the embryos, providing the first evidence of direct translocation of photosynthate from a symbiont to a vertebrate host. PMID- 23038737 TI - Adaptation to different salinities exposes functional specialization in the intestine of the sea bream (Sparus aurata L.). AB - The processing of intestinal fluid, in addition to a high drinking rate, is essential for osmoregulation in marine fish. This study analyzed the long-term response of the sea bream (Sparus aurata L.) to relevant changes of external salinity (12, 35 and 55 p.p.t.), focusing on the anterior intestine and in the less-often studied rectum. Intestinal water absorption, epithelial HCO(3)(-) secretion and gene expression of the main molecular mechanisms (SLC26a6, SLC26a3, SLC4a4, atp6v1b, CFTR, NKCC1 and NKCC2) involved in Cl(-) and HCO(3)(-) movements were examined. The anion transporters SLC26a6 and SLC26a3 are expressed severalfold higher in the anterior intestine, while the expression of Atp6v1b (V type H(+)-ATPase beta-subunit) is severalfold higher in the rectum. Prolonged exposure to altered external salinity was without effect on water absorption but was associated with concomitant changes in intestinal fluid content, epithelial HCO(3)(-) secretion and salinity-dependent expression of SLC26a6, SLC26a3 and SLC4a4 in the anterior intestine. However, the most striking response to external salinity was obtained in the rectum, where a 4- to 5-fold increase in water absorption was paralleled by a 2- to 3-fold increase in HCO(3)(-) secretion in response to a salinity of 55 p.p.t. In addition, the rectum of high salinity acclimated fish shows a sustained (and enhanced) secretory current (I(sc)), identified in vitro in Ussing chambers and confirmed by the higher expression of CFTR and NKCC1 and by immunohistochemical protein localization. Taken together, the present results suggest a functional anterior-posterior specialization with regard to intestinal fluid processing and subsequently to salinity adaptation of the sea bream. The rectum becomes more active at higher salinities and functions as the final controller of intestinal function in osmoregulation. PMID- 23038738 TI - Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in hyp mice. AB - We have previously confirmed a paradoxical mineralizing enthesopathy as a hallmark of X-linked hypophosphatemia. X-linked hypophosphatemia is the most common of the phosphate-wasting disorders mediated by elevated fibroblast growth factor 23 (FGF23) and occurs as a consequence of inactivating mutations of the PHEX gene product. Despite childhood management of the disease, these complications of tendon and ligament insertion sites account for a great deal of the disease's morbidity into adulthood. It is unclear whether the enthesopathy occurs in other forms of renal phosphate-wasting disorders attributable to high FGF23 levels. Here we describe two patients with autosomal recessive hypophosphatemic rickets due to the Met1Val mutation in dentin matrix acidic phosphoprotein 1 (DMP1). In addition to the biochemical and skeletal features of long-standing rickets with elevated FGF23 levels, these individuals exhibited severe, debilitating, generalized mineralized enthesopathy. These data suggest that enthesophytes are a feature common to FGF23-mediated phosphate-wasting disorders. To address this possibility, we examined a murine model of FGF23 overexpression using a transgene encoding the secreted form of human FGF23 (R176Q) cDNA (FGF23-TG mice). We report that FGF23-TG mice display a similar mineralizing enthesopathy of the Achilles and plantar facial insertions. In addition, we examined the impact of standard therapy for phosphate-wasting disorders on enthesophyte progression. We report that fibrochondrocyte hyperplasia persisted in Hyp mice treated with oral phosphate and calcitriol. In addition, treatment had the untoward effect of further exacerbating the mineralization of fibrochondrocytes that define the bone spur of the Achilles insertion. These studies support the need for newer interventions targeted at limiting the actions of FGF23 and minimizing both the toxicities and potential morbidities associated with standard therapy. PMID- 23038739 TI - The Scribble/Lgl/Dlg polarity protein complex is a regulator of blood-testis barrier dynamics and spermatid polarity during spermatogenesis. AB - During spermatogenesis, spermiogenesis that releases sperm into the tubule lumen and restructuring of the blood-testis barrier (BTB) that accommodates the transit of preleptotene spermatocytes take place simultaneously, but at the opposite ends of the seminiferous epithelium. These events are tightly regulated and coordinated; however, neither the underlying mechanism(s) nor the involving molecules are known. Herein, the Scribble/Lgl (Lethal giant larvae)/Dlg (Discs large) polarity complex was shown to regulate spermatid polarity during spermiogenesis and tight junction (TJ)-permeability barrier via changes in protein distribution at the apical ectoplasmic specialization and the BTB during the epithelial cycle, respectively. Scribble, Lgl2, and Dlg1 were found to be expressed by Sertoli and germ cells. Scribble also displayed stage-specific expression at the BTB, being highest at stages VII-VIII, colocalizing with TJ proteins occludin and ZO-1. Unlike components of other polarity complex modules, such as partitioning-defective 6, the knockdown of which by RNA interference was found to impede Sertoli cell TJ barrier, a knockdown of the Scribble complex (i.e. simultaneous knockdown of Scribble, Lgl and Dlg or Lgl alone; but not Scribble or Dlg alone) both in vitro and in vivo promoted the TJ integrity. This was mediated by reorganizing actin filament network at the Sertoli cell-cell interface, which, in turn, affected changes in the localization and/or distribution of occludin and/or beta-catenin at the BTB. These knockdowns also perturbed F-actin organization at the Sertoli cell-spermatid interface, thereby modulating spermatid adhesion and polarity at the apical ectoplasmic specialization. In summary, the Scribble/Lgl/Dlg complex participates in the regulation of BTB dynamics and spermatid adhesion/polarity in the testis. PMID- 23038740 TI - Evidence that dopamine acts via kisspeptin to hold GnRH pulse frequency in check in anestrous ewes. AB - Recent work has implicated stimulatory kisspeptin neurons in the arcuate nucleus (ARC) as important for seasonal changes in reproductive function in sheep, but earlier studies support a role for inhibitory A15 dopaminergic (DA) neurons in the suppression of GnRH (and LH) pulse frequency in the nonbreeding (anestrous) season. Because A15 neurons project to the ARC, we performed three experiments to test the hypothesis that A15 neurons act via ARC kisspeptin neurons to inhibit LH in anestrus: 1) we used dual immunocytochemistry to determine whether these ARC neurons contain D2 dopamine receptor (D2-R), the receptor responsible for inhibition of LH in anestrus; 2) we tested the ability of local administration of sulpiride, a D2-R antagonist, into the ARC to increase LH secretion in anestrus; and 3) we determined whether an antagonist to the kisspeptin receptor could block the increase in LH secretion induced by sulpiride in anestrus. In experiment 1, 40% of this ARC neuronal subpopulation contained D2-R in breeding season ewes, but this increased to approximately 80% in anestrus. In experiment 2, local microinjection of the two highest doses (10 and 50 nmol) of sulpiride into the ARC significantly increased LH pulse frequency to levels 3 times that seen with vehicle injections. Finally, intracerebroventricular infusion of a kisspeptin receptor antagonist completely blocked the increase in LH pulse frequency induced by systemic administration of sulpiride to anestrous ewes. These results support the hypothesis that DA acts to inhibit GnRH (and LH) secretion in anestrus by suppressing the activity of ARC kisspeptin neurons. PMID- 23038742 TI - Inbreeding or population structure? PMID- 23038741 TI - Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status. AB - OBJECTIVE: To clarify whether genetic and common infectious backgrounds are distinct, according to anti-aquaporin 4 (AQP4) antibody status in Japanese patients with neuromyelitis optica (NMO). METHODS: We analysed human leucocyte antigen (HLA)-DRB1 and HLA-DPB1 alleles, and IgG antibodies against Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus and Epstein-Barr virus nuclear antigen (EBNA) in 116 patients with NMO, including 39 patients with neuromyelitis optica spectrum disorder (NMOSD), 145 multiple sclerosis (MS) patients and 367 unrelated healthy controls. 77 NMO/NMOSD patients were seropositive for AQP4 antibody while 39 were seronegative. RESULTS: Compared with healthy controls, NMO/NMOSD patients showed a significantly lower frequency of DRB1*0901 and significantly higher frequencies of DRB1*1602 and DPB1*0501, which conferred susceptibility to anti-AQP4 antibody positive NMO/NMOSD, but not antibody negative NMO/NMOSD. DRB1*0901 was a common protective allele, irrespective of the presence or absence of anti-AQP4 antibody. Anti-H pylori and anti-C pneumoniae antibodies were more commonly detected in anti-AQP4 antibody positive NMO/NMOSD patients than healthy controls. Antibody negative NMO/NMOSD patients did not differ from healthy controls regarding the presence of these antibodies. The presence or absence of antibodies against varicella zoster virus and EBNA did not vary among the groups. The frequencies of antibodies against these four pathogens were not significantly different between MS patients and healthy controls. CONCLUSIONS: Our results suggest that HLA-DRB1*1602 and DPB1*0501 alleles and H pylori and Chlamydia pneumonia infection are risk factors only for anti-AQP4 antibody positive NMO/NMOSD but not for anti-AQP4 antibody negative NMO/NMOSD. PMID- 23038743 TI - Transcriptomic analysis identifies candidate genes and functional networks controlling the response of porcine peripheral blood mononuclear cells to mitogenic stimulation. AB - It is difficult to obtain phenotypic data on disease susceptibility directly from swine in an industry setting. The magnitude of the proliferative response of peripheral blood mononuclear cells (PBMC) to the T cell mitogen concanavalin A (Con A) has long been used as an indirect measure of the responsiveness of the immune system to antigenic stimulation. This trait is known to exhibit moderate heritability in swine, but little is known about the identity of the genes that control the response. In this study, we carried out a time-course microarray experiment to measure gene expression at 3 different stages (3, 20, and 68 h) poststimulation of PBMC with Con A. A total of 46, 452, and 418 differentially expressed (DifEx) genes were identified at each time point, respectively. Expression changes for a subset of these genes were subsequently confirmed by real-time PCR. Functional annotation analyses of the microarray results successfully identified sets of genes involved in processes associated with multiple aspects of cell division, such as DNA and protein synthesis, and control of mitosis. However, the discovery of genes that controlled the response of PBMC to mitogen was limited with this approach, because the drastic changes in the transcriptional program necessitated by cells undergoing division masked changes in smaller immune response gene sets. Pathway and network analyses that focused on immune cells proved to be a more effective strategy for the identification of genes that coordinate aspects of the mitogenic response that are specific to PBMC. The cytokine gene IL15 was shown to be central to the highest scoring network at 20 h and affect the expression of 16 other DifEx genes, including some genes known to regulate T cell activation, such as IL7R, JUN, TNFRSF9, and ZAP70. The IL15 gene maps to a previously identified QTL interval for immune responsiveness to Con A on SSC 8, which also contains the related IL2 gene. At 68 h, a distinct downregulation of major histocompatibility complex class II antigen presentation genes was observed. Overall, the gene expression profile of the Con A-stimulated porcine PBMC points to a Th(1) bias in immune activation. Further work is required to determine whether polymorphisms linked to genes identified in this study affect this immune response trait in pig populations and whether the trait itself correlates with decreased susceptibility to intracellular pathogens in swine. PMID- 23038744 TI - Components of the accuracy of genomic prediction in a multi-breed sheep population. AB - In genome-wide association studies, failure to remove variation due to population structure results in spurious associations. In contrast, for predictions of future phenotypes or estimated breeding values from dense SNP data, exploiting population structure arising from relatedness can actually increase the accuracy of prediction in some cases, for example, when the selection candidates are offspring of the reference population where the prediction equation was derived. In populations with large effective population size or with multiple breeds and strains, it has not been demonstrated whether and when accounting for or removing variation due to population structure will affect the accuracy of genomic prediction. Our aim in this study was to determine whether accounting for population structure would increase the accuracy of genomic predictions, both within and across breeds. First, we have attempted to decompose the accuracy of genomic prediction into contributions from population structure or linkage disequilibrium (LD) between markers and QTL using a diverse multi-breed sheep (Ovis aries) data set, genotyped for 48,640 SNP. We demonstrate that SNP from a single chromosome can achieve up to 86% of the accuracy for genomic predictions using all SNP. This result suggests that most of the prediction accuracy is due to population structure, because a single chromosome is expected to capture relationships but is unlikely to contain all QTL. We then explored principal component analysis (PCA) as an approach to disentangle the respective contributions of population structure and LD between SNP and QTL to the accuracy of genomic predictions. Results showed that fitting an increasing number of principle components (PC; as covariates) decreased within breed accuracy until a lower plateau was reached. We speculate that this plateau is a measure of the accuracy due to LD. In conclusion, a large proportion of the accuracy for genomic predictions in our data was due to variation associated with population structure. Surprisingly, accounting for this structure generally decreased the accuracy of across breed genomic predictions. PMID- 23038745 TI - Bayesian genome-wide association analysis of growth and yearling ultrasound measures of carcass traits in Brangus heifers. AB - Data from developing Brangus heifers (3/8 Brahman-Bos indicus * 5/8 Angus-Bos taurus; n ~ 802 from 67 sires) registered with International Brangus Breeders Association were analyzed to detect QTL associated with growth traits and ultrasound measures of carcass traits. Genotypes were from BovineSNP50 (Infinium BeadChip, Illumina, San Diego, CA; 53,692 SNP). Phenotypes included BW collected at birth and ~205 and 365 d of age, and yearling ultrasound assessment of LM area, percent intramuscular fat, and depth of rib fat. Simultaneous association of SNP windows with phenotype were undertaken with Bayes C analyses, using GenSel software. The SNP windows were ~ 5 SNP in length. Analyses fitted a mixture model that treated SNP effects as random, with an assumed fraction pi = 0.999 having no effect on phenotype. Bootstrap analyses were used to obtain significance values for the SNP windows with the greatest contribution to observed variation. The SNP windows with P < 0.01 were considered as QTL associated with a trait in which case their location was queried from dbSNP and the presence of a previously reported QTL in that location was checked in CattleQTLdb. For 9 traits, QTL were mapped to 139 regions on 25 chromosomes. Forty-one of these QTL were already described in CattleQTLdb, so 98 are new additions. The SNP windows on chromosomes 1, 3, and 6 were associated with multiple traits (i.e., 205- and 365- d BW, and ADG from birth to 205 and 365 d of age). Several chromosomes harbored regions associated with multiple traits; however, the SNP that comprised the window often varied among traits (i.e., chromosomes 1, 3, 4, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 20, 21, 22, 24, 28, and 29). Results from whole genome association of SNP with growth and ultrasound carcass traits in developing Brangus heifers confirmed several published QTL and detected several new QTL. PMID- 23038746 TI - Use of different levels of ground endophyte-infected tall fescue seed during heat stress to separate characteristics of fescue toxicosis. AB - Studies of fescue toxicosis using whole seed diets show reduced feed intake and thermoregulatory ability, but much of the seed passes undigested through the animal. Cattle were fed ground tall fescue seed at different levels to potentially facilitate digestion and absorption of toxins and identify toxin sensitivity for major characteristics of the condition [i.e., hyperthermia, reduced feed intake (FI), reduced blood prolactin]. Steers (n = 18; 350 kg BW) were housed in the Brody Climatology Laboratory at thermoneutrality (TN; 19 degrees C) and randomly assigned to daily diet treatments with either ground endophyte-infected [E+; low and high doses at 20 and 40 MUg ergovaline/(kg BW/d), respectively] or endophyte-free [E-; control at 0 MUg ergovaline/(kg BW/d)] tall fescue seed. After 12 d at TN, animals received 2 d of transition to heat stress (HS; 36 degrees C daytime, 25 degrees C nighttime) and maintained for 14 more days. Cattle were fed twice daily at 0800 and 1600 h, with water ad libitum. Feed intake was measured at 0700 h, with skin and rectal temperatures, and respiration rate at 0600, 1100, 1600, and 2100 h. Blood was sampled on selected days for prolactin and leptin determinations. Steers fed ground E+ diet decreased (P <= 0.0001) FI below controls at TN, with no dose effect. Maximum FI reduction with E+ treatment was 25% at TN, with an additional 46% decrease during HS (P <= 0.05). By the end of HS, E+ FI increased (P > 0.05) to that of E-, suggesting recovery. Prolactin was reduced (P <= 0.05) in high E+ cattle below controls at study end. Leptin blood concentrations were unaffected by E+ treatment (P > 0.05) but was reduced (P <= 0.05) by the end of HS. Pattern of rectal temperature response to HS showed a more rapid initial increase and decline for both E+ groups compared with controls (P <= 0.05). Skin temperature was the only variable that identified E+ dose differences. Although there were no treatment differences at TN, skin temperature was lower (P <= 0.05) for high E+ steers compared with controls during HS when air temperature was reduced each day. In general, FI was more responsive to E+ toxins than body temperature or blood prolactin, declining even at TN and exhibiting dynamic activity during HS. Although body temperature response to E+ toxins appears to stabilize during HS, this is misleading as rapid change in air temperature exposes effects on skin temperature. PMID- 23038747 TI - EXTENSION EDUCATION SYMPOSIUM: reinventing extension as a resource--what does the future hold? AB - The mission of the Cooperative Extension Service, as a component of the land grant university system, is to disseminate new knowledge and to foster its application and use. Opportunities and challenges facing animal agriculture in the United States have changed dramatically over the past few decades and require the use of new approaches and emerging technologies that are available to extension professionals. Increased federal competitive grant funding for extension, the creation of eXtension, the development of smartphone and related electronic technologies, and the rapidly increasing popularity of social media created new opportunities for extension educators to disseminate knowledge to a variety of audiences and engage these audiences in electronic discussions. Competitive grant funding opportunities for extension efforts to advance animal agriculture became available from the USDA National Institute of Food and Agriculture (NIFA) and have increased dramatically in recent years. The majority of NIFA funding opportunities require extension efforts to be integrated with research, and NIFA encourages the use of eXtension and other cutting-edge approaches to extend research to traditional clientele and nontraditional audiences. A case study is presented to illustrate how research and extension were integrated to improve the adoption of AI by beef producers. Those in agriculture are increasingly resorting to the use of social media venues such as Facebook, YouTube, LinkedIn, and Twitter to access information required to support their enterprises. Use of these various approaches by extension educators requires appreciation of the technology and an understanding of how the target audiences access information available on social media. Technology to deliver information is changing rapidly, and Cooperative Extension Service professionals will need to continuously evaluate digital technology and social media tools to appropriately integrate them into learning and educational opportunities. PMID- 23038749 TI - Clinical nursing research recognized by thomson reuters with its first impact factor. PMID- 23038748 TI - Evaluation of a mitochondrial voltage sensor, (18F fluoropentyl)triphenylphosphonium cation, in a rat myocardial infarction model. AB - Radiolabeled lipophilic cationic compounds, such as (18)F-labeled phosphonium salt, accumulate in the mitochondria through a negative inner transmembrane potential. The purpose of this study was to develop and evaluate ((18)F fluoropentyl)triphenylphosphonium salt ((18)F-FPTP) as a myocardial PET agent. METHODS: A reference compound of (18)F-FPTP was synthesized via 3-step nucleophilic substitution reactions and was radiolabeled via 2-step nucleophilic substitution reactions of no-carrier-added (18)F-fluoride. Accumulations of (18)F FPTP, (3)H-tetraphenylphosphonium, and (99m)Tc-sestamibi were compared in a cultured embryonic cardiomyoblast cell line (H9c2). The biodistribution of (18)F FPTP was assessed using BALB/c mice. The (18)F-FPTP small-animal PET study was performed in Sprague-Dawley rats with or without left coronary artery (LCA) ligation. RESULTS: (18)F-FPTP was synthesized with a radiochemical yield of 15% 20% and radiochemical purity of greater than 98%. Specific activity was greater than 6.3 TBq/MUmol. Cell uptake of (18)F-FPTP was more than 15-fold higher in H9c2 than in normal fibroblasts (human normal foreskin fibroblasts). Selective collapse of mitochondrial membrane potential substantially decreased cellular uptake for (18)F-FPTP and (3)H-tetraphenylphosphonium, compared with that for (99m)Tc-sestamibi. The biodistribution data in mice (n = 24) showed rapid blood clearance and high accumulation in the heart. Heart-to-blood ratios at 10 and 30 min were 54 and 133, respectively. Heart-to-lung and heart-to-liver ratios at 10, 30, and 60 min were 4, 4, and 7 and 4, 5, and 7, respectively. Dynamic small animal PET for 60 min after injection of (18)F-FPTP showed an initial spike of radioactivity, followed by retention in the myocardium and rapid clearance from the background. (18)F-FPTP small-animal PET images in LCA-occluded rats demonstrated sharply defined myocardial defects in the corresponding area of the myocardium. The myocardial defect size measured by (18)F-FPTP small-animal PET correlated closely with the hypoperfused area measured by quantitative 2,3,5 triphenyltetrazolium chloride staining (r(2) = 0.92, P < 0.001). CONCLUSION: The excellent pharmacokinetics of (18)F-FPTP and its correlation with 2,3,5 triphenyltetrazolium chloride staining in normal and LCA-occluded rats suggest that this molecular probe may have a high potential as a mitochondrial voltage sensor for PET. This probe may also allow high throughput, with multiple daily studies and a wide distribution of PET myocardial imaging in the clinic. PMID- 23038750 TI - Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE): rationale and design of a randomised controlled trial of a cardiovascular preventive polypill based strategy in India and Europe. AB - The use of preventive medications in people at high risk of cardiovascular disease is conceptually straightforward, yet in practice the adoption of such measures is disappointingly low, plus there is wide international variation in preventive therapies. Several barriers might explain this shortfall and variation, but the simplicity and economy of a polypill-based strategy might overcome some barriers. The 'Use of a Multidrug Pill In Reducing cardiovascular Events' (UMPIRE) trial assesses whether a polypill strategy (by combining aspirin, a statin and two blood pressure lowering agents) would improve adherence to guideline-indicated therapies and would lower both blood pressure and cholesterol, in people with established cardiovascular disease. UMPIRE, running in India and three European countries (England, Ireland and the Netherlands), is an open, randomised, controlled trial designed to include 1000 participants in India and 1000 in Europe, with a followup of 12-24 months. Participants were randomised to one of two versions of the polypill or relegated to usual care. The primary study outcomes were the self-reported use of aspirin, a statin and at least two blood pressure lowering agents; as well as changes in blood pressure and cholesterol. Secondary outcomes included: any cardiovascular events, reasons for stopping medications, serious adverse events and perceived changes in quality of life. Interpretation of the study data will be enhanced by health, economic and process-related evaluations. UMPIRE is registered with the European Clinical Trials database, as EudraCT: 2009-016278-34 and the Clinical Trials Registry, India as CTRI/2010/091/000250. The trial was part of the 'Single Pill Against Cardiovascular Events (SPACE)' collaboration, which encompasses the 'IMProving Adherence using Combination Therapy (IMPACT)' and 'Kanyini Guidelines Adherence with the Polypill (Kanyini-GAP)' trials. PMID- 23038751 TI - Attenuation of plasma annexin A1 in human obesity. AB - Obesity-related metabolic disorders are characterized by mild chronic inflammation, leukocyte infiltration, and tissue fibrosis as a result of adipocytokine production from the expanding white adipose tissue. Annexin A1 (AnxA1) is an endogenous glucocorticoid regulated protein, which modulates systemic anti-inflammatory processes and, therefore, may be altered with increasing adiposity in humans. Paradoxically, we found that plasma AnxA1 concentrations inversely correlated with BMI, total percentage body fat, and waist-to-hip ratio in human subjects. Plasma AnxA1 was also inversely correlated with plasma concentrations of the acute-phase protein, C-reactive protein (CRP), and the adipocytokine leptin, suggesting that as systemic inflammation increases, anti-inflammatory AnxA1 is reduced. In addition, AnxA1 gene expression and protein were significantly up-regulated during adipogenesis in a human adipocyte cell line compared to vehicle alone, demonstrating for the first time that AnxA1 is expressed and excreted from human adipocytes. These data demonstrate a failure in the endogenous anti-inflammatory system to respond to increasing systemic inflammation resulting from expanding adipose tissue, a condition strongly linked to the development of type 2 diabetes and cardiovascular disease. These data raise the possibility that a reduction in plasma AnxA1 may contribute to the chronic inflammatory phenotype observed in human obesity. PMID- 23038752 TI - Impaired myogenesis in estrogen-related receptor gamma (ERRgamma)-deficient skeletal myocytes due to oxidative stress. AB - Specialized contractile function and increased mitochondrial number and oxidative capacity are hallmark features of myocyte differentiation. The estrogen-related receptors (ERRs) can regulate mitochondrial biogenesis or mitochondrial enzyme expression in skeletal muscle, suggesting that ERRs may have a role in promoting myogenesis. Therefore, we characterized myogenic programs in primary myocytes isolated from wild-type (M-ERRgammaWT) and muscle-specific ERRgamma(-/-) (M ERRgamma(-/-)) mice. Myotube maturation and number were decreased throughout differentiation in M-ERRgamma(-/-) primary myocytes, resulting in myotubes with reduced mitochondrial content and sarcomere assembly. Compared with M-ERRgammaWT myocytes at the same differentiation stage, the glucose oxidation rate was reduced by 30% in M-ERRgamma(-/-) myotubes, while medium-chain fatty acid oxidation was increased by 34% in M-ERRgamma(-/-) myoblasts and 36% in M ERRgamma(-/-) myotubes. Concomitant with increased reliance on mitochondrial beta oxidation, H(2)O(2) production was significantly increased by 40% in M-ERRgamma( /-) myoblasts and 70% in M-ERRgamma(-/-) myotubes compared to M-ERRgammaWT myocytes. ROS activation of FoxO and NF-kappaB and their downstream targets, atrogin-1 and MuRF1, was observed in M-ERRgamma(-/-) myocytes. The antioxidant N acetyl cysteine rescued myotube formation and atrophy gene induction in M ERRgamma(-/-) myocytes. These results suggest that loss of ERRgamma causes metabolic defects and oxidative stress that impair myotube formation through activation of skeletal muscle atrophy pathways. PMID- 23038753 TI - Methylation of RASSF1A gene promoter is regulated by p53 and DAXX. AB - Inactivation of the tumor suppressor Ras-association domain family 1 isoform A (RASSF1A) due to epigenetic silencing occurs in a variety of human cancers, and still largely unknown are the regulators and mechanisms underlying RASSF1A gene promoter methylation. Herein, we report that this methylation is regulated by p53 and death-associated protein 6 (DAXX) in acute lymphoblastic leukemia (ALL). We found that p53 bound to the RASSF1A promoter, recruiting DAXX as well as DNA methyltransferase 1 (DNMT1) for DNA methylation, which subsequently resulted in inactivation of RASSF1A in wild-type p53 ALL cells. Although the presence of p53 was required for the recruitment of DAXX and DNMT1 to the RASSF1A promoter, fluctuation in p53 protein levels did not affect the rates of RASSF1A methylation. Conversely, methylation of RASSF1A promoter was critically controlled by DAXX, as the enforced overexpression of DAXX led to enhanced RASSF1A promoter methylation, whereas inhibition of DAXX reduced RASSF1A methylation. Interestingly, we found that the p53/DAXX-mediated RASSF1A methylation regulated murine double minute 2 (MDM2) protein stability in ALL. Our results reveal a novel function for p53 in the methylation of RASSF1A promoter by its interaction with DAXX. Discovery of this mechanism provides new insight into the interactions among the tumor-related factors p53, RASSF1A, DAXX, and MDM2 in cancer pathogenesis. PMID- 23038754 TI - A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice. AB - Alzheimer's disease (AD), one of the leading neurodegenerative disorders of older adults, which causes major socioeconomic burdens globally, lacks effective therapeutics without significant side effects. Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been reported that cyclin-dependent kinase 5 (Cdk5), a critical neuronal kinase, is hyperactivated in AD brains and is, in part, responsible for the above pathology. Here we show that a modified truncated 24-aa peptide (TFP5), derived from the Cdk5 activator p35, penetrates the blood-brain barrier after intraperitoneal injections, inhibits abnormal Cdk5 hyperactivity, and significantly rescues AD pathology (up to 70-80%) in 5XFAD AD model mice. The mutant mice, injected with TFP5 exhibit behavioral rescue, whereas no rescue was observed in mutant mice injected with either saline or scrambled peptide. However, TFP5 does not inhibit cell cycle Cdks or normal Cdk5/p35 activity, and thereby has no toxic side effects (even at 200 mg/kg), a common problem in most current therapeutics for AD. In addition, treated mice displayed decreased inflammation, amyloid plaques, NFTs, cell death, and an extended life by 2 mo. These results suggest TFP5 as a potential therapeutic, toxicity-free candidate for AD. PMID- 23038756 TI - PTEN regulates TLR5-induced intestinal inflammation by controlling Mal/TIRAP recruitment. AB - Defective IL-10 allele is a risk factor for intestinal inflammation. Indeed, IL 10(-/-) mice are predisposed to spontaneous colitis in the presence of intestinal microbiota, indicating that microbial factors contribute to developing intestinal inflammation. By recognizing flagellin, TLR5 plays a quintessential role in microbial recognition in intestinal epithelial cells. Here, we treated flagellin (1.0 MUg/mouse/d) in mouse colon and found that it elicited colonic inflammation in IL-10(-/-) mice, characterized with tissue hypertrophy, inflamed epithelium, and enhanced cytokine production in the colon (MPO, KC, IL-6; >=2-fold; P < 0.05). These inflammatory effects were dramatically inhibited in TLR5(-/-);IL-10( /-) mice. Intestinal epithelium specific PTEN deletion significantly attenuated flagellin-promoted colonic inflammation in IL-10(-/-) mice. As a molecular mechanism that PTEN deletion inhibited TLR5-elicited responses, we hypothesized that PTEN regulated TLR5-induced responses by controlling the involvement of Mal in TLR5 engagement. Mal interacted with TLR5 on flagellin, and Mal deficiency inhibited flagellin-induced responses in intestinal epithelial cells. Similarly, Mal(-/-);IL-10(-/-) mice showed reduced flagellin-promoted responses. Furthermore, PTEN deletion disrupted Mal-TLR5 interaction, resulting in diminished TLR5-induced responses. PTEN deletion impeded Mal localization at the plasma membrane and suppressed Mal-TLR5 interaction. These results suggest that, by controlling Mal recruitment, PTEN regulates TLR5-induced inflammatory responses. PMID- 23038757 TI - Regulation of RCAN1 translation and its role in oxidative stress-induced apoptosis. AB - Abnormal expression of regulator of calcineurin 1 (RCAN1) has been implicated in Alzheimer's disease (AD) and Down's syndrome (DS). There are two major isoforms of RCAN1, isoforms 1 and 4. RCAN1 isoform 1 is predominantly expressed in the brain, particularly in neurons. In this report, we showed that there are two translation start codons in RCAN1 exon 1 serving as a functional translation initiation site to generate a longer 41-kDa isoform 1 (RCAN1.1L) and a shorter 31 kDa isoform 1 (RCAN1.1S). The first translation initiation site has higher translation efficiency than the downstream second one, and the translation initiation of two AUG sites is by a Cap-dependent mechanism. Short-term expression of RCAN1.1L protected SH-SY5Y cells from oxidative stress-induced apoptosis by inhibiting caspase-3 activation. However, long-term accumulation of RCAN1.1L in SH-SY5Y cells promoted oxidative stress-induced apoptosis via caspase 3 activation, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that the apoptosis ratio was increased to 499.03 +/- 47.56% in SH 1.1L cells compared with 283.93 +/- 28.66% in control cells. Furthermore, we found that RCAN1.1L is significantly elevated in the AD brains and patients with DS. RCAN1.1S is expressed at a low level in both human cells and brain tissues. Our results defined the regulatory mechanism underlying RCAN1 expression and the roles of RCAN1.1 in oxidative stress-induced neurodegeneration in AD and DS pathogenesis. PMID- 23038755 TI - Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. AB - The accumulation of aggregated amyloid-beta (Abeta) in amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation-glial fibrillary acid protein (Gfap) and vimentin (Vim)-in transgenic mice expressing mutant human amyloid precursor protein and presenilin-1 (APP/PS1). The gene deletions increased amyloid plaque load: APP/PS1 Gfap(-/-)Vim(-/-) mice had twice the plaque load of APP/PS1 Gfap(+/+)Vim(+/+) mice at 8 and 12 mo of age. APP expression and soluble and interstitial fluid Abeta levels were unchanged, suggesting that the deletions had no effect on APP processing or Abeta generation. Astrocyte morphology was markedly altered by the deletions: wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap(-/-)Vim(-/-) astrocytes had little process hypertrophy and lacked contact with adjacent plaques. Moreover, Gfap and Vim gene deletion resulted in a marked increase in dystrophic neurites (2- to 3-fold higher than APP/PS1 Gfap(+/+)Vim(+/+) mice), even after normalization for amyloid load. These results suggest that astrocyte activation limits plaque growth and attenuates plaque-related dystrophic neurites. These activities may require intimate contact between astrocyte and plaque. PMID- 23038758 TI - Predictive impact of RRM1 protein expression on vinorelbine efficacy in NSCLC patients randomly assigned in a chemotherapy phase III trial. AB - BACKGROUND: Platinum-based doublets (PBDs) remain the cornerstone of treatment in non-small-cell lung cancer (NSCLC) and may include gemcitabine. A biomarker predicting sensitivity to this antimetabolite would represent a major step forward. Accordingly, we explored the predictive role of ribonucleotide reductase subunit M (RRM1) in advanced NSCLC. PATIENTS AND METHODS: A total of 443 patients were randomly assigned to regimen A [paclitaxel (Taxol) and cisplatin with gemcitabine] or regimen B (cisplatin and vinorelbine). Immunohistochemical evaluation of RRM1 was correlated to clinical end-points. RESULTS: A total of 261 (58.9%) patients had representative tissue samples for RRM1 evaluation. Disease control rate, progression-free survival (PFS) and overall survival (OS) were substantially improved in patients with RRM-negative (neg) tumors receiving regimen B when compared with patients with RRM-positive (pos) tumors (68.8% versus 31.2%, P = 0.046, 6.90 months versus 3.93 months, P = 0.000 and 11.57 months versus 7.4 months, P = 0.002, respectively). Interaction analysis between RRM1-neg status and adenocarcinomas yielded a hazard ratio (HR) of 0.36 for death (P = 0.000). CONCLUSIONS: RRM1 protein expression was without any predictive impact in patients treated with cisplatin, paclitaxel and gemcitabine. Surprisingly, the predictive power was demonstrated in the cisplatin and vinorelbine arm and may suggest that RRM1 is involved in vinorelbine sensitivity warranting further research. PMID- 23038760 TI - Whole-body 18FDG-PET/CT or whole-body gadolinium-enhanced MRI for distant staging? PMID- 23038759 TI - Management of anticancer treatment in patients under chronic dialysis: results of the multicentric CANDY (CANcer and DialYsis) study. AB - BACKGROUND: One million people worldwide benefit from chronic dialysis, with an increased rate in Western countries of 5% yearly. Owing to increased incidence of cancer in dialyzed patients, the management of these patients is challenging for oncologists/nephrologists. PATIENTS AND METHODS: The CANcer and DialYsis (CANDY) retrospective multicenter study included patients under chronic dialysis who subsequently had a cancer (T0). Patients were followed up for 2 years after T0. Prescriptions of anticancer drugs were studied with regard to their renal dosage adjustment/dialysability. RESULTS: A total of 178 patients from 12 institutions were included. The mean time between initiation of dialysis and T0 was 30.8 months. Fifty patients had received anticancer drug treatment. Among them, 72% and 82% received at least one drug needing dosage and one drug to be administered after dialysis sessions, respectively. Chemotherapy was omitted or prematurely stopped in many cases where systemic treatment was indicated or was often not adequately prescribed. CONCLUSIONS: Survival in dialysis patients with incident cancer was poor. It is crucial to consider anticancer drug treatment in these patients as for non-dialysis patients and to use current available specific drug management recommendations in order to (i) adjust the dose and (ii) avoid premature elimination of the drug during dialysis sessions. PMID- 23038761 TI - Lobular endocervical glandular hyperplasia and peritoneal pigmentation associated with Peutz-Jeghers syndrome due to a germline mutation of STK11. PMID- 23038762 TI - Prospective study to assess fluid accumulation and tenosynovial changes in the aromatase inhibitor-induced musculoskeletal syndrome: 2-year follow-up data. AB - BACKGROUND: Aromatase inhibitors (AIs) frequently lead to the AI-induced musculoskeletal syndrome (AIMSS). Looking into its pathophysiology, 6 months of AI therapy thickens the tendon sheath with intra-articular fluid (IAF) retention and loss of grip strength. We here report 24-month follow-up data. PATIENTS AND METHODS: A prospective cohort study of 33 postmenopausal breast cancer patients received adjuvant endocrine therapy; 27 received an AI and 6 received tamoxifen. At baseline, 6 and 24 months patients had a rheumatologic examination, including a grip strength test, and magnetic resonance imaging of both hands and wrists. The primary end point was tenosynovial changes; secondary end points were changes in morning stiffness, grip strength and IAF. RESULTS: Twenty-three AI and 5 tamoxifen patients completed all investigations. Between month 6 and 24, IAF further increased in AI users (P = 0.04) but not in tamoxifen users, and grip strength further decreased in both groups. The worsened tenosynovial changes were strongly correlated with a decrease in grip strength. At 24 months, morning stiffness continued to be present in over a third of AI users. CONCLUSION: AIMSS represents a substantial problem in breast cancer patients. It is associated with tenosynovial changes, IAF retention, joint stiffness and loss of grip strength that do not improve with prolonged use. PMID- 23038763 TI - Vernal keratoconjunctivitis: an update. AB - Vernal keratoconjunctivitis (VKC) is a bilateral, usually seasonally recurrent, allergic inflammation of the conjunctiva, characterised by limbal gelatinous hypertrophy and/or upper tarsal giant conjunctival papillae. Although rare in temperate regions, it represents an important cause of hospital referral in many parts of Africa and Asia. Clinical and immunohistochemical studies suggest that IgE-dependent (type I allergic) and IgE-independent (type IV allergic) mechanisms are involved in the immunopathogenesis of VKC, in which various inflammatory cells, including different T cell subpopulations play an active role via a cascade of chemical mediators. Endocrine, genetic, neurogenic, environmental and socioeconomic risk factors have been identified. However, its aetiology and pathophysiology remain unclear. The clinical course of this disease is usually benign and self-limiting, but a minority of patients will face very debilitating and sight threatening complications. Topical corticosteroids are often used during flare-ups in combination with mast cell stabilizers as maintenance treatment for VKC. However this management is unsatisfactory in controlling severe cases and avoiding recurrences. Non-steroidal immune modulators such as ciclosporin A and tacrolimus are promising alternatives, but tolerance to these agents needs to be improved and production costs reduced. The purpose of this review is to give an update on its epidemiology, immunopathogenesis and management. PMID- 23038764 TI - Impact of changing oxygenation policies on retinopathy of prematurity in a neonatal unit in Argentina. AB - AIMS: To assess the impact of different oxygenation policies on the rate and severity of retinopathy of prematurity (ROP). METHODS: Between January 2003 and December 2006, infants of 1500 g birthweight (BW) or less and/or 32 weeks gestational age (GA) or less, and larger, more mature infants with risk factors for ROP were examined through three different time periods: period 1: high target oxygen saturation levels (88-96%) and treatment at threshold ROP; period 2: low target oxygen saturation levels (83-93%) and treatment at threshold ROP; period 3: low target oxygen saturation and treatment at type 1 ROP. RESULTS: Type 1 ROP was detected more frequently in babies of 32 weeks GA or less (50/365, 13.7%) than in more mature babies (15/1167, 1.3%; p<0.001). The rate of type 1 ROP in period 1 was 6.9%; period 2, 3.6% and period 3, 1.8%. Rates of stage 3 ROP declined over time in both BW/GA groups (from 9.0% to 4.1% to 2.0%) as did rates of plus disease (from 7.5% to 3.6% to 1.8%). Mean BW and GA declined from period 1 to period 3, and death rates remained unchanged. 74.4% of babies received all the examinations required; 48.1% of treatments were undertaken after discharge from the neonatal unit. CONCLUSIONS: Lower target oxygen saturation was associated with a lower rate of severe ROP without increasing mortality, and changed the characteristics of affected babies. Screening criteria need to remain wide enough to identify all babies at risk of ROP needing treatment. PMID- 23038765 TI - Prevalence of blindness in children. PMID- 23038766 TI - Genetic basis of kidney cancer: role of genomics for the development of disease based therapeutics. AB - Kidney cancer is not a single disease; it is made up of a number of different types of cancer, including clear cell, type 1 papillary, type 2 papillary, chromophobe, TFE3, TFEB, and oncocytoma. Sporadic, nonfamilial kidney cancer includes clear cell kidney cancer (75%), type 1 papillary kidney cancer (10%), papillary type 2 kidney cancer (including collecting duct and medullary RCC) (5%), the microphalmia-associated transcription (MiT) family translocation kidney cancers (TFE3, TFEB, and MITF), chromophobe kidney cancer (5%), and oncocytoma (5%). Each has a distinct histology, a different clinical course, responds differently to therapy, and is caused by mutation in a different gene. Genomic studies identifying the genes for kidney cancer, including the VHL, MET, FLCN, fumarate hydratase, succinate dehydrogenase, TSC1, TSC2, and TFE3 genes, have significantly altered the ways in which patients with kidney cancer are managed. While seven FDA-approved agents that target the VHL pathway have been approved for the treatment of patients with advanced kidney cancer, further genomic studies, such as whole genome sequencing, gene expression patterns, and gene copy number, will be required to gain a complete understanding of the genetic basis of kidney cancer and of the kidney cancer gene pathways and, most importantly, to provide the foundation for the development of effective forms of therapy for patients with this disease. PMID- 23038767 TI - PUB-NChIP--"in vivo biotinylation" approach to study chromatin in proximity to a protein of interest. AB - We have developed an approach termed PUB-NChIP (proximity utilizing biotinylation with native ChIP) to purify and study the protein composition of chromatin in proximity to a nuclear protein of interest. It is based on coexpression of (1) a protein of interest, fused with the bacterial biotin ligase BirA, together with (2) a histone fused to a biotin acceptor peptide (BAP), which is specifically biotinylated by BirA-fusion in the proximity of the protein of interest. Using the RAD18 protein as a model, we demonstrate that the RAD18-proximal chromatin is enriched in some H4 acetylated species. Moreover, the RAD18-proximal chromatin containing a replacement histone H2AZ has a different pattern of H4 acetylation. Finally, biotin pulse-chase experiments show that the H4 acetylation pattern starts to resemble the acetylation pattern of total H4 after the proximity of chromatin to RAD18 has been lost. PMID- 23038768 TI - A calibrated human Y-chromosomal phylogeny based on resequencing. AB - We have identified variants present in high-coverage complete sequences of 36 diverse human Y chromosomes from Africa, Europe, South Asia, East Asia, and the Americas, representing eight major haplogroups. After restricting our analysis to 8.97 Mb of the unique male-specific Y sequence, we identified 6662 high confidence variants, including single-nucleotide polymorphisms (SNPs), multi nucleotide polymorphisms (MNPs), and indels. We constructed phylogenetic trees using these variants, or subsets of them, and recapitulated the known structure of the tree. Assuming a male mutation rate of 1 * 10(-9) per base pair per year, the time depth of the tree (haplogroups A3-R) was ~101,000-115,000 yr, and the lineages found outside Africa dated to 57,000-74,000 yr, both as expected. In addition, we dated a striking Paleolithic male lineage expansion to 41,000-52,000 yr ago and the node representing the major European Y lineage, R1b, to 4000 13,000 yr ago, supporting a Neolithic origin for these modern European Y chromosomes. In all, we provide a nearly 10-fold increase in the number of Y markers with phylogenetic information, and novel historical insights derived from placing them on a calibrated phylogenetic tree. PMID- 23038770 TI - Dual targeting of aminoacyl-tRNA synthetases to the mitochondrion and complex plastid in chlorarachniophytes. AB - In plants, many nucleus-encoded proteins are targeted to both mitochondria and plastids, and this process is generally mediated by ambiguous N-terminal targeting sequences that are recognized by receptors on both organelles. In many algae, however, plastids were acquired by secondarily engulfing green or red algae, which were retained within the endomembrane system. Protein targeting to these secondary plastids is more complex, and because they do not reside directly in the cytoplasm, dual targeting cannot function as it does in plant cells. Here we investigate dual targeting of aminoacyl-tRNA synthetases (aaRSs) in chlorarachniophytes, which are complex algae that possess secondary plastids and a relict nucleus derived from a green algal endosymbiont. Chlorarachniophytes have four genome-containing compartments, but almost all the aaRSs are nucleus encoded and present in fewer than four copies (some as few as two), suggesting multiple targeting. We characterized the subcellular localization of two classes, HisRS (three copies) and GlyRS (two copies), using GFP fusion proteins. In both cases, one copy was dually targeted to mitochondria and plastids, but unlike plants this was mediated by translation initiation variants. We also found that the periplastidal compartment (the relict green algal cytoplasm) lacks both GlyRS and a cognate tRNA, suggesting that pre-charged host tRNAs are imported into this compartment. Leader analysis of other aaRSs suggests that alternative translation is a common strategy for dual targeting in these complex cells. Overall, dual targeting to mitochondria and plastids is a shared feature of plastid-bearing organisms, but the increased complexity of trafficking into secondary plastids requires a different strategy. PMID- 23038769 TI - Mechanism of polarized lysosome exocytosis in epithelial cells. AB - Fusion of lysosomes with the plasma membrane is a calcium-dependent process that is crucial for membrane repair, limiting pathogen entry and clearing cellular debris. In non-polarized cells, lysosome exocytosis facilitates rapid resealing of torn membranes. Here, we investigate the mechanism of lysosome exocytosis in polarized epithelia, the main barrier between the organism and the external environment and the first line of defense against pathogens. We find that in polarized Madin-Darby canine kidney (MDCK) cells, calcium ionophores or pore forming toxins cause lysosomes to fuse predominantly with the basolateral membrane. This polarized exocytosis is regulated by the actin cytoskeleton, membrane cholesterol and the clathrin adaptor AP-1. Depolymerization of actin, but not microtubules, causes apical lysosome fusion, supporting the hypothesis that cortical actin is a barrier to exocytosis. Overloading lysosomes with cholesterol inhibits exocytosis, suggesting that excess cholesterol paralyzes lysosomal traffic. The clathrin adaptor AP-1 is responsible for accurately targeting syntaxin 4 to the basolateral domain. In cells lacking either the ubiquitous AP-1A or the epithelial-specific AP-1B, syntaxin 4 is non-polar. This causes lysosomes to fuse with both the apical and basolateral membranes. Consistent with these findings, RNAi-mediated depletion of syntaxin 4 inhibits basolateral exocytosis in wild-type MDCK, and both apical and basolateral exocytosis in cells lacking AP-1A or AP-1B. Our results provide fundamental insight into the molecular machinery involved in membrane repair in polarized epithelia and suggest that AP-1 is a crucial regulator of this process. PMID- 23038771 TI - The motor protein myosin 1G functions in FcgammaR-mediated phagocytosis. AB - Phagocytosis is the force-dependent complex cellular process by which immune cells engulf particles. Although there has been considerable progress in understanding ligand-receptor-induced actin polymerisation in pushing the membrane around the particle, significantly less is known about how localised contractile activities regulate cup closure in coordination with the actin cytoskeleton. Herein, we show that the unconventional class-I myosin, myosin 1G (Myo1G) is localised at phagocytic cups following Fcgamma-receptor (FcgammaR) ligation in macrophages. This progressive recruitment is dependent on the activity of phosphoinositide 3-kinase and is particularly important for engulfment of large particles. Furthermore, point mutations in the conserved pleckstrin homology-like domain of Myo1G abolishes the localisation of the motor protein at phagocytic cups and inhibits engulfment downstream of FcgammaR. Binding of Myo1G to both F-actin and phospholipids might enable cells to transport phospholipids towards the leading edge of cups and to facilitate localised contraction for cup closure. PMID- 23038773 TI - Restricted diffusion of OXPHOS complexes in dynamic mitochondria delays their exchange between cristae and engenders a transitory mosaic distribution. AB - Mitochondria are involved in cellular energy supply, signaling and apoptosis. Their ability to fuse and divide provides functional and morphological flexibility and is a key feature in mitochondrial quality maintenance. To study the impact of mitochondrial fusion/fission on the reorganization of inner membrane proteins, oxidative phosphorylation (OXPHOS) complexes in mitochondria of different HeLa cells were tagged with fluorescent proteins (GFP and DsRed-HA), and cells were fused by polyethylene glycol treatment. Redistribution of the tagged OXPHOS complexes was then followed by means of immunoelectron microscopy, two color super-resolution fluorescence microscopy and single molecule tracking. In contrast to outer membrane and matrix proteins, which mix quickly and homogeneously upon mitochondrial fusion, the mixing of inner membrane proteins was decelerated. Our data suggest that the composition of cristae is preserved during fusion of mitochondria and that cristae with mixed OXPHOS complexes are only slowly and successively formed by restricted diffusion of inner membrane proteins into existing cristae. The resulting transitory mosaic composition of the inner mitochondrial membrane illuminates mitochondrial heterogeneity and potentially is linked to local differences in function and membrane potential. PMID- 23038774 TI - Shox2 regulates progression through chondrogenesis in the mouse proximal limb. AB - In humans, loss of SHOX gene function is responsible for the mesomelic short stature characteristic of Turner syndrome, Leri-Weill dyschondrosteosis, and Langer dysplasia. In a mouse model of SHOX deficiency, Prrx1-Cre-driven limb specific deletion of the paralogous gene Shox2 results in severe rhizomelia. In this study, we show that Col2a1-Cre-driven deletion of Shox2 in developing chondrocytes also results in shortening of the stylopodial skeleton (i.e. humerus, femur) and that this rhizomelia is due to precocious chondrocyte maturation and hypertrophy. We demonstrate, using the micromass culture model system, that increased BMP activity triggers accelerated maturation and hypertrophy in Col2a1-Cre Shox2 mutant chondrocytes and we confirm in vivo that elevated transcript levels and expanded expression domains of Bmp2 and 4 are associated with premature formation of the hypertrophic zone in mutant humeri. In micromass cultures of Prrx1-Cre Shox2 mutant limb cells, we find that Shox2 deletion in undifferentiated mesenchymal cells results in increased BMP activity that enhances early chondrogenesis, but is insufficient to provoke chondrocyte maturation and hypertrophy. Similarly, shRNA-mediated Shox2 knockdown in multipotent C3H10T1/2 cells and primary mouse bone marrow mesenchymal stem cells results in spontaneous chondrogenesis in the absence of chondrostimulation, but again fails to induce progression through the later stages of chondrogenic differentiation. Importantly, exogenous BMP supplementation can overcome the block to maturation and hypertrophy caused by Shox2 depletion prior to overt chondrogenesis. Thus, we provide evidence that Shox2 regulates progression through chondrogenesis at two distinct stages--the onset of early differentiation and the transition to maturation and hypertrophy. PMID- 23038772 TI - The Hippo pathway member Yap plays a key role in influencing fate decisions in muscle satellite cells. AB - Satellite cells are the resident stem cells of skeletal muscle. Mitotically quiescent in mature muscle, they can be activated to proliferate and generate myoblasts to supply further myonuclei to hypertrophying or regenerating muscle fibres, or self-renew to maintain the resident stem cell pool. Here, we identify the transcriptional co-factor Yap as a novel regulator of satellite cell fate decisions. Yap expression increases during satellite cell activation and Yap remains highly expressed until after the differentiation versus self-renewal decision is made. Constitutive expression of Yap maintains Pax7(+) and MyoD(+) satellite cells and satellite cell-derived myoblasts, promotes proliferation but prevents differentiation. In contrast, Yap knockdown reduces the proliferation of satellite cell-derived myoblasts by ~40%. Consistent with the cellular phenotype, microarrays show that Yap increases expression of genes associated with Yap inhibition, the cell cycle, ribosome biogenesis and that it represses several genes associated with angiotensin signalling. We also identify known regulators of satellite cell function such as BMP4, CD34 and Myf6 (Mrf4) as genes whose expression is dependent on Yap activity. Finally, we confirm in myoblasts that Yap binds to Tead transcription factors and co-activates MCAT elements which are enriched in the proximal promoters of Yap-responsive genes. PMID- 23038775 TI - Autocrine and paracrine unpaired signaling regulate intestinal stem cell maintenance and division. AB - The Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway is involved in the regulation of intestinal stem cell (ISC) activity to ensure a continuous renewal of the adult Drosophila midgut. Three ligands, Unpaired 1, Unpaired 2 and Unpaired 3 (Upd1, Upd2 and Upd3, respectively) are known to activate the JAK/STAT pathway in Drosophila. Using newly generated upd mutants and cell-specific RNAi, we showed that Upd1 is required throughout the fly life to maintain basal turnover of the midgut epithelium by controlling ISC maintenance in an autocrine manner. A role of Upd2 and Upd3 in basal conditions is discernible only in old gut, where they contribute to increased ISC abnormal division. Finally, upon an acute stress such as oral bacterial infection, we showed that Upd3 is released from enterocytes and has an additive effect with Upd2 to promote rapid epithelial regeneration. Taken together, our results show that Upd ligands are required to maintain the midgut homeostasis under both normal and pathological states. PMID- 23038776 TI - N-terminal horseshoe conformation of DCC is functionally required for axon guidance and might be shared by other neural receptors. AB - Deleted in colorectal cancer (DCC) is a receptor for the axon guidance cues netrin-1 and draxin. The interactions between these guidance cues and DCC play a key role in the development of the nervous system. In the present study, we reveal the crystal structure of the N-terminal four Ig-like domains of DCC. The molecule folds into a horseshoe-like configuration. We demonstrate that this horseshoe conformation of DCC is required for guidance-cue-mediated axonal attraction. Structure-based mutations that disrupt the DCC horseshoe indeed impair its function. A comparison of the DCC horseshoe with previously described horseshoe structures has revealed striking conserved structural features and important sequence signatures. Using these signatures, a genome-wide search allows us to predict the N-terminal horseshoe arrangement in a number of other cell surface receptors, nearly all of which function in the nervous system. The N terminal horseshoe appears to be evolutionally selected as a platform for neural receptors. PMID- 23038778 TI - Activation of the PTHRP/adenylate cyclase pathway promotes differentiation of rat XEN cells into parietal endoderm, whereas Wnt/beta-catenin signaling promotes differentiation into visceral endoderm. AB - During early mammalian development, primitive endoderm (PrE) is specified and segregated away from the pluripotent epiblast. At a later developmental stage, PrE forms motile parietal endoderm (PE) lying proximal to the trophectoderm, and visceral endoderm (VE) that contacts the developing epiblast and extraembryonic ectoderm. Mouse extraembryonic endoderm (XEN) cells were isolated and became widely used to study signals governing lineage specification. Rat XEN cell lines have also been derived, but were distinguished from mouse by expression of SSEA1 and Oct4. We showed here that rat XEN cells grown in the presence of a GSK3 inhibitor or overexpressing beta-catenin exhibited enhanced formation of cell contacts and decreased motility. Rat XEN cells treated with BMP4 revealed similar morphological changes. Furthermore, we observed that rat XEN cells cultured with GSK3 inhibitor formed adhesion and tight junctions, and acquired bottom-top polarity, indicating the formation of VE cells. In contrast, forskolin, an activator of the cAMP pathway, induced the disruption of cell contacts in rat XEN cells. Treatment with forskolin induced PE formation and epithelial-mesenchymal transition (EMT) in rat XEN cells. Using microarray and real-time PCR assays, we found that VE versus PE formation of rat XEN cells was correlated with change in expression levels of VE or PE marker genes. Similar to forskolin, EMT was prompted upon treatment of rat XEN cells with recombinant parathyroid hormone related peptide (PTHRP), an activator of the cAMP pathway in vivo. Taken together, our data suggest that rat XEN cells are PrE-like cells. The activation of Wnt or BMP4 pathways in rat XEN cells leads to the acquisition of VE characteristics, whereas the activation of the PTHRP/cAMP pathway leads to EMT and the formation of PE. PMID- 23038777 TI - Hypoxia induces downregulation of soluble guanylyl cyclase beta1 by miR-34c-5p. AB - Soluble guanylyl cyclase (sGC) is the principal receptor for nitric oxide (NO) and crucial for the control of various physiological functions. The beta1 subunit of sGC is obligatory for the biological stability and activity of the sGC heterodimer. MicroRNAs (miRNAs) are important regulators of gene expression and exert great influences on diverse biological activities. The aim of the present study was to determine whether or not the expression of sGCbeta1 is specifically regulated by miRNAs. We report that miR-34c-5p directly targets sGCbeta1 under hypoxia. Bioinformatics analysis of the sGCbeta1 3'-untranslated region (3'-UTR) revealed a putative binding site for miR-34b-5p and miR-34c-5p, but only miR-34c 5p inhibited luciferase activity through interaction with sGCbeta1 3'-UTR in HEK293T cells. Site-directed mutagenesis of the putative miR-34c-5p binding site abolished the negative regulation of luciferase expression. Overexpression of miR 34c-5p repressed the expression of sGCbeta1 in stable cell lines, which was reversed by miR-34c-5p-specific sponge. Inoculation of mouse lung tissues in vitro with lentivirus bearing miR-34c-5p significantly decreased both the expression of sGCbeta1 and NO-stimulated sGC activity, which was also rescued by miR-34c-5p-specific sponge. Furthermore, we identified the putative Sp1-binding site in the promoter region of miR-34c-5p. Luciferase reporter constructs revealed that Sp1 directly binds to the wild-type promoter of miR-34c-5p, which was confirmed by chromatin immunoprecipitation. In summary, these findings reveal that miR-34c-5p directly regulates sGCbeta1 expression, and they identify the key transcription factor Sp1 that governs miR-34c-5p expression during hypoxia. PMID- 23038779 TI - Involvement of the mRNA binding protein CRD-BP in the regulation of metastatic melanoma cell proliferation and invasion by hypoxia. AB - We have previously shown that the mRNA binding protein CRD-BP is overexpressed in human melanomas, where it promotes cell survival and resistance to chemotherapy. The present study investigates the role of hypoxia, a common characteristic of the tumor microenvironment, in the regulation of CRD-BP expression and melanoma cell responses. We found that hypoxia increases CRD-BP levels in metastatic melanoma cell lines but not in melanocytes or primary melanoma cells. Hypoxic stimulation transcriptionally regulates CRD-BP by facilitating the acetylation of histones within the CRD-BP gene and by modulating the extent of HIF1alpha binding to the CRD-BP promoter. Hypoxia significantly enhances the proliferative and invasive potential of metastatic melanoma cells but not that of normal or primary melanoma cells. Furthermore, inhibition of CRD-BP impairs the ability of metastatic cells to proliferate and invade in response to hypoxia. These findings identify CRD-BP as a novel effector of hypoxic responses that is relevant for the selection of metastatic cells. This work also describes a previously unknown role for CRD-BP in the regulation of melanoma cell invasion and highlights the importance of the hypoxic microenvironment in determining cell fate. PMID- 23038780 TI - Drosophila embryos close epithelial wounds using a combination of cellular protrusions and an actomyosin purse string. AB - The repair of injured tissue must occur rapidly to prevent microbial invasion and maintain tissue integrity. Epithelial tissues in particular, which serve as a barrier against the external environment, must repair efficiently in order to restore their primary function. Here we analyze the effect of different parameters on the epithelial wound repair process in the late stage Drosophila embryo using in vivo wound assays, expression of cytoskeleton and membrane markers, and mutant analysis. We define four distinct phases in the repair process, expansion, coalescence, contraction and closure, and describe the molecular dynamics of each phase. Specifically, we find that myosin, E-cadherin, Echinoid, the plasma membrane, microtubules and the Cdc42 small GTPase respond dynamically during wound repair. We demonstrate that perturbations of each of these components result in specific impairments to the wound healing process. Our results show that embryonic epithelial wound repair is mediated by two simultaneously acting mechanisms: crawling driven by cellular protrusions and actomyosin ring contraction along the leading edge of the wound. PMID- 23038781 TI - Regulation of synapse composition by protein acetylation: the role of acetylated cortactin. AB - Protein acetylation affects synaptic plasticity and memory, but its effects on synapse composition have not been addressed. We found that protein acetylation promotes the dendritic clustering of the excitatory postsynaptic scaffold protein PSD95 in hippocampal neurons, without affecting the total levels of this protein. Cortactin, an F-actin-binding protein enriched in dendritic spines, is a substrate for acetylation and has a role in spine morphogenesis. Recent studies showed that cortactin acetylation changes its ability to bind F-actin and regulates cellular motility, but the function of cortactin acetylation in neuronal cells is so far unknown. We tested whether acetylation of cortactin influences its morphogenic function by overexpressing wild-type cortactin, or the mimetic mutants for acetylated or deacetylated cortactin, in hippocampal neurons, and found that cortactin acetylation has an impact on PSD95 clustering, independent from its function as actin dynamics regulator. Moreover, acetylated cortactin can rescue the reduction in PSD95 clustering mediated by knockdown of cortactin. We also found that acetylation of cortactin is correlated with decreased cortactin interaction with p140Cap and Shank1, and with lower cortactin phosphorylation at tyrosine 421. The neurotrophin BDNF promoted the acetylation of cortactin in hippocampal neurons, suggesting that BDNF may regulate excitatory synapses and PSD95 dendritic clustering at least in part by changing the acetylation level of cortactin. Our findings unravel an unsuspected role for cortactin acetylation in the regulation of PSD95 dendritic clustering, which may work in concert with cortactin's role in spine development. PMID- 23038782 TI - MDC1 and RNF8 function in a pathway that directs BRCA1-dependent localization of PALB2 required for homologous recombination. AB - The PALB2 protein is associated with breast cancer susceptibility and Fanconi anemia. Notably, PALB2 is also required for DNA repair by homologous recombination (HR). However, the mechanisms that regulate PALB2, and the functional significance of its interaction with the BRCA1 breast cancer susceptibility protein, are poorly understood. Here, to better understand these processes, we fused PALB2, or the PALB2(L21P) mutant which cannot bind to BRCA1, with the BRCT repeats that are present in, and which localize, BRCA1. Our results yield important insights into the regulation of PALB2 function. Both fusion proteins can bypass BRCA1 to localize to sites of DNA damage. Further, the localized fusion proteins are functional, as determined by their ability to support the assembly of RAD51 foci, even in the absence of the capacity of PALB2 to bind BRCA1. Strikingly, the localized fusion proteins mediate DNA double strand break (DSB)-initiated HR and resistance to mitomycin C in PALB2-deficient cells. Additionally, we show that the BRCA1-PALB2 heterodimer, rather than the PALB2-PALB2 homodimer, mediates these responses. Importantly, we offer the first insight into how BRCA1-dependent recruitment of PALB2 is integrated with other DNA damage signaling pathways. We find that PALB2 localization depends on the presence of MDC1, RNF8, RAP80 and Abraxas upstream of BRCA1. Thus, PALB2 may link HR to a key ubiquitin-related signaling pathway that responds to DSBs. PMID- 23038783 TI - Is patellofemoral joint osteoarthritis an under-recognised outcome of anterior cruciate ligament reconstruction? A narrative literature review. AB - Patellofemoral joint (PFJ) osteoarthritis (OA) is a prevalent disease capable of being a potent source of knee symptoms. Although anterior cruciate ligament (ACL) injury and reconstruction (ACLR) are well-established risk factors for the development of tibiofemoral joint OA, PFJ OA after ACL reconstruction has gone largely unrecognised. This is despite the high prevalence of anterior knee pain after ACLR, which can reduce the capacity for physical activity and quality of life. The susceptibility of the PFJ to degenerative change after ACLR may have implications for current rehabilitation strategies. This review summarises the evidence describing the prevalence of PFJ OA after ACLR and examines why this compartment may be at increased risk of early onset OA after ACLR. Strategies that address the modifiable factors for risk of PFJ OA may aid in alleviating joint loads and symptoms for people after ACLR. PMID- 23038784 TI - A survey of state medical licensing boards: can the travelling team physician practice in your state? AB - This was a study that surveyed state medical licensing boards in the USA, to see if they have laws or exemptions for travelling team physicians to practice medicine on their own team, while travelling to that state. Surveys were sent to 58 medical boards, with legislative data being obtained for 54. Eighteen states (33%) allow team physicians travelling with their team to practice medicine with their home-state license. Thirty-six states (67%) do not have a legal pathway to allow the practice of medicine without a license: 27 (50%) do not allow the practice of medicine without a license from their state, 6 (11%) have an exemption for a 'consultant' to act in concert with a home-state physician (though this is not applicable to the team physician) and 3 (6%) do not have an exemption, but recognise that it happens without their involvement. A second survey was sent to 20 malpractice carriers, identified by an internet search to represent a diverse sample, to see if these companies offered policies that would cover the team physician, and if they also had licensure requirements. Of the 11 that responded, only 2 companies would provide coverage regardless of individual state licensing requirements, 5 companies would provide coverage to a provider who travels, but would require the provider to be licensed in any state they travel to and 4 companies would not provide coverage out of the home state, regardless of licensure. The American Medical Society for Sports Medicine is working on a Federal patch for this problem. PMID- 23038785 TI - Measuring the impacts of the Winter Youth Olympic Games 2012 the impact - stakeholder approach. PMID- 23038786 TI - Development and validation of a new method for the registration of overuse injuries in sports injury epidemiology: the Oslo Sports Trauma Research Centre (OSTRC) overuse injury questionnaire. AB - BACKGROUND: Current methods for injury registration in sports injury epidemiology studies may substantially underestimate the true burden of overuse injuries due to a reliance on time-loss injury definitions. OBJECTIVE: To develop and validate a new method for the registration of overuse injuries in sports. METHODS: A new method, including a new overuse injury questionnaire, was developed and validated in a 13-week prospective study of injuries among 313 athletes from five different sports, cross-country skiing, floorball, handball, road cycling and volleyball. All athletes completed a questionnaire by email each week to register problems in the knee, lower back and shoulder. Standard injury registration methods were also used to record all time-loss injuries that occurred during the study period. RESULTS: The new method recorded 419 overuse problems in the knee, lower back and shoulder during the 3-month-study period. Of these, 142 were classified as substantial overuse problems, defined as those leading to moderate or severe reductions in sports performance or participation, or time loss. Each week, an average of 39% of athletes reported having overuse problems and 13% reported having substantial problems. In contrast, standard methods of injury registration registered only 40 overuse injuries located in the same anatomical areas, the majority of which were of minimal or mild severity. CONCLUSION: Standard injury surveillance methods only capture a small percentage of the overuse problems affecting the athletes, largely because few problems led to time loss from training or competition. The new method captured a more complete and nuanced picture of the burden of overuse injuries in this cohort. PMID- 23038787 TI - Warm-up exercise can reduce exercise-induced bronchoconstriction. PMID- 23038788 TI - Adherence to statins is associated with reduced incidence of idiopathic venous thromboembolism: real-life data from a large healthcare maintenance organisation. AB - OBJECTIVE: Previous reports on the association between statin use and venous thromboembolism (VTE) did not examine patient adherence to medications, thus their applicability in a real life setting is questionable. Our objective was to investigate the association between the use of statins and incidence of first ever idiopathic VTE. DESIGN: A retrospective cohort study. SETTINGS: A large healthcare maintenance organisation. PATIENTS: Included were statin initiators aged 30 years or older since 2003 who did not have a statin prescription for at least 4 years before that and had at least 18 months follow-up. Excluded were patients with known risk factors for VTE. End of follow-up was defined as the first of the following: leaving Maccabi Healthcare Services, death, VTE or October 27, 2010. INTERVENTIONS: Prescription drug purchase data was analysed in order to evaluate the association between statin use and adherence and between VTE prevention. MAIN OUTCOME MEASURES: VTE diagnosis during follow-up. RESULTS: The study population included 127 822 subjects (53 618 females). The follow-up period was comprised of 594 190 patient years, and included 1375 VTE cases and 5 year cumulative incidence rate of 1.15%. Cox regression analysis demonstrated a significantly lower VTE risk of 19% and 22% in the more adherent patient groups, compared to the risk for the lowest adherence group. The simvastatin dose, the most frequently prescribed statin, was negatively associated with the risk of VTE. CONCLUSIONS: In a real life healthcare maintenance organisation setting, better adherence to statins is associated with a reduced risk of first ever idiopathic VTE events. PMID- 23038789 TI - Time from emerging heart failure symptoms to cardiac resynchronisation therapy: impact on clinical response. AB - OBJECTIVE: To investigate whether time from onset of heart failure signs and/or symptoms (ie, progression to stage C/D heart failure) until implantation affects reverse remodelling and clinical outcome after cardiac resynchronisation therapy (CRT). DESIGN: Cohort study of consecutive CRT patients, implanted between 1 October 2008 and 30 April 2011. SETTING: Single tertiary care centre (Ziekenhuis Oost-Limburg, Genk, Belgium). PATIENTS: Consecutive CRT patients (n=172; 71+/-9 years), stratified into tertiles according to the time since first heart failure signs and/or symptoms at implantation. MAIN OUTCOME MEASURES: Change in left ventricular dimensions, New York Heart Association (NYHA) functional class and freedom from all-cause mortality or heart failure admission. RESULTS: Baseline renal function was better in patients implanted earlier after emerging heart failure symptoms (estimated glomerular filtration rate=73+/-20 vs 63+/-23 vs 58+/ 26 ml/min/1.73 m(2) for tertiles, respectively). After 6 months, decreases in left ventricular end-diastolic/systolic diameter and improvement in NYHA functional class were similar among tertiles. Freedom from all-cause mortality or heart failure admission was better in patients with early implantation (p value=0.042). However, this was not the case in patients with preserved renal function (p value=0.794). Death from progressive heart failure was significantly more frequent in patients implanted later in their disease course. CONCLUSIONS: Reverse left ventricular remodelling after CRT is not affected by the duration of heart failure. However, clinical outcome is better in patients implanted earlier in their disease course, which probably relates to better renal preservation. PMID- 23038790 TI - Transcatheter aortic valve implantation in a patient with previous Starr-Edwards mitral valve prosthesis. PMID- 23038791 TI - Establishing the cost-effectiveness of percutaneous coronary intervention for chronic total occlusion in stable angina: a decision-analytic model. AB - BACKGROUND: In the setting of chronic stable angina, successful percutaneous coronary intervention (PCI) of chronic total occlusions (CTO) has been shown to produce significant symptom improvement with some evidence for survival benefit. However, the economic basis for this procedure has not been established compared with optimal medical treatment (OMT) of chronic stable angina. OBJECTIVE: The aim of this study was to determine the cost-effectiveness of CTO-PCI in chronic stable angina using a Markov model. DESIGN: The transition probabilities, utilities and costs related to CTO-PCI and OMT used to inform the model were derived from literature and our experience. Implications with respect to cost and quality of life were calculated. Sensitivity analyses were based on factors noted to influence model outcome. RESULTS: In the reference case, mean age 60 years, rate of successful CTO-PCI 67.9%, and mean transition probabilities, utilities and costs as defined by literature and clinical experience, the strategy of CTO PCI incurred higher costs relative to OMT (US$31 512 vs US$27 805), but also accumulated greater quality-adjusted life-years (QALYs) (2.38 vs 1.99), yielding a cost-effectiveness ratio of US$9505 per QALY. Sensitivity analyses showed the utility of OMT and utilities postsuccessful and postunsuccessful CTO-PCI to be the most influential drivers of outcome. Procedural success held limited influence over model outcome at particular utility threshold values. CONCLUSIONS: On the basis of the supporting evidence, this decision-analytic model suggests that CTO-PCI is cost-effective in a patient population with severe symptoms. Quality-of-life metrics should be employed in future appropriateness criteria developed for CTO-PCI. PMID- 23038792 TI - Surgical outcomes of severe tricuspid regurgitation: predictors of adverse clinical outcomes. AB - BACKGROUND: Although recent studies contributed to an improved understanding of the prognosis of patients undergoing tricuspid valve (TV) surgery, the data are limited to certain causes of tricuspid regurgitation (TR) or types of surgery. OBJECTIVE: This study aimed to identify predictors of clinical outcomes of patients undergoing TV surgery for severe TR of various aetiologies. DESIGN: A retrospective cohort study. SETTING: A single tertiary referral centre. PATIENTS: 449 consecutive patients (152 men, aged 56.2+/-12. 3 years) who underwent TV surgery (397 repairs and 52 replacements) due to severe TR between 1997 and 2010. MAIN OUTCOME MEASURES: The primary outcome of interest was death from any cause. RESULTS: The early death rate was 4.2% (n=19) and 101 patients died in the late period (median follow-up of 63.3 months; range 0-210.4 months). The 5- and 10 year survival rates were 82.4+/-1.9% and 71.7+/-2.8%, respectively. Cox regression analysis revealed that age (HR=1.03; 95% CI 1.01 to 1.05), male gender (HR=1.96; 95% CI 1.29 to 2.99), New York Heart Association functional class IV (HR=2.08; 95% CI 1.31 to 3.30), presence of liver cirrhosis (HR=2.51; 95% CI 1.11 to 5.68) and preoperative levels of haemoglobin (HR=0.89; 95% CI 0.80 to 0.99), albumin (HR=0.52; 95% CI 0.33 to 0.81) and estimated glomerular filtration rate (HR=0.86; 95% CI 0.78 to 0.95) were independent determinants of mortality. Procedural type (p=0.58) or causes of TR (p=0.97), however, were not predictive of mortality. CONCLUSIONS: Long-term survival after TV surgery for severe TR was affected by several preoperative factors including advanced heart failure symptom, comorbidity, end-organ dysfunction and laboratory abnormalities, but not by the type of surgery or causes of TR. PMID- 23038793 TI - Fluconazole inhibits human adrenocortical steroidogenesis in vitro. AB - The antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human adrenocortical steroidogenesis were compared. The effects on steroidogenesis were examined in primary cultures of nine human adrenocortical tissues and two human adrenocortical carcinoma cell lines. Moreover, the effects on mRNA expression levels of steroidogenic enzymes and cell growth were assessed. Ketoconazole significantly inhibited 11 deoxycortisol (H295R cells; maximum inhibition 99%; EC(50) 0.73 MUM) and cortisol production (HAC15 cells; 81%; EC(50) 0.26 MUM and primary cultures (mean EC(50) 0.75 MUM)). In cultures of normal adrenal cells, ketoconazole increased pregnenolone, progesterone, and deoxycorticosterone levels, while concentrations of 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, and androstenedione decreased. Fluconazole also inhibited 11-deoxycortisol production in H295R cells (47%; only at 1 mM) and cortisol production in HAC15 cells (maximum inhibition 55%; EC(50) 35 MUM) and primary cultures (mean EC(50) 67.7 MUM). In the cultures of normal adrenals, fluconazole suppressed corticosterone, 17-hydroxypregnenolone, and androstenedione levels, whereas concentrations of progesterone, deoxycorticosterone, and 11-deoxycortisol increased. Fluconazole (1 mM) slightly increased STAR mRNA expression in both cell lines. Neither compound affected mRNA levels of other steroidogenic enzymes or cell number. In conclusion, by inhibiting 11beta-hydroxylase and 17-hydroxylase activity, pharmacological concentrations of fluconazole dose dependently inhibit cortisol production in human adrenocortical cells in vitro. Although fluconazole seems less potent than ketoconazole, it might become an alternative for ketoconazole to control hypercortisolism in CS. Furthermore, patients receiving fluconazole because of mycosis might be at risk for developing adrenocortical insufficiency. PMID- 23038794 TI - Involvement of miRNAs in ovarian follicular and luteal development. AB - Although much progress has been made in the genetic dissection of biological networks involved in follicular/luteal development in the mammalian ovary, the gene regulation mechanisms involved are still poorly understood. Over the last 10 years, miRNAs have emerged as master regulators of tissue growth and differentiation in animals. However, compared with other body tissues, little is still known about the functional involvement of miRNAs in the ovary. Several studies have identified miRNA populations specifically associated with the development of follicles and corpora lutea, particularly in relation to the follicular-luteal transition, and the functional involvement of some of these miRNAs has been characterised in vitro and/or in vivo. Specifically, three different miRNAs, miR-224, miR-378 and miR-383, have shown to be involved in regulating aromatase expression during follicle development. In addition, miR-21 has been identified as promoting follicular cell survival during ovulation, and pro-angiogenic miR-17-5p and let-7b were shown to be necessary for normal development of the corpus luteum. Experimental evidence for the involvement of several other miRNAs in different aspects of follicle/luteal development has also been obtained. In addition, many of these studies exemplify the challenges associated with identifying physiologically relevant targets of ovarian miRNAs. Continuous advances in this field will be considerably facilitated by progress in understanding miRNA physiology in other body systems and will eventually lead to a much better understanding of the control of follicular/luteal development. In turn, through the potential offered by miRNA diagnostics and miRNA therapeutics, this new knowledge should bring considerable benefits to reproductive medicine. PMID- 23038796 TI - The role of opioid substitution treatment in reducing HIV transmission. PMID- 23038795 TI - Opiate substitution treatment and HIV transmission in people who inject drugs: systematic review and meta-analysis. AB - OBJECTIVE: To quantify the effect of opiate substitution treatment in relation to HIV transmission among people who inject drugs. DESIGN: Systematic review and meta-analysis of prospective published and unpublished observational studies. DATA SOURCES: Search of Medline, Embase, PsychINFO, and the Cochrane Library from the earliest year to 2011 without language restriction. REVIEW METHODS: We selected studies that directly assessed the impact of opiate substitution treatment in relation to incidence of HIV and studies that assessed incidence of HIV in people who inject drugs and that might have collected data regarding exposure to opiate substitution treatment but not have reported it. Authors of these studies were contacted. Data were extracted by two reviewers and pooled in a meta-analysis with a random effects model. RESULTS: Twelve published studies that examined the impact of opiate substitution treatment on HIV transmission met criteria for inclusion, and unpublished data were obtained from three additional studies. All included studies examined methadone maintenance treatment. Data from nine of these studies could be pooled, including 819 incident HIV infections over 23,608 person years of follow-up. Opiate substitution treatment was associated with a 54% reduction in risk of HIV infection among people who inject drugs (rate ratio 0.46, 95% confidence interval 0.32 to 0.67; P<0.001). There was evidence of heterogeneity between studies (I(2)=60%, chi(2)=20.12, P=0.010), which could not be explained by geographical region, site of recruitment, or the provision of incentives. There was weak evidence for greater benefit associated with longer duration of exposure to opiate substitution treatment. CONCLUSION: Opiate substitution treatment provided as maintenance therapy is associated with a reduction in the risk of HIV infection among people who inject drugs. These findings, however, could reflect comparatively high levels of motivation to change behaviour and reduce injecting risk behaviour among people who inject drugs who are receiving opiate substitution treatment. PMID- 23038797 TI - Radioprotective properties of tocopherol succinate against ionizing radiation in mice. AB - Threats of nuclear and other radiologic exposures have been increasing but no countermeasure for acute radiation syndrome has been approved by regulatory authorities. In prior publications we have demonstrated the efficacy of tocopherol succinate (TS) as a promising radiation countermeasure with the potential to protect against lethal doses of ionizing radiation exposure. The aim of this study was to gain further insight regarding how TS protects mice against a lethal dose of radiation. CD2F1 mice were injected subcutaneously with 400 mg/kg of TS, and 24 h later exposed to (60)Co gamma-radiation. Intestinal tissues or spleen/thymus were harvested after irradiation and analyzed for CD68-positive inflammatory cells and apoptotic cells by immunostaining of jejunal cross sections. Comet assay was used to analyze DNA damage in various tissues. Phospho histone H3(pH3) and the proliferating cell nuclear antigen (PCNA) were used as mitotic markers for immunostaining jejunal cross-sections. We observed that injecting TS significantly decreased the number of CD68-positive cells, DNA damage and apoptotic cells (BAX, caspase 3 and cleaved poly(ADP-ribose) polymerase-positive cells) as judged by various apoptotic pathway markers. TS treatment also increased proliferating cells in irradiated mice. Results of this study further support our contention that TS protects mice against lethal doses of ionizing radiation by inhibiting radiation-induced apoptosis and DNA damage while enhancing cell proliferation. PMID- 23038798 TI - The contested realm of displaying dead bodies. PMID- 23038799 TI - Photographing human subjects in biomedical disciplines: an Islamic perspective. AB - Visual recording of human subjects is commonly used in biomedical disciplines for clinical, research, legal, academic and even personal purposes. Guidelines on practice standards of biomedical recording have been issued by certain health authorities, associations and journals, but none of the literature discusses this from an Islamic perspective. This article begins with a discussion on the general rules associated with visual recording in Islam, followed by modesty issues in biomedical recording and issues of informed consent and confidentiality. In order to be deemed ethical from the Islamic perspective, all the aforementioned criteria must conform to, or not contradict, Islamic teaching. PMID- 23038800 TI - Spontaneous abortion and unexpected death: a critical discussion of Marquis on abortion. AB - In his classic paper, 'Why abortion is immoral', Don Marquis argues that what makes killing an adult seriously immoral is that it deprives the victim of the valuable future he/she would have otherwise had. Moreover, Marquis contends, because abortion deprives a fetus of the very same thing, aborting a fetus is just as seriously wrong as killing an adult. Marquis' argument has received a great deal of critical attention in the two decades since its publication. Nonetheless, there is a potential challenge to it that seems to have gone unnoticed. A significant percentage of fetuses are lost to spontaneous abortion. Once we bring this fact to our attention, it becomes less clear whether Marquis can use his account of the wrongness of killing to show that abortion is the moral equivalent of murder. In this paper, I explore the relevance of the rate of spontaneous abortion to Marquis' classic anti-abortion argument. I introduce a case I call Unexpected Death in which someone is about to commit murder, but, just as the would-be murderer is about to strike, his would-be victim dies unexpectedly. I then ask: what does Marquis' account of killing imply about the moral status of what the would-be murderer was about to do? I consider four responses Marquis could give to this question, and I examine what implications these responses have for Marquis' strategy of using his account of the wrongness of killing an adult to show that abortion is in the same moral category. PMID- 23038801 TI - Electroconvulsive therapy, the placebo effect and informed consent. AB - Major depressive disorder is not only the most widespread mental disorder in the world, it is a disorder on the rise. In cases of particularly severe forms of depression, when all other treatment options have failed, the use of electroconvulsive therapy (ECT) is a recommended treatment option for patients. ECT has been in use in psychiatric practice for over 70 years and is now undergoing something of a restricted renaissance following a sharp decline in its use in the 1970s. Despite its success in treating severe depression there is continued debate as to the effectiveness of ECT: in some studies, it is argued that ECT is marginally more effective than sham ECT. In addition, there is still no clear explanation of how ECT works; among the range of hypotheses proposed it is claimed that ECT may work by harnessing placebo effects. In light of the uncertainties over the mechanism of action of ECT and given the risk of serious side effects that ECT may produce, I contend that the process of informed consent must include comprehensive accounts of these uncertainties. I examine the possible consequences of providing adequate information to potential ECT patients, including the consideration that ECT may still prove to be effective even if physicians are open about the possibility of it working as a placebo. I conclude that if we value patient autonomy as well as the professional reputation of medical practitioners, a fuller description of ECT must be provided to patients and their carers. PMID- 23038802 TI - Response to the commentaries of Melissa S Anderson and Murray J Dyck. AB - Anderson and Dyck claim that the current trend of almost exclusively using citation-based evaluative metrics to assess the research output of scholars is unsound. I agree with them in this, but I feel that, for practical reasons, this system will not disappear in the near future, so we must concentrate on making it fairer. Both commentators doubt whether numerically expressing each contributor's relative contribution is feasible. I admit that an important precondition for this task is the possibility of an informed, democratic debate among equals about the relative contribution of each contributor to the article. Mechanisms should be established to protect vulnerable researchers in the academic field in the same way as safeguards exist today to protect vulnerable research participants. Theoretically, however, I think that the fair allocation of authorship credit is possible, and much of this task is already being performed routinely when contributors determine the order of their names in the byline, being well aware of the widespread assumption that this order mostly mirrors the order of their relative contributions. All they would have to do as an additional task is to express this order in numbers. If they cannot reach a consensus, they could always choose not to express their relative contribution in numbers, in which case the presumption would be that they contributed equally. My proposal could, at best, make the system fairer and, at worst, not reduce the options that evaluators already have. PMID- 23038803 TI - Genetic and antigenic characterization of invasive endemic serogroup B Neisseria meningitidis from Ontario, Canada, in 2001-2010. AB - This study examined the antigenic and genetic diversity of serogroup B Neisseria meningitidis (MenB) recovered from invasive meningococcal disease (IMD) cases in Ontario, Canada, over the period 2001-2010 during which no MenB outbreaks had occurred. MenB was found to be responsible for 39 % of all IMD cases, with the remaining cases caused mainly by serogroups Y (28 %), C (23.5 %) and W135 (8 %). One hundred and ninety-three individual MenB case isolates were collected and characterized. Of the 88 sequence types (STs) identified, 75 were grouped into 14 known clonal complexes (CCs), whilst 13 STs were not assigned to any known CC. Fifty-seven different PorA genotypes and 88 STs defined the diversity of invasive MenB in Ontario, which supported the endemic nature of MenB disease in Ontario. Despite the presence of the hypervirulent ST-41/44 and ST-32 CCs, no single ST was predominant and responsible for a large number of IMD cases. Although the Quebec outbreak clone of ST-269 was also found in Ontario, the 20 case isolates were genetically diverse: they grouped into seven STs and did not have a predominant PorA genotype. eburst analysis identified a new CC responsible for 14.5 % of the MenB case isolates. The six most common PorA variable region 2 (VR2) genotypes (VR2-9, -4, -14, -16, -13-1 and -16-3) were found in 67 % of invasive MenB isolates. PMID- 23038804 TI - Characterization of rotavirus causing acute diarrhoea in children in Kathmandu, Nepal, showing the dominance of serotype G12. AB - Diarrhoeal diseases are a major problem in developing countries. Though precise data on childhood mortality associated with diarrhoeal diseases in Nepal are not available, it has been estimated that approximately 25 % of child deaths are associated with diarrhoeal disease, particularly acute diarrhoea. The purpose of this study was to assess the incidence of rotavirus causing acute diarrhoea in children less than 5 years of age. A total of 525 children with acute diarrhoea in a children's hospital of Kathmandu, Nepal, were enrolled between April and September 2011. The incidence of acute diarrhoea due to rotavirus was 25.9 % (136/525) as determined by ELISA. The percentage of rotavirus-infected males was higher (64.5 %) than females (35.5 %). The frequency of rotavirus cases was higher in children less than 2 years of age, among which the majority of cases (80.2 %) were in children between 6 and 24 months old (P<0.01). Genotypic characterization by RT-PCR revealed that the serotype G12 represented 55.9 % of cases in this study associated with P-types of either P[6], P[4] or P[8]. Further to this, a total of eight G/P combinations were identified, G12P[6] being the most common strain type of rotavirus in Nepal, with a prevalence rate of 46.4 %. The aim of this study was to find out the major genotypes of rotavirus causing acute diarrhoea in children. PMID- 23038805 TI - MaHog1, a Hog1-type mitogen-activated protein kinase gene, contributes to stress tolerance and virulence of the entomopathogenic fungus Metarhizium acridum. AB - Fungal biocontrol agents have great potential in integrated pest management. However, poor efficacy and sensitivity to various adverse factors have hampered their wide application. In eukaryotic cells, Hog1 kinase plays a critical role in stress responses. In this study, MaHog1 (GenBank accession no. EFY85878), encoding a member of the Hog1/Sty1/p38 mitogen-activated protein kinase family in Metarhizium (Me.) acridum, was identified. Targeted gene disruption was used to analyse the role of MaHog1 in virulence and tolerance of adverse factors. Mutants with MaHog1 depletion showed increased sensitivity to high osmotic stress, high temperature and oxidative stress, and exhibited remarkable resistance to cell wall-disturbing agents. These results suggest that Hog1 kinase has a conserved function in regulating multistress responses among fungi, and that MaHog1 might influence cell wall biogenesis in Me. acridum. Bioassays conducted with topical inoculation and intrahaemocoel injection revealed that MaHog1 is required for both penetration and postpenetration development of Me. acridum. MaHog1 disruption resulted in a significant reduction in virulence, likely due to the combination of a decrease in conidial germination, a reduction in appressorium formation and a decline in growth rate in insect haemolymph, which might be caused by impairing fungal tolerance of various stresses during infection. PMID- 23038806 TI - Population subdivision and the detection of recombination in non-typable Haemophilus influenzae. AB - The disparity in diversity between unencapsulated (non-typable; NT) and encapsulated, serotypable Haemophilus influenzae (Hi) has been recognized for some time. It has previously been suggested that the wider diversity evidenced within NTHi compared with typable lineages may be due to different rates of recombination within the encapsulated and NT populations. To examine whether there is evidence for different levels of recombination within typable and NT lineages of Hi, we performed a statistical genetic analysis of 819 distinct genotypes of Hi to explore the congruence of serotype with population genetic clustering, and to identify patterns of recombination within the Hi population. We find that a significantly larger proportion of NT isolates show evidence of recombination, compared with typable isolates, and also that when admixture is present, the total amount of recombination per strain is greater within NT isolates, compared with the typable population. Furthermore, we demonstrate significant heterogeneity in the number of admixed individuals between NT lineages themselves, while such variation was not observed in typable lineages. This variability suggests that factors other than the presence of capsule are important determinants of recombination rate in the Hi population. PMID- 23038807 TI - The two-component system ChrSA is crucial for haem tolerance and interferes with HrrSA in haem-dependent gene regulation in Corynebacterium glutamicum. AB - We recently showed that the two-component system (TCS) HrrSA plays a central role in the control of haem homeostasis in the Gram-positive soil bacterium Corynebacterium glutamicum. Here, we characterized the function of another TCS of this organism, ChrSA, which exhibits significant sequence similarity to HrrSA, and provide evidence for cross-regulation of the two systems. In this study, ChrSA was shown to be crucial for haem resistance of C. glutamicum by activation of the putative haem-detoxifying ABC-transporter HrtBA in the presence of haem. Deletion of either hrtBA or chrSA resulted in a strongly increased sensitivity towards haem. DNA microarray analysis and gel retardation assays with the purified response regulator ChrA revealed that phosphorylated ChrA acts as an activator of hrtBA in the presence of haem. The haem oxygenase gene, hmuO, showed a decreased mRNA level in a chrSA deletion mutant but no significant binding of ChrA to the hmuO promoter was observed in vitro. In contrast, activation from P(hmuO) fused to eyfp was almost abolished in an hrrSA mutant, indicating that HrrSA is the dominant system for haem-dependent activation of hmuO in C. glutamicum. Remarkably, ChrA was also shown to bind to the hrrA promoter and to repress transcription of the paralogous response regulator, whereas chrSA itself seemed to be repressed by HrrA. These data suggest a close interplay of HrrSA and ChrSA at the level of transcription and emphasize ChrSA as a second TCS involved in haem-dependent gene regulation in C. glutamicum, besides HrrSA. PMID- 23038808 TI - Anaerobic utilization of toluene by marine alpha- and gammaproteobacteria reducing nitrate. AB - Aromatic hydrocarbons are among the main constituents of crude oil and represent a major fraction of biogenic hydrocarbons. Anthropogenic influences as well as biological production lead to exposure and accumulation of these toxic chemicals in the water column and sediment of marine environments. The ability to degrade these compounds in situ has been demonstrated for oxygen- and sulphate-respiring marine micro-organisms. However, if and to what extent nitrate-reducing bacteria contribute to the degradation of hydrocarbons in the marine environment and if these organisms are similar to their well-studied freshwater counterparts has not been investigated thoroughly. Here we determine the potential of marine prokaryotes from different sediments of the Atlantic Ocean and Mediterranean Sea to couple nitrate reduction to the oxidation of aromatic hydrocarbons. Nitrate dependent oxidation of toluene as an electron donor in anoxic enrichment cultures was elucidated by analyses of nitrate, nitrite and dinitrogen gas, accompanied by cell proliferation. The metabolically active members of the enriched communities were identified by RT-PCR of their 16S rRNA genes and subsequently quantified by fluorescence in situ hybridization. In all cases, toluene-grown communities were dominated by members of the Gammaproteobacteria, followed in some enrichments by metabolically active alphaproteobacteria as well as members of the Bacteroidetes. From these enrichments, two novel denitrifying toluene-degrading strains belonging to the Gammaproteobacteria were isolated. Two additional toluene degrading denitrifying strains were isolated from sediments from the Black Sea and the North Sea. These isolates belonged to the Alphaproteobacteria and Gammaproteobacteria. Serial dilutions series with marine sediments indicated that up to 2.2*10(4) cells cm(-3) were able to degrade hydrocarbons with nitrate as the electron acceptor. These results demonstrated the hitherto unrecognized capacity of alpha- and gammaproteobacteria in marine sediments to oxidize toluene using nitrate. PMID- 23038809 TI - Impaired glycogen synthesis causes metabolic overflow reactions and affects stress responses in the cyanobacterium Synechocystis sp. PCC 6803. AB - The biosynthesis of glycogen or starch is one of the main strategies developed by living organisms for the intracellular storage of carbon and energy. In phototrophic organisms, such polyglucans accumulate due to carbon fixation during photosynthesis and are used to provide maintenance energy for cell integrity, function and viability in dark periods. Moreover, it is assumed that glycogen enables cyanobacteria to cope with transient starvation conditions, as observed in most micro-organisms. Here, glycogen accumulates when an appropriate carbon source is available in sufficient amounts but growth is inhibited by lack of other nutrients. In this study, the role of glycogen in energy and carbon metabolism of phototrophic cyanobacteria was first analysed via a comparative physiological and metabolic characterization of knockout mutants defective in glycogen synthesis. We first proved the role of glycogen as a respiratory substrate in periods of darkness, the role of glycogen as a reserve to survive starvation periods such as nitrogen depletion and the role of glycogen synthesis as an ameliorator of carbon excess conditions in the model organism Synechocystis sp. PCC 6803. We provide striking new insights into the complex carbon and nitrogen metabolism of non-diazotrophic cyanobacteria: a phenotype of sensitivity to photomixotrophic conditions and of reduced glucose uptake, a non-bleaching phenotype based on an impaired acclimation response to nitrogen depletion and furthermore a phenotype of energy spilling. This study shows that the analysis of deficiencies in glycogen metabolism is a valuable tool for the identification of metabolic regulatory principles and signals. PMID- 23038810 TI - Alkylation sensitivity screens reveal a conserved cross-species functionome. AB - To identify genes that contribute to chemotherapy resistance in glioblastoma, we conducted a synthetic lethal screen in a chemotherapy-resistant glioblastoma derived cell line with the clinical alkylator temozolomide (TMZ) and an siRNA library tailored toward "druggable" targets. Select DNA repair genes in the screen were validated independently, confirming the DNA glycosylases uracil-DNA glycosylase (UNG) and A/G-specific adenine DNA glycosylase (MYH) as well as methylpurine-DNA glycosylase (MPG) to be involved in the response to high dose TMZ. The involvement of UNG and MYH is likely the result of a TMZ-induced burst of reactive oxygen species. We then compared the human TMZ sensitizing genes identified in our screen with those previously identified from alkylator screens conducted in Escherichia coli and Saccharomyces cerevisiae. The conserved biologic processes across all three species compose an alkylation functionome that includes many novel proteins not previously thought to impact alkylator resistance. This high-throughput screen, validation and cross-species analysis was then followed by a mechanistic analysis of two essential nodes: base excision repair (BER) DNA glycosylases (UNG, human and mag1, S. cerevisiae) and protein modification systems, including UBE3B and ICMT in human cells or pby1, lip22, stp22 and aim22 in S. cerevisiae. The conserved processes of BER and protein modification were dual targeted and yielded additive sensitization to alkylators in S. cerevisiae. In contrast, dual targeting of BER and protein modification genes in human cells did not increase sensitivity, suggesting an epistatic relationship. Importantly, these studies provide potential new targets to overcome alkylating agent resistance. PMID- 23038811 TI - Reovirus: a targeted therapeutic--progress and potential. AB - Medical therapy of patients with malignancy requires a paradigm shift through development of new drugs with a good safety record and novel mechanisms of activity. While there is no dearth of such molecules, one particular agent, "reovirus" is promising by its ability to target cancer cells with aberrant signaling pathways. This double-stranded RNA virus has been therapeutically formulated and has rapidly progressed from preclinical validation of anticancer activity to a phase III registration study in platinum refractory metastatic squamous cell carcinoma of the head and neck. During this process, reovirus has shown safety both as a single agent when administered intratumorally and intravenously, as well as in combination therapy, with multiple chemotherapeutics such as gemcitabine, carboplatin/paclitaxel, and docetaxel; and similarly with radiation. The scientific rationale for its development as an anticancer agent stems from the fact that it preferentially replicates in and induces lyses of cells with an activated Kras pathway. As documented in many previous studies, the initial observation of greater tropism in Kras-compromised situation might certainly not be the sole and possibly not even the predominant reason for enhanced virulence. All the same, scientists have emphasized on Kras optimistically due to its high prevalence in various types of cancers. Incidence of Kras mutation has been found to be highest in pancreatic cancer (85%-90%) followed by colorectal (35-45%) and lung (25-30%). Reovirus, in fact has the potential not only as a therapy but also as a tool to unravel the aberrant cellular pathway leading to carcinogenicity. PMID- 23038813 TI - Genomic (in)stability of the breast tumor microenvironment. AB - The breast tumor microenvironment plays an active role in tumorigenesis. Molecular alterations have been identified in tumor-associated stroma; however, there is considerable debate as to whether the stroma is characterized by genomic instability or whether detection of chromosomal alterations reflects technological artifact rather than the true genomic content of the tumor microenvironment. Thus, breast stroma specimens from 112 women undergoing reductive mammoplasty (n = 7), prophylactic mastectomy (n = 6), or mastectomy for a breast disease (n = 99) were frozen in optimal cutting temperature medium. Allelic imbalance (AI) analysis was conducted using a panel of 52 microsatellite markers in 484 stromal specimens from 98 women, of which 92% had no detectable AI events. When compared with previously generated AI data from 77 formalin-fixed, paraffin-embedded (FFPE) stroma specimens, 42% of which harbored at least one detectable AI event, the frequency of AI in the FFPE specimens (4.62%) was significantly higher (P < 0.001) than that found in frozen specimens (0.45%). This comparison of AI between FFPE and research-grade specimens suggests that past reports of AI in breast stroma reflect artifact in the archival specimens caused by formalin-fixation, paraffin-embedding and tissue storage. Furthermore, SNP data were generated from a subset of 86 stromal specimens using SNP arrays and copy number alterations were identified using Partek Genomics Suite. For 95% of the specimens, no detectable copy number alterations were found and the 11 changes that were detected were small and not shared between specimens. These data, therefore, support a model in which the tumor microenvironment is genetically stable. PMID- 23038814 TI - The Endocrine Society Laureate Awards. PMID- 23038812 TI - Targeting tumor cell invasion and dissemination in vivo by an aptamer that inhibits urokinase-type plasminogen activator through a novel multifunctional mechanism. AB - Data accumulated over the latest two decades have established that the serine protease urokinase-type plasminogen activator (uPA) is a potential therapeutic target in cancer. When designing inhibitors of the proteolytic activity of serine proteases, obtaining sufficient specificity is problematic, because the topology of the proteases' active sites are highly similar. In an effort to generate highly specific uPA inhibitors with new inhibitory modalities, we isolated uPA binding RNA aptamers by screening a library of 35 nucleotides long 2'-fluoro pyrimidine RNA molecules using a version of human pro-uPA lacking the epidermal growth factor-like and kringle domains as bait. One pro-uPA-binding aptamer sequence, referred to as upanap-126, proved to be highly specific for human uPA. Upanap-126 delayed the proteolytic conversion of human pro-uPA to active uPA, but did not inhibit plasminogen activation catalyzed by two-chain uPA. The aptamer also inhibited the binding of pro-uPA to uPAR and the binding of vitronectin to the preformed pro-uPA/uPAR complex, both in cell-free systems and on cell surfaces. Furthermore, upanap-126 inhibited human tumor cell invasion in vitro in the Matrigel assay and in vivo in the chick embryo assay of cell escape from microtumors. Finally, upanap-126 significantly reduced the levels of tumor cell intravasation and dissemination in the chick embryo model of spontaneous metastasis. Together, our findings show that usage of upanap-126 represents a novel multifunctional mechanistic modality for inhibition of uPA-dependent processes involved in tumor cell spread. PMID- 23038815 TI - The Endocrine Society 2012 Laureate Awards. PMID- 23038816 TI - Frank Vellios, 1922 to 2011. PMID- 23038817 TI - Raise your profile to gain promotion. PMID- 23038818 TI - High blood pressure may increase risk of dementia in older women. Controlling vascular problems now could extend brain health for many years. PMID- 23038819 TI - What's for dinner? Your heart is asking for vegetables. Antioxidants and nutrients in veggies help maintain cardiovascular health. PMID- 23038820 TI - Your chances of surviving a heart attack are better than ever. Unfortunately, the likelihood you will have one is growing. PMID- 23038821 TI - Understand the power of Plavix. This antiplatelet drug prevents in-stent clots in women as well as men. PMID- 23038822 TI - What do you think about whole-body scans to detect cardiovascular disease? PMID- 23038823 TI - My blood pressure fluctuates wildly. Some days, it is in the 160s; other days, its 90 or 91. I am on a beta-blocker, but I think it is because my doctor doesn't know what to do with me. I am not feeling well. Should I see a cardiologist or another type of doctor? PMID- 23038824 TI - My father had bypass surgery and a carotid endarterectomy. He had low blood pressure and was of average weight, but didn't exercise. I exercise, have normal blood pressure and cholesterol and keep my weight down, but with a family history of heart disease, do I need to do anything more? PMID- 23038825 TI - My cholesterol was on the high end of normal, and my doctor put me on a statin. My cholesterol is now rock-bottom low! But the last blood test said my liver enzymes were elevated. She wants me to get another test in a couple of months. I'm worried these pills are damaging my liver. Is there anything I can do to protect it so I can continue taking them? PMID- 23038826 TI - Occasionally, I have atrial fibrillation. I hate it, but I hate taking medications, too. My doctor wants me to go on amiodarone. Can you tell me if it has any side effects? I need to decide which is worse--the problem or the medication? PMID- 23038827 TI - I recently tried a drink made from acai berries. It is supposed to be the best source of antioxidants, but it gave me stomach cramps. Should I try it again? PMID- 23038828 TI - Ask the doctor. I have hyperthyroidism and my doctor wants me to undergo radioactive iodine treatment. Its seems a bit scary. Must I do it? PMID- 23038829 TI - Ask the doctor. I am 70 and have had all the usual childhood diseases and shots. What immunizations do I need now? PMID- 23038830 TI - How to avoid joint surgery. Try these tips to get more life out of your own joints. PMID- 23038831 TI - Revitalizing sun-damaged skin. It's not too late to protect your skin from the sun, and even reverse the damage that's already been done. PMID- 23038832 TI - CDC urges universal hepatitis C screening for baby boomers. PMID- 23038833 TI - Treatment. Bone marrow transplant eliminated detectable HIV. PMID- 23038834 TI - Research. Experts say rate of HIV infection among black MSM is 'shocking'. PMID- 23038835 TI - Report. Ugandan health campaign leads to large drop in viral loads. PMID- 23038836 TI - Incentives necessary for reducing racial care disparities. PMID- 23038837 TI - Prisons. Inmate with HIV may proceed with ADA discrimination claim. PMID- 23038838 TI - Medical. Woman failed to present expert witnesses to support claims. PMID- 23038839 TI - SSI. ALJ properly determined that woman with HIV could work. PMID- 23038840 TI - Workers' comp. Worker exposed to HIV was not entitled to additional benefits. PMID- 23038841 TI - Perinatal HIV consultation in Mississippi: a service area with limited access to providers. PMID- 23038842 TI - A human rights-based approach to HIV health care. PMID- 23038844 TI - News from Capitol Hill. What can we expect in federal spending 2012 and beyond? PMID- 23038843 TI - Written materials are a low-cost tool that can improve outcomes. PMID- 23038845 TI - Universal vs. targeted screening for Chlamydia trachomatis and Neisseria gonorrhoeae among HIV-infected older adults. PMID- 23038846 TI - Infants exposed to HIV drugs in womb. PMID- 23038847 TI - Possession, use, and transfer of select agents and toxins; biennial review. Final rule. AB - In accordance with the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, the Centers for Disease Control and Prevention (CDC) located within the Department of Health and Human Services (HHS) has reviewed the list of biological agents and toxins that have the potential to pose a severe threat to public health and safety and is republishing that list. As a result of our review, we have added Chapare virus, Lujo virus, and SARS-associated coronavirus (SARS-CoV) to the list of HHS select agents and toxins. We have also removed from the list of HHS and overlap select agents and toxins, or excluded from compliance with part 73, the agents and toxins described in the Executive Summary. Further, in accordance with Executive Order 13546, "Optimizing the Security of Biological Select Agents and Toxins in the United States," HHS/CDC has designated those select agents and toxins that present the greatest risk of deliberate misuse with the most significant potential for mass casualties or devastating effects to the economy, critical infrastructure; or public confidence as "Tier 1" agents; established new security requirements for entities possessing Tier 1 agents, including the requirement to conduct pre-access assessments and on going monitoring of personnel with access to Tier 1 agents and toxins; and made revisions to the regulations to clarify regulatory language concerning security, training, biosafety, and incident response. In a companion document published in this issue of the Federal Register, the United States Department of Agriculture (USDA) has made parallel regulatory changes. PMID- 23038848 TI - [Medical care of fungal infection based on the Guidelines of the Infectious Diseases Society of America: Febrile neutropenia]. PMID- 23038849 TI - [Q & A. Hepatic tumor complicated with alcoholic liver cirrhosis]. PMID- 23038850 TI - [Q & A. Enteritis found in a young man]. PMID- 23038851 TI - [Q & A. Intra-hepatic multiple nodules developing following treatment of hepatic calculi]. PMID- 23038852 TI - [My technique. Method of esophagus-gastric tube anastomosis]. PMID- 23038853 TI - [An example of patient dropouts in therapy at a psychiatric hospital]. PMID- 23038854 TI - [Patient dropouts, nonadherence and re-work programs]. PMID- 23038855 TI - Learning the wrong lessons? Science and fisheries management in the Chesapeake Bay blue crab fishery. AB - This paper argues that information produced and then taken up for policy decision making is a function of a complex interplay within the scientific community and between scientists and the broader policy network who are all grappling with issues in a complex environment with a high degree of scientific uncertainty. The dynamics of forming and re-forming the scientific community are shaped by political processes, as are the directions and questions scientists attend to in their roles as policy advisors. Three factors: 1) social construction of scientific communities, 2) the indeterminacy of science, and 3) demands by policy makers to have concrete information for decision making; are intertwined in the production and dissemination of information that may serve as the basis for policy learning. Through this process, however, what gets learned may not be what is needed to mitigate the problem, be complete in terms of addressing multiple causations, or be correct. PMID- 23038856 TI - Justice, community knowledge, and waste facility siting in Taiwan. AB - This article examines justice in the context of a controversial industrial waste facility siting in a Hakka (a minority ethnic group) town in Taiwan. It provides analysis of local perceptions of disproportionate risk, community knowledge claims, and the challenges of citizens to the controversial environmental impact assessment process. It explores knowledge disputes among regulators, developers, and local activists; it considers the struggle of local actors for recognition and inclusion in decision-making; and it argues for the development of institutional procedures that promote dialogue among stakeholders in order to avoid the preemption of debate, the control of the frame by the government and experts, and the centralization of power. PMID- 23038857 TI - Environmental conflicts, research projects and the generation of collective expectations: a case study of a land regeneration project in Tuzla, Bosnia and Herzegovina. AB - Locally based research projects may generate multiple and competing expectations from local actors, particularly when they deal with local issues that are perceived as affecting the local quality of life, such as land regeneration. The sociology of expectations provides an entry point through which the expectations of research projects in the context of an environmental conflict can be investigated. This article analyzes a case study of a project (RECOAL) whose remit was to develop regeneration solutions for coal ash disposal sites in the western Balkans.The sociology of expectations is applied here to explain the linkage between the emergence of political discourses and collective expectations. The analysis suggests that the emergence of collective future orientations of locally based research projects needs to be understood with reference to the specific political positions from which such orientations are expressed. While expectations may shape the political debate, the political debate is also generative of such expectations. PMID- 23038858 TI - Science, governance, and public participation: an analysis of decision making on genetic modification in Aotearoa/New Zealand. AB - The acceptance of public participation in science and technology governance in liberal democratic contexts is evident in the institutionalization of a variety of mechanisms for participation in recent decades. Yet questions remain about the extent to which institutions have actually transformed their policy practice to embrace democratic governance of techno-scientific decision making. A critical discourse analysis of the response to public participation by the Environmental Risk ManagementAuthority (ERMA), the key decision-making body on genetic modification in Aotearoa/New Zealand, in a specific case demonstrates that ERMA systematically marginalized concerns raised by the public about risk management, ethics, and ecological, economic, and cultural issues in order to give primacy to a positivist, technological worldview. Such delegitimization of public perspectives pre-empts the possibility of the democratic governance of science. PMID- 23038859 TI - Public participation in genomics research in the Netherlands: validating a measurement scale. AB - Nowadays, new technologies, like genomics, cannot be developed without the support of the public. However, although interested, the public does not always actively participate in science issues when offered the opportunity via public participation activities. In a study aimed at validating a measurement scale, first, we investigated if public participation existed, and, secondly, we investigated how levels of public participation in genomics research varied among groups. Finally, we studied which factors predicted public participation. Results were based on a questionnaire with four subsamples. Results confirmed, first of all, the internal consistency of the measurement scale to assess levels of public participation. Secondly, the groups differed significantly with regard to their levels of participation in genomics research. Finally, the findings revealed that information-seeking behaviour, knowledge and education were main predictors of public participation, while interest, social involvement, and trust and influence had some influence together with age and gender. PMID- 23038860 TI - Gene myths in public perceptions. AB - In this article I examine myths in the gene science debate, and their use as a tool in analysis of popular perceptions and public opinion of genetic science and gene technology. In daily language myth means something untrue, though theories of myth present them as carriers of knowledge and truth. I understand myth as a narrative, a cultural construct that aims to describe the world, its origin, and its constituent elements. I compare scholars' usage of myths, considering their implications. I conclude that i) As an analytical tool the concept of myth is too loosely defined, or understood through theories which leave out context, social relations and interaction. This provides limited insight about myths and myth making in present day society. ii) An updated understanding of myths, including location/context and interaction/process would enrich analysis. PMID- 23038861 TI - Public attitudes to the promotion of genomic crop studies in Japan: correlations between genomic literacy, trust, and favourable attitude. AB - This study aimed to assess public attitudes in Japan to the promotion of genomic selection in crop studies and to examine associated factors. We analysed data from a nationwide opinion survey. A total of 4,000 people were selected from the Japanese general population by a stratified two-phase sampling method, and 2,171 people participated by post; this survey asked about the pros and cons of crop related genomic studies promotion, examined people's scientific literacy in genomics, and investigated factors thought to be related to genomic literacy and attitude. The relationships were examined using logistic regression models stratified by gender. Survey results showed that 50.0% of respondents approved of the promotion of crop-related genomic studies, while 6.7% disapproved. No correlation was found between literacy and attitude towards promotion. Trust in experts, belief in science, an interest in genomic studies and willingness to purchase new products correlated with a positive attitude towards crop-related genomic studies. PMID- 23038862 TI - [Doctor Pean teaching at the Saint-Louis hospital its discovery of vessel clamping, by Henri Gervex (1852-1929)]. AB - The oil painting by Gervex Avant l'operation is analysed as far as art-history in general is concerned, and also for a more precise history of medical portraiture. PMID- 23038863 TI - [The French maritime health police in the 19th century]. AB - The French law of 1822 created a homogeneous maritime health police all along the French coastline. Noteworthy in many respects, it was however very binding since it included some penalties of an extraordinary harshness as hard labour or even death. It was first disputed by those against the theory of contagion and the maritime and commercial circles, but subsequently it became overtaken by scientific knowledge despite numerous facilities and some important remodelling decrees were decided, one of them in 1876 just before the Pasteur revolution and another in 1896. The aim was then not only to prevent, epidemics (plague, cholera, yellow fever) crossing the borders of the national country, but also to prevent them from spreading out of their original cradles. Later it was the beginning of the sanitary international cooperation with the training of special eastern practitioners who could take sanitary precautions close to the sources of infection. PMID- 23038864 TI - [History of prostatic adenomectomy]. AB - Treatment of the prostate hypertrophy has long been limited to that of its complications and particularly to retention linked with congestion of this gland. The different operating techniques appear only in the 19th century in parallel with a better knowledge in the pathogenesis of this gland; the different schools in urology competing with various approaches from perinea to hypogastria surgery. The 21st century and its innovating technologies bring in a new era where the laser and coeliosurgery will find their respective place. PMID- 23038865 TI - [The seven wounds Ernst Junger at the time of the Great War. Reflection of the health service of the imperial army]. AB - Thanks to Ernt Junger's amazing career--and despite his many injuries--we have a great view of the German Imperial Army's sanitary corps. This can be observed from the actions of the stretcher-bearers to German hospitals in general, and with the organization of their sanitary transport, as well as their medico surgical concerns. We can see, therefore, that very few differences existed with the French medico-surgical structures except for the fact that,from the very beginning, Imperial medical warfare was able to adjust to the changes from field to trench situations. Thanks to its adaptable system of triage, and its ability to offer the most coherent medico-surgical choices and options, it was possible to save time. It enabled surgical actions in places that were close to the battlefield. Furthermore, we have been able to find out about the personal experience of an exceptional 20th century writer who later became a great European citizen. PMID- 23038866 TI - [Traffic accidents during the Roman empire: to go to the doctor o to the god?]. AB - A few pages by Galen and an inscription from Roman Egypt testify to two psychological attitudes towards diseases and accidents: either you feel responsible and go to the doctor, or you think you are in the hands of some god. PMID- 23038867 TI - [From sworn physicians at the Chatelet de Paris to forensic physicians. The birth of a professionalization (1692-1801)]. AB - The phrase 'Forensic Medicine' appeared in 1777. Previously the notion was mixed up with medical science and limited to record the state of a desecrate or a dead body. Medical doctors and surgeons were in charge of writing the reports. Forensic medicine became institutionalized since 1750. The first treatise of forensic medicine was written by the chairman of Forensic Medicine at the Health School in Paris, Paul Augustin Mahon de la Houssaye about its specific methods. He contributed to create a link between medicine and law so as to let the Forensic Scientist take an active part in public health policy. PMID- 23038868 TI - [The Firmin case (1794-1799) and the absence of crime legislation on "insanity" during the French Revolution]. AB - Examining the so-called "affaire Firmin" (1794-1799), the author wonders about the reason (idealistic or political) for the lack a special law on insanity defense during the French revolution, and she tries to find a link the present state of the law. PMID- 23038869 TI - [The art of improvising. The practice of medico-legal autopsies in the 19th century]. AB - Murder is perpetrated, suicide is committed and lethal accidents happen everywhere, even in the heart of the French country. In the 19th century, law often appealed to the lights of experts. During criminal investigation, improvisation and men's adaptation were important, although forensic autopsy was official and necessary. Sometimes the magistrates appealed to young people, not used to that kind of reports, who could only remind some bits of the forensic courses they had followed when they were students. As for the specialists, the circumstances often led them to examine--as Baudelaire would say--the "decaying carcass," in a dark and suffocating ruined house, on the kitchen table, and with a simple scapel. PMID- 23038870 TI - [Augustin Cabanes (1862-1928). The reasons of a missed appointment with posterity]. AB - On the occasion of the 150th anniversary of Augustin Cabanes' birth (1862-1928), we analyse the very controversial contributions of the author of the Histoire eclairee par la clinique--but also of many works and articles--to the history of medicine and to historical medicine. PMID- 23038871 TI - [Contributions of radiology to surgery. A history older than a century]. AB - The discovery of X rays was immediately highly valued by all the surgeons. At its beginnings, radiology only allowed to objectivize the lesions of the bones and to localize the radio-opaque foreign bodies. WWI materialized this synergy and after the conflict every hospital had to have a radiological department. By slow and progressive technological advances, radiology managed to visualize other organs. The two world wars generated new methods permitting the diagnosis of otherwise unsuspected lesions. Finally, after the demonstration of the anatomy, radiological research started to investigate the function of the organs. A brief look of the major steps of this collaboration shall be topic of this talk. PMID- 23038872 TI - Prevention and intervention on the care continuum. PMID- 23038873 TI - Disparities in the geography of mental health: implications for social work. AB - This article reviews recent theory and research on geographic disparities in mental health and their implications for social work. It focuses on work emerging from the fields of mental health geography, psychiatric epidemiology, and social work, arguing that a wide range of spatial disparities in mental health are important to understand but that of greatest relevance are inequities, or disparities, that violate fundamental norms of fairness and social justice. Research is reviewed on geographic variations in subjective well-being and mental health, on personality (using the five-factor model), and on psychopathology as well as several studies on the disparate implementation of mental health policy and services. Critical is the need to simultaneously assess, on the one hand, differential patterns of mental health conditions and, on the other, the services and policies designed to address them--the fact that considering only one dimension often leads to unintended consequences. Many of the most outstanding disparities have been found to exist at the local level, between towns and neighborhoods, and are based on socioeconomic conditions. This review concludes by discussing the implications of geographic disparities in mental health for allocation decisions and for social work practice, including decisions about the most efficacious mix of services at both the community and clinical practice levels. PMID- 23038874 TI - In-home intervention with families in distress: changing places to promote change. AB - This article examines the benefits of in-home family therapy with severely distressed families through the analysis of four cases that demonstrate the creative use of this intervention with families whose children were placed in a full-time day care facility. Although the efficacy of home intervention with distressed families has been documented, the case illustrations here analyze the process more fully--the how and the why it works. The first three cases explicate the contribution of home intervention to the engagement of social worker and client. Each case highlights how home intervention enhances the therapeutic alliance by promoting change from a different starting point--the client (home as a secure base for change), the worker (viewing the client from a different perspective), and the client-worker interaction (power sharing in setting boundaries). The fourth case (in vivo narrative reconstruction) serves as a striking example of how the home--as a multisystemic, intergenerational container of the family's past, present, and future--can be enlisted as a partner in reconstructing silenced chapters of the family narrative. PMID- 23038875 TI - Family-based crisis intervention with suicidal adolescents in the emergency room: a pilot study. AB - The prevailing model of care for psychiatric patients in the emergency room (ER) is evaluation and disposition, with little or no treatment provided. This article describes the results of a pilot study of a family-based crisis intervention (FBCI) for suicidal adolescents and their families in a large, urban pediatric ER. FBCI is an intervention designed to sufficiently stabilize patients within a single ER visit so that they can return home safely with their families. Of the 100 suicidal adolescents and their families in the sample, 67 met eligibility criteria for FBCI. Demographic and clinical characteristics and disposition outcomes from the sample were compared with those obtained retrospectively from a matched comparison group (N = 150). Statistical analyses compared group inpatient admission rates and disposition outcomes. Patients in the pilot cohort were significantly less likely to be hospitalized than were those in the comparison group (36 percent versus 55 percent). Only two of the patients in the FBCI cohort were hospitalized immediately after receiving the intervention during their ER visit. FBCI with suicidal adolescents and their families during a single ER visit is feasible and safely limits the need for inpatient psychiatric hospitalization, thereby avoiding disruption of family, academic, and social activities and increasing use of less intrusive and more cost-effective psychiatric treatment. PMID- 23038876 TI - Critical reflection to identify gaps between espoused theory and theory-in-use. AB - Critical reflection (CR) is a process by which one may identify the assumptions governing one's actions, question them, and develop alternative behaviors. This article presents two cases that demonstrate the use of CR to raise social workers' awareness of gaps between what Schon and Argryis term social workers' "espoused theories" and the "theories-in-use" that actually guide social workers' practice and to help them to develop more effective models of practice based on the understanding they gain. With this, the cases also show that CR can be a painful, even wrenching, process, in which practitioners confront previously unacknowledged qualities or tendencies in themselves that can evoke strong feelings. PMID- 23038877 TI - American Bar Association Supplementary Guidelines for the Mitigation Function of Defense Teams in Death Penalty Cases: implications for social work. AB - When a client faces a penalty of death, defense attorneys may call on social workers in many capacities: mitigation specialist, expert witness, consulting specialist, direct witness, or defense-initiated victim outreach worker. The American Bar Association set forth standards for capital defense attorneys, which led an interdisciplinary team to produce the "Supplementary Guidelines for the Mitigation Function of Defense Teams in Death Penalty Cases" to promote the exceptional competence and diligence required when the consequence is life or death. This article summarizes the "Supplementary Guidelines," with implications for social work practice--that is, professional responsibility, competence, interviewing skill, knowledge of behavioral and mental impairment, records review, life history compilation, data interpretation, witness support, law related knowledge, and testimony. The social work, which is scrutinized in a court of law, requires cultural competence, diverse oral and written communication skills, diligence, and the highest ethical standards. PMID- 23038878 TI - Deaths in the desert: the human rights crisis on the U.S.-Mexico border. AB - Many would acknowledge that immigration is a major issue in the United States and that immigration reform should be a priority. However, there is little attention to the human rights crisis on the U.S.-Mexican border. As a result of tightened border security since 1994, it is estimated that over 5,000 migrants have died in the Sonoran desert. The criminalization of immigration has resulted in a human rights crisis in three areas: (1) the rise of deaths and injuries of migrants crossing the border in harsh and remote locations, (2) the use of mass hearings to prosecute apprehended migrants, and (3) abuses of migrants in immigration detention. These policies and practices have serious repercussions for the affected vulnerable population. Despite recent legislation designed to discourage undocumented immigration, such as Arizona's Senate Bill 1070, the deterrence strategy has not diminished migration--it has only increased the suffering and deaths of migrants. Humanitarian groups are working to prevent more deaths but also have been targeted for criminalization. The profession's ethics compel social workers to work with humanitarian organizations to prevent more deaths and to advocate for humane immigration reform. PMID- 23038880 TI - Where is social work in the social entrepreneurship movement? PMID- 23038879 TI - Free tax assistance and the earned income tax credit: vital resources for social workers and low-income families. AB - As the United States' economy continues to experience challenges, more families at or near the poverty level fall prey to predatory financial practices. Their vulnerability to these operations is increased by a lack of knowledge of asset building resources and alternative financial services. This article focuses on Volunteer Income Tax Assistance (VITA)--a free income tax preparation program, which is a vital resource available to low-income families. Unfortunately, VITA is largely underused and often unknown to economically strained families and to the social workers and other professionals to whom these families turn for assistance. This article concludes with policy and practice implications for social workers and other professionals engaged in providing services to financially vulnerable families. PMID- 23038881 TI - Losing touch in social work practice. PMID- 23038882 TI - Prostate cancer incidence and mortality among Puerto Ricans: an updated analysis comparing men in Puerto Rico with US racial/ethnic groups. AB - OBJECTIVE: Prostate cancer is the most common cancer and the most common cause of cancer death among men in Puerto Rico (PR). Socioeconomic and racial/ethnic disparities with regard to prostate cancer incidence have been reported in the United States of America (US); however, detailed information regarding health disparities in PR is scarce. METHODS: Age-standardized rates for prostate cancer incidence and mortality were calculated based on the world standard population using data from the PR Central Cancer Registry and the National Cancer Institute SEER program. The age-specific relative risks were calculated using Poisson regression models. In addition, incidence and mortality rates in PR were compared by socioeconomic position (SEP) at the municipal level. RESULTS: For the period from 1992 to 2004, the incidence and mortality trends of prostate cancer decreased in all racial/ethnic groups except for PR men and US Hispanics (USH). Non-Hispanic whites (NHW), non-Hispanic blacks (NHB), and USH had higher incidence of prostate cancer than did PR men; however, PR men aged 85+ yrs and USH aged 45-54 yrs/85+ yrs, respectively, had higher incidences than did NHW and USH. Nonetheless, men in PR had a higher mortality than did USH and NHW. PR men aged 55-64 years with the highest SEP had a 40% higher mortality of prostate cancer than did those with the lowest SEP. CONCLUSION: Areas of concern include the higher mortality of prostate cancer in PR as compared with the USH and NHW in the US. Further research should be performed to guide the design and implementation of prostate cancer prevention and education programs that can increase early detection in PR men. PMID- 23038883 TI - Distribution and correlates of the metabolic syndrome in adults living in the San Juan Metropolitan Area of Puerto Rico. AB - OBJECTIVE: This study evaluated correlates of the metabolic syndrome among adults living in Puerto Rico, a Hispanic subpopulation disproportionately affected by diabetes. METHODS: A probability cluster design was used to select a sample of households of the San Juan Metropolitan Area in Puerto Rico. A total of 858 persons aged 21-79 years completed a face-to-face interview, blood pressure and anthropometric measurements, blood sampling and spot urine. Logistic regression was employed to assess correlates of the metabolic syndrome. RESULTS: Of 368 (42.9%) of adults who met the criteria for metabolic syndrome, elevated fasting glucose (49.8%), abdominal obesity (48.6%), and reduced HDL cholesterol (45.8%) were the most prevalent diagnostic criteria. In a multivariable logistic model that simultaneously adjusted for sociodemographic characteristics and health behaviors, older age, high school educational attainment or less, no alcohol intake, and lack of moderate-to-vigorous physical activity remained significantly (p < 0.05) associated to the metabolic syndrome. However, the associations for male gender, some college education, and current smoking > or = 20 cigarettes/day had borderline significance. Further controlling for inflammatory markers slightly attenuated the strength of most of these associations but remained significantly (p < 0.05) associated to the metabolic syndrome with only a few exceptions. Middle and upper tertiles of hs-CRP, fibrinogen, and PLl-1 and an elevated albumin-to-creatinine ratio were also associated (p < 0.05) with the metabolic syndrome. CONCLUSION: Enhancing public education regarding modifiable risk factors for the metabolic syndrome and providing optimal medical management of individual metabolic disturbances among those at risk through preventive lifestyle changes should be placed as a public health priority for Puerto Rico. PMID- 23038885 TI - Knowledge of legal rights among persons living with HIV/AIDS in Puerto Rico: implications for stigma management. AB - OBJECTIVE: To determine the level of understanding that people living with HIV/ AIDS (PLWHA) in Puerto Rico have in terms of their own legal rights; to ascertain how the members of this population manage the violation/s of these rights in the event that such violations occurred. METHODS: A mixed-method design was used to accomplish our objectives. One hundred and three participants completed a questionnaire; an in-depth interview was also conducted with 10 members of the sample group. RESULTS: Quantitative results show that the most recognized rights among the participants were the right to have sex (n = 98; 95%) and the right to marry (n = 90; 87%). Most participants inaccurately indicated that PLWHA are forced by law to disclose their HIV serostatus both to their partners (n = 69; 67%) and to their physicians (n = 70; 68%). The results from qualitative analysis indicate that most of the participants had experienced discrimination, though none reported these occurrences to the legal authorities. CONCLUSION: Findings suggest that there is a need to improve the implementation of the public policy that protects PLWHA who live in Puerto Rico from discrimination. Future interventions aimed at reducing HIV-related stigma should consider providing information about legal rights and strategies for managing stigma and discrimination. Healthcare professionals play an important role in the promotion of the rights of PLWHA in Puerto Rico. PMID- 23038884 TI - Association between vitamin D levels and blood pressure in a group of Puerto Ricans. AB - OBJECTIVE: Hypertension is a global public health problem. The apparent association between vitamin D (VitD) and blood pressure (BP) has been studied in several populations but not in a Puerto Rican population. Therefore, we determined the association between serum 25(OH)D levels and BP in a convenience sample in Puerto Rico. METHODS: A cross-sectional study of patients attending a local laboratory with an order for serum 25(OH)D levels was performed. Participants completed a questionnaire that solicited the following information: age, sex, weight, height, VitD intake, and history of both sun exposure and hypertension. BP was measured by a phlebotomist on-site and classified according to the Joint National Committee; serum 25(OH)D levels were taken from the record, and VitD status was classified as either optimal (25(OH)D > or = 30 ng/dl) or non optimal (< 30 ng/dl). Mean, standard deviation, and percentiles were used for descriptive analysis. VitD status and BP were compared by gender, age, and body mass index (BMI) using ANOVA or chi-square. The association between VitD status and blood pressure was assessed by polytomous logistic regression adjusting for several variables. RESULTS: Two hundred nineteen individuals were included in the analysis; most were females aged 21 to 50 years who were overweight/obese; 53% of the total population was pre-hypertensive or hypertensive; 60% had non-optimal VitD status; and the sun exposure index was 19.6. No significant associations were found between VitD status and blood pressure after adjusting for age, sex, BMI, total VitD intake, and solar exposure index. CONCLUSION: VitD status was not found to be associated with blood pressure in this sample population; more studies with a larger sample population are needed to determine whether such an association does in fact exist. PMID- 23038887 TI - Central nervous system hemangiopericytoma, retrospective four year pathology case series. AB - Hemangiopericytomas (HPC) are uncommon, aggressive, difficult to diagnose tumors mostly found in the extremities and pelvis and very rarely within the Central Nervous System(CNS). CNS HPC closely mimics meningioma, which is a much more frequent benign tumor, while HPC is potentially lethal, thus correct diagnosis of HPC is vital. Due to the very low frequency of CNS HPC, local experience with this tumor is very limited. For this reason a retrospective four year review of CNS pathology cases was performed to observe the frequency of CNS HPC, histopathology, immunohistochemistry, correlate the proportion of HPCto meningiomas and compare these with the literature. Results showed that our past pathologic assessment of HPC as well as the incidence is consistent with the literature, while the ratio of HPC to meningioma was above expected. This is the first local study dealing with the pathology of CNS HPC, which discloses an adequate clinic-pathologic assessment within the UPR premises as reflected by pathologic-epidemiologic findings coincident with the literature. A discrepancy of the HPC to meningioma ratio was found. Further studies are warranted to delve into the etiologies of this discrepancy as the issue has major implications due to the benign and malignant behavior respectively of meningioma and HPC. PMID- 23038886 TI - Prescribing patterns and safety of mezclitas for respiratory illnesses. AB - OBJECTIVE: To evaluate the prescribing patterns of compound mixtures of cough and cold liquid medications, known as mezclitas, which are prescribed to patients with respiratory illnesses in Puerto Rico. Secondary objectives include assessing the potential safety of these mixtures and patients' perception of them. METHODS: Using a cross sectional study approach, a convenience sample was obtained from five pharmacies in Puerto Rico, from October 2008 to October 2009. Patients were asked to complete a 9-item questionnaire about demographic information, in addition to their mezclita prescription data. RESULTS: The mean age of patients was 43 years with a range of less than 12 months to 101 years. For children < four years of age, 71% were prescribed cough and cold medications. Sixty-four percent of the prescriptions were given to females. The most prevalent ingredient employed was guaifenesin, which appeared in about 77% of the mezclitas. 'Common cold' was the principal diagnosis for 62% of the prescriptions, of which 75% of these prescriptions contained a corticosteroid and 17% contained a beta2 agonist bronchodilator. The top medical prescribing specialty was general medicine (51%). Thirty-eight percent of hypertensive patients were prescribed a decongestant. The majority of diabetic patients (60%) were dispensed a corticosteroid. Most (74%) patients reported that they had a rapid and good response to their mezclita. CONCLUSION: Mezclitas were most commonly prescribed for acute symptoms of upper respiratory illness by general physicians despite possible side effects. This study suggests that the prescription patterns of mezclitas do not always consider evidence-based medicine treatment guidelines. PMID- 23038888 TI - Intravitreal bevacizumab for peripapillary subretinal neovascular membrane associated to papilledema: a case report. AB - The purpose of this report is to document the use of bevacizumab as treatment of peripapillary subretinal neovascular membrane associated to idiopathic intracranial hypertension. This case reports a 31-year-old obese female with chronic papilledema due to idiopathic intracranial hypertension that developed an acute submacular hemorrhage due to a choroidal neovascular membrane in her left eye. Two separate intravitreal injections of bevacizumab (1.25 mg/0.5 ml) were administered with six weeks apart. Fourteen weeks after the initial injection her visual acuity improved to 20/40 in her left eye with associated angiographic resolution of the hemorrhage. Bevacizumab appears to be an effective option for patients who have subretinal neovascular membranes due to papilledema. Although choroidal neovascularization may have different pathogenic mechanisms, our case report demonstrates encouraging results without adverse ocular or systemic side effects. PMID- 23038889 TI - A rare cause of fetal bilateral hydronephrosis secondary to meatal stenosis. PMID- 23038890 TI - Turning the tide in the Caribbean: a call to strengthen the evidence for a sustainable response to HIV/AIDS. PMID- 23038891 TI - A preliminary profile of HIV risk in a clinic-based sample of MSM in Puerto Rico: implications for sexual health promotion interventions. AB - OBJECTIVE: Puerto Rico has one of the fastest growing HIV epidemics in the United States and--consistent with patterns observed in the Caribbean region as a whole- data on new infections shows the increased influence of sexual transmission in the local epidemic. Historically, both epidemiology and prevention activities have focused primarily on the islands' large heroin injector population. Although the available surveillance data indicate high rates of STIs and HIV among men who have sex with men (MSM), there has been little social and behavioral research among MSM and hence little empirical information to inform intervention development and planning. METHODS: Given the absence of data on MSM and their importance in the emerging epidemic on the island, this paper describes a sample of MSM patients in an STI/HIV treatment center in the San Juan metropolitan area between October 2009 and June 2011 (n = 120). Assessment of sexual risk includes measures of onset of oral, vaginal, and anal sex, as well as current sexual practices and partner characteristics. Self-reported history of STI diagnoses and current HIV status are described. RESULTS: Overall, MSM evidenced relatively large numbers of multiple, concurrent sexual partners, substantial age discordance among partners, and limited condom use. Relative to HIV-negative MSM, HIV-positive MSM have had more cumulative male sexual partners in anal intercourse (p = 0.005). HIV-negative MSM were more likely to have had sex without a condom at last receptive anal intercourse (p = 0.012) as well as at last insertive anal sex intercourse (p = 0.001). CONCLUSION: Priorities for advancing HIV interventions for MSM are delineated, including the need for targeted sexual health interventions, mental health services, and improved strategies for engaging and retaining MSM in health services. PMID- 23038892 TI - HIV and incarceration in the Caribbean: the experiences of Puerto Rico and Jamaica. AB - Worldwide, HIV has disproportionally affected incarcerated populations since early in the epidemic. Current trends in the Caribbean demonstrate that correctional facilities house most at-risk individuals. The experience of incarceration and the HIV epidemic in the Caribbean are as diverse as the region. In this paper we present descriptive information from Puerto Rico and Jamaica as two unique examples of current efforts to address HIV among prisoners. While different, these countries provide a comparison of correctional health care in a sexually driven epidemic versus one where injecting drug use plays a major role, bridging cultural differences, and contrasting approaches in the provision of HIV services relevant for other Caribbean countries. While the evidence of effective interventions within correctional facilities in the Caribbean is limited, the knowledge gained through the services implemented and research completed in different countries can facilitate the process of developing and testing new interventions. The experience of these islands and coordinating lessons learned and innovations from throughout the region can assist in developing a resourceful way forward. PMID- 23038893 TI - Biomedical HIV prevention strategies: state of the art and implications for public health policy in the Caribbean. AB - Recent advances in the field of biomedical prevention have induced optimism among both the scientific community and the public in general. The discussion of the research evidence is complemented with a discussion of the implications of this evidence for the Caribbean, highlighting the issues and controversies that should be considered in order to encourage and advance the responsible consideration of biomedical strategies. Traditionally, HIV prevention strategies have been characterized as predominantly behavior, social or biomedical. In practice, however, some strategies defy classification: even when they rely on technological or pharmaceutical elements, they have to be adopted by a society and the individuals within it. Moreover, whatever the strategy used, it will have to be distributed, implemented and made available through health care systems or other means. And its cost will be absorbed by specific funders or by society in general. Given the current historical context of the HIV/AIDS epidemic and the array of strategies required to control it, these distinctions (biomedical vs. behavior) can hinder the collaborations required to provide the needed combinations of strategies. The efficacy of the diverse strategies range from: 99% for programs to prevent MTCT, 63% for pre-exposure prophylaxis (PrEP), 96% for treatment as prevention, 39% for vaginal microbicides (54% with good adherence), post exposure prophylaxis (PEP), 31% for a vaccine and 53-60% for medical voluntary adult circumcision. To curtail and eliminate the HIV/AIDS epidemic in the future, expansion and scaled-up implementation of combinations of such strategies will be needed. PMID- 23038894 TI - Forging a sustainable response to HIV/AIDS in the Caribbean--the strategic role of a regional conference. AB - The paper provides a rationale for a Caribbean HIV/AIDS Conference as a key ingredient to the regional response mechanism. This initiative stems from the need to address crucial elements of the regional response within the realities of the present regional economic situation and global financial climate, as well as epidemiological and demographic trends. A mixed method approach was adopted for this study, drawing on both primary and secondary data collection techniques. A small survey of leaders and senior practitioners formed the basis of the primary data collection phase, complemented by key informant interviews. The paper proposes a model for a Caribbean HIV Conference that can better position the regional response in line with the present global and local socio-economic and health landscape. Central to this model is the repositioning of the Conference from an "Event" to being an "Activity" in the regional planning agenda and the positioning of the Conference as a fundamental fixture of the region's health calendar. The positive externalities from the synergies developed around the Conference can be identified in terms of the quantifiable costs savings to Agencies. The less quantifiable path relates to networking, exchanges and stronger regional ties that are facilitated through the activity. The main findings of the survey of health leaders indicate significant support for an ongoing regional conference. The results therefore endorse the location of a Conference entity together with the relevant support mechanisms as a key feature on the Caribbean's health landscape. PMID- 23038895 TI - Report of the 2012 capacity building for HIV-HPV clinical trials recruitment among minority underserved populations of Hispanic origin in Puerto Rico. PMID- 23038896 TI - Vinculo: a Latin American psychoanalytic concept. PMID- 23038897 TI - The concepts of vinculo and dialectical spiral: a bridge between intra- and intersubjectivity. AB - The authors explore the psychoanalytic concepts of vinculo and dialectical spiral within the context of a historical review of the development of psychoanalysis in the Rio de la Plata region of Uruguay and Argentina. In particular, they discuss the work of Enrique Pichon-Riviere, Madeleine and Willy Baranger, and Jose Bleger. Illustrative clinical material is included from a case described by Bleger. Convergences and divergences are noted between the theoretical and clinical approaches of these authors, on the one hand, and those of more traditionally Freudian, Kleinian, and other schools of analysis, on the other. Also, the authors underline some questions about the nature of vinculo that are currently under discussion in the Rio de la Plata. PMID- 23038898 TI - Vinculo as a relationship between others. PMID- 23038899 TI - Deconstructing vinculo. PMID- 23038900 TI - Links and perspectives on the individual and the group. PMID- 23038901 TI - A silent yet radical future revolution: Winnicott's innovative perspective. AB - The author begins with an examination of two unpublished notes by Melanie Klein, written in 1953 and tracked down by Hinshelwood (2008). In these notes, the role of the study of projective identification as a tool that can permit the analyst to master countertransferential difficulties is highlighted; in 1953, this is the most advanced point of psychoanalytic investigations into unconscious object relations. The author also considers Winnicott's essays "Primitive Emotional Development" (1945) and "Hate in the Countertransference" (1947). In the former, Winnicott begins to inquire into the relationship between subjectivity and objectivity, in relation both to the birth of the mind and to the analyst's psychic functioning. Ultimately, the author demonstrates that the origins of an extraordinary transformation of psychoanalytic theory are contained in Winnicott's essay on countertransference of 1947. In fact, the Winnicottian conception of psychic functioning is founded on the radical and absolutely innovative principle by which the object's unconscious functioning, as well as its transformations caused by the subject's unconscious, must be investigated and transformed in order for the subject to be capable of beginning a psychic transformation. PMID- 23038902 TI - The reluctance to self-disclose: reflexive or reasoned? AB - Despite a growing body of clinical literature advocating the thoughtful and judicious use of self-disclosure in psychoanalysis, there remains a reflexive reluctance to intervene in this way by many analysts of various theoretical persuasions. Why is this the case? Four motives for this reflexive reluctance to self-disclose are discussed: (1) theoretical reasons; (2) psychoanalytic authoritarianism; (3) fears of influencing the patient through suggestion; and (4) the analyst's personality characteristics. Examining the reasons for this state of affairs should help to reduce the rigidity or orthodoxy with which clinical psychoanalysis is practiced. PMID- 23038903 TI - Bodily manifestations in the psychoanalytic process. AB - The broadening scope of psychoanalysis has brought to the fore patients whose unconscious conflicts tend to be literally played out on the stage of the body. In these cases, the body seems to be predominantly used in a concrete, not symbolic, way in order to express underlying conflicts. In a similar vein, transference and countertransference can be manifested via the body. The authors briefly discuss some of the literature on body-mind issues, and then present an extended case report to illustrate bodily manifestations in the psychoanalytic process. PMID- 23038904 TI - Becoming a mother by "AID" within a lesbian couple: the issue of the third. AB - Using data from clinical psychoanalytic research on lesbian couples undertaking Artificial Insemination by Donor (AID), this article explores the position of the third as it appears in the family project of lesbian couples. The third is examined through the analysis of constructions surrounding the image of the anonymous donor, the impact of the medical act of insemination on the women's psychic economy, and the search for other promising bases for triangulation. The complexity of the issue of the third in same-sex parenting is highlighted. Excerpts from clinical interviews with two lesbian couples are used to illustrate and support the authors' hypotheses. PMID- 23038905 TI - The uncanny in a dream. AB - In previous publications, the author has focused on particular types of inclusions in dreams (Mahon 2002a, 2002b, 2005a, 2007). In this paper, the author explores an instance of the uncanny in a dream and speculates on the particular function such an inclusion might have served. A patient dreamed about the name of an author, Thomas B. Costain, which he believed at first to be a fictitious dream concoction. In fact, all his initial associations dealt with this dream inclusion as if it had no connection to reality. When he later Googled the name, he was surprised to uncannily discover that the "fictitious" name was in fact the real name of a moderately well-known author. His subsequent discovery-that one of the author's books, The Silver Chalice, "re-minded" him of silver paper chalices that his father used to make for him as a child-jolted him further. This revived repression of not only the author's name, but also of its significant connection to repressed genetic memories, filled him with a sense of awe, as though he had suddenly been awakened from a hypnotic spell. If dream experience in general can be considered uncanny, the dream work deployed this particular inclusion of an uncanny, "fictitious" representation of reality for complex dynamic reasons, the author maintains. PMID- 23038906 TI - [Sergei Sergeevich Iudin (1891-1954) (commemorating the 120th anniversary of his birthday in memories of his contemporaries and in memory of the outstanding Iudin phenomenon)]. PMID- 23038907 TI - [Surgical resection in combination with stereotaxic cryodestruction in patients with supratentorial gliomas in functionally significant areas of the brain: possibilities of using combined surgical treatment and its results]. AB - A combined method of surgical treatment of glial tumors of the brain is proposed for decreasing risk of complications. The method includes microsurgical ablation of the main volume of the neoplasm and stereotaxic cryodestruction of the residual part of the tumor. Combined surgical treatment was used in 12 patients. The results obtained show that the proposed method elevates the efficacy of surgical method, facilitates increased indices of survival rate and maintenance of quality of life of the patients at the tolerant level. PMID- 23038908 TI - [A new view on the problem of nonneoplastic stenosis of the major duodenal papilla. Results of a prospective investigation]. AB - The article contains results of a continuous prospective investigation of the normal course of the major duodenal papilla stenosis in 167 patients. It was revealed that the course of the disease was benign, pain syndrome became inconsiderable in the course of time, the degree of changes in biochemical analysis of blood was not significant. The development of complications (choledocholithiasis, acute pancreatitis, jaundice) was noted in 6-14% of the patients, depending on the presence or absence of GID. The data obtained allow suggestion of an algorithm of managing the patients. PMID- 23038909 TI - [The possibilities of combined methods of minimally invasive interventions in treatment of benign diseases and lesions of the bile ducts]. AB - The authors have shown the possibilities of minimally invasive operations under ultrasonic, endoscopic and radiological control in treatment of patients with lesions and strictures of the bile ducts. The experience is based on an analysis of operations on 68 patients. In most patients the patency of ducts was restored without using open traditional operations due to the developed and used combined minimally invasive operations. PMID- 23038910 TI - [Fulminant acute pancreatitis. Are there objective criteria of the disease?]. AB - A retrospective analysis has been made of the results of the diagnosis and treatment of 71 patients having severe pancreatitis. As a result, factors were revealed which restrict the possibilities of conservative treatment associated with pessimistic prognosis of the disease. Among them there are pancretitis specific organic abnormalities (pulmonary, cardio-vascular, renal dysfunctions), diffused pancreonecrosis and infection of destructive zones. All the parameters in question are included in the proposed model of prognosis of the fulminant course of pancreatitis having high diagnostic accuracy up to 88.3%. PMID- 23038911 TI - [New approach to treatment of patients with chronic fibrosing pancreatitis by laser tunneling of the pancreas]. AB - Laser tunneling of the pancreas for stimulation of neoangiogenesis, regeneration and reverse of sclerotic changes was performed in 20 patients with fibrosclerotic pancreatitis. Nine of them were men and eleven were women. The age of the patients ranged from 27 to 71 years. The results of clinical trial testify for the possibility of safe and effective application of laser tunneling of the pancreas in patients with chronic pancreatitis. One of the significant features of the treatment was pain relief and improved quality of life of these patients. PMID- 23038912 TI - [Effects of immunotropic therapy on the structure of system-forming indices in patients with urgent surgical pathology]. AB - An investigation of system-forming indices of severity of the state and intoxication in 276 patients with urgent surgical pathology depending on using immunotropic medicines has revealed differences in the significance of factors of system-forming indices and functional load on the inflammation mechanisms depending on the inclusion of immunotropic medicines in the complex treatment. PMID- 23038913 TI - [Application of compressing mini-screws in treatment of patients with intra articular fractures]. AB - The authors present an experience with the application of compressing headless mini-screws (Herbert screws) in treatment of intra-articular fractures in 37 patients. The mini-screws were used both singly and in combination with other metallic constructions. Long-term results of the treatment were followed up in 21 patients (6 months), in 14 of them excellent results were noted, in 5--good, in 1 -satisfactory and in 1--unsatisfactory results. One complication was notes as the formation of a false articulation of the radius neck. An analysis of the results showed that the application of mini-screws allowed performing stable osteosynthesis after anatomical reposition of the articular surfaces, obtaining good anatomical and functional results and shorter period of treatment. PMID- 23038914 TI - [Application of intramedullary blocked osteosynthesis for treatment of patients with open fractures of the shin and femur in combined injuries]. AB - Actual problems of using intramedullary blocked osteosynthesis for open fractures of the shinbones and femoral bones in patients with combined injuries are considered. The most optimal terms of operative treatment were established depending on the severity of the injuries by ISS scale and on classification of injuries of the soft tissues by Gastillo-Andersen. The schemes of antibacterial prophylactics of infectious complications are proposed both during operation and at the postoperative period. Under consideration are the questions of intraoperative boring of the bone marrow canal of the shinbones and femoral bones in severe combined injuries. PMID- 23038915 TI - [Inadequate operations for carcinoma of the thyroid gland]. AB - An analysis of observations of 81 patients has shown that inadequate operations might be followed by the appearance of continuing growth of the tumor in 24.7% of cases. Reoperations made for clinical-laboratory indications are followed by residual tumors in 61.29%. After inadequate operations the patients must be under active observation. PMID- 23038917 TI - [Primary hyperparathyroidism in oncological practice]. AB - In the period from 1999 till 2009 there were 18 patients (14 women and 4 men) with adenomas of the parathyroid gland (PTG). Solitary lesions of the bones were diagnosed in 12 of them, 6 patients had multiple lesions. In 5 patients bone lesions were combined with nephrolithiasis and cholelithiasis. Operations resulted in osteodystrophy, normalization of hormonal and biochemical indices. One adenoma of PTG was found in 17 patients, in one woman there were two adenomas on both sides of the trachea, but they were diagnosed not at once. Reoperation gave recovery of the patient. PMID- 23038916 TI - [The ultrasound diagnosis of regional recurrent cancer of the thyroid gland]. AB - Examination of 220 patients was performed using ultrasound investigation (USI) in B-regimen, color and energy Doppler encoding, 3D-reconstruction of image and sonoelastography. There were 49 recurrences in the regional lymph nodes. Main semiotic signs of regional recurrences were identified. USI with the application of the methods described is highly informative: sensitivity--94.2%, specificity- 92.5%, accuracy--91.7%. PMID- 23038918 TI - [Indications and results of colostomy for anorectal malformations in girls]. AB - On the basis of an analysis of 122 cases the authors present options on the strategy and methods of operations depending on the anatomical patterns, the degree of anorectal malformations and the type of coexisting pathology, the technique of placing unnatural anus. Preference is given to a one-stage surgical method, the indications to the graded treatment with the formation of colostomy are described in detail. PMID- 23038919 TI - [A new method of gastrostomy as a stage of surgical treatment of esophageal burns]. AB - The method of gastrostomy can be used as a stage of treatment of patients with cicatricial strictures of the esophagus due to chemical burn (for gullet bougienage by the directing thread). Localization of the dotted gastrostomy on the anterior wall of the stomach provides safety of the intraorganic main vessel in different variants of extraorganic angio-architectonics. PMID- 23038920 TI - [Results of palliative operations in patients with "neglected" thyroid cancer]. AB - An analysis of 169 palliative surgical interventions out of 581 patients with "neglected" papillary, follicular and medullary thyroid cancer was made for the period from 1975 to 2010.The majority of the patients was older than 60 years, 40 of them had hematogenic dissemination. In 10 (6.2%) cases palliative operations were completed with a permanent tracheostomy through the perforation in the lower flap of that wound that decreased postoperative purulence up to 12.5%. Five years later 48 (40.3%) patients were alive from 119 patients with papillary and follicular thyroid cancer and only 10 (26.3%) with medullary cancer. Longer than 10 years 36 (28.9%) patients with papillary and follicular thyroid cancer survived that supports the validity of palliative interventions. PMID- 23038921 TI - [Choledocholithiasis in nonstandard situations: possibilities of combined methods of minimally invasive intervention]. AB - The possibilities of minimally invasive combined interventions were shown in treatment of 49 patients with choledocholithiasis in nonstandard situations. The worked out and used minimally invasive combined operations allow ablation of concrements from bile ducts in patients who had undergone such operations as Billroth-II gastric resection and extirpation of the stomach and when cannulation of the major duodenal papilla is not possible. The authors have extended the possible application of minimally invasive methods of lithoextraction in patients with choledocholithiasis in nonstandard situations. PMID- 23038922 TI - [Long-term results of antiandrogenous therapy of prostate cancer]. AB - The results of observation of 135 patents with prostate cancer who underwent bilateral subcapsular orchiectomy at the period from 1998 to 2010 allowed generalization of 5- and 10- year survival of the patients which was (67.84 +/- 4.05)% and (48.4 +/- 5.4)% corrected as (80.54 +/- 3.5)% and (69.28 +/- 6.22)% respectively. Criteria of prognosis of outcomes of antiandrogenous therapy were worked out by the results of multifactor analysis. The overall 5- and 10- year survival in the group of patients of low risk of lethal outcome was 90.21 and 72.81%, intermediate risk--71.80% and 52.11% and in the group of high risk 35.29 and 12.83% corrected as 98.08 and 98.08%; 94.20 and 81.32%; 38.02 and 20.01% respectively. The most significant factors influencing the duration of the patients' life were the stage of the disease, degree of cellular differentiation, age of the patient. PMID- 23038923 TI - [Asymptomatic course of spontaneous internal carotid artery dissection of atherosclerosis genesis]. PMID- 23038924 TI - [Malignant tumor of the parathyroid gland located in the posterior mediastinum]. PMID- 23038925 TI - [Algorithm of clinical assessment of the hemostasiogram indices in surgical practice]. AB - On the basis of literature data and personal clinical experience the author gives clinical interpretation of hemostasiogram tests used in clinical practice and an algorithm of the clinical analysis of the hemostasiogram allowing detection of concrete disorders in the hemostasis mechanisms and decision on the pathogenetically substantiated program of therapy for bleedings in surgical practice. PMID- 23038926 TI - [Ischemia-reperfusion--a universal mechanism of pathogenesis of critical states in emergency surgery]. AB - On the basis of literature data and personal investigations the authors discuss the questions of pathogenesis of critical states in sepsis and polytrauma taken as an example. PMID- 23038927 TI - [Preoccupation with technical aspects--as a necessary and important component of the present-day surgery]. PMID- 23038928 TI - [Antonin Nikolaevich Filatov--an outstanding national surgeon and transfusiologist (commemorating the 110th anniversary of his birthday)]. PMID- 23038929 TI - [Meconium peritonitis: current interpretation, diagnostics, strategy of treatment]. PMID- 23038931 TI - [Contribution of the Leningrad surgeons in the development of national surgery for 50 years of the Soviet State (Vestnik Khir.-1967.-No 11.-P. 6-12)]. PMID- 23038930 TI - [History of the development of pollicization in Russia]. PMID- 23038932 TI - Population based health and care: what does the new dental professional need to know? PMID- 23038933 TI - The use of dental therapists as examiners in dental epidemiological surveys. AB - Practitioners in Dental Public Health often need to find more cost-efficient ways of providing services, whilst assisting with the personal and professional development of colleagues. This paper gives an example of how these competencies were deployed in relation to an epidemiology programme. PMID- 23038934 TI - A service evaluation of patient pathways and care experiences of dentally anxious adult patients. AB - OBJECTIVE: To investigate the current patient pathways used by dentally anxious adults in Sheffield and identify how the patient experience could be improved. DESIGN: Questionnaires gathered stakeholder perceptions of referral pathways and services for dentally anxious adult patients. Completed questionnaires were returned by 113 dentally anxious patients who had engaged with specialised dental services and 111 general dental practitioners (GDPs) (28% and 52% response rates). RESULTS: The recommendations for improving dental care experience of the anxious were: increased guidance and information to GDPs regarding available care pathways; improved availability of psychological services; and more opportunities and choice for patients in the long-term management of dental anxiety. CONCLUSIONS: The findings from the service evaluation suggest ways in which dental services could be developed to improve the care experiences of dentally anxious adult patients. PMID- 23038935 TI - Assessment and validation of the oral impact on daily performance (OIDP) instrument among adults in Karnataka, South India. AB - OBJECTIVES: The objective of the study was to test the applicability of abbreviated version of the oral impact on daily performance (OIDP) inventory among the adults visiting dental outreach centre in Karnataka, South India. BASIC RESEARCH DESIGN: Cross sectional study. CLINICAL SETTING: Dental outreach centre in Udupi District, Karnataka. PARTICIPANTS: 312 adults aged 35-44 years attending the centre. INTERVENTIONS: Face-to-face interview followed by oral health examination. The questionnaire in Kannada version of OIDP, perceived general and oral health and satisfaction with dental appearance were used. MAIN OUTCOME MEASURES: Reliability and Validity of OIDP instrument, Prevalence of oral impacts in study population. RESULTS: Majority of the participants (71.2%) reported oral health problems affecting at least one daily performance in the 6 months preceding the survey. The performance most affected was 'eating' (52.2%) followed by 'cleaning teeth' (32.4%). Cronbach's alpha for the OIDP frequency items was 0.70. Construct validity was proved by significant association of OIDP scores and self-rated oral, general health status and perceived satisfaction with appearance of teeth; with those more satisfied having fewer oral impacts (p < 0.001). Criterion validity was demonstrated in that the OIDP scores increased significantly as the number of decayed and missing teeth increased (p < 0.001). CONCLUSION: The Kannada version of OIDP had excellent psychometric properties for applicability among the adults in Karnataka. Thus, the study highlighted the limits of focusing exclusively on normative needs and suggested the incorporation of oral quality of life measures into the oral healthcare services. PMID- 23038936 TI - The dental health of 5 year-old children living in Damascus, Syria. AB - OBJECTIVE: The aim was to record the dental health of 5 year old Syrian children attending nursery schools in Damascus City and to compare the dmft data with reported parental behaviors in relation to oral health. METHODS: Dental examination criteria were based on those published by WHO. A questionnaire was distributed to the parents of the child participants, which recorded, social information and oral health practices. Chi square tests and multiple logistic regressions were used to determine risk factors for dental caries. RESULTS: The mean dmft was 3.27 (sd 3.71) and 61% of the sample had caries present. Children with poor oral hygiene (p < 0.0001) and not attending a dental clinic for preventive advice (p = 0.001) were at risk for having caries regardless of all variables included in analysis. CONCLUSION: A high proportion of 5 year-olds suffer from dental caries and population based preventive programs should be implemented. PMID- 23038937 TI - Oral impacts and their association with tooth loss in Sri Lankan adults. AB - OBJECTIVES: To determine the prevalence of oral impacts and the association between tooth loss and oral impacts in Sri Lankan adults. BASIC RESEARCH DESIGN: A cross-sectional study where the data were collected by means of a pre-tested interviewer administered questionnaire and an oral examination. PARTICIPANTS: 916 > or = 40 year olds from the Colombo district. MAIN OUTCOME MEASURES: Oral impacts were assessed using a validated Sinhalese translation of the Oral Health Impact Profile-14. RESULTS: The prevalence of oral impacts was 27%. The most commonly reported impacts were in the domain of physical pain: "pain" and "uncomfortable to eat". Of the 14 oral impacts, tooth loss was associated with only 6 impacts. According to the multiple logistic regression analysis, the prevalence of oral impacts was independently associated with the number of missing teeth, missing anterior teeth and the number of natural occluding premolar pairs. CONCLUSIONS: The number of missing teeth and the position of teeth were associated with the reporting of oral impacts in this sample of adults. As the position of missing teeth was related to oral impacts, it could be concluded that all missing teeth do not have the same adverse effect on the physical and psychosocial well-being of the subjects. PMID- 23038938 TI - Oral health related quality of life among older adults in Central China. AB - AIM: To obtain information about the impact of oral health status on the quality of life in older adults in Central China, and furthermore, to investigate the influence of various demographic and socio-economic factors on oral health related quality of life (OHRQoL). METHODS: This study comprised a stratified random sample of 1,000 older adults in Central China. Questionnaires including demographic factors, education and income level, denture wearing status and Oral Health Impact Profile (OHIP)-14 were used in a face-to-face interview. RESULTS: Of the study population 82% stated that they had some forms of problems related to their quality of life. The mean value of the simple count and single summary item scores for OHIP-14 were 0.47 (sd 0.50) and 6.83 (sd 6.84) respectively for the entire study population. "Uncomfortable to eat" and "taste worse" were the two most common problems reported using the simple count method for OHIP-14, while the "physical pain" being the highest scored domain of the measure. When the effect of all independent variables was analysed in multivariate analysis, education level and denture wearing status were significantly (p < 0.05) associated with the OHRQoL measure. CONCLUSIONS: In this Chinese older adult sample, education level and denture wearing status were related to having oral problems as estimated using the OHIP-14. PMID- 23038940 TI - Caries in five different socio-economic clusters in Orebro county. AB - AIM: This study assessed the prevalence of socio-demographic clusters in a Swedish county and the relationship of socio-demographic clusters and caries. METHODS: All 2-19-year-olds (n = 58,573) who attended a routine check-up in Orebro County in 2005-2007 were involved in this study. Initially, two-stage cluster analyses were used to identify outliers. Secondly, the Ward method which is a hierarchical clustering method was used to conduct the final analysis. Bivariate logistic regression was also used to study the relationship between cluster membership and caries. The smallest study unit used in the initial analysis for geographical area is known as key code area, which is a geographical entity defined by the municipalities themselves. Decayed surface (DS/ds) has been used as a measure of dental caries. RESULTS: The county of Orebro clustered in five different socioeconomic clusters. Each cluster was defined by proportion of people over 75 years, native-born, single parents, and those with low incomes and low level of education. Odds ratio (OR) for having DS/ds > 0 in the last dental check-up during 2005-2007 was 1.5 (cluster 1), 1.3 (cluster 2), 1.4 (cluster 3) and 3.8 (cluster 4) compared with the most socioeconomically favoured cluster (cluster 5). CONCLUSION: Cluster analysis of socioeconomic data is a useful tool to identify neighbourhoods with different socio-economic conditions. PMID- 23038939 TI - High levels of periodontal disease among the older adult population in San Juan, Puerto Rico. AB - The Puerto Rican Elderly Dental Health Study is the first to evaluate the periodontal status of a representative sample in Puerto Rico. OBJECTIVE: To assess the periodontal status among the elderly population in San Juan. BASIC RESEARCH DESIGN: Three dentists were trained and standardised by the US National Health and Nutrition Examination Survey (NHANES) reference examiner. They examined elders aged 70-97 in the San Juan area from participants in a representative cohort of the Puerto Rican elderly. Probing depth (PD), attachment loss (AL), and tooth mobility were assessed among the dentate participants on 4 sites on all teeth excluding third molars. We used the CDC-AAP definitions for moderate periodontitis (> or = 2 teeth with AL > or = 4mm at interproximal sites or > or = 2 teeth with PD > or = 5mm at interproximal sites) and severe periodontitis (> or = 2 teeth with AL > or = 6mm at interproximal sites and > or = 1 teeth with PD > or = 5mm at interproximal sites). RESULTS: The participation rate was 47%, 183 individuals, mean age 77.9 (sd 5.9), and 67% were females. Mean number of teeth was 15.8 (sd 6.8), and tooth mobility was present in 18% of participants. Mean PD was 1.5 (sd 0.6) and mean AL was 2.8 mm (sd1.5). The prevalence of moderate and severe periodontitis (CDC-AAP) was 44.5% compared to 20.7% in the NHANES 1999-2004 survey among 75 years and older. CONCLUSIONS: Our study showed high levels of severe and moderate periodontal disease among Puerto Rican older adults. Further research is needed to understand the reasons for the high prevalence. PMID- 23038941 TI - Root caries in 35-44 and 65-74 year-olds in Turkey. AB - OBJECTIVE: To assess the prevalence and related factors of root caries in Turkish 35-44 and 65-74 year-olds. BASIC RESEARCH DESIGN: In this cross-sectional study, using a proportional stratified cluster sampling, 1,631 subjects aged 35-44 years and 1,545 aged 65-74 years were examined. Data were collected via a structured, pre-tested face-to-face administered questionnaire and oral examination following WHO 1997 guidance. Statistical significance was evaluated with chi2 test and binary logistic regression analyses to determine the significance of explanatory variables. RESULTS: The prevalence of root caries was 20.1% in dentate 35-44 year olds, 28.4% in 65-74 year-olds. Mean decayed root increased significantly with the increasing number of retained natural teeth (p = 0.010 for 35-44 and p < 0.001 for 65-74 year-olds). First molars were the most affected by root caries in both age groups. For adults, being male (OR = 1.37), rural residence (OR =1.50), being unschooled (OR = 3.07), no tooth brushing (OR = 1.83) and never visiting dentist (OR = 2.03) were the predictors of the presence of root caries. For elderly, rural residence (OR = 1.54), no tooth brushing (OR = 1.89), and never visiting dentist (OR = 2.38) were the determinants of root caries. CONCLUSION: There is a need for the increased implementation of oral health measures with increasing age in Turkey. PMID- 23038942 TI - Dental anxiety levels in British servicemen and women. AB - OBJECTIVES: The objectives of the study were to determine: 1, the level of dental anxiety in British Service personnel; 2 whether there was a difference in dental anxiety levels across the three Services; and, 3, the relationship between number of operational tours and level of dental anxiety. BASIC RESEARCH DESIGN: Cross sectional questionnaire survey of individuals attending 3 Armed Services dental treatment centres in the UK. The questionnaires were completed between February 2008 and April 2009. PARTICIPANTS: 50 patients each from the Royal Navy, Army and Royal Air Force, selected consecutively from those attending the centres for treatment. There was a 100% response rate. MAIN MEASURES: Dental fear as assessed by the Dental Fear Survey (DFS) and scores on a scale of fear of dental injections. RESULTS: 27% of the Armed Services experienced severe dental anxiety: a level similar to that found in the general population. There was no difference in the level of dental anxiety or fear of dental injections across the three Armed Services. There was no relationship between number of operational tours undertaken and level of dental anxiety. CONCLUSIONS: Dental anxiety is found amongst members of the British Armed Services at levels similar to that in the general population. This represents a challenge for service provision, particularly in operational settings. PMID- 23038943 TI - Sexual correlates of gagging and dental anxiety. AB - OBJECTIVE: Both oro-related behavioural and sexual dysfunctions are non-life threatening conditions which can have an impact on individual well-being. Possible common features include intra-body penetration, giving control to another person, and experiencing encounters that can sometimes be subjectively experienced as aggressive and/or abusive. The present study examined possible sexual correlates of dental anxiety and gagging. BASIC RESEARCH DESIGN: A total of 448 individuals, who applied for sex therapy at the Sexual Medicine Center, Sheba Medical Center, Tel-Hashomer, Israel, completed the following sexual and dental functioning questionnaires: International Index of Erectile Function (men only), Female Sexual Function Index and difficulties with sexual penetration (women only), dental anxiety, gagging reflex and dentist preference (entire population). RESULTS: Higher gagging reflex was associated with problems in sexual penetration and history of sexual abuse in women (especially one that included vaginal penetration). It was also associated with dental anxiety and higher preference for dentist of the same gender for both genders. CONCLUSIONS: The study shows that gagging reflex can bear sexual connotations, especially in women. PMID- 23038944 TI - Oral hygiene education in adolescence based on the Precaution Adoption Process Model. AB - OBJECTIVE: The present study hypothesised that interventions based on the Precaution Adoption Process Model (PAPM) are more effective than the conventional approach in modifying oral hygiene behaviour in adolescents. METHOD: A stratified random sampling method was used with subject groups (classrooms) randomly allocated to a control or to one of intervention groups (conventional instruction or PAPM). Short-term and long-term results were assessed after 3 and 12 months. The study sample comprised 254 12-13 year olds whose plaque levels were assessed by two outcome measures, namely the Quantitative Plaque Percent Index and its derivative the Ratio of Plaque % Change. RESULTS: Subject retention rate was 69%. The most substantial decrease in plaque scores was in the PAPM group (12% after 3 months, 18% after 12 months), while the smallest reduction was in the control group (4% after 3 months and 12% after 12 months). There was a trend of reduction in plaque levels (p < 0.001) in all study groups from baseline to the 12 month follow-up. CONCLUSIONS: The intervention based on the Precaution Adoption Process Model was only slightly more effective in changing adolescent oral hygiene behaviour as compared to the conventional approach. The positive change in the control group was unexpected and needs further exploration. PMID- 23038945 TI - Professional careers of graduates from one UK dental school. AB - AIM: The aim of this study was to consider reported working patterns of dentists and retention of the dental workforce. METHOD: Three cohorts of dental graduates from the University of Birmingham (n = 505) were tracked using the General Dental Council (GDC) register to assess retention of the workforce. A questionnaire was sent to these graduates to explore changes in working patterns over time and to investigate the factors which had influenced their choice of job location. RESULTS: A high proportion (90.9%) of the dental graduates included in this tracking exercise were found on the GDC register on the census date. A slightly higher proportion of female graduates (10.3%) than male graduates (8.0%) could not be traced on the current register (p = 0.37). A change in working patterns over time was demonstrated, with more general dental practitioners reporting a shorter working week. 'Availability of jobs' was the factor reported by most respondents to be important in determining job location. CONCLUSION: This study provides evidence of changing work patterns over time. Furthermore, although the majority of the study sample remained on the GDC register, there appeared to have been a gradual loss of subjects from the dental workforce over time. Changes such as these may affect the provision of services and the impact of investment in training. Further research in this area is warranted. PMID- 23038946 TI - Just say "Om". PMID- 23038947 TI - The gain game. PMID- 23038948 TI - Role reversal. PMID- 23038949 TI - 2012. People to know. PMID- 23038950 TI - Great expectations. PMID- 23038951 TI - An unwelcome alliance. PMID- 23038952 TI - Sweet somethings. PMID- 23038953 TI - [Peculiarities of delivery of specific surgical assistance to wounded during counter-terrorist and peacemaking operations on North Caucasia]. AB - The organization of surgical care for the wounded in various local wars and armed conflict has its own characteristics, the study of which is necessary to optimize the planning of medical evacuation support of troops. It is based on the concept on an early specialized surgical care. The paper discusses the problematic issues of medical care to the wounded in past peacekeeping operations, and analyze features of specialized surgical care. PMID- 23038954 TI - [Hypertensive crisis: problems of diagnostics and paradigm of the treatment]. AB - Analysis of causes of increase of the uncomplicated hypertensive crisis (HC) from 46 to 61% indicates that in the half of cases the cause was only high ABP with minimal clinical symptomatology. To refer all cases of the catadrome of hypertensive disease to hypertensive crisis is inappropriately. It is recommended to use with such concepts as "complicated" and "uncomplicated" HC also term "catadrome of hypertensive disease (instability of ABP)". It allows to except the hyperdiagnosis of HC and to optimize indication for hospital admission. There are recommendations for medical actions in case of complicated and uncomplicated HC and catadrome of hypertensive disease. PMID- 23038955 TI - [The directions of activity of the medical service on prophylaxis and early revealing of tuberculosis in the Armed Forces of the Russian Federation]. AB - The basic directions of system of antituberculous actions in the Armed Forces of the Russian Federation includes: 1) non-admission of citizens, sick of tuberculosis, on military service; 2) allocation of group of persons with the raised risk of tuberculosis among all military servicemen, dispensary dynamic supervision over them and carrying out of chemoprophylaxis; 3) revealing of tuberculosis among military servicemen at preventive medical inspections (including fluorography), and also in case of reference for medical aid with the symptoms specifying on possibility of tuberculosis; 4) carrying out antiepidemic actions in military unit, in case of revealing patient, sick of tuberculosis, well-timed, qualitatively and in full. The major stage of antituberculous actions is a profound medical examination of young reinforcement (recruits under service call and under the contract) after the arrival in army. Preventive actions in group of persons with the raised risk of tuberculosis also are a priority for the medical service of military unit. Final desinfection, controllable emergency chemoprophylaxis and extraordinary fluorography of contact persons under epidemic indications are crucial important for decrease of morbidity in the army focuses of tuberculosis. PMID- 23038956 TI - [Psychogenetic neurological disorders in draft age personnel]. AB - The tendency of psychogenetic neurological disorders increases with predominance in young persons being students of high schools, students of military, technical and other lyceum was shown. The origin of diseases are psychotraumas (family, work), stress. Also genetic and hereditary factors take place that are indicative for individual rehabilitation organization. The basics of psychosomatic diseases pathogenesis are the disintegration mechanisms in brain structure activity,the disorders of integrative apparatus which provides the relationship between somatic, emotional and vegetative functions. The confirmation of brain work disintegration is achieved by modern computer diagnostic systems. As psychogenic diseases increase the need in methods of computer electroencephalography, evoked potentials, and rheoencephalography application is more actual. PMID- 23038957 TI - [Some epidemiological aspects of respiratory diseases in in-country forces of the ministry of internal affairs of the Russian Federation in 1998-2011]. AB - The authors analyzed the rate of respiratory diseases among the contingent of the in-country forces of the Ministry of Internal Affairs of the Russian Federation for the last 14 years. It was noted that the rate of respiratory diseases in 2009 2011 is higher than in 1998-2007. It is concerned with cold aggression and factors of intermigling of contingent, and also with mistakes of prevention actions. Improvement of life quality during all types of military service, improvement of prevention measures is necessary for the complex prevention of respiratory diseases. PMID- 23038958 TI - [Rate of injuries in military men of the North Fleet]. AB - Statistics of the rate of injuries in military men of the North Fleet during 2002 2010 is analyzed. Over the specified period rate of injuries, poisonings and consequences of influence of other external actions was 30,06% among the conscripts, 30,23% among the contract military men. The authors analyzed reasons and circumstances of injuries, prevention measures, and orgnisation of military physician expertise and indemnity insurance for the military men injured during the service. Ways of improvement of the system of injury prevention on the North Fleet are suggested. PMID- 23038959 TI - [Modern approaches to the planning of the medical material support in conditions of daily activities]. AB - There are requirements producing to the planning in modem social and economic conditions: solidarity, participation, continuity, flexibility, accuracy. The authors made a conclusion that the main target of the planning of the medical material support is creating of conditions for highly effective function of the system of medical material support on the basis of long-time forecast of status and development of inner and outer factors. PMID- 23038960 TI - [Medical service of the Armed Forces of Great Britain (review of foreign internet publications)]. AB - The present review is dedicated to organization and principles of operation of the Medical service of the Armed Forces of Great Britain. At the beginning of the review a brief description of British Armed Forces and their medical service is presented. Then the particular key elements of the medical service such as the medical services of the Armed Forces major components, inpatient care, medical supplies, research, medical care at an operation theater, medical personnel training are considered. The special attention is paid to the Joint Medical Command formed four years ago as a prototype for the future integration and centralization of the whole medical service. The cooperation with the civil health care has played an increasing role in the organization of British military medicine. That is why the review includes the short description of the major structure of the British civil health care system--the National Health Service. PMID- 23038961 TI - [Founder of Petersburg surgical school]. AB - Life and career journey of outstanding national surgeon, talented organizer of healthcare, well-known social activist and founder of the St. Petersburg school of surgery, Honored Scientist of the RSFSR Professor Sergei Petrovich Fyodorov is presented. PMID- 23038962 TI - [About the signumanistics of medical units and departments of North-West of Russia]. AB - Armbands, indicating belonging of the military man to the Armed forces, to separate type, alliance or military unit or department, are an integral part of modern military uniform. Author presents some armbands of military-medical units and departments locating on the North-West of Russia. Different variants of the armbands are suggested. Rules of construction and adoption of the armbands are recommended according to heraldic laws and directive documents. The article allows to learn about famous armbands of military-medical service and is of special interest to further development of heraldic theme of units and departments of medical service of the Armed Forces of the Russian Federation. PMID- 23038963 TI - [Reference book for doctors of medical and prophylaxis profile and labor protection specialits]. PMID- 23038964 TI - [Treatment for recurrent hairy cell leukemia]. AB - AIM: To give data on the frequency of recurrent hairy cell leukemia (HCL) and to characterize the immediate and late results of its treatment in this group of patients. MATERIALS AND METHODS: The data on the frequency of recurrences were analyzed in 165 patients with HCL after remission achieved by the purine analogue cladribin in the period 1995 to 2011. The treatment of recurrent HCL included splenectomy, interferon-a, cladribin, and rituximab. RESULTS: After a course of cladribin therapy, the total frequency of recurrent HCL was 22%. The high (47%) frequency of recurrences was found in young patients (less than 45 years) as compared to that (9%) in older patients. A combination of cladribin and rituximab showed a high efficacy in treating the early recurrence of HCL. CONCLUSION: The differences found in the frequency of recurrences give grounds to incorporate rituximab into the standard therapy regimen for HCL in young patients and in patients with early disease recurrence. PMID- 23038965 TI - [The first results of treatment for adult acute myeloid leukemia according to the AML-01.10 protocol of the Research Group of the Hematology Centers of Russia]. AB - AIM: To give the preliminary results of the AML-01.10 Russian multicenter randomized trial to treat adult acute myeloid leukemia (AML), the basic principle of which is to use high-dose anthracycline antibiotics in induction/consolidation. SUBJECTS AND METHODS: By December 2011, 145 patients with AML had been randomized from 18 hematology centers of 15 cities and towns of the Russian Federation; the median age of all the patients was 44 years. Seventy one patients were analyzed in August 2011 (a 1.5-year follow-up). RESULTS: The efficiency of 2 courses 7+3 using high-dose daunorubicin (60 mg/m2 per administration) and continuous infusion of cytarabine during the second course was high and comparable with that in the use of a high-dose HAM protocol as a second induction course and can achieve a complete remission in 74.6%. The protocol toxicity evaluated from its early mortality (11.3%) and its death in complete remission (16.6%) was permissible, particularly by taking into consideration the multicenter pattern of the trial. At the completion of analysis, 53 (68.8%) out of the 77 patients on whom the data on their vital status were available were alive. In this follow-up period, the frequency of recurrences was 19.2% (10/52). Only 3 (4.2%) patients out of the 71 patients in whom the efficiency of the protocol had been completely evaluated underwent allogeneic bone marrow transplantation. CONCLUSION: The total high dose (720 mg/m2) of anthracycline antibiotics, which is used in the period of induction and consolidation, determines the long periods of myelosuppression and intercourse intervals. Protocol deviations (no course of consolidation therapy, lower-dose idarubicin during consolidation therapy, a course of low-dose cytarabine, between the courses of induction and consolidation chemotherapy, and very long intercourse intervals) were recorded in a total of 20 (28%) patients. PMID- 23038966 TI - [Complex karyotype is a marker of very poor prognosis in over 70-year-old patients with acute myeloid leukemia and extended types of myelodysplastic syndrome and high comorbidity index]. AB - AIM: To identify a category of persons with very low overall survival (OS) rates, whose intensive chemotherapy is unreasonable, amongst the patients with acute myeloid leukemia (AML) with extended forms of myelodysplastic syndrome (MDS) and complex karyotype. MATERIALS AND METHODS: OS rates were retrospectively analyzed in 41 patients with AML and 26 with MDS; their median age was 61 years (range 15 to 77 years). Thirty-four (50.7%) patients received standard induction courses; 19 (28.4%) patients had low-intensity therapy. Restraining therapy was used to treat 14 (20.9%) patients. The length of follow-up was 1.5 to 171 months. RESULTS: Irrespective of the type of disease, the median OS was 6 months. A difference in OS was found when the patients were divided into 4 age groups: those who were under 40 years of age (n = 11 ), 41-60 years (n = 21), 61-69 years (n = 21), and > or = 70 years (n = 14). With age, the median OS decreased from 9.5 to 4 months (p = 0.041). Multivariate analysis revealed that the intensity of induction courses was the cause that affected OS. High comorbidity index and, first of all, cardiovascular diseases were the main reason for discontinuing standard chemotherapy courses in patients aged 70 years or older. CONCLUSION: Standard induction courses of cytostatic therapy are not indicated for patients aged > or = 70 years with AML and extended stages of MDS with complex karyotype and high comorbidity index. PMID- 23038967 TI - [Dynamic beta-endorphin determination in hematologic patients]. AB - AIM: To perform a dynamic study of beta-endorphin, hypoxia-inducible factor 1alpha (HIF-1alpha), and cytokines in hematologic patients. SUBJECTS AND METHODS: Fifty-nine patients with different types of acute leukemia (AL), 30 with anaplastic anemia (AA), 24 with thrombocytopenic purpura, and 20 healthy volunteers were examined during their 40-day stay at 3200 m above sea level. beta Endorphin and HIF-la were measured by a sandwich-type enzyme immunoassay using the Abcam antibodies. Cytokines (interleukin (IL)-2, IL-6, and tumor necrosis factor-alpha) were estimated by enzyme immunoassay applying the Pro Con kits (Saint Petersburg). RESULTS: Serum beta-endorphin concentrations were 1.5-2-fold above the normal values in the majority of patients with AL. The patients with initial leukocytosis at onset of disease were noted to have elevated white blood cell beta-endorphin concentrations up to 85.9 +/- 22.4 pg/ml; moreover, during chemotherapy this index increased about two times (170.74 +/- 33.8 pg/ml). There was a direct correlation between the concentrations of beta-endorphin and HIF 1alpha (r = 0.9) and an inverse correlation between the levels of IL-6 and beta endorphin (r = -0.7). On ascending to 3200 m, under the conditions of hypoxic hypoxia the patients with AA or idiopathic thrombocytopenic purpura showed a considerable increase in serum beta-endorphin concentrations, mainly in the acute period of being at high altitudes. CONCLUSION: Stress factors (tumor, use of cytostatics, pain, anemia, hypoxia, high environment temperature) stimulate the elaboration of beta-endorphin, particularly in the white blood cells of patients with AL during chemotherapy. The highest elevation in the index was seen during acute adaptation to hypoxic hypoxia. PMID- 23038968 TI - [Treatment of acute host-versus-graft reaction in patients after allogeneic hematopoietic cell transplantation with multipotent mesenchymal stromal cells from a bone marrow donor]. AB - AIM: To evaluate the efficiency of administration of multipotent mesenchymal stromal cells obtained from a bone marrow donor for the treatment of an acute host-versus-graft reaction (HVGR) resistant to therapy with glucocorticosteroids (GCS). SUBJECTS AND METHODS: The experience in treating 6 patients with GCS resistant acute HVGR following allogeneic hematopoietic stem cell transplantation is given. The patients were intravenously injected cultured multipotent mesenchymal stromal cells (MMSC) in a dose of 10(6) per kg body weight. RESULTS: Four weeks after MMSC administration, a complete or partial response was obtained in 3 cases; clinical improvement was noted in 2; one patient showed no response. MMSC therapy proved to be effective in 5 of the 6 cases with acute HVGR resistant to GCS therapy. CONCLUSION: MMSC therapy turned out to be effective in case of acute HVGR resistant to GCS therapy. PMID- 23038969 TI - [The specific features of renal lesion in Burkitt's lymphoma]. AB - AIM: To analyze the causes of renal lesion in patients with Burkitt's lymphoma (BL) and to develop optimal treatment policy. MATERIALS AND METHODS: The data of examination and treatment were analyzed in 20 patients with BL (14 men and 6 women aged 15 to 57 years (median age 24 years)) who had been followed up for renal lesion at the Hematology Research Center (HRC) in 2003 to 2011. When admitted to hospital, all the patients were found to have ureteric compression, renal parenchymal tumor infiltration, massive tumor cytolysis syndrome (MTCS). Polychemotherapy (PCT) was performed in accordance with the original intensive BL M-04 protocol. The extent of the process was estimated according to the classification developed by S.B.Murphy: L3 variant B of acute lymphoblastic leukemia in 10 cases; Stage IV in 2; Stage III in 8. Acute renal failure (ARF) was identified in 13 patients. A control group comprised 36 patients with BL without ARF who had been followed up at the HRC in 2003 to 2011 and included into the BL-M-04 protocol. The ratio of patients with bone marrow lesion was 7:13 and 9:36 in the BL + ARF and BL-ARF groups, respectively. RESULTS: Decreased urine specific gravity and proteinuria (0.4 to 1.3 g/l) were the first manifestations of renal lesion and were seen in approximately 50% of all cases both on admission to hospital and in the first stages of PCT (10 and 9, 8 and 7 of the 20 cases, respectively). Microhematuria more commonly developed after initiation of PCT (7 and 3 of the 20 cases, respectively). ARF was diagnosed in 13 patients (24% of the 55 BL patients followed up at HRC in 2003 to 2011). One female patient developed ARF after the start of PCT. Twelve patients developed this condition at the onset of disease; in 4 patients, ARF existing prior to PCT began progressing after drug administration. The etiology of ARF was generally mixed. At the onset of disease, MTCS (n = 6) and specific renal parenchymal infiltration (n=6) were more common causes of ARF. Postrenal anuria was present in 2 cases. ARF after PCT initiation resulted from the toxic effects of methotrexate and MTCS (3 and 4 cases, respectively). ARF regressed in the early periods: in the prophase (n = 4) and during or the first PCT block A (n = 9). The BL patients with ARF, as compared to those without the latter, showed a statistically significant earlier onset of myelotoxic agranulocytosis (MTA): on day 3 of an intercourse interval (95 CI from 0 to 3 days) versus its day 5 (95% CI from 2 to 5 days) and a statistically significant longer duration of MTA--12 days (95% CI from 7 to 16 days) versus 7 days (95% Cl from 3 to 10 days); they were observed to have more severe mucositis. Despite the longer intercourse interval, 10 patients with ARF achieved remission; 4 patients died from therapy-refractory sepsis and 1 patient from thrombocytopenia. In the patients with ARF, mortality rates were significantly higher than in those without ARF (33% versus 10%; p = 0.04). CONCLUSION: Although there is a high risk of worsening renal dysfunction, PCT is a necessary condition for ARF resolution in BL. PMID- 23038970 TI - [Effect of bortezomib on the efficiency of hematopoietic stem cell mobilization in patients with multiple myeloma]. AB - AIM: To study the results of mobilizing and collecting autologous hematopoietic stem cells (HSC) in patients with multiple myeloma (MM) receiving bortezomib as part of induction therapy regimens. MATERIALS AND METHODS: In June 2001 to April 2010, the Department of Bone Marrow Transplantation, Hematology Research Center, Ministry of Health and Social Development of Russia, mobilized autologous HSC in 93 patients with MM, by using cyclophosphan (CF) and granulocyte colony stimulating factor. The analysis covered 73 patients who received VAD and/or bortezomib-containing courses as induction therapy. Group 1 comprised 30 patients whose induction therapy was performed as 3-4 courses of VAD. Group 2 included 19 patients who had 2-4 courses of PAD or 4-8 courses of bortezomib + dexamethasone in addition to 1-3 courses of VAD. Group 3 combined 24 patients who used 6-8 courses of bortezomib + dexamethasone or 3-4 courses of PAD + 4-6 courses of bortezomib + dexamethasone. RESULTS: In Group 1 patients whose induction therapy was performed as 3-4 courses of VAD, baseline peripheral blood CD34+ cell counts were 3,575 +/- 631 in 1 ml, which was statistically significantly higher than those in Group 2 patients who had bortezomib-containing courses in addition to VAD courses. In Group 2 patients, premobilization CD34+ cell counts were 2,164 +/ 516 in 1 ml. The lowest blood CD34+ cell levels (1,586 -/+ 405 in 1 ml) were observed in Group 3 patients in whom bortezomib was used as first-line therapy. In Group 1 patients, the maximum peripheral blood counts of CD34+ cells were 322,287 +/- 73,994 in 1 ml, which was significantly higher than their maximum level in Groups 2 (231,624 +/- 39,708 in 1 ml) and 3 (161,007 +/- 44,266 in 1 ml) patients. The efficiency of mobilization proved to be high; more than 4.0.10(6)/kg of CD34+ cells were collected in all the patients with bortezomib containing induction therapy, which allowed two autologous HSC transplantations to be carried out. CONCLUSION: Adding bortezomib at the stage of induction has no significant impact on the results of HSC mobilization and collection. By taking into account the possibility of achieving a complete or very good partial response in 40-60% of the patients using the bortezomib-containing regimens as first-line therapy, bortezomib should be considered as an essential drug as part of induction therapy. PMID- 23038971 TI - [Primary lymphomas of bones and soft tissues: comparative assessment of treatment results]. AB - AIM: To evaluate the efficiency of intensive polychemotherapy (PCT) in adult patients having diffuse large B-cell lymphoma (DLBL) of bones and soft tissues with and without poor prognostic factors (PPF). SUBJECTS AND METHODS: Out of 58 enrolled patients, 51 were diagnosed as having DLBL. Burkitt's lymphoma (BL) was diagnosed in 6 patients. One patient had marginal zone B-cell lymphoma. Thirty five patients with DLBL (10 patients with PPF and 25 without PPF) and 3 patients with BL were treated with the CHOP/R-CHOP regimen. The NHL-BFM-90 program was used in 3 patients with BL and 16 with DLBL (15 patients with PPF and 1 patient without PPF). RESULTS: After radiotherapy, the patient with marginal zone B-cell lymphoma achieved a 20-month remission; three BL patients receiving CHOP died. All the BL patients receiving NHL-BFM-90 achieved complete remissions of 48 to 72 months. In 9 patients having DLBL without PPF, who received CHOP, five-year overall and event-free survival rates were 100%; in 22 patients with PPF, these were 50 and 45%, respectively. In the patients with and without PPF, who received CHOP/R-CHOP, the survival rates differed statistically significantly (p = 0.01; logrank test). In the group of 15 patients having DLBL with PPF, who were treated with the NHL-BFM-90 protocol, 14 achieved an average remission of 17 months. In the patients having DLBL with PPF who used NHF-BFM-90, therapeutic efficiency was significantly higher (p = 0.05; Fisher's exact test). CONCLUSION: Differential therapy for primary lymphomas of bones and soft tissues indicated that the NHL BFM-90 protocol used in the PPF group was significantly more effective than the CHOP regimens. PMID- 23038972 TI - [Invasive mycoses during hematopoietic stem cell transplantation]. AB - AIM: To define the frequency, etiology, and risk factors of invasive mycoses (IM) in patients with allogeneic (allo) and autologous (auto) hematopoietic stem cell transplantation (HSCT) and to evaluate the impact of IM on overall survival (OS). MATERIALS AND METHODS: Data on 356 patients after allo-HSCT (n = 237) and auto HSCT (n = 119) from 2000 to 2010 were analyzed. The diagnosis of IM was established according to the EORTC/MSG 2008 criteria. RESULTS: The incidence of myocardial infarction (MI) was 19.1%; that was 23.2 and 10.9% in allo-HSCT and auto-HSCT recipients, respectively. The incidence of MI following allo-HSCT was significantly higher than that after auto-HSCT. Aspergillus spp. (82.3%), Candida spp. (11.8%), zygomycetes (Mucor spp., Rhizopus spp.) (4.4%), and Cryptococcus neoformans (1.5%) are involved in the etiology of MI. Its risk factors are acute lymphoblastic leukemia; non-myeloablative conditioning regimen; use of fludarabine and antilymphocyte globulin; peripheral blood stem cells as a source for grafting; long-term lymphopenia, neutropenia; use of granulocyte colony stimulating factor (G-CSF); acute graft-versus-host reaction; grade 3-4 mucositis; infections, such as cytomegalovirus, sepsis. The development of MI in HSCT recipients did not significantly reduce one-year OS after allo-HSCT and auto HSCT--53.6 and 55% and 86.7 and 90.3% (with and without MI, respectively). In patients with invasive aspergillosis, OS (12 weeks after IM being diagnosed) was significantly longer in those with other invasive mycoses (91.3 and 50%, respectively). CONCLUSION: The incidence of MI after allo-HSCT was higher than that after auto-HSCT. MI induced by the fungal genus Aspergillus spp. was most common. Along with known risk factors, there was a poor prognostic factor, such as G-CSF. The development of MI failed to affect one-year OS, which was indicative of the adequate quality of its early diagnosis and therapy. The prognosis was poor in patients with invasive candidiasis, zygomycosis, and cryptococcosis. Investigations need to be continued to specify the reasons for high morbidity rates and the factors provoking discussion by investigators worldwide. PMID- 23038973 TI - [Microcirculatory investigations in hemophilia patients]. AB - AIM: to evaluate microcirculation (MC) and its influencing factors in hemophilia patients. SUBJECTS AND METHODS: In 44 hemophilia patients with recurrent hemarthrosis, laser Doppler flowmetry was used to evaluate resting MC above the index fingers, knee and ankle joints during an occlusion test, with allowance made for muscle and adipose tissue mass. RESULTS: The increased perfusion value above the afflicted joints was found to correspond to the phase of an exacerbation of posthemorrhagic inflammation and to be a risk factor of recurrent hemarrthrosis. Analysis of the occlusion test above the knee joints and index fingers revealed a diminished MC reserve and a tendency to precapillary spasm. MC changes were more pronounced in a shortage of muscle and adipose tissue mass. CONCLUSION: Hemophilia patients must regularly do physical exercises to make skeletal muscles develop well in order to prevent an exacerbation of the joint inflammatory process. PMID- 23038974 TI - [Deposition of 51Cr-labeled donor platelets in health and myelosuppressive thrombocytopenias]. AB - AIM: To study the deposition of donor platelets (DP) in myelosuppressive thrombocytopenia (TP) in patients with acute leukemia (AL) or lymphosarcoma (LSA), by using a radionuclide label (51Cr) for DP. SUBJECTS AND METHODS: Complex clinical, hematological and radionuclide studies were conducted in 63 patients divided into 3 groups: 1) 7 healthy volunteers (a control group); 2) 37 patients with AL; 3) 19 patients with LSA. RESULTS: Changes were found in the deposition of labeled DPs used to prevent and treat hemorrhagic syndrome in myelosuppressive TP in patients with AL or LSA. In AL, this function was established to be virtually completely suppressed whereas in LSA, some functional activity of mononuclear phagocytes was preserved. Different degrees of suppression of this function were probably related to the nature of these diseases and particularly due to varying degrees of leukemic infiltration of depot organs. A mechanism for increased consumption of transfused DP in profound TP, one of the causes of which is the myelosuppression as a result of programmed polychemotherapy, cannot be ruled out. CONCLUSION: By and large, the radionuclide labeling technique for DP may be useful in specifying a number of uncertain mechanisms for derangements of the thrombocytic component of hemostasis in oncohematologic diseases. PMID- 23038975 TI - [Acquired hemorrhagic coagulopathy due to contact with the rodenticide brodifacoum in the Nutcracker bait]. AB - Rodenticide (RD) application is the most effective chemical procedure against rodents. RDs containing indirect-action anticoagulants have received currently wide acceptance. When the recommended standards for handling these agents and precautionary measures in their use are violated, there may be poisoning, the main manifestation of which is hemorrhagic coagulation. The paper provides a literature review on poisoning by RDs having anticoagulant properties. This communication gives a detailed description of a clinical case of poisoning with brodifacoum contained in the ready-to-use Nutcracker bait due to long-term exposure to the rat poison that has a cumulative effect. Careful history data collection and coagulogram analysis make it possible to establish a correct clinical diagnosis and to use appropriate therapy that leads to patient recovery. PMID- 23038976 TI - [The silicone spleen (description of a clinical case)]. AB - The paper describes a rare case of verified foreign body (silicone) migration into the spleen. The specific feature of this clinical case is a rare clinical finding through histological study and the use of inductively coupled plasma-mass spectrometry for the determination of silicone in splenic tissues. PMID- 23038977 TI - [Crystalline histiocytosis]. AB - The paper describes a case of diagnosis of the rare monoclonal secretion associated disease crystalline histiocytosis with kidney and bone marrow involvement. The female patient with multiple myeloma (MM) was found to have intralysosomal crystals in the cells of the bone marrow (histiocytes, plasmocytes), kidneys proper (mesangiocytes, podocytes), and subsequently in those of a kidney graft. Lower secreted monoclonal IgG and ceased Bence-Jones protein secretion after MM chemotherapy were accompanied by improved and stabilized kidney graft function. However, a repeat morphological study of a renal biopsy specimen showed that the crystalline inclusions were preserved in the podocytes. By comparing the immunological and renal responses, it is reasonable to suggest that monoclonal IgG rather than Bence-Jones protein is of value in the pathogenesis of crystal formation. PMID- 23038978 TI - [Differential diagnosis of Wegener's granulomatosis and extranodal NK/T-cell lymphoma, nasal type]. AB - Men aged over 40 years more commonly develop NK/T-cell lymphomas (NK/T-CL). The paper describes a case of NK/T-CL in a 20-year-old man. Despite the fact that the disease (nasal septum perforation, hard palate bone destruction, recurrent nasopharyngeal bleeding, considerable weight loss, and high erythrocyte sedimentation rate,) progressed rapidly for 5 months, the patient was found to be diagnosed as having Wegener' granulomatosis (WG). Repeated incisional biopsies showed massive necrotic changes with no clear histological verification of the diagnosis. The absence of lung and kidney lesions typical of WG, the lack of antineutrophil antibodies, and the detection of Epstein-Barr virus DNA in blood could presume NK/T-CL and confirm it by extended biopsy to have materials sufficient for morphological and immunomorphological studies. This observation shows that the disease may occur at a young age and rapidly progress; only early diagnosis can improve prognosis in patients with this type of lymphomas. PMID- 23038979 TI - [A case of spontaneous chylothorax complicating pregnancy]. AB - The paper gives a clinical case of left-sided chylothorax developing in a young woman in the second half of pregnancy due to thrombosis of the left internal jugular vein, left subclavian vein, and brachiocephalic trunk. Cesarean section was made. Medical treatment thereafter proved to be effective. The possible mechanisms for spontaneous venous thrombosis and chylothorax during pregnancy and the methods of their diagnosis and treatment are discussed. PMID- 23038980 TI - High-performance carbon nanotube transparent conductive films by scalable dip coating. AB - Transparent conductive carbon nanotube (CNT) films were fabricated by dip-coating solutions of pristine CNTs dissolved in chlorosulfonic acid (CSA) and then removing the CSA. The film performance and morphology (including alignment) were controlled by the CNT length, solution concentration, coating speed, and level of doping. Using long CNTs (~10 MUm), uniform films were produced with excellent optoelectrical performance (~100 Omega/sq sheet resistance at ~90% transmittance in the visible), in the range of applied interest for touch screens and flexible electronics. This technique has potential for commercialization because it preserves the length and quality of the CNTs (leading to enhanced film performance) and operates at high CNT concentration and coating speed without using surfactants (decreasing production costs). PMID- 23038981 TI - Kinetics of photoinduced electron transfer between DNA bases and triplet 3,3',4,4'-benzophenone tetracarboxylic acid in aqueous solution of different pH's: proton-coupled electron transfer? AB - The kinetics of triplet state quenching of 3,3',4,4'-benzophenone tetracarboxylic acid (BPTC) by DNA bases adenine, adenosine, thymine, and thymidine has been investigated in aqueous solution using time-resolved laser flash photolysis. The observation of the BPTC ketyl radical anion at lambda(max) = 630 nm indicates that one electron transfer is involved in the quenching reactions. The pH dependence of the quenching rate constants is measured in detail. As a result, the chemical reactivity of the reactants is assigned. The bimolecular rate constants of the quenching reactions between triplet BPTC and adenine, adenosine, thymine, and thymidine are k(q) = 2.3 * 10(9) (4.7 < pH < 9.9), k(q) = 4.0 * 10(9) (3.5 < pH < 4.7), k(q) = 1.0 * 10(9) (4.7 < pH < 9.9), and k(q) = 4.0 * 10(8) M(-1) s(-1) (4.7 < pH < 9.8), respectively. Moreover, it reveals that in strong basic medium (pH = 12.0) a keto-enol tautomerism of thymine inhibits its reaction with triplet BPTC. Such a behavior is not possible for thymidine because of its deoxyribose group. In addition, the pH-dependence of the apparent electrochemical standard potential of thymine in aqueous solution was investigated by cyclic voltammetry. The DeltaE/DeltapH ~ -59 mV/pH result is characteristic of proton-coupled electron transfer. This behavior, together with the kinetic analysis, leads to the conclusion that the quenching reactions between triplet BPTC and thymine involve one proton-coupled electron transfer. PMID- 23038983 TI - Analysis of congenital disorder of glycosylation-Id in a yeast model system shows diverse site-specific under-glycosylation of glycoproteins. AB - Asparagine-linked glycosylation is a common post-translational modification of proteins in eukaryotes. Mutations in the human ALG3 gene cause changed levels and altered glycan structures on mature glycoproteins and are the cause of a severe congenital disorder of glycosylation (CDG-Id). Diverse glycoproteins are also under-glycosylated in Saccharomyces cerevisae alg3 mutants. Here we analyzed site specific glycosylation occupancy in this yeast model system using peptide-N glycosidase F to label glycosylation sites with an asparagine-aspartate conversion that creates a new endoproteinase AspN cleavage site, followed by proteolytic digestion, and detection of peptides and glycopeptides by LC-ESI MS/MS. We used this analytical method to identify and measure site-specific glycosylation occupancy in alg3 mutant and wild type yeast strains. We found decreased site-specific N-glycosylation occupancy in the alg3 knockout strain preferentially at Asn-Xaa-Ser sequences located in secondary structural elements, features previously associated with poor glycosylation efficiency. Furthermore, we identified 26 previously experimentally unverified glycosylation sites. Our results provide insights into the underlying mechanisms of disease in CDG-Id, and our methodology will be useful in site-specific glycosylation analysis in many model systems and clinical applications. PMID- 23038982 TI - Aqueous extract of dried fruit of Berberis vulgaris L. in acne vulgaris, a clinical trial. AB - Berberis vulgaris L. (barberry) is a very well-known herb in traditional medicine. Apart from its anti-inflammatory and antibacterial properties, the antilipogenic effect of barberry on the sebaceous glands in animals may further suggest it could be employed as an anti-acne agent. This study examined the effect of oral aqueous extract of barberry on acne vulgaris. Adolescents aged 12 17 years with moderate to severe acne vulgaris were randomly given oral gelatin capsules containing either aqueous extract of dried barberry (600 mg daily for 4 weeks, n = 25) or placebo (n = 24). Counts of facial noninflamed, inflamed, and total acne lesions, as well as the Michaelson's acne severity score were documented at baseline and at weeks 2 and 4. Both groups were comparable in terms of the patients' characteristics and baseline variables. After 4 weeks, the mean number of noninflamed, inflamed, and total lesions as well as mean Michaelson's acne severity score declined significantly by 43.25 +/- 10.88% (median: 42.11%), 44.53 +/- 11.78% (median: 45.45%), 44.64 +/- 8.46% (median: 46.15%), and 44.38 +/ 8.25% (median: 44.07%), respectively, among the extract receivers (p <.001 for all the changes). Similar changes were not significant in the placebo group. No notable complication or side effect was reported in relation to barberry. In conclusion, oral aqueous extract of dried barberry is a safe, well-tolerated, and effective choice in teenagers with moderate to severe acne vulgaris. PMID- 23038984 TI - Semiconductor nanorod self-assembly at the liquid/air interface studied by in situ GISAXS and ex situ TEM. AB - We study the self-assembly of colloidal CdSe/CdS nanorods (NRs) at the liquid/air interface combining time-resolved in situ grazing-incidence small angle X-ray scattering (GISAXS) and ex situ transmission electron microscopy (TEM). Our study shows that NR superstructure formation occurs at the liquid/air interface. Short NRs self-assemble into micrometers long tracks of NRs lying side by side flat on the surface. In contrast, longer NRs align vertically into ordered superstructures. Systematic variation of the NR length and initial concentration of the NR dispersion allowed us to tune the orientation of the NRs in the final superstructure. With GISAXS, we were able to follow the dynamics of the self assembly. We propose a model of hierarchical self-organization that provides a basis for the understanding of the length-dependent self-organization of NRs at the liquid/air interface. This opens the way to new materials based on NR membranes and anisotropic thin films. PMID- 23038985 TI - The regulation of apoptosis in intrauterine growth restriction: a study of Bcl-2 and Bax gene expression in human placenta. AB - OBJECTIVE: In this study, we assessed Bcl-2 and Bax gene expression patterns in human placental samples from intrauterine growth restriction (IUGR) pregnancies using normal pregnancy as control. METHODS: We compared Bcl-2 and Bax gene expression in placental samples from all IUGR pregnancies treated in our clinic between 1 January 2010-1 January 2011 vs. 140 normal pregnancy samples from the same study period. We also assessed clinical parameters such as maternal age, gestational weight gain, gestational body mass index (BMI) change, and maternal birth weight. RESULTS: In IUGR, the Bcl-2 gene was underexpressed compared to normal pregnancy. There was no difference in the Bax gene activity in the two groups. The degree of growth restriction within the IUGR group did not correlate with Bcl-2 or Bax gene activity. CONCLUSIONS: Our study revealed that it is the reduced inhibitory activity of the Bcl-2 gene rather than an enhanced stimulatory activity of the Bax gene in the background of the increased apoptosis observed in IUGR. IUGR appears to be more common with maternal age around 20 years and above 35 years. Gestational weight gain and gestational BMI change also predict the risk for IUGR. PMID- 23038986 TI - Implications of ketogenic diet on weight gain, motor activity and cicatrization in Wistar rats. AB - The ketogenic diet (KD) was initially developed for the treatment of pharmacoresistant epilepsy and a possible alternative for the obesity treatment, dyslipidemia, resistance to insulin, and nonalcoholic steatosis. However, few studies evaluate the diet effects in rats behavior or cicatrization. The objective of this work was to analyze the influence of the ketogenic diet on the weight gain, emotional behavior of the rats submitted to experimental models such as elevated plus maze (EPM) and open field (OF). The cicatrization time and leukocyte differentiations were also observed. Twenty male Wistar rats of two months age were divided into two groups. One was submitted to ketogenic diet (KD), and the control group (Co) was fed on commercial rations. After 7 days, the animals were weighed and submitted to EPM and OF. A small surgical incision was made and their blood was collected to a leukocyte count. It was verified that the rats from the KD presented less weight gain as compared with the rats from the Co (p < 0.05). The KD did not reveal differences on the behavior measures in the EPM model, but in the OF presented an ambulatory activity significantly bigger. The animals from the KD presented a cicatrization significantly better than Co after 72 h (p = 0.0035) and 96 h (p < 0.1). There was no difference between the groups for leukocyte count. Our results suggest that the KD can interfere on rats deambulation in animal models and improve the cicatrization response. PMID- 23038987 TI - Determination of glucosamine in fungal cell walls by high-performance liquid chromatography (HPLC). AB - Glucosamine (GlcN) is a major and valuable component in the cell wall of zygomycetes fungi. In this study, a time independent and accurate method was developed for the determination of GlcN. In this method, the cell wall was treated via a two-stage sulfuric acid process, and chitin and chitosan were fully deacetylated, partially depolymerized, and converted to GlcN oligosaccharides. Then, the oligosaccharides were deaminated to 2,5-anhydromannose using nitrous acid. Finally, 2,5-anhydromannose was analyzed by high performance liquid chromatography (HPLC). The determinations of pure GlcN solutions were stable at least for 10 days, while those of the conventional colorimetric method were not stable for more than one hour. The alkali insoluble material (AIM) of biomass of purely yeast-like, mostly yeast-like, and filamentous forms of the fungus Mucor indicus was analyzed by the developed method. The respective GlcN content of AIM of the fungus was 0.232, 0.204, and 0.458 (g/g). PMID- 23038988 TI - The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA. AB - Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis. PMID- 23038989 TI - Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women. AB - OBJECTIVES: Bazedoxifene/conjugated estrogens (BZA/CE) has demonstrated efficacy in improving vasomotor and vulvar/vaginal atrophy symptoms in postmenopausal women. This study evaluated the endometrial safety of BZA/CE and effects on bone mineral density (BMD) compared with CE/medroxyprogesterone acetate (MPA) and placebo. METHODS: The Selective estrogens, Menopause, And Response to Therapy (SMART)-4 trial was a 1-year, multicenter, double-blind, randomized, placebo- and active-controlled, phase-3 study in non-hysterectomized, postmenopausal women (n = 1061; aged 40 -< 65 years). Subjects received BZA 20 mg/CE 0.45 or 0.625 mg, CE 0.45 mg/MPA 1.5 mg, or placebo daily. Primary endpoints were the incidence of endometrial hyperplasia and the change in lumbar spine BMD at 1 year. Secondary endpoints included the change in total hip BMD and rates of amenorrhea and breast pain. RESULTS: At 1 year, no cases of endometrial hyperplasia were identified in the BZA 20-mg/CE 0.45-mg group, while three cases (1.1%) were confirmed for the BZA 20-mg/CE 0.625-mg group (95% one-sided confidence interval upper limit < 4%). Both BZA/CE doses significantly increased lumbar spine and total hip BMD versus placebo (p <= 0.001) and showed low incidences of bleeding and breast tenderness, similar to placebo and significantly lower than for CE 0.45 mg/MPA 1.5 mg (p < 0.05). BZA/CE treatment was generally safe and well tolerated. CONCLUSIONS: BZA 20 mg/CE 0.45 and 0.625 mg significantly improved BMD while maintaining endometrial safety and showed a favorable safety/tolerability profile over 1 year. BZA/CE may be a promising therapy for treating menopausal symptoms and preventing osteoporosis in non-hysterectomized, postmenopausal women. PMID- 23038990 TI - Insights into the photochemical transformation of iodine in aqueous systems: humic acid photosensitized reduction of iodate. AB - Marine aerosol is highly enriched in iodine, mostly in the form of iodate (IO(3)( )) ions, compared to its relative abundance in seawater. This paper describes a laboratory study of the photochemical reduction of IO(3)(-) in the presence of humic acid. Spectroscopic analysis showed that ~20% of IO(3)(-) was converted to "free" iodide (I(-)) ions and this fraction remained constant as a function of time. Direct detection of an organically fixed fraction (i.e., ~ 80%) was not possible, but a number of test reactions with surrogate organic compounds containing functional groups identified in humic acid structures indicate that efficient substitution of iodine occurs at aromatic 1,2 diol sites. These iodinated humic acids are stable with respect to photolysis at near-UV/visible wavelengths and are likely to account for a significant proportion of the soluble iodine-containing organic material occurring within aerosols. In the lower atmosphere, oxidation of I(-) to I(2) in marine aerosol occurs mostly through the uptake of O(3), with H(2)O(2) playing a very minor role. A model of iodine chemistry in the open ocean tropical boundary layer, which incorporates these experimental results, is able to account for the observed enrichment of iodine in marine aerosol. PMID- 23038991 TI - Early cardiac evaluation in children with non-specific mitochondrial disease with isolated mitochondrial respiratory chain complex I defect. AB - AIMS: We evaluated echocardiography and electrocardiography (ECG) results in children with non-specific mitochondrial disease (MD) in order to study early cardiac involvement, a well-known complication of the disease. METHODS: Among non specific MD children whose isolated mitochondrial respiratory chain complex I defect was confirmed by muscle biopsy and satisfied the criteria of MD, 27 who had no cardiac symptoms were evaluated by echocardiography and ECG. RESULTS: Three (11.1%) out of the 27 non-specific MD patients had left ventricular ejection fraction of less than 55% and two of them (7.4%) had fractional shortening of less than 26%. ECG abnormalities were observed in 16 of the non specific MD patients (59.3%). Prolongation of heart rate-corrected QT interval was seen in 11 (40.7%) and widening of the QRS interval in eight (29.6%). Left ventricular ejection fraction and fractional shortening of the patients were significantly decreased compared with those in the control group while heart rate corrected QT interval was prolonged in the former group. QRS interval was more widened in non-specific MD patients, but without statistical significance. CONCLUSION: The potentially severe cardiac involvement observed in our subjects suggests that early cardiac evaluation after confirming the diagnosis of MD and regular follow-up tests should be strongly recommended in children even in cases without typical cardiac manifestations. PMID- 23038992 TI - Barcoding of aphids (Hemiptera, Aphididae and Adelgidae): proper usage of the global data set. AB - Basics of DNA barcoding suppose the creation and operation of an extensive library based on reliably (including possibility for validation) identified specimens. Therefore, information concerning morphological identification of the individual samples used for DNA barcoding, for example, identification keys and descriptions used, must be clearly explained. In addition, the maximum available data set of sequences must be used. Access to currently private data appears to be of special interest, especially when such possibility is provided by the database regulations, because it encourages the cooperation of research and saves both time and resources. The cryptic aphid species complexes Aphis oenotherae holoenotherae and A. pomi-spiraecola are used to illustrate the above statements. PMID- 23038993 TI - Letter to the editor: successful use of electroconvulsive therapy for refractory anxiety in Parkinson's disease. AB - Electroconvulsive therapy (ECT) in Parkinson's disease has been the subject of occassional publications. Generally it has been successfully used in treating severe depression, and rare case reports describe its benefit in psychosis unresponsive to standard antipsychotic drugs. This report describes two patient with idiopathic PD and severe anxiety who responded well to ECT. ECT should be considered for PD patients with severe behavioral problems not responsive to medications. PMID- 23038994 TI - Comparison of endometrial regenerative cells and bone marrow stromal cells. AB - BACKGROUND: Endometrial regenerative cells (ERC) and bone marrow stromal cells (BMSC) are being used in clinical trials. While they have been reported to have similar characteristics, they have not been directly compared. METHODS: We compared micro RNA (miRNA) and gene expression profiles, soluble cytokine and growth factor levels and ability to inhibit ongoing mixed leukocyte reaction (MLR) of ERC and BMSC each derived from 6 healthy subjects. RESULTS: ERC and BMSC miRNA and gene expression profiles were similar, but not identical; more differences were noted in the expression of genes than in miRNAs. Genes overexpressed in ERCs were more likely to be in immune and inflammation pathways and those overexpressed in BMSCs were more likely to be in stem cell and cancer signaling pathways. In addition, the levels of IL-8 and ICAM-1 were greater in ERC supernatants while the levels of HGF, VEGF, IL-6, CXCL12, TGFB1 and TGFB2 were greater in BMSC supernatants. Additionally, ERC demonstrated greater inhibition of the proliferation of mixed leukocyte cultures. CONCLUSIONS: These results suggest that the in vivo effects of ERC and BMSC may differ. Multiple properties of stromal cells are responsible for their in vivo effectiveness and ERC may be more effective for some of the clinical applications and BMSC for others. Studies in animal models or clinical trials will be required to more fully characterize the differences between ERC and BMSC. PMID- 23038996 TI - Acquired progressive kinking of the hair in a Korean female adolescent. PMID- 23038995 TI - Antioxidant and anti-inflammatory activities of selected Chinese medicinal plants and their relation with antioxidant content. AB - BACKGROUND: The main aim of this study is to evaluate the antioxidant and anti inflammatory properties of forty four traditional Chinese medicinal herbal extracts and to examine these activities in relation to their antioxidant content. METHODS: The antioxidant activities were investigated using DPPH radical scavenging method and yeast model. The anti-inflammatory properties of the herbal extracts were evaluated by measuring their ability to inhibit the production of nitric oxide and TNF-alpha in RAW 264.7 macrophages activated by LPS and IFN- gamma, respectively. The cytotoxic effects of the herbal extracts were determined by Alomar Blue assay by measuring cell viability. In order to understand the variation of antioxidant activities of herbal extracts with their antioxidant contents, the total phenolics, total flavonoids and trace metal (Mg, Mn, Cu, Zn, Se and Mo) quantities were estimated and a correlation analysis was carried out. RESULTS: Results of this study show that significant levels of phenolics, flavonoids and trace metal contents were found in Ligustrum lucidum, Paeonia suffuticosa, Salvia miltiorrhiza, Sanguisorba officinalis, Spatholobus suberectus, Tussilago farfara and Uncaria rhyncophylla, which correlated well with their antioxidant and anti-inflammatory activities. Some of the plants displayed high antioxidant and anti-inflammatory activities but contained low levels of phenolics and flavonoids. Interestingly, these plants contained significant levels of trace metals (such as Zn, Mg and Se) which are likely to be responsible for their activities. CONCLUSIONS: The results indicate that the phenolics, flavonoids and trace metals play an important role in the antioxidant activities of medicinal plants. Many of the plants studied here have been identified as potential sources of new antioxidant compounds. PMID- 23038997 TI - Bone tissue response to BMP-2 adsorbed on amorphous microporous silica implants. AB - AIM: To evaluate bone regeneration potential of bone morphogenetic protein-2 (BMP 2) adsorbed on amorphous microporous silica (AMS). MATERIALS & METHODS: Four implants [titanium as control (CTR); AMS-coated titanium (AMS), BMP-2 adsorbed on titanium (CTR+BMP) and AMS (AMS+BMP)] were implanted randomly in the tibiae of 20 New Zealand white rabbits. Bone specimens with implants were retrieved 2/4 weeks post implantation and analysed histologically and histomorphometrically. Bone fraction was measured in initial bone-free area (bone regeneration area, BRA) and in the area with initial bone-implant contact [bone adaptation area (BAA)] (BF(BRA) & BF(BAA) ). Bone-implant contact was measured in BRA (BIC(BRA) ). In vitro BMP-2 release profiles were determined to evaluate the impact of the carrier surface. Mixed models were used for statistical analysis. RESULTS: BMP-2 release profiles were different for CTR+BMP and AMS+BMP. BIC(BRA) and BF(BRA) were significantly increased after 4 weeks compared to 2 weeks for AMS, CTR+BMP and AMS+BMP. However, no differences between the implant types were observed within both healing periods. BF(BAA) for CTR+BMP was smaller than that for CTR and AMS+BMP after 4 weeks. Despite slower BMP-2 release, AMS+BMP did not stimulate bone regeneration. CTR+BMP caused bone resorption at the bone-implant interface. CONCLUSIONS: BMP-2 functionalized implant surfaces failed to stimulate bone regeneration and osseointegration. PMID- 23038998 TI - Use of Haemate((r)) P as immune tolerance induction in patients with severe haemophilia A who failed previous induction attempts: a multicentre observational study. AB - Immune tolerance induction (ITI) can eliminate factor VIII (FVIII) inhibitory antibodies that appear during FVIII replacement therapy. If first-line ITI fails, switching to a different FVIII concentrate, especially one containing von Willebrand factor (VWF), has been advocated. The objective of the study was to assess the efficacy and safety of Haemate((r)) P, a plasma-derived FVIII concentrate containing high levels of VWF, as ITI in severe haemophilia A patients who had failed at least one prior ITI attempt with a different FVIII concentrate. In this multicentre, observational study, Haemate((r)) P was administered at a starting dose of 83-308 IU kg(-1) day(-1) (1500-6000 IU day( 1)). Efficacy was assessed by standard criteria (e.g. Bethesda titre, FVIII recovery and half-life), and bleeding characteristics. Nine patients from six haemophilia centres were treated with Haemate((r)) P after failing one (n = 2), two (n = 5) or three (n = 2) prior ITI courses. The median time from inhibitor detection to Haemate((r)) P treatment was 5.4 years. The median Haemate((r)) P dose was 134 IU kg(-1), and the median treatment duration 32 months. During median of 47 months of follow-up, complete response, partial response and treatment failure were observed in one, three and five patients respectively. Five patients experienced seven adverse events (AEs), including two serious AEs (sepsis). Haemate((r)) P was discontinued due to an AE in one patient with a partial response. Haemate((r)) P salvage ITI resulted in complete or partial tolerization in four of nine patients (44%) who had failed previous ITI attempts using different FVIII concentrates. PMID- 23039000 TI - Coagulation factor X Arg386 specifically affects activation by the intrinsic pathway: a novel patient mutation. PMID- 23039001 TI - Preparation for pyeloplasty for ureteropelvic junction obstruction using a patient-specific laparoscopic simulator: a case report. AB - INTRODUCTION: Training systems for laparoscopic surgery are useful for basic training but are not suitable for specific training corresponding to the condition of a given patient. We, therefore, have developed an unusual training system: a patient-specific simulator for laparoscopic surgery. When specific data of each individual patient are entered, this system helps surgeons perform a "rehearsal" operation. We applied this technique in laparoscopic surgery by using volume data obtained by multislice computed tomography imaging. CASE PRESENTATION: A 39-year-old Japanese woman consulted a doctor because of back pain and underwent pyeloplasty after an examination revealed a ureteropelvic junction obstruction. Computed tomography data showed that the network of arteries and veins was very complicated. Therefore, we decided to use our simulator before performing surgery. Simulation was helpful because we could obtain information about the complicated vessel network and "rehearse" the procedure. CONCLUSIONS: Our simulator allows surgeons to perform a sham operation with different perspectives and tactile sensations and has received favorable reviews from users. PMID- 23038999 TI - Impact of empirical treatment in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. bacteremia. A multicentric cohort study. AB - BACKGROUND: The objective of this study is to analyze the factors that are associated with the adequacy of empirical antibiotic therapy and its impact in mortality in a large cohort of patients with extended-spectrum beta-lactamase (ESBL)--producing Escherichia coli and Klebsiella spp. bacteremia. METHODS: Cases of ESBL producing Enterobacteriaceae (ESBL-E) bacteremia collected from 2003 through 2008 in 19 hospitals in Spain. Statistical analysis was performed using multivariate logistic regression. RESULTS: We analyzed 387 cases ESBL-E bloodstream infections. The main sources of bacteremia were urinary tract (55.3%), biliary tract (12.7%), intra-abdominal (8.8%) and unknown origin (9.6%). Among all the 387 episodes, E. coli was isolated from blood cultures in 343 and in 45.71% the ESBL-E was multidrug resistant. Empirical antibiotic treatment was adequate in 48.8% of the cases and the in hospital mortality was 20.9%. In a multivariate analysis adequacy was a risk factor for death [adjusted OR (95% CI): 0.39 (0.31-0.97); P = 0.04], but not in patients without severe sepsis or shock. The class of antibiotic used empirically was not associated with prognosis in adequately treated patients. CONCLUSION: ESBL-E bacteremia has a relatively high mortality that is partly related with a low adequacy of empirical antibiotic treatment. In selected subgroups the relevance of the adequacy of empirical therapy is limited. PMID- 23039003 TI - Eyelid allergic contact dermatitis caused by ethyl cyanoacrylate-containing eyelash adhesive. PMID- 23039002 TI - Allergic contact dermatitis caused by sodium metabisulfite: a challenging allergen: a case series and literature review. AB - BACKGROUND: Sulfites, preservatives and antioxidants used in the cosmetic, pharmaceutical and food industry are contact allergens whose relevance seems to be difficult to establish. OBJECTIVES: To perform a retrospective study on patients patch tested with a sulfite. Materials and methods. Between 1990 and 2010, 2763 patients were patch tested with sodium metabisulfite. The reactions were considered to be relevant if there was a clear relationship between the dermatitis and sulfite exposure. RESULTS: One hundred and twenty-four (4.5%) of 2763 patients patch tested positively to sodium metabisulfite. The most frequent localizations of the lesions were the face (40.3%) and the hands (24.2%). Six patients also reported systemic symptoms. Thirteen cases (10.5%) were occupational, 10 of them presenting with hand eczema. Sodium metabisulfite was the single allergen found in 76 cases (61.3%). The reactions were considered to be relevant in 80 cases (64.5%), of which 11 were occupational. CONCLUSIONS: Allergic contact dermatitis caused by sulfites is frequent and often relevant. One should be aware of possible relevant sources of exposure, particularly in occupational settings such as hairdressing and the food industry, and in pharmaceutical and cosmetic products. Patch testing with sodium metabisulfite, which seems to be the best indicator for sulfite contact allergy, is also useful in cases of immediate reactions to sulfite-containing products. PMID- 23039004 TI - Occupational allergic contact dermatitis caused by eyelash extension glues. PMID- 23039005 TI - Allergic contact dermatitis caused by a cyanoacrylate-containing false eyelash glue. PMID- 23039006 TI - Systemic allergic dermatitis following airborne exposure to 1,2-benzisothiazolin 3-one. PMID- 23039007 TI - Follow-up of the monitored levels of preservative sensitivity in Europe: overview of the years 2001-2008. PMID- 23039008 TI - Systemic allergic dermatitis presumably caused by formaldehyde derived from aspartame. PMID- 23039009 TI - Occupational protein contact dermatitis from wheat flour with IgE reactivity against alpha-amylase inhibitor. PMID- 23039010 TI - Allergic contact dermatitis caused by C30-38 olefin/isopropyl maleate/MA copolymer in cosmetics. PMID- 23039013 TI - Genetic position of Bahrain natives among wider Middle East populations according to Alu insertion polymorphisms. AB - BACKGROUND: The genetic differentiation of Bahrain natives is unclear because of the absence of adequate genetic studies. AIM: Eight Alu insertion polymorphisms have been analysed in Bahrainis and southern Iranians to examine the origins of Bahrainis and to determine their genetic position among wider Middle East populations. SUBJECTS AND METHODS: Two representative samples of 97 Bahrainis and 65 southern Iranians have been determined. Genetic relationships among populations have been estimated by a principal component plot based on the R matrix software. Mantel tests have been used to check the statistical significance of correlation between genetic and geographic distances. RESULTS: The results show that Bahrainis are in an intermediate genetic position between Emirians and Southern Iranians. Although a general significant correlation between genetic and geographic distances was found between the 16 populations included in the analysis, a lack of this correlation may occur in some particular situations such as the case of populations from southern Iran, United Arab Emirates (UAE) and Bahrain, separated by the Persian Gulf. CONCLUSION: The results support the idea that Bahrainis ancestors were mainly emigrants from Arabia and Iran. In addition the results show that the Iranian component may reach 69.2% of the current genetic pool of Bahrainis. PMID- 23039012 TI - IGF2/ApaI polymorphism associated with birth weight in children of the region of Petrolina-PE, Brazil. AB - Insulin-like growth factor 2 (IGF2) gene has an important role in fetal growth. It was investigated association of the IGF2/ApaI polymorphism with low birth weight and normal birth weight (as control) in children attended in Hospital Dom Malan Petrolina, PE-Brazil. The genotype frequencies did not differ statistically between low birth weight (AA = 16.22%, AG = 43.24%, GG = 40.54%) and control (AA = 20% AG = 35%, GG= 45% groups) and the allele frequencies were not significantly different (p > 0.05).The observed genotype frequencies in both groups did not deviate significantly from Hardy-Weinberg equilibrium. Then, no significant correlation was found for this polymorphism in the population studied. PMID- 23039014 TI - The effect of garlic tablet on pro-inflammatory cytokines in postmenopausal osteoporotic women: a randomized controlled clinical trial. AB - INTRODUCTION: Menopause is one of the important causes of osteoporosis which results from estrogen deficiency. In addition, some clinical and experimental evidence indicates that there is an association between increasing pro inflammatory cytokine activity and postmenopausal bone loss. The purpose of this study was to determine the effect of garlic tablet on pro-inflammatory cytokines in postmenopausal osteoporotic women. METHODS: The present study was a double blind randomized controlled clinical trial in Yazd conducted during November 2009 until July 2010. The sample included 44 postmenopausal osteoporotic women who were randomly assigned into two groups: the garlic group (GG) and the placebo group (PG). Participants in GG took two garlic tablets daily for 1 month and the participants in PG took placebo tablets in the same manner. Serum interlukin-1, interlukin-6, and tumor necrosis factor alpha (TNF-alpha) were measured using the ELISA method before and after the intervention. Also, 24-hour dietary recall was recorded for estimation of daily intake of some nutrients. Data were analyzed using SPSS software. RESULTS: There was no statistically significant difference between interlukin-1 and interlukin-6 in the two groups before and after the intervention. The mean of TNF-alpha did not show any statistically significant difference between the two groups before and after the intervention, but it was significantly reduced by about 47% (from 31.14+/-50.53 to 19.33+/-22.19 ng/ml, P value = 0.05) in GG after the intervention, However, no significant difference was seen in PG. CONCLUSIONS: The present study produced some evidence for an immunomodulatory effect of garlic, as well as the modulation of cytokine production. PMID- 23039016 TI - Walking during body-weight-supported treadmill training and acute responses to varying walking speed and body-weight support in ambulatory patients post-stroke. AB - Rehabilitating walking in ambulatory patients post-stroke, with training that is safe, task-specific, intensive, and of sufficient duration, can be challenging. Some challenges can be met by using body-weight-supported treadmill training (BWSTT). However, it is not known to what degree walking characteristics are similar during BWSTT and overground walking. In addition, important questions regarding the training protocol of BWSTT remain unanswered, such as how proportion of body-weight support (BWS) and walking speed affect walking characteristics during training. The objective was therefore to investigate if and how kinematic walking characteristics are different between overground walking and treadmill walking with BWS in ambulatory patients post-stroke, and the acute response of altering walking speed and percent BWS during treadmill walking with BWS. A cross-sectional repeated-measures design was used. Ambulating patients post-stroke walked in slow, preferred, and fast walking speed overground and at comparable speeds on the treadmill with 20% and 40% BWS. Kinematic walking characteristics were obtained using a kinematic sensor attached over the lower back. Forty-four patients completed the protocol. Kinematic walking characteristics were similar during treadmill walking with BWS, compared to walking overground. During treadmill walking, choice of walking speed had greater impact on kinematic walking characteristics than proportion of BWS. Faster walking speeds tended to affect the kinematic walking characteristics positively. This implies that in order to train safely and with sufficient intensity and duration, therapists may choose to include BWSTT in walking rehabilitation also for ambulatory patients post-stroke without aggravating gait pattern during training. PMID- 23039017 TI - Perceived value of stroke outcome measures across the post-acute care continuum: a qualitative case study. AB - Connecting the continuum of post-acute care stroke services may be important for easing patients' transition between settings and facilitating recovery and community reintegration. The use of outcome measures is suggested as one means of connecting the continuum. The purpose of this qualitative case study is to describe administrators' and physiotherapists' perceived value of an outcomes program across the post-acute care stroke continuum at a rehabilitation hospital. Data were collected through individual interviews and focus groups with 18 participants. Three themes emerged on the value of the outcomes program: 1) enhanced communication; 2) supports clinical decision-making; and 3) value of objective data. These findings lend support for the use of standardized outcome measures by physiotherapists in stroke rehabilitation. Findings from this study may be useful for organizations and physiotherapists who wish to integrate outcome measures into practice. PMID- 23039018 TI - The intra- and inter-rater reliability of the tragus wall distance (TWD) measurement in non-pathological participants ages 18-34. AB - OBJECTIVES: To assess intra-rater and inter-rater reliability of the tragus wall distance (TWD) measurement in non-pathologic individuals aged 18-34. BACKGROUND: Physical therapists evaluate posture as a component of health status. A literature review suggests need for reliable clinical tools to assess head position. METHODS: The TWD measurement is the horizontal distance between the tragus, the auricular cartilaginous flap anterior to the external auditory meatus, and a wall. Sixty-three adults aged 18-34 years were consecutively assigned to three raters for double-blinded repeated measures of TWD distance. Statistical analyses included descriptive statistics of the sample, interclass correlation coefficient (ICC), analysis of variance (ANOVA), t-tests (p < 0.05), and Pearson correlation coefficients to quantify correlations between raters and repeated measures. RESULTS: ANOVA results for intra-rater reliability indicated consistency among individual raters. All raters demonstrated significant correlations across repeated measures, ICC = 0.92-0.94. ANOVA and t-test results did not support inter-rater reliability. However, ICC = 0.90, standard error of measurement = 0.22, and Pearson R = 0.84 supported inter-rater reliability. The evidence suggests that although the absolute TWD measurement values may not be reliable among raters, relative change between TWD measures demonstrates high inter-rater reliability. CONCLUSIONS: TWD measurement has high intra-rater reliability. TWD measurement of a single patient by multiple raters is not supported. PMID- 23039019 TI - Risk factors for No. 12p and No. 12b lymph node metastases in advanced gastric cancer in China. AB - BACKGROUND: The risk factors for No. 12p and No. 12b lymph node (LN) metastases in advanced gastric cancer (GC) remain controversial. The aim of this study was to investigate the risk factors for No. 12p and No. 12b LN metastases in advanced GC. METHODS: From January 1999 to December 2005, a retrospective analysis of 163 patients with advanced GC who underwent D2 lymphadenectomy in addition to No. 12p and No. 12b LN dissections was conducted. Potential clinicopathological factors that could influence No. 12p and No. 12b LN metastases were statistically analyzed. RESULTS: There were 15 cases (9.2%) with No. 12p LN metastases and 5 cases (3.1%) with synchronous No. 12b LN metastases. A logistic regression analysis revealed that the Borrmann type (III/IV versus I/II, P = 0.029), localization (lesser/circular versus greater, P = 0.025), and depth of invasion (pT4 versus pT2/pT3, P = 0.009) were associated with 11.1-, 3.8-, and 5.6-fold increases, respectively, for risk of No. 12p and No. 12b LN metastases. A logistic regression analysis also showed that No. 5 (P = 0.006) and No. 12a (P = 0.004) LN metastases were associated with 6.9- and 11.3-fold increases, respectively, for risk of No. 12p and No. 12b LN metastases. In addition, significant differences in 5-year survival of patients with and without No. 12p and No. 12b LN metastases were observed (13.3% versus 35.1%, P = 0.022). CONCLUSION: We conclude that Borrmann type, localization, and depth of invasion are significant variables for identifying patients with No. 12p and No. 12b LN metastases. Individuals with No. 5 or No. 12a LN metastases should be on high alert for the possibility of additional metastases to the No. 12p and No. 12b LNs. PMID- 23039020 TI - Degradation of BMS-753493, a novel epothilone folate conjugate anticancer agent. AB - BMS-753493 is a folate-targeted candidate being developed for the treatment of cancer. As part of preformulation efforts, our aim was twofold - to understand the major degradation pathways and, study its kinetics of degradation to aid drug product development. Given the complexity of degradation, BMS-748285, the epothilone moiety of BMS-753493 was used as model compound to evaluate the major degradation pathway viz; macrolactone versus aziridine ring hydrolysis. Hydrolysis of BMS-753493 was studied in the pH range of 1.5-9.4 in 0.05 M buffers at 0.5 ionic strength and 5-40 degrees C. Three major pathways were identified; carbonate ester hydrolysis and hydrolysis of aziridine and macrolactone rings resulting in addition products with identical masses (m/z = 794) in the pH range of 5-7.5. Similarly, two addition products, D1 and D2 (m/z = 555) were also formed on hydrolysis of BMS-748285 under neutral pH conditions. The reaction products from BMS-748285 were isolated and characterized using LC-MS and LC-SPE NMR (1-D 1H and 2-D HMBC, heteronuclear single quantum coherence) analyses. LC NMR analysis indicated an intact aziridine ring and opened macrolactone ring, resulting in D1 and D2, an isomeric hydroxy acid pair resulting from an alkyl oxygen cleavage. By analogy to BMS-748285, BMS-753493 was also postulated to undergo alkyl cleavage of the macrolactone, forming two epimeric hydroxy acids under neutral pH. The pH-stability data were also consistent with these findings. Additionally, the degradation kinetics for BMS-753493, indicated a U-shaped pH stability profile with maximum stability at pH 7. Based on the stability and solubility considerations, the pH range of 6-7 was optimal for an injectible drug product development. PMID- 23039021 TI - Identification of autophagic vacuoles and regulators of autophagy in villous trophoblast from normal term pregnancies and in fetal growth restriction. AB - Fetal growth restriction (FGR) is a serious pregnancy complication associated with increased perinatal mortality and morbidity. Although the majority of cases with FGR result from placental dysfunction, the pathophysiology is incompletely understood. Autophagy is a physiological form of cell degradation exacerbated by nutrient and oxygen restriction, which are both thought to play a role in the aetiology of FGR. We hypothesized that autophagy is present in the normal human placenta and is exaggerated in FGR. Autophagy was assessed in electron micrographs from normal and FGR placentas and by Western blotting for LC3B and LAMP-2. The localization of regulators of autophagy was examined by immunohistochemistry. Culture of BeWo cells was used to investigate whether nutrient and/or oxygen deprivation can induce autophagy in trophoblast. Autophagy predominantly localized to the syncytiotrophoblast layer and autophagosomes were more frequent in FGR. The regulators LAMP-2, LC3B, Beclin-1, ATG 5, ATG9 and ATG16L1 were all present in villous trophoblast. LAMP-2 immunostaining was more punctate in FGR. In BeWo cells, culture in reduced oxygen tension and/or serum depleted conditions led to the appearance of autophagosomes which was associated with changes in LAMP-2 configuration. We conclude that autophagy in human term placenta may be involved in the placental dysfunction present in FGR. PMID- 23039022 TI - Access to medicines, market failure and market intervention: a tale of two regimes. AB - This study explores how an 'Intellectual Property Rights (IPR)/trade regime' has generated a particular set of problems regarding access to medicines despite patents on drugs being presented as economically necessary for reward and future drug innovation. These problems have also inspired and informed activities by so called new actors in global health. This study argues that a parallel 'pro-access regime' has developed in order to correct some of the most high-profile issues associated with a dysfunctional global pharmaceutical market, especially problems regarding price and innovation that have been exacerbated by stringent global patent rights on new drugs. Therefore, the IPR/trade regime's basic role in global-health governance diverges from how it has been framed and understood, not least of all by its constituent agents and donors. The pro-access regime encompasses new actors in health such as Global Health Partnerships (e.g., GAVI Alliance and the Global Fund to Fight AIDS, Tuberculosis and Malaria), major philanthropic foundations (e.g., the Gates and Clinton Foundations) and new access initiatives (e.g., UNITAID). The study problematises these actors' governance roles with respect to the overarching authority of the IPR/trade regime and makes a case that the two regimes should be understood as being closely connected with respect to the governance of access to medicines and the global political economy of pharmaceuticals. PMID- 23039023 TI - Mondia whitei, a medicinal plant from Africa with aphrodisiac and antidepressant properties: a review. AB - This paper reviews the literature concerning the ethnobotany, phytochemistry, and pharmacology of Mondia whitei, which is also known as Mondia whytei, African ginger or simply as mondia. Mondia is used in many parts of Africa as a traditional remedy to improve appetite and libido, as a galactagogue, as a fertility medication, and as an antidepressant. In African countries, where it is used medicinally, the most commonly cited use is as an aphrodisiac. The scientific studies reviewed in this report employed either in vivo rodent models or isolated organ techniques, and therefore the results cannot be directly extrapolated to humans. Nevertheless, these studies provide scientific evidence that support the traditional uses of mondia as an aphrodisiac and an antidepressant. Based on the safety data available in the literature, mondia is reasonably expected to be safe when prepared and used according to traditional practices. PMID- 23039024 TI - Linking 31P magnetic shielding tensors to crystal structures: experimental and theoretical studies on metal(II) aminotris(methylenephosphonates). AB - The (31)P chemical shift tensor of the phosphonate group [RC-PO(2)(OH)](-) is investigated with respect to its principal axis values and its orientation in a local coordinate system (LCS) defined from the P atom and the directly coordinated atoms. For this purpose, six crystalline metal aminotris(methylenephosphonates), MAMP.xH(2)O with M = Zn, Mg, Ca, Sr, Ba, and (2Na) and x = 3, 3, 4.5, 0, 0, and 1.5, respectively, were synthesized and identified by diffraction methods. The crystal structure of water-free BaAMP is described here for the first time. The principal components of the (31)P shift tensor were determined from powders by magic-angle-spinning NMR. Peak assignments and orientations of the chemical shift tensors were established by quantum chemical calculations from first principles using the extended embedded ion method. Structure optimizations of the H-atom positions were necessary to obtain the chemical shift tensors reliably. We show that the (31)P tensor orientation can be predicted within certain error limits from a well-chosen LCS, which reflects the pseudosymmetry of the phosphonate environment. PMID- 23039025 TI - Global proteomic screening of protein allergens and advanced glycation endproducts in thermally processed peanuts. AB - Peanuts (Arachis hypogaea) are the cause of one of the most prevalent food allergies worldwide. Thermal processing (e.g., roasting) of peanuts and peanut containing foods results in complex chemical reactions that alter structural conformations of peanut proteins, preventing accurate detection of allergens by most immunochemical and targeted screening methodologies. To improve food allergen detection and support more accurate food labeling, traditional methods for peanut protein extraction were modified to include protein denaturants and solubilization agents. Qualitative characterization by SDS-PAGE and Western blot analyses of raw and variably roasted peanut extracts confirmed improvements in total protein recovery and provided evidence for the incorporation of Ara h 1, Ara h 3, and, to a lesser extent, Ara h 2 into high molecular weight protein complexes upon roasting. Relative quantification of allergens in peanut lysates was accomplished by label-free spectral feature (MS1) LC-MS/MS methodologies, by which peanut allergen peptides exhibiting a differential MS response in raw versus roasted peanuts were considered to be candidate targets of thermal modification. Identification of lysine-modified Maillard advanced glycation endproducts (AGE) by LC-MS/MS confirmed the formation of (carboxymethyl)lysine (CML), (carboxyethyl)lysine (CEL), and pyrraline (Pyr) protein modifications on Ara h 1 and Ara h 3 tryptic peptides in roasted peanut varieties. These results suggest that complex processed food matrices require initial analysis by an untargeted LC-MS/MS approach to determine optimum analytes for subsequent targeted allergen analyses. PMID- 23039026 TI - A torquoselective 6pi electrocyclization approach to reserpine alkaloids. AB - A highly torquoselective thermal triene 6pi electrocyclization controls the relative stereochemistry between the C3 and C18 stereocenters of the dodecahydroindolo[2,3-a]benzo[g]quinolizine skeleton of reserpine-type alkaloids. Employing a tandem cross-coupling/electrocyclization protocol allowed us to form the requisite triene and ensure its subsequent cyclization. A novel low temperature dibromoketene acetal Claisen rearrangement established the requisite exocyclic dienylbromide precursor for the palladium-catalyzed cross-coupling reaction. PMID- 23039027 TI - Global minima of protonated water clusters (H2O)20H+ revisited. AB - A graph-theoretical analysis is performed on the (H(2)O)(20) "edge-sharing pentagonal prism" cluster to find proton configurations that yield the lowest cluster total energies. Using the low-energy structures, we create models for protonated (H(2)O)(20)H(+) clusters that compete energetically with "cage-like" structures proposed earlier in the literature. We perform benchmarking between different theoretical methods and observe significant stabilization of compact versus polyhedral clusters due to long-range electron correlation effects, which make the comparison between different cluster morphologies difficult using density functional theory only. All methodologies that we used (up to the second level of Moller-Plesset perturbation theory (MP2)) agree that for protonated clusters, the cage-like morphology proposed in [ Chem. Phys. Lett. 2000, 324, 279 288] is the most stable one. We study in detail several (H(2)O)(20)H(+) cluster structures and suggest that the energetics in small protonated water clusters is dominated by the competition of open polyhedral structures, favored by the Eigen H(9)O(4)(+) species, against van der Waals interaction and "ice rules", which both favor compact structural motifs such as the prismatic particle. We demonstrate this tendency using ab initio calculations for prismatic, dodecahedral, and cage-like clusters, while the "magic number" cluster (H(2)O)(n)H(+), n = 21, is observed to minimize all competing energy contributions simultaneously. We emphasize the utility of the cage-like cluster as a model template for ice-related atmospheric reactions and benchmark the GPAW density functional theory code for making such calculations. PMID- 23039028 TI - In-depth analysis of the Magnaporthe oryzae conidial proteome. AB - The filamentous fungus Magnaporthe oryzae (M. oryzae) is the causative agent of rice blast disease and presents a significant threat to worldwide rice production. To establish the groundwork for future research on the pathogenic development of M. oryzae, a global proteomic study of conidia was performed. The filter aided sample preparation method (FASP) and anion StageTip fractionation combined with long, optimized shallow 210 min nanoLC gradients prior to mass spectrometry analysis on an Orbitrap XL was applied, which resulted in a doubling of protein identifications in comparison to our previous GeLC analysis. Herein, we report the identification of 2912 conidial proteins at a 1% protein false discovery rate (FDR) and we present the most extensive study performed on M. oryzae conidia to date. A similar distribution between identified proteins and the predicted proteome was observed when subcellular localization analysis was performed, suggesting the detected proteins build a representative portion of the predicted proteome. A higher percentage of cytoplasmic proteins (associated with translation, energy, and metabolism) were observed in the conidial proteome relative to the whole predicted proteome. Conversely, nuclear and extracellular proteins were less well represented in the conidial proteome. Further analysis by gene ontology revealed biological insights into identified proteins important for central metabolic processes and the physiology of conidia. PMID- 23039029 TI - Structural insights into the function of the nicotinate mononucleotide:phenol/p cresol phosphoribosyltransferase (ArsAB) enzyme from Sporomusa ovata. AB - Cobamides (Cbas) are cobalt (Co) containing tetrapyrrole-derivatives involved in enzyme-catalyzed carbon skeleton rearrangements, methyl-group transfers, and reductive dehalogenation. The biosynthesis of cobamides is complex and is only performed by some bacteria and achaea. Cobamides have an upper (Cobeta) ligand (5'-deoxyadenosyl or methyl) and a lower (Coalpha) ligand base that contribute to the axial Co coordinations. The identity of the lower Coalpha ligand varies depending on the organism synthesizing the Cbas. The homoacetogenic bacterium Sporomusa ovata synthesizes two unique phenolic cobamides (i.e., Coalpha (phenolyl/p-cresolyl)cobamide), which are used in the catabolism of methanol and 3,4-dimethoxybenzoate by this bacterium. The S. ovata ArsAB enzyme activates a phenolic lower ligand prior to its incorporation into the cobamide. ArsAB consists of two subunits, both of which are homologous (~35% identity) to the well-characterized Salmonella enterica CobT enzyme, which transfers nitrogenous bases such as 5,6-dimethylbenzimidazole (DMB) and adenine, but cannot utilize phenolics. Here we report the three-dimensional structure of ArsAB, which shows that the enzyme forms a pseudosymmetric heterodimer, provide evidence that only the ArsA subunit has base:phosphoribosyl-transferase activity, and propose a mechanism by which phenolic transfer is facilitated by an activated water molecule. PMID- 23039031 TI - Prospective clinical audit of chloral hydrate administration practices in a neonatal unit. AB - AIM: Chloral hydrate is generally considered a safe and effective single dosing procedural sedative for neonates in the clinical setting. However, its safety profile as a repetitive dosing maintenance sedative is largely unknown. This study aimed to document current administration practices of chloral hydrate in the Neonatal Unit, Royal Children's Hospital, Melbourne, Australia, over a 6 month period. METHODS: Patients who had been prescribed chloral hydrate during the specified audit period were recruited into the study and prospectively followed for a period of 28 days, or until they were discharged from the unit. Demographic data were collected on recruitment, and daily documentation of chloral hydrate administration was recorded. RESULTS: A total of 238 doses of chloral hydrate were administered to a cohort of 32 patients during the study period. The majority of the audited doses (84%) were ordered as repeating doses. Doses were more likely to be given at night than during the day, and the median dosage for repetitive dosing was found to be above the study site's recommended dosing range. Pre-dose and/or post-dose assessment of distress/agitation accompanied dosage approximately half of the time. The audit did not reveal any recognisable pattern of sedation maintenance or weaning process for patients who received multiple doses. CONCLUSIONS: Health-care professionals caring for hospitalised infants should be made aware of the potential risks of chloral hydrate as a repetitive dosing sedative, and of the importance of systematically evaluating the appropriateness and effectiveness of utilising such pharmacological intervention for managing and treating distress. PMID- 23039032 TI - Quantitative atomic resolution force imaging on epitaxial graphene with reactive and nonreactive AFM probes. AB - Atomic force microscopy (AFM) images of graphene and graphite show contrast with atomic periodicity. However, the contrast patterns vary depending on the atomic termination of the AFM tip apex and the tip-sample distance, hampering the identification of the atomic positions. Here, we report quantitative AFM imaging of epitaxial graphene using inert (carbon-monoxide-terminated) and reactive (iridium-terminated) tips. The atomic image contrast is markedly different with these tip terminations. With a reactive tip, we observe an inversion from attractive to repulsive atomic contrast with decreasing tip-sample distance, while a nonreactive tip only yields repulsive atomic contrast. We are able to identify the atoms with both tips at any tip-sample distance. This is a prerequisite for future structural and chemical analysis of adatoms, defects, and the edges of graphene nanostructures, crucial for understanding nanoscale graphene devices. PMID- 23039033 TI - The challenge of pain evaluation in haemophilia: can pain evaluation and quantification be improved by using pain instruments from other clinical situations? AB - Pain is a critical aspect in the lives of individuals with congenital haemophilia A or B. Initially, pain serves as a warning sign for an active bleeding event; however, after multiple bleeding episodes, pain may become chronic, debilitating, and distracting. It is essential that pain instruments be developed and validated for use in persons with haemophilia, especially in paediatric cohorts, so that new therapies to treat acute bleeds can be assessed in a standardized manner. This review evaluates the existing pain instruments utilized in the English language haemophilia literature and compares their features and practicality with instruments published for other clinical pain scenarios associated with non coagulopathic disease states, such as cancer and surgical convalescence, in paediatric, adolescent, and adult populations. In clinical trials involving haemophilia cohorts, few pain instruments have been validated. Only one instrument has addressed pain specifically in individuals less than 16 years of age. In contrast, multiple instruments have been applied extensively to other pain situations, especially in the paediatric oncology area, where the age range extends to less than 3 years. We conclude that trials quantifying pain in haemophilia would benefit from the addition and validation of instruments in use in other pain situations. Suggestions for modifying the pain instruments currently used in haemophilia are presented, specifically to address paediatric haemophilia cohorts. PMID- 23039030 TI - Inflammatory biomarker changes and their correlation with Framingham cardiovascular risk and lipid changes in antiretroviral-naive HIV-infected patients treated for 144 weeks with abacavir/lamivudine/atazanavir with or without ritonavir in ARIES. AB - Propensity for developing coronary heart disease (CHD) is linked with Framingham defined cardiovascular risk factors and elevated inflammatory biomarkers. Cardiovascular risk and inflammatory biomarkers were evaluated in ARIES, a Phase IIIb/IV clinical trial in which 515 antiretroviral-naive HIV-infected subjects initially received abacavir/lamivudine + atazanavir/ritonavir for 36 weeks. Subjects who were virologically suppressed by week 30 were randomized 1:1 at week 36 to either maintain or discontinue ritonavir for an additional 108 weeks. Framingham 10-year CHD risk scores (FRS) and risk category of <6% or >=6%, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) were assessed at baseline, week 84, and week 144. Biomarkers were stratified by FRS category. When ritonavir boosted/nonboosted treatment groups were combined, median hsCRP did not change significantly between baseline (1.6 mg/liter) and week 144 (1.4 mg/liter) in subjects with FRS <6% (p=0.535) or with FRS >=6% (1.9 mg/liter vs. 2.0 mg/liter, respectively; p=0.102). Median IL-6 was similar for subjects with FRS <6% (p=0.267) at baseline (1.6 pg/ml) and week 144 (1.4 pg/ml) and for FRS >=6% (2.0 pg/ml vs. 2.2 pg/ml, respectively; p=0.099). Median Lp-PLA(2) decreased significantly (p<0.001) between baseline (197 nmol/min/ml) and week 144 (168 nmol/min/ml) in subjects with FRS <6% and with FRS >=6% (238 nmol/min/ml vs. 175 nmol/min/ml, respectively; p<0.001). In conclusion, in antiretroviral-naive subjects treated with abacavir-based therapy for 144 weeks, median inflammatory biomarker levels for hsCRP and IL-6 generally remained stable with no significant difference between baseline and week 144 for subjects with either FRS <6% or FRS >=6%. Lp-PLA(2) median values declined significantly over 144 weeks for subjects in either FRS stratum. PMID- 23039035 TI - Prolonged urinary leakage in the postoperative period of renal hydatic cyst treatment with oral desmopressin: a case report. AB - INTRODUCTION: Prolonged extravasation after renal and ureter surgeries is a bothersome situation for both the patient and the doctor. It is usually related to the suture line not being watertight. The contact between urine and the edges of the wound also delay healing of the wound. In this situation, the first thing to do is to break the contact between the wound and the urine by inserting an adequate stent. Sometimes, this process is not enough. We approached this problem with a different treatment method for a case involving prolonged drainage. CASE PRESENTATION: A 52-year-old Caucasian woman who presented at our clinic with right flank pain was operated on due to a renal hydatic cyst, and cyst removal was performed. On follow-up, prolonged urinary leakage was observed and a desmopressin treatment was started on the patient. Drainage was greatly reduced after desmopressin was started and there was no drainage on the fifth day. CONCLUSION: Prolonged extravasation is a bothersome situation and there can be many reasons for this. Whenever traditional approaches are not enough, oral desmopressin therapy can be started reliably if there are no contraindications for the patient. Eventually, contact between urine and the suture site will cease and therefore the fever and healing time will be shortened. PMID- 23039034 TI - Lopinavir/Ritonavir versus Lamivudine peri-exposure prophylaxis to prevent HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS 12174. AB - BACKGROUND: Postnatal transmission of HIV-1 through breast milk remains an unsolved challenge in many resource-poor settings where replacement feeding is not a safe alternative. WHO now recommends breastfeeding of infants born to HIV infected mothers until 12 months of age, with either maternal highly active antiretroviral therapy (HAART) or peri-exposure prophylaxis (PEP) in infants using nevirapine. As PEP, lamivudine showed a similar efficacy and safety as nevirapine, but with an expected lower rate of resistant HIV strains emerging in infants who fail PEP, and lower restrictions for future HIV treatment. Lopinavir/ritonavir (LPV/r) is an attractive PEP candidate with presumably higher efficacy against HIV than nevirapine or lamivudine, and a higher genetic barrier to resistance selection. It showed an acceptable safety profile for the treatment of very young HIV-infected infants. The ANRS 12174 study aims to compare the risk of HIV-1 transmission during and safety of prolonged infant PEP with LPV/r (40/10 mg twice daily if 2-4 kg and 80/20 mg twice daily if >4 kg) versus Lamivudine (7,5 mg twice daily if 2-4 kg, 25 mg twice daily if 4-8 kg and 50 mg twice daily if >8 kg) from day 7 until one week after cessation of BF (maximum 50 weeks of prophylaxis) to prevent postnatal HIV-1 acquisition between 7 days and 50 weeks of age. METHODS: The ANRS 12174 study is a multinational, randomised controlled clinical trial conducted on 1,500 mother-infant pairs in Burkina Faso, South Africa, Uganda and Zambia. We will recommend exclusive breastfeeding (EBF) until 26th week of life and cessation of breastfeeding at a maximum of 49 weeks in both trial arms.HIV-uninfected infants at day 7 (+/- 2 days) born to HIV-1 infected mothers not eligible for HAART who choose to breastfeed their infants.The primary endpoint is the acquisition of HIV-1 (as assessed by HIV-1 DNA PCR) between day 7 and 50 weeks of age. Secondary endpoints are safety (including resistance, adverse events and growth) until 50 weeks and HIV-1-free survival until 50 weeks. DISCUSSION: This study will provide a new evidence-based intervention to support HIV-1-infected women not eligible for HAART to safely breastfeed their babies. PMID- 23039036 TI - Buccal bone plate remodeling after immediate implants with or without synthetic bone grafting and flapless surgery: a histomorphometric and fluorescence study in dogs. AB - OBJECTIVE: The aim of this study was to evaluate the buccal bone plate remodeling after immediate implantation using the flapless approach with or without bone graft into the gap between the implant and the buccal bone. MATERIAL AND METHODS: Eight dogs had the mandibular bicuspids extracted without flaps, and four implants were installed on each side, totaling eight implants per animal. Randomly, in one side, the implants were positioned at the bone crest level (equicrestal), and on the opposite side, the implants were positioned 2 mm subcrestal. All the implants were positioned 2.0 mm from the buccal bone plate (gap) and associated or not with grafting material. Therefore, the following treatments were performed: implants subcrestal test (SCTG) with bone graft and control (SCCG) without bone graft, and equicrestal test (ECTG) with bone graft and control (ECCG) without bone graft. One week following the surgeries, metallic prostheses were installed. Bone markers were administered 1, 2, 4, and 12 weeks after implant placement for fluorescence analysis. Ground sections were prepared from 12-week healing biopsies, and histomorphometry was performed. RESULTS: The histomorphometric evaluation presents significant better results for the ECTG in the vertical crestal bone resorption, but the other parameters showed better results for the SCCG. The fluorescence evaluation in adjacent areas showed numerically different results between groups with a small decrease at 12 weeks, except for the SCCG, which was higher at this time. The distant area showed a continuous increase in the marked bone. CONCLUSION: The equicrestally placed implants presented little or no loss of the buccal bone wall. The subcrestally positioned implants presented loss of buccal bone, regardless of the use of bone graft. However, the buccal bone was always coronal to the implant shoulder. Both the equicrestal and subcrestal groups were benefited in the early stages of bone healing as evidenced by the fluorescence analysis. PMID- 23039037 TI - Evidence-based antioxidant activity of the essential oil from Fructus A. zerumbet on cultured human umbilical vein endothelial cells' injury induced by ox-LDL. AB - BACKGROUND: The essential oil from Fructus Alpiniae zerumbet (FAZ) is its principal bioactive ingredient, and is widely used in Miao folk herbs in Guizhou province for the treatment of gastrointestinal and cardiovascular diseases. Several studies have confirmed that FAZ ameliorates hyperlipidemia and atherosclerosis. Because endothelial dysfunction often accompanies cardiovascular diseases, especially hyperlipidemia and atherosclerosis, the present study concentrated on evaluating the endothelial protective effects of the essential oil from FAZ (EOFAZ) on oxidized low-density lipoprotein (ox-LDL)-induced injury of cultured human umbilical vein endothelial cells (HUVECs) and on the regulation of oxidative stress. METHODS: Cell viability was analyzed with the MTT assay and trypan blue exclusion staining (TBES). Cell injury was assessed by lactate dehydrogenase (LDH) release. Biochemical enzymatic methods were used to evaluate the oxidative stress, including the lipid peroxidation product, malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). RESULTS: The redox status of HUVECs was significantly exacerbated after exposure to ox-LDL. EOFAZ protected HUVECs against ox-LDL injury as assessed by the MTT assay, TBES and LDH release. Furthermore, EOFAZ ameliorated the oxidative stress by elevating the activities of SOD, CAT and GSH-Px, and increasing the GSH levels, in addition to attenuating the MDA contents. CONCLUSIONS: The present data provide the first experimental evidence that EOFAZ protects endothelial cells against ox-LDL-induced injury, and indicate that this protection involves ameliorating the redox status. PMID- 23039038 TI - Association of salivary levels of the bone remodelling regulators sRANKL and OPG with periodontal clinical status. AB - AIM: To determine the variations in salivary concentrations of sRANKL, osteoprotegerin (OPG) and its ratio, regarding the periodontal status. MATERIALS AND METHODS: Ninety-seven chronic periodontitis (CP) subjects and 43 healthy controls were selected. Periodontal status was assessed based on full-mouth clinical periodontal measurements. sRANKL and OPG salivary levels were analysed by ELISA. The association between these analytes and its ratio with CP was analysed individually and adjusted for confounding using a binary logistic regression model. RESULTS: sRANKL and sRANKL/OPG ratio were increased, whereas OPG was decreased in CP compared with healthy controls subjects. Although univariate analysis revealed a positive association of sRANKL salivary levels >=6 pg/ml, OPG salivary levels <=131 pg/ml and sRANKL/OPG ratio >=0.062 with CP, after logistic regression analysis only the latter parameter was strongly and independently associated with disease status. Confounding and interaction effects of ageing and smoking habit on sRANKL and OPG levels could be noted. CONCLUSION: Although salivary concentrations of sRANKL, OPG and its ratio may act as indicators of the amount/extent of periodontal breakdown, the mutual confounding and synergistic biological interactive effects related to ageing and smoking habit of the susceptible host may also promote the tissue destruction in CP. PMID- 23039039 TI - A Turkish trichothiodystrophy patient with homozygous XPD mutation and genotype phenotype relationship. AB - Trichothiodystrophy (TTD) is a rare, recessive condition involving multiple organs and systems. Four genes associated with nuclear excision repair have been described in the molecular etiology of TTD. There is a significant heterogeneity of clinical and laboratory findings of TTD, even in individuals carrying the same mutation. Worldwide, approximately 120 cases have been reported, mostly from Western populations and the mutations are compound heterozygous. We herein present clinical and laboratory findings of a female patient with a homozygous mutation, R722W, in the XPD gene. To date, two patients who carry the same mutation have been reported. Our genotype-phenotype correlation study showed patients who carry R722W mutation have a more severe TTD phenotype than other types of mutations. PMID- 23039042 TI - Chinese Head Trauma Data Bank: Effect of gender on the outcome of patients with severe traumatic brain injury. AB - Gender may be related with the outcome of patients with acute traumatic brain injury. We explored the effect of gender on the outcome of 7145 patients with acute traumatic brain injury. There was no statistical difference between male and female in the causes of trauma, age, GCS score, CT findings, and surgical management. The mortality of patients with 7145 acute head trauma in male and female was 7.48% and 7.22% respectively with the corresponding unfavorable outcomes of 16.05% and 17.23% respectively (P>0.05 in both cases). The mortality of 1626 patients with severe traumatic brain injury in male and female was 19.68% and 20.72% respectively with the corresponding unfavorable outcomes of 46.96% and 48.85% respectively (P>0.05 in both cases). Our data suggest that gender does not play a role in the outcome of patients with acute traumatic brain injury. PMID- 23039041 TI - Providing predictive testing for Huntington disease via telehealth: results of a pilot study in British Columbia, Canada. AB - Predictive testing (PT) for Huntington disease (HD) usually requires several in person appointments which acts as a barrier to testing for those from remote regions. This pilot study reports the use of telehealth PT to examine whether such telehealth testing improves access to HD PT while maintaining quality of care and support. Individuals underwent PT via the telehealth protocol or standard in-person protocol and were asked to complete surveys regarding their experience. Results reveal no significant differences between the in-person tested and telehealth-tested groups with respect to quality of care, information, counselling and support. The majority of participants in both groups stated that pre-test counselling had provided them with sufficient knowledge about the advantages and disadvantages of undergoing testing, the opportunity to ask questions, and the ability to make an informed decision. The majority of participants in both groups were satisfied by the manner in which results were delivered and stated they had received sufficient information regarding the implications of these results. This study reveals that telehealth PT improves access while maintaining quality of care and support. PMID- 23039040 TI - Proteomics-based identification of haptoglobin as a favourable serum biomarker for predicting long-term response to splenectomy in patients with primary immune thrombocytopenia. AB - BACKGROUND: Splenectomy is the most effective treatment for patients with primary immune thrombocytopenia (ITP) who fail to respond to steroid therapy. Thus far, there is no effective means to predict the long-term haematological response of the procedure. The purpose of this study was to identify serum biomarkers as predictors of long-term response based on a proteomics approach. METHODS: The serum samples of ITP patients were collected before splenectomy and seven days after surgery. After depletion of the abundant serum proteins, pooled preoperative serum samples from four responders to splenectomy, four nonresponders and four healthy controls were subjected to two-dimensional gel electrophoresis (2-DE). Nine protein spots with at least a five-fold alteration in expression between responders and nonresponders were all identified as haptoglobin (Hp) by matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometer (MS) analysis. The validation of serum Hp expression was performed using enzyme-linked immunosorbent assays (ELISA) in thirty-seven responders, thirteen nonresponders and twenty-one healthy controls. RESULTS: The preoperative serum levels of Hp in the nonresponders (925.9 +/- 293.5 MUg/ml) were significantly lower than those in the responders (1417.4 +/- 315.0 MUg/ml, p <0.001) and the healthy controls (1409.1 +/- 354.2 MUg/ml, p <0.001), while there was no significant difference between the latter two groups. The postoperative serum levels of Hp in responders and nonresponders were (1414.1 +/- 225.0 MUg/ml) and (952.9 +/- 202.4 MUg/ml), respectively. There were no significant differences between the serum Hp levels before and after surgery in both responders and nonresponders (p>0.05). The preoperative serum levels of Hp did not significantly correlate with preoperative platelet count of the same blood samples (r = 0.244, p = 0.087), while it positively correlated with postoperative peak platelet count (r = 0.622, p < 0.001). The optimal cutoff value of preoperative serum Hp levels (1173.80 MUg/ml) derived from the receiver operating characteristic (ROC) curve led to 78.4% sensitivity and 84.6% specificity. CONCLUSIONS: These results suggest that serum Hp levels may serve as a favourable predictor for the long-term response to splenectomy in ITP and may help to understand the pathophysiological differences between responders and nonresponders. PMID- 23039043 TI - Nitric oxide inhibits succinate dehydrogenase-driven oxygen consumption in potato tuber mitochondria in an oxygen tension-independent manner. AB - NO (nitric oxide) is described as an inhibitor of plant and mammalian respiratory chains owing to its high affinity for COX (cytochrome c oxidase), which hinders the reduction of oxygen to water. In the present study we show that in plant mitochondria NO may interfere with other respiratory complexes as well. We analysed oxygen consumption supported by complex I and/or complex II and/or external NADH dehydrogenase in Percoll-isolated potato tuber (Solanum tuberosum) mitochondria. When mitochondrial respiration was stimulated by succinate, adding the NO donors SNAP (S-nitroso-N-acetyl-DL-penicillamine) or DETA-NONOate caused a 70% reduction in oxygen consumption rate in state 3 (stimulated with 1 mM of ADP). This inhibition was followed by a significant increase in the Km value of SDH (succinate dehydrogenase) for succinate (Km of 0.77+/-0.19 to 34.3+/-5.9 mM, in the presence of NO). When mitochondrial respiration was stimulated by external NADH dehydrogenase or complex I, NO had no effect on respiration. NO itself and DETA-NONOate had similar effects to SNAP. No significant inhibition of respiration was observed in the absence of ADP. More importantly, SNAP inhibited PTM (potato tuber mitochondria) respiration independently of oxygen tensions, indicating a different kinetic mechanism from that observed in mammalian mitochondria. We also observed, in an FAD reduction assay, that SNAP blocked the intrinsic SDH electron flow in much the same way as TTFA (thenoyltrifluoroacetone), a non-competitive SDH inhibitor. We suggest that NO inhibits SDH in its ubiquinone site or its Fe-S centres. These data indicate that SDH has an alternative site of NO action in plant mitochondria. PMID- 23039044 TI - Improved mode assignment for molecular crystals through anisotropic terahertz spectroscopy. AB - We report the anisotropic terahertz response of oxalic acid and sucrose crystals in the 0.2-3.0 THz range using terahertz time domain spectroscopy on large, single crystals. We compare the observed anisotropic response with the response calculated using solid-state density functional theory and find good agreement in the orientation dependence and relative intensities of the crystal phonons. It was found that oxalic dihydrate can be reversibly converted to anhydrous by controlled relative humidity. In addition, oxalic acid was found to have a large birefringence with Deltan = 0.3, suggesting the material may be useful for terahertz polarization manipulation. Sucrose has a smaller birefringence of Deltan = 0.05, similar to that of x-cut quartz. The anisotropic measurements provide both mode separation and symmetry determination to more readily achieve mode assignment for the more complex sucrose spectrum. PMID- 23039045 TI - Substituent exchange reactions of linear oligomeric aryloxyphosphazenes with sodium 2,2,2-trifluoroethoxide. AB - Side-group-exchange reactions have been studied for short-chain linear oligomeric phosphazenes, (RO)(4)P[N?P(OR(2))](n)OR (n = 6, 10, 20, and 40) as models for the corresponding linear high polymers (n ~ 15000). Specifically, the exchange behavior of oligomers where OR = OCH(2)CF(3), OC(6)H(5), OC(6)H(4)CHO-p, OC(6)H(4)CN-p, and OC(6)H(4)NO(2)-p with sodium trifluoroethoxide was examined. The ease of aryloxy group replacement by trifluoroethoxy increased with the electron-withdrawing character in the order OR = OC(6)H(5) ? OC(6)H(4)CHO-p < OC(6)H(4)CN-p < OC(6)H(4)NO(2)-p, but the reaction was efficient only if the phosphazene contained no more than 20 repeating units. However, attempts to force slower reactions by the use of excess sodium trifluoroethoxide induced secondary reactions at the trifluoroethoxy units already introduced to produce CF(3)CH(2)OCH(2)CF(3) and generate -O(-)Na(+) units in their place. The longest chain model underwent side-group-exchange reactions preferentially at the end units. These results are significant for the synthesis of phosphazene high polymers with fluoroalkoxy and aryloxy side groups. PMID- 23039046 TI - Validation of quantitative and qualitative methods for detecting allergenic ingredients in processed foods in Japan. AB - A labeling system for food allergenic ingredients was established in Japan in April 2002. To monitor the labeling, the Japanese government announced official methods for detecting allergens in processed foods in November 2002. The official methods consist of quantitative screening tests using enzyme-linked immunosorbent assays (ELISAs) and qualitative confirmation tests using Western blotting or polymerase chain reactions (PCR). In addition, the Japanese government designated 10 MUg protein/g food (the corresponding allergenic ingredient soluble protein weight/food weight), determined by ELISA, as the labeling threshold. To standardize the official methods, the criteria for the validation protocol were described in the official guidelines. This paper, which was presented at the Advances in Food Allergen Detection Symposium, ACS National Meeting and Expo, San Diego, CA, Spring 2012, describes the validation protocol outlined in the official Japanese guidelines, the results of interlaboratory studies for the quantitative detection method (ELISA for crustacean proteins) and the qualitative detection method (PCR for shrimp and crab DNAs), and the reliability of the detection methods. PMID- 23039047 TI - Coaxially electrospun scaffolds based on hydroxyl-functionalized poly(epsilon caprolactone) and loaded with VEGF for tissue engineering applications. AB - The aim of this study was to fabricate nanofibrous scaffolds based on blends of a hydroxyl functionalized polyester (poly(hydroxymethylglycolide-co-epsilon caprolactone), pHMGCL) and poly(epsilon-caprolactone) (PCL), loaded with bovine serum albumin (BSA) as a protein stabilizer and vascular endothelial growth factor (VEGF) as a potent angiogenic factor by means of a coaxial electrospinning technique. The scaffolds were characterized by scanning electron microscopy (SEM), fluorescence microscopy (FM), and differential scanning calorimetry (DSC). The scaffolds displayed a uniform fibrous structure with a fiber diameter around 700 nm. The release of BSA from the core of the fibers was studied by high performance liquid chromatography (HPLC), and it was shown that the coaxial scaffolds composed of blends of pHMGCL and PCL exhibited faster release than the comparative PCL scaffolds. VEGF was also incorporated in the core of the scaffolds, and the effect of the released protein on the attachment and proliferation of endothelial cells was investigated. It was shown that the incorporated protein preserved its biological activity and resulted in initial higher numbers of adhered cells. Thus, these bioactive scaffolds based on blends of pHMGCL/PCL loaded with VEGF can be considered as a promising candidate for tissue engineering applications. PMID- 23039048 TI - Synthesis and properties of ethylene-annulated di(perylene diimides). AB - A new synthetic method toward ethylene-annulated di(perylene diimides) from easily available ethylene-annulated di(perylene esters), which is conducted by ICl-induced cyclization and Mizoroki-Heck coupling of ethynylene-linked di(perylene esters), is reported. PMID- 23039049 TI - "Need for interventional studies on the impact of music in the perinatal period: results of a pilot study on women's preferences and review of the literature". AB - AIM OF THE STUDY: Studies investigating the impact of pre- or postnatal music exposure on child development are scarce. Therefore, we conducted this pilot study. MATERIAL AND METHODS: Five hundred pregnant women, 246 primigravidae, and 254 multigravidae were interviewed about listening to, singing and performing music during pregnancy and after birth. chi(2), Wilcoxon, and Mc Nemar tests were used to calculate significant differences. RESULTS: Prenatally, 361/500 women (72.2%) listened to music at least once/week, 129/500 women (25.8%) answered to sing at least once/week and 23/500 (4.6%) performed music regularly. While listening to music was equally distributed when considering maternal age, education and parity, singing was more frequent in mothers of advanced age (p = 0.031), higher education (p = 0.001), and parity (p = 0.001). In multigravidae, listening decreased from 72.4% prenatally to 59.2% post-natally (p < 0.002); however, singing increased from 36% to 46.4% (p < 0.001) from pre- to postnatally, both independent of education and maternal age. Singing during pregnancy was more frequent in women of higher qualification compared to secondary and basic education: 39.6% versus 20.8% and in women of maternal age> 30: 31.4% compared to < 30: 17.5% (p < 0.001). CONCLUSION: Our study should be a basis for further interventional programs relating to neurodevelopment and bonding. PMID- 23039051 TI - Disseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report. AB - BACKGROUND: Primary myelofibrosis is a myeloproliferative disorder characterized by bone marrow fibrosis, abnormal cytokine expression, splenomegaly and anemia. The activation of JAK2 and the increased levels of circulating proinflammatory cytokines seem to play an important role in the pathogenesis of myelofibrosis. Novel therapeutic agents targeting JAKs have been developed for the treatment of myeloproliferative disorders. Ruxolitinib (INCB018424) is the most recent among them. CASE PRESENTATION: To our knowledge, there is no evidence from clinical trials of an increased risk of tuberculosis during treatment with JAK inhibitors. Here we describe the first case of tuberculosis in a patient treated with Ruxolitinib, a male with a 12-year history of chronic idiopathic myelofibrosis admitted to our Institute because of fever, night sweats, weight loss and an enlarging mass in the left inguinal area for two months. CONCLUSION: Treatment with Ruxolitinib may have triggered the reactivation of latent tuberculosis because of an inhibition of Th1 response. Our case highlights the importance of an accurate screening for latent tuberculosis before starting an anti-JAK 2 treatment. PMID- 23039050 TI - In vitro toxicity assessment of amphiphillic polymer-coated CdSe/ZnS quantum dots in two human liver cell models. AB - Semiconductor quantum dots (Qdots) are a promising new technology with benefits in the areas of medical diagnostics and therapeutics. Qdots generally consist of a semiconductor core, capping shell, and surface coating. The semiconductor core of Qdots is often composed of group II and VI metals (e.g., Cd, Se, Te, Hg) that are known to have toxic properties. Various surface coatings have been shown to stabilize Qdots and thus shield cells from the toxic properties of their core elements. In this study, HepG2 cells and primary human liver (PHL) cells were chosen as in vitro tissue culture models of human liver to examine the possible adverse effects of tri-n-octylphosphine oxide, poly(maleic anhydride-alt-1 tetradecene) copolymer (TOPO-PMAT)-coated CdSe/ZnS Qdots (TOPO-PMAT Qdots). The TOPO-PMAT coating is desirable for increasing aqueous solubility and ease of conjugation to targeting moieties (e.g., aptamers and peptides). HepG2 cells avidly incorporated these TOPO-PMAT Qdots into subcellular vesicles. However, PHL cells did not efficiently take up TOPO-PMAT Qdots, but nonparenchymal cells did (especially Kupffer cells). No acute toxicity or morphological changes were noted in either system at the exposure levels used (up to 40 nM). However, cellular stress markers and pro-inflammatory cytokines/chemokines were increased in the PHL cell cultures, suggesting that TOPO-PMAT Qdots are not likely to cause acute cytotoxicity in the liver but may elicit inflammation/hepatitis, demonstrating the importance of relevant preclinical safety models. Thus, further in vivo studies are warranted to ensure that TOPO-PMAT-coated Qdots used in biomedical applications do not induce inflammatory responses as a consequence of hepatic uptake. PMID- 23039053 TI - Evidence-based treatments for female pattern hair loss: a summary of a Cochrane systematic review. AB - Female pattern hair loss (FPHL) or androgenic alopecia is the most common type of hair loss affecting women with reduced hair density and can have a serious psychological impact. It is characterized by progressive replacement of slow cycling terminal hair follicles by miniaturized, rapidly cycling vellus hair follicles. The frontal hair line may or may not be preserved. The aim of this review was to assess the evidence for the effectiveness and safety of the treatments available for FPHL. Searches included: Cochrane Skin Group Specialised Register, Cochrane Central Register of Controlled Clinical Trials in The Cochrane Library, MEDLINE, EMBASE, AMED, PsycINFO, LILACS and several ongoing trials registries (October 2011). Randomized controlled trials in women with FPHL were identified. Twenty-two trials, comprising 2349 participants, were included. A range of interventions was evaluated, with 10 studies examining varying concentrations of minoxidil. Pooled data from four studies indicated that a greater proportion of participants treated with minoxidil reported a moderate increase in their hair regrowth compared with placebo (relative risk 1.86, 95% confidence interval 1.42-2.43). There was no difference between the number of adverse events experienced in the twice daily minoxidil and the placebo intervention groups, except for a reported increase with minoxidil 5% twice daily. Single studies accounted for most of the other comparisons, which were assessed as either having high risk of bias and/or they did not address the prespecified outcomes for this review and provided limited evidence of either the effectiveness or safety of these interventions. Further well-designed, adequately powered randomized controlled trials investigating other treatment options are still required. PMID- 23039052 TI - An iTRAQ proteomics screen reveals the effects of the MDM2 binding ligand Nutlin 3 on cellular proteostasis. AB - Mouse double minute 2 (MDM2) participates in protein synthesis, folding, and ubiquitin-mediated degradation and is therefore a proteostasic hub protein. The MDM2 interactome contains over 100 proteins, yet stratification of dominant MDM2 interacting proteins has not been achieved. 8-plex iTRAQ (nanoLC-MS/MS) of MCF7 cells treated with the MDM2-binding ligand Nutlin-3 identified the most abundant cellular protein changes over early time points; 1,323 unique proteins were identified including 35 with altered steady-state levels within 2 h of Nutlin-3 treatment, identifying a core group of MDM2 related proteins. Six of these proteins were previously identified MDM2 interactors, and the effects of Nutlin-3 on the MDM2-nucleophosmin interaction (NPM) was further validated. This revealed that Nutlin-3 mediates the in vivo conversion of NPM from an oligomer to a monomer as an MDM2-dependent phenomenon, with Nutlin-3 stimulating MDM2 binding to a peptide motif derived from the oligomerization interface of NPM. These data form the first proteomic screen of Nutlin-3 in cells whereby we (i) identify the most abundant MDM2-interacting proteins whose steady-state levels change early after Nutlin-3 treatment; (ii) identify the first protein apart from p53, nucleophosmin (NPM), whose interaction with MDM2 can be stimulated allosterically by Nutlin-3; and (iii) raise the possibility that Nutlin-3 might act as a general agonist of other MDM2 protein-protein interactions. PMID- 23039054 TI - The securitisation of pandemic influenza: framing, security and public policy. AB - This article examines how pandemic influenza has been framed as a security issue, threatening the functioning of both state and society, and the policy responses to this framing. Pandemic influenza has long been recognised as a threat to human health. Despite this, for much of the twentieth century it was not recognised as a security threat. In the decade surrounding the new millennium, however, the disease was successfully securitised with profound implications for public policy. This article addresses the construction of pandemic influenza as a threat. Drawing on the work of the Copenhagen School, it examines how it was successfully securitised at the turn of the millennium and with what consequences for public policy. PMID- 23039055 TI - Prevalence of weight-related concerns and behaviours among New Zealand young people. AB - AIM: The study aims to describe the prevalence of weight loss behaviours and weight-related concerns among a nationally representative sample of adolescents in New Zealand. METHODS: Data for this study were collected as part of Youth'07, a nationally representative survey of the health and well-being of 9107 secondary school students in New Zealand. RESULTS: More than one third of males and 65% of females tried to lose weight in the past year. Approximately 10% of males and 29% of females reported using at least one of the unhealthy weight control behaviours in the past year (fasted, skipped meals, smoked, vomited, diet pills). Among females and males, using unhealthy weight control behaviours was most prevalent among those who were older, overweight and lived in high-deprivation areas. CONCLUSION: Unhealthy weight control behaviours among New Zealand adolescents are common and warrant future research and discussion to understand why so many young people use unhealthy weight loss strategies. PMID- 23039056 TI - Occlusal-supporting ability of individual maxillary and mandibular teeth. AB - This study aimed to analyse occlusal force, area and pressure for individual maxillary and mandibular teeth by assessing their occlusal-supporting abilities. Ninety-nine subjects (49 men and 50 women; average age, 24.7 +/- 3.4 years; range, 20-37 years) performed maximal voluntary clenching twice for 3 s in both the intercuspal position and the intercuspal position with sliding movement from edge-to-edge occlusion, with a pressure-sensitive sheet placed between the maxillary and mandibular dental arch. Occlusal force, area and pressure of individual teeth were calculated by colour development in the pressure-sensitive sheet with special analytical equipment and software. Occlusal contact condition of individual teeth was confirmed using the intra-occlusal record. All data were analysed using unpaired Student's t-test, Kruskal-Wallis test and Scheffe's test for multiple comparisons with a significance level of P < 0.05. The occlusal pressure in the intercuspal position with sliding movement from edge-to-edge occlusion was adopted as the representative occlusal-supporting ability for each individual tooth, although there were, in part, statistically significant differences in the effects of laterality, performance and gender. Overall, the occlusal pressure increased gradually from the central incisor, peaked at the canine or first premolar and decreased sharply-and significantly (P < 0.01) towards the second molar. We conclude that the occlusal pressure of individual teeth can be used as an indicator of occlusal-supporting ability. This is therefore proposed as a possible suitable parameter for epidemiologic research, specifically for verifying the relationship between occlusal-supporting ability and status of residual periodontal ligament support. PMID- 23039057 TI - Performance of titanium alloy sintered porous-surfaced (SPS) implants supporting mandibular overdentures during a 20-year prospective study. AB - OBJECTIVE: This study was undertaken to assess short, sintered porous-surfaced (SPS), press-fit implants with mandibular overdentures to restore edentulous patients with severe mandibular resorption. MATERIALS AND METHODS: Implant lengths of 7, 8, 9, and 10 mm were used, all with 2-mm polished collars, making the designed intrabony lengths 5, 6, 7, and 8 mm. Each patient received three non splinted implants placed using a two-stage protocol. RESULTS: Only 22 (with 53 implants) of the original 52 patients were available after 20 years. All but one of these patients was functioning with their implant-retained overdentures. Life table analysis accounted for all patients and implants, and showed a 20-year survival of 73.4%. Analysis of carefully standardized radiographs revealed mean cumulative bone loss after 20 years of 0.67 mm relative to the polished collar SPS junction. CONCLUSIONS: Short SPS implants with mandibular overdentures can provide an acceptable treatment over a 20-year period for fully edentulous patients with severe alveolar resorption. PMID- 23039058 TI - 'I don't want to hurt him.' Parents' experiences of learning to administer clotting factor to their child. AB - To explore the experiences and educational needs of parents learning to use an Implanted Central Venous Access Device (IVAD) to administer clotting factor to their child with haemophilia. Parents of children with haemophilia who had learnt to administer clotting factor via IVAD attended focus groups to discuss their experiences of the learning process. Data were transcribed and analyzed thematically. Parents described distress and trauma in dealing with the diagnosis and treatment of their child's haemophilia. It was within this context that parents began the IVAD education process. Four major themes emerged from the data: dealing with fear and anxiety; a supportive learning environment; establishing a ritual and empowerment and liberation. Parents identified a supportive learning environment as their critical need rather than a specific learning process. In addition, the concept of ritual emerged both as a mechanism for increasing the child's comfort with the procedure and as a valuable learning tool for their parents. This study highlights the importance of consulting consumers to understand their experience of illness and their educational needs. Patient and family education programs should not be limited to the provision of information, but must establish and incorporate the needs of the learner. PMID- 23039059 TI - Bullous pyoderma gangrenosum of the bilateral dorsal hands. AB - Pyoderma gangrenosum (PG) shows characteristic non-infectious ulcers that are commonly associated with systemic diseases such as inflammatory bowel diseases, myeloproliferative disorders or aortitis syndrome. The typical clinical appearance is undermining ulcers with reddish and irregular borders on the legs. As PG has these notable signs, the diagnosis is relatively easy and its treatment depends on the severity of underlying complications. We report a case of a 60 year-old Japanese man, diagnosed with bullous PG, who also had been suffering from myeloperoxidase antineutrophil cytoplasmic antibody-positive microscopic polyangiitis and pulmonary aspergillosis. This case displayed soft whitish ulcers that existed on the rough ulcer base, with irregular borders, on his bilateral dorsal hands. Initially, it seemed to be cutaneous secondary aspergillosis because the host was already infected with pulmonary aspergillosis in both lungs. The differential diagnosis of PG from aspergillosis was from the sterile bullae or neutrophilic bullae on his right forearm, which evolved into ulcers in a few days. This case was finally diagnosed as bullous PG and a topical glucocorticoid was very effective to epithelize the ulcers in 2-3 weeks. PMID- 23039060 TI - Tracheostomy with invasive ventilation for ALS patients: neurologists' roles in the US and Japan. AB - Our objective was to determine whether substantial differences in rates of TIV utilization in the U.S. and Japan are associated with the role of the treating neurologist. Questionnaires in English and Japanese were sent to neurologists who treated ALS patients in both countries. Questions included queries about rates of TIV use in their practices, level of encouragement of TIV use, the role of the neurologist in TIV decision making, management of patient/family requests to discontinue TIV once initiated, and personal choices if neurologists themselves had ALS. Results showed that 84% of American neurologists reported fewer than 10% of their patients had TIV, compared to 32% of Japanese. Americans less often encouraged TIV use (79% of American and 36% of Japanese seldom or never suggested or encouraged TIV). Finally, neurologists were asked whether they would choose TIV for themselves in the hypothetical scenario where they had ALS: over 70% of both groups declined TIV for themselves. In conclusion, consistent with past findings, Japanese neurologists were more likely to recommend TIV and more of their patients received TIV. Both groups believed their recommendations influence patient decisions. While Americans seldom recommended TIV to patients and most would not choose TIV for themselves, Japanese neurologists' recommendations and personal choices diverged. PMID- 23039061 TI - Methanolic extracts of Withania somnifera leaves, fruits and roots possess antioxidant properties and antibacterial activities. AB - BACKGROUND: Withania somnifera, also known as ashwagandha, is an important herb in ayurvedic and indigenous medical systems. The present study was designed to evaluate the antioxidant and antibacterial activities of an 80% aqueous methanolic extract of W. somnifera roots (WSREt), fruits (WSFEt) and leaves (WSLEt). METHODS: Several assays were performed to determine the antioxidant properties of this herb including 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging activity, ferric reducing antioxidant power (FRAP), ferrous chelation and inhibition of beta-carotene bleaching. RESULTS: The values for DPPH, FRAP, ferrous chelation and inhibition of beta carotene bleaching for the three types of extracts ranged from 101.73-801.93 MUg/ml, 2.26-3.29 mM Fe/kg, 0.22-0.65 mg/ml and 69.87-79.67%, respectively, indicating that W. somnifera, particularly the leaves, possesses significant antioxidant properties. The mean ascorbic acid content was 20.60-62.60 mg/100 g, and the mean anthocyanin content was 2.86-12.50 mg/100 g. Antibacterial activities were measured using the agar well diffusion method and five pathogenic Gram-negative bacteria: Escherichia coli, Salmonella typhi, Citrobacter freundii, Pseudomonas aeruginosa and Klebsiella pneumoniae. The leaf extracts displayed the highest activity against S. typhi (32.00 +/- 0.75 mm zone of inhibition), whereas the lowest activity was against K. pneumoniae (19.00 +/- 1.48 mm zone of inhibition). The lowest minimum inhibitory concentration value was 6.25 mg/ml, which was against S. typhi, followed by 12.5 mg/ml against E. coli. CONCLUSION: In addition to its antioxidant properties, W. somnifera exhibited significant antibacterial activities against Gram-negative bacteria, particularly S. typhi. PMID- 23039062 TI - Early-onset epileptic encephalopathy in a girl carrying a truncating mutation of the ARX gene: rethinking the ARX phenotype in females. AB - Severe early-onset epilepsy is due to a number of known causes, although a clear etiology is not identifiable in up to a third of all the cases. Pathogenic sequence variations in the ARX gene have been described almost exclusively in males, whereas heterozygous female relatives, such as mothers, sisters and even grandmothers have been largely reported as asymptomatic or mildly affected. To investigate the pathogenic role of ARX in refractory epilepsy of early onset even in females, we have screened the ARX sequence in a population of 50 female subjects affected with unexplained epileptic encephalopathy with onset in the first year of life. We report the identification of a novel truncating mutation of the coding region of the ARX gene in a girl with a structurally normal brain. Our findings confirm the role of ARX in the pathogenesis of early epilepsy and underline the importance of screening of the ARX gene in both male and female subjects with otherwise unexplained early onset epileptic encephalopathy. PMID- 23039063 TI - Protective factors in patients aged over 65 with stroke treated by physiotherapy, showing cognitive impairment, in the Valencia Community. Protection study in older people (EPACV). AB - BACKGROUND: Family function may have an influence on the mental health deterioration of the caregivers of dependent family members and it could have a varying importance on the care of dependents. Little attention has been paid to the preparation of minor stroke survivors for the recovery trajectory or the spouse for the caregiving role. Therefore, this study protocol intends to analyze the influence of family function on the protection of patients with stroke sequels needing physiotherapy in the family environment. METHODS/DESIGN: This is an analytical observational design, prospective cohort study and using a qualitative methodology by means of data collected in the "interviews of life". The study will be carried out by the Rehabilitation Service at Hospital of Elda in the Valencia Community.All patients that have been diagnosed with stroke and need physiotherapy treatment, having a dependency grade assigned and consent to participate in the study, will undergo a monitoring of one year in order to assess the predictive factors depending on the dependence of the people affected. DISCUSSION: Our research aims to analyze the perception of caregivers, their difficulties to work, and the influence of family function. Moreover, it aims to register the perception of the patients with stroke sequel over the care received and whether they feel protected in their family environment. PMID- 23039064 TI - The use of cluster and principal component analysis in the estimation of iron status in term newborns. AB - OBJECTIVE: To assess the relationship between parameters of iron homeostasis in infants and clinical features characterizing newborns and their mothers. METHODS: The goal of the present work was to determine nine iron status parameters, i.e. hepcidin, prohepcidin, soluble transferrin receptor, ferritin, total iron binding capacity, unsaturated iron binding capacity, transferrin saturation, erythropoietin and total iron concentration, in the cord blood of 57 term newborns as well as to determine the complete blood count in their mothers. Moreover, an appraisal of the relationships between all of the iron parameters, the mothers' hematological factors and 12 clinical attributes was carried out using both cluster analysis (CA) and principal component analysis (PCA). RESULTS: We found that hepcidin is not correlated with its precursor, but it is strongly positively correlated with the total iron concentration. The CA divided all of the 24 parameters into three clusters and showed that certain clinical features, e.g. the APGAR score, mother's age or parity are related to the hepcidin and prohepcidin concentration. CONCLUSION: We demonstrated that CA and PCA are efficacious methods for assessing the relationship between iron metabolism parameters in cord blood and large amounts of clinical characteristics. PMID- 23039065 TI - Scanning X-ray nanodiffraction: from the experimental approach towards spatially resolved scattering simulations. AB - : An enhancement on the method of X-ray diffraction simulations for applications using nanofocused hard X-ray beams is presented. We combine finite element method, kinematical scattering calculations, and a spot profile of the X-ray beam to simulate the diffraction of definite parts of semiconductor nanostructures. The spot profile could be acquired experimentally by X-ray ptychography. Simulation results are discussed and compared with corresponding X-ray nanodiffraction experiments on single SiGe dots and dot molecules. PMID- 23039066 TI - Effect of domain boundaries on the Raman spectra of mechanically strained graphene. AB - We investigate the effect of mechanical strain on graphene synthesized by chemical vapor deposition (CVD) transferred onto flexible polymer substrates by observing the change in the Raman spectrum and then compare this to the behavior of exfoliated graphene. Previous studies into the effect of strain on graphene have focused on mechanically exfoliated graphene, which consists of large single domains. However, for wide scale applications CVD produced films are more applicable, and these differ in morphology, instead consisting of a patchwork of smaller domains separated by domain boundaries. We find that under strain the Raman spectra of CVD graphene transferred onto a silicone elastomer exhibits unusual behavior, with the G and 2D band frequencies decreasing and increasing respectively with applied strain. This unusual Raman behavior is attributed to the presence of domain boundaries in polycrystalline graphene causing unexpected shifts in the electronic structure. This was confirmed by the lack of such behavior in mechanically exfoliated large domain graphene and also in large single-crystal graphene domains grown by CVD. Theoretical calculation of G band for a given large shear strain may explain the unexpected shifts while the shift of the Dirac points from the K point explain the conventional behavior of a 2D band under the strain. PMID- 23039067 TI - Dependence of mechanical properties of lacewing egg stalks on relative humidity. AB - Silk fibers are well known for their mechanical properties such as strength and toughness and are lightweight, making them an interesting material for a variety of applications. Silk mechanics mainly rely on the secondary structure of the underlying proteins. Lacewing egg stalk silk proteins obtain a cross-beta structure with individual beta strands aligned perpendicular to the fiber axis. This structure is in contrast with that of silks of spiders or silkworms with beta strands parallel to the fiber axis and to that of silks of honeybees with alpha helices arranged in coiled coils. On the basis of the cross-beta structure the mechanical properties of egg stalks are different from those of other silks concerning extensibility, toughness, and bending stiffness. Here we show the influence of relative humidity on the mechanical behavior of lacewing egg stalks and propose a model based on secondary structure changes to explain the differences on a molecular level. At low relative humidity, the stalks rupture at an extension of 3%, whereas at high relative humidity the stalks rupture at 434%. This dramatic increase corresponds to breakage of hydrogen bonds between the beta strands and a rearrangement thereof in a parallel-beta structure. PMID- 23039068 TI - The effect of luting cement thicknesses on the push-out bond strength of the fiber posts. AB - OBJECTIVE: The aim of this study was to evaluate the effect of luting cement thicknesses on the push-out bond strength of the fiber posts. MATERIALS AND METHODS: Sixty human maxillary canine teeth were endodontically treated. Post spaces were prepared and root specimens randomly divided into three groups: Group 1: etch-and-rinse (Variolink II/Exite DSC), Group 2: self-etch (Panavia F2.0/ED primer) and Group 3: self-adhesive (Clearfil SA Cement). Then each group was divided into four sub-groups according to the cement thickness, as follows: Sub group 1: 0.35 mm, Sub-group 2: 0.25 mm, Sub-group 3: 0.15 mm, and Sub-group 4: 0.05 mm. Three slices of 1 mm thickness were obtained from each root specimen (n = 15). Push-out tests were performed and data was analyzed with two-way ANOVA and Tukey tests. RESULTS: The etch-and-rinse system (Variolink II) had a significantly higher bond strength compared with the other systems (p < 0.05). The thickest cement group (0.35 mm) had a significantly lower bond strength compared with the 0.15 and 0.05 mm groups in the etch-and-rinse and self-adhesive groups (p < 0.05). In the self-etch group, the cement thicknesses did not significantly affect the bond strength (p > 0.05). CONCLUSIONS: The etch-and rinse system offered better bonding to root dentine than the self-adhesive and self-etch systems. The increases in cement thickness significantly reduced the bond strength of fiber posts to root dentine for both the etch-and-rinse and self adhesive systems. PMID- 23039069 TI - One-pot catalytic enantioselective synthesis of tetrahydropyridines via a nitro Mannich/hydroamination cascade. AB - The highly enantioselective preparation of synthetically useful tetrahydropyridine derivatives employing a one-pot nitro-Mannich/hydroamination cascade is reported. This approach utilizes an asymmetric organocatalytic nitro Mannich reaction followed by a gold-catalyzed alkyne hydroamination/isomerization sequence that yields the desired tetrahydropyridines in good yields and high diastereo- and enantioselectivities. PMID- 23039070 TI - Elongation and desaturation pathways in mammary gland epithelial cells are associated with modulation of fat and membrane composition. AB - The aim was to determine the relative role of each of the lactogenic hormones (insulin, prolactin and hydrocortisol) and their combinations in regulating elongation and desaturation of polyunsaturated fatty acids and subsequently on composition of cellular lipid compartments in mammary epithelia. Cultured cells of the mammary gland epithelial cell line HC11 were subjected to 48 h of hormonal treatment with different combinations of insulin, hydrocortisone and prolactin. Only the combination of all three hormones induced differentiation according to the marker beta-casein gene expression. Inclusion of insulin in the treatment medium increased total fatty acid amount by 50% and increased the concentration of monounsaturated fatty acids by 12% while decreasing that of saturated fatty acids by 35%. Changes in the levels of fatty acids by chain length and saturation paralleled mRNA expression of the desaturases and elongases, whose expression levels were regulated again by inclusion of all three hormones in the treatment medium. Gene expression levels of the Delta6 desaturase and elongase 5 genes (Elovl 5) increased by approximately 1.5-fold, whereas expression of Elovl 4 decreased in the presence of all three hormones. Insulin was the main hormone inducing compositional differences in membrane lipids, increasing phosphatidylethanolamine and phosphatidylinositol and decreasing sphingomyelin and cholesterol. The results indicate that mammary gland epithelial cells express five out of the seven known elongase subtypes which are regulated primarily by the processes of differentiation and produce major compositional changes in mammary gland epithelial cells. PMID- 23039071 TI - Key hydride vibrational modes in [NiFe] hydrogenase model compounds studied by resonance Raman spectroscopy and density functional calculations. AB - Hydrogenase proteins catalyze the reversible conversion of molecular hydrogen to protons and electrons. While many enzymatic states of the [NiFe] hydrogenase have been studied extensively, there are multiple catalytically relevant EPR-silent states that remain poorly characterized. Analysis of model compounds using new spectroscopic techniques can provide a framework for the study of these elusive states within the protein. We obtained optical absorption and resonance Raman (RR) spectra of (dppe)Ni(MU-pdt)Fe(CO)(3) and [(dppe)Ni(MU-pdt)(MU H)Fe(CO)(3)][BF(4)], which are structural and functional model compounds for the EPR-silent Ni-SI and Ni-R states of the [NiFe] hydrogenase active site. The studies presented here use RR spectroscopy to probe vibrational modes of the active site, including metal-hydride stretching vibrations along with bridging ligand-metal and Fe-CO bending vibrations, with isotopic substitution used to identify key metal-hydride modes. The metal-hydride vibrations are essentially uncoupled and represent isolated, localized stretching modes; the iron-hydride vibration occurs at 1530 cm(-1), while the nickel-hydride vibration is observed at 945 cm(-1). The significant discrepancy between the metal-hydride vibrational frequencies reflects the slight asymmetry in the metal-hydride bond lengths. Additionally, time-dependent density functional theory (TD-DFT) calculations were carried out to obtain theoretical RR spectra of these compounds. On the basis of the detailed comparison of theory and experiment, the dominant electronic transitions and significant normal modes probed in the RR experiments were assigned; the primary transitions in the visible wavelengths represent metal-to metal and metal-to-ligand charge transfer bands. Inherent properties of metal hydride vibrational modes in resonance Raman spectra and DFT calculations are discussed together with the prospects of observing such vibrational modes in metal-hydride-containing proteins. Such a combined theoretical and experimental approach may be valuable for characterization of analogous redox states in the [NiFe] hydrogenases. PMID- 23039072 TI - Can live xPlane imaging of the in-plane view of interventricular septum be used to detect fetal conotruncal anomalies? AB - OBJECTIVE: To evaluate the feasibility of live xPlane imaging visualizing the in plane view of IVS in the screening of the fetal conotruncal anomalies. METHOD: One hundred and fifty-two consecutive normal singleton fetuses and forty-eight fetal cardiac defects (27 conotruncal and 21 non-conotruncal cases), were enrolled in this study. The in-plane view of IVS was firstly acquired with live xPlane imaging and then judged whether it is normal or not by one operator. The focus was put on observing the relationship of pulmonary artery and aorta. The comparison between conotruncal and non-conotruncal anomalies in demonstrating the relationship of pulmonary artery and aorta was performed. RESULT: There were 27 cases of conotruncal anomalies enrolled in this study and 19 cases (70.4%) had the abnormal relationship of aorta and pulmonary artery in the in-plane view of IVS. In 21 cases of non-conotruncal CHDs, however, there were only 5 cases (23.8%) had the abnormal relationship in the in-plane view of IVS (p < 0.001). CONCLUSION: Live xPlane imaging of the in-plane view of IVS is feasible to detect the fetal conotruncal anomalies, which may potentially be a useful tool for the non-experienced operators to screen the fetal conotruncal anomalies. PMID- 23039073 TI - Total synthesis of (-)-tirandamycin C utilizing a desymmetrization protocol. AB - A highly stereoselective total synthesis of (-)-tirandamycin C has been achieved following a desymmetrization protocol developed in our group, Horner-Wadsworth Emmons olefination, acid-catalyzed ketalization, Still-Gennari (Z)-selective olefination, and Dieckmann cyclization as key reactions. PMID- 23039074 TI - Haemophilia & Exercise Project (HEP): the impact of 1-year sports therapy programme on physical performance in adult haemophilia patients. AB - Episodes of bleeding in people with haemophilia (PWH) are associated with reduced activity and limitations in physical performance. Within the scope of the 'Haemophilia & Exercise Project' (HEP) PWH were trained in a sports therapy programme. Aim of this study was to investigate subjective and objective physical performance in HEP-participants after 1 year training. Physical performance of 48 adult PWH was compared before and after sports therapy subjectively (HEP-Test-Q) and objectively regarding mobility (range of motion), strength and coordination (one-leg-stand) and endurance (12-min walk test). Sports therapy included an independent home training that had previously been trained in several collective sports camps. Forty-three controls without haemophilia and without training were compared to PWH. Of 48 PWH, 13 performed a regular training (active PWH); 12 HEP participants were constantly passive (passive PWH). Twenty-three PWH and 24 controls dropped out because of incomplete data. The activity level increased by 100% in active PWH and remained constant in passive PWH, and in controls (P <= 0.05). Only mobility of the right knee was significantly improved in active PWH (+5.8 +/- 5.3 degrees ) compared to passive PWH (-1.3 +/- 8.6 degrees ). The 12 min walk test proved a longer walking distance for active PWH (+217 +/- 199 m) compared to controls (-32 +/- 217 m). Active PWH reported a better subjective physical performance in the HEP-Test-Q domains 'strength & coordination', 'endurance' and in the total score (+9.4 +/- 13.8) compared to passive PWH (-5.3 +/- 13.5) and controls (+3.7 +/- 7.5). The 'mobility'-scale and one-leg-stand remained unchanged. Sports therapy increases the activity level and physical performance of PWH, whereby objective effects do not always correspond with subjective assessments. PMID- 23039075 TI - Premedication for neonatal intubation in Australia and New Zealand: a survey of current practice. AB - AIM: This study aims to describe the current approach to intubation premedication in neonatal intensive care units (NICUs) in Australia and New Zealand. METHODS: A literature review regarding intubation premedication in the newborn was carried out to inform questionnaire design. A web-based survey of 28 NICUs and two neonatal emergency transport services was conducted and supplemented by telephone contact to ensure completion. RESULTS: All the tertiary NICUs and neonatal emergency transport services in Australia and New Zealand use premedication for elective intubation of neonates. Eighty per cent of units have a written policy. There were 28 of 30 units (93%) that use muscle relaxants, mostly suxamethonium. The choice of sedative medication is varied. CONCLUSIONS: Australian and New Zealand neonatal units have a high use of intubation premedication including muscle relaxants, but vary considerably in their choice of sedative medication. PMID- 23039076 TI - Bone tissue response to implant surfaces functionalized with phosphate-containing polymers. AB - OBJECTIVES: Inorganic polyphosphates are said to stimulate the activity of osteoblast-like cells in vitro. The purpose of this study was to evaluate in vivo bone regeneration around implants treated with polyphosphoric acid (PPA) and phosphorylated pullulan (PPL). MATERIAL AND METHODS: Two types of implants with different surface roughness (R1: Sa ~ 0.23 MUm; R2: Sa ~ 1.35 MUm) were treated with three solutions (distilled water, 10%wt PPA, or 10%wt PPL) prior to implantation in both tibia of twelve female white rabbits. Each animal received six implants randomly positioned according to their surface roughness and treatment: R1 + water; R1 + PPA; R1 + PPL; R2 + water; R2 + PPA; R2 + PPL. Animals were sacrificed after 1 or 4 weeks, and samples were prepared for histological and histomorphometrical analysis. Bone regeneration areas were evaluated for bone-to-implant contact (BIC) and bone fraction (BF) in areas 100 and 500 MUm remote from the implant surface. Data were statistically analyzed by means of Friedman and Wilcoxon matched-pair tests (P < 0.05). RESULTS: After 1 week, bone tissue was rarely formed in the regeneration areas. After 4 weeks, implants treated with PPA presented higher ratios of BIC (R1 = 52.3 +/- 13.1; R2 = 54.6 +/- 11.0) than the ones treated with water (R1 = 24.1 +/- 15.1; R2 = 32.4 +/- 13.0). On the other hand, around the implant surface (100 MUm), PPL-treated implants induced higher BF (R1 = 78.3 +/- 34.1; R2 = 71.2 +/- 21.8) as compared with the water-treated ones (R1 = 46.1 +/- 22.0; R2 = 49.6 +/- 21.0). At 500 MUm, however, no statistically significant differences in BF were found among the groups evaluated (P > 0.05). Surface roughness influenced neither BIC nor BF. CONCLUSIONS: Implant surface treatment with phosphate-containing polymers may positively influence osseointegration. PMID- 23039077 TI - Exploring inhibition of Pdx1, a component of the PLP synthase complex of the human malaria parasite Plasmodium falciparum. AB - Malaria tropica is a devastating infectious disease caused by Plasmodium falciparum. This parasite synthesizes vitamin B6 de novo via the PLP (pyridoxal 5'-phosphate) synthase enzymatic complex consisting of PfPdx1 and PfPdx2 proteins. Biosynthesis of PLP is largely performed by PfPdx1, ammonia provided by PfPdx2 subunits is condensed together with R5P (D-ribose 5-phosphate) and G3P (DL glyceraldehyde 3-phosphate). PfPdx1 accommodates both the R5P and G3P substrates and intricately co-ordinates the reaction mechanism, which is composed of a series of imine bond formations, leading to the production of PLP. We demonstrate that E4P (D-erythrose 4-phosphate) inhibits PfPdx1 in a dose-dependent manner. We propose that the acyclic phospho-sugar E4P, with a C1 aldehyde group similar to acyclic R5P, could interfere with R5P imine bond formations in the PfPdx1 reaction mechanism. Molecular docking and subsequent screening identified the E4P hydrazide analogue 4PEHz (4-phospho-D-erythronhydrazide), which selectively inhibited PfPdx1 with an IC50 of 43 MUM. PfPdx1 contained in the heteromeric PLP synthase complex was shown to be more sensitive to 4PEHz and was inhibited with an IC50 of 16 MUM. Moreover, the compound had an IC50 value of 10 MUM against cultured P. falciparum intraerythrocytic parasites. To analyse further the selectivity of 4PEHz, transgenic cell lines overexpressing PfPdx1 and PfPdx2 showed that additional copies of the protein complex conferred protection against 4PEHz, indicating that the PLP synthase is directly affected by 4PEHz in vivo. These PfPdx1 inhibitors represent novel lead scaffolds which are capable of targeting PLP biosynthesis, and we propose this as a viable strategy for the development of new therapeutics against malaria. PMID- 23039078 TI - Incidence of beta-thalassemia carrier on 1495 couples in preconceptional period. AB - OBJECTIVE: This research, conducted on 1495 couples in preconceptional period, demonstrates how the study of globular resistance of erythrocytes (GRO) is not a first choice test and not useful as other more accurate tests to identify subjects with beta-thalassemia trait. Instead, the complete blood count (CBC) and the evaluation of HbA, HbA2 and HbF by high pressure liquid chromatography (HPLC) are essential. METHODS: Each couple arrived in our laboratory to screen for beta thalassemia. In case of patients with positive (240) or doubtful (112) results, we studied beta-globin gene. RESULTS: Of the 2990 subjects examined, we found 280 subjects with beta-thalassemia trait (9.36%). During biochemical tests, among 112 subjects with doubtful--normal GRO or altered GRO--results, 40 of them resulted positive for the molecular analysis, while 72 of them did not show mutations in beta-globin genes. The 2710 samples with non-carriers of beta-thalassemia trait presented as mean evaluation of HbA2 2.6%, while the 280 subjects with beta thalassemia trait presented as mean evaluation of HbA2 4.8%. Molecular study showed that the beta thalassemia phenotype is caused by a small number of mutations, whose regional distribution is typical. CONCLUSIONS: In the presence of thalassemic parameters in the CBC, the accurate and precise quantification of hemoglobin HbA2 is essential for the diagnosis of beta-thalassemia trait. DNA mutation analysis provides the most effective way to detect primary gene mutations. The mutations identified in this work can be identified with a simple and inexpensive kit. This means, in economic terms, a significant savings for health spending. PMID- 23039079 TI - Potent alpha-glucosidase and alpha-amylase inhibitory activities of standardized 50% ethanolic extracts and sinensetin from Orthosiphon stamineus Benth as anti diabetic mechanism. AB - BACKGROUND: In the present study, we tested a 50% ethanolic extract of Orthosiphon stamineus plants and its isolated bioactive compound with respect to their alpha-glucosidase and alpha-amylase inhibitory activities. METHODS: Bioactive flavonoid sinensetin was isolated from 50% ethanolic extract of Orthosiphon stamineus. The structure of this pure compound was determined on the NMR data and the alpha-glucosidase and alpha-amylase inhibitory activities of isolated sinensetin and 50% ethanolic extract of Orthosiphon stamineus were evaluated. RESULTS: In vitro studies of a 50% ethanolic extract of O. stamineus and the isolated sinensetin compound showed inhibitory activity on alpha glucosidase (IC50: 4.63 and 0.66 mg/ml, respectively) and alpha-amylase (IC50: 36.70 mg/ml and 1.13 mg/ml, respectively). Inhibition of these enzymes provides a strong biochemical basis for the management of type 2 diabetes via the control of glucose absorption. CONCLUSION: Alpha-glucosidase and alpha-amylase inhibition could the mechanisms through which the 50% ethanolic extract of O. stamineus and sinensetin exert their antidiabetic activity, indicating that it could have potential use in the management of non-insulin-dependent diabetes. PMID- 23039080 TI - Studying the flow dynamics of a karst aquifer system with an equivalent porous medium model. AB - The modeling of groundwater flow in karst aquifers is a challenge due to the extreme heterogeneity of its hydraulic parameters and the duality in their discharge behavior, that is, rapid response of highly conductive karst conduits and delayed drainage of the low-permeability fractured matrix after recharge events. There are a number of different modeling approaches for the simulation of the karst groundwater dynamics, applicable to different aquifer as well as modeling problem types, ranging from continuum models to double continuum models to discrete and hybrid models. This study presents the application of an equivalent porous model approach (EPM, single continuum model) to construct a steady-state numerical flow model for an important karst aquifer, that is, the Western Mountain Aquifer Basin (WMAB), shared by Israel and the West-Bank, using MODFLOW2000. The WMAB was used as a catchment since it is a well-constrained catchment with well-defined recharge and discharge components and therefore allows a control on the modeling approach, a very rare opportunity for karst aquifer modeling. The model demonstrates the applicability of equivalent porous medium models for the simulation of karst systems, despite their large contrast in hydraulic conductivities. As long as the simulated saturated volume is large enough to average out the local influence of karst conduits and as long as transport velocities are not an issue, EPM models excellently simulate the observed head distribution. The model serves as a starting basis that will be used as a reference for developing a long-term dynamic model for the WMAB, starting from the pre-development period (i.e., 1940s) up to date. PMID- 23039081 TI - Role of Helicobacter pylori in common rosacea subtypes: a genotypic comparative study of Egyptian patients. AB - Helicobacter pylori was incriminated as an etiological factor of rosacea. However, there is still controversy about this association. We conducted a comparative study in order to assess the role of H. pylori in rosacea patients who had dyspeptic symptoms. The study included 68 patients and 54 controls. Screening for H. pylori was performed and positive cases were referred for gastric endoscopy. The inflammatory response and bacterial density were evaluated in gastric biopsy. H. pylori vacA alleles, cagA and iceA genotypes were assessed by polymerase chain reaction. We found that 49 rosacea (72%) and 25 controls (46.3%) were infected with H. pylori. Thirty-one rosacea cases were papulopustular (PPR) while 18 were erythematotelangiectatic (ETR). Gastric ulceration was higher in PPR cases (38.7%) than ETR (11.1%) and controls (12%). A significant inflammatory reaction was observed more in PPR cases (74.2%) compared with 44.4% in ETR (P = 0.04) and 44% in controls (P = 0.02). Analysis of H. pylori genotypes revealed that vacA s1m1 was more identified in PPR cases (54.8%) compared with 22.2% in ETR (P = 0.03) and 16% in controls (P = 0.003). There was a significant elevation of cagA/vacA s1m1 positivity in PPR cases. After the eradication regimen of H. pylori, a significant improvement (P < 0.05) was observed in 15 out of 27 PPR cases (55.6%) compared with three out of 17 ETR (17.6%). We concluded that H. pylori has a significant role in rosacea patients who had dyspeptic symptoms. The PPR type is more influenced by H. pylori and this is regarded as being because of certain virulent strains that increase the inflammatory response in gastric mucosa and also in cutaneous lesions. PMID- 23039082 TI - Conosilane A, an unprecedented sesquiterpene from the cultures of basidiomycete Conocybe siliginea. AB - Conosilane A (1), a novel sesquiterpene with an unprecedented carbon skeleton, was isolated from the cultures of the basidiomycete Conocybe siliginea. Its structure was elucidated by extensive spectroscopic methods, and the absolute configuration was determined by single crystal X-ray diffraction analysis. Conosilane A was found to inhibit 11beta-hydroxysteroid dehydrogenase significantly. PMID- 23039083 TI - Ferroelectric control of magnetocrystalline anisotropy at cobalt/poly(vinylidene fluoride) interfaces. AB - Electric field control of magnetization is one of the promising avenues for achieving high-density energy-efficient magnetic data storage. Ferroelectric materials can be especially useful for that purpose as a source of very large switchable electric fields when interfaced with a ferromagnet. Organic ferroelectrics, such as poly(vinylidene fluoride) (PVDF), have an additional advantage of being weakly bonded to the ferromagnet, thus minimizing undesirable effects such as interface chemical modification and/or strain coupling. In this work we use first-principles density functional calculations of Co/PVDF heterostructures to demonstrate the effect of ferroelectric polarization of PVDF on the interface magnetocrystalline anisotropy that controls the magnetization orientation. We show that switching of the polarization direction alters the magnetocrystalline anisotropy energy of the adjacent Co layer by about 50%, driven by the modification of the screening charge induced by ferroelectric polarization. The effect is reduced with Co oxidation at the interface due to quenching the interface magnetization. Our results provide a new insight into the mechanism of the magnetoelectric coupling at organic ferroelectric/ferromagnet interfaces and suggest ways to achieve the desired functionality in practice. PMID- 23039084 TI - Thermal conductivity in porous silicon nanowire arrays. AB - The nanoscale features in silicon nanowires (SiNWs) can suppress phonon propagation and strongly reduce their thermal conductivities compared to the bulk value. This work measures the thermal conductivity along the axial direction of SiNW arrays with varying nanowire diameters, doping concentrations, surface roughness, and internal porosities using nanosecond transient thermoreflectance. For SiNWs with diameters larger than the phonon mean free path, porosity substantially reduces the thermal conductivity, yielding thermal conductivities as low as 1 W/m/K in highly porous SiNWs. However, when the SiNW diameter is below the phonon mean free path, both the internal porosity and the diameter significantly contribute to phonon scattering and lead to reduced thermal conductivity of the SiNWs. PMID- 23039085 TI - A systematic review of school-based alcohol and other drug prevention programs facilitated by computers or the internet. AB - ISSUES: The use of alcohol and drugs amongst young people is a serious concern and the need for effective prevention is clear. This paper identifies and describes current school-based alcohol and other drug prevention programs facilitated by computers or the Internet. APPROACH: The Cochrane Library, PsycINFO and PubMed databases were searched in March 2012. Additional materials were obtained from reference lists of papers. Studies were included if they described an Internet- or computer-based prevention program for alcohol or other drugs delivered in schools. KEY FINDINGS: Twelve trials of 10 programs were identified. Seven trials evaluated Internet-based programs and five delivered an intervention via CD-ROM. The interventions targeted alcohol, cannabis and tobacco. Data to calculate effect size and odds ratios were unavailable for three programs. Of the seven programs with available data, six achieved reductions in alcohol, cannabis or tobacco use at post intervention and/or follow up. Two interventions were associated with decreased intentions to use tobacco, and two significantly increased alcohol and drug-related knowledge. CONCLUSION: This is the first study to review the efficacy of school-based drug and alcohol prevention programs delivered online or via computers. Findings indicate that existing computer- and Internet-based prevention programs in schools have the potential to reduce alcohol and other drug use as well as intentions to use substances in the future. These findings, together with the implementation advantages and high fidelity associated with new technology, suggest that programs facilitated by computers and the Internet offer a promising delivery method for school-based prevention. PMID- 23039086 TI - Direct determination of sugar cane quality parameters by X-ray spectrometry and multivariate analysis. AB - Current methods for quality control of sugar cane are performed in extracted juice using several methodologies, often requiring appreciable time and chemicals (eventually toxic), making the methods not green and expensive. The present study proposes the use of X-ray spectrometry together with chemometric methods as an innovative and alternative technique for determining sugar cane quality parameters, specifically sucrose concentration, POL, and fiber content. Measurements in stem, leaf, and juice were performed, and those applied directly in stem provided the best results. Prediction models for sugar cane stem determinations with a single 60 s irradiation using portable X-ray fluorescence equipment allows estimating the % sucrose, % fiber, and POL simultaneously. Average relative deviations in the prediction step of around 8% are acceptable if considering that field measurements were done. These results may indicate the best period to cut a particular crop as well as for evaluating the quality of sugar cane for the sugar and alcohol industries. PMID- 23039087 TI - Dendritic spine density is altered in a mouse model of Cockayne syndrome. PMID- 23039089 TI - Spatial gene expression quantification: a tool for analysis of in situ hybridizations in sea anemone Nematostella vectensis. AB - BACKGROUND: Spatial gene expression quantification is required for modeling gene regulation in developing organisms. The fruit fly Drosophila melanogaster is the model system most widely applied for spatial gene expression analysis due to its unique embryonic properties: the shape does not change significantly during its early cleavage cycles and most genes are differentially expressed along a straight axis. This system of development is quite exceptional in the animal kingdom.In the sea anemone Nematostella vectensis the embryo changes its shape during early development; there are cell divisions and cell movement, like in most other metazoans. Nematostella is an attractive case study for spatial gene expression since its transparent body wall makes it accessible to various imaging techniques. FINDINGS: Our new quantification method produces standardized gene expression profiles from raw or annotated Nematostella in situ hybridizations by measuring the expression intensity along its cell layer. The procedure is based on digital morphologies derived from high-resolution fluorescence pictures. Additionally, complete descriptions of nonsymmetric expression patterns have been constructed by transforming the gene expression images into a three-dimensional representation. CONCLUSIONS: We created a standard format for gene expression data, which enables quantitative analysis of in situ hybridizations from embryos with various shapes in different developmental stages. The obtained expression profiles are suitable as input for optimization of gene regulatory network models, and for correlation analysis of genes from dissimilar Nematostella morphologies. This approach is potentially applicable to many other metazoan model organisms and may also be suitable for processing data from three dimensional imaging techniques. PMID- 23039088 TI - Topiramate's effects on cocaine-induced subjective mood, craving and preference for money over drug taking. AB - Topiramate, presumably through antagonism of excitatory glutaminergic pathways and facilitation of inhibitory gamma-aminobutyric acid neurons in the cortico mesolimbic system, might reduce cocaine's abuse liability. We tested whether topiramate (100 mg twice daily) would reduce the euphoria, subjective mood, craving and preference for cocaine over money induced by low and high doses (0.325 and 0.65 mg/kg i.v., respectively) of experimentally administered cocaine in 24 male and female, cocaine-dependent, non-treatment-seeking research volunteers in a university in-patient laboratory. We utilized a randomized, double-blind, placebo-controlled, within-subject, Latin-square cross-over design in which three experimental challenge doses of low-dose cocaine, high-dose cocaine and placebo were administered in counterbalanced order after 5 days of topiramate or matching placebo pre-treatments separated by a 1-week washout period (2006-2009). After placebo pre-treatments, cocaine produced dose-related increases in euphoria, stimulant effects, craving for more cocaine and monetary value of cocaine in a behavioral preference test of cocaine versus money choice. Topiramate pre-treatment reduced the cocaine-related craving and monetary value of high-dose cocaine while increasing the monetary value, euphoria and stimulant effects of low-dose cocaine. Validated and standardized human experimental methods evaluating the potential for topiramate to alter cocaine's abuse liability suggest that topiramate may reduce the reinforcing effects and craving induced by higher cocaine doses. Low-dose cocaine might appear to have some enhancement of its stimulant properties in the presence of topiramate's prominent sedative effects. PMID- 23039090 TI - Bilayer Mott system based on Ni(dmit)2 (dmit = 1,3-dithiole-2-thione-4,5 dithiolate) anion radicals: two isostructural salts exhibit contrasting magnetic behavior. AB - A new class of Ni(dmit)(2) anion radical salt (Et-2,5-DBrP)[Ni(dmit)(2)](2) (1) (Et-2,5-DBrP = ethyl-2,5-dibromopyridinium) was developed. Single-crystal X-ray diffraction analysis indicates that this salt contains two crystallographically independent anion layers in the crystal with effective Br...S halogen bonds between the cation and the anion. The crystal and electronic structures, and electrical and magnetic measurements reveal that 1 is a novel bilayer Mott system, in which two different Mott-insulating anion layers coexist in one crystal. Selective halogen substitution of Br with I at the 2-position in the cation affords the isostructural bilayer salt (Et-2I-5BrP)[Ni(dmit)(2)](2) (2) (Et-2I-5BrP = ethyl-2-iodo-5-bromopyridinium), while substitution at the 5 position results in a structural change, yielding the monolayer salt (Et-2Br 5IP)[Ni(dmit)(2)](2) (3) (Et-2Br-5IP = ethyl-2-bromo-5-iodopyridinium). These results indicate that the halogen bond plays an important role to realize the bilayer system, and that the crystal structure is controlled by tuning the strength of the halogen bond. The low temperature magnetic properties of the two isostructural salts 1 and 2 are significantly different, because they are affected by fluctuated spins that do not participate in the formation of short range antiferromagnetic domains. The bilayer salt generates the fluctuated spins more easily than conventional monolayer salts, and such fluctuated spins are expected to result in unique physical properties. PMID- 23039091 TI - Keratolysis exfoliativa (dyshidrosis lamellosa sicca): a distinct peeling entity. AB - BACKGROUND: Keratolysis exfoliativa (KE), also known as dyshidrosis lamellosa sicca, is a palmoplantar dermatosis characterized by air-filled blisters and collarette desquamation. It has been regarded as a subtype of dyshidrotic eczema, a fungal infection or a dermatophytid reaction. KE may also resemble acral peeling skin syndrome and localized epidermolysis bullosa simplex. Although KE is a common disorder, it is a rarely reported and is an under-recognized dermatosis. OBJECTIVES: To delineate the characteristic features of KE. METHODS: We investigated the clinical, immunohistopathological, ultrastructural and molecular features of KE. Patients were included from the clinical records. Additional diagnostic research consisted of mutation analysis of the candidate genes TGM5, KRT5, KRT14, FLG, SPINK6 and SPINK9. RESULTS: A total of 24 patients with KE were identified, six with familial and 18 with sporadic KE. Lesions consisted of air filled blisters only on palmoplantar skin, followed by collarette and lamellar peeling. Both light microscopy and electron microscopy showed cleavage and partially degraded corneodesmosomes within the stratum corneum, whereas immunofluorescence microscopy showed normal expression of corneodesmosomal components. No mutations were found in TGM5, KRT5/14 and SPINK6/9. There was no clear link with atopy or with FLG mutations. CONCLUSIONS: Our study suggests premature corneodesmolysis as the main pathological mechanism of this palmoplantar skin disorder. We conclude that KE appears to be a distinct peeling entity. PMID- 23039092 TI - Feto-placental nitric oxide, asymmetric dimethylarginine and vascular endothelial growth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia. AB - OBJECTIVE: To measure plasma nitric oxide (NO), asymmetric dimethylarginine (ADMA) and vascular endothelial growth factor (VEGF) levels and VEGF gene polymorphisms in fetal circulation in severe preeclampsia. METHODS: Cord vessels of singleton gestations complicated with severe preeclampsia 36 weeks or more (n = 31) and controls were sampled upon delivery for analyte measuring. Additionally, DNA was extracted from umbilical vein whole blood to determine the frequency of VEGF gene single nucleotide polymorphisms (SNPs): -2578 A/C, -1498 C/T, -1154 A/G, -634 C/G and +936 C/T. Coefficient correlations between analyte levels and placental and neonatal weight were calculated. RESULTS: NO plasma levels in umbilical vessels (artery and vein) were significantly higher in preeclampsia cases as compared to controls (4.67 +/- 3.0 vs. 0.82 +/- 0.90; 4.46 +/- 3.0 vs. 0.82 +/- 0.99 mmol/L, respectively, p = 0.0001 both). ADMA levels displayed a similar increased trend in both fetal vessels, but this did not reach statistical significance (2.57 +/- 1.03 vs. 2.34 +/- 0.57; 2.74 +/- 0.94 vs. 2.42 +/- 0.59 mmol/L, respectively, p > 0.05). VEGF was significantly lower in artery but not in vein in preeclampsia cases (200.48 +/- 225.62 vs. 338.61 +/- 287.03 pg/mL, p = 0.04). A significant positive correlation was found between NO and ADMA levels (artery and vein) among preeclampsia cases. Overall, the frequency of the studied VEGF gene SNPs did not differ among pre-eclamptic cases and controls; nevertheless, a significant trend toward lower umbilical vein VEGF levels was observed in pre-eclampsia cases in the presence of -2578 CC and -1154 AG genotypes. CONCLUSION: Near term gestations complicated with severe preeclampsia presented higher NO levels in fetal circulation, which correlated to ADMA and lower artery VEGF values. More research is warranted to confirm that selected VEGF SNPs may be associated with lower umbilical vein VEGF. PMID- 23039093 TI - Gestational diabetes mellitus and pregnancy outcomes among Chinese and South Asian women in Canada. AB - OBJECTIVE: To determine the association between Chinese or South Asian ethnicity and adverse neonatal and maternal outcomes for women with gestational diabetes compared to the general population. METHODS: A cohort study was conducted using population-based health care databases in Ontario, Canada. All 35,577 women aged 15-49 with gestational diabetes who had live births between April 2002 and March 2011 were identified. Their delivery hospitalization records and the birth records of their neonates were examined to identify adverse neonatal outcomes and adverse maternal outcomes. RESULTS: Compared to infants of mothers from the general population (55.5%), infants of Chinese mothers had a lower risk of an adverse outcome at delivery (42.9%, adjusted odds ratio 0.63, 95% confidence interval 0.58-0.68), whereas infants of South Asian mothers had a higher risk (58.9%, adjusted odds ratio 1.15, 95% confidence interval 1.07-1.23). Chinese women also had a lower risk of adverse maternal outcomes (32.4%, adjusted odds ratio 0.58, 95% confidence interval 0.54-0.63) compared to general population women (41.2%), whereas the risk for South Asian women was not different (39.4%, adjusted odds ratio 0.94, 95% confidence interval 0.88-1.02) from that of general population women. CONCLUSIONS: The risk of complications of gestational diabetes differs significantly between Chinese and South Asian patients and the general population in Ontario. Tailored interventions for gestational diabetes management may be required to improve pregnancy outcomes in high-risk ethnic groups. PMID- 23039094 TI - Southern ocean biogeography of tintinnid ciliates of the marine plankton. AB - Ciliate microzooplankton are important grazers in most pelagic ecosystems and among them, tintinnids, with their largely species-specific loricas, allow relatively easy assessment of questions of diversity and distributions. Herein, we present the results of a survey of species records of tintinnids from the Southern Ocean (locations below 40 degrees S) reported in 56 publications yielding 2,047 species records (synonyms included) from 402 locations. The 192 species reported can be parsed into two main groups: 32 endemic Southern Ocean species, known only from 40 degrees S and further south, and a second group of 181 widespread species, forms with extensive geographic ranges extending into the Southern Ocean. Widespread species reported from the Southern Ocean can be further divided into a group of 81 species, each recorded multiple times in the Southern Ocean waters and 70 apparent "stray" species which have only been found but once. The endemic and widespread species of the Southern Ocean show both distinct distributional patterns and morphological differences. The assemblage of Southern Ocean endemics is found mostly within the Antarctic zone delimited by the average location of the Polar Front and contains a relatively large portion of wide-mouthed forms. We give suggestions for future study. PMID- 23039095 TI - Biomechanical determinants of oxygen extraction during cross-country skiing. AB - To determine the relationship of muscle activation, force production, and cycle characteristics to O(2) extraction during high- and lower-intensity double poling (DP), nine well-trained male cross-country skiers performed DP on a treadmill for 3 min at 90% VO(2peak) followed by 6 min at 70%. During the final minute at each workload, arterial, femoral, and subclavian venous blood were collected for determination of partial pressure of O(2), partial pressure of CO(2), pH, and lactate. Electromyography (EMG) was recorded from six upper and lower body muscles, leg and pole forces were measured, and cardiorespiratory variables were monitored continuously. O(2) extraction was associated with time point of peak pole force (PF(peak)), duration of recovery, EMG activity, and lower body use. Arm O(2) extraction was lower than in the legs at both intensities (P < 0.001) and was reduced to a lesser extent upon decreasing the workload (P < 0.05). Arm root-mean-square EMG was higher during the poling phase and entire cycle compared with the legs (P < 0.001). Blood lactate was higher in the subclavian than in femoral vein and artery (P < 0.001) and independent of intensity. O(2) extraction was correlated to low muscle activation, later PF(peak) , prolonged poling time, and extensive dynamic lower body use. Cycle rate and recovery time were associated with O(2) extraction during high-intensity exercise only. PMID- 23039096 TI - Total synthesis and structural revision of lucentamycin A. AB - Lucentamycin A is a marine-derived peptide natural product harboring a unique 4 ethylidene-3-methylproline (Emp) subunit. The proposed structure of lucentamycin A and the core Emp residue have recently been called into question through synthesis. Here, we report the first total synthesis of lucentamycin A, which confirms that the ethylidene substituent in Emp bears an E geometry, in contrast to the originally assigned Z configuration. Synthesis of the desired (E)-Emp subunit required the implementation of a novel strategy starting from Garner's aldehyde. PMID- 23039097 TI - Multiple well systems with non-Darcy flow. AB - Optimization of groundwater and other subsurface resources requires analysis of multiple-well systems. The usual modeling approach is to apply a linear flow equation (e.g., Darcy's law in confined aquifers). In such conditions, the composite response of a system of wells can be determined by summating responses of the individual wells (the principle of superposition). However, if the flow velocity increases, the nonlinear losses become important in the near-well region and the principle of superposition is no longer valid. This article presents an alternative method for applying analytical solutions of non-Darcy flow for a single- to multiple-well systems. The method focuses on the response of the central injection well located in an array of equally spaced wells, as it is the well that exhibits the highest pressure change within the system. This critical well can be represented as a single well situated in the center of a closed square domain, the width of which is equal to the well spacing. It is hypothesized that a single well situated in a circular region of the equivalent plan area adequately represents such a system. A test case is presented and compared with a finite-difference solution for the original problem, assuming that the flow is governed by the nonlinear Forchheimer equation. PMID- 23039098 TI - Modernising the regulation of medical migration: moving from national monopolies to international markets. AB - BACKGROUND: Traditional top-down national regulation of internationally mobile doctors and nurses is fast being rendered obsolete by the speed of globalisation and digitisation. Here we propose a bottom-up system in which responsibility for hiring and accrediting overseas staff begins to be shared by medical employers, managers, and insurers. DISCUSSION: In this model, professional Boards would retain authority for disciplinary proceedings in response to local complaints, but would lose their present power of veto over foreign practitioners recruited by employers who have independently evaluated and approved such candidates' ability. Evaluations of this kind could be facilitated by globally accessible National Registers of professional work and conduct. A decentralised system of this kind could also dispense with time-consuming national oversight of continuing professional education and license revalidation, which tasks could be replaced over time by tighter institutional audit supported by stronger powers to terminate underperforming employees. SUMMARY: Market forces based on the reputation (and, hence, financial and political viability) of employers and institutions could continue to ensure patient safety in the future, while at the same time improving both national system efficiency and international professional mobility. PMID- 23039099 TI - Multiplicative synergistic risk of hepatocellular carcinoma development among hepatitis B and C co-infected subjects in HBV endemic area: a community-based cohort study. AB - BACKGROUND: There has been limited study on the effect of infection with different hepatitis C virus (HCV) genotypes on the risk of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) endemic regions of Asia. METHODS: Hazard ratios of HCC development were estimated for HBV and HCV co-infected subjects among a community-based prospective cohort. HCV genotype was determined in HCV RNA-positive samples. Incident HCC cases were identified through linkage to the cancer registry. RESULTS: HCC incidence was 79 per 100,000 person-years in the study population (50 incident cases among 6,694 individuals within 63,170 person-years with an average of 9.4 years of follow-up); seroprevalence of HBsAg and anti-HCV was 5.2% and 5.6%. Adjusted hazard ratios of HCC by HBsAg positivity and anti-HCV positivity were 13.3 (CI: 7.3-24.4) and 6.7 (CI: 3.6-12.6). HRs of HBV and HCV monoinfection, and HBV/HCV coinfection were 17.1 (CI: 8.4-34.8), 10.4 (CI: 4.9-22.1) and 115.0 (CI: 32.5-407.3). Multiplicative synergistic effect of HBV/HCV coinfection on HCC risk was also observed (synergy index: 4.5, CI: 1.3 15.5). Infection with HCV genotype 1 (HR: 29.7, CI: 13.6-46.8) and mixed infection with genotype 1 and 2 (HR: 68.7, CI: 16.4-288.4) significantly elevated HCC risk, much higher than HBV infection. CONCLUSIONS: The effect of differences in HCV genotype and the multiplicative synergistic effect of HBV/HCV coinfection on HCC risk shown in the present study underline the need for comprehensive identification of hepatitis infection status in order to prevent and control HCC in this HBV endemic area. PMID- 23039100 TI - Calmodulin-related CML24 interacts with ATG4b and affects autophagy progression in Arabidopsis. AB - Plants encounter environmental stress challenges that are distinct from those of other eukaryotes because of their relative immobility. Therefore, plants may have evolved distinct regulatory mechanisms for conserved cellular functions. Plants, like other eukaryotes, share aspects of both calcium- and calmodulin-based cellular signaling and the autophagic process of cellular renewal. Here, we report a novel function for an Arabidopsis calmodulin-related protein, CML24, and insight into ATG4-regulated autophagy. CML24 interacts with ATG4b in yeast two hybrid, in vitro pull-down and transient tobacco cell transformation assays. Mutants with missense mutations in CML24 have aberrant ATG4 activity patterns in in vitro extract assays, altered ATG8 accumulation levels, an altered pattern of GFP-ATG8-decorated cellular structures, and altered recovery from darkness induced starvation. Together, these results support the conclusion that CML24 affects autophagy progression through interactions with ATG4. PMID- 23039101 TI - Rhodium-catalyzed synthesis of diaryl sulfides using aryl fluorides and sulfur/organopolysulfides. AB - Substituted pentafluorobenzenes react with sulfur to give bis(4-substituted 2,3,5,6-tetrafluorophenyl) sulfides in the presence of RhH(PPh(3))(4), 1,2 bis(diphenylphosphino)benzene (dppBz), and tributylsilane. The reaction proceeds efficiently between room temperature and 80 degrees C. A comparative study of the reactivities of an organic trisulfide and a tetrasulfide showed notable substrate specificity. Di-tert-butyl tetrasulfide reacted with reactive aryl monofluorides and substituted pentafluorobenzenes. Di-tert-butyl trisulfide reacted with aryl monofluorides. The reactivity was explained on the basis of the difference in S-S bond energy. PMID- 23039102 TI - Identification of three novel HLA-DQA1 alleles: DQA1*01:08, DQA1*01:09 and DQA1*03:03:02. AB - Three novel alleles DQA1*01:08, 01:09 and 03:03:02 are described. All are single nucleotide substitutions. PMID- 23039103 TI - Near-surface oxidized sulfur modifications and self-assembly of thiol-modified aptamer on Au thin film substrates influenced by piranha treatment. AB - Self-assembly of thiol-modified oligonucleotides on Au films has great importance for biosensor applications. Prior to the self-assembly, a piranha treatment (PT) is commonly used to clean the Au surface. Here we report that near-surface oxidized sulfur modifications on Au thin films by PT for longer than 60 s have serious effects on the self-assembled monolayer (SAM) formation of thiol-modified single-stranded thrombin binding aptamer (s-TBA), and a PT time of 10-30 s is optimal for s-TBA SAM formation. These results have important implication to SAM formation of biomolecules, especially for the thiol-modified ones where a careful consideration of this key step could significantly enhance the SAM formation and biosensor performance. PMID- 23039104 TI - Phakomatosis pigmentovascularis Ib with left-sided hemihypertrophy, interdigital gaps and scoliosis: a unique case of phakomatosis pigmentovascularis. PMID- 23039105 TI - Combined effects of storage and processing on the bioactive compounds and pro apoptotic properties of color-fleshed potatoes in human colon cancer cells. AB - Potatoes can be stored for up to 1 year before being processed and consumed. The objective of this study was to determine the extent to which fresh and stored color-fleshed potatoes retain their anticancer properties after baking and chipping compared with unprocessed potatoes. We utilized white-, yellow-, and purple-fleshed potato clones and tested their phenolic and anthocyanin content, antioxidant activity, metabolite profile, and antiproliferative and pro-apoptotic properties. When compared with unprocessed samples, baking or chipping led to significant losses in the phenolic and anthocyanin content and antioxidant activity of the potatoes. However, with storage, total phenolic and anthocyanin content and antioxidant activity increased in baked samples while in the chipped samples they remained constant. Ethanolic extracts of baked and chipped samples suppressed proliferation and elevated apoptosis (p < 0.05) in HCT-116 (p53 wild type; ras mutated) and HT-29 (p53 mutated; ras wild-type) human colon cancer cell lines. Antiproliferative and pro-apoptotic properties of baked potatoes were similar to that of fresh potatoes, while chipping caused a significant suppression. Phenolic content and antioxidant activity of purple-fleshed potatoes, after baking, were comparable with those of anthocyanin-rich berries. Hence, purple-fleshed potatoes can be a healthier choice for consumers as they possess greater levels of bioactive compounds and anticancer properties even after processing as compared with their white- and yellow-fleshed counterparts. PMID- 23039107 TI - Hemopexin as biomarkers for analyzing the biological responses associated with exposure to silica nanoparticles. AB - Practical uses of nanomaterials are rapidly spreading to a wide variety of fields. However, potential harmful effects of nanomaterials are raising concerns about their safety. Therefore, it is important that a risk assessment system is developed so that the safety of nanomaterials can be evaluated or predicted. Here, we attempted to identify novel biomarkers of nanomaterial-induced health effects by a comprehensive screen of plasma proteins using two-dimensional differential in gel electrophoresis (2D-DIGE) analysis. Initially, we used 2D DIGE to analyze changes in the level of plasma proteins in mice after intravenous injection via tail veins of 0.8 mg/mouse silica nanoparticles with diameters of 70 nm (nSP70) or saline as controls. By quantitative image analysis, protein spots representing >2.0-fold alteration in expression were found and identified by mass spectrometry. Among these proteins, we focused on hemopexin as a potential biomarker. The levels of hemopexin in the plasma increased as the silica particle size decreased. In addition, the production of hemopexin depended on the characteristics of the nanomaterials. These results suggested that hemopexin could be an additional biomarker for analyzing the biological responses associated with exposure to silica nanoparticles. We believe that this study will contribute to the development of biomarkers to ensure the safety of silica nanoparticles. PMID- 23039106 TI - Review: microglia of the aged brain: primed to be activated and resistant to regulation. AB - Innate immunity within the central nervous system (CNS) is primarily provided by resident microglia. Microglia are pivotal in immune surveillance and also facilitate the co-ordinated responses between the immune system and the brain. For example, microglia interpret and propagate inflammatory signals that are initiated in the periphery. This transient microglial activation helps mount the appropriate physiological and behavioural response following peripheral infection. With normal ageing, however, microglia develop a more inflammatory phenotype. For instance, in several models of ageing there are increased pro inflammatory cytokines in the brain and increased expression of inflammatory receptors on microglia. This increased inflammatory status of microglia with ageing is referred to as primed, reactive or sensitized. A modest increase in the inflammatory profile of the CNS and altered microglial function in ageing has behavioural and cognitive consequences. Nonetheless, there are major differences in microglial biology between young and old age when the immune system is challenged and microglia are activated. In this context, microglial activation is amplified and prolonged in the aged brain compared with adults. The cause of this amplified microglial activation may be related to impairments in several key regulatory systems with age that make it more difficult to resolve microglial activation. The consequences of impaired regulation and microglial hyper activation following immune challenge are exaggerated neuroinflammation, sickness behaviour, depressive-like behaviour and cognitive deficits. Therefore the purpose of this review is to discuss the current understanding of age-associated microglial priming, consequences of priming and reactivity, and the impairments in regulatory systems that may underlie these age-related deficits. PMID- 23039108 TI - Comparison of five classification systems for interpreting electronic fetal monitoring in predicting neonatal status at birth. AB - OBJECTIVE: To compare the accuracy of five different classification systems for interpreting electronic fetal monitoring (EFM) when predicting neonatal status at birth, as determined by the umbilical cord arterial pH. METHODS: Ninety-seven cardiotocography traces were retrospectively interpreted according to five classification systems for EFM: Dublin Fetal Heart Rate Monitoring Trial (DFHRMT), Royal College of Obstetricians and Gynecologists (RCOG), Society of Obstetricians and Gynaecologists of Canada (SOGC), National Institute of Child Health and Human Development (NICHD) and Parer & Ikeda's. For each classification system, sensitivity, specificity, positive and negative predictive values were calculated. The capacity of the classifications to predict neonatal pH was also evaluated by receiver-operating characteristic (ROC) curves. Agreement between the five systems was estimated using weighted kappa statistic. RESULTS: Considering pH <=7.15 as the cutoff for low pH, the sensitivity and specificity values were 100 and 18% (DFHRMT); 100 and 15% (RCOG); 88 and 37% (SOGC); 67 and 92% (NICHD); 55 and 67% (Parer & Ikeda). The ROC curves showed that all classifications analyzed had a low discriminative capacity when predicting umbilical artery pH <=7.15. An excellent agreement was observed between DFHRMT and RCOG (weighted kappa value: 0.860). CONCLUSIONS: Parer & Ikeda and NICHD classifications had the highest specificity in detecting umbilical cord arterial pH <=7.15. The high specificity of the NICHD classification is hindered by a high percentage of "intermediate" traces (80%). Parer & Ikeda classification is the one that best classify as pathological only the traces of fetuses that are truly at risk of acidemia, thus avoiding unnecessary intervention. It also showed the best trade-off between sensitivity and specificity and the lowest rate of traces considered "intermediate." PMID- 23039109 TI - Risk of dislocation using large- vs. small-diameter femoral heads in total hip arthroplasty. AB - BACKGROUND: Dislocation remains a difficult problem in total hip arthroplasty. Large-diameter femoral heads may lower the incidence of dislocation by enhancing the jump distance and decreasing impingement, but their performance against small diameter heads has not been assessed. This study compared the mid-term radiographic and functional outcomes of two matched cohorts of patients undergoing total hip arthroplasty who had a high pre-operative risk for dislocation and who received either small-diameter (26- or 28-millimeters) or large-diameter (>=36-millimeters) femoral heads. METHODS: All patients who received large-diameter heads (>=36-millimeter) between 2002 and 2005, and who had pre-operative risk factors for dislocation, were identified in the institution's joint registry. Forty-one patients (52 hips) who received large diameter heads were identified, and these patients were matched to 48 patients (52 hips) in the registry who received small-diameter femoral heads. RESULTS: At mean final follow-up of 62 months (range, 49 to 101 months), both groups achieved excellent functional outcomes as measured by Harris Hip scores, with slightly better final scores in the large-diameter group (90 vs. 83 points). No patient showed any radiographic signs of loosening. No patient dislocated in the large diameter femoral head group; the smaller-diameter group had a greater rate of dislocation (3.8%, 2 out of 52). CONCLUSIONS: Large-diameter femoral head articulations may reduce dislocation rates in patients who have a high pre operative risk for dislocation while providing the same functional improvements and safety as small-diameter bearings. PMID- 23039110 TI - Comparison of safety and stability of C-2 pars and pedicle screws for atlantoaxial fusion: meta-analysis and review of the literature. AB - OBJECT: Some centers report a lower incidence of vertebral artery (VA) injury with C-2 pars screws compared with pedicle screws without sacrificing construct stability, despite biomechanical studies suggesting greater load failures with C 2 pedicle screws. The authors reviewed published series describing C-2 pars and pedicle screw implantation and atlantoaxial fusions and compared the incidence of VA injury, screw malposition, and successful atlantoaxial fusion with each screw type. METHODS: Online databases were searched for English-language articles between 1994 and April of 2011 describing the clinical and radiographic outcomes following posterior atlantoaxial fusion with C-1 lateral mass and either C-2 pars interarticularis or pedicle screws. Thirty-three studies describing 2975 C-2 pedicle screws and 11 studies describing 405 C-2 pars screws met inclusion criteria for the safety analysis. Seven studies describing 113 patients treated with C-2 pars screws and 20 studies describing 918 patients treated with C-2 pedicle screws met inclusion criteria for fusion analysis. Standard and formal meta-analysis techniques were used to compare outcomes. RESULTS: All studies provided Class III evidence. Ten instances of VA injury occurred with C-2 pedicle screws (0.3%) and no VA injury occurred with pars screws. The point estimate of VA injury for C-2 pedicle screws was 1.09% (95% CI 0.73%-1.63%) and was similar to that of C-2 pars screws (1.48%, 95% CI 0.62%-3.52%). Similarly, there was no statistically significant difference in the rate of clinically significant screw malpositions (1.14% [95% CI 0.77%-1.69%) vs 1.69% [95% CI 0.73%-3.84%]). Radiographically identified screw malposition occurred in a higher proportion of C-2 pedicle screws compared with C-2 pars screws (6.0% [95% CI 3.7%-9.6%] vs 4.0% [95% CI 2.0%-7.6%], p < 0.0001). Pseudarthrosis occurred in a greater proportion of patients treated with C-2 pars screws (5 [4.4%] of 113) compared with those treated with C-2 pedicle screws (2 [0.22%] of 900). Point estimates with 95% confidence intervals show a slightly higher rate of successful atlantoaxial fusion in the pedicle screw cohort (97.8% [CI 96.0%-98.8%] vs 93.5% [CI 86.6% 97.0%]; p < 0.0001). Q-testing ruled out heterogeneity between the study groups. CONCLUSIONS: With a thorough knowledge of axis anatomy, surgeons can place both C 2 pars and C-2 pedicle screws accurately with a small risk of VA injury or clinically significant malposition. There may be subtle trade-off of safety for rigidity when using axial pedicle instead of pars screws, and the decision to use either screw type must be made only after careful review of the preoperative CT imaging and must take into account the surgeon's expertise and the particular demands of the clinical scenario in any given case. PMID- 23039111 TI - Ultrafine Angelica gigas powder normalizes ovarian hormone levels and has antiosteoporosis properties in ovariectomized rats: particle size effect. AB - The root of Angelica gigas (Korean angelica) is traditionally used to treat women's ailments that are caused by an impairment of menstrual blood flow and cycle irregularities. This study evaluated the effect particle size of Korean angelica powder on its efficacy for treating estrogen-related symptoms of menopause. Initially, Korean angelica roots were pulverized into ultrafine powder, and orally administered to the rats at a concentration of 500 mg/kg body weight for 8 weeks. The effects of Korean angelica powder particle size on extraction yield, contents of bioactive compounds (decursin and decursinol angelate), levels of serum ovarian hormones (estradiol and progesterone), reproductive hormones (luteinizing hormone and follicle-stimulating hormone), and experimental osteoporosis parameters (mineral density, strength, and histological features) were determined. A significant increase (fivefold) in the contents of decursin and decursinol angelate in the extract of the ultrafine Korean angelica powder was observed compared to coarse Korean angelica powder. Rats were divided into sham-operated or ovariectomized (OVX) groups that were fed coarse (CRS) or ultrafine (UF) ground Korean angelica root. The serum levels of estradiol in the OVX_UF group were 19.2% and 54.1% higher than that of OVX_CRS group. Serum bone alkaline phosphatase/total-alkaline phosphatase index in the OVX_UF group was half that of the OVX_CRS group. In addition, less trabecular bone loss and thick cortical areas were observed in rats administered ultrafine powder. Therefore, ultrafine grinding may enhance the bioactivity of herbal medicines and be especially useful when their extracted forms lose bioactivity during processing, storage, and oral intake. PMID- 23039112 TI - Structure analysis and laxative effects of oligosaccharides isolated from bananas. AB - Banana oligosaccharides (BOS) were extracted with water, and then separated and purified using column chromatography. Gel penetration chromatography was used to determine the molecular weights. Thin layer chromatogram and capillary electrophoresis were employed to analyze the monosaccharide composition. The indican bond and structure of the BOS molecule were determined using Fourier transform infrared spectroscopy and nuclear magnetic resonance. Results showed that BOS were probably composed of eight beta-D-pyran glucose units linked with 1 >6 indican bonds. The laxative effects of BOS were investigated in mice using the method described in "Handbook of Technical Standards for Testing and Assessment of Health Food in China." The length of the small intestine over which a carbon suspension solution advanced in mice treated with low-, middle-, and high-dose BOS was significantly greater than that in the model group, suggesting that BOS are effective in accelerating the movement of the small intestine. PMID- 23039114 TI - Effect of nitrogen-containing impurities on the activity of perovskitic catalysts for the catalytic combustion of methane. AB - LaMnO(3), either pure or doped with 10 mol % Sr, has been prepared by flame pyrolysis in nanostructured form. Such catalysts have been tested for the catalytic flameless combustion of methane, achieving very high catalytic activity. The resistance toward poisoning by some model N-containing impurities has been checked in order to assess the possibility of operating the flameless catalytic combustion with biogas, possibly contaminated by S- or N-based compounds. This would be a significant improvement from the environmental point of view because the application of catalytic combustion to gas turbines would couple improved energy conversion efficiency and negligible noxious emissions, while the use of biogas would open the way to energy production from a renewable source by means of very efficient technologies. A different behavior has been observed for the two catalysts; namely, the undoped sample was more or less heavily poisoned, whereas the Sr-doped sample showed slightly increasing activity upon dosage of N-containing compounds. A possible reaction mechanism has been suggested, based on the initial oxidation of the organic backbone, with the formation of NO. The latter may adsorb more or less strongly depending on the availability of surface oxygen vacancies (i.e., depending on doping). Decomposition of NO may leave additional activated oxygen species on the surface, available for low-temperature methane oxidation and so improving the catalytic performance. PMID- 23039113 TI - Clinical decision support must be useful, functional is not enough: a qualitative study of computer-based clinical decision support in primary care. AB - BACKGROUND: Health information technology, particularly electronic decision support systems, can reduce the existing gap between evidence-based knowledge and health care practice but professionals have to accept and use this information. Evidence is scant on which features influence the use of computer-based clinical decision support (eCDS) in primary care and how different professional groups experience it. Our aim was to describe specific reasons for using or not using eCDS among primary care professionals. METHODS: The setting was a Finnish primary health care organization with 48 professionals receiving patient-specific guidance at the point of care. Multiple data (focus groups, questionnaire and spontaneous feedback) were analyzed using deductive content analysis and descriptive statistics. RESULTS: The content of the guidance is a significant feature of the primary care professional's intention to use eCDS. The decisive reason for using or not using the eCDS is its perceived usefulness. Functional characteristics such as speed and ease of use are important but alone these are not enough. Specific information technology, professional, patient and environment features can help or hinder the use. CONCLUSIONS: Primary care professionals have to perceive eCDS guidance useful for their work before they use it. PMID- 23039116 TI - HORMAD2 is essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity. AB - Meiotic chromosome segregation requires homologous pairing, synapsis and crossover recombination during meiotic prophase. The checkpoint kinase ATR has been proposed to be involved in the quality surveillance of these processes, although the underlying mechanisms remain largely unknown. In our present study, we generated mice lacking HORMAD2, a protein that localizes to unsynapsed meiotic chromosomes. We show that this Hormad2 deficiency hampers the proper recruitment of ATR activity to unsynapsed chromosomes. Male Hormad2-deficient mice are infertile due to spermatocyte loss as a result of characteristic impairment of sex body formation; an ATR- and gammaH2AX-enriched repressive chromatin domain is formed, but is partially dissociated from the elongated sex chromosome axes. In contrast to males, Hormad2-deficient females are fertile. However, our analysis of Hormad2/Spo11 double-mutant females shows that the oocyte number is negatively correlated with the frequency of pseudo-sex body formation in a Hormad2 gene dosage-dependent manner. This result suggests that the elimination of Spo11 deficient asynaptic oocytes is associated with the HORMAD2-dependent pseudo-sex body formation that is likely initiated by local concentration of ATR activity in the absence of double-strand breaks. Our results thus show a HORMAD2-dependent quality control mechanism that recognizes unsynapsis and recruits ATR activity during mammalian meiosis. PMID- 23039117 TI - Mothers' judgements about their child's weight: distinguishing facts from values. AB - BACKGROUND: Mothers' responses to questionnaire items assessing their child's weight status typically do not correspond to conventional clinical classifications based on body mass index (BMI). From this observation health professionals infer that mothers do not recognize overweight in their child. But the questions used have generally confounded factual judgements with values, so it is not clear whether the mothers are making factual errors, or differ from professionals in their values. METHODS: Cross-sectional study of population-based birth cohort at 6-8 years and their mothers (n = 540). An objective BMI matching task was used to determine the accuracy of mothers' recognition of their child's weight. Mothers matched their child to sex- and age-specific images of children of known BMI ranging from very thin to obese, and chose a descriptor of their child's weight of the kind used in previous research. RESULTS: Mothers tended to underestimate their child's BMI on the matching task. Matching errors significantly predicted mothers' description of their child's weight; those who overestimated their child's BMI on the matching task were more likely to say their child was overweight, while those who underestimated it were less likely to, independently of their child's actual BMI. CONCLUSIONS: Educational programmes aimed at parents of young primary school children need to address separately the factual and the evaluative components of their assessment of child weight. PMID- 23039118 TI - Bedside focused echocardiography as predictor of survival in cardiac arrest patients: a systematic review. AB - OBJECTIVES: The objective was to determine if focused transthoracic echocardiography (echo) can be used during resuscitation to predict the outcome of cardiac arrest. METHODS: A literature search of diagnostic accuracy studies was conducted using MEDLINE via PubMed, EMBASE, CINAHL, and Cochrane Library databases. A hand search of references was performed and experts in the field were contacted. Studies were included for further appraisal and analysis only if the selection criteria and reference standards were met. The eligible studies were appraised and scored by two independent reviewers using a modified quality assessment tool for diagnostic accuracy studies (QUADAS) to select the papers included in the meta-analysis. RESULTS: The initial search returned 2,538 unique papers, 11 of which were determined to be relevant after screening criteria were applied by two independent researchers. One additional study was identified after the initial search, totaling 12 studies to be included in our final analysis. The total number of patients in these studies was 568, all of whom had echo during resuscitation efforts to determine the presence or absence of kinetic cardiac activity and were followed up to determine return of spontaneous circulation (ROSC). Meta-analysis of the data showed that as a predictor of ROSC during cardiac arrest, echo had a pooled sensitivity of 91.6% (95% confidence interval [CI] = 84.6% to 96.1%), and specificity was 80.0% (95% CI = 76.1% to 83.6%). The positive likelihood ratio for ROSC was 4.26 (95% CI = 2.63 to 6.92), and negative likelihood ratio was 0.18 (95% CI = 0.10 to 0.31). Heterogeneity of the results (sensitivity) was nonsignificant (Cochran's Q: chi(2) = 10.63, p = 0.16, and I(2) = 34.1%). CONCLUSIONS: Echocardiography performed during cardiac arrest that demonstrates an absence of cardiac activity harbors a significantly lower (but not zero) likelihood that a patient will experience ROSC. In selected patients with a higher likelihood of survival from cardiac arrest at presentation, based on established predictors of survival, echo should not be the sole basis for the decision to cease resuscitative efforts. Echo should continue to be used only as an adjunct to clinical assessment in predicting the outcome of resuscitation for cardiac arrest. PMID- 23039120 TI - The design and development of surgical templates for premolar transplants in adolescents. AB - The aim of designing and fabricating the surgical templates was to assist the surgical component of premolar transplantation, by establishing and replicating the root dimensions of the donor premolar tooth. The correct template could be used to assess the socket preparation (width and depth) prior to placement of the transplant in the recipient site, obviating the need to repeatedly try the donor tooth for fit at the recipient site, thereby minimising trauma to the periodontal ligament of the donor tooth. Seventy-five mandibular premolars and 50 maxillary second premolars were selected with varying stages of root development. All teeth had been extracted for orthodontic reasons. The root was measured for its length (maxL) and maximum (maxW) and minimum width (minW) with digital callipers from standardised reference points. These measurements were then used in the design of premolar transplant templates. The mean measurements for second maxillary premolars were maxL 14.6 mm (+/- 1.7), maxW 8.3 mm (+/- 0.5) and minW 4.9 (+/- 0.3). The mean measurements for mandibular premolars were maxL 14.8 (+/- 1.6), maxW 7.4 (+/- 0.6) and minW 5.3 (+/- 0.5). From these measurements, a range of maxillary second premolar and mandibular premolar templates have been fabricated. These figures also inform the multidisciplinary planning process for the space requirements at the donor site prior to transplantation. PMID- 23039121 TI - In vivo accuracy of three electronic root canal length measurement devices: Dentaport ZX, Raypex 5 and ProPex II. PMID- 23039123 TI - Chlorophyll a phytylation is required for the stability of photosystems I and II in the cyanobacterium Synechocystis sp. PCC 6803. AB - In oxygenic phototrophic organisms, the phytyl 'tail' of chlorophyll a is formed from a geranylgeranyl residue by the enzyme geranylgeranyl reductase. Additionally, in oxygenic phototrophs, phytyl residues are the tail moieties of tocopherols and phylloquinone. A mutant of the cyanobacterium Synechocystis sp. PCC 6803 lacking geranylgeranyl reductase, DeltachlP, was compared to strains with specific deficiencies in either tocopherols or phylloquinone to assess the role of chlorophyll a phytylatation (versus geranylgeranylation). The tocopherol less Deltahpt strain grows indistinguishably from the wild-type under 'standard' light photoautotrophic conditions, and exhibited only a slightly enhanced rate of photosystem I degradation under strong irradiation. The phylloquinone-less DeltamenA mutant also grows photoautotrophically, albeit rather slowly and only at low light intensities. Under strong irradiation, DeltamenA retained its chlorophyll content, indicative of stable photosystems. DeltachlP may only be cultured photomixotrophically (due to the instability of both photosystems I and II). The increased accumulation of myxoxanthophyll in DeltachlP cells indicates photo-oxidative stress even under moderate illumination. Under high-light conditions, DeltachlP exhibited rapid degradation of photosystems I and II. In conclusion, the results demonstrate that chlorophyll a phytylation is important for the (photo)stability of photosystems I and II, which, in turn, is necessary for photoautotrophic growth and tolerance of high light in an oxygenic environment. PMID- 23039125 TI - The effect of dialect on the phonological analysis of Chinese-influenced Malaysian English speaking children. AB - This study investigates the effect of dialect on phonological analyses in Chinese influenced Malaysian English (ChME) speaking children. A total of 264 typically developing ChME speaking children aged 3-7 years participated in this cross sectional study. A single word naming task consisting of 195 words was used to elicit speech from the children. The samples obtained were transcribed phonetically and analysed descriptively and statistically. Phonological analyses were completed for speech sound accuracy, age of consonant acquisition, percentage of phonological process occurrence, and age of suppression for phonological processes. All these measurements differed based on whether or not ChME dialectal features were considered correct, with children gaining higher scores when ChME dialect features were considered correct. The findings of the present study provide guidelines for Malaysian speech-language pathologists and stress the need to appropriately consider ChME dialectal features in the phonological analysis of ChME speaking children. They also highlight the issues in accurate differential diagnosis of speech impairment for speech-language pathologists working with children from any linguistically diverse background. PMID- 23039124 TI - Fabrication of biopolymeric complex coacervation core micelles for efficient tea polyphenol delivery via a green process. AB - Nanoencapsulation is a promising method to improve the bioavailability of tea polyphenol (TPP). In this work, we adopted a green process to develop a new kind of complex coacervation core micelles (C3Ms) based on biopolymers for efficient tea polyphenol delivery. First, gelatin-dextran conjugate was synthesized using Maillard reaction. Then the C3Ms were produced by mixing gelatin-dextran conjugate with TPP. Variable factors on the self-assembly of the C3Ms were investigated. Under optimal conditions, the obtained C3Ms are of nanosize (average 86 nm in diameter) with narrow distribution. The formation of the C3Ms is attributed to hydrophobic interaction and hydrogen bonding instead of electrostatic interaction. Transmission electron microscope (TEM) and scanning electron microscope (SEM) results showed that C3Ms have a spherical shape with core-shell structure. zeta-Potential measurement suggested that the core is composed of gelatin with TPP, whereas the shell is composed of dextran segments. The encapsulation efficiency of the C3Ms is pH-independent, but the loading capacity is controllable and as high as 360 wt % (weight/weight of protein). In addition, the C3Ms show sustained release of TPP in vitro. MTT assay revealed that the C3Ms have comparable or even stronger cytotoxicity against MCF-7 cells than free TPP. PMID- 23039126 TI - Assessing bilingual Chinese-English young children in Malaysia using language sample measures. AB - One reason why specific language impairment (SLI) is grossly under-identified in Malaysia is the absence of locally- developed norm-referenced language assessment tools for its multilingual and multicultural population. Spontaneous language samples provide quantitative information for language assessment, and useful descriptive information on child language development in complex language and cultural environments. This research consisted of two studies and investigated the use of measures obtained from English conversational samples among bilingual Chinese-English Malaysian preschoolers. The research found that the language sample measures were sensitive to developmental changes in this population and could identify SLI. The first study examined the relationship between age and mean length of utterance (MLU(w)), lexical diversity (D), and the index of productive syntax (IPSyn) among 52 typically-developing (TD) children aged between 3;4-6;9. Analyses showed a significant linear relationship between age and D (r = .450), the IPsyn (r = .441), and MLU(w) (r = .318). The second study compared the same measures obtained from 10 children with SLI, aged between 3;8 5;11, and their age-matched controls. The children with SLI had significantly shorter MLU(w) and lower IPSyn scores than the TD children. These findings suggest that utterance length and syntax production can be potential clinical markers of SLI in Chinese-English Malaysian children. PMID- 23039127 TI - Synthesis of heterocycles via palladium-catalyzed carbonylations. PMID- 23039128 TI - Cloning and characterization of the beer foaming gene CFG1 from Saccharomyces pastorianus. AB - Foam production is an essential characteristic of beer, generated mainly from the proteins present in the malt and, to a minor extent, from the mannoproteins in brewer's yeast cell walls. Here, we describe the isolation and characterization of the novel fermentation gene CFG1 (Carlsbergensis foaming gene) from Saccharomyces pastorianus. CFG1 encodes the cell wall protein Cfg1p, a 105 kDa protein highly homologous to Saccharomyces cerevisiae cell wall mannoproteins, particularly those involved in foam formation, such as Awa1p and Fpg1p. Further characterization of Cfg1p revealed that this novel protein is responsible for beer foam stabilization. This report represents the first time that a brewing yeast foaming gene has been cloned and its action fully characterized. PMID- 23039130 TI - Involvement of Akt/NF-kappaB pathway in antitumor effects of parthenolide on glioblastoma cells in vitro and in vivo. AB - BACKGROUND: Glioblastoma is the most common and most aggressive form of malignant glioma and is very difficult to treat. Controlling tumour cell invasion and angiogenesis is essential to improve the prognosis of glioblastoma patients. Since constitutive activation of nuclear factor-kappaB (NF-kappaB) is necessary for tumour progression, NF-kappaB may be an important pharmacological target for this disease. Our study aimed to evaluate the antitumour effects of parthenolide, a NF-kappaB inhibitor, in two human glioblastoma cell lines (U87MG and U373) and in glioblastoma xenografts. Furthermore, we aimed to investigate the molecular mechanisms underlying these effects. METHODS: The anti-invasive and anti angiogenic effects of parthenolide were analysed using in vitro invasion and angiogenesis assays. Parthenolide-induced growth inhibition of glioblastoma cells in vitro was determined using the MTT (methyl thiazolyl tetrazolium) assay. In addition, the effect of parthenolide on orthotropic implantation in vivo was evaluated using an intracerebral human glioblastoma xenograft model. RESULTS: We found that parthenolide suppresses proliferation, invasion, and tumour- induced angiogenesis of glioblastoma cells. Molecular studies demonstrated that parthenolide suppresses gene and protein expression of angiogenic factors. Furthermore, parthenolide reduced Akt phosphorylation and activated mitochondrial signalling, suggesting that the antitumour function of parthenolide may be mediated not only by the inhibition of NF-kappaB but also by the inhibition of Akt signalling and the activation of apoptotic proteins. Parthenolide suppressed neovascularity and tumour growth in glioblastoma xenografts. CONCLUSION: The present study identified parthenolide as a new therapeutic agent for glioblastomas. PMID- 23039131 TI - The 'real world' utility of a web-based bipolar disorder screening measure. AB - OBJECTIVE: To determine whether those completing a self-report bipolar self-test measure and identified as having a likely bipolar disorder judged the self-test as useful and had a subsequent superior illness course. METHOD: We invited those completing the web-based Mood Swings Questionnaire (or MSQ) to provide contact details and contribute to a 3-month study evaluating their responses to being identified as having a likely bipolar disorder, any subsequent action taken and the impact of such actions on their illness trajectory. RESULTS: We analysed data received from 665 participants screening 'positive' on the MSQ and completing baseline and 3-month follow-up data. High rates of satisfaction with the MSQ were quantified, with respondents viewing the measure as informative, validating and/or motivating. Of those receiving a confirmed bipolar diagnosis, such clarification occurred on average 12 years after their first depressive episode. Most implemented self-management strategies irrespective of whether seeking formal diagnostic clarification or not. Participants improved on depressive, quality of life and overall functioning measures over the study period, but with results indicating (via analysis of three sample subsets differing by the degree of 'actions taken') that those who took assertive action and had the diagnosis confirmed had the most superior outcome. CONCLUSION: This is the first study to formally evaluate the clinical impact of a self-report bipolar disorder screening measure. High acceptance and superior outcomes quantified for those acting assertively in response to such a new diagnosis argue for its 'real world' utility. PMID- 23039132 TI - An efficient clustering algorithm for partitioning Y-short tandem repeats data. AB - BACKGROUND: Y-Short Tandem Repeats (Y-STR) data consist of many similar and almost similar objects. This characteristic of Y-STR data causes two problems with partitioning: non-unique centroids and local minima problems. As a result, the existing partitioning algorithms produce poor clustering results. RESULTS: Our new algorithm, called k-Approximate Modal Haplotypes (k-AMH), obtains the highest clustering accuracy scores for five out of six datasets, and produces an equal performance for the remaining dataset. Furthermore, clustering accuracy scores of 100% are achieved for two of the datasets. The k-AMH algorithm records the highest mean accuracy score of 0.93 overall, compared to that of other algorithms: k-Population (0.91), k-Modes-RVF (0.81), New Fuzzy k-Modes (0.80), k Modes (0.76), k-Modes-Hybrid 1 (0.76), k-Modes-Hybrid 2 (0.75), Fuzzy k-Modes (0.74), and k-Modes-UAVM (0.70). CONCLUSIONS: The partitioning performance of the k-AMH algorithm for Y-STR data is superior to that of other algorithms, owing to its ability to solve the non-unique centroids and local minima problems. Our algorithm is also efficient in terms of time complexity, which is recorded as O(km(n-k)) and considered to be linear. PMID- 23039133 TI - Peculiar fundus abnormalities and pathognomonic electrophysiological findings in a 14-month-old boy with NR2E3 mutations. AB - Enhanced S-cone syndrome is a rare, slowly progressive autosomal recessively inherited retinal degeneration related to mutations in the NR2E3 gene. Patients often present with night blindness, visual loss and visual field abnormalities. Patients with enhanced S-cone syndrome exhibit a variable clinical phenotype associated with various degrees of pigmentary changes and foveal schisis. We report a 14-month-old boy with an unusual funduscopic appearance. The diagnosis of enhanced S-cone syndrome was suggested by the uniquely abnormal electroretinographic pattern and was confirmed by the finding of homozygous NR2E3 mutations. PMID- 23039129 TI - Interleukin-33 in the human placenta. AB - OBJECTIVE: Interleukin-33 (IL-33) is the newest member of the IL-1 cytokine family, a group of key regulators of inflammation. The purpose of this study was to determine whether IL-33 is expressed in the human placenta and to investigate its expression in the context of acute and chronic chorioamnionitis. METHODS: Placental tissues were obtained from five groups of patients: 1) normal pregnancy at term without labor (n = 10); 2) normal pregnancy at term in labor (n = 10); 3) preterm labor without inflammation (n = 10); 4) preterm labor with acute chorioamnionitis and funisitis (n = 10); and 5) preterm labor with chronic chorioamnionitis (n = 10). Immunostaining was performed to determine IL-33 protein expression patterns in the placental disk, chorioamniotic membranes, and umbilical cord. mRNA expression of IL-33 and its receptor IL1RL1 (ST2) was measured in primary amnion epithelial and mesenchymal cells (AECs and AMCs, n = 4) and human umbilical vein endothelial cells (HUVECs, n = 4) treated with IL 1beta (1 and 10 ng/ml) and CXCL10 (0.5 and 1 or 5 ng/ml). RESULTS: 1) Nuclear IL 33 expression was found in endothelial and smooth muscle cells in the placenta, chorioamniotic membranes, and umbilical cord; 2) IL-33 was detected in the nucleus of CD14+ macrophages in the chorioamniotic membranes, chorionic plate, and umbilical cord, and in the cytoplasm of myofibroblasts in the Wharton's jelly; 3) acute (but not chronic) chorioamnionitis was associated with the presence of IL-33+ macrophages in the chorioamniotic membranes and umbilical cord; 4) expression of IL-33 or IL1RL1 (ST2) mRNA in AECs was undetectable; 5) IL 33 mRNA expression increased in AMCs and HUVECs after IL-1beta treatment but did not change with CXCL10 treatment; and 6) IL1RL1 (ST2) expression decreased in AMCs and increased in HUVECs after IL-1beta but not CXCL10 treatment. CONCLUSIONS: IL-33 is expressed in the nucleus of placental endothelial cells, CD14+ macrophages, and myofibroblasts in the Wharton's jelly. IL-1beta can induce the expression of IL-33 and its receptor. Protein expression of IL-33 is detectable in macrophages of the chorioamniotic membranes in acute (but not chronic) chorioamnionitis. PMID- 23039134 TI - Rhodium-catalyzed oxidative annulation of sulfonylhydrazones with alkenes. AB - An efficient rhodium-catalyzed tandem C-H bond olefination and annulation approach was developed to afford 1,2-dihydrophthalazines in good to excellent yields from easily accessible sulfonylhydrazones and alkenes. PMID- 23039135 TI - Nicorandil: do the dermatological and gastrointestinal risks outweigh the benefits? AB - BACKGROUND: Nicorandil has been available in the U.K. since 1994 for the prophylaxis and treatment of angina. Since the first reported case of nicorandil associated oral ulceration in 1997 complications elsewhere in the gastrointestinal tract have been reported. OBJECTIVES: Our case series highlights this serious drug complication. METHODS: We reviewed the records of all patients referred to our specialist stoma dermatology clinic who had stoma surgery for diverticular disease and all patients referred with persistent parastomal or perianal ulceration that was not attributable to Crohn's disease or pyoderma gangrenosum. Patient demographics, nicorandil ingestion, bowel involvement, stoma type, cutaneous ulceration and outcome were recorded. RESULTS: A total of 36 patients had stoma surgery performed as a consequence of diverticular disease. The proportion of patients taking nicorandil (in all cases at a dose of 40 mg or more daily) was one third, higher than expected. There was a higher incidence of enteric fistula formation and bowel perforation among those taking nicorandil, 92% (11/12) and 50% (6/12), respectively, compared with those not on the drug, 0% and 21% (5/24), respectively. In addition, parastomal ulceration was seen more often in those taking nicorandil, 100% (12/12), compared with those not, 8% (2/24). Even without a history of diverticular disease we observed a high incidence of bowel perforation and parastomal and/or perianal ulceration among patients taking nicorandil. In the vast majority of cases ulceration healed upon cessation of nicorandil. CONCLUSIONS: For those with diverticular disease taking nicorandil is strongly associated with fistula formation or bowel perforation; as such the risk-benefit equation for nicorandil needs careful consideration given that other nitrates are available. PMID- 23039136 TI - Formal total synthesis of (+)-neopeltolide. AB - This paper describes the formal total synthesis of (+)-neopeltolide, a cytotoxic macrolide isolated from the marine sponge Neopeltidae. The key features of the synthesis include an asymmetric Evans alkylation to fix the C9-methyl center, Jacobsen hydrolytic kinetic resolution of terminal epoxides followed by their regioselective opening to fix the stereocenters at the C11 and C13 positions, respectively, a Pd-catalyzed oxa-Michael reaction to construct the tetrahydropyran ring, and Yamaguchi macrolactonization to form the macrocyclic core of the molecule. PMID- 23039137 TI - How do keratinizing disorders and blistering disorders overlap? AB - Inherited keratinizing disorders are caused by mutations in the genes encoding cornified cell envelope proteins, enzymes and their inhibitors, adhesion molecules, cytoskeletal proteins and others in the epidermis. These molecules are known to regulate differentiation, proliferation and cell adhesions. Intriguingly, some keratinizing disorders show blistering skin lesions, while some inherited blistering disorders show abnormal keratinization. Therefore, hereditary keratinizing and blistering diseases are closely related and show overlapping genetic backgrounds. In this review, we overviewed keratinizing and blistering disorders in terms of overlapping of the two disease groups. Gene mutations in desmosomal components cause striate keratoderma, Naxos disease, epidermolytic palmoplantar keratoderma and plakophilin deficiency, which first show skin fragility and blisters and later hyperkeratosis. Gene mutations in hemidesmosomal components cause various forms of epidermolysis bullosa, some of which show hyperkeratosis on the nails, palms and soles, in addition to blister formation. Diseases with gene mutations in calcium pump proteins are Darier disease and Hailey-Hailey disease, which show clinicopathological overlaps and develop both keratinizing and blistering skin lesions. Finally, gene mutations in epidermal keratins cause epidermolysis bullosa simplex, epidermolytic ichthyosis, superficial epidermolytic ichthyosis, epidermolytic palmoplantar keratoderma and pachyonychia congenita/focal palmoplantar keratoderma, which show thickening of the palms and soles with underlying blister formation. In general, responsible proteins for diseases developing both keratinizing and blistering conditions are adhesion molecules, calcium pump proteins and keratins, but not connexins, cornified cell envelop proteins, enzymes or inhibitors. It is still unknown how particular keratinizing diseases develop blisters and vice versa. PMID- 23039138 TI - Developing the Diagnostic Adherence to Medication Scale (the DAMS) for use in clinical practice. AB - BACKGROUND: There is a need for an adherence measure, to monitor adherence services in clinical practice, which can distinguish between different types of non-adherence and measure changes over time. In order to be inclusive of all patients it needs to be able to be administered to both patients and carers and to be suitable for patients taking multiple medications for a range of clinical conditions. A systematic review found that no adherence measure met all these criteria. We therefore wished to develop a theory based adherence scale (the DAMS) and establish its content, face and preliminary construct validity in a primary care population. METHODS: The DAMS (consisting of 6 questions) was developed from theory by a multidisciplinary team and the questions were initially tested in small patient populations. Further to this, patients were recruited when attending a General Practice and interviewed using the DAMS and two other validated self-reported adherence measures, the Morisky-8 and Lu questionnaires. A semi-structured interview was used to explore acceptability and reasons for differences in responses between the DAMS and the other measures. Descriptive data were generated and Spearman rank correlation tests were used to identify associations between the DAMS and the other adherence measures. RESULTS: One hundred patients completed the DAMS in an average of 1 minute 28 seconds and reported finding it straightforward to complete. An adherence score could not be calculated for the 4(4%) patients only taking 'when required' medication. Thirty six(37.5%) of the remaining patients reported some non-adherence. Adherence ratings of the DAMS were significantly associated with levels of self reported adherence on all other measures Spearman Rho 0.348-0.719, (p < 0.01). Differences in trends could generally be explained by qualitative data. CONCLUSION: The DAMS has been developed for routine monitoring of adherence in clinical practice. It was acceptable to patients taking single or multiple medication and valid when tested against other adherence measures. However, 'when required' medication needs to be excluded. Further tests of the DAMS against objective measures such as MEMS are in progress and reliability needs to be established. Further investigation of the carers' version of the DAMS is required. PMID- 23039139 TI - Investigation of a non-invasive method of assessing the equine circadian clock using hair follicle cells. AB - BACKGROUND: A comprehensive understanding of the equine circadian clock involves the evaluation of circadian clock gene expression. A non-invasive and effective method for detecting equine clock gene expression has yet to be established. Currently, research surrounding this area has relied on collecting tissue biopsies or blood samples that can often be costly, time consuming and uncomfortable for the animal. METHODS: Five mares were individually stabled under a light-dark (LD) cycle that mimicked the external environmental photoperiod during a time of year corresponding with the vernal equinox. Hair follicles were collected every 4 h over a 24-h period by plucking hairs from the mane. RNA was extracted and quantitative (q) PCR assays were performed to determine temporal expression patterns for the core clock genes; ARNTL, CRY1, PER1, PER2, NR1D2 and the clock controlled gene, DBP. RESULTS: Repeated measures ANOVA for the clock gene transcripts PER1 and PER2 and the clock controlled gene, DBP, revealed significant variation in expression over time (p < .05, respectively). Cosinor analysis confirmed a significant 24-h temporal component for PER1 (p = .002) and DBP (p = .0033) and also detected rhythmicity for NR1D2 (p = .0331). CONCLUSIONS: We show that the extraction of RNA from equine hair follicle cells can identify the circadian 24 h oscillations of specific clock genes and a clock-controlled gene and therefore provide a valuable non-invasive method for evaluating the equine peripheral circadian clock. This method will serve as a useful tool for future evaluations of equine circadian rhythms and their response to environmental changes. PMID- 23039140 TI - Efficacy of inpatient treatment for atopic dermatitis evaluated by changes in serum cortisol levels. AB - When dealing with patients with severe atopic dermatitis (AD), inpatient treatment is useful for alleviating skin symptoms in short periods of time. We previously found that many severe AD patients had low serum cortisol levels at admission. The present study was undertaken to evaluate the efficacy of inpatient treatment in 29 adults with AD through comparisons of serum cortisol, plasma adrenocorticotropic hormone (ACTH), serum thymus and activation-regulated chemokine (TARC), and serum lactate dehydrogenase (LDH) levels at admission with those at the time of discharge. Serum cortisol and plasma ACTH levels were significantly higher at discharge. On the other hand, serum TARC and serum LDH were significantly lower at discharge. We examined whether the suppression of hypothalamic-pituitary-adrenocortical function that was seen at admission was attributable to disturbed circadian rhythms due to sleep disorders by analyzing hypothalamic-pituitary-adrenocortical function in relation to the presence/absence of sleep disorders, serum cortisol levels and daily urinary free cortisol. Of the 17 patients with low serum cortisol levels upon admission, 15 (88.2%) had sleep disorders upon admission. However, the daily urinary free cortisol increased significantly from 8.0 +/- 5.5 MUg/day (at admission) to 18.5 +/- 17.2 MUg/day (at discharge). These results suggested that the suppression of endocrine function seen at admission was not attributable to disturbed circadian rhythms due to sleep disorders but represented true suppression of the endocrine system. These results indicated that inpatient care was useful for treating patients with severe AD, enabling efficient improvement of the skin condition and recovery from suppressed endocrine function. PMID- 23039141 TI - The role of the exosporium in the environmental distribution of anthrax. AB - AIMS: To determine the contribution of the exosporium, the outer layer of the Bacillus anthracis spore, to soil attachment. Persistence of spores in soil and their ability to infect animals has been linked to a range of factors which include the presence of organic material and calcium (OMC), pH > 6.0, temperatures above 15.5 degrees C and cycles of local flooding which are thought to transport buried spores to the surface. METHODS AND RESULTS: The ability of wild type (exosporium +ve) and sonicated (exosporium -ve) spores to bind to soils which differed in their composition was determined using a flow-through soil column-based method. A statistically significant difference (P < 0.05) in the binding of wild type spores was observed with spores adhering more firmly to the soil with the highest OMC content. We also found that the removal of the exosporium increased the ability of the spore to adhere to both soil types. CONCLUSION: Structures within the exosporium affected the ability of B. anthracis spores to bind to different soil types. Not surprisingly, wild type spores adhered to soil which has been shown to favour the persistence of the pathogen. SIGNIFICANCE AND IMPACT OF THE STUDY: The ability to persist in and colonise the soil surface is a key requirement of a pathogen which infects grazing animals. By characterising the process involved, we will be better placed to develop strategies to disrupt the infection cycle. PMID- 23039142 TI - Role of recombination activating genes in the generation of antigen receptor diversity and beyond. AB - V(D)J recombination is the process by which antibody and T-cell receptor diversity is attained. During this process, antigen receptor gene segments are cleaved and rejoined by non-homologous DNA end joining for the generation of combinatorial diversity. The major players of the initial process of cleavage are the proteins known as RAG1 (recombination activating gene 1) and RAG2. In this review, we discuss the physiological function of RAGs as a sequence-specific nuclease and its pathological role as a structure-specific nuclease. The first part of the review discusses the basic mechanism of V(D)J recombination, and the last part focuses on how the RAG complex functions as a sequence-specific and structure-specific nuclease. It also deals with the off-target cleavage of RAGs and its implications in genomic instability. PMID- 23039143 TI - Effects of deep brain stimulation in the subthalamic nucleus or globus pallidus internus on step initiation in Parkinson disease: laboratory investigation. AB - OBJECT: Difficulty with step initiation, called "start hesitation," is related to gait bradykinesia and is an early hallmark of gait freezing in Parkinson disease (PD). Authors of this study investigated the effects of deep brain stimulation (DBS) and levodopa on step initiation before and 6 months after DBS surgery in 29 patients with PD who were randomized to either the bilateral subthalamic nucleus (STN) or globus pallidus internus (GPi) as the DBS site. METHODS: The authors measured the amplitude and duration of anticipatory postural adjustments (APAs), the feed-forward postural preparation that precedes the onset of voluntary step initiation, based on center-of-pressure displacements on a force plate. They also measured the length and velocity of the first step using a motion analysis system to study kinematics. Some of the patients (22) were from a large, multicenter, double-blind clinical trial, and all patients in the study (29, PD-DBS group) were randomized to DBS in either the bilateral STN (15 patients) or bilateral GPi (14 patients). Differences in step initiation were investigated in 2 conditions before surgery (off/on levodopa) and in 4 conditions after surgery (off/on levodopa combined with off/on DBS). Twenty-eight elderly healthy control volunteers (CTRL group) were also tested, and 9 control volunteers with PD who met the criteria for DBS (PD-C group) were tested at baseline and 6 months later. RESULTS: Patients in the PD-DBS group had smaller amplitudes and longer durations of APAs compared with those in the 28 healthy control volunteers in all conditions. Before surgery, APAs improved with levodopa. After surgery, the APAs were significantly worse than in the best-treatment state before surgery (DOPA condition), and responsiveness to levodopa decreased. No differences in APAs were detected between the STN and GPi groups. A comparison with PD control volunteers who did not undergo DBS surgery confirmed that a deterioration in step preparation was not related to disease progression. Step length and velocity were smaller in the PD-DBS group than in controls in all conditions. Before surgery, levodopa improved the length and velocity of the first step. Both step length and velocity were unchanged in the best-treatment state before surgery (DOPA condition) as compared with after surgery (DBS+DOPA), with only step velocity in the STN group getting worse after surgery. CONCLUSIONS: Six months of DBS in the STN or GPi impaired anticipatory postural preparation for step initiation, the opposite effect as with levodopa. Deep brain stimulation disrupted postural preparation more than step execution, suggesting independent motor pathways for preparation and execution of gait. Although turning the stimulators on after surgery combined with levodopa benefited the postural preparation to step, a comparison of pre- and postsurgery conditions suggests that either the surgery itself or 6 months of continuous stimulation may lead to an alteration of circuits or plastic changes that impair step initiation. PMID- 23039144 TI - Dose-dependent facilitation of peripheral nerve regeneration by bone marrow derived mononuclear cells: a randomized controlled study: laboratory investigation. AB - OBJECT: Bone marrow-derived stem cells enhance the rate of regeneration of neuronal cells leading to clinical improvement in nerve injury, spinal cord injury, and brain infarction. Recent experiments in the local application of bone marrow-derived mononuclear cells (BM-MNCs) in models of sciatic nerve transection in rats have suggested their beneficial role in nerve regeneration, although the effects of variable doses of stem cells on peripheral nerve regeneration have never been specifically evaluated in the literature. In this paper, the authors evaluated the dose-dependent role of BM-MNCs in peripheral nerve regeneration in a model of sciatic nerve transection in rats. METHODS: The right sciatic nerve of 60 adult female Wistar rats (randomized into 2 test groups and 1 control group, 20 rats in each group) underwent transection under an operating microscope. The cut ends of the nerve were approximated using 2 epineural microsutures. The gap was filled with low-dose (5 million BM-MNCs/100 MUl phosphate-buffered saline [PBS]) rat BM-MNCs in one group, high-dose (10 million BM-MNCs/100 MUl PBS) rat BM-MNCs in another group, and only PBS in the control group, and the approximated nerve ends were sealed using fibrin glue. Histological assessment was performed after 30 days by using semiquantitative and morphometric analyses and was done to assess axonal regeneration, percentage of myelinated fibers, axonal diameter, fiber diameter, and myelin thickness at distal-most sites (10 mm from site of repair), intermediate distal sites (5 mm distal to the repair site), and site of repair. RESULTS: The recovery of nerve cell architecture after nerve anastomosis was far better in the high-dose BM-MNC group than in the low-dose BM-MNC and control groups, and it was most evident (p < 0.02 in the majority of the parameters [3 of 4]) at the distal-most site. Overall, the improvement in myelin thickness was most significant with incremental dosage of BM-MNCs, and was evident at the repair, intermediate distal, and distal-most sites (p = 0.001). CONCLUSIONS: This study emphasizes the role of BM-MNCs, which can be isolated easily from bone marrow aspirates, in peripheral nerve injury and highlights their dose-dependent facilitation of nerve regeneration. PMID- 23039145 TI - Sliding dichotomy compared with fixed dichotomization of ordinal outcome scales in subarachnoid hemorrhage trials. AB - OBJECT: In randomized clinical trials of subarachnoid hemorrhage (SAH) in which the primary clinical outcomes are ordinal, it has been common practice to dichotomize the ordinal outcome scale into favorable versus unfavorable outcome. Using this strategy may increase sample sizes by reducing statistical power. Authors of the present study used SAH clinical trial data to determine if a sliding dichotomy would improve statistical power. METHODS: Available individual patient data from tirilazad (3552 patients), clazosentan (the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage trial [CONSCIOUS-1], 413 patients), and subarachnoid aneurysm trials (the International Subarachnoid Aneurysm Trial [ISAT], 2089 patients) were analyzed. Treatment effect sizes were examined using conventional fixed dichotomy, sliding dichotomy (logical or median split methods), or proportional odds modeling. Whether sliding dichotomy affected the difference in outcomes between the several age and neurological grade groups was also evaluated. RESULTS: In the tirilazad data, there was no significant effect of treatment on outcome (fixed dichotomy: OR = 0.92, 95% CI 0.80-1.07; and sliding dichotomy: OR = 1.02, 95% CI 0.87-1.19). Sliding dichotomy reversed and increased the difference in outcome in favor of the placebo over clazosentan (fixed dichotomy: OR = 1.06, 95% CI 0.65-1.74; and sliding dichotomy: OR = 0.85, 95% CI 0.52-1.39). In the ISAT data, sliding dichotomy produced identical odds ratios compared with fixed dichotomy (fixed dichotomy vs sliding dichotomy, respectively: OR = 0.67, 95% CI 0.55-0.82 vs OR = 0.67, 95% CI 0.53-0.85). When considering the tirilazad and CONSCIOUS-1 groups based on age or World Federation of Neurosurgical Societies grade, no consistent effects of sliding dichotomy compared with fixed dichotomy were observed. CONCLUSIONS: There were differences among fixed dichotomy, sliding dichotomy, and proportional odds models in the magnitude and precision of odds ratios, but these differences were not as substantial as those seen when these methods were used in other conditions such as head injury. This finding suggests the need for different outcome scales for SAH. PMID- 23039146 TI - Intradural anterior petrosectomy for petroclival meningiomas: a new surgical technique and results in 5 patients: technical note. AB - Excision of petroclival meningiomas remains a surgical challenge. Extradural anterior petrosectomy is widely used as a skull base approach for these tumors; however, this approach has significant procedure-related morbidity. The authors describe an alternative technique of tailored intradural petrosectomy for removal of petroclival meningiomas. This technique was used successfully in 5 patients. Gross-total or near-total resection was possible in 2 patients, whereas a subtotal removal was achieved in 3 patients, without significant morbidity. The petrous drilling was tailored depending on the extent of tumor. Transsylvian intradural anterior petrosectomy is a safe approach for petroclival meningiomas. This approach avoids problems related to subtemporal retraction and rationalizes the degree of bone drilling. PMID- 23039147 TI - Cavernous malformation. PMID- 23039148 TI - Awake mapping for resection of cavernous angioma and surrounding gliosis in the left dominant hemisphere: surgical technique and functional results: clinical article. AB - OBJECT: Maximal resection of symptomatic cavernous angioma (CA), including its surrounding gliosis if possible, has been recommended to minimize the risk of seizures or (re)bleeding. However, despite recent neurosurgical advances, such extensive CA removal is still a challenge in eloquent areas. The authors report a consecutive series of patients who underwent awake surgery for CA within the left dominant hemisphere in which intraoperative cortical-subcortical electrical stimulation was used. METHODS: Nine patients harboring a CA that was revealed by seizures in 6 cases and bleeding in 3 cases underwent resection. All CAs were located in the left dominant hemisphere: 3 temporal, 2 insular, 2 parietal, and 2 in the parietotemporal region. Awake mapping was performed in all cases by using intraoperative cortical-subcortical electrical stimulation and ultrasonography (except in 1 insular CA in which a neuronavigation system was used). RESULTS: Total removal of the CA was achieved in all patients, with identification and preservation of language and sensory-motor structures. In addition, the pericavernomatous gliosis was removed in 7 cases, according to the functional boundaries provided by intraoperative subcortical stimulation. In 2 cases, subcortical mapping revealed eloquent areas within the surrounding gliosis, which was voluntarily avoided. There was no postsurgical permanent deficit, no rebleeding, and no epilepsy in 7 cases (2 patients had rare seizures in the 1st year or two after surgery, and then complete arrest), with a mean follow-up of 28.5 months (range 3-64 months). CONCLUSIONS: These results suggest that intraoperative cortical-subcortical stimulation in awake patients represents a valuable adjunct to image-guided surgery with the aim of selecting the safer surgical approach for CAs involving eloquent areas. Moreover, such online mapping can be helpful when removing the pericavernomatous gliosis while preserving functional structures, which can persist within the hemosiderin rim. Thus, the authors propose that awake surgery be routinely considered, both to optimize the resection and to improve the quality of life through seizure control and avoidance of (re)bleeding for CAs located in the left dominant hemisphere. PMID- 23039149 TI - Medullary infarction as a poor prognostic factor after internal coil trapping of a ruptured vertebral artery dissection. AB - OBJECT: Internal coil trapping is a treatment method used to prevent rebleeding from a ruptured intracranial vertebral artery dissection (VAD). Postoperative medullary infarctions have been reported as a complication of this treatment strategy. The aim of this study was to determine the relationship between a postoperative medullary infarction and the clinical outcomes for patients with ruptured VADs treated with internal coil trapping during the acute stage of a subarachnoid hemorrhage (SAH). METHODS: A retrospective study identified 38 patients who presented between 2006 and 2011 with ruptured VADs and underwent internal coil trapping during the acute stage of SAH. The SAH was identified on CT scanning, and the diagnosis for VAD was rendered by cerebral angiography. Under general anesthesia, the dissection was packed with coils, beginning at the distal end and proceeding proximally. When VAD involved the origin of the posterior inferior cerebellar artery (PICA) with a large cerebellar territory, an occipital artery (OA)-PICA anastomosis was created prior to internal coil trapping. The pre- and postoperative radiological findings, clinical course, and outcomes were analyzed. RESULTS: The internal coil trapping was completed within 24 hours after admission. An OA-PICA anastomosis followed by internal coil trapping was performed in 5 patients. Postoperative rebleeding did not occur in any patient during a mean follow-up period of 16 months. The postoperative MRI studies showed medullary infarctions in 18 patients (47%). The mean length of the trapped VAD for the infarction group (15.7 +/- 6.0 mm) was significantly longer than that of the noninfarction group (11.5 +/- 4.3 mm) (p = 0.019). Three of the 5 patients treated with OA-PICA anastomosis had postoperative medullary infarction. The clinical outcomes at 6 months were favorable (modified Rankin Scale Scores 0-2) for 23 patients (60.5%) and unfavorable (modified Rankin Scale Scores 3-6) for 15 patients (39.5%). Of the 18 patients with postoperative medullary infarctions, the outcomes were favorable for 6 patients (33.3%) and unfavorable for 12 patients (66.7%). A logistic regression analysis predicted the following independent risk factors for unfavorable outcomes: postoperative medullary infarctions (OR 21.287 [95% CI 2.622-498.242], p = 0.003); preoperative rebleeding episodes (OR 7.450 [95% CI 1.140-71.138], p = 0.036); and a history of diabetes mellitus (OR 45.456 [95% CI 1.993-5287.595], p = 0.013). CONCLUSIONS: A postoperative medullary infarction was associated with unfavorable outcomes after internal coil trapping for ruptured VADs. Coil occlusion of the long segment of the VA led to medullary infarction, and an OA-PICA bypass did not prevent medullary infarction. A VA-sparing procedure, such as flow diversion by stenting, is an alternative treatment in the future, if this approach is demonstrated to effectively prevent rebleeding. PMID- 23039150 TI - Low-grade glioma surgery in eloquent areas: volumetric analysis of extent of resection and its impact on overall survival. A single-institution experience in 190 patients: clinical article. AB - OBJECT: A growing number of published studies have recently demonstrated the role of resection in overall survival (OS) for patients with gliomas. In this retrospective study, the authors objectively investigated the role of the extent of resection (EOR) in OS in patients with low-grade gliomas (LGGs). METHODS: Between 1998 and 2011, 190 patients underwent surgery for LGGs. All surgical procedures were conducted under corticosubcortical stimulation. The EOR was established by analyzing the pre- and postoperative volumes of the gliomas on T2 weighted MRI studies. The difference between the preoperative tumor volumes was also investigated by measuring the volumetric difference between the T2- and T1 weighted MRI images (DeltaVT2T1) to evaluate how the diffusive tumor-growing pattern affected the EOR achieved. RESULTS: The median preoperative tumor volume was 55 cm(3), and in almost half of the patients the EOR was greater than 90%. In this study, patients with an EOR of 90% or greater had an estimated 5-year OS rate of 93%, those with EOR between 70% and 89% had a 5-year OS rate of 84%, and those with EOR less than 70% had a 5-year OS rate of 41% (p < 0.001). New postoperative deficits were noted in 43.7% of cases, while permanent deficits occurred in 3.16% of cases. There were 41 deaths (21.6%), and the median follow up was 4.7 years. A further volumetric analysis was also conducted to compare 2 different intraoperative protocols (Series 1 [intraoperative electrical stimulation alone] vs Series 2 [intraoperative stimulation plus overlap of functional MRI/fiber tracking diffusion tensor imaging data on a neuronavigation system]). Patients in Series 1 had a median EOR of 77%, while those in Series 2 had a median EOR of 90% (p = 0.0001). Multivariate analysis showed that OS is influenced not only by EOR (p = 0.001) but also by age (p = 0.003), histological subtype (p = 0.005), and the DeltaVT2T1 value (p < 0.0001). Progression-free survival is similarly influenced by histological subtype (fibrillary astrocytoma, p = 0.003), EOR (p < 0.0001), and DeltaVT2T1 value (p < 0.0001), as is malignant progression-free survival (p = 0.003, p < 0.0001, and p < 0.0001, respectively). Finally, the study shows that the higher the DeltaVT2T1 value, the less extensive the currently possible resection, highlighting an apparent correlation between the DeltaVT2T1 value itself and EOR (p < 0.0001). CONCLUSIONS: The EOR and the DeltaVT2T1 values are the strongest independent predictors in improving OS as well as in delaying tumor progression and malignant transformation. Furthermore, the DeltaVT2T1 value may be useful as a predictive index for EOR. Finally, due to intraoperative corticosubcortical mapping and the overlap of functional data on the neuronavigation system, major resection is possible with an acceptable risk and a significant increase in expected OS. PMID- 23039151 TI - Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article. AB - OBJECT: Extent of resection (EOR) has been shown to be an important prognostic factor for survival in patients undergoing initial resection of glioblastoma (GBM), but the significance of EOR at repeat craniotomy for recurrence remains unclear. In this study the authors investigate the impact of EOR at initial and repeat resection of GBM on overall survival. METHODS: Medical records were reviewed for all patients undergoing craniotomy for GBM at the University of California San Francisco Medical Center from January 1, 2005, through August 15, 2009. Patients who had a second craniotomy for pathologically confirmed recurrence following radiation and chemotherapy were evaluated. Volumetric EOR was measured and classified as gross-total resection (GTR, > 95% by volume) or subtotal resection (STR, <= 95% by volume) after independent radiological review. Overall survival was compared between groups using univariate and multivariate analysis accounting for known prognostic factors, including age, eloquent location, Karnofsky Performance Status (KPS), and adjuvant therapies. RESULTS: Multiple resections were performed in 107 patients. Fifty-two patients had initial GTR, of whom 31 (60%) had GTR at recurrence, with a median survival of 20.4 months (standard error [SE] 1.0 months), and 21 (40%) had STR at recurrence, with a median survival of 18.4 months (SE 0.5 months) (difference not statistically significant). Initial STR was performed in 55 patients, of whom 26 (47%) had GTR at recurrence, with a median survival of 19.0 months (SE 1.2 months), and 29 (53%) had STR, with a median survival of 15.9 months (SE 1.2 months) (p = 0.004). A Cox proportional hazards model was constructed demonstrating that age (HR 1.03, p = 0.004), KPS score at recurrence (HR 2.4, p = 0.02), and EOR at repeat resection (HR 0.62, p = 0.02) were independent predictors of survival. Extent of initial resection was not a statistically significant factor (p = 0.13) when repeat EOR was included in the model, suggesting that GTR at second craniotomy could overcome the effect of an initial STR. CONCLUSIONS: Extent of resection at recurrence is an important predictor of overall survival. If GTR is achieved at recurrence, overall survival is maximized regardless of initial EOR, suggesting that patients with initial STR may benefit from surgery with a GTR at recurrence. PMID- 23039153 TI - Subarachnoid hemorrhage trials. PMID- 23039152 TI - Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial. AB - OBJECT: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a major cause of subsequent morbidity and mortality. Cilostazol, a selective inhibitor of phosphodiesterase 3, may attenuate cerebral vasospasm because of its antiplatelet and vasodilatory effects. A multicenter prospective randomized trial was conducted to investigate the effect of cilostazol on cerebral vasospasm. METHODS: Patients admitted with SAH caused by a ruptured anterior circulation aneurysm who were in Hunt and Kosnik Grades I to IV and were treated by clipping within 72 hours of SAH onset were enrolled at 7 neurosurgical sites in Japan. These patients were assigned to one of 2 groups: the usual therapy group (control group) or the add-on 100 mg cilostazol twice daily group (cilostazol group). The group assignments were done by a computer-generated randomization sequence. The primary study end point was the onset of symptomatic vasospasm. Secondary end points were the onset of angiographic vasospasm and new cerebral infarctions related to cerebral vasospasm, clinical outcome as assessed by the modified Rankin scale, and length of hospitalization. All end points were assessed for the intention-to-treat population. RESULTS: Between November 2009 and December 2010, 114 patients with SAH were treated by clipping within 72 hours from the onset of SAH and were screened. Five patients were excluded because no consent was given. Thus, 109 patients were randomly assigned to the cilostazol group (n = 54) or the control group (n = 55). Symptomatic vasospasm occurred in 13% (n = 7) of the cilostazol group and in 40% (n = 22) of the control group (p = 0.0021, Fisher exact test). The incidence of angiographic vasospasm was significantly lower in the cilostazol group than in the control group (50% vs 77%; p = 0.0055, Fisher exact test). Multiple logistic analyses demonstrated that nonuse of cilostazol is an independent factor for symptomatic and angiographic vasospasm. The incidence of new cerebral infarctions was also significantly lower in the cilostazol group than in the control group (11% vs 29%; p = 0.0304, Fisher exact test). Clinical outcomes at 1, 3, and 6 months after SAH in the cilostazol group were better than those in the control group, although a significant difference was not shown. There was also no significant difference in the length of hospitalization between the groups. No severe adverse event occurred during the study period. CONCLUSIONS: Oral administration of cilostazol is effective in preventing cerebral vasospasm with a low risk of severe adverse events. Clinical trial registration no. UMIN000004347, University Hospital Medical Information Network Clinical Trials Registry. PMID- 23039154 TI - The subthalamic nucleus at 3.0 Tesla: choice of optimal sequence and orientation for deep brain stimulation using a standard installation protocol: clinical article. AB - OBJECT: Reliable visualization of the subthalamic nucleus (STN) is indispensable for accurate placement of electrodes in deep brain stimulation (DBS) surgery for patients with Parkinson disease (PD). The aim of the study was to evaluate different promising new MRI methods at 3.0 T for preoperative visualization of the STN using a standard installation protocol. METHODS: Magnetic resonance imaging studies (T2-FLAIR, T1-MPRAGE, T2*-FLASH2D, T2-SPACE, and susceptibility weighted imaging sequences) obtained in 9 healthy volunteers and in 1 patient with PD were acquired. Two neuroradiologists independently analyzed image quality and visualization of the STN using a 6-point scale. Interrater reliability, contrast-to-noise ratios, and signal-to-noise ratios for the STN were calculated. For illustration of the anatomical accuracy, coronal T2*-FLASH2D images were fused with the corresponding coronal section schema of the Schaltenbrand and Wahren stereotactic atlas. RESULTS: The STN was best and reliably visualized on T2*-FLASH2D imaging (in particular, the coronal view). No major artifacts in the STN were observed in any of the sequences. Susceptibility-weighted, T2-SPACE, and T2*-FLASH2D imaging provided significantly higher contrast-to-noise ratio values for the STN than standard T2-weighted imaging. Fusion of the coronal T2*-FLASH2D and the digitized coronal atlas view projected the STN clearly within the boundaries of the STN found in anatomical sections. CONCLUSIONS: For 3.0-T MRI, T2*-FLASH2D (particularly the coronal view) provides optimal delineation of the STN using a standard installation protocol. PMID- 23039155 TI - Risk for symptomatic hemorrhage of cerebral cavernous malformations during pregnancy. AB - OBJECT: The threat of symptomatic hemorrhage from cerebral cavernous malformations (CCMs) during pregnancy remains poorly understood. The authors undertook this study to better define the risk of pregnancy-related hemorrhage in this population. METHODS: The records of female patients with sporadic (isolated lesions and negative family history) and familial forms of CCM, which were collected as part of the Barrow Neurological Institute CCM natural history study, were examined. Clinical data related to pregnancy, including type of delivery (vaginal or cesarean section) and any change in neurological status, were obtained from chart reviews and patient interviews. RESULTS: There were 168 pregnancies among 64 female patients with CCM (28 sporadic and 36 familial). Assuming an average of 46 weeks per pregnancy (40 weeks of gestation and 6 weeks of puerperium), patients were at risk for hemorrhage for a total of 148.6 years. Symptomatic hemorrhage (defined as new-onset or exacerbation of seizure activity or any change in neurological status) occurred during 5 pregnancies, with the most common symptom being seizures (4 cases). The overall risk for symptomatic hemorrhage was 3% per pregnancy; the risk was 1.8% per pregnancy in the sporadic group and 3.6% per pregnancy in the familial patients. There were 19 deliveries by cesarean section: 5 for obstetrical reasons, 8 for fear of possible hemorrhage, and 6 for unknown reasons. Vaginal delivery was performed without complications for the remaining 149 pregnancies. CONCLUSIONS: The authors' experience suggests that the risk of symptomatic hemorrhage from a CCM during pregnancy is not increased and that a history of CCM is not a contraindication to pregnancy or vaginal delivery. PMID- 23039156 TI - Congenital os odontoideum arising from the secondary ossification center without prior fracture. AB - The etiology of os odontoideum has been debated in the literature since the condition was initially described. The authors present the case of a 4-year-old girl who was found to have an os odontoideum with atlantoaxial instability after a motor vehicle collision. Imaging performed 3 years earlier demonstrated an incompletely ossified, cartilaginous, orthotopic os separated from the body of the odontoid process at the level of the secondary ossification center with a short odontoid process. This case presents the earliest imaging demonstration of the presence of a congenital orthotopic os odontoideum at the secondary ossification center. The authors review the pertinent literature and propose that the etiology of os odontoideum is multifactorial and related to the embryology and vascular supply to the odontoid process. PMID- 23039157 TI - Cooperative assembly of Zn cross-linked artificial tripeptides with pendant hydroxyquinoline ligands. AB - An artificial peptide with three pendant hydroxyquinoline (hq) ligands on a palindromic backbone was designed and used to form multimetallic assemblies. Reaction of the tripeptide with zinc acetate led to a highly fluorescent tripeptide duplex with three Zn(II) coordinative cross-links. The binding process was monitored using spectrophotometric absorbance and emission titrations; NMR spectroscopy and mass spectrometry confirmed the identity and stoichiometry of the product structure. Titrations monitoring duplex formation of the zinc tripeptide structure had a sigmoidal shape, equilibrium constant larger than the monomeric analogue, and a Hill coefficient >1, all of which indicate positive cooperativity. Photophysical characterization of the quantum yield, excited state lifetime, and polarization anisotropy are compared with the monometallic zinc-hq analogue. A higher than expected quantum yield for the trimetallic complex suggests a structure in which the central chromophore is shielded from solvent by pi-stacking with neighboring Zn(II) complexes. PMID- 23039158 TI - 3D micro-CT analysis of the interface voids associated with Thermafil root fillings used with AH Plus or a flowable MTA sealer. AB - AIM: To investigate nondestructively the percentage of 3D voids and marginal gaps in a pre-defined interface volume of interest (VOI) within root fillings produced by Thermafil Obturators with either a hydrophobic epoxy-resin-based sealer (AH Plus) or a hydrophilic flowable calcium-silicate sealer [mineral trioxide aggregate (MTA) Flow]. METHODOLOGY: Sixteen single root canals from extracted premolar teeth were prepared with ProTaper rotary instruments, randomly allocated into two groups (n = 8) and filled with size 30 Thermafil Obturators in association with AH Plus or MTA Flow sealers. The filled roots were stored at 37 degrees C in 5 mL of Hank's balanced salt solution (HBSS) used to represent body fluids and scanned after 7 days and 6 months using a high-resolution micro-CT. From each root, images of 3000 sections were analysed in 3D and binarized using a high-resolution micro-CT (4-MU resolution). The 3D distribution of voids (porosity and marginal gaps) at the gutta-percha-sealer-dentine interface was detected through a threshold grey level and expressed as percentage of the 40-MU thick pre-defined interface VOI (20 MU of interface dentine and 20 MU of gutta percha/sealer). A method of analysis based on the root canal segmentation was used, and coronal, middle and apical thirds considered separately. The percentage of 3D void volume was compared statistically using one-way anova (significance for P < 0.05). Environmental Scanning Electron Microscope with Energy Dispersive X-ray (ESEM-EDX) analysis was performed on the surface of both sealers after soaking in HBSS. RESULTS: Micro-CT detected gaps at the dentine-sealer interface in both groups. Void volumes wider than 10.21 MUm(3) with 1.35 MUm diameter were detected. Cul-de-sac-type voids (blind pores) and through-and-through voids (continuous pores) were discriminated. The apical thirds had a significantly lower 3D void volume (P < 0.05) than the middle and coronal thirds. The 3D void volume reduced significantly (P < 0.05) over time. ESEM-EDX analysis revealed that MTA Flow sealer created a dense apatite layer after 7 days of immersion in HBSS, whilst only sparse calcium phosphate deposits were detected on AH Plus even after 28 days. CONCLUSIONS: Micro-CT proved to be a powerful nondestructive 3D analysis tool for visualizing the porous internal microstructure of dental/endodontic materials at the interface with dentine. The proportion of voids was least in the apical third of root canals. Voids reduced over time in the presence of simulated body fluid. PMID- 23039160 TI - Comparative transcriptome profiling in winter wheat grown under different agricultural practices. AB - Wheat (Triticum aestivum L.), one of the three most important cereal crops worldwide, has a dominant position in Europe due to its adaptability and consumer acceptance particularly as an organic food commodity. Organic agriculture is developing rapidly, and its authenticity is presently a subject of great concern to food authorities, as incorrect labeling can represent commercial fraud. A comparative transcriptome profiling was conducted on winter wheat flag leaves of several cultivars growing in open fields under different agricultural production systems. Performing a microarray study, 10 transcripts differentially expressed in organic and conventional growing conditions were identified in Tommi and Centenaire cultivars. Transcript abundance profiles of selected probe sets were independently confirmed by quantitative reverse-transcription PCR analysis, tested on Tommi, Centenaire, and Cubus cultivars from different growing-year and geographical sites. Univariate and multivariate statistical analysis showed that the global wheat transcriptome is influenced by the agricultural system indicating a promising approach for analytical verification of the production system of wheat at the farm level. PMID- 23039159 TI - In vivo reflectance confocal microscopy of Basal cell carcinoma: feasibility of preoperative mapping of cancer margins. AB - BACKGROUND: Reflectance confocal microscopy (RCM) images skin at cellular resolution and has shown utility for the diagnosis of nonmelanoma skin cancer in vivo. It has the potential to define lesion margins before surgical therapy. OBJECTIVES: To investigate the feasibility of RCM in defining the margins of basal cell carcinoma before surgery. METHODS: The margins of 10 lesions were evaluated using RCM. Biopsies of the margins were used to confirm the results. A protocol was constructed to define margins. RCM was used to delineate preoperative surgical margins in 13 patients. Intraoperative frozen biopsy was used to confirm the margins. RESULTS: In seven of 10 (70.0%) cases, the margins of the cancer were identified suing RCM. The tumor island was the critical feature in identifying the margins. In 12 of 13 (92.3%) cases, frozen biopsy corroborated that the surgical margins delineated by RCM were clear. CONCLUSION: RCM imaging of the margins is feasible and demonstrates the possibility of preoperative mapping of cancer margins. PMID- 23039161 TI - Microsphere erosion in outer hydrogel membranes creating macroscopic porosity to counter biofouling-induced sensor degradation. AB - Biofouling and tissue inflammation present major challenges toward the realization of long-term implantable glucose sensors. Following sensor implantation, proteins and cells adsorb on sensor surfaces to not only inhibit glucose flux but also signal a cascade of inflammatory events that eventually lead to permeability-reducing fibrotic encapsulation. The use of drug-eluting hydrogels as outer sensor coatings has shown considerable promise to mitigate these problems via the localized delivery of tissue response modifiers to suppress inflammation and fibrosis, along with reducing protein and cell absorption. Biodegradable poly (lactic-co-glycolic) acid (PLGA) microspheres, encapsulated within a poly (vinyl alcohol) (PVA) hydrogel matrix, present a model coating where the localized delivery of the potent anti-inflammatory drug dexamethasone has been shown to suppress inflammation over a period of 1-3 months. Here, it is shown that the degradation of the PLGA microspheres provides an auxiliary venue to offset the negative effects of protein adsorption. This was realized by: (1) the creation of fresh porosity within the PVA hydrogel following microsphere degradation (which is sustained until the complete microsphere degradation) and (2) rigidification of the PVA hydrogel to prevent its complete collapse onto the newly created void space. Incubation of the coated sensors in phosphate buffered saline (PBS) led to a monotonic increase in glucose permeability (50%), with a corresponding enhancement in sensor sensitivity over a 1 month period. Incubation in serum resulted in biofouling and consequent clogging of the hydrogel microporosity. This, however, was partially offset by the generated macroscopic porosity following microsphere degradation. As a result of this, a 2-fold recovery in sensor sensitivity for devices with microsphere/hydrogel composite coatings was observed as opposed to similar devices with blank hydrogel coatings. These findings suggest that the use of macroscopic porosity can reduce sensitivity drifts resulting from biofouling, and this can be achieved synergistically with current efforts to mitigate negative tissue responses through localized and sustained drug delivery. PMID- 23039162 TI - A worldwide investigation of critical care research coordinators' self-reported role and professional development priorities: the winner survey. AB - AIMS AND OBJECTIVES: To describe the self-reported role and professional development priorities of research coordinators in different regions of the world. BACKGROUND: Research coordinators employed in critical care settings provide clinical and technical expertise in the development, conduct and completion of clinical research studies. Knowledge of this specialised role is well established in some parts of the world, yet emerging in others. DESIGN: Descriptive exploratory study involving research coordinators outside of Australia and New Zealand. METHOD: An anonymous, structured, multiple-choice, web based questionnaire conducted between April-May 2011. RESULTS: There were 80 respondents from North America (61%), Europe (29%) and Latin America (10%). The majority of respondents performed data collection and obtained informed consent, and half had presented study findings at conferences or wrote scholarly articles, despite a greater willingness to do so. Requisite skills for the research coordinator role included clinical research knowledge, creative problem solving and the ability to identify/resolve ethical questions. 'Best' reported aspects of the role were promotion of evidence-based clinical practice, intellectual stimulation and autonomy. 'Worst' aspects included heavy workload, lack of funding and recognition. CONCLUSION: Research coordinators working in critical care settings collect data, require clinical research knowledge and problem solving skills and are interested in, but have less confidence in, dissemination of research findings. They feel isolated with a lack of support and inadequate remuneration for the effort and time required to maintain the high standards of their role. This is outweighed by the satisfaction derived from promoting the research process and autonomy. Further observational studies aimed at clarifying and advancing the role of the research coordinator is warranted. RELEVANCE TO CLINICAL PRACTICE: This study offers insight into the global roles and responsibilities as reported by research coordinators employed in critical care settings. PMID- 23039163 TI - Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers. AB - BACKGROUND: While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer. METHODS: 221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results were compared to healthy controls (n = 2,465). RESULTS: The SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI 1.19-3.10; p = 0.009; SNP309TG+GG combined: OR 1.61; CI 1.15-2.27; p = 0.005). In contrast, the SNP285C allele reduced risk of BRCA1 related ovarian cancer in carriers of the SNP309G allele (OR 0.50; CI 0.24-1.04; p = 0.057). Censoring individuals carrying the SNP285C/309G haplotype from the analysis elevated the OR related to the SNP309G allele (OR 1.73; CI 1.23-2.45; p = 0.002). The mean age at disease onset was 3.1 years earlier in carriers of SNP309TG+GG as compared to carriers of SNP309TT (p = 0.068). No such associations were found in BRCA2 related ovarian cancer. CONCLUSIONS: Our results indicate the SNP309G allele to increase and the SNP285C allele to reduce the risk of BRCA1 related ovarian cancer. If confirmed in independent studies, this finding may have implications to counseling and decision-making regarding risk reducing measures in BRCA1 mutation carriers. PMID- 23039164 TI - Living in deprived urban districts increases perinatal health inequalities. AB - OBJECTIVE: Analyses of the effects of place of residence, socioeconomic status and ethnicity on perinatal mortality and morbidity in the Netherlands. METHODS: Epidemiological analysis of all singleton deliveries > 22 gestational weeks (871,889 live born and 5927 stillborn) from the Dutch National Perinatal Registry 2002-2006. Multiple logistic regression analysis was used to determine whether place of residence (deprived neighborhood, or not) contributed to the adverse perinatal outcome (defined as perinatal mortality, preterm birth, small for gestational age, congenital abnormalities or Apgar score <7, 5 min after birth), additional to individual pregnancy characteristics, demographic characteristics, ethnic background and socioeconomic class. RESULTS: Incidence of adverse perinatal outcome was 16.7%. After adjustment the excess risk for perinatal mortality in deprived districts was 21%, for preterm birth 16%, for small-for gestational age 11%, and for Apgar score <7 after 5 min 11%. CONCLUSIONS: Perinatal inequalities appear impressive in both urban and nonurban areas, with a significant additive risk of living in a deprived neighborhood. Excess risk for perinatal mortality generally outranges that for morbidity, suggesting both an etiological and prognostic pathway for neighborhood effects. A distinct pattern exists for congenital anomalies, for which first trimester adverse selection effects may be responsible. PMID- 23039165 TI - Neonatal levels of neurotrophic factors and risk of autism spectrum disorders. AB - OBJECTIVE: To examine levels of 3 neurotrophic factors (NTFs): Brain derived neurotrophic factor (BDNF), Neurotrophin-4 (NT-4), and transforming growth factor beta (TGF-beta) in dried blood spot samples of neonates diagnosed with autism spectrum disorders (ASD) later in life and frequency-matched controls. METHOD: Biologic samples were retrieved from the Danish Newborn Screening Biobank. NTFs for 414 ASD cases and 820 controls were measured using Luminex technology. Associations were analyzed with continuous measures (Tobit regression) as well as dichotomized at the lower and upper 10th percentiles cutoff points derived from the controls' distributions (logistic regression). RESULTS: ASD cases were more likely to have BDNF levels falling in the lower 10th percentile (odds ratios [OR], 1.53 [95% confidence intervals (CI), 1.04-2.24], P-value = 0.03). Similar pattern was seen for TGF-beta in females with ASD (OR, 2.36 [95% CI, 1.05-5.33], P-value = 0.04). For NT-4, however, ASD cases diagnosed with ICD-10 only were less likely to have levels in upper 10th percentile compared with controls (OR, 0.22 [95% CI, 0.05-0.98], P-value = 0.05). CONCLUSION: Results cautiously indicate decreased NTFs levels during neonatal period in ASD. This may contribute to the pathophysiology of ASD through impairments of neuroplasticity. Further research is required to confirm our results and to examine the potential therapeutic effects of NTFs in ASD. PMID- 23039166 TI - Patella re-alignment in children with a modified Grammont technique. AB - BACKGROUND AND PURPOSE: In skeletally immature patients, surgical options due to recurrent patella dislocation are limited, because bony procedures bear the risk of growth disturbances. In this retrospective study, we report the long-term functional and radiographic outcome in skeletally immature patients using the modified Grammont surgical technique. PATIENTS: Between 1999 and 2004, 65 skeletally immature knees (49 children) were treated with a modified Grammont procedure: an open lateral release and a shift of the patella tendon insertion below the growth plate on the tuberositas tibia, allowing the tendon to medialize. At mean 8 (5.6-11) years after surgery, 58 knees in 43 patients were evaluated by clinical examination, from functional scores (Lysholm, Tegner), and from radiographs of the knees. RESULTS: Mean Lysholm score was 82 postoperatively. Tegner score decreased from 6.2 to 5. Eight knees had a single dislocation within 3 months of surgery. 3 knees had repeated late dislocations, all with a high grade of trochlea dysplasia. 6 knees showed mild signs of osteoarthritis. No growth disturbances were observed. INTERPRETATION: The modified Grammont technique in skeletally immature patients allows restoration of the distal patella tendon alignment by dynamic positioning. Long-term results showed that there were no growth disturbances and that there was good functional outcome. However, patients with a high grade of trochlea dysplasia tended to re dislocate. PMID- 23039167 TI - The risk of revision due to dislocation after total hip arthroplasty depends on surgical approach, femoral head size, sex, and primary diagnosis. An analysis of 78,098 operations in the Swedish Hip Arthroplasty Register. AB - BACKGROUND AND PURPOSE: The effects of patient-related and technical factors on the risk of revision due to dislocation after primary total hip arthroplasty (THA) are only partly understood. We hypothesized that increasing the femoral head size can reduce this risk, that the lateral surgical approach is associated with a lower risk than the posterior and minimally invasive approaches, and that gender and diagnosis influence the risk of revision due to dislocation. PATIENTS AND METHODS: Data on 78,098 THAs in 61,743 patients performed between 2005 and 2010 were extracted from the Swedish Hip Arthroplasty Register. Inclusion criteria were a head size of 22, 28, 32, or 36 mm, or the use of a dual-mobility cup. The covariates age, sex, primary diagnosis, type of surgical approach, and head size were entered into Cox proportional hazards models in order to calculate the adjusted relative risk (RR) of revision due to dislocation, with 95% confidence intervals (CI). RESULTS: After a mean follow-up of 2.7 (0-6) years, 399 hips (0.5%) had been revised due to dislocation. The use of 22-mm femoral heads resulted in a higher risk of revision than the use of 28-mm heads (RR = 2.0, CI: 1.2-3.3). Only 1 of 287 dual-mobility cups had been revised due to dislocation. Compared with the direct lateral approach, minimally invasive approaches were associated with a higher risk of revision due to dislocation (RR = 4.2, CI: 2.3-7.7), as were posterior approaches (RR = 1.3, CI: 1.1-1.7). An increased risk of revision due to dislocation was found for the diagnoses femoral neck fracture (RR = 3.9, CI: 3.1-5.0) and osteonecrosis of the femoral head (RR = 3.7, CI: 2.5-5.5), whereas women were at lower risk than men (RR = 0.8, CI: 0.7 1.0). Restriction of the analysis to the first 6 months after the index procedure gave similar risk estimates. INTERPRETATION: Patients with femoral neck fracture or osteonecrosis of the femoral head are at higher risk of dislocation. Use of the minimally invasive and posterior approaches also increases this risk, and we raise the question of whether patients belonging to risk groups should be operated using lateral approaches. The use of femoral head diameters above 28 mm or of dual-mobility cups reduced this risk in a clinically relevant manner, but this observation was not statistically significant. PMID- 23039168 TI - Characterization of ten highly polymorphic microsatellite loci for the intertidal mussel Perna perna, and cross species amplification within the genus. AB - BACKGROUND: The brown mussel Perna perna (Linnaeus, 1758) is a dominant constituent of intertidal communities and a strong invader with multiple non native populations distributed around the world. In a previous study, two polymorphic microsatellite loci were developed and used to determine population level genetic diversity in invasive and native P. perna populations. However, higher number of microsatellite markers are required for reliable population genetic studies.In this context, in order to understand P. perna origins and history of invasion and to compare population genetic structure in native versus invaded areas, we developed 10 polymorphic microsatellite markers. FINDINGS: Described microsatellite markers were developed from an enriched genomic library. Analyses and characterization of loci using 20 individuals from a population in Western Sahara revealed on average 11 alleles per locus (range: 5-27) and mean gene diversity of 0.75 (range: 0.31 - 0.95). One primer pair revealed possible linkage disequilibrium while heterozygote deficiency was significant at four loci. Six of these markers cross-amplified in P. canaliculus (origin: New Zealand). CONCLUSIONS: Developed markers will be useful in addressing a variety of questions concerning P. perna, including dispersal scales, genetic variation and population structure, in both native and invaded areas. PMID- 23039169 TI - Regioselective ortho-arylation and alkenylation of N-alkyl benzamides with boronic acids via ruthenium-catalyzed C-H bond activation: an easy route to fluorenones synthesis. AB - A highly regioselective ruthenium-catalyzed ortho-arylation of substituted N alkyl benzamides with aromatic boronic acids in the presence of [{RuCl(2)(p cymene)}(2)], AgSbF(6), and Ag(2)O is described. Further, ortho-arylated N-alkyl benzamides were converted into fluorenones in the presence of trifluoroacetic anhydride and HCl. PMID- 23039170 TI - Staphylococcal superantigen-like protein 5 induces thrombotic and bleeding complications in vivo: inhibition by an anti-SSL5 antibody and the glycan Bimosiamose. PMID- 23039171 TI - Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. AB - BACKGROUND: Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-beta signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes. OBJECTIVES: We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis. METHODS: We performed a phase II double-blinded trial on patients with scleroderma with either morphoea involving > 20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) >= 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention. RESULTS: Twenty eight patients were included in the study with a mean age of 48.9 years (range 30 71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0.10 in imatinib group vs. -0.16 in placebo group, P = 0.098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups. CONCLUSIONS: This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements. PMID- 23039173 TI - Oxidative stress markers are not associated with outcomes after pediatric heart surgery. AB - OBJECTIVES: To investigate whether perioperative serum levels of oxidative stress markers, thiobarbituric acid reactive substances (TBARS), and carbonyl moieties are associated with outcomes in children after heart surgery. BACKGROUND: Oxidative stress markers are increased following heart surgery with cardiopulmonary bypass (CPB) and can play a role in ischemia-reperfusion injury, but its associations with myocardial dysfunction, low cardiac output syndrome (LCOS), and outcomes are not proven. METHODS: In a retrospective secondary analysis of a cohort study comprising 55 children (median age, 109 [2-611] days), we compared pre-, intra- and postoperative serum levels of TBARS and carbonyl moieties among patients with and without postoperative LCOS, cyanotic and acyanotic congenital heart disease (CHD), and survivors and nonsurvivors. We also assessed the independent effect of TBARS and carbonyl moieties peak levels on the mortality-adjusted hospital length of stay (aLOS). RESULTS: Patients who developed postoperative LCOS (n = 36) were significantly younger, more frequently cyanotic, more severely ill, and underwent more complex procedures with longer CPB. However, TBARS and carbonyl moieties serum levels did not change significantly over time. Moreover, they were not significantly different in patients with or without LCOS, cyanotic and acyanotic CHD, or survivors and nonsurvivors. There was a significant correlation between TBARS and tumor necrosis factor alpha (TNF-alpha) peak serum levels. Neither TBARS nor carbonyl moieties peak serum levels were independently associated with aLOS. CONCLUSIONS: In conclusion, oxidative stress markers TBARS and carbonyl moieties were not associated with the development of LCOS, the aLOS, or mortality in children after heart surgery with CPB. PMID- 23039172 TI - Both cardiovascular and non-cardiovascular comorbidity are related to health status in well-controlled type 2 diabetes patients: a cross-sectional analysis. AB - BACKGROUND: Type 2 diabetes patients have a decreased health-related quality of life compared to healthy persons, especially regarding physical functioning and well-being. Health-related quality of life is even lower in type 2 diabetes patients when other diseases co-exist. In contrast to earlier studies, we assessed the associations between the number and type of comorbidities and health status in well-controlled type 2 diabetes patients, in whom treatment goals for HbA1c, blood pressure and cholesterol had been reached. Approximately one in five type 2 diabetes patients belongs to this group. METHODS: Cross-sectional analysis was performed in 2086 well-controlled (HbA1c <=58 mmol/mol, systolic blood pressure <=145 mmHg, total cholesterol <=5.2 mmol/l and not using insulin) type 2 diabetes patients in general practice. Both number and type (cardiovascular and non-cardiovascular) of comorbidities were determined for each patient. Health status was assessed with the questionnaires Short Form-36 (SF-36) and EuroQol (EQ). The SF-36 generates eight dimensions of health and a Physical and Mental Component Score (PCS and MCS), scale: 0-100. The EQ consists of two parts: EQ-5D and EQ Visual Analogue Scale. Multivariable linear regression analysis was used to assess if number and type of comorbidities were associated with health status. RESULTS: Well-controlled type 2 diabetes patients with comorbidities had a much lower health status, with a decrease ranging from -1.5 for the MCS to -26.3 for role limitations due to physical problems, compared to those without. Health status decreased when the number of comorbidities increased, except for mental health, role limitations due to emotional problems, MCS and both EQ measures. In patients with both cardiovascular and non-cardiovascular comorbidity, physical functioning, role limitations due to physical problems and PCS were significantly lower than in patients with only cardiovascular comorbidity. Physical functioning was also lower compared to patients with only non-cardiovascular comorbidity. CONCLUSIONS: Even acceptable values of HbA1c, blood pressure and cholesterol in type 2 diabetes patients are not necessarily related with a good health status. We have shown that comorbidities have a large impact on health status. Physicians may take into account patient's health status and integrate the impact of comorbidities into diabetes care. PMID- 23039174 TI - Development and characterization of dexamethasone mesylate anchored on multi walled carbon nanotubes. AB - Dexamethasone conjugated multi wall carbon nanotubes (DEX-MWCNTs) were developed for controlled delivery of a doxorubicin HCl (DOX) with reduced toxicity. The DEX MWCNTs were prepared by sequential functionalization of MWCNTs. The DOX was physically loaded onto the purified raw MWCNTs and DEX-MWCNTs at pH 7.4 phosphate buffer solutions (PBS) and evaluated for entrapment efficiency, in vitro release, hemolytic toxicity and ex vivo studies on "A-549" lung epithelial cancer cell line. DOX was efficiently loaded into purified raw and DEX-MWCNTs formulation and the highest entrapment of DOX was found to be 92.6 +/- 0.5% in the case of DEX MWCNTS with good dispersion. In-vitro release of DOX was studied from the DOX/DEX MWCNTs at pH 5.5 and 7.4 (PBS), which displayed an initial faster followed by sustained release up to 200 h. Further, DOX/DEX-MWCNTs were found to be less hemolytic and more cytotoxic as compared to free DOX on "A-549" lung epithelial cancer cell line. PMID- 23039176 TI - Indirect supportive evidence for diagnosis of tuberculosis-related uveitis: from the tuberculin skin test to the new interferon gamma release assays. AB - PURPOSE: To evaluate clinical and paraclinical parameters for the indirect diagnosis of tuberculosis-related uveitis (TRU). METHODS: Prospective 2-year study in a tertiary referral centre. Patients with clinically suspected TRU were recruited. Demographical and clinical data were recorded. QuantiFERON((r)) -TB Gold (QFT), tuberculosis skin test (TST) and pulmonary X-ray were performed, and other possible uveitis aetiologies were ruled out. Further investigations were also performed case by case after consultation. After final assessment, standard antituberculosis therapy was started if TRU was considered highly probable. Finally, diagnosis of TRU was established according to current criteria and set as gold standard. Strength of association for TRU was determined by odds ratio and compared by appropriate tests. Concordance and binary classification tests were also assessed. RESULTS: The study included 103 patients, 54 men and 49 women. Mean age 45.6 years. Sixty-eight patients were Spanish-born and 35 were foreign-born. Final diagnosis included 33 (32%) cases of TRU and 70 (67%) cases with other diagnoses. Asian origin (OR = 3.50, p = 0.046), previous tuberculosis (TB) contact (OR = 2.61, p = 0.026), TB in the past (OR = 6.18, p = 0.004) and associated retinal vasculitis (OR = 7.85, p < 0.001) were significantly related to TRU. Sensitivity (S) and specificity (Sp) of the TST and QFT did not differ significantly (S 87% versus 90% and Sp 85% versus 82%, respectively) with fair agreement (k = 0.607). CONCLUSION: In a Western urban multi-ethnic population, patients from Asia, TB history or contact in the past and vasculitis are at higher risk of TRU. TST and QF are complementary providing enough S and Sp to support the diagnosis. PMID- 23039177 TI - Novel surgical technique for ossification of posterior longitudinal ligament in the thoracic spine. AB - Several surgical procedures have been developed to treat thoracic ossification of the posterior longitudinal ligament (OPLL). However, favorable surgical results are not always achieved, and consistent protocols and procedures for surgical treatment of thoracic OPLL have not been established. This technical note describes a novel technique to achieve anterior decompression via a single posterior approach. Three patients with a beak-type thoracic OPLL underwent surgery in which the authors' technique was used. Complete removal of the ossified PLL was achieved in all cases. With the patient in the prone position, the authors performed total resection of the posterior elements at the anterior decompression levels. This maneuver included not only laminectomies but also removal of the transverse processes and pedicles, which allowed space to be created bilaterally at the sides of the dural sac for the subsequent anterior decompression. The thoracic nerves at the levels of anterior decompression were ligated bilaterally and lifted up to manipulate the ossified ligament and the dural sac. An anterior decompression was then performed posteriorly. The PLL was floated without any difficulty. After exfoliation of the adhesions between the ossified ligament and the ventral aspect of the dural sac, the ossified PLL was removed. In every step of the anterior decompression, the space created in the bilateral sides of the dural sac allowed the surgeons to see the OPLL and anterolateral aspect of the dural sac directly and easily. After removal of the ossified PLL, posterior instrumented fusion was performed. This surgical procedure allows the surgeon to perform, safely and effectively, anterior decompression via a posterior approach for thoracic OPLL. PMID- 23039175 TI - Pain in experimental autoimmune encephalitis: a comparative study between different mouse models. AB - BACKGROUND: Pain can be one of the most severe symptoms associated with multiple sclerosis (MS) and develops with varying levels and time courses. MS-related pain is difficult to treat, since very little is known about the mechanisms underlying its development. Animal models of experimental autoimmune encephalomyelitis (EAE) mimic many aspects of MS and are well-suited to study underlying pathophysiological mechanisms. Yet, to date very little is known about the sensory abnormalities in different EAE models. We therefore aimed to thoroughly characterize pain behavior of the hindpaw in SJL and C57BL/6 mice immunized with PLP139-151 peptide or MOG35-55 peptide respectively. Moreover, we studied the activity of pain-related molecules and plasticity-related genes in the spinal cord and investigated functional changes in the peripheral nerves using electrophysiology. METHODS: We analyzed thermal and mechanical sensitivity of the hindpaw in both EAE models during the whole disease course. Qualitative and quantitative immunohistochemical analysis of pain-related molecules and plasticity-related genes was performed on spinal cord sections at different timepoints during the disease course. Moreover, we investigated functional changes in the peripheral nerves using electrophysiology. RESULTS: Mice in both EAE models developed thermal hyperalgesia during the chronic phase of the disease. However, whereas SJL mice developed marked mechanical allodynia over the chronic phase of the disease, C57BL/6 mice developed only minor mechanical allodynia over the onset and peak phase of the disease. Interestingly, the magnitude of glial changes in the spinal cord was stronger in SJL mice than in C57BL/6 mice and their time course matched the temporal profile of mechanical hypersensitivity. CONCLUSIONS: Diverse EAE models bearing genetic, clinical and histopathological heterogeneity, show different profiles of sensory and pathological changes and thereby enable studying the mechanistic basis and the diversity of changes in pain perception that are associated with distinct types of MS. PMID- 23039178 TI - Nations' income inequality predicts ambivalence in stereotype content: how societies mind the gap. AB - Income inequality undermines societies: The more inequality, the more health problems, social tensions, and the lower social mobility, trust, life expectancy. Given people's tendency to legitimate existing social arrangements, the stereotype content model (SCM) argues that ambivalence-perceiving many groups as either warm or competent, but not both-may help maintain socio-economic disparities. The association between stereotype ambivalence and income inequality in 37 cross-national samples from Europe, the Americas, Oceania, Asia, and Africa investigates how groups' overall warmth-competence, status-competence, and competition-warmth correlations vary across societies, and whether these variations associate with income inequality (Gini index). More unequal societies report more ambivalent stereotypes, whereas more equal ones dislike competitive groups and do not necessarily respect them as competent. Unequal societies may need ambivalence for system stability: Income inequality compensates groups with partially positive social images. PMID- 23039179 TI - Plasma trough levels of adalimumab and infliximab in terms of clinical efficacy during the treatment of psoriasis. AB - We examined the relation between adalimumab and infliximab plasma trough levels, anti-adalimumab and anti-infliximab antibody formation. We analyzed plasma from 32 adalimumab-treated and 20 infliximab-treated psoriasis patients for evaluating trough levels of each drug. The presence of anti-adalimumab and anti-infliximab antibodies was analyzed and the severity of psoriasis was evaluated. At week 28, 25 out of 32 and at week 48, 21 out of 30 adalimumab-treated patients maintained as more than PASI 75. At week 28, 12 out of 20 and at week 48, nine out of 18 infliximab-treated patients were evaluated as more than PASI 75. In patients treated with 40 mg adalimumab every other week, the mean trough level was 7.62 MUg/mL (range, 0.05-10.6) at week 48. In patients treated with 80 mg adalimumab every other week, the mean trough level was 8.61 MUg/mL (range, 0.08-13.5) at week 48. Mean trough level of infliximab-treated cases (4.1-5.2 mg/kg; mean, 4.6) was 4.64 MUg/mL (range, 0.03-16.9) at week 48. Anti-adalimumab antibody was detected in five out of 32 cases and anti-infliximab antibody was detected in six out of 20 cases, respectively, at weeks 24 and 48. The optimal cut-off values of adalimumab and infliximab concentration for more than PASI 75 were more than 7.84 MUg/mL and more than 0.92 MUg/mL, respectively. The trough levels of adalimumab and infliximab in psoriasis patients were positively associated with clinical response and were significantly lower in cases having anti-adalimumab or anti infliximab antibodies. PMID- 23039180 TI - Picture-based memory impairment screen for dementia. AB - OBJECTIVES: To develop and validate a picture-based memory impairment screen (PMIS) for the detection of dementia. DESIGN: Cross-sectional. SETTING: Outpatient clinics, Baby Memorial Hospital, Kozhikode city in the southern Indian state of Kerala. PARTICIPANTS: Three hundred four community-residing adults aged 55 to 94 with a mean education level of 8 years; 65 were diagnosed with dementia. MEASUREMENTS: PMIS: a culture-fair picture-based cognitive screen designed to be administered by nonspecialists. Diagnostic accuracy estimates (sensitivity, specificity, positive and negative predictive power) of PMIS cut-scores in detecting dementia (range 0-8). RESULTS: PMIS scores were worse in participants with dementia (1.5) than in controls (7.7, P < .001). At the optimal cut-score of 5, PMIS had a sensitivity of 95.4% (95% confidence interval (CI) = 90.3-100.0%) and a specificity of 99.2% (95% CI = 98.0-100.0%) for detecting dementia. In the 167 participants with <10 years of education, PMIS scores of five or less had a sensitivity of 97.8% (95% CI = 93.6-100.0%) and specificity of 99.2% (95% CI = 97.6-100.0%). The PMIS had better specificity than the Mini-Mental State Examination in detecting dementia, especially in older adults with low education. CONCLUSION: The PMIS is a brief and reliable screen for dementia in elderly populations with variable literacy rates. PMID- 23039181 TI - Differential regulation and impact of fucosyltransferase VII and core 2 beta1,6-N acetyl-glycosaminyltransferase for generation of E-selectin and P-selectin ligands in murine CD4+ T cells. AB - Ligands for E-selectin and P-selectin (E-lig and P-lig) are induced on CD4+ T cells upon differentiation into effector T cells. Glycosyltransferases, especially alpha 1,3-fucosyltransferase VII (FucT-VII) and core 2 beta1,6-N acetyl-glycosaminyltransferase I (C2GlcNAcT-I), are critical for their synthesis. We here analysed the signals that control the expression of E-lig, P-lig and mRNA coding for FucT-VII and C2GlcNAcT-I. In line with previous reports, we found that P-lig expression correlates with the regulation of C2GlcNAcT-I, whereas E-lig expression can occur at low levels of C2GlcNAcT-I mRNA but requires high FucT-VII mRNA expression. Interestingly, the two enzymes are regulated by different signals. Activation-induced C2GlcNAcT-I up-regulation under permissive (T helper type 1) conditions was strongly reduced by cyclosporin A (CsA), suggesting the involvement of T-cell receptor-dependent, calcineurin/NFAT-dependent signals in combination with interleukin-12 (IL-12) -mediated signals in the regulation of C2GlcNAcT-I. In contrast, expression of FucT-VII mRNA was not significantly inhibited by CsA. Interleukin-4 inhibited the expression of FucT-VII but IL-2 and IL-7 were found to support induction of FucT-VII and E-lig. E-selectin, P selectin and their ligands initially appeared to have rather overlapping functions. These findings however, unravel striking differences in the regulation of E-lig and P-lig expression, dictated by the dominance of FucT-VII and C2GlcNAcT-I, respectively, and their dependency on signals from either promiscuous or homeostatic cytokines (FucT-VII) or a strong T-cell receptor signal in combination with inflammatory cytokines in case of C2GlcNAcT-I. PMID- 23039183 TI - Identifying a structural preference in reduced rare-earth metal halides by combining experimental and computational techniques. AB - The structures of two new cubic {TnLa(3)}Br(3) (Tn = Ru, Ir; I4(1)32, Z = 8; Tn = Ru: a = 12.1247(16) A, V = 1782.4(4) A(3); Tn = Ir: a = 12.1738(19) A, V = 1804.2(5) A(3)) compounds belonging to a family of reduced rare-earth metal halides were determined by single-crystal X-ray diffraction. Interestingly, the isoelectronic compound {RuLa(3)}I(3) crystallizes in the monoclinic modification of the {TnR(3)}X(3) family, while {IrLa(3)}I(3) was found to be isomorphous with cubic {PtPr(3)}I(3). Using electronic structure calculations, a pseudogap was identified at the Fermi level of {IrLa(3)}Br(3) in the new cubic structure. Additionally, the structure attempts to optimize (chemical) bonding as determined through the crystal orbital Hamilton populations (COHP) curves. The Fermi level of the isostructural {RuLa(3)}Br(3) falls below the pseudogap, yet the cubic structure is still formed. In this context, a close inspection of the distinct bond frequencies reveals the subtleness of the structure determining factors. PMID- 23039182 TI - Plasmonic chiroptical response of silver nanoparticles interacting with chiral supramolecular assemblies. AB - Silver nanoparticles were prepared in aqueous solutions of chiral supramolecular structures made of chiral molecular building blocks. While these chiral molecules display negligible circular dichroism (CD) as isolated molecules, their stacking produced a significant CD response at room temperature, which could be eliminated by heating to 80 degrees C due to disordering of the stacks. The chiral stack plasmon coupling has induced CD at the surface plasmon resonance absorption band of the silver nanoparticles. Switching between two plasmonic CD induction mechanisms was observed: (1) Small Ag nanoparticles coated with large molecular stacks, where the induced plasmonic CD decayed together with the UV molecular CD bands on heating the solution, indicating some type of electromagnetic or dipole coupling mechanism. (2) Larger Ag nanoparticles coated with about a monolayer of molecules exhibited induced plasmonic CD that was temperature-independent. In this case it is estimated that the low chiroptical response of a molecular monolayer is incapable of inducing such a large chiroptical effect, and a model calculation shows that the plasmonic CD response may be the result of a slight chiral shape distortion of the silver nanoparticles. PMID- 23039184 TI - The activity of lowering intraocular pressure of cassiae seed extract in a DBA/2J mouse glaucoma model. AB - PURPOSE: To evaluate the activity of lowering intraocular pressure (IOP) by Cassiae seed in the DBA/2J mouse glaucoma model. METHODS: Young male (mean age: 3 months) inherited glaucoma mice (BDA/2J) were enrolled in this study. To evaluate the potential of Cassiae seed in the treatment of glaucoma, all subjects were divided into 6 groups. There were 1 sham group, positive control identified as group 2 topical brimonidine and group 3 oral acetazolamide, and groups 4-6 Cassiae seed extract (CSE) groups. The lactate dehydrogenase (LDH) level in the anterior aqueous humor and the changes of IOP were investigated. Contents of total polyphenol glycosides in the CSE were measured using a high-performance liquid chromatography (HPLC) method. Chromatographic separation was performed on a Cosmosil 5C(18)-MS reverse-phase HPLC column (4.6*250-mm i.d., 5 MUm) with methanol/0.1% H(3)PO(4) as the mobile phases in a gradient elution mode at a flow rate of 1.0 mL/min and an injection volume of 10 MUL. The wavelength of UV detector was set at 254 nm. RESULTS: The LDH level in the anterior aqueous humor and IOP significantly decreased after treatment with CSE. The IOP-lowering effect of CSE was comparable to those of oral acetazolamide and brimonidine instillation. There were no abnormal findings in the external appearance, and body weight change after treatment with CSE for 5 weeks. Chrysophanol and physcion were measured by an HPLC method to obtain total polyphenol glycosides of the CSE, and were involved in the IOP-lowering function. CONCLUSION: Cassiae seed may be safe and beneficial for treating glaucoma due to its significant IOP- and LDH-lowering activities. PMID- 23039185 TI - Avoiding steric congestion in dendrimer growth through proportionate branching: a twist on da Vinci's rule of tree branching. AB - Making defect-free macromolecules is a challenging issue in chemical synthesis. This challenge is especially pronounced in dendrimer synthesis where exponential growth quickly leads to steric congestion. To overcome this difficulty, proportionate branching in dendrimer growth is proposed. In proportionate branching, both the number and the length of branches increase exponentially but in opposite directions to mimic tree growth. The effectiveness of this strategy is demonstrated through the synthesis of a fluorocarbon dendron containing 243 chemically identical fluorine atoms with a MW of 9082 Da. Monodispersity is confirmed by nuclear magnetic resonance spectroscopy, mass spectrometry, and small-angle X-ray scattering. Growing different parts proportionately, as nature does, could be a general strategy to achieve defect-free synthesis of macromolecules. PMID- 23039186 TI - LFA-1 and ICAM-1 expression induced during melanoma-endothelial cell co-culture favors the transendothelial migration of melanoma cell lines in vitro. AB - BACKGROUND: Patients with metastatic melanoma have a poor median rate of survival. It is therefore necessary to increase our knowledge about melanoma cell dissemination which includes extravasation, where cancer cells cross the endothelial barrier. Extravasation is well understood during travelling of white blood cells, and involves integrins such as LFA-1 (composed of two chains, CD11a and CD18) expressed by T cells, while ICAM-1 is induced during inflammation by endothelial cells. Although melanoma cell lines cross endothelial cell barriers, they do not express LFA-1. We therefore hypothesized that melanoma-endothelial cell co-culture might induce the LFA-1/ICAM ligand/receptor couple during melanoma transmigration. METHODS: A transwell approach has been used as well as blocking antibodies against CD11a, CD18 and ICAM-1. Data were analyzed with an epifluorescence microscope. Fluorescence intensity was quantified with the ImageJ software. RESULTS: We show here that HUVEC-conditioned medium induce cell-surface expression of LFA-1 on melanoma cell lines. Similarly melanoma-conditioned medium activates ICAM-1 expression in endothelial cells. Accordingly blocking antibodies of ICAM-1, CD11a or CD18 strongly decrease melanoma transmigration. We therefore demonstrate that melanoma cells can cross endothelial monolayers in vitro due to the induction of ICAM-1 and LFA-1 occurring during the co-culture of melanoma and endothelial cells. Our data further suggest a role of LFA-1 and ICAM-1 in the formation of melanoma cell clumps enhancing tumor cell transmigration. CONCLUSION: Melanoma-endothelial cell co-culture induces LFA-1 and ICAM-1 expression, thereby favoring in vitro melanoma trans-migration. PMID- 23039187 TI - An exploratory study of positive and incongruent communication in young children with type 1 diabetes and their mothers. AB - BACKGROUND: The incidence of type 1 diabetes is increasing in young children. However, they are overlooked in treatment adherence and intervention research despite evidence that parents often experience difficulty securing their treatment cooperation, especially with the diet. We investigated positive and incongruent (i.e. the co-occurrence of contradictory verbal and non-verbal messages) communication in the mother-child dyad and their association with child adjustment and dietary adherence outcomes. METHODS: Participants were 23 6- to 8 year-old children with type 1 diabetes and their mothers. We conducted dietary adherence interviews with mothers and performed nutritional analyses to assess children's consumption of extrinsic sugars (e.g. confectionary). Mothers completed a standardized assessment of child psychological adjustment. Mothers and children engaged in a videotaped problem-solving task related to the dietary regimen, with maternal and child utterances and non-verbal behaviours analysed for positive dyadic and incongruent communication. RESULTS: Positive dyadic communication correlated with lower levels of child incongruent communication, fewer behavioural problems and better overall adjustment. Higher levels of maternal and child incongruent communication correlated with more behavioural and emotional problems and poorer overall adjustment. Higher levels of maternal incongruent communication correlated with poorer dietary adherence. CONCLUSIONS: Results converged to form a conceptually and empirically coherent pattern in that behavioural indices of poorer communication in both mother and child consistently correlated with poorer child adjustment outcomes. This study shows that specific features of dyadic, child and maternal communication could be targeted in developmentally sensitive interventions to promote positive communication in the home management of type 1 diabetes care for young children. PMID- 23039188 TI - Analysis of auditory and vestibular function in patients with unilateral Meniere's disease. AB - CONCLUSION: The percentage of the unilateral weakness of the caloric response also reflects the clinical progress of Meniere's disease (MD), including clinical hearing loss. OBJECTIVE: To evaluate the relationship between hearing status and vestibular function in patients with MD. METHODS: Seventy-nine patients with unilateral definite MD underwent bithermal air caloric testing, vestibular evoked myogenic potential (VEMP) testing, and pure tone audiometry (PTA). The stages of the disease, clinical hearing level of the diseased ears, and dPTA (the difference in hearing level between ears in each patient) were compared with the percentage of the unilateral weakness of the caloric response and the interaural amplitude difference (IAD) ratio of the VEMP response. RESULTS: Twenty ears (25.3%) revealed normal caloric responses and 59 ears (74.7%) showed reduced caloric responses. Testing revealed that the VEMPs were normal in 49 ears (62%), while 30 ears (38%) had abnormal VEMPs. The percentage of the unilateral weakness of the caloric response was positively correlated with the clinical hearing level of the diseased ears (p = 0.006) and the dPTA (p = 0.013). PMID- 23039189 TI - Life beyond the limits of knowledge: crystalline life in the popular science of Desiderius Papp (1895-1993). AB - The aim of this article is to show how, and in which context, astrobiological reasoning was employed before the establishment of astrobiology as a scientific discipline. By way of an example, I will discuss a popular science book published in 1931 by the Hungarian journalist Desiderius Papp. The author claims that this book represents an innovation in astrobiological reasoning, as it draws on contemporary biological research to conduct thought experiments, thereby coming up with concrete forms of possible extraterrestrial life. One of the most interesting of these forms was crystalline life. After a short overview on the history of this concept, this article will show how Papp drew on recent research by Otto Lehmann on liquid crystals to convey the idea that life may be based on other elements than carbon. The author concludes by arguing that popular science did not only make specialist knowledge accessible to a general public but also served to probe the limits of knowledge and point toward the situatedness of established categories and definitions. PMID- 23039190 TI - LPA5 receptor plays a role in pain sensitivity, emotional exploration and reversal learning. AB - Lysophosphatidic acid (LPA) is a bioactive lipid acting on the nervous system through at least 6 different G protein-coupled receptors. In this study, we examined mice lacking the LPA5 receptor using an extensive battery of behavioral tests. LPA5-deficient mice showed decreased pain sensitivity in tail withdrawal, faster recovery in one inflammatory pain procedure (complete Freund's adjuvant induced inflammation) and attenuated responses under specific neuropathic pain conditions. Notably, deletion of LPA5 also induced nocturnal hyperactivity and reduced anxiety in the mutant mice. Several exploratory tasks revealed signs of reduced anxiety in LPA5 knockout mice including increased visits to the arena center and reduced thigmotaxis in the open field, and more open arm entries in the elevated plus maze. Finally, LPA5 knockout mice also displayed marked reduction in social exploration, although several other tests indicated that these mice were able to respond normally to environmental stimuli. While learning and memory performance was not impaired in LPA5-deficient mice, we found differences, e.g., targeted swim strategy and reversal learning, as well as scheduled appetitive conditioning that might indicate differential motivational behavior. These results imply that LPA5 might be involved in both nociception and mechanisms of pain hypersensitivity, as well as in anxiety-related and motivational behaviors. These observations further support the proposed involvement of LPA signaling in psychopathology. PMID- 23039191 TI - Estimation of metagenome size and structure in an experimental soil microbiota from low coverage next-generation sequence data. AB - AIMS: A major challenge in metagenome studies is to estimate the true size of all combined genomes. Here, we present a novel approach to estimate the size of all combined genomes for low coverage next-generation sequencing (NGS) data through empirically determined copy numbers of random DNA fragments. METHODS AND RESULTS: Size estimates were made based on analyses of two experimental soil micro ecosystems - simulating soil with and without earthworms. Our analyses showed combined genome sizes of about log 11 nucleotides for each of the soil micro ecosystems, as estimated from qPCR determined copy numbers of random DNA fragments. This corresponds to more than 20000 unique bacterial genomes in each sample. There seemed, however, to be a bacterial subpopulation in the earthworm soil, not being present in the nonearthworm soil. To describe the structure of the metagenomes, both total DNA and amplified 16S rRNA gene sequence libraries were generated with 454-sequencing. Bioinformatic analysis of 454 sequence libraries showed a large functional but low taxonomic overlap between the samples with and without earthworms. A neutrality test indicated that rare species have a competitive advantage over abundant species in both micro-ecosystems providing a potential explanation for the large metagenome sizes. CONCLUSIONS: We have shown that the soil metagenome is very large and that the large size is probably a consequence of top-down selection of the dominant bacterial species. SIGNIFICANCE AND IMPACT OF THE STUDY: Estimates of metagenome size from low coverage NGS data will be important for guiding future NGS set-ups. PMID- 23039192 TI - The proposed GDM diagnostic criteria: a difference, to be a difference, must make a difference. AB - The new criteria for diagnosis of gestational diabetes mellitus proposed by the International Association of Diabetes in Pregnancy Study Group (IADPSG) transports back the controversy and the lack of agreement to the frontlines. The recommended criteria are based on results of the observational hyperglycemia and adverse pregnancy outcome study (HAPO). These criteria will increase the frequency of gestational diabetes diagnosis by 2-8 folds, depending upon ethnicity, and prevalence of obesity. Do the costs and implied resources justify using the proposed endpoints that will define pregnancy outcome and severity especially when the appropriate outcomes and odds ratio used to define the diagnosis are questionable? Furthermore, due to the large disparity around the globe in relation to the prevalence of gestational diabetes raises the question if single diagnostic criteria can be made to fit all?!? The current review analyzes the risks, costs and benefits that may influence the rate of gestational diabetes in relation to the worldwide prevalence. PMID- 23039193 TI - Determination of ammonia in water based on chemiluminescence resonance energy transfer between peroxymonocarbonate and branched NaYF4:Yb3+/Er3+ nanoparticles. AB - The ultraweak chemiluminescence (CL) from the reaction of hydrogen peroxide and carbonate is strongly enhanced by the branched NaYF(4):Yb(3+)/Er(3+) nanoparticle (NP) in the presence of aqueous ammonia. It was explained that ammonia catalyzes the decomposition of peroxymonocarbonate, which is the product of hydrogen peroxide mixing with bicarbonate, making the formation of (CO(2))(2)*, (O(2))(2)*, and (1)O(2). The excitation energy, carried by these emitter intermediates, can be transferred to NaYF(4):Yb(3+)/Er(3+) NP. The CL intensity is directly proportional to the concentration of ammonia present in the solution. A flow-injection CL system with high sensitivity, selectivity, and reproducibility is proposed for the determination of aqueous ammonia. The proposed method exhibited advantages in a larger linear range from 0.5 MUmol L( 1) to 50 MUmol L(-1) and a lower detection limit of 1.1 * 10(-8) mol L(-1) (S/N = 3). This method has been successfully applied to the evaluation of ammonia in water samples with recoveries from 95% to 108%. The relative standard deviations are 1.8% and 4.1% for intra-assay and inter-assay precision, respectively. PMID- 23039194 TI - Nurses' experiences providing bereavement follow-up: an exploratory study using feminist poststructuralism. AB - AIMS AND OBJECTIVES: To describe the experiences of nurses who provided bereavement follow-up with families after the death of a child or a pregnancy loss and explore facilitators, barriers and challenges. BACKGROUND: Bereavement follow-up after the death of a child has been identified as an indicator of quality end of life care by families and health care professionals. Research suggests communication with bereaved families can be challenging and intimidating for nurses, particularly those who have had limited experience. In-depth information about the personal, professional and institutional experiences of nurses providing this care is lacking. DESIGN: Eight registered nurses with experience in providing bereavement follow-up to families were interviewed. Purposive sampling provided information rich cases. METHODS: Feminist poststructuralism was the guiding theory and methodology used to uncover underlying discourses. This methodology uses the concepts of discourse analysis, subjectivity and agency to enable a critical understanding of the relationships. RESULTS: The nurses described complex interactions between themselves, the families, hospital practices and policy, and social norms around the discourses of death and professionalism. The importance of relationship, self-care and closure, professional boundaries, invisible nature of the practice and institutional support were prominent themes. Insights into the challenges and rewards of providing bereavement follow-up are discussed in the context of power relations, and recommendations for change are offered. CONCLUSIONS: Nurses in the study were strongly committed to providing ongoing care to families who had experienced the death of a child or a pregnancy loss. Relationships were important to bereavement follow-up care, and the connections with families were often emotional for the nurses. RELEVANCE TO CLINICAL PRACTICE: Nurses and other health professionals would benefit from increased support and education related to bereavement and communication with grieving families. Clarity related to institutional policies to support bereavement care is paramount in helping nurses and others in this work. PMID- 23039196 TI - Pseudomonas fluorescens N21.4 metabolites enhance secondary metabolism isoflavones in soybean (Glycine max) calli cultures. AB - Phytopharmaceuticals are plant secondary metabolites that are strongly inducible and especially sensitive to biotic changes. Plant cell cultures are a good alternative to obtain secondary metabolites, in case effective stimulation can be achieved. In this study, metabolic elicitors from two rhizobacteria able to enhance isoflavone content in soybean seedlings were tested on three different soybean calli cell lines. Results show that metabolic elicitors from Chryseobacterium balustinum Aur9 were not effective. However, there are at least two different metabolic elicitors from Pseudomonas fluorescens N21.4, one under 10 kDa and another over 10 kDa, that trigger isoflavone metabolism in the three cell lines with different isoflavone content. Elicitors from N21.4 achieved total isoflavone increases up to 29.7% (0.205 mg/g), 64.5% (0.487 mg/g), and 23.4% (0.726 mg/g) in the low-, intermediate-, and high-yield lines, respectively. Therefore, these elicitors have a great potential to enhance isoflavone production in cell cultures for development of functional ingredients. PMID- 23039195 TI - Mitochondrial dysfunction associated with increased oxidative stress and alpha synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. AB - BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra (SN). The familial form of PD, PARK2, is caused by mutations in the parkin gene. parkin knockout mouse models show some abnormalities, but they do not fully recapitulate the pathophysiology of human PARK2. RESULTS: Here, we generated induced pluripotent stem cells (iPSCs) from two PARK2 patients. PARK2 iPSC-derived neurons showed increased oxidative stress and enhanced activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. iPSC-derived neurons, but not fibroblasts or iPSCs, exhibited abnormal mitochondrial morphology and impaired mitochondrial homeostasis. Although PARK2 patients rarely exhibit Lewy body (LB) formation with an accumulation of alpha-synuclein, alpha-synuclein accumulation was observed in the postmortem brain of one of the donor patients. This accumulation was also seen in the iPSC-derived neurons in the same patient. CONCLUSIONS: Thus, pathogenic changes in the brain of a PARK2 patient were recapitulated using iPSC technology. These novel findings reveal mechanistic insights into the onset of PARK2 and identify novel targets for drug screening and potential modified therapies for PD. PMID- 23039197 TI - Differentiated hamster sebocytes exhibit apoptosis-resistant phenotype by the augmentation of intracellular calcium level in vitro. AB - Sebaceous glands play important roles in the maintenance of the skin barrier function by secreting sebum onto the skin surface. In our study, we demonstrated that differentiated hamster sebocytes (DHS) exhibited apoptosis resistance and the loss of Ca(2+) influx against a calcium ionophore, A23187 treatment, which induced both apoptosis and Ca(2+) influx in undifferentiated hamster sebocytes (unDHS). The Fluo-3-related signal of intracellular Ca(2+) in the DHS was higher than that in unDHS and was sustained even though there was a depletion of Ca(2+) from the culture medium. Furthermore, the intracellular Ca(2+) chelator, BAPTA AM, was found to decrease the Ca(2+) signal in the DHS, which induced apoptosis. Thus, these results provide novel evidence that the cell differentiation dependent increase in store-operated Ca(2+) release is associated with apoptosis resistance in the DHS. Moreover, these findings should accelerate the understanding of the mechanisms of sebogenesis and/or sebum production and secretion under physiological conditions. PMID- 23039198 TI - Improving on-time starts for patients scheduled with general anesthesia in a MRI suite. AB - OBJECTIVE: We applied quality improvement methodology to identify unnecessary, redundant parts of processes that can lead to delayed on-time starts for patients scheduled with general anesthesia (GA) in the radiology department. AIM: To address the issue of delayed on-time starts by improving work flow for the first patient scheduled with GA. BACKGROUND: Unplanned imaging in a high-volume MRI suite can result in a significant ripple effect throughout the day. Delayed on time starts can lead to patient, family, and staff dissatisfaction due to significant wait times. MATERIALS AND METHODS: The team conducted a 5 month improvement project. Baseline data were obtained from pilot time studies allowed the team to identify reasons why the first case was not starting on time and to identify several key drivers to improve the process. Using the framework of small tests of change or the Plan-Do-Study-Act model, our key interventions primarily focused on standardizing the processes for completing the preimaging evaluation and for anesthesia induction. The primary objective measure of successful on-time start was defined as obtaining the first MRI image within 10 min of the scheduled start time, for the first patients of the day scheduled with GA. The secondary outcome measure was the extent of the delay quantified in minutes. RESULTS: Prior to the initiation of the project, only 36% of the first patients scheduled with GA each day met the primary objective measure. At the conclusion of the project 84% started on time. The secondary measure also showed significant improvement. CONCLUSIONS: Process improvement projects in anesthesia can yield positive results, using small incremental standardized changes. We used a quality improvement methods to successfully improve on-time start for patients scheduled with GA in high-volume MRI suite. PMID- 23039199 TI - Visible light photocatalytic synthesis of benzothiophenes. AB - The photocatalytic reaction of o-methylthio-arenediazonium salts with alkynes yields substituted benzothiophenes regioselectively through a radical annulation process. Green light irradiation of eosin Y initiates the photoredox catalysis. The scope of the reaction was investigated by using various substituted diazonium salts and different alkynes. PMID- 23039200 TI - The protective effects of executive functions and episodic memory on gait speed decline in aging defined in the context of cognitive reserve. AB - OBJECTIVES: To evaluate whether levels of cognitive reserve (CR), as measured using the Wechsler Adult Intelligence Scale (WAIS)-III vocabulary test, moderated longitudinal associations between cognitive functions and decline in gait speed in a community-based cohort of older adults without dementia, specifically, whether the protective effect of executive function (EF) and episodic memory against decline in gait speed would be greater in individuals with higher CR. DESIGN: Longitudinal (median number of repeated annual gait speed measures, 3; maximum number of visits, 7). SETTING: General community. PARTICIPANTS: Seven hundred thirty-one community-residing individuals aged 70 and older without dementia were followed longitudinally with cognitive and gait evaluations at baseline and at annual visits. MEASUREMENTS: Decline in gait speed (cm/s) served as the primary outcome. The Free and Cued Selective Reminding Test (FCSRT) was used to assess episodic memory. The Digit Symbol Substitution Test (DSST) was used to assess attention and EF. The vocabulary test served as a marker for CR. RESULTS: Linear mixed effects model showed that gait speed declined over the follow-up period (P < .001). The significant three-way interactions of time by DSST by vocabulary (P = .01) and time by FCSRT by vocabulary (P = .02) revealed that levels of CR moderated the longitudinal associations between EF and episodic memory and gait speed decline. CONCLUSION: The protective effects of EF and episodic memory against gait speed decline in aging are greater in individuals with higher CR. PMID- 23039201 TI - Effects of topical application of growth factors followed by microneedle therapy in women with female pattern hair loss: a pilot study. PMID- 23039202 TI - Using intravital microscopy to observe bevacizumab-mediated anti-angiogenesis in human head and neck squamous cell carcinoma xenografts. AB - CONCLUSION: The study showed the value of using intravital microscopy (IVM) analysis for the study of neoangiogenesis. It demonstrated that the model and the analytical methodology could be used to evaluate in detail the effects of treatment strategies for solid tumours. OBJECTIVES: Neoangiogenesis is a key component of tumour progression, invasion and metastasis. In clinical trials monoclonal antibodies specific for vascular endothelial growth factor - VEGF (bevacizumab) - have been shown to significantly affect tumour progression when given in combination with standard chemotherapy, and also to improve the overall survival of patients. For squamous cell carcinoma of the head and neck (HNSCC), we still await definitive evidence of the effect of such treatment. The present study was designed to investigate the anti-angiogenesis effect of beviacizumab in green fluorescent protein (GFP)-labelled HNSCC xenografts using IVM technology. METHODS: We performed IVM and used image analysis for quantification of angiogenesis and of effects of bevacizumab on cell viability, combined with histochemical and immunohistochemical analysis to standardize the digital analysis of changes in tumour vascularization and cell viability. RESULTS: We found significant effects of bevacizumab on angiogenesis and cancer cell survival in HNSCC. Repeated injections of bevacizumab were found to provide the greatest effects. PMID- 23039203 TI - Effect modification by parental education on the associations of birth order and gender with learning achievement in adolescents. AB - BACKGROUND: A child's gender and ordinal position within a family have varied implications on his or her personality and cognitive development. However, little is known about whether or not parental educational level may moderate the effects of birth order and gender. METHODS: Basic Competence Test (BCT) scores of 290,588 young adolescents aged 15-16 years in Taiwan were analysed. Parental educational level was calculated as the highest educational attainment of the subjects' parents. The multiple linear regression model was used to assess the modification effects of parental educational levels on the associations of interest. RESULTS: After controlling for covariates, we noted a clear inverse relationship between birth order and BCT scores in Mandarin, Mathematics and Science. Additionally, boys had significantly lower mean scores in Mandarin, but had significantly higher mean scores in both Mathematics and Science. We also found the significant interactive effects of birth order, gender and parental educational attainment on BCT scores, in which the birth order and gender effects were more evident in higher-educated families than in lower-educated ones. CONCLUSIONS: This large cohort study confirmed that both birth order and gender may pose independent influences on BCT scores; moreover, such influences are significantly modified by parental educational attainment. PMID- 23039205 TI - Changes in the microbial community structure of bacteria, archaea and fungi in response to elevated CO(2) and warming in an Australian native grassland soil. AB - The microbial community structure of bacteria, archaea and fungi is described in an Australian native grassland soil after more than 5 years exposure to different atmospheric CO2 concentrations ([CO2]) (ambient, +550 ppm) and temperatures (ambient, + 2 degrees C) under different plant functional types (C3 and C4 grasses) and at two soil depths (0-5 cm and 5-10 cm). Archaeal community diversity was influenced by elevated [CO2], while under warming archaeal 16S rRNA gene copy numbers increased for C4 plant Themeda triandra and decreased for the C3 plant community (P < 0.05). Fungal community diversity resulted in three groups based upon elevated [CO2], elevated [CO2] plus warming and ambient [CO2]. Overall bacterial community diversity was influenced primarily by depth. Specific bacterial taxa changed in richness and relative abundance in response to climate change factors when assessed by a high-resolution 16S rRNA microarray (PhyloChip). Operational taxonomic unit signal intensities increased under elevated [CO2] for both Firmicutes and Bacteroidetes, and increased under warming for Actinobacteria and Alphaproteobacteria. For the interaction of elevated [CO2] and warming there were 103 significant operational taxonomic units (P < 0.01) representing 15 phyla and 30 classes. The majority of these operational taxonomic units increased in abundance for elevated [CO2] plus warming plots, while abundance declined in warmed or elevated [CO2] plots. Bacterial abundance (16S rRNA gene copy number) was significantly different for the interaction of elevated [CO2] and depth (P < 0.05) with decreased abundance under elevated [CO2] at 5-10 cm, and for Firmicutes under elevated [CO2] (P < 0.05). Bacteria, archaea and fungi in soil responded differently to elevated [CO2], warming and their interaction. Taxa identified as significantly climate-responsive could show differing trends in the direction of response ('+' or '-') under elevated CO2 or warming, which could then not be used to predict their interactive effects supporting the need to investigate interactive effects for climate change. The approach of focusing on specific taxonomic groups provides greater potential for understanding complex microbial community changes in ecosystems under climate change. PMID- 23039206 TI - Serum IFN-lambda1 is abnormally elevated in rheumatoid arthritis patients. AB - Interferon (IFN)-lambda1 is a newly described cytokine that is known for its proinflammatory activity in viral infection and in cancer. Because recent studies indicated that IFN-lambda can influence significantly the innate and adaptive immune response, we studied IFN-lambda in a prototypic systemic autoimmune disease, rheumatoid arthritis (RA). It was found that RA patients had higher mRNA levels in PBMC and higher serum levels of IFN-lambda1 in comparison with healthy matched controls and ankylosing spondylitis (AS) patients. Although there was no correlation between serum IFN-lambda1 and RA autoantibodies, RA patients that presented knee joint involvement displayed higher serum IFN-lambda1 than patients without knee joint involvement, suggesting that abnormally elevated IFN-lambda1 levels in RA can associate with knee joint disease. PMID- 23039207 TI - Increased HLA-E expression in white matter lesions in multiple sclerosis. AB - The molecular mechanisms underpinning central nervous system damage in multiple sclerosis (MS) are complex and it is widely accepted that there is an autoimmune component. Both adaptive and innate immune effector mechanisms are believed to contribute to tissue disease aetiology. HLA-E is a non-classical MHC class Ib molecule that acts as the ligand for the NKG2A inhibitory receptor present on natural killer (NK) and CD8+ cells. Peptide binding and stabilization of HLA-E is often considered to signal infection or cell stress. Here we examine the up regulation of HLA-E in MS brain tissue. Expression is significantly increased in white matter lesions in the brain of MS patients compared with white matter of neurologically healthy controls. Furthermore, using quantitative immunohistochemistry and confocal microscopy, we show increased HLA-E protein expression in endothelial cells of active MS lesions. Non-inflammatory chronic lesions express significantly less HLA-E protein, comparable to levels found in white matter from controls. Increased HLA-E protein levels were associated with higher scores of inflammation. These results suggest the potential for an effect in central nervous system pathogenesis from HLA-E modulation in stressed tissue. Co-localization with infiltrating CD8+ cells implicates a possible role for HLA-E restricted regulatory CD8+ cells, as has been proposed in other autoimmune diseases. PMID- 23039208 TI - Nodal involvement at nephrectomy is associated with worse survival: a stage-for stage and grade-for-grade analysis. AB - OBJECTIVES: To examine cancer-specific mortality in patients with nodal metastases relative to patients without nodal involvement at nephrectomy for non metastatic renal cell carcinoma in a population-based cohort. METHODS: A total of 11 374 non-metastatic renal cell carcinoma patients who underwent a lymph node dissection at nephrectomy were identified using the Surveillance, Epidemiology and End Results database (1988-2008). The 5-year cancer-specific mortality-free survival rates were examined according to the presence or absence of nodal involvement within the entire cohort, and stratified according to pathological tumor stage (pT1 vs pT2 vs pT3 vs pT4) and Fuhrman grade (I vs II vs III vs IV). Cox regression analyses for prediction of cancer-specific mortality were modeled to assess the effect of nodal metastases versus no nodal involvement in the entire population. Finally, separate Cox regression models were fitted within each pathological stage and grade. RESULTS: Overall, 1260 (11%) patients had nodal metastases at nephrectomy. The overall 5-year cancer-specific mortality free survival rates were 38.4 versus 83.8% in patients with nodal metastases and without nodal metastases, respectively. In multivariable analyses, amongst pT1, pT2, pT3 and pT4, patients with nodal metastases were 6.0-, 3.6-, 3.2- and 2.0 fold, respectively, more likely to die after nephrectomy (all P < 0.001). Similarly, amongst Fuhrman grade I, Fuhrman grade II, Fuhrman grade III and Fuhrman grade IV, patients with nodal metastases were 3.9-, 3.5-, 3.1- and 2.7 fold, respectively, more likely to die of cancer-specific mortality (all P < 0.001). CONCLUSIONS: Nodal involvement is an important determinant of higher cancer-specific mortality after nephrectomy. The detrimental effect of nodal metastases is particularly strong amongst patients with low-stage or low-grade non-metastatic renal cell carcinoma. PMID- 23039209 TI - Synthesis, structure, magnetism, and optical properties of Cs2Cu3DyTe4. AB - CsCu(3)DyTe(4) was prepared by reacting copper, dysprosium, and tellurium with cesium azide at 850 degrees C in a fused silica ampule. This new telluride crystallizes in the monoclinic space group C2/m with lattice dimensions of a = 16.462(4) A, b = 4.434(1) A, c = 8. 881(2) A, beta = 108.609(12) degrees with Z = 2. Its crystal structure is dominated by (infinity)(2){[Cu(3)DyTe(4)]}(1-) anionic layers separated by Cs(+) cations. The copper cations are disordered over three different tetrahedral sites. The [DyTe(6)](9-) polyhedra form infinite (infinity)(1){[DyTe(4)](5-)} chains. Magnetism studies conducted on this semiconductor suggest complex magnetic interactions between the Dy(3+) cations with a strong deviation from Curie-type behavior at low temperatures below 40 K. PMID- 23039210 TI - The changing epidemiology of bacteraemias in Europe: trends from the European Antimicrobial Resistance Surveillance System. AB - We investigated bacteraemia trends for five major bacterial pathogens, Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Enterococcus faecalis and Enterococcus faecium, and determined how expanding antimicrobial resistance influenced the total burden of bacteraemias in Europe. Aetiological fractions of species and antibiotic phenotypes were extracted from the European Antimicrobial Resistance Surveillance System (EARSS) database for laboratories, which consistently reported between 2002 and 2008. Trend analyses used generalized linear models. Robustness of results was assessed by iterative analysis for different geographic regions. From 2002 to 2008, the overall number of reports increased annually by 6.4% (95% confidence interval (CI) 6.2-6.5%), from 46 095 to 67 876. In the subset of laboratories providing denominator information, the overall incidence increased from 0.58/1000 patient-days to 0.90/1000 patient-days (7.2% per year; 95% CI 6.9-7.5%). The frequency of reported bacteraemia isolates of S. aureus and Streptococcus pneumoniae increased moderately, while increase in E. coli and Enterococcus faecium was more pronounced. Bacteraemias caused by methicillin-resistant S. aureus increased until 2005 (7.6% per year; 95% CI 6.1-9.1%), and then decreased (-4.8% per year; 95% CI -6.1 to -3.5%), whereas the number attributable to methicillin-sensitive S. aureus increased continuously (3.4% per year; 95% CI 3.0-3.7). Increasing rates of E. coli were mainly caused by antibiotic-resistant phenotypes. Our data suggest that the burden of bacterial bloodstream infection has been increasing for all species during EARSS surveillance. Trends were mainly driven by resistant strains and clearly dissociated between resistant and susceptible isolates. It appears that infections with resistant clones add to rather than replace infections caused by susceptible bacteria. As a consequence, expansion of antibiotic resistance creates an additional strain on healthcare systems. PMID- 23039211 TI - Ecological nanotoxicology: integrating nanomaterial hazard considerations across the subcellular, population, community, and ecosystems levels. AB - Research into the health and environmental safety of nanotechnology has seriously lagged behind its emergence in industry. While humans have often adopted synthetic chemicals without considering ancillary consequences, the lessons learned from worldwide pollution should motivate making nanotechnology compatible with environmental concerns. Researchers and policymakers need to understand exposure and harm of engineered nanomaterials (ENMs), currently nanotechnology's main products, to influence the ENM industry toward sustainable growth. Yet, how should research proceed? Standard toxicity testing anchored in single-organism, dose-response characterizations does not adequately represent real-world exposure and receptor scenarios and their complexities. Our approach is different: it derives from ecology, the study of organisms' interactions with each other and their environments. Our approach involves the characterization of ENMs and the mechanistic assessment of their property-based effects. Using high throughput/content screening (HTS/HCS) with cells or environmentally-relevant organisms, we measure the effects of ENMs on a subcellular or population level. We then relate those effects to mechanisms within dynamic energy budget (DEB) models of growth and reproduction. We reconcile DEB model predictions with experimental data on organism and population responses. Finally, we use microcosm studies to measure the potential for community- or ecosystem-level effects by ENMs that are likely to be produced in large quantities and for which either HTS/HCS or DEB modeling suggest their potential to harm populations and ecosystems. Our approach accounts for ecological interactions across scales, from within organisms to whole ecosystems. Organismal ENM effects, if propagated through populations, can alter communities comprising multiple populations (e.g., plant, fish, bacteria) within food webs. Altered communities can change ecosystem services: processes that cycle carbon, nutrients, and energy, and regulate Earth's waters and atmosphere. We have shown ENM effects on populations, communities, and ecosystems, including transfer and concentration of ENMs through food chains, for a range of exposure scenarios; in many cases, we have identified subcellular ENM effects mechanisms. To keep pace with ENM development, rapid assessment of the mechanisms of ENM effects and modeling are needed. DEB models provide a method for mathematically representing effects such as the generation of reactive oxygen species and their associated damage. These models account for organism-level effects on metabolism and reproduction and can predict outcomes of ENM-organism combinations on populations; those predictions can then suggest ENM characteristics to be avoided. HTS/HCS provides a rapid assessment tool of the ENM chemical characteristics that affect biological systems; such results guide and expand DEB model expressions of hazard. Our approach addresses ecological processes in both natural and managed ecosystems (agriculture) and has the potential to deliver timely and meaningful understanding towards environmentally sustainable nanotechnology. PMID- 23039212 TI - Clinical outcome of fresh and vitrified-warmed blastocyst and cleavage-stage embryo transfers in ethnic Chinese ART patients. AB - OBJECTIVES: This study sought to evaluate the outcome of fresh and vitrified warmed cleavage-stage and blastocyst-stage embryo transfers in patients undergoing ART treatment within an ethnic Chinese population. STUDY DESIGN: We compared the clinical results of embryo transfer on the 3rd (cleavage stage) or 5th (blastocyst stage) day after oocyte retrieval, including clinical pregnancy rates, implantation rates and multiple pregnancy rates. RESULTS: Our data showed that blastocyst transfer on day 5 did not significantly increase clinical pregnancy rate (41.07% vs 47.08%, p>0.05) and implantation rate (31.8% vs 31.2%, p>0.05) in patients under 35 years of age, in comparison with day 3 cleavage stage embryo transfer. In patients older than 35 years of age, the clinical pregnancy rate after blastocyst transfer was slightly decreased compared with cleavage stage embryo transfer (33.33% vs 42.31%, p>0.05). Unexpectedly, It was found that vitrified-warmed blastocyst transfer resulted in significantly higher clinical pregnancy rate (56.8%) and implantation rate (47%) compared with fresh blastocyst transfer in controlled stimulation cycles (41.07% and 31.8%, respectively). For patients under 35 years of age, the cumulative clinical pregnancy rate combining fresh and vitrified-warmed blastocyst transfer cycles were significantly higher compared to just cleavage-stage embryo transfer (70.1% versus 51.8%, p<0.05). However, the cumulative multiple pregnancy rates showed no significant difference between the two groups. CONCLUSIONS: In an ethnic Chinese patient population, fresh blastocyst transfer does not significantly increase clinical pregnancy rate. However, subsequent vitrified-warmed blastocyst transfer in a non-controlled ovarian hyperstimulation cycle dramatically improves clinical outcomes. Therefore, blastocyst culture in tandem with vitrified-warmed blastocyst transfer is recommended as a favourable and promising protocol in human ART treatment, particularly for ethnic Chinese patients. PMID- 23039213 TI - Targeting combinations of liposomal drugs to both tumor vasculature cells and tumor cells for the treatment of HER2-positive breast cancer. AB - PURPOSE: We used two ligand-modified liposomal drugs to selectively deliver two different chemotherapeutics to tumor cells (TC) and tumor vasculature endothelial (TV) cells, and examined the therapeutic effect of altering the order of treatment administration, and the effect of the temporal spacing of the treatments on the accumulation of a second dose of liposomes and therapeutic activity. METHODS: Studies were completed in an orthotopic mouse model of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, utilizing liposomal doxorubicin, targeted to TC via alphaHER2 Fab' fragments, and liposomal vincristine, targeted to CD13 on TV cells via NGR peptides. RESULTS AND DISCUSSION: Combination treatment with TV-targeted plus TC-targeted therapies was therapeutically superior to either single agent; switching the order of administration of the combination did not alter treatment efficacy. The tumor accumulation of a second dose of liposomes was increased if administered at 4 days after pre-treatment with TV-targeted therapy. Using a treatment schedule exploiting this increase, the dose of simultaneously administered combination therapy was halved without compromising therapeutic effect. CONCLUSION: Proof-of concept studies revealed the therapeutic potential of a dual-targeted two drug approach against HER2-positive breast cancer, and may be applicable to the treatment of other solid tumors. PMID- 23039214 TI - Introducing uncertainty in predictive modeling--friend or foe? AB - Uncertainty was introduced to chemical descriptors of 16 publicly available data sets to various degrees and in various ways in order to investigate the effect on the predictive performance of the state-of-the-art method decision tree ensembles. A number of strategies to handle uncertainty in decision tree ensembles were evaluated. The main conclusion of the study is that uncertainty to a large extent may be introduced in chemical descriptors without impairing the predictive performance of ensembles and without the predictive performance being significantly reduced from a practical point of view. The investigation further showed that even when distributions of uncertain values were provided, the ensembles method could generate equally effective models from single-point samples from these distributions. Hence, there seems to be no advantage in using more elaborate methods for handling uncertainty in chemical descriptors when using decision tree ensembles as a modeling method for the considered types of introduced uncertainty. PMID- 23039215 TI - Selective amine recognition driven by host-guest proton transfer and salt bridge formation. AB - The stepwise synthesis of ionizable p-tert-butylcalix[5]arenes 1a.H and 1b.H, featuring a fixed cone cavity endowed with a carboxyl moiety at the narrow rim, is described. Single-crystal X-ray analyses have shown that in the solid state 1a.H and 1b.H adopt a cone-out conformation with the carboxylic OH group pointing in, toward the bottom of the aromatic cavity, as a result of a three- or two center hydrogen-bonding pattern between the carboxyl group and the phenolic oxygen atom(s). The affinity of amines for calix[5]arene derivatives 1a.H and 1b.H was probed by (1)H NMR spectroscopy and single-crystal X-ray diffraction studies. These carboxylcalix[5]arenes are shown to selectively recognize linear primary amines--over branched, secondary, and tertiary amines--by a two-step process involving a proton transfer from the carboxyl to the amino group to provide the corresponding alkylammonium ion, followed by binding of the latter inside the cavity of the ionized calixarene. Proton transfer occurs only with linear primary amines, that is, when the best size and shape fit between host and substrate is achieved, while the other amines remain in their noncompeting unprotonated form. The role of the solvent in the ionization/complexation process is discussed. Structural studies on the n-BuNH(2) complexes with 1a.H and 1b.H provide evidence that binding of the in situ formed n-BuNH(3)(+) substrate to the cavity of the ionized macrocycle is ultimately secured, in the case of 1a.H, by the formation of an unprecedented salt-bridge interaction. PMID- 23039217 TI - Evolution of quality of life, mental health, and coping strategies in amyotrophic lateral sclerosis: a pilot study. AB - BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal, neurological disease, which can potentially impact mental health as well as the adaptation process of people who are affected. Most of the results available are cross-sectional. The aim of this study was to study the evolution of coping strategies, Quality of Life (QoL), and mental health in a sample of ALS patients. METHODS: Forty-nine patients with ALS were interviewed in order to obtain their demographic and medical data. Then, each one was asked to complete a questionnaire of coping strategies (Brief COPE), mental health (GHQ-28), and QoL (SF-36) at two different moments of the disease evolution. As many patients died in the interim, only 30 completed questionnaires at T2. The Wilcoxon test was used in order to compare mean scores between T1 and T2. RESULTS: On the GHQ-28, the differences concerned two dimensions: somatic disorders (Z=-2.15, p=0.03) and anxiety sleep disorders (Z=-2.07, p=0.04). We noted that mean scores increased between T1 and T2. Regarding coping strategies, only one tendency was found on the COPE. It concerned behavioral disengagement (Z=1.84, p=0.06), which was used more at T2 than at T1. Concerning QoL, one significant difference and one tendency between T1 and T2 were found. They involved pain (Z=2.52, p=0.01) and a tendency toward emotional role functioning (Z=-1.86, p=0.06). DISCUSSION: This study, the first to evaluate psychosocial aspects of ALS over time, underlines the importance of global, multidisciplinary, and adapted care. PMID- 23039216 TI - Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia. AB - BACKGROUND: We aimed at identifying variables predicting hypoglycemia in elderly type 2 diabetic patients and the relation to HbA1c values achieved. DESIGN: Prospective, observational registry in 3810 patients in primary care. Comparison of patients in different age tertiles: with an age < 60 (young, n=1,253), age 60 to < 70 (middle aged, n=1,184) to those >= 70 years (elderly, n=1,373). Odds Ratios (OR) with 95% confidence intervals (CI) were determined from univariable and multivariable regression analyses. RESULTS: Elderly patients had a later diabetes diagnosis, a longer diabetes duration, better glucose control and more frequent co-morbid disease conditions. Overall 10.7% of patients experienced any severity hypoglycemia within the last 12 months prior to inclusion. Higher rates of hypoglycemia were observed in the elderly than in the young after adjusting for differences in HbA1c, fasting and post-prandial blood glucose (OR 1.68; 95%CI 1.16-2.45). This was particularly true for hypoglycemic episodes without specific symptoms (OR 1.74; 95%CI 1.05-2.89). In a multivariate model stroke / transitory ischemic attack, the presence of heart failure, clinically relevant depression, sulfonylurea use and blood glucose self-measurement were associated with hypoglycemic events. CONCLUSION: Elderly patients are at an increased risk of hypoglycemia even at comparable glycemic control. Therefore identified variables associated with hypoglycemia in the elderly such as heart failure, clinically relevant depression, the use of sulfonylurea help to optimize the balance between glucose control and low levels of hypoglycemia. Asymptomatic hypoglycemia should not be disregarded as irrelevant but considered as a sign of possible hypoglycemia associated autonomic failure. PMID- 23039218 TI - Specialists' experiences and perspectives on the timing of referral to palliative care: a qualitative study. AB - BACKGROUND: Specialist referral practices regarding palliative care are variable and their decision-making practices regarding timing and communication remains an under-researched issue. More effective referral practices have been shown to enhance patient and carer experiences at the end of life, reduce the burden on pre-palliative care services, and even extend life expectancy in some cases. OBJECTIVE: The aim of this study was to examine the logics underpinning the timing of referral to palliative care according to a range of medical specialists in a regional center on the east coast of Australia, in order to facilitate improvements in referral practices. METHODS: We conducted semi-structured, qualitative interviews with 20 medical specialists and carried out a thematic analysis of the interview data, utilising the framework analysis approach and NVivo 9 software. Key themes were tested for rigour through inter-rater reliability. RESULTS: The major themes identified within this analysis of the interviews were: a) strategies for preparing for palliative care and the importance of planning timely referrals; b) perception of inter-professional variation and reasons for delayed or difficult referrals; and c) the importance of inter-specialty communication and cross-disciplinary dialogue. CONCLUSIONS: Significant barriers exist to the timely referral to palliative care, and, in order to improve patient and care quality of life and lessen clinical difficulties, further work is needed to develop streamlined practices that are sensitive to specialty needs and patient desires. PMID- 23039219 TI - Sit-stand and stand-sit transitions in older adults and patients with Parkinson's disease: event detection based on motion sensors versus force plates. AB - BACKGROUND: Motion sensors offer the possibility to obtain spatiotemporal measures of mobility-related activities such as sit-stand and stand-sit transitions. However, the application of new sensor-based methods for assessing sit-stand-sit performance requires the detection of crucial events such as seat on/off in the sensor-based data. Therefore, the aim of this study was to evaluate the agreement of detecting sit-stand and stand-sit events based on a novel body fixed-sensor method with a force-plate based analysis. METHODS: Twelve older adults and 10 patients with mild to moderate Parkinson's disease with mean age of 70 years performed sit-stand-sit movements while trunk movements were measured with a sensor-unit at vertebrae L2-L4 and reaction forces were measured with separate force plates below the feet and chair. Movement onsets and ends were determined. In addition, seat off and seat on were determined based on forces acting on the chair. Data analysis focused on the agreement of the timing of sit stand and stand-sit events as detected by the two methods. RESULTS: For the start and end of standing-up, only small delays existed for the start of forward trunk rotation and end of backward trunk rotation compared to movement onset/end as detected in the force-plate data. The end of forward trunk rotation had a small and consistent delay compared to seat off, whereas during sitting-down, the end of forward trunk rotation occurred earlier in relation to seat on. In detecting the end of sitting-down, backward trunk rotation ended after reaching the minimum in the below-feet vertical force signal. Since only small time differences existed between the two methods for detecting the start of sitting-down, longer movement durations were found for the sensor-based method. Relative agreement between the two methods in assessing movement duration was high (i.e. ICCs >= 0.75), except for duration of standing-up in the Parkinson's patients (ICC = 0.61). CONCLUSIONS: This study demonstrated high agreement of body-fixed-sensor based detection of sit-stand and stand-sit events with that based on force plates in older adults and patients with mild to moderate Parkinson's disease. Further development and testing is needed to establish reliability for unstandardized performance in clinical and home settings. PMID- 23039220 TI - Perception of Jordanian mothers to nursing support during their children hospitalisation. AB - AIMS AND OBJECTIVES: To describe Jordanian mothers' perceptions of nursing support provided during hospitalisation of their children and identify socio demographic characteristic of mothers and children associated with mothers' perceptions of nursing support. BACKGROUND: Nursing support is crucial to mothers to ease and relieve pain and stress experience during hospitalisation of their children. DESIGN: A cross-sectional design. METHOD: A total of 235 mothers who stayed with their children during their hospitalisations for medical or surgical health problems were recruited for the purpose of the study. Mothers of children of one month to two years old from two governmental hospitals in Amman-Jordan were interviewed over a period of two months. Data were collected using Nursing Parent Support Tool and demographic data questionnaire. RESULTS: This study showed that the perception of Jordanian mothers to nursing support was moderate (M = 3.23, SD = 0.95). Stepwise multiple regression analysis showed that mothers' satisfaction to nursing support and mothers' education explained (0.332) of the variance in the mother's perception of nursing support. CONCLUSION: Satisfaction with nursing care and level of education are important factors in Jordanian mothers' perception of nursing support. Nurses need to understand the importance of these factors when providing support and holistic care. RELEVANCE TO CLINICAL PRACTICE: To enhance high level of satisfaction of nursing care, paediatric nurses in the practice settings should establish parent support groups and provide educational materials that are beneficial for educated and uneducated parents. PMID- 23039221 TI - Copper(I)-catalyzed enantioselective incorporation of ketones to cyclic hemiaminals for the synthesis of versatile alkaloid precursors. AB - A general catalytic enantioselective method that can produce five-, six-, and seven-membered N-heterocycles possessing various ketone moieties starting from stable and easily available cyclic hemiaminals and ketones was developed. The method involves three successive steps in one pot (aldol addition, dehydration, and enantioselective intramolecular aza-Michael reaction), all of which are promoted by a chiral copper(I)-conjugated Bronsted base catalyst. This method is useful for rapid access to versatile chiral building blocks for the synthesis of drug-lead alkaloids. PMID- 23039222 TI - Chiral distortion of confined ice oligomers (N = 5,6). AB - Ice nuclei have been studied on the hexagonal boron nitride nanomesh (h BN/Rh(111)), a template with 2 nm wide molecule traps. Scanning tunneling microscopy shows confined clusters, where oligomers with three protrusions are particularly abundant. Together with local barrier height dI/dz maps, it is found that the dipoles of the water molecules arrange in a homodrome, which is consistent with density functional theory calculations. Hydrogen bonds toward the substrate identify h-BN/Rh(111) to be hydrophilic. The substrate distorts the hexamers (n = 6) and possibly pentamers (n = 5), where the experimentally observed footprints of the three protrusions appear more chiral than expected. PMID- 23039223 TI - Three pyrene-modified nucleotides: synthesis and effects in secondary nucleic acid structures. AB - Synthesis of three pyrene-modified nucleosides was accomplished using the CuAAC reaction. Hereby, pyrene is attached either to the 5'-position of thymidine or to the 2'-position of 2'-deoxyuridine through triazolemethylene linkers, or to the 2'-position of 2'-deoxyuridine through a more rigid triazole linker. The three nucleosides were incorporated into oligonucleotides, and these were combined in different duplexes and other secondary structures, which were analyzed by thermal stability and fluorescence studies. The three monomers were found to have different impacts on the nucleic acid complexes. Hence, pyrene attached to the 5' position shows a tendency for intercalation into the duplex as indicated by a general decrease in fluorescence intensity followed by an increase in duplex thermal stability. Pyrene attached to the 2'-position through a rigid triazole linker also shows a tendency for intercalation but with decrease in duplex stability, whereas the pyrene attached to the 2'-position through a triazolemethylene linker is primarily situated in the minor groove as indicated by an increase in fluorescence but here in most cases leading to increase in duplex stability. All three pyrene nucleotides lead to thermal stabilization of bulged duplexes and three-way junctions. In some cases when two pyrenes were introduced into the core of these complexes, the formation or disappearance of a fluorescence excimer band can be used to indicate the hybridization process. Hereby these oligonucleotides can act as specific recognition probes. PMID- 23039224 TI - Pain management during invasive procedures at Italian NICUs: has anything changed in the last five years? AB - OBJECTIVE: To ascertain the extent to which neonatal analgesia for invasive procedures has changed in the last 5 years since the publication of Italian guidelines. METHODS: We compared survey data for the years 2004 and 2010 on analgesia policy and practices for common invasive procedures at Italian Neonatal Intensive Care Units (NICUs); 75 NICUs answered questionnaires for both years and formed the object of this analysis. RESULTS: By 2010 analgesia practices for procedural pain had improved significantly for almost all invasive procedures (p < 0.05), both non-pharmacological and pharmacological methods being adopted by the majority of NICUs (unlike the situation in 2004). The routine use of medication for major invasive procedures was still limited, however (35% of lumbar punctures, 40% of tracheal intubations, 46% during mechanical ventilation). Postoperative pain treatment was still inadequate, and 41% of facilities caring for patients after surgery did not treat pain routinely. Pain monitoring had definitely improved since 2004 (p < 0.05), but not enough: only 21% and 17% of NICUs routinely assess pain during mechanical ventilation and after surgery, respectively. CONCLUSION: There have been improvements in neonatal analgesia practices in Italy since national guidelines were published, but pain is still undertreated and underscored, especially during major invasive procedures. It is mandatory to address the gap between the recommendations in the guidelines and clinical practice must be addressed through with effective quality improvement initiatives. PMID- 23039225 TI - One-pot oxidation/isomerization of Z-allylic alcohols with oxygen as stoichiometric oxidant. AB - A method for generating (E)-alpha,beta-unsaturated aldehydes from Z-allylic alcohols or E/Z-mixtures is described. The one-pot procedure involves a Cu catalyzed oxidation followed by an organocatalytic Z/E-isomerization with N,N dimethylaminopyridine (DMAP). PMID- 23039226 TI - Allergic contact dermatitis caused by Chinese herbal medicine, white mustard seed. PMID- 23039227 TI - Opinion controversy to chromium picolinate therapy's safety and efficacy: ignoring 'anecdotes' of case reports or recognising individual risks and new guidelines urgency to introduce innovation by predictive diagnostics? AB - Due to the important physiologic function of trivalent chromium in glucose/insulin homeostasis, some commercial organisations promote Cr3+ supplements in maintaining proper carbohydrate and lipid metabolism; regulation of reducing carbohydrate carvings and appetite; prevention of insulin resistance and glucose intolerance; regulation of body composition, including reducing fat mass and increasing lean body mass; optimal body building for athletes; losing weight; treatment of atypical depression as an antidepressant; and prevention of obesity and type 2 diabetes mellitus. On one hand, case reports are commented as 'nonevidence-based anecdotes'. On the other hand, a number of independent studies warn against adverse health outcomes assigned to chromium picolinate (CrPic) dietary application. This review analyses opinion controversies, demonstrates highly individual reactions towards CrPic dietary supplements and highlights risks when the dietary supplements are used freely as therapeutic agents, without application of advanced diagnostic tools to predict individual outcomes. PMID- 23039228 TI - Structure of RdxA--an oxygen-insensitive nitroreductase essential for metronidazole activation in Helicobacter pylori. AB - The RdxA oxygen-insensitive nitroreductase of the human gastric pathogen Helicobacter pylori is responsible for the susceptibility of this organism to the redox active prodrug metronidazole [2-(2-methyl-5-nitro-1H-imidazol-1 yl)ethanol]. Loss-of-function mutations in rdxA are primarily responsible for resistance to this therapeutic. RdxA exhibits potent NADPH oxidase activity under aerobic conditions and metronidazole reductase activity under strictly anaerobic conditions. In the present study, we report the crystal structure of RdxA, which is a homodimer exhibiting domain swapping and containing two molecules of FMN bound at the dimer interface. We have found a gap between the side chain of Tyr47 and the isoalloxazine ring of FMN that appears to be appropriate for substrate binding. The structure does not include residues 97-128, which correspond to a locally unstable part of the NTR from Escherichia coli, and might be involved in cofactor binding. Comparison of H. pylori RdxA with other oxidoreductases of known structure suggests that RdxA may belong to a new subgroup of oxidoreductases in which a cysteine side chain close to the FMN cofactor could be involved in the reductive activity. In this respect, the mutation of C159 to A or S (C159A/S) has resulted in a loss of metronidazole reductase activity but not NADPH oxidase activity. The RdxA structure enables the interpretation of the many loss-of-function mutations described previously, including those affecting C159, a residue whose interaction with FMN is required for the nitroreduction of metronidazole. The present studies provide unique insights into the redox behaviour of the flavin in this key enzyme for metronidazole activation, including a potential use in gene therapy. DATABASE: Structural data have been deposited in the Protein Data Bank under accession number 3QDL. PMID- 23039229 TI - Similar changes in muscle lipid metabolism are induced by chronic high-fructose feeding and high-fat feeding in C57BL/J6 mice. AB - The aim of the present study was to investigate the effects of high fructose and high fat feeding on muscle lipid metabolism and to illustrate the mechanisms by which the two different dietary factors induce muscle lipid accumulation. C57BL/J6 mice were fed either a standard, high-fructose (HFru) or high-fat diet. After 16 weeks feeding, mice were killed and plasma triglyceride (TG) and free fatty acid (FFA) levels were detected. In addition, muscle TG and long chain acyl CoA (LCACoA) content was determined, glucose tolerance was evaluated and the protein content of fatty acid translocase CD36 (FATCD36) in muscle was measured. Mitochondrial oxidative function in the muscle was evaluated by estimating the activity of oxidative enzymes, namely cytochrome oxidase (COx), citrate synthase (CS) and beta-hydroxyacyl CoA dehydrogenase (beta-HAD), and the muscle protein content of carnitine palmitoyltransferase-1 (CPT-1), cyclo-oxygenase (COX)-1 and proliferator-activated receptor coactivator (PGC)-1alpha was determined. Finally, sterol regulatory element-binding protein-1c (SREBP-1c) gene expression and fatty acid synthase (FAS) protein content were determined in muscle tissues. After 16 weeks, plasma TG and FFA levels were significantly increased in both the HFru and HF groups. In addition, mice in both groups exhibited significant increases in muscle TG and LCACoA content. Compared with mice fed the standard diet (control group), those in the HFru and HF groups developed glucose intolerance and exhibited increased FATCD36 protein levels, enzyme activity related to fatty acid utilization in the mitochondria and protein expressions of CPT-1, COX-1 and PGC 1alpha in muscle tissue. Finally, mice in both the HFru and HF groups exhibited increase SREBP-1c expression and FAS protein content. In conclusion, high fructose and high fat feeding lead to similar changes in muscle lipid metabolism in C57BL/J6 mice. Lipid accumulation in the muscle may be associated with increased expression of proteins related to lipid transportation and synthesis. PMID- 23039231 TI - The short-term response of yeast to potassium starvation. AB - Potassium is the major intracellular cation in most living cells, including yeasts. Although K(+) has been demonstrated to be necessary for diverse cellular functions, such as enzyme activation, additional, still uncharacterized cellular targets may exist. We show here that in Saccharomyces cerevisiae short-term potassium deprivation impacts in the mRNA level of over one thousand genes. Lack of potassium drastically alters sulfur metabolism (mainly Met and Cys metabolism), triggers an oxidative stress response and activates the retrograde pathway, possibly due to the ammonium accumulation that occurs through the Trk1 potassium transporter. We also observe a remarkable halt in the expression of genes required for ribosome biogenesis and translation, a decrease in expression of diverse components (cyclins, protein kinases) required for progression through the cell cycle and a blockage in septins assembly. Only specific subsets of these changes were observed in a strain deleted for the TRK1 and TRK2 genes growing in the presence of sufficient potassium (50 mM). Therefore, a shortage of potassium in the environment triggers an acute transcriptional response, which covers different aspects of the cell biology so far unexplored, and whose investigation will likely reveal novel functional roles for this cation. PMID- 23039230 TI - Oestrogen treatment of experimental autoimmune encephalomyelitis requires 17beta oestradiol-receptor-positive B cells that up-regulate PD-1 on CD4+ Foxp3+ regulatory T cells. AB - It is now well accepted that sex hormones have immunoregulatory activity and may prevent exacerbations in multiple sclerosis during pregnancy. Our previous studies demonstrated that oestrogen (17beta-oestradiol; E(2) ) protection against experimental autoimmune encephalomyelitis (EAE) is mediated mainly through oestrogen receptor-alpha (ERalpha) and the membrane receptor G-protein-coupled receptor 30 (GPR30) and is abrogated in the absence of B cells and the co inhibitory receptor, Programmed Death-1 (PD-1). To critically evaluate the cell source of the E2 and PD-1 co-inhibitory pathways in EAE regulation, we assessed the requirement for ERs on transferred B cells and downstream effects on expression of PD-1/PD-ligand on CD4+ Foxp3+ regulatory T (Treg) cells in B-cell replenished, E2-treated B-cell-deficient (MUMT-/-) mice with EAE. The results clearly demonstrated involvement of ERalpha and GPR30 on transferred B cells that mediated the protective E2 treatment effect on EAE and further showed an E2 mediated B-cell-dependent up-regulation of PD-1 on CD4+ Foxp3+ Treg cells. These findings identify regulatory B-cell populations as key players in potentiating Treg-cell activity during E2-mediated protection against EAE. PMID- 23039232 TI - Multiobjective particle swarm optimization: automated identification of structure activity relationship-informative compounds with favorable physicochemical property distributions. AB - The selection of active compounds for chemical optimization efforts typically requires the consideration of multiple properties beyond potency. Herein we introduce a multiobjective particle swarm optimization approach to automatically extract compound subsets from large data sets that reveal structure-activity relationship (SAR) information and display physicochemical property distributions that are indicative of favorable absorption, distribution, metabolism, and excretion (ADME) characteristics. The approach is based on Pareto optimization of multiple objectives and does not require subjective intervention. It is automated and can be easily modified. We have applied the method to screen 10 compound data sets of different composition and global SAR phenotypes. In five of these data sets, between one and more than hundred compound subsets were identified that represented discontinuous local SARs and had desirable property distributions. PMID- 23039233 TI - Tissue-conserving, yet radical surgery for extensive gas-forming soft tissue infections arising from perirectal abscess: report of a case. AB - BACKGROUND: Perirectal abscess is encountered commonly in surgical practice, and simple incision and drainage usually is sufficient. However, life-threatening sepsis may occur. In such instances, the high morbidity and mortality rates from the severe systemic inflammatory response syndrome (SIRS) associated with rapidly evolving necrotizing and gas-forming soft tissue infections are of major concern. METHODS: Case report and review of pertinent literature. RESULTS: A rare case of extensive necrotizing fasciitis of the torso arising from a perirectal abscess, in which the principles of radical surgical debridement were adhered to while minimizing disfigurement, is reported in a 19-year-old female. In some cases, despite the life-threatening nature of necrotizing fasciitis, it is possible to minimize tissue loss without compromising patient survival. CONCLUSION: Planning of the patient's site rehabilitation for maximum cosmetic outcome commences at the time of surgical debridement and is especially important for the young patient. PMID- 23039235 TI - Tigecycline use in patient with intra-abdominal abscess, beta-lactam allergy, and acute kidney injury. PMID- 23039234 TI - Fatal tetanus complicating an untreated mild open head injury: a case-illustrated review of cephalic tetanus. AB - BACKGROUND: Tetanus is now a rare disease in the Western world, but not so in developing countries. Cephalic tetanus, unlike some other local forms of the disease, is likely to be fatal. METHODS: We describe the clinical presentation of a case of fatal cephalic tetanus complicating an unattended open non-severe head injury with a review of the literature on the disease. RESULTS: Few cases of cephalic tetanus complicating head injury are found in the world literature, and many were diagnosed late. Cephalic tetanus from open or compound depressed skull fracture is even more rare. Our patient was a young male with an uncertain tetanus immunization history who sustained mild head injury (scalp laceration) and an unattended open depressed skull fracture in a motorcycle crash. He developed cephalic tetanus seven days later, presented late to our service, and died while being prepared for surgical debridement of his cranial wounds. At the immediate post-trauma medical contact, in an across-the-street "clinic," he had received suboptimal care for his head wound and inadequate tetanus prophylaxis. CONCLUSION: Cephalic tetanus is a rare form of the disease. Although it is preventable easily by well-established medical and surgical treatment paradigms, it continues to catch many clinicians disastrously unaware. PMID- 23039236 TI - Acinetobacter baumannii post-operative meningitis. PMID- 23039237 TI - Outcomes after unplanned admission to hospital in older people: ill-defined conditions as potential indicators of the frailty trajectory. AB - OBJECTIVES: To describe outcomes after unplanned hospital admission in older people and to determine whether disease trajectories in those admitted with ill defined conditions (symptoms and signs) are distinct from other diagnostic groups and consistent with known disease trajectories. DESIGN: Longitudinal follow-up after a retrospective cross-sectional study of emergency admissions to general internal and geriatric medicine units in one hospital. SETTING: Acute hospital in southern England. PARTICIPANTS: All people aged 65 and older with unplanned admissions to general internal and geriatric medicine inpatient units during 2002 (N = 5,312). MEASUREMENTS: Age, sex, comorbidity, presence of cognitive and mood disorders, residence, and primary diagnostic group at discharge. Outcomes were death up to 36 months from admission, any readmission, and readmission for ill defined conditions up to 36 months after discharge. RESULTS: There were significant differences in death rates between the diagnostic groups, with mortality being highest in individuals with a primary diagnosis of cancer and lowest in the ill-defined conditions group. Nearly 83% of the ill-defined conditions group survived the follow-up period. Adjusted Cox proportional hazard models indicated that, when age, sex, comorbidity, residence, and cognitive and mood disorders were accounted for, the ill-defined condition group had a lower risk of death but a higher risk of subsequent readmissions for ill-defined conditions than any other group. Overall readmission risk was highest for individuals admitted for a respiratory condition but was similar in all other diagnostic groups. CONCLUSION: The lower mortality risk associated with ill defined conditions is consistent with chronic rather than acute needs, but the pattern of mortality and readmission is more consistent with the frailty than the chronic organ system failure illness trajectory, suggesting that functional support needs may be more important in this group of individuals. PMID- 23039239 TI - Septic pulmonary embolism due to periodontal disease. AB - BACKGROUND AND OBJECTIVE: Septic pulmonary embolism due to periodontal disease (SPE-PD) is rarely reported and little is known about its clinical features. The purpose of this study was to evaluate the clinical and radiological features, as well as outcome, in SPE-PD. METHODS: Patients' records were retrospectively reviewed and 12 patients with SPE-PD were identified (10 men, mean age 60.5 years). The patients' demographic features, laboratory data, physical and radiological findings, and clinical outcomes were evaluated. RESULTS: All but one patient were smokers. Eight of the 12 patients had comorbidities including hypertension (58%) and/or diabetes mellitus (17%). Prevalent symptoms were fever (67%) and chest pain (58%). Only two patients fulfilled the criteria of systemic inflammatory response syndrome; most of the subjects were not clinically severely ill. Blood cultures were negative in all cases. Contrast-enhanced chest computed tomography (CT) showed multiple peripheral nodules in all 12 patients, wedge shaped peripheral lesions abutting on the pleura in 10 (83%) and a feeding-vessel sign in 9 (75%). All patients recovered from their illness after antimicrobial therapy concomitant with tooth extraction or periodontal care. The median duration of antibiotic administration was 51 days. CONCLUSIONS: Most patients with SPE-PD were not seriously ill. Contrast-enhanced chest CT appeared to be useful to diagnose SPE-PD. PMID- 23039238 TI - Several genetic polymorphisms interact with overweight/obesity to influence serum lipid levels. AB - BACKGROUND: Information about the interactions of single nucleotide polymorphisms (SNPs) and overweight/obesity on serum lipid profiles is still scarce. The present study was undertaken to detect ten SNPs and their interactions with overweight/obesity on serum lipid levels. METHODS: A total of 978 normal weight and 751 overweight/obese subjects of Bai Ku Yao were randomly selected from our previous stratified randomized cluster samples. Normal weight, overweight and obesity were defined as a body mass index (BMI) < 24, 24-28, and > 28 kg/m(2); respectively. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) A1 and ApoB levels were measured. Genotyping of ATP-binding cassette transporter A1 (ABCA-1) V825I, acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) rs1044925, low density lipoprotein receptor (LDL-R) AvaII, hepatic lipase gene (LIPC) -250G>A, endothelial lipase gene (LIPG) 584C>T, methylenetetrahydrofolate reductase (MTHFR) 677C>T, the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP) rs3757354, proprotein convertase subtilisin-like kexin type 9 (PCSK9) E670G, peroxisome proliferator activated receptor delta (PPARD) +294T>C, and Scavenger receptor class B type 1 (SCARB1) rs5888 was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The interactions were detected by factorial design covariance analysis. RESULTS: The genotypic and allelic frequencies of LIPC and PCSK9 were different between normal weight and overweight/obese subjects, the genotypic frequency of LIPG and allelic frequency of MYLIP were also different between normal weight and overweight/obese subjects (P < 0.05 0.001). The levels of TC, ApoA1 (ABCA-1); TC, LDL-C, ApoA1, ApoB and ApoA1/ApoB (LIPC); TG, HDL-C, and ApoA1 (LIPG); TC, HDL-C, LDL-C, ApoA1 and ApoB (MTHFR); HDL-C and ApoA1 (MYLIP) in normal weight subjects were different among the genotypes (P < 0.01-0.001). The levels of LDL-C, ApoB and ApoA1/ApoB (ABCA-1); HDL-C, ApoA1, ApoB and ApoA1/ApoB (LIPC); TC, HDL-C, ApoA1 and ApoB (LIPG); TC, TG, HDL-C, LDL-C, ApoA1 and ApoB (MTHFR); TC, TG and ApoB (MYLIP); TG (PCSK9); TG, ApoA1 and ApoB (PPARD); and TC, HDL-C, LDL-C, ApoA1 and ApoB (SCARB1) in overweight/obese subjects were different among the genotypes (P < 0.01-0.001). The SNPs of ABCA-1 (LDL-C and ApoA1/ApoB); LIPC (TC, LDL-C, ApoA1 and ApoB); LIPG (ApoB); MTHFR (TC, TG and LDL-C); MYLIP (TC and TG); PCSK9 (TG, HDL-C, ApoB and ApoA1/ApoB); PPARD (TG and ApoA1/ApoB); and SCARB1 (TG, ApoA1 and ApoB) interacted with overweight/obesity to influence serum lipid levels (P < 0.05 0.001). CONCLUSIONS: The differences in serum lipid levels between normal weight and overweight/obese subjects might partly result from different genetic polymorphisms and the interactions between several SNPs and overweight/obesity. PMID- 23039240 TI - Infectious pancreatic necrosis virus (IPNV) from salmonid fish enters, but does not replicate in, mammalian cells. AB - BACKGROUND: The aquatic birnavirus infectious pancreatic necrosis virus (IPNV) causes infectious pancreatic necrosis (IPN), a severe disease in farmed salmonid fish. IPNV has a very broad host range and infects many different species of fish as well as molluscs and crustaceans. Investigation of the host reservoir of a virus may reveal important molecular mechanisms governing the infection processes such as receptors and entry mechanisms. In the present work we have studied whether IPNV is able to infect cells with different mammalian origin. RESULTS: IPNV bound in a specific manner to a membrane protein of the rabbit kidney cell line RK-13 as shown by the use of a virus overlay protein binding assay (VOPBA). Six different mammalian cell lines were inoculated with IPNV and incubated in parallels at different temperatures. At 7 days post inoculation (dpi), IPNV was detected by indirect immunofluorescent antibody test (IFAT) in all the cell lines. Confocal microscopy confirmed intracellular presence of the virus. No apparent cytopathic effect (cpe) was observed in any of the cultures, and no viral replication was demonstrated with real-time RT-PCR. CONCLUSION: Our results show that IPNV is able to enter into a wide range of mammalian cells, and virus entry is most likely receptor mediated. We found no indication of IPNV replication in any of the mammalian cell lines tested. PMID- 23039243 TI - Switchable palladium-catalyst reaction of bromomethyl sulfoxides, CO, and N nucleophiles: aminocarbonylation at Csp3 versus oxidative carbonylation of amines. AB - The palladium-catalyzed reaction of alpha-bromomethyl sulfoxides, carbon monoxide, and N-nucleophiles follows different reaction pathways according to the catalytic system and the reaction conditions. The Pd-xantphos catalyst affords high yields of alpha-sulfinyl amides by an aminocarbonylation process and is the first example of this type of transformation for a nonbenzylic sp(3)-hybridized carbon. On the other hand, the oxidative carbonylation of amines occurs with alpha-bromomethyl sulfoxides, carbon monoxide, and catalytic Pd(PPh(3))(4) under aerobic conditions, yielding ureas and oxalamides from either primary or secondary amines. The reaction with ambident nucleophiles such as amino alcohols was highly selective and took place exclusively at the amino group despite the presence of the alcohol functionality. In parallel to the reaction paths for simple amines, amino alcohols were converted into hydroxy sulfinyl amides when the reaction was catalyzed by Pd-xantphos, while Pd(PPh(3))(4) catalyst afforded cyclic carbamates. The alkoxycarbonylation reaction of bromomethyl sulfoxides with simple alcohols and CO leading to the corresponding sulfinyl esters is also described. PMID- 23039241 TI - Laminin-1 (LM-111) in preeclampsia and systemic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antibodies. SLE has been associated with placental pathology, a finding that is also the determinant in preeclampsia (PE). Genetic evidence and serologic reports suggest laminin-1 (LM-111) as an immunogenic molecule and its polymorphic gene as a candidate gene for both disorders. OBJECTIVE: To evaluate the association between LAMA1 (rs543355) and LAMC1 (rs20563) polymorphisms and the presence of SLE and PE as well as to determine serum levels of anti-LM-111 autoantibodies in the PE group. METHODS: Group A: 169 women with PE and 172 healthy pregnant women. Group B: 204 women with SLE and 204 healthy women. Anti-LM-111 for group A was measured by ELISA and the genotyping was done by using a PCR system. RESULTS: Group A: Levels of anti LM-111 was similar in women with PE and the control group (p = 0.3). The allelic frequencies and genotypes did not show statistically significant differences for LAMA1 and LAMC1 polymorphisms. Group B: Significant differences between SLE patients and controls for rs543355 polymorphism were not observed. Nevertheless, LAMC1 rs20563 A-allele provided protection against the development of SLE (OR 0.73, 95%CI 0.55-0.96). CONCLUSIONS: Serum levels of anti-LM-111 at the third trimester of gestation do not seem to have any direct relationship with the presence of PE, and the SNPs evaluated are not associated with the risk of developing this disorder. LAMC1 polymorphism could be a protective factor for SLE. PMID- 23039244 TI - Coeliac disease--women's experiences in everyday life. AB - AIMS AND OBJECTIVES: To describe what life is like as a woman living with coeliac disease. BACKGROUND: The therapy for coeliac disease is a gluten-free diet, and if sufferers keep strictly to this, it is suggested that they will stay well. However, previous studies point out that people who are treated for coeliac disease, particularly women, experience various kinds of inconvenience in relation to having coeliac disease and to being treated with gluten-free diet. DESIGN: A qualitative research design was chosen. METHODS: A phenomenological approach as devised by Giorgi was used. Tape-recorded qualitative interviews with a total of 15 women who were being treated for coeliac disease were conducted in 2008 in Sweden. RESULTS: The results demonstrated that coeliac disease can influence women's lives in different ways. The general structure of being a woman with coeliac disease was described as a striving towards a normalised lifeworld. Three conditions necessary to achieve a normalised life were described, namely being secure, being in control and being seen and included. CONCLUSION: Understanding factors affecting the ability to live with coeliac disease as normally as possible can help caregivers, and others, to support these women in their aims. RELEVANCE TO CLINICAL PRACTICE: Nurses should help women to adopt facilitating thoughts in relation to the disease and, in so doing, help them to select appropriate coping strategies. PMID- 23039245 TI - Pelvic lymph node dissection for prostate cancer: adherence and accuracy of the recent guidelines. AB - OBJECTIVES: The 2004 National Comprehensive Cancer Network practice guidelines recommend pelvic lymph node dissection at radical prostatectomy. We sought to examine the adherence to the 2004 National Comprehensive Cancer Network guidelines and to test the their accuracy, as well as the accuracy of the most contemporary National Comprehensive Cancer Network, American Urological Association, and European Association of Urology guidelines to predict lymph node metastases. METHODS: A total of 33 037 radical prostatectomy patients were identified, between 2004 and 2006. Adherence to the 2004 National Comprehensive Cancer Network guidelines was calculated using three clinically plausible cut offs: 2, 5 and 10%. The accuracy was tested using the area under the curve. RESULTS: Overall, 63% of patients underwent pelvic lymph node dissection. Of those, 61, 49 and 45% were managed according to the 2004 National Comprehensive Cancer Network guideline cut-off of 2, 5 and 10%, respectively. The accuracy of all the examined guidelines ranged from 61% to 71%. The highest accuracy was recorded for the European Association of Urology and the 2004 National Comprehensive Cancer Network cut-off 5% guidelines. The lowest accuracy was recorded for the most contemporary National Comprehensive Cancer Network guideline. CONCLUSIONS: Adherence to the 2004 National Comprehensive Cancer Network guidelines was suboptimal. The accuracy of all the examined guidelines ranged from 61% to 71%. None of the examined guidelines can be regarded as an ideal indication for pelvic lymph node dissection. PMID- 23039247 TI - WHO Surgical Safety Checklist in otorhinolaryngology-head and neck surgery: specialty-related aspects of check items. AB - CONCLUSION: The WHO surgical checklist is well suited to otorhinolaryngology-head and neck surgery (ORL-HNS) and the users are satisfied with its content. OBJECTIVES: Use of the checklist will improve safety in operating rooms (ORs). The checklist has been taken into use in ORL-HNS, and preliminary experiences are promising. However, the checklist must be specific to the specialty in which it is used. The aim of this study was to evaluate the utility of the check items for ORL-HNS operations, with special reference to outpatient surgery. METHODS: The questionnaire study for the OR personnel was conducted at a tertiary academic hospital. Every item on the WHO checklist was evaluated and responders could provide freehand comments on the subject. RESULTS: In all, 101 responses were received from OR staff; the response rate was 95.3%. The users were mainly satisfied with the checklist's content for ORL-HNS operations. Mean scores of the importance of check items varied from 4.08 to 4.89 on a five-point scale. The item 'Allergy' had the highest score and 'Team members introduced' the lowest. A need to modify the checklist for in-hospital patients did not emerge. However, a more compact checklist for outpatient surgery carried out under local anaesthesia was suggested. PMID- 23039246 TI - Antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats is mediated by suppression of the intrarenal renin-angiotensin system. AB - The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (sEH) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids (EETs), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure-natriuresis relationship. Ren-2 transgenic rats (TGR), a model of angiotensin (Ang) II-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH inhibitor cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy)benzoic acid (c-AUCB; 26 mg/L) for 48 h. Then, the effects on blood pressure (BP), autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), and on the pressure natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP) were determined. Treatment with c-AUCB did not significantly change BP, renal autoregulation or pressure-natriuresis in normotensive HanSD rats. In contrast, c-AUCB treatment significantly reduced BP, increased intrarenal bioavailability of EETs and significantly suppressed AngII levels in TGR. However, treatment with c-AUCB did not significantly improve the autoregulatory efficiency of RBF and GFR in response to reductions of RAP and to restore the blunted pressure-natriuresis relationship in TGR. Together, the data indicate that the antihypertensive actions of sEH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin angiotensin system activity. PMID- 23039248 TI - Topical corticosteroids and hospital length of stay in children with eczema herpeticum. AB - There is concern that the use of topical corticosteroids in patients with eczema herpeticum may facilitate dissemination of herpes simplex virus and worsen disease. Our primary aim therefore was to determine whether topical corticosteroid use in children hospitalized with eczema herpeticum is associated with longer hospital length of stay (LOS). We performed a multicenter retrospective cohort study of 1,331 children ages 2 months to 17 years admitted with a diagnosis of eczema herpeticum between January 1, 2001, and March 31, 2010, to 42 tertiary care children's hospitals in the Pediatric Health Information System database. Multivariable linear regression models determined the association between receipt of topical corticosteroid therapy on the first day of hospitalization and the main outcome measure: LOS. Receipt of topical corticosteroid therapy on day 1 of hospitalization was not associated with a longer LOS on unadjusted or multivariable analysis (p = 0.75). Receipt of topical calcineurin inhibitors during the hospitalization was also not associated with a longer LOS (p = 0.12). Receipt of systemic corticosteroids was associated with an 18% adjusted longer LOS (95% confidence interval 2%-36%; p = 0.03). Further study is needed to identify which children with eczema herpeticum may benefit from topical corticosteroids, but their use during active infection is not associated with poorer outcomes, although the use of systemic corticosteroids was associated with a longer LOS and should be avoided in patients with eczema herpeticum pending future prospective study. PMID- 23039249 TI - Interleukin-15 receptor alpha expression in inflammatory bowel disease patients before and after normalization of inflammation with infliximab. AB - Interleukin-15 (IL-15) is a pro-inflammatory cytokine thought to contribute to the inflammation in inflammatory bowel diseases (IBD). The specific receptor chain IL-15Ralpha can be expressed as a transmembranous signalling receptor, or can be cleaved by a disintegrin and metalloprotease domain 17 (ADAM17) into a neutralizing, soluble receptor (sIL-15Ralpha). The aim of this study is to evaluate the expression of IL-15Ralpha in ulcerative colitis (UC) and Crohn's disease (CD) patients before and after infliximab (IFX) therapy. Gene expression of IL-15Ralpha, IL-15 and ADAM17 was measured at the mRNA level by quantitative reverse transcription-PCR in mucosal biopsies harvested before and after first IFX therapy. Concentrations of sIL-15Ralpha were measured in sera of patients by ELISA and IL-15Ralpha protein was localized in the gut by immunohistochemistry and immunofluorescence. Mucosal expression of IL-15Ralpha is increased in UC and CD patients compared with controls and it remains elevated after IFX therapy in both responder and non-responder patients. The concentration of sIL-15Ralpha in serum is also increased in UC patients when compared with controls and does not differ between responders and non-responders either before or after IFX. CD patients have levels of sIL-15Ralpha comparable to healthy controls before and after therapy. In mucosal tissues, IL-15Ralpha(+) cells closely resemble activated memory B cells with a pre-plasmablastic phenotype. To conclude, IBD patients have an increased expression of IL-15Ralpha mRNA in the mucosa. Expression is localized in B cells, suggesting that IL-15 regulates B-cell functions during bowel inflammation. No change in release of sIL-15Ralpha is observed in patients treated with IFX. PMID- 23039250 TI - Autophobing on liquid subphases driven by the interfacial transport of amphiphilic molecules. AB - We investigated the phenomenon of incomplete wetting of a high-energy liquid subphase by drops of pure amphiphilic molecules as well as drops of amphiphile solutions that are immiscible with the subphase. We show that amphiphiles escape across the contact line of the drop, move on the subphase/vapor interface, and form a submonolayer or full monolayer external to the drop. If this monolayer is sufficiently dense, then it can reduce the surface tension of the subphase, raise the contact angle of the drop, and prevent the drop from fully wetting the subphase. This phenomenon is called autophobing and has been extensively studied on solid substrates. For the liquid subphase studied here, we measure the surface tensions of the three relevant interfaces before and after the drop is deposited. The measured surface tension external to the drop shows that amphiphiles can move across the contact line and form a monolayer outside of the drop. In some cases, at equilibrium, the monolayer is in a sufficiently packed state to create the nonwetting condition. In other cases, at equilibrium the monolayer density is insufficient to lower the surface tension enough to achieve the nonwetting condition. Unlike on solid substrates where the formation of the monolayer external to the drop is kinetically hindered, the amphiphiles can move rapidly across the liquid subphase by Marangoni-driven surface transport, and local equilibrium is achieved. However, because the amphiphile inventory and subphase area are limited, the achievement of autophobing on a liquid subphase depends not only on the instrinsic subphase/amphiphile interaction but also on the total amphiphile inventory and area of the liquid subphase. PMID- 23039252 TI - The rule of fives, a simple way to stratify risk for primary gastrointestinal stromal tumors (GIST). AB - The current AJCC version 7 staging system is a lugubrious means to classify gastrointestinal stromal tumors with respect to their risk and need for adjuvant systemic therapy. The rule of fives, suggested here, is a means to quickly assess whether a given gastrointestinal stromal tumor is low vs intermediate-high risk. PMID- 23039251 TI - Tempering the reactivities of postulated alpha-oxo gold carbenes using bidentate ligands: implication of tricoordinated gold intermediates and the development of an expedient bimolecular assembly of 2,4-disubstituted oxazoles. AB - 2,4-Oxazole is an important structural motif in various natural products. An efficient modular synthesis of this structure has been achieved via a [3 + 2] annulation between a terminal alkyne and a carboxamide using a gold-catalyzed oxidation strategy. The postulated reactive intermediate, a terminal alpha-oxo gold carbene, previously known to be highly electrophilic and hence unlikely to be trapped by stoichiometric external nucleophiles, is coerced to react smoothly with the carboxamide en route to the oxazole ring by a P,N- or P,S-bidentate ligand such as Mor-DalPhos; in stark contrast, often-used ligands such as monodentate phosphines and N-heterocyclic carbenes are totally ineffective. The role of these bidentate phosphines in this reaction is attributed to the formation of a tricoordinated gold carbene intermediate, which is less electrophilic and hence more chemoselective when reacting with nucleophiles. The success in using bidentate phosphine ligands to temper the reactivities of in situ-generated gold carbenes is likely to open many new opportunities to apply oxidative gold catalysis to the development of novel methods, and the implication of tricoordinated gold intermediates in homogeneous gold catalysis should stimulate further advances in gold catalysis. PMID- 23039254 TI - Amniotic fluid myeloperoxidase in pregnancies complicated by preterm prelabor rupture of membranes. AB - OBJECTIVE: To determine amniotic fluid myeloperoxidase concentration in women with preterm prelabor rupture of the membranes with microbial invasion of the amniotic cavity and histological chorioamnionitis. METHODS: One hundred eighty one women with singleton pregnancies with a gestational age between 24+0 and 36+6 weeks were included in this study. Amniocenteses were performed, and myeloperoxidase concentration in the amniotic fluid was determined using ELISA. RESULT: Women with microbial invasion of the amniotic cavity had higher median myeloperoxidase concentration than women without this condition (149.2 ng/mL vs. 54.6 ng/mL; p = 0.0006). Women with the presence of histological chorioamnionitis had higher median myeloperoxidase concentration than women without histological chorioamnionitis (103.7 ng/mL vs. 50.0 ng/mL; p = 0.0001). The presence of both microbial invasion of the amniotic cavity and histological chorioamnionitis was associated with higher median myeloperoxidase concentration (456.0 ng/mL vs. 52.9 ng/mL; p < 0.0001). The results remained significant after adjusting for gestational age. CONCLUSIONS: Increased amniotic fluid myeloperoxidase in microbial invasion of the amniotic cavity and histological chorioamnionitis confirm a role of myeloperoxidase in preterm prelabor rupture of the membranes pathophysiology. PMID- 23039253 TI - DNA demethylation regulates the expression of miR-210 in neural progenitor cells subjected to hypoxia. AB - Several studies have identified a set of hypoxia-regulated microRNAs, among which is miR-210, whose expression is highly induced by hypoxia in various cancer cell lines. Recent studies have highlighted the importance of miR-210 and its transcriptional regulation by the transcription factor hypoxia-inducible factor-1 (HIF-1). We report here that the expression of miR-210 was highly induced in neural progenitor cells (NPCs) subjected to hypoxia. Specifically, treating hypoxic NPCs with the DNA demethylating agent 5-aza-2'-deoxycytidine significantly increased the expression of miR-210, even under normoxia; however, the activity of hypoxia-inducible factor-1 was unaffected. Further analysis of the miR-210 sequence revealed that it is embedded in a CpG island. Bisulfite sequencing of the miR-210 CpG island from NPCs grown under hypoxic conditions showed 24% CpG methylation in NPCs exposed to 20% O(2) , 18% in NPCs exposed to 3% O(2) , and 12% in NPCs exposed to 0.3% O(2) . In addition, the activity of DNA methyltransferases (DNMTs) in NPCs decreased after exposure to hypoxia. Specifically, the expression of DNMT3b decreased significantly after exposure to 0.3% O(2) . Thus, these results demonstrate that DNA demethylation regulates miR 210 expression in NPCs under both normoxia and hypoxia. PMID- 23039255 TI - Estimation of environment-related properties of chemicals for design of sustainable processes: development of group-contribution+ (GC+) property models and uncertainty analysis. AB - The aim of this work is to develop group-contribution(+) (GC(+)) method (combined group-contribution (GC) method and atom connectivity index (CI) method) based property models to provide reliable estimations of environment-related properties of organic chemicals together with uncertainties of estimated property values. For this purpose, a systematic methodology for property modeling and uncertainty analysis is used. The methodology includes a parameter estimation step to determine parameters of property models and an uncertainty analysis step to establish statistical information about the quality of parameter estimation, such as the parameter covariance, the standard errors in predicted properties, and the confidence intervals. For parameter estimation, large data sets of experimentally measured property values of a wide range of chemicals (hydrocarbons, oxygenated chemicals, nitrogenated chemicals, poly functional chemicals, etc.) taken from the database of the US Environmental Protection Agency (EPA) and from the database of USEtox is used. For property modeling and uncertainty analysis, the Marrero and Gani GC method and atom connectivity index method have been considered. In total, 22 environment-related properties, which include the fathead minnow 96-h LC(50), Daphnia magna 48-h LC(50), oral rat LD(50), aqueous solubility, bioconcentration factor, permissible exposure limit (OSHA-TWA), photochemical oxidation potential, global warming potential, ozone depletion potential, acidification potential, emission to urban air (carcinogenic and noncarcinogenic), emission to continental rural air (carcinogenic and noncarcinogenic), emission to continental fresh water (carcinogenic and noncarcinogenic), emission to continental seawater (carcinogenic and noncarcinogenic), emission to continental natural soil (carcinogenic and noncarcinogenic), and emission to continental agricultural soil (carcinogenic and noncarcinogenic) have been modeled and analyzed. The application of the developed property models for the estimation of environment-related properties and uncertainties of the estimated property values is highlighted through an illustrative example. The developed property models provide reliable estimates of environment-related properties needed to perform process synthesis, design, and analysis of sustainable chemical processes and allow one to evaluate the effect of uncertainties of estimated property values on the calculated performance of processes giving useful insights into quality and reliability of the design of sustainable processes. PMID- 23039257 TI - Harnessing the power of crowds: crowdsourcing as a novel research method for evaluation of acne treatments. AB - BACKGROUND: Crowdsourcing is a novel process of data collection that can provide insight into the effectiveness of acne treatments in real-world settings. Little is known regarding the feasibility of crowdsourcing as a means of collecting dermatology research data, the quality of collected data, and how the data compare to the published literature. OBJECTIVE: The objective of this analysis is to compare acne data collected from a medical crowdsourcing site with high quality controlled studies from peer-reviewed medical literature. METHODS: Crowdsourced data was collected from 662 online acne patients. Online patients reported data in a Likert-type format to characterize their symptom severity (740 total responses) and their treatment outcomes (958 total responses). The crowdsourced data were compared with meta-analyses and reviews on acne treatment from August 20, 2010 to August 20, 2011. RESULTS: We compared topical, oral systemic, alternative, phototherapy, and physical acne treatments of crowdsourced data to published literature. We focused on topical tretinoin due to the large number of online patient responses. While approximately 80% of tretinoin users observed clinical improvement after a 12-week treatment period in clinical trials, 46% of online users reported improvement in an unspecified time period. For most topical treatments, medication with high efficacy in clinical trials did not produce high effectiveness ratings based on the crowdsourced online data. CONCLUSION: While limitations exist with the current methods of crowdsourced data collection, with standardization of data collection and use of validated instruments, crowdsourcing will provide an important and valuable platform for collecting high-volume patient data in real-world settings. PMID- 23039259 TI - Oxygen minimum zones harbour novel viral communities with low diversity. AB - Oxygen minimum zones (OMZs) are oceanographic features that affect ocean productivity and biodiversity, and contribute to ocean nitrogen loss and greenhouse gas emissions. Here we describe the viral communities associated with the Eastern Tropical South Pacific (ETSP) OMZ off Iquique, Chile for the first time through abundance estimates and viral metagenomic analysis. The viral-to microbial ratio (VMR) in the ETSP OMZ fluctuated in the oxycline and declined in the anoxic core to below one on several occasions. The number of viral genotypes (unique genomes as defined by sequence assembly) ranged from 2040 at the surface to 98 in the oxycline, which is the lowest viral diversity recorded to date in the ocean. Within the ETSP OMZ viromes, only 4.95% of genotypes were shared between surface and anoxic core viromes using reciprocal BLASTn sequence comparison. ETSP virome comparison with surface marine viromes (Sargasso Sea, Gulf of Mexico, Kingman Reef, Chesapeake Bay) revealed a dissimilarity of ETSP OMZ viruses to those from other oceanic regions. From the 1.4 million non redundant DNA sequences sampled within the altered oxygen conditions of the ETSP OMZ, more than 97.8% were novel. Of the average 3.2% of sequences that showed similarity to the SEED non-redundant database, phage sequences dominated the surface viromes, eukaryotic virus sequences dominated the oxycline viromes, and phage sequences dominated the anoxic core viromes. The viral community of the ETSP OMZ was characterized by fluctuations in abundance, taxa and diversity across the oxygen gradient. The ecological significance of these changes was difficult to predict; however, it appears that the reduction in oxygen coincides with an increased shedding of eukaryotic viruses in the oxycline, and a shift to unique viral genotypes in the anoxic core. PMID- 23039261 TI - Encephalopathy: an unusual neurologic complication of autologous hematopoietic stem cell transplant in patients with multiple myeloma with renal failure. PMID- 23039260 TI - "Souls of the ancestor that knock us out" and other tales. A qualitative study to identify demand-side factors influencing malaria case management in Cambodia. AB - BACKGROUND: Appropriate case management of suspected malaria in Cambodia is critical given anti-malarial drug resistance in the region. Improving diagnosis and the use of recommended malarial treatments is a challenge in Cambodia where self-treatment and usage of drug cocktails is widespread, a notable difference from malaria treatment seeking in other countries. This qualitative study adds to the limited evidence base on Cambodian practices, aiming to understand the demand side factors influencing treatment-seeking behaviour, including the types of home treatments, perceptions of cocktail medicines and reasons for diagnostic testing. The findings may help guide intervention design. METHODS: The study used in-depth interviews (IDIs) (N = 16) and focus group discussions (FGDs) (N = 12) with Cambodian adults from malaria-endemic areas who had experienced malaria fever in the previous two weeks. Data were analysed using NVivo software. RESULTS: Findings suggest that Cambodians initially treat suspected malaria at home with home remedies and traditional medicines. When seeking treatment outside the home, respondents frequently reported receiving a cocktail of medicines from trusted providers. Cocktails are perceived as less expensive and more effective than full course, pre-packaged medicines. Barriers to diagnostic testing include a belief in the ability to self-diagnose based on symptoms, cost and reliance on providers to recommend a test. Factors that facilitate testing include recommendation by trusted providers and a belief that anti-malarial treatment for illnesses other than malaria can be harmful. CONCLUSIONS: Treatment-seeking behaviour for malaria in Cambodia is complex, driven by cultural norms, practicalities and episode related factors. Effective malaria treatment programmes will benefit from interventions and communication materials that leverage these demand-side factors, promoting prompt visits to facilities for suspected malaria and challenging patients' misconceptions about the effectiveness of cocktails. Given the importance of the patient-provider interaction and the pivotal role that providers play in ensuring the delivery of appropriate malaria care, future research and interventions should also focus on the supply side factors influencing provider behaviour. PMID- 23039262 TI - Heart or lung transplanted patients' retrospective views on information and support while waiting for transplantation. AB - AIMS AND OBJECTIVES: To describe the patients' retrospective experiences of the information and support they received while on the heart or lung transplant waiting list. BACKGROUND: Patients differ in the way that they cope with the time spent waiting for a heart or lung transplant. Patients must already before the transplantation be taught about a new lifestyle, risk factors, medication, food restrictions and exercise, so they can take an active role and responsibility for disease management after transplantation. Little is known about patients' experiences of information and support in these situations. DESIGN: Qualitative descriptive design. METHODS: Sixteen patients (16-67 year) were strategically selected from one transplant centre in Sweden and interviewed six months after heart or lung transplantation. Using content analysis, transcribed data were organised into subcategories that reflected emerging categories. RESULTS: Three categories that describe patients' experiences of information and support have been identified: 'Achieving confidence and trust by information and support', 'Experiencing a lack of input and understanding' and 'Struggling with a life threatening illness and an insecure future'. Each category consists of different subcategories. CONCLUSIONS: Information and support in connection to heart or lung transplantation are a complex and multifaceted issue involving patient related, family-related, disease-related and treatment-related factors as well as experiences related to the social situation, the healthcare system and society. Transplant patients are very vulnerable, and a deeper understanding of patients' experiences should help healthcare providers in optimising the care for these very sick patients. RELEVANCE TO CLINICAL PRACTICE: A holistic approach to the patient is necessary in meeting the needs of patients with chronic illness, especially patients with children at home, as well as the needs of their families. An important implication is the necessity to enhance awareness about transplant patients in society in general, in particular in other institutions, by sharing knowledge and by improving cooperation. PMID- 23039263 TI - High affinity crown ether complexes in water: thermodynamic analysis, evidence of crystallography and binding of NAD+. AB - Improving traditional crown ether to the water-soluble and high binding ability host molecule is critical to our efforts to model or mimic biological supramolecular systems. In this paper, we converted two traditional crown ethers, 1,5-dinaphtho-32-crown-8 and 1,5-dinaphtho-38-crown-10, into the water-soluble tetrasulfonated 1,5-dinaphtho-32-crown-8 and tetrasulfonated 1,5-dinaphtho-38 crown-10, evaluated their complexation with three dicationic bipyridiniums in aqueous solution by microcalorimetric titration, UV-vis, and NMR experiments, and then determined the crystal structures of three tetrasulfonatocrown ether bipyridinium complexes. The equilibrium association constants of tetrasulfonated 1,5-dinaphtho-32-crown-8 with these bipyridiniums reach up to 10(7) M(-1), while those of tetrasulfonated 1,5-dinaphtho-38-crown-10 are just in the range of 10(5) M(-1) order of magnitude. The thermodynamic data obtained show that the complexation of two tetrasulfonatocrown ethers with dicationic bipyridiniums is absolutely enthalpy-driven in water with an accompanying little entropic gain, and each monocationic pyridinium moiety in guest molecules can provide about -10 to -15 kJ.mol(-1) enthalpy contribution irrespective of the size of ether crowns. Moreover, we also investigated the recognition capability of the two water soluble crown ethers with NAD(+) and NADH by microcalorimetric titration and NMR experiments, indicating that tetrasulfonated 1,5-dinaphtho-32-crown-8 shows exclusive selectivity to NAD(+). The water-solubility and high affinity of this system as well as the flexible and non-preorganized characteristic of these crown ethers make it suitable to serve as a model for mimicking biological systems. PMID- 23039264 TI - Pleural effusions on the intensive care unit; hidden morbidity with therapeutic potential. AB - Despite 50-60% of intensive care patients demonstrating evidence of pleural effusions, there has been little emphasis placed on the role of effusions in the aetiology of weaning failure. Critical illness and mechanical ventilation lead to multiple perturbations of the normal physiological processes regulating pleural fluid homeostasis, and consequently, failure of normal pleural function occurs. Effusions can lead to deleterious effects on respiratory mechanics and gas exchange, and when extensive, may lead to haemodynamic compromise. The widespread availability of bedside ultrasound has not only facilitated earlier detection of pleural effusions but also safer fluid sampling and drainage. In the majority of patients, pleural drainage leads to improvements in lung function, with data from spontaneously breathing individuals demonstrating a consistent symptomatic improvement, while a meta-analysis in critically ill patients shows an improvement in oxygenation. The effects on respiratory mechanics are less clear, possibly reflecting heterogeneity of underlying pathology. Limited data on clinical outcome from pleural fluid drainage exist; however, it appears to be a safe procedure with a low risk of major complications. The current level of evidence would support a clinical trial to determine whether the systematic detection and drainage of pleural effusions improve clinical outcomes. PMID- 23039265 TI - Long-term sustained autoimmune response to beta cell specific zinc transporter (ZnT8, W, R, Q) in young adult patients with preserved beta cell function at diagnosis of diabetes. AB - The aim of this study was to examine whether autoantibodies to: ZnT8-Tryptophan (ZnT8WA), ZnT8-Arginine (ZnT8RA) or ZnT8-Glutamine (ZnT8QA) correlated with C peptide or other autoantibodies and to assess diagnostic sensitivity of ZnT8WRQA. Specimens from 270 newly diagnosed diabetic subjects (age 15-34 years) and after 5 years duration of disease were examined. Four linear regression models were used to dissect the importance of different factors from diagnosis for the respective difference of (logZnT8WA), (logZnT8RA) and (logZnT8QA); A) unadjusted model for: initial C-peptide, age, BMI, gender, clinical classification, ICA, GADA, IA-2A, (ZnT8WA/ZnT8RA/ZnT8QA); B) C-peptide corrected for clinical factors; C) C-peptide corrected for autoantibodies; D) C-peptide corrected for all factors. The least decrease of ZnT8WA was observed in patients with high initial C-peptide in all models A) p = 0.054; B) p = 0.021; C) p = 0.047 and D) p = 0.017. A less statistically significant decrease of ZnT8RA was observed in patients with high initial C-peptide in A) p = 0.038 and C) p = 0.047, but this finding was not confirmed in B or D. The decrease of ZnT8QA levels was not related to C-peptide in any model but correlated to age D) p = 0.049. Furthermore, patients with unclassifiable diabetes showed the least decrease in D) p = 0.035. ZnT8WA, ZnT8RA or ZnT8QA were identified as a single autoantibody in 3.8% (10/266) of patients, thereby increasing diagnostic sensitivity from 79.3% (211/266) to 83.1% (221/266). In conclusion, high initial C-peptide was the most important factor even after adjusting for other factors in patients positive for ZnT8WA or ZnT8RA to remain autoantibody positive 5 years after diagnosis. PMID- 23039266 TI - A dimerization defect caused by a glycine substitution at position 420 by serine in tissue-nonspecific alkaline phosphatase associated with perinatal hypophosphatasia. AB - Mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene cause hypophosphatasia (HPP), an inborn error of metabolism characterized by defects in bone and teeth mineralization accompanying subnormal levels of serum alkaline phosphatase activity. Missense mutations at position 420 of TNSALP (standard nomenclature), which convert glycine to serine [TNSALP (G420S)] or alanine [TNSALP (G420A)], have been reported in perinatal and childhood HPP, respectively. When expressed in COS-1 cells, both TNSALP mutants were indistinguishable from wild-type TNSALP [TNSALP (W)] as evidenced by immunofluorescence and western blotting. Nevertheless, the two TNSALP mutants did not show substantial alkaline phosphatase activity. In agreement with transiently transfected cells, TNSALP (G420S) expressed in a Tet-On inducible expression system lacked its alkaline phosphatase activity, although this mutant was anchored to the cell surface lipid bilayers by glycosylphosphatidylinositol as an 80 kDa mature form bearing complex-type oligosaccharides like TNSALP (W). Importantly, TNSALP (G420S) was found to largely fail to assemble into the homodimer in contrast to TNSALP (W). Taken together, these results demonstrate that the glycine residue at position 420 is crucial for the subunit interaction of TNSALP and hence its catalytic function without affecting trafficking of monomeric TNSALP. We conclude that the dimerization defect is the molecular basis for perinatal HPP associated with the genotype G420S/G420S. PMID- 23039268 TI - Evaluation of the absorption of methotrexate on cells and its cytotoxicity assay by using an integrated microfluidic device coupled to a mass spectrometer. AB - An integrated microfluidic device was developed for high-throughput drug screening with an online electrospray ionization quadrupole time-of-flight mass spectrometer (ESI-Q-TOF MS). The multiple gradient generator followed by an array of microscale cell culture chambers and on-chip solid-phase extraction (SPE) columns for sample pretreatment prior to mass analysis was integrated in the device which was fabricated in one single step. By using the combination system, the process for characterization of drug absorption and evaluation of cytotoxicity could be simultaneously realized. To validate the feasibility, the absorption of methotrexate and its effects on HepG2 and Caco-2 cells were investigated. With the increasing concentration of drugs, the percentage of apoptotic cells appeared in a dose-dependent fashion. By comparison with the results obtained from ESI-Q-TOF MS analysis and cytotoxicity assay, we found that higher intracellular drug concentration resulted in increased cell cytotoxicity. The technique presented herein provides an easy protocol to screen drugs rapidly with low drug consumption, high throughput, and high sensitivity. PMID- 23039271 TI - Crystal-to-crystal photoinduced reaction of dinitroanthracene to anthraquinone. AB - The photochemical reaction of 9,10-dinitroanthracene (DNO(2)A) to anthraquinone (AQ) + 2NO has been studied by means of lattice phonon Raman spectroscopy in the spectral region 10-150 cm(-1). In fact, crystal-to-crystal transformations are best revealed by following changes in the lattice modes, as even small modifications in the crystal structure lead to dramatic changes in symmetry and selection rules of vibrational modes. While analysis of the lattice modes allowed for the study of the physical changes, the chemical transformation was monitored by measuring the intramolecular Raman-active modes of both reactant and product. On the basis of the experimental data it has been possible, at a microscopic level, to infer crucial information on the reaction mechanism by simultaneously detecting molecular (vibrational modes) and crystal structure (lattice phonons) modifications during the reaction. At a macroscopic level we have detected an intriguing relationship between incident photons and mechanical strain, which manifests itself as a striking bending and unfolding of the specimens under irradiation. To clarify the mechanisms underlying the relationship between incoming light and molecular environment, we have extended the study to high pressure up to 2 GPa. It has been found that above 1 GPa the photoreaction becomes inhibited. The solid-state transformation has also been theoretically modeled, thus identifying the reaction pathway along which the DNO(2)A crystal lattice deforms to finally become the crystal lattice of the AQ product. PMID- 23039269 TI - Prevalence of human immunodeficiency virus infection among transgender men in Rawalpindi (Pakistan). AB - BACKGROUND: Transgender males are at high risk for sexually transmitted diseases including AIDS caused by the notorious Human Immunodeficiency Virus (HIV), yet little consideration is given by the policy makers, researchers and non governmental organizations (NGOs) towards this sensitive issue in Pakistan. METHODS: In this study, we have investigated the prevalence of HIV infection among 306 transgender males with a median age of 29 years (range 15-64 years) residing in Rawalpindi, Pakistan. Rapid HIV antibody-screening methods including the strip test and Enzyme Linked Immuno-absorbent tests were employed to detect HIV antibodies among the subjects. For further confirmation, Polymerase Chain Reaction (PCR) was carried out. Statistical analytical techniques utilized included logistic regression and chi-square. RESULTS: HIV-1 was found to be the predominant viral subtype. PCR confirmed 21.6% (Confidence Interval 0.17-0.26) of the respondents were reported being HIV positive. 15.7% of the transgender men who shave at home and 13.7% of the transgender men who were educated below 5th grade were found to have HIV. CONCLUSION: This study shows a very high prevalence of HIV among transgender males. Unawareness among these individuals about the ramifications of this infection owes largely to lack of education. The spread rate is alarming and HIV epidemic is imminent if awareness is not widespread. PMID- 23039272 TI - Structural evolution of electrospun composite fibers from the blend of polyvinyl alcohol and polymer nanoparticles. AB - Electrospinning provides a versatile method for generating fibrous materials from a large variety of substances, including polymers, composites, proteins, and nano/microcolloids. In particular, the incorporation of nano/microparticles with polymeric materials is beneficial to many of electrospun fibers with multiple functionalities. This report evaluates the spinnability of a polymer solution containing polymer nanoparticles obtained through electrospinning. Tunable structures of electrospun composite fibers were obtained from a blended solution of polyvinyl alcohol (PVA) and polystyrene nanospheres (PSNs). The in-fiber arrangements of polymer nanoparticle fibers, influenced by the PVA:PSN weight ratio, and the viscosity of the blended solution and the size of PSNs were systemically studied. Once PVA was determined to dominate the solution, the diameter of the electrospun PVA fibers was comparable to the diameters of the colloidal particles, which confined the nanospheres into string-on-bead and necklace-like structures. When PSNs occupied a large portion of the solution, PVA wrapped the PSNs, forming a blackberry-like aggregate and a uniform colloidal fiber. The results from the colloid electrospinning serve as references in the creation of novel composite fibers involving various polymer nanoparticles via electrospinning. The obtained composite fibers of the polymers and colloids are expected to have potential application in various areas. PMID- 23039270 TI - Tools to detect delirium superimposed on dementia: a systematic review. AB - OBJECTIVES: To identify valid tools to diagnose delirium superimposed on dementia. DESIGN: Systematic review of studies of delirium tools that explicitly included individuals with dementia. SETTING: Hospital. PARTICIPANTS: Studies were included if delirium assessment tools were validated against standard criteria, and the presence of dementia was assessed according to standard criteria that used validated instruments. MEASUREMENTS: PubMed, Embase, and Web of Science databases were searched for articles in English published between January 1960 and January 2012. RESULTS: Nine studies fulfilled the selection criteria. Of 1,569 participants, 401 had dementia, and 50 had delirium superimposed on dementia. Six delirium tools were evaluated. One study using the Confusion Assessment Method (CAM) with 85% of participants with dementia had high specificity (96-100%) and moderate sensitivity (77%). Two intensive care unit studies that used the CAM for the Intensive Care Unit (CAM-ICU) reported 100% sensitivity and specificity for delirium in 23 individuals with dementia. One study using electroencephalography reported sensitivity of 67% and specificity of 91% in a population with a 100% prevalence of dementia. No studies examined potential effects of dementia severity or subtype on diagnostic accuracy. CONCLUSIONS: The evidence base on tools for detection of delirium superimposed on dementia is limited, although some existing tools show promise. Further studies of existing or refined tools with larger samples and more-detailed characterization of dementia are required to address the identification of delirium superimposed on dementia. PMID- 23039273 TI - Climate change exacerbates interspecific interactions in sympatric coastal fishes. AB - Biological responses to warming are presently based on the assumption that species will remain within their bioclimatic envelope as environmental conditions change. As a result, changes in the relative abundance of several marine species have been documented over the last decades. This suggests that warming may drive novel interspecific interactions to occur (i.e. invasive vs. native species) or may intensify the strength of pre-existing ones (i.e. warm vs. cold adapted). For mobile species, habitat relocation is a viable solution to track tolerable conditions and reduce competitive costs, resulting in 'winner' species dominating the best quality habitat at the expense of 'loser' species. Here, we focus on the importance of warming in exacerbating interspecific interactions between two sympatric fishes. We assessed the relocation response of the cool-water fish Coris julis (a potential 'loser' species in warming scenarios) at increasing relative dominance of the warm-water fish Thalassoma pavo (a 'winner' species). These wrasses are widespread in the Mediterranean nearshore waters. C. julis tolerates cooler waters and is found throughout the basin. T. pavo is common along southern coasts, although the species range is expanding northwards as the Mediterranean warms. We surveyed habitat patterns along a thermo-latitudinal gradient in the Western Mediterranean Sea and manipulated seawater temperature under two scenarios (present day vs. projected) in outdoor arenas. Our results show that the cool-water species relocates to a less-preferred seagrass habitat and undergoes lower behavioural performance in warmer environments, provided the relative dominance of its warm-water antagonist is high. The results suggest that expected warming will act synergistically with increased relative dominance of a warm-water species to cause a cool-water fish to relocate in a less-preferred habitat within the same thermal environment. Our study highlights the complexity of climate change effects and has broad implications for predictive models of responses to warming. To achieve more accurate predictions, further consideration is needed of the pervasive importance of species interactions. We believe these fundamental issues to be addressed to understand the biotic consequences of climate change. PMID- 23039267 TI - Future pharmacological treatments for substance use disorders. AB - Substance use disorders represent a serious public health and social issue worldwide. Recent advances in our understanding of the neurobiological basis of the addictive processes have led to the development of a growing number of pharmacological agents to treat addictions. Despite this progress, there are no approved pharmacological treatments for cocaine, methamphetamine and cannabis addiction. Moving treatment development to the next stage will require novel ways of approaching substance use disorders. One such novel approach is to target individual vulnerabilities, such as cognitive function, sex differences and psychiatric comorbidities. This review provides a summary of promising pharmacotherapies for alcohol, opiate, stimulant and nicotine addictions. Many medications that target positive and negative reinforcement of drugs, as well as individual vulnerabilities to addiction, are in different phases of development. Clinical trials testing the efficacy of these medications for substance use disorder are warranted. PMID- 23039274 TI - XMetA, an allosteric monoclonal antibody to the insulin receptor, improves glycaemic control in mice with diet-induced obesity. AB - XMetA, a high-affinity, fully human monoclonal antibody, allosterically binds to and activates the insulin receptor (INSR). Previously, we found that XMetA normalized fasting glucose and glucose tolerance in insulinopenic mice. To determine whether XMetA is also beneficial for reducing hyperglycaemia due to the insulin resistance of obesity, we have now evaluated XMetA in hyperinsulinemic mice with diet-induced obesity. XMetA treatment of these mice normalized fasting glucose for 4 weeks without contributing to weight gain. XMetA also corrected glucose tolerance and improved non-high density lipoprotein cholesterol. These studies indicate, therefore, that monoclonal antibodies that allosterically activate the INSR, such as XMetA, have the potential to be novel agents for the treatment of hyperglycaemia in conditions associated with the insulin resistance of obesity. PMID- 23039275 TI - Haemoglobinuria among children with severe malaria attending tertiary care in Ibadan, Nigeria. AB - BACKGROUND: Haemoglobinuria is one of the manifestations of severe malaria and results from severe intravascular haemolysis. Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been implicated in its aetiology. Haemoglobinuria may be associated with severe anaemia and, less frequently, acute renal failure. METHODS: A prospective case-control study was carried out to determine the incidence of haemoglobinuria as confirmed by dipstick urinalysis, microscopy and spectrophotometric measurement, among children with severe malaria. A total of 251 children presenting at the Children's Emergency Ward with severe malaria were recruited over a period of 21 months. The G6PD status and the outcomes of severe malaria in children with and without haemoglobinuria was studied with respect to renal failure, the recurrence of haemoglobinuria and blood pressure changes over a three-month follow-up period. RESULTS: It was found that the incidence of haemoglobinuria among children with severe malaria is 19.1%. Children <5 years constituted 76.8% of all the study patients. Patients with haemoglobinuria had median age of 52.5 months, which was significantly higher than 35 months in patients without haemoglobinuria (p=0.001). Although, haemaglobinuria was commoner among boys (54.2%) than girls (45.8%), the difference was not statistically significant. There were no significant differences between children with and without haemoglobinuria regarding their nutritional status or parasite densities. Among the clinical features of the study patients, only jaundice was significantly associated with haemoglobinuria (p=0.0001). Renal failure occurred in three out of 48 children with haemoglobinuria and in none of the 203 without. There was not recurrence of haemoglobinuria in the follow-up period. At discharge, blood pressure was elevated in six children (one previously haemoglobinuric), but all returned to normal within the follow-up period. CONCLUSIONS: Haemoglobinuria was a prominent feature of severe malaria and it was significantly associated with jaundice at presentation. Haemoglobinuria was commoner in older children than younger children but not related to sex. G6PD deficiency was not an independent predictor of the occurrence or outcome of haemoglobinuria. Blood pressure was not affected by haemoglobinuria on admission nor during follow-up. PMID- 23039277 TI - Finally, a UK consensus on the use of HbA1c to diagnose diabetes. PMID- 23039276 TI - Dorsal vein complex preserving technique for intrafascial nerve-sparing laparoscopic radical prostatectomy. AB - OBJECTIVES: To describe a novel dorsal vein complex preserving technique for intrafascial nerve-sparing laparoscopic radical prostatectomy and to evaluate its postoperative outcomes. METHODS: A total of 109 patients who underwent laparoscopic radical prostatectomy by a single surgeon were evaluated, including 44 patients with dorsal vein complex preserving technique for intrafascial nerve sparing laparoscopic radical prostatectomy, 20 patients with conventional intrafascial nerve-sparing laparoscopic radical prostatectomy and 45 patients with non-nerve-sparing laparoscopic radical prostatectomy. Functional outcomes were evaluated using a self-administered questionnaire (Expanded Prostate Cancer Index Composite). Continence was defined as zero to one security pad per day. Oncological outcomes were evaluated based on positive surgical margin. RESULTS: In the dorsal vein complex preserving technique for intrafascial nerve-sparing laparoscopic radical prostatectomy group, the continence rate was 57%, 77% and 95% at 1, 3 and 12 months, respectively. The continence rate in the conventional intrafascial nerve-sparing laparoscopic radical prostatectomy group was 37%, 63% and 90%, and in the non-nerve-sparing laparoscopic radical prostatectomy group it was 23%, 57% and 82% at 1, 3, and 12 months, respectively. The dorsal vein complex preserving technique for intrafascial nerve-sparing laparoscopic radical prostatectomy group showed a significantly earlier recovery from incontinence compared with that in the conventional intrafascial nerve-sparing laparoscopic radical prostatectomy and non-nerve-sparing laparoscopic radical prostatectomy groups (log-rank test, P = 0.044 and P < 0.001). Similarly, the dorsal vein complex preserving technique for intrafascial nerve-sparing laparoscopic radical prostatectomy group tended to show a more early recovery in relation to urinary function of the Expanded Prostate Cancer Index Composite. Regarding sexual function, there were no significant differences between the dorsal vein complex preserving technique for intrafascial nerve-sparing laparoscopic radical prostatectomy and conventional intrafascial nerve-sparing laparoscopic radical prostatectomy groups. In pT2 patients, the positive surgical margin rate of the dorsal vein complex preserving technique for intrafascial nerve-sparing laparoscopic radical prostatectomy group (11%) was similar to that of the other two groups (conventional intrafascial nerve-sparing laparoscopic radical prostatectomy 7%; non-nerve-sparing laparoscopic radical prostatectomy 11%). CONCLUSIONS: The dorsal vein complex preserving technique for intrafascial nerve sparing laparoscopic radical prostatectomy technique provides early recovery from incontinence without adversely affecting the oncological outcome. PMID- 23039279 TI - Non-immune hydrops: Qatar experience. AB - OBJECTIVE: To describe the presenting signs, diagnostic findings, and outcomes of 64 cases of non-immune hydrops fetalis (NIHF) cases seen in Women's Hospital, Qatar during the years 2003-2011. METHOD: A retrospective chart review of patients with signs suggesting of NIHF was done. A detailed scan was performed and karyotyping and detailed investigations were offered. RESULTS: Average maternal age at diagnosis was 31 years. Fifty-six percent of the patients were diagnosed during the 2nd trimester. Most common presenting signs were: ascites, pleural effusion, scalp edema, skin edema, pericardial effusion, generalize edema and cystic hygroma. Two patients were positive for PV B19 infection. Fetal karyotyping performed in 78% of the patients showed abnormal chromosomes in 9 cases. Three patients showed fetal anemia with abnormal peak systolic velocity of the medial cerebral artery (MCA-PSV). Seventeen (27%) fetuses survived the perinatal period with live births occurring between gestational ages 30-41 weeks. Ten (59%) of the 17 babies survived post delivery (6 months post survival data). Major identifiable abnormalities that might have caused symptoms of hydrops were cardiac (23.43%), and chromosomal (14%). CONCLUSION: Non-immune hydrops fetalis is a complex problem. Establishment of a clear procedure for the follow up of such patients is extremely important. PMID- 23039280 TI - Decentral gene expression analysis: analytical validation of the Endopredict genomic multianalyte breast cancer prognosis test. AB - BACKGROUND: EndoPredict (EP) is a clinically validated multianalyte gene expression test to predict distant metastasis in ER-positive, HER2-negative breast cancer treated with endocrine therapy alone. The test is based on the combined analysis of 12 genes in formalin-fixed, paraffin-embedded (FFPE) tissue by reverse transcription-quantitative real-time PCR (RT-qPCR). Recently, it was shown that EP is feasible for reliable decentralized assessment of gene expression. The aim of this study was the analytical validation of the performance characteristics of the assay and its verification in a molecular pathological routine laboratory. METHODS: Gene expression values to calculate the EP score were assayed by one-step RT-qPCR using RNA from FFPE tumor tissue. Limit of blank, limit of detection, linear range, and PCR efficiency were assessed for each of the 12 PCR assays using serial samples dilutions. Different breast cancer samples were used to evaluate RNA input range, precision and inter-laboratory variability. RESULTS: PCR assays were linear up to Cq values between 35.1 and 37.2. Amplification efficiencies ranged from 75% to 101%. The RNA input range without considerable change of the EP score was between 0.16 and 18.5 ng/MUl. Analysis of precision (variation of day, day time, instrument, operator, reagent lots) resulted in a total noise (standard deviation) of 0.16 EP score units on a scale from 0 to 15. The major part of the total noise (SD 0.14) was caused by the replicate-to-replicate noise of the PCR assays (repeatability) and was not associated with different operating conditions (reproducibility). Performance characteristics established in the manufacturer's laboratory were verified in a routine molecular pathology laboratory. Comparison of 10 tumor samples analyzed in two different laboratories showed a Pearson coefficient of 0.995 and a mean deviation of 0.15 score units. CONCLUSIONS: The EP test showed reproducible performance characteristics with good precision and negligible laboratory-to laboratory variation. This study provides further evidence that the EP test is suitable for decentralized testing in specialized molecular pathological laboratories instead of a reference laboratory. This is a unique feature and a technical advance in comparison with existing RNA-based prognostic multigene expression tests. PMID- 23039281 TI - Pharmacy compounding primer for physicians: prescriber beware. AB - Since the development of federal standards for drug approval, the practice of medicine has historically involved the compounding of medications based on a physician's determination that a US FDA-approved product either did not exist, or could not be used for medical reasons. Today, prescriptions for non-FDA-approved compounded drugs may be driven by fanciful and largely unregulated pharmacy advertisements to physicians and patients and/or payer reimbursement policies, thus placing prescribers in the backseat for clinical decision making. This article outlines essential differences between FDA-approved drugs and compounded drugs and reasserts the primary medical role of physicians for determining what medical circumstances may necessitate treatment with non-FDA-approved products. In addition, liability concerns when prescribing non-FDA-approved drugs are discussed. While representing a US perspective, underlying principles apply globally in the setting of magistral and extemporaneous formulations produced outside national regulatory frameworks. PMID- 23039282 TI - Iridium-catalyzed asymmetric ring-opening of oxabenzonorbornadienes with phenols. AB - A novel iridium-catalyzed asymmetric ring-opening (ARO) reaction of oxabenzonorbornadienes with a variety of phenols was reported, which afforded the corresponding trans-2-phenoxy-1,2-dihydronaphthalen-1-ol products in high yields with moderate to excellent enantioselectivities (up to 98% ee) under mild conditions. The trans products are formed via the enantioselective cleavage of a bridgehead carbon-oxygen bond in 1 followed by S(N)2 nucleophilic attack by phenols. The effects of various bisphosphine ligands, Ag (I) salts, ammonium halides, bases, and solvents on the yield and enantioselectivity of the reaction were also investigated. The trans-configuration of the product 2a was confirmed by X-ray crystal structure analysis. A possible mechanism for the present catalytic reaction was proposed. PMID- 23039283 TI - GJB2 (Connexin 26) gene mutations among hearing-impaired persons in a Swedish cohort. AB - CONCLUSION: The most common mutation in the Swedish population was Connexin 26 (C*26) 35delG, which indicates that the percentage of Swedish persons with C*26 mutations and polymorphisms in the GJB2 gene among non-syndromic hearing-impaired (HI) persons is comparable to the rest of Europe. The results strongly support a Swedish policy to offer all children with diagnosed hearing impairment genetic tests for the C*26 35delG mutation. OBJECTIVES: The aim of the present study was to search for mutations in the GBJ2 gene among Swedish persons with non-syndromic hearing impairment to further clarify how common these mutations are in Sweden, one of the northernmost countries in Europe. METHODS: Seventy-nine patients with non-syndromic hearing impairment participated in the study. For 87% of the participants, a pure tone audiogram showed a severe or profound hearing impairment. Dried blood spots on filter paper, taken at 3-5 days of age in the Swedish nationwide neonatal screening programme for congenital disorders and saved in a biobank, were used for the molecular genetic analyses. RESULTS: The total number of subjects with one or two pathologic mutations or a mutation of unknown consequence found in the GJB2 gene was 28 of 79 (35%). Nineteen (19) persons (24%) were homozygotes for the 35delG mutation. PMID- 23039284 TI - Selective pharmacological inhibition of phosphoinositide 3-kinase p110delta opposes the progression of autoimmune diabetes in non-obese diabetic (NOD) mice. AB - During the progression of autoimmune (type 1) diabetes, T cells and macrophages infiltrate the pancreas, disrupt islet function, and destroy insulin-producing beta cells. B-lymphocytes, particularly innate like B-cell populations such as marginal zone B cells and B-1 cells, have been implicated in many autoimmune diseases, and non-obese diabetic (NOD) mice that lack B cells do not develop spontaneous autoimmune diabetes. Hence, inhibitors of B cell signaling pathways could be useful for limiting the autoimmune processes that contribute to type 1 diabetes. Signaling via phosphoinositide 3-kinase (PI3K) regulates many cellular processes. The p110delta isoform of PI3K is expressed primarily in cells of hematopoietic origin and the catalytic activity of p110delta is important for B cell migration, activation, proliferation, and antigen presentation. Because innate-like B cells are particularly sensitive to inhibition of p110delta activity, and p110delta inhibitors also suppress pro-inflammatory functions of other cell types that contribute to autoimmunity, we tested whether a p110delta inhibitor could delay the onset or reduce the incidence of autoimmune diabetes in NOD mice. We found that long-term preventative treatment of pre-diabetic NOD mice with IC87114, a highly selective small molecule inhibitor of p110delta, reduced the infiltration of inflammatory cells into the pancreatic islets and, accordingly, delayed and reduced the loss of glucose homeostasis. Moreover in a therapeutic treatment mode, IC87114 treatment conferred prolonged protection from progression to overt diabetes in a number of animals. These findings suggest that PI3Kdelta inhibitors could be useful for managing type 1 diabetes. PMID- 23039285 TI - Prevalence and risk factors for VRE colonisation in a tertiary hospital in Melbourne, Australia: a cross sectional study. AB - BACKGROUND: Vancomycin-resistant Enterococcus (VRE) has been established as a significant health-care associated problem since its first isolation in Australia in 1994. In this study, we measured the point prevalence and identified risk factors associated with vanB VRE colonisation in a tertiary care hospital in Melbourne, Australia where VRE has been endemic for 15 years. METHODS: A hospital wide point prevalence survey was conducted on October 13, 2008 with colonisation detected using rectal swab culture. Patient's demographic and medical information was collected through a review of medical records. Factors associated with VRE colonisation in univariate analysis were included in multivariate logistic regression model to adjust for confounding. RESULTS: The prevalence of VRE colonisation on the day of screening was 17.5% (95% CI, 13.7 to 21.9). VRE was detected from patients in each ward with the prevalence ranging from 3% to 29%. Univariate analysis showed the use of any antibiotic, meropenem, ciprofloxacin, diarrhoea and longer length of hospital stay were associated with increased risk of VRE colonisation (p<0.05). However, age, sex, proximity to VRE positive cases, use of other antibiotics including cephalosporins, vancomycin were not associated with increased risk (P>0.05). Multivariate analysis showed the exposure to meropenem (p=0.004), age (>=65 years) (p=0.036) and length of stay >=7 days (p<0.001) as independent predictors of VRE colonisation. CONCLUSION: Our study suggests that exposure to antibiotics may have been more important than recent cross transmission for a high prevalence of vanB VRE colonisation at our hospital. PMID- 23039286 TI - How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST-3). PMID- 23039287 TI - Believing is seeing: stroke thrombolysis remains unproven after the third International Stroke Trial (IST-3). PMID- 23039288 TI - Ultrasound features of interstitial ectopic pregnancy: The role of the non-expert emergency medicine sonologist. PMID- 23039289 TI - A primer for clinical researchers in the emergency department: Part IV: Multicentre research. AB - In this series we address key topics for clinicians who conduct research as part of their work in the ED. Multicentre research is conducted to enrol larger numbers of participants and improve the validity and generalisability of the findings. Little has been published outlining the practical mechanics of multicentre research in the ED. This article presents strategies for setting up, conducting and participating in multicentre studies in the Australian and international settings. We address the two major categories of multicentre research, collaborative group research based on a group of researchers from a moderate-sized number of EDs and large-scale investigator-led research where a central group of investigators leads a large pool of research sites. Although we focus on clinical trials, the basic principles also apply to multicentre observational studies. PMID- 23039290 TI - Perspectives of emergency department staff on the triage of mental health-related presentations: Implications for education, policy and practice. AB - OBJECTIVE: To explore ED staff perceptions of the factors that influence accuracy of triage for people with mental health problems. METHODS: This qualitative learning needs analysis used a descriptive exploratory design. Participants were Australian emergency nurses and doctors. We used a criterion-based sampling approach. Recruitment was facilitated by the College of Emergency Nursing Australasia and the Australasian College for Emergency Medicine. A semi structured interview schedule was developed. Telephone interviews were conducted, audio recorded and transcribed verbatim. Thematic analysis was used to identify factors perceived to affect triage outcomes and to explore strategies to optimise the accuracy of triage assessments. RESULTS: Thirty-six staff participated (16 nurses and 20 doctors). Four major factors were perceived to influence accuracy. These were: environmental factors (physical structure, time pressures, activity levels, and interruptions), policy and education (guidelines, training and resources), staff factors (knowledge, experience, attitudes) and patient factors (police presence, patient behaviour, clinical condition). Differences of opinion were expressed by emergency doctors about the validity of the time to treatment objectives included in the Australasian Triage Scale for mental health presentations, and the utility of the scale to differentiate urgency for psychiatric conditions. CONCLUSION: Clinical guidelines and training have been developed to support the use of the Australasian Triage Scale. Further evaluation of the application of this scale to assess mental health problems is indicated. Additional work is also required to reduce variance in urgency assignment based on staff knowledge and attitudes about the causes, assessment and early management of psychiatric disorders. PMID- 23039291 TI - Australian emergency clinicians' perceptions and use of the GIVE Clinical Trigger for identification of potential organ and tissue donors. AB - OBJECTIVES: In 2010 the Australian Organ and Tissue Authority introduced a nationally consistent indicator, the GIVE Clinical Trigger, for early identification of potential organ and tissue donors in EDs and intensive care units. This national survey of emergency clinicians aimed to assess emergency clinicians' perceptions and use of the Trigger. METHODS: National cross-sectional survey of Australasian College for Emergency Medicine (ACEM) fellows and trainees and members of the College of Emergency Nursing Australia (CENA); online questionnaire; 12 items addressing implementation of the GIVE Trigger; graded and free-text responses. RESULTS: Five hundred and ninety-nine (20.2%) of 2969 ACEM members and 212 (20.7%) of 1026 CENA members responded. Four hundred and seventy four respondents (62.7%) were familiar with the Trigger; 472 (63.8%) agreed it was easy to recognise patients who activated the Trigger; 490 (64.9%) had sufficient time to use the Trigger; 511 (67.7%) felt they had the necessary competence and knowledge to identify a potential donor; 464 (61.5%) felt competent and 501 (66.4%) felt comfortable referring a potential donor when identified. Overall 587 (77.7%) ED clinicians supported the use of the Trigger, but most (587 [77.7%]) perceived barriers to its use; 628 (80%) had never activated the Trigger and 557 (71%) had never referred a potential donor to relevant authorities. CONCLUSION: Most Australian emergency clinicians are familiar with and support the GIVE Clinical Trigger, and feel they have the necessary skills to use the Trigger; however, most perceive barriers to its use and have not yet used the Trigger. PMID- 23039292 TI - Unravelling relationships: Hospital occupancy levels, discharge timing and emergency department access block. AB - OBJECTIVES: To investigate the effect of hospital occupancy levels on inpatient and ED patient flow parameters, and to simulate the impact of shifting discharge timing on occupancy levels. METHODS: Retrospective analysis of hospital inpatient data and ED data from 23 reporting public hospitals in Queensland, Australia, across 30 months. Relationships between outcome measures were explored through the aggregation of the historic data into 21 912 hourly intervals. Main outcome measures included admission and discharge rates, occupancy levels, length of stay for admitted and emergency patients, and the occurrence of access block. The impact of shifting discharge timing on occupancy levels was quantified using observed and simulated data. RESULTS: The study identified three stages of system performance decline, or choke points, as hospital occupancy increased. These choke points were found to be dependent on hospital size, and reflect a system change from 'business-as-usual' to 'crisis'. Effecting early discharge of patients was also found to significantly (P < 0.001) impact overcrowding levels and improve patient flow. CONCLUSIONS: Modern hospital systems have the ability to operate efficiently above an often-prescribed 85% occupancy level, with optimal levels varying across hospitals of different size. Operating over these optimal levels leads to performance deterioration defined around occupancy choke points. Understanding these choke points and designing strategies around alleviating these flow bottlenecks would improve capacity management, reduce access block and improve patient outcomes. Effecting early discharge also helps alleviate overcrowding and related stress on the system. PMID- 23039293 TI - Improving stress testing compliance following chest pain presentations to the emergency department. AB - OBJECTIVES: To determine whether a booked appointment time improves early outpatient exercise stress testing (EST) guideline adherence in patients discharged from the ED following assessment for possible acute coronary syndrome (ACS). METHODS: In this pre and post study with a historical control group, patients classified as intermediate risk after negative ECG and serial troponin work-up for possible ACS were referred for EST. The intervention group were given an appointment time for EST at discharge, and the control group were given a referral but asked to book their own appointment. The primary outcome measure was the proportion in each group who attended for EST. Secondary outcomes were time to EST and rates of death, myocardial infarction and coronary revascularisation within 30 days in both groups. In addition, we explored reasons for non attendance for EST for the intervention group. RESULTS: There were 96 participants in the intervention group (mean age 55 +/- 3 years) and 121 controls (mean age 62 +/- 3 years). Seventy-two (75%) of the intervention group attended for EST compared with 38 (31%) of the control group, P < 0.001 after adjustment for differences in baseline variables. A poor understanding of the rationale for EST was a significant factor in patient non-attendance. CONCLUSION: Pre-booked appointment times for EST improve timely attendance among patients discharged from the ED with intermediate-risk ACS. Compliance might improve further with patient education. PMID- 23039294 TI - Analysis and impact of delays in ambulance to emergency department handovers. AB - OBJECTIVES: Delays in the clinical handover of patient care from emergency medical services (EMS) to the ED because of ED crowding are a substantial problem for many EMS systems. This study was conducted to quantify handover delays experienced by the Ambulance Service of New South Wales (ASNSW), and to investigate patient and system factors associated with handover delay. METHODS: A retrospective study of EMS dispatch and ambulance patient care records was conducted for all patients transported by ASNSW in January/April/July/October 2009. Patient characteristics and time intervals were summarised using descriptive statistics, with handover delay categorised as <30 min, 30-60 min and >=60 min. Times are reported as HH:MM:SS. Partial proportional odds models were used to investigate factors associated with delays. RESULTS: Of 141 381 transports, 12.5% of patients experienced a handover delay of 30-60 min, and 5% a delay of >=60 min. The median handover interval was 00:15:46 (IQR 00:08:58 00:24:52, maximum 08:43:13). Patients transported to large hospitals were more likely to experience a delay of >=30 min (odds ratio [OR] 14.57, 95% CI 11.41 18.60) or >=60 min (OR 15.75, 95% CI 12.27-20.23) than those transported to small hospitals. Patients in major cities were more likely to experience delays than those in other areas, and patients >=65 years were more likely to experience delays than those <16 years. Delays were most likely in winter. Cardiac and major trauma patients had the lowest likelihood of experiencing delays. CONCLUSIONS: Handover delays are relatively common at the EMS/ED interface in New South Wales, and are most pronounced at large hospitals, in urban areas and during winter. PMID- 23039295 TI - Bedside sonographic measurement of the inferior vena cava caval index is a poor predictor of fluid responsiveness in emergency department patients. AB - OBJECTIVES: Sonographic measurement of the inferior vena cava (IVC) caval index predicts central venous pressure in ED patients. Fluid responsiveness (FR) is a measure of preload dependence defined as an increase in cardiac output secondary to volume expansion. We sought to determine if the caval index is an accurate measurement of FR in ED patients. METHODS: We conducted a prospective, observational trial at an urban, academic, adult ED with an annual census >105 000. Included patients were clinically suspected of eu- and hypovolemia. Excluded patients were <18 years old, pregnant, incarcerated, sustained significant trauma or unable to consent. Supine IVC diameter was measured by bedside ultrasonography (M-Turbo; Sonosite, Bothwell, WA, USA). Caval index = [(expiratory IVC diameter - inspiratory IVC diameter)/expiratory IVC diameter] * 100. FR was defined as an increase in the cardiac index by >10% by impedance cardiography (BioZ; Sonosite) following passive leg raise. The primary outcome was analysed using Spearman correlations for non-parametric data and the area under the receiver operating characteristics curve by Wilcoxon method. RESULTS: Thirty patients were enrolled; four were excluded because of incomplete data collection. Thirty-one per cent (95% CI 13-48) of the patients were FR. The mean initial caval and cardiac index were 15.8% (95% CI 9.5-22) and 2.9 L/min/m(2) (95% CI 2.6-3.2), respectively. Caval index did not predict FR (receiver operating curve = 0.46, 95% CI 0.21 0.71, P = 0.63). CONCLUSION: Bedside sonographic measurement of IVC caval index does not predict FR in a heterogeneous ED patient population. Further research using this technique in targeted patient subsets and a variety of shock etiologies is needed. PMID- 23039296 TI - Prevalence of suicidality in asymptomatic adolescents in the paediatric emergency department and utility of a screening tool. AB - OBJECTIVE: Many authorities recommend screening adolescents for risk of suicide. The ED is a potential setting for such screening. The aim of this study is to explore the use of the Risk of Suicide Questionnaire (RSQ) as a screening tool for suicidality in patients who come to the ED without mental health concerns and without recent mental health history. The Suicide Ideation Questionnaire (SIQ) was the comparison standard. METHODS: A cross-sectional convenience sample of overtly psychiatrically asymptomatic adolescents presenting to a large paediatric ED underwent both the RSQ and SIQ. Adolescents with positive screens underwent formal assessment by mental health practitioners. RESULTS: Two hundred and one patients were identified and 110 consented to participate. One hundred participants completed both questionnaires. Twenty-two per cent of participants had positive RSQ (95% CI 14-31%). No adolescent yielded a positive SIQ: prevalence of suicidality was 0.0% (95% CI 0.0-3.6%). No participant showed suicidal ideation on formal review. One question in the RSQ - 'Has something very stressful happened to you in the past few weeks?' - accounted for the majority of false positive screens. CONCLUSION: The prevalence of suicidal ideation in asymptomatic patients presenting to this paediatric ED is very low. Using this selection method, the RSQ could not be validated, but would be unlikely to be suitable for screening this low-risk population with a high false positive rate. PMID- 23039297 TI - Capacity building in emergency care: An example from Madang, Papua New Guinea. AB - BACKGROUND: Divine Word University (DWU) is an emerging national university of Papua New Guinea (PNG) based in the provincial capital of Madang, providing training for Health Extension Officers (HEOs). HEOs form the backbone of healthcare delivery in PNG as clinicians, public health officers and health centre managers. Both campus-based and clinical teaching at the nearby Modilon Hospital is limited because of significant resource constraints. OBJECTIVE: This article describes a visiting clinical lecturer programme in which Australasian emergency physicians and emergency registrars deliver teaching to HEO students at DWU and Modilon Hospital. METHODS: Volunteer doctors are briefed pre-departure and given prepared educational tools. Visits are from 2 weeks to 3 months, and include the possibility of accredited training for emergency registrars through the Australasian College for Emergency Medicine. DWU provides secure accommodation and assistance with travel and visa logistics. Tasks for visiting lecturers include delivering campus-based teaching on emergency medicine (EM) topics, structured and opportunistic bedside tutorials, and clinical teaching and assistance with ED care alongside local EM clinicians. DISCUSSION: Programme evaluation has relied on qualitative feedback, which has been positive from all stakeholders. Visiting lecturers gain teaching skills and insights into the challenges of emergency healthcare delivery in an international, resource constrained setting. Local staff receive assistance and support as well as learning new teaching skills. Students receive increased interactive learning opportunities. CONCLUSION: This programme provides positive models of both emergency care capacity building in a resource-constrained setting and training in international EM for Australasian clinicians. PMID- 23039298 TI - Morbidity associated with amphetamine-related presentations to an emergency department: A record linkage study. AB - OBJECTIVE: Amphetamine use is a global public health problem. We examined hospitalisations in a cohort of 138 patients who presented with an amphetamine related problem to an ED in 2005. METHODS: A record linkage study, using the morbidity, ED and mortality databases in the Data Linkage Unit of the Department of Health, Western Australia. The main outcome measures were hospital separations and length of stay (LOS) 5 years before and 4 years after entry into the cohort. RESULTS: One hundred and thirty patients (94%) with an amphetamine-related presentation had a link with the hospital morbidity dataset. The most common diagnosis before and after cohort entry was mental disorders (before: F00-F99; 405 separations, total LOS 2570 days; after: 309 separations, total LOS 3671 days). Injury and poisoning was the next most common in both time periods. Men had an increased relative risk (RR) for all days of psychiatric care (RR 2.12, 95% CI 1.04-4.35). After adjusting for age and sex, the highest risks of increased LOS occurred within 1 year before (RR 2.22, 95% CI 1.01-4.91) and 2 years post entry into the cohort (RR 4.21, 95% CI 1.87-9.46 and RR 2.82, 95% CI 1.25-6.34). There were four (2.9%, 95% CI 0.9-7.7%) deaths, which occurred within 2 years post cohort entry. CONCLUSION: Amphetamine-related presentations to the ED are associated with a significant cluster of hospitalisations around that episode. This is most prominent for psychiatric diagnoses, with a large increase in the total LOS in the year following cohort entry. Counselling less risky behaviour might decrease the burden of illness. PMID- 23039300 TI - Inadequate acute hospital beds and the limits of primary care and prevention. AB - Metropolitan Australia is suffering from a serious shortage of acute hospital beds. Simplistic comparisons with the Organisation for Economic Co-operation and Development bed numbers are misleading because of the hybrid Australian public/private hospital system. The unavailability of most private beds for acute emergency cases and urban/rural bed imbalances have not been adequately considered. There is a lack of advocacy for acute bed availability. This attitude permeates government, health professions and the health bureaucracy. Planners, politicians, analysts and the media have adopted false hopes of reducing acute demand by prevention and primary care strategies, vital as these services are to a balanced healthcare system. This paper directly challenges the ideology that says Australia depends too heavily on hospital-based healthcare. Rebuilding the bed base requires recognition of the need for an adequate acute hospital service and strong advocacy for bed-based care in the medical and nursing professionals who should be driving policy. The forces opposing bed-based care are strong and solutions might include legislative definition of bed numbers and availability. PMID- 23039299 TI - Randomised trial of magnesium in the treatment of Irukandji syndrome. AB - OBJECTIVES: Irukandji syndrome is a distressing condition characterised by pain, hypertension and tachycardia. Some develop cardiac failure and there have been two reported deaths. Magnesium sulphate has become the standard of care despite minimal evidence. The aim of this study was to investigate if magnesium would reduce analgesic requirement and length of stay for patients with Irukandji syndrome. METHODS: This was a double-blind, randomised controlled clinical trial. Patients with Irukandji syndrome who required parenteral opioid analgesia were randomised to receive either 10 mmol of magnesium as a bolus, and then a 5 mmol/h magnesium infusion for 6 h or saline. Fentanyl patient-controlled analgesia was commenced to allow patients to self-regulate their pain relief. The primary outcome measure of the study was comparison of total analgesic requirements between the two groups. The secondary outcome measure was to compare length of stay. RESULTS: The study ran from November 2003 to May 2007. Thirty-nine patients were enrolled in the study; 26 were male with a median age of 28. Twenty-two received magnesium. There was no significant difference in the morphine equivalent dose used, peak CK, peak troponin, peak pulse, peak blood pressure, peak mean arterial pressure (MAP), percentage MAP rise and length of stay for those receiving magnesium compared with placebo. CONCLUSION: Our study did not demonstrate a benefit in the use of magnesium in the treatment of Irukandji syndrome. As such the current use of magnesium needs to be reconsidered until there is good evidence to support its use. PMID- 23039301 TI - Interstitial ectopic pregnancy presenting after failed termination of pregnancy. AB - Pregnant women frequently present to the ED for complaints related to the first trimester of pregnancy. The emergency physician must confirm the presence of an intrauterine pregnancy for many such complaints. Bedside ultrasound with well delineated criteria has become standard practice for many emergency physicians for this purpose. In the following case report, an interstitial pregnancy was identified by the emergency physician using bedside sonography in a 29-year-old woman presenting 2 weeks after dilation and aspiration for termination of pregnancy. The ED physician identified an inappropriately thin endomyometrial mantle raising suspicion for the diagnosis of an interstitial pregnancy. The case illustrates the importance of this uterine wall measurement given the otherwise normal appearance of a pregnancy within the uterus. PMID- 23039302 TI - Case of scrub typhus complicated by severe disseminated intravascular coagulation and death. AB - Scrub typhus is an infectious disease that is caused by Orientia tsutsugamushi. The authors describe an autopsied case of scrub typhus complicated with severe disseminated intravascular coagulation (DIC). An 82-year-old man complained of fever 4 days after climbing a mountain. The patient was admitted to an urban hospital, and meropenem and ceftriaxone were administered. The patient's condition deteriorated and he was transferred to a second hospital. On physical examination, a black scab was found and scrub typhus was suspected. Despite intensive treatment, the patient died on the fifth day. High levels of O. tsutsugamushi IgM antibody were confirmed. An autopsy revealed systemic vasculitis and perivasculitis. The endothelial tissue of the white pulp of the spleen was markedly infiltrated by plasma cells. The authors speculated that a severe immune reaction against O. tsutsugamushi enhanced an inflammatory response, leading to DIC. This case is a warning to doctors who are not familiar with scrub typhus. PMID- 23039303 TI - Why crisis resource management and evidence-based medicine make uncomfortable bedfellows. PMID- 23039305 TI - Emergency physicians are supertaskers. PMID- 23039308 TI - Thermally-induced phase transition of pseudorotaxane crystals: changes in conformation and interaction of the molecules and optical properties of the crystals. AB - This paper presents a pseudorotaxane that acts as a thermally driven molecular switch in the single-crystal state. Crystals of the cationic pseudorotaxane consisting of dibenzo[24]crown-8 (DB24C8) and N-(xylylammonium)-methylferrocene as the cyclic and axle component molecules, respectively, undergo crystalline phase transition at 128 degrees C with heating and 116 degrees C with cooling, according to differential-scanning-calorimetry measurements. X-ray crystallographic analyses revealed that the phase transition was accompanied by rotation of the 4-methylphenyl group of the axle component molecule and a simultaneous shift in the position of the PF(6)(-) counteranion. Crystalline phase transition changes the conformation and position of the DB24C8 molecule relative to the ammonium cation partially; the interaction between the cyclic component and the PF(6)(-) anion in the crystal changes to a greater extent. Moreover, there are changes in the vibration angle (theta) and birefringence (Deltan) on the (001) face of the crystal transitionally; theta is rotated by +12 degrees , and Deltan is decreased from 0.070 to 0.059 upon heating across the phase transition temperature. The phase transition and accompanying change in the optical properties of the crystal occur reversibly and repeatedly upon heating and cooling processes. The switching rotation of the aromatic plane of the molecule induces a change in the optical anisotropy of the crystal, which is regarded as a demonstration of a new type of optical crystal. Partial replacement of the PF(6)(-) anion with the bulkier AsF(6)(-) anion forms crystals with similar crystallographic parameters. An increase in the AsF(6)(-) content decreases the reversible-phase-transition temperature gradually down to 99 degrees C (T(end)) and 68 degrees C (T(exo)) ([AsF(6)(-)]:[PF(6)(-)] = 0.4:0.6). PMID- 23039306 TI - Evaluation of a real-time virtual intervention to empower persons living with HIV to use therapy self-management: study protocol for an online randomized controlled trial. AB - BACKGROUND: Living with HIV makes considerable demands on a person in terms of self-management, especially as regards adherence to treatment and coping with adverse side-effects. The online HIV Treatment, Virtual Nursing Assistance and Education (Virus de I'immunodeficience Humaine-Traitement Assistance Virtuelle Infirmiere et Enseignement; VIH-TAVIETM) intervention was developed to provide persons living with HIV (PLHIV) with personalized follow-up and real-time support in managing their medication intake on a daily basis. An online randomized controlled trial (RCT) will be conducted to evaluate the efficacy of this intervention primarily in optimizing adherence to combination anti-retroviral therapy (ART) among PLHIV. METHODS/DESIGN: A convenience sample of 232 PLHIV will be split evenly and randomly between an experimental group that will use the web application, and a control group that will be handed a list of websites of interest. Participants must be aged 18 years or older, have been on ART for at least 6 months, and have internet access. The intervention is composed of four interactive computer sessions of 20 to 30 minutes hosted by a virtual nurse who engages the PLHIV in a skills-learning process aimed at improving self-management of medication intake. Adherence constitutes the principal outcome, and is defined as the intake of at least 95% of the prescribed tablets. The following intermediary measures will be assessed: self-efficacy and attitude towards antiretroviral medication, symptom-related discomfort, and emotional support. There will be three measurement times: baseline (T0), after 3 months (T3) and 6 months (T6) of baseline measurement. The principal analyses will focus on comparing the two groups in terms of treatment adherence at the end of follow-up at T6. An intention-to-treat (ITT) analysis will be carried out to evaluate the true value of the intervention in a real context. DISCUSSION: Carrying out this online RCT poses various challenges in terms of recruitment, ethics, and data collection, including participant follow-up over an extended period. Collaboration between researchers from clinical disciplines (nursing, medicine), and experts in behavioral sciences information technology and media will be crucial to the development of innovative solutions to supplying and delivering health services. TRIAL REGISTRATION: CE 11.184 / NCT 01510340. PMID- 23039307 TI - A pharmacologic perspective on newly emerging T-cell manipulation technologies. AB - T cells are a multifaceted family pivotal in the operations of the immune system and many of its associated diseases. The pathway to understanding T cells has been marked by several pharmacological advances including the discoveries of ciclosporin, tacrolimus and the mTOR inhibitors which revolutionized transplant therapy along with providing relief for severe eczema, asthma and other immunological disorders towards the end of the last century. This article will revisit the current understanding and new developments in T cell pharmacology 10 years on from the TeGenero (TGN 1412) debacle and look at more recent successes with ex vivo antigen presenting cell incubation technologies; T cell receptor (TCR) engineering and adoptive T cell therapy both with chimaeric antibodies and also with modified T cell receptors themselves. Features of T cell biology will be explored and processes often highly unique to humans will be used to highlight what many are beginning to see as an exciting new monoclonal (T cell) frontier for drug development. PMID- 23039309 TI - MGA, a suppressor of MYC, is recurrently inactivated in high risk chronic lymphocytic leukemia. PMID- 23039310 TI - Screening for delirium using family caregivers: convergent validity of the Family Confusion Assessment Method and interviewer-rated Confusion Assessment Method. AB - OBJECTIVES: To explore agreement between the Family Confusion Assessment Method (FAM-CAM) for delirium identification and interviewer-rated CAM delirium ratings. DESIGN: Exploratory analysis of agreement. SETTING: Community. PARTICIPANTS: Fifty-two family caregivers and 52 elderly adults with preexisting impairment according to standardized cognitive testing. MEASUREMENTS: The interviewer-rating for delirium was determined by fulfillment of the CAM algorithm RESULTS: The total sample included 52 paired CAM:FAM-CAM assessments completed across 52 dyads of elderly adults with preexisting cognitive impairment and family caregivers. The point prevalence of delirium was 13% (7/52). Characteristics did not differ significantly between the groups with and without delirium. The FAM-CAM questions that mapped directly to the original four-item CAM algorithm had the best overall agreement with the interviewer-rated CAM (kappa = 0.85, 95% confidence interval (CI) = 0.65-1.0), sensitivity of 88% (95% CI = 47-99%), and specificity of 98% (95% CI = 86-100%). CONCLUSION: The FAM-CAM is a sensitive screening tool for detection of delirium in elderly adults with cognitive impairment using family caregivers, with relevance for research and clinical practice. PMID- 23039311 TI - Does body habitus of patients affect operative difficulty during retroperitoneal laparoscopic radical nephrectomy? AB - BACKGROUND AND PURPOSE: Because of the limited working space available during retroperitoneal laparoscopic radical nephrectomy (LRN), the body habitus of the patient is likely to affect the risk of operative difficulties. This study sought to determine whether anthropometric measurements based on CT and abdominal radiography could be used to predict operative difficulties during retroperitoneal LRN. PATIENTS AND METHODS: Between August 2004 and January 2012, 96 consecutive patients with preoperative CT and abdominal radiography examinations underwent retroperitoneal LRN for a T(1) or T(2) stage renal tumor at our institution. The association between anthropometric measurements and demographics of patients and operative duration, estimated blood loss (EBL), and perioperative complications were retrospectively analyzed. Multivariate analysis was performed, and P<0.05 was considered significant. RESULTS: Anterior perirenal fat distance (P=0.016) and distance from the 12th rib to the iliac crest (P=0.038) were independently associated with operative duration. Only anterior perirenal fat distance (P=0.001) was independently associated with EBL. No intraoperative complications and reoperations occurred. The occurrence or severity of postoperative complications was not significantly associated with anthropometric measurements. Body mass index >=25.0 kg/m(2) was not significantly associated with operative difficulties. CONCLUSION: The anterior perirenal fat distance and the distance from the 12th rib to the iliac crest can be used to predict operative difficulties during retroperitoneal LRN. PMID- 23039312 TI - Particulate matter air pollution and respiratory symptoms in individuals having either asthma or chronic obstructive pulmonary disease: a European multicentre panel study. AB - BACKGROUND: Particulate matter air pollution has been associated with adverse health effects. The fraction of ambient particles that are mainly responsible for the observed health effects is still a matter of controversy. Better characterization of the health relevant particle fraction will have major implications for air quality policy since it will determine which sources should be controlled.The RUPIOH study, an EU-funded multicentre study, was designed to examine the distribution of various ambient particle metrics in four European cities (Amsterdam, Athens, Birmingham, Helsinki) and assess their health effects in participants with asthma or COPD, based on a detailed exposure assessment. In this paper the association of central site measurements with respiratory symptoms and restriction of activities is examined. METHODS: At each centre a panel of participants with either asthma or COPD recorded respiratory symptoms and restriction of activities in a diary for six months. Exposure assessment included simultaneous measurements of coarse, fine and ultrafine particles at a central site. Data on gaseous pollutants were also collected. The associations of the 24 hour average concentrations of air pollution indices with the health outcomes were assessed in a hierarchical modelling approach. A city specific analysis controlling for potential confounders was followed by a meta-analysis to provide overall effect estimates. RESULTS: A 10 MUg/m3 increase in previous day coarse particles concentrations was positively associated with most symptoms (an increase of 0.6 to 0.7% in average) and limitation in walking (OR= 1.076, 95% CI: 1.026-1.128). Same day, previous day and previous two days ozone concentrations were positively associated with cough (OR= 1.061, 95% CI: 1.013-1.111; OR= 1.049, 95% CI: 1.016-1.083 and OR= 1.059, 95% CI: 1.027-1.091, respectively). No consistent associations were observed between fine particle concentrations, nitrogen dioxide and respiratory health effects. As for particle number concentrations negative association (mostly non-significant at the nominal level) was observed with most symptoms whilst the positive association with limitation of activities did not reach the nominal level of significance. CONCLUSIONS: The observed associations with coarse particles are in agreement with the findings of toxicological studies. Together they suggest it is prudent to regulate also coarse particles in addition to fine particles. PMID- 23039313 TI - Nutrition screening by nurses in dialysis. AB - AIMS AND OBJECTIVES: To determine whether a nurse-completed dialysis nutritional screening tool improves referral rates for nutritional support and compare nutrition sensitive biochemical indices, mortality rates and patient-centred quality of life outcomes between referred and non-referred dialysis patients. BACKGROUND: People with chronic kidney disease requiring dialysis are nutritionally at risk. Nutrition screening has been shown to identify dialysis patients who are nutritionally at risk to refer to dietitian expertise. DESIGN: Prospective cluster-randomised control trial. METHODS: Monthly nurse-completed nutrition screening was completed for six consecutive months using a validated four-item instrument measuring weight change, serum phosphate, serum potassium and appetite. Participants (n = 81) were haemodialysis patients from four satellite haemodialysis centres in one Australian metropolitan health service. Primary outcome measure was rate of referral to dietetic services for nutrition support for intervention vs. control groups at six months. Secondary outcome measures were blood pressure, biochemical indices and mortality for referred vs. non-referred patients at six and nine months, and generic and dialysis-specific quality of life for referred vs. non-referred at nine months was examined. RESULTS: There were three times as many dietetic referrals in the intervention group than in the control group (26.3 vs. 9.3%). Serum phosphate increased significantly more in the referred patients than the non-referred patients. There were no clinically significant changes between groups in quality of life, blood pressure, mortality rates or other biochemical indices at either six or nine months. CONCLUSION: Nurse-completed nutritional screening can lead to appropriate dietetic referrals for nutritional support by nutritional expert clinicians. RELEVANCE TO CLINICAL PRACTICE: This study is the first to demonstrate that monthly systematic nurse-completed nutritional screening can facilitate appropriate dietetic referrals that may lead to increased nutritional care for people in satellite dialysis centres. PMID- 23039314 TI - Inhaled corticosteroids increase the risk of oropharyngeal colonization by Streptococcus pneumoniae in children with asthma. AB - BACKGROUND AND OBJECTIVE: Recent studies have raised concerns about the link between use of inhaled corticosteroids (ICS) and risk of pneumonia in patients with chronic obstructive pulmonary disease. This cross-sectional study aimed to investigate the association between ICS and oropharyngeal colonization by Streptococcus pneumoniae (S. pneumoniae) among children (up to 18 years old) with asthma. METHODS: Two age-matched groups of patients were consecutively recruited: (i) exposed group: children who had persistent asthma and were being treated with daily ICS for at least 30 days and (ii) non-exposed group: children who had asthma and were not being treated with ICS at study entry. Oropharyngeal specimens from the tonsillar area and posterior pharyngeal wall were collected. S. pneumoniae was identified according to National Committee for Clinical Laboratory Standards recommendations. RESULTS: A total of 200 consecutive patients were recruited and 192 (96 in each group) were included in the analysis. In the exposed group, the mean daily dose of ICS was 400 ug of beclomethasone or equivalent and the mean duration of treatment was 8.6 months. The prevalence of oropharyngeal colonization by S. pneumoniae was higher in the exposed group compared with the non-exposed group (27.1% vs 8.3%, P = 0.001). After adjusting for potential confounders, use of ICS was an independent risk factor for oropharyngeal carriage of S. pneumoniae, with an adjusted prevalence ratio of 3.75 (95% confidence interval: 1.72-8.18, P = 0.001). CONCLUSIONS: Regular use of ICS is associated with an increased risk of having oropharyngeal colonization by S. pneumoniae in children with asthma. PMID- 23039315 TI - Reciprocal modulation of internal and external factors determines individual movements. AB - Movement is fundamental to individual and population dynamics, as it allows individuals to meet their basic requirements. Although movement patterns reflect interactions between internal and external factors, only few studies have examined the effects of these factors on movement simultaneously, and they generally focused on particular biological contexts (e.g. dispersal, foraging). However, the relative importance of these factors in driving individual routine movements might reflect a species' potential flexibility to cope with landscape changes and therefore buffer their potential impact on fitness. We used data from GPS collars on Scandinavian brown bears to investigate the relative role of these factors, as well as an additional factor (period of the year) on routine movements at two spatial scales (hourly and daily relocations). As expected, internal factors played a major role in driving movement, compared to external factors at both scales, but its relative importance was greater at a finer scale. In particular, the interaction between reproductive status and period of the year was one of the most influential variables, females being constrained by the movement capacity of their cubs in the first periods of the year. The effect of human disturbance on movement was also greater for females with cubs than for lone females. This study showed how reciprocal modulation of internal and external factors is shaping space use of brown bears. We stress that these factors should be studied simultaneously to avoid the risk of obtaining context dependent inferences. Moreover, the study of their relative contribution is also highly relevant in the context of multiple-use landscapes, as human activities generally affect the landscape more than they affect the internal states of an individual. Species or individuals with important internal constraints should be less responsive to changes in their environment as they have less freedom from internal constraints and should thus be more sensitive to human alteration of the landscape, as shown for females with cubs in this study. PMID- 23039316 TI - Editorial comment from Dr Nagashima to malignant mixed epithelial and stromal tumor of the kidney: report of the first male case. PMID- 23039317 TI - Mixed 14/16 helices in the gas phase: conformation-specific spectroscopy of Z (Gly)n, n = 1, 3, 5. AB - Single-conformation ultraviolet and infrared spectroscopy has been carried out on the neutral peptide series, Z-(Gly)(n)-OH, n = 1,3,5 (ZGn) and Z-(Gly)(5)-NHMe (ZG5-NHMe) in the isolated environment of a supersonic expansion. The N-terminal Z-cap (carboxybenzyl) provides an ultraviolet chromophore for resonant two-photon ionization (R2PI) spectroscopy. Conformation-specific infrared spectra were recorded in double resonance using resonant ion-dip infrared spectroscopy (RIDIRS). By comparing the experimental spectra with the predictions of DFT M05 2X/6-31+G(d) calculations, the structures could be characterized in terms of the sequence of intramolecular H-bonded rings of varying size. Despite the enhanced flexibility of the glycine residues, a total of only six conformers were observed among the four molecules. Two conformers for ZG1 were found with the major conformation taking on an extended, planar beta-strand conformation. Two conformers were observed for ZG3, with the majority of the population in a C11/C7/C7/pi(g-) structure that forms a full loop of the glycine chain. Both ZG5 molecules had their population primarily in a single conformation, with structures characteristic of the first stages of a "mixed" beta-helix. C14/C16 H bonded rings in opposing directions (N -> C and C -> N) tie the helix together, with nearest-neighbor C7 rings turning the backbone so that it forms the helix. phi/psi angles alternate in sign along the backbone, as is characteristic of the mixed, C14/C16 beta-helix. The calculated conformational energies of these structures are unusually stable relative to all others, with energies significantly lower than the PGI/PGII conformations characteristic of polyglycine structures in solution and in the crystalline form, where intermolecular H-bonds play a role. PMID- 23039318 TI - Management of bleeding in patients receiving conventional or new anticoagulants: a practical and case-based approach. AB - Anticoagulant drugs are highly effective for the prevention and treatment of venous and arterial thromboembolism. However, their use is also associated with an increased risk for bleeding, with an associated ~10% case-fatality rate. Appropriate strategies for the management and reversal of anticoagulant associated bleeding are clinically important and, ideally, should be standardized. These include general resuscitation, and diagnosis and local treatment of the bleeding source, and one or more of the following interventions: transfusion of red cells; transfusion of clotting factor replacements; and administration of anticoagulant antidotes and other prohaemostatic agents. Reversal strategies for the 'conventional' anticoagulants are based largely on clinical evidence, whereas evidence to guide the management of bleeding associated with 'new' anticoagulants is emerging. This review provides an evidence-based, but practical, patient-focused approach for the management of bleeding associated with the old and new anticoagulants. PMID- 23039319 TI - Comparison of amoxicillin/clavulanic acid high dose with cefdinir in the treatment of acute otitis media. AB - BACKGROUND: 10 days of amoxicillin/clavulanic acid high dose and 5 days of cefdinir have been the preferred first- or second-line antibiotics for treatment of children with acute otitis media (AOM) since 2004, as recommended by the American Academy of Pediatrics in the USA, but no head-to-head comparison study has been done. OBJECTIVE: The purpose of the study was to compare the clinical efficacy of amoxicillin/clavulanic acid high-dose therapy for 10 days with cefdinir therapy for 5 days for AOM at recommended doses. METHODS: This was an investigator-blind trial in young children 6-24 months old with no history of recurrent AOM who were randomly assigned to amoxicillin/clavulanic acid (80 mg/kg/day amoxicillin) or cefdinir (14 mg/kg/day), both in two divided doses. The diagnosis of AOM was based on specific clinical criteria by validated otoscopists at two AOM research centres. The outcome measure for clinical cure was resolution of all symptoms and signs of AOM except for persistence of middle-ear effusion at test-of-cure (TOC) 11-14 days after initiation of antibiotic treatment. Clinical failure was defined as persistence of symptoms and signs of AOM and the need for additional antibiotic therapy. Subjects lost to follow up or who had not taken at least 80% of the prescribed medication were classified as having an indeterminate response. Compliance was monitored using Medical Electronic Monitoring System (MEMS) caps and antibiotic bottle volume measurement at the TOC visit. A logistic regression model was used to estimate the association of age with cure rate. Full interactions in terms of age with treatment were included to estimate any age gradient differential. RESULTS: A total of 330 children (average age 13.1 months) with AOM were studied. At TOC, 256 children had clinical cure, 69 had clinical failure, and 5 were lost to follow-up. High-dose amoxicillin/clavulanic acid treated children had a better cure rate (86.5%) than cefdinir-treated patients (71.0%; p = 0.001). Cefdinir was correlated with less frequent cure outcomes as children increased in age between 6 and 24 months. The odds ratios for clinical cure per increasing month of age estimated from a logistic regression model for amoxicillin/clavulanic acid high dose and cefdinir treatment groups was 0.992 (95% CI 0.932, 1.056), p > 0.05 and 0.932 (95% CI 0.881, 0.986), p = 0.01. The differences in the odds ratios are significant at p < 0.002, indicating a stable clinical cure rate across the ages of children studied for amoxicillin/clavulanic acid and decreasing clinical cure rates as children increased in age for cefdinir. CONCLUSION: In children with bona fide AOM for whom clinical outcomes are assessed by validated otoscopists, 10 days of high-dose amoxicillin/clavulanic acid is significantly more effective than 5 days of cefdinir as therapy for AOM. Because of the identified age effect (correlated to child weight), higher doses of cefdinir may have led to a different conclusion; 10 days of cefdinir may also have led to a different conclusion. PMID- 23039320 TI - Phentermine and topiramate extended release (QsymiaTM): first global approval. AB - Vivus' proprietary oral capsule containing phentermine and extended-release (ER) topiramate has been approved in the US for the treatment of obesity. Phentermine is an appetite suppressant, while topiramate is an anti-epileptic medication. The once-daily formulation, known as QsymiaTM, is designed to produce weight loss by decreasing appetite and increasing satiety. The product is also in clinical development for sleep apnoea syndrome and type 2 diabetes mellitus. This article summarizes the milestones in the development of phentermine/topiramate ER leading to this first approval for obesity. PMID- 23039321 TI - Improved glycaemic control with vildagliptin added to insulin, with or without metformin, in patients with type 2 diabetes mellitus. AB - AIM: The aim of this study is to assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in type 2 diabetes mellitus (T2DM). METHODS: This is a multicentre, double-blind, placebo-controlled, parallel group, clinical trial in T2DM patients inadequately controlled by stable insulin therapy, with or without metformin. Patients received treatment with vildagliptin 50 mg bid or placebo for 24 weeks. RESULTS: In all, 449 patients were randomized to vildagliptin (n = 228) or placebo (n = 221). After 24 weeks, the difference in adjusted mean change in haemoglobin A1c (HbA1c) between vildagliptin and placebo was -0.7 +/- 0.1% (p < 0.001) in the overall study population, -0.6 +/- 0.1% (p < 0.001) in the subgroup also receiving metformin and -0.8 +/- 0.2% (p < 0.001) in the subgroup without metformin. Vildagliptin therapy was well tolerated and had a similarly low incidence of hypoglycaemia compared with placebo (8.4 vs. 7.2%, p = 0.66) in spite of improved glycaemic control, and was not associated with weight gain. (+0.1 vs. -0.4 kg). CONCLUSIONS: Vildagliptin 50 mg bid added to insulin significantly reduced HbA1c in patients with T2DM inadequately controlled by insulin, with or without metformin. Vildagliptin was well tolerated, with a safety profile similar to placebo. These results were achieved without weight gain or an increase in hypoglycaemia incidence or severity in spite of improved glycaemic control. PMID- 23039322 TI - Type and location of isocitrate dehydrogenase mutations influence clinical characteristics and disease outcome of acute myeloid leukemia. AB - Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) are genetic alterations in acute myeloid leukemia (AML). The aim of our study was to investigate the frequency and prognostic effect of IDH1/2 mutations together followed by an individual analysis of each substitution in a Hungarian cohort consisting of 376 patients with AML. IDH1(mut) and IDH2(mut) were mutually exclusive, detected in 8.5% and 7.5% of cases, respectively. IDH1/2(mut) was associated with: older age (p = 0.001), higher average platelet count (p = 0.001), intermediate karyotype (p < 0.0001), NPM1(mut) (p = 0.022) and lower mRNA expression level of ABCG2 gene (p = 0.006). Overall survival (OS), remission and relapse rates were not different in IDH1(mut) or IDH2(mut) vs. IDH(neg). IDH1(mut) and IDH2(mut) were associated differently with NPM1(mut); co-occurrence was observed in 14.3% of IDH1 R132C vs. 70% of R132H carriers (p = 0.02) and in 47.4% of IDH2 R140Q vs. 0% of R172K carriers (p = 0.02). IDH1 R132H negatively influenced OS compared to IDH(neg) (p = 0.02) or R132C (p = 0.019). Particular amino acid changes affecting the same IDH1 codon influence the clinical characteristics and treatment outcome in AML. PMID- 23039324 TI - The impact of artificial vehicle sounds for pedestrians on driver stress. AB - Electrically based vehicles have produced some concern over their lack of sound, but the impact of artificial sounds now being implemented have not been examined in respect to their effects upon the driver. The impact of two different implementations of vehicle sound on driver stress in electric vehicles was examined. A Nissan HEV running in electric vehicle mode was driven by participants in an area of congestion using three sound implementations: (1) no artificial sounds, (2) manually engaged sounds and (3) automatically engaged sounds. Physiological and self-report questionnaire measures were collected to determine stress and acceptance of the automated sound protocol. Driver stress was significantly higher in the manually activated warning condition, compared to both no artificial sounds and automatically engaged sounds. Implications for automation usage and measurement methods are discussed and future research directions suggested. PRACTITIONER SUMMARY: The advent of hybrid- and all electric vehicles has created a need for artificial warning signals for pedestrian safety that place task demands on drivers. We investigated drivers' stress differences in response to varying conditions of warning signals for pedestrians. Driver stress was lower when noises were automated. PMID- 23039323 TI - Biomechanical factors and physical examination findings in osteoarthritis of the knee: associations with tissue abnormalities assessed by conventional radiography and high-resolution 3.0 Tesla magnetic resonance imaging. AB - INTRODUCTION: We aimed to explore the associations between knee osteoarthritis (OA)-related tissue abnormalities assessed by conventional radiography (CR) and by high-resolution 3.0 Tesla magnetic resonance imaging (MRI), as well as biomechanical factors and findings from physical examination in patients with knee OA. METHODS: This was an explorative cross-sectional study of 105 patients with knee OA. Index knees were imaged using CR and MRI. Multiple features from CR and MRI (cartilage, osteophytes, bone marrow lesions, effusion and synovitis) were related to biomechanical factors (quadriceps and hamstrings muscle strength, proprioceptive accuracy and varus-valgus laxity) and physical examination findings (bony tenderness, crepitus, bony enlargement and palpable warmth), using multivariable regression analyses. RESULTS: Quadriceps weakness was associated with cartilage integrity, effusion, synovitis (all detected by MRI) and CR detected joint space narrowing. Knee joint laxity was associated with MRI detected cartilage integrity, CR-detected joint space narrowing and osteophyte formation. Multiple tissue abnormalities including cartilage integrity, osteophytes and effusion, but only those detected by MRI, were found to be associated with physical examination findings such as crepitus. CONCLUSION: We observed clinically relevant findings, including a significant association between quadriceps weakness and both effusion and synovitis, detected by MRI. Inflammation was detected in over one-third of the participants, emphasizing the inflammatory component of OA and a possible important role for anti-inflammatory therapies in knee OA. In general, OA-related tissue abnormalities of the knee, even those detected by MRI, were found to be discordant with biomechanical and physical examination features. PMID- 23039325 TI - Deletion of the TNFAIP3/A20 gene detected by FICTION analysis in classical Hodgkin lymphoma. AB - BACKGROUND: The TNFAIP3 gene, which encodes a ubiquitin-modifying enzyme (A20) involved in the negative regulation of NF-kappaB signaling, is frequently inactivated by gene deletions/mutations in a variety of B-cell malignancies. However, the detection of this in primary Hodgkin lymphoma (HL) specimens is hampered by the scarcity of Hodgkin Reed-Sternberg (HR-S) cells even after enrichment by micro-dissection. METHODS: We used anti-CD30 immunofluorescence with fluorescence in-situ hybridization (FISH) to evaluate the relative number of TNFAIP3/CEP6 double-positive signals in CD30-positive cells. RESULTS: From a total of 47 primary classical Hodgkin lymphoma (cHL) specimens, 44 were evaluable. We found that the relative numbers of TNFAIP3/CD30 cells were distributed among three groups, corresponding to those having homozygous (11%), heterozygous (32%), and no (57%) deletions in TNFAIP3. This shows that TNFAIP3 deletions could be sensitively detected using our chosen methods. CONCLUSIONS: Comparing the results with mutation analysis, TNFAIP3 inactivation was shown to have escaped detection in many samples with homozygous deletions. This suggests that TNFAIP3 inactivation in primary cHL specimens might be more frequent than previously reported. PMID- 23039326 TI - Clinical associations of anti-SSA/Ro60 and anti-Ro52/TRIM21 antibodies: Diagnostic utility of their separate detection. AB - Clinical associations of anti-SSA/Ro60 and anti-Ro52/TRIM21 antibodies are not yet fully established. In order to analyse the diagnostic utility of their separate detection, we retrospectively revised the clinical data of 200 anti SSA/Ro60 and/or anti-Ro52/TRIM21 positive patients identified by line immunoassay during ANA routine detection. Anti-SSA/Ro60 positive patients showed a significantly higher prevalence of autoimmune diseases (AIDs) independently on the presence of anti-Ro52/TRIM21 (OR 3.13, 95% CI 1.10-8.88, p = 0.032). Anti SSA/Ro60 was independently associated with systemic lupus erythematosus (SLE) when comparing with Sjogren's syndrome (SS) and other systemic AIDs (OR 3.46, 95% CI 1.08-11.06, p = 0.036). The more frequent specificity found in cutaneous lupus erythematosus (CLE) was also anti-SSA/Ro60. In contrast, detection of isolated anti-Ro52/TRIM21 was characteristic of SS (7/35, 20.0%), diffuse cutaneous systemic sclerosis (dcSSc) (3/4, 75.0%), primary biliary cirrhosis (PBC) (4/5, 80.0%) and, specially, of polymyositis/dermatomyositis (PM/DM) (6/6, 100%). In fact, anti-Ro52/TRIM21 was the only antibody detected in 4 out of the 6 PM/DM patients. Malignancies mainly account for the observed high prevalence of mono specific anti-Ro52/TRIM21 in patients with non-AIDs (10/15, 62.5%). In conclusion, this retrospective study supports the routine distinction of anti SSA/Ro60 and anti-Ro52/TRIM21 due to their different clinical associations. PMID- 23039328 TI - Awareness and regulation of emotions in deaf children. AB - In this study, deaf children's understanding of their own emotions was compared with that of hearing peers. Twenty-six deaf children (mean age 11 years) and 26 hearing children, matched for age and gender, were presented with various tasks that tap into their emotion awareness and regulation (coping) regarding the four basic emotions (happiness, anger, sadness, and fear). The findings suggest that deaf children have no difficulties in identifying their own basic emotions and the elicitors, or multiple emotions of opposite valence (happy and sad). Yet, they did show an impaired capacity to differentiate between their own emotions within the negative spectrum, which suggests a more generic evaluation of the situation. Deaf children's emotion regulation strategies showed a strong preference for approaching the situation at hand, but almost no deaf child reported the use of an avoidant tactic in order to diminish the negative impact of the situation. Overall, deaf children's emotion regulation strategies seemed less effective than those of their hearing peers. The implications for deaf children's emotional development are discussed. PMID- 23039327 TI - Ezrin overexpression predicts the poor prognosis of gastric adenocarcinoma. AB - BACKGROUND: Ezrin is a cytoskeletal protein that is involved in tumor growth and invasion. It has been suggested that Ezrin expression plays an important role in tumor metastasis. This study is aimed to investigate the clinicopathological significance of Ezrin overexpression in gastric adenocarcinomas. METHODS: Ezrin protein expression was examined by immunohistochemistry in 26 normal gastric mucosa, 32 dysplasia, and 277 gastric adenocarcinomas. The relationship between Ezrin expression and the clinicopathological features of gastric cancers was analyzed. In addition, a gastric cancer cell line, MKN-1, was also used for immunofluorescence staining to evaluate the distribution of Ezrin protein. RESULTS: Ezrin protein located in the cytoplasm and/or membrane in the migrating gastric cancer cells, and it mainly concentrated at the protrusion site; however, only cytoplasmic distribution was observed in the non-migrating cancer cells by immunofluorescence staining. The positive rate of Ezrin protein expression was significantly higher in gastric adenocarcinoma and dysplasia compared with that in the normal gastric mucosa. Moreover, expression frequency of Ezrin protein increased significantly in lymph node metastasis and late clinical stages. Consistently, strong expression of Ezrin was significantly correlated with poor prognosis of gastric cancer. CONCLUSION: The detection of Ezrin expression can be used as the marker for early diagnosis and prognosis of gastric adenocarcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2303598677653946. PMID- 23039329 TI - Children's and adolescents' tolerance for divergent beliefs: exploring the cognitive and affective dimensions of moral conviction in our youth. AB - Moral conviction predicts interpersonal tolerance in adults, but its role in children and adolescents is not as well understood. This study measured moral conviction for a variety of issues along two separate dimensions - cognitive and affective - in children and adolescents (4th-12th grade). Results showed that, like adults, when children and adolescents view an issue as moral, this is strongly predictive of both age groups' discomfort with divergent beliefs. But only for adolescents, and not children, did moral conviction play a role in that discomfort, as had previously been found with adults. The context in which the divergent beliefs were encountered also mattered, but more for adolescents than for children - both groups were most comfortable with divergent beliefs when they were encountered in distal relations. PMID- 23039330 TI - Moral reasoning and emotion attributions of adolescent bullies, victims, and bully-victims. AB - This study investigated different facets of moral development in bullies, victims, and bully-victims among Swiss adolescents. Extending previous research, we focused on both bullying and victimization in relation to adolescents' morally disengaged and morally responsible reasoning as well as moral emotion attributions. A total of 516 adolescents aged 12-18 (57% females) reported the frequency of involvement in bullying and victimization. Participants were categorized as bullies (14.3%), bully-victims (3.9%), and victims (9.7%). Moral judgment, moral justifications, and emotion attributions to a hypothetical perpetrator of a moral transgression (relational aggression) were assessed. Bullies showed more morally disengaged reasoning than non-involved students. Bully-victims more frequently indicated that violating moral rules is right. Victims produced more victim-oriented justifications (i.e., more empathy) but fewer moral rules. Among victims, the frequency of morally responsible justifications decreased and the frequency of deviant rules increased with age. The findings are discussed from an integrative moral developmental perspective. PMID- 23039331 TI - Acoustic differences between humorous and sincere communicative intentions. AB - Previous studies indicate that the acoustic features of speech discriminate between positive and negative communicative intentions, such as approval and prohibition. Two studies investigated whether acoustic features of speech can discriminate between two positive communicative intentions: humour and sweet sincerity, where sweet-sincerity involved being sincere in a positive, warm hearted way. In Study 1, 22 mothers read a book containing humorous, sweet sincere, and neutral-sincere images to their 19- to 24-month-olds. In Study 2, 41 mothers read a book containing humorous or sweet-sincere sentences and images to their 18- to 24-month-olds. Mothers used a higher mean F0 to communicate visual humour as compared to visual sincerity. Mothers used greater F0 mean, range, and standard deviation; greater intensity mean, range, and standard deviation; and a slower speech rate to communicate verbal humour as compared to verbal sweet sincerity. Mothers used a rising linear contour to communicate verbal humour, but used no specific contour to express verbal sweet-sincerity. We conclude that speakers provide acoustic cues enabling listeners to distinguish between positive communicative intentions. PMID- 23039332 TI - Children's event reports: factors affecting responses to repeated questions in vignette scenarios and event recall interviews. AB - When adults repeat questions, children often give inconsistent answers. This study aimed to test the claim that these inconsistencies occur because children infer that their first answer was unsatisfactory, and that the adult expects them to change their answer. Children aged 4, 6, and 8 years (N= 134) were asked about vignettes in which an adult repeated a question, with manipulation of the adult's overt dissatisfaction (high vs. low pressure) and knowledge about the information sought. On a separate occasion, the children were given an unrelated event recall interview containing repeated questions. All age groups showed sensitivity to adult dissatisfaction, interpreting question repetition as an implicit request for answer change more frequently in the high than in the low-pressure vignettes. Overall, however, these 'change-expected' interpretations were least frequent in the younger children, who were the most prone to shifting. Also there was no evidence that these interpretations were associated with more frequent shifting in the recall interview. The results do not provide clear support for a simple conversational inference account of shifting, especially in younger children. PMID- 23039335 TI - The histological appearance of the proximal aspect of the dorsal condylar sagittal ridge of the third metacarpal and metatarsal bone in young warmblood horses: normal appearance and correlation with detected radiographic variations. AB - The objective of this study is to describe the normal histological appearance of the dorsoproximal aspect of the sagittal ridge of the third metacarpal/metatarsal bone in young Warmblood horses, and to compare it to the different radiographic variations (irregular, indentation, lucency, notch) described at this level. A total of 25 metacarpo/metatarsophalangeal joints of 12 Warmblood horses were used. Five samples of each radiographically described group were selected for histological processing. Each category was compared with the normal control group. Each group showed a bone cortex, covered by hyaline cartilage and longitudinally aligned collagen fibres covered by loosely organized connective tissue proximally. The normal and irregular group showed a smooth bone cortex. In the indentation and lucency group, a depression in the cortex was detected. The notch group presented an expansion of the cortex. The collagen fibres and connective tissue were located in the depression in the indentation group whereas the location varied in the lucency and notch group. The radiologic detected differences are translated into detectable histological differences. Further research is warranted to determine whether these variations are developmental or congenital and to evaluate their potential influence on the joint function during hyperextension. PMID- 23039333 TI - The effects of young children's affiliations with prosocial peers on subsequent emotionality in peer interactions. AB - Preschoolers' (60 boys and 64 girls, M age = 50.73 months) affiliations with prosocial peers were observed in naturally occurring interactions and then examined in relation to positive and negative emotionality within their peer interactions one semester later. Greater affiliation with prosocial peers in the fall was related to enhanced positive emotionality (especially for girls) and decreased negative emotionality (especially for boys) in later peer interactions. These findings held when initial levels of the emotion were controlled and were found above and beyond variations in classroom levels of prosociality. The findings suggest that peers exert influence in early childhood and that these effects can positively affect the quality of young children's later peer interactions. PMID- 23039334 TI - Early humour production. AB - The current studies explored early humour as a complex socio-cognitive phenomenon by examining 2- and 3-year-olds' humour production with their parents. We examined whether children produced novel humour, whether they cued their humour, and the types of humour produced. Forty-seven parents were interviewed, and videotaped joking with their children. Other parents (N= 113) completed a survey. Parents reported children copy jokes during the first year of life, and produce novel jokes from 2 years. In play sessions, 3-year-olds produced mostly novel humorous acts; 2-year-olds produced novel and copied humorous acts equally frequently. Parents reported children smile, laugh, and look for a reaction when joking. In play sessions, 2- and 3-year-olds produced these behaviours more when producing humorous versus non-humorous acts. In both parent reports and play sessions, they produced novel object-based (e.g., underwear on head) and conceptual humour (e.g., 'pig says moo') and used wrong labels humorously (e.g., calling a cat a dog). Thus, parent report and child behaviour both confirm that young children produce novel humorous acts, and share their humour by smiling, laughing, and looking for a reaction. PMID- 23039338 TI - Spin-flop switching and memory in a molecular conductor. AB - We report the first observation of spin-flop-induced sharp positive magnetoresistance as large as 100% and nonvolatile magnetoresistive memory in a pi-d hybrid molecular conductor, (DIETSe)(2)FeCl(4) [DIETSe = diiode(ethylenedithio)tetraselenafulvalene]. The unprecedented magnetotransport phenomena originate from the coexistence of the spin density wave (SDW) of the quasi-one-dimensional (Q1D) pi electrons and the antiferromagnetic order of d electron spins, indicating the interplay between the electronic instability of Q1D pi electrons and local moments of antiferromagnetic d-electron spins. These findings offer new possibilities in molecular electronics/spintronics. PMID- 23039337 TI - Clinical characteristics of inferior vestibular neuritis. AB - CONCLUSIONS: Inferior vestibular neuritis (IVN) is a relatively minor subtype of vestibular neuritis (VN) and its clinical characteristics are unique. OBJECTIVES: To clarify clinical characteristics of IVN in comparison with conventional VN. METHODS: This was a retrospective case series review. Caloric responses and cervical vestibular evoked myogenic potential (cVEMP) responses were measured in 71 patients with VN. The patients were classified into three groups: (1) IVN group, who showed only asymmetrical cVEMP responses; (2) superior VN (SVN) group, who showed only asymmetrical caloric responses; (3) total VN (TVN) group, who showed asymmetrical responses in both tests. The clinical records of time course of subjective symptoms (duration of attack, duration of hospitalization, and time to remission) were reviewed and other profiles (age, sex, affected side, acute symptoms, and sequelae) were evaluated. RESULTS: Of the 71 patients with VN, 13 (18%) were classified as having IVN. The mean age and time to remission of patients with IVN (44.2 +/- 4.8 years, 0.9 +/- 0.5 months) were significantly lower and shorter, respectively, than those of patients with TVN (57.3 +/- 2.5 years, 4.9 +/- 4.7 months). There were no significant differences in other symptoms and profiles among the three groups. No patients with IVN showed benign paroxysmal positional vertigo as a sequela. PMID- 23039336 TI - Comprehensive lipidome profiling of isogenic primary and metastatic colon adenocarcinoma cell lines. AB - A "shotgun" lipidomics strategy consisting of sequential functional group selective chemical modification reactions coupled with high-resolution/accurate mass spectrometry and "targeted" tandem mass spectrometry (MS/MS) analysis has been developed and applied toward the comprehensive identification, characterization and quantitative analysis of changes in relative abundances of >600 individual glycerophospholipid, glycerolipid, sphingolipid and sterol lipids between a primary colorectal cancer (CRC) cell line, SW480, and its isogenic lymph node metastasized derivative, SW620. Selective chemical derivatization of glycerophosphoethanolamine and glycerophosphoserine lipids using a "fixed charge" sulfonium ion containing, d(6)-S,S'-dimethylthiobutanoylhydroxysuccinimide ester (d(6)-DMBNHS) reagent was used to eliminate the possibility of isobaric mass overlap of these species with the precursor ions of all other lipids in the crude extracts, thereby enabling their unambiguous assignment, while subsequent selective mild acid hydrolysis of plasmenyl (vinyl-ether) containing lipids using formic acid enabled these species to be readily differentiated from isobaric mass plasmanyl (alkyl-ether) containing lipids. Using this approach, statistically significant differences in the abundances of numerous lipid species previously identified as being associated with cancer progression or that play known roles as mediators in a range of physiological and pathological processes were observed between the SW480 and SW620 cells. Most notably, these included increased plasmanylcholine and triglyceride lipid levels, decreased plasmenylethanolamine lipids, decreased C-16 containing sphingomyelin and ceramide lipid levels, and a dramatic increase in the abundances of total cholesterol ester and triglyceride lipids in the SW620 cells compared to those in the SW480 cells. PMID- 23039339 TI - Listeriosis in pregnancy: case report and retrospective study. AB - BACKGROUND: Listeria monocytogenes usually causes mild maternal illness, but can be devastating to the fetus. CASE: Listeriosis in a pregnant patient successfully treated with empiric antibiotic therapy is described. After induced delivery, despite severe placental infection, a healthy infant was born. Additionally, archived placental specimens with similar pathological manifestation were evaluated for evidence of L. monocytogenes. CONCLUSION: It is important to emphasize the value of associating maternal data and clinical and laboratory findings of the newborn with the pathologic placental findings to get better results in the etiologic diagnosis of the listeriosis. PMID- 23039340 TI - High-polyphenol chocolate reduces endothelial dysfunction and oxidative stress during acute transient hyperglycaemia in Type 2 diabetes: a pilot randomized controlled trial. AB - AIMS: To investigate the effects of high-polyphenol chocolate upon endothelial function and oxidative stress in Type 2 diabetes mellitus during acute transient hyperglycaemia induced following a 75-g oral glucose challenge. METHODS: Ten subjects with Type 2 diabetes underwent a double-blinded randomized controlled crossover study. A 75-g oral glucose load was used to induce hyperglycaemia, which was administered to participants 60 min after they had ingested either low (control) or high-polyphenol chocolate. Participants undertook testing at weekly intervals, following an initial cocoa-free period. Endothelial function was assessed by both functional [reactive hyperaemia peripheral artery tonometry (EndoPAT-2000) and serum markers (including intercellular adhesion molecule 1, P selectin and P-selectin glycoprotein ligand 1]. Urinary 15-F2t-isoprostane adjusted for creatinine was used as an oxidative stress marker. Measurements were made at baseline and 2 h post-ingestion of the glucose load. RESULTS: Prior consumption of high-polyphenol chocolate before a glucose load improved endothelial function (1.7 +/- 0.1 vs. 2.3 +/- 0.1%, P = 0.01), whereas prior consumption of control chocolate resulted in a significant increase in intercellular adhesion molecule 1 (321.1 +/- 7.6 vs. 373.6 +/- 10.5 ng/ml, P = 0.04) and 15-F2t-isoprostane (116.8 +/- 5.7 vs. 207.1 +/- 5.7 mg/mol, P = 0.02). Analysis of percentage changes from baseline comparing control and high polyphenol chocolate showed a significant improvement for high-polyphenol chocolate in both measures of endothelial function (P < 0.05) and for urinary 15 F2t-isoprostane (P = 0.04). CONCLUSION: High-polyphenol chocolate protected against acute hyperglycaemia-induced endothelial dysfunction and oxidative stress in individuals with Type 2 diabetes mellitus. PMID- 23039343 TI - 'Left back' and the age-grade system: problem creation through problem solution. PMID- 23039342 TI - Nutritional ecology of entomophagy in humans and other primates. AB - Entomophagy is widespread among nonhuman primates and is common among many human communities. However, the extent and patterns of entomophagy vary substantially both in humans and nonhuman primates. Here we synthesize the literature to examine why humans and other primates eat insects and what accounts for the variation in the extent to which they do so. Variation in the availability of insects is clearly important, but less understood is the role of nutrients in entomophagy. We apply a multidimensional analytical approach, the right-angled mixture triangle, to published data on the macronutrient compositions of insects to address this. Results showed that insects eaten by humans spanned a wide range of protein-to-fat ratios but were generally nutrient dense, whereas insects with high protein-to-fat ratios were eaten by nonhuman primates. Although suggestive, our survey exposes a need for additional, standardized, data. PMID- 23039344 TI - Can gay and lesbian parents promote healthy development in high-risk children adopted from foster care? AB - Adoption is known to promote cognitive and emotional development in children from foster care, but policy debates remain regarding whether children adopted by gay and lesbian parents can achieve these positive outcomes. This study compared the cognitive development and behavior problems at 2, 12, and 24 months postplacement of 82 high-risk children adopted from foster care in heterosexual and gay or lesbian households. On average, children in both household types showed significant gains in cognitive development and maintained similar levels of behavior problems over time, despite gay and lesbian parents raising children with higher levels of biological and environmental risks prior to adoptive placement. Results demonstrated that high-risk children show similar patterns of development over time in heterosexual and gay and lesbian adoptive households. PMID- 23039345 TI - Unmet health and mental health need among adolescents: the roles of sexual minority status and child-parent connectedness. AB - Using a representative national sample from the National Longitudinal Study of Adolescent Health (Add Health) survey (N = 18,924), this article explores sexual minority status (SMS) and child-parent connectedness in relation to the unmet needs for health or mental health care among adolescents. Through the use of logistic regression models, data were analyzed to determine whether SMS and child parent connectedness predict unmet health and mental health need. In addition, models tested whether child-parent connectedness, sex or gender, and race or ethnicity interact with SMS to predict unmet need. Results show that both SMS and child-parent connectedness predict unmet health and mental health need. Being a sexual minority youth (SMY) significantly increases the odds of having an unmet need for health or mental health care; female SMY have the highest odds of an unmet mental health need. Child-parent connectedness is a predictor of unmet need regardless of SMS. Youth with lower levels of child-parent connectedness have significantly higher odds of an unmet health or mental health need. Findings call for service providers to address the unmet needs of SMY both in terms of outreach to youth and parents and to communicate the importance of the parental role in helping teens access care. PMID- 23039341 TI - Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status. AB - BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma. PMID- 23039346 TI - Understanding sexual orientation health disparities in smoking: a population based analysis. AB - Lesbian, gay, and bisexual populations are at elevated risk for tobacco use compared to their heterosexual peers. However, there is little research examining reasons for this disparity. Drawing on prior literature regarding psychosocial variables associated with both sexual orientation and smoking, the authors tested a path model of risk and protective factors to help explain sexual orientation differences in smoking using data from the Washington State Behavioral Risk Factor Surveillance System from 2003 to 2007. The authors estimated separate models for men and women, comparing lesbians or gays and bisexuals to heterosexuals. Results indicated that the explanatory variables accounted for most of the variance in this relationship, with both risk-enhancing and risk reducing pathways. Mental health, life dissatisfaction, alcohol use, exposure to tobacco marketing, and single relationship status were risk enhancers for most LGB participants. Health-care access and income level were risk enhancers for bisexual participants only. Neither emotional support nor attitudes and knowledge about tobacco use helped explain the relationship between sexual orientation and smoking. These findings have significant implications for tobacco prevention and control efforts in this high-risk population. PMID- 23039347 TI - Coping strategies and health in a national sample of sexual minority women. AB - Coping strategies have been shown to significantly influence mental and physical health among heterosexual and medically ill populations. These associations have not been thoroughly examined among sexual minority women, who are known to shoulder a high burden of disease. This study assesses the impact of adaptive and maladaptive coping on mental and physical health among 1,381 lesbian and bisexual women and examines the potential mediating role of maladaptive coping in explaining bisexual women's poorer health relative to lesbians. Participants completed a web-based survey that assessed demographic characteristics, social support, adaptive and maladaptive coping strategies, and mental and physical health. Maladaptive coping strategies, especially behavioral disengagement and self-blame, were significantly associated with mental and physical health. Coping was more strongly predictive of mental health than physical health, and maladaptive coping more strongly predictive of health outcomes than demographics, social support, and adaptive coping. Interactions between social support and coping were generally not significant. Additionally, bisexual women reported more adverse mental and physical health outcomes than lesbians, and maladaptive coping significantly mediated these relationships. Providers working with sexual minority women may wish to pay particular attention to maladaptive coping strategies, countering these with adaptive, empowerment-based interventions. PMID- 23039349 TI - Gay affirmative psychotherapy with lesbian, gay, and bisexual individuals: implications for contemporary psychotherapy research. AB - Although a fair amount has been written about gay affirmative psychotherapy, there has not been a clear consensus on what actually constitutes gay affirmative therapy. Because there are no real theoretical framework, operational definitions, or outcome measures, pychotherapists are left unsure about how to incorporate it into their practice and researchers are unsure how best to investigate it. This article offers recommendations to identify gay affirmative therapy as a culturally competent approach for working with lesbian, gay, and bisexual clients and offers future research directions including how to utilize the "coming out" narrative in gay affirmative therapy. PMID- 23039348 TI - Religious affiliation, internalized homophobia, and mental health in lesbians, gay men, and bisexuals. AB - Most religious environments in the United States do not affirm homosexuality. The authors investigated the relationship between exposure to nonaffirming religious environments and internalized homophobia and mental health in a sample of lesbians, gay men, and bisexuals (LGBs) in New York City. Guided by minority stress theory, the authors hypothesized that exposure to nonaffirming religious settings would lead to higher internalized homophobia, more depressive symptoms, and less psychological well-being. The authors hypothesized that Black and Latino LGBs would be more likely than White LGBs to participate in nonaffirming religious settings and would therefore have higher internalized homophobia than White LGBs. Participants were 355 LGBs recruited through community-based venue sampling and evenly divided among Black, Latino, and White race or ethnic groups and among age groups within each race or ethnic group, as well as between women and men. Results supported the general hypothesis that nonaffirming religion was associated with higher internalized homophobia. There was no main effect of nonaffirming religion on mental health, an unexpected finding discussed in this article. Latinos, but not Blacks, had higher internalized homophobia than Whites, and as predicted, this was mediated by their greater exposure to nonaffirming religion. PMID- 23039350 TI - Are two a family? Older single mothers assisted by sperm donation and their children revisited. AB - This study follows 40 older single-mother families created with the aid of sperm donation using either insemination or in vitro fertilization. The study is based on qualitative data obtained from the mothers 3 years after a previous study with these families. The mean age of the mothers at this time was about 47 years and of the children 7 years. The findings provide insights into the mothers' and children's current sociodemographic characteristics, physical health, socioemotional development and the children's reactions to the absence of a father at follow-up time. The majority of the children raised by these older single mothers have good health. The salient result is that at follow-up, 45% of these older single-mother families comprise a family unit with more than 1 child, clearly demonstrating these families' desire for a larger family than a mother child unit. The desire and attempts of the mothers in the sample to give birth to additional children using assisted conception demonstrate the divergence in the fertility patterns of Israeli society from other developed countries. PMID- 23039351 TI - Evaluating the content and reception of messages from incarcerated parents to their children. AB - In the current study, children's reactions to video messages from their incarcerated parents were evaluated. Previous research has yielded mixed results when it examined the impact of contact between incarcerated parents and their children; one reason for these mixed results may be a lack of attention to the quality of contact. This is the first study to examine the actual content and quality of a remote form of contact in this population. Participants included 186 incarcerated parents (54% mothers) who participated in a filming with The Messages Project and 61 caregivers of their children. Parental mood prior to filming the message and children's mood after viewing the message were assessed using the Positive and Negative Affect Scale. After coding the content of 172 videos, the data from the 61 videos with caregiver responses were used in subsequent path analyses. Analyses indicated that when parents were in more negative moods prior to filming their message, they displayed more negative emotions in the video messages ( = .210), and their children were in more negative moods after viewing the message ( = .288). Considering that displays of negative emotion can directly affect how children respond to contact, it seems important for parents to learn to regulate these emotional displays to improve the quality of their contact with their children. PMID- 23039352 TI - Emerging adults' perspectives on their relationships with mothers with mental illness: implications for caregiving. AB - Guided by a life course perspective, the current study examined whether emerging adults with and without mothers with affective disorders viewed their relationships with their mothers differently, and whether aspects of the emerging adult-mother relationship were associated with reports of caregiving for mothers. Reports from emerging adults with mothers with affective disorders (n = 46) were compared to reports from emerging adults with mothers without mental illness (n = 64). Results indicated that emerging adults with mothers with affective disorders reported significantly lower levels of affection, felt obligation, reciprocity, and future caregiving intentions, and significantly higher levels of role reversal in their relationships with their mothers. Reported current caregiving levels did not differ between emerging adults with and without mothers with affective disorders. Hierarchical multiple regression analyses generally indicated higher levels of felt obligation were associated with higher levels of caregiving, regardless of maternal mental health status. Results and future research directions are discussed from a life course perspective. PMID- 23039353 TI - Parental practices and political violence: the protective role of parental warmth and authority-control in Jewish and Arab Israeli children. AB - Parental warmth and parental authority-control patterns have been documented as practices with highest significance for children's well-being and development in a variety of life areas. Various forms of these practices have been shown to have a direct positive effect on children and also to protect children from adverse effects of numerous stressors. However, surprisingly, few studies have examined the role of these practices as possible protective factors for children exposed to intractable conflict and political violence. Participants in this study were Jewish (n = 88) and Arab (n = 105) Israeli families, with children aged 7-12.5 (M = 10.73, SD = 0.99). Children completed questionnaires assessing political violence exposure, behavioral, psychological, and social difficulties, and perceived paternal and maternal warmth. Mothers and fathers completed questionnaires assessing parental warmth, parental authority-control, and the child's difficulties. Results showed parental warmth to be a significant moderator of political violence, related to low levels of behavioral and social difficulties of children. Parental authority-control patterns were not protectors from adverse effects of political violence exposure. Maternal authoritarian authority-control showed an effect resembling a risk factor. Differential roles of parental warmth and authority-control, fathers' versus mothers' roles, and ethnic differences are discussed, and practical clinical implications are proposed. PMID- 23039354 TI - The impact of abuse and gender on psychopathology, behavioral disturbance, and psychotropic medication count for youth in residential treatment. AB - This study examined the relationship between gender, abuse history, and clinical change in a residential treatment program for youth with emotional and behavioral disturbance. Admission data and data collected after 1 year of treatment or at discharge were examined for 1,303 youth. Measures included the Suicide Probability Scale, Child Behavior Checklist, and the Diagnostic Interview Schedule for Children. Data also included medication count, demographic data, and history of sexual or physical abuse or both. At intake, girls scored significantly more pathologically than boys on 9 out of 12 measures. At intake, abused youth indicated more hostility, anxiety, and mood disorder symptoms as well as psychotropic medication usage than nonabused youth. Youth improved significantly on all outcome measures with treatment, although interaction effects indicate some differing treatment responses by abuse history or gender. After treatment, girls still scored significantly higher than boys on 6 of 8 outcome measures, and abused youth, especially youth experiencing both sexual and physical abuse, had significantly higher anxiety, affective, behavior, and eating disorder symptom counts and were on more psychotropic medications than nonabused youth. Although behaviorally focused treatment was associated with improvement on every measure, the most important implication of our study is that a singular treatment approach does not fit all youth completely as reflected by continuing treatment needs in our most troubled youth. Additional symptom-focused treatment and research attention must be given to girls and abused youth in residential care to maximize their therapeutic outcomes. PMID- 23039356 TI - Effects of mental health disorders on the risk of juvenile justice system involvement and recidivism among children placed in out-of-home care. AB - This study examined the effect of specific mental health disorders on the risk of juvenile justice system involvement and subsequent recidivism among maltreated children placed in out-of-home care. The sample was comprised of all children in Florida aged 7-17 years who were investigated for maltreatment and subsequently placed in out-of-home care between July 1, 2004, and June 30, 2005 (N = 5,720). Presence of mental health disorders and absence of a caregiver were both significantly associated with juvenile justice involvement. Among all examined mental health disorders, conduct disorder was the strongest predictor of juvenile justice involvement. Findings also indicated that, compared to children who did not have identified mental health disorders, children diagnosed with mental health disorders were approximately 80% more likely to experience recidivism. Implications of these findings are discussed. PMID- 23039355 TI - Institutional predictors of developmental outcomes among racially diverse foster care alumni. AB - Child welfare practitioners are confronted with the responsibility of relying on best practice to ensure children in foster care transition successfully into adulthood after leaving the foster care system. Yet, despite recent reforms and efforts to address their needs, research clearly shows that foster care alumni are still more likely to experience negative developmental outcomes compared to adults in the general population. The purpose of this study was to better understand how child-serving systems of care adequately prepare racially diverse foster care alumni to thrive. Controlling for gender, age, placement instability, and circumstances of exit from foster care, study findings highlighted salient racial and ethnic differences relative to which factors predicted the odds of mental health, education, and employment outcomes. Implications for developing and implementing culturally sensitive, evidence-based prevention and intervention programs to promote positive developmental outcomes among racially diverse foster care alumni are discussed. PMID- 23039358 TI - Catalytic enantioselective cross-couplings of secondary alkyl electrophiles with secondary alkylmetal nucleophiles: Negishi reactions of racemic benzylic bromides with achiral alkylzinc reagents. AB - We have developed a nickel-catalyzed method for the asymmetric cross-coupling of secondary electrophiles with secondary nucleophiles, specifically, stereoconvergent Negishi reactions of racemic benzylic bromides with achiral cycloalkylzinc reagents. In contrast to most previous studies of enantioselective Negishi cross-couplings, tridentate pybox ligands are ineffective in this process; however, a new, readily available bidentate isoquinoline-oxazoline ligand furnishes excellent ee's and good yields. The use of acyclic alkylzinc reagents as coupling partners led to the discovery of a highly unusual isomerization that generates a significant quantity of a branched cross-coupling product from an unbranched nucleophile. PMID- 23039360 TI - Hyperglycaemia is associated with impaired pulsatile insulin secretion: effect of basal insulin therapy. AB - AIM: Postprandial insulin pulsatility is impaired in patients with type 2 diabetes, but the effects of exogenous insulin therapy on pulsatile insulin secretion are not known. We addressed, whether pulsatile insulin secretion is related to glycaemic control, whether basal insulin supplementation increases postprandial insulin secretion, and if so, is this accomplished by a specific improvement in pulsatile insulin secretion? METHODS: Fourteen patients with type 2 diabetes underwent a mixed meal test before and after an 8-week treatment period with insulin glargine. Glucose, insulin and C-peptide levels were measured, and insulin pulsatility was determined by deconvolution analysis. RESULTS: Insulin treatment lowered fasting glycaemia from 179.6 +/- 7.5 mg/dl to 117.6 +/- 6.5 mg/dl (p < 0.001). Postprandial insulin and C-peptide levels increased significantly after the treatment period (p < 0.0001). The total calculated insulin secretion rate increased with insulin treatment (p = 0.0039), with non-significant increases in both pulsatile and non-pulsatile insulin secretion. Insulin pulse frequency was unchanged by the intervention. There was an inverse relationship between fasting and postprandial glycaemia and insulin pulse mass (r(2) = 0.51 and 0.56, respectively), whereas non-pulsatile insulin secretion was unrelated to either fasting or postprandial glucose concentrations (r(2) = 0.0073 and 0.031). CONCLUSIONS: Hyperglycaemia in type 2 diabetes is associated with a reduction in postprandial insulin secretion, specifically through a reduction in insulin pulsatility. Reducing chronic hyperglycaemia by basal insulin therapy enhances endogenous beta-cell function in the postprandial state. These data support the use of basal insulin regimens in the pharmacotherapy of overtly hyperglycaemic patients with type 2 diabetes. PMID- 23039361 TI - Editorial comment from Dr Laudone and Dr Silberstein to pelvic lymph node dissection for prostate cancer: adherence and accuracy of the recent guidelines. PMID- 23039359 TI - Research review: maternal prenatal distress and poor nutrition - mutually influencing risk factors affecting infant neurocognitive development. AB - BACKGROUND: Accumulating data from animal and human studies indicate that the prenatal environment plays a significant role in shaping children's neurocognitive development. Clinical, epidemiologic, and basic science research suggests that two experiences relatively common in pregnancy - an unhealthy maternal diet and psychosocial distress - significantly affect children's future neurodevelopment. These prenatal experiences exert their influence in the context of one another and yet, almost uniformly, are studied independently. SCOPE AND METHOD OF REVIEW: In this review, we suggest that studying neurocognitive development in children in relation to both prenatal exposures is ecologically most relevant, and methodologically most sound. To support this approach, we selectively review two research topics that demonstrate the need for dual exposure studies, including exemplar findings on (a) the associations between pregnant women's inadequate maternal intake of key nutrients - protein, fat, iron, zinc, and choline - as well as distress in relation to overlapping effects on children's neurocognitive development; and (b) cross-talk between the biology of stress and nutrition that can amplify each experience for the mother and fetus,. We also consider obstacles to this kind of study design, such as questions of statistical methods for 'disentangling' the exposure effects, and aim to provide some answers. CONCLUSION: Studies that specifically include both exposures in their design can begin to determine the relative and/or synergistic impact of these prenatal experiences on developmental trajectories - and thereby contribute most fully to the understanding of the early origins of health and disease. PMID- 23039362 TI - Expression levels of Lyn, Syk, PLCgamma2 and ERK in patients with chronic lymphocytic leukemia, and higher levels of Lyn are associated with a shorter treatment-free survival. AB - There is now strong evidence that B-cell receptor (BCR) signaling plays a major role in the development of chronic lymphocytic leukemia (CLL). The purpose of this study was to investigate the expression levels of some of the molecules involved in the signaling cascade originating from the BCR (Syk, Lyn, PLCgamma2, ERK) and analyze possible correlations of mRNA levels with biological/clinical features. Our study population consisted of 92 consecutive patients with newly diagnosed CLL. Several genes of BCR signaling (Lyn, Syk, PLCgamma2 and ERK) and ZAP-70 were measured by quantitative polymerase chain reaction (qPCR). The signaling molecules of BCR were strongly associated with each other, and ZAP-70 correlated well with Lyn, Syk, PLCgamma2 and ERK. Associations between treatment response and Lyn, Syk, PLCgamma2 and ERK were not found. Moreover, a higher level of Lyn mRNA was associated with a shorter treatment-free survival (TFS) (univariate analysis only; multivariate Cox analysis showed that only ZAP-70 and Binet stage were independent prognostic factors and associated with TFS). Though Lyn was not an independent prognostic factor, it still might be a new therapy target of CLL. BCR signaling provides perspectives for future development of an exciting new class of kinase inhibitors. PMID- 23039363 TI - Lupus autoimmunity altered by cellular methylation metabolism. AB - Modifications of both DNA and protein by methylation are key factors in normal T and B cell immune responses as well as in the development of autoimmune disease. For example, the failure to maintain the methylation status of CpG dinucleotides in DNA triggers T cell autoreactivity. Methylated proteins are known targets of autoimmunity, including the symmetrical dimethylarginine residues of SmD1 and SmD3 in SLE. Herein, we demonstrate that altering the metabolism of S adenosylmethionine (SAM), the major methyl donor for transmethylation reactions, can suppress T cell immunity. A by-product of SAM metabolism, 5'-deoxy-5' methylthioadenosine (MTA), and an indirect inhibitor of methyltransferases, inhibits T cell responses including T cell activation markers, Th1/Th2 cytokines and TCR-related signaling events. Moreover, treatment of the lupus-prone MRL/lpr mouse with MTA markedly ameliorates splenomegaly, lymphadenopathy, autoantibody titers as well as IgG deposition and cellular infiltration in the kidney. Incubation of cells with SAM, which increases intracellular MTA levels, inhibits both TCR-mediated T cell proliferation and BCR (anti-IgM)-triggered B cell proliferation in a dose-dependent manner. These studies define the central role of MTA and SAM in immune responses and provide a simple approach to altering lymphocyte transmethylation and T cell mediated autoimmune syndromes. PMID- 23039364 TI - Association of COMT Val158Met polymorphism and breast cancer risk: an updated meta-analysis. AB - BACKGROUND: Catechol-O-methyltransferase (COMT) is one of the most important enzymes involved in estrogen metabolism and its functional genetic polymorphisms may be associated with breast cancer (BC) risk. Many epidemiological studies have been conducted to explore the association between the COMT Val158Met polymorphism and breast cancer risk. However, the results remain inconclusive. In order to derive a more precise estimation of this relationship, a large meta-analysis was performed in this study. METHODS: Systematic searches of the PubMed, Embase and Cochrane Library were performed. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. RESULTS: A total of 56 studies including 34,358 breast cancer cases and 45,429 controls were included. Overall, no significant associations between the COMT Val158Met polymorphism and breast cancer risk were found for LL versus HH, HL versus HH, LL versus HL, recessive model LL versus HL+HH, and dominant model LL+HL versus HH. In subgroup analysis by ethnicity, source of controls, and menopausal status, there was still no significant association detected in any of the genetic models. CONCLUSION: Our meta-analysis results suggest that the COMT Val158Met polymorphism may not contribute to breast cancer susceptibility. VIRTUAL SLIDES: The virtual slides(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs4806123577708417. PMID- 23039367 TI - Sorbent coated glass wool fabric as a thin film microextraction device. AB - A new approach for thin film microextraction (TFME) with mixed-phase sorptive coating is presented. Carboxen/polydimethylsiloxane (CAR/PDMS) and polydimethylsiloxane/divinylbenzene (PDMS/DVB) TFME samplers were prepared using spin coating and glass wool fabric mesh as substrate. The samplers were easily tailored in size and shape by cutting tools. Good durability and flat-shape stability were observed during extraction, stirring in water, and thermal desorption. The latter characteristic obviates the need for an extra framed holder for rapid TFME and makes the samplers more robust and easier to deploy. The samplers combine the advantages of adsorptive solid-phase microextraction (SPME) and TFME, including one-step solvent-free extraction and preconcentration, direct thermal desorption, and enhanced sensitivity without sacrificing analysis time due to thin film geometry. The analytical performance of these new devices was demonstrated using water samples spiked with N-nitrosamines (NAs) as model compounds. Over an order of magnitude enhancement of extraction efficiencies was obtained for the model compounds compared with the SPME fibers of similar coatings and PDMS thin film membrane. The results of this study indicate that these novel thin film devices are promising for rapid and efficient microextraction of polar analytes in water. PMID- 23039366 TI - Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). We sought to quantify survival and determine factors predictive of mortality in a cohort of patients with CTD-associated PAH (CTD-PAH) in the current era of advanced PAH therapy. METHODS: Patients with right heart catheter proven CTD-PAH were recruited from six specialised PAH treatment centres across Australia and followed prospectively. Using survival methods including Cox proportional hazards regression, we modelled for all-cause mortality. Independent variables included demographic, clinical and hemodynamic data. RESULTS: Among 117 patients (104 (94.9%) with systemic sclerosis), during 2.6 +/- 1.8 (mean +/- SD) years of follow-up from PAH diagnosis, there were 32 (27.4%) deaths. One-, two- and three-year survivals were 94%, 89% and 73%, respectively. In multiple regression analysis, higher mean right atrial pressure (mRAP) at diagnosis (hazard ratio (HR) = 1.13, 95% CI: 1.04 to 1.24, P = 0.007), lower baseline six-minute walk distance (HR = 0.64, 95% CI: 0.43 to 0.97, P = 0.04), higher baseline World Health Organization functional class (HR = 3.42, 95% CI: 1.25 to 9.36, P = 0.04) and presence of a pericardial effusion (HR = 3.39, 95% CI: 1.07 to 10.68, P = 0.04) were predictive of mortality. Warfarin (HR = 0.20, 95% CI: 0.05 to 0.78, P = 0.02) and combination PAH therapy (HR = 0.20, 95% CI: 0.05 to 0.83, P = 0.03) were protective. CONCLUSIONS: In this cohort of CTD PAH patients, three-year survival was 73%. Independent therapeutic predictors of survival included warfarin and combination PAH therapy. Our findings suggest that anticoagulation and combination PAH therapy may improve survival in CTD-PAH. This observation merits further evaluation in randomised controlled trials. PMID- 23039368 TI - Side-chain-dependent helical conformation of amylose alkylcarbamates: amylose tris(ethylcarbamate) and amylose tris(n-hexylcarbamate). AB - Eight amylose tris(ethylcarbamate) (ATEC) samples ranging in the weight-average molar mass M(w) from 1.0 * 10(4) to 1.1 * 10(6) g mol(-1) and five amylose tris(n hexylcarbamate) (ATHC) samples of which M(w) varies from 4.9 * 10(4) to 2.2 * 10(6) g mol(-1) have been prepared from enzymatically synthesized amylose samples having narrow dispersity indices and no branching. Small-angle angle X-ray scattering (SAXS), light scattering, viscometry, and infrared (IR) absorption measurements were carried out for their dilute solutions, that is, ATEC in tetrahydrofuran (THF), 2-methoxyethanol (2ME), methanol (MeOH), and ATHC in THF and 1-propanol (1PrOH) to determine M(w), particle scattering functions, intrinsic viscosities, and IR spectra. SAXS and viscosity measurements were also made on ATEC in d- and l-ethyl lactates. The data were analyzed in terms of the wormlike cylinder model to estimate the helix pitch (or contour length) per residue h and the Kuhn segment length lambda(-1) (stiffness parameter, twice the persistence length). Both ATEC and ATHC have large lambda(-1) in THF, that is, 33 and 75 nm, respectively, and smaller lambda(-1) were obtained in alcohols, indicating that they have rigid helical conformation stabilized by intramolecular hydrogen bonds in THF. On the contrary, the helical structure estimated from the h value significantly depends on the alkyl side groups in a complex fashion, that is, h = 0.36 nm for ATEC, h = 0.29 nm for ATHC, and h = 0.26 nm for amylose tris(n-butylcarbamate) (ATBC). This is likely related to the bulkiness of side groups packed inside the amylosic helices. The solvent dependence of h, lambda( 1), and the fraction f(hyd) of intramolecular hydrogen bonds for ATEC can be explained by a current model as is the case with ATBC [ Terao , K. ; Macromolecules 2010 , 43 , 1061 ], in which each contour point along the chain takes loose helical and rigid helical sequences independently. PMID- 23039365 TI - Overexpression of CD44 accompanies acquired tamoxifen resistance in MCF7 cells and augments their sensitivity to the stromal factors, heregulin and hyaluronan. AB - BACKGROUND: Acquired resistance to endocrine therapy in breast cancer is a significant problem with relapse being associated with local and/or regional recurrence and frequent distant metastases. Breast cancer cell models reveal that endocrine resistance is accompanied by a gain in aggressive behaviour driven in part through altered growth factor receptor signalling, particularly involving erbB family receptors. Recently we identified that CD44, a transmembrane cell adhesion receptor known to interact with growth factor receptors, is upregulated in tamoxifen-resistant (TamR) MCF7 breast cancer cells. The purpose of this study was to explore the consequences of CD44 upregulation in an MCF7 cell model of acquired tamoxifen resistance, specifically with respect to the hypothesis that CD44 may influence erbB activity to promote an adverse phenotype. METHODS: CD44 expression in MCF7 and TamR cells was assessed by RT-PCR, Western blotting and immunocytochemistry. Immunofluorescence and immunoprecipitation studies revealed CD44-erbB associations. TamR cells (+/- siRNA-mediated CD44 suppression) or MCF7 cells (+/- transfection with the CD44 gene) were treated with the CD44 ligand, hyaluronon (HA), or heregulin and their in vitro growth (MTT), migration (Boyden chamber and wound healing) and invasion (Matrigel transwell migration) determined. erbB signalling was assessed using Western blotting. The effect of HA on erbB family dimerisation in TamR cells was determined by immunoprecipitation in the presence or absence of CD44 siRNA. RESULTS: TamR cells overexpressed CD44 where it was seen to associate with erbB2 at the cell surface. siRNA-mediated suppression of CD44 in TamR cells significantly attenuated their response to heregulin, inhibiting heregulin-induced cell migration and invasion. Furthermore, TamR cells exhibited enhanced sensitivity to HA, with HA treatment resulting in modulation of erbB dimerisation, ligand-independent activation of erbB2 and EGFR and induction of cell migration. Overexpression of CD44 in MCF7 cells, which lack endogenous CD44, generated an HA-sensitive phenotype, with HA-stimulation promoting erbB/EGFR activation and migration. CONCLUSIONS: These data suggest an important role for CD44 in the context of tamoxifen-resistance where it may augment cellular response to erbB ligands and HA, factors that are reported to be present within the tumour microenvironment in vivo. Thus CD44 may present an important determinant of breast cancer progression in the setting of endocrine resistance. PMID- 23039369 TI - Assessment of fluid status in CAPD patients using the body composition monitor. AB - AIMS AND OBJECTIVES: To assess the degree of overhydration in our peritoneal dialysis patients and to examine the factors contributing to overhydration. BACKGROUND: Volume control is critical for the success of peritoneal dialysis, but dry weight has been difficult to ascertain accurately. Chronic fluid overload and hypertension are among the leading causes of mortality in dialysis patients. DESIGN: A cross-sectional observational study. METHODS: The body composition monitor (Fresenius Medical Care, Bad Homburg, Germany) is a bioimpedance spectroscopy device that has been validated for the assessment of overhydration. We used this body composition monitor device on all patients on continuous ambulatory peritoneal dialysis at our institution who met the inclusion criteria to assess their degree of overhydration. RESULTS: Thirty four (17 men, 17 women; mean age 44.5 +/- 14.2 years) of a 45 continuous ambulatory peritoneal dialysis patients were enrolled. The mean overhydration was 2.4 +/- 2.4 l. Fifty per cent of the patients were >=2 l overhydrated. Overhydration correlated with male gender, low serum albumin, increasing number of antihypertensive agents and duration of dialysis. There was no difference in overhydration between diabetic and non-diabetic patients. Men were more overhydrated than women, had lower Kt/V and were older. Although, there was no difference in blood pressure between the genders, men had a trend towards a higher usage of antihypertensive agents. CONCLUSION: Our study demonstrates that overhydration is common in peritoneal dialysis patients. Blood pressure should ideally be controlled with adherence to dry weight and low salt intake rather than adding antihypertensive agents even in the absence of clinical oedema. RELEVANCE TO CLINICAL PRACTICE: Body composition monitor is a simple, reliable and inexpensive tool that can be routinely used in the outpatient clinic setting or home visit to adjust the dry weight and avoid chronic fluid overload in between nephrologists review. PMID- 23039370 TI - Functional outcomes of Vibrant Soundbridge applied on the middle ear windows in comparison with conventional hearing aids. AB - CONCLUSION: Vibrant Soundbridge (VSB) application to the middle ear windows yields better functional outcomes than conventional hearing aids. However, speech discrimination scores obtained with VSB and conventional hearing aids are similar. OBJECTIVE: To assess audiological outcomes of round and oval window applications of VSB in comparison with conventional hearing aids. METHODS: Nineteen adult patients were included in the study. The patients had mild to moderate, moderate or moderate to profound conductive or mixed hearing loss. During surgery the floating mass transducer (FMT) was placed on the round (n = 14) or oval (n = 5) window. After the surgery, audiometric evaluation and free field audiometric evaluation of both ears was carried out. RESULTS: The hearing thresholds in the low frequencies were not significantly different between the conventional hearing aids and VSB. The functional gains obtained with oval and round window approaches were similar except for 500 Hz. The hearing thresholds in the mid and high frequencies were significantly better with VSB than the conventional hearing aids. The functional gain in the low frequencies was not significantly different between VSB and conventional hearing aids. The functional gain in the other frequencies was significantly better with VSB than conventional hearing aids. PMID- 23039371 TI - The effect of posture category salience on decision times and errors when using observation-based posture assessment methods. AB - Observation-based posture assessment methods (e.g. RULA, 3DMatch) require classification of body postures into categories. This study investigated the effect of improving posture category salience (adding borders, shading and colour to the posture categories) on posture selection error rates and decision times of novice analysts. Ninety university students with normal or corrected normal visual acuity and who were not colourblind, were instructed to select posture categories as quickly and accurately as possible, in five salience conditions (Plain (no border, no shading, no colour); Grey Border; Red Border; Grey Shading (GS) and Red Shading (RS)) for images presented in randomised blocks (240 classifications made by each participant) on a computer interface. Participants responded quickest in the Border conditions, classifying postures about 5% faster than in the Plain condition. Coloured diagrams significantly reduced posture classification errors by approximately 1.5%. Overall, the best performance, based on both error rate and decision time combined, resulted from incorporating a Grey Border to the posture category diagrams; a simple enhancement that could be made to most current observation-based posture assessment tools. PRACTITIONER SUMMARY: The salience of posture diagrams used in observation-based posture assessment tools was evaluated with respect to analyst error rates and decision times. The best performance resulted from incorporating a grey border to the posture diagrams; a simple enhancement that can be made to most current observation-based posture assessment tools. PMID- 23039372 TI - Total synthesis of manzamine A and related alkaloids. AB - Total syntheses of three structurally complex marine natural products, manzamine A, ircinol A, and ircinal A, are reported. The route pivoted on the construction of a late-stage protecting-group-free pentacyclic enol triflate coupling partner, from which all three family members were accessed divergently via palladium catalyzed reactions. The rapid synthesis of this key pentacyclic enol triflate was achieved by a highly convergent union of five fragments through a stereoselective Michael addition, a three-component nitro-Mannich lactamization cascade, an unprecedented and highly stereoselective reductive nitro-Mannich cyclization cascade, a stereoselective organometallic addition, and a Z-selective alkene ring-closing metathesis. Altogether this chemistry has allowed the shortest synthetic route to date for manzamine A (18-step longest linear sequence) via a late-stage diversification point that is ideal for future manzamine A analogue synthesis. PMID- 23039373 TI - Early neonatal outcomes of volume guaranteed ventilation in preterm infants with respiratory distress syndrome. AB - BACKGROUND: Volume guaranteed (VG) synchronized intermittent mandatory ventilation (SIMV) is a novel mode of SIMV that provides automatic adjustment of the peak inspiratory pressure for ensuring a minimum set tidal volume and there are limited data about the effects of VG ventilation on short term neonatal outcomes in preterm infants with respiratory distress syndrome (RDS). OBJECTIVE: The main objective of this study was to evaluate the effect of VG ventilation on duration of ventilation and total supplemental oxygen. We also aimed to compare the early neonatal outcomes of VG ventilation versus conventional SIMV on short term outcomes in preterm babies with RDS who were given surfactant. METHODS: In this randomized controlled study, preterm infants who were admitted with RDS and given surfactant were divided into 2 groups: group 1 included infants ventilated on conventional SIMV (n = 30) and group 2 included infants ventilated on VG ventilation (n = 42). Neonatal morbidities such as air leak, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC) and duration of mechanical ventilation and total oxygen supplementation were all recorded. RESULTS: There were no significant differences between two groups in terms of demographic features. Infants ventilated with VG mode had significantly shorter duration of ventilation and need of total supplemental oxygen. The incidences of oxygen related short term complications including BPD, ROP, and IVH were also significantly lower in these infants compared with those ventilated with conventional SIMV. No significant differences were found between two groups with respect to NEC and air leak. CONCLUSION: In conclusion, VG ventilation in combination with surfactant treatment significantly reduced both duration of mechanical ventilation and early neonatal oxygen related morbidities including BPD, ROP and IVH in preterm infants with RDS. This data favors the use of VG ventilation in respiratory support of premature infants. PMID- 23039374 TI - Breakdown of high-performance monolayer MoS2 transistors. AB - Two-dimensional (2D) materials such as monolayer molybdenum disulfide (MoS(2)) are extremely interesting for integration in nanoelectronic devices where they represent the ultimate limit of miniaturization in the vertical direction. Thanks to the presence of a band gap and subnanometer thickness, monolayer MoS(2) can be used for the fabrication of transistors exhibiting extremely high on/off ratios and very low power dissipation. Here, we report on the development of 2D MoS(2) transistors with improved performance due to enhanced electrostatic control. Our devices show currents in the 100 MUA/MUm range and transconductance exceeding 20 MUS/MUm as well as current saturation. We also record electrical breakdown of our devices and find that MoS(2) can support very high current densities, exceeding the current-carrying capacity of copper by a factor of 50. Our results push the performance limit of MoS(2) and open the way to their use in low-power and low cost analog and radio frequency circuits. PMID- 23039375 TI - Pharmacological evaluation of a beta-hydroxyphosphonate analogue of l-carnitine in obese Zucker fa/fa rats. AB - In this study, we evaluated the effect of an analogue of l-carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty-four rats were treated for 5 weeks with l-carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l-carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l-carnitine and improves the pharmacological profile of l-carnitine. PMID- 23039376 TI - Mizoribine requires individual dosing due to variation of bioavailability. AB - BACKGROUND: Mizoribine (MZR) is an immunosuppressant used for the treatment of glomerular diseases, but there are few reports on the pharmacokinetics of MZR in children. METHODS: First, we performed a pharmacokinetic study on nine childhood onset glomerular disease patients. The MZR dosages ranged from 1.8 to 14.5 mg/kg/dose. Pharmacokinetic parameters were analyzed using 38 MZR concentration time curves. Second, nine patients who were newly treated with MZR were enrolled to validate the findings obtained from prior investigation. RESULTS: In the prior study, peak serum MZR concentration (C(max) ) was dose-dependent in each patient. Although proportionality between dosage and C(max) was observed in each patient, the regression coefficient was in a wide range from 0.075 to 1.04 and was specific to each patient. This variability was likely caused by individual variation of bioavailability. When the optimal time-point to monitor C(max) was investigated, the time-to-reach peak serum MZR concentration (T(max)) was similar among all the patients, which was from 2.5 to 3.5 h after administration of MZR. T(max) was most frequently observed at 3 h and the serum MZR concentration ratio relative to C(max) at 3 h was also highest (0.93 +/- 0.07). In the following study, it was validated that monitoring C(3) is reproducible and reliable after adjusting the dosage of MZR to obtain target serum concentration. CONCLUSION: Individual dosing is required to optimize C(max) in childhood-onset glomerular disease patients. The safe dosage of MZR for each patient could be predicted by evaluating the serum MZR concentration 3 h after administration. PMID- 23039377 TI - Ipsilateral adrenalectomy at the time of radical nephrectomy impacts overall survival. AB - Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Adrenal-sparing approaches should be utilized when performing radical nephrectomy unless there are specific concerns for adrenal involvement. Although current literature demonstrates 10-year cancer control equivalence with adrenal-sparing approaches, such approaches remain under used. Furthermore, we have yet to clearly define the long-term consequences of an iatrogenic solitary adrenal gland on overall patient health. In our study, we demonstrate worse overall survival in patients undergoing ipsilateral adrenalectomy with radical nephrectomy for renal cell carcinoma. We provide some of the only data demonstrating an association between adrenalectomy and long-term survival, and further emphasize the importance of adrenal-sparing approaches when performing radical nephrectomy. OBJECTIVE: To assess the impact of ipsilateral adrenalectomy on overall survival, we performed a population-level analysis. Ipsilateral adrenal-gland-sparing approaches during radical nephrectomy (RN) remain under-utilized and the long-term consequences of an iatrogenic solitary adrenal gland are poorly understood. PATIENTS AND METHODS: Using the Ontario Cancer Registry we identified 1651 patients in the province of Ontario, Canada, with pT1a renal cell carcinoma who underwent RN between 1995 and 2004. We linked individual patient information with pathological data from abstracted pathology reports and determined whether the ipsilateral adrenal gland was removed at the time of RN. We utilized univariable and multivariable (adjusting for age, gender, tumour size and tumour grade) Cox proportional hazard models and Kaplan-Meier curves to assess predictors of overall and cancer-specific survival. RESULTS: The overall rate of ipsilateral adrenalectomy at the time of RN was 30%. Median follow-up for the cohort was 109 months. Adrenal removal was associated with worse overall survival: 10-year mortality 26% compared with 20% for those in whom the adrenal gland was left in situ. Factors predictive of worse overall survival on multivariable analysis were increasing age (hazard ratio [HR] 1.07 per year, CI 1.06-1.08), high grade tumours (HR 1.38, 1.00-1.90) and having undergone ipsilateral adrenalectomy (HR 1.23, 1.00-1.50). Ipsilateral adrenalectomy was not predictive of cancer-specific survival (HR 1.18, 0.78-1.79). CONCLUSIONS: We demonstrated a significant association between ipsilateral adrenalectomy and overall survival. Our findings further support the importance of adrenal-sparing approaches at the time of RN. PMID- 23039378 TI - Mohs micrographic surgery for basal cell carcinomas: appropriateness of 'Rotterdam' criteria and predictive factors for three or more stages. AB - BACKGROUND: In the Netherlands basal cell carcinomas (BCC) are eligible for Mohs microscopic surgery (MMS) if certain criteria are fulfilled. OBJECTIVE: To study the MMS indication criteria practised at the department of dermatology of the Erasmus University Medical Center, Rotterdam and to identify predictive factors for extensive subclinical tumour spread among BCCs eligible for MMS. METHODS: Pre operative patient and tumour characteristics were derived retrospectively between January 2nd 2006 and December 28th 2009 from 1174 patient records, accounting for 1464 BCCs. Multivariate logistic regression models were used to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) for one vs. two or more stages and for narrow (<= 2 stages) vs. extensive subclinical spread (>= 3 stages). RESULTS: H-zone location [adjusted OR 1.51 (95% CI 1.16-1.96)], recurrent tumour [adjusted OR 1.50 (95% CI 1.11-2.02)], aggressive subtype [adjusted OR 1.25 (95% CI 1.01-1.56)] and tumour size >= 11 mm [adjusted OR 1.53 (95% CI 1.20-1.96)] were significantly associated with two or more stages. Predictive factors for extensive subclinical spread were recurrent tumour [adjusted OR 2.26 (95% CI 1.61-3.17)], tumour size >= 21 mm [adjusted OR 1.69 (95% CI 1.13-2.51)] and location in the H-zone [adjusted OR 1.68 (95% CI 1.15 2.46)]. CONCLUSION: 'Rotterdam' indication criteria used for MMS are appropriate. Predictors for extensive subclinical spread are important for patients' and surgeons' expectations prior to the operation about time span, defect size, reconstruction and possible associated morbidity. PMID- 23039380 TI - Serum free light chains as predictors of lymphomagenesis in patients with autosomal dominant hyper-immunoglobulin E syndrome (Job's syndrome). PMID- 23039379 TI - The I405V and Taq1B polymorphisms of the CETP gene differentially affect sub clinical carotid atherosclerosis. AB - BACKGROUND: Cholesteryl ester transfer protein (CETP) plays a major role in lipid metabolism, but studies on the association of CETP polymorphisms with risks of cardiovascular disease are inconsistent. This study investigated whether the CETP gene I405V and Taq1B polymorphisms modified subclinical atherosclerosis in an asymptomatic Brazilian population sample. METHODS: The polymorphisms were analyzed using polymerase chain reaction in 207 adult volunteers. Serum lipid profiles, oxLDL Ab titers, C-reactive protein and tumor necrosis factor-alpha concentrations and CETP and phospholipid transfer protein (PLTP) activities were determined, and common carotid artery intima-media thickness (cIMT) was measured using ultrasonography. RESULTS: No differences in cIMT were observed between the presence or absence of the minor B2 and V alleles in either polymorphism. However, inverse correlations between mean cIMT and CETP activity in the presence of these polymorphisms were observed, and positive correlations of these polymorphisms with PLTP activity and oxLDL Ab titers were identified. Moreover, logistic multivariate analysis revealed that the presence of the B2 allele was associated with a 5.1-fold (CI 95%, OR: 1.26 - 21.06) increased risk for cIMT, which was equal and above the 66th percentile and positively interacted with age. However, no associations with the V allele or CETP and PLTP activities were observed. CONCLUSIONS: None of the studied parameters, including CETP activity, explained the different relationships between these polymorphisms and cIMT, suggesting that other non-determined factors were affected by the genotypes and related to carotid atherosclerotic disease. PMID- 23039383 TI - Can botulinum toxin improve mood in depressed patients? AB - Depression has a number of significant symptoms such as depressed mood, lack of volition/energy, suicidal ideation, low concentration, sleep disturbance, anger, anxiety, psychomotor retardation, fear and sadness. In addition, various facial expressions such as frowning and sadness can also be easily recognized in depressed patients. In fact, major muscles involved in the development of such negative emotion have been reported in depressed patients, for instance, corrugators and procerus muscles in the glabellar regions of the face. Electromyography studies have also reported that depressed patients had overactivity of such grief muscles during different affective imagery paradigms. Furthermore, subjective emotion has also been found to be affected by differential facial expression via an image feedback system. Interestingly, anecdotal open-label studies have shown that botulinum toxin may have a role in treatment of depression and a recent randomized-placebo controlled study has also confirmed the effect of botulinum toxin in reduction of depressive symptoms for the first time. This article will discuss the putative role of botulinum toxin in a treatment of depression in the context of the clinical significance, limitations and future research directions. PMID- 23039381 TI - Therapeutic implications of protein homeostasis in demyelinating peripheral neuropathies. PMID- 23039384 TI - The multiple sclerosis depression rating scale. AB - Depression is a troublesome issue in the lives of people with multiple sclerosis (MS). However, there are many questions about how to measure depression in people with MS. Depression is a syndrome that is characterized by emotional, cognitive and somatic symptoms. Depression scales are usually designed to cover each of these domains but in MS there is concern that cognitive deficits and somatic symptoms related to the illness itself may inflate depressive symptom scores, potentially leading to false-positive ratings. Such misclassification may consume excessive resources in screening programs due to the triggering of unnecessary clinical assessments. In research, such misclassification could lead to bias. In an effort to address these issues, the authors of the article under evaluation have recently developed a new scale, the Multiple Sclerosis Depression Rating Scale. PMID- 23039385 TI - Deciphering the task of N-acetyl aspartate in migraine. AB - Migraine is a common neurological disorder producing significant personal and societal burden. In the evaluated study, serum concentrations of N-acetyl aspartate (NAA), a biomarker of neuronal integrity, was found to be decreased in patients suffering from migraine with aura. These interesting results suggest a dual clinical readout. Since migraine-with-aura patients show an increased risk for stroke; the evaluation of serum levels of NAA is crucial in the control of the conventional risk factors. In addition, the therapeutic metabolite monitoring of NAA may be helpful in the assessment of the chronicization process. PMID- 23039386 TI - Neurodegeneration in multiple sclerosis: novel treatment strategies. AB - In recent years it has become clear that the neuronal compartment already plays an important role early in the pathology of multiple sclerosis (MS). Neuronal injury in the course of chronic neuroinflammation is a key factor in determining long-term disability in patients. Viewing MS as both inflammatory and neurodegenerative has major implications for therapy, with CNS protection and repair needed in addition to controlling inflammation. Here, the authors' review recently elucidated molecular insights into inflammatory neuronal/axonal pathology in MS and discuss the resulting options regarding neuroprotective and regenerative treatment strategies. PMID- 23039387 TI - Commercially available accelerometry as an ecologically valid measure of ambulation in individuals with multiple sclerosis. AB - Ambulatory impairment is a prevalent consequence of multiple sclerosis (MS) that is often measured in controlled contexts using performance tests that lack ecological validity. This underscores the importance of considering alternative, ecologically valid approaches, such as commercially available accelerometers, for measuring community ambulation in individuals with MS. This consideration is warranted based on problems with existing measures of ambulation in MS (e.g., poor responsiveness and patient-clinician discordance); conceptual associations among MS pathology, impairment and gait function with relevance for the signal detected by accelerometers; assumptions that are empirically supported for the application of commercially available accelerometers as a measure of community ambulation; and evidence supporting the output of commercially available accelerometers as a measure of ambulation. Collectively, the authors believe the time is ripe for the application of commercially available accelerometers as an outcome measure of community ambulation in MS. Such an application has the potential to maximize the understanding of ambulatory impairments in real-world conditions for clinical research and practice involving individuals with MS. PMID- 23039388 TI - Behavioral interventions in multiple sclerosis: a biopsychosocial perspective. AB - Managing uncertainty is a major challenge associated with the diagnosis of multiple sclerosis (MS). In addition to physical symptoms, neuropsychiatric symptoms are highly prevalent in this disease. Depression in particular is more common in MS than in other chronic diseases. While substantial achievements have been made in the therapy of MS and an increasing number of immunomodulatory treatments are now available, the long-term benefits of these are still a matter of debate. Importantly, while the approved therapies show good efficacy on inflammatory lesions and relapse rate, and may slow certain aspects of disease progression, improvements in function have rarely been reported. On the other hand, behavioral interventions have recently been shown to significantly improve fatigue and depression as well as motor function. In addition, recent evidence suggests that group education or face-to-face behavioral interventions may decrease inflammatory disease activity (such as relapse rate or lesion formation measured by MRI). Therefore, behavioral interventions not only ameliorate symptoms but may have the potential to modify the disease process itself. PMID- 23039389 TI - Vitamin D in multiple sclerosis: implications for assessment and treatment. AB - Epidemiological and experimental evidence suggest that a poor vitamin D status is associated with an increased risk of developing multiple sclerosis (MS), and also an unfavorable disease course. Vitamin D may exert relevant effects both on the immune system and on resident cells within the CNS. The data from clinical trials is, however, restricted, and does not allow any conclusion on the effect of high dose vitamin D supplementation on disease course. The results from sufficiently powered studies will not be available for at least 2 years. MS patients are, however, prone to develop osteoporosis and have increased risk of fractures. Therefore, the authors advise that the serum concentration of 25-hydroxyvitamin D is monitored in order to prevent bone deficit, and that a serum level of 75-125 nmol/l is targeted. This level is sufficient for maintenance of bone health, is not known to be associated with adverse events, and is in the range that has been associated with low risk of developing MS and low disease activity. PMID- 23039390 TI - Disease-specific therapy of idiopathic inflammatory demyelinating disorders. AB - Central nervous system idiopathic inflammatory demyelinating disorders are a heterogenous group of diseases that share inflammation and demyelination as key features. Although the exact pathophysiology remains to be fully unveiled, these conditions are challenging to clinicians who seek specific therapeutic options for their patients. For two of these conditions, multiple sclerosis and neuromyelitis optica, there are now several possible therapies in an ever evolving field. This review will touch on the various idiopathic inflammatory demyelinating disorders and discuss the various treatment options currently available. PMID- 23039391 TI - Hypnic headache and caffeine. AB - Hypnic headache (HH) is a rare primary headache disorder primarily affecting patients over the age of 50 years. This headache entity occurs exclusively at night almost always at the same time. Imaging data as well as the strict circadian rhythm of headache attacks suggest a hypothalamic involvement in the underlying pathophysiology of this headache disorder. One interesting clinical feature about HH is its therapeutic response to caffeine as an acute as well as prophylactic agent. This review addresses the efficacy of caffeine in HH as well as in other headache disorders, and attempts to give insight into the analgesic properties of this substance. In addition, it depicts possible problems of caffeine consumption with regard to headache. PMID- 23039392 TI - The pharmacological treatment of migraine in children and adolescents: an overview. AB - The appropriate treatment of migraine requires an individually tailored approach and is based on bio-behavioral, nonpharmacological and pharmacological methods. The available data in the pertinent literature on pharmacologic approaches are few and contradictory. Drug approaches for migraine attack include acetaminophen, NSAIDs and triptans. Acetaminophen and ibuprofen are often effective, but some migraine attacks may be refractory. The triptans can be a useful therapeutic option in adolescents. The literature data on prophylaxis are conflicting: flunarizine and topiramate are probably effective; for other drugs (including cyproheptadine, amitriptyline, divalproate and levetiracetam) there is insufficient evidence in children. The results from the use of propranolol are conflicting, whereas nimodipine and clonidine have been shown to be noneffective. Further studies are needed based on larger samples, multicenter trials, patient selection from primary care centers, and precise respect of current international diagnostic criteria. Moreover, new parameters of treatment efficacy should be considered. PMID- 23039396 TI - Pooling expressed breastmilk to provide a consistent feeding composition for premature infants. AB - OBJECTIVE: We hypothesized that pooling a mother's expressed breastmilk for 24 hours compared with individual pump session collection of milk would provide a more consistent caloric product without increasing bacterial contamination. STUDY DESIGN: We investigated 24-hour pooled breastmilk collection by enrolling 19 mothers who were expressing milk for their infants. Mothers followed a standardized milk collection protocol for 4 study days: daily milk was pooled in a sterile 1-L bottle on Day 1, and on Day 2 milk was aliquoted for each pump session into a sterile 120-mL container. The next week the order of collection was reversed. Milk samples were plated, incubated, and evaluated for bacteria colonization. Milk samples were analyzed for protein, fat, and carbohydrate content. RESULTS: There was inherently less variability in the caloric and nutrient content of pooled milk compared with individual samples, in which caloric density varied by as much as 29%. Mother's milk had highly variable bacterial counts ranging from 0 to greater than 100,000 colonies/mL. High bacteria counts (>100,000 colonies/mL) occurred in 14.7% (31 of 211) of individual samples compared with 8.6% (three of 35) of pooled samples (p=0.39). CONCLUSIONS: Twenty-four-hour pooling of human milk reduces nutrient and caloric variability without increasing bacterial counts. PMID- 23039395 TI - A comparative evaluation of dimensional stability of three types of interocclusal recording materials-an in-vitro multi-centre study. AB - BACKGROUND: The introduction of different interocclusal recording materials has put clinicians in dilemma that which material should be used in routine clinical practice for precise recording and transferring of accurate existing occlusal records for articulation of patient's diagnostic or working casts in the fabrication of good satisfactory prosthesis. In the era of developing world of dentistry the different materials are introduced for interocclusal record with different brand names because of this; the utility of the material is confusing for successful delivery of prosthesis with lack of in vitro or in vivo studies which will predict the property of the material with utility recommendations. PURPOSE OF THE STUDY: The aim of this multicenter research is to evaluate the time dependent linear dimensional stability of three types of interocclusal recording materials; which gives very clear idea to clinicians in regard to its usage in routine practice and recommendations for usage of the different materials. Also to find out ideal time for articulation of three types of interocclusal recording materials with accuracy. MATERIALS AND METHOD: Commercially available and ADA approved Polyether bite registration paste (Ramitec), Poly vinyl siloxane bite registration paste (Jetbite) and Zinc oxide eugenol (ZOE) bite registration paste (Super bite) were used in the study.A stainless steel die was made according to modified American dental Associations (ADA) specification no. 19. Each one of the tested materials were manipulated according to manufacturers' instructions. The materials separated from die, 3 mins after their respective setting time, resulted in disks of standard diameter. Two parallel lines and three perpendicular lines reproduced on the surface. The distance between two parallel lines was measured at different time intervals i.e. 1 hour, 24, 48 and 72 hours by using travelling microscope (magnus) and compared with standard die measurements made according to ADA specification no.19 to find out the dimensional stability of these interocclusal recording materials. Total 120 samples were made for observation and results were subjected to statistical analysis. Statistical analysis was performed using analysis of variance (ANOVA) and then Tukey's Honestly Significant Difference (HSD) test for comparison among groups at the 0.05 level of significance. After statistical analysis of the data, results were obtained and analyzed for interpretation. RESULTS: The results shows significant difference between the dimensional stability of all three material at different intervals with p-value <0.05. Comparatively the polyether bite registration material showed less distortion with good dimensional stability compared to Poly vinyl siloxane bite (Jetbite), Zinc oxide eugenol(ZOE) bite (Super bite) at 1 hour, 24, 48, and 72 hours. CONCLUSION: The dimensional stability decreased with increase in time and is influenced by both material factor and time factor. Polyether was found to be more dimensionally stable interocclusal recording material, which was followed by Silicone and Zinc oxide eugenol (ZOE). The dimensional stability of Polyether was good. Zinc oxide eugenol is dimensionally more unstable when compared with polyether and polyvinyl siloxane. We recommend that the polyether interocclusal records must be articulated within 48 hours and Polyvinylsiloxane interocclusal records must be articulated within 24 hours and the ZOE should be articulated within 1 hour to get a correct restoration to have very minimum distortion and maximum satisfaction without failure of prosthesis. PMID- 23039397 TI - Simultaneous breast expression in breastfeeding women is more efficacious than sequential breast expression. AB - INTRODUCTION: Simultaneous (SIM) breast expression saves mothers time compared with sequential (SEQ) expression, but it remains unclear whether the two methods differ in milk output efficiency and efficacy. SUBJECTS AND METHODS: The Showmilk device (Medela AG, Baar, Switzerland) was used to measure milk output and milk ejection during breast expression (electric pump) in 31 Australian breastfeeding mothers of term infants (median age, 19 weeks [interquartile range, 10-33 weeks]). The order of expression type (SIM/SEQ) and breast (left/right) was randomized. RESULTS: SIM expression yielded more milk ejections (p <= 0.001) and greater amounts of milk at 2, 5, and 10 minutes (p <= 0.01) and removed a greater total amount of milk (p <= 0.01) and percentage of available milk (p<0.05) than SEQ expression. After SIM expression the cream content of both the overall (8.3% [p <= 0.05]) and postexpression (12.6% [p <= 0.001]) milk were greater. During SEQ expression, the breast expressed first had a shorter time to 50% and 80% of the total amount of milk than the breast expressed second (p <= 0.05), but, overall, a similar percentage of available milk was removed from both breasts. CONCLUSIONS: SIM expression stimulated more milk ejections and was a more efficient and efficacious method of expression, yielding milk with a higher energy content. PMID- 23039398 TI - The effect of advanced maternal age upon human milk fat content. AB - BACKGROUND: Little is known about the effect of maternal age on human milk (HM) composition. This study was designed to study fat content, estimated by creamatocrit (CMT), in HM collected in the first 2 weeks of life in older (>= 35 years) compared with younger (<35 years) mothers. STUDY DESIGN AND METHODS: Ninety lactating mothers (48 older, 42 younger) of newborns were recruited within the first 3 days of delivery. CMTs were measured at 72 hours, 7 days, and 14 days after delivery for HM in a capillary tube after centrifugation at 5,366 g for 5 minutes. RESULTS: The groups did not differ in terms of maternal height and diet, infant birth weight, gestational age (GA), or pregnancy weight gain. They differed significantly in terms of maternal age and parity. Mean colostrum CMT was significantly higher in the group of older mothers. Colostrum CMT correlated positively with maternal age (R(2)=0.11, p=0.006) and inversely with GA (R(2)=0.1, p=0.03) but did not relate with either maternal weight or body mass index. CMT at age 7 days and 2 weeks was not affected by maternal age or GA. In multivariate regression analysis colostrum CMT correlated significantly only with maternal age and GA (R(2)=0.3, p<0.001). CONCLUSIONS: Colostrum fat content of older mothers is much higher than that of younger mothers and inversely related with GA at delivery. This increase in colostrum fat content obtained from mothers with advanced age may be due to increased fat synthesis and excretion in milk, reduced water content of milk, or a combination of both. PMID- 23039399 TI - Breastfeeding practice and its association with respiratory symptoms and atopic disease in 1-3-year-old children in the city of Riyadh, central Saudi Arabia. AB - BACKGROUND: Saudi Arabia has a declining rate of breastfeeding and increasing levels of childhood asthma and atopic disease. In highly economically developed countries, breastfeeding of children at high risk of atopic disease reduces the likelihood of atopic dermatitis, wheezing associated with respiratory infections, and possibly asthma. This study investigated the prevalence of breastfeeding and its association with wheezing/asthma and atopic disease in 1-3-year-old children in Riyadh, Saudi Arabia. SUBJECTS AND METHODS: A cross-sectional study of children attending routine "well-baby" clinics in three Saudi State Hospitals in Riyadh. An interviewer administered a questionnaire to collect data on sociodemographics, breastfeeding, wheezing symptoms, asthma, and atopic disease. RESULTS: In total, 622 children 1-3 years old were recruited. Of these, 75% of children were ever breastfed, and 36% of children were fully breastfed, with 20% of children being fully breastfed for >= 3 months. Increasing duration of full breastfeeding was associated with a reduced likelihood of maternal reporting of her child having "ever wheezed," "wheezed' in the last 12 months," and "ever having asthma," with adjusted odds ratio for full breastfeeding >= 12 months versus never breastfed of 0.51 (95% confidence interval 0.29-0.90), 0.48 (0.26 0.88), and 0.46 (0.22-0.94), respectively. No associations were demonstrable between full or ever breastfeeding and atopic dermatitis/eczema, irrespective of family history of atopic disease. CONCLUSIONS: Although breastfeeding does not protect children from developing eczema in Riyadh, full breastfeeding is associated with reduced childhood wheezing and possibly asthma. Further efforts should be made to promote breastfeeding in Saudi Arabia. PMID- 23039400 TI - Is maternal depressive symptomatology effective on success of exclusive breastfeeding during postpartum 6 weeks? AB - AIM: The aim of this prospective study was to examine the relationship between success of exclusive breastfeeding and postpartum depressive symptomatology. Our hypothesis was that mothers with depressive symptoms initially fail exclusive breastfeeding. SUBJECTS AND METHODS: One hundred ninety-seven mothers were enrolled in the study. The participants were interviewed twice. The first visit was within the first 48 hours after birth. The Edinburgh Postnatal Depression Scale (EPDS) was completed by the participants. The second interview was performed at 6 weeks. Participants answered questions regarding methods of breastfeeding for 6 weeks, any methodological problems, and nipple pain. The EPDS was again completed by the participants at 6 weeks. All newborns were term infants. RESULTS: All the participants were divided into two groups: exclusive breastfeeding and mixed-feeding (partial breastfeeding and/or bottle feeding). Both groups were compared in terms of features, such as mode of delivery, parity, prevalence of depressive symptomatology (at 48 hours and 6 weeks), and delayed onset of lactation within the first 48 hours. Statistical significance was found for only three variables: delayed onset of lactation within the first 48 hours, gestational age, and the problems related to breastfeeding methods. CONCLUSIONS: Clinicians should pay special attention to any lactation difficulty during the first week postpartum. Early lactation difficulties are associated with greater risk of early termination of breastfeeding and lower breastfeeding success. PMID- 23039393 TI - Elevated immune-inflammatory signaling in mood disorders: a new therapeutic target? AB - Converging translational evidence has implicated elevated immune-inflammatory signaling activity in the pathoetiology of mood disorders, including major depressive disorder and bipolar disorder. This is supported in part by cross sectional evidence for increased levels of proinflammatory eicosanoids, cytokines and acute-phase proteins during mood episodes, and prospective longitudinal evidence for the emergence of mood symptoms in response to chronic immune inflammatory activation. In addition, mood-stabilizer and atypical antipsychotic medications downregulate initial components of the immune-inflammatory signaling pathway, and adjunctive treatment with anti-inflammatory agents augment the therapeutic efficacy of antidepressant, mood stabilizer and atypical antipsychotic medications. Potential pathogenic mechanisms linked with elevated immune-inflammatory signaling include perturbations in central serotonin neurotransmission and progressive white matter pathology. Both heritable genetic factors and environmental factors including dietary fatty-acid composition may act in concert to sustain elevated immune-inflammatory signaling. Collectively, these data suggest that elevated immune-inflammatory signaling is a mechanism that is relevant to the pathoetiology of mood disorders, and may therefore represent a new therapeutic target for the development of more effective treatments. PMID- 23039401 TI - Knowledge, attitude, and practices regarding early start of breastfeeding among pregnant, lactating women and healthcare workers in El-Minia University Hospital. AB - BACKGROUND: Breastfeeding within the first hour of life is a potential mechanism for health promotion and is considered to be an indicator of excellence of breastfeeding. This study was conducted to evaluate the knowledge, attitude, and practice regarding early breastfeeding initiation within the first hour of life in both the Pediatrics and Gynecology and Obstetrics Departments of Minia University Hospital, Minia, Egypt. SUBJECTS AND METHODS: A study was conducted on four groups of participants from both the Pediatrics and Gynecology and Obstetrics Departments of Minia University Hospital, each of them consisting of 30 individuals, using a questionnaire to assess the knowledge, attitude, and practice regarding early breastfeeding initiation for each group. RESULTS: Sixty percent of women delivered by spontaneous vaginal delivery and 16.7% of those delivered by cesarean section initiated breastfeeding within 30 minutes to 1 hour after birth. Forty percent of lactating women delivered by spontaneous vaginal delivery, 83.3% of lactating women delivered by cesarean section, and 36.7% of healthcare workers used prelacteal feed instead of early breastfeeding initiation. The most important factors affecting the breastfeeding initiation were maternal illness followed by immediate skin-to-skin contact. CONCLUSIONS: Although the majority of women participating in this study exhibited knowledge about early breastfeeding initiation, actual application of this practice was clearly deficient. In order to improve the rates of breastfeeding initiation within the first hour of life we should enhance vaginal delivery and prenatal classes and implement Baby-Friendly Hospital Initiative policies in both the Pediatrics and Gynecology and Obstetrics Departments of Minia University Hospital. PMID- 23039403 TI - Sitagliptin added to previously taken antidiabetic agents on insulin resistance and lipid profile: a 2-year study evaluation. AB - The aim of this study was to evaluate whether the positive effects of sitagliptin on glycemic control and insulin resistance were maintained also after 2 years of therapy and whether sitagliptin could be effective also in improving lipid profile. In this randomized, double-blind, placebo-controlled trial, 205 patients with type 2 diabetes in therapy with different antidiabetic drugs were randomized to add sitagliptin 100 mg once a day or placebo to their current therapy. We evaluated at the baseline and after 6, 12, 18, and 24 months the following parameters: body mass index, glycated hemoglobin (HbA1c ), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (Tg). Sitagliptin, added to previously taken antidiabetic agents, proved to be effective in improving glycemic profile, reducing HbA1c by -17.5%, FPG by -12.7%, PPG by -20.5%. Regarding insulin resistance, sitagliptin decreased FPI by -8.3% and HOMA-IR by 20.0%, confirming that what have been already reported in short-term studies can be applied also after 2 years of treatment. Sitagliptin also reduced body weight by -4.3%. Our study also showed the positive effect of sitagliptin on lipid profile; in particular, sitagliptin decreased TC by -13.3%, LDL-C by -20.4%, and Tg by -32.3%, and also increased HDL-C by + 13.6%. Sitagliptin proved to be effective on glycemic profile and insulin resistance even after 2 years of therapy and to be effective in improving body weight and lipid profile. PMID- 23039404 TI - Investigation of perceived image quality and colourfulness in mobile displays for different cultures, ambient illumination, and resolution. AB - This study explored the effects of culture, ambient illumination, and resolution on perceived image quality and colourfulness of mobile displays. Thirty Taiwanese and 30 American students participated in the experiment. Two types of culture (Taiwanese and American), two types of illumination level (1500 lux and 7000 lux), and five types of resolution level (320*240, 260*208, 200*160, 140*112, and 80*64) were investigated in the experiment. Interactions between culture and resolution, and between illumination and resolution, were found for both perceived image quality and colourfulness. The results indicated that subjects were able to detect smaller differences in perceived image quality but not for colourfulness, and Taiwanese subjects could detect smaller differences than could the American subjects for both perceived image quality and colourfulness. The results further indicated that Taiwanese subjects were able to detect smaller differences at most of the resolution levels for colourfulness in 1500 lux than were the American subjects. PRACTITIONER SUMMARY: This study found, from culture differences and ergonomics considerations, that Taiwanese subjects could detect smaller differences than could American subjects when evaluating perceived image quality and colourfulness on mobile displays. Mobile display manufacturers can use the results of this study as a reference for future mobile display design. PMID- 23039405 TI - Accurate measurements of infinite dilution activity coefficients using gas chromatography with static-wall-coated open-tubular columns. AB - Wall-coated open-tubular (WCOT) columns provide higher column efficiency and lower solute interfacial adsorption effect than packed columns. However, previous efforts used to measure the infinite dilution activity coefficient (gamma(infinity)) via a chromatographic technique have used packed columns, because the low carrier gas flow rate (U) and the small stationary phase amount (n(2)) in WCOT columns raise large errors. By rationally revising the gamma(infinity)-calculation equation for static-wall-coated open-tubular column, we observed that U and n(2) are not necessarily needed and the resulting error could be reduced, and WCOT column gas chromatography subsequently became a superior method for the accurate gamma(infinity) determination. In this study, we validate our revised gamma(infinity)-calculation equation by measuring gamma(infinity) in an ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate system, in which 55 organic compounds covering a wide range of functional groups were used as probe solutes and their gamma(infinity) values in the ionic liquid were determined at 40.0, 50.0, and 60.0 degrees C. Experimental error analysis shows that our revised equation remarkably reduces the error compared to the common gamma(infinity)-calculation equation. Our data is consistent with previously reported values obtained via other techniques, which further proves the credibility of our revised equation. The accurately determined gamma(infinity) values can be directly used to calculate the partial molar excess enthalpy, selectivity, and capacity, which will benefit for the rapid screening of solvents (especially ionic liquids) in separation approaches. PMID- 23039406 TI - Temporal processing of low-frequency sounds by seals (L). AB - In a recent study, Kastelein et al. [(2010) J. Acoust. Soc. Am. 127, 1135-1145] reported auditory integration times for harbor seals (Phoca vitulina) exceeding 3000 ms for 200 Hz tonal signals. This finding is unexpected and potentially significant given that time constants measured in mammals for tones above 1 kHz are typically less than 500 ms. To further explore this result, the hearing of another harbor seal was measured in air and water for 200 Hz tones with durations of 500 and 2500 ms. Threshold comparisons, as well as reaction time measures, revealed no gain in audibility as signal duration increased above 500 ms. PMID- 23039407 TI - An improved broadband matched field processor for geoacoustic inversion (L). AB - The approach proposed here requires that for each parameter combination in a search space only a minimum processor value (over frequencies) be retained. Thus all frequencies considered at that point will have processor values at least as great as the final value. Consequently, (1) the frequency most sensitive to a parameter dominates the search automatically and (2) resolution has improved with major sidelobe reduction. The method is intended primarily for geoacoustic inversion methods (where the signal-to-noise levels are high). PMID- 23039408 TI - Comment on plate modal wavenumber transforms in Sound and structural vibration [Academic Press (1987, 2007)] (L). AB - The wavenumber transform for rectangular, simply supported, isotropic thin plates has been rederived to correct a technical error found in the text Sound and Structural Vibration (Academic Press, 1985/2007) by Fahy/Fahy and Gardonio. The text states that the modal wavenumber corresponds to the peak of the wavenumber spectrum. While this is approximately true for higher-order modes, it does not hold for lower-order modes due to coupling between positive and negative wavenumber energy. The modal wavenumber is shown to be related to the zeros in the wavenumber spectrum by an integer multiple of 2pi normalized by the plate length. PMID- 23039409 TI - Transducer figure of merit (L). AB - An alternative formula for determining the volume-referenced, projector transducer figure of merit, FOM(v), is developed allowing an evaluation based on well known parameters that may be readily calculated or measured. This formula is also reduced to the special case of piezoelectric or magnetostrictive materials, allowing a FOM(v) comparison of transducer materials in addition to an evaluation of specific transducer designs. Sample results are given for transducer materials alone and a PZT-8 driven modal projector transducer operated in the monopole mode. PMID- 23039402 TI - Correlation of C-reactive protein haplotypes with serum C-reactive protein level and response to anti-tumor necrosis factor therapy in UK rheumatoid arthritis patients: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort. AB - INTRODUCTION: In many European countries, restrictions exist around the prescription of anti-tumor necrosis factor (anti-TNF) treatments for rheumatoid arthritis (RA). Eligibility and response to treatment is assessed by using the disease activity score 28 (DAS28) algorithm, which incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Although DAS28-CRP provides a more reliable measure of disease activity, functional variants exist within the CRP gene that affect basal CRP production. METHODS: DNA samples from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) were genotyped for rs1205, rs1800947, and rs3091244 by using either TaqMan or the Sequenom MassARRAY iPLEX system. RESULTS: Baseline CRP measurements were available for 599 samples with 442 also having data 6 months after treatment with an anti-TNF. For these 442 samples, the study had > 80% power to detect a clinically meaningful difference of 0.6 DAS28 Units for an allele frequency of 5%. Estimated haplotype frequencies corresponded with previous frequencies reported in the literature. Overall, no significant association was observed between any of the markers investigated and baseline CRP levels. Further, CRP haplotypes did not correlate with baseline CRP (P = 0.593), baseline DAS28-CRP (P = 0.540), or change in DAS28-CRP after treatment with an anti-TNF over a 6-month period (P = 0.302). CONCLUSIONS: Although CRP genotype may influence baseline CRP levels, in patients with very active disease, no such association was found. This suggests that genetic variation at the CRP locus does not influence DAS28-CRP, which may continue to be used in determining eligibility for and response to anti-TNF treatment, without adjusting for CRP genotype. PMID- 23039410 TI - Thermal model for piezoelectric transducers (L). AB - A lumped parameter equivalent circuit basis for calculating and allocating heat power sources in a transducer is presented along with experimental results. The simple model allows heat power calculations at resonance based on readily attainable parameters for transducers with uniform fields. Measured and finite element analysis of steady state thermal results are compared for the monopole mode of the single crystal driven modal transducer projector. The model serves as a physical and computational aid in the evaluation of piezoelectric transducer heating and may be used for evaluating highly coupled single crystal as well as ceramic piezoelectric transducers. PMID- 23039411 TI - Extraction of statistical properties of the point source response of a reverberant plate and application to parameter estimation (L). AB - The point source response of a reverberant solid plate is modeled through a nonstationary Poisson process based on the image-source method. The theoretical expectation of the envelope is then derived, taking into account the dispersive nature of plate waves, and validated by numerical results. Least-square curve fitting applied to an ensemble average over N realizations can then be used to identify useful parameters such as wave velocity, plate surface, or source receiver distance. It is shown that even values of N down to 1 (no averaging) allow a satisfying identification. Application to the estimation of the source receiver distance using a single sensor is finally highlighted to illustrate the promising potentialities of the measurement principle proposed. PMID- 23039412 TI - A more fundamental approach to the derivation of nonlinear acoustic wave equations with fractional loss operators (L). AB - A corrected derivation of nonlinear wave propagation equations with fractional loss operators is presented. The fundamental approach is based on fractional formulations of the stress-strain and heat flux definitions but uses the energy equation and thermodynamic identities to link density and pressure instead of an erroneous fractional form of the entropy equation as done in Prieur and Holm ["Nonlinear acoustic wave equations with fractional loss operators," J. Acoust. Soc. Am. 130(3), 1125-1132 (2011)]. The loss operator of the obtained nonlinear wave equations differs from the previous derivations as well as the dispersion equation, but when approximating for low frequencies the expressions for the frequency dependent attenuation and velocity dispersion remain unchanged. PMID- 23039413 TI - Analysis of a homemade Edison tinfoil phonograph. AB - Thomas Edison's phonograph was a landmark acoustic invention. In this paper, the phonograph is presented as a tool for education in acoustics. A brief history of the phonograph is outlined and an analogous circuit model that describes its dynamic response is discussed. Microphone and scanning laser Doppler vibrometer (SLDV) measurements were made on a homemade phonograph for model validation and inversion for unknown model parameters. SLDV measurements also conclusively illustrate where model assumptions are violated. The model elements which dominate the dynamic response are discussed. PMID- 23039414 TI - Two-dimensional acoustic scattering, conformal mapping, and the Rayleigh hypothesis. AB - Methods for solving two-dimensional scattering problems using conformal mappings are investigated. It is shown that their convergence relies on a mapped form of the Rayleigh hypothesis. It is concluded that methods based on conformal mappings offer no advantages over established methods in which the scattered field is expanded as a series of circular-cylindrical outgoing wavefunctions. PMID- 23039415 TI - Acoustic radiation force on a spherical particle in a fluid-filled cavity. AB - The acoustic pressure and radiation force acting on the spherical rigid particle located in a fluid-filled cylindrical vessel are determined as a function of the primary wave frequency making use of the solution of a problem of plane harmonic wave scattering on a spherical body. The problem is solved by the variables separation method. To satisfy the boundary conditions on cylindrical and spherical surfaces, the mutual expansions of spherical wave functions over the cylindrical ones and vice versa are used. Required constants in the solution are calculated from an infinite system of algebraic equations which is solved by a truncation method. It is established that the value of the radiation force is affected significantly by the presence of the cylindrical boundary surface. Depending on the frequency of the incident wave, the radiation force can change its direction. It is established that there are peak values of the force at some discrete values of the frequency. The mentioned peculiarities can stipulate specific localization effects and influence the motion of the particles in the cylindrical cavity under the influence of an acoustic wave. PMID- 23039416 TI - Unified modeling of turbulence effects on sound propagation. AB - Many aspects of outdoor sound propagation depend on the scattering effects induced by atmospheric turbulence. Standard analytical and numerical assessments of these effects make an a priori distinction between the scattering effects at large versus small angles. The present study evaluates the ability of a numerical model in overcoming this distinction. The model solves a set of two coupled equations for the sound pressure and vector acoustic velocity, with the finite difference time domain approach. It is first introduced and evaluated. The numerical predictions are compared to well-known analytical solutions in the case of two-dimensional plane wave propagation through turbulence. They are found to agree in the investigated scenarios. Hence, the finite-difference, time domain solution of the two coupled equations provides a unified, versatile numerical approach to investigating the effects of atmospheric turbulence on sound propagation. The comparison also provides original insights on the applicability and limitations of various methods used to investigate sound propagation through turbulence. PMID- 23039417 TI - Computational fluid dynamics simulation of sound propagation through a blade row. AB - The propagation of sound waves through a blade row is investigated numerically. A wave splitting method in a two-dimensional duct with arbitrary mean flow is presented, based on which pressure amplitude of different wave mode can be extracted at an axial plane. The propagation of sound wave through a flat plate blade row has been simulated by solving the unsteady Reynolds average Navier Stokes equations (URANS). The transmission and reflection coefficients obtained by Computational Fluid Dynamics (CFD) are compared with semi-analytical results. It indicates that the low order URANS scheme will cause large errors if the sound pressure level is lower than -100 dB (with as reference pressure the product of density, main flow velocity, and speed of sound). The CFD code has sufficient precision when solving the interaction of sound wave and blade row providing the boundary reflections have no substantial influence. Finally, the effects of flow Mach number, blade thickness, and blade turning angle on sound propagation are studied. PMID- 23039418 TI - Model-independent range localization of a moving source in shallow water. AB - A method for range localization with a single sensor in an ocean waveguide is derived. Range localization typically requires an accurate environmental acoustics model used for processing acoustic data on a multi-element array. Recently, an alternative method for estimating range has emerged based on the waveguide invariant which still requires either an array of sufficient horizontal extent or data from a moving source for which range rate is known. In analogy to the waveguide invariant derivation, it is shown that the magnitude of the square of the difference between the acoustic field at two different ranges contains information about the range interval, Deltar. Since the range interval is manifest in the time interval, Deltat between field measurements, range rate can be ascertained. Experimental results confirm this single sensor localization method. PMID- 23039419 TI - Bottom interacting sound at 50 km range in a deep ocean environment. AB - Data collected during the 2004 Long-range Ocean Acoustic Propagation Experiment provide absolute intensities and travel times of acoustic pulses at ranges varying from 50 to 3200 km. In this paper a subset of these data is analyzed, focusing on the effects of seafloor reflections at the shortest transmission range of approximately 50 km. At this range bottom-reflected (BR) and surface reflected, bottom-reflected energy interferes with refracted arrivals. For a finite vertical receiving array spanning the sound channel axis, a high mode number energy in the BR arrivals aliases into low mode numbers because of the vertical spacing between hydrophones. Therefore, knowledge of the BR paths is necessary to fully understand even low mode number processes. Acoustic modeling using the parabolic equation method shows that inclusion of range-dependent bathymetry is necessary to get an acceptable model-data fit. The bottom is modeled as a fluid layer without rigidity, without three dimensional effects, and without scattering from wavelength-scale features. Nonetheless, a good model-data fit is obtained for sub-bottom properties estimated from the data. PMID- 23039420 TI - Evidence for a common scale O(0.1) m that controls seabed scattering and reverberation in shallow water. AB - Analysis of the spectral content of long-range reverberation yields two observations. First, there is a remarkably similar scale, O(0.1) m, between three diverse continental shelf regions. This is surprising given the complexity and diversity of geologic processes. Second, there is strong evidence that the scale is associated with heterogeneities within the sediment. Thus, sediment volume scattering, not interface scattering, controls long-range reverberation from a few hundred hertz to several kilohertz. This is also unexpected given that at long ranges the vertical grazing angles are less than the critical angle, and hence the penetration of the acoustic field into the sub-bottom is expected to be modest. The consistency of the scale, O(0.1) m, suggests an underlying feature or mechanism that is consistent across many ostensibly diverse geological settings. Neither the feature nor mechanism is known at this time. PMID- 23039421 TI - Trans-dimensional matched-field geoacoustic inversion with hierarchical error models and interacting Markov chains. AB - This paper develops a trans-dimensional approach to matched-field geoacoustic inversion, including interacting Markov chains to improve efficiency and an autoregressive model to account for correlated errors. The trans-dimensional approach and hierarchical seabed model allows inversion without assuming any particular parametrization by relaxing model specification to a range of plausible seabed models (e.g., in this case, the number of sediment layers is an unknown parameter). Data errors are addressed by sampling statistical error distribution parameters, including correlated errors (covariance), by applying a hierarchical autoregressive error model. The well-known difficulty of low acceptance rates for trans-dimensional jumps is addressed with interacting Markov chains, resulting in a substantial increase in efficiency. The trans-dimensional seabed model and the hierarchical error model relax the degree of prior assumptions required in the inversion, resulting in substantially improved (more realistic) uncertainty estimates and a more automated algorithm. In particular, the approach gives seabed parameter uncertainty estimates that account for uncertainty due to prior model choice (layering and data error statistics). The approach is applied to data measured on a vertical array in the Mediterranean Sea. PMID- 23039422 TI - A stochastic response surface formulation for the description of acoustic propagation through an uncertain internal wave field. AB - A modeling and simulation study is performed in a littoral ocean waveguide subject to uncertainty in four quantities: source depth, tidal forcing, initial thermocline structure, and sediment sound speed. In this partially known shelf break environment, tidal forcing over a density-stratified water column produces internal tides and solitary wave packets. The resulting uncertainty in the space time oceanographic field is mapped into the sound speed distribution which, in turn, introduces uncertainty into the acoustic wave field. The latter is treated as a stochastic field whose intensity is described by a polynomial chaos expansion. The expansion coefficients are estimated through constrained multivariate linear regression, and an analysis of the chaos coefficients provides insight into the relative contribution of the uncertain acoustic and oceanographic quantities. Histograms of acoustic intensity are estimated and compared to a reference solution obtained through Latin Hypercube sampling. A sensitivity analysis is performed to illustrate the relative importance of the four contributions of incomplete information about the environment. The simulation methodology represents an end-to-end analysis approach including both oceanographic and acoustic field uncertainty where the latter is quantified using stochastic basis expansions in the form of a polynomial chaos representation. PMID- 23039423 TI - Humpback whale (Megaptera novaeangliae) song occurrence at American Samoa in long term passive acoustic recordings, 2008-2009. AB - Humpback whales (Megaptera novaeangliae) wintering in American Samoan waters belong to the endangered Oceania subpopulation (IUCN Red List), but survey effort in this region has been relatively limited. Humpback whale seasonal occurrence was assessed using long-term passive acoustic recordings from March 2008 to July 2009 at Tutuila, the most populous island of American Samoa, and October 2008 to September 2009 at the remote Rose Atoll, 240 km to the east. Humpback whale song occurred from mid-July through November at both locations. For days with song, the mean number of recordings per day with song was significantly greater at Tutuila than at Rose Atoll. Song incidence at Rose Atoll peaked at 82% of recordings/day in late September 2008, and at Tutuila 70-100% of recordings contained song in late August through early September 2009, when recording ceased. Song incidence at Rose Atoll decreased at midday and increased at midnight, whereas there was no significant diurnal pattern at Tutuila. The lower overall incidence of song and its episodic nature at Rose Atoll suggest lower densities of whales traveling through the likely smaller detection area there, whereas greater song incidence and longer peak periods at Tutuila suggest greater whale densities and longer residence times. PMID- 23039424 TI - Maximum-likelihood and other processors for incoherent and coherent matched-field localization. AB - This paper develops a series of maximum-likelihood processors for matched-field source localization given various states of information regarding the frequency and time variation of source amplitude and phase, and compares these with existing approaches to coherent processing with incomplete source knowledge. The comparison involves elucidating each processor's approach to source spectral information within a unifying formulation, which provides a conceptual framework for classifying and comparing processors and explaining their relative performance, as quantified in a numerical study. The maximum-likelihood processors represent optimal estimators given the assumption of Gaussian noise, and are based on analytically maximizing the corresponding likelihood function over explicit unknown source spectral parameters. Cases considered include knowledge of the relative variation in source amplitude over time and/or frequency (e.g., a flat spectrum), and tracking the relative phase variation over time, as well as incoherent and coherent processing. Other approaches considered include the conventional (Bartlett) processor, cross-frequency incoherent processor, pair-wise processor, and coherent normalized processor. Processor performance is quantified as the probability of correct localization from Monte Carlo appraisal over a large number of random realizations of noise, source location, and environmental parameters. Processors are compared as a function of signal-to-noise ratio, number of frequencies, and number of sensors. PMID- 23039425 TI - The effect of static pressure on the strength of inertial cavitation events. AB - Recent investigations of cavitation in fluids pressurized up to 30 MPa found that the intensity of light emissions increased by 1000-fold over that measured for single bubble sonoluminescence. A series of measurements is reported here to extend this original work by resolving the static pressure dependence of the shock wave and light emissions from the first and the most energetic collapses, along with the total shock wave energy and light emissions for the event. Each of these parameters was found to increase with the static pressure of the fluid. Furthermore, the energy of these shock wave and light emissions was found to increase in proportion to the stored acoustic energy in the system. These findings were corroborated using the Gilmore equation to numerically compute the work done by the liquid during the bubble collapse. The overall findings suggest that the increased collapse strength at high static pressure is due to the increased tension required to generate inertial cavitation, and not an increased pressure gradient between the interior of the vaporous bubble and the surrounding liquid. PMID- 23039426 TI - Dynamic response of an array of flexural plates in acoustic medium. AB - The dynamic response of a transducer array made up of circular flexural plates in immersion is analytically calculated. The calculation method includes three steps: (1) the calculation of parallel resonant frequency and the velocity profile of each plate, (2) the calculation of mutual acoustic impedance between the plates, and (3) the calculation of velocity response, including the mechanical and acoustic impedance. The calculation method is validated by both finite element analysis and measurement results of a fabricated capacitive micromachined ultrasonic transducer. Based on the calculated velocity, the near field pressure and the near-to-far field radiation patterns are presented. The flexural plate array in immersion displays two modes of operation. At low frequency, the mode shape of the transducer array is similar to that of a suspended plate and, at certain frequencies, two groups of plates move in opposite phase, which results in the cancellation of the average velocity. At high frequency, the mode shape is similar to that of a piston transducer; however, the near-field pressure distribution is similar to that of a resilient disk. PMID- 23039427 TI - Characterizing the low strain complex modulus of asphalt concrete specimens through optimization of frequency response functions. AB - Measured and finite element simulated frequency response functions are used to characterize the low strain (~10(-7)) complex moduli of an asphalt concrete specimen. The frequency response functions of the specimen are measured at different temperatures by using an instrumented hammer to apply a load and an accelerometer to measure the dynamic response. Theoretical frequency response functions are determined by modeling the specimen as a three-dimensional (3D) linear isotropic viscoelastic material in a finite element program. The complex moduli are characterized by optimizing the theoretical frequency response functions against the measured ones. The method is shown to provide a good fit between the frequency response functions, giving an estimation of the complex modulus between minimum 500 Hz and maximum 18|000 Hz depending on the temperature. Furthermore, the optimization method is shown to give a good estimation of the complex modulus master curve. PMID- 23039428 TI - Root locus analysis and design of the adaptation process in active noise control. AB - This paper applies root locus theory to develop a graphical tool for the analysis and design of adaptive active noise control systems. It is shown that the poles of the adaptation process performed in these systems move on typical trajectories in the z-plane as the adaptation step-size varies. Based on this finding, the dominant root of the adaptation process and its trajectory can be determined. The first contribution of this paper is formulating parameters of the adaptation process root locus. The next contribution is introducing a mechanism for modifying the trajectory of the dominant root in the root locus. This mechanism creates a single open loop zero in the original root locus. It is shown that appropriate localization of this zero can cause the dominant root of the locus to be pushed toward the origin, and thereby the adaptation process becomes faster. The validity of the theoretical findings is confirmed in an experimental setup which is implemented using real-time multi-threading and multi-core processing techniques. PMID- 23039429 TI - Approximate theory of reverberation in rectangular rooms with specular and diffuse reflections. AB - First, an approximate theory of reverberation in rectangular rooms is formulated as a specular reflection field based on the image source method. In the formulation, image sources are divided into axial, tangential, and oblique groups, which chiefly contribute to the corresponding groups of normal modes in wave acoustics. Consequently, the total energy decay consists of seven kinds of exponential decay curves. Second, considering surface scattering on walls with scattering coefficients, an integrated reverberation theory for nondiffuse field is developed, where the total field is divided into specular and diffuse reflection fields. The specular reflection field is simply formulated by substituting specular absorption coefficients, while the diffuse reflection field is assumed to be a perfectly diffuse field, of which energy is supplied from the specular reflection field at each reflection. Finally, a theoretical case study demonstrates how surface scattering affects the energy decay in rectangular rooms with changing the aspect ratio and the absorption distribution. PMID- 23039430 TI - On the spatial coherence in mixed sound fields and its application to signal-to diffuse ratio estimation. AB - Many applications in spatial sound recording and processing model the sound scene as a sum of directional and diffuse sound components. The power ratio between both components, i.e., the signal-to-diffuse ratio (SDR), represents an important measure for algorithms which aim at performing robustly in reverberant environments. This contribution discusses the SDR estimation from the spatial coherence between two arbitrary first-order directional microphones. First, the spatial coherence is expressed as function of the SDR. For most microphone setups, the spatial coherence is a complex function where both the absolute value and phase contain relevant information on the SDR. Secondly, the SDR estimator is derived from the spatial coherence function. The estimator is discussed for different practical microphone setups including coincident setups of arbitrary first-order directional microphones and spaced setups of identical first-order directional microphones. An unbiased SDR estimation requires noiseless coherence estimates as well as information on the direction-of-arrival of the directional sound, which usually has to be estimated. Nevertheless, measurement results verify that the proposed estimator is applicable in practice and provides accurate results. PMID- 23039431 TI - Absorption and impedance boundary conditions for phased geometrical-acoustics methods. AB - Defining accurate acoustical boundary conditions is of crucial importance for room acoustic simulations. In predicting sound fields using phased geometrical acoustics methods, both absorption coefficients and surface impedances of the boundary surfaces can be used, but no guideline has been developed on which boundary condition produces accurate results. In this study, various boundary conditions in terms of normal, random, and field incidence absorption coefficients and normal incidence surface impedance are used in a phased beam tracing model, and the simulated results are validated with boundary element solutions. Two rectangular rooms with uniform and non-uniform absorption distributions are tested. Effects of the neglect of reflection phase shift are also investigated. It is concluded that the impedance, random incidence, and field incidence absorption boundary conditions produce reasonable results with some exceptions at low frequencies for acoustically soft materials. PMID- 23039432 TI - The prediction of flanking sound transmission below the critical frequency. AB - Although reliable methods exist to predict the apparent sound reduction index of heavy, homogeneous isotopic building constructions, these methods are not appropriate for use with lightweight building constructions which typically have critical frequencies in or above the frequency range of interest. Three main methods have been proposed for extending the prediction of flanking sound transmission to frequencies below the critical frequency. The first method is the direct prediction which draws on a database of measurements of the flanking transmission of individual flanking paths. The second method would be a modification of the method in existing standards. This method requires the calculation of the resonant sound transmission factors. However, most of the approaches proposed to calculate the resonant sound transmission factor work only for the case of single leaf homogeneous isotropic building elements and therefore are not readily applicable to complex building elements. The third method is the measurement or prediction of the resonant radiation efficiency and the airborne diffuse field excited radiation efficiency which includes both the resonant and the non-resonant radiation efficiencies. The third method can currently deal with complex building elements if the radiation efficiencies can be measured or predicted. This paper examines these prediction methods. PMID- 23039433 TI - Fourier continuation methods for high-fidelity simulation of nonlinear acoustic beams. AB - On the basis of recently developed Fourier continuation (FC) methods and associated efficient parallelization techniques, this text introduces numerical algorithms that, due to very low dispersive errors, can accurately and efficiently solve the types of nonlinear partial differential equation (PDE) models of nonlinear acoustics in hundred-wavelength domains as arise in the simulation of focused medical ultrasound. As demonstrated in the examples presented in this text, the FC approach can be used to produce solutions to nonlinear acoustics PDEs models with significantly reduced discretization requirements over those associated with finite-difference, finite-element and finite-volume methods, especially in cases involving waves that travel distances that are orders of magnitude longer than their respective wavelengths. In these examples, the FC methodology is shown to lead to improvements in computing times by factors of hundreds and even thousands over those required by the standard approaches. A variety of one-and two-dimensional examples presented in this text demonstrate the power and capabilities of the proposed methodology, including an example containing a number of scattering centers and nonlinear multiple scattering events. PMID- 23039434 TI - Eigenvalues of the sample covariance matrix for a towed array. AB - It is well known that observations of the spatial sample covariance matrix (SCM, also called the cross-spectral matrix) reveal that the ordered noise eigenvalues of the SCM decay steadily, but common models predict equal noise eigenvalues. Random matrix theory (RMT) is used to derive and discuss properties of the eigenvalue spectrum of the data SCM for linear arrays, with an application to ocean acoustic data. Noise on the array is considered either incoherent or propagating acoustic noise that is coherent across the array. Using conventional three-dimensional or two-dimensional isotropic noise models with full or snapshot deficient observations, realizations of the SCM eigenvalues are explained using RMT. Deep-water towed-array data are analyzed and it is shown that the eigenvalues of the SCM compare well with theory. It is demonstrated how RMT can be applied to study eigenvalue spectrum estimation as dependent on array properties (element spacing to wavelength ratio) and data sampling (snapshots). Apart from explaining the observed noise eigenvalue spectrum, the improved model of the eigenvalue spectrum has important applications in array signal processing. PMID- 23039435 TI - Experimental localization of an acoustic sound source in a wind-tunnel flow by using a numerical time-reversal technique. AB - The possibility of using the time-reversal technique to localize acoustic sources in a wind-tunnel flow is investigated. While the technique is widespread, it has scarcely been used in aeroacoustics up to now. The proposed method consists of two steps: in a first experimental step, the acoustic pressure fluctuations are recorded over a linear array of microphones; in a second numerical step, the experimental data are time-reversed and used as input data for a numerical code solving the linearized Euler equations. The simulation achieves the back propagation of the waves from the array to the source and takes into account the effect of the mean flow on sound propagation. The ability of the method to localize a sound source in a typical wind-tunnel flow is first demonstrated using simulated data. A generic experiment is then set up in an anechoic wind tunnel to validate the proposed method with a flow at Mach number 0.11. Monopolar sources are first considered that are either monochromatic or have a narrow or wide-band frequency content. The source position estimation is well-achieved with an error inferior to the wavelength. An application to a dipolar sound source shows that this type of source is also very satisfactorily characterized. PMID- 23039436 TI - Tracking fin whales in the northeast Pacific Ocean with a seafloor seismic network. AB - Ocean bottom seismometer (OBS) networks represent a tool of opportunity to study fin and blue whales. A small OBS network on the Juan de Fuca Ridge in the northeast Pacific Ocean in ~2.3 km of water recorded an extensive data set of 20 Hz fin whale calls. An automated method has been developed to identify arrival times based on instantaneous frequency and amplitude and to locate calls using a grid search even in the presence of a few bad arrival times. When only one whale is calling near the network, tracks can generally be obtained up to distances of ~15 km from the network. When the calls from multiple whales overlap, user supervision is required to identify tracks. The absolute and relative amplitudes of arrivals and their three-component particle motions provide additional constraints on call location but are not useful for extending the distance to which calls can be located. The double-difference method inverts for changes in relative call locations using differences in residuals for pairs of nearby calls recorded on a common station. The method significantly reduces the unsystematic component of the location error, especially when inconsistencies in arrival time observations are minimized by cross-correlation. PMID- 23039437 TI - Imaging small three-dimensional elastic inclusions by an enhanced multiple signal classification method. AB - In this paper, an enhanced multiple signal classification (MUSIC) algorithm is introduced to retrieve small three-dimensional elastic inclusions. First, the multistatic response (MSR) matrix is built by two different ways depending on considering the multiple scattering effect or not. The eigenvalue structure of the MSR matrix is analyzed to identify the degenerate case of inclusions. Second, the pseudo-spectrum function is built with an optimal test direction on each node, where a balancing technique is employed to ensure the numerical stability. Benefitting from this MUSIC indicator, the degenerate inclusions can be located with a good performance against noise. Numerical simulations show the proposed method has wider applicability, better resolution, and more robust in the presence of noise than the standard MUSIC methods. PMID- 23039438 TI - Reconstruction of nonstationary sound fields based on the time domain plane wave superposition method. AB - A time-domain plane wave superposition method is proposed to reconstruct nonstationary sound fields. In this method, the sound field is expressed as a superposition of time convolutions between the estimated time-wavenumber spectrum of the sound pressure on a virtual source plane and the time-domain propagation kernel at each wavenumber. By discretizing the time convolutions directly, the reconstruction can be carried out iteratively in the time domain, thus providing the advantage of continuously reconstructing time-dependent pressure signals. In the reconstruction process, the Tikhonov regularization is introduced at each time step to obtain a relevant estimate of the time-wavenumber spectrum on the virtual source plane. Because the double infinite integral of the two-dimensional spatial Fourier transform is discretized directly in the wavenumber domain in the proposed method, it does not need to perform the two-dimensional spatial fast Fourier transform that is generally used in time domain holography and real-time near-field acoustic holography, and therefore it avoids some errors associated with the two-dimensional spatial fast Fourier transform in theory and makes possible to use an irregular microphone array. The feasibility of the proposed method is demonstrated by numerical simulations and an experiment with two speakers. PMID- 23039439 TI - Chinchilla middle-ear admittance and sound power: high-frequency estimates and effects of inner-ear modifications. AB - The middle-ear input admittance relates sound power into the middle ear (ME) and sound pressure at the tympanic membrane (TM). ME input admittance was measured in the chinchilla ear canal as part of a larger study of sound power transmission through the ME into the inner ear. The middle ear was open, and the inner ear was intact or modified with small sensors inserted into the vestibule near the cochlear base. A simple model of the chinchilla ear canal, based on ear canal sound pressure measurements at two points along the canal and an assumption of plane-wave propagation, enables reliable estimates of Y(TM,) the ME input admittance at the TM, from the admittance measured relatively far from the TM. Y(TM) appears valid at frequencies as high as 17 kHz, a much higher frequency than previously reported. The real part of Y(TM) decreases with frequency above 2 kHz. Effects of the inner-ear sensors (necessary for inner ear power computation) were small and generally limited to frequencies below 3 kHz. Computed power reflectance was ~0.1 below 3.5 kHz, lower than with an intact ME below 2.5 kHz, and nearly 1 above 16 kHz. PMID- 23039440 TI - Time-frequency domain filtering of evoked otoacoustic emissions. AB - Time-domain filtering is a standard analysis technique, which is used to disentangle the two main vector components of the distortion product otoacoustic emission response, exploiting their different phase-frequency relation. In this study, a time-frequency filtering technique based on the continuous wavelet transform is proposed to overcome the intrinsic limitations of the time-domain filtering technique and to extend it also to the analysis of stimulus-frequency and transient-evoked otoacoustic emissions. The advantages of the proposed technique are first discussed on a theoretical basis, then practically demonstrated by applying it to the analysis of synthesized and real otoacoustic data. The results show that the time-frequency approach can be empirically optimized to get effective separation of the components of the otoacoustic response associated with either different generation mechanisms or different generation places. Focusing on a single component of the otoacoustic response with a given time-frequency signature may also improve significantly the signal to-noise ratio, because the random noise contribution tends to be uniformly distributed on the time-frequency plane. PMID- 23039441 TI - Opposing and following vocal responses to pitch-shifted auditory feedback: evidence for different mechanisms of voice pitch control. AB - The present study describes a technique for analysis of vocal responses to auditory feedback pitch perturbations in which individual trials are first sorted according to response direction and then separately averaged in groups of upward or downward responses. In experiment 1, the stimulus direction was predictable (all upward) but magnitude was randomized between +100, +200, or +500 cents (unpredictable). Results showed that pitch-shift stimuli (PSS) of +100 and +200 cents elicited significantly larger opposing (compensatory) responses than +500 cent stimuli, but no such effect was observed for "following" responses. In experiment 2, subjects were tested in three blocks of trials where for the first two, PSS magnitude and direction were predictable (block 1+100 and block 2-100 cents), and in block 3, the magnitude was predictable (+/-100 cents) but direction was randomized (upward or downward). Results showed there were slightly more opposing than following responses for predictable PSS direction, but randomized directions led to significantly more opposing than following responses. Results suggest that predictability of stimulus direction and magnitude can modulate vocal responses to feedback pitch perturbations. The function and causes of the opposing and following responses are unknown, but there may be two different neural mechanisms involved in their production. PMID- 23039442 TI - Fast Fourier transform analysis of sounds made while swallowing various foods. AB - The cervical auscultation method was applied to investigate sounds generated while swallowing various foods with unique physical properties, including liquid (water), semiliquid (yogurt), and solid (konjac jelly). To study the differences among swallowing sounds for various foods, fast Fourier transform (FFT) analysis was applied to signals that were attributed to the flow of a food bolus, which is a swallowable soft mass of chewed food. An FFT program was developed that enabled the calculation of a spectrum for a specified region of time domain swallowing sound signals. The intensity of spectra in the frequency range between 400 and 1000 Hz significantly differed: liquid > semiliquid > solid. The FFT spectrum in this range was suggested to represent the frequency characteristics of the swallowing sounds of various foods. PMID- 23039443 TI - Evaluating the effects of olivocochlear feedback on psychophysical measures of frequency selectivity. AB - Frequency selectivity was evaluated under two conditions designed to assess the influence of a "precursor" stimulus on auditory filter bandwidths. The standard condition consisted of a short masker, immediately followed by a short signal. The precursor condition was identical except a 100-ms sinusoid at the signal frequency (i.e., the precursor) was presented before the masker. The standard and precursor conditions were compared for measurements of psychophysical tuning curves (PTCs), and notched noise tuning characteristics. Estimates of frequency selectivity were significantly broader in the precursor condition. In the second experiment, PTCs in the standard and precursor conditions were simulated to evaluate the influence of the precursor on PTC bandwidth. The model was designed to account for the influence of additivity of masking between the masker and precursor. Model simulations were able to qualitatively account for the perceptual data when outer hair cell gain of the model was reduced in the precursor condition. These findings suggest that the precursor may have reduced cochlear gain, in addition to producing additivity of masking. This reduction in gain may be mediated by the medial olivocochlear reflex. PMID- 23039444 TI - Auditory filter tuning inferred with short sinusoidal and notched-noise maskers. AB - The physiology of the medial olivocochlear reflex suggests that a sufficiently long stimulus (>100 ms) may reduce cochlear gain and result in broadened frequency selectivity. The current study attempted to avoid gain reduction by using short maskers (20 ms) to measure psychophysical tuning curves (PTCs) and notched-noise tuning characteristics, with a 4-kHz signal. The influence of off frequency listening on PTCs was evaluated using two types of background noise. Iso-level curves were derived using an estimate of the cochlear input/output (I/O) function, which was obtained using an off-frequency masker as a linear reference. The influence of masker duration on PTCs was assessed using a model that assumed long maskers (>20 ms) evoked gain reduction. The results suggested that the off-frequency masker was a valid linear reference when deriving I/O functions and that off-frequency listening may have occurred in auditory filters apical to the signal place. The iso-level curves from this growth-of-masking study were consistent with those from a temporal-masking-curve study by Eustaquio Martin and Lopez-Poveda [J. Assoc. Res. Otolaryngol. 12, 281-299. (2011)], suggesting that either approach may be used to derive iso-level curves. Finally, model simulations suggested that masker duration may not influence estimates of frequency selectivity. PMID- 23039445 TI - Intelligibility of whispered speech in stationary and modulated noise maskers. AB - This study investigated the role of natural periodic temporal fine structure in helping listeners take advantage of temporal valleys in amplitude-modulated masking noise when listening to speech. Young normal-hearing participants listened to natural, whispered, and/or vocoded nonsense sentences in a variety of masking conditions. Whispering alters normal waveform temporal fine structure dramatically but, unlike vocoding, does not degrade spectral details created by vocal tract resonances. The improvement in intelligibility, or masking release, due to introducing 16-Hz square-wave amplitude modulations in an otherwise steady speech-spectrum noise was reduced substantially with vocoded sentences relative to natural speech, but was not reduced for whispered sentences. In contrast to natural speech, masking release for whispered sentences was observed even at positive signal-to-noise ratios. Whispered speech has a different short-term amplitude distribution relative to natural speech, and this appeared to explain the robust masking release for whispered speech at high signal-to-noise ratios. Recognition of whispered speech was not disproportionately affected by unpredictable modulations created by a speech-envelope modulated noise masker. Overall, the presence or absence of periodic temporal fine structure did not have a major influence on the degree of benefit obtained from imposing temporal fluctuations on a noise masker. PMID- 23039447 TI - Auditory global-local processing: effects of attention and musical experience. AB - In vision, global (whole) features are typically processed before local (detail) features ("global precedence effect"). However, the distinction between global and local processing is less clear in the auditory domain. The aims of the present study were to investigate: (i) the effects of directed versus divided attention, and (ii) the effect musical training on auditory global-local processing in 16 adult musicians and 16 non-musicians. Participants were presented with short nine-tone melodies, each comprised of three triplet sequences (three-tone units). In a "directed attention" task, participants were asked to focus on either the global or local pitch pattern and had to determine if the pitch pattern went up or down. In a "divided attention" task, participants judged whether the target pattern (up or down) was present or absent. Overall, global structure was perceived faster and more accurately than local structure. The global precedence effect was observed regardless of whether attention was directed to a specific level or divided between levels. Musicians performed more accurately than non-musicians overall, but non-musicians showed a more pronounced global advantage. This study provides evidence for an auditory global precedence effect across attention tasks, and for differences in auditory global-local processing associated with musical experience. PMID- 23039448 TI - Better-ear glimpsing efficiency with symmetrically-placed interfering talkers. AB - In listening tasks where a target speech signal is spatially separated from a masking voice, listeners can often gain a substantial advantage in performance by attending to the ear with the better signal-to-noise ratio (SNR). However, this better-ear strategy becomes much more complicated when a target talker located in front of the listener is masked by interfering talkers positioned at symmetric locations to the left and right of the target. When this happens, there are no long-term SNR advantages at either ear and the only binaural SNR advantages available are the result of complicated better-ear glimpses that vary as a function of frequency and rapidly switch back and forth between the two ears according to the natural fluctuations in the relative levels of the two masking voices. In this study, a signal processing technique was used to take the better ear glimpses that would ordinarily be randomly distributed across the two ears in a binaural speech signal and move them all into the same ear. This resulted in a monaural signal that contained all the information available to an ideal listener using an optimal binaural glimpsing strategy. Speech intelligibility was measured with these optimized monaural stimuli and compared to performance with unprocessed binaural speech stimuli. Performance was similar in these two conditions, suggesting that listeners with normal hearing are able to efficiently extract information from better-ear glimpses that fluctuate rapidly across frequency and across the two ears. PMID- 23039446 TI - Differences between psychoacoustic and frequency following response measures of distortion tone level and masking. AB - The scalp-recorded frequency following response (FFR) in humans was measured for a 244-Hz pure tone at a range of input levels and for complex tones containing harmonics 2-4 of a 300-Hz fundamental, but shifted by +/-56 Hz. The effective magnitude of the cubic difference tone (CDT) and the quadratic difference tone (QDT, at F(2)-F(1)) in the FFR for the complex was estimated by comparing the magnitude spectrum of the FFR at the distortion product (DP) frequency with that for the pure tone. The effective DP levels in the FFR were higher than those commonly estimated in psychophysical experiments, indicating contributions to the DP in the FFR in addition to the audible propagated component. A low-frequency narrowband noise masker reduced the magnitude of FFR responses to the CDT but also to primary components over a wide range of frequencies. The results indicate that audible DPs may contribute very little to the DPs observed in the FFR and that using a narrowband noise for the purpose of masking audible DPs can have undesired effects on the FFR over a wide frequency range. The results are consistent with the notion that broadly tuned mechanisms central to the auditory nerve strongly influence the FFR. PMID- 23039449 TI - Restoration of loudness summation and differential loudness growth in hearing impaired listeners. AB - When normal-hearing (NH) listeners compare the loudness of narrowband and wideband sounds presented at identical sound pressure levels, the wideband sound will most often be perceived as louder than the narrowband sound, a phenomenon referred to as loudness summation. Hearing-impaired (HI) listeners typically show less-than-normal loudness summation, due to reduced cochlear compressive gain and degraded frequency selectivity. In the present study, loudness summation at 1 and 3 kHz was estimated monaurally for five NH and eight HI listeners by matching the loudness of narrowband and wideband noise stimuli. The loudness summation was measured as a function both of noise bandwidth and level. The HI listeners were tested unaided and aided using three different compression systems to investigate the possibility of restoring loudness summation in these listeners. A compression system employing level-dependent compression channels yielded the most promising outcome. The present results inform the development of future loudness models and advanced compensation strategies for the hearing impaired. PMID- 23039450 TI - The potential of onset enhancement for increased speech intelligibility in auditory prostheses. AB - Recent studies have shown that transient parts of a speech signal contribute most to speech intelligibility in normal-hearing listeners. In this study, the influence of enhancing the onsets of the envelope of the speech signal on speech intelligibility in noisy conditions using an eight channel cochlear implant vocoder simulation was investigated. The enhanced envelope (EE) strategy emphasizes the onsets of the speech envelope by deriving an additional peak signal at the onsets in each frequency band. A sentence recognition task in stationary speech shaped noise showed a significant speech reception threshold (SRT) improvement of 2.5 dB for the EE in comparison to the reference continuous interleaved sampling strategy and of 1.7 dB when an ideal Wiener filter was used for the onset extraction on the noisy signal. In a competitive talker condition, a significant SRT improvement of 2.6 dB was measured. A benefit was obtained in all experiments with the peak signal derived from the clean speech. Although the EE strategy is not effective in many real-life situations, the results suggest that there is potential for speech intelligibility improvement when an enhancement of the onsets of the speech envelope is included in the signal processing of auditory prostheses. PMID- 23039451 TI - Phonation threshold pressure and the elastic shear modulus: comparison of two mass model calculations with experiments. AB - Ishizaka and Flanagan's classic two-mass model of vocal fold motion is applied to small oscillations where the equations become linear and the aerodynamic driving force is described by an effective stiffness. The solution of these equations includes an analytic formula for the two eigenfrequencies; this shows that conjugate imaginary parts of the frequencies emerge beyond eigenvalue synchronization and that one of the imaginary parts becomes zero at a pressure signaling the instability associated with the onset of threshold. Using recent measurements by Fulcher et al. of intraglottal pressure distributions [J. Acoust. Soc. Am. 129, 1548-1553 (2011).] to inform the behavior of the entrance loss coefficients, an analytic formula for threshold pressure is derived. It fits most of the measurements Chan and Titze reported for their 2006 physical model of the vocal fold mucosa. Two sectors of the mass-stiffness parameter space are used to produce these fits. One is based on a rescaling of the typical glottal parameters of the original Ishizaka and Flanagan work. The second requires setting two of the spring constants equal and should be closer to the experimental conditions. In both cases, values of the elastic shear modulus are calculated from the spring constants. PMID- 23039452 TI - Subglottal resonances of adult male and female native speakers of American English. AB - This paper presents a large-scale study of subglottal resonances (SGRs) (the resonant frequencies of the tracheo-bronchial tree) and their relations to various acoustical and physiological characteristics of speakers. The paper presents data from a corpus of simultaneous microphone and accelerometer recordings of consonant-vowel-consonant (CVC) words embedded in a carrier phrase spoken by 25 male and 25 female native speakers of American English ranging in age from 18 to 24 yr. The corpus contains 17,500 utterances of 14 American English monophthongs, diphthongs, and the rhotic approximant [[inverted r]] in various CVC contexts. Only monophthongs are analyzed in this paper. Speaker height and age were also recorded. Findings include (1) normative data on the frequency distribution of SGRs for young adults, (2) the dependence of SGRs on height, (3) the lack of a correlation between SGRs and formants or the fundamental frequency, (4) a poor correlation of the first SGR with the second and third SGRs but a strong correlation between the second and third SGRs, and (5) a significant effect of vowel category on SGR frequencies, although this effect is smaller than the measurement standard deviations and therefore negligible for practical purposes. PMID- 23039453 TI - Development and perceptual assessment of a synthesizer of disordered voices. AB - A synthesizer is based on a nonlinear wave-shaping model of the glottal area, an algebraic model of the glottal aerodynamics as well as concatenated-tube models of the trachea and vocal tract. Voice disorders are simulated by way of models of vocal frequency jitter and tremor, vocal amplitude shimmer and tremor, as well as pulsatile additive noise. Six experiments have been carried out to assess the synthesizer perceptually. Three experiments involve the perceptual categorization of male synthetic and human stimuli and one the auditory discrimination between synthetic and human tokens. A fifth experiment reports the auditory discrimination between synthetic tokens with different levels of additive and modulation noise. A sixth experiment reports the scoring by expert listeners of male synthetic stimuli on equal-appearing interval scales grade-roughness breathiness (GRB). A first objective is to demonstrate the ability of the synthesizer to simulate vowel sounds that are valid exemplars of speech sounds produced by humans with voice disorders. A second objective is to learn how human expert raters perceptually map vocal frequency, additive and modulation noise as well as vowel categories into scores on GRB scales. PMID- 23039454 TI - Prosodic evaluation of accent distributions in spoken news bulletins of Flemish newsreaders. AB - The current article describes research on whether the goodness of a particular speaking style correlates with the way speakers distribute pitch accents in their speech. Study 1 analyzed two Flemish newsreaders, who, according to poll ratings, had previously been judged to represent a good vs bad speaker. A perception study in which participants had to assess the quality of spoken paragraphs produced by either of the two speakers confirmed that one speaker was rated as significantly and consistently better than the other one. An exploration of the accent distributions in those paragraphs showed that the accent distributions of the better speaker were more similar to the ones of a gold standard, i.e., the accent distributions as predicted by two independent intonation experts. Study 2 compared synthetic versions of a selection of the paragraphs of study 1, generated by a Dutch text-to-speech system. It compared three basically identical versions of the texts, except that they had different accent distributions according to the gold standard, or to distributions as observed in the productions of the two newsreaders. A perception study revealed that the versions of the bad speaker were rated as being significantly worse than the other versions. The two studies thus show that variation in accent distribution can indeed affect the way spoken texts are assessed in terms of their perceived quality. PMID- 23039455 TI - Variability in the relationships among voice quality, harmonic amplitudes, open quotient, and glottal area waveform shape in sustained phonation. AB - Increases in open quotient are widely assumed to cause changes in the amplitude of the first harmonic relative to the second (H1*-H2*), which in turn correspond to increases in perceived vocal breathiness. Empirical support for these assumptions is rather limited, and reported relationships among these three descriptive levels have been variable. This study examined the empirical relationship among H1*-H2*, the glottal open quotient (OQ), and glottal area waveform skewness, measured synchronously from audio recordings and high-speed video images of the larynges of six phonetically knowledgeable, vocally healthy speakers who varied fundamental frequency and voice qualities quasi-orthogonally. Across speakers and voice qualities, OQ, the asymmetry coefficient, and fundamental frequency accounted for an average of 74% of the variance in H1*-H2*. However, analyses of individual speakers showed large differences in the strategies used to produce the same intended voice qualities. Thus, H1*-H2* can be predicted with good overall accuracy, but its relationship to phonatory characteristics appears to be speaker dependent. PMID- 23039456 TI - Vowel formant dispersion as a measure of articulation proficiency. AB - The articulatory range of a speaker has previously been estimated by the shape formed by first and second formant measurements of produced vowels. In a majority of the currently available metrics, formant frequency measurements are reduced to a single estimate for a condition, which has adverse consequences for subsequent statistical testing. Other metrics provide estimates of size of vowel articulation changes only, and do not provide a method for studying the direction of the change. This paper proposes an alternative approach. Vowel formant frequencies are redefined as vectors originating from a defined center point of the vowel space fixed to a basic three-vowel frame. The Euclidean length of the vectors, the vowel formant dispersion (VFD), can be compared across conditions for evidence of articulatory expansions or reductions across conditions or speaker groups. Further, the angle component of the vowel vectors allows for analyses of direction of the reduction or expansion. Based on the range of investigations afforded by the VFD metric, and simulation experiments that compare its statistical properties with those of other proposed metrics, it is argued that the VFD procedure offers an enhanced view of vowel articulation change over rival metrics. PMID- 23039457 TI - Characterization of speech understanding in various types of noise. AB - This study examined (1) the effects of noise on speech understanding and (2) whether performance in real-life noises could be predicted based on performance in steady-state speech-spectrum-shaped noise. The noise conditions included a steady-state speech-spectrum-shaped noise and six types of real-life noise. Thirty normal-hearing adults were tested using sentence materials from the Cantonese Hearing In Noise Test (CHINT). To achieve the first aim, the performance-intensity function slopes in these noise conditions were estimated and compared. Variations in performance-intensity function slopes were attributed to differences in the amount of amplitude fluctuations and the presence of competing background speech. How well the data obtained in real-life noises fit the performance-intensity functions obtained in steady-state speech-spectrum shaped noises was examined for the second aim of the study. Four out of six types of noise yielded performance-intensity function slopes similar to that in steady state speech-spectrum-shaped noise. After accounting for individual differences in sentence reception threshold (SRT) and the offset between the signal-to-noise ratio for 50% intelligibility across different types of noise, performance in steady-state speech-spectrum-shaped noise was found to predict well the performance in most of the real-life noise conditions. PMID- 23039458 TI - The relative importance of spectral cues for vowel recognition in severe noise. AB - The importance of formants and spectral shape was investigated for vowel perception in severe noise. Twelve vowels were synthesized using two different synthesis methods, one where the original spectral detail was preserved, and one where the vowel was represented by the spectral peaks of the first three formants. In addition, formants F1 and F2 were suppressed individually to investigate the importance of each in severe noise. Vowels were presented to listeners in quiet and in speech-shaped noise at signal to noise ratios (SNRs) of 0, -5, and -10 dB, and vowel confusions were determined in a number of conditions. Results suggest that the auditory system relies on formant information for vowel perception irrespective of the SNR, but that, as noise increases, it relies increasingly on more complete spectral information to perform formant extraction. A second finding was that, while F2 is more important in quiet or low noise conditions, F1 and F2 are of similar importance in severe noise. PMID- 23039459 TI - A psychoacoustic method for studying the necessary and sufficient perceptual cues of American English fricative consonants in noise. AB - In a previous study on plosives, the 3-Dimensional Deep Search (3DDS) method for the exploration of the necessary and sufficient cues for speech perception was introduced (Li et al., (2010). J. Acoust. Soc. Am. 127(4), 2599-2610). Here, this method is used to isolate the spectral cue regions for perception of the American English fricatives /?, 3, s, z, f, v, theta, delta in time, frequency, and intensity. The fricatives are analyzed in the context of consonant-vowel utterances, using the vowel /alpha/. The necessary cues were found to be contained in the frication noise for /?, 3, s, z, f, v/. 3DDS analysis isolated the cue regions of /s, z/ between 3.6 and 8 [kHz] and /?, 3/ between 1.4 and 4.2 [kHz]. Some utterances were found to contain acoustic components that were unnecessary for correct perception, but caused listeners to hear non-target consonants when the primary cue region was removed; such acoustic components are labeled "conflicting cue regions." The amplitude modulation of the high-frequency frication region by the fundamental F0 was found to be a sufficient cue for voicing. Overall, the 3DDS method allows one to analyze the effects of natural speech components without initial assumptions about where perceptual cues lie in time-frequency space or which elements of production they correspond to. PMID- 23039460 TI - Set-size procedures for controlling variations in speech-reception performance with a fluctuating masker. AB - Adaptive signal-to-noise ratio (SNR) tracking is often used to measure speech reception in noise. Because SNR varies with performance using this method, data interpretation can be confounded when measuring an SNR-dependent effect such as the fluctuating-masker benefit (FMB) (the intelligibility improvement afforded by brief dips in the masker level). One way to overcome this confound, and allow FMB comparisons across listener groups with different stationary-noise performance, is to adjust the response set size to equalize performance across groups at a fixed SNR. However, this technique is only valid under the assumption that changes in set size have the same effect on percentage-correct performance for different masker types. This assumption was tested by measuring nonsense-syllable identification for normal-hearing listeners as a function of SNR, set size and masker (stationary noise, 4- and 32-Hz modulated noise and an interfering talker). Set-size adjustment had the same impact on performance scores for all maskers, confirming the independence of FMB (at matched SNRs) and set size. These results, along with those of a second experiment evaluating an adaptive set-size algorithm to adjust performance levels, establish set size as an efficient and effective tool to adjust baseline performance when comparing effects of masker fluctuations between listener groups. PMID- 23039461 TI - Perceptual effects of noise reduction by time-frequency masking of noisy speech. AB - Time-frequency masking is a method for noise reduction that is based on the time frequency representation of a speech in noise signal. Depending on the estimated signal-to-noise ratio (SNR), each time-frequency unit is either attenuated or not. A special type of a time-frequency mask is the ideal binary mask (IBM), which has access to the real SNR (ideal). The IBM either retains or removes each time-frequency unit (binary mask). The IBM provides large improvements in speech intelligibility and is a valuable tool for investigating how different factors influence intelligibility. This study extends the standard outcome measure (speech intelligibility) with additional perceptual measures relevant for noise reduction: listening effort, noise annoyance, speech naturalness, and overall preference. Four types of time-frequency masking were evaluated: the original IBM, a tempered version of the IBM (called ITM) which applies limited and non binary attenuation, and non-ideal masking (also tempered) with two different types of noise-estimation algorithms. The results from ideal masking imply that there is a trade-off between intelligibility and sound quality, which depends on the attenuation strength. Additionally, the results for non-ideal masking suggest that subjective measures can show effects of noise reduction even if noise reduction does not lead to differences in intelligibility. PMID- 23039462 TI - Evidence for language transfer leading to a perceptual advantage for non-native listeners. AB - Phonological transfer from the native language is a common problem for non-native speakers that has repeatedly been shown to result in perceptual deficits vis-a vis native speakers. It was hypothesized, however, that transfer could help, rather than hurt, if it resulted in a beneficial bias. Due to differences in pronunciation norms between Korean and English, Koreans in the U.S. were predicted to be better than Americans at perceiving unreleased stops-not only in their native language (Korean) but also in their non-native language (English). In three experiments, Koreans were found to be significantly more accurate than Americans at identifying unreleased stops in Korean, at identifying unreleased stops in English, and at discriminating between the presence and absence of an unreleased stop in English. Taken together, these results suggest that cross linguistic transfer is capable of boosting speech perception by non-natives beyond native levels. PMID- 23039463 TI - The separation between music and speech: evidence from the perception of Cantonese tones. AB - This study investigates the relationship between music and speech, testing whether musical training has any facilitatory effects on native tone language speakers. Some Cantonese tone pairs are merging in recent years. The merging subjects have poorer general lexical tone perception than the control subjects. Previous studies showed that musical training facilitates lexical tone perception of nontone language speakers, but it is unclear if the same is true for tone language speakers. Three groups of listeners (standard Cantonese, merging Cantonese, nontone) with and without musical training participated in AX discrimination tasks of Cantonese monosyllables and pure tones resynthesized from Cantonese lexical tones. Results show that while musical training enhances lexical tone perception of nontone listeners, it has little influence on Cantonese listeners. The findings suggest that the linguistic use of tones is more fundamental and more robust than musical tones. Our results are compatible with the idea that linguistic and musical mechanisms belong to separate but overlapping domains. PMID- 23039464 TI - Audibility of aliasing distortion in sawtooth signals and its implications for oscillator algorithm design. AB - This paper investigates the audibility threshold of aliasing in computer generated sawtooth signals. Listening tests were conducted to find out how much the aliased frequency components below and above the fundamental must be attenuated for them to be inaudible. The tested tones comprised the fundamental frequencies 415, 932, 1480, 2093, 3136, and 3951 Hz, presented at 60-dB SPL and 44.1-kHz sampling rate. The results indicate that above the fundamental the aliased components must be attenuated 0, 19, 26, 27, 32, and 41 dB for the corresponding fundamental frequencies, and below the fundamental the attenuation of 0, 3, 6, 11, 12, and 11 dB, respectively, is sufficient. The results imply that the frequency-masking phenomenon affects the perception of aliasing and that the masking effect is more prominent above the fundamental than below it. The A weighted noise-to-mask ratio is proposed as a suitable quality measure for sawtooth signals containing aliasing. It was shown that the bandlimited impulse train, the differentiated parabolic waveform, and the fourth-order polynomial bandlimited step function synthesis algorithms are perceptually alias-free up to 1, 2, and 4 kHz, respectively. General design rules for antialiasing sawtooth oscillators are derived based on the results and on knowledge of level-dependence of masking. PMID- 23039465 TI - Sound texture recognition through dynamical systems modeling of empirical mode decomposition. AB - This paper describes a system for modeling, recognizing, and classifying sound textures. The described system translates contemporary approaches from video texture analysis, creating a unique approach in the realm of audio and music. The signal is first represented as a set of mode functions by way of the Empirical Mode Decomposition technique for time/frequency analysis, before expressing the dynamics of these modes as a linear dynamical system (LDS). Both linear and nonlinear techniques are utilized in order to learn the system dynamics, which leads to a successful distinction between unique classes of textures. Five classes of sounds comprised a data set, consisting of crackling fire, typewriter action, rainstorms, carbonated beverages, and crowd applause, drawing on a variety of source recordings. Based on this data set the system achieved a classification accuracy of 90%, which outperformed both a Mel-Frequency Cepstral Coefficient based LDS-modeling approach from the literature, as well as one based on a standard Gaussian Mixture Model classifier. PMID- 23039466 TI - Hearing threshold shifts and recovery in harbor seals (Phoca vitulina) after octave-band noise exposure at 4 kHz. AB - Safety criteria for underwater sounds from offshore pile driving are needed to protect marine mammals. As a first step toward understanding effects of impulsive sounds, two harbor seals were exposed to octave-band white noise centered at 4 kHz at three mean received sound pressure levels (SPLs; 124, 136, and 148 dB re 1 MUPa) at up to six durations (7.5, 15, 30, 60, 120, and 240 min); mean received sound exposure level (SEL) range was 166-190 dB re 1 MUPa(2) s. Hearing thresholds were determined before and after exposure. Temporary hearing threshold shifts (TTS) and subsequent recovery were quantified as changes in hearing thresholds at 1-4, 4-8, 8-12, 48, and 96 min after noise exposure in seal 01, and at 12-16, 16-20, 20-24, 60, and 108 min after exposure in seal 02. Maximum TTS (1 4 min after 120 min exposure to 148 dB re 1 MUPa; 187 dB SEL) was 10 dB. Recovery occurred within ~60 min. Statistically significant TTSs (>2.5 dB) began to occur at SELs of ~170 (136 SPL, 60 min) and 178 dB re 1 MUPa(2) s (148 SPL, 15 min). However, SEL is not an optimal predictor of TTS for long duration, low SPL continuous noise, as duration and SPL play unequal roles in determining induced TTS. PMID- 23039543 TI - Introduction to the special issue on acoustic metamaterials. PMID- 23039544 TI - Scaling of membrane-type locally resonant acoustic metamaterial arrays. AB - Metamaterials have emerged as promising solutions for manipulation of sound waves in a variety of applications. Locally resonant acoustic materials (LRAM) decrease sound transmission by 500% over acoustic mass law predictions at peak transmission loss (TL) frequencies with minimal added mass, making them appealing for weight-critical applications such as aerospace structures. In this study, potential issues associated with scale-up of the structure are addressed. TL of single-celled and multi-celled LRAM was measured using an impedance tube setup with systematic variation in geometric parameters to understand the effects of each parameter on acoustic response. Finite element analysis was performed to predict TL as a function of frequency for structures with varying complexity, including stacked structures and multi-celled arrays. Dynamic response of the array structures under discrete frequency excitation was investigated using laser vibrometry to verify negative dynamic mass behavior. PMID- 23039545 TI - Determination of effective mass density and modulus for resonant metamaterials. AB - This work presents a method to determine the effective dynamic properties of resonant metamaterials. The longitudinal vibration of a rod with periodically attached oscillators was predicted using wave propagation analysis. The effective mass density and modulus were determined from the transfer function of vibration responses. Predictions of these effective properties compared favorably with laboratory measurements. While the effective mass density showed significant frequency dependent variation near the natural frequency of the oscillators, the elastic modulus was largely unchanged for the setup considered in this study. The effective mass density became complex-numbered when the spring element of the oscillator was viscoelastic. As the real part of the effective mass density became negative, the propagating wavenumber components disappeared, and vibration transmission through the metamaterial was prohibited. The proposed method provides a consistent approach for evaluating the effective parameters of resonant metamaterials using a small number of vibration measurements. PMID- 23039546 TI - Super-resolution imaging by resonant tunneling in anisotropic acoustic metamaterials. AB - The resonant tunneling effects that could result in complete transmission of evanescent waves are examined in acoustic metamaterials of anisotropic effective mass. The tunneling conditions are first derived for the metamaterials composed of classical mass-in-mass structures. It is found that the tunneling transmission occurs when the total length of metamaterials is an integral number of half wavelengths of the periodic Bloch wave. Due to the local resonance of building units of metamaterials, the Bloch waves are spatially modulated within the periodic structures, leading to the resonant tunneling occurring in the low frequency region. The metamaterial slab lens with anisotropic effective mass is designed by which the physics of resonant tunneling and the features for evanescent field manipulations are examined. The designed lens interacts with evanescent waves in the way of the propagating wavenumber weakly dependent on the spatial frequency of evanescent waves. Full-wave simulations validate the imaging performance of the proposed lens with the spatial resolution beyond the diffraction limit. PMID- 23039547 TI - Experimental demonstrations in audible frequency range of band gap tunability and negative refraction in two-dimensional sonic crystal. AB - The propagation of audible acoustic waves in two-dimensional square lattice tunable sonic crystals (SC) made of square cross-section infinitely rigid rods embedded in air is investigated experimentally. The band structure is calculated with the plane wave expansion (PWE) method and compared with experimental measurements carried out on a finite extend structure of 200 cm width, 70 cm depth and 15 cm height. The structure is made of square inclusions of 5 cm side with a periodicity of L = 7.5 cm placed inbetween two rigid plates. The existence of tunable complete band gaps in the audible frequency range is demonstrated experimentally by rotating the scatterers around their vertical axis. Negative refraction is then analyzed by use of the anisotropy of the equi-frequency surface (EFS) in the first band and of a finite difference time domain (FDTD) method. Experimental results finally show negative refraction in the audible frequency range. PMID- 23039548 TI - Design of an acoustic metamaterial lens using genetic algorithms. AB - The present work demonstrates a genetic algorithm approach to optimizing the effective material parameters of an acoustic metamaterial. The target device is an acoustic gradient index (GRIN) lens in air, which ideally possesses a maximized index of refraction, minimized frequency dependence of the material properties, and minimized acoustic impedance mismatch. Applying this algorithm results in complex designs with certain common features, and effective material properties that are better than those present in previous designs. After modifying the optimized unit cell designs to make them suitable for fabrication, a two-dimensional lens was built and experimentally tested. Its performance was in good agreement with simulations. Overall, the optimization approach was able to improve the refractive index but at the cost of increased frequency dependence. The optimal solutions found by the algorithm provide a numerical description of how the material parameters compete with one another and thus describes the level of performance achievable in the GRIN lens. PMID- 23039549 TI - Effects of periodicity perturbations on the transmission by underwater phononic crystals. AB - The effects of periodicity perturbations in underwater phononic crystal layers composed of noninterpenetrating rows of identical shells are investigated. The results for one row are obtained by using a multiple scattering method between shells. Then, taking into account the multiple reflections and transmissions between two adjacent rows, a Debye series method is used to calculate the reflection and transmission coefficients by a finite number of rows. The paper focuses on three kinds of perturbations: (i) variation of the inner radius of shells from row to row, (ii) increase in the spacing from row to row and of the number of rows, and (iii) substitution of simple steel rows by steel-polyethylene bilayers. It is shown by studying the transmission coefficient that the case (i) permits the insertion of narrow pass bands in the stop band while the two other cases (ii) and (iii) widen the stop band. The study intends to model simple underwater acoustic filters. PMID- 23039550 TI - Directional impulse response of a large cavity inside a sonic crystal. AB - Both temporal and directional responses of a cavity inside a two-dimensional sonic crystal are investigated. The size of the cavity is large compared to the lattice parameter and the wavelength for the frequency range of interest. Hence, a hybrid method to compute the response is proposed, combining multiscattering theory for the calculation of the reflective properties of the sonic crystal with a modified ray-tracing algorithm for the sound propagation within the cavity. The response of this enclosure displays resonances for certain frequency bands that depend on the geometry of the lattice and the cavity. When a full band gap exists in the sonic crystal, rays cannot propagate through the medium and total reflection occurs for all incidence angles, leading to strong resonances with an isotropic intensity field inside the cavity. When only some propagation directions are forbidden, total reflection occurs for certain ranges of incidence angles, and resonances can also be elicited but with a highly anisotropic intensity field. The spectrum of resonances of the cavity is strongly affected by changes in the lattice geometry, suggesting that they can be tailored to some extent, a feature that can lead to potential applications in architectural acoustics. PMID- 23039551 TI - Quasi-phase-matched backward second-harmonic generation by complementary media in nonlinear metamaterials. AB - High efficiency of the second-harmonic and sum-frequency generation can be obtained in optical superlattice by using the conventional quasi-phase-matched (QPM) method. Although this trick can be played on the acoustic wave, the media with negative nonlinear parameters are not common in acoustics. Furthermore, the QPM method used in acoustic metamaterials has been less studied. In this work, a protocol is provided to realize the QPM method by using nonlinear complementary media in acoustic metamaterials in order to obtain large backward second-harmonic generation. Compared with the conventional method, the method gains a broader bandwidth and can be used in both acoustic and electromagnetic waves. PMID- 23039552 TI - Acoustic metamaterials with circular sector cavities and programmable densities. AB - Considerable interest has been devoted to the development of various classes of acoustic metamaterials that can control the propagation of acoustical wave energy throughout fluid domains. However, all the currently exerted efforts are focused on studying passive metamaterials with fixed material properties. In this paper, the emphasis is placed on the development of a class of composite one-dimensional acoustic metamaterials with effective densities that are programmed to adapt to any prescribed pattern along the metamaterial. The proposed acoustic metamaterial is composed of a periodic arrangement of cell structures, in which each cell consists of a circular sector cavity bounded by actively controlled flexible panels to provide the capability for manipulating the overall effective dynamic density. The theoretical analysis of this class of multilayered composite active acoustic metamaterials (CAAMM) is presented and the theoretical predictions are determined for a cascading array of fluid cavities coupled to flexible piezoelectric active boundaries forming the metamaterial domain with programmable dynamic density. The stiffness of the piezoelectric boundaries is electrically manipulated to control the overall density of the individual cells utilizing the strong coupling with the fluid domain and using direct acoustic pressure feedback. The interaction between the neighboring cells of the composite metamaterial is modeled using a lumped-parameter approach. Numerical examples are presented to demonstrate the performance characteristics of the proposed CAAMM and its potential for generating prescribed spatial and spectral patterns of density variation. PMID- 23039553 TI - Electro-magnetically controlled acoustic metamaterials with adaptive properties. AB - A design of actively controlled metamaterial is proposed and discussed. The metamaterial consists of layers of electrically charged nano or micro particles exposed to external magnetic field. The particles are also attached to compliant layers in a way that the designed structure exhibits two resonances: mechanical spring-mass resonance and electro-magnetic cyclotron resonance. It is shown that if the cyclotron frequency is greater than the mechanical resonance frequency, the designed structure could be highly attenuative (40-60 dB) for vibration and sound waves in very broad frequency range even for wavelength much greater than the thickness of the metamaterial. The approach opens up wide range of opportunities for design of adaptively controlled acoustic metamaterials by controlling magnetic field and/or electrical charges. PMID- 23039554 TI - Effects of the local resonance on the wave propagation in periodic frame structures: generalized Newtonian mechanics. AB - This work is devoted to the study of the wave propagation in infinite two dimensional structures made up of the periodic repetition of frames. Such materials are highly anisotropic and, because of lack of bracing, can present a large contrast between the shear and compression deformabilities. Moreover, when the thickness to length ratio of the frame elements is small, these elements can resonate in bending at low frequencies when compressional waves propagate in the structure. The frame size being small compared to the wavelength of the compressional waves, the homogenization method of periodic discrete media is extended to situations with local resonance, and it is applied to identify the macroscopic behavior at the leading order. In particular, the local resonance in bending leads to an effective mass different from the real mass and to the generalization of the Newtonian mechanics at the macroscopic scale. Consequently, compressional waves become dispersive and frequency bandgaps occur. The physical origin of these phenomena at the microscopic scale is also presented. Finally, a method is proposed for the design of such materials. PMID- 23039555 TI - Anomalous wave propagation in a one-dimensional acoustic metamaterial having simultaneously negative mass density and Young's modulus. AB - A mechanical model representing an acoustic metamaterial that exhibits simultaneously negative mass density and negative Young's modulus was proposed. Wave propagation was studied in the frequency range of double negativity. In view of positive energy flow, it was found that the phase velocity in this range is negative. This phenomenon was also observed using transient wave propagation finite-element analyses of a transient sinusoidal wave and a transient wave packet. In contrast to wave propagation in the region of positive mass and modulus, the peculiar backward wave motion in the region of double negativity was clearly displayed. PMID- 23039556 TI - Homogenization theory for periodic distributions of elastic cylinders embedded in a viscous fluid. AB - A multiple-scattering theory is applied to study the homogenization of clusters of elastic cylinders distributed in a isotropic lattice and embedded in a viscous fluid. Asymptotic relations are derived and employed to obtain analytical formulas for the effective parameters of homogenized clusters in which the underlying lattice has a low filling fraction. It is concluded that such clusters behave, in the low frequency limit, as an effective elastic medium. Particularly, it is found that the effective dynamical mass density follows the static estimate; i.e., the homogenization procedure does not recover the non-linear behavior obtained for the inviscid case. Moreover, the longitudinal and transversal sound speeds do not show any dependence on fluid viscosity. Numerical simulations performed for clusters made of brass cylinders embedded in glycerin support the reliability of the effective parameters resulting from the homogenization procedure reported here. PMID- 23039557 TI - A quasi two-dimensional model for sound attenuation by the sonic crystals. AB - Sound propagation in the sonic crystal (SC) along the symmetry direction is modeled by sound propagation through a variable cross-sectional area waveguide. A one-dimensional (1D) model based on the Webster horn equation is used to obtain sound attenuation through the SC. This model is compared with two-dimensional (2D) finite element simulation and experiment. The 1D model prediction of frequency band for sound attenuation is found to be shifted by around 500 Hz with respect to the finite element simulation. The reason for this shift is due to the assumption involved in the 1D model. A quasi 2D model is developed for sound propagation through the waveguide. Sound pressure profiles from the quasi 2D model are compared with the finite element simulation and the 1D model. The result shows significant improvement over the 1D model and is in good agreement with the 2D finite element simulation. Finally, sound attenuation through the SC is computed based on the quasi 2D model and is found to be in good agreement with the finite element simulation. The quasi 2D model provides an improved method to calculate sound attenuation through the SC. PMID- 23039558 TI - Analysis of equivalent anisotropy arising from dual isotropic layers of acoustic media. AB - The equivalence between a single mass-anisotropic layer and two isotropic layers is analyzed by studying two systems: one consists of an anisotropic layer sandwiched between two arbitrarily chosen isotropic media; and the other consists of two isotropic layers, of a total thickness equal to that of the anisotropic layer, sandwiched between the same pair of isotropic media. The equivalence is established by matching the transmission and reflection coefficients of the two systems for an arbitrarily chosen incident angle. The first-order equivalence leads to exactly the same set of relations as often quoted in the literature. However, it was concluded that a full second-order equivalence is not possible unless the incident is normal to the surface, or the materials are isotropic. One of the requirements for the second-order equivalence is that the two isotropic layers must have their impedances matched. Together with the first order equivalence requirements, this gives a complete set of conditions for determining all the materials properties of the two isotropic layers. On the other hand, the unattainable full second-order equivalence can be alleviated by a proper placement of layers: by placing the heavier layer adjacent to the medium of greater acoustic impedance. Numerical examples show that this remedy in fact is more important than following the partial requirement for the second order equivalence when the equivalent isotropic layers are used in acoustic cloaking applications. PMID- 23039559 TI - Optimizing imperfect cloaks to perfection. AB - Transformation optics has been an essential tool for designing cloaking devices for electromagnetic and acoustic waves. All these designs have one requirement in common: material singularity. At the interface between the cloak and the cloaked region, some material properties have to approach infinity, while some others approach zero. This paper attempts to answer a central question in physically realizing such cloaks: is material singularity a requirement for perfect cloaking? This paper demonstrates that, through optimization, perfect cloaking can be achieved using a layered cloak construction without material singularity. Two examples are used for this demonstration. In one example, the initial design is based on the Cummer-Schurig prescription for acoustic cloaking that requires mass-anisotropic material. Another example uses the two isotropic layers to achieve the equivalent mass-anisotropy for each anisotropic layer. During the optimization processes, only material properties of cloaks' constituent layers are adjusted while the geometries remain unchanged. In both examples, the normalized total scattering cross section can be reduced to 0.002 (0.2%) or lower in numerical computations. The capabilities and other characteristics of the optimization in other tasks such as cloaking penetrable objects and isolating strong resonance in such objects are also explored. PMID- 23039560 TI - Special transformations for pentamode acoustic cloaking. AB - The acoustic cloaking theory of Norris [Proc. R. Soc. London, Ser. A 464, 2411 2434 (2008)] permits considerable freedom in choosing the transformation f from physical to virtual space. The standard process for defining cloak materials is to first define f and then evaluate whether the materials are practically realizable. In this paper, this process is inverted by defining desirable material properties and then deriving the appropriate transformations which guarantee the cloaking effect. Transformations are derived which result in acoustic cloaks with special properties such as (1) constant density, (2) constant radial stiffness, (3) constant tangential stiffness, (4) power-law density, (5) power-law radial stiffness, (6) power-law tangential stiffness, and (7) minimal elastic anisotropy. PMID- 23039561 TI - Transformation ray method: controlling high frequency elastic waves (L). AB - Elastic ray theory is a high frequency asymptotic approximation of solution of elastodynamic equation, and is widely used in seismology. In this paper, the form invariance under a general spatial mapping and high frequency wave control have been examined by transformation method. It is showed that with the constraint of major and minor symmetry of the transformed elastic tensor, the eikonal equation keeps its form under a general mapping, however, the transport equation loses its form except for conformal mapping. Therefore, the elastic ray path can be controlled in an exact manner by a transformation method, whereas energy distribution along the ray is only approximately controlled. An elastic rotator based on ray tracing method is also provided to illustrate the method and to access the approximation. PMID- 23039562 TI - On the measurement of airborne, angular-dependent sound transmission through supercritical bars. AB - The coincidence effect is manifested by maximal sound transmission at angles at which trace wave number matching occurs. Coincidence effect theory is well defined for unbounded thin plates using plane-wave excitation. However, experimental results for finite bars are known to diverge from theory near grazing angles. Prior experimental work has focused on pulse excitation. An experimental setup has been developed to observe coincidence using continuous- wave excitation and phased-array methods. Experimental results with an aluminum bar exhibit maxima at the predicted angles, showing that coincidence is observable using continuous waves. Transmission near grazing angles is seen to diverge from infinite plate theory. PMID- 23039563 TI - Striation-based beamforming for active sonar with a horizontal line array. AB - A physics-based method for beamforming signals measured on a horizontal array is developed with an application to underwater active sonar systems. The proposed striation-based beamformer coherently combines the pressure from each element in the array at different frequencies, and these frequencies are selected based on a striation hypothesis. The linear frequency shift and corresponding phase term introduced in the array weight vector accounts for multipath-induced fading, producing beam output with increased signal gain. The method is demonstrated using data collected on an array towed in the North Atlantic. The combination of the striation-based beamformer with the waveguide invariant concept to improve tracker performance is discussed. PMID- 23039564 TI - Corrected contact dynamics for the Steinecke and Herzel asymmetric two-mass model of the vocal folds. AB - The simplified two-mass model of human vocal folds, proposed by Steinecke and Herzel [J. Acoust. Soc. Am. 97(3), 1874-1884 (1995)], has seen widespread use throughout the speech community. Herein, an error is corrected in the contact loadings on colliding vocal folds with asymmetric tissue properties, as arises clinically in cases of unilateral paralysis. A revised contact model is proposed that remediates the erroneous asymmetric contact forces. The vibration regime map presented in Steinecke and Herzel illustrating the dynamical behavior of the system is revised using the corrected collision model. PMID- 23039565 TI - The effect of noise envelope modulation on quality judgments of noisy speech. AB - This study aims to evaluate how speech quality is affected by noise which varies in modulation from 0% (the lowest correlation with the speech envelope) to 100% (the highest correlation with the speech envelope). Using a scaled paired comparison forced-choice procedure, ten normal-hearing listeners rated overall preference, noisiness, and distortion of speech stimuli with different noise modulation percentages at 0, 10, and 20 dB signal-to-noise ratios. As noise modulation percentage increased, ratings for overall preference increased, ratings for distortion increased, and ratings for noisiness decreased. The noise modulation effects on quality ratings were significant, even at the same signal to-noise ratio. PMID- 23039566 TI - Range estimation for forward scattering of an underwater object with experimental verification. AB - A range estimation scheme is proposed when a moving object is located within the forward scattering coverage. It is based on acoustic field aberrations of the stable arrival caused by forward scattering of the moving object. The durations of acoustic field aberration are measured by transmitting a signal continuously, and then the range of the moving object is estimated if a priori knowledge of the moving speed is supposed to be known. The acoustic field aberrations of the experimental data are clearly observed after matched filtering, and the estimated ranges of the object agree well with the true values. PMID- 23039567 TI - Coherent reflection from surface gravity water waves during reciprocal acoustic transmissions. AB - During a recent experiment in Kauai, Hawaii, reciprocal transmissions were conducted between two acoustic transceivers mounted on the seafloor at a depth of 100 m. The passage of moving surface wave crests was shown to generate focused and intense coherent acoustic returns, which had increasing or decreasing delay depending on the direction of propagation relative to the direction of surface wave crests. It is shown that a rough surface two-dimensional parabolic equation model with an evolving sea surface can produce qualitative agreement with data for the dynamic surface returns. PMID- 23039568 TI - Ultrasonic properties in marrow-filled and water-filled bovine femoral trabecular bones in vitro. AB - Phase velocity and normalized broadband ultrasound attenuation (nBUA) were measured in 22 marrow-filled and water-filled bovine femoral trabecular bone samples. Replacement of marrow by water led to a significant increase in the mean phase velocity of 47 +/- 12 m/s (+3.1%), but a decrease in the mean nBUA of 10.4 +/- 2.9 dB/cm/MHz (-38.9%). All the ultrasonic properties in the marrow-filled and water-filled samples exhibited significant negative Pearson's correlation coefficients of r = -0.87 to -0.92 with porosity. High correlations were also observed between pairs of the ultrasonic properties, with r = 0.85 to 0.93. PMID- 23039569 TI - Statistical voice activity detection in kernel space. AB - This paper proposes a statistical voice activity detection method in a high dimensional kernel feature space by a nonlinear mapping. A Gaussian density model is presented using kernel principal component analysis to represent the nonlinear characteristics of the speech signal. The proposed approach offers a decision rule based on a multiple observation likelihood ratio test in the kernel space. PMID- 23039570 TI - Passive acoustic detection of closed-circuit underwater breathing apparatus in an operational port environment. AB - Divers constitute a potential threat to waterside infrastructures. Active diver detection sonars are available commercially but present some shortcomings, particularly in highly reverberant environments. This has led to research on passive sonar for diver detection. Passive detection of open-circuit UBA (underwater breathing apparatus) has been demonstrated. This letter reports on the detection of a diver wearing closed-circuit UBA (rebreather) in an operational harbor. Beamforming is applied to a passive array of 10 hydrophones in a pseudo-random linear arrangement. Experimental results are presented demonstrating detection of the rebreather at ranges up to 120 m and are validated by GPS ground truth. PMID- 23039571 TI - A non-spectrogram-correlation method of automatically detecting minke whale boings. AB - This letter introduces an algorithm for automatic detection of minke whale boing sounds. This method searches for frequency features of boings without calculating the continuous spectrogram of the data, thereby reducing computational time. The detector has been tested on 8 h of acoustic data recorded at the Station ALOHA Cabled Observatory in March 2007. This dataset was previously analyzed using the cross-correlation detector of XBAT and was verified by a human listener, as reported in Oswald et al. [(2011). J. Acoust. Soc. Am. 129, 3353-3360]. A comparison of results indicates that the detector introduced here generates fewer false alarms, and it recognizes low-SNR calls that are missed by XBAT. PMID- 23039572 TI - Aperiodicity effects on sound transmission through arrays of identical cylinders perpendicular to the ground. AB - Results of laboratory measurements of sound transmission through 5 * 10 arrays of meter long polyvinyl chloride pipes with lattice constants of 5 and 10 cm with filling fractions of 13% and 50% located either on medium density fibreboard or a layer of felt are reported. Ground effects and sonic crystal effects are found to be additive. Measurements and predictions show that, while there is little broadband advantage in a periodic configuration compared with a random one, a quasi-periodic arrangement in which the perturbation has a standard deviation equal to the scatterer diameter gives the best overall attenuation. PMID- 23039573 TI - Speech enhancement using a structured codebook. AB - Codebook-based speech enhancement methods that use trained codebooks of speech and noise spectra provide good performance even under non-stationary noise conditions. A drawback, however, is their high computational cost. For every pair of speech and noise codebook vectors, a likelihood score indicating how well that pair matches the observation is computed. In this paper, a method that identifies and performs only relevant likelihood computations by imposing a hierarchical structure on the speech codebook is proposed. The performance of the proposed method is shown to be close to that of the original scheme but at a significantly lower computational cost. PMID- 23039574 TI - Comparing live to recorded speech in training the perception of spectrally shifted noise-vocoded speech. AB - Two experimental groups were trained for 2 h with live or recorded speech that was noise-vocoded and spectrally shifted and was from the same text and talker. These two groups showed equivalent improvements in performance for vocoded and shifted sentences, and the group trained with recorded speech showed consistently greater improvements than untrained controls. Another group trained with unshifted noise-vocoded speech improved no more than untrained controls. Computer based training thus appears at least as effective as labor-intensive live-voice training for improving the perception of spectrally shifted noise-vocoded speech, and by implication, for training of users of cochlear implants. PMID- 23039575 TI - Averaging underwater noise levels for environmental assessment of shipping. AB - Rising underwater noise levels from shipping have raised concerns regarding chronic impacts to marine fauna. However, there is a lack of consensus over how to average local shipping noise levels for environmental impact assessment. This paper addresses this issue using 110 days of continuous data recorded in the Strait of Georgia, Canada. Probability densities of ~10(7) 1-s samples in selected 1/3 octave bands were approximately stationary across one-month subsamples. Median and mode levels varied with averaging time. Mean sound pressure levels averaged in linear space, though susceptible to strong bias from outliers, are most relevant to cumulative impact assessment metrics. PMID- 23039576 TI - Communication: Explicitly correlated four-component relativistic second-order Moller-Plesset perturbation theory. AB - We propose explicitly correlated Ansatz for four-component relativistic methods within the framework of the no-pair approximation. Kinetically balanced geminal basis is derived to satisfy the cusp conditions in the non-relativistic limit based on the Levy-Leblend-like equation. Relativistic variants of strong orthogonality projection operator (Ansatze 2alpha and 2beta) suitable for practical calculations are introduced by exploiting the orthogonal complement of the large-component basis. A pilot implementation is performed for the second order Moller-Plesset perturbation theory. PMID- 23039577 TI - Communication: On the isotope anomaly of nuclear quadrupole coupling in molecules. AB - The dependence of the nuclear quadrupole coupling constants (NQCC) on the interaction between electrons and a nucleus of finite size is theoretically analyzed. A deviation of the ratio of the NQCCs obtained from two different isotopomers of a molecule from the ratio of the corresponding bare nuclear electric quadrupole moments, known as quadrupole anomaly, is interpreted in terms of the logarithmic derivatives of the electric field gradient at the nuclear site with respect to the nuclear charge radius. Quantum chemical calculations based on a Dirac-exact relativistic methodology suggest that the effect of the changing size of the Au nucleus in different isotopomers can be observed for Au-containing molecules, for which the predicted quadrupole anomaly reaches values of the order of 0.1%. This is experimentally detectable and provides an insight into the charge distribution of non-spherical nuclei. PMID- 23039578 TI - Communication: Restoring full size extensivity in internally contracted multireference coupled cluster theory. AB - The reason for the lack of size extensivity in the valence space in current implementations of internally contracted multireference coupled cluster theories is the procedure used to eliminate redundant components from the cluster operator. We present a simple way to restore full size extensivity by performing this critical step in a basis of excitation operators that are normal ordered with respect to the multiconfigurational reference function. PMID- 23039579 TI - The Ehrenfest force field: Topology and consequences for the definition of an atom in a molecule. AB - The Ehrenfest force is the force acting on the electrons in a molecule due to the presence of the other electrons and the nuclei. There is an associated force field in three-dimensional space that is obtained by the integration of the corresponding Hermitian quantum force operator over the spin coordinates of all of the electrons and the space coordinates of all of the electrons but one. This paper analyzes the topology induced by this vector field and its consequences for the definition of molecular structure and of an atom in a molecule. Its phase portrait reveals: that the nuclei are attractors of the Ehrenfest force, the existence of separatrices yielding a dense partitioning of three-dimensional space into disjoint regions, and field lines connecting the attractors through these separatrices. From the numerical point of view, when the Ehrenfest force field is obtained as minus the divergence of the kinetic stress tensor, the induced topology was found to be highly sensitive to choice of gaussian basis sets at long range. Even the use of large split valence and highly uncontracted basis sets can yield spurious critical points that may alter the number of attraction basins. Nevertheless, at short distances from the nuclei, in general, the partitioning of three-dimensional space with the Ehrenfest force field coincides with that induced by the gradient field of the electron density. However, exceptions are found in molecules where the electron density yields results in conflict with chemical intuition. In these cases, the molecular graphs of the Ehrenfest force field reveal the expected atomic connectivities. This discrepancy between the definition of an atom in a molecule between the two vector fields casts some doubts on the physical meaning of the integration of Ehrenfest forces over the basins of the electron density. PMID- 23039580 TI - Increasing the applicability of density functional theory. III. Do consistent Kohn-Sham density functional methods exist? AB - The concept of a "consistent," Kohn-Sham (KS) density functional theory (DFT) is discussed, where the functional is able to provide good total energies and its self-consistent potential is such that the KS eigenvalues correspond to accurate approximations to the principal ionization potentials for the molecule. Today, none of the vast number of DFT approximations show this property. The one exception is the ab initio dft method built upon the optimized effective potential strategy for exchange and correlation. This qualifies as a DFT method because it represents the correlated density as a single determinant and by imposing that condition, generates local exchange and correlation operators which are used in self-consistent solutions of the orbitals and eigenvalues. Such a "consistent" DFT shares many of the properties of the Dyson equation, but without its frequency dependence and associated complications. The relationship between ab initio dft based on MBPT2 functional and GW method is discussed. Ab initio dft provides a self-consistent, frequency independent, effective independent particle alternative with a local correlation potential. PMID- 23039581 TI - Density functional theory for molecular multiphoton ionization in the perturbative regime. AB - A general implementation of the lowest nonvanishing order perturbation theory for the calculation of molecular multiphoton ionization cross sections is proposed in the framework of density functional theory. Bound and scattering wave functions are expanded in a multicentric basis set and advantage is taken of the full molecular point group symmetry, thus enabling the application of the formalism to medium-size molecules. Multiphoton ionization cross sections and angular asymmetry parameters have been calculated for the two- and four-photon ionization of the H(2) (+) molecule, for linear and circular light polarizations. Both fixed and random orientations of the target molecule have been considered. To demonstrate the efficiency of the proposed methodology, the two-photon cross section and angular asymmetry parameters for the HOMO and HOMO-1 orbital ionization of benzene are also presented. PMID- 23039582 TI - A generalized Irving-Kirkwood formula for the calculation of stress in molecular dynamics models. AB - In non-equilibrium molecular dynamics simulations, continuum mechanics quantities can be computed from the position and momentum of the particles based on the classical Irving-Kirkwood formalism. For practical purposes, the implementations of Irving-Kirkwood formulas often involve a spatial averaging using a smooth kernel function. The resulting formula for the stress has been known as Hardy stress. Usually results obtained this way still need to be further processed to reduce the fluctuation, e.g., by ensemble or time averaging. In this paper we extend Hardy's formulas by systematically incorporating both spatial and temporal averaging into the expression of continuum quantities. The derivation follows the Irving-Kirkwood formalism, and the average quantities still satisfy conservation laws in continuum mechanics. We will discuss the selection of kernel functions and present several numerical tests. PMID- 23039583 TI - Energy conserving, linear scaling Born-Oppenheimer molecular dynamics. AB - Born-Oppenheimer molecular dynamics simulations with long-term conservation of the total energy and a computational cost that scales linearly with system size have been obtained simultaneously. Linear scaling with a low pre-factor is achieved using density matrix purification with sparse matrix algebra and a numerical threshold on matrix elements. The extended Lagrangian Born-Oppenheimer molecular dynamics formalism [A. M. N. Niklasson, Phys. Rev. Lett. 100, 123004 (2008)] yields microcanonical trajectories with the approximate forces obtained from the linear scaling method that exhibit no systematic drift over hundreds of picoseconds and which are indistinguishable from trajectories computed using exact forces. PMID- 23039584 TI - Structural optimization of molecular clusters with density functional theory combined with basin hopping. AB - Identifying the energy minima of molecular clusters is a challenging problem. Traditionally, search algorithms such as simulated annealing, genetic algorithms, or basin hopping are usually used in conjunction with empirical force fields. We have implemented a basin hopping search algorithm combined with density functional theory to enable the optimization of molecular clusters without the need for empirical force fields. This approach can be applied to systems where empirical potentials are not available or may not be sufficiently accurate. We illustrate the effectiveness of the method with studies on water, methanol, and water + methanol clusters as well as protonated water and methanol clusters at the B3LYP+D/6-31+G* level of theory. A new lowest energy structure for H(+)(H(2)O)(7) is predicted at the B3LYP+D/6-31+G* level. In all of the protonated mixed water and methanol clusters, we find that H(+) prefers to combine with methanol rather than water in the lowest-energy structures. PMID- 23039585 TI - Semiclassical evaluation of kinetic isotope effects in 13-atomic system. AB - The semiclassical instanton approach discussed by Kryvohuz [J. Chem. Phys. 134, 114103 (2011)] is applied to calculate kinetic H/D isotope effect (KIE) of intramolecular hydrogen transfer in cis-1,3-pentadiene. All 33 vibrational degrees of freedom are treated quantum mechanically with semiclassical approximation. Nuclear quantum effects such as tunneling under the barrier and zero-point energy are automatically incorporated in the theory, and are shown to be responsible for the observed appreciable kinetic isotope effect in cis-1,3 pentadiene. Over the barrier passage is also automatically included. Numerical calculations are performed on an empirical valence bond potential energy surface and compared with the previous experimental and theoretical studies. An estimation of heavy-atom (12)C/(13)C KIE in the same system is also provided and the factors contributing to it are discussed. PMID- 23039586 TI - Efficient and accurate solver of the three-dimensional screened and unscreened Poisson's equation with generic boundary conditions. AB - We present an explicit solver of the three-dimensional screened and unscreened Poisson's equation, which combines accuracy, computational efficiency, and versatility. The solver, based on a mixed plane-wave/interpolating scaling function representation, can deal with any kind of periodicity (along one, two, or three spatial axes) as well as with fully isolated boundary conditions. It can seamlessly accommodate a finite screening length, non-orthorhombic lattices, and charged systems. This approach is particularly advantageous because convergence is attained by simply refining the real space grid, namely without any adjustable parameter. At the same time, the numerical method features O(NlogN) scaling of the computational cost (N being the number of grid points) very much like plane wave methods. The methodology, validated on model systems, is tailored for leading-edge computer simulations of materials (including ab initio electronic structure computations), but it might as well be beneficial for other research domains. PMID- 23039587 TI - Comparison of some dispersion-corrected and traditional functionals with CCSD(T) and MP2 ab initio methods: dispersion, induction, and basis set superposition error. AB - We compare dispersion and induction interactions for noble gas dimers and for Ne, methane, and 2-butyne with HF and LiF using a variety of functionals (including some specifically parameterized to evaluate dispersion interactions) with ab initio methods including CCSD(T) and MP2. We see that inductive interactions tend to enhance dispersion and may be accompanied by charge-transfer. We show that the functionals do not generally follow the expected trends in interaction energies, basis set superposition errors (BSSE), and interaction distances as a function of basis set size. The functionals parameterized to treat dispersion interactions often overestimate these interactions, sometimes by quite a lot, when compared to higher level calculations. Which functionals work best depends upon the examples chosen. The B3LYP and X3LYP functionals, which do not describe pure dispersion interactions, appear to describe dispersion mixed with induction about as accurately as those parametrized to treat dispersion. We observed significant differences in high-level wavefunction calculations in a basis set larger than those used to generate the structures in many of the databases. We discuss the implications for highly parameterized functionals based on these databases, as well as the use of simple potential energy for fitting the parameters rather than experimentally determinable thermodynamic state functions that involve consideration of vibrational states. PMID- 23039588 TI - Maintain rigid structures in Verlet based cartesian molecular dynamics simulations. AB - An algorithm is presented to maintain rigid structures in Verlet based cartesian molecular dynamics (MD) simulations. After each unconstrained MD step, the coordinates of selected particles are corrected to maintain rigid structures through an iterative procedure of rotation matrix computation. This algorithm, named as SHAPE and implemented in CHARMM program suite, avoids the calculations of Lagrange multipliers, so that the complexity of computation does not increase with the number of particles in a rigid structure. The implementation of this algorithm does not require significant modification of propagation integrator, and can be plugged into any cartesian based MD integration scheme. A unique feature of the SHAPE method is that it is interchangeable with SHAKE for any object that can be constrained as a rigid structure using multiple SHAKE constraints. Unlike SHAKE, the SHAPE method can be applied to large linear (with three or more centers) and planar (with four or more centers) rigid bodies. Numerical tests with four model systems including two proteins demonstrate that the accuracy and reliability of the SHAPE method are comparable to the SHAKE method, but with much more applicability and efficiency. PMID- 23039590 TI - Finite-temperature electronic simulations without the Born-Oppenheimer constraint. AB - The adiabatic approximation, typically assumed when performing standard Born Oppenheimer (BO) molecular dynamics, can become unreliable at finite temperature, and specifically when the temperature is larger than the electronic energy gap between the ground state and the low-lying excited states. In this regime, relevant for many important chemical processes, the non-adiabatic couplings between the electronic energy states can produce finite temperature effects in several molecular properties, such as the geometry, the vibrational frequencies, the binding energy, and several chemical reactions. In this work, we introduce a novel finite-temperature non-adiabatic molecular dynamics based on a novel covariant formulation of the electronic partition function. In this framework, the nuclei are not constrained to move in a specific electronic potential energy surface. Then, by using a rigorous variational upper bound to the free energy, we are led to an approximate partition function that can be evaluated numerically. The method can be applied to any technique capable to provide an energy value over a given wave function ansatz depending on several variational parameters and atomic positions. In this work, we have applied the proposed method within a quantum Monte Carlo (QMC) scheme. In particular, we consider in this first application only classical ions, but we explicitly include an electronic correlation (Jastrow) term in the wave function, by extending in this way the standard variational QMC method, from ground state to finite temperature properties. We show that our approximation reduces correctly to the standard ground-state Born-Oppenheimer (gsBO) at zero temperature and to the correct high temperature limit. Moreover, at temperatures large enough, this method improves the upper bound of the free energy obtained with a single BO energy surface, since within our approach it is possible to estimate the electron entropy of a correlated ansatz in an efficient way. We test this new method on the simple hydrogen molecule, where at low temperature we recover the correct gsBO low temperature limit. Moreover, we show that the dissociation of the molecule is possible at a temperature much smaller than the one corresponding to the gsBO energy surface, in good agreement with experimental evidence. Several extensions of the proposed technique are also discussed, as for instance the inclusion of quantum effects for ions and the calculation of critical (magnetic, superconducting) temperatures. PMID- 23039589 TI - Improved coarse-graining of Markov state models via explicit consideration of statistical uncertainty. AB - Markov state models (MSMs)--or discrete-time master equation models--are a powerful way of modeling the structure and function of molecular systems like proteins. Unfortunately, MSMs with sufficiently many states to make a quantitative connection with experiments (often tens of thousands of states even for small systems) are generally too complicated to understand. Here, I present a bayesian agglomerative clustering engine (BACE) for coarse-graining such Markov models, thereby reducing their complexity and making them more comprehensible. An important feature of this algorithm is its ability to explicitly account for statistical uncertainty in model parameters that arises from finite sampling. This advance builds on a number of recent works highlighting the importance of accounting for uncertainty in the analysis of MSMs and provides significant advantages over existing methods for coarse-graining Markov state models. The closed-form expression I derive here for determining which states to merge is equivalent to the generalized Jensen-Shannon divergence, an important measure from information theory that is related to the relative entropy. Therefore, the method has an appealing information theoretic interpretation in terms of minimizing information loss. The bottom-up nature of the algorithm likely makes it particularly well suited for constructing mesoscale models. I also present an extremely efficient expression for bayesian model comparison that can be used to identify the most meaningful levels of the hierarchy of models from BACE. PMID- 23039591 TI - Exploring constrained quantum control landscapes. AB - The broad success of optimally controlling quantum systems with external fields has been attributed to the favorable topology of the underlying control landscape, where the landscape is the physical observable as a function of the controls. The control landscape can be shown to contain no suboptimal trapping extrema upon satisfaction of reasonable physical assumptions, but this topological analysis does not hold when significant constraints are placed on the control resources. This work employs simulations to explore the topology and features of the control landscape for pure-state population transfer with a constrained class of control fields. The fields are parameterized in terms of a set of uniformly spaced spectral frequencies, with the associated phases acting as the controls. This restricted family of fields provides a simple illustration for assessing the impact of constraints upon seeking optimal control. Optimization results reveal that the minimum number of phase controls necessary to assure a high yield in the target state has a special dependence on the number of accessible energy levels in the quantum system, revealed from an analysis of the first- and second-order variation of the yield with respect to the controls. When an insufficient number of controls and/or a weak control fluence are employed, trapping extrema and saddle points are observed on the landscape. When the control resources are sufficiently flexible, solutions producing the globally maximal yield are found to form connected "level sets" of continuously variable control fields that preserve the yield. These optimal yield level sets are found to shrink to isolated points on the top of the landscape as the control field fluence is decreased, and further reduction of the fluence turns these points into suboptimal trapping extrema on the landscape. Although constrained control fields can come in many forms beyond the cases explored here, the behavior found in this paper is illustrative of the impacts that constraints can introduce. PMID- 23039592 TI - Recoupling of chemical shift anisotropy by R-symmetry sequences in magic angle spinning NMR spectroscopy. AB - (13)C and (15)N chemical shift (CS) interaction is a sensitive probe of structure and dynamics in a wide variety of biological and inorganic systems, and in the recent years several magic angle spinning NMR approaches have emerged for residue specific measurements of chemical shift anisotropy (CSA) tensors in uniformly and sparsely enriched proteins. All of the currently existing methods are applicable to slow and moderate magic angle spinning (MAS) regime, i.e., MAS frequencies below 20 kHz. With the advent of fast and ultrafast MAS probes capable of spinning frequencies of 40-100 kHz, and with the superior resolution and sensitivity attained at such high frequencies, development of CSA recoupling techniques working under such conditions is necessary. In this work, we present a family of R-symmetry based pulse sequences for recoupling of (13)C/(15)N CSA interactions that work well in both natural abundance and isotopically enriched systems. We demonstrate that efficient recoupling of either first-rank (sigma(1)) or second-rank (sigma(2)) spatial components of CSA interaction is attained with appropriately chosen gamma-encoded RN(n)(v) symmetry sequences. The advantage of these gamma-encoded RN(n)(v)-symmetry based CSA (RNCSA) recoupling schemes is that they are suitable for CSA recoupling under a wide range of MAS frequencies, including fast MAS regime. Comprehensive analysis of the recoupling properties of these RN(n)(v) symmetry sequences reveals that the sigma(1)-CSA recoupling symmetry sequences exhibit large scaling factors; however, the partial homonuclear dipolar Hamiltonian components are symmetry allowed, which makes this family of sequences suitable for CSA measurements in systems with weak homonuclear dipolar interactions. On the other hand, the gamma-encoded symmetry sequences for sigma(2)-CSA recoupling have smaller scaling factors but they efficiently suppress the homonuclear dipole-dipole interactions. Therefore, the latter family of sequences is applicable for measurements of CSA parameters in systems with strong homonuclear dipolar couplings, such as uniformly-(13)C labeled biological solids. We demonstrate RNCSA NMR experiments and numerical simulations establishing the utility of this approach to the measurements of (13)C and (15)N CSA parameters in model compounds, [(15)N]-N-acetyl-valine (NAV), [U-(13)C, (15)N]-alanine, [U-(13)C,(15)N]-histidine, and present the application of this approach to [U-(13)C/(15)N]-Tyr labeled C-terminal domain of HIV-1 CA protein. PMID- 23039593 TI - State and species selective energy flow in gas ensembles containing vibrationally excited O2. AB - State-to-state, collision-induced, energy transfer is followed to equilibrium through sequences of collision cycles in gas ensembles containing vibrationally excited oxygen molecules (v = 8 and 1) in several different atomic and molecular bath gases. Quantum state distributions for each of the constituent species are available at each stage of the ensemble's evolution and enable the dominant energy exchange mechanisms to be identified. Equilibration is generally a complex process that evolves through several phases of inter- and intra-molecular events, each with their characteristic response rate to collisions. The results suggest that single quantum state population loss rate constants, however precisely determined, may miss key features of the overall equilibration process. PMID- 23039594 TI - Full dimensional quantum-mechanical simulations for the vibronic dynamics of difluorobenzene radical cation isomers using the multilayer multiconfiguration time-dependent Hartree method. AB - Full dimensional multilayer multiconfiguration time-dependent Hartree (ML-MCTDH) calculations of the dynamics of the three difluorobenzene cationic isomers in five lowest-lying doublet electronic states using the ab initio multistate multimode vibronic coupling Hamiltonian (MMVCH) model are carried out using the Heidelberg MCTDH package. The same dynamical problems, but treated with the MCTDH scheme and using a reduced dimensional ab initio MMVCH model, have been previously reported [S. Faraji, H.-D. Meyer, and H. Koppel, "Multistate vibronic interactions in difluorobenzene radical cations. II Quantum dynamical simulations," J. Chem. Phys. 129, 074311 (2008)]. For easy comparison with the reduced dimensional results, 11D or 10D ML-MCTDH calculations are also performed. Extensive ML-MCTDH test calculations are performed to find appropriate ML-MCTDH wavefunction structures (ML-trees), and the convergence of the ML-MCTDH calculations are carefully checked to ensure accurate results. Based on the appropriate ML-trees, the photoelectron (PE) spectrum and the mass analyzed threshold ionization (MATI) spectrum are simulated, analyzed, and compared with corresponding experimental spectra. Because of its efficient simulation capability for large systems, ML-MCTDH calculations save a considerable amount of central processing unit (CPU)-time, even when a reduced dimensional MMVCH is used, i.e., the same reduced model as in the corresponding MCTDH calculations. Simulations of the experimental PE spectra by full dimensional ML-MCTDH calculations reproduced main peaks, which originate from different electronic states. The agreement is improved as compared to the reduced dimensionality calculations. Unfortunately, the experimental PE spectra are not very well resolved. Therefore, we compare our calculations additionally with highly resolved MATI spectra, which, however, are only available for the X state. Based on a series of ML-MCTDH simulations with longer propagation time for X, a number of vibrational modes, including fundamentals, their combinations, and overtones are simulated and assigned by comparing with the experimental assignments and the ab initio frequencies. Excellent correlation between the experimental and full dimensional ML-MCTDH results show that ML-MCTDH is accurate and very efficient and that the ab initio MMVCH model is very suitable for ML-MCTDH calculations. PMID- 23039595 TI - Al6H18: a baby crystal of gamma-AlH3. AB - Using global-minima search methods based on the density functional theory calculations of (AlH(3))(n) (n = 1-8) clusters, we show that the growth pattern of alanes for n >= 4 is dominated by structures containing hexa-coordinated Al atoms. This is in contrast to the earlier studies where either linear or ring structures of AlH(3) were predicted to be the preferred structures in which the Al atoms can have a maximum of five-fold coordination. Our calculations also reveal that the Al(6)H(18) cluster, with its hexa-coordination of the Al atoms, resembles the unit-cell of gamma-AlH(3), thus Al(6)H(18) is designated as the "baby crystal." The fragmentation energies of the (AlH(3))(n) (n = 2-8) along with the dimerization energies for even n clusters indicate an enhanced stability of the Al(6)H(18) cluster. Both covalent (hybridization) and ionic (charge) contribution to the bonding are the driving factors in stabilizing the isomers containing hexa-coordinated Al atoms. PMID- 23039596 TI - Electronic excitations of C60 fullerene calculated using the ab initio cluster expansion method. AB - The electronic excited states and optical absorption spectrum of C(60) fullerene below 6.2 eV (200 nm) were calculated using the ab initio many-body wavefunction theory of cluster expansion method: the symmetry-adapted cluster-configuration interaction method. Not only optically allowed states but also optically forbidden states were calculated for studying the observed weak absorptions in the visible region. The lowest calculated singlet excited state was the 1(1)G(g) state. The electron correlation effects are important in determining the energy levels of the four low-lying states that have the character of degenerated HOMO LUMO transition. The lowest optically allowed 1(1)T(1u) state was calculated at 3.67 eV; this is significantly higher than the energy values found in previous density functional calculations. The observed weak absorption around 3.08 eV appears to correspond to the optically forbidden 1(1)T(2u) state with intensity borrowing via vibronic couplings. PMID- 23039597 TI - Interaction of phenol with xenon and nitrogen: spectroscopic and computational characterization. AB - Intermolecular complexes of phenol with xenon and nitrogen are studied by infrared absorption spectroscopy in a neon matrix and by quantum chemistry calculations. The pi complex is theoretically the most stable 1:1 phenol???Xe structure, but it has no characteristic shifts in the calculated vibrational spectrum, which complicates its experimental characterization. However, the formation of the pi complex finds indirect but significant support from the experimental results. The calculated spectrum of the less stable H-bonded complex shows a number of characteristic absorptions, but they are not observed in the experiment, indicating the lack of its formation. For the phenol???Xe(n) (n = 2 4) complexes, the calculations predict substantial changes in the vibrational spectra, and the corresponding bands are observed in the matrices with large concentrations of xenon. Our experiments show the high efficiency of the formation of large xenon clusters in a neon matrix that can accommodate a major part of phenol molecules. In contrast to the case of xenon, the H-bonded 1:1 phenol???N(2) complex is found in a neon matrix, and the formation of large N(2) clusters embedding phenol molecules is relatively inefficient. PMID- 23039598 TI - Thermochemical analysis and kinetics aspects for a chemical model for camphene ozonolysis. AB - In this work, a chemical model for the camphene ozonolysis, leading to carbonyl final products, is proposed and discussed on the basis of the thermochemical properties and kinetic data obtained at density functional theory levels of calculation. The mechanism is initiated by the electrophilic attack of ozone to the double bond in camphene leading to a 1,2,3-trioxolane intermediate, which decomposes to peroxy radicals and carbonyl compounds in a total of 10 elementary reactions. The thermodynamic properties (enthalpy and entropies differences) are calculated at 298 K. For the thermochemical evaluation, theoretical calculations are performed with the B3LYP, MPW1PW91, and mPW1K density functionals and the basis sets 6-31G(d), 6-31G(2d,2p), 6-31+G(d,p), and 6-31+G(2d,2p). Eventually, single point calculations adopting the 6-311++G(2d,2p) basis set are performed in order to improve the electronic energies. The enthalpy profiles suggest highly exothermic reactions for the individual steps, with a global enthalpy difference of -179.18 kcal mol(-1), determined at the B3LYP/6-31+G(2d,2p) level. The Gibbs free energy differences for each step, at 298 K, calculated at the B3LYP/6 311++G(2d,2p)//B3LYP/6-31+G(2d,2p) level, are used to estimate the composition of a final product mixture under equilibrium conditions as 58% of camphenilone and 42% of 6,6-dimethyl-E-caprolactone-2,5-methylene. For the reaction kinetics, the bimolecular O(3) + camphene step is assumed to be rate determining in the global mechanism. A saddle point for the ozone addition to the double bond is located and rate constants are determined on the basis of the transition state theory. This saddle point is well represented by a loosely bound structure and corrections for the basis set superposition error (BSSE) are calculated, either by considering the effect over the geometry optimization procedure (here referred as CP1 procedure), or the effect of the BSSE over the electronic energy of a previously optimized geometry, included a posteriori (here referred as CP2). The rate constants, calculated at 298 K from the data obtained at the mPW1K/6 31+G(d,p), CP1/B3LYP//6-31+G(2d,2p), and CP2/B3LYP//6-31+G(2d,2p) levels (3.62 * 10(-18), 1.12 * 10(-18), and 1.39 * 10(-18) cm(3) molecule(-1) s(-1)), are found in good agreement with the available experimental data at the same temperature, 0.9 * 10(-18) cm(3) molecule(-1) s(-1) [R. Atkinson, S. M. Aschmann, and J. Arey, Atmos. Environ. 24, 2647 (1990)]. The importance of the BSSE corrections for the final rate constants must be pointed out. Furthermore, this work will contribute to a better understanding of the chemistry of monoterpenes in the atmosphere, as well as the implications for the phenomena of pollution. PMID- 23039599 TI - Application of the dressed-bound-state molecular strong-field approximation to above-threshold ionization of heteronuclear molecules: NO vs. CO. AB - We theoretically investigate high-order above-threshold ionization (HATI) of heteronuclear diatomic molecules applying the molecular strong-field approximation which includes dressing of the molecular bound state. We consider HATI of nitrogen monoxide molecules, which are characterized by the pi symmetry of their highest occupied molecular orbital. We show that the HATI spectra of NO exhibit characteristic interference structures. We analyze the differences and similarities of the HATI spectra of NO molecules and the spectra of CO (sigma symmetry) and O(2) (pi(g) symmetry) molecules. The symmetry properties of the molecular HATI spectra governed by linearly and elliptically polarized fields are considered in detail. The yields of high-energy electrons, contributing to the plateau region of the photoelectron spectra, strongly depend on the employed ellipticity. PMID- 23039600 TI - THz rotational spectrum of H2F+. AB - In view of recent tremendous advance in astronomical observations in the submillimeter to THz region brought by the Herschel space craft, laboratory high resolution spectroscopic investigations in that frequency region into unstable molecules, in particular, light hydride ions, are urgently needed. As a part of such endeavor, rotational transitions of H(2)F(+) were observed in the THz-region by using a tunable far-infrared spectrometer. These newly detected lines together with the submillimeter-wave lines obtained previously and the combination differences derived from infrared vibration-rotation lines were subject to a least-squares analysis that yielded a set of molecular constants with much better accuracy. The measured and predicted THz transition frequencies should prove to be a useful probe into detection of interstellar H(2)F(+). PMID- 23039601 TI - Solvation of fullerene and fulleride ion in liquid ammonia: structure and dynamics of the solvation shells. AB - Molecular dynamics simulations have been performed to investigate the solvation characteristics of neutral fullerene (C(60)) and charged fulleride anion (C(60)(5 )) in liquid ammonia. Potassium ions are present as counterions in the system containing fulleride ion. In addition to solvation characteristics, dynamical properties of solvation shells are also found out for both the neutral and anionic solutes. Our results reveal the presence of a rather large solvation shell of ammonia molecules around the C(60)(5-) ion. It is found that the ammonia molecules are more closely packed in the first solvation shell of C(60)(5-) than that of C(60). The distributions of ammonia molecules in the solvation shells of C(60) and C(60)(5-) solutes together with hydrogen bonding characteristics of the solvent in different solvation shells are investigated. It is found that the solvation of the small counterions (K(+)) in liquid ammonia is affected very little by the presence of the large C(60)(5-) anion. Regarding the dynamics of ammonia in solvation shells, it is found that the residence, translational and rotational dynamics of ammonia molecules differ significantly between the solvation shells of the neutral and charged fullerene solutes, especially in the first solvation shells. The average lifetimes of ammonia-ammonia hydrogen bonds are calculated from both continuous and intermittent hydrogen bond correlation functions. The calculations of binding energies reveal that the hydrogen bonds are weaker, hence short lived in the solvation shell of C(60)(5-) compared to those in the solvation shell of neutral C(60) and also in bulk liquid ammonia. PMID- 23039602 TI - Revisiting aqueous-acetone mixtures through the concept of molecular emulsions. AB - Aqueous acetone mixtures represent a good example of perfectly miscible liquids in reality, and that hard to mix in silico. This is related to a key problem in molecular simulations, which is to distinguish between strongly micro-segregated mixtures from phase-separated ones. The Kirkwood-Buff integrals of in silico aqueous mixtures are often found to be dramatically higher than the experimental ones, hinting at a possible underlying phase separation. This is the case for many combinations of the force field models chosen for water or for acetone. Herein, we demonstrate, through a proper handling of the tail of the correlation functions, that these high values of the Kirkwood-Buff integrals represent in fact a transient regime within the segregated spatial domains, and that they asymptotically settle down to values in much better agreement with the experimental ones. The concept central to this new approach is that of molecular emulsions, where the long range part of the correlations is modulated by the micro-segregated domains, and that it is necessary to take into this modulation in order to recover the correct thermodynamical properties. PMID- 23039603 TI - The phase diagram of ice Ih, II, and III: a quasi-harmonic study. AB - The phase diagram of ice Ih, II, and III is studied by a quasi-harmonic approximation. The results of this approach are compared to phase diagrams previously derived by thermodynamic integration using path integral and classical simulations, as well as to experimental data. The studied models are based on both flexible (q-TIP4P/F) and rigid (TIP4P/2005, TIP4PQ/2005) descriptions of the water molecule. Many aspects of the simulated phase diagrams are reasonably reproduced by the quasi-harmonic approximation. Advantages of this simple approach are that it is free from the statistical errors inherent to computer simulations, both classical and quantum limits are easily accessible, and the error of the approximation is expected to decrease in the zero temperature limit. We find that the calculated phase diagram of ice Ih, II, and III depends strongly on the hydrogen disorder of ice III, at least for cell sizes typically used in phase coexistence simulations. Either ice II (in the classical limit) or ice III (in the quantum one) may become unstable depending upon the proton disorder in ice III. The comparison of quantum and classical limits shows that the stabilization of ice II is the most important quantum effect in the phase diagram. The lower vibrational zero-point energy of ice II, compared to either ice Ih or III, is the microscopic origin of this stabilization. The necessity of performing an average of the lattice energy over the proton disorder of ice III is discussed. PMID- 23039604 TI - The influence of potassium on the growth of ultra-thin films of para-hexaphenyl on muscovite mica(001). AB - The interaction of potassium with mica(001) and its influence on the subsequent film growth of para-hexaphenyl (6P) was studied by Auger electron spectroscopy, thermal desorption spectroscopy, and atomic force microscopy (AFM). Freshly cleaved mica is covered with 0.5 monolayer (ML) of potassium. By intentional potassium deposition in ultra-high vacuum a saturation of 1 ML can be achieved, which is stable up to 1000 K. Additional potassium desorbs at around 350 K. The film morphology of 6P on mica(001) is significantly influenced by the potassium monolayer. On the freshly cleaved mica surface, which contains 1/2 ML of K, 6P forms needle-like islands which are composed of lying molecules. On the fully potassium covered mica surface 6P grows in form of dendritic islands, composed of standing molecules. The reason for this change is attributed to the removal of lateral electric fields which exist on the freshly cleaved mica surface, due to the specific arrangements of the atoms in the surface near region of mica. PMID- 23039605 TI - A periodic charge-dipole electrostatic model: parametrization for silver slabs. AB - We present an extension of the charge-dipole model for the description of periodic systems. This periodic charge-dipole electrostatic model (PCDEM) allows one to describe the linear response of periodic structures in terms of charge- and dipole-type gaussian basis functions. The long-range electrostatic interaction is efficiently described by means of the continuous fast multipole method. As a first application, the PCDEM method is applied to describe the polarizability of silver slabs. We find that for a correct description of the polarizability of the slabs both charges and dipoles are required. However a continuum set of parametrizations, i.e., different values of the width of charge- and dipole-type gaussians, leads to an equivalent and accurate description of the slabs polarizability but a completely unphysical description of induced charge density inside the slab. We introduced the integral squared density measure which allows one to obtain a unique parametrization which accurately describes both the polarizability and the induced density profile inside the slab. Finally the limits of the electrostatic approximations are also pointed out. PMID- 23039606 TI - Adsorption studies of C6H6 on Cu (111), Ag (111), and Au (111) within dispersion corrected density functional theory. AB - The adsorption energies and changes in surface work functions for benzene on unreconstructed Cu(111), Ag (111), and Au (111) at low coverages have been studied within the framework of dispersion corrected Kohn-Sham density functional theory. Corrections to account for long range dispersive effects between the adsorbate and metal substrate were incorporated via the exchange-hole dipole moment method of Becke and Johnson [J. Chem. Phys. 123, 154101 (2005)]. We show that the dispersion corrected calculations yield significantly improved adsorption energies and work function shifts that are in good agreement with experimental values. PMID- 23039607 TI - Colloidal cluster crystallization dynamics. AB - The crystallization dynamics of a colloidal cluster is modeled using a low dimensional Smoluchowski equation. Diffusion mapping shows that two order parameters are required to describe the dynamics. Using order parameters as metrics for condensation and crystallinity, free energy, and diffusivity landscapes are extracted from brownian dynamics simulations using bayesian inference. Free energy landscapes are validated against Monte Carlo simulations, and mean first-passage times are validated against dynamic simulations. The resulting model enables a low-dimensional description of colloidal crystallization dynamics. PMID- 23039608 TI - Hydrodynamic-induced enantiomeric enrichment of self-assemblies: role of the solid-liquid interface in chiral nucleation and seeding. AB - A simple hydrodynamic model has been developed to explain the experimentally observed chirality selection in stirred solutions of self-assembling achiral dyes. Selection depends on the stirring direction: the dichroic signal reverses its shape in clockwise or anti-clockwise rotations. Our model investigates the possible role of the liquid-solid interface in nucleating, growing, and transferring to the bulk of chiral seeds. The nucleation step requires a double modulation of the hydrodynamic field exhibiting different velocity along two orthogonal axes. Under a series of restrictions, such a condition is easily met at the solid-liquid interface and it is dictated by the boundary conditions and geometry of stirring. In stagnant conditions, growing helices made-up of self assembled achiral dyes have no chiral preference forming a racemic mixture that contains identical amount of right-handed (R) and left-handed (L) configurations. The application of a hydrodynamic torque (related to the velocity gradient and width of the helix) breaks down the original symmetry, a further velocity gradient perpendicular to the first one ensures, after averaging, a slightly different population of R and L conformations. The yields of the hydrodynamic induced chirality excess are extremely tiny, hence the suggested mechanism is significant only if next chirality amplification processes are efficient. Again, hydrodynamics provides a tool for the detachment of weakly bound aggregates once they have reached a critical length. Aggregates are transported in the bulk where the ripening process goes to completion. The efficiency of the surface catalytic effect strongly depends on the aggregate-surface sticking energy, reaching a maximum at intermediate sticking energies (of order of 10 kT). Numerical estimates show that the proposed mechanism is rather efficient, giving rise to entatiomeric excesses near (but smaller than) those experimentally found. PMID- 23039609 TI - Geometric percolation in polydisperse systems of finite-diameter rods: effects due to particle clustering and inter-particle correlations. AB - The impact of particle clustering and correlation upon the percolation behavior of polydisperse cylinders with finite hard core diameter is examined within an analogy to a lattice percolation problem. Percolation thresholds and percolation and backbone probabilities are explored as functions of the degree of clustering and extent of correlation among the inter-particle contacts. The percolation threshold and volume fractions occupied by the infinite network and by the cluster backbone are shown to be quite sensitive to the formation of inter connected cliques of particles and to the presence of correlation among particle contacts. PMID- 23039610 TI - Fast off-lattice Monte Carlo simulations of soft-core spherocylinders: isotropic nematic transition and comparisons with virial expansion. AB - We proposed a novel anisotropic soft-core potential for spherocylinders that takes into account the degree of overlap between two spherocylinders, thus superior to other soft-core spherocylinder models depending only on the minimum distance between two line segments representing spherocylinders, for example, that used by Vink and Schilling [Phys. Rev. E 71, 051716 (2005)]. Using Monte Carlo simulations in an isothermal-isobaric ensemble with replica exchange at different pressures and multiple histogram re-weighting technique, we studied the isotropic-nematic transition of both models, which recover the standard model of hard spherocylinders for liquid crystals as the repulsion strength epsilon -> infinity, and compared simulation results with virial expansion predictions. We found that isotropic-nematic transition still occurs at high enough densities even for small epsilon, and that virial expansion predictions become more accurate with increasing aspect ratio of spherocylinders and should be exact in the limit of infinitely large aspect ratio. PMID- 23039611 TI - Insertion of nanoparticles into polymer brush under variable solvent conditions. AB - In this work, two-dimensional lattice-based self-consistent field theory is used to study the free energy cost associated with the insertion of a nanoparticle into a polymer brush. The nanoparticle is modeled as a cylinder and the self consistent field equations are formulated on a cylindrical lattice. The use of two-dimensional formalism makes it possible to take into account the distortion of the brush density profile due to the embedded nanoinclusion. The insertion free energy penalty is analyzed as a function of the particle size, the brush grafting density, and the solvent quality. In agreement with the earlier simulation work, we find that the insertion free energy cost increases both with the particle size and the brush grafting density and decreases with deteriorating solvent quality. For nanoparticles located deep inside the brush, the insertion free energy is shown to scale with either squared (good solvent) or cubed (poor solvent) monomer volume fraction profile, in agreement with the earlier theoretical results. For shallow nanoinclusions located close to the brush surface, the insertion free energy is shown to scale linearly with the monomer volume fraction profile under both good and theta solvent conditions, again in agreement with the earlier work. PMID- 23039612 TI - Effect of polydispersity, bimodality, and aspect ratio on the phase behavior of colloidal platelet suspensions. AB - We use a fundamental-measure density functional for hard board-like polydisperse particles, in the restricted-orientation approximation, to explain the phase behaviour of platelet colloidal suspensions studied in recent experiments. In particular, we focus our attention on the behavior of the total packing fraction of the mixture, eta, in the region of two-phase isotropic-nematic coexistence as a function of mean aspect ratio, polydispersity, and fraction of total volume gamma occupied by the nematic phase. In our model, platelets are polydisperse in the square section, of side length sigma, but have constant thickness L (and aspect ratio kappa = L/ < 1, with the mean side length). Good agreement between our theory and recent experiments is obtained by mapping the real system onto an effective one, with excluded volume interactions but with thicker particles (due to the presence of long-ranged repulsive interactions between platelets). The effect of polydispersity in both shape and particle size has been taken into account by using a size distribution function with an effective mean-square deviation that depends on both polydispersities. We also show that the bimodality of the size distribution function is required to correctly describe the huge two-phase coexistence gap and the nonlinearity of the function gamma(eta), two important features that these colloidal suspensions exhibit. PMID- 23039613 TI - Sequence-dependent thermodynamics of a coarse-grained DNA model. AB - We introduce a sequence-dependent parametrization for a coarse-grained DNA model [T. E. Ouldridge, A. A. Louis, and J. P. K. Doye, J. Chem. Phys. 134, 085101 (2011)] originally designed to reproduce the properties of DNA molecules with average sequences. The new parametrization introduces sequence-dependent stacking and base-pairing interaction strengths chosen to reproduce the melting temperatures of short duplexes. By developing a histogram reweighting technique, we are able to fit our parameters to the melting temperatures of thousands of sequences. To demonstrate the flexibility of the model, we study the effects of sequence on: (a) the heterogeneous stacking transition of single strands, (b) the tendency of a duplex to fray at its melting point, (c) the effects of stacking strength in the loop on the melting temperature of hairpins, (d) the force extension properties of single strands, and (e) the structure of a kissing-loop complex. Where possible, we compare our results with experimental data and find a good agreement. A simulation code called oxDNA, implementing our model, is available as a free software. PMID- 23039614 TI - The spontaneous curvature of the water-hydrophobe interface. AB - The temperature-dependent solvation of hydrophobic solutes in water is investigated by large-scale molecular dynamics simulations. A simultaneous fit of solvation free energies for spheres and cylinders with radii up to R = 2 nm yields a negative Tolman length on the order of 1 A at room temperature, equivalent to a spontaneous curvature that favors water droplets over cavities. Pronounced crossover effects of the surface free energy are analyzed in terms of higher-order curvature corrections and water-discreteness effects. PMID- 23039615 TI - Structural stability of proteins in aqueous and nonpolar environments. AB - A protein folds into its native structure with the alpha-helix and/or beta-sheet in aqueous solution under the physiological condition. The relative content of these secondary structures largely varies from protein to protein. However, such structural variability is not exhibited in nonaqueous environment. For example, there is a strong trend that alcohol induces a protein to form alpha-helices, and many of the membrane proteins within the lipid bilayer consists of alpha-helices. Here we investigate the structural stability of proteins in aqueous and nonpolar environments using our recently developed free-energy function F = (Lambda - TS)/(k(B)T(0)) = Lambda/(k(B)T(0)) - S/k(B) (T(0) = 298 K and the absolute temperature T is set at T(0)) which is based on statistical thermodynamics. Lambda/(k(B)T(0)) and S/k(B) are the energetic and entropic components, respectively, and k(B) is Boltzmann's constant. A smaller value of the positive quantity, -S, represents higher efficiency of the backbone and side-chain packing promoted by the entropic effect arising from the translational displacement of solvent molecules or the CH(2), CH(3), and CH groups which constitute nonpolar chains of lipid molecules. As for Lambda, in aqueous solution, a transition to a more compact structure of a protein accompanies the break of protein-solvent hydrogen bonds: As the number of donors and acceptors buried without protein intramolecular hydrogen bonding increases, Lambda becomes higher. In nonpolar solvent, lower Lambda simply implies more intramolecular hydrogen bonds formed. We find the following. The alpha-helix and beta-sheet are advantageous with respect to -S as well as Lambda and to be formed as much as possible. In aqueous solution, the solvent-entropy effect on the structural stability is so strong that the close packing of side chains is dominantly important, and the alpha helix and beta-sheet contents are judiciously adjusted to accomplish it. In nonpolar solvent, the solvent-entropy effect is substantially weaker than in aqueous solution. Lambda is crucial and the alpha-helix is more stable than the beta-sheet in terms of Lambda, which develops a tendency that alpha-helices are exclusively chosen. For a membrane protein, alpha-helices are stabilized as fundamental structural units for the same reason, but their arrangement is performed through the entropic effect mentioned above. PMID- 23039616 TI - Aggregation of non-polar solutes in water at different pressures and temperatures: the role of hydrophobic interaction. AB - Due to the importance of the hydrophobic interaction in protein folding, we decided to study the effect of pressure and temperature on the phase transitions of non-polar solutes in water, and thereby their solubility, using molecular dynamics simulations. The main results are: (1) within a certain range, temperature induces the aggregation of Lennard-Jones particles in water; and (2) pressure induces disaggregation of the formed clusters. From the simulated data, a non-monotonic coexistence curve for the binary system was obtained, from which a critical point of T(c) = 383 +/- 9 K and p(c) = 937 +/- 11 bar was determined. The results are in accordance with previous experimental evidence involving transitions of hydrocarbons in water mixtures, and protein unfolding. PMID- 23039617 TI - BDflex: a method for efficient treatment of molecular flexibility in calculating protein-ligand binding rate constants from brownian dynamics simulations. AB - A method developed by Northrup et al. [J. Chem. Phys. 80, 1517 (1984)] for calculating protein-ligand binding rate constants (k(a)) from brownian dynamics (BD) simulations has been widely used for rigid molecules. Application to flexible molecules is limited by the formidable computational cost to treat conformational fluctuations during the long BD simulations necessary for k(a) calculation. Here, we propose a new method called BDflex for k(a) calculation that circumvents this problem. The basic idea is to separate the whole space into an outer region and an inner region, and formulate k(a) as the product of k(E) and eta(d), which are obtained by separately solving exterior and interior problems. k(E) is the diffusion-controlled rate constant for the ligand in the outer region to reach the dividing surface between the outer and inner regions; in this exterior problem conformational fluctuations can be neglected. eta(d) is the probability that the ligand, starting from the dividing surface, will react at the binding site rather than escape to infinity. The crucial step in reducing the determination of eta(d) to a problem confined to the inner region is a radiation boundary condition imposed on the dividing surface; the reactivity on this boundary is proportional to k(E). By confining the ligand to the inner region and imposing the radiation boundary condition, we avoid multiple-crossing of the dividing surface before reaction at the binding site and hence dramatically cut down the total simulation time, making the treatment of conformational fluctuations affordable. BDflex is expected to have wide applications in problems where conformational fluctuations of the molecules are crucial for productive ligand binding, such as in cases where transient widening of a bottleneck allows the ligand to access the binding pocket, or the binding site is properly formed only after ligand entrance induces the closure of a lid. PMID- 23039618 TI - Point/Counterpoint: PET-based GTV definition is the future of radiotherapy treatment planning. PMID- 23039619 TI - Effects of different parameters in the fast scanning method for HIFU treatment. AB - PURPOSE: High-intensity focused ultrasound is a promising method for the noninvasive treatment of benign and malignant tumors. This study analyzes the effects of scanning path, applied power, and geometric characteristics of the transducer on ablation using fast scanning method, a new scanning method that uses high-intensity focused ultrasound at different blood perfusion levels. METHODS: Two transducers, six scanning paths, and three focal patterns were used to examine the ablation results of the fast scanning method using power densities from 1.35 * 10(7) W/m(3) to 4.5 * 10(7) W/m(3) and blood perfusion rates from 2 * 10(-3) ml/ml/s to 16 * 10(-3) ml/ml/s. The Pennes equation was solved using the finite-difference time-domain method to simulate the heating procedure. RESULTS: Based on the results of the fast-scanning method, the different scanning paths exhibited small effect on the total treatment time supported by both simulation and least-square fit. Similar-sized lesions can result from the five different repeated paths, whereas a random path may lead to relative large fluctuations in ablation volume because of asymmetry of the lesions. Higher power levels increase the lesion volume and decrease the treatment time required for ablating a target area using the fast scanning method, whereas increased blood perfusion has the opposite effect on ablation volume and treatment time. A symmetric lesion can be produced through fast scanning method using a 65-element and a 90-element transducer. However, lesion production using the same operation scheme differs between the two transducers. CONCLUSIONS: Unlike traditional scanning methods, fast scanning method produces a planned lesion regardless of scanning path, as long as the path consists of repeated subsequences. This attribute makes fast scanning method an easy-operation scheme that produces relatively large symmetric lesions in homogeneous tissues. Applied power is the most important factor; however, high blood perfusion levels can limit or even hinder the full ablation of the target area. Therefore, tissue perfusion and transducer type should be given special attention to ensure the success and safety of ablation treatment. PMID- 23039620 TI - Second cancer incidence risk estimates using BEIR VII models for standard and complex external beam radiotherapy for early breast cancer. AB - PURPOSE: To compare organ specific cancer incidence risks for standard and complex external beam radiotherapy (including cone beam CT verification) following breast conservation surgery for early breast cancer. METHOD: Doses from breast radiotherapy and kilovoltage cone beam CT (CBCT) exposures were obtained from thermoluminescent dosimeter measurements in an anthropomorphic phantom in which the positions of radiosensitive organs were delineated. Five treatment deliveries were investigated: (i) conventional tangential field whole breast radiotherapy (WBRT), (ii) noncoplanar conformal delivery applicable to accelerated partial beast irradiation (APBI), (iii) two-volume simultaneous integrated boost (SIB) treatment, (iv) forward planned three-volume SIB, and (v) inverse-planned three volume SIB. Conformal and intensity modulated radiotherapy methods were used to plan the complex treatments. Techniques spanned the range from simple methods appropriate for patient cohorts with a low cancer recurrence risk to complex plans relevant to cohorts with high recurrence risk. Delineated organs at risk included brain, salivary glands, thyroid, contralateral breast, left and right lung, esophagus, stomach, liver, colon, and bladder. Biological Effects of Ionizing Radiation (BEIR) VII cancer incidence models were applied to the measured mean organ doses to determine lifetime attributable risk (LAR) for ages at exposure from 35 to 80 yr according to radiotherapy techniques, and included dose from the CBCT imaging. RESULTS: All LAR decreased with age at exposure and were lowest for brain, thyroid, liver, and bladder (<0.1%). There was little dependence of LAR on radiotherapy technique for these organs and for colon and stomach. LAR values for the lungs for the three SIB techniques were two to three times those from WBRT and APBI. Uncertainties in the LAR models outweigh any differences in lung LAR between the SIB methods. Constraints in the planning of the SIB methods ensured that contralateral breast doses and LAR were comparable to WBRT, despite their added complexity. The smaller irradiated volume of the ABPI plan contributed to a halving of LAR for contralateral breast compared with the other plan types. Daily image guided radiotherapy (IGRT) for a left breast protocol using kilovoltage CBCT contributed <10% to LAR for the majority of organs, and did not exceed 22% of total organ dose. CONCLUSIONS: Phantom measurements and calculations of LAR from the BEIR VII models predict that complex breast radiotherapy techniques do not increase the theoretical risk of second cancer incidence for organs distant from the treated breast, or the contralateral breast where appropriate plan constraints are applied. Complex SIB treatments are predicted to increase the risk of second cancer incidence in the lungs compared to standard whole breast radiotherapy; this is outweighed by the threefold reduction in 5 yr local recurrence risk for patients of high risk of recurrence, and young age, from the use of radiotherapy. APBI may have a favorable impact on risk of second cancer in the contralateral breast and lung for older patients at low risk of recurrence. Intensive use of IGRT increased the estimated values of LAR but these are dominated by the effect of the dose from the radiotherapy, and any increase in LAR from IGRT is much lower than the models' uncertainties. PMID- 23039621 TI - A study of respiration-correlated cone-beam CT scans to correct target positioning errors in radiotherapy of thoracic cancer. AB - PURPOSE: There is increasingly widespread usage of cone-beam CT (CBCT) for guiding radiation treatment in advanced-stage lung tumors, but difficulties associated with daily CBCT in conventionally fractionated treatments include imaging dose to the patient, increased workload and longer treatment times. Respiration-correlated cone-beam CT (RC-CBCT) can improve localization accuracy in mobile lung tumors, but further increases the time and workload for conventionally fractionated treatments. This study investigates whether RC-CBCT guided correction of systematic tumor deviations in standard fractionated lung tumor radiation treatments is more effective than 2D image-based correction of skeletal deviations alone. A second study goal compares respiration-correlated vs respiration-averaged images for determining tumor deviations. METHODS: Eleven stage II-IV nonsmall cell lung cancer patients are enrolled in an IRB-approved prospective off-line protocol using RC-CBCT guidance to correct for systematic errors in GTV position. Patients receive a respiration-correlated planning CT (RCCT) at simulation, daily kilovoltage RC-CBCT scans during the first week of treatment and weekly scans thereafter. Four types of correction methods are compared: (1) systematic error in gross tumor volume (GTV) position, (2) systematic error in skeletal anatomy, (3) daily skeletal corrections, and (4) weekly skeletal corrections. The comparison is in terms of weighted average of the residual GTV deviations measured from the RC-CBCT scans and representing the estimated residual deviation over the treatment course. In the second study goal, GTV deviations computed from matching RCCT and RC-CBCT are compared to deviations computed from matching respiration-averaged images consisting of a CBCT reconstructed using all projections and an average-intensity-projection CT computed from the RCCT. RESULTS: Of the eleven patients in the GTV-based systematic correction protocol, two required no correction, seven required a single correction, one required two corrections, and one required three corrections. Mean residual GTV deviation (3D distance) following GTV-based systematic correction (mean +/- 1 standard deviation 4.8 +/- 1.5 mm) is significantly lower than for systematic skeletal-based (6.5 +/- 2.9 mm, p = 0.015), and weekly skeletal-based correction (7.2 +/- 3.0 mm, p = 0.001), but is not significantly lower than daily skeletal-based correction (5.4 +/- 2.6 mm, p = 0.34). In two cases, first-day CBCT images reveal tumor changes-one showing tumor growth, the other showing large tumor displacement-that are not readily observed in radiographs. Differences in computed GTV deviations between respiration correlated and respiration-averaged images are 0.2 +/- 1.8 mm in the superior inferior direction and are of similar magnitude in the other directions. CONCLUSIONS: An off-line protocol to correct GTV-based systematic error in locally advanced lung tumor cases can be effective at reducing tumor deviations, although the findings need confirmation with larger patient statistics. In some cases, a single cone-beam CT can be useful for assessing tumor changes early in treatment, if more than a few days elapse between simulation and the start of treatment. Tumor deviations measured with respiration-averaged CT and CBCT images are consistent with those measured with respiration-correlated images; the respiration-averaged method is more easily implemented in the clinic. PMID- 23039622 TI - Automatic atlas-based segmentation of the breast in MRI for 3D breast volume computation. AB - PURPOSE: Breast density is considered a significant risk factor and an important biomarker influencing the later risk of breast cancer. Prior breast segmentation is required when quantifying breast density with MRI in order to calculate the total breast volume and exclude nonbreast surrounding tissues. This paper describes an automatic 3D breast volume segmentation approach. METHODS: The method is based on 3D local edge detection using phase congruency and Poisson surface reconstruction to extract the total breast volume. The boundary localization framework is integrated to a subsequent shape atlas-based segmentation using a Laplacian framework. RESULTS: The 3D segmentation achieves breast-air and breast-chest wall boundary localization errors with a median of 1.36 mm and 2.68 mm, respectively, and an average volume error of 153.8 cm(3) when tested on 409 MRI datasets. Furthermore, the breast volume assessment technique will produce a 5.3% variability in the estimation of breast density in the tested population. CONCLUSIONS: The fully automated segmentation approach of the breast in MRI allows the computation of total breast volume, a step required for breast density assessment. The use of features invariant to image intensity and a shape atlas to reinforce shape consistency are attractive characteristics of the method. Error analysis demonstrates that 5.3% variability in the estimation of breast density incurred by the method is an acceptable trade-off. PMID- 23039623 TI - Laser speckle contrast imaging: multifractal analysis of data recorded in healthy subjects. AB - PURPOSE: The monitoring of microvascular blood flow can now be performed with laser speckle contrast imaging (LSCI), a new noninvasive laser-based technique. LSCI images have good spatial and temporal resolutions. Nevertheless, from now, few processing of these data have been performed to have a better knowledge on their properties. We herein propose a multifractal analysis of LSCI data recorded in the forearm of healthy subjects, based on the method from Halsey et al., one of the popular methods using the box-counting technique. METHODS: In laser speckle contrast image time sequences, we studied time evolution of pixel values, as well as time evolution of pixel values averaged in regions of interest (ROI) of different sizes. The results are compared with the ones obtained with single point laser Doppler flowmetry (LDF) signals recorded simultaneously to LSCI images. RESULTS: Our work shows that, for the range of scales studied and with the method from Halsey et al., time evolution of pixel values present narrow multifractal spectra, reminding the ones of monofractal data. However, we observe that when LSCI pixel values are averaged in ROI large enough and followed with time, the multifractal spectra become larger and closer to the ones of LDF signals. CONCLUSIONS: Single pixels from laser speckle contrast images may not possess the same multifractal properties as LDF signals. These findings could now be compared with the ones obtained with other ranges of scales and with data recorded from pathological subjects. PMID- 23039624 TI - Segmentation of artifacts and anatomy in CT metal artifact reduction. AB - PURPOSE: Metal objects present in x-ray computed tomography (CT) scans are accompanied by physical phenomena that render CT projections inconsistent with the linear assumption made for analytical reconstruction. The inconsistencies create artifacts in reconstructed images. Metal artifact reduction algorithms replace the inconsistent projection data passing through metals with estimates of the true underlying projection data, but when the data estimates are inaccurate, secondary artifacts are generated. The secondary artifacts may be as unacceptable as the original metal artifacts; therefore, better projection data estimation is critical. This research uses computer vision techniques to create better estimates of the underlying projection data using observations about the appearance and nature of metal artifacts. METHODS: The authors developed a method of estimating underlying projection data through the use of an intermediate image, called the prior image. This method generates the prior image by segmenting regions of the originally reconstructed image, and discriminating between regions that are likely to be metal artifacts and those that are likely to represent anatomical structures. Regions identified as metal artifact are replaced with a constant soft-tissue value, while structures such as bone or air pockets are preserved. This prior image is reprojected (forward projected), and the reprojections guide the estimation of the underlying projection data using previously published interpolation techniques. The algorithm is tested on head CT test cases containing metal implants and compared against existing methods. RESULTS: Using the new method of prior image generation on test images, metal artifacts were eliminated or reduced and fewer secondary artifacts were present than with previous methods. The results apply even in the case of multiple metal objects, which is a challenging problem. The authors did not observe secondary artifacts that were comparable to or worse than the original metal artifacts, as sometimes occurred with the other methods. The accuracy of the prior was found to be more critical than the particular interpolation method. CONCLUSIONS: Metals produce predictable artifacts in CT images of the head. Using the new method, metal artifacts can be discriminated from anatomy, and the discrimination can be used to reduce metal artifacts. PMID- 23039625 TI - Reduction of prostate intrafraction motion using gas-release rectal balloons. AB - PURPOSE: To analyze prostate intrafraction motion using both non-gas-release (NGR) and gas-release (GR) rectal balloons and to evaluate the ability of GR rectal balloons to reduce prostate intrafraction motion. METHODS: Twenty-nine patients with NGR rectal balloons and 29 patients with GR balloons were randomly selected from prostate patients treated with proton therapy at the University of Florida Proton Therapy Institute (Jacksonville, FL). Their pretreatment and post treatment orthogonal radiographs were analyzed, and both pretreatment setup residual error and intrafraction-motion data were obtained. Population histograms of intrafraction motion were plotted for both types of balloons. Population planning target-volume (PTV) margins were calculated with the van Herk formula of 2.5Sigma + 0.7sigma to account for setup residual errors and intrafraction motion errors. RESULTS: Pretreatment and post-treatment radiographs indicated that the use of gas-release rectal balloons reduced prostate intrafraction motion along superior-inferior (SI) and anterior-posterior (AP) directions. Similar patient setup residual errors were exhibited for both types of balloons. Gas-release rectal balloons resulted in PTV margin reductions from 3.9 to 2.8 mm in the SI direction, 3.1 to 1.8 mm in the AP direction, and an increase from 1.9 to 2.1 mm in the left-right direction. CONCLUSIONS: Prostate intrafraction motion is an important uncertainty source in radiotherapy after image-guided patient setup with online corrections. Compared to non-gas-release rectal balloons, gas-release balloons can reduce prostate intrafraction motion in the SI and AP directions caused by gas buildup. PMID- 23039626 TI - Using statistical measures for automated comparison of in-beam PET data. AB - PURPOSE: Positron emission tomography (PET) is considered to be the state of the art technique to monitor particle therapy in vivo. To evaluate the beam delivery the measured PET image is compared to a predicted beta(+)-distribution. Nowadays the range assessment is performed by a group of experts via visual inspection. This procedure is rather time consuming and requires well trained personnel. In this study an approach is presented to support human decisions in an automated and objective way. METHODS: The automated comparison presented uses statistical measures, namely, Pearson's correlation coefficient (PCC), to detect ion beam range deviations. The study is based on 12 in-beam PET patient data sets recorded at GSI and 70 artificial beam range modifications per data set. The range modifications were 0, 4, 6, and 10 mm water equivalent path length (WEPL) in positive and negative beam directions. The reference image to calculate the PCC was both an unmodified simulation of the activity distribution (Test 1) and a measured in-beam PET image (Test 2). Based on the PCCs sensitivity and specificity were calculated. Additionally the difference between modified and unmodified data sets was investigated using the Wilcoxon rank sum test. RESULTS: In Test 1 a sensitivity and specificity over 90% was reached for detecting modifications of +/-10 and +/-6 mm WEPL. Regarding Test 2 a sensitivity and specificity above 80% was obtained for modifications of +/-10 and -6 mm WEPL. The limitation of the method was around 4 mm WEPL. CONCLUSIONS: The results demonstrate that the automated comparison using PCC provides similar results in terms of sensitivity and specificity compared to visual inspections of in-beam PET data. Hence the method presented in this study is a promising and effective approach to improve the efficiency in the clinical workflow in terms of particle therapy monitoring by means of PET. PMID- 23039627 TI - Is RapidArc more susceptible to delivery uncertainties than dynamic IMRT? AB - PURPOSE: Rotational IMRT has been adopted by many clinics for its promise to deliver treatments in a shorter amount of time than other conventional IMRT techniques. In this paper, the authors investigate whether RapidArc is more susceptible to delivery uncertainties than dynamic IMRT using fixed fields. METHODS: Dosimetric effects of delivery uncertainties in dose rate, gantry angle, and MLC leaf positions were evaluated by incorporating these uncertainties into RapidArc and sliding window IMRT (SW IMRT) treatment plans for five head-and-neck and five prostate cases. Dose distributions and dose-volume histograms of original and modified plans were recalculated and compared using Gamma analysis and dose indices of planned treatment volumes (PTV) and organs at risk (OAR). Results of Gamma analyses using passing criteria ranging from 1%-1 mm up to 5%-3 mm were reported. RESULTS: Systematic shifts in MLC leaf bank positions of SW IMRT cases resulted in 2-4 times higher average percent differences than RapidArc cases. Uniformly distributed random variations of 2 mm for active MLC leaves had a negligible effect on all dose distributions. Sliding window cases were much more sensitive to systematic shifts in gantry angle. Dose rate variations during RapidArc must be much larger than typical machine tolerances to affect dose distributions significantly; dynamic IMRT is inherently not susceptible to such variations. CONCLUSIONS: RapidArc deliveries were found to be more tolerant to variations in gantry position and MLC leaf position than SW IMRT. This may be attributed to the fact that the average segmental field size or MLC leaf opening is much larger for RapidArc. Clinically acceptable treatments may be delivered successfully using RapidArc despite large fluctuations in dose rate and gantry position. PMID- 23039628 TI - Reliability of predicting image signal-to-noise ratio using noise equivalent count rate in PET imaging. AB - PURPOSE: Several investigators have shown that noise equivalent count rate (NECR) is linearly proportional to the square of image signal-to-noise ratio (SNR) when PET images are reconstructed using filtered back-projection. However, to our knowledge, none have shown a similar relationship in fully 3D ordered-subset expectation maximization (OSEM) reconstruction. This paper has two aims. The first is to investigate the NECR-SNR relationship for 3D-OSEM reconstruction using phantom studies while the second aim is to evaluate the NECR-SNR relationship using patient data. METHODS: An anthropomorphic phantom was scanned on a GE Discovery-STE (DSTE) PET/CT scanner in 3D mode with an initial activity concentration of 66.34 kBq/cc. PET data were acquired over the lower chest/upper abdomen region in dynamic mode. The experiment was repeated with the same activity concentration on a GE Discovery-RX (DRX) scanner. Care was taken to place the phantom at identical positions in both scanners. PET data were then reconstructed using 3D Reprojection (3D-RP) and 3D-OSEM with different reconstruction parameters and the NECR and SNR for each frame/image were calculated. SNR(2) was then plotted versus the NECR for each scanner, reconstruction method and parameters. In addition, 40 clinical PET/CT studies from the two scanners (20 patients/scanner) were evaluated retrospectively. The patient studies from each scanner were further divided into two subgroups of body mass indices (BMI). Each PET study was acquired in 3D mode and reconstructed using both 3D-OSEM and 3D-RP. The NECR and SNR of the bed position covering the patient liver were calculated for each patient and averaged for each subgroup. Comparisons of the NECR and SNR between scanner types and BMIs were performed using a t-test and a p value less than 0.05 was considered significant. RESULTS: Phantom results showed that SNR(2) versus NECR was linear for 3D-RP reconstruction across all activity concentration on both scanners, as expected. However, when 3D-OSEM was used, this relationship was nonlinear at activity concentrations beyond the peak NECR on both scanners. On the other hand, the plot of SNR(2) versus trues count rate was linear for 3D-OSEM across all activity concentrations on both scanners independent of reconstruction parameters used. In addition, for activity concentrations <30kBq/cc, phantom results showed a higher SNR (by 12 +/- 10%; p < 0.05) and NECR for the DRX scanner compared to DSTE for 3D-RP reconstruction. However, for 3D-OSEM reconstruction, these two scanners had similar SNRs (different by 2% +/- 9%; p > 0.05), despite having different NECRs. Patient studies showed a statistically significant difference in NECR as well as the SNR for 3D-RP reconstruction between the two scanners. However, no statistically significant difference was found for 3D-OSEM. A statistically significant difference in both NECR and SNR were found between the different BMI subgroups for both 3D-RP and 3D-OSEM reconstructions. CONCLUSIONS: For the scanners and reconstruction algorithm used in this study, our results suggest that the image SNR cannot be predicted by the NEC when using 3D-OSEM reconstruction particularly for those clinical applications requiring high activity concentration. Instead, our results suggest that image SNR varies with activity concentration and is dominated by the 3D-OSEM reconstruction algorithm and its associated parameters, while not being affected by the scanner type for the range of activity concentrations usually found in the clinic. PMID- 23039629 TI - Relationship between x-ray illumination field size and flat field intensity and its impacts on x-ray imaging. AB - PURPOSE: X-ray cone-beam CT (CBCT) is being increasingly used for various clinical applications, while its performance is still hindered by image artifacts. This work investigates a new source of reconstruction error, which is often overlooked in the current CBCT imaging. The authors find that the x-ray flat field intensity (I(0)) varies significantly as the illumination volume size changes at different collimator settings. A wrong I(0) value leads to inaccurate CT numbers of reconstructed images as well as wrong scatter measurements in the CBCT research. METHODS: The authors argue that the finite size of x-ray focal spot together with the detector glare effect cause the I(0) variation at different illumination sizes. Although the focal spot of commercial x-ray tubes typically has a nominal size of less than 1 mm, the off-focal-spot radiation covers an area of several millimeters on the tungsten target. Due to the large magnification factor from the field collimator to the detector, the penumbra effects of the collimator blades result in different I(0) values for different illumination field sizes. Detector glare further increases the variation, since one pencil beam of incident x-ray is scattered into an area of several centimeters on the detector. In this paper, the authors study these two effects by measuring the focal spot distribution with a pinhole assembly and the detector point spread function (PSF) with an edge-spread function method. The authors then derive a formula to estimate the I(0) value for different illumination field sizes, using the measured focal spot distribution and the detector PSF. Phantom studies are carried out to investigate the accuracy of scatter measurements and CT images with and without considering the I(0) variation effects. RESULTS: On our tabletop system with a Varian Paxscan 4030CB flat-panel detector and a Varian RAD-94 x-ray tube as used on a clinical CBCT system, the focal spot distribution has a measured full-width-at-half-maximum (FWHM) of around 0.4 mm, while non negligible off-focal-spot radiation is observed at a distance of over 2 mm from the center. The measured detector PSF has an FWHM of 0.510 mm, with a shape close to Gaussian. From these two distributions, the author calculate the estimated I(0) values at different collimator settings. The I(0) variation mainly comes from the focal spot effect. The estimation matches well with the measurements at different collimator widths in both horizontal and vertical directions, with an average error of less than 3%. Our method improves the accuracy of conventional scatter measurements, where the scatter is measured as the difference between fan beam and cone-beam projections. On a uniform water cylinder phantom, more accurate I(0) suppresses the unfaithful high-frequency signals at the object boundaries of the measured scatter, and the SPR estimation error is reduced from 0.158 to 0.014. The proposed I(0) estimation also reduces the reconstruction error from about 20 HU on the Catphan(c)600 phantom in the selected regions of interest to less than 4 HU. CONCLUSIONS: The I(0) variation is identified as one additional error source in x-ray imaging. By measuring the focal-spot distribution and detector PSF, the authors propose an accurate method of estimating the I(0) value for different illumination field sizes. The method obtains more accurate scatter measurements and therefore facilitates scatter correction algorithm designs. As correction methods for other CBCT artifacts become more successful, our research is significant in further improving the CBCT imaging accuracy. PMID- 23039630 TI - Dosimetric properties of radiophotoluminescent glass detector in low-energy photon beams. AB - PURPOSE: A radiophotoluminescent glass rod dosimeter (RGD) has recently become commercially available. It is being increasingly used for dosimetry in radiotherapy to measure the absorbed dose including scattered low-energy photons on the body surface of a patient and for postal dosimetry audit. In this article, the dosimetric properties of the RGD, including energy dependence of the dose response, reproducibly, variation in data obtained by the RGD for each energy, and angular dependence in low-energy photons, are discussed. METHODS: An RGD (GD 301, Asahi Techno Glass Corporation, Shizuoka, Japan) was irradiated with monochromatic low-energy photon beams generated by synchrotron radiation at Photon Factory, High Energy Accelerator Research Organization (KEK). The size of GD-301 was 1.5 mm in diameter and 8.5 mm in length and the active dose readout volume being 1 mm diameter and 0.6 mm depth located 0.7 mm from the end of the detector. The energy dependence of the dose response and reproducibility and variation were investigated for RGDs irradiated with a plastic holder and those irradiated without the plastic holder. Response of the RGD was obtained by not only conventional single field irradiation but also bilateral irradiation. Angular dependence of the RGD was measured in the range of 0 degrees -90 degrees for 13, 17, 40, and 80 keV photon beams by conventional single field irradiation. RESULTS: The dose responses had a peak at around 40 keV. For the energy range of less than 25 keV, all dose response curves steeply decreased in comparison with the ratio of mass energy absorption coefficient of the RGD to that of air. As for the reproducibility and variation in data obtained by the RGD, the coefficient of variance increased with decrease in photon energy. Furthermore, the variation for bilateral irradiation was less than that for single field irradiation. Regarding angular dependence of the RGD, for energies of 13 and 17 keV, the response decreased with increase in the irradiation angle, and the minimum values were 93.5% and 86%, respectively. CONCLUSIONS: Our results showed the dosimetric properties of the RGD, including the energy dependence of the dose response, reproducibly, variation, and angular dependence in low-energy photons and suggest that the accuracy of the absorbed dose in low-energy photons is affected by the readout method and the distribution of radiophotoluminescence centers in the RGD. PMID- 23039631 TI - Correlation of free-response and receiver-operating-characteristic area-under-the curve estimates: results from independently conducted FROC/ROC studies in mammography. AB - PURPOSE: From independently conducted free-response receiver operating characteristic (FROC) and receiver operating characteristic (ROC) experiments, to study fixed-reader associations between three estimators: the area under the alternative FROC (AFROC) curve computed from FROC data, the area under the ROC curve computed from FROC highest rating data, and the area under the ROC curve computed from confidence-of-disease ratings. METHODS: Two hundred mammograms, 100 of which were abnormal, were processed by two image-processing algorithms and interpreted by four radiologists under the FROC paradigm. From the FROC data, inferred-ROC data were derived, using the highest rating assumption. Eighteen months afterwards, the images were interpreted by the same radiologists under the conventional ROC paradigm; conventional-ROC data (in contrast to inferred-ROC data) were obtained. FROC and ROC (inferred, conventional) data were analyzed using the nonparametric area-under-the-curve (AUC), (AFROC and ROC curve, respectively). Pearson correlation was used to quantify the degree of association between the modality-specific AUC indices and standard errors were computed using the bootstrap-after-bootstrap method. The magnitude of the correlations was assessed by comparison with computed Obuchowski-Rockette fixed reader correlations. RESULTS: Average Pearson correlations (with 95% confidence intervals in square brackets) were: Corr(FROC, inferred ROC) = 0.76[0.64, 0.84] > Corr(inferred ROC, conventional ROC) = 0.40[0.18, 0.58] > Corr (FROC, conventional ROC) = 0.32[0.16, 0.46]. CONCLUSIONS: Correlation between FROC and inferred-ROC data AUC estimates was high. Correlation between inferred- and conventional-ROC AUC was similar to the correlation between two modalities for a single reader using one estimation method, suggesting that the highest rating assumption might be questionable. PMID- 23039633 TI - 4D patient dose reconstruction using online measured EPID cine images for lung SBRT treatment validation. AB - PURPOSE: This study aims to develop an EPID-guided 4D patient dose reconstruction framework and to investigate its feasibility for lung SBRT treatment validation. METHODS: Both the beam apertures and tumor movements were detected based on the continuously acquired EPID images during the treatment. Instead of directly using the transit photon fluence measured by the EPID, this method reconstructed the entrance fluence with the measured beam apertures and the delivered MUs. The entrance fluence distributions were sorted into their corresponding phases based on the detected tumor motion pattern and then accumulated for each phase. Together with the in-room 4DCT taken before every treatment to consider the interfractional-motion, the entrance fluence was then used for the patient dose calculation. Deformable registration was performed to sum up the phase doses for final treatment assessment. The feasibility of using the transit EPID images for entrance fluence reconstruction was evaluated against EPID in-air measurements. The accuracy of 3D- and 4D-dose reconstruction was validated by experiments with a motor-driven cylindrical diode array for six clinical-SBRT plans. RESULTS: The average difference between the measured and reconstructed fluence maps was within 0.16%. The reconstructed 3D-dose showed a less than 1.4% difference for the CAX dose and at least a 98.3% gamma-passing-rate (2%/2 mm) for the peripheral dose. Distorted dose distributions were observed in the measurement with the moving phantom. The comparison between the measured and the reconstructed 4D-dose without considering temporal information failed the gamma-evaluation for most cases. In contrast, when temporal information was considered, the dose distortion phenomena were successfully represented in the reconstructed dose (97.6%-99.7% gamma-passing rate). CONCLUSIONS: The proposed method considered uncertainties of the beam delivery system, the interfractional- and intrafractional-motion, and the interplay effect. The experimental validation demonstrates that this method is practical and accurate for online or offline SBRT patient dose verification. PMID- 23039632 TI - Characterization of statistical prior image constrained compressed sensing. I. Applications to time-resolved contrast-enhanced CT. AB - PURPOSE: Prior image constrained compressed sensing (PICCS) is an image reconstruction framework that takes advantage of a prior image to improve the image quality of CT reconstructions. An interesting question that remains to be investigated is whether or not the introduction of a statistical model of the photon detection in the PICCS reconstruction framework can improve the performance of the algorithm when dealing with high noise projection datasets. The goal of the research presented in this paper is to characterize the noise properties of images reconstructed using PICCS with and without statistical modeling. This paper investigates these properties in the clinical context of time-resolved contrast-enhanced CT. METHODS: Both numerical phantom studies and an Institutional Review Board approved human subject study were used in this research. The conventional filtered backprojection (FBP), and PICCS with and without the statistical model were applied to each dataset. The prior image used in PICCS was generated by averaging over FBP reconstructions from different time frames of the time-resolved CT exam, thus reducing the noise level. Numerical studies were used to evaluate if the noise characteristics are altered for varying levels of noise, as well as for different object shapes. The dataset acquired in vivo was used to verify that the conclusions reached from numerical studies translate adequately to a clinical case. The results were analyzed using a variety of qualitative and quantitative metrics such as the universal image quality index, spatial maps of the noise standard deviations, the noise uniformity, the noise power spectrum, and the model-observer detectability. RESULTS: The noise characteristics of PICCS were shown to depend on the noise level contained in the data, the level of eccentricity of the object, and whether or not the statistical model was applied. Most differences in the characteristics were observed in the regime of low incident x-ray fluence. No substantial difference was observed between PICCS with and without statistics in the high fluence domain. Objects with a semi-major axis ratio below 0.85 were more accurately reconstructed with lower noise using the statistical implementation. Above that range, for mostly circular objects, the PICCS implementation without the statistical model yielded more accurate images and a lower noise level. At all levels of eccentricity, the noise spatial distribution was more uniform and the model-observer detectability was greater for PICCS with the statistical model. The human subject study was consistent with the results obtained using numerical simulations. CONCLUSIONS: For mildly eccentric objects in the low noise regime, PICCS without the noise model yielded equal or better noise level and image quality than the statistical formulation. However, in a vast majority of cases, images reconstructed using statistical PICCS have a noise power spectrum that facilitated the detection of model lesions. The inclusion of a statistical model in the PICCS framework does not always result in improved noise characteristics. PMID- 23039634 TI - Auto calibration of a cone-beam-CT. AB - PURPOSE: This paper introduces a novel autocalibration method for cone-beam-CTs (CBCT) or flat-panel CTs, assuming a perfect rotation. The method is based on ellipse-fitting. Autocalibration refers to accurate recovery of the geometric alignment of a CBCT device from projection images alone, without any manual measurements. METHODS: The authors use test objects containing small arbitrarily positioned radio-opaque markers. No information regarding the relative positions of the markers is used. In practice, the authors use three to eight metal ball bearings (diameter of 1 mm), e.g., positioned roughly in a vertical line such that their projection image curves on the detector preferably form large ellipses over the circular orbit. From this ellipse-to-curve mapping and also from its inversion the authors derive an explicit formula. Nonlinear optimization based on this mapping enables them to determine the six relevant parameters of the system up to the device rotation angle, which is sufficient to define the geometry of a CBCT-machine assuming a perfect rotational movement. These parameters also include out-of-plane rotations. The authors evaluate their method by simulation based on data used in two similar approaches [L. Smekal, M. Kachelriess, S. E, and K. Wa, "Geometric misalignment and calibration in cone-beam tomography," Med. Phys. 31(12), 3242-3266 (2004); K. Yang, A. L. C. Kwan, D. F. Miller, and J. M. Boone, "A geometric calibration method for cone beam CT systems," Med. Phys. 33(6), 1695-1706 (2006)]. This allows a direct comparison of accuracy. Furthermore, the authors present real-world 3D reconstructions of a dry human spine segment and an electronic device. The reconstructions were computed from projections taken with a commercial dental CBCT device having two different focus to-detector distances that were both calibrated with their method. The authors compare their reconstruction with a reconstruction computed by the manufacturer of the CBCT device to demonstrate the achievable spatial resolution of their calibration procedure. RESULTS: Compared to the results published in the most closely related work [K. Yang, A. L. C. Kwan, D. F. Miller, and J. M. Boone, "A geometric calibration method for cone beam CT systems," Med. Phys. 33(6), 1695 1706 (2006)], the simulation proved the greater accuracy of their method, as well as a lower standard deviation of roughly 1 order of magnitude. When compared to another similar approach [L. Smekal, M. Kachelriess, S. E, and K. Wa, "Geometric misalignment and calibration in cone-beam tomography," Med. Phys. 31(12), 3242 3266 (2004)], their results were roughly of the same order of accuracy. Their analysis revealed that the method is capable of sufficiently calibrating out-of plane angles in cases of larger cone angles when neglecting these angles negatively affects the reconstruction. Fine details in the 3D reconstruction of the spine segment and an electronic device indicate a high geometric calibration accuracy and the capability to produce state-of-the-art reconstructions. CONCLUSIONS: The method introduced here makes no requirements on the accuracy of the test object. In contrast to many previous autocalibration methods their approach also includes out-of-plane rotations of the detector. Although assuming a perfect rotation, the method seems to be sufficiently accurate for a commercial CBCT scanner. For devices which require higher dimensional geometry models, the method could be used as a initial calibration procedure. PMID- 23039635 TI - Automatic assistance to Parkinson's disease diagnosis in DaTSCAN SPECT imaging. AB - PURPOSE: In this work, an approach to computer aided diagnosis (CAD) system is proposed as a decision-making aid in Parkinsonian syndrome (PS) detection. This tool, intended for physicians, entails fully automatic preprocessing, normalization, and classification procedures for brain single-photon emission computed tomography images. METHODS: Ioflupane[(123)I]FP-CIT images are used to provide in vivo information of the dopamine transporter density. These images are preprocessed using an automated template-based registration followed by two proposed approaches for intensity normalization. A support vector machine (SVM) is used and compared to other statistical classifiers in order to achieve an effective diagnosis using whole brain images in combination with voxel selection masks. RESULTS: The CAD system is evaluated using a database consisting of 208 DaTSCAN images (100 controls, 108 PS). SVM-based classification is the most efficient choice when masked brain images are used. The generalization performance is estimated to be 89.02 (90.41-87.62)% sensitivity and 93.21 (92.24 94.18)% specificity. The area under the curve can take values of 0.9681 (0.9641 0.9722) when the image intensity is normalized to a maximum value, as derived from the receiver operating characteristics curves. CONCLUSIONS: The present analysis allows to evaluate the impact of the design elements for the development of a CAD-system when all the information encoded in the scans is considered. In this way, the proposed CAD-system shows interesting properties for clinical use, such as being fast, automatic, and robust. PMID- 23039636 TI - Segmentation of malignant gliomas through remote collaboration and statistical fusion. AB - PURPOSE: Malignant gliomas represent an aggressive class of central nervous system neoplasms. Correlation of interventional outcomes with tumor morphometry data necessitates 3D segmentation of tumors (typically based on magnetic resonance imaging). Expert delineation is the long-held gold standard for tumor segmentation, but is exceptionally resource intensive and subject to intrarater and inter-rater variability. Automated tumor segmentation algorithms have been demonstrated for a variety of imaging modalities and tumor phenotypes, but translation of these methods across clinical study designs is problematic given variation in image acquisition, tumor characteristics, segmentation objectives, and validation criteria. Herein, the authors demonstrate an alternative approach for high-throughput tumor segmentation using Internet-based, collaborative labeling. METHODS: In a study of 85 human raters and 98 tumor patients, raters were recruited from a general university campus population (i.e., no specific medical knowledge), given minimal training, and provided web-based tools to label MRI images based on 2D cross sections. The labeling goal was characterized as to extract the enhanced tumor cores on T1-weighted MRI and the bright abnormality on T2-weighted MRI. An experienced rater manually constructed the ground truth volumes of a randomly sampled subcohort of 48 tumor subjects (for both T1w and T2w). Raters' taskwise individual observations, as well as the volume wise truth estimates via statistical fusion method, were evaluated over the subjects having the ground truth. RESULTS: Individual raters were able to reliably characterize (with >0.8 dice similarity coefficient, DSC) the gadolinium-enhancing cores and extent of the edematous areas only slightly more than half of the time. Yet, human raters were efficient in terms of providing these highly variable segmentations (less than 20 s per slice). When statistical fusion was used to combine the results of seven raters per slice for all slices in the datasets, the 3D agreement of the fused results with expertly delineated segmentations was on par with the inter-rater reliability observed between experienced raters using traditional 3D tools (approximately 0.85 DSC). The cumulative time spent per tumor patient with the collaborative approach was equivalent to that with an experienced rater, but the collaborative approach could be achieved with less training time, fewer resources, and efficient parallelization. CONCLUSIONS: Hence, collaborative labeling is a promising technique with potentially wide applicability to cost-effective manual labeling of medical images. PMID- 23039637 TI - Detailed high-accuracy megavoltage transmission measurements: a sensitive experimental benchmark of EGSnrc. AB - PURPOSE: There are three goals for this study: (a) to perform detailed megavoltage transmission measurements in order to identify the factors that affect the measurement accuracy, (b) to use the measured data as a benchmark for the EGSnrc system in order to identify the computational limiting factors, and (c) to provide data for others to benchmark Monte Carlo codes. METHODS: Transmission measurements are performed at the National Research Council Canada on a research linac whose incident electron parameters are independently known. Automated transmission measurements are made on-axis, down to a transmission value of ~1.7%, for eight beams between 10 MV (the lowest stable MV beam on the linac) and 30 MV, using fully stopping Be, Al, and Pb bremsstrahlung targets and no fattening filters. To diversify energy differentiation, data are acquired for each beam using low-Z and high-Z attenuators (C and Pb) and Farmer chambers with low-Z and high-Z buildup caps. Experimental corrections are applied for beam drifts (2%), polarity (2.5% typical maximum, 6% extreme), ion recombination (0.2%), leakage (0.3%), and room scatter (0.8%)-the values in parentheses are the largest corrections applied. The experimental setup and the detectors are modeled using EGSnrc, with the newly added photonuclear attenuation included (up to a 5.6% effect). A detailed sensitivity analysis is carried out for the measured and calculated transmission data. RESULTS: The developed experimental protocol allows for transmission measurements with 0.4% uncertainty on the smallest signals. Suggestions for accurate transmission measurements are provided. Measurements and EGSnrc calculations agree typically within 0.2% for the sensitivity of the transmission values to the detector details, to the bremsstrahlung target material, and to the incident electron energy. Direct comparison of the measured and calculated transmission data shows agreement better than 2% for C (3.4% for the 10 MV beam) and typically better than 1% for Pb. The differences can be explained by acceptable photon cross section changes of <=0.4%. CONCLUSIONS: Accurate transmission measurements require accounting for a number of influence quantities which, if ignored, can collectively introduce errors larger than 10%. Accurate transmission calculations require the use of the most accurate data and physics options available in EGSnrc, particularly the more accurate bremsstrahlung angular sampling option and the newly added modeling of photonuclear attenuation. Comparison between measurements and calculations implies that EGSnrc is accurate within 0.2% for relative ion chamber response calculations. Photon cross section uncertainties are the ultimate limiting factor for the accuracy of the calculated transmission data (Monte Carlo or analytical). PMID- 23039638 TI - Motion mitigation in intensity modulated particle therapy by internal target volumes covering range changes. AB - PURPOSE: Particle therapy offers benefits over conventional photon therapy but also introduces sensitivity to changes in the water-equivalent path length (WEPL) in case of target motion, e.g., breathing. Target motion can be addressed by the internal target volume (ITV) approach, defined as the CTV plus target movement. In photon therapy, the ITV can be constructed as the geometric union of CTVs in all motion states (GEO-ITV) of a 4D-CT, but this does not account for WEPL changes. An ITV including WEPL-changes can be defined as the union of all CTVs transformed to a WEPL-equivalent axis along beam's eye view. The resulting WEPL ITV is field-specific and thus unsuitable for intensity modulated particle therapy (IMPT). The purpose of this study was an IMPT-compatible ITV by splitting geometrical motion and field-specific WEPL changes, following ICRU 78 recommendations. METHODS: For all fields, the GEO-ITV was used as a common target. This identical geometry for all fields was mapped to an enlarged WEPL extent with a field-specific transformation. As the dose distribution is determined by the WEPL, this is sufficient to achieve equivalent dose coverage as for a geometrically enlarged target volume. The WEPL enlargement is only visible to the specific field and therefore does not increase the target volume of other fields. This avoids unnecessary lateral field extensions, reducing the dose to normal tissue. Homogeneous dose coverage in IMPT is achieved only if the inhomogeneous doses from the individual fields match up during delivery. As the course of the WEPL within each motion phase differs, this cannot be guaranteed by optimizing the fields only in the reference phase. The WEPL-ITV for the reference phase can be amended by CTVs from a subset of motion phases (4D-WEPL-ITV). Here, end-exhale as the reference phase was combined with end-inhale to cover the whole motion range. The GEO-ITV, WEPL-ITV, and 4D-WEPL-ITV were applied in an IMPT simulation of a lung cancer patient case using a four-field geometry and the heart as an OAR. A static plan of the CTV in end-exhale was computed for reference. The CTV was moving approximately 20 mm in SI and was partly overlapping the heart. For a single fraction a target dose of 17.7 GyE was prescribed, with a 50% maximum dose for the heart. RESULTS: With 21 rescans to counter interplay, the homogeneity (D5-D95) was 17.0%, 9.0%, 6.0%, and 3.5% for the GEO-ITV, WEPL-ITV, 4D-WEPL-ITV, and a 3D CTV plan computed for reference, respectively. Due to the overlap, the 50% maximum dose was violated by all plans, with V50 of 3.8%, 3.5%, 3.7%, and 2.0% for the four plans. CONCLUSIONS: A 4D-WEPL ITV method was developed that is suitable for IMPT, covers range changes, and drastically improves dose homogeneity in the target without increasing the OAR dose. PMID- 23039639 TI - Monte Carlo simulation of photon buildup factors for shielding materials in diagnostic x-ray facilities. AB - PURPOSE: A simulation of buildup factors for ordinary concrete, steel, lead, plate glass, lead glass, and gypsum wallboard in broad beam geometry for photons energies from 10 keV to 150 keV at 5 keV intervals is presented. METHODS: Monte Carlo N-particle radiation transport computer code has been used to determine the buildup factors for the studied shielding materials. RESULTS: An example concretizing the use of the obtained buildup factors data in computing the broad beam transmission for tube potentials at 70, 100, 120, and 140 kVp is given. The half value layer, the tenth value layer, and the equilibrium tenth value layer are calculated from the broad beam transmission for these tube potentials. CONCLUSIONS: The obtained values compared with those calculated from the published data show the ability of these data to predict shielding transmission curves. Therefore, the buildup factors data can be combined with primary, scatter, and leakage x-ray spectra to provide a computationally based solution to broad beam transmission for barriers in shielding x-ray facilities. PMID- 23039640 TI - Traceable micro-CT scaling accuracy phantom for applications requiring exact measurement of distances or volumes. AB - PURPOSE: Volumetric x-ray microcomputed tomography (CT) can be employed in a variety of quantitative research applications such as image-guided interventions or characterization of medical devices. To ensure the highest geometric fidelity of images for these applications, a phantom and image processing algorithm have been developed to calibrate the scaling accuracy of micro-CT scanners to a traceable standard and provide corrections to image voxel sizing. METHODS: The calibration phantom contains six borosilicate beads whose separations have been measured to a traceable standard. An image processing algorithm compares the known separations of the beads to their separations in micro-CT images. A least squares solution is used to determine linear scaling correction factors along each of the three scanner axes to minimize errors in the bead separations within the images by correcting the image voxel size. The correction factors were applied to images of a similar phantom with beads at different positions to evaluate the ability of the correction factors to reduce errors at points independent of the fiducial locations in the calibration phantom. The calibration phantom was used to evaluate the scaling accuracy of five different micro-CT scanners representing four different scanner models. RESULTS: In two of the five scanners evaluated, the correction factors significantly reduced the mean error in bead separations in the images from 0.17% to 0.05% and from 0.37% to 0.07% of the actual bead separations, respectively. Scanners yielding similar voxel sizes possessed comparable geometric errors after correction using the phantom. CONCLUSIONS: Although the magnitude of the corrections is small, such corrections can be important for demanding micro-CT applications. Even if no voxel size correction is required, the phantom provides an easily implemented method to verify the geometric fidelity of micro-CT scanners to a traceable standard of measurement. PMID- 23039641 TI - An enhanced reconstruction algorithm to extend CT scan field-of-view with z-axis consistency constraint. AB - PURPOSE: To further improve the image quality, in particularly, to suppress the boundary artifacts, in the extended scan field-of-view (SFOV) reconstruction. METHODS: To combat projection truncation artifacts and to restore truncated objects outside the SFOV, an algorithm has previously been proposed based on fitting a partial water cylinder at the site of the truncation. Previous studies have shown this algorithm can simultaneously eliminate the truncation artifacts inside the SFOV and preserve the total amount of attenuation, owing to its emphasis on consistency conditions of the total attenuation in the parallel sampling geometry. Unfortunately, the water cylinder fitting parameters of this 2D algorithm are inclined to high noise fluctuation in the projection samples from image to image, causing anatomy boundaries artifacts, especially during helical scans with higher pitch (>=1.0). To suppress the boundary artifacts and further improve the image quality, the authors propose to use a roughness penalty function, based on the Huber regularization function, to reinforce the z dimensional boundary consistency. Extensive phantom and clinical tests have been conducted to test the accuracy and robustness of the enhanced algorithm. RESULTS: Significant reduction in the boundary artifacts is observed in both phantom and clinical cases with the enhanced algorithm. The proposed algorithm also reduces the percent difference error between the horizontal and vertical diameters to well below 1%. It is also noticeable that the algorithm has improved CT number uniformity outside the SFOV compared to the original algorithm. CONCLUSIONS: The proposed algorithm is capable of suppressing boundary artifacts and improving the CT number uniformity outside the SFOV. PMID- 23039642 TI - A nonlinear lag correction algorithm for a-Si flat-panel x-ray detectors. AB - PURPOSE: Detector lag, or residual signal, in a-Si flat-panel (FP) detectors can cause significant shading artifacts in cone-beam computed tomography reconstructions. To date, most correction models have assumed a linear, time invariant (LTI) model and correct lag by deconvolution with an impulse response function (IRF). However, the lag correction is sensitive to both the exposure intensity and the technique used for determining the IRF. Even when the LTI correction that produces the minimum error is found, residual artifact remains. A new non-LTI method was developed to take into account the IRF measurement technique and exposure dependencies. METHODS: First, a multiexponential (N = 4) LTI model was implemented for lag correction. Next, a non-LTI lag correction, known as the nonlinear consistent stored charge (NLCSC) method, was developed based on the LTI multiexponential method. It differs from other nonlinear lag correction algorithms in that it maintains a consistent estimate of the amount of charge stored in the FP and it does not require intimate knowledge of the semiconductor parameters specific to the FP. For the NLCSC method, all coefficients of the IRF are functions of exposure intensity. Another nonlinear lag correction method that only used an intensity weighting of the IRF was also compared. The correction algorithms were applied to step-response projection data and CT acquisitions of a large pelvic phantom and an acrylic head phantom. The authors collected rising and falling edge step-response data on a Varian 4030CB a Si FP detector operating in dynamic gain mode at 15 fps at nine incident exposures (2.0%-92% of the detector saturation exposure). For projection data, 1st and 50th frame lag were measured before and after correction. For the CT reconstructions, five pairs of ROIs were defined and the maximum and mean signal differences within a pair were calculated for the different exposures and step response edge techniques. RESULTS: The LTI corrections left residual 1st and 50th frame lag up to 1.4% and 0.48%, while the NLCSC lag correction reduced 1st and 50th frame residual lags to less than 0.29% and 0.0052%. For CT reconstructions, the NLCSC lag correction gave an average error of 11 HU for the pelvic phantom and 3 HU for the head phantom, compared to 14-19 HU and 2-11 HU for the LTI corrections and 15 HU and 9 HU for the intensity weighted non-LTI algorithm. The maximum ROI error was always smallest for the NLCSC correction. The NLCSC correction was also superior to the intensity weighting algorithm. CONCLUSIONS: The NLCSC lag algorithm corrected for the exposure dependence of lag, provided superior image improvement for the pelvic phantom reconstruction, and gave similar results to the best case LTI results for the head phantom. The blurred ring artifact that is left over in the LTI corrections was better removed by the NLCSC correction in all cases. PMID- 23039643 TI - Quantitative comparison of noise texture across CT scanners from different manufacturers. AB - PURPOSE: To quantitatively compare noise texture across computed tomography (CT) scanners from different manufacturers using the noise power spectrum (NPS). METHODS: The American College of Radiology CT accreditation phantom (Gammex 464, Gammex, Inc., Middleton, WI) was imaged on two scanners: Discovery CT 750HD (GE Healthcare, Waukesha, WI), and SOMATOM Definition Flash (Siemens Healthcare, Germany), using a consistent acquisition protocol (120 kVp, 0.625/0.6 mm slice thickness, 250 mAs, and 22 cm field of view). Images were reconstructed using filtered backprojection and a wide selection of reconstruction kernels. For each image set, the 2D NPS were estimated from the uniform section of the phantom. The 2D spectra were normalized by their integral value, radially averaged, and filtered by the human visual response function. A systematic kernel-by-kernel comparison across manufacturers was performed by computing the root mean square difference (RMSD) and the peak frequency difference (PFD) between the NPS from different kernels. GE and Siemens kernels were compared and kernel pairs that minimized the RMSD and |PFD| were identified. RESULTS: The RMSD (|PFD|) values between the NPS of GE and Siemens kernels varied from 0.01 mm(2) (0.002 mm(-1)) to 0.29 mm(2) (0.74 mm(-1)). The GE kernels "Soft," "Standard," "Chest," and "Lung" closely matched the Siemens kernels "B35f," "B43f," "B41f," and "B80f" (RMSD < 0.05 mm(2), |PFD| < 0.02 mm(-1), respectively). The GE "Bone," "Bone+," and "Edge" kernels all matched most closely with Siemens "B75f" kernel but with sizeable RMSD and |PFD| values up to 0.18 mm(2) and 0.41 mm(-1), respectively. These sizeable RMSD and |PFD| values corresponded to visually perceivable differences in the noise texture of the images. CONCLUSIONS: It is possible to use the NPS to quantitatively compare noise texture across CT systems. The degree to which similar texture across scanners could be achieved varies and is limited by the kernels available on each scanner. PMID- 23039644 TI - Implementation of dual-energy technique for virtual monochromatic and linearly mixed CBCTs. AB - PURPOSE: To implement dual-energy imaging technique for virtual monochromatic (VM) and linearly mixed (LM) cone beam CTs (CBCTs) and to demonstrate their potential applications in metal artifact reduction and contrast enhancement in image-guided radiation therapy (IGRT). METHODS: A bench-top CBCT system was used to acquire 80 kVp and 150 kVp projections, with an additional 0.8 mm tin filtration. To implement the VM technique, these projections were first decomposed into acrylic and aluminum basis material projections to synthesize VM projections, which were then used to reconstruct VM CBCTs. The effect of VM CBCT on the metal artifact reduction was evaluated with an in-house titanium-BB phantom. The optimal VM energy to maximize contrast-to-noise ratio (CNR) for iodine contrast and minimize beam hardening in VM CBCT was determined using a water phantom containing two iodine concentrations. The LM technique was implemented by linearly combining the low-energy (80 kVp) and high-energy (150 kVp) CBCTs. The dose partitioning between low-energy and high-energy CBCTs was varied (20%, 40%, 60%, and 80% for low-energy) while keeping total dose approximately equal to single-energy CBCTs, measured using an ion chamber. Noise levels and CNRs for four tissue types were investigated for dual-energy LM CBCTs in comparison with single-energy CBCTs at 80, 100, 125, and 150 kVp. RESULTS: The VM technique showed substantial reduction of metal artifacts at 100 keV with a 40% reduction in the background standard deviation compared to a 125 kVp single energy scan of equal dose. The VM energy to maximize CNR for both iodine concentrations and minimize beam hardening in the metal-free object was 50 keV and 60 keV, respectively. The difference of average noise levels measured in the phantom background was 1.2% between dual-energy LM CBCTs and equivalent-dose single-energy CBCTs. CNR values in the LM CBCTs of any dose partitioning are better than those of 150 kVp single-energy CBCTs. The average CNR for four tissue types with 80% dose fraction at low-energy showed 9.0% and 4.1% improvement relative to 100 kVp and 125 kVp single-energy CBCTs, respectively. CNRs for low contrast objects improved as dose partitioning was more heavily weighted toward low-energy (80 kVp) for LM CBCTs. CONCLUSIONS: Dual-energy CBCT imaging techniques were implemented to synthesize VM CBCT and LM CBCTs. VM CBCT was effective at achieving metal artifact reduction. Depending on the dose partitioning scheme, LM CBCT demonstrated the potential to improve CNR for low contrast objects compared to single-energy CBCT acquired with equivalent dose. PMID- 23039645 TI - Tissue characterization using a phantom to validate four-dimensional tissue deformation. AB - PURPOSE: This project proposes using a real tissue phantom for 4D tissue deformation reconstruction (4DTDR) and 4D deformable image registration (DIR) validation, which allows for the complete verification of the motion path rather than limited end-point to end-point of motion. METHODS: Three electro-magnetic tracking (EMT) fiducials were implanted into fresh porcine liver that was subsequently animated in a clinically realistic phantom. The animation was previously shown to be similar to organ motion, including hysteresis, when driven using a real patient's breathing pattern. For this experiment, 4DCTs and EMT traces were acquired when the phantom was animated using both sinusoidal and recorded patient-breathing traces. Fiducial were masked prior to 4DTDR for reconstruction. The original 4DCT data (with fiducials) were sampled into 20 CT phase sets and fiducials' coordinates were recorded, resulting in time-resolved fiducial motion paths. Measured values of fiducial location were compared to EMT measured traces and the result calculated by 4DTDR. RESULTS: For the sinusoidal breathing trace, 95% of EMT measured locations were within 1.2 mm of the measured 4DCT motion path, allowing for repeatable accurate motion characterization. The 4DTDR traces matched 95% of the EMT trace within 1.6 mm. Using the more irregular (in amplitude and frequency) patient trace, 95% of the EMT trace points fitted both 4DCT and 4DTDR motion path within 4.5 mm. The average match of the 4DTDR estimation of the tissue hysteresis over all CT phases was 0.9 mm using a sinusoidal signal for animation and 1.0 mm using the patient trace. CONCLUSIONS: The real tissue phantom is a tool which can be used to accurately characterize tissue deformation, helping to validate or evaluate a DIR or 4DTDR algorithm over a complete motion path. The phantom is capable of validating, evaluating, and quantifying tissue hysteresis, thereby allowing for full motion path validation. PMID- 23039646 TI - Measured dose rate constant from oncology patients administered 18F for positron emission tomography. AB - PURPOSE: Patient exposure rate measurements verify published patient dose rate data and characterize dose rates near 2-18-fluorodeoxyglucose ((18)F-FDG) patients. A specific dose rate constant based on patient exposure rate measurements is a convenient quantity that can be applied to the desired distance, injection activity, and time postinjection to obtain an accurate calculation of cumulative external radiation dose. This study reports exposure rates measured at various locations near positron emission tomography (PET) (18)F FDG patients prior to PET scanning. These measurements are normalized for the amount of administered activity, measurement distance, and time postinjection and are compared with other published data. METHODS: Exposure rates were measured using a calibrated ionization chamber at various body locations from 152 adult oncology patients postvoid after a mean uptake time of 76 min following injection with a mean activity of 490 MBq (18)F-FDG. Data were obtained at nine measurement locations for each patient: three near the head, four near the chest, and two near the feet. RESULTS: On contact with, 30 cm superior to and 30 cm lateral to the head, the mean (75th percentile) dose rates per unit injected activity at 60 min postinjection were 0.482 (0.511), 0.135 (0.155), and 0.193 (0.223) MUSv/MBq h, respectively. On contact with, 30 cm anterior to, 30 cm lateral to and 1 m anterior to the chest, the mean (75th percentile) dose rates per unit injected activity at 60 min postinjection were 0.623 (0.709), 0.254 (0.283), 0.190 (0.218), and 0.067 (0.081) MUSv/MBq h respectively. 30 cm inferior and 30 cm lateral to the feet, the mean (75th percentile) dose rates per unit injected activity at 60 min postinjection were 0.024 (0.022) and 0.039 (0.044) MUSv/MBq h, respectively. CONCLUSIONS: The measurements for this study support the use of 0.092 MUSv m(2)/MBq h as a reasonable representation of the dose rate anterior from the chest of patients immediately following injection. This value can then be reliably scaled to the desired time and distance for planning and staff dose evaluation purposes. At distances closer than 1 m, a distance-specific dose rate constant of 0.367 MUSv/MBq h at 30 cm is recommended for accurate calculations. An accurate patient-specific dose rate constant that accounts for patient specific variables (e.g., distribution and attenuation) will allow an accurate evaluation of the dose rate from a patient injected with an isotope rather than simply utilizing a physical constant. PMID- 23039647 TI - Development and optimization of a beam shaper device for a mobile dedicated IOERT accelerator. AB - PURPOSE: The aim of this study was to design and build a prototype beam shaper to be used on a dedicated mobile accelerator that protects organs at risk within the radiation field and conforms the beam to the target geometry during intraoperative electron radiotherapy (IOERT). A dosimetric characterization of the beam shaper device was performed based on Monte Carlo (MC) simulations, as well as experimental data, at different energies, field sizes, and source to skin distances. METHODS: A mobile light intraoperative accelerator (LIAC((r)), Sordina, Italy) was used. The design of the beam shaper prototype was based on MC simulations (BEAMnrc/OMEGA and DOSXYZnrc code) for a selection of materials and thicknesses, as well as for dosimetric characterization. Percentage depth dose (PDD) and profile measurements were performed using a p-type silicon diode and a commercial water phantom, while output factors were measured using a PinPoint ion chamber in a PMMA phantom. Planar doses in planes of interest were carried out using radiochromic films (Gafchromic(TM) EBT and EBT2) in PMMA and in a Solid Water((r)) phantom. Several experimental set-ups were investigated with the beam shaper device fixed on the top of the phantom, varying both the short side of the rectangular field and the air gap between the device and the phantom surface, simulating the clinical situation. The output factors (OFs) were determined using different geometrical set-ups and energies. RESULTS: The beam shaper prototype consists of four blades sliding alongside each other and mounted on a special support at the end of the 10 cm diameter PMMA circular applicator. Each blade is made of an upper layer of 2.6 cm of Teflon((r)) and a lower layer of 8 mm of stainless steel. All rectangles inscribed in a 5 cm diameter can be achieved in addition to any "squircle-shaped" field. When one side of the rectangular field is held constant and the second side is reduced, both R(50) and R(max) move towards the phantom surface. Comparing the PDDs obtained with the 5 cm circular applicator and with a 4.4 * 4.4 cm(2) square field (that is the equivalent square of the 5 cm circular field) obtained with the beam shaper, a different behavior was observed in the region extending from the surface to a depth of 50% of the maximum dose. Isodoses measured for rectangular fields used for clinical cases (i.e., 4 * 9 cm(2) 8 MeV) are shown, with different air gaps. For each energy investigated, the normalized OFs slowly increase, when the length of the side decreases down to about 4 cm, and then rapidly decreases for smaller field widths. MC simulation showed an excellent agreement with experimental data (<2%). CONCLUSIONS: The beam shaper device is able to provide square/rectangular/squircle fields with adequate dose homogeneity for mobile dedicated accelerators, thus allowing conformal treatment with IOERT. Monte Carlo simulation can be a very useful tool to simulate any clinical set up and can be used to create a data set to calculate MUs, thereby increasing the accuracy of the delivered dose during IOERT procedures. PMID- 23039648 TI - Measurement of joint kinematics using a conventional clinical single-perspective flat-panel radiography system. AB - PURPOSE: The ability to accurately measure joint kinematics is an important tool in studying both normal joint function and pathologies associated with injury and disease. The purpose of this study is to evaluate the efficacy, accuracy, precision, and clinical safety of measuring 3D joint motion using a conventional flat-panel radiography system prior to its application in an in vivo study. METHODS: An automated, image-based tracking algorithm was implemented to measure the three-dimensional pose of a sparse object from a two-dimensional radiographic projection. The algorithm was tested to determine its efficiency and failure rate, defined as the number of image frames where automated tracking failed, or required user intervention. The accuracy and precision of measuring three dimensional motion were assessed using a robotic controlled, tibiofemoral knee phantom programmed to mimic a subject with a total knee replacement performing a stair ascent activity. Accuracy was assessed by comparing the measurements of the single-plane radiographic tracking technique to those of an optical tracking system, and quantified by the measurement discrepancy between the two systems using the Bland-Altman technique. Precision was assessed through a series of repeated measurements of the tibiofemoral kinematics, and was quantified using the across-trial deviations of the repeated kinematic measurements. The safety of the imaging procedure was assessed by measuring the effective dose of ionizing radiation associated with the x-ray exposures, and analyzing its relative risk to a human subject. RESULTS: The automated tracking algorithm displayed a failure rate of 2% and achieved an average computational throughput of 8 image frames/s. Mean differences between the radiographic and optical measurements for translations and rotations were less than 0.08 mm and 0.07 degrees in-plane, and 0.24 mm and 0.6 degrees out-of-plane. The repeatability of kinematics measurements performed using the radiographic tracking technique was better than +/-0.09 mm and 0.12 degrees in-plane, and +/-0.70 mm and +/-0.07 degrees out-of plane. The effective dose associated with the imaging protocol used was 15 MUSv for 10 s of radiographic cine acquisition. CONCLUSIONS: This study demonstrates the ability to accurately measure knee-joint kinematics using a single-plane radiographic measurement technique. The measurement technique can be easily implemented at most clinical centers equipped with a modern-day radiographic x ray system. The dose of ionizing radiation associated with the image acquisition represents a minimal risk to any subjects undergoing the examination. PMID- 23039649 TI - Characterization of aortic remodeling following Kawasaki disease: toward a fully developed automatic biparametric model. AB - PURPOSE: Mechanical properties of the arteries are essential in assessing cardiovascular diseases. New imaging modalities that allow mapping strain, shear and elasticity distributions within the arterial wall are rapidly evolving. Very recently, our group introduced an iterative optical flow-based elastography method devoted to B-mode data. In this paper, the authors propose an adaptation of the optical flow method to investigate aortic remodeling following Kawasaki disease, an early childhood vasculitis. Namely, displacement and strain of the aortic wall are used to assess aortic stiffness in this human disease model. The authors also introduce a fully developed automatic method to support postprocessing data analysis. METHODS: The sequalae of Kawasaki disease on the ascending aorta were examined in children. The pathologic population (n = 4) was 15.00 +/- 2.45 years old, while the healthy control population (n = 5) was 13.13 +/- 0.18 years old. B-mode data were digitally recorded with commercially available cardiac echocardiography machines. RESULTS: Kawasaki disease had a very significant impact on the aortic stiffness. Indeed, pathologic subjects' aortic wall strain estimate was significantly lower compared to healthy controls (2.75% +/- 0.56% versus 4.24% +/- 0.65%, respectively; p < 0.001). Similarly, displacement of the aortic wall was also significantly lower compared to controls (p < 0.001). CONCLUSIONS: The potential of the optical flow-based method to quantify aortic wall remodeling in a human disease model was demonstrated. The authors now intend to extend this investigation to a larger pathologic cohort with various degrees of vasculitis severity. PMID- 23039650 TI - Evaluation of the Gafchromic((r)) EBT2 film for the dosimetry of radiosurgical beams. AB - PURPOSE: Radiosurgery uses small fields and high-radiation doses to treat intra- and extracranial lesions in a single session. The lack of a lateral electronic equilibrium and the presence of high-dose gradients in these fields are challenges for adequate measurements. The availability of radiation detectors with the high spatial resolution required is restricted to only a few. Stereotactic diodes and EBT radiochromic films have been demonstrated to be good detectors for small-beam dosimetry. Because the stereotactic diode is the standard measurement for the dosimetry of radiosurgical beams, the goal of this work was to perform measurements with the radiochromic film Gafchromic((r)) EBT2 and compare its results with a stereotactic diode. METHODS: Total scatter factors, tissue maximum, and off-axis ratios from a 6 MV small photon beams were measured using EBT2 radiochromic film in a water phantom. The film-measured data were evaluated by comparing it with the data measured with a stereotactic field diode (IBA-Dosimetry). RESULTS: The film and diode measurements had excellent agreement. The differences between the detectors were less than or equal to 2.0% for the tissue maximum and the off-axis ratios. However, for the total scatter factors, there were significant differences, up to 4.9% (relative to the reference field), for field sizes less than 1.0 cm. CONCLUSIONS: This work found that the Gafchromic((r)) EBT2 film is adequate for small photon beam measurements, particularly for tissue maximum and off-axis ratios. However, careful attention must be taken when measuring output factors of small beams below 1.0 cm due to the film's energy dependence. The measurement differences may be attributable to the film's active layer composition because EBT2 incorporates higher Z elements (i.e., bromide and potassium), hence revealing a potential energy dependence for the dosimetry of small photon beams. PMID- 23039652 TI - The effects of incidence angle on film dosimetry and their consequences in IMRT dose verification. AB - PURPOSE: The dosimetric accuracy of EDR2 radiographic film has been rigorously assessed in regular and intensity modulated beams for various incidence angles, including the parallel and perpendicular orientation. There clearly exists confusion in literature regarding the effect of film orientation. The primary aim is to clarify potential sources of the confusion and to gain physical insight into the film orientation effect with a link to radiochromic film as well. METHODS: An inverse pyramid IMRT field, consisting of six regular and elongated 3 * 20 cm(2) field segments, was studied in perpendicular and parallel orientation. Assessment of film self-perturbation and intrinsic directional sensitivity were also included in the experiments. Finally, the authors investigated the orientational effect in composite beams in the two extreme orientations, i.e., perpendicular and parallel. RESULTS: The study of an inverse pyramid dose profile revealed good agreement between the perpendicular film and the diamond detector within 0.5% in the low-scatter regions for both 6 and 18 MV. The parallel oriented film demonstrated a 3% under-response at 5-cm (6 MV) depth against the perpendicular orientation, but both orientations over responded equally in the central region, which received only scattered dose, at both 5- and 20-cm depths. In a regular 6-MV 5 * 5 cm(2) field, a 4.1% lower film response was observed in the parallel orientation compared to perpendicular orientation. The under response gradually increased to 6% when reducing the field size to 0.5 * 5 cm(2). On the other hand, the film showed a 1.7% lower response in parallel orientation for the large field size of 20 * 20 cm(2) at 5-cm depth but the difference disappeared at 10 cm. At 18 MV, similar but somewhat lower differences were found between the two orientations. The directional sensitivity of the film diminishes with increasing field size and depth. Surprisingly a composite IMRT beam consisting of 20 adjacent strip segments also produced a significant orientational dependence of film response, notwithstanding the large total field size of 20 * 20 cm(2). CONCLUSIONS: This analysis allowed the development of a hypothesis about the physics behind the orientational dependence of film response in general and to formulate precautions when using film dosimetry in the dosimetric verification of multibeam treatments. PMID- 23039651 TI - Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy. AB - PURPOSE: Peptide receptor radionuclide therapy (PRRT) delivers high absorbed doses to kidneys and may lead to permanent nephropathy. Reliable dosimetry of kidneys is thus critical for safe and effective PRRT. The aim of this work was to assess the feasibility of planning PRRT based on 3D radiobiological dosimetry (3D RD) in order to optimize both the amount of activity to administer and the fractionation scheme, while limiting the absorbed dose and the biological effective dose (BED) to the renal cortex. METHODS: Planar and SPECT data were available for a patient examined with (111)In-DTPA-octreotide at 0.5 (planar only), 4, 24, and 48 h post-injection. Absorbed dose and BED distributions were calculated for common therapeutic radionuclides, i.e., (111)In, (90)Y and (177)Lu, using the 3D-RD methodology. Dose-volume histograms were computed and mean absorbed doses to kidneys, renal cortices, and medullae were compared with results obtained using the MIRD schema (S-values) with the multiregion kidney dosimetry model. Two different treatment planning approaches based on (1) the fixed absorbed dose to the cortex and (2) the fixed BED to the cortex were then considered to optimize the activity to administer by varying the number of fractions. RESULTS: Mean absorbed doses calculated with 3D-RD were in good agreement with those obtained with S-value-based SPECT dosimetry for (90)Y and (177)Lu. Nevertheless, for (111)In, differences of 14% and 22% were found for the whole kidneys and the cortex, respectively. Moreover, the authors found that planar-based dosimetry systematically underestimates the absorbed dose in comparison with SPECT-based methods, up to 32%. Regarding the 3D-RD-based treatment planning using a fixed BED constraint to the renal cortex, the optimal number of fractions was found to be 3 or 4, depending on the radionuclide administered and the value of the fixed BED. Cumulative activities obtained using the proposed simulated treatment planning are compatible with real activities administered to patients in PRRT. CONCLUSIONS: The 3D-RD treatment planning approach based on the fixed BED was found to be the method of choice for clinical implementation in PRRT by providing realistic activity to administer and number of cycles. While dividing the activity in several cycles is important to reduce renal toxicity, the clinical outcome of fractionated PRRT should be investigated in the future. PMID- 23039653 TI - Effect of radiation induced current on the quality of MR images in an integrated linac-MR system. AB - PURPOSE: In integrated linac-MRI systems, the RF coils are exposed to the linac's pulsed radiation, leading to a measurable radiation induced current (RIC). This work (1) visualizes the RIC in MRI raw data and determines its effect on the MR image signal-to-noise ratio (SNR) (b) examines the effect of linac dose rate on SNR degradations, (c) examines the RIC effect on different MRI sequences, (d) examines the effect of altering the MRI sequence timing on the RIC, and (e) uses a postprocessing method to reduce the RIC signal from the MR raw data. METHODS: MR images were acquired on the linac-MR prototype system using various imaging sequences (gradient echo, spin echo, and bSSFP), dose rates (0, 50, 100, 150, 200, and 250 MU/min) and repetition times (TR) with the gradient echo sequence. The images were acquired with the radiation beam either directly incident or blocked from the RF coils. The SNR was calculated for each of these scenarios, showing a loss in SNR due to RIC. Finally, a postprocessing method was applied to the image k-space data in order to remove partially the RIC signal and recover some of the lost SNR. RESULTS: The RIC produces visible spikes in the k-space data acquired with the linac's radiation incident on the RF coils. This RIC leads to a loss in imaging SNR that increases with increasing linac dose rate (15%-18% loss at 250 MU/min). The SNR loss seen with increasing linac dose rate appears to be largely independent of the MR sequence used. Changing the imaging TR had interesting visual effects on the appearance of RIC in k-space due to the timing between the linac's pulsing and the MR sequence, but did not change the SNR loss for a given linac dose rate. The use of a postprocessing algorithm was able to remove much of the RIC noise spikes from the MR image k-space data, resulting in the recovery of a significant portion, up to 81% (Table II), of the lost image SNR. CONCLUSIONS: The presence of RIC in MR RF coils leads to a loss of SNR which is directly related to the linac dose rate. The RIC related loss in SNR is likely to increase for systems that are able to provide larger than 250 MU/min dose. Some of this SNR loss can be recovered through the use of a postprocessing algorithm, which removes the RIC artefact from the image k-space. PMID- 23039654 TI - Estimation of the two-dimensional presampled modulation transfer function of digital radiography devices using one-dimensional test objects. AB - PURPOSE: The modulation transfer function (MTF) of medical imaging devices is commonly reported in the form of orthogonal one-dimensional (1D) measurements made near the vertical and horizontal axes with a slit or edge test device. A more complete description is found by measuring the two-dimensional (2D) MTF. Some 2D test devices have been proposed, but there are some issues associated with their use: (1) they are not generally available; (2) they may require many images; (3) the results may have diminished accuracy; and (4) their implementation may be particularly cumbersome. This current work proposes the application of commonly available 1D test devices for practical and accurate estimation of the 2D presampled MTF of digital imaging systems. METHODS: Theory was developed and applied to ensure adequate fine sampling of the system line spread function for 1D test devices at orientations other than approximately vertical and horizontal. Methods were also derived and tested for slit nonuniformity correction at arbitrary angle. Techniques were validated with experimental measurements at ten angles using an edge test object and three angles using a slit test device on an indirect-detection flat-panel system [GE Revolution XQ/i (GE Healthcare, Waukesha, WI)]. The 2D MTF was estimated through a simple surface fit with interpolation based on Delaunay triangulation of the 1D edge-based MTF measurements. Validation by synthesis was also performed with simulated images from a hypothetical direct-detection flat-panel device. RESULTS: The 2D MTF derived from physical measurements yielded an average relative precision error of 0.26% for frequencies below the cutoff (2.5 mm(-1)) and approximate circular symmetry at frequencies below 4 mm(-1). While slit analysis generally agreed with the results of edge analysis, the two showed subtle differences at frequencies above 4 mm(-1). Slit measurement near 45 degrees revealed radial asymmetry in the MTF resulting from the square pixel aperture (0.2 mm * 0.2 mm), a characteristic which was not necessarily appreciated with the orthogonal 1D MTF measurements. In simulation experiments, both slit- and edge-based measurements resolved the radial asymmetries in the 2D MTF. The average absolute relative accuracy error in the 2D MTF between the DC and cutoff (2.5 mm(-1)) frequencies was 0.13% with average relative precision error of 0.11%. Other simulation results were similar to those derived from physical data. CONCLUSIONS: Overall, the general availability, acceptance, accuracy, and ease of implementation of 1D test devices for MTF assessment make this a valuable technique for 2D MTF estimation. PMID- 23039655 TI - Dosimetry of (125)I and (103)Pd COMS eye plaques for intraocular tumors: report of Task Group 129 by the AAPM and ABS. AB - Dosimetry of eye plaques for ocular tumors presents unique challenges in brachytherapy. The challenges in accurate dosimetry are in part related to the steep dose gradient in the tumor and critical structures that are within millimeters of radioactive sources. In most clinical applications, calculations of dose distributions around eye plaques assume a homogenous water medium and full scatter conditions. Recent Monte Carlo (MC)-based eye-plaque dosimetry simulations have demonstrated that the perturbation effects of heterogeneous materials in eye plaques, including the gold-alloy backing and Silastic insert, can be calculated with reasonable accuracy. Even additional levels of complexity introduced through the use of gold foil "seed-guides" and custom-designed plaques can be calculated accurately using modern MC techniques. Simulations accounting for the aforementioned complexities indicate dose discrepancies exceeding a factor of ten to selected critical structures compared to conventional dose calculations. Task Group 129 was formed to review the literature; re-examine the current dosimetry calculation formalism; and make recommendations for eye-plaque dosimetry, including evaluation of brachytherapy source dosimetry parameters and heterogeneity correction factors. A literature review identified modern assessments of dose calculations for Collaborative Ocular Melanoma Study (COMS) design plaques, including MC analyses and an intercomparison of treatment planning systems (TPS) detailing differences between homogeneous and heterogeneous plaque calculations using the American Association of Physicists in Medicine (AAPM) TG-43U1 brachytherapy dosimetry formalism and MC techniques. This review identified that a commonly used prescription dose of 85 Gy at 5 mm depth in homogeneous medium delivers about 75 Gy and 69 Gy at the same 5 mm depth for specific (125)I and (103)Pd sources, respectively, when accounting for COMS plaque heterogeneities. Thus, the adoption of heterogeneous dose calculation methods in clinical practice would result in dose differences >10% and warrant a careful evaluation of the corresponding changes in prescription doses. Doses to normal ocular structures vary with choice of radionuclide, plaque location, and prescription depth, such that further dosimetric evaluations of the adoption of MC-based dosimetry methods are needed. The AAPM and American Brachytherapy Society (ABS) recommend that clinical medical physicists should make concurrent estimates of heterogeneity-corrected delivered dose using the information in this report's tables to prepare for brachytherapy TPS that can account for material heterogeneities and for a transition to heterogeneity-corrected prescriptive goals. It is recommended that brachytherapy TPS vendors include material heterogeneity corrections in their systems and take steps to integrate planned plaque localization and image guidance. In the interim, before the availability of commercial MC-based brachytherapy TPS, it is recommended that clinical medical physicists use the line-source approximation in homogeneous water medium and the 2D AAPM TG-43U1 dosimetry formalism and brachytherapy source dosimetry parameter datasets for treatment planning calculations. Furthermore, this report includes quality management program recommendations for eye-plaque brachytherapy. PMID- 23039656 TI - Dosimetric perturbations due to an implanted cardiac pacemaker in MammoSite((r)) treatment. AB - PURPOSE: To investigate dose perturbations for pacemaker-implanted patients in partial breast irradiation using high dose rate (HDR) balloon brachytherapy. METHODS: Monte Carlo (MC) simulations were performed to calculate dose distributions involving a pacemaker in Ir-192 HDR balloon brachytherapy. Dose perturbations by varying balloon-to-pacemaker distances (BPD = 50 or 100 mm) and concentrations of iodine contrast medium (2.5%, 5.0%, 7.5%, and 10.0% by volume) in the balloon were investigated for separate parts of the pacemaker (i.e., battery and substrate). Relative measurements using an ion-chamber were also performed to confirm MC results. RESULTS: The MC and measured results in homogeneous media without a pacemaker agreed with published data within 2% from the balloon surface to 100 mm BPD. Further their dose distributions with a pacemaker were in a comparable agreement. The MC results showed that doses over the battery were increased by a factor of 3, compared to doses without a pacemaker. However, there was no significant dose perturbation in the middle of substrate but up to 70% dose increase in the substrate interface with the titanium capsule. The attenuation by iodine contrast medium lessened doses delivered to the pacemaker by up to 9%. CONCLUSIONS: Due to inhomogeneity of pacemaker and contrast medium as well as low-energy photons in Ir-192 HDR balloon brachytherapy, the actual dose received in a pacemaker is different from the homogeneous medium-based dose and the external beam-based dose. Therefore, the dose perturbations should be considered for pacemaker-implanted patients when evaluating a safe clinical distance between the balloon and pacemaker. PMID- 23039657 TI - EPID-based verification of the MLC performance for dynamic IMRT and VMAT. AB - PURPOSE: In advanced radiotherapy treatments such as intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT), verification of the performance of the multileaf collimator (MLC) is an essential part of the linac QA program. The purpose of this study is to use the existing measurement methods for geometric QA of the MLCs and extend them to more comprehensive evaluation techniques, and to develop dedicated robust algorithms to quantitatively investigate the MLC performance in a fast, accurate, and efficient manner. METHODS: The behavior of leaves was investigated in the step and-shoot mode by the analysis of integrated electronic portal imaging device (EPID) images acquired during picket fence tests at fixed gantry angles and arc delivery. The MLC was also studied in dynamic mode by the analysis of cine EPID images of a sliding gap pattern delivered in a variety of conditions including different leaf speeds, deliveries at fixed gantry angles or in arc mode, and changing the direction of leaf motion. The accuracy of the method was tested by detection of the intentionally inserted errors in the delivery patterns. RESULTS: The algorithm developed for the picket fence analysis was able to find each individual leaf position, gap width, and leaf bank skewness in addition to the deviations from expected leaf positions with respect to the beam central axis with sub-pixel accuracy. For the three tested linacs over a period of 5 months, the maximum change in the gap width was 0.5 mm, the maximum deviation from the expected leaf positions was 0.1 mm and the MLC skewness was up to 0.2 degrees . The algorithm developed for the sliding gap analysis could determine the velocity and acceleration/deceleration of each individual leaf as well as the gap width. There was a slight decrease in the accuracy of leaf performance with increasing leaf speeds. The analysis results were presented through several graphs. The accuracy of the method was assessed as 0.01 mm for both the gap size and peak position determination. CONCLUSIONS: This study provides fast, easy, and accurate test methods for routine QA of the MLC performance and helps in faster troubleshooting of MLC problems in both IMRT and VMAT treatments. PMID- 23039658 TI - Report of the Task Group 186 on model-based dose calculation methods in brachytherapy beyond the TG-43 formalism: current status and recommendations for clinical implementation. AB - The charge of Task Group 186 (TG-186) is to provide guidance for early adopters of model-based dose calculation algorithms (MBDCAs) for brachytherapy (BT) dose calculations to ensure practice uniformity. Contrary to external beam radiotherapy, heterogeneity correction algorithms have only recently been made available to the BT community. Yet, BT dose calculation accuracy is highly dependent on scatter conditions and photoelectric effect cross-sections relative to water. In specific situations, differences between the current water-based BT dose calculation formalism (TG-43) and MBDCAs can lead to differences in calculated doses exceeding a factor of 10. MBDCAs raise three major issues that are not addressed by current guidance documents: (1) MBDCA calculated doses are sensitive to the dose specification medium, resulting in energy-dependent differences between dose calculated to water in a homogeneous water geometry (TG 43), dose calculated to the local medium in the heterogeneous medium, and the intermediate scenario of dose calculated to a small volume of water in the heterogeneous medium. (2) MBDCA doses are sensitive to voxel-by-voxel interaction cross sections. Neither conventional single-energy CT nor ICRU/ICRP tissue composition compilations provide useful guidance for the task of assigning interaction cross sections to each voxel. (3) Since each patient-source applicator combination is unique, having reference data for each possible combination to benchmark MBDCAs is an impractical strategy. Hence, a new commissioning process is required. TG-186 addresses in detail the above issues through the literature review and provides explicit recommendations based on the current state of knowledge. TG-43-based dose prescription and dose calculation remain in effect, with MBDCA dose reporting performed in parallel when available. In using MBDCAs, it is recommended that the radiation transport should be performed in the heterogeneous medium and, at minimum, the dose to the local medium be reported along with the TG-43 calculated doses. Assignments of voxel-by voxel cross sections represent a particular challenge. Electron density information is readily extracted from CT imaging, but cannot be used to distinguish between different materials having the same density. Therefore, a recommendation is made to use a number of standardized materials to maintain uniformity across institutions. Sensitivity analysis shows that this recommendation offers increased accuracy over TG-43. MBDCA commissioning will share commonalities with current TG-43-based systems, but in addition there will be algorithm-specific tasks. Two levels of commissioning are recommended: reproducing TG-43 dose parameters and testing the advanced capabilities of MBDCAs. For validation of heterogeneity and scatter conditions, MBDCAs should mimic the 3D dose distributions from reference virtual geometries. Potential changes in BT dose prescriptions and MBDCA limitations are discussed. When data required for full MBDCA implementation are insufficient, interim recommendations are made and potential areas of research are identified. Application of TG-186 guidance should retain practice uniformity in transitioning from the TG-43 to the MBDCA approach. PMID- 23039659 TI - A method of dose reconstruction for moving targets compatible with dynamic treatments. AB - PURPOSE: To develop a method that allows a commercial treatment planning system (TPS) to perform accurate dose reconstruction for rigidly moving targets and to validate the method in phantom measurements for a range of treatments including intensity modulated radiation therapy (IMRT), volumetric arc therapy (VMAT), and dynamic multileaf collimator (DMLC) tracking. METHODS: An in-house computer program was developed to manipulate Dicom treatment plans exported from a TPS (Eclipse, Varian Medical Systems) such that target motion during treatment delivery was incorporated into the plans. For each treatment, a motion including plan was generated by dividing the intratreatment target motion into 1 mm position bins and construct sub-beams that represented the parts of the treatment that were delivered, while the target was located within each position bin. For each sub-beam, the target shift was modeled by a corresponding isocenter shift. The motion incorporating Dicom plans were reimported into the TPS, where dose calculation resulted in motion including target dose distributions. For experimental validation of the dose reconstruction a thorax phantom with a moveable lung equivalent rod with a tumor insert of solid water was first CT scanned. The tumor insert was delineated as a gross tumor volume (GTV), and a planning target volume (PTV) was formed by adding margins. A conformal plan, two IMRT plans (step-and-shoot and sliding windows), and a VMAT plan were generated giving minimum target doses of 95% (GTV) and 67% (PTV) of the prescription dose (3 Gy). Two conformal fields with MLC leaves perpendicular and parallel to the tumor motion, respectively, were generated for DMLC tracking. All treatment plans were delivered to the thorax phantom without tumor motion and with a sinusoidal tumor motion. The two conformal fields were delivered with and without portal image guided DMLC tracking based on an embedded gold marker. The target dose distribution was measured with a radiochromic film in the moving rod and compared with the reconstructed doses using gamma tests. RESULTS: Considerable interplay effects between machine motion and target motion were observed for the treatments without tracking. For nontracking experiments, the mean 2 mm/2% gamma pass rate over all investigated scenarios was 99.6% between calculated and measured doses. For tracking experiments, the mean gamma pass rate was 99.4%. CONCLUSIONS: A method for accurate dose reconstruction for moving targets with dynamic treatments was developed and experimentally validated in a variety of delivery scenarios. The method is suitable for integration into TPSs, e.g., for reconstruction of the dose delivered to moving tumors or calculation of target doses delivered with DMLC tracking. PMID- 23039660 TI - Characterization of distensibility, plaque burden, and composition of the atherosclerotic carotid artery using magnetic resonance imaging. AB - PURPOSE: Arterial distensibility is a marker that can measure vessel wall functional and structural changes resulting from atherosclerosis with applications including estimation of mechanical properties of the wall. We sought to assess the feasibility of using magnetic resonance imaging (MRI) to include wall distensibility in the characterization of atherosclerotic carotid arteries and to analyze the relationship between distensibility and morphological and compositional plaque features. METHODS: Five healthy volunteers were imaged with a multiple-slice CINE MR sequence twice, within 24 h, to determine the interscan reproducibility of distensibility measurements. Twenty-one subjects with >15% carotid stenosis and the five healthy volunteers were imaged using a multicontrast carotid MRI protocol to characterize arterial wall morphology and composition. Normalized wall index (wall area/total vessel area), maximum wall thickness and, if present, percentages of wall area occupied by calcification and lipid-rich necrotic core were determined. A multiple-slice CINE MR sequence was added to the multicontrast protocol to measure the distensibility coefficient (DC) at several locations spanning the bifurcation. The intraclass correlation coefficient (ICC) and the coefficient of variation were used to assess the reproducibility of DC measurements made on the healthy subjects. The DC was compared between arterial segments and between the healthy and diseased groups. Furthermore, within the diseased group, DC was correlated to plaque morphology and composition at each location as well as that averaged over the plaque. RESULTS: Distensibility measurements were highly reproducible: ICC (95% confidence interval) was 0.998 (0.96-1.0) for the common carotid segment and 0.990 (0.92-1.0) for the internal carotid segment. In healthy volunteers, we found significantly higher distensibility in the common segment of the carotid artery compared to the internal carotid segment (mean +/- SD = 4.56 +/- 1.02 versus 3.56 +/- 1.32 * 10(-5)/Pa; p < 0.05). However, no segmental differences were seen in the diseased group (3.25 +/- 1.84 versus 3.26 +/- 1.60 * 10(-5)/Pa; p = 0.607). Location-to-location changes in DC were not found to correlate to changes in the local plaque morphology or composition nor were average DC found to be associated with aggregate plaque features. CONCLUSIONS: These results demonstrate the feasibility of MRI to measure distensibility in the carotid artery and to presumably detect changes in distensibility due to age and/or disease. The results suggest that the effect of atherosclerosis on local distensibility may not strongly depend upon the specific underlying plaque features in mild to moderate stenotic carotid lesions though more diffuse or nonlocal changes in arterial distensibility could not be ruled out. PMID- 23039661 TI - Application of Zernike polynomials towards accelerated adaptive focusing of transcranial high intensity focused ultrasound. AB - PURPOSE: To study the phase aberrations produced by human skulls during transcranial magnetic resonance imaging guided focused ultrasound surgery (MRgFUS), to demonstrate the potential of Zernike polynomials (ZPs) to accelerate the adaptive focusing process, and to investigate the benefits of using phase corrections obtained in previous studies to provide the initial guess for correction of a new data set. METHODS: The five phase aberration data sets, analyzed here, were calculated based on preoperative computerized tomography (CT) images of the head obtained during previous transcranial MRgFUS treatments performed using a clinical prototype hemispherical transducer. The noniterative adaptive focusing algorithm [Larrat et al., "MR-guided adaptive focusing of ultrasound," IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57(8), 1734-1747 (2010)] was modified by replacing Hadamard encoding with Zernike encoding. The algorithm was tested in simulations to correct the patients' phase aberrations. MR acoustic radiation force imaging (MR-ARFI) was used to visualize the effect of the phase aberration correction on the focusing of a hemispherical transducer. In addition, two methods for constructing initial phase correction estimate based on previous patient's data were investigated. The benefits of the initial estimates in the Zernike-based algorithm were analyzed by measuring their effect on the ultrasound intensity at the focus and on the number of ZP modes necessary to achieve 90% of the intensity of the nonaberrated case. RESULTS: Covariance of the pairs of the phase aberrations data sets showed high correlation between aberration data of several patients and suggested that subgroups can be based on level of correlation. Simulation of the Zernike-based algorithm demonstrated the overall greater correction effectiveness of the low modes of ZPs. The focal intensity achieves 90% of nonaberrated intensity using fewer than 170 modes of ZPs. The initial estimates based on using the average of the phase aberration data from the individual subgroups of subjects was shown to increase the intensity at the focal spot for the five subjects. CONCLUSIONS: The application of ZPs to phase aberration correction was shown to be beneficial for adaptive focusing of transcranial ultrasound. The skull-based phase aberrations were found to be well approximated by the number of ZP modes representing only a fraction of the number of elements in the hemispherical transducer. Implementing the initial phase aberration estimate together with Zernike-based algorithm can be used to improve the robustness and can potentially greatly increase the viability of MR ARFI-based focusing for a clinical transcranial MRgFUS therapy. PMID- 23039662 TI - Quantification of arterial flow using digital subtraction angiography. AB - PURPOSE: In this paper, a method for the estimation of arterial hemodynamic flow from x-ray video densitometry data is proposed and validated using an in vitro setup. METHODS: The method is based on the acquisition of three-dimensional rotational angiography and digital subtraction angiography sequences. A modest contrast injection rate (between 1 and 4 ml/s) leads to a contrast density that is modulated by the cardiac cycle, which can be measured in the x-ray signal. An optical flow based approach is used to estimate the blood flow velocities from the cyclic phases in the x-ray signal. RESULTS: The authors have validated this method in vitro, and present three clinical cases. The in vitro experiments compared the x-ray video densitometry results with the gold standard delivered by a flow meter. Linear correlation analysis and regression fitting showed that the ideal slope of 1 and intercept of 0 were contained within the 95 percentile confidence interval. The results show that a frame rate higher than 50 Hz allows measuring flows in the range of 2 ml/s to 6 ml/s within an accuracy of 5%. CONCLUSIONS: The in vitro and clinical results indicate that it is feasible to estimate blood flow in routine interventional procedures. The availability of an x-ray based method for quantitative flow estimation is particularly clinically useful for intra-cranial applications, where other methods, such as ultrasound Doppler, are not available. PMID- 23039663 TI - Patient radiation doses in interventional cardiology in the U.S.: advisory data sets and possible initial values for U.S. reference levels. AB - PURPOSE: To determine patient radiation doses from interventional cardiology procedures in the U.S and to suggest possible initial values for U.S. benchmarks for patient radiation dose from selected interventional cardiology procedures [fluoroscopically guided diagnostic cardiac catheterization and percutaneous coronary intervention (PCI)]. METHODS: Patient radiation dose metrics were derived from analysis of data from the 2008 to 2009 Nationwide Evaluation of X ray Trends (NEXT) survey of cardiac catheterization. This analysis used identified data and did not require review by an IRB. Data from 171 facilities in 30 states were analyzed. The distributions (percentiles) of radiation dose metrics were determined for diagnostic cardiac catheterizations, PCI, and combined diagnostic and PCI procedures. Confidence intervals for these dose distributions were determined using bootstrap resampling. RESULTS: Percentile distributions (advisory data sets) and possible preliminary U.S. reference levels (based on the 75th percentile of the dose distributions) are provided for cumulative air kerma at the reference point (K(a,r)), cumulative air kerma-area product (P(KA)), fluoroscopy time, and number of cine runs. Dose distributions are sufficiently detailed to permit dose audits as described in National Council on Radiation Protection and Measurements Report No. 168. Fluoroscopy times are consistent with those observed in European studies, but P(KA) is higher in the U.S. CONCLUSIONS: Sufficient data exist to suggest possible initial benchmarks for patient radiation dose for certain interventional cardiology procedures in the U.S. Our data suggest that patient radiation dose in these procedures is not optimized in U.S. practice. PMID- 23039664 TI - Positional accuracy of novel x-ray-image-based dynamic tumor-tracking irradiation using a gimbaled MV x-ray head of a Vero4DRT (MHI-TM2000). AB - PURPOSE: To verify the positional accuracy of a novel x-ray-image-based dynamic tumor-tracking (DTT) irradiation technique using the gimbaled MV x-ray head of a Vero4DRT (MHI-TM2000). METHODS: Verification of the x-ray-image-based DTT was performed using three components: a three-dimensional moving phantom with a steel ball target, a laser displacement gauge, and an orthogonal kV x-ray imaging subsystem with a gimbaled MV x-ray head and the system controller of the Vero4DRT. The moving phantom was driven based on seven periodic patterns [peak-to peak amplitude (A): 20-40 mm, breathing period (T): 2-5 s] and 15 patients' aperiodic respiratory patterns (A: 6.5-22.9 mm, T: 1.9-5.8 s). The target position was detected in real time with the orthogonal kV x-ray imaging subsystem using the stereo vision technique. Subsequently, the Vero4DRT predicted the next position of the target, and then the gimbaled MV x-ray head tracked the corresponding orientation of the target. The displacements of the target were measured synchronously using the laser displacement gauge. The difference between the target positions predicted by the Vero4DRT and those measured by the laser displacement gauge was computed as the prediction error (E(P)), and the difference between the target positions tracked by the gimbaled MV x-ray head and predicted target positions was computed as the mechanical error (E(M)). Total tracking system error (E(T)) was defined as the difference between the tracked and measured target positions. RESULTS: The root mean squares (RMSs) of E(P), E(M), and E(T) were up to 0.8, 0.3, and 0.7 mm, respectively, for the periodic patterns. Regarding the aperiodic patterns, the median RMSs of E(P), E(M), and E(T) were 1.2 (range, 0.9-1.8) mm, 0.1 (range, 0.1-0.5) mm, and 1.2 (range, 0.9 1.8) mm, respectively. From the results of principal component analysis, tracking efficiency, defined as the ratio of twice the RMS of E(T) to A, was improved for patients with high respiratory function (R = 0.91; p < 0.01). CONCLUSIONS: The present study demonstrated that the Vero4DRT is capable of high-accuracy x-ray image-based DTT. E(T) was caused primarily by E(P), and E(M) was negligible. Furthermore, principal component analysis showed that tracking efficiency could be improved with this system, especially for patients with high respiratory function. PMID- 23039665 TI - Evaluation of metal artifacts in MVCT systems using a model based correction method. AB - PURPOSE: To evaluate the performance of a model based image reconstruction method in reducing metal artifacts in the megavoltage computed tomography (MVCT) images of a phantom representing bilateral hip prostheses and to compare with the filtered-backprojection (FBP) technique. METHODS: An iterative maximum likelihood polychromatic algorithm for CT (IMPACT) is used with an additional model for the pair/triplet production process and the energy dependent response of the detectors. The beam spectra for an in-house bench-top and TomoTherapyTM MVCTs are modeled for use in IMPACT. The empirical energy dependent response of detectors is calculated using a constrained optimization technique that predicts the measured attenuation of the beam by various thicknesses (0-24 cm) of solid water slabs. A cylindrical (19.1 cm diameter) plexiglass phantom containing various cylindrical inserts of relative electron densities 0.295-1.695 positioned between two steel rods (2.7 cm diameter) is scanned in the bench-top MVCT that utilizes the bremsstrahlung radiation from a 6 MeV electron beam passed through 4 cm solid water on the Varian Clinac 2300C and in the imaging beam of the TomoTherapyTM MVCT. The FBP technique in bench-top MVCT reconstructs images from raw signal normalized to air scan and corrected for beam hardening using a uniform plexiglass cylinder (20 cm diameter). The IMPACT starts with a FBP reconstructed seed image and reconstructs the final image in 150 iterations. RESULTS: In both MVCTs, FBP produces visible dark shading in the image connecting the steel rods. In the IMPACT reconstructed images this shading is nearly removed and the uniform background is restored. The average attenuation coefficients of the inserts and the background are very close to the corresponding values in the absence of the steel inserts. In the FBP images of the bench-top MVCT, the shading causes 4% 9.5% underestimation of electron density at the central inserts with an average of (6.3 +/- 1.8)% for the range of electron densities studied. In the uniform plexiglass background, the shadow creates 0.8%-4.7% underestimation of electron density with an average of (2.9 +/- 1.2)%. In the corresponding IMPACT images, the underestimation in the shaded plexiglass background is 0.3%-1.8% with an average of (0.9 +/- 0.5)% and 1.4%-6.8% with an average of (2.8 +/- 2.7)% in the central insert region. In the FBP images of the TomoTherapyTM MVCT, this shading creates 2.6%-6.7% underestimation of electron density with an average of (3.7 +/- 1.4)% at the central inserts and 5.9%-7.2% underestimation in the background with an average of (6.4 +/- 0.5)%. In the IMPACT images, the uniform background between the steel rods is restored with 0.3%-1.0% underestimation of electron density with an average of (0.7 +/- 0.3)%. The corresponding underestimation at the central inserts of the IMPACT images is -0.4%-0.1% with an average of (-0.1 +/- 0.2)%. CONCLUSIONS: The shading metal artifact has been nearly removed in MVCT images using the IMPACT algorithm with the accurate geometry of the system, proper modeling of energy dependent response of detectors, and all relevant photon interaction processes. This results less than 1% difference in electron density in the background plexiglass and less than 3% averaged over the range of electron densities investigated. PMID- 23039666 TI - Optimization of the x-ray monitoring angle for creating a correlation model between internal and external respiratory signals. AB - PURPOSE: To perform dynamic tumor tracking irradiation with the Vero4DRT (MHI TM2000), a correlation model [four dimensional (4D) model] between the displacement of infrared markers on the abdominal wall and the three-dimensional position of a tumor indicated by a minimum of three implanted gold markers is required. However, the gold markers cannot be detected successfully on fluoroscopic images under the following situations: (1) overlapping of the gold markers; and (2) a low intensity ratio of the gold marker to its surroundings. In the present study, the authors proposed a method to readily determine the optimal x-ray monitoring angle for creating a 4D model utilizing computed tomography (CT) images. METHODS: The Vero4DRT mounting two orthogonal kV x-ray imaging subsystems can separately rotate the gantry along an O-shaped guide-lane and the O-ring along its vertical axis. The optimal x-ray monitoring angle was determined on CT images by minimizing the root-sum-square of water equivalent path lengths (WEPLs) on the orthogonal lines passing all of the gold markers while rotating the O-ring and the gantry. The x-ray monitoring angles at which the distances between the gold markers were within 5 mm at the isocenter level were excluded to prevent false detection of the gold markers in consideration of respiratory motions. First, the relationship between the WEPLs (unit: mm) and the intensity ratios of the gold markers was examined to assess the validity of our proposed method. Second, our proposed method was applied to the 4D-CT images at the end-expiration phase for 11 lung cancer patients who had four to five gold markers. To prove the necessity of the x-ray monitoring angle optimization, the intensity ratios of the least visible markers (minimum intensity ratios) that were estimated from the WEPLs were compared under the following conditions: the optimal x-ray monitoring angle and the angles used for setup verification. Additionally, the intra- and interfractional variations in the intensity ratio were examined from the optimal x-ray monitoring angle. RESULTS: A negative strong correlation was observed between the WEPL (x) and the intensity ratio (y) (y = 6.57 exp[-0.0125x] + 1, R = -0.88 [95% confidence interval: -0.85 to -0.90], p < 0.01). Our proposed method effectively avoided having the x-ray beam pass through high-density structures, although there were large interpatient variations in the optimal x-ray monitoring angle because of the geometric arrangement between the gold markers and the anatomical structures. The minimum intensity ratios that were estimated from the WEPLs at the optimal x-ray monitoring angle ranged from 1.43 to 2.48, which was an average of 1.27 times (range, 1.02-1.66) higher than the angles used for setup verification. The maximum intra- and interfractional decreases in the intensity ratio were 0.23 and 0.17, respectively. CONCLUSIONS: The authors demonstrated that the optimal x-ray monitoring angle for creating a 4D model can improve the visibility of gold markers. PMID- 23039667 TI - On the significance of density-induced speed of sound variations on US-guided radiotherapy. AB - PURPOSE: To show the effect of speed of sound (SOS) aberration on ultrasound guided radiotherapy (US-gRT) as a function of implemented workflow. US systems assume that SOS is constant in human soft tissues (at a value of 1540 m/s), while its actual nonuniform distribution produces small but systematic errors of up to a few millimeters in the positions of scanned structures. When a coregistered computerized tomography (CT) scan is available, the US image can be corrected for SOS aberration. Typically, image guided radiotherapy workflows implementing US systems only provide a CT scan at the simulation (SIM) stage. If changes occur in geometry or density distribution between SIM and treatment (TX) stage, SOS aberration can change accordingly, with a final impact on the measured position of structures which is dependent on the workflow adopted. METHODS: Four basic scenarios were considered of possible changes between SIM and TX: (1) No changes, (2) only patient position changes (rigid rotation-translation), (3) only US transducer position changes (constrained on patient's surface), and (4) patient tissues thickness changes. Different SOS aberrations may arise from the different scenarios, according to the specific US-gRT workflow used: intermodality (INTER) where TX US scans are compared to SIM CT scans; intramodality (INTRA) where TX US scans are compared to SIM US scans; and INTERc and INTRAc where all US images are corrected for SOS aberration (using density information provided by SIM CT). For an experimental proof of principle, the effect of tissues thickness change was simulated in the different workflows: a dual layered phantom was filled with layers of sunflower oil (SOS 1478 m/s), water (SOS 1482 m/s), and 20% saline solution (SOS 1700 m/s). The phantom was US scanned, the layer thicknesses were increased and the US scans were repeated. The errors resulting from the different workflows were compared. RESULTS: Theoretical considerations show that workflows implementing SOS correction based on SIM-CT scan (INTERc, INTRAc) give null errors in all scenarios except when tissues thickness changes, where an error proportional to the degree of change in SOS maps between SIM and TX (DeltaSOS) occurs. An uncorrected workflow such as INTER produces in all scenarios a pure SOS error, while uncorrected INTRA produces a null error for rotation-translation of the patient, a DeltaSOS error for changing tissues thickness and an error proportional to the degree of SOS distribution change along the different lines of view when shifting the transducer. The dual layered phantom demonstrated experimentally that the effect of SOS change between SIM and TX is clinically nonrelevant, being less than the intrinsic resolution of imaging systems, even when a substantial change in thicknesses is applied, provided that a SIM-CT-based SOS aberration correction is applied. Noncorrected workflows produce errors up to 4 mm for INTER and to 3 mm for INTRA in the phantom test. CONCLUSIONS: A SOS correction is advantageous for all US-gRT workflows and clinical cases, where the effect of SOS change can be considered a second order effect. PMID- 23039668 TI - Mapping of distributions of a local b-matrix cross-term strength using diffusion tensor MRI in patients with Alzheimer's disease. AB - PURPOSE: Mapping of the distribution of local susceptibility strength could be very important in understanding the mechanisms of progression in neurodegenerative diseases, due to depositions of iron and iron-containing plaques. The goal of this study is to map the voxelwise distribution of local cross-term b-value (b(c)) effect caused by interactions between the external and internal gradients, in subjects with Alzheimer's disease (AD), mild cognitive impairment (MCI), and cognitively normal (CN) elderly, using a diffusion tensor (DT) MRI. METHODS: Two DT-MRI experiments were conducted with opposite polarities of the external diffusion-sensitizing gradients, and the authors modeled the 3 * 3 tensor matrix of b(c) maps and drove a rotationally independent mean b(c) (i.e., MB(c)) maps. To test whether AD has higher cross-term gradients than MCI and/or CN, 15 AD patients, 18 MCI patients, and 16 CN controls were acquired from DT-MRI data, with six diffusion encoding directions, five b-values (0, 160, 360, 640, and 1000 s/mm(2)), and positively and negatively alternating polarities of the external diffusion-sensitizing gradients. The b(c) and MB(c) maps were calculated and were spatially normalized into a study specific template for all subjects. The differences of MB(c) maps across the three subject groups were investigated with voxelwise one-way ANOVA tests for each b-value. The differences of MB(c) maps, among the four b-values, were also investigated with a voxelwise one-way within-subject ANOVA test for each group. RESULTS: The authors successfully mapped the local cross-term strength, using a DT-MRI data in the three groups. The MB(c) differences between the groups were increased with increasing b-values. Compared with the CN group and the MCI group, MB(c) values in the AD group were significantly increased. However, compared with the CN group, MB(c) values in the MCI group were not significantly different for all the b-values. CONCLUSIONS: In order to map the b-matrix cross-term effect, the authors developed a rotationally invariant index of MB(c), and the index was applied in AD, MCI, and CN subjects. In the AD group, compared with the MCI and CN groups, MB(c) values were increased. AD patients may have much more local intrinsic gradients in the brain than those MCI or CN subjects. MB(c) maps may be used to detect the intrinsically susceptible materials in the human brain, such as iron-containing plaques in the brain with AD. PMID- 23039669 TI - SlicerRT: radiation therapy research toolkit for 3D Slicer. AB - PURPOSE: Interest in adaptive radiation therapy research is constantly growing, but software tools available for researchers are mostly either expensive, closed proprietary applications, or free open-source packages with limited scope, extensibility, reliability, or user support. To address these limitations, we propose SlicerRT, a customizable, free, and open-source radiation therapy research toolkit. SlicerRT aspires to be an open-source toolkit for RT research, providing fast computations, convenient workflows for researchers, and a general image-guided therapy infrastructure to assist clinical translation of experimental therapeutic approaches. It is a medium into which RT researchers can integrate their methods and algorithms, and conduct comparative testing. METHODS: SlicerRT was implemented as an extension for the widely used 3D Slicer medical image visualization and analysis application platform. SlicerRT provides functionality specifically designed for radiation therapy research, in addition to the powerful tools that 3D Slicer offers for visualization, registration, segmentation, and data management. The feature set of SlicerRT was defined through consensus discussions with a large pool of RT researchers, including both radiation oncologists and medical physicists. The development processes used were similar to those of 3D Slicer to ensure software quality. Standardized mechanisms of 3D Slicer were applied for documentation, distribution, and user support. The testing and validation environment was configured to automatically launch a regression test upon each software change and to perform comparison with ground truth results provided by other RT applications. RESULTS: Modules have been created for importing and loading DICOM-RT data, computing and displaying dose volume histograms, creating accumulated dose volumes, comparing dose volumes, and visualizing isodose lines and surfaces. The effectiveness of using 3D Slicer with the proposed SlicerRT extension for radiation therapy research was demonstrated on multiple use cases. CONCLUSIONS: A new open-source software toolkit has been developed for radiation therapy research. SlicerRT can import treatment plans from various sources into 3D Slicer for visualization, analysis, comparison, and processing. The provided algorithms are extensively tested and they are accessible through a convenient graphical user interface as well as a flexible application programming interface. PMID- 23039670 TI - An efficient protocol for radiochromic film dosimetry combining calibration and measurement in a single scan. AB - PURPOSE: Radiochromic film provides dose measurement at high spatial resolution, but often is not preferred for routine evaluation of patient-specific intensity modulated radiation therapy (IMRT) plans owing to ease-of-use factors. The authors have established an efficient protocol that combines calibration and measurement in a single scan and enables measurement results to be obtained in less than 30 min. This avoids complications due to postexposure changes in radiochromic film that delay the completion of a measurement, often for up to 24 h, in commonly used methods. In addition, the protocol addresses the accuracy and integrity of the measurement by eliminating environmental and interscan variability issues. METHODS: The authors collected dose-response data from six production lots of Gafchromic EBT3 film and three production lots of EBT2 film at doses up to 480 cGy. In this work, the authors used seven different scanners of two different models-Epson 10000XL and V700; postexposure times before scanning from 30 min to 9 days; ambient temperatures for scanning spanning 11 degrees C; and two film orientations. Scanning was in 48-bit RGB format at 72 dpi resolution. Dose evaluation was conducted using a triple-channel dosimetry method. To evaluate the measurement protocol, patient specific IMRT and volumetric modulated arc therapy (VMAT) plans were exposed onto EBT3 films on a Varian Trilogy Linac. Film scanning was done following the protocol under a number of different conditions and the dose maps were analyzed to demonstrate the equivalence of results. RESULTS: The results indicated that the dose-response data could be fit by a set of related rational functions leading to the description of a generic calibration curve. A simplified dosimetry protocol was established where dose-response data for a specific film lot, scanner, and scanning conditions could be derived from two films exposed to known doses. In most cases only one calibrated exposure was required since the dose for one of the films could be zero. Using the Gamma test criterion of 2%/2 mm to evaluate the measurements, similar passing rates ranging between about 95% and 99% for the fields studied were obtained from application films digitized under a variety of conditions all of them different than the conditions under which the calibration films were scanned. CONCLUSIONS: The authors have developed a simplified and efficient protocol to measure doses delivered by an IMRT or VMAT plan using only the patient film, one calibration film, one unexposed film, and applying a single scan to acquire a digital image for calculation and analysis. The simplification and timesaving offer a potential practical solution for using radiochromic film for routine treatment plan quality assurance without sacrificing spatial resolution for convenience. PMID- 23039671 TI - Methodology for registration of distended rectums in pelvic CT studies. AB - PURPOSE: Accurate delineation of the rectum is of high importance in off-line adaptive radiation therapy since it is a major dose-limiting organ in prostate cancer radiotherapy. The intensity-based deformable image registration (DIR) methods cannot create a correct spatial transformation if there is no correspondence between the template and the target images. The variation of rectal filling, gas, or feces, creates a non correspondence in image intensities that becomes a great obstacle for intensity-based DIR. METHODS: In this study the authors have designed and implemented a semiautomatic method to create a rectum mask in pelvic computed tomography (CT) images. The method, that includes a DIR based on the demons algorithm, has been tested in 13 prostate cancer cases, each comprising of two CT scans, for a total of 26 CT scans. RESULTS: The use of the manual segmentation in the planning image and the proposed rectum mask method (RMM) method in the daily image leads to an improvement in the DIR performance in pelvic CT images, obtaining a mean value of overlap volume index = 0.89, close to the values obtained using the manual segmentations in both images. CONCLUSIONS: The application of the RMM method in the daily image and the manual segmentations in the planning image during prostate cancer treatments increases the performance of the registration in presence of rectal fillings, obtaining very good agreement with a physician's manual contours. PMID- 23039672 TI - Verification of dosimetric accuracy on the TrueBeam STx: rounded leaf effect of the high definition MLC. AB - PURPOSE: The dosimetric leaf gap (DLG) in the Varian Eclipse treatment planning system is determined during commissioning and is used to model the effect of the rounded leaf-end of the multileaf collimator (MLC). This parameter attempts to model the physical difference between the radiation and light field and account for inherent leakage between leaf tips. With the increased use of single fraction high dose treatments requiring larger monitor units comes an enhanced concern in the accuracy of leakage calculations, as it accounts for much of the patient dose. This study serves to verify the dosimetric accuracy of the algorithm used to model the rounded leaf effect for the TrueBeam STx, and describes a methodology for determining best-practice parameter values, given the novel capabilities of the linear accelerator such as flattening filter free (FFF) treatments and a high definition MLC (HDMLC). METHODS: During commissioning, the nominal MLC position was verified and the DLG parameter was determined using MLC defined field sizes and moving gap tests, as is common in clinical testing. Treatment plans were created, and the DLG was optimized to achieve less than 1% difference between measured and calculated dose. The DLG value found was tested on treatment plans for all energies (6 MV, 10 MV, 15 MV, 6 MV FFF, 10 MV FFF) and modalities (3D conventional, IMRT, conformal arc, VMAT) available on the TrueBeam STx. RESULTS: The DLG parameter found during the initial MLC testing did not match the leaf gap modeling parameter that provided the most accurate dose delivery in clinical treatment plans. Using the physical leaf gap size as the DLG for the HDMLC can lead to 5% differences in measured and calculated doses. CONCLUSIONS: Separate optimization of the DLG parameter using end-to-end tests must be performed to ensure dosimetric accuracy in the modeling of the rounded leaf ends for the Eclipse treatment planning system. The difference in leaf gap modeling versus physical leaf gap dimensions is more pronounced in the more recent versions of Eclipse for both the HDMLC and the Millennium MLC. Once properly commissioned and tested using a methodology based on treatment plan verification, Eclipse is able to accurately model radiation dose delivered for SBRT treatments using the TrueBeam STx. PMID- 23039673 TI - Prostate segmentation by sparse representation based classification. AB - PURPOSE: The segmentation of prostate in CT images is of essential importance to external beam radiotherapy, which is one of the major treatments for prostate cancer nowadays. During the radiotherapy, the prostate is radiated by high-energy x rays from different directions. In order to maximize the dose to the cancer and minimize the dose to the surrounding healthy tissues (e.g., bladder and rectum), the prostate in the new treatment image needs to be accurately localized. Therefore, the effectiveness and efficiency of external beam radiotherapy highly depend on the accurate localization of the prostate. However, due to the low contrast of the prostate with its surrounding tissues (e.g., bladder), the unpredicted prostate motion, and the large appearance variations across different treatment days, it is challenging to segment the prostate in CT images. In this paper, the authors present a novel classification based segmentation method to address these problems. METHODS: To segment the prostate, the proposed method first uses sparse representation based classification (SRC) to enhance the prostate in CT images by pixel-wise classification, in order to overcome the limitation of poor contrast of the prostate images. Then, based on the classification results, previous segmented prostates of the same patient are used as patient-specific atlases to align onto the current treatment image and the majority voting strategy is finally adopted to segment the prostate. In order to address the limitations of the traditional SRC in pixel-wise classification, especially for the purpose of segmentation, the authors extend SRC from the following four aspects: (1) A discriminant subdictionary learning method is proposed to learn a discriminant and compact representation of training samples for each class so that the discriminant power of SRC can be increased and also SRC can be applied to the large-scale pixel-wise classification. (2) The L1 regularized sparse coding is replaced by the elastic net in order to obtain a smooth and clear prostate boundary in the classification result. (3) Residue based linear regression is incorporated to improve the classification performance and to extend SRC from hard classification to soft classification. (4) Iterative SRC is proposed by using context information to iteratively refine the classification results. RESULTS: The proposed method has been comprehensively evaluated on a dataset consisting of 330 CT images from 24 patients. The effectiveness of the extended SRC has been validated by comparing it with the traditional SRC based on the proposed four extensions. The experimental results show that our extended SRC can obtain not only more accurate classification results but also smoother and clearer prostate boundary than the traditional SRC. Besides, the comparison with other five state-of-the-art prostate segmentation methods indicates that our method can achieve better performance than other methods under comparison. CONCLUSIONS: The authors have proposed a novel prostate segmentation method based on the sparse representation based classification, which can achieve considerably accurate segmentation results in CT prostate segmentation. PMID- 23039674 TI - Multiresolution MR elastography using nonlinear inversion. AB - PURPOSE: Nonlinear inversion (NLI) in MR elastography requires discretization of the displacement field for a finite element (FE) solution of the "forward problem", and discretization of the unknown mechanical property field for the iterative solution of the "inverse problem". The resolution requirements for these two discretizations are different: the forward problem requires sufficient resolution of the displacement FE mesh to ensure convergence, whereas lowering the mechanical property resolution in the inverse problem stabilizes the mechanical property estimates in the presence of measurement noise. Previous NLI implementations use the same FE mesh to support the displacement and property fields, requiring a trade-off between the competing resolution requirements. METHODS: This work implements and evaluates multiresolution FE meshes for NLI elastography, allowing independent discretizations of the displacements and each mechanical property parameter to be estimated. The displacement resolution can then be selected to ensure mesh convergence, and the resolution of the property meshes can be independently manipulated to control the stability of the inversion. RESULTS: Phantom experiments indicate that eight nodes per wavelength (NPW) are sufficient for accurate mechanical property recovery, whereas mechanical property estimation from 50 Hz in vivo brain data stabilizes once the displacement resolution reaches 1.7 mm (approximately 19 NPW). Viscoelastic mechanical property estimates of in vivo brain tissue show that subsampling the loss modulus while holding the storage modulus resolution constant does not substantially alter the storage modulus images. Controlling the ratio of the number of measurements to unknown mechanical properties by subsampling the mechanical property distributions (relative to the data resolution) improves the repeatability of the property estimates, at a cost of modestly decreased spatial resolution. CONCLUSIONS: Multiresolution NLI elastography provides a more flexible framework for mechanical property estimation compared to previous single mesh implementations. PMID- 23039676 TI - The use of exit detector sinograms to detect anatomical variations for patients extending beyond the TomoTherapy field of view: a feasibility study. AB - PURPOSE: This work describes an independent method to use the TomoTherapy Hi-ART megavoltage CT imaging system for daily monitoring of anatomical changes of cancer patients whose anatomy extends beyond the imaging field of view. METHODS: The imaging detector response to changes in attenuating media was measured using water-equivalent plastic. Weight loss was simulated using an anthropomorphic phantom and determining the system's ability to detect the weight loss. Layers of tissue-equivalent bolus were added to an anthropomorphic pelvis phantom and CT simulations of the phantom were conducted, one in which the phantom and bolus were both within the TomoTherapy imaging field of view, and another in which the couch was raised so that the bolus was outside the field of view. Gynecological treatment plans were developed using the TomoTherapy treatment planning system, and successive fractions of the plan were then delivered to the phantom. Weight loss was simulated by removing a 0.5 cm layer of bolus following each fraction. The exit detector sinograms were obtained from each fraction, and ratios of sinograms were calculated relative to a reference sinogram for which all bolus was in place. Histograms of ratio sinograms were determined and used to correlate with simulated weight loss. Exit detector sinograms and ratio histograms were also retrospectively analyzed for five patients all of whose anatomies extended beyond the imaging field of view and all of whom experienced weight variations exceeding 10% during treatment. RESULTS: Exit detector signal is well correlated to changes in attenuator thickness as demonstrated in both slab and anthropomorphic phantom geometries. Measured and expected signal increases agreed to within less than 2% for simulated weight loss on the anthropomorphic phantom. Exit detector signals for pelvic patients with significant weight loss variations were consistent with phantom measurements. CONCLUSIONS: The analysis of the ratio sinograms for the phantom measurements and real patients indicated that exit detector sinograms can be used to detect relative changes in patient anatomy for each fraction as a means of in vivo quality assurance. PMID- 23039675 TI - Cupping artifact correction and automated classification for high-resolution dedicated breast CT images. AB - PURPOSE: To develop and test an automated algorithm to classify the different tissues present in dedicated breast CT images. METHODS: The original CT images are first corrected to overcome cupping artifacts, and then a multiscale bilateral filter is used to reduce noise while keeping edge information on the images. As skin and glandular tissues have similar CT values on breast CT images, morphologic processing is used to identify the skin mask based on its position information. A modified fuzzy C-means (FCM) classification method is then used to classify breast tissue as fat and glandular tissue. By combining the results of the skin mask with the FCM, the breast tissue is classified as skin, fat, and glandular tissue. To evaluate the authors' classification method, the authors use Dice overlap ratios to compare the results of the automated classification to those obtained by manual segmentation on eight patient images. RESULTS: The correction method was able to correct the cupping artifacts and improve the quality of the breast CT images. For glandular tissue, the overlap ratios between the authors' automatic classification and manual segmentation were 91.6% +/- 2.0%. CONCLUSIONS: A cupping artifact correction method and an automatic classification method were applied and evaluated for high-resolution dedicated breast CT images. Breast tissue classification can provide quantitative measurements regarding breast composition, density, and tissue distribution. PMID- 23039677 TI - The radiobiological P(+) index for pretreatment plan assessment with emphasis on four-dimensional radiotherapy modalities. AB - PURPOSE: Radiation treatment modalities will continue to emerge that promise better clinical outcomes albeit technologically challenging to implement. An important question facing the radiotherapy community then is the need to justify the added technological effort for the clinical return. Mobile tumor radiotherapy is a typical example, where 4D tumor tracking radiotherapy (4DTRT) has been proposed over the simpler conventional modality for better results. The modality choice per patient can depend on a wide variety of factors. In this work, we studied the complication-free tumor control probability (P(+)) index, which combines the physical complexity of the treatment plan with the radiobiological characteristics of the clinical case at hand and therefore found to be useful in evaluating different treatment techniques and estimating the expected clinical effectiveness of different radiation modalities. METHODS: 4DCT volumes of 18 previously treated lung cancer patients with tumor motion and size ranging from 2 mm to 15 mm and from 4 cc to 462 cc, respectively, were used. For each patient, 4D treatment plans were generated to extract the 4D dose distributions, which were subsequently used with clinically derived radiobiological parameters to compute the P(+) index per modality. RESULTS: The authors observed, on average, a statistically significant increase in P(+) of 3.4% +/- 3.8% (p < 0.003) in favor of 4DTRT. There was high variability among the patients with a <0.5% up to 13.4% improvement in P(+). CONCLUSIONS: The observed variability in the improvement of the clinical effectiveness suggests that the relative benefit of tracking should be evaluated on a per patient basis. Most importantly, this variability could be effectively captured in the computed P(+). The index can thus be useful to discriminate and hence point out the need for a complex modality like 4DTRT over another. Besides tumor mobility, a wide range of other factors, e.g., size, location, fractionation, etc., can affect the relative benefits. Application of the P(+) objective is a simple and effective way to combine these factors in the evaluation of a treatment plan. PMID- 23039678 TI - Liver motion during cone beam computed tomography guided stereotactic body radiation therapy. AB - PURPOSE: Understanding motion characteristics of liver such as, interfractional and intrafractional motion variability, difference in motion within different locations in the organ, and their complex relationship with the breathing cycles are particularly important for image-guided liver SBRT. The purpose of this study was to investigate such motion characteristics based on fiducial markers tracked with the x-ray projections of the CBCT scans, taken immediately prior to the treatments. METHODS: Twenty liver SBRT patients were analyzed. Each patient had three fiducial markers (2 * 5-mm gold) percutaneously implanted around the gross tumor. The prescription ranged from 2 to 8 fractions per patient. The CBCT projections data for each fraction (~650 projections/scan), for each patient, were analyzed and the 2D positions of the markers were extracted using an in house algorithm. In total, >55 000 x-ray projections were analyzed from 85 CBCT scans. From the 2D extracted positions, a 3D motion trajectory of the markers was constructed, from each CBCT scans, resulting in left-right (LR), anterior posterior (AP), and cranio-caudal (CC) location information of the markers with >55 000 data points. The authors then analyzed the interfraction and intrafraction liver motion variability, within different locations in the organ, and as a function of the breathing cycle. The authors also compared the motion characteristics against the planning 4DCT and the RPMTM (Varian Medical Systems, Palo Alto, CA) breathing traces. Variations in the appropriate gating window (defined as the percent of the maximum range at which 50% of the marker positions are contained), between fractions were calculated as well. RESULTS: The range of motion for the 20 patients were 3.0 +/- 2.0 mm, 5.1 +/- 3.1 mm, and 17.9 +/- 5.1 mm in the planning 4DCT, and 2.8 +/- 1.6 mm, 5.3 +/- 3.1 mm, and 16.5 +/- 5.7 mm in the treatment CBCT, for LR, AP, and CC directions, respectively. The range of respiratory period was 3.9 +/- 0.7 and 4.2 +/- 0.8 s during the 4DCT simulation and the CBCT scans, respectively. The authors found that breathing-induced AP and CC motions are highly correlated. That is, all markers moved cranially also moved posteriorly and vice versa, irrespective of the location. The LR motion had a more variable relationship with the AP/CC motions, and appeared random with respect to the location. That is, when the markers moved toward cranial-posterior direction, 58% of the markers moved to the patient-right, 22% of the markers moved to the patient-left, and 20% of the markers had minimal/none motion. The absolute difference in the motion magnitude between the markers, in different locations within the liver, had a positive correlation with the absolute distance between the markers (R(2) = 0.69, linear-fit). The interfractional gating window varied significantly for some patients, with the largest having 29.4%-56.4% range between fractions. CONCLUSIONS: This study analyzed the liver motion characteristics of 20 patients undergoing SBRT. A large variation in motion was observed, interfractionally and intrafractionally, and that as the distance between the markers increased, the difference in the absolute range of motion also increased. This suggests that marker(s) in closest proximity to the target be used. PMID- 23039680 TI - Definition of parameters for quality assurance of flattening filter free (FFF) photon beams in radiation therapy. AB - PURPOSE: Flattening filter free (FFF) beams generated by medical linear accelerators have recently started to be used in radiotherapy clinical practice. Such beams present fundamental differences with respect to the standard filter flattened (FF) beams, making the generally used dosimetric parameters and definitions not always viable. The present study will propose possible definitions and suggestions for some dosimetric parameters for use in quality assurance of FFF beams generated by medical linacs in radiotherapy. METHODS: The main characteristics of the photon beams have been analyzed using specific data generated by a Varian TrueBeam linac having both FFF and FF beams of 6 and 10 MV energy, respectively. RESULTS: Definitions for dose profile parameters are suggested starting from the renormalization of the FFF with respect to the corresponding FF beam. From this point the flatness concept has been translated into one of "unflatness" and other definitions have been proposed, maintaining a strict parallelism between FFF and FF parameter concepts. CONCLUSIONS: Ideas for quality controls used in establishing a quality assurance program when introducing FFF beams into the clinical environment are given here, keeping them similar to those used for standard FF beams. By following the suggestions in this report, the authors foresee that the introduction of FFF beams into a clinical radiotherapy environment will be as safe and well controlled as standard beam modalities using the existing guidelines. PMID- 23039679 TI - MR/PET quantification tools: registration, segmentation, classification, and MR based attenuation correction. AB - PURPOSE: Combined MR/PET is a relatively new, hybrid imaging modality. A human MR/PET prototype system consisting of a Siemens 3T Trio MR and brain PET insert was installed and tested at our institution. Its present design does not offer measured attenuation correction (AC) using traditional transmission imaging. This study is the development of quantification tools including MR-based AC for quantification in combined MR/PET for brain imaging. METHODS: The developed quantification tools include image registration, segmentation, classification, and MR-based AC. These components were integrated into a single scheme for processing MR/PET data. The segmentation method is multiscale and based on the Radon transform of brain MR images. It was developed to segment the skull on T1 weighted MR images. A modified fuzzy C-means classification scheme was developed to classify brain tissue into gray matter, white matter, and cerebrospinal fluid. Classified tissue is assigned an attenuation coefficient so that AC factors can be generated. PET emission data are then reconstructed using a three-dimensional ordered sets expectation maximization method with the MR-based AC map. Ten subjects had separate MR and PET scans. The PET with [(11)C]PIB was acquired using a high-resolution research tomography (HRRT) PET. MR-based AC was compared with transmission (TX)-based AC on the HRRT. Seventeen volumes of interest were drawn manually on each subject image to compare the PET activities between the MR based and TX-based AC methods. RESULTS: For skull segmentation, the overlap ratio between our segmented results and the ground truth is 85.2 +/- 2.6%. Attenuation correction results from the ten subjects show that the difference between the MR and TX-based methods was <6.5%. CONCLUSIONS: MR-based AC compared favorably with conventional transmission-based AC. Quantitative tools including registration, segmentation, classification, and MR-based AC have been developed for use in combined MR/PET. PMID- 23039681 TI - Computer-aided classification of breast masses using speckle features of automated breast ultrasound images. AB - PURPOSE: To develop an ultrasound computer-aided diagnosis (CAD) system using speckle features of automated breast ultrasound (ABUS) images. METHODS: The ABUS images of 147 pathologically proven breast masses (76 benign and 71 malignant cases) were used. For each mass, a volume of interest (VOI) was cropped to define the tumor area, and the average number of speckle pixels within a VOI was calculated. In addition, first-order and second-order statistical analyses of the speckle pixels were used to quantify the information of gray-level distributions and the spatial relations among the pixels. Receiver operating characteristic curve analysis was used to evaluate the performance. RESULTS: The proposed CAD system based on speckle patterns achieved an accuracy of 84.4% (124/147), a sensitivity of 83.1% (59/71), a specificity of 85.5% (65/76), and an Az of 0.91. The performance indices of the speckle features were comparable to the performance indices of the morphological features, which include shape and ellipse-fitting features (p-value > 0.05). Furthermore, combining speckle and morphological features yielded an Az that was significantly better than the Az of the morphological features alone (0.96 vs 0.91, p-value = 0.0154). CONCLUSIONS: The results suggest that the proposed speckle features, while combined with morphological features, are promising for the classification of breast masses detected using ABUS. PMID- 23039682 TI - Analysis and comparison of two methods for motion correction in PET imaging. AB - PURPOSE: Although there have been various proposed methods for positron emission tomography (PET) motion correction, there is not sufficient evidence to answer which method is better in practice. This investigation aims to characterize the behavior of the two main motion-correction approaches in terms of convergence and image properties. METHODS: For the first method, reconstruct-transform-average (RTA), reconstructions of each gate are transformed to a reference gate and averaged. In the second method, motion-compensated image reconstruction (MCIR), motion information is incorporated within the reconstruction. Both techniques studied were based on the ordered subsets expectation maximization algorithm. Motion information was obtained from a dynamic MR acquisition performed on a human volunteer and concurrent PET data were simulated from the dynamic MR data. The two approaches were assessed statistically using multiple realizations to accurately define the noise properties of the reconstructed images. RESULTS: MCIR successfully recovers the true values of all regions, whereas RTA has high bias due to the limited count-statistics and interpolation errors during the transformation step. In addition, RTA noise is very small and stabilized, whereas in MCIR noise becomes progressively greater with the number of iterations and therefore MCIR outperforms RTA in terms of MSE only if noise is treated. For example, MCIR with postfiltering results in MSE up to 42% lower than RTA. CONCLUSIONS: This study indicates that MCIR may provide superior performance overall to RTA if noise is minimized. However, in applications where quantification is not the main objective RTA can be a practical and simple method to correct for motion. PMID- 23039683 TI - Robust methods for automatic image-to-world registration in cone-beam CT interventional guidance. AB - PURPOSE: Real-time surgical navigation relies on accurate image-to-world registration to align the coordinate systems of the image and patient. Conventional manual registration can present a workflow bottleneck and is prone to manual error and intraoperator variability. This work reports alternative means of automatic image-to-world registration, each method involving an automatic registration marker (ARM) used in conjunction with C-arm cone-beam CT (CBCT). The first involves a Known-Model registration method in which the ARM is a predefined tool, and the second is a Free-Form method in which the ARM is freely configurable. METHODS: Studies were performed using a prototype C-arm for CBCT and a surgical tracking system. A simple ARM was designed with markers comprising a tungsten sphere within infrared reflectors to permit detection of markers in both x-ray projections and by an infrared tracker. The Known-Model method exercised a predefined specification of the ARM in combination with 3D-2D registration to estimate the transformation that yields the optimal match between forward projection of the ARM and the measured projection images. The Free-Form method localizes markers individually in projection data by a robust Hough transform approach extended from previous work, backprojected to 3D image coordinates based on C-arm geometric calibration. Image-domain point sets were transformed to world coordinates by rigid-body point-based registration. The robustness and registration accuracy of each method was tested in comparison to manual registration across a range of body sites (head, thorax, and abdomen) of interest in CBCT-guided surgery, including cases with interventional tools in the radiographic scene. RESULTS: The automatic methods exhibited similar target registration error (TRE) and were comparable or superior to manual registration for placement of the ARM within ~200 mm of C-arm isocenter. Marker localization in projection data was robust across all anatomical sites, including challenging scenarios involving the presence of interventional tools. The reprojection error of marker localization was independent of the distance of the ARM from isocenter, and the overall TRE was dominated by the configuration of individual fiducials and distance from the target as predicted by theory. The median TRE increased with greater ARM-to-isocenter distance (e.g., for the Free-Form method, TRE increasing from 0.78 mm to 2.04 mm at distances of ~75 mm and 370 mm, respectively). The median TRE within ~200 mm distance was consistently lower than that of the manual method (TRE = 0.82 mm). Registration performance was independent of anatomical site (head, thorax, and abdomen). The Free-Form method demonstrated a statistically significant improvement (p = 0.0044) in reproducibility compared to manual registration (0.22 mm versus 0.30 mm, respectively). CONCLUSIONS: Automatic image-to-world registration methods demonstrate the potential for improved accuracy, reproducibility, and workflow in CBCT-guided procedures. A Free-Form method was shown to exhibit robustness against anatomical site, with comparable or improved TRE compared to manual registration. It was also comparable or superior in performance to a Known-Model method in which the ARM configuration is specified as a predefined tool, thereby allowing configuration of fiducials on the fly or attachment to the patient. PMID- 23039684 TI - Positron emission mammography (PEM): effect of activity concentration, object size, and object contrast on phantom lesion detection. AB - PURPOSE: To characterize the relationship between lesion detection sensitivity and injected activity as a function of lesion size and contrast on the PEM (positron emission mammography) Flex Solo II scanner using phantom experiments. METHODS: Phantom lesions (spheres 4, 8, 12, 16, and 20 mm diameter) were randomly located in uniform background. Sphere activity concentrations were 3 to 21 times the background activity concentration (BGc). BGc was a surrogate for injected activity; BGc ranged from 0.44-4.1 kBq/mL, corresponding to 46-400 MBq injections. Seven radiologists read 108 images containing zero, one, or two spheres. Readers used a 5-point confidence scale to score the presence of spheres. RESULTS: Sensitivity was 100% for lesions >=12 mm under all conditions except for one 12 mm sphere with the lowest contrast and lowest BGc (60% sensitivity). Sensitivity was 100% for 8 mm spheres when either contrast or BGc was high, and 100% for 4 mm spheres only when both contrast and BGc were highest. Sphere contrast recovery coefficients (CRC) were 49%, 34%, 26%, 14%, and 2.8% for the largest to smallest spheres. Cumulative specificity was 98%. CONCLUSIONS: Phantom lesion detection sensitivity depends more on sphere size and contrast than on BGc. Detection sensitivity remained >=90% for injected activities as low as 100 MBq, for lesions >=8 mm. Low CRC in 4 mm objects results in moderate detection sensitivity even for 400 MBq injected activity, making it impractical to optimize injected activity for such lesions. Low CRC indicates that when lesions <8 mm are observed on PEM images they are highly tracer avid with greater potential of clinical significance. High specificity (98%) suggests that image statistical noise does not lead to false positive findings. These results apply to the 85 mm thick object used to obtain them; lesion detectability should be better (worse) for thinner (thicker) objects based on the reduced (increased) influence of photon attenuation. PMID- 23039685 TI - Skin dose in longitudinal and transverse linac-MRIs using Monte Carlo and realistic 3D MRI field models. AB - PURPOSE: The magnetic fields of linac-MR systems modify the path of contaminant electrons in photon beams, which alters patient skin dose. To accurately quantify the magnitude of changes in skin dose, the authors use Monte Carlo calculations that incorporate realistic 3D magnetic field models of longitudinal and transverse linac-MR systems. METHODS: Finite element method (FEM) is used to generate complete 3D magnetic field maps for 0.56 T longitudinal and transverse linac-MR magnet assemblies, as well as for representative 0.5 and 1.0 T Helmholtz MRI systems. EGSnrc simulations implementing these 3D magnetic fields are performed. The geometry for the BEAMnrc simulations incorporates the Varian 600C 6 MV linac, magnet poles, the yoke, and the magnetic shields of the linac-MRIs. Resulting phase-space files are used to calculate the central axis percent depth doses in a water phantom and 2D skin dose distributions for 70 MUm entrance and exit layers using DOSXYZnrc. For comparison, skin doses are also calculated in the absence of magnetic field, and using a 1D magnetic field with an unrealistically large fringe field. The effects of photon field size, air gap (longitudinal configuration), and angle of obliquity (transverse configuration) are also investigated. RESULTS: Realistic modeling of the 3D magnetic fields shows that fringe fields decay rapidly and have a very small magnitude at the linac head. As a result, longitudinal linac-MR systems mostly confine contaminant electrons that are generated in the air gap and have an insignificant effect on electrons produced further upstream. The increase in the skin dose for the longitudinal configuration compared to the zero B-field case varies from ~1% to ~14% for air gaps of 5-31 cm, respectively. (All dose changes are reported as a % of D(max).) The increase is also field-size dependent, ranging from ~3% at 20 * 20 cm(2) to ~11% at 5 * 5 cm(2). The small changes in skin dose are in contrast to significant increases that are calculated for the unrealistic 1D magnetic field. For the transverse configuration, the entrance skin dose is equal or smaller than that of the zero B-field case for perpendicular beams. For a 10 * 10 cm(2) oblique beam the transverse magnetic field decreases the entry skin dose for oblique angles less than +/-20 degrees and increases it by no more than 10% for larger angles up to +/-45 degrees . The exit skin dose is increased by 42% for a 10 * 10 cm(2) perpendicular beam, but appreciably drops and approaches the zero B-field case for large oblique angles of incidence. CONCLUSIONS: For longitudinal linac-MR systems only a small increase in the entrance skin dose is predicted, due to the rapid decay of the realistic magnetic fringe fields. For transverse linac-MR systems, changes to the entrance skin dose are small for most scenarios. For the same geometry, on the exit side a fairly large increase is observed for perpendicular beams, but significantly drops for large oblique angles of incidence. The observed effects on skin dose are not expected to limit the application of linac-MR systems in either the longitudinal or transverse configuration. PMID- 23039686 TI - On possible temperature dependence of plastic scintillator response. PMID- 23039690 TI - Modelling noise in biochemical reaction networks. PMID- 23039691 TI - Linear noise approximation is valid over limited times for any chemical system that is sufficiently large. AB - The linear noise approximation (LNA) is a way of approximating the stochastic time evolution of a well-stirred chemically reacting system. It can be obtained either as the lowest order correction to the deterministic chemical reaction rate equation (RRE) in van Kampen's system-size expansion of the chemical master equation (CME), or by linearising the two-term-truncated chemical Kramers-Moyal equation. However, neither of those derivations sheds much light on the validity of the LNA. The problematic character of the system-size expansion of the CME for some chemical systems, the arbitrariness of truncating the chemical Kramers-Moyal equation at two terms, and the sometimes poor agreement of the LNA with the solution of the CME, have all raised concerns about the validity and usefulness of the LNA. Here, the authors argue that these concerns can be resolved by viewing the LNA as an approximation of the chemical Langevin equation (CLE). This view is already implicit in Gardiner's derivation of the LNA from the truncated Kramers-Moyal equation, as that equation is mathematically equivalent to the CLE. However, the CLE can be more convincingly derived in a way that does not involve either the truncated Kramers-Moyal equation or the system-size expansion. This derivation shows that the CLE will be valid, at least for a limited span of time, for any system that is sufficiently close to the thermodynamic (large-system) limit. The relatively easy derivation of the LNA from the CLE shows that the LNA shares the CLE's conditions of validity, and it also suggests that what the LNA really gives us is a description of the initial departure of the CLE from the RRE as we back away from the thermodynamic limit to a large but finite system. The authors show that this approach to the LNA simplifies its derivation, clarifies its limitations, and affords an easier path to its solution. PMID- 23039692 TI - Non-linear corrections to the time-covariance function derived from a multi-state chemical master equation. AB - The time-covariance function captures the dynamics of biochemical fluctuations and contains important information about the underlying kinetic rate parameters. Intrinsic fluctuations in biochemical reaction networks are typically modelled using a master equation formalism. In general, the equation cannot be solved exactly and approximation methods are required. For small fluctuations close to equilibrium, a linearisation of the dynamics provides a very good description of the relaxation of the time-covariance function. As the number of molecules in the system decrease, deviations from the linear theory appear. Carrying out a systematic perturbation expansion of the master equation to capture these effects results in formidable algebra; however, symbolic mathematics packages considerably expedite the computation. The authors demonstrate that non-linear effects can reveal features of the underlying dynamics, such as reaction stoichiometry, not available in linearised theory. Furthermore, in models that exhibit noise-induced oscillations, non-linear corrections result in a shift in the base frequency along with the appearance of a secondary harmonic. PMID- 23039693 TI - Simulation of mRNA diffusion in the nuclear environment. AB - A mathematical model is devised to study the diffusion of mRNA in the nucleus from the site of synthesis to a nuclear pore where it is exported to the cytoplasm. This study examines the role that nuclear structure can play in determining the kinetics of export by considering models in which elements of the nuclear skeleton and confinement by chromatin direct the mRNA movement. As a rule, a dense chromatin layer favours rapid export by reducing the effective volume for diffusion. However, it may also result in a heavy tail in the export time distribution because of the low mobility of molecules that accidentally find their way deep into the dense layer. An anisotropic solid-state transport system can also assist export. There exist both an optimal ratio of the anisotropy and an optimal depth of the solid-state transport layer that favour rapid export. PMID- 23039694 TI - Anomalous diffusion and multifractional Brownian motion: simulating molecular crowding and physical obstacles in systems biology. AB - There have been many recent studies from both experimental and simulation perspectives in order to understand the effects of spatial crowding in molecular biology. These effects manifest themselves in protein organisation on the plasma membrane, on chemical signalling within the cell and in gene regulation. Simulations are usually done with lattice- or meshless-based random walks but insights can also be gained through the computation of the underlying probability density functions of these stochastic processes. Until recently much of the focus had been on continuous time random walks, but some very recent work has suggested that fractional Brownian motion may be a good descriptor of spatial crowding effects in some cases. The study compares both fractional Brownian motion and continuous time random walks and highlights how well they can represent different types of spatial crowding and physical obstacles. Simulated spatial data, mimicking experimental data, was first generated by using the package Smoldyn. We then attempted to characterise this data through continuous time anomalously diffusing random walks and multifractional Brownian motion (MFBM) by obtaining MFBM paths that match the statistical properties of our sample data. Although diffusion around immovable obstacles can be reasonably characterised by a single Hurst exponent, we find that diffusion in a crowded environment seems to exhibit multifractional properties in the form of a different short- and long-time behaviour. PMID- 23039695 TI - Influence of cell-to-cell variability on spatial pattern formation. AB - Many spatial patterns in biology arise through differentiation of selected cells within a tissue, which is regulated by a genetic network. This is specified by its structure, parameterisation and the noise on its components and reactions. The latter, in particular, is not well examined because it is rather difficult to trace. The authors use suitable local mathematical measures based on the Voronoi diagram of experimentally determined positions of epidermal plant hairs (trichomes) to examine the variability or noise in pattern formation. Although trichome initiation is a highly regulated process, the authors show that the experimentally observed trichome pattern is substantially disturbed by cell-to cell variations. Using computer simulations, they find that the rates concerning the availability of the protein complex that triggers trichome formation plays a significant role in noise-induced variations of the pattern. The focus on the effects of cell noise yields further insights into pattern formation of trichomes. The authors expect that similar strategies can contribute to the understanding of other differentiation processes by elucidating the role of naturally occurring fluctuations in the concentration of cellular components or their properties. PMID- 23039696 TI - Primary care in the Asia-Pacific region: challenges and solutions. PMID- 23039697 TI - Study of polymer particles suspensions for electrophoretic deposition. AB - Recently a great interest has been expressed in electrophoretic deposition (EPD) of polymers, both as particles and as chains. It is generally accepted that also for polymer particles, the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory is valid, therefore, in principle, polymer suspensions suitable for EPD could be easily obtained by dispersing polymer particles in an aqueous or nonaqueous medium. Nevertheless, this work demonstrated that in order to obtain good quality deposits based on poly(ether ether ketone) (PEEK) and poly(tetrafluoroethylene) (PTFE), some additives have to be used. In the case of PEEK, a dispersant providing citrate anions was successfully used, whereas for PTFE a steric suspension stabilization was reached by adding polyvinylpyrrolidone (PVP). In such a way, codeposition of PEEK and PTFE was achieved. The efficiency of the EPD process was demonstrated by means of differential scanning calorimetry (DSC) measurements. A thermal program consisting of heat/cool/heat cycles at a low rate was used in order to evaluate the crystalline amount of each polymer in the deposits. In order to explain the obtained results, it needed to also consider the dimension and structural characteristic of the polymer particles. PMID- 23039698 TI - Intramuscular injections in newborns: analgesic treatment and sex-linked response. AB - AIM: To compare the analgesic effect of three treatments to relieve the pain produced by intramuscular injections (IMI) in term newborns, and to assess sex linked differences in their response to pain. MATERIAL AND METHODS: We studied 62 babies. Each baby received antibiotic IMIs for clinical aims. During each IMI, one of the following analgesic treatments was utilized: oral 33% glucose (OG), sensorial saturation (SS), or topic anesthetic cream (TAC). SS is a validated analgesic method, based on the combination of three stimulations (tactile, acoustic and gustative). During the IMI, pain level was assessed with the use of the DAN scale, a validated neonatal pain scale. All babies who received three distinct analgesic procedures for three distinct IMIs were enrolled. Mean pain scores of the three analgesic treatment groups were compared. We then compared mean pain scores of females vs males in the whole cohort and within each treatment group. RESULTS: The 95% Confidence Intervals of pain scores were 5.6 6.5 for TAC, 1.4-2.3 for OG and 0.6-1.2 for SS: when treated with TAC, babies' pain scores were significantly higher than with OG or SS (p <0.0001); when treated with OG, babies' pain scores were higher than SS (p = 0.002). Females' mean pain score was significantly higher than males' mean pain score: (95% CI: 2.9-4.1 vs 2.0-3.1; p = 0.01). OG and SS produced significantly higher mean DAN scores in females than in males. Also in the TAC group females' mean DAN scores were higher than males, though this last difference was not statistically significant. CONCLUSION: This is the first study to show the effectiveness of nonpharmacologic analgesia in relieving IMI pain. It is also the first study to clearly show that the sex differences in pain perception are present since birth. PMID- 23039699 TI - Incisional hernia rate may increase after single-port cholecystectomy. AB - BACKGROUND: The major concerns of single-port cholecystectomy are port-site hernia and cost. Essentially, a larger transumbilical incision is more likely to increase the incidence of incisional hernia. The effect of single-port cholecystectomy on hospital cost is controversial. This study evaluated single port cholecystectomy and traditional four-port cholecystectomy with respect to perioperative outcomes, hospital cost, and postoperative complications. PATIENTS AND METHODS: Between January 2010 and March 2011, 52 patients underwent single port cholecystectomy, and 111 patients underwent traditional laparoscopic cholecystectomy. We used equal instruments in patients undergoing operation with the same surgical technique. Demographics, diagnosis, operative data, complications, length of hospital stay, and cost were compared between the two groups. RESULTS: The patients undergoing laparoscopic cholecystectomy were significantly older than patients undergoing single-port cholecystectomy (55.8+/ 13.8 years versus 48.7+/-12.7 years, P=.002). The trocar site hernia rate was 1.8% in laparoscopic cholecystectomy, and the port-site hernia rate was 5.8% in single-port cholecystectomy. This is the highest rate reported in the literature for port-site hernia following single-port cholecystectomy. Surgical techniques were not different in terms of conversion to open surgery, postoperative hospital stay, and operative time. The relative cost of single-port cholecystectomy versus laparoscopic cholecystectomy was 1.54. CONCLUSIONS: Although single-port cholecystectomy seems to be a feasible surgical technique, it is not superior over the traditional laparoscopic cholecystectomy. Single-port cholecystectomy is equal to laparoscopic cholecystectomy with respect to conversion to open surgery, postoperative hospital stay, and operative time, but it is associated with high hospital cost and high port-site hernia rate. PMID- 23039700 TI - Commentary on "Incisional hernia rate may increase after single-port cholecystectomy". PMID- 23039701 TI - Commentary on "Feasibility and safety of functional cholecystectomy by pure NOTES: a pilot animal study". PMID- 23039702 TI - Robotic-assisted neck dissection through a pre- and post-auricular hairline incision: preclinical study. AB - The introduction of robotics in head and neck surgery has facilitated access to the contents of the neck region using less cosmetically obtrusive incisions. Robotic systems offer a three-dimensional viewing, tremor filtration, and articulating distal arms that mimic natural hand and wrist movements. We hypothesized that these characteristics would allow for the performance of a robotic-assisted selective and comprehensive neck dissection via combined pre- and post-auricular incisions. We were able to demonstrate adequate access in a cadaver, using a combination of conventional, endoscopic, and robotic surgical manipulation. Thus preclinical cadaver studies support the ability to perform robotic-assisted neck dissection via combined pre- and post-auricular incisions. PMID- 23039703 TI - Minimally invasive phasic treatment protocol for the treatment of extrahepatic bile duct stones. AB - OBJECTIVES: To identify the optimal treatment for extrahepatic bile duct stones using endoscopy, laparoscopy, and the combination of the two in different conditions and to develop phasic treatment protocols for their minimally invasive treatment. PATIENTS AND METHODS: Of 2718 cases of extrahepatic bile duct stones collected from June 2005 to December 2011, 50 were randomly selected to receive open bile duct exploration and T-tube drainage, serving as the control group. For the rest, a one-scope protocol, two-scope protocol (two-scope protocol A or two scope protocol B), or three-scope protocol was adopted according to the specific conditions of stones and the endoscopic treatment results. The treatment outcomes and postoperative clinical indicators of the minimally invasive treatment protocols were analyzed and compared with those of the control group. RESULTS: Among the 2668 cases of extrahepatic bile duct stones receiving the phasic minimally invasive treatment, the treatment success rate was 97.79%, and there were no severe postoperative complications. Compared with the control group, the minimally invasive treatment protocols had higher success rates, less trauma, and significantly shortened hospital stays. CONCLUSIONS: The protocols were applied step by step based on the different types and levels of extrahepatic bile duct stones, fully embodying the advantages of the combined minimally invasive treatment of endoscopy and laparoscopy, thus expanding the scope of minimally invasive surgical treatment for extrahepatic bile duct stones and improving treatment success rate. PMID- 23039704 TI - The role of endoscopy in bariatrics: past, present, and future. AB - The exponential increase in the rate of obesity and its associated co-morbidities has increased the demand for bariatric surgery. Over the past few decades, surgical weight reduction by gastric restriction, malabsorption, or a combination of both has been the preferred approach to achieve sustained weight loss in the morbidly obese. Although extremely effective, surgical procedures carry significant complications and risk with mortality rates of 1%. Because of the cost, surgical risk, and complications, there is a demand for less invasive procedures. Endoscopic approaches include placement of endoluminal space occupying devices, stapling devices to reduce gastric volume, barrier devices to reduce small bowel absorptive area, and methods to regulate gastric emptying. Current and ongoing studies have delivered promising results across many aspects of endoscopic approaches. However, many technical obstacles still exist that have to be resolved with further research before endoscopic bariatrics can be widely deployed. At present the role of endoscopy is well established in preoperative evaluation as well as in recognition and management of many postoperative complications in bariatrics. In this article, we review the current and future endoscopic methods for weight reduction that are either in practice or in testing. PMID- 23039705 TI - Laparoscopic gastric mobilization in postcricoid cancer surgery. AB - AIM: Postcricoid cancer is an aggressive neoplasm that presents specific therapeutic problems. This study compares laparoscopic stomach mobilization following total pharyngolaryngoesophagectomy (TPLE) with open mobilization following TPLE with respect to postoperative recovery, perioperative morbidity, and mortality. SUBJECTS AND METHODS: This is a retrospective study in a contemporary series of patients with resectable postcricoid cancer from a single institute (Gujarat Cancer & Research Institute, M.P. Shah Cancer Hospital, Ahmedabad, Gujarat, India). Twenty-five consecutive patients who underwent laparoscopic TPLE were compared with 40 patients who underwent open TPLE from January 2006 to December 2010. RESULTS: Laparoscopic and open TPLE procedures were compared with respect to patient demographics, operative information (blood loss, duration), and complications. The mean duration of surgery was 3.5 hours in the laparoscopic group and 5.5 hours in the open group. The respective mean blood loss was 290 mL and 460 mL. The respective mean time to full oral intake was 10 days and 11 days. The respective average duration of hospitalization was 13 days and 17 days. In the laparoscopic group, 3 (12%) and 4 (16%) patients had pneumonic consolidation and wound infection, respectively, compared with 8 (20%) and 8 (20%) patients in the open group. In the laparoscopic group, there were two (8%) perioperative deaths, compared with four (10%) in the open group. CONCLUSIONS: Laparoscopic TPLE is safe with less morbidity and mortality and quicker postoperative recovery compared with open surgery. PMID- 23039706 TI - Thoracoscopic vertebral body stapling for treatment of scoliosis in young children. AB - PURPOSE: The management of juvenile idiopathic scoliosis (JIS) in young children can be challenging. Vertebral body stapling (VBS) is a new alternate to bracing and is intended to reduce or eliminate the need for subsequent spinal fusion. In concept, VBS of the anterior spine inhibits curve progression, thus stabilizing the spine as the child grows. There is a paucity of data in the pediatric population on its effectiveness. Therefore, we reviewed our experience with thoracoscopic VBS in children with juvenile scoliosis. SUBJECTS AND METHODS: After Institutional Review Board approval was obtained, a retrospective study was conducted on all patients who underwent thoracoscopic VBS for scoliosis from January 2007 to December 2010. Only patients with a follow-up of at least 2 years were included in this study group. Data obtained were demographics, indications for VBS, degree of curvature, treatment, complications, and follow-up. Cobb angle was used to measure the initial degree of curvature on a standing posterior anterior spine radiograph. RESULTS: During the study period, 11 patients underwent thoracoscopic VBS for JIS using single lung ventilation in a lateral position. Of those, 7 patients ages 8-11 years (mean, 9 years) with a mean body mass index of 17 kg/m(2) (+/-2.9 kg/m(2)) had at least a 2-year follow-up and make up the study group for this review. Indications for stapling in these 7 patients were progression of scoliosis (n=3), noncompliance with brace (n=3), and double curve with progression (n=1). The mean preoperative Cobb angle was 34.1+/ 5 degrees (range, 25 degrees -41 degrees ), and the mean immediate postoperative Cobb angle was 23+/-5 degrees (range, 16 degrees -30 degrees ). The staples encompassed a mean number of 6.4 vertebral bodies. The mean duration of chest drainage was 2.7 days (range, 2-6 days), and the mean length of hospitalization was 3.9 days (range, 3-7 days). The mean operative time was 156.2+/-39.5 minutes (range, 101-214 minutes). There were no intraoperative complications or mortality. Postoperatively, 1 patient developed a pleural effusion on the contralateral side that required drainage. These 7 patients have been followed up for a mean of 34 months (range, 29-44 months). The mean Cobb angle at last follow up was 24.7 degrees (range, 15-38 degrees ). No patient has required postoperative bracing or spinal fusion. CONCLUSIONS: Thoracoscopic VBS is a safe and effective method of treatment for progressive scoliosis in young children. Pediatric surgeons may be asked to assist their spine surgeons with this new approach to juvenile scoliosis. PMID- 23039707 TI - Open versus laparoscopic appendectomy in the pediatric population: a literature review and analysis of complications. AB - BACKGROUND: This study aims to compare the results of laparoscopic and open appendectomy (LA and OA, respectively) in a pediatric population with particular attention to complications analysis. SUBJECTS AND METHODS: A literature search was performed using Medline, Cochrane, Embase, Sci Search, Lilacs, and PubMed databases on all studies published during the 14-year interval of 1997-2010. Comparative studies of LA versus OA in the pediatric population were included in these studies. Data concerning operative time, length of hospital stay, postoperative complications, postoperative pain, and surgical trauma were recorded. RESULTS: We recorded 52 studies, but 26 of these were excluded from our analysis because they were neither relevant nor related to the adolescent population. The 26 studies analyzed showed a population of 123,628 children and adolescents (ages 0-18 years) who underwent appendectomy by laparoscopic (LA, 42,213 [34.1%]) and open (OA, 81,415 [65.9%]) techniques. Our analysis showed that patients undergoing LA presented a lower incidence of surgical wound infection, lower incidence of postoperative ileus, a lower use of analgesics in the postoperative period, an earlier resumption of normal diet, a shorter hospitalization, and a more rapid recovery to resume normal activities compared with patients undergoing OA. This study, comparing LA versus OA in children, failed to identify any major difference between the two techniques in terms of formation of intra-abdominal abscesses. As for operative time, our analysis showed globally a significant reduced operative time in OA versus LA in complicated appendicitis, but in simple appendicitis the operative time seems to be the same. CONCLUSIONS: Our analysis of the literature showed that the LA technique presents several advantages compared with the OA technique. For this reason, if a child is hospitalized today for appendicitis treatment in a pediatric center where the laparoscopic approach is unavailable, he or she should be placed on antibiotics and transferred to a center that offers the laparoscopic approach. PMID- 23039708 TI - Laparoscopic fundoplication in children with ventriculo-peritoneal shunts. AB - BACKGROUND: Children with ventriculo-peritoneal (V-P) shunts have a significant risk of morbidity and mortality from infections. Many of these patients have other co-morbidities and may require subsequent abdominal surgery, including fundoplication with or without gastrostomy placement. The aim of our study was to assess the outcomes of laparoscopic fundoplication in children with a V-P shunt in situ. SUBJECTS AND METHODS: A retrospective review of a prospectively maintained database on children who underwent laparoscopic fundoplication with a V-P shunt in situ at the time of surgery between July 1998 and March 2011 was conducted. Primary outcomes included intra- and postoperative complications as well as shunt-related problems within a 6-month period after surgery. The subset of children with V-P shunts was compared with those who underwent fundoplication without shunts. Variables were compared using the two-tailed Student's t test, chi-squared test, or Fisher's exact test. Significance was defined as P<=.05. RESULTS: Out of a total of 343 children who underwent fundoplication, 11 (6 girls, 5 boys) had a V-P shunt in situ at the time of surgery (3.2%). The median age at laparoscopy was 2.2 years (range, 0.7-13.8 years). Weight at surgery ranged from 5.8 to 39.0 kg (median, 12.0 kg). The operating time (without gastrostomy placement) was 105 minutes (range, 80-140 minutes). In 6 patients (55%) moderate to severe adhesions were documented, but only 1 child required conversion to open surgery because of bleeding from the omentum. In a second patient the colon was perforated during insertion of the percutaneous endoscopic gastrostomy (PEG) and repaired laparoscopically. There was no postoperative shunt dysfunction or infection related to the laparoscopic procedure. There was no significant difference between V-P shunt patients and the main cohort regarding operating time, conversion to open surgery, need for admission to a high-care unit, opiate requirements, time to full feeds, and length of hospital stay. CONCLUSIONS: These data suggest that laparoscopic fundoplication is feasible in children with previous V-P shunt placement. Although there were considerable adhesions in approximately half of these patients, the rate for conversion to open surgery was low. Complications associated with simultaneous PEG insertion occur and should be anticipated by placing the gastrostomy under laparoscopic guidance. PMID- 23039709 TI - Implementing a simplified neonatal resuscitation protocol-helping babies breathe at birth (HBB) - at a tertiary level hospital in Nepal for an increased perinatal survival. AB - BACKGROUND: Reducing neonatal death has been an emerging challenge in low and middle income countries in the past decade. The development of the low cost interventions and their effective delivery are needed to reduce deaths from birth asphyxia. This study will assess the impact of a simplified neonatal resuscitation protocol provided by Helping Babies Breathe (HBB) at a tertiary hospital in Nepal. Perinatal outcomes and performance of skilled birth attendants on management of intrapartum-related neonatal hypoxia will be the main measurements. METHODS/DESIGN: The study will be carried out at a tertiary level maternity hospital in Nepal. A prospective cohort-study will include a six-month baseline a six month intervention period and a three-month post intervention period. A quality improvement process cycle will introduce the neonatal resuscitation protocol. A surveillance system, including CCD cameras and pulse oximeters, will be set up to evaluate the intervention. DISCUSSION: Along with a technique to improve health workers performance on the protocol, the study will generate evidence on the research gap on the effectiveness of the simplified neonatal resuscitation protocol on intrapartum outcome and early neonatal survival. This will generate a global interest and inform policymaking in relation to delivery care in all income settings. TRIAL REGISTRATION: ISRCTN97846009. PMID- 23039710 TI - Age-related changes in ocular vestibular-evoked myogenic potentials via galvanic vestibular stimulation and bone-conducted vibration modes. AB - CONCLUSION: The age-related changes in ocular vestibular-evoked myogenic potentials (oVEMPs) elicited by galvanic vestibular stimulation (GVS) and bone conducted vibration (BCV) might be attributed to the morphological degeneration of the vestibular system. OBJECTIVE: This study employed GVS and BCV modes for eliciting oVEMPs in healthy subjects to explore the effect of aging on the vestibulo-ocular reflex (VOR) pathway. METHODS: Sixty-nine healthy subjects (aged 22-69 years) were divided into 5 groups of 12-19 subjects by decades of age. All subjects underwent oVEMPs using GVS and BCV modes. The prevalence and parameters of oVEMPs, including nI latency, pI latency, nI-pI interval, and nI-pI amplitude were measured and compared. RESULTS: The prevalences of GVS-oVEMPs had nonsignificant differences among all age groups, whereas that of BCV-oVEMPs in the over-60 group was significantly lower than those in the under-60 groups. In GVS-oVEMPs, the group over 60 years had significantly longer nI, pI latencies, and smaller amplitudes when compared with those under 60 years. In BCV-oVEMPs, the nI and pI latencies in the over-60 group were significantly longer than those of the under-60 groups, while the nI-pI amplitudes of groups over 50 years were significantly smaller than those of groups under 50 years. All oVEMP parameters exhibited significant differences between GVS- and BCV-oVEMPs in each age group. PMID- 23039712 TI - Gingival crevicular fluid adrenomedullin level in individuals with and without diabetes mellitus type 2. AB - BACKGROUND AND OBJECTIVE: Adrenomedullin, an antimicrobial peptide, has biological applications in many tissues, but its main attribute is its ability to lower arterial pressure. The plasma adrenomedullin level is elevated in pathophysiological conditions such as arterial hypertension, acute coronary syndrome, renal diseases, diabetes mellitus and periodontal diseases. The aim of this study was to compare the amounts of adrenomedullin in the gingival crevicular fluid of periodontally healthy individuals, individuals with chronic periodontitis, periodontally healthy individuals with diabetes mellitus type 2 and individuals with chronic periodontitis and diabetes mellitus type 2. MATERIAL AND METHODS: Eighty-four individuals were included in this study: 21 periodontally healthy individuals; 21 individuals with chronic periodontitis; 21 periodontally healthy individuals with diabetes mellitus type 2; and 21 individuals with chronic periodontitis and diabetes mellitus type 2. An ELISA was performed to measure the adrenomedullin levels in gingival crevicular fluid. RESULTS: Groups with diabetes mellitus type 2 (periodontally healthy individuals and individuals with chronic periodontitis) had significantly higher periodontal clinical indices than did nondiabetes mellitus groups (periodontally healthy individuals and individuals with chronic periodontitis). The group of individuals with chronic periodontitis and diabetes mellitus type 2 had a significantly higher total adrenomedullin level compared with the other groups. Also, a significantly higher total adrenomedullin level was found in diabetes mellitus type 2 groups (periodontally healthy individuals and individuals with chronic periodontitis) compared with nondiabetes mellitus groups (periodontally healthy individuals and individuals with chronic periodontitis). CONCLUSIONS: An increased adrenomedullin level was found in individuals with chronic periodontitis and also in individuals with diabetes mellitus. It is thought that the effect of diabetes mellitus on the pathogenesis of chronic periodontitis could have been achieved through antimicrobial peptides such as adrenomedullin, or that increased adrenomedullin was released in individuals with diabetes mellitus in order to ensure no further periodontal tissue loss. PMID- 23039711 TI - The alcohol use disorders identification test (AUDIT): validation of a Nepali version for the detection of alcohol use disorders and hazardous drinking in medical settings. AB - BACKGROUND: Alcohol problems are a major health issue in Nepal and remain under diagnosed. Increase in consumption are due to many factors, including advertising, pricing and availability, but accurate information is lacking on the prevalence of current alcohol use disorders. The AUDIT (Alcohol Use Disorder Identification Test) questionnaire developed by WHO identifies individuals along the full spectrum of alcohol misuse and hence provides an opportunity for early intervention in non-specialty settings. This study aims to validate a Nepali version of AUDIT among patients attending a university hospital and assess the prevalence of alcohol use disorders along the full spectrum of alcohol misuse. METHODS: This cross-sectional study was conducted in patients attending the medicine out-patient department of a university hospital. DSM-IV diagnostic categories (alcohol abuse and alcohol dependence) were used as the gold standard to calculate the diagnostic parameters of the AUDIT. Hazardous drinking was defined as self reported consumption of >=21 standard drink units per week for males and >=14 standard drink units per week for females. RESULTS: A total of 1068 individuals successfully completed the study. According to DSM-IV, drinkers were classified as follows: No alcohol problem (n=562; 59.5%), alcohol abusers (n= 78; 8.3%) and alcohol dependent (n=304; 32.2%). The prevalence of hazardous drinker was 67.1%. The Nepali version of AUDIT is a reliable and valid screening tool to identify individuals with alcohol use disorders in the Nepalese population. AUDIT showed a good capacity to discriminate dependent patients (with AUDIT >=11 for both the gender) and hazardous drinkers (with AUDIT >=5 for males and >=4 for females). For alcohol dependence/abuse the cut off values was >=9 for both males and females. CONCLUSION: The AUDIT questionnaire is a good screening instrument for detecting alcohol use disorders in patients attending a university hospital. This study also reveals a very high prevalence of alcohol use disorders in Nepal. PMID- 23039713 TI - Strong and dynamic CO2 sorption in a flexible porous framework possessing guest chelating claws. AB - Using a bis-triazolate ligand and tetrahedral Zn(II) ion, we synthesized a flexible porous coordination polymer functionalized with pairs of uncoordinated triazolate N-donors that can be used as guest chelating sites to give very high CO(2) adsorption enthalpy and CO(2)/N(2) selectivity. The dynamic CO(2) sorption behavior could be monitored well by single-crystal X-ray diffraction. PMID- 23039714 TI - MolFind: a software package enabling HPLC/MS-based identification of unknown chemical structures. AB - In this paper, we present MolFind, a highly multithreaded pipeline type software package for use as an aid in identifying chemical structures in complex biofluids and mixtures. MolFind is specifically designed for high-performance liquid chromatography/mass spectrometry (HPLC/MS) data inputs typical of metabolomics studies where structure identification is the ultimate goal. MolFind enables compound identification by matching HPLC/MS-based experimental data obtained for an unknown compound with computationally derived HPLC/MS values for candidate compounds downloaded from chemical databases such as PubChem. The downloaded "bins" consist of all compounds matching the monoisotopic molecular weight of the unknown. The computational HPLC/MS values predicted include retention index (RI), ECOM(50) (energy required to fragment 50% of a selected precursor ion), drift time, and collision induced dissociation (CID) spectrum. RI, ECOM(50), and drift time models are used for filtering compounds downloaded from PubChem. The remaining candidates are then ranked based on CID spectra matching. Current RI and ECOM(50) models allow for the removal of about 28% of compounds from PubChem bins. Our estimates suggest that this could be improved to as much as 87% with additional chemical structures included in the computational models. Quantitative structure property relationship-based modeling of drift times showed a better correlation with experimentally determined drift times than did Mobcal cross sectional areas. In 23 of 35 example cases, filtering PubChem bins with RI and ECOM(50) predictive models resulted in improved ranking of the unknown compounds compared to previous studies using CID spectra matching alone. In 19 of 35 examples, the correct candidate was ranked within the top 20 compounds in bins containing an average of 1635 compounds. PMID- 23039715 TI - Effects of rotation amplitude on arm movement when rotating a spherical object. AB - Arm movements when rotating a spherical object were experimentally investigated. Twelve volunteers participated in the experiment and were asked to rotate a sphere for a large range of amplitude. Results showed that subjects anticipated their posture at the beginning of object manipulation even for low rotation amplitudes. The way of anticipation strongly depended on rotation direction. The end-state comfort hypothesis, effects of joint limits and principle of minimum work were examined for explaining motion control. The anticipation would ensure a better end-state comfort while avoiding joint limits in case of higher amplitude of object rotation. Meanwhile, it should not deteriorate the comfort at the beginning of manipulation too much. High postural variability for low rotation amplitude tasks suggested that there might exist a range of postures of similar level of comfort. These findings will be useful in developing human behaviour based motion simulations for digital human. PRACTITIONER SUMMARY: Arm movement was investigated when rotating a spherical object with a large range of amplitude. The end-state comfort hypothesis, effects of joint limits and principle of minimum work were examined for explaining motion control. Results will be helpful for a better design of rotary controls and for developing motion simulation algorithms. PMID- 23039716 TI - The start of something. PMID- 23039717 TI - Reimbursement agreements. PMID- 23039720 TI - Ten questions with ....Tim Reeves. PMID- 23039723 TI - What's the Prognosis? Making infusion systems safer. PMID- 23039727 TI - What you can do now interim: technology applications to help achieve IV-IT interoperability. PMID- 23039728 TI - Creating a culture of safety: reducing hospital noise. PMID- 23039729 TI - The IT practitioner and his patients. PMID- 23039730 TI - How to make the most of e-mails. PMID- 23039731 TI - Find a work/life balance with your management strategy. PMID- 23039732 TI - Imaging executive plans to 'stay ahead of the game'. PMID- 23039733 TI - A standardized approach to clinical engineering. PMID- 23039734 TI - Modification and customization of medical equipment. PMID- 23039735 TI - Gas chromatography systems. PMID- 23039736 TI - A tool you can use. PMID- 23039739 TI - The maintenance of gas modules. PMID- 23039740 TI - When is a biomed shop ready for a working supervisor? PMID- 23039741 TI - Comparison of test methods to screen for residual chemical contamination on medical device surfaces. AB - Reprocessing medical devices involves several steps including cleaning and disinfection or sterilization. Chemical residuals can occur at various stages of reprocessing. These residues could interfere with device function and potentially harm patients. These solutions are composed of a combination of various chemicals and their residues are highly diluted post rinsing, therefore, it is difficult to find a sensitive and rapid method to detect toxicity due to chemical residues. This study focused on (1) finding the levels of residues that are cytotoxic using two mammalian cell lines and Daphnia magna, and (2) evaluating two test methods, Total Organic Carbon (TOC) and the Luminescent Bacteria Test (LBT), to measure residual chemicals levels. The two mammalian cell lines were equal in their cytotoxicity responses. However, Daphnia were more sensitive to some chemical residue than the two mammalian cell lines. TOC and LBT were able to detect the presence of residue well below the levels that were determined to cause mammalian cytotoxicity. LBT was more sensitive for some chemicals and TOC for others, both in solution and in simulated cleaning and rinsing for the limited number of solutions tested in this study. PMID- 23039742 TI - The study and design of a wireless ECG monitoring system. AB - This paper describes a research project on wireless electrocardiogram (ECG) monitoring systems. A detection and measurement processor designed by a MSP430 microcontroller accomplishes the analog-to-digital conversion, digital filtering, QRS wave detection, and heart rate calculation. The data of detection can be sent to the central controller and personal computer (PC) by wireless on-chip MG2455 through a ZigBee network. This design can be used widely in home healthcare, community healthcare, and sports training, as well as in healthcare facilities, due to its characteristics of low power consumption, small size, and reliability. PMID- 23039743 TI - Making the case for consistent alarm labeling. PMID- 23039744 TI - Impact of obstetrical brachial plexus injury on parents. AB - BACKGROUND: The aim of this study was to describe the impact of obstetrical brachial plexus palsy (OBPP) on parents and to investigate the effect of the severity of OBPP and the age of the children on parents. METHODS: A total of 106 parents (with a mean age of 30.14 +/- 5.01 years) of children with OBPP were included in the study. The functional level of the children was assessed by the Active Movement Scale, whereas the impact of OBPP on the parents was assessed by the Turkish version of the Impact on Family Scale. RESULTS: The parents appeared to be moderately affected by their child's disorder. Financial, social, personal, mastery parameters and total impact values were 52% (27-77%), 65% (46-114%), 49% (31-67%), 51% (28-74%) and 56% (40-72%), respectively. Root involvement and the age of the children did not make a statistically significant difference in the level of impact. CONCLUSIONS: Detailed knowledge of the impact of OBPP on families might provide a chance to support affected families in coping with the situation and decrease their burden in providing care for the children. It is crucial to evaluate and provide social support to parents of children with OBPP. PMID- 23039745 TI - Fragment molecular orbital study on electron tunneling mechanisms in bacterial photosynthetic reaction center. AB - The tunneling mechanisms of electron transfers (ETs) in photosynthetic reaction center of Blastochloris viridis are studied by the ab initio fragment molecular orbital (FMO) method combined with the generalized Mulliken-Hush (GMH) and the bridge Green function (GF) calculations of the electronic coupling T(DA) and the tunneling current method for the ET pathway analysis at the fragment-based resolution. For the ET from batctriopheophytin (H(L)) to menaquinone (MQ), a major tunneling current through Trp M250 and a minor back flow via Ala M215, Ala M216, and His M217 are quantified. For the ET from MQ to ubiquinone, the major tunneling pathway via the nonheme Fe(2+) and His L190 is identified as well as minor pathway via His M217 and small back flows involving His L230, Glu M232, and His M264. At the given molecular structure from X-ray experiment, the spin state of the Fe(2+) ion, its replacement by Zn(2+), or its removal are found to affect the T(DA) value by factors within 2.2. The calculated T(DA) values, together with experimentally estimated values of the driving force and the reorganization energy, give the ET rates in reasonable agreement with experiments. PMID- 23039746 TI - Patented TGR5 modulators: a review (2006 - present). AB - INTRODUCTION: The G protein-coupled receptor TGR5 is a key player of the bile acid signaling network, and its activation has been proved to increase the glycemic control, to enhance energy expenditure and to exert anti-inflammatory actions. Accordingly, TGR5 ligands have emerged in drug discovery and preclinical appraisals as promising agents for the treatment of liver diseases, metabolic syndrome and related disorders. AREAS COVERED: Recent advances in the field of TGR5 modulators are reviewed, with a particular attention on patent applications and peer-reviewed publications in the past 6 years. EXPERT OPINION: Activation of TGR5 showed to protect mice from diabesity and insulin resistance, to improve liver functions, as well as to attenuate the development of atherosclerosis. However, although the efficacy of TGR5 agonists in mice is encouraging, further studies are needed to determine their potential in humans and to evaluate carefully the balance between the therapeutic benefits and adverse effects associated with the target. The development of new TGR5 selective ligands to support studies in animal models will surely facilitate the understanding of the complexity of TGR5 signaling network. PMID- 23039747 TI - Against excess. PMID- 23039748 TI - New Zealand to establish fit for purpose regulation for new psychoactive substances. PMID- 23039749 TI - The dangerous charms of the unknown. PMID- 23039750 TI - Supply always comes on the heels of demand: what effects do control strategies have on drug users themselves? PMID- 23039751 TI - Commentary on Steingrimsson et al. (2012): an equal right to addiction. PMID- 23039752 TI - Commentary on Vickerman et al. (2012): Reducing hepatitis C virus among injection drug users through harm reduction programs. PMID- 23039753 TI - Commentary on Sims et al. (2012): A timely response to the impact of smoke-free public places on the most exposed children. PMID- 23039754 TI - Methadone treatment centers and crime: the journal publishes both invited and unsolicited letters. PMID- 23039756 TI - No quick fix for legal highs. PMID- 23039758 TI - Formatt: Correcting protein multiple structural alignments by incorporating sequence alignment. AB - BACKGROUND: The quality of multiple protein structure alignments are usually computed and assessed based on geometric functions of the coordinates of the backbone atoms from the protein chains. These purely geometric methods do not utilize directly protein sequence similarity, and in fact, determining the proper way to incorporate sequence similarity measures into the construction and assessment of protein multiple structure alignments has proved surprisingly difficult. RESULTS: We present Formatt, a multiple structure alignment based on the Matt purely geometric multiple structure alignment program, that also takes into account sequence similarity when constructing alignments. We show that Formatt outperforms Matt and other popular structure alignment programs on the popular HOMSTRAD benchmark. For the SABMark twilight zone benchmark set that captures more remote homology, Formatt and Matt outperform other programs; depending on choice of embedded sequence aligner, Formatt produces either better sequence and structural alignments with a smaller core size than Matt, or similarly sized alignments with better sequence similarity, for a small cost in average RMSD. CONCLUSIONS: Considering sequence information as well as purely geometric information seems to improve quality of multiple structure alignments, though defining what constitutes the best alignment when sequence and structural measures would suggest different alignments remains a difficult open question. PMID- 23039760 TI - Population and age-group trends in weekend sun protection and sunburn over two decades of the SunSmart programme in Melbourne, Australia. AB - BACKGROUND: In response to the high skin cancer burden in Australia, the multicomponent, community-wide SunSmart programme has worked since 1988 to reduce excessive sun exposure. OBJECTIVE: To examine trends in key sun-protection behaviours and sunburn for the Melbourne population from 1987 to 2007, and examine for the first time patterns of change among age groups. METHODS: Representative cross-sectional weekly telephone surveys of weekend sun protection and sunburn were conducted over 11 of the summers in the period 1987-88 to 2006 07. Trends were analysed for the population and for age groups, adjusting for ambient temperature and ultraviolet radiation, which are environmental determinants of sun-related behaviour and sunburn. RESULTS: The general pattern of trends suggests two distinct periods, one with rapid improvement in behaviours (more sunscreen use, less unprotected body exposure and less sunburn) from 1987 88 to 1994-95, and the second from 1997-98 to 2006-07 with fewer changes in behaviours noted. The age-group analyses showed a similar pattern of change over time across groups, with a few notable exceptions. CONCLUSIONS: The similarity of the pattern of trends among age groups suggests that external influences including the SunSmart programme's activity had a relatively similar impact across the population. Sun-related behaviours continue to be amenable to change. More recent relative stability with some declines in sun protection suggests further intensive campaigns and other strategies may be needed to maintain previous successes and to achieve more universal use of sun protection. PMID- 23039759 TI - Regulation of adipocyte autophagy--the potential anti-obesity mechanism of high density lipoprotein and ApolipoproteinA-I. AB - Obesity is reaching epidemic worldwide and is risk factor for cardiovascular disease and type 2 diabetes. Although plasma high density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) are inversely correlated to obesity, whether HDLs have anti-obesity effect remains unclear until a recent study reporting the direct anti-obesity effect of apoA-I and its mimetic peptide. However, the mechanism is not fully understood. Increasing adipose energy expenditure through attainment of brown adipocyte phenotype in white adipose tissue is considered a potential strategy to combat obesity. Specific inhibition of autophagy in adipose tissue is associated with reduced adiposity which is attributed to the attainment of brown adipocyte phenotype in white adipose tissue and the increased energy expenditure. HDL and apoA-I could activate PI3K-Akt-mTORC1 signaling which negatively regulates autophagy. The links between HDL/apoA-I and autophagy brings a new understanding on the anti-obesity effect of HDL and apoA-I. PMID- 23039761 TI - Lack of association between maternal periodontal status and adverse pregnancy outcomes: a multicentric epidemiologic study. AB - OBJECTIVE(S): The aim of this study was to explore the relationship between periodontal health and pregnancy outcomes in a large cohort of Italian postpartum women. METHODS: 750 postpartum women were enrolled in a case-control study within 5 days from delivery at three Italian obstetric clinics. Cases were defined as those mothers who delivered an infant weighing under 2500 g (LBW) and/or had premature delivery and/or delivered small for gestational age newborns (SGA) and/or experienced preeclampsia/pregnancy induced hypertension (PE/PIH) or preterm premature rupture of membranes (pPROM) during pregnancy. All women received comprehensive oral and dental examination. Associations between adverse pregnancy outcome and exposures of interest were evaluated by the use of multivariate logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There was no significant difference between cases and controls with respect to country of birth, age, place of residence, educational achievement, smoking, and periodontal status. By definition, infant birth weight [2,750 g (IQR = 2,300-3,200 g) and 3,275, (IQR = 3,010-3,538 g) p < 0.001, respectively] and gestational age at delivery [259 days (IQR = 245-273) and 273 days (IQR = 266-280), p < 0.01, respectively] were significantly lower in cases than in controls. In multivariate analyses, a borderline association was found between poor obstetric outcomes and current smokers (OR: 1.5; 95% CI: 0.1 2.5). Finally, after adjusting for smoking status neither country of birth, nor age or place of residence or education or periodontitis were associated with a significantly increased risk of adverse pregnancy outcome. CONCLUSION(S): Our data failed to demonstrate the association between periodontitis and an adverse pregnancy outcome such as preterm birth, low birth weight, preeclampsia, intrauterine growth restriction, and premature rupture of membranes. PMID- 23039762 TI - Prevalence of hepatopathy in type 1 diabetic children. AB - BACKGROUND: The Prevalence of liver disease among diabetics has been estimated to be between 17% and 100%. Most of these data were obtained from adult studies. The aim of our study was to screen for liver disease among type 1 diabetic children. METHODS: Children with type 1 diabetes following in clinic have been examined for existence of liver disease, from November 2008 to November 2009. All were subjected to the following: History, physical examination, liver function tests, fasting lipid profile, HbA1C, and ultrasound of the liver. A hyperechogenic liver and/or hepatomegaly on ultrasound were attributed most likely to excess glycogen or fat in the liver, after negative extensive work-up to rule out other underlying liver disease. RESULTS: 106 children with type 1 diabetes were studied: age ranged between 8 months to 15.5 years, sixty two patients were females. Twenty two patients (21%) were identified to have abnormal findings on ultrasound of the liver: 10 patients had hepatomegaly and 12 had hyperechogenic liver. The group with hyperechogenic liver had poorer glycemic control than patients with normal liver (Mean HbA1c 12.14% Vs 10.7%; P value = 0.09). Hyperechogenic liver resolved in 60% at 6 months follow-up upon achieving better glycemic control. CONCLUSIONS: Hyperechogenic liver and/or hepatomegaly are not uncommon in children with type 1 diabetes and tend to be more prevalent among children with poor glycemic control. Type 1 diabetes related hepatopathy is reversible by optimizing glycemic control. Because of its safety, and reliability, ultrasound can be used to screen for hepatopathy in type 1 diabetic child. PMID- 23039763 TI - Noncatalytic hydrothermal elimination of the terminal D-glucose unit from malto- and cello-oligosaccharides through transformation to D-fructose. AB - Noncatalytic hydrothermolyses of malto- and cello-oligosaccharides (di-, tri-, tetraose), linked by alpha- and beta-1,4-glycosidic bonds, respectively, were investigated at 100-140 degrees C. In situ (13)C NMR spectroscopy was applied to elucidate the position and pathways of the glycosidic bond breakage and the dependence of the hydrolysis rate on the bond type. Spectral analysis was carried out quantitatively as a function of time with the mass balance confirmed, and it was shown for both the malto- and the cello-oligosaccharides that the terminal D glucose unit with a free anomeric carbon is selectively eliminated after transformation to D-fructose. Site-selective breakage of the glycosidic bonds proceeded on the order of hours. The initial apparent rates for terminal hydrolysis were found to be independent of the degree of oligomerization but dependent on the type of glycosidic bond. Rate constants were larger for the alpha-1,4-linked malto-oligosaccharides by a factor of 3-4 than for the beta-1,4 linked cello-oligosaccharides. The pathways and mechanisms for the malto- and cello-oligosaccharide hydrothermolyses are common and can be understood in terms of the elementary reactions of the di- and monosaccharides. PMID- 23039764 TI - Reducing musculoskeletal disorders among computer operators: comparison between ergonomics interventions at the workplace. AB - Typing is associated with musculoskeletal disorders (MSDs) caused by multiple risk factors. This control study aimed to evaluate the efficacy of a workplace intervention for reducing MSDs among computer workers. Sixty-six subjects with and without MSD were assigned consecutively to one of three groups: ergonomics intervention (work site and body posture adjustments, muscle activity training and exercises) accompanied with biofeedback training, the same ergonomics intervention without biofeedback and a control group. Evaluation of MSDs, body posture, psychosocial status, upper extremity (UE) kinematics and muscle surface electromyography were carried out before and after the intervention in the workplace and the motion lab. Our main hypothesis that significant differences in the reduction of MSDs will exist between subjects in the study groups and controls was confirmed (chi(2) = 13.3; p = 0.001). Significant changes were found in UE kinematics and posture as well. Both ergonomics interventions effectively reduced MSD and improved body posture. PRACTITIONER SUMMARY: This study aimed to test the efficacy of an individual workplace intervention programme among computer workers by evaluating musculoskeletal disorders (MSDs), body posture, upper extremity kinematics, muscle activity and psychosocial factors were tested. The proposed ergonomics interventions effectively reduced MSDs and improved body posture. PMID- 23039765 TI - Post-glucose load changes of plasma key metabolite and insulin concentrations during pregnancy and lactation in ewes with different susceptibility to pregnancy toxaemia. AB - Insulin resistance during late gestation may act as a predisposing factor of ovine pregnancy toxaemia (OPT). To evaluate the insulin action on energy metabolism in ewes with different susceptibilities to OPT, intravenous glucose tolerance tests (1 mmol glucose/kg body weight) were performed in 5.6 +/- 0.7 year old, slightly underfed German Blackheaded Mutton ewes [high-risk (HR) ewes] and 2.5 year old, overnourished Finnish Landrace ewes [low-risk (LR) ewes] during mid and late pregnancy, during early lactation and during the dry period. Plasma samples were analysed for glucose, insulin, non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (beta-HB). The glucose elimination rate and the glucose stimulated first-phase insulin secretion were significantly (p < 0.05) lower in the HR, in relation to the LR group combining the data of all gestational stages. The basal rate of lipolysis was significantly increased in the HR ewes during late pregnancy, but the NEFA clearance after the glucose load was similar in both groups during all reproductive stages. Plasma beta-HB concentrations decreased only in the LR ewes after the glucose load during late pregnancy. Results indicate an insulin resistance in the HR ewes regarding the glucose utilization and the ketone body formation during late pregnancy. The insulin resistance in the HR ewes may represent one predisposing factor responsible for the susceptibility to OPT. Further scientific work is necessary to elucidate whether this insulin resistance was due to breed, age or nutritional state. PMID- 23039768 TI - Mobility or lack thereof. PMID- 23039767 TI - Structure-based design and synthesis of benzothiazole phosphonate analogues with inhibitors of human ABAD-Abeta for treatment of Alzheimer's disease. AB - Amyloid binding alcohol dehydrogenase, a mitochondrial protein, is a cofactor facilitating amyloid-beta peptide (Abeta) induced cell stress. Antagonizing Abeta ABAD interaction protects against aberrant mitochondrial and neuronal function and improves learning memory in the Alzheimer's disease mouse model. Therefore, it offers a potential target for Alzheimer's drug design, by identifying potential inhibitors of Abeta-ABAD interaction. 2D QSAR methods were applied to novel compounds with known IC(50) values, which formed a training set. A correlation analysis was carried out comparing the statistics of the measured IC(50) with predicted values. These selectivity-determining descriptors were interpreted graphically in terms of principle component analyses, which are highly informative for the lead optimization process with respect to activity enhancement. A 3D pharmacophore model also was created. The 2D QSAR and 3D pharmacophore models will assist in high-throughput screening. In addition, ADME descriptors were also determined to study their pharmacokinetic properties. Finally, amyloid binding alcohol dehydrogenase molecular docking study of these novel molecules was undertaken to determine whether these compounds exhibit significant binding affinity with the binding site. We have synthesized only the compounds that have shown the best drug-like properties as candidates for further studies. PMID- 23039771 TI - A roundtable discussion: embracing the mobile revolution. PMID- 23039766 TI - Dysphagia as a risk factor for mortality in Niemann-Pick disease type C: systematic literature review and evidence from studies with miglustat. AB - Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological deterioration and premature death, and has an estimated birth incidence of 1:120,000. Mutations in the NPC1 gene (in 95% of cases) and the NPC2 gene (in approximately 4% of cases) give rise to impaired intracellular lipid metabolism in a number of tissues, including the brain. Typical neurological manifestations include vertical supranuclear gaze palsy, saccadic eye movement abnormalities, cerebellar ataxia, dystonia, dysmetria, dysphagia and dysarthria. Oropharyngeal dysphagia can be particularly problematic as it can often lead to food or fluid aspiration and subsequent pneumonia. Epidemiological data suggest that bronchopneumonia subsequent to food or fluid aspiration is a major cause of mortality in NP-C and other neurodegenerative disorders. These findings indicate that a therapy capable of improving or stabilising swallowing function might reduce the risk of aspiration pneumonia, and could have a positive impact on patient survival. Miglustat, currently the only approved disease-specific therapy for NP-C in children and adults, has been shown to stabilise key neurological manifestations in NP-C, including dysphagia. In this article we present findings from a systematic literature review of published data on bronchopneumonia/aspiration pneumonia as a cause of death, and on the occurrence of dysphagia in NP-C and other neurodegenerative diseases. We then examine the potential links between dysphagia, aspiration, pneumonia and mortality with a view to assessing the possible effect of miglustat on patient lifespan. PMID- 23039772 TI - 'This process is just beginning': connecting mobile medical devices. PMID- 23039773 TI - The promise of wireless: an overview of a device-to-cloud mHealth solution. PMID- 23039774 TI - 'The future of medicine': the emergency room and mobile health. PMID- 23039775 TI - mHealth and developing countries: a successful obstetric care model in Uganda. PMID- 23039776 TI - Electronic medical records and mHealth anytime, anywhere. PMID- 23039777 TI - mHealth consumer apps: the case for user-centered design. PMID- 23039778 TI - Early detection of the deteriorating patient: the case for a multi-parameter patient-worn monitor. PMID- 23039779 TI - Medical device interoperability and data integration to clinical information systems: medical device data alignment. PMID- 23039780 TI - Interoperability for device manufacturers: building a personal, connected health ecosystem. PMID- 23039781 TI - Validation and verification of WLAN medical devices. PMID- 23039782 TI - The regulatory perspective: Q&A with FDA's Bakul Patel. PMID- 23039783 TI - One company's experience: blazing the trail with the first FDA-approved medical imaging app. PMID- 23039784 TI - Enabling mHealth while assuring compliance: reliable and secure information access in a mobile world. AB - An increasingly mobile clinical workforce rapidly adopting consumer devices to access mobile, cloud-based applications, complemented by the wide range of mobile storage devices and other portable electronics, such as digital cameras, MP3 players, can make it difficult to efficiently assure compliance without impacting user productivity. This article reviewed a number of healthcare use cases and introduced comprehensive concepts and possible automated solutions to meet the requirements of a highly complex infrastructure of devices accessing confidential information. PMID- 23039785 TI - Ferroelectric tunnel memristor. AB - Strong interest in resistive switching phenomena is driven by a possibility to develop electronic devices with novel functional properties not available in conventional systems. Bistable resistive devices are characterized by two resistance states that can be switched by an external voltage. Recently, memristors-electric circuit elements with continuously tunable resistive behavior have emerged as a new paradigm for nonvolatile memories and adaptive electronic circuit elements. Employment of memristors can radically enhance the computational power and energy efficiency of electronic systems. Most of the existing memristor prototypes involve transition metal oxide resistive layers where conductive filaments formation and/or the interface contact resistance control the memristive behavior. In this paper, we demonstrate a new type of memristor that is based on a ferroelectric tunnel junction, where the tunneling conductance can be tuned in an analogous manner by several orders of magnitude by both the amplitude and the duration of the applied voltage. The ferroelectric tunnel memristors exhibit a reversible hysteretic nonvolatile resistive switching with a resistance ratio of up to 10(5) % at room temperature. The observed memristive behavior is attributed to the field-induced charge redistribution at the ferroelectric/electrode interface, resulting in the modulation of the interface barrier height. PMID- 23039786 TI - Successful management of an arytenoid chondrosarcoma in a dog. AB - An eight-year-old Doberman pinscher was presented with a four-week history of inspiratory stridor, dysphonia, inappetence and weight loss. Inspiratory stridor was apparent and became more pronounced during gentle compression of the larynx. Previous investigations, including laryngoscopy, had revealed the presence of a left-sided arytenoid mass. Histological examination of pinch biopsies was not diagnostic. The mass was removed by resection of the arytenoid cartilage through a ventral laryngotomy allowing salvage of the cuneiform process. Histological examination of the laryngeal mass was consistent with a chondrosarcoma, grade I, infiltrating the arytenoid cartilage. Re-examination at 12 months showed complete resolution of the clinical signs and no signs of metastatic disease. To the authors' knowledge this is the first report of successful surgical intervention for laryngeal chondrosarcoma. This case demonstrates that resection via a ventral laryngotomy may be a viable and curative therapeutic option for some sarcomas of the larynx. PMID- 23039787 TI - Enhanced H2 uptake in solvents confined in mesoporous metal-organic framework. AB - Hydrogen uptake at 298 K and 30 bar in hybrid sorbents consisting of n-hexane confined in MIL-101 is found to be 22 times larger than in sole n-hexane. The enhanced solubility in MIL-101, found to be 3 times larger than in mesoporous silica of similar pore size, highlights the key roles played by surface chemistry and accessible surface area. PMID- 23039788 TI - Assessing the health benefits of advice services: using research evidence and logic model methods to explore complex pathways. AB - Poverty is positively associated with poor health; thus, some healthcare commissioners in the UK have pioneered the introduction of advice services in health service locations. Previous systematic reviews have found little direct evidence for a causal relationship between the provision of advice and physical health and limited evidence for mental health improvement. This paper reports a study using a broader range of types of research evidence to construct a conceptual (logic) model of the wider evidence underpinning potential (rather than only proven) causal pathways between the provision of advice services and improvements in health. Data and discussion from 87 documents were used to construct a model describing interventions, primary outcomes, secondary and tertiary outcomes following advice interventions. The model portrays complex causal pathways between the intervention and various health outcomes; it also indicates the level of evidence for each pathway. It can be used to inform the development of research designed to evaluate the pathways between interventions and health outcomes, which will determine the impact on health outcomes and may explain inconsistencies in previous research findings. It may also be useful to commissioners and practitioners in making decisions regarding development and commissioning of advice services. PMID- 23039789 TI - Short-term exercise worsens cardiac oxidative stress and fibrosis in 8-month-old db/db mice by depleting cardiac glutathione. AB - Moderate exercise improves cardiac antioxidant status in young humans and animals with Type-2 diabetes (T2D). Given that both diabetes and advancing age synergistically decrease antioxidant expression in most tissues, it is unclear whether exercise can upregulate cardiac antioxidants in chronic animal models of T2D. To this end, 8-month-old T2D and normoglycemic mice were exercised for 3 weeks, and cardiac redox status was evaluated. As expected, moderate exercise increased cardiac antioxidants and attenuated oxidative damage in normoglycemic mice. In contrast, similar exercise protocol in 8-month-old db/db mice worsened cardiac oxidative damage, which was associated with a specific dysregulation of glutathione (GSH) homeostasis. Expression of enzymes for GSH biosynthesis [gamma glutamylcysteine synthase, glutathione reductase] as well as for GSH-mediated detoxification (glutathione peroxidase, glutathione-S-transferase) was lower, while toxic metabolites dependent on GSH for clearance (4-hydroxynonenal) were increased in exercised diabetic mice hearts. To validate GSH loss as an important factor for such aggravated damage, daily administration of GSH restored cardiac GSH levels in exercised diabetic mice. Such supplementation attenuated both oxidative damage and fibrotic changes in the myocardium. Expression of transforming growth factor beta (TGF-beta) and its regulated genes which are responsible for such profibrotic changes were also attenuated with GSH supplementation. These novel findings in a long-term T2D animal model demonstrate that short-term exercise by itself can deplete cardiac GSH and aggravate cardiac oxidative stress. As GSH administration conferred protection in 8-month-old diabetic mice undergoing exercise, supplementation with GSH-enhancing agents may be beneficial in elderly diabetic patients undergoing exercise. PMID- 23039790 TI - EPR study of the astaxanthin n-octanoic acid monoester and diester radicals on silica-alumina. AB - The radical intermediates of the n-octanoic monoester and n-octanoic diester of astaxanthin were detected by pulsed EPR measurements carried out on the UV produced radicals on silica-alumina artificial matrix and characterized by density functional theory (DFT) calculations. Previous Mims ENDOR for astaxanthin detected the radical cation and neutral radicals formed by proton loss from the C3 (or C3') position and from the methyl groups. Deprotonation of the astaxanthin neutral radical formed at the C3 (or C3') position resulted in a radical anion. DFT calculations for astaxanthin showed that the lowest energy neutral radical forms by proton loss at the C3 (or C3') position of the terminal ring followed by proton loss at the methyl groups of the polyene chain. Contrary to astaxanthin where proton loss can occur at either end of the symmetrical radical, for the diester of astaxanthin, this loss is prevented at the cyclohexene ends and is favored for its methyl groups. The monoester of astaxanthin, however, allows formation of the neutral radical at C3' and prevents its formation at the opposite end where the ester group is attached. At the terminal ring without the ester group attached, migration of proton from hydroxyl group to carbonyl group facilitates resonance stabilization, similarly to already published results for astaxanthin. However, cw EPR shows no evidence of a monoester radical anion formed. This study suggests the different radicals of astaxanthin and its esters that would form in a preferred environment, either hydrophobic or hydrophilic, depending on their structure. PMID- 23039792 TI - Development of a simple method for protein conjugation by copper-free click reaction and its application to antibody-free Western blot analysis. AB - There are currently many methods available for labeling proteins in order to study their structure and function. However, the utility of these methods is hampered by low efficiency, slow reaction rates, nonbiocompatible reaction conditions, large-sized labeling groups, and the requirement of specific side chains such as cysteine or lysine. In this study, a simple and efficient method for protein labeling was developed, in which an azide-containing amino acid was introduced into a protein and conjugated to a labeling reagent by strain-promoted azide-alkyne cycloaddition (SPAAC). This method allowed us to label proteins by simply mixing a protein and a labeling reagent in physiological conditions with a labeling yield of approximately 80% in 120 min. In addition, the specificity of SPAAC made it possible to analyze the expression level of a protein quantitatively by simple mixing and SDS-PAGE analysis with no need for antibodies or multistep incubations. Because the genetic incorporation of the azide containing amino acid can be generally applied to any protein and the SPAAC reaction is highly specific, this method should prove useful for labeling and analyzing proteins. PMID- 23039793 TI - Psychological condition in patients with an acoustic tumor. AB - CONCLUSIONS: This study showed that patients with acoustic tumor (AT) with hearing loss in the contralateral side had severe mood disturbances. It is important for physicians to provide patients who have better hearing in the tumor side with adequate information regarding the possibility of profound bilateral hearing loss and how to communicate with others in such situations. OBJECTIVES: We examined the pretreatment status as regards neurosis and/or depression of patients with an AT using the Cornell Medical Index (CMI) and Self-rating Depression Scale (SDS) and clarified the relationship with the patients' background. METHODS: We enrolled 30 patients with unilateral AT between 1997 and 2010. At the time of diagnosis, we examined each patient's psychological condition, sex, age, laterality, tumor size, hearing level on bilateral side, facial paresis, headache, and canal paresis. RESULTS: In all, 20.0% of AT patients were diagnosed with neurosis using the CMI and 26.7% had depression according to the SDS. chi(2) analysis showed that patients with AT with hearing deterioration on the contralateral side had mental illness significantly more often than those with normal hearing on the contralateral side. Multivariable regression analysis revealed that the pretreatment status of hearing level on the contralateral side significantly affected the patients' psychological condition. PMID- 23039791 TI - The role of ionic interactions in the adherence of the Staphylococcus epidermidis adhesin SdrF to prosthetic material. AB - Staphylococcus epidermidis infections are common complications of prosthetic device implantation. SdrF, a surface protein, appears to play a critical role in the initial colonization step by adhering to type I collagen and DacronTM. The role of ionic interactions in S. epidermidis adherence to prosthetic material was examined. SdrF was cloned and expressed in Lactococcus lactis. The effect of pH, cation concentration, and detergents on adherence to different types of plastic surfaces was assessed by crystal violet staining and bacterial cell counting. SdrF, in contrast with controls and other S. epidermidis surface proteins, bound to hydrophobic materials such as polystyrene. Binding was an ionic interaction and was affected by surface charge of the plastic, pH, and cation concentration. Adherence of the SdrF construct was increased to positively charged plastics and was reduced by increasing concentrations of Ca(2+) and Na(+). Binding was optimal at pH 7.4. Kinetic studies demonstrated that the SdrF B domain as well as one of the B subdomains was sufficient to mediate binding. The SdrF construct also bound more avidly to GoretexTM than the lacotococcal control. SdrF is a multifunctional protein that contributes to prosthetic devices infections by ionic, as well as specific receptor-ligand interactions. PMID- 23039794 TI - Children's and adolescents' understanding of their small ventricular septal defects. AB - BACKGROUND: Congenital heart disease is common yet poorly understood in childhood. We reviewed the understanding of older children and adolescents with the commonest congenital heart defect, namely, a small ventricular septal defect (VSD), through a questionnaire and/or their drawings of their abnormality. METHODS: As part of a wider study, older children and adolescents with a small VSD were asked to draw a picture of their cardiac defect in addition to completing a questionnaire. RESULTS: Twelve of an initial cohort of 20 participants, who were between the ages of 8 and 20 years, completed a drawing of their malformation. Further drawings were obtained from five additional participants recruited from a private practice over the next few years. There were almost equal number of male and female participants overall. Nearly all participants had a limited understanding of their cardiac abnormality as reflected by their drawings. Nevertheless none reported restricting their physical activity. CONCLUSION: While most older children and adolescents did not seem to have a clear understanding of their small VSD, it did not appear to affect their daily activity. The participants placed a greater reliance on the information provided by their parents rather than their doctor, emphasizing the importance of informing both the parents and the patient. PMID- 23039795 TI - Secreted frizzled-related protein 4 expression is positively associated with responsiveness to cisplatin of ovarian cancer cell lines in vitro and with lower tumour grade in mucinous ovarian cancers. AB - BACKGROUND: Ovarian cancer is one of the most lethal malignancies in women, as it is frequently detected at an advanced stage, and cancers often become refractory to chemotherapy. Evidence suggests that dysregulation of pro-apoptotic genes plays a key role in the onset of chemoresistance. The secreted Frizzled-Related Protein (sFRP) family is pro-apoptotic and also a negative modulator of the Wnt signalling cascade. Studies have demonstrated that the re-expression of sFRPs, in particular sFRP4, is associated with a better prognosis, and that experimentally induced expression results in cell death. RESULTS: In vitro experimental models determined that sFRP4 was differentially expressed in chemosensitive (A2780) and chemoresistant (A2780 ADR and A2780 Cis) ovarian cell lines, with chemosensitive cells expressing significantly higher levels of sFRP4. Transfection of the chemoresistant cell lines with sFRP4 significantly increased their sensitivity to chemotherapy. Conversely, silencing of sFRP4 expression in the chemosensitive cell line resulted in a corresponding increase in chemoresistance. Comparison of sFRP4 expression in tumour biopsies revealed a positive trend between sFRP4 expression and tumour grade, with mucinous cyst adenocarcinomas exhibiting significantly decreased sFRP4 levels compared to mucinous borderline tumours. CONCLUSIONS: This study indicates a role for sFRP4 as a predictive marker of chemosensitivity in ovarian cancer and suggests that this pathway may be worth exploiting for novel therapies. PMID- 23039797 TI - Periprocedural variations of platelet reactivity during elective percutaneous coronary intervention. AB - BACKGROUND: Percutaneous coronary intervention (PCI) modulates platelet reactivity (PR). OBJECTIVES: To assess: (i) the impact of coronary interventions on periprocedural variations (Delta) of PR; (ii) whether DeltaPR correlates with periprocedural myocardial infarction (PMI); and (iii) the mechanisms of these variations in vitro. METHODS AND RESULTS: We enrolled 65 patients on aspirin (80 100 mg day(-1)) and clopidogrel (600 mg, 12 h before PCI): 15 with coronary angiography (CA group), 40 with PCI (PCI group), and 10 with rotational atherectomy plus PCI (RA group). PR was assessed by ADP, high-sensitivity ADP and thrombin receptor activator peptide 6 tests prior to, immediately after and 24 h after the procedure. E-selectin and ICAM-1 were assessed prior to and immediately after the procedure. In vitro, PR was measured during pulsatile blood flow at baseline, after balloon inflation and after stent implantation in six porcine carotid arteries and five plastic tubes. PR declined in the CA group, but significantly increased in the PCI and RA groups immediately postprocedure, and decreased to baseline at 24 h. DeltaPR increased across the three groups (P < 0.0001). In the PCI group, DeltaPR was directly related to total inflation time (r = 0.435, P = 0.005) and total stent length (r = 0.586, P < 0.001). The change in E-selectin significantly and inversely correlated with DeltaPR (P < 0.001). No correlation was found with sICAM-1. PR increased significantly more in patients with PMI than in patients without PMI (P = 0.013). In vitro, platelet activation was observed in the presence of carotid arteries but not in the presence of plastic tubes. CONCLUSIONS: Despite dual antiplatelet therapy, PCI affected platelet function proportionally to procedural complexity and the extent of vascular damage. PMID- 23039798 TI - [Carbon dioxide insufflation in endoscopy - Luxury or need?]. PMID- 23039796 TI - Impact of atopic dermatitis and loss-of-function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) and loss-of-function mutations in the filaggrin gene (FLG) are both associated with chronic irritant contact dermatitis (ICD). As FLG mutations also are a major risk factor for AD, it is not clear whether FLG mutations are an independent risk factor for ICD or whether the risk is mediated by AD. OBJECTIVES: To investigate the relative contribution and interaction of FLG mutations and AD in German patients with occupational ICD and controls (vocational school apprentices). METHODS: A total of 634 patients and 393 controls were genotyped for R501X, 2282del4, R2447X and S3247X. Current or past flexural eczema was used as an indicator of AD. RESULTS: FLG mutations were found in 15.9% of the patients with ICD and 8.3% of the controls, with a crude odds ratio (OR) of 2.09 [95% confidence interval (CI) 1.33-3.28] for the combined genotype. The adjusted OR for FLG mutations, corrected for AD, was 1.62 (95% CI 1.01-2.58). Subjects with AD were at approximately three times higher risk of developing ICD than controls (OR 2.89; 95% CI 2.09-3.99). There was no evidence of an interaction between these two risk factors. CONCLUSIONS: Our results indicate that both FLG mutations and AD increase the risk of ICD. Individuals with concurrent FLG mutations and AD are at the highest risk of developing ICD. PMID- 23039799 TI - Analysis of alarming signals for the progression of atrophic gastritis to dysplasia. AB - BACKGROUND AND AIMS: atrophic gastritis (AG) and dysplasia are precancerous lesions, with which early surveillance of disease progression is particularly important for patients. The present study aimed to explore potential alarming signals for atrophic gastritis progression towards dysplasia. METHODS: clinical data for patients with AG in the Digestive Endoscopy Center of Guangzhou Nanfang Hospital between 2001 and 2011 were retrospectively reviewed. Survival analysis, dichotomous logistic regression analysis and rank correlation analysis were carried out. RESULTS: in 234 patients with atrophic gastritis, after follow up of 0.5, 1, 2, 5 and 10 years, the occurrence rates of dysplasia were respectively 2.3, 4.4, 9.6, 19.3, and 42.4%. Patients with AG combined with antral ulcer or gastric angle ulcer, had a higher risk for dysplasia than patients with simple AG (OR = 2.427, 95%Cl 1.069 ~ 5.511, p = 0.034; OR = 2.961, 95%Cl 1.336 ~ 6.564, p = 0.008). The constituent ratios of moderate to severe dysplasia were respectively 8.6, 2.7 and 1.2% (p = 0.000) in three patient groups: AG combined with antral ulcer/gastric angle ulcer (n = 255), antral ulcer/gastric angle ulcer alone (n = 1,389), and AG alone (n = 3,106). The Spearman correlation coefficients between a) Hp infection; and b) atrophy, intestinal metaplasia and dysplasia were -0.114 (p = 0.078), -0.169 (p = 0.009) and 0.064 (p > 0.05), respectively. CONCLUSIONS: long follow-up interval and gastric ulcer may be alarming signals for the progression of AG to dysplasia. But in patients with atrophy, intestinal metaplasia or dysplasia, Hp infection may not be a risk factor for these lesions aggravated, further studies are required to confirm it. PMID- 23039800 TI - Results on prognostic value of mutations in localized gastrointestinal stromal tumors (GIST) in one single center. AB - INTRODUCTION: to study the prognostic value of mutations in KIT or PDGFRA in gastrointestinal stromal tumors (GIST) managed in our department. MATERIALS AND METHODS: forty five patients with localized GIST underwent surgery between 1998 and 2010. Thirty six patients were enrolled in a retrospective study. DNA was isolated from 3 to 5 im sections of fixed and paraffin-embedded tissue. Exon 9, 11, 13 and 17 of c-kit gene and exon 12 and 18 of PDGFRA were amplified by PCR and sequenced. RESULTS: tumors with mutations were larger at the surgery and showed higher mitotic count (p < 0.05). The mutations were found in 22 patients (61.2%), 18 had mutations in exon 11 of c-kit gene. PDGFRA mutations were located in exon 12. The 5-years relapsefree survival rate for patients with tumors having mutations was 38% and 100% for patients without mutations (p < 0.01). The 5-year survival rate was significantly worse for patients with mutations (20 vs. 97%, p < 0.01), with tumors larger than 5 cm (28 vs. 97%, p < 0.01) and with > 50 mitosis/HPF (42 vs. 88%, p < 0.03). Multivariate analyses indicated that the mutations, mitotic counts, and tumor size were independent prognostic factors for survival in patients with localized GIST. CONCLUSIONS: in this series, having a detected mutation is a poor prognostic factor with significantly increased recurrence rate and shortens survival. PMID- 23039801 TI - [Comparison between insufflation with air or carbon dioxide during the colonoscopy in sedated patients with propofol]. AB - OBJECTIVES: compare the intensity of pain experienced after colonoscopy with air or with CO2 and evaluate the safety of CO2 in colonoscopies performed with moderate/deep sedation. MATERIALS AND METHODS: individuals undergoing ambulatory colonoscopy without exclusion criteria (severe respiratory disease, morbid obesity) were randomized in air or CO2 group. We recorded different variables prior to, during and upon completion of the colonoscopy, performing monitoring using pulse oximetry and capnography. Each patient rated, using a visual numeric scale, the intensity of post-colonoscopy pain at different moments. RESULTS: 141 individuals in the air group (sex M/F 63/78, age 24-83) and the CO2 group (sex M/F 59/70, age 24-82). No significant differences existed in the recorded variables in both groups except for the greater number of explorations performed by an endoscopist in training (TE) in the air group compared to those by a more experienced endoscopist (SE). CO2 in expired air, episodes of oxygen desaturation and of apnoea and dose of propofol, of midazolam were similar in both groups. No episodes of hypercapnea or any complication requiring cardiopulmonary resuscitation measures were recorded. The pain in the air group was significantly higher at 15 minutes and at 1, 3 and 6 hours after the endoscopy, equalising at 24 hours. After multivariant adjustment for type of doctor (TE vs. SE) the differences observed in pain intensity for each group were maintained. CONCLUSIONS: a) the use of CO2 in colonoscopy causes significantly less pain in the first 6 hours after the procedure; b) its use in patients with moderate/deep sedation is safe; and c) performance of the endoscopic technique is not modified, nor are times reduced. PMID- 23039802 TI - Sustained relief of obstructive symptoms for the remaining life of patients following placement of an expandable metal stent for malignant colorectal obstruction. AB - BACKGROUND: self-expanding metal stents are currently being used as a definitive palliative treatment for malignant colorectal obstruction in patients with incurable disease. Few studies have followed large numbers of patients from stent placement until death, and those few have reported conflicting results in the long-term clinical outcome data. AIMS: this study evaluated the clinical effectiveness of stent placement for malignant colorectal obstruction throughout the patients lives and related factors affecting stent patency, clinical success and complications. METHODS: this was a multicentre, retrospective study of 89 consecutive patients who had undergone attempted expandable stent placement for symptomatic malignant colorectal obstruction during a 10-year period. Data were collected to analyse the sustained relief of obstructive symptoms throughout the patients lives, as well as the technical success, immediate clinical success, stent patency, complications, reinterventions, survival, prognostic factors associated with stent patency and long-term clinical efficacy and risk factors for complications. RESULTS: technical and immediate clinical success were achieved in 95.5% and 91.0% of patients, respectively. A total of 68 out of 89 patients (76.4%) maintained relief of obstruction from stent implantation until death without reintervention. Twenty patients (22.5%) had complications including perforation (n = 4; 4.5%), stent obstruction (n = 8; 9.0%), migration (n = 5; 5.6%) and haemorrhage (n = 3; 3.4%). Stent-related mortality was seen in 1 patient (1.1%). The estimated median survival and estimated mean stent patency were 87.0 and 322.7 days, respectively. In total, 12 of the initial 89 patients (13.5%) needed a colostomy for long-term relief of the obstructive symptoms. Univariate and multivariate analysis detected no significant prognostic factors associated with stent patency, long term clinical efficacy and risk factors for complications; however, the multivariate logistic model revealed a non significant trend by which the use of chemotherapy was a risk factor for migration (OR = 11.89; p = 0.06). CONCLUSIONS: for palliation of incurable malignant colorectal obstruction, expandable stents can provide sustained relief of obstruction in approximately 75% of patients. The procedure is associated with acceptable morbidity, need for reintervention and minimal mortality. PMID- 23039803 TI - [Preparation for colonoscopy: types of scales and cleaning products]. AB - Adequate bowel preparation is essential before a colonoscopy, allowing us to make a proper examination of the entire mucosa. The ideal method of colon cleansing should be fast, safe, and get a proper cleaning with minimal discomfort for the patient. Today we have a wide variety of colon cleansing products, information sometimes becomes confused. A good colon preparation depends partly on correct choice of the same, but also upon dietary restriction. Knowledge of all these products, with their advantages and limitations, we can make a better selection for each patient, and although the efficacy is comparable, is the experience of the browser, patient preferences, and the degree of compliance with the instructions preparation, which greatly influence the results. PMID- 23039804 TI - [Endoscopic removal of intrauterine device penetrated through the rectal wall]. PMID- 23039805 TI - [Giant splenomegaly and non-Hodking's lymphoma]. PMID- 23039807 TI - [Barrett's esophagus]. PMID- 23039806 TI - [Giant duodenal ulcer perforation: a case of innovative repair with an antrum gastric patch]. AB - BACKGROUNDS: the treatment of a perforated giant duodenal ulcer (GUDs) represents a formidable surgical challenge regarding the duodenal wall defect repair in severe peritonitis setting. A high incidence of dehiscence and hospital mortality (15-40%- has been reported with the majority of the techniques). We report a case of GUDs perforation successfully treated with a subtotal gastrectomy and a gastric patch with the remnant antrum, for repairing the duodenal defect. CASE REPORT: a 63-years-old man with antecedents of peptic ulcer disease presents a large duodenal ulcer perforation with 48 hrs delay and associated with severe peritonitis and a retroperitoneal collection. A subtotal gastrectomy with Billroth II reconstruction and reconstruction of the duodenal defect with a patch of the remnant antrum was carried out. The patient was discharged at 17th postoperative day with good tolerance. DISCUSSION: the duodenal defect repair with a patch of the remant antrum, represents a valid alternative in similar circumstances. To our knowledge, it appears to be the first clinical description of this technique. PMID- 23039808 TI - [Recurrent acute pancreatitis as clinical presentation of hydatid disease of the liver]. PMID- 23039809 TI - [Colonic metastasis of diffuse signet ring cells gastric carcinoma]. PMID- 23039810 TI - Verrucous carcinoma of the esophagus. PMID- 23039811 TI - A rare cause of intestinal obstruction in the adult: duodenal diaphragm. PMID- 23039812 TI - [Rare esophageal tumors of mesenchymal origen]. PMID- 23039813 TI - Colonic metastases from non-small cell lung cancer. PMID- 23039814 TI - Cardiovascular function in women with recurrent miscarriage, pre-eclampsia and/or intrauterine growth restriction. AB - OBJECTIVE: To investigate prepregnancy cardiovascular function and risk factors in women with previous pregnancy complications. METHODS: Thirty-four women with previous normal pregnancy (controls), 26 with unexplained recurrent miscarriage (RM) and 14 with pre-eclampsia (PE) and/or intrauterine growth restriction (IUGR), planning to conceive were recruited. Brachial and central blood pressures (BP), cardiac output (CO), peripheral vascular resistance (PVR), aortic stiffness, blood biochemistry and platelet aggregation were assessed. RESULTS: Women with previous PE/IUGR had higher brachial diastolic BP (78 +/- 9 vs 71 +/- 7 mmHg; p = 0.03), central systolic BP (107 +/- 10 vs 99 +/- 8 mmHg; p = 0.03), mean arterial pressure (92 +/- 10 vs 84 +/- 8 mmHg; p = 0.01) and PVR (1499 +/- 300 vs 1250 +/- 220 dynes.s(-1) cm(-5); p = 0.005), than the controls. No differences were observed in either cardiovascular function or blood biochemistry in women with unexplained RM compared with the controls. Women with previous PE/IUGR though not with RM had a stronger family history of cardiovascular disease (CVD) than controls. CONCLUSIONS: Women with previous PE and/or IUGR had higher BP and PVR compared with controls, which may predispose them to CVD later in life. However, in the absence of underlying vascular pathology, women with unexplained RM did not have abnormal cardiovascular function. Prepregnancy period provides an opportunity to identify cardiovascular risks in relation to previous obstetric history. PMID- 23039815 TI - Influence of connector groups on the interactions of substituents with carbon centered radicals. AB - High-level G3X(MP2)-RAD calculations have been carried out to examine the effect of interposing a "connector" group (W) on the interaction between a substituent (X) and the radical center in carbon-centered radicals ((*)CH(2)-W-X). The connector groups include -CH(2)-, -CH?CH-, -C=C-, -p-C(6)H(4)-, -m-C(6)H(4)-, and -o-C(6)H(4)-, and the substituents include H, CF(3), CH(3), CH?O, NH(2), and CH?CH(2). Analysis of the results is facilitated by introducing two new quantities termed radical connector energies and molecule connector energies. We find that the -CH(2)- connector effectively turns off pi-electron effects but allows the transmission of sigma-electron effects, albeit at a reduced level. The effect of a substituent X attached to the -CH?CH- and -C=C- connector groups is to represent a perturbation of the effect of the connector groups themselves (i.e., CH?CH(2) and C=CH). PMID- 23039816 TI - 3D spirals with controlled chirality fabricated using metal-assisted chemical etching of silicon. AB - The ability to fabricate 3D spiraling structures using metal-assisted chemical etching (MaCE) is one of the unique advantages of MaCE over traditional etching methods. However, control over the chirality of the spiraling structures has not been established. In this work, a systematic parametric study was undertaken for MaCE of star-shaped catalysts, examining the influence of arm shape, arm length, number of arms, center core diameter, and catalyst thickness on the rotation direction. This data was used to identify a set of geometric parameters that reliably induce rotation in a predefined direction such that large arrays of 3D spiraling structures can be fabricated with the same chirality. Electroless deposition into the MaCE template was used to examine the full etch path of the catalyst and an experimental fit was established to control rotation angle by adjusting the catalyst's center core diameter. The ability to fabricate large arrays of 3D spiraling structures with predefined chirality could have important applications in photonics and optoelectronics. PMID- 23039817 TI - Uncertainty of the sample size reduction step in pesticide residue analysis of large-sized crops. AB - To estimate the uncertainty of the sample size reduction step, each unit in laboratory samples of papaya and cucumber was cut into four segments in longitudinal directions and two opposite segments were selected for further homogenisation while the other two were discarded. Jackfruit was cut into six segments in longitudinal directions, and all segments were kept for further analysis. To determine the pesticide residue concentrations in each segment, they were individually homogenised and analysed by chromatographic methods. One segment from each unit of the laboratory sample was drawn randomly to obtain 50 theoretical sub-samples with an MS Office Excel macro. The residue concentrations in a sub-sample were calculated from the weight of segments and the corresponding residue concentration. The coefficient of variation calculated from the residue concentrations of 50 sub-samples gave the relative uncertainty resulting from the sample size reduction step. The sample size reduction step, which is performed by selecting one longitudinal segment from each unit of the laboratory sample, resulted in relative uncertainties of 17% and 21% for field-treated jackfruits and cucumber, respectively, and 7% for post-harvest treated papaya. The results demonstrated that sample size reduction is an inevitable source of uncertainty in pesticide residue analysis of large-sized crops. The post-harvest treatment resulted in a lower variability because the dipping process leads to a more uniform residue concentration on the surface of the crops than does the foliar application of pesticides. PMID- 23039818 TI - Differential expression of TNFR1 (CD120a) and TNFR2 (CD120b) on subpopulations of human monocytes. AB - BACKGROUND: Three subpopulations of monocytes can be distinguished in human blood: classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++). CD16 expressing monocytes are expanded in patients with sarcoidosis and in various other inflammatory diseases. In sarcoidosis, it is unclear whether either intermediate, nonclassical or both CD16 expressing monocytes are responsible for this increase. Data relating to the monocyte subpopulations is receiving increasing attention, but the expression of TNF receptors on these subpopulations has not been studied thus far. The aim of this study was to determine frequencies of monocyte subpopulations and their expression of TNFR1 and TNFR2 in both sarcoidosis patients and healthy controls. METHODS: Peripheral blood cells of sarcoidosis patients and healthy controls were stained for the markers HLA-DR, CD14, CD16, CD120a and CD120b. Cells were measured on a FACSCalibur and analyzed with FlowJo. We used Student's t-test and a parametric One-way ANOVA for statistical analysis. RESULTS: Sarcoidosis patients had a significant higher frequency of intermediate monocytes than healthy controls. Significant differences in TNF receptor expression were found between the monocyte subpopulations, both in sarcoidosis patients as well as in healthy controls: intermediates expressed more TNFR1 than classicals and nonclassicals and nonclassicals expressed more TNFR2 than intermediates, whereas intermediates showed higher expression than classicals. CONCLUSIONS: In both sarcoidosis patients and healthy controls intermediate monocytes show the highest expression level of TNFR1 among monocyte subpopulations and nonclassical monocytes show the highest expression level of TNFR2. These findings, as wells as the higher frequency of intermediate monocytes in sarcoidosis patients, provide evidence for the existence of two functionally-distinct CD16 expressing monocyte subpopulations. PMID- 23039819 TI - Antimicrobial efficacy of 0.05% cetylpyridinium chloride mouthrinses. AB - This study evaluated the antimicrobial activity of two commercially available 0.05% cetylpyridinium chloride (CPC) mouthrinses with or without alcohol and examined its antimicrobial activity on oral bacterial species including fresh clinical isolates compared to a chlorhexidine mouthrinse and a control fluoride mouthrinse without CPC. Two different approaches were used to evaluate antimicrobial activity. First, the minimum inhibitory concentration (MIC) was determined for each mouthrinse against a panel of 25 micro-organisms including species associated with dental caries, gingivitis and periodontitis. Second, supragingival dental plaque obtained from 15 adults was incubated with the four mouthrinses to evaluate antimicrobial activity on micro-organisms in oral biofilms. Both CPC mouthrinses exhibited lower MIC's, that is, greater antimicrobial activity, against oral Gram-negative bacteria especially periodontal pathogens and species implicated in halitosis such as Aggregatibacter actinomycemcomitans, Campylobacter rectus, Eikenella corrodens, Porphyromonas gingivalis, Prevotella intermedia and Solobacterium moorei than the control mouthrinse. Ex-vivo tests on supragingival plaque micro-organisms demonstrated significantly greater antimicrobial activity by the CPC mouthrinses (>90% killing, P < 0.001) and the chlorhexidine rinse (>98% killing, P < 0.05) compared to the control fluoride mouthrinse. Whilst the chlorhexidine mouthrinse was most effective, mouthrinses containing 0.05% CPC formulated with or without alcohol demonstrated broad-spectrum antimicrobial activity against both laboratory strains and supragingival plaque bacteria compared to a control mouthrinse without CPC. SIGNIFICANCE AND IMPACT OF STUDY: These in vitro and ex-vivo studies provide a biological rationale for previous clinical studies demonstrating the efficacy of CPC mouthrinses in reducing supragingival plaque and plaque associated gingivitis. PMID- 23039820 TI - Structure-based identification of aporphines with selective 5-HT(2A) receptor binding activity. AB - Selective blockade of the serotonin 5-HT(2A) receptor is a useful therapeutic approach for a number of disorders, including schizophrenia, insomnia and ischaemic heart disease. A series of aporphines were docked into a homology model of the rat 5-HT(2A) receptor using AutoDock. Selected compounds with high in silico binding affinities were screened in vitro using radioligand-binding assays against rat serotonin (5-HT(1A) and 5-HT(2A)) and dopamine (D1 and D2) receptors. (R)-Roemerine and (+/-)-nuciferine were found to have high affinity for the 5 HT(2A) receptor (K(i) = 62 and 139 nM, respectively), with (R)-roemerine showing 20- to 400-fold selectivity for the 5-HT(2A) receptor over the 5-HT(1A), D1 and D2 receptors. Investigation into the ligand-receptor interactions suggested that the selectivity of (R)-roemerine is due to it having stronger H-bonding and dipole-dipole interactions with several of the key residues in the 5-HT(2A) receptor-binding site. PMID- 23039821 TI - Work and health among immigrants and native Swedes 1990-2008: a register-based study on hospitalization for common potentially work-related disorders, disability pension and mortality. AB - BACKGROUND: There are many immigrants in the Swedish workforce, but knowledge of their general and work-related health is limited. The aim of this register-based study was to explore whether documented migrant residents in Sweden have a different health status regarding receipt of a disability pension, mortality and hospitalization for lung, heart, psychiatric, and musculoskeletal disorders compared with the native population, and if there were variations in relation to sex, geographical origin, position on the labor market, and time since first immigration. METHODS: This study included migrants to Sweden since 1960 who were 28-47 years old in 1990, and included 243 860 individuals. The comparison group comprised a random sample of 859 653 native Swedes. These cohorts were followed from 1991 to 2008 in national registers. The immigrants were divided into four groups based on geographic origin. Hazard ratios for men and women from different geographic origins and with different employment status were analyzed separately for the six outcomes, with adjustment for age, education level, and income. The influence of length of residence in Sweden was analyzed separately. RESULTS: Nordic immigrants had increased risks for all investigated outcomes while most other groups had equal or lower risks for those outcomes than the Swedes. The lowest HRs were found in the EU 15+ group (from western Europe, North America, Australia and New Zealand). All groups, except Nordic immigrants, had lower risk of mortality, but all had higher risk of disability pension receipt compared with native Swedes. Unemployed non-Nordic men displayed equal or lower HRs for most outcomes, except disability pension receipt, compared with unemployed Swedish men. A longer time since first immigration improved the health status of men, while women showed opposite results. CONCLUSIONS: Employment status and length of residence are important factors for health. The contradictory results of low mortality and high disability pension risks need more attention. There is great potential to increase the knowledge in this field in Sweden, because of the high quality registers. PMID- 23039822 TI - Outcome of Clostridium difficile-associated disease in solid organ transplant recipients: a prospective and multicentre cohort study. AB - Clostridium difficile-associated disease (CDAD) is the most common cause of nosocomial diarrhea. Information about CDAD in solid organ transplant (SOT) recipients is scarce. To determine its epidemiology and risk factors, we conducted a cohort study in which 4472 SOT patients were prospectively included in the RESITRA/REIPI (Spanish Research Network for the Study of Infection in Transplantation) database between July 2003 and July 2006. Forty-two episodes of CDAD were diagnosed in 36 patients. The overall incidence was 0.94%. Median onset of infection was 31.5 days (range 6-741); in half the cases, onset occurred during the first month after transplantation. In 26% of cases, there was no previous antibiotic use. Independent risk factors for CDAD using Cox regression analysis were previous use of first- and second-generation cephalosporins (HR 3.68; 95%CI 1.8-7.52; P < 0.001), ganciclovir prophylactic use (HR 3.09; 95%CI 1.44-6.62; P = 0.004) and corticosteroid use before transplantation (HR 2.95; 95%CI 1.1-7.9; P = 0.031). There were no deaths related to CDAD. In summary, the incidence of CDAD in SOT was low, most cases were diagnosed soon after transplantation and the prognosis was good. PMID- 23039823 TI - Prominent thermodynamical interaction with surroundings on nanoscale memristive switching of metal oxides. AB - This study demonstrates the effect of surroundings on a memristive switching at nanoscale by utilizing an open top planar-type device. NiO(x) and CoO(x) planar type devices have exhibited a memristive behavior under atmospheric pressure, whereas TiO(2-x) planar-type devices did not show a memristive switching even under the same surroundings. A memristive behavior of TiO(2-x) planar-type devices has emerged when reducing an ambient pressure and/or employing a SiO(2) passivation layer. These results reveal that a thermodynamical interaction with surroundings critically determines the occurrence of memristive switching via varying a stability of nonstoichiometry. Since this effect tends to be more significant for smaller devices with larger specific surface area, tailoring the surrounding effect by an appropriate passivation will be essential for high density devices. PMID- 23039824 TI - Blunted sleep-time relative blood pressure decline increases cardiovascular risk independent of blood pressure level--the "normotensive non-dipper" paradox. AB - Numerous studies have consistently shown an association between blunted sleep time relative blood pressure (BP) decline (non-dipping) and increased cardiovascular disease (CVD) risk in hypertension. Normotensive persons with a non-dipper BP profile also have increased target organ damage, namely, increased left ventricular mass and relative wall thickness, reduced myocardial diastolic function, increased urinary albumin excretion, increased prevalence of diabetic retinopathy, and impaired glucose tolerance. It remains a point of contention, however, whether the non-dipper BP pattern or just elevated BP, alone, is the most important predictor of advanced target organ damage and future CVD events. Accordingly, we investigated the role of dipping status and ambulatory BP level as contributing factors for CVD morbidity and mortality in the MAPEC (Monitorizacion Ambulatoria para Prediccion de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study. We prospectively studied 3344 individuals (1718 men/1626 women), 52.6 +/- 14.5 (mean +/- SD) yrs of age, during a median follow-up of 5.6 yrs. BP was measured by ambulatory monitoring (ABPM) for 48 h at baseline, and again annually or more frequently (quarterly) if treatment adjustment was required in treated hypertensive patients. At baseline, those with ABPM-substantiated hypertension were randomized to one of two treatment-time regimen groups: (i) ingestion of all prescribed hypertension medications upon awakening or (ii) ingestion of the entire dose of >=1 of them at bedtime. Those found to be normotensive at baseline were untreated but followed and evaluated by repeated ABPM like the hypertensive patients. Participants were divided into four investigated categories on the basis of dipping status and ambulatory BP: (i) dipper vs. non-dipper, and (ii) normal ambulatory BP if the awake systolic (SBP)/diastolic (DBP) BP means were <135/85 mm Hg and the asleep SBP/DBP means were <120/70 mm Hg, and elevated ambulatory BP otherwise. Cox survival analyses, adjusted for significant confounding variables, documented that non-dippers had significantly higher CVD risk than dippers, whether they had normal (p = .017) or elevated ambulatory BP (p < .001). Non-dippers with normal awake and asleep SBP and DBP means, who accounted for 21% of the studied population, had similar hazard ratio (HR) of CVD events (1.61 [95% confidence interval, CI: 1.09-2.37]) as dippers with elevated ambulatory BP (HR: 1.54 [95% CI: 1.01-2.36]; p = .912 between groups). These results remained mainly unchanged for treated and untreated patients analyzed separately. Our findings document that the risk of CVD events is influenced not only by ambulatory BP elevation, but also by blunted nighttime BP decline, even within the normotensive range, thus supporting ABPM as a requirement for proper CVD risk assessment in the general population. The elevated CVD risk in "normotensive" individuals with a non-dipper BP profile represents a clear paradox, as those persons do not have "normal BP" or low CVD risk. Our findings also indicate the need to redefine the concepts of normotension/hypertension, so far established on the unique basis of BP level, mainly if not exclusively measured at the clinic, independently of circadian BP pattern. PMID- 23039825 TI - Expression of the sweetpotato R2R3-type IbMYB1a gene induces anthocyanin accumulation in Arabidopsis. AB - R2R3-type MYB transcription factors (TFs) play important roles in transcriptional regulation of anthocyanins. The R2R3-type IbMYB1 is known to be a key regulator of anthocyanin biosynthesis in the storage roots of sweetpotato. We previously showed that transient expression of IbMYB1a led to anthocyanin pigmentation in tobacco leaves. In this article, we generated transgenic Arabidopsis plants expressing the IbMYB1a gene under the control of CaMV 35S promoter, and the sweetpotato SPO and SWPA2 promoters. Overexpression of IbMYBa in transgenic Arabidopsis produced strong anthocyanin pigmentation in seedlings and generated a deep purple color in leaves, stems and seeds. Reverse transcription-polymerase chain reaction analysis showed that IbMYB1a expression induced upregulation of several structural genes in the anthocyanin biosynthetic pathway, including 4CL, CHI, F3'H, DFR, AGT, AAT and GST. Furthermore, overexpression of IbMYB1a led to enhanced expression of the AtTT8 (bHLH) and PAP1/AtMYB75 genes. high-performance liquid chromatography analysis revealed that IbMYB1a expression led to the production of cyanidin as a major core molecule of anthocyanidins in Arabidopsis, as occurs in the purple leaves of sweetpotato (cv. Sinzami). This result shows that the IbMYB1a TF is sufficient to induce anthocyanin accumulation in seedlings, leaves, stems and seeds of Arabidopsis plants. PMID- 23039826 TI - A method for fast analysis of volatile components of Citrus aurantium L. leaves. AB - To avoid the traditional and time consuming hydrodistillation, the analyses of volatile components in leaves of Citrus aurantium L. were carried out by a simple microwave distillation followed by headspace single drop microextraction (MD-HS SDME) coupled to gas chromatography-mass spectrometry (GC-MS). The headspace volatile compounds were collected after irradiation using a single drop of n heptadecan. The extraction conditions were optimized using the relative peak areas as index. The chemical composition of the MD-HS-SDME extracts was confirmed according to their retention indexes and mass spectra. Forty-one components were extracted and identified by using the MD-HS-SDME method. Limonene (62%), Linalool (7.47%), trans-beta-Ocimene (3.47%), Caryophyllene (2.05%), alpha- Bisabolene (1.8%) and Myrcene (1.18%) were the major constituents. PMID- 23039827 TI - Postsynthetic ligand and cation exchange in robust metal-organic frameworks. AB - Postsynthetic ligand and metal ion exchange (PSE) processes are shown to readily occur in several "inert" metal-organic frameworks (MOFs), including zeolitic imidazolate frameworks (ZIFs). Ligand exchange can occur between solid samples, as was demonstrated under relatively mild conditions with two robust, topologically distinct MOFs, MIL-53(Al) and MIL-68(In). Interestingly, ligand PSE is not observed with MIL-101(Cr), which is attributed to the kinetic inertness of the Cr(III) ion. In addition to ligand exchange, metal ion (cation) PSE was also studied between intact MOF microcrystalline particles. Metal ion transfer between MIL-53(Al) and MIL-53(Fe) was readily observed. These PSE reactions were monitored and the products characterized by a number of techniques, including aerosol time-of-flight mass spectrometry, which permits single-particle compositional analysis. To show the potential synthetic utility of this approach, the PSE process was used to prepare the first Ti(IV) analogue of the robust UiO 66(Zr) framework. Finally, experiments to rule out mechanisms other than PSE (i.e., aggregation, dissolution/recrystallization) were performed. The results demonstrate that PSE, of either ligands or cations, is common even with highly robust MOFs such as UiO-66(Zr), MILs, and ZIFs. Furthermore, it is shown that PSE is useful in preparing novel materials that cannot be obtained via other synthetic methods. PMID- 23039828 TI - Frataxin deficiency unveils cell-context dependent actions of insulin-like growth factor I on neurons. AB - BACKGROUND: Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by deficiency of the mitochondrial iron chaperone frataxin (Fxn). FRDA has no cure, but disease-modifying strategies to increase frataxin are under study. Because insulin-like growth factor I (IGF-I) has therapeutic effects in various types of cerebellar ataxia and exerts protective actions on mitochondrial function, we explored the potential Fxn-stimulating activity of this growth factor on brain cells. RESULTS: IGF-I normalized frataxin levels in frataxin-deficient neurons and astrocytes through its canonical Akt/mTOR signaling pathway. IGF-I also stimulated frataxin in normal astrocytes but not in normal neurons, whereas IGF-I stimulated the Akt/mTOR pathway in both types of cells. This cell context dependent action of IGF-I on neurons suggested that the intrinsic regulation of Fxn in neurons is different than in astrocytes. Indeed, neurons express much higher levels of frataxin and are much more sensitive to Fxn deficiency than astrocytes; i.e.: only neurons die in the absence of frataxin. In addition, the half-life of frataxin is shorter in neurons than in astrocytes, while after blockade of the proteasome only neurons responded to IGF-I with an increase in frataxin levels. We also explore a potential therapeutic utility of IGF-I in FRDA like transgenic mice (YG8R mice) and found that treatment with IGF-I normalized motor coordination in these moderately ataxic mice. CONCLUSION: Exposure to IGF-I unveiled a cell-specific regulation of frataxin in neurons as compared to astrocytes. Collectively, these results indicate that IGF-I exerts cell-context neuroprotection in frataxin deficiency that maybe therapeutically effective. PMID- 23039829 TI - Adsorption from oligomer-monomer solutions on the surfaces modified with end grafted chains. AB - A density functional theory has been applied to study adsorption from oligomer monomer solutions on solid surfaces modified with end-grafted polymers. Chains are modeled as freely jointed tangent spheres. All spherical species interact via Lennard-Jones (12-6) potential. The grafted chains are not attracted by the surface. Fluid molecules interact with the substrate via Lennard-Jones (9-3) potential. It is shown how a shape of the relative excess adsorption isotherms depends on such parameters as the oligomer length, the grafting density, oligomer substrate interactions, oligomer-grafted chains interactions, and oligomer monomer interactions in the bulk solution. As attractive interactions between free and grafted chains strengthen, the relative excess adsorption isotherm can change from negative, through S-shaped with an adsorption azeotropic point, to positive in the whole concentration region. A change of oligomer-monomer interactions causes the opposite effects. For low grafting densities of attractive bonds, the relative excess of oligomers increases, reaches a maximum, and decreases. The structure of surface layers is also analyzed. PMID- 23039830 TI - Hyaluronate tethered, "smart" multiwalled carbon nanotubes for tumor-targeted delivery of doxorubicin. AB - The present study reports the optimized synthesis, physicochemical characterization, and biological evaluation of a novel, multiwalled carbon nanotube-hyaluronic acid (MWCNT-HA) conjugate, complexed with an anticancer agent, Doxorubicin (DOX) via pi-pi stacking interaction. The therapeutic conjugate was concomitantly labeled with a near-infrared fluorescent dye, Alexa Flour-647 (AF-647), and radiotracer Technetium-99m ((99m)Tc) to track its whereabouts both in vitro and in vivo via optical and scintigraphic imaging techniques. Covalent functionalization of MWCNTs with HA facilitated their internalization into human lung adenocarcinoma, A549 cells via hyaluronan receptors (HR) mediated endocytosis. Internalized nanotubes showed lysosomal trafficking, followed by low pH-triggered DOX release under endolysosomal conditions. Consequently, DOX-loaded HA-MWCNTs exhibited 3.2 times higher cytotoxicity and increased apoptotic activity than free DOX in equivalent concentrations. Organ distribution studies in Ehlrich ascites tumor (EAT) bearing mice model indicated that tumor specific localization of (99m)Tc-MWCNT-HA-DOX is significantly higher than both free drug and nontargeted MWCNTs. Pharmacodynamic studies in chemically breast-cancer-induced rats showed that the tumor-growth inhibitory effect of HA-MWCNT-DOX was 5 times higher than free DOX in equivalent concentration. DOX delivered through HA-MWCNTs was devoid of any detectable cardiotoxity, hepatotoxicity, or nephrotoxicity. All these promising attributes make HA-MWCNTs a "smart" platform for tumor-targeted delivery of anticancer agents. PMID- 23039831 TI - The process of kinetochore assembly in yeasts. AB - High fidelity chromosome segregation is essential for efficient transfer of the genetic material from the mother to daughter cells. The kinetochore (KT), which connects the centromere DNA to the spindle apparatus, plays a pivotal role in this process. In spite of considerable divergence in the centromere DNA sequence, basic architecture of a KT is evolutionarily conserved from yeast to humans. However, the identification of a large number of KT proteins paved the way of understanding conserved and diverged regulatory steps that lead to the formation of a multiprotein KT super-complex on the centromere DNA in different organisms. Because it is a daunting task to summarize the entire spectrum of information in a minireview, we focus here on the recent understanding in the process of KT assembly in three yeasts: Saccharomyces cerevisiae, Schizosaccharomyces pombe and Candida albicans. Studies in these unicellular organisms suggest that although the basic process of KT assembly remains the same, the dependence of a conserved protein for its KT localization may vary in these organisms. PMID- 23039832 TI - Factors associated with faith-based health counselling in the United States: implications for dissemination of evidence-based behavioural medicine. AB - Health counselling is an evidence-based behavioural medicine approach and the most commonly reported form of faith-based health interventions. Yet, no research has explored the factors influencing the implementation of faith-based health counselling. Therefore, this study examined individual, organisational and environmental factors associated with offering/not offering faith-based health counselling programmes within faith-based organisations. A national, internet based, opt-in, cross-sectional survey of faith leaders (N = 676) was conducted (March-December 2009) to assess faith leaders' demographic information, health status, fatalism, health-related attitudes and normative beliefs, attitudes towards health counselling, institutional and occupational information, and perceptions of parent organisation support for health and wellness interventions. Most faith leaders reported offering some type of health counselling in the past year [n = 424, 62.7%, 95% CI (59.0, 66.3)]. Results of a multivariate logistic regression showed that faith leaders reporting greater proxy efficacy (OR = 1.40, P = 0.002), greater comfort in speaking with church members about health (OR = 1.25, P = 0.005), greater perceived health (OR = 1.27, P = 0.034), and who worked at larger churches (OR >= 3.2, P <= 0.001) with greater parent organisation support (OR = 1.33, P = 0.002) had significantly higher odds of offering faith based health counselling. Church size and parent organisation support for faith based health interventions appear to be important factors in the presence of faith leader health counselling. The content of faith leader health counselling training should aim to increase faith leaders' confidence that church members will successfully change their health behaviours as a result of the health counselling and increase faith leaders' comfort in speaking with church members about health. Future research is needed to examine efficacious and effective dissemination methods such as the use of internet trainings, CD ROM materials and incorporating health counselling into seminary school. PMID- 23039833 TI - Introduction to special issue on Alzheimer's disease. PMID- 23039834 TI - Neonatal suppurative parotitis over the last 4 decades: report of three new cases and review. AB - BACKGROUND: Neonatal suppurative parotitis is a rare disease. Only 32 cases were reported in the English-language literature between 1970 and 2004. METHODS: We searched Medline for acute, neonatal, bacterial, suppurative, parotitis, facial, preauricular swelling starting from 1970, limiting our search to the English language literature. We reviewed all the reported cases together with three more managed in our department. RESULTS: We identified nine new cases since 2004. The total number of patients reviewed was 44, including our patients. Most of them were male (77%). The majority developed unilateral inflamed parotid swelling (77%) and exuded pus from the ipsilateral Stensen duct. Fever was seen in fewer than half of them (47%). Premature babies constituted a third of the patients. Staphylococcus aureus was the leading causative agent (61%). Most patients responded well to conservative treatment with antibiotics (77%). The most frequently used combination of antibiotics was an anti-staphylococcal agent with either an aminoglycoside or a third-generation cephalosporin. A minority required surgical drainage. No deaths were reported in the group studied after 1970. CONCLUSION: Neonatal suppurative parotitis is rare but easy to diagnose and if readily treated with appropriate antibiotics the outcome is excellent. PMID- 23039835 TI - Conceptual framework for performance assessment: competency, competence and performance in the context of assessments in healthcare--deciphering the terminology. AB - BACKGROUND: The definitions of performance, competence and competency are not very clear in the literature. The assessment of performance and the selection of tools for this purpose depend upon a deep understanding of each of the above terms and the factors influencing performance. AIM: In this article, we distinguish between competence and competency and explain the relationship of competence and performance in the light of the Dreyfus model of skills acquisition. We briefly critique the application of the principles described by Miller to the modern assessment tools and distinguish between assessment of actual performance in workplace settings and the observed performance, demonstrated by the candidates in the workplace or simulated settings. RESULTS: We describe a modification of the Dreyfus model applicable to assessments in healthcare and propose a new model for the assessment of performance and performance rating scale (PRS) based on this model. CONCLUSION: We propose that the use of adapted versions of this PRS will result in benchmarking of performance and allowing the candidates to track their progression of skills in various areas of clinical practice. PMID- 23039836 TI - Mini-CEX as a workplace-based assessment tool for interns in an emergency department--does cost outweigh value? AB - BACKGROUND: The mini-clinical evaluation exercise (mini-CEX) has been proposed as a method to address the deficiencies of in-training assessment for junior doctors. AIM: Our study aimed to determine the feasibility and value of adding mini-CEX assessments to the existing assessment processes for an intern cohort in the emergency department (ED). METHODS: Interns undertook four mini-CEX assessments with senior ED medical officers, in addition to their standard in training assessment processes. Assessment results and time taken to perform the mini-CEX assessments were recorded. Interns and assessors completed a survey regarding their perceptions of the mini-CEX assessment process. RESULTS: The total time taken for mini-CEX assessments during the study period was 36.51 h. If extrapolated over a year this would represent an additional direct cost to the ED of more than $A 80,000 per year. No additional interns were identified as underperforming through the addition of the mini-CEX. The mini-CEX assessment process was perceived as generally positive. Both interns and assessors felt that it provided a valid assessment of intern performance, and enabled timely and specific feedback. Significant practical difficulties in arranging and conducting mini-CEX assessments in the workplace were identified. CONCLUSION: There was a significant cost to the ED as a result of adding mini-CEX encounters to interns' performance assessment. No change in summative outcome occurred for this study cohort. PMID- 23039837 TI - Shunt survival after failed endoscopic treatment of hydrocephalus. AB - OBJECT: It is not known whether previous endoscopic third ventriculostomy (ETV) affects the risk of shunt failure. Different epochs of hydrocephalus treatment at the CURE Children's Hospital of Uganda (CCHU)-initially placing CSF shunts in all patients, then attempting ETV in all patients, and finally attempting ETV combined with choroid plexus cauterization (CPC) in all patients-provided the opportunity to assess whether prior endoscopic surgery affected shunt survival. METHODS: With appropriate institutional approvals, the authors reviewed the CCHU clinical database to identify 2329 patients treated for hydrocephalus from December 2000 to May 2007. Initial ventriculoperitoneal (VP) shunt placement was performed in 900 patients under one of three circumstances: 1) primary nonselective VP shunt placement with no endoscopy (255 patients); 2) VP shunt placement at the time of abandoned ETV attempt (with or without CPC) (370 patients); 3) VP shunt placement subsequent to a completed but failed ETV (with or without CPC) (275 patients). We analyzed time to shunt failure using the Kaplan-Meier method to construct survival curves, Cox proportional hazards regression modeling, and risk-adjusted analyses to account for possible confounding differences among these groups. RESULTS: Shunt failure occurred in 299 patients, and the mean duration of follow-up for the remaining 601 was 28.7 months (median 18.8, interquartile range 4.1-46.3). There was no significant difference in operative mortality (p = 0.07 by log-rank and p = 0.14 by Cox regression adjusted for age and hydrocephalus etiology) or shunt infection (p = 0.94, log-rank) among the 3 groups. There was no difference in shunt survival between patients treated with primary shunt placement and those who underwent shunt placement at the time of an abandoned ETV attempt (adjusted hazard ratio [HR] 1.14, 95% CI 0.86-1.51, p = 0.35). Those who underwent shunt placement after a completed but failed ETV (with or without CPC) had a lower risk of shunt failure (p = 0.008, log-rank), with a hazard ratio (adjusted for age at shunting and etiology) of 0.72 (95% CI 0.53-0.98), p = 0.03, compared with those who underwent primary shunt placement without endoscopy; but this was observed only in patients with postinfectious hydrocephalus (PIH) (adjusted HR 0.55, 95% CI 0.36-0.85, p = 0.007), and no effect was apparent for hydrocephalus of noninfectious etiologies (adjusted HR 0.98, 95% CI 0.64-1.50, p = 0.92). Improved shunt survival after failed ETV in the PIH group may be an artifact of selection arising from the inherent heterogeneity of ventricular damage within that group, or a consequence of the timing of shunt placement. The anticipated benefit of CPC in preventing future ventricular catheter obstruction was not observed. CONCLUSIONS: A paradigm for infant hydrocephalus involving intention to treat by ETV with or without CPC had no adverse effect on mortality or on subsequent shunt survival or infection risk. This study failed to demonstrate a positive effect of prior ETV or CPC on shunt survival. PMID- 23039838 TI - Evaluation of salvage techniques for infected baclofen pumps in pediatric patients with cerebral palsy. AB - OBJECT: Intrathecal baclofen therapy has been used successfully for intractable spasticity in children with cerebral palsy. Infections are rare, but they are potentially life threatening if complicated by bacteremia or meningitis. Treatment without removal of the system is desirable if it can be done safely and effectively. METHODS: The Authors reviewed the records of 207 patients ranging from 3 to 18 years of age with cerebral palsy who underwent placement or revision of a baclofen pump. They identified 38 patients with suspected or documented infectious complications. Initial attempts were made to eradicate infection with the devices in situ in all patients. Methods and effectiveness of pump salvage were evaluated. RESULTS: Of the 38 patients identified, 13 (34.2%) had documented infections; 11 had deep wound/pocket empyemas and 2 had meningitis. Eight patients with deep wound infections received intravenous antibiotics alone. All required pump explantation. The remaining 3 patients underwent a washout procedure as well; the infection was cured in 1 patient. Both patients with meningitis received intravenous and intrathecal antibiotics, and both required device explantation. In addition, 25 patients (65.8%) had excessive or increasing wound erythema. No objective criteria to document a superficial infection were present. The wounds were considered suspicious and were managed with serial examinations and oral antibiotics. The erythema resolved in 24 of the 25 patients. CONCLUSIONS: In general, observation, wound care, and oral antibiotics are sufficient for wounds that are suspicious for superficial infection. For deep seated infection, antibiotic therapy alone is generally insufficient and explantation is required. Washout procedures can be considered, but failures are common. PMID- 23039839 TI - Familial nonsyndromic craniosynostosis with specific deformity of the cranium. AB - An otherwise healthy, developmentally normal 3-week-old male infant presented with complex multisuture craniosynostosis involving the metopic suture and bilateral coronal sutures with frontal prominence and hypotelorism. Frontal craniectomy and bilateral frontoorbital advancement remodeling were performed at the age of 5 months. The postoperative course was uneventful. The child's development was normal up to 8 months after the operation. His father and grandfather had similar specific deformities of the cranium, but no anomaly of the extremities was found, and conversation suggested that their intelligence was normal, excluding the possibility of syndromic craniosynostosis. A DNA analysis revealed large-scale copy number polymorphism of chromosome 4 in the patient and his family, which may include the phenotype of the cranium. Neither FGFR mutation nor absence of a TWIST1 mutation in the sequence from 291 to 1087, which includes DNA binding, Helix1, Loop, and Helix2, was identified. The patient apparently had a rare case of familial nonsyndromic craniosynostosis. The authors plan further genomic analysis of this family and long-term observation of the craniofacial deformity of this patient. PMID- 23039840 TI - Editorial: Endoscopic third ventriculostomy. PMID- 23039841 TI - Neurological deterioration after foramen magnum decompression for Chiari malformation type I: old or new pathology? AB - OBJECT: Decompression of the foramen magnum is widely accepted as the procedure of choice for patients with Chiari malformation Type I (CM-I). This study was undertaken to determine the mechanisms responsible for neurological deterioration after foramen magnum decompression and the results of secondary interventions. METHODS: Between 1987 and 2010, 559 patients with CM-I presented, 107 of whom had already undergone a foramen magnum decompression, which included a syrinx shunt in 27 patients. Forty patients who were neurologically stable did not undergo another operation. Sixty-seven patients with progressive symptoms received a recommendation for surgery, which was refused by 16 patients, while 51 patients underwent a total of 61 secondary operations. Hospital and outpatient records, radiographic studies, and intraoperative images were analyzed. Additional follow up information was obtained by telephone calls and questionnaires. Short-term results were determined after 3 and 12 months, and long-term outcomes were evaluated using Kaplan-Meier statistics. RESULTS: Sixty-one secondary operations were performed after a foramen magnum decompression. Of these 61 operations, 15 involved spinal pathologies not related to the foramen magnum (spinal group), while 46 operations were required for a foramen magnum issue (foramen magnum group). Except for occipital pain and swallowing disturbances, the clinical course was comparable in both groups. In the spinal group, 5 syrinx shunt catheters were removed because of nerve root irritations or spinal cord tethering. Eight patients underwent a total of 10 operations on their cervical spine for radiculopathies or a myelopathy. No permanent surgical morbidity occurred in this group. In the foramen magnum group, 1 patient required a ventriculoperitoneal shunt for hydrocephalus 7 months after decompression. The remaining 45 secondary interventions were foramen magnum revisions, of which 10 were combined with craniocervical fusion. Intraoperatively, arachnoid scarring with obstruction of the foramen of Magendie was the most common finding. Complication rates for foramen magnum revisions were similar to first decompressions, whereas permanent surgical morbidity was higher at 8.9%. Postoperative clinical improvements were marginal in both surgical groups. With the exception of 1 patient who underwent syrinx catheter removal and had a history of postoperative meningitis, all patients in the spinal group were able to be stabilized neurologically. Long-term results in the foramen magnum group revealed clinical stabilizations in 66% for at least 5 years. CONCLUSIONS: Neurological deterioration in patients after a foramen magnum decompression for CM-I may be related to new spinal pathologies, craniocervical instability, or recurrent CSF flow obstruction at the foramen magnum. Whereas surgery for spinal pathologies is regularly followed by clinical stabilization, the rate of long term success for foramen magnum revisions was limited to 66% for 5 years due to severe arachnoid scarring in a significant proportion of these patients. Therefore, foramen magnum revisions should be restricted to patients with progressive symptoms. PMID- 23039842 TI - Institutional care versus home care for the elderly in a rural area: cost comparison in rural Japan. AB - INTRODUCTION: The rise in institutional care costs, such as that associated with care in chronic hospitals or nursing homes, is a serious social concern in Japan, and this is particularly so in rural areas which are more rapidly aging than others. This has led to a proposal to reduce costs by deinstitutionalizing the disabled elderly. However, the actual financial benefit of deinstitutionalizing the disabled elderly is unclear. OBJECTIVE: To examine the effectiveness of deinstitutionalizing the disabled elderly with the aim of cost reduction. METHODS: This study utilized a cross-sectional design and complete census survey. The participants were 139 residents of a rural town in Hokkaido who were institutionalized as of 1 July 2007, and whose Care Needs Levels were classified according to Long-Term Care Insurance (LTCI) in Japan. Of these, 87 participants were considered candidates for deinstitutionalization. Participants who were considered unable to stay alone at home, such as those with behavioral problems, at risk of falling, or in need of hospital medical care, were excluded. Data were collected on institutional care costs, and an original questionnaire was distributed asking institutional staff about participant characteristics and physical function levels. Existing costs were collected and costs were calculated if participants were discharged from institutions to their homes. RESULTS: Approximately 20% of participants lived alone, and 80% had a severe disability. The estimated costs of discharging patients to their homes were higher than existing institutional care costs for 98% of participants. The gap in cost tended to be greater in patients with higher care needs. CONCLUSION: The deinstitutionalization of disabled elderly is not an effective measure to help reduce healthcare costs in rural areas of Japan. PMID- 23039843 TI - Structure and properties of Fe(n), Fe(n)-, and Fe(n)+ clusters, n = 7-20. AB - The electronic and geometrical structures of the Fe(n), Fe(n)(-), and Fe(n)(+) series (n = 7-20) are studied using all-electron density functional theory with the generalized gradient approximation. Equilibria of the geometrical configurations of the lowest total energy states in all three series are found to be similar except for Fe(9)(-), Fe(9)(+), Fe(10)(-), Fe(10)(+), Fe(15)(-), and Fe(19)(+). Our computed ionization energies of the neutrals, vertical electron detachment energies, and energies of Fe atom abstraction are in good agreement with experiment. It is found that the one-electron model corresponding to the change in the total magnetic moment of +/-1.0MU(B) due to either attachment or detachment of an electron is valid in most cases. The exceptions are Fe(4)(+), Fe(10)(-), Fe(10)(+), Fe(12)(-), Fe(13)(+), and Fe(14)(+), where the change in the total magnetic moment is +3MU(B) (Fe(10)(-) and Fe(12)(-)), -3MU(B) (Fe(4)(+), Fe(11)(+), and Fe(14)(+)), and -9MU(B) (Fe(13)(+)). The reason for an anomalously large quenching of the total spin magnetic moment in Fe(13)(+) is explained. Our computed total spin magnetic moments per atom match the recent experimental values within the experimental uncertainty bars. PMID- 23039845 TI - Cutaneous strongyloidiasis: direct finding of worms on skin potassium hydroxide examination. PMID- 23039844 TI - Molecular adaptation and resilience of the insect's nuclear receptor USP. AB - BACKGROUND: The maintenance of biological systems requires plasticity and robustness. The function of the ecdysone receptor, a heterodimer composed of the nuclear receptors ECR (NR1H1) and USP (NR2B4), was maintained in insects despite a dramatic divergence that occurred during the emergence of Mecopterida. This receptor is therefore a good model to study the evolution of plasticity. We tested the hypothesis that selection has shaped the Ligand-Binding Domain (LBD) of USP during evolution of Mecopterida. RESULTS: We isolated usp and cox1 in several species of Drosophilidae, Tenebrionidae and Blattaria and estimated non synonymous/synonymous rate ratios using maximum-likelihood methods and codon based substitution models. Although the usp sequences were mainly under negative selection, we detected relaxation at residues located on the surface of the LBD within Mecopterida families. Using branch-site models, we also detected changes in selective constraints along three successive branches of the Mecopterida evolution. Residues located at the bottom of the ligand-binding pocket (LBP) underwent strong positive selection during the emergence of Mecopterida. This change is correlated with the acquisition of a large LBP filled by phospholipids that probably allowed the stabilisation of the new Mecopterida structure. Later, when the two subgroups of Mecopterida (Amphiesmenoptera: Lepidoptera, Trichoptera; Antliophora: Diptera, Mecoptera, Siphonaptera) diverged, the same positions became under purifying selection. Similarly, several positions of the heterodimerisation interface experienced positive selection during the emergence of Mecopterida, rapidly followed by a phase of constrained evolution. An enlargement of the heterodimerisation surface is specific for Mecopterida and was associated with a reinforcement of the obligatory partnership between ECR and USP, at the expense of homodimerisation. CONCLUSIONS: In order to explain the episodic mode of evolution of USP, we propose a model in which the molecular adaptation of this protein is seen as a process of resilience for the maintenance of the ecdysone receptor functionality. PMID- 23039846 TI - Crossing the threshold: gene flow, dominance and the critical level of standing genetic variation required for adaptation to novel environments. AB - Genetic architecture plays an important role in the process of adaptation to novel environments. One example is the role of allelic dominance, where advantageous recessive mutations have a lower probability of fixation than advantageous dominant mutations. This classic observation, termed 'Haldane's sieve', has been well explored theoretically for single isolated populations adapting to new selective regimes. However, the role of dominance is less well understood for peripheral populations adapting to novel environments in the face of recurrent and maladaptive gene flow. Here, we use a combination of analytical approximations and individual-based simulations to explore how dominance influences the likelihood of adaptation to novel peripheral environments. We demonstrate that in the face of recurrent maladaptive gene flow, recessive alleles can fuel adaptation only when their frequency exceeds a critical threshold within the ancestral range. PMID- 23039847 TI - Program planners' perspectives of promotora roles, recruitment, and selection. AB - OBJECTIVE: Program planners work with promotoras (the Spanish term for female community health workers) to reduce health disparities among underserved populations. Based on the Role-Outcomes Linkage Evaluation Model for Community Health Workers (ROLES) conceptual model, we explored how program planners conceptualized the promotora role and the approaches and strategies they used to recruit, select, and sustain promotoras. DESIGN: We conducted semi-structured, in depth interviews with a purposive convenience sample of 24 program planners, program coordinators, promotora recruiters, research principal investigators, and other individuals who worked closely with promotoras on United States-based health programs for Hispanic women (ages 18 and older). RESULTS: Planners conceptualized the promotora role based on their personal experiences and their understanding of the underlying philosophical tenets of the promotora approach. Recruitment and selection methods reflected planners' conceptualizations and experiences of promotoras as paid staff or volunteers. Participants described a variety of program planning and implementation methods. They focused on sustainability of the programs, the intended health behavior changes or activities, and the individual promotoras. CONCLUSION: To strengthen health programs employing the promotora delivery model, job descriptions should delineate role expectations and boundaries and better guide promotora evaluations. We suggest including additional components such as information on funding sources, program type and delivery, and sustainability outcomes to enhance the ROLES conceptual model. The expanded model can be used to guide program planners in the planning, implementing, and evaluating of promotora health programs. PMID- 23039848 TI - A novel wheat alpha-amylase inhibitor gene, TaHPS, significantly improves the salt and drought tolerance of transgenic Arabidopsis. AB - On the basis of microarray analyses of the salt-tolerant wheat mutant RH8706-49, a previously unreported salt-induced gene, designated as TaHPS [Triticum aestivum hypothetical (HPS)-like protein], was cloned. Real-time quantitative polymerase chain reaction analyses showed that expression of the gene was induced by abscisic acid, salt and drought. The encoded protein was found to be localized mainly in the plasma membranes. Transgenic Arabidopsis plants overexpressing TaHPS were more tolerant to salt and drought stresses than non-transgenic wild type (WT) plants. Under salt stress, the root cells of the transgenic plants secreted more Na+ and guard cells took up more Ca2+ ions. Compared with wild-type plants, TaHPS-expressing transgenic plants showed significantly lower amylase activity and glucose and malic acid levels. Our results showed that the expression of TaHPS inhibited amylase activity, which subsequently led to a closure of stomatal apertures and thus improved plant tolerance to salt and drought. PMID- 23039849 TI - The space of togetherness--a caring encounter. AB - Encounters in relation to the nurse-patient relationship are often discussed within nursing and caring literature without a reflection on the actual meaning of the concept. Assuming that an encounter is essential for nursing care, this article seeks to create a deeper understanding of the concept through a hermeneutic approach to texts by the philosophers Buber and Marcel. Presence, recognition, availability and mutuality seem to be essential prerequisites for an encounter. As these prerequisites are fulfilled within and between human beings who encounter each other, it is possible to speak of a space of togetherness, a mutual existence, where life's mystery shines forth and caring is realized. The challenge lies in creating these encounters within nursing care. PMID- 23039850 TI - Synthesis and evaluation of thiouracil derivatives as dipeptidyl peptidase IV inhibitors. AB - A series of thiouracil derivatives were designed, synthesized and screened for in vitro inhibition of dipeptidyl peptidase IV. The SAR study indicated the influence of substituted chemical modifications on thiouracil scaffold. Compounds 8 (IC(50) = 0.32 MUM), 9 (IC(50) = 0.29 MUM), and 12 (IC(50) = 0.25 MUM) showed excellent dipeptidyl peptidase IV inhibition having heterocyclic substituted piperazine with acetamide linker resulted as most potent dipeptidyl peptidase IV inhibitors among all the compounds screened. Single dose (10 mg/kg) of the compounds 8, 9, and 12 significantly reduced glucose excursion during oral glucose tolerance test in streptozotocin-induced diabetic rat model. The present study on substituted thiouracil derivatives shows good-to-moderate inhibitory potential of dipeptidyl peptidase IV enzyme. PMID- 23039851 TI - The benefit of early treatment without rescreening in women with a history of gestational diabetes. AB - OBJECTIVE: In this center, women with a history of gestational diabetes (GDM) are treated without rescreening from early pregnancy in any subsequent pregnancies, commencing with a low glycemic diet and insulin if and when indicated. The objective of this study was to see if this practice reduced the incidence of macrosomia compared with the index pregnancy. METHOD: The analysis was confined to women who required insulin in the subsequent pregnancy. RESULTS: Among 369 women who were prospectively identified with a history of previous GDM, 95 required insulin - the study cohort. Insulin treatment was commenced at an earlier gestation in the subsequent pregnancy. The incidence of macrosomia was significantly less in the subsequent pregnancy in the group of women who required insulin in both pregnancies (p = 0.02). CONCLUSION: This data suggests early treatment is of benefit to this high-risk group in the reduction of macrosomia. PMID- 23039852 TI - A novel method for overexpression of peroxisome proliferator-activated receptor gamma in megakaryocyte and platelet microparticles achieves transcellular signaling. AB - BACKGROUND: Microparticles are submicrometer vesicles that contain RNA and protein derived from their parent cells. Platelet and megakaryocyte microparticles represent 80% of circulating microparticles, and their numbers are elevated in diseases such as cancer and type 2 diabetes. The ability of microparticles to transport protein, lipid and RNA to target cells, as a means of transcellular communication, remains poorly understood. Determining the influence that microparticles have on circulating cells is essential for understanding their role in health and in disease. OBJECTIVES: To develop a novel approach to modify the composition of platelet microparticles, and understand how such changes impact their transcellular communication. METHODS: This novel model utilizes a lentiviral technology to alter the transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) content of megakaryoblastic cell lines and primary megakaryocytes, and also the protein composition of generated platelets and microparticles. The subsequent microparticles were isolated and added to target cells for assessment of uptake and resultant signaling events. RESULTS: We successfully engineered microparticles to contain green fluorescent protein and elevated levels of PPARgamma. We found that these altered microparticles could be internalized by the monocytic cell line THP-1 and primary human microvascular endothelial cells. Importantly, microparticle delivered PPARgamma was shown to increase the expression of fatty acid-binding protein 4 (FABP4), which is a known PPARgamma target gene in THP-1 cells. CONCLUSION: This proof-of-concept modification of megakaryocyte, platelet and microparticle composition and subsequent change in target cell physiology is an important new tool to address transcellular communication of microparticles. PMID- 23039853 TI - Oxygen intercalation under graphene on Ir(111): energetics, kinetics, and the role of graphene edges. AB - Using X-ray photoemission spectroscopy (XPS) and scanning tunneling microscopy (STM) we resolve the temperature-, time-, and flake size-dependent intercalation phases of oxygen underneath graphene on Ir(111) formed upon exposure to molecular oxygen. Through the applied pressure of molecular oxygen the atomic oxygen created on the bare Ir terraces is driven underneath graphene flakes. The importance of substrate steps and of the unbinding of graphene flake edges from the substrate for the intercalation is identified. With the use of CO titration to selectively remove oxygen from the bare Ir terraces the energetics of intercalation is uncovered. Cluster decoration techniques are used as an efficient tool to visualize intercalation processes in real space. PMID- 23039854 TI - Anisotropic nanocrystal dissolution observation by in situ transmission electron microscopy. AB - In this study, some keys in the knowledge of nanocrystals dissolving by the direct phenomenon observations are provided through in situ transmission electron microscopy experiments. The new characteristic of anisotropic nanoparticles dissolving is discussed and correlated with the evolution of the crystal to reach a minimum surface free energy (Gibbs-Wulff theorem), which has an impact on the nanocrystal ripening models. The process whereby the ripening occurs was identified and correlated to the adparticle motion. PMID- 23039855 TI - Compliance with children's television food advertising regulations in Australia. AB - BACKGROUND: The objective of this study was to assess the effectiveness of the Australian co-regulatory system in limiting children's exposure to unhealthy television food advertising by measuring compliance with mandatory and voluntary regulations. An audit was conducted on food and beverage television advertisements broadcast in five major Australian cities during children's programming time from 1st September 2010 to 31st October 2010. The data were assessed against mandatory and voluntary advertising regulations, the information contained in an industry report of breaches, and the Australian Guide to Healthy Eating. RESULTS: During the two months of data collection there were a total of 951 breaches of the combined regulations. This included 619 breaches of the mandatory regulations (CTS) and 332 breaches of the voluntary regulations (RCMI and QSRI). Almost 83% of all food and beverages advertised during children's programming times were for foods classified as 'Extras' in the Australian Guide to Healthy Eating. There were also breaches in relation to the amount of advertising repetition and the use of promotional appeals such as premium offers, competitions, and endorsements by popular children's characters. The self regulatory systems were found to have flaws in their reporting and there were errors in the Australian Food and Grocery Council's compliance report. CONCLUSIONS: This audit suggests that current advertising regulations are inadequate. Regulations need to be closely monitored and more tightly enforced to protect children from advertisements for unhealthy foods. PMID- 23039856 TI - Plasma citrulline may be a good marker of intestinal functions in intestinal dysfunction. AB - BACKGROUND: Plasma citrulline has been reported to be a good indicator of intestinal functional volume in patients with intestinal dysfunction. We reconfirmed the facts and also investigated the dynamic changes of plasma citrulline in acute-phase patients with intestinal dysfunction. METHODS: We measured plasma citrulline in six patients with intestinal dysfunction who were in the acute and chronic phase for more than 6 months. RESULTS: Four patients out of six could be withdrawn from total parenteral nutrition, and their plasma citrulline level dynamically changed according to their intestinal states and finally increased up to 15 nmol/mL. Two patients, who could not be withdrawn from parenteral nutrition, showed very low levels of plasma citrulline throughout the treatment course (under 15 nmol/mL). CONCLUSION: The cut-off level of plasma citrulline indicating permanent intestinal dysfunction may be 15 nmol/mL in our data. In the acute phase, plasma citrulline changed dynamically according to the intestinal state and may be a good indicator of fluctuating intestinal functions. Thus, although only a few patients were enrolled in this study, plasma citrulline may be a good indicator of stable-state as well as acute-unstable-state intestinal functions. PMID- 23039858 TI - Essential role of an unknown gene aziU3 in the production of antitumor antibiotic azinomycin B verified by utilizing optimized genetic manipulation systems for Streptomyces sahachiroi. AB - Streptomyces sahachiroi ATCC 33158 produces the potent antitumor antibiotic azinomycin B, which is featured with a set of unusual functionalized moieties. However, the genetic analyses of azinomycin B biosynthetic pathway are hampered by the low efficiency of S. sahachiroi genetic manipulation. In this study, we developed two efficient DNA transfer systems for S. sahachiroi ATCC 33158 by optimizing a variety of parameters known to affect intergeneric conjugation and protoplast transformation. High efficiencies of 4 * 10(2) transformants per MUg DNA and 2.47 * 10(-4) conjugants per recipient were achieved when using the integrative vector pJTU2554. With the use of these improved genetic manipulation systems, aziU3 was discovered to play a key role in the biosynthesis of azinomycin B. In-frame deletion and complementation experiments demonstrated clearly that aziU3 is essential for azinomycin B biosynthesis. Changing the native promoter and insertion of an additional aziU3 gene copy resulted in two mutant strains over-producing azinomycin B. Real-time PCR verified that overexpression of aziU3 significantly improved the azinomycin B production in these mutant strains. PMID- 23039857 TI - Compound I is the reactive intermediate in the first monooxygenation step during conversion of cholesterol to pregnenolone by cytochrome P450scc: EPR/ENDOR/cryoreduction/annealing studies. AB - Cytochrome P450scc (CYP11A1) catalyzes conversion of cholesterol (CH) to pregnenolone, the precursor to all steroid hormones. This process proceeds via three sequential monooxygenation reactions: two stereospecific hydroxylations with formation first of 22R-hydroxycholesterol (22-HC) and then 20alpha,22R dihydroxycholesterol (20,22-DHC), followed by C20-C22 bond cleavage. Herein we have employed EPR and ENDOR spectroscopy to characterize the intermediates in the first hydroxylation step by 77 K radiolytic one-electron cryoreduction and subsequent annealing of the ternary oxy-cytochrome P450scc-cholesterol complex. This approach is fully validated by the demonstration that the cryoreduced ternary complex of oxy-P450scc-CH is catalytically competent and hydroxylates cholesterol to form 22-HC with no detectable formation of 20-HC, just as occurs under physiological conditions. Cryoreduction of the ternary complex trapped at 77 K produces predominantly the hydroperoxy-ferriheme P450scc intermediate, along with a minor fraction of peroxo-ferriheme intermediate that converts into a new hydroperoxo-ferriheme species at 145 K. This behavior reveals that the distal pocket of the parent oxy-P450scc-cholesterol complex exhibits an efficient proton delivery network, with an ordered water molecule H-bonded to the distal oxygen of the dioxygen ligand. During annealing of the hydroperoxy-ferric P450scc intermediates at 185 K, they convert to the primary product complex in which CH has been converted to 22-HC. In this process, the hydroperoxy-ferric intermediate decays with a large solvent kinetic isotope effect, as expected when proton delivery to the terminal O leads to formation of Compound I (Cpd I). (1)H ENDOR measurements of the primary product formed in deuterated solvent show that the heme Fe(III) is coordinated to the 22R-O(1)H of 22-HC, where the (1)H is derived from substrate and exchanges to D after annealing at higher temperatures. These observations establish that Cpd I is the agent that hydroxylates CH, rather than the hydroperoxy-ferric heme. PMID- 23039859 TI - Empathy of medical students and personality: evidence from the Five-Factor Model. AB - The main aim of this study was to test hypothetical associations between personality dimensions and empathy scores in medical students. The Portuguese version of NEO-FFI was administered in order to characterize participants in terms of five personality traits: Neuroticism, Extraversion, Agreeableness, Openness to Experience, and Conscientiousness. Self-reported empathy measures were obtained with the Portuguese version of the Jefferson Scale of Physician Empathy (JSPE-spv), a Likert-type questionnaire specifically developed for administration in health sciences settings that measures domains, such as compassionate care and perspective taking. Correlation analysis, multivariate analysis of covariance, and logistic regression analysis were conducted. The results confirmed positive associations between agreeableness, openness to experience and empathy, and did not support our hypothesis of negative associations between neuroticism and empathy. It is suggested that that the personality of students should be taken into account in programs to enhance empathy in undergraduate medical education. PMID- 23039860 TI - Perceived overprotection, instrumental support and rehabilitation use in elders with vision loss: a longitudinal perspective. AB - OBJECTIVES: This study's purpose was to investigate changes in perceived overprotection - a problematic aspect of close relationships - over time in relationship to instrumental support receipt and vision rehabilitation service use in a sample of older adults with vision impairment. METHODS: Participants were 584 older adults with chronic vision impairment who were interviewed three times over a 12-month period. Longitudinal data were analysed using a latent growth curve methodology to examine change over time in perceived overprotection and instrumental support in relation to vision rehabilitation service use. MAIN OUTCOME MEASURES: Self-reported levels of overprotection and receipt of instrumental support. Results. Over time perceived overprotection increased but not instrumental support. While perceived overprotection was positively associated with instrumental support initially, over time this relationship did not emerge. Perceived overprotection and instrumental support functioned as predictors of vision rehabilitation hours. However, over time vision rehabilitation service use did not influence these social supports. CONCLUSIONS: Perceived overprotection increases over time, yet this change is unaffected by rehabilitation service use and instrumental support. Both family members and elders need to be involved in the vision rehabilitation process and educated about how some level of independence can be regained. PMID- 23039861 TI - JBIR-129 and -139, cytotoxic 34-membered polyol macrolides of microbial origin. AB - New 34-membered polyol macrolides JBIR-129 (1) and JBIR-139 (2) were isolated from the culture of the terrestrial Streptomyces RK74. The planar structures of 1 and 2 were established on the basis of 1D and 2D NMR, ESI-TOF-MS, IR, and UV spectra. The relative configurations of the sugar units were determined by analyzing vicinal 1H-1H coupling constants and steric information. Both 1 and 2 showed cytotoxic activity against human ovarian adenocarcinoma SKOV-3 cells with IC50 values of 0.3 and 0.4 MUM, respectively. PMID- 23039862 TI - Evolution of transcriptional regulation in closely related bacteria. AB - BACKGROUND: The exponential growth of the number of fully sequenced genomes at varying taxonomic closeness allows one to characterize transcriptional regulation using comparative-genomics analysis instead of time-consuming experimental methods. A transcriptional regulatory unit consists of a transcription factor, its binding site and a regulated gene. These units constitute a graph which contains so-called "network motifs", subgraphs of a given structure. Here we consider genomes of closely related Enterobacteriales and estimate the fraction of conserved network motifs and sites as well as positions under selection in various types of non-coding regions. RESULTS: Using a newly developed technique, we found that the highest fraction of positions under selection, approximately 50%, was observed in synvergon spacers (between consecutive genes from the same strand), followed by ~45% in divergon spacers (common 5'-regions), and ~10% in convergon spacers (common 3'-regions). The fraction of selected positions in functional regions was higher, 60% in transcription factor-binding sites and ~45% in terminators and promoters. Small, but significant differences were observed between Escherichia coli and Salmonella enterica. This fraction is similar to the one observed in eukaryotes.The conservation of binding sites demonstrated some differences between types of regulatory units. In E. coli, strains the interactions of the type "local transcriptional factor gene" turned out to be more conserved in feed-forward loops (FFLs) compared to non-motif interactions. The coherent FFLs tend to be less conserved than the incoherent FFLs. A natural explanation is that the former imply functional redundancy. CONCLUSIONS: A naive hypothesis that FFL would be highly conserved turned out to be not entirely true: its conservation depends on its status in the transcriptional network and also from its usage. The fraction of positions under selection in intergenic regions of bacterial genomes is roughly similar to that of eukaryotes. Known regulatory sites explain 20+/-5% of selected positions. PMID- 23039864 TI - Deposition patterns of porcelain coatings obtained by electrophoretic deposition in acetone. Part 1. Voltage and time effect. AB - Homogeneous surface morphologies are of interest to form different functional coatings. In order to verify if these morphologies could be observed and controlled in an electrophoretic cell, voltage and time effect have been studied on the deposition patterns of porcelain particle on a stainless steel substrate. The suspensions were prepared at 1 wt % of porcelain submicronic particles using acetone as dispersing media. The EPD experiments were carried out at 400, 600, and 800 V at deposition times of 1, 15, 30, 45, and 60 s. The morphology of the particle deposit patterns were characterized by scanning electron microscopy. At 1 s, submicronic particles without any pattern formation were observed on the stainless steel substrate. At subsequent deposition times, the patterns evolved from worm like forms to ring like forms and finally to labyrinth-type agglomerates of particles depending on voltage and deposition times. At deposition times longer than 60 s, the particle deposit patterns were difficult to observe. The coatings obtained at deposition times below this value were subjected to thermal treatments at 900 degrees C for 2 h. The patterns were maintained after the sintering process, exhibiting dense, homogeneous, and crack free surface coatings. PMID- 23039865 TI - The economic and quality of life burden associated with Parkinson's disease: a focus on symptoms. AB - Parkinson's disease (PD) imposes a significant economic burden on the healthcare system. As the population continues to age and shifts to include a larger proportion of persons 65 years and older, the economic burden related to PD will continue to escalate. Clinicians should be mindful of striving for efficiency, making prudent choices, and allocating resources appropriately. The majority of treatment costs in PD are associated with advancing disease; specifically, the costs related to increasing need for care. Early identification of motor and non motor signs and symptoms of disease allows for earlier treatment. Through early treatment strategies, symptom control is improved and patients will likely have less need for care. This leads to improvements in quality of life (QoL) and functional independence and reduced caregiver burden and thus results in decreased costs. In addition, although research thus far has not clearly demonstrated the ability of an agent to provide disease modification, as new, potentially neuroprotective therapeutic interventions are developed and become available as treatment options, the recognition of early disease will be more important. If earlier treatment with neuroprotective agents leads to slowing of disease progression, the result may be less need for care and decreased costs for patients with PD. This may have a measurable impact by improving QoL measures for both the patient and caregivers. PMID- 23039863 TI - Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain. AB - Chemotherapy, especially if prolonged, disrupts attention, working memory and speed of processing in humans. Most cancer drugs that cross the blood-brain barrier also decrease adult neurogenesis. Because new neurons are generated in the hippocampus, this decrease may contribute to the deficits in working memory and related thought processes. The neurophysiological mechanisms that underlie these deficits are generally unknown. A possible mediator is hippocampal oscillatory activity within the theta range (3-12 Hz). Theta activity predicts and promotes efficient learning in healthy animals and humans. Here, we hypothesised that chemotherapy disrupts learning via decreases in hippocampal adult neurogenesis and theta activity. Temozolomide was administered to adult male Sprague-Dawley rats in a cyclic manner for several weeks. Treatment was followed by training with different types of eyeblink classical conditioning, a form of associative learning. Chemotherapy reduced both neurogenesis and endogenous theta activity, as well as disrupted learning and related theta-band responses to the conditioned stimulus. The detrimental effects of temozolomide only occurred after several weeks of treatment, and only on a task that requires the association of events across a temporal gap and not during training with temporally overlapping stimuli. Chemotherapy did not disrupt the memory for previously learned associations, a memory independent of (new neurons in) the hippocampus. In conclusion, prolonged systemic chemotherapy is associated with a decrease in hippocampal adult neurogenesis and theta activity that may explain the selective deficits in processes of learning that describe the 'chemobrain'. PMID- 23039866 TI - Improving outcomes through early diagnosis of Parkinson's disease. AB - Current diagnostic modalities in Parkinson's disease (PD) are limited by the fact that they identify PD by the presence of motor symptoms; by this point, over 60 percent of all dopamine neurons within specific regions of the basal ganglia may have been lost. Nonmotor symptoms manifest in PD long before motor symptoms, and the early presence of nonmotor symptoms offers an opportunity for early diagnosis and early treatment of PD, with consequent benefits to patient quality of life and potential treatment cost savings. Numerous different premotor symptoms have been identified; diminished olfactory function and REM behavioral sleep disorders (RBDs) may be particularly suitable for the purposes of early diagnosis. Olfactory testing, while in itself not specific for PD, has been shown to offer very high degrees of sensitivity and specificity in distinguishing PD from healthy controls and from other forms of parkinsonism, particularly when accompanied by other means of detection, such as sonography, motor symmetry evaluation, and magnetic resonance imaging (MRI)/diffusion tensor imaging. Biological biomarkers--including protein panels and autoantibody testing--have demonstrated excellent diagnostic capacity, and a recently identified 5-gene panel has been shown to have high specificity and sensitivity in distinguishing early PD from healthy controls and advanced PD. Increasingly sophisticated neuroimaging techniques are also proving capable of early PD detection and differentiation from other parkinsonian types. These recent developments in PD diagnosis underscore the necessity of rethinking what PD is and how, and when, it can be diagnosed. PMID- 23039867 TI - Early treatment of Parkinson's disease: opportunities for managed care. AB - The diagnosis and treatment of Parkinson's disease (PD) typically occur when the disease has already progressed to a relatively advanced stage in which motor symptoms are clearly evident and substantial neurophysiological damage has already taken place. Nonmotor symptoms, which account for a large proportion of PD symptoms, usually emerge much earlier and offer both an early indication for treatment and a therapeutic target. A growing body of data from the medical literature points to several critical advantages that may be associated with early therapeutic intervention in PD. The most evident benefit of early intervention is a reduction in symptoms, particularly dyskinesia, and the delay of levodopa initiation. Clinical trials suggest but have yet to conclusively demonstrate that early treatment can slow disease progression. Both the diminishment of symptoms and the potential for slowing disease progression have large implications for improving patient quality of life. The enormous direct costs associated with PD would also likely be reduced over the long term with earlier treatment. The great majority of costs attributable to PD occur when the disease is at its most advanced stage and when symptoms are most severe. An early treatment strategy that diminishes symptoms and that has the potential to slow disease progression could have a meaningful impact on PD expenditures. Adherence, too, must be taken into consideration, particularly since PD patients are generally poorly adherent to prescribed therapies, especially therapies with complex dosing schedules. Taking advantage of more convenient and adherencefriendly drug formulations may further help to improve outcomes and lower costs in PD. PMID- 23039868 TI - Development and validation of the self-management profile for type 2 diabetes (SMP-T2D). AB - BACKGROUND: This study evaluated the measurement properties of a newly developed instrument - the Self-Management Profile for Type 2 Diabetes (SMP-T2D). METHODS: The 18-item SMP-T2D assesses 12 constructs: level and perceived ease of performance in five self-care domains (blood glucose monitoring, medication taking, healthy eating, being physically active, and coping), and two global constructs (ease of weight management, confidence with ability to manage diabetes). Validation analyses were based on two studies involving 240 patients with T2D, Study 1 (Clinicaltrials.gov #NCT00637273) with SMP-T2D administration supplemented by SMP-T2D retest one week later, and Study 2 (Clinical trials.gov #NCT00877890) with SMP-T2D administration supplemented by 24-week SMP-T2D follow up after medication change. Validation included clinical indicators and measures of patient reported quality of life, psychological well-being and treatment outcomes. RESULTS: All multi-item SMP-T2D measures showed acceptable internal consistency (alphas = 0.71 to 0.87); ten measures had test-retest reliability >0.75. Correlations among SMP-T2D measures and between SMP-T2D measures and validation measures, which were as hypothesized, provided evidence of convergent and discriminant validity. Scores for six SMP-T2D measures improved significantly during Study 2. Multiple regression analysis showed independent associations between change in SMP-T2D measures and change in trial outcomes from baseline to end-of-study. CONCLUSIONS: Two studies provide preliminary evidence regarding the reliability, validity and responsiveness of the SMP-T2D. Further research on the utility of the instrument is needed. PMID- 23039870 TI - The role of zinc in the prevention of diabetic cardiomyopathy and nephropathy. AB - Zinc (Zn) is one of the essential trace elements and has numerous physiological functions. Zn acts as an antioxidant and also as a part of other antioxidant related proteins, such as metallothionein (MT) and Zn-copper superoxide dismutase. Zn deficiency often occurs in patients with diabetes. Therefore, the effect of Zn deficiency or Zn supplementation on diabetes-induced cardiac and renal pathogeneses has been explored. Diabetes was induced by streptozotocin (STZ) in mice and rats. Zn deficiency was induced by chronic treatment of diabetic mice with Zn chelator N,N,N,N-Tetrakis(2-pyridylmethyl)-1,2 ethylenediamine (TPEN) for 4 months. For Zn supplementation study, diabetic mice or rats were treated with Zn for 3 months. Inflammation, fibrosis, and histopathological changes in the heart and kidney of these diabetic mice and rats were examined by western blotting assay, immunohistochemical and fluorescent staining. Results showed that diabetes induced cardiac and renal oxidative damage, inflammation and fibrosis, which were reversed by Zn supplementation that also induced cardiac and renal MT synthesis. Furthermore, Zn deficiency was found to significantly enhance the renal damage induced by diabetes. Several clinical observations also support the preventive effect of Zn in the development of diabetic cardiomyopathy and nephropathy. Therefore, Zn plays an important role in the protection of the heart and kidney against diabetes-induced oxidative damage, inflammation, and fibrosis. These studies suggested that diabetic patients should be monitored and treated for Zn deficiency to avoid the acceleration of diabetes induced cardiac and renal injury. PMID- 23039871 TI - Bayesian tests of measurement invariance. AB - Random item effects models provide a natural framework for the exploration of violations of measurement invariance without the need for anchor items. Within the random item effects modelling framework, Bayesian tests (Bayes factor, deviance information criterion) are proposed which enable multiple marginal invariance hypotheses to be tested simultaneously. The performance of the tests is evaluated with a simulation study which shows that the tests have high power and low Type I error rate. Data from the European Social Survey are used to test for measurement invariance of attitude towards immigrant items and to show that background information can be used to explain cross-national variation in item functioning. PMID- 23039872 TI - Ethnic minority women's experience of maternity services in England. AB - OBJECTIVES: Provision for ethnic minority groups has been acknowledged as integral to good maternity care in England and ethnicity has been highlighted as an indicator of both poorer clinical outcomes and poorer experiences. Improving outcomes and services is dependent on understanding women's interaction with both service delivery and provision. The aim of this study was to explore Black and minority ethnic (BME) women's experiences of contemporary maternity care in England. DESIGN: A UK-wide survey which investigated core aspects of maternity care sought the views of BME women about their experiences. A random sample of women were selected by the Office for National Statistics from birth registration in England and invited to complete a questionnaire three months after the birth. In a secondary analysis, text responses to open-ended questions about their maternity care were analysed using thematic analysis. RESULTS: Sixty per cent of the 368 women who self-identified as BME responded with open text. Themes that emerged related to 'feeling cared for,' with subthemes of 'expectations of care' and 'policies, rules and organisational pressures'; 'staff attitudes and communication' with sub-themes of 'please believe me,' 'hospital as a safe place,' 'choices denied' and 'being sensitive and supportive would help,' and 'ethnicity and culture' with sub-themes of 'stereotyping' and 'improving the quality of care.' CONCLUSION: The findings highlight issues affecting the quality of maternity care that BME women in England receive. Many issues are not unique to BME women; however, the findings reflect some seemingly enduring issues and coherence with other wider international findings, particularly in relation to post-natal care and staff attitudes. Actually being cared for and supported across their child-bearing experience are needs that women themselves identified as critical for care providers to recognise and respond to. The failures of care provision described should inform the development of services. PMID- 23039873 TI - Relation between lipoprotein subfractions and TSH levels in the cardiovascular risk among women with subclinical hypothyroidism. AB - OBJECTIVE: Subclinical hypothyroidism (SCH) is a common condition associated with increased cardiovascular risk. A standard treatment is yet to be established, as there is no consensus on the TSH cut-off values which should be used as indicators. Thus, the aim of this study was to assess cardiovascular risk in patients with SCH and to differentiate it according to TSH levels. DESIGN: This was an observational study conducted in an academic medical centre. PATIENTS: The study population consisted of 95 middle-aged women recently diagnosed with SCH and 65 euthyroid controls. MEASUREMENTS: We measured anthropometric parameters, lipid cardiovascular risk markers and lipoprotein subclasses of HDL and LDL. RESULTS: Patients with SCH exhibited a significant increase in triglycerides and atherogenic index of plasma and a significant reduction in HDL-cholesterol with respect to the control group after adjusted by age and BMI. A similar lipid profile was observed in both SCH groups. However, patients with TSH levels higher than 10 mIU/l showed a significant reduction in LDL particle size, which was associated with a higher prevalence of atherogenic pattern B. CONCLUSIONS: Our findings indicate that cardiovascular risk is affected in patients with TSH levels over 10 mIU/l, who have a lipid profile characteristic of atherogenic dyslipidemia. PMID- 23039869 TI - BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and beta-amyloid production in Alzheimer's disease. AB - Alzheimer's disease (AD) is a complex age-related pathology, the etiology of which has not been firmly delineated. Among various histological stigmata, AD affected brains display several cellular dysfunctions reflecting enhanced oxidative stress, inflammation process and calcium homeostasis disturbance. Most of these alterations are directly or indirectly linked to amyloid beta-peptides (Abeta), the production, molecular nature and biophysical properties of which likely conditions the degenerative process. It is particularly noticeable that, in a reverse control process, the above-described cellular dysfunctions alter Abeta peptides levels. beta-secretase betaAPP-cleaving enzyme 1 (BACE1) is a key molecular contributor of this cross-talk. This enzyme is responsible for the primary cleavage generating the N-terminus of "full length" Abeta peptides and is also transcriptionally induced by several cellular stresses. This review summarizes data linking brain insults to AD-like pathology and documents the key role of BACE1 at the cross-road of a vicious cycle contributing to Abeta production. PMID- 23039874 TI - Body mass index and risk of total and type-specific stroke in Chinese adults: results from a longitudinal study in China. AB - BACKGROUND: The prevalence rate of overweight and obese has been escalating over the past two decades in China. Even so, the association between obesity and stroke still remains unclear to some extent. AIMS: The aim of this study was to elucidate the association between body mass index and stroke in a large Chinese population cohort. METHODS: A cohort of 26 607 Chinese people, aged over 35 years, was investigated in 1987. Baseline information of body weight and height was used to calculate BMI (weight in kilograms divided by height in meters squared, kg/m(2) ). Cox proportional hazards model was fitted to estimate hazard ratios of stroke adjusted for age, educational level, smoking and alcohol consumption. RESULTS: The 11-year follow-up revealed (241 149 person-years) a total of 1108 stroke events (614 ischemic, 451 hemorrhagic, and 44 undefined stroke). Body mass index >= 30.0 was an independent risk factor for stroke both in men and women. Compared with normal weight, hazard ratios for total stroke were 0.74 in men underweight (95% confidence interval: 0.53~1.03), 1.63 overweight (95% confidence interval: 1.35~1.96), and 2.20 with obesity (95% confidence interval: 1.47~3.30); and with ischemic stroke, hazard ratios were 0.52 in those underweight (95% confidence interval: 0.30~0.89), 2.08 overweight (95% confidence interval: 1.65~2.62), and 3.80 with obesity (95% confidence interval: 2.47~5.86). In women, the corresponding hazard ratios for total stroke were 0.79 underweight (95% confidence interval: 0.58~1.07), 1.42 overweight (95% confidence interval: 1.16~1.73), and 1.57 with obesity (95% confidence interval: 1.06~2.31); and for those with ischemic stroke, 0.92 underweight (95% confidence interval: 0.59~1.43), 1.90 overweight (95% confidence interval: 1.44~2.50), and 2.42 with obesity (95% confidence interval: 1.50~3.93). There appeared an evident dose-response relationship between body mass index and the risk of developing stroke, which still appeared, however, adjusted low for hypertension, diabetes, and heart disease. Decreased risk for stroke in the leanest group was confined to men only. No association was found between body mass index and hemorrhagic stroke in both genders. CONCLUSIONS: Our data suggest that body mass index was an independent risk factor for total and ischemic stroke but not for hemorrhagic stroke in both genders. Association between body mass index and stroke was extremely mediated by hypertension, diabetes, and heart disease. Decreased risk for the leanest group was confined to men. PMID- 23039875 TI - Re-mating across years and intralineage polygyny are associated with greater than expected levels of inbreeding in wild red deer. AB - The interaction between philopatry and nonrandom mating has important consequences for the genetic structure of populations, influencing co-ancestry within social groups but also inbreeding. Here, using genetic paternity data, we describe mating patterns in a wild population of red deer (Cervus elaphus) which are associated with marked consequences for co-ancestry and inbreeding in the population. Around a fifth of females mate with a male with whom they have mated previously, and further, females frequently mate with a male with whom a female relative has also mated (intralineage polygyny). Both of these phenomena occur more than expected under random mating. Using simulations, we demonstrate that temporal and spatial factors, as well as skew in male breeding success, are important in promoting both re-mating behaviours and intralineage polygyny. However, the information modelled was not sufficient to explain the extent to which these behaviours occurred. We show that re-mating and intralineage polygyny are associated with increased pairwise relatedness in the population and a rise in average inbreeding coefficients. In particular, the latter resulted from a correlation between male relatedness and rutting location, with related males being more likely to rut in proximity to one another. These patterns, alongside their consequences for the genetic structure of the population, have rarely been documented in wild polygynous mammals, yet they have important implications for our understanding of genetic structure, inbreeding avoidance and dispersal in such systems. PMID- 23039876 TI - Involvement of plasma membrane peroxidases and oxylipin pathway in the recovery from phytoplasma disease in apple (Malus domestica). AB - Apple trees (Malus domestica Borkh.) may be affected by apple proliferation (AP), caused by 'Candidatus Phytoplasma mali'. Some plants can spontaneously recover from the disease, which implies the disappearance of symptoms through a phenomenon known as recovery. In this article it is shown that NAD(P)H peroxidases of leaf plasma membrane-enriched fractions exhibited a higher activity in samples from both AP-diseased and recovered plants. In addition, an increase in endogenous SA was characteristic of the symptomatic plants, since its content increased in samples obtained from diseased apple trees. In agreement, phenylalanine ammonia lyase (PAL) activity, a key enzyme of the phenylpropanoid pathway, was increased too. Jasmonic acid (JA) increased only during recovery, in a phase subsequent to the pathological state, and in concomitance to a decline of salicylic acid (SA). Oxylipin pathway, responsible for JA synthesis, was not induced during the development of AP-disease, but it appeared to be stimulated when the recovery occurred. Accordingly, lipoxygenase (LOX) activity, detected in plasma membrane-enriched fractions, showed an increase in apple leaves obtained from recovered plants. This enhancement was paralleled by an increase of hydroperoxide lyase (HPL) activity, detected in leaf microsomes, albeit the latter enzyme was activated in either the disease or recovery conditions. Hence, a reciprocal antagonism between SA- and JA-pathways could be suggested as an effective mechanism by which apple plants react to phytoplasma invasions, thereby providing a suitable defense response leading to the establishment of the recovery phenomenon. PMID- 23039877 TI - VKORC1 mutations detected in patients resistant to vitamin K antagonists are not all associated with a resistant VKOR activity. AB - BACKGROUND: The VKORC1 gene codes for the VKORC1 enzyme, which is responsible for the reduction of vitamin K epoxide into vitamin K. VKORC1 enzyme is the target of vitamin K antagonists (VKA). Twenty-eight rare single mutations in the VKORC1 coding sequence have been reported from resistant patients receiving unusually high doses of VKA to achieve therapeutic anticoagulation. OBJECTIVES: It has been suggested that these mutations are responsible for the resistant phenotype, while biochemical consequences of these mutations on the VKORC1 enzyme have not yet been evaluated. Therefore, the aim of this study was to investigate the causality of the VKORC1 mutations in the resistance phenotype. METHODS: Wild-type VKORC1 and its spontaneous mutants were expressed in Pichia pastoris and susceptibility to VKA was assessed by the in vitro determination of kinetic and inhibition constants. RESULTS AND CONCLUSIONS: The in vitro analysis revealed that six mutations only (A26P, A41S, V54L, H68Y, I123N and Y139H) were associated with increase in K(i) , suggesting their involvement in the resistance phenotype observed in patients. A41S and H68Y led to selective resistance, respectively, to indane-1,3-dione and 4-hydroxycoumarine derivatives. The other mutations did not increase the K(i). Furthermore, 10 mutations (S52L, S52W, W59L, W59R, V66M, V66G, G71A, N77S, N77T and L128R) led to an almost complete loss of activity. These results suggest the existence of other resistance mechanisms. PMID- 23039878 TI - Prevalence of Demodex folliculorum and Demodex brevis in childhood malnutrition and malignancy. AB - BACKGROUND: Hair follicle mites, Demodex folliculorum and Demodex brevis, are known to accompany immune-deficiency states, however no study so far has investigated their presence in malnutrition. In this study we aimed to determine the prevalence of those mites in childhood malnutrition, malignancy and risk factors. METHODS: One hundred children with malnutrition, 31 children with malignancy and 63 children without any chronic disease and infection were included in this study. History, physical examination, anthropometric measurements and routine laboratory findings were recorded. Demodex spp. were investigated by standard superficial skin biopsies. RESULTS: Demodex was found in 25 patients (25%), 10 patients (32.3%), and one patient (1.6%) among malnutrition, malignancy, and control groups, respectively (P = 0.001). By using multilogistic regression binary method, it was found that malnutrition, malignancy and low socioeconomic level increased the risk 17.37 times (P = 0.006), 27.29 times (P = 0.002), and 2.3 times (P = 0.037), respectively. Of 22 children who were evaluated after 6 months, 13 (59.1%) were negative for Demodex. In 11 (84.6%) of those 13, nutritional status was improved. CONCLUSION: Demodex was detected in approximately in one-quarter and one-third of children with malnutrition and malignancy, respectively. Eliminating the cause of immunosuppression, such as poor nutritional status, seems also to be an effective method for eliminating Demodex. PMID- 23039879 TI - High-performance plastic platinized counter electrode via photoplatinization technique for flexible dye-sensitized solar cells. AB - A photoplatinization technique was proposed to deposit Pt on a thin TiO(2) layer modified indium tin oxide-coated polyethylene naphthalate (ITO/PEN) substrate at low temperature (about 50 degrees C after 1 h of UV irradiation) for the first time. The fabrication process includes coating and hydrolyzing the tetra-n-butyl titanate to form a TiO(2)-modified layer and the photoplatinization of the modified substrate in H(2)PtCl(6)/2-propanol precursor solution under UV irradiation. The obtained platinized electrodes were used as counter electrodes (CE) for flexible dye-sensitized solar cells (FDSCs). The well-optimized platinized electrode showed high optical transmittance, up to 76.5% between 400 and 800 nm (T(av)), and the charge transfer resistance (R(ct)) was as low as 0.66 Omega cm(2). A series of characterizations also demonstrated the outstanding chemical/electrochemical durability and mechanical stability of the platinized electrode. The FDSCs with TiO(2)/Ti photoanodes and the obtained CEs achieved a power conversion efficiency (PCE) up to 8.12% under rear-side irradiation (AM 1.5 illumination, 100 mW cm(-2)). The obtained CEs were also employed in all-plastic bifacial DSCs. When irradiated from the rear side, the bifacial FDSC yielded a PCE of 6.26%, which approached 90% that of front-side irradiation (6.97%). Our study revealed that, apart from serving as a functional layer for deposition of Pt, the thin TiO(2) layer modification on ITO/PEN substrates also played an important role in improving the transparency and the mechanical properties of the CE. The effect of the thickness of the TiO(2) layer for Pt coating on the performance of the CE was also investigated. PMID- 23039880 TI - Participation of HIV prevention programs among men who have sex with men in two cities of China--a mixed method study. AB - BACKGROUND: Although various HIV prevention programs targeting men who have sex with men (MSM) are operating in China, whether and how these programs are being utilized is unclear. This study explores participation of HIV prevention programs and influencing factors among MSM in two cities in China. METHODS: This is a mixed-method study conducted in Beijing and Chongqing. A qualitative study consisting of in-depth interviews with 54 MSM, 11 key informants, and 8 focus group discussions, a cross-sectional survey using respondent-driven sampling among 998 MSM were conducted in 2009 and 2010 respectively to elicit information on MSM's perception and utilization of HIV prevention programs. Qualitative findings were integrated with quantitative multivariate factors to explain the quantitative findings. RESULTS: Fifty-six percent of MSM in Chongqing and 75.1% in Beijing ever participated in at least one type of HIV prevention program (P=0.001). Factors related to participation in HIV prevention programs included age, ethnicity, income, HIV risk perception, living with boyfriend, living in urban area, size of MSM social network, having talked about HIV status with partners, and knowing someone who is HIV positive. Reasons why MSM did not participate in HIV prevention programs included logistical concerns like limited time for participation and distance to services; program content and delivery issues such as perceived low quality services and distrust of providers; and, cultural issues like HIV-related stigma and low risk perception. CONCLUSIONS: The study shows that there is much room for improvement in reaching MSM in China. HIV prevention programs targeting MSM in China may need to be more comprehensive and incorporate the cultural, logistic and HIV-related needs of the population in order to effectively reach and affect this population's risk for HIV. PMID- 23039881 TI - Measurement of thyroid stimulating immunoglobulins using a novel thyroid stimulating hormone receptor-guanine nucleotide-binding protein, (GNAS) fusion bioassay. AB - Hyperthyroidism, defined by overproduction of thyroid hormones, has a 2-3% prevalence in the population. The most common form of hyperthyroidism is Graves' disease. A diagnostic biomarker for Graves' disease is the presence of immunoglobulins which bind to, and stimulate, the thyroid stimulating hormone receptor (TSHR), a G-protein coupled receptor (GPCR). We hypothesized that the ectopically expressed TSHR gene in a thyroid stimulating immunoglobulin (TSI) assay could be engineered to increase the accumulation of the GPCR pathway second messenger, cyclic AMP (cAMP), the molecule measured in the assay as a marker for pathway activation. An ectopically expressing TSHR-mutant guanine nucleotide binding protein, (GNAS) Chinese hamster ovary (CHO) cell clone was constructed using standard molecular biology techniques. After incubation of the new clone with sera containing various levels of TSI, GPCR pathway activation was then quantified by measuring cAMP accumulation in the clone. The clone, together with a NaCl-free cell assay buffer containing 5% polyethylene glycol (PEG)6000, was tested against 56 Graves' patients, 27 toxic thyroid nodule patients and 119 normal patients. Using receiver operating characteristic analysis, when comparing normal with Graves' sera, the assay yielded a sensitivity of 93%, a specificity of 99% and an efficiency of 98%. Total complex precision (within-run, across runs and across days), presented as a percentage coefficient of variation, was found to be 7.8, 8.7 and 7.6% for low, medium and high TSI responding serum, respectively. We conclude that the performance of the new TSI assay provides sensitive detection of TSI, allowing for accurate, early detection of Graves' disease. PMID- 23039882 TI - Skin- and gut-homing molecules on human circulating gammadelta T cells and their dysregulation in inflammatory bowel disease. AB - Changes in phenotype and function of gammadelta T cells have been reported in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Dysregulation of lymphocyte migration plays a key role in IBD pathogenesis; however, data on migratory properties of gammadelta T cells are scarce. Human circulating gammadelta T cells from healthy controls (n = 27), patients with active CD (n = 15), active UC (n = 14) or cutaneous manifestations of IBD (n = 2) were characterized by flow cytometry. Circulating gammadelta T cells in healthy controls were CD3(hi) and expressed CD45RO. They expressed gut homing molecule beta7 but not gut-homing molecule corresponding chemokine receptors (CCR)9, or skin-homing molecules cutaneous lymphocyte-associated antigen (CLA) and CCR4, despite conventional T cells containing populations expressing these molecules. CCR9 expression was increased on gammadelta T cells in CD and UC, while skin-homing CLA was expressed aberrantly on gammadelta T cells in patients with cutaneous manifestations of IBD. Lower levels of CD3 expression were found on gammadelta T cells in CD but not in UC, and a lower proportion of gammadelta T cells expressed CD45RO in CD and UC. Enhanced expression of gut-homing molecules on circulating gammadelta T cells in IBD and skin-homing molecules in cutaneous manifestations of IBD may be of clinical relevance. PMID- 23039883 TI - Innate and adaptive immune gene expression profiles as biomarkers in human type 1 diabetes. AB - The mRNA levels of a set of immune-related genes were analysed with peripheral blood samples from at-risk, new-onset and long-term type 1 diabetes (T1D) patients, in comparison to those from healthy controls. The selected set includes T lymphocyte genes [CD3G and cytotoxic T lymphocyte-associated antigen 4 (CTLA4)], B lymphocyte genes (CD19 and CD20) and myeloid cell-related genes [CD11b, Toll-like receptor (TLR)-9, arginase (ARG1)]. Also included is a subset of the S100 family members that has been documented recently as regulatory elements of innate immunity. Samples from patients with long-term T1D had a reduced level of mRNA for most of selected innate and adaptive immune genes. No such reduction was detected in samples collected from at-risk or new-onset T1D patients. Analyses of regulatory gene expression ratios revealed a dynamic disproportion of CTLA4 versus CD3G expression in samples from at-risk, new-onset and long-term T1D patients. These changes could serve as immunological biomarkers for the status of the immune system during T1D progression and therapeutic interventions. PMID- 23039884 TI - Antibody combination therapy targeting CD25, CD70 and CD8 reduces islet inflammation and improves glycaemia in diabetic mice. AB - Destruction of pancreatic islets in type 1 diabetes is caused by infiltrating, primed and activated T cells. In a clinical setting this autoimmune process is already in an advanced stage before intervention therapy can be administered. Therefore, an effective intervention needs to reduce islet inflammation and preserve any remaining islet function. In this study we have investigated the role of targeting activated T cells in reversing autoimmune diabetes. A combination therapy consisting of CD25-, CD70- and CD8-specific monoclonal antibodies was administered to non-obese diabetic (NOD) mice with either new onset diabetes or with advanced diabetes. In NOD mice with new-onset diabetes antibody combination treatment reversed hyperglycaemia and achieved long-term protection from diabetes (blood glucose <13.9 mmol/l) in >50% of mice. In contrast, in the control, untreated group blood glucose levels continued to increase and none of the mice were protected from diabetes (P < 0.0001). Starting therapy early when hyperglycaemia was relatively mild proved critical, as the mice with advanced diabetes showed less efficient control of blood glucose and shorter life span. Histological analysis (insulitis score) showed islet preservation and reduced immune infiltration in all treated groups, compared to their controls. In conclusion, antibody combination therapy that targets CD25, CD70 and CD8 results in decreased islet infiltration and improved blood glucose levels in NOD mice with established diabetes. PMID- 23039885 TI - FOXP3, CBLB and ITCH gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4(+) CD25(high) T cells in multiple sclerosis. AB - Expression of the forkhead box protein 3 (FoxP3) transcription factor is regulated by the E3 ubiquitin ligases Itch and Cbl-b and induces regulatory activity CD4(+) CD25(high) T cells. Treatment with interferon (IFN)-beta enhances regulatory T cell activity in multiple sclerosis (MS). We studied the phenotype of CD4(+) CD25(high) T cells in MS by flow cytometry and its relationship with expression of the FOXP3, ITCH and CBLB genes. We found that untreated MS patients had lower cell surface expression of cytotoxic T lymphocyte antigen 4 (CTLA-4) on CD4(+) CD25(high) T cells and higher intracellular CTLA-4 expression than healthy controls. Cell surface expression of CTLA-4 on CD4(+) CD25(high) T cells correlated with expression of FOXP3 mRNA in untreated patients and increased significantly with time from most recent injection in patients treated with IFN-beta. FOXP3 mRNA expression correlated with CBLB and ITCH and T helper type 2 cytokine mRNA expression in MS patients. These data link expression of FOXP3, CBLB and ITCH mRNA and CTLA-4 expression on the surface of CD4(+) CD25(high) T cell in MS. We hypothesize that this may reflect alterations in the inhibitory effect of CTLA-4 or in regulatory T cell function. PMID- 23039886 TI - Treatment with Fms-like tyrosine kinase 3 ligand reverses lung dendritic cell immunoparalysis and ameliorates zymosan-induced secondary lung injury in mice. AB - Depletion and dysfunction of dendritic cells in the lung can induce local immunoparalysis, which often leads to multiple organ dysfunction syndrome (MODS) associated mortality. A therapeutic strategy that reverses this immunoparalysis is required. In the present study, we examined the effects of in vivo Fms-like tyrosine kinase 3 ligand (Flt3L) treatment on zymosan (zym)-induced secondary lung injury and dendritic cell (DC) immunoparalysis. BALBc mice were divided randomly into four groups (20/group): (1) sham [intraperitoneal (i.p.) saline] + vehicle [subcutaneous (s.c.) 0.01% mouse serum albumin]; (2) sham + Flt3L (s.c.); (3) zym (i.p.) + vehicle; and (4) zym + Flt3L. Injections were for 9 consecutive days; 12 days later we examined: survival rate (monitored for 12 days); lung tissue histopathology (haematoxylin and eosin staining); plasma indices of lung function (pH, PaO(2) , PaCO(2) , HCO(3) (-) ); DC subsets in lung tissue; and lung DCs production of interleukin (IL)-12p70 and IL-10. Zym administration resulted in increased mortality associated with significant lung histopathological changes and abnormal blood gas indices; however, these pathological changes were ameliorated by Flt3L treatment. Zym injections also resulted in significant reductions in DC subsets recovered from lungs [CD11c(+) major histocompatibility complex (MHC)-II/I-A(d+) , CD11c(+) CD11b(+) and CD11c(+) B220(+) ]. Importantly, in-vivo Flt3L treatment reversed these trends for DC immunoparalysis by increasing the percentages of recovered DC subsets concomitant with increased DC production of IL-12 p70 and decreased IL-10 production. These results suggest that Flt3L may have therapeutic potential for reversing DC immunoparalysis and ameliorating lung injury secondary to MODS. PMID- 23039887 TI - Optimizing dendritic cell vaccine for immunotherapy in multiple myeloma: tumour lysates are more potent tumour antigens than idiotype protein to promote anti tumour immunity. AB - Dendritic cells (DCs) are the most potent antigen-presenting cells and are the mediators of T cell immunity. Many investigators have explored the potential of using DCs as a vaccine for tumour-derived antigens in immunotherapy of B cell malignancies, and the results have been disappointing. To search for better tumour antigens to improve the efficacy of DC-based immunotherapy in myeloma, we evaluated and compared the efficacy of the vaccination of DCs pulsed with idiotype (Id) or tumour lysate in the 5TGM1 myeloma mouse model. Our results showed that Id- or tumour lysate-pulsed DC vaccines protected mice efficiently against developing myeloma, retarded tumour growth, induced tumour regression against established tumour and protected surviving mice from tumour rechallenge. The therapeutic responses were associated with an induction of strong humoral immune responses, including anti-Id or anti-lysate antibodies, and cellular immune responses including myeloma-specific CD8(+) cytotoxic T lymphocytes, CD4(+) type 1 T helper cells and memory T cells in mice receiving Id- or tumour lysate-pulsed DC vaccines. In addition, our studies showed that tumour lysate pulsed DCs were more potent vaccines than the Id-pulsed DC vaccines to promote anti-tumour immunity in the model. This information will be important for improving the strategies of DC-based immunotherapy for patients with myeloma and other B cell tumours. PMID- 23039888 TI - Elevated neutrophil elastase and acrolein-protein adducts are associated with W256 regression. AB - The involvement of granulocytes in immune response against cancer is not well understood. Depending on the cytokine milieu in which they act and on their oxidative burst, granulocytes may play either an inhibitory or stimulatory role in tumour growth. Unsaturated fatty acids, essential components of cellular membranes and storage lipids, are susceptible to granulocyte-derived reactive oxygen species (ROS). ROS can induce lipid peroxidation (LPO) resulting in the destruction of biomembranes. Thus, murine W256 tumour progressing and tumour regressing animal models were used to study the involvement of plasma inflammatory mediators and oxidative burst of circulating granulocytes in malignant destruction and detrimental tumour growth. The involvement of LPO derived aldehydes (i.e. acrolein, 4-hydroxy-2-nonenal and malondialdehyde) and myeloperoxidase (MPO) appearance in the granulocyte anti-cancer response were further evaluated. The results obtained revealed a significant increase in neutrophil elastase in animals with regressing tumour. Furthermore, the presence of MPO in tumour microenvironment was accompanied by the formation of acrolein only 5 h after tumour transplantation and its presence increased during tumour regression. Later, at an early stage of tumour regression, the presence of other LPO-derived aldehydes were also observed. The results obtained suggest that elevated neutrophil elastase and initiation of LPO may play an important role in the tumour development leading to tumour regression. PMID- 23039889 TI - Normal ageing is associated with an increase in Th2 cells, MCP-1 (CCL1) and RANTES (CCL5), with differences in sCD40L and PDGF-AA between sexes. AB - We have observed T helper type 2 (Th2) polarization of systemic immunity in patients with metastatic malignant melanoma. We hypothesized that similar changes in systemic immunity occur with ageing and may be permissive for the development of melanoma. We analysed the peripheral blood of 389 healthy blood donors. All subjects were profiled for peripheral blood T cell and B cell subsets, and 58 of these subjects were profiled for antigen-specific cytotoxic T cell subsets [cytomegalovirus (CMV), influenza and melanoma antigen recognized by T cells 1 (MART-1)]. Ninety-five separate healthy subjects underwent profiling of 42 plasma cytokines. Ageing was associated positively with CD4(+) CD294(+) Th2 cells, and associated negatively with CD3(+) T cells, cytotoxic T cells and T helper cells. Ageing was also associated negatively with CMV-, influenza- and MART-1-specific naive and CD8(+) T cells. There were significant increases in plasma monocyte chemotactic protein 1 (MCP-1) (CCL1) and regulated upon activation normal T cell expressed and secreted (RANTES) (CCL5) with age. We observed differences in cytokine profiles between males and females; specifically, women had higher levels of sCD40L and PDGF-AA. In summary, we demonstrated in healthy blood donors that ageing was associated with an increase in cellular Th2 bias and a decline in total numbers of T cells. Additionally, there was an increase in MCP-1 and RANTES with ageing. Women had higher levels of sCD40L and PDGF-AA than men. PMID- 23039890 TI - Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease. AB - To clarify the association between factors regulating DNA methylation and the prognosis of autoimmune thyroid diseases (AITDs), we genotyped single nucleotide polymorphisms in genes encoding DNA methyltransferase 1 (DNMT1), DNMT3A, DNMT3B, methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), which are enzymes essential for DNA methylation. Subjects for this study included 125 patients with Hashimoto's disease (HD), including 48 patients with severe HD and 49 patients with mild HD; 176 patients with Graves' disease (GD), including 79 patients with intractable GD and 47 patients with GD in remission; and 83 healthy volunteers (control subjects). The DNMT1+32204GG genotype was more frequent in patients with intractable GD than in patients with GD in remission. Genomic DNA showed significantly lower levels of global methylation in individuals with the DNMT1+32204GG genotype than in those with the AA genotype. The MTRR+66AA genotype was observed to be more frequent in patients with severe HD than in those with mild HD. The DNMT1+14395A/G, DNMT3B-579G/T, MTHFR+677C/T and +1298A/C polymorphisms were not correlated with the development or prognosis of AITD. Our study indicates that the DNMT1+32204GG genotype correlates with DNA hypomethylation and with the intractability of GD, and that the MTRR+66AA genotype may correlate with the severity of HD. PMID- 23039891 TI - T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections. AB - Common variable immunodeficiency disorders (CVID) are a group of heterogeneous conditions that have in common primary failure of B cell function, although numerous T cell abnormalities have been described, including reduced proliferative response and reduced regulatory T cells. This study compared the T cell phenotype of CVID patients subdivided into clinical phenotypes as well as patients with partial antibody deficiencies [immunoglobulin (Ig)G subclass deficiency and selective IgA deficiency], X-linked agammaglobulinaemia (XLA) and healthy and disease controls. Absolute numbers of T cell subpopulations were measured by four-colour flow cytometry: naive T cells, central and effector memory and terminally differentiated (TEM) T cells, using CD45RA and CCR7 expression. Early, intermediate and late differentiation status of T cells was measured by CD27/CD28 expression. Putative follicular T cells, recent thymic emigrants and regulatory T cells were also assessed. Significant reduction in naive CD4 T cells, with reduced total CD4 and recent thymic emigrant numbers, was observed in CVID patients, most pronounced in those with autoimmune cytopenias or polyclonal lymphoproliferation. These findings suggest a lack of replenishment by new thymically derived cells. CD8 naive T cells were reduced in CVID patients, most significantly in the autoimmune cytopenia subgroup. There was a reduction in early differentiated CD4 and CD8 T cells and increased CD8 TEM in the CVID patients, particularly autoimmune cytopenia and polyclonal lymphoproliferation subgroups, suggesting a more activated T cell phenotype, due perhaps to an antigen-driven process. XLA patients had significantly reduced putative follicular T cells, which may depend on B cells for survival, while no significant alterations were observed in the T cells of those with IgG subclass deficiency or selective IgA deficiency. PMID- 23039892 TI - Dysregulated immunophenotypic attributes of plasmacytoid but not myeloid dendritic cells in HIV-1 infected individuals in the absence of highly active anti-retroviral therapy. AB - Dendritic cells (DC) in HIV-1-infected individuals are decreased and their dysfunction has been implicated in HIV-1 immunopathogenesis. The mechanism of their dysfunction remains unclear, thus we analysed the expression of membrane molecules associated with immune regulation and DC activation in myeloid (mDC) and plasmacytoid DC (pDC) in therapy-naive and highly active anti-retroviral therapy (HAART)-treated HIV-1(+) patients. DC from healthy controls, untreated HIV-1(+) and HAART-treated patients were assessed by flow cytometry for expression of: anergy and apoptosis inducing molecules [programmed death (PD)-1 and its ligands PD-L1 and PD-L2], inhibitory and regulatory T cell-inducing molecules [immunoglobulin-like transcript (ILT)-3 and ILT-4], interferon (IFN) alpha inhibitory receptor (ILT-7) and co-stimulatory molecules (CD80, CD83, and CD86). pDC from untreated HIV-1(+) patients expressed significantly lower levels of ILT-7 compared to healthy controls, while HAART-treated patients showed normal expression. pDC were also found to express moderately higher levels of PD-L1 and ILT-3 and lower levels of PD-L2 receptors in untreated patients compared to controls and HAART-treated patients. No significant changes were observed in mDC. There were no associations between the percentages and levels of expression of these molecules by pDC and viral load or CD4 T cell count. In conclusion, pDC but not mDC from HIV-1(+) patients with active viraemia display higher levels of apoptosis and T regulatory-inducing molecules and may be predisposed to chronically produce IFN-alpha through down-regulation of ILT-7. HAART restored normal expression levels of these receptors. PMID- 23039893 TI - Bead-size directed distribution of Pseudomonas aeruginosa results in distinct inflammatory response in a mouse model of chronic lung infection. AB - Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients is characterized by biofilms, tolerant to antibiotics and host responses. Instead, immune responses contribute to the tissue damage. However, this may depend on localization of infection in the upper conductive or in the peripheral respiratory zone. To study this we produced two distinct sizes of small alginate beads (SB) and large beads (LB) containing P. aeruginosa. In total, 175 BALB/c mice were infected with either SB or LB. At day 1 the quantitative bacteriology was higher in the SB group compared to the LB group (P < 0.003). For all time points smaller biofilms were identified by Alcian blue staining in the SB group (P < 0.003). Similarly, the area of the airways in which biofilms were identified were smaller (P < 0.0001). A shift from exclusively endobronchial to both parenchymal and endobronchial localization of inflammation from day 1 to days 2/3 (P < 0.05), as well as a faster resolution of inflammation at days 5/6, was observed in the SB group (P < 0.03). Finally, both the polymorphonuclear neutrophil leucocyte (PMN) mobilizer granulocyte colony-stimulating factor (G CSF) and chemoattractant macrophage inflammatory protein-2 (MIP-2) were increased at day 1 in the SB group (P < 0.0001). In conclusion, we have established a model enabling studies of host responses in different pulmonary zones. An effective recognition of and a more pronounced host response to infection in the peripheral zones, indicating that increased lung damage was demonstrated. Therefore, treatment of the chronic P. aeruginosa lung infection should be directed primarily at the peripheral lung zone by combined intravenous and inhalation antibiotic treatment. PMID- 23039894 TI - B cell activating factor (BAFF) in the natural history of chronic hepatitis C virus liver disease and mixed cryoglobulinaemia. AB - B cell activating factor (BAFF) plays a crucial role in the process of development, maturation and activation of B lymphocytes. Chronic hepatitis C virus (HCV) infection is characterized by multiple B cell disorders. It is a major cause of type II mixed cryoglobulinaemia (MC). We measured serum BAFF levels in several clinical situations to elucidate the potential role of BAFF in chronic HCV infection. We used a commercially available solid phase enzyme-linked immunosorbent assay. We estimated serum BAFF in stored sera from uninfected controls (n = 8), patients with chronic hepatitis B virus infection HBV (n = 5) and chronic HCV infection with (n = 16) and without mixed cryoglobulinaemia (n = 14). In two patients with HCV and MC we correlated BAFF with HCV RNA after pegylated interferon (peg-I). We correlated serum BAFF levels at baseline and at 12 weeks with treatment response: sustained virological response SVR (n = 5), non responders (n = 6) and relapsers (n = 2). Finally, we estimated BAFF levels after complete depletion of B cells with rituximab in patients with chronic HCV with MC (n = 3). Serum levels of BAFF were increased in chronic HCV with MC, but not in chronic HBV infection, suggesting an association between BAFF and cryoglobulinaemia. Peg-I increased BAFF levels in serum and this paralleled HCV RNA very closely. Serum BAFF levels at week 12 of therapy with peg-I and R were significantly higher in responders than non-responders. Finally, B cell depletion was associated with markedly increased levels of BAFF. PMID- 23039896 TI - Interactions between nitrate-reducing and sulfate-reducing bacteria coexisting in a hydrogen-fed biofilm. AB - To explore the relationships between denitrifying bacteria (DB) and sulfate reducing bacteria (SRB) in H(2)-fed biofilms, we used two H(2)-based membrane biofilm reactors (MBfRs) with or without restrictions on H(2) availability. DB and SRB compete for H(2) and space in the biofilm, and sulfate (SO(4)(2-)) reduction should be out-competed when H(2) is limiting inside the biofilm. With H(2) availability restricted, nitrate (NO(3)(-)) reduction was proportional to the H(2) pressure and was complete at a H(2) pressure of 3 atm; SO(4)(2-) reduction began at H(2) >= 3.4 atm. Without restriction on H(2) availability, NO(3)(-) was the preferred electron acceptor, and SO(4)(2-) was reduced only when the NO(3)(-) surface loading was <= 0.13 g N/m(2)-day. We assayed DB and SRB by quantitative polymerase chain reaction targeting the nitrite reductases and dissimilatory sulfite reductase, respectively. Whereas DB and SRB increased with higher H(2) pressures when H(2) availability was limiting, SRB did not decline with higher NO(3)(-) removal flux when H(2) availability was not limiting, even when SO(4)(2-) reduction was absent. The SRB trend reflects that the SRB's metabolic diversity allowed them to remain in the biofilm whether or not they were reducing SO(4)(2-). In all scenarios tested, the SRB were able to initiate strong SO(4)(2-) reduction only when competition for H(2) inside the biofilm was relieved by nearly complete removal of NO(3)(-). PMID- 23039897 TI - Categorization of nitrobenzenes for repeated dose toxicity based on adverse outcome pathways. AB - Adoption of the data-gap filling method for complex endpoints such as repeated dose toxicity (RDT) and reproductive/developmental toxicity is one of the most important issues affecting international chemical management at present. A categorization method based on adverse outcome pathways (AOPs) has recently been investigated for such complex endpoints. In this paper, we report results of the categorization of nitrobenzenes for RDT based on the AOPs obtained by analysing the detailed RDT test reports for 24 different nitrobenzenes already evaluated. In most RDT testing of nitrobenzenes without hydroxyl groups or acid groups, findings related to haemolytic anaemia and liver effects were observed at low dosages. It was, therefore, possible to assume common AOPs for haemolytic anaemia and liver effects induced by these nitrobenzenes. As a result, a group of nitrobenzenes was defined as a single category for both haemolytic anaemia and liver effects, respectively, based on these AOPs. PMID- 23039898 TI - Expenditures for medicaid patients treated with exenatide compared with other diabetes management regimens. AB - OBJECTIVE: To compare Medicaid spending among patients with type 2 diabetes mellitus (T2DM) receiving exenatide or other add-on therapies. STUDY DESIGN: Medicaid data in patients with T2DM were compared among those who initiated exenatide, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or basal insulin. Patients were on a regimen of metformin and/or sulfonylurea for 30 days and continued the next-line therapy for at least 90 days. METHODS: Total inpatient, outpatient, prescription, and total annual health expenditures were compared for 1 year following treatment initiation. Regression analyses were conducted to compare spending; analyses controlled for patient characteristics, year of initiation, and prior therapy. Propensity score matching was used to match patients receiving exenatide with those receiving other therapies, and analyses were repeated with matched cohorts. RESULTS: Of 23,966 eligible patients, 1345 initiated exenatide and 22,621 initiated other therapies. In the unmatched analysis, medical spending was significantly lower in those given exenatide compared with those given other therapies for inpatient ($1945 vs $3893), prescription ($4505 vs $5714), and total costs ($11,830 vs $15,459) (P <.01 for all); outpatient spending was not significantly different ($5380 vs $5853, P = .15). In the matched analysis (n = 1345 for exenatide, n = 1345 non exenatide), patients receiving exenatide had significantly lower spending in all 4 categories: inpatient ($1945 vs $4242), outpatient ($5380 vs $6826), prescription ($4505 vs $5878), and total ($11,830 vs $16,945) (P <.01 for all). CONCLUSION: Patients with T2DM receiving exenatide had lower annual Medicaid claims costs compared with patients receiving other therapies. PMID- 23039895 TI - Extracellular factors and immunosuppressive drugs influencing insulin secretion of murine islets. AB - Approximately 60% of transplanted islets undergo apoptosis within the first week post-transplantation into the liver attributed to poor engraftment, immune rejection and toxicity of immunosuppressive drugs. Understanding how extracellular matrix (ECM) components, immunosuppressive drugs and proinflammatory cytokines affect insulin secretion will contribute to an improved clinical outcome of islet transplantations. In this study, functional activity of isolated murine islets was measured by glucose-stimulated insulin secretion (GSIS) and by electrophysiological measurements using patch-clamp. Cultivating islets with soluble fibronectin or laminin, as opposed to with coated laminin, markedly increased GSIS. Addition of cyclosporin A reduced GSIS and suppressed glucose-induced spike activity. Tacrolimus affected neither GSIS nor spike activity, indicating a different mechanism. To evaluate the influence of proinflammatory cytokines, islets were incubated with interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha or with supernatants from cultured Kupffer cells, the main mediators of inflammation in the hepatic sinusoids. IL-1beta exerted a bimodal effect on insulin secretion, stimulating below 2 ng/ml and suppressing above 10 ng/ml. Soluble laminin in combination with a stimulatory IL 1beta concentration further increased insulin secretion by 20% compared to IL 1beta alone, while with high IL-1beta concentrations soluble laminin slightly attenuated GSIS inhibition. TNF-alpha alone did not affect GSIS, but with stimulatory IL-1beta concentrations completely abolished it. Similarly, supernatants derived from Kupffer cells exerted a bimodal effect on GSIS. Our data suggest that improved insulin secretion of transplanted islets could be achieved by including soluble laminin and low IL-1beta concentrations in the islet cultivation medium, and by a simultaneous inhibition of cytokine secretion from Kupffer cells. PMID- 23039899 TI - Circadian genes Period 1 and Period 2 in the nucleus accumbens regulate anxiety related behavior. AB - It has been suggested for some time that circadian rhythm abnormalities underlie the development of multiple psychiatric disorders. However, it is unclear how disruptions in individual circadian genes might regulate mood and anxiety. Here we found that mice lacking functional mPeriod 1 (mPer1) or mPeriod 2 (mPer2) individually did not have consistent behavioral abnormalities in measures of anxiety-related behavior. However, mice deficient in both mPer1 and mPer2 had an increase in levels of anxiety-like behavior in multiple measures. Moreover, we found that mPer1 and mPer2 expression was reduced in the nucleus accumbens (NAc) after exposure to chronic social defeat stress, a paradigm that led to increased anxiety-related behavior. Following social defeat, chronic treatment with fluoxetine normalized Per gene expression towards wild-type levels. Knockdown of both mPer1 and mPer2 expression via RNA interference specifically in the NAc led to a similar increase in anxiety-like behavior as seen in the mutant animals. Taken together, these results implicate the Per genes in the NAc in response to stress and the development of anxiety. PMID- 23039900 TI - Retinal proteome analysis in a mouse model of oxygen-induced retinopathy. AB - To identify proteins that are involved in the molecular mechanisms of oxygen induced retinopathy (OIR), a well-established model of blinding ischemic retinopathy, we quantitatively analyzed the retinal proteome in a mouse model of OIR. OIR was induced by exposing C57BL/6 mice on postnatal day 7 (P7) to 75% hyperoxia for 5 days, followed by 5 days in room air. Retinas from mice on P12 and P17, the hyperoxic and hypoxic phases, respectively, and control groups were examined using isobaric tags for relative and absolute quantitation (iTRAQ) and nano-LC-ESI-MS/MS. In total, 1422 retinal proteins were identified: 699 from the iTRAQ experiment and 1074 by nano-LC-ESI-MS/MS. Compared with control retinas in the iTRAQ study, OIR retinas upregulated and downregulated 21 and 17 proteins, respectively, in P17 retinas and 25 and 14 proteins, respectively, in P12 retinas. Of the differentially expressed proteins, the retinal expression of crystallin proteins, Muller cell-associated proteins, neurodegeneration associated proteins, and angiogenesis-associated proteins, such as 150-kDa oxygen regulated protein (ORP150), were analyzed. ORP150 colocalized to the neovascular tufts, and knockdown of ORP150 by siRNA decreased the levels of secreted VEGF in cultured retinal pigment epithelial cells. Moreover, intravitreal administration of siRNA targeting ORP150 significantly reduced the retinal neovascularization in OIR. In conclusion, our proteomic discovery method, coupled with targeted approaches, revealed many proteins that were differentially regulated in the mouse model of OIR. These proteins, including ORP150, are potential novel therapeutic targets for the treatment of proliferative ischemic retinopathy. PMID- 23039901 TI - Acute deterioration and death with necrotizing enteritis associated with Lawsonia intracellularis in 4 weanling horses. PMID- 23039902 TI - The importance of spleen, spleen iron, and splenectomy for determining total body iron load, ferrikinetics, and iron toxicity in thalassemia major patients. AB - The importance of spleen, spleen iron and splenectomy has been investigated in 28 male and 19 female beta-thalassemia major (beta-TauMU), adult patients. In one study, an increase from about five (615 g; 19.5 * 11.0 * 6.0 cm) to twenty (2030 g; 25.0 * 17.5 * 12.0 cm) times higher than the normal size and weight of spleen has been observed in twenty patients following splenectomy. In a second study, the mean size for the liver (19.4 cm, range 13.5-26.0 cm) and spleen (15.6 cm, range 7.0-21.0 cm) measured by magnetic resonance imaging (MRI) and by ultrasound imaging for spleen (15.1 cm, range 9.0-21.0 cm) of 16 patients indicated that on average the spleen is about 80% of the size of the liver. In the third study, comparison of the iron load using MRI T(2)* and iron grading of stained biopsies indicated that substantial but variable amounts of excess iron are stored in the spleen (0-40%) in addition to that in the liver. Following splenectomy, total body iron storage capacity is reduced, whereas serum ferritin (p = 0.0085) and iron concentration in other organs appears to increase despite the reduction in the rate of transfusions (p = 0.0001) and maintenance of hemoglobin levels (p = 0.1748). Spleen iron seems to be cleared faster than liver iron using effective chelation protocols. Spleen iron is a major constituent of the total body iron load in beta-TauMU patients and should be regularly monitored and targeted for chelation. Normalization of the body iron stores at an early age could maintain the spleen in near normal capacity and secondary effects such as cardiac and other complications could be avoided. PMID- 23039903 TI - Yellow is pale: the complications and challenges of late diagnosis of extrahepatic biliary atresia. AB - Extrahepatic biliary atresia classically presents in the neonatal period with jaundice and pale stools. The lack of bile pigment in stool can be unrecognised, delaying diagnosis and surgical treatment. Vitamin K is given at birth to reduce the risk of haemorrhagic disease of the newborn, but this may be inadequate to prevent the development of coagulopathy secondary to fat soluble vitamin malabsorption. We present the case of a 3 month old infant who presented with an intracerebral haemorrhage and coagulopathy thought to be secondary to fat malabsorption resulting from delayed diagnosis of extrahepatic biliary atresia. This was despite the perinatal administration of intramuscular vitamin K. His parents did not recognise the stool pallor as being abnormal. This case illustrates the importance of educating parents on the significance of pale stools, and also the risk of coagulopathy in extrahepatic biliary atresia despite perinatal intramuscular vitamin K. PMID- 23039904 TI - The stress signalling pathway nuclear factor E2-related factor 2 is activated in the liver of sows during lactation. AB - BACKGROUND: It has recently been shown that the lactation-induced inflammatory state in the liver of dairy cows is accompanied by activation of the nuclear factor E2-related factor 2 (Nrf2) pathway, which regulates the expression of antioxidant and cytoprotective genes and thereby protects tissues from inflammatory mediators and reactive oxygen species (ROS). The present study aimed to study whether the Nrf2 pathway is activated also in the liver of lactating sows. FINDINGS: Transcript levels of known Nrf2 target genes, UGT1A1 (encoding glucuronosyltransferase 1 family, polypeptide A1), HO-1 (encoding heme oxygenase 1), NQO1 (encoding NAD(P)H dehydrogenase, quinone 1), GPX1 (encoding glutathione peroxidase), PRDX6 (encoding peroxiredoxin 6), TXNRD1 (encoding thioredoxin reductase 1), and SOD (encoding superoxide dismutase), in the liver are significantly elevated (between 1.7 and 3.1 fold) in lactating sows compared to non-lactating sows. The inflammatory state in the liver was evidenced by the finding that transcript levels of genes encoding acute phase proteins, namely haptoglobin (HP), fibrinogen gamma (FGG), complement factor B (CFB), C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP), were significantly higher (2 to 8.7 fold) in lactating compared to non-lactating sows. CONCLUSIONS: The results of the present study indicate that the Nrf2 pathway in the liver of sows is activated during lactation. The activation of Nrf2 pathway during lactation in sows might be interpreted as a physiologic means to counteract the inflammatory process and to protect the liver against damage induced by inflammatory signals and ROS. PMID- 23039905 TI - Women's views on and adherence to low-molecular-weight heparin therapy during pregnancy and the puerperium. AB - BACKGROUND: Non-adherence to prescribed medication represents a significant factor associated with treatment failure. Pregnant women identified at risk of venous thromboembolism are increasingly being prescribed low-molecular-weight heparin (LMWH) during pregnancy and the puerperium. It is important to understand women's views on and adherence to LMWH during pregnancy and the puerperium, so that women gain maximum benefit from the treatment. OBJECTIVES: To monitor women's adherence to enoxaparin, when prescribed during pregnancy and the puerperium, and explore their beliefs about the enoxaparin therapy prescribed. PATIENTS/METHODS: A prospective cohort study involving 95 nullparous and multiparous women prescribed enoxaparin for recognized antenatal indications. Adherence to enoxaparin was assessed through self-completion of a diary, additionally verified through laboratory tests. An adapted beliefs about medication questionnaire was administered to women during their pregnancy. RESULTS: Women were highly adherent to enoxaparin: antenatally, mean percentage adherence 97.92%; postnatally, mean percentage adherence 93.37% (paired t-test, P = 0.000). In the cohort of women we followed, their perceived necessity for enoxaparin therapy outweighed any concerns they had regarding enoxaparin antenatally, necessity-concerns differential 2.20. In some women, however, this perceived necessity does decrease postnatally. CONCLUSIONS: Our results suggest that most women prescribed enoxaparin are highly adherent to their therapy during the antenatal period and that women's antenatal beliefs about enoxaparin are able to predict a decrease in postnatal adherence. Our results have important clinical implications, particularly when women are initiated on LMWH just during the postnatal period. PMID- 23039907 TI - Modeling biological activities of nanoparticles. AB - Products are increasingly incorporating nanomaterials, but we have a poor understanding of their adverse effects. To assess risk, regulatory authorities need more experimental testing of nanoparticles. Computational models play a complementary role in allowing rapid prediction of potential toxicities of new and modified nanomaterials. We generated quantitative, predictive models of cellular uptake and apoptosis induced by nanoparticles for several cell types. We illustrate the potential of computational methods to make a contribution to nanosafety. PMID- 23039906 TI - Evidence for 5S rDNA horizontal transfer in the toadfish Halobatrachus didactylus (Schneider, 1801) based on the analysis of three multigene families. AB - BACKGROUND: The Batrachoididae family is a group of marine teleosts that includes several species with more complicated physiological characteristics, such as their excretory, reproductive, cardiovascular and respiratory systems. Previous studies of the 5S rDNA gene family carried out in four species from the Western Atlantic showed two types of this gene in two species but only one in the other two, under processes of concerted evolution and birth-and-death evolution with purifying selection. Here we present results of the 5S rDNA and another two gene families in Halobatrachus didactylus, an Eastern Atlantic species, and draw evolutionary inferences regarding the gene families. In addition we have also mapped the genes on the chromosomes by two-colour fluorescence in situ hybridization (FISH). RESULTS: Two types of 5S rDNA were observed, named type alpha and type beta. Molecular analysis of the 5S rDNA indicates that H. didactylus does not share the non-transcribed spacer (NTS) sequences with four other species of the family; therefore, it must have evolved in isolation. Amplification with the type beta specific primers amplified a specific band in 9 specimens of H. didactylus and two of Sparus aurata. Both types showed regulatory regions and a secondary structure which mark them as functional genes. However, the U2 snRNA gene and the ITS-1 sequence showed one electrophoretic band and with one type of sequence. The U2 snRNA sequence was the most variable of the three multigene families studied. Results from two-colour FISH showed no co localization of the gene coding from three multigene families and provided the first map of the chromosomes of the species. CONCLUSIONS: A highly significant finding was observed in the analysis of the 5S rDNA, since two such distant species as H. didactylus and Sparus aurata share a 5S rDNA type. This 5S rDNA type has been detected in other species belonging to the Batrachoidiformes and Perciformes orders, but not in the Pleuronectiformes and Clupeiformes orders. Two hypotheses have been outlined: one is the possible vertical permanence of the shared type in some fish lineages, and the other is the possibility of a horizontal transference event between ancient species of the Perciformes and Batrachoidiformes orders. This finding opens a new perspective in fish evolution and in the knowledge of the dynamism of the 5S rDNA. Cytogenetic analysis allowed some evolutionary trends to be roughed out, such as the progressive change in the U2 snDNA and the organization of (GATA)n repeats, from dispersed to localized in one locus. The accumulation of (GATA)n repeats in one chromosome pair could be implicated in the evolution of a pair of proto-sex chromosomes. This possibility could situate H. didactylus as the most highly evolved of the Batrachoididae family in terms of sex chromosome biology. PMID- 23039908 TI - Extragastrointestinal stromal tumor of the mesoappendix: CT findings and a review of the literature. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are nonepithelial, mesenchymal neoplasms that rarely occur in children. CASE PRESENTATION: We present a unique case of a GIST that developed outside the gastrointestinal tract within the mesoappendix of a 6-year old boy. Computed tomography (CT) revealed a slightly lobulated, homogeneous soft-tissue mass, with marked contrast enhancement. CONCLUSION: This case study provides new insight into the CT appearance of extragastrointestinal stromal tumors. PMID- 23039910 TI - What is the best approach to the teenage patient presenting with nonclassical congenital adrenal hyperplasia: should we always treat with glucocorticoids? AB - Patients with Congenital adrenal hyperplasia due to partial deficiency in the enzyme 21-hydroxylase can present in childhood or adolescence with signs of adrenal androgen excess. Strategies to reduce the impact of androgen excess in females include cosmetic measures as well as antiandrogens and agents such as the combined oral contraceptive pill. Glucocorticoid may not be appropriate straightaway but can be introduced if other measures are ineffective or when pregnancy is planned. PMID- 23039909 TI - Neuropsychological test performance and cognitive reserve in healthy aging and the Alzheimer's disease spectrum: a theoretically driven factor analysis. AB - Accurate measurement of cognitive function is critical for understanding the disease course of Alzheimer's disease (AD). Detecting cognitive change over time can be confounded by level of premorbid intellectual function or cognitive reserve and lead to under- or over-diagnosis of cognitive impairment and AD. Statistical models of cognitive performance that include cognitive reserve can improve sensitivity to change and clinical efficacy. We used confirmatory factor analysis to test a four-factor model composed of memory/language, processing speed/executive function, attention, and cognitive reserve factors in a group of cognitively healthy older adults and a group of participants along the spectrum of amnestic mild cognitive impairment to AD (aMCI-AD). The model showed excellent fit for the control group (chi(2) = 100; df = 78; CFI = .962; RMSEA = .049) and adequate fit for the aMCI-AD group (chi(2) = 1750; df = 78; CFI = .932; RMSEA = .085). Although strict invariance criteria were not met, invariance testing to determine if factor structures are similar across groups yielded acceptable absolute model fits and provide evidence in support of configural, metric, and scalar invariance. These results provide further support for the construct validity of cognitive reserve in healthy and memory impaired older adults. PMID- 23039911 TI - Genome-wide assessment in Escherichia coli reveals time-dependent nanotoxicity paradigms. AB - The use of engineered nanomaterials (eNM) in consumer and industrial products is increasing exponentially. Our ability to rapidly assess their potential effects on human and environmental health is limited by our understanding of nanomediated toxicity. High-throughput screening (HTS) enables the investigation of nanomediated toxicity on a genome-wide level, thus uncovering their novel mechanisms and paradigms. Herein, we investigate the toxicity of zinc-containing nanomaterials (Zn-eNMs) using a time-resolved HTS methodology in an arrayed Escherichia coli genome-wide knockout (KO) library. The library was screened against nanoscale zerovalent zinc (nZn), nanoscale zinc oxide (nZnO), and zinc chloride (ZnCl(2)) salt as reference. Through sequential screening over 24 h, our method identified 173 sensitive clones from diverse biological pathways, which fell into two general groups: early and late responders. The overlap between these groups was small. Our results suggest that bacterial toxicity mechanisms change from pathways related to general metabolic function, transport, signaling, and metal ion homeostasis to membrane synthesis pathways over time. While all zinc sources shared pathways relating to membrane damage and metal ion homeostasis, Zn-eNMs and ZnCl(2) displayed differences in their sensitivity profiles. For example, ZnCl(2) and nZnO elicited unique responses in pathways related to two-component signaling and monosaccharide biosynthesis, respectively. Single isolated measurements, such as MIC or IC(50), are inadequate, and time resolved approaches utilizing genome-wide assays are therefore needed to capture this crucial dimension and illuminate the dynamic interplay at the nano-bio interface. PMID- 23039912 TI - College students and sexual consent: unique insights. AB - Sexual assault continues to be a salient health concern, especially among college women. Because assault is often defined in terms of consent, prevention efforts hinge on promoting the definition and the obtainment of consent as a mechanism to reduce assault. Despite the focus on consent promotion, research specifically examining consent in general and among college students specifically is limited. College students (n = 185) were recruited to participate in an open-ended survey in which they were asked to report how they indicated consent and interpreted their partners' consent to engage in a range of sexual behaviors. Content analysis was utilized to qualitatively analyze responses. In the current study, data were assessed for emerging themes across all items. In examining participants' responses, four distinct themes emerged: (a) endorsement of the traditional sexual script; (b) women are responsible for performing oral sex; (c) men's consent to sex can be aggressive; and (d) men utilize deception to obtain consent to sex. Findings suggest that men are conceptualized as sexual initiators and women as sexual gatekeepers, and that men's sexual pleasure is primary whereas women's experience of pleasure is secondary. Findings articulate the need for more pointed research aimed at assessing sexual consent among college students. PMID- 23039913 TI - Predicting the outcome of a cognitive-behavioral group training for patients with unexplained physical symptoms: a one-year follow-up study. AB - BACKGROUND: Although Cognitive-Behavioral Therapy (CBT) is effective for Unexplained Physical Symptoms (UPS), some therapists in clinical practice seem to believe that CBT outcome will diminish if psychiatric comorbidity is present. The result is that patients with a psychiatric comorbidity are redirected from treatment for UPS into treatment for mental health problems. To explore whether this selection and allocation are appropriate, we explored whether CBT outcomes in UPS could be predicted by variables assessed at baseline and used in routine practice assessments. METHODS: Patients (n=162) with UPS classified as undifferentiated somatoform disorder or chronic pain disorder were followed up until one year after they had attended a CBT group training. The time-points of the follow-up were at the end of CBT (immediate outcome), three months after CBT (short-term outcome), and one year after CBT (long-term outcome).CBT outcome was measured using the Physical Component Summary of the SF-36, which was the primary outcome measure in the randomized controlled trial that studied effectiveness of the CBT group training. Predictors were: 1.) psychological symptoms (global severity score of SCL-90), 2.) personality-disorder characteristics (sum of DSM IV axis II criteria confirmed), 3.) psychiatric history (past presence of DSM-IV axis I disorders), and 4.) health-related quality of life in the mental domain (mental component summary of SF-36). The effect of this predictor set was explored using hierarchical multiple regression analyses into which these predictors had been entered simultaneously, after control for: a.) pretreatment primary outcome scores, b.) age, c.) gender, d.) marital status, and e.) employment. RESULTS: The predictor set was significant only for short-term CBT outcome, where it explained 15% of the variance. A better outcome was predicted by more psychological symptoms, fewer personality-disorder characteristics, the presence of a psychiatric history, and a better quality of life in the mental domain. CONCLUSIONS: As the predictors do not seem to predict CBT outcome consistently over time, the need for selection and allocation of patients for CBT is doubtful. It seems that this would unnecessarily deprive patients of effective treatment. TRIAL REGISTRATION: Nederlands Trial Register, NTR1609. PMID- 23039914 TI - Efficacy and adverse effects of (R)-9-(2-phosphonylmethoxypropyl)-2,6 diaminopurine in feline immunodeficiency virus-infected cats. AB - BACKGROUND: (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine (PMPDAP) is active against feline immunodeficiency virus (FIV) in vitro, and is less toxic than other acyclic nucleoside phosphonates. Its efficacy in naturally infected cats has not been evaluated in large controlled studies. HYPOTHESIS/OBJECTIVES: PMPDAP is effective in naturally FIV-infected cats with minimal adverse effects. ANIMALS: Forty-five privately owned cats naturally infected with FIV. METHODS: Prospective, randomized, placebo-controlled, double-blinded clinical study. Cats were randomly assigned to be treated with PMPDAP (25 mg/kg) daily, PMPDAP 3 times a week, or placebo for a period of 6 weeks. RESULTS: Administration of PMPDAP to FIV-infected cats did not lead to detectable improvements in clinical, virological, or immunological variables. Proviral load (FIV copies/10(6) cells) did not change significantly during treatment (placebo group: from 9505 +/- 10119 to 8564 +/- 8615; PMPDAP 3 times a week: from 4818 +/- 4426 to 5041 +/- 6197; PMPDAP daily: from 3525 +/- 5038 to 3167 +/- 5824). There was a significant decrease of red blood cell counts (*10(12) /L) (from 8.91 +/- 1.82 to 7.34 +/- 1.79 in cats treated 3 times per week (P < .001), and from 8.96 +/- 1.13 to 6.01 +/- 1.36 in cats treated daily (P < .001)), as well as of packed cell volume, and hemoglobin in both groups receiving PMPDAP. CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of PMPDAP was not associated with significant improvements in clinical, immunological, or virological parameters, but treatment was associated with adverse effects, mainly anemia. Thus, PMPDAP, as administered in this study, cannot be recommended for treatment of FIV-infected cats. PMID- 23039915 TI - High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. AB - BACKGROUND: Chemokines and their receptors are known to play important roles in the tumorigenesis of many malignancies. The aim of this study was to evaluate the prognostic impact of the expression of the chemokine SDF-1 and its receptors CXCR4 and CXCR7 in patients with renal cell carcinoma. METHODS: The expression of CXCR4, CXCR7 and SDF-1 in specimens from 97 renal cell carcinoma patients was evaluated by immunohistochemistry on a tissue microarray. These results were correlated with the clinicopathological parameters and survival of the patients. RESULTS: CXCR4 and CXCR7 were expressed in all patients, whereas SDF-1 was expressed in 61 patients (62.9%). No association was observed between the expression of CXCR4, CXCR7 or SDF-1 and the clinical or pathological data except between SDF-1 expression and Fuhrman's grade (P = 0.015). Patients with high expression of CXCR4, CXCR7 and SDF-1 had shorter overall survival and recurrence free survival than those with low expression. In a multivariate analysis, the high expression of CXCR4, CXCR7 and SDF-1 correlated with poor overall survival and recurrence-free survival independent of gender, age, AJCC stage, lymph node status, metastasis, histologic variant and Fuhrman's grade. CONCLUSIONS: High levels of CXCR4, CXCR7 and SDF-1 were associated with poor overall survival and recurrence-free survival in renal cell carcinoma patients. CXCR4, CXCR7 and SDF-1 may serve as useful prognostic markers and therapeutic targets for renal cell carcinoma. PMID- 23039916 TI - Use of abundance ratios of somatic coliphages and bacteriophages of Bacteroides thetaiotaomicron GA17 for microbial source identification. AB - Water contaminated with human faeces is a risk to human health and management of water bodies can be improved by determining the sources of faecal pollution. Field studies show that existing methods are insufficient and that different markers are required. This study proposes the combined use of two microbial indicators, the concentrations of which are presented as ratios. This provides a more reliable approach to identifying faecal sources as it avoids variation due to treatment or ageing of the contamination. Among other indicators, bacteriophages have been proposed as rapid and cheap indicators of faecal pollution. Samples analysed in this study were derived from wastewater treatment plants (raw sewage, secondary and tertiary effluents and raw sewage sludge) river water, seawater and animal related wastewater. The abundance ratios of faecal coliforms and Bacteroides phages, either strain RYC2056 (non-specific for faecal origin) or strain GA17 (specific for human pollution), and among somatic coliphages and phages infecting both Bacteroides strains, were evaluated. The results indicate that the ratio of somatic coliphages and phages infecting Bacteroides strain GA17, which is specific to human faecal sources, provides a robust method for discriminating samples, even those presenting different levels and ages of pollution, and allows samples polluted with human faeces to be distinguished from those containing animal faecal pollution. This method allows the generation of numerical data that can be further applied to numerical methods for faecal pollution discrimination. PMID- 23039917 TI - Kinetic study of cis-dichloroethylene (cis-DCE) and vinyl chloride (VC) dechlorination using green rusts formed under varying conditions. AB - Abiotic degradation of cis-dichloroethylene (cis-DCE) and vinyl chloride (VC) was investigated using Fe hydroxides obtained by hydrolyzing Fe(II) salts over a pH range of 7.7-8.0. Within this narrow pH range, a green rust (GR) precipitated. The dechlorination reactivity of the resulting GR precipitates increased with the dissolved Fe(II) concentration remaining in solution after precipitation. Controls run using only the dissolved Fe(II) supernatant were not reactive, suggesting the relative amount of Fe(II) on the surface of precipitated GRs was the causative agent in the relative reactivity. To test this, a series of GR batches with varying dissolved Fe(II) concentrations were prepared by acid-base titration and examined for cis-DCE and VC dechlorination kinetics under reducing conditions. X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) analyses of these batches were performed to characterize the bulk mineralogy and the excess surface Fe(II), respectively. Cis-DCE and VC dechlorination results along with solid phase characterization show that different surface Fe(II)/Fe(III) compositions are responsible for the different reactivity of GRs formed within the GR precipitation zone. PMID- 23039918 TI - Fat, oil and grease deposits in sewers: characterisation of deposits and formation mechanisms. AB - Fat, oil and grease deposits (FOG) in sewers are a major problem and can cause sewer overflows, resulting in environmental damage and health risks. Often simplistically portrayed as cooling of fats, recent research has suggested that saponification may be involved in FOG formation. However there are still questions about the mechanisms effecting transformations in sewers and the role and source of metal cations involved in saponification. This study characterises FOG deposits from pumping stations, sewers and sewage works from different water hardness zones across the UK. The sites all had previous problems with FOG and most catchments contained catering and food preparation establishments. The FOG deposits were highly variable with moisture content ranging from 15 to 95% and oil content from 0 to 548 mg/g. Generally the pumping stations had lower moisture content and higher fat content, followed by the sewers then the sewage works. The water in contact with the FOG had high levels of oil (mean of about 800 mg/L) and this may indicate poor kitchen FOG management practices. FOG fatty acid profiles showed a transformation from unsaturated to saturated forms compared to typical cooking oils. This seems to relate to ageing in the sewer network or the mechanism of formation, as samples from pumping stations had higher proportions of C18:1 compared to C16. This may be due to microbial transformations by bacteria such as Clostridium sp. in a similar process to adipocere formation. There was an association between water hardness and increased Ca levels in FOG along with harder deposits and higher melting points. A link between FOG properties and water hardness has not been previously reported for field samples. This may also be due to microbial processes, such as biocalcification. By developing the understanding of these mechanisms it may be possible to more effectively control FOG deposits, especially when combined with promotion of behavioural change. PMID- 23039919 TI - High level multiple antibiotic resistance among fish surface associated bacterial populations in non-aquaculture freshwater environment. AB - Freshwater fish, Alburnus alburnus (bleak), were captured from Lake Mogan, situated in Ankara, during spring. The surface mucus of the fish was collected and associated bacteria were cultured and isolated. By sequencing PCR-amplified 16S RNA encoding genes, the isolates were identified as members of 12 different genera: Acinetobacter, Aeromonas, Bacillus, Brevundimonas, Gordonia, Kocuria, Microbacterium, Mycobacterium, Pseudomonas, Rhodococcus, and Staphylococcus, in addition to one strain that was unidentified. The mucus-dwelling bacterial isolates were tested for resistance against ampicillin, kanamycin, streptomycin and chloramphenicol. About 95% of the isolates were found to be resistant to ampicillin, 93% to chloramphenicol, and 88% to kanamycin and streptomycin. A Microbacterium oxydans and the unidentified environmental isolate were resistant to all four antibiotics tested at very high levels (>1600 MUg/ml ampicillin and streptomycin; >1120 MUg/ml kanamycin; >960 MUg/ml chloramphenicol). Only a Kocuria sp. was sensitive to all four antibiotics at the lowest concentrations tested (3.10 MUg/ml ampicillin and streptomycin; 2.15 MUg/ml kanamycin; 1.85 MUg/ml chloramphenicol). The rest of the isolates showed different resistance levels. Plasmid isolations were carried out to determine if the multiple antibiotic resistance could be attributed to the presence of plasmids. However, no plasmid was detected in any of the isolates. The resistance appeared to be mediated by chromosome-associated functions. This study indicated that multiple antibiotic resistance at moderate to high levels is common among the current phenotypes of the fish mucus-dwelling bacterial populations in this temperate, shallow lake which has not been subjected to any aquaculturing so far but under anthropogenic effect being in a recreational area. PMID- 23039921 TI - First-trimester abortion in women with medical conditions: release date October 2012 SFP guideline #20122. AB - Most women undergoing first-trimester abortion are healthy. However, abortion providers also encounter women with a wide variety of medical conditions, some of which are serious and complex. When such a condition exists, consultation with the woman's physician or a specialist can facilitate decision making regarding hospital referral and additional preparations that may be required. Medical conditions may determine the approach to abortion. Surgical abortion is preferred when mifepristone or methotrexate is contraindicated. Medication abortion may be preferred when lithotomy position is not possible or in patients with extreme obesity. Limited data suggest that women treated with anticoagulation therapy bleed more than other women during surgical abortion, although this additional bleeding may be clinically unimportant. The decision to temporarily discontinue anticoagulation therapy will depend on the agent used and the underlying risk of thrombosis. According to the American Heart Association, additional antibiotics are not recommended to prevent endocarditis in women with cardiac lesions during surgical abortion. We review specific recommendations for women with common medical conditions. In some women, highly effective postabortion contraception is essential to prevent pregnancy-related morbidity. The U.S. Medical Eligibility Criteria for Contraceptive Use, 2010, provides guidance for method selection for women with medical problems. PMID- 23039920 TI - Regulation of the ventral tegmental area by the bed nucleus of the stria terminalis is required for expression of cocaine preference. AB - Lateral hypothalamus (LH) orexin neurons are essential for the expression of a cocaine place preference. However, the afferents that regulate the activity of these orexin neurons during reward behaviors are not completely understood. Using tract tracing combined with Fos staining, we examined LH afferents for Fos induction during cocaine preference in rats. We found that the ventral bed nucleus of the stria terminalis (vBNST) was a major input to the LH orexin cell field that was significantly Fos-activated during cocaine conditioned place preference (CPP). Inactivation of the vBNST with baclofen plus muscimol blocked expression of cocaine CPP. Surprisingly, such inactivation of the vBNST also increased Fos induction in LH orexin neurons; as activity in these cells is normally associated with increased preference, this result indicates that a vBNST orexin connection is unlikely to be responsible for CPP that is dependent on vBNST activity. Because previous studies have revealed that vBNST regulates dopamine cells in the ventral tegmental area (VTA), which is known to be involved in CPP and other reward functions, we tested whether vBNST afferents to the VTA are necessary for cocaine CPP. We found that disconnection of the vBNST and VTA (using local microinjections of baclofen plus muscimol unilaterally into the vBNST and contralateral VTA) significantly attenuated expression of cocaine preference. However, blocking ionotropic glutamatergic afferents to the VTA from the vBNST did not significantly reduce cocaine preference. These results indicate that a non-glutamatergic vBNST-VTA projection is involved in expression of cocaine preference. PMID- 23039922 TI - Sex selection: what role for providers. PMID- 23039923 TI - Management of venous access devices by Advanced Practice Nursing teams: more research needed. PMID- 23039924 TI - Development and preliminary validation of a patient-reported outcome measure for swallowing after total laryngectomy (SOAL questionnaire). AB - OBJECTIVES: To develop and validate a laryngectomee-specific questionnaire to investigate swallowing function. This paper describes the generation of questionnaire items, pretesting with laryngectomees and a preliminary validation. DESIGN: This study employed 2 phases: questionnaire development and questionnaire validation. Items were developed from patient (n = 10) and clinician (n = 6) focus groups. Content checking, acceptability and face validity were determined through pretesting with 10 laryngectomees and via consensus feedback from 35 speech and language therapists. During preliminary validation, the 17-item final questionnaire was administered to 3 different groups. Discrimination amongst groups was established by comparing questionnaire responses of a laryngectomee group (n = 19) with known dysphagic (n = 19) and non-dysphagic groups (n = 20). Questionnaire responses from the reference dysphagic group were compared with an instrumental assessment of swallowing, the modified barium swallow (MBS). SETTING: Large urban teaching hospital. PARTICIPANTS: Speech and language therapists, laryngectomees, non-dysphagic volunteers, post-radiotherapy dysphagic patients. MAIN OUTCOME MEASURE: Preliminary validation of SOAL questionnaire. RESULTS: Normal, laryngectomee and dysphagic groups had significantly different SOAL scores, as did laryngectomees with different degrees of swallowing impairment (Kruskall Wallis, P << 0.001). The subjective SOAL score had a strong positive correlation with the reference measure of ratings on the MBS (r = 0.5; P = 0.03). CONCLUSIONS: The swallowing outcome after laryngectomy (SOAL) questionnaire is a simple, self-administered tool to assess swallowing function post-total laryngectomy. Further specific testing with a laryngectomy cohort is necessary for full validation. Its potential value lies in screening for dysphagia in clinics or during long-term follow-up of laryngectomees. PMID- 23039925 TI - Micellization of dodecyltrimethylammonium bromide in water-dimethylsulfoxide mixtures: a multi-length scale approach in a model system. AB - The micellization in mixed solvent was studied using conductimetry, density measurements (molar volumes), and small angle neutron scattering (SANS) to explore dodecyltrimethylammonium bromide (DTABr) micelle formation throughout the entire composition range of water-dimethylsulfoxide (DMSO) mixtures. As the concentration of DMSO was increased in the mixture, the critical micelle concentration (CMC) increased, the aggregation number decreased and the ionization degree increased, until no aggregates could be detected any more for DMSO molar fraction higher than 0.51. The results were consistent with the presence of globular micelles interacting via a coulombic potential. The experimental CMC values and aggregation numbers were successfully reconciled with a molecular thermodynamic model describing the micellization process in solvent mixtures (R. Nagarajan and C.-C. Wang, Langmuir 16 (2000) 5242). The structural and thermodynamic characterization of the micelles agreed with the prediction of a dissymmetric solvation of the surfactant entity: the hydrocarbon chain was surrounded only by DMSO while the polar head was surrounded only by water. The decrease in the ionization degree was due to the condensation of the counterions and was definitely linked to the geometrical characteristics of the aggregates and by no means to the CMC or salinity. This multi-technique study provides new insight into the role of solvation in micellization and the reason for the decrease in ionization degree, emphasizing the dissymmetric solvation of the chain by DMSO and the head by water. This is the first time that, for a given surfactant in solvent mixtures, micellization is described using combined analysis from molecular to macroscopic scale. PMID- 23039926 TI - Train the trainer? A randomized controlled trial of a multi-tiered oral health education programme in community-based residential services for adults with intellectual disability. AB - OBJECTIVES: To assess the impact of a multi-tiered oral health education programme on care staff caring for people with intellectual disability (ID). METHODS: Postal questionnaires were sent to all care staff of a community-based residential care service for adults, randomly assigned to control and intervention groups. A specifically developed training programme was delivered to residential staff nominees, who then trained all staff within the intervention group. The control group received no training. Post-test questionnaires were sent to both groups. Paired-samples t-test was used to compare oral health-related knowledge (K) and behaviour, attitude and self-efficacy (BAS) scores. RESULTS: Of the initial 219 respondents, 154 (response rate between 40% and 35.8%, with attrition rate of 29.7% from baseline to repeat) returned completed questionnaires at post-test (M=8.5 months, range=6.5-11 months). Control and intervention groups were comparable for general training, employment and demographic variables. In the intervention group, mean Knowledge Index score rose from K=7.2 to K=7.9 (P<0.001) and mean BAS scale score rose from BAS=4.7 to BAS=5.4 (P<0.001). There was no statistically significant increase in mean scores from test (K=7.0, BAS=4.7) to post-test (K=7.2, BAS=4.9) for the control group. CONCLUSIONS: Mean scores regarding knowledge, attitude, self-efficacy and reported behaviour increased significantly at 8.5 months in staff where training was provided. The results indicate that a multi-tiered training programme improved knowledge, attitude, self-efficacy and reported behaviour amongst staff caring for people with ID. PMID- 23039927 TI - Multitargeted drug development: Discovery and profiling of dihydroxy substituted 1-aza-9-oxafluorenes as lead compounds targeting Alzheimer disease relevant kinases. AB - Alzheimer disease (AD) turned out to be a multifactorial process leading to neuronal decay. So far merely single target structures which attribute to the AD progression have been considered to develop specific drugs. However, such drug developments have been disappointing in clinical stages. Multitargeting of more than one target structure determines recent studies of developing novel lead compounds. Protein kinases have been identified to contribute to the neuronal decay with CDK1, GSK-3beta and CDK5/p25 being involved in a pathological tau protein hyperphosphorylation. We discovered novel lead structures of the dihydroxy-1-aza-9-oxafluorene type with nanomolar activities against CDK1, GSK 3beta and CDK5/p25. Structure-activity relationships (SAR) of the protein kinase inhibition are discussed within our first compound series. One nanomolar active compound profiled as selective protein kinase inhibitor. Bioanalysis of a harmless cellular toxicity and of the inhibition of tau protein phosphorylation qualifies the compound for further studies. PMID- 23039928 TI - Detection for gene-gene co-association via kernel canonical correlation analysis. AB - BACKGROUND: Currently, most methods for detecting gene-gene interaction (GGI) in genomewide association studies (GWASs) are limited in their use of single nucleotide polymorphism (SNP) as the unit of association. One way to address this drawback is to consider higher level units such as genes or regions in the analysis. Earlier we proposed a statistic based on canonical correlations (CCU) as a gene-based method for detecting gene-gene co-association. However, it can only capture linear relationship and not nonlinear correlation between genes. We therefore proposed a counterpart (KCCU) based on kernel canonical correlation analysis (KCCA). RESULTS: Through simulation the KCCU statistic was shown to be a valid test and more powerful than CCU statistic with respect to sample size and interaction odds ratio. Analysis of data from regions involving three genes on rheumatoid arthritis (RA) from Genetic Analysis Workshop 16 (GAW16) indicated that only KCCU statistic was able to identify interactions reported earlier. CONCLUSIONS: KCCU statistic is a valid and powerful gene-based method for detecting gene-gene co-association. PMID- 23039929 TI - Mechanisms and implications of alpha-HCH enrichment in melt pond water on Arctic sea ice. AB - During the summer of 2009, we sampled 14 partially refrozen melt ponds and the top 1 m of old ice in the pond vicinity for alpha-hexachlorocyclohexane (alpha HCH) concentrations and enantiomer fractions (EFs) in the Beaufort Sea. alpha-HCH concentrations were 3 - 9 times higher in melt ponds than in the old ice. We identify two routes of alpha-HCH enrichment in the ice over the summer. First, atmospheric gas deposition results in an increase of alpha-HCH concentration from 0.07 +/- 0.02 ng/L (old ice) to 0.34 +/- 0.08 ng/L, or ~20% less than the atmosphere-water equilibrium partitioning concentration (0.43 ng/L). Second, late season ice permeability and/or complete ice thawing at the bottom of ponds permit alpha-HCH rich seawater (~0.88 ng/L) to replenish pond water, bringing concentrations up to 0.75 +/- 0.06 ng/L. alpha-HCH pond enrichment may lead to substantial concentration patchiness in old ice floes, and changed exposures to biota as the surface meltwater eventually reaches the ocean through various drainage mechanisms. Melt pond concentrations of alpha-HCH were relatively high prior to the late 1980-s, with a Melt pond Enrichment Factor >1 (MEF; a ratio of concentration in surface meltwater to surface seawater), providing for the potential of increased biological exposures. PMID- 23039930 TI - Evolving concepts of developmental auditory processing disorder (APD): a British Society of Audiology APD special interest group 'white paper'. AB - Children with listening difficulties, but normal audiometry, may be diagnosed with APD. The diagnosis is typically based on poor performance on tests of perception of both non-speech and speech stimuli. However, non-speech test results correlate only weakly with evaluations of speech-in-noise processing, cognitive skills, and caregiver evaluations of listening ability. The interpretation of speech test results is confounded by the involvement of language processing mechanisms. Overall, listening ability is associated more with higher-level, cognitive and analytic processing than with lower-level sensory processing. Current diagnosis of a child with APD, rather than another problem (e.g. language impairment, LI), is determined more by the referral route than by the symptoms. Co-occurrence with other learning problems suggests that APD may be a symptom of a more varied neurodevelopmental disorder. Alternately, APD has been proposed as a cause of language-based disorders, but there is no one to-one mapping between listening and language among individuals. Screening for APD may be most appropriately based on a well-validated, caregiver questionnaire that captures the fundamental problem of listening difficulties and identifies areas for further assessment and management. This approach has proved successful for LI, and may in future serve as a metric to help assess other, objective testing methods. PMID- 23039931 TI - Can repetitive magnetic stimulation improve cognition in schizophrenia? Pilot data from a randomized controlled trial. AB - BACKGROUND: Working memory represents a core cognitive domain that is impaired in schizophrenia for which there are currently no satisfactory treatments. Repetitive transcranial magnetic stimulation (rTMS) targeted over the dorsolateral prefrontal cortex has been shown to modulate neurophysiological mechanisms linked to working memory in schizophrenia and improves working memory performance in healthy subjects and might therefore represent a treatment modality for schizophrenia patients. The objectives were to evaluate the effects of rTMS on working memory performance in schizophrenia patients and evaluate whether rTMS normalizes performance to healthy subject levels. METHODS: In a 4 week randomized double-blind sham-controlled pilot study design, 27 medicated schizophrenia patients were tested at the Centre for Addiction and Mental Health (a university teaching hospital that provides psychiatric care to a large urban catchment area and serves as a tertiary referral center for the province of Ontario). Patients performed the verbal working memory n-back task before and after rTMS magnetic resonance image targeted bilaterally sequentially to left and right dorsolateral prefrontal cortex 750 pulses/side at 20 Hz for 20 treatments. The main outcome measure was mean magnitude of change in the n-back accuracy for target responses with active (n = 13) or sham (n = 12) rTMS treatment course. RESULTS: The rTMS significantly improved 3-back accuracy for targets compared with placebo sham (Cohen's d = .92). The improvement in 3-back accuracy was also found to be at a level comparable to healthy subjects. CONCLUSIONS: These pilot data suggest that bilateral rTMS might be a novel, efficacious, and safe treatment for working memory deficits in patients with schizophrenia. PMID- 23039933 TI - Characterisation and evaluation of pharmaceutical solvates of Atorvastatin calcium by thermoanalytical and spectroscopic studies. AB - BACKGROUND: Atorvastatin calcium (ATC), an anti-lipid biopharmaceutical class II drug, is widely prescribed as a cholesterol-lowering agent and is presently the world's best-selling medicine. A large number of crystalline forms of ATC have been published in patents. A variety of solid forms may give rise to different physical properties. Therefore, the discovery of new forms of this unusual molecule, ATC, may still provide an opportunity for further improvement of advantageous properties. RESULTS: In the present work, eight new solvates (Solvate I-VIII) have been discovered by recrystallization method. Thermal behaviour of ATC and its solvates studied by DSC and TGA indicate similar pattern suggesting similar mode of entrapment of solvent molecules. The type of solvent present in the crystal lattice of the solvates is identified by GC-MS analysis and the stoichiometric ratio of the solvents is confirmed by 1HNMR. The high positive value of binding energy determined from thermochemical parameters indicates deep inclusion of the solvent molecules into the host cavity. The XRPD patterns point towards the differences in their crystallanity, however, after desolvation solvate II, III, IV, V and VIII transform to isostructral amorphous desolvated solvates. The order of crystallinity was confirmed by solution calorimetric technique as the enthalpy of solution is an indirect measure of lattice energy. All the solvates behaved endothermically following the order solvate-VIII (1-butanol solvate) < solvate-I (isoproplyate) < solvate-V (methanol solvate) < solvate-III (ethonalate) < solvate-VI (acetone ethanol solvate) < solvate-IV (t-butanol solvate) < solvate-II (THF solvate) < solvate-VII (mixed hemi-ethanol hydrate). The positive value of the heat capacity of the solvate formation provides information about the state of solvent molecules in the host lattice. The solvents molecules incorporated in the crystal lattice induced local chemical environment changes in the drug molecules which are observed in 13CP/MAS NMR spectral changes. CONCLUSIONS: Aqueous solubility of solvate-VIII was found to be maximum, however, solvate-I and VIII showed better reduction in total cholesterol and triglyceride levels as compared to atorvastatin against triton induced dyslipidemia. PMID- 23039934 TI - Congenital lumbar hernia: 20 years' single centre experience. AB - AIM: Congenital lumbar hernia is an uncommon anomaly with only few cases reported in the English literature. This study was done to study the incidence, associated conditions, management and complications of congenital lumbar hernia repair in paediatric patients. METHODS: Retrospective study of all patients over a period of 20 years (January 1990 to January 2010) was analysed. RESULTS: A total of 18 patients (two bilateral hernias) were encountered in this series. All were in the age group of 1 day to 6 years. All the patients were operated by open technique. Primary repair was done in 14 patients and prosthetic meshplasty in two. Two patients could not be operated. The average follow-up period was 3 years. There was no follow-up loss in our study. There was no evidence of recurrence in this series. CONCLUSION: Up until now, the total number of cases is 68. The large size of hernia defect (>10 cm) may determine the use of prosthetic mesh repair. Proper surgical treatment, either primary repair or hernioplasty, provides adequate management of this condition. PMID- 23039936 TI - Ultrasonographic diagnosis of syringohydromyelia and segmental hypoplasia of the lumbar spinal cord in a calf. PMID- 23039935 TI - Excessive daytime sleepiness assessed by the Epworth Sleepiness Scale and its association with health related quality of life: a population-based study in China. AB - BACKGROUND: Excessive daytime sleepiness (EDS) is a common condition worldwide that has many negative effects on people who were afflicted with it, especially on their health-related quality of life (HRQOL). The Epworth Sleepiness Scale (ESS) is a commonly used method for evaluating EDS in English-speaking countries. This paper reported the prevalence of subjective EDS in China as assessed by the Mandarin version of the ESS; tested the scale's response rate, reliability and validity; and investigated the relationship between ESS scores and HRQOL. METHODS: A population-based sample of 3600 residents was selected randomly in five cities in China. The demographic information was collected, subjective EDS was assessed by the Mandarin version of the ESS (ESS scores >10), and HRQOL was evaluated by the Mandarin version of the 36-item Short Form Health Survey (SF 36). RESULTS: The Mandarin version of ESS had very few missing responses, and the average response rate of its eight items was 97.92%. The split-half reliability coefficient and Cronbach's alpha coefficient were 0.81 and 0.80, respectively. One factor was identified by factor analysis with an eigenvalue of 2.78. The ESS scores showed positive skewness in the selected sample, with a median (Q1, Q3) of 6 (3, 0). 644 (22.16%) respondents reported subjective EDS, and all of the scores of the eight dimensions of the SF-36 were negatively correlated with ESS scores. CONCLUSIONS: The Mandarin version of ESS is an acceptable, reliable, and valid tool for measuring EDS. In addition, subjective EDS is common in China, based on the ESS results, and impairs HRQOL. PMID- 23039937 TI - Mothers' knowledge about foreign body aspiration in young children. AB - OBJECTIVE: To evaluate parents' knowledge regarding foreign body aspiration (FBA) and determine the factors that are associated with lack of knowledge. METHODS: An 8-item questionnaire regarding knowledge of FBA was developed and distributed at regular check-ups for children younger than 24 months old. RESULTS: Out of the 1766 questionnaires distributed, 1603 were recovered and most of them (1539) were answered by mothers. After omitting 49 questionnaires with incomplete data, 1490 questionnaires answered by mothers were analyzed. Only 4.3% [95% CI 3.3-5.3] of mothers did not recognize a small toy as a cause of FBA, while 20.2% [95% CI 18.2 22.2] did not know that peanuts and other nuts can be causes of FBA, and 48.1% [95% CI 45.5-50.6] did not know that they should not give peanuts to a child younger than 3 years old. Regarding clinical signs, 27.7% [95% CI 25.4-30.0] and 41.8% [95% CI 39.3-44.3] of mothers did not know that sudden choking and sudden coughing were symptoms suggesting FBA, respectively. Being a mother with a child younger than 12 months old and being a mother with a first child were independent risk factors for lack of knowledge about FBA, regardless of the age of the mother. CONCLUSIONS: A substantial number of mothers lack knowledge regarding FBA. To prevent FBA and to make timely diagnoses, parents, especially mothers with children younger than 12 months old and mothers with a first child should be given adequate information. PMID- 23039938 TI - Language: a critical determinant of intervention and outcome in Pediatric Otolaryngology. PMID- 23039939 TI - More than problem-solving: critical reflections on the 'problematisation' of alcohol-related violence in Kings Cross. PMID- 23039932 TI - Genetic schizophrenia risk variants jointly modulate total brain and white matter volume. AB - BACKGROUND: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. METHODS: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. RESULTS: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2 = .048, p = 1.6 * 10(-4)) and white matter volume (R2 = .051, p = 8.6 * 10(-5)) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n = 2020) was much smaller than the entire set of SNPs that modulated disease status (n = 14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. CONCLUSIONS: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia. PMID- 23039940 TI - A validation study of quantum dot multispectral imaging to evaluate hormone receptor status in ductal carcinoma in situ of the breast. AB - The assessment of hormone receptors, including estrogen receptor and progesterone receptor, has become a standard practice in breast cancer management. However, the need for multiple sections to evaluate each receptor individually by conventional immunohistochemistry may preclude the analysis on some core biopsies with a limited amount of tumors. The aim of the study was to validate the quantitative analysis of nuclear markers estrogen receptor and progesterone receptor by quantum dot-based immunohistochemistry using a multispectral imaging system in ductal carcinoma in situ of the breast. Consecutive sections from a total of 17 cases of ductal carcinoma in situ with excisional biopsies or mastectomies were stained with conventional immunohistochemistry and quantum dot based, single- and double-labeled immunohistochemistry for estrogen receptor and progesterone receptor. The semiquantitative results from double-labeled, quantum dot-based immunohistochemistry were compared with those from single-labeled, quantum dot-based immunohistochemistry as well as from conventional immunohistochemistry. There was good concordance between double- and single labeled quantum dot-based immunohistochemistry, and quantum dot-based immunohistochemistry correlated well with conventional immunohistochemistry (Spearman correlation coefficient range from 0.884 to 0.958, P < .001). The findings proved the validity and accuracy of quantum dot-based multiplex, multispectral technique in detecting 2 tumor markers in the same cellular compartment simultaneously on a single slide. This technique may enhance our ability to assess multiple breast tumor markers in specimens with limited available tissue. However, several technical and logistic issues await significant improvement before this novel technique can be justified for routine clinical application. PMID- 23039941 TI - Perceived Breastfeeding Support Assessment Tool (PBSAT): development and testing of psychometric properties with Pakistani urban working mothers. AB - INTRODUCTION: breast feeding is an essential source of nutrition among young babies; however, in Pakistan a gradual decline in prevalence of breast feeding, especially among urban working mothers, has been reported. Previous studies among Pakistani urban working mothers have revealed that ensuring exclusivity and continuation of breast feeding is challenging if social and/or workplace environmental support is minimal or absent. This problem indicated a crucial need to assess availability of breast-feeding support for Pakistani urban working mothers by using a comprehensive, reliable, and validated tool in their national language (Urdu). PURPOSE: to develop and test the psychometric properties of the 'Perceived Breastfeeding Support Assessment Tool' (PBSAT) that can gauge Pakistani urban working mothers' perceptions about breast-feeding support. METHODOLOGY: this methodological research was undertaken in five phases. During phase I, a preliminary draft of the PBSAT was developed by using the Socio ecological model, reviewing literature, and referring to two United States based tools. In Phase II, the instrument was evaluated by seven different experts, and, in Phase III, the instrument was revised, translated, and back translated. In Phase IV, the tool was pilot tested among 20 participants and then modified on the basis of statistical analysis. In Phase V, the refined instrument was tested on 200 breast-feeding working mothers recruited through purposive sampling from the government and private health-care settings in Karachi, Pakistan. Approvals were received from the Ethical Review Committees of the identified settings. FINDINGS: the 29-item based PBSAT revealed an acceptable inter-rater reliability of 0.95, and an internal consistency reliability coefficient (Cronbach's alpha) of 0.85. A construct validity assessment through Exploratory Factor Analysis revealed that the PBSAT has two dimensions, 'workplace environmental support' (12 items; alpha=0.86) and 'social environmental support' (17 items; alpha=0.77). CONCLUSION: the study developed a 29-item based two-dimensional tool (in Urdu) that has acceptable psychometric properties. The PBSAT is context specific, comprehensive, and user-friendly, so it can be administered by health-care workers, employers, policy makers, and researchers to improve the quality of services of breast-feeding urban working mothers, and could ultimately improve child health in Pakistan. PMID- 23039942 TI - Maternal trait personality and childbirth: the role of extraversion and neuroticism. AB - BACKGROUND: anxiety during pregnancy and childbirth can increase risk of complications and interventions for both mother and infant. Although considerable work has explored fear of childbirth and anxiety during labour and subsequent birth outcomes there has been less consideration of the role of more stable maternal personality upon childbirth. Traits of neuroticism and extraversion are however predictive of health outcomes in other fields potentially through biological, psychological and social mechanisms. The aim of the current research was thus to examine the relationship between trait personality and childbirth experience. METHODS: seven hundred and fifty-five mothers with an infant aged 0-6 months completed a self-report questionnaire including the Ten Item Personality Measure and descriptions of birth experience including mode of birth [vaginal vs. caesarean section] and complications [failure to progress, fetal distress, post partum haemorrhage, assisted birth and severe tear]. FINDINGS: personality traits were significantly associated with birth experience. Specifically mothers scoring low in extraversion and emotional stability were significantly more likely to have a caesarean section and experience a number of complications during labour and birth including an assisted birth, fetal distress, failure to progress and a severe tear. Findings were independent of maternal age, education and parity. CONCLUSIONS: the personality traits of extraversion and emotional stability appear to facilitate likelihood of normal birth. Potential explanations for this include biological (physiological reactivity, pain thresholds, oxytocin and dopamine release) and psychological (coping mechanisms, social support, self efficacy) factors. The findings have important implications for antenatal education and support during labour. PMID- 23039944 TI - A novel T(H)17-type cell is rapidly increased in the liver in response to acetaminophen-induced liver injury: T(H)17 cells and the innate immune response. AB - Helper T (T(H)) cells are an important part of the adaptive immune system. It is hypothesized that one type of helper T-cell, T(H)17 cells, play an important role in idiosyncratic drug-induced liver failure, and it was found that interleukin (IL)-17, the signature cytokine of T(H)17 cells, was elevated in most patients with idiosyncratic drug-induced liver failure. However, it was also found that IL 17 was elevated in some patients with acetaminophen (APAP)-induced liver failure. It is unlikely that APAP-induced liver failure is mediated by the adaptive immune system, but there are other cells such as macrophages and natural killer (NK) cells that also produce IL-17. Therefore, the phenotype of cells that produce IL 17 was studied in a mouse model of APAP-induced liver toxicity. To the authors' surprise, it was found that most of the IL-17 producing cells in the liver were T(H)17 cells, and they were increased within hours of APAP treatment. This is too fast for a response of the adaptive immune system. These data suggest that T(H)17 cells can be part of the innate immune response; however, it is unclear what role they play in the pathogenesis of APAP-induced hepatotoxicity. PMID- 23039943 TI - Efficient distinction of invasive aquatic plant species from non-invasive related species using DNA barcoding. AB - Biological invasions are regarded as threats to global biodiversity. Among invasive aliens, a number of plant species belonging to the genera Myriophyllum, Ludwigia and Cabomba, and to the Hydrocharitaceae family pose a particular ecological threat to water bodies. Therefore, one would try to prevent them from entering a country. However, many related species are commercially traded, and distinguishing invasive from non-invasive species based on morphology alone is often difficult for plants in a vegetative stage. In this regard, DNA barcoding could become a good alternative. In this study, 242 samples belonging to 26 species from 10 genera of aquatic plants were assessed using the chloroplast loci trnH-psbA, matK and rbcL. Despite testing a large number of primer sets and several PCR protocols, the matK locus could not be amplified or sequenced reliably and therefore was left out of the analysis. Using the other two loci, eight invasive species could be distinguished from their respective related species, a ninth one failed to produce sequences of sufficient quality. Based on the criteria of universal application, high sequence divergence and level of species discrimination, the trnH-psbA noncoding spacer was the best performing barcode in the aquatic plant species studied. Thus, DNA barcoding may be helpful with enforcing a ban on trade of such invasive species, such as is already in place in the Netherlands. This will become even more so once DNA barcoding would be turned into machinery routinely operable by a nonspecialist in botany and molecular genetics. PMID- 23039945 TI - Compounded progesterone: why is it acceptable to Australian women? AB - OBJECTIVES: To determine factors influencing compounded progesterone products' acceptability amongst Australian women who use them. STUDY DESIGN: A cross sectional survey of 366 women from all states of Australia who had been dispensed a compounded progesterone product, using the 'Perspectives on Progesterone' questionnaire. MAIN OUTCOME MEASURES: Descriptive statistics and a logistic regression model of acceptability. Acceptability was measured by respondents' willingness to recommend progesterone therapy to other women with a similar condition to their own and whether they had talked about their experience to other women. RESULTS: Australian women who use compounded progesterone tend to be highly educated. They were treating symptoms associated with menopause transition or hormone deficiency. The most common dosage form being used was transdermal cream. More than half the respondents reported improvement for mood swings or irritability (73%), foggy thinking (58%), hot flushes (56%), sleeping problems (55%), and anxiety (54%). Side effects were minimal with the weight gain being the most frequently reported (10%). There was no difference in symptom improvement between those who use progesterone alone or in combination with other hormones. The compounded progesterone acceptability model contains symptom improvement (very large effect size) perception that progesterone is natural and safe (large effect size), number of unexpected benefits (medium effect size) and treatment tailored to suit them (medium effect size). Concerns about other treatments or other treatments being ineffective did not contribute to acceptability. CONCLUSIONS: Acceptance of compounded progesterone therapy depends on symptom improvement, perception of safety and naturalness and tailored therapy. PMID- 23039947 TI - Enhanced cell disruption strategy in the release of recombinant hepatitis B surface antigen from Pichia pastoris using response surface methodology. AB - BACKGROUND: Cell disruption strategies by high pressure homogenizer for the release of recombinant Hepatitis B surface antigen (HBsAg) from Pichia pastoris expression cells were optimized using response surface methodology (RSM) based on the central composite design (CCD). The factors studied include number of passes, biomass concentration and pulse pressure. Polynomial models were used to correlate the above mentioned factors to project the cell disruption capability and specific protein release of HBsAg from P. pastoris cells. RESULTS: The proposed cell disruption strategy consisted of a number of passes set at 20 times, biomass concentration of 7.70 g/L of dry cell weight (DCW) and pulse pressure at 1,029 bar. The optimized cell disruption strategy was shown to increase cell disruption efficiency by 2-fold and 4-fold for specific protein release of HBsAg when compared to glass bead method yielding 75.68% cell disruption rate (CDR) and HBsAg concentration of 29.20 mg/L respectively. CONCLUSIONS: The model equation generated from RSM on cell disruption of P. pastoris was found adequate to determine the significant factors and its interactions among the process variables and the optimum conditions in releasing HBsAg when validated against a glass bead cell disruption method. The findings from the study can open up a promising strategy for better recovery of HBsAg recombinant protein during downstream processing. PMID- 23039948 TI - Epidermal-type FABP is a predictive marker of clinical response to systemic treatment and ultraviolet therapy in psoriatic skin lesions. PMID- 23039946 TI - Complete genome sequence and metabolic potential of the quinaldine-degrading bacterium Arthrobacter sp. Rue61a. AB - BACKGROUND: Bacteria of the genus Arthrobacter are ubiquitous in soil environments and can be considered as true survivalists. Arthrobacter sp. strain Rue61a is an isolate from sewage sludge able to utilize quinaldine (2 methylquinoline) as sole carbon and energy source. The genome provides insight into the molecular basis of the versatility and robustness of this environmental Arthrobacter strain. RESULTS: The genome of Arthrobacter sp. Rue61a consists of a single circular chromosome of 4,736,495 bp with an average G + C content of 62.32%, the circular 231,551-bp plasmid pARUE232, and the linear 112,992-bp plasmid pARUE113 that was already published. Plasmid pARUE232 is proposed to contribute to the resistance of Arthrobacter sp. Rue61a to arsenate and Pb2+, whereas the linear plasmid confers the ability to convert quinaldine to anthranilate. Remarkably, degradation of anthranilate exclusively proceeds via a CoA-thioester pathway. Apart from quinaldine utilization, strain Rue61a has a limited set of aromatic degradation pathways, enabling the utilization of 4 hydroxy-substituted aromatic carboxylic acids, which are characteristic products of lignin depolymerization, via ortho cleavage of protocatechuate. However, 4 hydroxyphenylacetate degradation likely proceeds via meta cleavage of homoprotocatechuate. The genome of strain Rue61a contains numerous genes associated with osmoprotection, and a high number of genes coding for transporters. It encodes a broad spectrum of enzymes for the uptake and utilization of various sugars and organic nitrogen compounds. A. aurescens TC-1 is the closest sequenced relative of strain Rue61a. CONCLUSIONS: The genome of Arthrobacter sp. Rue61a reflects the saprophytic lifestyle and nutritional versatility of the organism and a strong adaptive potential to environmental stress. The circular plasmid pARUE232 and the linear plasmid pARUE113 contribute to heavy metal resistance and to the ability to degrade quinaldine, respectively. PMID- 23039949 TI - Epileptic spasms: experience with a high-dose oral corticosteroid protocol. AB - AIM: To audit clinical practice and assess early outcomes for infants with epileptic spasms after an agreed initial treatment protocol was adopted. METHODS: We reviewed all cases of epileptic spasms diagnosed between July 2007 and June 2009 and assessed adherence to protocol, remission by day 14, spasm recurrence and side effects. The protocol required that infants be treated with high-dose oral prednisolone except those with tuberous sclerosis complex (TSC) who were treated with vigabatrin. RESULTS: Twenty-eight infants (age 3-14 months, 17 male) were newly diagnosed. Six (21%) had no cause identified (cryptogenic), six (21%) had TSC and 16 (57%) had other non-TSC symptomatic aetiologies. Twenty-three were treated per protocol and five were not. The proportion with remission by day 14 of treatment was 100% in the cryptogenic group (all treated per protocol), 64% in those with non-TSC symptomatic aetiologies treated per protocol, 20% in those with non-TSC symptomatic aetiologies treated not per protocol and 17% in infants with TSC (all treated per protocol). Of 17 infants who received prednisolone, two were admitted for management of febrile illness. CONCLUSION: Our experience with high-dose oral prednisolone for treatment of epileptic spasms suggests that it is effective and tolerable. The greater proportion of non-TSC symptomatic patients with timely cessation of spasms when treated by this protocol supports the use of high-dose oral prednisolone as the treatment of choice. Given the poor response of children with TSC to treatment with vigabatrin, early use of steroid therapy deserves consideration. PMID- 23039950 TI - Sunflower genetic, genomic and ecological resources. AB - Long a major focus of genetic research and breeding, sunflowers (Helianthus) are emerging as an increasingly important experimental system for ecological and evolutionary studies. Here, we review the various attributes of wild and domesticated sunflowers that make them valuable for ecological experimentation and describe the numerous publicly available resources that have enabled rapid advances in ecological and evolutionary genetics. Resources include seed collections available from germplasm centres at the USDA and INRA, genomic and EST sequences, mapping populations, genetic markers, genetic and physical maps and other forward- and reverse-genetic tools. We also discuss some of the key evolutionary, genetic and ecological questions being addressed in sunflowers, as well as gaps in our knowledge and promising areas for future research. PMID- 23039951 TI - Thermoluminescent dosimetry in total body irradiation. AB - The aim of this paper was to develop a thermoluminescent dosimetry method for the absorbed dose determination of 6 MeV high-energy electron beams by thermoluminescent dosimetry. Total body irradiation (TBI) was performed using four dual fields angled at 252 degrees and 285 degrees in high-dose rate (HDR) mode. TBI measurements were investigated to estimate the absorbed dose in different anatomical parts of the patient. Experimental results were obtained using thermoluminescent detectors and solid water phantoms. The TL response of the dosimeters, as a function of the high-energy electron beam (HEEB) absorbed dose, was linear, from 0.1 to 500 cGy. The entrance skin dose (ESD) and isodose distribution on the surface of the treatment were investigated graphically. PMID- 23039952 TI - [Pneumatic tube system for blood products transport]. AB - Blood product transport from blood bank to the patient care areas of hospitals is a key step in the transfusion process. The pneumatic tube system is now widely used in hospitals. Strict performance specifications must be respected to guarantee blood safety: robustness, easy to use and respect the constraints imposed to blood products. To secure the disposal of blood products ordered to a carrier (delivery step), a security device must be deployed (video camera, barcode reading, fax, chip), allowing in particular to limit the risk of addressing error when sending (in the case of device with several arrival stations) or picked up by the wrong carrier. PMID- 23039953 TI - [Managing of excessive bleeding after cardiac surgery under cardiopulmonary bypass]. AB - The occurrence of abnormal bleeding in postoperative cardiac surgery performed under cardiopulmonary bypass is relatively common. If the option of reoperation is not retained, the initiation of medical treatment is inevitable. Next to the transfusion of blood products, other therapies were often used empirically and as "off-label". The place of each in a future regimen should be based on well conducted clinical studies to determine the optimal risk/benefit ratio. PMID- 23039954 TI - [Current trends in plasma transfusion for patients with severe hemorrhage]. AB - Recent changes in plasma transfusion practices for severe hemorrhage are largely related to the recognition of an early endogenous coagulopathy associated with traumatic injury. Observational and mostly retrospective data suggest improved survival rates with high-dose plasma therapy, up to a 1:1 ratio of fresh frozen plasma to packed red blood cells, but the quality of evidence is limited. Putting it into practice raises many issues (early identification of patients at risk of massive bleeding, extrapolation to non-trauma settings, alternative or adjunctive treatments, among others) that are discussed in this brief review. PMID- 23039955 TI - [Computerization of hospital blood banks in France]. AB - In France, most blood products are delivered by the etablissement francais du sang, directly to the recipients, and hospital blood banks deliver a minor part, but are independent from it. However that may be, hospital blood banks are hazardous activities regarding to recipients, blood products, blood supply of the hospital and regional blood supply. Because of the high risk level, a computerized information system is compulsory for all hospital blood banks, except for those only devoted to vital emergency transfusion. On the field, the integration of computerization in the different processes is very heterogeneous. So, it has been decided to publish guidelines for computerizing hospital blood banks information systems and production management. They have been built according to risk assessment and are intended to minimize those risks. The principle is that all acquisition and processing of data about recipients or blood products and tracking, must be fully computerized and that the result of all manual processes must be checked by computer before proceeding to the next step. The guidelines list the different processes and, for each of them, the functions the software must play. All together, they form the basic level all hospital blood banks should reach. Optional functions are listed. Moreover, the guidelines are also aimed to be a common tool for regional health authorities who supervise hospital blood banks. PMID- 23039956 TI - [How to write, how to implement and how to evaluate a practice guideline in order to improve quality of care?]. AB - Initiatives of clinical practices improvement have been gradually developing in France for 20 years. Nevertheless, effective implementation of change is still difficult for numerous reasons. The use of clinical practices guidelines is one of the different ways of improvement. It is however necessary to adapt these national guidelines to the specificities of the hospital and the team, to ensure implementation and appropriation by the professionals. These recommendations are thus translated into applicable and concrete standard operating procedures. These documents have to be built by and for the concerned professionals. They are also communication and training tools, precise, directive, uniform in terms of presentation and attractive visually. Once drafted, they have to be distributed widely to the professionals to facilitate implementation. The simple distribution of the recommendations is insufficient to modify the clinical practices and require association of several methods of promotion for an optimal appropriation. How then to make sure of their effective use? Practices evaluation is one of the steps of continuous professional development, including continuous training and analysis of clinical practices by using methods promoted by the "Haute Autorite de sante". One of them is the clinical audit; use of method assessing non pertinent treatment is interesting too. Analysis of the non-conformities and gaps between theory and practice allows identifying various possible causes (professional, institutional, organizational or personal) in order to implement corrective action plans, in a logic of continuous improvement. PMID- 23039957 TI - [Transfusion support of haematological malignancies in 2012: evolution of the recommendations]. PMID- 23039958 TI - [Perioperative aspects of blood transfusion in paediatrics]. AB - In pediatric elective surgery, the main indications of blood transfusion are cardiac surgery, neurosurgery and abdominal tumors. Blood saving techniques are also available. The transfusion threshold has to take into account the physiological age-related particularities. Underestimation of blood loss and delayed transfusion are associated with a severe morbidity. In the absence of specific literature, the management of hemorrhagic shock is based on extrapolation of the adult recommendations. PMID- 23039959 TI - [Computers to facilitate the quality of blood products orders]. AB - The decision to order component blood products is perhaps the most critical step in patient's transfusion safety. A variety of techniques used to bring about behavioural changes in the transfusion practices of physicians have been met with limited success. Computerized order entry (CPOE) and decision support systems have been demonstrated to improve the quality of orders in terms of legibility and completeness. In addition, CPOE systems have been shown to affect physician ordering behaviour and to reduce the percentage of inappropriate orders. However, CPOE systems with poorly interfaced designs can result in usability problems and finally in order errors. Evaluation of the system has to guide CPOE systems' evolutions to aid in patient safety. PMID- 23039960 TI - [Transfusion-associated circulatory overload]. AB - A working group of the French National Hemovigilance Committee has been in charge of heightening awareness of Transfusion-Associated Circulatory Overload (TACO) among physicians and nurses. This multidisciplinary group has produced the present document that focuses on epidemiological data provided by the French haemovigilance network, physiopathology, diagnosis, treatment and specific actions that could prevent or minimize the risk of TACO. PMID- 23039961 TI - [Diagnosis and treatment of trauma-induced coagulopathy]. AB - Trauma-induced coagulopathy is frequent and complex, and is responsible for an impairment of trauma outcome. Diagnosis of trauma coagulopathy is usually done with standard biology but recently new technics arose and gave us the opportunity to have faster information on coagulopathy with quick INR measure or clot formation study with thrombelastometry. Treatment of the coagulopathy should be done earlier in the course of trauma. Two strategies are possible that include either the association of RBC, platelet and FFP in a predefined ratio, or the use of factor concentrates guided with thrombelastometry. Treatment of favouring factors such as hypothermia, acidosis and hypocalcemia is also mandatory. PMID- 23039962 TI - [New training tools in haemovigilance]. AB - The transfusion of blood and blood products is a complex, multi-professional task which is liable to errors from donor to recipient. Simulation is a new training tool in medicine which may result with an improvement for safety and quality of care without any risk for the patient. Different simulators are available: haptic system and low fidelity mannequin for technical skills, software, full scale intermediate to high fidelity mannequin, actors and virtual reality. For haemovigilance training, actors and intermediate to high fidelity mannequins could be used to simulate complex professional situations with identity mistake and crisis management. The environment of full scale simulation is expensive and need technical and pedagogic skills. PMID- 23039963 TI - [Computerization of hospital blood banks in France: what has been done and what remains to be done]. AB - French regulation requires hospital blood banks to have data processing of their blood transfusion activities. In order to help them to achieve this goal, guidelines were published by an official working party. For their diffusion, a study was launched to assess current gaps between guidelines and reality. Analysis of the first forty responses shows: 1) computerization is already set up for main blood banks and is going well for the others; 2) most of guideline functionalities are now working in main blood banks; but some points need specific developments; 3) taken as a whole, other blood banks are further from guideline requirements, even if some have already reached the goal; 4) guidelines are able to point out to all hospital blood banks what remains to be done. PMID- 23039965 TI - Prognostic value of American Thoracic Society criteria for non-tuberculous mycobacterial disease: a retrospective analysis of 120 cases with four years of follow-up. AB - BACKGROUND: Non-tuberculous mycobacteria (NTM) cause disease in healthy and immunocompromised patients. The American Thoracic Society (ATS) 2007 diagnostic criteria were devised to distinguish NTM disease from airway colonization. The aim of this study was to evaluate the prognostic value of the ATS criteria. METHODS: In a 4-y follow-up study that ended on 8 June 2006, we retrospectively analyzed the symptoms, underlying diseases, and mortality of 120 adult non-HIV patients with NTM culture findings obtained between 1990 and 1998. We categorized the patients according to the 2007 ATS NTM case definition into positive and negative groups. RESULTS: Only 61/120 patients (51%) fulfilled the ATS criteria for NTM disease. As compared to ATS-negative subjects, the ATS-positive group showed lower age, a higher proportion of females, and fewer fatal underlying diseases. Among ATS-negative subjects, 46/59 (78%) did not fulfil the microbiological criteria and 43/59 (73%) did not fulfil the radiological criteria. Mycobacterium avium complex (MAC) comprised 61% of isolations in the ATS-positive and 47% in the ATS-negative group (p = 0.15). No significant difference in median survival time was found between the groups: ATS-positive 7.4 y (95% confidence interval (CI) 0.2-14.6) and ATS-negative 5.3 y (95% CI 3.0 7.6). No significant difference was found in symptoms except fatigue, which was more common in the ATS-positive (56% vs 37%, p = 0.04). Symptoms lasted for less than a year in 48%, which suggests a more rapid disease progression than has previously been reported. CONCLUSIONS: The fulfillment of ATS criteria was poorly associated with any difference in prognosis, and based on our findings would be a poor prognostic marker. PMID- 23039964 TI - GeneFriends: an online co-expression analysis tool to identify novel gene targets for aging and complex diseases. AB - BACKGROUND: Although many diseases have been well characterized at the molecular level, the underlying mechanisms are often unknown. Nearly half of all human genes remain poorly studied, yet these genes may contribute to a number of disease processes. Genes involved in common biological processes and diseases are often co-expressed. Using known disease-associated genes in a co-expression analysis may help identify and prioritize novel candidate genes for further study. RESULTS: We have created an online tool, called GeneFriends, which identifies co-expressed genes in over 1,000 mouse microarray datasets. GeneFriends can be used to assign putative functions to poorly studied genes. Using a seed list of disease-associated genes and a guilt-by-association method, GeneFriends allows users to quickly identify novel genes and transcription factors associated with a disease or process. We tested GeneFriends using seed lists for aging, cancer, and mitochondrial complex I disease. We identified several candidate genes that have previously been predicted as relevant targets. Some of the genes identified are already being tested in clinical trials, indicating the effectiveness of this approach. Co-expressed transcription factors were investigated, identifying C/ebp genes as candidate regulators of aging. Furthermore, several novel candidate genes, that may be suitable for experimental or clinical follow-up, were identified. Two of the novel candidates of unknown function that were co-expressed with cancer-associated genes were selected for experimental validation. Knock-down of their human homologs (C1ORF112 and C12ORF48) in HeLa cells slowed growth, indicating that these genes of unknown function, identified by GeneFriends, may be involved in cancer. CONCLUSIONS: GeneFriends is a resource for biologists to identify and prioritize novel candidate genes involved in biological processes and complex diseases. It is an intuitive online resource that will help drive experimentation. GeneFriends is available online at: http://genefriends.org/. PMID- 23039966 TI - Factors associated with unintended pregnancy, poor birth outcomes and post-partum contraceptive use among HIV-positive female adolescents in Kenya. AB - BACKGROUND: Although the experiences of unintended pregnancies and poor birth outcomes among adolescents aged 15-19 years in the general population are well documented, there is limited understanding of the same among those who are living with HIV. This paper examines the factors associated with experiencing unintended pregnancies, poor birth outcomes, and post-partum contraceptive use among HIV positive female adolescents in Kenya. METHODS: Data are from a cross-sectional study that captured information on pregnancy histories of HIV-positive female adolescents in four regions of Kenya: Coast, Nairobi, Nyanza and Rift Valley provinces. Study participants were identified through HIV and AIDS programs in the four regions. Out of a total of 797 female participants, 394 had ever been pregnant with 24% of them experiencing multiple pregnancies. Analysis entails the estimation of random-effects logit models. RESULTS: Higher order pregnancies were just as likely to be unintended as lower order ones (odds ratios [OR]: 1.2; 95% confidence interval [CI]: 0.8-2.0) while pregnancies occurring within marital unions were significantly less likely to be unintended compared to those occurring outside such unions (OR: 0.1; 95% CI: 0.1-0.2). Higher order pregnancies were significantly more likely to result in poor outcomes compared to lower order ones (OR: 2.5; 95% CI: 1.6-4.0). In addition, pregnancies occurring within marital unions were significantly less likely to result in poor outcomes compared to those occurring outside such unions (OR: 0.3; 95% CI: 0.1-0.9). However, experiencing unintended pregnancy was not significantly associated with adverse birth outcomes (OR: 1.3; 95% CI: 0.5-3.3). There was also no significant difference in the likelihood of post-partum contraceptive use by whether the pregnancy was unintended (OR: 0.9; 95% CI: 0.5-1.5). CONCLUSIONS: The experience of repeat unintended pregnancies among HIV-positive female adolescents in the sample is partly due to inconsistent use of contraception to prevent recurrence while poor birth outcomes among higher order pregnancies are partly due to abortion. This underscores the need for HIV and AIDS programs to provide appropriate sexual and reproductive health information and services to HIV positive adolescent clients in order to reduce the risk of undesired reproductive health outcomes. PMID- 23039967 TI - Second malignant neoplasms in childhood malignant brain tumour: a long-term population-based study. AB - AIM: To provide a profile of second malignant neoplasms (SMN) in patients with childhood primary malignant brain tumour originating from neuroepithelial tissues with latest data in a population-based study. METHODS: Surveillance, Epidemiology, and End Results (SEER) database (1973-2007) was used to identify above-stated patients. SMN patients were further identified, and standardised incidence ratios (SIRs) and excess absolute risks (EARs) for risk-factor-decided subgroups were calculated. Univariate and multivariate analyses of the association between cumulative incidence of SMN and the risk factors were performed in the whole population. RESULTS: A total of 106 patients were identified as having SMNs. EARs peaked at age at primary diagnosis of 10-14. Males had higher SIRs and EARs than females. Both SIRs and EARs increased after 1990. Age was statistically significant in both univariable and multivariable analyses for cumulative incidence of SMN and RT was not significant in both the analyses, in the whole population of 9075 patients. After follow-up recalculation, matched patients in the >=1990 group had slightly shorter median interval between primary and secondary cancer than those in the <1990 group, but with no significance. CONCLUSION: The risk of SMN in children with primary malignant brain tumours in a more advanced treatment era might have changed. During making further advances in the treatment of these neoplasms, minimising toxicities while maintaining promising prognostic outcomes will keep being our goal. PMID- 23039968 TI - Impact of counselling on exclusive breast-feeding practices in a poor urban setting in Kenya: a randomized controlled trial. AB - OBJECTIVE: To determine the impact of facility-based semi-intensive and home based intensive counselling in improving exclusive breast-feeding (EBF) in a low resource urban setting in Kenya. DESIGN: A cluster randomized controlled trial in which nine villages were assigned on a 1:1:1 ratio, by computer, to two intervention groups and a control group. The home-based intensive counselling group (HBICG) received seven counselling sessions at home by trained peers, one prenatally and six postnatally. The facility-based semi-intensive counselling group (FBSICG) received only one counselling session prenatally. The control group (CG) received no counselling from the research team. Information on infant feeding practices was collected monthly for 6 months after delivery. The data gathering team was blinded to the intervention allocation. The outcome was EBF prevalence at 6 months. SETTING: Kibera slum, Nairobi. SUBJECTS: A total of 360 HIV-negative women, 34-36 weeks pregnant, were selected from an antenatal clinic in Kibera; 120 per study group. RESULTS: Of the 360 women enrolled, 265 completed the study and were included in the analysis (CG n 89; FBSICG n 87; HBICG n 89). Analysis was by intention to treat. The prevalence of EBF at 6 months was 23.6% in HBICG, 9.2% in FBSICG and 5.6% in CG. HBICG mothers had four times increased likelihood to practise EBF compared with those in the CG (adjusted relative risk = 4.01; 95% CI 2.30, 7.01; P=0.001). There was no significant difference between EBF rates in FBSICG and CG. CONCLUSIONS: EBF can be promoted in low socio economic conditions using home-based intensive counselling. One session of facility-based counselling is not sufficient to sustain EBF. PMID- 23039969 TI - Primer design for identifying economically important Liriomyza species (Diptera: Agromyzidae) by multiplex PCR. AB - Leafminer flies, especially, Liriomyza huidobrensis, Liriomyza sativae and Liriomyza trifolii, are quarantine species in many countries. Their morphological similarity makes identification difficult. To develop a rapid, reliable, sensitive and simple molecular identification method using multiplex PCR, we newly sequenced the mitochondrial cytochrome oxidase I (COI) genes of Liriomyza bryoniae, Liriomyza chinensis, L. huidobrensis, L. sativae, L. trifolii, Chromatomyia horticola and four parasitoid species. We aligned them with all the COI sequences of the leafminer flies found in the international DNA nucleotide sequence databases (DDBJ/EMBL/GenBank). We then designed species-specific primers to allow us to differentiate between L. bryoniae, L. chinensis, L. huidobrensis, L. sativae, and L. trifolii. PMID- 23039975 TI - What is your diagnosis? Hypospadias. PMID- 23039970 TI - Effect of sample stratification on dairy GWAS results. AB - BACKGROUND: Artificial insemination and genetic selection are major factors contributing to population stratification in dairy cattle. In this study, we analyzed the effect of sample stratification and the effect of stratification correction on results of a dairy genome-wide association study (GWAS). Three methods for stratification correction were used: the efficient mixed-model association expedited (EMMAX) method accounting for correlation among all individuals, a generalized least squares (GLS) method based on half-sib intraclass correlation, and a principal component analysis (PCA) approach. RESULTS: Historical pedigree data revealed that the 1,654 contemporary cows in the GWAS were all related when traced through approximately 10-15 generations of ancestors. Genome and phenotype stratifications had a striking overlap with the half-sib structure. A large elite half-sib family of cows contributed to the detection of favorable alleles that had low frequencies in the general population and high frequencies in the elite cows and contributed to the detection of X chromosome effects. All three methods for stratification correction reduced the number of significant effects. EMMAX method had the most severe reduction in the number of significant effects, and the PCA method using 20 principal components and GLS had similar significance levels. Removal of the elite cows from the analysis without using stratification correction removed many effects that were also removed by the three methods for stratification correction, indicating that stratification correction could have removed some true effects due to the elite cows. SNP effects with good consensus between different methods and effect size distributions from USDA's Holstein genomic evaluation included the DGAT1-NIBP region of BTA14 for production traits, a SNP 45kb upstream from PIGY on BTA6 and two SNPs in NIBP on BTA14 for protein percentage. However, most of these consensus effects had similar frequencies in the elite and average cows. CONCLUSIONS: Genetic selection and extensive use of artificial insemination contributed to overlapped genome, pedigree and phenotype stratifications. The presence of an elite cluster of cows was related to the detection of rare favorable alleles that had high frequencies in the elite cluster and low frequencies in the remaining cows. Methods for stratification correction could have removed some true effects associated with genetic selection. PMID- 23039976 TI - Pathology in practice. Intraerythrocytic infection with organisms consistent with a large Babesia sp. PMID- 23039971 TI - Triple negative breast cancer in Moroccan women: clinicopathological and therapeutic study at the National Institute of Oncology. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. This is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. The aim of this study is to determine the clinicopathological, therapeutic features and outcomes associated with this type of breast cancer. METHODS: This is a retrospective study of confirmed triple negative breast cancer females collected at the National institute of oncology of Rabat in Morocco, between January 2007 and December 2008. Epidemiological, clinical, histological, therapeutic and evolutive data were analyzed. OS and DFS rates were estimated by Kaplan-Meier analysis. RESULTS: A total of one 152 patients with breast cancer, were identified as having triple-negative breast cancer (16,5%). The median age at diagnosis was 46 years. 130 patients (86%) had infiltrating ductal carcinoma and thirteen had medullar carcinoma (9%). 84 cases (55%) were grade III Scarff-Bloom Richardson (SBR). 48 % had positive lymph nodes, and 5 % had distant metastases at diagnosis. According TNM staging, 12 patients (8%) had stage I, 90 patients (60%) had stage II and the 43(28%) had stage III. 145 patients received surgery. 41 (28%) had conservative surgery and 104 (72%) received radical mastectomy with axillary lymph nodes dissection. 14 patients with advanced tumors or inflammatory breast cancer have received neoadjuvant chemotherapy and four patients (28%) had complete pathologic response. From 131 patients how received adjuvant chemotherapy, 99 patients (75,5%) had Anthracycline based chemotherapy) and 27 patients (20,6%) had sequential Anthracycline and docetaxel,. Seven patients with metastatic disease received anthracycline-based regimen in the first line metastatic chemotherapy. The median follow-up time was 46 months (range 6,1 -60 months). Overall survival at 5 years for all patients was 76,5%. CONCLUSION: These results suggest that most TNBC characteristics in Moroccan patients are in accordance with literature data, especially concerning young age at diagnosis high grade tumors, advanced stage at diagnosis, and short time to relapse. Although the high response rate to chemotherapy, the overall prognosis of this subset of tumors remains poor. PMID- 23039977 TI - Pathology in practice. Cutaneous, nonepitheliotropic T-cell lymphoma. PMID- 23039978 TI - Employment of female and male graduates of US veterinary medical colleges, 2012. PMID- 23039979 TI - Accuracy of radiographic vertebral heart score and sphericity index in the detection of pericardial effusion in dogs. AB - OBJECTIVE: To evaluate the diagnostic accuracy of radiographically derived measurements of vertebral heart score (VHS) and sphericity index (SI) in the detection of pericardial effusion (PE) in dogs. DESIGN: Retrospective case control study. Animals-51 dogs with PE associated with various cardiac disorders, 50 dogs with left- or right-sided cardiac disorders without PE, 50 dogs with bilateral cardiac disorders without PE, and 50 healthy dogs. PROCEDURES: Measurements of VHS on lateral (lateral VHS) and ventrodorsal (ventrodorsal VHS) radiographs, SI on lateral (lateral SI) and ventrodorsal (ventrodorsal SI) radiographs, and global SI (mean of lateral SI and ventrodorsal SI) were obtained. Receiver operating characteristic curves were calculated to evaluate the diagnostic accuracy of the radiographic indexes at differentiating dogs with PE from those with other cardiac disorders without PE. RESULTS: Measurements of lateral and ventrodorsal VHS were significantly higher in dogs with PE, compared with values for all dogs without PE. Measurements of lateral, ventrodorsal, and global SI were significantly lower in dogs with PE, compared with values for all dogs without PE. Cutoff values of > 11.9, > 12.3, and <= 1.17 for lateral VHS, ventrodorsal VHS, and global SI, respectively, were the most accurate radiographic indexes for identifying dogs with PE. CONCLUSIONS AND CLINICAL RELEVANCE: Cardiac silhouettes of dogs with PE were larger and more rounded, compared with those of dogs with other cardiac disorders without PE. Objective radiographic indexes of cardiac size and roundness were only moderately accurate at distinguishing dogs with PE from dogs with other cardiac disorders without PE. PMID- 23039980 TI - Comparison of efficacy, safety, and convenience of selamectin versus ivermectin for treatment of Trixacarus caviae mange in pet guinea pigs (Cavia porcellus). AB - OBJECTIVE: To determine the efficacy and safety of topical administration of selamectin and to compare selamectin treatment with a common ivermectin protocol for the treatment of natural infestation with Trixacarus caviae in pet guinea pigs. DESIGN: Clinical trial. ANIMALS: 17 mixed-breed pet guinea pigs with active mite infestation. PROCEDURES: Guinea pigs were randomly allocated to receive a single dose of selamectin topically (15 mg/kg [6.8 mg/lb]) or ivermectin (400 MUg/kg [181.8 MUg/lb], SC) every 10 days for 4 injections. Microscopic examination of skin scrapings from all animals was performed at 10-day intervals for 60 days, and the presence of mites or mite eggs was recorded. The efficacies of the 2 treatment protocols were compared at every time point. RESULTS: Pruritus resolved by day 10 in all animals. Animals were microscopically mite-free on days 30 and 40 in the selamectin and ivermectin treatment groups, respectively, but groups did not differ significantly in regard to the number of mite-positive animals at any timepoint. Recurrence of infection was not noted in either treatment group. No adverse reactions were observed in any of the treated animals. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that a single topical application of selamectin at a dose of 15 mg/kg or repeated SC injection of ivermectin at a dose of 400 MUg/kg can eliminate T caviae mites from guinea pigs within 30 and 40 days, respectively. Although effectiveness did not significantly differ between the 2 treatments, the convenience associated with the single topical dose of selamectin made it a preferable treatment modality for both patients and owners. PMID- 23039981 TI - Baclofen toxicosis in dogs and cats: 145 cases (2004-2010). AB - OBJECTIVE: To identify dogs and cats with baclofen toxicosis and characterize the patient population, clinical signs, and outcome. DESIGN: Retrospective case series. ANIMALS: 140 dogs and 5 cats with baclofen toxicosis. PROCEDURES: An animal poison control center electronic database was reviewed from November 2004 through April 2010 to identify dogs and cats with baclofen toxicosis. Information on signalment, clinical signs, and amount of baclofen ingested was obtained. Clinical signs were categorized as CNS, gastrointestinal, general malaise, cardiovascular, respiratory, or urogenital. Follow-up communications were performed to determine overall outcome. RESULTS: Dogs had a median age of 0.67 years (range, 0.1 to 15 years) and cats of 1 year (range, 0.7 to 16 years). Of 145 patients, 133 (92%) developed clinical signs of baclofen toxicosis. A total of 259 signs fell within defined categories: CNS (121/259 [46.7%]), gastrointestinal (69/259 [26.6%]), general malaise (27/259 [10.4%]), cardiovascular (23/259 [8.9%]), respiratory (14/259 [5.4%]), and urogenital (5/259 [1.9%]). For 68 dogs with known survival status, survival rate was 83.8% (57/68); of these dogs, the amount of baclofen ingested was known for 53 (46 survivors and 7 nonsurvivors). Amount of baclofen ingested was significantly lower in survivor dogs (median, 4.2 mg/kg [1.91 mg/lb]; range, 0.61 to 61 mg/kg [0.28 to 27.7 mg/lb]), compared with nonsurvivor dogs (median, 14 mg/kg [6.4 mg/lb]; range, 2.3 to 52.3 mg/kg [1.04 to 23.77 mg/lb]. Of 5 cats, 2 survived, 1 died, and 2 had unknown outcomes. CONCLUSIONS AND CLINICAL RELEVANCE: Clinical signs of baclofen toxicosis occurred in most patients, with the CNS being the system most commonly affected. PMID- 23039982 TI - Tumor thrombus formation in two dogs with insulinomas. AB - CASE DESCRIPTION: A 9-year-old sexually intact male Staffordshire Bull Terrier and a 9-year-old neutered male Boxer were evaluated for intermittent neurologic signs including muscle tremors, ataxia, episodic collapse, disorientation, and seizures. CLINICAL FINDINGS: Both dogs had low blood glucose and high serum insulin concentrations. Results of abdominal ultrasonography were unremarkable for both dogs. Exploratory laparotomy revealed a mass that extended from the body of the pancreas into the pancreaticoduodenal vein in each dog. TREATMENT AND OUTCOME: Marginal resection of pancreatic masses was performed, and tumor thrombi were removed via venotomy in both dogs. Histologic evaluation indicated the masses were pancreatic islet cell tumors with tumor thrombi. Clinical signs resolved following surgical resection of tumors and tumor thrombi, and the dogs were euglycemic during the follow-up period (17 and 45 months after surgery). CLINICAL RELEVANCE: Although gross tumor thrombus formation has been identified in humans with insulinomas, tumor thrombi have not been previously reported for dogs with insulinomas. Surgical removal of tumor thrombi via venotomy seemed to be well tolerated by the dogs. Tumor thrombus formation did not seem to adversely affect prognosis for the 2 dogs of this report. PMID- 23039983 TI - Evaluation of foal production following intracytoplasmic sperm injection and blastocyst culture of oocytes from ovaries collected immediately before euthanasia or after death of mares under field conditions. AB - OBJECTIVE: To evaluate the efficiency of foal production following intracytoplasmic sperm injection (ICSI) and blastocyst culture of oocytes from mares that died or were euthanized under field conditions. DESIGN: Prospective case series. ANIMALS: 16 mares (age, 3 to 19 years) that died or were euthanized for various causes. PROCEDURES: Ovaries were collected immediately before euthanasia (n = 10) or after death (6). Ovaries were transported to the laboratory for oocyte recovery (15 mares), or oocytes were recovered at a remote location and shipped to the laboratory (1). Oocytes underwent ICSI, and presumptive zygotes were cultured for 7 to 10 days. Blastocysts were shipped to embryo transfer facilities for transcervical transfer to recipient mares. RESULTS: Ovaries were processed 30 minutes to 12 hours (mean +/- SD, 4.6 +/- 3.3 hours) after mares' deaths. A mean of 14.1 +/- 8.6 oocytes/mare were cultured, and 110 of 225 (49%) matured. Twenty-one blastocysts developed after ICSI and were transferred to recipient mares. Thirteen pregnancies were established; 10 healthy foals were produced from 6 donor mares. The number of blastocysts produced per mare and number of live foals produced per mare were significantly correlated with the number of oocytes recovered. CONCLUSIONS AND CLINICAL RELEVANCE: Foals were produced from mares after death or euthanasia under field conditions. Proportions of foals born overall (10 foals/16 mares) and mares from which >= 1 foal was produced (6/16) were greater than those reported following recovery and oviductal transfer of oocytes to inseminated recipients after death of donor mares under field conditions. PMID- 23039985 TI - Effect of orally administered electrolyte solution formulation on abomasal luminal pH and emptying rate in dairy calves. AB - OBJECTIVE: To determine the effects of 3 commercially available, orally administered electrolyte solutions (OAEs) on abomasal luminal pH and emptying rate in dairy calves, compared with the effect of orally administered milk replacer. DESIGN: Randomized crossover study. ANIMALS: 6 male dairy calves (age, 12 to 31 days). PROCEDURES: Calves were surgically instrumented with an abomasal cannula and were administered 4 treatments in randomized order: all-milk protein milk replacer, high-glucose high-bicarbonate OAE, high-glucose high-bicarbonate OAE containing glycine, and low-glucose OAE containing acetate and propionate. Abomasal luminal pH was measured with a miniature glass pH electrode prior to treatment administration and every second afterward for 24 hours. RESULTS: Feeding of orally administered milk replacer resulted in a rapid increase in mean abomasal luminal pH from 1.3 to 5.8, followed by a gradual decrease to preprandial values by 8 hours afterward (mean 24-hour pH, 3.2). High-glucose high bicarbonate OAEs caused a large and sustained increase from 1.3 to 7.5 (mean 24 hour pH, 4.1 for the solution without glycine and 3.5 for the solution with glycine). In contrast, feeding of the acetate-containing OAE was followed by only a mild and transient increase (mean 24-hour pH, 2.1); luminal pH returned to preprandial values by 3 hours after ingestion. CONCLUSIONS AND CLINICAL RELEVANCE: Ingestion of a bicarbonate-containing OAE resulted in sustained abomasal alkalinization in dairy calves. Because persistently high abomasal luminal pH may facilitate growth of enteropathogenic bacteria, administration of OAEs containing a high bicarbonate concentration (> 70mM) is not recommended for calves with diarrhea. PMID- 23039986 TI - Echocardiographic findings and clinical signs in dairy cows with primary cardiac lymphoma: 7 cases (2007-2010). AB - OBJECTIVE: To describe echocardiographic and clinical findings in cattle with cardiac manifestation of lymphoma. DESIGN: Retrospective case series. ANIMALS: 7 adult Holstein dairy cows with cardiac lymphoma. PROCEDURES: Medical and necropsy records of all cows that underwent transthoracic echocardiography from January 2007 through April 2010 because of clinical signs of cardiac diseases or bovine lymphoma were reviewed. The diagnosis of cardiac manifestation of lymphoma was confirmed by necropsy examination or cytologic evaluation of pericardial fluid obtained by pericardiocentesis. RESULTS: Most commonly, cows had clinical signs of right-sided congestive heart failure secondary to cardiac tamponade with moderate to severe anechoic pericardial effusion (5/7 cows). In 2 cows, tachycardia was the only clinical sign in relation to cardiac disease and a heterogenic mass was observed protruding into the right atrium. CONCLUSIONS AND CLINICAL RELEVANCE: The use of transthoracic echocardiography aided in the diagnosis of primary cardiac lymphoma in cows. Transthoracic echocardiography may help to quantify the severity of pericardial effusion and to orient needle placement for pericardiocentesis to determine a final diagnosis. A mass within the right atrium was also suggestive of cardiac lymphoma and should be differentiated from mural bacterial endocarditis. PMID- 23039987 TI - Evaluation of Cytauxzoon felis infection status in captive-born wild felids housed in an area endemic for the pathogen. AB - OBJECTIVE: To determine whether apparently healthy captive-born wild felids that were not native to North America and were housed in an area endemic for Cytauxzoon felis harbored the pathogen. DESIGN: Prospective observational case series. ANIMALS: 11 captive-born wild felids that were (1 bobcat [Lynx rufus] and 1 cougar [Puma concolor]) or were not (1 lion [Panthera leo] and 8 tigers [Panthera tigris]) native to North America and 6 domestic cats (5 pets and 1 feral). PROCEDURES: Blood was collected, and a PCR assay for C felis was performed. The C felis 18S rRNA gene sequence was characterized in samples that tested positive. Blood smears were evaluated microscopically for intraerythrocytic organisms consistent with C felis. Blood smears from an additional 6 feral domestic cats found dead on the study premises were also evaluated. RESULTS: 4 tigers and 6 domestic cats without clinical signs of disease tested positive for C felis infection via PCR assay; intraerythrocytic organisms consistent with C felis were identified in smears from 1 C felis infected tiger (which also had azotemia) and in smears from 11 of 12 domestic cats. Possible erythrocytic inclusions were identified in 1 tiger that tested negative for C felis. Sequences of C felis 18S rRNA amplicons from all infected tigers shared > 99.8% identity with reported C felis sequences from North American domestic cats and were identical to amplicons from domestic cats on the premises. CONCLUSIONS AND CLINICAL RELEVANCE: Captive tigers without clinical signs of disease tested positive for C felis. The PCR assay for C felis appeared to be more reliable than cytologic detection of piroplasms in tigers. PMID- 23039988 TI - Ethnic and gender differences in rates of congenital adrenal hyperplasia in Western Australia over a 21 year period. AB - AIM: To evaluate the incidence, sex distribution, ethnicity, age at diagnosis, clinical presentation and morbidity of all childhood-onset congenital adrenal hyperplasia (CAH) cases in Western Australia (WA) between 1990 and 2010, a state where newborn screening for CAH is not in place. METHODS: The total number of all known CAH cases was identified. Case files were reviewed retrospectively to determine clinical details. Classical CAH (C-CAH) was defined as patients presenting before 6 months of age and non-classical (NC-CAH) as presenting after 6 months. RESULTS: Of the 41 CAH cases (26 female) born in WA, 5(12.2%) were of Aboriginal ethnicity. CAH was due to 21-hydroxylase deficiency in 40 cases. Of those with 21-hydroxylase deficiency, 37 were C-CAH (25 female) and 3 NC-CAH (all male). The incidence of C-CAH in WA was estimated to be 0.67 per 10, 000 live births (1:14, 869). The incidence rate ratio of Aboriginal compared with non Aboriginal C-CAH was 2.45 (95% confidence interval 0.96-6.29). The mean age of diagnosis of C-CAH cases was lower in females (8.9 +/- 2.5 days) compared to males (23.4 +/- 9.8 days). Among these males, 72.7% presented initially with adrenal crisis. CONCLUSION: The estimated incidence of classical CAH is similar to composite worldwide data. The increased female-to-male ratio is not in keeping with the expected sex distribution seen in a recessively inherited disease. The delayed diagnosis in males, with a significant proportion presenting with adrenal crisis, could be avoided with newborn screening. The higher rate of CAH in patients with Aboriginal ethnicity is a novel observation. PMID- 23039989 TI - Metabolic control and treatment patterns in patients with type 1 diabetes in Castilla-La Mancha: the DIAbetes tipo 1 in Castilla La Mancha study. AB - OBJECTIVE: To assess glycemic control, the degree of control of cardiovascular risk factors, and treatment schemes used in patients with type 1 diabetes mellitus (T1DM) in Castilla-La Mancha (Spain). PATIENTS AND METHODS: A cross sectional, multicenter study on adult patients with T1DM seen at outpatient endocrinology clinics for 12 months (from September 2009 to August 2010). Diabetes duration was > 5 years in all cases. Sociodemographic, clinical, anthropometric, and laboratory variables were collected, as well as treatment data. A multivariate logistic regression analysis was used to assess variables independently associated to good glycemic control. RESULTS: A total of 1465 patients (48.5% women) with a mean age of 39.4+/-13.5 years and a mean diabetes duration of 19.4+/-10.6 years, were enrolled. Mean glycosylated hemoglobin (HbA1c) level was 7.8%, and 26% had HbA1c values <=7%. Predictors of good glycemic control (HBA1c <=7%) included intensive insulin treatment [odds ratio (OR): 2.56], non-smoking status (OR: 1.66), and a higher educational level (OR: 1.33). Fifteen percent of patients were obese, 35% had dyslipidemia, 23% were hypertensive, and 26% smoked. Four or more of the recommended control goals were achieved by 68% of patients, but more than 33% required additional drug treatment. CONCLUSIONS: Glycemic control was inadequate in this cohort of T1DM patients. Promotion of healthy attitudes and intensification of insulin treatment may improve glycemic control. Prevalence of cardiovascular risk factors is high, although a great proportion of patients achieve good lipid and blood pressure control. PMID- 23039991 TI - Disseminated sparganosis in a cynomolgus macaque (Macaca fascicularis). AB - An adult male cynomolgus macaque (Macaca fascicularis) from Mauritius arrived at our facility in France after a 1-year period of quarantine in Spain. Clinical examination soon after arrival revealed the presence of numerous firm cutaneous and subcutaneous nodules (0.1-0.5 cm diameter) in the scrotal and inguinal areas, and persistent mild eosinophilia. On necropsy examination additional similar nodules were found in the peritoneum and abdominal wall, omentum and mesentery. Microscopical examination revealed disseminated eosinophilic granulomas containing tapeworm larvae identified as Spirometra erinaceieuropaei by direct sequencing of the cox1 gene. PMID- 23039990 TI - Identification, characterization, and utilization of genome-wide simple sequence repeats to identify a QTL for acidity in apple. AB - BACKGROUND: Apple is an economically important fruit crop worldwide. Developing a genetic linkage map is a critical step towards mapping and cloning of genes responsible for important horticultural traits in apple. To facilitate linkage map construction, we surveyed and characterized the distribution and frequency of perfect microsatellites in assembled contig sequences of the apple genome. RESULTS: A total of 28,538 SSRs have been identified in the apple genome, with an overall density of 40.8 SSRs per Mb. Di-nucleotide repeats are the most frequent microsatellites in the apple genome, accounting for 71.9% of all microsatellites. AT/TA repeats are the most frequent in genomic regions, accounting for 38.3% of all the G-SSRs, while AG/GA dimers prevail in transcribed sequences, and account for 59.4% of all EST-SSRs. A total set of 310 SSRs is selected to amplify eight apple genotypes. Of these, 245 (79.0%) are found to be polymorphic among cultivars and wild species tested. AG/GA motifs in genomic regions have detected more alleles and higher PIC values than AT/TA or AC/CA motifs. Moreover, AG/GA repeats are more variable than any other dimers in apple, and should be preferentially selected for studies, such as genetic diversity and linkage map construction. A total of 54 newly developed apple SSRs have been genetically mapped. Interestingly, clustering of markers with distorted segregation is observed on linkage groups 1, 2, 10, 15, and 16. A QTL responsible for malic acid content of apple fruits is detected on linkage group 8, and accounts for ~13.5% of the observed phenotypic variation. CONCLUSIONS: This study demonstrates that di-nucleotide repeats are prevalent in the apple genome and that AT/TA and AG/GA repeats are the most frequent in genomic and transcribed sequences of apple, respectively. All SSR motifs identified in this study as well as those newly mapped SSRs will serve as valuable resources for pursuing apple genetic studies, aiding the apple breeding community in marker-assisted breeding, and for performing comparative genomic studies in Rosaceae. PMID- 23039992 TI - RANKL employs distinct binding modes to engage RANK and the osteoprotegerin decoy receptor. AB - Osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB (RANK) are members of the tumor necrosis factor receptor (TNFR) superfamily that regulate osteoclast formation and function by competing for RANK ligand (RANKL). RANKL promotes osteoclast development through RANK activation, while OPG inhibits this process by sequestering RANKL. For comparison, we solved crystal structures of RANKL with RANK and RANKL with OPG. Complementary biochemical and functional studies reveal that the monomeric cytokine-binding region of OPG binds RANKL with ~500-fold higher affinity than RANK and inhibits RANKL-stimulated osteoclastogenesis ~150 times more effectively, in part because the binding cleft of RANKL makes unique contacts with OPG. Several side chains as well as the C-D and D-E loops of RANKL occupy different orientations when bound to OPG versus RANK. High affinity OPG binding requires a 90s loop Phe residue that is mutated in juvenile Paget's disease. These results suggest cytokine plasticity may help to fine-tune specific tumor necrosis factor (TNF)-family cytokine/receptor pair selectivity. PMID- 23039993 TI - [A randomised prospective comparative study between laparoscopic cholecystectomy and single port cholecystectomy in a major outpatient surgery unit]. AB - INTRODUCTION: The aim of this study is to compare laparoscopic cholecystectomy (LC) with that performed using single umbilical incision laparoscopic surgery (SILS) in a major outpatient surgery (MOS) unit. MATERIAL AND METHODS: A total of 50 patients with symptomatic cholelithiasis were prospectively randomised between October 2009 and June 2011, with 26 of them subjected to SILS, and 24 to CL. The variables analysed were, postoperative pain, analgesia requirements, presence of nausea/vomiting, operation time, complications, outpatient success rate, and aesthetic results. RESULTS: There were no differences as regards postoperative pain, analgesia rescue, nausea/vomiting, or operation time (SILS 54 +/- 21 min, CL 48.5 +/- 17 min, P=.29). There was one case of morbidity in the SILS group which required further surgery. The outpatient surgical procedure was completed in 77% of patients of the SILS group, and in 83% of the CL group. Six patients (23%) from the SILS group, and 4 (17%) from the CL group remained in the unit for more than 24h (P=.58). The aesthetic results were subjectively assessed as "very good" in the SILS group, and "good" in the CL group. CONCLUSION: SILS cholecystectomy is feasible and safe when comparing it with laparoscopic cholecystectomy in selected patients, and obtains similar results when performed in a MOS unit. Larger studies are needed to determine the real benefits of this approach before recommending it as a routine technique. With more experienced surgical teams and greater awareness of the patients could possibly increase the number of candidates for outpatient cholecystectomy. PMID- 23039994 TI - Designing synthetic regulatory networks capable of self-organizing cell polarization. AB - How cells form global, self-organized structures using genetically encoded molecular rules remains elusive. Here, we take a synthetic biology approach to investigate the design principles governing cell polarization. First, using a coarse-grained computational model, we searched for all possible simple networks that can achieve polarization. All solutions contained one of three minimal motifs: positive feedback, mutual inhibition, or inhibitor with positive feedback. These minimal motifs alone could achieve polarization under limited conditions; circuits that combined two or more of these motifs were significantly more robust. With these design principles as a blueprint, we experimentally constructed artificial polarization networks in yeast, using a toolkit of chimeric signaling proteins that spatially direct the synthesis and degradation of phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)). Circuits with combinatorial motifs yielded clear foci of synthetic PIP(3) that can persist for nearly an hour. Thus, by harnessing localization-regulated signaling molecules, we can engineer simple molecular circuits that reliably execute spatial self organized programs. PMID- 23039995 TI - Changes in brain morphology in albinism reflect reduced visual acuity. AB - Albinism, in humans and many animal species, has a major impact on the visual system, leading to reduced acuity, lack of binocular function and nystagmus. In addition to the lack of a foveal pit, there is a disruption to the routing of the nerve fibers crossing at the optic chiasm, resulting in excessive crossing of fibers to the contralateral hemisphere. However, very little is known about the effect of this misrouting on the structure of the post-chiasmatic visual pathway, and the occipital lobes in particular. Whole-brain analyses of cortical thickness in a large cohort of subjects with albinism showed an increase in cortical thickness, relative to control subjects, particularly in posterior V1, corresponding to the foveal representation. Furthermore, mean cortical thickness across entire V1 was significantly greater in these subjects compared to controls and negatively correlated with visual acuity in albinism. Additionally, the group with albinism showed decreased gyrification in the left ventral occipital lobe. While the increase in cortical thickness in V1, also found in congenitally blind subjects, has been interpreted to reflect a lack of pruning, the decreased gyrification in the ventral extrastriate cortex may reflect the reduced input to the foveal regions of the ventral visual stream. PMID- 23039996 TI - Self-relevance modulates brain responses to angry body expressions. AB - In a social context, the direction of the body of surrounding agents indicates whether one is the potential target of an impending action or simply an observer, and thus influences the way one processes and reacts to their emotional expressions. The present functional magnetic resonance imaging experiment investigated how self-relevance influences anger processing in the brain by independently manipulating target (oriented to self or to other) and emotion (neutral and anger). The perception of body expression of anger elicits activity in a previously identified network that includes the amygdala, the fusiform gyrus, the superior temporal sulcus and the premotor cortex. Activity within this network is independent of body direction and is parametrically modulated by the intensity of the bodily emotional expression. Moreover, the ventromedial prefrontal cortex and somatosensory cortices responded preferentially to anger expressions oriented to self. We suggest that these brain areas may participate in the selection of specific behavioural strategies when one is the potential target of someone's anger. PMID- 23039998 TI - Unanswered questions about the role of axillary dissection in women with invasive breast cancer and sentinel node metastasis. PMID- 23039999 TI - Clinical significance and management of sentinel node micrometastasis in invasive breast cancer. AB - Axillary node status is one of the most important prognostic indicators in patients with invasive breast cancer. Sentinel node biopsy allows an exhaustive examination of the lymph node and has led to an increased detection rate of small tumor deposits. Patients with micrometastatic deposits can have nonsentinel node involvement, including macrometastatic deposits. Sentinel node micrometastases are associated with an adverse impact on disease recurrence and survival. Axillary dissection does not offer an advantage in reducing the incidence of disease recurrence or survival. However, the long-term outcomes can be improved with the use of adjuvant chemotherapy, and it would be reasonable to consider systemic treatment in these patients. PMID- 23040001 TI - Magnetic resonance imaging features in triple-negative breast cancer: comparison with luminal and HER2-overexpressing tumors. AB - BACKGROUND: It has been ascertained that triple-negative (TN) breast cancer is characterized by an aggressive clinical course and a poor prognosis. The purpose of our study was to compare the magnetic resonance imaging (MRI) features of the 3 major different breast cancer subtypes (TN, luminal, and human epidermal growth factor receptor 2 [HER2]-overexpressing) and to suggest the criteria that might predict TN phenotype. MATERIALS AND METHODS: From October 2007 to April 2011, we studied 77 patients with histologically confirmed TN breast cancer who underwent breast MRI. We randomly included 148 patients with non-TN breast cancer (110 luminal and 38 HER-overexpressing) as a control group. We evaluated the clinicopathologic data, the MRI morphologic and kinetic features, the signal intensity on T2-weighted images, and the apparent diffusion coefficient (ADC). RESULTS: Our results confirmed that TN tumors are more aggressive, are usually diagnosed at a younger age compared with the other study groups, and show benign morphologic features with MRI. Backward stepwise logistic regression identified some parameters as independent predictors of TN-type lesions: age, size, shape, presence of edema, and infiltrative characteristics. The receiver operating characteristic (ROC) curve, built with 4 of 5 these factors as criteria to predict TN status, showed a 0.664 area under the curve (AUC) value (sensitivity 58.4%, specificity 73.2%). The inclusion of the fifth criterion showed a 0.699 AUC value (sensitivity, 49.4%; specificity, 89.4%). CONCLUSION: We identified the clinicoradiologic parameters that are independent predictors of TN breast lesions, which might be helpful for earlier prediction of the TN status of a breast lesion. PMID- 23040002 TI - Prognostic value of circulating tumor cells according to immunohistochemically defined molecular subtypes in advanced breast cancer. AB - BACKGROUND: Breast cancer is a heterogeneous disease. Circulating tumor cell (CTC) enumeration might be useful to identify different risk categories within each molecular subtype. METHODS: We retrospectively analyzed 203 consecutive patients with metastatic breast cancer with baseline CTC enumeration performed with CellSearch (Veridex Corp, Warren, NJ) between March 2005 and July 2011. Patients were categorized into 3 prognostic groups based on the number of CTCs (0, 1-4, and >= 5) and into 5 categories based on tumor biological characteristics: luminal-A (estrogen receptor [ER] and progesterone receptor [PR] > 1%, grade 1/2, human epidermal growth factor 2 [HER2]-negative [HER2(-)], Ki67 value < 14%); luminal-B (ER and/or PR > 1%, grade 3, HER2(-), Ki67 value > 14%); luminal-B HER2-positive [HER2(+)] (ER and/or PR > 1%, any grade, HER2(+), Ki-67 value any); HER2(+) (HER2 overexpressed/fluorescence in situ hybridization [FISH] amplified, ER and PR absent); triple negative (TN) (ER and PR 0%, HER2 not overexpressed/FISH not amplified). RESULTS: Median age was 57 years (range 31-78 years). Twenty-seven patients (13.3%) had luminal-A category, 105 (51.7%) patients had luminal-B, 29 (14.3%) patients had luminal-B HER2(+), 24 patients (11.8%) had HER2(+), and 18 patients (8.9%) had TN. CTCs were mostly found in patients with luminal-A/luminal-B HER2(-) subtype. At multivariable analysis, CTC count was a significant predictive factor for overall survival (OS) in all molecular subtypes (log-rank P < .01). Patients with 0 CTCs/7.5 mL blood and all subtypes, except HER2(+), seem to perform better compared with other categories. CONCLUSION: These findings confirm CTCs as an important prognostic factor for metastatic breast cancer in all molecular subtypes. Larger studies could help identify metastatic breast cancer subgroups in which CTC analysis would be particularly useful. PMID- 23040000 TI - Phase II study of gemcitabine and bevacizumab as first-line treatment in taxane pretreated, HER2-negative, locally recurrent or metastatic breast cancer. AB - BACKGROUND: In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine. PATIENTS: Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane containing regimen in the neoadjuvant and/or adjuvant setting with a >= 12-month disease-free interval. METHODS: This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m(2)) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%). CONCLUSION: Although the gemcitabine bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination. PMID- 23040003 TI - A pictorial journey through variants of ductal carcinoma in situ (DCIS) and DCIS mimickers. AB - Unusual variants of DCIS and DCIS mimickers are presented in this article. Examples of DCIS with a high propensity for underdiagnosis or misclassification, pertinent immunoperoxidase workups, the results of prognostic/predictive markers, and relevant clinical follow-up are also provided in certain cases. The currently controversial entities are also discussed. PMID- 23040004 TI - Impact of body mass index on survival outcome among women with early stage triple negative breast cancer. AB - BACKGROUND: The aim of this retrospective study was to examine the prognostic impact of obesity among women with early stage triple receptor-negative breast cancer (TN), a subtype of breast cancer known to be associated with poor prognosis. PATIENTS AND METHODS: Women with stage I-III TN breast cancer diagnosed between 1990 and 2010 were identified. The cohort was divided into 3 groups according to BMI: normal or underweight (BMI < 25), overweight (BMI 25 29.9), and obese (BMI >= 30). Distant disease-free survival (DDFS) was estimated using the Kaplan-Meier product limit method and compared across groups using log rank statistic. Cox proportional hazards models were then used to determine the association of DDFS and BMI after adjusting for patient and tumor characteristics. RESULTS: Of 2311 patients, we identified 794 (34.3%), 692 (30%), and 825 (35.7%), who had BMI of < 25, 25 to 29.9, and >= 30, respectively. Median follow-up was 39 months (range, 1-233 months). Five-year DDFS was 61%, 62%, and 62% among patients with BMI of <25, 25 to 29.9, and >= 30, respectively. On multivariate analysis, compared with patients with BMI <25, patients with BMI 25 29.9 (hazard ratio [HR] = 1.04; 95% confidence interval [CI], 87-1.25; P = .66) and those with BMI >= 30 (HR = 0.99; 95% CI, 83-1.18; P = .89) did not have a significant increase in risk of distant metastases. When the models were stratified by menopausal status similar results were obtained. CONCLUSIONS: Patients with TN disease have a poor prognostic outcome regardless of BMI category. As such, the results of this study indicate that obesity does not function as a prognostic indicator among patients with TN disease. PMID- 23040005 TI - Sentinel lymph node involvement in ductal carcinoma in-situ of the breast: two different causes. PMID- 23040006 TI - Increasing student nurses' knowledge of breastfeeding in baccalaureate education. AB - Nurses are the largest group of health care professionals capable of providing crucial support to new parents (Marzalik, 2004). However, studies show that nurses' knowledge of breastfeeding is inadequate and most nursing programs do not include breastfeeding in their curriculum. Therefore nursing graduates enter the field of maternal child care with little or no ability to assist new mothers. A pilot program was implemented at a major university to evaluate the effect of adding specific breastfeeding content to the nursing curriculum. A pre-post-test method was used to evaluate nursing students who were provided a comprehensive lecture on evidence-based breastfeeding information with audiovisual components and resources. This education pilot showed the inclusion of breastfeeding education significantly increased student knowledge of the benefits and nutritional value of breastfeeding and management of lactation complications. PMID- 23040007 TI - Transient therapy-related surge in serum tumor biomarkers: characterizing behavior and postulating its biologic role. AB - A phenomenon of serum tumor biomarker surge or flare that ensues shortly after initiating cancer therapy and that may precede the actual therapeutic response related decline is poorly understood and remains under-appreciated. However, it may have a significant clinical implication as it could be misinterpreted in clinical practice as therapeutic failure and lead to a premature discontinuation of potentially effective therapy. Therefore, in the present study, attempts have been made to understand the behavior of this phenomenon with respect to a reported median incidence, duration, and its relationship to clinical response. The results of these analyses suggest a significantly lower incidence of this phenomenon with carcinoembryonic antigen (CEA) as determined in colorectal cancer and prostate specific antigen (PSA) in prostate cancer as compared to the other biomarkers studied (p=0.006). Furthermore, regardless of the type of biomarker or the extent of its incidence, a therapy-related initial surge appears to correlate with eventual response to therapy. Although, the biologic significance of this phenomenon is currently elusive, two distinct hypothesis-generating cases with CEA and alpha-fetoprotein (AFP) are presented that, if supported by further research, would provide insights into the role of a biomarker surge in overall tumor growth control by cancer therapy. PMID- 23040008 TI - Emergence of OXA-48-producing Enterobacteriaceae in Switzerland. PMID- 23040009 TI - Low prevalence of vancomycin heteroresistance among meticillin-resistant Staphylococcus aureus causing bacteraemia in Hong Kong. PMID- 23040010 TI - Occurrence of OXA-48 and VIM-1 carbapenemase-producing Enterobacteriaceae in Egypt. PMID- 23040011 TI - Anatomic brain disease in hemodialysis patients: a cross-sectional study. AB - BACKGROUND: Although dialysis patients are at high risk of stroke and have a high burden of cognitive impairment, there are few reports of anatomic brain findings in the hemodialysis population. Using magnetic resonance imaging of the brain, we compared the prevalence of brain abnormalities in hemodialysis patients with that in a control population without known kidney disease. STUDY DESIGN: Cross sectional cohort. SETTING & PARTICIPANTS: 45 maintenance hemodialysis patients and 67 controls without reported kidney disease, both without history of known stroke. PREDICTOR: The primary predictor was dialysis status. Covariates included demographics (age, race, and sex), vascular risk factors (diabetes and hypertension), and cardiovascular disease (coronary artery disease and congestive heart failure). OUTCOMES: Magnetic resonance imaging of the brain features, including severity of white matter disease and cerebral atrophy (sulcal prominence and ventricular atrophy), hippocampal size, and small-/large-vessel infarcts. MEASUREMENTS: Semiquantitative scale (0-9 for white matter disease and cerebral atrophy, 0-3 for hippocampal size) and infarct prevalence. RESULTS: Mean ages of hemodialysis patients and controls were 55 +/- 17 (SD) and 53 +/- 13 years, respectively. In comparison to controls, hemodialysis patients had more severe white matter disease (1.6 vs 0.7) and cerebral atrophy (sulcal prominence, 2.3 vs 0.6; ventricular enlargement, 2.3 vs 0.9; hippocampal size, 1.3 vs 1.0), with all P < 0.001. In multivariable analyses, hemodialysis status was associated independently with worse white matter disease and atrophy grades. Hemodialysis patients also had a higher prevalence of small- (17.8%) and large- (7.8%) vessel infarcts than controls (combined, 22% vs 0%; P < 0.001). LIMITATIONS: The dialysis cohort likely is healthier than the overall US hemodialysis population, partly limiting generalizability. CONCLUSIONS: Hemodialysis patients have more white matter disease and cerebral atrophy compared with controls without known kidney disease. Hemodialysis patients also have a high prevalence of unrecognized infarcts. PMID- 23040013 TI - Plasma pharmacokinetics and milk residues of flunixin and 5-hydroxy flunixin following different routes of administration in dairy cattle. AB - The objective of this study was to determine if the plasma pharmacokinetics and milk elimination of flunixin (FLU) and 5-hydroxy flunixin (5OH) differ following intramuscular and subcutaneous injection of FLU compared with intravenous injection. Twelve lactating Holstein cows were used in a randomized crossover design study. Cows were organized into 2 groups based on milk production (<20 or >30 kg of milk/d). All cattle were administered 2 doses of 1.1mg of FLU/kg at 12 h intervals by intravenous, intramuscular, and subcutaneous injections. The washout period between routes of administration was 7d. Blood samples were collected from the jugular vein before FLU administration and at various time points up to 36 h after the first dose of FLU. Composite milk samples were collected before FLU administration and twice daily for 5d after the first dose of FLU. Samples were analyzed by ultra-HPLC with mass spectrometric detection. For FLU plasma samples, a difference in terminal half-life was observed among routes of administration. Harmonic mean terminal half-lives for FLU were 3.42, 4.48, and 5.39 h for intravenous, intramuscular, and subcutaneous injection, respectively. The mean bioavailability following intramuscular and subcutaneous dosing was 84.5 and 104.2%, respectively. The decrease in 5OH milk concentration versus time after last dose was analyzed with the nonlinear mixed effects modeling approach and indicated that both the route of administration and rate of milk production were significant covariates. The number of milk samples greater than the tolerance limit for each route of administration was also compared at each time point for statistical significance. Forty-eight hours after the first dose, 5OH milk concentrations were undetectable in all intravenously injected cows; however, one intramuscularly injected and one subcutaneously injected cow had measurable concentrations. These cows had 5OH concentrations above the tolerance limit at the 36-h withdrawal time. The high number of FLU residues identified in cull dairy cows by the United States Department of Agriculture Food Safety Inspection Service is likely related to administration of the drug by an unapproved route. Cattle that received FLU by the approved (intravenous) route consistently eliminated the drug before the approved withdrawal times; however, residues can persist beyond these approved times following intramuscular or subcutaneous administration. Cows producing less than 20 kg of milk/d had altered FLU milk clearance, which may also contribute to violative FLU residues. PMID- 23040012 TI - Distinct composition of bovine milk from Jersey and Holstein-Friesian cows with good, poor, or noncoagulation properties as reflected in protein genetic variants and isoforms. AB - The objective of this study was to examine variation in overall milk, protein, and mineral composition of bovine milk in relation to rennet-induced coagulation, with the aim of elucidating the underlying causes of milk with impaired coagulation abilities. On the basis of an initial screening of 892 milk samples from 42 herds with Danish Jersey and Holstein-Friesian cows, a subset of 102 samples was selected to represent milk with good, poor, or noncoagulating properties (i.e., samples that within each breed represented the most extremes in regard to coagulation properties). Milk with good coagulation characteristics was defined as milk forming a strong coagulum based on oscillatory rheology, as indicated by high values for maximum coagulum strength (G'(max)) and curd firming rate (CFR) and a short rennet coagulation time. Poorly coagulating milk formed a weak coagulum, with a low G'(max) and CFR and a long rennet coagulation time. Noncoagulating milk was defined as milk that failed to form a coagulum, having G'(max) and CFR values of zero at measurements taken within 1h after addition of rennet. For both breeds, a lower content of total protein, total casein (CN) and kappa-CN, and lower levels of minerals (Ca, P, Mg) were identified in poorly coagulating and noncoagulating milk in comparison with milk with good coagulation properties. Liquid chromatography/electrospray ionization-mass spectrometry revealed the presence of a great variety of genetic variants of the major milk proteins, namely, alpha(S1)-CN (variants B and C), alpha(S2)-CN (A), beta-CN (A(1), A(2), B, I, and F), kappa-CN (A, B, and E), alpha-lactalbumin (B), and beta-lactoglobulin (A, B, and C). In poorly coagulating and noncoagulating milk samples of both breeds, the predominant composite genotype of alpha(S1)-, beta-, and kappa-CN was BB-A(2)A(2)-AA, which confirmed a genetic contribution to impaired milk coagulation. Interestingly, subtle variations in posttranslational modification of CN were observed between the coagulation classes in both breeds. Poorly coagulating and noncoagulating milk contained a lower fraction of the least phosphorylated alpha(S1)-CN form, alpha(S1)-CN 8P, relative to total alpha(S1)-CN, along with a lower fraction of glycosylated kappa-CN relative to total kappa-CN. Thus, apparent variation was observed in the milk and protein composition, in the genetic makeup of the major milk proteins, and in the posttranslational modification level of CN between milk samples with either good or impaired coagulation ability, whereas the composition of poorly coagulating and noncoagulating milk was similar. PMID- 23040014 TI - A decade of improvement: New York State fluid milk quality. AB - The microbiological and sensory qualities of New York State (NYS) fluid milk products were assessed as part of an ongoing fluid milk quality program. Commercially packaged pasteurized fluid milk samples were collected twice a year over the 10-yr period from 2001 to 2010 from 14 NYS dairy processing facilities and analyzed at the Milk Quality Improvement Program (MQIP) laboratory. Each sample was tested throughout refrigerated storage (6 degrees C) on day initial, 7, 10, and 14 for standard plate count (SPC), coliform count (CC), and sensory quality. Over the 10-yr period, the percentage of samples with bacterial numbers below the Pasteurized Milk Ordinance (PMO) limit of 20,000 cfu/mL at d 14 postprocessing ranged from a low of 21.1% in 2002 to a high of 48.6% in 2010. Percent samples positive for coliforms during that same period ranged from a high of 26.6% in 2002 to a low of 7.5% in 2007. Mean d 14 sensory scores ranged from a low of 6.0 in 2002 to a high of 7.3 in 2007. Samples contaminated with coliforms after pasteurization have significantly higher SPC counts and significantly lower sensory scores on d 14 of shelf-life than those not contaminated with coliforms. Product factors such as fat level were not significantly associated with SPC, CC, or sensory quality of the product, whereas the factor processing plant significantly affected overall product quality. This study demonstrates that overall fluid milk quality in NYS, as determined by microbiological and sensory analyses, has improved over the last decade, and identifies some challenges that remain. PMID- 23040015 TI - Behavioral changes in dairy cows with mastitis. AB - Mastitis is a frequent and painful disease in dairy cows. However, pain detection and alleviation in mastitic cows has been overlooked. The objectives of this study were to measure behavioral changes in dairy cows with clinical mastitis and to investigate the effect of intramammary infusion of an antibiotic on lying behavior and behavior during milking. In experiment 1, 42 lactating cows were used: 14 mastitic cows and 28 control cows. Mastitic and control cows were subjected to an evaluation of pain responses on d 1 (mastitis detection day), and 2, 3, and 7d after the last antibiotic treatment (d 10+). The antibiotic treatment was administered to mastitic cows twice a day, starting on d 1, for at least 3 consecutive days. Behavioral changes were evaluated by measuring lying behavior, reactivity during milking (stepping, lifting, and kicking), weight distribution, and hock-to-hock distance. Overall, mastitic cows spent less time lying down on d 2 compared with control cows. The percentage of time lying on the mastitic quarter side did not differ significantly between mastitic and control cows. No differences were observed between control and mastitic cows on the number of steps per 24h on each day. Restless behavior during milking did not differ between treatments. Restless behaviors differed significantly within mastitic cows between days. Frequency of kicks per minute was higher on d 1 compared with d 2, frequency of lifts was higher on d 1 and 2 compared with d 10+, and frequency of steps was higher on d 2 compared with d 10+. The variability of weight that mastitic cows applied to the leg on the mastitic quarter side was higher on d 1 than on d 10+. For control cows, the variability in weight applied to the homologous leg of the mastitic quarter side leg was higher on d 1 compared with d 2 and 3. The hock-to-hock distance did not differ between treatments. Mild clinical mastitis might not cause sufficient pain to observe marked changes in behaviors. However, cows showed differences in lying time and reactivity during milking and slight differences in the laterality of lying. To further develop methodologies for assessing pain in mastitic cows, it is worth applying the methodologies used in this study to cows with moderate to severe mastitis, followed by their validation using analgesic treatment, to ensure that any change is a pain-specific behavior rather than a simple reflex. In experiment 2, no effect of intramammary infusion of the antibiotic was observed on lying behavior or behavior during milking. Cows with mild clinical mastitis present behavioral changes in lying behavior and at milking time, which could be associated with discomfort. PMID- 23040016 TI - Characterization of Staphylococcus aureus isolates in milk and the milking environment from small-scale dairy farms of Sao Paulo, Brazil, using pulsed-field gel electrophoresis. AB - This research aimed to evaluate the occurrence of Staphylococcus aureus isolates in milk and in the milking environment of 10 small-scale farms (<400 L/d) located in the regions of Franca and Ribeirao Preto, state of Sao Paulo, Brazil. Two hundred twenty samples of milk were collected from individual cows, along with 120 samples from bulk tank milk, 389 samples from milking equipment and utensils (teat cups, buckets, and sieves), and 120 samples from milkers' hands. Fifty-six Staph. aureus strains were isolated from 849 analyzed samples (6.6%): 12 (5.5%) from milk samples of individual cows, 26 (21.7%) from samples of bulk tank milk, 14 (3.6%) from samples collected from equipment and utensils, and 4 (3.3%) from samples from milkers' hands. Pulsed-field gel electrophoresis typing of the 56 Staph. aureus isolates by SmaI restriction enzyme resulted in 31 profiles (pulsotypes) arranged in 12 major clusters. Results of this study indicate a low incidence, but wide distribution of Staph. aureus strains isolated from raw milk collected from individual cows and surfaces of milkers' hands and milking equipment in the small-scale dairy farms evaluated. However, the high percentage of bulk milk samples found with Staph. aureus is of public health concern because raw, unprocessed milk is regularly consumed by the Brazilian population. PMID- 23040017 TI - ADSA Foundation Scholar Award: Trends in culture-independent methods for assessing dairy food quality and safety: emerging metagenomic tools. AB - Enhancing the quality and safety of dairy food is critical to maintaining the competitiveness of dairy products in the food and beverage market and in reinforcing consumer confidence in the dairy industry. Raw milk quality has a significant effect on finished product quality. Several microbial groups found in raw milk have been shown to adversely affect the shelf life of pasteurized milk. Current microbiological criteria used to define milk quality are based primarily on culture-dependent methods, some of which are perceived to lack the desired sensitivity and specificity. To supplement traditional methods, culture independent methods are increasingly being used to identify specific species or microbial groups, and to detect indicator genes or proteins in raw milk or dairy products. Some molecular subtyping techniques have been developed to track the transmission of microbes in dairy environments. The burgeoning "-omics" technologies offer new and exciting opportunities to enhance our understanding of food quality and safety in relation to microbes. Metagenomics has the potential to characterize microbial diversity, detect nonculturable microbes, and identify unique sequences or other factors associated with dairy product quality and safety. In this review, fluid milk will be used as the primary example to examine the adequacy and validity of conventional methods, the current trend of culture independent methods, and the potential applications of metagenomics in dairy food research. PMID- 23040018 TI - Effects of feeding wheat straw or orchardgrass at ad libitum or restricted intake during the dry period on postpartum performance and lipid metabolism. AB - The objectives of this study were to investigate the effects of forage source [wheat straw (WS) or orchardgrass hay (OG)] and total amount of diet dry matter fed [ad libitum or restricted to 70% of predicted dry matter intake (DMI)] prepartum on postpartum performance. The study design was a 2*2 factorial design with 10 cows per treatment. Treatments were WS total mixed ration (TMR) ad libitum, OG TMR ad libitum, WS TMR restricted, and OG TMR restricted. The WS TMR (dry matter basis) contained 30% WS, 20.7% corn silage, 10.0% alfalfa hay, 18.2% ground corn, 16.8% soybean meal, and 4.3% molasses mineral mix (14.7% CP, 1.5 Mcal/kg of net energy for lactation, 37.0% neutral detergent fiber). The OG TMR contained 30% OG, 46.2% corn silage, 10.0% alfalfa hay, 9.5% soybean meal, and 4.3% molasses (14.2% CP, 1.5 Mcal/kg of net energy for lactation, 41.0% neutral detergent fiber). Cows received 1 lactation diet after calving (17.7% CP, 1.6 Mcal/kg of net energy for lactation, 27.3% neutral detergent fiber). Total diet DMI prepartum was higher for ad libitum than for restricted as designed, but forage source had no effect on DMI. Total tract apparent digestibilities of DM and NDF were greater for OG than for WS. Postpartum DMI expressed as a percentage of body weight for the first week of lactation was higher for ad libitum than for restricted diets. Postpartum DMI during the first 30 d of lactation was higher for OG than for WS, but no effect was observed for the amount fed prepartum. Milk yield during the first week of lactation was higher for OG than for WS; however, during the first 30 d, 3.5% fat-corrected milk yield and yield of milk fat were highest for OG TMR restricted and WS TMR ad libitum. Prepartum treatments had a limited effect on pre- and postpartum lipid metabolism; however, cows fed WS TMR ad libitum had the highest postpartum beta-hydroxybutyrate. Eating behavior was observed by 10-min video scans of 24-h video surveillance for 5d pre- and postpartum. Prepartum eating time and eating bouts tended to be greater by WS than for OG, and postpartum eating time per kilogram of neutral detergent fiber intake tended to be greater for WS than for OG. Results indicate that forage source and amount of DM fed prepartum affected postpartum performance and tended to alter the behavior of cows in tie-stall barns. PMID- 23040019 TI - Elaboration of a probiotic oblea from whey fermented using Lactobacillus acidophilus or Bifidobacterium infantis. AB - A novel probiotic product was developed, which was formulated as an oblea (wafer type dehydrated traditional Mexican dessert) using goat sweet whey fermented with Bifidobacterium infantis or Lactobacillus acidophilus. To obtain the probiotic oblea, the fermented whey was formulated with prebiotic carbohydrates (inulin and resistant starch) and gelatin, and the preparation was poured onto a polytetrafluoroethylene-coated nonstick baking pan, dried in a convection oven, and finally dehydrated at a low relative humidity and room temperature (23+/-2 degrees C). The amounts of prebiotic carbohydrates and gelatin to be used in the formulation were determined by a factorial experimental design. An untrained sensory panel evaluated 3 quality characteristics (film formation, homogeneity, and smoothness) in the final product. Three different drying temperatures were tested, namely, 40, 55, and 70 degrees C. Bacterial survival at each temperature was determined by viable plate-counting. The best formulation, based on the quality characteristics tested, consisted of 58.33% (vol/vol) of fermented whey, 8.33% (vol/vol) of 6% (wt/vol) resistant starch dispersion, 16.66% (vol/vol) of 15% (wt/vol) inulin solution, and 16.66% (vol/vol) of a 10% (wt/vol) gelatin solution. Drying at 55+/-2 degrees C for 2.66+/-0.22 h allowed for concentrations of probiotic bacteria above 9 log(10) cfu/g, which is above the minimum concentration required in a probiotic product. PMID- 23040020 TI - Validation of mid-infrared spectrometry in milk for predicting body energy status in Holstein-Friesian cows. AB - Cow energy balance is known to be associated with cow health and fertility; therefore, routine access to data on energy balance can be useful in both management and breeding decisions to improve cow performance. The objective of this study was to determine if individual cow milk mid-infrared spectra (MIR) could be useful to predict cow energy balance across contrasting production systems. Direct energy balance was calculated as the differential between energy intake and energy output in milk and maintenance (maintenance was predicted using body weight). Body energy content was calculated from (change in) body weight and body condition score. Following editing, 2,992 morning, 2,742 midday, and 2,989 evening milk MIR records from 564 lactations on 337 Scottish cows, managed in a confinement system on 1 of 2 diets, were available. An additional 844 morning and 820 evening milk spectral records from 338 lactations on 244 Irish cows offered a predominantly grazed grass diet were also available. Equations were developed to predict body energy status using the milk spectral data and milk yield as predictor variables. Several different approaches were used to test the robustness of the equations calibrated in one data set and validated in another. The analyses clearly showed that the variation in the validation data set must be represented in the calibration data set. The accuracy (i.e., square root of the coefficient of multiple determinations) of predicting, from MIR, direct energy balance, body energy content, and energy intake was 0.47 to 0.69, 0.51 to 0.56, and 0.76 to 0.80, respectively. This highlights the ability of milk MIR to predict body energy balance, energy content, and energy intake with reasonable accuracy. Very high accuracy, however, was not expected, given the likely random errors in the calculation of these energy status traits using field data. PMID- 23040021 TI - Effects of calcium salts of polyunsaturated fatty acids on productive and reproductive parameters of lactating Holstein cows. AB - Two experiments evaluated milk production, serum progesterone and insulin, and reproductive performance of lactating Holstein cows receiving or not receiving Ca salts of polyunsaturated fatty acids (PUFA), or receiving Ca salts of PUFA at different daily frequencies. In experiment 1, 1,125 cows randomly distributed in 10 freestall barns were enrolled. Barns were assigned randomly to receive a high concentrate diet containing (PF) or not containing (control, CON) 1.1% (dry matter basis) Ca salts of PUFA. Diets were offered 6 times daily, whereas the Ca salts of PUFA were included in the PF treatment in the first feeding of the day. In experiment 2, 1,572 cows were randomly distributed in 10 freestall barns, which were assigned randomly to receive a diet similar to PF, but with Ca salts of PUFA included only in the first feeding of the day (PF1X), or equally distributed across all 6 feedings (PF6X). During both experiments, cows were artificially inseminated 12 h after the onset of estrus. Once per month, cows that did not conceive to artificial insemination were assigned to a fixed-time embryo transfer protocol. Pregnancy was determined via transrectal ultrasonography 28 and 60 d after expected ovulation. Pregnancy loss was considered in cows that were pregnant on d 28 but nonpregnant on d 60. During both experiments, feed intake, milk yield, and milk protein and fat content were recorded weekly. Blood samples were collected concurrently with embryo transfer. During experiment 1, feed intake was similar between treatments. Compared with CON, PF cows had greater milk yield (37.8 vs. 35.3 kg/d), and reduced milk fat content (3.41 vs. 3.55%). However, PF cows had reduced pregnancy losses per service compared with CON (12.6 vs. 18.3%). Serum progesterone was greater and serum insulin tended to be greater in primiparous cows receiving PF compared with CON cohorts (4.50 vs. 3.67 ng of progesterone/mL, and 10.4 vs. 7.5 uUI of insulin/mL). During experiment 2, no treatment effects were detected for feed intake, milk yield, or milk fat, whereas PF1X cows tended to have reduced pregnancy losses per service compared with PF6X (14.4 vs. 18.4%). In summary, feeding Ca salts of PUFA to dairy cows increased milk production, did not alter feed intake, and reduced pregnancy losses per service. Further, the total daily amount of Ca salts of PUFA should be fed during the first feeding of the day to optimize its benefits on pregnancy maintenance of dairy cows. PMID- 23040022 TI - Short communication: Identification of coagulase-negative staphylococcus species from goat milk with the API Staph identification test and with transfer RNA intergenic spacer PCR combined with capillary electrophoresis. AB - Coagulase-negative staphylococci (CNS) are the most commonly isolated bacteria from goat milk, but they have often been identified with phenotypic methods, which may have resulted in misclassification. The aims of this paper were to assess the amount of misclassification of a phenotypic test for identifying CNS species from goat milk compared with transfer RNA intergenic spacer PCR (tDNA PCR) followed by capillary electrophoresis, and to apply the tDNA-PCR technique on different capillary electrophoresis equipment. Milk samples were collected from 416 does in 5 Californian dairy goat herds on 3 occasions during lactation. In total, 219 CNS isolates were identified at the species level with tDNA-PCR and subjected to the API 20 Staph identification test kit (API Staph; bioMerieux, Durham, NC). If the same species was isolated multiple times from the same udder gland, only the first isolate was used for further analyses, resulting in 115 unique CNS isolates. According to the tDNA-PCR test, the most prevalent CNS species were Staphylococcus epidermidis, Staphylococcus caprae, and Staphylococcus simulans. Typeability with API staph was low (72%). Although the API Staph test was capable of identifying the majority of Staph. epidermidis and Staph. caprae isolates, sensitivity for identification of Staph. simulans was low. The true positive fraction was high for the 3 most prevalent species. It was concluded that the overall performance of API Staph in differentiating CNS species from goat milk was moderate to low, mainly because of the low typeability, and that genotypic methods such as tDNA-PCR are preferred. PMID- 23040023 TI - Cow and herd variation in milk urea nitrogen concentrations in lactating dairy cattle. AB - Milk urea nitrogen (MUN) is correlated with N balance, N intake, and dietary N content, and thus is a good indicator of proper feeding management with respect to protein. It is commonly used to monitor feeding programs to achieve environmental goals; however, genetic diversity also exists among cows. It was hypothesized that phenotypic diversity among cows could bias feed management decisions when monitoring tools do not consider genetic diversity associated with MUN. The objective of the work was to evaluate the effect of cow and herd variation on MUN. Data from 2 previously published research trials and a field trial were subjected to multivariate regression analyses using a mixed model. Analyses of the research trial data showed that MUN concentrations could be predicted equally well from diet composition, milk yield, and milk components regardless of whether dry matter intake was included in the regression model. This indicated that cow and herd variation could be accurately estimated from field trial data when feed intake was not known. Milk urea N was correlated with dietary protein and neutral detergent fiber content, milk yield, milk protein content, and days in milk for both data sets. Cow was a highly significant determinant of MUN regardless of the data set used, and herd trended to significance for the field trial data. When all other variables were held constant, a percentage unit change in dietary protein concentration resulted in a 1.1mg/dL change in MUN. Least squares means estimates of MUN concentrations across herds ranged from a low of 13.6 mg/dL to a high of 17.3 mg/dL. If the observed MUN for the high herd were caused solely by high crude protein feeding, then the herd would have to reduce dietary protein to a concentration of 12.8% of dry matter to achieve a MUN concentration of 12 mg/dL, likely resulting in lost milk production. If the observed phenotypic variation is due to genetic differences among cows, genetic choices could result in herds that exceed target values for MUN when adhering to best management practices, which is consistent with the trend for differences in MUN among herds. PMID- 23040024 TI - Determination of trace elements in bovine semen samples by inductively coupled plasma mass spectrometry and data mining techniques for identification of bovine class. AB - The reproductive performance of cattle may be influenced by several factors, but mineral imbalances are crucial in terms of direct effects on reproduction. Several studies have shown that elements such as calcium, copper, iron, magnesium, selenium, and zinc are essential for reproduction and can prevent oxidative stress. However, toxic elements such as lead, nickel, and arsenic can have adverse effects on reproduction. In this paper, we applied a simple and fast method of multi-element analysis to bovine semen samples from Zebu and European classes used in reproduction programs and artificial insemination. Samples were analyzed by inductively coupled plasma spectrometry (ICP-MS) using aqueous medium calibration and the samples were diluted in a proportion of 1:50 in a solution containing 0.01% (vol/vol) Triton X-100 and 0.5% (vol/vol) nitric acid. Rhodium, iridium, and yttrium were used as the internal standards for ICP-MS analysis. To develop a reliable method of tracing the class of bovine semen, we used data mining techniques that make it possible to classify unknown samples after checking the differentiation of known-class samples. Based on the determination of 15 elements in 41 samples of bovine semen, 3 machine-learning tools for classification were applied to determine cattle class. Our results demonstrate the potential of support vector machine (SVM), multilayer perceptron (MLP), and random forest (RF) chemometric tools to identify cattle class. Moreover, the selection tools made it possible to reduce the number of chemical elements needed from 15 to just 8. PMID- 23040025 TI - Use of multivariate factor analysis to define new indicator variables for milk composition and coagulation properties in Brown Swiss cows. AB - The aim of this study was to elucidate the structure of relationships between milk yield, composition, and coagulation properties of Brown Swiss cattle. Multivariate factor analysis was used to derive new synthetic variables that can be used for selection purposes. For this reason, genetic parameters of these new variables were estimated. Individual records on milk yield, fat and protein percentages, casein content, lactose percentage, somatic cell count, titratable acidity, and pH were taken on 1,200 Italian Brown Swiss cows located in 38 herds. Factor analysis was able to extract 4 latent variables with an associated communality equal to 70% of the total original variance. The 4 latent factors were interpreted as indicators of milk composition, coagulation, acidity, and mammary gland health, respectively. Factor scores calculated for each animal exhibited coherent patterns along the lactation and across different parities. Estimation of genetic parameters of factor scores carried out with a multiple trait Bayesian hierarchical model showed moderate to low heritabilities (raging from 0.10 to 0.23) and genetic correlations (from -0.15 to 0.46). Results of the present study support the hypothesis of a simpler structure that controls, at least in part, the covariance of milk composition and coagulation properties. Moreover, extracted variables may be useful for both breeding and management purposes, being able to represent, with a single value for each animal, complex traits such as milk coagulation properties or health status of the mammary gland. PMID- 23040026 TI - Starch addition in renneted milk gels: partitioning between curd and whey and effect on curd syneresis and gel microstructure. AB - Milk gels were made by renneting and acidifying skim milk containing 5 different starches, and then compressed by centrifugation to express whey and simulate curd syneresis during the manufacture of low-fat cheese. A series of 17 starches were examined, with 5 starches being selected for in-depth analysis: a modified waxy corn starch (WC), a waxy rice starch (WR), an instant tapioca starch (IT), a modified tapioca starch (MT), and dextrin (DX). Milks containing WC, WR, and DX were given a 72 degrees C heat treatment, whereas those containing IT and MT had a 30-min treatment at 66 degrees C that matched their optimum gelatinization treatments. Curd yields were calculated by weight, estimated starch content in whey was measured gravimetrically by alcohol precipitation, and starch retention in curd was calculated. Curd yields were 13.1% for the control milk (no added starch) and 18.4, 20.7, 21.5, 23.5, and 13.2% for the gels containing starches WC, WR, IT, MT, and DX, respectively. Estimated starch retentions in the curd were, respectively, 71, 90, 90, 21, and 1%. Laser scanning confocal microscopy was used to determine the location of the starches in the curd and their interaction with the protein matrix. Waxy corn, WR, and IT starches have potential to improve texture of low-fat cheese because they had high retention in the curd and they generated interruptions in the protein matrix network that may have helped limit extensive protein-protein interactions. Modified tapioca starch interfered with formation of the protein structure of the curd and produced a soft noncohesive gel, even though most (79%) of the MT starch was lost in the whey. Few distinct starch particles were present in the MT curd network. Dextrin was not retained in the curd and did not disrupt the protein network, making it unsuitable for use in low-fat cheese. PMID- 23040027 TI - Effect of oral calcium bolus supplementation on early-lactation health and milk yield in commercial dairy herds. AB - The objective of this study was to evaluate the effect of supplementation with oral Ca boluses after calving on early-lactation health and milk yield. Cows in their second lactation or greater (n=927) from 2 large dairies in Wisconsin were enrolled during the summer of 2010. Both herds were fed supplemental anions during the prefresh period and less than 1% of fresh cows were treated for clinical milk fever. Cows were scored before calving for lameness and body condition, and then randomly assigned to either a control group or an oral Ca bolus-supplemented group. Control cows received no oral Ca boluses around calving. Cows in the oral Ca bolus group received 2 oral Ca boluses (Bovikalc, Boehringer Ingelheim, St. Joseph, MO), one bolus 0 to 2h after calving and the second 8 to 35 h after calving. The oral Ca bolus administration schedule allowed fresh cows to be restrained in headlocks only once daily. Whole-blood samples were collected immediately before the second oral Ca bolus was given and were analyzed for ionized Ca (Ca(2+)) concentration. Early-lactation health events were recorded and summed for each cow. Only 6 cases (0.6% of calvings) of clinical milk fever occurred during the trial, and only 14% of cows tested were hypocalcemic (Ca(2+) less than 1.0 mmol/L) at 8 to 35 h after calving. Mean Ca(2+) concentrations were not different between the control and oral Ca bolus supplemented groups. Blood samples from the cows given oral Ca boluses were collected an average of 20.6 h after administration of the first bolus. Subpopulations of cows with significant responses to oral Ca bolus supplementation were identified based on significant interactions between oral Ca bolus supplementation and covariates in mixed multiple regression models. Lame cows supplemented with oral Ca boluses averaged 0.34 fewer health events in the first 30 d in milk compared with lame cows that were not supplemented with oral Ca boluses. Cows with a higher previous lactation mature-equivalent milk production (greater than 105% of herd rank) and supplemented with oral Ca boluses produced 2.9 kg more milk at their first test after calving compared with cows with higher previous lactation milk yields that were not supplemented. Results of this study indicate that lame cows and higher producing cows responded favorably to supplementation with oral Ca boluses. Supplementing targeted subpopulations of cows with oral Ca boluses was beneficial even for dairies with a very low incidence of hypocalcemia. PMID- 23040028 TI - Technical note: Development of a challenge model for Streptococcus uberis mastitis in dairy heifers. AB - A challenge model for experimentally inducing Streptococcus uberis mastitis in bred dairy heifers was developed. Qualifying heifers (n=7) exhibited antibody titers of <1:10,000 against Strep. uberis antigens and were free of intramammary infections (IMI). Two contralateral quarters of each heifer were assigned to receive an infusion of Strep. uberis (1,000 to 2,000 cfu); remaining quarters served as unchallenged controls. For a successful challenge and infection, 3 of 4 consecutive mammary secretion samples had to culture positive for Strep. uberis. Six of the 7 heifers were challenged successfully in both infused quarters with a mean dose of 1,080 cfu; once confirmed, infections were treated with a one-time infusion of nonlactating cow therapy. Before challenge, mammary secretion leukocyte counts averaged 8.4*10(6)/mL in all quarters. At 24h after challenge, leukocyte count increased to 18.4*10(6)/mL in challenged quarters, peaking on d 5 at 24.3*10(6)/mL; unchallenged quarters remained at <=10.4*10(6)/mL, but increased to 15.2*10(6)/mL on d 7 and then decreased. Before challenge, macrophages predominated (81%) in mammary secretions followed by lymphocytes (15.3%) and neutrophils (3.7%). By 24h after challenge, neutrophils increased in challenged quarters and predominated for the duration of the trial (65.3 to 70%), whereas macrophages predominated in unchallenged control quarters (65.2 to 75.2%). The challenge model was successful in establishing Strep. uberis IMI in 85.7% of animals, and IMI were controlled (100% cure) by administering nonlactating cow therapy. All heifers calved free of IMI and antimicrobial residues, with milk production similar to that of herd mates and with somatic cell counts (SCC) <200,000 cells/mL. PMID- 23040029 TI - Monitoring dry period intramammary infection incidence and elimination rates using somatic cell count measurements. AB - The objective of the study was to evaluate the predictive ability of the herd dry period (DP) intramammary infection (IMI) incidence and elimination rates derived from predry and postcalving somatic cell count (SCC) measurements [quarter-level SCC and dairy herd improvement (DHI) composite-level SCC] for monitoring the herd DP IMI incidence and elimination rates. A cohort of 91 Canadian dairy herds was followed from 2007 to 2008. In each herd, a sample of 15 cows was selected each year, and a series of 2 predry and 2 postcalving quarter milk samples were collected. Routine milk bacteriological culture was conducted to identify IMI, SCC was measured on the quarter milk samples, and composite SCC of the last predry and first postcalving DHI tests were obtained. Mastitis pathogens were grouped into 3 categories: major pathogens, minor pathogens, and any pathogens. For each herd, DP bacteriological culture-derived IMI incidence and elimination rates were computed using quarter milk culture data. Similarly, SCC-derived herd incidence and elimination rates were computed using quarter and DHI composite level SCC measurements and using various SCC thresholds to define new and eliminated IMI. Linear regression was used to compare herd quarter-level and composite-level SCC-derived herd incidence and elimination with DP bacteriological culture-derived IMI incidence and elimination. Herd DP incidences computed by using quarter-level SCC, and with most of the SCC thresholds tested, were significant predictors of the DP major, minor, and any IMI incidences (F test; P<=0.05). The highest coefficients of determination (R(2)) were obtained with thresholds of 200,000 (R(2): 12%) and 50,000 cells/mL (R(2): 25%) for predicting major and minor IMI, respectively. When using composite DHI SCC measurements, however, substantial losses of predictive power were seen for minor and any IMI incidences compared with quarter-level SCC. For DP major IMI incidence, composite SCC yielded similar, but modest, predictive power when a cutoff value of 150,000 cells/mL was chosen to define new IMI. To predict DP elimination rates, the value of quarter-level SCC seemed limited to predicting the DP major IMI elimination rate. Composite SCC, on the other hand, showed modest predictive power for major and minor IMI elimination rates, with thresholds of 200,000 and 50,000 cells/mL, respectively. Results from the current study suggest that quarter and composite SCC-derived rates could be used as substitutes for bacteriological culture-derived rates for some groups of mastitis pathogens. PMID- 23040030 TI - Mean-reversion in income over feed cost margins: evidence and implications for managing margin risk by US dairy producers. AB - With the increased volatility of feed prices, dairy farm managers are no longer concerned with managing only milk price volatility, but are considering the adoption of risk management programs that address income over feed cost (IOFC) margin risk. Successful margin risk management should be founded on an understanding of the behavior of IOFC margins. To that end, we have constructed forward IOFC margins using Class III milk, corn, and soybean meal futures prices. We focus on the characteristics of the term structure of forward IOFC margins, that is, the sequence of forward margins for consecutive calendar months, all observed on the same trading day. What is apparent from the shapes of these term structures is that both in times when margins were exceptionally high and in times when they were disastrously low, market participants expected that a reversal back to average margin levels would not come quickly, but rather would take up to 9 mo. Slopes of the forward margin term structure before and after most of the major swings in IOFC indicate these shocks were mostly unanticipated, whereas the time needed for recovery to normal margin levels was successfully predicted. This suggests that IOFC margins may exhibit slow mean-reverting, rather than predictable cyclical behavior, as is often suggested in the popular press. This finding can be exploited to design a successful catastrophic risk management program by initiating protection at 9 to 12 mo before futures contract maturity. As a case study, we analyzed risk management strategies for managing IOFC margins that used Livestock Gross Margin for Dairy Cattle insurance contracts and created 2 farm profiles. The first one represents dairy farms that grow most of their feed, whereas the second profile is designed to capture the risk exposure of dairy farms that purchase all their dairy herd, dry cow, and heifer feed. Our case study of this program encompasses the 2009 period, which was characterized by exceptionally poor IOFC margin conditions. We analyzed the dynamics of realized IOFC margins in 2009 under 4 different risk management strategies and found that optimal strategies that were founded on the principles delineated above succeeded in reducing the decline in IOFC margins in 2009 by 93% for the Home-Feed profile and by 47% for the Market-Feed profile, and they performed substantially better than alternative strategies suggested by earlier literature. PMID- 23040031 TI - Enhanced n-3 phospholipid content reduces inflammatory responses in bovine endothelial cells. AB - Uncontrolled inflammation contributes to the increased incidence and severity of infectious diseases in periparturient dairy cattle. The objective of this study was to determine if increasing n-3 fatty acid (FA) content and altering the profile of vasoactive eicosanoids could attenuate endothelial cell inflammatory responses. Bovine aortic endothelial cells (BAEC) were cultured with free FA mixtures that mimic the plasma NEFA composition during the first week of lactation of dairy cows or with a free FA mixture supplemented with a higher proportion of n-3 FA, including eicosapentaenoic and docosahexaenoic acids. The effects of increasing the docosahexaenoic and eicosapentaenoic acid content of BAEC on the expression of proinflammatory mediators and eicosanoid biosynthesis was assessed. Culturing BAEC with enriched concentrations of n-3 FA decreased the expression of proinflammatory cytokines, adhesion molecules, and reactive oxygen species with a concomitant increase in the biosynthesis of proresolving eicosanoids, including resolvins, protectins, and lipoxins. This study showed for the first time that increasing the n-3 FA content of endothelial cell phospholipids could alter the expression of eicosanoids and control the magnitude of inflammatory responses. Future studies are necessary to elucidate the mechanisms by which resolvins, protectins, and lipoxins may modify endothelial inflammatory pathways necessary to reduce the severity and duration of disease in periparturient cows. PMID- 23040032 TI - Bovine hepatic and adipose retinol-binding protein gene expression and relationship with tumor necrosis factor-alpha. AB - Retinol-binding protein (RBP) is the main transport system for retinol in circulation, is a relatively small protein with one binding site for retinol in the all-trans form, and is bound to transthyretin. The objectives of this study were to characterize the temporal pattern of bovine hepatic mRNA expression of RBP during the periparturient period and to determine if a relationship exists between the expression of RBP and that of tumor necrosis factor (TNF)-alpha in dairy cows. In experiment 1, we assessed hepatic mRNA expression of RBP during the periparturient period. Liver tissues were sampled from periparturient dairy cows (n=9) at -21, -4, +1, +7, and +21 relative to parturition and frozen in liquid N(2). Total RNA was extracted from each tissue sample and cDNA was generated. Gene expressions of RBP and beta-actin (as a housekeeping gene) were measured as relative quantity using reverse transcription-PCR. Data were analyzed using cycle threshold values, adjusted to beta-actin, and significance was determined at P<0.05. Serum samples (-21, -4, +1, +7, and +21 relative to parturition) were analyzed for retinol concentration using a standard HPLC-based method. Cows had variable expression of hepatic RBP and serum retinol over the transition period, with a decline near parturition and a rebound toward prepartum levels later in lactation. In experiment 2, liver and visceral (intestinal) adipose tissues were sampled from dairy cows (n=28) at slaughter. Expression of RBP and TNF-alpha was detected in all samples and variations among cows were highly significant for both genes. Across tissues, expression of RBP was positively correlated with that of TNF-alpha (r=0.60). Within adipose tissue, expression of RBP and TNF-alpha was weakly correlated (r=0.23), whereas in hepatic tissue, expression was strongly correlated (r=0.62). In experiment 3, late-lactation dairy Holstein cows were blocked by parity and feed intake, and randomly assigned to control, recombinant bovine (rb)TNF challenge, or pair-fed control treatment (n=5/treatment). Cows were injected with either rbTNF (subcutaneous injection of 2 ug/kg of body weight in saline) or sterile saline (control and pair-fed control animals) once daily for 7d. Liver biopsy was performed on d 7 and samples were processed for expression of RBP and TNF-alpha. Although TNF challenge caused an upregulation of hepatic TNF-alpha expression, as expected, it did not alter hepatic RBP expression. Overall, the temporal pattern of hepatic RBP gene expression during the periparturient period followed, to a great extent, that of plasma retinol. Although a strong positive correlation was previously detected between bovine hepatic RBP and TNF-alpha transcripts, rbTNF challenge did not cause alter RBP expression. These observations collectively imply that regulation of RBP at the transcription level is influenced by physiological state but may be independent from that of transthyretin, which is altered by proinflammatory stimuli (such as TNF-alpha) via induction of transcription factor nuclear factor-interleukin 6. PMID- 23040033 TI - Assessment of an accelerometer system for detection of estrus and treatment with gonadotropin-releasing hormone at the time of insemination in lactating dairy cows. AB - Two experiments were conducted to evaluate an accelerometer system (Heatime; SCR Engineers Ltd., Netanya, Israel) to manage reproduction in lactating dairy cows. In experiment 1, lactating Holstein cows (n=112) were fitted with an accelerometer system and were treated with GnRH followed 7d later by PGF(2alpha) to synchronize estrus. A total of 89 cows that had a follicle >10mm in diameter and a functional corpus luteum at the PGF(2alpha) injection that regressed by 48 h after induction of luteolysis were included in the analysis. Overall, 71% of cows were detected in estrus by the accelerometer system and 95% of cows showing estrus ovulated within 7d after induction of luteolysis. Of the cows not detected in estrus by the accelerometer system, 35% ovulated within 7d after induction of luteolysis. Duration of estrus activity (mean +/- SD) was 16.1+/-4.7 h and was neither affected by parity nor milk production. Intervals (means +/- SD) from induction of luteolysis, onset of activity, peak raw activity, and peak weighted activity to ovulation was 82.2+/-9.5, 28.7+/-8.1, 20.4+/-7.8, and 16.4+/-7.4 h, respectively, and the interval from AI to ovulation was 7.9+/-8.7 h, but ranged from -12 to 26 h. In experiment 2, cows were assigned randomly to receive an intramuscular injection of GnRH at artificial insemination (AI) after detection of estrus by the accelerometer system or receive no treatment (control). Nine hundred seventy-nine AI services from 461 cows were analyzed. Treatment with GnRH at AI did not affect fertility at 35 or 65 d after AI, and no interaction was detected between treatment and season or treatment and AI number. Overall, two thirds of the cows that were considered properly synchronized were inseminated based on the accelerometer system and ovulated after AI. The remaining cows either were not inseminated because they were not detected in estrus or would not have had a chance to conceive to AI because they failed to ovulate after estrus. Furthermore, mean time of AI in relation to ovulation determined by the accelerometer system was acceptable for most of the cows that displayed estrus; however, variability in the duration of estrus and timing of AI in relation to ovulation could lead to poor fertility in some cows. For lactating dairy cows detected in estrus by the accelerometer system, treatment with GnRH at the time of AI without reference to the onset of estrus did not increase fertility. PMID- 23040034 TI - Lack of association between PICALM rs3851179 polymorphism and Alzheimer's disease in Chinese population and APOEepsilon4-negative subgroup. AB - Recently, the association between PICALM rs3851179 polymorphism and Alzheimer's disease (AD) was investigated in the Chinese population by 3 independent studies. However, both allele and genotype tests failed to reveal any association. The association was identified only in the APOEepsilon4-negative subgroup. We think that the failure to replicate the association may be because of the relatively small sample size. In this research, we reinvestigated the association using all the samples from these 3 studies (n = 2486, and 1202 cases and 1284 control subjects). We failed to replicate this association between the rs3851179 polymorphism and AD in all samples and the APOEepsilon4-negative subgroup. Our results indicate that rs3851179 may not be an AD susceptibility locus in the Chinese population and the APOEepsilon4-negative subgroup. PMID- 23040036 TI - [Not Available]. PMID- 23040037 TI - [Not Available]. AB - OBJECTIVE: To report the results of a survey directed at medical and nursing staff as a method of improving the quality of procedures, in accordance with standard ISO 9001:2000. METHOD: Cross-sectional study using a self-administered questionnaire. A sample size of 405 was calculated as 405, for nurses and 337 for medical staff, assuming an overall percentage of satisfaction of 80%, with a precision of 3.5% and an alpha risk of 0.05. RESULTS: The response rate was 46.4% for nursing staff and 24.3% for medical personnel. The overall satisfaction was favourable in 80.3% of nurses and 96.3% of doctors. The best valued item by both groups was the friendliness of the pharmacist. The worst valued by nursing staff, was the compliance to the agreed opening times for dispensing orders, and for doctors, the pharmacy opening times. CONCLUSIONS: The perceived satisfaction by nursing and medical staff is one of the most useful sources of information for establishing improvement processes for accreditation in accordance with ISO 9001:2000. PMID- 23040035 TI - Personality and resilience to Alzheimer's disease neuropathology: a prospective autopsy study. AB - Alzheimer's disease (AD) neuropathology is found at autopsy in approximately 30% of cognitively normal older individuals. We examined whether personality traits are associated with such resilience to clinical dementia in individuals with AD neuropathology. Broad factors and specific facets of personality were assessed up to 28 years (mean 11 +/- 7 years) before onset of dementia and up to 30 years (mean 15 +/- 7 years) before death in a cohort (n = 111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: odds ratio, 2.0; 95% confidence interval, 1.2-3.5), or lower scores on order and competence (conscientiousness: odds ratio, 0.4; 95% confidence interval, 0.2-0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r = 0.26), low agreeableness (r = -0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for the extent of neurofibrillary tangles and Abeta neuritic plaques. In sum, a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology. PMID- 23040038 TI - [Not Available]. AB - OBJECTIVE: To determine the occult mortality in the extra-hospital setting. PATIENTS AND METHOD: Retrospective study included patients who required health care using the Andalusian Emergency Services from January 2002 to June 2002 and who remained at home or were transferred to an Emergency department of a hospital in a normal ambulance as they were not considered to be in need of emergency assistance. RESULTS: Of the 562 patients who met the inclusion criteria of this study, 17 patients died after this care, which was an occult mortality of 3%, 8 of whom had remained at home. CONCLUSIONS: The occult mortality in this study is not insignificant; it affects all ages and is mainly due to respiratory disorders. PMID- 23040039 TI - [Not Available]. AB - OBJECTIVE: To analyse the written complaints made by users of the Primary Health Centre in Taco, Tenerife (Spain). METHOD: We designed an observational, cross sectional study. All the complaint forms from the period 2003-2004 were analysed. We used the ODDUS classification system. RESULTS: A total of 126 complaints were made, representing 2.0 complaints per thousand inhabitants/year. Fifty nine percent were answered in the following month. Seventy three percent were women with a mean age of 40.3+/-12.1 years (range, 19-75). They were directed at the family doctor (31.7%), management (29.4%) and administration (16.7%). The most common complaints by categories were: a) organisation-administration (47.6%), related to a disagreement with institutional rules (11.1%), difficulties with reception desk (10.3%), suspension/cancellation of an appointment (10.3%), and appointment programme (7.1%); b) care (45.2%) referring to delay in care (28.6%) and inappropriate treatment (9.5%); c) limitations of the building infrastructure (7.1%). CONCLUSIONS: The family physician is the person who receives the majority of complaints, mainly due to a delay in treating the patient. Complaints made by users in Primary Care are a useful method of finding out patient dissatisfaction. They can help us to improve the quality of the assistance in Health Centre. PMID- 23040040 TI - [Not Available]. AB - OBJECTIVE: To find out and analyse the opinion of elderly users on the care received in specialised medicine when they are referred from a primary care centre. MATERIAL AND METHOD: Qualitative study from March to September 2006 in the Finca Espana-La Laguna Basic Health Area, Tenerife (Spain). The participants: users older than 65 years who had visited the referred specialised care centre more than once. The data was collected from 3 group interviews, 6 individual interviews and participant observation. They were recorded on a digital tape recorder and transcribed. RESULTS: Perceptions and expectations centre on: long waiting times, difficult accessibility due to the lack of parking space and information points, health system in which they do not feel represented, lack of professionals and lack of information and interest due to the saturation of surgeries. CONCLUSIONS: Their perceptions are determined by their age, emphasizing information on the part of the professionals. Our results indicate areas to improve quality of care with the user as main source (more parking space, information points and mechanisms for their participation). PMID- 23040041 TI - [Not Available]. AB - OBJECTIVES: To assess the main features and determining factors of inappropriate admission and hospital stay in relationship with a new clinical management model. METHODS: Study population included all patients discharged from the Hospital Clinic-University of Barcelona. The review tool was the medical and surgical Appropriateness Evaluation Protocol (AEP). We reviewed the clinical records of a representative sample of all discharged patients. Two independent and well trained AEP reviewers were used for each record review. A multivariate analysis was performed, using admission and inappropriate hospital stay as independent variables. RESULTS: A total of 401 admissions were reviewed. Twenty-eight (6.9%) were deemed to be inappropriate. Elective admission, admission over the week-end and being admitted to a medical ward were the predictive variables identified for inappropriate admissions. Of all 2,187 hospital stays reviewed, 267 (12.2%) were deemed to be inappropriate. An inappropriate admission, total length of stay, type of insurance coverage and discharge type were the predictive variables identified for inappropriate hospital stays. CONCLUSIONS: The new organization and clinical management model, developed by the Patient Focused Care Institutes, showed very acceptable levels of inappropriate admissions and hospital stays. Surgical services have benefited most from this new organization. Care provided to patients with medical conditions, notably those patients with multiple and chronic conditions, make up most of the inappropriateness identified. PMID- 23040042 TI - [Not Available]. AB - This article presents the technique of content analysis, its concept, definition, methodology, advantages and limitations. Content analysis is a highly useful tool based on the analysis and interpretation of documented sources. The aim is to identify the codes used by the agents of discourse, the manifest content, the context in which the content arises and the message is developed to discover and reveal the underlying contents. The objective is not just to find out whether it is transmitted literally, but also if all this could effectively influence or determine the message. PMID- 23040043 TI - [Not Available]. AB - Diagnostic tests are a very important element in ensuring the quality of health care provided as they make, essential on occasions, a contribution to the improvement of diagnostic accuracy, and with this, therapeutic decisions. Technological development, the increased possibilities of diagnostic tests, and the growing demand for those by society means that equipment, and therefore, the number of studies carried out has grown considerably. This increased use of high technology diagnostic tests in the last few years has generated an imbalance between their supply and demand. Several studies have also pointed to the inadequate use of the most sophisticated diagnostic tests. Using a review of the scientific and grey literature, a search was made for detailed information on the variability in the provision and the requests made as regards magnetic resonance imaging (MRI) and computed axial tomography (CAT), as well as real and recommended waiting times. Strategies developed by different organisations to try to manage demand were also searched for: tools for the clinical prioritisation of patients, tools to improve the indication for use, and for assessing the appropriate use of these tests. To correct the imbalance created by the supply and demand, it seems that different strategies need to be developed and applied to influence both binomials of the equation. The strategies applied should take into account methods that have shown to be more effective in changing clinical practice, as well as those elements associated with the health context in which they have been developed. PMID- 23040044 TI - [Not Available]. PMID- 23040045 TI - [Not Available]. PMID- 23040046 TI - Immunoreactivity assessment of hepatitis C virus NS3 protease and NS5A proteins expressed in TOPO cloning system. AB - BACKGROUND: Hepatitis C virus (HCV) is a major cause of acute and chronic liver disease. Numerous screening assays based on the detection of immunoresponses to HCV structural and nonstructural proteins have been designed. Various studies have demonstrated genotype-specific differences in anti-HCV antibody responses to different HCV proteins. METHODS: Full-length NS3 protease and N-terminally truncated NS5A were expressed using pET TOPO 102/D system. Antigenicity of the purified recombinant proteins was assessed by immunoblotting and indirect enzyme linked immunosorbent assay (ELISA). Furthermore, anti-HCV antibody responses to the recombinant proteins were evaluated in three prevalent genotypes in Iran. RESULTS: We were able to express and purify NS5A and NS3 protease using TOPO cloning system. The HCV NS3 protease and NS5A produced in BL21 Star (DE3) was immunoreactive. Our results demonstrate that NS3 protease and NS5A have good immunoreactivity, but they are not sufficient for detecting all HCV-positive sera. No significant genotype-specific differences were detected in immunoresponses to the recombinant proteins. CONCLUSION: In conclusion, we successfully isolated, expressed, and purified substantial amount of HCV NS3 protease and N-terminally truncated NS5A, and used them as capturing antigens in a screening ELISA assay with high sensitivity, reproducibility, and specificity. Accordingly, it is well confirmed that TOPO cloning system can be used as a dynamic system in order to express higher amount of immunoreactive viral proteins. PMID- 23040047 TI - Environmental hazards of pesticides from pineapple crop production in the Rio Jimenez watershed (Caribbean Coast, Costa Rica). AB - This study aimed to characterize environmental hazards of pesticides from pineapple production in riparian communities along the Jimenez River watershed. To achieve our objectives riparian ecological quality indices on riparian habitat and macroinvertebrate assemblages were combined with toxicity assays, fish biomarkers, physico-chemical water analysis and pesticide environmental hazards. During two consecutive years and two periods (July and October), three reference and four impacted sites were monitored. The ecological quality of benthic macroinvertebrates and of riparian habitats deteriorated from the reference sites downstream to the polluted reaches along the Jimenez River area affected by pineapple plantations. The toxicity of water to Daphnia magna also increased towards downstream reaches. Biomarkers of fish of the species Poecilia gillii and Bryconamericus scleroparius transplanted across the studied sites evidenced a clear anticholinergic effect towards downstream sites as well as increased levels of lipid peroxidation. Different pesticide residues were frequently detected in water samples collected across the Jimenez River watershed with herbicides (ametryn, bromacil, diuron), organophosphorus insecticides (diazinon and ethoprophos) and triazole fungicides being the greatest reaching levels above 1 MUg L(-1) in downstream sites. Principal component and environmental hazard analysis of physico-chemical and biological responses established clear relationships among habitat deterioration and the ecological quality of macroinvertebrate communities, high levels of herbicides and poor plant growth, high levels of organophosphorus insecticides in water and anticholinesterase effects on fish, D. magna mortality and deterioration of macroinvertebrate communities. Fungicide and herbicide residue levels were also related with high levels of lipid peroxidation and high activities of glutathione S transferase in fish liver, respectively. These results indicated, thus, that riparian habitat deterioration due to deforestation and land use for agriculture and pesticide contamination are affecting river ecosystems. PMID- 23040048 TI - Sample preparation induced artifacts in cryo-electron tomographs. AB - We investigated the effects of sample preparation and of the exposure to an electron beam on particles in cryo-electron tomographs. Various virus particles with icosahedral symmetry were examined, allowing a comparison of symmetrically related components that should be identical in structure but might be affected differently by these imaging artifacts. Comparison of tomographic reconstructions with previously determined structures established by an independent method showed that neither freezing nor electron beam exposure produced a significant amount of shrinkage along the z axis (thickness). However, we observed damage to regions of the particles located close to the surface of the vitreous ice. PMID- 23040049 TI - Correction of step artefact associated with MRI scanning of long bones. AB - 3D models of long bones are being utilised for a number of fields including orthopaedic implant design. Accurate reconstruction of 3D models is of utmost importance to design accurate implants to allow achieving a good alignment between two bone fragments. Thus for this purpose, CT scanners are employed to acquire accurate bone data exposing an individual to a high amount of ionising radiation. Magnetic resonance imaging (MRI) has been shown to be a potential alternative to computed tomography (CT) for scanning of volunteers for 3D reconstruction of long bones, essentially avoiding the high radiation dose from CT. In MRI imaging of long bones, the artefacts due to random movements of the skeletal system create challenges for researchers as they generate inaccuracies in the 3D models generated by using data sets containing such artefacts. One of the defects that have been observed during an initial study is the lateral shift artefact occurring in the reconstructed 3D models. This artefact is believed to result from volunteers moving the leg during two successive scanning stages (the lower limb has to be scanned in at least five stages due to the limited scanning length of the scanner). As this artefact creates inaccuracies in the implants designed using these models, it needs to be corrected before the application of 3D models to implant design. Therefore, this study aimed to correct the lateral shift artefact using 3D modelling techniques. The femora of five ovine hind limbs were scanned with a 3T MRI scanner using a 3D vibe based protocol. The scanning was conducted in two halves, while maintaining a good overlap between them. A lateral shift was generated by moving the limb several millimetres between two scanning stages. The 3D models were reconstructed using a multi threshold segmentation method. The correction of the artefact was achieved by aligning the two halves using the robust iterative closest point (ICP) algorithm, with the help of the overlapping region between the two. The models with the corrected artefact were compared with the reference model generated by CT scanning of the same sample. The results indicate that the correction of the artefact was achieved with an average deviation of 0.32+/-0.02 mm between the corrected model and the reference model. In comparison, the model obtained from a single MRI scan generated an average error of 0.25+/-0.02 mm when compared with the reference model. An average deviation of 0.34+/-0.04 mm was seen when the models generated after the table was moved were compared to the reference models; thus, the movement of the table is also a contributing factor to the motion artefacts. PMID- 23040050 TI - Toward verified and validated FE simulations of a femur with a cemented hip prosthesis. AB - BACKGROUND: Verified and validated CT-based high-order finite element (FE) methods were developed that predict accurately the mechanical response of patient specific intact femurs. Here we extend these capabilities to human femurs undergoing a total hip replacement using cemented prostheses. METHODS: A fresh frozen human femur was CT-scanned and thereafter in vitro loaded in a stance position until fracture at the neck. The head and neck were removed and the femur was implanted with a cemented prosthesis. The fixed femur was CT-scanned and loaded through the prosthesis so that strains and displacements were measured. High-order FE models based on the CT scans, mimicking the experiments, were constructed to check the simulations prediction capabilities. RESULTS: The FE models were verified and results were compared to the experimental observations. The correlation between the experimental and FE strains and displacements were (R(2)=0.97, EXP=0.96FE+0.02) for the intact femur and (R(2)=0.90, EXP=0.946FE+0.0012) for the implanted femur. This is considered a good agreement considering the uncertainties encountered by the heavy distortion embedded in the CT scan of the metallic prosthesis. DISCUSSION: The patient-specific FE model of the fresh-frozen femur with the cemented metallic prosthesis showed a good correlation to experimental observations, both when considering surface strains, displacements and strains on the prosthesis. The relatively short timescale to generate and analyze such femurs (about 6h) make these analyses a very attractive tool to be used in clinical practice for optimization prostheses (dimensions, location and configuration), and allow to quantify the stress shielding. PMID- 23040051 TI - Lumbar spinal loads vary with body height and weight. AB - Knowledge about spinal loading is required for designing and preclinical testing of spinal implants. It is assumed that loading of the spine depends upon body weight and height, as well as on the spine level, but a direct measurement of the loading conditions throughout the spine is not yet possible. Here, computer models can allow an estimation of the forces and moments acting in the spine. The objective of the present study was to calculate spinal loads for different postures and activities at several levels of the thoracolumbar spine for various combinations of body height and weight. A validated musculoskeletal model, together with commercially available software (AnyBody Technology), were used to calculate the segmental loads acting on the centre of the upper endplate of the vertebrae T12 to L5. The body height was varied between 150 and 200 cm and the weight between 50 and 120 kg. The loads were determined for five standard static postures and three lifting tasks. The resultant forces and moments increased approximately linearly with increasing body weight. The body height had a nearly linear effect on the spinal loads, but in almost all loading cases, the effect on spinal loads was stronger for variation of body weight than of body height. Spinal loads generally increased from cranial to caudal. The presented data now allow the estimation of the spinal load during activities of daily living on a subject specific basis, if body height and weight are known. PMID- 23040052 TI - Reducing the number of fish in bioconcentration studies for plant protection products by reducing the number of test concentrations. AB - Fish bioconcentration tests are time consuming, expensive, and use many animals. Alternative methods that replace, reduce or refine the use of fish for BCF testing would therefore be of value. Test guidelines generally require that bioconcentration factors (BCFs) are determined at two exposure concentrations. However, recent revisions to the OECD Test Guideline for BCF testing (TG 305) provide the option to use only one exposure concentration, when justification is provided, although two concentrations may still be required for some regulatory purposes. Analysis of 55 studies on plant protection products demonstrates that BCF values do not significantly differ between the two exposure concentrations. This analysis therefore provides evidence to support the revision of OECD TG 305, and in particular provides justification for using the one test concentration approach for plant protection product active substances. PMID- 23040055 TI - The development of macrophages from human CD34+ haematopoietic stem cells in serum-free cultures is optimized by IL-3 and SCF. AB - The derivation of human macrophages from peripheral blood monocytes remains a convenient method for the study of macrophage biology. However, for macrophage differentiation, a significant proportion of development has occurred prior to the monocyte stage; monocyte subsets also have varying potential for differentiation. Differentiation of macrophages from a less mature precursor, such as CD34+ haematopoietic stem cells, can further inform with regard to the development of macrophage-lineage cells. CD34+ cells were cultured in serum-free medium containing Flt3L, SCF, IL-3, IL-6 and M-CSF. Using differing combinations of growth factors, the effect on cell proliferation and differentiation to adherent macrophage-like cells was determined. The proliferative response of CD34+ cells to M-CSF was determined during the initial phase of cell culture. Thirteen combinations of SCF, IL-3, IL-6 and M-CSF were then compared to determine the optimum combination for proliferation. Adherence was used to isolate mature macrophages, and the macrophage-like phenotype was confirmed by analyses of surface markers, histo-morphology and phagocytosis. This study refines the means by which large numbers of macrophages are obtained under serum free conditions from haematopoietic precursors. PMID- 23040056 TI - Presence of CTAK/CCL27, MCP-3/CCL7 and LIF in human colostrum and breast milk. AB - Human colostrum and breast milk are known to contain high levels of cytokines and chemokines, which are thought to contribute to the development of the newborn. The aim of this study was to investigate the difference in the presence and levels of 21 soluble cytokines and chemokines in paired samples of human colostrum (day 2 after delivery) and breast milk (day 4-5 after delivery) by using the multiplex technology. Of the 21 cytokine investigated in 10 pairs of samples, only beta-NGF was absent in both colostrum and milk, while INF-alpha2, SCF and TNF-beta were present in colostrum but not in human milk. As a general rule, colostrum contained higher concentrations of cytokines and chemokines with respect to breast milk. The majority of cytokines, detected in colostrum alone or in colostrum and human milk (IL-1alpha, IL-2Ralpha, IL-3, IL-16, IL-18, GRO alpha, HGF, IFN-alpha2, M-CSF, MIF, MIG, TNF-beta, SDF-1alpha, TRAIL) have been described in previous studies, while for the first time we describe the presence of additional cytokines either in colostrum alone (SCF) or in both colostrum and breast milk (CTAK/CCL27, MCP-3/CCL7, LIF). Our data confirm and expand previous studies showing that some cytokines/chemokines, which might contribute to the development of the gastro-intestinal and nervous systems, are overexpressed in human colostrum and breast milk, and might contribute to the development of these systems. PMID- 23040059 TI - Gaze fluctuations are not additively decomposable: reply to Bogartz and Staub. AB - Our previous work interpreted single-lognormal fits to inter-gaze distance (i.e., "gaze steps") histograms as evidence of multiplicativity and hence interactions across scales in visual cognition. Bogartz and Staub (2012) proposed that gaze steps are additively decomposable into fixations and saccades, matching the histograms better and illustrating how additive processes can generate tailed histograms. In this reply, we consider the validity of fixation-versus-saccade distinctions, reviewing eye-movement literature and re-analyzing our original data. Careful examination of empirical literature undermines rigid fixation versus-saccade distinctions. By comparing original gaze-step series with surrogate data, we present new evidence that temporal clustering in gaze-step data reflects interactive rather than additive processes. We conclude by discussing the relation between traditional notions of interactivity between components and complex-systems notions of interactivity across scales. PMID- 23040058 TI - On the importance of considering individual profiles when investigating the role of auditory sequential deficits in developmental dyslexia. AB - The goal of this study was to gain a better understanding of the relationship between non-verbal auditory disorders and developmental dyslexia. This question has led to conflicting results in the literature, which we argued might be due to a failure to consider the heterogeneity of dyslexic profiles. This study included three groups of adult participants: unimpaired readers and dyslexic readers with or without a phonological deficit. Auditory temporal processing deficits, as measured by stream segregation thresholds, were present in most dyslexic participants with phonological disorders. In contrast, most dyslexic participants with preserved phonological skills had normal auditory stream segregation thresholds. Overall, the present study leads to a better understanding of the relationship between phonological and sequential auditory processing disorders in developmental dyslexia. In addition, it demonstrates for the first time the importance of considering the heterogeneity of individual cognitive profiles when investigating the role of auditory deficits in developmental dyslexia. PMID- 23040057 TI - Advancement of the 10-species subgingival Zurich biofilm model by examining different nutritional conditions and defining the structure of the in vitro biofilms. AB - BACKGROUND: Periodontitis is caused by a highly complex consortium of bacteria that establishes as biofilms in subgingival pockets. It is a disease that occurs worldwide and its consequences are a major health concern. Investigations in situ are not possible and the bacterial community varies greatly between patients and even within different loci. Due to the high complexity of the consortium and the availability of samples, a clear definition of the pathogenic bacteria and their mechanisms of pathogenicity are still not available. In the current study we addressed the need of a defined model system by advancing our previously described subgingival biofilm model towards a bacterial composition that reflects the one observed in diseased sites of patients and analysed the structure of these biofilms. RESULTS: We further developed the growth media by systematic variation of key components resulting in improved stability and the firm establishment of spirochetes in the 10-species subgingival Zurich biofilm model. A high concentration of heat-inactivated human serum allowed the best proliferation of the used species. Therefore we further investigated these biofilms by analysing their structure by confocal laser scanning microscopy following fluorescence in situ hybridisation. The species showed mutual interactions as expected from other studies. The abundances of all organisms present in this model were determined by microscopic counting following species specific identification by both fluorescence in situ hybridisation and immunofluorescence. The newly integrated treponemes were the most abundant organisms. CONCLUSIONS: The use of 50% of heat-inactivated human serum used in the improved growth medium resulted in significantly thicker and more stable biofilms, and the quantitative representation of the used species represents the in vivo community of periodontitis patients much closer than in biofilms grown in the two media with less or no human serum. The appearance of T. denticola, P. gingivalis, and T. forsythia in the top layer of the biofilms, and the high abundance of T. denticola, reflects well the microbial situation observed at diseased sites. The improved model biofilms will allow further investigations of interactions between individual species and of the effects of atmospheric or nutritional changes, as well as interactions with tissue cells. PMID- 23040060 TI - Kisspeptide in the estrous mare: is it an appropriate ovulation-inducing agent? AB - Kisspeptides (KiSS) are a recently discovered family of neuropeptides with a central role in regulating the onset of reproductive function in all animals studied to date. We have established biological and physiological evidence for KiSS signaling in the mare. The objective of the current study was to evaluate the physiological and behavioral responses of mares repeatedly given the equine specific kisspeptpin decapeptide (eKp-10, YRWNSFGLRY-NH(2)) in an effort to shorten the interovulatory period. Administration of eKp-10 (0.5 mg iv every 4 h) to mares beginning on Day 16 postovulation (Group 2) or in estrus (Group 3) did not shorten the mean +/- SEM interovulatory interval compared with untreated (Group 1) controls (21.9 +/- 1.2, 22 +/- 1.2, and 21.5 +/- 1.5 days in Groups 1 to 3, respectively; N = 6 per group), nor was there a significant difference in follicle diameter before ovulation among groups, nor number of days treated with eKp-10 for Groups 2 and 3. Mean daily concentrations of FSH, the preovulatory LH surge (timing, mean, and peak concentrations), and mean progesterone concentrations from the newly formed CL were not significantly different among groups. The initiation of treatment was negatively correlated with sexual receptivity (scored 0 to 5: no interest to strong interest) and serum estradiol concentrations, indicating that eKp-10 can significantly disrupt normal sexual receptivity in the estrous mare. This effect on sexual receptivity was short lived (< 72 h) and the overall change in sexual receptivity score was not significantly different between Groups 2 and 3 (-1.2 +/- 0.5 and -1.4 +/- 0.4, respectively). However, the day of the cycle that treatment was initiated significant affected the decline in sexual receptivity score, such that the later in the cycle that treatment was initiated, the greater the estimated decrease in sexual receptivity. In conclusion, the linear hypothalamic-pituitary mechanism for KiSS described in other species was not appropriate for the horse and administration of eKp-10 in the seasonally estrous mare may have been outside of the hormone's normal physiological context. PMID- 23040061 TI - Association between mRNA abundance of functional sperm function proteins and fertility of Holstein bulls. AB - Although the existence of a complex population of mRNA in sperm is well documented, its role has not been completely elucidated. The objective of this study was to determine the relationship of mRNA abundance of sperm specific proteins and sire conception rates (SCR; a fertility index) in Holstein bulls. Samples of sperm from a single collection from commercial Holstein bulls (N = 34) were used to evaluate relative mRNA expression of adenylate kinase (AK) 1, integrin beta (IB) 5, Doppel, nerve growth factor, tissue inhibitors of metalloproteinases (TIMP) 2, lactate dehydrogenase C 1, small nuclear ribonucleoprotein polypeptide N, outer dense fiber 2, and phospholipase C zeta (PLCz) 1 in sperm. With the exception of lactate dehydrogenase C 1 and outer dense fiber 2, the mRNA abundances of these proteins were greater (P < 0.05) for high fertility (> +2 to <= 4 SCR) bulls compared with average (>= 2 to <= +2) and low fertility (> -2 to <= -4) bulls. Of all the multivariate regression models tested, a combination of AK1, IB5, TIMP2, small nuclear ribonucleoprotein polypeptide N, and PLCz1 accounted for 97.4% of the variance in SCR scores. In the absence of PLCz1, the combination of AK1, IB5, Doppel, nerve growth factor, TIMP, and small nuclear ribonucleoprotein polypeptide N accounted for 96.6% of the variance in SCR scores. In addition, immunocytochemistry confirmed that the sperm-specific protein markers evaluated in this study were present in sperm. In conclusion, frozen-thawed semen from bulls with higher AK1, IB5, TIMP, small nuclear ribonucleoprotein polypeptide N 2 and PLCz1 mRNA abundances in the sperm had greater correlations with sire fertility index and may possess greater probabilities of siring calves. PMID- 23040063 TI - The unfolded protein response: a multifaceted regulator of lipid and lipoprotein metabolism. AB - Elevated levels of circulating lipids are the major cause of cardiovascular disease, but beneficial outcomes might be realized by targeting lipid carriers. Two papers in this issue of Cell Metabolism (So et al., 2012; Wang et al., 2012) demonstrate how modulation of one arm of the unfolded protein response can decrease plasma levels of VLDL particles and their associated lipids. PMID- 23040062 TI - Longitudinal fecal hormone analysis for monitoring reproductive activity in the female polar bear (Ursus maritimus). AB - The objective was to identify suitable enzyme immunoassays to monitor gonadal and placental function in the female polar bear. Immunoreactive progesterone, progesterone metabolite (PdG), estrogen, and androgen metabolite (T) concentrations were measured in fecal samples collected over 24 mo from captive female bears (N = 20). Whereas fecal extracts produced displacement curves parallel to the standard curve for each respective steroid, T and PdG more accurately reflected reproductive events. Concentrations of fecal T increased (P < 0.05) during the breeding season, and brief spikes were associated with estrus and mating. A postovulatory increase in PdG was not always detected, but sustained baseline T after mating appeared consistent with ovulation. Parturient bears excreted higher PdG concentrations (P < 0.05) during expected time of embryo implantation in Fall, and a late gestational rise in fecal T occurred 30 days prepartum. Many nonparturient bears also had a PdG rise in the Fall, suggesting they experienced either pregnancy loss or a pseudopregnancy. Differentiating pregnant and pseudopregnant states was not achieved using fecal PdG alone, but when combined with fecal T, comprehensive diagnoses could be made. Nonparturient bears demonstrated elevated (P < 0.05) fecal T during summer months, whereas parturient bears did not. In summary, noninvasive hormone monitoring techniques were established for the female polar bear. Although this study was directed at facilitating management and breeding efforts of captive polar bears, the methods could be applied to studies of reproductive function in wild populations. PMID- 23040064 TI - Antibiotic exposure promotes fat gain. AB - Recent research suggests that obesity may be influenced not only by dietary and genetic risk factors, but also by the trillions of microorganisms inhabiting our gastrointestinal tract. Consistent with this notion, Cho et al. (2012) use mice to demonstrate that subtherapeutic antibiotic treatment promotes adiposity. PMID- 23040065 TI - PPAR-Upsilon pathway to vascular dysfunction. AB - Humans with dominant-negative (DN) mutations in PPAR-Upsilon develop early onset hypertension. A recent study by Pelham et al. (2012) shows that loss of PPAR Upsilon repression of the Rho kinase pathway leads to altered vascular function via a smooth-muscle-dependent pathway that is independent of NO and oxidant stress. PMID- 23040066 TI - Fate through fat: lipid metabolism determines stem cell division outcome. AB - Distinctive metabolism associated with particular cell states is increasingly being defined in normal and malignant cells. Ito et al. (2012) now show that fatty acid oxidation is associated with hematopoietic stem cells and determines whether they undergo symmetric or asymmetric cell division, driving a fundamental property of the stem cell state. PMID- 23040067 TI - Human beta cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. AB - A significant portion of the genome is transcribed as long noncoding RNAs (lncRNAs), several of which are known to control gene expression. The repertoire and regulation of lncRNAs in disease-relevant tissues, however, has not been systematically explored. We report a comprehensive strand-specific transcriptome map of human pancreatic islets and beta cells, and uncover >1100 intergenic and antisense islet-cell lncRNA genes. We find islet lncRNAs that are dynamically regulated and show that they are an integral component of the beta cell differentiation and maturation program. We sequenced the mouse islet transcriptome and identify lncRNA orthologs that are regulated like their human counterparts. Depletion of HI-LNC25, a beta cell-specific lncRNA, downregulated GLIS3 mRNA, thus exemplifying a gene regulatory function of islet lncRNAs. Finally, selected islet lncRNAs were dysregulated in type 2 diabetes or mapped to genetic loci underlying diabetes susceptibility. These findings reveal a new class of islet-cell genes relevant to beta cell programming and diabetes pathophysiology. PMID- 23040068 TI - Cullin-3 regulates vascular smooth muscle function and arterial blood pressure via PPARgamma and RhoA/Rho-kinase. AB - Dominant-negative (DN) mutations in the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) cause hypertension by an unknown mechanism. Hypertension and vascular dysfunction are recapitulated by expression of DN PPARgamma specifically in vascular smooth muscle of transgenic mice. DN PPARgamma increases RhoA and Rho-kinase activity, and inhibition of Rho kinase restores normal reactivity and reduces arterial pressure. RhoBTB1, a component of the Cullin-3 RING E3 ubiquitin ligase complex, is a PPARgamma target gene. Decreased RhoBTB1, Cullin-3, and neddylated Cullin-3 correlated with increased levels of the Cullin-3 substrate RhoA. Knockdown of Cullin-3 or inhibition of cullin-RING ligase activity in aortic smooth muscle cells increased RhoA. Cullin-RING ligase inhibition enhanced agonist-mediated contraction in aortic rings from normal mice by a Rho-kinase-dependent mechanism, and it increased arterial pressure in vivo. We conclude that Cullin-3 regulates vascular function and arterial pressure, thus providing a mechanistic link between mutations in Cullin-3 and hypertension in humans. PMID- 23040069 TI - IRE1alpha-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. AB - The unfolded protein response (UPR) is a signaling pathway required to maintain endoplasmic reticulum (ER) homeostasis and hepatic lipid metabolism. Here, we identify an essential role for the inositol-requiring transmembrane kinase/endoribonuclease 1alpha (IRE1alpha)-X box binding protein 1 (XBP1) arm of the UPR in regulation of hepatic very low-density lipoprotein (VLDL) assembly and secretion. Hepatocyte-specific deletion of Ire1alpha reduces lipid partitioning into the ER lumen and impairs the assembly of triglyceride (TG)-rich VLDL but does not affect TG synthesis, de novo lipogenesis, or the synthesis or secretion of apolipoprotein B (apoB). The defect in VLDL assembly is, at least in part, due to decreased microsomal triglyceride-transfer protein (MTP) activity resulting from reduced protein disulfide isomerase (PDI) expression. Collectively, our findings reveal a key role for the IRE1alpha-XBP1s-PDI axis in linking ER homeostasis with regulation of VLDL production and hepatic lipid homeostasis that may provide a therapeutic target for disorders of lipid metabolism. PMID- 23040071 TI - Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. AB - Insulin activates PI3-kinase (PI3K)/AKT to regulate glucose homeostasis in the peripheral tissues and the mediobasal hypothalamus (MBH) of rodents. We report that insulin infusion into the MBH or dorsal vagal complex (DVC) activated insulin receptors. The same dose of insulin that activated MBH PI3K/AKT did not in the DVC. DVC insulin instead activated Erk1/2 and lowered glucose production in rats and mice. Molecular and chemical inhibition of DVC Erk1/2 negated, while activation of DVC Erk1/2 recapitulated, the effects of DVC insulin. Circulating insulin failed to inhibit glucose production when DVC Erk1/2 was inhibited in normal rodents, while DVC insulin action was disrupted in high-fat-fed rodents. Activation of DVC ATP-sensitive potassium channels was necessary for insulin Erk1/2 and sufficient to inhibit glucose production in normal and high-fat-fed rodents. DVC is a site of insulin action where insulin triggers Erk1/2 signaling to inhibit glucose production and of insulin resistance in high-fat feeding. PMID- 23040070 TI - Silencing of lipid metabolism genes through IRE1alpha-mediated mRNA decay lowers plasma lipids in mice. AB - XBP1 is a key regulator of the unfolded protein response (UPR), which is involved in a wide range of physiological and pathological processes. XBP1 ablation in liver causes profound hypolipidemia in mice, highlighting its critical role in lipid metabolism. XBP1 deficiency triggers feedback activation of its upstream enzyme IRE1alpha, instigating regulated IRE1-dependent decay (RIDD) of cytosolic mRNAs. Here, we identify RIDD as a crucial control mechanism of lipid homeostasis. Suppression of RIDD by RNA interference or genetic ablation of IRE1alpha reversed hypolipidemia in XBP1-deficient mice. Comprehensive microarray analysis of XBP1 and/or IRE1alpha-deficient liver identified genes involved in lipogenesis and lipoprotein metabolism as RIDD substrates, which might contribute to the suppression of plasma lipid levels by activated IRE1alpha. Ablation of XBP1 ameliorated hepatosteatosis, liver damage, and hypercholesterolemia in dyslipidemic animal models, suggesting that direct targeting of either IRE1alpha or XBP1 might be a feasible strategy to treat dyslipidemias. PMID- 23040072 TI - TAp63 is a master transcriptional regulator of lipid and glucose metabolism. AB - TAp63 prevents premature aging, suggesting a link to genes that regulate longevity. Further characterization of TAp63-/- mice revealed that these mice develop obesity, insulin resistance, and glucose intolerance similar to those seen in mice lacking two key metabolic regulators, Silent information regulator T1 (Sirt1) and AMPK. While the roles of Sirt1 and AMPK in metabolism have been well studied, their upstream regulators are not well understood. We found that TAp63 is important in regulating energy metabolism by accumulating in response to metabolic stress and transcriptionally activating Sirt1, AMPKalpha2, and LKB1, resulting in increased fatty acid synthesis and decreased fatty acid oxidation. Moreover, we found that TAp63 lowers blood glucose levels in response to metformin. Restoration of Sirt1, AMPKalpha2, and LKB1 in TAp63-/- mice rescued some of the metabolic defects of the TAp63-/- mice. Our study defines a role for TAp63 in metabolism and weight control. PMID- 23040073 TI - Mitochondrial SKN-1/Nrf mediates a conserved starvation response. AB - SKN-1/Nrf plays multiple essential roles in development and cellular homeostasis. We demonstrate that SKN-1 executes a specific and appropriate transcriptional response to changes in available nutrients, leading to metabolic adaptation. We isolated gain-of-function (gf) alleles of skn-1, affecting a domain of SKN-1 that binds the transcription factor MXL-3 and the mitochondrial outer membrane protein PGAM-5. These skn-1(gf) mutants perceive a state of starvation even in the presence of plentiful food. The aberrant monitoring of cellular nutritional status leads to an altered survival response in which skn-1(gf) mutants transcriptionally activate genes associated with metabolism, adaptation to starvation, aging, and survival. The triggered starvation response is conserved in mice with constitutively activated Nrf and may contribute to the tumorgenicity associated with activating Nrf mutations in mammalian somatic cells. Our findings delineate an evolutionarily conserved metabolic axis of SKN-1/Nrf, further establishing the complexity of this pathway. PMID- 23040075 TI - Post-cardiac injury syndromes. An emerging cause of pericardial diseases. AB - The term "post-cardiac injury syndromes" includes post-myocardial infarction pericarditis, post-pericardiotomy syndrome, and post-traumatic pericarditis (iatrogenic, i.e. after percutaneous coronary or intracardiac interventions, such as pacemaker lead insertion, radiofrequency ablation, or non-iatrogenic, i.e. following blunt or penetrating trauma). All these conditions represent different clinical conditions characterized by an initial cardiac injury involving the pericardium/myocardium and/or pleura and the subsequent inflammatory syndrome ranging from simple, uncomplicated pericarditis to more complicated cases with pleuropericarditis, cardiac tamponade or massive pleural effusion. The etiopathogenesis is presumed to be immune-mediated in predisposed individuals that develop autoreactive reactions following the initial traumatic event. Treatment is essentially based on empirical anti-inflammatory therapy and adjunctive colchicine, which has been shown to be safe and efficacious for the prevention of pericarditis. PMID- 23040074 TI - Aldosterone and cardiovascular disease: the heart of the matter. AB - Aldosterone contributes to the endocrine basis of heart failure, and studies on cardiac aldosterone signaling have reinforced its value as a therapeutic target. Recent focus has shifted to new roles of aldosterone that appear to depend on coexisting pathologic stimuli, cell type, and disease etiology. This review evaluates recent advances in mechanisms underlying aldosterone-induced cardiac disease and highlights the interplay between aldosterone and Ca(2+)/calmodulin dependent protein kinase II, whose hyperactivity during heart failure contributes to disease progression. Increasing evidence implicates aldosterone in diastolic dysfunction, and there is a need to develop more targeted therapeutics such as aldosterone synthase inhibitors and molecularly specific antioxidants. Despite accumulating knowledge, many questions still persist and will likely dictate areas of future research. PMID- 23040076 TI - An original model to predict Intensive Care Unit length-of stay after cardiac surgery in a competing risk framework. AB - BACKGROUND: The aim of the study is to design a specific Intensive Care Unit length-of-stay risk model based on the preoperative factors and surgeries utilizing modeling strategies for time-to-event data in a prospective observational clinical study. METHODS: From January 2004 to April 2011 data on 3861 consecutive heart surgery patients were prospectively collected. ICU length of stay was analyzed as a time-to-event variable in a competing risk framework with death as competing risk. RESULTS: The median ICU-LOS was one day. All factors considered but gender was included in the multivariable modeling. In the final model, factors that mostly affected time-to-discharge from ICU were critical preoperative state (Relative Risk 0.41; 95% Confidence Interval: 0.29 0.58), emergency (0.41; 0.32-0.53), poor left ventricular dysfunction (0.50; 0.44 0.57) and serum creatinine>200 MUmol/L (0.54; 0.46-0.65). Most of the predictors had a time-dependent effect that decreased in the first fifteen days and was constant thereafter. After the plateau, the risk profile was changed as most of the factors were no longer significant, Conversely, the time-to-ICU death model included only two variables, critical perioperative state and serum creatinine>200 MUmol/L, with a constant RR of 9.1 and 3.37 respectively. CONCLUSIONS: ICU-LOS can be predicted by preoperative data and type of surgeries. The derived ICU-LOS prediction model is dynamic and most predictors have an effect that decreases with time. The algorithm can preoperatively predict ICU-LOS curves and could have a major role in the decision making-behavior of clinicians, resources' allocation and maximization of care for high-risk patients. PMID- 23040077 TI - The onset mechanisms of ventricular tachycardia. AB - Clinical and electrophysiological features of different initiation patterns of ventricular tachycardia (VT) have been widely studied. At least two different onset patterns of VT have been defined in the studies. Tachycardias, which are preceded by either a single or multiple ventricular ectopic activity, including a short-long-short sequence, are defined as nonsudden onset and those, which are not preceded by ventricular ectopy are defined as sudden onset. The knowledge of initiation pattern of VTs may have some clinical importance and can be essential for the selection of treatment strategies. The use of Holter electrocardiograms and analysis of intracardiac electrograms from implantable cardioverter defibrillators enables to evaluate the initiation patterns of VTs. PMID- 23040078 TI - Tissue engineered vascular grafts--preclinical aspects. AB - Tissue engineering enables the development of fully biological vascular substitutes that restore, maintain and improve tissue function in a manner identical to natural host tissue. However the development of the appropriate preclinical evaluation techniques for the generation of fully functional tissue engineered vascular graft (TEVG) is required to establish their safety for use in clinical trials and to test clinical effectiveness. This review gives an insight on the various preclinical studies performed in the area of tissue engineered vascular grafts highlighting the different strategies used with respect to cells and scaffolds, typical animal models used and the major in vivo evaluation studies that have been carried out. The review emphasizes the combined effort of engineers, biologists and clinicians which can take this clinical research to new heights of regenerative therapy. PMID- 23040079 TI - How much does AVR ST change help stratify patients with coronary disease? PMID- 23040080 TI - Should angiotensin receptor blockers be the cornerstone of antihypertensive treatment in patients with obesity? PMID- 23040081 TI - Analysis of oxidative stress expressed by urinary level of 8-hydroxy-2' deoxyguanosine and biopyrrin in atrial fibrillation: effect of sinus rhythm restoration. AB - BACKGROUND: Oxidative stress is considered to contribute to the pathological consequences of atrial fibrillation (AF). We examined the level of oxidative stress in AF patients and changes in its level following sinus rhythm restoration. METHODS: Oxidative stress level was evaluated by urinary 8-hydroxy 2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, and urinary biopyrrin, an oxidative metabolite of bilirubin. In Study 1, we compared 8 OHdG/creatinine levels between patients with permanent AF (AF-group, n=40) and sinus rhythm (SR-group, n=133). In Study 2, we examined the changes in 8-OHdG and biopyrrin levels in 36 patients with persistent AF following sinus rhythm restoration by electrical or pharmacological cardioversion (n=15) and radiofrequency catheter ablation (n=21). RESULTS: In Study 1, 8-OHdG/creatinine levels were significantly higher in AF-group than in SR-group (19.1 +/- 8.6 vs. 12.3 +/- 5.5 ng/mg, p<0.001). Multivariate analysis showed that the presence of AF was an independent factor that significantly correlated with 8-OHdG/creatinine level after adjustment for other covariates to oxidative stress (beta=0.36, p<0.001). Sinus rhythm was maintained at the chronic phase in patients of all Study 2 (7.2 +/- 5.8 months after cardioversion or catheter ablation). 8 OHdG/creatinine and biopyrrin/creatinine levels at the chronic phase were significantly lower than those before cardioversion or catheter ablation (8.7 +/- 3.2 vs. 21.7 +/- 15.1 ng/mg, p<0.0001 and 1.7 +/- 1.1 vs. 3.0 +/- 1.9 mU/mg, p<0.0001). CONCLUSIONS: Oxidative stress level is significantly increased in AF patients, but can be improved by restoration of sinus rhythm. The results suggest that the pathogenic process of AF is promoted by AF itself through the production of oxidative stress. PMID- 23040082 TI - Laparoscopic Mitrofanoff procedure using single 'U-Stitch' anastomosis: a way to make it simple. AB - OBJECTIVE: to describe and incorporate a modification of the fully laparoscopic Mitrofanoff (LM) procedure with the aim of diminishing operative time and technical difficulties, and to reproduce functional results. PATIENTS AND METHODS: Retrospective review of six patients with voiding dysfunction with indication for clean intermittent catheterization who did not require bladder augmentation and who underwent a fully LM procedure between January and November 2011. RESULTS: The mean operative time was 183.3 min with a mean hospital stay of 6.15 days. No complications were recorded during the surgical procedure. Postoperative hematuria is the most frequent complication associated with this technique. One patient presented appendicovesical anastomotic leak that resolved spontaneously after 8 days with abdominal drainage. There were no other postoperative complications on an average 6.8-month follow up. CONCLUSION: We believe fully LM is a feasible and reproducible approach. The U-Stitch appendix implantation technique reduces total operative time and makes the procedure technically easier. PMID- 23040083 TI - Health financing in fragile and post-conflict states: what do we know and what are the gaps? AB - There has been a growing concern with post-conflict and fragile states over the past decade, both in relation to their high level of health and development needs but also for the risk they pose to the wider international community. This paper presents an exploratory literature review to analyse the themes and findings of recent writing on one important pillar of the health system--health financing--in these countries. It finds that here is a growing but still very limited literature. Most of the insights from existing literature relate to the role of donors. There is a need for more work on access to care and equity over the post conflict period, the mix and sequencing of financing mechanisms, resource allocation, regulation, public financial management, payment systems and incentives at facility and health worker levels, and on overall health financing strategies and their possible contribution to wider state-building. Topics which have received attention, such as contracting and non-state actors, could benefit from more rigorous analysis with a longer time perspective. A longitudinal approach, which examines how decisions taken in the immediate post-conflict period may or may not influence longer term developments, would provide important insights. As health systems in fragile and post-conflict states are often forced to innovate, they can generate useful lessons for other settings too. PMID- 23040084 TI - Role of GIRK channels on the noradrenergic transmission in vivo: an electrophysiological and neurochemical study on GIRK2 mutant mice. AB - Dysfunctional noradrenergic transmission is related to several neuropsychiatric conditions, such as depression. Nowadays, the role of G protein-coupled inwardly rectifying potassium (GIRK)2 subunit containing GIRK channels controlling neuronal intrinsic excitability in vitro is well known. The aim of this study was to investigate the impact of GIRK2 subunit mutation on the central noradrenergic transmission in vivo. For that purpose, single-unit extracellular activity of locus coeruleus (LC) noradrenergic neurons and brain monoamine levels using the HPLC technique were measured in wild-type and GIRK2 mutant mice. Girk2 gene mutation induced significant differences among genotypes regarding burst activity of LC neurons. In fact, the proportion of neurons displaying burst firing was increased in GIRK2 heterozygous mice as compared to that recorded from wild-type mice. Furthermore, this augmentation was even greater in the homozygous genotype. However, neither the basal firing rate nor the coefficient of variation of LC neurons was different among genotypes. Noradrenaline and serotonin basal levels were altered in the dorsal raphe nucleus from GIRK2 heterozygous and homozygous mice, respectively. Furthermore, noradrenaline levels were increased in LC projecting areas such as the hippocampus and amygdale from homozygous mice, although not in the prefrontal cortex. Finally, potency of clonidine and morphine inhibiting LC activity was reduced in GIRK2 mutant mice, although the efficacy remained unchanged. Altogether, the present study supports the role of GIRK2 subunit-containing GIRK channels on the maintenance of tonic noradrenergic activity in vivo. Electric and neurochemical consequences derived from an altered GIRK2-dependent signalling could facilitate the understanding of the neurobiological basis of pathologies related to a dysfunctional monoaminergic transmission. PMID- 23040085 TI - DNA-binding domains of plant-specific transcription factors: structure, function, and evolution. AB - The families of the plant-specific transcription factors (TFs) are defined by their characteristic DNA-binding domains (DBDs), such as AP2/ERF, B3, NAC, SBP, and WRKY. Recently, three-dimensional structures of the DBDs, including those in complexes with DNA, were determined by NMR spectroscopy and X-ray crystallography. In this review we summarize the functional and evolutionary implications arising from structure analyses. The unexpected structural similarity between B3 and the noncatalytic DBD of the restriction endonuclease EcoRII allowed us to build structural models of the B3/DNA complex. Most of the DBDs of plant-specific TFs are likely to have originated from endonucleases associated with transposable elements. After the DBDs have been established in unicellular eukaryotes, they experienced extensive plant-specific expansion, by acquiring new functions. PMID- 23040086 TI - High temperature acclimation through PIF4 signaling. AB - Ambient temperature has direct consequences for plant functioning. Many plant species are able to adjust reproductive timing and development to optimize fitness to changes in ambient temperatures. Understanding the molecular networks of how plants cope with high temperatures is essential to counteract the effects of global warming and to secure future crop productivity. Several recent papers reported that Arabidopsis thaliana responses to changing light conditions and high temperature, and their underlying signaling mechanisms are highly similar and involve the basic helix-loop-helix (bHLH) transcription factor PHYTOCHROME INTERACTING FACTOR 4 (PIF4). In this opinion article we discuss the mechanisms of PIF4-mediated acclimation to increased ambient temperature with focus on timing of flowering and morphological acclimation. PMID- 23040087 TI - Beneficial effect of EPA (20:5 n-3 PUFA) on preventing venous thromboembolism: a rat tail thrombosis model experiment. PMID- 23040089 TI - [Not Available]. PMID- 23040088 TI - DTI voxelwise analysis did not differentiate older depressed patients from older subjects without depression. AB - INTRODUCTION: Neuroimaging has been widely used in studies to investigate depression in the elderly because it is a noninvasive technique, and it allows the detection of structural and functional brain alterations. Fractional anisotropy (FA) and mean diffusivity (MD) are neuroimaging indexes of the microstructural integrity of white matter, which are measured using diffusion tensor imaging (DTI). The aim of this study was to investigate differences in FA or MD in the entire brain without a previously determined region of interest (ROI) between depressed and non-depressed elderly patients. METHOD: Brain magnetic resonance imaging scans were obtained from 47 depressed elderly patients, diagnosed according to DSM-IV criteria, and 36 healthy elderly patients as controls. Voxelwise statistical analysis of FA data was performed using tract based spatial statistics (TBSS). RESULTS: After controlling for age, no significant differences among FA and MD parameters were observed in the depressed elderly patients. No significant correlations were found between cognitive performance and FA or MD parameters. CONCLUSION: There were no significant differences among FA or MD values between mildly or moderately depressed and non depressed elderly patients when the brain was analyzed without a previously determined ROI. PMID- 23040090 TI - [Not Available]. AB - AIMS: To assess patient expectations at general practitioner (GP) visits, and compare them with what GPs think about them. MATERIAL AND METHOD: Cross sectional study of patients attending GPs consultations. Physicians sample from Andalusia. Before the consultation patients were asked to select, from a list of 10 expectations, the most important they had for that particular visit. They were then asked to prioritise them into the 3 most and least important. Doctors received the list of 10 expectations and were asked to select which expectations they considered as the most important for a patient when consulting; doctors had also to prioritise the 3 most and least important expectations. RESULTS: The study included 805 patients, 140 physicians. Out of the list of ten expectations, patients marked as important for that particular visit an average of 7.7. 797 (99%) patients claimed the important ones for them were three or more, but 207 (30%) were not able to prioritise more than two. When doctors prioritised the most important expectation, within the first three, they coincided with patients in two of them: the first, (listening) and the third (explaining). Similarly, doctors coincided with patients in the two least important expectations: to be referred and to receive a prescription. Out of the list of ten expectations, doctors over-scored significantly the patients wishes for receiving a diagnosis (43%), advice (40%), to be referred (35%), to receive a prescription (25%), a test (17%) and be examined (15%). CONCLUSIONS: General expectations as regards physician-patient communication are more important for patients than other more specific ones. Generally, physicians agree with patients in this assessment, but they over-estimated patient wishes of receiving prescriptions, tests or to be referred. PMID- 23040091 TI - [Not Available]. AB - INTRODUCTION: Intimacy is one of the most common and less cared for aspects in health care. From real situations from diagnostic explorations to hospitalisation, the patient possibly sees him/herself subjected to constant aggression of the integrity of his values. When this is noted and taken into account by professionals and especially by the nurses, using various strategies implicit in the care given them, it proves to be one of the elements of major satisfaction and confidence shown in our clients. OBJECTIVES: To identify the characteristics associated with the concept of intimacy from a global perspective; that is, from a patient point of view, and from that of the nursing professionals themselves. MATERIAL AND METHOD: This was a qualitative study using a consensusof focal groups opinion, directed towards patients (and/or principal carers) admitted to the Nursing Service Unit of the Neurology Service of our hospital and a group of professionals in the same service. RESULTS: We have been able to verify that the opinion of professionals and patients coincide in some aspects leaving other exposed to expand our perspective with respect to the welfare offering that we do in order to improving it. CONCLUSIONS: This methodology for improved care puts a global focus on the approach to intimacy and attempts to show the connection between the care provided, the perceived quality of this, and the expectations of our clients. PMID- 23040092 TI - [Not Available]. AB - OBJECTIVE: To evaluate changes in quality over a 5-year period from the perspective of patients, in an attempt to meet their expectations in a new hospital. METHOD: The procedure takes as a reference the results of an opinion survey carried out in the hospital in 2001 and compares these results with those of annual surveys and completes them with information from written complaints and demands for accountability. RESULTS: During the period studied, 821 surveys (a response rate of 22.3%), 3,756 complaints and 105 demands for administrative accountability were received and processed. The surveys revealed a degree of satisfaction of 96%, and study of the changes detected significant differences in comfort and response capacity. The most common reasons for complaints were medical transport (15.3%), delays in receiving care (12.6%), and waiting lists (9.3%). The main reasons for demands for accountability (only 20% of which were accepted) were death or serious secondary outcomes (59%), and the principal causes were related to omissions (42.9%) or malpractice (22.9%). DISCUSSION: Patients' opinions tended to worsen slightly over the 5-year period studied, related to their increased expectations. Although the reasons for making complaints and demands were independent of the problems identified in patients' opinions and showed different dimensions, there were certain areas of overlap. Greater efforts are required in the area of emergency services and, of course, in problems related to comfort, improvement of which is easily achievable and evident with the inauguration of the new hospital. PMID- 23040093 TI - [Not Available]. AB - OBJECTIVE: To analyze the process of evaluating abstracts in the 2006 National Quality in Healthcare Conference in order to contribute to its continuous improvement, and to present its main scientific results. MATERIAL AND METHODS: DESIGN: descriptive study. 11 pairs of reviewers using explicit criteria evaluated abstracts. POPULATION: all the abstracts received. PROCESS: abstracts were accepted/rejected according to reviewers' concordant decisions. Disagreements were re-evaluated by 3 reviewers. Accepted abstracts were organized and distributed in the Conference according to the following criteria: total amount, available room and time, number of reviewers. The abstracts nominated for awards and which did not have discrepancies higher than 25 points were re evaluated by all the reviewers. Their presentations in the Conference were also reviewed by a panel of judges created for this purpose, according to an evaluation guide. RESULTS: 849 communications were received. Each reviewer evaluated a mean of 79 communications, obtaining an average score of 56 points. 762 communications were accepted (89.7%), 56.8% of them as a poster. Madrid (133) and Catalonia (124) had the highest amount of presentations in the Conference, but Cantabria and Murcia obtained the highest rates per million inhabitants. CONCLUSIONS: Despite the recently introduced changes, evaluating abstracts is a complex methodological process that still can be improved. It is conditioned by the need for limiting the extension of oral presentations and Conference time management. The scientific contribution to the Conference keeps rising. Its venue represents a geographic opportunity to encourage quality works. PMID- 23040094 TI - [Not Available]. AB - BACKGROUND: The 2002 Charter of Citizen Rights and Duties regarding Health and Healthcare establishes the Rights of health service users in Catalonia. There is limited information on the knowledge and perception of the Rights Charter and its observance among hospital professionals. OBJECTIVES: The current study tries to portray both the level of knowledge and perception of complying with these Rights among hospital workers. MATERIAL AND METHOD: A multi-center study was conducted on a sample of professional workers (n=963) representing ten hospitals belonging to the Public Utilization' Hospital Network of Catalonia. Professionals completed a structured form asking for socio-demographic and professional characteristics, Rights' knowledge and perception of their observance, provision of information of these in the hospital and preferred methods for providing this. Response frequencies were calculated for each item. Differences in knowledge and perception of observance of the Rights were analyzed by several individual characteristics of the respondents, by means the chi(2) test and estimation of frequency ratios with their 95% confidence intervals against a reference category. RESULTS: A total of 693 professionals (72%) responded, stating they knew 76.7% of the Rights, and considering 59.1% considered they respected them. A lower knowledge was demonstrated by non-care and general services professionals. The perception of their observance was more critical in women, qualified staff and night shift workers, while younger and graduate professionals had a more optimistic perception. Rights regarding the genetic make up of a person were lesser known (under 50%), whereas those regarding disease prevention, health promotion and protection, research and experimentation, and genetic make up were considered the least respected ones (under 50%). The level of knowledge was higher in care than non-care professionals for the ten Charter Rights groups. Noncare professionals had a perception of lower observance than care professionals, for the Rights related to the genetic make up of a patient and those related to research and experimentation (p<0.0001 in both cases). Performance in hospitals for providing information to professionals was reported by 56% of respondents, whereas actions addressed to users were reported by 71%. Preferred methods were written material, seminars and personalized information. CONCLUSIONS: Both the level of knowledge and perceived compliance to the Charter Rights, together with their low awareness in participant hospitals, promoting disseminating and learning methods in this area is recommended. PMID- 23040095 TI - [Not Available]. AB - Outsourcing and privatization of healthcare services are analyzed from management and economics perspectives, examining four types of outsourcing from the transaction costs theory: centres, clinical services, diagnostic-therapeutic support services, and ancillary services. Potential effects of outsourcing are analysed, addressing the advantages and risks, and putting it into the context of the Spanish NHS. Some final remarks are made regarding policy and research agenda. PMID- 23040096 TI - [Not Available]. PMID- 23040097 TI - Development and preliminary validation of an antibody filtration-assisted single dilution chemiluminometric immunoassay for potency testing of Piscirickettsia salmonis vaccines. AB - Challenge with live pathogens could be substituted by serology for many veterinary diseases, however little progress has been made in the development of alternative batch vaccine potency tests for fish. This study reports the development and preliminary validation of a single-dilution filtration-assisted chemiluminometric immunoassay (SD FAL-ELISA) applied to measure anti Piscirickettsia salmonis IgM in individual or pooled serum and mucus samples. The assay was set up to test a single-dilution of the sample. Serum SD FAL-ELISA yielded a sensitivity of 90% and a specificity of 96%. SD FAL-ELISA was applied to evaluate pooled and individual samples from P. salmonis challenge assessments. Relative-light units values (RLU) obtained by SD FAL-ELISA were proportional to antibody levels in serum. RLU values obtained from pooled and individual serum samples increased with the observed relative percent survival (RPS) values, indicating a correlation between protection and specific IgM levels. Results obtained for specific IgM in mucus samples was not related to the RPS, but discriminated the vaccine that yielded high RPS (86.4%) from the others (40.9 and 54.5%). This is the first report on the development of an indirect high throughput serological assessment for P. salmonis vaccine potency testing using both pooled or individual serum and cutaneous mucus samples. PMID- 23040098 TI - Primo vascular system as a new morphofunctional integrated system. AB - The purpose of this review is to describe the methodology, instruments, and subject animals used until now for studies of the meridian (Kyungrak) system and the primo vascular system (PVS). The PVS is observed as an anatomical system distributed in cavities, organs, and tissues throughout the body. We analyzed the most important points of the PVS based on the results obtained until the present. Our main effort has been directed to describing the main thesis relating to the morphological structures and their topography, the functional mechanisms of the PVS, and possible roles of the PVS in pathological processes. The substance of the PVS in all its aspects is as a system covering the whole body and regulating and coordinating the biological processes that are the basis for life. In conclusion, we suggest that the finding of the PVS represents the discovery of a new integrated morphological-functional system. PMID- 23040099 TI - Isolation and morphological features of primo vessels in rabbit lymph vessels. AB - Until now, even though intensive research has been dedicated to the primo vascular system (PVS) during these years, no statistical data on primo vessels and primo vessels in lymph flow have been available. Recently, the general morphological features of primo vessels in lymph vessels around the abdominal aorta were identified from microdissections of tissues from New Zealand White rabbits, and with Alcian blue staining, primo vessels in lymphatic vessels could be definitely identified under a digital microscope. The micro-dissected specimens in situ reveal rod-shaped nuclei stained by Acridine orange. The blue stained nuclei, which were distributed in a broken-lined stripe, formed a tube structure of about 20 MUm in diameter. The distance between the nuclei of two cells on neighboring aligned stripes, which is also the diameter of the micro tube, was measured to be about 5~10 MUm. The average length of the primo vessels was 2.4 mm, with the longest being 5.6 mm. The average size of the primo vessel was 50 MUm, and the average diameters of the primo and the lymph vessels were 26.0 MUm and 258.5 MUm, respectively. Occasionally, without the use of Alcian blue staining, milk-white transparent primo vessels were observed floating in lymph vessels. Thus, we suggest that the PVS might also have an important function connected with the lymph system. We also expect the traditional Korean meridian system to leave its invisible world during the last thousands of years and soon enter the visible scientific world. PMID- 23040100 TI - Primo vessel inside a lymph vessel emerging from a cancer tissue. AB - Primo vessels were observed inside the lymph vessels near the caudal vena cava of a rabbit and a rat and in the thoracic lymph duct of a mouse. In the current work we found a primo vessel inside the lymph vessel that came out from the tumor tissue of a mouse. A cancer model of a nude mouse was made with human lung cancer cell line NCI-H460. We injected fluorescent nanoparticles into the xenografted tumor tissue and studied their flow in blood, lymph, and primo vessels. Fluorescent nanoparticles flowed through the blood vessels quickly in few minutes, and but slowly in the lymph vessels. The bright fluorescent signals of nanoparticles disappeared within one hour in the blood vessels but remained much longer up to several hours in the case of lymph vessels. We found an exceptional case of lymph vessels that remained bright with fluorescence up to 24 hours. After detailed examination we found that the bright fluorescence was due to a putative primo vessel inside the lymph vessel. This rare observation is consistent with Bong-Han Kim's claim on the presence of a primo vascular system in lymph vessels. It provides a significant suggestion on the cancer metastasis through primo vessels and lymph vessels. PMID- 23040101 TI - A primo vascular system underneath the superior sagittal sinus in the brain of a rabbit. AB - The primo vascular systems (PVS) observed in the central nervous system have been limited to the ones floating in the cerebrospinal fluid. In those experiments, it was difficult to obtain the same results because the PVS was not fixed in a given anatomical position. In the current work, we report a finding of a PVS in a well defined location, namely, underneath the superior sagittal sinus in the sagittal fissure, so that repetition of the experiments is possible. This provides a cornerstone for PVS research because the lack of reproducible sample-taking hindered a deeper study of the PVS, such as RNA sequencing or RNA microarray. This obstacle can be overcome through the discovery in the current work. This PVS showed characteristics of the PVS observed in other organs. It showed the bundle structure of subvessels, the parallel distributions of F-actins, and the rod shaped nuclei. Furthermore, it had a primo node in front of the confluence of sinuses above the pineal body. It had branches shooting off from the main primo vessel in the subarachnoid space toward the cerebral hemispheres. The results indicate that this PVS underneath superior sagittal sinus has proper features to function as a flowing channel. PMID- 23040103 TI - Primo vascular system in the subarachnoid space of the spinal cord of a pig. AB - The primo vascular system was recently observed in the central nervous systems of rabbits and rats, but no investigations in large animals have been reported. In the present work we found a putative primo vascular system in the spinal cord of a pig. We obtained spines from four healthy pigs and fixed them with paraformaldehyde. The primo vessels were expected to lie in the subarachnoid space between the pia mater and the arachnoid mater. The composite of three membranes (the pia, the arachnoid, and the dura maters) wrapping the spinal cord was peeled off, isolated from the spine, and put on a slide glass. This composite was stained with 4',6'-Diamidino-2-phenylindole (DAPI) and phalloidin to show the nuclei and the f-actin, respectively, in the cells of the primo vessels. We observed eleven pieces of the putative primo vessels in the subarachnoid space of the spines at the thoracic spinal nerve area. They had the typical rod-shaped nuclei distributed in a broken line, and f-actin signals around nuclei. The lengths of the nuclei were 12-15 MUm, and the thicknesses of the primo vessels were 8~20 MUm, which were consistent with other primo vessels that had been observed in the various organs of rabbits, rats, and mice. In addition, we observed branching of the primo vessels, which is again an expected result from previous works. In conclusion, a primo vessel was observed in the subarachnoid space of the spinal cord of a pig. This was the first observation of a primo vessel in a large animal, and the staining method used to observe the primo vessel in a fixed sample was newly developed in this work. PMID- 23040102 TI - Visualization of the network of primo vessels and primo nodes above the pia mater of the brain and spine of rats by using Alcian blue. AB - By spraying and injecting Alcian blue into the lateral ventricle, we were able to visualize the network of the nerve primo vascular system above the pia mater of the brain and spine of rats. Staining these novel structures above the pia mater with 4',6-diamidino-2-phenylindole demonstrated that they coexisted in cellular and extracellular DNA forms. The cellular primo node consisted of many cells surrounded by rod-shaped nuclei while the extracellular primo node had a different morphology from that of a general cell in terms of DNA signals, showing granular DNA in a threadlike network of extracellular DNA. Also, differently from F-actin in general cells, the F-actin in the primo vessel was short and rod shaped. Light and transmission electron microscopic images of the PN showed that the nerve primo vascular system above the pia mater of the brain and spine was a novel dynamic network, suggesting the coexistence of DNA and extracellular DNA. Based on these data, we suggest that a novel dynamic system with a certain function exists above the pia mater of the central nerve system. We also discuss the potential of this novel network system in the brain and spine as related to acupuncture meridians and neural regeneration. PMID- 23040104 TI - Protocol for the observation of the primo vascular system in the lymph vessels of rabbits. AB - Molecular-level understanding of the structure and the functions of the lymphatic system has greatly enhanced the importance of this second circulation system, especially in connection with cancer metastasis and inflammation. Recently, a third circulatory system, the primo vascular system (PVS) was found in various parts of an animal's body, especially as threadlike structures floating in the lymphatic flow in lymph vessels. Although the medical significance of this emerging system will require much work in the future, at present, several important suggestions in connection with immune cells, stem cells, and cancer metastasis have already appeared. Experiments to observe the PVS in the lymph vessels near the caudal vena cava of rabbits and rats have been performed by several independent teams, but reproduction requires considerable skill and technical know-how. In this article, we provide a detailed protocol to detect the PVS inside the lymph vessels of a rabbit. Detection and isolation are the first steps in unraveling the physiological functions of the PVS, which awaits intensive research. PMID- 23040105 TI - Critical review and comments on B.H. Kim's work on the primo vascular system. AB - Two periods of primo vascular system (PVS) discovery exist. The first one includes the five reports of B. H. Kim made from 1962 to 1965. The second one is from 2002 until the present time and includes reports made mainly by the Seoul National University group using modern methods. The purpose of this article is to describe the claims in B. H. Kim's reports, to comment on the most important points of his claims, and to offer hypotheses for the morphological architecture and the function of the PVS. The PVS integrated the cardiovascular, nervous, and hormonal systems. Thus, the particularities of the various body systems are combined in the PVS. The PVS is not a simple circulatory system like the cardiovascular system. Its influence on all body systems is a combination of not only substances and signals but also energy and information. The primordial PVS is like a matrix for the vascular and the nervous systems, which are formed around the PVS. The PVS is duplicated by the vascular and the nervous systems in the very early stage of body development. This is the reason why the PVS combines the features of the vascular, the nervous, and the hormonal systems. Subsequently, all embryonic body systems have developed, the primordial PVS remains connected to them, but dominates and controls them as the primeval functional system. PMID- 23040106 TI - Developmental and comparative biological study of primo vascular system. PMID- 23040107 TI - Towards the Middle Palaeolithic in Western Europe: the case of Orgnac 3 (southeastern France). AB - The sequence of Orgnac 3 in southern Europe is dated to MIS 9 and the beginning of MIS 8. The site contains records of Upper Acheulian occupations with evidence of Middle Palaeolithic technological strategies at the top of the sequence. In order to address the question of gradual versus punctuated changes in the onset of the Middle Palaeolithic, nine criteria on subsistence strategies and technological behaviour were selected throughout the whole stratigraphic sequence to describe behavioural patterns. Results indicate a mosaic of changes in hominin subsistence and technical behaviour and attest to both gradual and punctuated changes over time. For the most part, they cannot be explained by environmental factors such as site formation processes or climatic transitions. Thus, behavioural change at Orgnac 3 may be interpreted as 'multifaceted,' with a combination of gradual and punctuated shifts by hominins inhabiting the area. Orgnac 3 may be considered as a 'key-site' for understanding the basis of the Neanderthal material world and possibly the onset of clearly differentiated traditions in Neanderthal populations. PMID- 23040109 TI - Sudden cardiac death in heart failure patients with preserved ejection fraction. AB - BACKGROUND: Whereas sudden cardiac death (SCD) risk has been recognized in heart failure (HF) patients with reduced ejection fraction (HFrEF), less is known about SCD risk in HF patients with preserved EF (HFpEF). We examined the incidence and predictors of SCD in HFpEF in a large population sample. METHODS AND RESULTS: Medical records of patients discharged with a primary diagnosis of HF from hospitals in Minneapolis-St Paul in 1995 and 2000 were abstracted. HFpEF was defined as EF >= 45%. SCD was defined as cardiac arrest or out-of-hospital death due to coronary heart disease (CHD) on death certificates. A total of 2,203 patients (age 70 +/- 11 years, 53% male) were included. The 787 patients (36%) with HFpEF were older, more often female and more likely to have hypertension than the 1,416 (64%) with HFrEF. All-cause mortality (52% vs 58%; P = .01) and SCD (6% vs 14%; P < .0001) rates were lower in HFpEF than in HFrEF 5 years after hospital discharge. Age, sex, CHD, and length of index hospitalization were the only independent predictors of SCD in HFpEF. CONCLUSIONS: Incidence of SCD in HFpEF is lower than in HFrEF. Present markers of SCD in HFpEF are sparse and insufficient to identify the patient at risk. PMID- 23040108 TI - Early post-treatment with 9-cis retinoic acid reduces neurodegeneration of dopaminergic neurons in a rat model of Parkinson's disease. AB - BACKGROUND: Retinoic acid (RA) is a biologically active derivative of vitamin A. Previous studies have demonstrated that RA has protective effects against damage caused by H2O2 or oxygen-glucose deprivation in mesangial and PC12 cells. Pretreatment with 9-cis-retinoic acid (9cRA) reduced infarction and TUNEL labeling in cerebral cortex as well as attenuated neurological deficits after distal middle cerebral artery occlusion in rats. The purpose of this study was to examine a protective role of 9cRA in dopaminergic (DA) neurons in a typical rodent model of Parkinson's disease (PD). RESULTS: The protective role of 9cRA was first examined in rat primary ventromesencephalic culture. Treatment with 9cRA significantly reduced 6-hydroxydopamine (6-OHDA)-mediated cell death and TUNEL labeling in cultured dopaminergic neurons. The protective effect was also examined in adult male rats. Animals received unilateral 6-OHDA lesioning at the left medial forebrain bundle on day 0. Methamphetamine -induced rotational behavior was examined on days 6, 20 and 30 after lesioning. Animals were separated into 2 groups to balance rotational behavior and lesion extent on day 6 and were treated with either 9cRA or vehicle (i.c.v. on day 7 + intra-nasal from day 8 to day 14). Post-treatment with 9cRA significantly reduced methamphetamine mediated ipislateral rotation at 20 and 30 days after lesioning. In vivo voltammetry was used to examine DA overflow in striatum. Treatment with 9cRA significantly increased KCl -evoked DA release in the lesioned striatum. 9cRA also increased tyrosine hydroxylase (+) cell number in the lesioned nigra as determined by unbiased stereology. CONCLUSION: Our data suggests that early post treatment with 9cRA has a protective effect against neurodegeneration in nigrostriatal DA neurons in an animal model of PD. PMID- 23040110 TI - Left ventricular assist device support and myocardial recovery in recent onset cardiomyopathy. AB - BACKGROUND: Left ventricular assist device (LVAD) support as bridge to recovery (BTR) is uncommon for subjects with chronic heart failure. Myocardial recovery is more evident in recent onset nonischemic cardiomyopathy (ROCM); however, the prevalence of BTR in this subset has not been addressed. METHODS AND RESULTS: We examined the use of LVAD support for subjects with ROCM in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) study. The overall cohort (n = 373) was 38% female, 21% black, with a mean age of 45 +/- 14 years. LVAD support was used in 3.8% (n = 14, 43% female, age 32 +/- 10). Of LVAD subjects, 57% (8/14) were BTR, including 73% (8/11) of subjects with symptoms <=4 months at the time of support. Left ventricular end-diastolic diameter (LVEDD) was smaller in BTR than nonrecovered (NR) subjects (P = .04). Myocardial inflammation was more common in BTR (75% versus 0%, P = .005), whereas fibrosis was less evident (25% versus 100%, P = .005). Of BTR subjects, 7/8 (87.5%) were alive and free of transplant with median follow-up of 19 months. CONCLUSION: In a multicenter registry of ROCM, BTR was common and occurred in the majority of subjects requiring LVAD support. Histology and LVEDD may assist in predicting potential for BTR in ROCM. PMID- 23040111 TI - Genetic variants of the renin-angiotensin-aldosterone system and reverse remodeling after cardiac resynchronization therapy. AB - BACKGROUND: Reverse remodeling (RR) after cardiac resynchronization therapy (CRT) is associated with favorable clinical outcomes in heart failure (HF). The renin angiotensin-aldosterone system (RAAS) is involved in the remodeling process. METHODS AND RESULTS: We assessed the association between RR and 8 common RAAS gene variants, which were determined by TaqMan assays, in 156 outpatients with chronic HF. RR was defined as a >15% decrease in left ventricular end systolic volume (LVESV) at 9 (interquartile range 7-12) months after CRT. We matched 76 patients who did not show RR (RR-) to 80 RR+ control subjects by age, sex, HF etiology, New York Heart Association (NYHA) functional class and left ventricular ejection fraction (LVEF). The frequency of the minor allele of the NR3C2 gene (rs5522 C/T), encoding the mineralocorticoid receptor, was higher in RR- than in RR (24/126 vs 10/150; P value after false discovery rate correction: <.0193). Conversely, LVESV decreased significantly less after CRT in carriers of the NR3C2 minor C allele (P = .02). After adjustment for age, sex, NYHA functional class, previous myocardial infarction, atrial fibrillation, and LVEF, RR- remained independently associated with NR3C2 C allele carriage (odds ratio 3.093, 95% confidence interval 1.253-7.632). CONCLUSIONS: The association of RR- after CRT with a common polymorphism in the mineralocorticoid receptor gene involved in aldosterone signaling suggests a possible role for variants in RAAS genes in progressive LV function decline, despite apparently effective CRT. PMID- 23040112 TI - Effect of adaptive servoventilation on muscle sympathetic nerve activity in patients with chronic heart failure and central sleep apnea. AB - BACKGROUND: Adaptive servoventilation (ASV) improves cardiac function and sympathetic nerve activity in patients with heart failure (HF). However, the mechanisms underlying these improvements remain obscure. METHODS AND RESULTS: We compared muscle sympathetic nerve activity (MSNA) and cardiorespiratory polygraphy and echocardiography findings at baseline and at 3.5 +/- 0.8 months' follow-up in 32 patients with HF (New York Heart Association functional class II or III; ejection fraction <45%) and central sleep apnea (CSA; apnea-hypopnea index [AHI] >=15/h) who consented (n = 20; ASV group) or declined (n = 12; non ASV group) to undergo ASV treatment. Compliance with ASV and changes in AHI were determined from data collected by integral counters in devices and from cardiorespiratory polygraphic findings, respectively. Ejection fraction and MSNA significantly changed in the ASV (both P < .001) but not the non-ASV group. Although changes in AHI and MSNA correlated, the average use of ASV did not. In contrast, changes in AHI and the average use of ASV were independent predictors of changes in ejection fraction (both P < .01). CONCLUSIONS: ASV decreases MSNA and improves cardiac function in association with suppression of CSA in patients with HF. PMID- 23040113 TI - Investigating pain in heart failure patients: the pain assessment, incidence, and nature in heart failure (PAIN-HF) study. AB - BACKGROUND: Patients with advanced heart failure (HF) have high rates of pain and other symptoms that diminish quality of life. We know little about the characteristics and correlates of pain in patients with advanced HF. METHODS AND RESULTS: We identified pain prevalence, location, character, severity, frequency, and correlates in 347 outpatients with advanced HF enrolled from hospices and clinics. We evaluated the correlation of pain with HF-related quality of life, mortality, symptoms and health problems, and current treatments for pain. Pain at any site was reported by 293 patients (84.4%), and 138 (39.5%) reported pain at more than one site. The most common site of pain was the legs below the knees (32.3% of subjects). Pain interfered with activity for 70% of patients. Pain was "severe" or "very severe" for 28.6% of subjects with chest pain, and for 38.9% of those with other sites of pain. The only medication reported to provide pain relief was opioids, prescribed for 34.1% of subjects (P = .001). The strongest predictors of pain were degenerative joint disease (DJD) (odds ratio [OR] 14.95, 95% confidence interval [CI] 3.9-56.0; P < .001), other arthritis (OR 2.8, 95% CI 1.20-6.62; P = .017), shortness of breath (OR 3.27, 95% CI 1.47-7.28; P = .004), and angina pectoris (OR 3.38, 95% CI 1.30-8.81; P = .013). CONCLUSIONS: Pain occurred at multiple sites in patients with advanced HF. Pain correlated with DJD or other arthritis, shortness of breath, and angina. Only opioid analgesics provided relief of pain. Future research should evaluate the etiology of and interventions to manage pain in patients with HF. PMID- 23040115 TI - Echocardiographic changes during treatment of acute decompensated heart failure: insights from the ESCAPE trial. AB - BACKGROUND: Long-term heart failure (HF) treatment has been shown to result in reverse chamber remodeling. However, it is unknown whether sizes of cardiac chambers acutely change during HF therapy and whether these changes are associated with favorable clinical outcomes. METHODS AND RESULTS: Using the Evaluation Study of Congestive Heart Failure and Pulsmonary Artery Catheterization Effectiveness (ESCAPE) trial database, echocardiographic parameters at baseline and discharge, changes from baseline to discharge, and their association with the combined endpoint of death or HF rehospitalization (HFH) at 6 months were evaluated in patients admitted with acute decompensated HF (ADHF). Also, the correlation between changes in invasive hemodynamic parameters compared with changes in echocardiographic parameters was analyzed. During the treatment of ADHF, right atrium, right ventricle, and inferior vena cava (IVC) sizes decreased acutely. Mitral regurgitation severity and mitral inflow parameters also improved significantly. However, the majority of acute changes in echocardiographic parameters did not have an impact on clinical outcome, except for the reduction in left ventricular (LV) end-diastolic and end-systolic volumes, which was associated with a reduction in the combined outcome of HFH or death. The change in invasive hemodynamics that best correlated with change in echocardiographic parameters was change in pulmonary capillary wedge pressure with change in IVC diameter and IVC collapsibility. CONCLUSIONS: This is the first study to identify the echocardiographic parameters that change during the treatment of ADHF and the echocardiographic parameters that most reliably correlate with invasive hemodynamic changes. Most changes in echocardiographic parameters were not associated with clinical outcomes, except for the reduction in LV volume, which was associated with a reduction in HFH or death. PMID- 23040114 TI - Associations between hemoglobin level, resource use, and medical costs in patients with heart failure: findings from HF-ACTION. AB - BACKGROUND: Reports that patients with heart failure and anemia incur greater costs and medical resource use have relied largely on data with limited clinical detail. METHODS: HF-ACTION, a large trial of exercise training in heart failure, recorded hemoglobin at baseline. Medical resource use and hospital bills for inpatient and emergency department visits were collected throughout the study. We analyzed hemoglobin as a continuous variable to evaluate relationships with medical resource use and costs over 1 year. RESULTS: Among 1,763 patients with baseline hemoglobin levels, those with lower hemoglobin levels tended to be older, African American, and women and to have more severe heart failure. Lower hemoglobin was significantly associated with more hospital admissions, inpatient days, outpatient visits, and urgent care or emergency department visits (all P < .005, unadjusted). Although cost outliers influenced estimates, these observations were distributed across hemoglobin levels. Mean 1-year costs across hemoglobin levels defined as <= 11, >11-12, >12-13, >13-14, >14-15, and >15 g/dL were $21,106, $20,189, $16,249, $17,989, $13,216, and $12,492, respectively (P < .001, unadjusted). Significant associations remained after multivariable adjustment. CONCLUSIONS: Patients with lower baseline hemoglobin levels experienced progressively greater resource use and higher costs. PMID- 23040116 TI - Increased exhaled nitric oxide levels after exercise in patients with chronic systolic heart failure with pulmonary venous hypertension. AB - BACKGROUND: Fractional exhaled nitric oxide (eNO) is recognized as a marker of pulmonary endothelial function. Oxidative stress is associated with systemic endothelial nitric oxide production, but its correlation with eNO in heart failure (HF) patients has not been described. Previous studies have reported increased eNO levels after exercise in symptomatic HF patients but decreased levels with pulmonary arterial hypertension. Our objective was to prospectively examine the potential myocardial and functional determinants of exercise-induced rise of eNO in HF. METHODS AND RESULTS: Thirty-four consecutive ambulatory patients with chronic systolic HF (left ventricular ejection fraction [LVEF] <=45%) underwent symptom-limited cardiopulmonary stress testing and echocardiography. eNO was determined immediately after exercise. Systemic endothelial dysfunction was assessed by asymmetric dimethylarginine (ADMA) and the L-arginine/ADMA ratio. In our study cohort (mean age 53 +/- 13 years, 76% male, median LVEF 31%, interquartile range [IQR] 25%-40%), the mean eNO was 23 +/ 9 ppb. eNO levels were higher in patients with diastolic dysfunction stages 2 or 3 than stage 1 or normal diastology (26.1 +/- 9 vs 19.5 +/- 7 ppb; P = .013). eNO had a positive correlation with estimated systolic pulmonary artery pressure (r = 0.57; P = .0009) and indexed left atrium volume (r = 0.43; P = .014), but it did not correlate with cardiopulmonary exercise test parameters, ADMA, or symptom score. CONCLUSIONS: In contrast to earlier reports, the increase in postexercise eNO observed in stable chronic systolic HF patients may be attributed to the presence of underlying pulmonary venous hypertension probably secondary to advanced diastolic dysfunction. PMID- 23040117 TI - Dipeptidyl peptidase 4 inhibition increases myocardial glucose uptake in nonischemic cardiomyopathy. AB - BACKGROUND: Glucose and fatty acids comprise the primary substrates for myocardial energy metabolism. The normal myocardium switches toward glucose metabolism in the setting of stress; the inability to affect such a switch is a fundamental mechanism behind "diabetic" or "insulin-resistant" cardiomyopathy. The purpose of this mechanistic study was to evaluate the effects of treatment with the dipeptidyl peptidase (DPP) 4 inhibitor sitagliptin on myocardial glucose uptake in patients with nonischemic cardiomyopathy. METHODS AND RESULTS: Twelve nondiabetic subjects with nonischemic cardiomyopathy underwent metabolic testing and assessment of myocardial glucose uptake by (18)F-fluorodeoxyglucose positron emission tomographic/computerized tomographic imaging at baseline and after 4 weeks of sitagliptin therapy. Sitagliptin therapy resulted in a significant increase in myocardial glucose uptake (19% increase; P = .04). Although most patients had at least a slight increase in glucose uptake, there was an overall bimodal response, with 6 patients ("responders") demonstrating large increases (>20%) in glucose uptake and 6 patients ("nonresponders") demonstrating <5% increases or slight decreases. Triglyceride-high-density lipoprotein ratios significantly dropped in the 6 responders compared with the 6 nonresponders (P < .02). CONCLUSIONS: Therapy with the DPP-4 inhibitor sitagliptin results in increased myocardial glucose uptake in nondiabetic patients with nonischemic cardiomyopathy. PMID- 23040119 TI - Campylobacter spp. - prevalence on pig livers and antimicrobial susceptibility. AB - The objective of the study was to determine the prevalence of Campylobacter spp. on surfaces of slaughtered pig livers. Multilocus sequence typing (MLST) was performed to determine the sequence types (STs) of selected Campylobacter coli isolates. Additionally, C. coli and Campylobacter jejuni isolates were tested for antimicrobial susceptibility by the broth dilution method. The minimal inhibitory concentrations were determined for erythromycin, gentamicin, ampicillin, ampicillin/sulbactam, nalidixic acid, ciprofloxacin, tetracycline and trimethoprim/sulphamethoxazole. Samples were taken during the slaughtering process in a slaughterhouse in Lower Saxony, Germany. Altogether, 10% of 1500 surfaces of pig livers from 50 fattening herds was found to be Campylobacter positive, with C. coli as the predominant species (76%) followed by C. jejuni (21%). Resistance to erythromycin and tetracycline was higher in C. jejuni compared to C. coli, whereas C. coli were more resistant to quinolone compared to C. jejuni. Fluoroquinolone resistance is usually associated with cross-resistance to quinolone, but in the presented investigation C. coli as well as C. jejuni showed a higher resistance to ciprofloxacin (28.6% and 20.0%, respectively) than to nalidixic acid (9.5% and 0%, respectively). A high genetic diversity of the C. coli isolates was demonstrated by MLST. Differences in STs and antimicrobial resistance pattern indicate that the Campylobacter strains originated from the pig itself and not from the slaughterhouse. A comparison of the STs with those reported in the C. jejuni/coli PubMLST database showed an overlap of porcine and human isolates, indicating that C. coli isolates from pigs should be considered as potential sources of human infection. PMID- 23040120 TI - Investigating effects of between- and within-host variability on Escherichia coli O157 shedding pattern and transmission. AB - Healthy cattle and their environment are the reservoir for the human pathogen Escherichia coli O157. In E. coli O157 epidemiology, supershedders have been loosely defined as cattle that shed high concentrations of E. coli O157 (>= 10(4)colony-forming cells (CFU)/g of feces) at a single (or multiple) cross section in time. Due to the variability in the pathogen shedding level among animals (between-host variability), as well as fluctuations in the level shed by a single animal (within-host variability), it is difficult to interpret fecal bacteria distributions, as well as to parse the relative contribution of between- and within-host variability to the observed shedding patterns at the pen level. We developed an agent-based model that integrates individual animal data on temporal fecal shedding dynamics with pen-level E. coli O157 transmission to study how the temporal (and aggregation) patterns of E. coli O157 shedding loads and prevalence arise at the pen level. We demonstrated that even without between host variability, the prevalence of animals with concentration of E. coli O157 in feces that exceeds 10(4)CFU/g is similar to that observed in cross-sectional field data. Both within-host and between-host variability can generate supershedders. PMID- 23040121 TI - How does the number of oral contraceptive pill packs dispensed or prescribed affect continuation and other measures of consistent and correct use? A systematic review. AB - BACKGROUND: The review was conducted to examine studies that assess whether the number of pill packs dispensed, or prescribed, affects method continuation and other measures of use. STUDY DESIGN: PubMed database was searched from inception through March 2012 for all peer-reviewed articles, in any language, that examined the effect of the number of oral contraceptive pill packs dispensed on method continuation, and other measures of use. The quality of each study was assessed using the United States Preventive Services Task Force grading system. RESULTS: Four studies met the inclusion criteria for this review. Studies that compared 1 vs. 12, 1 vs. 12-13, or 3 vs. 7 packs found increased method continuation. However, one study that examined the difference between providing one and then three packs versus providing four packs all at once did not find a difference in continuation. In addition to continuation, evidence from the individual studies included found that a greater number of pill packs was associated with fewer pregnancy tests, fewer pregnancies and less cost per client. A greater number of pill packs was, however, also associated with increased pill wastage. CONCLUSIONS: A small body of evidence suggests that dispensing a greater number of oral contraceptive pill packs may increase continuation of use. PMID- 23040122 TI - The price of emergency contraception in the United States: what is the cost effectiveness of ulipristal acetate versus single-dose levonorgestrel? AB - BACKGROUND: Ulipristal acetate (UPA) is a novel form of emergency contraception (EC) that appears to be more effective than the prevailing method, single-dose levonorgestrel (LNG). This study examines the cost-efficacy of UPA compared with LNG. STUDY DESIGN: A decision-analytic model was developed to compare the cost effectiveness of UPA versus LNG in preventing unintended pregnancy when taken within 120 h of unprotected intercourse. Univariate and bivariate sensitivity analyses, as well as Monte Carlo simulation and threshold analyses, were performed. RESULTS: Utilizing UPA instead of LNG would result in 37,589 fewer unintended pregnancies per 4,176,572 estimated US annual EC uses (UPA 54,295 pregnancies; LNG 91,884 pregnancies) and a societal savings of $116.3 million annually. Cost-effectiveness acceptability curve analyses suggest a 96% probability that UPA is more cost-effective at a willingness to pay $100,000 per quality-adjusted life year. CONCLUSIONS: UPA is cost-effective in preventing unintended pregnancy after unprotected intercourse. Efforts should be promoted to increase access to UPA. PMID- 23040123 TI - Hemoglobin measurement prior to initiating copper intrauterine devices: a systematic review. AB - BACKGROUND: Women using copper intrauterine devices (IUDs) frequently experience bleeding abnormalities. This review was conducted to evaluate the evidence regarding whether hemoglobin levels should be measured prior to copper IUD insertion. STUDY DESIGN: The PubMed database was searched from database inception through March 2012 for all peer-reviewed articles in any language concerning hemoglobin changes among women with anemia who have copper IUDs inserted. Articles were included if they reported changes in hemoglobin among anemic women over a specified period of time following copper IUD insertion. Articles were excluded in which there were no women with anemia at baseline or outcomes among women with anemia were not reported separately. For indirect evidence, articles were included which addressed hemoglobin changes among women without anemia who had copper IUDs inserted. The quality of each direct study was assessed using the US Preventive Services Task Force grading system. RESULTS: Four level I to II-2 studies of fair quality met inclusion criteria as direct evidence. Evidence from one randomized trial and one prospective cohort study showed no statistically significant changes in hemoglobin among copper IUD users with anemia, while two prospective cohort studies showed a statistically significant, but clinically small, mean decrease in hemoglobin levels over 12 months of follow-up. We also identified 21 studies examining changes in hemoglobin among healthy women using copper IUDs as indirect evidence; this body of evidence was not graded. These studies generally showed no clinically significant changes in hemoglobin levels with up to 5 years of follow-up. CONCLUSIONS: Limited fair-quality evidence was mixed but generally showed no clinically significant changes in hemoglobin among women with anemia who used copper IUDs for up to 12 months. Indirect evidence among healthy women using copper IUDs did not show clinically significant changes in hemoglobin levels when followed for up to 5 years of use. PMID- 23040124 TI - Pregnancies after hysteroscopic sterilization: a systematic review. AB - BACKGROUND: Female sterilization is the second most commonly used form of contraception in the United States. Newer approaches to female sterilization, including hysteroscopic methods, have been approved for use in the United States since 2002. Little is known about the occurrence and timing of pregnancies after these procedures. STUDY DESIGN: The objective of this systematic review was to identify evidence that assesses when and how often pregnancies occur following hysteroscopic sterilization. The PubMed database was searched for all studies published from database inception through March 2012 that reported whether or not pregnancies occurred following hysteroscopic sterilization. RESULTS: Twenty-four original research articles of fair quality met the inclusion criteria: 22 studies of women who underwent Essure(r) placement and 2 studies of women who underwent Adiana(r) placement. Eleven articles that documented bilateral tubal occlusion with hysterosalpingogram (HSG) or placement with X-ray or ultrasound following Essure(r) placement did not report any pregnancies with follow-up ranging from 7 months to 7 years. The remaining 11 articles identified 102 reported pregnancies. Eighteen of these pregnancies occurred prior to the 3-month period required before imaging for contraceptive reliability. Two articles did not report what follow-up imaging was performed among women after Essure(r) placement; one of these articles reported three pregnancies. Two reports from the same study of women who underwent Adiana(r) placement reported six pregnancies during the first year of follow-up, three pregnancies during the second year of follow-up and no pregnancies during the third year of follow-up. CONCLUSIONS: Fair-quality evidence suggests that among women who were followed beyond 3 months after hysteroscopic sterilization, pregnancies were rare and generally occurred among women who had no imaging follow-up or had inadequate confirmation of placement or occlusion. Few pregnancies occurred in women with documented bilateral tubal occlusion by HSG or correct placement at 3 months by ultrasound or X-ray. Only one study reported follow-up past 5 years. Further studies are needed to address the long-term effectiveness of hysteroscopic sterilization. PMID- 23040125 TI - Current status of contraceptive vaginal rings. AB - Contraceptive vaginal rings (CVR) offer a new, effective contraceptive option, expanding the available choices of hormonal contraception. Various ring prototypes have been evaluated: progestin-only rings and combined progestin estrogen rings, as well as different combination of progestins and estrogens. The progestin-only ring is intended for continuous use, whereas the combined ring has been designed for cyclic 3-week in/1-week out use, although several studies have explored alternative schemes of extended use. However, only two ring designs have reached the market: NuvaRing, a 1-month combined ring that releases etonogestrel and ethinylestradiol, and Progering, a 3-month progesterone-releasing ring for use in lactating women. A one year Nestorone/ethinyl estradiol CVR is approaching the final stages of development, as the Population Council is preparing to submit a new drug application to the Food and Drug Administration. The main advantages of CVRs are their effectiveness (similar or slightly better than the pill), ease of use without the need of remembering a daily routine, user ability to control initiation and discontinuation, nearly constant release rate allowing for lower doses, greater bioavailability and good cycle control with the combined ring, in comparison with oral contraceptives. Current prototypes in development include rings releasing progesterone receptor modulators, which would provide estrogen free contraception, as well as combined rings releasing estradiol, instead of ethinyl-estradiol, providing a safer profile. Furthermore, intensive efforts towards developing dual protection rings, providing both contraception and protection against reproductive tract infections, offer hope that this greatly needed technology will soon undergo clinical testing and will be in the hands of women worldwide in the near future. PMID- 23040126 TI - Vaginal ring delivery of selective progesterone receptor modulators for contraception. AB - Vaginal ring delivery of selective progesterone receptor modulators (SPRMs) is under development to address the limitations of current hormonal methods that affect use and effectiveness. This method would be appropriate for use in women with contraindications to, or preferences to avoid, estrogens. A contraceptive vaginal ring (CVR) also eliminates the need for daily dosing and therefore might improve the effectiveness of contraception. The principal contraceptive effect of SPRMs is the suppression of ovulation. One limiting factor of chronic SPRM administration is the development of benign endometrial thickening characterized as PRM-associated endometrial changes. Ulipristal acetate (UPA) is approved for use as an emergency contraceptive pill, but no SPRM is approved for regular contraception. The Population Council is developing an ulipristal acetate CVR for regular contraception. The CVR studied is of a matrix design composed of micronized UPA mixed in a silicone rubber matrix The target product is a ring designed for continuous use over 3 months delivering near steady-state drug levels that will suppress ovulation. Results from Phase 1 and 2 studies demonstrate that suppression of ovulation occurs with UPA levels above 6-7 ng/mL. PMID- 23040127 TI - Use of a checklist to rule out pregnancy: a systematic review. AB - BACKGROUND: Safe initiation of contraceptive methods requires that pregnancy be excluded. The World Health Organization has developed a list of criteria to assess pregnancy status. This review was conducted to evaluate the evidence regarding these criteria in excluding pregnancy. STUDY DESIGN: The PubMed database was searched from database inception through March 2012 for all peer reviewed articles in any language concerning the performance of a pregnancy checklist compared to urine pregnancy tests. The quality of each study was assessed using the United States Preventive Services Task Force grading system. RESULTS: Four analyses of data from three studies met inclusion criteria as direct evidence. All were diagnostic accuracy studies of fair quality that evaluated the performance of a pregnancy checklist compared with urine pregnancy test to rule out pregnancy. The performance of the checklist varied, with sensitivity ranging from 55-100% and specificity ranging from 39-89%. The negative predictive value was consistent across studies at 99-100%. CONCLUSION: All four analyses demonstrated high (99-100%) negative predictive value for the pregnancy checklist. PMID- 23040128 TI - Emergency contraception: clinical outcomes. AB - Emergency contraception (EC) is widely used to prevent unwanted pregnancy. This review considers the safety and efficacy of three commonly used methods -- levonorgestrel (LNG-EC), ulipristal acetate (UPA) and the copper intrauterine device. All are extremely safe, and side effects are minimal. Concerns about increased risks of ectopic pregnancy after EC use have proved unfounded, and possible teratogenic effects seem unlikely. Although the true effectiveness of EC is impossible to estimate, recent research suggests that LNG-EC prevents around 50% of expected pregnancies in women using the method within 72 h of intercourse, whereas UPA appeared to prevent almost two thirds of pregnancies. Emergency intrauterine device insertion probably prevents over 95% of pregnancies. However, although improved accessibility of EC has clearly led to increased use, it does not appear to have had any public health benefit in reducing unintended pregnancy rates. Most of the data on sexual behavior following improved access to EC do not show any detrimental effect on subsequent use of other more effective methods of contraception or on the incidence of unintended pregnancy or sexually transmitted infection. However, unless these other methods of contraception are also made easily available from pharmacies, improved access to EC risks unlinking its use with use of subsequent ongoing contraception. PMID- 23040129 TI - Added health benefits of the levonorgestrel contraceptive intrauterine system and other hormonal contraceptive delivery systems. AB - BACKGROUND: It has been recognized for well over half a century that hormonal preparations designed as contraceptives are also capable of offering health benefits through the treatment and prevention of benign gynecological disease and even some systemic conditions. Increasing attention is now being paid to the extent and detail of such added health benefits, and it is becoming clear that the long-acting, low-dose, hormonal contraceptive delivery systems may offer particular advantages in this regard. METHODS: Conventional databases were thoroughly searched, especially for publications from 2006 to 2012, which addressed non-contraceptive-related indications for therapy and prevention. RESULTS: A considerable literature now exists to demonstrate the multiple and substantial noncontraceptive health benefits of long-acting progestogen-releasing systems, especially the levonorgestrel-releasing intrauterine system. These benefits mainly relate to disturbances of menstruation and related symptoms, such as heavy menstrual bleeding (due to many causes); iron deficiency; pelvic pain, especially around endometriosis; and endometrial hyperplasia. The long-acting estrogen-progestogen systems may carry similar added health benefits to those of the combined oral contraceptives, but data are still lacking. CONCLUSION: Added health benefits are now becoming an important part of the contraceptive choice equation, and the long-acting delivery systems are recognized as suitable primary therapies for a range of gynecological disorders. PMID- 23040130 TI - Lower risk for Down syndrome associated with longer oral contraceptive use: a case-control study of women of advanced maternal age presenting for prenatal diagnosis. AB - BACKGROUND: Maternal trisomy 21 ovarian mosaicism might provide the major causative factor for fetal Down syndrome. The small proportion of trisomy 21 oocytes thought to be retarded in their maturation in comparison to normal disomic ones, and the maternal age effect can be based on an accumulation of trisomy 21 oocytes in the ovarian reserve. By lowering the number of unnecessary ovulations, a greater portion of disomic oocytes might be saved. STUDY DESIGN: Between September 2009 and September 2011, we performed genetic amniocentesis for fetal chromosomal analysis in 5222 pregnancies. We detected 119 structural or numerical chromosomal abnormalities. We collected data from 37 cases who were in advanced maternal age and where fetal trisomy 21, 18 or 13 was confirmed. We had 92 control patients. Detailed information was taken from those factors that influence the number of ovulations in reproductive life. RESULTS: From the factors checked, patients with a trisomic fetus had a shorter overall mean length of oral contraceptive pill use before the trisomic pregnancy (3.4 vs. 6.0 years, p<.0014), and the estimated number of mean ovulations was higher (274.6 vs. 224, p<.0003). CONCLUSION: We found that a history of longer oral contraceptive pill use and fewer ovulatory cycles were associated with fewer common trisomies of the fetus. Additional research is needed to rule out potential confounding factors, but our results are consistent with the maternal ovarian mosaicism causal model. PMID- 23040131 TI - The need for reproductive and sexual health discussions with adolescent and young adult cancer patients. AB - Reproductive health consistently ranks as one of the most important issues cited by adolescent and young adult (AYA) cancer survivors. Most literature on AYA cancer populations neglects broader reproductive health issues such as unintended pregnancies, contraception use and sexually transmitted infections, which, for cancer patients and survivors with compromised immune systems, can facilitate a multitude of future health problems. Lack of attention coupled with traditional risk-taking behaviors of AYAs poses a significant health risk to patients and survivors, particularly if fertility status is unknown or inaccurately assessed. AYA oncology patients and survivors are vulnerable to reproductive health complications that should be addressed prior to, during and after treatment; however, there are currently no tracking systems or evidence-based guidelines to discuss this subject with patients and survivors. Further research is needed to identify physician practices, AYA preferences and strategies for communication that can pave the way to establishing guidelines to discuss in oncology settings. PMID- 23040132 TI - Effect of interpregnancy interval after a mifepristone-induced abortion on neonatal outcomes in subsequent pregnancy. AB - BACKGROUND: The study evaluated effects of interpregnancy interval (IPI) on neonatal outcomes after mifepristone-induced abortion in the first pregnancy. STUDY DESIGN: This observational cohort study, conducted from 1998 to 2001 at antenatal clinics in Shanghai, Beijing, and Chengdu, China, included 4682 nulliparous women with one mifepristone-induced abortion in their first pregnancy, who were enrolled and followed up until delivery. We compared neonatal outcomes among women with different IPIs between their mifepristone-induced abortion and subsequent pregnancy. RESULTS: When compared to IPI of 18-24 months, there was an increased risk of the neonate being small for gestational age (SGA) [adjusted odds ratio (aOR): 2.01; 95% confidence interval (CI): 1.04-3.88] when IPI was <6 months; this risk was greater among women without a curettage history after abortion (aOR: 2.49; 95% CI: 1.13-5.50). The associations between IPI and preterm delivery (<37 weeks), low birth weight (<2500 g), mean birth weight and ponderal index were not statistically significant. CONCLUSIONS: The results indicate that an IPI <6 months after one mifepristone-induced abortion in first pregnancy is associated with an increased risk of SGA in the subsequent pregnancy. PMID- 23040133 TI - Laboratory screening prior to initiating contraception: a systematic review. AB - BACKGROUND: Certain contraceptive methods may increase the risk of adverse events for women with certain medical conditions, including some women with diabetes, hyperlipidemia, liver disease, cervical cancer, sexually transmitted infections (STIs) or human immunodeficiency virus (HIV). This review was conducted to evaluate the evidence regarding health outcomes among women with and without laboratory testing to identify certain medical conditions prior to initiating contraceptives. STUDY DESIGN: The PubMed database was searched from database inception through April 2012 for all peer-reviewed articles in any language evaluating health outcomes among women who initiated certain contraceptive methods and who had or had not received glucose, lipid, liver enzyme, cervical cytology, STI or HIV screening. RESULTS: The systematic review did not identify any relevant direct evidence. CONCLUSIONS: While certain methods of hormonal contraception may not be safe for use by some women with diabetes, hyperlipidemia or liver disease, there is little value in screening for these conditions in asymptomatic women prior to initiation of contraceptive methods due to the low prevalence of these conditions among women of reproductive age. Although intrauterine devices (IUDs) and cervical caps should not be initiated in women with cervical cancer, the high rates of cervical screening and low incidence of cervical cancer in the United States make this scenario unlikely. Although some women at risk for, or infected with, STIs or HIV should not undergo IUD insertion, if women have been screened for STIs or HIV according to guidelines, additional screening at the time of IUD insertion is not warranted. Requiring unnecessary laboratory screening prior to initiation of contraceptive methods may impose barriers to contraceptive access, and efforts to remove such barriers are critical in reducing unintended pregnancy. PMID- 23040134 TI - Adaptation of the World Health Organization's Selected Practice Recommendations for Contraceptive Use for the United States. AB - BACKGROUND: The Centers for Disease Control and Prevention (CDC) recently adapted global guidance on contraceptive use from the World Health Organization (WHO) to create the US Selected Practice Recommendations for Contraceptive Use (US SPR). The WHO guidance includes evidence-based recommendations on common, yet sometimes complex, contraceptive management questions. STUDY DESIGN: We determined the need and scope for the adaptation, conducted 30 systematic reviews of the scientific evidence and convened a meeting of health care professionals to discuss translation of the evidence into recommendations. RESULTS: The US SPR provides recommendations on contraceptive management issues such as how to initiate contraceptive methods, what regular follow-up is needed, and how to address problems, including missed pills and side effects such as unscheduled bleeding. CONCLUSION: The US SPR is intended to serve as a source of clinical guidance for providers in assisting women and men to initiate and successfully use contraception to prevent unintended pregnancy. PMID- 23040135 TI - Retention of intrauterine devices in women who acquire pelvic inflammatory disease: a systematic review. AB - BACKGROUND: Women using intrauterine devices (IUDs) are not protected against acquiring pelvic inflammatory disease (PID). If a woman has an IUD in place when she is diagnosed with PID, there is a theoretical concern that presence of an IUD might impact the course of treatment. This review was conducted to evaluate the evidence regarding whether an IUD should be retained or removed if a woman develops PID. STUDY DESIGN: The PubMed database was searched from database inception through April 2012 for all peer-reviewed articles in any language concerning PID in women using IUDs. Articles were included if they examined women with IUDs who developed PID and compared the clinical course of women in whom the IUD was retained versus women in whom the IUD was removed. Articles were excluded if the infection was diagnosed before or at the time of IUD insertion. The quality of each study was assessed using the United States Preventive Services Task Force grading system. RESULTS: Four fair-quality studies met inclusion criteria for this review. One randomized controlled trial showed that women with IUDs removed had longer hospitalizations than those with IUD retention (15% versus 4%, p<.01), although there were no differences in PID recurrences or subsequent pregnancies. Another randomized controlled trial showed no differences in laboratory parameters among women who retained the IUD when compared with women in whom the IUD was removed. One prospective cohort study showed that there were no differences in clinical or laboratory parameters during hospitalization; however, the IUD removal group had a higher proportion hospitalized for more than 2 weeks compared with the IUD retention group (33% versus 19%, p<.05). One randomized controlled trial showed that women who had the IUD removed experienced improved recovery in most clinical signs and symptoms compared with women who retained the IUD. CONCLUSIONS: Three fair-quality studies showed no difference in clinical or laboratory outcomes among women who retained IUDs when compared with women who had IUDs removed, and two of these studies showed that women who had IUDs removed had longer hospitalizations. In contrast, one fair quality study showed improved clinical signs and symptoms among women who had IUDs removed. Overall, women who retained their IUDs had similar or better outcomes than women who had their IUDs removed. PMID- 23040136 TI - Patient understanding of oral contraceptive pill instructions related to missed pills: a systematic review. AB - BACKGROUND: Instructions on what to do after pills are missed are critical to reducing unintended pregnancies resulting from patient non-adherence to oral contraceptive (OC) regimens. Missed pill instructions have previously been criticized for being too complex, lacking a definition of what is meant by "missed pills," and for being confusing to women who may not know the estrogen content of their formulation. To help inform the development of missed pill guidance to be included in the forthcoming US Selected Practice Recommendations, the objective of this systematic review was to evaluate the evidence on patient understanding of missed pill instructions. STUDY DESIGN: We searched the PubMed database for peer-reviewed articles that examined patient understanding of OC pill instructions that were published in any language from inception of the database through March 2012. We included studies that examined women's knowledge and understanding of missed pill instructions after exposure to some written material (e.g., patient package insert, brochure), as well as studies that compared different types of missed pill instructions on women's comprehension. We used standard abstract forms and grading systems to summarize and assess the quality of the evidence. RESULTS: From 1620 articles, nine studies met our inclusion criteria. Evidence from one randomized controlled trial (RCT) and two descriptive studies found that more women knew what to do after missing 1 pill than after missing 2 or 3 pills (Level I, good, to Level II-3, poor), and two descriptive studies found that more women knew what to do after missing 2 pills than after missing 3 pills (Level II-3, fair). Data from two descriptive studies documented the difficulty women have understanding missed pill instructions contained in patient package inserts (Level II-3, poor), and evidence from two RCTs found that providing written brochures with information on missed pill instructions in addition to contraceptive counseling significantly improved knowledge of how to manage missed pills for up to three months compared to contraceptive counseling alone (Level I, fair). Evidence from one RCT found that graphic-based missed pill instructions were better than text-only instructions (Level I, good), and data from two RCTs found that less information resulted in improved comprehension (Level I, good to fair). Evidence from one descriptive study found that many women missing pills did not intend to follow recommended actions per missed pill instructions despite understanding the guidance (Level II 3, poor). CONCLUSIONS: There is wide variability in the percent of women having correct knowledge on what to do when pills are missed after exposure to written missed pills instructions, with more women knowing what to do after missing 1 pill than after missing 2 or 3 pills. Women have difficulty understanding missed pill instructions contained in patient package inserts. Providing written brochures with information on missed pill instructions in addition to contraceptive counseling may improve knowledge of how to manage missed pills. Graphic-based missed pill instructions and those containing less information may result in improved comprehension. Even with clear instructions, many women missing pills may choose not to follow the recommended actions. PMID- 23040137 TI - Trends in contraceptive use. AB - BACKGROUND: In the past 50-60 years, desired and actual family size have decreased and contraceptive use has increased, especially in developing countries. Unmet need for modern contraceptives and unintended pregnancy levels remain significant. STUDY DESIGN: Data compiled by the United Nations and information from national surveys of women of reproductive age are used to examine trends. RESULTS: Oral contraceptives and condoms have been predominant methods in developed countries; sterilization has been the most common in Latin America and the Caribbean and Asia; hormonal methods, in Africa. Some 222 million women in developing countries have unmet need for modern contraceptives, resulting in 2012 in an estimated 54 million unintended pregnancies and 79,000 maternal deaths more than if they used modern methods. CONCLUSIONS: Improvements are needed in contraceptive information and services as well as in contraceptive methods themselves to increase couples' success in achieving their desired timing and number of children. PMID- 23040138 TI - Making of a vaccine preventing pregnancy without impairment of ovulation and derangement of menstrual regularity and bleeding profiles. AB - The story of making a vaccine against human chorionic gonadotropin (hCG) for control of fertility is briefly reviewed. The choice of hCG was made on the consideration that it is not involved in the cascade of hormones leading to ovulation; hence, antibodies against hCG would neither disturb ovulation nor normal production of sex hormones by the female. It would not react with any other tissue of the body because no organ of a healthy noncancerous female expresses hCG. International Committee for Contraception Research played a historic role in testing its immunogenicity, safety and reversibility in women in Finland, Sweden, Chile and Brazil. The Population Council also conducted valuable long-term studies (5 years) in New York in 63 rhesus monkeys, which demonstrated the lack of pathological consequences of antibodies cross-reactive with species luteinizing hormone. The first-ever efficacy trials on a birth control vaccine established high efficacy (one pregnancy in 1224 cycles) of anti-hCG antibodies at and above 50 ng/mL titers. Fertility was regained in the immediate next cycle, at titers falling below 35 ng/mL. A recombinant vaccine, hCGbeta-LTB, has been made, which is highly immunogenic in mice. It is due to undergo toxicology studies prior to resumption of clinical trials. An additional utility of this vaccine is likely in advanced-stage terminal cancers expressing hCG/subunits. PMID- 23040139 TI - Advance supply of emergency contraception: a systematic review. AB - BACKGROUND: Emergency contraceptive pills (ECPs) are an underutilized means to reduce unintended pregnancy. Advance provision of ECPs may increase timely use, thereby decreasing risk of unintended pregnancy. STUDY DESIGN: We searched MEDLINE and EMBASE through February 2012 for randomized, controlled trials (RCTs) pertaining to safety and efficacy of advance provision of ECP. The quality of each individual study was evaluated using the United States Preventive Services Task Force evidence grading system. RESULTS: The search strategy identified 714 articles. Seventeen papers reported on safety or efficacy of advance ECPs in adult or adolescent women. Any use of ECPs was two to seven times greater among women who received an advanced supply of ECP. However, a summary estimate (RR 0.90, 95% CI 0.69-1.18) of four RCTs did not demonstrate a significant reduction in unintended pregnancy over 12 months when advance provision was compared with standard provision of ECPs. Patterns of contraceptive use, pregnancy rates and incidence of sexually transmitted infections did not vary between treatment and control groups in the majority of studies among either adults or adolescents. CONCLUSION: Available evidence supports the safety of advance provision of ECPs. Efficacy of advance provision compared with standard provision of ECPs in reducing unintended pregnancy rates at the population level has not been demonstrated. PMID- 23040140 TI - Bleeding patterns with the levonorgestrel-releasing intrauterine system when used for heavy menstrual bleeding in women without structural pelvic pathology: a pooled analysis of randomized controlled studies. AB - BACKGROUND: The study was conducted to characterize the changes in bleeding pattern over time in women receiving the levonorgestrel-releasing intrauterine system (LNG-IUS) for heavy menstrual bleeding (HMB). The reduction in menstrual blood loss volume has been well documented elsewhere. STUDY DESIGN: Post hoc pooled analysis of the impact of the LNG-IUS on bleeding patterns in four comparator studies of medical and surgical treatment options for HMB. We enrolled women aged >=18 years with HMB without organic pathology. The change in the number of bleeding and spotting (B/S) days and bleeding patterns was assessed over the duration of the studies pooled. RESULTS: One hundred and sixty-three women received the LNG-IUS in randomized trials. Relative to pretreatment baseline, there was a transient increase in the mean number of bleeding days in the first month of treatment, which returned to baseline by the second month and declined thereafter. Although the number of spotting days also increased during the first month of treatment, these declined with continued use but remained elevated relative to baseline during the first year of treatment. CONCLUSION: In women with HMB, the LNG-IUS is associated with an initial increase in number of B/S days that improve over time. PMID- 23040141 TI - Feasibility and acceptability of routine human immunodeficiency virus testing in general practice: your views. AB - Early diagnosis of human immunodeficiency virus (HIV) leads to a decreased morbidity and mortality. General practice offers an important window for earlier diagnosis. The British HIV Association produced guidelines in 2008 advocating an increase in HIV testing, with specific references to primary care. This study explores the awareness of, and opinions towards, these guidelines within general practice. An email questionnaire was sent to 191 general practitioners nationwide, in both areas of high and low HIV prevalence. A total of 80 doctors replied, giving a response rate of 42%. In all, 44% of the respondents were unaware of the guidelines and 89% felt comfortable discussing and carrying out an HIV test themselves; of the 11% that did not, all but one were from low prevalence areas (P = 0.037). Respondents felt that main barrier to HIV testing was patient acceptability. Having read the guidelines, 70% believed it would be feasible to follow them in practice. Those who disagreed felt that time implications were the most important reason not to adopt the guidelines. Almost half the respondents were not aware of the guidelines; having read them, the majority felt that implementation is feasible. This demonstrates the necessity for better dissemination of these guidelines. This study found that the main barrier to performing an HIV test was felt to be patient acceptance, a contradiction to findings from recent pilot studies. PMID- 23040143 TI - A model of the cost-effectiveness of intensity-modulated radiotherapy in comparison with three-dimensional conformal radiotherapy for the treatment of localised prostate cancer. AB - AIMS: To determine the cost-effectiveness of intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiotherapy (3DCRT) for men with localised prostate cancer from a UK National Health Service perspective. MATERIALS AND METHODS: A discrete event simulation model was developed to simulate the progress of patients through advancing disease states until death from prostate cancer or other causes. Clinical effectiveness data for IMRT and 3DCRT were derived from a systematic review. Four scenarios were modelled based on different clinical studies. A probabilistic sensitivity analysis was undertaken and the incremental cost per quality adjusted life years (ICER) calculated. RESULTS: In scenarios where estimated survival was greater for IMRT than 3DCRT, IMRT was clearly cost-effective (ICER 95%),very good (90 94.9%), good (85-89.9%), sufficient (80-84.9%) and deficient (< 80%). RESULTS: Of the surgical criteria or judgements established in the CPG, the low deviations of nasal septum predominated (478;88.2%). The type of nasal septum deviation was not recorded in 56(9.4%) of the clinical files reviewed. The period between 2003 and 2005 gave results of a higher quality for the medical surgical performance of the Ear, Nose and Throat Department, with three excellent evaluations and three good for 37.5%, respectively, and one fair (12.5%) which we assume is due to the use of both tools (CPG and the tool for the assessment of adherence to it). CONCLUSIONS: The assessment of the adherence to the CPG in the patients operated on for deviation of nasal septum is a very useful tool to assess medical surgical performance in this disease, thus becoming a highly valued tool for the continued improvement of the quality of our medical care provided to our patients. PMID- 23040152 TI - [Not Available]. AB - Outsourcing and privatization of healthcare services are analyzed from Management and Economics perspectives, exploring form the Transaction Costs theory four types of outsourcing: centres, clinical services, diagnostic-therapeutic support services, and ancillary services. Potential effects of externalization are analysed, addressing the advantages and risks, and putting it into the context of the Spanish NHS. Some final remarks are made regarding policy and research agenda. PMID- 23040153 TI - [Not Available]. AB - In the last decades the health policies of developed countries and those of professionals are directing their activities towards the citizen as the focal point of the health system. The citizens also demand an active role in health related decision-making processes. In this context, the development and use of clinical practice guidelines (CPGs) are instruments of encounter between policies, citizens and professionals but they create many methodological and operational difficulties. The objective of this work is to provide general guidelines to help the different players to incorporate patients in the development of CPGs and to adapt the patient CPG version (CPG-P). A structured review has been carried out on methodological documents on CPGs and documents oriented towards the production of CPG-P (or related documents). After analysing the information, we propose three areas of development (contents, design and evaluation) and two areas for the participation of patients in CPGs: patients as a members of the guideline development group and/or as members of the CPG-P development group. The process of participation of citizens is not a simple one, it requires planning and sensitivity to those involved, but there is no doubt that it adds value to the introduction of CPGs. PMID- 23040154 TI - [Not Available]. PMID- 23040155 TI - Give me 'strength to change': insights into a social marketing campaign in the North of England. AB - AIM: In this paper, we report on how formative research was utilised to design a social marketing campaign commissioned by a Primary Care Trust within an area of high social deprivation in the North of England. BACKGROUND: Men represent the majority of perpetrators of domestic violence and there is increasing interest in developing services for this group with the aim of changing abusive behaviour. However, men are known to be less likely to engage in help-seeking behaviours, and this reticence has been attributed to the social construction of masculinity. A further barrier for men seeking help in relation to domestic violence is the cultural construction of domestic violence. METHODS: Formative research was undertaken to explore the perceptions and attitudes of a community population of males (n584). Focus groups explored barriers and drivers to help-seeking and identified effective communication messages. FINDINGS: These findings were translated into the 'Strength to Change' campaign that minimised stigmatisation and blame while emphasising help-seeking as a 'strength' rather than a perceived weakness. Social marketing techniques facilitated an in-depth appreciation of local barriers to help-seeking and generated context-specific messages to encourage take-up of a new service for male perpetrators. PMID- 23040156 TI - Selective occlusion of the portal vein while maintaining hepatic artery blood flow during partial hepatectomy: a new method for preventing ischemia-reperfusion injury? PMID- 23040157 TI - Psychological effects of stillbirth. AB - Despite the high prevalence globally, the death of a baby to stillbirth is an often misunderstood and disenfranchised loss. Mothers, fathers, and families struggle to cope with the immediate and long-lasting effects of a baby's death which can last for years and sometimes decades. In addition, providers can be adversely affected by stillbirth, particularly when met with experiential avoidance and a sense of guilt and failure. There is little evidence on intervention efficacy in acute grief following perinatal death; however, there is a growing body of scientific literature on the efficacy of mindfulness-based interventions in treating anxiety, depression, and other biopsychosocial maladies as well as improving patient satisfaction with psychosocial care. This paper explores one such intervention model, ATTEND (attunement, trust, therapeutic touch, egalitarianism, nuance, and death education), as a means to improve psychosocial care during both acute and chronic states of bereavement. Whereas the death of a baby to stillbirth is the ultimate paradox for providers and patients - the convergence of life and death and the fundamental contradiction it represents - with proper care and compassion, families stand a better chance in the face of such indescribable loss and they need not suffer alone. PMID- 23040158 TI - The prevalence of mental health and pain symptoms in general population samples reporting nonmedical use of prescription opioids: a systematic review and meta analysis. AB - Nonmedical prescription opioid use (NMPOU) has become a substantial public health concern in North America. Existing epidemiological data suggest an association between NMPOU and mental health or pain symptoms in different populations, although these correlations are not systematically assessed. To address this gap, a systematic search, review, and meta-analysis were completed separately for both mental health problem symptoms and pain in general population samples reporting NMPOU. Overall, 9 unique epidemiological studies were identified and included in the review. The pooled prevalence of any mental health symptoms in general population samples reporting NMPOU was 32% (95% confidence interval [CI]: 24-40). Specifically, the pooled prevalence of depression was 17% (95% CI: 14-19) and the prevalence of anxiety in general population samples of NMPOU was 16% (95% CI: 1 30) The pooled prevalence of pain in the population of interest was found to be 48% (95% CI: 37-59). This systematic review found evidence for disproportionately high prevalence levels of mental health problems and pain among general population samples reporting NMPOU. While the data reviewed cannot interpret dynamics of potential causality, these findings have implications for interventions for NMPOU, as well as medical practice involving prescription opioids. PERSPECTIVE: This systematic review and meta-analysis found evidence for disproportionately elevated rates of select mental health and pain problems in epidemiological studies based on general population samples reporting NMPOU. While causality cannot be established, these comorbidities may influence NMPOU behavior and hence ought to be considered in preventive and treatment interventions. PMID- 23040159 TI - Personal semantics: at the crossroads of semantic and episodic memory. AB - Declarative memory is usually described as consisting of two systems: semantic and episodic memory. Between these two poles, however, may lie a third entity: personal semantics (PS). PS concerns knowledge of one's past. Although typically assumed to be an aspect of semantic memory, it is essentially absent from existing models of knowledge. Furthermore, like episodic memory (EM), PS is idiosyncratically personal (i.e., not culturally-shared). We show that, depending on how it is operationalized, the neural correlates of PS can look more similar to semantic memory, more similar to EM, or dissimilar to both. We consider three different perspectives to better integrate PS into existing models of declarative memory and suggest experimental strategies for disentangling PS from semantic and episodic memory. PMID- 23040160 TI - Obsessive-compulsive symptom dimensions correlate to specific gray matter volumes in treatment-naive patients. AB - BACKGROUND: Clinical and sociodemographic findings have supported that OCD is heterogeneous and composed of multiple potentially overlapping and stable symptom dimensions. Previous neuroimaging investigations have correlated different patterns of OCD dimension scores and gray matter (GM) volumes. Despite their relevant contribution, some methodological limitations, such as patient's previous medication intake, may have contributed to inconsistent findings. METHOD: Voxel-based morphometry was used to investigate correlations between regional GM volumes and symptom dimensions severity scores in a sample of 38 treatment-naive OCD patients. Several standardized instruments were applied, including an interview exclusively developed for assessing symptom dimensions severity (DY-BOCS). RESULTS: Scores on the "aggression" dimension were positively correlated with GM volumes in lateral parietal cortex in both hemispheres and negatively correlated with bilateral insula, left putamen and left inferior OFC. Scores on the "sexual/religious" dimension were positively correlated with GM volumes within the right middle lateral OFC and right DLPFC and negatively correlated with bilateral ACC. Scores on the "hoarding" dimension were positively correlated with GM volumes in the left superior lateral OFC and negatively correlated in the right parahippocampal gyrus. No significant correlations between GM volumes and the "contamination" or "symmetry" dimensions were found. CONCLUSIONS: Building upon preexisting findings, our data with treatment-naive OCD patients have demonstrated distinct GM substrates implicated in both cognitive and emotion processing across different OCS dimensions. PMID- 23040161 TI - The interaction between sleep quality and academic performance. AB - Sleep quality has significant effects on cognitive performance and is influenced by multiple factors such as stress. Contrary to the ideal, medical students and residents suffer from sleep deprivation and stress at times when they should achieve the greatest amount of learning. In order to examine the relationship between sleep quality and academic performance, 144 medical students undertaking the pre-clinical board exam answered a survey regarding their subjective sleep quality (Pittsburgh sleep quality index, PSQI), grades and subjective stress for three different time points: semester, pre- and post-exam. Academic performance correlated with stress and sleep quality pre-exam (r = 0.276, p < 0.001 and r = 0.158, p < 0.03, note that low performance meant low sleep quality and high stress), however not with the stress or sleep quality during the semester and post-exam. 59% of all participants exhibited clinically relevant sleep disturbances (PSQI > 5) during exam preparation compared to 29% during the semester and 8% post-exam. This study shows that in medical students it is not the generally poor sleepers, who perform worse in the medical board exams. Instead students who will perform worse on their exams seem to be more stressed and suffer from poor sleep quality. However, poor sleep quality may negatively impact test performance as well, creating a vicious circle. Furthermore, the rate of sleep disturbances in medical students should be cause for intervention. PMID- 23040162 TI - Integration of immunotherapy into the management of advanced prostate cancer. AB - Until recently, the only therapy shown to improve survival in men with metastatic castration-resistant prostate cancer (mCRPC) had been chemotherapy, usually reserved for symptomatic patients. However, sipuleucel-T, a cellular product directed toward a specific antigen, prostatic acid phosphatase, was Food and Drug Administration (FDA) approved in 2010 in the United States, based on phase 3 data showing improved overall survival in men with minimal or no symptoms due to mCRPC compared with placebo. Subsequently, several other promising immunotherapeutic approaches have advanced to study in the phase 3 setting, including ipilimumab and PROSTVAC. The demonstration of efficacy of immunotherapy in prostate cancer provides a new treatment option for men with no or few symptoms early in the course of mCRPC. Since sipuleucel-T was approved, several drugs that favorably impact survival have also been approved or are close to approval in the United States. These agents include cabazitaxel, abiraterone, radium-223, and MDV3100. There are many unresolved issues about sipuleucel-T, such as best timing in the course of mCRPC, the role for booster therapy, and the role of combinations with other active drugs, including other immune-modulating approaches. There are also many questions regarding sequencing of these new agents and, given the number of other promising agents in phase 3 trials, these questions will become more complicated, underscoring the need for better predictors of benefit for the individual patient. PMID- 23040163 TI - A 22-year-old graduate student with bizarre behavior. PMID- 23040164 TI - Bath salts: not as harmless as they sound. PMID- 23040166 TI - Emergency nursing resource: non-invasive temperature measurement in the emergency department. PMID- 23040167 TI - Recognizing chronic sorrow in the habitual ED patient. PMID- 23040168 TI - Disaster planning considerations involving the geriatric patient: part II. PMID- 23040169 TI - Transforming care in a large inner city university hospital emergency department. PMID- 23040170 TI - Translating cell-free fetal DNA technology: structural lessons from non-invasive RhD blood typing. PMID- 23040173 TI - Using suggestion to modulate automatic processes: from Stroop to McGurk and beyond. AB - Cognitive scientists typically classify cognitive processes as either controlled or automatic. Whereas controlled processes are slow and effortful, automatic processes are fast and involuntary. Over the past decade, we have propelled a research trajectory investigating how top-down influence in the form of suggestion can allow individuals to modulate the automaticity of cognitive processes. Here we present an overarching array of converging findings that collectively indicate that certain individuals can derail involuntary processes, such as reading, by "unringing" the proverbial bell. We examine replications of these effects from both our own laboratory and independent groups, and extend our Stroop findings to several other well-established automatic paradigms, including the McGurk effect. We thus demonstrate how, in the case of highly suggestible individuals, suggestion seems to wield control over a process that is likely even more automatic than the Stroop effect. Finally, we present findings from two novel experimental paradigms exploring the potential of shifting automaticity in the opposite direction - i.e., transforming, without practice, a controlled task into one that is automatic. Drawing on related evidence from the neuroscience of contemplative practices, we discuss how these findings pave the road to a more scientific understanding of voluntary control and automaticity, and expound on their possible experimental and therapeutic applications. PMID- 23040172 TI - Identification of wild soybean miRNAs and their target genes responsive to aluminum stress. AB - BACKGROUND: MicroRNAs (miRNAs) play important regulatory roles in development and stress response in plants. Wild soybean (Glycine soja) has undergone long-term natural selection and may have evolved special mechanisms to survive stress conditions as a result. However, little information about miRNAs especially miRNAs responsive to aluminum (Al) stress is available in wild soybean. RESULTS: Two small RNA libraries and two degradome libraries were constructed from the roots of Al-treated and Al-free G. soja seedlings. For miRNA identification, a total of 7,287,655 and 7,035,914 clean reads in Al-treated and Al-free small RNAs libraries, respectively, were generated, and 97 known miRNAs and 31 novel miRNAs were identified. In addition, 49 p3 or p5 strands of known miRNAs were found. Among all the identified miRNAs, the expressions of 30 miRNAs were responsive to Al stress. Through degradome sequencing, 86 genes were identified as targets of the known miRNAs and five genes were found to be the targets of the novel miRNAs obtained in this study. Gene ontology (GO) annotations of target transcripts indicated that 52 target genes cleaved by conserved miRNA families might play roles in the regulation of transcription. Additionally, some genes, such as those for the auxin response factor (ARF), domain-containing disease resistance protein (NB-ARC), leucine-rich repeat and toll/interleukin-1 receptor-like protein (LRR TIR) domain protein, cation transporting ATPase, Myb transcription factors, and the no apical meristem (NAM) protein, that are known to be responsive to stress, were found to be cleaved under Al stress conditions. CONCLUSIONS: A number of miRNAs and their targets were detected in wild soybean. Some of them that were responsive to biotic and abiotic stresses were regulated by Al stress. These findings provide valuable information to understand the function of miRNAs in Al tolerance. PMID- 23040174 TI - The role of working memory capacity in the control of recollection. AB - The links between control over recollection and working memory capacity (WMC) were investigated using event-related potentials (ERPs) and behavioural assays. Electrophysiological evidence for a relationship between greater control over recollection and higher scores on a measure of WMC was obtained. In addition, people with high WMC who first completed a task requiring cognitive control showed no electrophysiological evidence for control over recollection on a subsequent task. This outcome suggests a causal link between control over recollection and the availability of WMC, in so far as the consequence of completing the first task was a reduction in WMC that impacted on completion of the subsequent task. All participants also completed a final recall task, on which they were asked to remember the stimuli they had encountered during the task in which ERPs were acquired. Only those participants who showed electrophysiological evidence for the exertion of control over recollection showed differences between the likelihoods of recalling stimuli over which control either had or had not been exerted. In combination, the findings provide insights into the conditions under which control over recollection occurs, and make a strong argument for including individual difference measures of resource availability when assessing how and when people exert control over what they remember. PMID- 23040176 TI - The expanding scope of air pollution monitoring can facilitate sustainable development. AB - This paper explores technologies currently expanding the physical scope of air pollution monitoring and their potential contributions to the assessment of sustainable development. This potential lies largely in the ability of these technologies to address issues typically on the fringe of the air pollution agenda. Air pollution monitoring tends to be primarily focused on human health, and largely neglects other aspects of sustainable development. Sensor networks, with their relatively inexpensive monitoring nodes, allow for monitoring with finer spatiotemporal resolution. This resolution can support more conclusive studies of air pollution's effect on socio-ecological justice and human quality of life. Satellite observation of air pollution allows for wider geographical scope, and in doing so can facilitate studies of air pollution's effects on natural capital and ecosystem resilience. Many air pollution-related aspects of the sustainability of development in human systems are not being given their due attention. Opportunities exist for air pollution monitoring to attend more to these issues. Improvements to the resolution and scale of monitoring make these opportunities realizable. PMID- 23040177 TI - Sexual selection in a polygynous rodent (Ctenomys talarum): an analysis of fighting capacity. AB - The South American subterranean rodent genus Ctenomys (Caviomorpha: Octodontoidea), which uses both claws and teeth to dig, shows striking morphological adaptations to its specialized mode of life. Among other traits, the genus has evolved a powerful jaw musculature and procumbent incisors that are used for dento-excavation. Behavioral observations indicate that these traits are also used during male aggressive encounters, which characterize the polygynous mating system of one of the species of the genus, Ctenomys talarum. A question emerges about sexual selection: could it have induced further changes in traits primarily evolved as adaptations for digging? To address this issue, we studied functional and morphological attributes of the jaw and incisors in specimens of C. talarum. Incisor bite forces were measured on wild females and males from a local population (Mar de Cobo; Buenos Aires Province) by means of a strain gauge load cell force transducer. Museum specimens coming from the same population were studied to assess anatomical attributes of both sexes. Since this species exhibits dimorphism in body size, the possible effect of body mass on the studied traits was analyzed. Males and females showed significant differences in biting performance and mandibular width, but when size was taken into account these differences disappeared. However, other dimorphic traits can vary with a certain independence with respect to size, particularly the 2nd moment of area of the incisors and, to a lesser extent, incisor procumbency. The former geometrical parameter, which is proportional to the bending strength, was highly dimorphic. This fact suggests that, during aggressive encounters between males, biting would place large bending loads on the incisors. PMID- 23040175 TI - Famous face identification in temporal lobe epilepsy: support for a multimodal integration model of semantic memory. AB - This study aims to demonstrate that the left and right anterior temporal lobes (ATLs) perform critical but unique roles in famous face identification, with damage to either leading to differing deficit patterns reflecting decreased access to lexical or semantic concepts but not their degradation. Famous face identification was studied in 22 presurgical and 14 postsurgical temporal lobe epilepsy (TLE) patients and 20 healthy comparison subjects using free recall and multiple choice (MC) paradigms. Right TLE patients exhibited presurgical deficits in famous face recognition, and postsurgical deficits in both famous face recognition and familiarity judgments. However, they did not exhibit any problems with naming before or after surgery. In contrast, left TLE patients demonstrated both pre- and postsurgical deficits in famous face naming but no significant deficits in recognition or familiarity. Double dissociations in performance between groups were alleviated by altering task demands. Postsurgical right TLE patients provided with MC options correctly identified greater than 70% of famous faces they initially rated as unfamiliar. Left TLE patients accurately chose the name for nearly all famous faces they recognized (based on their verbal description) but initially failed to name, although they tended to rapidly lose access to this name. We believe alterations in task demands activate alternative routes to semantic and lexical networks, demonstrating that unique pathways to such stored information exist, and suggesting a different role for each ATL in identifying visually presented famous faces. The right ATL appears to play a fundamental role in accessing semantic information from a visual route, with the left ATL serving to link semantic information to the language system to produce a specific name. These findings challenge several assumptions underlying amodal models of semantic memory, and provide support for the integrated multimodal theories of semantic memory and a distributed representation of concepts. PMID- 23040178 TI - Spatial learning and memory retention in the grey bamboo shark (Chiloscyllium griseum). AB - Like other vertebrates, fish can learn to solve a wide variety of tasks; however, many of their cognitive abilities, particularly in cartilaginous fishes, still remain unknown. This study investigated memory retention capabilities of spatial learning tasks in the grey bamboo shark (Chiloscyllium griseum, n=8) after behavioural training in a two-choice experiment (T-maze). Sharks learned to obtain food at a goal location, either by performing a specific turn response or by using a variety of external landmarks for guidance. Following successful training, sharks were subjected to several training breaks ranging from one to six weeks, after which they were tested again for memory retention capabilities. Sharks successfully mastered the spatial tasks after 5-21 sessions and retained this knowledge in the absence of reinforcement for a period of up to six weeks. This is the first study to show that sharks, like stingrays and other vertebrates, can solve spatial tasks and retain spatial knowledge for an extended period of time, possibly aiding them in activities such as food retrieval, predator avoidance, mate choice and habitat selection. PMID- 23040179 TI - Hollowing or cavitation during follicular lumen formation in the differentiating thyroid of grass snake Natrix natrix L. (Lepidosauria, Serpentes) embryos? An ultrastructural study. AB - The mechanism of follicular lumen differentiation during thyroid gland morphogenesis in vertebrate classes is still unclear and the current knowledge regarding the origin and the mechanism of follicular lumen formation during thyroid differentiation in reptiles is especially poor. The present study reports on an ultrastructural investigation of thyroid follicle formation and follicular lumen differentiation in grass snake (Natrix natrix L.) embryos. The results of this study show that the earliest morphogenesis of the presumptive thyroid follicles in grass snake embryos appears to be similar to that described in embryos of other vertebrate classes; however, differences appeared during the later stages of its differentiation when the follicular lumen was formed. The follicular lumen in grass snake embryos was differentiated by cavitation; during thyroid follicle formation, a population of centrally located cells was cleared through apoptosis to form the lumen. This manner of follicular lumen differentiation indicates that it has an extracellular origin. It cannot be excluded that other types of programmed cell death also occur during follicular lumen formation in this snake species. PMID- 23040180 TI - Morphology matches mtDNA lineages in the southern smooth snake (Coronella girondica) from Iberia. AB - The rise of molecular techniques in the study of evolutionary histories has resulted in a gradual abandonment of morphological characters as the only sources of phylogenetic inference. However, morphological characters may be valuable for phylogenetic reconstruction, especially for tracking adaptive changes across phylogeographic groups defined by genetic markers. We examined the discriminative power of morphological characters between four mitochondrial clades covering almost the entire distribution area of the smooth snake Coronella girondica in the Western Mediterranean. We detected three characters showing sexual dimorphism (relative tail length, number of ventral and of subcaudal scale counts) and, more interestingly, two characters (number of subcaudal and of dorsal rows) displaying interclade differences. Almost all C. girondica examined had 21 dorsal rows except those from a narrow coastal belt in the south-eastern Iberian Peninsula, which had 19 dorsal rows. The distribution of these specimens matches a mitochondrial clade that originated approximately 1.4-2.0 million years ago. Both of these morphological characters support a Betic lineage with a rather well defined contact zone with the other Iberian lineage, which has been maintained even without the existence of current geographic barriers. The long-term survival of the Betic lineage throughout the Pleistocene climatic oscillations suggests a systematic revision within C. girondica. PMID- 23040181 TI - Robust linear and non-linear models of NIR spectroscopy for detection and quantification of adulterants in fresh and frozen-thawed minced beef. AB - This study aimed to evaluate the potential of near infrared spectroscopy (NIRS) as a fast and non-destructive tool for detecting and quantifying different adulterants in fresh and frozen-thawed minced beef. Partial least squares regression (PLSR) models were built under cross validation and tested with different independent data sets, yielding determination coefficients (R(P)(2)) of 0.96, 0.94 and 0.95 with standard error of prediction (SEP) of 5.39, 5.12 and 2.08% (w/w) for minced beef adulterated by pork, fat trimming and offal, respectively. The performance of the developed models declined when the samples were in a frozen-thawed condition, yielding R(P)(2) of 0.93, 0.82 and 0.95 with simultaneous augments in the SEP of 7.11, 9.10 and 2.38% (w/w), respectively. Linear discriminant analysis (LDA), partial least squares-discriminant analysis (PLS-DA) and non-linear regression models (logistic, probit and exponential regression) were developed at the most relevant wavelengths to discriminate between the pure (unadulterated) and adulterated minced beef. The classification accuracy resulting from both types of models was quite high, especially the LDA, PLS-DA and exponential regression models which yielded 100% accuracy. The current study demonstrated that the VIS-NIR spectroscopy can be utilized securely to detect and quantify the amount of adulterants added to the minced beef with acceptable precision and accuracy. PMID- 23040182 TI - DINO and Medina coronary bifurcation lesion classifications. PMID- 23040184 TI - [Not Available]. PMID- 23040183 TI - Transradial percutaneous iliac intervention, a feasible alternative to the transfemoral route. AB - BACKGROUND: Percutaneous angioplasty for atherosclerotic iliac disease is commonly performed via the femoral and/or brachial route. In the coronary field a transradial approach has been shown to reduce both major and minor access site bleedings, in experienced hands. However, this route has not yet been well studied for the majority of peripheral interventions, like those involving the iliac arteries. METHODS: We investigated the feasibility and safety of a transradial approach in a consecutive series of patients undergoing percutaneous iliac intervention at our center, comparing it to a similar series of patients treated with a transfemoral approach in the same period. Endpoints of the study were procedural success, duration of procedure and event free survival at one month. RESULTS: From our database we enrolled 42 patients undergone iliac percutaneous interventions (21 with a transradial and 21 with a transfemoral approach); the 2 populations had similar baseline characteristics. Procedural success was achieved in all of our patient population. Among the secondary study endpoints analyzed we observed similar duration of the procedure and one-month clinical follow up. Technical aspects of the transradial approach are discussed. CONCLUSIONS: A transradial approach is feasible for the treatment of atherosclerotic iliac disease and does not increase procedural time in experienced hands. Further studies are needed to confirm if this approach is as safe as the transfemoral one. PMID- 23040185 TI - [Not Available]. PMID- 23040186 TI - [Not Available]. AB - OBJECTIVES: To assess the frequency of adverse events (AE) in an intensive care unit (ICU), to detect where they occur, to grade the confidence that an AE is due to medical management and if it is avoidable, to assess their consequences and to determine which patient factors are associated with AE. MATERIAL AND METHOD: We performed a prospective cohort study from October 2005 to May 2006 in the adult ICU at Hospital Universitario, Salamanca. Each day a physician reviewed all patients' medical records. The patient general information, AE screening and AE analysis forms were filled out. An AE was defined as an unintentional injury or complication that results in disability at the time of discharge, death or prolonged ICU stay, that is caused by health care management and that is written in the medical record. RESULTS: Of the 160 admissions studied, 33 (20.63%) were identified as having 37 AE as the primary reason for admission to the unit. 72 AE were identified during ICU stay (45 AE each 100 admissions). Nosocomial infection was the main AE (64.9% and 47.2% respectively); 13.5% AE as the primary reason for admission to the unit and 9.7% AE identified during ICU stay were evaluated as strongly avoidable. These AE lead to an increase in ICU stay and were caused mainly in operating theatre. The major patient factors associated with AE were overweight (relative risk [RR]=6.82; 95% confidence interval [CI], 1.3-34.2) and diabetes mellitus (RR=5.94; 95% CI, 2.2-15.9). CONCLUSIONS: The frequency of AE in our ICU is within the range reported in the literature. Few AE were evaluated as strongly avoidable; these events indicate opportunities for improvement. ICU can be used as AE observation unit, since as well as causing them, it receives AE caused by other units. PMID- 23040187 TI - [Not Available]. AB - OBJECTIVE: To know the current situation on the implementation of the patient identification systems in hospital centres in Catalonia. METHODS: Interviews carried out with nurse managers of Catalonian hospitals on patient identification systems, implementation in the different hospital services and data used in the system. RESULTS: Of the 75 centres studied, 90.7% used some kind of patient identification system. Only 26.7% of the interviewed centers had patient identification systems in all its hospital services. The most used identity data were patient name and surname (100%), clinical history number (79.4%), birth date (67.6%) and bed number (66.2%). 77.3% of the centres used only one patient identification system, and the most used was the wristband (85.3%). A wristband identification protocol was used in only 67.2% of the centres and 50% of all the centres had some problem with its use. CONCLUSIONS: There is good level of implementation of patient identification systems in Catalonia, nevertheless greater use of these systems and their standardisation needs to be promoted in all hospital services, as well as continuously monitoring compliance. PMID- 23040188 TI - [Not Available]. AB - INTRODUCTION: The evaluation of quality care in surgical service is a basic management tool and it is part of the health services contract. The study of patient opinion on health care received is an important aspect in the evaluation of quality care. OBJECTIVE: The aim of this study is to find out patient opinion on the satisfaction of the surgical care received. MATERIAL AND METHOD: Cross sectional study. Period of the study: January- December 2007. Opinions on the level of satisfaction level were obtained through a questionnaire. A SERCAL adapted model was used to define the variables on patient satisfaction with the surgery service. RESULTS: The mean score on overall satisfaction of the service was of 9.31 (0-10 scale). The personalised, guaranteed care offered by health professionals and the room, were very positively evaluated. The information received, pain relief and the hospital stay were evaluated as adequate. The confidence in the surgery service was 96.7%. Knowing the names of the health staff and the food were the worse valued factors. CONCLUSIONS: Results of the study show an adequate level of satisfaction with the health care; nevertheless areas of improvement are detected where action is needed (identification of staff, coordination and food). PMID- 23040189 TI - [Not Available]. AB - INTRODUCTION: Bundles are groups of interventions to reduce nosocomial infection rates. We evaluated the current status of ventilatorassociated pneumonia bundle compliance in our hospital to propose an improvement plan on the basis of the results. PATIENTS AND METHOD: Bundle includes: raising the head of the bed (30 degrees , daily assessment of sedation requirements, peptic ulcer disease and deep venous thrombosis prophylaxis. It was evaluated in the intensive care unit (ICU) and two postoperative recovery units (called REA1 and REA3) from June 25 until July 20, 2007. RESULTS: In ICU, 222 observations were made (189 complete), in REA1 34 observations (26 complete) and in REA3, 35 observations (27 complete). Bundle compliance was 77.2% in ICU, 50% in REA1 and 70.2% in REA3. Lowest compliance component was raising the head of the bed (UCI, 85.8%; REA1, 57.6%, and REA3, 69%). Improved interventions proposed were to include standardized requirements for raising the head of the bed to 45 degrees , to empower nurses to make daily "sedation vacations" (interruption of sedation to point of alertness) and mention in medical history when an item cannot be carried out. CONCLUSIONS: Improvement strategies through bundles are a quick and easy way to obtain process indicators that help us improve the prevention of nosocomial infections. PMID- 23040190 TI - [Not Available]. AB - We present a map of 24 indicators to measure the quality of care given to patients with acute poisoning attended in the emergency department. These include structural indicators (availability of protocols, stocks of antidotes, analytical tests, gastric lavage tubes), process indicators (correct indication of gut decontamination techniques, indications for renal and extra-renal purification, use of antidotes, indication of toxicological analyses, ECG, delays in care, psychiatric referrals, judicial notifications), indicators of results (mortality, compliance with minimum basic data set of poisonings, continuing staff education) and administrative indicators (publications). PMID- 23040191 TI - [Not Available]. PMID- 23040192 TI - [Not Available]. PMID- 23040193 TI - Factors predictive of distal stent graft-induced new entry after hybrid arch elephant trunk repair with stainless steel-based device in aortic dissection. AB - OBJECTIVES: Stent graft-induced new entry (SINE) has been increasingly observed after thoracic endovascular aortic repair of aortic dissection. We illustrate the possible mechanism by exploring predictive factors of late distal SINE after hybrid arch elephant trunk repair for aortic dissection. METHODS: From November 2006, to May 2011, 20 of 99 patients underwent hybrid arch repair using the elephant trunk graft as the proximal landing zone. After a mean follow-up period of 27.9 +/- 12.0 months, 12 patients had late distal SINE events and the others were free of events. False lumen remodeling level was observed and maximal longitudinal diameter, average of longitudinal and transverse maximal diameter, circumference, and area of true lumen were analyzed for precise size selection of stent graft before and after the procedure. Taper ratio, true lumen:aorta ratio, prestent grafting oversizing ratio, poststent grafting oversizing ratio, and expansion mismatch ratio of distal true lumen were proposed and calculated for further evaluation of the mechanism of late distal SINE. RESULTS: Only the area oversizing ratio between true lumen and the distal selected stent graft at the presumed distal end of stent grafting was found as a significant predictive factor of SINE before procedure (4.00 +/- 2.96 vs 1.98 +/- 0.66 for SINE vs non SINE, respectively; P = .031). The significant difference of the expansion mismatch ratio of true lumen between the 2 groups was found not only in the size measurement of mean diameter (1.48 +/- 0.29 vs 1.22 +/- 0.15; P = .039), but also in the area (2.39 +/- 0.85 vs 1.58 +/- 0.42; P = .031) and circumference (1.43 +/ 0.27 vs 1.18 +/- 0.14; P = .016) after stent grafting. CONCLUSIONS: We found that taper ratio is not an optimal criteria for stent graft size selection and distal oversizing calculated by true-lumen area is a significant factor causing delayed distal SINE. Use of the prestenting area oversizing ratio should be limited. PMID- 23040194 TI - Incidence of postoperative atrial fibrillation in patients undergoing minimally invasive versus median sternotomy valve surgery. AB - BACKGROUND: Atrial fibrillation (AF) after cardiac surgery is associated with increased morbidity and hospital length of stay. Our objective was to determine whether a minimally invasive approach to isolated valve surgery reduced the incidence of postoperative AF. METHODS: Patients without a history of arrhythmia, who underwent isolated aortic or mitral valve surgery between January 2005 and August 2011, were included. The incidence of postoperative AF in those who underwent a minimally invasive approach was compared with that of patients undergoing median sternotomy surgery. Resource utilization was approximated on the basis of intensive care unit and total hospital lengths of stay. RESULTS: A total of 571 patients were identified (413 minimally invasive and 158 median sternotomy). No significant differences in baseline characteristics existed between groups. The incidence of postoperative AF (25% vs 37%; P = .002), use of intraoperative blood products (52% vs 83%; P < .001), and prolonged intubation (>=24 hours) (12% vs 20%; P = .008) were significantly less in the minimally invasive group. The intensive care unit and hospital lengths of stay were 45 hours (interquartile range [IQR], 28-66 hours) versus 53 hours (IQR, 45-91 hours) (P < .001), and 5 days (IQR, 4-7 days) versus 8 days (IQR, 6-11 days) (P < .001) for the minimally invasive and median sternotomy groups, respectively. Multivariable analysis revealed a decreased risk of postoperative AF in patients undergoing minimally invasive surgery (odds ratio, 0.4; 95% confidence intervals, 0.24-0.66; P < .001). CONCLUSIONS: A minimally invasive approach for isolated valve surgery reduces postoperative AF and resource use when compared with median sternotomy. PMID- 23040195 TI - False traumatic aneurysm of the aortic arch. Retrograde cerebral perfusion obliged. A case report. PMID- 23040196 TI - Commentary on: Radical prostatectomy versus observation for localized prostate cancer. PMID- 23040197 TI - Hidden in plain sight: the history of marketing and urology. PMID- 23040198 TI - Absence of rapid and linear progressive motile spermatozoa "grade A" in semen specimens: does it change intrauterine insemination outcomes? AB - OBJECTIVE: To evaluate the predictive value of the absence of rapid and linear progressive motile spermatozoa "grade A" on the intrauterine insemination success rates. METHODS: The present retrospective case-control study included 338 couples in their first intrauterine insemination cycles. All intrauterine insemination cycles were preceded by ovarian stimulation with recombinant follicle-stimulating hormone starting on cycle day 3 with a standard protocol. A single intrauterine insemination was performed 36-40 hours after human chorionic gonadotropin administration. Multivariate analysis was performed to define the independent predictors of intrauterine insemination success. The main outcome measure, the clinical pregnancy rate per cycle, was assessed in 3 different categories, according to the total motile sperm count (TMSC). RESULTS: Multivariate logistic regression analysis identified a 2.7 times increased chance of clinical pregnancy in the presence of grade A spermatozoa, after adjustment for female and male age (P = .023, 95% confidence interval 1.149-6.359). The influence of the absence of grade A spermatozoa on the clinical pregnancy rate was significant when the TMSC was 5-10 * 10(6) (0% vs 9.2%, respectively, P = .033). CONCLUSION: The absence of grade A spermatozoa decreased the intrauterine insemination success rates in couples with male factor subfertility, especially when the TMSC was <10 * 10(6). In vitro fertilization, instead of intrauterine insemination, might be a more effective treatment option for couples with a TMSC <10 * 10(6) and no grade A spermatozoa. PMID- 23040199 TI - Unusual videourodynamic finding: massive scrotal cystocele. AB - Urinary bladder involvement within inguinal hernias occurs in up to 4% of patients. However, massive extension of the bladder into the scrotum, or scrotal cystocele, is very rare, with less than 30 reported cases. The presenting symptoms vary. Most patients will have some element of voiding dysfunction. However, some patients will present with renal failure, sepsis, or bladder necrosis, although others will remain asymptomatic.(1-4) We report a patient who presented with irritative voiding symptoms and a large, right-sided hydrocele. On evaluation of his voiding symptoms, he was found to have a large scrotal cystocele. PMID- 23040200 TI - Forensic cultures in historical perspective: technologies of witness, testimony, judgment (and justice?). AB - This article explores the history of forensic science in terms of ideologies and institutions rather than developing technique. It presents an analytical framework for characterising forensic institutions and practices, past and present. That framework highlights the distinct issues of means of witness, accredited testimony, and the reaching of juridical decisions. The article applies the framework by comparing four forensic 'formations,' (or 'cultures') which have been prominent at various times and places in the western world from the early modern period onward: these are the central European heritage of the Caroline code, a eugenically-oriented forensic enterprise of late nineteenth century America, the forensic perspective in nineteenth-century British India, and the representation of forensic certainty in contemporary American popular culture. The article concludes with a critique of what seems an increasingly common expectation: that forensic science evolves independently of legal institutions, and can ultimately displace them. PMID- 23040201 TI - New classification of lymphaticovenular anastomosis: nomenclature and technique. PMID- 23040202 TI - Prospective study on complications following a lower body lift after massive weight loss. AB - BACKGROUND: Lower body lift procedures are in high demand following the increase of massive weight loss patients. As surgical complication rates in this patient group are generally high, patients need to be prepared for risk factors and complications in lower body lift surgery. The aim of this study was to identify the complications and possible risk factors of a lower body lift as concrete data for this procedure are limited. METHODS: A prospective study on 50 consecutive patients who underwent a lower body lift procedure was performed. Measures included co-morbidities and complications. Risk factors assessed included patient age, gender, highest lifetime body mass index (BMI) (BMI max), current BMI, excess weight loss (EWL), type of weight loss and nicotine consumption. RESULTS: There were 50 patients (44 females, six males) with a mean age of 41+/-10.8 years and a mean EWL of 86.4+/-15.6%. Mean BMI max was 49.5+/-10.5 kg m(-2), current BMI was 27.8+/-4.0 kg m(-2). A total of 35 (70%) patients developed at least one complication. Five patients (10%) suffered a major complication that necessitated surgical revision. Wound dehiscence occurred in 30 patients (60%), followed by seroma in 17 patients (34%). A surgical complication was directly related to BMI max (p=0.02) and age of the patient at the time of surgery (p=0.03). CONCLUSIONS: The overall complication rate following a lower body lift was 70%, which is comparable with that known for high-risk patient groups. The most important risk factors are BMI max and age of the patient (Clinical trial registration number (ISRCTN): NCT01551862). PMID- 23040205 TI - Potential role of genetic markers in the management of kidney cancer. AB - CONTEXT: Kidney cancer is not a single entity but comprises a number of different types of cancer that occur in the kidney including renal cell tumours as the most common type. Four major renal cell tumour subtypes can be distinguished based on morphologic and genetic characteristics. To individualise therapy and to improve the prognosis in patients with renal cell tumours, accurate subtyping, definition of individual course of disease, and the prediction of therapy response are necessary. OBJECTIVE: To discuss the potential role of genetic markers in the management of kidney cancer. EVIDENCE ACQUISITION: A Medline search was conducted to identify original articles, review articles, and editorials addressing the role of genetic alterations in kidney cancer management. Keywords included kidney neoplasms, genetics, SNP, gene expression, miRNA, classification, diagnosis, drug therapy, prognosis, and therapy. The articles with the highest level of evidence were identified and critically reviewed. This review is the result of an interactive peer-reviewing process by an expert panel of co-authors. EVIDENCE SYNTHESIS: Each subtype is characterised by specific genetic, epigenetic, and expression patterns that potentially can be used to subclassify renal cell tumours in cases of ambivalent histopathology. Molecular signatures and single alterations in primary tumours are associated with aggressiveness and prognosis. Germline polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters, and drug targets seem to be associated with toxicity and response in patients receiving targeted therapy. CONCLUSIONS: Significant advances have been achieved in the molecular analysis of renal cancer. Validation of findings is greatly needed to implement genetic markers in the management of renal cancer. This should lead to improved diagnosis, prognosis, and personalised therapy in this heterogeneous disease. PMID- 23040203 TI - Investigating a cluster of vulvar cancer in young women: a cross-sectional study of genital human papillomavirus prevalence. AB - BACKGROUND: Vulvar cancer is a relatively rare malignancy, which occurs most often in postmenopausal women. We have previously identified a geographic cluster of vulvar cancer in young Indigenous women living in remote communities in the Arnhem Land region of Australia. In this population, we investigated the prevalence of oncogenic human papillomavirus (HPV) infection in anogenital samples (vulvar/vaginal/perianal area and cervix) and compared the overall, type specific and multiple infection prevalence between sites. METHODS: A cross sectional survey of 551 Indigenous women aged 18-60 years was undertaken in 9 Arnhem Land communities. Women were consented for HPV detection and genotyping collected by a combined vulvar/vaginal/perianal (VVP) sweep swab and a separate PreservCyt endocervical sample collected during Pap cytology screening. HPV DNA testing was undertaken using PCR with broad spectrum L1 consensus PGMY09/11 primers with genotyping of positive samples by Roche Linear Array. The primary outcomes were the prevalence of cervical and VVP high-risk (HR) HPV. RESULTS: The prevalence of VVP HR-HPV was 39%, which was significantly higher than the cervical HR-HPV prevalence (26%, p<0.0001). HPV-16 was the most common genotype detected in both sites (VVP 11%, cervical 6%). HPV-16 infection peaked in women aged <20 years; however, there was a marked decline in cervical HPV-16 prevalence with age (p=0.007), whereas following an initial decline, the prevalence of VVP HPV-16 remained constant in subsequent age-groups (p=0.835). CONCLUSIONS: In this population experiencing a cluster of vulvar cancer, the prevalence of cervical oncogenic HPV infection was similar to that reported by studies of other Australian women; however there was a significantly higher prevalence of vulvar/vaginal/perianal infection to cervical. The large discrepancy in HPV prevalence between anogenital sites in this population may represent more persistent infection at the vulva. This needs further investigation, including the presence of possible environmental and/or genetic factors that may impair host immunity. PMID- 23040204 TI - EAU guidelines on surgical treatment of urinary incontinence. AB - CONTEXT: The European Association of Urology (EAU) guidelines on urinary incontinence published in March 2012 have been rewritten based on an independent systematic review carried out by the EAU guidelines panel using a sustainable methodology. OBJECTIVE: We present a short version here of the full guidelines on the surgical treatment of patients with urinary incontinence, with the aim of dissemination to a wider audience. EVIDENCE ACQUISITION: Evidence appraisal included a pragmatic review of existing systematic reviews and independent new literature searches based on Population, Intervention, Comparator, Outcome (PICO) questions. The appraisal of papers was carried out by an international panel of experts, who also collaborated in a series of consensus discussions, to develop concise structured evidence summaries and action-based recommendations using a modified Oxford system. EVIDENCE SUMMARY: The full version of the guidance is available online (www.uroweb.org/guidelines/online-guidelines/). The guidance includes algorithms that refer the reader back to the supporting evidence and have greater accessibility in daily clinical practice. Two original meta-analyses were carried out specifically for these guidelines and are included in this report. CONCLUSIONS: These new guidelines present an up-to-date summary of the available evidence, together with clear clinical algorithms and action-based recommendations based on the best available evidence. Where high-level evidence is lacking, they present a consensus of expert panel opinion. PMID- 23040206 TI - Oncologic outcomes and survival in pT0 tumors after radical nephroureterectomy for upper tract urothelial carcinoma: results from of a large multicenter international collaborative study. PMID- 23040207 TI - Comparative effectiveness research in urology: a step toward better therapeutic decision making. PMID- 23040208 TI - A phase 3, double-blind, randomised, parallel-group, placebo-controlled study of oral weekly alendronate for the prevention of androgen deprivation bone loss in nonmetastatic prostate cancer: the Cancer and Osteoporosis Research with Alendronate and Leuprolide (CORAL) study. AB - BACKGROUND: Androgen-deprivation therapy (ADT) induces loss of bone mineral density (BMD) and increases the risk of fractures in patients with prostate cancer (PCa). We sought to determine whether a weekly dose of alendronate, an oral bisphosphonate, could reduce this unwanted side-effect. OBJECTIVE: To assess whether once-weekly oral alendronate therapy would maintain or improve BMD in men initiating ADT for localised PCa. DESIGN, SETTING, AND PARTICIPANTS: A multicentre, double-blind, randomised, placebo-controlled study, we included hormonally naive PCa patients initiating ADT with leuprolide acetate 30 mg intramuscularly every 4 mo. INTERVENTION: Patients were randomised to receive either oral alendronate 70 mg once weekly or placebo for 1 yr. Both groups received daily calcium 1g and vitamin D 400 international units. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Changes in BMD (at the lumbar spine [LS] and total hip [TH]) and bone markers. RESULTS AND LIMITATIONS: One hundred ninety one subjects were enrolled, and 186 were randomised between alendronate (n=84) and placebo (n=102). The alendronate group demonstrated a mean spine BMD increase of 1.7% compared with -1.9% in the placebo group (p<0.0001). Alendronate also increased the BMD at the hip (percent change: 0.7%) compared to placebo (-1.6%). Median urinary N-terminal crosslinking telopeptide of type I collagen (Ntx) values decreased by 3.5% in the alendronate group and increased by 16.5% in the placebo arm, even after adjusting for centre (p=0.510) and baseline urinary Ntx (p<0.0001). Bone-specific alkaline phosphatase (BSAP) decreased a median of 2.25% in the alendronate group and increased a median of 3.12% in the placebo arm, regardless of centre or baseline BSAP or other covariates (p<0.0001). The safety and tolerability profile was similar for the two treatment groups. CONCLUSIONS: Although the study was closed early because of slow accrual, it showed that weekly oral alendronate prevented bone loss and increased bone mass in addition to decreasing bone turnover in patients initiating ADT for localised PCa, with few related side-effects. PMID- 23040210 TI - Temperature, nitrogen dioxide, circulating respiratory viruses and acute upper respiratory infections among children in Taipei, Taiwan: a population-based study. AB - OBJECTIVE: This study investigated whether outpatient visits of acute upper respiratory infections for children aged less than 15 years are associated with temperature, air pollutants and circulating respiratory viruses in Taipei, Taiwan, from 2003 to 2007. METHODS: Outpatient records for acute upper respiratory infections (ICD9 CM codes: 460, 462, 463,464, 465.9 and 487) in a randomly selected sample (n=39,766 children in 2005) was used to estimate the cumulative relative risks (RR) associated with average temperature lasting for 8 days (lag 0-7 days), air pollutants (NO2, O3 and PM(2.5)) lasting for 6 days (lag 0-5 days), and virus-specific positive isolation rate lasting for 11 days (lag 0 10 days) using distributed lag non-linear models after controlling for relative humidity, wind speed, day of week, holiday effects and long-term trend. RESULTS: Average temperature of 33 degrees C was associated with the lowest risk for outpatient visits of acute upper respiratory infections. Relative to 33 degrees C, cumulative 8-day RR was highest at 15 degrees C of ambient average temperature [RR=1.94; 95% confidence interval (CI): 1.78, 2.11]. With the first quartile as reference, cumulative 6-day RRs were 1.25 (95% CI: 1.21, 1.29) for NO2, 1.04 (95% CI: 1.01, 1.06) for O3, and 1.00 (95% CI: 0.98, 1.03) for PM(2.5) at the 95th percentile. Per-standard deviation (SD) increase of virus-specific isolation rate for influenza type A (SD=13.2%), type B (SD=8.76%), and adenoviruses (SD=5.25%) revealed statistical significance for overall 11-day RRs of 1.02 (95% CI: 1.01, 1.03), 1.05 (95% CI: 1.03, 1.06) and 1.04 (95% CI: 1.03, 1.05), respectively. CONCLUSIONS: Current study suggested a positive association between outpatient visits for acute upper respiratory infections and ambient environment factors, including average temperature, air pollutants, and circulating respiratory viruses. PMID- 23040209 TI - Intratunical injection of human adipose tissue-derived stem cells prevents fibrosis and is associated with improved erectile function in a rat model of Peyronie's disease. AB - BACKGROUND: Peyronie's disease (PD) is a connective tissue disorder of the tunica albuginea (TA). Currently, no gold standard has been developed for the treatment of the disease in its active phase. OBJECTIVE: To test the effects of a local injection of adipose tissue-derived stem cells (ADSCs) in the active phase of a rat model of PD on the subsequent development of fibrosis and elastosis of the TA and underlying erectile tissue. DESIGN, SETTING, AND PARTICIPANTS: A total of 27 male 12-wk-old Sprague-Dawley rats were divided in three equal groups and underwent injection of vehicle (sham), 0.5-MUg [corrected] transforming growth factor (TGF)-beta1 in a 50-MUl vehicle in either a PD or a PD plus ADSC group in the dorsal aspect of the TA. INTERVENTION: The sham and PD groups were treated 1 d after TGF-beta1 injection with intralesional treatment of vehicle, and the PD plus ADSC group received 1 million human-labeled ADSCs in the 50-MUl vehicle. Five weeks after treatment, six rats per group underwent erectile function measurement. Following euthanasia, penises were harvested for histology and Western blot. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The ratio of intracavernous pressure to mean arterial pressure (ICP/MAP) upon cavernous nerve stimulation, elastin, and collagen III protein expression and histomorphometric analysis of the penis. Statistical analysis was performed by analysis of variance followed by the Tukey-Kramer test for post hoc comparisons or the Mann-Whitney test when applicable. RESULTS AND LIMITATIONS: Erectile function significantly improved after ADSC treatment (ICP/MAP 0.37 in PD vs 0.59 in PD plus ADSC at 5-V stimulation; p=0.03). PD animals developed areas of fibrosis and elastosis with a significant upregulation of collagen III and elastin protein expression. These fibrotic changes were prevented by ADSC treatment. CONCLUSIONS: This study is the first to test stem cell therapy in an animal model of PD. Injection of ADSCs into the TA during the active phase of PD prevents the formation of fibrosis and elastosis in the TA and corpus cavernosum. PMID- 23040212 TI - Imaging of dysplasia epiphysealis hemimelica (Trevor's disease). AB - Dysplasia epiphysealis hemimelica (DEH; synonyms; Trevor's or Trevor Fairbank disease) is a rare developmental disorder of the skeleton characterized by asymmetric osteochondral overgrowth of the cartilage of a medial or lateral epiphysis or epiphyseal equivalent. Imaging plays an important role in the diagnosis and management of DEH and in assessing the need for biopsy to differentiate it from more sinister diseases. There is no recent comprehensive review of the imaging of DEH and the purpose of this article is to describe the modern radiological manifestations of DEH. PMID- 23040211 TI - Coordinating GWAS results with gene expression in a systems immunologic paradigm in autoimmunity. AB - There has been considerable progress in our understanding of the genetic architecture of susceptibility to inflammatory diseases in recent years: several hundred susceptibility loci have been discovered in genome-wide association studies (GWAS) of human populations. This success has created an important challenge in identifying the functional consequences of these risk-associated variants and in elucidating how the repercussions of individual susceptibility loci integrate to yield dysregulation of immune pathways and, ultimately, syndromic clinical phenotypes. The integration of GWAS association signals with high-resolution transcriptome and other genomic data that capture the dynamics of cellular state and function in the context of individual's collection of susceptibility alleles has proven to be a successful avenue of investigation. The rapid pace of methodological development in this area has been coupled with an accumulation of experimental data that makes the elucidation of complex biological networks underlying susceptibility to these common inflammatory diseases a reasonable goal in the near future. PMID- 23040215 TI - Statins are better than fibrates in patients with a previous venous thromboembolism. PMID- 23040213 TI - Risk factors for metastasis to para-aortic lymph nodes in gastric cancer: a single institution study in China. AB - BACKGROUND: Para-aortic lymph node (PAN) dissection is performed in some gastric cancer patients with extensive lymph node involvement. However, there is no consensus on selection of patients that will benefit from this high risk dissection. This study was to identify risk factors for PAN metastasis in gastric cancer. MATERIALS AND METHODS: A total of 174 patients with gastric cancer who underwent D2 lymphadenectomy plus para-aortic nodal dissection in Tianjin Medical University Cancer Institute and Hospital from January 2001 to December 2010 were enrolled in the study. The association between clinicopathologic factors and para aortic nodal invasion was analyzed. RESULTS: Forty-seven patients (27.0%) had PAN metastases. Pathologic N stage was a significant risk factor for PAN metastasis after adjusting for other factors. A significant difference was shown in the proportion of PAN metastases between the N0/N1 group and N2/N3 group (6.2% versus 45.2%, P < 0.001, OR = 12.620). Lymph node station 9 showed a much higher odds ratio with PAN metastases than other routinely retrieved stations. CONCLUSION: N stage and perigastric nodal status were important and independent risk factors for PAN metastasis, which may be useful for identifying patients at high risk of PAN metastasis who could benefit from PAN dissection. PMID- 23040216 TI - Relationship between NADPH oxidase p22phox C242T, PARP-1 Val762Ala polymorphisms, angiographically verified coronary artery disease and myocardial infarction in South Indian patients with type 2 diabetes mellitus. AB - INTRODUCTION: There has been compelling evidence for the role of oxidative stress in the pathogenesis of cardiovascular complications in type 2 diabetes mellitus (T2DM). We analyzed the association of C242T and Val762Ala polymorphisms of NADPH oxidase p22phox and poly (ADP-ribose) polymerase-1 (PARP-1) genes respectively with coronary artery disease (CAD) and its severity, myocardial infarction (MI) and cardiovascular risk factors in T2DM patients. MATERIALS AND METHODS: We screened 283 T2DM patients, inclusive of 160 with angiographically defined CAD, 73 with and 89 without MI and 121 T2DM individuals with no evidence of CAD for the two gene polymorphisms. RESULTS: The 242T and 762Ala alleles were significantly more frequent in T2DM subjects without CAD than those with CAD, thereby associating them with a significant protective effect against development of CAD [p=0.002 (C242T); 0.02 (Val762Ala)]. The association was further characterized by a relatively lower frequency of 242T and 762Ala alleles in T2DM patients with multi (MVD)/triple vessel disease respectively [p=0.003 (C242T); 0.02 (Val762Ala)]. Conversely, the genotype and allele frequencies of these polymorphisms were not significantly different in T2DM+CAD patients with or without MI. Stratification of risk by putative risk factors for CAD revealed a significant interaction with these polymorphisms. Multiple logistic regression analysis revealed a significant and independent association of C242T and Val762Ala polymorphisms and other putative risk factors with CAD/MVD in T2DM individuals. CONCLUSIONS: Our observations indicate a significant relationship between p22phox C242T and PARP-1 Val762Ala polymorphisms, CAD and its severity, but not with occurrence of MI in T2DM individuals with significant coronary stenoses. PMID- 23040217 TI - Quality indicators in radiation oncology. AB - Oncologic specialty societies and multidisciplinary collaborative groups have dedicated considerable effort to developing evidence-based quality indicators (QIs) to facilitate quality improvement, accreditation, benchmarking, reimbursement, maintenance of certification, and regulatory reporting. In particular, the field of radiation oncology has a long history of organized quality assessment efforts and continues to work toward developing consensus quality standards in the face of continually evolving technologies and standards of care. This report provides a comprehensive review of the current state of quality assessment in radiation oncology. Specifically, this report highlights implications of the healthcare quality movement for radiation oncology and reviews existing efforts to define and measure quality in the field, with focus on dimensions of quality specific to radiation oncology within the "big picture" of oncologic quality assessment efforts. PMID- 23040218 TI - Postmastectomy hypofractionated and accelerated radiation therapy with (and without) subcutaneous amifostine cytoprotection. AB - PURPOSE: Postmastectomy radiation therapy (PMRT) provides major local control and survival benefits. More aggressive radiation therapy schemes may, however, be necessary in specific subgroups, provided they are safely administered. We report the tolerance and efficacy of a highly accelerated and hypofractionated regimen (HypoARC). METHODS AND MATERIALS: One hundred twelve high-risk patients who had undergone mastectomy received 10 consecutive fractions of 3.5 Gy in 12 days (thoracic wall and axillary/supraclavicular areas). Two consecutive additional fractions of 4 Gy were given to the surgical scar area (electrons 8-10 MeV) and 1 3.5-Gy fraction to the axilla (in cases with extensive nodal involvement). A minimum follow-up of 24 months (median, 44 months) was allowed before analysis. Of 112 patients, 21 (18.7%) refused to receive amifostine, the remaining receiving tolerance-based individualized doses (500-1000 mg/day subcutaneously). RESULTS: By use of a dose individualization algorithm, 68.1%, 11%, and 18.7% of patients received 1000 mg, 750 mg, and 500 mg/day of amifostine. Patchy moist skin desquamation outside and inside the booster fields was noted in 14 of 112 (12.5%) and 26 of 112 (23.2%) patients, respectively. No case of acute pneumonitis was recorded. High amifostine dose offered a significant skin protection. Within a median follow-up time of 44 months, moderate subcutaneous edema outside and within the booster thoracic area was noted in 5 of 112 (4.4%) and 8 of 112 (7.1%) cases, respectively. Intense asymptomatic radiographic findings of in field lung fibrosis were noted in 4 of 112 (3.6%) patients. Amifostine showed a significant protection against lung and soft tissue fibrosis. A 97% projected 5-year local relapse free survival and 84% 5-year disease specific survival were recorded. Lack of steroid receptor expression, simple human epidermal growth factor 2 positivity, or triple negative phenotype defined higher metastasis rates but had no effect on local control. CONCLUSIONS: PMRT with HypoARC showed an excellent early and short-term late toxicity profile, and amifostine further reduced early and late radiation sequelae. Encouraging local control rates are obtained in high-risk subgroups. PMID- 23040219 TI - Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. AB - Charged particle therapy (CPT) delivered with either protons, helium ions, or carbon ions, has been used to treat uveal melanoma. The present analysis was performed to systematically evaluate the efficacy and adverse effects of CPT for uveal melanoma. We searched EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and SciVerse Scopus and cross-referenced recent systematic reviews through January 2012. Two independent reviewers identified clinical trials and observational studies of CPT (protons, helium ions, and carbon ions). These reviewers extracted data and assessed study quality. Twenty-seven studies enrolling 8809 uveal melanoma patients met inclusion criteria. The rate of local recurrence was significantly less with CPT than with brachytherapy (odds ratio [OR] = 0.22, 95% confidence interval [CI], 0.21-0.23). There were no significant differences in mortality or enucleation rates. Results were robust in multiple sensitivity analyses. CPT was also associated with lower retinopathy and cataract formation rates. Data suggest better outcomes may be possible with charged particle therapy with respect to local recurrence, retinopathy, and cataract formation rates. The overall quality of the evidence is low, and higher quality comparative effectiveness studies are needed to provide better evidence. PMID- 23040220 TI - Dosimetric impact of using the Acuros XB algorithm for intensity modulated radiation therapy and RapidArc planning in nasopharyngeal carcinomas. AB - PURPOSE: To assess the dosimetric implications for the intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy with RapidArc (RA) of nasopharyngeal carcinomas (NPC) due to the use of the Acuros XB (AXB) algorithm versus the anisotropic analytical algorithm (AAA). METHODS AND MATERIALS: Nine-field sliding window IMRT and triple-arc RA plans produced for 12 patients with NPC using AAA were recalculated using AXB. The dose distributions to multiple planning target volumes (PTVs) with different prescribed doses and critical organs were compared. The PTVs were separated into components in bone, air, and tissue. The change of doses by AXB due to air and bone, and the variation of the amount of dose changes with number of fields was also studied using simple geometric phantoms. RESULTS: Using AXB instead of AAA, the averaged mean dose to PTV70 (70 Gy was prescribed to PTV70) was found to be 0.9% and 1.2% lower for IMRT and RA, respectively. It was approximately 1% lower in tissue, 2% lower in bone, and 1% higher in air. The averaged minimum dose to PTV70 in bone was approximately 4% lower for both IMRT and RA, whereas it was approximately 1.5% lower for PTV70 in tissue. The decrease in target doses estimated by AXB was mostly contributed from the presence of bone, less from tissue, and none from air. A similar trend was observed for PTV60 (60 Gy was prescribed to PTV60). The doses to most serial organs were found to be 1% to 3% lower and to other organs 4% to 10% lower for both techniques. CONCLUSIONS: The use of the AXB algorithm is highly recommended for IMRT and RapidArc planning for NPC cases. PMID- 23040222 TI - Treatment-related morbidity in prostate cancer: a comparison of 3-dimensional conformal radiation therapy with and without image guidance using implanted fiducial markers. AB - PURPOSE: To estimate the prevalence of rectal and urinary dysfunctional symptoms using image guided radiation therapy (IGRT) with fiducials and magnetic resonance planning for prostate cancer. METHODS AND MATERIALS: During the implementation stages of IGRT between September 2008 and March 2010, 367 consecutive patients were treated with prostatic irradiation using 3-dimensional conformal radiation therapy with and without IGRT (non-IGRT). In November 2010, these men were asked to report their bowel and bladder symptoms using a postal questionnaire. The proportions of patients with moderate to severe symptoms in these groups were compared using logistic regression models adjusted for tumor and treatment characteristic variables. RESULTS: Of the 282 respondents, the 154 selected for IGRT had higher stage tumors, received higher prescribed doses, and had larger volumes of rectum receiving high dosage than did the 128 selected for non-IGRT. The follow-up duration was 8 to 26 months. Compared with the non-IGRT group, improvement was noted in all dysfunctional rectal symptoms using IGRT. In multivariable analyses, IGRT improved rectal pain (odds ratio [OR] 0.07 [0.009 0.7], P=.02), urgency (OR 0.27 [0.11-0.63], P=<.01), diarrhea (OR 0.009 [0.02 0.35], P<.01), and change in bowel habits (OR 0.18 [0.06-0.52], P<.010). No correlation was observed between rectal symptom levels and dose-volume histogram data. Urinary dysfunctional symptoms were similar in both treatment groups. CONCLUSIONS: In comparison with men selected for non-IGRT, a significant reduction of bowel dysfunctional symptoms was confirmed in men selected for IGRT, even though they had larger volumes of rectum treated to higher doses. PMID- 23040221 TI - Quality Research in Radiation Oncology analysis of clinical performance measures in the management of gastric cancer. AB - BACKGROUND: The specific aim was to determine national patterns of radiation therapy (RT) practice in patients treated for stage IB-IV (nonmetastatic) gastric cancer (GC). METHODS AND MATERIALS: A national process survey of randomly selected US RT facilities was conducted which retrospectively assessed demographics, staging, geographic region, practice setting, and treatment by using on-site record review of eligible GC cases treated from 2005 to 2007. Three clinical performance measures (CPMs), (1) use of computed tomography (CT)-based treatment planning; (2) use of dose volume histograms (DVHs) to evaluate RT dose to the kidneys and liver; and (3) completion of RT within the prescribed time frame; and emerging quality indicators, (i) use of intensity modulated RT (IMRT); (ii) use of image-guided tools (IGRT) other than CT for RT target delineation; and (iii) use of preoperative RT, were assessed. RESULTS: CPMs were computed for 250 eligible patients at 45 institutions (median age, 62 years; 66% male; 60% Caucasian). Using 2000 American Joint Committee on Cancer criteria, 13% of patients were stage I, 29% were stage II, 32% were stage IIIA, 10% were stage IIIB, and 12% were stage IV. Most patients (43%) were treated at academic centers, 32% were treated at large nonacademic centers, and 25% were treated at small to medium sized facilities. Almost all patients (99.5%) underwent CT-based planning, and 75% had DVHs to evaluate normal tissue doses to the kidneys and liver. Seventy percent of patients completed RT within the prescribed time frame. IMRT and IGRT were used in 22% and 17% of patients, respectively. IGRT techniques included positron emission tomography (n=20), magnetic resonance imaging (n=1), respiratory gating and 4-dimensional CT (n=22), and on-board imaging (n=10). Nineteen percent of patients received preoperative RT. CONCLUSIONS: This analysis of radiation practice patterns for treating nonmetastatic GC indicates widespread adoption of CT-based planning with use of DVH to evaluate normal tissue doses. Most patients completed adjuvant RT in the prescribed time frame. IMRT and IGRT were not routinely incorporated into clinical practice during the 2005-2007 period. These data will be a benchmark for future Quality Research in Radiation Oncology GC surveys. PMID- 23040224 TI - Toxicities affecting quality of life after chemo-IMRT of oropharyngeal cancer: prospective study of patient-reported, observer-rated, and objective outcomes. AB - PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) aiming to spare the salivary glands and swallowing structures would reduce or eliminate the effects of xerostomia and dysphagia on quality of life (QOL). METHODS AND MATERIALS: In this prospective, longitudinal study, 72 patients with stage III-IV oropharyngeal cancer were treated uniformly with definitive chemo IMRT sparing the salivary glands and swallowing structures. Overall QOL was assessed by summary scores of the Head Neck QOL (HNQOL) and University of Washington QOL (UWQOL) questionnaires, as well as the HNQOL "Overall Bother" question. Quality of life, observer-rated toxicities (Common Toxicity Criteria Adverse Effects scale, version 2), and objective evaluations (videofluoroscopy assessing dysphagia and saliva flow rates assessing xerostomia) were recorded from before therapy through 2 years after therapy. Correlations between toxicities/objective evaluations and overall QOL were assessed using longitudinal repeated measures of analysis and Pearson correlations. RESULTS: All observer rated toxicities and QOL scores worsened 1-3 months after therapy and improved through 12 months, with minor further improvements through 24 months. At 12 months, dysphagia grades 0-1, 2, and 3, were observed in 95%, 4%, and 1% of patients, respectively. Using all posttherapy observations, observer-rated dysphagia was highly correlated with all overall QOL measures (P<.0001), whereas xerostomia and mucosal and voice toxicities were significantly correlated with some, but not all, overall QOL measures, with lower correlation coefficients than dysphagia. Late overall QOL (>=6 or >=12 months after therapy) was primarily associated with observer-rated dysphagia, and to a lesser extent with xerostomia. Videofluoroscopy scores, but not salivary flows, were significantly correlated with some of the overall QOL measures. CONCLUSION: After chemo-IMRT, although late dysphagia was on average mild, it was still the major correlate of QOL. Further efforts to reduce swallowing dysfunction are likely to yield additional gains in QOL. PMID- 23040225 TI - [Not Available]. PMID- 23040223 TI - Preoperative 3-Tesla multiparametric endorectal magnetic resonance imaging findings and the odds of upgrading and upstaging at radical prostatectomy in men with clinically localized prostate cancer. AB - PURPOSE: To investigate whether 3-T esla (3T) multiparametric endorectal MRI (erMRI) can add information to established predictors regarding occult extraprostatic or high-grade prostate cancer (PC) in men with clinically localized PC. METHODS AND MATERIALS: At a single academic medical center, this retrospective study's cohort included 118 men with clinically localized PC who underwent 3T multiparametric erMRI followed by radical prostatectomy, from 2008 to 2011. Multivariable logistic regression analyses in all men and in 100 with favorable-risk PC addressed whether erMRI evidence of T3 disease was associated with prostatectomy T3 or Gleason score (GS) 8-10 (in patients with biopsy GS <=7) PC, adjusting for age, prostate-specific antigen level, clinical T category, biopsy GS, and percent positive biopsies. RESULTS: The accuracy of erMRI prediction of extracapsular extension and seminal vesicle invasion was 75% and 95%, respectively. For all men, erMRI evidence of a T3 lesion versus T2 was associated with an increased odds of having pT3 disease (adjusted odds ratio [AOR] 4.81, 95% confidence interval [CI] 1.36-16.98, P=.015) and pGS 8-10 (AOR 5.56, 95% CI 1.10-28.18, P=.038). In the favorable-risk population, these results were AOR 4.14 (95% CI 1.03-16.56), P=.045 and AOR 7.71 (95% CI 1.36-43.62), P=.021, respectively. CONCLUSIONS: Three-Tesla multiparametric erMRI in men with favorable-risk PC provides information beyond that contained in known preoperative predictors about the presence of occult extraprostatic and/or high grade PC. If validated in additional studies, this information can be used to counsel men planning to undergo radical prostatectomy or radiation therapy about the possible need for adjuvant radiation therapy or the utility of adding hormone therapy, respectively. PMID- 23040226 TI - [Not Available]. AB - INTRODUCTION: As a result of a prioritised improvement action during the second self-assessment using the EFQM Excellence Model carried out in Sierrallana Hospital (Cantabria, Spain), it was decided to form a Benchmarking Network between Hospitals. The objective of this work is to present how this action was developed to create the Benchmarking Network "Red.7". MATERIAL AND METHODS: Using the 2004 "Catalogo Nacional de Hospitales "we pre-selected hospitals which could be compared with ours. We asked for information on results indicators in the Health Services of the different regions and we selected those hospitals that could be integrated into the Benchmarking Network. We contacted the top management of the selected hospitals in order to offer them the possibility of participating in the Network. Finally we organised a scientific session to create the Network. RESULTS: We pre-selected 74 hospitals from 12 regions and 18 of them were selected. Seven of these 18 hospitals responded to our invitation, of which one decided to not participate. Finally the Benchmarking Network was created with 7 hospitals: Fundacion Alcorcon; El Bierzo, Morales Messeguer, San Jorge, Sierrallana, Son Llatzer and Valle del Nalon, hospital. CONCLUSIONS: The use of the EFQM Excellence Model permitted us to detect a gap in the comparison of results and best practices with other hospitals from the National Health Service, and we have been able to form an integrated Benchmarking Network with hospitals similar to ours in the different regions. PMID- 23040227 TI - [Not Available]. AB - INTRODUCTION: To develop a methodological tool for use in the analysis and management of the health service quality inhibitory factors (HSQIF). METHODS: A nominal discussion group was used as a research technique. A total of 18 hospital directors from the Mexican State of Jalisco participated in a workshop. Half of them came from the private sector, and the others from public hospitals. The hospital directors came from different counties such as Guadalajara, Zapopan, Tlaquepaque and Tonala. RESULTS: Cultural and organizational constraints were major issues found as health services quality inhibitors. Two examples are: the weakness of the quality culture and the lack of management commitment to quality. Lack of strategic planning and the absence of management by process were also found to be linked with the poor hospital management performance. The findings were used to design a test that would detect the main categories of quality inhibitor factors of the organizations. The main categories included, deficient infrastructure, organizational and cultural constraints, poor hospital management, poor human resources management and lack of compliance with the hospital norms were among the main ones included. CONCLUSIONS: The point of view of directors was used to identify the main health services quality inhibitor factors of private and public hospitals from Jalisco, Mexico. The findings should help to develop a methodological tool for the analysis and decision making to correct them. PMID- 23040228 TI - [Not Available]. AB - INTRODUCTION: The Minimum Basic Data Set (MBDS) is the most used database in the National Health System. The objective of this study is to evaluate the quality, in terms of coding errors of the administrative variables of the MBDS in the Basque Country Health Service. MATERIAL AND METHODS: A retrospective, descriptive study by means of reviewing 768 clinical histories from 11 hospitals. STUDY PERIOD: the year 2005. The data obtained in the clinical histories were considered comparison standard and the level of discrepancy with the MBDS was established. The administrative variable measured were: sex, dates of birth, admission, discharge and of the first intervention, admission type and circumstances at discharge, department and physician responsible at discharge. The chi(2) was used to measure the between-hospital variability of the percentage discrepancy between the clinical histories and the MBDS records. RESULTS: There were 213,091 discharge reports analysed. The percentage errors in the MBDS varied between 0.7% in the sex variable and 24.9% in the physician responsible variable. The variability between hospitals was statistically significant (p=0.001). Good quality was observed in the records of the six variables: sex, date of birth, admission date, discharge date, admission type and medical department responsible. The records were lacking in the date of first intervention and the physician responsible variables. PMID- 23040229 TI - [Not Available]. AB - INTRODUCTION: The increase in health care expenditure threatens the financial sustainability of health systems, and is leading to reforms in hospital use. The length of preoperative stay (POS) depends on the number of interventions and cancellations, but also possibly related to the care process itself (complexity, severity) and the patient (age, sex, comorbidity) with repercussions on the total stay and direct costs. There have been investigations on the length of POS in Spain and its possible relationships with these variables, hospital access (urgent or scheduled) and clinical type (originally medical or surgical). MATERIALS AND METHODS: Descriptive and comparative analysis with ANOVA and linear regression of the episodes of the Minimal Data Set 2005 which have resulted in surgery, through variables (relative weight, cost, number of secondary diagnoses and procedures, mortality, stay, age and sex) using SPSS version 15 for Windows, a p<0.05 being established as statistically significant. RESULTS: The POS averaged 2.92 days, higher in urgent in-patient surgical (5.80) and medical (5.44) procedures, and by age groups and gender was higher in men (7.51) and women (6.31) of 70-74 years with surgical emergencies, but there is a direct link with age in scheduled medical inpatients. There was statistically significant relationship of POS with the length of stay, the relative weight, cost and other variables, all dependent on the severity and complexity. CONCLUSIONS: The POS depends on determining factors such as hospital planning and organization, but also depends on some factors of the process and the patient. Ageing should not cause problems in the emergency surgical in-patient, but must be best managed in the scheduled ones. Adequate management of preoperative studies is essential to reduce the POS, the length of stay and the direct costs of hospitalization. PMID- 23040230 TI - [Not Available]. AB - INTRODUCTION: The purpose of this article is to present a model for clinical risk management based on technological and organisational advances with proven effect. Designed for a single clinical Unit, the model is open to other notification systems and health care clinical units. MATERIAL AND METHOD: The model has three implementation phases. The first phase involved studying the existing safety system and objectively measured the culture of patient safety. The second phase included development and implementation of a system for the management of critical incidents with creation of a team of specialists. The third phase was the development of the technological and organizational base for horizontal and vertical integration, for internal and external training, and opening the system to other clinical units. RESULTS: We found an unstructured, non-confidential, potentially punitive model of clinical risk management without efficacy criteria. There was an unsatisfactory safety culture level for all of the evaluation issues. The introduction of a system for critical incident management gave the basis for the optimization and evaluation of the patient safety related processes. CONCLUSIONS: Our model for clinical risk management is a simple, useful and efficient example for introducing a patient safety strategy in a hospital clinical unit. PMID- 23040231 TI - [Not Available]. AB - OBJECTIVE: To evaluate the effectiveness of interventions aimed at reducing inappropriate hospital use, identified with diagnosis-independent and explicit criteria methods. MATERIAL AND METHODS: Systematic review of the literature to identify evaluative studies of interventions for reducing inappropriate hospital use, followed by a narrative synthesis of their characteristics and results. Works were included in English, French or Spanish languages, with experimental, quasi-experimental or observational designs, and with or without group control. RESULTS: We found 15 evaluative studies (2 randomised clinical trials, 8 quasi experimental with control group and 5 with beforeafter without control group designs), the majority of them carried out in the United States (3 in Spain). The heterogeneity in hospital characteristics, hospitalisation units, patients characteristics, sampling unit, instruments, and presentation of results limited the quantitative synthesis. Feedback and administrative interventions were the most common. All the studies except 2 were positive, showing reductions in several outcomes (percentage of inappropriate stays, inappropriate admissions or inappropriate stays in the day previous to discharge, and in the length of stay). Intensive interventions that combined educational, feedback, self-assesment and administrative components showed the best results. CONCLUSIONS: The literature review suggests that several interventions are effective to reduce inappropriate hospital use, particularly if they are direct, active, reach the doctors and combine several components. PMID- 23040232 TI - [Not Available]. PMID- 23040233 TI - [Not Available]. PMID- 23040234 TI - Comparison of invasive pneumococcal disease caused by serotype 19A and non-19A pneumococci in children: more empyema in serotype 19A invasive pneumococcal disease. AB - OBJECTIVE: To delineate whether serotype 19A invasive pneumococcal disease (IPD) comprised significantly more necrotizing pneumonia and empyema in children, we compared the clinical characteristics between serotype 19A and non-19A IPD. METHODS: Between January 2007 and December 2011, cases of children with IPD who were treated at the National Taiwan University Hospital were reviewed. Patients were assigned to the 19A group or the non-19A group based on the serotype. Their demographic data, clinical course, laboratory results, diagnosis, complications, and sequelae were collected and analyzed. RESULTS: Overall, 27 patients were included in the 19A group and 29 patients in the non-19A group. Compared with non 19A group, serotype 19A tended to cause IPD in patients without major underlying diseases (p = 0.015). Bacteremia without pneumonia or meningitis was found more frequently in the non-19A group (45% vs. 11%, p = 0.01), and pneumonia with or without empyema occurred significantly more frequently in the 19A group (89% vs. 52%, p = 0.006). Patients in the19A group had longer duration of fever (12 vs. 3 days, p = 0.01), and required more intensive care (78% vs. 41%, p = 0.01) and more video-assisted thoracoscopic surgery (74% vs. 28%, p = 0.001). CONCLUSION: In comparison with the other serotypes, serotype 19A IPD has significantly more empyema which required more video-assisted thoracoscopic surgery and more intensive care. PMID- 23040235 TI - Viral etiology of bronchiolitis among pediatric inpatients in northern Taiwan with emphasis on newly identified respiratory viruses. AB - PURPOSE: Viral etiology of bronchiolitis in children in Taiwan has been fragmentary. We conducted a prospective study to figure out the viral epidemiology of bronchiolitis in Taiwan. MATERIALS AND METHODS: From January 2009 to March 2011, a total of 113 children with bronchiolitis, aged <2 years, hospitalized in Chang Gung Children's Hospital were randomly selected for viral etiology investigation. Nasopharyngeal aspirates were obtained from each case and sent for viral detection by tissue culture, antigen test, and polymerase chain reaction. RESULTS: A total of 120 viruses were detected from 113 children. Positive viral etiology was identified in 86 (76%) children. Mixed viral pathogens were found in 28 cases (25%). Respiratory syncytial virus (RSV) was the most common pathogen and was identified in 43.4% of the cases. Human bocavirus (hBoV) was the second most common identified virus (in 19.5%), followed by human metapneumovirus (hMPV), rhinovirus, influenza viruses, and coronavirus OC43. In terms of clinical characteristics, no significant difference was found among the children with bronchiolitis either caused by different single or mixed viral infection. CONCLUSION: RSV was the most common etiologic agent for children with bronchiolitis in Taiwan. Newly identified viruses, including hMPV and hBoV, were also among the common causative agents. Clinical characteristics were not significantly different among the children with bronchiolitis caused by different viruses. PMID- 23040236 TI - Stenotrophomonas maltophilia bloodstream infection: comparison between community onset and hospital-acquired infections. AB - BACKGROUND/PURPOSE: Stenotrophomonas maltophilia has been recognized as an important nosocomial pathogen, but few reports have discussed S. maltophilia infection in the community settings. This study aimed to reveal characteristics of patients with community-onset S. maltophilia bloodstream infection (SMBSI), to specify the subgroup of healthcare-associated (HCA) infection in the community onset group and to compare them with hospital-acquired (HA) SMBSI patients. MATERIALS AND METHODS: Medical charts of adult patients with SMBSI presenting to a medical center in southern Taiwan from May 2008 to October 2011 were reviewed and analyzed retrospectively. RESULTS: Among 153 patients, we observed a high percentage (38.6%) of SMBSI to be community onset. Among community-onset SMBSI, 45.8% were community-acquired (CA) and 54.2% were HCA. The crude mortality rates were 11.1%, 18.8%, and 60.6% in the CA, HCA, and HA groups, respectively. Structural/mechanical abnormalities were observed in 32.7% of all cases, and 60% of those were related to malignancy. Independent risk factors for mortality in community-onset SMBSI were liver cirrhosis, liver metastasis, and a high Pitt bacteremia score, whereas structural/mechanical abnormalities and a high Pitt bacteremia score related to increased mortality in HA SMBSI. CONCLUSION: Community-onset S. maltophilia infection deserves attention. Patients with community-onset SMBSI have reduced disease severity and lower mortality rate when compared to HA SMBSI. Underlying structural/mechanical abnormalities, especially those caused by malignancies, are common in SMBSI cases and should be investigated when bacteremia occurs. PMID- 23040237 TI - rrs and rpsL mutations in streptomycin-resistant isolates of Mycobacterium tuberculosis from Mexico. AB - BACKGROUND/PURPOSE: Mutations in rpsL and rrs genes are associated with resistance to streptomycin in tuberculosis, but important geographical variation exists in these mutations. The goal of this study was to characterize these mutations in isolates of streptomycin-resistant mycobacteria originating from southeast Mexico. METHODS: Mycobacteria were isolated from patients with suspected drug-resistant tuberculosis. Susceptibility tests were carried out using the fluorometric method, and rrs and rpsL DNA sequencing was performed by capillary electrophoresis. RESULTS: Some 136 drug-resistant isolates were recovered, of which 91(67%) exhibited resistance to streptomycin. Mutations in rpsL were observed in 18 isolates (19%) in codons 43 (A->G, K/R, n = 12) and 88 (A->G, K/R, n = 4; A->C, K/Q, n = 2). Mutations in rrs were observed in 26 isolates (28%). These were at nucleotides 513 (A->C, n = 8) and 516 (C->T, n = 6), and six novel mutations at nucleotides 483 (A->T, n = 2), 485 (A->G, n = 2), 496 (G->A, n = 2), 795 (C->T, n = 6), 870 (C->T, n = 3), and 907 (A->C, n = 3), with some isolates showing more than one mutation. Finally, 47 (52%) of the isolates showed no mutation. CONCLUSION: The variety and presence or absence of the mutations found suggest the circulation of an important diversity of strains and the existence of additional mechanisms contributing to streptomycin resistance in the region. PMID- 23040238 TI - Methicillin-resistant Staphylococcus aureus bacteremia in hemodialysis and nondialysis patients. AB - BACKGROUND/PURPOSE: Increased mortality has been reported in patients treated with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia with high minimum inhibitory concentration (MIC) values within the susceptibility range. However, this finding has not been verified in hemodialysis patients, who have much higher invasive MRSA infection rates than nondialysis patients. We aimed at comparing vancomycin MICs between hemodialysis and nondialysis patients, and identifying predictors of high vancomycin MICs and infection-related mortality in hemodialysis patients with MRSA bacteremia. METHODS: Patients with MRSA bacteremia from January 2008 through December 2009 were enrolled. Vancomycin MIC was determined for each first isolate using the Etest method. Clinical characteristics and vancomycin MICs were compared between hemodialysis and nondialysis patients. Factors associated with high vancomycin MIC (2 MUg/mL) and infection-related mortality in hemodialysis patients were analyzed. RESULTS: A total of 162 MRSA bacteremia episodes were identified. Forty-four (27.0%) isolates were obtained from hemodialysis patients and 118 (73.0%) from nondialysis patients. Diabetes (63.3% vs. 39.8%, p = 0.007) and prior vancomycin exposure in 30 days (31.8% vs. 12.7%, p = 0.005) were more prevalent in hemodialysis group than in nondialysis group. A higher prevalence of vancomycin MIC of 2 MUg/mL was observed in hemodialysis group in comparison with nondialysis group (11.4% vs. 1.7%, p = 0.016). In following analyses of hemodialysis group, patients with initial presentation of septic shock had a higher risk of vancomycin MIC of 2 MUg/mL than nonseptic shock patients (100.0% vs. 38.5% p = 0.014). Infection-related mortality was associated with age, Acute Physiology and Chronic Health Evaluation II (APACHE-II) score >15, presence of septic shock, receipt of mechanical ventilation, and failure to remove source of bacteremia in univariate analysis. CONCLUSION: Hemodialysis patients with MRSA bacteremia are more likely to have a high vancomycin MIC (2 MUg/mL) compared with nondialysis patients. Infection-related mortality is associated with the patient's clinical manifestations, including age, APACHE-II score >15, presence of septic shock, receipt of mechanical ventilation, and failure to remove source of bacteremia. Treatment selection should be tailored according to the patient's clinical condition. PMID- 23040239 TI - Analysis of alpha-lactalbumin-, beta-lactoglobulin-, and casein-specific IgE among children with atopic diseases in a tertiary medical center in Northern Taiwan. AB - BACKGROUND: Cow's milk allergy is the first manifestation of the allergic march, because cow's milk proteins are the first foreign proteins consumed in large quantities by infants. The aim of this study was to determine which of these proteins causes the greatest sensitization in Taiwanese individuals, and its correlation with atopic patients. METHODS: We retrospectively reviewed the medical records of atopic patients who were treated at the National Taiwan University Hospital from January 2009 to March 2011. A total of 190 patients were enrolled and tested for isolated cow's milk protein (alpha-lactalbumin, beta lactoglobulin, and casein) sensitization. These patients were further divided into atopic dermatitis and non-atopic dermatitis subgroups, and also grouped by age. Differences in sensitization to cow's milk proteins between groups were analyzed using the non-parametric Mann-Whitney U-test. RESULTS: The sensitization rate to alpha-lactalbumin-specific IgE was 60%, followed by beta-lactoglobulin (46.84%) and casein (40.53%). The levels of specific IgE antibodies against alpha lactalbumin, beta-lactoglobulin, and casein were higher in patients with atopic dermatitis (1.8, 1.19, 0.95 vs. 0.77, 0.55, 0.40 kUA/L). The younger age group had higher mean specific IgE antibodies against cow's milk proteins than the older age groups. CONCLUSION: There was a different distribution of cow's milk protein sensitization in Taiwanese patients in our study, with alpha-lactalbumin being most common as compared to casein in Western countries. Among the patients with cow's milk sensitization, the atopic dermatitis group had significantly higher cow's milk protein-specific IgE antibodies as compared to the non-atopic dermatitis group. PMID- 23040240 TI - Type 2 diabetes mellitus and 20 year incidence of periodontitis and tooth loss. AB - AIMS: The objective of this study was to evaluate the prospective associations between type 2 diabetes mellitus (T2DM) and the risk of periodontitis and tooth loss. METHODS: 35,247 male participants of the Health Professionals Follow-Up Study who were dentate, free of periodontitis and cancer at baseline, were followed from 1986 to 2006. Data on self-reported diabetes, periodontitis, tooth loss and potential confounders were collected at baseline and biennially through mailed questionnaires. The multivariable adjusted relationships between diabetes and first report of periodontitis and tooth loss were estimated using time varying Cox models. RESULTS: There were 3009 incident self-reported periodontitis and 10,017 tooth loss events over 591,941 person-years. Men with T2DM showed a 29% (HR=1.29; 95% CI: 1.13-1.47) increased risk of periodontitis compared to those without, when adjusted for age, race, smoking, BMI, fruit and vegetable intake, physical activity, alcohol consumption and dental profession. Men with T2DM with total fruit and vegetable intake < median were 49% as likely to report incident periodontitis compared to those without T2DM (HR=1.49; 95% CI: 1.23 1.80; p-value for interaction=0.03). The multivariable adjusted risk of tooth loss was 1.10 (95% CI: 1.02-1.18). CONCLUSIONS: Type 2 diabetes mellitus was associated with a significantly greater risk of self-reported periodontitis. PMID- 23040241 TI - The organisation of mind. PMID- 23040242 TI - Gender disparity in tuberculosis cases in eastern and western provinces of Pakistan. AB - BACKGROUND: Although globally, the number of notified TB cases is higher for males, a few countries in the Eastern Mediterranean Region (Afghanistan; Lebanon; Iran and Pakistan) of the World Health Organization have a relatively higher number of female cases. Pakistan ranks fifth amongst the highest TB burden countries and poses a rich ground for exploratory research to address the gender differences in TB cases. It is uniquely neighboured by India on the East, having higher number of cases in males than in females, and by Afghanistan and Iran on the West, having higher number of cases in females than in males. The objective is to see whether these gender differences are evenly distributed across the country or vary by geographies, to enable effective targeting of TB control strategies. METHODS: Cross-sectional analysis was carried out on secondary data, obtained from National Tuberculosis Program. Disaggregated at the provincial level, the sex-specific case notification rates (CNR) were calculated and trends over a 10-year span (2001-2010) were examined. Sex-specific differences for the four Pakistani provinces were analyzed using chi-square test and odds ratios with corresponding confidence intervals. Cumulative countrywide sex-specific notification rates were used as the reference group. RESULTS: The trends for 2001 2010 in the western provinces of Pakistan show higher female CNR as compared to those seen in the eastern provinces having slightly higher male CNR. The proportions of female notified TB cases are approximately twice as high in the western provinces when compared to the eastern provinces and Pakistan over all. CONCLUSIONS: These findings suggest that females are particularly affected by TB disease burden in the west parts of Pakistan. This gender disparity requires a coordinated regional and international effort to further explore triggers and moderators of increased acquisition and progression of TB disease among females in the region to guarantee effective TB control. PMID- 23040243 TI - The influence of substrate on DNA transfer and extraction efficiency. AB - The circumstances surrounding deposition of DNA profiles are increasingly becoming an issue in court proceedings, especially whether or not the deposit was made by primary transfer. In order to improve the currently problematic evaluation of transfer scenarios in court proceedings, we examined the influence a variety of nine substrate types (six varieties of fabric, plywood, tarpaulin, and plastic sheets) has on DNA transfer involving blood. DNA transfer percentages were significantly higher (p=0.03) when the primary substrate was of non-porous material (such as tarpaulin, plastic or, to a lesser degree, wood) and the secondary substrate porous (such as fabrics). These findings on transfer percentages confirm the results of previous studies. Fabric composition was also shown to have a significant (p=0.03) effect on DNA transfer; when experiments were performed with friction from a variety of fabrics to a specific weave of cotton, transfer percentages ranged from 4% (flannelette) to 94% (acetate). The propensity for the same nine substrates to impact upon the efficiency of DNA extraction procedures was also examined. Significant (p=0.03) differences were found among the extraction efficiencies from different materials. When 15MUL of blood was deposited on each of the substrates, the lowest quantity of DNA was extracted from plastic (20ng) and the highest quantities extracted from calico and flannelette (650ng). Significant (p<0.05) differences also exist among the DNA extraction yield from different initial blood volumes from all substrates. Also, significantly greater (p<0.05) loss of DNA was seen during concentration of extracts with higher compared to lower initial quantities of DNA. These findings suggest that the efficiency of extraction and concentration impacts upon the final amount of DNA available for analysis and that consideration of these effects should not be ignored. The application of correction factors to adjust for any variation among extraction and concentration efficiencies among substrates is proposed. PMID- 23040244 TI - Developmental validation of Mini-DogFiler for degraded canine DNA. AB - Dogs (Canis lupus familiaris) are kept as pets in 39% of American households and are, therefore, a significant source of potentially probative biological evidence. As with any biological evidence, degradation can occur as a consequence of environmental exposure causing fracturing of the DNA and a resulting loss of intact template. Degraded human DNA analysis has benefited from the application of primer sets that amplify shorter nuclear sequences for core STR loci (miniSTRs), resulting in improved DNA profiles. This same approach was applied to our core canine STR loci. The 16-locus "DogFiler" panel was redesigned into three panels of miniSTRs for analysis of degraded canine DNA, with all primer pairs producing amplicons below 205 base pairs in length. These new miniSTR marker panels - known as Mini-DogFiler - were validated according to SWGDAM guidelines, and concordance with the original 16-locus multiplex was demonstrated through genotyping 1244 samples. The combination of these miniSTRs and a half-volume reaction increased the amplification success of degraded and low copy number canine biological samples resulting in a near three-fold increase in reportable alleles. This assemblage of miniSTRs along with the DogFiler panel and associated allelic ladder are the first non-human DNA profiling system to parallel the human forensic paradigm. PMID- 23040245 TI - Implantation metastasis of malignant fibrous histiocytoma along the stereotactic biopsy tract. PMID- 23040246 TI - Intrathecal bupivacaine for arachnoiditis ossificans: a case report. PMID- 23040247 TI - Symptom clusters among multiethnic groups of cancer patients with pain. AB - OBJECTIVE: Considering recent inconsistent findings on ethnic differences in cancer pain experience, there is a need to clarify the association of ethnicity to cancer pain experience through diverse approaches. However, there currently exist only a small number of studies on ethnic differences in cancer pain experience in general, and few symptom cluster studies specifically related to ethnic differences in cancer pain experience. The purpose of this study was to cluster cancer patients who reported similar cancer pain experience, and to determine ethnic differences in the clusters. METHOD: This was a secondary analysis of the data from a larger Internet study on cancer pain experience of four major ethnic groups of cancer patients in the United States. Only 388 subjects who responded to the questions on cancer pain, cancer symptoms, and functional status were included for this secondary analysis. The data were analyzed using hierarchical cluster analysis and multinomial logistic analysis. RESULTS: A three-cluster solution was adopted: 1) Cluster 1 with low pain, low symptoms, and high functional status, 2) Cluster 2 with moderate pain, low symptoms, and moderate functional staus, and 3) Cluster 3 with high pain, moderate symptoms, and low functional status. In Cluster 2, there were ethnic difference in the cancer pain and funtional status scores; Asian Americans reported lower pain scores than did other ethnic groups, and African Americans had higher funtional status scores than did other ethnic groups. In Cluster 3, there were ethnic difference in the symptom scores (p < 0.05); African Americans reported higher symptom scores than did whites. SIGNIFICANCE OF RESULTS: The results of this study add an important piece of information on ethnic differences in symptom clusters. This study suggests further national scope studies on clustering multiethnic groups of cancer patients by cancer pain experience. PMID- 23040248 TI - Introduction: bladder cancer. PMID- 23040250 TI - Use of preclinical models to assess the therapeutic potential of new drug candidates for bladder cancer. AB - The purpose of this review is to demonstrate a successful use of preclinical models of bladder cancer to confirm the therapeutic potential of new promising drug candidates. The bladder has long been thought to be an ideal target for investigating therapies. When developing a new antineoplastic pharmaceutical agent, the bladder should be considered for use as an experimental model demonstrating initial proof of concept that if successful can be later assessed in further cancer indications. Non-muscle-invasive bladder carcinoma can be removed by transurethral resection but these cancers tend to recur in most patients. Conventional treatments decrease the recurrence rate but are associated with side effects and frequent failures. Thus, there is an obvious need for the development of highly effective targeted therapies with limited side effects. Accordingly, a double-promoter vector was developed, expressing diphtheria toxin A (DTA) under control of two different regulatory promoter sequences, H19 and IGF2. This vector was then used to transfect and to eradicate tumor cells in bladder cancer models, effectively destroying tumor cells without affecting normal cells. Our studies demonstrate the potential efficacy of the therapeutic vector and should be a solid base for future clinical studies. These models illuminate the path for future investigations of new drug candidates for bladder cancer. PMID- 23040251 TI - Radiologic imaging of patients with bladder cancer. AB - Imaging has an ancillary but important role in the detection, staging, and follow up of bladder cancer. Computed tomography urography (CTU) has widely replaced intravenous urography (IVU) and is currently the imaging modality most commonly used for the initial evaluation of patients with or suspected of having bladder tumors, as CTU allows a fast and comprehensive evaluation of the urinary tract in a single exam. Magnetic resonance imaging (MRI) affords better soft tissue contrast, which allows for more accurate staging than can be achieved with other imaging modalities; the role of MRI in bladder cancer is expected to grow. Despite myriad technical advances, imaging of the bladder has several limitations and technical challenges. The performance of the common and some promising newer imaging modalities in the evaluation of bladder cancer are discussed. PMID- 23040252 TI - Management of non-muscle-invasive (superficial) bladder cancer. AB - Non-muscle-invasive (superficial) bladder cancer (NMIBC) represents 80% of incident cases of bladder cancer, and is characterized by a generally good prognosis, with a tendency to remain localized. Only 10%-20% of cases progress to invasion and/or metastasis. The biggest problem in management is the potential for local recurrence, and this will occur with relatively predictable prognostic determinants. Gene expression and other cell surface determinant are associated with outcome. In most cases, successful management is predicated on careful history taking and physical assessment, meticulous endoscopic assessment, and transurethral resection of bladder tumor tissue where indicated. Histology determines the potential for recurrence. Options of treatment include repeat resection, immunologic therapy via intravesical instillation, and the use of intravescally administered cytotoxic agents, including mitomycin C, doxorubicin, gemcitabine, and selected investigational compounds. Of importance, as some cases have the potential to invade and metastasize, timing of cystectomy for recurrent, high-risk tumors is important to avoid unnecessary morbidity and mortality. PMID- 23040253 TI - Innovations in radical cystectomy and pelvic lymph node dissection. AB - Radical cystectomy with bilateral pelvic lymphadenectomy remains the gold standard in the surgical management of muscle-invasive urothelial carcinoma of the bladder and provides optimal locoregional cancer control in conjunction with perioperative cisplatin-based chemotherapy. Improvements in preoperative staging can aid in the identification of patients who may optimally benefit from neoadjuvant chemotherapy and determine candidacy for orthotopic neobladder reconstruction. Innovations in surgical technique and perioperative care have helped to minimize patient morbidity and preserve long-term urinary and sexual function while maintaining oncologic control. The use of minimally invasive surgical approaches has grown dramatically in urologic surgery over the past decade and the preliminary results of robot-assisted laparoscopic radical cystectomy have been reported recently. Anatomic pelvic and iliac lymphadenectomy is crucial for precise pathologic staging and may improve patient survival by removing micrometastatic disease. PMID- 23040249 TI - Prognostic value of cell-cycle regulation biomarkers in bladder cancer. AB - The determination of prognosis in bladder cancer is currently based on staging methods that rely primarily on the pathological stage of a tumor with limited objective correlates. The development and progression of bladder cancer involve alterations in several cellular pathways. Dysregulation in markers associated with cell-cycle regulation has been the most extensively examined molecular aberration in this cancer. Individual alterations of these markers have been associated with disease outcome, with several observations suggesting that their prognostic potential is independent of pathological stage. While many individual molecules in the cell growth receptor signaling, p53, and retinoblastoma (Rb) pathways have been identified, there is a general lack of consensus on which markers can be adopted in the clinical setting. More recent studies have suggested that the combination of markers as concise panels may be more beneficial in determining the degree of aggressiveness of a given tumor and its impending outcome than individual markers alone. This review will discuss alterations in molecules within pathways controlling cell-cycle regulation in the context of bladder cancer, and their impact on patient outcome when examined individually and in combination. PMID- 23040254 TI - Current role of radiation therapy for bladder cancer. AB - Radiation therapy continues to expand its role in the management of bladder cancer. Utilization of chemoradiation as part of the management increases the likelihood of keeping the native bladder and has a positive impact on quality of life, without compromising cure. There remains sustained interest in the concept of bladder conservation as an organ-sparing approach that is potentially equivalent to radical cystectomy as regards disease-specific survival. In addition, radiation therapy may play a meaningful role in the management of non muscle-invasive bladder cancer by reducing the likelihood of local recurrence and preventing or delaying cystectomy. Recently, techniques of radiation therapy have improved considerably and the role of radiation therapy has subsequently expanded and led to better outcomes, as has a better understanding of the biology of fractionation and tumor response. PMID- 23040255 TI - Neoadjuvant and adjuvant chemotherapy approaches for invasive bladder cancer. AB - Deeply invasive bladder cancer, representing approximately 20% of incident cases, is cured by radical cystectomy or radiotherapy in less than 50% of cases. In an effort to improve cure rates, based on objective response rates in metastatic disease of 40%-70% from combination chemotherapy regimens, systemic chemotherapy has been incorporated into programs of definitive treatment for this disease. Several randomized trials and a meta-analysis have confirmed a survival benefit from neoadjuvant chemotherapy followed by definitive local treatment, reflecting both median survival figures and cure rates. Despite several promising phase II trials, no randomized trial of classical adjuvant chemotherapy for bladder cancer has demonstrated an overall survival benefit, despite increments in disease-free survival. Molecular prognostication has been studied in an effort to improve the utility of systemic therapy for invasive non-metastatic bladder cancer, but randomized trials have not shown associated survival benefit. Despite level 1 evidence of a survival benefit from neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) or cisplatin, methotrexate, and vinblastine (CMV) chemotherapy, more than 50% of incident cases do not receive such treatment. PMID- 23040256 TI - New therapeutic challenges in advanced bladder cancer. AB - Treatment of advanced bladder cancer continues to be challenging. Despite initial high response rates with conventional cisplatin-based chemotherapy regimens, 5 year survival is suboptimal at 5% to 20%. Limited advances have been made in chemotherapy, including the design of the triplet regimen and the incorporation of dose intensification (dose-dense) formulations. Novel therapies are desperately needed for first- and second-line therapies and for both fit and unfit patients. Research efforts are now focused on several different areas of therapy, including new chemotherapeutic agents and targeted therapies. Although the use of targeted therapies has failed as of today to demonstrate benefit, a large list of new agents are being studied in properly designed and very promising phase II and III trials. A better understanding of tumor biology and identifying pathways critical for tumorigenesis can provide potential strategies for therapeutic intervention. Understanding the set of changes at the individual patient level hopefully will enable personalized treatment for patients with urothelial cancer. PMID- 23040257 TI - Current status of targeted therapy in metastatic transitional cell carcinoma of the bladder. AB - Urothelial bladder cancer is the second most common genitourinary GU cancer and is among the deadliest and most expensive cancers to treat. The introduction of new regimens improving outcomes of bladder cancer has been slow compared to other GU cancers. This is despite the fact that understanding of the genetic make up of this disease is relatively old. Based on this knowledge, many targets have been identified and therapeutic strategies laid out. This article reviews the literature on the biology of the bladder cancer as it relates to identification of targets. It also provides a review of the data from clinical trials that were designed to test the therapeutic strategies that exploit these targets. PMID- 23040258 TI - Small cell bladder cancer: biology and management. AB - Small cell bladder cancer (SCBC) is a rare and aggressive form of bladder cancer. It exhibits similar biological behavior to small cell lung carcinoma. Untreated, it is associated with a very poor prognosis. Appropriate oncologic surgery remains the mainstay of treatment of this disease but is not curative alone in the majority of the cases. Adding systemic therapy to the treatment regimen has been shown to improve survival. The most common chemotherapy regimens used in published series include a platinum complex plus etoposide, although doxorubicin based regimens and standard urothelial cancer regimens also have been associated with response. Despite robust chemotherapy responses, metastatic disease is associated with relapse and a median overall survival of 18 months or less. Better understanding of the molecular alterations driving SCBC may facilitate the development of new therapeutic strategies and improved outcomes. PMID- 23040259 TI - Urachal adenocarcinoma: a clinician's guide for treatment. AB - Urachal carcinoma is a rare non-urothelial malignancy frequently involving the midline or dome of the bladder due to direct extension from the urachal ligament, the structure from which this tumor arises. Nearly always an adenocarcinoma, it is important to recognize the diagnosis upfront due to the differences in surgery and chemotherapy as compared to traditional urothelial cancer. For patients with surgically resectable tumors, a partial cystectomy with en-bloc resection of the urachal ligament with the bladder dome and umbilicus is required to appropriately control the tumor. Leaving the umbilicus in place provides inadequate control and has been associated with a higher risk of relapse. A lymph node dissection also may help in the control of this cancer. While there is yet no proven role for neoadjuvant or adjuvant chemotherapy, combinations of 5-fluoruracil with cisplatin are active in those with metastases. Since the activity of this combination also has lead to surgical consolidation of node-positive disease, one might consider the potential for benefit from perioperative chemotherapy. A higher risk of relapse following surgery has been reported in those with positive margins, lymph node involvement, involvement of the peritoneal surface, or where the umbilicus was not resected en-bloc, and may predict a group of patients where the risk of relapse is sufficiently high enough to consider adjuvant chemotherapy. A recent clinical trial of 5-fluorouracil, leucovorin, gemcitabine, and cisplatin has recently completed accrual in metastatic urachal carcinoma, with patients now in long-term follow-up. PMID- 23040260 TI - Senior adult oncology: three cases of advanced cancer in patients of advanced age. PMID- 23040262 TI - Obstructive sleep apnea: looking at the whole picture. PMID- 23040264 TI - [What patients need to know about the risk of bone fracture and its prevention]. AB - Post-menopausal osteoporosis is one of the classic complications of prolonged estrogen deficiency associated with menopause. It is defined as a state of the skeleton characterized by decreased bone strength with an increased risk of fracture. The natural history of osteoporosis and, in particular, the rapid increase in fracture recurrence after a first major fracture should justify a priori an approach for early detection of women at higher risk from the early postmenopausal phase. It is more of a chronic disease that requires support in the long term, in the absence of a truly curative treatment. Indeed, currently available therapies can at best reduce the incidence of fractures by about 50%, especially at the vertebral site, but do not cancel the disease. Moreover, duration of treatment is currently recommended for 5 to 10 years, which does not allow to consider that a single molecule could be taken "for the whole life". The fracture risk assessment based on the combination of densitometric measurement by DXA and the search for clinical risk factors is a prerequisite to any therapy. The first choice of treatment is especially important for a relatively young woman with high fracture risk. In early menopause (generally within the first decade of post-menopausal) and in the absence of contraindication, menopausal hormone therapy should remain the preferred option for first-line whenever possible. Raloxifene is an interesting alternative, due to its mechanisms of action and multiplicity of targets with, in particular, its preventive effect on the risk of estrogen receptor-positive breast cancer. It is only when there are contraindications to one or the other of these two molecules, that other osteoporosis treatments can be discussed. They should nevertheless be considered only in women whose 10-year-fracture risk is significantly increased. Indeed, it is mainly in this high risk of fracture, particularly because of an age greater than 65 years and a history of vertebral fracture, that their antifracture efficacy has been validated. In addition, it is mostly beyond this age that the question of the prevention of hip fracture has to be considered. PMID- 23040265 TI - [Identification of barriers to routine HIV testing prescription by midwifes and doctors in Guadeloupe]. AB - OBJECTIVES: Guadeloupe is the second highest French area for diagnosis and prevalence of HIV infection and AIDS. In October 2009, the French High Health Authority has published guidelines for a more systematic HIV screening. The goal of this study is to identify the limitations in HIV testing prescription by the Guadeloupian prescribers according to these new recommendations. MATERIALS AND METHODS: Data were collected with a questionnaire submitted to physicians and midwives after random selection. RESULTS: Among 285 randomly selected prescribers, 67 midwives and 40 physicians participated from August to December 2010. The main limitations to HIV testing prescription were: a consultation for another purpose, patient or his life style were known, and lack of HIV infection symptoms. Some characteristics of more easily screened patient did not match with those who had been newly diagnosed in Guadeloupe. Finally, both quantitative and qualitative knowledge of these new recommendations was insufficient. CONCLUSION: Implementation of these new testing recommendations should give emphasis to the systematic and annual nature of HIV testing for whole population. It should also insist on distinction between HIV testing and diagnosis of a symptomatic patient. PMID- 23040266 TI - [Prolactinoma: from quest of pregnancy to delivery]. AB - Prolactinoma is the most frequent hormone-secreting pituitary tumor (100 for million patients) and a major cause of both female and male reproductive function disorders. Physician, gynecologist, urologist and sexologist can face this situation during their career. As part of the fertility restoration, treatment gives very satisfactory results. With adequate management, most women are expected to achieve successful pregnancies. The natural history of these tumors during pregnancy depends on their size with a risk of a clinically relevant estimate between 5 to 30 %. Their management is complex, requiring finding balance between effects of pregnancy on tumor growth and potential risks of overtreatment on fetal development. The aim of this study is to discuss the management of prolactinoma on woman before, during and after pregnancy, and to evaluate the medical and surgical alternatives regarding the actual literature. PMID- 23040263 TI - Neuronal damage and functional deficits are ameliorated by inhibition of aquaporin and HIF1alpha after traumatic brain injury (TBI). AB - The present study, using a rodent model of closed-head diffuse traumatic brain injury (TBI), investigated the role of dysregulated aquaporins (AQP) 4 and 9, as well as hypoxia inducible factor -1alpha(HIF-1alpha) on brain edema formation, neuronal injury, and functional deficits. TBI was induced in adult (400-425 g), male Sprague-Dawley rats using a modified Marmarou's head impact-acceleration device (450 g weight dropped from 2m height). Animals in each treatment group were administered intravenous anti-AQP4 or -AQP9 antibodies or 2-Methoxyestradiol (2ME2, an inhibitor of HIF-1alpha) 30 min after injury. At 24h post-TBI, animals (n=6 each group) were sacrificed to examine the extent of brain edema by water content, as well as protein expression of AQP and HIF-1alpha by Western immune blotting. At 48-hours post-TBI, neuronal injury (n=8 each group) was assessed by FluoroJade (FJ) histochemistry. Spatial learning and memory deficits were evaluated by radial arm maze (n=8 each group) up to 21 days post-TBI. Compared to non-injured controls, significant (p<0.05) increases in the expression of AQP4 and -9 were detected in the brains of injured animals. In addition, significant (p<0.05) brain edema after TBI was associated with increases (p <0.05) both in neuronal injury (FJ labeling) and neurobehavioral deficits. Selective inhibition of either AQP4 or -9, or HIF-1alpha significantly (p<0.05) decreased the expression of the proteins. In addition, inhibition of the AQPs and HIF-1alpha significantly (p<0.05) ameliorated brain edema, as well as the number of injured neurons in cortical layers II/III and V/VI, striatum and hippocampal regions CA1/CA3. Finally, compared to the non-treated TBI animals, AQP or HIF-1alpha inhibition significantly (p<0.01) improved neurobehavioral outcomes after TBI. Taken together, the present data supports a causal relation between HIF-AQP mediated cerebral edema, secondary neuronal injury, and tertiary behavioral deficits post-TBI. The data further suggests that upstream modulation of the molecular patho-trajectory effectively ameliorates both neuronal injury and behavioral deficits post-TBI. PMID- 23040267 TI - [Pregnancy and Ehlers-Danlos vascular syndrome: patients' care and complications]. AB - INTRODUCTION: Elhers-Danlos vascular syndrome type IV (EDS4) is a hereditary pathology of the connective tissue responsible for an increased risk of lethal arterial, uterine and digestive complications during and after pregnancy. PATIENTS AND METHODS: We describe the obstetrical care, the nature and frequency of complications related to pregnancy of patients with EDS4 and their relatives. RESULTS: Twenty-seven pregnancies were studied including 23 deliveries, 18 vaginal deliveries and five caesarean, no maternal death and two major life threatening complications (8.7%) were recorded which could be directly linked to EDS4 (rupture of the biscupid valve pillar after vaginal delivery and a rupture of the caecum after a prophylactic caesarean). Ten deliveries underwent epidural anesthesia without complication. Six perineal injuries (33.3%) were observed. CONCLUSION: Pregnancy in patient with EDS4 needs obstetrical cares in a special unit's motivated medical team with intensive care and surgical disponibilities. PMID- 23040269 TI - [Not Available]. PMID- 23040270 TI - [Not Available]. AB - OBJECTIVE: To determine the effectiveness of a model centred in the admission unit that prioritises the daily assignment of available hospital beds. MATERIAL AND METHODS: This model started on June 1st 2005 with the implementation of a series of interventions: 1) Definition of the proceedings of the admission unit; 2) A daily planning decision-making meeting; 3) Opening of a 24-hour emergency department holding unit; 4) Priority bed assignment system; and 5) Appropriateness of emergency medical and elective surgical admissions. We used 8 parameters obtained from the hospital automated database. The data have been analysed in three different annual periods: 2004 (before intervention), 2005 (intervention) and 2006 (after ntervention). RESULTS: Number of emergencies seen: 2004 (124,301), 2005 (123,390),2006 (129,389); number emergency admissions: 2004 (13,629), 2005 (14,649), 2006 (11,690); number of elective admissions: 2004 (12,320), 2005 (12,791), 2006 (13,615); ED admission rate: 2004 (11.0 %), 2005 (11.9 %), 2006 (9.2 %), P=.004; emergency pressure: 2004 (52.5 %), 2005 (53.4 %), 2006 (46.2 %), P=.002; ED mean length of stay per patient: 2004 (9h 45m), 2005 (6h 46m), 2006 (5h 39m); number of emergency admissions waiting for a hospital bed at 8 a.m: 2004 (5341), 2005 (4484), 2006 (2787); elective surgical interventions cancellation rate: 2004 (3.4 %), 2005 (3.7 %), 2006 (2.6 %), P=.002. CONCLUSIONS: Centralized assignment of hospital beds by the admission unit has proved to be an effective tool for hospital management. PMID- 23040271 TI - [Not Available]. AB - OBJECTIVE: To identify the characteristics, needs and difficulties of training of health professionals in health care and inter-professional communication and discover mechanisms for improvement and a desirable educational profile for implementing a training strategy. MATERIAL AND METHOD: Qualitative, descriptive and interpretive study carried out between September 2006 and July 2007 at the initiative of the Direccion General de Asistencia Sanitaria-Servicio Murciano de Salud (SMS) and the Direccion General de Calidad Asistencial, Formacion e Investigacion Sanitaria-Consejeria de Sanidad of Murcia, Spain. Participants included 11 doctors, 5 nurses, 1 psychologist and 1 primary and specialised care journalist and the Consejeria de Sanidad of Murcia. 2 focus groups were used with sampling by structural saturation, recording of speeches on audiovisual support, verbatim transcript and content analysis. RESULTS: We must encourage attitude changes and acquire the tools for proper care in everyday situations. It is also necessary to rethink subject matter and approaches, define the profile of teachers and develop collaboration and motivation mechanisms. Training in health care communication and inter-professional communication is crucial but it is limited, self-taught, poorly structured and generalistic. It has difficulties associated with attendance, outreach and recognition. CONCLUSIONS: A strategic plan for training communication must be based on a human perspective. Its integration must be undertaken by the institution, and universal with the interests and needs felt and expressed by professionals and citizens. PMID- 23040272 TI - [Not Available]. AB - OBJECTIVE: To find out patients' opinions of e-medicine, obtaining general ideas related to three relevant aspects: electronic health records (EHR), the web as an information source and use of e-mail. DESIGN: Qualitative phenomenological study, analysing the content of group interviews. Content analysis was performed by the three researchers. PARTICIPANTS: Urban patients. Internet and e-mail practical knowledge. VARIABLES: age and gender, districts with different socio-economic levels. SETTING: San Sebastian (Spain). RESULTS: Four focal groups, with 35 people, 12 under 25 years old, 10 over 65, and 16 women. EHR valuation was very positive. Computer use does not change the health worker-patient relationship. It must spread to the home setting, and be available from any point, creating another kind of relationship, regardless of the distance. Single EHR for all the suppliers. Patients consider themselves authorised to manipulate it. Participants use the web as an information source, looking for safe sources and specific information, and to verify health workers information. The relationship with doctors is irreplaceable. E-mail is a useful alternative for specific needs. It would force a redesign of working schedule and to define the conditions of use. CONCLUSIONS: New technologies are widely used. Acceptance is practically unanimous. Ideas such as continuous care by the same person are very innovative. It seems that we are faced with a powerful technology, which could improve and facilitate patient care, as patient awareness of their individual rights coincides with unlimited access to the information. PMID- 23040273 TI - [Not Available]. AB - A good way to promote breastfeeding is to implement the Ten Steps to Successful Breastfeeding of UNICEF. However, this is not an easy task and there are many difficulties prior to success. Based on our experience on the subject, supported by our recent accreditation as a Baby-friendly hospital, we have analyzed various doubts and problems that we think are important in order to enhance breastfeeding in a hospital setting: how to begin, how to train the health personnel and keep them updated, when and how to supplement breastfeeding, how to promote the activity of support groups, how to improve the support to the mother after discharge, how much time may be necessary, etc. Furthermore, we comment on factors that we consider important and that may be essential for success. PMID- 23040268 TI - Lipoprotein(a) metabolism: potential sites for therapeutic targets. AB - Lipoprotein(a) [Lp(a)] resembles low-density lipoprotein (LDL), with an LDL lipid core and apolipoprotein B (apoB), but contains a unique apolipoprotein, apo(a). Elevated Lp(a) is an independent risk factor for coronary and peripheral vascular diseases. The size and concentration of plasma Lp(a) are related to the synthetic rate, not the catabolic rate, and are highly variable with small isoforms associated with high concentrations and pathogenic risk. Apo(a) is synthesized in the liver, although assembly of apo(a) and LDL may occur in the hepatocytes or plasma. While the uptake and clearance site of Lp(a) is poorly delineated, the kidney is the site of apo(a) fragment excretion. The structure of apo(a) has high homology to plasminogen, the zymogen for plasmin and the primary clot lysis enzyme. Apo(a) interferes with plasminogen binding to C-terminal lysines of cell surface and extracellular matrix proteins. Lp(a) and apo(a) inhibit fibrinolysis and accumulate in the vascular wall in atherosclerotic lesions. The pathogenic role of Lp(a) is not known. Small isoforms and high concentrations of Lp(a) are found in healthy octogenarians that suggest Lp(a) may also have a physiological role. Studies of Lp(a) function have been limited since it is not found in commonly studied small mammals. An important aspect of Lp(a) metabolism is the modification of circulating Lp(a), which has the potential to alter the functions of Lp(a). There are no therapeutic drugs that selectively target elevated Lp(a), but a number of possible agents are being considered. Recently, new modifiers of apo(a) synthesis have been identified. This review reports the regulation of Lp(a) metabolism and potential sites for therapeutic targets. PMID- 23040274 TI - [Not Available]. AB - The debate about the "right to die with dignity" will only be productive if the words used are constructed properly. "Euthanasia" is probably the word that most needs further clarification. This word is frequently abused and still remains unclear. Five scenarios around end-of-life care can be highlighted: euthanasia and assisted suicide, withholding or withdrawal of life sustaining therapies, refusal of treatment or withdrawal of consent, palliative sedation and withdrawal of treatment because of patient death. This work supports the hypothesis that Spanish society has reached a sufficient ethical and legal consensus on the lastfour scenarios, which should never been considered "euthanasia" but forms of dignified death and good clinical practice. So, the mainstream of the Spanish debate on the "right to die" should not be based on these four scenarios but on the first, the question of "euthanasia and assisted suicide", which remain open to further discussion. PMID- 23040275 TI - [Not Available]. PMID- 23040276 TI - Interplay between Fur and HNS in controlling virulence gene expression in Salmonella typhimurium. AB - Salmonella enterica is responsible for a large number of diseases in a wide-range of hosts. Two of the global regulators involved in controlling gene expression during the infection cycle of the bacterium are Fur and HNS. In this paper, we demonstrate computationally that Fur and HNS have disproportionately high density of binding sites in the Pathogenicity Islands on the Salmonella chromosome. Moreover, the frequency of binding sites for the two proteins is correlated throughout the genome of the organism. These results indicate a complex interplay between Fur and HNS in regulating cellular global behavior. PMID- 23040278 TI - Numerical investigation of white matter anisotropic conductivity in defining current distribution under tDCS. AB - The study investigates the impact of white matter directional conductivity on brain current density under the influence of Transcranial direct current stimulation (tDCS). The study employed different conductivity estimation algorithms to represent conductivity distribution in the white matter (WM) of the brain. Two procedures, one mathematically driven and the second one based on the Diffusion tensor imaging (DTI) are considered. The finite element method has been applied to estimate the current density distribution across the head models. Strengths and weaknesses of these algorithms have been compared by analyzing the variation in current density magnitude and distribution patterns with respect to the isotropic case. Results indicate that anisotropy has a profound influence on the strength of current density (up to ~50% in WM) as it causes current flow to deviate from its isotropically defined path along with diffused distribution patterns across the gray and WM. The extent of this variation is highly correlated with the degree of the anisotropy of the regions. Regions of high anisotropy and models of fixed anisotropic ratio displayed higher and wider degree of variations across the structures (topographic variations up to 48%), respectively. In contrast, models, which are correlated with the magnitude of local diffusion tensor behaved in a less exacerbated manner (~10% topographic changes in WM). Anisotropy increased the current density strength across the cortical gyri under and between the stimulating electrodes, whereas a significant drop has been recorded in deeper regions of the GM (max % difference ~+/-10). In addition, it has been observed that Equivalent isotropic trace algorithm is more suitable to incorporate directional conductivity under tDCS paradigm, than other considered approaches, as this algorithm is computationally less expensive and insensitive to the limiting factor imposed by the volume constraint. PMID- 23040279 TI - Delirium in the hospital setting: do not let our patients "going off the ploughed track". PMID- 23040261 TI - C-reactive protein distribution and correlation with traditional cardiovascular risk factors in the Italian population. AB - BACKGROUND: C-reactive protein (CRP) increases during an inflammatory response; its plasma levels are believed to be an independent predictor of future atherosclerotic disease. We report the distribution of plasma levels of CRP and its possible relationship with other cardiovascular risk factors in an Italian cohort. METHODS: CRP was assessed in frozen plasma samples of 1949 participants in the CHECK study (2001-2005), which collected clinical and biochemical data from randomly selected subjects (40-79 years) in the setting of Italian general practice. RESULTS: Median CRP (interquartile range) was higher in women (1.42 [0.58-2.86] vs 1.28 [0.58-2.50]; p=.163), in people aged >= 65 years (1.74 [0.89 3.34] vs 1.11 [0.52-2.45]; p<.001), in patients with obesity (2.37 [1.27-4.15] vs 1.16 [0.52-2.41]; p<.001), metabolic syndrome (2.12 [1.16-3.72] vs 1.10 [0.50 2.38]; p<.001), or higher cardiovascular risk (2.03 [1.01-3.42] vs 1.19 [0.53 2.50]; p<.001). Stepwise regression analysis showed significant associations (R(2)=.264) of circulating log(e)CRP with body mass index, fibrinogen, apoB, age, gender, smoking habits, physical inactivity, creatinine levels, and systolic blood pressure. CONCLUSION: This study provides epidemiological data of CRP in the Italian population and reinforces the existing evidences about the close correlation between CRP and markers of inflammation and adiposity. PMID- 23040280 TI - Understanding terminology of delirium and long-term cognitive impairment in critically ill patients. AB - Delirium, an acute brain dysfunction, frequently affects intensive care unit (ICU) patients during the course of a critical illness. Besides the acute morbidities, ICU survivors often experience long-term sequelae in the form of cognitive impairment (LTCI-CI). Though delirium and LTCI-CI are associated with adverse outcomes, little is known on the terminology used to define these acute and chronic co-morbidities. The use of a correct terminology is a key factor to spread the knowledge on clinical conditions. Therefore, we first review the epidemiology, definition of delirium and its related terminology. Second, we report on the epidemiology of LTCI-CI and compare its definition to other forms of cognitive impairments. In particular, we define mild cognitive impairment, dementia and finally postoperative cognitive dysfunction. Future research is needed to interpret the trajectories of LTCI-CI, to differentiate it from neurodegenerative diseases and to provide a formal disease classification. PMID- 23040277 TI - Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species. AB - Signal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococcus species, especially Staphylococcus aureus. Here we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococcus species. PMID- 23040282 TI - Pharmacologic prevention and treatment of delirium in critically ill and non critically ill hospitalised patients: a review of data from prospective, randomised studies. AB - Delirium occurs commonly in acutely ill hospitalised patients, particularly in the elderly or in cardiac or orthopaedic surgery patients, or those in intensive care units (ICUs). Delirium worsens outcome. Pharmaceutical agents such as antipsychotics and, in the critically ill, dexmedetomidine, are considered therapeutic despite uncertainty regarding their efficacy and safety. Using MEDLINE, we reviewed randomised controlled trials (RCTs) published between 1977 and April 2012 evaluating a pharmacologic intervention to prevent or treat delirium in critically ill and non-critically ill hospitalised patients. The number of prospective RCTs remains limited. Any conclusions about pharmacologic efficacy are limited by the small size of many studies, the inconsistency by which non-pharmacologic delirium prevention strategies were incorporated, the lack of a true placebo arm and a failure to incorporate ICU and non-ICU clinical outcomes. A research framework for future evaluation of the use of medications in both ICU and non-ICU is proposed. PMID- 23040283 TI - Delirium: clinical approach and prevention. AB - Delirium, defined as an acute fluctuating change in mental state, with consciousness and cognitive impairment, has been found to have a high incidence in hospitalised patients, as well as being associated with increased morbidity and mortality, prolonged stays in the intensive care unit (ICU) and in hospital and higher costs. However, delirium is not easy to detect, since its diagnosis is mainly clinical. Yet the importance of early diagnosis and possible prevention in the different clinical scenarios is clear, to improve patient prognosis. This review provides a practical approach to delirium management through: (a) its classification and diagnosis utilising validated tools and (b) the use of non pharmacological protocols and of an early prediction model to identify high-risk patients, who are more likely to benefit from pharmacological prophylaxis. PMID- 23040284 TI - An update on delirium in the postoperative setting: prevention, diagnosis and management. AB - Delirium is a serious and pervasive problem in the postoperative setting. Research to date has identified a number of key risk factors implicated in the development of delirium after surgical intervention, including advanced age, pre existing cognitive impairment, lower pre-morbid functional status and history of psychiatric illness. Efforts to prevent postoperative delirium in the form of multi-component programs and prophylactic administration of medications have yielded some positive results. Studies investigating the effectiveness of various antipsychotics in the treatment of postoperative delirium have demonstrated somewhat mixed outcomes. Recent research has identified more sophisticated management of pain and sedation protocols as a way to prevent or mitigate delirium, with promising results. This chapter reviews the most recent literature pertaining to the prevention, diagnosis and management of postoperative delirium. PMID- 23040281 TI - Epidemiology and risk factors for delirium across hospital settings. AB - Delirium is one of the most common causes of acute end-organ dysfunction across hospital settings, occurring in as high as 80% of critically ill patients that require intensive care unit (ICU) care. The implications of this acute form of brain injury are profound. Across many hospital settings (emergency department, general medical ward, postoperative and ICU), a patient who experiences delirium is more likely to experience increased short- and long-term mortality, decreases in long-term cognitive function, increases in hospital length of stay and increased complications of hospital care. With the development of reliable setting-specific delirium-screening instruments, researchers have been able to highlight the predisposing and potentially modifiable risk factors that place patients at highest risk. Among the large number of risk factors discovered, administration of potent sedative medications, most notably benzodiazepines, is most consistently and strongly associated with an increased burden of delirium. Alternatively, in both the hospital and ICU, delirium can be prevented with the application of protocols that include early mobility/exercise. Future studies must work to understand the epidemiology across settings and focus upon modifiable risk factors that can be integrated into existing delirium prevention and treatment protocols. PMID- 23040285 TI - Delirium in the fast-track surgery setting. AB - Postoperative delirium (PD) and postoperative cognitive dysfunction (POCD) are two separate syndromes of cognitive decline after major surgery, especially in the elderly. Pathogenesis is multifactorial with some common risk factors, and to reduce the risk, a multimodal approach is necessary. The fast-track methodology is becoming a well-established perioperative care regime with possible preventive effects for postoperative cognitive decline, including reduced pain and use of opioids, and early mobilisation with early discharge (<=3 days) to preoperative environment after total hip/knee arthroplasty (THA/TKA). The fast-track set-up seems to be associated with a lower frequency of PD and early POCD after THA/TKA. Thus, in a series of 225 patients >=60 years, no cases of PD were seen and the incidence of POCD was reduced by more than 50% at 1 week postoperatively compared to previous studies. In conclusion, the fast-track methodology may reduce the incidence of postoperative cognitive decline after surgery. PMID- 23040288 TI - Optimising the recognition of delirium in the intensive care unit. AB - Delirium affects up to 80% of critically ill patients and negatively influences patient outcome. Consensus guidelines advocate that a validated screening tool like the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC) be used to identify delirium rather than a subjective approach. The CAM-ICU and ICDSC have the most rigorous psychometric data to support their use. The differences between these two instruments are far less important to the outcome of patients than the regular and reliable use of either in routine ICU care. Implementation of a large-scale delirium screening effort is both feasible and sustainable and should be accompanied by both didactic and bedside education. An ICU clinical road map should be used on a daily basis that promotes delirium assessment, establishes a targeted sedation goal and defines the analgesic/sedative regimen that is best suited to maintain patient comfort, prevent delirium and promote wakefulness. PMID- 23040287 TI - Delirium detection and monitoring outside the ICU. AB - Delirium affects many patients in hospital settings but is under-detected and associated with a range of adverse health-care outcomes, including institutionalisation and elevated mortality. Detection is essential because it leads to identification and management of precipitants and assessment and management of distress caused by hallucinations and delusions. Moreover, delirium may affect communication and, thus, assessment of pain. This is important because inadequate analgesia may cause agitation and prolong the delirium. Here, we provide an overview of the main features of delirium. Informal and formal methods of assessment of the features are covered. We describe some of the main rating scales used in delirium screening and severity grading. Incorporating formal and systematic screening and assessment into everyday clinical practice can substantially improve delirium diagnosis and treatment. PMID- 23040286 TI - Delirium: is sleep important? AB - Delirium and poor sleep quality are common and often co-exist in hospitalised patients. A link between these disorders has been hypothesised but whether this link is a cause-and-effect relationship or simply an association resulting from shared mechanisms is yet to be determined. Potential shared mechanisms include: abnormalities of neurotransmitters, tissue ischaemia, inflammation and sedative exposure. Sedatives, while decreasing sleep latency, often cause a decrease in slow wave sleep and stage rapid eye movement (REM) sleep and therefore may not provide the same restorative properties as natural sleep. Mechanical ventilation, an important cause of sleep disruption in intensive care unit (ICU) patients, may lead to sleep disruption not only from the discomfort of the endotracheal tube but also as a result of ineffective respiratory efforts and by inducing central apnoea events if not properly adjusted for the patient's physiologic needs. When possible, efforts should be made to optimise the patient-ventilator interaction to minimise sleep disruptions. PMID- 23040290 TI - High prevalence of overweight and obesity in adults with Crohn's disease: associations with disease and lifestyle factors. AB - BACKGROUND AND AIMS: Obesity and overweight are major public health issues. Although traditionally associated with weight loss, there is now evidence that increasing Body Mass Index (BMI) and overweight are emerging features of Crohn's disease (CD) and may be associated with more severe disease course. The aim of the study was to determine the prevalence of overweight and obesity in patients with CD compared with matched healthy controls and to identify disease-specific and generic factors associated with current BMI in this group. METHODS: This was a prospective case-control study (n=200), comprising 100 CD outpatients and 100 age-, sex- and socioeconomically-matched healthy controls. BMI, Crohn's disease activity index (CDAI), clinical and lifestyle factors and circulating inflammatory markers were assessed. RESULTS: Overall, 40% of patients with CD were overweight/obese (BMI >= 25 kg/m(2)) compared with 52% of controls (P = 0.206). On regression analysis, higher current BMI was significantly associated with disease specific factors, namely lower disease activity (CDAI) and lower white cell count, suggesting stable disease, as well as older age and lower physical activity. BMI was not significantly associated with the need for surgery or the need for corticosteroids. We identified a novel association between higher BMI and higher CRP, a marker linked both with obesity in the general population and with CD. CONCLUSIONS: Overweight was common in out-patients with CD and appeared to reflect current wellness, older age and sedentary lifestyles. The potential long-term implications of high BMI for CRP and inflammatory load merit further study. PMID- 23040289 TI - Future directions of delirium research and management. AB - Delirium is a prevalent organ dysfunction in critically ill patients associated with significant morbidity and mortality, requiring advancements in the clinical and research realms to improve patient outcomes. Increased clinical recognition and utilisation of delirium assessment tools, along with clarification of specific risk factors and presentations in varying patient populations, will be necessary in the future. To improve predictive models for outcomes, the continued development and implementation of delirium assessment tools and severity scoring systems will be required. The interplay between the pathophysiological pathways implicated in delirium and resulting clinical presentations and outcomes will need to guide the development of appropriate prevention and treatment protocols. Multicentre randomised controlled trials of interventional therapies will then need to be performed to test their ability to improve clinical outcomes. Physical and cognitive rehabilitation measures need to be further examined as additional means of improving outcomes from delirium in the hospital setting. PMID- 23040291 TI - Reply to Dr. Joob et al.'s letter. PMID- 23040292 TI - Effects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: towards translational challenge models for drug discovery in Alzheimer's disease. AB - Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the 'Swedish' mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans. PMID- 23040293 TI - MUNIX and incremental stimulation MUNE in ALS patients and control subjects. AB - OBJECTIVE: This study compares the new Motor Unit Number Estimation (MUNE) technique, MUNIX, with the more common incremental stimulation MUNE (IS-MUNE) with respect to reproducibility in healthy subjects and as potential biomarker of disease progression in patients with ALS. METHODS: Thirteen ALS patients and 48 control subjects were prospectively investigated - both groups were studied with MUNIX and IS-MUNE applied on the abductor digiti minimi (ADM) muscle. Additional retest was performed on 14 control subjects. Follow-up tests were carried out on 6 patients. The analysis included measures of reproducibility (Intraclass Correlation Coefficient (ICC)) and diagnostic performance (Receiver Operating Characteristic (ROC) analysis). RESULTS: Test-retest reproducibility was low to moderate for MUNIX and IS-MUNE (ICC=0.38 and 0.56, respectively). Repeated MUNIX and IS-MUNE measurements on the same subject had a mean percentage difference (MPD) of 20% and 46%, respectively (p=0.039). In the control group, the coefficient of variation was markedly lower for MUNIX than for IS-MUNE (26% and 44%, respectively, p<0.0005). In ALS patients MUNIX had a notably better responsiveness in follow-up than IS-MUNE (percent change per month, 9.4 versus 5.6, p=0.046). ROC analysis suggested similar diagnostic accuracy of both tests. CONCLUSIONS: MUNIX is a useful MUNE indicator when assessing progression of lower motor neuron affection in ALS. Furthermore, MUNIX displayed lower intrasubject variability, but no evident better diagnostic yield compared with IS-MUNE. SIGNIFICANCE: This study has established comparative assessment of MUNIX and IS MUNE performance in test-retest setting and as diagnostic tests on a distal muscle in ALS patients. PMID- 23040294 TI - Potential approximation in realistic Laplacian computation. AB - OBJECTIVE: This paper aims to improve the shortcomings of the extant methodologies for realistic Laplacian (RL) computation, and correct the erroneous claims published in the past. METHODS: We implemented several variants of RL computation methods, using various potential approximation techniques and different regularization approaches. The individual variants of the RL computation were tested using simulations based on a realistic head model computed with the boundary element method (BEM). The results which disagreed with previously published works were further analyzed, and the reasons for the disagreement were identified. RESULTS: We identified the best regularization techniques for the surface potential approximation, and we showed that once these techniques are used there is often little difference between various potential approximations, which is in contrast with previous claims that promoted the radial basis function (RBF) approximation. Further, our analysis shows that the RBF approximation suffers from Runge phenomenon, which cannot be mitigated simultaneously for both deep and shallow sources; therefore, its good performance is guarantied only if a priori knowledge about the source depth is available. CONCLUSIONS: The previously published methodology for RL computation was not optimal. Improvements are possible if the newly suggested approach is used. SIGNIFICANCE: The methodology presented in our paper allows more efficient utilization of the RL, providing a useful tool for processing of high density EEG recordings. Presented techniques allow to achieve high EEG spatial resolution, and avoid unnecessary spatial blurring caused by the problems in the previously published RL methodology. PMID- 23040295 TI - Commentary on 'Availability of supervised exercise programs and the role of structured home-based exercise in peripheral arterial disease'. PMID- 23040296 TI - Part One: For the motion. All TEVAR patients must be followed lifelong by annual CTA/MRA. [Pro]. PMID- 23040297 TI - Biomechanical concepts applicable to minimally invasive fracture repair in small animals. AB - Understanding the basic biomechanical principles of surgical stabilization of fractures is essential for developing an appropriate preoperative plan as well as making prudent intraoperative decisions. This article aims to provide basic biomechanical knowledge essential to the understanding of the complex interaction between the mechanics and biology of fracture healing. The type of healing and the outcome can be influenced by several mechanical factors, which depend on the interaction between bone and implant. The surgeon should understand the mechanical principles of fracture fixation and be able to choose the best type of fixation for each specific fracture. PMID- 23040298 TI - Minimally invasive plate osteosynthesis fracture reduction techniques in small animals. AB - Indirect fracture reduction is used to align diaphyseal fractures in small animals when using minimally-invasive fracture repair. Indirect reduction achieves functional fracture reduction without opening the fracture site. The limb is restored to length and spatial alignment is achieved to ensure proper angular and rotational alignment. Fracture reduction can be accomplished using a variety of techniques and devices, including hanging the limb, manual traction, distraction table, external fixators, and a fracture distractor. PMID- 23040299 TI - Perioperative imaging in minimally invasive osteosynthesis in small animals. AB - Perioperative imaging using various appropriate modalities is critical to the successful planning and performance of any orthopedic surgery. Although not an absolute prerequisite, the use of intraoperative imaging considerably facilitates the smooth and effective execution of minimally invasive osteosynthesis (MIO). However, the risk of overexposure to radiation is real, particularly when considering its insidious effect over time. Therefore, the primary concern of the surgeon must be safety of the surgical team. This article outlines basic, simple steps that will be effective in reducing radiation exposure, which in turn will make MIO a safe alternative to open reduction and internal fixation. PMID- 23040300 TI - External fixators and minimally invasive osteosynthesis in small animal veterinary medicine. AB - Modern external skeletal fixation (ESF) is a very versatile system that is well suited to the ideals of minimally invasive osteosynthesis (MIO). It offers variable-angle, locked fixation that can be applied with minimal to no disruption of the fracture zone. Technological advances in ESF have fostered the ability to use more simple frame applications than in previous generations. Even when rigid bilateral or multiplanar frames are required, timely staged-disassembly is easy to perform and allows for a gradual shift of loading from the frame to the healing bony column. Hybrid ESF is ideally suited for the MIO treatment of many juxta-articular fractures and osteotomies. Adherence to the principles of ESF and postoperative care is essential to overcome the various disadvantages that are inherent to ESF. PMID- 23040301 TI - Interlocking nails and minimally invasive osteosynthesis. AB - Interlocking nailing of long bone fractures has long been considered the gold standard osteosynthesis technique in people. Thanks to improvements in the locking mechanism design and nail profile, a recently developed veterinary angle stable nail has become the first true intramedullary fixator providing accurate and consistent repair stability while allowing semirigid fixation. As a result, indications for interlocking nailing have expanded to include treatment of periarticular fractures, corrections of angular deformities and revisions of failed plate osteosyntheses. Perfectly suited for minimally invasive osteosynthesis, interlocking nailing is an attractive and effective alternative to bone plating and plate-rod fixation technique. PMID- 23040302 TI - Percutaneous pinning for fracture repair in dogs and cats. AB - This article describes the technique of percutaneous pinning in dogs and cats. Only acute fractures evaluated within the first 48 hours after trauma are selected for percutaneous pinning. Reduction is performed with careful manipulation of the fracture to minimize the trauma to the growth plate. After ensuring the fracture is reduced anatomically, smooth pins of appropriate size are inserted through stab incisions. Depending on the anatomic location, the pins are cut flush with bone or bent. The main advantages of this technique are the minimal surgical trauma and lower perioperative morbidity. PMID- 23040303 TI - MIPO techniques for the humerus in small animals. AB - Knowledge of regional and topographic anatomy is paramount for success when using minimally invasive plate osteosynthesis (MIPO) for fracture management. Preoperative planning is essential for an optimal outcome and reducing stress among the surgical team; factors to consider include biologic assessment, mechanical assessment, clinical assessment, portal placement, and implant selection. MIPO is a useful technique for the direct or indirect reduction of humeral diaphyseal fractures. Implants should span the length of the bone for ease of implant application and to optimize the mechanical advantage of the implant. After surgery, incision care and controlled activity are 2 primary considerations. PMID- 23040304 TI - Minimally invasive plate osteosynthesis in small animals: radius and ulna fractures. AB - Minimally invasive plate osteosynthesis (MIPO) is a biologically friendly approach to fracture reduction and stabilization that is applicable to many radius and ulna fractures in small animals. An appropriate knowledge of the anatomy of the antebrachium and careful preoperative planning is essential. This article describes the MIPO technique, which entails stabilization of the fractured radius with a bone plate and screws that are applied without performing an extensive open surgical approach. This technique results in good outcomes, including a rapid time to union and return of function. PMID- 23040305 TI - Minimally invasive osteosynthesis techniques of the femur. AB - Indirect reduction techniques and carefully planned and executed direct reduction techniques result in maximal preservation of the biology of the fracture site and bone fragments. These techniques, coupled with the use of small soft tissue windows for the insertion of instruments and implants, result in minimal additional trauma to the soft tissues and fracture fragments. Without direct visualization, minimally invasive osteosynthesis (MIO) techniques are more demanding than open reduction and internal fixation; however, the biologic advantages are vast. As such, MIO techniques represent a fascinating new armamentarium in fracture fixation. PMID- 23040306 TI - Minimally invasive plate osteosynthesis: tibia and fibula. AB - Fractures of the tibia and fibula are common in dogs and cats and occur most commonly as a result of substantial trauma. Tibial fractures are often amenable to repair using the minimally invasive plate osteosynthesis (MIPO) technique because of the minimal soft tissue covering of the tibia and relative ease of indirect reduction and application of the implant system on the tibia. Treatment of tibial fractures by MIPO has been found to reduce surgical time, reduce the time for fracture healing, and decrease patient morbidity, while at the same time reducing complications compared with traditional open reduction and internal fixation. PMID- 23040307 TI - Minimally invasive repair of meta-bones. AB - Metacarpal and metatarsal fractures are common injuries in small animals and, in most of the cases, can be treated by minimally invasive techniques. Bone plates applied through epi-periosteal tunnels can stabilize meta-bones. Meta-bones III and IV are stabilized by dorsally applied plates. Meta-bones II and V are stabilized using plates applied medially and laterally. The scarcity of soft tissue coverage and the simple anatomy of meta-bones make these fractures amenable to fixation by using minimally invasive techniques. This practice should reduce morbidity and enhance healing time. PMID- 23040308 TI - Minimally invasive osteosynthesis technique for articular fractures. AB - Articular fractures require accurate reduction and rigid stabilization to decrease the chance of osteoarthritis and joint dysfunction. Articular fractures have been traditionally repaired by arthrotomy and internal fixation. Recently, minimally invasive techniques have been introduced to treat articular fractures, reducing patient morbidity and improving the accuracy of reduction. A variety of techniques, including distraction, radiographic imaging, and arthroscopy, are used with the minimally invasive osteosynthesis technique of articular fractures to achieve a successful repair and outcome. PMID- 23040309 TI - Minimally invasive repair of sacroiliac luxation in small animals. AB - Sacroiliac fracture-luxation is a common injury that is associated with ilial and acetabular fractures of the opposite hemipelvis. Sacroiliac fracture-luxation results in an unstable pelvis and potentially collapse of the pelvic canal. A minimally invasive technique for repair of sacroiliac-fracture luxation is a viable option for repair of this injury and has considerable benefits. Reduction and fixation using a minimally invasive technique provides results comparable to an open technique without the associated morbidity of an open technique. Exact screw placement is facilitated by fluoroscopy to make sure that the disk space or vertebral canal is not penetrated yet allows an adequate length of screw purchase in the sacrum. PMID- 23040311 TI - Minimally invasive fracture repair. PMID- 23040310 TI - Percutaneous plate arthrodesis in small animals. AB - Arthrodesis is an elective surgical procedure designed to eliminate articular pain and dysfunction by deliberate osseous fusion. A percutaneous approach can be used to perform tarsal and carpal arthrodeses in dogs and cats. Intraoperative imaging facilitates cartilage debridement performed with a burr inserted through stab incisions. The plate is introduced through an epiperiosteal tunnel and secured with screws inserted through the skin insertion incisions. Additional screws can be placed through separate stab incisions. The primary advantage of this technique is a decreased risk of soft tissue complications such as plantar necrosis or wound dehiscence. Preliminary clinical results are promising. PMID- 23040312 TI - A review of international trends in mercury management and available options for permanent or long-term mercury storage. AB - Although mercury (Hg) is a poisonous substance that has harmful effects on the environment and in humans, it is widely used in industrial facilities and in goods for daily use. Given the recent recognition of the risk posed by Hg exposure, the international society is trying to reduce the use of and demand for Hg by implementing more stringent regulations. Relevant policies and laws recommend alternatives to Hg or prohibit the use of Hg in certain applications. In addition, it is recommended that the amount of Hg used in Hg-containing products be reduced or that manufacturers discontinue such products. Disposal methods for elemental Hg include landfill, incineration, stabilization/solidification, and permanent storage. In this review, the major sources of Hg and expected amount of surplus Hg are described after summarizing international policies and plans for Hg management. In addition, a study on the establishment of proper storage facilities was performed by comparing existing Hg storage technologies with newly designed technologies for facilities where surplus Hg may be stored permanently. PMID- 23040314 TI - Biocatalytic oxidation of phenolic compounds by bovine methemoglobin in the presence of H2O2: quantitative structure-activity relationships. AB - In the present work, 13 p-substituted phenols with different functional groups have been systematically evaluated as metHb substrates by means of HPLC analysis. Non-hyperbolic kinetics were observed and Hill coefficients in the 0.37-1.00 range were obtained. The catalytic constants and the Hill coefficients were found to be quantitatively correlated with two independent variables: the energy level of the highest-occupied molecular orbital (E(HOMO)), which describes the intrinsic redox activity of the substrates and the pK(a)-values, which are related to substrate ionization. Oxygen evolution in the presence of each phenol derivative was also measured, and good correlation between peroxidase-like and catalase-like activities of the protein was observed. It is also shown that bovine metHb, although less active than other peroxidases, may represent a good alternative from an economical point of view for phenol removal processes. The equations here obtained may serve as a basis to further explore the potential use of metHb-mediated reactions in the treatment of phenols in wastewaters and to predict which phenol will be removed most efficiently under this treatment with satisfactory reliability. PMID- 23040313 TI - Mechanistic investigations of Se(VI) treatment in anoxic groundwater using granular iron and organic carbon: an EXAFS study. AB - The removal of aqueous Se(VI) from a simulated groundwater by granular iron (GI), organic carbon (OC), and a mixture of these reactive materials (GI-OC) was evaluated in laboratory batch experiments. The experiments were performed under anoxic conditions to simulate subsurface treatment. A total reaction time of 120 h (5 d) was chosen to investigate the rapid changes in speciation occurring over reaction times that are reasonable for permeable reactive barrier (PRB) systems. After 120 h, concentrations of Se decreased by >90% in the GI system, 15% in the OC system and 35% in the GI-OC mixture. Analysis of the materials after contact with Se using synchrotron-radiation based X-ray absorption spectroscopy (XAS) indicated the presence of Se(IV) and Se(0) on the margins of GI grains after 6h with evidence of SeO and SeSe bonding, whereas Se(VI) was not observed. After 72 h, Se(0) was the only form of Se present in the GI experiments. In the OC batches, the XAS analysis indicated binding consistent with sorption of aqueous Se(VI) onto the OC with only minor reduction to Se(IV) and Se(0) after 120 h. Selenium XAS spectra collected for the GI-OC mixture were consistent with spectra for Se(IV) and Se(0) on both the margins of GI grains and OC particles, suggesting that the presence of dissolved Fe may have mediated the reduction of sorbed Se(VI). The results suggest that the application of granular Fe is effective at inducing aqueous Se removal in anoxic conditions through reductive precipitation processes. PMID- 23040315 TI - Removal of FePO4 and Fe3(PO4)2 crystals on the surface of passive fillers in Fe0/GAC reactor using the acclimated bacteria. AB - As past studies presented, there is obvious defect that the fillers in the Fe(0)/GAC reactor begin to be passive after about 60 d continuous running, although the complicated, toxic and refractory ABS resin wastewater can be pretreated efficiently by the Fe(0)/GAC reactor. During the process, the Fe(3)(PO(4))(2) and FePO(4) crystals with high density in the passive film are formed by the reaction between PO(4)(3-) and Fe(2+)/Fe(3+). Meanwhile, they obstruct the formation of macroscopic galvanic cells between Fe(0) and GAC, which will lower the wastewater treatment efficiency of Fe(0)/GAC reactor. In this study, in order to remove the Fe(3)(PO(4))(2) and FePO(4) crystals on the surface of the passive fillers, the bacteria were acclimated in the passive Fe(0)/GAC reactor. According to the results, it can be concluded that the Fe(3)(PO(4))(2) and FePO(4) crystals with high density in the passive film could be decomposed or removed by the joint action between the typical propionic acid type fermentation bacteria and sulfate reducing bacteria (SRB), whereas the PO(4)(3-) ions from the decomposition of the Fe(3)(PO(4))(2) and FePO(4) crystals were released into aqueous solution which would be discharged from the passive Fe(0)/GAC reactor. Furthermore, the remained FeS and sulfur (S) in the passive film also can be decomposed or removed easily by the oxidation of the sulfur-oxidizing bacteria. This study provides some theoretical references for the further study of a cost effective bio-regeneration technology to solve the passive problems of the fillers in the zero-valent iron (ZVI) or Fe(0)/GAC reactor. PMID- 23040316 TI - Distinct structural alterations independently contributing to working memory deficits and symptomatology in paranoid schizophrenia. AB - Schizophrenia is considered a brain disease with a quite heterogeneous clinical presentation. Studies in schizophrenia have yielded a wide array of correlations between structural and functional brain changes and clinical and cognitive symptoms. Reductions of grey matter volume (GMV) in the prefrontal and temporal cortex have been described which are crucial for the development of positive and negative symptoms and impaired working memory (WM). Associations between GMV reduction and positive and negative symptoms as well as WM impairment were assessed in schizophrenia patients (symptomatology in 34, WM in 26) and compared to healthy controls (36 total, WM in 26). GMV was determined by voxel-based morphometry and its relation to positive and negative symptoms as well as WM performance was assessed. In schizophrenia patients, reductions of GMV were evident in anterior cingulate cortex, ventrolateral prefrontal cortex (VLPFC), superior temporal cortex, and insula. GMV reductions in the superior temporal gyrus (STG) were associated with positive symptom severity as well as WM impairment. Furthermore, the absolute GMV of VLPFC was strongly related to negative symptoms. These predicted WM performance as well as processing speed. The present results support the assumption of two distinct pathomechanisms responsible for impaired WM in schizophrenia: (1) GMV reductions in the VLPFC predict the severity of negative symptoms. Increased negative symptoms in turn are associated with a slowing down of processing speed and predict an impaired WM. (2) GMV reductions in the temporal and mediofrontal cortex are involved in the development of positive symptoms and impair WM performance, too. PMID- 23040317 TI - Towards a primate model of Gilles de la Tourette syndrome: anatomo-behavioural correlation of disorders induced by striatal dysfunction. AB - INTRODUCTION: Gilles de la Tourette syndrome (GTS) is characterized by abnormal movements (tics) often associated with behavioural disorders. Neuropathological data from GTS patients have suggested that aberrant activation of distinct striatal functional territories could produce a large spectrum of GTS symptoms. In a monkey model, injections of GABA-antagonist into the striatum enabled us to produce tic-like movements, hyperactivity and stereotyped behaviours. These effects had similarities with simple motor tics, hyperactivity and compulsive behaviours observed in GTS patients. In this study, we first aimed to identify the neuronal circuits involved in the different behavioural effects using anatomical antero/retrograde tracer in monkeys. We also compared the neuronal circuits thus obtained with the available neuro-anatomical data on GTS patients. METHODS: Using injections of axonal tracer into different functional parts of the striatum of eight monkeys, we identified cortical, thalamic and basal ganglia regions related to the expression of tic-like movements, hyperactivity and stereotyped behaviours induced in response to microinjection of GABA-antagonist. RESULTS: In this monkey model, different anatomical circuits involving distinct cortical and thalamic areas and sub-territories of the basal ganglia underpinned movement and behavioural disorders. Thus, tic-like movements were associated with neuronal labelling within the sensorimotor network, mostly in the medial and lateral premotor cortex and sensorimotor parts of the basal ganglia. Neuronal labelling in the prefrontal dorso-lateral cortex and associative territories of the basal ganglia was related to hyperactivity disorder and stereotyped behaviours were linked to the orbitofrontal cortex and limbic part of the basal ganglia. CONCLUSIONS: These results support the hypothesis that different behavioural effects could arise from distinct but inter-digitated neuronal circuits. As these behavioural disorders shared some similarities with simple motor tics, hyperactivity and compulsive behaviours observed in GTS patients, this model could be a good tool for future studies involving the modulation of neuronal circuits, such as deep brain stimulation. PMID- 23040318 TI - Congenital fistula from the left main coronary artery to the left atrium presenting with an acute myocardial infarction. PMID- 23040319 TI - Historical perspectives of The American Association for Thoracic Surgery: Herbert C. Maier (1908-1993). PMID- 23040320 TI - Video-assisted thoracoscopic surgical lobectomy with limited en bloc resection of superior sulcus tumor. PMID- 23040321 TI - Current results of open total arch replacement versus hybrid thoracic endovascular aortic repair for aortic arch aneurysm: a meta-analysis of comparative studies. PMID- 23040322 TI - Intraoperative transesophageal echocardiographic guidance for robotically assisted coronary sinus atrial septal defect repair. PMID- 23040323 TI - Mild postoperative acute kidney injury and outcomes after surgery for congenital heart disease. AB - OBJECTIVE: The effect of mild acute kidney injury (AKI) on outcomes after heart surgery in children is unclear. We sought to characterize the epidemiology of mild AKI associated with surgery for congenital heart disease (CHS-AKI) in children. METHODS: We conducted a single-center, retrospective cohort study of 693 patients (aged 6 days-18 years) who underwent heart surgery in 2009. The prevalence of AKI within 72 hours of surgery was determined using the 3-stage Acute Kidney Injury Network criteria. Factors associated with both hospital length of stay and AKI were used in a proportional hazards model to test the association of stage 1 AKI with hospital length of stay. RESULTS: The median age of the patients was 11.5 months (interquartile range, 3-54 months). Eighteen percent of the cohort had single ventricle heart disease and 54% underwent RACHS 1 category 3 or higher surgery. The prevalence of stages 1, 2, and 3 AKI in this cohort was 11% (n = 77), 3% (n = 19), and 1% (n = 8), respectively. Factors independently associated with AKI were prematurity, single ventricle physiology, peak postoperative lactic acid concentration, cardiopulmonary bypass time, and a history of heart surgery. Stage 2 or greater CHS-AKI was associated with hospital length of stay (adjusted hazard ratio [AHR], 0.53; 95% confidence interval [CI], 0.33-0.87; P = .01), but stage 1 was not (AHR, 0.85; 95% CI, 0.66-1.10; P = .22). CONCLUSIONS: AKI occurs after surgery for congenital heart disease but may be less common than previously reported. Although moderate to severe CHS-AKI is independently associated with prolonged recovery after heart surgery, mild disease does not appear to be. PMID- 23040324 TI - Left-sided robotic thoracic duct clipping for chylothorax. PMID- 23040325 TI - Epidemic trend of measles in Shandong Province, China, 1963-2005. AB - OBJECTIVES: Although measles is a vaccine-preventable infectious disease and the measles vaccine is safe and effective, it still poses a serious threat to the health of children and susceptible populations in China every year. This study aimed to investigate the epidemiological characteristics of measles in Shandong Province, China, including its spatial distribution pattern, in order to have a precise prediction of measles epidemics for better public health strategic planning and resource allocation. STUDY DESIGN: Longitudinal data study. METHODS: This study was based on the surveillance data set of measles from all 17 regions (cities) in Shandong Province between 1963 and 2005. Geographical Information Systems and piecewise exponential smoothing of logarithmic transformed data were applied with consideration of the spatial and temporal features of the data. The parameters of epidemic peaks were estimated by filtering off the drifting long term trends. RESULTS: Measles presented in almost all regions in Shandong Province with different spatial distribution over the 43-year study period. The incidence of measles was very high in the pre-vaccination period, with an average incidence of 617.61/100,000 population in 1963. With the implementation of vaccination, the average incidence of measles decreased to 3.63/100,000 population in 2005, the periodicity died out and the trend remained at a stable low level. Outbreaks have been reported recently. CONCLUSIONS: This study identified the effects of different strategies on the incidence of measles observed in Shandong, China, and will provide valuable information to assist local and national public health policy making. There are still some challenges to improve vaccination coverage and efficacy in order to eliminate measles in China. Strengthening surveillance will be essential in the framework of the anticipated global elimination campaign for measles. PMID- 23040326 TI - Influence of histology and biomarkers on first-line treatment of advanced non small cell lung cancer in routine care setting: baseline results of an observational study (FRAME). AB - FRAME is a prospective observational study of first-line treatments for advanced non-small cell lung cancer (NSCLC). This interim analysis examines the influence of histology and biomarkers on therapeutic decisions. Baseline characteristic, treatment, and diagnostic procedure data were collected on European patients with stage IIIB/IV NSCLC who were treated with any first-line platinum-based doublet, with or without targeted agents, in routine clinical practice. A total of 1567 patients were observed in 11 countries between April 2009 and February 2011. Patients were mostly non-Asian (96.4%), male (71.5%), smokers (84.4%) with stage IV NSCLC (76.6%) and a performance status of 0-1 (82.2%). Median age was 64 years (range, 33-87). First-line treatments were platinum-based combinations with pemetrexed (36.3%), gemcitabine (23.0%), vinorelbine (19.2%), taxanes (18.9%), or other (2.6%), with concurrent targeted agents in 8.4% of patients (mainly bevacizumab, 7.3%). Diagnosis was based on histology in 70.6%, cytology in 20.3%, and both in 9.1% of patients. The final diagnosis was nonsquamous in 72.2% (including 'not otherwise specified [NOS]' in 11.0%), squamous in 24.4%, and other in 3.4% of patients, with the most common reasons for NOS diagnosis being 'subtyping not technically possible' (42.9%) and 'not important for treatment decision' (40.5%). Only 1.1% (6 patients) in the pemetrexed cohort and 0.9% (1 patient) of patients who received bevacizumab had squamous cell carcinoma. At least one immunohistochemical (IHC) marker was used in 53.5% of patients (thyroid transcription factor-1 [TTF-1]: 47.5%, cytokeratin 7 [CK7]: 38.6%, cytokeratin 5/6 [CK5/6]: 17.9%, p63: 8.8%, cluster of differentiation 56 [CD56]: 4.2%, cytokeratin 14 [CK14]: 1.9%, and other: 24.2%). Testing for additional biomarkers was less common, with the most common being for epidermal growth factor receptor (EGFR) mutation status (26.0%). Physician-reported key factors influencing treatment choice were 'histopathological/cytological diagnosis' (77.4%), 'performance status' (63.2%), and 'age' (52.8%). Similar factors were identified using logistic regression models. Frequent histological testing was observed, likely resulting in few NOS diagnoses. In addition, IHC and predictive biomarkers were routinely assessed. Histology, performance status, and age were key factors influencing first-line treatment choice in the routine care of patients with advanced NSCLC. Clinical Trials. gov registry identifier number: NCT01067794. PMID- 23040327 TI - Transposable element small RNAs as regulators of gene expression. AB - Transposable elements (TEs) are a source of endogenous small RNAs in animals and plants. These TE-derived small RNAs have been traditionally treated as functionally distinct from gene-regulating small RNAs, such as miRNAs. Two recent reports in Drosophila and Arabidopsis have blurred the lines of this distinction. In both examples, epigenetically and developmentally regulated bursts in TE expression produce gene-regulating small RNAs. In the Drosophila early embryo, maternally deposited TE-derived PIWI-interacting small RNAs (piRNAs) play a role in regulating the nanos mRNA through small RNA binding sites in the nanos 3' untranslated region (UTR). In Arabidopsis, when Athila retrotransposons are epigenetically activated, their transcripts are processed into small RNAs, which directly target the 3'UTR of the genic oligouridylate binding protein 1B (UBP1b) mRNA. Based on these two examples, we suggest that other TE-derived small RNAs regulate additional genes and propose that, through small RNAs, the epigenetic status of TEs could widely influence the genic transcriptome. PMID- 23040328 TI - Labial ecthyma gangrenosum in an immunocompromised infant with leukemia: heightening awareness for the urologist. AB - Ecthyma gangrenosum (EG) is a cutaneous infection most commonly associated with Pseudomonas aeruginosa sepsis. EG generally occurs in immunocompromised hosts, such as patients with severe neutropenia. EG presents as erythematous, hemorrhagic, or necrotic macules or plaques, most commonly in the perineal or gluteal areas, but can occur elsewhere. EG is a dermatologic emergency in immunocompromised patients and should be included in the differential diagnosis when urologists are asked to evaluate perineal lesions. We describe the case of a highly immunocompromised infant with labial EG to highlight the importance of prompt clinical diagnosis and of multidisciplinary medical and surgical management. PMID- 23040329 TI - From the Naples emergency to the waste-to-energy miracle. How and why the Italian newspapers' coverage of the 2008 waste emergency in Naples influenced local public opinion's attitude towards a waste-to-energy plant in Turin. PMID- 23040331 TI - Assessment and management of delirium: a focus on hepatic encephalopathy. AB - This purpose of this article is to promote comprehensive assessment, differential evaluation and provision of care which optimizes benefit while minimizing burden. Delirium is a debilitating neuropsychiatric complication that is highly prevalent in palliative care. It is multifactorial and may be related to infection, disease progression, metabolic state or medication toxicity. There are three proposed sub types of delirium with the hypoactive/ hypoalert variant being most often underdiagnosed and undertreated. The inadequate management of all types of delirium is associated with increased personal and family distress, lengthier hospital stays, and escalating healthcare costs. This article reviews the assessment, diagnosis and treatment for delirium in general and hepatic encephalopathy in particular. A number of valid and reliable tools are discussed, as they assist in screening, symptom appraisal, diagnosis, and treatment planning. It is recognized that nurses are particularly well positioned to make bedside observations, to document changes over time, and to educate and support patients and their families. Searching for the etiology of delirium, developing individualized plans of care consistent with patient goals, and endorsing the benefit of consultation/referral are discussed as key roles for palliative care providers from all disciplines. New and novel therapies in the management of hepatic encephalopathy are discussed, as they expand treatment options for patients at all points along the trajectory of liver disease. PMID- 23040334 TI - [Not Available]. PMID- 23040336 TI - Current status of periodontal risk assessment. AB - Chronic periodontitis is a destructive chronic inflammatory disease of bacterial etiology. Mounting evidence confirms that not all patients are susceptible to inflammatory periodontal disease, and further, that the extent and severity of its clinical manifestation varies as a function of individual risk. Risk assessment models are needed to target treatment effectively. Contemporary risk assessment, as applied to periodontal disease, represents an innovative approach to managing periodontitis. The central intent of this paper is to review the current view of risk assessment as it relates to the diagnosis and management of chronic periodontitis, as well as to consider a number of such applications that can be incorporated into daily practice. PMID- 23040337 TI - State of the science: chronic periodontitis and systemic health. AB - CONTEXT: Inflammatory periodontal diseases exhibit an association with multiple systemic conditions. Currently, there is a lack of consensus among experts on the nature of these associations and confusion among health care providers and the public on how to interpret this rapidly growing body of science. This article overviews the current evidence linking periodontal diseases to diabetes, cardiovascular disease, osteoporosis, preterm low birth weight babies, respiratory diseases, and rheumatoid arthritis. EVIDENCE ACQUISITION: Evidence was taken from systematic reviews, clinical trials, and mechanistic studies retrieved in searches of the PubMed electronic database. The available data provide the basis for applied practical clinical recommendations. EVIDENCE SYNTHESIS: Evidence is summarized and critically reviewed from systematic reviews, primary clinical trials, and mechanistic studies CONCLUSIONS: Surrogate markers for chronic periodontitis, such as tooth loss, show relatively consistent but weak associations with multiple systemic conditions. Despite biological plausibility, shorter-term interventional trials have generally not supported unambiguous cause-and-effect relationships. Nevertheless, the effective treatment of periodontal infections is important to achieve oral health goals, as well as to reduce the systemic risks of chronic local inflammation and bacteremias. Inflammatory periodontal diseases exhibit an association with multiple systemic conditions. With pregnancy as a possible exception, the local and systemic effects of periodontal infections and inflammation are usually exerted for many years, typically among those who are middle-aged or older. It follows that numerous epidemiological associations linking chronic periodontitis to age associated and biologically complex conditions such as diabetes, cardiovascular disease, osteoporosis, respiratory diseases, rheumatoid arthritis, certain cancers, erectile dysfunction, kidney disease and dementia, have been reported. In the coming years, it seems likely that additional associations will be reported, despite adjustments for known genetic, behavioral and environmental confounders. Determining cause-and-effect mechanisms is more complicated, especially in circumstances where systemic effects may be subtle. Currently, however, there is a lack of consensus among experts on the nature of these associations and confusion among health care providers and the public on how to interpret this rapidly growing body of science. This article overviews the current evidence linking periodontal diseases to diabetes, cardiovascular disease, osteoporosis, preterm/low birth weight babies, respiratory diseases, and rheumatoid arthritis. PMID- 23040338 TI - Clinical applications of digital 2-D and 3-D radiography for the periodontist. AB - CONTEXT: Although there has been rapid development of imaging technology within dentistry, there has been limited evidence-based research documenting the benefits of digital radiography. EVIDENCE: We searched MEDLINE for relevant studies and review papers demonstrating clinical applications, limitations, and advancements within digital radiography. EVIDENCE SYNTHESIS: Two-dimensional (2 D) and 3-D digital radiography has become a powerful diagnostic tool for simple and complex procedures, including implant reconstruction. Recent advancements have reduced radiation exposure, increased resolution, and improved detection capabilities of complementary metal oxide semiconductor (CMOS) and cone-beam computed tomography (CBCT) sensors. The current review summarizes such advances and outlines advanced CBCT implant-planning techniques. CONCLUSIONS: While evidence-based research grows, the logistic, diagnostic, and planning improvements of 2-D and 3-D digital radiography are irrefutable with the potential to supplant conventional techniques. PMID- 23040339 TI - Local and systemic antimicrobial therapy in periodontics. AB - CONTEXT: This review aimed to update the current evidence on the efficacy of the adjunctive use of local and systemic antimicrobials in the treatment of periodontitis and to assess whether it might improve the clinical limitations and shortcomings of standard nonsurgical treatment in the management of periodontitis. EVIDENCE ACQUISITION: Relevant randomized clinical trials (RCT) with more than 3 months of follow-up, published from 2010 to 2012 for systemic antimicrobials and from 2008 to 2012 for local antimicrobials, were searched in Medline and critically analyzed. Scientific evidence evaluated in different systematic reviews and reviews presented at European and World Workshops were also included. Only adjunctive therapies were considered in the present review: articles comparing debridement alone or plus placebo, versus debridement plus systemic or local antimicrobials were included. EVIDENCE SYNTHESIS: Adjunctive systemic antimicrobials have been evaluated both in aggressive and chronic periodontitis: in aggressive periodontitis, amoxicillin and metronidazole have been extensively studied, reporting clinical and microbiological benefits; in chronic periodontitis, different products are under scrutiny, such as azithromycin. The clinical efficacy of local antimicrobials, although extensively demonstrated, is still surrounded by a constant debate on the cost-effectiveness evaluation and on its adequate indications. CONCLUSIONS: Despite the clinical efficacy of the adjunctive use of local and systemic antimicrobials, demonstrated in RCTs and in systematic reviews, there is a lack of evidence to support well defined clinical protocols, including products and dosages. PMID- 23040340 TI - Nonsurgical treatment of periodontitis. AB - CONTEXT: Scaling and root planing (SRP) is the gold standard treatment for most patients with chronic periodontitis. Nevertheless, in the last years, different therapeutic strategies have been proposed to improve the results of SRP and hence to avoid the need of periodontal surgical interventions in some patients with advanced periodontitis. They are based on modifications of standard therapies (such as enhancement of instrument tip designs), on development of new technologies (such as lasers), or development of alternative treatment protocols (eg, full-mouth disinfection). The purpose of this review is, therefore, to update the scientific evidence based on randomized clinical trials (RCT) evaluating these advanced nonsurgical therapies that have been published between January 2010 and March 2012. EVIDENCE ACQUISITION: RCTs published between January 2010 and March 2012 have been selected. Previous systematic reviews were used as a start point. Three distinct aspects were evaluated independently: the modification of conventional instruments, the advent of new technologies, and the development of new treatment protocols. EVIDENCE SYNTHESIS: Twenty-two publications were selected: 4 were related to modifications of standard therapies (new tip designs and local anesthetics), 14 to new technologies (new ultrasonic devices, air abrasive systems, endoscope and lasers), and 4 to new treatment protocols. CONCLUSIONS: These technological advances and the development of new protocols may improve patient-related outcomes and cost-effectiveness, although they have not shown significant differences in efficacy when compared with conventional SRP. PMID- 23040341 TI - Minimally invasive surgical techniques in periodontal regeneration. AB - A review of the current scientific literature was undertaken to evaluate the efficacy of minimally invasive periodontal regenerative surgery in the treatment of periodontal defects. The impact on clinical outcomes, surgical chair-time, side effects and patient morbidity were evaluated. An electronic search of PUBMED database from January 1987 to December 2011 was undertaken on dental journals using the key-word "minimally invasive surgery". Cohort studies, retrospective studies and randomized controlled clinical trials referring to treatment of periodontal defects with at least 6 months of follow-up were selected. Quality assessment of the selected studies was done through the Strength of Recommendation Taxonomy Grading (SORT) System. Ten studies (1 retrospective, 5 cohorts and 4 RCTs) were included. All the studies consistently support the efficacy of minimally invasive surgery in the treatment of periodontal defects in terms of clinical attachment level gain, probing pocket depth reduction and minimal gingival recession. Six studies reporting on side effects and patient morbidity consistently indicate very low levels of pain and discomfort during and after surgery resulting in a reduced intake of pain-killers and very limited interference with daily activities in the post-operative period. Minimally invasive surgery might be considered a true reality in the field of periodontal regeneration. The observed clinical improvements are consistently associated with very limited morbidity to the patient during the surgical procedure as well as in the post-operative period. Minimally invasive surgery, however, cannot be applied at all cases. A stepwise decisional algorithm should support clinicians in choosing the treatment approach. PMID- 23040342 TI - The development of guided regeneration: making the impossible possible and the unpredictable predictable. AB - Using their perspectives as early participants in guided regeneration development, the authors review the history of guided regeneration: from the precursive studies leading to the development of guided tissue regeneration for periodontium, through the development of guided bone regeneration for implants, to the long-term performance studies validating effectiveness. Landmark publications, original patents, and reviews are used to trace the therapy's development. By examining key studies and the scientists and clinicians who conducted them, the authors present clinical and biomaterials lessons learned and discuss developments that could shape the next guided regeneration developments. PMID- 23040343 TI - Protein and peptide-based therapeutics in periodontal regeneration. AB - Protein and peptide-based therapeutics provide a unique strategy for controlling highly specific and complex biologic actions that cannot be accomplished by simple devices or chemical compounds. This article reviews some of the key characteristics and summarizes the clinical effectiveness of protein and peptide based therapeutics targeting periodontal regeneration. EVIDENCE ACQUISITION: A literature search was conducted of randomized clinical trials and systematic reviews evaluating protein and peptide-based therapeutics for the regeneration of periodontal tissues of at least 6 months duration. Data sources included PubMed and Embase electronic databases, hand-searched journals, and the ClinicalTrials.gov registry. EVIDENCE SYNTHESIS: Commercially marketed protein and peptide-based therapeutics for periodontal regeneration provide gains in clinical attachment level and bone formation that are comparable or superior to other regenerative approaches. Results from several clinical trials indicate that protein and peptide-based therapies can accelerate repair and regeneration when compared with other treatments and that improvements in clinical parameters continue beyond 12 months. Protein and peptide-based therapies also exhibit the capacity to increase the predictability of treatment outcomes. CONCLUSIONS: Clinical and histologic studies support the effectiveness of protein- and peptide based therapeutics for periodontal regeneration. Emerging evidence suggests that the delivery devices/scaffolds play a critical role in determining the effectiveness of this class of therapeutics. PMID- 23040344 TI - Esthetic soft tissue management for teeth and implants. AB - CONTEXT: Can newly introduced graft materials be successfully used in soft tissue augmentation around teeth and dental implants? EVIDENCE ACQUISITION: An electronic search on the PubMed database for English articles published before March 31, 2012, was performed using the following key words: "root coverage," "soft tissue graft," "periodontal plastic surgery," "subepithelial connective graft (SCTG)," "acellular dermal matrix (ADM)," "guided tissue regeneration based root coverage (GTRC)," "recession defects," "mucogingival defects," "collagen matrix," "living cellular construct (LCC)," "mucograft," and "biologic agents." Literature featuring new soft tissue graft materials, such as ADM, collagen matrix, GTRC, and biologic agents, were included. EVIDENCE SYNTHESIS: Data showed (1) allogeneic grafts were comparable to SCTG in terms of mean complete root coverage (CRC), mean root coverage (RC), and mean amount of keratinized tissue (KT) gain; (2) xenogeneic collagen matrix was as comparable to SCTG in terms of mean amount of KT gain around teeth and dental implants but inferior in achieving RC; (3) GTRC was inferior to SCTG in terms of mean CRC and mean RC; (4) LCC was inferior to free gingival graft in terms of mean amount of KT gain but was superior in esthetics and patient satisfaction; and (5) adjunctive use of biologic agents did not exert a significant effect on mean CRC, mean RC, and mean amount of KT gain. CONCLUSIONS: Although these new materials do not surpass the gold standard (SCTG), they do provide improved patient satisfaction and esthetics, are available in abundance, and lead to reduced postoperative discomfort and surgical time. PMID- 23040345 TI - A review on alveolar ridge preservation following tooth extraction. AB - CONTEXT: The question that clinicians face is whether the use of bone replacement grafts and/or barrier membranes enhance their ability to provide for the future placement of a dental implant or to maximize ridge dimensions following the extraction of a tooth versus no additional treatments. EVIDENCE ACQUISITION: The evidence was obtained by search of Entrez PubMed and manual search of The International Journal of Oral and Maxillofacial Implants, The International Journal of Periodontics & Restorative Dentistry, Clinical Oral Implant Research, The Journal of Periodontology, The Journal of Clinical Periodontology, and The Compendium of Continuing Education in Dentistry. Key search words included Guided Bone Regeneration, Dental Extraction, Tooth Extraction, Bone Replacement Graft, Alveolar Ridge. The years of search included from January 2011 through February 2012. EVIDENCE SYNTHESIS: The recurring theme was that there was considerable heterogeneity to study designs, time periods, and methods of evaluation. This created great difficulty in trying to answer with good high-quality evidence questions about the techniques and materials to be used for maximizing regeneration at the time of tooth extraction or in which situations this ought to be used. CONCLUSIONS: There appears to be consensus from the reviewed literature supporting ridge preservation techniques as a whole. Multiple studies demonstrated less ridge resorption occurring when alveolar ridge preservation procedures were used versus the placement of no graft material in fresh alveolar sockets. The analysis did not show any grafting materials demonstrating a clear benefit over any others or that a barrier membrane is necessary. The evidence is also too premature about whether socket preservation efforts require primary closure. In the emerging area of growth factors, there is no high-quality evidence to either support or refute their use. BACKGROUND: Tooth extraction is one of the most widely performed procedures in dentistry today and it has been historically well documented that this procedure may induce significant dimensional changes of the alveolar ridge. The dilemma that clinicians face is how to manage tooth extractions to provide for the future placement of a dental implant or to maximize ridge dimensions for the fabrication of a fixed or removable prosthesis. If performed inadequately, the resulting deformity can be a considerable obstacle to the esthetic, phonetic, and functional results that both our patients and we clinicians expect at this current time. PMID- 23040346 TI - Maxillary sinus elevation by lateral window approach: evolution of technology and technique. AB - CONTEXT: The maxillary sinus elevation procedure has become an important pre prosthetic surgical procedure for the creation of bone volume in the edentulous posterior maxilla for the placement of dental implants. Research and clinical experience over the past 30 years has increased the predictability of this procedure as well as reduced patient morbidity. EVIDENCE ACQUISITION: Data on grafting materials and implant survival rates comes from 10 published evidence based reviews that include all relevant published data from 1980 to 2012. Supporting clinical material comes from the experience of the authors. EVIDENCE SYNTHESIS: The evidence-based reviews report and compare the implant survival rates utilizing various grafting materials, implant surfaces, and the use or non use of barrier membranes over the lateral window. Clinical studies report on complication rates utilizing piezoelectric surgery and compare them to complication rates with rotary instrumentation. CONCLUSIONS: The conclusions of all the evidence-based reviews indicate that the utilization of bone replacement grafts, rough-surfaced implants, and barrier membranes result in the most positive outcomes when considering implant survival. Further, the utilization of piezoelectric surgery, rather than rotary diamond burs, for lateral window preparation and membrane separation leads to a dramatic reduction in the occurrence of the intraoperative complications of bleeding and membrane perforation. PMID- 23040347 TI - An evidence-based protocol for immediate rehabilitation of the edentulous patient. AB - CONTEXT: A procedure using 4 dental fixtures with an immediate-loaded prosthesis for totally edentulous patients is the focus of an evidence-based analysis that uses modern methodologies to review an innovative clinical technique. The long term outcomes for this surgical and prosthetic treatment for previously or newly edentulated patients by clinical teams worldwide, as well as the author's clinical personal data in a referral-based private practice, are reported in this investigation. EVIDENCE ACQUISITION: An independent research dentist performed the literature review using terms that would identify articles commensurate with this article. The search years for keywords were limited to 2010 and 2011 because the purpose of the article was limited to current thinking and evidence on this specific technique. In this article, the author elected to restrict the literature search to journals that are commonly read and received in his clinical practice on a monthly basis. Because of the specific nature of this procedure, all historical references to the "all-on-4" procedure were also included in the database inquiries. EVIDENCE SYNTHESIS: The literature search revealed that the investigated technique has been reported worldwide by multiple authors using retrospective clinical analyses. In the maxillary jaw, the range of implants placed was 27 to 980 fixtures with 1 to 7 years of follow-up, demonstrating a cumulative implant success rate range of 92.5% to 100%. The mandibular arch demonstrated cumulative success rates of 93.8% to 100% with 1 to 10 years of follow-up with a range of 18 to 980 fixtures being placed. The investigator's own personal clinical statistics compared favorably with other clinical teams, with a total of 120 fixtures being placed in both jaws with 6 years of follow-up with a cumulative survival implant success rate of 100%. Continuous stability of the definitive final prosthesis was above 99% in the largest reported review and 100% for this author's private practice. CONCLUSION: Based on extensive reporting by multiple clinicians, the technique investigated is grounded in good bioengineering basic science, and demonstrates long-term clinical outcomes that can provide highly predictable long-term prosthetic stability for the edentulous patient. This highly focused critically appraised review of individual articles using 4 implants to support a fixed dental prosthesis provides clinicians and patients with a protocol that conservatively and immediately reduces the morbidity associated with the loss of teeth and removable prostheses traditional used to negate edentulism. PMID- 23040348 TI - Implant interactions with orthodontics. AB - Many situations arise in which orthodontic therapy in conjunction with implant modalities is beneficial, relevant or necessary. These situations might entail orthodontic treatment preparatory to the placement of an implant, such as in the site preparation for implant placement. Traditionally, this has been somewhat well understood, but there are certain guidelines that must be adhered to as well as diagnostic steps that must be followed. Provision of adequate space for implant placement is of paramount importance, but there is also the consideration of tissue manipulation and remodeling which orthodontic therapy can achieve very predictably and orthodontists should be well versed in harnessing and employing this modality of site preparation. In this way, hopeless teeth that are slated for extraction can still be utilized by orthodontic extraction to augment tissues, both hard and soft, thereby facilitating site development. On the corollary, and representing a significant shift in treatment sequencing, there are many situations in which orthodontic mechanotherapy can be simplified, expedited, and facilitated by the placement of an implant and utilization as an integral part of the mechanotherapy. Implants have proven to provide excellent anchorage, and have resulted in a new class of anchorage known as "absolute anchorage". Implants can be harnessed as anchors both in a direct and indirect sense, depending upon the dictates of the case. Further, this has led to the development of orthodontic miniscrew systems and techniques, which can have added features such as flexibility in location and placement, as well as ease of use and removal. As orthodontic appliances evolve, the advent of aligner therapy has become mainstream and well accepted, and many of the aforementioned combined treatment modalities can and should be incorporated into this relatively new treatment modality as well. PMID- 23040349 TI - Therapy of peri-implant diseases. Where is the evidence? AB - Peri-implant diseases are a common problem in dentistry today and no definitive treatment protocol exists for their treatment. The purpose of this review was to examine the evidence concerning the management of these diseases. The evidence provided suggests that peri-mucositis can be managed with use of mechanical nonsurgical therapy. Peri-implantitis does not respond to nonsurgical therapy. Various surgical methods have been proposed for management of peri-implantitis with some success; however, no single method can be promoted based on the current evidence. PMID- 23040350 TI - Dentin hypersensitivity. AB - CONTEXT: In dental practice, dentin hypersensitivity is a commonly presenting condition, which consists of sharp pain arising from exposed dentin in response to a varied assortment of stimuli; for example, dietary factors, such as an ice cold beverage, to even environmental considerations, such as the exposure to atmospheric air on a cold winter's day. The heterogeneity of this presentation, ranging from minor inconvenience to the patient, to a near incapacitating quality of-life disturbance, as well as the wide range of treatment strategies, as is discussed in this article, certainly pose a challenge to the clinician. EVIDENCE ACQUISITION: A search was performed on the MEDLINE database (2002 to present) by way of OVID. Search terms, such as dentin hypersensitivity and variants (eg, dentinal hypersensitivity, cervical dentin hypersensitivity) were used. Select references of review-type articles from the original search were sought. EVIDENCE SYNTHESIS: Efforts were made to identify multiple comparative clinical treatment studies that were of highest quality study design-specifically, randomized control trials. Efforts also were made to identify rigorous meta-analysis in the literature on the subject of dentin hypersensitivity treatment. CONCLUSION: Although multiple treatment approaches appear to provide clinical success in managing dentin hypersensitivity, the entire body of clinical research literature is far from being unequivocal in pronouncing one superior strategy. Equally as important is the clinician's consideration of the predisposing factors that initially localized the lesion on the tooth surface. Together, personalized preventive measures and therapies focusing on disrupting pathophysiology form the core of effective dentin hypersensitivity management. PMID- 23040351 TI - Antiresorptives and osteonecrosis of the jaw. AB - Osteonecrosis of the jaw (ONJ) is an uncommon condition noted to occur in patients who are receiving osteoclast-targeted antiresorptive therapy. The incidence of ONJ in patients taking oral antiresorptives for the management of osteoporosis is low (approximately 1:100,000), whereas it is higher (~10%) in patients taking intravenous bisphosphonates for the treatment of metastatic bone diseases. The etiology and pathophysiology of ONJ is unclear. No established preventive or treatment modalities are currently available. Although ONJ is a rare condition, it is imperative for oral care providers to have updated knowledge, as a large number of patients on antiresorptives are seeking oral care. In this comprehensive review, we focus on ONJ and bisphosphonate therapy and dissect the currently available evidence to establish a clinical approach to assess risk, preventive measures, and management of ONJ. PMID- 23040352 TI - A review of common oral pathology lesions, with a focus on periodontology and implantology. AB - The recognition, diagnosis, and management of common oral conditions requires knowledge of the lesion's clinical characteristics as well as the underlying pathology of the lesion. A thorough medical history, knowledge of normal anatomy, and a complete head and neck examination are necessary for the early recognition of oral lesions. Once any oral pathology is noted, clinical characteristics of size, location, texture, color, symptoms, and duration are necessary to arrive at a working plan and eventually a definitive diagnosis. In the end, the diagnosis often requires a biopsy or culture of the lesion. The clinical and histopathologic and/or mycologic correlation renders a final diagnosis leading to therapeutic options. A thorough knowledge of common oral lesions will allow the dentist/specialist to provide proper therapy or allow for referral to an oral medicine or oral surgery specialist. This review covers common infectious, reactive/traumatic, white, red, and bone lesions, as well as the vesiculobullous/desquamative gingival conditions, with a focus on periodontology and implantology. We cover the etiology, clinical features, histopathology, and treatment of each oral pathological condition. PMID- 23040353 TI - Oral manifestations of systemic autoimmune and inflammatory diseases: diagnosis and clinical management. AB - CONTEXT: Systemic autoimmune and inflammatory diseases often manifest oral lesions in their earliest stages, and early diagnosis, which may be spurred by a dental examination, is key for improved outcomes. After systemic diagnosis, oral lesions benefit from specialized care by dentists in collaboration with the medical team. This review aims to educate dental clinicians about the most relevant systemic autoimmune and inflammatory conditions with accompanying oral lesions, their implications for health, and management strategies supported by the biomedical literature and clinical experience. Ulcerative conditions including Behcet and Crohn diseases are discussed, along with rheumatic conditions including Sjogren syndrome, lupus erythematosus, and rheumatoid arthritis. EVIDENCE ACQUISITION: Evidence was accumulated through PubMed searches using pertinent keywords for each subsection. References were reviewed and original publications examined to verify the accuracy of the information. We focused on evidence included in current reviews and randomized trials. Recommendations were supported by multiple studies and consensus expert opinion. EVIDENCE SYNTHESIS: Disease phenotypes described and clinical recommendations were synthesized from best-quality evidence available for each disease. Efforts were made to describe evidence selection within each disease section. CONCLUSIONS: Dentists play an important role in the early detection and multidisciplinary medical management of complex autoimmune diseases. It is important to recognize prevalent medical and dental issues and special needs of patients with autoimmune conditions. The management of many inflammatory conditions is similar, and often begins with the use of topical steroids, analgesics, and antimicrobial treatments, in addition to careful attention to oral hygiene and appropriate fluoride usage. In this brief review, we aim to discuss the presentation/prevalence, diagnosis, and treatment of oral manifestations encountered in autoimmune, autoinflammatory and systemic chronic inflammatory diseases. Systemic autoimmune conditions are estimated to affect 5% to 8% of Americans.(1) Oral manifestations are encountered with high frequency, and are often the first clinical signs or symptoms of the general disease. Optimal management of complex autoimmune diseases requires a multidisciplinary medical team including dentists to care for lesions of the oral cavity. The dental practitioner may be asked to play a primary role in the diagnosis of such conditions and to participate with other health professionals working together to achieve effective clinical management. To aid in this process, we discuss in this article the current general knowledge of systemic autoimmune conditions that present with prevalent oral manifestations. The focus is on the diagnosis and management of the oral component of each disease. Importantly, whereas the etiology and pathogenesis and systemic clinical presentation may vary, presentation in the oral cavity is often similar and many conditions involve oral ulcerations. For this reason, we discuss the differential diagnosis and management of the most common oral ulcerations in a general section and subsequently address individual conditions that present with oral ulcerations. Similarly, treatment of various autoimmune/inflammatory oral conditions is often common and involves modulation or suppression of the immune response locally and/or systemically and will be therefore addressed in a common section as well as individually for each disease when unique treatment regimens are recommended. We present here our general treatment recommendations based on clinical experience and literature review; however, it is critical that good clinical judgment and specifics of an individual case should determine the appropriate dental/oral medicine intervention for a specific patient. PMID- 23040354 TI - Image analyzing method to evaluate in situ bioluminescence from an obligate anaerobe cultivated under various dissolved oxygen concentrations. AB - An image analyzing method was developed to evaluate in situ bioluminescence expression, without exposing the culture sample to the ambient oxygen atmosphere. Using this method, we investigated the effect of dissolved oxygen concentration on bioluminescence from an obligate anaerobe Bifidobacterium longum expressing bacterial luciferase which catalyzes an oxygen-requiring bioluminescent reaction. PMID- 23040355 TI - ENU mutagenesis identifies the first mouse mutants reproducing human beta thalassemia at the genomic level. AB - Forward genetic screens have been performed in many species to identify phenotypes in specific organ systems. We have undertaken a large-scale N-ethyl-N nitrosourea (ENU) mutagenesis screen to identify dominant mutations that perturb erythropoiesis in mice. Mutant mice that displayed an erythrocyte mean cell volume (MCV) greater than three standard deviations from the population mean were identified. Two of these lines, RBC13 and RBC14, displayed a hypochromic, microcytic anemia, accompanied by a marked reticulocytosis, splenomegaly and diminished red cell survival. Timed pregnancies from heterozygous intercrosses revealed that a quarter of the embryos displayed severe anemia and did not survive beyond embryonic day (E) 18.5, consistent with homozygous beta thalassemia. Genetic complementation studies with a beta-thalassemia mouse line reproduced the embryonic lethality in compound heterozygotes and a genomic custom capture array and massively parallel sequencing of the beta-globin locus identified the causative mutations. The RBC13 line displayed a nonsense mutation at codon 40 in exon 2 of the beta-major gene, invoking parallels with the common beta(0)39 thalassemia mutation seen in humans. The RBC14 line exhibited a mutation at the polyadenylation signal of the beta-major gene, exactly replicating a human beta-thalassemia mutation. The RBC13 and RBC14 lines are the first beta-thalassemia mouse models that reproduce human beta-thalassemia at the genomic level, and as such highlight the power of ENU mutagenesis screens in generating mouse models of human disease. PMID- 23040357 TI - A variety of diseases with a common trunk. PMID- 23040356 TI - BCL11B, FLT3, NOTCH1 and FBXW7 mutation status in T-cell acute lymphoblastic leukemia patients. AB - T-cell acute lymphoblastic leukemia is a heterogeneous malignancy originating from developing lymphocyte precursors likely due to mutations in genes regulating thymocyte differentiation. Here, we characterized mutation status of BCL11B and FLT3 genes, presumably involved in T-ALL, together with FBXW7 and NOTCH1 as known players in T-ALL in 65 pediatric T-cell acute lymphoblastic leukemia patients. We also aimed at the assessment of prognostic value of NOTCH1 and FBXW7 mutations in ALL-IC BFM 2002 protocol. FLT3 and BCL11B mutations were detected in 3% and 2% of patients, respectively. FBXW7 mutations were observed in 8% of patients, while NOTCH1 was mutated in 40%. No correlation was found between NOTCH1 and FBXW7 mutations and traditionally used clinical factors or molecular features. In total we have detected nine mutations, which have not been previously described by others. Eight of them were found in NOTCH1 and one in BCL11B gene. Observed frequencies of NOTCH1 and FBXW7 are in line with previous reports, thus confirming postulated participation of these two genes in T-ALL pathomechanism. Moreover, we report on mutation frequency of FLT3 and BCL11B, not extensively studied in T-ALL so far. Finally, we suggest a putative role of BLC11B as an oncogene in T-ALL pathogenesis. PMID- 23040358 TI - IgG4-related diseases. AB - Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a fascinating condition recognised as a systemic disease in 2003 [1,2]. The first link between autoimmunity affecting the pancreas, elevated serum IgG4 concentrations and large numbers of IgG4-positive plasma cells in pancreatic tissue was described only 2 years earlier [3]. Since then, many diseases that have long been viewed organ specific are now considered within the spectrum of IgG4-RD. Practically any organ can be affected, having in common a key pathological feature consisting in dense lymphocyte and plasma cell infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and often an elevated serum IgG4 concentration. While good clinical response to steroid therapy is observed, immunosuppressive or B-cell depleting therapy can be required. It is important to distinguish the IgG4-RD from traditional organ-specific autoimmune disease to guide therapy. PMID- 23040359 TI - Retroperitoneal fibrosis. AB - Retroperitoneal fibrosis is a rare syndrome hallmarked by a fibrosclerotic tissue in the retroperitoneum, often leading to encasement of the ureters. About two thirds of cases of retroperitoneal fibrosis are idiopathic, while the remaining cases are secondary to a variety of different causes, including drugs, tumors and infections. Idiopathic retroperitoneal fibrosis may be associated with abdominal aorta aneurysms, with vasculitis of the thoracic aorta and of epi-aortic vessels, or both. Most patients present with abdominal and/or low back pain. Serum markers of inflammation are usually, but not invariably, elevated. The diagnosis is secured by computed tomography or magnetic resonance imaging, which typically show an enhancing retroperitoneal mass medially dislodging the ureters. Positron emission tomography can be useful to document the extent and metabolic activity of the inflammatory process. Treatment rests on glucocorticoids with a tapering scheme variably combined with immunosuppressive agents. In cases of ureter obstruction, relief of obstruction by stenting or ureterolysis is required. PMID- 23040360 TI - Eosinophilic fasciitis (Shulman disease). AB - The eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by symmetrical and painful swelling with a progressive induration and thickening of the skin and soft tissues. The diagnosis of EF is often based on the association of characteristic skin or subcutaneous abnormalities and a thickened fascia with an inflammatory infiltration, mostly composed of lymphocytes and eosinophils. A peripheral eosinophilia is frequently present, but is not mandatory for the EF diagnosis. The diagnosis might be helped by a muscle magnetic resonance imaging which typically may evidence an increased signal intensity within the fascia and marked fascia enhancement after gadolinium administration at the acute phase of the disease. Differential diagnoses should be ruled out, including eosinophilia-myalgia syndrome (EMS) after L-tryprophane ingestion, hypereosinophilic syndromes (HES), systemic sclerosis, Churg-Strauss syndrome, and/or peripheral T cell lymphomas with cutaneous involvement. Due to the scarcity of the EF disease, there is no consensual therapeutic strategy. However, oral corticosteroids remain the mainstay treatment and may be associated to an immunosuppressive drug such as methotrexate in patients with morphea-like lesions or an unsatisfactory response to corticosteroids alone. PMID- 23040361 TI - Osteo-articular manifestations of amyloidosis. AB - Whether it is overload disease or mispleated proteins, amyloid is a great pretender. This is especially true for all of the osteo-articular manifestations of amyloid light chain (AL) amyloidosis, which may mimic rheumatoid arthritis, polymyalgia rheumatica, a myeloma or a bone tumour. To improve the prognosis, AL amyloidosis must be considered in front of atypical osteo-articular manifestations. Amyloidosis Ab2M of chronic haemodialysis (members' arthropathy and destructive spondylitis) is a specific entity that needs to be differentiated from other osteoarthropathies of chronic renal failure. It has become exceptional since the progress of haemodialysis. Finally transthyretin amyloidosis(ATTR) can be responsible for carpal tunnel syndrome(CTS) in its genetic and senile form. Although amyloidosis is rare, it represents one of the aetiologies of CSC, regardless of its type. In the specific context of haemodialysis, this poses no difficulty for the clinician. Yet AL amyloidosis must be considered more often, as must senile amyloidosis ATTR in the elderly. It seems obvious that the anatomo pathologic analysis with specific staining with Congo red - see typing - should be systematically performed in the case of surgical neurolysis. Amyloidosis is defined by the extracellular deposit of proteins which share common tinctorial affinities, a fibril aspect under electron microscopy and spatial conformation called beta pleated. Once regarded as a mere overload disease, it is currently considered as a disease of misfolded proteins. Indeed, it is certain that abnormalities of spatial pattern play an essential role in the responsibility for the pathology of many proteins whose amyloid fibre is the final common way. They involve both changes in the conformation of proteins and other major in vivo interactions between amyloid protein and the extracellular matrix. In most cases, amyloidosis represents the bulk of histopathological lesions and its pathogenic role is certain. In other cases, it is only one elementary lesion of the disease and its role is controversial. The amyloidosis responsible for osteo-articular manifestations are the AL immunoglobulin amyloidosis, the beta2-microglobulin amyloidosis in patients under haemodialysis and finally the amyloidosis of transthyretin (genetic and senile). Rheumatological manifestations of immunoglobulin amyloidosis are numerous and often indicative of the disease. Deposits affect joint and periarticular structures. The most common presentation is a progressively developing bilateral symmetric polyarthritis with negative immunology and absent specific structural abnormalities. Carpal tunnel syndrome (CTS) is very common and should suggest the aetiology. Other clinical representations are rarer as an isolated bone tumour (amyloidoma) or integrating systemic AL amyloidosis. beta 2-Microglobulin amyloidosis occurs in patients under chronic haemodialysis. It is responsible for CTS, arthralgia and above all a specific destructive spondyloarthropathy. The transthyretin amyloidosis also causes CTS. PMID- 23040362 TI - Biological treatment in adult-onset Still's disease. AB - Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder that is characterised by high spiking fever, arthritis or arthralgia, and evanescent rash. Many other systemic manifestations may occur. Pathogenesis of AOSD remains partially unknown but a major role has been recently attributed to pro inflammatory Th1 cytokines, including tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-6 and IL-18. Despite limited evidence, mainly based on observational studies and the extrapolation to AOSD of the results of a few controlled studies that have been conducted in children with systemic juvenile idiopathic arthritis, biological agents represent a major therapeutic advances for patients with AOSD refractory to conventional treatment or presenting life threatening manifestations. Both IL-1 and IL-6 blockade may be more effective than TNF-alpha blockers. Although debatable, therapeutic strategies are proposed. PMID- 23040363 TI - Nephrogenic systemic fibrosis: a systemic fibrosing disease resulting from gadolinium exposure. AB - Nephrogenic systemic fibrosis (NSF) is an iatrogenic fibrosing disorder that primarily affects individuals with chronic kidney disease (CKD) following exposure to gadolinium-based contrast agents (GBCAs) during imaging procedures. NSF is characterised by skin thickening, tethering and hyperpigmentation; flexion contractures of joints; and extracutaneous fibrosis. This article reviews the history, clinical manifestations, epidemiology, histopathology and pathophysiology of this disabling disease. PMID- 23040364 TI - Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives. AB - The term 'autoinflammatory disease' was first proposed in 1999 to encompass some of the distinct clinicopathologic features of a group of monogenic conditions, characterised by recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells. It was subsequently observed that several of these conditions were caused by mutations in proteins involved in the innate immune response, including, among others, components of the NLRP3 inflammasome, cytokine receptors (tumour necrosis factor receptor 1 (TNFR1)) and receptor antagonists (interleukin 1 receptor antagonist (IL-1RA)). More recently, additional mechanisms linking innate immune-mediated inflammation with a variety of cellular processes, including protein misfolding, oxidative stress and mitochondrial dysfunction, have been recognised to play a role in the pathogenesis of some monogenic autoinflammatory conditions, and also in more common diseases such as type 2 diabetes (T2D), previously perceived as a metabolic disorder, but reclassified as a chronic inflammatory condition. NLRP3 inflammasome activation is induced by islet amyloid polypeptides (IAPPs) in T2D and this condition may, in future, be more commonly treated with targeted anti cytokine therapies. Caspase 1 activation and release of IL-1beta/IL-1 family members is central to the pathogenesis of many autoinflammatory syndromes, as evidenced by the effectiveness of anti-IL-1 biologics in treating these disorders. However, many patients continue to experience symptoms of chronic inflammation, and it will be necessary to translate discoveries on the immunopathology of these conditions into more effective therapies. For example, in tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), the pathogenesis may vary with each mutation and therefore future approaches to treatment of individual patients will require a more tailored approach based on genetic and functional studies. PMID- 23040365 TI - Catastrophic antiphospholipid syndrome (CAPS). AB - Catastrophic antiphospholipid syndrome (CAPS) is a very severe variant of the classic APS, characterised by clinical evidence of multiple organ involvement developing over a very short period of time, histopathological evidence of multiple small vessel occlusions and laboratory confirmation of the presence of antiphospholipid antibodies (aPL), usually in high titre. Although patients with catastrophic APS represent less than 1% of all patients with APS, this is usually a life-threatening condition. In this article, we aimed to review the state-of the art about current knowledge in pathogenesis, clinical manifestations, diagnosis and treatment strategies in CAPS. PMID- 23040366 TI - Multicentric reticulohistiocytosis and fibroblastic rheumatism. AB - Multicentric reticulohistiocytosis (MRH) and fibroblastic rheumatism (FR) are uncommon disorders with similar joint and skin manifestations. They are usually included among the non-Langerhans histiocytoses, but recent insights drive some criticism. The diagnosis is often challenging and must be confirmed by the histological typical features. If the skin manifestations are missing, the arthritic complaints may be confused with those of other rheumatic disorders. In these cases, only a careful clinical and radiological evaluation leads to the correct diagnosis. The natural course of the diseases may rapidly develop into disabling manifestations, making an aggressive treatment strongly recommendable. There is emerging evidence that anti-tumour necrosis factor-alpha agents and bisphosphonates are promising drugs for MRH, while a course of methotrexate and steroids seems to be the best option for FR. Finally, the clinician should be aware that in many cases MRH, but not FR, is associated with a large number of systemic manifestations and with malignancy. This eventuality must be accurately ruled out. PMID- 23040367 TI - Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis. AB - BACKGROUND: Platelet-activating factor (PAF) is an important mediator and correlates with anaphylaxis severity. How well PAF correlates with severity relative to histamine or tryptase is not known. OBJECTIVE: To analyze the levels of PAF, histamine, and tryptase as a function of severity in patients with acute allergic reactions. METHODS: PAF, histamine, and tryptase levels were measured in blood samples collected from 23 healthy volunteers and from 41 patients during acute allergic reactions. Reactions were stratified by severity from grade 1 (least severe) to grade 3 (most severe). RESULTS: Among the 3 reaction grades, there were significant differences by ANOVA for PAF (P < .0001). The proportion of elevated PAF values increased across severity groups (P = .0009). Increased PAF levels were observed in 20%, 66.7%, and 100% of the patients with grades 1, 2, and 3 allergic reactions, respectively. While the proportion of elevated histamine values increased from 40% to 57% to 70% across grades 1, 2, and 3, respectively, these were not significantly different (P = .40). For tryptase, the proportion of elevated values increased monotonically from 0 in grade 1 to 4.8% in grade 2 to 60% in grade 3 (P = .0002). CONCLUSIONS: The PAF level was significantly elevated in proportion to the severity of acute allergic reactions. Whereas the PAF level was elevated in all patients with severe anaphylaxis, this was not true for either histamine or tryptase. Neither histamine nor tryptase showed as good correlations with severity scores as did PAF. These data are consistent with a pivotal role for PAF as a mediator of anaphylaxis. PMID- 23040368 TI - Pharmacoeconomic advantages of subcutaneous versus intravenous immunoglobulin treatment in a Canadian pediatric center. PMID- 23040369 TI - Comparison of MRI features and surgical outcome among the subtypes of focal cortical dysplasia. AB - PURPOSE: Focal cortical dysplasia (FCD) is the most common pathological diagnosis in patients who have undergone surgical treatment for intractable neocortical epilepsy. However, presurgical identification of MRI abnormalities in FCD patients remains difficult, and there are no highly sensitive imaging parameters available that can reliably differentiate among FCD subtypes. The purpose of our study was to investigate the surgical outcome in FCD patients with identifiable MRI abnormalities and to evaluate the prognostic role of the various MRI features and the characteristics of FCD pathology. METHODS: We retrospectively recruited epilepsy patients who had undergone surgical treatment for refractory epilepsy with focal MRI abnormalities and the pathological diagnosis of FCD. We evaluated the surgical outcome according to the pathological subtypes, and studied the prognostic roles of various MRI features. We used recently proposed three-tiered FCD classification system which included FCD type III when FCD occurs in association with other potentially epileptogenic pathologies. RESULTS: A total of 69 patients were included, and 68.1% of patients became seizure free. Patients with FCD type III had a lower chance for achieving seizure freedom (7/15) than in patients with isolated FCD (FCD types I and II) (40/54, p=0.044). Cortical thickness and blurring of gray-white matter junction were more common in isolated FCD than in FCD type III, but most MRI features failed to differentiate between FCD types I and II, and only the transmantle sign was specific for FCD type II. We failed to find a prognostic value of specific MRI abnormalities of prognostic value in terms of post-epilepsy surgery outcome in FCD patients. CONCLUSIONS: Our study showed that patients with FCD III have poor surgical outcome. Typical MRI features of isolated FCD such as cortical thickness and blurring of gray-white matter junction were less common in FCD type III and only transmantle sign was helpful in differentiating between FCD types I and II. PMID- 23040370 TI - Catastrophising and normalising in patient's accounts of their seizure experiences. AB - PURPOSE: To extend our previous research demonstrating that linguistic/interactional features in patients' talk can assist the challenging differential diagnosis of epilepsy and psychogenic nonepileptic seizures (PNES) by exploring the differential diagnostic potential of references to non co present persons (third parties). METHOD: Initial encounters were recorded between 20 seizure patients (13 with PNES, seven with epilepsy) who were subsequently diagnosed by the recording of typical seizures with video-EEG. An analyst blinded to the medical diagnoses coded and analysed transcripts. RESULTS: There were no significant differences between the two diagnostic groups in terms of the total number of third party references or references made spontaneously by patients without prompting from the doctor. However, patients with PNES made significantly more prompted references to third parties (p=0.022). 'Castrophising' third party references were made in 12/13 (92.3%) of encounters with PNES patients and 1/7 (14.3%) of encounters with epilepsy patients (p=0.001, OR 72, 95% CI=3.8-1361.9). Normalising references were identified in 2/13 (15.4%) of encounters in the PNES and 6/7 (85.7%) of encounters in the epilepsy groups (p=0.004, OR 33, 95% CI=2.5 443.6). CONCLUSION: There are significant differences in how patients with epilepsy or patients with PNES refer to third parties. Patients with PNES are more likely to be prompted to tell doctors what others have told them about their seizures. Patients using third party references to catastrophise their seizure experiences are more likely to have PNES, whilst patients who use third party references to normalise their life with seizures are more likely to have epilepsy. PMID- 23040371 TI - Direct electron transfer with enzymes on nanofiliform titanium oxide films with electron-transport ability. AB - Direct electron transfer (DET) from biomolecules to electrode is a process without electron-mediators, thus superior selectivity and sensitivity is expected in order to monitor electron transfer between electrode and biomolecules without any mediator interference. However, DET is difficult because a redox center which is an electron active center of proteins such as enzymes is buried deep. So, a unique electrode nanostructure to reach the redox center is a critical factor. Here we have systematically investigated terms for DET using various nanofiliformed electrode morphologies and enzyme concentrations. It is pointed out that the reaction site is below 100 nm, the ration amounts of adsorbed enzyme per surface area are below 1.0 are contributed to the DET. As a great application, we have developed a biosensor monitoring the hydrogen peroxide (H(2)O(2)) detecting capability from peroxidase directly. For the fabricated HRP/nTOF/Ti-electrodes observed the catalytic current value was linear according to the increase in the concentration of H(2)O(2) up to 100 MUM, which indicates a good potential for an H(2)O(2) biosensor. PMID- 23040372 TI - A method for fluorescence sensing of adenosine and alkaline phosphatase based on the inhibition of S-adenosylhomocysteine hydrolase activity. AB - This study presents a simple fluorescent method for the sensitive and selective detection of adenosine, based on adenosine inhibiting S-adenosylhomocysteine hydrolase (SAHH)-catalyzed hydrolysis of S-adenosylhomocysteine (SAH). Because of homocysteine (HCys) belonging to the thiol and amino groups, 2,3 naphthalenedicarboxaldehyde (NDA) can selectively react with HCys to form a 6 membered ring without the addition of nucleophiles. Electrospray ionization mass spectrometry was used to obtain the molecular mass of the resulting products, which is helpful in proposing the possible reaction mechanism between NDA and HCys. When SAHH catalyzed the cleavage of SAH, the generated HCys reacted with NDA to form highly fluorescent products with a quantum yield of 34%. The addition of adenosine to an SAH solution resulted in the inhibition of SAHH activity. Consequently, HCys production decreased with an increase in adenosine concentration. Under optimal NDA derivatization conditions, the SAHH-based probe showed a limit of detection (at a signal-to-noise ratio of 3) for adenosine of 0.3 MUM. Selectivity of the SAHH-based probe is more than 100-fold for adenosine over any adenosine analog. We validated the applicability of this probe by determining adenosine concentration in urine samples. The SAHH-based probe was also used to evaluate the activity and inhibition of alkaline phosphatase, which can convert adenosine monophosphate to adenosine. PMID- 23040373 TI - Response to DeGroff. PMID- 23040374 TI - Painful polyneuropathy associated with restless legs syndrome. Clinical features and sensory profile. AB - BACKGROUND: The association of restless legs syndrome (RLS) with polyneuropathy, and its prevalence, have been evaluated differently throughout various studies. As subtypes of polyneuropathy characterized by neuropathic pain seem to be preferentially associated with RLS, we intended to investigate the prevalence and the features of RLS occurring with painful neuropathy, and to define whether there is a specific sensory phenotype. METHODS: We prospectively investigated 58 consecutive patients with distal symmetric polyneuropathy and neuropathic pain or dysesthesia, using a bedside protocol for sensory assessment. RLS was diagnosed with an interview assessing the International RLS Study Group diagnostic criteria. RESULTS: Overall, RLS was reported by 21 patients (36.2%), but it was occurring at the time of the evaluation in 12 patients (20.7%), significantly more than in controls. RLS was chronic in nine patients and remitting intermittent in 12 patients. No difference was demonstrated between patients with or without RLS. Comparing patients with chronic RLS and remitting-intermittent RLS, the latter had more severe electrophysiological changes, whereas hyperalgesia, suggesting central sensitization, was significantly more frequent in chronic RLS patients. CONCLUSIONS: RLS is frequently associated with painful polyneuropathy, in keeping with the hypothesis that its occurrence is favored by small fiber involvement. It represents a heterogeneous entity, differentiated in chronic and remitting-intermittent subtypes, possibly conditioned by indolent or aggressive neuropathy course and phenomena of central sensitisation. PMID- 23040375 TI - Pharyngeal electrical stimulation for dysphagia associated with multiple sclerosis: a pilot study. AB - OBJECTIVE: Treatment options for dysphagia associated with multiple sclerosis (MS) are currently limited. In this study we investigated whether intraluminal electrical pharyngeal stimulation facilitates swallowing recovery in dysphagic MS patients. PATIENTS AND METHODS: Twenty dysphagic MS patients were randomized to receive 5 Hz "real" pharyngeal stimulation (10 patients) for 10 min or "sham" pharyngeal stimulation for 10 min (10 patients). Patients were evaluated by videofluoroscopic, and electromyographic examinations, and by the Penetration/Aspiration Scale (PAS) performed before (T0) and immediately after the last session of 5 consecutive days of electrical pharyngeal stimulation (T1), and then after two (T2), and four (T3) weeks of 5 consecutive days of pharyngeal electrical stimulation. RESULTS: Patients who received "real" stimulation showed a significant improvement in all the swallowing outcome measures as compared with those receiving "sham" stimulation. CONCLUSIONS: No specific treatment for oro pharyngeal dysphagia related to MS has been described to date. Our preliminary findings suggest a potential benefit of intraluminal electrical pharyngeal stimulation for the treatment of dysphagia caused by MS. PMID- 23040377 TI - [Not Available]. PMID- 23040376 TI - [Cranial subdural hygromas secondary to epidural anesthesia]. PMID- 23040378 TI - Transcatheter closure of patent ductus arteriosus using the amplatzer duct occluder in infants under one year of age. AB - INTRODUCTION AND OBJECTIVES: Percutaneous closure of patent ductus arteriosus (PDA) is a well-established technique. We evaluated the usefulness of the Amplatzer duct occluder for the percutaneous closure of patent ductus arteriosus in 29 children under 1 year of age. METHODS: The patients' mean age was 8.9+/-2.8 months and their mean weight was 6.4+/-1.5kg. In addition, 24.1% of patients were aged 6 months or less and 17.2% weighed 5kg or less. All completed follow-up (0.5 36 months). RESULTS: The minimum PDA diameter was 3.16+/-1.24 mm. The device was implanted successfully in 26 patients (89.6%). Failures were due to either the device migrating to the descending aorta, persistent moderate leakage, or to difficulty in the advancement of the device. No deaths were associated with the procedure. Three major complications occurred in two patients (10.3%). Aortography showed initial total occlusion in 65.5% of patients. At 3-month follow-up, total occlusion was observed in 96.1% of patients. Ultimately, closure was achieved successfully in 25 of the 29 patients (86.2%). During follow-up, four patients exhibited mild left pulmonary artery stenosis and one exhibited mild stenosis of the descending aorta. CONCLUSIONS: In children under 1 year of age, percutaneous closure of patent ductus arteriosus using an Amplatzer occluder was a safe and effective procedure. It is possible that improvements in the design of the occluder could decrease the complication rate. PMID- 23040379 TI - [Not Available]. PMID- 23040380 TI - [Not Available]. PMID- 23040381 TI - [Not Available]. PMID- 23040383 TI - [Not Available]. PMID- 23040382 TI - [Not Available]. PMID- 23040384 TI - Heterologous osteosarcomatous and rhabdomyosarcomatous elements in dedifferentiated solitary fibrous tumor: further support for the concept of dedifferentiation in solitary fibrous tumor. AB - Dedifferentiation within solitary fibrous tumor is a rare and only recently characterized phenomenon. It differs from malignant solitary fibrous tumor in that there is abrupt transition between classical solitary fibrous tumor and the dedifferentiated component. The latter is a high-grade sarcoma, which can exhibit a number of morphologies, but heterologous differentiation is exceptionally rare. We report a case of dedifferentiated solitary fibrous tumor, with heterologous osteosarcomatous and rhabdomyosarcomatous elements, arising in the deep soft tissue of the thigh of a 59-year-old man. This comprised morphologically and immunohistochemically typical solitary fibrous tumor, juxtaposed to pleomorphic, high-grade malignant neoplasm of 2 distinct lineages. The sharp demarcation between well-differentiated and dedifferentiated components is typical of the dedifferentiation seen in other mesenchymal neoplasms. This expands the range of histopathology of this rare, newly characterized type of malignant progression in solitary fibrous tumor. PMID- 23040385 TI - Synthesis and characterization of ampelopsin glucosides using dextransucrase from Leuconostoc mesenteroides B-1299CB4: glucosylation enhancing physicochemical properties. AB - Novel ampelopsin glucosides (AMPLS-Gs) were enzymatically synthesized and purified using a Sephadex LH-20 column. Each structure of the purified AMPLS-Gs was determined by nuclear magnetic resonance, and the ionic product of AMPLS-G1 was observed at m/z 505 (C21H22O13.Na)+ using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AMPLS-G1 was identified as ampelopsin-4'-O-alpha-D-glucopyranoside. The optimum condition for AMPLS-G1, determined using response surface methodology, was 70 mM ampelopsin, 150 mM sucrose, and 1 U/mL dextransucrase, which resulted in an AMPLS-G1 yield of 34 g/L. The purified AMPLS-G1 displayed 89-fold increased water solubility and 14.5 fold browning resistance compared to those of AMPLS and competitive inhibition against tyrosinase with a K(i) value of 40.16 MUM. This value was smaller than that of AMPLS (K(i)=62.56 MUM) and much smaller than that of beta-arbutin (K(i)=514.84 MUM), a commercial active ingredient of whitening cosmetics. These results indicate the potential of AMPLS and AMPLS-G1 as superior ingredients for functional cosmetics. PMID- 23040386 TI - Characterization of a novel thermostable beta-glucosidase from a metagenomic library of termite gut. AB - A novel beta-glucosidase-encoding gene, bgl-gs1, which was identified from a positive fosmid clone in a metagenomic library of the gut of Globitermes brachycerastes, [corrected] encodes a 455 amino acid polypeptide that contains a catalytic domain belonging to glycoside hydrolase family 1 (GH1). It was expressed in Escherichia coli BL21 (DE3) and the expression product showed a molecular mass of ~51.7 kDa by SDS-PAGE. The optimal temperature and pH for the activity of the purified recombinant enzyme Bgl-gs1 with p-nitrophenyl-beta-D glucoside (pNPG) were 90 degrees C and 6.0, respectively. The specific activities of Bgl-gs1 on pNPG and salicin were 110 and 14U/mg of protein, respectively, and its K(m) values were 0.18 and 2.59 mM, respectively. The residual activity of Bgl gs1 was maintained above 70% after the recombinant enzyme was incubated at 75 degrees C and pH 6.0 for 2h, and its half-life at 90 degrees C was approximately 1h in the presence of 4mM pNPG. Bgl-gs1 showed synergistic effect with either a crude enzyme mixture of the fungal strain Trichoderma reesei Rut-C30 or a fusion protein (TcE1) created from the cellobiohydrolase cbh1 gene of T. reesei and endoglucanase from Acidothermus cellulolyticus; 87 and 137% increases in hydrolytic efficiency were noted on microcrystalline cellulose, respectively. These results suggest that the thermostable beta-glucosidase Bgl-gs1 is a likely candidate for industrial applications. PMID- 23040388 TI - Characterization and PCR application of a new high-fidelity DNA polymerase from Thermococcus waiotapuensis. AB - The family B DNA polymerase gene from the euryarchaeon Thermococcus waiotapuensis (Twa) contains an open reading frame of 4404 bases that encodes 1467 amino acid residues. The gene is split by two intein-coding sequences that forms a continuous open reading frame with the three polymerase exteins. Twa DNA polymerase genes with (whole gene) and without (genetically intein-spliced) inteins were expressed in Escherichia coli Rosetta(DE3)pLysS. The inteins of the expressed whole gene were easily spliced during purification. The molecular mass of the purified Twa DNA polymerase was about 90 kDa, as estimated by SDS-PAGE. The optimal pH for Twa DNA polymerase activity was 6.0 and the optimal temperature was 75 degrees C. The enzyme was activated by magnesium ions. The half-life of the enzyme at 99 degrees C was about 4 h. The optimal buffer for PCR with Twa DNA polymerase was 50 mM Tris-HCl (pH 8.2), 2.0 mM MgCl2, 30 mM KCl, 2.0 mM (NH4)2SO4, 0.01% Triton X-100, and 0.005% BSA. The PCR fidelity of Twa DNA polymerase was higher than Pfu, KOD and Vent DNA polymerases. A ratio of 15:1 Taq:Twa DNA polymerase efficiently facilitated long-range PCR. PMID- 23040387 TI - Fluorescence monitoring of trypsin adsorption in layer-by-layer membrane systems. AB - A combined fluorescence analysis, involving the use of steady-state fluorescence and fluorescence anisotropy was used, allowing eliciting information about the structural changes induced on trypsin after exposure to membrane surfaces with diverse chemistry, designed through a layer-by-layer methodology. Using this monitoring strategy it was possible to understand the influence of the surface chemistry on the structural characteristics of the attached proteins and how they relate to changes of their activity resulting from the adsorption process. This knowledge may be used to direct the development of surfaces with suitable chemistry, leading enzymatic-based processes with improved performance. The results obtained show clearly that trypsin exposed to different membrane surfaces, changes its conformation, either if it adsorbs to the membrane or if it remains in solution. A significant loss of enzymatic activity was observed upon the adsorption process, for the adsorbed and non-adsorbed protein. This loss of the trypsin activity was correlated with the presence of molecular unfolding events that mediate trypsin-membrane surface interactions and the decrease of the molecular mobility of the adsorbed trypsin, which was shown to be dependent on the chemical characteristics of the membrane surface. Changes on the selectivity of the adsorbed trypsin were also observed, and may be ruled by the strength of the enzyme-surface interactions established. PMID- 23040389 TI - Characterization and PCR applications of dUTPase from the hyperthermophilic euryarchaeon Thermococcus pacificus. AB - We cloned and sequenced the gene encoding Thermococcus pacificus dUTPase (Tpa dUTPase). The Tpa dUTPase gene consists of 471 bp and encodes a 156-amino acid protein. The deduced amino acid sequence of Tpa dUTPase has high sequence similarity with other archaeal dUTPases. The Tpa dUTPase had an 18-kDa major protein band consistent with the 17,801 Da molecular mass calculated based on the amino acid sequence. The specific activity of Tpa dUTPase on dUTP at 85 degrees C was 90,909 U/mg. For Tpa dUTPase activity, we determined an optimum pH of 8.5 and temperature of 85 degrees C. Magnesium ions strongly induced activity, with an optimum concentration of 0.75 mM. The half-life of the enzyme at 94 degrees C was about 7 h. The specific activity of the Tpa dUTPase on dUTP was about 10-20 fold higher than that of Tpa dUTPase on dCTP. Tpa dUTPase enhanced the PCR amplification efficiency of long targets when Pfu and Vent DNA polymerases were used. PMID- 23040390 TI - Recovery of purified lactonic sophorolipids by spontaneous crystallization during the fermentation of sugarcane molasses with Candida albicans O-13-1. AB - Numerous studies have focused on how to obtain high yield of sophorolipids using low-cost materials as substrates, and there has been various work on the experimental methods for purifying lactonic sophorolipids. These studies have not yet obtained satisfied results in combining a low-cost fermentation process and the purification of lactonic sophorolipids. This study establishes a fed-batch fermentation process of purifying sophorolipids from Candida albicans O-13-1 using low-cost sugarcane molasses as the substrate. In the optimized conditions of this research, using sugarcane molasses as a substrate and product synthesis based on the temperature stage-controlled fermentation, our result indicates that sophorolipids production could reach 108.7 g/L. More importantly, lactonic sophorolipids can crystallize and precipitate during our established fermentation process. The structures and content of sophorolipids separated from the fermentation broth and sophorolipids crystallized in the fermentation broth were analyzed by a scanning electron microscope (SEM) and liquid chromatography-mass spectrometry (LC-MS). The fermentation process produced 90.5 g/L crystallized lactonic sophorolipids with 90.51% purity. This is an energy-saving and low-cost method to obtain such pure lactonic sophorolipids. PMID- 23040391 TI - Evaluation of structure and hydrolysis activity of Candida rugosa Lip7 in presence of sub-/super-critical CO2. AB - This work aimed to assess the effect of sub-/super-critical CO2 on the structure and activity of Candida rugosa Lip7 (CRL7) in its solution form. The structure was examined by SDS-PAGE gel electrophoresis, circular dichroism (CD) and fluorescence spectra photometry. Results revealed that the primary structure remained intact after sub-/super-critical CO2 treatment, and the secondary structure altered at the pressure of 10 MPa and temperature 40 degrees C for 30 min incubation, but it was reflex to its native form with increasing incubation time up to 150 min under 10 MPa and 40 degrees C. Meanwhile, the tertiary structure via fluorescence spectra analysis showed that the intensity of the maximal emission wavelength at 338 nm decreased under the conditions of 10 MPa and 40 degrees C for 150 min. Furthermore, the residue hydrolysis activity and kinetics constants (V(max) and K(m)) of CRL7 treated with sub-/super-critical CO2 were also investigated. In cases of 6 MPa and 35 degrees C, or 10 MPa and 40 degrees C for 30 min, activity variance of CRL7 was maybe caused by its secondary structure alteration. But in case of 10 MPa and 40 degrees C for 150 min, the tertiary structure change was perhaps responsibility for CRL7 activity enhancement. PMID- 23040392 TI - Crystal structure of a lactosucrose-producing enzyme, Arthrobacter sp. K-1 beta fructofuranosidase. AB - Arthrobacter sp. K-1 beta-fructofuranosidase (ArFFase), a glycoside hydrolase family 68 enzyme, catalyzes the hydrolysis and transfructosylation of sucrose. ArFFase is useful for producing a sweetener, lactosucrose (4(G)-beta-D galactosylsucrose). The primary structure of ArFFase is homologous to those of levansucrases, although ArFFase catalyzes mostly hydrolysis when incubated with sucrose alone, even at high concentration. Here, we determined the crystal structure of ArFFase in unliganded form and complexed with fructose. ArFFase consisted of a five-bladed beta-propeller fold as observed in levansucrases. The structure of ArFFase was most similar to that of Gluconacetobacter diazotrophicus levansucrase (GdLev). The structure of the catalytic cleft of ArFFase was also highly homologous to that of GdLev. However, two amino acid residues, Tyr232 and Pro442 in ArFFase, were not conserved between them. A tunnel observed at the bottom of the catalytic cleft of ArFFase may serve as a water drain or its reservoir. PMID- 23040393 TI - Cellulosic ethanol production by combination of cellulase-displaying yeast cells. AB - As an effort to find suitable endoglucanases to generate cellulolytic yeast strains, two fungal endoglucanases, Thermoascus aurantiacus EGI and Trichoderma reesei EGII, and two bacterial endoglucanases, Clostridium thermocellum CelA and CelD, were expressed on the yeast surface, and their surface expression levels, pH- and temperature-dependent enzyme activities, and substrate specificities were analyzed. T. aurantiacus EGI showed similar patterns of pH- and temperature dependent activities to those of T. reesei EGII which has been widely used due to its high enzyme activity. Although EGII showed higher carboxymethyl cellulose (CMC) degradation activity than EGI, EGI showed better activity toward phosphoric acid swollen cellulose (PASC). For ethanol production from PASC, we combined three types of yeast cells, each displaying T. aurantiacus EGI, T. reesei CBHII (exoglucanase) and Aspergillus aculeatus BGLI (beta-glucosidase), instead of co expressing these enzymes in a single cell. In this system, ethanol production can be easily optimized by adjusting the combination ratio of each cell type. A mixture of cells with the optimized EGI:CBHII:BGLI ratio of 6:2:1 produced 1.3 fold more ethanol (2.1g/l) than cells composed of an equal amount of each cell type, suggesting the usefulness of this system for cellulosic ethanol production. PMID- 23040394 TI - Boronate affinity chromatography of cells and biomacromolecules using cryogel matrices. AB - Boronate affinity chromatography involves the interaction between cis-diol containing molecules and the hydroxyl group of boronate. Boronate affinity based cryogel chromatography matrices have been developed and the ligands were immobilized by two methods i.e., grafting of the boronate ligand on to the matrix and by copolymerization of monomer containing boronate with other co-monomer. The boronate grafted cryogel column was used to capture adherent and non-adherent cells and the captured cells were recovered at different fructose concentrations as an eluting agent, in chromatography mode. It was found that the adherent cells could be recovered at relatively higher fructose concentration (0.5M) than non adherent cells which could be recovered by using low fructose concentration (0.1M). This might be due to the difference in the content of glycoprotein in adherent and non-adherent cells. In this way a new separation method can be devised for the fractionation of adherent and non-adherent cells. In another study, a copolymerized boronate cryogel column was developed for the separation of RNA from the bacterial crude extract without any pre-processing. RNA molecules were specifically retained in the cryogel column due to interaction between 2,3' diol group of ribose sugar in RNA and the hydroxyl group of boronate. The DNA molecules were passed through the column uninteracted due to absence of 2' hydroxyl group. Later, bound RNA molecules were recovered from the boronate affinity cryogel column. PMID- 23040395 TI - Biosorption of uranium by magnetically modified Rhodotorula glutinis. AB - Adsorption of uranium from aqueous solution onto the magnetically modified yeast cell, Rhodotorula glutinis, was investigated in a batch system. Factors influencing sorption such as initial solution pH, biomass dosage, contact time, temperature, initial uranium concentration and other common cations were analyzed. Sorption isotherm, kinetic and thermodynamic studies of uranium on magnetically modified R. glutinis were also carried out. The temperature dependent equilibrium data agreed well with the Langmuir model. Kinetic data obtained at different temperatures were simulated using pseudo-first-order and pseudo-second-order kinetic models, the pseudo-second-order kinetic model was found to describe the data better with correlation coefficients near 1.0. The thermodynamic parameters, DeltaH degrees , DeltaS degrees and DeltaG degrees were calculated from the sorption data gained at different temperatures. These thermodynamic parameters showed that the sorption process was endothermic and spontaneous. All results indicated that magnetically modified R. glutinis can be a potential sorbent for uranium wastewater treatment. PMID- 23040396 TI - Enhancement of tacrolimus productivity in Streptomyces tsukubaensis by the use of novel precursors for biosynthesis. AB - In this report the optimization of biosynthesis of tacrolimus, the immunosupressant widely used in transplantology and dermatology was described. The enhancement of the productivity of Streptomyces tsukubaensis strain was achieved by development of new precursors of tacrolimus biosynthesis, which should allow to reduce the costs of the process. The enrichment of the fermentation medium in pyridine-2-carboxylic acid (picolinic acid), piperidine-2 carboxylic acid (pipecolic acid), pyridine-3-carboxylic acid (nicotinic acid) or pyridine-3-carboxylic acid amide (nicotinamide) caused significant growth of the productivity of tacrolimus: 7-fold, 6-fold, 3-fold and 5-fold, respectively. The optimum concentration of the precursors in medium was 0.0025-0.005%. The investigation of the kinetics of tacrolimus biosynthesis together with the analysis of the impact of tested compounds on the culture growth and NAD (nicotinamide adenine dinucleotide) concentration in S. tsukubaensis cells enables to put forward a hypothesis concerning the mechanism of action of tested culture medium additives. The compounds active as tacrolimus precursors (pipecolic and picolinic acids) are more effective than these active mainly as the growth promoters (nicotinamide and nicotinic acid). Nicotinamide and nicotinic acid--vitamin B3 components--promote S. tsukubaensis growth most probably due to the stimulation of NAD/NADP biosynthesis. PMID- 23040397 TI - Enzyme catalyzed electricity-driven water softening system. AB - Hardness in water, which is caused by divalent cations such as calcium and magnesium ions, presents a major water quality problem. Because hard water must be softened before use in residential applications, there is great interest in the saltless water softening process because, unlike ion exchange softeners, it does not introduce additional ions into water. In this study, a saltless hardness removal driven by bioelectrochemical energy produced through enzymatic oxidation of glucose was proposed and investigated. Glucose dehydrogenase was coated on a carbon electrode to catalyze glucose oxidation in the presence of NAD+ as a cofactor/mediator and methylene green as an electrocatalyst. The results showed that electricity generation stimulated hardness removal compared with non electricity conditions. The enzymatic water softener worked upon a 6h batch operation per day for eight days, and achieved an average hardness removal of 46% at a high initial concentration of 800 mg/L as CaCO3. More hardness was removed at a lower initial concentration. For instance, at 200mg/L as CaCO3 the enzymatic water softener removed 76.4+/-4.6% of total hardness. The presence of magnesium ions decreased hardness removal because of its larger hydrated radius than calcium ions. The enzymatic water softener removed 70-80% of total hardness from three actual hard water samples. These results demonstrated a proof-of-concept that enzyme catalyzed electricity generation can be used to soften hard water. PMID- 23040398 TI - A protein from Pleurotus eryngii var. tuoliensis C.J. Mou with strong removal activity against the natural steroid hormone, estriol: purification, characterization, and identification as a laccase. AB - A protein with strong removal activity against the natural estrogen estriol was purified from a culture supernatant of Pleurotus eryngii var. tuoliensis C.J. Mou. The protein was characterized as a laccase and had a molecular mass of 60kDa on SDS-PAGE. The enzyme was most active at pH 7.0 and 50 degrees C. The partial N terminal amino acid sequence of the enzyme showed homology with laccases from mushrooms, such as Pleurotus ostreatus, Coriolus versicolor (current name: Trametes versicolor), Pycnoporus cinnabarinus, and P. eryngii. A recombinant yeast assay confirmed that laccase treatment was very efficient for removing the estrogenic activity of steroid estrogens. Our results suggest that the enzyme may be applicable as a potential factor for removing natural steroid hormones. PMID- 23040399 TI - Shared secrets versus secrets kept private are linked to better adolescent adjustment. AB - It is a household notion that secrecy is bad while sharing is good. But what about shared secrets? The present research adopts a functional analysis of sharing secrets, arguing that it should negate harmful consequences generally associated with secrecy and serves important interpersonal functions in adolescence. A survey study among 790 Dutch adolescents showed that, in line with hypotheses, shared secrets (1) were kept by more adolescents than private secrets, (2) were not linked to maladjustment and (3) were linked to higher interpersonal functioning. Whereas private secrecy was associated with increased delinquency, physical complaints, depressive mood, loneliness, and with lower quality relationships, shared secrecy was associated only with more interpersonal competence. Moreover, sharing a secret was specifically linked to a higher quality relationship with the confidant, and sharing with parents was linked with less delinquency, whereas sharing with a best friend was linked with less loneliness and more interpersonal competence. PMID- 23040401 TI - The effect of the DNA preparation method on the sensitivity of PCR for the detection of Trypanosoma evansi in rodents and implications for epidemiological surveillance efforts. AB - Trypanosoma evansi is responsible for the most largely distributed animal trypanosomosis, affecting a wide range of wild and domestic animals. Its surveillance requires the implementation of standardized and reliable diagnostic tools. Although the development of polymerase chain reaction (PCR) tools has greatly improved our diagnostic capacity, factors affecting their sensitivity need to be acknowledged and accounted for in the interpretation of results. The targeted gene and the primer design have already been shown to greatly affect the sensitivity of a PCR, and the best-performing sets of primers have been previously identified. However, the sensitivity of the PCR is also largely influenced by the DNA extraction or sample preparation method. In this paper, we selected 6 DNA extraction or blood sample preparation methods representative of what would be used in a budget-constrained setting: phenol-chloroform, Chelex((r)), Flexigen (Qiagen((r))) kit, Genekam((r)) kit and two original protocols using sodium hydroxide. We studied the effects of the preparation method on the detection limit of the subsequent PCR. Our results show that the extraction method strongly affects the PCR sensitivity. The classical phenol chloroform extraction method allowed for the PCR with the lowest detection limit. Some combinations of extraction method and primer set had detection limits that were not compatible with their use as a reliable diagnostic test, and would severely reduce the performance of a surveillance program. Therefore, we encourage laboratories to carefully select their sample preparation and PCR protocols, depending on the aimed sensitivity, cost, safety, time requirement and objectives. PMID- 23040402 TI - Recipient of the Solomon A. Berson award in health sciences from New York university College of Medicine in 2011. PMID- 23040403 TI - Literature-based recommendations for suicide assessment in the emergency department: a review. AB - BACKGROUND: Suicidal ideation and attempted suicide are important presenting complaints in the Emergency Department (ED). The Joint Commission established a National Patient Safety Goal that requires screening for suicidal ideation to identify patients at risk for suicide. OBJECTIVES: Given the emphasis on screening for suicidal ideation in the general hospital and ED, it is important for Emergency Physicians to be able to understand and perform suicide risk assessment. METHODS: A review of literature was conducted using PubMed to determine important elements of suicide assessment in adults, ages 18 years and over, in the ED. Four typical ED cases are presented and the assessment of suicide risk in each case is discussed. RESULTS: The goal of an ED evaluation is to appropriately determine which patients are at lowest suicide risk, and which patients are at higher or indeterminate risk such that psychiatry consultation is warranted while the patient is in the ED. Emergency clinicians should estimate this risk by taking into account baseline risk factors, such as previous suicide attempts, as well as acute risk factors, such as the presence of a suicide plan. CONCLUSION: Although a brief screening of suicide risk in the ED does not have the sensitivity to accurately determine which patients are at highest risk of suicide after leaving the ED, patients at lowest risk may be identified. In these low-risk patients, psychiatric holds and real-time psychiatric consultation while in the ED may not be needed, facilitating more expeditious dispositions from the ED. PMID- 23040404 TI - Ancestral gene and "complementary" antibody dominate early ontogeny. AB - According to N.K. Jerne the somatic generation of immune recognition occurs in conjunction with germ cell evolution and precedes the formation of the zygote, i.e. operates before clonal selection. We propose that it is based on interspecies inherent, ancestral forces maintaining the lineage. Murine oogenesis may be offered as a model. So in C57BL/10BL sera an anti-A reactive, mercapto ethanol sensitive glycoprotein of up to now unknown cellular origin, but exhibiting immunoglobulin M character, presents itself "complementary" to a syngeneic epitope, which encoded by histocompatibility gene A or meanwhile accepted ancestor of the ABO gene family, arises predominantly in ovarian tissue and was detected statistically significant exclusively in polar glycolipids. Reports either on loss, pronounced expressions or de novo appearances of A-type structures in various conditions of accelerated growth like germ cell evolution, wound healing, inflammation and tumor proliferation in man and ABO related animals might show the dynamics of ancestral functions guarantying stem cell fidelity in maturation and tissue renewal processes. Procedures vice versa generating pluripotent stem cells for therapeutical reasons may indicate, that any artificially started growth should somehow pass through the germ line from the beginning, where according to growing knowledge exclusively the oocyte's genome provides a completely channeling ancestral information. In predatory animals such as the modern-day sea anemone, ancestral proteins, particularly those of the p53 gene family govern the reproduction processes, and are active up to the current mammalian female germ line. Lectins, providing the dual function of growth promotion and defense in higher plants, are suggested to represent the evolutionary precursors of the mammalian immunoglobulin M molecules, or protein moiety implying the greatest functional diversity in nature. And apart from any established mammalian genetic tree, a common vetch like Vicia cracca, may represent an ancient model of protected reproduction mirroring A-reactive "complementarity" already in a plant. The in its seeds developed, and from the number of chromosomes depending amount of an anti-A(1) specific glycoprotein suggests promotion of germination while simultaneously exerting protection from a soil bacterium, which intriguingly is immobilized by human anti-A immunoglobulin as well. Moreover, in a mammalian ovary the lectin of Dolichos biflorus detects again histo (blood) group A-determining N-acetyl-d-galactosamine epitopes, here signalizing activity of embryonic stem cells. So apparently based on identical, ancestral structures, the dual function of growth promotion and defense, predetermined in a plant genome, might be preserved right up to dominate early mammalian ontogeny. PMID- 23040405 TI - A comparison of 2 methods of vaginal cuff closure during robotic hysterectomy. AB - OBJECTIVE: To compare 2 methods of vaginal cuff closure with regard to safety, ease of use, and postoperative outcome. METHODS: All patients undergoing robotic assisted total hysterectomy by a gynecologic oncologist from July 1, 2010, to July 1, 2011, at Northwestern Memorial Prentice Women's Hospital were included in a retrospective analysis. Providers used either 2-0 monofilament synthetic absorbable suture to close the vaginal cuff in a running fashion, secured with an absorbable suture clip at the angles and then knotted in the middle, or 2-0 absorbable unidirectional barbed suture with a welded-loop closure in a running fashion. RESULTS: A total of 134 patients underwent robotic-assisted total hysterectomy. The 2-0 tied monofilament closure was used in 58 patients, and the 2-0 barbed knotless closure was used in 76 patients. There were no instances of vaginal cuff dehiscence or vaginal cuff cellulitis. Rates of vaginal spotting and bleeding were comparable between the groups (12.0% spotting in the monofilament suture group vs 13.0% spotting in the barbed suture group). All vaginal cuff bleeding resolved on its own without significant intervention. CONCLUSION: The use of either a 2-0 welded-loop unidirectional barbed suture or a 2-0 monofilament absorbable suture to close the vaginal cuff is safe and well tolerated. PMID- 23040406 TI - Community-based newborn resuscitation among frontline providers in a low-resource country. AB - OBJECTIVE: To evaluate a birth asphyxia management program among community midwives in a low-resource rural setting. METHODS: Concise training with provision of positive-pressure ventilation devices was implemented in Indonesia in 2005. The effectiveness of the intervention among community-based midwives between October 2007 and September 2008 was evaluated. The intervention cohort was compared with a neighboring control cohort. RESULTS: Overall, 242 intervention and 106 control midwives were surveyed. In total, 3116 births were attended, 84.0% of deliveries occurred at home, and 97.4% of midwives had not previously owned a resuscitation device. When positive-pressure ventilation was administered, newborn survival on day 1 was equivalent in the 2 cohorts (88.4% versus 84.4%; P=0.66). However, significantly more newborns in the intervention group underwent ventilation (risk ratio 2.3; 95% confidence interval, 1.4-8.0). The intervention group had significantly greater scores on both knowledge (t[144.35]=10.52; P<0.001) and confidence (t[134.17]=11.66; P<0.001). CONCLUSION: Focused community-based resuscitation training and device delivery resulted in a significantly increased proportion of newborns receiving life-saving positive pressure breaths, in addition to improved provider knowledge and confidence. Furthermore, the program demonstrated the establishment of an effective training infrastructure within a disrupted health system. PMID- 23040407 TI - Hospital work shifts and days of occurrence of maternal deaths in 6 hospitals in the Upper West Region of Ghana. PMID- 23040408 TI - Maternal morbidity in early pregnancy in rural northern Bangladesh. AB - OBJECTIVE: To determine the burden of maternal morbidity in early pregnancy in rural northern Bangladesh. METHODS: A cross-sectional analysis was performed on baseline morbidity data from 42 896 pregnant women enrolled in a vitamin A supplementation trial. One-week histories for 31 defined symptoms were collected at 5-12 weeks of gestation. Ten illnesses were defined, compatible with ICD-10 diagnoses and WHO definitions. Prevalence, duration, and treatment-seeking behaviors were determined for each symptom and illness. Risk of wasting malnutrition was compared between symptomatic and asymptomatic women. RESULTS: In total, 93.1% of women reported at least 1 symptom. The most frequent symptoms were poor appetite (53.3%), vaginal discharge (48.7%), and nausea (48.1%), each of which lasted 22-27 days. The most prevalent illnesses were anemia (36.4%), morning sickness (17.2%), excessive vomiting (7.0%), and reproductive tract infections (6.7%). Symptoms that prompted treatment seeking included jaundice, high-grade fever, and swelling of hands and face. Odds ratios for malnutrition were higher among women with symptoms of anemia (1.30; 95% confidence interval [CI], 1.24-1.36), vaginal discharge (1.37; 95% CI, 1.31-1.43), and high-grade fever (1.23; 95% CI, 1.10-1.37) than among those without symptoms. CONCLUSION: Women in rural Bangladesh report substantial morbidity in the first trimester. PMID- 23040409 TI - Modification of the Wise pattern breast reduction for oncological mammaplasty of upper outer and upper inner quadrant breast tumours: a technical note and case series. AB - The upper outer quadrant of the breast is the most common site for the incidence of breast cancer, and the upper inner quadrant the most cosmetically sensitive area. If an oncoplastic approach is considered however, these quadrants do not fall within the classical Wise pattern for oncological mammoplasty. We use a simple modification of the Wise pattern that facilitates oncological mammoplasty of tumours in these quadrants without the need for secondary or extended pedicles. In planning this modification excision of skin overlying the tumour is usually also possible. The modification of the Wise pattern technique that we use is described as a technical note, and a case series of 11 patients who underwent this procedure is presented. To date there have been no recurrences. This is a simple cosmetically acceptable modification of the Wise pattern breast reduction for oncological mammoplasty. PMID- 23040410 TI - Gut metabotypes govern health effects of dietary polyphenols. AB - Polyphenols are thought to be responsible for some of the health effects conferred by a diet rich in fruit and vegetables. Both the formation of bioactive polyphenol-derived metabolites and the modulation of colonic microbiota contribute to these health benefits. Therefore, one cannot infer biological responses from dietary intake records without considering polyphenol-microbiota interactions. However, the latter are complex and subject to large interindividual variability, leading to different polyphenol-metabolizing phenotypes or 'metabotypes'. Based on accurate measurements of intake, exposure and effect on carefully selected samples, the physiological relevance of dietary polyphenols can be evaluated for each metabotype. Ultimately, this will lead to predictive modeling and the development of (personalized) functional foods and other nutraceuticals with maximized health benefits. PMID- 23040411 TI - The role of membrane transport in metabolic engineering of plant primary metabolism. AB - Plant cells are highly compartmentalized and so is their metabolism. Most metabolic pathways are distributed across several cellular compartments, which requires the activities of membrane transporters to catalyze the flux of precursors, intermediates, and end products between compartments. Metabolites such as sucrose and amino acids have to be transported between cells and tissues to supply, for example, metabolism in developing seeds or fruits with precursors and energy. Thus, rational engineering of plant primary metabolism requires a detailed and molecular understanding of the membrane transporters. This knowledge however still lags behind that of soluble enzymes. Recent advances include the molecular identification of pyruvate transporters at the chloroplast and mitochondrial membranes and of a new class of transporters called SWEET that are involved in the release of sugars to the apoplast. PMID- 23040412 TI - Oncologists' perspectives on concurrent palliative care in a National Cancer Institute-designated comprehensive cancer center. AB - OBJECTIVE: The purpose of this study was to understand oncology clinicians' perspectives about the care of advanced cancer patients following the completion of the ENABLE II (Educate, Nurture, Advise, Before Life Ends) randomized clinical trial (RCT) of a concurrent oncology palliative care model. METHOD: This was a qualitative interview study of 35 oncology clinicians about their approach to patients with advanced cancer and the effect of the ENABLE II RCT. RESULTS: Oncologists believed that integrating palliative care at the time of an advanced cancer diagnosis enhanced patient care and complemented their practice. Self assessment of their practice with advanced cancer patients comprised four themes: (1) treating the whole patient, (2) focusing on quality versus quantity of life, (3) "some patients just want to fight," and (4) helping with transitions; timing is everything. Five themes comprised oncologists' views on the complementary role of palliative care: (1) "refer early and often," (2) referral challenges: "Palliative" equals "hospice"; "Heme patients are different," (3) palliative care as consultants or co-managers, (4) palliative care "shares the load," and (5) ENABLE II facilitated palliative care integration. SIGNIFICANCE OF RESULTS: Oncologists described the RCT as holistic and complementary, and as a significant factor in adopting concurrent care as a standard of care. PMID- 23040413 TI - L-arginine enriched biscuits improve endothelial function and glucose metabolism: a pilot study in healthy subjects and a cross-over study in subjects with impaired glucose tolerance and metabolic syndrome. AB - OBJECTIVE: The aim of this study was to evaluate the effects of a new L-arginine enriched biscuit on endothelial function, insulin sensitivity/secretion and body composition. MATERIALS/METHODS: The project was composed of two studies. The first study was an acute pilot postprandial study in 7 healthy subjects that evaluated bio-availability and vascular effects of L-arginine-enriched biscuits that contained 6.6 gL-arginine, 21.9 g carbohydrates, 3.6 g protein, 7.5 g fat and 4.3 g dietary fiber compared with placebo biscuits and 6.6 g powdered L arginine. Subjects underwent the tests in random order, in at least 14-day intervals. The second study was a double-blind crossover study in 15 obese subjects with IGT and MS. These subjects consumed 6.6 g of L-arginine-enriched biscuits or placebo biscuits in a 1600 kcal diet. Each study period lasted 2 weeks with a 2-week washout in between. Endothelial function, glucose tolerance, insulin sensitivity and insulin secretion were evaluated at the end of each intervention period. RESULTS: In the first study, the groups that received the L arginine-enriched biscuits and the powdered L-arginine had similarly increased L arginine, NOx and cGMP levels and post-ischemic blood flow (PI-BF). In both cases, these levels were significantly higher than those in the placebo biscuit recipient group. In the second study, the L-arginine-enriched biscuit recipient group displayed increased L-arginine, NOx, cGMP, PI-BF, and Matsuda index levels, whereas their circulating glucose, proinsulin/insulin ratio and fat mass were decreased compared with the placebo biscuit recipient group. CONCLUSIONS: L Arginine-enriched biscuits with low sugar and protein content enhance endothelial function and improve glucose metabolism, insulin sensitivity and insulin secretion in subjects with IGT and MS. PMID- 23040414 TI - Brain-derived neurotrophic factor and its relation to leptin in obese children before and after weight loss. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a regulator of energy homeostasis and food intake through hypothalamic signaling. Currently, data regarding BDNF in children with obesity are lacking. We evaluated serum BDNF concentrations in obese children, both before and after lifestyle intervention, in reference to those of lean children. METHODS: A total of 90 (24 normal weight; 66 obese) children were studied utilizing a cross-sectional clinical outpatient study design. In addition, longitudinal data analysis was performed in 30 obese children participating in a lifestyle intervention for one year. RESULTS: Fasting serum BDNF concentrations were higher in obese vs. normal weight children (BDNF 20.3+/-1.0 vs. 12.5+/-1.7 ng/mL, respectively, mean+/-SEM, p<0.001) and correlated significantly to BMI standard deviation score (r=0.426, p<0.001), and leptin (r=0.414, p<0.01). BDNF concentrations were not regulated in response to food, 60 min after ingestion of a liquid test meal. After one year lifestyle intervention, delta BDNF correlated significantly to delta leptin (r=0.475, p<0.01), but not to changes of insulin resistance index HOMA-IR, systolic and diastolic blood pressure, HDL, LDL, and triglycerides. In a multiple stepwise linear regression adjusted for pubertal stage, age, sex, and BMI, delta BDNF correlated significantly (p<0.05) to delta leptin and delta triceps skinfold and in tendency to delta subscapularis skinfold thickness (p=0.050). CONCLUSIONS: Our results in children do not indicate a significant relationship between BDNF and insulin resistance or cardiovascular risk factors. However, the correlation between changes of BDNF and changes of leptin suggests a relationship between BDNF and fat mass. PMID- 23040415 TI - Survival of patients treated surgically for synchronous single-organ metastatic NSCLC and advanced pathologic TN stage. AB - INTRODUCTION: Patients with stage IV metastatic non-small cell lung cancer (NSCLC) are generally not considered for surgery due to their poor median survival ranging from 4 to 11 months. However published results suggested that carefully selected patients with oligometastatic disease may benefit from resection of both the primary and metastatic sites in a multidisciplinary treatment approach. The aim of the study was to analyze and detect prognostic factors in surgically treated patients with synchronous single-organ metastasis from NSCLC. METHODS: This is a retrospective single-center study including 29 patients with synchronous single-organ metastatic NSCLC who underwent lung resection and local treatment of the metastasis between 2002 and 2008. Overall survival was estimated from the date of lung surgery until last follow-up. The impact on survival of nine variables (age, pT, pN, site of metastasis, presence of solitary metastasis, R-resection status, presence of neoadjuvant or adjuvant treatment, tumor histology) were further assessed. RESULTS: Twenty-nine patients (20 males, 69%) with a median age of 62 (from 44 to 77) were included. Site of metastatic disease was the brain in 19, the lung in 8 and the adrenal glands in 2 patients. Histology was adenocarcinoma in 21, large-cell carcinoma in 3, squamous cell carcinoma in 2 and other in 3 patients. Type of lung resection performed for primary tumors were pneumonectomy in 3, bilobar resection in 3, lobar resection in 17 and sublobar resection in 6 patients. Survival at 1 and 5 years for the overall population reached 65% and 36%, respectively. Median survival was 20.5 months. Univariate regression model analysis identified pathologic T stage as a predictor of survival. Patients with pT1-2 behaved statistically significantly better (p=0.007) compared to patients with pT3-4 tumors. No impact on survival for the other 8 variables has been shown. CONCLUSIONS: The 5-year survival rate of 36% confirms that multimodality treatment including surgical lung resection should be considered in the therapy of single-site metatastatic NSCLC for selected patients. Pathologic T stage appeared to have significant impact on predicting patient survival. PMID- 23040417 TI - Genotypic diversity of clinical Coxiella burnetii isolates from Portugal based on MST and MLVA typing. AB - The temporal and spatial diversity of Coxiella burnetii genotypes associated with human and animal disease in Portugal was analysed using a 6-locus multiple-locus variable-number tandem repeat analysis (MLVA) and a 10-locus multi-spacer sequence typing (MST) panel. Fifteen cultured C. burnetii isolates from 13 Q fever patients and a stillborn goat and 6 additional PCR-positive ruminant tissue samples obtained during 2006-2011 were included in this study. Seven MLVA genotypes (types S-Y) were obtained, including 4 new MLVA types (U, V, W, and X), all corresponding to 3 MST profiles (types 4, 8, and 13) previously reported from France and Spain. MLVA types U-Y, all belonging to MST type 4, were found in acute Q fever patients from the districts of Evora, Faro, Lisbon, and Setubal. Different MLVA types were associated with goats from Castelo Branco district (S) and chronic Q fever patients from both Castelo Branco and Lisboa districts (S and T), matching with MST types 13 and 8, respectively. In conclusion, a genotypic diversity of C. burnetii consistent with a non-outbreak situation was identified. The involvement of different genotypes in acute and chronic Q fever was found, linking one of the chronic genotypes to goats from the eastern region of the country. PMID- 23040416 TI - Re-evaluation of the prognostic value of visceral pleura invasion in Stage IB non small cell lung cancer using the prospective multicenter ACOSOG Z0030 trial data set. AB - PURPOSE: This study seeks to clarify the modern prognostic significance of visceral pleura invasion (VPI) in Stage IB (T2aN0M0) non-small cell lung cancer (NSCLC) within the context of the 7th edition TNM classification using the data set from a recent prospective multicenter trial. PATIENTS AND METHODS: 1111 early stage NSCLC patients participating in the ACOSOG Z0030 trial (1990-2004) underwent curative pulmonary resection. After excluding T2b tumours (>5 cm and <= 7 cm) and non-size-based T2 factors other than VPI, 289 patients were categorized as Stage IB NSCLC - T2aN0M0 - according to the AJCC 7th edition classification. The patients were divided into three groups according to size and VPI: tumours <= 3 cm with VPI (Group I, "VPI-alone", n=83), tumours>3 cm and <= 5 cm without VPI (Group II, "Size-alone", n=156), and tumours>3 cm and <= 5 cm with VPI (Group III, "VPI+Size", n=50). Multivariate Cox regression analysis was used to assess the association of VPI and size with survival, adjusting for age, gender, histology and type of resection. RESULTS: VPI in Stage IB was identified in 133 patients (46.0%). Survival analysis in these patients identified an optimal cutpoint for survival based on size of 3.1cm. Group III (VPI+Size) had a 5-year survival rate of 55.0% significantly shorter when compared to Group I (VPI alone=68.3%, p=0.009), and Group II (Size-alone=67.2%, p=0.021). No difference was found between Groups I and II. Multivariable analysis showed that VPI associated with size was an independent negative prognostic factor of long-term survival, along with older age and limited resection. CONCLUSIONS: Stage IB patients with VPI and tumours>3 cm and <= 5 cm have significantly worse prognosis than those with 'T2a' tumours on the basis of VPI or tumour size alone. This finding would suggest upstaging these patients from the current IB status to Stage IIA. PMID- 23040418 TI - CT-guided 125I brachytherapy for mediastinal metastatic lymph nodes recurrence from esophageal carcinoma: effectiveness and safety in 16 patients. AB - OBJECTIVES: To retrospectively evaluate effectiveness and safety of CT-guided (125)I brachytherapy in 16 patients with mediastinal metastatic lymph nodes recurrence from esophageal carcinoma. MATERIALS AND METHODS: Sixteen metastatic lymph nodes in 16 patients were percutaneously treated in 19 (125)I brachytherapy sessions. Each metastatic lymph node was treated with computed tomographic (CT) guidance. Follow-up contrast material-enhanced CT or positron emission tomographic (PET) scans were reviewed and the treatment's effectiveness was evaluated. RESULTS: Months are counted from the first time of (125)I brachytherapy and the median duration of follow-up was 11 months (range, 5-16 months). The local control rates after 3, 6, 10 and 15 months were 75.0, 50.0, 42.9 and 33.3% respectively. At the time of writing, four patients are alive without evidence of recurrence at 16, 9, 16 and 9 months. The 4 patients presented good control of local tumor and no systemic recurrence, and survived throughout the follow-up period. The other 12 patients died of multiple hematogenous metastases 5-15 months after brachytherapy. A small amount of local hematoma occurred in 2 patients that involved applicator insertion through the lung. Two patients presented pneumothorax with pulmonary compression of 30 and 40% after the procedure and recovered after drainage. One patient had minor displacement of radioactive seeds. Severe complications such as massive bleeding and radiation pneumonitis did not occur. CONCLUSION: (125)I radioactive seed implantation is effective and may be safely applied to mediastinal metastatic lymph nodes recurrence from esophageal carcinoma. PMID- 23040419 TI - [Not Available]. PMID- 23040420 TI - [Not Available]. PMID- 23040421 TI - Differential expression of pro-inflammatory cytokines in endometrial tissue of buffaloes with clinical and sub-clinical endometritis. AB - The objective of this study was to investigate the endometrial expression of pro inflammatory cytokines (IL1beta, IL6, IL8 and TNFalpha) along with TLR4 and CD14 in normal and endometritic buffaloes. The genitalia were collected in the abattoir and divided into three groups as normal (gr. I=12), clinical endometritis (CE, gr. II=12) based on positive color reaction to white side test of uterine discharge and sub-clinical endometritis (SCE, gr. III=12) based on endometrial cytology (presence of >=5% PMNs) and histopathology. The equal numbers of genitalia were grouped into follicular and luteal stage in each group. Endometrial tissue scrapings were used for total RNA extraction and cDNA was transcribed and amplified by Real time PCR. The results showed several fold higher expression of all cytokine transcripts in CE (gr. II), whereas significant up-regulation of CD14 (1 to 2-fold), IL6 (15 to 36-fold), IL8 (8 to 14-fold) and TNFalpha (10 to 11-fold) mRNA was observed in SCE. This indicates that the evaluation of expression patterns of certain cytokines gene holds promise to diagnose the severity and degree of uterine inflammation. PMID- 23040423 TI - Tackling the global diabetes burden: will screening help? PMID- 23040422 TI - Screening for type 2 diabetes and population mortality over 10 years (ADDITION Cambridge): a cluster-randomised controlled trial. AB - BACKGROUND: The increasing prevalence of type 2 diabetes poses a major public health challenge. Population-based screening and early treatment for type 2 diabetes could reduce this growing burden. However, uncertainty persists around the benefits of screening for type 2 diabetes. We assessed the effect of a population-based stepwise screening programme on mortality. METHODS: In a pragmatic parallel group, cluster-randomised trial, 33 general practices in eastern England were randomly assigned by the method of minimisation in an unbalanced design to: screening followed by intensive multifactorial treatment for people diagnosed with diabetes (n=15); screening plus routine care of diabetes according to national guidelines (n=13); and a no-screening control group (n=5). The study population consisted of 20,184 individuals aged 40-69 years (mean 58 years), at high risk of prevalent undiagnosed diabetes, on the basis of a previously validated risk score. In screening practices, individuals were invited to a stepwise programme including random capillary blood glucose and glycated haemoglobin (HbA(1c)) tests, a fasting capillary blood glucose test, and a confirmatory oral glucose tolerance test. The primary outcome was all-cause mortality. All participants were flagged for mortality surveillance by the England and Wales Office of National Statistics. Analysis was by intention-to screen and compared all-cause mortality rates between screening and control groups. This study is registered, number ISRCTN86769081. FINDINGS: Of 16,047 high risk individuals in screening practices, 15,089 (94%) were invited for screening during 2001-06, 11,737 (73%) attended, and 466 (3%) were diagnosed with diabetes. 4137 control individuals were followed up. During 184,057 person-years of follow up (median duration 9.6 years [IQR 8.9-9.9]), there were 1532 deaths in the screening practices and 377 in control practices (mortality hazard ratio [HR] 1.06, 95% CI 0.90-1.25). We noted no significant reduction in cardiovascular (HR 1.02, 95% CI 0.75-1.38), cancer (1.08, 0.90-1.30), or diabetes-related mortality (1.26, 0.75-2.10) associated with invitation to screening. INTERPRETATION: In this large UK sample, screening for type 2 diabetes in patients at increased risk was not associated with a reduction in all-cause, cardiovascular, or diabetes related mortality within 10 years. The benefits of screening might be smaller than expected and restricted to individuals with detectable disease. FUNDING: Wellcome Trust; UK Medical Research Council; National Health Service research and development support; UK National Institute for Health Research; University of Aarhus, Denmark; Bio-Rad. PMID- 23040424 TI - New developments for the delivery of burns care research in the UK. PMID- 23040426 TI - [Not Available]. PMID- 23040425 TI - Epidemiology of operative burns at Kijabe Hospital from 2006 to 2010: pilot study of a web-based tool for creation of the Kenya Burn Repository. AB - INTRODUCTION: In order to implement effective burn prevention strategies, the WHO has called for improved data collection to better characterize burn injuries in low and middle income countries (LMIC). This study was designed to gather information on burn injury in Kenya and to test a model for such data collection. METHODS: The study was designed as a retrospective case series study utilizing an electronic data collection tool to assess the scope of burn injuries requiring operation at Kijabe Hospital from January 2006 to May 2010. Data were entered into a web-based tool to test its utility as the potential Kenya Burn Repository (KBR). RESULTS: 174 patients were included. The median age was 10 years. There was a male predominance (59% vs. 41%). Findings included that timing of presentation was associated with burn etiology (p=0.009). Length of stay (LOS) was associated with burn etiology (p<0.001). Etiology differed depending on the age group, with scald being most prominent in children (p=0.002). CONCLUSIONS: Burn injuries in Kenya show similarities with other LMIC in etiology and pediatric predominance. Late presentation for care and prolonged LOS are areas for further investigation. The web-based database is an effective tool for data collection and international collaboration. PMID- 23040427 TI - Somatosensory amplification in schizophrenia is associated with preserved neuropsychological function. AB - BACKGROUND: Some alexithymic features are similar to negative symptoms of schizophrenia, while somatosensory amplification has been defined as an abnormal perceptual style that could be related to hallucinations and positive schizophrenic symptoms. This study analyzed whether both psychological constructs are related to the type of clinical symptoms and to the neuropsychological performance of patients with schizophrenia. METHODS: Thirty-seven patients with schizophrenia were assessed psychologically (20-item Toronto Alexithymia Scale and Somatosensory Amplification Scale), clinically, and neuropsychologically and were compared with a control group of healthy subjects (n= 37). RESULTS: No differences were found in alexithymia or somatosensory amplification between patients and controls and there was no relationship between the two psychological variables and the type of psychotic symptoms in the patient group. However, among patients with schizophrenia, somatosensory amplification was related to significantly better neuropsychological performance than that found in alexithymic subjects and in patients in general. CONCLUSIONS: Alexithymia was unrelated to negative symptoms and to the neuropsychological performance of patients with schizophrenia, and as a psychological construct seems to be separate from the disease. However, in patients with an amplifier style, neuropsychological performance was highly similar to that found in healthy controls, raising the possibility of studying somatosensory amplification as a psychological variable that is potentially related to the clinical and neuropsychological outcomes of patients with schizophrenia. PMID- 23040428 TI - Attitude toward antipsychotic medication as a predictor of antipsychotic treatment discontinuation in first-episode early-onset psychosis. AB - BACKGROUND: Antipsychotic drug discontinuation is a key risk factor in psychotic relapses. Clinical relapse is related to poor outcome, especially in the earlier stages of psychotic illness. The attitude toward treatment during the acute phase of a first episode of psychosis has been proposed as one of the main determinants of treatment discontinuation. However, the relationship between attitude toward antipsychotic medication and treatment discontinuation in the adolescent population has not been properly assessed. METHODS: Adolescents, aged 12-18 years old, consecutively admitted to an adolescent unit with a first lifetime admission for a first episode of psychosis were asked to participate in a randomized, flexible-dose, 6-month controlled trial of olanzapine vs. quetiapine. Attitude toward antipsychotic medication was assessed using the 10-item Drug Attitude Inventory (DAI). The outcome variable was all-cause treatment discontinuation over the 6-month follow- up. The study sample was composed of 42 patients [34 boys (82.9%), eight girls (17.1%), mean age +/- SD: 16.1+/-1.3]. RESULTS: Of the 42 patients, only 29 (69%) continued the medication throughout the entire 6-month follow-up, while 13 (31%) discontinued the medication. DAI scores were greater than zero at all assessments, indicating that the general attitude of the patients toward medication was positive. Higher DAI scores at baseline were related to lower all-cause treatment discontinuation [adjusted hazard ratio (HR) = 0.81 (95% CI: 0.68-0.96), P=0.016], while DAI scores at 15 days were unrelated to treatment discontinuation [adjusted HR=1.0 (95% CI: 0.82-1.23), P=0.998]. CONCLUSIONS: A better attitude toward antipsychotic medication at a first lifetime psychiatric admission for a first early-onset psychotic episode was significantly related to lower all-cause antipsychotic treatment discontinuation. PMID- 23040429 TI - Course of cognitive functioning in first-episode psychosis: a comparison between schizophrenia and non schizophrenia psychosis. AB - AIMS: To describe the course of cognitive functioning in first-episode psychosis and to determine possible differences in the degree and trajectory of cognitive deficits between schizophrenia and non-schizophrenia first-episode psychosis. METHOD: We assessed attention, working memory, and executive functioning in 57 patients with first-episode psychosis both at baseline and at 1-year of follow up. RESULTS: For the overall group, significant reductions were found in the percentage of omission and commission errors for the sustained attention task (p<0.001 and p=0.001, respectively), in the total time to complete the Stroop-I task (p<0.001), in the percentage of omission errors for the working memory task (p=0.001), and in the percentage of perseverative errors for the Wisconsin card sorting test (WCST; p<0.001), as well as a significant increase in the number of categories completed in the WCST (p<0.001). The remaining cognitive variables analyzed remained stable (4 of the 10 variables tested). The pattern of change was similar for patients with schizophrenia (n=20) and non-schizophrenia (n=37) in the areas of attention and working memory. For executive functioning, the non schizophrenia group showed a more beneficial pattern of change. No significant differences were detected in cognitive performance among subgroups at baseline or at the 1-year follow-up. CONCLUSION: The course of cognitive deficits in first episode psychosis showed significant improvements over the 1-year period in the areas of attention, working memory and executive functioning. Neuropsychological performance did not seem to be specific enough to distinguish between patients with schizophrenia and non-schizophrenia first-episode psychosis, at least during the first year. PMID- 23040430 TI - Spanish consensus on physical health of patients with bipolar disorder. AB - BACKGROUND AND OBJECTIVE: Patients with bipolar disorder have much higher physical morbidity and mortality rates than the general population. In addition to a higher mortality rate from suicide, these patients also have a higher prevalence of physical disorders. The aim of this consensus, promoted by the Spanish Societies of Psychiatry and Biological Psychiatry in collaboration with the General Practitioners' Societies, was to establish practical recommendations on procedures for detection, prevention and intervention in the somatic diseases that coexist with bipolar disorder in order to improve the quality of life and life expectancy of these patients. METHOD: The Spanish Societies of Psychiatry and Biological Psychiatry designated a scientific committee that selected 32 expert psychiatrists and 10 experts from other medical specialties. Working groups were formed for each specialty for the purpose of adapting the guidelines applied in the general population to patients with bipolar disorder. A systematic review of medical comorbidity and mortality in these patients was carried out and two multidisciplinary consensus meetings were held. RESULTS: The literature review revealed an increased risk of hypertension, obesity, smoking, pulmonary diseases, migraine and HIV infection among patients with bipolar disorder. There was also evidence of higher mortality rates from cardiovascular and respiratory diseases and infections, as well as from suicide. The expert group reached a consensus on a series of basic measures to detect medical comorbidity applicable to the monitoring of these patients. The resulting recommendations will be accepted and disseminated by the promoting societies. CONCLUSIONS: The recommendations generated by the Spanish Consensus on the Physical Health of Patients with Bipolar disorder include the most important aspects for the improvement of the psychosocial functioning, quality of life and life expectancy of these patients. PMID- 23040431 TI - Rare variants in GJA5 are associated with early-onset lone atrial fibrillation. AB - BACKGROUND: Genetic factors are believed to be important in early-onset lone atrial fibrillation (AF). The gene GJA5 encodes the gap-junction protein Cx40, which together with Cx43 is responsible for the electrical coupling of the atrial cardiomyocytes. The regulatory single nucleotide polymorphism rs10465885 in GJA5 was recently associated with early-onset lone AF (< 60 years) and was also found to be strongly associated with Cx40 messenger RNA levels. We hypothesized that this gene would have a strong effect in patients with a more selected phenotype, and that the findings regarding rs10465885 could be replicated in this group. METHODS: The coding region and flanking intron sequences of GJA5 were resequenced in 342 patients with onset of lone AF before the age of 50 (mean age at onset 34 +/- 9 years), and in 216 controls. The single nucleotide polymorphism rs10465885 was genotyped in 342 patients and 534 control subjects and odds ratios were calculated for different genetic models. RESULTS: Genotyping of rs10465885 showed that the patients with early-onset lone AF were more likely to carry the A allele compared with controls (odds ratio = 1.30; P = 0.011). When resequencing GJA5, we identified the mutation A96S, previously associated with lone AF, which was not present in our control subjects or in any publicly available database or the National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI EVS; 10,758 alleles). CONCLUSIONS: We show a highly significant association between the A allele of rs10465885 and onset of lone AF before age 50. This opposes a previous study, wherein the G allele was found to be associated with AF, and makes it impossible to exclude that the associations are coincidental. PMID- 23040432 TI - Association between nonalcoholic fatty liver disease and cardiovascular risk in obese children and adolescents. AB - BACKGROUND: The recent rise in the prevalence of obesity likely explains nonalcoholic fatty liver disease (NAFLD) epidemic worldwide. We evaluated cardiac functions, cardiovascular risk, and associated parameters with grades of NAFLD in obese children. METHODS: Four hundred obese children were enrolled in the study. Obese children with NAFLD were classified in 2 subgroups according to ultrasonographic visualizing. Ninety-three obese children with NAFLD (mean age 11.73 +/- 2.72 years in group 2 and 12.69 +/- 2.61 years in group 3) were compared with 307 age- and sex-matched non-NAFLD obese children and 150 control subjects. Laboratory parameters were measured during the fasting state. Pulsed and tissue Doppler echocardiography were performed. Intima-media (IMT) and epicardial adipose tissue (EAT) thicknesses were measured. RESULTS: NAFLD groups had a significantly higher body mass index (29.15 +/- 3.42 and 30.46 +/- 4.60; P < 0.001), total adipose tissue mass (37.95 +/- 4.46% and 46.57 +/- 6.45%; P < 0.001), higher insulin, alanine aminotransferase, and aspartate aminotransferase levels. Increased end-systolic thickness of the interventricular septum (P < 0.001), larger left ventricular mass (P < 0.003) and index (P < 0.003) were found in NAFLD groups. Children with NAFLD had higher Tei index values. Also, carotid artery IMT and EAT thickness were significantly higher in obese children. Waist and hip circumference, total cholesterol level, total adipose tissue mass, and interventricular septum were statistically different in NAFLD groups. CONCLUSIONS: Children with NAFLD had mildly altered left and right ventricular functions and all obese children had increased IMT and EAT thickness. Also, grade of liver steatosis was positively correlated with total adipose tissue mass and interventricular septum systolic thickness. PMID- 23040433 TI - Reply to letter from Gu et al. PMID- 23040434 TI - Age, race, sex, stage, and incidence of cutaneous lymphoma. AB - The T- and B-cell cutaneous lymphomas (CLs) are relatively rare, and information regarding clinical presentation and differences among racial groups might be helpful in determining the best course of clinical care. Data from nearly 5000 patients with CL from the SEER (Surveillance, Epidemiology and End Results Program) registry were evaluated. Nonwhite racial groups present with mycosis fungoides (MF) at an earlier age compared with white, and African American (AA) have increased risk of presenting with higher T-stage compared with white patients. These findings have significant implications regarding need for earlier diagnosis and understanding the reasons for racial disparity in age and stage of presentation. BACKGROUND: The incidence of the T- and B-cell CLs has been well documented, but information pertaining to racial incidence by age, and by burden of disease (stage) have not been extensively documented. MATERIALS AND METHODS: The SEER 2004-2008 public use database was investigated. The relative incidence of CL in different races and age groups was examined. Univariate and multivariate stepwise logistic regression was performed for the likelihood of presenting at a higher stage. RESULTS: Of 4496 patients diagnosed with CL between 2004 and 2008; 1713 patients were diagnosed with MF, 1518 with non-MF cutaneous T-cell lymphoma, and 1265 patients with cutaneous B-cell lymphoma. For MF, there was a trend for females to be less likely to present with a higher T-stage (T3-T4) than males (odds ratio [OR], 0.73) on multivariate analysis (P = .06). For race, AA had a significantly increased risk of presenting with higher T-stage (T3-T4) MF (OR, 1.72) on multivariate analysis (P = .02), compared with white patients. For white, AA, Asian/Pacific Islander, and Native American/other/unknown, the mean age at diagnosis was 59.2, 51.5, 51.3, and 53.8. These groups presented at a significantly different age than white (P = .0001, 0.0001, and 0.0006). CONCLUSION: Nonwhite racial groups present with MF at an earlier age compared with white, and AA have increased risk of presenting with higher T-stage compared with white. These findings have significant implications regarding need for earlier diagnosis and understanding the reasons for racial disparity in age and stage of presentation. PMID- 23040435 TI - Impact of age group on febrile neutropenia risk assessment and management in patients with diffuse large B-cell lymphoma treated with R-CHOP regimens. AB - Improving the management of elderly patients with lymphoma is of increasing relevance. One thousand one hundred thirteen patients with diffuse large B-cell lymphoma (DLBCL) received rituximab (R)-CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) in an observational study. Both older and younger patients failed to receive growth factor support in accordance with international guidelines; patients 65 years and older were more susceptible to febrile neutropenia (FN) and its consequences. Better application of guidelines could reduce rates of FN and improve outcomes. BACKGROUND: The incidence of diffuse large B-cell lymphoma (DLBCL) is increasing in the elderly population, which is a more challenging population to treat because of comorbidities and enhanced sensitivity to chemotherapy toxicities. This analysis evaluated the impact of age group on assessment of febrile neutropenia (FN) risk, supportive care management, and chemotherapy delivery. METHODS: The IMPACT non Hodgkin lymphoma (NHL) trial was an observational study conducted in Europe and Australia. This analysis included 1113 patients with DLBCL treated with rituximab (R)-CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) every 14 days (n = 409) or every 21 days (n = 704). Outcomes were reported for ages < 65 years and >= 65 years. The primary outcome in this analysis was the proportion of patients assessed by investigators as having an overall high (>= 20%) FN risk who received granulocyte colony stimulating factor (G-CSF) primary prophylaxis. RESULTS: For R-CHOP-14, investigators assessed 78% of younger patients and 80% of older patients with >= 20% risk of FN, although 14% of younger and 19% of older high-risk patients did not receive G-CSF primary prophylaxis. For R-CHOP-21, investigators assessed 52% of younger and 71% of older patients with >= 20% risk of FN; however, 61% of younger and 47% of older high-risk patients did not receive G-CSF primary prophylaxis. Regardless of chemotherapy regimen, rates of FN and unplanned hospitalization were higher in older patients, and delivery of chemotherapy was poorer. CONCLUSION: Adherence to G-CSF guidelines in patients assessed with high FN risk was suboptimal in patients with DLBCL receiving R-CHOP chemotherapy, with substantial proportions of both younger and older patients receiving R-CHOP-21 failing to receive optimal G-CSF support. Better application of guidelines could reduce FN rates and improve outcomes. PMID- 23040436 TI - Lack of expression of MTAP in uncommon T-cell lymphomas. AB - The majority of peripheral T-cell lymphomas were found to lack methylthioadenosine phosphorylase, an enzyme that is essential for the salvage of adenine from methylthioadenosine, a product of polyamine synthesis. Importantly, tumors that lack this enzyme have been shown to be more sensitive to inhibitors of de novo purine synthesis (6-thioguanine, methotrexate). BACKGROUND: T-cell lymphomas, in particular peripheral T-cell lymphoma (PTCL), angioimmunoblastic T cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL), have only limited and noncurative treatment options. PATIENTS AND METHODS: We report here that a high percentage of PTCL, AITL, and ALCL lack the enzyme methylthioadenosine phosphorylase (MTAP), as do T-cell leukemia and T-cell lymphoblastic leukemia. MTAP-deficient cells cannot cleave endogenous methylthioadenosine to adenine and 5-methylthioribose-1-phosphate, a precursor of methionine, and as a result have enhanced sensitivity to inhibitors of de novo purine biosynthesis. A recently introduced antifolate, pralatrexate, which has been shown to inhibit de novo purine biosynthesis, has been approved for treatment of PTCL and may have an increasing role in therapy. An alternative strategy involving coadministration of methylthioadenosine and high-dose 6 thioguanine has been proposed and may prove to be selectively toxic to MTAP deficient uncommon lymphomas. CONCLUSION: Thus the consequences of MTAP deficiency suggest that new therapeutic interventions for T-cell lymphoma may be feasible. PMID- 23040437 TI - An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single agent carfilzomib in patients with relapsed and refractory multiple myeloma. AB - An open-label single-arm multicenter pilot phase II study of the next-generation selective proteasome inhibitor carfilzomib was conducted in 46 patients with relapsed and refractory multiple myeloma (MM) after >= 2 previous therapies. The best overall response rate (ORR) was 16.7%, with a median duration of response of 7.2 months. This pilot study was the first phase II single-agent trial conducted with carfilzomib. BACKGROUND: Carfilzomib is a next-generation selective proteasome inhibitor that irreversibly binds its target and has demonstrated single-agent activity in patients with bortezomib-resistant multiple myeloma (MM). PX-171-003-A0, an open-label single-arm multicenter pilot phase II study, enrolled 46 patients with relapsed MM after >= 2 previous therapies including bortezomib and an immunomodulator (thalidomide or lenalidomide) and disease refractory to the last treatment regimen preceding study entry. METHODS: Patients received carfilzomib 20 mg/m(2) intravenously on days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles. Responses in 42 evaluable patients were assessed per International Myeloma Working Group Uniform Response Criteria, with minimal response assessed per European Group for Blood and Marrow Transplantation (EBMT) criteria. RESULTS: The primary endpoint of best ORR was 16.7%, including 7 partial responses. Median duration of response was 7.2 months. Clinical benefit response (CBR) rate was 23.8% with a median duration of response of 13.8 months. The most common treatment-emergent adverse events (AEs) of any grade were anemia (73.9%), fatigue (69.6%), and thrombocytopenia (50.0%). Notably, peripheral neuropathy and neuropathy-related AEs were generally mild and infrequent. CONCLUSION: This pilot study was the first phase II single-agent trial conducted with carfilzomib. Based on these findings, the study was amended to test a higher carfilzomib dose in an additional 250 patients (PX-171-003-A1). PMID- 23040438 TI - Phase I trial of vorinostat combined with bortezomib for the treatment of relapsing and/or refractory multiple myeloma. AB - Preclinical studies have shown that targeted combination therapy consisting of vorinostat and bortezomib has antitumor activity in multiple myeloma (MM). We examined this drug combination in advanced relapsing and/or refractory MM patients (n = 34). Although the maximum tolerated dose was not reached, the study found this combination regimen generally well tolerated and clinically active in relapsed and/or refractory MM patients. BACKGROUND: Development of targeted therapies for MM has improved response rates and increased patient survival, but ultimately the disease becomes refractory and progresses. Vorinostat combined with bortezomib has demonstrated synergistic antiproliferative and proapoptotic activity in preclinical models of MM. The objectives of this study were to determine the maximum tolerated dose for vorinostat with bortezomib in patients with advanced MM and to evaluate the clinical benefit of this new drug combination. PATIENTS AND METHODS: Patients >= 18 years old with relapsed and/or refractory MM were enrolled into escalating dose cohorts of vorinostat and bortezomib combination therapy. Thirty-four patients were enrolled and were evaluable for safety and efficacy analyses. RESULTS: All patients reported adverse events, 89% of which were mild to moderate in severity. Thirteen patients experienced 29 serious adverse events, 12 (41%) of which were considered drug related. The maximum tolerated dose was not reached. Partial responses were observed in 9 (27%) patients. Minimal responses were observed in 2 additional patients (6%), and another 20 patients (59%) experienced disease stabilization. CONCLUSION: Vorinostat with bortezomib is generally well-tolerated and has clinical activity in patients with relapsed and/or refractory MM. Response rates were similar in patients previously exposed to bortezomib and patients who were naive to bortezomib therapy. PMID- 23040439 TI - [Not Available]. PMID- 23040440 TI - [Not Available]. PMID- 23040441 TI - [Not Available]. PMID- 23040442 TI - [Benign intracranial hypertension in a hemodialysis patient: consider the fistula]. AB - Benign intracranial hypertension (BIH) is a syndrome characterized by the abnormal elevation of the intracranial pressure in the absence of a mass lesion or hydrocephalus, and with normal composition of the cerebrospinal fluid. We report a case of BIH in a chronic hemodialysis patient with no signs of intraocular inflammation or neurologic abnormalities. Treatment with acetazolamide followed by corticosteroids failed to improve the signs of BIH. However, after correction of the radiocephalic arteriovenous fistula of the left upper extremity, which demonstrated excessive flow, BIH symptoms completely disappeared. CONCLUSION: When managing BIH in a hemodialysis patient, consider the fistula. PMID- 23040443 TI - Bevacizumab versus ranibizumab in the treatment of exudative age-related macular degeneration: a retrospective study of 58 patients. AB - AIM: To compare the efficacy and safety of bevacizumab versus ranibizumab in the treatment of patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Retrospective case-controlled series of 30 patients treated with intravitreal bevacizumab and 28 patients treated with intravitreal ranibizumab for exudative AMD. Main outcomes measured included best-corrected visual acuity (BCVA), central macular thickness (CMT) and foveal thickness, quantity of subretinal fluid, neovessel size and total number of injections over the first year treatment period. A secondary outcome was the report of any adverse events in both groups. RESULTS: BCVA stabilized and increased from LogMAR 0.70 to 0.47 in the bevacizumab group and from 0.55 to 0.54 in the ranibizumab group (P>0.05). CMT decreased in the bevacizumab group from 369 to 284 MUm and in the ranibizumab group from 340 to 271 MUm (P>0.05). The number of injection was significantly lower (4.8) in the bevacizumab group than in the ranibizumab group (5.8) (P<0.05). No serious ocular adverse events were noted in both groups. CONCLUSION: This retrospective study failed to show a difference in visual and anatomic outcomes between bevacizumab and ranibizumab. The number of re-treatment was lower in the bevacizumab group (P=0.03). PMID- 23040444 TI - [Congenital retinal macrovessel]. PMID- 23040445 TI - [Combined treatment with photodynamic therapy and intravitreal dexamethasone implant (Ozurdex((r))) for circumscribed choroidal hemangioma]. AB - PURPOSE: We report a case of symptomatic circumscribed choroidal hemangioma (CCH) treated by photodynamic therapy (PDT) combined with injection of an intravitreal dexamethasone implant (IDI) (Ozurdex((r))). CASE REPORT: A 39-year-old woman was referred to our outpatient clinic for a progressive decrease in vision of her right eye, measured at 20/25, due to subretinal exudation (SRE) associated with juxtapapillary CCH. Basal diameter of the CCH was 6mm, and its height was 2mm. Treatment consisted of injection of an IDI followed 15 days later by PDT with a single spot covering the tumor (intensity of 600 mW/cm(2) for 83 seconds [50 J/cm(2)]). Six weeks after PDT, we noted improvement of the vision to 20/20, complete resolution of SRE, and tumor flattening. No side-effects were observed. Anatomic and functional results remained unchanged over 9 months of follow-up. CONCLUSIONS: This case suggests that IDI (Ozurdex((r))) potentiates the effect of PDT with less risk of local side-effects than triamcinolone acetonide. Further evaluation of this protocol remains necessary. Nonetheless, combined treatment with injection of IDI followed 15 days later by PDT for the treatment of symptomatic CCH may prove to be a sound alternative to radiotherapy and may be more efficacious than PDT alone. PMID- 23040446 TI - [Effects of peroxynitrite derived from nitric oxide on cultured bovine ocular explants]. AB - INTRODUCTION: Several studies have reported a significant production of nitric oxide (NO) with peroxynitrite formation in the setting of intraocular inflammation. In a previous study, we showed the cytotoxic effect of nitrites and nitrates, stable metabolites of NO, on the various tissues forming the layers of the eye, with variable degrees of tissue sensitivity. This study aims to investigate the effect of peroxynitrite on whole ocular bovine explants in culture. METHODS: Healthy ocular bovine eyes, obtained immediately upon enucleation, were dissected and samples were taken from the anterior and posterior segments, and then cultured in DMEM supplemented with 10% fetal bovine serum, 2mM L-glutamine and antibiotics. Cultures were treated with 3-morpholino sydonimin N-ethyl-carbamide (SIN-1) (molecule which produces NO and superoxide anion O(2)(.-)) at varying concentrations (100 to 500 MUM) over 24 hours. After incubation, the explants were fixed in 10% buffered formalin, and histological study was performed. RESULTS: Most of the structures showed changes on tissue and cellular levels after incubation with the peroxynitrite donor and various responses depending on the concentration used. These observations reflect variable concentration-dependent tissue sensitivity. The epithelia (cornea, iris and ciliary process) showed high sensitivity in comparison with sclera, which developed greater resistance. CONCLUSION: In all, our results indicate a deleterious effect of peroxynitrite on bovine ocular structures in vitro. This effect is proportional to the concentration used. These results corroborate those reported by other teams and suggest the role of peroxynitrite derived from NO in the ocular lesions observed in the setting of uveitis. PMID- 23040447 TI - Cellular repressor E1A-stimulated genes controls phenotypic switching of adventitial fibroblasts by blocking p38MAPK activation. AB - AIMS: Phenotypic modulation of adventitial fibroblasts (AFs) plays an important role in the pathogenesis of proliferative vascular diseases. The current study aimed to identify the role of cellular repressor E1A-stimulated genes (CREG), a critical mediator in the maintenance of vascular homeostasis, in AF phenotypic modulation and adventitial remodeling. METHOD AND RESULTS: Using in situ double immunofluorescence staining, we ascertained that CREG expression was significantly down-regulated in the adventitia after vascular injury, and its expression pattern was conversely correlated with the expression of smooth muscle alpha-actin (alpha-SMA), a marker for differentiation of AFs into myofibroblasts. In vitro data confirmed the association of CREG in angiotensin II (Ang II) induced AF differentiation. Additionally, overexpression of CREG attenuated Ang II-induced alpha-SMA expression in AFs. CREGoverexpressing AFs showed decreased levels of proliferation on days 2-5 following stimulation by Ang II compared with controls, with changes in the cell cycle profile as shown by BrdU incorporation assay and fluorescence activated cell sorting analysis. Moreover, wound healing assay and transwell migration model demonstrated that upregulation of CREG expression inhibited Ang II-induced AF migration. We found that CREG-mediated its counterbalancing effects in Ang II-induced phenotypic modulation, proliferation and migration by inhibition of the p38MAPK signaling pathway, validated by pharmacological blockade of p38MAPK with SB 203580 and by overexpression of p38MAPK with transfectants expressing constitutively active p38alphaMAPK. CONCLUSION: Our findings suggest that CREG is a novel AF phenotypic modulator in a p38MAPK-dependent manner. Modulating CREG on the local vascular wall may become a new therapeutic target against proliferative vascular diseases. PMID- 23040448 TI - Neutrophil/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients undergoing angiography. AB - BACKGROUND: White blood cell count is an independent predictor of cardiovascular events and mortality. Neutrophil/lymphocyte ratio (NLR) is a biomarker that can single out individuals at risk for vascular events. OBJECTIVE: To evaluate whether NLR adds additional information beyond that provided by conventional risk factors and biomarkers for coronary artery disease (CAD) severity and adverse outcome, in a large cohort of consecutive patients referred for coronary angiography. MATERIALS AND METHODS: NLR was computed from the absolute values of neutrophils and lymphocytes from the complete blood count of 3005 consecutive patients undergoing coronary angiography for various indications. CAD severity was determined by an interventional cardiologist unaware of the study aims. The association between NLR and CAD severity was assessed by logistic regression and the association between NLR and 3-years outcome were analyzed using Cox regression models, adjusting for potential clinical, metabolic, and inflammatory confounders. RESULTS: The cohort was divided into 3 groups according to the NLR value (<2, 2-3, and >3). NLR was independently associated with CAD severity and it contributed significantly to the regression models. Patients with NLR >3 had more advanced obstructive CAD (OR = 2.45, CI 95% 1.76-3.42, p < 0.001) and worse prognosis, with a higher rate of major CVD events during up to 3 years of follow up (HR = 1.55, CI 95% 1.09-2.2, p = 0.01). CONCLUSION: Neutrophil/lymphocyte ratio is independently associated with CAD severity and 3-years outcome. NLR value appears additive to conventional risk factors and commonly used biomarkers. PMID- 23040449 TI - Inflammatory bowel disease and pregnancy: lack of knowledge is associated with negative views. AB - BACKGROUND: Enabling women with inflammatory bowel diseases (IBD) to have successful pregnancies requires complex decisions. The study aimed to assess patients' views on IBD and pregnancy and to evaluate any association with subject knowledge. METHODS: General attitudes of females with IBD were assessed on fertility, medication use, delivery mode and pregnancy outcomes. Attitudes regarding personal situation were assessed in participants nulliparous since IBD diagnosis. Knowledge of pregnancy-related issues in IBD was assessed by the Crohn's and Colitis Pregnancy Knowledge Score 'CCPKnow'. RESULTS: Of 145 participants 68% of participants agreed with need for medical therapy for flares during pregnancy, but 24% felt it more important to tolerate symptoms. 36% believed that all IBD medication is harmful to unborn children. Of 96 women nulliparous after IBD diagnosis, 46% were worried about infertility, 75% expressed concern about passing IBD to offspring and 30% considered not having children. Nearly all participants worried about the effects of IBD on pregnancy and the effects of pregnancy on IBD. General attitudes that 'medication should be stopped prior to conception' (P<0.001), 'pregnant women should avoid all IBD drugs' (P<0.001), and 'put up with symptoms' (P<0.001) were associated with significantly lower CCPKnow scores. CONCLUSION: Over a third of patients considered IBD medication harmful to unborn children. Fear of infertility and concerns about inheritance may explain high rates of voluntary childlessness. Attitudes contrary to medical evidence were associated with significantly lower knowledge. Young women with IBD, particularly those with poor knowledge, should be offered education and counselling about pregnancy-related issues. PMID- 23040450 TI - Reply to Dr. Yamamoto's letter. PMID- 23040451 TI - Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. PMID- 23040452 TI - Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. PMID- 23040453 TI - Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. PMID- 23040454 TI - Surgical residents' perception of the 16-hour work day restriction: concern for negative impact on resident education and patient care. AB - BACKGROUND: Effective July 1, 2011, the Accreditation Council for Graduate Medical Education (ACGME) instituted a 16-hour duty period limitation for postgraduate year I (PGY I) residents. Our aim was to assess the attitudes and perception of general surgery residents regarding the new duty hour limitation as well as the transfer of care process under the new guidelines. STUDY DESIGN: An anonymous, web-based survey was conducted nationally 7 months after the institution of the 16-hour duty limitation. RESULTS: A total of 464 completed surveys were analyzed. Overall, 75% of residents expressed dissatisfaction with the new duty hour limitation. PGY II to V residents reported a higher level of dissatisfaction compared with PGY I residents (87% vs 54%, p < 0.01). Eighty-nine percent of PGY II to V residents responded that there has been a shift of responsibilities from the PGY I class to PGY II to V residents, with 73% reporting increased fatigue as a result. Seventy-five percent of PGY I and 94% of PGY II to V residents expressed concerns about the adverse impact of the restrictions on the education of PGY I residents (p < 0.01). Residents at all PGY training levels reported encountering problems due to inadequate sign-outs (PGY I, 59%; PGY II to V, 85%; p < 0.01). Sixty-two percent of PGY I residents and 54% of PGY II to V residents believed that the new 16-hour duty restriction contributes to inadequate sign-outs (p = NS). Most PGY II to V residents (86%) believe there is a decreased level of patient ownership due to the work hour restrictions. CONCLUSIONS: The results of the survey suggest that the majority of general surgery residents are concerned over the potential negative impact of the duty limitation on resident education and patient care. Further research is needed to address these concerns. PMID- 23040455 TI - Erectile dysfunction. AB - Erectile dysfunction is a common clinical entity that affects mainly men older than 40 years. In addition to the classical causes of erectile dysfunction, such as diabetes mellitus and hypertension, several common lifestyle factors, such as obesity, limited or an absence of physical exercise, and lower urinary tract symptoms, have been linked to the development of erectile dysfunction. Substantial steps have been taken in the study of the association between erectile dysfunction and cardiovascular disease. Erectile dysfunction is a strong predictor for coronary artery disease, and cardiovascular assessment of a non cardiac patient presenting with erectile dysfunction is now recommended. Substantial advances have occurred in the understanding of the pathophysiology of erectile dysfunction that ultimately led to the development of successful oral therapies, namely the phosphodiesterase type 5 inhibitors. However, oral phosphodiesterase type 5 inhibitors have limitations, and present research is thus investigating cutting-edge therapeutic strategies including gene and cell based technologies with the aim of discovering a cure for erectile dysfunction. PMID- 23040456 TI - Peutz-Jeghers syndrome: capsule endoscopy to stage disease. PMID- 23040457 TI - A review of demineralized bone matrices for spinal fusion: the evidence for efficacy. AB - BACKGROUND AND PURPOSE: Autologous Iliac Crest Bone Grafting (ICBG) is considered the gold-standard graft choice for spinal arthrodesis; however, it is associated with donor site morbidity and a limited graft supply. Bone graft alternatives to replace autograft and augment arthrodesis are a topic of ongoing research. This article will review properties of Demineralized Bone Matrix (DBM) and review the evidence for its use, including animal models and human clinical trials. METHODS: A systematic and critical review of the English-language literature was conducted on Pubmed, Cochrane, CINAHL, and Google Scholar using search key terms such as 'Demineralized Bone Matrix', 'Spine' and 'Fusion'. Papers that were included were original research articles in peer-reviewed journals that investigated fusion outcomes. Scientific validity of articles was appraised using the PRISMA methodology. Articles were critically examined and compared according to study design, DBM type, outcomes, and results. Primary outcome of interest was fusion rate. Secondary outcomes included Oswestry Disability Index; Short Form-36 survey; Odom's criteria; Visual Analog Scale neurologic pain score; Japanese Orthopedic Association myelopathy score; Neck Disability and Ishihara Curvature Indices; and pseudarthrosis and surgical failure rates. RESULTS: Demineralized Bone Matrix has been evaluated in animal models and human clinical trials of spine fusion. Results of animal studies indicate variation in performance within and among DBM products. The majority of human clinical trials report high fusion rates when DBM is employed as a graft extender or a graft enhancer. Few prospective randomized controlled trials have been performed comparing DBM to autologous iliac crest bone graft in spine fusion. CONCLUSIONS: Although many animal and human studies demonstrate comparable efficacy of DBM when combined with autograft or compared to autograft alone, additional high level of evidence studies are required to clearly define the indications for its use in spine fusion surgeries and the appropriate patient population that will benefit from DBM. PMID- 23040458 TI - Stature estimation from the lengths of the growing foot-a study on North Indian adolescents. AB - BACKGROUND AND AIMS: Stature estimation is considered as one of the basic parameters of the investigation process in unknown and commingled human remains in medico-legal case work. Race, age and sex are the other parameters which help in this process. Stature estimation is of the utmost importance as it completes the biological profile of a person along with the other three parameters of identification. The present research is intended to formulate standards for stature estimation from foot dimensions in adolescent males from North India and study the pattern of foot growth during the growing years. METHODS: 154 male adolescents from the Northern part of India were included in the study. Besides stature, five anthropometric measurements that included the length of the foot from each toe (T1, T2, T3, T4, and T5 respectively) to pternion were measured on each foot. The data was analyzed statistically using Student's t-test, Pearson's correlation, linear and multiple regression analysis for estimation of stature and growth of foot during ages 13-18 years. RESULTS: Correlation coefficients between stature and all the foot measurements were found to be highly significant and positively correlated. Linear regression models and multiple regression models (with age as a co-variable) were derived for estimation of stature from the different measurements of the foot. Multiple regression models (with age as a co-variable) estimate stature with greater accuracy than the regression models for 13-18 years age group. CONCLUSIONS: The study shows the growth pattern of feet in North Indian adolescents and indicates that anthropometric measurements of the foot and its segments are valuable in estimation of stature in growing individuals of that population. PMID- 23040459 TI - 3T tractography of the median nerve: optimisation of acquisition parameters and normative diffusion values. AB - PURPOSE: To define the optimal acquisition parameters for diffusion tensor imaging of the median nerve at the wrist and to measure the diffusion values. PATIENTS AND METHODS: The wrists of 14 healthy volunteers were explored using 3T MRI with a dedicated wrist coil. Each examination consisted of six sequences, varying the number of directions (15-20-30) and the b values (500-800-1000 2000s/mm(2)). The tractography images were evaluated by two radiologists using a qualitative scale with six levels. The diffusion and anisotropy coefficients (ADC and FA) were measured and the values compared with the data in the literature. RESULTS: Median nerve tractography was successfully achieved in all sequences. The 20 direction sequence with b=1000s/mm(2) seemed to provide the best results for a reasonable acquisition time (5'38"). The diffusion values showed large interindividual variations. CONCLUSION: Optimisation of acquisitions parameters is important in peripheral nerve tractography, and may facilitate a routine use of the technique. The images obtained are easy to analyse but the diffusivity and anisotropy coefficients are too variable, however, to be used in practice. PMID- 23040461 TI - Social competence: an evolutionary approach. AB - 'Social competence' refers to the ability of an individual to optimise its social behaviour depending on available social information. Although such ability will enhance social interactions and thus raise Darwinian fitness, its evolutionary and ecological significance has been largely ignored. Social competence is based on behavioural flexibility. We propose that the study of social competence requires an integrative approach that aims to understand how the brain translates social information into flexible behavioural responses, how flexibility might be constrained by the developmental history of an individual or by trade-offs with other (ecological) competences, and how social plasticity feeds back on fitness. Finally we propose a hypothesis of how social competence can become a driver of social evolution. PMID- 23040460 TI - Gut bacteria associated with different diets in reared Nephrops norvegicus. AB - The impact of different diets on the gut microbiota of reared Nephrops norvegicus was investigated based on bacterial 16S rRNA gene diversity. Specimens were collected from Pagasitikos Gulf (Greece) and kept in experimental rearing tanks, under in situ conditions, for 6months. Treatments included three diets: frozen natural (mussel) food (M), dry formulated pellet (P) and starvation (S). Gut samples were collected at the initiation of the experiment, and after 3 and 6months. Tank water and diet samples were also analyzed for bacterial 16S rRNA gene diversity. Statistical analysis separated the two groups fed or starved (M and P vs. S samples). Most gut bacteria were not related to the water or diet bacteria, while bacterial diversity was higher in the starvation samples. M and P samples were dominated by Gammaproteobacteria, Epsilonproteobacteria and Tenericutes. Phylotypes clustering in Photobacterium leiognathi, Shewanella sp. and Entomoplasmatales had high frequencies in the M and P samples but low sequence frequencies in S samples. The study showed that feeding resulted in the selection of specific species, which also occurs in the natural population, and might be associated with the animal's nutrition. PMID- 23040462 TI - Understanding and managing conservation conflicts. AB - Conservation conflicts are increasing and need to be managed to minimise negative impacts on biodiversity, human livelihoods, and human well-being. Here, we explore strategies and case studies that highlight the long-term, dynamic nature of conflicts and the challenges to their management. Conflict management requires parties to recognise problems as shared ones, and engage with clear goals, a transparent evidence base, and an awareness of trade-offs. We hypothesise that conservation outcomes will be less durable when conservationists assert their interests to the detriment of others. Effective conflict management and long-term conservation benefit will be enhanced by better integration of the underpinning social context with the material impacts and evaluation of the efficacy of alternative conflict management approaches. PMID- 23040463 TI - Heterogeneity of selection and the evolution of resistance. AB - The evolution of resistance to pesticides and drugs by pests and pathogens is a textbook example of adaptation to environmental changes and a major issue in both public health and agronomy. Surprisingly, there is little consensus on how to combine selection pressures (i.e., molecules used in the treatment of pests or pathogens) over space and time to delay or prevent this evolutionary process. By reviewing theoretical models and experimental studies, we show that higher levels of heterogeneity of selection are associated with longer-term sustainability of pest or pathogen control. The combination of molecules usually outcompetes other resistance management strategies, such as Responsive alternation, Periodic application, or Mosaic, because it ensures 'multiple intragenerational killing'. A strategic deployment over space and/or time of several combinations can ensure 'multiple intergenerational killing', further delaying the evolution of resistance. PMID- 23040464 TI - [Not Available]. PMID- 23040465 TI - [Not Available]. PMID- 23040466 TI - [Not Available]. PMID- 23040467 TI - [Not Available]. PMID- 23040468 TI - Suicide attempts and suicide in Iran: results of national hospital surveillance data. PMID- 23040469 TI - Predicting language: MEG evidence for lexical preactivation. AB - It is widely assumed that prediction plays a substantial role in language processing. However, despite numerous studies demonstrating that contextual information facilitates both syntactic and lexical-semantic processing, there exists no direct evidence pertaining to the neural correlates of the prediction process itself. Using magnetoencephalography (MEG), this study found that brain activity was modulated by whether or not a specific noun could be predicted, given a picture prime. Specifically, before the noun was presented, predictive contexts triggered enhanced activation in left mid-temporal cortex (implicated in lexical access), ventro-medial prefrontal cortex (previously associated with top down processing), and visual cortex (hypothesized to index the preactivation of predicted form features), successively. This finding suggests that predictive language processing recruits a top-down network where predicted words are activated at different levels of representation, from more 'abstract' lexical semantic representations in temporal cortex, all the way down to visual word form features. The same brain regions that exhibited enhanced activation for predictive contexts before the onset of the noun showed effects of congruence during the target word. To our knowledge, this study is one of the first to directly investigate the anticipatory stage of predictive language processing. PMID- 23040470 TI - Pluripotency network in embryonic stem cells: maybe Leibniz was right all along. AB - The transcription factors Tcf3 and Nanog regulate many genes in embryonic stem cells, but according to two reports in this issue of Cell Stem Cell (Festuccia et al., 2012, Martello et al., 2012), only one, Esrrb, encoding an orphan nuclear hormone receptor, truly matters in the maintenance of self-renewal. PMID- 23040471 TI - The satellite cell builds its nest under Notch's guidance. AB - Recently in Developmental Cell, Brohl et al. (2012) reported that Notch regulates muscle stem cell homing to its niche. Notch is required when myogenic cells cease producing new fibers and become sequestered between a newly forming basement membrane and the muscle fiber surface: the position that defines them as satellite cells. PMID- 23040472 TI - Order from chaos: single cell reprogramming in two phases. AB - The generation of induced pluripotent stem cells (iPSCs) is considered to be stochastic with a minute fraction of cells becoming pluripotent. Recently in Cell, Buganim et al. (2012) changed this view using single cell analyses to reveal a stochastic early and hierarchical late phase, with implications for productive alternative reprogramming strategies. PMID- 23040473 TI - Hematopoietic stem cells burn fat to prevent exhaustion. AB - Ito et al. (2012) recently report in Nature Medicine that fatty acid oxidation (FAO) regulated by PPARdelta controls asymmetric division in hematopoietic stem cells (HSCs). This metabolic mechanism prevents HSC exhaustion and is downstream of the promyelocytic leukemia protein PML, suggesting therapeutic implications for HSC function and disease. PMID- 23040474 TI - Identifying the stem cell of the intestinal crypt: strategies and pitfalls. AB - Decades ago, two nonoverlapping crypt stem cell populations were proposed: Leblond's Crypt Base Columnar (CBC) cell and Potten's +4 cell. The identification of CBC markers including Lgr5 has confirmed Leblond's predictions that CBC cells are anatomically distinct, long-lived stem cells that permanently cycle. While Potten originally described +4 cells as proliferative and unusually radiation sensitive, recent efforts to identify +4 stem cells have focused on the identification of cells that are quiescent and radiation-resistant. Here, we describe commonalities and discrepancies between the individual studies and discuss challenges of marker-based lineage tracing. PMID- 23040475 TI - Asymmetric stem cell division: precision for robustness. AB - Asymmetric cell division (ACD) produces two daughter cells with distinct fates or characteristics. Many adult stem cells use ACD as a means of maintaining stem cell number and thus tissue homeostasis. Here, we review recent progress on ACD, discussing conservation between stem and non-stem cell systems, molecular mechanisms, and the biological meaning of ACD. PMID- 23040476 TI - Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. AB - Reprogramming of somatic cells into neurons provides a new approach toward cell based therapy of neurodegenerative diseases. A major challenge for the translation of neuronal reprogramming into therapy is whether the adult human brain contains cell populations amenable to direct somatic cell conversion. Here we show that cells from the adult human cerebral cortex expressing pericyte hallmarks can be reprogrammed into neuronal cells by retrovirus-mediated coexpression of the transcription factors Sox2 and Mash1. These induced neuronal cells acquire the ability of repetitive action potential firing and serve as synaptic targets for other neurons, indicating their capability of integrating into neural networks. Genetic fate-mapping in mice expressing an inducible Cre recombinase under the tissue-nonspecific alkaline phosphatase promoter corroborated the pericytic origin of the reprogrammed cells. Our results raise the possibility of functional conversion of endogenous cells in the adult human brain to induced neuronal fates. PMID- 23040477 TI - Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells. AB - Embryonic stem cell (ESC) self-renewal efficiency is determined by the level of Nanog expression. However, the mechanisms by which Nanog functions remain unclear, and in particular, direct Nanog target genes are uncharacterized. Here we investigate ESCs expressing different Nanog levels and Nanog(-/-) cells with distinct functionally inducible Nanog proteins to identify Nanog-responsive genes. Surprisingly, these constitute a minor fraction of genes that Nanog binds. Prominent among Nanog-reponsive genes is Estrogen-related receptor b (Esrrb). Nanog binds directly to Esrrb, enhances binding of RNAPolII, and stimulates Esrrb transcription. Overexpression of Esrrb in ESCs maintains cytokine-independent self-renewal and pluripotency. Remarkably, this activity is retained in Nanog(-/ ) ESCs. Moreover, Esrrb can reprogram Nanog(-/-) EpiSCs and can rescue stalled reprogramming in Nanog(-/-) pre-iPSCs. Finally, Esrrb deletion abolishes the defining ability of Nanog to confer LIF-independent ESC self-renewal. These findings are consistent with the functional placement of Esrrb downstream of Nanog. PMID- 23040478 TI - Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal. AB - Inhibition of glycogen synthase kinase-3 (Gsk3) supports mouse embryonic stem cells (ESCs) by modulating Tcf3, but the critical targets downstream of Tcf3 are unclear. We analyzed the intersection between genome localization and transcriptome data sets to identify genes repressed by Tcf3. Among these, manipulations of Esrrb gave distinctive phenotypes in functional assays. Knockdown and knockout eliminated response to Gsk3 inhibition, causing extinction of pluripotency markers and loss of colony forming capability. Conversely, forced expression phenocopied Gsk3 inhibition or Tcf3 deletion by suppressing differentiation and sustaining self-renewal. Thus the nuclear receptor Esrrb is necessary and sufficient to mediate self-renewal downstream of Gsk3 inhibition. Leukaemia inhibitory factor (LIF) regulates ESCs through Stat3, independently of Gsk3 inhibition. Consistent with parallel operation, ESCs in LIF accommodated Esrrb deletion and remained pluripotent. These findings highlight a key role for Esrrb in regulating the naive pluripotent state and illustrate compensation among the core pluripotency factors. PMID- 23040479 TI - The Par complex and integrins direct asymmetric cell division in adult intestinal stem cells. AB - The adult Drosophila midgut is maintained by intestinal stem cells (ISCs) that generate both self-renewing and differentiating daughter cells. How this asymmetry is generated is currently unclear. Here, we demonstrate that asymmetric ISC division is established by a unique combination of extracellular and intracellular polarity mechanisms. We show that Integrin-dependent adhesion to the basement membrane induces cell-intrinsic polarity and results in the asymmetric segregation of the Par proteins Par-3, Par-6, and aPKC into the apical daughter cell. Cell-specific knockdown and overexpression experiments suggest that increased activity of aPKC enhances Delta/Notch signaling in one of the two daughter cells to induce terminal differentiation. Perturbing this mechanism or altering the orientation of ISC division results in the formation of intestinal tumors. Our data indicate that mechanisms for intrinsically asymmetric cell division can be adapted to allow for the flexibility in lineage decisions that is required in adult stem cells. PMID- 23040480 TI - Coordination of satellite cell activation and self-renewal by Par-complex dependent asymmetric activation of p38alpha/beta MAPK. AB - In response to muscle injury, satellite cells activate the p38alpha/beta MAPK pathway to exit quiescence, then proliferate, repair skeletal muscle, and self renew, replenishing the quiescent satellite cell pool. Although satellite cells are capable of asymmetric division, the mechanisms regulating satellite cell self renewal are not understood. We found that satellite cells, once activated, enter the cell cycle and a subset undergoes asymmetric division, renewing the satellite cell pool. Asymmetric localization of the Par complex activates p38alpha/beta MAPK in only one daughter cell, inducing MyoD, which permits cell cycle entry and generates a proliferating myoblast. The absence of p38alpha/beta MAPK signaling in the other daughter cell prevents MyoD induction, renewing the quiescent satellite cell. Thus, satellite cells employ a mechanism to generate distinct daughter cells, coupling the Par complex and p38alpha/beta MAPK signaling to link the response to muscle injury with satellite cell self-renewal. PMID- 23040482 TI - Reconstitution of mouse spermatogonial stem cell niches in culture. AB - Spermatogonial stem cells (SSCs) reside in specific niches within seminiferous tubules. These niches are thought to secrete chemotactic factors for SSCs, because SSCs migrate to them upon transplantation. However, the identity of these chemotactic molecules remains unknown. Here, we established a testis feeder cell culture system and used it to identify SSC chemotactic factors. When seeded on testis cells from infertile mice, SSCs migrated beneath the Sertoli cells and formed colonies with a cobblestone appearance that were very similar to those produced by hematopoietic stem cells. Cultured cells maintained SSC activity and fertility for at least 5 months. Cobblestone colony formation depended on GDNF and CXCL12, and dominant-negative GDNF receptor transfection or CXCL12 receptor deficiency reduced SSC colonization. Moreover, GDNF upregulated CXCL12 receptor expression, and CXCL12 transfection in Sertoli cells increased homing efficiency. Overall, our findings identify GDNF and CXCL12 as SSC chemotactic factors in vitro and in vivo. PMID- 23040483 TI - Liver histopathology in Baltic eelpout (Zoarces viviparus) - A baseline study for use in marine environmental monitoring. AB - The use of liver histopathology in various fish species as a biomarker in marine monitoring programmes to assess the biological effect of exposure to anthropogenic contaminants is well established. However, although the eelpout (Zoarces viviparus) has repeatedly been recommended as an appropriate bioindicator for monitoring purposes in the Baltic Sea, information on histopathological liver alterations of this species is scarce. In order to obtain an overview, a total of 1070 eelpout, collected in the period between spring 2001 and winter 2010 from 34 sampling sites distributed over large parts of the Baltic Sea, were histologically analyzed. Liver lesions were recorded and classified according to established liver lesion categories. A high prevalence of non specific and early toxicopathic non-neoplastic hepatic lesions was recorded. In contrast, pre-neoplastic lesions were observed only in rare cases and neoplastic changes were absent. A comparison with published data on other fish species revealed that the observed alterations may indicate effects of environmental stressors including contaminants. The results of the present study, thus, support the application of eelpout liver histopathology in environmental monitoring. PMID- 23040481 TI - Signaling from the sympathetic nervous system regulates hematopoietic stem cell emergence during embryogenesis. AB - The first adult-repopulating hematopoietic stem cells (HSCs) emerge in the aorta gonads-mesonephros (AGM) region of the embryo. We have recently identified the transcription factor Gata3 as being upregulated in this tissue specifically at the time of HSC emergence. We now demonstrate that the production of functional and phenotypic HSCs in the AGM is impaired in the absence of Gata3. Furthermore, we show that this effect on HSC generation is secondary to the role of Gata3 in the production of catecholamines, the mediators of the sympathetic nervous system (SNS), thus making these molecules key components of the AGM HSC niche. These findings demonstrate that the recently described functional interplay between the hematopoietic system and the SNS extends to the earliest stages of their codevelopment and highlight the fact that HSC development needs to be viewed in the context of the development of other organs. PMID- 23040484 TI - [Not Available]. PMID- 23040485 TI - [Not Available]. PMID- 23040487 TI - [Not Available]. PMID- 23040486 TI - [Not Available]. PMID- 23040488 TI - [Not Available]. PMID- 23040489 TI - Clinical impact of switching conventional enzyme immunoassay with nucleic acid amplification test for suspected Clostridium difficile-associated diarrhea. AB - The impact of a new Clostridium difficile nucleic acid amplification test (NAAT) on antibiotic utilization in patients with suspected C difficile infection was assessed. This single-center, cross-sectional study of 270 patients demonstrated that the use of NAAT decreased antibiotic expenditure by reducing prolonged empiric days of therapy in these patients. PMID- 23040490 TI - Lifting the lid on toilet plume aerosol: a literature review with suggestions for future research. AB - BACKGROUND: The potential risks associated with "toilet plume" aerosols produced by flush toilets is a subject of continuing study. This review examines the evidence regarding toilet plume bioaerosol generation and infectious disease transmission. METHODS: The peer-reviewed scientific literature was searched to identify articles related to aerosol production during toilet flushing, as well as epidemiologic studies examining the potential role of toilets in infectious disease outbreaks. RESULTS: The studies demonstrate that potentially infectious aerosols may be produced in substantial quantities during flushing. Aerosolization can continue through multiple flushes to expose subsequent toilet users. Some of the aerosols desiccate to become droplet nuclei and remain adrift in the air currents. However, no studies have yet clearly demonstrated or refuted toilet plume-related disease transmission, and the significance of the risk remains largely uncharacterized. CONCLUSION: Research suggests that toilet plume could play a contributory role in the transmission of infectious diseases. Additional research in multiple areas is warranted to assess the risks posed by toilet plume, especially within health care facilities. PMID- 23040491 TI - Device-associated infection rates, device use, length of stay, and mortality in intensive care units of 4 Chinese hospitals: International Nosocomial Control Consortium findings. AB - BACKGROUND: Little data exist on the burden of device-associated health care associated infection (DA-HAI) in China. This study examined the DA-HAI rate and evaluated its association with device use (DU), length of stay (LOS), and mortality in intensive care units (ICUs) in 4 Chinese hospitals. METHODS: This was a prospective cohort surveillance study conducted in 7 ICUs in 4 hospitals. We applied International Nosocomial Control Consortium methods and Centers for Disease Control and Prevention (CDC)/National Health and Safety Network (NHSN) definitions to determine rates of central line-associated blood stream infection (CLABSI), ventilator-associated pneumonia (VAP), catheter-associated urinary tract infection (CAUTI), DU, crude extra length of hospital stay (LOS), and mortality. RESULTS: Between August 2008 and July 2010, there were a total of 2,631 admissions to the 7 ICUs in the study hospitals. The rate of VAP was 10.46/1,000 mechanical ventilator (MV)-days, the CLABSI rate was 7.66/1,000 central line (CL)-days, and the CAUTI rate was 1.29/1,000 urinary catheter (UC) days. Pooled DU ratios were 0.43 for MV, 0.71 for CL, and 0.76 for UC. Crude extra LOS was 15 days for patients with CLABSI, 20.5 days for patients with VAP, and 27 days for patients with CAUTI. Crude extra mortality was 14% for patients with CLABSI, 22% for patients with VAP, and 43% for patients with CAUTI. CONCLUSIONS: In the study ICUs, VAP and CLABSI rates were higher than CDC/NHSN's reported data, and LOS and mortality were increased. Compared with the CDC/NHSN and INICC data, the pooled DU ratio for MV was similar, and DU ratios for CL and UC use ratios were slightly higher. PMID- 23040492 TI - Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. AB - Sequencing of gene-coding regions (the exome) is increasingly used for studying human disease, for which copy-number variants (CNVs) are a critical genetic component. However, detecting copy number from exome sequencing is challenging because of the noncontiguous nature of the captured exons. This is compounded by the complex relationship between read depth and copy number; this results from biases in targeted genomic hybridization, sequence factors such as GC content, and batching of samples during collection and sequencing. We present a statistical tool (exome hidden Markov model [XHMM]) that uses principal-component analysis (PCA) to normalize exome read depth and a hidden Markov model (HMM) to discover exon-resolution CNV and genotype variation across samples. We evaluate performance on 90 schizophrenia trios and 1,017 case-control samples. XHMM detects a median of two rare (<1%) CNVs per individual (one deletion and one duplication) and has 79% sensitivity to similarly rare CNVs overlapping three or more exons discovered with microarrays. With sensitivity similar to state-of-the art methods, XHMM achieves higher specificity by assigning quality metrics to the CNV calls to filter out bad ones, as well as to statistically genotype the discovered CNV in all individuals, yielding a trio call set with Mendelian inheritance properties highly consistent with expectation. We also show that XHMM breakpoint quality scores enable researchers to explicitly search for novel classes of structural variation. For example, we apply XHMM to extract those CNVs that are highly likely to disrupt (delete or duplicate) only a portion of a gene. PMID- 23040493 TI - Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata. AB - Uterine leiomyomata (UL), the most prevalent pelvic tumors in women of reproductive age, pose a major public health problem given their high frequency, associated morbidities, and most common indication for hysterectomies. A genetic component to UL predisposition is supported by analyses of ethnic predisposition, twin studies, and familial aggregation. A genome-wide SNP linkage panel was genotyped and analyzed in 261 white UL-affected sister-pair families from the Finding Genes for Fibroids study. Two significant linkage regions were detected in 10p11 (LOD = 4.15) and 3p21 (LOD = 3.73), and five additional linkage regions were identified with LOD scores > 2.00 in 2q37, 5p13, 11p15, 12q14, and 17q25. Genome-wide association studies were performed in two independent cohorts of white women, and a meta-analysis was conducted. One SNP (rs4247357) was identified with a p value (p = 3.05 * 10(-8)) that reached genome-wide significance (odds ratio = 1.299). The candidate SNP is under a linkage peak and in a block of linkage disequilibrium in 17q25.3, which spans fatty acid synthase (FASN), coiled-coil-domain-containing 57 (CCDC57), and solute-carrier family 16, member 3 (SLC16A3). By tissue microarray immunohistochemistry, we found elevated (3-fold) FAS levels in UL-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival. FASN represents the initial UL risk allele identified in white women by a genome-wide, unbiased approach and opens a path to management and potential therapeutic intervention. PMID- 23040494 TI - An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome associated atrioventricular septal defects. AB - About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and ~65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans. PMID- 23040495 TI - Population genetic inference from personal genome data: impact of ancestry and admixture on human genomic variation. AB - Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in today's African Americans dates back to European gene flow happening only 7-8 generations ago. PMID- 23040496 TI - Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia. AB - Motile cilia are essential components of the mucociliary escalator and are central to respiratory-tract host defenses. Abnormalities in these evolutionarily conserved organelles cause primary ciliary dyskinesia (PCD). Despite recent strides characterizing the ciliome and sensory ciliopathies through exploration of the phenotype-genotype associations in model organisms, the genetic bases of most cases of PCD remain elusive. We identified nine related subjects with PCD from geographically dispersed Amish communities and performed exome sequencing of two affected individuals and their unaffected parents. A single autosomal recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function. Airway epithelial cells isolated from PCD-affected individuals had markedly reduced HEATR2 levels, absent dynein arms, and loss of ciliary beating. MicroRNA-mediated silencing of the orthologous gene in Chlamydomonas reinhardtii resulted in absent outer dynein arms, reduced flagellar beat frequency, and decreased cell velocity. These findings were recapitulated by small hairpin RNA-mediated knockdown of HEATR2 in airway epithelial cells from unaffected donors. Moreover, immunohistochemistry studies in human airway epithelial cells showed that HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly. The identification of HEATR2 contributes to the growing number of genes associated with PCD identified in both individuals and model organisms and shows that exome sequencing in family studies facilitates the discovery of novel disease-causing gene mutations. PMID- 23040498 TI - Illuminating potential technical artifacts of DNA-methylation array probes. PMID- 23040497 TI - Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31 32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death. PMID- 23040499 TI - Cross-reactive DNA microarray probes lead to false discovery of autosomal sex associated DNA methylation. PMID- 23040500 TI - Coparenting in teen mothers and their children's fathers: evidence from the early childhood longitudinal study-birth cohort. AB - OBJECTIVE: (1) To describe coparenting among adolescent mothers and the biological fathers of their children. (2) To examine the effects of coparenting on young children's social-emotional development and whether these effects vary by father's residence status, parental education, and child characteristics. METHODS: Secondary analysis was conducted with the Early Childhood Longitudinal Study-Birth Cohort, which is a nationally representative sample of U.S. children born in 2001. The subsample used in this study includes 400 children whose biological mothers, aged 15-19, participated when their children were 2 years and 4 years old and whose biological fathers (residential and nonresidential) participated at 4 years. Cooperative coparenting and coparenting conflict were measured at child age 2 years. Children's social skills and problem behavior were measured at child age 4 years. RESULTS: Mother- and father-reported coparenting conflict were associated with child behavior problems, more strongly among boys (b = 1.31, P < .01) than girls (b = -0.13, P > .05). Mother-reported coparenting conflict also predicted lower child social skills (b = -1.28, P < .05); the association of father-reported coparenting conflict with social skills was moderated by child race and father education. CONCLUSIONS: Coparenting conflict between adolescent parents influences child adjustment. Practitioners working with teen mothers should encourage father participation at medical visits and other clinical contacts and should address the relationship between the parents, whether or not they are living together, as part of routine care. PMID- 23040501 TI - Inhibition of the human epithelial calcium channel TRPV6 by 2-aminoethoxydiphenyl borate (2-APB). AB - TRPV6, a highly calcium-selective member of the transient receptor potential (TRP) channel superfamily, is a major pathway for calcium absorption in the fetal and adult body. It is expressed abundantly in the duodenum, the placenta and exocrine tissues. TRVP6 was postulated to contribute to store-operated calcium channel (SOC) activity in certain cell types such as exocrine cells. In this study, we tested 2-APB, a widely used SOC inhibitor on human TRPV6 (hTRPV6) activity using fluorescence imaging, patch clamp and radioactive tracer techniques in transiently and stably transfected HEK293 cells. We found that the basal calcium and cadmium influx was higher in HEK293 cells transfected with hTRPV6 than in non-transfected cells. 2-APB inhibited hTRPV6 activity in both transient and stably transfected cells. This effect was slightly sensitive toward extracellular calcium. The extracellular sodium concentration did not affect the inhibition of hTRPV6 by 2-APB. However, N-methyl-d-glucamine significantly diminished the inhibitory effect of 2-APB presumably through direct interaction with this compound. Furthermore, 2-APB inhibited the activity of TRPV6 orthologs but not human TRPV5. 2-APB may serve as a parental compound for the development of therapeutic strategies specifically targeting the hTRPV6 calcium channel. PMID- 23040502 TI - Teaching receiver operating characteristic analysis: an interactive laboratory exercise. AB - RATIONALE AND OBJECTIVES: Despite its fundamental importance in the evaluation of diagnostic tests, receiver operating characteristic (ROC) analysis is not easily understood. The purpose of this project was to create a learning experience that resulted in an intuitive understanding of the basic principles of ROC analysis. MATERIALS AND METHODS: An interactive laboratory exercise was developed for a class about radiology testing taught within a clinical epidemiology course between 2000 and 2009. The physician students in the course were clinical fellows from various medical specialties who were enrolled in a graduate degree program in clinical investigation. For the exercise, the class was divided into six groups. Each group interpreted radiographs from a set of 50 exams of the peripheral skeleton to determine the presence or absence of an acute fracture. Data from the class were pooled and given to each student. Students calculated the area under the ROC curve (AUC) corresponding to overall class performance. A binormal ROC curve was also fitted to the data from each class year. RESULTS: The laboratory exercise was conducted for 8 years with approximately 20-30 students per year. The mean AUC over the eight laboratory classes was 0.72 with a standard deviation of 0.08 (range, 0.60-0.85). CONCLUSION: With some simplifications in design, an observer study can be conducted in a laboratory classroom setting. Participatory data collection promotes the intuitive understanding of ROC analysis principles. PMID- 23040503 TI - Application of threshold-bias independent analysis to eye-tracking and FROC data. AB - RATIONALE AND OBJECTIVES: Studies of medical image interpretation have focused on either assessing radiologists' performance using, for example, the receiver operating characteristic (ROC) paradigm, or assessing the interpretive process by analyzing their eye-tracking (ET) data. Analysis of ET data has not benefited from threshold-bias independent figures of merit (FOMs) analogous to the area under the receiver operating characteristic (ROC) curve. The aim was to demonstrate the feasibility of such FOMs and to measure the agreement between FOMs derived from free-response ROC (FROC) and ET data. METHODS: Eight expert breast radiologists interpreted a case set of 120 two-view mammograms while eye position data and FROC data were continuously collected during the interpretation interval. Regions that attract prolonged (>800 ms) visual attention were considered to be virtual marks, and ratings based on the dwell and approach-rate (inverse of time-to-hit) were assigned to them. The virtual ratings were used to define threshold-bias independent FOMs in a manner analogous to the area under the trapezoidal alternative FROC (AFROC) curve (0 = worst, 1 = best). Agreement at the case level (0.5 = chance, 1 = perfect) was measured using the jackknife and 95% confidence intervals (CI) for the FOMs and agreement were estimated using the bootstrap. RESULTS: The AFROC mark-ratings' FOM was largest at 0.734 (CI 0.65 0.81) followed by the dwell at 0.460 (0.34-0.59) and then by the approach-rate FOM 0.336 (0.25-0.46). The differences between the FROC mark-ratings' FOM and the perceptual FOMs were significant (P < .05). All pairwise agreements were significantly better then chance: ratings vs. dwell 0.707 (0.63-0.88), dwell vs. approach-rate 0.703 (0.60-0.79) and rating vs. approach-rate 0.606 (0.53-0.68). The ratings vs. approach-rate agreement was significantly smaller than the dwell vs. approach-rate agreement (P = .008). CONCLUSIONS: Leveraging current methods developed for analyzing observer performance data could complement current ways of analyzing ET data and lead to new insights. PMID- 23040504 TI - Genomic stability in reprogramming. AB - The genetic stability of induced pluripotent stem (iPS) cells has a significant impact on their potential use in regenerative medicine and basic research. Analysis of the genomic integrity of iPS cells suggests a tendency to develop aberrations ranging from whole chromosome trisomies to single nucleotide mutations. Furthermore, fluctuations in telomere elongation and changes in mitochondrial DNA are also observed. Some mutations may already exist in the founder cells or result from prolonged culturing, however, many of the mutations occur during the reprogramming event. Thus, great care should be given to the initial characterization and subsequent culturing of new iPS cell lines in order to avoid the use of potentially aberrant cells. PMID- 23040505 TI - The cultural context of diagnosis: the case of Vincent van Gogh. AB - Hardly anyone has been posthumously diagnosed as much as Vincent van Gogh. This article does not attempt to add yet another illness to the long list, nor indeed to make any definite statement about the 'right diagnosis'. Rather, it attempts to place the diagnoses actually made during his lifetime into their historical and cultural context. It examines how these diagnoses were imbedded in the medical paradigms popular at the time, and how these paradigms in their turn relate to the general cultural context of the era. It also shows how the 'patient' reacted to the diagnoses presented to him and to the underlying medical paradigms. Those who give diagnoses and those who receive them are involved in the same cultural context, taking for granted the medical fashions of their times, including the biases incorporated in them. PMID- 23040506 TI - Factors associated with injuries occurred on slope intersections and in snow parks compared to on-slope injuries. AB - In alpine winter sports, external risk factors as snow and weather conditions as well as slope characteristics (width, steepness, slope intersections, and snow parks) should be considered when investigating potential risk factors. Therefore, ski patrol injury reports were used to compare factors associated with injuries occurred on slope intersections and in snow parks compared to on-slope injuries. Multivariate regression analysis revealed that in comparison to injuries occurring on ski slopes, collisions with other persons (OR: 2.1, 95% CI: 1.3-3.4) and arm injuries (OR: 2.1, 95% CI: 1.3-3.5) were more likely associated with injuries occurring on slope intersections while male gender (OR: 3.5, 95% CI: 2.1 5.7), younger age (OR: 1.1, 95% CI: 1.0-1.1), slushy/soft snow conditions (OR: 1.9, 95% CI: 1.1-3.3), knee injuries (OR: 0.4, 95% CI: 0.2-0.8) and back injuries (OR: 5.5, 95% CI: 3.0-10.2) were more likely associated with injuries which occurred in snow parks. In conclusion, injuries on slope intersections and in snow parks differ in some factors from injuries sustained on ski slopes. PMID- 23040507 TI - How does a modal shift from short car trips to cycling affect road safety? AB - Governments aim to promote a shift from car to bicycle, but concerns about road safety seem to represent an important argument against this encouragement. This study examines the road safety impact of a modal shift from short car trips to cycling in Dutch municipalities. The road safety effect is estimated using Accident Prediction Models (APMs) that account for the non-linearity of risk. APMs are developed utilizing Negative Binomial regression. This study is the first to develop APMs using crash and mobility data from municipalities, and utilizing these models to estimate the effects of changing modal splits of current car and bicycle use to modal splits that actually exist in these municipalities. The results suggest that, under conditions such as in Dutch municipalities, transferring short trips made by cars to bicycles does not change the number of fatalities, but increases the number of serious road injuries. The neutral effect on fatalities, despite the high fatality risk for cyclists, can be explained by there being fewer cars on the road to pose a risk to others, the shorter length of bicycle trips compared to the car trips they replace, and the "safety in numbers" phenomenon. The rise in the number of serious road injuries is due wholly to the high number of cycling crashes with no other vehicle involved. The effect of a modal shift is dependent on the age of the population in which the shift is concentrated, and can be influenced by measures affecting cyclists' injury risk. PMID- 23040508 TI - Does facing traffic improve pedestrian safety? AB - This study was designed to evaluate the potential safety importance of the walking direction along a road by examining pedestrian accidents as a function of exposure to risk. The study was limited to rural two-lane roads with no pavement or pedestrian lane. The accident data included police-reported road accidents from Finland between 2006 and 2010 in which a motorized vehicle had struck a pedestrian walking along the road. There were 18 accidents involving a fatally injured pedestrian and 87 accidents involving a non-fatally injured pedestrian. The exposure data collected from the roughly 3400km included 258 pedestrians. The main finding was that the mean effect of facing traffic compared to walking with traffic was a 77% decrease in fatal and in non-fatal injury pedestrian accidents. The results further showed that the effects were greater for main roads than for secondary roads. The main implication of this study is that information about the importance of facing traffic should be reinforced with specific information about its substantial safety benefits. PMID- 23040509 TI - Courts and health care rationing: the case of the Brazilian Federal Supreme Court. AB - The recognition that access to health care is a constitutional right in Brazil has resulted in a situation in which citizens denied treatments by the public health care system have brought lawsuits against health authorities, claiming that their right to health was violated. This litigation forces the courts to decide between a patient-centred and a population-centred approach to public health - a choice that forces the courts to assess health care rationing decisions. This article analyses the judgments of the Brazilian Federal Supreme Court in right to health cases, arguing that the Court's recent decisions have been contrary to their long-standing stance against rationing. In 2009, the Court organized a public hearing to discuss this topic with civil society and established criteria to determine when rationing would be legal. However, I argue that these criteria for health care rationing do not adequately address the most difficult health care distribution dilemmas. They force the health care system to keep their rationing criteria implicit and make population-centred concerns secondary to individual-centred ones. PMID- 23040510 TI - NIa-pro of Papaya ringspot virus interacts with papaya methionine sulfoxide reductase B1. AB - A chloroplast-localized papaya methionine sulfoxide reductase B1 (PaMsrB1) interacting with Papaya ringspot virus (PRSV) NIa-Pro was identified using a Sos recruitment two-hybrid system (SRS). SRS analysis of several deletion mutants of PRSV NIa-Pro and PaMsrB1 demonstrated that the C-terminal (residues 133-239) fragment of PRSV NIa-Pro and residues 112-175 of PaMsrB1 were necessary for this interaction between PRSV NIa-Pro and PaMsrB1. MsrB1 can repair Met-oxidized proteins damaged by reactive oxygen species (ROS). We confirmed that PRSV infection leads to ROS accumulation and a slight upregulation of level PaMsrB1 mRNA in papaya. This interaction between PaMsrB1 with PRSV NIa-Pro may disturb the import of PaMsrB1 into the chloroplasts. These results suggest that this specific interaction could interfere with PaMsrB1 into the chloroplasts to scavenge ROS caused by PRSV infection. This may be a novel mechanism of PRSV towards the host defense. PMID- 23040511 TI - Mycobacterium simiae pulmonary infection unmasked during immune reconstitution in an HIV patient. AB - Highly active antiretroviral therapy in human immunodeficiency virus (HIV) patients may trigger the onset of immune reconstitution inflammatory syndrome (IRIS). Among HIV patients with IRIS, infections are commonly due to Mycobacterium tuberculosis and nontuberculous mycobacteria. We report the first case in Spain and the second in Europe of Mycobacterium simiae pulmonary infection unmasked during immune reconstitution in an HIV patient. PMID- 23040513 TI - Aclimatacion y cambios producidos en los registros fonocardiograficos durante una escalada a gran altitud. PMID- 23040512 TI - Investigation of Mycoplasma pneumoniae infection in pediatric population from 12,025 cases with respiratory infection. AB - Although Mycoplasma pneumoniae (MP) is a major pathogen of primary atypical pneumonia in children, the clinical and laboratory characteristics of MP infection in large pediatric population are less reported. Here, we retrospectively analyzed 12,025 hospitalized children with respiratory infection by using serology and polymerase chain reaction (PCR) methods simultaneously. The results showed that 2433 (20.23%) children had MP infection, which mainly occurred in November to April. The presence of sore throat and pharyngitis was peculiar to MP infection. The positive percentage of MP-DNA was higher than that of MP-IgM in children aged <1 (P < 0.0001) and 1-3 years (P < 0.0001). Moreover, the positive rate of P1 gene, the key adhesion gene for MP infection, was higher in children with MP infection than in those with other pathogens (P < 0.0001). Our work provides the clinical information of children MP infection and highlights the superiority of PCR and potential usage of P1 as a diagnosis target for MP infection. PMID- 23040514 TI - [Not Available]. PMID- 23040515 TI - [Not Available]. PMID- 23040516 TI - [Not Available]. PMID- 23040517 TI - An ABA-regulated putative RNA-binding protein affects seed germination of Arabidopsis under ABA or abiotic stress conditions. AB - Diverse RNA-binding proteins (RBPs) have increasingly been determined to perform crucial roles in posttranscriptional regulation of RNA metabolism during plant response to abscisic acid (ABA) or abiotic stresses, but the functional roles of a variety of ABA-responsive RBPs in ABA and stress response remain poorly understood. Here, we characterized an ABA-regulated putative RBP (At3g54770) in Arabidopsis thaliana, designated ARP1, for its role in response to ABA or abiotic stresses. The expression of ARP1 was markedly downregulated by ABA, and ARP1 is localized to the nucleus. Interestingly, both overexpression and knockout of ARP1 resulted in delayed seed germination under ABA, high salt, or dehydration stress conditions. The identical phenotypes of ARP1-overexpressing plants and the arp1 null mutant indicate that a tight regulation of ARP1 transcript is required for normal function. Transcript levels of several germination-responsive genes were modulated by ARP1 under ABA. Taken together, the results of the present study demonstrate that ARP1 affects ABA-regulated seed germination of Arabidopsis, and indicate that the regulation of posttranscriptional RNA metabolism is critical in plant response to ABA or abiotic stresses. PMID- 23040518 TI - Reduction of spoilage of chilled vacuum-packed lamb by psychrotolerant clostridia. AB - Methods for the reduction of spoilage, of lamb, by psychrotolerant clostridia were investigated including exposure to air, hot and cold water spray washing and tyndallisation. Initially vegetative cells of psychrotolerant clostridia associated with spoilage of chilled vacuum-packed meat were exposed to aerobic cooked meat medium at room temperature (21 degrees C) to determine how long they remained viable. Survival of strains varied from 2h to 3 days. Vegetative cells of Clostridium estertheticum subsp. estertheticum survived 7 days at 10 degrees C with little reduction in viable numbers. This ruled out exposure to air as a practical method for reducing spoilage. Trials were also carried out on chilled vacuum-packed lamb inoculated with spores of Cl. estertheticum subsp. estertheticum. The time until inoculated packs reached the loss of vacuum stage varied from 38 to 53 days. Hot and cold water washing extended the shelf life by 12 to 13 days in comparison to untreated packs. PMID- 23040519 TI - Parenting processes and aggression: the role of self-control among Turkish adolescents. AB - The present study examined the direct and indirect relationships between parenting processes (parental closeness, parental monitoring, and parental peer approval), low self-control, and aggression. Participants were 546 adolescents aged 14-18 attending state high schools in Turkey. Participants completed a questionnaire that included measures of parenting processes, self-control, and aggression. Findings provided evidence of both direct and indirect effects of maternal and paternal parenting processes on aggression through low self-control. Specifically, results showed that maternal closeness, paternal peer approval and both maternal and paternal monitoring were positively and directly related to low self-control, and indirectly related to aggression through low self-control. Together, parenting processes and low self-control explained 21% of the variance in aggression. Implications for self-control theory and directions for future research are discussed. PMID- 23040520 TI - [Technicians and ultrasound]. PMID- 23040521 TI - A randomized controlled trial to evaluate the effects of high-dose versus low dose of arginine therapy on hepatic function tests in argininosuccinic aciduria. AB - OBJECTIVE: To compare the effects of combinatorial therapy with low-dose arginine and a nitrogen scavenging agent (sodium phenylbutyrate) vs. monotherapy with high dose arginine on liver function tests in patients with argininosuccinic aciduria (ASA). STUDY DESIGN: Twelve patients with ASA were enrolled in a double-blind, placebo-controlled, cross-over study design. Subjects were randomized to receive either a low-dose of arginine therapy (100 mg . kg(-1) . d(-1)) combined with sodium phenylbutyrate (500 mg . kg(-1) . d(-1)) (LDA arm) or a high-dose of arginine alone (500 mg . kg(-1) . d(-1)) (HDA arm) for one week. At the end of one week of therapy, liver function tests were assessed and metabolite fluxes were measured using a multi-tracer stable isotope protocol. RESULTS: Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and measures of synthetic functions of the liver were the primary outcomes. Subjects had significantly increased levels of argininosuccinate (P<0.03) and AST levels (P<0.01) after treatment with high-dose arginine. In the subset of subjects with elevated AST or ALT, treatment with high-dose of arginine was associated with further increases in plasma levels of both aminotransferases. Whereas subjects had increased arginine and citrulline flux with high-dose arginine therapy, the glutamine flux was not different between the two treatment arms. The synthetic liver functions as assessed by prothrombin time, INR, and coagulation factor levels were not different between the HDA and LDA arms. CONCLUSIONS: Administering higher doses of arginine in subjects with ASA results in increases in AST and ALT levels, especially in the subset of patients with elevated baseline aminotransferases. Hence, low-dose arginine sufficient to normalize arginine levels in plasma combined with nitrogen scavenging therapy should be considered as a therapeutic option for treatment of ASA in patients with elevations of hepatic aminotransferases. PMID- 23040522 TI - Apolipoprotein E and familial longevity. AB - Exceptional longevity is associated with substantial heritability. The epsilon4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the epsilon2 allele with decreased mortality, although inconsistently. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n = 2307) and spouse controls (n = 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE epsilon4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p = 0.005 and OR, 0.70; p = 0.002) and the likelihood of carrying an APOE epsilon2 allele was higher (OR, 1.5; p = 0.007) among family members in the offspring generation than among their spouse controls. Our findings support the hypothesis that both reduction in the frequency of the epsilon4 allele and increase in the frequency of the epsilon2 allele contribute to longevity. PMID- 23040524 TI - Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. AB - OBJECTIVE: To examine the available evidence to assess if cryopreservation of all embryos and subsequent frozen embryo transfer (FET) results in better outcomes compared with fresh transfer. DESIGN: Systematic review and meta-analysis. SETTING: Centers for reproductive care. PATIENT(S): Infertility patient(s). INTERVENTION(S): An exhaustive electronic literature search in MEDLINE, EMBASE, and the Cochrane Library was performed through December 2011. We included randomized clinical trials comparing outcomes of IVF cycles between fresh and frozen embryo transfers. MAIN OUTCOME MEASURE(S): The outcomes of interest were ongoing pregnancy rate, clinical pregnancy rate, and miscarriage. RESULT(S): We included three trials accounting for 633 cycles in women aged 27-33 years. Data analysis showed that FET resulted in significantly higher ongoing pregnancy rates and clinical pregnancy rates. CONCLUSION(S): Our results suggest that there is evidence that IVF outcomes may be improved by performing FET compared with fresh embryo transfer. This could be explained by a better embryo-endometrium synchrony achieved with endometrium preparation cycles. PMID- 23040523 TI - Serum insulin-like factor 3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose human chorionic gonadotropin: a randomized, controlled trial. AB - OBJECTIVE: To study the potential role for using serum biomarkers, including insulin-like factor 3 (INSL3), 17alpha-hydroxyprogesterone, antimullerian hormone, and inhibin B, as correlates of intratesticular T (IT-T) concentrations in men. DESIGN: Prospective, randomized, controlled trial. SETTING: University based medical center. PATIENT(S): Thirty-seven healthy men aged 18-50 years. INTERVENTION(S): All men received the GnRH antagonist acyline, plus very low doses of hCG (0 IU, 15 IU, 60 IU, or 125 IU) SC every other day or 7.5 g T gel daily (75 mg delivered). The IT-T concentrations obtained by percutaneous testicular aspiration with simultaneous serum protein and steroid concentrations were measured at baseline and after 10 days of treatment. MAIN OUTCOME MEASURE(S): Intratesticular and serum hormone and gonadotropin concentrations. RESULT(S): After 10 days of gonadotropin suppression, serum INSL3 decreased by more than 90% and correlated highly with IT-T concentrations. In contrast, serum inhibin B, antimullerian hormone, and 17alpha-hydroxyprogesterone did not correlate with IT-T. Serum INSL3 increased with the dose of hCG administered and returned to baseline after treatment. CONCLUSION(S): Serum INSL3 correlates highly with IT-T and serum T concentrations during acute gonadotropin suppression in men. Human chorionic gonadotropin stimulates dose-dependent increases in INSL3 and IT-T in healthy men and might be a useful biomarker of IT-T concentration in some clinical settings. CLINICAL TRIAL REGISTRATION NUMBER: NCT# 00839319. PMID- 23040525 TI - Involvement of the inflammasome in abnormal semen quality of men with spinal cord injury. AB - OBJECTIVE: To study the mechanism leading to elevated semen cytokines in men with spinal cord injury (SCI) and to understand if inflammasome pathways are involved in this process. To investigate inflammasome components and end-product cytokines in semen of SCI and control subjects. DESIGN: Prospective study. SETTING: Major university medical center. PATIENT(S): Men with and without SCI (n = 28 per group). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Seminal plasma concentrations of caspase-1, interleukin (IL) 1beta, and IL-18 were quantified by ELISA. Caspase-1 in sperm fractions and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) in seminal plasma and sperm fractions were identified by Western blot. Localization of proteins in sperm was accomplished by immunocytochemistry. RESULT(S): ASC, caspase-1, IL 1beta, and IL-18 concentrations were elevated in the seminal plasma of SCI subjects compared with control subjects. ASC and caspase-1 were elevated in sperm cells of SCI subjects. Immunocytochemistry revealed that ASC was located in the acrosome, equatorial segment, and midpiece, and caspase-1 in the midpiece. CONCLUSION(S): This study provides the first evidence of ASC in human semen and demonstrates the involvement of inflammasome proteins in semen of men with SCI. These findings suggest an immunologic basis for abnormal semen quality in men with SCI. PMID- 23040526 TI - Pregnancy in dark winters: implications for fetal bone growth? AB - OBJECTIVE: To prospectively examine the prevalence of hypovitaminosis D in pregnancy and to correlate maternal and fetal vitamin D to fetal anthropometry. DESIGN: A prospective cohort study. SETTING: Tertiary referral maternity hospital. PATIENT(S): Sixty pregnant women. INTERVENTION(S): Serum 25 hydroxyvitamin D (25OHD) was measured in early pregnancy, at 28 weeks, and in cord blood at delivery. MAIN OUTCOME MEASURE(S): The prevalence of hypovitaminosis D and the relationship between fetal growth and serum 25OHD concentrations. RESULT(S): Two subgroups were analyzed to examine results in the context of seasonal variation in 25OHD: a winter and a summer cohort. Fetal anthropometry was assessed at 20 and 34 weeks, and at delivery the neonatal anthropometry was recorded. There was a high prevalence of hypovitaminosis D ranging from 33% to 97%, with a marked seasonal variation. Fetal 25OHD concentrations correlated with all biometry at 20 weeks. In the winter cohort, a correlation was found between early pregnancy 25OHD and femur length at 20 weeks, and between 28-week 25OHD and femur length at 34 weeks. Infant length was shorter in those with early pregnancy 25OHD less than the median (52.1 vs. 53.6 cm). CONCLUSION(S): The high prevalence of maternal hypovitaminosis D during winter months in northern latitudes may have detrimental effects on fetal skeletal growth. PMID- 23040527 TI - Variance in total levels of phospholipase C zeta (PLC-zeta) in human sperm may limit the applicability of quantitative immunofluorescent analysis as a diagnostic indicator of oocyte activation capability. AB - OBJECTIVE: To examine whether similar levels of phospholipase C zeta (PLC-zeta) protein are present in sperm from men whose ejaculates resulted in normal oocyte activation, and to examine whether a predominant pattern of PLC-zeta localization is linked to normal oocyte activation ability. DESIGN: Laboratory study. SETTING: University laboratory. PATIENT(S): Control subjects (men with proven oocyte activation capacity; n = 16) and men whose sperm resulted in recurrent intracytoplasmic sperm injection failure (oocyte activation deficient [OAD]; n = 5). INTERVENTION(S): Quantitative immunofluorescent analysis of PLC-zeta protein in human sperm. MAIN OUTCOME MEASURE(S): Total levels of PLC-zeta fluorescence, proportions of sperm exhibiting PLC-zeta immunoreactivity, and proportions of PLC zeta localization patterns in sperm from control and OAD men. RESULT(S): Sperm from control subjects presented a significantly higher proportion of sperm exhibiting PLC-zeta immunofluorescence compared with infertile men diagnosed with OAD (82.6% and 27.4%, respectively). Total levels of PLC-zeta in sperm from individual control and OAD patients exhibited significant variance, with sperm from 10 out of 16 (62.5%) exhibiting levels similar to OAD samples. Predominant PLC-zeta localization patterns varied between control and OAD samples with no predictable or consistent pattern. CONCLUSION(S): The results indicate that sperm from control men exhibited significant variance in total levels of PLC-zeta protein, as well as significant variance in the predominant localization pattern. Such variance may hinder the diagnostic application of quantitative PLC-zeta immunofluorescent analysis. PMID- 23040528 TI - Validation of a clinical risk scoring system, based solely on clinical presentation, for the management of pregnancy of unknown location. AB - OBJECTIVE: To assess a scoring system to triage women with a pregnancy of unknown location. DESIGN: Validation of prediction rule. SETTING: Multicenter study. PATIENT(S): Women with a pregnancy of unknown location. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Scores assigned to factors identified at clinical presentation, total score calculated to assess risk of ectopic pregnancy (EP) in women with a pregnancy of unknown location, and a proposed three-tiered clinical action plan. RESULT(S): The cohort of 1,400 women (284 ectopic pregnancies, 759 miscarriages, and 357 intrauterine pregnancies) was more diverse than the original cohort used to develop the decision rule. The recommendations of the action plan were low risk, intermediate risk, and high risk; the recommendation based on the model score was compared with clinical diagnosis. A total of 29.4% intrauterine pregnancies were identified for less frequent follow-up observation, and 18.4% nonviable gestations were identified for more frequent follow-up observation (to rule out an ectopic pregnancy) compared with intermediate risk (i.e., monitor in current standard fashion). For a decision of possible less frequent monitoring, the specificity was 90.8% (89.0-92.6) with negative predictive value of 79.0% (76.7-81.3). For a decision of more intense follow-up observation, the specificity was 95.0% (92.7-97.2). Test characteristics using the scoring system were replicated in the diverse validation cohort. CONCLUSION(S): A scoring system based on symptoms at presentation has value to stratify risk and influence the intensity of outpatient surveillance for women with pregnancy of unknown location but does not serve as a diagnostic tool. PMID- 23040529 TI - Disclosure of duplicative studies: damned if you don't. AB - Duplicative publication requires duplicative editorializing. There are many forms of lesser redundancy such as unacknowledged secondary analyses of randomized clinical trials, fragmentation of studies with concurrent submission to various journals, and serial updating of observational studies. These practices result in publication bias. We have revised our instructions to authors to include disclosure of similar articles that are published, in press, or submitted to other journals to the editors upon submission. PMID- 23040530 TI - Autonomy following revascularisation in 80-year-old patients with critical limb ischaemia. AB - OBJECTIVES: We wanted to compare autonomy recovery after open and endovascular infrainguinal surgery for critical limb ischaemia (CLI) in octogenarians. MATERIALS AND METHODS: We performed a retrospective analysis of 167 consecutive CLI octogenarians who underwent infrainguinal open surgery (OS) or endovascular surgery (ES) between 2003 and 2008. OS and ES groups were compared in terms of autonomy level (Parker score), survival, limb salvage and patency rates. RESULTS: Preoperative autonomy level was similar in both groups (OS n = 109, ES n = 58) but 6-month postoperative autonomy level was better after ES (p = 0.01). There was a trend towards better survival after OS (74% at 1 year, 62% at 2 years, 32% at 4 years with OS and 68%, 50%, 17% respectively for ES p = 0.06), but no difference regarding limb salvage (91% at 1 year, 90% at 2 years, 89% at 4 years for OS and 94%, 87%, 86% respectively for ES, p = 0.939) and primary patency (76% at 1 year, 59% at 2 years, 50% at 4 years for OS and 82%, 75%, 32% respectively for ES, p = 0.467). CONCLUSIONS: ES is justified in CLI octogenarians, because it allows restoring a higher autonomy level, with limb salvage and patency rates comparable to OS. PMID- 23040531 TI - Enhancement of antigen presenting ability in the leukemic plasmacytoid dendritic cell line (PMDC05) by lentiviral vector-mediated transduction of CD80 gene. AB - PMDC05, a leukemic plasmacytoid dendritic cell (pDC) line which was established in our laboratory, showed a capacity of generating antigen-specific cytotoxic T lymphocytes (CTLs). In order to enhance an antigen presenting ability of PMDC05, PMDC05 was transduced with CD80 gene by lentiviral vector, which was named as PMDC11. PMDC11 displayed a strong antigen presenting ability even without any stimulation, and by culturing with stimulators such as calcium ionophore PMDC11 gained a more potent antigen presenting ability. Our data suggested PMDC11 could be applied as antigen presenting cells more efficiently in adoptive cellular immunotherapy for tumors and severe infections in comparison with PMDC05. PMID- 23040532 TI - Symposium on Myeloid Neoplasms on June 9, 2012 in honor of Dr. John M. Bennett. PMID- 23040533 TI - Clinical value of metabolic tumor volume by PET/CT in extranodal natural killer/T cell lymphoma. AB - This study investigated whether metabolic tumor volume (MTV) by PET/CT as indicator of extent of lymphoma burden would be a prognostic factor in stage I(E)/II(E) extranodal natural killer/T cell lymphoma (ENKTCL). Eighty patients with stage I(E)/II(E) ENKTCL in the upper aerodigestive tract underwent PET/CT at diagnosis were enrolled and 32 patients received upfront radiotherapy (RTx). MTV was measured on PET/CT images by the extranodal region above SUV, 2.5. Receiver operating curve analyses indicated that an MTV of 35.2 cm(3) was the ideal cut off to distinguish between low and high MTV groups. Clinical outcomes were compared according to several prognostic factors (age, stage, high performance status [PS], high International Prognostic Index, elevated lactate dehydrogenase [LDH], local tumor invasiveness [LTI], high MTV and up-front RT). High PS, elevated LDH, LTI, high MTV and upfront RT were associated with survivals. In multivariate analysis, high MTV (PFS, HR=4.170, 95% CI=1.714-10.147, p=0.002; OS, HR=4.102, 95% CI=1.617-10.408, p=0.003) and up-front RT (PFS, HR=0.410, 95%CI=0.178-0.946, p=0.037; OS, HR=0.365, 95% CI=0.152-0.872, p=0.023) were significant independent prognostic factors. Upfront RTx and extent of tumor burden, as measured by the MTV, had significant prognostic value in patients with ENKTCL. PMID- 23040534 TI - HLA-E and HLA class I molecules on bone marrow and peripheral blood polymorphonuclear cells of myelodysplatic patients. AB - Relevance of immune-dysregulation for emergence, dominance and progression of dysplastic clones in myelodysplastic syndromes (MDS) was suggested, but valuable or predictive criteria on this involvement are lacking. We previously reported that reduced T-regulatory cells (Treg) and high CD54 expression on T cell identify a sub-group of patients in whom an immune-pathogenesis might be inferred. Here, we suggest the occurrence of immune-selection of dysplastic clones in a subgroup of MDS patients, with reduced HLA-I and HLA-E on PMN, and propose that an altered immune profile might represent a valuable criterion to classify Low/Int-1 patients on the basis of immune-pathogenesis of MDS. PMID- 23040536 TI - Effect of temperature, relative humidity and rainfall on rotavirus infections in Kolkata, India. AB - Rotavirus is a common viral cause of severe diarrhoea. For the underlying cause of rotavirus seasonality, the meteorological factor has been suspected, whereas quantitative correlation between seasonality and meteorological factor has not been fully investigated. In this study, we investigated the correlation of temporal patterns of the isolation rate of rotavirus with meteorological condition (temperature, relative humidity, rainfall) in Kolkata, India. We used time-series analysis combined with spectral analysis and least squares method. A 1-year cycle explained underlying variations of rotavirus and meteorological data. The 1-year cycle for rotavirus data was correlated with an opposite phase to that for meteorological data. Relatively high temperature could be associated with a low value of isolation rate of rotavirus in the monsoon season. Quantifying a correlation of rotavirus infections with meteorological conditions might prove useful in predicting rotavirus epidemics and health services could plan accordingly. PMID- 23040535 TI - Pilot study of nurse-led rheumatic heart disease echocardiography screening in Fiji--a novel approach in a resource-poor setting. AB - We designed a pilot study of a training module for nurses to perform rheumatic heart disease echocardiography screening in a resource-poor setting. The aim was to determine whether nurses given brief, focused, basic training in echocardiography could follow an algorithm to potentially identify cases of rheumatic heart disease requiring clinical referral, by undertaking basic two dimensional and colour Doppler scans. Training consisted of a week-long workshop, followed by 2 weeks of supervised field experience. The nurses' skills were tested on a blinded cohort of 50 children, and the results were compared for sensitivity and specificity against echocardiography undertaken by an expert, using standardised echocardiography definitions for definite and probable rheumatic heart disease. Analysis of the two nurses' results revealed that when a mitral regurgitant jet length of 1.5 cm was used as the trigger for rheumatic heart disease identification, they had a sensitivity of 100% and 83%, respectively, and a specificity of 67.4% and 79%, respectively. This pilot supports the principle that nurses, given brief focused training and supervised field experience, can follow an algorithm to undertake rheumatic heart disease echocardiography in a developing country setting to facilitate clinical referral with reasonable accuracy. These results warrant further research, with a view to developing a module to guide rheumatic heart disease echocardiographic screening by nurses within the existing public health infrastructure in high-prevalence, resource-poor regions. PMID- 23040537 TI - Dual-energy CT and its potential use for quantitative myocardial CT perfusion. AB - Application of quantitative myocardial CT perfusion (CTP) for the assessment of coronary artery disease may have a significant effect on patient care as the functional significance of a coronary stenosis can be evaluated through absolute measurement of the downstream myocardial perfusion (MP) both at rest and under exercise or pharmacologic stress. A main challenge of myocardial CTP is beam hardening (BH), arising from the polychromatic nature of x-rays used in CT scanning and the presence of highly attenuating contrast agent in the heart chambers during the CT acquisition. The BH effect induces significant nonuniform shifts in CT numbers which, if uncorrected, can lead to inaccurate assessment of MP. With the recent developments of dual-energy CT (DECT) scanning on clinical scanners, the BH effect on MP measurement could be reduced with the generation of monochromatic images relatively free of BH artifacts from the acquired dual energy data. Here, we review the different techniques of acquiring dual-energy scans and generating monochromatic images, followed by discussion on the progress of developing a DECT technique with reduced radiation dose for quantitative myocardial CTP. PMID- 23040538 TI - Automated assessment of heart chamber volumes and function in patients with previous myocardial infarction using multidetector computed tomography. AB - BACKGROUND: Left ventricular (LV), right ventricular (RV), and left atrial (LA) volumes and functions contain important prognostic information in ischemic heart disease. Because multidetector computed tomography (MDCT) has high spatial resolution, this method may be optimal to obtain this information. OBJECTIVE: We evaluated automated assessment for MDCT, by comparing it with cardiac magnetic resonance (CMR). METHODS: Fifty-three patients with previous myocardial infarction were scanned with 1.5 Tesla CMR and 64-slice MDCT. End-diastolic volume, end-systolic volume, stroke volume, and ejection fraction (EF) were assessed for the left and right ventricle with automatic MDCT software and manual CMR software. LV myocardial mass and cyclic changes in LA volume were derived. RESULTS: The mean age of patients was 61 +/- 10 years, 40 (75%) were men. Automated MDCT segmentation was possible in all but 2 patients. The average duration of image processing was 21 +/- 4 minutes by CMR and 11 +/- 4 minutes by MDCT. Bland-Altman plots showed good agreement between MDCT and CMR with only small bias. LVEF by CMR was 56% +/- 10% and by MDCT 61% +/- 11%, mean difference of -5% (limits of agreement, -18% to 8%), and P < 0.001. RVEF by CMR was 60% +/- 5% and by MDCT 56% +/- 8%, mean difference of 5% (limits of agreement, -10% to 20%), and P < 0.001. LA fractional change by CMR was 49% +/- 9% and by MDCT 45% +/- 9%, mean difference of 4% (limits of agreement, -12% to 20%), and P <= 0.001. CONCLUSION: LV, RV, and LA volumes and functions may be evaluated fast and reliably with the use of automated assessment and cardiac MDCT, with good agreement to CMR. Accurate assessment of cardiac chambers with MDCT appears possible in clinical practice. PMID- 23040539 TI - Diagnosis of anomalous origin and course of coronary arteries using non-contrast cardiac CT scan and detection features. AB - BACKGROUND: Anomalous origin and course of coronary arteries (AOCA) is a potential cause of sudden cardiac death. Coronary CT angiography (coronary CTA) enables detailed 3-dimensional visualization of AOCA. Data are limited about the diagnostic performance of noncontrast cardiac CT obtained during coronary calcium scan for detecting AOCA. OBJECTIVE: We assessed the feasibility of using noncontrast cardiac CT for detecting AOCA. METHODS: Participants had noncontrast cardiac CT and coronary CTA performed (2005-2010). Cases had AOCA as diagnosed with coronary CTA. Controls were without AOCA. Noncontrast cardiac CT images were independently evaluated for AOCA by a cardiologist and a radiologist blinded to prior AOCA diagnosis. Detection features to assist AOCA diagnosis on noncontrast cardiac CT were evaluated. RESULTS: The study enrolled 54 cases and 155 controls. Sensitivity and specificity for detecting AOCA were 82% (95% CI, 69%-90%) and 90% (95% CI, 85%-94%) for observer 1, respectively, and 82% (95% CI, 69%-90%) and 85% (95% CI, 79%-90%) for observer 2, respectively. Average sensitivity and specificity were 82% and 88%, respectively. Interobserver agreement (Cohen kappa) was kappa = 0.65 (95% CI, 0.53-0.76). Inability to visualize the right coronary artery (RCA) origin at the right sinus significantly predicted RCA anomaly. Inability to visualize the left main coronary artery branching point into the left anterior descending coronary artery and the left circumflex coronary artery significantly predicted left coronary artery anomaly. CONCLUSION: Noncontrast cardiac CT in conjunction with detection features has the potential for use in the diagnosis of AOCA. A prospective study is needed for validation and to determine the modality's accuracy for detecting AOCA. PMID- 23040540 TI - Oxytocin, stress and social behavior: neurogenetics of the human oxytocin system. AB - The neuropeptide oxytocin has had key roles throughout mammalian evolution in the regulation of complex social cognition and behaviors, such as attachment, parental care, pair-bonding, as well as social exploration and recognition. Recently, studies have begun to provide evidence that the function of this neuropeptide is impaired in mental disorders associated with social deficits. In this review, we focus on the genetic mechanisms of inter-individual variation in the social neuropeptide signaling. We discuss molecular genetic studies which identified variations in specific genes contributing to individual differences in social behavior and cognition, with a focus on the gene coding for the oxytocin receptor (OXTR) emerging as a particularly promising candidate. We conclude that molecular studies are warranted to elucidate functional consequences of variants that have shown stable associations with sociobehavioral phenotypes. With regard to the variability in individual responses to oxytocin administration, we advocate the need for pharmacogenetic approaches in order to test how the efficacy of oxytocin administration is modulated by genetic variation of OXTR or other genes involved in oxytocin signaling. PMID- 23040541 TI - Neurogenetics and auditory processing in developmental dyslexia. AB - Dyslexia is a polygenic developmental reading disorder characterized by an auditory/phonological deficit. Based on the latest genetic and neurophysiological studies, we propose a tentative model in which phonological deficits could arise from genetic anomalies of the cortical micro-architecture in the temporal lobe. PMID- 23040542 TI - Teleconsultation in paediatric orthopaedics in Djibouti: evaluation of response performance. AB - BACKGROUND: Djibouti has no paediatric orthopaedics department and three options are available for difficult cases: transfer of the patient to another country; overseas mission transfer to Djibouti by a specialised surgical team; and management by a local orthopaedic surgeon receiving guidance from an expert. The extreme poverty of part of the population of Djibouti often precludes the first two options. Telemedecine can allow the local orthopaedic surgeon to receive expert advice. HYPOTHESES AND STUDY DESIGN: We prospectively recorded all the paediatric orthopaedics teleconsultations that occurred between November 2009 and November 2011. Our objective was to assess the performance of the teleconsultations. We hypothetized that this option was influential in decision making. MATERIALS AND METHODS: We assessed the influence of the teleconsultation on patient management (i.e., change in the surgical indication and/or procedure). We then used the electronic patient records to compare the actual management to that recommended retrospectively by two independent orthopaedic surgeon consultants who had experience working overseas. Finally, we assessed the clinical outcomes in the patients. RESULTS: Of 48 teleconsultations for 39 patients, 13 dealt with diagnostic problems and 35 with therapeutic problems. The teleconsultation resolved the diagnostic uncertainties in 90% of cases. Advice from the expert modified the management in 37 (77%) teleconsultations; the change was related to the surgical indication in 18 cases, the surgical technique in 13 cases, and both in six cases. Agreement between the advice from the independent consultants and the treatment delivered by the local surgeon was 2.2/3. Clinical outcomes were good or very good in 31 (81%) of the 38 treated patients. CONCLUSIONS: This study establishes the feasibility and usefulness of paediatric orthopaedics teleconsultations in Djibouti. The introduction of telemedicine has changed our approach to challenges raised by patients in remote locations or precarious situations. Input from experts considerably benefits patient management. LEVEL OF EVIDENCE: III, prospective comparative study. PMID- 23040543 TI - Efficacy of a CD22-targeted antibody-saporin conjugate in a xenograft model of precursor-B cell acute lymphoblastic leukemia. AB - Targeted therapies, such as those using imatinib and rituximab, have revolutionized the treatment of Philadelphia chromosome-positive and CD20 positive acute lymphoblastic leukemia (ALL) respectively, yet these therapies are effective in only a subset of patients and remission is generally not durable. The next generation of targeted therapies includes the use of antibodies conjugated to potent cytotoxic agents and are classified as antibody drug conjugates (ADC). For B-lineage ALL, CD22 is an ideal target for ADC therapy because it is expressed on the majority of B-lineage ALL cells and because antibody binding mediates receptor internalization. HB22.7-SAP is a conjugate of our anti-CD22 monoclonal antibody (mAb), HB22.7, and the ribosome inhibiting protein, saporin (SAP). In vitro, HB22.7-SAP effectively bound to CD22 on the surface of pre-B ALL cell lines and exhibited potent and specific cytotoxicity. In a NOD/SCID xenograft mouse model of pre-B ALL, when compared to the vehicle treated control, HB22.7-SAP increased the median survival time from 20 days to over 50 days without significant toxicity. PMID- 23040544 TI - Inhibitory actions of a local neural reflex on propulsive activity of the esophageal striated muscle portion in rats. AB - The aim of the present study was to clarify functional roles of a local neural reflex in propulsive activity of the rat esophageal striated muscle. Firstly, we established a method for measuring the volume of fluid expelled from an isolated esophageal segment to evaluate propulsive activity. Electrical stimulation to vagus nerves induced propulsion of intraluminal solution in the esophageal segment. The vagally evoked propulsion was abolished in the presence of d tubocurarine. Next, this quantitative method was applied to examine the functional roles of intrinsic nerves in the esophagus. Capsaicin, a stimulant of primary afferents, inhibited the vagally mediated propulsion. A nitric oxide synthase inhibitor or a selective tachykinin NK(1) receptor antagonist significantly blocked the inhibitory effect of capsaicin. These findings suggest that the local neural reflex, which consists of tachykininergic and nitrergic neurons, might participate in modulation of propulsive activity in the striated muscle portion of the rat esophagus. PMID- 23040546 TI - Time dependent history improves QT interval estimation in atrial fibrillation. AB - PURPOSE: It is not recommended to perform QTc estimation in patients with atrial fibrillation (AF). We evaluated multiple QT interval correction formulas, including a novel time-dependent history approach, in an effort to identify the best method for correcting the QT interval in patients with AF. The ideal correction results in independence between the QTc estimate and HR. METHODS: Per beat characteristics were derived using SuperECG (Mortara Instrument). Offline beat-to-beat QTc interval estimates were constructed using standard formulae and averaged (2-10) groups constructed. RESULTS: Seventy-one patients were included, age 67 +/- 10 years, 69% men. Mean-mean QTc intervals varied by correction (range 394-459 ms). Averaging resulted in the same mean-mean QTc estimate, but significantly reduced variability by up to 55%. Time-dependent RR interval history reduced variability the most (Delta 80%), increased QT/RR dynamics (m=.03 vs .17), and was independent with HR (m = 0.0008). CONCLUSIONS: Our data suggests that QTc interval estimation in patients with AF can be performed reliably using time-dependent history (RRc) outperforming other correction methods. PMID- 23040545 TI - Patient-physician communication about complementary and alternative medicine in a radiation oncology setting. AB - PURPOSE: Despite the extensive use of complementary and alternative medicine (CAM) among cancer patients, patient-physician communication regarding CAM therapies remains limited. This study quantified the extent of patient-physician communication about CAM and identified factors associated with its discussion in radiation therapy (RT) settings. METHODS AND MATERIALS: We conducted a cross sectional survey of 305 RT patients at an urban academic cancer center. Patients with different cancer types were recruited in their last week of RT. Participants self-reported their demographic characteristics, health status, CAM use, patient physician communication regarding CAM, and rationale for/against discussing CAM therapies with physicians. Multivariate logistic regression was used to identify relationships between demographic/clinical variables and patients' discussion of CAM with radiation oncologists. RESULTS: Among the 305 participants, 133 (43.6%) reported using CAM, and only 37 (12.1%) reported discussing CAM therapies with their radiation oncologists. In multivariate analyses, female patients (adjusted odds ratio [AOR] 0.45, 95% confidence interval [CI] 0.21-0.98) and patients with full-time employment (AOR 0.32, 95% CI 0.12-0.81) were less likely to discuss CAM with their radiation oncologists. CAM users (AOR 4.28, 95% CI 1.93-9.53) were more likely to discuss CAM with their radiation oncologists than were non-CAM users. CONCLUSIONS: Despite the common use of CAM among oncology patients, discussions regarding these treatments occur rarely in the RT setting, particularly among female and full-time employed patients. Clinicians and patients should incorporate discussions of CAM to guide its appropriate use and to maximize possible benefit while minimizing potential harm. PMID- 23040547 TI - Influence of education and age on the abbreviated mental test in Chinese nursing home older adults. PMID- 23040548 TI - Epidemiology, natural history, and indications for treatment of rotator cuff tears. AB - The etiology of rotator cuff disease is likely multifactorial, including age related degeneration and microtrauma and macrotrauma. The incidence of rotator cuff tears increases with aging with more than half of individuals in their 80s having a rotator cuff tear. Smoking, hypercholesterolemia, and genetics have all been shown to influence the development of rotator cuff tearing. Substantial full thickness rotator cuff tears, in general, progress and enlarge with time. Pain, or worsening pain, usually signals tear progression in both asymptomatic and symptomatic tears and should warrant further investigation if the tear is treated conservatively. Larger (>1-1.5 cm) symptomatic full-thickness cuff tears have a high rate of tear progression and, therefore, should be considered for earlier surgical repair in younger patients if the tear is reparable and there is limited muscle degeneration to avoid irreversible changes to the cuff, including tear enlargement and degenerative muscle changes. Smaller symptomatic full-thickness tears have been shown to have a slower rate of progression, similar to partial thickness tears, and can be considered for initial nonoperative treatment due to the limited risk for rapid tear progression. In both small full-thickness tears and partial-thickness tears, increasing pain should alert physicians to obtain further imaging as it can signal tear progression. Natural history data, along with information on factors affecting healing after rotator cuff repair, can help guide surgeons in making appropriate decisions regarding the treatment of rotator cuff tears. The management of rotator cuff tears should be considered in the context of the risks and benefits of operative versus nonoperative treatment. Tear size and acuity, the presence of irreparable changes to the rotator cuff or glenohumeral joint, and patient age should all be considered in making this decision. Initial nonoperative care can be safely undertaken in older patients (>70 years old) with chronic tears; in patients with irreparable rotator cuff tears with irreversible changes, including significant atrophy and fatty infiltration, humeral head migration, and arthritis; in patients of any age with small (<1 cm) full-thickness tears; or in patients without a full-thickness tear. Early surgical treatment can be considered in significant (>1 cm-1.5 cm) acute tears or young patients with full-thickness tears who have a significant risk for the development of irreparable rotator cuff changes. PMID- 23040549 TI - Imaging evaluation of the rotator cuff. AB - The rotator cuff is a complex network of interwoven tendons that plays a key role in glenohumeral movement and stability. Cuff abnormality is a common source of shoulder pain, but the clinical presentation is often nonspecific and, as a result, diagnostic imaging, especially magnetic resonance imaging, plays a key role in evaluating these patients. This article reviews imaging modalities available for evaluating the cuff, normal cuff anatomy, and common pathologic conditions that affect it. PMID- 23040550 TI - Arthroscopic rotator cuff repair: techniques in 2012. AB - Techniques for arthroscopic partial-thickness and full-thickness RTC repairs continue to advance. When selecting an RTC repair technique, it is important to identify the tear pattern and adhere to the fundamentals of tendon mobilization and footprint preparation. Partial RTC tears greater than 50% in thickness can be reproducibly repaired with tear completion or transtendinous techniques with good clinical outcomes. Based on the available literature, small, less than 1-cm RTC tears can effectively be repaired with single-row techniques. Tears sized 1 cm to 3 cm can be repaired with either single-row, double-row, or transosseous equivalent techniques based on surgeon comfort, tendon quality, and tissue mobility. Tears greater than 3 cm have shown superior results when transosseous equivalent techniques are used. Further clinical studies are needed to definitively conclude the ideal RTC repair technique. PMID- 23040551 TI - Biologics in the management of rotator cuff surgery. AB - The rotator cuff enthesis is not reestablished after a rotator cuff repair. Instead, a scar-mediated healing response occurs at the tendon-bone interface, which is notably weaker than the native enthesis and thus more prone to failure. Biological augmentation through growth factors, AASs, biomimetic scaffolds, or siRNA therapy has the potential to enhance the healing response. The ultimate key, however, is in determining which of these enables a more regenerative healing response of the native tissue rather than enhanced production of scar tissue. In addition, the optimal combination of factors, dosing, and delivery methods remains to be clearly elucidated. Biological augmentation and tissue engineering for tendon healing remains promising, but much work still needs to be done. PMID- 23040552 TI - Outcomes of rotator cuff surgery: what does the evidence tell us? AB - Rotator cuff disease accounts for more than 4.5 million annual visits to a physician, and more than 75,000 surgical repairs are performed a year. Surgical techniques have evolved from all open repairs to all arthroscopic repairs being the most commonly used. The purpose of this article is to review the current evidence regarding the outcomes of surgical techniques in rotator cuff surgery. Reported outcomes have been favorable with open, mini-open, and arthroscopic repairs. Recently, a committee sponsored by the AAOS published a clinical practice guideline summary regarding the management of rotator cuff tears. The guidelines touched aspects of both nonoperative and operative repair. In regard to operative repair, the committee could not recommend a modality of surgical repair (eg, arthroscopic vs open) as a superior method, citing a lack of comparative studies. The theoretical advantage of arthroscopic surgery lies in smaller soft tissue dissection and the ability to evaluate and treat the glenohumeral joint. However, no study using patient-based outcomes has shown superiority compared with open or mini-open repairs. With the method of surgical repair not changing outcomes, investigation has recently focused on optimizing bone-tendon healing in rotator cuff repair. Double-row fixation allows for a more anatomic reapproximation of the rotator cuff footprint on the greater tuberosity versus single-row and has been shown to be biomechanically superior. Despite this, no clinical studies have shown superiority of one type of repair versus the other. The AAOS committee citing similar evidence gave a weak recommendation for the use of achieving tendon-to-bone healing with double-row fixation. Transosseous-equivalent repair, which provides a high compressive force on the tendon-to-bone interface of repair, is the newest fixation method under investigation to optimize healing. The use of collagen and biologic augmentation has gained interest as researchers are attempting to optimize rotator cuff healing. There is moderate evidence against the use of porcine small intestine submucosa xenograft patches. Other commercially available collagen augments have yet to be proven as either beneficial or detrimental. Other than PRP, which has not shown to have any benefit augmenting repair, no biologic augment has been investigated clinically. Overall, rotator cuff surgery portends a good outcome for appropriately selected patients. However, there is not much high-quality evidence-based research that can be used to conclude what surgical treatments are superior or appropriate for a given patient. Future research should be aimed at identifying whether and in whom rotator cuff healing is appropriate to better identify surgical candidates as well as to determine the best surgical repair strategy. PMID- 23040553 TI - Rotator cuff tears in overhead athletes. AB - The rotator cuff is under significant stress during overhead athletics, which can predictably lead to a certain spectrum of rotator cuff injuries in this population. Although the cause is often multifactorial; tensile overload, outlet impingement, and internal impingement are common causes of cuff pathologic conditions in this group. Identification of symptomatic rotator cuff disease can be challenging in the overhead athlete because abnormalities of the rotator cuff are common in asymptomatic throwers and rotator cuff pathologic conditions often occur in conjunction with other injuries. Although nonoperative options should be exhausted, surgical treatment is typically necessary for any rotator cuff tear for which conservative treatment fails. Tear thickness has been classically used to determine the surgical approach, with tears involving less than 50% of the tendon thickness treated with debridement and more substantial tears treated with formal repair. However, some authors and some noted surgeons with experience in managing this patient population have more recently advocated a higher threshold of tendon involvement before considering formal repair. Multiple repair options have been described, but few reports have focused specifically on the outcomes of rotator cuff surgery in overhead athletes. The limited available data do lead, however, to a few reasonable conclusions. Surgical results typically correlate with tear severity. Partial-thickness tears treated with arthroscopic debridement and management of concomitant pathologic conditions seem to have fairly good outcomes in the literature, with most athletes able to return to activity at their preinjury level. Full-thickness tears, however, have fared much more poorly in the overhead athlete, with largely dismal outcomes after surgical repair. What is abundantly clear is that further refinement of surgical options is necessary to improve patient outcomes after rotator cuff repair in this particularly challenging patient population and to allow more consistent return to sports. Identification of symptomatic rotator cuff disease can be challenging in the overhead athlete because abnormalities of the rotator cuff are common in asymptomatic throwers and rotator cuff pathologic conditions often occur in conjunction with other injuries. Although nonoperative options should be exhausted, surgical treatment is typically necessary for any rotator cuff tear for which conservative treatment fails. Tear thickness has been classically used to determine the surgical approach, with tears involving less than 50% of the tendon thickness treated with debridement and more substantial tears treated with formal repair. However, some authors and some noted surgeons with experience in managing this patient population have more recently advocated a higher threshold of tendon involvement before considering formal repair. Multiple repair options have been described, but few reports have focused specifically on the outcomes of rotator cuff surgery in overhead athletes. The limited available data do lead, however, to a few reasonable conclusions. Surgical results typically correlate with tear severity. Partial-thickness tears treated with arthroscopic debridement and management of concomitant pathologic conditions seem to have fairly good outcomes in the literature, with most athletes able to return to activity at their preinjury level. Full-thickness tears, however, have fared much more poorly in the overhead athlete, with largely dismal outcomes after surgical repair. What is abundantly clear is that further refinement of surgical options is necessary to improve patient outcomes after rotator cuff repair in this particularly challenging patient population and to allow more consistent return to sports. PMID- 23040554 TI - Failed rotator cuff surgery, evaluation and decision making. AB - Rotator cuff repair is very likely to be clinically successful when performed well and rehabilitated properly, especially when judged with patient satisfaction outcome scores. A healed rotator cuff tendon will likely result in an improved and lasting clinical result. Recurrent tears will still be present despite optimal mobilization and fixation of the rotator cuff to bone, especially in large tears with retraction and atrophy. Failure of rotator cuff repairs is multifactorial with biologic factors, such as age, tear size, and fatty infiltration probably most critical. Other patient-related factors (ie, diabetes, smoking), recurrent trauma, and technical error at the time of surgery also contribute to rotator cuff repair failure. When managing a patient with a symptomatic re-tear, revision rotator cuff repair can be a very successful procedure, but patient selection is critical and managing patient expectations is paramount. Ideal candidates for revision rotator cuff repair have minimal muscle atrophy, minimal tendon retracted, preoperative forward elevation of greater than 90 degrees , a functioning deltoid, and no evidence of cuff tear arthropathy. PMID- 23040555 TI - Revision rotator cuff repair. AB - The management of patients with a failed rotator cuff repair is challenging. Revision arthroscopic repairs can be entertained in select patients when realistic outcomes are understood. Complete evaluation of the shoulder is needed to identify and treat potential confounding pain generators. The ability to determine if a recurrent tear is repairable is difficult, because there are no established criteria to make this determination. If a recurrent tear is found to be repairable, the results of the surgery are encouraging, although persistent limitations in shoulder function are common. Strategies to improve the rates of tendon healing should be used and include the use of stronger repair constructs, when possible, and implementation of a slower rehabilitation progression. PMID- 23040556 TI - Nonarthroplasty options for the management of massive and irreparable rotator cuff tears. AB - Massive, irreparable rotator cuff tears remain a clinical challenge. In low demand patients, debridement of the tear may relieve pain. Partial repair using the technique of margin convergence decreases the size of the tear gap and reduces strain. Biceps tenotomy or tenodesis has a role in providing pain relief in massive rotator cuff tears. Tendon transfers offer good results in patients with massive, irreparable rotator cuff tears. The treatment modality specifically chosen for the massive, irreparable rotator cuff tear must be tailored to the individual patient, their needs and expectations, and their ability to comply with intensive rehabilitation. PMID- 23040557 TI - Reverse total shoulder arthroplasty for irreparable rotator cuff tears and cuff tear arthropathy. AB - Based on the available literature, we believe that reverse shoulder arthroplasty is a reasonable treatment modality in patients with CTA and massive irreparable cuff tears. RSA has been shown to increase patient function and decrease pain. There are still a high number of complications related to this procedure; however, with stringent patient selection criteria and meticulous technique, high patient satisfaction scores are typically achieved in these patients, at least in the short term. Further studies are required to evaluate the efficacy these devices in the long term. PMID- 23040560 TI - Is patient satisfaction in primary care dependent on structural and organizational characteristics among providers? Findings based on data from the national patient survey in Sweden. AB - In parallel to market-like reforms in Swedish primary care, the gathering and compilation of comparative information about providers, for example through survey tools, has been improved. Such information is increasingly being used to guide individuals' choice of provider and payers' assessments of provider performance, often without critically reflecting about underlying factors affecting the results. The purpose of this study was to analyze variation in patient satisfaction, with respect to organizational and structural factors, including the mix of registered individuals, among primary care providers, based on information from a national patient survey in primary care and register data in three Swedish county councils. Systematic variation in patient satisfaction was found with respect to both organizational and structural factors, including characteristics of registered individuals. Smaller practices and practices where a high proportion of all visits were with a doctor were associated with higher patient satisfaction. Also practices where registered individuals had a low level of social deprivation and a high overall illness on average were associated with higher patient satisfaction. Factors that are of relevance for how well providers perform according to patient surveys are more or less possible to control for providers. This adds to the complexity for the use of such information by individuals and payers to assess provider performance. PMID- 23040561 TI - Biological validation of bio-engineered red blood cell productions. AB - The generation in vitro of cultured red blood cells (cRBC) could become an alternative to classical transfusion products. However, even when derived from healthy donors, the cRBC generated in vitro from hematopoietic stem cells may display alterations resulting from a poor controlled production process. In this context, we attempted to monitor the quality of the transfusion products arising from new biotechnologies. For that purpose, we developed an in vitro erythrophagocytosis (EP) test with the murine fibroblast cell line MS-5 and human macrophages (reference method). We evaluated 38 batches of cRBC, at the stage of reticulocyte, generated from CD34(+) cells isolated from placental blood or by leukapheresis. We showed that (i) the EP test performed with the MS-5 cell line was sensitive and can replace human macrophages for the evaluation of cultured cells. (ii) The EP tests revealed disparities among the batches of cRBC. (iii) The viability of the cells (determined by calcein-AM test), the expression of CD47 (antiphagocytosis receptor) and the externalization of phosphatidylserine (PS, marker of phagocytosis) were not critical parameters for the validation of the cRBC. (iv) Conversely, the cell deformability determined by ektacytometry was inversely correlated with the intensity of the phagocytic index. Assuming that the culture conditions directly influence the quality of the cell products generated, optimization of the production mode could benefit from the erythrophagocytosis test. PMID- 23040562 TI - Comparison of the rates of phenol advanced oxidation in deionized and tap water within a dielectric barrier discharge reactor. AB - Electric non-thermalizing discharges provide promising novel means to induce oxidation of organic pollutants in water. The decomposition of phenol in solutions prepared with deionized (milliQ) and tap water was studied and compared in a Dielectric Barrier Discharge (DBD) reactor. Interestingly, a significant rate increase was found in tap with respect to milliQ water. Control experiments proved that this was not the effect of conductivity or of traces of iron or of residual active chlorine from the depuration process operated in the aqueducts of Italian cities. The same increase in efficiency as observed in tap water was instead obtained when phenol was treated in solutions containing bicarbonate anions in the same concentration as present in tap water, an effect attributed to buffering of the solution pH. The role of pH has been investigated thoroughly by measuring the process efficiency over a wide pH range, from 2 to 10, by using different buffer systems to probe reactivity at near neutral pH, the most relevant for drinking water applications, and by testing the effect of different buffer concentrations. These latter experiments failed to detect any significant kinetic effect attributable to the well known reactivity of bicarbonate as quencher of OH radicals. PMID- 23040563 TI - Transformation impacts of dissolved and solid phase Fe(II) on trichloroethylene (TCE) reduction in an iron-reducing bacteria (IRB) mixed column system: a mathematical model. AB - In this research, we conducted trichloroethylene (TCE) reduction in a column filled with iron and iron-reducing bacteria (IRB) and developed a mathematical model to investigate the critical reactions between active species in iron/IRB/contaminant systems. The formation of ferrous iron (Fe(II)) in this system with IRB and zero-valent iron (ZVI, Fe(0)) coated with a ferric iron (Fe(III)) crust significantly affected TCE reduction and IRB respiration in various ways. This study presents a new framework for transformation property and reducing ability of both dissolved (Fe(II)(dissolved)) and solid form ferrous iron (Fe(II)(solid)). Results showed that TCE reduction was strongly depressed by Fe(II)(solid) rather than by other inhibitors (e.g., Fe(III) and lactate), suggesting that Fe(II)(solid) might reduce IRB activation due to attachment to IRB cells. Newly exposed Fe(0) from the released Fe(II)(dissolved) was a strong contributor to TCE reduction compared to Fe(II)(solid). In addition, our research confirmed that less Fe(II)(solid) production strongly supported long-term TCE reduction because it may create an easier TCE approach to Fe(0) or increase IRB growth. Our findings will aid the understanding of the contributions of iron media (e.g., Fe(II)(solid), Fe(II)(dissolved), Fe(III), and Fe(0)) to IRB for decontamination in natural groundwater systems. PMID- 23040564 TI - QSAR-like models: a potential tool for the selection of PhACs and EDCs for monitoring purposes in drinking water treatment systems--a review. AB - Recent studies have demonstrated the presence of trace-level pharmaceutically active compounds (PhACs) and endocrine disrupting compounds (EDCs) in a number of finished drinking waters (DWs). Since there is sparse knowledge currently available on the potential effects on human health associated with the chronic exposure to trace levels of these Emerging Contaminants (ECs) through routes such as DW, it is suggested that the most appropriate criterion is a treatment criterion in order to prioritize ECs to be monitored during DW preparation. Hence, only the few ECs showing the lowest removals towards a given DW Treatment (DWT) process would serve as indicators of the overall efficiency of this process and would be relevant for DW quality monitoring. In addition, models should be developed for estimating the removal of ECs in DWT processes, thereby overcoming the practical difficulties of experimentally assessing each compound. Therefore, the present review has two objectives: (1) to provide an overview of the recent scientific surveys on the occurrence of PhACs and EDCs in finished DWs; and (2) to propose the potential of Quantitative-Structure-Activity-Relationship-(QSAR) like models to rank ECs found in environmental waters, including parent compounds, metabolites and transformation products, in order to select the most relevant compounds to be considered as indicators for monitoring purposes in DWT systems. PMID- 23040565 TI - Colchicine after pulmonary vein isolation to prevent the early recurrence of atrial fibrillation: mollifying an inflammatory response? PMID- 23040566 TI - Elevated pre-operative serum peptides for collagen I and III synthesis result in post-surgical atrial fibrillation. AB - OBJECTIVES: This study sought to determine if serum markers for collagen I and III synthesis, the carboxyl terminal peptide from pro-collagen I (PICP) and the amino terminal peptide from pro-collagen III (PIIINP), correlate with left atrial (LA) fibrosis and post-operative atrial fibrillation (AF). BACKGROUND: AF after cardiac surgery is associated with adverse outcomes. We recently demonstrated that LA fibrosis is associated with post-operative AF in patients with no previous history of AF. METHODS: Fifty-four patients having cardiac surgery without a history of AF consented to left and right atrial biopsies and a pre operative peripheral blood draw. Picrosirius red staining quantified the percentage of fibrosis, and reverse transcriptase polymerase chain reaction assessed atrial tissue messenger ribonucleic acid transcripts involved in the fibrosis pathway. PICP and PIIINP levels were measured using an enzyme immunosorbent assay. RESULTS: Eighteen patients developed AF, whereas 36 remained in normal sinus rhythm. LA fibrosis was higher in patients who developed AF versus normal sinus rhythm (6.13 +/- 2.9% vs. 2.03 +/- 1.9%, p = 0.03). LA messenger ribonucleic acid transcripts for collagen I, III, transforming growth factor, and angiotensin were 1.5- to 2.0-fold higher in AF patients. Serum PICP and PIIINP levels were highest in AF versus normal sinus rhythm (PICP: 451.7 +/- 200 ng/ml vs. 293.3 +/- 114 ng/ml, p = 0.006; PIIINP: 379 +/- 286 pg/ml vs. 191.6 +/- 162 pg/ml, p = 0.01). Furthermore, there was a linear correlation between LA fibrosis and serum PICP levels (R(2) = 0.2; p = 0.01), and of the markers, only PICP was independently associated with AF. CONCLUSIONS: This demonstrates that serum PICP and PIIINP levels correlate with the presence of LA fibrosis and may act as predictors for post-operative AF even in the absence of previous history of AF. PMID- 23040567 TI - Percutaneous treatment of patent foramen ovale and atrial septal defects. AB - Percutaneous treatment of inter-atrial septal defects has undergone exponential growth in the past 2 decades. Improved percutaneous devices and interventional techniques with low complication rates make this procedure an attractive therapeutic option for congenital atrial septal defects (ASD). Although indications for catheter-based ASD closure are well-documented, those for catheter-based patent foramen ovale (PFO) closure are still evolving. Results from 2 randomized clinical trials question the benefit of percutaneous PFO closure, but concern has also been raised about the efficacy of the device used in those trials. This review will focus on the anatomy, associated syndromes, detection, and data for percutaneous closure of both PFOs and ASDs. PMID- 23040568 TI - Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. AB - OBJECTIVES: The purpose of this study was to investigate whether peripheral endothelial dysfunction could predict the occurrence of cardiovascular events in patients with heart failure (HF) with normal left ventricular ejection fraction (HFNEF). BACKGROUND: Endothelial dysfunction plays an important role in HF, but the relation between peripheral endothelial dysfunction and prognosis in HFNEF remains unknown. METHODS: We conducted a prospective cohort study of 321 patients with HFNEF. We evaluated cardiac function by echocardiography measuring the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (E/e'), noninvasively assessed peripheral endothelial function by reactive hyperemia-peripheral arterial tonometry (RH-PAT) as the RH-PAT index (RHI), and followed cardiovascular events. RESULTS: A total of 59 patients had a cardiovascular event. Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in the low RHI group than in the high RHI group (mean follow-up: 20 months; log-rank test: p < 0.001). Multivariate Cox hazard analysis identified RHI (per 0.1) (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.67 to 0.94; p = 0.007), E/e' (Ln[E/e'] [per 0.1]) (HR: 1.15; 95% CI: 1.04 to 1.26; p = 0.006), and B-type natriuretic peptide (BNP) (Ln[BNP] [per picogram/milliliter]) (HR: 1.81; 95% CI: 1.44 to 2.28; p < 0.001) as independent predictors of cardiovascular events. The C-statistics for cardiovascular events substantially increased when the RHI was added to the HFNEF prognostic 5 factors (PF5)-age, diabetes, New York Heart Association classification, HF hospitalization history, and left ventricular ejection fraction-which were identified in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Study) (PF5 alone: 0.671; PF5 + RHI: 0.712). The net reclassification index was significant after addition of the RHI (19.0%, p = 0.01). CONCLUSIONS: Peripheral endothelial dysfunction independently correlated with future cardiovascular events, adding incremental clinical significance for risk stratification in patients with HFNEF. (Endothelial Dysfunction Assessed by Reactive Hyperemia Peripheral Arterial Tonometry and Heart Failure with Preserved Left Ventricular Ejection Fraction; UMIN000002640). PMID- 23040569 TI - Endothelial dysfunction: a pathophysiologic factor in heart failure with preserved ejection fraction. PMID- 23040570 TI - Colchicine for prevention of early atrial fibrillation recurrence after pulmonary vein isolation: a randomized controlled study. AB - OBJECTIVES: The purpose of the present study was to test the potential of colchicine, an agent with potent anti-inflammatory action, to reduce atrial fibrillation (AF) recurrence after pulmonary vein isolation in patients with paroxysmal AF. BACKGROUND: Proinflammatory processes induced by AF ablation therapy have been implicated in postablation arrhythmia recurrence. METHODS: Patients with paroxysmal AF who received radiofrequency ablation treatment were randomized to a 3-month course of colchicine 0.5 mg twice daily or placebo. C reactive protein (CRP) and interleukin (IL)-6 levels were measured on day 1 and on day 4 of treatment. RESULTS: In the 3-month follow-up, recurrence of AF was observed in 27 (33.5%) of 80 patients of the placebo group versus 13 (16%) of 81 patients who received colchicine (odds ratio: 0.38, 95% confidence interval: 0.18 to 0.80). Gastrointestinal side-effects were the most common symptom among patients receiving active treatment. Diarrhea was reported in 7 patients in the colchicine group (8.6%) versus 1 in the placebo group (1.3%, p = 0.03). Colchicine led to higher reductions in CRP and IL-6 levels: the median difference of CRP and IL-6 levels between days 4 and 1 was -0.46 mg/l (interquartile range: 0.78 to 0.08 mg/l) and -0.10 mg/l (-0.30 to 0.10 pg/ml), respectively, in the placebo group versus -1.18 mg/l (-2.35 to -0.46 mg/l) and -0.50 pg/ml (-1.15 to 0.10 pg/ml) in the colchicine group (p < 0.01 for both comparisons). CONCLUSIONS: Colchicine is an effective and safe treatment for prevention of early AF recurrences after pulmonary vein isolation in the absence of antiarrhythmic drug treatment. This effect seems to be associated strongly with a significant decrease in inflammatory mediators, including IL-6 and CRP. PMID- 23040571 TI - Association of cigarette smoking from adolescence to middle-age with later total and cardiovascular disease mortality: theHarvard Alumni Health Study. PMID- 23040572 TI - Genes and coronary artery disease: where are we? AB - Susceptibility to coronary artery disease (CAD) is claimed to be 40% to 60% inherited, but until recently genetic risk factors predisposing to CAD have been elusive. Comprehensive prevention of CAD requires manipulation of genetic risk. The availability of microarrays of single-nucleotide polymorphisms enabling genome-wide association studies (GWAS) led to the discovery of 33 genetic risk variants for CAD. Surprisingly, 23 risk variants mediate their risk through unknown mechanisms, with only 10 associating with hypertension or lipids. Thus, there are several mechanisms contributing to the pathogenesis of CAD yet to be elucidated. The first risk variant discovered by GWAS was 9p21.3, which occurs in 75% of all populations except African, with a mean increased risk of 25% per copy. Of the 33 variants for CAD, the increased risk varies from 6% to 92% with a mean increased risk of 18%, occurring on average in 47% of the population. The maximum number of risk alleles per individual would be 66. In the CARDIoGRAM (Coronary Artery Disease Genome-wide Replication and Meta Analysis) study of 23 variants, the average per individual was 17, the minimum 7, and the maximum 37. The top 10th percentile has an odds ratio of 1.88 and the lowest percentile an odds ratio of 0.55. Routine genetic screening is unlikely until management is improved by genetic testing. Risk variants should provide pathophysiological insights and targets for novel therapy. While risk variants are less potent predictors of CAD, compared with biomarkers, they have the advantage of not changing in one's lifetime and are unaffected by diet, sex, age, or medication. PMID- 23040573 TI - Does rubidium-82 PET have superior accuracy to SPECT perfusion imaging for the diagnosis of obstructive coronary disease?: A systematic review and meta analysis. AB - OBJECTIVES: The purpose of this study was to evaluate the accuracy of rubidium (Rb)-82 positron emission tomography (PET) for the diagnosis of obstructive coronary artery disease (CAD) in comparison to single-photon emission tomography (SPECT). BACKGROUND: Myocardial perfusion imaging is widely used in the assessment of patients with known or suspected CAD. PET using Rb-82 has potential advantages over SPECT that may make it more accurate and that reduce radiation exposure compared with SPECT but has increased costs. Comparisons of these technologies are highly relevant for policy makers and practice guidelines. However, studies directly comparing Rb-82 PET with contemporary SPECT have been limited. METHOD: The authors therefore undertook a systematic review of studies where either Rb-82 PET or technetium-99m SPECT with both attenuation correction and electrocardiography-gating were used as a diagnostic test for obstructive CAD with invasive coronary angiogram as a reference standard. These technologies were then compared. RESULTS: Fifteen PET and 8 SPECT studies (1,344 and 1,755 patients, respectively) met inclusion criteria and pooled accuracy using weighted averages according to the size of the patient population was determined for PET and SPECT with sensitivities of 90% (confidence interval [CI]: 0.88 to 0.92) and 85% (CI: 0.82 to 0.87) and specificities of 88% (CI: 0.85 to 0.91) and 85% (CI: 0.82 to 0.87), respectively. Summary receiver-operating characteristic curves were computed: area under the curve was 0.95 and 0.90 for PET and SPECT, respectively (p < 0.0001). There was heterogeneity among study populations and some studies were limited by referral bias. CONCLUSIONS: Rb-82 PET is accurate for the detection of obstructive CAD and, despite advances in SPECT technology, remains superior. More widespread use of Rb-82 PET may be beneficial to improve CAD detection. PMID- 23040574 TI - Perceived stress in myocardial infarction: long-term mortality and health status outcomes. AB - OBJECTIVES: This study sought to determine the association of chronic stress with long-term adverse outcomes after acute myocardial infarction (AMI). BACKGROUND: Chronic stress has been shown to be associated with the development of cardiovascular disease and, in the case of particular types of stress such as job and marital strain, with recurrent adverse events after AMI. Little is known, however, about the association of chronic stress with mortality and adverse health status outcomes in a general AMI population. METHODS: In a cohort of 4,204 AMI patients from 24 U.S. hospitals completing the Perceived Stress Scale-4 (sum scores ranging from 0 to 16) during hospitalization, moderate/high stress over the previous month was defined as scores in the top 2 quintiles (scores of 6 to 16). Detailed data on sociodemographics, psychosocial status, and clinical characteristics were collected at baseline. Outcomes included patients' 1-year health status, assessed with the Seattle Angina Questionnaire, Short Form-12, and EuroQol Visual Analog Scale, and 2-year mortality. RESULTS: AMI patients with moderate/high stress had increased 2-year mortality compared with those having low levels of stress (12.9% vs. 8.6%; p < 0.001). This association persisted after adjusting for sociodemographics, clinical factors (including depressive symptoms), revascularization status, and GRACE (Global Registry of Acute Coronary Events) discharge risk scores (hazard ratio: 1.42: 95% confidence interval: 1.15 to 1.76). Furthermore, moderate/high stress was independently associated with poor 1-year health status, including a greater likelihood of angina, worse disease-specific and generic health status, and worse perceived health (p < 0.01 for all). CONCLUSIONS: Moderate/high perceived stress at the time of an AMI is associated with adverse long-term outcomes, even after adjustment for important confounding factors. Future studies need to examine whether stress mediates observed racial and socioeconomic disparities and whether novel interventions targeting chronic stress and coping skills can improve post-AMI outcomes. PMID- 23040576 TI - Left bundle branch block after transcatheter aortic valve implantation: inconsequential or a clinically important endpoint? PMID- 23040575 TI - SeQuentPlease World Wide Registry: clinical results of SeQuent please paclitaxel coated balloon angioplasty in a large-scale, prospective registry study. AB - OBJECTIVES: This study sought to assess the safety and efficacy of paclitaxel coated balloon (PCB) angioplasty in an international, multicenter, prospective, large-scale registry study. BACKGROUND: In small randomized trials, PCB angioplasty was superior to uncoated balloon angioplasty for treatment of bare metal stent (BMS) and drug-eluting stent (DES) restenosis. METHODS: Patients treated with SeQuent Please PCBs were included. The primary outcome measure was the clinically driven target lesion revascularization (TLR) rate at 9 months. RESULTS: At 75 centers, 2,095 patients with 2,234 lesions were included. The TLR rate was 5.2% after 9.4 months. Definite vessel thrombosis occurred in 0.1%. PCB angioplasty was performed in 1,523 patients (72.7%) with DES or BMS restenosis and 572 patients (27.3%) with de novo lesions. The TLR rate was significantly lower in patients with PCB angioplasty for BMS restenosis compared with DES restenosis (3.8% vs. 9.6%, p < 0.001). The TLR rate did not differ for PCB angioplasty of paclitaxel-eluting stent and non-paclitaxel-eluting sten restenosis (8.3% vs. 10.8%, p = 0.46). In de novo lesions (small vessels), the TLR rate was low and did not differ between PCB angioplasty with and without additional BMS implantation (p = 0.31). CONCLUSIONS: PCB angioplasty in an all comers, prospective, multicenter registry was safe and confirmed in a large population the low TLR rates seen in randomized clinical trials. PCB angioplasty was more effective in BMS restenosis compared with DES restenosis, with no difference regarding the type of DES. PMID- 23040577 TI - Predictive factors and long-term clinical consequences of persistent left bundle branch block following transcatheter aortic valve implantation with a balloon expandable valve. AB - OBJECTIVES: This study evaluated the predictive factors and prognostic value of new-onset persistent left bundle branch block (LBBB) in patients undergoing transcatheter aortic valve implantation (TAVI) with a balloon-expandable valve. BACKGROUND: The predictors of persistent (vs. transient or absent) LBBB after TAVI with a balloon-expandable valve and its clinical consequences are unknown. METHODS: A total of 202 consecutive patients with no baseline ventricular conduction disturbances or previous permanent pacemaker implantation (PPI) who underwent TAVI with a balloon-expandable valve were included. Patients were on continuous electrocardiographic (ECG) monitoring during hospitalization and 12 lead ECG was performed daily until hospital discharge. No patient was lost at a median follow-up of 12 (range: 6 to 24) months, and ECG tracing was available in 97% of patients. The criteria for PPI were limited to the occurrence of high degree atrioventricular block (AVB) or severe symptomatic bradycardia. RESULTS: New-onset LBBB was observed in 61 patients (30.2%) after TAVI, and had resolved in 37.7% and 57.3% at hospital discharge and 6- to 12-month follow-up, respectively. Baseline QRS duration (p = 0.037) and ventricular depth of the prosthesis (p = 0.017) were independent predictors of persistent LBBB. Persistent LBBB at hospital discharge was associated with a decrease in left ventricular ejection fraction (p = 0.001) and poorer functional status (p = 0.034) at 1-year follow-up. Patients with persistent LBBB and no PPI at hospital discharge had a higher incidence of syncope (16.0% vs. 0.7%; p = 0.001) and complete AVB requiring PPI (20.0% vs. 0.7%; p < 0.001), but not of global mortality or cardiac mortality during the follow-up period (all, p > 0.20). New-onset LBBB was the only factor associated with PPI following TAVI (p < 0.001). CONCLUSIONS: Up to 30% of patients with no prior conduction disturbances developed new LBBB following TAVI with a balloon-expandable valve, although it was transient in more than one third. Longer baseline QRS duration and a more ventricular positioning of the prosthesis were associated with a higher rate of persistent LBBB, which in turn determined higher risks for complete AVB and PPI, but not mortality, at 1 year follow-up. PMID- 23040578 TI - Markers of collagen synthesis, atrial fibrosis, and the mechanisms underlying atrial fibrillation. PMID- 23040579 TI - Value-based insurance design in cardiology: using "clinical nuance" to improve quality of care and contain costs. PMID- 23040580 TI - Effect of cardiac resynchronization therapy on the risk of first and recurrent ventricular tachyarrhythmic events in MADIT-CRT. AB - OBJECTIVES: This study aimed to evaluate the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the risks of first and recurrent ventricular tachyarrhythmic events (VTEs) in the MADIT-CRT. BACKGROUND: Reverse remodeling associated with CRT-D therapy was suggested to reduce arrhythmic risk. However, the effect of the device on the risk of recurrent VTEs among patients who experience a first arrhythmic event has not been investigated. METHODS: The CRT-D versus defibrillator-only risks for first and subsequent fast VTEs (>180 beats/min) were assessed by Cox proportional hazards and Andersen-Gill proportional intensity regression modeling, respectively, in efficacy analyses recognizing active device-type during follow-up. RESULTS: Multivariate analysis showed that CRT-D was associated with a significant 29% (p = 0.003) reduction in the risk of a first VTE, with a pronounced effect among patients with left bundle branch block (LBBB) (hazard ratio [HR]: 0.58; p < 0.001) and no significant effect among non-LBBB patients (HR: 1.05; p = 0.82, p for the difference = 0.02). Patients with LBBB who experienced a first VTE had no change in the risk of subsequent VTEs with CRT-D (HR: 0.98; p = 0.85). In contrast, the risk of recurrent VTEs with CRT-D was significantly increased among non-LBBB patients (HR: 3.62; p = 0.002, p for the difference = 0.009). Recurrent VTEs increased the risk of subsequent heart failure or death. CONCLUSIONS: In MADIT-CRT, active treatment with CRT-D was associated with a significant reduction in the risk of life-threatening VTEs. However, our findings suggest that CRT-D does not reduce the risk of subsequent VTEs in patients who experience a first arrhythmic event and may increase subsequent arrhythmic risk in non-LBBB patients. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271). PMID- 23040581 TI - The impact of reducing cardiovascular medication copayments on health spending and resource utilization. AB - OBJECTIVES: The aim of this study was to evaluate the impact of reductions in statin and clopidogrel copayments on cardiovascular resource utilization, major coronary events, and insurer spending. BACKGROUND: Copayments are widely used to contain health spending but cause patients to reduce their use of essential cardiovascular medications. Reducing copayments for post-myocardial infarction secondary prevention has beneficial effects, but the impact of this strategy for lower risk patients and other drugs remains unclear. METHODS: An evaluation was conducted of health care spending and resource use by a large self-insured employer that reduced statin copayments for patients with diabetes or vascular disease and reduced clopidogrel copayments for all patients prescribed this drug. Eligible individuals in the intervention company (n = 3,513) were compared with a control group from other companies without such a policy (n = 49,803). Analyses were performed using segmented regression models with generalized estimating equations. RESULTS: Lowering copayments was associated with significant reductions in rates of physician visits (relative change: statin users 0.80; 95% confidence interval [CI]: 0.57 to 0.98; clopidogrel users: 0.87; 95% CI: 0.59 to 0.96) and hospitalizations and emergency department admissions (relative change: statin users 0.90; 95% CI: 0.80 to 0.92; clopidogrel users: 0.89; 95% CI: 0.74 to 0.90) although not major coronary events. Patient out-of-pocket spending for drugs and other medical services decreased (relative change: statin users 0.79; 95% CI: 0.75 to 0.83; clopidogrel users 0.74; 95% CI: 0.66 to 0.82). Providing more generous coverage did not increase overall spending (relative change: statin users 1.03; 95% CI: 0.97 to 1.09; clopidogrel users 0.94; 95% CI: 0.87 to 1.03). CONCLUSIONS: Lowering copayments for statins and clopidogrel was associated with reductions in health care resource use and patient out-of-pocket spending. The policy appeared cost neutral with respect to overall health spending. PMID- 23040583 TI - Ramping up evidence-based ventricular assist device care. PMID- 23040582 TI - Drug-eluting balloon for treatment of superficial femoral artery in-stent restenosis. AB - OBJECTIVES: The purpose of this prospective registry was to evaluate the safety and efficacy, at 1 year, of the use of drug-eluting balloons (DEB) for the treatment of superficial femoral artery (SFA) in-stent restenosis (ISR). BACKGROUND: The use of the self-expanding nitinol stent has improved the patency rate of SFA after percutaneous transluminal angioplasty (PTA). As the population with SFA stenting continues to increase, occurrence of ISR has become a serious problem. The use of DEB has showed promising results in reducing restenosis recurrence in coronary stents. METHODS: From December 2009 to December 2010, 39 consecutive patients underwent PTA of SFA-ISR in our institution. All patients underwent conventional SFA PTA and final post-dilation with paclitaxel-eluting balloons (IN.PACT, Medtronic, Minneapolis, Minnesota). Patients were evaluated up to 12 months. RESULTS: Technical and procedural success was achieved in every patient. No in-hospital major adverse cardiac and cerebrovascular events occurred. At 1 year, 1 patient died due to heart failure. Primary endpoint, primary patency rate at 12 months, was obtained in 92.1% (35 patients). At 1 year, patients were asymptomatic for claudication, and duplex assessment demonstrated lack of recurrent restenosis (100% rate of Secondary patency). The presence of an occlusive restenosis at the time of treatment was not associated with an increased restenosis rate, when compared with non-occlusive restenosis, at 1 year. CONCLUSIONS: The data suggest that adjunctive use of DEB for the treatment of SFA-ISR represents a potentially safe and effective therapeutic strategy. These data should be considered hypothesis-generating to design a randomized trial. PMID- 23040585 TI - Long-term evaluation of endothelial function in Kawasaki disease patients. AB - BACKGROUND: Kawasaki disease is an acute systemic vasculitis. Cardiac complications are frequent and include endothelial dysfunction in patients with coronary anomalies. So far, the presence of endothelial dysfunction in patients with no coronary lesions has not been demonstrated. Peripheral arterial tonometry (Endo-PAT) measures the microvascular function in response to local ischaemia and has been validated in adult population, but its use in children is scarce. Aim To evaluate endothelial dysfunction in children as a long-term complication after Kawasaki disease using Endo-PAT. METHODS: We evaluated two groups of subjects: (1) Kawasaki disease patients over 11 years of age, diagnosed for >5 years, with no coronary lesions, or any other risk factors for cardiovascular disease; (2) control group of individuals without cardiovascular risk factors. Patients and controls were clinically accessed. Endo-PAT was performed to determine reactive hyperaemia index and augmentation index. RESULTS: A total of 35 individuals (21 males, age 21 +/- 6 years) were evaluated (group 1: 19; controls: 16). Kawasaki disease patients presented significant lower reactive hyperaemia index (1.68 +/- 0.49 versus 2.31 +/- 0.53; p = 0.001). Augmentation index was similar in both groups (-10 +/- 7 versus -11 +/- 5; p > 0.005). Most patients with Kawasaki disease disclosed endothelial dysfunction (68%) compared with only 12% in controls. CONCLUSIONS: Endo-PAT is feasible and reproducible in the child population. Endothelial dysfunction is a frequent long-term complication in patients after Kawasaki disease with normal appearing coronary arteries. However, these results need validation in a larger population. PMID- 23040584 TI - Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuous-flow left ventricular assist devices: the Columbia ramp study. AB - OBJECTIVES: This study sought to develop a novel approach to optimizing continuous-flow left ventricular assist device (CF-LVAD) function and diagnosing device malfunctions. BACKGROUND: In CF-LVAD patients, the dynamic interaction of device speed, left and right ventricular decompression, and valve function can be assessed during an echocardiography-monitored speed ramp test. METHODS: We devised a unique ramp test protocol to be routinely used at the time of discharge for speed optimization and/or if device malfunction was suspected. The patient's left ventricular end-diastolic dimension, frequency of aortic valve opening, valvular insufficiency, blood pressure, and CF-LVAD parameters were recorded in increments of 400 rpm from 8,000 rpm to 12,000 rpm. The results of the speed designations were plotted, and linear function slopes for left ventricular end diastolic dimension, pulsatility index, and power were calculated. RESULTS: Fifty two ramp tests for 39 patients were prospectively collected and analyzed. Twenty eight ramp tests were performed for speed optimization, and speed was changed in 17 (61%) with a mean absolute value adjustment of 424 +/- 211 rpm. Seventeen patients had ramp tests performed for suspected device thrombosis, and 10 tests were suspicious for device thrombosis; these patients were then treated with intensified anticoagulation and/or device exchange/emergent transplantation. Device thrombosis was confirmed in 8 of 10 cases at the time of emergent device exchange or transplantation. All patients with device thrombosis, but none of the remaining patients had a left ventricular end-diastolic dimension slope >-0.16. CONCLUSIONS: Ramp tests facilitate optimal speed changes and device malfunction detection and may be used to monitor the effects of therapeutic interventions and need for surgical intervention in CF-LVAD patients. PMID- 23040586 TI - [Specific hazards of transfusion in medical units]. AB - In France, more than 1100 hospitals have medical wards with specialty units that perform transfusions and use about 40% of all labile blood products. Due to patients suffering from multiple pathologies, repeated transfusions or use of platelet concentrates, these hospital units encounter specific and more frequent transfusion hazards than other wards. The incidence rate of transfusion associated cardiac overload, anti-erythrocyte, -HLA or -HPA allo-immunisations or transfusion-induced hemochromatosis, is high. Platelet concentrates may also cause severe allergic reactions. They are still under-reported, though immediate or delayed effects on patients or care processes are considerable. The prevention of these adverse reactions or of their consequences requires careful prescription, properly planned and organised patient stays, particularly at the day hospital, with special attention to coordination of doctors and nurses. Labelling errors of blood group samples or blood administration to the wrong patient are the most frequent serious adverse events. Main underlying causes are: a poor understanding of specific hazards of transfusion in medical wards, routine, multiple transfusions and permanent or occasional working overload. So, both doctors and nurses should do their best to improve organisation and systematically comply with good clinical practice. PMID- 23040587 TI - Predicting and preventing heart failure rehospitalizations: is there a role for implantable device diagnostics? PMID- 23040588 TI - Effects of serum n-3 to n-6 polyunsaturated fatty acids ratios on coronary atherosclerosis in statin-treated patients with coronary artery disease. AB - A low ratio of n-3 to n-6 polyunsaturated fatty acids has been associated with cardiovascular events. However, the effects of this ratio on coronary atherosclerosis have not been fully examined. The purpose of the present study was to evaluate the correlations between the n-3 to n-6 polyunsaturated fatty acid ratio and coronary atherosclerosis. Coronary atherosclerosis in nonculprit lesions in the percutaneous coronary intervention vessel was evaluated using virtual histology intravascular ultrasound in 101 patients at the time of percutaneous coronary intervention and 8 months after statin therapy. Forty-six patients (46%) showed atheroma progression and the remaining 55 patients (54%) showed atheroma regression at 8-month follow-up. Significant negative correlations were observed between percentage change in plaque volume and change in the eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (r = -0.190, p = 0.05), docosahexaenoic acid (DHA)/AA ratio (r = -0.231, p = 0.02), and EPA+DHA/AA ratio (r = -0.240, p = 0.02). Furthermore, percentage change in the fibrous component volume was negatively and significantly correlated with change in the EPA/AA ratio (r = -0.206, p = 0.04) and EPA+DHA/AA ratio (r = -0.217, p = 0.03). Multivariate regression analysis showed that change in the EPA+DHA/AA ratio was a significant predictor of percentage change in plaque volume and fibrous component volume (beta = -0.221, p = 0.02, and beta = -0.200, p = 0.04, respectively). In conclusion, decreases in serum n-3 to n-6 polyunsaturated fatty acid ratios are associated with progression in coronary atherosclerosis evaluated using virtual histology intravascular ultrasound in statin-treated patients with coronary artery disease. PMID- 23040589 TI - Comparison of early strut coverage between zotarolimus- and everolimus-eluting stents using optical coherence tomography. AB - There have been no optical coherence tomographic (OCT) data directly comparing the pattern of strut coverage between the 2 second-generation drug-eluting stents in the early period. The aim of this prospective study was to evaluate early strut coverage using optical coherence tomography 3 months after Resolute zotarolimus-eluting stent (ZES-R) or everolimus-eluting stent (EES) implantation in de novo coronary artery lesions. A total of 40 patients who were suitable for the OCT procedure and consented to the study protocol were randomized 1:1 to receive either ZES-R or EES. Among these patients, 35 stented lesions (18 ZES-R, 17 EES) in 34 patients were evaluated by optical coherence tomography immediately and 3 months after stent implantation. Neointimal hyperplasia thickness, percentage of uncovered struts, and the proportion of malapposed struts were measured at 1-mm intervals. An uncovered strut was defined as having a neointimal hyperplasia thickness of 0 MUm. At the 3-month OCT evaluation, mean neointimal hyperplasia thickness (ZES-R vs EES 74 +/- 41 vs 75 +/- 35 MUm, p = 0.89) and mean percentage of uncovered struts (ZES-R vs EES 6.2 +/- 6.9 vs 4.7 +/- 5.1%, p = 0.62) were not significantly different between the groups. The percentage of malapposed struts was also similar between the groups (0.7 +/- 2.2% for ZES-R and 0.7 +/- 1.7% for EES, p = 0.64). Thrombi were documented in 3 stents (1 [5.6%] in a ZES-R vs 2 [11.8%] in EES, p = 0.60). In conclusion, early stent strut coverage on the basis of serial OCT evaluation was comparable between ZES-R and EES 3 months after stent implantation. PMID- 23040590 TI - Left ventricular reverse remodeling in long-term (>12 years) survivors with idiopathic dilated cardiomyopathy. AB - Little is known about left ventricular (LV) reverse remodeling (LVRR) in long term survivors with idiopathic dilated cardiomyopathy. We studied 59 patients with idiopathic dilated cardiomyopathy who had a potential clinical and echocardiographic follow-up period of >12 years. LVRR was defined as LV end diastolic dimension <= 55 mm and fractional shortening >= 25% on the last echocardiogram. Of the 59 patients, 38 died (heart failure in 20, sudden death in 11, and other causes in 7), 2 underwent transplantation, and 19 survived. In the survivors, the LV size had significantly decreased and LV fractional shortening had significantly increased on the last echocardiogram. LVRR occurred in 37% of the survivors. The remaining 63% of the survivors still had LV dysfunction, but the LV end-systolic dimension had decreased significantly. In patients who died or underwent transplantation, the LV size significantly increased. No patient who died or underwent transplantation had LVRR. In conclusion, >60% of the long-term (>12 years) survivors with idiopathic dilated cardiomyopathy still had LV systolic dysfunction, but the LV end-systolic dimension had decreased significantly. In contrast, patients who died or underwent transplantation had significant LV enlargement. These results suggest that LVRR, even if it is not marked, is associated with a favorable prognosis. PMID- 23040591 TI - Meta-analysis of the relation of echocardiographic epicardial adipose tissue thickness and the metabolic syndrome. AB - Epicardial adipose tissue (EAT) is an emerging cardiometabolic risk factor, and its thickness can be measured using echocardiography. The relation of EAT to the metabolic syndrome (MS) is still unclear. A meta-analysis of published reports was performed to provide comprehensive insight on the association of EAT thickness as assessed by echocardiography and the MS. A systematic search was conducted for reports on echocardiographic EAT thickness in patients with and without the MS. Nine studies were identified. The pooled population consisted of 2,027 subjects, of whom 1,030 had the MS. EAT thickness was significantly higher in patients with the MS than in those without (standardized difference in means 1.15 mm, 95% confidence interval 0.78 to 1.53, p = 0.0001). Subgroup meta analysis showed no difference between patients with and those without the MS by MS criteria used and echocardiographic cardiac cycle of measurement but did show a significant difference by ethnicity, with a greater difference in Caucasian subjects (standardized difference in means 1.75 mm, 95% confidence interval 1.43 to 2.07) than in other ethnic groups. In conclusion, echocardiographic EAT thickness is significantly higher in patients with the MS than in those without, but differences exist by ethnicity. PMID- 23040592 TI - Angiographic features and cardiovascular risk factors in human immunodeficiency virus-infected patients with first-time acute coronary syndrome. AB - A matched cohort study was conducted comparing patients with first-time acute coronary syndromes infected with human immunodeficiency virus (HIV) to non-HIV infected patients with and without diabetes matched for smoking, gender, and type of acute coronary syndrome who underwent first-time coronary angiography. A total of 48 HIV-infected patients were identified from a national database. Coronary angiography showed that the HIV-infected patients had significantly fewer lesions with classification B2/C than the 2 control groups (p <0.001) but the same extent of multivessel disease. The HIV-infected patients were a decade younger than the non-HIV-infected controls and had significantly higher concentrations of total cholesterol (6.3 vs 4.8 and 4.5 mmol/L, p <0.0001), low-density lipoprotein (4.0 vs 2.9 and 2.5 mmol/L, p <0.001), and triglycerides (2.8 vs 1.0 and 1.4 mmol/L, p <0.01) compared to the nondiabetic and diabetic non-HIV-infected groups, respectively. In conclusion, HIV-infected patients with first-time acute coronary syndromes have fewer complex lesions than non-HIV-infected patients. This finding supports the idea that the pathogenesis of atherosclerotic disease in HIV patients is different from that in the general population. PMID- 23040593 TI - Prognostic usefulness of serial C-reactive protein measurements in ST-elevation acute myocardial infarction. AB - It has been reported that increased levels of C-reactive protein are related to adverse long-term prognosis in the setting of ST-segment elevation acute myocardial infarction (MI). In previous studies, the timing of C-reactive protein determination has varied widely. In the present study, serial high-sensitivity C reactive protein (hsCRP) measurements were performed to investigate if any of the measurements is superior regarding long-term prognosis. A total of 861 consecutive patients admitted for ST-segment elevation MI and treated with intravenous thrombolysis within the first 6 hours from the index pain were included. HsCRP levels were determined at presentation and at 24, 48, and 72 hours. The median follow-up time was 3.5 years. New nonfatal MI and cardiac death were the study end points. By the end of follow-up, cardiac death was observed in 22.4% and nonfatal MI in 16.1% of the patients. HsCRP levels were found to be increasing during the first 72 hours. Multivariate Cox regression analysis demonstrated that hsCRP levels at presentation were an independent predictor of the 2 end points (relative risk [RR] 2.8, p = 0.002, and RR 2.1, p = 0.03, for MI and cardiac death, respectively), while hsCRP levels at 24 hours did not yield statistically significant results (RR 1.4, p = 0.40, and RR 1.1, p = 0.80, for MI and cardiac death, respectively). The corresponding RRs at 48 hours were 1.2 (p = 0.5) for MI and 3.2 (p = 0.007) for cardiac death and at 72 hours were 1.6 (p = 0.30) for MI and 3.9 (p <0.001) for cardiac death. In conclusion, hsCRP levels at presentation represent an independent predictor for fatal and nonfatal events during long-term follow-up. HsCRP levels at 48 and 72 hours, which are close to peak hsCRP levels, independently predict only cardiac death. PMID- 23040594 TI - Safety and efficacy of everolimus-eluting stents versus sirolimus-eluting stents in women. AB - Drug-eluting stents have shown promising clinical results in the treatment of coronary artery disease, including in women. Studies with first-generation drug eluting stents, however, have reported higher rates of stent thrombosis (ST). The aim of this study was to evaluate the safety and efficacy of second-generation everolimus-eluting stents (EES) versus first-generation sirolimus-eluting stents (SES) in women. The study included 1,649 women; 1,152 (70%) received SES and 497 (30%) received EES. In-hospital and 1-, 6-, and 12-month clinical outcomes were analyzed and compared. Correlates of major adverse cardiac events and ST were identified. Baseline clinical characteristics were similar between stent types, although more peripheral vascular disease and family history of coronary artery disease were seen in the SES group, while more unstable angina pectoris at initial diagnosis was more prevalent in the EES group. The EES group had more type C and distal lesions. There was a higher rate of target vessel revascularization and major adverse cardiac events in the SES group (14.7% vs 10.8%, p = 0.04) at 1 year. ST tended to be higher in the SES group (1.5% vs 0.4%, p = 0.06) at 6 and 12 months. After adjustment, multivariate analysis indicated that the EES group was less likely to have target vessel revascularization and major adverse cardiac events (hazard ratio 0.67, 95% confidence interval 0.47 to 0.95, p = 0.024) and had lower rates of ST (hazard ratio 0.09, 95% confidence interval 0.01 to 0.70, p = 0.022) at 1 year. In conclusion, contemporary use of EES in women is associated with improvement in efficacy and safety profiles compared to SES; however, a large randomized trial is needed to confirm this conclusion. PMID- 23040595 TI - Comparison of Three-year outcomes after primary percutaneous coronary intervention in patients with left ventricular ejection fraction <40% versus >= 40% (from the HORIZONS-AMI trial). AB - Left ventricular (LV) dysfunction and multivessel disease (MVD) have been associated with greater mortality after ST-segment elevation myocardial infarction. The aim of this study was to evaluate the impact of LV dysfunction and MVD in patients with ST-segment elevation myocardial infarctions treated with primary percutaneous coronary intervention (PCI). Patients from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial treated with primary PCI in whom baseline LV function was assessed using left ventriculography were included in this study. Early and late (3-year) outcomes were examined in groups of patients with reduced (<40%) and preserved (>= 40%) LV ejection fractions (LVEFs), further stratified by the presence of MVD. A total of 2,430 patients were included. Patients with reduced LVEFs were older; were more likely to be women; were more likely to have histories of myocardial infarction, PCI, and heart failure; and were more likely to present in heart failure. Patients with reduced LVEFs had greater 30-day (8.9% vs 0.9%, hazard ratio 9.81, 95% confidence interval 5.23 to 18.42, p <0.0001) and 3-year (17.1% vs 3.7%, hazard ratio 5.03, 95% confidence interval 3.37 to 7.50, p <0.0001) mortality. Among patients with LVEFs <30% (n = 45), 30% to 40% (n = 157), 40% to 50% (n = 373), 50% to 60% (n = 659), and >= 60% (n = 1,196), 3-year mortality was 29.4%, 13.5%, 6.4%, 3.8%, and 2.9%, respectively (p for trend <0.0001). MVD was associated with greater mortality in patients with preserved but not reduced LVEFs. By multivariate analysis, LV dysfunction was the strongest predictor of 30-day and 3-year mortality. In conclusion, the presence of LV dysfunction as assessed on baseline left ventriculography in patients who undergo primary PCI in the contemporary era is a powerful predictor of early and late mortality, regardless of the extent of coronary artery disease. PMID- 23040596 TI - Development of a method to risk stratify patients with heart failure for 30-day readmission using implantable device diagnostics. AB - The aim of the present study was to evaluate whether diagnostic data collected after a heart failure (HF) hospitalization can identify patients with HF at risk of early readmission. The diagnostic data from cardiac resynchronization therapy defibrillator (CRT-D) devices can identify outpatient HF patients at risk of future HF events. In the present retrospective analysis of 4 studies, we identified patients with CRT-D devices, with a HF admission, and 30-day postdischarge follow-up data. The evaluation of the diagnostic data for impedance, atrial fibrillation, ventricular heart rate during atrial fibrillation, loss of CRT-D pacing, night heart rate, and heart rate variability was modeled to simulate a review of the first 7 days after discharge on the seventh day. Using a combined score created from the device parameters that were significant univariate predictors of 30-day HF readmission, 3 risk groups were created. A Cox proportional hazards model adjusting for age, gender, New York Heart Association class, and length of stay during the index hospitalization was used to compare the groups. The study cohort of 166 patients experienced a total of 254 HF hospitalizations, with 34 readmissions within 30 days. Daily impedance, high atrial fibrillation burden with poor rate control (>90 beat/min) or reduced CRT-D pacing (<90% pacing), and night heart rate >80 beats/min were significant univariate predictors of 30-day HF readmission. Patients in the "high"-risk group for the combined diagnostic had a significantly greater risk (hazard ratio 25.4, 95% confidence interval 3.6 to 179.0, p = 0.001) compared to the "low"-risk group for 30-day readmission for HF. In conclusion, device-derived HF diagnostic criteria evaluated 7 days after discharge identified patients at significantly greater risk of a HF event within 30 days after discharge. PMID- 23040597 TI - Prasugrel monitoring and bleeding in real world patients. AB - The aim of this study was to evaluate platelet reactivity and 30-day bleeding events in patients treated with prasugrel 10 mg after acute coronary syndromes. A total of 444 patients with acute coronary syndromes treated with percutaneous coronary intervention and prasugrel 10 mg/day were monitored by measurement of the vasodilator-stimulated phosphoprotein (VASP) index 2 to 4 weeks after hospital discharge. Platelet reactivity was also assessed using the VerifyNow P2Y(12) assay and light transmission aggregometry. Bleeding events (per the Bleeding Academic Research Consortium [BARC] definition) and ischemic events (death, myocardial infarction, and definite stent thrombosis) were collected over 30 days of follow-up. Two thirds of the patients presented with ST-segment elevation myocardial infarctions, 28.8% had diabetes, and 12.4% were aged >75 years. High on-treatment platelet reactivity according to 3 prespecified definitions (VASP index >= 50%, platelet reactivity >= 235 P2Y(12) reaction units, and residual platelet reactivity >= 46.2%) was found in 6.8%, 3.4%, and 3.2% of patients, respectively. Obesity (body mass index >30 kg/m(2)) and multivessel disease were the only independent factors associated with high on treatment platelet reactivity (p = 0.006 and p = 0.045, respectively). At 30 days, there was no major bleeding complication (BARC grade 3 or 5), and 1.6% of patients had recurrent ischemic events. Nuisance bleeding (BARC grade 1) and minor bleeding (BARC grade 2) occurred in 14.2% (n = 63) and 2.5% (n = 11) of patients, respectively, but were not predicted by VASP index. In conclusion, patients with acute coronary syndromes receiving maintenance doses of prasugrel have low rates of HPR and ischemic events within the first month. Minor or minimal bleeding is frequent, but not major bleeding. VASP was poorly correlated with the risk for minor or minimal bleeding. PMID- 23040598 TI - Prognostic usefulness of the change in N-terminal pro B-type natriuretic peptide levels to predict mortality in a single community cohort aged >= 70 years. AB - The levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) are closely related to cardiac abnormalities and adverse outcomes in the general population. However, little is known about the course of NT-proBNP levels over time, the underlying conditions, and the prognostic effect of changes. To investigate these issues, we measured the NT-proBNP levels (Elecsys 2010, Roche Diagnostics) in community-dwellers participating in the Prospective Investigation of the Vasculature in Uppsala Seniors study at 70 (n = 1,005) and 75 (n = 817) years of age. The total follow-up was 8.0 years. In subjects with available results from both examinations, the median NT-proBNP levels increased from 106 pg/ml (25th to 75th percentile 62 to 174) to 125 pg/ml (25th to 75th percentile 73-234; p <0.001). The change in NT-proBNP levels was positively and independently related to male gender, baseline information on ischemic electrocardiographic changes, renal dysfunction, impaired left ventricular ejection fraction, and intercurrent cardiovascular events (e.g., myocardial infarction, stroke, or coronary revascularization). The change in NT-proBNP levels independently predicted mortality after the measurements at 75 years of age (all-cause mortality, adjusted hazard ratio 2.4, 95% confidence interval 1.6 to 3.6; cardiovascular mortality, adjusted hazard ratio 2.3, 95% confidence interval 1.2 to 4.5). Compared to those without significant NT-proBNP changes (n = 606), subjects with increasing levels (n = 162) had markedly increased all-cause mortality (adjusted hazard ratio 4.3, 95% confidence interval 2.1 to 8.8). No subject with decreasing NT-proBNP levels (n = 49) died. In conclusion, repeat measurements of NT-proBNP might add useful information to the routine clinical assessment in subjects aged >= 70 years, because changes in their levels were associated with cardiovascular risk indicators and strongly predictive of mortality. PMID- 23040599 TI - Gender differences in calls to 9-1-1 during an acute coronary syndrome. AB - Calling 911 during acute coronary syndromes (ACS) decreases time to treatment and may improve prognosis. Women may have more atypical ACS symptoms compared to men, but few data are available on differences in gender and ACS symptoms in calling 911. In this study, patient interviews and structured chart reviews were conducted to determine gender differences in calling 911. Calls to 911 were assessed by self-report and validated by medical chart review. Of the 476 patients studied, 292 (61%) were diagnosed with unstable angina and 184 (39%) with myocardial infarctions (MIs). Overall, only 23% of patients called 911. Similar percentages of women and men with unstable angina called 911 (15% and 13%, respectively, p = 0.59). In contrast, women with MIs were significantly more likely to call 911 than men (57% vs 28%, p <0.001). After adjustment for sociodemographic factors, health insurance status, history of MI, the left ventricular ejection fraction, Global Registry of Acute Coronary Events (GRACE) score, and ACS symptoms, women were 1.79 times more likely to call 911 during an MI than men (prevalence ratio 1.79, 95% confidence interval 1.22 to 2.64, p <0.01). In conclusion, the findings of the present study suggest that initiatives to increase calls to 911 are needed for women and men. PMID- 23040600 TI - Analysis of the prevalence of cardiovascular disease and associated risk factors for European-American and African-American populations in the state of Pennsylvania 2005-2009. AB - We examined the burden of cardiovascular disease (CVD) and its associated risk factors using statewide representative data from the Pennsylvania Behavior Risk Factors Surveillance System. The data from 35,576 subjects aged >= 18 years participating in the Pennsylvania Behavior Risk Factors Surveillance System in 2005, 2007, and 2009 were analyzed. The age-adjusted prevalence rates of CVD were computed. Logistic regression analysis was applied to examine associations between the risk factors and CVD prevalence, with adjustment for confounding variables. The results showed that no significant changes in the prevalence of CVD, coronary heart disease, and stroke were observed in either European Americans or African Americans from 2005 to 2009 (p >0.05). African Americans had significantly greater CVD rates than European Americans. Although smoking rates significantly decreased, several other CVD risk factors (i.e., obesity, hypertension, and hypercholesterolemia) significantly increased from 2005 to 2009 in European Americans. Similar changes were observed in African Americans, although these changes did not reach statistical significance. Logistic regression analysis indicated that African Americans had a 35% greater risk of CVD. Education level less than high school, smoking, obesity, hypertension, and diabetes were significantly and positively associated with CVD. In conclusion, no significant achievements in CVD control and risk factor reduction were observed from 2005 to 2009 in Pennsylvania. Additional aggressive control of hypertension, obesity, and diabetes for both European and African Americans must be made to reduce the burden of CVD. PMID- 23040601 TI - Usefulness of fractional flow reserve to improve diagnostic efficiency in patients with non-ST elevation myocardial infarction. AB - Myocardial fractional flow reserve (FFR) has emerging clinical utility and prognostic value in medically stabilized patients with non-ST-segment elevation myocardial infarction (NSTEMI). The aim of this study was to investigate whether measurement of FFR compared to coronary angiography alone improves diagnostic efficiency in patients with NSTEMIs. One hundred consecutive patients with NSTEMIs who had previously undergone clinically indicated FFR measurements were included. In a simulated decision exercise, 5 interventional cardiologists retrospectively and independently reviewed the clinical history and coronary angiogram of each patient and then made a treatment decision. FFR results were then disclosed, and the same cardiologists were asked to review their initial treatment decisions. A p value <0.05 indicates a difference between cardiologists. The proportion of patients allocated to each treatment option initially differed among the 5 cardiologists (p = 0.0061). Forty-two percent of all FFR measurements were made in culprit lesions. After FFR disclosure, the number of patients in whom the treatment decisions made by each cardiologist independently conformed (and so represented the majority with >= 3 of the 5 cardiologists) increased from 65% to 91% (p = 0.0094). After FFR disclosure, the cardiologists changed their initial treatment plans in 46% of patients (p = 0.0016). Changes in favor of medical therapy occurred in 24% of patients (p = 0.0016), and this increase was associated with reductions in "deferred" management (p = 0.0067), single-vessel percutaneous coronary intervention (p = 0.0052), and multivessel percutaneous coronary intervention (p = 0.046). In conclusion, FFR measurement reduced diagnostic variability and changed cardiologists' treatment decisions for patients with NSTEMIs. PMID- 23040602 TI - Liver ethoxyresorufin-O-deethylase and brain acetylcholinesterase in two freshwater fish species of South America; the effects of seasonal variability on study design for biomonitoring. AB - Responses at low levels of biological organization to evaluate environmental changes and water quality have been used for many years. South America is no different, and recently biochemical endpoints in fish have been used to assess the impacts of industrial and sewage effluents on wild fish populations. For Chilean native freshwater fish, basic biological data is scarce and data on 7 ethoxyresorufin-O-deethylase (EROD) and Acetylcholinesterase (AChE) activity is practically absent. Moreover, extensive variation in these two biochemical endpoints exists among species and seasons. In this article we evaluate seasonal variation in liver EROD and brain AChE activities in Trichomycterus areolatus and Percilia gillissi, two widely distributed native freshwater fish species in central Chile. We observed a marked seasonality in hepatic EROD activity in both species, with maximums for P. gillissi during winter months and sex differences in February, July, August and December. T. areolatus showed no sex differences, and peaks in EROD activity in the middle of summer, winter and late spring. Species differences in EROD activity were observed with activity being 1-2 orders of magnitude higher in P. gillissi compared to T. areolatus. Scarce seasonal variation and no sex related differences in brain AChE for both species were observed. Multivariate analysis (PCA) indicated that physical water quality parameters had some degree of responsibility for the seasonal responses found. The seasonal variability data of these biochemical endpoints were used to optimize study design for future monitoring programs, planning timing of sampling, increasing statistical power by collecting specific sample sizes required. PMID- 23040603 TI - Alkaline detergent combined with a routine ward bedpan washer disinfector cycle eradicates Clostridium difficile spores from the surface of plastic bedpans. AB - The cleaning efficiency of a ward bedpan washer disinfector was evaluated using various cycle parameters and detergent to determine which conditions could effectively eliminate Clostridium difficile spores from the surface of bedpans. Results revealed that the regular intensive cycle with thermal conditions of 85 degrees C for 60 seconds plus the addition of an alkaline detergent was sufficient to eradicate C difficile spores. However, these thermal conditions alone, without detergent, were not adequate. PMID- 23040604 TI - Serological survey of mumps immunity among health care workers in the Catalonia region of Spain. AB - Susceptible health care workers are at risk of acquiring and transmitting mumps to or from patients. A survey was carried out in 639 health care workers from tertiary public hospitals and primary care centers in the Catalonia region of Spain during 2009 to determine the prevalence of immunity to mumps among this group. The prevalence of immune health care workers was 87.5% (95% confidence interval, 84.7-89.9). Vaccination with 2 doses of vaccine should be reinforced in health care workers to minimize the risk of mumps transmission in health care settings. PMID- 23040606 TI - Impact of terminal cleaning and disinfection on isolation of Acinetobacter baumannii complex from inanimate surfaces of hospital rooms by quantitative and qualitative methods. AB - Quantitative broth cultures were obtained from hospital rooms newly vacated by patients positive for multidrug-resistant Acinetobacter baumannii complex (ABC) before and after terminal cleaning and disinfection. Of 10 ABC-positive precleaned room surfaces, 6 (60%) remained culture-positive after terminal cleaning and disinfection. Of a total of 16 room surfaces with detectable ABC by the quantitative method, 5 (31.2%; 95% confidence interval, 13.9%-55.8%) were also culture-positive by the qualitative technique. PMID- 23040605 TI - An outbreak of Burkholderia cepacia bacteremia in hospitalized hematology patients selectively affecting those with acute myeloid leukemia. AB - BACKGROUND: Burkholderia cepacia complex (Bcc) is a group of common environmental bacteria that preferentially colonize and infect patients with cystic fibrosis but are also emerging as nosocomial pathogens, possibly due to their resistance to disinfectants and antimicrobials. METHODS: We investigated a 3-month outbreak of Bcc bacteremia among hospitalized hematology patients. Environmental investigation and infection control measures were implemented. A retrospective, cross-sectional study was conducted to identify risk factors. RESULTS: Bcc was repeatedly isolated from the blood of 9 patients without central venous catheter who did not easily respond to targeted antibiotic treatment and 3 died of the infection. A point source was not identified and horizontal spread was suspected. Strict infection control measures terminated the outbreak. Interestingly, diagnosis of acute myeloid leukemia but not neutropenia or prior chemotherapy was a risk factor for infection acquisition. Neutropenia was positively correlated with infection duration. CONCLUSIONS: Bcc is not only a serious threat among immunocompromized hematology patients, but is also transmissible in clinical settings. Acute myeloid leukemia appears to confer additional risk for infection acquisition. PMID- 23040607 TI - Validation of central line-associated bloodstream infection data in a voluntary reporting state: New Mexico. AB - BACKGROUND: In New Mexico, voluntary submission of central line-associated bloodstream infection (CLABSI) surveillance data via the National Healthcare Safety Network (NHSN) began in July 2008. Validation of CLABSI data is necessary to ensure quality, accuracy, and reliability of surveillance efforts. METHODS: We conducted a retrospective medical record review of 123 individuals with positive blood cultures who were admitted to adult intensive care units (ICU) at 6 New Mexico hospitals between November 2009 and March 2010. Blinded reviews were conducted independently by pairs of reviewers using standardized data collection instruments. Findings were compared between reviewers and with NHSN data. Discordant cases were reviewed and reconciled with hospital infection preventionists. RESULTS: Initially, 118 individuals were identified for medical record review. Seven ICU CLABSI events were identified by the reviewers. Data submitted to the NHSN revealed 8 ICU CLABSI events, 5 of which had not been identified for medical record review and 3 of which had been determined by reviewers to not be ICU CLABSI cases. Comparison of final case determinations for all 123 individuals with NHSN data resulted in a sensitivity of 66.7%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 96.5% for ICU CLABSI surveillance. CONCLUSIONS: There is need for ongoing quality improvement and validation processes to ensure accurate NHSN data. PMID- 23040608 TI - Decreasing incidence of Staphylococcus aureus bacteremia over 9 years: greatest decline in community-associated methicillin-susceptible and hospital-acquired methicillin-resistant isolates. AB - BACKGROUND: The impact of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) emergence on the epidemiology of S aureus bacteremia (SAB) is not well documented. METHODS: This was an observational study of adult (aged >=18 years) inpatients with SAB in a single 808-bed teaching hospital during 2002-2003, 2005-2006, 2008-2009, and 2010 with period-stratified SAB rate, onset mode, patient characteristics, and outcome. RESULTS: We encountered a total of 1,098 cases over the entire study period. The rate decreased steadily over time (from 6.64/10(3) discharges in 2002-2003 to 6.49/10(3) in 2005-2006, 5.24/10(3) in 2008-2009, and 5.00/10(3) in 2010; P = .0001), with a greater decline in community-associated cases (0.99/10(3), 0.77/10(3), 0.58/10(3), and 0.40/10(3), respectively; P = .0005) compared with health care-associated cases (5.65/10(3), 5.72/10(3), 4.66/10(3), and 4.60/10(3), respectively; P = .005). The decline was principally in MSSA (3.11/10(3), 2.21/10(3), 2.24/10(3), and 1.75/10(3), respectively; P = .00006), including both community-associated (P = .0002) and health care-associated cases (P = .006). Although overall rate changes in MRSA were not significant (P = .09), hospital onset MRSA decreased markedly (P < .00001), whereas CA-MRSA increased (P = .03). The all-cause 100-day mortality rate did not change significantly (25.6% for 2002 2003, 25.2% for 2005-2006, 28.1% for 2008-2009, and 32.2% for 2010; P = .10). Differences in MSSA/MRSA-associated mortality decreased (20.1% vs 30.6%, P = .03 for 2002-2003; 18.1% vs 28.9%, P = .05 for 2005-2006; 21.7% vs 32.9%, P = .05 for 2008-2009; and 29.3% vs 34.9, P = .5 for 2010). CONCLUSIONS: SAB incidence is decreasing, with the greatest decline in community-associated MSSA and hospital onset MRSA cases. Most health care-associated cases currently are community onset. MRSA/MSSA-related mortality is comparable. These changes are likely related to the emergence of CA-MRSA and the inpatient-to-outpatient shift in health care. PMID- 23040609 TI - Endoscopic management of necrotizing pancreatitis. PMID- 23040610 TI - [Massive retroperitoneal hematoma in an anticoagulated patient]. PMID- 23040611 TI - Organizing pneumonia as another pathological finding in pandemic influenza A (H1N1). PMID- 23040612 TI - [Noninvasive ventilation: when, how and where?]. PMID- 23040613 TI - HIV testing in black Africans living in England. AB - We examined the uptake of HIV testing in black Africans living in England before the introduction of national testing guidelines. Analyses were conducted using data from an anonymous self-completed questionnaire linked to oral fluid samples to establish HIV status in black Africans attending community venues in England in 2004. Of 946 participants, 44% had ever been tested for HIV and 29% had been tested in the previous 24 months. Of those with undiagnosed HIV, 45% had previously had a negative HIV test. Almost a third of people tested in the UK had been at general practice. Uptake of HIV testing was not associated with perceived risk of HIV. These findings highlight the need for the implementation of national HIV testing guidelines in the UK, including the promotion of testing in general practice. Regular testing in black Africans living in the UK should be promoted regardless of their HIV test history. PMID- 23040614 TI - SHIP2 signalling at the plasma membrane, in the nucleus and at focal contacts. AB - Phosphoinositide 5-phosphatases are critical enzymes in modulating the concentrations of PI(3,4,5)P(3), PI(4,5)P(2) and PI(3,5)P(2). The SH2 domain containing inositol 5-phosphatases SHIP1 and SHIP2 belong to this family of enzymes very much involved in physiopathology and development. Therefore activity and localization of the enzymes are particularly important taking into account both catalytic and non-catalytic mechanisms of the SHIP phosphatases. Several different mechanisms have been reported for SHIP2 targeting that often result from specific protein:protein interactions. In unstimulated astrocytoma cells, SHIP2 has a perinuclear and cytoplasmic localization. In serum-stimulated cells, SHIP2 can be localized at the plasma membrane and at focal contacts in polarized cells. A phosphorylated form of SHIP2 on S132 can be found in the nucleus and nuclear speckles. When present at the plasma membrane, SHIP2 may control the intracellular level of PI(3,4,5)P(3) thereby producing PI(3,4)P(2). When present in the nucleus, SHIP2 probably associates to other nuclear proteins such as lamin A/C and could potentially control nuclear PI(4,5)P(2). Finally, its presence at focal adhesions and lamellipodia could suggest a role in cell adhesion and migration. It is proposed that the complex phenotype observed in SHIP2 mutant mice in tissue development and growth could result from the addition of plasma membrane and nuclear effects consecutive to SHIP2 alteration. PMID- 23040616 TI - Editorial: Prostate cancer screening: perhaps a little patience is the answer. PMID- 23040615 TI - Recent trends in human Brucella canis infection. AB - There is little information in the literature regarding the clinical progress of brucellosis in patients affected by other diseases. We report Brucella canis human infection link to Gaucher's disease and Guillain Barre syndrome and discuss complications observed in a case with infective endocarditis. The three cases described came from areas of socio-economic deprivation and scarce epidemiological information where the healthcare personnel did not even consider such diagnosis. The growth of large urban populations deprived from basic services has created a new set of global health challenges. Changes in the urban environment due to slum communities' expansion have resulted in increased dog populations in the peridomiciliary environment. Eleven laboratory employees working with the strains found and their identification were examined. Sanitary authorities should focus on the zoonotic aspect of B. canis considering the dramatic increase of canine roamers near urban centers. PMID- 23040617 TI - Legends in urology. PMID- 23040618 TI - Guest editorial: Bilateral orchidectomy should not be considered an obsolete alternative for metastatic cancer of the prostate. PMID- 23040620 TI - Quality improvement of reporting standards for ablative studies: where do we stand? PMID- 23040619 TI - Role of tumor location in selecting patients for percutaneous versus surgical cryoablation of renal masses. AB - INTRODUCTION: To characterize the relationship between tumor location and choice in selecting surgical cryoablation (SCA) versus percutaneous cryoablation (PCA) for treatment of renal masses. MATERIALS AND METHODS: MEDLINE search was performed to identify studies in which cryoablation was used as therapy for renal masses. Tumor location was stratified as anterior, posterior, or lateral. Lesions were also described by endophycity (endo-, meso-, or exophytic) and polarity (upper, mid, or lower pole). Treating specialty was stratified as urology, radiology, or both. Comorbidity reporting rates were indexed for each manuscript. RESULTS: Thirty-seven manuscripts included 2344 lesions treated by SCA or PCA formed the basis for the analysis. Comparing SCA versus PCA series, anterior/posterior designation was reported in 31% versus 47% of series; endophycity designation was reported in 17% versus 40% of series; and polarity designation was reported in 48% versus 47% of series (all p values > 0.05). Amongst those lesions treated by SCA, 44% were anterior lesions and 28% were posterior, while among PCA-treated lesions 9% were anterior and 81% were posterior. Tumor location description was entirely absent in 32% (14/44) of published series. CONCLUSIONS: Despite data that tumor location is integral to choice of treatment for renal mass, anatomic tumor descriptors are vastly underreported in the cryotherapy literature. Nearly one third of masses treated with SCA are on the posterior surface of the affected kidney, and may be amenable to PCA, thus avoiding risk of general anesthesia and intraabdominal dissection in comorbid cohorts. Better reporting of objective measures of tumor anatomy and location in cryosurgery literature may facilitate standardization of treatment protocols in patients with renal mass. PMID- 23040621 TI - Long term results after complication of "prophylactic" suburethral tape placement. AB - INTRODUCTION: To report the long term result following complications that arose after "prophylactic" placement of midurethral sling (MUS) during prolapse repair. MATERIALS AND METHODS: After institutional review board approval, the records of patients who presented with complications of prophylactic MUS and had a minimum 1 year follow up after repair of their complication were reviewed. Data collected included age, body mass index, operative note documenting primary procedure and type of prophylactic MUS, indication for prophylactic MUS, presenting complaint, duration and severity of symptoms since MUS placement, operative events if any, and outcomes after repair of the complication. RESULTS: Between 2007 and 2009, ten patients presented with complications of prophylactic MUS and underwent transvaginal suburethral tape excision. At a median 35 (mean 36) month follow up post-MUS excision, a secondary midurethral stricture, an infected paravesical retropubic tape, and symptomatic incontinence and/or secondary anterior compartment prolapse requiring additional repair in five patients, occurred. Three patients experienced residual lower urinary tract symptoms (LUTS). Pain resolved in all four patients. CONCLUSION: "Prophylactic" placement of a MUS can be fraught with complications requiring MUS removal, followed by additional corrective surgery in some, and persistent LUTS managed by continuous pharmacological therapy in others, thus requiring careful consideration and full patient agreement. PMID- 23040622 TI - Placement of prophylactic midurethral sling at time of hysterectomy...are the potential associated problems worth the additional cost and risk? PMID- 23040623 TI - Treatment of infertility in 31 men with spinal cord injury. AB - INTRODUCTION: The majority of men with a spinal cord injury (SCI) are infertile due to ejaculatory dysfunction and poor semen quality. The goal of this retrospective study is to present the outcomes of assisted reproductive technology (ART) in a group of couples with SCI male partners. MATERIALS AND METHODS: A review was conducted of the records of 31 couples with SCI male partners who were treated at the Institut de readaptation Gingras-Lindsay-de Montreal, at PROCREA Cliniques or at a hospital center. A semen sample was obtained either by manual stimulation, penile vibratory stimulation, electroejaculation or testicular sperm extraction. ART technique was selected according to the sperm parameters. RESULTS: The mean age of the men was 29 years (23-48) and of their female partners, 29 years (25-41). The average sperm count was 110.4 M/mL +/- 16.2 M/mL and the average sperm motility rate was 12.3% +/- 16.5%. Among the 10 couples treated with intravaginal insemination, 9 pregnancies occurred among 7 couples. No pregnancies resulted from intrauterine insemination (2 cases). Among the 18 couples treated with in vitro fertilization, 12 pregnancies were reported among 10 couples. The pregnancy rate/cycle was 43%. Following these ART techniques, the pregnancy rate reached 55%. Three pregnancies occurred from the use of donor sperm in 7 couples. Overall, 20 men with a SCI (64% of the group) became fathers to at least one child. CONCLUSIONS: Fertility treatments are effective for couples with SCI male partners and secondary infertility. PMID- 23040624 TI - Optimizing fertility potential in spinal cord injured men. PMID- 23040625 TI - Contemporary management of small renal masses: does practice environment matter? AB - INTRODUCTION: Population based studies imply underutilization of renal preservation for managing small renal mass (SRMs). Limited information is available regarding the impact of practice environment on SRM treatment. We evaluated practice patterns for SRMs in the context of a urologist's practice environment. MATERIALS AND METHODS: Survey instrument querying practice type (private versus academic/academic affiliation) was distributed to urologists of the Mid-Atlantic section of the American Urological Association. Physicians were presented three case scenarios (exophytic 2.5 cm SRM in a healthy 55-year-old, healthy 75-year-old, and comorbid 75-year-old patient) and were queried on management. RESULTS: Of the 281 respondents who manage kidney cancer, 92 practiced in an academic environment, and 189 were private practitioners. Thirty four percent had completed residency training within 10 years, 25% between 11-20 years, and 41% over 20 years. For SRMs in a healthy 55-year-old, over 95% of practicing nephrologists advocated nephron-sparing treatments. Nonetheless, private practitioners were more likely to perform a radical nephrectomy (6% versus 0%, p = 0.03) and less likely perform a partial nephrectomy (79% versus 91%, p = 0.01) than academic counterparts. We observed an increase in the percentage of urologists offering thermal ablation (38% versus 12%, p < 0.0001) and observation (29% versus 1%, p < 0.0001) with a corresponding decline in the use of partial nephrectomy (32% versus 83%, p < 0.0001) in the 75-year-old versus 55-year-old patient. When considering management of a SRM in 75-year-old patients (healthy or comorbid), private practitioners were more likely to offer a thermal ablative procedure when compared to academic urologists (41% versus 32%, p = 0.05). CONCLUSIONS: Over 95% of urologists espouse renal preservation strategies for a SRM in a healthy, young patient. Private practitioners are more likely to perform a radical (and less likely a partial) nephrectomy in this cohort. While surveillance is increasingly utilized for SRMs in the elderly patient, private practitioners are more likely to recommend active treatment via thermal ablation when compared to academic counterparts. PMID- 23040626 TI - The impact of perioperative blood transfusion on survival following radical cystectomy for urothelial carcinoma. AB - INTRODUCTION: Perioperative blood transfusion (PBT) has been shown to contribute to cancer progression and mortality. This study sought to determine the impact of PBT during radical cystectomy on cancer-specific survival (CSS) and overall survival (OS). MATERIALS AND METHODS: The Columbia University Urologic Oncology Database was reviewed for patients who underwent a RC from 1989 to 2010 (n = 638). PBT was defined as non-autologous packed red blood cells (PRBC) received during the same hospital stay as the radical cystectomy. Clinical and pathological variables were compared between the cohorts and survival analysis was performed with the Kaplan-Meier and Cox-regression methods. The primary outcomes were CSS and OS. RESULTS: Of 638 patients identified, 209 patients (32.8%) underwent PBT with an average of 2.21 +/- 1.66 units transfused PRBC. Mean age was 68.1 +/- 11.2 years; median follow up was 25.5 months (range 1-164 months). The number of units of PRBC transfused was inversely associated with OS (HR 1.12; p = 0.008) and CSS (HR 1.12; p = 0.049) on univariable analysis. Additionally, Kaplan-Meier analysis demonstrated a significant difference in OS (p = 0.0211) in patients who received more units of PRBC. However, on multivariable analysis, the number of units of PRBC transfused was not an independent predictor of outcome for CSS (p = 0.300) or OS (p = 0.246). CONCLUSIONS: Each additional unit of PRBC received during radical cystectomy is associated with a decrease in survival. However, after controlling for clinical and pathologic factors which predict survival, PBT does not have an independent affect upon CSS or OS. PMID- 23040627 TI - Mid term outcomes of initial 250 case experience with GreenLight 120W-HPS photoselective vaporization prostatectomy for benign prostatic hyperplasia: comparison of prostate volumes < 60 cc, 60 cc-100 cc and > 100 cc. AB - INTRODUCTION: The aim of this study was to compare the efficacy of GreenLight 120W-HPS (American Medical Systems, Minnetonka, Minnesota, USA) laser vaporization for men with obstructive benign prostatic hyperplasia (BPH) according to prostate volumes < 60 cc, 60 cc-100 cc and > 100 cc. MATERIAL AND METHODS: The clinical data of 250 men with symptomatic BPH who underwent photoselective vaporization prostatectomy (PVP) by a single surgeon between July 2007 and August 2009 were retrospectively analyzed. Prostate volumes were measured by using transrectal ultrasonography (TRUS). Functional evaluations were performed at 3, 6 and 12 months with a prostate-specific antigen (PSA) obtained at 6 months. All men were stratified into three groups according to TRUS volume. RESULTS: Among the 250 consecutive PVP patients, 134, 76 and 40 men had prostate volumes < 60 cc, 60 cc-100 cc and > 100 cc, respectively. Mean laser time and delivered energy were 31, 44 and 59 minutes; 163, 309 and 473 kJ respectively (p < 0.01 for all). At 1 year, mean International Prostate Symptom Score (IPSS) improved by 69%, 63% and 50%, Qmax increased by 194%, 175% and 162% and post void residual (PVR) decreased by 88%, 81% and 71%, respectively (p < 0.01 for all). Mean decrease in preoperative PSA at 6 months was 63%, 52% and 41% (p < 0.01), respectively. Hospital stay, catheterization time and complication rates were comparable between groups, however retreatment rates were significantly higher for prostates >100 cc (1.5% versus 2.6% versus 9%; p = 0.02). CONCLUSIONS: Although larger prostates require more time and energy delivery, PVP is safe and efficacious for patients with lower urinary tract symptoms (LUTS) regardless of prostate size. Laser vaporization for glands > 100 cc appears to have a reduced reduction in PSA and a higher 9% rate of retreatment indicating that PVP for larger prostates remains to be optimized. PMID- 23040628 TI - The presence of detrusor muscle in the pathological specimen after transurethral resection of primary pT1 bladder tumors and its relationship to operator experience. AB - INTRODUCTION: To assess the quality of transurethral resection of bladder tumors (TURBTs) performed by "senior" and "junior" urologists for pT1 tumors in terms of detrusor muscle (DM) presence and recurrence rate at 3 month first cystoscopy (RR FC). Non-muscle invasive bladder cancer (NMIBC) is a heterogeneous group with differing biological potentials. Tumors invading lamina propria (pT1) have an increased propensity for recurrence and progression. Accurate staging at the time of primary TURBT, including the presence of DM, is crucial to avoid understaging and unnecessary delay in definitive treatment. MATERIALS AND METHODS: We analyzed our maintained bladder tumor database (TURBTs from 2002 to 2009) and selected patients diagnosed with pT1 bladder tumors. Data on surgeon status, tumor characteristics (size, TNM stage 2009, grade, DM presence) and RR-FC were retrieved. Surgeons were stratified into "senior" and "junior" according to the years of prior training. RESULTS: Of the 340 TURBTs for pT1 tumors, "senior" and "junior" surgeons performed 237 (69.7%) and 103 (30.3%), respectively. Overall, 238 (70%) TURBTs had DM in the specimen, including 175 (73.8%) and 63 (61.3%) for the "senior" and "junior" operators, respectively (p = 0.02). The overall RR-FC was 37.4% (n = 127) and was significantly different for DM presence and DM absence (30.7% versus 52.9%; p = 0.01). On multivariate analysis, tumor recurrence was associated with "junior" operator experience independent of the presence or absence of DM (OR = 2.33 [1.45-3.74]) p = 0.01). CONCLUSIONS: The presence of DM in a primary TURBT for pT1 NMIBC is directly associated with operator experience, with an associated increased 3 month recurrence rate for "junior" resectionists. PMID- 23040629 TI - Single surgeon's experience with laparoscopic versus robotic partial nephrectomy: perioperative outcomes/complications and influence of tumor characteristics on choice of therapy. AB - INTRODUCTION: Laparoscopic (LPN) and robotic partial nephrectomy (RPN) may offer similar advantages for nephron-sparing surgery (NSS). We evaluated the perioperative outcomes and complications of LPN versus RPN and sought to evaluate if one technique may have more favorable outcomes over another based on tumor characteristics. MATERIALS AND METHODS: All patients who underwent LPN and RPN by a single surgeon were retrospectively reviewed. The surgeon almost exclusively performed LPN from February 2009 to January 2011 and RPN from January 2011 to January 2012. Patient demographics, tumor characteristics, perioperative outcomes, short term renal functional data, and complications were reviewed. Operative time (OT), warm ischemia time (WIT), and estimated blood loss (EBL) were evaluated for each technique when tumor characteristics were divided by size, location, distance to collecting system, and overall tumor complexity based on nephrometry scoring. RESULTS: Of 39 laparoscopic cases and 30 robotic cases, there were no significant differences in perioperative outcomes, short term renal functional data, or complications between the two groups except for WIT which was shorter in the LPN group (p = 0.006). For medium complexity tumors, OT was less for LPN compared to RPN (p = 0.04); for high complexity tumors, EBL was reduced for RPN compared to LPN cases (p = 0.003). When tumor characteristics were individualized, LPN may be superior to RPN for WIT for small, anterior and exophytic tumors, and tumors located > 5 mm from the collecting system. LPN and RPN appear more equivocal for WIT in posteriorly located tumors. Reduced EBL may be a benefit with RPN for larger tumors. CONCLUSIONS: Although WIT was less in patients undergoing LPN compared to RPN, perioperative outcomes and complications remain similar. RPN may be beneficial for approaching more difficult, posterior tumors, whereas LPN may be a better technique for WIT for simple, accessible renal tumors. Reduced EBL may be a benefit for RPN for highly complex tumors. PMID- 23040630 TI - A rare case of solitary metastatic non-seminomatous malignant germ cell tumor to the prostate. AB - Testicular cancer is the most common solid malignancy of men aged 15-40 years and metastasizes in a predictable manner via lymphatic spread. Involvement of metastatic testicular cancer to the prostate is an exceedingly rare event which has only been previously described in patients with seminomatous germ cell tumors. In this report, we present a case of a 42-year-old man who presented with metastatic testicular cancer to the prostate 8 years after his original diagnosis of a mixed germ cell left testicular tumor. PMID- 23040631 TI - Robotic assisted laparoscopic repair of vesico-vaginal fistula: the extravesical approach. AB - The optimal method of vesico-vaginal fistula (VVF) repair remains undetermined. Almost all previous descriptions of laparoscopic/robotic fistula repair involve utilizing a vertical cystotomy to identify the fisula. Avoidance of an intravesical approach to vesico-vaginal fistula repair may decrease patient morbidity. Patient selection, patient positioning, fistula recognition, port placement, intra-operative dissection techniques, flap formation, and repair are outlined in this video of robotic repair of vesico-vaginal fistula utilizing an extravesical approach. The extravesical robotic repair has been successfully utilized in two patients with VVF following hysterectomy. This manuscript and video demonstrates that vesico-vaginal fistulae can be repaired with a robotic assisted extravesical approach avoiding the morbidity of a large cystotomy. PMID- 23040632 TI - Holmium laser endourethrotomy and litholapaxy of an occult prostatic utricle calculus. AB - Prostatic utricle (PU) stones are rare and the surgical treatment of such PU anomalies has proved challenging given their location adjacent to the posterior urethra and proximity to important fertility and continence structures. We report the case of a 58-year-old male with hypospadias, microphallus, and irritative lower urinary tract symptoms (LUTS) found to have a large PU stone. He underwent successful complete endoscopic removal of the stone via transurethral unroofing and holmium laser litholapaxy. We conclude that it is an effective alternative to other surgical techniques once size of the stone and the patient's individual anatomy are considered. PMID- 23040633 TI - Sacral nerve stimulation for neuromodulation of the lower urinary tract. AB - Sacral neuromodulation (SNM) has become a standard treatment option for patients suffering from urinary urge incontinence, urgency-frequency, and/or nonobstructive urinary retention refractory to conservative and pharmacologic treatment. Since its initial development, the manufacturer of InterStim therapy (Medtronic, Inc., Minneapolis, MN, USA), has introduced technical modifications, while surgeons and researchers have adapted and published various innovations and alterations of the implantation technique. In this article, we feature our SNM technique including patient selection, comprehensive dialogue/evaluation, procedure details, and appropriate follow up. Although there is often great variability in patients with lower urinary tract dysfunction, we maintain that great success can be achieved with a systematic and methodical approach to SNM. PMID- 23040634 TI - Partial nephrectomy: novel closure technique using bovine pericardium. AB - Partial nephrectomy (PN) has gained popularity over the past two decades as an alternative to radical nephrectomy (RN) in patients with small renal masses. Morbidity and mortality from PN have been shown to be lower than from RN, while oncologic outcomes have been shown to be equivalent for tumors < 7 cm. PN has become increasingly popular in academic centers, but the general urologic community continues to lag behind. The reason for this is not known, but may be related to the relatively high complication rate, including delayed complications associated with inadequate closure. Here we describe a novel PN closure technique that provides additional strength and hemostasis by incorporating bovine pericardium. PMID- 23040635 TI - Open clinical uro-oncology trials in Canada. PMID- 23040636 TI - Abstracts of the mid-Atlantic Section of the American Urological Association 70th annual meeting October 11-14, 2012, Philadelphia, Pennsylvania. PMID- 23040638 TI - Multi-objective optimization framework for networked predictive controller design. AB - Networked Control Systems (NCSs) often suffer from random packet dropouts which deteriorate overall system's stability and performance. To handle the ill effects of random packet losses in feedback control systems, closed over communication network, a state feedback controller with predictive gains has been designed. To achieve improved performance, an optimization based controller design framework has been proposed in this paper with Linear Matrix Inequality (LMI) constraints, to ensure guaranteed stability. Different conflicting objective functions have been optimized with Non-dominated Sorting Genetic Algorithm-II (NSGA-II). The methodology proposed in this paper not only gives guaranteed closed loop stability in the sense of Lyapunov, even in the presence of random packet losses, but also gives an optimization trade-off between two conflicting time domain control objectives. PMID- 23040637 TI - High mobility group box 1 released from necrotic cells enhances regrowth and metastasis of cancer cells that have survived chemotherapy. AB - The role of the high mobility group box 1 (HMGB1) protein in chemotherapy-induced cell death was examined. CT26 mouse colon cancer cells were treated with trichostatin A (TSA; apoptosis inducer) or doxorubicin (DXR; necrosis inducer). DXR increased HMGB1 concentration in CT26 cell culture medium, whereas TSA did not. In a CT26 bilateral subcutaneous tumour model, DXR or TSA was injected in a single tumour. After injection, serum HMGB1 concentration in DXR-treated mice was 10 times higher than that in TSA-treated mice. After DXR treatment, the contralateral and remnant tumours showed more pronounced growth than did those treated with TSA. In mouse models, lung and liver metastasis was enhanced by DXR but not by TSA. DXR-enhanced metastasis was abrogated by anti-HMGB1 antibody treatment. In a cancer dormancy model, DXR induced regrowth of quiescent CT26 cells. HMGB1 induced tumour necrosis factor-alpha secretion via Toll-like receptor (TLR)4 in U937 monocytes; however, HMGB1 decreased the number of U937 cells, resulting in restriction of immune activation via receptor for advanced glycation endproducts (RAGE). RAGE showed a more pronounced effect on nuclear factor kappa B activation than did TLR4 in CT26 cells. These findings suggest that HMGB1 released from necrotic cancer cells treated with a necrosis inducer enhances regrowth and metastasis of remnant cancer cells via RAGE activation. PMID- 23040639 TI - Enhanced cascade control for a class of integrating processes with time delay. AB - Unlike self-regulating processes, cascade control strategies for control of integrating processes with time delay are limited. A novel series cascade control structure to enhance the closed loop performance is proposed for integrating and time delay processes. The proposed controller structure has only two controllers and a setpoint filter. The inner loop controller is designed based on IMC approach and the primary setpoint filter is based on optimal performance index. The primary load disturbance rejection controller, a PID controller in series with a lead/lag compensator, is designed on the basis of the desired closed-loop complementary sensitivity function. The robustness analysis is carried out using Kharitonov's theorem. Simulation results demonstrate the efficacy of the proposed method by showing satisfactory nominal and robust performances. PMID- 23040640 TI - Chronic exertional compartment syndrome in adductor pollicis muscle: case report. AB - We report a case of chronic exertional compartment syndrome in the adductor pollicis that was confirmed by measuring elevated compartment pressure. Specific finding of magnetic resonance imaging, increased T2 signal intensity in the involved compartment, was also useful for the diagnosis. Pain was relieved by fasciotomy through a volar approach. PMID- 23040641 TI - Effect of osteochondroma location on forearm deformity in patients with multiple hereditary osteochondromatosis. AB - PURPOSE: Multiple hereditary osteochondromatosis (MHO) is an autosomal-dominant skeletal dysplasia that may result in forearm deformity. The purpose of this study was 2-fold: to describe the natural history of forearm deformity in patients with MHO, with particular attention to those who develop radial head dislocation, and to determine predictors of deformity. METHODS: We retrospectively reviewed charts of all patients with MHO evaluated at our institution. Patients with the presence of a radiographically visible osteochondroma in the forearm were divided into 5 groups or types based on location of the osteochondroma(s). Radiographic measurements included radial articular angle, percent ulnar variance, radial bow, radial length, ulnar length, and ulnar bow. The predictive values of each measure were statistically evaluated for each type with relation to radial head dislocation. RESULTS: Of 146 patients with MHO, 102 patients (70%) had forearm involvement. Appropriate anteroposterior and lateral radiographs were available on 48 patients (76 forearms). Average age at initial radiographic evaluation was 12 years (range, 2-18 y). Average follow up period was 7 years (range 1-19 y). Thirteen forearms demonstrated radial head dislocation, with all but 1 reported in the type 1 limbs (solitary distal ulna osteochondroma). Radial head dislocation was noted in 34% (12/35 forearms) of type 1 limbs. CONCLUSIONS: Forearms with isolated osteochondromas of the distal ulna are the ones most likely to develop radial head dislocation. Because the ulna growth is disproportionately less than radial growth, the soft tissues may act as a tether, linking the distal radius and ulna, and lead to radial head dislocation. Changes in radiographic measurements may predict limbs at risk for radial head dislocation. PMID- 23040643 TI - Exeter short stems compared with standard length Exeter stems: experience from the Australian Orthopaedic Association National Joint Replacement Registry. AB - The standard Exeter stem has a length of 150 mm with offsets 37.5 to 56 mm. Shorter stems of lengths 95, 115 and 125 mm with offsets 35.5 mm or less are available for patients with smaller femurs. Concern has been raised regarding the behavior of the smaller implants. This paper analyzed data from the Australian Orthopaedic Association National Joint Replacement Registry comparing survivorship of stems of offset 35.5 mm or less with the standard stems of 37.5 mm offset or greater. At 7 years, there was no significant difference in the cumulative percent revision rate in the short stems (3.4%, 95% CI 2.4-4.8%) compared with the standard length stems (3.5%, 95% CI 3.3-3.8%) despite its use in a greater proportion of potentially more difficult developmental dysplasia of the hip cases. PMID- 23040642 TI - Corticoplasty for improved appearance of hands with Ollier disease. AB - PURPOSE: Only a few treatment options are available for Ollier disease, especially for improving appearance. The purpose of this study was to evaluate the efficacy of partial resection of the cortical bone with curettage of the tumor (corticoplasty) for treating hand deformity in Ollier disease. METHODS: Five hands (3 patients, 30 metacarpals and phalanges) were examined. Windows of thin cortical bone were elevated, the tumors were excised, and the cortex was trimmed and replaced to enhance the appearance. Artificial bone substitute was used as the graft material for 17 lesions to fill the vacant medullary cavity. The other 13 bones had corticoplasty without grafting. Reduction of bone diameter on radiographs and patient satisfaction were rated after an average of 24 months. RESULTS: On average, bony union was achieved 9 weeks after surgery (range, 4-12) in all cases. Morphologic changes on radiographs were rated as excellent or good. Complications and tumor recurrence were not observed, and the range of finger motion and grip strength did not decrease. The level of satisfaction with the outcome was very satisfied for 4 hands and satisfied for the remaining hand. CONCLUSIONS: Corticoplasty for Ollier disease resulted in cosmetic improvement without functional deterioration. PMID- 23040644 TI - Harmonic focus versus electrocautery in axillary lymph node dissection for breast cancer: a randomized clinical study. AB - BACKGROUND: Electrocautery has been proven to be associated with prolonged serous drainage that might result in several complications in patients requiring axillary lymph node dissection for breast cancer. We proposed that the Harmonic Focus might outperform electrocautery in axillary lymph node dissection, resulting in shorter operative times and reduced postoperative complications. PATIENTS AND METHODS: One hundred twenty-eight women with confirmed T1-3 N1-2 breast cancer were randomly assigned to undergo mastectomy or breast-conserving surgery with axillary dissection by using Harmonic Focus or electrocautery. Sixty four has surgery with Harmonic Focus (group A) and 64 with electrocautery (group B) by the same surgical team. Operative time, blood loss, total drainage volume and days, incidence of seroma, hematoma, pain score, and flap necrosis were recorded. RESULTS: Using Harmonic Focus significantly diminished operative time, blood loss, total drainage volume, days of stay, and visual analogue scale as compared with traditional electrocautery. There was no statistical difference between the 2 groups regarding seroma, hematoma, and flap necrosis. CONCLUSION: Axillary lymph node dissection using Harmonic Focus is feasible, safe, and a more comfortable design for the surgeon. PMID- 23040645 TI - Polychlorinated dibenzo-p-dioxin and dibenzofuran and polychlorinated biphenyl emissions from different smelting stages in secondary copper metallurgy. AB - Secondary copper production has received much attention for its high emissions of polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) reported in previous studies. These studies focused on the estimation of total PCDD/F and polychlorinated biphenyl (PCB) emissions from secondary copper smelters. However, large variations in PCDD/F and PCB emissions reported in these studies were not analyzed and discussed further. In this study, stack gas samples at different smelting stages (feeding-fusion, oxidation and deoxidization) were collected from four plants to investigate variations in PCDD/F and PCB emissions and characteristics during the secondary copper smelting process. The results indicate that PCDD/F emissions occur mainly at the feeding-fusion stage and these emissions contribute to 54-88% of the total emissions from the secondary copper smelting process. The variation in feed material and operating conditions at different smelting stages leads to the variation in PCDD/F emissions during the secondary copper smelting process. The total PCDD/F and PCB discharge (stack gas emission+fly ash discharge) is consistent with the copper scrap content in the raw material in the secondary copper smelters investigated. On a production basis of 1 ton copper, the total PCDD/F and dl-PCB discharge was 102, 24.8 and 5.88 MUg TEQ t(-1) for the three plants that contained 100%, 30% and 0% copper scrap in their raw material feed, respectively. PMID- 23040646 TI - A priori assessment of ecotoxicological risks linked to building a hospital. AB - Hospital wastewaters contain a large number of chemical pollutants such as disinfectants, detergents, and drug residues. A part of these pollutants is not eliminated by traditional urban waste water treatment plants, leading to a major risk for the aquatic ecosystems receiving these effluents. After having formulated a specific methodology in order to assessment ecotoxicological risk for such a situation, we applied it to the project to build a new hospital shared by several towns in the French Alps. This methodology is based on the ecotoxicological characterisation of the hospital wastewater using a battery of three chronic bioassays (Pseudokirchneriella subcapitata, Heterocypris incongruens and Brachionus calyciflorus) and of genotoxicity tests (Ames fluctuation assay on Salmonella typhimurium, and a Fpg-modified comet assay on the trout liver cell line RTL-W1). The formulated methodology highlights a moderate risk of the hospital wastewater for the organisms of the water column of the river concerned. Nevertheless, this discharge contributes significantly to the global ecotoxicological risk when taking into account all the releases of the watershed into the river. This leads to recommending the implementation of a specific treatment system in the urban WWTP, or upstream to it, in view to protecting the aquatic organisms. PMID- 23040647 TI - Mass transfer coefficients for volatilization of polychlorinated biphenyls from the Hudson River, New York measured using micrometeorological approaches. AB - Air-water exchange is an important process controlling the fate of many organic chemicals in the environment. Modeling this process is hampered by the lack of direct observations. Thus, the purpose of this work was to derive direct measurements of the mass transfer coefficients for air-water exchange (v(aw)) of polychlorinated biphenyls (PCBs) that may be used to check the validity of values derived from tracer gas experiments. v(aw) values for PCBs were determined using previously published turbulent fluxes divided by the corresponding dissolved phase concentrations. The median v(aw) values for each homolog decreased with increasing molecular weight and ranged from 0.29 for hexachlorobiphenyls to 2.2 m d(-1) for monochlorobiphenyls with a propagated uncertainty of about 70%, lower than in previous studies. Due to relatively low wind speeds and possible sorption of PCBs to colloids, these numbers may be biased low. These field measurements of v(aw) differ by as much as a factor of 23 from predictions based on the widely used Whitman two-film model. Therefore a new formulation for the calculation of v(aw) based on field measurements is needed. This study demonstrates that micrometeorological approaches are a viable option for the measurement of v(aw) for hydrophobic organics such as PCBs and should be used to generate enough field data on the air-water exchange of hydrophobic organics to allow the development of new predictive models. PMID- 23040648 TI - Effect of DTPA on Cd solubility in soil--accumulation and subsequent toxicity to lettuce. AB - In a controlled environment experiment, using Cd spiked soil, lettuce plants were grown under a range of DTPA levels and were subsequently harvested to determine levels of phytoaccumulation. Cadmium phytoaccumulation significantly increased with increasing soil Cd level (P<0.05) but unexpectedly decreased with increasing DTPA levels, despite the fact that solubility of Cd was increased in the soil. Cadmium translocation (from root to shoot) increased after DTPA application. Lettuce growth was inhibited by both Cd and DTPA (at and above 10 and 500 mg kg( 1) respectively), as a result of higher Cd mobility and subsequent toxicity which was caused by DTPA higher dosages. Metal solubility in the soil (ranged between 2.8 and 26.5 mg kg(-1)) was found to be significantly higher (P<0.01) as compared to control with increasing DTPA levels even after 3 months of DTPA application. Cadmium tissue concentration in all DTPA treatments was less than in the corresponding control treatment, indicating a negative effect of DTPA application on Cd uptake. In conclusion, lettuce was an unsuitable plant species for Cd accumulation, at least when associated with a DTPA chelator. PMID- 23040649 TI - Heavy metal toxicity to bacteria - are the existing growth media accurate enough to determine heavy metal toxicity? AB - A new minimal medium was formulated considering the limitations of the existing media for testing heavy metal sensitivity to bacteria. Toxicity of cadmium and copper to three bacteria was investigated in the new medium and compared with three other media commonly used to study the effect of the toxic metals. Based on speciation data arrived at using ion-selective electrodes, the available free metal concentration in solution was highest in the MES-buffered medium. This finding was strongly supported by the estimated EC(50) values for the metals tested based on the toxicity bioassays. The free-ionic cadmium and copper concentrations in the medium provide more accurate determination of metal concentrations that affects the bacteria, than with most of other existing media. This will avoid doubts on other media and misleading conclusions relevant to the toxicity of heavy metals to bacteria and provides a better option for the study of metal-bacteria interactions. PMID- 23040650 TI - Effects of metal oxide nanoparticles on soil properties. AB - In recent years the behavior and properties of nanoparticles released to the environment have been studied extensively to better assess the potential consequences of their broad use in commercial products. The fate, transport and mobility of nanoparticles in soil were shown to be strongly dependent on environmental conditions. However, little is known about the possible effects of nanoparticles on soil chemical, physical and biological properties. In this study, two types of metal oxide nanoparticles, CuO and Fe(3)O(4) were mixed into two types of soil and the effects of the nanoparticles on various soil properties were assessed. Metal oxide nanoparticles were shown previously to catalyze the oxidation of organic pollutants in aqueous suspensions, and they were therefore expected to induce changes in the organic material in the soil, especially upon addition of an oxidant. It was found that the nanoparticles did not change the total amount of organic materials in the soil or the total organic carbon in the soil extract; however, three-dimensional fluorescence spectroscopy demonstrated changes in humic substances. The nanoparticles also affected the soil bacterial community composition, based on denaturing gradient gel electrophoresis (DGGE) fingerprinting, but had little impact on the macroscopic properties of the soil. PMID- 23040651 TI - Assessing travelers' knowledge and use of coca for altitude sickness. PMID- 23040652 TI - [Comparison of 3 combinations of 0.5% levobupivacaine and 1% mepivacaine in popliteal sciatic block in hallux valgus outpatient surgery]. AB - BACKGROUND: To compare 3 combinations of 0.5% levobupivacaine (L) and 1% mepivacaine (M) for popliteal block for hallux valgus surgery. METHODS: Prospective, double blind study of 120 patients undergoing unilateral hallux valgus outpatient surgery with posterior popliteal block with ultrasound-guided single injection. Patients were randomly allocated into three groups: G1: 20mL L+10mL M; G2: 10mL L+20mL M; and G3: 15mL L+15mL M. Recorded variables were: time of block, onset and reversal times for tibial and peroneal nerves block; postoperative pain until the 7(th) day by means of visual analogue scale (VAS), simple descriptive scale and the quality of nocturnal rest, complications, and patient satisfaction. ANOVA and chi2 were applied in the statistical analysis, with a P<0.05 considered significant. RESULTS: Groups were homogeneous for demographic and surgical characteristics. None of the patients required intraoperative complementary analgesia or anaesthesia. Block onset was significantly longer in G1 than in G2 and G3 (39.4+/-14.7 versus 32.2+/-16.5 and 33.2+/-12minutes). Recovery time from sensory and motor block was significantly longer in G1 than in G2 and G3 (29.5+/-9.3 versus 22.2+/-8.2 and 24.8+/ 7.9hours). Postoperative pain level was below VAS 30 (1-100) in the three groups; none of the patients experienced severe pain. Maximum pain level appeared at 24h postoperatively. Patient satisfaction was high and there were no complications. CONCLUSIONS: Block onset time and anaesthetic efficacy was adequate in the three groups. The combination of 20mL levobupivacaine 0.5% with 10mL mepivacaine 1% provide a good alternative for a lasting postoperative analgesia. PMID- 23040653 TI - [Reevaluation of the time course of the effect of propofol described with the Schnider pharmacokinetic model]. AB - BACKGROUND: The first order plasma-effect-site equilibration rate constant (k(e0)) links the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. This constant, calculated for each specific PK drug model, allowed us to predict the course of the effect in a target controlled infusion (TCI). The PK-PD model of propofol, published by Schnider et al., calculated a k(e0) value of 0.456min(-1) and a corresponding time to peak effect (t peak) of 1.6min. The aim of this study was to reevaluate the k(e0) value for the predicted Schnider model of propofol, with data from a complete effect curve obtained by monitoring the bispectral index (BIS). METHODS: The study included 35 healthy adult patients (18 90 years) scheduled for elective surgery with standard monitoring and using the BIS XP((r)) (Aspect), and who received a propofol infusion to reach a plasma target of 12 MUg/ml in 4min. The infusion was then stopped, obtaining a complete effect curve when the patient woke up. The AnestfusorTM (University of Chile) software was used to control the infusion pumps, calculate the plasma concentration plotted by Schnider PK model, and to store the BIS data every second. Loss (LOC) and recovery (ROC) of consciousness was assessed and recorded. Using a traditional parametric method using the "k(e0) Objective function" of the PK-PD tools for Excel, the individual and population k(e0) was calculated. Predictive Smith tests (Pk) and Student t test were used for statistical analysis. A P<.05 indicated significance. RESULTS: The evaluation included 21 male and 14 female patients (18 to 90 years). We obtained 1,001 (+/-182) EEG data and the corresponding calculated plasma concentration for each case. The population k(e0) obtained was 0.144min(-1) (SD+/-0.048), very different from the original model (P<.001). This value corresponds with a t peak of 2.45min. The predictive performance (Pk) for the new model was 0.9 (SD+/-0.03), but only 0.78 (SD+/-0.06) for the original (P<.001). With a baseline BIS of 95.8 (SD+/-2.34), the BIS at LOC was 77.48 (SD+/-9.6) and 74.65(SD+/-6.3) at ROC (P=.027). The calculated Ce in the original model at LOC and ROC were 5.9 (SD+/-1.35)/1.08 MUg/ml (SD+/-0.32) (P<.001), respectively, and 2.3 (SD+/-0.63)/2.0 MUg/ml (SD+/ 0.65) (NS) for the new model. The values between LOC/ROC were significantly different between the 2 models (P<.001). No differences in k(e0) value were found between males and females, but in the new model the k(e0) was affected by age as a covariable (0.26-[age*0.0022]) (P<.05). CONCLUSIONS: The dynamic relationship between propofol plasma concentrations predicted by Schnider's pharmacokinetic model and its hypnotic effect measured with BIS was better characterized with a smaller k(e0) value (slower t1/2k(e0)) than that present in the original model, with an age effect also not described before. PMID- 23040654 TI - [Rett syndrome: double epidural catheter for the control of postoperative pain after scoliosis surgery. A literature review]. AB - Rett syndrome is a severe and incapacitating neurological disease caused by a structural defect in the short arm of the X chromosome (Xq28). It affects females and consists of multiple and progressive neurological impairments that start from a young age, leading to lifelong disability and dependency. Scoliosis appears in more than 50% of patients and requires surgical correction in cases where the curvature is severe. Pre-anaesthetic assessment is essential in order to identify the risk factors and thus reduce the morbidity and mortality associated with the surgical procedure. We present the case of a patient affected by this syndrome and scoliosis, who was scheduled to have an instrumented thoracolumbar spine arthrodesis with general anaesthesia, which passed without incident. We evaluate the specific details of this syndrome, its potential complications, and its management from an anaesthetic point of view, emphasising the control of postoperative pain using a double epidural catheter with an infusion of local anaesthetics and fentanyl. PMID- 23040655 TI - Patient and practice factors affecting growth of infants with systemic-to pulmonary shunt. AB - BACKGROUND: On recognising poor growth following neonatal palliation with a systemic-to-pulmonary shunt, we sought to determine how patient- and procedure related factors impact growth, paying attention to the role of the primary cardiologist in this process. METHODS: In a retrospective review, neonates (133 patients) receiving modified systemic-to-pulmonary artery shunts from 2002 to 2009 were studied and outpatient visits were reviewed. Patients with single- and two-ventricle circulations after shunt takedown were compared using weight-for age z-score. RESULTS: Single-ventricle patients had a higher weight-for-age z score at neonatal surgery than two-ventricle patients (-0.4 +/- 1.0 compared with -1.2 +/- 0.9, with p < 0.001), but they had a greater drop in the weight-for-age z-score to the first outpatient visit (-1.1 +/- 0.7 compared with -0.8 +/- 0.7, with p = 0.02). After the first outpatient visit, the weight-for-age z-score was not significantly different between single-ventricle and two-ventricle patients. From multivariate analysis, a lower number of nutritional interventions by cardiologists was significantly associated with poor growth (p = 0.03). Poor growth was not associated with race, use of feeding tube, exclusive formula use, or proximity to surgical centre. CONCLUSION: The significant drop in the weight for-age z-score from neonatal surgery to first outpatient visit suggests that these patients may receive inadequate nutrition. The poorest performers received the least number of outpatient changes to their diet. This finding underscores the critical role of the primary cardiologist in optimising weight gain through adjustments in nutrition. PMID- 23040656 TI - Early use of thrust manipulation versus non-thrust manipulation: a randomized clinical trial. AB - The purpose of this study was to investigate the comparative effectiveness of early use of thrust (TM) and non-thrust manipulation (NTM) in sample of patients with mechanical low back pain (LBP). The randomized controlled trial included patients with mechanically reproducible LBP, >= age 18-years who were randomized into two treatment groups. The main outcome measures were the Oswestry Disability Index (ODI) and a Numeric Pain Rating Scale (NPRS), with secondary measures of Rate of Recovery, total visits and days in care, and the work subscale of the Fears Avoidance Beliefs Questionnaire work subscale (FABQ-w). A two-way mixed model MANCOVA was used to compare ODI and pain, at baseline, after visit 2, and at discharge and total visits, days in care, and rate of recovery (while controlling for patient expectations and clinical equipoise). A total of 149 subjects completed the trial and received care over an average of 35 days. There were no significant differences between TM and NTM at the second visit follow-up or at discharge with any of the outcomes categories. Personal equipoise was significantly associated with ODI and pain. The findings suggest that there is no difference between early use of TM or NTM, and secondarily, that personal equipoise affects study outcome. Within-groups changes were significant for both groups. PMID- 23040657 TI - Incidence and effect of acute kidney injury after transcatheter aortic valve replacement using the new valve academic research consortium criteria. AB - Acute kidney injury (AKI) is associated with a poor prognosis after transcatheter aortic valve replacement (TAVR). A paucity of data exists regarding the incidence and effect of AKI after TAVR using the new recommended Valve Academic Research Consortium criteria. At Columbia University Medical Center, 218 TAVR procedures (64.2% transfemoral, 35.8% transapical) were performed from 2008 to July 2011. The creatinine level was evaluated daily until discharge. Using the Valve Academic Research Consortium definitions, the 30-day and 1-year outcomes were compared between patients with significant AKI (AKI stage 2 or 3) and those without significant AKI (AKI stage 0 or 1). Significant AKI occurred in 18 patients (8.3%). Of these 18 patients, 10 (55.6%) had AKI stage 3 and 9 (50%) required dialysis. AKI was associated with a lower baseline mean transvalvular gradient (37.6 +/- 11.4 vs 45.6 +/- 14.8 mm Hg for no AKI, p = 0.03). After TAVR, the AKI group had a greater hemoglobin decrease (3.6 +/- 2.0 vs 2.4 +/- 1.3 g/dl, p = 0.01), greater white blood cell elevation at 72 hours (21.09 +/- 12.99 vs 13.18 +/- 4.82 * 10(3)/MUl, p = 0.001), a more severe platelet decrease (118 +/- 40 vs 75 +/- 43 * 10(3)/MUl, p <0.0001), and longer hospitalization (10.7 +/- 6.4 vs 7.7 +/- 8.5 days, p <0.001). One stroke (5.6%) occurred in the AKI group compared with 3 (1.5%) in the group without AKI (p = 0.29). The 30-day and 1-year rates of death were significantly greater in the AKI group than in the no-AKI group (44.4% vs 3.0%, hazard ratio 18.1, 95% confidence interval 6.25 to 52.20, p <0.0001; and 55.6% vs 16.0%, hazard ratio 6.32, 95% confidence interval 3.06 to 13.10, p <0.0001, respectively). Periprocedural life-threatening bleeding was the strongest predictor of AKI after TAVR. In conclusion, the occurrence of AKI, as defined by the Valve Academic Research Consortium criteria, is associated with periprocedural complications and a poor prognosis after TAVR. PMID- 23040658 TI - Role of serum N-terminal pro-brain natriuretic peptide measurement in diagnosis of cardiac involvement in patients with anderson-fabry disease. AB - Enzyme replacement therapy has the potential to delay or reverse adverse cardiac remodeling in Anderson-Fabry disease (AFD); however, the current indications for enzyme replacement therapy rely on detecting relatively advanced features of the disease. We aimed to determine the relation between the serum N-terminal pro brain natriuretic peptide (NT-proBNP) concentration and cardiac abnormalities in patients with AFD. We hypothesized that it might help to detect early disease. NT proBNP was measured under at rest conditions in 117 patients with AFD (age 48 +/- 15 years, 46.2% men). All patients underwent clinical evaluation with electrocardiography and echocardiography. The median NT-proBNP concentration was 24 pmol/L (range <5 to 6,059). Of the 117 patients, 67 (57%) had elevated, age corrected, NT-proBNP levels. In the 56 patients (48%) with normal echocardiographic findings, the NT-proBNP levels were greater than the age predicted cutoffs in 10 of 25 patients with abnormal electrocardiographic findings and 3 of 31 patients with normal electrocardiographic findings (p <0.05). On multiple regression analysis, age, creatinine, left atrial volume index, E/Ea, and the presence of abnormal electrocardiographic findings were independently associated with log NT-proBNP (R(2) = 0.67, p <0.05). In conclusion, NT-proBNP concentrations were elevated in patients with AFD and early cardiac involvement, suggesting its measurement could assist in decisions regarding the timing of enzyme replacement therapy. PMID- 23040659 TI - A novel dielectric barrier discharge reactor with photocatalytic electrode based on sintered metal fibers for abatement of xylene. AB - A novel dielectric barrier discharge (DBD) reactor was made for the abatement of xylene. This reactor has a photocatalytic electrode prepared by a modified anodic oxidation method which was proposed in this work. The photocatalytic electrode has nano-TiO(2) deposited on sintered metal fiber (SMF). The reactor using the nano-TiO(2)/SMF electrode shows much better performance in abating xylene compared with reactors using other electrodes such as resistance wire or SMF. The conversion ratio of xylene reaches 92.7% in the novel reactor at a relatively voltage (23.6 kV). This ratio is much higher than the conversion ratios of xylene in the traditional reactors with resistance wire or SMF electrodes, which are ~64.7%. The selectivity of CO(2) of the reactor using the nano-TiO(2)/SMF electrode (300 pps, 23.6 kV) was observed to be 86.6%, which is about twice as large as that of a traditional reactor using a resistance wire electrode. If a traditional DBD reactor is replaced by the novel reactor, at the same specific input energy, the energy yield can increase from 0.391 to 0.556 mg/kJ. Finally, the xylene decomposition mechanism with the nano-TiO(2)/SMF electrode was also briefly discussed. PMID- 23040660 TI - Comparison of Spirulina platensis microalgae and commercial activated carbon as adsorbents for the removal of Reactive Red 120 dye from aqueous effluents. AB - Spirulina platensis microalgae (SP) and commercial activated carbon (AC) were compared as adsorbents to remove Reactive Red 120 (RR-120) textile dye from aqueous effluents. The batch adsorption system was evaluated in relation to the initial pH, contact time, initial dye concentration and temperature. An alternative kinetic model (general order kinetic model) was compared with the traditional pseudo-first order and pseudo-second order kinetic models. The equilibrium data were fitted to the Langmuir, Freundlich and Liu isotherm models, and the thermodynamic parameters were also estimated. Finally, the adsorbents were employed to treat a simulated dye-house effluent. The general order kinetic model was more appropriate to explain RR-120 adsorption by SP and AC. The equilibrium data were best fitted to the Liu isotherm model. The maximum adsorption capacities of RR-120 dye were found at pH 2 and 298 K, and the values were 482.2 and 267.2 mg g(-1) for the SP and AC adsorbents, respectively. The thermodynamic study showed that the adsorption was exothermic, spontaneous and favourable. The SP and AC adsorbents presented good performance for the treatment of simulated industrial textile effluents, removing 94.4-99.0% and 93.6-97.7%, respectively, of the dye mixtures containing high saline concentrations. PMID- 23040661 TI - Preparation of acrylic acid-modified chitin improved by an experimental design and its application in absorbing toxic organic compounds. AB - Chitin grafted poly (acrylic acid) (chi-g-PAA) is synthesized and characterized as an adsorbent of toxic organic compounds. Chi-g-PAA copolymers are prepared using of ammonium cerium (IV) nitrate (Ce(4+)) as the initiator. The highest grafting percentage of AA in chitin obtained using the traditional technique is 163.1%. A maximum grafting percentage of 230.6% is obtained using central composite design (CCD). Experimental results are consistent with theoretical calculations. The grafted copolymer is characterized by Fourier transform Infrared spectroscopy and solid state (13)C NMR. A representative chi-g-AA copolymer is hydrolyzed to a type of sodium salt (chi-g-PANa) and used in the adsorption of malachite green (MG), methyl violet (MV), and paraquat (PQ) in aqueous. The monolayer adsorption capacities of these substances are 285.7, 357.1, and 322.6 mg/g-adsorbent, respectively. Thermodynamic calculations show that the adsorption of MG, MV, and PQ are more favored at diluted solutions. The high adsorption capacity of chi-g-PANa for toxic matter indicates its potential in the treatment of wastewater and emergency treatment of PQ-poisoned patients. PMID- 23040662 TI - Identification of salivary antigenic markers discriminating host exposition between two European ticks: Rhipicephalus sanguineus and Dermacentor reticulatus. AB - To succeed blood meal, ticks inject salivary proteins to mammalian hosts, eliciting an antibody response against these foreign antigens. Although this immune response has been proposed as a surrogate marker of exposure to tick bites, identification of the corresponding antigens remains elusive. For this aim, a comparison by immunoblots of the kinetic IgG responses to protein salivary gland extracts from two European tick species, Rhipicephalus sanguineus or Dermacentor reticulatus, in rabbits was performed. A singularity in the immune patterns was observed according to rabbit exposure status and depending on the antigen source. Six and five bands were found specifically associated to R. sanguineus and to D. reticulatus exposures, respectively. The identity of these salivary antigenic proteins was determined using an original immunoproteomic approach. The utilization of these tick salivary proteins as biomarker candidates to discriminate R. sanguineus and/or D. reticulatus tick exposure or to develop anti-tick vaccines is discussed. PMID- 23040663 TI - E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity. AB - Protein aggregation and ordered fibrillar amyloid deposition inside and outside of the central nervous system cells is the common pathologic hallmark of most aging-related neurodegenerative disorders. Dominant mutations in the gene encoding superoxide dismutase 1 (SOD1) protein are linked to familial amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive degeneration of motor neurons, leading to muscle paralysis and death. The major histochemical hallmark in the remaining motor neurons of ALS is the intracellular accumulation of ubiquitinated inclusions consisting of insoluble aberrant protein aggregates. However, the molecular pathomechanisms underlying the process have been elusive. Here for the first time, we report that E6-AP, a homologous to E6 AP C terminus-type E3 ubiquitin ligase depleted in ALS mouse models before neurodegeneration. E6-AP coimmunoprecipitates with the SOD1 protein and is predominantly mislocalized in mutant SOD1-containing inclusion bodies. Overexpression of E6-AP increases the ubiquitination and facilitates degradation of SOD1 proteins. Finally, we show that the overexpression of E6-AP suppresses the aggregation and cell death mediated by mutated SOD1 proteins and cellular protective effect is more prominent when E6-AP is overexpressed along with Hsp70. These data suggest that enhancing the activity of E6-AP ubiquitin ligase might be a viable therapeutic strategy to eliminate mutant SOD1-mediated toxicity in ALS. PMID- 23040665 TI - First Pan-Pacific Emergency Medicine Congress (PEMC). PMID- 23040666 TI - Thermal subjective sensations of motorcyclists. AB - The purpose of motorcycle clothing is to protect the motorcyclist not only against weather conditions but also against an unforeseen contact with other objects. Nevertheless, the use of such clothing, especially in summer, is related to overheating of the motorcyclist's body. Therefore, it would be advisable to ensure that appropriate protection is not provided at the expense of disturbing the thermal balance. In order to explore the matter of overheating and a feeling of discomfort, research was carried out among 242 active motorcyclists. The results have revealed that the problem of discomfort occurs regardless of the type of motorcycle clothing used. The findings were confirmed by motorcyclists' subjective sensation. This provided the grounds to conclude that attention should be paid to the issue of thermal comfort and solutions should be looked for with respect to the construction of clothing itself and the applied materials. Simultaneously, the survey results showed the importance of knowledge about the impact of motorcycle clothing on the human body and a need for its dissemination in order to allow a conscious coexistence among road users. PMID- 23040664 TI - CCL2 affects beta-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer's disease. AB - Neuroinflammation affects the pathobiology of Alzheimer's disease (AD). Notably, beta-amyloid (Abeta) deposition induces microglial activation and the subsequent production of proinflammatory neurotoxic factors. In maintaining brain homeostasis, microglial plasticity also enables phenotypic transition between toxic and trophic activation states. One important control for such cell activation is through the CC-chemokine ligand 2 (CCL2) and its receptor, the CC chemokine receptor 2. Both affect microglia and peripheral macrophage immune responses and for the latter, cell ingress across the blood-brain barrier. However, how CCL2-CC-chemokine receptor 2 signaling contributes to AD pathogenesis is not well understood. To this end, we now report that CCL2 deficiency influences behavioral abnormalities and disease progression in Abeta precursor protein/presenilin-1 double-transgenic mice. Here, increased cortical and hippocampal Abeta deposition is coincident with the formulation of Abeta oligomers. Deficits in peripheral Abeta clearance and in scavenger, neuroprogenitor, and microglial cell functions are linked to deficient Abeta uptake. All serve to accelerate memory dysfunction. Taken together, these data support a role of CCL2 in innate immune functions relevant to AD pathogenesis. PMID- 23040667 TI - Effects of local decidua on trophoblast invasion and spiral artery remodeling in focal placenta creta - an immunohistochemical study. AB - OBJECTIVES: Placenta creta is an increasingly prevalent cause of maternal morbidity/mortality. Decidua is at least focally defective and extravillous trophoblast (EVT) may be abnormal. The study aims to compare differences in migratory trophoblast and spiral artery remodeling between areas with and without decidua at the placental implantation site. STUDY DESIGN: Sixteen (12 creta, 4 non-creta) caesarean hysterectomy specimens were studied immunohistochemically. Invasive EVT and multinucleate trophoblast giant cells (MTGC) were quantified; confluent EVT (>5 opposed EVTs) and spiral artery remodeling were assessed semi quantitatively. RESULTS: In 6 cases, placenta creta was focal. Compared to placenta creta with local decidua, cases without local decidua had increased interstitial EVT cells (*200 field) (SEM 45.6 [4.9] vs. 80.5 [3.9], p < 0.0001), fewer multinucleate trophoblast giant cells (expressed as a percentage of total EVT) (0.8 [0.3] vs. 31.5 [2.2]% p < 0.0001) and EVT was more confluent (p < 0.0001). In contrast, placenta creta cases with local decidua had a greater degree of spiral artery remodeling (mean remodeling score 1.65 [0.07] vs. 1.13 [0.05], p < 0.0001) associated with increased intramural trophoblast (p = 0.0008). The only difference between placenta creta with local decidua and normal placentation cases was an increased number of interstitial EVT cells in creta cases (45.6 [4.9] vs. 24.8 [3.2], p = 0.04). CONCLUSIONS: Numbers of interstitial EVT are increased in placenta creta, more so in cases without local decidua. Despite this spiral artery modeling is reduced in placenta creta cases with no decidua. The results emphasize the crucial role of decidua in control of trophoblast invasion and spiral artery remodeling. PMID- 23040668 TI - Correlates of negative physical health in call center shift workers. AB - The call center industry, a burgeoning sector is characterized by unique job demands, which render it susceptible to high attrition rates and negative health concerns. This study examined the relationship between job stress from interpersonal factors, job stress from work factors, coping, inadequate sleep, and negative physical health reports among call center shift workers (n = 239), a relatively under-researched population. Inadequate sleep and job stress from interpersonal factors were associated with negative physical health outcome for the participants in this study. Further, spending longer in the call center industry was associated with negative health outcome for the shift worker participants. PMID- 23040669 TI - Influenza-associated excess mortality in southern Brazil, 1980-2008. AB - In order to estimate influenza-associated excess mortality in southern Brazil, we applied Serfling regression models to monthly mortality data from 1980 to 2008 for pneumonia/influenza- and respiratory/circulatory-coded deaths for all ages and for those aged >=60 years. According to viral data, 73?5% of influenza viruses were detected between April and August in southern Brazil. There was no clear influenza season for northern Brazil. In southern Brazil, influenza associated excess mortality was 1?4/100,000 for all ages and 9?2/100,000 person years for persons aged >=60 years using underlying pneumonia/influenza-coded deaths and 10?0/100,000 for all ages and 86?6/100,000 person-years for persons aged >=60 years using underlying respiratory/circulatory-coded deaths. Influenza associated excess mortality rates for southern Brazil are similar to those published for other countries. Our data support the need for continued influenza surveillance to guide vaccination campaigns to age groups most affected by this virus in Brazil. PMID- 23040670 TI - [Hepatic space occupying lesions in a diabetic patient]. PMID- 23040671 TI - [Facial skin lesion in an eleven year old child]. PMID- 23040672 TI - [The obstetrics and gynaecology departments in the French public hospitals: an updated overview]. AB - Restructuring the surgery and gynecology-obstetrics departments taking place now raise many interrogations. It appears as a mandatory necessity to some people and as a tribute to financial strategies to others to the detriment of quality and accessibility of care. Its effect is to clarify a good amount of socioeconomical and medical indicators. The plans of perinatality for the obstetrical aspect and the thresholds of activity for the surgical aspect constitute the major lines of these restructurings. A survey soliciting all the French public hospitals was used to assess the state of obstetrics and gynecology departments in the light of these recent restructurings. Medical demography, preserving and improving the quality and continuity of care, efficiency of the technical supports are discriminating criteria of the involved challenges. Such restructurings have an impact on the doctor's lives, which looks globally positive and a good omen to complete this remodeling process. The activity was safeguarded by a redistribution and a refocusing of institutions. One should not minimize the social impact of these changes, with a potential deterioration of working conditions (internal professional reclassifications, mobility obligation towards other sites). It thus appears that the deep changes which affect the small size institutions will be able to achieve well only if they are clearly done (information) and truly integrated in their medical project. PMID- 23040673 TI - Periprosthetic fractures in the resurfaced hip--a case report and review of the literature. AB - Traumatic periprosthetic fractures adjacent a hip resurfacing prosthesis are rare. When proximal fractures are encountered the obvious surgical solution is to revise to a large head stemmed femoral component. A previously well functioning implant may however be retained as various non-operative and operative treatment options exist. This paper reports the case history of a traumatic periprosthetic fracture successfully treated with cannulated screw fixation and reviews the current literature. PMID- 23040674 TI - Increased morbidity and mortality after bilateral femoral shaft fractures: myth or reality in the era of damage control? AB - INTRODUCTION: Bilateral femoral shaft fractures have been reported to be an independent risk factor for morbidity and mortality; however, the value of these studies is limited due to small sample sizes and the timing of these studies before the establishment of damage control orthopaedics. The objective of this study was to compare the incidence of morbidity and mortality in patients with bilateral vs. unilateral femoral shaft fractures in the era of damage control orthopaedics. METHODS: Retrospective analysis of the TraumaRegister DGU from 2002 to 2005. Inclusion criteria were uni- or bilateral femoral shaft fractures and complete demographic data documentation. Univariate data analysis and logistic regression analysis were performed with SPSS. RESULTS: Between 2002 and 2005, 776 patients with unilateral and 118 patients with bilateral femoral shaft fractures were identified. Patients with bilateral femoral shaft fractures had a significantly higher Injury Severity Score (ISS) (29.5 vs. 25.7 points), a significantly higher incidence of pulmonary (34.7% vs. 20.6%) and multiple organ failure (25.0% vs. 14.6%) as well as a significantly higher mortality rate (16.9% vs. 9.4%). In the overall patient population, early total care (ETC) was significantly more often performed in patients with unilateral femoral shaft fractures (50.9% vs. 33.6%). Logistic regression analysis revealed no significant association between bilateral femoral shaft fractures and multiple organ failure or mortality; however, bilateral femoral shaft fractures are an independent risk factor for pulmonary failure. Subgroup analysis revealed that the impact of the bilateral femoral shaft fracture was especially pronounced in patients with an ISS<25 points. DISCUSSION: Bilateral femoral shaft fractures are an independent risk factor for pulmonary failure but not for multiple organ failure or mortality. The impact of the additional femoral shaft fracture for pulmonary failure appears to be especially pronounced in the less severely injured patients, whose injuries are often underestimated when stratified with the ISS. Patients with bilateral femoral shaft fractures have significantly more often severe abdominal injuries as well as severe blood loss which may account for the increased mortality rate. Therefore, the presence of bilateral femoral shaft fractures should be recognised as an increased risk for systemic complications. PMID- 23040675 TI - Availability and potential impact of international rotations in emergency medicine residency programs. AB - BACKGROUND: Interest in international emergency medicine (IEM) is growing. With the globalization of medicine, IEM as a field has expanded from disaster relief efforts to opportunities for resident education. Numerous accounts have been published voicing the educational benefits of international rotations (IRs). As such, many residencies now offer opportunity for IRs. OBJECTIVE: To evaluate the availability and utilization of IRs in emergency medicine (EM) residency programs. METHODS: EM residency program directors were surveyed from the 126 Accreditation Council for Graduate Medical Education-accredited programs with >=2 years of residency graduates. Directors were asked about availability of IR, categorized as: 1) required; 2) elective (with or without pre-designated sites); or 3) not available. RESULTS: One hundred eleven (88%) program directors reported data on 2240 graduates over 2 years. IRs were offered by 101 (91%) programs. No program required an IR. Among programs offering IRs, most (69%) did not have pre designated sites. Eighty-nine of 101 programs (88%) allowing IRs had at least one resident completing an IR; 23 of 111 programs (21%) had more than 30% resident participation in IRs. Programs offering IRs at pre-designated sites had 210 of 727 (29%) residents complete an IR, compared to 272 of 1469 (19%) in programs without pre-designated sites (p < 0.001). Four-year programs had twice as many IR participants (32%) compared to 3-year programs (17%; p < 0.001). CONCLUSIONS: More residents participated in IRs when a pre-designated site was available compared to programs without. This suggests that programs interested in supporting IRs consider developing pre-designated sites to accommodate residents. PMID- 23040676 TI - Career breaks and changes of sector: challenges for the revalidation of pharmacists. AB - BACKGROUND: Taking a career break or moving between sectors of practice (for example, between patient-facing and non-patient-facing roles) often has been assumed to pose a risk for pharmacists' fitness to practice. However, it is not clear what the nature of that risk is, or what its implications are for professional revalidation. OBJECTIVES: To explore: (i) the experiences of pharmacists who either return to practice following a career break or move from one sector of practice to another; and (ii) the experiences of those who support or observe pharmacists undergoing one of these changes. METHODS: Eighteen registered pharmacists in Northern Ireland, all of whom had either undergone a change in practice themselves or had supported another pharmacist through a change in practice, took part in a telephone-based interview. During the interviews, each participant was invited to reflect upon his or her experiences of the change and suggest ways in which such processes should be handled in the future. The interview transcripts were thematically analysed using template analysis. RESULTS: A number of themes captured the issues discussed relating to changes in practice. Firstly, there is a variety of circumstances surrounding a change in practice; secondly, there are various ways in which a pharmacist can prepare for a change in practice; thirdly, a number of factors were thought to facilitate or hinder the process. Finally, training and development needs were identified for pharmacists undergoing a change. CONCLUSIONS: A revalidation scheme for pharmacists should make provision for registrants who have taken a career break or changed sector. Such registrants would benefit from resources to support them through the change in practice; these resources could come from peers, employers, or the regulator. PMID- 23040677 TI - Non-traumatic spinal cord ischaemia in childhood - clinical manifestation, neuroimaging and outcome. AB - BACKGROUND: Spinal cord ischaemia is rare in childhood and information on clinical presentation and outcome is scarce. METHODS: This is a retrospective analysis of eight patients and 75 additional cases from the literature. Data search included: patient's age, primary manifestation, risk factors, neuroimaging and outcome. RESULTS: Five female and three male patients gave consent to participate. Mean age was 12.5 years (10-15 years). Six patients presented with paraplegia; this was preceded by pain in four. Brown Sequard syndrome and quadriparesis were the two others' presenting condition. Sensation levels were thoracolumbar in seven cases. Bladder dysfunction only or bladder and bowel dysfunction were reported in eight and five patients respectively. Time to maximal symptom manifestation was <12 h in 7/8. Risk factors included surgery, minor trauma, recent infection, and thrombophilia. Mean follow-up was 3.3 years (0.25-6.3 years). Three patients remained wheelchair-dependent and three patients were ambulatory without aid. Bladder function recovered fully in five children. Most affected aspects of quality of life were physical and mental well-being and self-perception. T2-weighted-MR images showed pencil-like hyperintensity (8/8) in sagittal and H-shaped or snake-eyes-like lesion (6/8) in axial views. Analyses of all 83 patients were in congruence with the above results of the study group. CONCLUSION: Spinal cord ischaemia in childhood presenting with pain, paraplegia, and bladder dysfunction has high morbidity concerning motor problems and quality of life. Acute arterial ischaemic event in children seems similar to adult events with respect to clinical presentation and, surprisingly, also in outcome. PMID- 23040678 TI - Balancing metabolites in drought: the sulfur assimilation conundrum. AB - A key plant response to drought is the accumulation of specific sets of metabolites that act as osmoprotectants, osmolytes, antioxidants, and/or stress signals. An emerging question is: how do plants regulate metabolism to balance the 'competing interests' between metabolites during stress? Recent research connects primary sulfur metabolism (e.g., sulfate transport in the vasculature, its assimilation in leaves, and the recycling of sulfur-containing compounds) with the drought stress response. In this review, we highlight key steps in sulfur metabolism that play significant roles in drought stress signaling and responses. We propose that a complex balancing act is required to coordinate primary and secondary sulfur metabolism during the drought stress response in plants. PMID- 23040679 TI - Quality improvement of forensic mental health evaluations and reports of youth in the Netherlands. AB - Quality improvement of forensic mental health evaluations and reports is needed, but little information is available on how this can be attained, and relatively little conceptual analysis has been undertaken. The STAR, a standardized evaluation instrument of the quality of forensic mental health reports of youth, is developed on the basis of concept mapping to clarify the different perspectives on usability of these reports. Psychometric data are provided, demonstrating the reliability and supporting the validity of the STAR. The Dutch forensic context is described to better understand the development and psychometric properties of this standardized instrument. Quality improvement possibilities of forensic mental health evaluations and reports are discussed. PMID- 23040680 TI - Comparison of teicoplanin and vancomycin in vitro activity on clinical isolates of Staphylococcus aureus. AB - Ninety-one clinical isolates of Staphylococcus aureus have been tested with the Kirby Bauer and the Etest(r) method to determine the susceptibility to glycopeptides in the 2007-2010 period. Five strains (5.5%) were resistant to vancomycin and nine (9.9%) to teicoplanin. Teicoplanin showed a median minimal inhibitory concentration (MIC) of 1 mg/l (range 0.125-24 mg/l), an MIC50 of 1 mg/l, and an MIC90 of 2 mg/l; vancomycin had a median MIC of 1.5 mg/l (range 0.38 4 mg/l), an MIC50 of 1.5 mg/l, and an MIC90 of 2 mg/l. More isolates were distributed on higher values of MIC for vancomycin. Inhibition halos induced by vancomycin-impregnated paper diskettes were slightly larger than those by teicoplanin. Glycopeptide resistance among methicillin-resistant Staphylococcus aureus in Italy is an underestimated phenomenon, possibly due to the described underestimation of glycopeptides MICs by the automatic broth microdilution method, when compared to agar MIC assays. A teicoplanin MIC creep, as reported for vancomycin, cannot be assumed. PMID- 23040681 TI - Activity of plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece. AB - The in vitro activity of plazomicin was evaluated against 300 multidrug resistant (MDR) (carbapenemase and/or ESBL-producing) isolates from four hospitals in Athens, an area where carbapenemase-producing organisms are endemic. Most of the isolates were also resistant to the legacy aminoglycosides with the MIC50/MIC90 to tobramycin, amikacin and gentamicin being 32/>32, 32/>32 and 4/>8 MUg/ml, respectively. ACHN-490 retained activity (MICs <= 4 MUg/ml) against all isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. tested with MIC50 and MIC90 of 1 and 2 MUg/ml, respectively, irrespective of their MDR phenotype and it represents a promising alternative for the treatment of the most problematic Gram-negative pathogens. PMID- 23040682 TI - Predominance of hospital-associated MRSA among cystic fibrosis patients in a Turkish reference cystic fibrosis centre. AB - Methicillin-resistant Staphylococcus aureus (MRSA) strains are the major causative agents of numerous hospital- and community-acquired infections. Increasing prevalence of MRSA in cystic fibrosis (CF) populations is reported all over the world. Although there are papers reporting the prevalence and genetic backgrounds of MRSA isolates from different settings in Turkey, there is no information regarding the situation in the CF community. This study was conducted to characterize the MRSA strains recovered from CF patients followed-up at a Turkish reference CF centre. Microbiological testing of isolates was performed via conventional microbiological techniques. Molecular characterization of MRSA isolates was carried out by SCCmec typing by multiplex PCR and PVL gene determination. Among a total of 604 CF patients included in the study, 325 patients were found to harbour S. aureus (53.8%). Of those 325 patients, 24 were positive for MRSA during their follow-up (7.4%). Thirty-two MRSA isolates from these patients were chosen for further assessment of molecular characteristics. Twenty-six MRSA isolates exhibited a pattern like SCCmec type III (81.2%) and six consecutive MRSA isolates of a single patient revealed SCCmec type IV (18.7%). Our findings definitely support the need for further surveillance studies for CF MRSA strains and highlight the need for infection control measures in the setting of CF centres. PMID- 23040683 TI - In vitro and in vivo pharmacokinetic/pharmacodynamic activity of clofoctol. AB - The aim of the study was to examine the In vitro susceptibility of clinical isolates of respiratory pathogens to clofoctol compared with amoxicillin and erythromycin, and to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationships of clofoctol using a murine pneumonia infection model. Strains clinically isolated from patients between 2005 and 2009 were used to examine susceptibility: penicillin-susceptible Streptococcus pneumoniae, penicillin resistant S. pneumoniae, Streptococcus pyogenes, methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, and Haemophilus influenzae. The In vitro activity of clofoctol against clinical isolates has essentially remained unchanged over recent years. The MIC50 and MIC90 of clofoctol against penicillin-resistant S. pneumoniae are lower than that of amoxicillin and erythromycin. The area under curve/minimum inhibitory concentration (AUC/MIC) ratio is the PK/PD parameter that best correlates with in vivo clofoctol efficacy; the value of AUC/MIC required to achieve the maximum effect in this study was 75.5. PMID- 23040684 TI - Uracil-tegafur/leucovorin and mitomycin C salvage therapy in patients with advanced colorectal cancer: a phase II study. AB - We investigated the efficacy and safety of oral Uracil/tegafur (UFT) with leucovorin and mitomycin C (MMC) as third-line treatment for patients with extensively pretreated metastatic colorectal cancer (mCRC). This was a multicenter, prospective phase II study. Patients received MMC 7 mg/m2 on day 1 and UFT 300 mg/m2 with leucovorin 90 mg, both divided into three daily doses, on days 1-28 every 5 weeks. All patients had failed prior treatment with irinotecan, oxaliplatin, fluoropyrimidine, bevacizumab, and cetuximab. The primary endpoint was tumor control rate evaluated after 2 cycles. Twenty-one patients were included: median age was 66 years (41.1-87.8 years). Tumor control rate was observed in 26.7% of the 15 patients evaluable for response. Median overall survival was 6.4 months. Grade 3 adverse events were asthenia, anorexia, and vomiting. In patients with mCRC who have progressed after as many as two prior therapies, the combination of UFT/leucovorin and MMC is safe and may produce a short stabilization of disease in approximately 25% of patients. PMID- 23040685 TI - Mucinous histology of colon cancer predicts poor outcomes with FOLFOX regimen in metastatic colon cancer. AB - Mucinous adenocarcinoma (MA) of colorectal cancer seems associated with reduced responsiveness to chemotherapy. The overexpression of markers of resistance to fluorouracil and oxaliplatin has recently been demonstrated. We revised the outcomes of metastatic MA of the colon treated with FOLFOX. From January 2002 to December 2009, we treated 198 patients with metastatic colon cancer, of which 21 (10.6%) had diagnosis of MA and were compared with 42 control patients with non mucinous adenocarcinoma (NMA). In MA group, three patients [14%; inhibitory concentration 95: +/- 7.5%] reached partial response, and in NMA group, two patients obtained complete response and 16 obtained partial response with an overall response rate of 43% (inhibitory concentration 95: +/- 7.6%) with a significant statistical difference (P = 0.027). Median progression-free survival for MA group was 4 months with respect to 8 months for NMA (P = 0.0001); regarding overall survival, we registered a median of 8 months with respect to 18 months for MA and NMA (P = 0.001). In multivariate analysis, MA histology, Eastern Cooperative Oncology Group performance status 2, more than two metastatic sites, and peritoneal metastatic involvement resulted in negative independent prognostic factors. Also in our study, MA is connected to poor prognosis and reduced activity of chemotherapy. In the absence of randomised studies, it may be convenient to analyse this subgroup of patients within the large trials carried out on colorectal cancer. PMID- 23040686 TI - The efficacy and toxicity of irinotecan with leucovorin and bolus and continuous infusional 5-fluorouracil (FOLFIRI) as salvage therapy for patients with advanced gastric cancer previously treated with platinum and taxane-based chemotherapy regimens. AB - There is no established standard salvage chemotherapy in the second-line setting for patients with advanced gastric cancer (AGC) pre-treated with platinum and taxane-based chemotherapy. Our study aims to evaluate the safety and efficacy of FOLFIRI regimen (irinotecan with leucovorin and bolus and continuous infusion with 5-fluorouracil) as a salvage chemotherapy regimen in patients with AGC. Medical records of 97 patients with AGC who received second-line FOLFIRI regimen between March 2006 and February 2011 were examined. Complete and partial responses were observed in 3 (3.1%) and 23 (23.7%) patients, respectively. The median time to progression (TTP) was 3.5 months (95% CI: 2.4-4.6) and the median overall survival (OS) was 10.5 months (95% CI: 8.8-12.2). The most common observed grade 3/4 toxicities were neutropenia (23.7%), diarrhea (6.2%), and stomatitis (5.2%). FOLFIRI regimen is safe and effective in the second-line treatment of AGC patients pre-treated with cisplatin and taxanes. PMID- 23040687 TI - Extreme hypothyroidism associated with sunitinib treatment for metastatic renal cancer. AB - Although thyroid abnormalities are reported with the use of tyrosine kinase inhibitors, patients rarely require replacement therapy. The initial multicentre studies of sunitinib for metastatic renal cancer did not report hypothyroidism in fatigued patients, and thyroid tests were not routinely monitored. More recent studies, however, suggest that up to 70% of patients develop thyroid test abnormalities during treatment with sunitinib. Despite these concerns, the clinical relevance of sunitinib-induced hypothyroidism is uncertain since thyroid gland recovery is the norm in most patients. We report a case of a patient with metastatic papillary renal cell cancer on combination anti-angiogenic therapy with sunitinib, who developed unusually high thyroid stimulating hormone levels and severe symptoms despite receiving L-thyroxine. Our case also illustrates the complexity of managing sunitinib-associated thyroid dysfunction, which may be accompanied by transient thyroiditis, hyperthyroidism, and profound hypothyroidism. PMID- 23040688 TI - Long-term treatment with linezolid in a patient with osteomyelitis undergoing hemodialysis. AB - Anemia and/or thrombocytopenia are the most relevant adverse effects of linezolid treatment. We report the case of a patient under hemodialysis who developed osteomyelitis involving the amputation stump of the left limb due to a vancomycin resistant and teicoplanin-resistant Enterococcus faecium successfully treated with linezolid for 6 months. Close monitorization of the patient probably contributed to maintenance of treatment with linezolid despite hematological alterations observed, which could be attributed to either the underlying patient's clinical condition or antimicrobial treatment. PMID- 23040689 TI - Brivudin induced delirium: a case report. AB - Brivudin is an oral antiviral agent used to treat herpes zoster infections. Common side effects of brivudin include nausea and headache. This report describes delirium in a patient who used brivudin for herpes zoster treatment, which consequently remitted after drug cessation on the fourth day of medication use. To our knowledge, no such side effect has been reported to date. However, it is important that clinicians who prescribe brivudin are aware that treatment cessation is likely to result in total clinical recovery. PMID- 23040690 TI - Recombinant human endostatin (endostar) decreased recurrent ascites, pleural fluid and ascitic VEGF in a case of advanced mesothelioma. AB - We report a case of 43-year-old male with advanced malignant mesothelioma (MM) with a large amount of fluid in the pleural and peritoneal cavity. The addition of endostar to the gemcitabine-cisplatin regimen gave a prompt and significant improvement of clinical symptoms and disappearance of ascites. The patient is still progression free after 27 months. Endostar, in combination with chemotherapy should be explored in the treatment of MM, especially its effect on pleural and ascitic fluid. PMID- 23040691 TI - First report of KPC-producing Klebsiella pneumoniae in Croatia. AB - In February 2011, a 78-year-old male patient was admitted to Clinical Hospital Center Zagreb with subdural haematoma. Klebsiella pneumoniae with reduced susceptibility to carbapenems was isolated. PCR revealed the presence of bla(KPC), bla(TEM), and bla(SHV) genes. Sequencing of bla(KPC) gene identified K. pneumoniae carbapenemase (KPC)-2 beta-lactamase. The strain belonged to ST37 clone by multilocus sequence typing. Infection control efforts limited the spread of KPC-producing clone of K. pneumoniae in our hospital so far. To our knowledge, this is the first report of a KPC-producing K. pneumoniae in Croatia. PMID- 23040692 TI - Bordetella holmesii endocarditis in a patient with systemic lupus erythematous treated with immunosuppressive agents. PMID- 23040693 TI - Weekly high-dose liposomal amphotericin B for secondary prophylaxis of invasive fungal disease in immunocompromised children: experience from a pediatric case series. PMID- 23040694 TI - Occurrence of Sjogren syndrome in a long-term survivor patient with metastatic colon carcinoma treated with GOLFIG regimen. PMID- 23040695 TI - Clinical outcomes of 1,578 Chinese patients with breast benign diseases after ultrasound-guided vacuum-assisted excision: recurrence and the risk factors. AB - BACKGROUND: The aim of this study was to evaluate the clinical outcomes of 1,578 patients with breast benign diseases after excisions and the risk factors. METHODS AND RESULTS: With a median follow-up of 34 months, 69 patients were identified to have recurrence (local recurrence: 45; new lesion: 24). Univariate and multivariate analyses revealed that multiple lesions, a larger lesion size, and a hematoma were independent risk factors for recurrence. Patients with in situ recurrence tended to have fewer lesions and more samples taken per lesion. Patients with new lesions tended to have multiple lesions. After re-excisions, there was no second recurrence events observed in the patients with local recurrence (0/30), whereas 5 patients with new lesions (5/14) were noted to have second recurrence events. CONCLUSIONS: Ultrasound-guided vacuum-assisted biopsy for the complete excision of breast benign diseases is safe and effective. Local recurrence and new lesions may have different clinicopathological features and underlying mechanisms. Different management might be given to patients with a different pattern of recurrence. PMID- 23040697 TI - Neurophysiological pain assessment: how to objectify a subjective phenomenon? PMID- 23040696 TI - Association of tobacco and alcohol use with earlier development of colorectal pathology: should screening guidelines be modified to include these risk factors? AB - BACKGROUND: Current guidelines for colorectal cancer (CRC) screening recommend initial screening at 50 years of age for normal-risk patients. Alcohol and tobacco use can be associated with an earlier onset of CRC and possibly polyps. METHODS: We reviewed all colonoscopies performed at our institution from January to December 2007. Patient data were collected on age, sex, tobacco and alcohol history, and the presence of colon lesions. RESULTS: Our data included 663 patients (643 men and 20 women) with a mean age of 60.7 years (range 23-89 years); 68.5% were current/former tobacco users, 53.7% were current/former alcohol users, 37.6% had used both, and 21.7% had used neither. Colonoscopy findings were as follows 64% of patients had no lesions, 30.6% had tubular polyps, 3.5% had villous polyps, and 2% had cancer. The current use of tobacco, alcohol, or both was associated with the early development of colon pathology (ie, 66.9 years, 61.1 years, and 59.2 years [P < .05], respectively). In nonusers, the mean age was 67.7 years. CONCLUSIONS: Our work confirms that the use of alcohol and tobacco is associated with an earlier onset of colon pathology. Consideration should be given to modifying screening guidelines to include these habits as "high-risk" factors. PMID- 23040698 TI - Contact heat and cold, mechanical, electrical and chemical stimuli to elicit small fiber-evoked potentials: merits and limitations for basic science and clinical use. AB - Laser-evoked potentials are the most extensively validated method to objectively assess nociceptive pathway function in humans. Here, we review merits and shortcomings of alternative techniques using different principles of stimulus generation to stimulate Adelta- or C-fibers. Fast ramp contact heat stimuli yield reproducible responses; however, stimulus location needs to be changed to reduce peripheral habituation, and the limited steepness of temperature ramps may result in response jitter and absence of averaged responses even in some healthy subjects. Inverse temperature ramps can serve to evoke cool evoked potentials to specifically test the cold pathway; the clinical impact of such findings is promising but uncertain to date, and availability of devices optimized for this purpose is currently limited. Mechanical stimuli excite low- or high-threshold mechanoreceptors depending on both the probe surface and the applied force. Electrical stimuli can be used to excite nerve fibers directly in the epidermis, the mucosa of the gut, or the tooth pulp. Principle limitation of the applicability of mechanical and electrical stimuli is the inevitable co excitation of tactile (Abeta-) fibers. The nasal mucosa can be stimulated using pulsed-CO(2) air streams, which excite chemo-nociceptors; although these stimuli are specific to excite thin trigeminal afferents, their use is limited as it is restricted to a relatively small region. Current data do not allow a comparative analysis on their respective diagnostic values. Quantification of analgesic efficacy in healthy subjects has been established and may be useful in phase I and IIa clinical trials. PMID- 23040699 TI - Estimation of intraepidermal fiber density by the detection rate of nociceptive laser stimuli in normal and pathological conditions. AB - The variability of warm and heat pain sensitivity between body regions is usually ascribed to differences in intraepidermal nerve fiber (IENF) density. However, although crucial to assess the function of the thermo-nociceptive system, especially in the context of small fiber neuropathies, the relationship between psychophysical performance and IENF density is poorly understood. Here, we examine the hypothesis according to which the nociceptive system must receive a critical amount of afferent information to generate a conscious percept and/or a behavioral response. The amount of nociceptive information is defined by the stimulus, but also by the state of the nervous system encoding, transmitting and processing the afferent input. Furthermore, this amount may be expected to depend on the number of activated IENF, itself dependent on the size of the stimulated surface area as well as the density of IENF. By characterizing the relationship between psychophysical responses to nociceptive stimuli, size of the stimulated surface area and IENF density estimated using skin biopsies in healthy subjects as well as experimental and pathological conditions of reduced IENF density, we were able to estimate the number of nociceptive afferents required to elicit a conscious percept. Convergent results were obtained across the different experiments, indicating that the detection rate to brief small-diameter CO(2) laser pulses could be used to estimate IENF density and, hence, to diagnose and quantify denervation in small fiber neuropathies. PMID- 23040700 TI - Modulations of pain sensations. AB - Representation of time may affect pain perception. We investigated a group of volunteers looking at different clocks while they were being exposed to the same intensity of pain in two experiments. In one case, they saw the actual time, while in the other, they gazed at a clock that made it seem like the stimulation was shortened, even though it wasn't. These results show that simply believing that time is on your side can make anything more bearable. The results were not influenced by the color of the clock (red or green), or the presence of indexes such as (sad or smiling) smileys. The effects were maximal for high intensities of stimulation (pain threshold +1 degrees C) if the stimulation lasted for at least 25s but were absent if the stimulation was short (15 min). These results suggest that pain modulation by time context is mainly available for long and intense painful stimulations. The right upper and posterior parietal cortex may support this effect. These findings are discussed with regard to previous literature of pain modulations but also with regard to the concept of the "pain matrix", its inputs and the temporal dynamics of its constitutive responses. PMID- 23040701 TI - The posterior insular-opercular region and the search of a primary cortex for pain. AB - To be considered specific for nociception, a cortical region should: (a) have plausible connections with ascending nociceptive pathways; (b) be activated by noxious stimuli; (c) trigger nociceptive sensations if directly stimulated; and (d) tone down nociception when injured. In addition, lesions in this area should have a potential to develop neuropathic pain, as is the case of all lesions in nociceptive pathways. The single cortical region approaching these requirements in humans encompasses the suprasylvian posterior insula and its adjoining medial operculum (referred to as "PIMO" in this review). This region does not contain, however, solely nociceptive networks, but represents in primates the main sensory receiving area of the spinothalamic system, and as such contributes to the processing of thermo-sensory, nociceptive, C-fibre tactile, and visceral input. Nociception (and, a fortiori, pain) should therefore not be considered as a separate sensory modality, like vision or audition, but rather as one component of a global system subtending the most primitive forms of somatosensation. Although a clear functional segregation of PIMO sub-areas has not yet been achieved, some preferential distribution has been described in humans: pain related networks appear preferentially distributed within the posterior insula, and non-noxious thermal processing in the adjacent medial operculum. Thus, spinothalamic sub-modalities may be partially segregated in the PIMO, in analogy with the separate representation of dorsal column input from joint, muscle spindle and tactile afferents in S1. Specificity, however, may not wholly depend on ascending 'labelled lines' but also on cortical network properties driven by intrinsic and extrinsic circuitry. Given its particular anatomo-functional properties, thalamic connections, and tight relations with limbic and multisensory cortices, the PIMO region deserves to be considered as a third somatosensory region (S3) devoted to the processing of spinothalamic inputs. PMID- 23040702 TI - Steady-state evoked potentials to study the processing of tactile and nociceptive somatosensory input in the human brain. AB - The periodic presentation of a sensory stimulus induces, at certain frequencies of stimulation, a sustained electroencephalographic response of corresponding frequency, known as steady-state evoked potentials (SS-EP). In visual, auditory and vibrotactile modalities, studies have shown that SS-EP reflect mainly activity originating from early, modality-specific sensory cortices. Furthermore, it has been shown that SS-EP have several advantages over the recording of transient event-related brain potentials (ERP), such as a high signal-to-noise ratio, a shorter time to obtain reliable signals, and the capacity to frequency tag the cortical activity elicited by concurrently presented sensory stimuli. Recently, we showed that SS-EP can be elicited by the selective activation of skin nociceptors and that nociceptive SS-EP reflect the activity of a population of neurons that is spatially distinct from the somatotopically-organized population of neurons underlying vibrotactile SS-EP. Hence, the recording of SS EP offers a unique opportunity to study the cortical representation of nociception and touch in humans, and to explore their potential crossmodal interactions. Here, (1) we review available methods to achieve the rapid periodic stimulation of somatosensory afferents required to elicit SS-EP, (2) review previous studies that have characterized vibrotactile and nociceptive SS-EP, (3) discuss the nature of the recorded signals and their relationship with transient event-related potentials and (4) outline future perspectives and potential clinical applications of this technique. PMID- 23040703 TI - Cognitive aspects of nociception and pain: bridging neurophysiology with cognitive psychology. AB - The event-related brain potentials (ERPs) elicited by nociceptive stimuli are largely influenced by vigilance, emotion, alertness, and attention. Studies that specifically investigated the effects of cognition on nociceptive ERPs support the idea that most of these ERP components can be regarded as the neurophysiological indexes of the processes underlying detection and orientation of attention toward the eliciting stimulus. Such detection is determined both by the salience of the stimulus that makes it pop out from the environmental context (bottom-up capture of attention) and by its relevance according to the subject's goals and motivation (top-down attentional control). The fact that nociceptive ERPs are largely influenced by information from other sensory modalities such as vision and proprioception, as well as from motor preparation, suggests that these ERPs reflect a cortical system involved in the detection of potentially meaningful stimuli for the body, with the purpose to respond adequately to potential threats. In such a theoretical framework, pain is seen as an epiphenomenon of warning processes, encoded in multimodal and multiframe representations of the body, well suited to guide defensive actions. The findings here reviewed highlight that the ERPs elicited by selective activation of nociceptors may reflect an attentional gain apt to bridge a coherent perception of salient sensory events with action selection processes. PMID- 23040704 TI - Pain and sleep: from reaction to action. AB - Sleep disruption by painful stimuli is frequently observed both in clinical and experimental conditions. Nociceptive stimuli produce significantly more arousals (30% of stimuli) than non-nociceptive ones. However, even if they do not interrupt sleep, they can trigger a variety of other reactions. Reflex behaviours in response to nociceptive stimuli can be observed during all sleep stages, and are more likely to occur in association with an arousal than alone. Cardiac activation represents a robust sympathetically driven effect preserved whatever the state of vigilance, even if its magnitude can be modulated by a concomitant cortical arousal. Not withstanding these reactions, incorporation of nociceptive stimuli into dream content remains limited. At cortical level, laser-evoked potential studies demonstrate that the processing of nociceptive stimulations is partly conserved during all sleep stages. Furthermore, when nociceptive stimulations interrupt sleep, the cortical response presents a late component suggesting that the stimulation has to be cognitively processed in order to produce a subsequent arousal. More complex reactions to nociceptive stimulations were occasionally reported. In this context, an epileptic patient with intracerebral electrodes implanted for therapeutic purposes allowed us extending these observations. This patient exhibited finger lifts in response to stimulations delivered during paradoxical (REM) sleep. This motor reaction was previously used during wakefulness to indicate that the stimulation had been perceived. When these finger lifts occurred a systematic re-activation of the anterior cingulate preceded each movement. This observation suggests that during PS, not only the processing of sensory inputs but also the capacity for the sleeper to intentionally indicate his perception could be preserved under particular circumstances. PMID- 23040705 TI - Clinical usefulness of laser evoked potentials. AB - Several papers were published since the first clinical applications of laser evoked potentials (LEPs) in disorders of the nociceptive system. While studies produced until five years ago were mostly addressed at identifying lesions of the nociceptive system, more recent papers used LEPs as an instrumental tool for the diagnosis of neuropathic pain. LEPs have also proved useful in demonstrating the pathophysiological mechanisms underlying different types of neuropathic pain (e.g., paroxystic and ongoing neuropathic pain). This is of utmost importance, as pain treatment should take physiopathological mechanisms, rather than etiology into account. Although there are still some limits for the routine use of LEPs as a diagnostic tool, this review of the literature demonstrates that LEP recording has become mandatory for the functional assessment of patients with hypoalgesia or neuropathic pain. PMID- 23040706 TI - Why did so many German doctors join the Nazi Party early? AB - During the Weimar Republic in the mid-twentieth century, more than half of all German physicians became early joiners of the Nazi Party, surpassing the party enrollments of all other professions. From early on, the German Medical Society played the most instrumental role in the Nazi medical program, beginning with the marginalization of Jewish physicians, proceeding to coerced "experimentation," "euthanization," and sterilization, and culminating in genocide via the medicalization of mass murder of Jews and others caricatured and demonized by Nazi ideology. Given the medical oath to "do no harm," many postwar ethical analyses have strained to make sense of these seemingly paradoxical atrocities. Why did physicians act in such a manner? Yet few have tried to explain the self selected Nazi enrollment of such an overwhelming proportion of the German Medical Society in the first place. This article lends insight into this paradox by exploring some major vulnerabilities, motives, and rationalizations that may have predisposed German physicians to Nazi membership-professional vulnerabilities among physicians in general (valuing conformity and obedience to authority, valuing the prevention of contamination and fighting against mortality, and possessing a basic interest in biomedical knowledge and research), economic factors and motives (related to physician economic insecurity and incentives for economic advancement), and Nazi ideological and historical rationalizations (beliefs about Social Darwinism, eugenics, and the social organism as sacred). Of particular significance for future research and education is the manner in which the persecution of Jewish physician colleagues was rationalized in the name of medical ethics itself. Giving proper consideration to the forces that fueled "Nazi Medicine" is of great importance, as it can highlight the conditions and motivations that make physicians susceptible to misapplications of medicine, and guide us toward prevention of future abuse. PMID- 23040707 TI - Psychological assessment of torture survivors: essential steps, avoidable errors, and helpful resources. AB - This article provides ideas, information, and resources that may be helpful in conducting psychological evaluations of people who have been tortured. The first section discusses essential steps, including achieving competence; clarifying the purpose; selecting methods appropriate to the individual, the purpose, and the situation; addressing issues of culture and language; maintaining awareness of ways in which the presence of third parties and recording can affect the assessment; attending carefully to similarities, echoes, and triggers; and actively searching for ways to transcend our own limited experiences and misleading expectations. The second section discusses avoiding five common errors that undermine these evaluations: mismatched validity; confirmation bias; confusing retrospective and prospective accuracy (switching conditional probabilities); ignoring the effects of low base rates; and misinterpreting dual high base rates. The third section identifies resources on the web (e.g., major centers, legal services, online courses, information about asylum and refuge, networks of torture survivors, human rights organizations providing information and services, guides to assessment) that people working with torture survivors, refugees, and asylum-seekers may find helpful. PMID- 23040708 TI - Planning, writing, and editing forensic psychiatric reports. AB - Forensic psychiatric reports are often the final product of a psychiatrist's work in a particular case because most cases do not go to trial but instead are settled through negotiation or plea bargaining. This article addresses the planning, writing, and editing of forensic reports. Planning a report requires thorough data gathering, and thoughtful organization of the report into specific subheadings. Throughout the report there should be a clear separation of factual data from professional opinions. Ten pitfalls of report writing are identified. The most important part of the forensic report is the opinion section. The evidence for the opinion should begin with the strongest points and the reasons supporting the opinion should be completely explained. Finally, ethical issues are addressed. PMID- 23040709 TI - Challenges in interfacing between forensic and general mental health: a Japanese perspective. AB - This article highlights the characteristics of forensic mental health services in Japan, with special emphasis on outpatient treatment of offenders with mental disorders, and discusses the potential implications of the Japanese experience in view of Western trends. The literature suggests that forensic patients tend to be left behind by the overall psychiatric reforms in developed countries. The recent law reform on forensic mental health in Japan is intended to be compatible with the contemporary ideas of psychiatry, such as normalization and community-based care. The primary objective of the new legislation is to provide intensive psychiatric treatment to offenders with mental disorders, attaching great importance to their re-integration into society. However, the system has already been faced with major challenges, including the insufficiency of human and financial resources in community and the accumulation of long-stay, treatment resistant patients in special facilities. This article stresses the importance of active participation of general mental health services in the rehabilitation of offenders with mental disorders. PMID- 23040710 TI - Changes in bone mineral density after surgical intervention for primary hyperparathyroidism. AB - BACKGROUND: Patients with primary hyperparathyroidism often lack classic symptoms but can have reductions in bone mineral density and increased fracture risk. We sought to determine bone mineral density improvement after successful surgery and associated factors. METHODS: A review of patients with osteopenia or osteoporosis with curative parathyroidectomy and both pre- and postoperative dual-energy X-ray absorptiometry bone mineral density scans was conducted. We compared patients with declining (<0%), moderate improvement (0.1-5%), and significant improvement (>5%) on dual-energy X-ray absorptiometry bone mineral density scans. RESULTS: We identified 420 patients who underwent a dual-energy X-ray absorptiometry bone mineral density scan preoperatively and within 36 months postoperatively. At the most affected site, 38% had significant improvement, 31% moderate improvement, and 31% declining bone mineral density. Patients who significantly improved were younger (P = .01), had lesser preoperative dual-energy X-ray absorptiometry (P = .001), and had greater preoperative levels of parathyroid hormone (P = .04), serum calcium (P = .03), and preoperative urinary calcium. There was no difference in outcomes between sex and with preoperative bisphosphonate use. Average hip and spine bone mineral density had similar responses to surgery. CONCLUSION: Bone mineral density improves in up to 75% of patients after curative parathyroidectomy for primary hyperparathyroidism. The hip and lumbar spine responded similarly. Younger patients and those with severe primary hyperparathyroidism may derive the most skeletal benefits from parathyroidectomy, but the uniform positive response supports parathyroidectomy in patients with osteoporosis and possibly osteopenia. PMID- 23040711 TI - Yield of repeat fine-needle aspiration biopsy and rate of malignancy in patients with atypia or follicular lesion of undetermined significance: the impact of the Bethesda System for Reporting Thyroid Cytopathology. AB - BACKGROUND: Atypia/follicular lesion of undetermined significance (A/FLUS) is a new category in the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) for which repeat fine-needle aspiration biopsy (FNAB) is recommended. METHODS: A retrospective review was completed to evaluate the impact of the BSRTC on management of nodular thyroid disease. Patients were divided into pre-BSRTC and BSRTC groups. A comparative analysis of cytopathologic diagnoses and rates of repeat FNAB and malignancy was completed. RESULTS: FNAB was performed in 730 patients: 337 pre-BSRTC and 393 BSRTC. There was a decrease in follicular/Hurthle cell neoplasm (FN/HCN; 9.5% vs 3.6%, P = .001) but no difference in the rate of malignancy (6.5% vs 6.4%, P = 1.0). Fewer operations (29% vs 21%, P = .02) and more repeat FNABs (3.9% vs 11%, P < .001) were performed in the BSRTC group. Sixty-one (16%) patients had A/FLUS, 56 with complete follow-up. Repeat FNAB in 26 patients was benign (11), A/FLUS (6), suspicious for malignancy (4), FN/HCN (2), and nondiagnostic (3). Thirty-two (57%) patients underwent thyroidectomy, and 6 patients (19%) were diagnosed with cancer. CONCLUSION: The BSRTC resulted in more frequent repeat FNAB, fewer thyroidectomies and no change in malignancy rate. In patients with A/FLUS, repeat FNAB was definitive in 65% with a rate of malignancy of 19%. PMID- 23040712 TI - Number of lymph nodes removed during modified radical neck dissection for papillary thyroid cancer does not influence lateral neck recurrence. AB - BACKGROUND: This study examines the relationship between the number of lymph nodes removed during modified radical neck dissection and the incidence of disease recurrence. METHODS: A retrospective review of 117 patients with papillary thyroid cancer and lateral neck involvement (levels 2-5) who underwent modified radical neck dissection was performed. Data were analyzed for patient demographics, operative procedure, lymph node involvement, complications, radioactive iodine therapy, and disease recurrence. RESULTS: Of 117 patients who underwent modified radical neck dissection, the median follow-up of the entire study group was 25 months (range, 1-256 months). Recurrent disease was found in 8% of patients, with a median time to recurrence of 35 months. The median number of lymph nodes removed during modified radical neck dissection was similar in recurrent and nonrecurrent patients (P = .78). There was also no difference in the median number of positive lymph nodes removed (P = .14) between these 2 groups. On multivariate analysis, however, the number of positive lymph nodes (odds ratio, 1.16 [95% confidence interval, 1.01-1.34]) and tumor size (odds ratio, 1.60 [95% confidence interval, 1.03-2.49]) were independent predictors of recurrence of disease after modified radical neck dissection. CONCLUSION: Recurrence of papillary thyroid cancer after modified radical neck dissection is unrelated to the number of lymph nodes removed. This study suggests that attempts to maximize the number of lymph nodes removed during modified radical neck dissection for papillary thyroid cancer may not be necessary. PMID- 23040713 TI - Cerebral embolization in asymptomatic versus symptomatic patients after carotid stenting. AB - BACKGROUND: Previous studies have investigated the development of new ischemic brain lesions on diffusion-weighted magnetic resonance imaging (DW-MRI) after carotid artery stenting (CAS). The rate of ischemic brain injury after CAS for asymptomatic stenosis has not been extensively studied but is presumed to be less likely than in symptomatic patients. This study assessed the occurrence of cerebral embolization after CAS for asymptomatic vs symptomatic carotid stenosis. METHODS: During an 18-month period, 40 patients undergoing CAS under filter embolic protection were prospectively evaluated. Transcranial Doppler (TCD) during CAS and preprocedural and 24-hour postprocedural DW-MRI were used to assess cerebral embolization. Univariate and nonparametric analyses were used to compare differences in cerebral embolization after CAS in asymptomatic and symptomatic patients. RESULTS: CAS was performed for 23 asymptomatic (58%) and 17 symptomatic (42%) carotid stenoses. The median microembolic counts detected by TCD were 285 (interquartile range [IQR], 182-376) for asymptomatic and 313 (IQR, 170-426) for symptomatic carotid stenosis (P=.6). DW-MRI was available for assessment in 20 asymptomatic and 14 symptomatic patients. New acute cerebral emboli detected with DW-MRI occurred in 10 asymptomatic (50%) and 7 symptomatic patients (50%) undergoing CAS (P=.9). The ipsilateral and total median number of DW-MRI lesions between groups were not statistically significantly different at, respectively, 1 (IQR, 0-2.5) and 1.5 (IQR, 0-3) for asymptomatic vs 0.5 (IQR, 0 2) and 0.5 (IQR, 0-3) for symptomatic carotid stenosis (P>.5). One asymptomatic patient sustained a minor stroke after CAS. No new neurologic events occurred in symptomatic patients. The 30-day stroke-death rate was 2.5% in this series. CONCLUSIONS: Cerebral embolization, as detected by TCD and DW-MRI, occurs with a similar frequency after CAS for asymptomatic and symptomatic carotid stenosis. Because postprocedural ischemic brain injury occurs in approximately half of asymptomatic patients, the safety of CAS under filter embolic protection for asymptomatic carotid stenosis is uncertain and warrants further study. PMID- 23040715 TI - Do forensic practitioners distinguish between testifying and consulting experts? A pilot study. AB - Forensic mental health professionals (n=44) reviewed a series of statements that an attorney might make to a consulting or testifying expert. Each statement was rated for its degree of appropriateness to either the consulting or the testifying role. In light of increasing attention paid to this topic in the forensic practice literature, as well as long-standing distinctions recognized by the legal profession, it was originally hypothesized that participants would differentiate clearly between these roles; however, results of this pilot study indicate that forensic practitioners do not possess a consistent sense of which activities rest most comfortably within testimonial as opposed to consulting duties. PMID- 23040716 TI - [Ultrasound measurement of carotid stenosis: recommendations from the Spanish Society of Neurosonology]. AB - In Spain, approximately 28% of ischaemic strokes have an atherothrombotic cause, and most are due to carotid stenosis. Ultrasound is the most commonly used technique for diagnosing carotid stenosis. Changes in blood flow velocity at the point of maximum stenosis, together with haemodynamic changes in proximal regions (common carotid artery) and distal regions (poststenotic internal carotid, ophthalmic artery, and the circle of Willis), allow us to measure carotid stenosis precisely. This review explains the methodology to be followed when evaluating carotid stenosis ultrasonographically, according to the recommendations from the Spanish Society of Neurosonology (SONES). We review the findings that permit us to measure the degree of extracranial carotid stenosis using both carotid and transcranial ultrasound, with particular emphasis on the importance of assessing indirect signs. PMID- 23040717 TI - Vocal cord paralysis as a manifestation of myasthenia gravis with anti-MuSK antibodies. PMID- 23040718 TI - [Precision in historical quotations. Reply]. PMID- 23040719 TI - Complete bilateral horizontal internuclear ophthalmoplegia as a sign of multiple sclerosis relapse. PMID- 23040720 TI - Antibiotic prophylaxis for selected gynecologic surgeries. AB - BACKGROUND: Antibiotic prophylaxis for surgery is commonly used and is recommended by multiple organizations. OBJECTIVE: To critically review gynecology specific data regarding surgical antibiotic prophylaxis in selected benign gynecologic surgeries. SEARCH STRATEGY: MEDLINE and Cochrane databases were searched from inception to July 2010. SELECTION CRITERIA: Randomized controlled trials of benign vaginal, cervical, transcervical, abdominal, or laparoscopic procedures other than hysterectomy comparing prophylactic antibiotic use with placebo or with another antibiotic. Outcomes of interest were postoperative infections, additional treatments, and adverse events. DATA COLLECTION AND ANALYSIS: In total, 19 trials met the inclusion criteria. Studies were individually assessed for methodologic quality, then grouped by procedure and evaluated for evidence quality. MAIN RESULTS: There was no difference in infectious outcome for loop electrosurgical excision, hysteroscopic ablation, or laparoscopy, although evidence quality was poor. Fair evidence supports antibiotic prophylaxis for suction curettage or laparotomy. There were insufficient data regarding vaginal surgery prophylaxis. CONCLUSION: Antibiotic prophylaxis may be beneficial in first-trimester suction curettage and laparotomy. No advantage was found for loop electrosurgical excision, hysteroscopy, or laparoscopic gynecologic surgery. Newer procedures and vaginal surgery lack research and merit study. PMID- 23040721 TI - A novel application of propensity score matching to estimate Alcoholics Anonymous' effect on drinking outcomes. AB - BACKGROUND: Randomized controlled trials (RCTs) of mutual aid, including Alcoholics Anonymous (AA), are notoriously difficult to conduct and correlational studies are problematic to interpret due to potential confounds. METHODS: A secondary analysis was conducted of Project MATCH, a RCT of alcoholism treatments. Although MATCH did not randomly assign subjects to AA vs. no AA, the 12 step facilitation (TSF) condition did result in a higher proportion of subjects attending community AA meetings than in the other two treatment conditions. The key inference is that there exists a latent subgroup in MATCH who attended AA only because its constituents received TSF, not because of the "normal" factors leading to self-selection of AA. A novel application of propensity score matching (PSM) allowed four latent AA-related subgroups to be identified to estimate an unconfounded effect of AA on drinking outcomes. RESULTS: The study hypothesis was supported: subjects who consistently attended AA solely due to their exposure to TSF (the "Added AA" subgroup) had better drinking outcomes than equivalent subjects who did not consistently attend AA, but would have so attended, had they been exposed to TSF (the "Potential AA" subgroup); this indicates an AA effect on drinking. CONCLUSIONS: The analysis presents evidence that consistent AA attendance improves drinking outcomes, independent of "normal" confounding factors that make correlations between AA attendance and outcomes difficult to interpret. PMID- 23040722 TI - Retrograde orbital atherectomy in an occluded superficial femoral artery. AB - Superficial femoral artery (SFA) is commonly diseased in patients with symptomatic peripheral arterial disease. Endovascular treatments have been more effectively used for SFA occlusions with new techniques and devices. Retrograde popliteal access has been used as an alternative to increase the success rate of percutaneous transluminal angioplasty (PTA) of SFA after a failed antegrade attempt. Although orbital atherectomy (OA) has been used effectively to treat SFA occlusions, there are no reports of use of OA by retrograde popliteal approach. PMID- 23040723 TI - Preoperative staging of invasive bladder cancer with dynamic gadolinium-enhanced magnetic resonance imaging: results from a prospective study. AB - OBJECTIVE: To evaluate the accuracy of dynamic gadolinium-enhanced magnetic resonance imaging (DGE-MRI) to detect extravesical bladder cancer (BC) and lymph node-positive disease in patients with invasive BC. MATERIAL AND METHODS: In a prospective single-center study from 2004 to 2009, patients with clinically invasive BC, who were candidates for curative surgery, underwent preoperative DGE MRI. Radiologic T and N staging was determined by 2 MRI expert radiologists, and the interobserver agreement was calculated. The sensitivity, specificity, positive and negative predictive values, and accuracy of radiologic staging in differentiating lymph node-negative organ-confined vs nonorgan-confined BC and negative vs positive nodal disease was determined and compared with the postoperative pathologic staging as the reference standard method. RESULTS: A total of 122 patients (72 men) with a mean age of 67.8 years were included. Pathologic examination revealed invasive BC in 80/122 (65.5%), including stage pT4 in 15/122 (12.3%), pT3 in 27/122 (22.1%), and pT2 in 38/122 (31.1%), and 27 patients (22.1%) had node-positive disease. The interobserver agreement for T and N staging according to the kappa score was 0.44 and 0.49, respectively. The sensitivity, specificity, and accuracy of DGE-MRI in differentiating lymph node negative organ-confined from nonorgan-confined BC was 87.5%, 47.6%, and 74% and for the detection of positive nodal disease was 40.7%, 91.5%, and 80.3%, respectively. CONCLUSION: We have presented the results of the largest cohort of patients with invasive BC underwent preoperative DGE-MRI. Although DGE-MRI improved T and N staging of invasive BC, it is still not the ideal modality and needs a standardized protocol for interpretation of the imaging findings. PMID- 23040724 TI - Metabolic syndrome: a potential and independent risk factor for erectile dysfunction in the Chinese male population. AB - OBJECTIVE: To determine the potential effect of metabolic syndrome (MetS) and its components on erectile dysfunction (ED) in Chinese men. MATERIALS AND METHODS: Data were collected from the Fangchenggang Area Male Healthy and Examination Survey from September 2009 to December 2009, and 3197 men were finally included. The MetS was defined using the updated National Cholesterol Education Program Adult Treatment Panel III for Asian Americans. ED was assessed using the 5-item International Index Erectile Function. The association between MetS and ED is presented as the odds ratios (ORs), with 95% confidence intervals (CIs) estimated using a logistic regression model. RESULTS: After adjustments for age, smoking, alcohol drinking, physical activity, education, and body mass index, our results showed that subjects with MetS had a significantly greater risk of ED (OR 1.34, 95% CI 1.04-1.72; P = .02), especially in middle-age (40-59 years) men (OR 2.43, 95% CI 1.71-3.47; P <.001). Of the MetS components, abnormal fasting blood glucose was the most significantly independent factor of MetS for ED (OR 1.31, 95% CI 1.11-1.55; P = .002). CONCLUSION: Our data have shown that MetS is a potential and independent risk factor for ED in Chinese men, especially in middle age men, MetS can be recognized as a warning signal for ED. Abnormal fasting blood glucose was the most significantly independent factor of MetS for ED in Chinese men. PMID- 23040725 TI - Mechanistic relationship of all-terrain vehicles and pediatric renal trauma. AB - OBJECTIVE: To identify and discuss the mechanistic risk factors associated with genitourinary (GU) trauma in pediatric all-terrain vehicle (ATV) accidents. MATERIALS AND METHODS: A retrospective analysis of all pediatric trauma admissions to a level 1 trauma center from 2005 to August 2011 was performed. We identified all pediatric patients who presented with GU trauma related to an ATV accident. The demographics, injury data, mechanism of injury, and treatment records of these children were investigated. RESULTS: A total of 304 pediatric patients were admitted with ATV-related injuries during the study period. Of these 304 patients, 10 (3.2%) had experienced GU injuries. An analysis of the mechanism revealed that 9 of the 10 had been thrown from the ATV; 1 event was described as a rollover accident. All 10 patients sustained renal trauma: 9 renal lacerations of various grades and 1 renal pedicle injury. Hematuria was observed in all cases. Spleen and liver lacerations were commonly associated injuries (40% and 30%, respectively). CONCLUSION: Pediatric ATV-related GU injuries remain an uncommon, yet serious, problem. Renal trauma is the most commonly encountered GU injury and can be suspected by the presence of hematuria. Analysis of the mechanism of injury suggests that ejection from the ATV places pediatric patients at the greatest risk of renal injury. Additional research is recommended concerning the mechanistic relationship of ATV-related GU trauma. PMID- 23040726 TI - Comparison of extracorporeal shock wave lithotripsy for inferior caliceal calculus between children and adults: a retrospective analysis--why do results vary? AB - OBJECTIVE: To retrospectively evaluate the effectiveness of extracorporeal shock wave lithotripsy (ESWL) for inferior caliceal calculi <= 20 mm in size and compare the results between children and adults. MATERIALS AND METHODS: From January 2004 to January 2012, ESWL was performed for inferior caliceal calculi in 230 children and 1006 adults. The Dornier compact alpha-K1025163 (Dornier Med Tech) was used. The success rates, number of ESWL sessions required, and auxiliary procedures used were evaluated in a comparative manner. RESULTS: The overall stone-free rate (for both stone sizes) was 82.2% for children and 40% for the adults. Of the children, 17% had a residual stone compared with 47.8% of the adults. ESWL was unsuccessful in 0.8% of children and 12.2% of adults. The mean number of ESWL sessions required in children and adults was 1.43 (range 1-4) and 2.13 (range 1-4), respectively. Repeat treatment was required in 31% of the children and 65% of the adults. Auxiliary procedures were required in 5.2% of the children and 16.2% of the adults. Complications were seen in 5.6% of the children and 15% of the adults. CONCLUSION: The results of ESWL for inferior caliceal calculi <= 20 mm in adults remains poor but not so in children. Children can achieve high stone-free rates, require a fewer number of ESWL sessions than adults to be stone free, and have a lower need for repeat treatment and auxiliary procedures, and have fewer complications. PMID- 23040727 TI - Contemporary use of titanium staples for orthotopic urinary diversion. AB - Orthotopic reconstruction is often the preferred form of urinary diversion after radical cystectomy. Traditionally, a reservoir is created by hand sewing a detubularized segment of bowel, most commonly the ileum, into a pouch. However, with the advent of minimally invasive surgery, some investigators have reintroduced the idea of using titanium staples to create an orthotopic urinary diversion. This could potentially make the reconstruction technically easier and less time consuming, especially during laparoscopic and robotic-assisted surgery. We have reviewed the recent data on the use of titanium staples for the construction of an orthotopic urinary diversion. PMID- 23040728 TI - Editorial comment. PMID- 23040729 TI - Pubic hair grooming injuries presenting to U.S. emergency departments. AB - OBJECTIVE: To describe the demographics and mechanism of genitourinary (GU) injuries related to pubic hair grooming in patients who present to U.S. emergency departments (EDs). MATERIALS AND METHODS: The National Electronic Injury Surveillance System contains prospectively collected data from patients who present to EDs with consumer product-related injuries. The National Electronic Injury Surveillance System is a stratified probability sample, validated to provide national estimates of all patients who present to U.S. EDs with an injury. We reviewed the National Electronic Injury Surveillance System to identify incidents of GU injury related to pubic hair grooming for 2002-2010. The variables reviewed included age, race, gender, injury type, location (organ) of injury, hospital disposition, and grooming product. RESULTS: From 2002 to 2010, an observed 335 actual ED visits for GU injury related to grooming products provided an estimated 11,704 incidents (95% confidence interval 8430-15,004). The number of incidents increased fivefold during that period, amounting to an estimated increase of 247 incidents annually (95% confidence interval 110-384, P = .001). Of the cohort, 56.7% were women. The mean age was 30.8 years (95% confidence interval 28.8-32.9). Shaving razors were implicated in 83% of the injuries. Laceration was the most common type of injury (36.6%). The most common site of injury was the external female genitalia (36.0%). Most injuries (97.3%) were treated within the ED, with subsequent patient discharge. CONCLUSION: Most GU injuries that result from the use of grooming products are minor and involve the use of razors. The demographics of patients with GU injuries from grooming products largely paralleled observations about cultural grooming trends in the United States. PMID- 23040732 TI - Discovery of new non-steroidal FXR ligands via a virtual screening workflow based on Phase shape and induced fit docking. AB - Farnesol X receptor (FXR) is a member of the metabolic nuclear receptor (NR) superfamily of regulatory proteins. FXR was recognized to be a transcriptional sensor for bile acids, and now it has been shown that activating FXR has important roles in controlling bile acid homeostasis, lipoprotein and glucose metabolism, and hepatic regeneration. For the sake of discovering new, potent non steroidal FXR ligands, we have established a virtual screening workflow by using Phase Shape and induced fit docking (IFD). Phase shape was performed based on a combination of shape-only and atom types or pharmacophore modes. The results indicated that the pharmacophore mode yielded the best result for our system. The best receptor model was chosen by evaluating the cross-IFD models induced by three crystal structures 3DCT, 3FLI and 3OKI. The Enamine database was screened by the proposed workflow and 50 molecules were selected and purchased for bioassays. Among them, two compounds were found to be the new, potent FXR ligands in cell-based assay. PMID- 23040731 TI - Viridin analogs derived from steroidal building blocks. AB - Naturally occurring furanosteroids such as viridin and wortmannin have long been known as potent inhibitors of the lipid kinase PI-3K. We have been interested in directly accessing analogs of these complex natural products from abundant steroid feedstock materials. In this communication, we describe the synthesis of viridin/wortmannin hybrid molecules from readily available building blocks that function as PI-3K inhibitors and maintain their electrophilic properties. The compounds also show anti-proliferative effects against a breast cancer line. PMID- 23040733 TI - Evaluation of the number of opportunities for hand hygiene in hospital: a new methodological approach. AB - OBJECTIVE: To assess the number of alcohol-based hand rubbing (ABHR) opportunities in different wards of a university hospital. MATERIALS AND METHODS: The amount of care procedures was measured in nine wards (4 medical wards, 4 surgical wards, 1 intensive care unit) over a two-year period. We converted the number of care procedures into a number of ABHR opportunities using the definition provided by the World Health Organization that takes in account the nature of the care procedure and the number of healthcare workers involved in. We compared these data with those obtained by other authors and the theoretical minimal number of ABHR opportunities defined by the French Ministry of Health. RESULTS: 1,252,671 care procedures (with a mean period of 734 days/department, 122,866 days of hospitalization and 21,905 patients) were converted into ABHR opportunities. The mean number of care procedures and ABHR per day and per patient was 6.1 and 35 for the medical departments, 7.6 and 49 for the surgery departments, 14.8 and 237 for the intensive care unit, respectively. CONCLUSION: Our methodological approach strengthens the results of previous observational studies. Here, we showed that the number of ABHR opportunities is far higher than that defined by the French Ministry of Health to measure the hand hygiene hospital endeavour. PMID- 23040734 TI - Resource utilization in the emergency department of a tertiary care university based hospital in Tokyo before and after the 2011 Great East Japan earthquake and tsunami. AB - INTRODUCTION: The objective of this study was to determine the resource utilization of a tertiary care Japanese emergency department (ED) that was not immediately adjacent to the area of the 2011 Great East Japan earthquake and tsunami. METHODS: A retrospective chart review was performed at a tertiary care university-based urban ED located approximately 290 km from the primary site of destruction secondary to an earthquake measuring 9.0 on the Richter Scale and the resulting tsunami. All patients who presented for a period of twelve days before and twelve days after the disaster were included. Data were collected using preformed data collection sheets, and stored in an Excel file. Abstracted data included gender, time in the ED, intravenous fluid administration, blood transfusion, oxygen, laboratories, electrocardiograms (ECGs), radiographs, ultrasound, diagnoses, surgical and medical referrals, and prescriptions written. Ten percent of the charts were reviewed for accuracy, and an error rate reported. Data were analyzed using 2-tailed t-tests, Fisher's exact tests or rank sum tests. Bonferroni correction was used to adjust P values for multiple comparisons. RESULTS: Charts for 1193 patients were evaluated. The error rate for the abstracted data was 3.2% (95% CI, 2.4%-4.1%). Six hundred fifty-seven patients (53% male) were evaluated in the ED after the earthquake, representing a 23% increase in patient volume. Mean patient time spent in the ED decreased from 61 minutes to 52 minutes (median decrease from 35 minutes to 32 minutes; P = .005). Laboratory utilization decreased from 51% to 43% (P = .006). The percentage of patients receiving prescriptions increased from 48% to 54% (P = .002). There was no change in the number of patients evaluated for surgical complaints, but there was an increase in the number treated for medical or psychiatric complaints. CONCLUSION: There was a significant increase in the number of people utilizing the ED in Tokyo after the Great East Japan earthquake and tsunami. Time spent in the ED was decreased along with laboratory utilization, possibly reflecting decreased patient acuity. This information may help in the allocation of national resources when planning for disasters. PMID- 23040735 TI - Standardizing the use of the Continuous Performance Test in schizophrenia research: a validation study. AB - BACKGROUND: The Continuous Performance Test (CPT) has emerged as the most commonly administered measure of sustained attention, but use of discrepant versions reduces the ability of researchers and clinicians to accurately draw cross-study conclusions. In an effort to standardize use of the CPT, this study compared four versions of the Identical Pairs CPT for their reliability and ability to discriminate between patients with schizophrenia and healthy volunteers. The relationship of performance on the different versions of the CPT with measures of psychopathology, functioning, and other aspects of cognition was also examined. METHODS: Performance on the 2-digit, 3-digit, 4-digit, and Shapes Identical Pairs CPT was assessed at three test sessions over five weeks, during which subjects also completed the Brief Assessment of Cognition in Schizophrenia (BACS) and questionnaires assessing psychopathology and functioning. RESULTS: All four CPTs discriminated between patients with schizophrenia and healthy volunteers, but there were no statistical differences in sensitivity among the versions. The 3-digit CPT showed non-statistical advantages in that it had high test-retest reliability, low potential for a ceiling effect, and a very low rate of false alarms. There were also moderate correlations between CPT performance and performance of the BACS subtests, but no significant correlations between CPT performance and measures of psychopathology and functioning. CONCLUSIONS: While all versions of the CPT tested here had good psychometric characteristics, the 3 digit CPT-IP has some advantages in repeated measures studies such as clinical trials. PMID- 23040736 TI - Looking at the other side of the coin: a meta-analysis of self-reported emotional arousal in people with schizophrenia. AB - Abnormalities in emotional experience have long been viewed as core features of schizophrenia. Numerous studies indicate that people with schizophrenia report less pleasure than controls when reporting non-current feelings using trait, hypothetical, prospective, and retrospective emotional self-report formats; however, current research has demonstrated that schizophrenia patients and controls do not differ in their subjective reactions to emotional stimuli in most laboratory studies. Although substantial attention has been paid to studies examining self-reported valence in schizophrenia, subjective reports of arousal in response to affective stimuli have been neglected. Understanding the role of arousal in schizophrenia is imperative given that valence and arousal are differentially associated with physiological and behavioral responses. To understand the role of self-reported arousal, a meta-analysis of 26 published studies employing laboratory emotion induction paradigms in patients with schizophrenia and healthy controls was conducted. Medline, PsycINFO, Web of Science, and PubMed electronic databases and reference lists from identified articles were used as data sources. Using a random effects model, analyses demonstrated that controls and people with schizophrenia reported similar levels of subjective arousal in response to pleasant and unpleasant stimuli; however, people with schizophrenia reported experiencing greater arousal than controls in response to neutral stimuli. Furthermore, moderator analyses suggested that gender and methodological factors, such as rating scale and stimulus type, may affect these patterns of results and play a key role in determining whether patients and controls differ in self-reported arousal. PMID- 23040737 TI - Best immunohistochemical panel in distinguishing adenocarcinoma from squamous cell carcinoma of lung: tissue microarray assay in resected lung cancer specimens. AB - The emergence of the targeted therapies for non-small cell lung carcinoma (NSCLC) has generated a need for accurate histologic subtyping of NSCLC. In this study, we assessed the utility of immunohistochemical markers that could be helpful in distinction between adenocarcinoma (ADC) and squamous cell carcinoma (SCC). We performed a battery of immunohistochemistry using tissue microarray for napsin-A, Thyroid transcription factor 1 (TTF-1), p63, cytokeratin (CK) 5/6, thrombomodulin (CD141), Epithelial-related antigen (MOC-31), carcinoembryonic antigen (CEA), Cyclooxygenase 2 (COX-2), high-molecular-weight CK (HMWCK), p27kip1 (p27), and Rb protein in 129 resected primary NSCLC with 81 ADCs and 48 SCCs and 10 metastatic ADC to the lung (primary in colon, 7 cases; stomach, 2 cases; vagina, 1 case). Cases of ADC and SCC were morphologically unequivocal and solid tumors with no definite squamous or glandular differentiation were excluded for this analysis. Napsin-A and TTF-1 were positive in 81% and 70% of ADC and in 0% and 2% of SCC, respectively, whereas P63 and CK5/6 were positive in 91% and 90% of SCC and in 9% and 4% of ADC, respectively (P < .001). CD141 stained significantly higher in SCC over ADC (positive in 2% of ADC and 46% of SCC. MOC-31, CEA, COX-2, HMWCK, p27, and Rb appeared to be not useful markers in distinction between ADC and SCC because of their low specificity. None of metastatic ADC to the lung showed positive for napsin-A and TTF-1. It was evident that combination of napsin-A, TTF 1, CK5/6, and p63 was the best immunohistochemical panel in differentiating ADC from SCC of the lung in this study. CD141 appeared to be a potential new marker for SCC with high specificity. Cyclooxygenase 2, MOC-31, CEA, HMWCK, p27, and Rb showed less specificity for differentiation ADC from SCC. PMID- 23040738 TI - The association between lower birth weight and comorbid generalised anxiety and major depressive disorder. AB - OBJECTIVE: Studies testing the association between birth weight and depression or anxiety have found inconsistent results and there has been a lack of research on the possible relationship between birth weight and comorbid anxiety and depression. We tested for an association between lower birth weight and major depression, generalised anxiety and comorbid generalised anxiety and major depression. METHOD: Data was taken from 2113 mothers and their offspring participating in the Mater University Study of Pregnancy (MUSP) birth cohort. Generalised anxiety, major depression and comorbid generalised anxiety and major depression at 21 years were tested for associations with birth weight using multinomial logistic regression. RESULTS: Lower birth weight was found to predict comorbid generalised anxiety and major depression, but did not predict either generalised anxiety or major depression. LIMITATIONS: We were unable to specify comorbidity by the primary disorder, or by the severity or recurrence of the depression. CONCLUSION: Previous associations found between birth weight and mental health may reflect a specific link between lower birth weight and comorbid generalised anxiety and major depressive disorders. As neither disorder individually was associated with lower birth weight, this may suggest that this developmental origin represents a unique risk pathway to comorbidity not shared with either discrete disorder. PMID- 23040739 TI - An open trial of pregabalin as an acute and maintenance adjunctive treatment for outpatients with treatment resistant bipolar disorder. AB - BACKGROUND: Pregabalin is a structural analog of GABA, similar to gabapentin. It does not have a FDA indication for any psychiatric disorder in the USA. There has been one case report of the successful use of pregabalin as an augmenting agent in a patient with Bipolar Disorder (BD). In the present open label study, not subsidized by the manufacturer, the investigators prospectively evaluated the acute and maintenance efficacy of pregabalin as an adjunctive medication for a group of treatment refractory outpatients with BD. METHODS: Older adolescent and adult outpatients with any type of DSM-IV diagnosed BD, who were considered treatment nonresponders to multiple standard medications for BD, were treated with adjunctive pregabalin. The baseline mood state before initiation of pregabalin was compared to the mood state after an acute trial of pregabalin using the Clinical Global Impression-Bipolar Version Scale (CGI-BP). All acute responders were treated for a minimum of two months. Follow-up maintenance treatment data was obtained for the acute pregabalin responders for three years after the 18 month acute phase of the study. RESULTS: Fifty-eight total patients were treated adjunctively with pregabalin. Twenty-four (41%) were rated as acute responders. For the acute responders, pregabalin produced either a mood stabilizing effect, antidepressant effect or antimanic effect. Intolerable side effects were the most common reason (79%) for a failed acute trial of pregabalin. None of the side effects resulted in serious medical complications. No patient abused pregabalin, and there were no adverse drug-drug interactions despite an average of 3.3 concurrent other psychiatric medications. The maintenance data revealed that 10 (42%) of the original 24 acute pregabalin responders were still taking pregabalin as an add-on medicine for an average of 45.2 months (range 42 48, SD: 2.35). LIMITATIONS: This study has an open label observation design. CONCLUSIONS: The results of this preliminary open study suggest that pregabalin is a safe and effective acute and maintenance adjunctive treatment for a significant number of treatment-resistant outpatients with any type of BPD. It appears to have mood stabilizing and antidepressant properties in addition to antimanic effects. Similar studies using a double-blind, randomly controlled design would be useful to confirm the reliability and validity of the results of this study. PMID- 23040740 TI - Procedures to recover DNA from pre-molar and molar teeth of decomposed cadavers with different post-mortem intervals. AB - A task-force to resolve 26 pending forensic caseworks was carried out. We tested four different protocols to extract DNA from molar and pre-molar teeth from 26 cadavers with post-mortem intervals from 2 months to 12 years. We compared the amount of DNA and DNA profiles with the time elapsed between death and laboratory procedures. Molar or pre-molar teeth were removed from the corpses, cleaned, and DNA was extracted using 2 or 12h of incubation on lysis buffer and filtered using concentration column or precipitated with isopropanol. DNA profiles were obtained using PowerPlex16TM System PCR Amplification Kit, AmpFlSTR((r)) YfilerTM and/or mtDNA sequencing. Complete DNA profiles comparison and statistical evaluation allowed unambiguous identification of the 26 victims. No significant differences were observed in the amount of DNA obtained with the distinct incubation times. The use of concentration column resulted in an increased amount of DNA when compared to isopropanol. However, the lower concentration of DNA obtained with isopropanol seemed to have been compensated by the higher purity. No significant differences in the number of amplified loci were found. A non-significant tendency was found between the amount of total DNA recovered and the time elapsed between death and laboratory procedures. The increase of post-mortem time did not interfere in the analysed autosomal loci. In conclusion, molar and pre-molar teeth were shown to be good candidates to obtain satisfactory DNA profiles, suggesting the high potential of tooth samples as source for DNA typing independently of the decomposed corpse's time or laboratory procedures. PMID- 23040742 TI - Management of incidentally found nonfunctional pituitary tumors. AB - Clinically nonfunctioning pituitary adenomas range from those causing significant hypothalamic/pituitary dysfunction and visual field compromise to those being completely asymptomatic, detected either at autopsy or as incidental findings on imaging scans performed for other reasons (often referred to as pituitary incidentalomas). Growth of nonfunctioning pituitary adenomas without treatment occurs in about 10% of microadenomas and 24% of macroadenomas. In the absence of hypersecretion, hypopituitarism, or visual-field defects, periodic screening by magnetic resonance imaging may detect enlargement. Potential indications for surgery are growth of a pituitary incidentaloma, the development of visual-field defects, or the development of hypopituitarism. PMID- 23040741 TI - Imaging the pituitary and parasellar region. AB - Magnetic resonance imaging is the fundamental imaging tool for the evaluation of tumors and other lesions of the pituitary gland and infundibulum. Abnormalities may arise within the pituitary itself, from vestigial embryologic remnants, or from surrounding tissues. Correct diagnosis rests on accurate assessment of lesion location, imaging appearance, and clinical presentation. This article reviews the radiologic evaluation of lesions within the sella and suprasellar cistern, focusing on common masses and pseudomasses of the pituitary and sellar region that neurosurgeons are most likely to encounter in clinical practice. PMID- 23040743 TI - Endoscopic surgery for pituitary tumors. AB - The endoscopic transsphenoidal approach to the sella turcica has been developed and refined for the treatment of pituitary lesions. Studies comparing endoscopic transsphenoidal surgery with the traditional microscopic transsphenoidal technique have found equivalent or improved rates of tumor resection and hormonal remission, and equal or lower rates of complications. This procedure affords improved panoramic visualization, illumination, surgical freedom, and mobility. This approach facilitates two-handed microdissection and the ability to look around corners using angled lenses, promoting maximal tumor resection and preservation of the pituitary gland. Experience, technologic advancements, and improved instrumentation are likely to contribute to improved surgical outcomes. PMID- 23040744 TI - External beam radiation therapy and stereotactic radiosurgery for pituitary adenomas. AB - This article discusses contemporary use of external beam radiotherapy and stereotactic radiosurgery for pituitary adenoma patients. Specific techniques are discussed. In addition, indications and outcomes, including complications, are detailed. PMID- 23040745 TI - Management of large aggressive nonfunctional pituitary tumors: experimental medical options when surgery and radiation fail. AB - Pituitary adenomas are generally considered benign tumors; however, a subset of these tumors displays aggressive behavior and are not easily cured. The protocol for nonsurgical treatment of aggressive pituitary lesions is less standardized than that of other central nervous system tumors. Aggressive surgical treatment, radiation, dopamine agonists, antiangiogenic drugs, and other chemotherapeutics all have roles in the treatment of aggressive pituitary tumors. More studies are needed to improve outcomes for patients with aggressive pituitary tumors. PMID- 23040746 TI - Clinical management of pituitary carcinomas. AB - Pituitary carcinomas are defined as malignant primary neoplasms of the adenohypophysis with either systemic or craniospinal metastases. Although pituitary adenomas are common, pituitary carcinomas only make up 0.1% to 0.2% of all pituitary tumors. Prognosis is very poor with approximately 66% mortality in the first year of diagnosis. Although effective medical and surgical treatments are available for pituitary adenomas, pituitary carcinomas require a multimodality treatment including surgery, hormonal therapy, cytotoxic chemotherapy, and radiation with limited success. Here we review the clinical behavior and pathologic characteristics of pituitary carcinomas and the recent advances in potential therapies for this malignant disease. PMID- 23040747 TI - Visual outcomes after treatment of pituitary adenomas. AB - Pituitary adenomas frequently manifest with neuro-ophthalmic symptoms and signs. The location of the pituitary gland makes involvement of both the visual pathways and the ocular motor cranial nerves likely when there is adenomatous expansion. A sudden expression of visual loss or diplopia commonly accompanies pituitary apoplexy. Several preoperative neuro-ophthalmic indicators help predict posttreatment outcomes and help determine the best intervention. Treatments themselves may also cause neuro-ophthalmic complications. The current literature and avenues of future research are reviewed. PMID- 23040749 TI - Neurosurgical treatment of Cushing disease. AB - Cushing disease (CD) is caused by overproduction of adrenocorticotropin by a pituitary adenoma (or, rarely, carcinoma). The diagnosis of CD requires distinguishing it from other hypercortisolemic states with a thorough endocrine workup. CD remains a primarily surgical disease, with remission rates of 70% to 95% following microscopic or endoscopic transsphenoidal surgery. PMID- 23040750 TI - Medical management of persistent and recurrent cushing disease. AB - Recent evidence supports the notion that the incidence of Cushing disease is higher than previously thought. Transphenoidal surgery, in the hands of experienced neurosurgeons, is currently considered the first-line treatment of choice. However, an examination of remission and recurrence rates in long-term follow-up studies reveals that potentially up to 40% to 50% of patients could require additional treatment. If left untreated, the resultant morbidity and mortality are high. Successful clinical management of patients with Cushing disease remains a challenge. The development of new therapeutic agents has been eagerly anticipated. This article discusses the results of currently available and promising new therapeutic agents used to treat this challenging disease. PMID- 23040748 TI - Management options for persistent postoperative acromegaly. AB - This article presents management options for the patient with acromegaly after noncurative surgery. The current evidence for repeat surgery, adjuvant medical therapy with somatostatin analogues, dopamine agonists, the growth hormone receptor antagonist pegvisomant, combination medical therapy, and radiotherapy in the context of persistent postoperative disease are summarized. The relative advantages and disadvantages of each of these treatment modalities are explored, and a general treatment algorithm that integrates these modalities is proposed. PMID- 23040751 TI - Medical versus surgical management of prolactinomas. AB - Prolactinomas are the most common hormone-secreting pituitary adenomas, comprising 40% of all pituitary tumors. Prolactinomas present a unique challenge for clinicians, as these tumors are amenable to either medical or surgical treatments based on patients' comorbidities, tolerance to medical treatment, and the response of tumors to medical treatment. Rare prolactinomas that are unresponsive to either medical or surgical treatment modalities may be responsive to radiation therapy. This article reviews the recent advancements in the management of prolactinomas. PMID- 23040752 TI - Hypopituitarism and central diabetes insipidus: perioperative diagnosis and management. AB - Pituitary tumors are a unique class of intracranial neoplasms with the potential to disrupt hormone function and water metabolism. Preoperative and postoperative endocrine assessment is mandatory to recognize and promptly treat new deficiencies and identify those that have resolved. Close collaboration among neurosurgical, endocrine, and anesthetic teams is equally vital during the perioperative period. Appropriate patient education at the time of discharge regarding the symptoms of diabetes insipidus, hyponatremia, and adrenal insufficiency is increasingly important. PMID- 23040753 TI - Neurosurgery Clinics of North America. Management of pituitary tumors. Preface. PMID- 23040754 TI - A call for scientifically-rigorous, community-based "actionable intelligence" to promote the academic achievement of African American boys: an introduction to Fantuzzo, LeBoeuf, Rouse, and Chen (2012) and commentaries. AB - This introduction briefly summarizes the featured article and commentaries making up this commissioned set of papers on the topic of the Black-White achievement gap and, more specifically, risk and protective factors for young African American boys' school success. Each paper highlights important considerations for advancing scholarship, practice, and policy aimed at promoting equity in education. A case is made that in order to advance scientific knowledge of this issue and its application, dialogue across disciplines, methodological traditions, and contexts is needed. PMID- 23040755 TI - Academic achievement of African American boys: a city-wide, community-based investigation of risk and resilience. AB - In light of persistent Black-White achievement gaps for boys, this study examined publicly monitored risks believed to be associated with being behind academically for an entire subpopulation of African American boys in a large urban public school district. Also examined were indicators of academic engagement hypothesized to mediate the relations between risks and low achievement. Findings indicated that the Black-White achievement gap for boys was matched by a comparable difference in risk experiences. Multilevel linear regression models controlling for poverty found that both the type and accumulation of risk experiences explained a significant amount of variation in reading and mathematics achievement for the subpopulation of African American boys. Socio familial risks were related to the poorest academic outcomes. Academic engagement indicators significantly mediated relations between risks and achievement. Implications of this research for collective school and community actions to make race, gender, and place matter in educational public policy were discussed. PMID- 23040756 TI - Data and development: revisit the framework. PMID- 23040757 TI - Academic achievement of African American boys: bringing African American girls into the picture. PMID- 23040758 TI - Reflections on the "Black-white Achievement Gap". PMID- 23040759 TI - Nonparametric statistical tests for single-case systematic and randomized ABAB...AB and alternating treatment intervention designs: new developments, new directions. AB - In this four-investigation Monte Carlo simulation study, we examined the properties of nonparametric randomization and permutation statistical tests applied to single-case ABAB...AB and alternating treatment designs based on either systematically alternating or randomly determined phase assignments. Contrary to previous admonitions, when appropriately conceptualized nonparametric tests were conducted the systematic designs maintained Type I error rates at or less than their nominal values whenever either no or positive autocorrelation was present in the series. Statistical power for all designs varied as a function of both the number of phases and the number of observations per phase. It was concluded that to increase methodological rigor and statistical precision in the face of autocorrelation, (a) whenever possible, researchers should adopt a randomization scheme in assigning the orders in which the A and B phases are administered and (b) in situations where randomized phase assignment is not feasible, researchers should adopt a systematic phase assignment scheme consisting of individually alternating A and B observations, with a cost of sacrificing some degree of statistical power. Implications for single-case intervention research in school psychology are discussed. PMID- 23040760 TI - A systematic evidence review of school-based group contingency interventions for students with challenging behavior. AB - The purpose of this review was to synthesize the research underlying group contingency interventions to determine whether there is sufficient evidence to support their use for managing the classroom behavior of students with behavioral difficulties. An application of the What Works Clearinghouse (WWC) procedures for evaluating single-subject research revealed that the research investigating group contingencies demonstrated sufficient rigor, evidence, and replication to label the intervention as evidence-based. These findings were further supported across five quantitative indices of treatment effect. The results associated with the application of the WWC procedures and quantitative evaluations were supplemented with additional systematic coding of methodological features and study characteristics to evaluate the populations and conditions under which the effects of the group contingency best generalize. Findings associated with this coding revealed that the lack of detailed reporting across studies limited our ability to determine for whom and under what conditions group contingencies are best suited. PMID- 23040761 TI - Reasons for African American student attrition from school psychology programs. AB - This phenomenological study used a series of three in-depth interviews with seven African American participants, for a total of 21 interviews, to explore their experiences in the specialist and doctoral level school psychology programs they left prior to obtaining a professional entry-level degree. The study's purpose was to investigate what factors contributed to participants' attrition. Findings indicate that misalignment between participants' career aims and the practice of school psychology (as presented in the programs they left) contributed to attrition. Poor relationships with school psychology faculty and program cohort peers also played a role in participants' decisions to leave school psychology programs. Results offer a unique lens into racial issues in school psychology. Recommendations for faculty and others interested in preventing African Americans' attrition from school psychology graduate education are discussed. PMID- 23040762 TI - Teacher-child relationships, behavior regulation, and language gain among at-risk preschoolers. AB - Many preschoolers from low socioeconomic-status (SES) backgrounds demonstrate lags in their language development, and preschool participation is viewed as an important means for mitigating these lags. In this study, we investigated how teacher-child relationship quality and children's behavior regulation within preschool classrooms were associated with grammar gain for low-SES preschoolers. Direct child measures and indirect teacher reports were used to assess child language gain, teacher-child relationship quality, and behavior regulation for 173 preschool children enrolled in targeted-enrollment preschool classrooms. Hierarchical linear modeling showed a positive link between close teacher-child relationships and preschoolers' grammar gain during the school year. Interestingly, a significant interaction between conflicted teacher-child relationships and children's behavior regulation indicated that multiple factors are associated with children's language development in the area of grammar. Nurturing classroom environments and strong behavior regulation abilities may act as protective mechanisms for preschoolers from disadvantaged backgrounds. PMID- 23040763 TI - Cyber nursing--health 'experts' approaches in the post-modern era of virtual performances: a nethnography study. AB - BACKGROUND: The imperative to gather information online and to become an 'expert' by locating effective advice for oneself and others is a fairly new support phenomenon in relation to health advice. The creation of new positions for health 'experts' within the space of the Internet has been addressed as a cybernursing activity. A focused analysis of communication in health forums might give insight into the new roles that are available for health experts in cyberspace. AIM: The aim of this study is to describe approaches to being an 'expert' in lifestyle health choice forums on the Internet and to elaborate on the communicative performances that take place in the forums. METHOD: An archival and cross sectional observational forum study was undertaken using principles for conducting ethnographic research online. 2640 pages of data from two health Internet forums were gathered and analyzed. FINDINGS: The results reveal three distinctive types of experts that emerge in the forums: (1) those that build their expertise by creating a presence in the forum based on lengthy and frequent postings, (2) those who build a presence through reciprocal exchanges with individual posters with questions or concerns, and (3) those who build expertise around a "life long learning" perspective based on logic and reason. DISCUSSION: The results suggest that experts not only co-exist in the forums, but more importantly they reinforce each others' positions. This effect is central; alongside one another, the posts of the three types of experts we identify constitute a whole for those seeking the forum for advice and support. Users are provided with strong opinions and advice, support and Socratic reasoning, and a problem-oriented approach. The Internet is now an integral part of everyday living, not least of which among those who seek and offer support in cyberspace. As such, cyber nursing has become an important activity to monitor, and formal health care professionals and nursing researchers must stay abreast of developments. PMID- 23040764 TI - Lesser incidence of accidental catheter removal with femoral versus radial arterial access. AB - BACKGROUND: Arterial catheterization is a frequent procedure in Intensive Care Units (ICUs). Accidental catheter removal (ACR) can cause severe and potentially life-threatening complications such as severe bleeding and vascular damage. Few data are available on accidental arterial catheter removal, and no studies have been found comparing the incidence of ACR between different arterial catheter sites. OBJECTIVE: To compare the incidence of ACR in femoral and radial arterial catheters. RESEARCH DESIGN: Retrospective study. SETTING: A polyvalent ICU. SUBJECTS: All consecutive patients subjected to femoral or radial arterial catheterization. MEASURES: The incidence of ACR per 100 catheter-days between groups was compared using Poisson regression. We considered ACR as the presence of unintended removal produced by the patient or healthcare personnel. RESULTS: A total of 2419 radial and 1085 femoral arterial catheters were inserted and remained in situ during 14,742 and 6497 days, respectively. We detected 45 cases of ACR with the femoral access and 162 cases with the radial access. The ACR rate was lower with the femoral access (4.1% vs 6.7% in the case of the radial access; p=0.003). Poisson regression analysis confirmed a lower incidence of ACR with the femoral versus the radial access (0.69 vs 1.10 ACR events per 100 catheter-days; OR 0.6, p=0.006, CI95% 0.01-0.83). CONCLUSIONS: The incidence of ACR was found to be lower with the femoral than with the radial arterial catheters. In order to improve patient safety, it could be interesting to exhaustively monitor the incidence of ACR and adopt preventive measures, since ACR can give rise to serious complications. PMID- 23040766 TI - Infections occurring in adult patients receiving mechanical circulatory support: the two-year experience of an Italian National Referral Tertiary Care Center. AB - OBJECTIVE: Infection during mechanical circulatory support is a frequent adverse complication. We analyzed infections occurring in this population in a national tertiary care center, and assessed the differences existing between the setting of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). DESIGN, SETTING, AND PARTICIPANTS: An observational study was made of patients treated with ECMO or VAD in the San Raffaele Scientific Institute (Italy) between 2009 and 2011. INTERVENTIONS: None. RESULTS: Thirty-nine percent of the 46 patients with ECMO and 69% of the 15 patients with VAD developed infection. We observed a mortality rate of 36.1% during mechanical circulatory support and of 55.7% during the global hospitalization period. Although Gram negative infections were predominant overall, patients with ECMO were more prone to develop Candida infection (29%), and patients with VAD tended to suffer Staphylococcus infection (18%). Patients with infection had longer ECMO support (p=0.03), VAD support (p=0.01), stay in the intensive care unit (p=0.002), and hospital admission (p=0.03) than patients without infection. Infection (regression coefficient=3.99, 95% CI 0.93-7.05, p=0.02), body mass index (regression coefficient=0.46, 95% CI 0.09-0.83, p=0.02), fungal infection (regression coefficient=4.96, 95% CI 1.42-8.44, p=0.009) and obesity (regression coefficient=10.47, 95% CI 1.77-19.17, p=0.02) were predictors of the duration of ECMO support. Stepwise logistic regression analysis showed the SOFA score at the time of implant (OR=12.33, 95% CI 1.15-132.36, p=0.04) and VAD (OR=1.27, 95% CI 1.04-1.56, p=0.02) to be associated with infection. CONCLUSIONS: Infection is a major challenge during ECMO and VAD support. Each mechanical circulatory support configuration is associated with specific pathogens; fungal infections play a major role. PMID- 23040767 TI - [Herpes simplex virus type 1 pneumonia in a male with familial lung fibrosis]. PMID- 23040768 TI - Novel and simple approach using synthesized nickel nanoparticles to control blood sucking parasites. AB - The present study was on assessment of the anti-parasitic activities of nickel nanoparticles (Ni NPs) against the larvae of cattle ticks Rhipicephalus (Boophilus) microplus and Hyalomma anatolicum (a.) anatolicum (Acari: Ixodidae), fourth instar larvae of Anopheles subpictus, Culex quinquefasciatus and Culex gelidus (Diptera: Culicidae). The metallic Ni NPs were synthesized by polyol process from Ni-hydrazine as precursor and Tween 80 as both the medium and the stabilizing reagent. The synthesized Ni NPs were characterized by Fourier transform infrared (FTIR) spectroscopy analysis which indicated the presence of Ni NPs. Synthesized Ni NPs showed the X-ray diffraction (XRD) peaks at 42.76 degrees , 53.40 degrees , and 76.44 degrees , identified as 111, 220, and 200 reflections, respectively. Scanning electron microscopy (SEM) analysis of the synthesized Ni NPs clearly showed that the Ni NPs were spherical in shape with an average size of 150 nm. The Ni NPs showed maximum activity against the larvae of R. (B.) microplus, H. a. anatolicum, A. subpictus, C. quinquefasciatus and C. gelidus with LC(50) values of 10.17, 10.81, 4.93, 5.56 and 4.94 mg/L; r(2) values of 0.990, 0.993, 0.992, 0.950 and 0.988 and the efficacy of Ni-hydrazine complexes showed the LC(50) values of 20.35, 22.72, 8.29, 9.69 and 7.83 mg/L; r(2) values of 0.988, 0.986, 0.989, 0.944 and 0.978, respectively. The findings revealed that synthesized Ni NPs possess excellent larvicidal parasitic activity. To the best of our knowledge, this is the first report on larvicidal activity of blood feeding parasites using synthesized Ni NPs. PMID- 23040769 TI - Effect of ricinoleic acid esters from castor oil (Ricinus communis) on the oocyte yolk components of the tick Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae). AB - Rhipicephalus sanguineus are bloodsucking ectoparasites, whose main host is the domestic dog, thus being present in urban areas and closely located to people. Eventually, this tick species parasitize humans and can become a potential vector of infectious diseases. Methods to control this type of pest have been the focus of many research groups worldwide. The use of natural products is increasingly considered nowadays, due to the low toxicity levels to the host and low waste generation to the environment. This study tested the effect of ricinoleic acid esters from castor oil (as an potential acaricide) on the reproductive system of R. sanguineus females, more specifically on the vitellogenesis process. For this, two groups were established: the control group (CG) and the treatment group (TG) with five rabbits in each (New Zealand White), used as hosts. NaCl and ester were added to rabbits' food and offered to the hosts. After full engorgement, the females were collected and had their ovaries extracted. The ticks ovaries were submitted to histochemical techniques so the effects of esters could be observed over polysaccharides, proteins and lipids yolk. Changes in the deposition of yolk components were observed. This caused modifications on elements of polysaccharide origin and on glycoprotein compounds, interfering in the final yolk synthesis and compromising the development of the future embryo. PMID- 23040771 TI - [Critical care medicine in healthcare reform: its role and orientation]. PMID- 23040770 TI - Conflicting results of serological, PCR and microscopic methods clarify the various risk levels of canine babesiosis in Slovakia: a complex approach to Babesia canis diagnostics. AB - We have performed a survey of Babesia canis prevalence within group of dogs living in Southern and Western Slovakia. Blood samples and sera from 217 dogs, including individuals suspected of having babesiosis, were examined by nested PCR RFLP, light microscopy and indirect fluorescence antibody test (IFAT). The detection of B. canis DNA revealed the highest number of infected dogs in the region of Nove Zamky, with 23 B. canis-positive blood samples (35.4%, n=65), followed by an area close to Komarno (both areas of Southern Slovakia), where 1 dog out of 52 collected (1.9%) had detectible B. canis DNA in the blood stream. The serological method revealed an opposing pattern, with only 3 dogs (4.8%, n=63) sampled at Nove Zamky presenting IgG antibodies against B. canis, while in Komarno region such antibodies were detected in 15 dogs (28.8%, n=52). This discrepancy may be because the majority of samples from Nove Zamky were dogs suspected of an acute phase of canine babesiosis, whereas dogs at Komarno were sampled during a vaccination campaign, and thus were without any clinical signs of the disease. The latter group contains evidently recovered carriers of IgG against B. canis. Hence, the combination of PCR-based and serological methods enabled us to discover both recently infected as well as recovered dogs, thus obtaining a more realistic view on the epidemiological situation. Remarkably, we did not find any positive samples in the vicinity of Stupava (district Malacky, Western Slovakia), either by PCR-RFLP, microscopy or IFAT (n=100). Considering the numerous falsely diagnosed cases of canine babesiosis, we suggest that light microscopy as the simplest and most accessible diagnostic test. Southern Slovakia was confirmed as an area of high risk of canine babesiosis, whereas conclusions about B. canis spreading over Western Slovakia should be considered with wariness. PMID- 23040772 TI - [The comparative analysis of the common reasons of invasive ventilator alarms between medical and specialist intensive care unit]. AB - OBJECTIVE: To analyze the common reasons of invasive ventilator alarms between medical intensive care unit (ICU) and specialist ICU, and its related management methods. METHODS: Patients admitted to medical ICU and specialist ICU from January to December in 2011 of the First Hospital of China Medical University were studied. Ventilator alarms and their reasons need to be handle by the front line doctors, respiratory therapists, attending physicians or medical ICU doctors were analyzed and compared. RESULTS: There were 375 ventilator alarms of the 59 patients in the medical ICU, incidence of the top three alarms parameters were high airway pressure alarms for 21.87%, high tide volume alarms for 15.73% and high minute ventilation alarms for 14.13%. In specialist ICU there were a total of 403 ventilator alarms with 249 patients, incidence of the top three alarms parameters were high airway pressure alarms for 32.51%, low airway pressure alarms for 15.38%, high respiratory rate alarms for 10.42%. The incidence of high airway pressure and low airway pressure alarms in medical ICU were significantly lower than the specialist ICU (21.87% vs. 32.51%, 8.53% vs. 15.38%, both P<0.01), and the incidence of high minute ventilation and high tidal volume alarms in medical ICU were higher than specialist ICU (14.13% vs. 7.20%, 15.73% vs. 9.68%, P<0.01 and P<0.05). The top three causes of the alarms were aerosol inhalation, sputum blockage, and oxygen battery expired in medical ICU, and sputum blockage, respiratory distress, and pipeline leak and oxygen expired battery in specialist ICU. The reasons of sputum blockage, tubes factors (intubation position change, pipeline water) and improper alarm parameters setting in medical ICU was significantly lower than those in specialist ICU (10.93% vs. 17.12%, 1.87% vs. 4.47%, 1.33% vs. 3.72%, 1.60% vs. 3.97%, all P<0.05). High tidal volume, high minute ventilation and serious breath-side filter blockage because of aerosol inhalation in medical ICU were significantly higher than those in specialist ICU (18.93% vs. 3.97%, P<0.01). CONCLUSION: Doctors in medical ICU and specialist ICU should understand the ventilator alarms characteristics, prevention, detect and timely problems management. PMID- 23040773 TI - [Effect of 45 degree angle semirecumbent position on ventilator-associated pneumonia in mechanical ventilated patients: a meta-analysis]. AB - OBJECTIVE: To systemically analyze the effect of 45 degree angle semirecumbent position on the incidence of ventilator-associated pneumonia (VAP) and other outcomes in mechanical ventilated patients, and to evaluate whether 45 degree angle semirecumbent position is superior to 25 degree angle-30 degree angle head of bed (HOB). METHODS: The randomized controlled trials (RCTs) comparing the effect of different HOB on the outcomes of mechanical ventilated patients were searched (from 1st January 1990 to 20th July 2012) from five databases including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, China Knowledge Resource Integrated Database (CNKI), and Wanfang Database. Meta analysis was conducted using RevMan 5.0 software. RESULTS: Data extracted from five RCTs with a total of 427 patients were analyzed. The risks of developing clinically diagnosed VAP were significantly lower among the patients in semirecumbent 45 degree angle position compared to the patients in lower position [15.96% (34/213) vs. 26.64% (57/214), relative risk (RR)=0.57, 95% confidence interval (95%CI) 0.39 to 0.83, P=0.003], while no significant differences were detected between the two groups regarding the mortality rate [27.04% (53/196) vs. 28.22% (57/202), RR=0.93, 95%CI 0.68 to 1.27, P=0.66], the length of intensive care unit (ICU) stay [weighted mean difference (WMD)=-0.45, 95%CI -1.08 to 0.18, P=0.16] and the percentage of antibiotics treatment [71.11% (32/45) vs. 60.87% (28/46), RR=1.14, 95%CI 0.85 to 1.53, P=0.37]. Two of the five trials (91 patients) were included in the sub-analysis between 45 degree angle group (45 patients) and 25 degree angle-30 degree angle group (46 patients). The results showed that comparing with 25 degree angle-30 degree angle, 45 degree angle semirecumbent position had no significance in improving patients' clinical outcomes. CONCLUSION: This study proved that the clinically preferred semirecumbent 45 degree angle position did have effect in reducing the incidence of VAP, nevertheless, whether it's superior to 25 degree angle-30 degree angle needs to be confirmed by larger-scale, higher-quality RCTs. PMID- 23040774 TI - [The relationships between oxygenation index and prognosis in acute respiratory failure patients treated by invasive mechanical ventilation]. AB - OBJECTIVE: To investigate the effect of oxygenation index (PaO(2)/FiO(2)) on patients' prognosis through comparative analyzing the monitoring indicators of acute respiratory failure patients treated by invasive mechanical ventilation. METHODS: Data from 91 acute respiratory failure patients treated by invasive mechanical ventilation in respiration intensive care unit (ICU) of the General Hospital of PLA of Lanzhou from November 2006 to August 2011 were retrospectively analyzed. Patients were divided into survival group (n=55) and death group (n=36) by the outcome, the critical severity scores of the diseases and changes in blood gas analysis during ventilation were compared, and their correlation with prognosis were analyzed. RESULTS: There were no significant differences in acute physiology and chronic health evaluationIII (APACHEIII) score, multiple organ dysfunction syndrome (MODS) score, acute lung injury (ALI) score between survival and death group before ventilation (62.77+/-22.92 vs. 74.62+/-25.77, 6.46+/-2.45 vs. 6.62+/-3.03, 1.90+/-0.57 vs. 2.10+/-0.73, all P>0.05). There was no significant difference in PaO(2)/FiO(2) between survival and death group on the first day of mechanical ventilation (132.18+/-67.29 mm Hg vs. 139.24+/-78.36 mm Hg, P>0.05). PaO(2)/FiO(2) in survival group were significantly higher than that in death group on the 3 days and 7 days of mechanical ventilation (3 days: 205.47+/-74.71 mm Hg vs. 149.76+/-70.38 mm Hg, 7 days: 225.37+/-67.20 mm Hg vs. 120.94+/-85.58 mm Hg, P<0.05 and P<0.01). CONCLUSIONS: The present study demonstrated that the level of PaO(2)/FiO(2) is related with the prognosis of acute respiratory failure patients treated by invasive mechanical ventilation. Continuously monitoring the changes in PaO(2)/FiO(2) can be used as an important reference index to evaluate the prognosis of critical patients. PMID- 23040775 TI - [Effect of prone position on the oxygenation of patients with acute respiratory distress syndrome after failure recruitment maneuvers at high altitudes]. AB - OBJECTIVE: To assess the effect of prone position on the oxygenation of patients with acute respiratory distress syndrome (ARDS) after recruitment maneuvers (RM) failure at high altitudes. METHODS: Forty-one ARDS patients who were invalid for RM therapy at the altitude of 2260 metres area hospital were enrolled[mean oxygenation index (PaO(2)/FiO(2)) increased than RM<20% considered as RM invalid]. All were divided into acute respiratory distress syndrome (ARDSp) and extra-acute respiratory distress syndrome (ARDSexp) based on different etiology, and each group was randomly divided into the supine and the prone position group, i.e. that ARDSp prone position group (n=11), ARDSp supine group (n=9), ARDSexp prone position group (n=10), and ARDSexp supine group (n=11). Before ventilation and 1, 2, 3, 4 hours after ventilation, arterial partial pressure of oxygen (PaO(2)), PaO(2)/FiO(2), static lung compliance (Cst), airway resistance (Raw) were monitored. RESULTS: One hour after ventilation in ARDSexp prone position group, PaO(2)/FiO(2) was significantly higher than before ventilation (157.4+/ 40.6 mm Hg vs. 129.3+/-48.7 mm Hg, P<0.05), and increased by ventilation time, peaked at 4 hours (219.1+/-41.1 mm Hg). Within 3 hours ventilation in ARDSexp prone position group, PaO(2)/FiO(2) was significantly higher compared with the other three groups, and there were no significant differences among the other three groups. PaO(2)/FiO(2) in ARDSp prone position group and ARDSexp prone position group at 4 hours of ventilation were significantly higher compared with the corresponding supine group (208.8+/-39.7 mm Hg vs. 127.4+/-47.1 mm Hg, 219.1+/-41.1 mm Hg vs. 124.9+/-50.8 mm Hg, both P<0.05). There was no statistically significant difference in Cst before and after ventilation, and there was no significant changes among the groups. Raw in ARDSp prone position group at 4 hours of ventilation were significantly reduced than before ventilation (6.8+/-1.7 cm H(2)O*L(-1)*s(-1) vs. 10.7+/-1.8 cm H(2)O*L(-1)*s(-1), P<0.05), and significantly lower than the other three groups. There was no statistically significant difference in RAW among other three groups at each time point. CONCLUSION: Prone position can improve RM oxygenation invalid ARDS patients at high altitudes. PMID- 23040776 TI - [Study of automated acid-base mapping on diagnose and treatment of community acquired pneumonia in emergency department]. AB - OBJECTIVE: To analyze the value of automated acid-base mapping on diagnose and treatment of patients with community acquired pneumonia (CAP) in emergency department. METHODS: According to medical history, pulmonary function test, diagnosing guideline of chronic obstructive pulmonary disease (COPD), 111 patients with CAP were divided into two groups: single CAP group (n=56) and COPD complicated with CAP group [acute exacerbation of chronic obstructive pulmonary disease (AECOPD) group, n=55]. After enquiring medical history, arterial blood samples were drawn for blood gas analysis and automated acid-base mapping was analyzed. RESULTS: Arterial blood gas analysis showed arterial carbon dioxide partial pressure (PaCO(2)), HCO(3)(-), base excess of AECOPD group were obviously higher than those in CAP group (PaCO(2): 7.714+/-2.414 kPa vs. 5.896+/-1.308 kPa, HCO(3)(-): 30.767+/-7.185 mmol/L vs. 25.014+/-3.043 mmol/L, BE: 4.345+/-5.371 mmol/L vs. -0.354+/-3.180 mmol/L, all P<0.01). Automated acid-base mapping showed acid-base disturbance of AECOPD group was 89.1% and CAP group was 66.1%. Chi square analysis were done for patients of normal (10.9%, 33.9%), acute respiratory acidosis (12.7%, 14.3%), chronic respiratory acidosis (49.1%, 10.7%), respiratory alkalosis (7.3%, 14.3%), metabolic acidosis (12.7%, 17.9%), metabolic alkalosis (12.7%, 8.9%) between AECOPD group and CAP group, and statistical significance was found between AECOPD group and single CAP group (chi (2)=24.421, P=0.001). Advanced Chi-square analysis for patients of normal, acute respiratory acidosis, respiratory alkalosis, metabolic acidosis, metabolic alkalosis were done and showed no statistical difference (chi (2)=5.280, P=0.260). It is indicated chronic respiratory acidosis occurrences rate in AECOPD patients was higher than single CAP patients. CONCLUSIONS: Our study demonstrated that automated acid-base mapping may be helpful for emergency physician to rapidly recognize multi-acid-base disturbance in patients with CAP, and to promptly identify acute or chronic phase of respiratory disease. PMID- 23040777 TI - [Effects of simvastatin on lipopolysaccharide induced alpha-subunit epithelial sodium channel mRNA in rat lung alveolar type II epithelial cells]. AB - OBJECTIVE: To study the impact of simvastatin on alpha-subunit epithelial sodium channel (alpha-ENaC) mRNA expression in primary culture alveolar typeII (ATII) epithelial cell of rats induced by lipopolysaccharide (LPS) in vitro. METHODS: ATII of primary generation were isolated from adult Sprague-Dawley (SD) rats. The cells were randomly divided into five groups: blank control group, LPS injured group (final concentration of LPS 1 mg/L), simvastatin low and high concentration groups (final concentration of simvastatin 20 MUmol/L, 30 MUmol/L, respectively), solution control group. Then, after being intervened for 1, 12 and 24 hours, the level of human tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were monitored by enzyme-linked immunosorbent assay (ELISA), and alpha-ENaC mRNA expression was tested by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: After being intervened for 1, 12 and 24 hours, expressions of TNF-alpha and IL-1beta in LPS injured group were obviously higher than those in blank control group. Expressions of TNF-alpha and IL-1beta at 1, 12 and 24 hours in simvastatin low concentration group were significantly decreased compared with those in LPS injured group (TNF-alpha 1 hour: 1178.80+/-127.43 ng/L vs. 2336.00+/-170.04 ng/L, 12 hours: 1003.60+/-59.61 ng/L vs. 2479.80+/-210.41 ng/L, 24 hours: 695.80+/-25.24 ng/L vs. 1167.60+/ 132.72 ng/L; IL-beta 1 hour: 285.00+/-42.60 ng/L vs. 429.60+/-27.39 ng/L, 12 hours: 238.60+/-24.12 ng/L vs. 822.20+/-12.74 ng/L, 24 hours: 213.40+/-17.87 ng/L vs. 637.60+/-22.96 ng/L, all P<0.05). Expressions of TNF-alpha and IL-1beta in high concentration group were decreased more obviously than those in low concentration group (TNF-alpha 1 hour: 965.60+/-24.45 ng/L vs. 1178.80+/-127.43 ng/L, 12 hours: 522.80+/-16.89 ng/L vs. 1003.60+/-59.61 ng/L, 24 hours: 252.40+/ 17.64 ng/L vs. 695.80+/-25.24 ng/L; IL-1beta 1 hour: 225.60+/-34.44 ng/L vs. 285.00+/-42.60 ng/L, 12 hours: 190.60+/-17.64 ng/L vs. 238.60+/-24.12 ng/L, 24 hours: 152.80+/-14.70 ng/L vs. 213.40+/-17.87 ng/L, all P<0.05), but increased compared with those in blank control group. After being intervened for 1 hour, no evident changes were observed in expression of alpha-ENaC mRNA in all groups. After being intervened for 12 hours and 24 hours, evident decrease in expression of alpha-ENaC mRNA (A value) was observed in LPS injured group compared with blank control group (12 hours: 0.211+/-0.021 vs. 0.496+/-0.027, 24 hours: 0.253+/ 0.030 vs. 0.482+/-0.030, both P<0.05). Expressions of alpha-ENaC mRNA in simvastatin low concentration group evidently increased compared with those in LPS injured group (12 hours: 0.363+/-0.030 vs. 0.211+/-0.021, 24 hours: 0.309+/ 0.024 vs. 0.253+/-0.030, both P<0.05). Expressions of alpha-ENaC mRNA in simvastatin high concentration group increased more obviously compared with those in low concentration group (12 hours: 0.413+/-0.034 vs. 0.363+/-0.030, 24 hours: 0.346+/-0.024 vs. 0.309+/-0.024, both P<0.05), but decreased compared with blank control group. No evident difference in expressions of all indexes in solution control group was observed compared with those in blank control group. CONCLUSIONS: High dose simvastatin could improve alpha-ENaC mRNA expression in primary culture ATII epithelial cells of rats. This may act by modulation the level of TNF-alpha and IL-1beta. PMID- 23040778 TI - [Effects of unfractionated heparin on expression of metalloproteinase-2 and -9 in acute lung injury rats]. AB - OBJECTIVE: To determine the activation of matrix metalloproteinase (MMP-2, MMP-9) in rats with acute lung injury (ALI) and the effects of unfractionated heparin (UFH) on the levels. METHODS: Eighteen male Wistar rats were divided into control group, ALI group and UFH group, with 6 rats in each group by means of random number table. ALI was induced by administering a bolus injection of lipopolysaccharide (LPS) via the caudal vein at a dose of 6 mg/kg. In UFH group the rats were treated intravenously with 100 U/kg of UFH 15 minutes before the injection of LPS. In control group, the rats were treated with the same volume of normal saline. Serum levels of MMP-2 and MMP-9 were measured by enzyme linked immunosorbent assay (ELISA) at 1, 3, 6 hours via femoral vein. Six hours after the injection of reagents, the rats were sacrificed and lung tissue samples were collected for mRNA analysis of the MMP-2 and MMP-9 by real-time fluorescence quantitate reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: Compared with control group, the content of MMP-2 and MMP-9 in serum of ALI group were increased, and reached the peak at 6 hours (MMP-2: 2.86+/-0.40 MUg/L vs. 1.21+/-0.24 MUg/L, MMP-9: 2.54+/-0.29 MUg/L vs. 1.15+/-0.34 MUg/L, both P<0.01); they were down-regulated in UFH group at 6 hours (MMP-2: 1.92+/-0.31 MUg/L vs. 2.86+/-0.40 MUg/L, MMP-9: 1.82+/-0.26 MUg/L vs. 2.54+/-0.29 MUg/L, both P<0.05). Compared with control group, the mRNA expressions of MMP-2 and MMP-9 in the lung tissue of ALI group were increased at 6 hours (MMP-2 mRNA: 1.88+/-0.09 vs. 1.00+/ 0.10, MMP-9 mRNA: 3.15+/-0.47 vs. 1.00+/-0.17, both P<0.01); they were down regulated in UFH group (MMP-2 mRNA: 1.26+/-0.14 vs. 1.88+/-0.09, P<0.01; MMP-9 mRNA: 2.06+/-0.68 vs. 3.15+/-0.47, P<0.05), but still above the control group (both P<0.05). CONCLUSIONS: The present study demonstrated that the level of MMP 2 and MMP-9 increased in rats with ALI. UFH could exert protective effects by inhibiting expression of MMP-2 and MMP-9 in serum and lung tissue, in both mRNA and protein expression. PMID- 23040779 TI - [The effects of three dosages of nebulized unfractionated heparin on alveolar coagulation and tissue inflammation injury in endotoxin-induced acute lung injury rat model]. AB - OBJECTIVE: To observe the effects of three dosages of nebulized unfractionated heparin (UFH) on alveolar coagulation, inflammation and lung histology in endotoxin-induced acute lung injury rat model, and investigate the appropriated dose of local UFH in managing intrapulmonary coagulopathy. METHODS: Twenty-nine male Wistar rats were divided into control (n=5) and UFH group (n=24) in table of random number, which were duplicated to be endotoxin-induced ALI rat model with lipopolysaccharide (LPS) injecting by intravenous route. The UFH group was divided into three subgroups, which were administered once with 6, 12 and 18 U/g aerosolized UFH in 10 ml at 2 hours after challenge, respectively, while the control group was simply nebulized with normal saline. All rats were sacrificed at 6 hours after intravenous administration of LPS, bronchoalveolar lavage was performed, and the fluid was collected. Enzyme-linked immune sorbent assay (ELISA) was used to measure the level of thrombin-antithrombin complex (TATc), tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage fluid (BALF), and lung wet/dry (W/D) weight ratio, histology score were recorded. RESULTS: At 6 hours after LPS-induced lung injury, the levels of TATc and TNF-alpha, lung W/D weight ratio and histology score in 6 U/g and 12 U/g group were all lower than those of control group significantly (TATc: 0.959+/-0.681 MUg/L, 1.165+/-0.854 MUg/L vs. 2.141+/-0.791 MUg/L, TNF-alpha: 4.449+/-5.054 ng/L, 9.096+/-4.099 ng/L vs. 18.184+/-3.869 ng/L, W/D weight ratio: 7.018+/-1.137, 7.367+/-0.349 vs. 8.472+/-0.614, histology score: 16.0+/-1.0, 16.5+/-1.5 vs. 19.6+/-0.4, P<0.05 or P<0.01). There was no significant difference in the comparisons between the subgroups of UFH in TATc level in BALF and lung histology score. For the TNF alphalevel in BALF, 18 U/g group evidently exceeded that of 6 U/g group (15.503+/ 8.753 ng/L vs. 4.449+/-5.054 ng/L, P<0.01), and lung W/D weight ratio in 18 U/g group was also significantly higher comparing to 6 U/g (8.850+/-1.157 vs. 7.018+/ 1.137, P<0.05) and 12 U/g group (8.850+/-1.157 vs. 7.367+/-0.349, P<0.05). CONCLUSION: It was appropriate for the dose of nebulized UFH to be administered no more than 12 U/g in ALI treatment, which was enough to inhibit alveolar coagulant cascade, decrease early inflammatory response and alleviate lung tissue injury. PMID- 23040780 TI - [The expression of alpha-smooth muscle actin during the lung injury induced by hyperoxia]. AB - OBJECTIVE: To explore the expression of alpha-smooth muscle actin (alpha-SMA) during the lung injury induced by hyperoxia in infantile rats. METHODS: Sixty four male Sprague-Dawley (SD) rats about 3 weeks were randomly assigned into normal control group which exposured to room air [fraction of inspired oxygen (FiO(2)) was 0.21] and hyperoxia exposure group (95%O(2)) according to random digits table. Eight rats in each group were randomly sacrificed at day 1, 7, 14 and 21.Pulmonary tissue remodeling was observed by hematoxylin-eosin (HE) staining. Immunohistochemistry method was performed to evaluate the expression of alpha-SMA in pulmonary tissue, further Western blotting was also made to determine the expression of alpha-SMA. RESULTS: The early histopathologic changes after HE were inflammation and edema in pulmonary tissue, while the later changes were interstitial hyperplasia and fibroblast proliferation. The expression of alpha-SMA was very slight in bronchial epithelium, alveolar epithelium and alveolar interstitium in normal control group, but increased with the time of hyperoxia exposure prolonged and peaked at 21st day. Western blotting detected that the expression of alpha-SMA after hyperoxia exposure for 1 day and 7 days in hyperoxia exposure group presented no difference compared with normal control group (1.02+/-0.12 vs. 1.00+/-0.13, 1.05+/-0.14 vs. 0.99+/-0.12, both P>0.05), but the expression of alpha-SMA after hyperoxia exposure for 14 days and 21 days was increased compared with normal control group (1.27+/-0.21 vs. 1.05+/-0.15, 2.26+/-0.28 vs. 1.05+/-0.14, P<0.05 and P<0.01). CONCLUSIONS: Pulmonary fibrosis remodeling was caused by hyperoxia exposure. The expression of alpha-SMA in pulmonary tissue in hyperoxia exposure groups obviously increased, and could play an important role in pulmonary fibrosis remodeling. PMID- 23040781 TI - [The effects of postconditioning with propofol on Toll-like receptor 4 expression in the lung tissue of rat with acute lung injury]. AB - OBJECTIVE: To investigate the effect of postconditioning with propofol on Toll like receptor 4 (TLR4) expression in the lung tissue in lipopolysaccharide (LPS) induced acute lung injury (ALI) rats. METHODS: Thirty Sprague-Dawley (SD) rats were randomly assigned to control group, ALI group, and propofol postcondition group (each n=10). The model of ALI was reproduced by intravenous injection of LPS (8 mg/kg for 30 minutes) into the rats, equivalent normal saline was injected into the rats of control group. The rats were postconditioned with propofol injected intravenously by 20 mg/kg bolus dose and then continuously by 40 mg*kg( 1)*h(-1) with a constant speed for 1 hour. The rats were sacrificed 6 hours after drug injection. Lung wet/dry weight (W/D) ratio and lung permeability index (LPI) was taken. Tumor necrosis factor-alpha (TNF-alpha) level in bronchoalveolar lavage fluid (BALF) was detected using enzyme linked immunosorbent assay (ELISA) method and TLR4 mRNA expression in lung tissue was assessed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The lung W/D ratio, LPI, TLR4 mRNA and TNF-alpha in BALF were all increased in ALI group compared with control group [lung W/D ratio: 5.30+/-0.28 vs. 4.21+/-0.14, LPI (*10(-3)): 8.7+/-2.2 vs. 3.3+/-2.0, TLR4 mRNA: 2.451+/-0.028 vs. 0.998+/-0.021, TNF-alpha: 643.46+/-62.31 ng/L vs. 120.43+/-12.65 ng/L, all P<0.05]. The above indexes were significantly reduced in the propofol group than those in the ALI group [lung W/D ratio: 4.68+/-0.19 vs. 5.30+/-0.28, LPI (*10(-3)): 5.8+/-2.0 vs. 8.7+/-2.2, TLR4 mRNA: 1.126+/-0.025 vs. 2.451+/-0.028, TNF-alpha: 290.53+/-32.01 ng/L vs. 643.46+/-62.31 ng/L, all P<0.05], but still higher than those in control group (all P<0.05). CONCLUSION: Postconditioning with propofol may alleviate ALI via reducing TLR4 mRNA expression, and inhibit the waterfall-like inflammatory reaction. PMID- 23040782 TI - [Effects of glutathione ethyl ester on smoke inhalation lung injury]. AB - OBJECTIVE: To investigate the effects of glutathione (GSH) precursor glutathione ethyl ester (GSEt) on smoke inhalation induced lung injury rats. METHODS: Sixty healthy male Sprague-Dawley (SD) rats were divided into groups by random digits table method, which included normal group, model group, GSEt high dose group and GSEt low dose group. Smoke inhalation induced lung injury rats model was established. GSEt treatments were given through intraperitoneal injection for 50 mg/kg or 150 mg/kg 5 minutes after the injury. Arterial blood gas analysis was monitored at 2, 12 and 24 hours after injury in each group. Rats were sacrificed for lungs, and bronchoalveolar lavage fluid (BALF) was collected for analysis of GSH activity; and the activity of GSH, catalase (CAT) and glutathione reductase (GR) were detected in pulmonary tissue homogenate.The changes of pulmonary tissue pathology was observed through light microscope. RESULTS: Compared to normal group, arterial partial pressure of oxygen (PaO(2)) in model group were decreased significantly in each time; the activity of GSH in BALF, and the activity of GSH, CAT, GR in lung tissue were also observed decreased significantly. Compared with model group, GSEt treatment (150 mg/kg) with the PaO(2) advanced at 12 hours (82.9+/-7.0 mm Hg vs. 63.9+/-6.5 mm Hg, P<0.05), the activity of GSH was increased at the 12 hours and 24 hours (12 hours: 2.19+/-0.41 mg/g vs. 0.79+/ 0.21 mg/g, 24 hours: 1.75+/-0.47 mg/g vs. 0.67+/-0.10 mg/g, both P<0.05); the activity of CAT in GSEt low dose group (50 mg/kg) was increased at the 24 hours and the same increase was also observed in GSEt high dose group (150 mg/kg) at 12 hours and 24 hours (low dose group 24 hours: 70.1+/-5.5 U/g vs. 56.3+/-5.0 U/g; high dose group 12 hours: 90.9+/-8.1 U/g vs. 67.9+/-6.1 U/g, 24 hours: 94.7+/-7.7 U/g vs. 56.3+/-5.0 U/g, all P<0.05); the activity of GR in GSEt high dose group was increased at 24 hours (5.25+/-0.77 mmol/g vs. 4.37+/-0.64 mmol/g, P<0.05). The histological abnormality of lung tissue was alleviated after application of GSEt (150 mg/kg) 12 hours later, less inflammatory cells infiltration and no punctate hemorrhage in lung tissues. CONCLUSION: GSEt can enhance antioxidant capacity in lung tissues, it have a good protection for pulmonary injury. PMID- 23040783 TI - [Domestic imipenem cilastatin sodium for the treatment of severe aspiration pneumonia, a curative effect observation]. AB - OBJECTIVE: To evaluate the efficacy and safety of domestic imipenem cilastatin sodium for the treatments of severe aspiration pneumonia. METHODS: A randomize, open, parallel-controlled trial was conducted. Sixty-eight patients with severe aspiration pneumonia were divided into trial group (n=36) and control group (n=32) by random distribution method. The application of trial group domestic imipenem cilastatin sodium was 1.0 g intravenous drip, every 6-8 hours for 7-14 days. The control group application with imported injection imipenem cilastatin sodium was 1.0 g intravenous drip, every 6-8 hours for 7-14 days. The highest daily temperature (T), heart rate (HR), breathing rate (RR), pulse blood oxygen saturation (SpO(2)), blood oxygen partial pressure (PaO(2)), inhaled oxygen concentration (FiO(2)), oxygenation index (PaO(2)/FiO(2)), airway peak pressure (Paw), minute ventilation (MV) and white blood count (WBC), pro calcitonin (PCT), high-sensitivity C-reactive protein (hs-CRP) index before and 1, 3, 7 days after treatment, and liver and kidney function, chest X-rays, and sputum cultures of drug sensitive test were conducted. And the effectiveness and safety were determined according to the standards. RESULTS: After treatment indexes of the two groups were obviously improved, i. e. T, HR, RR, Paw, MV, the WBC, PCT, CRP were gradually declined, PaO(2)/FiO(2) was gradually raised. There were statistical significance before and 3 days after treatment in the trial and the control group [T: 37.35+/-0.91 centigrade vs. 38.43+/-1.06 centigrade, 37.28+/ 0.88 centigrade vs. 38.35+/-1.11 centigrade; HR: 90.25+/-10.60 bpm vs. 118.94+/ 15.46 bpm, 89.31+/-11.17 bpm vs. 124.34+/-17.87 bpm; RR: 25.14+/-3.17 bpm vs. 32.28+/-4.49 bpm, 24.81+/-2.43 bpm vs. 33.13+/-4.17 bpm; Paw: 23.03+/-3.04 cm H(2)O vs. 33.22+/-4.59 cm H(2)O, 22.75+/-3.22 cm H(2)O vs. 33.63+/-4.79 cm H(2)O; MV: 8.67+/-1.26 L/min vs. 11.80+/-2.01 L/min, 8.88+/-1.45 L/min vs. 13.21+/-2.90 L/min; WBC: 11.26+/-1.96 *10(9)/L vs. 14.57+/-3.10 *10(9)/L, 12.28+/-3.38 *10(9)/L vs. 15.25+/-4.93 *10(9)/L; PCT: 6.90+/-5.46 MUg/L vs. 16.97+/-7.93 MUg/L, 6.17+/-6.13 MUg/L vs. 21.26+/-11.54 MUg/L; CRP: 85.50+/-37.91 mg/L vs. 120.17+/-45.47 mg/L, 94.31+/-38.51 mg/L vs. 142.34+/-53.57 mg/L; PaO(2)/ FiO(2): 182.06+/-40.88 mm Hg vs. 98.67+/-20.62 mm Hg, 184.09+/-43.78 mm Hg vs. 96.22+/-22.59 mm Hg, all P<0.05]. There was no significant change in SpO(2) before and after treatment in two groups. And the total clinical effective rate in trial and control group were 83.4% and 81.2%, adverse reaction rate were 13.9% and 9.4%, bacterial removal rate were 90.3% and 87.0% respectively, and there was no significant difference between the two groups (all P>0.05). CONCLUSION: Domestic imipenem cilastatin sodium can effectively control severe aspiration pneumonia, and it is safe and effective antibiotics. PMID- 23040784 TI - [A comparative study between thrombolysis and anticoagulation alone in 153 acute pulmonary embolism patients]. PMID- 23040785 TI - [Respiratory tract hypohydration in mechanical ventilation patients: a clinical observation study in 67 patients]. PMID- 23040786 TI - Assessing efficacy of indacaterol in moderate and severe COPD patients: a 12-week study in an Asian population. AB - INTRODUCTION: This post hoc analysis evaluated the efficacy of indacaterol, a novel inhaled once-daily long-acting beta(2)-agonist, by disease severity (GOLD 2005) in patients with moderate-to-severe COPD from six Asian countries/areas (Hong Kong, India, Japan, Korea, Singapore, Taiwan). METHODS: Data from a 12 week, double-blind, placebo-controlled, parallel-group study in patients randomized to indacaterol 150 MUg, indacaterol 300 MUg or placebo once daily were analyzed based on baseline disease severity (moderate or severe). Endpoints were: trough FEV(1) (average of 23 h 10 min and 23 h 45 min post-dose values), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) at Week 12. Safety data were collected. RESULTS: Of 347 patients randomized, 59.7% had moderate, and 40.3% had severe COPD. Least squares means (LSMs) indacaterol-placebo differences in trough FEV(1) at Week 12 exceeded the pre specified minimal clinically important difference (MCID) of 0.12L and were statistically superior (p < 0.001) for indacaterol (150 MUg, 300 MUg) versus placebo in the two subgroups [0.19L, 0.20L (moderate); 0.15L, 0.19L (severe) respectively]. LSM TDI scores for both indacaterol doses versus placebo in both subgroups were statistically superior (p < 0.05) and clinically meaningful (>=1 unit). Both indacaterol doses showed improvements in LSM SGRQ total scores at Week 12 which exceeded the MCID (4 units) versus placebo in both subgroups, with indacaterol 300 MUg-placebo difference in the severe subgroup being statistically significant (p < 0.01). Overall incidence of adverse events was lower with indacaterol than with placebo across both subgroups. CONCLUSIONS: Indacaterol demonstrated clinically relevant improvements versus placebo in lung function, dyspnea and health status in Asian COPD patients irrespective of disease severity. CLINICAL TRIALS IDENTIFIER: NCT00794157. PMID- 23040787 TI - Analysis of sub-bandage pressure of compression bandages during exercise. AB - The sub-bandage pressure produced by any compression bandaging system is likely to vary during the physical activities taken by the patient. It is of significant importance to understand the variation of sub-bandage pressure during the exercise of calf muscle pump. The present paper aims to analyse the dominating factors and their interactions on the sub-bandage pressure during exercise. In this work the circumferential change of the leg because of the exercise of the calf muscle pump (expansion or contraction) is simulated using expansion or contraction actions of an air bladder placed on a mannequin. The study has been carried out using an indigenously developed prototype by pumping or squeezing of air in air bladder using cylinder-piston arrangement. A series of commercially available bandages were studied and the impact of the major factors, namely bandage extensibility (E), bandage tension (T) and the amount of bladder expansion or contraction (A) on the sub-bandage pressure during one cycle of expansion or contraction of air bladder have been analysed. Different levels of the factors have been chosen and a complete factorial design was prepared to obtain the sub-bandage pressure at all combination of the levels of the factors. The results showed that the sub-bandage pressure variations were higher for short stretch bandage under dynamic mode (p value < 0.05). The variation in sub-bandage pressure were increased by increasing the amount of expansion or contraction of the air bladder and also increased when the bandage was wrapped at higher tension level (p-value < 0.05). N-way ANOVA results showed that some of the interactions effects of these above factors (EA and AT) also significantly affecting the sub bandage pressure variations (p-value < 0.05). The prototype provides a simpler method to assess the bandage behaviour under different conditions without doing in vivo sub-bandage pressure measurement, and hence could be used to evaluate and compare the effectiveness of different compression bandage under different conditions, prior to their application on the wounded leg. PMID- 23040788 TI - The search for the holy grail: doing more with less. PMID- 23040789 TI - Feeding biomechanics and theoretical calculations of bite force in bull sharks (Carcharhinus leucas) during ontogeny. AB - Evaluations of bite force, either measured directly or calculated theoretically, have been used to investigate the maximum feeding performance of a wide variety of vertebrates. However, bite force studies of fishes have focused primarily on small species due to the intractable nature of large apex predators. More massive muscles can generate higher forces and many of these fishes attain immense sizes; it is unclear how much of their biting performance is driven purely by dramatic ontogenetic increases in body size versus size-specific selection for enhanced feeding performance. In this study, we investigated biting performance and feeding biomechanics of immature and mature individuals from an ontogenetic series of an apex predator, the bull shark, Carcharhinus leucas (73-285cm total length). Theoretical bite force ranged from 36 to 2128N at the most anterior bite point, and 170 to 5914N at the most posterior bite point over the ontogenetic series. Scaling patterns differed among the two age groups investigated; immature bull shark bite force scaled with positive allometry, whereas adult bite force scaled isometrically. When the bite force of C. leucas was compared to those of 12 other cartilaginous fishes, bull sharks presented the highest mass-specific bite force, greater than that of the white shark or the great hammerhead shark. A phylogenetic independent contrast analysis of anatomical and dietary variables as determinants of bite force in these 13 species indicated that the evolution of large adult bite forces in cartilaginous fishes is linked predominantly to the evolution of large body size. Multiple regressions based on mass-specific standardized contrasts suggest that the evolution of high bite forces in Chondrichthyes is further correlated with hypertrophication of the jaw adductors, increased leverage for anterior biting, and widening of the head. Lastly, we discuss the ecological significance of positive allometry in bite force as a possible "performance gain" early in the life history of C. leucas. PMID- 23040790 TI - [Medication errors in anesthesia: a Moroccan university hospitals survey]. AB - INTRODUCTION: Medication errors are a major public health problem because of their morbidity and financial costs. In anesthesia, few articles publications, mostly retrospective, have assessed its incidence and outcomes. By our prospective study, we intend to identify and describe the drug errors in anesthesia in four university hospitals in Morocco. MATERIAL AND METHODS: After approval of our ethics committee, a prospective study was conducted in nine hospitals affiliated to four university hospitals (Rabat, Casablanca, Fes and Marrakech) from October 2009 to June 2010. Data collection was carried out by an anesthesiologist at each hospital who was designated by the investigator. Informations were based on practitioner's statements. Medication errors were divided into distinct categories: substitution errors, omission errors, errors of the way of administration, dosage and dilution errors. The consequences were classified into four levels according to their severity. RESULTS: During the study period, 9199 anesthetic procedures were reported (mean response of 36%). General anesthesia was performed in 75% of patients. Sixteen cases of drug errors were reported (an incidence of 1/575 with 1/405 in a pediatric setting). The drugs involved were dominated by hypnotics (six cases/16) and morphine (four cases/16). Medication errors were mainly due to labeling mistakes (seven cases/16) and to attention deficit due to fatigue and stress (seven other cases) leading to substitution error in most of cases (10 cases/16. Errors were mainly made by the less experienced practitioners (14 cases/16). They occurred during the induction phase (seven cases/16) as well as during the interview process (nine cases/16), and also during emergent surgeries (seven errors/16) as well as during elective ones (nine errors/16). No errors caused death. Pulmonary edema (recognized as a grade III severity incident) was secondary to inappropriate administration of adrenaline. CONCLUSION: Our study helped us to set recommendations, which are approved by the Moroccan pharmacovigilance center, and in accordance with the international committees to prevent the occurrence of medication errors in our daily anesthetic practice. PMID- 23040791 TI - Anesthesia and postoperative analgesia after percutaneous hallux valgus repair in ambulatory patients. AB - BACKGROUND: Postoperative pain is often severe after hallux valgus repair. Sciatic nerve blocks with long-acting local anesthetics have been recommended for surgical anesthesia and postoperative analgesia. However, a novel percutaneous approach may require less analgesia and make the procedure suitable for ambulatory care. We thus tested the hypothesis that mid-foot block and sciatic nerve blocks provide comparable surgical anesthesia and postoperative analgesia, but that patients ambulate independently sooner after mid-foot block. STUDY DESIGN: Prospective, randomized study. METHODS: Forty patients scheduled for ambulatory percutaneous hallux valgus repair were randomly assigned to two anesthesia and analgesia blocks: foot infiltration achieved by a mild foot block, or sciatic nerve block (30mL of 7.5% ropivacaine for each block). Surgery was performed without sedation or additional analgesia. Both groups were given oral paracetamol/codeine and ketoprofene systematically; tramadol was added if necessary. Walking ability and pain scores were assessed for 48 postoperative hours. RESULTS: Demographic and morphometric characteristics, and duration of surgery were similar in each group. Pain scores were comparable and low in each group at rest and while walking. The time to ambulation without assistance was significantly less for patients in the infiltration group (3.8+/-1.4hours) than patients in the sciatic group (19.2+/-9.5hours; P<0.0001). CONCLUSION: After percutaneous hallux valgus repair, mid-foot block and sciatic nerve block provided comparable postoperative analgesia. However, mid-foot block seems preferable since the time to ambulation without assistance is much reduced. PMID- 23040792 TI - Vaginal bleeding leading to incidental diagnosis of ovarian torsion in an infant with 21 hydroxylase deficiency congenital adrenal hyperplasia. PMID- 23040793 TI - Random luteinizing hormone often remains pubertal in children treated with the histrelin implant for central precocious puberty. AB - OBJECTIVE: To investigate the use of random ultrasensitive (US) luteinizing hormone (LH) levels to monitor children being treated with a histrelin implant for central precocious puberty (CPP). STUDY DESIGN: This was a prospective, uncontrolled, observational study at a pediatric endocrinology tertiary center. Thirty-three children (26 girls; mean age 7.2 +/- 2.5 years) treated with a histrelin implant for CPP were enrolled. A random US LH measurement was obtained at 6 months, and a gonadotropin-releasing hormone analog stimulation test was performed at 12 months. Clinic visits occurred at baseline and at 6-month intervals. RESULTS: In 59% of the patients (17 of 29), the 6-month random US LH exceeded the prepubertal range of <=0.3 IU/L. In contrast, gonadotropin-releasing hormone analog stimulation tests revealed complete hypothalamic-pituitary-gonadal axis suppression (peak LH <4 IU/L) in all 31 patients who underwent testing. US LH levels were highly correlated with peak stimulated LH levels. The mean peak stimulated LH level was higher in patients with a pubertal random LH than in those with a prepubertal random LH (1.2 +/- 0.5 IU/L vs 0.5 +/- 0.1 IU/L; P < .01). No patient had clinical evidence of pubertal progression. CONCLUSION: The random US LH level does not revert to a prepubertal range in more than one-half of patients with a histrelin implant and documented hypothalamic-pituitary gonadal axis suppression. Long-term studies are needed to elucidate the optimal strategy for monitoring treatment in children with CPP. PMID- 23040794 TI - Prevalence and clinical correlates of explosive outbursts in Tourette syndrome. AB - The aim of this study was to examine the prevalence and clinical correlates of explosive outbursts in two large samples of individuals with Tourette syndrome (TS), including one collected primarily from non-clinical sources. Participants included 218 TS-affected individuals who were part of a genetic study (N=104 from Costa Rica (CR) and N=114 from the US). The relationships between explosive outbursts and comorbid attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), tic severity, and prenatal and perinatal complications were examined using regression analyses. Twenty percent of participants had explosive outbursts, with no significant differences in prevalence between the CR (non-clinical) and the US (primarily clinical) samples. In the overall sample, ADHD, greater tic severity, and lower age of tic onset were strongly associated with explosive outbursts. ADHD, prenatal exposure to tobacco, and male gender were significantly associated with explosive outbursts in the US sample. Lower age of onset and greater severity of tics were significantly associated with explosive outbursts in the CR sample. This study confirms previous studies that suggest that clinically significant explosive outbursts are common in TS and associated with ADHD and tic severity. An additional potential risk factor, prenatal exposure to tobacco, was also identified. PMID- 23040795 TI - Posttraumatic stress and depression symptoms as correlates of deliberate self harm among community women experiencing intimate partnerviolence. AB - Deliberate self-harm (DSH) among women in the general population is correlated separately with posttraumatic stress, depression, and abuse during childhood and adulthood. The prevalence of these DSH correlates is particularly high among women exposed to intimate partner violence (IPV), yet few studies have examined DSH among this high-risk population and none have examined these correlates simultaneously. Two hundred and twelve IPV-victimized women in the community participated in a 2-h retrospective interview. One-third reported current or past DSH. Discriminant analysis was used to examine which posttraumatic stress and depression symptoms and types of current IPV and childhood abuse were uniquely associated with current DSH. Findings show that women who currently use DSH reported greater severity of posttraumatic stress numbing symptoms and more severe sexual IPV compared to women who used DSH only in the past. Examining factors that are associated with women's current DSH in this population is critical so that a focus on DSH can be integrated into the treatment plans of women who are receiving mental health care, but also so that women who are not receiving such care can be referred to adequate mental health services. PMID- 23040796 TI - Severely impaired health status at diagnosis of Pompe disease: a cross-sectional analysis to explore the potential utility of neonatal screening. AB - Since the introduction of enzyme replacement therapy for Pompe disease, awareness and early diagnosis have gained importance. Because the therapy is most effective when started early and methods for dried bloodspot screening for Pompe disease are currently being explored, neonatal screening is getting increased attention. The objective of this study was to investigate the gains that might be achieved with earlier diagnosis by neonatal screening. For this purpose we analyzed the health and functional status of non-screened patients with Pompe disease at the time of diagnosis. Previously collected clinical data and results of an international patient-reported questionnaire were used. Cross-sectional data of 53 patients with Pompe disease diagnosed between 1999 and 2009 (aged 0-64 years) were analyzed. According to the World Health Organization's International Classification of Functioning, Disability and Health the following domains are described: body function, activity, participation and contextual factors. In all patients with classic infantile Pompe disease cardiac function, hearing, muscle strength and motor development were considerably impaired at the time of clinical diagnosis. The use of oxygen and/or nasogastric tube-feeding was reported in more than 70% of these cases. Most children, adolescents and adults had advanced muscle weakness and impaired respiratory function at the time of their diagnosis, causing varying degrees of handicap. About 12% of them used a walking device and/or respiratory support at the time of diagnosis. The severely impaired health status reported here provides a strong argument for earlier diagnosis and to further explore the potential of neonatal screening for Pompe disease. PMID- 23040798 TI - The childbearing concerns and related information needs and preferences of women of reproductive age with a chronic, noncommunicable health condition: a systematic review. AB - BACKGROUND: Certain chronic health conditions and their treatments may compromise women's fertility; some chronic conditions are more likely to affect women of reproductive age than others, and some are heritable. All have implications for women's future childbearing and fertility management. OBJECTIVE: The aim of this systematic review was to identify the concerns about childbearing and related information needs and preferences of women with a chronic, noncommunicable health condition. METHOD: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses procedure. Relevant social science and medical science databases (Ovid MEDLINE, ProQuest, and CINAHL plus) were searched for peer-reviewed, English-language papers published from 1995 to August 2012 of empirical research using quantitative or qualitative methods. RESULTS: Of the 5,350 articles identified, 29 met inclusion criteria and were reviewed. Despite variation in methods, the studies demonstrated consistently that women with a chronic health condition are concerned about childbearing and have questions about the reproductive implications of their condition. The evidence suggests that there is less consistency about women's preferences for the mode and timing of information about the effect of the condition and its treatment on childbearing. Most research to date has focused on the needs and experiences of women with cancer; there is almost none about other noncommunicable conditions. CONCLUSION: There are serious evidence gaps about the childbearing concerns and related information needs and preferences of women with chronic, noncommunicable health conditions. Research is required to address these gaps and to inform the development of appropriate tools to assist women in this situation with their childbearing decisions. PMID- 23040797 TI - The BASIL survival prediction model in patients with peripheral arterial disease undergoing revascularization in a university hospital setting and comparison with the FINNVASC and modified PREVENT scores. AB - BACKGROUND: Critical limb ischemia carries a significant risk of morbidity and mortality. The development of scores to predict risk can aid clinical decision making. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial investigators developed a model to predict death, which has not been previously validated. METHODS: Data were collected in a prospectively maintained database on all patients who underwent angioplasty or arterial bypass for peripheral artery disease in a university hospital between January 2008 and June 2010. The main outcome measures were all-cause mortality and amputation-free survival at 3, 6, 12, and 24 months after the index intervention. The BASIL survival predictor, Finland National Vascular (FINNVASC) registry, and Edifoligide for the Prevention of Infrainguinal Vein Graft Failure (PREVENT) models were applied and receiver-operating characteristic (ROC) curve analysis was used to evaluate their predictive power. RESULTS: Data on 342 patients were collected. Patients with isolated iliac disease or claudication were excluded. The 6-, 12-, and 24-month all-cause mortality rates were 11.6%, 17.9%, and 26.8%, respectively. The area under the ROC curve (95% confidence interval) using the BASIL score to predict mortality at 6, 12, and 24 months was 0.700 (0.60-0.80; P<.001), 0.651 (0.56-0.74; P<.003), and 0.681 (0.59-0.74; P<.001), respectively. ROC curve analysis indicated that the performance of the BASIL score in this cohort was comparable to other validated predictive scores. CONCLUSIONS: The BASIL survival prediction model can moderately predict short-term and medium-term mortality in patients with limb ischemia and may be a useful adjunct to decision making in everyday clinical practice. PMID- 23040799 TI - The Komen-Planned parenthood controversy: bringing the politics of breast cancer advocacy to the forefront. PMID- 23040800 TI - Women's perspectives on ultrasound viewing in the abortion care context. AB - PURPOSE: In recent years, states have passed a range of regulations regarding ultrasound procedures in abortion care. Abortion rights opponents have promoted ultrasound viewing, believing that women who view their own ultrasound images are likely to be dissuaded from abortion. Abortion rights advocates, in contrast, routinely oppose these regulations, citing concerns that ultrasound viewing in the abortion context will be emotionally difficult for women. However, no empirical research has examined the effects of ultrasound viewing in unwanted pregnancies. METHODS: We conducted in-depth interviews with 20 respondents who received an ultrasound as part of their abortion care in one of two states in the American heartland. Interview transcripts were analyzed using grounded theory and a matrix technique for discussion of ultrasound viewing and regulations about ultrasound viewing. RESULTS: Respondents' accounts offer support for anti abortion claims that ultrasound viewing can dissuade women from abortion, as well as support for abortion rights claims that viewing an ultrasound can cause emotional difficulty for a woman planning to abort. Interviews point to unexpected outcomes of ultrasound viewing, including reports that viewing better enabled respondents to cope with their abortion. CONCLUSIONS: Ultrasound viewing does not have a singular effect. These data suggest that current assumptions about viewing effects are inaccurate, or at the least incomplete. We do not find support for legislating mandatory ultrasound viewing in abortion care. Questions about clinical care practices are best address in the medical context, not the legislative arena. PMID- 23040801 TI - Conducting a needs assessment for women and girls using a gender analysis framework: the Philadelphia Ujima Coalition for a Healthier Community experience. AB - INTRODUCTION: Despite a century of work toward gender equality, sex and gender disparities in health remain. Morbidity and mortality rates as well as quality of care received differ between men and women. The Philadelphia Ujima Coalition for a Healthier Community is composed of 23 academic, social service, wellness, faith based, governmental, and healthcare organizations. The coalition, funded by the U.S. Department of Health and Human Services, Office on Women's Health, used a community participatory framework to conduct a gender-informed needs assessment of priority areas for women's health. METHODS: A four-tiered approach was used: 1) Coalition members identified priority areas; 2) we analyzed data from the Southeastern Pennsylvania 2010 Household Health Survey to identify gender differences in health; 3) using a gender analysis framework, we conducted interviews with "key informant" stakeholders; and 4) we conducted a community health assessment including 160 women. We used a participatory process to rank priority areas. RESULTS: Sex and gender disparities in health outcomes and behaviors were observed. Data were used to identify gender barriers and norms that influence health practices and behaviors, defining priority areas for the health of women and girls. Effective health promotion strategies were also identified. CONCLUSIONS: A gender-integrated needs assessment of girls and women can reveal priority areas and gender-related objectives that should be included in health promotion programming for girls and women. PMID- 23040802 TI - Neuromodulation of neuronal circuits: back to the future. AB - All nervous systems are subject to neuromodulation. Neuromodulators can be delivered as local hormones, as cotransmitters in projection neurons, and through the general circulation. Because neuromodulators can transform the intrinsic firing properties of circuit neurons and alter effective synaptic strength, neuromodulatory substances reconfigure neuronal circuits, often massively altering their output. Thus, the anatomical connectome provides a minimal structure and the neuromodulatory environment constructs and specifies the functional circuits that give rise to behavior. PMID- 23040803 TI - Orphan GPCRs and neuromodulation. AB - Most G protein-coupled receptors (GPCRs) started as orphan GPCRs. Matching them to known neuromodulators led to the elucidation of the broad diversity of the neuroreceptor families. Moreover, orphan GPCRs have also been used as targets to discover novel neuromodulators. These discoveries have had profound impact on our understanding of brain function. Here, I present an overview of how some of the novel neuropeptides have enlarged our comprehension of responses that direct sleep/wakefulness, the onset of obesity and the feeding response. I also discuss other advances gained from orphan GPCR studies such as the concept of specificity in neuromodulation or of receptors acting as sensors instead of synaptic transmitters. Finally, I suggest that the recently discovered neuromodulators may hold the keys to our understanding of higher brain functions and psychiatric disorders. PMID- 23040804 TI - Modulating neuromodulation by receptor membrane traffic in the endocytic pathway. AB - Cellular responsiveness to many neuromodulators is controlled by endocytosis of the transmembrane receptors that transduce their effects. Endocytic membrane trafficking of particular neuromodulator receptors exhibits remarkable diversity and specificity, determined largely by molecular sorting operations that guide receptors at trafficking branchpoints after endocytosis. In this Review, we discuss recent progress in elucidating mechanisms mediating the molecular sorting of neuromodulator receptors in the endocytic pathway. There is emerging evidence that endocytic trafficking of neuromodulator receptors, in addition to influencing longer-term cellular responsiveness under conditions of prolonged or repeated activation, may also affect the acute response. Physiological and pathological consequences of defined receptor trafficking events are only now being elucidated, but it is already apparent that endocytosis of neuromodulator receptors has a significant impact on the actions of therapeutic drugs. The present data also suggest, conversely, that mechanisms of receptor endocytosis and molecular sorting may themselves represent promising targets for therapeutic manipulation. PMID- 23040805 TI - Dopaminergic modulation of synaptic transmission in cortex and striatum. AB - Among the many neuromodulators used by the mammalian brain to regulate circuit function and plasticity, dopamine (DA) stands out as one of the most behaviorally powerful. Perturbations of DA signaling are implicated in the pathogenesis or exploited in the treatment of many neuropsychiatric diseases, including Parkinson's disease (PD), addiction, schizophrenia, obsessive compulsive disorder, and Tourette's syndrome. Although the precise mechanisms employed by DA to exert its control over behavior are not fully understood, DA is known to regulate many electrical and biochemical aspects of neuronal function including excitability, synaptic transmission, integration and plasticity, protein trafficking, and gene transcription. In this Review, we discuss the actions of DA on ionic and synaptic signaling in neurons of the prefrontal cortex and striatum, brain areas in which dopaminergic dysfunction is thought to be central to disease. PMID- 23040807 TI - Endocannabinoid signaling and synaptic function. AB - Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces endocannabinoids as potent regulators of synaptic function but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought. PMID- 23040806 TI - Neuromodulation by extracellular ATP and P2X receptors in the CNS. AB - Extracellular adenosine 5' triphosphate (ATP) is a widespread cell-to-cell signaling molecule in the brain, where it activates cell surface P2X and P2Y receptors. P2X receptors define a protein family unlike other neurotransmitter gated ion channels in terms of sequence, subunit topology, assembly, and architecture. Within milliseconds of binding ATP, they catalyze the opening of a cation-selective pore. However, recent data show that P2X receptors often underlie neuromodulatory responses on slower time scales of seconds or longer. Herein, we review these findings at molecular, cellular and systems levels. We propose that, while P2X receptors are fast ligand-gated cation channels, they are most adept at mediating slow neuromodulatory functions that are more widespread and more physiologically utilized than fast ATP synaptic transmission in the CNS. PMID- 23040808 TI - Peptide neuromodulation in invertebrate model systems. AB - Neuropeptides modulate neural circuits controlling adaptive animal behaviors and physiological processes, such as feeding/metabolism, reproductive behaviors, circadian rhythms, central pattern generation, and sensorimotor integration. Invertebrate model systems have enabled detailed experimental analysis using combined genetic, behavioral, and physiological approaches. Here we review selected examples of neuropeptide modulation in crustaceans, mollusks, insects, and nematodes, with a particular emphasis on the genetic model organisms Drosophila melanogaster and Caenorhabditis elegans, where remarkable progress has been made. On the basis of this survey, we provide several integrating conceptual principles for understanding how neuropeptides modulate circuit function, and also propose that continued progress in this area requires increased emphasis on the development of richer, more sophisticated behavioral paradigms. PMID- 23040811 TI - Orienting and reorienting: the locus coeruleus mediates cognition through arousal. AB - Mood, motivation, attention, and arousal are behavioral states having a profound impact on cognition. Behavioral states are mediated though the peripheral nervous system and neuromodulatory systems in the brainstem. The noradrenergic nucleus locus coeruleus is activated in parallel with the autonomic system in response to biological imperatives. These responses can be spontaneous, to unexpected salient or threatening stimuli, or they can be conditioned responses to awaited behaviorally relevant stimuli. Noradrenaline, released in forebrain structures, will facilitate sensory processing, enhance cognitive flexibility and executive function in the frontal cortex, and promote offline memory consolidation in limbic structures. Central activation of neuromodulatory neurons and peripheral arousal, together, prepare the organism for a reorientation or reset of cortical networks and an adaptive behavioral response. PMID- 23040812 TI - Neuromodulation by oxytocin and vasopressin. AB - Oxytocin (OT) and vasopressin (VP) are two closely related neuropeptides, widely known for their peripheral hormonal effects. Specific receptors have also been found in the brain, where their neuromodulatory actions have meanwhile been described in a large number of regions. Recently, it has become possible to study their endogenous neuropeptide release with the help of OT/VP promoter-driven expression of fluorescent proteins and light-activated ion channels. In this review, I summarize the neuromodulatory effects of OT and VP in different brain regions by grouping these into different behavioral systems, highlighting their concerted, and at times opposite, effects on different aspects of behavior. PMID- 23040809 TI - Neuropeptide transmission in brain circuits. AB - Neuropeptides are found in many mammalian CNS neurons where they play key roles in modulating neuronal activity. In contrast to amino acid transmitter release at the synapse, neuropeptide release is not restricted to the synaptic specialization, and after release, a neuropeptide may diffuse some distance to exert its action through a G protein-coupled receptor. Some neuropeptides such as hypocretin/orexin are synthesized only in single regions of the brain, and the neurons releasing these peptides probably have similar functional roles. Other peptides such as neuropeptide Y (NPY) are synthesized throughout the brain, and neurons that synthesize the peptide in one region have no anatomical or functional connection with NPY neurons in other brain regions. Here, I review converging data revealing a complex interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation. PMID- 23040814 TI - Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. AB - Serotonin (5-HT) shapes brain networks during development and modulates a wide spectrum of essential neuronal functions ranging from perception and cognitive appraisal to emotional responses in the mature brain. Deficits in 5-HT-moderated synaptic signaling fundamentally impact the pathophysiology and long-term outcome of neurodevelopmental disorders. Our understanding of how 5-HT-dependent modulation of circuit configuration influences social cognition and emotional learning has been enhanced by recent insight into the molecular and cellular mechanisms of synapse formation and plasticity. In this review, we discuss emerging concepts as to how defects in synaptic plasticity impact our biosocial brain and how recent findings regarding 5-HT's role in brain development and function provide insight into the cellular and physiological basis of neurodevelopmental disorders. PMID- 23040810 TI - Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. AB - Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors. PMID- 23040813 TI - The fibroblast growth factor family: neuromodulation of affective behavior. AB - In this review, we propose a broader view of the role of the fibroblast growth factor (FGF) family in modulating brain function. We suggest that some of the FGF ligands together with the FGF receptors are altered in individuals with affective disorder and modulate emotionality in animal models. Thus, we propose that members of the FGF family may be genetic predisposing factors for anxiety, depression, or substance abuse; that they play a key organizing role during early development but continue to play a central role in neuroplasticity in adulthood; and that they work not only over extended time frames, but also via rapid signaling mechanisms, allowing them to exert an "on-line" influence on behavior. Therefore, the FGF family appears to be a prototype of "switch genes" that are endowed with organizational and modulatory properties across the lifespan, and that may represent molecular candidates as biomarkers and treatment targets for affective and addictive disorders. PMID- 23040818 TI - Twenty-five lessons from computational neuromodulation. AB - Neural processing faces three rather different, and perniciously tied, communication problems. First, computation is radically distributed, yet point-to point interconnections are limited. Second, the bulk of these connections are semantically uniform, lacking differentiation at their targets that could tag particular sorts of information. Third, the brain's structure is relatively fixed, and yet different sorts of input, forms of processing, and rules for determining the output are appropriate under different, and possibly rapidly changing, conditions. Neuromodulators address these problems by their multifarious and broad distribution, by enjoying specialized receptor types in partially specific anatomical arrangements, and by their ability to mold the activity and sensitivity of neurons and the strength and plasticity of their synapses. Here, I offer a computationally focused review of algorithmic and implementational motifs associated with neuromodulators, using decision making in the face of uncertainty as a running example. PMID- 23040815 TI - Stress-related neuropeptides and addictive behaviors: beyond the usual suspects. AB - Addictive disorders are chronic, relapsing conditions that cause extensive disease burden. Genetic factors partly account for susceptibility to addiction, but environmental factors such as stressful experiences and prolonged exposure of the brain to addictive drugs promote its development. Progression to addiction involves neuroadaptations within neurocircuitry that mediates stress responses and is influenced by several peptidergic neuromodulators. While corticotrophin releasing factor is the prototypic member of this class, recent work has identified several additional stress-related neuropeptides that play an important role in regulation of drug intake and relapse, including the urocortins, nociceptin, substance P, and neuropeptide S. Here, we review this emerging literature, discussing to what extent the properties of these neuromodulators are shared or distinct and considering their potential as drug targets. PMID- 23040819 TI - [Fever as the presenting manifestation of colon cancer: a case series of 11 patients]. AB - INTRODUCTION: Fever happens frequently in colon cancer but it is rarely the presenting manifestation. PATIENTS AND METHODS: We report a case series of patients with colon cancer revealed by fever in the three military hospitals in Paris. RESULTS: Of the 11 patients studied, seven were men and four were women, and their mean age was 70 years. Cancer was localized in the sigmoid colon (n=6), left colon (n=3) and right colon (n=2). Cancer staging (UICC TNM classification 2002) was respectively pTis (n=1), I (n=4), II (n=3) and III (n=3). Fever was the only reason for admission and two patients had a recurrent fever of unknown origin. All patients but one had bacterial infection. Blood cultures grew up in six cases, Escherichia coli (n=3), Streptococcus gallolyticus (ex bovis) (n=2) and anaerobic bacteria (n=1). There was one case of infective endocarditis caused by S. gallolyticus. Imaging showed a liver abscess (n=3) and a colon cancer complicated by an abscess (n=3). In seven patients, a familial history of colon cancer and symptoms of underlying colic disease were present (neglected rectal bleeding, iron deficiency anaemia, clinical evidence of an abdominal mass). CONCLUSIONS: Fever may reveal colon cancer at an early stage. Its main cause is a bacterial infection, such as bacteremia or abscess. Fever of unknown origin is a rare presentation. Detailed history, careful clinical examination and analysis of imaging contribute to recommend the prescription of colonoscopy. PMID- 23040820 TI - Remodeling the nuclear membrane during closed mitosis. AB - The mitotic spindle assembly and chromosome segregation in eukaryotes must be coordinated with the nuclear envelope (NE) remodeling. In a so-called 'open' mitosis the envelope of the mother nucleus is dismantled allowing the cytoplasmic spindle microtubules to capture the chromosomes. Alternatively, cells undergoing 'closed' mitosis assemble the intranuclear spindle and divide the nucleus without ever losing the nucleocytoplasmic compartmentalization. Here we focus on the mechanisms underlying mitotic NE dynamics in unicellular eukaryotes undergoing a closed nuclear division, paying specific attention to the emerging roles of the lipid biosynthesis machinery in this process. We argue that lessons learned in these organisms may be generally relevant to understanding the NE remodeling and the evolution of mitotic mechanisms throughout the eukaryotic domain. PMID- 23040816 TI - Neuromodulation of brain states. AB - Switches between different behavioral states of the animal are associated with prominent changes in global brain activity, between sleep and wakefulness or from inattentive to vigilant states. What mechanisms control brain states, and what are the functions of the different states? Here we summarize current understanding of the key neural circuits involved in regulating brain states, with a particular emphasis on the subcortical neuromodulatory systems. At the functional level, arousal and attention can greatly enhance sensory processing, whereas sleep and quiet wakefulness may facilitate learning and memory. Several new techniques developed over the past decade promise great advances in our understanding of the neural control and function of different brain states. PMID- 23040821 TI - Positive parental attitudes to participating in research involving newborn screened infants with CF. AB - BACKGROUND: Information regarding recruitment of infants to research studies following the diagnosis of cystic fibrosis (CF) via newborn screening (NBS) is not currently available. This study aimed to assess parental attitudes and the feasibility of recruiting and retaining both NBS infants with CF and healthy control infants to a longitudinal, observational study. METHODS: All infants underwent pulmonary function tests (PFTs) at ~3 and ~12months of age. Infants with CF had additional combined chest high resolution computed tomography (HRCT), bronchoscopy and broncho-alveolar lavage (BAL) at ~12months of age. Parental attitude questionnaires (PAQs) were administered to all parents following the ~3month PFTs and to parents of infants with CF after completion of all tests at ~12months. RESULTS: 86% (92/107) of families whose infant had CF consented to participate, of whom 92% had PFTs at ~3months of age with 99% of these having PFTs at ~12months of age. Recruitment of healthy controls was feasible but more challenging; 29% of those contacted agreed to participate; 73% of these had PFTs at ~3months of age; of whom 83% had repeated PFTs at ~12months of age. Completed PAQs were received from 71% of parents, (both of CF and healthy infants) at ~3months and from 58% parents of infants with CF at ~12months. Responses from the PAQs were generally positive, 95% of parents indicated they would recommend participation in such studies to other families. Discrepancies between responses at 3 and 12months suggested that parental understanding of what the research entailed developed during the course of the study. CONCLUSIONS: The high recruitment and retention rates for newly diagnosed CF NBS infants to this observational study are encouraging. These findings will help inform future study design both in the field of CF and other conditions diagnosed by NBS. PMID- 23040817 TI - Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. AB - This review describes unique neuromodulatory influences on working memory prefrontal cortical (PFC) circuits that coordinate cognitive strength with arousal state. Working memory arises from recurrent excitation within layer III PFC pyramidal cell NMDA circuits, which are afflicted in aging and schizophrenia. Neuromodulators rapidly and flexibly alter the efficacy of these synaptic connections, while leaving the synaptic architecture unchanged, a process called dynamic network connectivity (DNC). Increases in calcium-cAMP signaling open ion channels in long, thin spines, gating network connections. Inhibition of calcium cAMP signaling by stimulating alpha2A-adrenoceptors on spines strengthens synaptic efficacy and increases network firing, whereas optimal stimulation of dopamine D1 receptors sculpts network inputs to refine mental representation. Generalized increases in calcium-cAMP signaling during fatigue or stress disengage dlPFC recurrent circuits, reduce firing and impair top-down cognition. Impaired DNC regulation contributes to age-related cognitive decline, while genetic insults to DNC proteins are commonly linked to schizophrenia. PMID- 23040823 TI - Effect of hospital culture on blood transfusion in cardiac procedures. AB - BACKGROUND: In our effort to reduce the use of blood products in cardiac operations in a health care system, we noted variations in transfusion practices among facilities. Interestingly, surgeons practicing at the same hospital had similar transfusion rates. We sought to quantitate the contribution of hospital influence on individual surgeons' transfusion practices. METHODS: Blood transfusion data for coronary artery bypass graft operations at 12 Providence Health & Services facilities between January 2008 and June 2011 were reviewed. Frequency of perioperative blood transfusion, amount of transfusion, components transfused, and timing of transfusions were compared. Variation among surgeons at the same institution vs between institutions was computed based on multilevel mixed-effect logistic and linear regression models. Intraclass correlation coefficients were calculated. RESULTS: A total of 5,744 nonemergency first-time coronary artery bypass graft procedures were performed by 42 not-low volume (n>30 in 2.5 years) surgeons at 12 Providence Health & Services hospitals during the 3.5-year study period. Frequency, amount, timing, and blood component usage were different among facilities but relatively similar for surgeons within a facility. The variance of red blood cell transfusion rate among hospitals (.82) is more than two times that among surgeons practicing within the same hospital (.35). Thus, surgeons contribute 30% to the variation, and 70% of the total variation can be explained by the hospital effect. CONCLUSIONS: In our multihospital system, the hospital that a surgeon practices at plays a larger role in determining blood utilization than the individual surgeon's preference. PMID- 23040822 TI - Obesity increases operating room time for lobectomy in the society of thoracic surgeons database. AB - BACKGROUND: Obesity has become a major epidemic in the United States. Although research suggests obesity does not increase major morbidity or mortality after thoracic operations, it likely results in greater use of health care resources. METHODS: We examined all patients in The Society of Thoracic Surgeons General Thoracic Surgery database with primary lung cancer who underwent lobectomy from 2006 to 2010. We investigated the impact of body mass index (BMI) on total operating room time using a linear mixed-effects regression model and multiple imputations to account for missing data. Secondary outcomes included postoperative length of stay and 30-day mortality. Covariates included age, sex, race, forced expiratory volume, smoking status, Zubrod score, prior chemotherapy or radiation, steroid use, number of comorbidities, surgical approach, hospital lobectomy volume, hospital percent obesity, and the addition of mediastinoscopy or wedge resection. RESULTS: A total of 19,337 patients were included. The mean BMI was 27.3 kg/m2, with 4,898 patients (25.3%) having a BMI of 30 kg/m2 or greater. The mean total operating room time, length of stay, and 30-day mortality were 240 minutes, 6.7 days, and 1.8%, respectively. For every 10-unit increase in BMI, mean operating room time increased by 7.2 minutes (range, 4.8 to 8.4 minutes; p<0.0001). Higher hospital lobectomy volume and hospital percentage of obese patients did not affect the association between BMI and operative time. Body mass index was not associated with 30-day mortality or increased length of stay. CONCLUSIONS: Increased BMI is associated with increased total operating room time, regardless of institutional experience with obese patients. PMID- 23040824 TI - Total arch replacement in patients with aortic dissection with an isolated left vertebral artery. AB - BACKGROUND: The presence of an isolated left vertebral artery requires changes in the aortic arch reconstruction techniques and cerebral protection methods in patients with total arch replacement. The best method for surgical repair of the isolated left vertebral artery is controversial. We retrospectively reviewed our experience of total arch replacement in patients with aortic dissection with this vessel anomaly. METHODS: Between August 2003 and December 2008, 21 patients with aortic dissection (type A dissection, n = 20; type B dissection, n = 1) with an isolated left vertebral artery underwent total arch replacement under hypothermic cardiopulmonary bypass combined with selective cerebral perfusion. Concomitant stented elephant trunk was implanted in 20 patients. RESULTS: There was no in hospital death. Injury to the spinal cord occurred in 2 patients with chronic dissection using stented elephant trunk implantation. One had weakness in the left lower extremity, and the other patient had paraparesis: both recovered during the follow-up period. One patient experienced transient neurologic deficit, and acute renal failure was observed in 1 patient: both recovered completely before hospital discharge. CONCLUSIONS: Acceptable results were obtained in patients with aortic dissection with an isolated left vertebral artery. Although there was no clear evidence that the spinal cord injury was related to the isolated left vertebral artery using stented elephant trunk implantation, the isolated left vertebral artery was constructed as soon as possible in patients with this vessel anomaly. PMID- 23040825 TI - Total arch replacement under flow monitoring during selective cerebral perfusion using a single pump. AB - BACKGROUND: Flow in individual vessels is passively determined when a single pump is used for selective cerebral perfusion during aortic arch surgery. We installed a Doppler flowmeter in the circuit and measured flow in the supraaortic vessels to determine flow distribution during selective cerebral perfusion. METHODS: We cannulated and perfused three supraaortic vessels using a single pump in 203 patients who underwent elective (n = 158) or emergency or urgent (n = 45) total arch replacement using a four-branched prosthetic graft. Flow rates in each branch were continuously monitored during selective cerebral perfusion. RESULTS: The respective mean flow rates in the brachiocephalic, left common carotid, and left subclavian arteries and total flow rates were 5.8, 3.3, 3.4, and 12.5 mL.kg( 1).min(-1). The ratios of flow in these vessels to total flow were 46.5%, 26.5%, and 27.0%, respectively, and they were not affected by the total flow rate. In hospital mortality rates among the patients who underwent elective and emergency or urgent surgery were 1.9% (n = 3) and 11.1% (n = 5), respectively, and the rates of postoperative stroke were 2.5% (n = 4) and 8.9% (n = 4), respectively. Total flow in the supraaortic vessels during selective cerebral perfusion was significantly lower in patients with neurologic complications than in those without (732 versus 806 mL/min; p = 0.034). CONCLUSIONS: Flow monitoring showed that selective perfusion using a single pump adequately distributed flow among all supraaortic vessels. This monitoring system might help to improve brain protection and outcomes during total aortic arch replacement. PMID- 23040826 TI - Major infection after pediatric cardiac surgery: external validation of risk estimation model. AB - BACKGROUND: A multivariable risk estimation model, in which the primary outcome was major infection, was recently developed and published using The Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database. We have applied this risk estimation model to our congenital heart surgery program over a 16-year time interval to validate this risk estimation model and verify its specific risk factors for major infection. METHODS: Using complete and verified data, we selected patients in whom major procedures had been classified using both Aristotle Basic Score and Risk Adjustment for Congenital Heart Surgery (RACHS-1) and created a multivariable model in which primary outcome was major infection (septicemia, mediastinitis, or endocarditis). We checked the STS risk estimation model for major infection. We also assessed the significance of the STS risk factors in our program. RESULTS: A total of 6,314 patients were analyzed. We identified 197 (3.1%) major infections (septicemia 3%, endocarditis 0.015%, mediastinitis 0.09%). Hospital mortality, ventilation time, and length of stay were greater in patients with major infections. The following preoperative risk factors identified by the STS risk estimation model were significant in multivariate analysis in our patients: young age, high complexity, medium complexity, previous operation, and preoperative ventilation (p<0.0001). Estimated infection risk ranged from 0.32% to 11.58%. The model discrimination was good (c index, 0.808). Risks of infections after most common congenital heart surgery procedures were similar in both studies (rs=0.952, p=0.0003). CONCLUSIONS: Our external validation study confirmed that the STS model can be used as a preoperative risk stratification tool for major infection risk at the single institutional level. PMID- 23040827 TI - beta-Blockers improve survival of patients with chronic obstructive pulmonary disease after coronary artery bypass grafting. AB - BACKGROUND: beta-Blockers are known to improve survival of patients with cardiovascular disease, but their administration in patients with chronic obstructive pulmonary disease (COPD) remains controversial. The aim of the present study was to assess the effect of beta-blocker administration in patients with COPD undergoing coronary artery bypass grafting. METHODS: A total of 388 consecutive patients with COPD who underwent isolated coronary artery bypass grafting were studied, and clinical follow-up was completed. Diagnosis of COPD was based on preoperative forced expiration volume; exacerbation episodes were defined as a pulsed-dose prescription of prednisolone or a hospital admission for an exacerbation. Two propensity-matched cohorts of 104 patients each either receiving or not receiving beta-blockers were identified. RESULTS: At baseline, there was no significant difference among groups. After a median follow-up of 36 months, there were 8 deaths in 104 patients (7.7%) receiving beta-blockers versus 19 deaths in 104 patients (18.3%) who did not receive beta-blockers (p = 0.03). Kaplan-Meyer analysis showed a survival of 91.8% +/- 2.8% for patients taking beta-blockers versus 80.6% +/- 4.0% for control subjects (chi(2), 29.4; p = 0.003; hazard ratio, 0.38). In addition, beta-blocker administration did not increase rates of COPD exacerbation, which was experienced by 46 of 104 patients (44.2%) receiving beta-blockers versus 45 of 104 patients (43.3%) not receiving beta-blockers (p = 0.99). CONCLUSIONS: This study showed that in patients with COPD undergoing coronary artery bypass grafting the administration of beta blockers is safe and significantly improves survival at mid-term follow-up. Further randomized studies are needed to confirm these findings. PMID- 23040828 TI - Outcome of septal myectomy for obstructive hypertrophic cardiomyopathy in children and young adults. AB - BACKGROUND: Obstructive hypertrophic cardiomyopathy (HCM) is an important cause of heart failure in children, but there are limited data addressing outcome of myectomy in children. Our objective was to evaluate the early and late results of septal myectomy in pediatric HCM. METHODS: We reviewed 127 consecutive patients (62% male) who underwent transaortic septal myectomy for obstructive HCM from January 1975 to December 2010 at 21 or less years of age. Mean age at operation was 12.9 +/- 5.5 years. Preoperatively, mean maximum instantaneous gradient was 89 mm Hg and 95% had significant systolic anterior motion (SAM) with mitral regurgitation (MR). Implantable cardioverter defibrillator (ICD) and permanent pacemaker prior to surgery was present in 21 patients (17%) and 15 (11.7%), respectively. RESULTS: Transaortic extended left ventricular septal myectomy was performed in all patients with no early deaths. Iatrogenic morbidity included new aortic valve regurgitation requiring repair in 7 (5.5%), mitral regurgitation needing repair in 2 (1.5%), ventricular septal defect in 1 (1%), and heart block requiring permanent pacemaker in 1 (1%). An ICD was implanted postoperatively in 8 during the same hospital admission. Mean MIG decreased from 89 to 6 mm Hg (p < 0.0001). Postoperatively, residual chordal SAM was present in 23% with mild or no MR; moderate MR was detected in 1 patient. Four patients (3%) died late during the mean follow-up period of 8.3 years (maximum, 37 years); 1 death was sudden. Overall survival was 98.6%, 94.9%, 92.4%, and 92.4% at 5, 10, 15, and 20 years, respectively. Freedom from any cardiac reoperation was 91.2%, 87.8%, 78.7%, and 72.7% at 5, 10, 15, and 20 years, respectively. Repeat septal myectomy was performed in 6 patients (5%). At late follow-up, 95% were in New York Heart Association functional class I or II and 25 patients underwent late ICD placement. CONCLUSIONS: Septal myectomy is safe and effective in children with obstructive HCM, but limited exposure may increase risk of aortic or mitral valve injury. Late survival is better than the previously published untreated natural history of HCM. Patient selection and surgical expertise remain critical components of septal myectomy, especially before considering a prophylactic myectomy in a seemingly asymptomatic patient. PMID- 23040829 TI - Finite element static displacement optimization of 20-100 kHz flexural transducers for fully portable ultrasound applicator. AB - This paper focuses on the development of a finite-element model and subsequent stationary analysis performed to optimize individual flexural piezoelectric elements for operation in the frequency range of 20-100kHz. These elements form the basic building blocks of a viable, un-tethered, and portable ultrasound applicator that can produce intensities on the order of 100mW/cm(2) spatial-peak temporal-peak (I(SPTP)) with minimum (on the order of 15V) excitation voltage. The ultrasound applicator can be constructed with different numbers of individual transducer elements and different geometries such that its footprint or active area is adjustable. The primary motivation behind this research was to develop a tether-free, battery operated, fully portable ultrasound applicator for therapeutic applications such as wound healing and non-invasive transdermal delivery of both naked and encapsulated drugs. It is shown that careful selection of the components determining applicator architecture allows the displacement amplitude to be maximized for a specific frequency of operation. The work described here used the finite-element analysis software COMSOL to identify the geometry and material properties that permit the applicator's design to be optimized. By minimizing the excitation voltage required to achieve the desired output (100mW/cm(2)I(SPTP)) the power source (rechargeable Li-Polymer batteries) size may be reduced permitting both the electronics and ultrasound applicator to fit in a wearable housing. PMID- 23040830 TI - Effects of ezetimibe added to statin therapy on markers of cholesterol absorption and synthesis and LDL-C lowering in hyperlipidemic patients. AB - OBJECTIVE: Statins inhibit cholesterol synthesis but can upregulate cholesterol absorption, with higher doses producing larger effects. Ezetimibe inhibits cholesterol absorption but also upregulates synthesis. We tested whether ezetimibe added to on-going statin therapy would be most effective in lowering LDL-cholesterol (LDL-C) in subjects on high-potency statins and whether these effects would be related to alterations in cholesterol absorption (beta sitosterol) and synthesis (lathosterol) markers. METHODS: Hypercholesterolemic subjects (n = 874) on statins received ezetimibe 10 mg/day. Plasma lipids, lathosterol, and beta-sitosterol were measured at baseline and on treatment. Subjects were divided into low- (n = 133), medium- (n = 582), and high- (n = 159) statin potency groups defined by predicted LDL-C-lowering effects of each ongoing statin type and dose (reductions of ~20-30%, ~31-45%, or ~46-55%, respectively). RESULTS: The high-potency group had significantly lower baseline lathosterol (1.93 vs. 2.58 vs. 3.17 MUmol/l; p < 0.001) and higher baseline beta-sitosterol values (6.21 vs. 4.58 vs. 4.51 MUmol/l, p < 0.001) than medium-/low-potency groups. Ezetimibe treatment in the high-potency group produced significantly greater reductions from baseline in LDL-C than medium-/low-potency groups (-29.1% vs. -25.0% vs. -22.7%; p < 0.001) when evaluating unadjusted data. These effects and group differences were significantly (p < 0.05) related to greater beta sitosterol reductions and smaller lathosterol increases. However, LDL-C reduction differences between groups were no longer significant after controlling for placebo effects, due mainly to modest LDL-C lowering by placebo in the high potency group. CONCLUSION: Patients on high-potency statins have the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline, and the greatest reduction in absorption markers and the smallest increases in synthesis markers with ezetimibe addition. Therefore, such patients may be good candidates for ezetimibe therapy if additional LDL-C lowering is needed. PMID- 23040832 TI - Obesity paradox: differential effects on cancer and noncancer mortality in patients with type 2 diabetes mellitus. AB - OBJECTIVE: To investigate associations between body mass index (BMI) and cause specific mortality in patients with type 2 diabetes mellitus (T2DM). METHODS: Prospective follow-up of a nationally representative cohort of 89,056 Taiwanese patients with T2DM recruited since 1995. Vital status was matched with the National Death Certificate Database until the end of 2006. Self-reported body weight and height were used to calculate BMI, which was treated either as a continuous or categorical variable (underweight, <18.5; normal, 18.5-22.9; overweight, 23.0-24.9; obesity I, 25.0-29.9; and obesity II, >=30.0 kg/m(2)). Causes of death were classified as all-cause, cancer, diabetes complications (macrovascular and microvascular), and other. Cox regression was used to estimate the hazard ratios. RESULTS: A total of 26,951 patients (30.3% of the cohort) died during follow-up (cancer 5.4%, diabetes complications 17.4%, and other causes 7.5%). As a continuous variable, BMI was inversely associated with mortality from all-cause, cancer, diabetes complications, and other causes, with respective adjusted hazard ratios (95% confidence intervals) of 0.942 (0.939-0.946), 0.966 (0.958-0.975), 0.935 (0.930-0.939), and 0.942 (0.935-0.949). Compared to normal weight, underweight was significantly predictive for any of causes of death, while overweight, obesity I, and obesity II were all significantly associated with mortality in an inverse pattern. After excluding patients with a follow-up duration <2 years, most BMI categories were not significantly predictive of mortality from cancer, suggesting a potential bias of cancer-induced weight loss. CONCLUSIONS: The obesity paradox, mainly observed in noncancer mortality, exists in patients with T2DM, suggesting a survival advantage in obese diabetic patients. PMID- 23040831 TI - Adiponectin, systolic blood pressure, and alcohol consumption are associated with more aortic stiffness progression among apparently healthy men. AB - OBJECTIVE: Limited data are available about risk factors for the progression of aortic stiffness in healthy population. We examined several risk factors as possible independent predictors of aortic stiffness progression among a population-based sample of US men. METHODS: A total of 240 men (40-49 years) free of CVD at baseline from the Pittsburgh site of the ERA JUMP study were evaluated. Aortic stiffness was measured as carotid-femoral pulse wave velocity at baseline and after 4.6 +/- 0.2 (mean +/- SD) years of follow-up. Progression of aortic stiffness was evaluated as relative annual change in carotid-femoral pulse wave velocity (% change/year). Using linear regression, both baseline potential risk factors and their annual changes were evaluated as possible risk factors for aortic stiffness progression. Baseline age, follow-up time, race, heart rate, and medications use were forced in all models. RESULTS: During follow-up, relative to baseline level, aortic stiffness increased 0.3% +/- 5.3% per year. In final models, the independent predictors of degree of aortic stiffness progression were lower levels of adiponectin (P = 0.03), higher levels of systolic blood pressure (P = 0.03), greater annual change in systolic blood pressure (P = 0.04), and alcohol consumption >= 2 times/week (P = 0.02). Adiponectin levels within the third (9.8 MUg/Ml <= adiponectin < 13.0 MUg/mL) and the fourth (adiponectin >= 13.0 MUg/mL) quartiles were associated with an improvement in relative annual aortic stiffness progression (P = 0.02, P = 0.01, respectively) compared to levels within the first quartile (adiponectin <= 7.0 MUg/mL). CONCLUSION: Among apparently healthy men, lower levels of baseline adiponectin could be a novel marker for greater risk of aortic stiffness progression. Longitudinal research is required to evaluate whether adiponectin change over time would have similar association with aortic stiffness progression. PMID- 23040833 TI - Cost-utility analysis of tiotropium versus usual care in patients with COPD in the UK and Belgium. AB - OBJECTIVE: To evaluate the cost-utility of adding tiotropium to usual care versus usual care alone for patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in the UK and Belgium. METHODS: A four-state Markov model was developed with three disease severity states (moderate, severe, very severe) and death. Severity was based on post-bronchodilator FEV1 and transitions were based on outcomes of the Understanding Potential Long Term Impacts on Function with Tiotropium (UPLIFT(r)) trial. Utilities were derived from EQ-5D scores for a subset of UPLIFT(r) patients. UK costs were evaluated separately for England (E), and for Scotland, Wales and Northern Ireland (SWNI). Belgian (B) costs were obtained from local sources. Uncertainty was assessed by deterministic and probabilistic sensitivity analysis (PSA). RESULTS: Adding tiotropium to usual care resulted in an incremental cost per patient of ?969 (B), L796 (E), and L812 (SWNI), and incremental QALYs of 0.052 (B), and 0.051 (E, SWNI). The four-year incremental cost-effectiveness ratios (ICER) were ?18,617 (B), L15,567 (E) and L15,890 (SWNI) per QALY. Probability of tiotropium being cost-effective at L30,000 (?50,000) per QALY gained was greater than 60%. CONCLUSIONS: At willingness to pay thresholds of L(?) 30,000 per QALY gained, adding tiotropium to usual care is cost-effective. PMID- 23040834 TI - Long-term follow-up of patients operated with Uvulopalatopharyngoplasty from 1985 to 1991. AB - OBJECTIVES: Short-term outcome and side effects after Uvulopalatopharyngoplasty (UPPP) are well recognized. However, there is a lack of knowledge of the long term outcome and side effects after this surgery. This study was completed to investigate the outcome and side effects 20 years after UPPP for snoring and obstructive sleep apnoea. METHODS: Medical records of patients who underwent UPPP surgery for sleep apnoea and snoring between 1985 and 1991 were investigated retrospectively. A specific questionnaire focusing on the present health profile, side effects of previous UPPP surgery and present sleeping patterns of patients was mailed out. RESULTS: UPPP patients, 186 (including 11 females) were identified. Of these, 35 (19%) had passed away and 7 (4%) were not located. 129 patients (mean: age 68 years, range 43-83) of the possible 144 patients answered the questionnaire (response rate 90%). At follow-up, 41 patients (32%) used continuous positive airway pressure (CPAP). 66 of the patients (52%) were satisfied with the result of the operation, but 61 (47%) were not satisfied. 49 patients (38%) reported persistent side effects (problems with nasal regurgitation 18 (14%), swallowing 26 (20%), changed voice 15 (12%), and pain in the oral cavity 15 (12%). CONCLUSION: Almost 50% of patients operated with UPPP were not satisfied with the result of the operation after about 20 years, and one third used CPAP at follow-up. A large proportion of patients still experienced side effects, which, after this time, are likely to be permanent. PMID- 23040836 TI - Spatial rotational orientation ability in standing children with cerebral palsy. AB - This study quantified perception and reorientation ability after passive horizontal rotations in thirteen children with cerebral palsy (CP). They stood barefoot on a platform in front of a fixed reference point (static posture task, SPT) and were then blindfolded and passively rotated with six velocity profiles (maximum angular velocity: 57 degrees /s; rotation amplitudes: +/-90 degrees , +/ 180 degrees and +/-360 degrees ). After the perturbation, the blindfolded children were asked to point to the fixed reference point with their preferred hand (pointing task, PT) and to step back to the initial position on the stationary platform (reorientation task, RT). In order to gain further insight into rotational attitude, the results were comparatively examined with body segment rotations determined using standardized gait analysis (gait task, GT). The kinematic evaluations were conducted using an optoelectronic system: for SPT, PT and RT we confined the analysis, in the horizontal plane, to the head and upper pointing arm of the subject and to the platform; for GT a full body analysis was performed. When CP children were passively rotated towards their more affected side, they overestimated the imposed angle in PT but under reproduced it in RT. A higher variability emerged in left-hemiplegic children, confirming that the spatial disorganization is predominantly related to right brain lesion. Patients tended to rotate in GT towards the more affected side while in RT they showed an opposite trend. PMID- 23040835 TI - [Benefits of flexible visitation in the intensive care units for the family of critical patients]. AB - AIM: To identify, analyze and summarize the main effects that may be related to flexible visitation policies for the relatives of critically ill adults. METHOD: A review of the literature was conducted in the following databases: PubMed, CINAHL, PsycINFO, Cochrane Library and CUIDEN. Thematic content analysis was used to evaluate selected articles. RESULTS: Fifteen articles were included in this review. Four main themes emerged from the thematic content analysis. Themes included the main effects of flexible visitation policies for the family of the critical patients such as: improvement of satisfaction, reduction of anxiety and stress, satisfaction regarding their own family needs, and the role of the family in the patient's care. CONCLUSION: According to the existing evidence, flexible visitation policies appear to be both beneficial and decisive. It seems to be necessary to favor the participation of the family in the care of the intensive patient as well as the acquisition of a more prominent role the visitation context and in their relationship with the patient. PMID- 23040837 TI - Cost-effectiveness analysis of primary arthroscopic stabilization versus nonoperative treatment for first-time anterior glenohumeral dislocations. AB - PURPOSE: The purpose of this study was to compare the cost-effectiveness of initial observation versus surgery for first-time anterior shoulder dislocation. METHODS: The clinical scenario of first-time anterior glenohumeral dislocation was simulated using a Markov model (where variables change over time depending on previous states). Nonoperative outcomes include success (no recurrence) and recurrence; surgical outcomes include success, recurrence, and complications of infection or stiffness. Probabilities for outcomes were determined from published literature. Costs were tabulated from Medicare Current Procedural Terminology data, as well as hospital and office billing records. We performed microsimulation and probabilistic sensitivity analysis running 6 models for 1,000 patients over a period of 15 years. The 6 models tested were male versus female patients aged 15 years versus 25 years versus 35 years. RESULTS: Primary surgery was less costly and more effective for 15-year-old boys, 15-year-old girls, and 25-year-old men. For the remaining scenarios (25-year-old women and 35-year-old men and women), primary surgery was also more effective but was more costly. However, for these scenarios, primary surgery was still very cost-effective (cost per quality-adjusted life-year, <$25,000). After 1 recurrence, surgery was less costly and more effective for all scenarios. CONCLUSIONS: Primary arthroscopic stabilization is a clinically effective and cost-effective treatment for first time anterior shoulder dislocations in the cohorts studied. By use of a willingness-to-pay threshold of $25,000 per quality-adjusted life-year, surgery was more cost-effective than nonoperative treatment for the majority of patients studied in the model. LEVEL OF EVIDENCE: Level II, economic and decision analysis. PMID- 23040838 TI - beta-Adrenergic regulation of the cardiac Na+-K+ ATPase mediated by oxidative signaling. AB - Activation of beta-adrenergic receptors (ARs) elicits responses arising from protein kinase A (PKA)-mediated phosphorylation of target proteins that regulate Ca(2+)-dependent excitation-contraction coupling. Some important targets for beta AR- and PKA-dependent pathways, including the sarcolemmal Na(+)-K(+) pump, also undergo oxidative modifications in response to activation of receptor-coupled redox signaling pathways in cardiac myocytes. Here, we highlight how beta(1)- and beta(3)-AR signaling have opposing effects on functionally important oxidative modification of the Na(+)-K(+) pump molecular complex and how the addition of redox dependence to the canonical phosphorylation dependence of the scheme for beta-AR signaling in general expands its versatility but also its complexity. The expanded scheme integrates increased oxidative stress into the pathophysiological effects of adrenergic hyperactivity and provides mechanistic explanation for the efficacy of beta-AR blockers in heart failure in which raised intracellular Na(+) levels are detrimental-an explanation not provided by traditionally held views on beta-AR-mediated regulation of the pump function. PMID- 23040840 TI - Highlights in clinical autonomic neuroscience: new insights into autonomic dysfunction in autism. AB - Investigations of autonomic nervous system biomarkers in autism have been sparse relative to its prevalence. Recent studies of children with autism spectrum disorders (ASD) have increasingly drawn correlations between autonomic findings and psychosocial behavior. Studies of heart rate variability, pupil size, salivary alpha-amylase, and electrodermal responsiveness have shown that children with ASD differ from normally developing children in their autonomic responsiveness to visualizing human faces and other mental tasks. While some results have conflicted, much of the data appears to support the theory of a hypersympathetic state in autism insufficiently attenuated by vagal parasympathetic influences. To what degree these differences in autonomic physiology might influence cognitive processing and behavior rather than simply being epiphenomena of a pervasive disorder of brain development is as yet unclear. PMID- 23040841 TI - Exercise-induced hypotension in autonomic disorders. AB - The autonomic nervous system closely integrates a range of vital processes, including, cardiovascular function. Physical activity, or exercise, requires a range of integrated autonomic and cardiovascular adjustments in order to maintain homeostasis. Pathological conditions that result in dysfunction of the autonomic nervous system, such as autonomic failure, can therefore jeopardize the control of blood pressure resulting in hypotension and have serious implications for health. Exercise induced hypotension, defined as a >= 10 mmHg fall in systolic blood pressure during exercise, can be a significant symptom/event for autonomic failure, as well as other autonomic disorder, patients, including, Multiple System Atrophy and Spinal Cord Injury, and can reduce physical capacity, orthostatic tolerance, result in falls, complicate management and reduce quality of life. The likely mechanisms do not appear to be an altered cardiac output or active muscle vasodilation response to exercise, but rather, a lack of and/or a blunted increase in sympathetic nerve activity during exercise and/or excessive vasodilation in the splanchnic circulation. The severity of exercise induced hypotension seems to be higher during dynamic relative to static exercise. The possible management strategies for exercise induced hypotension include both non pharmacological, e.g., reducing risk factors, and pharmacological measures, such as sympathomimetics, but studies on other pharmacological agents are limited. PMID- 23040842 TI - Depression and the global economic crisis: is there hope? PMID- 23040843 TI - Fire without smoke: targeting smokeless tobacco use. PMID- 23040839 TI - Genetic pathways of vascular calcification. AB - Vascular calcification is an independent risk factor for cardiovascular disease. Arterial calcification of the aorta and coronary, carotid, and peripheral arteries becomes more prevalent with age. Genome-wide association studies have identified regions of the genome linked to vascular calcification, and these same regions are linked to myocardial infarction risk. The 9p21 region linked to vascular disease and inflammation also associates with vascular calcification. In addition to these common variants, rare genetic defects can serve as primary triggers of accelerated and premature calcification. Infancy-associated calcific disorders are caused by loss-of-function mutations in ENPP1, an enzyme that produces extracellular pyrophosphate. Adult-onset vascular calcification is linked to mutations in NTE5, another enzyme that regulates extracellular phosphate metabolism. Common conditions that secondarily enhance vascular calcification include atherosclerosis, metabolic dysfunction, diabetes, and impaired renal clearance. Oxidative stress and vascular inflammation, along with biophysical properties, converge with these predisposing factors to promote soft tissue mineralization. Vascular calcification is accompanied by an osteogenic profile, and this osteogenic conversion is seen within the vascular smooth muscle as well as the matrix. Here, we review the genetic causes of medial calcification in the smooth muscle layer, focusing on recent discoveries of gene mutations that regulate extracellular matrix phosphate production and the role of S100 proteins as promoters of vascular calcification. PMID- 23040844 TI - Europe and global health: looking for a leader. PMID- 23040845 TI - Time for heroes: public health leadership in the 21st century. PMID- 23040846 TI - Mental health and the 2012 US election. PMID- 23040848 TI - George Alleyne: the champ. PMID- 23040849 TI - Prediabetes and the risk of diabetes. PMID- 23040850 TI - Prediabetes and the risk of diabetes. PMID- 23040851 TI - Prediabetes and the risk of diabetes. PMID- 23040852 TI - Risk factors for non-communicable diseases in prison populations. PMID- 23040855 TI - Risk factors for non-communicable diseases in prison populations. PMID- 23040858 TI - Turbulent times in southern European science. PMID- 23040857 TI - Magnetically controlled growing rods for scoliosis in children. PMID- 23040859 TI - Magnetically controlled growing rods for scoliosis in children. PMID- 23040860 TI - The emperor's new framework for mental health in England. PMID- 23040861 TI - Sex workers and HIV: missed opportunities. PMID- 23040862 TI - Bulla in the lung. PMID- 23040863 TI - Acute angle closure glaucoma after sertraline. AB - Glaucoma is a rare complication of selective serotonin reuptake inhibitor treatment. We report a case of acute angle closure glaucoma related to sertraline. PMID- 23040865 TI - Affective set-shifting deficits in patients with major depression in remission. AB - While numerous studies have focused on neuropsychological deficits during acute depressive episodes, results have been inconsistent for patients in remission. This case-control study aimed to explore whether remitted patients show deficits in an affective shifting task that has proven sensitive to assess emotional cognitive deficits in acute depression. 69 fully remitted depressed patients were compared with 76 matched healthy subjects in their performance of a picture-based affective shifting task. Compared to healthy subjects, remitted patients show impaired go/no-go performance during shift, but not during non-shift conditions, reflecting a specific deficit in affective set-shifting. Impaired performance concerns omissions rather than false alarms or response times and is correlated with the duration of illness, but not the number of depressive episodes, time since remission or age. Our findings suggest that affective set-shifting deficits are also present during remission of depressive symptoms. These deficits may particularly concern enhanced inhibitory control and seem to develop over the course of the illness independent of acute episodes. PMID- 23040864 TI - Lasp1 is down-regulated in NMDA receptor antagonist-treated mice and implicated in human schizophrenia susceptibility. AB - Mice treated with MK-801, a non-competitive antagonist of the N-methyl-d-aspartic (NMDA) acid receptor, are important animal models for schizophrenia studies. In the present study, we compared protein expression levels in the hippocampus of mice treated with MK-801 (0.6 mg/kg) or saline once daily for 7 days. Changes in the proteome were detected by two-dimensional electrophoresis, and the six proteins exhibiting differential expression were identified by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. Down-regulation of one of these proteins, Lasp1 (LIM and SH3 protein 1), in MK-801-treated mice was confirmed by western blotting and immunohistochemical analyses. Lasp1 is a multidomain protein that may recruit signaling molecules to the actin-based cytoskeleton and is known to concentrate in synaptic sites of hippocampal neurons. We next investigated whether polymorphisms in the human LASP1 gene were associated with schizophrenia in the Korean population. A single-nucleotide polymorphism in the LASP1 gene promoter region was associated with schizophrenia susceptibility. Our results suggest that LASP1 might be associated with NMDA receptor antagonism and schizophrenia susceptibility and, thus, might be involved in the pathophysiology of schizophrenia. PMID- 23040866 TI - Apolipoprotein E mimetic is more effective than apolipoprotein A-I mimetic in reducing lesion formation in older female apo E null mice: a commentary. PMID- 23040867 TI - Serum glycated albumin predicts the progression of carotid arterial atherosclerosis. AB - INTRODUCTION: We investigated the association between the ratio of serum glycated albumin (GA) levels to hyperglycemic levels (GA/A1c ratio) and the progression of carotid artery atherosclerosis. METHODS: For this retrospective longitudinal study we recruited patients who had undergone carotid IMT measurement twice and been tested consecutively for both A1c and GA levels every 3 or 6 months. The subjects were classified into two groups based on non-progression (group I) and progression (group II) of carotid IMT. Mean values of A1c and GA and the GA/A1c ratio were compared between groups. RESULTS: Of the 218 subjects (122 men and 96 women), group II (n=77) showed significantly higher baseline systolic BP, eGFR, GA, GA/A1c ratio, and progression of carotid IMT (Delta IMT) than group I (n = 141). The mean A1c level tended to be higher in group II than in group I (p = 0.054). By Spearman's correlation test, baseline diastolic BP, total cholesterol, triglyceride, GA, and GA/A1c were significantly associated with Delta IMT in group II but not in group I. In multivariate regression analysis, serum level of GA and GA/HbA1c ratio predicted progression of IMT after adjustment for other risk factors in both models applied. CONCLUSION: We suggest that glycated albumin is not only a useful glycemic index but also might be an atherogenic protein in the development of diabetic atherosclerosis. PMID- 23040868 TI - Aortic calcification: Novel insights from familial hypercholesterolemia and potential role for the low-density lipoprotein receptor. AB - Once thought to be a passive process of calcium accrual in arterial vascular beds, vascular calcification is considered to be a tightly regulated process mediated by osteoblast-like cells under the dys-regulated interplay of shear stress, metabolites, cytokines and transcription factors. Unfortunately, without effective medical interventions to prevent or regress vascular calcification, this process directly contributes to cardiovascular morbidity and mortality. We have previously shown that patients with familial hypercholesterolemia (FH) have severe, premature aortic calcification and calcific aortic stenosis. We showed an age-related gene-dosage effect of deletion of the low-density lipoprotein receptor (LDL-R) gene on aortic calcification in human subjects with FH. The LDL R deficient mouse and transgenic mice overexpressing the LDL-R degrading protein PCSK9 also exhibit aortic calcification, not fully explained by increased LDL cholesterol levels. Taken together, these data suggests a novel role for the LDL R in the inhibition of vascular calcification. Understanding the molecular role of the LDL-R and its signaling partners in vascular calcification will be instrumental in identifying novel therapies for a common age-related process associated with a large burden of disease. PMID- 23040869 TI - [Giant left ventricular pseudoaneurysm: a silent catastrophe]. PMID- 23040870 TI - [Relationship between leptin and body mass and metabolic syndrome in an adult population]. AB - OBJECTIVE: To analyze the relationship between leptin and obesity expressed as body mass index (BMI) and certain components of the metabolic syndrome (MS) in an adult population. METHODS: The study included 103 subjects, 42 men and 61 women, aged over 30 years, clinically defined as non-diabetic but with personal or family history of cardiovascular disease. All subjects underwent fasting blood measurements of leptin, insulin, glucose, glucose after ingestion of 75g glucose, HDL cholesterol and triglycerides, and insulin resistance (IR) and BMI were calculated. RESULTS: BMI as an index of overall adiposity was strongly associated with serum leptin. BMI rose as serum leptin levels increased from the first to the third tertile; the correlation between leptin and BMI was strong, r=0.524 in men and r=0.603 in women, with high statistical significance (p<0.001); BMI was the best predictor of hyperleptinemia on ROC analysis, with area under the curve (AUC)=0.81 in men and 0.84 in women. The association between leptin and obesity (BMI >=30kg/m(2)) showed high odds ratios (OR) in both sexes (10.11 in men, 6.00 in women) on univariate regression analysis and 9.30 in men and 8.21 in women on multivariate regression analysis. Hyperinsulinemia and IR strongly influenced hyperleptinemia. Leptin was the best predictor of IR in both sexes (AUC=0.89 in men and 0.85 in women), and IR in men (AUC=0.79) and hyperinsulinemia in women (AUC=0.78) were the best predictors of hyperleptinemia after BMI. The correlations between leptin and IR, and leptin and insulinemia, were strong in both sexes. With regard to MS components, increased serum levels of the study variables were observed as leptin concentrations rose from the first to the third tertile (with the exception of HDL cholesterol, which decreased). CONCLUSION: Elevated serum leptin, particularly in obese individuals, should be taken as a warning sign of energy imbalance, poor diet, hyperinsulinemia, insulin resistance, or changes in other metabolic risk factors that are strongly associated with cardiovascular disease and type 2 diabetes. PMID- 23040871 TI - [Biomarkers of functional class in systolic heart failure: the relevance of copeptin]. AB - INTRODUCTION: Functional class is an important predictor of prognosis in chronic heart failure (CHF). However, it is often subjective and poorly reproducible. OBJECTIVE: We sought to identify diagnostic markers of high functional class. METHODS: We prospectively studied 37 patients with symptomatic CHF and ejection fraction<40%. The study protocol included clinical evaluation, echocardiography (M-mode, 2D, Doppler and tissue Doppler) and laboratory tests including copeptin, vasopressin and NT-proBNP. We compared patients in NYHA class II with those in NYHA class>II. Overall mortality was assessed at 18 months. RESULTS: Mortality was higher in the more advanced symptomatic stages (p<0.05). Patients in NYHA class>II had higher creatinine, copeptin and NT-proBNP levels (p<0.05). E/E', E septum distance, pulmonary artery systolic pressure (PASP) and inferior vena cava (IVC) dimensions were also significantly greater (p<0.05). The biomarkers copeptin (area under the curve [AUC]=0.76, p<0.01) and NT-proBNP (AUC=0.81, p<0.01) and the echocardiographic parameters PASP (AUC=0.88, p<0.01) and IVC inspiratory diameter (AUC=0.91, p<0.01) showed the best performance for diagnosis of functional class>II. In multivariate regression analysis only PASP and serum creatinine were independent predictors of NYHA functional class>II. CONCLUSION: Copeptin and NT-proBNP have high sensitivity and specificity in the diagnosis of functional classes with prognostic impact and may be useful in defining a standardized functional classification. The structural and hemodynamic echocardiographic changes associated with NYHA class>II were left ventricular filling pressure, PASP and central venous pressure. PMID- 23040872 TI - Trachoma elimination in remote Indigenous Northern Territory communities: baseline health-promotion study. AB - Identify trachoma knowledge, attitudes and practice of staff in clinics, schools and community workplace settings to optimise trachoma-elimination health promotion programs in the Katherine West Health Board region of the Northern Territory. Prior to the introduction of a suite of health promotion resources the Indigenous Eye Health Unit and Katherine West Health Board conducted a baseline survey of open, multi-choice and closed questions regarding knowledge, attitudes and practices in relation to trachoma with 72 staff members over a 6-month period in 2010-11. Data were analysed for differences between settings. Two significant barriers and one enabling factor were identified. One in five staff members in clinics and 29% of staff members in schools were unaware they lived and worked in a trachoma-endemic area. One-third of school staff and 38% of clinic staff considered it normal for children to have dirty faces. However, the majority of participants felt comfortable talking about hygiene issues with others. The presence of dirty faces in young Indigenous children underpins the continuing prevalence of trachoma. Increasing the awareness of the health effects of children's nasal and ocular secretions and changing community acceptance of dirty faces as the norm will reduce the risk of trachoma and other childhood infections. Staff in clinics, schools and community work settings can play a role in trachoma elimination by actively encouraging clean faces whenever they are dirty and by including face washing in holistic hygiene and health education. Staff in schools may need additional support. Trachoma-elimination health promotion should increase awareness of trachoma prevalence and encourage all who work and live in remote Indigenous communities to take action to promote facial cleanliness and good hygiene practices. PMID- 23040873 TI - One followed by many?-Long-term effects of a celebrity suicide on the number of suicidal acts on the German railway net. AB - BACKGROUND: Following the railway suicide of Robert Enke, a famous German football goal keeper, short-term copycat effects have been found. Main aims of the present study were to analyze long-term effects of this incidence and to compare them with overall national suicide data, as well as to investigate possible "anniversary effects". METHODS: For long-term effects, the number of railway suicidal acts in the two years before and after Robert Enke's suicide (10th November 2009) were compared. For anniversary effects, the corresponding 2 week-periods in 2009, 2010 and 2011 were analyzed. Incidence ratios with 95% confidence intervals were computed. RESULTS: Compared to the two years before Enke's suicide the incidence ratio of the number of railway suicidal acts in the 2-year-period following this event increased by 18.8% (95% confidence interval (CI)=11.0-27.1%; p<0.001). The median number of suicidal acts per day increased from 2 to 3 (p<0.001). This effect remains significant after excluding short-term 2-week effects of Enke's suicide. An anniversary effect was not present. The increase of fatal railway suicides between 2007 and 2010 (25%) was significantly different from that for the total number of suicides in Germany (6.6%) (p<0.0001). LIMITATIONS: Due to missing data, analyses regarding gender were limited and regarding age not feasible. CONCLUSIONS: Long-term effects of Enke's suicide on railway suicidal acts in Germany in the sense of copycat behavior are probable as this increase cannot be explained by corresponding changes of the total number of suicides in Germany. PMID- 23040874 TI - Subthreshold bipolar disorder in a U.S. national representative sample: prevalence, correlates and perspectives for psychiatric nosography. AB - OBJECTIVE: There is growing clinical and epidemiological evidence that undiagnosed bipolar features are source of clinical heterogeneity in major depressive disorder (MDD). This study examined and compared the prevalence and correlates of lifetime major depressive episode plus subthreshold hypomania D(m) with pure MDD, bipolar II disorder, and bipolar I disorder. METHOD: Data were drawn from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a large cross-sectional survey (n=43,093) representative of the U.S. population. RESULTS: The lifetime prevalences were 2.53% for D(m), 1.12% for bipolar II disorder, 2.19% for bipolar I disorder and 10.70% for pure MDD. All bipolar disorders (i.e., D(m), BP-II, and BP-I) were half as frequent as MDD. Lifetime and 12-month psychiatric comorbidity, course and clinical characteristics, symptoms, health status and treatment-seeking rates were significantly different in participants with lifetime D(m) when compared to participants with pure MDD, but not when compared to participants with bipolar II disorder. LIMITATIONS: Subthreshold hypomania diagnostic was based on the lifetime presence of at least one of the three screening questions for criterion A for hypomania, without a lifetime history of manic or hypomanic episode. This narrow definition, both in terms of the choice of hypomanic symptoms and their duration, could have led to an underestimation of the proportion of participants with a lifetime history of D(m). In addition, the cross-sectional nature of this study does not allow causal associations to be drawn. CONCLUSIONS: Our data confirm and extend evidence of the clinical significance and validity of a subthreshold bipolarity-specifier applied to individuals with DSM-IV MDD. Major depression with subthreshold hypomania could be more accurately incorporated into the bipolar II disorder diagnosis. PMID- 23040875 TI - Label-free detection of sub-nanomolar lead(II) ions in aqueous solution using a metal-based luminescent switch-on probe. AB - A label-free oligonucleotide-based luminescent switch-on assay has been developed for the selective detection of sub-nanomolar Pb(2+) ions in aqueous solution and real water samples. An iridium(III) complex was employed as a G-quadruplex specific luminescent probe and a guanine rich DNA (PS2.M, 5' GTG(3)TAG(3)CG(3)T(2)G(2)-3') was employed as recognition unit for Pb(2+) ions. The PS2.M exists in a single-stranded conformation in the absence of Pb(2+) ions, and the weak binding of the iridium(III) probe to ssDNA results in a weak luminescence signal. Upon binding to Pb(2+) ions, the single-stranded DNA sequence (PS2.M) is induced into a G-quadruplex conformation, which greatly enhances the luminescence emission of the iridium(III) probe. The assay can detect Pb(2+) ions in aqueous media with a limit of detection of 600 pM. It also exhibits good selectivity for Pb(2+) ions over other heavy metal ions. Furthermore, the application of the assay for the detection of Pb(2+) ions in spiked river water samples has been demonstrated. PMID- 23040876 TI - Femtogram-level detection of Clostridium botulinum neurotoxin type A by sandwich immunoassay using nanoporous substrate and ultra-bright fluorescent suprananoparticles. AB - We report a simple, robust fluorescence biosensor for the ultra-sensitive detection of Clostridium botulinum Neurotoxin Type A (BoNT/A) in complex, real world media. High intrinsic signal amplification was achieved through the combined use of ultra-bright, photostable dye-doped nanoparticle (DOSNP) tags and high surface area nanoporous organosilicate (NPO) thin films. DOSNP with 22 nm diameter were synthesized with more than 200 times equivalent free dye fluorescence and conjugated to antibodies with average degree of substitution of 90 dyes per antibody, representing an order of magnitude increase compared with conventional dye-labeled antibodies. The NPO films were engineered to form constructive interference at the surface where fluorophores were located. In addition, DOSNP-labeled antibodies with NPO films increased surface roughness causing diffuse scattering resulting in 24% more scattering intensity than dye labeled antibody with NPO films. These substrates were used for immobilization of capture antibodies against BoNT/A, which was further quantified by DOSNP-labeled signal antibodies. The combination of optical effects enhanced the fluorescence and, therefore, the signal-to-noise ratio significantly. BoNT/A was detected in PBS buffer down to 21.3 fg mL(-1) in 4 h. The assay was then extended to several complex media and the four-hour detection limit was found to be 145.8 fg mL(-1) in orange juice and 164.2 fg mL(-1) in tap water, respectively, demonstrating at least two orders of magnitude improvement comparing to the reported detection limit of other enzyme-linked immunosorbent assays (ELISA). This assay, therefore, demonstrates a novel method for rapid, ultra-low level detection of not only BoNT/A, but other analytes as well. PMID- 23040877 TI - Real-time study of a DNA strand displacement reaction using dual polarization interferometry. AB - A DNA strand displacement reaction on a solid-liquid interface was investigated using dual polarization interferometry. This effective analytical technique allows the real-time, simultaneous determination of the thickness, density, and mass of a biological layer. The displacement process was examined, and the changes in thickness, density, and mass were determined. Injection of the displacement DNA resulted in an increase in density and a decrease in mass and thickness, which indicated that a portion of the target DNA was displaced from the double-stranded DNA (dsDNA). The effects of the displacement DNA concentration and toehold length on the displacement efficiency were also examined. Increasing the displacement DNA concentration and the toehold length increased the changes in mass and the displacement efficiency. At the concentration of 0.2 MUM, the toeholds with 4, 5, 6, and 7 bases had displacement percentages of 24.54%, 25.99%, 30.16%, and 70.41%, respectively. At displacement DNA concentrations exceeding that of the dsDNA, the displacement percentage was not concentration-dependent. Above a certain concentration, the percentage remained stable with increasing concentration. Comparison using different toehold sequences showed that the displacement efficiency increases with increasing bonding force between the base pairs. PMID- 23040878 TI - Lost in transition--a review of qualitative literature of newly qualified Registered Nurses' experiences in their transition to practice journey. AB - The failure of newly qualified Registered Nurses to be appropriately transitioned into the new practice has been mentioned in numerous nursing literatures. Along with the need to decrease turnover rates, increase satisfaction rate of nurses and improve patient outcomes, nursing educators in Singapore are interested in the experiences of these nurses in their transition to practice journey. In this paper, the author attempts to critically review qualitative research conducted in that area to identify why nurses are leaving the profession and how nursing educators in Singapore can reduce stress and uncertainty in the newly qualified Registered Nurses during their transition to practice journey. In conducting a qualitative literature review, the author aims to explore interpretation of these nurses' subjective experiences and description of their social context, ultimately paying attention to lay knowledge as human behaviour is context specific rather than being represented in the quantitative form. PMID- 23040879 TI - Combining insights from quantile and ordinal regression: child malnutrition in Guatemala. AB - Chronic child undernutrition is a persistent problem in developing countries and has been the focus of hundreds of studies where the primary intent is to improve targeting of public health and economic development policies. In national level cross-sectional studies undernutrition is measured as child stunting and the goal is to assess differences in prevalence among population subgroups. Several types of regression modeling frameworks have been used to study childhood stunting but the literature provides little guidance in terms of statistical properties and the ease with which the results can be communicated to the policy community. We compare the results from quantile regression and ordinal regression models. The two frameworks can be linked analytically and together yield complementary insights. We find that reflecting on interpretations from both models leads to a more thorough analysis and forces the analyst to consider the policy utility of the findings. Guatemala is used as the country focus for the study. PMID- 23040880 TI - Postburn shoulder medial-adduction contracture: anatomy and treatment with trapeze-flap plasty. AB - BACKGROUND: Shoulder-adduction contractures after burn, most frequent among big joints, cause functional deficiency of the upper limb and, therefore, benefits from surgical correction. Many reconstructive techniques and flaps have been suggested for contracture treatment, but the problem in choosing an adequate reconstructive technique based on the anatomy of the contracture remains. Shoulder-adduction contracture has been given less emphasis in research than any other type and its surgical reconstructive technique remains of concern. METHODS: Anatomic features of scar shoulder-adduction contractures were studied in 346 patients, personally operated upon. This allowed us to classify all contractures into three types: edge, medial and total. New surgical techniques specifically for medial contractures were developed. RESULTS: Eighty percent of patients had edge contractures in which the axillary fossa was spared. In 20% of patients, axilla, including the hairy dome, was involved. These cases were anatomically classified into two types: medial, making up 30% of the cases, when contracted scars involved only axilla, and total caused by scars, tightly surrounding the shoulder joint. The scars, causing medial contracture, form a crescent-shaped fold along the medial axillary line. The fold's sheets are scars in which there is skin surface surplus in width, which allows the contracture release with local tissues. Surface deficiency in length has a trapezoid form. Medial contracture can be successfully treated with opposite transposition of trapezoid adipose-scar flaps prepared from both sheets of the fold. CONCLUSION: Medial shoulder adduction contracture is a newly described type with specific anatomic features. Contracture can be successfully treated with local tissues using trapeze-flap plasty. PMID- 23040881 TI - An association study of functional polymorphic genes IRF-1, IFNGR-1, and IFN gamma with disease progression, aspartate aminotransferase, alanine aminotransferase, and viral load in chronic hepatitis B and C. AB - BACKGROUND: Investigational approaches based on genome-wide association studies have proven useful in identifying genetic predictors for many diseases, including susceptibility to chronic hepatitis B and C. In these studies, the majority of genetic variants that have shown a positive association have been identified in genes involved in the immune response. In this study IFN-gamma, IFNGR-1, and IRF 1 genes were analyzed for their role in susceptibility to the development of chronic hepatitis B and chronic hepatitis C in a Turkish population. METHODS: Polymorphic genes IRF-1 (-410, -388), IFNGR-1 (-56, -611), and IFN-gamma (+874) were analyzed in a total of 400 individuals: 100 chronic hepatitis B patients, 100 hepatitis B carriers, 100 chronic hepatitis C patients, and 100 healthy controls. A single base primer extension assay was used. Correlations between genes and gender, viral load, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were also investigated. RESULTS: The IRF-1 gene at positions -388 and -410 were observed to be candidate gene markers for susceptibility to the development of chronic hepatitis B and C (p<0.05). IFN gamma +874 and IFNGR-1 (-56 and -611) correlated with chronic hepatitis B but not chronic hepatitis C. Correlation of functional genotype with viral load and AST and ALT levels revealed an association of IFN-gamma +874 and IFNGR-1 -611 with chronic hepatitis C and IFN-gamma +874 with viral load and chronic hepatitis B (p<0.05). CONCLUSIONS: Findings suggest that IFN-gamma (+874), IRF-1 (-410, 388), and IFNGR-1 (-56, -611) are candidate gene markers for determining patient susceptibility to the development of chronic hepatitis B and C. PMID- 23040883 TI - The effect of osteocyte apoptosis on signalling in the osteocyte and bone lining cell network: a computer simulation. AB - Osteocytes play a critical role in the regulation of bone remodelling by translating strain due to mechanical loading into biochemical signals transmitted through the interconnecting lacuno-canalicular network to bone lining cells (BLCs) on the bone surface. This work aims to examine the effects of disruption of that intercellular communication by simulation of osteocyte apoptosis in the bone matrix. A model of a uniformly distributed osteocyte network has been developed that simulates the signalling through the network to the BLCs based on strain level. Bi-directional and asymmetric communication between neighbouring osteocytes and BLCs is included. The effect of osteocyte apoptosis is examined by preventing signalling at and through the affected cells. The simulation shows that apoptosis of only 3% of the osteocyte cells leads to a significant reduction in the peak signal at the BLCs. Furthermore, experiments with the model confirm how important the location and density of the apoptotic osteocytes are to the signalling received at the bone surface. With 5% and 9% osteocyte apoptosis, the mean peak BLC levels were reduced by 25% and 37% respectively. Such a significant reduction in the signal at the BLCs may explain a possible mechanism that leads to the increased remodelling and eventual bone loss observed with osteoporosis. More generally, it provides a unique framework for a broader exploration of the role of osteocyte and bi-directional and asymmetric cell-cell communication in mechanotransduction, and the effects of disruption to that communication. PMID- 23040882 TI - Cell viability in intervertebral disc under various nutritional and dynamic loading conditions: 3d finite element analysis. AB - In this study, a new cell density model was developed and incorporated into the formulation of the mechano-electrochemical mixture theory to investigate the effects of deprivation of nutrition supply at boundary source, degeneration, and dynamic loading on the cell viability of intervertebral disc (IVD) using finite element methods. The deprivation of nutrition supply at boundary source was simulated by reduction in nutrition level at CEP and AF boundaries. Cases with 100%, 75%, 60%, 50% and 30% of normal nutrition level at both CEP and AF boundaries were modeled. Unconfined axial sinusoidal dynamic compressions with different combinations of amplitude (u=10%+/- 2.5%, +/- 5%) and frequency (f=1, 10, 20 cycle/day) were applied. Degenerated IVD was modeled with altered material properties. Cell density decreased substantially with reduction of nutrition level at boundaries. Cell death was initiated primarily near the NP-AF interface on the mid-plane. Dynamic loading did not result in a change in the cell density in non-degenerated IVD, since glucose levels did not fall below the minimum value for cell survival; in degenerated IVDs, we found that increasing frequency and amplitude both resulted in higher cell density, because dynamic compression facilitates the diffusion of nutrients and thus increases the nutrition level around IVD cells. The novel computational model can be used to quantitatively predict both when and where cells start to die within the IVD under various kinds of nutritional and mechanical conditions. PMID- 23040886 TI - Leukotriene D4 and methacholine bronchial provocation tests for identifying leukotriene-responsiveness subtypes. AB - BACKGROUND: Both leukotriene D(4) (LTD(4)) and methacholine bronchial provocation tests are measurements of airway responsiveness; however, their correlation and distinction remain unexplored. OBJECTIVES: We sought to compare the 2 tests and classify leukotriene-responsiveness subtypes in asthmatic patients. METHODS: In this randomized cross-over study we enrolled healthy subjects and asthmatic patients with different control statuses. All subjects underwent both tests with a 2- to 14-day interval. Distribution and correlation of cumulative doses inducing a 20% decrease in FEV(1), LTD(4)/methacholine potency ratio, diagnostic value, and adverse events were recorded and analyzed. Asthmatic patients with a lower cumulative dose for LTD(4) and a higher leukotriene/methacholine potency ratio than geometric means were regarded as leukotriene responsive. RESULTS: Twenty patients with uncontrolled, 22 with partly controlled, and 20 with controlled asthma and 21 healthy subjects were enrolled. Geometric means of cumulative doses for LTD(4) and methacholine (0.272 nmol vs 0.945 MUmol) were lowest in patients with uncontrolled asthma, followed by those with partly controlled (0.387 nmol vs 1.933 MUmol) and controlled (1.484 nmol vs 3.946 MUmol) asthma. The average potency ratio was highest in those with partly controlled asthma (5000.2), followed by those with uncontrolled (3477.7) and controlled (2702.6) asthma. Eighteen leukotriene-responsive asthmatic patients (29.03%) with a cumulative dose of LTD(4) of 0.533 nmol or less and a potency ratio of 3647 or greater were identified. Adverse events, including tachypnea and chest tightness, were similar and mild. No serious adverse event was reported. CONCLUSION: Diagnostic value and safety were ideal in both tests. The combination of cumulative dose for LTD(4) and potency ratio might be useful to identify leukotriene-responsive asthmatic patients. PMID- 23040885 TI - Further replication studies of the EVE Consortium meta-analysis identifies 2 asthma risk loci in European Americans. AB - BACKGROUND: Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk. OBJECTIVES: We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis. METHODS: We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis. RESULTS: Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos. CONCLUSIONS: This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations. PMID- 23040888 TI - Early-life folate levels are associated with incident allergic sensitization. PMID- 23040889 TI - Breast cancer research in Asia: adopt or adapt Western knowledge? AB - The incidence and mortality of breast cancer continues to rise rapidly in Asian countries. However, most of our current knowledge on breast cancer has been generated in Western populations. As the socio-economic profile, life style and culture of Asian and Western women are substantially different, and genetic backgrounds vary to some extent, we need to answer the question on whether to 'adopt' or 'adapt' Western knowledge before applying it in the Asian setting. It is generally accepted that breast cancer risk factors, which have mainly been studied in Western populations are similar worldwide. However, the presence of gene-environment or gene-gene interactions may alter their importance as causal factors across populations. Diagnostic and prognostic study findings, including breast cancer prediction rules, are increasingly shown to be 'setting specific' and must therefore be validated in Asian women before implementing them in clinical care in Asia. Interventional research findings from Caucasian patients may not be applicable in patients in Asia due to differences in tumour biology/profiles, metabolism of drugs and also health beliefs which can influence treatment acceptance and adherence. While breast cancer research in Asia is warranted in all domains of medical research, it is felt that for Asian breast cancer patients, needs are highest for diagnostic and prognostic studies. International clinical trials meanwhile need to include breast cancer patients from various Asian settings to provide an insight into the effectiveness of new treatment modalities in this part of the world. PMID- 23040884 TI - Allergic Rhinitis and its Impact on Asthma (ARIA): achievements in 10 years and future needs. AB - Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIA World Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children. PMID- 23040887 TI - Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. AB - BACKGROUND: Hypereosinophilic syndromes (HESs) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet many patients become corticosteroid refractory or develop corticosteroid toxicity. Mepolizumab, a humanized monoclonal anti-IL-5 antibody, showed corticosteroid-sparing effects in a double blind, placebo-controlled study of FIP1L1/PDGFRA-negative, corticosteroid responsive subjects with HESs. OBJECTIVE: We evaluated long-term safety and efficacy of mepolizumab (750 mg) in HES. METHODS: MHE100901 is an open-label extension study. The primary end point was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of antimepolizumab antibodies were also explored. RESULTS: Seventy eight subjects received 1 to 66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range, 4-302 weeks). The most common dosing interval was 9 to 12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including 1 death, were reported by the investigator as possibly due to mepolizumab in 3 subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone free without other HES medications for >= 12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew before study completion for death (n = 4), lack of efficacy (n = 6), or other reasons. CONCLUSION: Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES. PMID- 23040890 TI - Sexual transmission of predicted CXCR4-tropic HIV-1 likely originating from the source partner's seminal cells. AB - We present a case of sexual transmission of HIV-1 predicted to have CXCR4-tropism during male-to-male sexual exposure. Phylogenetic analyses exclude cell-free virus in the seminal plasma of the source partner and possibly point to the seminal cells as the origin of the transmission event. PMID- 23040892 TI - Conformational analysis of two novel cytotoxic C2-substituted pyrrolo[2,3 f]quinolines in aqueous media, organic solvents, membrane bilayers and at the putative active site. AB - We have performed: (i) conformational analysis of two novel cytotoxic C2 substituted pyrrolo[2,3-f]quinolines 5e and 5g in deuterated dimethylsulfoxide (DMSO-d(6)) utilizing NOE results from NMR spectroscopy; (ii) molecular dynamics (MD) calculations in water, DMSO and dimyristoyl phosphatidylcholine bilayers and (iii) molecular docking and MD calculations on DNA nucleotide sequences. The obtained results for the two similar in structure molecules showed differences in: (i) their conformational properties in silico and in media that reasonably simulate the biological environment; (ii) the way they are incorporated into the lipid bilayers and therefore their diffusion ability and (iii) molecular docking capacity as it is depicted from their different binding scores. PMID- 23040893 TI - Synthesis of 1,5-diarylhaloimidazole analogs and their inhibitory activities against PGE2 production from LPS-treated RAW 264.7 cells. AB - A number of 1,5-diarylimidazole analogs were synthesized and evaluated their inhibitory activities of cyclooxygenase-2 catalyzed prostaglandin E(2) production. Reactions of 1,5-diarylimidazoles with halogenating reagents (NCS, NBS, NIS) afforded halogenated analogs. Among the analogs tested, compounds Ib, IIa, IIb and IIe exhibited significantly improved inhibitory activities against COX-2-mediated PGE(2) production from LPS-induced RAW 264.7 cells compared to those of the parent 1,5-diarylimidazoles. Especially, the analogs Ib (IC(50)=0.55 MUM) and IIa (IC(50)=0.58 MUM) showed best results. Halogenation on the 1,5 diarylimidazole ring enhanced inhibitory activities against COX-2 catalyzed PGE(2) production, however, inhibitory activities were significantly varied by position(s) and species of the substituted halogen(s). PMID- 23040891 TI - Tubular cell HIV-entry through apoptosed CD4 T cells: a novel pathway. AB - We hypothesized that HIV-1 may enter tubular cells by phagocytosis of apoptotic fragments of HIV-1-infected T cells infiltrating tubular interstitium. The study was designed to evaluate the interaction of programmed death-1 (PD-1) receptors on CD4 T cells and programmed death ligand-1 (PD-L1) on tubular cells (HK2 and HRPTEC, primary tubular cells). Co-cultivation of HIV-1 infected lymphocytes (HIV LY) with HK2s/HRPTECs resulted in T cell apoptosis, uptake of the apoptosed HIV LY by HK2s/HRPTECs, tubular cell activation and HIV expression. Cytochalasin-B inhibited tubular cell HIV-LY uptake and anti-PD-L1 antibody inhibited HIV-LY apoptosis and tubular cell HIV-LY uptake, activation and HIV expression. These observations do indicate induction of apoptosis of T cells due to interaction of PD-1 and PD-L1 upon co-cultivation and subsequent phygocytosis of HIV-laden apoptotic bodies by tubular cells and thus the transfer of HIV-1 into tubular cells. These findings identify a novel pathway that facilitates HIV-1 entry into tubular cell. PMID- 23040894 TI - Pyrido[1,2-a]pyrimidin-4-ones as antiplasmodial falcipain-2 inhibitors. AB - Plasmodium falciparum cysteine protease falcipain-2 (FP-2) is a promising target for antimalarial chemotherapy and inhibition of this protease affects the growth of parasite adversely. A series of pyrido[1,2-a]pyrimidin-4-ones were synthesized and evaluated for their in vitro FP-2 inhibitory potential. Compounds (14,17) showed excellent FP-2 inhibition and can serve as lead compounds for further development of potent FP-2 inhibitors as potential antimalarial drugs. PMID- 23040896 TI - Trimeric purine nucleoside phosphorylase: exploring postulated one-third-of-the sites binding in the transition state. AB - Transition-state analogue inhibitors, immucillins, were reported to bind to trimeric purine nucleoside phosphorylase (PNP) with the stoichiometry of one molecule per enzyme trimer [Miles, R. W.; Tyler, P. C.; Furneaux, R. H.; Bagdassarian, C. K.; Schramm, V. L. Biochem. 1998, 37, 8615]. In attempts to observe and better understand the nature of this phenomenon we have conducted calorimetric titrations of the recombinant calf PNP complexed with immucillin H. However, by striking contrast to the earlier reports, we have not observed negative cooperativity and we got the stoichiometry of three immucillin molecules per enzyme trimer. Similar results were obtained from fluorimetric titrations, and for other inhibitors bearing features of the transition state. However, we observed apparent cooperativity between enzyme subunits and apparent lower stoichiometry when we used the recombinant enzyme not fully purified from hypoxanthine, which is moped from Escherichia coli cells. Results presented here prove that one-third-of-the-sites binding does not occur for trimeric PNP, and give the highly probable explanation why previous experiments were interpreted in terms of this phenomenon. PMID- 23040895 TI - Adamantyl carboxamides and acetamides as potent human 11beta-hydroxysteroid dehydrogenase type 1 inhibitors. AB - The modulation of 11beta-HSD1 activity with selective inhibitors has beneficial effects on various metabolic disorders including insulin resistance, dyslipidemia and obesity. Here we report the discovery of a series of novel adamantyl carboxamide and acetamide derivatives as selective inhibitors of human 11beta HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Optimization based on an initially identified 11beta-HSD1 inhibitor (3) led to the discovery of potent inhibitors with IC(50) values in the 100 nM range. These compounds are also highly selective 11beta-HSD1 inhibitors with no activity against 11beta-HSD2 and 17beta-HSD1. Compound 15 (IC(50)=114 nM) with weak inhibitory activity against the key human cytochrome P450 enzymes and moderate stability in incubation with human liver microsomes is worthy of further development. Importantly, compound 41 (IC(50)=280 nM) provides a new lead that incorporates an adamantyl group surrogate and should enable further series diversification. PMID- 23040898 TI - Management of psychotropic medication side effects in children and adolescents. AB - This article is a review of several of the most concerning side effects of psychotropic medications in children and adolescents. An emphasis is placed on review of the prevalence, presentation, monitoring, and evidence-based management of these side effects. PMID- 23040897 TI - Appropriate and judicious use of psychotropic medications in youth. AB - The issue of prescribing psychotropic medications is one that stirs much emotion and debate among parents and providers alike. This article is presented as a primer on the appropriate and judicious use of psychotropic medications in youth. Rather than focusing on any specific class of medications or on any clinical condition, the article presents best practices as well as key clinical pearls regarding the art and science of psychopharmacology in youth. PMID- 23040899 TI - Interventions for youth at high risk for bipolar disorder and schizophrenia. AB - Increasing evidence from retrospective and prospective studies is beginning to validate criteria to identify individuals at high risk for developing bipolar disorder or schizophrenia. In parallel, intervention trials are evaluating the efficacy and tolerability of pharmacologic and nonpharmacologic approaches for the treatment of subthreshold and possibly prodromal presentations in these high risk populations with the ultimate objective of mitigating illness progression. This article reviews current evidence for candidate interventions for high-risk individuals to guide future research in this rapidly emerging field. A clinical vignette describing antidepressant-induced manic symptoms in an adolescent with a family history of bipolar disorder is provided. PMID- 23040901 TI - Psychiatric pharmacogenomics in pediatric psychopharmacology. AB - This article provides an overview of where psychiatric pharmacogenomic testing stands as an emerging clinical tool in modern psychotropic prescribing practice, specifically in the pediatric population. This practical discussion is organized around the state of psychiatric pharmacogenomics research when choosing psychopharmacologic interventions in the most commonly encountered mental illnesses in youth. As with the rest of the topics on psychopharmacology for children and adolescents in this publication, a clinical vignette is presented, this one highlighting a clinical case of a 16 year old genotyped during hospitalization for recalcitrant depression. PMID- 23040900 TI - The neural effects of psychotropic medications in children and adolescents. AB - Little is known about the neurobiological effects of psychotropic medications used in the treatment of children and adolescents diagnosed with a psychiatric disorder. This review provides a synopsis of the literature demonstrating the neural effects associated with exposure to psychotropic medication in youth using multimodal neuroimaging. The article concludes by illustrating how, taken together, these studies suggest that pharmacological interventions during childhood do indeed affect brain structure and function in a detectable manner, and the effects appear to be ameliorative. PMID- 23040902 TI - Psychopharmacologic treatment for pediatric anxiety disorders. AB - Anxiety is an innate emotion that all humans experience, especially during early childhood in periods of significant growth and development. Treatment strategies exist for anxiety disorders that cause significant dysfunction and impairment in youth. This article provides a current overview of the literature on psychopharmacologic management of pediatric anxiety disorders. Potential side effects and complications of psychotropic medications are reviewed. The treatment of anxiety disorders in patients with comorbid conditions is explored, addressing the impact on treatment course and pharmacologic recommendations. A clinical vignette describing a 10-year-old boy with increasing anxiety is presented describing in-hospital and outpatient treatment and therapies. PMID- 23040903 TI - Depression. AB - This article reviews the assessment and treatment for depression in children and adolescents, emphasizing the implementation of evidence-based treatments into clinical care. Past trials of antidepressant medications are reviewed, as well as the clinical use of antidepressants and pharmacologic strategies for refractory illness or in the context of comorbid conditions. Clinicians who treat youth now have a body of empiric research to help guide treatment decisions; however, personalized treatment based on associated symptoms, comorbid conditions, contextual factors, and psychiatric history is essential. Further research is needed in the pharmacologic treatment of depressed youth, including expanding the study of non-SSRI antidepressants, augmentation and adjunctive strategies, and treatment in patients with comorbid conditions. PMID- 23040904 TI - Psychopharmacologic treatment of obesity and eating disorders in children and adolescents. AB - This review discusses the evidence base for medications that are currently used for obesity and eating disorders, including their Food and Drug Administration approval status by disorder and age group, contraindications, and major adverse effects. Investigational agents currently being considered, issues related to psychiatric and medical comorbidity, limitations of pharmacologic strategies, and recommendations for treatment are also addressed. PMID- 23040905 TI - Pediatric sleep pharmacology. AB - This article reviews common sleep disorders in children and pharmacologic options for them. Discussions of pediatric sleep pharmacology typically focus on treatment of insomnia. Although insomnia is a major concern in this population, other conditions of concern in children are presented, such as narcolepsy, parasomnias, restless legs syndrome, and sleep apnea. PMID- 23040906 TI - Empirical evidence for psychopharmacologic treatment in early-onset psychosis and schizophrenia. AB - Psychotic symptoms presenting in youth can be clinically complex and require that a child and adolescent psychiatrist use significant skill in making a diagnosis and initiating treatment. There are a number of illnesses to rule out before making a diagnosis of early-onset schizophrenia in particular. Psychosis in youth has significant associated morbidity and places high demands not only on families but also on the medical and educational systems. More effective pharmacologic and nonpharmacologic treatments for psychosis are needed. Nonpharmacologic therapies targeting relatively treatment-resistant domains of dysfunction such as neurocognition are also necessary as adjunctive treatments to our extant pharmacologic agents. PMID- 23040907 TI - Pharmacologic treatment of bipolar disorder in children and adolescents. AB - This review focuses mainly on published articles regarding the treatment of school-aged children and adolescents with pediatric bipolar disorder. In light of systematic reviews, large randomized controlled trial data are emphasized wherever possible. This review addresses the treatment of acute manic/mixed episodes, including combination treatment, the preliminary literature regarding bipolar depression among youth, treatment in the face of comorbid conditions, and maintenance treatment. Suggestions regarding future directions are offered. A clinical vignette describing a teen with bipolar disorder is presented and bipolar medications, dosing, efficacy, side effects, contraindications, and succinct comments on each medication are summarized. PMID- 23040908 TI - Pharmacotherapy of pediatric attention-deficit/hyperactivity disorder. AB - This article describes the practical use of available attention deficit/hyperactivity disorder (ADHD) pharmacotherapies, their formulations and durations of action, and the extent of Food and Drug Administration approvals. It provides data on short-term and long-term safety of these medications, their use in ADHD with comorbid conditions, and strategies for formulating individualized, effective, and well-tolerated pharmacotherapy treatment plans. A clinical vignette focusing on a male child with ADHD is presented. Summaries are presented of ADHD pharmacotherapies and Food and Drug Administration approval status, atomoxetine and stimulant comparator trials, adverse effects and ADHD pharmacotherapy, and delivery system and duration of effect. PMID- 23040909 TI - Psychopharmacology of autism spectrum disorder: evidence and practice. AB - Children with autism spectrum disorder present with a high rate of maladaptive behaviors and comorbid psychopathology. Psychopharmacologic treatment is frequently used in this population and is particularly associated with comorbid mental illness and increasing age. Successful treatment of presenting problems, however, is most likely achieved through consideration of multiple potential etiologic factors, only some of which may respond to pharmacologic intervention. The evidence base for targeting specific symptoms and disorders with psychopharmacology in children with autism spectrum disorder is expanding rapidly and offers guidance for practicing clinicians. The current evidence for symptom specific treatment is presented. PMID- 23040910 TI - Better and safer pharmacotherapy for youth with psychiatric illness. PMID- 23040911 TI - A delicate surgical method for cancer treatment is welcome. PMID- 23040912 TI - Fertility and pregnancy outcomes after uterine artery occlusion with or without myomectomy. AB - Uterine artery occlusion (UAO) is one of the minimally invasive procedures used to treat uterine fibroids. It has demonstrated the potential to reduce fibroid growth and related symptoms with few complications and adverse effects. Meanwhile, it may preserve the uterus and ovarian blood supply to allow pregnancy in women with symptomatic fibroids. Similarly, myomectomy is an alternative to hysterectomy in the treatment of symptomatic fibroids, especially for patients who want to maintain fertility. However, only few articles have focused on fertility and pregnancy outcomes after the combined procedures of UAO and myomectomy. We reviewed the effects of UAO with or without myomectomy on fertility and pregnancy outcomes by searching the MEDLINE biomedicine database, using uterine artery occlusion, myomectomy and pregnancy as key words. In conclusion, conception and term pregnancy were possible after these procedures, but evidence on whether risks of abortion and preterm birth have been increasing simultaneously remains inconclusive. Therefore, good counseling on benefits and risks of pregnancy outcomes before performing these procedures is mandatory. PMID- 23040913 TI - Extending platinum-free interval in partially platinum-sensitive recurrent ovarian cancer by a non-platinum regimen: its possible clinical significance. AB - Response to platinum retreatment in recurrent epithelial ovarian cancer is related to the platinum-free interval (PFI). The recommended and most accepted chemotherapy in the treatment of platinum-sensitive (PFI > 6 months) recurrence is platinum-based combination regimens. Patients with a PFI of 6-12 months are often considered partially platinum-sensitive (PPS) because lower response rates to subsequent platinum retreatment have been identified. Controversies and uncertainties still exist in this population of patients regarding the best treatment and the most effective therapeutic agents. It is proposed that extending the PFI with non-platinum agents may enhance the response to and the outcome of subsequent rechallenge with platinum. In this review, we discuss the treatment for PPS recurrent ovarian cancer and the possible clinical significance of extending PFI with intent to improve the medical care of PPS recurrence. PMID- 23040914 TI - DNA methylation patterns of imprinting centers for H19, SNRPN, and KCNQ1OT1 in single-cell clones of human amniotic fluid mesenchymal stem cell. AB - OBJECTIVE: To test the hypothesis that human amniotic fluid mesenchymal stem cells contain a unique epigenetic signature in imprinting centers of H19, SNRPN, and KCNQ1OT1 during in vitro cell culture. MATERIALS AND METHODS: By bisulfite genomic sequencing, we analyzed the imprinting centers of three imprinted genes (including H19, SNRPN, and KCNQ1OT/) in a total of six single-cell clones of human amniotic fluid mesenchymal stem cells at cell passages 7, 8, 9, and 10 during in vitro cell culture. RESULTS: The imprinting centers of H19 and KCNQ1OT1 showed hypermethylation at passage 7 in all single-cell clones of human amniotic fluid mesenchymal stem cells, and there was no significant change in DNA methylation patterns during in vitro cell culture. The imprinting centers of SNRPN showed variable methylation patterns at passage 7 in six single-cell clones, and DNA methylation patterns varied during in vitro cell culture from passages 8 to 10. CONCLUSION: In conclusion, human amniotic fluid mesenchymal stem cells contain a unique epigenetic signature during in vitro cell culture. H19 and KCNQ1OT1 possessed a substantial degree of hypermethylation status, and variable DNA methylation patterns of SNRPN was observed during in vitro cell culture of human amniotic fluid mesenchymal stem cells. Our results urge further understanding of epigenetic status of human amniotic fluid mesenchymal stem cells before it is applied in cell replacement therapy. PMID- 23040915 TI - Short-term outcomes of fetoscopic laser surgery for severe twin-twin transfusion syndrome from Taiwan single center experience: demonstration of learning curve effect on the fetal outcomes. AB - OBJECTIVE: To evaluate the learning curve effect on fetal outcomes while using fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS) as managed by a newly established single center in Taiwan. MATERIALS AND METHODS: Between October 2005 and October 2010, women diagnosed to have TTTS before 26 weeks of gestation were offered FLP surgery. Cases were divided into first-half and second-half groups to evaluate the learning effect on fetal outcomes including at least one survival rate, two survival rate, and gestational age of delivery. RESULTS: A total of 44 cases with a median gestational age of 20.1 weeks (range 16-25) at operation were included in the study. Overall, both twins survived in 22 (50.0%) cases, whereas only one twin was born alive in 13 (29.5%), and neither was born alive in the remaining nine cases (20.5%). The total survival rate was 64.8%. When comparing the first-half 22 cases and the second half 22 cases, there were significant improvements in total survival rate (54.7% vs. 75.0%, p = 0.045), a prolonged interval between operation and delivery (62.1 vs. 89.1 days, p = 0.042), and more advanced gestational age of delivery (28.3 vs. 33.0 weeks, p = 0.008) in the second-half 22 cases. CONCLUSIONS: With increasing experience in using fetoscopic guide laser therapy for TTTS, the fetal survival rate could be improved with advanced gestational age at delivery. PMID- 23040916 TI - Three-dimensional ultrasonography measurement of fetal nasal bone length during the midtrimester in Taiwanese women. AB - OBJECTIVE: To evaluate the normal range of the fetal nasal bone length (NBL) in Taiwanese women using three-dimensional (3D) ultrasound, and compare the NBL of normal fetuses with Down syndrome to determine its significance in screening for trisomy 21. MATERIALS AND METHODS: A total of 102 consecutive fetuses and another 7 fetuses with trisomy 21, determined by karyotyping at 15-22 weeks' gestation, were evaluated with 3D ultrasound before amniocentesis at Changhua Christian Hospital between November 2003 and April 2004. RESULTS: The normal range for NBL in the second trimester in the Taiwanese population was investigated, and a linear relationship with gestational age was noted. The NBL increased with advancing gestational age (NBL in cm=0.0264*gestational age in weeks -0.042 (R(2)=0.2416). The median of the biparietal diameter/nasal bone length ratio had a stable value which tended to change minimally between 15 and 22 weeks of gestation. Chromosomally normal fetuses had statistically longer nasal bones than fetuses with Down syndrome (p=0.014). CONCLUSION: We present a reference range for 3D ultrasound measurement of the fetal NBL. A short nasal bone at 15 to 22 weeks is associated with a high risk of trisomy 21. PMID- 23040917 TI - Gynecological surgery caused vesicovaginal fistula managed by Latzko operation. AB - OBJECTIVE: In developed countries, vesicovaginal fistula (VVF) is a rare complication after gynecological surgery. In this report, the Latzko procedure was used to repair VVF to evaluate its safety and efficacy. MATERIALS AND METHODS: Between 1991 and 2009, cases in which VVF developed after various gynecological surgeries and repaired using the Latzko procedure were included. The cause of VVF and outcome after Latzko procedure were reported. The previous published reports regarding Latzko procedure were also listed and compared. The median follow-up period was 8 years. RESULTS: Six cases of VVF were documented in this period. All fistulas were simple type with a fistular size of less than 2cm. In three of six cases, fistulas developed after a hysterectomy for carcinoma in situ of cervix. Of those remaining, one case developed after staging an operation for endometrial adenocarcinoma, while the other two cases occurred after hysterectomy for myoma. Five cases were repaired successfully. One case had postoperative complications such as fever and urinary tract infection. Intraoperative blood loss and hospital stay were minimal. There was no recurrence of VVF postoperatively among successful cases during the follow-up period. CONCLUSION: Adequate exposure of the fistular site is a key point to a successful repair. The Latzko method is a minimal access procedure for VVF repair. This technique may be considered a first-line treatment of VV fistula. PMID- 23040918 TI - Clinical outcome after laparoscopic assisted vaginal hysterectomy with transvaginal uterosacral ligament fixation. AB - OBJECTIVE: We report here the clinical outcome of a simplified method to suspend the vaginal cuff during laparoscopic assisted vaginal hysterectomy. MATERIALS AND METHODS: This is a retrospective study. Fifty patients underwent laparoscopic assisted vaginal hysterectomy and received transvaginal uterosacral ligament fixation for vaginal cuff support (LAVHUS). Follow-up examinations were conducted for at least 24 months and included vaginal examination with prolapse grading using the POP-Q system. Subjective outcomes were measured using a questionnaire that asked patients to describe postoperative lower urinary tract symptoms and satisfaction with the procedure. RESULTS: The mean follow-up duration was 106 weeks (range 102-120 weeks).The postoperative POP-Q point C and total vaginal length were effectively sustained during this period. There were no intraoperative or postoperative complications, and no adverse postoperative lower urinary tract symptoms were reported. CONCLUSION: The present study demonstrated satisfactory subjective and objective clinical outcomes following LAVHUS. PMID- 23040919 TI - The cellular uptake and cytotoxic effect of curcuminoids on breast cancer cells. AB - OBJECTIVE: Curcuminoids (including curcumin) are natural antioxidants demonstrating potent chemopreventive properties against several forms of cancer. This study investigated the antiproliferative and induced apoptotic effects of curcuminoids on three cell lines isolated from human breast adenocarcinoma and ductal carcinoma (MDA-MB-231, MDA-MB-435S, and MCF-7). MATERIALS AND METHODS: This study developed a highly sensitive, reproducible assay method using high pressure liquid chromatography to quantify the cellular uptake of curcuminoids by breast cancer cells and quantitate its effect on inhibition of proliferation and activation of apoptosis in breast cancer cells. RESULTS: Results indicate that curcuminoids inhibited cell proliferation and activation of apoptosis in the cell lines in this study. Both effects were observed to increase in proportion to the cellular uptake of curcuminoids; cellular uptake increased following an increase in the dosage of curcuminoids. CONCLUSION: The inhibition of proliferation and increased apoptosis of breast cancer cells appears to be associated with the uptake of curcuminoids by cancer cells. PMID- 23040920 TI - Term pregnancy with umbilical cord prolapse. AB - OBJECTIVE: To investigate the incidence, management, and perinatal and long-term outcomes of term pregnancies with umbilical cord prolapse (UCP) at Mackay Memorial Hospital, Taipei, from 1998 to 2007. MATERIALS AND METHODS: For this retrospective study, we reviewed the charts, searched a computerized birth database, and contacted the families by telephone to acquire additional follow-up information. RESULTS: A total of 40 cases of UCP were identified among 40,827 term deliveries, an incidence of 0.1%. Twenty-six cases (65%) were delivered by emergency cesarean section (CS). Of the neonates, 18 had an Apgar score of <7 at 1 minute, 10 of these scores being sustained at 5 minutes after birth, and three infants finally died. Eleven UCPs occurred at the vaginal delivery of a second twin, and nine with malpresentation. All of the infants who had good perinatal outcomes also had good long-term outcomes. Poor perinatal outcomes occurred in cases where there was a delayed diagnosis, or an inability to carry out an emergency CS or a prompt vaginal delivery. CONCLUSION: Early detection of UCP and expeditious delivery are crucial to good perinatal outcomes. An emergency CS remains the mainstream management. Multiparous women whose cervixes are nearly fully dilated and who are expecting babies relatively smaller than their elder brothers or sisters born vaginally may still have vaginal deliveries managed by well-experienced birth teams, with good perinatal outcomes. Otherwise, vaginal delivery is not recommended and CS is the wiser choice. PMID- 23040921 TI - Aging and recurrent urinary tract infections are associated with bladder dysfunction in type 2 diabetes. AB - OBJECTIVE: The objective of this study was to demonstrate the diversity of urodynamic findings and temporal effects on bladder dysfunction in diabetes as well as to evaluate the predisposing factors that attenuate the storage and voiding function of diabetic women. MATERIAL AND METHODS: In this prospective study, 181 women with type 2 diabetes mellitus (DM) and lower urinary tract dysfunction underwent complete urogynecological evaluations and urodynamic studies. The patients' histories of DM and the treatment agents used were documented from chart records and interviews. The urodynamic diagnoses were recategorized into two groups for comparison, namely overactive detrusor (detrusor overactivity and/or increased bladder sensation as well as mixed incontinence) and voiding dysfunction (detrusor hyperactivity with insufficient contractility and detrusor underactivity with poor voiding efficiency) in order to evaluate the temporal effect of DM on diabetic bladder dysfunction. RESULTS: The development of bladder dysfunction showed a trend involving time-dependent progression, beginning with storage problems (i.e. advancing from urodynamic stress incontinence to detrusor overactivity and/or increased bladder sensation) and eventually led to impaired voiding function. The duration of DM relative to the urodynamic diagnoses of these women was longer in women with voiding dysfunction (6.8 +/- 2.8 years with urodynamic stress incontinence, 7.3 +/- 6.5 years with detrusor overactivity and/or increased bladder sensation, and 10.4 +/- 8.3 years with women with voiding dysfunction). Notwithstanding these findings, stepwise logistic regression analysis indicated that age and recurrent urinary tract infections were the two independent factors associated with developing voiding dysfunction. CONCLUSION: The urodynamic study revealed a temporal effect on bladder function, and women with diabetic voiding dysfunction were found to have had a longer duration of DM than women with an overactive detrusor. However, aging and recurrent urinary tract infections are the two independent factors that contribute to impaired voiding function and diabetic bladder dysfunction. PMID- 23040923 TI - Comparison of Ki-67 proliferative index between eutopic and ectopic endometrium: a case control study. AB - OBJECTIVE: In this study, the Ki-67 proliferative indices among the stages of the endometriosis were compared to clarify whether the proliferation was increased with increasing disease stage. MATERIALS AND METHODS: Thirty-eight patients who underwent surgery either by laparotomy or by laparoscopy with the diagnosis of endometriosis and 21 patients, as controls, who underwent hysterectomy with the diagnosis of myoma uteri and without any endometrial pathology at our hospital between 2005 and 2007 were studied. Biopsy specimens of endometriotic foci and endometriomas in study group, and eutopic endometrium of hysterectomy specimens of control group were studied. RESULTS: Fifty-nine patients were divided into Group 1 (21 patients in control), Group 2 (19 patients in stage I and II of endometriosis), and Group 3 (19 patients in stage III and IV). A moderate correlation between the stage of endometriosis and the degree of Ki-67 staining was found. When Ki-67 immunohistochemical staining was considered according to the threshold value for CA-125 (35 U/mL), Ki-67 positivity was increased with the increase in CA-125 value, but this increase was not statistically significant. CONCLUSION: Endometriosis shows some characteristics of tumors such as high rate of invasion, getting autonomy, and proliferation as the disease progresses with subsequent damage to target organs. When the stage of the disease increases, environment becomes more suitable for increased proliferation and invasion. In this study, the increase in proliferative activity as the severity increases is shown by the increase in Ki-67 index. As more studies are being conducted in this field, pathogenesis will be clarified, which could help in the development of new treatment modalities. PMID- 23040922 TI - Three-dimensional ultrasound in the prenatal diagnosis of osteogenesis imperfecta. AB - OBJECTIVE: Fetal osteogenesis imperfecta (OI) is a heterogeneous group of collagen disorders characterized by bone fragility, blue sclerae, deafness, and dentinogenesis imperfecta. Ultrasonography is acknowledged as a reliable diagnostic modality for the prenatal diagnosis of OI, especially type II. In the past, two-dimensional (2D) ultrasound (US) has been applied as the mainstay of prenatal diagnosis of OI. In this series, we report our work of detecting OI using three-dimensional (3D) US. MATERIAL AND METHODS: We reviewed our computer database of prenatal diagnosis of OI at the National Cheng Kung University Hospital from April 1996 to July 2010. All the cases were scanned by 2D and 3D US. In total, six cases of fetal OI were diagnosed. RESULTS: Compared with 2D US, 3D US can detect fetal OI precisely, and provide additional vivid illustration after various modes of reconstruction that 2D US cannot. CONCLUSION: In conclusion, 3D US may contribute significantly to the detection of OI in utero and provide a novel visual depiction of this defect after reconstruction. The technique may thus substantially assist in prenatal diagnosis as well as consultations for fetal OI. PMID- 23040924 TI - The significance of amplitude and duration of fetal heart rate acceleration in non-stress test analysis. AB - OBJECTIVE: This study was conducted to assess the relative significance of the amplitude versus the duration of accelerations in non-stress test (NST) analysis. MATERIALS AND METHODS: A total of 3055 normal fetal heart rate (FHR) tracings at 30-42 weeks' gestation were analyzed by automated FHR analyzing software. Accelerations were classified as one of four combinations of amplitude and duration: 15 bpm-15 seconds (Acc15-15), 15 bpm-10 seconds (Acc15-10), 10 bpm-15 seconds (Acc10-15) and 10 bpm-10 seconds (Acc10-10). We estimated the correlation among the FHR acceleration combinations using correlation analysis based on linear regression models. RESULTS: Linear regression models demonstrated statistically significant linear associations between Acc15-15 and Acc15-10 (r(2) = 0.998, p < 0.0001) and between Acc10-10 and Acc10-15 (r(2) = 0.989, p < 0.0001). There was significant association based on amplitude and relatively low correlation based on duration (Pearson correlation coefficient = 0.99 between Acc10-10 and Acc10-15, and 0.99 between Acc15-15 and Acc15-10). In the relationships of the FHR-work values, amplitude was a more important component of FHR acceleration than duration [Acc10-10 (1.67 beat) < Acc10-15 (2.50 beats) = Acc15-10 (2.50 beats) < Acc15-15 (3.75 beats)]. CONCLUSION: Amplitude was a more significant component of FHR acceleration than duration in the computerized analysis of NST. PMID- 23040925 TI - Do lower urinary tract symptoms (LUTS) predispose the individuals to more admissions in Taiwanese women? - A preliminary report. AB - OBJECTIVE: Lower urinary tract symptoms (LUTS) are highly prevalent, and increase significantly as age advances. However, whether LUTS predispose women to more admissions and/or operations has not been well reported. We studied the risks of admissions among women with or without LUTS. MATERIALS AND METHODS: Based on a nationwide population-based database, the risks of admissions among women of National Health Insurance enrollees with at least one outpatient service claim, with the coding of LUTS during 2001-2004, were compared with those without LUTS for the following 2 years. RESULTS: Total admission rates (per 1000 person-years) were significantly higher in women with LUTS, as compared with the controls; 309.7 versus 173.6, respectively. The adjusted incidence rate ratio (IRR)=1.79 and 95% confidence interval (CI)=1.63-1.95. The adjusted IRRs=1.78 (95% CI=1.56 2.03), 2.02 (95% CI=1.75-2.33), 1.53 (95% CI=1.29-1.81), 2.09 (95% CI=1.13-3.86), 1.40 (95% CI=1.21-1.63), and 4.48 (95% CI=3.37-5.96) in the departments of internal medicine, gynecology, surgery, psychiatry, orthopedics and urology, respectively; all p values < 0.05. Meanwhile, the operation rates were also higher in women with LUTS, as compared with controls, in total and in the departments of gynecology, orthopedics, and surgery; all p values < 0.05. CONCLUSIONS: The preliminary data showed a higher risk of admissions and operations among women with LUTS. The possible explanations included: more co morbidities, a poorer quality of life, a lower threshold of admission, or potential early symptoms of either medical or surgical conditions. This highlights a broad understanding of multiple and overlapping systems in LUTS. PMID- 23040926 TI - Rapid positive confirmation of mosaicism for a small supernumerary marker chromosome as r(8) by interphase fluorescence in situ hybridization, quantitative fluorescent polymerase chain reaction, and array comparative genomic hybridization on uncultured amniocytes in a pregnancy with fetal pyelectasis. AB - OBJECTIVE: This study aimed at presenting prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome (sSMC) derived from chromosome 8 by fluorescence in situ hybridization (FISH), quantitative fluorescent polymerase chain reaction (QF-PCR), and array comparative genomic hybridization (aCGH) on uncultured amniocytes. MATERIALS, METHODS, AND RESULTS: A 32-year-old woman underwent amniocentesis at 19 weeks of gestation because of fetal pyelectasis. Amniocentesis revealed a de novo ring shaped sSMC in two of 21 colonies of cultured amniocytes. Repeated amniocentesis at 22 weeks of gestation revealed a karyotype of 47,XY,+mar[8]/46,XY[32] in cultured amniocytes. Spectral karyotyping and FISH confirmed that the sSMC was derived from chromosome 8. She underwent a third amniocentesis at 26 weeks of gestation. Oligonucleotide-based aCGH analysis on uncultured amniocytes demonstrated a 43 Mb genomic gain in chromosome 8 encompassing 8p22->q12.1. Polymorphic DNA marker analysis of the uncultured amniocytes revealed a maternal origin of the sSMC and excluded uniparental disomy 8. Interphase FISH analysis showed three D8Z2 signals in 8/40 (20%) of uncultured amniocytes. The cultured amniocytes had a karyotype of 47,XY,+r(8)(p22q12.1)[3]/46,XY[37]. The pregnancy was carried to term, and an apparently normal baby, weighing 3300 g, was delivered with mild hydronephrosis but no other phenotypic abnormalities. The cord blood was found to have a karyotype of 47,XY,+r(8)(p22q12.1)[2]/46,XY[38]. CONCLUSION: Prenatal diagnosis of fetal pyelectasis should alert obstetricians of chromosome aberration. Interphase FISH, QF-PCR, and aCGH analyses on uncultured amniocytes are helpful in rapid positive confirmation of an sSMC detected at amniocentesis. PMID- 23040927 TI - Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from ring chromosome 2. AB - OBJECTIVE: To present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from ring chromosome 2 [r(2)]. METHODS AND RESULTS: A 35-year-old woman underwent amniocentesis at 17 weeks of gestation, because of advanced maternal age. Amniocentesis revealed a de novo ring-shaped sSMC in 11 of 23 colonies of cultured amniocytes. Repeated amniocenteses were made. The sSMC was characterized by array comparative genomic hybridization (aCGH), interphase fluorescence in situ hybridization (FISH) and quantitative fluorescent polymerase chain reaction (QF-PCR) on uncultured amniocytes. In uncultured amniocytes, aCGH showed a 39.49 Mb genomic gain in chromosome 2 encompassing 2q11.2->q21.2, interphase FISH revealed a mosaic level of 52% (52/100 cells), and QF-PCR manifested a diallelic pattern for chromosome 2, with gene dosage increase in the paternal allele of proximal 2q-specific DNA markers. In cultured amniocytes, the sSMC was characterized by metaphase FISH, spectral karyotyping (SKY) and multicolor banding (MCB) to contain the centromere and proximal 2q, and the karyotype was 47,XX,+r(2)(p11.1q21.2)[14]/46,XX[11]. The pregnancy was terminated. The fetus postnatally manifested facial dysmorphisms. Postnatal cytogenetic analyses revealed the karyotypes of 47,XX,+r(2)[12]/46,XX[28] in cord blood, 47,XX,+r(2)[7]/46,XX[33] in umbilical cord, 47,XX,+r(2)[13]/47,XX,+idic r(2)[3]/46,XX[24] in placenta and 47,XX,+r(2)[8]/47,XX,+idic r(2)[1]/46,XX[31] in amnion. CONCLUSION: Molecular cytogenetic techniques such as aCGH, interphase FISH and QF-PCR on uncultured amniocytes, and SKY, MCB and metaphase FISH on cultured amniocytes are useful for characterization of the nature of a prenatally detected sSMC. PMID- 23040928 TI - Extensive hepatic infarction in severe preeclampsia as part of the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): evolution of CT findings and successful treatment with plasma exchange therapy. AB - OBJECTIVE: We describe the serial computed tomography (CT) findings of extensive hepatic infarction and successful plasma exchange therapy in a severe preeclamptic woman with postpartum HELLP syndrome. CASE REPORT: A 38 year-old woman presented with elevated blood pressure of 140-180/90-120 mmHg and 3+ proteinuria at 28 weeks of gestation. Two days after admission, the patient suddenly complained of severe epigastric pain and headache. Her blood pressure rose sharply to 195/120 mmHg. A 980 g female was delivered by emergency cesarean section. Following delivery, the patient's clinical condition and laboratory values deteriorated, with progressive liver insufficiency (peak AST level = 4246 IU/L, ALT = 3685 IU/L, LDH = 6237 IU/L, platelets = 72,000/mm(3)). Two consecutive plasma exchanges (PEX) were undertaken on the 3(rd) and 4(th) postpartum day. A contrast-enhanced CT of the abdomen performed 8 days postpartum showed geographically wedge-shaped areas of low attenuation, with a mottled appearance in the right hepatic lobe. Shortly thereafter, the patient recovered and all laboratory parameters gradually normalized 3 weeks after delivery. Follow up CT-scan of the liver 2 months postpartum showed no evidence of infarction, with complete recovery. CONCLUSION: We recommend that severely ill patients with HELLP syndrome having epigastric pain should undergo CT imaging of the liver. A trial of postpartum PEX therapy should be considered for treatment of the HELLP syndrome complicated with hepatic infarction, which is recalcitrant to conventional medical management, and fails to abate within 72-96 hours of delivery. PMID- 23040929 TI - Follicular variant of papillary thyroid carcinoma arising from a dermoid cyst: a rare malignancy in young women and review of the literature. AB - OBJECTIVE: Benign or mature cystic teratomas, also known as dermoid cysts, are composed of mature tissues, which can contain elements of all three germ cell layers. Malignant transformation of a mature cystic teratoma is more common in postmenopausal women, however, it can also, rarely, be identified in younger women. We present a case of a 19-year-old woman with malignant transformation of an ovarian mature cystic teratoma. CASE REPORT: Our case was a 19-year-old woman, who was diagnosed postoperatively with follicular variant of papillary thyroid carcinoma in a mature cystic teratoma. She underwent right cystectomy for adnexal mass. Postoperative metastatic workup revealed a non-metastatic disease and the patient did not undergo any further treatment. After 2 months, a near-total thyroidectomy was performed. Serum thyroglobulin levels were monitored on follow up and the patient is asymptomatic. CONCLUSION: Malignant transformation of a dermoid cyst is a rare ovarian neoplasm. We believe that unilateral oophorectomy or cystectomy is a reasonable treatment option for cases in which there is no evidence of capsular invasion, vascular invasion or gross metastasis, and preservation of fertility is desired. Total thyroidectomy was diagnosed in selected cases. Serial serum thyroglobulin should be used as a tumor marker for follow-up. PMID- 23040930 TI - Double-balloon cervical ripening catheter works well as an intrauterine balloon tamponade in post-abortion massive hemorrhage. AB - OBJECTIVE: Clinical experience in the management of post-abortion hemorrhage is limited. CASE REPORTS: Two women with severe post-abortion hemorrhage were reported. One case occurred after methotrexate treatment of Cesarean scar pregnancy and the other occurred after abortion surgery. Both patients were successfully treated with a double-balloon cervical ripening catheter inducing intrauterine balloon tamponade. CONCLUSION: Use of a double-balloon cervical ripening catheter either before or after systemic methotrexate treatment is one of the choices in the management of severe post-abortion hemorrhage and can prevent the use of more invasive and/or destructive procedures. PMID- 23040931 TI - Monozygotic twins with trisomy 18 of paternal origin: prenatal diagnosis and molecular cytogenetic characterization in a pregnancy with one structurally abnormal living fetus and one intrauterine fetal demise. AB - OBJECTIVE: To present prenatal diagnosis and molecular cytogenetic characterization of trisomy 18 in a monozygotic twin pregnancy, with one structurally abnormal living fetus and one intrauterine fetal demise. CASE REPORT: A 38-year-old woman was referred for amniocentesis at 16 weeks of gestation because of advanced maternal age. Prenatal ultrasound revealed a monozygotic twin pregnancy, with one structurally abnormal living fetus, and one fetal demise. The body structure details of the dead fetus could not be identified, whereas holoprosencephaly and omphalocele were identified in the living fetus on prenatal ultrasound. Quantitative fluorescent polymerase chain reaction assays using polymorphic DNA markers specific for chromosome 21 and chromosome 18, were applied to the uncultured amniocytes in the amniotic cavity of the living fetus and the cultured amniocytes in the amniotic cavity of the fetus with intrauterine fetal demise. The specimen showed a dosage ratio of 2:1 (paternal:maternal) for chromosome 18-specific markers in both twins. The result was consistent with monozygosity and trisomy 18, and the trisomy 18 was possibly caused by a paternal second meiotic division non-disjunction error or a postzygotic mitotic error. Conventional cytogenetic analysis revealed a karyotype of 47,XY,+18 in both twins. The pregnancy was terminated at 19 weeks of gestation, and a 2g small-for-date macerated twin A and a 166g malformed twin B were delivered. Twin A manifested cebocephaly and omphalocele, and twin B manifested premaxillary agenesis and omphalocele. CONCLUSION: The present case provides evidence that fetal wastage may occur in one of the co-twins in monozygotic twins associated with trisomy 18, and this may in part explain the very rare occurrence of living monozygotic twins with trisomy 18. PMID- 23040932 TI - Pure partial monosomy 3p (3p25.3 -> pter): prenatal diagnosis and array comparative genomic hybridization characterization. AB - OBJECTIVE: The purpose of this case report is to present prenatal diagnosis and molecular cytogenetic characterization of pure partial monosomy 3p (3p25.3 -> pter) by array comparative genomic hybridization (aCGH) and quantitative fluorescent polymerase chain reaction (QF-PCR) on uncultured amniocytes. CASE REPORT: A 35-year-old, gravida 2, para 0, woman underwent amniocentesis at 19 weeks of gestation because of advanced maternal age. Her husband was 37 years of age. She had experienced one intrauterine fetal death. Amniocentesis during this pregnancy revealed a distal deletion of chromosome 3p. The parental karyotypes were normal. Prenatal ultrasonography findings were unremarkable. At 22 weeks of gestation, she underwent repeated amniocentesis, and aCGH investigation using CytoChip Oligo Array on uncultured amniocytes revealed a 9.29-Mb deletion of 3p26.3p25.3 [arr 3p26.3p25.3 (64,096-9,357,258 bp) *1] encompassing the genes of CHL1, CNTN4, CRBN, LRRN1, ITPR1, and SRGAP3, but not involving the markers D3S1263 and D3S3594. Polymorphic DNA marker analysis on uncultured amniocytes showed a paternal origin of the deletion. Cytogenetic analysis of cultured amniocytes revealed a karyotype of 46,XX,del(3)(p25.3). At 24 weeks of gestation, prenatal ultrasonography findings of the brain, heart, and other internal organs were unremarkable. The pregnancy was subsequently terminated, and an 886-g female fetus was delivered with brachycephaly, hypertelorism, a short and thick nose, micrognathia and low-set ears. CONCLUSION: In this case, aCGH has characterized a 3p deleted region with haploinsufficiency of the neurodevelopmental genes associated with cognitive deficit and mental retardation but without involvement of the congenital heart disease susceptibility locus, and QF-PCR has determined a paternal origin of the deletion. aCGH and QF-PCR help to delineate the genomic imbalance in prenatally detected de novo chromosome aberration, and the information acquired is useful for genetic counseling. PMID- 23040933 TI - Exaggerated placenta site in placenta previa: an imaging differential diagnosis of placenta accreta, placental site trophoblastic tumor and molar pregnancy. PMID- 23040934 TI - Primary gallbladder carcinoma presenting as advanced-stage ovarian cancer. PMID- 23040935 TI - Squamous cell carcinoma occurring in the pelvis after total hysterectomy and bilateral salpingo-oophorectomy for an ovarian mature teratoma with malignant transformation. PMID- 23040936 TI - Tuberculosis of the uterine cervix. PMID- 23040937 TI - Rapid progression of synchronous ovarian and endometrial cancers with massive omental carcinomatosis. PMID- 23040938 TI - Laparoscopic adhesiolysis and marsupialization of a rapidly progressing pelvic pseudocyst. PMID- 23040939 TI - Ovarian pregnancy following intrauterine insemination. PMID- 23040940 TI - Retroperitoneal gossypiboma 25 years after abdominal hysterectomy. PMID- 23040941 TI - Peritoneal papillary serous cystadenocarcinoma at a previous laparoscopic trocar site. PMID- 23040942 TI - Limb salvage treatment in a 25-year-old woman with stage IVB endometrial cancer presenting with hip bone metastasis. PMID- 23040943 TI - Hysteroscopic surgery can be performed around the day of ovulation without affecting implantation. PMID- 23040944 TI - Usefulness of interphase FISH on uncultured amniocytes for rapid confirmation of low-level trisomy 7 mosaicism in a pregnancy with fetal intrauterine growth restriction and microcephaly. PMID- 23040945 TI - Rapid positive confirmation of trisomy 21 mosaicism at amniocentesis by interphase FISH, QF-PCR and aCGH on uncultured amniocytes. PMID- 23040946 TI - Rapid aneuploidy diagnosis of trisomy 18 by array comparative genomic hybridization using uncultured amniocytes in a pregnancy with fetal arachnoid cyst detected in late second trimester. PMID- 23040947 TI - Prenatal diagnosis and array comparative genomic hybridization characterization of a de novo X;Y translocation. PMID- 23040948 TI - Was acute renal failure induced by ureter catheters? PMID- 23040949 TI - Factors influencing the occurrence of pelvic cellulitis in women undergoing laparoscopic-assisted vaginal hysterectomy. PMID- 23040950 TI - Acute ischemic stroke in gamma-sarcoglycanopathy. PMID- 23040951 TI - [Primary antibiotic prophylaxis of spontaneous bacterial peritonitis in cirrhotic patients is a matter of target!]. PMID- 23040952 TI - [Revisiting IgG subclass measurement]. PMID- 23040953 TI - [Drug dependence: Progress in neurobiology and perspectives in therapeutics]. AB - The knowledge on neurobiology of drug dependence substantially progressed with animal models. All drug of abuse share the effect of an increase of dopamine in nucleus accumbens that contributes to induce dependence. Chronic drug use disrupts numerous neurotransmission systems (glutamate, serotonin, neuropeptides...) and this may participate in relapse. Therapeutic approaches are classified in two types: agonist strategies consist of drug replacement by medicine acting on the same target and strategies using medicines acting on multiple neurotransmission systems. PMID- 23040955 TI - [Cannabis: Use and dependence]. AB - The main characteristics of cannabis dependence are craving, persistent desire or unsuccessful efforts to cut down or control cannabis use and important social, occupational, or recreational activities given up or reduced because of cannabis use. Withdrawal symptoms include insomnia, irritability, anger, restlessness, depression, mood swings and cravings. Regular cannabis use induces cognitive impairment, especially of attention, episodic memory and working memory. Alcohol and other substances abuse or dependence are frequently found in patients with cannabis dependence. Psychiatric comorbidities are frequent in patients with cannabis dependence, in particular anxiety disorders, mood disorders, and personality disorders. The treatment of cannabis dependence includes behavioral psychotherapy, especially motivational interviewing and cognitive-behavioral therapy, alongside treatment of co-occurring mental health and substance use conditions. There are currently no available pharmacological treatment interventions for cannabis dependence. The treatment of cannabis dependence and withdrawal remains nonspecific. PMID- 23040954 TI - [Addictive behavior among the elderly]. AB - Addictive behavior still persists among the elderly, mainly concerning substance abuse, such as alcohol, tobacco or psychotropic drugs and addictive practices such as gambling. Illegal substances or cyber-addictions appear much less often. The environment (place of residence or care) and/or economic factors may influence behavior and practices. The incidence of somatic illness or psychiatric disorders, such as cognitive impairment among the elderly patients, complicates even further the presentation of addictive disorders and their treatment. The age factor does not seem to lessen the suffering felt by the patient and care is required in an equal manner for all ages. Prevention (maintenance of personal autonomy and quality of life throughout the ageing process) plays an essential role along with the offer of care. The lack of scientific data such as the absence of validation for adult care among the elderly, leave wide scope for epidemiological, clinical and theoretical research. PMID- 23040956 TI - Comparison of CT and DWI findings in ischemic stroke patients within 3 hours of onset. AB - This study compared the detection rate of ischemic lesions within 3 hours of onset by computed tomography (CT) and diffusion-weighted magnetic resonance imaging (DWI). The study group comprised 130 patients (71 men; median age, 75 years) with an anterior territory stroke who underwent CT and DWI within 3 hours of onset. The lesions revealed on CT and DWI were assessed using the CT-Alberta Stroke Program Early CT Score (ASPECTS) and DWI-ASPECTS, and detection rates were compared for each ASPECTS region. The detection rate of ischemic lesions was higher on DWI than on CT (76.9% v 30.0%; P < .001). The DWI-ASPECTS score was not correlated with the CT-ASPECTS score (r = 0.51; P < .001). Ischemic lesions were detected in the insula (59.2% for DWI vs 15.4% for CT; P < .001), lentiform nucleus (43.8% v 20.0%; P < .001), and the M1 (30.8% v 6.9%, P < .001), M2 (50.8% v 6.2%; P = .006), M3 (28.5% v 3.1%; P = .006), M4 (32.3% v 6.9%; P < .001), M5 (48.5% v 10.8%; P < .001), and M6 (31.5% v 4.6%, P = .012) areas of the middle cerebral artery. DWI detected ischemic lesions significantly more frequently than CT in all ASPECTS regions except the caudate head and internal capsule. PMID- 23040957 TI - Unilateral opercular infarction presenting with Foix-Chavany-Marie Syndrome. AB - A 76-year-old man with a history of pontine, cerebellar infaction suddenly became speechless during the procedure of percutaneous coronary intervention. On examination, he was unable to close his mouth voluntarily, but spontaneous closing was preserved when smiling. He had anarthria and hypophonia, although his comprehension was preserved. He also had a severe dysphagia. Radiological studies revealed an acute stroke in the left anterior operculum, indicating Foix-Chavany Marie Syndrome (FCMS) caused by a unilateral opercular lesion. Pathophysiology of the previous cases reported as unilateral FCMS remains controversial, but in our case, it could be delineated by the combination of the new lesion in the unilateral operculum and the old one in the contralateral pons. Since FCMS is not only related to biopercular lesions, we should consider thorough radiologic examination to clarify its anatomic basis. PMID- 23040958 TI - Mind the gap: Response to Garcia-Ruiz PJ (2011) Gait disturbances in Parkinson disease. Did freezing of gait exist before levodopa? Journal of the Neurological Sciences 307: 15-17. PMID- 23040959 TI - Rituximab reduces attacks in Chinese patients with neuromyelitis optica spectrum disorders. AB - We evaluated the safety and efficacy of rituximab in seven Chinese patients with neuromyelitis optica (NMO) or neuromyelitis optica syndrome disorders (NMOSD) in a tertiary medical center in Hong Kong. After rituximab induction, five patients became relapse-free and two had 50% reduction of relapses over a median follow-up of 24 months. No further deterioration of functional status, measured by the Expanded Disability Status Scale, was observed in all patients. Infusions were well tolerated except in two patients who developed transient hypotension. Rituximab reduced clinical relapse and prevented neurological deterioration in a small cohort of Chinese patients with NMO or NMOSD. PMID- 23040960 TI - Early tolerability and safety of fingolimod in clinical practice. AB - BACKGROUND: Fingolimod is approved by the U.S. Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. Several screening studies and a first-dose observation (FDO) period are recommended due to adverse effects observed in clinical trials. OBJECTIVE: The objective of this study is to describe the early experience with fingolimod, including startup, tolerability and safety in a large academic multiple sclerosis (MS) center. METHODS: Patients prescribed fingolimod from September 2010 to July 2011 were identified through electronic medical records. Demographics, MS disease history, pre-treatment screening studies, FDO experience during shared medical visits and three month follow-up data were analyzed. RESULTS: Three hundred ninety-one patients were prescribed fingolimod of whom 317 started the medication and were included in the analysis. Fingolimod was most frequently used in relapsing remitting MS (n=256, 80.8%) and was prescribed as a first-line agent in 11 cases (3.5%). FDO was uneventful in 308 patients (96.8%). Adverse events during FDO were self limited and included symptomatic bradycardia (n=3), chest tightness (n=2) and hypertension (n=1). Fingolimod was discontinued in 30 patients (9.5%) at three months. Adverse effects leading to discontinuation by more than one patient included headache (n=4), macular edema (n=3), nausea (n=3) and hypertension (n=2). CONCLUSIONS: Fingolimod was well tolerated during FDO and adverse events were self limited. The shared medical visit is an appropriate setting for FDO. Adverse effects were similar to those described in clinical trials but the discontinuation rate was higher. PMID- 23040961 TI - Hemolacria: case report. AB - Hemolacria is a very rare entity which literally means "bloody tears". Conjunctivitis, capillary hemangioma, conjunctival telangiectasia, trauma, retrograde epistaxis and nasal and paranasal neoplasms may play a role in its etiology. In our case report, a 11-year-old female patient who presented with the complaint of bilateral epistaxis accompanied by bloody tears that had been present for 2 years and whose endoscopic examination revealed hyperemia and increased vascularity in the nasal cavity mucosa was discussed together with a review of the literature. PMID- 23040962 TI - Preoperative computed tomography of suspected thyroglossal duct cysts in children under 10-years-of-age. AB - OBJECTIVE: The purpose of this study was to evaluate the preoperative computed tomography (CT) features of thyroglossal duct cysts (TDCs), with the main purpose of evaluating criteria helpful in differentiating TDCs from other lesions in children under 10-years-of-age. METHODS: A retrospective chart review was performed at Chonnam National University Hospital for the period of March 2005 to June 2011. Pediatric patients under 10-years-of-age with suspected TDCs were divided into two groups depending on their histopathologic diagnosis. RESULTS: Of the 29 pediatric patients with suspected TDCs, 16 patients (55%) had histopathologically confirmed TDCs. Thirteen patients (45%) had dermoid cysts (n=6), ranula (n=3), and inflammatory lesions (n=4). There were no statistically significant differences between the preoperative CT findings and the final histopathologic diagnosis of TDC. There were no major complications resulting from surgical interventions. CONCLUSION: CT is not helpful in differentiating TDC from other lesions in children under 10-years-of-age. Therefore, we suggest that preoperative CT of suspected TDCs in children should be performed more selectively. PMID- 23040963 TI - Removal of impacted cerumen in children using an aural irrigation system. AB - OBJECTIVES: Impacted cerumen in the ear canal is a common problem that can cause discomfort or prevent assessment. Cerumen removal can have deleterious side effects if performed improperly. We created an aural irrigation system which is currently not available on the market to provide a continuous flow of water at a regulated pressure and temperature. The purposes of this study were to (1) evaluate the safety and efficacy of this aural irrigation system in children and (2) determine the success rate of cerumen disimpaction when used by an allied health professional. METHODS: The following were evaluated in a nurse-run clinic: (1) referral patterns; (2) extent of canal occlusion; (3) cerumen consistency; (4) peak water pressure used; (5) patient discomfort; (6) efficacy of removal. Each ear was recorded as a separate event. RESULTS: 302 procedures were performed on 244 children (mean age 7.6 +/- 4.1 years (range 0.5-18.3 years)). Patients were most commonly referred by an Otolaryngologist (63%), parent (17%), hearing aid provider (10%) or audiologist (9%). The most common reasons for referral were difficulty seeing the tympanic membrane (42%), fitting a hearing aid (20%) or performing an audiogram (11%). Prior to irrigation, 98% of canals were partially or fully occluded. After irrigation (mean peak pressure=488.21 +/- 18.61 mm Hg (range 390-590 mm Hg), 92% of canals were completely free of cerumen (99% clear enough for evaluation or treatment). There was mild or no discomfort in 99% of patients and there were no incidences of trauma. CONCLUSIONS: An aural irrigation system can be effective at clearing impacted cerumen from pediatric ear canals with minimal discomfort and no trauma and can be successfully employed in a completely nurse-run clinic. PMID- 23040964 TI - Easy and accurate calculation of programmed temperature gas chromatographic retention times by back-calculation of temperature and hold-up time profiles. AB - Linear retention indices are commonly used to identify compounds in programmed temperature gas chromatography (GC), but they are unreliable unless the original experimental conditions used to measure them are stringently reproduced. However, differences in many experimental conditions may be properly taken into account by calculating programmed-temperature retention times of compounds from their measured isothermal retention vs. temperature relationships. We call this approach "retention projection". Until now, retention projection has been impractical because it required very precise, meticulous measurement of the temperature vs. time and hold-up time vs. temperature profiles actually produced by a specific GC instrument to be accurate. Here we present a new, easy-to-use methodology to precisely measure those profiles: we spike a sample with 25 n alkanes and use their measured, programmed-temperature retention times to precisely back-calculate what the instrument profiles must have been. Then, when we use those back-calculated profiles to project retention times of 63 chemically diverse compounds, we found that the projections are extremely accurate (e.g. to +/-0.9 s in a 40 min ramp). They remained accurate with different temperature programs, GC instruments, inlet pressures, flow rates, and with columns taken from different batches of stationary phase while the accuracy of retention indices became worse the more the experimental conditions were changed from the original ones used to measure them. We also developed new, open-source software (http://www.retentionprediction.org/gc) to demonstrate the system. PMID- 23040965 TI - Usefulness of the European Epidemic Intelligence Information System in the management of an outbreak of listeriosis, Belgium, 2011. AB - A cluster of time-linked cases and the identification of a clonal strain suggest the occurrence of an outbreak of listeriosis in Belgium in 2011, presumably due to the consumption of hard cheese made with pasteurised milk and produced by a Belgium manufacturer. The outbreak clone was identified as Listeria monocytogenes serovar 1/2a, sensitive to arsenic and cadmium and of multilocus sequence typing MLST-type 37. Food investigation of this outbreak was facilitated by the European Epidemic Intelligence Information System and data exchanged between French and Belgium listeriosis surveillance systems. PMID- 23040966 TI - Influenza-associated hospitalisations in Finland from 1996 to 2010: unexpected age-specific burden during the influenza A(H1N1)pdm09 pandemic from 2009 to 2010. AB - To assess the burden of influenza on the Finnish healthcare system, we analysed hospitalisations during 1996-2010 using the International Classification of Diseases codes potentially related to influenza and its complications from the national hospital discharge registry. To compare the influenza A(H1N1)pdm09 pandemic with previous influenza seasons in 1996-2009, we calculated hospitalisation rates by age- and diagnostic groups. We built a negative binomial regression model based on times series analysis to assess the impact of the pandemic. Influenza-associated hospitalisation rates were higher during the pandemic compared to pre-pandemic influenza seasons for 5-24 year-olds (incidence rate ratio (IRR): 1.52, 95% confidence interval (CI): 1.44-1.60) and 25-64 year olds (IRR: 1.33, 95% CI: 1.29-1.36), but did not differ for persons aged >= 65 years (IRR: 0.98, 95% CI: 0.97-1.00). Hospitalisation rates exceeded the upper limit of the prediction line by 177% in 5-24 year-olds, 66% in 0-4 year-olds and 57% in 25-64 year-olds. During the influenza season of 2003/04, all age groups had higher-than-expected hospitalisation rates, whereas other seasonal peaks were only notable among persons aged >= 65 years. These age-specific differences in the hospital burden underscore the importance of the continuous surveillance of hospitalisations in order to evaluate immunisation priorities for seasonal influenza and pandemic preparedness including use of antiviral medication. PMID- 23040967 TI - What really happens to tuberculosis patients classified as lost to follow-up in West Yorkshire? AB - Tuberculosis (TB) patients who do not complete treatment pose a potential public health risk. In West Yorkshire, local clinicians suspected that this risk was overestimated by the national Enhanced Tuberculosis Surveillance system. We audited patients who failed to complete treatment and were categorised as lost-to follow-up (LTFU) between 2004 and 2008, using a combination of hand searching existing records and obtaining additional information from clinicians. In the study period 2,031 TB cases with reported outcome were notified in West Yorkshire, 23% (n=474) did not complete treatment, and 199 (42%) of those were categorised as LTFU 12 months after notification. Of these 199, 49% (n=98) remained LTFU after the audit, 51% (n=101) were re-classified to the following categories: 24% (n=47) transferred abroad, 16% (n=31) recommenced and completed treatment, 6% (n=13) transferred to another clinic in the United Kingdom (UK), and 5% (n=10) died. These patients therefore no-longer posed a public health risk. Further training for clinicians to improve accuracy of outcome reporting has been initiated. Nationally, the collection of treatment outcome data needs to be strengthened and extending the follow-up for treatment outcome monitoring should be considered. PMID- 23040969 TI - The emerging field of transport engineering of plant specialized metabolites. AB - From a biotechnological perspective transport processes represent attractive targets for modulation of metabolite levels and are the foundation for the emerging field of transport engineering. Potential applications of transport engineering include control of metabolite accumulation in a tissue-specific manner in crop plants as well as increased yields of commercially valuable compounds produced in synthetic biology approaches. Within specialized metabolism, recent advances include identification of not only vacuolar but now also plasma membrane-localized transporters and neo-functionalization of members of primary metabolite transporter families to include specific roles in transport of specialized metabolites. As glucosinolates are specialized metabolites of the model plant Arabidopsis, glucosinolate transport processes emerge as a model system for studying transport of specialized metabolites. PMID- 23040970 TI - Ab initio determination of geometries and vibrational characteristics of building blocks of organic super-conductors: TTF and its derivatives. AB - Molecular behavior of the building block {[2-(1,3-dithiole-2-ylidene)-1,3 dithiole] = tetrathiafulvalene (TTF)} of organic superconductors have been investigated along with its three derivatives, namely, {[2-(1,3-dioxole-2 ylidene)-1,3-dioxole] = tetraoxafulvalene (TOF)}; [2,2]-bi -[[1,3] oxathiolylidene] = Der I and 2-(3H-Furan-2-ylidene)-[1,3] oxathiole = Der II. The properties of the molecules such as molecular geometries, frontier MOs and vibrational spectra have been investigated by using DFT method at the B3LYP level employing 6-311++G(d,p) basis set. The geometrical parameters and atomic charges on various atomic sites of the TTF, TOF, Ders I and II suggest extended conjugation in these systems. The present calculations lead to the reassignments for of some of the fundamentals and new interpretations for some of the observed IR and Raman frequencies. One of the two modes involved in the Fermi resonance giving rise to the doublet 1555 and 1564 cm(-1) needed to be revised and another doublet 3083 and 3108 cm(-1) could be interpreted as a Fermi resonance doublet. Out of the two nu(C = C) modes under the a(1) species, the lower frequency mode is assigned to the nu(C = C) of the ring and the higher one to the nu(C = C) of the central C = C bond contrary to the assignment reported in literature. The conducting properties of these molecules depend mainly on this mode. PMID- 23040971 TI - Guilt by dissociation: guilt primes augment the relationship between dissociative tendencies and state dissociation. AB - We examined the influence of guilt on the relationship between dissociative tendencies and state dissociation during mirror-gazing in a non-clinical sample. Dissociative tendencies correlated with state dissociation following guilt primes, but not after negative or neutral primes. This suggests that guilt augments the relationship between dissociative tendencies and state dissociation. PMID- 23040972 TI - Self-organisation, inference and cognition: comment on "Consciousness, crosstalk, and the mereological fallacy: an evolutionary perspective" by Rodrick Wallace. PMID- 23040973 TI - Psychosocial health and levels of employment in 851 hypopituitary Swedish patients on long-term GH therapy. AB - CONTEXT: The psychosocial health and working capacity in hypopituitary patients receiving long-term growth hormone (GH) therapy are unknown. OBJECTIVE: Psychosocial health and levels of employment were compared between GH deficient (GHD) patients on long-term replacement and the general population. DESIGN AND PARTICIPANTS: In a Swedish nationwide study, 851 GHD patients [101 childhood onset (CO) and 750 adult onset (AO)] and 2622 population controls answered a questionnaire regarding current living, employment and educational level, alcohol consumption and smoking habits. The median time on GH therapy for both men and women with CO GHD was 9 years and for AO GHD 6 years, respectively. RESULTS: As compared to the controls, the GHD patients were less often working full time, more often on sick leave/disability pension, and to a larger extent alcohol abstainers and never smokers (all; P<0.05). Predominantly CO GHD women and men, but to some extent also AO GHD women and men, lived less frequently with a partner and more often with their parents. Particularly AO GHD craniopharyngioma women used more antidepressants, while AO GHD men with a craniopharyngioma used more analgesics. CONCLUSIONS: A working capacity to the level of the general population was not achieved among hypopituitary patients, although receiving long term GH therapy. Patients were less likely to use alcohol and tobacco. The CO GHD population lived a less independent life. PMID- 23040974 TI - Cleaning sorbents used in matrix solid-phase dispersion with sonication: application to the estimation of polycyclic aromatic hydrocarbons at ng/g levels in marine sediments. AB - This study shows that ultrasonic assisted extraction is a good practise for removing impurities from sorbents used for matrix-solid phase dispersion (MSPD). A previous washing of the sorbent with an organic solvent or mixture of solvents eliminates part of the interferences, but this treatment is not enough for the quantification of PAHs at ng/g levels. It is demonstrated that the determination of traces of polycyclic aromatic hydrocarbons (PAHs) in solid samples processed by matrix-solid phase dispersion (MSPD) may be severely affected by the presence of sorbent impurities. Different extraction solvents and sonication conditions have been tested, and on the basis of the results obtained a new approach is presented for cleaning sorbents typically used in MSPD such C(18), silica or Florisil. The utility of the described approach has been illustrated by analysing by liquid chromatography and fluorescence detection different marine sediments. PMID- 23040975 TI - A comparison of the chromatographic properties of silica gel and silicon hydride modified silica gels. AB - The retention properties of a silica gel column and a type C silica (silicon hydride) column for bases, sugars and polar acids were compared in hydrophilic interaction chromatography (HILIC) mode with formic acid or ammonium acetate as aqueous phase modifiers. The type C silica column was much more retentive for a series of model bases than the silica gel column and, surprisingly, retention of bases increased on the type C silica column when, the higher pH, ammonium acetate containing mobile phase was used. The retention of sugars was greater on the type C silica column than on the silica gel column and also increased on the type C silica column with increased pH suggesting either a silanophilic mechanism of retention or some unknown mechanism. Three type C silica based columns, type C silica, cogent diamond hydride and a beta-pinene modified column, which it was hoped might exert some additional stereochemical discrimination, were tested for metabolomic profiling of urine. In general the unmodified type C silica column gave the strongest retention of the many polar metabolites in urine and could provide a useful complement to established HILIC methods for metabolomic profiling. PMID- 23040976 TI - Potential advantage of constant pressure versus constant flow gradient chromatography for the analysis of small molecules. AB - A recent model designed to predict the variation of the flow rate with time in constant pressure (cP) gradient chromatography was validated from an experimental viewpoint for non-retained gradients (methanol-water), incompressible eluent (P<250 bar), and in absence of pressure effects on the analyte retention pattern (small molecules). Experimental data confirmed that cP and constant flow (cF) gradients are strictly equivalent if the analysis time is kept constant. The same model was also used to predict the gradient kinetic performance of cP versus cF gradients when the constraint was the maximum inlet pressure at which the column and/or the HPLC system can safely be run. For linear volume gradients of methanol in water (5-95% in volume) and a maximum pressure of 250 bar, the same peak capacity as that in cF mode is predicted in cP mode. Also, a reduction of the analysis time by 17.3% was expected. These theoretical results were confirmed by separating a real mixture of about twenty small molecules on either one or two 4.6 mm * 150 mm columns packed with 3.5 MUm Bridge Ethylene Hybrid (BEH) C(18) particles and run at flow rates smaller than 0.8 mL/min and at a maximum inlet pressure of 250 bar. The experimental gain in analysis time was 17.6% (1 column) and 20.1% (2 columns in series) for a virtually insignificant loss of peak capacity (-4%). PMID- 23040977 TI - Impact of mobile phase composition on the performance of porous polymeric monoliths in the elution of small molecules. AB - The influence of mobile phase solvent composition and consequently retention factor on the chromatographic performance for a set of small molecules was studied using a commercially available poly(styrene-co-divinyl benzene) analytical scale porous polymeric monolithic column as an example. Chromatographic elution performance was studied across retention factors from close to 0 up to 100 realized for a set of structurally similar small molecules in a binary reversed-phase solvent environment of acetonitrile and water. By altering the mobile phase composition from volume fractions of acetonitrile of just 10% (v/v) to only acetonitrile it was systematically shown that gel porosity of the monolithic column plays a dominant role in modulating mass transport and the associated chromatographic efficiency in a consistent manner. Up to a sixfold difference in plate height was recorded for the most strongly retained hydrophobic solute (ethylbenzene) at a constant, low flow velocity simply by varying the amount of acetonitrile in the mobile phase. Plate height curves recorded for the set of solutes that comprise benzene, toluene, ethylbenzene as well as phenol and benzyl alcohol further demonstrate the importance of functional group content of the solute and the modulated porous gel structure on mass transport. These results highlight some important practical considerations for characterizing the chromatographic properties of any polymeric monolithic column. First, it is imperative that any chromatographic performance characterization using plate height data explicitly considers the influence of mobile phase composition, retention factor, molecular size and functional groups of the probe solute. Second, as the physicochemical conditions of the material are directly reflected in the gel porosity, a range of different mobile phase compositions, retention factors and probe-specific effects must be investigated to yield a fair appraisal of the chromatographic performance. PMID- 23040978 TI - How changing the particle structure can speed up protein mass transfer kinetics in liquid chromatography. AB - The mass transfer kinetics of a few compounds (uracil, 112 Da), insulin (5.5 kDa), lysozyme (13.4 kDa), and bovine serum albumin (BSA, 67 kDa) in columns packed with several types of spherical particles was investigated under non retained conditions, in order to eliminate the poorly known contribution of surface diffusion to overall sample diffusivity across the porous particles in RPLC. Diffusivity across particles is then minimum. Based on the porosity of the particles accessible to analytes, it was accurately estimated from the elution times, the internal obstruction factor (using Pismen correlation), and the hindrance diffusion factor (using Renkin correlation). The columns used were packed with fully porous particles 2.5 MUm Luna-C(18) 100 A, core-shell particles 2.6 MUm Kinetex-C(18) 100 A, 3.6 MUm Aeris Widepore-C(18) 200 A, and prototype 2.7 MUm core-shell particles (made of two concentric porous shells with 100 and 300 A average pore size, respectively), and with 3.3 MUm non-porous silica particles. The results demonstrate that the porous particle structure and the solid-liquid mass transfer resistance have practically no effect on the column efficiency for small molecules. For them, the column performance depends principally on eddy dispersion (packing homogeneity), to a lesser degree on longitudinal diffusion (effective sample diffusivity along the packed bed), and only slightly on the solid-liquid mass transfer resistance (sample diffusivity across the particle). In contrast, for proteins, this third HETP contribution, hence the porous particle structure, together with eddy dispersion govern the kinetic performance of columns. Mass transfer kinetics of proteins was observed to be fastest for columns packed with core-shell particles having either a large core-to-particle ratio or having a second, external, shell made of a thin porous layer with large mesopores (200-300 A) and a high porosity (~/=0.5-0.7). The structure of this external shell seems to speed up the penetration of proteins into the particles. A stochastic model of the penetration of bulky proteins driven by a concentration gradient across an infinitely thin membrane of known porosity and pore size is suggested to explain this mechanism. Yet, under retained conditions, surface diffusion speeds up the mass transfer into the mesopores and levels the kinetic performance of particles built with either one or two porous shells. PMID- 23040979 TI - Synthesis of polychlorinated terphenyl mixtures and gas chromatography with mass spectrometry data of tetra- to octachlorinated ortho-, meta-, and para terphenyls. AB - Polychlorinated terphenyls (PCTs) are a class of polyhalogenated compounds previously used in similar applications as polychlorinated biphenyls (PCBs). According to present knowledge all industrial production was closed in the 1970s. The total PCT manufacture reached about 5% of the production of PCBs. Unlike the PCBs, PCTs have been scarcely analyzed in environmental samples mostly due to analytical difficulties. PCTs were synthesized by the chlorination of technical terphenyl which consists of ortho-, meta- and para-terphenyls. This procedure led to very complex mixtures of polychlorinated compounds whose composition, especially with regard to the terphenyl backbones, remained unknown. Here we report the individual chlorination of the three terphenyl backbones to mixtures of Tetra- to OctaCTs, respectively. The average degree of chlorination of the ortho-, meta- and para-PCTs ranged from 6.8 to 7.4. These products were analyzed by gas chromatography with mass spectrometry in electron ionization (GC/EI-MS) and electron capture negative ion (GC/ECNI-MS) modes. The elution order of isomers was ortho-PCTs?meta-PCTs= 30 years (mean age 45.6 years, 45% men) free of CVD at baseline were followed for a median of 9.3 years to assess risk for CVD. We assessed the predictability of definitions of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III), the International Diabetes Federation (IDF), the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI), and the joint interim statement (JIS) on development of CVD. Hazard ratios (HRs) were calculated using Cox proportional-hazards models. The receiver operating characteristic (ROC) curve was also used to compare discriminative power of these MetS definitions in predicting CVD events. RESULTS: Compared to other definitions, the JIS identified more participants (41.8%) having MetS. First CVD events occurred in 311 subjects. After adjustment for potential confounders, the HRs of the NCEP-ATP III, AHA/NHLBI, IDF and JIS definitions for incident CVD were 1.55 (1.21-2.00), 1.73 (1.35-2.20), 1.54 (1.22 1.94) and 1.70 (1.34-2.17), respectively. All definitions showed higher HRs for females in comparison to males (P<0.05). ROC analysis showed no significant difference in the discriminative power of different MetS definitions in predicting CVD events (P>0.05). CONCLUSIONS: In the current study, compared to each other none of the definitions showed a superior discriminative power in predicting CVD; although, all definitions were more predictive in females than in males. PMID- 23041002 TI - Effective sleep apnoea treatment improves cardiac function in patients with chronic heart failure. AB - BACKGROUND: Sleep disordered breathing (SDB) is highly prevalent in patients with chronic heart failure (CHF) and is associated with adverse effects on cardiac geometry and function. Continuous positive airway pressure (CPAP) has been proved an effective treatment modality for obstructive sleep apnoea (OSA), whereas adaptive servoventilation (ASV) is more effective in patients with central sleep apnoea (CSA). The impact of selection of therapy and effective apnoea alleviation on cardiac performance and reverse left ventricular remodelling (r-LVR) has not yet been evaluated. METHODS: Eighty five patients with stable CHF were screened for SDB and underwent polysomnography and treatment according to the type of SDB. Clinical evaluation and a comprehensive echocardiographic study was performed before initiation of therapy and after six months of effective treatment (ventilator use >5h/day with AHI <5 events/h). RESULTS: Seventeen compliant patients under effective treatment were included in the analysis (8 OSA under Autoset CPAP and 9 CSA under ASV). In both groups, a significant improvement in all measured, conventional and TDI LV systolic indexes was recorded, including LVEF (32% +/- 6% vs. 27% +/- 6%, p<0.001). A decrease in LV end-systolic volume (189 +/- 94 ml vs. 211 +/- 88 ml, p=0.015, difference >10%) was indicative of r LVR. Furthermore, RV systolic parameters were also increased (TAPSE, p<0.001; systolic TDI wave from lateral tricuspid annular aspect, p=0.001), whereas right heart dimensions and areas were diminished, indicating better pulmonary haemodynamics. Moreover, a significant improvement in patients' clinical status, as evaluated by New York Heart Association Class was also documented at the end of six months follow-up. CONCLUSIONS: Effective alleviation of SDB in CHF patients is associated with significant improvements in LV and RV systolic function and r-LVR. Longitudinal studies are needed to evaluate effects on morbidity and mortality. PMID- 23041004 TI - Hamartoma of mature cardiac myocytes in adults and young: case report and literature review. PMID- 23041005 TI - Concentric left ventricular remodeling and aortic stiffness: a comparison of obesity and hypertension. AB - BACKGROUND: Increased thoracic ascending aortic stiffness is thought to contribute to concentric left ventricular hypertrophy and increased mortality, a pattern seen in hypertension. As such, aortic stiffness and increased left ventricular mass are candidates by which obesity increases cardiovascular risk. However, obesity is characterized predominantly by increased abdominal aortic stiffness and with eccentric left ventricular hypertrophy. METHODS: We aimed to establish whether or not, in addition to these changes, there is also an element of concentric remodeling in obesity that was predicted by ascending aortic stiffness. 301 subjects underwent cardiovascular magnetic resonance imaging to measure regional aortic distensibility and left ventricular morphology. To compare obesity with hypertension, subjects were separated into groups by hypertensive status and body mass index. RESULTS: In comparison to normotensive subjects, hypertension was linked with concentric remodeling (a 17% increase in left ventricular mass:volume ratio (LVM:VR), (p<0.001)) and reduced ascending aortic distensibility (by 64%,p<0.001). LVM:VR was negatively correlated with ascending aortic distensibility (R=-0.36,p<0.01). Obesity, in the absence of hypertension, was associated with elevated left ventricular mass when compared to normal weight normotensive subjects (by 27%, p<0.01), in an eccentric pattern with cavity dilatation (p<0.01). However, LVM:VR was also 14% larger than in normal weight normotensive subjects (p<0.01), indicative of additional concentric remodeling. LVM:VR in obesity was, however, not correlated with ascending aortic distensibility when adjusted for mean arterial pressure (R=-0.14,p<0.14). CONCLUSION: In summary, despite the predominantly eccentric pattern of left hypertrophy in obesity there is a concentric element of hypertrophy that, unlike in hypertension, is not linked to increased ascending aortic stiffness. PMID- 23041006 TI - Head-up tilt testing for diagnosing vasovagal syncope: a meta-analysis. AB - BACKGROUND: A systematic evaluation focused on sensitivity and specificity of head-up tilt testing (HUT) for diagnosing vasovagal syncope has not been previously performed. We conducted a meta-analysis of studies comparing HUT outcome between patients with syncope of unknown origin and control subjects without previous syncope. METHODS: We searched Pubmed and Embase databases for all English-only articles concerning case-control studies estimating the diagnostic yield of HUT, and selected 55 articles, published before March 2012, including 4361 patients and 1791 controls. The influence of age, test duration, tilt angle, and nitroglycerine or isoproterenol stimulation on tilt testing outcome was analyzed. RESULTS: Head-up tilt testing demonstrated to have a good overall ability to discriminate between symptomatic patients and asymptomatic controls with an area under the summary receiver-operating characteristics curve of 0.84 and an adjusted diagnostic odds ratio of 12.15 (p<0.001). A significant inverse relationship between sensitivity and specificity of tilt testing for each study was observed (p<0.001). At multivariate analysis, advancing age and a 60 degrees tilt angle showed a significant effect in reducing sensitivity and increasing specificity of the test. Nitroglycerine significantly raised tilt testing sensitivity by maintaining a similar specificity in comparison to isoproterenol. CONCLUSIONS: The results from this meta-analysis show the high overall performance of HUT for diagnosing vasovagal syncope. Our findings provide useful information for evaluating clinical and instrumental parameters together with pharmacological stressors influencing HUT accuracy. This could allow the drawing of tilt testing protocols tailored on the diagnostic needs of each patient with unexplained syncope. PMID- 23041007 TI - Effects of ganglionated plexi ablation on ventricular electrophysiological properties in normal hearts and after acute myocardial ischemia. AB - BACKGROUND: Ganglionated plexi (GP) ablation has been shown to play an important role in atrial fibrillation (AF) initiation and maintenance. Also, GP ablation increases chances for prevention of AF recurrence. This study investigated the effects of GP ablation on ventricular electrophysiological properties in normal dog hearts and after acute myocardial ischemia (AMI). METHODS: Fifty anesthetized dogs were assigned into normal heart group (n=16) and AMI heart group (n=34). Ventricular dynamic restitution, effective refractory period (ERP), electrical alternans and ventricular fibrillation threshold (VFT) were measured before and after GP ablation in the normal heart group. In the AMI heart group, the incidence of ventricular arrhythmias and VFT were determined. RESULTS: In the normal heart group, GP ablation significantly prolonged ERP, facilitated electrical alternans but did not increase ERP dispersion, the slope of restitution curves and its spatial dispersion. Also, GP ablation did not cause significant change of VFT. In the AMI heart group, the incidence of ventricular arrhythmias after GP ablation was significantly higher than that in the control group or the GP plus stellate ganglion (SG) ablation group (P<0.05). Spontaneous VF occurred in 8/12, 1/10 and 2/12 dogs in the GP ablation group, the GP plus SG ablation group and the control group, respectively (P<0.05). VFT in the GP ablation group showed a decreased trend though a significant difference was not achieved compared with the control or the GP plus SG ablation group. CONCLUSIONS: GP ablation increases the risk of ventricular arrhythmias in the AMI heart compared to the normal heart. PMID- 23041008 TI - Dilated cardiomyopathy in patients with mutations in anoctamin 5. AB - BACKGROUND: Homozygous mutations in ANO5, a gene encoding anoctamin 5, a putative calcium-activated chloride channel, have recently been reported in patients with adult-onset myopathies or isolated high-CK levels. Cardiomyopathy has not previously been reported in these populations despite a proven expression of anoctamin 5 in the cardiac muscle. METHODS: Patients presenting for the management of high-CK levels or overt myopathy with proven ANO5 mutations were prospectively investigated between June 2010 and March 2012 in Pitie Salpetriere Hospital, according to a standardised protocol. Neurological and cardiological clinical examinations, CK assessment, electrocardiogram (ECG), and echocardiography were performed, as well as cardiac MRI and coronary CT angiography in patients with left ventricular (LV) dysfunction. RESULTS: Our study included 19 consecutive patients (male=15, age=46.2 +/- 12.7 years) from 16 families. Five had asymptomatic high-CK levels and 14 had overt myopathy. One patient had a personal history of stable coronary artery disease with normal ventricular function. ECG showed ventricular premature beats in one patient. Echocardiography displayed LV dilatation in two patients, LV dysfunction in one, and both abnormalities in two who fulfilled criteria for dilated cardiomyopathy which was confirmed by cardiac MRI and normal CT angiography. CONCLUSIONS: Dilated cardiomyopathy is a potential complication in patients with myopathies due to mutations in the ANO5 gene whose screening requires specific procedures. PMID- 23041009 TI - Recurrent fulminant myocarditis associated with diffuse large B-cell lymphoma. PMID- 23041010 TI - Respiratory ventricular area changes measured with real-time cardiac magnetic resonance: a new, accurate, and reproducible approach for the diagnosis of pericardial constriction. PMID- 23041011 TI - A reduction in total isovolumic time with cardiac resynchronisation therapy is a predictor of clinical outcomes. AB - BACKGROUND: Total isovolumic time (t-IVT) reflects left ventricular (LV) asynchrony (when the ventricle is neither ejecting nor filling). It is prolonged in left bundle branch block (LBBB). Cardiac resynchronisation therapy (CRT) is a treatment for patients with heart failure, reduced LV ejection fraction and LBBB. CRT shortens t-IVT, but the long-term clinical benefit of such reduction after CRT has not been studied in this patient group. METHODS: Seventy-three patients who underwent CRT had t-IVT measured before and after CRT implantation. The study end-point was a composite of unplanned heart failure hospitalisation and all cause mortality. RESULTS: Baseline t-IVT showed considerable scatter: 30 patients had t-IVT values longer than 15s/min (upper 95% limit of normal). The change in t IVT with CRT was also variable: t-IVT shortened in 50 patients (from 16.2 +/- 4.8s/min to 11.7 +/- 3.7s/min: group A), and lengthened in 23 patients (from 11.7 +/- 4.2s/min to 14.5 +/- 4.33 s/min: group B). The magnitude of change in t-IVT with CRT negatively correlated with baseline t-IVT (r=-0.619, p<0.001); thus t IVT (significantly longer in group A than group B before CRT: 16.2 +/- 4.8s/min vs. 11.7 +/- 4.2s/min, p<0.001) became significantly shorter in group A compared to group B after CRT (11.7 +/- 3.7s/min vs. 14.5 +/- 4.3s/min, p=0.005). After follow-up of 30 months, 70% group A patients had event-free survival compared to 39% group B patients. The presence of any fall in t-IVT after CRT was an independent predictor of event-free survival. CONCLUSION: T-IVT is a marker of global cardiac asynchrony that has predictive capacity on functional, symptomatic, and mortality endpoints in patients with advanced heart failure. PMID- 23041012 TI - Clinical significance of fat infiltration in the moderator band and right ventricular myocardium in multislice CT, and its association with abnormal conduction seen in electrocardiogram. AB - PURPOSE: We evaluated the clinical significance of fat infiltration in the moderator-band (MB) of the right ventricle (RV) and in the RV myocardium (RVM) and its association with conduction abnormalities in the electrocardiogram. MATERIALS AND METHODS: 132 subjects (58 male; age 59 +/- 27 years) with no findings of organic-disease (all right and left side hearts were normal) undergoing electrocardiogram-gated non-contrast multislice-CT (Light-Speed-Ultra 16) were retrospectively analyzed for the presence of fat infiltrating the MB or RVM. RESULTS: MB fat infiltration was detected in 42 subjects, but these individuals showed no significant differences in the incidence of right bundle branch-block, mean QRS-width or standard-deviation of the QRS-axis, which would have suggested the presence of hemi left bundle branch-block. Only age (64.3 vs 57.9 years, p=0.025) was significantly different in subjects with MB fat infiltration. But logistic regression showed none of the factor associated with increased presence of MB fat infiltration. RVM fat infiltration was detected in 35 subjects, again with no significant differences in the incidence of right bundle branch-block, QRS width or standard-deviation of the QRS axis. Only age (65.9 vs 57.8 years, p=0.001) and gender (71% vs 51% female, p=0.033) were significantly different in subjects with RVM fat infiltration. Logistic regression showed age (Odd-ratio=1.05 and 95% CI=1.01-1.08 p=0.008) and female sex (Odd-ratio=2.44 and 95% CI=1.03-5.88; p=0.043) were associated with increased RV fat infiltration. CONCLUSIONS: MB or RVM fat infiltration seen on CT may not indicate organized abnormal myocardial conduction, but RVM fat infiltration may indicate only degeneration due to aging, especially in females. PMID- 23041013 TI - WITHDRAWN: Abrupt occlusion of renal artery during renal denervation. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23041014 TI - Weather, pollution, and acute myocardial infarction in Hong Kong and Taiwan. AB - BACKGROUND: Several previous studies examined the association between acute myocardial infarction (AMI) incidence and temperature and/or air pollution. Results of these studies have been inconsistent and few studies have been done in cities with sub-tropical or tropical climates. METHODS: Daily data on AMI hospitalizations, mean temperature and humidity, and pollutants, were collected for 2000-2009 for three warm-climate Asian cities. Poisson Generalized Additive Models were used to regress daily AMI counts on temperature, humidity, and pollutants while controlling for day of the week, long-term trends and seasonal effects. Smoothing splines allowing non-linear associations were used for temperature and humidity while pollutants were modeled as linear terms. RESULTS: A 1 degrees C drop below a threshold temperature of 24 degrees C was significantly (p<.0001) associated with AMI hospitalization increases of 3.7% (average lag 0-13 temperature) in Hong Kong, 2.6% (average lag 0-15) in Taipei, and 4.0% (average lag 0-11) in Kaohsiung. No significant heat effects were observed. Among pollutants same day nitrogen dioxide (NO2) levels were the strongest predictors in all three cities, with a 10mg/m(3) increase in NO2 being associated with a 1.1% rise in AMI hospitalization in Hong Kong, and a 10 ppb rise being associated with 4.4% and 2.6% rises in Taipei and Kaohsiung, respectively. CONCLUSIONS: Cool temperatures and higher NO2 levels substantially raised AMI risk in these warm-climate cities and the effect sizes we observed were stronger than those found in previous studies. More attention should be paid to the health dangers of cold weather in warm-climate cities. PMID- 23041016 TI - N-acetyl cysteine for the conversion of atrial fibrillation into sinus rhythm after cardiac surgery: a prospective, randomized, double-blind, placebo controlled pilot study. PMID- 23041015 TI - Residual platelet activation through protease-activated receptors (PAR)-1 and -4 in patients on P2Y12 inhibitors. AB - BACKGROUND: Dual antiplatelet therapy with aspirin and thienopyridines has improved outcomes of patients after coronary stent implantation. However, current knowledge suggests that thrombin generation is not affected by inhibition of the P2Y12 receptor, and therefore, platelet activation may still occur. METHODS: The response to agonists specific for protease-activated receptors (PAR)-1 and -4 was tested by multiple electrode impedance aggregometry in 82 patients on stable doses of clopidogrel or prasugrel, and in 55 healthy controls. RESULTS: Based on the consensus cut-off value for adenosine diphosphate (ADP) responsiveness, only one out of 19 patients on prasugrel, but 22 out of 63 patients on clopidogrel had high on-treatment residual platelet reactivity in response to exogenous ADP (p=0.01). Among the patients with adequate ADP P2Y12 receptor inhibition (n=59), we still observed 32 patients (54.2%) with normal response to the PAR-1 activator SFLLRN (26 patients on clopidogrel, 81.2%; 6 patients on prasugrel, 18.8%), and 37 patients (63.8%) with a normal response to the PAR-4 activator AYPGKF (29 patients on clopidogrel, 78.4%; 8 patients on prasugrel, 21.6%). The degree of PAR-agonists inducible platelet activation was directly correlated with the activation induced by ADP (r>0.5 and p<0.001 for both agonists). Moreover, SFLLRN and AYPGKF inducible platelet reactivities were strongly correlated (r=0.75, p<0.001). CONCLUSION: PAR responsiveness is preserved in the majority of patients with adequate clopidogrel-mediated inhibition of the platelet P2Y12 receptor, and still in about 20% of those with adequate inhibition by prasugrel. PMID- 23041017 TI - Coronary artery disease and HIV; getting to the HAART of the matter. AB - Premature coronary disease is an important emerging paradigm affecting contemporary HIV patients. Through immune reconstruction HIV causes multisystem pathology. Recent advances in the treatment of AIDS, mainly highly active retroviral therapy (HAART), have transformed this previously terminal illness to a chronic disease. However, an interplay between traditional risk factors in a high risk predominantly male population together with the effect of the long term use of HAART in inducing a metabolic syndrome is leading to a premature and aggressive coronary artery disease phenotype not previously recognised. An association between HAART and increased cardiovascular events appears to exist. However, currently this risk appears to be low, and HAART is vital to maintain adequate viral suppression and disease control. HAART- and viral-associated dyslipidaemia can pose a significant challenge to the clinician as drug interactions may precipitate drug toxicity. In our institution a varied phenotypic pattern of coronary disease is seen angiographically from severe atherosclerotic calcific disease through to aneurysm formation and thrombotic occlusion. This is illustrated by case studies. There is a need for aggressive primary and secondary prevention strategies in this important sub-group of patients with a multi-disciplinary approach required in the management including cardiologists, metabolic physicians and lipidologists. PMID- 23041018 TI - Promoter variants of VTN are associated with vascular disease. AB - BACKGROUND: Vitronectin is involved in the whole process of atherosclerosis. Our aim is to determine the association of VTN functional promoter variants with different types of vascular disease, and conclude the roles of vitronectin involved in vascular disease. METHODS: Gel shift assays and luciferase reporter assays were used to determine the impact of variants on promoter activity. The correlation of plasma vitronectin levels with the variant was assessed in normal controls. The association of the variant with vascular disease was determined in 3 case-control studies. RESULTS: A strong linkage disequilibrium was found between rs2227721 and rs2227720 in VTN promoter in Chinese (r(2)=1.0). Both variants resulted in a decreased transcription activity, and rs2227721 decreased the binding efficiency of transcription factor YY1 to the region. The rs2227721 was correlated with plasma vitronectin levels in normal controls (r=-0.207, P=0.028). The rs2227721 was associated with susceptibility of vascular disease; the odds ratios among subjects carrying rs2227721-T allele were 1.298 (95% Confidence Interval-CI, 1.033-1.631) for non-MI CAD (P<0.05), 1.346 (95% CI, 1.068-1.695) for chronic MI (P<0.05), 1.486 (95% CI, 1.145-1.928) for acute MI (P<0.001), and 1.619 (95% CI, 1.108-2.366) for deep venous thrombosis (P<0.05). CONCLUSION: VTN promoter haplotype would be a novel genetic marker for vascular disease. PMID- 23041019 TI - Note from the editors: a new virus bringing back memories from the past. PMID- 23041020 TI - Detection of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. AB - We present two real-time reverse-transcription polymerase chain reaction assays for a novel human coronavirus (CoV), targeting regions upstream of the E gene (upE) or within open reading frame (ORF)1b, respectively. Sensitivity for upE is 3.4 copies per reaction (95% confidence interval (CI): 2.5-6.9 copies) or 291 copies/mL of sample. No cross-reactivity was observed with coronaviruses OC43, NL63, 229E, SARS-CoV, nor with 92 clinical specimens containing common human respiratory viruses. We recommend using upE for screening and ORF1b for confirmation. PMID- 23041021 TI - Novel coronavirus associated with severe respiratory disease: case definition and public health measures. AB - Two cases of rapidly progressive acute respiratory infection in adults associated with a novel coronavirus have generated an international public health response. The two infections were acquired three months apart, probably in Saudi Arabia and Qatar. An interim case definition has been elaborated and was published on the World Health Organization website on 25 September 2012. PMID- 23041023 TI - Survey of delivery of prophylactic immunoglobulins following exposure to a measles case. AB - In France, almost 23,000 cases of measles and 10 deaths have been reported between January 2008 and August 2012. French health authorities recommend delivery of human polyvalent immunoglobulins in the event of exposure to a measles case for some categories of unvaccinated persons (children under the age of 12 months, immunocompromised persons and pregnant women), within six days after exposure and following laboratory confirmation of the contact case. We carried out a postal survey among 368 French hospital pharmacies to evaluate the number of persons affected by this measure between 1 January 2010 and 31 August 2011, to describe the characteristics of these patients and to evaluate the application of the recommendations in terms of delay between exposure and immunoglobulin delivery, and confirmation of the contact case. The response rate to the survey was 73%. In total, 400 immunoglobulin deliveries were listed, most of them for children under the age of one year, and 84% of the 250 administrations with available information occurred within six days after exposure, as recommended. However, only 48% of the 209 treated contacts with available information were laboratory-confirmed when the immunoglobulins were delivered. This survey is the first evaluation of this recommendation since its introduction in 2005 and suggests that the recommendations may need to be updated. PMID- 23041022 TI - I-MOVE: a European network to measure the effectiveness of influenza vaccines. AB - Since 2007, the European Centre for Disease Prevention and Control (ECDC) has supported I-MOVE (influenza monitoring vaccine effectiveness), a network to monitor seasonal and pandemic influenza vaccine effectiveness (IVE) in the European Union (EU) and European Economic Area (EEA). To set up I-MOVE, we conducted a literature review and a survey on methods used in the EU/EEA to measure IVE and held expert consultations to guide the development of generic protocols to estimate IVE in the EU/EEA. On the basis of these protocols, from the 2008/09 season, I-MOVE teams have conducted multicentre case-control, cohort and screening method studies, undertaken within existing sentinel influenza surveillance systems. The estimates obtained include effectiveness against medically attended laboratory-confirmed influenza and are adjusted for the main confounding factors described in the literature. I-MOVE studies are methodologically sound and feasible: the availability of various study designs, settings and outcomes provides complementary evidence, facilitating the interpretation of the results. The IVE estimates have been useful in helping to guide influenza vaccine policy at national and European level. I-MOVE is a unique platform for exchanging views on methods to estimate IVE. The scientific knowledge and experience in practical, managerial and logistic issues can be adapted to monitor surveillance of the effectiveness of other vaccines. PMID- 23041024 TI - Wettability of bare and fluorinated silanes: a combined approach based on surface free energy evaluations and dipole moment calculations. AB - The assessment of the surface free energy (SFE) of a material permits to control and predict a large number of physicochemical properties of a solid surface and its reactivity. Here, the surface energies of a series of bare and fluorinated silanes are determined by means of different semi-empirical models on the grounds of contact angle determinations for different solvents. Literature data are also considered in order to produce a series of films with increasing SFE. Wetting envelopes (WE) are obtained for the various surfaces in order to predict the wettability of the films by numerous commonly employed solvents. The polar and disperse components of the surface energies are obtained by the Owens-Wendt-Rabel Kaelbe (OWRK) method; the values of the polar components are compared with gas phase dipole moments obtained by theoretical calculations employing semi empirical Hamiltonians. The sequences of the polar components of the SFE and of the calculated dipole moments for the different molecules are strictly the same. The interplay between theoretical and experimental approaches proves efficient in predicting the behavior of different systems and it could be employed in tuning the SFE of a solid surface with respect to its final applications. PMID- 23041025 TI - The Langmuir monolayer adsorption model of organic matter into effective pores in activated carbon. AB - A model of Langmuir monolayer liquid adsorption into effective pores was used to study the monolayer adsorption capacity by theory calculation. The activated carbon (AC) from rice husk with NaOH activation was selected as adsorbent to uptake phenol and methylene blue (MB). Materials were characterized by N(2) adsorption, infrared spectroscopy (IR), and ultraviolet spectrophotometer (UV). In adsorption kinetics, it was observed that the experimental data were well explained by the pseudo second-order equation. Moreover, the Langmuir isotherm was more suitable to explicate results than Freundlich isotherm, implying the monolayer adsorption. Basing on the molecule diameter of 0.72 nm and cross sectional area of 0.414 nm(2) for phenol, the theoretical adsorption capacities were close to the actual values with small relative error (<7%). Due to the large molecule size of MB (0.98 nm, 0.749 nm(2)), the sample with wider pores activated at 900 degrees C exhibited the higher adsorption capacity than AC at 700 degrees C. And the capillary condensation increased the adsorption capacities, consistent with the order of average pore diameter for ACs. From the model, it indicated that the adsorbent was suitable for adsorption when its critical pore width was two times of adsorbate molecule diameter. PMID- 23041026 TI - Core-shell nanoparticles as prodrugs: possible cytotoxicological and biomedical impacts of batch-to-batch inconsistencies. AB - Numerous samples of magnetite@silica and magnetite@silica@silane core-shell nanoparticles, previously used as prodrugs, were prepared by an experienced chemist, using the same identical equipment and the same lots of reagents. Their surface analyses showed batch-to-batch chemical variations: no two batches were found to have the same surface chemistries, showing unexpected Si-O bond scission and amine oxidation. Because the preparations used reactions recognized to be mild, and bond scission and oxidation were never previously reported for similar reactions on larger surfaces, the Fe(3)O(4) nanoparticles that form the nanoparticle core appear to have acted as catalysts for these side reactions. The intended use of these nanoparticles, as drug carriers, is discussed in terms of cytotoxicological and biomedical consequences. PMID- 23041027 TI - Tumor-associated macrophages and angiogenesis: a statistical correlation that could reflect a critical relationship in ameloblastoma. AB - Neoplasm growth is determined not only by the tumor cells themselves, but also by the tumor microenvironment. Increased densities of macrophages and activation of angiogenesis have been identified as common events in the progression of several neoplasms. Ameloblastoma is one of the most frequent odontogenic tumors and an excellent model for the study of neoplasm progression due to the different clinical variants that it exhibits. Here, by immunohistochemical studies using antibodies against CD68 and CD34, we evaluated the density of macrophages and microvessels associated to 45 paraffin-embedded ameloblastomas. In solid/multicystic ameloblastoma (SMA), we observed significantly higher densities of both macrophages and microvessels than in unicystic (UA) and desmoplastic (DA) ameloblastomas. Likewise, higher densities of macrophages and microvessels were found in UA than in DA. Furthermore, a predominance of intratumoral and peritumoral macrophage infiltrates was seen in SMA, while in UA, both macrophages and microvessels were also detected in the wall of the cysts. In contrast, DA had scant macrophages and microvessels, mainly situated distant from tumoral cells. In addition, a high correlation between macrophage and microvessel densities was observed in the samples (r=0.9623). Our results suggest that these two tumor microenvironmental elements could have an important role during ameloblastoma progression. PMID- 23041028 TI - The influence of physical activity in the progression of experimental lung cancer in mice. PMID- 23041029 TI - A biomechanical analysis of the effects of low-Dye taping on arch deformation during gait. AB - BACKGROUND: The low-Dye technique serves to limit hindfoot pronation and medial arch collapse. Few studies exist that investigate the effects on medial arch deformation from a biomechanical perspective. METHODS: Kinematic data was collected using a Motion Analysis System. Foot function of 21 healthy adults was assessed during the stance phase of gait. Subjects were evaluated prior to and immediately following the low-Dye tape application, as well as at 48 h. Foot deformation was assessed during the stance phase of gait using the calcaneus, navicular and 1st metatarsal head markers to calculate the medial longitudinal arch angle (MLA) and the dynamic arch height index (dAHI). Paired t-tests were used to assess low-Dye tape effectiveness. RESULTS: There was a significant 19.3% reduction in MLA immediately after application of the tape. However only 4.01% reduction remained in deformation after 48 h. The MLA deformation findings were consistent with the AHI change, showing a significant change in the arch deformation between Pre and Post0 low-Dye taping. The effects were short-lived. CONCLUSIONS: There are measurable changes to medial arch height and amount of arch height deformation during gait following low-Dye taping. Although changes were present immediately after application, results were diminished 48 h after application. PMID- 23041030 TI - A case-control study of wicket spikes using video-EEG monitoring. AB - PURPOSE: To investigate clinical characteristics associated with wicket spikes in patients undergoing long-term video-EEG monitoring. METHODS: A case-control study was performed in 479 patients undergoing video-EEG monitoring, with 3 age- (+/-3 years) and gender-matched controls per patient with wicket spikes. Logistic regression was utilized to investigate the association between wicket spikes and other factors, including conditions that have been previously associated with wicket spikes. RESULTS: Wicket spikes were recorded in 48 patients. There was a significantly higher prevalence of dizziness/vertigo (p=0.002), headaches (p=0.005), migraine (p=0.015), and seizures (p=0.016) in patients with wickets. The majority of patients with wicket spikes did not exhibit epileptiform activity on EEG; however, patients with history of seizures were more likely to have wickets (p=0.017). There was no significant difference in the prevalence of psychogenic non-epileptic seizures between the groups. Wickets were more common on the left, during sleep, and more likely to be first recorded on day 1-2 of monitoring. CONCLUSIONS: Patients with wicket spikes are more likely to have dizziness/vertigo, headaches, migraine, and seizures. Patients with history of seizures are more likely to have wickets. The prevalence of psychogenic non epileptic seizures is not significantly higher in patients with wickets. PMID- 23041031 TI - Long-term results of vagal nerve stimulation for adults with medication-resistant epilepsy who have been on unchanged antiepileptic medication. AB - PURPOSE: Several studies suggest that vagal nerve stimulation (VNS) is an effective treatment for medication-resistant epileptic patients, although patients' medication was usually modified during the assessment period. The purpose of this prospective study was to evaluate the long-term effects of VNS, at 18 months of follow-up, on epileptic patients who have been on unchanged antiepileptic medication. METHODS: Forty-three patients underwent a complete epilepsy preoperative evaluation protocol, and were selected for VNS implantation. After surgery, patients were evaluated on a monthly basis, increasing stimulation 0.25mA at each visit, up to 2.5mA. Medication was unchanged for at least 18 months since the stimulation was started. The outcome was analysed in relation to patients' clinical features, stimulation parameters, epilepsy type, magnetic resonance imaging (MRI) results, and history of prior brain surgery. RESULTS: Of the 43 operated patients, 63% had a similar or greater than 50% reduction in their seizure frequency. Differences in the responder rate according to stimulation intensity, age at onset of epilepsy, duration of epilepsy before surgery, previous epilepsy surgery and seizure type, did not reach statistical significance. Most side effects were well tolerated. CONCLUSIONS: 62.8% of our series of 43 medication-resistant epileptic patients experienced a significant long-term seizure reduction after VNS, even in a situation of on unchanged medical therapy. Patient characteristics predictive of VNS responsiveness remain subject to investigation. Controlled studies with larger sample sizes, on VNS for patients with medication-resistant epilepsy on unchanged medication, are necessary to confirm VNS efficacy for drug-resistant epilepsy, and to identify predictive factors. PMID- 23041032 TI - Clinical phenotypes within non-surgical patients with mesial temporal lobe epilepsy caused by hippocampal sclerosis based on response to antiepileptic drugs. AB - PURPOSE: To evaluate evolution and elucidate clinical phenotypes related to prognosis of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) treated exclusively with antiepileptic drugs (AED). METHODS: Forty-seven out of 68 MTLE-HS patients treated between January 2005 and June 2010 were retrospectively studied for demographic, clinical and outcome data. The population was divided into drug-responder and drug-resistant patients; the latter was divided, according to the duration of the seizure-free periods along their evolution, into patients with at least one seizure-free period longer than one year and those with shorter periods. Variables were compared between drug responders vs drug-resistants and drug-resistants with long seizure-free periods vs drug-resistants without it. RESULTS: There were 7 (15%) drug-responders, 39 (83%) drug-resistants and 1 patient (2%) with an undetermined response. Eighteen (46%) drug-resistant individuals had seizure-free periods longer than one year, with mean duration of 46 months (3.8 years). Since no factor was statistically associated with long seizure-free period within drug-resistants, we can clinically distinguish two phenotypes: women with left HS and late onset of seizures, with poor prognosis, and men with right HS and earlier appearance of seizures, attaining a better outcome. Twenty out of 47 (42.5%) patients followed an intermittent pattern of epilepsy. CONCLUSIONS: Non-surgical MTLE-HS drug resistant patients can achieve long seizure-free periods with AED, but relapses are common. Female gender, left or bilateral lesion and later onset of seizures seem to be bad prognosis factors within MTLE-HS drug-resistant patients. PMID- 23041033 TI - Cytokine production in immortalized porcine alveolar macrophages infected with porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically significant viral pathogens for pig production worldwide. PRRSV primarily infects cells of the monocyte/macrophage lineage such as porcine alveolar macrophages (PAMs), and is generally known to suppress normal macrophage function and regulate innate immune responses to viral infection. A continuous PRRSV-permissive porcine monocyte-derived cell line was previously generated to facilitate virus propagation and advance research on the biology and immunology of PRRSV. With the availability of this valuable tool, we first sought to explore modulation of inflammatory cytokine expression in PAM-pCD163 cells infected with each genotype PRRSV and to establish an in vitro system for immune function studies using PRRSV isolates. PMID- 23041034 TI - Evaluation of the partial renewal of in situ phytoplankton microcosms and application to the impact assessment of bentazon and dimethenamid. AB - Microcosms, each consisting of 2L natural surface seawater maintained in 2.3-L glass bottles, were immersed at a depth of 6m. The renewal of 10% of microcosm volumes was carried out every other day. Phytoplankton-containing seawater was used for renewal (previously filtered through 25-, 50- or 200-MUm cut-off). Phytoplankton community pigment analysis (by HPLC) and flow cytometry analysis were performed. After 13 days, data exhibited phytoplankton characteristics in microcosms in the same range as that of the natural surrounding sea water over the same period. Furthermore, in these microcosms, a negative correlation was observed between the filtration cut-off used for renewal water, and the total cell count. Herbicides were tested as commercial mixtures at 1, 10 and 100 MUgL( 1) active substance. Both Frontier(r) (dimethenamid) and Basamais(r) (bentazon) induced significant modifications of the phytoplankton populations at every concentration tested. Such results suggest a possible disturbance in polluted coastal areas. PMID- 23041035 TI - Somatic symptoms and psychological characteristics associated with insomnia in postmenopausal women. AB - OBJECTIVE: The aim of the study was to assess the association of sleep disturbance with psychological characteristics, somatic symptoms and previously identified risk factors. METHODS: Data were from 148,938 postmenopausal women enrolled in The Women's Health Initiative who provided cross-sectional information about psychological characteristics, somatic symptoms and the character of their sleep. Overall sleep quality was based on the Women's Health Initiative Insomnia Rating Scale (WHI IRS), a measure that assessed five types of sleep disturbance. RESULTS: Three factors accounted for nearly 20% of the variation in the WHI IRS: a scale for somatic symptoms, daytime restlessness and either depression or emotional well-being. Other independently associated factors were night sweats, pain and worry about expressing anger. Several factors that had been linked to sleep disturbance in other studies were found to have at most a weak independent association in this analysis. These included income, education, marital status, activity level, obesity level, hot flashes, coffee drinking and smoking. CONCLUSION: Factors strongly associated with sleep disturbance in this study deserve further evaluation to determine the reasons for the association and whether the associations suggest possible treatments for sleep disturbance. PMID- 23041036 TI - Sorption of perfluorooctane sulfonate to carbon nanotubes in aquatic sediments. AB - To date, sorption of organic compounds to nanomaterials has mainly been studied for the nanomaterial in its pristine state. However, sorption may be different when nanomaterials are buried in sediments. Here, we studied sorption of Perfluorooctane sulfonate (PFOS) to sediment and to sediment with 4% multiwalled carbon nanotubes (MWCNTs), as a function of factors affecting PFOS sorption; aqueous concentration, pH and Ca(2+) concentration. Sorption to MWCNT in the sediment-MWCNT mixtures was assessed by subtracting the contribution of PFOS sorption to sediment-only from PFOS sorption to the total sediment-MWCNT mixture. PFOS Log K(D) values ranged 0.52-1.62 L kg(-1) for sediment and 1.91-2.90 L kg( 1) for MWCNT present in the sediment. The latter values are relatively low, which is attributed to fouling of MWCNT by sediment organic matter. PFOS sorption was near-linear for sediment (Freundlich exponent of 0.92 +/- 0.063) but non-linear for MWCNT (Freundlich exponent of 0.66 +/- 0.03). Consequently, the impact of MWCNT on sorption in the mixture was larger at low PFOS aqueous concentration. Effects of pH and Ca(2+) on PFOS sorption to MWCNT were statistically significant. We conclude that MWCNT fouling and PFOS concentration dependency are important factors affecting PFOS-MWCNT interactions in sediments. PMID- 23041038 TI - Mechanisms of phosphorus removal by cement-bound ochre pellets. AB - Hydrous ferric oxide (here termed 'ochre') sludge, an abundant waste product produced from the treatment of acid mine drainage (AMD), was used in this study for the removal of phosphorus (in the form of phosphate ions) from contaminated waters. The phosphorus uptake capacities of both raw and pelletized AMD solids were compared using batch and column tests. Addition of a cement binder to the AMD solids during pellet production led to significantly increased P-loading of the resultant solids compared to the raw sludge. Additionally, the pellets were found to continue to remove P in tests up to 7 d in duration whereas the unbound AMD sludge appeared to approach equilibrium with phosphate solution after approximately 60 min of contact time. In line with previous studies P uptake by the AMD solids was found to be primarily via adsorption. By contrast calcium phosphate precipitation was found to be the dominant removal mechanism for the cement-bound ochre pellets with a relatively small proportion of removal attributable to the AMD solids. SEM-EDX analysis of the surface of used pellets showed a Ca:P molar ratio close to that of hydroxyapatite (HAP). Continuous column tests on these pellets showed a rapid decrease in P removal capacity by the pellets over time, attributable to the formation of a passivating HAP surface layer. PMID- 23041037 TI - Reuse of washing effluent containing oxalic acid by a combined precipitation acidification process. AB - This study aims at evaluating the reuse feasibility of effluent produced by the soil washing of mine tailings with oxalic acid. Alkaline chemicals such as NaOH, Ca(OH)(2), and Na(2)CO(3) are used for the precipitation of arsenic and heavy metals in the effluent containing oxalic acid. All of the target contaminants are removed with very high efficiency (up to 100%) at high pH. The precipitation using NaOH at pH 9 is determined to be the most cost-effective method for the removal of arsenic as well as heavy metals in the effluent. The effluent decontaminated by NaOH is consecutively reused for the soil washing of raw mine tailings, resulting in considerable efficiency. Furthermore, even more arsenic and heavy metals are extracted from raw mine tailings by acidifying the decontaminated effluent under the alkaline condition, compared with direct reuse of the decontaminated effluent. Here, the oxalic acid, which is a weak complex forming ligand as well as a weak acid, has noticeable effects on both soil washing and effluent treatment by precipitation. It extracts efficiently the contaminants from the mine tailings without adverse change of soil and also makes possible the precipitation of the contaminants in the effluent unlike strong chelating reagent. Reuse of the washing effluent containing oxalic acid would make the existing soil washing process more environment-friendly and cost effective. PMID- 23041039 TI - Plague: history and contemporary analysis. AB - Plague has caused ravaging outbreaks, including the Justinian plague and the "black death" in the Middle Ages. The causative agents of these outbreaks have been confirmed using modern molecular tests. The vector of plague during pandemics remains the subject of controversy. Nowadays, plague must be suspected in all areas where plague is endemic in rodents when patients present with adenitis or with pneumonia with a bloody expectorate. Diagnosis is more difficult in the situation of the reemergence of plague, as in Algeria for example, told by the first physician involved in that outbreak (NM). When in doubt, it is preferable to prescribe treatment with doxycycline while waiting for the test results because of the risk of fatality in individuals with plague. The typical bubo is a type of adenitis that is painful, red and nonfluctuating. The diagnosis is simple when microbiological analysis is conducted. Plague is a likely diagnosis when one sees gram-negative bacilli in lymph node aspirate or biopsy samples. Yersinia pestis grows very easily in blood cultures and is easy to identify by biochemical tests and MALDI-TOF mass spectrometry. Pneumonic plague and septicemic plague without adenitis are difficult to diagnose, and these diagnoses are often made by chance or retrospectively when cases are not part of an epidemic or related to another specific epidemiologic context. The treatment of plague must be based on gentamicin or doxycycline. Treatment with one of these antibiotics must be started as soon as plague is suspected. Analysis of past plague epidemics by using modern laboratory tools illustrated the value of epidemic buboes for the clinical diagnosis of plague; and brought new concepts regarding its transmission by human ectoparasites. PMID- 23041040 TI - Voriconazole hepatotoxicity in severe liver dysfunction. AB - There are no studies regarding to these effects in patients with severe liver dysfunction. OBJECTIVES: The aims of this study were to characterize voriconazole hepatotoxicity in patients with severe liver dysfunction and to compare it with a matched cohort treated with liposomal amphotericin B. METHODS: This is an observational study, in which adults patients treated with at least 4 doses of voriconazole were included. Patients treated with liposomal amphotericin B were used as control group. RESULTS: Sixty nine percent of patients treated with voriconazole showed changes in liver function tests (LFTs) during therapy. They showed elevated transaminases in 35%, cholestasis in 15% or a combination of both in 45%. According to the CTC classification, all patients with hepatotoxicity had a severe reaction. The Roussel Uclaf Causality Assessment Method score in all patients with hepatotoxicity was greater than 8. There was a correlation between initial loading dose greater than 300 mg (4.5 mg/kg) and the risk of hepatotoxicity (p < 0.001). The control group developed alterations in the LFTs in only 10.3% of patients. CONCLUSION: Voriconazole should be used with caution in patients with severe liver dysfunction and following liver transplantation, with frequent monitoring of LFTs or using liposomal amphotericin B instead. PMID- 23041041 TI - Rational design of apoptosis signal-regulating kinase 1 inhibitors: discovering novel structural scaffold. AB - Increased activity of apoptosis signal-regulating kinase 1 (ASK1) is associated with a number of human disorders and the inhibitors of ASK1 may become important compounds for pharmaceutical application. Here we report novel ASK1 inhibitor scaffold, namely 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one, that has been identified using virtual screening and biochemical tests. A series of derivatives has been synthesized and evaluated in vitro towards human protein kinase ASK1. It was revealed that the most active compounds 4-((5Z)-5-{[5-(4 bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid and 6-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3 thiazolidin-3-yl)hexanoic acid inhibit ASK1 with IC50 of 0.2 MUM. Structure activity relationships of 33 derivatives of 5-(5-Phenyl-furan-2-ylmethylene)-2 thioxo-thiazolidin-4-one have been studied and binding mode of this chemical class has been predicted. PMID- 23041042 TI - Identification and characterization of novel catalytic bioscavengers of organophosphorus nerve agents. AB - In an effort to discover novel catalytic bioscavengers of organophosphorus (OP) nerve agents, cell lysates from a diverse set of bacterial strains were screened for their capacity to hydrolyze the OP nerve agents VX, VR, and soman (GD). The library of bacterial strains was identified using both random and rational approaches. Specifically, two representative strains from eight categories of extremophiles were chosen at random. For the rational approach, the protein sequence of organophosphorus hydrolase (OPH) from Brevundimonas diminuta was searched against a non-redundant protein database using the Basic Local Alignment Search Tool to find regions of local similarity between sequences. Over 15 protein sequences with significant sequence similarity to OPH were identified from a variety of bacterial strains. Some of these matches were based on predicted protein structures derived from bacterial genome sequences rather than from bona fide proteins isolated from bacteria. Of the 25 strains selected for nerve agent testing, three bacterial strains had measurable levels of OP hydrolase activity. These strains are Ammoniphilus oxalaticus, Haloarcula sp., and Micromonospora aurantiaca. Lysates from A. oxalaticus had detectable hydrolysis of VR; Haloarcula sp. had appreciable hydrolysis of VX and VR, whereas lysates from M. aurantiaca had detectable hydrolysis of VR and GD. PMID- 23041043 TI - TRPM2 channel activation following in vitro ischemia contributes to male hippocampal cell death. AB - Hippocampal CA1 neurons are particularly sensitive to ischemic damage, such as experienced following cardiac arrest and cardiopulmonary resuscitation. In recent years transient receptor potential M2 (TRPM2) channels have been identified as mediators of ischemic damage. We previously demonstrated that neuroprotective strategies targeting TRPM2 channels preferentially protect male cortical neurons from ischemic injury both in vitro and in vivo. It is important to determine the role of TRPM2 in ischemic injury of hippocampal neurons as this population of neurons are particularly sensitive to ischemic injury and are therapeutic targets. Here we report significantly decreased neuronal cell death following in vitro ischemia preferentially in male hippocampal neurons using TRPM2 inhibitors or knockdown of TRPM2 expression. Electrophysiological characterization of sex stratified cultures shows similar levels of functional TRPM2 channel expression in male and female hippocampal neurons under basal conditions. In contrast, recordings made during reperfusion following in vitro ischemia revealed that TRPM2 channels are activated only in male neurons, resulting in rapid and complete depolarization. These findings provide strong evidence for TRPM2 as a target for protection against cerebral ischemia in male brain and helps define a molecular cell death pathway that is differentially engaged in male and female neurons. PMID- 23041044 TI - Bisphenol A attenuates phenylbiguanide-induced cardio-respiratory reflexes in anaesthetized rats. AB - Bisphenol A (BPA), a toxic chemical released from plastics, produces respiratory arrest and hypotension after a latency. The latency was similar to the reflex apnoea induced by the vagal C fibre stimulation. Therefore, the present study was undertaken to examine the effects of chronic and acute exposure to BPA on cardio respiratory reflexes elicited by phenylbiguanide (PBG). Acute and chronic experiments were performed on adult female rats. In chronic experiments, the animals were ingested with pellets containing BPA (2 MUg/kg body weight) or without BPA (time-matched control) for 30 days. Subsequently, the animals were anaesthetized and prepared for recording blood pressure, ECG and respiratory excursions. PBG was injected through jugular vein to evoke reflexes in these animals. In acute experiments, the PBG reflexes were obtained before and after injecting BPA/ethanol. Also vagal afferent activity was recorded in some rats. In time-matched control rats, PBG produced bradycardia, hypotension and tachypnoea over a period of time. The maximal changes were around 50-65%. In BPA treated group, the PBG-induced heart rate and respiratory frequency changes were attenuated significantly. Acute exposure of animals to BPA (35 mg/kg body weight) for 30 min also attenuated the PBG-induced responses significantly. The attenuation of the PBG reflex responses by BPA in acute experiments was associated with decreased vagal afferent activity. The present results indicate that BPA attenuates the protective cardio-respiratory reflexes due to decreased vagal afferent activity. PMID- 23041045 TI - Long term depression of MNTB-LSO synapses is expressed postsynaptically in developing circling mice. AB - Early onset long term depression (LTD) during the first postnatal week has rarely been demonstrated at the medial nucleus of trapezoid body (MNTB) - lateral superior olive (LSO) synapses in spite of many favorable conditions, such as depolarizing synapses and glutamate co-release from MNTB terminals. Thus, we tested the early expression of LTD at MNTB-LSO synapses during the first postnatal week using circling mice, whose main transmitter is glutamate at MNTB LSO synapses. Tetanic stimulation on MNTB elicited LTD of postsynaptic currents recorded at LSO neurons in P0-P3 homozygous (cir/cir) mice (45.8 +/- 0.3% of the control, n = 7) and heterozygous (+/cir) mice (43.3 +/- 0.4% of the control, n = 7). The magnitude of LTD decreased in P8-P12 heterozygous (+/cir) mice (84.5 +/- 0.3% of the control, n = 7), but was maintained in P8-P12 homozygous (cir/cir) mice (38.2 +/- 0.3% of the control, n = 9). Glutamatergic LTD observed in homozygous (cir/cir) mice and glycinergic LTD observed heterozygous (+/cir) mice showed similar pattern of change. As currents induced by the pressure application of glycine on LSO neurons were reduced by tetanic stimulation in P0-P3 heterozygous (+/cir) mice, LTD was thought to occur at postsynaptic sites. Our results suggest that LTD might occur in vivo and participate in the synaptic silencing and strengthening of MNTB-LSO synapses, which is most active during the first postnatal week. PMID- 23041046 TI - Seasonality of striatal dopamine synthesis capacity in Parkinson's disease. AB - Recent neuroimaging evidence suggests that the healthy human brain dopaminergic system may show seasonal rhythmicity, as striatal dopamine synthesis capacity has been reported to be higher during fall and winter. There is additional evidence about season of birth effects on morbidity in several neuropsychiatric disorders. We investigated possible seasonal changes in dopamine synthesis capacity in a relatively large sample of Parkinson's disease patients. 6-[(18)F]fluoro-l-DOPA brain PET scans for 109 Parkinson's disease patients were performed during different seasons and the effects of season of scanning and season of birth on striatal tracer uptake were studied, controlling for covariates such as age, sex and disease severity. The patients scanned during fall and winter had 15% higher tracer uptake in the right putamen compared to patients scanned during spring and summer (p=0.04). Patients born during winter and spring had 10% higher dopamine synthesis capacity in the left caudate (p=0.008), 8% higher capacity in the right caudate (p=0.04) and 16% higher capacity in the putamen contralateral to the side of predominant motor symptoms (p=0.02) compared to patients born during summer and fall (after correcting for differences in age, sex, disease severity, scanner and season of scanning). The results suggest that there are seasonal oscillations also in the hypoactive dopaminergic system of Parkinson's disease patients. Findings concerning season of birth further suggest that there may be gestational or perinatal seasonal factors, which influence dopaminergic function in adulthood. PMID- 23041047 TI - c-Jun N-terminal phosphorylation is essential for hippocampal synaptic plasticity. AB - c-Jun N-terminal kinase (JNK), a member of the MAPK family, is an important regulatory factor of synaptic plasticity as well as neuronal differentiation and cell death. Recently, JNK has been reported to modulate synaptic plasticity by the direct phosphorylation of synaptic proteins. The specific role of c-Jun phosphorylation in JNK mediated synaptic plasticity, however, remains unclear. In this study, we investigated the effects of c-Jun phosphorylation on synaptic structure and function by using c-Jun mutant mice, c-JunAA, in which the active phosphorylation sites at serines 63 and 73 were replaced by alanines. The gross hippocampal anatomy and number of spines on hippocampal pyramidal neurons were normal in c-JunAA mice. Basal synaptic transmission, input-output ratios, and paired-pulse facilitation (PPF) were also no different in c-JunAA compared with wild-type mice. Notably, however, the induction of long-term potentiation (LTP) at hippocampal CA3-CA1 synapses in c-JunAA mice was impaired, whereas induction of long-term depression (LTD) was normal. These data suggest that phosphorylation of the c-Jun N-terminus is required for LTP formation in the hippocampus, and may help to better characterize JNK-mediated modulation of synaptic plasticity. PMID- 23041048 TI - Global profiling of protein kinase activities in cancer cells by mass spectrometry. AB - Protein kinases have important functions in the control of cell biology and are implicated in several diseases including cancer. Here we describe a technique to quantify protein kinase activity in a global fashion and without preconception of the kinases that may be active in the cell or tissue under investigation. In Global Kinase Activity Profiling (GKAP), protein kinases present in experimental cell lysates phosphorylate endogenous substrates, also present in the lysate, under defined conditions. Reaction products are then quantified using standard phosphoproteomic techniques based on LC-MS/MS. The technique thus allows measuring the combined activities of kinases targeting common substrates, which are detected as phosphopeptides by LC-MS/MS. Almost four hundred kinase reactions could be quantified in a human epithelial cell line, 177 of which increased in response to EGF treatment while others decreased in cells exposed to the kinase inhibitors LY294002 or U0126. GKAP also detected marked differences in the patterns of kinase activities in human leukemia cell lines with different sensitivities to kinase inhibitors. These results reveal that GKAP detects and quantifies hundreds of kinase activities modulated by growth factors or pharmacological inhibitors, and that these activities correlate with the phenotypes of cancer cells and their responses to kinase inhibitors. PMID- 23041049 TI - Preoperative chemotherapy and the risk of hepatotoxicity and morbidity after liver resection for metastatic colorectal cancer: a single institution experience. AB - BACKGROUND: Patients undergoing liver resection for colorectal cancer liver metastasis (CRCLM) are often treated with chemotherapy before surgery. However, the associations between chemotherapy, liver injury, perioperative outcomes, and other confounding factors remain unclear. This study investigates the effect of preoperative chemotherapy for CRCLM on nontumoral liver histology and perioperative outcomes in a contemporary cohort. STUDY DESIGN: Five hundred six patients underwent hepatic resection for CRCLM between April 2003 and March 2007. Histologic evaluation of nontumoral liver parenchyma for sinusoidal dilatation, steatosis, and steatohepatitis was performed in 384 cases for which tissue was available. Patient factors, tumor characteristics, chemotherapy regimens, histology of nontumoral liver, and perioperative morbidity were analyzed. RESULTS: Two hundred fifty patients (65%) received preoperative chemotherapy for a median duration of 24 weeks. Irinotecan, increased body mass index (BMI), and diabetes mellitus (DM) were associated with hepatic steatosis and steatohepatitis. Sinusoidal dilatation was not associated with chemotherapy or any clinicopathologic factors. Perioperative blood transfusion was independently associated with an increased risk of any complication. Major postoperative complications were independently associated with major (>= 3 segments) resections (57%) and perioperative blood transfusion. The use of any preoperative chemotherapy decreased the odds of major complications. Liver-related complications were independently associated with major resection and blood transfusion, but not with chemotherapy. Three postoperative deaths (0.8%) occurred, all in patients who were not treated with chemotherapy and had no evidence of liver injury. CONCLUSIONS: With appropriate patient selection, liver resection for CRCLM can be safely performed in patients treated with preoperative chemotherapy. PMID- 23041050 TI - Retained surgical items: a problem yet to be solved. AB - BACKGROUND: Retained surgical items (RSI) continue to occur. Large RSI studies are few due to low RSI frequency in single institutions and the medicolegal implications. Consequently, RSI risks are not fully defined, with discrepancies persisting among published studies. The goals of this study were to better define risk factors for RSI, to clarify previously discrepant risk factors, and to evaluate other potential contributors to RSI occurrence, such as trainee presence during an operation. STUDY DESIGN: Multicenter case-match study of RSI risk factors was conducted between January 2003 and December 2009. Cases complicated by RSI were identified at participating centers using clinical quality improvement and adverse event reporting data. Case match controls (non-RSI) were selected from same or similar-type cases performed at each respective institution. Retained surgical item risk factors were evaluated by univariate and multivariate conditional logistic regression. RESULTS: Fifty-nine RSIs and 118 matched controls were analyzed (RSI incidence 1 in 6,975 or 59 in 411,526). Retained surgical items occurred despite use of confirmatory x-rays (13 of 27 instances) and/or radiofrequency tagging (2 of 32 instances). Among previously discrepant results, we confirmed that body mass index, unexpected intraoperative events, and procedure duration were associated with increased RSI risk. The occurrence of any safety variance, and specifically an incorrect count at any time during the procedure, was associated with elevated RSI risk. Trainee presence was associated with 70% lower RSI risk compared with trainee absence. CONCLUSIONS: Longer duration of surgery, safety variances, and incorrect counts during the procedure result in elevated RSI risk. The possible positive influence of trainee presence on RSI risk deserves additional study. Our findings highlight the need for zero tolerance for safety omissions, continued study and development of novel approaches to RSI reduction, and establishing anonymous RSI reporting systems to better track both the incidence and risks associated with this problem, which has yet to be solved. PMID- 23041051 TI - The kinase RSK2 modulates the sensitivity of ovarian cancer cells to cisplatin. AB - Platinum-based chemotherapy (e.g. cisplatin, carboplatin) is standard of care for many types of cancer including ovarian cancer, however, the efficacy of treatment is hampered by the development of therapy resistance. The mechanisms behind platinum resistance are not completely understood. Here, we have investigated the role of the family of p90 Ribosomal S6 kinases (RSK), important downstream mediators of ERK1/2, in the response to cisplatin chemotherapy. Strikingly, whereas treatment with cisplatin did not alter the levels of RSK1 in response to cisplatin treatment, the structurally related RSK2 protein was downregulated in an ovarian cancer cell line (A2780). Furthermore, we found that knockdown of RSK2, in contrast to knockdown of RSK1, gave rise to enhanced cisplatin sensitivity in a cisplatin sensitive as well as a cisplatin-resistant A2780 cell line. These results indicate that RSK2 is regulated in response to cisplatin treatment, and this downregulation may contribute to the cytotoxic action of cisplatin. Since RSK2 is frequently amplified in a growing number of cancers, this may have implications for the sensitivity of these tumours to platinum-based cytotoxics. PMID- 23041052 TI - Dynamic DNA methylation: a prime candidate for genomic metaplasticity and behavioral adaptation. AB - DNA methylation was once considered to be a static epigenetic modification whose primary function was restricted to directing the development of cellular phenotype. However, it is now evident that the methylome is dynamically regulated across the lifespan: during development as a putative mechanism by which early experience leaves a lasting signature on the genome and during adulthood as a function of behavioral adaptation. Here, we propose that experience-dependent variations in DNA methylation, particularly within the context of learning and memory, represent a form of genomic metaplasticity that serves to prime the transcriptional response to later learning-related stimuli and neuronal reactivation. PMID- 23041053 TI - The Allen Human Brain Atlas: comprehensive gene expression mapping of the human brain. AB - The Allen Human Brain Atlas is a freely available multimodal atlas of gene expression and anatomy comprising a comprehensive 'all genes-all structures' array-based dataset of gene expression and complementary in situ hybridization (ISH) gene expression studies targeting selected genes in specific brain regions. Available via the Allen Brain Atlas data portal (www.brain-map.org), the Atlas integrates structure, function, and gene expression data to accelerate basic and clinical research of the human brain in normal and disease states. PMID- 23041054 TI - Risk reduction assessment of waterborne Salmonella and Vibrio by a chlorine contact disinfectant point-of-use device. AB - Unsafe drinking water continues to burden developing countries despite improvements in clean water delivery and sanitation, in response to Millennium Development Goal 7. Salmonella serotype Typhi and Vibrio cholerae bacteria can contaminate drinking water, causing waterborne typhoid fever and cholera, respectively. Household water treatment (HWT) systems are widely promoted to consumers in developing countries but it is difficult to establish their benefits to the population for specific disease reduction. This research uses a laboratory assessment of halogenated chlorine beads treating contaminated water to inform a quantitative microbial risk assessment (QMRA) of S. Typhi and V. cholerae disease in a developing country community of 1000 people. Laboratory challenges using seeded well water resulted in log10 reductions of 5.44 (+/- 0.98 standard error (SE)) and 6.07 (+/- 0.09 SE) for Salmonella serotype Typhimurium and V. cholerae, respectively. In well water with 10% sewage and seeded bacteria, the log10 reductions were 6.06 (+/- 0.62 SE) and 7.78 (+/- 0.11 SE) for S. Typhimurium and V. cholerae, respectively. When one infected individual was contributing to the water contamination through fecal material leaking into the water source, the risk of disease associated with drinking untreated water was high according to a Monte Carlo analysis: a median of 0.20 (interquartile range [IQR] 0.017-0.54) for typhoid fever and a median of 0.11 (IQR 0.039-0.20) for cholera. If water was treated, risk greatly decreased, to a median of 4.1 * 10(-7) (IQR 1.6 * 10(-8) to 1.1 * 10(-5)) for typhoid fever and a median of 3.5 * 10(-9) (IQR 8.0 * 10(-10) to 1.3 * 10(-8)) for cholera. Insights on risk management policies and strategies for public health workers were gained using a simple QMRA scenario informed by laboratory assessment of HWT. PMID- 23041055 TI - Spontaneous flocking in human groups. AB - Flocking behaviour, as a type of self-organised collective behaviour, is described as the spatial formation of groups without global control and explicit inter-individual recruitment signals. It can be observed in many animals, such as bird flocks, shoals or herds of ungulates. Spatial attraction between humans as the central component of flocking behaviour has been simulated in a number of seminal models but it has not been detected experimentally in human groups so far. The two other sub-processes of this self-organised collective movement - collision avoidance and alignment - are excluded or held constant respectively in this study. We created a computer-based, multi-agent game where human players, represented as black dots, moved on a virtual playground. The participants were deprived of social cues about each other and could neither communicate verbally nor nonverbally. They played two games: (1) Single Game, where other players were invisible, and (2) Joint Game, where each player could see players' positions in a local radius around himself/herself. We found that individuals approached their neighbours spontaneously if their positions were visible, leading to less spatial dispersion of the whole group compared to moving alone. We conclude that human groups show the basic component of flocking behaviour without being explicitly instructed or rewarded to do so. PMID- 23041056 TI - Growing self-organizing trees for autonomous hierarchical clustering. AB - This paper presents a new unsupervised learning method based on growing processes and autonomous self-assembly rules. This method, called Growing Self-organizing Trees (GSoT), can grow both network size and tree topology to represent the topological and hierarchical dataset organization, allowing a rapid and interactive visualization. Tree construction rules draw inspiration from elusive properties of biological organization to build hierarchical structures. Experiments conducted on real datasets demonstrate good GSoT performance and provide visual results that are generated during the training process. PMID- 23041057 TI - Laboratory diagnostics of dengue fever: an emphasis on the role of commercial dengue virus nonstructural protein 1 antigen rapid test. AB - BACKGROUND/PURPOSE(S): In 2008, the Dengue NS1 Ag STRIP (Bio-Rad Laboratories, Marnes-la-Coquette, France) was introduced to routine dengue diagnostics in Taiwan, in addition to real-time reverse-transcription polymerase chain reaction (PCR), virus isolation, and capture immunoglobulin (Ig)M/IgG enzyme-linked immunosorbent assay (ELISA). This study aimed to evaluate the benefit of this assay and factors influencing the results of these diagnostic tests. METHODS: Retrospectively, the authors enrolled laboratory-confirmed adult dengue patients from July 2008 to January 2012 in a tertiary hospital. The sensitivities of each test alone and in combination were analyzed by the duration of illness (early stage: day 0-day 3 and late stage: day 4-day 8). The factors influencing sensitivity of the Dengue NS1 Ag STRIP were examined. RESULTS: There were 392 patients enrolled. The overall sensitivity of the Dengue NS1 Ag STRIP was 68.37% and PCR was 71.94%. With the assistance of the Dengue NS1 Ag STRIP, a diagnosis was made in 10.97% of patients without the need for second convalescent samples, and 4.34% more cases were detected. Independent factors for reduced Dengue NS1 Ag STRIP sensitivity were dengue virus (DENV) IgG seropositivity and a sample taken after the fifth day of illness. At the early stage, the PCR and the Dengue NS1 Ag STRIP combination had the highest sensitivity rate than other combinations. At the late stage, a combination of the Dengue NS1 Ag STRIP and capture IgM/IgG ELISA had better sensitivity rates. PCR and capture IgM/IgG ELISA in combination had sensitivity above 90% through the course of illness. CONCLUSION: Dengue NS1 Ag STRIP is a useful tool for early dengue diagnosis. Its use can increase the diagnostic sensitivity and decrease the need of convalescent samples. Seeking treatment late (days postonset > 4) and DENV IgG seropositivity independently decrease the sensitivity of the Dengue NS1 Ag STRIP. PMID- 23041059 TI - Spectral discrimination of cerebral amyloid lesions after peripheral application of luminescent conjugated oligothiophenes. AB - In vivo imaging of pathological protein aggregates provides essential knowledge of the kinetics and implications of these lesions in the progression of proteopathies, such as Alzheimer disease. Luminescent conjugated oligothiophenes are amyloid-specific ligands that bind and spectrally distinguish different types of amyloid aggregates. Herein, we report that heptamer formyl thiophene acetic acid (hFTAA) passes the blood-brain barrier after systemic administration and specifically binds to extracellular beta-amyloid deposits in the brain parenchyma (Abeta plaques) and in the vasculature (cerebral beta-amyloid angiopathy) of beta amyloid precursor protein transgenic APP23 mice. Moreover, peripheral application of hFTAA also stained intracellular lesions of hyperphosphorylated Tau protein in P301S Tau transgenic mice. Spectral profiling of all three amyloid types was acquired ex vivo using two-photon excitation. hFTAA revealed a distinct shift in its emission spectra when bound to Abeta plaques versus Tau lesions. Furthermore, a spectral shift was observed for Abeta plaques versus cerebral beta-amyloid angiopathy, indicating that different amyloid types and structural variances of a specific amyloid type can be distinguished. In conclusion, by adding spectral signatures to amyloid lesions, our results pave the way for a new area of in vivo amyloid imaging, allowing in vivo differentiation of amyloid (sub)types and monitoring changes of their structure/composition over time. PMID- 23041060 TI - Nephrogenic systemic fibrosis: evidence for oxidative stress and bone marrow derived fibrocytes in skin, liver, and heart lesions using a 5/6 nephrectomy rodent model. AB - Nephrogenic systemic fibrosis (NSF) is associated with gadolinium-based magnetic resonance imaging (MRI) contrast exposure in the setting of acute or chronic renal compromise. It has been proposed that circulating fibrocytes mediate the disease. A study was conducted to determine whether bone marrow-derived fibroblast precursors are involved in contributing to organ fibrosis in MRI contrast-treated rodents with renal insufficiency. Rats status post 5/6 nephrectomy underwent bone marrow transplant from human placental alkaline phosphatase (hPAP)-expressing donors. After engraftment, animals were treated with gadolinium-based MRI contrast (2.5 mmol/kg IP), during weekdays for 4 weeks, or an equivalent volume of normal saline. Dermal cellularity in the contrast treated group was fourfold that of control. Skin cells from the contrast-treated group demonstrated greater hPAP expression with co-expression of pro-collagen I and alpha-smooth muscle actin-positive stress fibers. Donor and host cells expressed CD34. Dihydroethidium staining of skin was greater in the contrast treated animals, indicating oxidative stress. This was abrogated when the animals were co-administered the superoxide dismutase mimetic tempol. In conclusion, a bone marrow-derived cell population is increased in the dermis of MRI contrast treated rodents. The cell markers are consistent with fibrocytes mediating the disease. These changes correlate with oxidative stress and expression of Nox4, suggestive of a novel therapeutic target. Elucidation of the mechanisms of MRI contrast-induced fibrosis may aid in discovering therapies to this devastating disease. PMID- 23041061 TI - Epithelial-to-mesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205. AB - Docetaxel is a standard chemotherapy for patients with metastatic prostate cancer. However, the response is rather limited and not all of the patients benefit from this treatment. To uncover key mechanisms of docetaxel insensitivity in prostate cancer, we have established docetaxel-resistant sublines. In this study, we report that docetaxel-resistant cells underwent an epithelial-to mesenchymal transition during the selection process, leading to diminished E cadherin levels and up-regulation of mesenchymal markers. Screening for key regulators of an epithelial phenotype revealed a significantly reduced expression of microRNA (miR)-200c and miR-205 in docetaxel-resistant cells. Transfection of either microRNA (miRNA) resulted in re-expression of E-cadherin. Functional assays confirmed reduced adhesive and increased invasive and migratory abilities. Furthermore, we detected an increased subpopulation with stem cell-like properties in resistant cells. Tissue microarray analysis revealed a reduced E cadherin expression in tumors after neoadjuvant chemotherapy. Low E-cadherin levels could be linked to tumor relapse. The present study uncovers epithelial-to mesenchymal transition as a hallmark of docetaxel resistance. Therefore, we suggest that this mechanism is at least in part responsible for chemotherapy failure, with implications for the development of novel therapeutics. PMID- 23041062 TI - Aquaporin 3 expression is up-regulated by TGF-beta1 in rat peritoneal mesothelial cells and plays a role in wound healing. AB - Aquaporin 3 (AQP3) is expressed in many tissues including the peritoneum and kidney. In cultured mesothelial cells, glucose up-regulates AQP3, which may be important for water transport through the peritoneal membrane. However, there has been no research into the role of AQP3 in human peritoneal mesothelial cell (HPMC) migration or peritoneal fibrosis. We investigated the effects of transforming growth factor-beta1 (TGF-beta1) on AQP3 expression in HPMCs. We also investigated the role of AQP3 in the peritoneal wound healing process in rats. Chronic exposure to glucose-containing solution increased peritoneal myofibroblasts, with TGF-beta1 and AQP3 expression in a model of long-term peritoneal dialysis. In vitro, TGF-beta1 induced AQP3 expression in HPMCs. AQP3 knockdown by small-interfering RNA inhibited TGF-beta1-induced AQP3 and alpha smooth muscle actin expression and also slowed HPMC migration. AQP3 overexpression induced faster migration of HPMCs. Treatment with an extracellular signal-regulated kinase inhibitor and p38 kinase inhibitor attenuated TGF-beta1 induced AQP3 expression in HPMCs. These data suggest that TGF-beta1 induces AQP3 and that AQP3 has a critical role in TGF-beta-induced HPMC migration. These findings provide evidence of a novel role for AQP3 in peritoneal fibrosis and wound healing. The effect of TGF-beta1 on AQP3 expression in HPMCs is mediated, at least in part, by ERK and p38 signaling. PMID- 23041058 TI - Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. AB - Reactive metabolites from carcinogens and oxidative stress can drive genetic mutations, genomic instability, neoplastic transformation, and ultimately carcinogenesis. Numerous dietary phytochemicals in vegetables/fruits have been shown to possess cancer chemopreventive effects in both preclinical animal models and human epidemiological studies. These phytochemicals could prevent the initiation of carcinogenesis via either direct scavenging of reactive oxygen species/reactive nitrogen species (ROS/RNS) or, more importantly, the induction of cellular defense detoxifying/antioxidant enzymes. These defense enzymes mediated by Nrf2-antioxidative stress and anti-inflammatory signaling pathways can contribute to cellular protection against ROS/RNS and reactive metabolites of carcinogens. In addition, these compounds would kill initiated/transformed cancer cells in vitro and in in vivo xenografts via diverse anti-cancer mechanisms. These mechanisms include the activation of signaling kinases (e.g., JNK), caspases and the mitochondria damage/cytochrome c pathways. Phytochemicals may also have anti-cancer effects by inhibiting the IKK/NF-kappaB pathway, inhibiting STAT3, and causing cell cycle arrest. In addition, other mechanisms may include epigenetic alterations (e.g., inhibition of HDACs, miRNAs, and the modification of the CpG methylation of cancer-related genes). In this review, we will discuss: the current advances in the study of Nrf2 signaling; Nrf2-deficient tumor mouse models; the epigenetic control of Nrf2 in tumorigenesis and chemoprevention; Nrf2 mediated cancer chemoprevention by naturally occurring dietary phytochemicals; and the mutation or hyper-expression of the Nrf2-Keap1 signaling pathway in advanced tumor cells. The future development of dietary phytochemicals for chemoprevention must integrate in vitro signaling mechanisms, relevant biomarkers of human diseases, and combinations of different phytochemicals and/or non-toxic therapeutic drugs, including NSAIDs. PMID- 23041063 TI - Recovery of mature hepatocytic phenotype following bile ductular transdifferentiation of rat hepatocytes in vitro. AB - We previously demonstrated that mature rat hepatocytes transdifferentiate to bile ductular cells when cultured in a three-dimensional collagen-rich matrix. Here, we show that the phenotype of transdifferentiated hepatocytes can be reversed by modulating culture conditions. Spheroidal aggregates of hepatocytes were cultured within a collagen gel matrix in the presence of serum and tumor necrosis factor alpha. Spheroids transformed into ductular structures composed of small cuboidal cells, lost the expression of hepatocytic markers, whereas aberrantly expressed bile ductular markers. The transdifferentiated cells were then retrieved from the gels, plated on surfaces coated with a basement membrane-like material, and cultured in serum-free media. Cells spontaneously formed spheroidal aggregates and recovered hepatocytic phenotype. Dexamethasone (Dex), which suppressed the phosphorylation of ERK and Jun N-terminal kinase, facilitated the recovery, and the combination with interleukin-6 or oncostatin M resulted in the recovery of hepatocyte nuclear factor 4 alpha protein expression and the typical hepatocytic morphology, and a decrease in the expression of bile ductular markers. A cDNA microarray analysis revealed that the hepatocyte-specific mRNA expression profile was recovered in these cells. Our results demonstrate that hepatocytes are able to recover their phenotypes following bile ductular transdifferentiation, suggesting that hepatocytic and bile ductular phenotypes may be mutually reversible. PMID- 23041064 TI - The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. AB - T-bet is a critical transcription factor for T helper 1 (Th1) cell differentiation. To study the regulation and functions of T-bet, we developed a T bet-ZsGreen reporter mouse strain. We determined that interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) were redundant in inducing T-bet in mice infected with Toxoplasma gondii and that T-bet did not contribute to its own expression when induced by IL-12 and IFN-gamma. By contrast, T-bet and the transcription factor Stat4 were critical for IFN-gamma production whereas IFN-gamma signaling was dispensable for inducing IFN-gamma. Loss of T-bet resulted in activation of an endogenous program driving Th2 cell differentiation in cells expressing T-bet ZsGreen. Genome-wide analyses indicated that T-bet directly induced many Th1 cell related genes but indirectly suppressed Th2 cell-related genes. Our study revealed redundancy and synergy among several Th1 cell-inducing pathways in regulating the expression of T-bet and IFN-gamma, and a critical role of T-bet in suppressing an endogenous Th2 cell-associated program. PMID- 23041065 TI - The transcription factors Thpok and LRF are necessary and partly redundant for T helper cell differentiation. AB - T helper (Th) cells are critical for defenses against infection and recognize peptides bound to class II major histocompatibility complex (MHC II) molecules. Although transcription factors have been identified that direct Th cells into specific effector fates, whether a "master" regulator controls the developmental program common to all Th cells remains unclear. Here, we showed that the two transcription factors Thpok and LRF share this function. Although disruption of both factors did not prevent the generation of MHC II-specific T cells, these cells failed to express Th cell genes or undergo Th cell differentiation in vivo. In contrast, T cells lacking Thpok, which only displayed LRF-dependent functions, contributed to multiple effector responses, both in vitro and in vivo, with the notable exception of Th2 cell responses that control extracellular parasites. These findings identify the Thpok-LRF pair as a core node of Th cell differentiation and function. PMID- 23041066 TI - Intramedullary spinal sarcoidosis masquerading as cervical stenosis. AB - OBJECTIVE: Intramedullary spinal sarcoidosis is a difficult diagnosis to make because of its nonspecific clinical and imaging features and its imitation of other common spine disorders. We present a patient with intramedullary spinal sarcoidosis that mimicked spinal cord injury from a cervical disk herniation. METHODS: Relevant information was extracted from the patient's medical and imaging records. A thorough literature review subsequently was performed. RESULTS: A 59-year-old woman presented to our institution with several months of intermittent parathesias, pain, and subjective weakness in her right upper and lower extremities. Magnetic resonance imaging of the cervical spine demonstrated a large osteophyte-disk complex at C4-5 adjacent to a small area of intramedullary spinal cord enhancement. The patient underwent C4-5 anterior cervical diskectomy and fusion for the osteophyte-disk complex. She initially improved postoperatively but subsequently worsened after a few months. Because of more prominent spinal cord enhancement, a posterior laminectomy and biopsy of the enhancing lesion was performed. Intramedullary spinal sarcoidosis was diagnosed, and she was treated medically with steroids and immunosuppressive agents. CONCLUSION: Spinal sarcoidosis can mimic more common disease processes, such as cervical spondylosis. It is an important consideration in the diagnosis of intramedullary or intradural lesions of the spinal cord because early medical treatment may improve the course of the disease process. Surgery should be limited to biopsy for diagnostic purposes. PMID- 23041067 TI - Current status of pipeline embolization device in the treatment of intracranial aneurysms: a review. AB - OBJECTIVE: Pipeline embolization device (PED) implantation is a novel endovascular treatment option for the treatment of intracranial aneurysms. It is emerging as a useful alternative to coiling and to open surgery, and its use is increasing worldwide. We performed a literature review to examine its efficacy, technical challenges, and safety. METHODS: PubMed database was used to identify all articles relating to PED. RESULTS: The review outlines the indications for PED, its technical aspects, complications, and clinical outcomes. CONCLUSIONS: PED offers an alternative to endovascular coiling for aneurysms with complex morphology. The indication for its use has evolved from the limited scope of treatment of giant aneurysms with wide necks to the inclusion of smaller aneurysms. The procedural safety profile of PED is comparable with or possibly superior to balloon-remodeling or stent-assisted coil embolization in specific circumstances. However, questions remain regarding the incidence of post procedural subarachnoid hemorrhage. Ongoing monitoring and meticulous documentation of PED postimplantation safety is strongly recommended. PMID- 23041068 TI - Normal saline injection via lumbar puncture for the treatment of acute tonsillar herniation: a report of 45 cases. AB - OBJECTIVE: Current treatment of apnea attributable to acute tonsillar herniation often is inadequate. This study was undertaken to verify the clinical usefulness of normal saline injection via lumbar puncture for the treatment of apnea secondary to acute tonsillar herniation. METHODS: Between 1969 and 2009, 45 patients who had not regained spontaneous respiratory function after external ventricular drainage or removal of a supratentorial lesion via open craniotomy received an injection of normal saline via lumbar puncture. Patient data were retrospectively analyzed. RESULTS: Eleven of the 45 patients regained spontaneous breathing and recovered fully (24.4%). Sixteen patients regained spontaneous breathing but died later (35.6%), and 18 patients did not regain spontaneous respiration (40.0%). The overall rate of effectiveness of injected normal saline was therefore 60.0%. CONCLUSION: For patients with tonsillar hernia who did not regain spontaneous respiration after external ventricular drainage or removal of a supratentorial lesion, an aggressive approach may be considered. Injection of normal saline via lumbar puncture could improve outcome in some of these patients. PMID- 23041069 TI - Prognostic value of computed tomography-evident cerebral infarcts in adult patients with tuberculous meningitis and hydrocephalus treated with an external ventricular drain. AB - OBJECTIVE: Tuberculous meningitis (TBM) frequently is complicated by hydrocephalus and cerebral infarction. Previous studies have shown radiologic evidence of cerebral infarction in TBM to be an indicator of poor outcome in both adults and children. Our objective was to assess short-term mortality in adult patients with TBM and hydrocephalus treated with an external ventricular drain and to assess the prognostic value of cerebral infarction on admission computed tomography imaging within this cohort. METHODS: This was a retrospective case series based on an adult intensive care unit admissions database, analyzing demographic, clinical, diagnostic, and radiologic data against short-term mortality. RESULTS: A total of 25 patients managed from 2005 to 2011 were identified. Three patients were excluded. Mean age was 31 years. British Medical Research Council clinical severity grading was grade I in 9.1%, grade II in 31.8%, and grade III in 59.1%. Short-term mortality was 68.2% overall. Cerebral infarction on admission scanning was seen in 10 patients (45.5%). Prevalence of infarcts was not significantly higher in HIV-positive patients (50.0% vs. 42.9%). Mortality in the group with infarcts was 100%, compared with 41.7% in the group without infarcts. Mortality in patients with an admission Glasgow Coma Scale of 8 or less was 91.7%. Mortality in the HIV-positive group was slightly greater, but this increase did not reach statistical significance (71.4% vs. 57.1% P = 0.6). Univariate analysis showed presence of infarcts at admission, Glasgow Coma Scale <=8 at admission and age of 30 years or more to be significantly related to mortality. There was also a statistically significantly increased mortality according to British Medical Research Council grade. CONCLUSION: TBM with hydrocephalus requiring cerebrospinal diversion carries a significant short-term mortality. Within this cohort, the group of patients who have computed tomography evident cerebral infarcts at admission has an even worse outcome, with a significantly greater short-term mortality prevalence. PMID- 23041071 TI - Death receptors and mitochondria: two prime triggers of neural apoptosis and differentiation. AB - BACKGROUND: Stem cell therapy is a strategy far from being satisfactory and applied in the clinic. Poor survival and differentiation levels of stem cells after transplantation or neural injury have been major problems. Recently, it has been recognized that cell death-relevant proteins, notably those that operate in the core of the executioner apoptosis machinery are functionally involved in differentiation of a wide range of cell types, including neural cells. SCOPE OF REVIEW: This article will review recent studies on the mechanisms underlying the non-apoptotic function of mitochondrial and death receptor signaling pathways during neural differentiation. In addition, we will discuss how these major apoptosis-regulatory pathways control the decision between differentiation, self renewal and cell death in neural stem cells and how levels of activity are restrained to prevent cell loss as final outcome. MAJOR CONCLUSIONS: Emerging evidence suggests that, much like p53, caspases and Bcl-2 family members, the two prime triggers of cell death pathways, death receptors and mitochondria, may influence proliferation and differentiation potential of stem cells, neuronal plasticity, and astrocytic versus neuronal stem cell fate decision. GENERAL SIGNIFICANCE: A better understanding of the molecular mechanisms underlying key checkpoints responsible for neural differentiation as an alternative to cell death will surely contribute to improve neuro-replacement strategies. PMID- 23041070 TI - Implication of intestinal VDR deficiency in inflammatory bowel disease. AB - BACKGROUND: To investigate the function of the intestinal Vdr gene in inflammatory bowel disease (IBD), in conjunction with the discovery of possible metabolic markers for IBD using intestine-specific Vdr knockout mice. METHODS: Vdr(DeltaIEpC) mice were generated, phenotyped and treated with a time-course of 3% dextran sulfate sodium (DSS) to induce colitis. Colitis was diagnosed by evaluating clinical symptoms and intestinal histopathology. Gene expression analysis was carried out. In addition, metabolic markers of IBD were explored by metabolomics. RESULTS: Vdr(DeltaIEpC) mice showed abnormal body size, colon structures and feces color. Calcium, collagen, and intestinal proliferation related gene expression were all decreased, and serum alkaline phosphatase was highly increased. In the acute model which was treated with 3% DSS for six days, Vdr(DeltaIEpC) mice showed a high score of IBD symptoms; enlarged mucosal layer and damaged muscularis layer. In the recovery experiment model, where mice were treated with 3% DSS for four days and water for three days, Vdr(DeltaIEpC) mice showed a high score of IBD symptoms; severe damage of mucosal layer and increased expression of genes encoding proinflammatory cytokines. Feces metabolomics revealed decreased concentrations of taurine, taurocholic acid, taurodeoxycholic acid and cholic acid in Vdr(DeltaIEpC) mice. CONCLUSIONS: Disruption of the intestinal Vdr gene showed phenotypical changes that may exacerbate IBD. These results suggest that VDR may play an important role in IBD. GENERAL SIGNIFICANCE: VDR function has been implicated in IBD. This is of value for understanding the etiology of IBD and for development of diagnostic biomarkers for IBD. PMID- 23041072 TI - Characterization of substrate and product specificity of the purified recombinant glycogen branching enzyme of Rhodothermus obamensis. AB - BACKGROUND: Glycogen and starch branching enzymes catalyze the formation of alpha(1->6) linkages in storage polysaccharides by rearrangement of preexisting alpha-glucans. This reaction occurs through the cleavage of alpha(1->4) linkage and transfer in alpha(1->6) of the fragment in non-reducing position. These enzymes define major elements that control the structure of both glycogen and starch. METHODS: The kinetic parameters of the branching enzyme of Rhodothermus obamensis (RoBE) were established after in vitro incubation with different branched or unbranched alpha-glucans of controlled structure. RESULTS: A minimal chain length of ten glucosyl units was required for the donor substrate to be recognized by RoBE that essentially produces branches of DP 3-8. We show that RoBE preferentially creates new branches by intermolecular mechanism. Branched glucans define better substrates for the enzyme leading to the formation of hyper branched particles of 30-70nm in diameter (dextrins). Interestingly, RoBE catalyzes an additional alpha-4-glucanotransferase activity not described so far for a member of the GH13 family. CONCLUSIONS: RoBE is able to transfer alpha(1 >4)-linked-glucan in C4 position (instead of C6 position for the branching activity) of a glucan to create new alpha(1->4) linkages yielding to the elongation of linear chains subsequently used for further branching. This result is a novel case for the thin border that exists between enzymes of the GH13 family. GENERAL SIGNIFICANCE: This work reveals the original catalytic properties of the thermostable branching enzyme of R. obamensis. It defines new approach to produce highly branched alpha-glucan particles in vitro. PMID- 23041073 TI - Neuroscience and approach/avoidance personality traits: a two stage (valuation motivation) approach. AB - Many personality theories link specific traits to the sensitivities of the neural systems that control approach and avoidance. But there is no consensus on the nature of these systems. Here we combine recent advances in economics and neuroscience to provide a more solid foundation for a neuroscience of approach/avoidance personality. We propose a two-stage integration of valuation (loss/gain) sensitivities with motivational (approach/avoidance/conflict) sensitivities. Our key conclusions are: (1) that valuation of appetitive and aversive events (e.g. gain and loss as studied by behavioural economists) is an independent perceptual input stage--with the economic phenomenon of loss aversion resulting from greater negative valuation sensitivity compared to positive valuation sensitivity; (2) that valuation of an appetitive stimulus then interacts with a contingency of presentation or omission to generate a motivational 'attractor' or 'repulsor', respectively (vice versa for an aversive stimulus); (3) the resultant behavioural tendencies to approach or avoid have distinct sensitivities to those of the valuation systems; (4) while attractors and repulsors can reinforce new responses they also, more usually, elicit innate or previously conditioned responses and so the perception/valuation motivation/action complex is best characterised as acting as a 'reinforcer' not a 'reinforcement'; and (5) approach-avoidance conflict must be viewed as activating a third motivation system that is distinct from the basic approach and avoidance systems. We provide examples of methods of assessing each of the constructs within approach-avoidance theories and of linking these constructs to personality measures. We sketch a preliminary five-element reinforcer sensitivity theory (RST 5) as a first step in the integration of existing specific approach-avoidance theories into a coherent neuroscience of personality. PMID- 23041074 TI - Surgical treatment of Tourette syndrome. AB - In severely affected, treatment resistant patients with Tourette syndrome (TS) new therapeutic strategies are urgently needed. Since 1999, 34 studies including more than 90 patients have been performed to investigate the efficacy and safety of deep brain stimulation (DBS) in the treatment of tics resulting in the vast majority of patients in an improvement of tics and in some patients even of comorbidities. Both surgery-related (e.g., bleeding, infection) and stimulation related adverse events (e.g., loss of energy, blurred vision) seem to occur only in a minority of patients and not to cause significant impairment, respectively. Since randomized controlled studies including a larger number of patients are still lacking, up to now, no definite conclusion can be drawn. Therefore, at present time DBS is recommended only in adult, treatment resistant, and severely affected patients. However, most experts have no doubt that DBS is indeed effective in the treatment of tics. Future studies should aim to identify which target in which patient is optimal depending on the individual symptomatology. PMID- 23041075 TI - The effects of sulfur mustard exposure and freezing on transdermal penetration of tritiated water through ex vivo pig skin. AB - The percutaneous absorption of tritiated water ((3)H(2)O) through sulfur mustard (SM) exposed abdominal pig skin was measured using in vitro Franz-type static diffusion cells. The barrier function to water permeation following exposure to liquid SM for 8 min and excision 3h later did not change significantly. A small, but statistically significant difference (P<0.05) in steady state penetration (Jss), permeability coefficient (Kp) and lag time (t(L)) of (3)H(2)O was observed between fresh skin and skin stored frozen (-20 degrees C) for up to two weeks. Steady-state penetration and Kp values were significantly higher (P < 0.05) in skin stored frozen compared with fresh skin. Fresh naive skin had an average Kp of 1.65 * 10(-3) cm h(-1), whereas frozen naive skin was 2.04 * 10(-3) cm h(-1). Fresh SM exposed skin had a mean Kp of 1.72 * 10(-3) cm h(-1), whereas frozen SM exposed skin was 2.31 * 10(-3) cm h(-1). Lag times were also shorter (P<0.05) in skin that had been stored frozen. Frozen, SM-exposed porcine abdominal skin may be used for in vitro penetration studies, but effects of treatment and storage on the barrier layer should be taken into account. PMID- 23041076 TI - Rough virulent strain of Brucella ovis induces pro- and anti-inflammatory cytokines in reproductive tissues in experimentally infected rams. AB - The ovine brucellosis caused by Brucella ovis has tropism for reproductive tissues but until now the mechanism of bacterial persistence is not understood. Cytokine expression profiles were studied for 8 months in rams after being experimentally infected with the rough virulent strain of B. ovis (R-B. ovis) to study the pathogenesis of B. ovis and immune mechanism possibly associated to bacteria tropism and persistence. The messenger RNA (mRNA) expression levels of interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, IL-10, IL-12, interferon-gamma (INF-gamma) and tumour necrosis factor-alpha (TNF-alpha) cytokines were quantified by real-time quantitative RT-PCR (qRT-PCR) in reproductive tissues (epididymus, testicles, ampolae, vesicular glands and bulbourethral glands), and non-reproductive (liver, spleen and kidneys) tissues at 30, 60, 120 and 240 days post infection (dpi). During the acute phase of infection at 30 dpi, the host immune response was most notable demonstrating an up-regulation of several cytokines in reproductive tissues, including the epididymus (IL-6, IL-1beta and IL-1alpha), testicles (INF-gamma and IL-12), bulbourethral glands (IL-6 and TNF alpha) and ampolae (INF-gamma, IL-10, IL-1beta and IL-1alpha). During the development of infection, cytokine gene expression levels decreased, providing evidence of immunosuppression and evidence of immune evasion that favoured persistence of chronic R-B. ovis infection. During the chronic phase of R-B. ovis infection (120 and 240 dpi), cytokine production was down-regulated in the epididymus (IL-1beta and IL-1alpha), testicles (INF-gamma and IL-12), and ampolae (INF-gamma, IL-10, IL-1beta and IL-1alpha), with the exception of the bulbourethral glands (IL-6 and TNF-alpha) and epididymus (IL-6); in these tissues, R-B. ovis infection resulted in up-regulation of the pro-inflammatory cytokine IL-6. Herein, we report cytokine expression profiles in tissues of rams experimentally infected with the rough strain of B. ovis, which are associated with bacterial persistence and macrophage activation. PMID- 23041077 TI - Quantitative mass spectrometry-based assay development and validation: from small molecules to proteins. AB - Mass spectrometry (MS) has emerged as a powerful analytical tool for the identification, characterization and quantification of various biomolecules (small molecules, drug metabolites and proteins) in biological specimens. The use of mass spectrometers in the clinical diagnostic laboratories have gained popularity due to its ease of development of new assays, ability to measure multiple analytes in a single analytical run, low volume requirements and low reagent costs. Novel technological advancements in ionization sources, instrumentation and software have increased the popularity of these platforms. Consequently, a number of home-brew assays, utilizing the power of MS, are being developed and validated for clinical diagnostic use. In this review, we will discuss the two phases that precede method implementation: method development and validation for both small molecule analysis and protein quantification using liquid chromatography tandem mass spectrometry (LC-MS/MS). Some of the challenges facing protein quantification will be highlighted and an outlook for the future of laboratory medicine and MS will be provided. PMID- 23041078 TI - Anatomical and functional damage in experimental glaucoma. AB - Glaucoma is a progressive neurodegenerative disease caused by retinal ganglion cell (RGC) loss. One important risk factor for glaucoma is elevated intraocular pressure and thus many animal models are based on spontaneous or induced ocular hypertension (OHT). Using these models it has been shown that RGCs initially suffer an impairment of the active axonal transport that progresses to a lack of passive diffusion along the axon. This axonal damage eventually causes the death of the parent RGCs in pie-shaped sectors of the retina, but there is also diffuse RGC loss, without involving displaced amacrine cells. Recent data show that OHT results in a protracted insult to the inner and outer retina that causes functional alterations and ultimately, degeneration and death of cones. PMID- 23041080 TI - [HRT: state of knowledge in 2012]. PMID- 23041079 TI - Communication between gastrointestinal bacteria and the nervous system. AB - In the past few years, intestinal microbiota has emerged as a novel target for the treatment of gut-brain axis alterations. These include functional gastrointestinal disorders, such as irritable bowel syndrome (IBS), which can be comorbid with stress-related psychiatric conditions. Thus, modulation of the microbiota (e.g. with the use of probiotics) could be proposed as a novel strategy not only for the treatment of IBS but also as an adjuvant for psychiatric treatment of anxiety and depression. PMID- 23041081 TI - [Menopause and cardiovascular risk]. AB - Estrogenic deficiency of menopause is not only responsible to the precocious occurrence of climateric troubles but exposes at increased risk of osteoporosis, metabolic troubles, and cardiovascular complications. We believed for a long time that the hormonal treatment prescription could prevent cardiovascular risk. Then, initial analysis of the great controlled study WHI and HERS causes unfavorable judgment of overall risk-benefit balance evaluation. However, the situation isn't so contrasted, and many arguments are in favor of vascular benefit with hormonal replacement therapy (HRT). Menopause and HRT influence the cardiovascular risk factors. The oral-estrogen taking conducts to significant decrease of LDL cholesterol rate, and significant increase of HDL and triglyceride plasma levels. Otherwise, there is a decrease of insulin-resistance and incidence of type 2 diabetes in substituted women. At least, oral estrogens seem to be responsible of deleterious effect pro-inflammatory and prothrombotic. The transdermal taking would limit these effects. During the precocious stage of atheromatous plaque formation, estradiol has a really protective function, with endothelial effect, limiting the induction and the activation of proinflammatory cells. On the contrary, when plaques are formed, giving estrogens could be harmful, because it could facilitate plaque rupture by pro-inflammatory effect. In 1998, then in 2002, the publication of the two main controlled study WHI and HERS removes the legitimacy of HRT in cardiovascular prevention terms, however, post-hoc analysis since published, have moderate the initial version: more and more convincing arguments suggest vascular benefit of HRT, if it begins just after menopause and probably before the existence of advanced atheromatous plaque, bringing the notion of the opportunity window. In contrary of oral taking, transdermal estrogens do not seem to be associated with a significant increase risk in the risk of thromboembolism or cerebrovascular events (stroke). At last, the choice of associated progestatif is essential, concerning the improvement of lipid profile among the human being or towards the prevention of atheroma among the animal, this hormones are able to attenuate or to stop benefits effects of estradiol. In practice, and according to AFSSAPS recommendations, the doctor will make a personalised and rigorous prescription of HRT, at minimal effective dose, associating healthy life style and dietetics measures, and after having given detailed information to the patient. PMID- 23041082 TI - Molecular cloning, characterization and expression analysis of ATG1 in the silkworm, Bombyx mori. AB - Atg1 is a Serine/Threonine protein kinase that plays a pivotal role in autophagy. A complete coding sequence of ATG1 is not available for the silkworm, Bombyx mori which is a good model for studying the autophagic process. In the present study we isolated two full-length cDNAs of 2175 (transcript variant A) and 2271 (transcript variant B) bases representing ATG1 in the silkworm. Phylogenetic analysis indicated that BmATG1 was closely related to orthologs of other insects. The encoded BmAtg1 proteins shared extensive homology with orthologs from yeast to mammals, showing high conservation at the N-terminal region where the catalytic domain and ATP- and Mg-binding sites are located. A de novo prediction of the three-dimensional structure for each protein is presented. We used real time RT-PCR to quantify dynamic changes in mRNA copy number of BmATG1 in the midgut and fat body of fifth instar larvae undergoing starvation, as well as in other tissues of silkworm at the end of last larval instar. Our qPCR results revealed that BmATG1 expression levels at the end of larval life were comparable in the midgut, fat body and Malpighian tubules, while these were higher in the gonads; moreover, the mRNA copy number of ATG1 was very different among the anterior, middle and posterior silk glands. Real-time PCR analysis also showed that starvation significantly influenced BmATG1 mRNA copy number in the fat body of silkworm, inducing an upregulation 24h after food withdrawal, with only a slight effect in the midgut. Low expression levels of BmATG1 were observed in both tissues of control animals up to the second day of spinning phase. PMID- 23041083 TI - Sequence of Leptospira santarosai serovar Shermani genome and prediction of virulence-associated genes. AB - Leptospirosis, a widespread zoonosis, is a re-emerging infectious disease caused by pathogenic Leptospira species. In Taiwan, Leptospira santarosai serovar Shermani is the most frequently isolated serovar, causing both renal and systemic infections. This study aimed to generate a L. santarosai serovar Shermani genome sequence and categorize its hypothetical genes, particularly those associated with virulence. The genome sequence consists of 3,936,333 nucleotides and 4033 predicted genes. Additionally, 2244 coding sequences could be placed into clusters of orthologous groups and the number of genes involving cell wall/membrane/envelope biogenesis and defense mechanisms was higher than that of other Leptospira spp. Comparative genetic analysis based on BLASTX data revealed that about 73% and 68.8% of all coding sequences have matches to pathogenic L. interrogans and L. borgpetersenii, respectively, and about 57.6% to saprophyte L. biflexa. Among the hypothetical proteins, 421 have a transmembrane region, 172 have a signal peptide and 17 possess a lipoprotein signature. According to PFAM prediction, 32 hypothetical proteins have properties of toxins and surface proteins mediated bacterial attachment, suggesting they may have roles associated with virulence. The availability of the genome sequence of L. santarosai serovar Shermani and the bioinformatics re-annotation of leptospiral hypothetical proteins will facilitate further functional genomic studies to elucidate the pathogenesis of leptospirosis and develop leptospiral vaccines. PMID- 23041084 TI - Association of three polymorphisms of scavenger receptor class BI gene (exon8, exon1, intron5) with coronary stenosis in a coronary Tunisian population. AB - BACKGROUND: The potential role of scavenger receptor class BI (gene name SCARB1) in the regulation of lipoproteins metabolism and atherosclerosis has attracted considerable interest. We tested the relationship of SCARB1 polymorphisms with significant coronary stenosis (SCS) and lipid profile in a coronary Tunisian population. METHODS: Three SCARB1 polymorphisms (exon8 (C/T), exon1 (G/A), intron5 (C/T)) were studied in 316 Tunisian patients undergoing coronary angiography. SCS was defined as a luminal narrowing of >= 50% in at least one major coronary artery. Lipid profile was measured. Genotyping was performed using PCR-RFLP. RESULTS: Individuals with TT genotypes of exon8 were associated with higher concentrations of plasma HDL-C and ApoAI in the group without SCS. Carriers of T allele of exon8 were associated with 41% lower risk of SCS. This protective effect seemed to be particularly significant in women, nondiabetics and nonsmokers. Subjects homozygous for the variant allele of intron5 were significantly associated with an increased risk of SCS, particularly in smokers. AA genotype of exon1 was associated with an increased risk of SCS in diabetics and in patients with metabolic syndrome. The (CAT) haplotype was associated with increase in the risk of SCS compared to the wild haplotype and had a 4-fold greater risk of SCS than patients with haplotype (TGC) which seems to be the most protective against SCS. CONCLUSION: Carriers of T allele of exon8 in SCARB1 seemed to increase HDL-C and ApoAI concentrations and reduce the risk of SCS. The intron5, exon1 and (CAT) haplotype seemed to have an atherogenic effect. PMID- 23041085 TI - Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element. AB - Iron is essential for the human being, involving in oxygen transport, energy metabolism and DNA synthesis. Iron homeostasis is tightly governed by the hepcidin-ferroportin axis, of which hepcidin is the master regulator. Excess iron is associated with various diseases including osteopenia and osteoporosis, which are closely related to the alternation of the endogenous estrogen level. To verify the biological effect of estrogen on iron metabolism, we established a mouse model of estrogen deficiency by ovariectomy. We demonstrated that the hemoglobin content and serum iron level decreased, whereas the tissue iron level in liver and spleen increased in the ovariectomized mice. Moreover, the transcription of hepatic hepcidin was elevated in ovariectomized mice compared to the control mice. We further demonstrated that there was an estrogen response element (ERE) in the promoter region of the hepcidin gene. The assay using the luciferase reporter system confirmed the existence of a functional ERE in the hepcidin promoter, as the estradiol treatment reduced hepcidin expression in cells transfected with ERE-intact construct, with no response to estradiol in cells transfected with ERE-devoid construct. In conclusion, estrogen greatly contributes to iron homeostasis by regulating hepatic hepcidin expression directly through a functional ERE in the promoter region of hepcidin gene. These findings might help build a better understanding towards the etiology of postmenopausal osteoporosis accompanied by excess tissue iron (such as iron retention of osteoclasts in bone) under estrogen deficiency. PMID- 23041086 TI - Use of measles supplemental immunization activities (SIAs) as a delivery platform for other maternal and child health interventions: opportunities and challenges. AB - Measles supplementary immunization activities (SIAs) offer children in countries with weaker immunization delivery systems like India a second opportunity for measles vaccination. They could also provide a platform to deliver additional interventions, but the feasibility and acceptability of including add-ons is uncertain. We surveyed Indian programme officers involved in the current (2010 2012) measles SIAs concerning opportunities and challenges of using SIAs as a delivery platform for other maternal and child health interventions. Respondents felt that an expanded SIA strategy including add-ons could be of great value in improving access and efficiency. They viewed management challenges, logistics, and safety as the most important potential barriers. They proposed that additional interventions be selected using several criteria, of which importance of the health problem, safety, and contribution to health equity figured most prominently. For children, they recommended inclusion of basic interventions to address nutritional deficiencies, diarrhoea and parasites over vaccines. For mothers, micronutrient interventions were highest ranked. PMID- 23041087 TI - The Functional Dexterity Test: test-retest reliability analysis and up-to date reference norms. AB - STUDY DESIGN: Clinical measurement. INTRODUCTION: Among the available tests for fine finger dexterity, the Functional Dexterity Test (FDT) has been indicated as a valid instrument to measure outcome in different conditions. PURPOSE OF THE STUDY: To analyze test-retest reliability, to study the influence of gender, age and hand dominance on the FDT score, and to collect reference norms for adult and elderly age-groups. METHODS: Test-retest reliability was calculated with the Intraclass Correlation Coefficient (ICC) and Standard Error of Measurement (SEM) in a subgroup of 324 healthy volunteers. An enlarged sample of 698 subjects, tested at least once, was used to present stratified data for age group, sex, and hand dominance, and ANOVA was used to investigate statistically significant differences between groups. RESULTS: The FDT showed excellent reliability (ICC > 0.90; SEM: <2 s for net times; <3 s for total scores). Age, gender and hand dominance significantly influenced FDT scores (p < 0.05), but no interaction between variables was found. CONCLUSIONS: FDT is confirmed as reliable, and up-to date reference norms over a broad range of ages of the Italian adult population have been provided. LEVEL OF EVIDENCE: NA. PMID- 23041088 TI - [Oxcarbazepine poisoning: cross-reaction with tricyclic antidepressants]. PMID- 23041089 TI - Diverse left ventricular morphology and predictors of short-term outcome in patients with stress-induced cardiomyopathy. AB - BACKGROUND: There is paucity of data with regard to the clinical spectrum according to left ventricle (LV) morphological variation in stress-induced cardiomyopathy (SCMP) patients, and still there is controversy in terms of prognosis since some people believe that the published in-hospital mortality data of patients with SCMP are underestimated. Therefore, we sought to investigate the morphological features of LV and in-hospital outcome of patients with SCMP and explored predictors of short-term prognosis. METHODS: This was a multicenter, observational study of 208 SCMP patients. Morphological features of LV were determined by echocardiography and were divided into typical (apical) and atypical ballooning types, which were subcategorized into mid-LV ballooning and basal 'inverted' ballooning type. All-cause mortality of patients with SCMP during hospitalization was recorded. RESULTS: The apical ballooning type was most common (67.3%) in SCMP followed by the mid-LV ballooning type (28.3%), and the basal 'inverted' ballooning type (4.3%). There were no differences in stressor types and in-hospital mortality between patients with typical and atypical SCMP. Notably, all the in-hospital mortality of SCMP patients occurred in patients with physical stressors, where age, shock, and LV ejection fraction were the independent risk factors for predicting in-hospital mortality. CONCLUSIONS: SCMP patients showed diverse patterns of LV morphology, but there were no definite differences on clinical spectrum among SCMP patients presenting various LV morphological patterns. In terms of short-term prognosis, underlying physical conditions combined with old age, hemodynamic compromise, and low LV systolic function might be the most important factors in SCMP patients. PMID- 23041090 TI - Gender-related differences in patients with acute heart failure: management and predictors of in-hospital mortality. AB - AIM AND METHODS: Gender-related differences in clinical phenotype, in-hospital management and prognosis of acute heart failure (AHF) patients have been previously reported in European and US registries. The ALARM-HF survey is the first to include a cohort of 4953 patients hospitalized for AHF in 666 hospitals in 6 European countries, Mexico and Australia. RESULTS: Women accounted for 37% of the study population, were older and had higher rates of de novo heart failure (45% vs 36%, p<0.001) than men. An acute coronary syndrome (ACS) was the predominant precipitating factor in both genders, but to a lesser extent in females (30% vs 42%, p<0.001). Between genders comparison showed higher incidence of atrial fibrillation, valvular heart disease, diabetes, obesity, anemia and depression in women (p<0.05). Similarly, women had higher left ventricular ejection fraction (LVEF) on admission (42 +/- 15% vs 36 +/- 13%, p<0.001) and systolic blood pressure (135 +/- 40 mm Hg vs 131 +/- 39 mm Hg, p=0.001) than men. On the other hand, men had more often coronary artery disease, renal failure and chronic obstructive pulmonary disease (p<0.05). Importantly, in-hospital mortality was similar in both genders (11.1% in females vs 10.5% in males, p=0.475), and its common predictors were: systolic blood pressure at admission, creatinine>1.5mg/dL and diabetes. Furthermore, recent ACS, valvular heart disease and dementia contributed to prognosis in women, while LVEF, hypertension and anemia were independent predictors in men. CONCLUSION: Among patients with AHF, there are significant differences in co-morbidities, precipitating factors and predictors of in-hospital mortality between genders. Nevertheless, in-hospital mortality remains similar between genders. PMID- 23041091 TI - New insights into cirrhotic cardiomyopathy. AB - Cirrhotic cardiomyopathy designates a cardiac dysfunction, which includes reduced cardiac contractility with systolic and diastolic dysfunction, and presence of electrophysiological abnormalities in particular prolongation of the QT interval. Several pathophysiological mechanisms including reduced beta-receptor function seem involved in the autonomic and cardiac dysfunction. Cirrhotic cardiomyopathy can be revealed by tissue Doppler imaging but is best demasked by physical or pharmacological stress. Liver transplantation may revert cardiac dysfunction but surgery and shunt insertion may also aggravate the condition. Moreover, cirrhotic cardiomyopathy may contribute to heart failure after invasive procedures and to development of hepatic nephropathy as part of a cardiorenal syndrome. Whether beta-blockers have a deleterious effect in this clinical situation remains to be settled. PMID- 23041092 TI - Prognostic value of plasma von Willebrand factor and its cleaving protease ADAMTS13 in patients with atrial fibrillation. AB - BACKGROUND: The von Willebrand factor (vWF) is essential for platelet adhesion and arterial thrombosis. It is degraded into less active multimers by ADAMTS13. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 antigen levels. The vWF/ADAMTS13-ratio might help to estimate the pro thrombotic risk of patients with AF. We therefore investigated whether a high ratio of vWF/ADAMTS13, independently of clinical risk scores, predicts major adverse cardiovascular events (MACE) in patients with AF. METHODS: This prospective longitudinal single center study included 269 patients with AF. Blood samples were analyzed for vWF and ADAMTS13-antigen concentration by means of enzyme-linked immunoassay kits. RESULTS: After adjustment for all univariable predictors for MACE (p <= 0.1), ADAMTS13<=49.77% (HR 1.833 (95% CI 1.089-3.086); p=0.023) and vWF/ADAMTS13-ratio>27.57 (HR 2.174 (95% CI 1.238-3.817); p=0.007) remained independently associated with outcome. vWF>1434.92 mU/ml (HR 1.539 (95% CI 0.883-2.682); p=0.128) alone failed to independently predict MACE. In patients with low and intermediate risk for MACE according to the CHADS2-score the addition of high vWF/ADAMTS13-ratio levels (>27.57) had significant impact on the patients' outcome. CONCLUSION: A high ratio of vWF/ADAMTS13 independently predicts MACE in patients with AF. Therefore, vWF and its cleaving protease ADAMTS13 might play an important role in the development and perpetuation of vascular disease in AF patients. This might be a novel target for future treatment strategies or an additional help for risk stratification in AF patients. PMID- 23041093 TI - Incorporating glomerular filtration rate or creatinine clearance by the modification of diet in renal disease equation or the Cockcroft-Gault equations to improve the global accuracy of the Age, Creatinine, Ejection Fraction [ACEF] score in patients undergoing percutaneous coronary intervention. AB - BACKGROUND: The aim of the present study was to appraise the comparative ability of different ACEF models incorporating glomerular filtration rate or creatinine clearance estimated by the Modification of Diet in Renal Disease [ACEFMDRD] or Cokcroft-Gault [ACEFCG] equations, respectively, over the original ACEF score (ACEFSrCr) in patients undergoing percutaneous coronary intervention (PCI). METHODS: A total of 537 patients were analyzed by different measures of discrimination, calibration and net reclassification improvement (NRI). RESULTS: A significant gradient in all-cause mortality was consistently seen with all the models at 30 days, 1 year and 5 years. The comparison of the three models showed that the best balance in terms of discrimination and calibration for all-cause mortality was offered by the ACEFCG at 30 days, the ACEFMDRD at 1 year and similarly by the ACEFCG and ACEFMDRD at 5 years. At 30 days, the NRI was +32.9% for ACEFMDRD over ACEFSrCr and +16% for ACEFCG over ACEFSrCr. At 1 year, the NRI was 13.8% for ACEFMDRD over ACEFSrCr and -7.8% for ACEFCG over ACEFSrCr. At 5 years, the NRI was +7.7% for both the ACEFMDRD and the ACEFCG over the ACEFSrCr. CONCLUSIONS: In patients undergoing PCI, the ACEF score is associated with satisfactory early-, mid- and long-term discrimination regardless of the definition of renal function. However, incorporating glomerular filtration rate or creatinine clearance by the MDRD or CG formulas in the ACEF score yields superior calibration compared with the original SrCr-based equation, with the ACEFMDRD displaying superior reclassification ability over the ACEFCG and ACEFSrCr at 30 days and 1 year. PMID- 23041094 TI - Successful percutaneous endovascular retrieval of a coil in the left ventricle which migrated during embolization for pulmonary arteriovenous malformation. PMID- 23041095 TI - Genetic variability on adiponectin gene affects myocardial infarction risk: the role of endothelial dysfunction. AB - BACKGROUND: Adiponectin is an adipokine with an important role in cardiovascular system conferring anti-inflammatory and anti-atherogenic effects. Two common single nucleotide polymorphisms (SNP) on adiponectin gene, rs2241766 and rs1501299, have been associated with insulin resistance and diabetes mellitus risk however their effects on cardiovascular risk remain unclear. We examined the impact of rs2241766 and rs1501299 on circulating adiponectin levels, endothelial function and cardiovascular disease risk. METHODS: We recruited in total 594 subjects; 462 patients with angiographically confirmed coronary artery disease (CAD) and 132 controls matched for age and gender. rs2241766 and rs1501299 were genotyped by polymerase chain reaction and restriction endonuclease digestion. Serum adiponectin levels were determined by enzyme-linked immunosorbent assay. Endothelial function was assessed by the flow mediated dilatation (FMD) of the brachial artery. RESULTS: rs2241766 had no effects on circulating adiponectin levels or FMD. In subjects without CAD, carriers of the T/T alleles at rs1501299 had lower adiponectin levels (p=0.001) and impaired endothelial function (p<0.05). After multivariate adjustment none of the SNPs had any effect on CAD risk. However, carriers of the T allele at rs1501299 were at increased myocardial infarction (MI) risk, independently of classic risk factors (OR=2.558 [95%CI=1.587-4.123], p=0.0001). The number of T alleles in both SNPs was strongly associated with MI history (p=0.0001). CONCLUSIONS: rs1501299 polymorphism of adiponectin gene affects circulating adiponectin levels and endothelial function in subjects without CAD. Presence of the T variant at rs1501299 on adiponectin gene is independently associated with increased myocardial infarction risk. PMID- 23041096 TI - Hypertension after repair of aortic coarctation--a systematic review. AB - Hypertension continues to be a common and potentially serious problem in patients who have undergone anatomically successful repair of aortic coarctation. OBJECTIVE: To assess the prevalence of hypertension after aortic coarctation repair, the factors that affect the prevalence and the hypotheses behind hypertension in this cohort of patients. DESIGN: A systematic review of all articles reporting on systolic blood pressure (SBP) in patients who have undergone aortic coarctation repair. DATA SOURCES: An electronic search of all English articles using PUBMED and The Cochrane Controlled Trials Register was performed. A manual search of references lists of relevant studies and a search of conference abstracts were also conducted. INCLUSION CRITERIA: We restricted inclusion to articles published between 1987 and 2012 that reported on SBP in patients who have undergone aortic coarctation repair. DATA EXTRACTION: Independent extraction of articles was performed by two authors using predefined data fields. One author then proceeded to extract information of interest from these articles. RESULTS: The first search yielded 12,914 articles. After screening titles, abstracts and full text articles 26 articles were included in this review article. In papers reporting the prevalence of hypertension late after anatomically satisfactory coarctation repair, the median prevalence was 32.5% (range 25-68%). CONCLUSION: Hypertension remains a common complication following aortic coarctation repair. Factors that influence the reported prevalence of hypertension include the age at the time of surgery, age at follow up, the method used to measure blood pressure and the type of intervention performed. PMID- 23041097 TI - Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis. AB - BACKGROUND: Flow-mediated dilation (FMD) is an accepted technique to quantify endothelial function and has shown to have prognostic value for future cardiovascular disease (CVD). The predictive strength of FMD in CVD patients compared to populations not diagnosed for CVD warrants further investigation. We systematically reviewed prospective studies that investigated the association between brachial FMD and future cardiovascular events, with particular focus on the role of underlying health status. METHODS: To obtain eligible studies, several literature databases were systematically searched through March 2011. Pooled overall risk estimates were calculated separately for continuous risk estimates for CVD (per 1% higher FMD) and for categorical risk estimates for CVD (having high vs. low FMD), based on random-effects models. RESULTS: A total of 23 studies including 14,753 subjects were eligible for inclusion in the meta analysis. For studies reporting continuous risk estimates, the pooled overall CVD risk was 0.92 (95%CI: 0.88; 0.95) per 1% higher FMD. The observed association seemed stronger (P-value<0.01) in diseased populations than in asymptomatic populations (0.87 (95%CI: 0.83; 0.92) and 0.96 (95%CI: 0.92; 1.00) per 1% higher FMD, respectively). For studies reporting categorical risk estimates, the pooled overall CVD risk for high vs. low FMD was similar in both types of populations, on average 0.49 (95%CI: 0.39; 0.62). CONCLUSIONS: Our findings show that brachial FMD is inversely associated with future CVD events, with some indications for a stronger relation in diseased populations. Endothelial dysfunction may be considered relevant for classifying subjects in terms of CVD risk. PMID- 23041098 TI - Influence of midwall fibrosis on diastolic dysfunction in non-ischemic cardiomyopathy. PMID- 23041099 TI - Physical activity in relation to cardiac risk markers in secondary prevention of coronary artery disease. AB - BACKGROUND: The relationship between physical activity and cardiac risk markers in secondary prevention for patients with coronary artery disease (CAD) is uncertain. The aims of the study were therefore to examine the level of physical activity in patients with CAD, and to investigate the association between physical activity and cardiac risk markers. METHODS: In total, 332 patients, mean age, 65 +/- 9.1 years, diagnosed with CAD at a university hospital were included in the study 6 months after their cardiac event. Physical activity was measured with a pedometer (steps/day) and two questionnaires. Investigation of cardiac risk markers included serum lipids, oral glucose-tolerance test, twenty-four hour blood pressure and heart rate monitoring, smoking, body-mass index (BMI), waist hip ratio, and muscle endurance. The study had a cross-sectional design. RESULTS: The patients performed a median of 7,027 steps/day. After adjustment for confounders, statistically significant correlations between steps/day and risk markers were found with regard to; high-density lipoprotein cholesterol (HDL-C) (r=0.19, p<0.001), muscle endurance measures (r ranging from 0.19 to 0.25, p=0.001 or less) triglycerides (r=-0.19, p<0.001), glucose-tolerance (r=-0.23, p<0.001), BMI (r=-0.21, p<0.001), 24-h heart rate recording during night (r= 0.17, p=0.004), and average 24-h heart rate (r=-0.13, p=0.02). CONCLUSIONS: A relatively high level of physical activity was found among patients with CAD. There was a weak, but significant, association between pedometer steps/day and HDL-C, muscle endurance, triglycerides, glucose-tolerance, BMI and 24-h heart rate, indicating potential positive effects of physical activity on these parameters. However, before clinical implications can be formed, more confirmatory data are needed. PMID- 23041100 TI - Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease. AB - BACKGROUND: The objective of this prospective study was to assess the efficacy of exercise training as add-on to medical therapy in patients with congenital heart disease associated pulmonary arterial hypertension (CHD-APAH). METHODS: Patients with invasively confirmed CHD-APAH received in-hospital exercise training for 3 weeks and continued at home. Efficacy parameters were evaluated at baseline, after 3 and 15 weeks. Medical treatment remained unchanged. Worsening events and survival rate were assessed in a follow-up period of 21 +/- 14 months. RESULTS: Twenty consecutive CHD-APAH patients (16 female, 4 male, mean pulmonary arterial pressure 60 +/- 23 mm Hg) were included. Patients significantly improved the mean distance walked in 6 min compared to baseline by 63 +/- 47 m after 3 weeks (p<0.001) and by 67 +/- 59 m after 15 weeks (p=0.001). Quality of life-score (p=0.05), peak oxygen consumption (p=0.002) and maximal workload (p=0.003) improved significantly by exercise training after 15 weeks. The 1- and 2-year survival rates were 100%, the transplantation-free survival rate was 100% after 1 year and 93% after 2 years. CONCLUSION: Exercise training as add-on to medical therapy may be effective in patients with CHD-APAH and improved work capacity, quality of life and further prognostic relevant parameters. It was associated with an excellent long-term survival. Further randomized controlled studies are needed to confirm these results. PMID- 23041101 TI - Menopausal transition enhances the atherogenic risk of smoking in middle aged women. AB - BACKGROUND: The presence of cardiovascular risk factors during the menopausal transition could be critical in the development of atherosclerosis. In the present study, we evaluated whether the menopausal transition has impact on traditional and newly discussed risk factors. METHODS: Six hundred ninety nine women from population-based study underwent ultrasound measurement of the intima media thickness of the common carotid arteries (CIMT) - Prague Pre and Postmenopausal Females study (3PMFs). In addition, 40 women selected according to reproductive and smoking status were examined with regard to number of circulating endothelial progenitor cells, markers of reverse cholesterol transport and sex hormones, including their fluctuation - Hormone Variability study (HVs). RESULTS: Age, smoking, body mass index, systolic blood pressure and HDL cholesterol were independently associated with the CIMT in 3PMFs group. The increase in the CIMT with age was markedly steeper in current/past smokers than in non-smokers among perimenopausal women (p for equality of slopes=0.005). This difference was not observed in premenopausal and menopausal women. In the HVs group, endothelial progenitor cells and reverse cholesterol transport were substantially higher while triglycerides and fluctuation of free testosterone were lower in non-smokers than in smokers in menopausal transition. In contrast, in menopausal women, the fluctuation of free testosterone was higher in non smokers; no other differences between smokers and non-smokers were detected. CONCLUSIONS: These results suggest that atherogenic effect of smoking may be enhanced during menopausal transition. The mechanism could be impaired reparative vascular processes, impaired reverse cholesterol transport and rapidly changing status of sex hormones. PMID- 23041102 TI - [Pancreatic metastases due to renal carcinoma. Our cases and a literature review]. AB - OBJECTIVE: To analyse the cases of pancreatic metastases due to renal carcinoma operated on in our hospital between the years 2000 and 2011. MATERIAL AND METHODS: A retrospective study using the variables of 8 patients who were subjected to surgery of pancreatic metastases due to renal carcinoma, and a comparison of our data with those from the literature. RESULTS: The incidence of metastatic disease of the pancreas due to renal carcinoma in our series was 1.2%. All the metastases were metachronous, with both sexes being affected equally. The mean time between resection of the renal tumour and the diagnosis of the metastasis was 12.42 years (range: 1.62-30.13 years). The therapeutic approach to the pancreatic lesions was surgical in all cases. Seven patients are currently still alive. CONCLUSION: Metastatic disease of the pancreas due to renal carcinoma is uncommon (1%-2.8%). The interval between the primary resection and the metastasis can be quite long. Pancreatic metastasis must always be suspected in patients who present with a pancreatic mass and a history of renal carcinoma. Aggressive surgical treatment is recommended in selected cases. The surgery in these cases improves survival and the quality of life. PMID- 23041103 TI - [Hepatic metastasis marking before neoadjuvant chemotherapy for their subsequent location and resection using non-anatomical hepatectomy]. PMID- 23041104 TI - The surgical mask (facemask) 'ear Sling'. PMID- 23041105 TI - The influence of different VEGF administration protocols on the perfusion of epigastric flaps in rats. AB - In this study we investigated the impact of the time at which vascular endothelial growth factor (VEGF) was given on the overall survival of flaps and time of the achievement of full perfusion in the rat epigastric flap model. Epigastric flaps were raised in 144 rats. VEGF was given to 108 rats at different time points. Perioperatively blood flow, velocity, haemoglobin (Hb) concentration, and oxygen saturation were measured non-invasively using laser Doppler spectrophotometry. On postoperative days 3, 5, 7, or 10, the pedicle of the flap was ligated. One week later, the flap was harvested for immunohistochemical assessment of the density of microvessels. Differences significant from those in the control group were found in all specimens 3 and 5 days after the first operation, whereas no differences in the area of necrosis were detected after 7 and 10 days. Preoperative values of measured Hb (p<0.0001, 95% confidence interval (CI) 0.57 to 1.02), flow (p<0.0001, 95% CI -0.32 to 0.13), and velocity (p<0.0001, 95% CI 0.48 to 1.89) predicted necrosis. After ligation of the pedicle, SO2 (p<0.0001, 95% CI -1.12 to -0.83) and flow (p<0.0001, 95% CI -0.38 to -0.26) were prognostic factors. The topical use of VEGF increases overall survival of flaps and decreases the time needed for a free flap to achieve full perfusion. The time of application of VEGF has no part in the postoperative course. The perfusion of vascularised free flaps in their wound beds was achieved between postoperative days 5 and 7 in the control group and postoperative days 3 and 5 after VEGF had been given. PMID- 23041106 TI - Activations of GABAergic signaling, HSP70 and MAPK cascades are involved in baicalin's neuroprotection against gerbil global ischemia/reperfusion injury. AB - Baicalin, a flavonoid compound isolated from the plant Scutellaria baicalensis Georgi, is known as a protective agent against delayed neuronal cell death after ischemia/reperfusion. To investigate the neuroprotective mechanism of baicalin, the present study was conducted to explore whether the alterations of GABAergic signaling, heat shock protein 70 (HSP70) and mitogen-activated protein kinases (MAPKs) were involved in its neuroprotection on gerbils global ischemia. The bilateral carotid arteries were occluded by 5 min and baicalin at the dose of 200 mg/kg was intraperitoneally injected into the gerbils immediately after cerebral ischemia. Seven days after reperfusion, neurological deficit was scored and changes in hippocampal neuronal cell death were assessed by Nissl staining as well as NeuN immunohistochemistry. The mRNA and protein expressions of GABAergic signal molecules (GABA(A)R alpha1, GABA(A)R gamma2, KCC2 and NKCC1) were determined in ischemic hippocampus by real-time RT-PCR and Western blot, respectively. In addition, HSP70 and MAPKs cascades (ERK, JNK and p38) were also detected using western blot assay. Our results illustrated that baicalin treatment significantly facilitated neurological function, suppressed the ischemia-induced neuronal damage. Besides, administration of baicalin also caused a striking increase of GABA(A)R alpha1, GABA(A)R gamma2 and KCC2 together with the decrease of NKCC1 at mRNA and protein levels in gerbils hippocampus following an ischemic insult. Furthermore, the protein expressions of HSP70 and phosphorylated ERK (p-ERK) were evidently augmented while the phosphorylated JNK (p-JNK) and phosphorylated p38 (p-p38) were strikingly diminished in ischemic gerbils with baicalin treatment. These findings suggest that baicalin activates GABAergic signaling, HSP70 and MAPKs cascades in global ischemia, which may be a mechanism underlying the baicalin's neuroprotection. PMID- 23041107 TI - Population, mortality and place of death in Germany (1950-2050) - implications for end-of-life care in the future. AB - OBJECTIVES: European populations are ageing, but data on the associated end-of life care needs are scarce. This study aimed to analyse population, mortality and place of death (PoD) trends in Germany since 1950, and to project mortality by PoD until 2050. STUDY DESIGN AND METHODS: Secondary analysis of national statistics on population, mortality and PoD by age and gender. Future numbers and proportions of deaths by PoD - hospital deaths (HDs) and non-hospital deaths (NHDs) - were based on recent trends (2005-2009). Linear models accounted for the effect of age and gender. RESULTS: The German population increased by 19.0% between 1950 and 2002, and has remained relatively stable ever since. However, it is expected that it will decrease (15.4%) from 2009 to 2050 (from 81.8 to 69.4 million). The annual number of deaths has shown an increasing trend, except for a decrease in 1975-2004. A 26.0% increase is expected from 2009 to 2050 (854,544 to 1,077,000 deaths). Older people (age >= 75 years) will account for 87.8% of all deaths in 2050 (64.4% in 2009). The proportion of HDs was stable, with an annual mean of 47.0% (range 44.9-47.8%). The models estimated that most people will continue to die outside of hospital in 2050 (48.6 or 54.1%), and absolute numbers of both HDs and NHDs will increase from 2009 to 2050 [HD: by 20.1 million (30.6%); NHD: by 35.5 million (17.0%)]. CONCLUSIONS: Unlike in other industrialized countries, most people in Germany die outside of hospital. The need to plan for growing end-of-life care needs and ageing is urgent in Germany but also applies to the rest of Europe. A joint European policy must inform national strategies. PMID- 23041108 TI - Do transition towns have the potential to promote health and well-being? A health impact assessment of a transition town initiative. AB - OBJECTIVES: Climate change and energy vulnerability present significant challenges for the development and sustainability of our communities. The adverse effects will most likely impact on those already experiencing poverty, as energy and food costs will rise, thus increasing inequalities in health. Transition town initiatives seek to build cohesive sustainable communities to prepare for a future with limited oil and a changing climate. Increasingly, public health practitioners are interested in the role of transition towns as a community development initiative, and their potential to support the wider public health agenda. Health impact assessment (HIA) is an evidence-based process that aims to predict the positive and negative impacts of a strategy, proposal or development. The HIA process provides an opportunity to promote sustainable communities by ensuring that new strategies and developments are considered in the context of their contribution to the health and well-being of local populations. The aim of this study was to use an HIA to examine the potential health and well-being benefits of two related transition town initiatives. STUDY DESIGN: A rapid HIA to consider the potential lifestyle changes and health and well-being impacts of Transition Together/Transition Streets (TT/TS) projects. METHODS: An HIA template was used to assess key documents related to the TT/TS initiatives and those related to the characteristics of the community. Additionally, meetings with 12 key informants (four involved in TT/TS and eight purposively selected for their local knowledge) were held using the HIA template to focus the discussion. RESULTS: The findings highlight the associated lifestyle changes such as increased physical activity and healthy eating, and possible social and well being benefits of engagement in such an initiative. Engagement may be limited to those already concerned about environmental issues. CONCLUSION: This paper illustrates the important links between transition towns and the wider public health agenda, and demonstrates how an HIA can be applied to a community-based initiative. It provides a means by which transition town initiatives can demonstrate health and well-being benefits, whilst raising concerns about inclusivity and equity. PMID- 23041109 TI - A new NARX-based Granger linear and nonlinear casual influence detection method with applications to EEG data. AB - A new NARX-based Granger linear and nonlinear casual influence detection method is presented in this paper to address the potential for linear and nonlinear models in data with applications to human EEG data analysis. Considering two signals initially, the paper introduces four indexes to measure the linearity and nonlinearity of a single signal, and one signal influencing the second signal. This method is then extended to the time-varying and multivariate cases. An adaptation of an Orthogonal Least Squares routine is employed to select the significant terms in the models. A numerical example is provided to illustrate the effectiveness of the new algorithms together with the application to real EEG data collected from 4 patients. PMID- 23041110 TI - MICEST: a potential tool for non-invasive detection of molecular changes in Alzheimer's disease. AB - Myo-inositol (mIns) is a marker of glial cells proliferation and has been shown to increase in early Alzheimer's disease (AD) pathology. mIns exhibits a concentration dependent chemical-exchange-saturation-transfer (CEST) effect (MICEST) between its hydroxyl groups and bulk water protons. Using the endogenous MICEST technique brain mIns concentration and glial cells proliferation can be mapped at high spatial resolution. The high resolution mapping of mIns was performed using MICEST technique on ~20 months old APP-PS1 transgenic mouse model of AD as well as on age matched wild type (WT) control (n=5). The APP-PS1 mice show ~50% higher MICEST contrast than WT control with concomitant increase in mIns concentration as measured through proton spectroscopy. Immunostaining against glial-fibric-acidic protein also depicts proliferative glial cells in larger extent in APP-PS1 than WT mice, which correspond to the higher mIns concentration. Potential significance of MICEST in early detection of AD pathology is discussed in detail. PMID- 23041111 TI - Role for endogenous estrogen in prepubertal Sertoli cell maturation. AB - Reducing prepubertal endogenous estrogens led to increased numbers of Sertoli cells and the associated increased testicular size and testicular sperm production capacity in boars. The increased number of Sertoli cells might be due to a longer time for proliferation; delayed differentiation of Sertoli cells during suppressed endogenous estrogens would be consistent with this hypothesized, prolonged proliferation interval. This study used immunohistochemical detection of anti-Mullerian hormone (AMH), a marker of immature Sertoli cells, and of CDKN1B, a cell cycle inhibitor associated with more mature Sertoli cells, to determine if suppressing endogenous estrogens detectably delayed "differentiation" of porcine Sertoli cells. Testes were from littermate pairs of boars previously treated with Letrozole, an aromatase inhibitor, or vehicle, from the first week of age until tissue collection at 2, 3, 4, 5 or 6 months of age. Four animals were examined at each age following Letrozole treatment and their corresponding littermates evaluated following treatment with vehicle. Amount of AMH protein in Sertoli cells decreased with age of boar and could not be detected at 6 months of age. The AMH labeling was greater in the Letrozole-treated boars compared with littermate vehicle controls at 4 months of age (P=0.03). The percentage of CDKN1B-labeled Sertoli cells apparently increased with age through 5 months of age. At 4 and 5 months of age, the mean percentage of CDKN1B-labeled Sertoli cells was less in the Letrozole treated animals than in the vehicle control animals (P = 0.03 and 0.04, respectively). These results are consistent with the hypothesis that continual inhibition of aromatase (and concomitatant reduced estrogen synthesis) causes a delay in Sertoli cell maturation in boars. PMID- 23041112 TI - 1927-nm fractional resurfacing of facial actinic keratoses: a promising new therapeutic option. AB - BACKGROUND: Actinic keratoses (AK) are precancerous epidermal proliferations commonly present on chronically sun-damaged skin. These lesions are among the most often treated dermatologic conditions. OBJECTIVE: We sought to investigate the 6-month safety, tolerance, and efficacy of nonablative 1927-nm fractional resurfacing of facial AK. METHODS: This was a prospective clinical trial of 24 individuals with facial photodamage and AK receiving up to 4 treatments with the fractionated 1927-nm nonablative thulium laser. RESULTS: At 6 months, an 86.6% reduction in absolute number of lesions was noted by independent physician assessment. In addition, at this same time point, patients reported marked or noticeable improvement in overall photodamage. LIMITATIONS: This prospective study does not provide safety, tolerance, and efficacy data beyond 6 months of follow-up, nor does it identify the precise mechanism of action involved in AK clearance after 1927-nm resurfacing. CONCLUSION: The clinical and histologic findings, as well as the reported patient satisfaction and safety, suggest that the treatment of AK and photodamage with a fractionated 1927-nm nonablative thulium laser is a promising new therapeutic option. PMID- 23041113 TI - Phlorotannin-rich Ecklonia cava reduces the production of beta-amyloid by modulating alpha- and gamma-secretase expression and activity. AB - Beta-amyloid (Abeta) is a major pathogenic peptide in Alzheimer's disease (AD) and is generated by the processing of amyloid precursor protein (APP). We have previously reported that the brown algae Ecklonia cava, which has anti-oxidant and anti-inflammatory functions, decreased Abeta production and further aggregation in HEK293 cells expressing the APP Swedish mutation. Here, we show the reduction mechanism of Abeta production using the butanol extract of Ecklonia cava through the examination of expression and activity of alpha-, beta-, and gamma-secretase. Treatment with the extract resulted in the activation of alpha secretase with a contrasting decrease in its mRNA and protein expression. This activation was consistent with the translocation of the extract into the plasma membrane of the secretase. Gamma-secretase activity was lowered by E. cava, and this effect may be due to the decreased expression of PSEN1 mRNA and protein. In addition, the basal nuclear location of PSEN1, which may affect chromosome missegregation in neurodegenerative disease, was reduced by the extract, despite the significance of this finding remains unclear. Taken together, these results led us to conclude that E. cava regulated the expression and activity of gamma secretase and alpha-secretase, leading to a reduction in Abeta production by the stable cells. Our data indicate that E. cava is a novel natural-product candidate for AD treatment, although further in vivo studies are needed. PMID- 23041114 TI - Trichinella infections in animals and humans in sub-Saharan Africa: a review. AB - The aim of this review is to provide information on Trichinella infection in humans, livestock and wildlife in sub-Saharan Africa mainly focusing on geographical distribution of species/genotypes, biology, host range, life cycles and to identify research gaps. Trichinella britovi, Trichinella nelsoni and Trichinella zimbabwensis and one genotype (Trichinella T8) are known to occur in sub-Saharan Africa. Distinct geographic ranges with overlapping of some taxa in some areas have been observed. Genetic variants of T. nelsoni has been reported to occur among parasites originating from Eastern and Southern Africa and sequence heterogeneity also occurs among T. zimbabwensis isolates originating from different regions of Zimbabwe and South Africa. Field observations so far indicate that sylvatic Trichinella infections in the region are common in carnivores (mammals and reptiles) and to a lesser extent in omnivores. Cannibalism, scavenging and predation appear to be the most important routes of transmission and maintenance of the sylvatic cycles of the Trichinella taxa. To date, human trichinellosis has been documented in only four sub-Saharan countries (8.7%, 4/46). Bushpigs and warthogs have been the source of human infection with T. britovi and T. nelsoni being the aetiological agents. An increase in bushmeat trade and the creation of Transfrontier Conservation Areas (TFCAs) may have increased the risk of human trichinellosis in the region. With the creation of TFCAs in the region, sampling of wildlife hosts from protected areas of most sub Sahara African countries is required to fully map the distribution of Trichinella species/genotypes in this region. More structured field surveys are still needed to determine the sylvatic host distribution of the different Trichinella taxa. Biological data of the Trichinella taxa in both wild and domestic animals of sub Saharan Africa is very limited and further research is required. PMID- 23041115 TI - BMP2 induces segment-specific skeletal regeneration from digit and limb amputations by establishing a new endochondral ossification center. AB - Bone morphogenetic proteins (BMPs) are required for bone development, the repair of damage skeletal tissue, and the regeneration of the mouse digit tip. Previously we showed that BMP treatment can induce a regeneration response in mouse digits amputated at a proximal level of the terminal phalangeal element (P3) (Yu et al., 2010). In this study, we show that the regeneration-inductive ability of BMP2 extends to amputations at the level of the second phalangeal element (P2) of neonatal digits, and the hindlimb of adult limbs. In these models the induced regenerative response is restricted in a segment-specific manner, thus amputated skeletal elements regenerate distally patterned skeletal structures but does not form joints or more distal skeletal elements. Studies on P2 amputations indicate that BMP2-induced regeneration is associated with a localized proliferative response and the transient expression of established digit blastema marker genes. This is followed by the formation of a new endochondral ossification center at the distal end of the bone stump. The endochondral ossification center contains proliferating chondrocytes that establish a distal proliferative zone and differentiate proximally into hypertrophic chondrocytes. Skeletal regeneration occurs from proximal to distal with the appearance of osteoblasts that differentiate in continuity with the amputated stump. Using the polarity of the endochondral ossification centers induced by BMP2 at two different amputation levels, we show that BMP2 activates a level-dependent regenerative response indicative of a positional information network. In summary, our studies provide evidence that BMP2 induces the regeneration of mammalian limb structures by stimulating a new endochondral ossification center that utilizes an existing network of positional information to regulate patterning during skeletal regeneration. PMID- 23041116 TI - Genetic dissection of midbrain dopamine neuron development in vivo. AB - Midbrain dopamine (MbDA) neurons are partitioned into medial and lateral cohorts that control complex functions. However, the genetic underpinnings of MbDA neuron heterogeneity are unclear. While it is known that Wnt1-expressing progenitors contribute to MbDA neurons, the role of Wnt1 in MbDA neuron development in vivo is unresolved. We show that mice with a spontaneous point mutation in Wnt1 have a unique phenotype characterized by the loss of medial MbDA neurons concomitant with a severe depletion of Wnt1-expressing progenitors and diminished LMX1a expressing progenitors. Wnt1 mutant embryos also have alterations in a hierarchical gene regulatory loop suggesting multiple gene involvement in the Wnt1 mutant MbDA neuron phenotype. To investigate this possibility, we conditionally deleted Gbx2, Fgf8, and En1/2 after their early role in patterning and asked whether these genetic manipulations phenocopied the depletion of MbDA neurons in Wnt1 mutants. The conditional deletion of Gbx2 did not result in re positioning or distribution of MbDA neurons. The temporal deletion of Fgf8 did not result in the loss of either LMX1a-expressing progenitors nor the initial population of differentiated MbDA neurons, but did result in a complete loss of MbDA neurons at later stages. The temporal deletion and species specific manipulation of En1/2 demonstrated a continued and species specific role of Engrailed genes in MbDA neuron development. Notably, our conditional deletion experiments revealed phenotypes dissimilar to Wnt1 mutants indicating the unique role of Wnt1 in MbDA neuron development. By placing Wnt1, Fgf8, and En1/2 in the context of their temporal requirement for MbDA neuron development, we further deciphered the developmental program underpinning MbDA neuron progenitors. PMID- 23041117 TI - An economical biorefinery process for propionic acid production from glycerol and potato juice using high cell density fermentation. AB - An economically sustainable process was developed for propionic acid production by fermentation of glycerol using Propionibacterium acidipropionici and potato juice, a by-product of starch processing, as a nitrogen/vitamin source. The fermentation was done as high-cell-density sequential batches with cell recycle. Propionic acid production and glycerol consumption rates were dependent on initial biomass concentration, and reached a maximum of 1.42 and 2.30 g L(-1) h( 1), respectively, from 50 g L(-1) glycerol at initial cell density of 23.7 gCDW L(-1). Halving the concentration of nitrogen/vitamin source resulted in reduction of acetic and succinic acids yields by ~39% each. At glycerol concentrations of 85 and 120 g L(-1), respectively, 43.8 and 50.8 g L(-1) propionic acid were obtained at a rate of 0.88 and 0.29 g L(-1) h(-1) and yield of 84 and 78 mol%. Succinic acid was 13 g% of propionic acid and could represent a potential co product covering the cost of nitrogen/vitamin source. PMID- 23041118 TI - Experimentally induced blood stage malaria infection as a tool for clinical research. AB - A system for experimentally induced blood stage malaria infection (IBSM) with Plasmodium falciparum by direct intravenous inoculation of infected erythrocytes was developed at the Queensland Institute of Medical Research (QIMR) more than 15 years ago. Since that time, this system has been used in several studies to investigate the protective effect of vaccines, the clearance kinetics of parasites following drug treatment, and to improve understanding of the early events in blood stage infection. In this article, we will review the development of IBSM and the applications for which it is being employed. We will discuss the advantages and disadvantages of IBSM, and finish by describing some exciting new areas of research that have been made possible by this system. PMID- 23041119 TI - Re: Multicentre survey of radiologically inserted gastrostomy feeding tube (RIG) in the UK. PMID- 23041120 TI - Value of tricuspid annular plane systolic excursion and peak systolic velocity in children with pulmonary hypertension. PMID- 23041121 TI - The next generation recombinant human cytomegalovirus vaccine candidates-beyond gB. AB - Human cytomegalovirus (HCMV) infects the majority of the global population and persists within the infected host for life; infection of healthy adults rarely leads to severe acute clinical symptoms. In contrast, HCMV is a leading infectious cause of congenital disease and a common cause of complications in transplant recipients. A vaccine to prevent HCMV disease in these populations is a widely recognized medical need. We review recent advances in our understanding of the candidate vaccine antigens and published clinical trial data for the four most recent HCMV vaccine candidates: a gB subunit adjuvanted with MF59, a DNA vaccine expressing gB and pp65, alphavirus replicon particles (VRPs) expressing gB and a pp65-IE1 fusion protein, and a pp65 peptide vaccine. The candidates are safe, although some adverse events were reported for an adjuvanted variant of the pp65 peptide vaccine. The gB/MF59 vaccine elicited strong humoral responses with limited durability. The gB/pp65 DNA vaccine elicited cellular immunity, and the pp65 peptide vaccine elicited modest cellular immunity, but only when formulated with an adjuvant. Only the VRP vaccine expressing gB and pp65-IE1 elicited both humoral and cellular immunity. The gB/MF59 vaccine showed a short-term 50% efficacy at preventing infection of seronegative women and significantly reduced viremia and need for antivirals in solid organ transplant recipients, and the gB/pp65 DNA vaccine showed signs of clinical benefit in hematopoietic stem cell transplant recipients. Importantly, the partial efficacy of the subunit and DNA vaccines is new evidence that both humoral and cellular immunity contribute to controlling HCMV-related disease. These data show the clinical feasibility of a recombinant HCMV vaccine. We discuss areas for potential improvements in the next generation of vaccine candidates. PMID- 23041122 TI - Adjuvants and inactivated polio vaccine: a systematic review. AB - Poliomyelitis is nearing universal eradication; in 2011, there were 650 cases reported globally. When wild polio is eradicated, global oral polio vaccine (OPV) cessation followed by use of universal inactivated polio vaccine (IPV) is believed to be the safest vaccination strategy as IPV does not mutate or run the risk of vaccine derived outbreaks that OPV does. However, IPV is significantly more expensive than OPV. One strategy to make IPV more affordable is to reduce the dose by adding adjuvants, compounds that augment the immune response to the vaccine. No adjuvants are currently utilized in stand-alone IPV; however, several have been explored over the past six decades. From aluminum, used in many licensed vaccines, to newer and more experimental adjuvants such as synthetic DNA, a diverse group of compounds has been assessed with varying strengths and weaknesses. This review summarizes the studies to date evaluating the efficacy and safety of adjuvants used with IPV. PMID- 23041123 TI - Adverse events following a third dose of measles, mumps, and rubella vaccine in a mumps outbreak. AB - During a 2009-2010 mumps outbreak in a New York State village, a third dose of measles, mumps, and rubella (MMR) vaccine was administered to children in three schools as a control measure. Information on local and systemic adverse events (AE) was collected by a self-report survey distributed to all children in grades 6-12. A comprehensive search for AE following MMR vaccination was conducted using physician records and the Vaccine Adverse Events Reporting System (VAERS). A literature search was performed for published reports pertaining to AE associated with mumps-containing vaccine, using the Jeryl-Lynn strain, from 1969 to 2011. A total of 1755 individuals received the third dose; 1597 (91.0%) returned the survey. Of those, 115 (7.2%) reported at least one local or systemic AE in the 2 weeks following vaccination. The most commonly reported AE were "pain, redness, or swelling at the injection site" (3.6%) and "joint or muscle aches" (1.8%). No serious AE were reported in the survey, physician records or through VAERS. The proportions of AE found in the present study were lower than or within the range of those reported in prior studies of first- and second-dose MMR vaccine studies. The results of this study suggest that a third dose of MMR vaccine administered in an outbreak setting is safe, with injection site reactions reported more frequently than systemic reactions. However, to assess risk for rare or serious AE after a third dose of MMR vaccine, longer term studies would be required. PMID- 23041124 TI - Childhood immunization reporting laws in the United States: current status. AB - CONTEXT: Immunization Information Systems (IIS), or registries, were developed to improve effectiveness and efficiency in immunization services. Complex laws that govern IIS and immunization records are developed at the state-level, interact with each other, and may impact utility for all immunization stakeholders. As states develop Health Information Exchange laws they may also interact with IIS laws. OBJECTIVES: To provide immunization stakeholders an overview of the laws applicable to healthcare providers and health departments. Comparisons are provided to illustrate the trends since the previous studies. METHODS: IIS relevant statutes, regulations and ordinances of jurisdictions (states, large cities) of 56 "Grantees" receiving funding under the 317b Public Health Service Act were identified via legal databases then systematically reviewed for authorization, reporting and consent requirements. Key provisions were coded and mapped according to 131 variables. RESULTS: Including subsections, 984 laws across Grantees relate to immunization records, falling under many administrative sections of state and city government. Most Grantees have more than one law that addresses immunization records reporting, exchange and privacy protections. Not all of these laws are in alignment, but there is a trend toward increased Grantee IIS authorizing laws, mandated reporting and implied consent provisions. Of the 56 Grantees, 37 (66%) had IIS authorizing laws, and 46 (82%) had laws addressing healthcare provider and vital statistics reporting. However, much variation remains, even within the provisions of these laws. The coding instrument received 93.7% agreement and a K-alpha of 0.791. CONCLUSIONS: The trend toward laws that encourage participation should continue to improve functionality and value, but inconsistencies among laws should be addressed, both across jurisdictions within states and between different states. They may impair the value of the information that is collected. Greater uniformity could improve the overall usefulness of IIS. PMID- 23041125 TI - A Vaxfectin((r))-adjuvanted HSV-2 plasmid DNA vaccine is effective for prophylactic and therapeutic use in the guinea pig model of genital herpes. AB - Here we describe studies in the guinea pig model of genital herpes to evaluate a novel plasmid DNA (pDNA) vaccine encoding the HSV-2 glycoprotein D and UL46 and UL47 genes encoding tegument proteins VP11/12 and VP 13/14 (gD2/UL46/UL47), formulated with a cationic lipid-based adjuvant Vaxfectin((r)). Prophylactic immunization with Vaxfectin((r))-gD2/UL46/UL47 significantly reduced viral replication in the genital tract, provided complete protection against both primary and recurrent genital skin disease following intravaginal HSV-2 challenge, and significantly reduced latent HSV-2 DNA in the dorsal root ganglia compared to controls. We also examined the impact of therapeutic immunization of HSV-2 infected animals. Here, Vaxfectin((r))-gD2/UL46/UL47 immunization significantly reduced both the frequency of recurrent disease and viral shedding into the genital tract compared to controls. This novel adjuvanted pDNA vaccine has demonstrated both prophylactic and therapeutic efficacy in the guinea pig model of genital herpes and warrants further development. PMID- 23041126 TI - Purification and characterization of a novel histone H2A specific protease (H2Asp) from chicken liver nuclear extract. AB - The proteolysis of the N- or the C-terminal tails of histones have recently emerged as a novel form of irreversible posttranslational modifications of histones. However, there are very few reports describing purification of a histone specific protease. Here, we report a histone H2A specific protease (H2Asp) activity in the chicken liver nuclear extract. The H2Asp was purified to homogeneity and was found to be a ~10.5kDa protein. It demonstrated high specificity to histone H2A and was an aspartic acid like protease as shown by protease inhibition assay. The H2Asp, in the in vitro cleavage assay generated a single clipped H2A product which comigrated along with histone H4 in the SDS-PAGE and migrated as a single band when single H2A was used as substrates. The expression of H2Asp was independent of age and was tissue specific, which was demonstrated only in the nuclear extracts of chicken liver and not from the same of other tissues like brain, muscles and erythrocytes. It was also seen that H2Asp activity also exists in other classes of vertebrates from Pisces to Mammals. This report forms the first such report describing purification of a histone H2A specific protease. PMID- 23041127 TI - Regulation of interlocking gene regulatory network subcircuits by a small molecule inhibitor of retinoblastoma protein (RB) phosphorylation: cancer cell expression of HLA-DR. AB - The induction of the major histocompatibility (MHC), antigen-presenting class II molecules by interferon-gamma, in solid tumor cells, requires the retinoblastoma tumor suppressor protein (Rb). In the absence of Rb, a repressosome blocks the access of positive-acting, promoter binding proteins to the MHC class II promoter. However, a complete molecular linkage between Rb expression and the disassembly of the MHC class II repressosome has been lacking. By treating A549 lung carcinoma cells with a novel small molecule that prevents phosphorylation mediated, Rb inactivation, we demonstrate that Rb represses the synthesis of an MHC class II repressosome component, YY1. The reduction in YY1 synthesis correlates with the advent of MHC class II inducibility; with loss of YY1 binding to the promoter of the HLA-DRA gene, the canonical human MHC class II gene; and with increased Rb binding to the YY1 promoter. These results support the concept that the Rb gene regulatory network (GRN) subcircuit that regulates cell proliferation is linked to a GRN subcircuit regulating a tumor cell immune function. PMID- 23041128 TI - Inpatient care of the elderly in Brazil and India: assessing social inequalities. AB - The rapidly growing older adult populations in Brazil and India present major challenges for health systems in these countries, especially with regard to the equitable provision of inpatient care. The objective of this study was to contrast inequalities in both the receipt of inpatient care and the length of time that care was received among adults aged over 60 in two large countries with different modes of health service delivery. Using the Brazilian National Household Survey from 2003 and the Indian National Sample Survey Organisation survey from 2004 inequalities by wealth (measured by income in Brazil and consumption in India) were assessed using concentration curves and indices. Inequalities were also examined through the use of zero-truncated negative binomial models, studying differences in receipt of care and length of stay by region, health insurance, education and reported health status. Results indicated that there was no evidence of inequality in Brazil for both receipt and length of stay by income per capita. However, in India there was a pro-rich bias in the receipt of care, although once care was received there was no difference by consumption per capita for the length of stay. In both countries the higher educated and those with health insurance were more likely to receive care, while the higher educated had longer stays in hospital in Brazil. The health system reforms that have been undertaken in Brazil could be credited as a driver for reducing healthcare inequalities amongst the elderly, while the significant differences by wealth in India shows that reform is still needed to ensure the poor have access to inpatient care. Health reforms that move towards a more public funding model of service delivery in India may reduce inequality in elderly inpatient care in the country. PMID- 23041129 TI - Drug release modification by interpolymer interaction between countercharged types of Eudragit(r) RL 30D and FS 30D in double-layer films. AB - Interpolymer interactions between the countercharged methacrylate copolymers Eudragit((r)) RL 30D (polycation) and Eudragit((r)) FS 30D (polyanion), were investigated in conditions mimicking the gastrointestinal environment. The formation of inter-macromolecular ionic bonds between Eudragit((r)) RL 30D and Eudragit((r)) FS 30D was investigated using FT-IR spectroscopy and modulated DSC. The FT-IR spectra of the tested polymeric matrices are characterized by visible changes in the observed IR region indicating the interaction between chains of two oppositely charged copolymers. A new band at 1570 cm(-1) appeared which was assigned to the absorption of the carboxylate groups that form the ionic bonds with the quaternary ammonium groups. Moreover, while increasing the pH values from pH 5.8 to 7.4, a decrease of the intensity of the band at 960 cm(-1) (quaternary ammonium group vibration) was observed. All binary mixtures were characterized by the presence of only one and narrow Tg, pointing to sample homogeneity, because of the compatibility of components. As a result of electrostatic interaction between the copolymer chains during swelling, the resulting Tg is decreased significantly and was dependent on the quantity of copolymers present in the structure of polycomplexes formed. Overall, the interaction between countercharged copolymers during passage in gastrointestinal tract can strongly modify the release profile of the model drug diclofenac sodium. PMID- 23041130 TI - Monitoring industrial pharmaceutical crystallization processes using acoustic emission in pure and impure media. AB - Acoustic emission (AE) which has been successfully applied for monitoring a rather wide variety of solids elaboration processes was almost never evaluated in the field of industrial pharmaceutical crystallization. Few papers reported that solution crystallization processes give rise to acoustic emission signals that could be related to the development of the basic crystallization phenomena. This study is intended to demonstrate new perspectives opened up by the possible use of acoustic emission (AE) as a non-intrusive and non destructive sensor for monitoring solution crystallization with a particular focus being put on the presence of impurities in real industrial processes. The wealth of acquired AE information is highlighted and it is suggested that such information could allow the design of innovative multipurpose sensing strategies. It is shown notably that AE provides a very early detection of nucleation events, much before the onset of the so-called "nucleation burst". It is also shown that AE brings new insight into the effect of impurities on both the development of the crystallization process and the quality of the crystallized product. PMID- 23041131 TI - Fast dissolving eutectic compositions of curcumin. AB - The bioactive herbal ingredient curcumin was screened with pharmaceutically acceptable coformers to discover solid-state forms of high solubility. Mechano chemical grinding of curcumin with cocrystal formers in a fixed stoichiometry ratio resulted in binary eutectic compositions of curcumin-coformer with nicotinamide (1:2), ferulic acid (1:1), hydroquinone (1:1), p-hydroxybenzoic acid (1:1), and l-tartaric acid (1:1). The eutectic nature of the product crystalline solids was established by differential scanning calorimetry, and the absence of hydrogen-bonded crystalline phases such as cocrystals/salts was ascertained by powder X-ray diffraction, IR-Raman, and solid-state NMR spectroscopy. The best case of CUR-NAM eutectic exhibits 10-fold faster IDR and 6-times higher AUC compared to crystalline curcumin. PMID- 23041132 TI - The influence of supercritical carbon dioxide (SC-CO2) processing conditions on drug loading and physicochemical properties. AB - Poor water solubility of drugs can complicate their commercialisation because of reduced drug oral bioavailability. Formulation strategies such as increasing the drug surface area are frequently employed in an attempt to increase dissolution rate and hence, improve oral bioavailability. Maximising the drug surface area exposed to the dissolution medium can be achieved by loading drug onto a high surface area carrier like mesoporous silica (SBA-15). The aim of this work was to investigate the impact of altering supercritical carbon dioxide (SC-CO(2)) processing conditions, in an attempt to enhance drug loading onto SBA-15 and increase the drug's dissolution rate. Other formulation variables such as the mass ratio of drug to SBA-15 and the procedure for combining the drug and SBA-15 were also investigated. A model drug with poor water solubility, fenofibrate, was selected for this study. High drug loading efficiencies were obtained using SC CO(2), which were influenced by the processing conditions employed. Fenofibrate release rate was enhanced greatly after loading onto mesoporous silica. The results highlighted the potential of this SC-CO(2) drug loading approach to improve the oral bioavailability of poorly water soluble drugs. PMID- 23041133 TI - Identification of aero-allergens from Rhizopus oryzae: an immunoproteomic approach. AB - Airborne fungal spores bearing allergens are the causative agent for inducing immediate hypersensitive reaction in sensitive individuals. In this study the potential aeroallergens have been reported for the first time from Rhizopus oryzae a common airborne mold. Clinical data based on SPT was further confirmed by ELISA. IgE reactive bands were revealed by one-dimensional immunoblotting. A 44 kDa major reactive band was found in all immunoblots. For precise identification of allergens, an immuno-proteomic approach was taken with a combination of 2-Dimensional gel electrophoresis and Mass-spectrometry. 2D map of spore-mycelial protein was confronted with pooled sera and several IgE reactive spots were detected, most of which were glycoproteins and except for one, which has no antigenic determinacy after metaperiodate modification. Each of those spots was identified by MALDI-TOF-TOF. Some bioinformatic approaches were taken to predict the signal peptide and subcellular localization of each protein. Major 44 kDa allergen was identified as Aspartyl endopeptidase. Sequence information was extracted from MS/MS spectra of two tryptic peptides generated from the 44 kDa endopeptidase. Multiple alignments with other reported aspartyl protease allergens showed significant homology. Allergenicity assessment of this protein was performed in silico and identified as a potential putative allergen. PMID- 23041134 TI - Protein haptenation by amoxicillin: high resolution mass spectrometry analysis and identification of target proteins in serum. AB - Allergy towards wide spectrum antibiotics such as amoxicillin (AX) is a major health problem. Protein haptenation by covalent conjugation of AX is considered a key process for the allergic response. However, the nature of the proteins involved has not been completely elucidated. Human serum albumin (HSA) is the most abundant protein in plasma and is considered a major target for haptenation by drugs, including beta-lactam antibiotics. Here we report a procedure for immunological detection of AX-protein adducts with antibodies recognizing the lateral chain of the AX molecule. With this approach we detected human serum proteins modified by AX in vitro and identified HSA, transferrin and immunoglobulins heavy and light chains as prominent AX-modified proteins. Since HSA was the major AX target, we characterized AX-HSA interaction using high resolution LTQ orbitrap MS. At 0.5mg/mL AX, we detected one main AX-HSA adduct involving residues Lys 190, 199 or 541, whereas higher AX concentrations elicited a more extensive modification. In molecular modeling studies Lys190 and Lys 199 were found the most reactive residues towards AX, with surrounding residues favoring adduct formation. These findings provide novel tools and insight for the study of protein haptenation and the mechanisms involved in AX-elicited allergic reactions. PMID- 23041135 TI - iTRAQ-based quantitative proteomic analysis for identification of oligodendroglioma biomarkers related with loss of heterozygosity on chromosomal arm 1p. AB - The oligodendroglioma (OG) type of glial cell tumors accounts for 2-5% of primary brain neoplasms and 4-15% of gliomas diagnosed worldwide. Allelic losses on 1p, or on 1p and 19q, correlate with chemotherapy response and good prognosis in OG patients; however, the underlying mechanisms are not yet clearly defined. Therefore, we utilized a quantitative proteomics strategy that combined 8-plex isobaric tags for relative and absolute quantitation (iTRAQ) labeling and two dimensional liquid chromatography-tandem mass spectrometry (2D-LC/MS/MS) to identify molecular signatures, reveal mechanisms, and develop predictive markers of OG patients with 1p loss of heterozygosity (LOH). An initial screening of four OG patients with 1p LOH and four without were identified, and 449 differentially expressed proteins were quantified, 13 of which were significantly different between the two groups. Analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway suggested that 1p LOH may affect the actin network in OG. The differential expression of four of the 13 candidates (UBA1, ubiquitin-like modifier activating enzyme 1; ATP6V1E1, ATPase, H+ transporting, lysosomal 31 kDa, V1 subunit E1; MAP2, microtubule-associated protein 2; and HMGB1, high mobility group protein B1) was validated in 39 additional OG samples using immunohistochemistry. Decision tree modeling indicated that MAP2 expression is a powerful predictor of 1p LOH. Our results not only demonstrate the utility of iTRAQ-based high-throughput quantitative proteomic analysis in glioma research, but also provide novel markers that may help to reveal the mechanisms of 1p LOH associated chemosensitivity, and to design diagnostic and prognostic assays and therapeutics for OG. PMID- 23041136 TI - Longitudinal associations of cannabis and illicit drug use with depression, suicidal ideation and suicidal attempts among Nova Scotia high school students. AB - OBJECTIVE: To examine associations of cannabis and other illicit drug use with depression, suicidal ideation and suicidal attempts over a two year period during adolescence. METHODS: Nine hundred and seventy-six school students in four high schools in northern Nova Scotia, Canada, were surveyed in grade 10 and followed up in grade 12. Assessments of past 30 day cannabis and illicit drug use as well as mental health variables (risk of depression, suicidal ideation and suicide attempts) were obtained at baseline (2000 and 2001) and follow-up two years later (2002 and 2003). Generalized estimating equations modelled depression, suicidal ideation and attempts among illicit drug users and non-users. RESULTS: Illicit drug use with or without cannabis use was significantly associated with higher odds of depression, suicidal ideation and suicide attempt. Heavy cannabis use alone predicted depression but not suicidal ideation or attempt. CONCLUSIONS: Illicit drug use, with and without accompanying cannabis use, among high school students increases the risk of depression, suicidal ideation and suicidal attempts. Heavy cannabis use alone predicts depression but not suicidal ideation or attempts. PMID- 23041137 TI - Use of cassette-electrode microbial fuel cell for wastewater treatment. AB - Cassette-electrode microbial fuel cells (CE-MFCs) have been developed for the conversion of biomass wastes into electric energy. The present study modified CE MFC for its application to wastewater treatment and examined its utility in a long-term (240 days) experiment to treat a synthetic wastewater, containing starch, yeast extract, peptone, plant oil, and a detergent (approximately 500 mg of total chemical oxygen demand [COD] per liter). A test MFC reactor (1 l in capacity) was equipped with 10 cassette electrodes with total anode and cathode projection areas of 1440 cm(2), and the operation was initiated by inoculating with rice paddy-field soil. It was demonstrated that CE-MFC achieved COD removal rates of 80% at hydraulic-retention times of 6 h or greater, and electricity was generated at a maximum power density of 150 mW m(-2) and Coulombic efficiency of 20%. Microbial communities established on anodes of CEs were analyzed by pyrosequencing of PCR-amplified 16S rRNA gene fragments, showing that Geobacter, Clostridium, and Geothrix were abundantly detected in anode biofilms. These results demonstrate the utility of CE-MFC for wastewater treatment, in which Geobacter and Geothrix would be involved in the electricity generation. PMID- 23041138 TI - In silico screening of triple reaction knockout Escherichia coli strains for overproduction of useful metabolites. AB - For efficient production of industrially useful metabolites by microorganisms, it is important to design metabolic networks suitable for production. For this purpose, constraint-based metabolic flux simulation is a powerful tool to predict the effect of reaction knockouts on target productivity. In this study, using constraint-based metabolic simulation, in silico screening was performed to identify knockout candidate sets that increase the productivity of 1-butanol, 1 propanol, and 1,3-propanediol by engineered Escherichia coli. Metabolic changes caused by all possible sets of triple reaction knockouts were evaluated using a reduced metabolic model, which was constructed to significantly reduce the computational cost. The results demonstrated the strategies to improve target productivity by gene disruption; some of them could not be achieved by previous screening methods. Such knockout strategies can support further improvements of the target productivity. PMID- 23041139 TI - Monoclonal antibodies against large oval aggregates of Abeta1-42. AB - Abnormal cerebral accumulation of amyloid beta protein(1-42) (Abeta(1-42)) is one of the hallmarks of Alzheimer's disease (AD). Abeta(1-42) aggregates exist in two distinct forms: fibrils that are composed of highly ordered beta-sheets and amorphous aggregates that differ in size and toxicity. Here, we generated large oval aggregates (LOA) 369 +/- 81 nm and 224 +/- 92 nm in size on their major and minor axes, respectively, as measured by tapping-mode atomic force microscopy. LOA were produced by slow rotation of high concentrations (0.22 mM, 1.0 mg/mL) of Abeta(1-42) for 16 h at 37 degrees C in the presence of 2.2 mM Abeta(16-20), which prevents the fibril formation, and purified with 0.22-MUm filters. Analysis with thioflavin T showed that LOA have little beta-sheet structure on their surfaces. Monoclonal antibodies that react with LOA, but not the fibril forms, were screened from 960 mouse hybridoma cell lines, and seven antibodies consisting of four IgG and three IgM antibodies were obtained. Four IgG monoclonal antibodies showed cross-reactivity of <10% against the monomer and fibril forms and amorphous aggregates that passed through 0.22-MUm filters. Among the four antibodies, the antibody that was designated as 31-2 exhibited the highest reactivity against LOA and showed the lowest reactivity against the fibril forms. On the basis of these results, a unique epitope on the surface of LOA was suggested. The 31-2 antibody may be useful for future basic research and therapeutic applications for AD. PMID- 23041140 TI - Performance of methanogenic reactors in temperature phased two-stage anaerobic digestion of swine wastewater. AB - The present study investigated the shifts in the chemical profiles of a two-phase anaerobic digestion system in methanogenic and acidogenic reactors for the treatment of swine wastewater. Acidogenic and methanogenic digesters were used with overall HRTs ranging from 27 to 6 d. In the optimized thermophilic/acidogenic phase throughout the entire experimental period, VS was reduced by 13.8% (1.6%); however, COD hardly decreased because of the thermophilic hydrolysis of organic materials, such as carbohydrates, proteins, and lipids, without any significant consumption of volatile fatty acids. In the methanogenic/mesophilic phase, COD was reduced by 65.8 (1.1)% compared to a 47.4 (2.9)% reduction in VS reduction efficiency with the gradual increase in methane production during a methanogenic HRT between 25 and 10 d. A high protein degradation rate was observed in the optimized acidogenic phase, which is assumed to be due to the low content of carbohydrates in raw swine wastewater as well as the readily thermophilic hydrolysis of proteins. Two-phase systems of anaerobic digestion consisting of optimized thermophilic and mesophilic methanogenic digesters showed a stable performance with respect to VS reduction efficiency with OLRs less than 3 g VS/L.d, in other words, more than 10 days of methanogenic HRT in this study. PMID- 23041141 TI - Antarctic ice core samples: culturable bacterial diversity. AB - Culturable bacterial abundance at 11 different depths of a 50.26 m ice core from the Tallaksenvarden Nunatak, Antarctica, varied from 0.02 to 5.8 * 10(3) CFU ml( 1) of the melt water. A total of 138 bacterial strains were recovered from the 11 different depths of the ice core. Based on 16S rRNA gene sequence analyses, the 138 isolates could be categorized into 25 phylotypes belonging to phyla Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria. All isolates had 16S rRNA sequences similar to previously determined sequences (97.2-100%). No correlation was observed in the distribution of the isolates at the various depths either at the phylum, genus or species level. The 25 phylotypes varied in growth temperature range, tolerance to NaCl, growth pH range and ability to produce eight different extracellular enzymes at either 4 or 18 degrees C. Iso-, anteiso-, unsaturated and saturated fatty acids together constituted a significant proportion of the total fatty acid composition. PMID- 23041142 TI - Comparison of the protection of ferrets against pandemic 2009 influenza A virus (H1N1) by 244 DI influenza virus and oseltamivir. AB - The main antivirals employed to combat seasonal and pandemic influenza are oseltamivir and zanamivir which act by inhibiting the virus-encoded neuraminidase. These have to be deployed close to the time of infection and antiviral resistance to the more widely used oseltamivir has arisen relatively rapidly. Defective interfering (DI) influenza virus is a natural antiviral that works in a different way to oseltamivir and zanamivir, and a cloned version (segment 1 244 DI RNA in a cloned A/PR/8/34 virus; 244/PR8) has proved effective in preclinical studies in mice. The active principle is the DI RNA, and this is thought to interact with all influenza A viruses by inhibiting RNA virus synthesis and packaging of the cognate virion RNA into nascent DI virus particles. We have compared the ability of DI virus and oseltamivir to protect ferrets from intranasal 2009 pandemic influenza virus A/California/04/09 (A/Cal, H1N1). Ferrets were treated with a single 2 MUg intranasal dose of 244 DI RNA delivered as 244/PR8 virus, or a total of 25mg/kg body weight of oseltamivir given as 10 oral doses over 5 days. Both DI virus and oseltamivir reduced day 2 infectivity and the influx of cells into nasal fluids, and permitted the development of adaptive immunity. However DI virus, but not oseltamivir, significantly reduced weight loss, facilitated better weight gain, reduced respiratory disease, and reduced infectivity on days 4 and 6. 244 DI RNA was amplified by A/Cal by >25,000-fold, consistent with the amelioration of clinical disease. Treatment with DI virus did not delay clearance or cause persistence of infectious virus or DI RNA. Thus in this system DI virus was overall more effective than oseltamivir in combatting pandemic A/California/04/09. PMID- 23041143 TI - Neutralization of dengue virus in the presence of Fc receptor-mediated phagocytosis distinguishes serotype-specific from cross-neutralizing antibodies. AB - Although several vaccine candidates are presently in various phases of clinical trials, the field still lacks an effective tool to determine protective immunity. The presence of cross-neutralizing antibodies limits a serological approach to identify the etiology and distinguish lifelong from short-lived humoral protection. A recent study indicated that cross-reactive but not serotype specific antibodies require high antibody concentration to co-ligate FcgammaRIIB and inhibit infection. Here, we tested if these differences could allow us to distinguish serotype-specific from cross-neutralizing antibodies. Using 30 blinded early convalescent serum samples from patients with virologically confirmed dengue, we demonstrate that neutralization in the presence of FcgammaR mediated phagocytosis in THP-1 correctly identifies the DENV serotype of the infection in 93.3% of the cases compared to 76.7% with plaque reduction neutralization test. Our findings could provide a new approach for evaluating DENV neutralization and suggest that in addition to blocking specific ligand receptor interactions for viral entry, antibodies must prevent viral uncoating during FcgammaR-mediated phagocytosis for complete humoral protection. PMID- 23041144 TI - Reliability of the test of wheeled mobility (TOWM) and the short Wheelie test. AB - OBJECTIVE: To assess the reliability of the Test of Wheeled Mobility (TOWM) and the Wheelie test. DESIGN: Cohort study. SETTING: Gymnasium. PARTICIPANTS: Manual wheelchair users (N=30, age 23-53y) with a spinal cord injury. INTERVENTION: Participants performed the 30 skills of the TOWM and the 8 skills of the Wheelie test twice. Ability, time, and anxiety scores were assessed on field. Quality scores were assessed by video analysis. MAIN OUTCOME MEASURES: Test-retest reliability was evaluated for the ability, time, anxiety, and quality scores of both tests. Intrarater and interrater reliability were determined on the basis of quality scores of 20 participants. Intraclass coefficient and nonparametric statistics were applied, as well as standard error of measurement, method error (ME), coefficient variation of ME, minimal detectable change (95% confidence), and technical error of measurement. RESULTS: Test-retest reliability: no significant differences between t1 and t2 in the ability, quality, and time scores, except for anxiety scores. Standard error of measurement, ME, coefficient variation of ME, and minimal detectable change (95% confidence) values were low for the ability and quality total score and higher for the time and anxiety total score. Intrarater and interrater reliability interclass correlation coefficients of both tests ranged between .91 and .99. Interrater relative technical error of measurement for the TOWM and the Wheelie test total quality score was 3.7% and 6.3%, respectively, and intrarater relative technical error of measurement was 4.3% and 6.1%, respectively. Interclass correlation coefficients per individual tasks ranged between .88 and 1.00, except for "level propulsion forward," which showed low interclass correlation coefficient scores (interrater: .49; intrarater: .44; test-retest: .43). CONCLUSIONS: Based on ability and quality total scores, the TOWM and the Wheelie test are reliable when assessing the wheeled mobility of manual wheelchair users with spinal cord injury. The quality criteria of 1 task from the TOWM and 3 tasks from the Wheelie test need to be refined. PMID- 23041145 TI - Postural stability in patients with knee osteoarthritis: comparison with controls and evaluation of relationships between postural stability scores and International Classification of Functioning, Disability and Health components. AB - OBJECTIVES: To assess the differences in postural stability between patients with knee osteoarthritis and controls without knee osteoarthritis, and to evaluate possible relations between postural stability scores and International Classification of Functioning, Disability and Health (ICF) components. DESIGN: An age-matched, case-controlled trial with a cross-sectional design. SETTING: A teaching hospital. PARTICIPANTS: Patients with knee osteoarthritis (n=73) and age matched controls (n=60). INTERVENTIONS: Data on patients' postural stability and additional health-related variables were collected using various instruments. These included the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Inventory, the World Health Organization Quality of Life Brief Version, the physical function test (chair-rising time), the Chinese version of the Western Ontario and McMaster Universities Osteoarthritis Index, the Chinese version of the Knee Injury and Osteoarthritis Outcome Score, and the Biodex Stability System. MAIN OUTCOME MEASURES: A comparison of postural stability in patients with knee osteoarthritis versus that of controls was performed. The relation between postural stability scores for patients with knee osteoarthritis and ICF components was evaluated. Pearson correlation tests were used to determine the variables that correlated with postural stability among these patients. RESULTS: Patients with knee osteoarthritis displayed lower overall postural stability than controls (scores of 0.7 vs. 0.5, P=.006) and scored lower on the environmental domain of the World Health Organization Quality of Life Brief Version (62.2 vs 66.8, P=.014). For patients with knee osteoarthritis, postural stability was weakly associated with the ICF components of body functions and structures, including pain (r=.33-.34, P=.004), physical fatigue (r=.28, P=.016), and reduced motivation (r=.30, P=.011). Weak to moderate associations between postural stability and the ICF components of activities and participation were found; the relevant ICF variables included reduced activity (r=.38, P=.001), physical domain and function (r=.34-.48, P=.001 to P<.004), activities of daily living (r=.51, P<.001), and sports and recreation (r=.35, P=.003). A moderate association between postural stability and the ICF components of personal and environmental factors was observed, including age (r=.52, P<.001) and quality of life (r=0.4, P=.001). CONCLUSIONS: Patients with knee osteoarthritis displayed lower postural stability and achieved lower scores in the environmental domain of quality-of-life measures than did controls. The postural stability of patients with knee osteoarthritis was weakly to moderately associated with the following ICF components: body functions and structures, activities and participation, and personal and environmental factors. PMID- 23041146 TI - Assistive walking device use and knee osteoarthritis: results from the Health, Aging and Body Composition Study (Health ABC Study). AB - OBJECTIVES: To identify factors that predicted incident use of assistive walking devices (AWDs) and to explore whether AWD use was associated with changes in osteoarthritis of the knee. DESIGN: Prospective cohort study. SETTING: Community. PARTICIPANTS: Older adults (N=2639) in the Health, Aging and Body Composition (Health ABC) Study including a subset of 874 patients with prevalent knee pain. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Incident use of AWDs, mean Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores, and the frequency of joint space narrowing on knee radiographs over a 3 year time period. RESULTS: AWD use was initiated by 9% of the entire Health ABC cohort and 12% of the knee pain subset. Factors that predicted use in both groups were age >=73 (entire cohort: odds ratio [OR]=2.07; 95% confidence interval [CI], 1.43-3.01; knee pain subset: OR=1.87; 95% CI, 1.16-3.03), black race (entire cohort: OR=2.95; 95% CI, 2.09-4.16; knee pain subset: OR=3.21; 95% CI, 2.01 5.11), and lower balance ratios (entire cohort: OR=3.18; 95% CI, 2.21-4.59; knee pain subset: OR=3.77; 95% CI, 2.34-6.07). Mean WOMAC pain scores decreased slightly over time in both AWD and non-AWD users. Twenty percent of non-AWD users and 28% of AWD users had radiographic progression in joint space narrowing of the tibiofemoral joint in at least 1 knee. Fourteen percent of non-AWD users and 12% of AWD users had radiographic progression in joint space narrowing in the patellofemoral joint in at least 1 knee. CONCLUSIONS: AWDs are frequently used by older adults. Knee pain and balance problems are significant reasons why older adults initiate use of an AWD. In an exploratory analysis, there was no consistent relation between the use or nonuse of an AWD and WOMAC pain scores or knee joint space narrowing progression. Further studies of the relation of use of AWDs to changes in knee osteoarthritis are needed. PMID- 23041147 TI - Differentiation between pathogenic serotype 1 isolates of Marek's disease virus and the Rispens CVI988 vaccine in Australia using real-time PCR and high resolution melt curve analysis. AB - Two real-time PCR assays were developed which enable quantitation and differentiation between pathogenic Australian isolates of Marek's disease virus (MDV) serotype 1 and the serotype 1 vaccine strain Rispens CVI988. The assays are based on a DNA sequence variation in the meq gene between pathogenic and vaccinal MDV1 which has been confirmed by sequencing of 20 Australian field strains of MDV. Complete specificity has been demonstrated in samples containing pathogenic MDV (n=20), Rispens (3 commercial vaccine strains), or both. The limit of detection of both the Rispens-specific and the pathogenic MDV1-specific assays was 10 viral copies/reaction. The tests successfully differentiated and quantified MDV in mixtures of pathogenic and vaccinal Rispens virus. A high resolution melt curve analysis targeting the same SNP used for the real-time PCR assays was also developed which successfully detected sequence variation between Md5, six Australian MDV1 isolates and the three Rispens vaccines. However it was ineffective at differentiating mixtures of pathogenic and vaccinal MDV1. The real time PCR assays have both diagnostic and epidemiological applications as they enable differentiation and quantitation of Rispens CVI988 and pathogenic MDV1 in co-infected chickens in Australia. PMID- 23041148 TI - Contrary effects of sphingosine-1-phosphate on expression of alpha-smooth muscle actin in transforming growth factor beta1-stimulated lung fibroblasts. AB - Transforming growth factor-beta1 (TGFbeta1) plays a pivotal role in fibrosis in various organs including the lung. Following pulmonary injury, TGFbeta1 stimulates conversion of fibroblasts to myofibroblasts that are mainly characterized by up-regulation of alpha-smooth muscle actin (alphaSMA) expression, and the resulting excess production of extracellular matrix proteins causes fibrosis with loss of alveolar function. The present study was undertaken to define the role of the sphingosine-1-phosphate (S1P) pathway in TGFbeta1 induced expression of alphaSMA in human fetal lung fibroblasts, HFL1 cells. Analysis of mRNA revealed the existence of S1P(1), S1P(2), and S1P(3) receptor mRNAs. Treatment with TGFbeta1 increased sphingosine kinase (SphK) activity and S1P(3) receptor mRNA at 24h after stimulation, and pharmacological data showed the involvement of sphingomyelinase, SphK, and S1P(3) receptor in the TGFbeta1 induced up-regulation of alphaSMA with and without serum. Treatment with pertussis toxin and S1P(1) receptor antagonist W146 enhanced alphaSMA expression by TGFbeta1/serum, and S1P decreased and increased alphaSMA levels with and without serum, respectively. TGFbeta1 increased cyclooxygenase-2 expression in a manner dependent on serum and the sphingomyelinase/SphK pathway, and the response was decreased by pertussis toxin. Prostaglandin E(2), formed by TGFbeta1/serum stimulation, decreased the TGFbeta1-induced expression of alphaSMA via EP prostanoid receptor. These data suggest that S1P formed by TGFbeta1 stimulation has diverse effects on the expression of alphaSMA, inhibition via the S1P(1) receptor-mediated and serum-dependent expression of cyclooxygenase-2 and the resulting formation of prostaglandin E(2), and stimulation via the S1P(3) receptor in a serum-independent manner. PMID- 23041149 TI - Involvement of the sigma1 receptor in the antidepressant-like effects of fluvoxamine in the forced swimming test in comparison with the effects elicited by paroxetine. AB - We studied the involvement of the sigma(1) receptor in the antidepressant-like effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in DBA/2 mice using the forced swimming test. The effects of the selective sigma(1) receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine (BD1047) at 1mg/kg significantly antagonized the anti-immobility elicited by fluvoxamine (10mg/kg). However, the anti-immobility effects elicited by another SSRI, paroxetine (5m/kg), were not altered by BD1047. The selective sigma(1) receptor agonist 2S-(2alpha,6alpha,11R(*))-1,2,3,4,5,6-hexahydro-6,11 dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol ((+)SKF-10047) elicited dose-dependent anti-immobility effects in DBA/2 mice. BD1047 significantly blocked the anti-immobility effects induced by (+)SKF-10047 at 10mg/kg. These results suggested that the sigma(1) receptor was associated with fluvoxamine induced antidepressant-like effects but not with paroxetine-induced antidepressant-like effects. PMID- 23041150 TI - Astragaloside IV attenuates Toll-like receptor 4 expression via NF-kappaB pathway under high glucose condition in mesenchymal stem cells. AB - Diabetic hyperglycemia causes a variety of pathological changes. Astragaloside IV (AS-IV) was widely used for the treatment of cardiovascular diseases in China. The aim of this study was to determine the effect of AS-IV on bone marrow mesenchymal stem cells (MSCs) and the underlying mechanism in diabetes. We used reverse transcription polymerase chain reaction and western blotting to determine the expression of Toll-like receptor 4 (TLR4), matrix metalloproteinase-2 (MMP-2) and NF-kappaB p65 in MSCs under high glucose (HG) with or without pretreatment with AS-IV. The surface expression of TLR4 was checked by flow cytometry and the expression of TNF-alpha and MCP-1 were detected by ELISA in diabetes patients treated with AS-IV. AS-IV promoted the proliferation of MSCs and attenuated the increased expression of TLR4 induced by HG. In addition, AS-IV decreased the HG induced translocation of NF-kappaB p65 and increased the MMP-2 expression in MSCs. AS-IV decreased the TLR4, TNF-alpha and MCP-1 expression in patients. Collectively,our data revealed that AS-IV attenuated TLR4 expression through the NF-kappaB signaling pathway in MSCs. PMID- 23041151 TI - The secreted Klotho protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice. AB - Klotho was identified as the responsible gene in a mutant mouse line whose disruption results in a variety of premature aging-related phenotypes. Nonetheless, the related mechanisms were still unknown. Many studies report that dietary phosphate restriction and genetic ablation of vitamin D pathways indirectly reverse premature aging processes in these mice. Furthermore, transgenic overexpression of klotho in mice extends their life span through inhibition of insulin and IGF1 signaling. We found that intraperitoneal injection of recombinant soluble Klotho protein at dose of 0.02 mg/kg every other day effectively extends the life span of kl/kl mice by 17.4%. Soluble Klotho administration also ameliorated premature aging-related phenotype, such as growth retardation, premature thymus involution and vascular calcification, and effectively enhanced urinary phosphate excretion in kl/kl mice. Klotho treatment attenuated renal fibrosis through down-regulation of transforming growth factor beta signaling as well as reduced cellular senescence through down-regulation of p21-cip1 mRNA levels. In addition, soluble Klotho treatment significantly reduced both renal and aorta calcium deposits. In conclusion, our study shows the therapeutic potential of soluble Klotho protein to treat age-related disorders in mice. PMID- 23041152 TI - Intrathecal endothelin-1 has antinociceptive effects in rat model of postoperative pain. AB - Endothelin-1 is known to be a potent vasoconstrictor. Administration of endothelin-1 to the central nervous system (CNS) induces antinociceptive effects. Nociceptive stimuli affect dorsal root ganglion (DRG) neurons and neurons/astrocytes/microglia in the dorsal horn of the spinal cord. Surgical incision in the plantar aspect of the rat hindpaw is a model for postoperative pain, and withdrawal thresholds reportedly decrease around the incision. We hypothesized that intrathecal endothelin-1 would have antinociceptive effects in this model, and affect DRG neurons and microglia/neurons in the dorsal horn. Intrathecal endothelin-1 partially restored the withdrawal threshold (which was decreased by plantar incision). BQ-123, and BQ-788 (specific endothelin ET(A)- and ET(B)-receptor antagonists, respectively) attenuated the increase in withdrawal threshold induced by endothelin-1. Phosphorylation of extracellular signal-regulated kinase (ERK) in DRG neurons and microglial activation/ERK phosphorylation in the dorsal horn were observed following the incision. Endothelin-1 decreased the incision-induced increase in the numbers of phosphorylated ERK-positive neurons in DRG and activated microglia in the dorsal horn, without affecting the numbers of phosphorylated ERK-positive neurons in the dorsal horn. BQ-123 or BQ-788 partially suppressed these endothelin-1-induced alterations. Our results show that the pain threshold, which is decreased by surgical stimuli, is partially restored by intrathecal endothelin-1 through both endothelin ET(A)- and ET(B)- receptors in DRG neurons and microglia in the spinal cord. Endothelin-1 administration to the CNS may be worth considering as a new candidate for the treatment of postoperative pain and to mitigate prolonged periods of pain. PMID- 23041153 TI - Cleistanthoside A tetraacetate-induced DNA damage leading to cell cycle arrest and apoptosis with the involvement of p53 in lung cancer cells. AB - Lung cancer is the leading cause of cancer-related death worldwide and resistance to chemotherapeutic drugs is the major obstacle for effective treatment. The present study investigated the anticancer potential of cleistanthoside A tetraacetate (CAT), a derivative of cleistanthoside A from Phyllanthus taxodiifolius Beille on human lung cancer cells, LU-1. Multiple molecular approaches were used in this study and include measuring the anti-proliferative effect of CAT in LU-1 cells using flow cytometry; evaluating the induction of apoptosis by monitoring DNA fragmentation, phosphatidylserine externalization and activation of caspase-3 activity; and assaying the expression of regulatory proteins involved in cell cycle arrest and apoptosis using immunoblots. CAT potently inhibited LU-1 proliferation through an early G1 arrest with down regulation of cdk4/6 and cyclin D1 proteins. CAT also inhibited DNA topoisomerase IIalpha activity resulting in DNA damage and increased the expression of the p53 protein with the subsequent induction of apoptosis. A decrease in the Bcl-2/Bax ratio, activation of caspase-3 activity and cleavage of PARP accompanied apoptosis. CAT is highly toxic to lung cancer and its primary targets are the inhibition of topoisomerase IIalpha activity and inducing apoptosis through a G1 arrest. These properties indicate that CAT is a promising anticancer agent for treatment of lung cancer. PMID- 23041154 TI - Inhibition of H2O2-induced cell death through FOXO1 modulation by EUK-172 in SK-N MC cells. AB - It has been suggested that excess accumulation of reactive oxygen species, termed oxidative stress, may lead to neuronal death resulting in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. In oxidative stress induced cell death numerous transcription factors are thought to be involved. One of them is Forkhead box protein O1 (FOXO1) that governs many genes involved in oxidative stress resistance, DNA repair, cell cycle arrest, proliferation and apoptosis. Apparently, FOXO1 activity is tightly linked to post translational modifications including phosphorylation and acetylation, which are modulated by many factors such as oxidative stress. Reactive oxygen species, as the major players in oxidative stress, guide FOXO1 nuclear localization at least by simultaneous c-Jun N-terminal kinase (JNK) activation and Akt/PKB activity suppression. Here, we showed that a synthetic salen-manganese derivative (EUK 172) with strong catalase activity reduced oxidative stress evident through marked reduction in intracellular reactive oxygen species, protein carbonylation and lipid peroxidation. In addition, our results indicated that EUK-172 not only reduced the FOXO1 protein content, but also it inhibited FOXO1 nuclear translocation in H(2)O(2)-exposed SK-N-MC cells. These events attenuated caspase 3 activity and bax/Bcl-2 ratio leading to higher viability of the H(2)O(2) treated SK-N-MC cells. PMID- 23041155 TI - Imipramine protects mouse hippocampus against tunicamycin-induced cell death. AB - Endoplasmic reticulum (ER) stress is implicated in various diseases. Recently, some reports have suggested that the sigma-1 receptor may play a role in ER stress, and many antidepressants have a high affinity for the sigma-1 receptor. In the present study, we focused on imipramine, a widely used antidepressant, and investigated whether it might protect against the neuronal cell death induced by tunicamycin, an ER stress inducer. In mouse cultured hippocampal HT22 cells, imipramine inhibited cell death and caspase-3 activation induced by tunicamycin, although it did not alter the elevated expressions of 78 kDa glucose-regulated protein (GRP78) and C/EBP-homologous protein (CHOP). Interestingly, in such cells application of imipramine normalized the expression of the sigma-1 receptor, which was decreased by treatment with tunicamycin alone. Additionally, NE-100, a selective sigma-1 receptor antagonist, abolished the protective effect of imipramine against such tunicamycin-induced cell death. Imipramine inhibited the reduction of mitochondrial membrane potential induced by tunicamycin, and NE-100 blocked this modulating effect of imipramine. Furthermore, in anesthetized mice intracerebroventricular administration of tunicamycin decreased the number of neuronal cells in the hippocampus, particularly in the CA1 and dentate gyrus (DG) areas, and 7 days' imipramine treatment (10mg/kg/day; i.p.) significantly suppressed these reductions in CA1 and DG. These findings suggest that imipramine protects against ER stress-induced hippocampal neuronal cell death both in vitro and in vivo. Such protection may be partly due to the sigma-1 receptor. PMID- 23041156 TI - Extracellular and intracellular esterase processing of SCFA-hexosamine analogs: implications for metabolic glycoengineering and drug delivery. AB - This report provides a synopsis of the esterase processing of short chain fatty acid (SCFA)-derivatized hexosamine analogs used in metabolic glycoengineering by demonstrating that the extracellular hydrolysis of these compounds is comparatively slow (e.g., with a t(1/2) of ~4 h to several days) in normal cell culture as well as in high serum concentrations intended to mimic in vivo conditions. Structure-activity relationship (SAR) analysis of common sugar analogs revealed that O-acetylated and N-azido ManNAc derivatives were more refractory against extracellular inactivation by FBS than their butanoylated counterparts consistent with in silico docking simulations of Ac(4)ManNAc and Bu(4)ManNAc to human carboxylesterase 1 (hCE1). By contrast, all analogs tested supported increased intracellular sialic acid production within 2h establishing that esterase processing once the analogs are taken up by cells is not rate limiting. PMID- 23041157 TI - Development of triazene prodrugs for ADEPT strategy: new insights into drug delivery system based on carboxypeptidase G2 activation. AB - Six novel urea triazene prodrugs have been synthesized to apply in antibody directed enzyme prodrug therapy (ADEPT). The chemical and plasmatic stability of l-glutamate triazene prodrugs were evaluated and the chemical reactivity was mainly attributed to an intramolecular catalysis promoted by the neighbouring carboxylate group of the glutamic moiety. These prodrugs showed an elevated binding to plasma proteins. The L-glutamate triazenes were evaluated as prodrugs of the alkylating agent's monomethyltriazenes, by activation of the bacterial enzyme carboxypeptidase G2 (CPG2). The synthesized prodrugs have been shown to be good substrates for CPG2, and therefore new candidates for ADEPT strategy. PMID- 23041158 TI - Supposed to be rare cause of intestinal obstruction; abdominal cocoon: report of two cases. AB - Abdominal cocoon, or sclerosing encapsulating peritonitis, is supposed to be rare cause of intestinal obstruction. It is characterized by totally or partially encasement of small bowel with a thick, fibrotic, cocoon-like membrane. We think this entity is not rare as previously thought. We reported two case's clinical and imaging findings which diagnosed abdominal cocoon by surgery to increase awareness of this diagnosis. PMID- 23041159 TI - The feasibility study of US-MRI virtual navigation in the shoulder. AB - PURPOSE: The aim of this study was to evaluate the feasibility of ultrasound sonography (US)-magnetic resonance imaging (MRI) virtual navigation in the shoulder. METHODS: We selected 10 healthy volunteers and 10 patients with supraspinatus tendinitis to fuse in the shoulder with a Virtual Navigator System. We selected five internal marks as follows: (1) 1 acromion, 2 the point of junction between the supraspinatus muscle and the tendon, 3 the point of the middle in the surface of the head of humerus in the plane of 2, 4 the point of attachment of the supraspinatus tendon in the great tuberosity of humerus, and 5 the point of the middle in the surface of the head of humerus in the plane of 4. To make three, four, and five marks in different combinations in the process of image fusion successively, it should be based on these points. The observed targets included coincidence, stability, and accuracy in the sonography and magnetic resonance images by two radiologists. RESULTS: The supraspinatus tendon of the 10 volunteers and the lesions of 10 patients with supraspinatus tendinitis could be fused between the sonography image and the magnetic resonance image. The effect of the combination of 2+3+4+5 in the group with four-point internal marks was most satisfactory (P<.05). CONCLUSION: The process of the combination of 2+3+4+5 in the group with four-point internal marks is considered the best method, and the application of US-MRI virtual navigation is regarded feasible in the shoulder. PMID- 23041160 TI - Primary nasopharyngeal non-Hodgkin's lymphoma: imaging patterns on MR imaging. AB - OBJECTIVES: To summarize the distinct imaging features of different subtypes of primary nasopharyngeal non-Hodgkin's lymphomas (NHLs). MATERIALS AND METHODS: Clinical data and magnetic resonance imaging findings of 71 patients with histologically proven primary nasopharyngeal NHLs were retrospectively reviewed. The tumor distribution, signal intensity, lesion texture, contrast enhancement properties, extra-chamber involvement, regional structure invasion, and cervical lymphadenopathy were evaluated and compared between different subtypes of NHLs. RESULTS: Of the patients, 70.4% had B-cell lymphomas; 64.8% had symmetrical and diffuse involvement of nasopharynx walls; and 19.7% had superficial ulcerations. Extra-chamber involvement and regional structure invasion occurred in most patients. The frequency of neck node involvement was up to 83.10%; 62.7% of them were bilateral involvement. Patients with T-cell or nature killer/T-cell NHLs had a higher incidence of superficial ulcerations, nasal cavity, and paranasal sinus invasion than B-cell NHLs (P<.05). Patients with B-cell NHLs had a higher incidence of cervical lymphadenopathy specifically in Level VA and parotid region than T-cell or nature killer/T-cell (NK/T-cell) NHLs (P<.05). CONCLUSION: Primary nasopharyngeal NHLs had some characteristic imaging features and different subtypes of nasopharyngeal NHLs had some distinct imaging features. PMID- 23041161 TI - MR differentiation of low-grade chondrosarcoma from enchondroma. AB - PURPOSE: To evaluate magnetic resonance (MR) imaging for the discrimination between low-grade chondrosarcoma and enchondroma. MATERIALS AND METHODS: MR images of 34 patients who were confirmed with low-grade chondrosarcoma or enchondroma were retrospectively reviewed. After review of medical records, MR findings in 18 patients with low-grade chondrosarcoma and 16 patients with enchondroma were compared. MR images were retrospectively reviewed for the lesion location (central or eccentric; epiphysis, metaphysic, or diaphysis), margin, contour, mineralized matrix, endosteal scalloping, cortical expansion, cortical destruction, soft tissue mass formation, and periosteal reaction. Signal intensity, the patterns of contrast enhancement (unilocular or multilobular), soft tissue mass, and adjacent abnormal bone marrow and soft tissue signal were also reviewed. Statistical analysis was performed with chi-square test. RESULTS: The patients with low-grade chondrosarcoma had a significantly higher incidence of MR findings (P<.05): predominantly intermediate signal on T1-weighted images [72% (13/18) in low-grade chondrosarcoma vs. 25% (4/16) in enchondroma], multilocular appearance on contrast-enhanced T1-weighted images [83% (15/18) vs. 44% (7/16)], cortical destruction [33% (6/18) vs. 0% (0/16)], a soft tissue mass [28% (5/18) vs. 0% (0/16)], adjacent bone marrow and soft tissue abnormal signal [22% (4/18) vs. 0% (0/16)], and an involvement of the epiphysis or flat bone [56% (10/18) vs. 19% (3/16)]. CONCLUSION: MR imaging shows helpful features for differentiating low-grade chondrosarcoma from enchondroma. PMID- 23041162 TI - Quantification of lung perfusion blood volume (lung PBV) by dual-energy CT in pulmonary embolism before and after treatment: preliminary results. AB - The purpose was to investigate the quantification of lung perfusion blood volume (PBV) by dual-energy computed tomography (CT) in patients with pulmonary embolism (PE) before and after treatment. Twenty-five patients with PE underwent dual energy CT angiography before and after treatment. In all 25 patients, pulmonary CT confirmed that there was no PE after treatment. This preliminary study demonstrated the possibility that quantification of lung PBV may reflect parenchymal arterial perfusion before and after treatment, including the compensatory increase of lung perfusion. PMID- 23041163 TI - A literature review of the language needs of nursing students who have English as a second/other language and the effectiveness of English language support programmes. AB - Australia is increasingly becoming a culturally diverse country, with this trend being reflected in nursing education as significant numbers of students enrol from backgrounds where English is a second/other language (ESL). These students will enable the provision of culturally competent care that a culturally diverse health system requires (Ohr et al., 2010), however they require significant levels of support to not only achieve academically in their nursing programme, but also to perform at the expected level during clinical placements (Boughton et al., 2010). Difficulties communicating with colleagues, patients and their families in the clinical setting have been identified among the challenges that ESL nurses face (Boughton et al., 2010; Jeong et al., 2011). A review of the literature indicates sporadic research into the education of nurses from ESL backgrounds. This paper discusses and raises awareness of common themes such as the challenges of adjusting to Western culture and using the advanced and technical English required by higher education and healthcare. This paper also discusses mixed results reported from a number of English language support programmes. This indicates a need for further research in this area to strengthen support for these nurses who can assist in the provision of culturally competent care. PMID- 23041164 TI - The pursuit of excellence and innovation in service user involvement in nurse education programmes: report from a travel scholarship. AB - The involvement of service users and carers in nurse education is increasing, with the new standards for pre-registration nurse education in the UK, which require nurse education providers to demonstrate how they are involving users and carers in the planning, delivery, teaching and evaluation of nursing curricula (Nursing and Midwifery Council, 2010). A travel scholarship provided the opportunity to explore best practice in this area, focussing on identifying support systems and processes that enable user involvement. The scholarship was undertaken in the UK and Ireland during a 4 week study tour between June and July 2011, during which I visited 15 universities, and met with nurse education staff, users and carers involved in nurse education programmes. Prerequisite processes, the spectrum and variety of involvement activities, quality assurance and evaluation; and sustainability of user involvement in nurse education are reported in this paper. Service users and carers are an under-utilised resource, and as experts by experience have much to offer students and staff by increased involvement in nurse education programmes. The importance of values, enthusiasm and relationships, the cornerstones that strengthen user involvement; often sustain such partnerships. PMID- 23041165 TI - Incomplete swallowing and retracted tongue maneuvers for electromyographic signal normalization of the extrinsic muscles of the larynx. AB - PURPOSE: To investigate which muscular maneuvers provide larger electric activity (EA) of the suprahyoid (SH) and infrahyoid (IH) muscles to be used as surface electromyography (SEMG) signal normalization reference. METHODS: The electrical potentials of the SH and IH muscles of 12 subjects were evaluated using six muscular maneuvers, involving the position of the tongue and effort. It was selected as maximum voluntary sustained activity maneuver, the one having the minor coefficient of variation and the smallest value for each muscle group. The EA signal was converted using the root mean square in microvolts. It was considered then the maximum signal of each maneuver as the difference between the mean of three measures and the resting potential. RESULTS: The maneuvers that provided higher mean potentials with minor coefficient of variation and smallest P value were incomplete swallowing (IS) with effort (mean potential equal to 56.73+/-8.68 with coefficient of variation of 15.30%) in SH group, and tongue retracted with mouth open (TROM, mean potential equal to 46.57+/-7.83 with coefficient of variation of 16.81%) in IH group. CONCLUSION: The IS with effort and TROM maneuvers should be considered for signal normalization in these muscles, respectively, and may provide conditions for using the SEMG in voice clinic. SIGNIFICANCE: The use of normalization standards in researches of SH and IH muscles in the voice area will allow comparisons among future works. PMID- 23041166 TI - Prevention of infective endocarditis: between progress in scientific knowledge and the lack of randomized trials. PMID- 23041167 TI - Very long-term outcomes following drug-eluting stent implantation for unprotected left main coronary artery stenosis: a single center experience. AB - INTRODUCTION AND OBJECTIVES: Encouraging results at long-term follow-up have been reported from non-randomized registries and randomized trials following percutaneous coronary intervention with drug-eluting stent implantation for unprotected left main stenosis. However, information on very long-term (>5-year) outcomes is limited. The aim of this study was to assess the very long-term outcomes (6-years) following drug-eluting stent implantation for left main disease. METHODS: All consecutive patients with unprotected left main stenosis electively treated with drug-eluting stent implantation, between March 2002 and May 2005, were analyzed according to the location of the left main lesion (distal bifurcation vs ostial/body). RESULTS: The study included 149 patients: 113 with distal bifurcation and 36 with ostial/body lesion. Triple-vessel disease was significantly higher in the distal than in the ostial/body group (52.2% vs 33.2%, P=.05). At 6-years of follow-up, the cumulative major adverse cardiovascular event rate was 41.6% (45.1% distal vs 30.6% ostial/body, P=0.1), including 18.8% any death (22.1% distal vs 8.3% ostial/body, P=.08), 3.4% myocardial infarction (3.5% distal vs 2.8% ostial/body, P=1), and 15.4% target lesion revascularization (18.6% distal vs 5.6% ostial/body, P=.06). The composite of cardiac death and myocardial infarction was 10.7% (13.3% distal vs 2.8% ostial/body, P=.1) while the definite/probable stent thrombosis rate was 1.4% (all in the distal group). CONCLUSIONS: At 6-year clinical follow-up, percutaneous coronary intervention with drug-eluting stent implantation for unprotected left main disease was associated with acceptable rates of cardiac death, myocardial infarction and stent thrombosis. Favorable long-term outcomes in ostial/body lesions compared to distal bifurcation lesions were confirmed at long-term clinical follow-up. PMID- 23041168 TI - Cytokine expression in trichloroethylene-induced hypersensitivity dermatitis: an in vivo and in vitro study. AB - The purpose of this study was to address the association between cytokine expression and the hypersensitivity dermatitis induced by trichloroethylene (TCE) exposure. 28 TCE-induced hypersensitivity dermatitis patients, 22 TCE exposed workers and 22 non-exposed controls were enrolled in the study. The serum levels of interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor (TNF)-alpha were analyzed using a magnetic colorbead-based multiplex assay. The patients showed significantly higher levels of serum IL-1beta (p=0.033 and p=0.015), IL-6 (p<0.001), IL-8 (p<0.001 and p=0.002) and TNF-alpha (p=0.009 and p=0.005) than the TCE exposed workers and non-exposed controls. There was a significantly positive correlation among these cytokine concentrations, but no significant correlation was found between these cytokine concentrations and the disease duration in patient group. We further compared the effects of trichloroethanol (TCOH) and trichloroacetic acid (TCA), two major metabolites of TCE, on cytokine expression in keratinocyte cell line (HaCaT). IL-1alpha, IL-6, IL-8 and TNF-alpha concentrations were tested using enzyme-linked immunosorbent assay (ELISA) after HaCaT cells were treated with different concentrations of TCOH or TCA for 24h. We found that TCOH, but not TCA, increased the levels of IL-1alpha and IL-6 in a dose-dependent manner. We also found that TCOH activated the nuclear factor kappa B (NF-kappaB) pathway. Bay 11-7082 (NF-kappaB inhibitor) significantly attenuated the TCOH-induced production of IL-6 in HaCaT cells, but IL-1alpha production was not affected. In conclusions, it is suggested that IL-1beta, IL-6, IL-8 and TNF alpha were associated with TCE-induced hypersensitivity dermatitis. TCOH induced IL-6 expression through activation of the NF-kappaB pathway in HaCaT cells and may play an integral role in TCE-induced skin hypersensitivity. PMID- 23041169 TI - Taurine attenuates methamphetamine-induced autophagy and apoptosis in PC12 cells through mTOR signaling pathway. AB - Methamphetamine (METH), a commonly abused psychostimulant, has been shown to induce neuronal damage by causing reactive oxygen species (ROS) formation, apoptosis and autophagy. Taurine (2-aminoethanesulfonic acid) is involved in several physiological actions in the brain, including neuroprotection, osmoregulation and neurotransmission. In this study, we investigate the protective effect of taurine against METH-induced neurotoxicity in PC12 cells and the underlying mechanism. The results showed that taurine significantly increased the cell viability inhibited by METH. LC3-II expression was elevated by METH treatment, whereas such increase was obviously attenuated by taurine. Co treatment of taurine strongly reversed the decline of antioxidase activities induced by METH. Moreover, phosphorylated mammalian target of rapamycin (p-mTOR) was significantly inhibited by METH, whereas complementation of taurine markedly increased the expression of p-mTOR in PC12 cells, rather than phosphorylated Erk. Interestingly, taurine-induced decreasing expression of LC3-II was partially blocked by pretreatment of RAD001, an mTOR inhibitor. These results indicated that taurine inhibits METH-induced autophagic process through activating mTOR rather than Erk signaling. Collectively, our study shows that taurine protects METH-induced PC12 cells damage by attenuating ROS production, apoptosis and autophagy, at least in part, via mTOR signaling pathway. PMID- 23041170 TI - Effect of acute aluminum phosphide exposure on rats: a biochemical and histological correlation. AB - Aluminum phosphide (AlP), a widely used fumigant and rodenticide leads to high mortality if ingested. Its toxicity is due to phosphine liberated when it comes in contact with moisture. The exact mechanism of action of phosphine is not known. In this study male Wistar rats were used. The animals received a single dose (20mg AlP/kg body weight i.g.) orally. Basic serum biochemical parameters, activity of mitochondrial complexes, antioxidant enzymes and parameters of oxidative stress, individual mitochondrial cytochrome levels were measured along with tissue histopathology and immunostaining for cytochrome c and compared with controls. The serum levels of creatinine kinase-MB, lactate dehydrogenase, magnesium and cortisol were higher (p<0.01); the activities of mitochondrial complexes I, II, IV were observed to be significantly decreased in liver tissue in treated rats (p<0.01). The activity of catalase was lower (p<0.05) with a significant increase in lipid peroxidation (p<0.05) whereas superoxide dismutase and glutathione peroxidase were unaffected in them. There was a significant decrease in all the cytochromes in brain and liver tissues (p<0.05) with the exception of cytochrome b in brain, the levels of which remained same. Histopathology revealed congestion in most organs with centrizonal hemorrhagic necrosis in liver. Ultra structural changes indicating mitochondrial injury was observed in heart, liver and kidney tissues. There was also a marked reduction in the cytochrome-c immunostaining compared to the controls. Toxicity due to AlP appears to result as a consequence of both-energy insufficiency and oxidative stress, with a possible and preferential interaction with the tissue cytochromes. PMID- 23041171 TI - Seizure prediction using EEG spatiotemporal correlation structure. AB - A seizure prediction algorithm is proposed that combines novel multivariate EEG features with patient-specific machine learning. The algorithm computes the eigenspectra of space-delay correlation and covariance matrices from 15-s blocks of EEG data at multiple delay scales. The principal components of these features are used to classify the patient's preictal or interictal state. This is done using a support vector machine (SVM), whose outputs are averaged using a running 15-minute window to obtain a final prediction score. The algorithm was tested on 19 of 21 patients in the Freiburg EEG data set who had three or more seizures, predicting 71 of 83 seizures, with 15 false predictions and 13.8 h in seizure warning during 448.3 h of interictal data. The proposed algorithm scales with the number of available EEG signals by discovering the variations in correlation structure among any given set of signals that correlate with seizure risk. PMID- 23041172 TI - Tongue biting in epileptic seizures and psychogenic events: an evidence-based perspective. AB - Tongue biting (TB) may occur both in seizures and in psychogenic non-epileptic events (PNEEs). We undertook a systematic review to determine sensitivity, specificity, and likelihood ratios (LR) of TB. Five studies (222 epilepsy patients and 181 subjects with PNEEs) were included. There was a statistically significant higher prevalence of TB (both without further specifications on site of lesions and lateral TB) in patients with seizures. Pooled accuracy measures of TB (no further specifications) were sensitivity 38%, specificity 75%, pLR 1.479 (95% CI 1.117-1.957), and nLR 0.837 (95% CI 0.736-0.951). Pooled measures of lateral TB were sensitivity 22%, specificity 100%, pLR 21.386 (95% CI 1.325 345.169), and nLR 0.785 (95% CI 0.705-0.875). Only a pooled analysis of data demonstrated a statistically significant pLR for lateral TB. Lateral TB but not 'any' TB has diagnostic significance in distinguishing seizures from PNEEs, supporting the diagnosis of seizures. Tongue biting without further specifications has, therefore, no value in the differential diagnosis between seizures and PNEEs. PMID- 23041173 TI - Route learning impairment in temporal lobe epilepsy. AB - Memory impairment on neuropsychological tests is relatively common in temporal lobe epilepsy (TLE) patients. However, memory has been rarely evaluated in more naturalistic settings. This study assessed TLE (n=19) and control (n=32) groups on a real-world route learning (RL) test. Compared to the controls, the TLE group committed significantly more total errors across the three RL test trials. Route learning errors correlated significantly with standardized auditory and visual memory and visual-perceptual test scores in the TLE group. In the TLE subset for whom hippocampal data were available (n=14), RL errors also correlated significantly with left hippocampal volume. This is one of the first studies to demonstrate real-world memory impairment in TLE patients and its association with both mesial temporal lobe integrity and standardized memory test performance. The results support the ecological validity of clinical neuropsychological assessment. PMID- 23041174 TI - Independent and symmetric seizures from parasagittal cortex: is this a feature of profound hypoglycemia? AB - Two patients presented with severe hypoglycemia and parasagittal homotopic cerebral hemisphere injury. Days after the initial insult, bilateral, independent, periodic lateralized epileptiform discharges and frequent seizures emerged from the affected homotopic cerebral cortices in both patients. We speculate that synaptic rescaling and increased spontaneous discharges in isolated cerebral cortex may cause epileptogenesis in severe hypoglycemia. Bilateral but temporally independent parasagittal seizures could be a feature of severe hypoglycemia. PMID- 23041175 TI - Epilepsy across the spectrum: promoting health and understanding. A summary of the Institute of Medicine report. AB - Approximately 1 in 26 people will develop epilepsy at some point in their lives. Although epilepsy is one of the nation's most common neurological disorders, public understanding is limited. A complex spectrum of disorders, epilepsy affects an estimated 2.2 million people in the United States. Living with epilepsy is about more than just seizures; it is often defined in practical terms, such as challenges, uncertainties, and limitations in school, social situations, employment, driving, and independent living. People with epilepsy are also faced with health and community services that are fragmented, uncoordinated, and difficult to obtain. The Institute of Medicine's report (2012) [1], Epilepsy across the spectrum: promoting health and understanding, examines the public health dimensions of epilepsy with a focus on (a) public health surveillance and data collection and integration; (b) population and public health research; (c) health policy, health care, and human services; and (d) education for providers, people with epilepsy and their families, and the public. The report's recommendations range from the expansion of collaborative epilepsy surveillance efforts to the independent accreditation of epilepsy centers, to the coordination of public awareness efforts, and to the engagement of people with epilepsy and their families in education, dissemination, and advocacy activities. Given the current gaps in epilepsy knowledge, care, and education, there is an urgent need to take action-across multiple dimensions-to improve the lives of people with epilepsy and their families. The realistic, feasible, and action-oriented recommendations in this report can help enable short- and long-term improvements for people with epilepsy. PMID- 23041176 TI - Reduced cell number in the hindgut epithelium disrupts hindgut left-right asymmetry in a mutant of pebble, encoding a RhoGEF, in Drosophila embryos. AB - Animals often show left-right (LR) asymmetry in their body structures. In some vertebrates, the mechanisms underlying LR symmetry breaking and the subsequent signals responsible for LR asymmetric development are well understood. However, in invertebrates, the molecular bases of these processes are largely unknown. Therefore, we have been studying the genetic pathway of LR asymmetric development in Drosophila. The embryonic gut is the first organ that shows directional LR asymmetry during Drosophila development. We performed a genetic screen to identify mutations affecting LR asymmetric development of the embryonic gut. From this screen, we isolated pebble (pbl), which encodes a homolog of a mammalian RhoGEF, Ect2. The laterality of the hindgut was randomized in embryos homozygous for a null mutant of pbl. Pbl is a multi-functional protein required for cytokinesis and the epithelial-to-mesenchymal transition in Drosophila. Consistent with Pbl's role in cytokinesis, we found reduced numbers of cells in the hindgut epithelium in pbl homozygous embryos. The specific expression of pbl in the hindgut epithelium, but not in other tissues, rescued the LR defects and reduced cell number in embryonic pbl homozygotes. Embryos homozygous for string (stg), a mutant that reduces cell number through a different mechanism, also showed LR defects of the hindgut. However, the reduction in cell number in the pbl mutants was not accompanied by defects in the specification of hindgut epithelial tissues or their integrity. Based on these results, we speculate that the reduction in cell number may be one reason for the LR asymmetry defect of the pbl hindgut, although we cannot exclude contributions from other functions of Pbl, including regulation of the actin cytoskeleton through its RhoGEF activity. PMID- 23041177 TI - Roles of Wnt8a during formation and patterning of the mouse inner ear. AB - Fgf and Wnt signalling have been shown to be required for formation of the otic placode in vertebrates. Whereas several Fgfs including Fgf3, Fgf8 and Fgf10 have been shown to participate during early placode induction, Wnt signalling is required for specification and maintenance of the otic placode, and dorsal patterning of the otic vesicle. However, the requirement for specific members of the Wnt gene family for otic placode and vesicle formation and their potential interaction with Fgf signalling has been poorly defined. Due to its spatiotemporal expression during placode formation in the hindbrain Wnt8a has been postulated as a potential candidate for its specification. Here we have examined the role of Wnt8a during formation of the otic placode and vesicle in mouse embryos. Wnt8a expression depends on the presence of Fgf3 indicating a serial regulation between Fgf and Wnt signalling during otic placode induction and specification. Wnt8a by itself however is neither essential for placode specification nor redundantly required together with Fgfs for otic placode and vesicle formation. Interestingly however, Wnt8a and Fgf3 are redundantly required for expression of Fgf15 in the hindbrain indicating additional reciprocal interactions between Fgf and Wnt signalling. Further reduction of Wnt signalling by the inactivation of Wnt1 in a Wnt8a mutant background revealed a redundant requirement for both genes during morphogenesis of the dorsal portion of the otic vesicle. PMID- 23041178 TI - A testing time for koalas. PMID- 23041179 TI - Chiari-like malformation: a substantive health and welfare problem in the Cavalier King Charles spaniel. PMID- 23041180 TI - Temporal structure of the rat's behavior in elevated plus maze test. AB - Aim of the research was to evaluate, by means of quantitative and multivariate temporal pattern analyses, the behavior of Wistar rat in elevated plus maze (EPM) test. On the basis of an ethogram encompassing 24 behavioral elements, quantitative results showed that 130.14 +/- 8.01 behavioral elements occurred in central platform and in closed arms (protected zones), whereas 88.62 +/- 6.04 occurred in open arms (unprotected zones). Percent distribution was characterized by a prevalence of sniffing, walking and vertical exploration. Analysis of minute by-minute duration evidenced a decrease for time spent in open arms and central platform and an increase for time spent in closed arms. As to multivariate t pattern analysis, 126 different temporal patterns were detected. Behavioral stripes, summarizing distribution of such t-patterns along time, showed that several t-patterns were not homogeneously distributed along the test observational period: t-patterns encompassing behavioral events occurring prevalently in central platform-open arms were observed during the first minutes, whereas t-patterns structured on the basis of events occurring mainly in central platform-closed arms were detected during the last minutes. Therefore, during the observation in elevated plus maze, rat's behavior undergoes significant rearrangements of its temporal features. Present research demonstrates, for the first time, the existence of complex and significantly timed behavioral sequences in the activity of Wistar rats tested in elevated plus maze. Application of t pattern analysis can provide useful tools to characterize the behavioral dynamics of anxiety-related rodent behavior and differentiate the effect of various anxioselective substances. PMID- 23041181 TI - Higher, faster, stronger: the effect of dynamic stimuli on response preparation and CNV amplitude. AB - The contingent negative variation (CNV) is a slow negative shift in the electroencephalogram (EEG), observed during response preparation. To optimalize the CNV paradigm, this study developed a task using dynamic stimuli and next combined this task with a Go/No-go test. In the first experiment, 19 healthy volunteers were subjected to the classic Traffic light (TL) task and the new dynamic Lines task. In the Lines task, response time was faster and CNV amplitude was larger compared to the TL task. In the second experiment, 20 healthy participants were tested on a Go/No-go version of the Lines task. Response times increased as the probability of response requirement decreased. CNV amplitude was larger when probability of response requirement was higher. In conclusion, the dynamic task promotes response preparation. The new tasks may be especially valuable in groups with attention difficulties (i.e. elderly or ADHD patients). PMID- 23041182 TI - Fish oil supplementation and physical exercise program: distinct effects on different memory tasks. AB - Both fish oil supplementation and physical exercise are able to induce benefits to mental health by providing an improvement in cognitive performance and enhancing neuroplasticity and protection against neurological lesions. The aim of the present study was to investigate the cognitive effects in rats of the: (1) a diary and prolonged fish oil supplementation (85 mg/kg/day) initiated from prenatal period to the midlife (300 day/old); (2) moderate physical exercise in treadmill initiated from adolescent period to midlife and (3) association of fish oil supplementation and moderate physical exercise protocol during the same period. Animals were submitted to the habituation in the open-field, object recognition and to the plus-maze discriminative avoidance tasks. Our results demonstrated that a diary and prolonged fish oil supplementation can facilitate the persistence of the long-term habituation and recognition memories without, however, affecting the discriminative avoidance memory. Conversely, although the program of physical exercise exerted no effects on habituation or objects recognition, it was able to potentiate the persistence of the discriminative avoidance memory. Such promnestic effects (induced by both fish oil supplementation and physical exercise) were not accompanied by alterations in emotionality or locomotor activity. Our findings suggest that fish oil supplementation, initiated from prenatal period to midlife, and physical exercise program applied throughout the life induced distinctly a better cognitive performance. PMID- 23041183 TI - Fluorescence-guided brain tumor surgery. PMID- 23041184 TI - The rich club: networks and the importance of connections. PMID- 23041185 TI - Solitaire FR--a promising new device for acute ischemic stroke treatment. PMID- 23041186 TI - Modulating memory. PMID- 23041187 TI - Frequency modulation detection as a measure of temporal processing: age-related monaural and binaural effects. AB - The detection of low-rate frequency modulation (FM) carried by a low-frequency tone has been employed as a means of assessing the fidelity of temporal fine structure coding. Detection of low-rate FM can be made more acute, relative to the monaural case, by the addition of a pure tone to the contralateral ear. This study examined whether FM detection in the 500-Hz region could be further improved by using a binaural stimulation mode where the modulator was antiphasic across the two ears. The study also sought to determine whether these dichotic FM conditions were beneficial in identifying the emergence of a temporal fine structure processing deficiency relatively early in the aging process. Young, mid aged, and older listeners (n = 12 per group) were tested. The results demonstrated better FM acuity in the dichotic task irrespective of listener age. Dichotic FM detection also differentiated between age groups more definitively than diotic detection, especially in terms of distinguishing mid-aged from older listeners. In the group of older listeners, dichotic FM detection was weakly associated with absolute sensitivity to the carrier. In addition, this group failed to show a dichotic benefit in the presence of a marked asymmetry in sensation level across ears. The overall pattern of results suggests that dichotic FM measurements have advantages over monaural measurements for the purposes of assessing age-related temporal processing effects, although a marked asymmetry in absolute thresholds across ears could undermine these advantages. PMID- 23041188 TI - Autophagosomes accumulate in differentiated and hypertrophic adipocytes in a p53 independent manner. AB - Autophagy is induced by several kinds of stress, including oxidative, genotoxic, endoplasmic reticulum and nutrient stresses. The tumor suppressor p53, which is a stress sensor, plays a critical role in the regulation of autophagy. Although p53 is required for starvation (nutrient deficient stress)-induced autophagy, it is still not clear whether p53 is also required for the autophagy observed in differentiated and hypertrophic adipocytes, which accumulate excessive amounts of nutrients in the form of triglycerides. In this study, we demonstrated that starvation induces autophagy in p53-proficient adipocytes, but not in p53 deficient adipocytes as previously reported. On the other hand, autophagy was equally observed in both p53-deficient and -proficient differentiated and hypertrophic adipocytes. Similar results were obtained by in vivo analysis using white adipose tissue of high-fat diet-induced obese mice. Moreover, unexpectedly, the autophagy observed in the differentiated and hypertrophic adipocytes involved increased accumulation of autophagosomes and decreased autophagic flux. Thus, we concluded that in differentiated and hypertrophic adipocytes autophagosomes accumulate in a p53-independent manner, and this accumulation is caused by reduced autophagic flux. PMID- 23041189 TI - Treatment of a methylmalonyl-CoA mutase stopcodon mutation. AB - There are limited treatment options for the metabolic disorder methylmalonic aciduria. The disorder can be caused by nonsense mutations within the methylmalonyl-CoA mutase gene, resulting in the production of a truncated protein with little or no catalytic activity. We used a genomic reporter assay and mouse primary cell lines which carry a stop-codon mutation in the human methylmalonyl CoA mutase gene to test the effects of gentamicin and PTC124 for stop-codon read through potential. Fibroblast cell lines were established from methylmalonic aciduria knockout-stop codon mice. Addition of gentamicin to the culture medium caused a 1.5- to 2-fold increase in mRNA expression of the human methylmalonyl CoA mutase gene. Without treatment the cells contained 19% of the normal levels of methylmalonyl-CoA mutase enzyme activity which increased to 32% with treatment, suggesting a functional improvement. Treatment with PTC124 increased the amount of human methylmalonyl-CoA mutase gene mRNA by 1.6+/-0.3-fold and a trend suggesting increased enzyme activity. The genomic reporter assay, BAC_MMA(*)EGFP, expresses enhanced green fluorescent protein when read-through of the stop codon occurs. Using flow cytometry, RT-real-time PCR and enzyme assay, read-through was measured. Treatment with PTC124 at 20MUmol/L resulted in a significant increase in enhanced green fluorescent protein, a 2-fold increase in mRNA expression and a trend to a slight increase in enzyme activity. The clinical relevance of these effects may be tested in mouse models of MMA carrying nonsense mutations in the methylmalonyl-CoA mutase gene. Pharmacological approaches have the advantage of providing a broader effect on multiple tissues, which will benefit many different disorders with similar nonsense mutations. PMID- 23041190 TI - Oligomerization of the transmembrane domain of IRE1alpha in SDS micelles. AB - IRE1alpha (Inositol-requiring enzyme 1 alpha), an endoplasmic reticulum (ER) resident sensor for mammalian unfolded protein response, is a type I transmembrane protein which has a bifunctional enzyme containing kinase and RNase domains. Although the luminal domain and cytosolic domain of IRE1alpha are thought to play crucial roles in regulating the protein activity, no functional and structural studies of the transmembrane domain exist thus far. Herein, using CD spectroscopy, we report that the transmembrane domain of the IRE1alpha is alpha-helical in a membrane-like environment. In addition, SDS-PAGE and FRET analyses support that the transmembrane domain forms oligomers in SDS micelles. Thus, the study would provide insights into how the transmembrane domain plays a role in regulating the IRE1alpha protein activity. PMID- 23041192 TI - Natural Arabidopsis brx loss-of-function alleles confer root adaptation to acidic soil. AB - Soil acidification is a major agricultural problem that negatively affects crop yield. Root systems counteract detrimental passive proton influx from acidic soil through increased proton pumping into the apoplast, which is presumably also required for cell elongation and stimulated by auxin. Here, we found an unexpected impact of extracellular pH on auxin activity and cell proliferation rate in the root meristem of two Arabidopsis mutants with impaired auxin perception, axr3 and brx. Surprisingly, neutral to slightly alkaline media rescued their severely reduced root (meristem) growth by stimulating auxin signaling, independent of auxin uptake. The finding that proton pumps are hyperactive in brx roots could explain this phenomenon and is consistent with more robust growth and increased fitness of brx mutants on overly acidic media or soil. Interestingly, the original brx allele was isolated from a natural stock center accession collected from acidic soil. Our discovery of a novel brx allele in accessions recently collected from another acidic sampling site demonstrates the existence of independently maintained brx loss-of-function alleles in nature and supports the notion that they are advantageous in acidic soil pH conditions, a finding that might be exploited for crop breeding. PMID- 23041191 TI - Learned recognition of maternal signature odors mediates the first suckling episode in mice. AB - BACKGROUND: Soon after birth, all mammals must initiate milk suckling to survive. In rodents, this innate behavior is critically dependent on uncharacterized maternally derived chemosensory ligands. Recently, the first pheromone sufficient to initiate suckling was isolated from the rabbit. Identification of the olfactory cues that trigger first suckling in the mouse would provide the means to determine the neural mechanisms that generate innate behavior. RESULTS: Here we use behavioral analysis, metabolomics, and calcium imaging of primary sensory neurons and find no evidence of ligands with intrinsic bioactivity, such as pheromones, acting to promote first suckling in the mouse. Instead, we find that the initiation of suckling is dependent on variable blends of maternal "signature odors" that are learned and recognized prior to first suckling. CONCLUSIONS: As observed with pheromone-mediated behavior, the response to signature odors releases innate behavior. However, this mechanism tolerates variability in both the signaling ligands and sensory neurons, which may maximize the probability that this first essential behavior is successfully initiated. These results suggest that mammalian species have evolved multiple strategies to ensure the onset of this critical behavior. PMID- 23041193 TI - Brain structure links loneliness to social perception. AB - Loneliness is the distressing feeling associated with the perceived absence of satisfying social relationships. Loneliness is increasingly prevalent in modern societies and has detrimental effects on health and happiness. Although situational threats to social relationships can transiently induce the emotion of loneliness, susceptibility to loneliness is a stable trait that varies across individuals [6-8] and is to some extent heritable. However, little is known about the neural processes associated with loneliness (but see [12-14]). Here, we hypothesized that individual differences in loneliness might be reflected in the structure of the brain regions associated with social processes. To test this hypothesis, we used voxel-based morphometry and showed that lonely individuals have less gray matter in the left posterior superior temporal sulcus (pSTS)--an area implicated in basic social perception. As this finding predicted, we further confirmed that loneliness was associated with difficulty in processing social cues. Although other sociopsychological factors such as social network size, anxiety, and empathy independently contributed to loneliness, only basic social perception skills mediated the association between the pSTS volume and loneliness. Taken together, our results suggest that basic social perceptual abilities play an important role in shaping an individual's loneliness. PMID- 23041194 TI - Plasma membrane tethering of the cortical ER necessitates its finely reticulated architecture. AB - The cortical endoplasmic reticulum (ER) is an intricate network of tubules and cisternae tightly associated with the plasma membrane (PM) in plants, yeast, and the excitable cell types in metazoans [1-5]. How the ER is attached to the cell cortex and what necessitates its highly reticulated architecture remain largely unknown. Here, we identify the integral ER vesicle-associated membrane protein associated proteins (VAPs), previously shown to control the composition of phosphoinositides at the ER-PM contact sites [6, 7], as major players in sustaining the ER-PM tethering in fission yeast. We show that genetic conversion of the reticulated ER structure to the cisternal morphology shields large areas of the PM, preventing the actomyosin division ring assembly at the equatorial cortex. Using a combination of VAP mutants where the cortical ER is detached from the PM and a set of artificial ER-PM tethers suppressing this phenotype, we demonstrate that the PM footprint of the cortical ER is functionally insulated from the cytosol. In cells with prominent ER-PM contacts, fine reticulation of the ER network may have emerged as a critical adaptation enabling a uniform access of peripheral protein complexes to the inner surface of the plasma membrane. PMID- 23041195 TI - The retinotopic organization of striate cortex is well predicted by surface topology. AB - In 1918, Gordon Holmes combined observations of visual-field scotomas across brain-lesioned soldiers to produce a schematic map of the projection of the visual field upon the striate cortex. One limit to the precision of his result, and the mapping of anatomy to retinotopy generally, is the substantial individual variation in the size, volumetric position, and cortical magnification of area V1. When viewed within the context of the curvature of the cortical surface, however, the boundaries of striate cortex fall at a consistent location across individuals. We asked whether the surface topology of the human brain can be used to accurately predict the internal, retinotopic function of striate cortex as well. We used fMRI to measure polar angle and eccentricity in 25 participants and combined their maps within a left-right, transform-symmetric representation of the cortical surface. These data were then fit using a deterministic, algebraic model of visual-field representation. We found that an anatomical image alone can be used to predict the retinotopic organization of striate cortex for an individual with accuracy equivalent to 10-25 min of functional mapping. This indicates tight developmental linkage of structure and function within a primary, sensory cortical area. PMID- 23041196 TI - STIM1 juxtaposes ER to phagosomes, generating Ca2+ hotspots that boost phagocytosis. AB - BACKGROUND: Endoplasmic reticulum (ER) membranes are recruited to phagosomes, but the mechanism and functional significance of this ER recruitment is not known. Here, we show that the ER Ca(2+) sensor stromal interaction molecule 1 (STIM1) sustains high-efficiency phagocytosis by recruiting thin ER cisternae that interact productively but do not fuse with phagosomes. RESULTS: Endogenous STIM1 was recruited to phagosomes upon ER Ca(2+) depletion in mouse neutrophils, and exogenous YFP-STIM1 puncta coincided with localized Ca(2+) elevations around phagosomes in fibroblasts expressing phagocytic receptors. STIM1 ablation decreased phagocytosis, ER-phagosome contacts, and periphagosomal Ca(2+) elevations in both neutrophils and fibroblasts, whereas STIM1 re-expression in Stim1(-/-) fibroblasts rescued these defects, promoted the formation and elongation of tight ER-phagosome contacts upon ER Ca(2+) depletion and increased the shedding of periphagosomal actin rings. Re-expression of a signaling deficient STIM1 mutant unable to open Ca(2+) channels recruited ER cisternae to the vicinity of phagosomes but failed to rescue phagocytosis, actin shedding, and periphagosomal Ca(2+) elevations. The periphagosomal Ca(2+) hotspots were decreased by extracellular Ca(2+) chelation and by Ca(2+) channels inhibitors, revealing that the Ca(2+) ions originate at least in part from phagosomes. CONCLUSIONS: Our findings indicate that STIM1 recruits ER cisternae near phagosomes for signaling purposes and that the opening of phagosomal Ca(2+) channels generates localized Ca(2+) elevations that promote high-efficiency phagocytosis. PMID- 23041197 TI - Alpha oscillations serve to protect working memory maintenance against anticipated distracters. AB - When operating in a complex world, it is essential to have mechanisms that can suppress distracting information. Such mechanisms might be related to neuronal oscillations, which are known to be involved in gating of incoming information. We here apply a working memory (WM) task to investigate how neuronal oscillations are involved in the suppression of distracting information that can be predicted in time. We used a modified Sternberg WM task in which distracters were presented in the retention interval, while we recorded the ongoing brain activity using magnetoencephalography. The data revealed a robust adjustment of the phase of alpha oscillations in anticipation of the distracter. In trials with strong phase adjustment, response times to the memory probe were reduced. Further, the power of alpha oscillations increased prior to the distracter and predicted performance. Our findings demonstrate that the doors of perception close when a distracter is expected. The phase adjustment of the alpha rhythm adds to the computational versatility of brain oscillations, because such a mechanism allows for modulating neuronal processing on a fine temporal scale. PMID- 23041198 TI - Public behaviour and the response to pandemic influenza. PMID- 23041199 TI - Public response to the 2009 influenza A H1N1 pandemic: a polling study in five countries. AB - BACKGROUND: Many important strategies to reduce the spread of pandemic influenza need public participation. To assess public receptivity to such strategies, we compared adoption of preventive behaviours in response to the 2009 H1N1 influenza pandemic among the public in five countries and examined whether certain non pharmaceutical behaviours (such as handwashing) were deterrents to vaccination. We also assessed public support for related public health recommendations. METHODS: We used data from simultaneous telephone polls (mobile telephone and landline) in Argentina, Japan, Mexico, the UK, and the USA. In each country, interviews were done in a nationally representative sample of adults, who were selected by the use of random digit dial techniques. The questionnaire asked people whether or not they had adopted each of various preventive behaviours (non pharmaceutical--such as personal protective and social distancing behaviour--or vaccinations) to protect themselves or their family from H1N1 at any point during the pandemic. Two-tailed t tests were used for statistical analysis. FINDINGS: 900 people were surveyed in each country except the USA where 911 people were contacted. There were wide differences in the adoption of preventive behaviours between countries, although certain personal protective behaviours (eg, handwashing) were more commonly adopted than social distancing behaviours (eg, avoiding places where many people gather) across countries (53-89%vs 11-69%). These non-pharmaceutical behaviours did not reduce the likelihood of getting vaccinated in any country. There was also support across all countries for government recommendations related to school closure, avoiding places where many people gather, and wearing masks in public. INTERPRETATION: There is a need for country-specific approaches in pandemic policy planning that use both non pharmaceutical approaches and vaccination. FUNDING: US Centers for Disease Control and Prevention and the National Public Health Information Coalition. PMID- 23041200 TI - Impact of novel mutations of herpes simplex virus 1 and 2 thymidine kinases on acyclovir phosphorylation activity. AB - The acyclic analogue of guanosine acyclovir (ACV) constitutes the first-line drug for the treatment of herpes simplex virus (HSV) infections. ACV activation requires primophosphorylation by virus-encoded HSV thymidine kinase (TK). In 95% of cases, HSV resistance to ACV is associated with mutations located in TK. The aim of this work was to address the question of the potential involvement of novel HSV-1 and HSV-2 TK mutations in reduced susceptibility to ACV using a novel nonradioactive method, based on luminescent quantitation of ADP, for the evaluation of in vitro phosphorylation activity of TK. All recombinant TKs tested exhibited significantly lower ACV phosphorylation activities in comparison with those of reference KOS or gHSV-2 TKs (p<0.015), therefore indicating that amino acid changes Y53D, L170P, R176W, A207P (HSV-1) and S66P, A72S, I101S, M183I (HSV 2) were likely to be involved in HSV resistance to ACV. PMID- 23041202 TI - Tongue reduction for macroglossia in Beckwith Wiedemann syndrome: review and application of new technique. AB - Beckwith Wiedemann syndrome (BWS) is a rare, congenital overgrowth disorder that is characterized by macroglossia, anterior abdominal wall defects, visceromegaly, gigantism, and neonatal hypoglycaemia. Macroglossia may contribute to anterior open bite malocclusion with prognathism, speech articulation disturbances, drooling and the perception of intellectual disability. It was the purpose of this study to review a series of BWS patients who underwent surgical reduction of the tongue by a modified technique with respect to aesthetic and functional outcomes. Seven BWS patients, age 6 months to 21 months, had a 'stellate/anterior wedge' reduction with an anterior rotation flap and were followed up from 4 months to 9 years postoperatively. Assessment of aesthetics together with tongue morphology and mobility were recorded and a postoperative speech evaluation was performed. Minor contour deformities were present in two patients during function but all parents were satisfied with the results. The speech pathology assessment results indicated positive outcomes for speech, oral structure and function, and feeding for all children assessed. This modified technique allows for an adequate reduction of tongue volume with conservation of motor and sensory function as well as preservation of anatomical contour. PMID- 23041201 TI - Development and evaluation of a thermosensitive vaginal gel containing raltegravir+efavirenz loaded nanoparticles for HIV prophylaxis. AB - The objective of this investigation was to develop a thermosensitive vaginal gel containing raltegravir+efavirenz loaded PLGA nanoparticles (RAL+EFV-NPs) for pre exposure prophylaxis of HIV. RAL+EFV-NPs were fabricated using a modified emulsion-solvent evaporation method and characterized for size and zeta potential. The average size and surface charge of RAL+EFV-NP were 81.8+/-6.4 nm and -23.18+/-7.18 mV respectively. The average encapsulation efficiency of raltegravir and efavirenz was 55.5% and 98.2% respectively. Thermosensitive vaginal gel containing RAL+EFV-NPs was successfully prepared using a combination of Pluronic F127 (20% w/v) and Pluronic F68 (1% w/v). Incorporation RAL+EFV-NPs in the gel did not result in nanoparticle aggregation and RAL+EFV-NPs containing gel showed thermogelation at 32.5 degrees C. The RAL+EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC(90) of RAL+EFV NPs was lower than raltegravir+efavirenz (RAL+EFV) solution but did not reach significance. Compared to control HeLa cells without any treatment, RAL+EFV-NPs or blank gel were not cytotoxic for 14 days in vitro. The intracellular levels of efavirenz in RAL+EFV-NPs treated HeLa cells were above the EC(90) for 14 days whereas raltegravir intracellular concentrations were eliminated within 6 days. Transwell experiments of NPs-in-gel demonstrated rapid transfer of fluorescent nanoparticles from the gel and uptake in HeLa cells within 30 min. These data demonstrate the potential of antiretroviral NP-embedded vagina gels for long-term vaginal pre-exposure prophylaxis of heterosexual HIV-1 transmission. PMID- 23041203 TI - Tracheotomy-related morbidity and mortality: what else can we do to reduce them? PMID- 23041204 TI - Implications of rationing and the European Working Time Directive on aesthetic breast surgery: a study of trainee exposure in 2005 and 2011. AB - BACKGROUND: There are concerns that current trainees may be lacking operative experience in aesthetic and functional breast surgeries. Reduced exposure to such cases during training may stem from rationing, EWTD compliance, and an increasingly consultant-led service. These issues are examined in a single NHS hospital, with analysis of trends over time, and are contrasted with the changes that have occurred in a related private hospital. METHODS: A single NHS hospital trusts database was retrospectively analysed for all aesthetic breast surgeries from 2005 to 2011, noting the total number of cases and the grade of the principal surgeon. The analysis was repeated in a related private sector hospital in the same catchment area. RESULTS: A statistically significant drop of 55% of NHS aesthetic breast surgeries performed in 2011 compared to 2005 was demonstrated with an increasing trend for consultant led procedures. The NHS caseload decline was matched by a corresponding increase of 57% within the private sector. CONCLUSIONS: Current trainees in plastic surgery face a significant reduction in operative exposure to aesthetic breast surgeries compared to their predecessors due to the EWTD working hours, surgical rationing policies, and an increasingly consultant led service. Approaches to maintaining training standards are discussed. PMID- 23041205 TI - pi-shaped lymphaticovenular anastomosis for head and neck lymphoedema: a preliminary study. AB - BACKGROUND: Head and neck lymphoedema secondary to jugular lymphadenectomy is a severe issue, without efficient solution. Successful treatment of lymphoedema of the upper and lower limbs has become possible with supermicrosurgical lymphaticovenular anastomosis. The technique based on two end-to-side anastomosis is named pi-shaped lymphaticovenular anastomosis. We have evaluated this method for chronic head and neck lymphoedema. METHODS: From November 2010 to April 2011, four patients with a chronic head and neck lymphoedema were treated by pi-shaped lymphaticovenular anastomosis. Three patients had a unilateral lymphoedema, and one patient had a bilateral lymphoedema. The mean age of the patients was 63.2 years (range, 46-77 years). The mean duration of the lymphoedema was 2.6 years (range, 1-5). Every patient was operated under local anaesthesia through a face lift skin incision. One pi-shaped lymphaticovenular anastomosis was performed at each operative site. RESULTS: The average operative time to perform one pi-shaped lymphaticovenular anastomosis was 1.9 h (range, 1.8-2.5). The calibre of lymphatic vessels used for lymphaticovenular anastomosis ranged from 0.3 to 0.7 mm (average, 0.5). A venous back-flow was found in seven lymphaticovenular anastomosis (70%). Three patients (75%) had a qualitative improvement of skin tissue and a significant circumferential reduction after surgery. The average circumferential differential reduction rate was 3.7% (range, 0.6-7.8) (p=0.006). The average cross-sectional area differential reduction rate was 7.2% (range, 1.2 15.1) (p=0.007). The average volume differential reduction rate was 6.9% (range, 2-14.8) (p=0.05). CONCLUSIONS: The authors present a new option to treat head and neck lymphoedema. pi-Shaped lymphaticovenular anastomosis is an effective method to reduce the severity of skin tissue fibrosis and lymphoedema volume. Further studies with larger groups of patients are required to confirm the outcome of this preliminary study. EBM Level=level 4. PMID- 23041206 TI - T cell subsets and colorectal cancer: discerning the good from the bad. AB - Tumor-specific T cells must overcome a multitude of suppressive mechanisms to destroy cancerous cells effectively. Furthermore, it appears that the tumor microenvironment facilitates the development of highly immunosuppressive T cells, which may also allow subsequent tumor progression. In colorectal cancer, the relationship between regulatory T cells (e.g. FoxP3(+) Tregs) and tumor prognosis and progression is less clear, despite their well-documented ability to impinge on anti-tumor immune responses. Here we explore our current knowledge of colorectal TIL heterogeneity, deciphering subsets which may be of benefit or detriment. PMID- 23041207 TI - Bistability in Purkinje neurons: ups and downs in cerebellar research. AB - The output of cerebellar Purkinje cells has been characterized extensively and theories regarding the role of simple spike (SS) and complex spike (CS) patterns have evolved through many different studies. A bistable pattern of SS output can be observed in vitro; however, differing views exist regarding the occurrence of bistable SS output in vivo. Bistability in Purkinje cell output is characterized by abrupt transitions between tonic firing and quiescence, usually evoked by synaptic inputs to the neuron. This is in contrast to the trimodal pattern of activity which has been found in vitro and in vivo when climbing fiber input to Purkinje cells is removed. The mechanisms underlying bistable membrane properties in Purkinje cells have been determined through in vitro studies and computational analysis. In vitro studies have further established that Purkinje cells possess the ability to toggle between firing states, but in vivo studies in both awake and anesthetized animals have found conflicting results as to the presence of toggling in the intact circuit. Here, we provide an overview of the current state of research on bistability, examining the mechanisms underlying bistability and current findings from in vivo studies. We also suggest possible reasons for discrepancies between in vivo studies and propose future studies which would aid in clarifying the role of bistability in the cerebellar circuit. PMID- 23041208 TI - Involvement of oncogenic K-ras on cell migration stimulated by lysophosphatidic acid receptor-2 in pancreatic cancer cells. AB - Lysophosphatidic acid (LPA) mediates a variety of cellular responses with atleast six G protein-coupled transmembrane receptors (LPA receptor-1 (LPA(1)-LPA(6))). The interaction between LPA receptors and other cellular molecules on the biological function is not fully understood. Recently, we have reported that LPA(1) suppressed and LPA(3) stimulated cell migration of pancreatic cancer cells. In the present study, to evaluate the function of LPA(2) on motile and invasive activities of pancreatic cancer cells, we generated Lpar2 knockdown (HPD sh2) cells from hamster pancreatic cancer cells and measured their cell migration ability. In cell motility and invasive assays with an uncoated Cell Culture Insert, HPD-sh2 cells showed significantly lower intrinsic activity than control (HPD-GFP) cells. Since K-ras mutations were frequently detected in pancreatic cancer, we next investigated whether oncogenic K-ras is involved in cell migration induced by LPA(2) using K-ras knockdown (HPD-K2) cells. The cell motile ability of HPD-K2 cells was significantly lower than that of control cells. To confirm LPA(2) increases cell migration activity, cells were pretreated with dioctylglycerol pyrophosphate (DGPP) which is the antagonist of LPA(1)/LPA(3). The cell motile and invasive abilities of DGPP -treated HPD-GFP cells were markedly higher than those of untreated cells, but DGPP did not stimulate cell migration of HPD-K2 cells. These results suggest that cell migration activity of pancreatic cancer cells stimulated by LPA(2) may be enhanced by oncogenic K-ras. PMID- 23041209 TI - Mesoderm is committed to hemato-endothelial and cardiac lineages in human embryoid bodies by sequential exposure to cytokines. AB - Human embryonic stem (hES) cells can differentiate into cells of the three germ layers in vitro and serve as a powerful resource to study mechanisms involved in cell fate decisions. However, it is difficult to promote the directed and efficient differentiation of hES cells toward a specific lineage. Here we establish a stepwise strategy for generating hemato-endothelial and cardiac precursors from hES cells in single culture conditions. The efficiency of committing hES cells to three cell lineages was significantly higher with our approach than with exposure to single or multiple cytokines. Efficiency was determined using quantitative analysis by gene expression, flow cytometry, and colony assays. Several cytokines were sufficient to drive the efficient differentiation of hES cells into specific lineages. Each of these factors appeared to regulate specific steps of differentiation: BMP4 promoted the efficient formation of mesoderm; bFGF induced the differentiation of these mesodermal precursors to the hemangioblast fate; VEGF and TPO were required for the production of committed hematopoietic progenitors. This stepwise control of differentiation in vitro leads to a high frequency of hemato-endothelial and cardiac precursors derived from hES cells and offers a unique model for studying the molecular and cellular events that regulate hematopoiesis and cardiogenesis. PMID- 23041210 TI - Monitoring of unfractionated heparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent (PiCT(r)). AB - PURPOSE: To achieve sufficient and safe anticoagulation with unfractionated heparin (UFH) a close and reliable drug monitoring is necessary. In general, the activated partial thromboplastin time (APTT) is used for this purpose. In acute phase response, however, the APTT test procedure might be unreliable e.g. with false low results in the presence of elevated factor VIII. In this so called heparin resistance, measurement of anti-Xa activity is recommended over APTT to avoid potentially harmful dose escalation. A combination of anti-Xa measurement and global hemostatic testing with ROTEM(r) employing the anti-Xa sensitive PiCT(r) reagent showed high correlation with enoxaparin levels. This test modification could also be suitable for monitoring UFH. Aim of the study was to evaluate the correlation between PiCT(r)-ROTEM(r) and levels of UFH. METHODS: In this in-vitro study blood samples from healthy volunteers were spiked with UFH and subjected to different ROTEM(r) tests. RESULTS: There was a linear correlation between UFH level and clotting time (CT) in the PiCT(r)-ROTEM(r) test with an excellent correlation coefficient of 0.92. Additional endpoints showed similar results (PiCT(r)-ROTEM(r) MaxVel r = -0.85 and PiCT(r)-ROTEM(r) t_MaxVel r = 0.88). CONCLUSIONS: As a point-of-care applicable tool ROTEM(r) is immediately at hand. If further clinical studies confirm sensitivity in heparin resistance, PiCT(r)-ROTEM(r) could permit rapid UFH dose adjustments especially required in critical illness with acute phase response. PMID- 23041211 TI - Influence of saliva flow rate stimulated by gum-chewing on salivary concentrations of catecholamine metabolites. AB - BACKGROUND: The measurement of homovanillic acid (HVA) and 3-methoxy-4 hydroxyphenylglycol (MHPG) in saliva is useful for diagnosis of some psychiatric disorders. Gum-chewing increases salivation and is sometimes used to collect an adequate sample volume of saliva within a shorter time. However, the rate of saliva production may affect the salivary concentrations of these catecholamine metabolites. We clarified whether the salivary concentrations of HVA and MHPG are dependent on the rate of salivation. METHODS: Stimulated saliva was collected from healthy volunteers chewing a tasteless and flavorless chewing gum after unstimulated saliva was collected without gum-chewing. The salivary HVA and MHPG concentrations were measured using newly developed LC/ESI-MS/MS methods. RESULTS: The salivary HVA and MHPG concentrations were reproducibly measured when saliva was collected without gum-chewing (unstimulated saliva). In contrast, their salivary concentrations significantly decreased when salivation was stimulated by gum-chewing (p<0.05, Wilcoxon signed-rank test). CONCLUSIONS: Stimulated saliva by gum-chewing should be used with caution in the measurement of the catecholamine metabolites. LogD is a useful indicator, when predicting whether the salivary concentration of a compound is dependent on the rate of salivation. PMID- 23041212 TI - Systematic monitoring of standardization and harmonization status with commutable EQA-samples--five year experience from the Netherlands. AB - BACKGROUND: Equivalence of results among laboratories is a major mission for medical laboratories. Monitoring of test equivalence is structurally integrated in the Dutch External Quality Assessment (EQA) scheme since 2005. Commutable poolsera, single donation "spy" sera and biological variance tolerance limits have been introduced in the EQA scheme for evaluation of the degree of test equivalence and its determinants. METHODS: In the annual cycle scheme 24 samples, covering the (patho)physiological measuring range for 17 analytes, are assayed by 220 participating laboratories at biweekly intervals. Test equivalence was evaluated by calculating overall median interlaboratory coefficients of variation (CVs) and its bias and imprecision components. Data from 2005 and 2010 schemes are evaluated to investigate trends in performance and success of standardization efforts. RESULTS: Overall median interlaboratory CVs in 2010 were mostly better than in 2005. Median interlaboratory CVs became <5% for electrolytes and substrates, and <10% for enzymes. Improvement in median interlaboratory CVs over these five years is mainly explained by improved method standardization, especially for enzymes and creatinine. CONCLUSION: The Dutch EQA-program proves to be a powerful instrument to evaluate test equivalence. It allows monitoring standardization efforts in a highly effective way and gives insight into remaining standardization potential. PMID- 23041213 TI - Analytical and biological validation of a multiplex immunoassay for acute kidney injury biomarkers. AB - BACKGROUND: Acute kidney injury (AKI) is a dynamic process that can involve inflammatory, hypoxic, and structural changes to the kidney. We evaluated a multiplex panel of markers representing different AKI mechanisms as a tool to provide integrated assessment of AKI status in a single assay. METHODS: Urinary cystatin C (CysC), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1) and interleukin-18 (IL-18) were measured by multiplex electrochemiluminescence immunoassay. Analytical performance was compared to the biological and pathological variation of these markers in human samples. RESULTS: Linearity was established over a 3- to 4-log range for all markers, which spanned the reference ranges established from healthy donors. Imprecision was below 15%, comparing favorably with the observed biological variation of these markers. Control patients fell within donor-derived reference ranges for most markers, but a subset of patients showed CysC and KIM-1 elevations in the absence of documented AKI. CONCLUSION: The multiplex assay is reliable for simultaneous quantitation of CysC, IL-18, KIM-1 and NGAL in human urine, and performs at levels sufficient for clinical application. The observed differences in biological variability and baseline levels suggest that clinical strategies to detect AKI will need to vary depending upon the specific markers used. PMID- 23041214 TI - Shift of high-density lipoprotein size distribution toward large particles in patients with proteinuria. AB - BACKGROUND: The potential atheroprotective role of the different HDL subclasses may depend on the metabolic factors that affect their plasma concentrations. The kidney is supposed to be one of the main catabolic sites for these lipoproteins. However, little is known about the impact of proteinuria on HDL size distribution and HDL structure. The aim of this study is to establish the influence of proteinuria on HDL size distribution and cholesterol plasma concentration of HDL subclasses. METHODS: Forty patients within a range of proteinuria from 0.2 to 10.0 g/g estimated by the urinary protein-to-creatinine ratio and 40 healthy controls were enrolled in the study. HDL subclasses were separated by sequential ultracentrifugation followed by a polyacrylamide gradient electrophoresis; gels were stained enzymatically for cholesterol and with Coomasie blue for proteins. HDL size distribution and plasma concentration of the five HDL subclasses were calculated by optical densitometry. RESULTS: When determined by protein, large HDL2b and HDL2a relative proportions were higher in patients than in control subjects, whereas the contrary was observed for small HDL3b and 3c. Consistently, HDL3a, 3b, and 3c were negatively correlated with proteinuria when data were adjusted by age, gender, body mass index, and blood pressure. Size distribution followed a different pattern when determined by cholesterol, suggesting an abnormal lipid composition that was further supported by a protein-to-cholesterol ratio significantly higher in most of the HDL subclasses in proteinuric patients than in the control group. Moreover, proteinuria statistically explains the HDL2b and HDL3c cholesterol plasma concentrations. CONCLUSIONS: Proteinuria is associated with a shift of HDL size distribution towards large particles and cholesterol-poor HDL subclasses. These results support the idea of a selective loss by the kidney of small HDL in patients with proteinuria; whether these abnormalities reflect an impaired reverse cholesterol transport and an increased risk of coronary heart disease remains to be elucidated. PMID- 23041215 TI - Measurement of dehydroepiandrosterone sulfate (DHEAS) in serum and cerebrospinal fluid by isotope-dilution liquid chromatography tandem mass spectrometry. PMID- 23041216 TI - LC-MS/MS analysis of plasma lyso-Gb3 in Fabry disease. AB - BACKGROUND: Fabry disease is a complex, multisystemic and clinically heterogeneous disease, with elevated excretion of globotriaosylceramide (Gb(3)) and globotriaosylsphingosine (lyso-Gb(3)) accumulating in biological fluids caused by deficiency of the enzyme, lysosomal alpha-galactosidase A. Our aims were to propose a tandem mass spectrometry fragmentation mechanism for lyso Gb(3), to develop and validate a simple, and robust methodology for the measurement of plasma lyso-Gb(3) using LC-MS/MS in large Fabry cohorts and in controls. Response to treatment was also evaluated. METHOD: A solid-phase extraction procedure was used to process plasma samples. The 1-beta-D glucosylsphingosine (GSG) internal standard was chosen for its commercial availability. A liquid chromatography method was devised to allow the co-elution of the GSG internal standard with lyso-Gb(3), thus compensating for system variability and reducing the matrix effect. A multiple reaction monitoring method was developed, working in positive electrospray ionization. RESULTS: The validation of the method provided good accuracy and precision: intraday and interday biases of less than 8% and 5%, respectively, and intraday and interday CVs of <12% and 7%, respectively. Limit of detection was 0.7 nmol/l and limit of quantification was 2.5 nmol/l. Plasma samples were stable for up to 6h at room temperature, 48 h at 4 degrees C, and 20 weeks at -20 degrees C. Regarding untreated Fabry patients, the mean lyso-Gb(3) concentrations were 170 nmol/l for males and 9.7 nmol/l for females, and for treated patients, 40.2 nmol/l for males and 7.5 nmol/l for females. CONCLUSION: A robust LC-MS/MS methodology is presented for plasma lyso-Gb(3) quantification. PMID- 23041217 TI - Circulating microparticles in severe preeclampsia. AB - The present study aimed to evaluate microparticles (MPs) from different sources in women with severe preeclampsia (PE) compared with normotensive pregnant women and non-pregnant women. This case-control study evaluated 28 pregnant women with severe PE, 30 normotensive pregnant women, and 29 non-pregnant women. MPs from neutrophils, endothelial cells, monocytes, platelets, leukocytes, erythrocytes, and syncytiotrophoblast were evaluated using flow cytometry. A higher total number of MPs were observed in women with severe PE compared with normotensive pregnant women and non-pregnant women (P=0.004 and P=0.001, respectively). MPs derived from erythrocytes were increased in women with severe PE compared with normotensive pregnant women (P=0.002). A trend towards association was observed between platelet count and the number of MPs derived from platelets (P=0.09) in severe PE group. A positive correlation was also found between the number of endothelial cell-derived MPs and the number of platelet-derived MPs, leukocyte derived MPs, neutrophil-derived MPs, and lymphocyte-derived MPs (P<0.05) in severe PE pregnant women. MP counts can be increased in severe PE, and erythrocyte and endothelial cell-derived MPs seem to be associated to severe PE. PMID- 23041218 TI - Age-related changes in serum levels of insulin-like growth factor-II and its binding proteins correlate with calcaneal bone mineral density among post menopausal South-Indian women. AB - BACKGROUND: Insulin-like growth factor (IGF) system components are important regulators of bone metabolism, which have a predominant role in determining bone mineral density (BMD). While the serum levels of IGF-I are regulated by various systemic hormones and growth factors, IGF-II levels reflect the skeletal production relative to physical activity, mechanical loading, aging, race etc. Though various studies have been carried out among women of different ethnic groups to understand the relationship between serum levels of IGF-II and BMD, the results seem to be quite inconclusive. METHODS: We evaluated the same, recruiting South-Indian women who engage themselves in a wide variety of physical activities pertaining to their profession and life style. RESULTS: Serum levels of IGF-II and IGF binding protein (IGFBP)-3 showed positive correlation with calcaneal BMD, whereas IGFBP-4 showed negative correlation. These IGF system components exhibited similar correlations with serum bone formation markers and opposite trend with bone resorption marker. While both IGF-II and IGFBP-3 levels were observed to be decreased with aging and menopause, IGFBP-4 levels increased. CONCLUSIONS: The alterations in serum levels of IGF-II and its binding proteins due to aging and menopause could be some of the major contributors of decreased calcaneal BMD observed among elderly women. PMID- 23041219 TI - Site specific/targeted delivery of gemcitabine through anisamide anchored chitosan/poly ethylene glycol nanoparticles: an improved understanding of lung cancer therapeutic intervention. AB - Gemcitabine (2', 2'-difluorodeoxycytidine) is a deoxycytidine analog with significant antitumor activity against variety of cancers including non-small cell lung cancer. However, rapid metabolism and shorter half-life of drug mandate higher dose and frequent dosing schedule which subsequently results into higher toxicity. Therefore, there is a need to design a vector which can reduce the burden of frequent dosing and higher toxicity associated with the use of gemcitabine. In this study, we investigated the possibility of improving the targeting potential by employing the surface modification on Chitosan/poly(ethylene glycol) (CTS/PEG) Nanoparticles. We demonstrate formulation and characterization of chitosan/poly(ethylene glycol)-anisamide (CTS/PEG-AA) and compared its efficiency with CTS/PEG and free gemcitabine. Our results reveal its sizeable compatibility, comparatively less organ toxicity and higher antitumor activity in vitro as well as in vivo. This wealth of information surfaces the potential of CTS/PEG-AA nanoparticles as a potent carrier for drug delivery. In brief, this novel carrier opens new avenues for drug delivery which better meets the needs of anticancer research. PMID- 23041220 TI - How to ventilate term babies. AB - Infants born at term frequently require mechanical ventilation and suffer significant mortality and morbidity. Yet, there have been few randomised trials (RCTs) exclusively of term born infants and when term born infants have been included in studies, a sub-analysis of their results has rarely been undertaken. The limited evidence demonstrates in term born infants that there are no benefits in using rates >60bpm during conventional mechanical ventilation (CMV) or using synchronous intermittent mandatory ventilation. Pressure support ventilation may reduce their work of breathing (WOB). During volume targeted ventilation, a volume targeted (VT) level of 6mls/kg reduces the WOB compared to a lower level or no VT. High frequency oscillatory ventilation in infants born at or near term with severe respiratory failure does not reduce mortality, oxygen dependency at 28 days or intracranial haemorrhage. RCTs with long term outcome are required to determine the optimum ventilatory modes in term born infants. PMID- 23041221 TI - Urine gonadotropin and estradiol levels in female very-low-birth-weight infants. AB - BACKGROUND: The postnatal activation of the hypothalamic-pituitary-gonadal axis is more exaggerated in preterm than in full-term born infants and may be important for future reproductive function. AIM: The objective of this study was to investigate the postnatal activation of the hypothalamic-pituitary-gonadal axis in female very-low-birth-weight infants. STUDY DESIGN: We performed serial measurements of gonadotropin and estradiol levels in urine samples of female very low-birth-weight infants collected at 1 and 4weeks postnatal age, at 32weeks postmenstrual age, at expected date of delivery and at the corrected age of three and six months. SUBJECTS: Twenty-two very-low-birth-weight infants (gestational age 25.4-30.1weeks), participating in the Neonatal Insulin Replacement Therapy in Europe trial, were included in this study. OUTCOME MEASURES: Gonadotropin and estradiol levels were measured in serial urine samples. RESULTS: Longitudinal analysis shows that after birth FSH and LH levels increase until 32weeks postmenstrual age (4weeks postnatal age) and then decrease until 3months corrected age (26weeks postnatal age). Estradiol levels decrease from 28weeks postmenstrual age (1week postnatal age) until 6months corrected age (39weeks postnatal age). CONCLUSIONS: Serial urine sampling for measurement of gonadotropin and estradiol levels provides an accurate description of the postnatal activation of the hypothalamic-pituitary-gonadal axis in very-low-birth weight girls. Levels of FSH and LH peak at a mean postmenstrual age of 32weeks (postnatal age of 4weeks) whereas estradiol levels are highest shortly after birth. PMID- 23041222 TI - Transcription factors expressed in embryonic and adult olfactory bulb neural stem cells reveal distinct proliferation, differentiation and epigenetic control. AB - TF genomic markers associated with neurogenesis, proliferation, differentiation, and epigenetic control in human embryonic neural stem cells (hENSC(, and adult human olfactory bulb neural stem cells (OBNSC) were studied by immunohistochemistry (IHC) and DNA microarray. The biological impact of TF gene changes in the examined cell types was estimated using DAVID to specify a different GO class and signaling pathway based on KEGG database. Eleven, and twenty eight TF genes were up-regulated (fold change<=2-39) in OBNSC, and hENSC respectively. KEGG pathway analysis for the up-regulated TF genes revealed significant enrichments for the basal transcription factor pathway, and Notch signaling pathway in OBNSCs, and hENSCs, respectively. Immunofluorescence analysis revealed a significantly greater number of beta-tubulin III (TUBB3), MAP, glial fibrillary acidic protein (GFAP), and O4 in hENSC when compared to those in OBNSC. Furthermore, the expression of epigenetic-related TF-genes SMARCC1, TAF12, and UHRF1 increased significantly in OBNSC when compared with hENSC. PMID- 23041223 TI - Inhibitory effects of salvianolic acid B on CCl(4)-induced hepatic fibrosis through regulating NF-kappaB/IkappaBalpha signaling. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hepatic fibrosis, a precursor of liver cirrhosis, is a consequence of severe liver damage that occurs in many patients with chronic liver diseases. Salvianolic acid B (SA-B) is one of water soluble compounds derived from Salvia miltiorrhiza Bunge (Danshen in Chinese) widely used for chronic liver diseases. In this study we investigated the protective effects of SA-B on CCl(4)-induced hepatic fibrosis. MATERIALS AND METHODS: Hepatic fibrosis in rats was induced by carbon tetrachloride (CCl(4)). Rats were divided into four groups, including normal controls (N group), model (M group), low SA-B of 10mg/kg body weight (L group), or high SA-B of 20mg/kg body weight (H group). After 6 weeks, macroscopic features of the liver and weight ratio of liver to body were measured. Liver fibrosis of the rats was evaluated by HE and Massion staining. Activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were checked with automated biochemistry analyzer. Serum levels of hyaluronic acid (HA), type IV collagen (IV-C), Laminin (LN) and procollagen III peptide (PIIIP) were detected by radioimmunoassay (RIA). The expression of NF-kappaB and IkappaBalpha was detected by western blotting. RESULTS: SA-B was shown to reduce CCl(4)-induced hepatic fibrosis in rats. The serum levels of ALT, AST, and TBIL were significantly lower in the SA-B treatment groups than in the M group. Compared the M group, the serum levels of HA, LN, IV C and PIIIP were decreased markedly after treatment with SA-B, especially in the H group. Treatment with SA-B at 10-20mg/kg (L and N groups, respectively) dose dependently decreased the expression of NF-kappaB in the nucleolus and increased the expression levels of NF-kappaB and IkappaBalpha protein in the cytoplasm compared to that of the M group. CONCLUSIONS: This study reveals that SA-B could prevent the progression of liver angiogenesis and alleviate liver fibrosis possibly by regulating the expression of NF-kappaB and IkappaBalpha. PMID- 23041224 TI - Ching-fang-pai-tu-san inhibits the release of influenza virus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ching-fang-pai-tu-san (CFPTS) is a Chinese herbal decoction that is used as a cure for the common cold, fever, headache, and poor circulation. However, no previous studies have investigated the mode of action of CFPTS against influenza virus infections. To investigate the antiviral mechanism of CFPTS, we examined viral entry, transcription, translation, viral glycoprotein hemagglutinin (HA) transport, and budding of the influenza virus. MATERIALS AND METHODS: The antiviral activity of nontoxic concentrations of CFPTS against influenza virus A/WSN/33 was examined by assaying (neutralization assay) its inhibition of the virus-induced cytopathic effects. The mode of CFPTS action was first examined with a time-of-addition assay of synchronized infections, followed by monitoring HA transport by immunofluorescence microscopy. Viral endocytosis was evaluated with attachment and penetration assays. The inhibition of viral replication was measured by quantitative real-time PCR, immunoblotting, and immunofluorescence microscopy. We also performed assays related to the inhibition of viral entry, such as neuraminidase activity and hemagglutinin activity assays. RESULTS: Based on the inhibition of the virus-induced cytopathic effect in Madin Darby canine kidney cells, the EC(50) of CFPTS was about 1.44 +/- 0.22 mg/mL against influenza virus A/WSN/33. CFPTS displayed a broad spectrum of inhibitory activities against different strains of influenza A virus, as well as some enteroviruses. However, this extract proved less effective against clinical oseltamivir-resistant strains and influenza B viruses. CFPTS did not suppress viral RNA or protein synthesis. According to a time-of-addition assay, the antiviral mechanism of CFPTS may involve viral budding or intracellular viral glycoprotein transport. A plaque reduction assay showed that CFPTS reduced both the plaque size and plaque quantity. The intracellular transport of viral glycoprotein hemagglutinin was blocked by CFPTS by immunofluorescence microscopic analysis. Thus, it is possible that the antiviral mechanism of CFPTS might inhibit the assembly of progeny virions and/or their subsequent release. CONCLUSIONS: Our results give scientific support to the use of CFPTS in the treatment of influenza virus infections. CFPTS has potential utility in the management of seasonal pandemics of influenza virus infections, like other clinically available drugs. PMID- 23041225 TI - Outcome of peripheral facial palsy in children - a catamnestic study. AB - BACKGROUND: Even though the etiologies, therapies and prognoses of acute peripheral facial palsy (PFP) differ among children and adults, not many studies focus on children. METHODS: We performed a retrospective study of 84 children, aged 10 months to 16 3/12 years, who were seen at the Children's Hospital of Eastern Switzerland between 1998 and 2007 due to PFP. Data about etiology, diagnostics and therapy were gathered from medical files, the outcome by questionnaires. Among 9 patients with residual symptoms, 6 returned for a follow up visit and the results were documented with photographs. Recovery was graded by the House-Brackmann scale. RESULTS: There were 83 unilateral and 1 bilateral case(s) of FP; neuroborreliosis (NB) causing 26 cases (31.0%), other infections 6 cases (7.1%) and toxicity of methotrexat 1 case (1.2%); 51 cases (60.7%) were classified as idiopathic (IPFP). Between the months June and November, the number of cases with NB rose to 53.3%, while there was no case between the months of January and April. Only 4 patients with IPFP received steroids. 75 patients (89.3%) recovered completely (HB-Grade I). 9 patients (10.7%) showed slight residual symptoms (HB-Grade II). Of these, 6 had IPFP, 1 had NB and 2 had otitis media (OM). DISCUSSION: Almost a third of all palsies were caused by NB; during summer and fall, NB accounted for over half the cases. Patients with borreliosis showed a higher recovery rate than those with OM or IPFP. Almost 90% of the patients investigated recovered completely, even without steroid treatment. Residual symptoms were slight. PMID- 23041226 TI - High intake of whole grains and beans pattern is inversely associated with insulin resistance in healthy Korean adult population. AB - We investigated the association between dietary patterns and insulin resistance in the 3871 healthy Korean adults from the 2007 to 2008 Korea National Health and Nutrition Examination Survey. The whole grains and beans pattern was associated with lower prevalence of insulin resistance (OR for highest quintile=0.80, 95% CI=0.61-1.03, P for trend=0.013). PMID- 23041227 TI - Accuracy of continuous glucose monitoring system during exercise in type 2 diabetes. AB - The concordance of continuous glucose monitoring system (CGMS) and finger-stick blood glucose (FSBG) was assessed in patients with type 2 diabetes during daily activities and two different exercise sessions. Agreement between FSBG and CGMS becomes weaker during exercise, but more than 90% of the CGMS readings are within acceptable range. PMID- 23041228 TI - Pim kinases in cancer: diagnostic, prognostic and treatment opportunities. AB - PIM proteins belong to a family of ser/thr kinases composed of 3 members, PIM1, PIM2 and PIM3, with greatly overlapping functions. PIM kinases are mainly responsible for cell cycle regulation, antiapoptotic activity and the homing and migration of receptor tyrosine kinases mediated via the JAK/STAT pathway. PIM kinases have been found to be upregulated in many hematological malignancies and solid tumors. Although these kinases have been described as weak oncogenes, they are heavily targeted for anticancer drug discovery. The present review summarizes the discoveries made to date regarding PIM kinases as driving oncogenes in the process of tumorigenesis and their validation as drug targets. PMID- 23041229 TI - 2-Deoxy-D-glucose cooperates with arsenic trioxide to induce apoptosis in leukemia cells: involvement of IGF-1R-regulated Akt/mTOR, MEK/ERK and LKB-1/AMPK signaling pathways. AB - While the anti-tumor efficacy of 2-deoxy-D-glucose (2-DG) is normally low in monotherapy, it may represent a valuable radio- and chemo-sensitizing agent. We here demonstrate that 2-10 mM 2-DG cooperates with arsenic trioxide (ATO) and other antitumor drugs to induce apoptosis in human myeloid leukemia cell lines. Using ATO and HL60 as drug and cell models, respectively, we observed that 2 DG/ATO combination activates the mitochondrial apoptotic pathway, as indicated by Bid-, and Bax-regulated cytochrome c and Omi/HtrA2 release, XIAP down-regulation, and caspase-9/-3 pathway activation. 2-DG neither causes oxidative stress nor increases ATO uptake, but causes inner mitochondria membrane permeabilization as well as moderate ATP depletion, which nevertheless do not satisfactorily explain the pro-apoptotic response. Surprisingly 2-DG causes cell line-specific decrease in LKB-1/AMPK phosphorylation/activation, and also causes Akt/mTOR/p70S6K and MEK/ERK activation, which is prevented by co-treatment with ATO. The use of kinase-specific pharmacologic inhibitors and/or siRNAs reveals that apoptosis is facilitated by AMPK inactivation and restrained by Akt and ERK activation, and that Akt and ERK activation mediates AMPK inhibition. Finally, 2-DG stimulates IGF-1R phosphorylation/activation, and co-treatment with IGF-1R inhibitor prevents 2-DG effects on Akt, ERK and AMPK, and facilitates 2-DG-provoked apoptosis. In summary 2-DG elicits IGF-1R-mediated AMPK inactivation and Akt and ERK activation, which facilitates or restrain apoptosis, respectively. 2-DG provoked AMPK inactivation increases the apoptotic efficacy of ATO, while in turn ATO-provoked Akt and ERK inactivation may increase the efficacy of 2-DG as anti tumor drug. PMID- 23041230 TI - Rat CYP24A1 acts on 20-hydroxyvitamin D(3) producing hydroxylated products with increased biological activity. AB - 20-Hydroxyvitamin D(3) (20(OH)D(3)), the major product of CYP11A1 action on vitamin D(3), is biologically active and is produced in vivo. As well as potentially having important physiological actions, it is of interest as a therapeutic agent due to its lack of calcemic activity. In the current study we have examined the ability of CYP24A1, the enzyme that inactivates 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), to metabolize 20(OH)D(3). Rat CYP24A1 was expressed in Escherichia coli, purified by Ni-affinity chromatography and assayed with substrates incorporated into phospholipid vesicles which served as a model of the inner mitochondrial membrane. In this system CYP24A1 metabolized 1,25(OH)(2)D(3) with a catalytic efficiency 1.4-fold higher than that seen for 25 hydroxyvitamin D(3) (25(OH)D(3)). CYP24A1 hydroxylated 20(OH)D(3) to several dihydroxy-derivatives with the major two identified by NMR as 20,24 dihydroxyvitamin D(3) (20,24(OH)(2)D(3)) and 20,25-dihydroxyvitamin D(3) (20,25(OH)(2)D(3)). The catalytic efficiency of CYP24A1 for 20(OH)D(3) metabolism was more than 10-fold lower than for either 25(OH)D(3) or 1,25(OH)(2)D(3) and no secondary metabolites were produced. The two major products, 20,24(OH)(2)D(3) and 20,25(OH)(2)D(3), caused significantly greater inhibition of colony formation by SKMEL-188 melanoma cells than either 1,25(OH)(2)D(3) or the parent 20(OH)D(3), showing that CYP24A1 plays an activating, rather than an inactivating role on 20(OH)D(3). PMID- 23041231 TI - The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II. AB - Dovitinib (TKI258/CHIR258) is a multi-kinase inhibitor in phase III development for the treatment of several cancers. Dovitinib is a benzimidazole-quinolinone compound that structurally resembles the bisbenzimidazole minor groove binding dye Hoechst 33258. Dovitinib bound to DNA as shown by its ability to increase the DNA melting temperature and by increases in its fluorescence spectrum that occurred upon the addition of DNA. Molecular modeling studies of the docking of dovitinib into an X-ray structure of a Hoechst 33258-DNA complex showed that dovitinib could reasonably be accommodated in the DNA minor groove. Because DNA binders are often topoisomerase I (EC 5.99.1.2) and topoisomerase II (EC 5.99.1.3) inhibitors, the ability of dovitinib to inhibit these DNA processing enzymes was also investigated. Dovitinib inhibited the catalytic decatenation activity of topoisomerase IIalpha. It also inhibited the DNA-independent ATPase activity of yeast topoisomerase II which suggested that it interacted with the ATP binding site. Using isolated human topoisomerase IIalpha, dovitinib stabilized the enzyme-cleavage complex and acted as a topoisomerase IIalpha poison. Dovitinib was also found to be a cellular topoisomerase II poison in human leukemia K562 cells and induced double-strand DNA breaks in K562 cells as evidenced by increased phosphorylation of H2AX. Finally, dovitinib inhibited the topoisomerase I-catalyzed relaxation of plasmid DNA and acted as a cellular topoisomerase I poison. In conclusion, the cell growth inhibitory activity and the anticancer activity of dovitinib may result not only from its ability to inhibit multiple kinases, but also, in part, from its ability to target topoisomerase I and topoisomerase II. PMID- 23041232 TI - Targeting peroxisome proliferator-activated receptor-beta/delta in colon cancer: how to aim? AB - Peroxisome proliferator-activated receptor-beta/delta (PPARdelta) is a ubiquitously expressed, ligand-activated transcriptional factor that performs diverse critical functions in normal cells (e.g., fatty acid metabolism, obesity, apoptosis, and inflammation). Various studies in humans have found that PPARdelta is upregulated in primary colorectal cancers; however, these findings have been challenged by those of other reports. Similarly, various in vitro and in vivo mechanistic pre-clinical models have yielded data demonstrating that PPARdelta promotes colonic tumorigenesis, but other models have yielded data that contradicts this notion. Definitive studies are therefore needed to establish the exact role of PPARdelta in human colorectal tumorigenesis and to provide a theoretical basis for PPARdelta therapeutic targeting. PMID- 23041234 TI - Reduced neutrophil superoxide production among healthy older adults in response to acute psychological stress. AB - Ageing is associated with higher morbidity and mortality, and declining immune function, termed immunesenescence. The present study examined the effects of an acute laboratory psychological stress task on innate immunity, specifically neutrophil function, among older adults. The two functional assays used were phagocytosis of Escherichia coli and stimulated superoxide production. Participants were 17 (11 female) older adults (mean age 75.7, SD=7.06 years). Blood samples to determine neutrophil function by flow cytometry were taken at the end of resting baseline, during an acute stress task and during recovery. The stress task was an 8-minute time-pressured mental arithmetic challenge with social evaluation. There was a significant reduction in neutrophil superoxide production, p=.017, eta(2)(p)=.240, associated with the stress task relative to baseline, but no effect on phagocytosis. The results of this study could contribute to explaining the increased risk of infection in older adults, particularly those subject to frequent stress exposures. Future research is needed to explore the underlying mechanisms of acute stress effects on human neutrophil function in older adults in greater detail. PMID- 23041233 TI - Current concepts for injury prevention in athletes after anterior cruciate ligament reconstruction. AB - Ligament reconstruction is the current standard of care for active patients with an anterior cruciate ligament (ACL) rupture. Although the majority of ACL reconstruction (ACLR) surgeries successfully restore the mechanical stability of the injured knee, postsurgical outcomes remain widely varied. Less than half of athletes who undergo ACLR return to sport within the first year after surgery, and it is estimated that approximately 1 in 4 to 1 in 5 young, active athletes who undergo ACLR will go on to a second knee injury. The outcomes after a second knee injury and surgery are significantly less favorable than outcomes after primary injuries. As advances in graft reconstruction and fixation techniques have improved to consistently restore passive joint stability to the preinjury level, successful return to sport after ACLR appears to be predicated on numerous postsurgical factors. Importantly, a secondary ACL injury is most strongly related to modifiable postsurgical risk factors. Biomechanical abnormalities and movement asymmetries, which are more prevalent in this cohort than previously hypothesized, can persist despite high levels of functional performance, and also represent biomechanical and neuromuscular control deficits and imbalances that are strongly associated with secondary injury incidence. Decreased neuromuscular control and high-risk movement biomechanics, which appear to be heavily influenced by abnormal trunk and lower extremity movement patterns, not only predict first knee injury risk but also reinjury risk. These seminal findings indicate that abnormal movement biomechanics and neuromuscular control profiles are likely both residual to, and exacerbated by, the initial injury. Evidence based medicine (EBM) strategies should be used to develop effective, efficacious interventions targeted to these impairments to optimize the safe return to high risk activity. In this Current Concepts article, the authors present the latest evidence related to risk factors associated with ligament failure or a secondary (contralateral) injury in athletes who return to sport after ACLR. From these data, they propose an EBM paradigm shift in postoperative rehabilitation and return-to-sport training after ACLR that is focused on the resolution of neuromuscular deficits that commonly persist after surgical reconstruction and standard rehabilitation of athletes. PMID- 23041235 TI - Mismatch negativity (MMN) to successive deviants within one hierarchically structured auditory object. AB - The Mismatch Negativity (MMN), a component of the event-related potential (ERP), is elicited by a deviant following a series of standard stimuli. The present study addressed the question whether two deviants occurring successively in one hierarchically organized auditory object would elicit separate MMN responses. An example of such an object is a VC syllable (vowel+consonant). In a passive oddball protocol, the syllables [ox] and [E?] were presented both as standards and deviants so that both phonemes, the vowel and the consonant, changed in the respective deviant. Two negative responses were found in the deviant-minus standard difference waves. Due to the latencies these effects could not be interpreted as separate MMN responses to the phonemic changes. Instead, the first effect (108ms) was taken as an N1 modulation whereas the second negativity (168ms) was interpreted as an MMN mainly reflecting the change of the initial vowel. Furthermore, the present data were statistically compared with related results from Steinberg et al. (2010a, b) obtained partly from the same stimuli presented in oddball blocks with simple mono-phonemic deviances due to changing vowels. Higher MMN amplitudes were found for the syllable [E?] in the present data compared to those previous findings. Although this difference was only present for one of the stimulus syllables, it is discussed as a possible indicator of an anticipatory MMN enhancement due to the predictability of the second change in the deviant of the present experiment. PMID- 23041236 TI - From genes to stroke subtypes. PMID- 23041237 TI - Microcystic macular oedema, thickness of the inner nuclear layer of the retina, and disease characteristics in multiple sclerosis: a retrospective study. AB - BACKGROUND: Microcystic macular oedema (MMO) of the retinal inner nuclear layer (INL) has been identified in patients with multiple sclerosis (MS) by use of optical coherence tomography (OCT). We aimed to determine whether MMO of the INL, and increased thickness of the INL are associated with disease activity or disability progression. METHODS: This retrospective study was done at the Johns Hopkins Hospital (Baltimore, MD, USA), between September, 2008, and March, 2012. Patients with MS and healthy controls underwent serial OCT scans and clinical assessments including visual function. OCT scanning, including automated intraretinal layer segmentation, yielded thicknesses of the retinal nerve fibre layer, the ganglion cell layer plus inner plexiform layer, the INL plus outer plexiform layer (the combined thickness of these layers was used as a surrogate measure of INL thickness), and the outer nuclear layer. Patients with MS also underwent annual brain MRI scans. Disability scores were compared with the Wilcoxon rank-sum test. Mixed-effects linear regression was used to compare OCT measures and letter-acuity scores. Logistic regression was used to examine the relations of baseline OCT thicknesses with clinical and radiological parameters. FINDINGS: 164 patients with MS and 60 healthy controls were assessed. Mean follow up was 25.8 months (SD 9.1) for patients with MS and 22.4 months (11.4) for healthy controls. Ten (6%) patients with MS had MMO during at least one study visit; MMO was visible at baseline in four of these patients. Healthy controls did not have MMO. Patients with MS and MMO had higher baseline MS severity scores (median 5.93 [range 2.44-8.91]) than those who did not have MMO at any time during the study (151 patients; 3.81 [0.13-9.47]; p=0.032), although expanded disability status scale (EDSS) scores were not significantly different (5.2 [1.0 6.5] for patients with MS and MMO vs 2.5 [0.0-8.0] for those without MMO; p=0.097). The eyes of patients with MS and MMO (12 eyes) versus those without MMO (302 eyes) had lower letter-acuity scores (100% contrast, p=0.017; 2.5% contrast, p=0.031; 1.25% contrast, p=0.014), and increased INL thicknesses (p=0.003) at baseline. Increased baseline INL thickness in patients with MS was associated with the development of contrast-enhancing lesions (p=0.007), new T2 lesions (p=0.015), EDSS progression (p=0.034), and relapses in patients with relapsing remitting MS (p=0.008) during the study. MMO was not associated with disease activity during follow-up. INTERPRETATION: Increased INL thickness on OCT is associated with disease activity in MS. If this finding is confirmed, INL thickness could be a useful predictor of disease progression in patients with MS. FUNDING: National Multiple Sclerosis Society, National Eye Institute, Braxton Debbie Angela Dillon and Skip Donor Advisor Fund. PMID- 23041238 TI - Microcystic macular oedema in MS: T2 lesion or black hole? PMID- 23041240 TI - Patients newly diagnosed with clinical type 2 diabetes mellitus but presenting with HbA1c within normal range: 19-year mortality and clinical outcomes. AB - AIMS: To investigate whether long-term mortality or clinical outcomes differed between patients diagnosed with type 2 diabetes mellitus and presenting with HbA1c within or above normal range at time of diagnosis. METHODS: Data were from a population-based sample of 1136 individuals with newly diagnosed type 2 diabetes mellitus. The diagnosis was confirmed with a single fasting whole blood/plasma glucose >=7.0/8.0mmol/l. The median time from day of diagnosis until end of follow up was 18.8years. Patients were grouped according to normal HbA1c and elevated HbA1c at diagnosis. The effect of elevated HbA1c on a number of clinical outcomes and all-cause mortality was assessed in Cox regression models. RESULTS: At diagnosis, 97 patients (8.5%) had an HbA1c level within normal range. Age (mean (SD)) at diagnosis was 64.5 (11.5) years. Both unadjusted and adjusted hazard ratios for the effect of HbA1c on mortality and other outcomes were not statistically significant. CONCLUSIONS: Patients who are diagnosed with type 2 diabetes mellitus by means of elevated fasting whole blood/plasma glucose but have HbA1c within reference range at diagnosis do not seem to have a relatively benign long-term clinical course. Therefore new diagnostic procedures should preferably be able to identify these individuals. PMID- 23041241 TI - Synthetic multicellularity. AB - The ability to synthesize biological constructs on the scale of the organisms we observe unaided is probably one of the more outlandish, yet recurring, dreams humans have had since they began to modify genes. This review brings together recent developments in synthetic biology, cell and developmental biology, computation, and technological development to provide context and direction for the engineering of rudimentary, autonomous multicellular ensembles. PMID- 23041242 TI - Apicoplast triose phosphate transporter (TPT) gene knockout is lethal for Plasmodium. AB - The C3, C5, C6 type sugar phosphate transporters bring sugars inside apicoplast, thus providing energy, reducing power and elements like carbon to apicoplast. Plasmodium berghei has two C3 type sugar phosphate transporters in the membrane of apicoplast: triose phosphate transporter (TPT) and phosphoenolpyruvate transporter (PPT). Here we report that P. berghei TPT knockout parasites failed to survive. However, PPT knockout parasite behaved similar to the wild type in the blood stages. The absence of PPT in other life stages, leads to defects in the development of parasite and was required at both mosquito as well as liver stages. This study also underlines the essentiality of triose transporters for apicoplast and its downstream pathways. PMID- 23041239 TI - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. AB - BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2.8*10(-16)) and ZFHX3 (p=2.28*10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32*10(-5)) and HDAC9 (p=2.03*10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5*10(-6). However, we were unable to replicate any of these novel associations in the replication cohort. INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS). PMID- 23041243 TI - Process analytical tools for monitoring, understanding, and control of pharmaceutical fluidized bed granulation: A review. AB - Fluidized bed granulation is a widely applied wet granulation technique in the pharmaceutical industry to produce solid dosage forms. The process involves the spraying of a binder liquid onto fluidizing powder particles. As a result, the (wetted) particles collide with each other and form larger permanent aggregates (granules). After spraying the required amount of granulation liquid, the wet granules are rapidly dried in the fluid bed granulator. Since the FDA launched its Process Analytical Technology initiative (and even before), a wide range of analytical process sensors has been used for real-time monitoring and control of fluid bed granulation processes. By applying various data analysis techniques to the multitude of data collected from the process analyzers implemented in fluid bed granulators, a deeper understanding of the process has been achieved. This review gives an overview of the process analytical technologies used during fluid bed granulation to monitor and control the process. The fundamentals of the mechanisms contributing to wet granule growth and the characteristics of fluid bed granulation processing are briefly discussed. This is followed by a detailed overview of the in-line applied process analyzers, contributing to improved fluid bed granulation understanding, modeling, control, and endpoint detection. Analysis and modeling tools enabling the extraction of the relevant information from the complex data collected during granulation and the control of the process are highlighted. PMID- 23041244 TI - Reference range of thyroid function (FT3, FT4 and TSH) among Indian adults. AB - OBJECTIVES: To generate thyroid hormone reference norms using electro chemiluminescence technique. DESIGN AND METHODS: Cross sectional study on apparently normal 4349 Delhi adults (18-86 years). Predetermined exclusion criteria (goiter, hypoechogenicity or nodularity on ultrasound, elevated anti thyroid peroxidase antibody, hypo or hyperthyroidism and family history of thyroid dysfunction) excluded 2433 subjects leaving 1916 (916 males and 1000 females) as the reference population. RESULTS: Mean age and BMI of the reference population were 41.2 +/- 18.1 years and 24.5 +/- 4.4 kg/m(2) respectively. Median urinary iodine excretion was 233.6 MUg/L (79-458;3rd-97th centile). The population was categorized into various age groups (18-30, 31-40, 41-50, 51-60, 61-70 and >= 70 years). Overall FT3 and FT4 values in the reference population irrespective of age, ranged from 2.4-8.8 (mean 4.6 +/- 0.9) pmol/L and 10.1-24.8 (mean 15.40 +/- 2.0) pmol/L, respectively. Mean TSH value in the reference population was 2.2 +/- 0.9 mIU/L which was significantly lower than that of total population (3.8 +/- 6.1; p<0.001). CONCLUSION: FT3 values were observed to be significantly higher in men than women (p=0.001). The centiles (3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th and 97th) of FT3, FT4 and TSH were derived for reference purposes in Indian adults. This community based study in Indian adults has established mean reference intervals for FT3, FT4 and TSH for different age groups for both sexes separately using strict exclusion criteria. These can be used as reference norms for Indian adults. PMID- 23041245 TI - Day-to-day variation of urinary NGAL and rational for creatinine correction. AB - OBJECTIVES: The number of clinical studies evaluating the new tubular biomarker urinary neutrophil gelatinase-associated lipocalin (U-NGAL) in urine are increasing. There is no consensus whether absolute U-NGAL concentrations or urinary NGAL/creatinine (U-NGAL/Cr) ratios should be used when chronic tubular dysfunction is studied. The aim was to study the biological variation of U-NGAL in healthy subjects and the rational for urinary creatinine (U-Cr) correction in two different study samples. DESIGN AND METHODS: To study biological variation of U-NGAL and U-NGAL/Cr ratio and the association between U-NGAL and U-Cr in healthy subjects 13 young males and females (median age 29 years) collected morning urine in 10 consecutive days. Additionally, a random subsample of 400 males from a population-based cohort (aged 78 years) collecting 24-hour urine during 1 day was studied. RESULTS: The calculated biological variation for absolute U-NGAL was 27% and for U-NGAL/Cr ratio, 101%. Absolute U-NGAL increased linearly with U-Cr concentration (the theoretical basis for creatinine adjustment) in the older males (R=0.19, P<0.001) and with borderline significance in the young adults (R=0.16, P=0.08). The U-NGAL/Cr ratio was, however, negatively associated with creatinine in the older males (R=-0.14, P<0.01) and in the young adults (R=-0.16, P=0.07) indicating a slight "overadjustment." CONCLUSIONS: The study provides some support for the use of U-NGAL/Cr ratio but the rather large biological variation and risk of possible overadjustment need to be considered. Both absolute U-NGAL and U-NGAL/Cr ratios should be reported for the estimation of chronic tubular dysfunction. PMID- 23041246 TI - Assessment of the diagnostic performances of IgA heavy and light chain pairs in patients with IgA monoclonal gammopathy. AB - OBJECTIVES: Preliminary results of the IgA HevyliteTM assay including the establishment of the 95% reference interval and assessment of the specificity and sensitivity in different populations are reported. DESIGN AND METHODS: The concentrations of IgA heavy and light chains (HLC) enabling to determine an IgAkappa/IgAlambda ratio were quantified in 119 apparently healthy individuals to generate 95% reference intervals. The specificity of this assay was assessed in 48 patients with an isolated polyclonal IgA increase. In a retrospective analysis of 68 patients with a monoclonal component type IgA (MC-IgA) identified by serum immunofixation (IFE), IgA HLC ratio values were compared with known results for serum protein electrophoresis (SPE) and free light chain (FLC) ratios. RESULTS: The 95% reference range obtained in 119 controls (0.91-2.04) was close to that quoted by the manufacturer (0.80-2.04). Eight of the 48 patients (16.7%) with a polyclonal IgA increase had an IgA HLC ratio above the upper limit of the 95% reference interval. The IgA HLC ratio identified 65 (95.6%) among 68 patients with MC-IgA identified on the basis of IFE. For 34 of these patients (50%), MC IgA was not detected by SPE due to its co-migration with alpha-2 or beta globulins. CONCLUSIONS: Compared with serum IFE, the IgA HLC ratio has a sensitivity of 95.6%. Further studies are needed to assess the specificity of the IgA HLC ratio in patients with an isolated polyclonal increase of serum IgA. PMID- 23041247 TI - Inflammatory cystic odontogenic lesions. PMID- 23041248 TI - Stress, asthma, and respiratory infections: pathways involving airway immunology and microbial endocrinology. AB - Stress and infections have long been independently associated with asthma pathogenesis and exacerbation. Prior research has focused on the effect of psychological stress on Th cells with particular relevance to atopic asthma. In this review, we propose new perspectives that integrate the role of infection in the relationship between psychological stress and asthma. We highlight the essential role of the mucosal epithelia of the airways in understanding the interaction between infections and the stress-asthma relationship. In addition, we review findings suggesting that psychological stress not only modulates immune processes, but also the pathogenic qualities of bacteria, with implications for the pathogenesis and exacerbation asthma. PMID- 23041249 TI - Technical aspects and inter-laboratory variability in native peptide profiling: the CE-MS experience. AB - Mass spectrometry platforms have attracted a lot of interest in the last 2 decades as profiling tools for native peptides and proteins with clinical potential. However, limitations associated with reproducibility and analytical robustness, especially pronounced with the initial SELDI systems, hindered the application of such platforms in biomarker qualification and clinical implementation. The scope of this article is to give a short overview on data available on performance and on analytical robustness of the different platforms for peptide profiling. Using the CE-MS platform as a paradigm, data on analytical performance are described including reproducibility (short-term and intermediate repeatability), stability, interference, quantification capabilities (limits of detection), and inter-laboratory variability. We discuss these issues by using as an example our experience with the development of a 273-peptide marker for chronic kidney disease. Finally, we discuss pros and cons and means for improvement and emphasize the need to test in terms of comparative clinical performance and impact, different platforms that pass reasonably well analytical validation tests. PMID- 23041250 TI - Methemoglobin exposure produces toxicological effects in macrophages due to multiple ROS spike induced apoptosis. AB - Macrophages are an integral part of the immune system, required to produce a robust immune response against an infectious organism. Presence of methemoglobin in body fluids such as blood, cerebrospinal fluid and urine is associated with tissue damage. We tested cytotoxic effects of MetHb and underlying molecular events in mouse macrophage cell line J774A.1. MetHb exposure dose dependently reduced macrophage viability in an MTT assay. Light microscopy and scanning electron microscopic (SEM) observation of MetHb treated macrophage indicated death (less number of cells per field), severe damage to membrane structure and accumulation of particulate matter in the cytosol. The macrophage death during MetHb exposure was due to induction of apoptosis as indicated by annexin-V/FITC staining and DNA fragmentation analysis. MetHb treatment generated a periodic ROS spikes with time in the macrophage cytosol to develop oxidative stress. Scavenging ROS spikes with NAC, mannitol or PBN dose dependently protected macrophages against MetHb induced toxicity, apoptosis and cellular membrane damage. Our work highlighted the contributions of MetHb mediated toxicity toward macrophage and its potential role in tissue damage and immune depression during malaria and other hemolytic disorders. PMID- 23041251 TI - Urinary incontinence, related factors and menopause-related quality of life in mid-aged women assessed with the Cervantes Scale. AB - OBJECTIVE: To determine urinary incontinence (UI) prevalence, related factors and menopause-related quality of life (QoL) in mid-aged Colombian women. METHODS: A total of 1739 women aged 40-59 were surveyed with the 31 item Cervantes Scale (CS) and a socio-demographic questionnaire. Item 18 of the scale was used to categorize the degree of UI. Remaining 30 items (Adjusted global score) were used to assess global menopause-related QoL. RESULTS: Median age of the sample was 46 years. A 26.0% of women presented some degree of UI, rated as moderate to severe in 16.4% of cases. Adjusted global CS scores (excluding item 18) significantly increased with the severity of UI. Mean scores for item 18 were found to be significantly higher in relation to age, menopausal status, body mass index values, lower education and unemployment status. Multiple linear regression analysis determined that age, postmenopausal status and ethnicity (Mestizo) were significantly related to higher item 18 scores, and thus more severe UI. CONCLUSION: This is the first study to report UI prevalence in a large mid-aged Latin American female population in which age, menopausal status and ethnicity were related factors. PMID- 23041252 TI - Molecular analysis of hepatitis E virus from farm rabbits in Inner Mongolia, China and its successful propagation in A549 and PLC/PRF/5 cells. AB - Rabbit hepatitis E virus (HEV) strains have recently been isolated in several areas of China and in the US and France. However, the host range, distribution and zoonotic potential of these HEV strains remain unknown and their propagation in cultured cells has not yet been reported. A total of 211 4-month-old rabbits raised on a farm in Inner Mongolia were tested for the presence of anti-HEV antibodies and HEV RNA. Overall, 121 rabbits (57.3%) tested positive for anti-HEV antibodies, and 151 (71.6%) had detectable HEV RNA. The 174 HEV strains recovered from these viremic rabbits, including two distinct strains each from 23 rabbits, differed from each other by up to 13.6% in a 412-nucleotide (nt) sequence within ORF2, and were 89.3-95.9% identical to the reported rabbit HEV strains in other provinces of China. Three representative Inner Mongolian strains, one each from three phylogenetic clusters, whose entire genomic sequences were determined, shared 79.6-96.7% identities with reported rabbit HEV strains within the entire or 242- to 1349-nt partial genomic sequence. Rabbit HEV strains recovered from liver tissues of rabbits with a high HEV load propagated efficiently in human cell lines (A549 and PLC/PRF/5 cells), suggesting the potential zoonotic risk of rabbit HEV. PMID- 23041253 TI - Delivery style moderates study habits in an online nutrition class. AB - OBJECTIVE: To report how the design of an online class affected student ability to stay on task, find critical resources, and communicate with the instructor via e-mail. METHODS: Audiorecorded focus group meetings at a United States university featured a structured approach to discussions among undergraduate students enrolled in an Internet nutrition class. Meeting transcripts were read and reread by a trained investigator, who coded concepts until themes coalesced, which were authenticated by college students taking online classes. RESULTS: Three themes emerged that described factors moderating study habits in an Internet nutrition course: keeping up, e-mail fatigue, and wayfinding. CONCLUSIONS AND IMPLICATIONS: A well-designed online course plans for productive study habits by posting a schedule of events and maintaining a predictable pattern, supporting navigation that stimulates exploration and return visits to critical information, and constructing e-mail messages that convey a concise message and maximize "open and read." PMID- 23041255 TI - Efficacy of antidepressants on orofacial pain: a systematic review. AB - Orofacial pain is a common complaint with multiple diagnoses. There is controversy about the effectiveness of antidepressants for the management of orofacial pain disorders. In order to be able to make a best evidence choice between available antidepressants for the treatment of orofacial pain, a systematic review was conducted of existing randomized controlled trials of antidepressants. Trials were identified from the Pubmed database up to March 2012, from references in retrieved reports and from references in review articles. Six articles were found and included in this review. Four studies were randomized placebo-controlled trials and two studies were randomized active controlled trials. Two independent investigators reviewed these articles using a 15-item checklist. All six trials were of high quality according to the 15-item criteria. Nevertheless there was limited evidence to support the effectiveness of antidepressants in orofacial pain disorders, because of the heterogeneity of treatment modalities and the low number of randomized controlled trials per diagnose. More randomized controlled trials are needed to come to a firm conclusion for the use of antidepressants for orofacial pain disorders. PMID- 23041256 TI - The general characteristics of acute urticaria attacks and the factors predictive of progression to chronic urticaria. AB - BACKGROUND: The natural history of progression from acute urticaria (AU) to chronic urticaria (CU) remains poorly understood. This study aimed to investigate the potential triggers of AU attacks and factors associated with their duration, as well as the factors which may be predictive of progression to CU. METHODS: The study included 281 AU patients (AU group). Data were obtained from 207 AU patients retrospectively and from 74 AU patients prospectively. The CU group consisted of 953 patients, whose data were previously published. RESULTS: According to the medical history, the most common potential triggers of AU attacks were drugs (38.1%); infections (35.2%); stress (24.7%); and foods (17.8%). Attack duration was shorter in cases in which food (p=0.04) or infection (p=0.04) was the suspected trigger. Patients with a history of rhinitis (p=0.04) and food allergy (p=0.04), and positive skin prick test results for pollens (p=0.02) and dog (p=0.02) also had attacks of shorter duration. Patients with asthma had attacks of longer duration (p=0.01). Based on history and/or provocation test results, the prevalence of non-steroidal anti-inflammatory drug hypersensitivity (NSAIDH) was significantly higher in the CU group than the AU group (24.9% vs. 4.3%, respectively, (p<0.01)), as was antibiotic hypersensitivity (10.6% vs. 4.6%, respectively, (p<0.01)) and food allergy (18.3% vs. 3.9%, respectively, (p<0.01)). NSAIDH (OR: 7.97; 95%CI: 4.33-14.66; p<0.01) and food allergy (OR: 5.17; 95%CI: 2.71-9.85; p<0.01) were observed to be independent factors associated with CU. CONCLUSIONS: As NSAIDH and food allergy were associated with CU, their presence should be carefully evaluated in patients with AU in order to predict progression to CU. PMID- 23041257 TI - Apoptosis induced neurotoxicity of Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) via mitochondria-mediated pathway in PC12 cells. AB - The severe toxicity of antitumor organotin (IV) compounds limits their application in clinic, however, the toxic mechanism is still unclear. Di-n-butyl di-(4-chlorobenzohydroxamato) Tin (IV) (DBDCT), an antitumor agent with high activity and obvious neurotoxicity was chosen as a typical diorganotin (IV) compound to investigate its neurotoxic mechanism using PC12 cells and comprehensive methods. Treatment with DBDCT resulted in a dose- and time dependent growth inhibition of PC12 cells. The changes in cell morphology were observed using light microscopy, fluorescence microscopy and transmission electron microscopy. PC12 cell apoptosis induced by DBDCT was confirmed by annexin V/propidium iodide staining, and characterized by cleavage of caspase-9 and caspase-3 proteins. DBDCT induced the release of cytochrome c from the mitochondria to the cytosol and the generation of reactive oxygen species. DBDCT up-regulated the expression of Bax, down-regulated the expression of Bcl-2, and significantly increased the ratio of Bax/Bcl-2. DBDCT also caused the phosphorylation of JNK and p38(MAPK). In rats exposed to DBDCT, apoptosis was also observed in brain, as shown by the detection of cleaved caspase-9 and caspase-3 proteins and increased TUNEL positive staining. In conclusion, the results demonstrated that DBDCT caused the neurotoxicity by inducing apoptosis via mitochondria-mediated pathway. PMID- 23041258 TI - Aerobic training as an adjunctive therapy to enzyme replacement in Pompe disease. AB - BACKGROUND: Aerobic exercise may be used in conjunction with enzyme replacement therapy (ERT) to attenuate cardiovascular deconditioning, skeletal muscle wasting, and loss of motor function in Pompe disease (glycogen storage disease type II; GSDII), but the effects on lysosomal glycogen content and macroautophagy have not been defined to date. PURPOSE: The main objectives of this study were to determine if acute aerobic exercise enhances 24-h uptake of recombinant human enzyme (rhGAA; Myozyme(r) [aim 1]) and if endurance training improves disease pathology when combined with ERT [aim 2] in Pompe mice. METHODS: For the first aim in our study, Pompe mutant mice (6(neo)/6(neo)) were grouped into ERT (Myozyme(r) injection only [40 mg/kg]) and ERT+EX (Myozyme(r) injection followed by 90 min treadmill exercise) cohorts, and enzyme uptake was assessed in the heart and quadriceps 24h post injection. For the second aim of our study, mutant mice were randomized into control, endurance-trained, enzyme-treated, or combination therapy groups. Exercised animals underwent 14 weeks of progressive treadmill training with or without biweekly Myozyme(r) injections (40 mg/kg) and tissues were harvested 1 week post last treatment. RESULTS: Myozyme(r) uptake (GAA activity) was not improved in ERT+EX over ERT alone at 24-h post injection. Endurance exercise training, with or without ERT, improved aerobic capacity and normalized grip strength, motor function, and lean mass (P<0.05), but did not reduce glycogen content or normalize macroautophagy beyond traditional enzyme replacement therapy. CONCLUSIONS: Endurance training is beneficial as an adjunctive therapy to ERT in Pompe disease, although it works by mechanisms independent of a reduction in glycogen content. PMID- 23041259 TI - Akt inactivation induces endoplasmic reticulum stress-independent autophagy in fibroblasts from patients with Pompe disease. AB - Pompe disease (glycogen storage disease type II) is an autosomal recessive neuromuscular disorder arising from a deficiency of lysosomal acid alpha glucosidase (GAA). Accumulation of autophagosomes is a key pathological change in skeletal muscle fibers and fibroblasts from patients with Pompe disease and is implicated in the poor response to enzyme replacement therapy (ERT). We previously found that mutant GAA-induced endoplasmic reticulum (ER) stress initiated autophagy in patient fibroblasts. However, the mechanism of induction of autophagy in fibroblasts from Pompe disease patients lacking ER stress remains unclear. In this study, we show that inactivated Akt induces ER stress independent autophagy via mTOR suppression in patient fibroblasts. Activated autophagy as evidenced by increased levels of LC3-II and autophagic vesicles was observed in patient fibroblasts, whereas PERK phosphorylation reflecting the presence of ER stress was not observed in them. These patient fibroblasts showed decreased levels of not only phosphorylated Akt, but also phosphorylated p70 S6 kinase. Treatment with insulin, which acts as an activator of the Akt signaling pathway, resulted in increased phosphorylation of both Akt and p70 S6 kinase and suppression of autophagy in patient fibroblasts. In addition, following combination treatment with recombinant human GAA plus insulin, enhanced localization of the enzymes with lysosomes was observed in patient fibroblasts. These findings define a critical role of Akt suppression in the induction of autophagy in fibroblasts from patients with Pompe disease carrying an ER stress non-inducible mutation, and they provide evidence that insulin may potentiate the effect of ERT. PMID- 23041260 TI - Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas. AB - Inadequate cross-linking between collagen lamellae is a characteristic feature of keratoconus corneas. The formation of covalent bonds between collagen and elastin fibrils, which maintain the biomechanical properties of the cornea, is mediated by the cuproenzyme lysyl oxidase and four lysyl oxidase-like enzymes. The aim of this study was to determine the distribution of lysyl oxidase and the total lysyl oxidase activity (lysyl oxidase and the four lysyl oxidase-like enzymes) in control and keratoconic corneas. Seven control and eight keratoconic corneas were used for the imunohistochemical detection of lysyl oxidase in corneal cryosections using two different antibodies. The total lysyl oxidase activity in the culture medium of corneal fibroblasts from six explanted keratoconic and four control corneas was measured using a fluorometric assay in the presence and absence of the lysyl oxidase inhibitor beta-aminopropionitrile and determined as the production of H(2)O(2) in nM per MUg of total protein. In the control tissue, the most intense signal for lysyl oxidase was present in the corneal epithelium, in which perinuclear dots brightly projecting from more or less homogenous cytoplasmic staining may represent the lysyl oxidase propeptide. Less intense staining was present in keratocytes, the extracellular matrix and in the corneal endothelium. The epithelium of the limbus and the perilimbal conjunctiva showed intense to very intense staining. The distribution of lysyl oxidase was clearly decreased in at least five of the eight keratoconic specimens. The most marked signal reduction was observed in the stromal matrix and in keratocytes. Moreover, the signal in pathological specimens revealed a more irregular pattern, including the presence of intra- and extracellular clumps in the epithelium. Interestingly, endothelial cells showed no or very weak staining in areas just beneath negative stromal tissue. The mean activity of total lysyl oxidase in the keratoconic samples (2.60 +/- 2.23 nM H(2)O(2)/MUg of total protein) was more than 2.5-fold lower than in control tissue (6.83 +/- 2.53 nM H(2)O(2)/MUg of total protein), and the decrease was statistically significant (p = 0.0178). The location of lysyl oxidase in the healthy cornea, limbus and perilimbal conjunctiva was described. We hypothesize that the restricted lysyl oxidase distribution in keratoconic corneas, and particularly the decrease of total lysyl oxidase activity in cultured keratoconic fibroblasts, is one potential reason for the inadequate collagen cross-linking that is a hallmark of this disease. PMID- 23041261 TI - A novel 7 bp deletion in PRPF31 associated with autosomal dominant retinitis pigmentosa with incomplete penetrance in an Indian family. AB - To localize and identify the gene linked with non-syndromic autosomal dominant retinitis pigmentosa (adRP) with high but not complete penetrance in an Indian family. A detailed family history and clinical data were recorded. A genome-wide scan by 2-point linkage analysis using nearly 400 fluorescently labeled microsatellite markers in combination with multipoint lod score and haplotype analysis was carried out. Mutation screening was performed in the candidate gene by bidirectional sequence analysis of the amplified products. A maximum 2-point lod score of 3.553 at theta = 0.0 was obtained with marker D19S572. Haplotype analysis placed the RP locus distal to marker D19S572, in close proximity to the gene for pre-mRNA processing factor 31 (PRPF31) at 19q13.42. Mutation screening in all 14 exonic regions and adjacent flanking intronic sequences of PRPF31 revealed a novel 7 bp deletion, c.59_65del7 (p.Gly20AlafsX43), in the first coding exon of PRPF31. This leads to a premature termination codon (PTC) in the next exon, 43 amino acids downstream. The observed 7 bp deletion in PRPF31 was identified in all the tested 10 affected members and in an unaffected individual, consistent with a high, but not the complete penetrance of c.59_65del7 (p.Gly20AlafsX43). This deletion was not observed in other tested six unaffected family members or in 100 ethnically matched control subjects. The present study describes mapping of a locus for non-syndromic adRP at 19q13.42 (RP11 locus) in a family of Indian origin and identifies a novel deletion, c.59_65del7, in PRPF31 within the mapped interval. Since the mutant PRPF31 is truncated relatively close to the N-terminus of the protein, haploinsufficiency rather than aberrant protein formation is likely to be the underlying mechanism of the disease. The present findings further substantiate the role of PRPF31 that encodes a component of the spliceosome complex in relation to ADRP. PMID- 23041262 TI - Abcc6 deficiency in the mouse leads to calcification of collagen fibers in Bruch's membrane. AB - Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by mineralization of connective tissue, which leads to pathology in eye, skin and blood vessels. The disease is caused by mutations in ABCC6. To learn more about PXE eye pathology, we analyzed Bruch's membrane (BM) of the eye of an Abcc6 knockout mouse. With age, BM differences between Abcc6-/- and wild type mice became apparent. At two years of age, von Kossa staining indicated clear calcification of BM in Abcc6-/- mice, and not in healthy controls. Electron microscopy revealed BM changes as early as at 10 months of age: Fibrous structures with abnormal high electron-density were present in the central layers of BM of Abcc6-/- mice. EDX (Energy Dispersive X-ray) analysis demonstrated that these structures contained elevated levels of Ca, P and O. Since some of these electron-dense structures showed a banding pattern with periodicity of about 50 nm, they most likely represent calcified collagen fibers. Immunoelectron microscopy showed that the calcified structures were positive for collagen III. Remarkably, the elastic layer of BM appeared to have a normal ultrastructure, even in 2.5 year old Abcc6-/- mice. Our results suggest that Abcc6 deficiency in the mouse causes calcification of BM. While PXE is considered to affect primarily the elastic fibers, we found predominantly mineralization of collagen fibers. PMID- 23041263 TI - Cloning, expression and purification of Atlantic salmon (Salmo salar, L.) neuroglobin. AB - Neuroglobin (Ngb) exists only in small amounts in salmon brain. In order to study the protein in more detail salmon neuroglobin (sNgb) was cloned, heterologously expressed in Escherichia coli and purified. The protein had red color and showed the characteristic peaks at 411nm (metNgb), 415nm (carboxyNgb) and 424nm (deoxyNgb). Western analysis showed that sNgb reacted weakly against a rabbit anti human neuroglobin (hNgb) and strongly to a sNgb specific antibody. Our 3D homology model of the sNgb indicated modifications adjacent to and in the O(2)/CO binding site. This may correlate to differences in substrate affinities for the sNgb compared to the hNgb. Also sNgb contained shorter helixes and longer interhelical loops typical for psychrophilic proteins. PMID- 23041266 TI - Identification of Staphylococcus saprophyticus isolated from patients with urinary tract infection using a simple set of biochemical tests correlating with 16S-23S interspace region molecular weight patterns. AB - The emergence of Staphylococcus spp. not only as human pathogens, but also as reservoirs of antibiotic resistance determinants, requires the development of methods for their rapid and reliable identification in medically important samples. The aim of this study was to compare three phenotypic methods for the identification of Staphylococcus spp. isolated from patients with urinary tract infection using the PCR of the 16S-23S interspace region generating molecular weight patterns (ITR-PCR) as reference. All 57 S. saprophyticus studied were correctly identified using only the novobiocin disk. A rate of agreement of 98.0% was obtained for the simplified battery of biochemical tests in relation to ITR PCR, whereas the Vitek I system and novobiocin disk showed 81.2% and 89.1% agreement, respectively. No other novobiocin-resistant non-S. saprophyticus strain was identified. Thus, the novobiocin disk is a feasible alternative for the identification of S. saprophyticus in urine samples in laboratories with limited resources. ITR-PCR and the simplified battery of biochemical tests were more reliable than the commercial systems currently available. This study confirms that automated systems are still unable to correctly differentiate CoNS species and that simple, reliable and inexpensive methods can be used for routine identification. PMID- 23041267 TI - A novel high-resolution melting analysis-based method for Yersinia pseudotuberculosis genotyping. AB - Yersinia pseudotuberculosis is an enteric pathogen that is environmentally widespread and is known to cause human and animal infections. The development of a fast and inexpensive typing system is necessary to facilitate epidemiological studies of Y. pseudotuberculosis infections. In this study, we aimed to develop a method of Y. pseudotuberculosis genotyping based on determining differences in single-nucleotide polymorphisms (SNPs) using a high-resolution melting analysis (HRMA). Using a set of nine primer pairs, ten SNPs were screened from sequences in the 16S rRNA, glnA, gyrB and recA sequences of 12 Y. pseudotuberculosis strains that were deposited in the GenBank database. The genetic diversity of a collection of 40 clinical Y. pseudotuberculosis strains was determined using the HRMA method and the multilocus sequence typing (MLST) technique was used for comparison. Different melting profiles were found in five out of a total of nine analyzed fragments. A phylogenetic tree was constructed from the nucleotides that were identified in the nine analyzed fragments, and the tree demonstrated that Y. pseudotuberculosis strains were separated into two groups. The first cluster was composed of strains from the 1/O:1a serogroup and the second of strains from the 2/O:3 serogroup. The separation into two clusters based on distinct bio serogroups of Y. pseudotuberculosis was consistent with the results in the MLST database. The simple and highly reproducible HRMA assay developed by us may be used as a rapid and cost-effective method to genotype Y. pseudotuberculosis strains of O:1 and O:3 serogroups and it can complement sequence-based methods facilitating epidemiological studies of this Yersinia species. PMID- 23041264 TI - Epigenetic transgenerational inheritance of vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers. AB - The endocrine disruptor vinclozolin has previously been shown to promote epigenetic transgenerational inheritance of adult onset disease in the rat. The current study was designed to investigate the transgenerational actions of vinclozolin on the mouse. Transient exposure of the F0 generation gestating female during gonadal sex determination promoted transgenerational adult onset disease in F3 generation male and female mice, including spermatogenic cell defects, testicular abnormalities, prostate abnormalities, kidney abnormalities and polycystic ovarian disease. Pathology analysis demonstrated 75% of the vinclozolin lineage animals developed disease with 34% having two or more different disease states. Interestingly, the vinclozolin induced transgenerational disease was observed in the outbred CD-1 strain, but not the inbred 129 mouse strain. Analysis of the F3 generation sperm epigenome identified differential DNA methylation regions that can potentially be utilized as epigenetic biomarkers for transgenerational exposure and disease. PMID- 23041265 TI - Molecular and biological role of the FOXP3 N-terminal domain in immune regulation by T regulatory/suppressor cells. AB - Regulatory T (Treg) cells are essential in preventing the host from developing certain autoimmune diseases and limiting excessive immune responses against pathogens. The normal function of most Treg cells requires sustained expression of functional FOXP3, a member of the FOXP family transcription factors. FOXP3 is distinct from other subfamily members because of its unique proline rich amino (N)-terminal domain. Mutations in this region are occasionally identified in certain patients with X-linked autoimmunity-allergic dysregulation syndrome (XLAAD) and similar mutations also increase susceptibility of autoimmune diseases in rodent models. Previous analyses of the FOXP3 N-terminal domain revealed a role in nuclear import, interaction with other transcription factors, and as sites of specific post-translational modifications of FOXP3 that contribute to FOXP3 stability. PMID- 23041268 TI - Genetic manipulation of pathogenicity loci in non-Typhimurium Salmonella. AB - The traditional genetic tools used in Salmonella enterica serovar Typhimurium rely heavily on a high-transducing mutant of bacteriophage P22. P22 recognizes its hosts by the structure of their O-antigens, which vary among serovars of Salmonella; therefore, it cannot be used in most non-Typhimurium Salmonella, including the majority of those causing food-borne illnesses in both humans and livestock. Bacteriophage P1 infects a variety of enteric bacteria, including galE mutants of serovar Typhimurium; however, the degree to which the presence of coimmune prophages, the lack of required attachment sites or the lack of host factors act as barriers to using phage P1 in natural isolates of Salmonella is unknown. Here, we show that recombineering can be used to make virtually any serovar of Salmonella susceptible to P1 infection; as a result, P1 can be utilized for facile genetic manipulation of non-Typhimurium Salmonella, including movement of very large pathogenicity islands. A toolkit for easy manipulation of non-Typhimurium serovars of Salmonella is described. PMID- 23041269 TI - A combined sequence-based and fragment-based characterization of microbial eukaryote assemblages provides taxonomic context for the Terminal Restriction Fragment Length Polymorphism (T-RFLP) method. AB - Microbial eukaryotes in seawater samples collected from two depths (5 m and 500 m) at the USC Microbial Observatory off the coast of Southern California, USA, were characterized by cloning and sequencing of 18S rRNA genes, as well as DNA fragment analysis of these genes. The sequenced genes were assigned to operational taxonomic units (OTUs), and taxonomic information for the sequence based OTUs was obtained by comparison to public sequence databases. The sequences were then subjected to in silico digestion to predict fragment sizes, and that information was compared to the results of the T-RFLP method applied to the same samples in order to provide taxonomic context for the environmental T-RFLP fragments. A total of 663 and 678 sequences were analyzed for the 5m and 500 m samples, respectively, which clustered into 157 OTUs and 183 OTUs. The sequences yielded substantially fewer taxonomic units as in silico fragment lengths (i.e., following in silico digestion), and the environmental T-RFLP resulted in the fewest unique OTUs (unique fragments). Bray-Curtis similarity analysis of protistan assemblages was greater using the T-RFLP dataset compared to the sequence-based OTU dataset, presumably due to the inability of the fragment method to differentiate some taxa and an inability to detect many rare taxa relative to the sequence-based approach. Nonetheless, fragments in our analysis generally represented the dominant sequence-based OTUs and putative identifications could be assigned to a majority of the fragments in the environmental T-RFLP results. Our empirical examination of the T-RFLP method identified limitations relative to sequence-based community analysis, but the relative ease and low cost of fragment analysis make this method a useful approach for characterizing the dominant taxa within complex assemblages of microbial eukaryotes in large datasets. PMID- 23041270 TI - Long term outcome of single event multilevel surgery in spastic diplegia with flexed knee gait. AB - Distal hamstring lengthening (DHL) is a commonly performed procedure in flexed knee gait. However, the necessity of this procedure has been challenged due to the concerns on adverse effects in long-term follow-up. This retrospective study was undertaken to investigate the long-term outcome of single event multilevel surgery (SEMLS), including bilateral DHL, in ambulatory patients with cerebral palsy using 3D gait analysis. Twenty-nine ambulatory patients with spastic diplegic cerebral palsy who had undergone SEMLS including bilateral DHL were included. 3D gait analysis was performed preoperatively, 1 year postoperatively and over 10 years postoperatively. Preoperative temporal parameters, kinematics and GDI were compared with values obtained 1 and 10 year follow-up visits. The mean age of patients at time of first surgery was 8.3 years (range, 5.4-16.3 years), and mean time from first surgery to last 3D gait analysis was 11.8 years (range, 10.0-13.3 years). Mean pelvic tilt was not changed significantly after SEMLS including DHL. Mean knee flexion at initial contact decreased from 31.1 degrees preoperatively to 26.0 degrees at 1 year postoperatively (p=0.065), and then decreased significantly to 23.6 degrees at 10 years postoperatively (p=0.038) versus the preoperative value. Mean GDI score significantly improved from 69.4 preoperatively to 77.9 at 1 year postoperatively (p=0.003) and continuously improved to 82.2 at 10 years postoperatively (p=0.017). Single event multilevel surgery including DHL provides a favorable outcome 10 years postoperatively in patients with spastic diplegic cerebral palsy. PMID- 23041271 TI - Pyrrolidinediones reduce the toxicity of thiazolidinediones and modify their anti diabetic and anti-cancer properties. AB - Thiazolidinediones have been established as a drug class of significant importance in the treatment of Type II diabetes mellitus and have more recently displayed emergent potential as anti-cancer agents. However, their toxicity has hampered clinical development and usage in both therapeutic areas. Studies to date have implicated that the thiazolidinedione ring is responsible for the generation of reactive metabolites after metabolism. As an attempt to improve their safety profiles, we considered the bioisosteric replacement of the thiazolidinedione ring with a chemically conserved pyrrolidinedione heterocyclic system. Using pyrrolidinedione analogs of the thiazolidinedione drugs troglitazone (TGZ), rosiglitazone (RGZ), and pioglitazone (PGZ), we evaluated their PPAR(gamma) activities, anti-cancer properties as well as toxicological effects. Of significance, both pyrrolidinedione analogs demonstrated reduced toxicity. Pharmacologically, they also displayed diminished PPAR(gamma) binding and ap2 gene expression in a mouse pre-adipocyte cell line 3T3-L1, but enhanced anti-cancer properties based on the suppression of liver cancer cell line (Huh-7) proliferation and the expression of tumor marker, afp. Overall, this study ascertains the general contribution of the thiazolidinedione ring to their cytotoxicity and proposes the applicability of the pyrrolidinedione ring as a selective and safer choice in anti-diabetic and cancer chemotherapeutics for future drug design. PMID- 23041273 TI - Aldosterone and angiotensin: Role in diabetes and cardiovascular diseases. AB - The present review shall familiarize the readers with the role of renin angiotensin aldosterone system (RAAS), which regulates blood pressure, electrolyte and fluid homeostasis. The local RAAS operates in an autocrine, paracrine and/or intracrine manner and exhibits multiple physiological effects at the cellular level. In addition to local RAAS, there exists a complete pancreatic RAAS which has multi-facet role in diabetes and cardiovascular diseases. Aldosterone is known to mediate hyperinsulinemia, hypertension, cardiac failure and myocardial fibrosis while angiotensin II mediates diabetes, endothelial dysfunction, vascular inflammation, hypertrophy and remodeling. As the understanding of this biology of RAAS increases, it serves to exploit this for the pharmacotherapy of diabetes and cardiovascular diseases. PMID- 23041272 TI - Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPARgamma and adenosine. AB - Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Known cardioprotective and anti-inflammatory properties of resveratrol have spurred investigation of the mechanisms involved. The present study explored potential atheroprotective actions of resveratrol on cholesterol metabolism in cells of the arterial wall, including human macrophages and arterial endothelium. Using QRT-PCR and Western blotting techniques, we measured expression of the proteins involved in reverse cholesterol transport (ABCA1, ABCG1 and SR-B1) and the scavenger receptors responsible for uptake of modified cholesterol (CD36, SR-A1 and LOX-1). We analyzed the effect of resveratrol on apoA-1-and HDL-mediated cholesterol efflux in human THP-1 macrophages. The effect of resveratrol on oxLDL internalization and foam cell formation were evaluated using confocal and light microscopy. Our data indicate that resveratrol regulates expression of major proteins involved in cholesterol transport, promotes apoA-1 and HDL-mediated efflux, downregulates oxLDL uptake and diminishes foam cell formation. Mechanistically, resveratrol effects were dependent upon PPAR-gamma and adenosine 2A receptor pathways. For the first time we demonstrate that resveratrol regulates expression of the cholesterol metabolizing enzyme cytochrome P450 27-hydroxylase, providing efficient cholesterol elimination via formation of oxysterols. This study establishes that resveratrol attenuates lipid accumulation in cultured human macrophages via effects on cholesterol transport. Further in vivo studies are needed to determine whether resveratrol may be an additional resource available to reduce lipid deposition and atherosclerosis in humans. PMID- 23041274 TI - Antitumor efficacy of dexamethasone-loaded core-crosslinked polymeric micelles. AB - In the current study, core-crosslinked polymeric micelles (DEX-PMs) loaded with three different DEX derivatives designed to display different drug release kinetics, were evaluated for cancer therapy and compared to another effective nanomedicine formulation (long-circulating liposomes encapsulating dexamethasone, LCL-DEX). Pharmacokinetic studies with both radiolabeled dexamethasone and polymer showed that these polymeric systems have long circulating half-lives and may accumulate at the tumor site to a higher extent than liposomes. The in vitro drug release profiles and circulating drug levels in the blood stream show that DEX-PMs with dexamethasone covalently entrapped via a sulfone ester-containing linker (DMSL2) have prolonged circulation time and intermediate drug release kinetics compared to the other polymeric DEX-releasing systems. Furthermore, as the free dexamethasone circulating levels were similar when administered as DMSL2 PM or LCL-DEX, these systems were evaluated simultaneously for antitumor efficacy in B16F10 melanoma bearing mice. The corticosteroid-targeted systems inhibited tumor growth to a similar extent and both increased survival compared to free drug. Recently antitumor efficacy of targeted formulations has been correlated with a systemic effect: a decrease of white blood cell count. In this study all three polymeric systems, liposomes as well as free drug had similar effects on the number of circulating white blood cells, although white blood cell counts recovered faster in the group receiving free drug. In conclusion, corticosteroid targeting with a polymeric system or a liposomal system translates in similar therapeutic effects. The proven high versatility of the PM with possible optimization and adjustment of the drug release to that required by the therapeutic application, clearly demonstrates the potential of these systems for the treatment of chronic inflammatory diseases including cancer. PMID- 23041275 TI - Orally active desulfated low molecular weight heparin and deoxycholic acid conjugate, 6ODS-LHbD, suppresses neovascularization and bone destruction in arthritis. AB - The regulation of angiogenesis is an interesting area to consider for novel therapeutic approaches to rheumatoid arthritis (RA). Chemically modified heparins have been developed as possible candidates for angiogenesis inhibitor; however, they have a major clinical drawback in exhibiting poor oral bioavailability. Here, orally absorbable O-desulfated low molecular weight heparin (ODS-LMWH) derivatives were newly synthesized by conjugating 2-O- or 6-O-desulfated LMWH with deoxycholic acid (DOCA) or bisDOCA (a dimer of DOCA), and their physicochemical properties, antiangiogenic potency and pharmacokinetic profiles were assessed. After selecting the best candidate among those derivatives, its therapeutic efficacy on arthritis was investigated in a murine collagen antibody induced arthritis (CAIA) model. ODS-LMWH derivatives significantly inhibited the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) and basic fibroblast growth factor (bFGF)-induced angiogenesis in the Matrigel plug assay. Among all the compounds, 6ODS-LHbD showed the highest oral bioavailability in rats (19.3%). In the CAIA mouse model, 6ODS-LHbD (10 mg/kg, p.o., S.I.D.) significantly inhibited neovascularization in the joint, the increase of hind-paw thickness, and the structural damage in the bone. Therefore, 6ODS-LHbD would be a promising candidate for an orally active drug for the treatment of RA. PMID- 23041276 TI - Genetic blockage of endocytic pathways reveals differences in the intracellular processing of non-viral gene delivery systems. AB - Detailed understanding of the uptake mechanisms and intracellular processing of nonviral gene delivery systems will allow design of more effective carriers. This work gets insight into the intracellular kinetics of pDNA delivered by polyethyleneimine (PEI), cationic lipid DOTAP and calcium phosphate (CaP) precipitates. Amount of cell- and nuclear-associated pDNA was quantified by qRT PCR at multiple time points after transfection. Moreover, the impact of specific endocytic pathways on the cell entry and intracellular kinetics of pDNA was studied by inhibition (blockage) of either clathrin- or dynamin-mediated endocytosis by using both genetically manipulated cell lines and chemical inhibitors of endocytosis. Quantitative analysis of defined kinetic parameters revealed that neither cellular nor nuclear uptake of pDNA correlated with transgene expression, emphasizing the importance of the post-nuclear processes in overall transfection efficacy. Changes in transgene expression observed upon blockage of endocytosis was carrier dependent and correlated relatively well with the changes at the cellular and nuclear uptake levels but not with the amount of cell-associated pDNA. Due to low specificity of chemical inhibitors and activation of alternative endocytosis pathways after genetic blockage of endocytosis neither of these methods is optimal for studying the role of endocytosis. Therefore, one should be careful when interpreting the obtained results from such studies and not to trust the data obtained only from one method. PMID- 23041277 TI - Photoexcitation of tumor-targeted corroles induces singlet oxygen-mediated augmentation of cytotoxicity. AB - The tumor-targeted corrole particle, HerGa, displays preferential toxicity to tumors in vivo and can be tracked via fluorescence for simultaneous detection, imaging, and treatment. We have recently uncovered an additional feature of HerGa in that its cytotoxicity is enhanced by light irradiation. In the present study, we have elucidated the cellular mechanisms for HerGa photoexcitation-mediated cell damage using fluorescence optical imaging. In particular, we found that light irradiation of HerGa produces singlet oxygen, causing mitochondrial damage and cytochrome c release, thus promoting apoptotic cell death. An understanding of the mechanisms of cell death induced by HerGa, particularly under conditions of light-mediated excitation, may direct future efforts in further customizing this nanoparticle for additional therapeutic applications and enhanced potency. PMID- 23041280 TI - How to use... lupus anticoagulants. PMID- 23041278 TI - Surface modified poly(beta amino ester)-containing nanoparticles for plasmid DNA delivery. AB - The use of biodegradable polymers provides a potentially safe and effective alternative to viral and liposomal vectors for the delivery of plasmid DNA to cells for gene therapy applications. In this work we describe the formulation of a novel nanoparticle (NP) system containing a blend of poly(lactic-co-glycolic acid) and a representative poly(beta-amino) ester (PLGA and PBAE respectively) for use as gene delivery vehicles. Particles of different weight/weight (wt/wt) ratios of the two polymers were characterized for size, morphology, plasmid DNA (pDNA) loading and surface charge. NPs containing PBAE were more effective at cellular internalization and transfection (COS-7 and CFBE41o-) than NPs lacking the PBAE polymer. However, along with these delivery benefits, PBAE exhibited cytotoxic effects that presented an engineering challenge. Surface coating of these blended particles with the cell-penetrating peptides (CPPs) mTAT, bPrPp and MPG via a PEGylated phospholipid linker (DSPE-PEG2000) resulted in NPs that reduced surface charge and cellular toxicity to levels comparable with NPs formulated with only PLGA. Additionally, these coated nanoparticles showed an improvement in pDNA loading, intracellular uptake and transfection efficiency, when compared to NPs lacking the surface coating. Although all particles with a CPP coating outperformed unmodified NPs, respectively, bPrPp and MPG coating resulted in 3 and 4.5* more pDNA loading than unmodified particles and approximately an order of magnitude improvement on transfection efficiency in CFBE41o- cells. These results demonstrate that surface-modified PBAE containing NPs are a highly effective and minimally toxic platform for pDNA delivery. PMID- 23041279 TI - Absence of CCL2 is sufficient to restore hippocampal neurogenesis following cranial irradiation. AB - Cranial irradiation for the treatment of brain tumors causes a delayed and progressive cognitive decline that is pronounced in young patients. Dysregulation of neural stem and progenitor cells is thought to contribute to these effects by altering early childhood brain development. Earlier work has shown that irradiation creates a chronic neuroinflammatory state that severely and selectively impairs postnatal and adult neurogenesis. Here we show that irradiation induces a transient non-classical cytokine response with selective upregulation of CCL2/monocyte chemoattractant protein-1 (MCP-1). Absence of CCL2 signaling in the hours after irradiation is alone sufficient to attenuate chronic microglia activation and allow the recovery of neurogenesis in the weeks following irradiation. This identifies CCL2 signaling as a potential clinical target for moderating the long-term defects in neural stem cell function following cranial radiation in children. PMID- 23041281 TI - Empathy and distress: two distinct but related emotions in response to infant crying. AB - This study examined a largely overlooked, yet potentially important, association between empathy and distress in cry responding. The cry stimulus included a 1-min long video clip of a 4-week-old, crying, male infant. Participants reported their dispositional empathy and distress, perceived aversiveness of the cry stimulus, response emotions, and intention to intervene with the crying infant. Empathy and distress covaried positively both in disposition and in cry responding. Response empathy and distress were related to their corresponding dispositional emotions, but response empathy was also related to dispositional distress. Perceived aversiveness interacted with response distress in predicting response empathy. Both response empathy and distress appeared to be important determinants of intention to intervene. Overall, empathy and distress in response to infant crying appeared more closely related than previously thought. Implications concerning the regulation of emotions in cry responding are discussed. PMID- 23041282 TI - Interdomain allostery promotes assembly of the poly(A) mRNA complex with PABP and eIF4G. AB - Many RNA-binding proteins contain multiple single-strand nucleic acid-binding domains and assemble into large multiprotein messenger ribonucleic acid protein (mRNP) complexes. The mechanisms underlying the self-assembly of these complexes are largely unknown. In eukaryotes, the association of the translation factors polyadenylate-binding protein-1 (PABP) and eIF4G is essential for high-level expression of polyadenylated mRNAs. Here, we report the crystal structure of the ternary complex poly(A)(11).PABP(1-190).eIF4G(178-203) at 2.0 A resolution. Our NMR and crystallographic data show that eIF4G interacts with the RRM2 domain of PABP. Analysis of the interaction by small-angle X-ray scattering, isothermal titration calorimetry, and electromobility shift assays reveals that this interaction is allosterically regulated by poly(A) binding to PABP. Furthermore, we have confirmed the importance of poly(A) for the endogenous PABP and eIF4G interaction in immunoprecipitation experiments using HeLa cell extracts. Our findings reveal interdomain allostery as a mechanism for cooperative assembly of RNP complexes. PMID- 23041283 TI - The direction of protein entry into the proteasome determines the variety of products and depends on the force needed to unfold its two termini. AB - Poorly structured domains in proteins enhance their susceptibility to proteasomal degradation. To learn whether the presence of such a domain near either end of a protein determines its direction of entry into the proteasome, directional translocation was enforced on several proteasome substrates. Using archaeal PAN 20S complexes, mammalian 26S proteasomes, and cultured cells, we identified proteins that are degraded exclusively from either the C or N terminus and some showing no directional preference. This property results from interactions of the substrate's termini with the regulatory ATPase and could be predicted based on the calculated relative stabilities of the N and C termini. Surprisingly, the direction of entry into the proteasome affected markedly the spectrum of peptides released and consequently influenced the efficiency of MHC class I presentation. Thus, easily unfolded termini are translocated first, and the direction of translocation influences the peptides generated and presented to the immune system. PMID- 23041284 TI - Reciprocal regulation of Akt and Oct4 promotes the self-renewal and survival of embryonal carcinoma cells. AB - Signaling via the Akt serine/threonine protein kinase plays critical roles in the self-renewal of embryonic stem cells and their malignant counterpart, embryonal carcinoma cells (ECCs). Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription. Phosphorylation of Oct4 by Akt resulted in dissociation of Oct4 from the AKT1 promoter, which activated AKT1 transcription and promoted cell survival. Therefore, a site specific, posttranslational modification of the Oct4 protein orchestrates the regulation of its stability, subcellular localization, and transcriptional activities, which collectively promotes the survival and tumorigenicity of ECCs. PMID- 23041285 TI - Gene density, transcription, and insulators contribute to the partition of the Drosophila genome into physical domains. AB - The mechanisms responsible for the establishment of physical domains in metazoan chromosomes are poorly understood. Here we find that physical domains in Drosophila chromosomes are demarcated at regions of active transcription and high gene density that are enriched for transcription factors and specific combinations of insulator proteins. Physical domains contain different types of chromatin defined by the presence of specific proteins and epigenetic marks, with active chromatin preferentially located at the borders and silenced chromatin in the interior. Domain boundaries participate in long-range interactions that may contribute to the clustering of regions of active or silenced chromatin in the nucleus. Analysis of transgenes suggests that chromatin is more accessible and permissive to transcription at the borders than inside domains, independent of the presence of active or silencing histone modifications. These results suggest that the higher-order physical organization of chromatin may impose an additional level of regulation over classical epigenetic marks. PMID- 23041286 TI - RNA polymerase II collision interrupts convergent transcription. AB - Antisense noncoding transcripts, genes-within-genes, and convergent gene pairs are prevalent among eukaryotes. The existence of such transcription units raises the question of what happens when RNA polymerase II (RNAPII) molecules collide head-to-head. Here we use a combination of biochemical and genetic approaches in yeast to show that polymerases transcribing opposite DNA strands cannot bypass each other. RNAPII stops but does not dissociate upon head-to-head collision in vitro, suggesting that opposing polymerases represent insurmountable obstacles for each other. Head-to-head collision in vivo also results in RNAPII stopping, and removal of collided RNAPII from the DNA template can be achieved via ubiquitylation-directed proteolysis. Indeed, in cells lacking efficient RNAPII polyubiquitylation, the half-life of collided polymerases increases, so that they can be detected between convergent genes. These results provide insight into fundamental mechanisms of gene traffic control and point to an unexplored effect of antisense transcription on gene regulation via polymerase collision. PMID- 23041287 TI - Molecular machinery for insertion of tail-anchored membrane proteins into the endoplasmic reticulum membrane in mammalian cells. AB - Tail-anchored (TA) membrane proteins destined for the secretory pathway are posttranslationally inserted into the endoplasmic reticulum (ER) membrane, but the molecular machinery for this insertion in mammalian cells remains elusive. Here we reveal a mammalian protein complex that drives the membrane insertion. We identify calcium-modulating cyclophilin ligand (CAML) as a mammal-specific receptor for TRC40, an ATPase targeting newly synthesized TA proteins, and show that CAML mediates membrane insertion of TA proteins. We show that CAML binds to WRB, an evolutionarily conserved TRC40 receptor, through the transmembrane domains and that CAML and WRB synergistically insert TA proteins into the membrane. Mutagenesis of CAML demonstrates that binding of TRC40 to CAML is required to ensure synergistic membrane insertion. Thus, identification of CAML and WRB as components of the TRC40 receptor complex represents a crucial mechanism for driving ER membrane insertion of TA proteins in mammalian cells. PMID- 23041288 TI - Applying evidence to patient care: from population health to individual patient values. AB - What are the health status and health needs of people with epilepsy? How do clinicians and patients choose between alternative interventions for the same condition? Are health interventions used effectively in the community, and do they improve health? How can we translate findings from regulatory clinical trials to the real world? These and similar questions are the subject of applied translational research. This evolving and broad-ranging area of research involves the application of basic sciences such as epidemiology, biostatistics, economics, and behavioral science to the assessment of health, health interventions, and outcomes. However, despite its palpable importance, applied translational research remains underfunded and underutilized. Using their own innovative research as a prototype, two young and promising investigators provide insights not only into the enormous potential but also the gaps and hurdles of two specific areas of applied translational research, i.e., clinical decision analysis and health services research. The message is clear that if we are to understand and improve the health of people with epilepsy in clinics, hospitals, and communities, we must substantially increase research capacity to address the many gaps that thwart our progress in applied research in epilepsy. PMID- 23041289 TI - Magnetoencephalographic analysis of paroxysmal fast activity in patients with epileptic spasms. AB - PURPOSE: This study sought to demonstrate the origin and propagation of paroxysmal fast activity (PFA) in patients with epileptic spasms (ESs), using time-frequency analyses of magnetoencephalogram (MEG) PFA recordings. METHODS: A 204-channel helmet-shaped MEG, with a 600Hz sampling rate, was used to examine PFA in 3 children with ESs. We analyzed MEG recordings of PFA by short-time Fourier transform and the aberrant area or high-power spectrum was superimposed onto reconstructed three-dimensional magnetic resonance images as moving images. One ictal discharge was collected. One child and one adult with PFA due to Lennox Gastaut syndrome were also examined for comparison. RESULTS: All four PFAs in Patient 1 and five PFAs in Patient 3 were generated from one hemisphere. In Patient 2, four of seven PFAs were generated from one hemisphere and the remaining three were generated from both hemispheres. In Patient 3, one ictal MEG showed ictal discharges that were generated from the same area as the PFA, although the electroencephalogram showed no discharge. In Patients with Lennox Gastaut syndrome, all 10 PFAs were generated from bilateral hemispheres simultaneously. CONCLUSION: Short-time Fourier transform analyses of MEG PFA can show the origin and form of propagation of PFA. These results suggest that ESs are representative of focal seizures and the mechanism of PFA is different between ESs and Lennox-Gastaut syndrome. PMID- 23041290 TI - Endothelin-1 induces hypoxia inducible factor 1alpha expression in pulmonary artery smooth muscle cells. AB - Endothelin-1 (ET-1) dose-dependently increased HIF1alpha expression in pulmonary artery smooth muscle cells (PASMCs). Inhibition of protein synthesis did not affect ET-1-induced HIF1alpha expression. The maximum effect of ET-1 was similar to that caused by proteasome inhibitor MG132. Further study indicates that ET-1 also dose-dependently stimulated calcineurin activation, specific calcineurin inhibitor cyclosporine A (CsA), abolished ET-1-induced HIF1alpha elevation, and reversed ET-1-induced RACK1 (receptor of activated protein kinase C 1) de phosphorylation. Endothelin receptor A was found to specifically mediate the effects of ET-1. To examine whether RACK1 is particularly involved in proteasome dependent HIF1alpha degradation, RACK1 was silenced by siRNA transfection. Cells lacking RACK1 exhibited significant elevation of HIF1alpha protein level. Taken together, our study suggests that ET-1 suppressed proteasome-dependent HIF1alpha degradation by calcineurin-dependent RACK1 de-phosphorylation. PMID- 23041292 TI - Activation of calcium-insensitive phospholipase A(2) (iPLA(2)) by P2X(7) receptors in murine peritoneal macrophages. AB - Free fatty acid releases are triggered by PLA2 activation and are substrates for many enzymes such as cyclooxygenases. These reactions are responsible for the production of many prostaglandins implicated in the inflammation yet many purinergic receptors have been implicated in diseases characterised by chronic inflammation. The role of P2X receptors was evaluated in LPS-primed murine peritoneal macrophages which were labelled with either [(3)H]-oleic acid or [(3)H]-arachidonic acid. Ten MUmolar thapsigargin and 1mM ATP stimulated the release of both unsaturated acids. ATP had no effect at 10 MUM and ivermectin had no effect on the response to ATP. The response to ATP was inhibited by magnesium and was not observed with cells from P2X(7)(-/-) mice. The response to ATP was not affected by the removal of extracellular calcium and was inhibited by arachidonyltrifluoromethyl ketone and bromoenol lactone but not by pyrrophenone. The release of the [(3)H]-fatty acids by ATP and thapsigargin was diminished by PD-98058, an inhibitor of MEK-1. It was concluded that in LPS-primed macrophages, P2X(7) receptors, not P2X(4) receptors, activated an iPLA(2) and promoted the release of unsaturated fatty acids secondary to the activation of a kinase. This response might contribute to the inflammation provoked by extracellular ATP. PMID- 23041293 TI - Effects of tissue hydration on nanoscale structural morphology and mechanics of individual Type I collagen fibrils in the Brtl mouse model of Osteogenesis Imperfecta. AB - Type I collagen is the most abundant protein in mammals, and is a vital part of the extracellular matrix for numerous tissues. Despite collagen's importance, little is known about its nanoscale morphology in tissues and how morphology relates to mechanical function. This study probes nanoscale structure and mechanical properties of collagen as a function of disease in native hydrated tendons. Wild type tendon and tendon from the Brtl/+ mouse model of Osteogenesis Imperfecta were investigated. An atomic force microscope (AFM) was used to image and indent minimally-processed collagen fibrils in hydrated and dehydrated conditions. AFM was used because of the ability to keep biological tissues as close to their native in situ conditions as possible. The study demonstrated phenotypic difference in Brtl/+ fibril morphology and mechanics in hydrated tendon which became more compelling upon dehydration. Dried tendons had a significant downward shift in fibril D-periodic spacing versus a shift up in wet tendons. Nanoscale changes in morphology in dry samples were accompanied by significant increases in modulus and adhesion force and decreased indentation depth. A minimal mechanical phenotype existed in hydrated samples, possibly due to water masking structural defects within the diseased fibrils. This study demonstrates that collagen nanoscale morphology and mechanics are impacted in Brtl/+ tendons, and that the phenotype can be modulated by the presence or absence of water. Dehydration causes artifacts in biological samples which require water and this factor must be considered for studies at any length scale in collagen-based tissues, especially when characterizing disease-induced differences. PMID- 23041294 TI - Needle-like grains across growth lines in the coral skeleton of Porites lobata. AB - The skeletal texture and crystal morphology of the massive reef-building coral Porites lobata were observed from the nano- to micrometer scale using an analytical transmission electron microscope (ATEM). The skeletal texture consists of centers of calcification (COCs) and fiber area. Fiber areas contain bundles of needle-like aragonite crystals that are elongated along the crystallographic c axis and are several hundred nanometers to one micrometer in width and several micrometers in length. The size distribution of aragonite crystals is relatively homogeneous in the fibers. Growth lines are observed sub-perpendicular to the direction of aragonite growth. These growth lines occur in 1-2 MUm intervals and reflect a periodic contrast in the thickness of an ion-spattered sample and pass through the interior of some aragonite crystals. These observations suggest that the medium filled in the calcification space maintains a CaCO3-supersaturated state during fiber growth and that a physical change occurs periodically during the aragonite crystals of the fiber area. PMID- 23041291 TI - Cytochrome P450 2J2 is protective against global cerebral ischemia in transgenic mice. AB - Cytochrome P450 epoxygenase metabolites of arachidonic acid, EETs, have multiple cardiovascular effects, including reduction of blood pressure, protection against myocardial ischemia-reperfusion injury, and attenuation of endothelial apoptosis. This study investigated the hypothesis that transgenic mice with endothelial overexpression of CYP2J2 (Tie2-CYP2J2-Tr) would be protected against global cerebral ischemia induced by bilateral common carotid artery occlusion (BCCAO) and action mechanisms of EETs on cerebral ischemia in cultures of astrocytes exposed to oxygen-glucose deprivation (OGD). Tie2-CYP2J2-Tr mice had significantly increased CYP2J2 expression, increased 14,15-EET production, increases regional cerebral blood flow (rCBF) and microvascular density, decreased ROS production, decreased brain infarct size and apoptosis after ischemia compared to wild type mice, these were associated with increased activation of the PI3K/AKT and apoptosis-related protein in ischemic brain. Addition of exogenous EETs or CYP2J2 transfection attenuated OGD-induced apoptosis in astrocytes via activation of PI3K/AKT and anti-apoptosis pathways. However, these effects were reduced by pretreatments with inhibitor of the PI3K (LY294002) and 14,15-EET (14,15-EEZE), respectively. These results indicate that CYP2J2 overexpression exerts marked neuroprotective effects against ischemic injury by a mechanism linked to increased level of circulating EETs and increases CBF and reduction of apoptosis. PMID- 23041295 TI - Recycled water for stream flow augmentation: benefits, challenges, and the presence of wastewater-derived organic compounds. AB - Stream flow augmentation with recycled water has the potential to improve stream habitat and increase potable water supply, but the practice is not yet well understood or documented. The objectives of this report are to present a short review illustrated by a case study, followed by recommendations for future stream flow augmentation projects. Despite the fact that wastewater discharge to streams is commonplace, a water agency pursuing stream flow augmentation with recycled water will face unique challenges. For example, recycled water typically contains trace amounts of organic wastewater-derived compounds (OWCs) for which the potential ecological risks must be balanced against the benefits of an augmentation project. Successful stream flow augmentation with recycled water requires that the lead agency clearly articulate a strong project rationale and identify key benefits. It must be assumed that the public will have some concerns about water quality. Public acceptance may be better if an augmentation project has co-benefits beyond maintaining stream ecosystems, such as improving water system supply and reliability (i.e. potable use offset). Regulatory or project specific criteria (acceptable concentrations of priority OWCs) would enable assessment of ecosystem impacts and demonstration of practitioner compliance. Additional treatment (natural or engineered) of the recycled water may be considered. If it is not deemed necessary or feasible, existing recycled water quality may be adequate to achieve project goals depending on project rationale, site and water quality evaluation, and public acceptance. PMID- 23041296 TI - Isolation and characterization of LIGHT (TNFSF14) gene homologue in zebrafish (Danio rerio). AB - The tumor necrosis factor superfamily (TNFSF) proteins are cytokines involved in many biological processes. In this study, the TNF superfamily member 14 (TNFSF14, LIGHT) has been isolated from zebrafish Danio rerio (designated zLIGHT). The full length open reading frame (ORF) of zLIGHT cDNA consists of 708 bp encoding a protein of 235 amino acids. The zLIGHT open reading frame (ORF) genomic sequence consists of three introns and four exons, is about 9.9 kb in size. Real-time quantitative PCR (qPCR) analysis suggested that zLIGHT was predominantly expressed in zebrafish spleen. The soluble LIGHT (zsLIGHT) had been cloned into the pSUMO vector, SDS-PAGE and Western blotting analysis confirmed that the recombinant protein SUMO-zsLIGHT was efficiently expressed in Escherichia coli BL21 (DE3). Laser scanning confocal microscopy analysis showed that SUMO-zsLIGHT could bind to its receptors on T cells. LIGHT is involved in many important biological effects, including up-regulating proinflammatory chemokines, cytokines, inducing cell death, apoptosis, and enhancing T cell survival. Zebrafish may conduct as a model animal for further research on LIGHT. PMID- 23041297 TI - Processing of prosodic changes in natural speech stimuli in school-age children. AB - Speech prosody conveys information about important aspects of communication: the meaning of the sentence and the emotional state or intention of the speaker. The present study addressed processing of emotional prosodic changes in natural speech stimuli in school-age children (mean age 10 years) by recording the electroencephalogram, facial electromyography, and behavioral responses. The stimulus was a semantically neutral Finnish word uttered with four different emotional connotations: neutral, commanding, sad, and scornful. In the behavioral sound-discrimination task the reaction times were fastest for the commanding stimulus and longest for the scornful stimulus, and faster for the neutral than for the sad stimulus. EEG and EMG responses were measured during non-attentive oddball paradigm. Prosodic changes elicited a negative-going, fronto-centrally distributed neural response peaking at about 500 ms from the onset of the stimulus, followed by a fronto-central positive deflection, peaking at about 740 ms. For the commanding stimulus also a rapid negative deflection peaking at about 290 ms from stimulus onset was elicited. No reliable stimulus type specific rapid facial reactions were found. The results show that prosodic changes in natural speech stimuli activate pre-attentive neural change-detection mechanisms in school-age children. However, the results do not support the suggestion of automaticity of emotion specific facial muscle responses to non-attended emotional speech stimuli in children. PMID- 23041298 TI - Broad ranges of affinity and specificity of anti-histone antibodies revealed by a quantitative peptide immunoprecipitation assay. AB - Antibodies directed against histone posttranslational modifications (PTMs) are critical tools in epigenetics research, particularly in the widely used chromatin immunoprecipitation (ChIP) experiments. However, a lack of quantitative methods for characterizing such antibodies has been a major bottleneck in accurate and reproducible analysis of histone modifications. Here, we report a simple and sensitive method for quantitatively characterizing polyclonal and monoclonal antibodies for histone PTMs in a ChIP-like format. Importantly, it determines the apparent dissociation constants for the interactions of an antibody with peptides harboring cognate or off-target PTMs. Analyses of commercial antibodies revealed large ranges of affinity, specificity and binding capacity as well as substantial lot-to-lot variations, suggesting the importance of quantitatively characterizing each antibody intended to be used in ChIP experiments and optimizing experimental conditions accordingly. Furthermore, using this method, we identified additional factors potentially affecting the interpretation of ChIP experiments. PMID- 23041299 TI - Analysis of structure-function relationships in the colibactin-maturating enzyme ClbP. AB - pks genomic island of Escherichia coli is involved in the synthesis of the non ribosomal peptide-type genotoxin colibactin, which has been suggesting as affecting the host immune response and having an impact on cancer development. The pks-encoded enzyme ClbP is an atypical peptidase that contributes to the synthesis of colibactin. In this work, we identified key features of ClbP. Bacterial fractionation and Western-blot analysis revealed the docking of ClbP to the bacterial inner membrane via a C-terminal domain harboring three predicted transmembrane helices. Whereas only one helix was necessary for the location in the inner membrane, the complete sequence of the C-terminal domain was necessary for ClbP bioactivity. In addition, the N-terminal sequence of ClbP allowed the SRP/Sec/YidC- and MreB-dependent translocation of the enzymatic domain in the periplasmic compartment, a feature also essential for ClbP bioactivity. Finally, the comparison of ClbP structure with that of the paralogs FmtA-like and AmpC revealed at an extremity of the catalytic groove a negative electrostatic potential surface characteristic of ClbP. Site-directed mutagenesis experiments identified in this zone two aspartic residues that were important for ClbP bioactivity. Overall, these results suggest a model for precolibactin activation by ClbP and pave a way for the design of inhibitors targeting colibactin production. PMID- 23041301 TI - Modeling neurogenesis impairment in Down syndrome with induced pluripotent stem cells from Trisomy 21 amniotic fluid cells. AB - Down syndrome (DS), or Trisomy 21 (T21) syndrome, one of the most common chromosomal abnormalities, is caused by an extra duplication of chromosome 21. In studies of neuron development, experimental models based on human cells are considered to be the most desired and accurate for basic research. The generation of diseased induced pluripotetn stem (iPS) cell is a critical step in understanding the developmental stages of complex neuronal diseases. Here, we generated human DS iPS cell lines from second trimester amniotic fluid (AF) cells with T21 by co-expressing Yamanaka factors through lentiviral delivery and subsequently differentiated them into neuronal progenitor cells (NPCs) for further analyses. T21 AF-iPS cells were characterized for the expression of pluripotent markers and for their ability to differentiate into all three germ layers by forming embryoid bodies in vitro and teratomas in vivo. The T21 AF-iPS cells maintained their unique pattern of chromosomal karyotypes: three pairs of chromosome 21. The level of amyloid precursor protein was significantly increased in NPCs derived from T21 AF-iPS cells compared with NPCs from normal AF-iPS cells. The expression levels of miR-155 and miR-802 in T21 AF-iPS-NPCs were highly elevated in the presence of low expression of MeCP2. We observed that T21 iPS-NPCs generated fewer neurons compared with controls. T21 iPS-NPCs exhibit developmental defects during neurogenesis. Our findings suggest that T21 AF-iPS cells serve as a good source to further elucidate the impairment neurogenesis of DS and the onset of Alzheimer's disease. PMID- 23041300 TI - The weight-bearing scanogram technique provides better coronal limb alignment than the navigation technique in open high tibial osteotomy. AB - BACKGROUND: Successful outcomes following high tibial osteotomy (HTO) require precise realignment of the mechanical axis of the lower extremity. The present study investigated whether the weight-bearing limb scanogram (WBS) technique provided a more accurate mechanical axis realignment than the navigation technique in open high tibial osteotomy (OHTO). METHODS: This prospective study involved 80 knees (78 patients) undergoing OHTO. The WBS technique was used in 40 knees and the navigation technique in 40 knees. Each technique was performed by a different surgeon in a different hospital. Postoperative coronal limb alignment was assessed using the weight-bearing line (WBL) ratio on full-length standing hip-to-ankle radiographs. RESULTS: We found that the mean postoperative WBL ratio was greater in the WBS compared to the navigation group (p=0.001), and hence the ratio for the WBS group was closer to the ratio target of 62%. There was a greater proportion of WBL ratio outliers in the navigation group than the WBS group (25% vs. 10%, p=0.034). CONCLUSION: We conclude that the WBS technique was more accurate than the navigation technique for restoration of coronal leg alignment in OHTO. LEVEL OF EVIDENCE: Level II. PMID- 23041302 TI - Analgesic effectiveness of transversus abdominis plane blocks after hysterectomy: a meta-analysis. AB - To determine the effectiveness of transversus abdominis plane blocks in gynecological surgery by systematic review and meta-analysis. Embase, MEDLINE and the Cochrane Library (CENTRAL) bibliographic databases were searched using a Cochrane Library search strategy modified for gynecological surgery. We included randomized controlled trials comparing transversus abdominis plane block with no block or placebo block. We retrieved 681 citations from which we included five published studies (225 randomized participants) which fulfilled our inclusion criteria, and identified a further six ongoing studies. Quality was assessed across six risk of bias domains: randomization sequence generation, allocation concealment, blinding, missing outcome data, selective reporting and other biases. Data were meta-analyzed where possible and presented as mean differences with 95% confidence intervals. Study quality was moderate. Compared with no block or saline placebo, transversus abdominis plane block provided significantly less postoperative pain at rest on a 10 cm visual analog scale at 2h (mean difference 2.14 cm, 95% confidence interval (CI) -3.57 to -0.71) but not at 24h postoperatively (-0.52 cm, 95% CI -1.49 to 0.45). Pain on movement showed similar results. Transversus abdominis plane block resulted in significantly less postoperative requirement for morphine use at 24h (-11.76 mg, 95% CI -18.77 to 4.75) but not at 48 h (-16.01 mg, 95% CI -39.40 to 7.39). Evidence exists for the short-term efficacy (within 24 h) of transversus abdominis plane blocks during hysterectomy in terms of reported pain and morphine consumption, which may not be sustained at 48 h. Updates to this review should be undertaken periodically, and until further robust evidence is available, anesthetists should not rush to adopt this procedure into routine practice. PMID- 23041303 TI - Association between donor and recipient TCF7L2 gene polymorphisms and the risk of new-onset diabetes mellitus after liver transplantation in a Han Chinese population. AB - BACKGROUNDS & AIMS: New-onset diabetes mellitus (NODM) is a frequent and serious complication arising after liver transplantation (LT). Transcription factor 7 like 2 (TCF7L2) polymorphisms have been reported to strongly associate with type 2 diabetes. In addition, the donor liver plays a vital role in regulating blood glucose levels. In this study, we aim at evaluating the association between donor and recipient TCF7L2 gene polymorphisms with NODM after LT. METHODS: A total of 125 patients undergoing primary LT, without a history of diabetes were included. Four single nucleotide polymorphisms (rs290487, rs7903146, rs11196205, and rs12255372), closely associated with type 2 diabetes in the Eastern Asia population, were genotyped and analyzed. RESULTS: Both donor and recipient rs290487 polymorphisms (CC vs. TT genotype) were found to be significantly associated with NODM. In multivariate analysis, donor rs290487 genetic variation (OR = 2.172 per each C allele, p = 0.015), blood tacrolimus levels at 1 month post-LT >10 ng/ml (OR = 3.264, p = 0.017), and recipient age >55 years (OR = 2.638, p = 0.043) were identified as independent risk factors of NODM. Furthermore, donor rs290487 CC genotype could predict a high probability (>40%) of the onset of NODM. Predictive model containing donor rs290487 polymorphism showed a significantly higher prognostic ability on NODM than the model with only clinical parameters (p = 0.031). CONCLUSIONS: Donor TCF7L2 rs290487 polymorphism is associated with an increased risk of NODM after LT and has a potential clinical value for the prediction of NODM. PMID- 23041304 TI - Hepatocellular carcinoma locoregional therapies for patients in the waiting list. Impact on transplantability and recurrence rate. AB - The practice of treating candidates for liver transplantation (LT) for hepatocellular carcinoma (HCC), with locoregional therapies, is common in most transplant centers. However, for T1 tumors and expected waiting times to LT <6 months, there is no evidence that these treatments are beneficial. For T2 tumors and for longer waiting times, neo-adjuvant treatments are usually performed with transarterial chemoembolization (TACE), ablation techniques and liver resection in selected cases. The treatment choice should be based on the BCLC staging system. At present, there is no evidence of the superiority of ablation/resection vs. TACE, but some studies showed better results of the former in achieving a complete response. The response to neo-adjuvant treatments should be evaluated through mRECIST criteria, but few studies adopted these criteria and properly analyzed factors affecting response. The simultaneous evaluation of the impact of neo-adjuvant therapies on dropout rate, post-LT HCC recurrence and patient survival is rarely reported. Tumor stage and volume, alpha-fetoprotein levels, response to treatments and liver function affect pre-LT outcomes. These same factors, together with vascular invasion and poor tumor differentiation, are major determinants of poor post-LT outcomes. Due to the low number of prospective studies with well-defined entry criteria and the variability of results, the role of downstaging is still to be defined. Novel molecular markers seem promising for the estimation of prognosis and/or response to treatments. With a persistent scarcity of organ donors, neo-adjuvant treatments can help identify patients with different probabilities of cancer progression, and consequently balance the priority of HCC and non-HCC-candidates through revised additional scores for HCC. PMID- 23041305 TI - Dysbalance in sympathetic neurotransmitter release and action in cirrhotic rats: impact of exogenous neuropeptide Y. AB - BACKGROUND & AIMS: Splanchnic vasodilation is an essential disturbance in portal hypertension. Increased systemic sympathetic nerve activity is well known, but potential corresponding vascular desensitization is incompletely characterized. Release of splanchnic sympathetic neurotransmitters noradrenaline (NA) and co transmitter neuropeptide Y (NPY) remains to be elucidated. Finally, the effects of exogenous NPY on these mechanisms are unexplored. METHODS: Portal vein ligated cirrhotic, and control rats were used for in vitro perfusion of mesenteric arteries. Depletion of vascular pressure response was induced by repetitive electric sympathetic perivascular nerve stimulation (PNS) and performed in the absence and presence of exogenous NPY. Additionally, PNS-induced release of NA and NPY was measured. RESULTS: Mesenteric PNS-induced pressure response was lower in portal hypertension. Depletion of the pressure response to PNS, representing the degree of desensitization, was enhanced in portal hypertension. NA release was elevated, whereas NPY release was attenuated in cirrhosis. Administration of exogenous NPY led to marked recovery from desensitization and vasoconstrictive improvement in cirrhotic rats, being associated with more pronounced decrease of NA release. CONCLUSIONS: Pronounced depletion of splanchnic arterial pressure response to repetitive sympathetic nerve stimulation in cirrhosis is partly attributable to altered NA release as well as to deficient NPY release. External NPY restores vascular contractility and attenuates pathologically elevated NA release in the portal hypertensive mesenteric vasculature, revealing post-, and prejunctional effects at the vascular smooth muscle motor endplate; therefore outlining encouraging therapeutic strategies. PMID- 23041306 TI - Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green. AB - BACKGROUND & AIMS: Although recent advances in preoperative imaging have enabled accurate estimation of the regional liver volume with venous occlusion, the extent of functional decrease in such regions remains unclear. In this study, the portal uptake function in postoperative veno-occlusive regions and non-veno occlusive regions was evaluated by intraoperative fluorescent imaging after intravenous injection of indocyanine green (ICG). METHODS: In 22 liver resection patients and 23 recipients and 18 donors of liver transplantation, fluorescent intensity on the remnant liver or the liver graft was evaluated in real time following intravenous injection of ICG (0.0025 mg per 1 ml of remnant liver volume). RESULTS: Plateau ICG concentrations were significantly lower in the veno occlusive regions (C(VO)) than in the non-veno-occlusive regions (C(Non)) in liver resection patients (median [range], 0.75 [0.29-2.0]MUg/ml vs. 3.0 [0.46 6.4]MUg/ml, p<0.001), donors (0.69 [0.29-1.9]MUg/ml vs. 2.4 [0.46-6.4]MUg/ml, p<0.001), and recipients (0.75 [0.34-1.8]MUg/ml vs. 1.8 [0.54-6.4]MUg/ml, p<0.001). Distributions of the C(VO)/C(Non) and the ratio of the hepatic uptake rate constant in the veno-occlusive regions to that in non-veno-occlusive regions were both around 40% (mean +/- standard deviation, 0.36 +/- 0.17 and 0.42 +/- 0.16, respectively). When the functional remnant liver volume was calculated as a sum of non-veno-occlusive regions and veno-occlusive regions multiplied by C(VO)/C(Non), its ratio to the total liver volume was correlated with the improved postoperative/preoperative ratio of prothrombin time. CONCLUSIONS: Portal uptake function in veno-occlusive regions is approximately 40% of that in non-veno-occlusive regions. Intraoperative ICG-fluorescent imaging enables real time evaluation of the extent of the functional decrease in veno-occlusive regions, enhancing accurate estimation of the hepatic functional reserve for determining the surgical indications and procedures. PMID- 23041307 TI - Host-targeting agents for prevention and treatment of chronic hepatitis C - perspectives and challenges. AB - Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma worldwide. Furthermore, HCV-induced liver disease is a major indication of liver transplantation. In the past years, direct-acting antivirals (DAAs) targeting HCV enzymes have been developed. DAAs increase the virologic response to anti-HCV therapy but may lead to selection of drug resistant variants and treatment failure. To date, strategies to prevent HCV infection are still lacking and antiviral therapy in immunocompromised patients, patients with advanced liver disease and HIV/HCV-co-infection remains limited. Alternative or complementary approaches addressing the limitations of current antiviral therapies are to boost the host's innate immunity or interfere with host factors required for pathogenesis. Host-targeting agents (HTAs) provide an interesting perspective for novel antiviral strategies against viral hepatitis since they have (i) a high genetic barrier to resistance, (ii) a pan-genotypic antiviral activity, and (iii) complementary mechanisms of action to DAAs and might therefore act in a synergistic manner with current standard of care or DAAs in clinical development. This review highlights HTAs against HCV infection that have potential as novel antivirals and are in preclinical or clinical development. PMID- 23041308 TI - Next generation sequencing of the Ago2 interacting transcriptome identified chemokine family members as novel targets of neuronal microRNAs in hepatic stellate cells. AB - BACKGROUND & AIMS: After myofibroblastic transdifferentiation, hepatic stellate cells (HSC), mainly involved in liver fibrosis by extracellular matrix production, exhibit an altered growth factor profile including increased expression of neuronal mediators. Here, we analyzed putative targets of neuronal microRNAs miR-9, miR-125b, and miR-128 by deep sequencing of the transcript population, interacting with the miRNA/Argonaute 2 (Ago2) complex in myofibroblastic HSC. METHODS: MicroRNA expression was quantified by real-time PCR in primary HSC, isolated from the rat or human liver. Myofibroblastic HSC were transfected either with mimics or inhibitors of miR-9, miR-125b, and miR-128. RNA from immunoprecipitated Ago2-miRNA/transcript complexes was purified and used for next generation sequencing. Additionally, gene expression was investigated in quiescent and activated primary HSC, treated with the miR-128 mimic or inhibitor, by microarray analysis. RESULTS: During myofibroblastic transdifferentiation of HSC, miR-9, miR-125b, and miR-128 expression was markedly increased. Transcriptome analysis of Ago2 bound mRNA by deep sequencing identified a broad spectrum of transcripts that interact with neuronal miRNAs in myofibroblastic HSC. In particular, in HSC overexpressing miR-128, many members of the chemokine family were bound to the Ago2 repression complex. Furthermore, a comprehensive profiling of gene expression demonstrates the high impact of neuronal miRNAs on the chemokine network. CONCLUSIONS: Ago2 immunoprecipitation followed by deep sequencing is a useful tool to identify novel miRNA targets. Upregulation of neuronal miR-9, miR-125b, and miR-128 during myofibroblastic transition and the identified interaction with a wide range of chemokines and chemokine receptors suggest a prominent role of neuronal miRNAs in the inflammatory response of HSC during fibrosis. PMID- 23041309 TI - [Cancers of the nasal cavity and paranasal sinuses: clinicopathological, etiological and therapeutic aspects]. AB - Sinonasal cancers are rare and are often associated with occupational exposure that should be researched. Their diagnosis is often delayed. Carcinomas are the most common histological variety. The aim of the present report is to review the main scientific literature about sinonasal cancer to identify their clinicopathological features, and their main causes and treatment modalities. The treatment of these tumors is surgical, usually followed by radiotherapy. PMID- 23041310 TI - Non-monotonic dose effects of in utero exposure to di(2-ethylhexyl) phthalate (DEHP) on testicular and serum testosterone and anogenital distance in male mouse fetuses. AB - Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant. Epidemiological studies suggest that DEHP decreases masculinization of male fetuses. Numerous rat studies report DEHP reduces fetal testosterone production at doses greatly exceeding human exposure. We fed pregnant CD-1 mice 0.5-500,000 MUg/kg/day DEHP from gestation day (GD) 9-18 and examined mothers and male fetuses on GD 18. We assessed non-monotonic dose-response by adding a quadratic term to a simple linear regression model. Except at the 500,000 MUg/kg/day dose, DEHP stimulated an increase in maternal and fetal serum testosterone and increased anogenital distance (AGD). Non-monotonic dose-response curves were noted for AGD and maternal, and testis testosterone (P values 0.013-0.021). Because data from our highest dose (500,000 MUg/kg/day) did not differ significantly from controls, this dose could have been incorrectly assumed to be the NOAEL had we only tested very high doses, as is typical in studies for regulatory agencies. PMID- 23041311 TI - DSIF restricts NF-kappaB signaling by coordinating elongation with mRNA processing of negative feedback genes. AB - NF-kappaB is central for immune response and cell survival, and its deregulation is linked to chronic inflammation and cancer through poorly defined mechanisms. IkappaBalpha and A20 are NF-kappaB target genes and negative feedback regulators. Upon their activation by NF-kappaB, DSIF is recruited, P-TEFb is released, and their elongating polymerase II (Pol II) C-terminal domain (CTD) remains hypophosphorylated. We show that upon DSIF knockdown, mRNA levels of a subset of NF-kappaB targets are not diminished; yet much less IkappaBalpha and A20 protein are synthesized, and NF-kappaB activation is abnormally prolonged. Further analysis of IkappaBalpha and A20 mRNA revealed that a significant portion is uncapped, unspliced, and retained in the nucleus. Interestingly, the Spt5 C terminal repeat (CTR) domain involved in elongation stimulation through P-TEFb is dispensable for IkappaBalpha and A20 regulation. These findings assign a function for DSIF in cotranscriptional mRNA processing when elongating Pol II is hypophosphorylated and define DSIF as part of the negative feedback regulation of NF-kappaB. PMID- 23041312 TI - Programmed cell-to-cell variability in Ras activity triggers emergent behaviors during mammary epithelial morphogenesis. AB - Variability in signaling pathway activation between neighboring epithelial cells can arise from local differences in the microenvironment, noisy gene expression, or acquired genetic changes. To investigate the consequences of this cell-to-cell variability in signaling pathway activation on coordinated multicellular processes such as morphogenesis, we use DNA-programmed assembly to construct three-dimensional MCF10A microtissues that are mosaic for low-level expression of activated H-Ras. We find two emergent behaviors in mosaic microtissues: cells with activated H-Ras are basally extruded or lead motile multicellular protrusions that direct the collective motility of their wild-type neighbors. Remarkably, these behaviors are not observed in homogeneous microtissues in which all cells express the activated Ras protein, indicating that heterogeneity in Ras activity, rather than the total amount of Ras activity, is critical for these processes. Our results directly demonstrate that cell-to-cell variability in pathway activation within local populations of epithelial cells can drive emergent behaviors during epithelial morphogenesis. PMID- 23041313 TI - Developmental plasticity is bound by pluripotency and the Fgf and Wnt signaling pathways. AB - Plasticity is a well-known feature of mammalian development, and yet very little is known about its underlying mechanism. Here, we establish a model system to examine the extent and limitations of developmental plasticity in living mouse embryos. We show that halved embryos follow the same strict clock of developmental transitions as intact embryos, but their potential is not equal. We have determined that unless a minimum of four pluripotent cells is established before implantation, development will arrest. This failure can be rescued by modulating Fgf and Wnt signaling to enhance pluripotent cell number, allowing the generation of monozygotic twins, which is an otherwise rare phenomenon. Knowledge of the minimum pluripotent-cell number required for development to birth, as well as the different potentials of blastomeres, allowed us to establish a protocol for splitting an embryo into one part that develops to adulthood and another that provides embryonic stem cells for that individual. PMID- 23041314 TI - A gradient of ATP affinities generates an asymmetric power stroke driving the chaperonin TRIC/CCT folding cycle. AB - The eukaryotic chaperonin TRiC/CCT uses ATP cycling to fold many essential proteins that other chaperones cannot fold. This 1 MDa hetero-oligomer consists of two identical stacked rings assembled from eight paralogous subunits, each containing a conserved ATP-binding domain. Here, we report a dramatic asymmetry in the ATP utilization cycle of this ring-shaped chaperonin, despite its apparently symmetric architecture. Only four of the eight different subunits bind ATP at physiological concentrations. ATP binding and hydrolysis by the low affinity subunits is fully dispensable for TRiC function in vivo. The conserved nucleotide-binding hierarchy among TRiC subunits is evolutionarily modulated through differential nucleoside contacts. Strikingly, high- and low-affinity subunits are spatially segregated within two contiguous hemispheres in the ring, generating an asymmetric power stroke that drives the folding cycle. This unusual mode of ATP utilization likely serves to orchestrate a directional mechanism underlying TRiC/CCT's unique ability to fold complex eukaryotic proteins. PMID- 23041315 TI - The KRAB-ZFP/KAP1 system contributes to the early embryonic establishment of site specific DNA methylation patterns maintained during development. AB - De novo DNA methylation is an essential aspect of the epigenetic reprogramming that takes place during early development, yet factors responsible for its instatement at particular genomic loci are poorly defined. Here, we demonstrate that the KRAB-ZFP-mediated recruitment of KAP1 to DNA in embryonic stem cells (ESCs) induces cytosine methylation. This process is preceded by H3K9 trimethylation, and genome-wide analyses reveal that it spreads over short distances from KAP1-binding sites so as to involve nearby CpG islands. In sharp contrast, in differentiated cells, KRAB/KAP1-induced heterochromatin formation does not lead to DNA methylation. Correspondingly, the methylation status of CpG islands in the adult mouse liver correlates with their proximity to KAP1-binding sites in ESCs, not in hepatocytes. Therefore, KRAB-ZFPs and their cofactor KAP1 are in part responsible for the establishment during early embryogenesis of site specific DNA methylation patterns that are maintained through development. PMID- 23041317 TI - A truncated form of IKKalpha is responsible for specific nuclear IKK activity in colorectal cancer. AB - Nuclear IKKalpha regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKKalpha activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples and found a significant association between the presence of nuclear IKK and malignancy. Importantly, the nucleus of tumor cells contains an active IKKalpha isoform with a predicted molecular weight of 45 kDa (p45-IKKalpha) that includes the kinase domain but lacks several regulatory regions. Active nuclear p45-IKKalpha forms a complex with nonactive IKKalpha and NEMO that mediates phosphorylation of SMRT and histone H3. Proteolytic cleavage of FL-IKKalpha into p45-IKKalpha is required for preventing the apoptosis of CRC cells in vitro and sustaining tumor growth in vivo. Our findings identify a potentially druggable target for treating patients with advance refractory CRC. PMID- 23041316 TI - Reactivation of latent HIV-1 by inhibition of BRD4. AB - HIV-1 depends on many host factors for propagation. Other host factors, however, antagonize HIV-1 and may have profound effects on viral activation. Curing HIV-1 requires the reduction of latent viral reservoirs that remain in the face of antiretroviral therapy. Using orthologous genetic screens, we identified bromodomain containing 4 (BRD4) as a negative regulator of HIV-1 replication. Antagonism of BRD4, via RNA interference or with a small molecule inhibitor, JQ1, both increased proviral transcriptional elongation and alleviated HIV-1 latency in cell-line models. In multiple instances, JQ1, when used in combination with the NF-kappaB activators Prostratin or PHA, enhanced the in vitro reactivation of latent HIV-1 in primary T cells. These data are consistent with a model wherein BRD4 competes with the virus for HIV-1 dependency factors (HDFs) and suggests that combinatorial therapies that activate HDFs and antagonize HIV-1 competitive factors may be useful for curing HIV-1 infection. PMID- 23041318 TI - Nucleocytoplasmic coagulation: an injury-induced aggregation event that disulfide crosslinks proteins and facilitates their removal by plasmin. AB - Cellular injury causes a myriad of processes that affect proteostasis. We describe nucleocytoplasmic coagulation (NCC), an intracellular disulfide dependent protein crosslinking event occurring upon late-stage cell death that orchestrates the proteolytic removal of misfolded proteins. In vitro and in vivo models of neuronal injury show that NCC involves conversion of soluble intracellular proteins, including tubulin, into insoluble oligomers. These oligomers, also seen in human brain tissue following neurotrauma, act as a cofactor and substrate for the plasminogen-activating system. In plasminogen(-/-) mice, levels of misfolded beta-tubulin were elevated and its clearance delayed following neurotrauma, demonstrating a requirement for plasminogen in the removal of NCC constituents. While additional in vivo studies will further dissect this phenomenon, our study clearly shows that NCC, a process analogous to the formation of thrombi, generates an aggregated protein scaffold that limits release of cellular components and recruits clearance mechanisms to the site of injury. PMID- 23041319 TI - Lysine deacetylases Hda1 and Rpd3 regulate Hsp90 function thereby governing fungal drug resistance. AB - The molecular chaperone Hsp90 is a hub of protein homeostasis and regulatory circuitry. Hsp90 function is regulated by posttranslational modifications including acetylation in mammals; however, whether this regulation is conserved remains unknown. In fungi, Hsp90 governs the evolution of drug resistance by stabilizing signal transducers. Here, we establish that pharmacological inhibition of lysine deacetylases (KDACs) blocks the emergence and maintenance of Hsp90-dependent resistance to the most widely deployed antifungals, the azoles, in the human fungal pathogen Candida albicans and the model yeast Saccharomyces cerevisiae. S. cerevisiae Hsp90 is acetylated on lysine 27 and 270, and key KDACs for drug resistance are Hda1 and Rpd3. Compromising KDACs alters stability and function of Hsp90 client proteins, including the drug-resistance regulator calcineurin. Thus, we establish acetylation as a mechanism of posttranslational control of Hsp90 function in fungi, functional redundancy between KDACs Hda1 and Rpd3, as well as a mechanism governing fungal drug resistance with broad therapeutic potential. PMID- 23041320 TI - Two mechanisms produce mutation hotspots at DNA breaks in Escherichia coli. AB - Mutation hotspots and showers occur across phylogeny and profoundly influence genome evolution, yet the mechanisms that produce hotspots remain obscure. We report that DNA double-strand breaks (DSBs) provoke mutation hotspots via stress induced mutation in Escherichia coli. With tet reporters placed 2 kb to 2 Mb (half the genome) away from an I-SceI site, RpoS/DinB-dependent mutations occur maximally within the first 2 kb and decrease logarithmically to ~60 kb. A weak mutation tail extends to 1 Mb. Hotspotting occurs independently of I-site/tet reporter-pair position in the genome, upstream and downstream in the replication path. RecD, which allows RecBCD DSB-exonuclease activity, is required for strong local but not long-distance hotspotting, indicating that double-strand resection and gap-filling synthesis underlie local hotspotting, and newly illuminating DSB resection in vivo. Hotspotting near DSBs opens the possibility that specific genomic regions could be targeted for mutagenesis, and could also promote concerted evolution (coincident mutations) within genes/gene clusters, an important issue in the evolution of protein functions. PMID- 23041321 TI - [Mechanical restraint: its use in intensive cares]. AB - OBJECTIVE: To analyze the impact of the use of mechanical restraint (MR) or physical restraints in a Critical Care unit and to evaluate the procedure. BASIC PROCEDURES: A descriptive, prospective study. INCLUSION CRITERIA: patients who required MR from March to June 2010. VARIABLES: demographic, clinical presentation, indications, techniques and devices. A statistical analysis with mean, standard deviation and percentages using the program SPSS 14.0. RESULTS: A total of 85 cases were studied: 65.9% male, mean age 64.19 (+/-17.9), NEMS 29.3 (+/-8.2). Incidence of MR: 15.6%. Main indication for MR: Risk of serious disruption of treatment processes (80%). Decision nurse (94.1%). Urgent action: (85.9%). Registration procedure: 57.6%. Information to the family: 9.4%. Previous actions: verbal containment (100%), pharmacological (48.2%). CONCLUSIONS: There is a relevant incidence of MR. The principal reason is that of avoiding interruption of the therapeutic process. The nurse makes the initial decision. Necessary information/training of professionals for legal and ethical repercussions is needed. PMID- 23041322 TI - Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease. AB - BACKGROUND & AIMS: Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1. METHODS: Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1-56 years; average, 12.7 +/- 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1. RESULTS: Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patient's height correlated inversely with platelet count (R(2) = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct. CONCLUSIONS: Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation; ClinicalTrials.gov number, NCT00068224. PMID- 23041323 TI - The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. AB - BACKGROUND & AIMS: Abnormal delivery of bile acids (BAs) to the colon as a result of disease or therapy causes constipation or diarrhea by unknown mechanisms. The G protein-coupled BA receptor TGR5 (or GPBAR1) is expressed by enteric neurons and endocrine cells, which regulate motility and secretion. METHODS: We analyzed gastrointestinal and colon transit, as well as defecation frequency and water content, in wild-type, knockout, and transgenic mice (trg5-wt, tgr5-ko, and tgr5 tg, respectively). We analyzed colon tissues for contractility, peristalsis, and transmitter release. RESULTS: Deoxycholic acid inhibited contractility of colonic longitudinal muscle from tgr5-wt but not tgr5-ko mice. Application of deoxycholic acid, lithocholic acid, or oleanolic acid (a selective agonist of TGR5) to the mucosa of tgr5-wt mice caused oral contraction and caudal relaxation, indicating peristalsis. BAs stimulated release of the peristaltic transmitters 5 hydroxytryptamine and calcitonin gene-related peptide; antagonists of these transmitters suppressed BA-induced peristalsis, consistent with localization of TGR5 to enterochromaffin cells and intrinsic primary afferent neurons. tgr5-ko mice did not undergo peristalsis or transmitter release in response to BAs. Mechanically induced peristalsis and transmitter release were not affected by deletion of tgr5. Whole-gut transit was 1.4-fold slower in tgr5-ko than tgr5-wt or tgr5-tg mice, whereas colonic transit was 2.2-fold faster in tgr5-tg mice. Defecation frequency was reduced 2.6-fold in tgr5-ko and increased 1.4-fold in tgr5-tg mice compared with tgr5-wt mice. Water content in stool was lower (37%) in tgr5-ko than tgr5-tg (58%) or tgr5-wt mice (62%). CONCLUSIONS: The receptor TGR5 mediates the effects of BAs on colonic motility, and deficiency of TGR5 causes constipation in mice. These findings might mediate the long-known laxative properties of BAs, and TGR5 might be a therapeutic target for digestive diseases. PMID- 23041324 TI - Activation of nuclear factor-kappaB in acinar cells increases the severity of pancreatitis in mice. AB - BACKGROUND & AIMS: Nuclear factor-kappaB (NF-kappaB) is activated during early stages of pancreatitis. This transcription factor regulates genes that control many cell activities, including inflammation and survival. There is evidence that activation of NF-kappaB protects against pancreatitis, and, in other cases, that it promotes this disease. We compared the effects of NF-kappaB in different mouse models of pancreatitis to understand these complications. METHODS: To model constitutive activation of NF-kappaB, we expressed a transgene that encodes its p65 subunit or the inhibitor of kappaB kinase (IKK)2 in pancreatic acinar cells of mice. We analyzed effects on pancreatic tissues and levels of NF-kappaB target genes in these mice and compared them with mice that did not express transgenic p65 or IKK2 (controls). RESULTS: Transgenic expression of p65 led to compensatory expression of the inhibitory subunit IKB-alpha and, therefore, no clear phenotype. However, p65 transgenic mice given injections of cerulein, to induce acute pancreatitis, had higher levels of NF-kappaB activity in acinar cells, greater levels of inflammation, and more severe outcomes than control mice. In contrast, constitutive expression of IKK2 directly increased the activity of NF kappaB in acinar cells and induced pancreatitis. Prolonged activity of IKK2 (3 months) resulted in activation of stellate cells, loss of acinar cells, and fibrosis, which are characteristics of chronic pancreatitis. Co-expression of IKK2 and p65 greatly increased the expression of inflammatory mediators and the severity of pancreatitis, compared with control mice. CONCLUSIONS: The level of NF-kappaB activation correlates with the severity of acute pancreatitis in mice. Longer periods of activation (3 months) lead to chronic pancreatitis. These findings indicate that strategies to inactivate NF-kappaB might be used to treat patients with acute or chronic pancreatitis. PMID- 23041325 TI - Multispectral endoscopic imaging of colorectal dysplasia in vivo. PMID- 23041327 TI - The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice. AB - BACKGROUND & AIMS: Non-alcoholic steatohepatitis is characterized by hepatic steatosis with inflammation. Although steatosis is benign and reversible, inflammation can increase liver damage. Hepatic inflammation has been associated with accumulation of cholesterol in lysosomes of Kupffer cells. 27 Hydroxycholesterol (27HC), a derivative of cholesterol formed by CYP27A1, can mobilize cholesterol from the lysosomes to the cytoplasm. We investigated whether 27HC can change the intracellular distribution cholesterol and reduce hepatic inflammation in mice. METHODS: We transplanted bone marrow from irradiated wild type or Cyp27a1(-/-) mice to mice that do not express the low density lipoprotein receptor (Ldlr(-/-)), which are hyperlipidemic; 9 weeks later, mice were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 3 months. In a separate experiment, Ldlr(-/-) mice were given subcutaneous injections of 27HC and placed on regular chow or HFC diets for 3 weeks. Blood and liver tissues samples were collected and analyzed for intracellular cholesterol distribution and inflammation. RESULTS: In Ldlr(-/-) mice that received bone marrow transplants from Cyp27a1(-/-) mice, lysosomes of Kupfer cells had a greater accumulation of cholesterol than those of mice that received bone marrow from wild-type mice, after the HFC diet. Liver histology and gene expression analyses showed increased inflammation and liver damage in mice given bone marrow transplants from Cyp27a1(-/-) mice and placed on the HFC diet. Administration of 27HC to Ldlr(-/-) mice, following the HFC diet, reduced the accumulation of lysosomal cholesterol and hepatic inflammation, compared with mice that were not given 27HC. CONCLUSIONS: Accumulation of cholesterol in lysosomes of Kupfer cells promotes hepatic inflammation in mice. The cholesterol derivative 27HC reduces accumulation of cholesterol in lysosomes and might be used to treat non-alcoholic steatohepatitis. PMID- 23041326 TI - Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis. AB - BACKGROUND & AIMS: Interleukin (IL)-8 has an important role in initiating inflammation in humans, attracting immune cells such as neutrophils through their receptors CXCR1 and CXCR2. IL-8 has been proposed to contribute to chronic inflammation and cancer. However, mice do not have the IL-8 gene, so human cancer cell lines and xenograft studies have been used to study the role of IL-8 in colon and gastric carcinogenesis. We generated mice that carry a bacterial artificial chromosome that encompasses the entire human IL-8 gene, including its regulatory elements (IL-8Tg mice). METHODS: We studied the effects of IL-8 expression in APCmin(+/-) mice and IL-8Tg mice given azoxymethane and dextran sodium sulfate (DSS). We also examined the effects of IL-8 expression in gastric cancer in INS-GAS mice that overexpress gastrin and IL-8Tg mice infected with Helicobacter felis. RESULTS: In IL-8Tg mice, expression of human IL-8 was controlled by its own regulatory elements, with virtually no messenger RNA or protein detectable under basal conditions. IL-8 was strongly up-regulated on systemic or local inflammatory stimulation, increasing mobilization of immature CD11b(+)Gr-1(+) myeloid cells (IMCs) with thioglycolate-induced peritonitis, DSS induced colitis, and H. felis-induced gastritis. IL-8 was increased in colorectal tumors from patients and IL-8Tg mice compared with nontumor tissues. IL-8Tg mice developed more tumors than wild-type mice following administration of azoxymethane and DSS. Expression of IL-8 increased tumorigenesis in APCmin(+/-) mice compared with APCmin(+/-) mice that lack IL-8; this was associated with increased numbers of IMCs and angiogenesis in the tumors. CONCLUSIONS: IL-8 contributes to gastrointestinal carcinogenesis by mobilizing IMCs and might be a therapeutic target for gastrointestinal cancers. PMID- 23041328 TI - Real-time optical biopsy of colon polyps with narrow band imaging in community practice does not yet meet key thresholds for clinical decisions. AB - BACKGROUND & AIMS: Accurate optical analysis of colorectal polyps (optical biopsy) could prevent unnecessary polypectomies or allow a "resect and discard" strategy with surveillance intervals determined based on the results of the optical biopsy; this could be less expensive than histopathologic analysis of polyps. We prospectively evaluated real-time optical biopsy analysis of polyps with narrow band imaging (NBI) by community-based gastroenterologists. METHODS: We first analyzed a computerized module to train gastroenterologists (N = 13) in optical biopsy skills using photographs of polyps. Then we evaluated a practice based learning program for these gastroenterologists (n = 12) that included real time optical analysis of polyps in vivo, comparison of optical biopsy predictions to histopathologic analysis, and ongoing feedback on performance. RESULTS: Twelve of 13 subjects identified adenomas with >90% accuracy at the end of the computer study, and 3 of 12 subjects did so with accuracy >=90% in the in vivo study. Learning curves showed considerable variation among batches of polyps. For diminutive rectosigmoid polyps assessed with high confidence at the end of the study, adenomas were identified with mean (95% confidence interval [CI]) accuracy, sensitivity, specificity, and negative predictive values of 81% (73% 89%), 85% (74%-96%), 78% (66%-92%), and 91% (86%-97%), respectively. The adjusted odds ratio for high confidence as a predictor of accuracy was 1.8 (95% CI, 1.3 2.5). The agreement between surveillance recommendations informed by high confidence NBI analysis of diminutive polyps and results from histopathologic analysis of all polyps was 80% (95% CI, 77%-82%). CONCLUSIONS: In an evaluation of real-time optical biopsy analysis of polyps with NBI, only 25% of gastroenterologists assessed polyps with >=90% accuracy. The negative predictive value for identification of adenomas, but not the surveillance interval agreement, met the American Society for Gastrointestinal Endoscopy-recommended thresholds for optical biopsy. Better results in community practice must be achieved before NBI-based optical biopsy methods can be used routinely to evaluate polyps; ClinicalTrials.gov number, NCT01638091. PMID- 23041329 TI - Health benefits and cost effectiveness of endoscopic and nonendoscopic cytosponge screening for Barrett's esophagus. AB - BACKGROUND & AIMS: We developed a model to compare the health benefits and cost effectiveness of screening for Barrett's esophagus by either CytospongeTM or by conventional endoscopy vs no screening, and to estimate their abilities to reduce mortality from esophageal adenocarcinoma. METHODS: We used microsimulation modeling of a hypothetical cohort of 50-year-old men in the United Kingdom with histories of gastroesophageal reflux disease symptoms, assuming the prevalence of Barrett's esophagus to be 8%. Participants were invited to undergo screening by endoscopy or Cytosponge (invitation acceptance rates of 23% and 45%, respectively), and outcomes were compared with those from men who underwent no screening. We estimated the number of incident esophageal adenocarcinoma cases prevented and the incremental cost-effectiveness ratio of quality-adjusted life years (QALYs) of the different strategies. Patients found to have high-grade dysplasia or intramucosal cancer received endotherapy. Model inputs included data on disease progression, test accuracy, post-treatment status, and surveillance protocols. Costs and benefits were discounted at 3.5% per year. Supplementary and sensitivity analyses comprised esophagectomy management of high-grade dysplasia or intramucosal cancer, screening by ultrathin nasal endoscopy, and different assumptions of uptake of screening invitations for either strategy. RESULTS: We estimated that compared with no screening, Cytosponge screening followed by treatment of patients with dysplasia or intramucosal cancer costs an additional $240 (95% credible interval, $196-$320) per screening participant and results in a mean gain of 0.015 (95% credible interval, -0.001 to 0.029) QALYs and an incremental cost-effectiveness ratio of $15.7 thousand (K) per QALY. The respective values for endoscopy were $299 ($261-$367), 0.013 (0.003-0.023) QALYs, and $22.2K. Screening by the Cytosponge followed by treatment of patients with dysplasia or intramucosal cancer would reduce the number of cases of incident symptomatic esophageal adenocarcinoma by 19%, compared with 17% for screening by endoscopy, although this greater benefit for Cytosponge depends on more patients accepting screening by Cytosponge compared with screening by endoscopy. CONCLUSIONS: In a microsimulation model, screening 50-year-old men with symptoms of gastroesophageal reflux disease by Cytosponge is cost effective and would reduce mortality from esophageal adenocarcinoma compared with no screening. PMID- 23041330 TI - Deletion of IkappaBalpha activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A. AB - BACKGROUND & AIMS: The transcription factor nuclear factor-kappaB (NF-kappaB) (a heterodimer of NF-kappaB1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-kappaB promotes or protects against AP. We used the NF-kappaB inhibitor protein, inhibitor of kappaB (IkappaB)alpha, to study the roles of NF-kappaB in the development of AP in mice. METHODS: IkappaBalpha or the combination of IkappaBalpha and RelA selectively were deleted from pancreas of mice using the Cre/locus of cross-over P strategy; cerulein or L arginine were used to induce AP. We performed microarray analyses of the IkappaBalpha- and RelA-deficient pancreata. DNA from healthy individuals and patients with acute or chronic pancreatitis were analyzed for variants in coding regions of alpha-1-antichymotrypsin. RESULTS: Mice with pancreas-specific deletion of IkappaBalpha had constitutive activation of RelA and a gene expression profile consistent with NF-kappaB activation; development of AP in these mice was attenuated and trypsin activation was impaired. However, AP was fully induced in mice with pancreas-specific deletion of IkappaBalpha and RelA. By using genome-wide expression analysis, we identified a cluster of NF-kappaB regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in IkappaBalpha-deficient mice. Lentiviral-mediated expression of Spi2A reduced the development of AP in C57BL/6 and RelA-deficient mice. However, we did not correlate any variants of alpha-1-antichymotrypsin, the human homologue of Spi2a, with acute or chronic pancreatitis. CONCLUSIONS: Pancreas-specific deletion of IkappaBalpha results in nuclear translocation of RelA and reduces AP induction and trypsin activation in mice after administration of cerulein or L-arginine. Constitutive activation of RelA up-regulates Spi2A, which protects mice against the development of AP. PMID- 23041332 TI - Sampling challenges in nursing home research. AB - BACKGROUND: Research on end-of-life care in nursing homes is hampered by challenges in retaining facilities in samples through study completion. Large scale longitudinal studies in which data are collected on-site can be particularly challenging. OBJECTIVES: To compare characteristics of nursing homes that dropped from the study to those that completed the study. METHODS: One hundred two nursing homes in a large geographic 2-state area were enrolled in a prospective study of end-of-life care of residents who died in the facility. The focus of the study was the relationship of staff communication, teamwork, and palliative/end-of-life care practices to symptom distress and other care outcomes as perceived by family members. Data were collected from public data bases of nursing homes, clinical staff on site at each facility at 2 points in time, and from decedents' family members in a telephone interview. RESULTS: Seventeen of the 102 nursing homes dropped from the study before completion. These non completer facilities had significantly more deficiencies and a higher rate of turnover of key personnel compared to completer facilities. A few facilities with a profile typical of non-completers actually did complete the study after an extraordinary investment of retention effort by the research team. CONCLUSION: Nursing homes with a high rate of deficiencies and turnover have much to contribute to the goal of improving end-of-life care, and their loss to study is a significant sampling challenge. Investigators should be prepared to invest extra resources to maximize retention. PMID- 23041331 TI - Inactivation of Patched1 in mice leads to development of gastrointestinal stromal like tumors that express Pdgfralpha but not kit. AB - BACKGROUND & AIMS: A fraction of gastrointestinal stromal tumor (GIST) cells overexpress the platelet-derived growth factor receptor (PDGFR)A, although most overexpress KIT. It is not known if this is because these receptor tyrosine kinases have complementary oncogenic potential, or because of heterogeneity in the cellular origin of GIST. Little also is known about why Hedgehog (HH) signaling is activated in some GIST. HH binds to and inactivates the receptor protein patched homolog (PTCH). METHODS: Ptch was conditionally inactivated in mice (to achieve constitutive HH signaling) using a Cre recombinase regulated by the lysozyme M promoter. Cre-expressing cells were traced using R26R-LacZ reporter mice. Tumors were characterized by in situ hybridization, immunohistochemistry, immunoblot, and quantitative reverse-transcriptase polymerase chain reaction analyses. Cell transformation was assessed by soft agar assay. RESULTS: Loss of Ptch from lysozyme M-expressing cells resulted in the development of tumors of GIST-like localization and histology; these were reduced when mice were given imatinib, a drug that targets KIT and PDGFRA. The Hh signaling pathway was activated in the tumor cells, and Pdgfralpha, but not Kit, was overexpressed and activated. Lineage tracing revealed that Cre-expressing intestinal cells were Kit-negative. These cells sometimes expressed Pdgfralpha and were located near Kit-positive interstitial cells of Cajal. In contrast to KIT, activation of PDGFRA increased anchorage-independent proliferation and was required for tumor formation in mice by cells with activated HH signaling. CONCLUSIONS: Inactivation of Ptch in mice leads to formation of GIST-like tumors that express Pdgfralpha, but not Kit. Activation of Pdgfralpha signaling appears to facilitate tumorigenesis. PMID- 23041333 TI - Adsorption of diuron, fluridone and norflurazon on single-walled and multi-walled carbon nanotubes. AB - The sorption behaviors of diuron (DIU), fluridone (FLU) and norflurazon (NOR) by a single-walled carbon nanotube (SWCNT) and three multi-walled carbon nanotubes (MWCNT) samples including MWCNT10 (<10nm, outer diameter), MWCNT20 (10-20 nm), and MWCNT40 (20-40 nm) were investigated. All adsorption isotherms were nonlinear and were well fitted with the Freundlich model and Dubinin Ashtakhov (DA) model. The linear relationships between the organic carbon (OC)-normalized saturated adsorption capacity (Q(0)(OC)) and surface area (SA) suggest that SA is presumably responsible for the adsorption of DIU and NOR on CNTs. While FLU, DIU, and NOR OC-normalized distribution coefficients (logK(OC)) of CNTs increased with increasing their hydrophobicity (logK(OW)) and the positive relationships between the logK(OW)-normalized logK(OC) (i.e., logK(OC)/logK(OW)) of FLU, DIU, and NOR and their hydrogen bonding ability indicate that the adsorption of FLU, DIU and NOR was mainly controlled by the hydrophobic interaction and hydrogen bonding. The higher logK(OC) or Q(0)(OC) values of MWCNT10 and SWCNT relative to other large MWCNTs and carbonaceous adsorbents suggest that MWCNT10 has the potential to serve as an adsorbent used to reduce the mobility of herbicides in agricultural and environmental applications. PMID- 23041334 TI - Bayesian inference of structural brain networks. AB - Structural brain networks are used to model white-matter connectivity between spatially segregated brain regions. The presence, location and orientation of these white matter tracts can be derived using diffusion-weighted magnetic resonance imaging in combination with probabilistic tractography. Unfortunately, as of yet, none of the existing approaches provide an undisputed way of inferring brain networks from the streamline distributions which tractography produces. State-of-the-art methods rely on an arbitrary threshold or, alternatively, yield weighted results that are difficult to interpret. In this paper, we provide a generative model that explicitly describes how structural brain networks lead to observed streamline distributions. This allows us to draw principled conclusions about brain networks, which we validate using simultaneously acquired resting state functional MRI data. Inference may be further informed by means of a prior which combines connectivity estimates from multiple subjects. Based on this prior, we obtain networks that significantly improve on the conventional approach. PMID- 23041335 TI - Rapid event-related near-infrared spectroscopy detects age-related qualitative changes in the neural correlates of response inhibition. AB - Near-infrared spectroscopy (NIRS) is a promising neuroimaging tool for the study of human cognition. Here, we show that event-related NIRS is able to detect age related differences in the neural processing in a simple visual Go/NoGo task using a relatively fast (stimulus onset asynchrony approx. 1.4s) event-related design together with a model-based analysis approach. Subjects were healthy young (<30 years) and elderly (>60 years) adults. Behaviorally, old adults were slower but more accurate than young adults. The event-related analysis approach of NIRS data allowed us to contrast activation of successfully inhibited NoGo stimuli with that of correctly answered Go stimuli. Both age-groups showed frontal activation differences between these events in oxy- (HbO; increase) and deoxyhemoglobin (HbR; decrease). Between age groups, differences in HbR were found in right dorsolateral frontal (old>young), right temporal/postcentral/precentral and left precentral/inferior frontal (young>old) channels. These differences are in line with age-associated activation changes in inhibition detected with functional magnetic resonance imaging. The present study successfully separated the neural correlates of response inhibition from errors of commission/omission and provides data from multiple simultaneously recorded optodes. Furthermore, these results demonstrate the feasibility of using NIRS to investigate neural processes related to aging and dementia, in particular in patients for which other neuroimaging techniques are contraindicated. In the future, functional phenotyping of successful aging in respect to executive performance may be feasible. PMID- 23041337 TI - Cranial electrotherapy stimulation and transcranial pulsed current stimulation: a computer based high-resolution modeling study. AB - The field of non-invasive brain stimulation has developed significantly over the last two decades. Though two techniques of noninvasive brain stimulation- transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)--are becoming established tools for research in neuroscience and for some clinical applications, related techniques that also show some promising clinical results have not been developed at the same pace. One of these related techniques is cranial electrotherapy stimulation (CES), a class of transcranial pulsed current stimulation (tPCS). In order to understand further the mechanisms of CES, we aimed to model CES using a magnetic resonance imaging (MRI)-derived finite element head model including cortical and also subcortical structures. Cortical electric field (current density) peak intensities and distributions were analyzed. We evaluated different electrode configurations of CES including in-ear and over-ear montages. Our results confirm that significant amounts of current pass the skull and reach cortical and subcortical structures. In addition, depending on the montage, induced currents at subcortical areas, such as midbrain, pons, thalamus and hypothalamus are of similar magnitude than that of cortical areas. Incremental variations of electrode position on the head surface also influence which cortical regions are modulated. The high-resolution modeling predictions suggest that details of electrode montage influence current flow through superficial and deep structures. Finally we present laptop based methods for tPCS dose design using dominant frequency and spherical models. These modeling predictions and tools are the first step to advance rational and optimized use of tPCS and CES. PMID- 23041338 TI - Oscillatory alpha-band suppression mechanisms during the rapid attentional shifts required to perform an anti-saccade task. AB - Neuroimaging has demonstrated anatomical overlap between covert and overt attention systems, although behavioral and electrophysiological studies have suggested that the two systems do not rely on entirely identical circuits or mechanisms. In a parallel line of research, topographically-specific modulations of alpha-band power (~8-14 Hz) have been consistently correlated with anticipatory states during tasks requiring covert attention shifts. These tasks, however, typically employ cue-target-interval paradigms where attentional processes are examined across relatively protracted periods of time and not at the rapid timescales implicated during overt attention tasks. The anti-saccade task, where one must first covertly attend for a peripheral target, before executing a rapid overt attention shift (i.e. a saccade) to the opposite side of space, is particularly well-suited for examining the rapid dynamics of overt attentional deployments. Here, we asked whether alpha-band oscillatory mechanisms would also be associated with these very rapid overt shifts, potentially representing a common neural mechanism across overt and covert attention systems. High-density electroencephalography in conjunction with infra-red eye-tracking was recorded while participants engaged in both pro- and anti-saccade task blocks. Alpha power, time-locked to saccade onset, showed three distinct phases of significantly lateralized topographic shifts, all occurring within a period of less than 1s, closely reflecting the temporal dynamics of anti-saccade performance. Only two such phases were observed during the pro-saccade task. These data point to substantially more rapid temporal dynamics of alpha-band suppressive mechanisms than previously established, and implicate oscillatory alpha-band activity as a common mechanism across both overt and covert attentional deployments. PMID- 23041339 TI - Activation of neurokinin-1 receptor by substance P inhibits melanogenesis in B16 F10 melanoma cells. AB - Skin pigmentation plays a number of valuable roles and its regulation is a complex process that is controlled by different factors. Substance P (SP) regulates many biological functions, including neurogenic inflammation, pain, and stress. However, to date, the regulatory role of SP in the control of melanogenesis has not been elucidated. The present study was designed to investigate the effects of SP on melanogenesis and to elucidate its underlying mechanism(s). After treatment for 48 h in mouse B16-F10 melanoma cells, SP (1 and 10nM) significantly down-regulated tyrosinase activity and melanin content. Importantly, western blot analysis revealed the presence of neurokinin-1 receptor (NK-1 R) in B16-F10 cells and the activation of it after SP treatment. It was also found that preincubation with NK-1 receptor antagonist Spantide I could partially reversed SP-induced down-regulations of tyrosinase activity, melanin content and the expression of tyrosinase and tyrosinase-related protein 1. Furthermore, SP could remarkably inhibit the expressions of microphtalmia associated transcription factor (MITF) and p-p38 MAPK and stimulated p-p70 S6K1. These effects could also be partially reversed by the pretreatment with Spantide I. These results collectively suggested that SP inhibited melanogenesis in B16 F10 cells, which might be attributed to the fact that SP induces the activation of NK-1 receptor, stimulates the phosphorylation of p70 S6K1 and inhibits that of p38 MAPK, decreases the tyrosinase and tyrosinase-related protein 1 expression through MITF, finally resulting in the suppression of melanogenesis. These observations in vitro indicated that the regulation of the SP/NK-1 receptor system might be a useful novel management for skin pigmentation. PMID- 23041340 TI - Re: "snodgraft" technique for the treatment of primary distal hypospadias: pushing the envelope: m. S. Silay, h. Sirin, a. Tepeler, T. Karatag, a. Armagan, k. Horasanli and C. Miroglu j urol 2012; 188: 938-942. PMID- 23041342 TI - HMGB1 release by urothelial carcinoma cells is required for the in vivo antitumor response to Bacillus Calmette-Guerin. AB - PURPOSE: Prior series showed that a portion of urothelial carcinoma cells exposed to bacillus Calmette-Guerin undergoes nonapoptotic cell death and release of the chemokine HMGB1. We evaluated the role of tumor cell derived HMGB1 in mediating the in vivo antitumor effect of bacillus Calmette-Guerin. MATERIALS AND METHODS: The murine urothelial carcinoma cell line MB49 was engineered to express a shRNA construct targeting HMGB1. The shRNA expressing cell line underwent characterization to ensure its comparability to the parental MB49 cell line. An orthotopic tumor model was used to compare the in vivo antitumor efficacy of bacillus Calmette-Guerin in the parental cell line (24 control and 24 bacillus Calmette-Guerin treated) vs the HMGB1 knockdown line (23 control and 21 treated). RESULTS: Expression of the shRNA construct decreased HMGB1 expression and its release in response to bacillus Calmette-Guerin. The parental and shRNA cell lines showed similar in vitro doubling time and cytotoxicity in response to bacillus Calmette-Guerin. Treatment significantly decreased tumor volume vs controls in parental MB49 tumor bearing mice (p = 0.036). Tumor volume in treated mice inoculated with the shRNA cell line was higher than that in sham treated shRNA controls (p = 0.12). Of the bacillus Calmette-Guerin treated mice tumor volume was significantly lower in parental tumor bearing mice vs the shRNA group (p <0.00001). ANOVA revealed a significant interaction between the cell line (shRNA vs parental) and the bacillus Calmette-Guerin effect (p = 0.0076). CONCLUSIONS: The direct tumor response to bacillus Calmette-Guerin, culminating in HMGB1 release, may be an important contributor to the clinical efficacy of bacillus Calmette-Guerin. PMID- 23041343 TI - A prospective randomized trial of povidone-iodine prophylactic cleansing of the rectum before transrectal ultrasound guided prostate biopsy. AB - PURPOSE: Transrectal ultrasound guided prostate biopsy can lead to urinary tract infections in 3% to 11% and sepsis in 0.1% to 5% of patients. We investigated the efficacy of rectal cleansing with povidone-iodine before transrectal ultrasound guided prostate biopsy to reduce infectious complications. MATERIALS AND METHODS: Between 2009 and 2011, 865 men were prospectively randomized to rectal cleansing (421) or no cleansing (444) before transrectal ultrasound guided prostate biopsy. Patients received ciprofloxacin prophylaxis and rectal swab cultures were obtained before transrectal ultrasound guided prostate biopsy. Patients completed a telephone interview 7 days after undergoing the biopsy. The primary end point was the rate of infectious complications, a composite end point of 1 or more of 1) fever greater than 38.0C, 2) urinary tract infection or 3) sepsis (standardized definition). Chi-square significance testing was performed for differences between groups and a multivariate analysis was performed to assess risk factors for infectious complications. RESULTS: Infectious complications were observed in 31 (3.5%) patients, including 11 (2.6%) treated and 20 (4.5%) control patients (p = 0.15). Sepsis was observed in 4 (1.0%) treated and 7 (1.6%) control patients (p = 0.55). On multivariate analysis resistance to ciprofloxacin in the rectal swab culture (p = 0.002) and a history of taking ciprofloxacin in the 3 months preceding transrectal ultrasound guided prostate biopsy (p = 0.009) predicted infectious complications. CONCLUSIONS: Rectal cleansing with povidone iodine before transrectal ultrasound guided prostate biopsy was safe, but the 42% relative risk reduction of infectious complications was not statistically significant. Patients who have received ciprofloxacin within 3 months of transrectal ultrasound guided prostate biopsy should be considered for alternate prophylaxis or possibly a delay of biopsy beyond 3 months. PMID- 23041344 TI - Inpatient urological surgery at critical access hospitals in the United States. AB - PURPOSE: To better understand urological care delivery in rural communities, we evaluated the utilization, outcomes and costs of inpatient urological surgery at critical access hospitals. MATERIALS AND METHODS: Using data from the AHA (American Hospital Association) and NIS (Nationwide Inpatient Sample), we identified all urological surgical admissions to critical and noncritical access hospitals from 2005 through 2009. We compared the distribution of urological procedures, hospital mortality, length of stay and costs for patients undergoing common urological operations at critical vs noncritical access hospitals. RESULTS: Of the 1,292 critical and 3,760 noncritical access hospitals reporting to the AHA 450 (35%) and 1,372 (36%), respectively, had at least 1 year of data available in the NIS. We identified 333,925 urological surgical admissions, including 2,286 (0.7%) to critical access hospitals. Overall, at least 1 inpatient urological operation was performed at only 45% of critical access hospitals vs 91% of noncritical access hospitals (p <0.001). The distribution of urological surgeries differed between critical and noncritical access hospitals (p <0.001) with a greater prevalence of operations for benign indications at critical access hospitals. For 6 common inpatient urological surgeries we found no meaningful difference in in-hospital mortality and prolonged length of stay between patients treated at critical vs noncritical access hospitals. However, costs at critical access hospitals were universally higher. CONCLUSIONS: Inpatient urological surgery is performed at only a few critical access hospitals. While in-hospital mortality and length of stay are largely indistinguishable between critical and noncritical access hospitals, the higher costs at critical access hospitals may pose a challenge to improving rural access to urological care. PMID- 23041336 TI - Random forest-based similarity measures for multi-modal classification of Alzheimer's disease. AB - Neurodegenerative disorders, such as Alzheimer's disease, are associated with changes in multiple neuroimaging and biological measures. These may provide complementary information for diagnosis and prognosis. We present a multi modality classification framework in which manifolds are constructed based on pairwise similarity measures derived from random forest classifiers. Similarities from multiple modalities are combined to generate an embedding that simultaneously encodes information about all the available features. Multi modality classification is then performed using coordinates from this joint embedding. We evaluate the proposed framework by application to neuroimaging and biological data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Features include regional MRI volumes, voxel-based FDG-PET signal intensities, CSF biomarker measures, and categorical genetic information. Classification based on the joint embedding constructed using information from all four modalities out performs the classification based on any individual modality for comparisons between Alzheimer's disease patients and healthy controls, as well as between mild cognitive impairment patients and healthy controls. Based on the joint embedding, we achieve classification accuracies of 89% between Alzheimer's disease patients and healthy controls, and 75% between mild cognitive impairment patients and healthy controls. These results are comparable with those reported in other recent studies using multi-kernel learning. Random forests provide consistent pairwise similarity measures for multiple modalities, thus facilitating the combination of different types of feature data. We demonstrate this by application to data in which the number of features differs by several orders of magnitude between modalities. Random forest classifiers extend naturally to multi-class problems, and the framework described here could be applied to distinguish between multiple patient groups in the future. PMID- 23041345 TI - Altered tubulin assembly dynamics with N-homocysteinylated human 4R/1N tau in vitro. AB - Tau isoforms promote neuronal integrity through binding and stabilization of microtubule proteins (MTP). It has been shown that hyperphosphorylation of tau contributes to Alzheimer's disease (AD) pathology and related tauopathies. However, other pathogenic modifications of tau have not been well characterized. It is well accepted that elevated level of homocysteine (Hcy) is associated with neurodegenerative diseases such as AD. As a result of N-homocysteinylation of lysine residues, Hcy becomes a component of proteins, as a protein-homocystamide adduct, which affects protein structure and function. Here we demonstrate that N homocysteinylation of human tau (4R/1N isoform) inhibits its function via impaired tau-tubulin specific binding and MTP assembly dynamics in vitro. PMID- 23041346 TI - Iron-sulfur cluster coordination in the [FeFe]-hydrogenase H cluster biosynthetic factor HydF. AB - Iron-sulfur cluster coordination was probed in the [FeFe]-hydrogenase H cluster maturation scaffold HydF. Putative Cys thiol and His imidazole ligation identified through multiple sequence alignments and structural studies were subjected to amino acid substitution and the variants were biochemically characterized. The results implicate a role for C304, C353, C356, and H306 of Clostridium acetobutylicum HydF in FeS cluster binding. Individual ligand substitutions affect both [4Fe-4S] and [2Fe-2S] cluster coordination suggesting shared coordination or cluster interconversion. Substitutions at C353 and H306 appear to preferentially impact the presence of the [2Fe-2S] cluster complement of the resulting variants of HydF. The results implicate a potential role for these residues in biosynthesis specifically and potential in bridging the [4Fe 4S] cluster to 2Fe subcluster biosynthetic intermediates. PMID- 23041347 TI - Design, synthesis, and bioevaluation of benzamides: novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, Abeta aggregation, and beta-secretase. AB - Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. In this study, we conducted a structure based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework. Compound 2e, characterized by a central benzamide moiety linked to an isoquinoline at one side and acetophenone at the other, was the most potent candidate with K(i) of 6.47nM against human AChE. Particularly, it showed simultaneous inhibitory effects against BChE, Abeta aggregation, and beta secretase. We therefore conclude that compound 2e is a very promising multi function lead for the treatment of AD. PMID- 23041348 TI - Antioxidant role of amyloid beta protein in cell-free and biological systems: implication for the pathogenesis of Alzheimer disease. AB - In contrast to many studies showing the pro-oxidative nature of amyloid peptide, this work shows that aggregated Abeta42 peptide in varying concentrations (2-20 MUM) in cell-free systems inhibits the formation of hydroxyl radicals and H(2)O(2) from a mixture of iron (20 MUM FeSO(4)) and ascorbate (2mM) as measured by benzoate hydroxylation assay and coumarin carboxylic acid assay. Aggregated Abeta42 in similar concentrations further prevents protein and lipid oxidation in isolated rat brain mitochondria incubated alone or with FeSO(4) and ascorbate. Moreover, mitochondria exposed to FeSO(4) and ascorbate show enhanced formation of reactive oxygen species and this phenomenon is also abolished by aggregated Abeta42. It is suggested that the antioxidant property of Abeta42 in various systems is mediated by metal chelation and it is nearly as potent as a typical metal chelator, such as diethylenetriaminepentaacetic acid, in preventing oxidative damage. However, aggregated Abeta42 causes mitochondrial functional impairment in the form of membrane depolarization and a loss of phosphorylation capacity without involving reactive oxygen species in the process. Thus, the present results suggest that the amyloid peptide exhibits a protective antioxidant role in biological systems, but also has toxic actions independent of oxidative stress. PMID- 23041350 TI - Method for the simultaneous determination of free/protein malondialdehyde and lipid/protein hydroperoxides. AB - A simple and sensitive method is presented for the simultaneous quantification (spectrophotometric and spectrofluorimetric) of the main lipid and protein peroxidation products after their initial fractionation: free malondialdehyde (FrMDA), protein-bound malondialdehyde (PrMDA), total hydroperoxides (LOOH), and protein hydroperoxides (PrOOH). FrMDA and PrMDA (released from proteins by alkaline hydrolysis) are measured after the reaction of MDA with thiobarbituric acid (TBA) under acidic conditions, by the specific fluorimetric quantification of the resulting MDA-(TBA)2 adduct chromophore. The measurement of LOOH and PrOOH is based on the reaction of Fe(3+) (resulting from the reaction of LOOH and PrOOH with Fe(2+)) with xylenol orange (XO) and the photometric quantification of the resulting XO-Fe complex. The sensitivity of the assays for FrMDA/PrMDA and LOOH/PrOOH is 20 and 100pmol, respectively. The method was applied successfully on human plasma and can be used for the evaluation of oxidative stress in both basic and clinical research. PMID- 23041349 TI - In vitro oxidative inactivation of human presequence protease (hPreP). AB - The mitochondrial peptidasome called presequence protease (PreP) is responsible for the degradation of presequences and other unstructured peptides including the amyloid-beta peptide, whose accumulation may have deleterious effects on mitochondrial function. Recent studies showed that PreP activity is reduced in Alzheimer disease (AD) patients and AD mouse models compared to controls, which correlated with an enhanced reactive oxygen species production in mitochondria. In this study, we have investigated the effects of a biologically relevant oxidant, hydrogen peroxide (H(2)O(2)), on the activity of recombinant human PreP (hPreP). H(2)O(2) inhibited hPreP activity in a concentration-dependent manner, resulting in oxidation of amino acid residues (detected by carbonylation) and lowered protein stability. Substitution of the evolutionarily conserved methionine 206 for leucine resulted in increased sensitivity of hPreP to oxidation, indicating a possible protective role of M206 as internal antioxidant. The activity of hPreP oxidized at low concentrations of H(2)O(2) could be restored by methionine sulfoxide reductase A (MsrA), an enzyme that localizes to the mitochondrial matrix, suggesting that hPreP constitutes a substrate for MsrA. In summary, our in vitro results suggest a possible redox control of hPreP in the mitochondrial matrix and support the protective role of the conserved methionine 206 residue as an internal antioxidant. PMID- 23041351 TI - The nitric oxide donor sodium nitroprusside regulates polyamine and proline metabolism in leaves of Medicago truncatula plants. AB - Nitric oxide (NO), polyamines, and proline have all been suggested to play key roles in a wide spectrum of physiological processes and abiotic stress responses. Although exogenous application of polyamines has been shown to induce NO production, the effect of NO on polyamine biosynthesis has not yet been elucidated. Several reports exist that demonstrate the protective action of sodium nitroprusside (SNP), a widely used NO donor, which acts as a signal molecule in plants responsible for the regulation of the expression of many defense-related enzymes. This study attempted to provide a novel insight into the effects of application of low (100 MUMU) and high (2.5 mM) concentrations of SNP on the biosynthesis of two major abiotic stress response-related metabolites, polyamines and proline, in mature (40 day) and senescing (65 day) Medicago truncatula plants. Physiological data showed that long-term (24 h), higher SNP concentration resulted in decreased photosynthetic rate and stomatal conductance followed by intracellular putrescine and proline accumulation, as a result of an increase in biosynthetic arginine decarboxylase (ADC) and Delta(1) -pyrroline-5 carboxylate synthetase (P5CS) enzymatic activity, respectively. Further analysis of polyamine oxidase (PAO)/diamine oxidase (DAO) polyamine catabolic enzymes indicated that DAO enzymatic activity increased significantly in correlation with putrescine accumulation, whereas PAO activity, involved in spermidine/spermine degradation, increased slightly. Moreover, transcriptional analysis of polyamine and proline metabolism genes (P5CS, P5CR, ADC, SPMS, SPDS, SAMDC, PAO, DAO) further supported the obtained data and revealed a complex SNP concentration-, time-, and developmental stage-dependent mechanism controlling endogenous proline and polyamine metabolite production. This is the first report to provide a global analysis leading to a better understanding of the role of the widely used NO donor SNP in the regulation of key stress-related metabolic pathways. PMID- 23041352 TI - Intestinal drug transporters: an overview. AB - The importance of drug transporters as one of the determinants of pharmacokinetics has become increasingly evident. While much research has been conducted focusing the role of drug transporters in the liver and kidney less is known about the importance of uptake and efflux transporters identified in the intestine. Over the past years the effects of intestinal transporters have been studied using in vivo models, in situ organ perfusions, in vitro tissue preparations and cell lines. This review aims to describe up to date findings regarding the importance of intestinal transporters on drug absorption and bioavailability, highlighting areas in need of further research. Wu and Benet proposed a Biopharmaceutics Drug Disposition Classification System (BDDCS) that allows the prediction of transporter effects on the drug disposition of orally administered drugs. This review also discusses BDDCS predictions with respect to the role of intestinal transporters and intestinal transporter-metabolizing enzyme interplay on oral drug pharmacokinetics. PMID- 23041353 TI - Cannabidiol administration into the bed nucleus of the stria terminalis alters cardiovascular responses induced by acute restraint stress through 5-HT1A receptor. AB - Systemic administration of cannabidiol (CBD) is able to attenuate cardiovascular responses to acute restraint stress through activation of 5-HT1A receptors. Previous results from our group suggest that the bed nucleus of the stria terminalis (BNST) is involved in the antiaversive effects of the CBD. Moreover, it has been proposed that synapses within the BNST influence restraint-evoked cardiovascular changes, in particular by an inhibitory influence on the tachycardiac response associated to restraint stress. Thus, the present work investigated the effects of CBD injected into the BNST on cardiovascular changes induced by acute restraint stress and if these effects would involve the local activation of 5-HT1A receptors. The exposition to restraint stress increased both blood pressure and heart rate (HR). The microinjection of CBD (30 and 60 nmol) into the BNST enhanced the restraint-evoked HR increase, in a dose-dependent manner, without affecting the pressor response. The selective 5-HT1A receptor antagonist WAY100635 by itself did not change the cardiovascular responses to restraint stress, but blocked the effects of CBD. These results showed that CBD microinjected into the BNST enhanced the HR increase associated with acute restraint stress without affecting the blood pressure response. Although these results are not in agreement with those observed after systemic administration of CBD, they are similar to effects observed after reversible inactivation of the BNST. Moreover, similar to the effects observed after systemic administration, CBD effects in the BNST seem to depend on activation of 5-HT1A receptors. PMID- 23041354 TI - Magnetic resonance imaging as an early indicator of clinical outcome in patients with metastatic colorectal carcinoma treated with cetuximab or panitumumab. AB - We show that detection, by week-2 magnetic resonance imaging, of tumor shrinkage >10% in response to therapy with cetuximab or panitumumab for metastatic colorectal carcinoma represents an early indicator of clinical outcome because it is predictive of the prolongation of progression-free survival and overall survival. PURPOSE: The early identification of patients with metastatic colorectal carcinoma who are likely to benefit from treatment with panitumumab or cetuximab remains of paramount importance. We evaluated whether the early tumor shrinkage assessed by magnetic resonance imaging (MRI) is predictive of long-term outcome to these epidermal growth factor receptor-targeted therapies. PATIENTS AND METHODS: Thirty-nine patients with chemorefractory metastatic colorectal carcinoma were treated with cetuximab or panitumumab. The patients were evaluated by unenhanced MRI at baseline, week 2, and week 8 after the beginning of the treatment and by contrast-enhanced computed tomography within 3 months. Early response was defined as a tumor shrinkage >= 10% at week-2 MRI, whereas response by contrast-enhanced computed tomography was defined according to standard Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: At week-2 MRI, 15 (38.5%) of 39 patients had an early response. Eleven (73.3%) of these 15 early responders then presented a partial response by contrast-enhanced computed tomography, whereas none of the 24 early nonresponders obtained a partial response (P < .0005, Fisher exact test). Median progression-free survival (PFS) was 29.7 and 8 weeks in patients with or without early response, respectively (hazard ratio [HR] 0.156 [95% CI, 0.069-0.355]; P < .0001)]. The median overall survival (OS) was 80 weeks in patients with early response and 23.3 weeks in those without early response, respectively (HR 0.154 [95% CI, 0.057-0.420]; P < .00005]). CONCLUSIONS: Early detection of tumor response by week-2 MRI without contrast medium is associated with a prediction of clinical outcome in patients with metastatic colorectal carcinoma treated with cetuximab or panitumumab. PMID- 23041356 TI - African swine fever virus transcription. AB - African swine fever virus (ASFV), a large, enveloped, icosahedral dsDNA virus, is currently the only known DNA-containing arbovirus and the only recognized member of the family Asfarviridae. Its genome encodes more than 150 open reading frames that are densely distributed, separated by short intergenic regions. ASFV gene expression follows a complex temporal programming. Four classes of mRNAs have been identified by its distinctive accumulation kinetics. Gene transcription is coordinated with DNA replication that acts as the main switch on ASFV gene expression. Immediate early and early genes are expressed before the onset of DNA replication, whereas intermediate and late genes are expressed afterwards. ASFV mRNAs have a cap 1 structure at its 5'-end and a short poly(A) tail on its 3' end. Transcription initiation and termination occurs at very precise positions within the genome, producing transcripts of definite length throughout the expression program. ASFV devotes approximately 20% of its genome to encode the 20 genes currently considered to be involved in the transcription and modification of its mRNAs. This transcriptional machinery gives to ASFV a remarkable independence from its host and an accurate positional and temporal control of its gene expression. Here, we review the components of the ASFV transcriptional apparatus, its expression strategies and the relevant data about the transcriptional cis-acting control sequences. PMID- 23041355 TI - A new type F Wolbachia from Splendidofilariinae (Onchocercidae) supports the recent emergence of this supergroup. AB - Wolbachia are vertically transmitted endosymbiotic bacteria of arthropods and onchocercid nematodes. It is commonly accepted that they co-evolved with their filarial hosts, and have secondarily been lost in some species. However, most of the data on the Wolbachia/Onchocercidae relationship have been derived from studies on two subfamilies, the Dirofilariinae and the Onchocercinae, which harbour parasites of humans and domestic animals. Within the last few years, analyses of more diverse material have suggested that some groups of Onchocercidae do not have Wolbachia, such as recently studied Splendidofilariinae from birds. This study takes advantage of the analysis of additional Splendidofilariinae, Rumenfilaria andersoni from a Finnish reindeer and Madathamugadia hiepei from a South African gecko, using PCR, immunohistochemical staining and whole-mount fluorescent analysis to detect Wolbachia and describe its strains. A DNA barcoding approach and phylogenetic analyses were used to investigate the symbiosis between Wolbachia and the Onchocercidae. A new supergroup F Wolbachia was demonstrated in M. hiepei, representing the first filarial nematode harbouring Wolbachia described in a non-mammalian host. In the adult, Wolbachia infects the female germline but not the hypodermis, and intestinal cells are also infected. The phylogenetic analyses confirmed a recent emergence of supergroup F. They also suggested several events of horizontal transmission between nematodes and arthropods in this supergroup, and the existence of different metabolic interactions between the filarial nematodes and their symbionts. PMID- 23041357 TI - Laboratory methods to study African swine fever virus. AB - We summarize findings of comparative studies in different cells cultures susceptible to ASFV infection, through the analysis of virus components and infectious virus particles production, as alternative means to grow field and laboratory ASFV strains. We also provide different methods to assay the infectivity of ASFV samples and to purify the infective virus particles. Finally we describe the general strategy to construct virus deletion mutants that can be engineered to obtain attenuated ASFV strains suitable for vaccine approaches. PMID- 23041358 TI - Multiple roles of the capsid protein in the early steps of HIV-1 infection. AB - The early steps of HIV-1 infection starting after virus entry into cells up to integration of its genome into host chromosomes are poorly understood. From seminal work showing that HIV-1 and oncoretroviruses follow different steps in the early stages post-entry, significant advances have been made in recent years and an important role for the HIV-1 capsid (CA) protein, the constituent of the viral core, has emerged. CA appears to orchestrate several events, such as virus uncoating, recognition by restriction factors and the innate immune system. It also plays a role in nuclear import and integration of HIV-1 and has become a novel target for antiretroviral drugs. Here we describe the different functions of CA and how they may be integrated into one or more coherent models that illuminate the early events in HIV-1 infection and their relations with the host cell. PMID- 23041360 TI - Survival and impact of clinical prognostic factors in surgically treated metastatic renal cell carcinoma. AB - BACKGROUND: The survival impact of metastasectomy for metastatic renal cell carcinoma (mRCC) is still an active research field, particularly in the multimodal/targeted therapy era. OBJECTIVE: To determine the survival impact of clinical prognostic factors and their application to stratification of patients according to their prognosis so clinicians may be aided in their management of mRCC. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, bi-institutional cohort study of 109 consecutive patients (71 male and 38 female; median age: 62 yr (range: 25-82 yr) with renal cell carcinoma (RCC) who underwent partial or radical nephrectomy and at least one metastasectomy for mRCC. INTERVENTION: Metastasis resection from various anatomic sites with the aim of completely removing detected lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox regression models were used to analyse the impact of clinical prognostic factors on cancer-specific survival (CSS). Kaplan Meier analysis with the log-rank test was used to compare CSS. Receiver operating characteristic (ROC) analysis was performed to test accuracy of prognostic groups. The alpha error for statistical significance was set at 0.05. RESULTS AND LIMITATIONS: Multivariable analysis revealed that primary tumour T stage >= 3 (hazard ratio [HR]: 2.8; p<0.01), primary tumour Fuhrman grade >= 3 (HR: 2.3; p<0.03), nonpulmonary metastases (HR: 3.1; p<0.03), disease-free interval <= 12 mo (HR: 2.3; p<0.058), and multiorgan metastases (HR: 2.5; p<0.04) were independent pretreatment prognostic factors. Leuven-Udine (LU) prognostic groups based on these covariates were created and analysed with Kaplan-Meier and log rank tests. The 2- and 5-yr CSS were significantly different; the respective group A CSS rates were 95.8% and 83.1%; group B, 89.9% and 56.4%; group C, 65.6% and 32.6%; and group D, 24.7% and 0% (p<0.0001). ROC analysis on the accuracy of prognostic grouping revealed respective areas under the curve of 0.87 and 0.88 at 2 and 5 yr. Main limitations to present study are the retrospective design and the presence of different metastasis sites. CONCLUSIONS: LU prognostic groups could be considered an accurate clinical tool to stratify patients according to prognosis and aid clinicians in the management of mRCC. PMID- 23041362 TI - A multidisciplinary study of iron transport and storage in the marine green alga Tetraselmis suecica. AB - The iron uptake and storage systems of terrestrial/higher plants are now reasonably well understood with two basic strategies being distinguished: strategy I involves the induction of a Fe(III)-chelate reductase (ferrireductase) along with Fe(II) or Fe(III) transporter proteins while strategy II plants have evolved sophisticated systems based on high-affinity, iron specific, binding compounds called phytosiderophores. In contrast, there is little knowledge about the corresponding systems in marine, plant-like lineages. Herein we report a study of the iron uptake and storage mechanisms in the green alga Tetraselmis suecica. Short term radio-iron uptake studies indicate that iron is taken up by Tetraselmis in a time and concentration dependent manner consistent with an active transport process. Based on inhibitor and other studies it appears that a reductive-oxidative pathway such as that found in yeast and the green alga Chlamydomonas reinhardtii is likely. Upon long term exposure to (57)Fe we have been able, using a combination of Mossbauer and X-ray absorption spectroscopies, to identify three metabolites. The first exhibits Mossbauer parameters typical of a [Fe(4)S(4)](2+) cluster and which accounts for approximately 10% of the total intracellular iron pool. The second displays a spectrum typical of a [Fe(II)O(6)] system accounting for approximately 2% of the total pool. The largest component (ca. 85+%) consists of polymeric iron-oxo mineral species with parameters between that of the crystalline ferrihydrite core of animal ferritins and the amorphous hydrated ferric phosphate of bacterial and plant ferritins. PMID- 23041363 TI - An oral carbapenem, but only now intravenous penicillin: the paradox of Japanese antimicrobials. AB - At present there is a profound paradox in antimicrobial use and development in Japan. A tightly held domestic pharmaceutical market with significant barriers to the importation and registration of foreign agents, has spurred domestic pharmaceutical companies to develop a vast range of antimicrobials. Many Japanese developed antimicrobials are now used globally. A negative consequence of this environment, however, is the lack of availability of several 'workhorse' narrow spectrum agents to treat patients in Japan. Absent agents include anti staphylococcal penicillins and until recently, intravenous benzylpenicillin. In substitution for these unavailable agents, patients are frequently administered broader spectrum antimicrobials. This change offers no additional benefit to the patient and is potentially contributing to treatment failure and high rates of antimicrobial resistance amongst key bacterial pathogens in Japan. The situation in Japan illustrates the broader global challenges faced in integrating the development of new antimicrobial agents with maintaining the supply and use of older and less profitable agents. PMID- 23041364 TI - Is early virological response as predictive of the hepatitis C treatment response in dialysis patients as in non-uremic patients? AB - OBJECTIVE: The aim of the present study was to determine whether hepatitis C virus (HCV) RNA present at week 12 is a good predictor of the response to interferon (IFN) monotherapy in hemodialysis patients with hepatitis C. METHODS: Hemodialysis patients with hepatitis C who were treated between 1997 and 2008 with IFN monotherapy for 48 weeks without dose reduction were included. The predictive value of HCV RNA at week 12 for achieving a sustained virological response (SVR) was determined. RESULTS: Forty patients (mean age 47+/-9 years; 75% males and 80% with genotype 1) were included. Septal fibrosis or cirrhosis was observed in 38% of these patients. Twelve (30%) of the 40 patients achieved SVR. HCV RNA was undetectable at week 12 in 68%. The positive predictive value of HCV RNA at week 12 was 45% and the negative predictive value was 100%. CONCLUSIONS: The presence of HCV RNA at week 12 had a high negative predictive value for SVR in hemodialysis patients with chronic hepatitis C treated with IFN for 48 weeks. Therefore, if HCV RNA is detected at week 12, treatment should be discontinued due to the low probability of a sustained response. PMID- 23041365 TI - Age and other risk factors of pneumonia among residents of Polish long-term care facilities. AB - BACKGROUND: Pneumonia is one of the leading causes of morbidity and mortality in the elderly population. Nursing home-acquired pneumonia (NHAP) is probably the largest health problem in long-term care facilities (LTCFs). It is the second most common infection in LTCFs and frequently requires hospitalization. The aim of this study was to investigate the incidence rate of NHAP among LTCF residents, its microbial etiology, and the frequency of multidrug-resistant microorganisms. Risk factors for NHAP were analyzed. METHODS: This was a prospective study conducted on a group of 217 elderly subjects aged >=65 years, recruited from the inhabitants of LTCFs, with disabled elderly individuals living in the community serving as controls. Continuous surveillance was carried out from December 1, 2009 to November 30, 2010. RESULTS: The incidence rate of NHAP in the observed population of Polish residents was 0.6/1000 resident-days. Vulnerability to NHAP was due to the poor general condition of residents, expressed by low Barthel index values (relative risk (RR) 1.6), the activities of daily living (ADL) score (RR 1.7), the Katz scale (RR 1.2), and limited physical activity (RR 1.6). Also significant were malnutrition (RR 2.3), the use of a bladder catheter (RR 1.3), dysphagia (RR 1.7), tracheotomy tube (RR 3.1), and gastric feeding tube (RR 3.5). Enterobacteriaceae were the predominant etiological agents of NHAP (56.3%). CONCLUSIONS: The significance of risk factors for NHAP among residents in LTCFs was confirmed. Unfortunately, we also found that a lack of proper supervision with regard to the microbiology of infections is characteristic of Polish health care and LTCFs. There is an opportunity to improve the medical care of patients with severe disabilities, limit the rise in antimicrobial resistance and the need for hospitalization, and improve the prognosis. PMID- 23041366 TI - [Cost-effectiveness of a chemotherapy predictive test]. AB - BACKGROUND: In breast cancer, adjuvant chemotherapy is often prescribed as a precautionary measure and sometimes unnecessarily. A diagnostic test based on estimating the risk of recurrence at 10 years for women with breast cancer in early stage has been developed (Oncotype DX((r))). METHOD: A Markov's model was adapted to evaluate the long-term effect of this test in terms of costs and life years gained in French clinical practice for patients with ER+, HER2-, node negative early-stage breast cancer. Input data were obtained from an international meta-analysis evaluating the proportions of patients in which the genetic test led to changes in the oncologist's decision. Costs and epidemiological data were specific to France. The analysis was conducted in accordance with methodological recommendations from the Haute Autorite de sante. RESULTS: The test is associated with net cost savings of ?570 per patient (?1,600 with productivity loss) from societal perspective and gains of 0.15 life-years and 0.14 quality-adjusted life-years per patient. CONCLUSIONS: The use of the test represents efficient use of health care resources in French practice. This test provides an opportunity to optimize treatment prescription by avoiding unnecessary chemotherapies and by prescribing chemotherapy to women who would not have received it based on standard decision criteria. PMID- 23041367 TI - Diffusive release of uranium from contaminated sediments into capillary fringe pore water. AB - Despite remediation efforts at the former nuclear weapons facility, leaching of uranium (U) from contaminated sediments to the ground water persists at the Hanford site 300 Area. Flooding of contaminated capillary fringe sediments due to seasonal changes in the Columbia River stage has been identified as a source for U supply to ground water. We investigated U release from Hanford capillary fringe sediments by packing sediments into reservoirs of centrifugal filter devices and saturating them with Columbia River water for 3 to 84days at varying solution-to solid ratios. After specified times, samples were centrifuged. Within the first three days, there was an initial rapid release of 6-9% of total U, independent of the solution-to-solid ratio. After 14days of reaction, however, the experiments with the narrowest solution-to-solid ratios showed a decline in dissolved U concentrations. The removal of U from the solution phase was accompanied by removal of Ca and HCO(3)(-). Geochemical modeling indicated that calcite could precipitate in the narrowest solution-to-solid ratio experiment. After the rapid initial release in the first three days for the wide solution-to-solid ratio experiments, there was sustained release of U into the pore water. This sustained release of U from the sediments had diffusion-limited kinetics. PMID- 23041368 TI - Peritoneal splenosis mimicking peritoneal carcinomatosis: a case report. PMID- 23041370 TI - Structures of the Phactr1 RPEL domain and RPEL motif complexes with G-actin reveal the molecular basis for actin binding cooperativity. AB - The Phactr family of PP1-binding proteins and the myocardin-related transcription factor family of transcriptional coactivators contain regulatory domains comprising three copies of the RPEL motif, a G-actin binding element. We report the structure of a Phactr1 G-actin?RPEL domain complex. Three G-actins surround the crank-shaped RPEL domain forming a closed helical assembly. Their spatial relationship is identical to the RPEL-actins within the pentavalent MRTF G actin?RPEL domain complex, suggesting that conserved cooperative interactions between actin?RPEL units organize the assembly. In the trivalent Phactr1 complex, each G-actin?RPEL unit makes secondary contacts with its downstream actin involving distinct RPEL residues. Similar secondary contacts are seen in G actin?RPEL peptide crystals. Loss-of-secondary-contact mutations destabilize the Phactr1 G-actin?RPEL assembly. Furthermore, actin-mediated inhibition of Phactr1 nuclear import requires secondary contact residues in the Phactr1 N-terminal RPEL N motif, suggesting that it involves interaction of RPEL-N with the C-terminal assembly. Secondary actin contacts by actin-bound RPEL motifs thus govern formation of multivalent actin?RPEL assemblies. PMID- 23041369 TI - Structure of NPP1, an ectonucleotide pyrophosphatase/phosphodiesterase involved in tissue calcification. AB - Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) converts extracellular nucleotides into inorganic pyrophosphate, whereas its close relative NPP2/autotaxin hydrolyzes lysophospholipids. NPP1 regulates calcification in mineralization-competent tissues, and a lack of NPP1 function underlies calcification disorders. Here, we show that NPP1 forms homodimers via intramembrane disulfide bonding, but is also processed intracellularly to a secreted monomer. The structure of secreted NPP1 reveals a characteristic bimetallic active site and a nucleotide-binding groove, but it lacks the lipid binding pocket and open tunnel present in NPP2. A loop adjacent to the nucleotide binding site, which is disordered in NPP2, is well ordered in NPP1 and might promote nucleotide binding. Remarkably, the N-terminal somatomedin B-like domains of NPP1, unlike those in NPP2, are flexible and do not contact the catalytic domain. Our results provide a structural basis for the nucleotide pyrophosphatase activity of NPP1 and help to understand how disease-causing mutations may affect NPP1 structure and function. PMID- 23041371 TI - Biomarker responses and accumulation of hazardous substances in mussels (Mytilus trossulus) transplanted along a pollution gradient close to an oil terminal in the Gulf of Finland (Baltic Sea). AB - Baltic Sea blue mussels (Mytilus trossulus) were used as sentinel organisms to detect the biological effects of chemical contamination in the low salinity environment. Mussels naturally adapted to a salinity of ca. 6.0 PSU were caged for 30 days at four sites along an assumed pollution gradient (salinity ca. 4.5 PSU) in the vicinity of Finland's largest oil refinery and harbor Kilpilahti in the Gulf of Finland. Tissue concentrations and accumulation rates of especially organic contaminants (PAHs, PCBs and organotins) were clearly elevated at the innermost coastal stations near the harbor area. Biological effects of contaminant exposure on caged mussels were evaluated by measuring a suite of biomarkers including catalase, glutathione S-transferase, superoxide dismutase, glutathione reductase, lipid peroxidation, acetylcholinesterase activity and lysosomal membrane stability. Mussels transplanted near the harbor area were able to elevate their antioxidant defense in response to environmental contamination. Reduced morphometric condition index and soft tissue growth rate together with increased lipid peroxidation and low lysosomal membrane stability were also observed at the most contaminated site. The results suggest that caging of M. trossulus for four weeks at lower salinity is a feasible method for the detection of environmental pollution also in low salinity areas of the Baltic Sea. PMID- 23041372 TI - Skin and soft tissue infections due to Panton-Valentine leukocidin producing Staphylococcus aureus. AB - OBJECTIVE: The authors had for aim to describe the epidemiological and clinical characteristics, and the treatment of patients presenting with skin and soft tissue infections due to Panton-Valentine leukocidin (PVL) producing Staphylococcus aureus in the Nord-Pas-de-Calais (NPDC) region, North of France. METHODS: We included patients presenting with PVL producing S. aureus infection from seven hospitals in the NPDC region, between February 2004 and April 2008. We retrospectively collected patient data using a standardized questionnaire. The features of patients presenting with skin and soft tissue were then analyzed. RESULTS: PVL producing S. aureus was isolated from 64 patients. Fifty-four patients presented with skin and soft tissue infections. The mean age of patients was 23.8 years (63% male patients). The mean number of persons living with the infected patient was 4.5 (vs. 2.5 in NPDC). The lesions were abscesses with inflammatory signs in 64.8% of the cases (20% were necrotic). Among the patients, 70.3% carried a methicillin resistant strain. Antibiotics per os were used for 83.3% of patients; the first-line antibiotics were considered inadequate in 53.3% of the cases. Among the patients, 83.3% underwent surgery. Fourteen out of 38 patients with available data had been exposed to antibiotic therapy during the three months before hospital management. CONCLUSION: Recent exposure to antibiotics and living with a high number of persons are reasons to suspect a PVL producing S. aureus infection in patients with skin abscess. PMID- 23041373 TI - Developmental treatment with bisphenol A causes few alterations on measures of postweaning activity and learning. AB - Widespread bisphenol A (BPA) exposure necessitates increased knowledge of its potential effects for better risk assessment and regulatory guidance. Here, female Sprague-Dawley rats, reared in low exogenous estrogen environments and bred at adulthood, were gavaged on gestational days 6-21 with vehicle (VEH), 2.5 or 25.0 MUg/kg/day BPA, or 5.0 or 10.0 MUg/kg/day ethinyl estradiol (EE2). Offspring were orally treated on postnatal days (PNDs) 1-21 with the same dose their dam received. A naive control group (NC) was not gavaged. Post-weaning, one offspring/sex/litter (n=11-12/sex/group) was assessed for the typical behaviors measured in developmental neurotoxicology studies. At PND 29, novelty preference was unaffected by treatment; however, relative to the VEH group, males and females of both EE2 groups were more active. VEH males appeared somewhat hypoactive in open field assessments at PNDs 40-42 and, as a result, males of the BPA and EE2 groups were significantly more active. Latency to locate the Barnes maze escape box at PNDs 47-50 was increased in males and females of the 5.0 MUg/kg/day EE2 group. Relative to other male groups, VEH males exhibited an increased startle response on the first trial block at PND 54 and thus, males of both BPA groups and the 10.0 MUg/kg/day EE2 group exhibited a significantly decreased startle response. PNDs 43-44 motor coordination and PNDs 75-79 water maze performance were unaffected by treatment. These results indicate few consistent or dose-related effects resulting from developmental treatment with BPA at these doses. Few of these behaviors, however, were sexually dimorphic which may prove more sensitive. PMID- 23041374 TI - Patterns of venom production and temporal polyethism in workers of Jerdon's jumping ant, Harpegnathos saltator. AB - Ants are chemical factories, and among their more noticeable products are their venoms. Though many studies have addressed the properties and activities of ant venoms, basic venom-related physiological questions, such as how venom production and replacement may vary with age, are rarely addressed. The answers to these questions are fundamental to understanding the physiological capabilities of these organisms, as well as the parameters within which potential optimization of their investment in venom production must take place. The only previous investigation into venom production in ants found it to be limited to early life in workers of the fire ant, Solenopsis invicta (Haight and Tschinkel, 2003). Because similar studies have not been conducted for comparison, it is unclear whether or not this is a common physiological pattern in ants. As a parsimonious way to address this question, and, more generally, to increase the currently scant information available regarding the venom-producing capabilities of ants, the longevity, temporal polyethism, age-related venom production, and age-related venom replacement capabilities of workers of Jerdon's jumping ant, Harpegnathos saltator were investigated. Longevity varied from 10 days to nearly 2 years, with a median lifespan of 206 days. Workers remained in the nest when young, transitioned to outside work (foraging) after 50 days of age, and reached a plateau in their tendency to be outside the nest at 74 days of age. They eclosed with empty venom sacs, filled them by about 57 days of age, and were able to replace venom at all three ages tested (though at a higher rate when aged 100 days than 30 and 206). So, venom-production ability is not limited to early life in H. saltator workers, and aspects of venom physiology and exploratory behavior appear to coincide in a manner likely to result in foraging efficiency benefits; venom sacs reach fullness around the age workers begin their foraging careers, and venom replacement rate is highest around the age workers become the most dedicated foragers. PMID- 23041375 TI - Barometric pressure influences host-orientation behavior in the larva of a dipteran ectoparasitoid. AB - Rain and temperature have been awarded as the most important weather factors that influence insect behavior. Barometric pressure studies have been relegated to a secondary place mainly because most studies deal with adult insects where temperature and water availability are the main environmental factors that influence behavior. We studied the influence of barometric pressure on the host orientation behavior in Mallophora ruficauda, an ectoparasitoid with an active host-seeking larval stage. Our results show that a steeper decrease in barometric pressure than expected by regular variation reduced orientation to host chemical cues. This study is the first to show a correlation between changes in the barometric pressure and the seeking behavior of parasitoid soil-dwelling larvae. Our results show that in this kind of insects, ambient factors other than temperature, water availability and light, can influence and have a profound impact on the process of parasitism. We discuss the influence of this behavior on a task so important for parasitoids as host location, and highlight the importance of including such information in parasitoid foraging ecology and climatic change studies. PMID- 23041376 TI - Identification of immunological expressed sequence tags in the mealworm beetle Tenebrio molitor. AB - Understanding the evolutionary ecology of immune responses to persistent infection could provide fundamental insight into temporal dynamics or interactive mechanisms that could be co-opted for antibiotic treatment regimes. Additionally, identification of novel molecules involved in these processes could provide novel compounds for biotechnological development. The beetle Tenebrio molitor displays a high level of induced antimicrobial activity coincident with persistent immuno resistant Staphylococcus aureus, and is the first invertebrate model for persistent infection. Here we present expressed sequence tags (ESTs) detected by suppression-subtraction hybridization of Tenebrio larvae after infection with S. aureus. Amongst others, we identified mRNAs coding for various oxidative enzymes and two antimicrobial peptides. These ESTs provide a foundation for mechanistic study of Tenebrio's immune system. PMID- 23041378 TI - An epidemiological survey of moyamoya disease, unilateral moyamoya disease and quasi-moyamoya disease in Japan. AB - OBJECTIVES: Moyamoya disease (MMD) is a unique occlusive disease of the bilateral internal carotid arteries in which, compensation for occlusion results in an enrichment of collateral arteries at the base of the brain. However, the epidemiology of unilateral MMD (typical angiographic evidence of MMD unilaterally with equivocal contralateral findings), and quasi-MMD (MMD present with inherited or acquired disorders) is poorly known. Here, a nationwide epidemiological survey was conducted to estimate the total numbers of patients, the annual incidence rates and prevalences of MMD, unilateral MMD and quasi-MMD in Japan. PATIENTS AND METHODS: The neurosurgery, neurology and pediatrics departments that were listed in Japanese resident training programs were recruited to participate in this survey. Questionnaires were directly mailed to 2998 departments in February 2006. RESULTS: A total of 1183 departments replied to the questionnaire (39.5% response rate). It was estimated that there were 6670.9 MMD patients, 840.5 unilateral MMD patients and 430.4 quasi-MMD patients in Japan. The annual incidence rates of MMD, unilateral MMD and quasi-MMD are 1.13, 0.23 and 0.11/100,000, respectively, and the prevalences are 5.22, 0.66 and 0.34/100,000, respectively. These patients were mainly treated by neurosurgeons. An estimated total of 929.1 surgical interventions are performed in Japan annually. CONCLUSION: This nationwide study reports the current epidemiologic status of MMD, unilateral MMD and quasi-MMD in Japan. PMID- 23041377 TI - A new effective assay to detect antimicrobial activity of filamentous fungi. AB - The search for new antimicrobial compounds and the optimization of production methods turn the use of antimicrobial susceptibility tests a routine. The most frequently used methods are based on agar diffusion assays or on dilution in agar or broth. For filamentous fungi, the most common antimicrobial activity detection methods comprise the co-culture of two filamentous fungal strains or the use of fungal extracts to test against single-cell microorganisms. Here we report a rapid, effective and reproducible assay to detect fungal antimicrobial activity against single-cell microorganisms. This method allows an easy way of performing a fast antimicrobial screening of actively growing fungi directly against yeast. Because it makes use of an actively growing mycelium, this bioassay also provides a way for studying the production dynamics of antimicrobial compounds by filamentous fungi. The proposed assay is less time consuming and introduces the innovation of allowing the direct detection of fungal antimicrobial properties against single cell microorganisms without the prior isolation of the active substance(s). This is particularly useful when performing large screenings for fungal antimicrobial activity. With this bioassay, antimicrobial activity of Hypholoma fasciculare against yeast species was observed for the first time. PMID- 23041379 TI - Treatment of blood blister-like aneurysms of the internal carotid artery with stent-assisted coil embolization. AB - OBJECTIVES: Blood blister-like aneurysms (BBAs) are aneurysms arising from the nonbranching arterial trunk, which are usually small and located at the anterior wall of supraclinoid internal carotid artery. These aneurysms are quite dangerous due to their fragile neck. This paper aims to evaluate the application of stent assisted coil embolization in the treatment of BBAs. METHODS: A retrospective review of the aneurysm database in our institution identified 8 patients carrying BBAs planned to be treated by stent-assisted coil embolization. The clinical characteristics, angiographic outcome, and follow-up results were reviewed. RESULTS: Stent-assisted coil embolization was successfully performed in 5 cases (62.5%). Two procedures were treated with sole stent deployment (25%). One patient suffered intra-operative rupture (12.5%) and endovascular trapping was performed. The modified Rankin scale (mRs) score in living patients at discharge was 1 in four cases, 2 in one case, and 3 in one case. Two patients died of post operative hemorrhage (25%). The mRs score at 9-36 months' follow-up was 0 in four cases, 1 in one case, and 2 in one case. All patients were followed up angiographically, and regrowth was observed in three patients, who accepted further endovascular treatments. CONCLUSION: Stent-assisted coil embolization may probably reduce the mortality, but may not be a cure for all BBAs. PMID- 23041380 TI - Duration of xylogenesis in black spruce lengthened between 1950 and 2010. AB - BACKGROUND AND AIMS: Reconstructions have identified the 20th century as being uniquely warm in the last 1000 years. Changes in the phenology of primary meristems converged toward increases in length of the growing season. Has the phenology of secondary meristem changed during the last century, and to what extent? METHODS: Timings of wood formation in black spruce, Picea mariana, were monitored for 9 years on a weekly timescale at four sites in the boreal forest of Quebec, Canada. Models for assessing xylem phenology were defined and applied to reconstruct onset, ending and duration of xylogenesis between 1950 and 2010 using thermal thresholds on chronologies of maximum and minimum temperatures. KEY RESULTS: All sites exhibited increasing trends of both annual and May-September temperatures, with the greatest changes observed at the higher latitudes. Phenological events in spring were more affected than those occurring in autumn, with cambial resumptions occurring 0.5-0.8 d decade(-1) earlier. The duration of xylogenesis has lengthened significantly since 1950, although the models supplied wide ranges of variations, between 0.07 and 1.5 d decade(-1), respectively. CONCLUSIONS: The estimated changes in past cambial phenology demonstrated the marked effects of the recent increase in temperature on the phenological traits of secondary meristems. In the long run, the advancement of cambial activity could modify the short time window for growth of boreal species and dramatically affect the dynamics and productivity of trees in these temperature-limited ecosystems. PMID- 23041381 TI - Rate heterogeneity in six protein-coding genes from the holoparasite Balanophora (Balanophoraceae) and other taxa of Santalales. AB - BACKGROUND AND AIMS: The holoparasitic flowering plant Balanophora displays extreme floral reduction and was previously found to have enormous rate acceleration in the nuclear 18S rDNA region. So far, it remains unclear whether non-ribosomal, protein-coding genes of Balanophora also evolve in an accelerated fashion and whether the genes with high substitution rates retain their functionality. To tackle these issues, six different genes were sequenced from two Balanophora species and their rate variation and expression patterns were examined. METHODS: Sequences including nuclear PI, euAP3, TM6, LFY and RPB2 and mitochondrial matR were determined from two Balanophora spp. and compared with selected hemiparasitic species of Santalales and autotrophic core eudicots. Gene expression was detected for the six protein-coding genes and the expression patterns of the three B-class genes (PI, AP3 and TM6) were further examined across different organs of B. laxiflora using RT-PCR. KEY RESULTS: Balanophora mitochondrial matR is highly accelerated in both nonsynonymous (d(N)) and synonymous (d(S)) substitution rates, whereas the rate variation of nuclear genes LFY, PI, euAP3, TM6 and RPB2 are less dramatic. Significant d(S) increases were detected in Balanophora PI, TM6, RPB2 and d(N) accelerations in euAP3. All of the protein-coding genes are expressed in inflorescences, indicative of their functionality. PI is restrictively expressed in tepals, synandria and floral bracts, whereas AP3 and TM6 are widely expressed in both male and female inflorescences. CONCLUSIONS: Despite the observation that rates of sequence evolution are generally higher in Balanophora than in hemiparasitic species of Santalales and autotrophic core eudicots, the five nuclear protein-coding genes are functional and are evolving at a much slower rate than 18S rDNA. The mechanism or mechanisms responsible for rapid sequence evolution and concomitant rate acceleration for 18S rDNA and matR are currently not well understood and require further study in Balanophora and other holoparasites. PMID- 23041382 TI - How does the mite Varroa destructor kill the honeybee Apis mellifera? Alteration of cuticular hydrcarbons and water loss in infested honeybees. AB - Several factors threaten the health of honeybees; among them the parasitic mite Varroa destructor and the Deformed Wing Virus play a major role. Recently, the dangerous interplay between the mite and the virus was studied in detail and the transition, triggered by mite feeding, from a benign covert infection to a devastating viral outbreak, characterized by an intense viral replication, associated with some characteristic symptoms, was described. In order to gain insight into the events preceding that crucial transition we carried out standardized lab experiments aiming at studying the effects of parasitization in asymptomatic bees to establish a relationship between such effects and bee mortality. It appears that parasitization alters the capacity of the honeybee to regulate water exchange; this, in turn, has severe effects on bee survival. These results are discussed in light of possible novel strategies aiming at mitigating the impact of the parasite on honeybee health. PMID- 23041384 TI - Numb/Numbl-Opo antagonism controls retinal epithelium morphogenesis by regulating integrin endocytosis. AB - Polarized trafficking of adhesion receptors plays a pivotal role in controlling cellular behavior during morphogenesis. Particularly, clathrin-dependent endocytosis of integrins has long been acknowledged as essential for cell migration. However, little is known about the contribution of integrin trafficking to epithelial tissue morphogenesis. Here we show how the transmembrane protein Opo, previously described for its essential role during optic cup folding, plays a fundamental role in this process. Through interaction with the PTB domain of the clathrin adaptors Numb and Numbl via an integrin-like NPxF motif, Opo antagonizes Numb/Numbl function and acts as a negative regulator of integrin endocytosis in vivo. Accordingly, numb/numbl gain-of-function experiments in teleost embryos mimic the retinal malformations observed in opo mutants. We propose that developmental regulator Opo enables polarized integrin localization by modulating Numb/Numbl, thus directing the basal constriction that shapes the vertebrate retina epithelium. PMID- 23041383 TI - Combinatorial assembly of developmental stage-specific enhancers controls gene expression programs during human erythropoiesis. AB - Gene-distal enhancers are critical for tissue-specific gene expression, but their genomic determinants within a specific lineage at different stages of development are unknown. Here we profile chromatin state maps, transcription factor occupancy, and gene expression profiles during human erythroid development at fetal and adult stages. Comparative analyses of human erythropoiesis identify developmental stage-specific enhancers as primary determinants of stage-specific gene expression programs. We find that erythroid master regulators GATA1 and TAL1 act cooperatively within active enhancers but confer little predictive value for stage specificity. Instead, a set of stage-specific coregulators collaborates with master regulators and contributes to differential gene expression. We further identify and validate IRF2, IRF6, and MYB as effectors of an adult-stage expression program. Thus, the combinatorial assembly of lineage-specific master regulators and transcriptional coregulators within developmental stage-specific enhancers determines gene expression programs and temporal regulation of transcriptional networks in a mammalian genome. PMID- 23041386 TI - Molecular phylogeny of the western South Atlantic Sciaenidae based on mitochondrial and nuclear data. AB - Fragments of mitochondrial (COI and rRNA 16S) and nuclear (Tmo-4C4) genes were sequenced to evaluate the phylogenetic relationships among 15 genera of the western South Atlantic Sciaenidae, two freshwater genera and the northwest Pacific Larimichthys crocea. Our results suggest a great diversification for the western Atlantic assemblage; the monophyly of Macrodon, Menticirrhus and Plagioscion genera; the distinctiveness of Bardiella, Stellifer and Ophioscion as belonging to the same clade; the possible existence of two distinct groups in Stellifer; the closer relationship between Lonchurus and Paralonchurus; the non monophyly of Cynoscion; and the remarkable diversification of Larimus breviceps populations in the Brazilian coast. This is the most comprehensive study evaluating the phylogenetic relationships of the western Atlantic sciaenid and provides a guide for future studies within this family. PMID- 23041387 TI - Effects of detector-source distance and detector bias voltage variations on time resolution of general purpose plastic scintillation detectors. AB - Effects of source-detector distance and the detector bias voltage variations on time resolution of a general purpose plastic scintillation detector such as BC400 were investigated. (133)Ba and (207)Bi calibration sources with and without collimator were used in the present work. Optimum source-detector distance and bias voltage values were determined for the best time resolution by using leading edge timing method. Effect of the collimator usage on time resolution was also investigated. PMID- 23041385 TI - Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging. AB - Circulating microRNAs (miRs) have been investigated as diagnostic/prognostic biomarkers in human diseases. However, little is known about their expression throughout the aging process. Eleven healthy individuals aged 20, 80 and 100 years underwent miR plasma profiling. The validation cohort consisted of 111 healthy adults (CTR) aged 20-105 years and included 30 centenarians. In addition, 34 patients with cardiovascular disease (CVD) and 15 healthy centenarian offspring (CO) were enrolled. An exploratory factorial analysis grouped the miRs into three main factors: factor 1 primarily higher in 20-year-old subjects, but these differences did not reach statistical significance, factor 2 primarily higher in octogenarians and factor 3 primarily higher in centenarians. MiR-21, the most highly expressed miR of factors 2 and 3, was further validated, confirming the differences in the age groups. MiR-21 expression was higher in the CVD patients and lower in the CO compared to the age-matched CTR. MiR-21 was correlated with C-reactive protein and fibrinogen levels. TGF-beta signaling was the predicted common pathway targeted by miRs of factors 2 and 3. TGF-betaR2 mRNA, a validated miR-21 target, showed the highest expression in the leukocytes from a subset of the octogenarians. Our findings suggest that miR-21 may be a new biomarker of inflammation. PMID- 23041388 TI - Radiation survey of aircraft and heavy machinery scrap. AB - This study was conducted primarily to survey aircraft and heavy machinery at 30 locations within Khartoum State using handheld radiation survey meters to detect and identify any radiation sources that might be present and to estimate radiation dose levels. The survey has resulted in detection of 16 sealed sources of (90)Sr and one of (226)Ra in aircraft scrap. Of course, (90)Sr sources are used in military aircraft as temperature sensors while (226)Ra is used for indicating fuel levels. These sources were found intact without spreading radioactivity contamination; however, none was detected in heavy machine scrap. The levels of radiation dose measured at 0.1m from the source fall within the range of 25.1-40.2 MUSv/h with an average value of 33.52 +/- 4.06 MUSv/h. These orphan sources have been separated from the scrap, tested for possible leakage, conditioned and stored in waste management facility. The result of this study has revealed without doubt that the scrap constitute a serious source of public exposure and highlights the importance of legislation making radiation monitoring of scrap in the country mandatory before it is sold to metal industry for reprocessing. PMID- 23041389 TI - Natural radionuclides in drinking waters in Serbia. AB - Gross alpha and beta activities, (3)H, (226)Ra, (232)Th and (40)K activities were measured in bottled mineral water produced in Serbia in order to assess its radiological quality. In 11 samples of tap water and in 1 sample of spring waters gross alpha and beta activity were determined. The natural activity concentration of alpha and beta emitting radionuclides are within the range recommended by World Health Organization. The tritium concentration in bottled mineral waters ranged from 0.023 +/- 0.012 to 0.046 +/- 0.006 Bq l(-1). The activity of (226)Ra, (232)Th and (40)K were below the minimum detectable activity. In order to evaluate the annual effective dose for different classes of age, a conservative dosimetric calculation was carried out. PMID- 23041390 TI - Kinetic study of fission product activity released inside containment under loss of coolant transients in a typical MTR system. AB - Based on continuous release of fission product (FP) activity from fuel to the coolant and then to the containment, a kinetic model is developed for source term after a LOCA in a typical MTR type system. The time dependent source, re suspension rate, decay of fission products, leakage, deposition on surfaces, and re-circulation of air through filters are employed with a partial prompt source plus a time varying source. Releases of different FP activities are simulated for various release rates. PMID- 23041391 TI - Optimization of the solid-phase synthesis of [18F] radiolabeled peptides for positron emission tomography. AB - Establishing improved methods for the radiolabeling of peptides with fluorine-18 via solid-phase peptide synthesis (SPPS) is desirable for the efficient synthesis of peptide-based molecular imaging agents. This work focuses on the development of a standardized platform to facilitate the reliable and efficient synthesis of high-purity fluorine-18 radiolabeled peptides for in vivo imaging with positron emission tomography (PET). Seven commercially available resins were selected for solid-phase radiolabeling of the model peptide VQAAIDYING with 4 [(18)F]fluorobenzoic acid ([(18)F]FBA). A wide range of radiochemical yields (18.8 +/- 1.5% to 41.2 +/- 5.3%) was obtained using standard conditions (coupling: 3 eq amino acid, 3 eq HATU, 6 eq DIPEA, 1.5 h, r.t.; cleavage: 94% TFA, 3 h, r.t.). After modification of coupling reagents and employing heated reactions to 37 degrees C, radiochemical yields were improved by as much as 35.3% over standard conditions. When the optimized conditions were applied to the synthesis of [(18)F]FBA-PEG(28)-A20FMDV2, which targets the alpha(v)beta(6) integrin in vivo, radiochemical yields improved by as much as 73.4% over those obtained using standard coupling and cleavage conditions. This platform can be utilized to improve the synthesis of peptide-based molecular probes for molecular imaging with PET. PMID- 23041392 TI - Quantification of the radio-metabolites of the serotonin-1A receptor radioligand [carbonyl-11C]WAY-100635 in human plasma: an HPLC-assay which enables measurement of two patients in parallel. AB - [Carbonyl-(11)C]WAY-100635 is a potent and effective antagonist for the 5-HT(1A) receptor subtype. We aimed to assess the status of [carbonyl-(11)C]WAY-100635 and its main radio-metabolites, [carbonyl-(11)C]desmethyl-WAY-100635 and [carbonyl (11)C]cyclohexanecarboxylic acid, on the basis of an improved radio-HPLC method. Common methods were characterized by preparative HPLC columns with long runtimes and/or high flow rates. Considering the short half-life of C-11, we developed a more rapid and solvent saving HPLC assay, allowing a fast, efficient and reliable quantification of these major metabolites. PMID- 23041394 TI - Investigating ischemic stroke costs and filling a critical knowledge gap. PMID- 23041395 TI - Concussion education: a (gentle) knock on the head for all of us. PMID- 23041393 TI - Kidney proximal tubular epithelial-specific overexpression of netrin-1 suppresses inflammation and albuminuria through suppression of COX-2-mediated PGE2 production in streptozotocin-induced diabetic mice. AB - Inflammation plays a key role in the development and progression of diabetic kidney disease; however, the role of the anti-inflammatory molecule netrin-1 in diabetic kidney disease is unknown. We examined the role of netrin-1 in diabetes induced kidney inflammation and injury using tubule-specific netrin-1 transgenic mice. Diabetes was induced using streptozotocin in wild-type and netrin-1 transgenic animals. Kidney function, fibrosis, glucose excretion, albuminuria, and inflammation were evaluated. The mechanism of netrin-1-induced suppression of inflammation was studied in vitro using a proximal tubular epithelial cell line. Diabetes was associated with increased infiltration of neutrophils and macrophages, chemokine expression, and tubular epithelial cell apoptosis in kidney. These changes were minimal in kidney of netrin-1 transgenic mice. In addition, diabetes induced a large increase in the excretion of prostaglandin E2 (PGE2) in urine, which was suppressed in netrin-1 transgenic mice. Netrin-1 induced suppression of PGE2 production was mediated through suppression of NFkappaB-mediated cyclooxygenase-2 (COX-2) in renal tubular epithelial cells. Furthermore, netrin-1 also increased albumin uptake by proximal tubular epithelial cells through the PI3K and ERK pathways without increasing glucose uptake. These findings suggest that netrin-1 is a major regulator of inflammation and apoptosis in diabetic nephropathy and may be a useful therapeutic molecule for treating chronic kidney diseases such as diabetic nephropathy. PMID- 23041396 TI - Vasospasm post pituitary surgery: systematic review and 3 case presentations. AB - BACKGROUND: Vasospasm is a known complication of aneurysmal subarachnoid hemorrhage and is a major cause of neurological morbidity and mortality. It is infrequently associated with pituitary adenoma surgery. We report three cases and present a systematic review of the literature with a view towards guiding neurosurgeons in the prevention and management of this complication. RESULTS: Including our experience, vasospasm complicating pituitary adenoma surgery has been documented in 29 patients (mean age of 45). All cases occurred in the setting of a postoperative hemorrhage: 21 had a subarachnoid hemorrhage and 10 had a postoperative hematoma requiring evacuation. Initial clinical appearance of delayed cerebral ischemia attributable to vasospasm occurred from postoperative Days 2-13 (most commonly Day 5). Digital subtraction angiography and medical management were the most common diagnostic and therapeutic strategies, respectively. Glasgow Outcome Scores were <=3 in 59% of cases. Univariate logistic regression identified later diagnosis of vasospasm and surgery for hematoma evacuation to be independently associated with better outcomes. CONCLUSION: Vasospasm should be considered in the differential diagnosis of patients demonstrating altered mental or neurological status following pituitary surgery, particularly if there has been postoperative hemorrhage of any degree. Prompt treatment should be instituted to optimize outcome. PMID- 23041397 TI - Predictors of cognitive impairment severity in rural patients at a memory clinic. AB - OBJECTIVE: Patients with dementia benefit from early assessment and diagnosis. In an attempt to identify factors leading to delay in referral, we investigated socio-demographic, clinical, and functional predictors of greater severity of cognitive impairment in dementia patients presenting to a memory clinic in Saskatoon, Saskatchewan. METHODS: Data collection began in 2004 at the Rural and Remote Memory Clinic in Saskatoon, where non-institutionalized patients were referred by their family physicians. The patient and caregiver questionnaires and assessments administered at the clinic day appointment provided the socio demographic, clinical, and functional patient variables, as well as the caregiver stress and burden variables. The dependent variable was patient cognitive impairment, as measured by Modified Mini-Mental State Examination (3MS) scores. Variables underwent univariate linear regression with 3MS scores in order to determine possible associations. A multiple regression analysis was conducted to determine predictors of cognitive impairment severity at clinic presentation. RESULTS: Our sample included 198 patients (62% female). The mean age was 73.9 years (SD=9.2). We found that an age and gender interaction, years of formal education, Functional Activities Questionnaire score, and Brief Symptom Inventory score were significantly associated with 3MS scores (p<0.05). CONCLUSIONS: Increased cognitive impairment at presentation was predicted by fewer years of formal education, poorer functional ability, and less caregiver psychological distress. There was a significant interaction between age and gender: younger females were more cognitively impaired than younger males at clinic day, while in older patients, males were more cognitively impaired than females. PMID- 23041398 TI - Diagnostic challenges revealed from a neuropsychiatry movement disorders clinic. AB - BACKGROUND: Abnormal movements are frequently associated with psychiatric disorders. Optimized management and diagnosis of these movements depends on correct labeling. However, there is evidence of reduced accuracy in the labeling of these movements, which could result in sub-optimal care. OBJECTIVE: To determine the consensus inter-rater reliability between a movement disorders neurologist and physicians referring from the community for phenomenology and diagnoses of individuals with co-existing psychiatric conditions and movement disorders. METHOD: Charts of all consecutive patients seen in a combined Movement Disorders and Neuropsychiatry Clinic between 2001-2009 were reviewed retrospectively. Consensus estimates and kappa values for inter-rater reliability were determined for phenomenology and diagnostic terms for the respective referring source and movement disorders neurologist for each patient. RESULTS: A total of 106 charts were reviewed (62 men and 44 women). Agreement for phenomenology terms ranged from 0% (psychogenic) to 73% (tremor). Only 3 terms had kappa values that met or exceeded criteria for moderate inter-rater reliability. Agreement for diagnosis terms was highest for tardive dyskinesia (83%), drug induced tremor (33%), and drug induced parkinsonism (20%). In 18 of the 22 charts (82%), a diagnosis was made of drug induced movement disorder (DIMD) by the referring physician. In contrast, a diagnosis of DIMD was made in only 54 of 106 charts (51%) after the patients were assessed in the clinic. CONCLUSIONS: A movement disorders specialist frequently disagreed with referring physicians' identification of patient phenomenology and diagnosis. This suggests that clinicians would benefit from educational resources to assist in characterizing abnormal movements. PMID- 23041399 TI - Improvement in thrombolytic therapy administration in acute stroke with feedback. AB - BACKGROUND: The benefits of intravenous recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke is time dependent. Guidelines recommend a door to-needle (DTN) time of less than 60 minutes. METHODS: A retrospective audit of 730 stroke charts from 2008 - 2011 was conducted at Health Sciences Centre. 158 patients treated with IV rt-PA were identified. The time intervals between Emergency Department (ED) arrival, administration of rt-PA and uninfused brain computed axial tomographic scan (CT) were recorded. From this, CT to needle times were calculated. During November 2010 to January 2011 feedback was given to neurologists, ED physicians, ED nurses, and CT technologists. This raised awareness and emphasized the importance of this time driven protocol. RESULTS: The median DTN times for 2008, 2009, and 2010 were 69, 71 and 76 minutes respectively. The median CT-to-needle time for this time period was 47 minutes. In 2011 (n =58) the median DTN time was 49 minutes and the median CT-to-needle was 18 minutes, which were marked improvements (p<0.00005 and p<0.005, respectively). In 2008-2010 only 31% of treated patients (n=100) received rt-PA within 60 minutes, whereas in 2011 this increased to 64%. CONCLUSIONS: Dramatic improvements in DTN times and in the percentage of patients receiving rt-PA treatment within 60 minutes were observed in 2011 after feedback was provided regarding the suboptimal performance. Prior to receiving feedback, DTN times were similar to national median DTN times. All centres administering rt-PA for acute ischemic stroke should monitor their clinical performance and give feedback on a regular basis. PMID- 23041400 TI - Impact of disability status on ischemic stroke costs in Canada in the first year. AB - BACKGROUND: Longitudinal, patient-level data on resource use and costs after an ischemic stroke are lacking in Canada. The objectives of this analysis were to calculate costs for the first year post-stroke and determine the impact of disability on costs. METHODOLOGY: The Economic Burden of Ischemic Stroke (BURST) Study was a one-year prospective study with a cohort of ischemic stroke patients recruited at 12 Canadian stroke centres. Clinical history, disability, health preference and resource utilization information was collected at discharge, three months, six months and one year. Resources included direct medical costs (2009 CAN$) such as emergency services, hospitalizations, rehabilitation, physician services, diagnostics, medications, allied health professional services, homecare, medical/assistive devices, changes to residence and paid caregivers, as well as indirect costs. Results were stratified by disability measured at discharge using the modified Rankin Score (mRS): non-disabling stroke (mRS 0-2) and disabling stroke (mRS 3-5). RESULTS: We enrolled 232 ischemic stroke patients (age 69.4 +/- 15.4 years; 51.3% male) and 113 (48.7%) were disabled at hospital discharge. The average annual cost was $74,353; $107,883 for disabling strokes and $48,339 for non-disabling strokes. CONCLUSIONS: An average annual cost for ischemic stroke was calculated in which a disabling stroke was associated with a two-fold increase in costs compared to NDS. Costs during the hospitalization to three months phase were the highest contributor to the annual cost. A "back of the envelope" calculation using 38,000 stroke admissions and the average annual cost yields $2.8 billion as the burden of ischemic stroke. PMID- 23041401 TI - Effect of statin on progression of symptomatic intracranial atherosclerosis. AB - BACKGROUND: Symptomatic intracranial atherosclerosis (ICAS) is a dynamic disease that frequently progresses. Statins have been shown to have anti-atherosclerotic activity. We therefore investigated whether statins could prevent progression of ICAS. METHODS: This retrospective cohort study assessed 55 patients with acute ischemic stroke and symptomatic ICAS in the middle cerebral or basilar arteries as shown on magnetic resonance angiography (MRA), with follow-up MRA performed more than 1 year after the index stroke. Change in ICAS was classified as progressive, regressive, or stable. Baseline clinical characteristics and risk factor control during follow-up were assessed, and laboratory tests were performed at the time of follow-up MRA. The statin group was defined as patients regularly treated with statins for more than 75% of the follow-up period; the remaining patients were defined as the non-statin group. RESULTS: At a median follow-up time of 21.8 months (range, 11.8-66.1 months), the statin group consisted of 26 (47.3%) patients and the non-statin group of 29 (52.7%). During follow-up, 6 (10.9%) patients progressed, 14 (25.5%) regressed, and 35 (63.6%) remained stable. Statin treatment was significantly associated with non progression of ICAS (p=0.024). Two patients in the non-statin group had recurrent strokes. Border-zone infarcts were associated with progression of ICAS (3/6, 50%; p=0.007), whereas risk factors and inflammatory biomarkers were not related to progression. CONCLUSIONS: Treatment with statins may prevent progression of symptomatic ICAS. Prospective randomized controlled trials are required to confirm that statins protect against such progression. PMID- 23041402 TI - Occipital stimulation for chronic migraine: patient selection and complications. AB - BACKGROUND: Chronic migraine is a significant cause of disability world-wide and occipital region stimulation (OS) has been proposed to treat it. While participating in an industry-sponsored pilot trial of OS, we aimed to collect data regarding our surgical complications and long term usage of OS in our chronic migraine patients. METHODS: Ten patients (8 female, median age 46.5 years) were enrolled based on criteria established by the sponsoring company, screened in the headache clinic, and followed for a median of 33 months. We did not access data collected by industry for this report and instead collected our own data prospectively, including predominant location of headache, location of paresthesia evoked by OS, and complications. RESULTS: Adverse events included three possible early infections requiring antibiotics but not hardware removal, one late implantable pulse generator erosion requiring removal, one generator malfunction requiring revision, and loss of paresthetic coverage requiring four revisions in four patients. Two patients experienced new symptoms requiring psychiatric intervention. Five patients had no benefit and have been explanted. Of those who remain using their device, the proportion of their pre-operative pain located in the occipital region was 0.62 +/- 0.14, whereas in those patients who have been explanted, the proportion was 0.31 +/- 0.18 (t = 3.15, p=0.01). CONCLUSIONS: Complication rates with OS are higher than those seen with other stimulation techniques, despite identical hardware and similar surgery. The location of migraine pain did predict outcome, and suggests that only those with primarily occipital region headache are candidates for this therapy. PMID- 23041403 TI - Cerebrospinal fluid IL-21 levels in Neuromyelitis Optica and multiple sclerosis. AB - BACKGROUND: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are inflammatory demyelinating diseases of human central nervous system (CNS) with complex pathogenesis. IL-21/IL-21R regulates activation, proliferation and survival of both T cells and B cells, which are involved in the pathogenesis of NMO and MS. High levels of serum IL-21 were observed in NMO patients. However, concentration of cerebrospinal fluid (CSF) IL-21 in MS and NMO patients still remain unknown. OBJECT: To detect the CSF concentration of IL-21 in NMO and MS patients and to evaluate its relationship with disease activity, particularly concerned about its impact on humoral immunity. METHODS: CSF IL-21 was detected by an enzyme-linked immunosorbent assay (ELISA) in NMO patients (n=21), MS patients (n=20) and controls (n=16). RESULTS: CSF concentration of the IL-21 was noticeably elevated in NMO (p=0.012) and borderline significantly increased in MS (p=0.115). In addition, this occurrence was associated with humoral immune activity as shown by a correlation between IL-21 and complement in NMO cohort (p=0.023) and high IL-21 levels in autoantibody-positive subgroup (p=0.027). CONCLUSIONS: The concentration of CSF IL-21 was noticeably elevated and might have a positive correlation with humoral immune activity in NMO. PMID- 23041404 TI - Hemangioblastoma stromal cells show committed stem cell phenotype. AB - BACKGROUND: Hemangioblastomas are benign vascular tumors of the central nervous system that occur sporadically or in association with von Hippel-Lindau disease. These tumors are characteristically composed of a dense capillary network with intervening stromal/interstitial cells. To date, the histogenesis of hemangioblastoma remains unclear. We hypothesize that hemangioblastomas arise from a defective mesodermal stem cell, which gives rise to the atypical vasculature. METHODS: To test our hypothesis, we have characterized the cellular composition of hemangioblastomas by immunophenotyping pluripotent and committed stem cells and vascular endothelial cells. RESULTS: Our findings show that hemangioblastoma endothelial cells are positive for CD133, a stem and progenitor cell marker. Vascular endothelial cells also expressed nuclear Oct4. In addition to the endothelium, both CD133 and Oct4 were present in stromal and perivascular cells. Interestingly, neither the endothelium nor the stromal cells expressed Sox2 or Nanog suggesting a committed stem cell phenotype. CONCLUSIONS: From these findings, we believe that hemangioblastoma stromal cells are committed stem cells producing both vascular cell types. The findings also show an unusual CD133 positive endothelial phenotype in hemangioblastoma. PMID- 23041405 TI - Pregnancy-induced cystic degeneration of fibrous dysplasia. PMID- 23041406 TI - Critically appraised topic. Temporal lobe epilepsy and hippocampal stimulation. PMID- 23041407 TI - Partial agenesis of corpus callosum in Sanjad-Sakati syndrome (p-ACC). PMID- 23041408 TI - Pituicytoma of the neurohypophysis: analysis of cell proliferation biomarkers. PMID- 23041411 TI - KDEL peptide gold nanoconstructs: promising nanoplatforms for drug delivery. AB - Gold nanoparticles (AuNPs) have been widely investigated as potential nanocarriers for drug delivery. In the present study, AuNPs were conjugated to a peptide that has a C-terminal Lys-Asp-Glu-Leu (KDEL) motif. In a pulse-chase study, time-course sampling revealed that AuNP-delivered KDEL peptides were rapidly localized to the endoplasmic reticulum (ER) in 5 to 15 min, and after 1h the majority of peptides were localized to the ER. Clathrin-coated vesicles and Golgi apparatus were also involved during the intracellular trafficking of KDEL peptide gold (AuNP-KDEL) nanoconstructs. Furthermore, overexpression of KDEL receptor (KDELR) significantly enhanced KDEL peptide uptake in both free and AuNP conjugated forms. These data indicate that the AuNP-KDEL nanoconstructs are internalized via a clathrin-mediated pathway and trafficked to the ER via a retrograde transport pathway, bypassing the lysosomal degradation pathway. Thus, this novel approach to development of nanoconstruct-based drug delivery has the potential to evade intracellular degradation, enhancing drug efficacy. FROM THE CLINICAL EDITOR: In this study, gold nanoparticles were conjugated to a peptide with KDEL motif, resulting in internalization via a clathrin-mediated pathway and trafficking to the ER via retrograde transport meanwhile bypassing the lysosomal degradation pathway. This method results in a potential evasion of intracellular degradation, and enhanced drug efficacy. PMID- 23041409 TI - Higher nitrate-reducer diversity in macrophyte-colonized compared to unvegetated freshwater sediment. AB - Freshwater macrophytes stimulate rhizosphere-associated coupled nitrification denitrification and are therefore likely to influence the community composition and abundance of rhizosphere-associated denitrifiers and nitrate reducers. Using the narG gene, which encodes the catalytic subunit of the membrane-bound nitrate reductase, as a molecular marker, the community composition and relative abundance of nitrate-reducing bacteria were compared in the rhizosphere of the freshwater macrophyte species Littorella uniflora and Myriophyllum alterniflorum to nitrate-reducing communities in unvegetated sediment. Microsensor analysis indicated a higher availability of oxygen in the rhizosphere compared to unvegetated sediment, with a stronger release of oxygen from the roots of L. uniflora compared to M. alterniflorum. Comparison of narG clone libraries between samples revealed a higher diversity of narG phylotypes in association with the macrophyte rhizospheres compared to unvegetated sediment. Quantitative PCR targeting narG- and 16S rRNA-encoding genes pointed to a selective enrichment of narG gene copies in the rhizosphere. The results suggested that the microenvironment of macrophyte rhizospheres, characterized by the release of oxygen and labile organic carbon from the root system, had a stimulating effect on the diversity and relative abundance of rhizosphere-associated nitrate reducers. PMID- 23041410 TI - In vitro radiosensitization by gold nanoparticles during continuous low-dose-rate gamma irradiation with I-125 brachytherapy seeds. AB - This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources. HeLa cell cultures incubated with and without AuNP were irradiated with an I-125 seed plaque designed to produce a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at low-dose rates ranging from 2.1 to 4.5cGy/h. Residual gammaH2AX was measured 24h after irradiation and used to compare radiation damage to the cells with and without AuNP. The data demonstrate that the biological effect when irradiating in the presence of 0.2mg/ml concentration of AuNP is about 70%-130% greater than without AuNP. Meanwhile, without radiation, the AuNP showed minimal effect on the cancer cells. These findings provide in vitro evidence that AuNP may be employed as radiosensitizers during continuous LDR brachytherapy. FROM THE CLINICAL EDITOR: In this basic science paper, the application of gold nanoparticles as radiosensitizing agents for low dose rate gamma radiation therapy is discussed, demonstrating efficacy in cell culture models. PMID- 23041412 TI - Cell-penetrating peptides released from thermosensitive nanoparticles suppress pro-inflammatory cytokine response by specifically targeting inflamed cartilage explants. AB - Cell-penetrating anti-inflammatory peptide KAFAKLAARLYRKALARQLGVAA (KAFAK) has the ability to suppress pro-inflammatory cytokines TNF-alpha and IL-6 when released from degradable and non-degradable poly(NIPAm-AMPS) nanoparticles. In vitro human macrophage model with THP1 human monocytes and ex vivo bovine knee cartilage tissue both showed a dose-dependent suppression of pro-inflammatory cytokines when treated with KAFAK-loaded poly(NIPAm-AMPS) nanoparticles. When bovine knee cartilage explants were treated with KAFAK-loaded poly(NIPAm-AMPS) nanoparticles, rapid and highly selective targeting of only damaged tissue occurred. This study has demonstrated selective targeting and therapeutic efficacy of KAFAK when released from both degradable and non-degradable poly(NIPAm-AMPS) nanoparticles in in vitro and ex vivo models. As a result, poly(NIPAm-AMPS) nanoparticles loaded with KAFAK could be a very effective tool to treat osteoarthritis. FROM THE CLINICAL EDITOR: Inflammatory arthritis remains a major medical problem with substantial socio-economic impact. Anti-inflammatory KAFAK peptide when released from degradable and non-degradable poly(NIPAm-AMPS) nanoparticles has the ability to penetrate cells and suppress pro-inflammatory cytokines, resulting in rapid and highly selective targeting of only damaged tissue in bovine knee cartilage explants. This approach may provide a very effective future tool in addressing osteoarthritis. PMID- 23041413 TI - Current status and controversies in adrenal incidentalomas. AB - Adrenal incidentalomas (AI) are serendipitously discovered lesions during abdominal imaging studies that need to be investigated for evidence of hormonal hypersecretion and/or malignancy. Because imaging modalities can reliably identify lesions that carry a high risk of malignancy, we focus on the identification of hypersecretory lesions and those with subclinical activity, particularly Cushing syndrome. Because diverse diagnostic tests and cut-offs are employed, the prevalence of hypersecretory AI varies widely, and there is controversy regarding their long-term sequelae. In this article we provide information regarding current radiological means to define the nature of AI, and the most appropriate biochemical tests for delineating hypersecretory states. We also discuss the duration and intensity of AI follow-up as well as the identification of AI that require specific therapeutic intervention. PMID- 23041414 TI - Classification of ligand molecules in PDB with fast heuristic graph match algorithm COMPLIG. AB - A fast heuristic graph-matching algorithm, COMPLIG, was devised to classify the small-molecule ligands in the Protein Data Bank (PDB), which are currently not properly classified on structure basis. By concurrently classifying proteins and ligands, we determined the most appropriate parameter for categorizing ligands to be more than 60% identity of atoms and bonds between molecules, and we classified 11,585 types of ligands into 1946 clusters. Although the large clusters were composed of nucleotides or amino acids, a significant presence of drug compounds was also observed. Application of the system to classify the natural ligand status of human proteins in the current database suggested that, at most, 37% of the experimental structures of human proteins were in complex with natural ligands. However, protein homology- and/or ligand similarity-based modeling was implied to provide models of natural interactions for an additional 28% of the total, which might be used to increase the knowledge of intrinsic protein metabolite interactions. PMID- 23041416 TI - GLUT12 functions as a basal and insulin-independent glucose transporter in the heart. AB - Glucose uptake from the bloodstream is the rate-limiting step in whole body glucose utilization, and is regulated by a family of membrane proteins called glucose transporters (GLUTs). Although GLUT4 is the predominant isoform in insulin-sensitive tissues, there is recent evidence that GLUT12 could be a novel second insulin-sensitive GLUT. However, its physiological role in the heart is not elucidated and the regulation of insulin-stimulated myocardial GLUT12 translocation is unknown. In addition, the role of GLUT12 has not been investigated in the diabetic myocardium. Thus, we hypothesized that, as for GLUT4, insulin regulates GLUT12 translocation to the myocardial cell surface, which is impaired during diabetes. Active cell surface GLUT (-4 and -12) content was quantified (before and after insulin stimulation) by a biotinylated photolabeled assay in both intact perfused myocardium and isolated cardiac myocytes of healthy and type 1 diabetic rodents. GLUT localization was confirmed by immunofluorescent confocal microscopy, and total GLUT protein expression was measured by Western blotting. Insulin stimulation increased translocation of GLUT 4, but not -12, in the healthy myocardium. Total GLUT4 content of the heart was decreased during diabetes, while there was no difference in total GLUT12. Active cell surface GLUT12 content was increased in the diabetic myocardium, potentially as a compensatory mechanism for the observed downregulation of GLUT4. Collectively, our data suggest that, in contrast to GLUT4, insulin does not mediate GLUT12 translocation, which may function as a basal GLUT located primarily at the cell surface in the myocardium. PMID- 23041415 TI - Crystal structure of Delta(185-243)ApoA-I suggests a mechanistic framework for the protein adaptation to the changing lipid load in good cholesterol: from flatland to sphereland via double belt, belt buckle, double hairpin and trefoil/tetrafoil. AB - Apolipoprotein A-I (apoA-I) is the major protein of plasma high-density lipoproteins (HDLs), macromolecular assemblies of proteins and lipids that remove cell cholesterol and protect against atherosclerosis. HDL heterogeneity, large size (7.7-12 nm), and ability to exchange proteins have prevented high-resolution structural analysis. Low-resolution studies showed that two apoA-I molecules form an antiparallel alpha-helical "double belt" around an HDL particle. The atomic resolution structure of the C-terminal truncated lipid-free Delta(185-243)apoA-I, determined recently by Mei and Atkinson, provides unprecedented new insights into HDL structure-function. It allows us to propose a molecular mechanism for the adaptation of the full-length protein to increasing lipid load during cholesterol transport. ApoA-I conformations on small, midsize, and large HDLs are proposed based on the tandem alpha-helical repeats and the crystal structure of Delta(185 243)apoA-I and are validated by comparison with extensive biophysical data reported by many groups. In our models, the central half of the double belt ("constant" segment 66-184) is structurally conserved while the N- and C-terminal half ("variable" segments 1-65 and 185-243) rearranges upon HDL growth. This includes incremental unhinging of the N-terminal bundle around two flexible regions containing G39 and G65 to elongate the belt, along with concerted swing motion of the double belt around G65-P66 and G185-G186 hinges that are aligned on various-size particles, to confer two-dimensional surface curvature to spherical HDLs. The proposed conformational ensemble integrates and improves several existing HDL models. It helps provide a structural framework necessary to understand functional interactions with over 60 other HDL-associated proteins and, ultimately, improve the cardioprotective function of HDL. PMID- 23041418 TI - [Blood products transport, pedagogy and application]. AB - Transport products blood and samples of human blood is one of the keys of transfusional safety forcing all actors to update their know how and to comply with rigorous rules and high level capabilities requirements. This must lead blood transfusion institutes and medical and biologic laboratories to implement specific process insuring safe transport, preservation and avaibility of the items in accordance with patients' therapic needs. Training and regular valuation of involved actors make necessary to update tools and training methods. E learning allows a fast and homogeneous learning. PMID- 23041417 TI - Biodistribution and renal clearance of biocompatible lung targeted poly(ethylene glycol) (PEG) nanogel aggregates. AB - A novel stabilized aggregated nanogel particle (SANP) drug delivery system was prepared for injectable passive lung targeting. Gel nanoparticles (GNPs) were synthesized by irreversibly cross-linking 8 Arm PEG thiol with 1,6-hexane-bis vinylsulfone (HBVS) in phosphate buffer (PB, pH 7.4) containing 0.1% v/v TweenTM 80. Aggregated nanogel particles (ANPs) were generated by aggregating GNPs to micron-size, which were then stabilized (i.e., SANPs) using a PEG thiol polymer to prevent further growth-aggregation. The size of SANPs, ANPs and GNPs was analyzed using a Coulter counter and transmission electron microscopy (TEM). Stability studies of SANPs were performed at 37 degrees C in rat plasma, phosphate buffered saline (PBS, pH 7.4) and PB (pH 7.4). SANPs were stable in rat plasma, PBS and PB over 7 days. SANPs were covalently labeled with HiLyte FluorTM 750 (DYE-SANPs) to facilitate ex vivo imaging. Biodistribution of intravenous DYE SANPs (30 MUm, 4 mg in 500 MUL PBS) in male Sprague-Dawley rats was compared to free HiLyte FluorTM 750 DYE alone (1mg in 500 MUL PBS) and determined using a Xenogen IVIS(r) 100 Imaging System. Biodistribution studies demonstrated that free DYE was rapidly eliminated from the body by renal filtration, whereas DYE SANPs accumulated in the lung within 30 min and persisted for 48 h. DYE-SANPs were enzymatically degraded to their original principle components (i.e., DYE-PEG thiol and PEG-VS polymer) and were then eliminated from the body by renal filtration. Histological evaluation using H & E staining and broncho alveolar lavage (BAL) confirmed that these flexible SANPs were not toxic. This suggests that because of their flexible and non-toxic nature, SANPs may be a useful alternative for treating pulmonary diseases such as asthma, pneumonia, tuberculosis and disseminated lung cancer. PMID- 23041419 TI - What happens if people start drinking mouthwash as surrogate alcohol? A quantitative risk assessment. AB - Mouthwash ingestion has been observed in settings of restricted availability to alcoholic beverages such as in hospitals, prisons or military establishments. The literature offers limited evidence that ingredients of mouthwash may have health effects above the effects of ethanol. This study provides a quantitative risk assessment based on analysis of 30 mouthwash samples. All investigated brands contained alcohol, most of them menthol (93%), eucalyptol (90%), benzoic acid (87%), methyl salicylate (67%), and thymol (30%). For low risk drinking scenarios with average levels, only ethanol will exceed acceptable daily intakes (ADI). In worst case scenarios for alcohol dependent consumers ingesting 100g ethanol per day in the form of mouthwash, methyl salicylate will also exceeded the ADI by a factor of 17. The margin of exposure (MOE) for methyl salicylate, benzoates and thymol was below 100 for average scenarios, and below 10 for worst case scenarios, but ethanol is still the most toxic ingredient with MOE below 1. The occasional or even chronic ingestion of mouthwash may not cause health effects except the effects of ethanol alone. Only in extreme exposures, ingredients such as thymol or methyl salicylate could exacerbate the effects of ethanol, especially by contributing to metabolic acidosis. PMID- 23041420 TI - Coexisted components of Salvia miltiorrhiza enhance intestinal absorption of cryptotanshinone via inhibition of the intestinal P-gp. AB - Cryptotanshinone, derived from the roots of Salvia miltiorrhiza Bge and Salvia przewalskii Maxim, is the major active component and possesses significant antibacterial, antidermatophytic, antioxidant, anti-inflammatory and anticancer activities. The objective of this study was to investigate the intestinal absorptive characteristics of cryptotanshinone as well as the absorptive behavior influenced by co-administration of the diterpenoid tanshinones and danxingfang using an in vitro everted rat gut sac model. The results showed a good linear correlation between cryptotanshinone of absorption and the incubation time from 10 to 70min. The concentration dependence showed that a non-linear correlation existed between the cryptotanshinone absorption and the concentration at 100 MUg/ml. Coexisting diterpenoid tanshinones and danxingfang could significantly enhance the absorption of cryptotanshinone. Coexisting diterpenoid tanshinones and danxingfang, which influenced cryptotanshinone's absorption, manifested as similar to that of the P-glycoprotein inhibitor. The underlying mechanism of the improvement of oral bioavailability was proposed that coexisting diterpenoid tanshinones and danxingfang could decrease the efflux transport of cryptotanshinone by P-glycoprotein. PMID- 23041421 TI - A human TOP2A core DNA binding X-ray structure reveals topoisomerase subunit dynamics and a potential mechanism for SUMO modulation of decatenation. PMID- 23041422 TI - How to distinguish methyl-cytosine from cytosine with high fidelity. AB - Methylation of cytosines in the DNA is central to the epigenetic code. The patterns along the DNA formed by these chemical marks instruct the cell which proteins to express and their faithful maintenance after replication are vital to the organism's life. Although Dnmt1 is the enzyme catalyzing the methylation reaction, it was found that UHRF1 (ubiquitin-like, containing PHD and RING finger domain 1) is the protein that actually recognizes hemi-methylated CpG sites. Nevertheless, the physical mechanism driving the strikingly robust distinction between hemi-methylated and unmethylated sites is not known. In this paper, we show that the large difference in the binding affinities of UHRF1 to these sites is possible not due to the presence of the methyl group itself but is a result of the accompanying changes in the distribution of the electrons around the cytosine ring. In particular, methylation reduces the dipole moment of cytosine and, as a consequence, unmethylated DNA in its unbound state in water is more stable than hemi-methylated DNA. Furthermore, the interaction energy of hemi-methylated DNA bound to UHRF1 with its surrounding is stronger than that of unmethylated DNA. Thus, the change in the electronic structure of cytosine upon methylation destabilizes the unbound state and stabilizes the bound state rendering discrimination with high fidelity possible. PMID- 23041424 TI - One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1beta. AB - Interleukin-1beta (IL-1beta) is a key orchestrator in inflammatory and several immune responses. IL-1beta exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1beta monoclonal antibodies. Canakinumab is known to neutralize IL-1beta by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1beta bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1beta signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1beta. Furthermore, we characterized the epitopes on IL-1beta employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1beta and provide insight into the mechanisms leading to their distinct modulation of IL-1beta signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1beta causes competitive inhibition of the association of IL-1beta and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1beta and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1beta pathway attenuation. PMID- 23041423 TI - Electron microscopy and 3D reconstruction reveals filamin Ig domain binding to F actin. AB - Filamin A (FLNa) is an actin-binding protein that cross-links F-actin into networks of orthogonally branched filaments. FLNa also directs the networks to integrins while responding to mechanochemical signaling pathways. Flexible, 160 nm-long FLNa molecules are tail-to-tail dimers, each subunit of which contains an N-terminal calponin homology (CH)/actin-binding domain connected by a series of 24 immunoglobulin (Ig) repeats to a dimerization site at their C-terminal end. Whereas the contribution of the CH domains to F-actin affinity is weak (apparent K(a)~10(5)), the binding of the intact protein to F-actin is strong (apparent K(a)~10(8)), suggesting involvement of additional parts of the molecule in this association. Indeed, previous results indicate that Ig repeats along FLNa contribute significantly to the strength of the actin filament interaction. In the current study, we used electron microscopy and three-dimensional reconstruction to elucidate the structural basis of the Ig repeat-F-actin binding. We find that FLNa density is clearly delineated in reconstructions of F actin complexed either with a four-Ig-repeat segment of FLNa containing Ig repeat 10 or with immunoglobulin-like filamin A repeat (IgFLNa)10 alone. The mass attributable to IgFLNa10 lies peripherally along the actin helix over the N terminus of actin subdomain 1. The IgFLNa10 interaction appears to be specific, since no other individual Ig repeat or fragment of the FLNa molecule examined, besides ones with IgFLNa10 or CH domains, decorated F-actin filaments or were detected in reconstructions. We conclude that the combined interactions of CH domains and the IgFLNa10 repeat provide the binding strength of the whole FLNa molecule and propose a model for the association of IgFLNa10 on actin filaments. PMID- 23041427 TI - Salvage banding for failed Roux-en-Y gastric bypass. AB - BACKGROUND: After Roux-en-Y gastric bypass (RYGB), a substantial number of patients do not achieve successful long-term weight loss. In cases of loss of restriction, the application of an adjustable gastric band ("salvage banding") over the gastric pouch, or gastrojejunostomy, could prevent weight regain or increase weight loss. The objective of this literature review is to provide an overview of the studies that report the effect of salvage banding after failed RYGB. METHODS: A systemic literature search was conducted in PubMed, Google Scholar, Medline, the Cochrane Library, and the online websites of specific bariatric surgery journals to identify all relevant studies describing salvage banding after failed RYGB. RESULTS: Seven studies, with a total of 94 patients, were included for a systemic literature review. Inclusion criteria for salvage banding varied from unsuccessful weight loss to technical pouch failure. After salvage banding, all studies reported further weight loss, varying from 55.9% 94.2% excess body mass index loss (EBMIL) after 12-42 months of follow-up. In the included study group, 18% (17/94) of the patients developed long-term complications requiring a re-revision in 17% (16/94) of the cases. CONCLUSION: The results of all 9 studies that were included in this review report a further increase in weight loss after salvage banding for failed RYGB. In case of insufficient weight loss or technical pouch failure after RYGB, all reports suggest that salvage banding is a safe and feasible revisional procedure. Prospective studies are necessary to determine to the success of direct application of an adjustable gastric band in primary RYGB. PMID- 23041425 TI - Salt anions promote the conversion of HypF-N into amyloid-like oligomers and modulate the structure of the oligomers and the monomeric precursor state. AB - An understanding of the solution factors contributing to the rate of aggregation of a protein into amyloid oligomers, to the modulation of the conformational state populated prior to aggregation and to the structure/morphology of the resulting oligomers is one of the goals of present research in this field. We have studied the influence of six different salts on the conversion of the N terminal domain of Escherichiacoli HypF (HypF-N) into amyloid-like oligomers under conditions of acidic pH. Our results show that salts having different anions (NaCl, NaClO(4), NaI, Na(2)SO(4)) accelerate oligomerization with an efficacy that follows the electroselectivity series of the anions (SO(4)(2-)>= ClO(4)(-)>I(-)>Cl(-)). By contrast, salts with different cations (NaCl, LiCl, KCl) have similar effects. We also investigated the effect of salts on the structure of the final and initial states of HypF-N aggregation. The electroselectivity series does not apply to the effect of anions on the structure of the oligomers. By contrast, it applies to their effect on the content of secondary structure and on the exposure of hydrophobic clusters of the monomeric precursor state. The results therefore indicate that the binding of anions to the positively charged residues of HypF-N at low pH is the mechanism by which salts modulate the rate of oligomerization and the structure of the monomeric precursor state but not the structure of the resulting oligomers. Overall, the data contribute to rationalize the effect of salts on amyloid-like oligomer formation and to explain the role of charged biological macromolecules in protein aggregation processes. PMID- 23041428 TI - Comment on: Risk stratification of serious adverse events after gastric bypass in the Bariatric Outcomes Longitudinal Database. PMID- 23041429 TI - The future of preventive medicine: polypill prescriptions in the context of Plato's physical perspective. PMID- 23041430 TI - Serum vaspin levels in women with and without gestational diabetes mellitus during pregnancy and postpartum. AB - Although vaspin is regarded an insulin-sensitizing adipokine, its role in gestational diabetes mellitus (GDM) is currently unknown. We aimed to evaluate serum vaspin levels and their correlation with insulin resistance in women with and without GDM. Forty-four women with GDM [GDM Group - 20 managed with diet only (GDM-diet) and 24 with diet plus insulin (GDM-insulin)] and 44 age-matched pregnant women with normal glucose tolerance (Control Group) were studied. Serum glucose, lipids, uric acid, insulin and vaspin were measured at the 2nd and 3rd trimester of pregnancy and postpartum. The quantitative insulin sensitivity check index (QUICKI) and homeostasis model of assessment-insulin resistance (HOMA-IR) were calculated. Circulating vaspin levels decreased significantly postpartum in all groups (p<0.001), but did not differ between GDM or GDM Subgroups and Control Group in any time point. At the 3rd trimester of pregnancy vaspin was positively correlated to insulin (p=0.022), HOMA-IR (p=0.016) and triglycerides (p=0.033) and negatively correlated to QUICKI (p=0.016) in the GDM women, but not in the Controls. These correlations were not observed at the 2nd trimester or postpartum. Vaspin, in contrast to HOMA-IR, could not independently predict GDM in binary logistic regression. In patients with GDM, insulin treatment did not affect vaspin levels. In conclusion, our data suggest that vaspin levels gradually decrease from the 2nd trimester to postpartum; however, decreases are similar between women with or without GDM. Serum vaspin cannot independently predict GDM and it is not affected by the degree of glucose metabolism deregulation or the exogenous administration of insulin. PMID- 23041431 TI - Classification accuracies of physical activities using smartphone motion sensors. AB - BACKGROUND: Over the past few years, the world has witnessed an unprecedented growth in smartphone use. With sensors such as accelerometers and gyroscopes on board, smartphones have the potential to enhance our understanding of health behavior, in particular physical activity or the lack thereof. However, reliable and valid activity measurement using only a smartphone in situ has not been realized. OBJECTIVE: To examine the validity of the iPod Touch (Apple, Inc.) and particularly to understand the value of using gyroscopes for classifying types of physical activity, with the goal of creating a measurement and feedback system that easily integrates into individuals' daily living. METHODS: We collected accelerometer and gyroscope data for 16 participants on 13 activities with an iPod Touch, a device that has essentially the same sensors and computing platform as an iPhone. The 13 activities were sitting, walking, jogging, and going upstairs and downstairs at different paces. We extracted time and frequency features, including mean and variance of acceleration and gyroscope on each axis, vector magnitude of acceleration, and fast Fourier transform magnitude for each axis of acceleration. Different classifiers were compared using the Waikato Environment for Knowledge Analysis (WEKA) toolkit, including C4.5 (J48) decision tree, multilayer perception, naive Bayes, logistic, k-nearest neighbor (kNN), and meta-algorithms such as boosting and bagging. The 10-fold cross-validation protocol was used. RESULTS: Overall, the kNN classifier achieved the best accuracies: 52.3%-79.4% for up and down stair walking, 91.7% for jogging, 90.1% 94.1% for walking on a level ground, and 100% for sitting. A 2-second sliding window size with a 1-second overlap worked the best. Adding gyroscope measurements proved to be more beneficial than relying solely on accelerometer readings for all activities (with improvement ranging from 3.1% to 13.4%). CONCLUSIONS: Common categories of physical activity and sedentary behavior (walking, jogging, and sitting) can be recognized with high accuracies using both the accelerometer and gyroscope onboard the iPod touch or iPhone. This suggests the potential of developing just-in-time classification and feedback tools on smartphones. PMID- 23041432 TI - Density thresholds for Mopeia virus invasion and persistence in its host Mastomys natalensis. AB - Well-established theoretical models predict host density thresholds for invasion and persistence of parasites with a density-dependent transmission. Studying such thresholds in reality, however, is not obvious because it requires long-term data for several fluctuating populations of different size. We developed a spatially explicit and individual-based SEIR model of Mopeia virus in multimammate mice Mastomys natalensis. This is an interesting model system for studying abundance thresholds because the host is the most common African rodent, populations fluctuate considerably and the virus is closely related to Lassa virus but non pathogenic to humans so can be studied safely in the field. The simulations show that, while host density clearly is important, sharp thresholds are only to be expected for persistence (and not for invasion), since at short time-spans (as during invasion), stochasticity is determining. Besides host density, also the spatial extent of the host population is important. We observe the repeated local occurrence of herd immunity, leading to a decrease in transmission of the virus, while even a limited amount of dispersal can have a strong influence in spreading and re-igniting the transmission. The model is most sensitive to the duration of the infectious stage, the size of the home range and the transmission coefficient, so these are important factors to determine experimentally in the future. PMID- 23041433 TI - Effects of seasonal variation patterns on recurrent outbreaks in epidemic models. AB - Transmission of infectious diseases often depends on seasonal variability. Mathematical epidemic models driven by seasonal forcing have been widely explored to understand recurrent outbreaks of infectious diseases. Here we present an effective method to examine the impact of seasonal variation patterns on epidemic dynamics. The idea is to represent the seasonal variability as a piecewise constant function and analyze the seasonally forced epidemic model by means of a numerical shooting method for switched dynamical systems. Several illustrative examples demonstrate that our method is useful to elucidate the effects of various types of seasonality in outbreak behavior. First, we clarify an effect of the shape of seasonal forcing by comparing sinusoidal and square wave forcing functions. Second, we demonstrate that not only the intensity of seasonality but also its temporal variation pattern significantly influences the outbreak pattern. Finally, we reveal the mechanisms of transitions between different outbreak patterns in an epidemic model driven by realistic term-time seasonal forcing and one driven by seasonal forcing estimated from real data. Our results suggest that accurately estimated seasonal variability is necessary for better understanding the dynamics of infectious diseases. PMID- 23041434 TI - Assessing biomarkers in synovial fluid: consider the kinetics of clearance. PMID- 23041435 TI - The effect of platelet-rich plasma on the regenerative therapy of muscle derived stem cells for articular cartilage repair. AB - OBJECTIVE: Platelet-rich plasma (PRP) is reported to promote collagen synthesis and cell proliferation as well as enhance cartilage repair. Our previous study revealed that the intracapsular injection of muscle derived stem cells (MDSCs) expressing bone morphogenetic protein 4 (BMP-4) combined with soluble Flt-1 (sFlt1) was effective for repairing articular cartilage (AC) after osteoarthritis (OA) induction. The current study was undertaken to investigate whether PRP could further enhance the therapeutic effect of MDSC therapy for the OA treatment. METHODS: MDSCs expressing BMP-4 and sFlt1 were mixed with PRP and injected into the knees of immunodeficient rats with chemically induced OA. Histological assessments were performed 4 and 12 weeks after cell transplantation. Moreover, to elucidate the repair mechanisms, we performed in vitro assays to assess cell proliferation, adhesion, migration and mixed pellet co-culture of MDSCs and OA chondrocytes. RESULTS: The addition of PRP to MDSCs expressing BMP-4 and sFlt1 significantly improved AC repair histologically at week 4 compared to MDSCs expressing BMP-4 and sFlt1 alone. Higher numbers of cells producing type II collagen and lower levels of chondrocyte apoptosis were observed by MDSCs expressing BMP-4 and sFlt1 and mixed with PRP. In the in vitro experiments, the addition of PRP promoted proliferation, adhesion and migration of the MDSCs. During chondrogenic pellet culture, PRP tended to increase the number of type II collagen producing cells and in contrast to the in vivo data, it increased cell apoptosis. CONCLUSIONS: Our findings indicate that PRP can promote the therapeutic potential of MDSCs expressing BMP-4 and sFlt1 for AC repair (4 weeks post-treatment) by promoting collagen synthesis, suppressing chondrocyte apoptosis and finally by enhancing the integration of the transplanted cells in the repair process. PMID- 23041436 TI - Osteoarthritis as a disease of mechanics. AB - Mechanics means relating to or caused by movement or physical forces. In this paper, I shall contend that osteoarthritis (OA) is almost always caused by increased physical forces causing damage to a joint. While examples of joint injury causing OA are numerous, I shall contend that most or almost all OA is caused in part by mechanically induced injury to joint tissues. Further, once joint pathology has developed, as is the case for almost all clinical OA, pathomechanics overwhelms all other factors in causing disease progression. Treatments which correct the pathomechanics have long lasting favorable effects on pain and joint function compared with treatments that suppress inflammation which have only temporary effects. I shall lastly contend that the mechanically induced joint injury leads to variable inflammatory responses but that the role of this inflammation in worsening structural damage in an already osteoarthritic joint has not yet been proven. PMID- 23041437 TI - Cartilage boundary lubricating ability of aldehyde modified proteoglycan 4 (PRG4 CHO). PMID- 23041439 TI - Endogenous opiates and behavior: 2011. AB - This paper is the thirty-fourth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2011 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17). PMID- 23041438 TI - Cationic agent contrast-enhanced computed tomography imaging of cartilage correlates with the compressive modulus and coefficient of friction. AB - OBJECTIVE: The aim of this study is to evaluate whether contrast-enhanced computed tomography (CECT) attenuation, using a cationic contrast agent (CA4+), correlates with the equilibrium compressive modulus (E) and coefficient of friction (MU) of ex vivo bovine articular cartilage. METHODS: Correlations between CECT attenuation and E (Group 1, n = 12) and MU (Group 2, n = 10) were determined using 7 mm diameter bovine osteochondral plugs from the stifle joints of six freshly slaughtered, skeletally mature cows. The equilibrium compressive modulus was measured using a four-step, unconfined, compressive stress-relaxation test, and the coefficients of friction were determined from a torsional friction test. Following mechanical testing, samples were immersed in CA4+, imaged using MUCT, rinsed, and analyzed for glycosaminoglycan (GAG) content using the 1,9 dimethylmethylene blue (DMMB) assay. RESULTS: The CECT attenuation was positively correlated with the GAG content of bovine cartilage (R(2) = 0.87, P < 0.0001 for Group 1 and R(2) = 0.74, P = 0.001 for Group 2). Strong and significant positive correlations were observed between E and GAG content (R(2) = 0.90, P < 0.0001) as well as CECT attenuation and E (R(2) = 0.90, P < 0.0001). The CECT attenuation was negatively correlated with the three coefficients of friction: CECT vs MU(static) (R(2) = 0.71, P = 0.002), CECT vs MU(static_equilibrium) (R(2) = 0.79, P < 0.001), and CECT vs MU(kinetic) (R(2) = 0.69, P = 0.003). CONCLUSIONS: CECT with CA4+ is a useful tool for determining the mechanical properties of ex vivo cartilage tissue as the attenuation significantly correlates with the compressive modulus and coefficient of friction. PMID- 23041440 TI - TGF-beta-1 up-regulates extra-cellular matrix production in mouse hepatoblasts. AB - Fetal liver is the major embryonic hematopoietic organ and is extrinsically colonized by circulating hematopoietic stem cells (HSCs). Integrin beta-1 expression on HSCs is crucial for colonization, suggesting that interaction of Integrin beta-1 with extra-cellular matrix (ECM) factors promotes HSC adherence to fetal liver. However, little is known about how ECM production is regulated in fetal liver. Here we used flow cytometry to sort fetal liver compartments and detected ECM gene and protein expression predominantly in sorted hepatoblasts. mRNA and protein analysis suggested that TGF-beta-1 expressed by hepatoblasts, sinusoid endothelial cells and hematopoietic cells, binds to the TGF-beta receptor type-2 expressed on hepatoblasts to stimulate ECM production. Intra cardiac injection of TGF-inhibitors into mouse embryos dramatically decreased fetal liver ECM gene expression. Taken together, our observations suggest that hepatoblasts predominantly produce ECM factors under control of TGF-beta-1 in fetal liver. PMID- 23041441 TI - Thiazolidinedione use and cancer incidence in type 2 diabetes: a systematic review and meta-analysis. AB - AIMS: Evidence suggests thiazolidinediones (TZDs) may modify the relationship between type 2 diabetes and cancer incidence. We aimed to summarize data from randomized controlled trials (RCTs) and observational studies to examine risk of overall and site-specific cancers with TZD use in individuals with type 2 diabetes. METHODS: We searched 12 key biomedical databases and seven grey literature sources up to June 2011, without language restrictions. We performed separate meta-analyses according to cancer site and study design, comparing ever use to never-use of TZDs, and pioglitazone alone. RESULTS: The search yielded 1338 unique citations; we included four RCT, seven cohort and nine nested case control studies, contributing data from 2.5 million people. Estimates from observational studies suggested any TZD use was associated with a decreased risk of colorectal (pooled RR: 0.93, 95%CI 0.87-1.00, P=0.04, I(2)=30%), lung (pooled RR: 0.91, 95%CI 0.84-0.98, P=0.02, heterogeneity (I(2))=35%) and breast (pooled RR: 0.89, 95%CI 0.81-0.98, P=0.02, I(2)=44%) cancer. Risk of overall cancer with TZD use was not significantly modified in RCTs (pooled RR: 0.92, 95%CI 0.79-1.07, P=0.26, I(2)=0%) or observational studies (pooled OR: 0.95, 95%CI 0.78-1.16, P=0.63, I(2)=70%). Pioglitazone use was, however, associated with a decreased risk of overall cancer (colorectal, lung, breast, prostate and renal sub-sites combined) in observational studies (pooled RR: 0.95, 95%CI 0.91-0.99, P=0.009, I(2)=0%). CONCLUSIONS: Our findings suggest that use of TZDs is associated with a modest but significantly decreased risk of lung, colorectal and breast cancers. Results were limited by the paucity of studies designed to answer our research question. Further evaluation of TZD use, cancer risk factors and potential confounders is required. PMID- 23041442 TI - Hypoglycaemia and somnambulism: a case report. AB - Sleepwalking (somnambulism) is a sleep disorder classified as a parasomnia. Sleepwalkers develop motor activities that may be simple or complex: they can get out of bed, walk, urinate and even leave the house while remaining unconscious and unable to communicate. It is difficult to wake a sleepwalker, but it is not dangerous - as many people think. Sleepwalking cases have been caused by jet lag, the consumption of narcotics, sedatives and alcohol, cardiac problems such as arrhythmias, and other medical conditions, including epilepsy, asthma and apnoea. In a quick search of the literature, only one case due to hypoglycaemia has been reported, describing a patient with type 1 diabetes whose sleepwalking was triggered by nocturnal hypoglycaemia. Our present case was similar, and our report also describes how it occurred and how the condition was remedied. PMID- 23041443 TI - Serum levels of alpha-smooth muscle actin and c-Met as biomarkers of the degree of severity of Henoch-Schonlein purpura nephritis. AB - Approximately 40% of patients with Henoch-Schonlein purpura (HSP) develop Henoch Schonlein purpura nephritis (HSPN) after 4 to 6 weeks of subcutaneous hemorrhaging. Immunoglobulin-A nephropathy (IgAN) and HSPN have numerous similarities, which can cause difficulty in correctly diagnosing the disorder during a differential diagnosis. The pathogenesis of the 2 diseases is not clear. We enrolled 137 patients with HSPN, 107 patients with IgAN, and 28 healthy (control) patients in our study. The levels of alpha-smooth muscle actin (alpha SMA), c-Met, and Gal-deficient IgA1 (Gd-IgA1) in the 3 patient groups were determined and compared. The alpha-SMA, c-Met, and Gd-IgA1 levels and the clinical data from the patients with HSPN were analyzed for any correlations. The alpha-SMA and c-Met levels of the HSPN group were significantly higher than those of the IgAN and healthy control groups (P < 0.01). The Gd-IgA1 levels of the HSPN and IgAN groups were significantly different from the Gd-IgA1 level of the healthy control group (P < 0.01). The alpha-SMA levels of the HSPN group were positively correlated with blood urea nitrogen levels, serum creatinine levels, hematuria index, and proteinuria levels (P < 0.01). The c-Met levels of the HSPN group were positively correlated with the blood urea nitrogen and serum creatinine levels (P < 0.01). There were no significant differences among the alpha-SMA, c-Met, and Gd-IgA1 levels or the clinical data for the child and adult patients with HSPN. The serum levels of alpha-SMA and c-Met in patients with HSPN may be associated with the degree of disease severity. Gd-IgA1 is involved in the common immunologic pathogenesis of HSPN and IgAN. PMID- 23041445 TI - Application of gas chromatography-triple quadrupole mass spectrometry to the determination of sterol components in biological samples in consideration of the ionization mode. AB - The hyphenation of gas chromatography (GC) and triple quadrupole mass spectrometry is a promising approach to increase sensitivity and selectivity as compared to single quad mass spectrometry. We present in this paper the application of GC-triple quadrupole mass spectrometry for determination of sterol components in biological samples. Due to the fact that sterols are quite small molecules an appropriate ionization mode has to be found for advantageous exploitation of the triple quad function. Electron ionization (EI), positive and negative chemical ionization (PCI, NCI) have been tested regarding sensitivity improvement in oxysterol and bile acid analysis in plasma samples. Target analytes were 24-, 25- and 27-hydroxycholesterol, 7beta-hydroxycholesterol, 7 ketocholesterol, 3beta,5alpha,6beta-cholestanetriol, cholic acid, chenodeoxycholic acid, deoxycholic acid and lithocholic acid. In contrast to bile acids, oxysterols could be analyzed with the highest degree of sensitivity by application of PCI in multiple reaction monitoring mode whereas 7beta hydroxycholesterol and 7-ketocholesterol showed even better results with NCI. PMID- 23041447 TI - Evaluating model fit to determine if logarithmic transformations are necessary in allometry: a comment on the exchange between Packard (2009) and Kerkhoff and Enquist (2009). PMID- 23041448 TI - Dynamic neural networking as a basis for plasticity in the control of heart rate. AB - A model is proposed in which the relationship between individual neurons within a neural network is dynamically changing to the effect of providing a measure of "plasticity" in the control of heart rate. The neural network on which the model is based consists of three populations of neurons residing in the central nervous system, the intrathoracic extracardiac nervous system, and the intrinsic cardiac nervous system. This hierarchy of neural centers is used to challenge the classical view that the control of heart rate, a key clinical index, resides entirely in central neuronal command (spinal cord, medulla oblongata, and higher centers). Our results indicate that dynamic networking allows for the possibility of an interplay among the three populations of neurons to the effect of altering the order of control of heart rate among them. This interplay among the three levels of control allows for different neural pathways for the control of heart rate to emerge under different blood flow demands or disease conditions and, as such, it has significant clinical implications because current understanding and treatment of heart rate anomalies are based largely on a single level of control and on neurons acting in unison as a single entity rather than individually within a (plastically) interconnected network. PMID- 23041446 TI - The effect of lung stretch during sleep on airway mechanics in overweight and obese asthma. AB - Both obesity and sleep reduce lung volume and limit deep breaths, possibly contributing to asthma. We hypothesize that increasing lung volume dynamically during sleep would reduce airway resistance in asthma. Asthma (n=10) and control (n=10) subjects were studied during sleep at baseline and with increased lung volume via bi-level positive airway pressure (BPAP). Using forced oscillations, respiratory system resistance (R(rs)) and reactance (X(rs)) were measured during sleep and R(rs) was partitioned to upper and lower airway resistance (R(up), R(low)) using an epiglottic pressure catheter. R(rs) and R(up) increased with sleep (p<0.01) and X(rs) was decreased in REM (p=0.02) as compared to wake. R(rs), R(up), and R(low), were larger (p<0.01) and X(rs) was decreased (p<0.02) in asthma. On BPAP, R(rs) and R(up) were decreased (p<0.001) and X(rs) increased (p<0.01), but R(low) was unchanged. High R(up) was observed in asthma, which reduced with BPAP. We conclude that the upper airway is a major component of R(rs) and larger lung volume changes may be required to alter R(low). PMID- 23041444 TI - Model membranes to shed light on the biochemical and physical properties of ezrin/radixin/moesin. PMID- 23041449 TI - Prediction of core cancer genes using multi-task classification framework. AB - Cancer is deemed as a highly heterogeneous disease specific to cell type and tissue origin. All cancers, however, share a common pathogenesis. Therefore, it is widely believed that cancers may share common mechanisms. In this study, we introduce a novel strategy based on multi-tasking learning methods to predict core cancer genes shared by multiple cancers in the hope of elucidating common cancer mechanisms. Our strategy uses two multi-tasking learning algorithms, one for feature selection and the other for validation of selected features. The combined use of two methods results in more robust classifiers and reliable selected features. The top 73 significant features, mapped to 72 genes, are selected as core cancer genes. The effectiveness of the 73 features is further demonstrated in a blind test conducted on an independent test data. The biological significance of these genes is evaluated using systems biology analyses. Extensive functional, pathway and network analysis confirms findings in previous studies and brings new insights into common cancer mechanisms. Our strategy can be used as a general method to find important genes from large gene expression datasets on the genomic level. The selected genes can be used to predict cancers. PMID- 23041451 TI - Common alleles that influence autophagy and the risk for inflammatory bowel disease. AB - Genetic studies of inflammatory bowel disease (IBD) have identified multiple risk loci that contain genes involved in autophagy. Although autophagy was traditionally considered to be a homeostatic response to ensure the recycling of cellular materials, it has now been additionally established to have roles in immunity and inflammation. In this review, we highlight how genetics have begun to identify a broader role for autophagy as a key pathway in Crohn's disease (CD). We review recent studies that have implicated autophagy in the regulation of mucosal homeostasis, including roles in intracellular defense, vesicular trafficking, and inflammatory signaling. Finally, we discuss studies that have begun to demonstrate how CD risk polymorphisms cause defects in autophagy and promote a breakdown of intestinal homeostasis. PMID- 23041450 TI - Comparison of the performance of IFA, CFA, and ELISA assays for the serodiagnosis of acute Q fever by quality assessment. AB - The indirect immunofluorescence assay (IFA) is considered the reference method for diagnosing Q fever, but serology is also performed by complement fixation assay (CFA) or enzyme-linked immunosorbent assay (ELISA). However, comparability between these assays is not clear, and therefore a quality assessment was performed. A total of 25 serum samples from negative controls, Q fever patients, and a serial diluted high-positive sample were analyzed in 10 Dutch laboratories. Six laboratories performed CFA, 5 performed IFA, and 5 performed ELISAs. Three international reference laboratories from Australia, France, and the USA also participated in this study. Qualitative values between laboratories using the same methods were within close range, and all 3 methods correctly identified acute Q fever patients. The IFA, ELISA, and CFA are all suitable serodiagnostic assays to diagnose acute Q fever, but the IFA remains an important tool in the follow-up of patients and in identifying patients at risk for developing chronic Q fever. PMID- 23041452 TI - Human genetics offers an emerging picture of common pathways and mechanisms in autoimmunity. AB - In genetic studies of autoimmune and inflammatory diseases, one clear finding that has emerged from genome-wide association studies is that a substantial fraction of variation modifying risk in one disease also contributes mediate risk to multiple, additional autoimmune and inflammatory diseases. The unexpected magnitude of this overlap presents the unique opportunity to dissect the pathogenic mechanisms underlying multiple disease states in the expectation that this may lead to both more sensitive diagnostics and novel therapies. Here, we review the current evidence for this shared genetic architecture and, based on these data, outline models for shared pathways, the underlying hypotheses for them, how these models can be tested and validated. PMID- 23041453 TI - Activity of single-agent bevacizumab in patients with metastatic renal cell carcinoma previously treated with vascular endothelial growth factor tyrosine kinase inhibitors. AB - PURPOSE: The activity of systemic agents after progression when using vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in patients with metastatic renal cell carcinoma (mRCC) is poorly characterized. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab has a broad US Food and Drug Administration label and National Comprehensive Cancer Network guideline level 2b recommendation in this setting; we thus explored our institutional experience in this population. METHODS: We conducted a retrospective analysis of patients with mRCC who were treated with bevacizumab in the second- and/or third-line settings; the primary endpoint was progression-free survival (PFS). Overall response rates (ORR), overall survival (OS), and toxicity were analyzed. RESULTS: Twenty-one patients were treated with bevacizumab: the median age was 63 years old; 80% were white and 14% were black; 80% had clear cell histology. All the patients had prior VEGFR TKI therapy; 43% had prior mTOR inhibitor; the median number of prior therapies was 3. The median PFS was 4.4 months (95% CI, 2.8-9.6 months), and the median OS was 19.4 months (95% CI, 9.9-NR months). ORR was 9.5%; 52% of subjects had stable disease as best response, and 52% had disease progression. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4 and 13.2 months, respectively. Grade 3 to 4 toxicities included fatigue (29%), dehydration (24%), failure to thrive (10%), constipation (10%), and muscle weakness (10%). CONCLUSIONS: Single-agent bevacizumab has acceptable toxicity and moderate disease-stabilizing activity in selected patients with mRCC who have failed prior VEGFR TKI and mTOR inhibitors. These data support clinical benefit to continued ongoing VEGF inhibition. Further prospective studies of bevacizumab alone or with alternative targeted agents in previously treated populations with mRCC are warranted. PMID- 23041454 TI - Salvage intensity-modulated radiation therapy for locally recurrent prostate cancer after cryotherapy. AB - BACKGROUND: To summarize our results of intensity-modulated radiation therapy (IMRT) for prostate adenocarcinoma after cryotherapy failure. MATERIALS AND METHODS: Patients underwent IMRT with curative intent for biochemically recurrent prostate cancer after cryotherapy. Radiation was delivered to a minimum dose of 72 Gy (range, 72-81 Gy). Acute and late treatment-related gastrointestinal and genitourinary effects were scored according to Common Toxicity Criteria version 3.0. Prostate-specific antigen failure was defined by Radiation Therapy Oncology Group-American Society for Therapeutic Radiology and Oncology 2006 consensus definition. RESULTS: Nine patients were treated from 2008 to 2010. The median follow-up was 31 months (range, 15-40 months). The mean preradiotherapy prostate specific antigen was 4.3 ng/mL (range, 1.07-15.6 ng/mL). The median elapsed time between cryotherapy and IMRT was 20.5 months (range, 8.5-56.5 months). Biochemical control was achieved in 7 patients. Two patients developed distant metastases shortly after completion of radiotherapy. No patients experienced grade 3 or higher toxicities. CONCLUSIONS: Our results suggest that high-dose IMRT after cryotherapy failure is well tolerated, without severe morbidity. The results also showed that IMRT can render a significant number of patients biochemically free of disease after initial cryotherapy. High-dose IMRT should be considered as a treatment option for these potentially salvageable cases. PMID- 23041455 TI - Urea-induced unfolding of Glossoscolex paulistus hemoglobin, in oxy- and cyanomet forms: a dissociation model. AB - The urea effect on the giant extracellular hemoglobin of Glossoscolex paulistus (HbGp) stability was studied by analytical ultracentrifugation (AUC) and small angle X-ray scattering (SAXS). AUC data show that the sedimentation coefficient distributions curves c (S), at 1.0 mol/L of urea, display a single peak at 57 S, associated to the undissociated protein. The increase in urea concentration, up to 4.0 mol/L, induces the appearance of smaller species, due to oligomeric dissociation. The sedimentation coefficients and molecular masses are 9.2S and 204 kDa for the dodecamer (abcd)(3), 5.5S and 69 kDa for the tetramer (abcd), 4.1S and 52 kDa for the trimer (abc) and 2.0 S and 17 kDa for the monomer d, respectively. SAXS data show initially a decrease in the I(0) values due to the oligomeric dissociation, and then, above 4.0 mol/L of denaturant, for oxy-HbGp, and above 6.0 mol/L for cyanomet-HbGp, an increase in the maximum dimension and gyration radius is observed, due to the unfolding process. According to AUC and SAXS data the HbGp unfolding is described by two phases: the first one, at low urea concentration, below 4.0 mol/L, characterizes the oligomeric dissociation, while the second one, at higher urea concentration, is associated to the unfolding of dissociated species. Our results are complementary to a recent report based on spectroscopic observations. PMID- 23041456 TI - The Substrate-Activity-Screening methodology applied to receptor tyrosine kinases: a proof-of-concept study. AB - Protein kinases are widely recognized as important therapeutic targets due to their involvement in signal transduction pathways. These pathways are tightly controlled and regulated, notably by the ability of kinases to selectively phosphorylate a defined set of substrates. A wide variety of disorders can arise as a consequence of abnormal kinase-mediated phosphorylation and numerous kinase inhibitors have earned their place as key components of the modern pharmacopeia. Although "traditional" kinase inhibitors typically act by preventing the interaction between the kinase and ATP, thus stopping substrate phosphorylation, an alternative approach consists in disrupting the protein-protein interaction between the kinase and its downstream partners. In order to facilitate the identification of potential chemical starting points for substrate-site inhibition approaches, we desired to investigate the application of Substrate Activity Screening to kinases. We herein report a proof-of-concept study demonstrating, on a model tyrosine kinase, that the key requirements of this methodology can be met. Namely, using peptides as model substrates, we show that a simple ADP-accumulation assay can be used to monitor substrate efficiency and that efficiency can be optimized in a modular manner. More importantly, we demonstrate that structure-efficiency relationships translate into structure activity relationships upon conversion of the substrates into inhibitors. PMID- 23041458 TI - Noninvasive 2-dimensional monitoring of strain in the detrusor muscle in patients with lower urinary tract symptoms using ultrasound strain imaging. AB - PURPOSE: Pressure flow studies and filling cystometry are currently the standard diagnostic urodynamic tests for lower urinary tract symptoms. A noninvasive ultrasound based method for 2-dimensional monitoring of deformation (or strain) in the detrusor muscle may provide insight into detrusor muscle structural and dynamic properties related to pressure in physiological and disease conditions. MATERIALS AND METHODS: In a male patient population with lower urinary tract symptoms, strain in the detrusor muscle (perpendicular to the bladder wall) was estimated based on 2-dimensional radio frequency ultrasound imaging. The estimated strain was correlated to detrusor pressure and urinary flow rate using Spearman's correlation coefficient. RESULTS: Twenty men (mean +/- SD age 66 +/- 6 years) with lower urinary tract symptoms were included in the study. Ultrasound data acquisition was successful in 13 patients. In 7 patients data acquisition failed due to out-of-plane motion of the bladder wall during voiding or as a result of patient movement during acquisition. The estimated strain correlated positively with detrusor pressure in the 5 patients with an isovolumetric detrusor contraction (Spearman's 0.70-0.99, p <0.05). Of 8 patients with urinary voiding during detrusor muscle contraction this correlation was significantly positive in 5 patients (Spearman's 0.52-0.81, p <0.05). CONCLUSIONS: In 13 of 20 patients with lower urinary tract symptoms we demonstrated that strain in the detrusor muscle can be estimated using ultrasound imaging. The estimated strain correlated positively with the detrusor pressure. Optimal results were obtained in the pre-voiding phase, suggesting that ultrasound strain imaging can possibly be used to monitor detrusor muscle activity in real time. PMID- 23041457 TI - Lymphopenia is an independent predictor of inferior outcome in clear cell renal carcinoma. AB - PURPOSE: A low absolute lymphocyte count is a likely index of poor systemic immunity that may be associated with aggressive features and inferior survival in patients with clear cell renal cell carcinoma. MATERIALS AND METHODS: To determine the absolute lymphocyte count we retrospectively analyzed the preoperative blood count of 430 patients with a mean age of 60 years treated with primary surgical resection at our cancer center. Absolute lymphocyte count values as a continuous variable and at a level below 1,300 cells per MUl, which was our lowest reference value, were correlated with nuclear grade, pathological stage and TNM stage. We used the Kaplan-Meier method to estimate overall survival, stratified by absolute lymphocyte count status. RESULTS: As a continuous variable, low absolute lymphocyte count was associated with higher grade (p = 0.009), and higher pT stage (p = 0.034) and TNM stage (p <0.0001). Lymphopenia below 1,300 cells per MUl was associated with high grade (p = 0.0043), pT stage (p = 0.051) and TNM stage (p <0.0001). At a median followup of 33.5 months lymphopenia was associated with inferior overall survival in a univariate model (p <0.0001), and on multivariate analysis independent of pT, N and M stages, patient age, grade, smoking history and comorbidities (p = 0.0102). Lymphopenia was also associated with inferior overall survival in a subset of young patients (age 60 years or less) with no distant metastasis (p = 0.014). CONCLUSIONS: In 430 patients with clear cell renal cell carcinoma lymphopenia was associated with lower overall survival independent of pT and TNM stages, nuclear grade, age, tobacco smoking and comorbidity index. PMID- 23041459 TI - Mechanisms of action and effects of antibodies on the cells of the allograft. PMID- 23041460 TI - The virulence of Staphylococcus aureus correlates with strain genotype in a chicken embryo model but not a nematode model. AB - Staphylococcus aureus infections are of major importance in human and veterinary medicine. Studies of the virulence of this bacterium are complicated by inconsistent results obtained in different animal models. We searched for an uncomplicated and inexpensive model suitable to study virulence of poultry strains of S. aureus using a genome-wide approach. We determined that a useful model would clearly differentiate strains of high and low virulence, and that this would generally correlate with the genetic relatedness among strains. To this end Gallus gallus (chicken) embryo and Caenorhabditis elegans (nematode) models were selected, and their response to challenge by a set of well characterized Staphylococcus strains was evaluated. The chicken embryo model allowed to determine variation in virulence among strains of poultry and human origin. The survival of embryos ranged from 0% to almost 100% for the various strains. In contrast, variation in virulence of most strains in the nematode model was comparable, regardless of their origin or genotype, demonstrating limited usefulness of this model. Most importantly, a clear correlation was found between the virulence level in the embryo model and the genotype of the tested poultry strains. Our findings indicate the potential usefulness of embryo model for future identification of host-specific adaptations and virulence factors in S. aureus. PMID- 23041461 TI - Molecular characterization of the rice protein RSS1 required for meristematic activity under stressful conditions. AB - Post embryonic growth of plants depends on cell division activity in the shoot and root meristems, in conjunction with subsequent cell differentiation. Under environmental stress conditions, where plant growth is moderately impaired, the meristematic activity is maintained by mechanisms as yet unknown. We previously showed that the rice protein RSS1, whose stability is regulated depending on the cell cycle phases, is a key factor for the maintenance of meristematic activity under stressful conditions. RSS1 interacts with a catalytic subunit of protein phosphatase 1 (PP1), but other molecular characteristics are largely unknown. Here we show that RSS1 interacts with all the PP1 expressed in the shoot apex of rice. This interaction requires one of the conserved regions of RSS1, which is important for RSS1 function. Interestingly, the recombinant RSS1 protein is highly resistant to heat with respect to its anti-coagulability and binding activity to PP1. The features of RSS1 are reminiscent of those of inhibitor-2 of animals, although it is likely that the mode of function of RSS1 is different from that of inhibitor-2. Noticeably, RSS1 binds to PP1 under extremely high ionic strength conditions in vitro. Therefore, RSS1 possibly functions by forming a stable complex with PP1. PMID- 23041462 TI - Purification and structural characterization of the voltage-sensor domain of the hERG potassium channel. AB - The hERG (human ether a go-go related gene) potassium channel is a voltage-gated potassium channel playing important roles in the heart by controlling the rapid delayed rectifier potassium current. The hERG protein contains a voltage-sensor domain (VSD) that is important for sensing voltage changes across the membrane. Mutations in this domain contribute to serious heart diseases. To study the structure of the VSD, it was over-expressed in Escherichia coli and purified into detergent micelles. Lyso-myristoyl phosphatidylglycerol (LMPG) was shown to be a suitable detergent for VSD purification and folding. Secondary structural analysis using circular dichroism (CD) spectroscopy indicated that the purified VSD in LMPG micelles adopted alpha-helical structures. Purified VSD in LMPG micelles produced dispersed cross-peaks in a (15)N-HSQC spectrum. Backbone resonance assignments for residues from transmembrane segments S3 and S4 of VSD also confirmed the presence of alpha-helical structures in this domain. Our results demonstrated that structure of VSD can be investigated using NMR spectroscopy. PMID- 23041463 TI - Easy parameter identifiability analysis with COPASI. AB - BACKGROUND AND SCOPE: Differential equation systems modeling biochemical reaction networks can only give quantitative predictions, when they are in accordance with experimental data. However, even if a model can well recapitulate given data, it is often the case that some of its kinetic parameters can be arbitrarily chosen without significantly affecting the simulation results. This indicates a lack of appropriate data to determine those parameters. In this case, the parameter is called to be practically non-identifiable. Well-identified parameters are paramount for reliable quantitative predictions and, therefore, identifiability analysis is an important topic in modeling of biochemical reaction networks. Here, we describe a hidden feature of the free modeling software COPASI, which can be exploited to easily and quickly conduct a parameter identifiability analysis of differential equation systems by calculating likelihood profiles. The proposed combination of an established method for parameter identifiability analysis with the user-friendly features of COPASI offers an easy and rapid access to parameter identifiability analysis even for non-experts. AVAILABILITY: COPASI is freely available for academic use at http://www.copasi.org. PMID- 23041464 TI - Putative mitochondrial polypeptides coded by expanded quadruplet codons, decoded by antisense tRNAs with unusual anticodons. AB - Weak triplet codon-anticodon interactions render ribosome-free translation unlikely. Some modern tRNAs read quadruplet codons (tetracodons), suggesting vestigial ribosome-free translation. Here, mitochondrial genomes are explored for tetracoded overlapping protein coding (tetra)genes. Occasional single tetracodons within regular mitochondrial genes coevolve positively/negatively with antisense tRNAs with predicted reduced/expanded anticodons (depending on taxon), suggesting complex tetra-decoding mechanisms. Transcripts of antisense tRNAs with unusual anticodons are more abundant than of homologues with regular anticodons. Assuming overlapping tetracoding with silent 4th tetracodon position, BLAST aligns 10 putative tetragenes spanning 17% of regular human mitochondrial protein coding tricodons with 14 GenBank proteins. Various tests including predicted peptide secondary structures, 3rd codon position (of the regular main frame of the protein coding gene) conservation against replicational deamination mutation gradients, and circular code usage (overlapping genes avoid using circular code codons) confirm tetracoding in these overlapping tetragenes with silent 4th position, but not for BLAST-predicted tetragenes assuming silent 2nd or 3rd positions. This converges with tetradecoding mechanisms that are more compatible with silent 4th, than at other, tetracodon positions. Tetracoding increases with (a) GC-contents, perhaps conserved or switched on in high temperature conditions; (b) usage of theoretically predicted 'tessera' tetracodons; (c) 12s rRNA stability; and d) antisense tRNA numbers with predicted expanded anticodons. Most detected tetragenes are not evolutionarily conserved, apparently reflect specific, transient adaptations. Tetracoding increases with mammal longevity. PMID- 23041465 TI - The Met-genotype of the BDNF Val66Met polymorphism is associated with reduced Stroop interference in elderly. AB - Aging is accompanied by impairments of executive functions that rely on the functional integrity of fronto-striatal networks. This integrity is modulated by the release of neurotrophins like the brain-derived-neurotrophic factor (BDNF). Here, we investigate effects of the functional BDNF Val66Met polymorphism on interference processing in 131 healthy elderly subjects using event-related potentials (ERPs). In a Stroop task, participants had to indicate the name or the colour of colour-words while colour was either compatible or incompatible with the name. We show that susceptibility to Stroop-interference is affected by the BDNF Val66Met polymorphism: the Met-allele carriers showed better performance and enhanced N450 in interference trials. Other processes necessary to prepare and allocate cognitive resources to a particular task were not affected by BDNF Val66Met polymorphism, underlining the specificity of the observed effects. The observed performance and ERP difference is possibly due to dopamine related effects of BDNF in fronto-striatal networks, where it putatively mediates a shift in the balance of the direct and indirect pathway involved in inhibitory functions. PMID- 23041466 TI - How many potential drug-drug interactions cause adverse drug reactions in hospitalized patients? AB - BACKGROUND: Potential drug-drug interactions (DDIs) are frequent in drug prescription but clinically significant are the ones which can result in changes of therapeutic effect of one of the two drugs or in adverse drug reactions (ADRs). The aim of this study was to assess the potential DDIs as well as the DDIs which cause adverse drug reactions (ADRs) in an internal medicine department hospitalized patients. METHODS: The prospective study included all patients admitted between November 2010 and January 2011 in an internal medicine ward. Information on patients' demographics and their medication use history was obtained from each patient by interview. In addition, medical history, medication use during hospitalization, and relevant laboratory and clinical data were obtained from medical records. Potential DDIs were identified using the Thomson Micromedex program. Each patient was monitored during the hospitalization period in order to detect the ADRs resulting from DDI's if present. RESULTS: Three hundred and five patients were enrolled in this study during 3 months. Of 1279 potential DDIs, Fourteen led to 13 ADRs out of which 8 were serious and caused hospital admission or prolongation of hospitalization. There was a statistically significant association between ADRs related to DDIs and the presence of ATC (Anatomical Therapeutic Chemical) C medication during hospitalization and the length of hospital stay, in the multivariate analysis. CONCLUSION: Awareness of the most commonly occurring DDIs should be raised by the utilization of drug-drug interaction guides in the Romanian clinical practice which can help prescribers and pharmacists prevent DDI related ADRs. PMID- 23041467 TI - Effect of clustering of metabolic syndrome factors on capillary and cerebrovascular impairment. AB - BACKGROUND: Hypertension and metabolic disorders, attended by impaired microcirculation, represent major risk factors for cerebrovascular impairment, as well as being individual components of the metabolic syndrome (MetS). Aim of the study was to establish whether mild hypertensives, aged <=65years, may be affected by progressive microvascular damage impairing cerebrovascular perfusion, related to a progressive clustering of MetS components. METHODS: Twenty-two normotensives with no MetS component (NTN-0), 29 hypertensives with no (HTN-0), 30 with one (HTN-1), 29 with two (HTN-2), 27 with three (HTN-3), 25 with all four (HTN-4) MetS components, were recruited. The study required office and twenty four hour ambulatory blood pressure monitoring and video capillaroscopy. Functional (fCD), anatomical (aCD) and recruited (RECR) phalangeal skin capillarity were assessed. Cerebral vasodilatory reserve was measured by the breath-holding index (BHI), using transcranial Doppler, in HTN-1 and HTN-2 with MetS. RESULTS: The fCD and aCD were reduced in hypertensives and progressively reduced in those with MetS, while RECR was also impaired. BHI was lower in HTN-2 than in HTN-1 (p<0.001). BHI was correlated with fCD in HTN-1 (.396, p: .046), HNT-2 (.497, p: .011), and with aCD in HTN-2 (.494, p: .012), by partial Pearson test. DISCUSSION: The findings show that hypertensives exhibit an increasing microvascular rarefaction with MetS progression and that an impaired cerebral perfusion occurs when the MetS is established. The data underline the importance of preventing MetS in mild hypertensives, as it causes microvascular damage and impairs cerebral arterial perfusion. PMID- 23041468 TI - Identification of mitochondria translation elongation factor Tu as a contributor to oxidative damage of postburn myocardium. AB - Mitochondrial damage plays an important role in mediating postburn cardiac injury. To elucidate the pivotal mitochondrial proteins and pathways underlying postburn cardiac injury, mitochondria were purified from control and postburn rat hearts. 2-dimensional gel electrophoresis (2-DE) and HPLC-chip-MS/MS analyses revealed 9 differentially expressed proteins, 3 of which were further validated by Western blotting. The differential expression of these mitochondrial proteins was accompanied by increased levels of oxidative cardiac damage and decreased levels of cardiac output. One of the differentially expressed proteins, mitochondria translation elongation factor Tu (EF-Tumt), was hypothesized to contribute crucially to postburn oxidative cardiac damage. The small interfering RNA (siRNA)-mediated downregulation of EF-Tumt in cultured rat cardiomyocytes increased reactive oxygen species (ROS) generation and protein carbonyl levels, and led to cell damage. The potential pathway of this process was associated with respiratory chain complex I deficiency. Together, these results demonstrate the mitochondrial responses to severe burn, and indicate a pathway by which decreased EF-Tumt expression mediates oxidative damage in postburn myocardium. PMID- 23041469 TI - Comprehensive analysis of endoplasmic reticulum-enriched fraction in root tips of soybean under flooding stress using proteomics techniques. AB - Flooding is a serious problem for soybean cultivation because it markedly reduces growth and grain yields. Here, 2 proteomics techniques were used to evaluate whether endoplasmic reticulum (ER)-enriched fraction is altered in soybean under flooding stress. Two-day-old soybeans were treated with flooding for 2 days, and rough ER-enriched fraction was then purified from root tips. Flooding-responsive protein of ER-enriched fraction was identified using gel-free and 1D-gel based proteomics techniques, and 117 proteins were increased and 212 proteins were decreased in soybean root tips in response to flooding stress. Among the identified proteins, 111 were functionally categorized as being involved in protein synthesis, post-translational modification, protein folding, protein degradation, and protein activation. Among differentially regulated proteins, the mRNA expression levels of 14 proteins that were predicted to be localized in the ER were analyzed. Notably, 3-ketoacyl-CoA reductase 1 was up-regulated and eight genes related to stress, hormone metabolism, cell wall and DNA repair were down regulated within 1 day under flooding conditions. In addition, the expression of luminal-binding protein 5 was specifically induced in flood-stressed roots, whereas arabinogalactan protein 2 and methyltransferase PMT2 were down-regulated. Taken together, these results suggest that flooding mainly affects the function of protein synthesis and glycosylation in the ER in root tips of soybean. PMID- 23041470 TI - Comments about the severe fracture concept used in the 2012 update of French guidelines for the pharmacological treatment of postmenopausal osteoporosis, by Briot et al. PMID- 23041471 TI - Idiopathic avascular necrosis of the femoral heads in five members of a Moroccan family. AB - Avascular necrosis (AVN) is idiopathic in about 40% of cases. The pathophysiology of avascular necrosis remains incompletely elucidated. Here, we report a case that underlines the role for inherited factors in AVN of the femoral heads. Idiopathic AVN of the femoral heads occurred in five members of the same family (a woman, her two paternal aunts, her male paternal cousin and her female paternal cousin) at a mean age of 42.4 years (range, 33-58 years). Standard pelvic radiographs showed Arlet and Ficat stage 4 AVN in three patients and stage 3 in two patients. None of the patients had a history of glucocorticoid therapy, alcohol abuse, or trauma. All five patients underwent investigations for a cause, including blood cell counts, a lipid profile, coagulation tests, testing for antinuclear antibodies, hemoglobin electrophoresis, ultrasonography of the abdomen, and standard radiographs of the long limb bones. The results were normal or negative, ruling out known hereditary causes of AVN such as sickle cell anemia and Gaucher disease. Many cases of familial AVN of the femoral head have been described in patients with sickle cell anemia or Gaucher disease. However, only five families with idiopathic familial AVN of the femoral heads have been reported (three in the US and two in Taiwan). All the patients in these families had isolated bilateral AVN of the femoral heads without AVN at other sites. PMID- 23041472 TI - How "reversible" is telomeric aging? AB - A critical question in human health is the malleability of telomere length. Telomere length, sampled at one point during adult life, is predictive of certain types of cancer and other immune and metabolic-related diseases. We now know from basic studies that the telomere/telomerase maintenance system plays a causal role in accelerating biologic aging and promoting disease processes. One can develop short telomeres for a multitude of reasons. Historical factors such as genetics, prenatal conditions, and early adversity, contribute to adult telomere length; however, current stress and lifestyle are also associated. If these modifiable predictors are causal factors in telomere shortening, there is a tremendous opportunity to improve maintenance and possibly even lengthen telomeres with behavioral interventions. This minireview discusses our current understanding of telomere lengthening and questions facing the field. Several small-scale stress reduction/wellness studies show promising findings, suggesting that cell aging can be slowed or reversed in vivo over short periods. Moreover, possible mechanisms are discussed, that take into account actual telomeric lengthening, such as that which occurs through telomerase-mediated elongation, or mechanisms resulting in "pseudo-telomeric lengthening" as might occur from changes in cell type distribution. There is a strong need for more translational clinical to bench research to address mechanistic questions in experimental models. In addition, well-designed intervention research that examines both telomeres and potential mediators of change can further enhance our understanding of malleability, mechanism, and clinical implications of telomere lengthening. Cancer Prev Res; 5(10); 1163-8. (c)2012 AACR. PMID- 23041473 TI - PPARgamma agonists target aromatase via both PGE2 and BRCA1. AB - Obesity is a well-recognized risk factor for postmenopausal breast cancer. Although the underlying mechanisms are not clearly defined, aromatase is thought to play a pivotal role in connecting obesity-associated inflammation with postmenopausal breast cancer. It has been well established that both the proinflammatory prostaglandin E(2) (PGE(2)) and the BRCA1 tumor-suppressor gene regulate aromatase expression. In this issue of the journal (beginning on p. 1183), Subbaramaiah and colleagues improve our understanding of the molecular mechanisms by which PPARgamma inhibits aromatase expression. They found that pioglitazone, a PPARgamma agonist, inhibited aromatase expression by inhibition of PGE(2) signaling and upregulation of BRCA1. Their findings provide potential targets for preventing or treating obesity-related breast cancer. PMID- 23041474 TI - Urinary ochratoxin A and ochratoxin alpha in pregnant women. AB - This study determined exposure of pregnant women to ochratoxin A (OTA). Forty samples of first-void urine samples from Croatian women in the third trimester of pregnancy were analyzed for OTA and its major metabolite ochratoxin alpha (OTalpha). The subjects filled a short food frequency questionnaire (FFQ). Analysis was performed by HPLC-FLD following liquid-liquid extraction. All samples were subjected in parallel to enzymatic treatment (beta glucuronidase/aryl sulfatase) to release OTA and OTalpha from the conjugates. The median urinary levels of OTA and OTalpha before treatment were 0.02 (range: nd 1.07) ng/mL and 0.16 (nd-1.86) ng/mL; the concentrations after enzyme hydrolysis were 0.02 (nd-1.11) ng/mL and 1.18 (0.11-7.57) ng/mL. While OTalpha levels increased significantly following enzymatic treatment, evidence for OTA conjugation was weak. The ratio of urinary OTalpha medians after and before hydrolysis was 1.5 times higher than previously reported for nonpregnant female subjects, possibly indicating upregulated metabolism and/or elimination of the mycotoxin and metabolites in pregnancy. The mean daily dietary OTA intake calculated from FFQs (1.08+/-0.57 ng/kg body weight) was well below the provisional tolerable daily intake and the greatest contributors to intake were cereal products, fruit juices, chocolate and coffee. PMID- 23041475 TI - RNAIII inhibiting peptide against foreign-body infection by methicillin-resistant Staphylococcus aureus. PMID- 23041476 TI - Plasma membrane calcium ATPases and related disorders. AB - The plasma membrane Ca(2+) ATPases (PMCA pumps) cooperate with other transport systems in the plasma membrane and in the organelles in the regulation of cell Ca(2+). They have high Ca(2+) affinity and are thus the fine tuners of cytosolic Ca(2+). They belong to the superfamily of P-type ATPases: their four basic isoforms share the essential properties of the reaction cycle and the general membrane topography motif of 10 transmembrane domains and three large cytosolic units. However they also differ in other important properties, e.g., tissue distribution and regulatory mechanisms. Their chief regulator is calmodulin, that removes their C-terminal cytosolic tail from autoinhibitory binding sites next to the active site of the pump, restoring activity. The number of pump isoforms is increased to over 30 by alternative splicing of the transcripts at a N-terminal site (site A) and at site C within the C-terminal calmodulin binding domain: the splice variants are tissue specific and developmentally regulated. The importance of PMCAs in the maintenance of cellular Ca(2+) homeostasis is underlined by the disease phenotypes, genetic or acquired, caused by their malfunction. Non-genetic PMCA deficiencies have long been considered possible causative factors in disease conditions as important as cancer, hypertension, or neurodegeneration. Those of genetic origin are better characterized: some have now been discovered in humans as well. They concern all four PMCA isoforms, and range from cardiac dysfunctions, to deafness, to hypertension, to cerebellar ataxia. PMID- 23041477 TI - Carbon monoxide releasing molecule-2 CORM-2 represses global protein synthesis by inhibition of eukaryotic elongation factor eEF2. AB - Carbon monoxide (CO) is an endogenous gaseous transmitter that exerts antiproliferative effects in many cell types, but effects of CO on the translational machinery are not described. We examined the effects of the carbon monoxide releasing molecule-2 (CORM-2) on critical steps in translational signaling and global protein synthesis in pancreatic stellate cells (PSCs), the most prominent collagen-producing cells in the pancreas, whose activation is associated with pancreatic fibrosis. PSCs were isolated from rat pancreatic tissue and incubated with CORM-2. CORM-2 prevented the decrease in the phosphorylation of eukaryotic elongation factor 2 (eEF2) caused by serum. By contrast, the activation dependent phosphorylation of initiation factor 4E binding protein 1 (4E-BP1) was inhibited by CORM-2 treatment. The phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) and eukaryotic initiation factor 4E (eIF4E) were not affected by CORM-2 treatment. In consequence, CORM-2 mediated eEF2 phosphorylation and inactivation of 4E-BP1 suppressed global protein synthesis. These observations were associated with inhibition of phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling and increased intracellular calcium and cAMP levels. The CORM-2 mediated inhibition of protein synthesis resulted in downregulation of cyclin D1 and cyclin E expression, a subsequent decline in the phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and cell growth arrest at the G(0)/G(1) phase checkpoint of the cell cycle. Our results suggest the therapeutic application of CO releasing molecules such as CORM-2 for the treatment of fibrosis, inflammation, cancer, or other pathologic states associated with excessive protein synthesis or hyperproliferation. However, prolonged exogenous application of CO might also have negative effects on cellular protein homeostasis. PMID- 23041478 TI - A mathematical model for coupling within-host and between-host dynamics in an environmentally-driven infectious disease. AB - This work presents a new model for the linking of within- and between-host dynamics. We use this as a conceptual model for the dynamics of Toxoplasma gondii, in which the parasite's life cycle includes interactions with the environment. We postulate the infection process to depend on the size of the infective inoculum that susceptible hosts may acquire by interacting with a contaminated environment. Because the dynamical processes associated with the within- and between-host occur on different time scales, the model behaviors can be analyzed by using a singular perturbation argument, which allows us to decouple the full model by separating the fast- and slow-systems. We define new reproductive numbers for the within-host and between host dynamics for both the isolated systems and the coupled system. Particularly, the reproduction number for the between-host (slow) system dependent on the parameters associated with the within-host (fast) system in a very natural way. We show that these reproduction numbers determine the stability of the infection-free and the endemic equilibrium points. Our model may present a so-called backward bifurcation. PMID- 23041479 TI - Non-smooth plant disease models with economic thresholds. AB - In order to control plant diseases and eventually maintain the number of infected plants below an economic threshold, a specific management strategy called the threshold policy is proposed, resulting in Filippov systems. These are a class of piecewise smooth systems of differential equations with a discontinuous right hand side. The aim of this work is to investigate the global dynamic behavior including sliding dynamics of one Filippov plant disease model with cultural control strategy. We examine a Lotka-Volterra Filippov plant disease model with proportional planting rate, which is globally studied in terms of five types of equilibria. For one type of equilibrium, the global structure is discussed by the iterative equations for initial numbers of plants. For the other four types of equilibria, the bounded global attractor of each type is obtained by constructing appropriate Lyapunov functions. The ideas of constructing Lyapunov functions for Filippov systems, the methods of analyzing such systems and the main results presented here provide scientific support for completing control regimens on plant diseases in integrated disease management. PMID- 23041480 TI - Quality of publications in emergency medicine. AB - OBJECTIVE: The objective of this study is to describe emergency medicine (EM) publications in terms of methodology, approval by institutional review board, method of consent, external validity, and setting (eg, prehospital or emergency department). METHODS: The 12 top-ranked emergency journals were selected. We manually reviewed the last 30 original articles in each EM journal, to represent more than 2 months of publications for all EM journals (range, 2-6 months). Only clinical original articles on human subjects were included. To ensure accurate data transcription, each article was read at least twice by 2 different reviewers and graded by written criteria using an extraction standard chart. RESULTS: Over the articles reviewed, 330 were analyzed. One hundred eighty-nine (57.3%) were prospective studies; 29 (8.8%) were randomized studies. Two hundred twenty-six studies (68.5%) mentioned an institutional review board approval or a waiver of authorization, and an informed consent was not mentioned in 227 (68.8%) of studies. Fifty-nine (17.9%) were conducted in a prehospital setting. Two hundred thirty-eight (72.1%) of these studies were at single-center institutions; the Unite States contributed 158 (47.9%) of the total publications. CONCLUSION: This study describes publications in the field of EM. Randomized studies represent 9% of publications, most studies are cross-sectional, and more than half have a retrospective design. We found that, in one-third of the studies, an institutional review board review was not mentioned and informed consent was not specified in two-thirds of the studies. Emergency medicine research volume, quality, and grants activity must increase in order for EM to progress within academic medicine. PMID- 23041481 TI - Opioid-induced hyperalgesia--worsening pain in opioid-dependent patients. PMID- 23041482 TI - Left-sided appendicitis in a 47-year-old man with previously undiagnosed intestinal malrotation. PMID- 23041483 TI - Successful endovascular treatment of subclavian artery dissection after compression trauma. PMID- 23041484 TI - Low-dose ketamine analgesia: patient and physician experience in the ED. AB - OBJECTIVE: Low-dose ketamine (LDK) may be useful for treatment for opioid tolerant patients. We conducted a survey of patients and their treating clinicians regarding LDK for analgesia. METHODS: Survey data included the following: vital signs and pain score before and after LDK, demographics, and adverse effects. Treating physicians were queried about reasons for use of LDK and overall satisfaction. RESULTS: Twenty-four patients were enrolled: 21 received LDK for analgesia, and 3 received LDK for sedation. Pain level on a visual analog scale (range, 1-10) after LDK was significantly decreased from 8.9 +/- 2.1 to 3.9 +/- 3.4 (P < .0001). Change in vital signs after administration of LDK was not statistically significant. Overall patient satisfaction with LDK was 55%, and overall physician satisfaction was 72%. Sixteen (67%) of patients would prefer LDK again, and 23 (96%) of physicians would use LDK again for analgesia. Four patients reported an adverse experience, but there were no emergence reactions. Race subanalysis revealed no difference in pain reduction, but whites were least satisfied compared with black and Hispanic patients (P = .02). Physician reasons for using LDK included opioid failure (88%), concern for respiratory depression (17%), concern for multiple opioid allergies (13%), and concern for hypotension (8%). Most (96%) physicians believed that LDK is underused. CONCLUSION: Low-dose ketamine may decrease patients' perception of pain. Most were satisfied with LDK for this purpose and would use it again. Whites were least satisfied with the use of LDK for analgesia. Physicians believed that ketamine is underused. PMID- 23041485 TI - Factors associated with the use of procedural sedation during incision and drainage procedures at a children's hospital. AB - OBJECTIVE: The incidence of skin and soft tissue infections requiring incision and drainage has increased. Little evidence exists about the use of procedural sedation (PS) for these procedures in children. Our objective was to determine factors associated with the use of PS during incision and drainage procedures at a tertiary children's hospital. METHODS: This was a nested cohort study that combined a retrospective medical record review with prospectively collected data for children 2 months to 18 years old who had an incision and drainage procedure performed at a children's hospital over a 1-year period. Procedural sedation was defined as the use of pharmacologic agents to alter patient consciousness. Patient, lesion (eg, size and induration), provider (eg, years of experience), and emergency department (eg, patient volume and wait time) factors were analyzed. Emergency department physicians were divided into tertiles by frequency of sedation (high/medium/low) to assess provider practice variation. chi(2) Analysis and multivariable logistic regression were used to identify factors associated with PS use. RESULTS: Of the 215 enrolled patients, 95 (44.2%) received PS. Ninety (94.7%) of 95 sedated patients received ketamine as their primary sedation agent. On univariate analysis, emergency department volume, wait time, duration of illness, and provider experience were not associated with PS use. With multivariable regression, patient age, abscess size, and provider frequency of sedation were all independently associated with the decision to sedate. CONCLUSIONS: Patient age and abscess size are independent predictors of the use of PS for incision and drainage procedures. Provider practice patterns are also independently associated with PS use. PMID- 23041486 TI - Atypical Lemierre syndrome, thrombophlebitis of the facial vein. PMID- 23041487 TI - The modulatory role of M2 muscarinic receptor on apomorphine-induced yawning and genital grooming. AB - The interaction between dopaminergic and cholinergic pathways in the induction of behavioral responses has been previously established. In the brain, M2 receptors are found predominantly in presynaptic cholinergic neurons as autoreceptors, and in dopaminergic neurons as heteroceptors, suggesting a control role of acetylcholine and dopamine release, respectively. Our aim was to investigate the role of M2 receptors on the yawning and genital grooming of rats induced by apomorphine, a dopaminergic receptor agonist, focusing on the interaction between cholinergic and dopaminergic pathways. Initially, the effect of atropine, a non selective muscarinic antagonist, on yawning and genital grooming induced by apomorphine (100 MUg/kg s.c.) was analyzed. Atropine doses of 0.5, 1 and 2 mg/kg i.p. were administered to Wistar rats 30 min before induction of the behavioral responses by apomorphine. Number of yawns and time spent genital grooming were quantified over a 60 min period. Apomorphine-induced yawning was increased by low dose (0.5 mg/kg i.p.) but not by high doses (1 and 2 mg/kg, i.p.) of atropine. Genital grooming was antagonized by 2 mg/kg i.p. of atropine and showed no changes at the other doses tested. Tripitramine, a selective M2 cholinergic antagonist, was used as a tool for distinguishing between M2 and all other muscarinic receptor subtypes in yawning and genital grooming. Tripitramine doses of 0.01, 0.02 and 0.04 MUmol/kg i.p. were administered to Wistar rats 30 min before apomorphine (100 MUg/kg s.c.). Number of yawns and time spent genital grooming were also quantified over a 60 min period. Tripitramine 0.01 MUmol/kg increased all parameters. Higher doses, which possibly block all subtypes of muscarinic receptor, did not modify the response of apomorphine, suggesting a non selective effect of tripitramine at these doses. Given that low doses of tripitramine increased the behavioral responses induced by apomorphine and that the main distribution of the M2 receptor is presynaptic, we raised the hypothesis that tripitramine may alter cholinergic and/or dopaminergic transmission in brain areas responsible for induction of yawning and genital grooming in rats, possibly by control of acetylcholine and/or dopamine release. In addition, the present study showed the involvement of M2 cholinergic receptors in the complex mechanisms of functional interactions between dopaminergic and cholinergic systems involved in the control of yawning and genital grooming. PMID- 23041488 TI - Melatonin modulates apoptosis and TRPM2 channels in transfected cells activated by oxidative stress. AB - Transient receptor potential melastatin-like 2 (TRPM2) is a non-selective Ca(2+) permeable cation channel and is known to be activated by H(2)O(2), one of the most important indicators of intracellular oxidative stress. A neurohormone melatonin may have a modulator role on TRPM2 channels activated by oxidative stress because it is a strong antioxidant. In this study we investigated the effects of melatonin on apoptosis, whole cell currents and Ca(2+) influx arising from TRPM2 channels activated by H(2)O(2). In whole-cell patch clamp experiments, TRPM2 channels in transfected Chinese hamster ovary (CHO) cells were activated by H(2)O(2). However, the currents were inhibited either by intracellular or by extracellular melatonin. When intracellular melatonin was introduced by pipette, TRPM2 channel currents were not activated by H(2)O(2) although H(2)O(2)-induced Ca(2+) gating and release were not blocked 2-aminoethyldiphenyl borate (2-APB). Cytosolic Ca(2+) release was measured by Fura-2 and was higher in H(2)O(2) groups than in control. Melatonin also inhibited apoptosis in the transfected cells. In conclusion, we observed modulator roles of intracellular and extracellular melatonin on Ca(2+) influx and apoptosis through a TRPM2 channel in transfected CHO cells. PMID- 23041490 TI - Stress free configuration of the human eye. AB - Numerical simulations of eye globes often rely on topographies that have been measured in vivo using devices such as the Pentacam or OCT. The topographies, which represent the form of the already stressed eye under the existing intraocular pressure, introduce approximations in the analysis. The accuracy of the simulations could be improved if either the stress state of the eye under the effect of intraocular pressure is determined, or the stress-free form of the eye estimated prior to conducting the analysis. This study reviews earlier attempts to address this problem and assesses the performance of an iterative technique proposed by Pandolfi and Holzapfel [1], which is both simple to implement and promises high accuracy in estimating the eye's stress-free form. A parametric study has been conducted and demonstrated reliance of the error level on the level of flexibility of the eye model, especially in the cornea region. However, in all cases considered 3-4 analysis iterations were sufficient to produce a stress-free form with average errors in node location <10(-6)mm and a maximal error <10(-4)mm. This error level, which is similar to what has been achieved with other methods and orders of magnitude lower than the accuracy of current clinical topography systems, justifies the use of the technique as a pre processing step in ocular numerical simulations. PMID- 23041489 TI - The food retail environment in school neighborhoods and its relation to lunchtime eating behaviors in youth from three countries. AB - This study examined the relation between the chain food retail environment surrounding schools, youths' lunchtime eating behavior, and youths' obesity levels across three countries. Participants consisted of 26,778 students 13-15 years old from 687 schools across Canada, Scotland and the US. The density of convenience stores, chain fast food restaurants, and chain cafes within 1 km of each school was measured. Lunchtime eating behaviors, weight, and height were self-reported. Although the density of chain food retailers was highest in the US, fewer American students (2.6%) routinely ate their lunch at a food retailer during the school week than did Canadian (7.7%) and Scottish (43.7%) students. The density of chain food retailers was associated with eating lunch at a food retailer in Canada only whereby students attending schools with 1-2, 3-4, and 5+ chain food retailers within 1 km from their schools were 1.39 (95% CI: 0.84 2.29), 1.87 (95% CI: 1.10-3.20), and 2.50 (95% CI: 1.56-4.01) times more likely to eat at a chain food retailer compared to students attending schools with no nearby chain food retailers. No associations were found between chain food retailer density and obesity. PMID- 23041491 TI - Atomic structure and ultrastructure of the Murex troscheli shell. AB - The structure of the gastropod Murex troscheli shell was investigated by using high-resolution scanning and transmission electron microscopies and high resolution synchrotron X-ray powder diffraction. Rietveld refinement of X-ray diffraction patterns revealed anisotropic distortions of the orthorhombic aragonite unit cell, reaching a maximum of about 0.2% (along the c-direction) with respect to geological aragonite. Lattice distortions are effectively relieved under mild annealing at temperatures between 150 degrees C and 250 degrees C. This relaxation correlated well with the loss of organic substance during annealing, measured by thermal gravimetric analysis. The shell ultrastructure consists of three orders of hierarchy, which is typical for crossed-lamellar layers. The third-order fiber-like lamellae, nearly 50 * 250 nm2 in cross-section, are heavily twinned, producing specific contrast features in transmission electron microscopy micrographs. So, higher orders of hierarchy are, in fact, twins, which boundaries are free of organic matter. PMID- 23041492 TI - Characterization of bacteriophage phiPto-bp6g, a novel phage that lyses Pseudomonas tolaasii causing brown blotch disease in mushrooms. AB - The bacteriophage, phiPto-bp6g, exhibited strong bactericidal activity against Pseudomonas tolaasii, the bacterium that causes brown blotch disease in cultivated mushrooms. Analysis of phage morphology with an electron microscope revealed that phiPto-bp6g contains an icosahedral head and a long tail, which is classified as the family of Siphoviridae. The phage was observed to lyse P. tolaasii in the broth about 4h after inoculation, indicating a putative lytic pathway exists during bacterial growth. The whole genome of phiPto-bp6g was completely sequenced, with a length of 26,499 bp and a G+C content of 42.7%. A total of 77 open reading frames (ORFs) as putative coding sequences were identified and annotated, whereas 43 ORFs possessed no homologs. Proteins of several ORFs showed similarity with proteins of a diverse group of phages, including Siphoviridae (5 ORFs), Myoviridae (11 ORFs), and Podoviridae (4 ORFs). Phage proteins were grouped into three categories based on their predicted functions: (i) DNA replication and nucleotide metabolism, (ii) phage particle formation, and (iii) host interaction. Since there is no identified gene encoding integrase and toxins in phage genome, phage phiPto-bp6g could be potentially applicable as a safe biological control reagent against brown blotch disease in mushroom cultivation. PMID- 23041493 TI - Evaluation of two quantitative PCR assays using Bacteroidales and mitochondrial DNA markers for tracking dog fecal contamination in waterbodies. AB - This study describes a comparative performance evaluation of two qPCR assays targeting a dog-associated Bacteroidales 16S rRNA genetic marker (CanBac-UCD) and a dog mitochondrial DNA (mtDNA) marker. The same fecal and environmental samples were assayed for the two markers thereby allowing direct comparison. A wide range of non-target species including, human, pig, horse, deer, mountain goat, bison, caribou, and moose were tested. Marker persistence was also monitored in freshwater microcosms. Both markers were prevalent in the canine samples collected in Regina, Saskatchewan and Calgary, Alberta, Canada (91% and 98% sensitivity, respectively). The mtDNA marker was detected exclusively in the target species while the CanBac-UCD marker was detected in all the non-target species (31% specificity). The CanBac-UCD marker exhibited faster decay in freshwater microcosms. The markers were rarely detected in the water samples collected from dog parks in Calgary and in Regina as well as from waterbodies and sewage influents in Saskatchewan, indicating possibly low to negligible levels of dog fecal contamination in the sampling areas. Altogether, the results of this study support the utility of the dog mtDNA assay in detecting dog fecal contamination in waterbodies. PMID- 23041494 TI - OEM--a new medium for rapid isolation of onion-pathogenic and onion-associated bacteria. AB - Onions (Allium cepa L.) are plagued by a number of bacterial pathogens including Pantoea ananatis, P. agglomerans, Burkholderia cepacia, Enterobacter cloacae, Pectobacterium carotovorum subsp. carotovorum, Xanthomonas axonopodis pv. axonopodis and several Pseudomonas spp. We developed a semi-selective medium, termed onion extract medium (OEM), to selectively and rapidly isolate bacteria pathogenic to and associated with onions and onion-related samples including bulbs, seeds, sets, transplant seedlings, soil and water. Most strains of interest grow sufficiently on OEM in 24h at 28 degrees C for tentative identification based on colony morphology, facilitating further characterization by microbiological and/or molecular means. PMID- 23041495 TI - Development of a simple, low-density array to detect methicillin-resistant Staphylococcus aureus and mecA dropouts in nasal swabs. AB - Detection of methicillin-resistant Staphylococcus aureus (MRSA) is important for prevention and control of MRSA infections, but the discovery of mecA dropouts and SCCmec junction sequences with homology to coagulase-negative staphylococci (CoNS) has challenged several real-time PCR tests. The objective of this study was to develop a user-friendly, gel element microarray test for MRSA detection, to estimate the analytical performance characteristics of the test on bacterial isolates, and to perform an initial evaluation of the test on nasopharyngeal swabs from patients known to have a high prevalence of S. aureus containing mecA dropouts. The assay limit of detection for the test was 250 fg (or less) of genomic DNA per amplification reaction (approximately 80 cell equivalents) and MRSA was consistently detected at a ratio of 1:12,000 in a non-target background. Of 87 bacterial isolates, the test accurately classified 86 (98.8%) overall, and correctly identified 14 mecA dropout specimens that were falsely positive in the BD GeneOhm MRSA test or BD GeneOhm StaphSR test. A retrospective analysis of 246 nasal swab samples acquired from a high-risk patient population (overall prevalence=10.8% by culture) resulted in 80.5% sensitivity (95% CI=68.4%, 92.6%) and 96.6% specificity. Of these 246 samples, 174 (71%) were positive for mecA, 86 (35%) were positive for S. aureus tufA and 46 (19%) were positive for a SCCmec junction sequence. To estimate method repeatability, 48 samples representing the full range of phenotypes, genotypes and microarray probe SNR values were tested in triplicate, with three discordant results for a concordance rate of 97.9% (141/144 tests). These data demonstrate that a very simple microarray test can identify mecA dropouts with high specificity in either cultured isolates or nasal swabs from a high-prevalence, high-risk patient population. However, the clinical sensitivity of the test will likely depend on local microbial ecology and the prevalence of mecA positive CoNS in any given patient population. PMID- 23041496 TI - Design and validation of a novel quantitative method for rapid bacterial enumeration using programmed stage movement scanning electron microscopy. AB - The adhesion of bacteria to surgical implants is the first stage of implant infection. The method for detecting bound bacteria is an important consideration in the study of bacterial adherence and colonisation. Enumeration of bacteria by direct visualisation techniques is labour intensive and time consuming. We have developed and validated a method for enumerating bacteria on porous material surfaces using programmed stage movement scanning electron microscopy and compared cumulative counts after 1-10 stage movements with absolute bacterial counts. We describe this method with three commercially sourced meshes used for abdominal wall hernia repair and with three different inoculums of Staphylococcus epidermidis. The results demonstrate significant correlation to the absolute count after five cumulative counts for all meshes analysed. The mean time saved by the cumulative counting method was 1h and 9 min per mesh. We conclude that advances in scanning electron microscopy and the advent of precise automated stage control have facilitated rapid data acquisition for bacterial counting purposes and that five cumulative counts at 1000* or 2500* magnification are a valid quantitative method for enumerating S. epidermidis bacteria on porous surfaces (with a pore size of up to 1.3 mm). PMID- 23041497 TI - Identification of RNA polymerase III-transcribed genes in eukaryotic genomes. AB - The RNA polymerase (Pol) III transcription system is devoted to the production of short, generally abundant noncoding (nc) RNAs in all eukaryotic cells. Previously thought to be restricted to a few housekeeping genes easily detectable in genome sequences, the set of known Pol III-transcribed genes (class III genes) has been expanding in the last ten years, and the issue of their detection, annotation and actual expression has been stimulated and revived by the results of recent high resolution genome-wide location analyses of the mammalian Pol III machinery, together with those of Pol III-centered computational studies and of ncRNA focused transcriptomic approaches. In this article, we provide an outline of distinctive features of Pol III-transcribed genes that have allowed and currently allow for their detection in genome sequences, we critically review the currently practiced strategies for the identification of novel class III genes and transcripts, and we discuss emerging themes in Pol III transcription regulation which might orient future transcriptomic studies. This article is part of a Special Issue entitled: Transcription by Odd Pols. PMID- 23041498 TI - Looking outward: content as a service starts to make sense. PMID- 23041500 TI - Plasma renin levels: the lower the better in terms of cardiovascular risk? PMID- 23041499 TI - Prevalence, correlates, and prognostic significance of QRS prolongation in heart failure with reduced and preserved ejection fraction. AB - AIMS: The independent clinical correlates and prognostic impact of QRS prolongation in heart failure (HF) with reduced and preserved ejection fraction (EF) are poorly understood. The rationale for cardiac resynchronization therapy (CRT) in preserved EF is unknown. The aim was to determine the prevalence of, correlates with, and prognostic impact of QRS prolongation in HF with reduced and preserved EF. METHODS AND RESULTS: We studied 25,171 patients (age 74.6 +/- 12.0 years, 39.9% women) in the Swedish Heart Failure Registry. We assessed QRS width and 40 other clinically relevant variables. Correlates with QRS width were assessed with multivariable logistic regression, and the association between QRS width and all-cause mortality with multivariable Cox regression. Pre-specified subgroup analyses by EF were performed. Thirty-one per cent had QRS >=120 ms. Strong predictors of QRS >=120 ms were higher age, male gender, dilated cardiomyopathy, longer duration of HF, and lower EF. One-year survival was 77% in QRS >=120 vs. 82% in QRS <120 ms, and 5-year survival was 42 vs. 51%, respectively (P < 0.001). The adjusted hazard ratio for all-cause mortality was 1.11 (95% confidence interval 1.04-1.18, P = 0.001) for QRS >=120 vs. <120 ms. There was no interaction between QRS width and EF. CONCLUSION: QRS prolongation is associated with other markers of severity in HF but is also an independent risk factor for all-cause mortality. The risk associated with QRS prolongation may be similar regardless of EF. This provides a rationale for trials of CRT in HF with preserved EF. PMID- 23041501 TI - Treatment with pharmacological PPARalpha agonists stimulates the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents. AB - BACKGROUND: Treatment of hyperlipidemic patients with fibrates, agonists of peroxisome proliferator-activated receptor alpha (PPARalpha), provokes muscle atrophy as a side effect. The molecular mechanism underlying this phenomenon is still unknown. We tested the hypothesis that activation of PPARalpha leads to an up-regulation of the ubiquitin proteasome system (UPS) which plays a major role in protein degradation in muscle. METHODS: Rats, wild-type and PPARalpha deficient mice (PPARalpha(-/-)) were treated with synthetic PPARalpha agonists (clofibrate, WY-14,643) to study their effect on the UPS and myofibrillar protein breakdown in muscle. RESULTS: In rats and wild-type mice but not PPARalpha(-/-) mice, clofibrate or WY-14,643 caused increases in mRNA and protein levels of the ubiquitin ligases atrogin-1 and MuRF1 in muscle. Wild-type mice treated with WY 14,643 had a greater 3-methylhistidine release from incubated muscle and lesser muscle weights. In addition, wild-type mice but not PPARalpha(-/-) mice treated with WY-14,643 had higher amounts of ubiquitin-protein conjugates, a decreased activity of PI3K/Akt1 signalling, and an increased activity of FoxO1 transcription factor in muscle. Reporter gene and gel shift experiments revealed that the atrogin-1 and MuRF1 promoter do not contain functional PPARalpha DNA binding sites. CONCLUSIONS: These findings indicate that fibrates stimulate ubiquitination of proteins in skeletal muscle which in turn stimulates protein degradation. Up-regulation of ubiquitin ligases is probably not mediated by PPARalpha-dependent gene transcription but by PPARalpha-dependent inhibition of the PI3K/Akt1 signalling pathway leading to activation of FoxO1. GENERAL SIGNIFICANCE: PPARalpha plays a role in the regulation of the ubiquitin proteasome system. PMID- 23041502 TI - 24S-hydroxycholesterol in plasma: a marker of cholesterol turnover in neurodegenerative diseases. AB - Brain cholesterol is mainly involved in the cell membrane structure, in signal transduction, neurotransmitter release, synaptogenesis and membrane trafficking. Impairment of brain cholesterol metabolism was described in neurodegenerative diseases, such as Multiple Sclerosis, Alzheimer and Huntington Diseases. Since the blood-brain barrier efficiently prevents cholesterol uptake from the circulation into the brain, de novo synthesis is responsible for almost all cholesterol present there. Cholesterol is converted into 24S-hydroxycholesterol (24OHC) by cholesterol 24-hydroxylase (CYP46A1) expressed in neural cells. Plasma concentration of 24OHC depends upon the balance between cerebral production and hepatic elimination and is related to the number of metabolically active neurons in the brain. Factors affecting brain cholesterol turnover and liver elimination of oxysterols, together with the metabolism of plasma lipoproteins, genetic background, nutrition and lifestyle habits were found to significantly affect its plasma levels. Either increased or decreased plasma 24OHC concentrations were described in patients with neurodegenerative diseases. A group of evidence suggests that reduced levels of 24OHC are related to the loss of metabolically active cells and the degree of brain atrophy. Inflammation, dysfunction of BBB, increased cholesterol turnover might counteract this tendency resulting in increased levels or, in some cases, in unsignificant changes. The study of plasma 24OHC is likely to offer an insight about brain cholesterol turnover with a limited diagnostic power. PMID- 23041503 TI - Commentary to the letter of Tjon et al. PMID- 23041504 TI - Differential effect of allogeneic versus syngeneic mesenchymal stem cell transplantation in MRL/lpr and (NZB/NZW)F1 mice. AB - MSC are being explored as a promising novel treatment for SLE. In this study, we: 1) assessed the differential effects of allogeneic versus syngeneic MSC transplantation on lupus-like disease, 2) explored the mechanisms by which MSC modulate disease, and 3) investigated whether lupus-derived-MSC have intrinsic immunomodulatory defects. We showed that in MRL/lpr mice and (NZB/NZW)F1 mice, both B6-MSC and lupus-MSC from young mice ameliorated SLE-like disease and reduced splenic CD3+CD4+ T lymphocytes and CD19+CD21+ B lymphocytes. However, lupus-MSC from older (NZB/NZW)F1 mice did not reduce spleen weights, glomerular IgG deposits, renal pathology, interstitial inflammation, CD3+CD4+ T lymphocytes or CD19+CD21+ B lymphocytes significantly. Thus MSC transplantation ameliorates SLE-like disease partly through decreasing CD4+ T cell and naive mature B cell numbers. Allogeneic MSC may be preferred over syngeneic lupus-derived-MSC given the decreased overall effectiveness of post-lupus-derived-MSC, which appears partially due to disease and not exclusively intrinsic defects in the MSC themselves. PMID- 23041505 TI - Increment thresholds for radial frequency trajectories produce a dipper function. AB - Radial frequency (RF) trajectories are a new class of stimuli that have been developed to study the visual perception of periodic motion (Or et al., 2011). These stimuli are described by a moving dot that traces a distorted path through space with periodic radial deformations whose frequency, amplitude, and phase can be independently specified. Here, we extend Or et al.'s findings by investigating how the discrimination of RF amplitude changes as a function of different reference amplitudes in a two-interval forced choice task. Using an RF3 trajectory (a pattern with three cycles of deformation along its trajectory), increment thresholds were measured at six different reference amplitudes: Detection (discriminating a circle from RF3), 1X (discriminating a pair of RF3 patterns, with the amplitude of one member of this pair set to (1X) threshold obtained from the detection condition), 2.5X, 5X, 10X, and 15X. Data show that sensitivity to changes in amplitude improves at 2.5X by a factor of about 2, recovers to detection threshold levels at 5X, and continues to rise at 10X and 15X. These results generalize across both radial frequency and the angular speed of the trajectory, and persist with low contrast trajectories. Our findings point to the existence of a neural mechanism that is sensitive to deviations from circular motion trajectories. PMID- 23041506 TI - Interacting effects of water temperature and dietary protein level on hematological parameters in Nile tilapia juveniles, Oreochromis niloticus (L.) and mortality under Streptococcus iniae infection. AB - Based on central composite rotatable experimental design and response surface method, the interacting effects of temperature (20 degrees C-34 degrees C) and dietary protein level (25%-50%) on hematological parameters including red blood cell (RBC), white blood cell (WBC) and hemoglobin (Hb) of juvenile Oreochromis niloticus were studied under laboratory conditions. The experiment lasted for 7 weeks. After the feeding trial, fish were challenged with Streptococcus iniae and mortality was recorded for within 8 days. Results showed that the linear and quadratic effects of temperature on RBC, WBC and Hb were highly significant (P < 0.01). When the dietary protein level was 25%-50%, the RBC, WBC and Hb were increased firstly and then decreased, but the linear and quadratic effects of protein level were insignificant (P > 0.05). The interacting effects of temperature and protein level on RBC and Hb were significant (P < 0.05). The regression equations of RBC, WBC and Hb toward the two factors of interest were established, with the coefficients of determination being 0.870, 0.836 and 0.881, respectively (P < 0.01). These equations could be used for prediction in practice. After the challenge, the mortalities for the combinations of 22.1 degrees C/28.7% and 20.0 degrees C/37.5% were significantly higher than 27.0 degrees C/37.5% (P < 0.05). The optimal temperature/dietary protein level combination was obtained at 27.9 degrees C/38.1% at which the lowest mortality (13.76%) was attained. This value was close to the optimal temperature/dietary protein level combination (29.4 degrees C/41.9%) for the greatest levels of RBC (2.560 * 10(6) MUL(-1)), WBC (270.648 * 10(3) MUL(-1)) and Hb (92.851 g L(-1)). The results of this study indicated that preferred temperature/dietary protein level combination might strengthen the non-specific immunity and reduce susceptibility to S. iniae. PMID- 23041507 TI - Trout oral VP2 DNA vaccination mimics transcriptional responses occurring after infection with infectious pancreatic necrosis virus (IPNV). AB - Time-course and organ transcriptional response profiles in rainbow trout Oncorhynchus mykiss were studied after oral DNA-vaccination with the VP2 gene of the infectious pancreatic necrosis virus (IPNV) encapsulated in alginates. The profiles were also compared with those obtained after infection with IPNV. A group of immune-related genes (stat1, ifn1, ifng, mx1, mx3, il8, il10, il11, il12b, tnf2, mhc1uda, igm and igt) previously selected from microarray analysis of successful oral vaccination of rainbow trout, were used for the RTqPCR analysis. The results showed that oral VP2-vaccination qualitatively mimicked both the time-course and organ (head kidney, spleen, intestine, pyloric ceca, and thymus) transcriptional profiles obtained after IPNV-infection. Highest transcriptional differential expression levels after oral vaccination were obtained in thymus, suggesting those might be important for subsequent protection against IPNV challenges. However, transcriptional differential expression levels of most of the genes mentioned above were lower in VP2-vaccinated than in IPNV infected trout, except for ifn1 which were similar. Together all the results suggest that the oral-alginate VP2-vaccination procedure immunizes trout against IPNV in a similar way as IPNV-infection does while there is still room for additional improvements in the oral vaccination procedure. Some of the genes described here could be used as markers to further optimize the oral immunization method. PMID- 23041509 TI - Morphological evaluation of the cerebral blood vessels in the late gestation fetal sheep following hypoxia in utero. AB - Hypoxia can significantly contribute to the development of permanent brain injury in the term neonate; however the response of cerebral blood vessels is not well understood. This study aimed to quantitatively measure vascular density and morphology using laminin immunohistochemistry as a marker of blood vessels, and determine the effects of a single, severe bout of hypoxia (umbilical cord occlusion, UCO) late in gestation on the developing cerebrovasculature in fetal sheep. At 124-126 days gestation singleton fetal sheep underwent surgery for implantation of catheters and placement of an inflatable cuff around the umbilical cord. A 10 min UCO or sham UCO (n=5) occurred at 132 days gestation. Fetal brains were collected at 24 h (n=5) or 48 h (n=4) after UCO for vascular density and morphology analysis of laminin immunohistochemistry. 48 h following a single, brief bout of severe hypoxia late in gestation decreased vascular density was seen in the caudate nucleus and no changes in vascular morphology occurred. However closer analysis revealed a significant shift in the frequency of smaller (<=10 MUm) to larger (<=100 MUm) perimeter blood vessels in periventricular and subcortical white matter. Close examination of the frequency distribution of vascular perimeter highlights that alterations in vascular morphology persist in the near term fetal brain for up to 48 h following a brief (10 min) hypoxia in white but not gray matter. These findings suggest that the near term brain may still be vulnerable to white matter injury following in utero hypoxia. PMID- 23041508 TI - Novel molecular targets associated with testicular dysgenesis induced by gestational exposure to diethylhexyl phthalate in the rat: a role for estradiol. AB - Significant research has been focused on phthalate-induced alterations in male reproductive development. Studies on rodents have prompted the notion that a syndrome exists in the human male which includes phenotypic alterations such as hypospadias, cryptorchidism, poor semen quality, and even testicular cancer. Each phenotype in this 'testicular dysgenesis syndrome' is predicated on reduction in testosterone production by the fetal Leydig cell. We sought to examine the relationship between dysgenesis and steroidogenic capacity in the fetal rat testis more stringently by incorporating lower exposures than those typically used, conducting a comprehensive, non-targeted quantitative evaluation of the fetal testis proteome, and relating alterations in individual proteins to the capacity of the fetal Leydig cell to produce testosterone, and histopathology of the fetal testis. Pregnant dams were dosed orally from gestation day (GD) 13-19 with 0, 10, or 100 mg diethylhexyl phthalate (DEHP)/kg body weight per day. Each endpoint was represented by 16l. Clustering of Leydig cells occurred before any significant decrease in the capacity of the GD19 Leydig cell to produce testosterone. At 100 mg DEHP/kg, testosterone production was reduced significantly, Leydig cell clusters became quite large, and additional dysgenetic changes were observed in the fetal testis. Of 23 proteins whose expression was altered significantly at both DEHP exposure levels, seven were found to be correlated with and predictive of the quantified endpoints. None of these proteins have been previously implicated with DEHP exposure. Notably, pathway analysis revealed that these seven proteins fit a pathway network in which each is regulated directly or indirectly by estradiol. PMID- 23041510 TI - Effects of combined treatment with eldecalcitol and alendronate on bone mass, mechanical properties, and bone histomorphometry in ovariectomized rats: a comparison with alfacalcidol and alendronate. AB - Eldecalcitol (ELD), a 2beta-hydroxypropyloxy derivative of 1alpha,25 (OH) 2D3, inhibits bone resorption more potently than alfacalcidol (ALF) while maintaining osteoblastic function in an ovariectomized (OVX) osteoporosis rat model. Alendronate (ALN), which is the most common bisphosphonate used for the treatment of osteoporosis, increases the bone mineral density (BMD) by suppressing bone resorption. In this study, we investigated the effects of combination treatments with ELD and ALN or with ALF and ALN on bone mass and strength in OVX rats. Seventy female rats, 32 weeks old, were assigned to seven groups: (1) a sham operated control group; (2) an OVX-control group; (3) an ELD group; (4) an ALF group; (5) an ALN group; (6) an ELD+ALN group; and (7) an ALF+ALN group. OVX rats were orally treated with ELD (0.015 MUg/kg), ALF (0.0375 MUg/kg), or ALN (0.2mg/kg) daily for 12 weeks. In both the lumbar spine and the femur, ELD and ALF monotherapy significantly increased the BMD, and ELD+ALN and ALF+ALN significantly increased the BMD, compared with ALN monotherapy, as an additive effect. In particular, ELD+ALN resulted in a significantly higher BMD than ALF+ALN in the femur. On mechanical testing of the lumbar spine, ELD and ALF monotherapy significantly increased the ultimate load, and ELD+ALN and ALF+ALN significantly increased the ultimate load compared with ALN monotherapy. In the femur, ELD, ELD+ALN, and ALF+ALN treatment significantly increased the ultimate load, compared with the OVX-control group, and ELD+ALN resulted in a significantly higher ultimate load than ALN monotherapy. A histomorphometric analysis showed that ELD monotherapy and ELD+ALN combination therapy had a potent inhibitory effect on bone resorption parameters (osteoclast surface and eroded surface), while maintaining bone formation parameters (osteoblast surface and osteoid surface). By contrast, ALF and ALF+ALN significantly lowered the histological parameters of both bone resorption and formation. These results suggested that ELD or ALF used in combination with ALN has therapeutic advantages over ALN monotherapy, with ELD+ALN combination treatment producing an especially beneficial anti-osteoporotic effect by inhibiting osteoclastic bone resorption and maintaining osteoblastic function, compared with ALF+ALN combination treatment. PMID- 23041512 TI - Combination treatment of stroke with sub-therapeutic doses of Simvastatin and human umbilical cord blood cells enhances vascular remodeling and improves functional outcome. AB - Human umbilical cord blood cells (HUCBCs) have been employed as a restorative treatment for experimental stroke. In this study, we investigated whether transplantation of sub-therapeutic doses of HUCBCs and Simvastatin enhances cerebral vascular remodeling after stroke. Adult male Wistar rats (n=34) were subjected to transient middle cerebral artery occlusion (MCAo) and treated with: phosphate-buffered solution (PBS, gavaged daily for 7 days); Simvastatin (0.5mg/kg, gavaged daily for 7 days); HUCBCs (1*10(6), injected once via tail vein); and combination Simvasatin with HUCBCs, starting at 24h after MCAo. There was no significant difference between Simvastatin- or HUCBC-monotherapy and MCAo alone group. Combination treatment 24h post-stroke significantly increased the perimeter of von Willebrand factor (vWF)-positive vessels, the diameter and density of alpha smooth muscle actin (alphaSMA)-positive arteries, and the percentage of 5-bromodeoxyuridine (BrdU)-positive endothelial cells (ECs) in the ischemic boundary zone (IBZ) compared with MCAo-alone or HUCBC-monotherapy 14 days after MCAo (p<0.05, n=8/group); Combination treatment significantly increased the densities of vWF-vessels and alphaSMA-arteries as well as the densities of BrdU-ECs and BrdU-positive smooth muscle cells (SMCs) in vascular walls in the IBZ compared with Simvastatin-monotherapy. Moreover, the increased BrdU-ECs and BrdU-SMCs were significantly correlated with neurological functional outcome 14 days after MCAo. Combination treatment also significantly increased the expression of Angiopoietin-1 (Ang1), Tie2 and Occludin in the IBZ (p<0.05, n=8/group). The in vitro experiments showed that combination treatment and Ang1 significantly increased capillary-like tube formation and arterial cell migration; anti-Ang1 significantly reduced combination treatment-induced tube formation and artery cell migration (p<0.05, n=6/group). These findings indicated that a combination of sub-therapeutic doses of Simvastatin and HUCBCs treatment of stroke increases Ang1/Tie2 and Occludin expression in the ischemic brain, amplifies endogenous angiogenesis and arteriogenesis, and enhances vascular remodeling which in concert may contribute to functional outcome after stroke. PMID- 23041511 TI - Beyond gap junctions: Connexin43 and bone cell signaling. AB - Connexin43 (Cx43) is the most abundant gap junction protein expressed in bone cells and plays a central role in cell-to-cell communication in the skeleton. Findings of the last decade uncovered functions of Cx43 hemichannels expressed on unopposed plasma cell membranes as mediators of the communication between bone cells and their extracellular milieu. Additionally, through its cytoplasmic C terminus domain, Cx43 serves as a scaffolding protein that associates with structural and signaling molecules leading to regulation of intracellular signaling, independent of channel activity. This perspective discusses the evidence demonstrating that via these diverse mechanisms Cx43 is a key component of the intracellular machinery responsible for signal transduction in bone in response to pharmacologic, hormonal and mechanical stimuli. This advance in the knowledge of the role of connexins increases our understanding of the pathophysiological mechanisms that regulate bone cell function and provides new opportunities to treat bone diseases. PMID- 23041513 TI - Brain CB1 receptor expression following lipopolysaccharide-induced inflammation. AB - Cannabinoid 1 receptors (CB(1)) are highly expressed on presynaptic terminals in the brain where they are importantly involved in the control of neurotransmitter release. Alteration of CB(1) expression is associated with a variety of neurological and psychiatric disorders. There is now compelling evidence that peripheral inflammatory disorders are associated with depression and cognitive impairments. These can be modeled in rodents with peripheral administration of lipopolysaccharide (LPS), but central effects of this treatment remain to be fully elucidated. As a reduction in endocannabinoid tone is thought to contribute to depression, we asked whether the expression of CB(1) in the CNS is altered following LPS treatment. CD1 mice received LPS (0.1-1mg/kg, ip) and 6h later activated microglial cells were observed only in circumventricular organs and only at the higher dose. At 24h, activated microglial cells were identified in other brain regions, including the hippocampus, a structure implicated in some mood disorders. Immunohistochemistry and real-time polymerase chain reaction (PCR) were utilized to evaluate the change of CB(1) expression 24h after inflammation. LPS induced an increase of CB(1) mRNA in the hippocampus and brainstem. Subsequent immunohistochemical analysis revealed reduced CB(1) in the hippocampus, especially in CA3 pyramidal layer. Analysis of co-localization with markers of excitatory and inhibitory terminals indicated that the decrease in CB(1) expression was restricted to glutamatergic terminals. Despite widespread microglial activation, these results suggest that peripheral LPS treatment leads to limited changes in CB(1) expression in the brain. PMID- 23041515 TI - Characterization of non-polio enterovirus isolates from acute flaccid paralysis children in Pakistan reflects a new genotype of EV-107. AB - Enteroviruses comprise a group of genetically diverse RNA viruses that usually cause respiratory illnesses, myocarditis, enteritis, meningitis, encephalitis and poliomyelitis. In this study, 23 non-polio enteroviruses, isolated during September-October 2009 from stool specimens of children suffering from acute flaccid paralysis (AFP) were subjected to serotype determination by using RIVM antiserum pools. Twenty-two isolates were identified as members of human enterovirus B (HEV-B) species except one that remained untypeable. Phylogenetic analysis of the untypeable isolate (PAKNIH-2009/23) based on the sequence of 5'UTR, capsid and 2A regions confirmed that this isolate is closely related to TN94-0349 strain of EV-107 serotype with 70.4% nucleotide similarity in VP1/2A junction, 79.4% in the capsid coding region and 89.1% in 5'UTR region respectively. Our data strongly suggests that PAKNIH-2009/23 is a genetically distinct strain of EV-107 currently circulating in Pakistan. This study also highlights the probable role of non-polio viral etiologies associated with AFP and needs to plan new strategies especially during the post polio eradication era. PMID- 23041514 TI - Lipidome and proteome of lipid droplets from the methylotrophic yeast Pichia pastoris. AB - Lipid droplets (LD) are the main depot of non-polar lipids in all eukaryotic cells. In the present study we describe isolation and characterization of LD from the industrial yeast Pichia pastoris. We designed and adapted an isolation procedure which allowed us to obtain this subcellular fraction at high purity as judged by quality control using appropriate marker proteins. Components of P. pastoris LD were characterized by conventional biochemical methods of lipid and protein analysis, but also by a lipidome and proteome approach. Our results show several distinct features of LD from P. pastoris especially in comparison to Saccharomyces cerevisiae. P. pastoris LD are characterized by their high preponderance of triacylglycerols over steryl esters in the core of the organelle, the high degree of fatty acid (poly)unsaturation and the high amount of ergosterol precursors. The high phosphatidylinositol to phosphatidylserine of ~7.5 ratio on the surface membrane of LD is noteworthy. Proteome analysis revealed equipment of the organelle with a small but typical set of proteins which includes enzymes of sterol biosynthesis, fatty acid activation, phosphatidic acid synthesis and non-polar lipid hydrolysis. These results are the basis for a better understanding of P. pastoris lipid metabolism and lipid storage and may be helpful for manipulating cell biological and/or biotechnological processes in this yeast. PMID- 23041516 TI - Treatment of aniline by catalytic wet air oxidation: comparative study over CuO/CeO2 and NiO/Al2O3. AB - The treatment of aniline by catalytic wet air oxidation (CWAO) was studied in a bubble reactor. The experiments were performed to investigate the effects of catalyst loading, temperature, reaction time, air flow rate, and pressure on aniline removal. The catalytic effects of the prepared nanostructured catalysts, CuO/CeO(2) (10% wt) and NiO/Al(2)O(3) (10% wt), on the CWAO treatment efficiency were also examined and compared. The prepared catalysts seem to be active having an aniline removal of 45.7% with CuO/CeO(2) and 41.9% with NiO/Al(2)O(3). The amount of N(2) formed was approximately the same for both of the catalysts. PMID- 23041517 TI - Theory of Planned Behavior and the Value-Belief-Norm Theory explaining willingness to pay for a suburban park. AB - This paper analyses whether the environmental profile of park visitors as defined by the components of the Theory of Planned Behavior and the Value-Belief-Norm Theory, determines their willingness to pay for park conservation. The sample consists of 194 visitors to a suburban Spanish park. Under these theories, it is shown that positive attitudes, a strong orientation towards biospheric and altruistic values with strong pro-environmental and normative beliefs determine the visitors' willingness to pay. Various fit statistics and the proportion of explained variance reveal that Theory of Planned Behavior has a greater influence on willingness to pay. The managers of urban spaces should direct their efforts to obtaining greater knowledge of people's attitudes, beliefs and pro environmental values given their importance in their decisions regarding economic valuation of this sort of resources. PMID- 23041518 TI - Modeling pollution control and performance in China's provinces. AB - The paper constructs a pollution control performance (PCP) evaluation model by introducing the norm of n-dimensional space. The PCP of 30 Chinese provinces for the period of 2003-2008 is evaluated based on the model and the factors influencing China's pollution control are further examined. It is found that: (1) China's PCP has improved rapidly but there is a large regional imbalance with the PCP of Eastern China being much better than that of Central and Western China; (2) to improve the level of China's PCP, government policies should consider industrial structure adjustment, restricting industry entries and increased investment in pollution abatement and R&D. PMID- 23041519 TI - Artemisinin inhibits lipopolysaccharide-induced interferon-beta production in RAW 264.7 cells: implications on signal transducer and activator of transcription-1 signaling and nitric oxide production. AB - Artemisinin is a well-known anti-malarial drug and has been shown to inhibit nitric oxide (NO) production. In this study, we investigated the effect of artemisinin on lipopolysaccharide (LPS)-induced production of IFN-beta and characterized the potential relationship between artemisinin-mediated inhibition of IFN-beta and NO production. Artemisinin suppressed IFN-beta production and mRNA expression in a dose-dependent manner in LPS-stimulated RAW 264.7 cells. LPS induced phosphorylation of signal transducer and activator of transcription-1 (STAT-1) was also inhibited by artemisinin treatment in RAW 264.7 cells. In addition, artemisinin suppressed LPS-induced production of NO in RAW 264.7 cells. Further study demonstrated that artemisinin-mediated inhibition of NO production and STAT-1 phosphorylation was reversed by addition of exogenous IFN-beta. Moreover, artemisinin does not affect IFN-beta-induced STAT-1 phosphorylation in RAW 264.7 cells. Collectively, these results suggest that the inhibition of IFN beta production by artemisinin and concomitant attenuation of STAT-1 activation might be involved in artemisinin-mediated inhibition of NO production in macrophages. PMID- 23041520 TI - Chemical profiling of Edelweiss (Leontopodium alpinum Cass.) extracts by micellar electrokinetic capillary chromatography. AB - This manuscript reports on the first CE-method suitable for analyzing twelve pharmacologically relevant compounds (flavonoids, caffeic acids and leontopodic acid) in the aerial parts of Leontopodium alpinum. By using a 60mM borax buffer containing 25mM SDS and 35% acetonitrile the analytes could be well resolved in 25min and accurately determined in different Edelweiss specimens. Method validation assured the compliance of the assay to ICH standards (correlation coefficients >=0.999, LOD <=7.2MUg/ml, LOQ <=23.0MUg/ml, recovery rates from 96.6 to 101.1%, intermediate precision <=7.01%, and repeatability <=5.52%). The quantitative results revealed a strong dependence of the content of phenolics on the growth status of the plants. In early stages no flavonoids were found, while during blooming all metabolites reached higher levels; commercially cultivated plant material showed the overall highest values (flavonoids: 0.25-0.34%, caffeic acids: 4.99-6.21%, leontopodic acid: 4.21-5.05%). PMID- 23041521 TI - Lobarin from the Sumatran lichen, Stereocaulon halei. AB - The diphenyl ether, lobarin (1) (syn. lobariol carboxylic acid) related to lobaric acid was isolated for the first time as a natural product along with five known compounds from Stereocaulon halei, a fruticose lichen collected in Indonesia. The structure of lobarin was elucidated by spectroscopic data analysis and its most stable conformers were determined by molecular mechanic dynamic calculations. A marked superoxide anion scavenging was found for compound 1 while no cytotoxicity on the B16 murine melanoma and HaCaT human keratinocyte cell lines was observed. PMID- 23041522 TI - Ultra-performance liquid-chromatography with tandem mass spectrometry performing pharmacokinetic and biodistribution studies of croomine, neotuberostemonine and tuberostemonine alkaloids absorbed in the rat plasma after oral administration of Stemonae Radix. AB - Stemonae Radix (Stemona tuberosa Lour, Bai Bu) is an important traditional Chinese medicinal (TCM) plant known for its antitussive activity. Croomine, neotuberostemonine and tuberostemonine alkaloids of Stemonae Radix are major components responsible for antitussive action. In this work, plasma pharmacokinetic and biodistribution characteristics of the three alkaloids after oral administration of Stemonae Radix are investigated using a rapid and sensitive UPLC-Q-TOF-HDMS method. Mass spectrometry (MS) was performed on a Waters Micromass high-definition technology with an electrospray ionization source in positive ion mode, with excellent MS mass accuracy and enhanced MS data acquisition. Separation of main alkaloids was achieved on a Waters BEH C(18) column by linear gradient elution. Data were analyzed and estimated by compartmental methods and pharmacokinetic parameters calculated using WinNonlin Professional version 5.1. It was found that croomine, neotuberostemonine and tuberostemonine had faster absorbed into the bloodstream, maintain the high plasma concentration, and pose a large AUC value. The biodistribution of neotuberostemonine and tuberostemonine showed that the higher levels were in liver, and lung. Croomine was discovered in brain and showed that it could cross the blood-brain barrier, indicating that croomine plays an antitussive effect as acting on the central nervous system. Neotuberostemonine and tuberostemonine were not discovered in brain, demonstrating that they play an antitussive effect as peripheral antitussive. This work suggests that the pharmacokinetics and biodistribution based-UPLC-Q-TOF-HDMS can provide a reliable tools for screening bioactive components contributing to pharmacological effects of medicinal herbs. PMID- 23041524 TI - Japonicones Q-T, four new dimeric sesquiterpene lactones from Inula japonica Thunb. AB - Four new dimeric sesquiterpene lactones (japonicones Q-T, 1-4) were isolated from the aerial part of Inula japonica Thunb., together with two known ones. Their structures were determined mainly by 1D and 2D NMR spectroscopic techniques including HSQC, (1)H-H COSY, HMBC, and NOESY. Herein, the inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages of 1-6 were evaluated; IC(50) values were tested as 8.5, 8.9, 4.3, 4.3, 4.2, and 9.2MUM, respectively. PMID- 23041523 TI - Impact of Pueraria candollei var. mirifica and its potent phytoestrogen miroestrol on expression of bone-specific genes in ovariectomized mice. AB - Miroestrol (MR) is a highly active phytoestrogen isolated from tuberous root of Pueraria candollei var. mirifica (PM). Modulatory effects of PM and MR on osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) mRNAs which are bone-specific genes were investigated in ovariectomized female ICR mice. After ovariectomy, expression of OPG mRNA was suppressed but that of RANKL was induced. Estradiol benzoate (E2) recovered OPG expression to the level comparable to the sham while that of RANKL was suppressed in ovariectomized mice. PM crude extract (PME) significantly down-regulated the expression of RANKL mRNA with no change in the OPG level whereas MR elevated the expression of OPG mRNA with lowering level of RANKL mRNA, resulting in the increased OPG/RANKL ratio, and consequently lead to lowering progression of osteoporosis at molecular level. These findings revealed potential of PME and MR on bone loss prevention via increasing the ratio of OPG to RANKL (osteoformation/osteoresorption) in liver of ovariectomized mice. Therefore, using PME and MR as alternative hormone replacement therapy of E2 might be beneficial recommended due to advantageous on regulation of osteoporosis related genes. PMID- 23041525 TI - Functional magnetic resonance imaging of sound pressure level encoding in the rat central auditory system. AB - Intensity is an important physical property of a sound wave and is customarily reported as sound pressure level (SPL). Invasive techniques such as electrical recordings, which typically examine one brain region at a time, have been used to study neuronal encoding of SPL throughout the central auditory system. Non invasive functional magnetic resonance imaging (fMRI) with large field of view can simultaneously examine multiple auditory structures. We applied fMRI to measure the hemodynamic responses in the rat brain during sound stimulation at seven SPLs over a 72 dB range. This study used a sparse temporal sampling paradigm to reduce the adverse effects of scanner noise. Hemodynamic responses were measured from the central nucleus of the inferior colliculus (CIC), external cortex of the inferior colliculus (ECIC), lateral lemniscus (LL), medial geniculate body (MGB), and auditory cortex (AC). BOLD signal changes generally increase significantly (p<0.001) with SPL and the dependence is monotonic in CIC, ECIC, and LL. The ECIC has higher BOLD signal change than CIC and LL at high SPLs. The difference between BOLD signal changes at high and low SPLs is less in the MGB and AC. This suggests that the SPL dependences of the LL and IC are different from those in the MGB and AC and the SPL dependence of the CIC is different from that of the ECIC. These observations are likely related to earlier observations that neurons with firing rates that increase monotonically with SPL are dominant in the CIC, ECIC, and LL while non-monotonic neurons are dominant in the MGB and AC. Further, the IC's SPL dependence measured in this study is very similar to that measured in our earlier study using the continuous imaging method. Therefore, sparse temporal sampling may not be a prerequisite in auditory fMRI studies of the IC. PMID- 23041526 TI - Statistical inference and multiple testing correction in classification-based multi-voxel pattern analysis (MVPA): random permutations and cluster size control. AB - An ever-increasing number of functional magnetic resonance imaging (fMRI) studies are now using information-based multi-voxel pattern analysis (MVPA) techniques to decode mental states. In doing so, they achieve a significantly greater sensitivity compared to when they use univariate frameworks. However, the new brain-decoding methods have also posed new challenges for analysis and statistical inference on the group level. We discuss why the usual procedure of performing t-tests on accuracy maps across subjects in order to produce a group statistic is inappropriate. We propose a solution to this problem for local MVPA approaches, which achieves higher sensitivity than other procedures. Our method uses random permutation tests on the single-subject level, and then combines the results on the group level with a bootstrap method. To preserve the spatial dependency induced by local MVPA methods, we generate a random permutation set and keep it fixed across all locations. This enables us to later apply a cluster size control for the multiple testing problem. More specifically, we explicitly compute the distribution of cluster sizes and use this to determine the p-values for each cluster. Using a volumetric searchlight decoding procedure, we demonstrate the validity and sensitivity of our approach using both simulated and real fMRI data sets. In comparison to the standard t-test procedure implemented in SPM8, our results showed a higher sensitivity. We discuss the theoretical applicability and the practical advantages of our approach, and outline its generalization to other local MVPA methods, such as surface decoding techniques. PMID- 23041527 TI - Epoch-specific functional networks involved in working memory. AB - Working memory (WM) is not a unitary construct. There are distinct processes involved in encoding information, maintaining it on-line, and using it to guide responses. The anatomical configurations of these processes are more accurately analyzed as functionally connected networks than collections of individual regions. In the current study we analyzed event-related functional magnetic resonance imaging (fMRI) data from a Sternberg Item Recognition Paradigm WM task using a multivariate analysis method that allowed the linking of functional networks to temporally-separated WM epochs. The length of the delay epochs was varied to optimize isolation of the hemodynamic response (HDR) for each task epoch. All extracted functional networks displayed statistically significant sensitivity to delay length. Novel information extracted from these networks that was not apparent in the univariate analysis of these data included involvement of the hippocampus in encoding/probe, and decreases in BOLD signal in the superior temporal gyrus (STG), along with default-mode regions, during encoding/delay. The bilateral hippocampal activity during encoding/delay fits with theoretical models of WM in which memoranda held across the short term are activated long-term memory representations. The BOLD signal decreases in the STG were unexpected, and may reflect repetition suppression effects invoked by internal repetition of letter stimuli. Thus, analysis methods focusing on how network dynamics relate to experimental conditions allowed extraction of novel information not apparent in univariate analyses, and are particularly recommended for WM experiments for which task epochs cannot be randomized. PMID- 23041528 TI - Similar neural mechanisms for perceptual guesses and free decisions. AB - When facing perceptual choices under challenging conditions we might believe to be purely guessing. But which brain regions determine the outcome of our guesses? One possibility is that higher-level, domain-general brain regions might help break the symmetry between equal-appearing choices. Here we directly investigated whether perceptual guesses share brain networks with other types of free decisions. We trained an fMRI-based pattern classifier to distinguish between two perceptual guesses and tested whether it was able to predict the outcome of similar non-perceptual choices, as in conventional free choice tasks. Activation patterns in the medial posterior parietal cortex cross-predicted free decisions from perceptual guesses and vice versa. This inter-changeability strongly speaks for a similar neural code for both types of decisions. The posterior parietal cortex might be part of a domain-general system that helps resolve decision conflicts when no choice option is more or less likely or valuable, thus preventing behavioural stalemate. PMID- 23041529 TI - Cortical thickness and central surface estimation. AB - Several properties of the human brain cortex, e.g., cortical thickness and gyrification, have been found to correlate with the progress of neuropsychiatric disorders. The relationship between brain structure and function harbors a broad range of potential uses, particularly in clinical contexts, provided that robust methods for the extraction of suitable representations of the brain cortex from neuroimaging data are available. One such representation is the computationally defined central surface (CS) of the brain cortex. Previous approaches to semi automated reconstruction of this surface relied on image segmentation procedures that required manual interaction, thereby rendering them error-prone and complicating the analysis of brains that were not from healthy human adults. Validation of these approaches and thickness measures is often done only for simple artificial phantoms that cover just a few standard cases. Here, we present a new fully automated method that allows for measurement of cortical thickness and reconstructions of the CS in one step. It uses a tissue segmentation to estimate the WM distance, then projects the local maxima (which is equal to the cortical thickness) to other GM voxels by using a neighbor relationship described by the WM distance. This projection-based thickness (PBT) allows the handling of partial volume information, sulcal blurring, and sulcal asymmetries without explicit sulcus reconstruction via skeleton or thinning methods. Furthermore, we introduce a validation framework using spherical and brain phantoms that confirms accurate CS construction and cortical thickness measurement under a wide set of parameters for several thickness levels. The results indicate that both the quality and computational cost of our method are comparable, and may be superior in certain respects, to existing approaches. PMID- 23041530 TI - A parcellation scheme based on von Mises-Fisher distributions and Markov random fields for segmenting brain regions using resting-state fMRI. AB - Understanding the organization of the human brain requires identification of its functional subdivisions. Clustering schemes based on resting-state functional magnetic resonance imaging (fMRI) data are rapidly emerging as non-invasive alternatives to cytoarchitectonic mapping in postmortem brains. Here, we propose a novel spatio-temporal probabilistic parcellation scheme that overcomes major weaknesses of existing approaches by (i) modeling the fMRI time series of a voxel as a von Mises-Fisher distribution, which is widely used for clustering high dimensional data; (ii) modeling the latent cluster labels as a Markov random field, which provides spatial regularization on the cluster labels by penalizing neighboring voxels having different cluster labels; and (iii) introducing a prior on the number of labels, which helps in uncovering the number of clusters automatically from the data. Cluster labels and model parameters are estimated by an iterative expectation maximization procedure wherein, given the data and current estimates of model parameters, the latent cluster labels, are computed using alpha-expansion, a state of the art graph cut, method. In turn, given the current estimates of cluster labels, model parameters are estimated by maximizing the pseudo log-likelihood. The performance of the proposed method is validated using extensive computer simulations. Using novel stability analysis we examine the sensitivity of our methods to parameter initialization and demonstrate that the method is robust to a wide range of initial parameter values. We demonstrate the application of our methods by parcellating spatially contiguous as well as non-contiguous brain regions at both the individual participant and group levels. Notably, our analyses yield new data on the posterior boundaries of the supplementary motor area and provide new insights into functional organization of the insular cortex. Taken together, our findings suggest that our method is a powerful tool for investigating functional subdivisions in the human brain. PMID- 23041531 TI - Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens. AB - Stimulation of sigma-1 receptors is reported to protect against oxidative stress. The present study uses cells and tissue from the human lens to elucidate the relationship between the sigma 1 receptor, ER stress and oxidative stress-induced damage. Exposure of the human lens cell line FHL124 to increasing concentrations of H(2)O(2) led to reduced cell viability and increased apoptosis. In response to 30 MUM H(2)O(2), levels of the ER stress proteins BiP, ATF6 and pEIF2alpha were significantly increased within 4h of exposure. Expression of the sigma 1 receptor was markedly increased in response to H(2)O(2). Application of 10 and 30 MUM (+) pentazocine, a sigma 1 receptor agonist, significantly inhibited the H(2)O(2) induced cell death. (+)-Pentazocine also suppressed the oxidative stress induced reduction of pro-caspase 12 and suppressed the induction of the ER stress proteins BiP and EIF2alpha. When applied to cultured human lenses, (+) pentazocine protected against apoptotic cell death, LDH release and against H(2)O(2) induced opacification. These data demonstrate that stimulation of the sigma 1 receptor provides significant protection from oxidative damage and is, therefore, a putative therapeutic approach to delay the onset of diseases that may be triggered by oxidative damage, including cataract formation. PMID- 23041532 TI - Diagnosis and management of circulatory arrest in pediatric ventricular assist device patients: presentation of two cases and suggested guidelines. AB - INTRODUCTION: Pediatric patients supported by ventricular assist devices (VADs) are becoming more common. No guidelines exist to provide an approach to diagnosis or management of circulatory arrest in these patients. We present two case reports of apparent circulatory arrest in pediatric VAD-supported patients at our institution. DISCUSSION: Diagnosis of circulatory arrest in VAD-supported patients can be challenging, especially with non-pulsatile flow devices. Traditional methods of diagnosis, such as pulse check and blood pressure, may be unreliable. Etiology may be primary device failure though other etiologies need to be considered. Treatment of the circulatory arrest depends on the etiology and type of VAD device being used. CONCLUSION: In the absence of strong literature on the approach to these patients, we present these case reports and our local institutional guidelines as a starting point for discussion. PMID- 23041533 TI - Impacting sudden cardiac arrest in the home: a safety and effectiveness study of privately-owned AEDs. AB - BACKGROUND: Sudden cardiac arrest (SCA) remains a major public health problem. The majority of SCA events occur in the home; however, scant data has been published regarding the effectiveness of privately owned AEDs. METHODS: The study, initiated in 2002 under prescription labeling, continued with over the counter availability in 2004 and was completed in 2009. Surveillance methods included annual surveys, follow-up phone calls, media reports, and use queries upon order of replacement pads. AED owners reporting emergency use of the device were contacted for an in-depth interview, and the ECG and event data in the device's internal memory were evaluated. RESULTS: 25 cases were identified in which an AED was used on a patient in SCA. Two uses were on children. The SCA was witnessed in 76% (19/25) of the cases. In 56% (14/25), the patient presented in VF and at least one shock was delivered. All 14 patients who were shocked had termination of VF; 6 (43%) required more than one shock due to refibrillation. Shock efficacy was 100% (25/25) for termination of VF for all delivered shocks. Of the patients with a witnessed arrest who were shocked, 67% (8/12) survived to hospital discharge. There were no circumstances of unsafe emergency use of the AED or harm to the patient, responder, or bystanders. CONCLUSIONS: People who purchase an AED for their home, even without previous AED experience, are able to use the device successfully in both adults and children. The high survival rate observed in this study demonstrates that lay responders with privately owned AEDs can successfully and safely use the devices. PMID- 23041534 TI - A human factors approach to observation chart design can trump health professionals' prior chart experience. AB - AIM: To determine whether experienced health professionals recognise patient deterioration more accurately and efficiently using (a) novel observation charts, designed from a human factors perspective, or (b) chart designs with which they have long-term experience. METHODS: Participants were 101 health professionals experienced in using either a multiple parameter track-and-trigger chart or a graphical chart with no track-and-trigger system. Participants were presented with realistic abnormal and normal patient observations recorded on six hospital observation charts of varying design quality, including the chart that participants were familiar with (or a very similar design). Across 48 trials, the participant was asked to specify if any of the vital sign observations were abnormal, or if all of the observations were normal. Participants' overall error rates (i.e., proportion of incorrect responses) and response times, the main outcome measures, were calculated for each observation chart. RESULTS: Participants made significantly fewer errors and responded significantly faster when using a novel user-friendly chart compared with all the other designs, including the charts that they were experienced with in a clinical setting. CONCLUSIONS: The findings suggest that, at least in the contexts examined, superior observation chart design appears to trump familiarity. Hence, hospitals motivated to improve the detection of patient deterioration should implement charts designed from a human factors perspective, rather than simply maintaining the status quo of reliance on clinical experience. PMID- 23041535 TI - An analysis of the introduction and efficacy of a novel training programme for ERC basic life support assessors. AB - AIM: Existing ERC BLS/AED accreditation procedures allow BLS instructors to assess the capability of BLS/AED providers, without undergoing additional training as an assessor. The reliability of instructor-based assessment has been questioned. This study sought to determine the efficacy of a simple training programme for BLS/AED instructors aimed at standardising assessment decisions. METHODS: An Assessment Training Programme (ATP) which provides additional, assessment-focused tuition for BLS instructors was introduced. Eighteen ERC accredited instructors participated in the study. Nine received standard ERC training (instructors); nine received additional training through the ATP (assessors). The assessment of 73 students' BLS/AED capabilities was carried out by an assessor, ERC instructor and ERC instructor trainer concurrently. Participants independently completed an ERC assessment form. Decisions for instructors and assessors were compared to the instructor trainers' decisions; those not agreeing were deemed to be incorrect. RESULTS: Instructors (49.3%) had lower raw pass rates than assessors (67.1%) and instructor trainers (64.4%). There was a significant difference in overall decisions between instructors and instructor trainers (p=0.035), and instructors and assessors (p=0.015). There was no difference between assessors and instructor trainers (p=0.824). Instructors were more prone to incorrectly failing candidates than assessors (sensitivities of 80.5% and 63.8% respectively, p=0.077). AED-capability decisions were significantly different from instructor trainers in both the instructor (p=0.007) and assessor groups (p=0.031). CONCLUSION: BLS instructors incorrectly fail candidates for reasons that should not normally constitute a true assessment failure. The ATP is an effective intervention to reduce false-failure rates and improve compliance with an experienced instructor trainer's decision. Consideration should be made to integrate such programmes into current BLS instructor accreditation procedures. PMID- 23041536 TI - Fascism and pacemakers. PMID- 23041537 TI - Neuroprotection mediated by the EP4 receptor avoids the detrimental side effects of COX-2 inhibitors following ischaemic injury. AB - Although COX-2 inhibition in animal models of ischaemia has shown neuroprotection, clinical trials revealed long term side effects with COX-2 inhibitors. A more focussed approach is necessary to retain the therapeutic effects of prostaglandins. This study investigated the role of the PGE(2) EP(4) receptor using both in vitro and in vivo models of ischaemia. To demonstrate whether targeting the EP(4) receptor is as neuroprotective as COX-2 inhibition, simultaneous experiments were carried out using a selective COX-2 inhibitor. Organotypic hippocampal sliced cultures, exposed to 2 h of oxygen glucose deprivation, were treated with; DMSO only, COX-2 inhibitor (NS-398), EP(4) agonist (L-902688) or EP(4) antagonist (GW627368X) and cell death was assessed. The EP(4) agonist and the COX-2 inhibitor significantly reduced cell death following in vitro ischaemia, whereas treatment with the EP(4) antagonist significantly increased cell death in hippocampal cultures. Following a 1 h occlusion of middle cerebral artery, mice were treated with the COX-2 inhibitor (10 mg kg, I.P), EP(4) agonist (0.75 MUg/kg, I.P) or vehicle (I.P), at the onset of reperfusion and again at 24 h post stroke. The COX-2 inhibitor and EP(4) agonist treated animals showed a significant reduction in infarct volume (P < .05) at 48 h post stroke compared to the vehicle treated group. These results show that selective activation of the EP(4) receptor following acute ischaemic damage is neuroprotective, and support the concept of targeting protective prostaglandin receptor signalling as a potential therapeutic target for cerebral stroke. PMID- 23041538 TI - Ischemia-induced synaptic plasticity drives sustained expression of calcium permeable AMPA receptors in the hippocampus. AB - Long lasting enhancement of synaptic transmission can be triggered by brief bursts of afferent stimulation, underlying long-term potentiation (LTP), and also by brief ischemia in a process known as i-LTP. The extent to which LTP and i-LTP rely on comparable cellular mechanisms remains unclear. Under physiological conditions, LTP induction drives transient expression of calcium-permeable AMPARs (CP-AMPARs) at synapses, whose ability to undergo plasticity is primed by endogenous activation of adenosine A(2A) receptors (A(2A)Rs). The present work thus addressed the contribution of CP-AMPARs and A(2A)Rs to i-LTP, which was induced in rat hippocampal slices by brief (10 min) oxygen/glucose deprivation (OGD). The amplitude of afferent-evoked excitatory postsynaptic currents (EPSCs) recorded from CA1 pyramidal neurons was decreased during OGD but gradually recovered toward values significantly above (157 +/- 17%) the baseline (100%) 40 50 min after re-oxygenation. This i-LTP was precluded by CP-AMPAR blockade (internal spermine (500 MUM) or extracellular NASPM (20 MUM) application) as well as by A(2A)R blockade with a selective antagonist (SCH 58261, 100 nM). OGD prompted sustained (>70 min) facilitation of mEPSC amplitude and frequency, and decreased mEPSC decay time, all of which were prevented by SCH 58261 (100 nM). The ability of NASPM (20 MUM) to acutely inhibit EPSCs 1 h after OGD, but not in control conditions nor in OGD-challenged slices when in the presence of SCH 58261 (100 nM), further supports sustained CP-AMPAR recruitment by i-LTP in an A(2A)R dependent way. We propose that although i-LTP may initially mimic LTP, failure of auto-regulated CP-AMPAR removal from synapses could constitute an early divergent event between these forms of plasticity. PMID- 23041539 TI - Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) has been implicated as a cause of hepatocellular carcinoma (HCC). We performed a systematic review of epidemiology studies to confirm the association between these disorders. METHODS: We searched PubMed for original reports published from January 1992 to December 2011 that evaluated the association between NAFLD, nonalcoholic steatohepatitis (NASH), cryptogenic cirrhosis presumed to be NASH-related, and the risk of HCC. Studies were categorized as offering potential direct evidence (eg, cohort studies) or indirect evidence (eg, case-control, cross-sectional, or case-series studies) for an association. We analyzed data from a total of 17 cohort studies (3 population based, 9 clinic based [6 limited to patients with cirrhosis], and 5 natural history), 18 case-control and cross-sectional studies, and 26 case series. RESULTS: NAFLD or NASH cohorts with few or no cases of cirrhosis cases had a minimal risk for HCC (cumulative HCC mortality of 0%-3% for study periods up to 20 y). Cohorts with NASH and cirrhosis had a consistently higher risk (cumulative incidence ranging from 2.4% over 7 y to 12.8% over 3 y). However, the risk for HCC was substantially lower in these cohorts than for cohorts with hepatitis C-related cirrhosis. Factors that increased risk among cohorts with NASH and cirrhosis could not be determined, because most studies were not sufficiently powered for multivariate analysis. CONCLUSIONS: This systematic review shows that despite several limitations, there is epidemiologic evidence to support an association between NAFLD or NASH and an increased risk of HCC; risk seems to be limited to individuals with cirrhosis. PMID- 23041540 TI - Population genetic structure of Schistosoma mansoni and Schistosoma haematobium from across six sub-Saharan African countries: implications for epidemiology, evolution and control. AB - We conducted the first meta-analysis of ten Schistosoma haematobium (one published and nine unpublished) and eight Schistosoma mansoni (two published and six unpublished) microsatellite datasets collected from individual schistosome infected school-children across six sub-Saharan Africa countries. High levels of genetic diversity were documented in both S. haematobium and S. mansoni. In S. haematobium populations, allelic richness did not differ significantly between the ten schools, despite widely varying prevalences and intensities of infection, but higher levels of heterozygote deficiency were seen in East than in West Africa. In contrast, S. mansoni populations were more diverse in East than West African schools, but heterozygosity levels did not vary significantly with geography. Genetic structure in both S. haematobium and S. mansoni populations was documented, at both a regional and continental scale. Such structuring might be expected to slow the spread to new areas of anti-schistosomal drug resistance should it develop. There was, however, limited evidence of genetic structure at the individual host level, which might be predicted to promote the development or establishment of drug resistance, particularly if it were a recessive trait. Our results are discussed in terms of their potential implications for the epidemiology and evolution of schistosomes as well as their subsequent control across sub-Saharan Africa. PMID- 23041541 TI - Genetic deletion of HRP2 and HRP3 in Indian Plasmodium falciparum population and false negative malaria rapid diagnostic test. AB - Genetic polymorphisms in diagnostic antigens are important factors responsible for variable performance of rapid diagnostic tests. Additionally, the failure of antigen expression due to gene deletion may also contribute to variable performance. We report Indian Plasmodium falciparum field isolates lacking both Pfhrp2 and Pfhrp3 genes leading to false negative results of rapid diagnostic tests. The study highlights need to determine the prevalence of P. falciparum isolates lacking these genes in larger field populations in India. PMID- 23041542 TI - Anti-inflammatory activity of novel ammonium glycyrrhizinate/niosomes delivery system: human and murine models. AB - Today there is a very great deal of interest among members of the global natural products community in investigating new plant constituents. Recent studies demonstrate that liquorice extracts are useful in the treatment of dermatitis, eczema, and psoriasis, with an efficacy comparable to that of corticosteroids. In this work, niosomes made up of surfactants (Tween 85 and Span 20) and cholesterol at various concentrations were prepared to investigate the potential application of niosomes for the delivery of ammonium glycyrrhizinate (AG), useful for the treatment of various inflammatory based diseases. Vesicles were characterized evaluating dimensions, zeta potential, anisotropy, drug entrapment efficiency, stability, cytotoxicity evaluation and skin tolerability. Release profiles of ammonium glycyrrhizinate/niosomes were evaluated in vitro using cellulose membranes. The best formulation was used to evaluate the in vitro/in vivo efficacy of the ammonium glycyrrhizinate/niosomes in murine and human models of inflammation. The AG-loaded non-ionic surfactant vesicles showed no toxicity, good skin tolerability and were able to improve the drug anti-inflammatory activity in mice. Furthermore, an improvement of the anti-inflammatory activity of the niosome delivered drug was observed on chemically induced skin erythema in humans. PMID- 23041543 TI - A novel chimeric cell-penetrating peptide with membrane-disruptive properties for efficient endosomal escape. AB - Efficient endocytosis into a wide range of target cells and low toxicity make the arginine-rich Tat peptide (Tat(11): YGRKKRRQRRR, residues 47-57 of HIV-1 Tat protein) an excellent transporter for delivery purposes. Unfortunately, molecules taken up by endocytosis undergo endosomal entrapment and possible metabolic degradation. Escape from the endosome is therefore actively researched. In this context, antimicrobial peptides (AMPs) provide viable templates for the design of new membrane-disruptive motifs. In particular the Cecropin-A and Melittin hybrids (CMs) are among the smallest and most effective peptides with membrane-perturbing abilities. Here we present a novel chimeric peptide in which the Tat(11) motif is fused to the CM(18) hybrid (KWKLFKKIGAVLKVLTTG, residues 1-7 of Cecropin-A and 2 12 of Melittin). When administered to cells, CM(18)-Tat(11) combines the two desired functionalities: efficient uptake and destabilization of endocytotic vesicle membranes. We show that this chimeric peptide effectively increases cargo molecule cytoplasm availability and allows the subsequent intracellular localization of diverse membrane-impermeable molecules (i.e. Tat(11)-EGFP fusion protein, calcein, dextrans, and plasmidic DNA) with no detectable cytotoxicity. The present results open the way to the rational engineering of "modular" cell penetrating peptides (CPPs) that combine (i) efficient translocation from the extracellular milieu into vesicles and (ii) efficient release of molecules from vesicles into the cytoplasm. PMID- 23041544 TI - Sorafenib-mediated targeting of the AAA+ ATPase p97/VCP leads to disruption of the secretory pathway, endoplasmic reticulum stress, and hepatocellular cancer cell death. AB - The molecular mechanisms and cellular targets of sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma (HCC), remain to be fully characterized. Recent studies have shown that sorafenib induces tumor cell death through the activation of endoplasmic reticulum stress signaling and/or autophagy in various cellular models. Using liver cancer-derived cell lines, we specifically show that the IRE1 and phosphorylated extracellular signal-regulated kinase arms of the unfolded protein response (UPR) become activated upon sorafenib treatment, whereas the ATF6 arm is inhibited. Our results also reveal that sorafenib treatment causes disruption to the secretory pathway, as witnessed by the fragmentation of the Golgi apparatus and the induction of autophagy. On the basis of these observations, we tested the relevance of the AAA+ ATPase p97/VCP as a potential functional target of sorafenib. Our results show that p97/VCP tyrosine phosphorylation is prevented upon sorafenib treatment, and that this can be correlated with enhanced membrane association. Moreover, we show that DBeQ, a recently discovered inhibitor of p97/VCP, enhances sorafenib-mediated toxicity in cultured cells. Our data show a novel mechanism for sorafenib mediated cell death in HCC, which depends on the integrity of the secretory pathway; and we identify p97/VCP phosphorylation as a potential target for improved sorafenib treatment efficacy in patients. PMID- 23041545 TI - Regression of human prostate cancer xenografts in mice by AMG 212/BAY2010112, a novel PSMA/CD3-Bispecific BiTE antibody cross-reactive with non-human primate antigens. AB - For treatment of patients with prostate cancer (PCa), we developed a novel T cell engaging (BiTE) antibody designated AMG 212 or BAY2010112 that is bispecific for prostate-specific membrane antigen (PSMA) and the CD3 epsilon subunit of the T cell receptor complex. AMG 212/BAY2010112 induced target cell-dependent activation and cytokine release of T cells, and efficiently redirected T cells for lysis of target cells. In addition to Chinese hamster ovary cells stably expressing human or cynomolgus monkey PSMA, T cells redirected by AMG 212/BAY2010112 also lysed human PCa cell lines VCaP, 22Rv1, MDA PCa 2b, C4-2, PC 3-huPSMA, and LnCaP at half maximal BiTE concentrations between 0.1 and 4 ng/mL (1.8-72 pmol/L). No lysis of PSMA-negative human PCa cell lines PC-3 and DU145 was observed. The subcutaneous (s.c.) formation of tumors from PC-3-huPSMA cells in NOD/SCID mice was significantly prevented by once daily intravenous (i.v.) injection of AMG 212/BAY2010112 at a dose level as low as 0.005 mg/kg/d. Rapid tumor shrinkage with complete remissions were observed in NOD/SCID mice bearing established s.c. 22Rv1 xenografts after repeated daily treatment with AMG 212/BAY2010112 by either the i.v. or s.c. route. Of note, 22Rv1 tumors were grown in the absence of human T cells followed by intraperitoneal injection of T cells 3 days before BiTE treatment. No effects on tumor growth were observed in the absence of human T cells or AMG 212/BAY2010112. On the basis of these preclinical results, AMG 212/BAY2010112 appears as a promising new BiTE antibody for the treatment of patients with PSMA-expressing PCa. PMID- 23041547 TI - Augmentation of therapeutic responses in melanoma by inhibition of IRAK-1,-4. AB - Toll-like receptors (TLR) are expressed by a variety of cancers, including melanoma, but their functional contributions in cancer cells are uncertain. To approach this question, we evaluated the effects of stimulating or inhibiting the TLR/IL-1 receptor-associated kinases IRAK-1 and IRAK-4 in melanoma cells where their functions are largely unexplored. TLRs and TLR-related proteins were variably expressed in melanoma cell lines, with 42% expressing activated phospho IRAK-1 constitutively and 85% expressing high levels of phospho-IRAK-4 in the absence of TLR stimulation. Immunohistochemical evaluation of melanoma tumor biopsies (n = 242) revealed two distinct patient populations, one that expressed p-IRAK-4 levels similar to normal skin (55%) and one with significantly higher levels than normal skin (45%). Levels of p-IRAK-4 levels did not correlate with clinical stage, gender, or age, but attenuated IRAK-1,-4 signaling with pharmacologic inhibitors or siRNA-enhanced cell death in vitro in combination with vinblastine. Moreover, in a xenograft mouse model of melanoma, the combined pharmacologic treatment delayed tumor growth and prolonged survival compared with subjects receiving single agent therapy. We propose p-IRAK-4 as a novel inflammation and prosurvival marker in melanoma with the potential to serve as a therapeutic target to enhance chemotherapeutic responses. PMID- 23041548 TI - Carbon source and myc expression influence the antiproliferative actions of metformin. AB - Epidemiologic and experimental data have led to increased interest in possible roles of biguanides in cancer prevention and/or treatment. Prior studies suggest that the primary action of metformin is inhibition of oxidative phosphorylation, resulting in reduced mitochondrial ATP production and activation of AMPK. In vitro, this may lead to AMPK-dependent growth inhibition if AMPK and its effector pathways are intact or to an energetic crisis if these are defective. We now show that the effect of exposure of several transformed cell lines to metformin varies with carbon source: in the presence of glutamine and absence of glucose, a 75% decrease in cellular ATP and an 80% decrease in cell number is typical; in contrast, when glucose is present, metformin exposure leads to increased glycolysis, with only a modest reduction in ATP level and cell number. Overexpression of myc was associated with sensitization to the antiproliferative effects of metformin, consistent with myc involvement in "glutamine addiction". Our results reveal previously unrecognized factors that influence metformin sensitivity and suggest that metformin-induced increase in glycolysis attenuates the antiproliferative effects of the compound. PMID- 23041546 TI - Control of SIV infection and subsequent induction of pandemic H1N1 immunity in rhesus macaques using an Ad5 [E1-, E2b-] vector platform. AB - Anti-vector immunity mitigates immune responses induced by recombinant adenovirus vector vaccines, limiting their prime-boost capabilities. We have developed a novel gene delivery and expression platform (Ad5 [E1-, E2b-]) that induces immune responses despite pre-existing and/or developed concomitant Ad5 immunity. In the present study, we evaluated if this new Ad5 platform could overcome the adverse condition of pre-existing Ad5 immunity to induce effective immune responses in prime-boost immunization regimens against two different infectious diseases in the same animal. Ad5 immune rhesus macaques (RM) were immunized multiple times with the Ad5 [E1-, E2b-] platform expressing antigens from simian immunodeficiency virus (SIV). Immunized RM developed cell-mediated immunity against SIV antigens Gag, Pol, Nef and Env as well as antibody against Env. Vaccinated and vector control RMs were challenged intra-rectally with homologous SIVmac239. During a 7-week follow-up, there was perturbation of SIV load in some immunized RM. At 7 weeks post-challenge, eight immunized animals (53%) did not have detectable SIV, compared to two RM controls (13%) (P<0.02; log-rank Mantel Cox test). There was no correlation of protective MHC contributing to infection control. The RM without detectable circulating SIV, now hyper immune to Ad5, were then vaccinated with the same Ad5 [E1-, E2b-] platform expressing H1N1 influenza hemagglutinin (HA). Thirty days post Ad5 [E1-, E2b-]-HA vaccination, significant levels of influenza neutralizing antibody were induced in all animals that increased after an Ad5 [E1-, E2b-]-HA homologous boost. These data demonstrate the versatility of this new vector platform to immunize against two separate disease targets in the same animal despite the presence of immunity against the delivery platform, permitting homologous repeat immunizations with an Ad5 gene delivery platform. PMID- 23041549 TI - Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment. AB - Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates protection against a wide variety of toxic insults to cells, including cytotoxic cancer chemotherapeutic drugs. Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance. In this study, we sought to examine whether this attribute could be exploited in cancer suicide gene therapy by using a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under the regulation of antioxidant response element (ARE), a cis-acting enhancer sequence that binds Nrf2. In human lung adenocarcinoma cells in which Nrf2 is constitutively overexpressed, ARE activity was found to be high under basal conditions. In this setting, ARE-HSV-TK was more effective than a vector in which HSV-TK expression was driven by a constitutively active promoter. In a mouse xenograft model of lung cancer, suicide gene therapy with LV-ARE-TK/GCV was effective compared with LV-PGK-TK/GCV in reducing tumor size. We conclude that ARE-regulated HSV-TK/GCV therapy offers a promising approach for suicide cancer gene therapy in cells with high constitutive ARE activity, permitting a greater degree of therapeutic targeting to those cells. PMID- 23041551 TI - Calibration of EuroSCORE II. PMID- 23041550 TI - Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium. AB - Overexpression of cyclin D1 is believed to endow mammary epithelial cells (MEC) with a proliferative advantage by virtue of its contribution to pRB inactivation. Accordingly, abrogation of the kinase-dependent function of cyclin D1 is sufficient to render mice resistant to breast cancer initiated by ErbB2. Here, we report that mouse cyclin D1(KE/KE) MECs (deficient in cyclin D1 activity) upregulate an autophagy-like process but fail to implement ErbB2-induced senescence in vivo. In addition, immortalized cyclin D1(KE/KE) MECs retain high rates of autophagy and reduced ErbB2-mediated transformation in vitro. However, highlighting its dual role during tumorigenesis, downregulation of autophagy led to an increase in senescence in cyclin D1(KE/KE) MECs. Autophagy upregulation was also confirmed in human mammary epithelial cells (HMEC) subjected to genetic and pharmacologic inhibition of cyclin D1 activity and, similar to our murine system, simultaneous inhibition of Cdk4/6 and autophagy in HMECs enhanced the senescence response. Collectively, our findings suggest a previously unrecognized function of cyclin D1 in suppressing autophagy in the mammary epithelium. PMID- 23041552 TI - What to do with functional mitral regurgitation: what do we really know and how can we find out? PMID- 23041553 TI - Genetic association of adiponectin with type 2 diabetes in Jordanian Arab population. AB - Adiponectin, a protein exclusively secreted by adipose tissue and present at low levels in obese individuals, is now widely recognized as a key determinant of insulin sensitivity and protection against obesity-associated metabolic syndrome. In Jordan, prevalence of diabetes (17.1%) is twice that of the United States (7.8%). In this study, we examined the contribution of the promoter variant rs266729 (-11377C>G) of the ADIPOQ gene as a risk factor for diabetic patients in Jordan. DNA was extracted from blood samples for patients and controls .Polymerase chain reaction and restriction fragment length polymorphism were used to genotype this variant. A total of 420 type 2 diabetic patients and 230 controls were successfully genotyped. The results showed a significant genotypic (p=0.00001) and allelic (p=0.01) association with variant in the diabetic patients as compared to controls. This suggests that the ADIPOQ gene plays a major role in increasing the risk of diabetes, at least in the Jordanian Arab population. PMID- 23041554 TI - Lack of an association of programmed cell death-1 PD1.3 polymorphism with risk of hepatocellular carcinoma susceptibility in Turkish population: a case-control study. AB - AIM: The programmed cell death-1 (PD-1) is a potent immunoregulatory molecule which is responsible for the negative regulation of T-cell activation and peripheral tolerance. Recently, overexpression of PD-1 has been reported to contribute to immune system evasion and poor survival of hepatocellular carcinoma (HCC). A common single nucleotide polymorphism in intron 4 of PD-1 gene called PD 1.3 has been reported to influence PD-1 expression, but its association with HCC has yet to be investigated. The aim of the present study was to investigate whether this polymorphism could be involved in the risk of HCC susceptibility. METHODS: The genotype frequency of PD-1.3 polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 236 subjects with HCC and 236 cancer-free control subjects matched on age, gender, smoking and alcohol status. RESULTS: No statistically significant differences were found in the genotype distributions of the PD-1.3 polymorphism among HCC and cancer-free control subjects (P=0.22). CONCLUSION: Our results demonstrate for the first time that the PD-1.3 polymorphism has not been in any major role in genetic susceptibility to hepatocellular carcinogenesis, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins. PMID- 23041555 TI - Insulin-like factor binding protein-3 promotes the G1 cell cycle arrest in several cancer cell lines. AB - Insulin-like growth factor binding protein-3 (IGFBP-3) is a multi-functional protein known to induce apoptosis of various cancer cells in an insulin-like growth factor (IGF)-dependent and IGF-independent manner. In our previous study, we found that IGFBP-3 induced apoptosis through the activation of caspases in 786 O cells. In this study, we further examined that whether IGFBP-3 induced apoptosis through the induction of cell cycle arrest in 786-O, A549 and MCF-7 cells. Our results showed that overexpressed IGFBP-3 resulted in typical apoptotic ultrastructures in A549 cells under transmission electron microscope. The result of flow cytometry analysis indicated that IGFBP-3 arrested the cell cycle at G1-S phase in 786-O, A549 and MCF-7 cells. In A549 cells, quantitative real-time PCR and Western blot analysis showed a significant change in the expression of cell cycle-regulated proteins-a decrease in cyclin E1 expression, an increase in p21 expression. These results indicate a possible mechanism for G1 cell cycle arrest by IGFBP-3. Taken together, cyclin E1 and p21 may play important roles in the IGFBP-3-inducing G1 cell cycle arrest and apoptosis in several human cancer cells. PMID- 23041557 TI - The complete mitochondrial genome of Arctic Calanus hyperboreus (Copepoda, Calanoida) reveals characteristic patterns in calanoid mitochondrial genome. AB - Copepoda is the most diverse and abundant group of crustaceans, but its phylogenetic relationships are ambiguous. Mitochondrial (mt) genomes are useful for studying evolutionary history, but only six complete Copepoda mt genomes have been made available and these have extremely rearranged genome structures. This study determined the mt genome of Calanus hyperboreus, making it the first reported Arctic copepod mt genome and the first complete mt genome of a calanoid copepod. The mt genome of C. hyperboreus is 17,910 bp in length and it contains the entire set of 37 mt genes, including 13 protein-coding genes, 2 rRNAs, and 22 tRNAs. It has a very unusual gene structure, including the longest control region reported for a crustacean, a large tRNA gene cluster, and reversed GC skews in 11 out of 13 protein-coding genes (84.6%). Despite the unusual features, comparing this genome to published copepod genomes revealed retained pan-crustacean features, as well as a conserved calanoid-specific pattern. Our data provide a foundation for exploring the calanoid pattern and the mechanisms of mt gene rearrangement in the evolutionary history of the copepod mt genome. PMID- 23041556 TI - The effect of chemokine receptor gene polymorphisms (CCR2V64I, CCR5-59029G>A and CCR5Delta32) on renal allograft survival in Pakistani transplant patients. AB - BACKGROUND: Gene polymorphisms of the chemokine receptors CCR2 and CCR5 (CCR2V64I, CCR5-59029G>A and CCR5Delta32) have been shown to be associated with renal allograft rejection. The aim of this study was to investigate the association of these polymorphisms with allograft rejection among Pakistani transplant patients. METHOD: A total of 606 renal transplant patients and an equal number of their donors were included in this study. DNA samples were used to amplify polymorphic regions of CCR2V64I, CCR5-59029G>A and CCR5Delta32 by polymerase chain reaction using sequence specific primers. The amplified products of CCRV64I and CCR5-59029G>A were digested with restriction enzymes (BsaB1 and Bsp12861) respectively. The CCR5Delta32 genotypes were determined by sizing the PCR amplicons. The association of these polymorphisms with the biopsy proven rejection and other clinical parameters was evaluated using the statistical software SPSS v.17. RESULTS: In this study, the G/G genotype of CCR2V64I was associated with a high frequency of allograft rejection (p=0.009; OR=2.14; 95% CI=1.2-3.7). Rejection episode(s) in the GA+AA genotypes were found to be significantly lower as compared to the GG genotype (p=0.009; OR=0.4; 95% CI=0.2 0.8). The Kaplan-Meier curve also indicated a reduced overall allograft survival for patients with the G/G genotype of CCR2V64I (59.2 +/- 1.4 weeks, log p=0.008). There was a significant association with rejection by female donors possessing the CCR2 GG genotype (p=0.02; OR=2.6; CI=1.1-6.3) and male donors with the CCR5 59029 GG genotype (p=0.004; OR=1.7; CI=1.03-3.01). CONCLUSION: This study shows an association of the CCR2V64I (G/G) genotype with renal allograft rejection. However, no such association was found for the CCR5 gene polymorphisms. Therapeutic interventions such as blocking the CCR2 receptor (especially G polymorphism) may yield better survival of renal allograft in this patient group. Further, chemokine receptors may be added to the spectrum of the immunogenetic factors that are known to be associated with renal allograft rejection. PMID- 23041558 TI - Functional analysis of HapMap SNPs. AB - Genome-wide association studies (GWAS) have successfully identified many genetic variants associated with complex diseases and traits. However, functional consequence of genetic variants studied in GWAS is not yet fully investigated, which would hinder the application of GWAS. We therefore performed a systematic functional analysis of HapMap SNPs, which have been most commonly used as the reference panel for GWAS. Our study highlights several characteristics of HapMap SNPs and identifies subsets of genetic variants with interesting functional implication. The results show that HapMap SNPs have good coverage within RefSeq genes, especially within known disease-related genes. On the other hand, only a small percentage of SNPs are non-synonymous SNPs while many SNPs are actually located at gene deserts. Moreover, many functionally important variants are not yet still interrogated. A redesigned SNP reference panel with additional functionally important variants would be useful to identify disease-causal variants in the future genome-wide studies. PMID- 23041559 TI - Clostridium difficile in young farm animals and slaughter animals in Belgium. AB - Faecal carriage of Clostridium difficile in healthy animals has been reported recently, especially in piglets and calves. However there is limited data about carriage in animals just prior to slaughter in Europe. The main objective of this study was to determine the presence of C. difficile in pigs and cattle at the slaughterhouse. C. difficile was isolated in 6.9% of the cattle at the slaughterhouse. None of the pig slaughter samples were positive for C. difficile after an enrichment time of 72 h. For complementary data, a short study was conducted in piglets and calves at farms. C. difficile was more prevalent in piglets (78.3%) than in calves (22.2%) on the farms. Regarding the piglet samples, 27.8% of the positive samples were detected without enrichment of stools. The PCR ribotype 078 was predominant in farm animals. Samples isolated from slaughter cattle presented the widest range in PCR-ribotype variety, and the most prevalent PCR ribotype was 118a UCL. The results of this study confirm that C. difficile is present in slaughter animals in Belgium with a large percentage of toxigenic strains also commonly found in humans. PMID- 23041560 TI - Processing statistics: an examination of focused and distributed attention using event related potentials. AB - Human observers show remarkable efficiency in statistical estimation; they are able, for instance, to estimate the mean size of visual objects, even if their number exceeds the capacity limits of focused attention. This ability has been understood as the result of a distinct mode of attention, i.e. distributed attention. Compared to the focused attention mode, working memory representations under distributed attention are proposed to be more compressed, leading to reduced working memory loads. An alternate proposal is that distributed attention uses less structured, feature-level representations. These would fill up working memory (WM) more, even when target set size is low. Using event-related potentials, we compared WM loading in a typical distributed attention task (mean size estimation) to that in a corresponding focused attention task (object recognition), using a measure called contralateral delay activity (CDA). Participants performed both tasks on 2, 4, or 8 different-sized target disks. In the recognition task, CDA amplitude increased with set size; notably, however, in the mean estimation task the CDA amplitude was high regardless of set size. In particular for set-size 2, the amplitude was higher in the mean estimation task than in the recognition task. The result showed that the task involves full WM loading even with a low target set size. This suggests that in the distributed attention mode, representations are not compressed, but rather less structured than under focused attention conditions. PMID- 23041561 TI - Chief nodal axes of a heterocentric astigmatic eye and the Thibos-Bradley achromatic axis. AB - Two kinds of axes are described as achromatic in the vision science literature: those of Le Grand and Ivanoff, originally proposed in the 1940s, and those of Thibos and Bradley proposed in the 1990s. Thibos-Bradley axes are based on chief nodal rays, that is, nodal rays that intersect the pupil at its center. By contrast Le Grand-Ivanoff achromatic axes are pupil independent. The purpose of this paper is to develop the linear optics of Thibos-Bradley achromatic axes and to examine the sense in which such axes can be said to be achromatic. Linear optics is used to define the chief nodal ray of an arbitrary optical system whose refracting elements may be heterocentric and astigmatic and with nonaligned principal meridians. The incident segment of the ray then defines what is called here the incident chief nodal axis and the emergent segment the emergent chief nodal axis. When applied to an eye they become the external and retinal chief nodal axes of the eye. The axes are infinite straight lines. Equations are derived, in terms of the properties of the eye, for the inclination and transverse positions of both axes at incidence onto the eye. An equation is also derived for the position of the retinal chief nodal axis at the retina. The locations of the axes are calculated for a particular model eye in Appendix A. The equations are specialized for the system consisting of an eye and a pinhole in front of it. For a reduced eye the external and retinal chief nodal axes coincide and are independent of the frequency of light; and, hence, the Thibos Bradley axes are strictly achromatic for that eye. However for more complicated eyes this is not usually the case; the external and retinal axes are usually distinct, dependent on frequency, and, hence, not strictly achromatic. It seems appropriate, therefore, to reserve the term achromatic axis for axes of the Le Grand-Ivanoff type and generalizations thereof, and to call Thibos-Bradley axes chief nodal axes. PMID- 23041562 TI - The slope of the psychometric function and non-stationarity of thresholds in spatiotemporal contrast vision. AB - The slope of the two-interval, forced-choice psychometric function (e.g. the Weibull parameter, beta) provides valuable information about the relationship between contrast sensitivity and signal strength. However, little is known about how or whether beta varies with stimulus parameters such as spatiotemporal frequency and stimulus size and shape. A second unresolved issue concerns the best way to estimate the slope of the psychometric function. For example, if an observer is non-stationary (e.g. their threshold drifts between experimental sessions), beta will be underestimated if curve fitting is performed after collapsing the data across experimental sessions. We measured psychometric functions for 2 experienced observers for 14 different spatiotemporal configurations of pulsed or flickering grating patches and bars on each of 8 days. We found beta~3 to be fairly constant across almost all conditions, consistent with a fixed nonlinear contrast transducer and/or a constant level of intrinsic stimulus uncertainty (e.g. a square law transducer and a low level of intrinsic uncertainty). Our analysis showed that estimating a single beta from results averaged over several experimental sessions was slightly more accurate than averaging multiple estimates from several experimental sessions. However, the small levels of non-stationarity (SD~0.8dB) meant that the difference between the estimates was, in practice, negligible. PMID- 23041563 TI - Evaluating the quality of interventions: improving pediatric nursing practice through research. PMID- 23041564 TI - Opportunities to create nurse-directed, evidence-based services and programs for children and youth with special health care needs and developmental disabilities. PMID- 23041565 TI - Hospital readmissions and repeat emergency department visits among children with medical complexity: an integrative review. AB - Children with medical complexity (CMC) have chronic conditions, intense healthcare needs, and high healthcare utilization. Proposed changes in the healthcare environment initiated by the Affordable Care Act have led to efforts toward preventing hospital readmissions. The purpose of this integrative review is to explore the current empirical literature and examine how hospital readmissions and repeat emergency department visits have been studied among CMC. A computer database search and ancestry search were conducted, resulting in a sample of 26 studies. The results of the integrative review are presented along with gaps in the literature and implications for nursing practice and research. PMID- 23041566 TI - SAP is required for the development of innate phenotype in H2-M3--restricted Cd8(+) T cells. AB - H2-M3--restricted T cells have a preactivated surface phenotype, rapidly expand, and produce cytokines upon stimulation, and, as such, are classified as innate T cells. Unlike most innate T cells, M3-restricted T cells also express CD8alphabeta coreceptors and a diverse TCR repertoire: hallmarks of conventional MHC Ia-restricted CD8(+) T cells. Although invariant NKT cells are also innate T cells, they are selected exclusively on hematopoietic cells (HC), whereas M3 restricted T cells can be selected on either hematopoietic or thymic epithelial cells. Moreover, their phenotypes differ depending on what cells mediate their selection. Although there is a clear correlation between selection on HC and development of innate phenotype, the underlying mechanism remains unclear. Signaling lymphocyte activation molecule-associated protein (SAP) is required for the development of invariant NKT cells and mediates signals from signaling lymphocyte activation molecule receptors that are exclusively expressed on HC. Based on their dual selection pathway, M3-restricted T cells present a unique model for studying the development of innate T cell phenotype. Using both polyclonal and transgenic mouse models, we demonstrate that although M3 restricted T cells are capable of developing in the absence of SAP, SAP is required for HC-mediated selection, development of preactivated phenotype, and heightened effector functions of M3-restricted T cells. These findings are significant because they directly demonstrate the need for SAP in HC-mediated acquisition of innate T cell phenotype and suggest that, due to their SAP dependent HC-mediated selection, M3-restricted T cells develop a preactivated phenotype and an intrinsic ability to proliferate faster upon stimulation, allowing for an important role in the early response to infection. PMID- 23041567 TI - Narrow groove and restricted anchors of MHC class I molecule BF2*0401 plus peptide transporter restriction can explain disease susceptibility of B4 chickens. AB - The MHC has genetic associations with many diseases, often due to differences in presentation of antigenic peptides by polymorphic MHC molecules to T lymphocytes of the immune system. In chickens, only a single classical class I molecule in each MHC haplotype is expressed well due to coevolution with the polymorphic TAPs which means that resistance and susceptibility to infectious pathogens are particularly easy to observe. Previously, structures of chicken MHC class I molecule BF2*2101 from B21 haplotype showed an unusually large peptide-binding groove that accommodates a broad spectrum of peptides to present as epitopes to CTLs, explaining the MHC-determined resistance of B21 chickens to Marek's disease. In this study, we report the crystal structure of BF2*0401 from the B4 (also known as B13) haplotype, showing a highly positively charged surface hitherto unobserved in other MHC molecules, as well as a remarkably narrow groove due to the allele-specific residues with bulky side chains. Together, these properties limit the number of epitope peptides that can bind this class I molecule. However, peptide-binding assays show that in vitro, BF2*0401 can bind a wider variety of peptides than are found on the surface of B4 cells. Thus, a combination of the specificities of the polymorphic TAP and the MHC results in a very limited set of BF2*0401 peptides with negatively charged anchors to be presented to T lymphocytes. PMID- 23041568 TI - Peroxisome proliferator-activated receptor gamma B cell-specific-deficient mice have an impaired antibody response. AB - Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARgamma, a ligand-activated transcription factor, has important anti-inflammatory and antiproliferative functions, and it has been associated with diseases including diabetes, scarring, and atherosclerosis, among others. PPARgamma is expressed in most bone marrow-derived cells and influences their function. PPARgamma ligands can stimulate human B cell differentiation and promote Ab production. A knowledge gap is that the role of PPARgamma in B cells under physiological conditions is not known. We developed a new B cell-specific PPARgamma (B-PPARgamma) knockout mouse and explored the role of PPARgamma during both the primary and secondary immune response. In this article, we show that PPARgamma deficiency in B cells decreases germinal center B cells and plasma cell development, as well as the levels of circulating Ag-specific Abs during a primary challenge. Inability to generate germinal center B cells and plasma cells is correlated to decreased MHC class II expression and decreased Bcl-6 and Blimp 1 levels. Furthermore, B-PPARgamma-deficient mice have an impaired memory response, characterized by low titers of Ag-specific Abs and low numbers of Ag experienced, Ab-secreting cells. However, B-PPARgamma-deficient mice have no differences in B cell population distribution within primary or secondary lymphoid organs during development. This is the first report, to our knowledge, to show that, under physiological conditions, PPARgamma expression in B cells is required for an efficient B cell-mediated immune response as it regulates B cell differentiation and Ab production. PMID- 23041569 TI - Degenerate recognition of MHC class I molecules with Bw4 and Bw6 motifs by a killer cell Ig-like receptor 3DL expressed by macaque NK cells. AB - The killer cell Ig-like receptors (KIRs) expressed on the surface of NK cells recognize specific MHC class I (MHC-I) molecules and regulate NK cell activities against pathogen-infected cells and neoplasia. In HIV infection, survival is linked to host KIR and MHC-I genotypes. In the SIV macaque model, however, the role of NK cells is unclear due to the lack of information on KIR-MHC interactions. In this study, we describe, to our knowledge, the first in-depth characterization of KIR-MHC interactions in pigtailed macaques (Macaca nemestrina). Initially, we identified three distinct subsets of macaque NK cells that stained ex vivo with macaque MHC-I tetramers loaded with SIV peptides. We then cloned cDNAs corresponding to 15 distinct KIR3D alleles. One of these, KIR049-4, was an inhibitory KIR3DL that bound MHC-I tetramers and prevented activation, degranulation, and cytokine production by macaque NK cells after engagement with specific MHC-I molecules on the surface of target cells. Furthermore, KIR049-4 recognized a broad range of MHC-I molecules carrying not only the Bw4 motif, but also Bw6 and non-Bw4/Bw6 motifs. This degenerate, yet peptide-dependent, MHC reactivity differs markedly from the fine specificity of human KIRs. PMID- 23041571 TI - Validation of a novel spiral mapping catheter for real-time recordings from the pulmonary veins during cryoballoon ablation of atrial fibrillation. AB - BACKGROUND: The Achieve mapping catheter allows real-time recordings from the pulmonary veins (PVs) during cryoballoon (CB) ablation of atrial fibrillation (AF). OBJECTIVE: To assess the clinical applicability of the Achieve mapping catheter and the value of real-time recordings from the PVs during CB. METHODS: Patients with paroxysmal AF undergoing CB ablation were studied. Recordings from the PVs were analyzed during (real-time recordings) and after CB ablation and validated by using a variable circumferential mapping catheter (Achieve group; n = 20). A comparison was made by using a group of patients in whom CB ablation with a guidewire and a variable circumferential mapping catheter was performed (Guidewire group; n = 20). RESULTS: Forty patients (age 58+/-11 years; ejection fraction 0.59+/-0.07; left atrial size 40+/-6 mm) with paroxysmal AF were included. In the Achieve group, real-time recordings from the PVs could be obtained in 40 of 80 (50%) PVs and could be seen more often at the left-sided PVs (25 of 39, 64%) than at the right-sided PVs (15 of 41, 37%; P = .02). Validation with a standard circumferential mapping catheter confirmed PV isolation in 75 of 80 (93%) PVs. After a single procedure and a follow-up of 14+/-4 months, 25 of 40 (63%) patients were in sinus rhythm with no significant difference between groups. CONCLUSIONS: The Achieve catheter can be used as a substitute for a guidewire during CB ablation, but real-time recordings can be obtained only in half of the PVs and are not sufficient to accurately confirm isolation of all PVs. PMID- 23041572 TI - Wide complex tachycardia with telltale termination: what is the mechanism? PMID- 23041570 TI - C5a receptor-dependent cell activation by physiological concentrations of desarginated C5a: insights from a novel label-free cellular assay. AB - The complement anaphylatoxins C3a, C5a, and desarginated C5a (C5a(desArg)) play critical roles in the induction of inflammation and the modulation of innate and acquired immune responses after binding to their G protein-coupled receptors, C3a receptor and C5a receptor (C5aR). The role of C5a(desArg) in inducing cell activation has been often neglected, because the affinity of C5a(desArg) for C5aR has been reported to be much lower than that of C5a. We have used a novel label free cellular assay to reassess the potential of C5a(desArg) to induce activation of transfected and primary immune cells. Our results indicate that physiological levels of C5a(desArg) induce significant levels of cell activation that are even higher than those achieved by stimulating cells with analogous concentrations of C5a. Such activation was strictly dependent on C5aR, because it was completely abrogated by PMX-53, a C5aR antagonist. Pharmacological inhibition of specific G proteins located downstream of C5aR indicated differential involvement of G(alpha) proteins upon C5aR engagement by C5a or C5a(desArg). Further, mass spectrometric characterization of plasma-derived C5a and C5a(desArg) provided important insight into the posttranslational modification pattern of these anaphylatoxins, which includes glycosylation at Asn(64) and partial cysteinylation at Cys(27). Although the context-specific physiological contribution of C5a(desArg) has to be further explored, our data suggest that C5a(desArg) acts as a key molecule in the triggering of local inflammation as well as the maintenance of blood surveillance and homeostatic status. PMID- 23041573 TI - Ventricular tachycardia/fibrillation early after defibrillator implantation in patients with hypertrophic cardiomyopathy is explained by a high-risk subgroup of patients. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) studies in patients with coronary artery disease report higher risk of ventricular tachycardia/fibrillation (VT/VF) early post-implant, potentially related to local proarrhythmic effects of ICD leads. OBJECTIVE: To characterize early and long term risk of ICD discharge for VT/VF in a large hypertrophic cardiomyopathy (HCM) cohort. METHODS: By using HCM multicenter registry data, we compared long-term risk of VT/VF subsequent to an early post-implant period (a priori defined as within 3 months of implant) between patients with or without VT/VF within 3 months after ICD implantation. RESULTS: Over a median follow-up of 4.3 years, 109 of 506 (22%) patients with HCM who received ICDs received at least 1 ICD discharge for VT/VF. Risk of first ICD discharge for VT/VF was highest in the first year post-implant (10.8% per person-year; 95% confidence interval 7.9-13.8) and particularly in the first 3 months (17.0% per person-year; 95% confidence interval 9.8-24.3). Patients with early VT/VF (<=3 months post-implant) were older, and more commonly had secondary prevention ICDs following cardiac arrest or systolic dysfunction (end-stage HCM with ejection fraction<50%). Only 2 of 247 (0.7%) patients with primary prevention ICDs and preserved systolic function had early VT/VF. Patients with VT/VF early post-implant (<=3 months) had more than 5 fold higher risk for future VT/VF during long-term follow-up compared with patients without early VT/VF (adjusted hazard ratio 5.4; 95% confidence interval 2.3-12.6). CONCLUSIONS: High-risk patients with HCM and VT/VF early after ICD implantation are particularly prone to subsequent VT/VF throughout follow-up. Early ICD interventions for VT/VF are largely confined to patients with prior cardiac arrest or systolic dysfunction and therefore more likely driven by higher arrhythmic risk rather than lead-related proarrhythmia. PMID- 23041574 TI - Overexpression of Kir2.1 channel in embryonic stem cell-derived cardiomyocytes attenuates posttransplantation proarrhythmic risk in myocardial infarction. AB - BACKGROUND: Cellular replacement strategies using embryonic stem cell-derived cardiomyocytes (ESC-CMs) have been shown to improve left ventricular (LV) ejection fraction and prevent LV remodeling post-myocardial infarction (MI). Nonetheless, the immature electrical phenotypes of ESC-CMs may increase the risk of ventricular tachyarrhythmias (VTs) and sudden death. OBJECTIVE: To investigate whether the forced expression of Kir2.1-encoded inward rectifying K(+) channels that are otherwise absent in ESC-CMs would attenuate their proarrhythmic risk after transplantation post-MI. METHODS: Mouse ESC line stably transduced with a lentivirus (LentV)-based doxycycline (DOX)-inducible system coexpressing the transgenes Kir2.1 and a dsRed (LentV-THM-Kir2.1-GFP/LentV-TR-KRAB-dsRed) was differentiated into ESC-CMs with (DOX(+)) or without (DOX(-)) treatment with DOX. Detailed in vitro and in vivo assessments of LV function and cardiac electrophysiology were measured 4 weeks after transplantation. RESULTS: ESC-CM DOX(+) with atrial and ventricular phenotype exhibited more hyperpolarizing resting membrane potential than did ESC-CM DOX(-) (P< .05). Transplantations of ESC-CM DOX(-) and ESC-CM DOX(+) both significantly improved LV ejection fraction, LV end-systolic diameter, end-systolic pressure-volume relationship, and positive maximal and negative pressure derivative (P< .05) at 4 weeks compared with the MI group; however, the DOX(-) group (22 of 40, 55%) had a significantly higher early sudden death rate than the DOX(+) group (13 of 40, 32.5%; P = .036). Telemetry monitoring revealed that the DOX(-) group (6.09%+/-3.65%) had significantly more episodes of spontaneous VT compared with the DOX(+) group (0.92%+/-0.81%; P< .05). In vivo programmed electrical stimulation at 2 weeks resulted in a significantly higher incidence of inducible VT in the DOX(-) group (9 of 16, 56.25%) compared with the DOX(+) group (3 of 16, 18.75%; P = .031). CONCLUSIONS: Forced expression of Kir2.1 in ESC-CMs improves their electrical phenotypes and lowers the risk of inducible and spontaneous VT after post-MI transplantation. PMID- 23041575 TI - Inhibition of Na+ channels ameliorates arrhythmias in a drug-induced model of Andersen-Tawil syndrome. AB - BACKGROUND: Andersen-Tawil syndrome (ATS1)-associated ventricular tachycardias (VTs) are initiated by frequent, hypokalemia-exacerbated, premature ventricular activity (PVA). We previously demonstrated that a guinea pig model of drug induced ATS1 (DI-ATS1) evidenced increased arrhythmias from regions with high Na(+)/Ca(2+)-exchange expression. OBJECTIVE: Therefore, we hypothesize that reduced cytosolic Na(+) entry through either cardiac isoform of or tetrodotoxin (TTX)-sensitive Na(+) channels during DI-ATS1 can ameliorate arrhythmia burden. METHODS: DI-ATS1 was induced with 10 MUM BaCl(2) and 2 mM extracellular K(+). Ca(2+) transients and conduction velocity (CV) were optically mapped with indo-1 and di-4-ANEPPS, respectively, from Langendorff-perfused guinea pig ventricles. RESULTS: Nonselective Na(+) channel blockade with 1 MUM flecainide reduced amplitude (Ca(A)), slowed left ventricular CV, reduced tissue excitability, and abolished the incidence of VT while decreasing the incidence of PVA relative to DI-ATS1. Selective, TTX-sensitive Na(+) channel blockade with TTX (100 nM) during DI-ATS1 decreased Ca(A) and decreased the inducibility of VTs and PVA relative to DI-ATS1 without slowing CV. Ranolazine altered Ca(A), left ventricular CV, tissue excitability, and reduced inducibility of VT and PVA in a concentration-dependent manner. None of the aforementioned interventions altered diastolic Ca(2+) levels or Ca(2+) transient decay time constant. CONCLUSIONS: These data suggest that cytosolic Na(+) entry and its modulation of Ca(2+) handling are necessary for arrhythmogenesis. During the loss of inward-rectifier K(+) current function, not only Na(+)/Ca(2+)-exchange dominance but Na(+) flux may determine arrhythmia burden. Therefore, selective inhibition of TTX-sensitive Na(+) channels may offer a potential therapeutic target to alleviate arrhythmias during states of Ca(2+) overload secondary to loss of inward-rectifier K(+) current function without compromising the excitability reserve. PMID- 23041577 TI - Mutation location matters in long QT syndrome type 2 (but behavior matters more). PMID- 23041576 TI - The ionic bases of the action potential in isolated mouse cardiac Purkinje cell. AB - BACKGROUND: Collecting electrophysiological and molecular data from the murine conduction system presents technical challenges. Thus, only little advantage has been taken of numerous genetically engineered murine models to study excitation through the cardiac conduction system of the mouse. OBJECTIVE: To develop an approach for isolating murine cardiac Purkinje cells (PCs), to characterize major ionic currents and to use the data to simulate action potentials (APs) recorded from PCs. METHODS: Light microscopy was used to isolate and identify PCs from apical and septal cells. Current and voltage clamp techniques were used to record APs and whole cell currents. We then simulated a PC AP on the basis of our experimental data. RESULTS: APs recorded from PCs were significantly longer than those recorded from ventricular cells. The prominent plateau phase of the PC AP was very negative (~-40 mV). Spontaneous activity was observed only in PCs. The inward rectifier current demonstrated no significant differences compared to ventricular myocytes (VMs). However, sodium current density was larger, and the voltage-gated potassium current density was significantly less in PCs compared with myocytes. T-type Ca(2+) currents (I(Ca,T)) were present in PCs but not VMs. Computer simulations suggest that I(Ca,T) and cytosolic calcium diffusion significantly modulate AP profile recorded in PCs, as compared to VMs. CONCLUSIONS: Our study provides the first comprehensive ionic profile of murine PCs. The data show unique features of PC ionic mechanisms that govern its excitation process. Experimental data and numerical modeling results suggest that a smaller voltage-gated potassium current and the presence of I(Ca,T) are important determinants of the longer and relatively negative plateau phase of the APs. PMID- 23041579 TI - Adenosine and sinus node dysfunction. PMID- 23041578 TI - Perioperative heart-type fatty acid binding protein levels in atrial fibrillation after cardiac surgery. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is common and associated with poor outcomes. Perioperative ischemia can alter arrhythmic substrate. OBJECTIVE: To demonstrate an association between perioperative measurements of heart-type fatty acid binding protein (HT-FABP), a sensitive marker of ischemic myocardial injury. METHODS: Blood samples from 63 inpatients undergoing coronary artery bypass surgery, valve surgery, or both were obtained before and up to 4 days after surgery. Continuous telemetry monitoring was used to detect POAF. Fifty-nine patients had at least 3 HT-FABP measurements. The relationship of enzyme-linked immunosorbent assay-measured HT-FABP with POAF was assessed by using joint logistic regression adjusted for age and surgery type. RESULTS: Thirty-five patients (55%) developed POAF; these were, on average, older (69.3+/ 10 years vs 60+/-11 years; P = .0019), with a higher prevalence of heart failure (43% vs 17%; P = .034), chronic obstructive lung disease (26% vs 4%; P = .017), preoperative calcium channel blocker use (29% vs 7%; P = .031), and more likely to undergo combined surgery (21% vs 11%, P = .049). The joint age- and coronary artery bypass surgery-adjusted model revealed that postoperative but not preoperative HT-FABP levels predicted POAF (coefficient 1.9+/-0.87; P = .03). Longer bypass time, prior infarction, and worse renal function were all associated with higher postoperative HT-FABP. CONCLUSIONS: A greater rise of HT FABP is associated with atrial fibrillation after cardiac surgery, suggesting that ischemic myocardial damage is a contributing underlying mechanism. Interventions that decrease perioperative ischemic injury may also decrease the occurrence of POAF. PMID- 23041580 TI - Identification of two-pore domain potassium channels as potent modulators of osmotic volume regulation in human T lymphocytes. AB - Many functions of T lymphocytes are closely related to cell volume homeostasis and regulation, which utilize a complex network of membrane channels for anions and cations. Among the various potassium channels, the voltage-gated K(V)1.3 is well known to contribute greatly to the osmoregulation and particularly to the potassium release during the regulatory volume decrease (RVD) of T cells faced with hypotonic environment. Here we address a putative role of the newly identified two-pore domain (K(2P)) channels in the RVD of human CD4(+) T lymphocytes, using a series of potent well known channel blockers. In the present study, the pharmacological profiles of RVD inhibition revealed K(2P)5.1 and K(2P)18.1 as the most important K(2P) channels involved in the RVD of both naive and stimulated T cells. The impact of chemical inhibition of K(2P)5.1 and K(2P)18.1 on the RVD was comparable to that of K(V)1.3. K(2P)9.1 also notably contributed to the RVD of T cells but the extent of this contribution and its dependence on the activation status could not be unambiguously resolved. In summary, our data provide first evidence that the RVD-related potassium efflux from human T lymphocytes relies on K(2P) channels. PMID- 23041581 TI - The role of the neuropeptide S system in addiction: focus on its interaction with the CRF and hypocretin/orexin neurotransmission. AB - Recent behavioral, pharmacological and molecular findings have linked the NPS system to drug dependence. Most of the evidence supports the possibility that increased NPS activity may contribute to shaping vulnerability to addiction, especially relapse. However, data suggesting that the anxiolytic-like properties of NPS may have protective effects on addiction have been also published. In addition, evidence from conditioned place preference experiments, though not unequivocal, suggests that NPS per se is devoid of motivational properties. Intriguingly, several effects of NPS on drugs of abuse appear to be mediated by downstream activation of brain corticotrophin releasing factor (CRF) and hypocretin-1/orexin-A (Hcrt-1/Ox-A) systems. The major objective of the present article is to review the existing work on NPS and addiction. Particular attention is devoted to the interpretation of findings revealing complex neuroanatomical and functional interactions between NPS, CRF, and the Hcrt-1/Ox-A systems. Original data aimed at shedding light on the role of NPS in reward processing are also shown. Finally, existing findings are discussed within the framework of addiction theories, and the potential of the NPS system as a treatment target for addiction is analyzed. PMID- 23041582 TI - Tips and tricks for successful manual morcellation: a response to "vaginal morcellation: a new strategy for large gynecological malignant tumors extraction. A pilot study". PMID- 23041583 TI - Angiogenesis in the course of enucleation-induced adrenal regeneration- expression of selected genes and proteins involved in development of capillaries. AB - Enucleation-induced rapid proliferation of adrenocortical cells and restoration of adrenals structure requires formation of new blood vessels. The performed studies aimed to select from around 30,000 transcripts, identified by means of Affymetrix((r)) Rat Gene 1.1 ST Array, the genes involved in angiogenesis in the course of enucleation-induced adrenal regeneration and to characterize their expression levels in regenerating gland between days 1 and 15 after surgery. At day 1 of regeneration almost 2000 genes showed more than 2-fold up/down regulation. At days 1-3 after surgery the highest expression demonstrated genes involved in the development of inflammation and blood clot formation. From around 2000 genes we selected genes involved in angiogenesis. During the regeneration 62 genes involved in angiogenesis were identified as up- or down-regulated. Some data were also validated by QPCR. Levels of Vegfa and Kdr (Vegfr-2) mRNAs were very low at day 1 of regeneration and remained unchanged thereafter. The highest expression of Figf gene was found at day 5 while that of Vwf gene at days 1 and 2 after surgery. Levels of Thy1 mRNA increased notably between days 2 and 5 of the experiment. In comparison to control rats, Mc2r (ACTH receptor) expression was lowered at day 1 of the experiment and remained unchanged thereafter. This suggests that enucleation-induced adrenal neoangiogenesis does not require elevated expression of ACTH receptor. Results of our studies strongly suggest that enucleation-induced adrenal regeneration is an angiogenesis-dependent process. Moreover, immunohistochemistry suggests that regenerating adrenal parenchymal cells release numerous angiogenic factors which paracrinally may regulate formation of new vessels. PMID- 23041584 TI - Meat consumption and cancer risk: is the definition of red meat always suitable? PMID- 23041585 TI - A multicenter, randomized trial of flat dosing versus intrapatient dose escalation of single-agent carboplatin as first-line chemotherapy for advanced ovarian cancer: an SGCTG (SCOTROC 4) and ANZGOG study on behalf of GCIG. AB - BACKGROUND: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing. PATIENTS AND METHODS: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS). RESULTS: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had >=1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value. CONCLUSIONS: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia. PMID- 23041586 TI - Psychological effect of exercise in women with breast cancer receiving adjuvant therapy: what is the optimal dose needed? AB - BACKGROUND: Several meta-analyses have examined the role of exercise interventions in improving psychological outcomes in cancer survivors but most did not focus on adjuvant therapy period and did not investigate the optimal dose of exercise needed. The present meta-analysis examines the impact of exercise interventions delivered at this particular period on fatigue, anxiety, depression, and quality of life (QoL) as well as dose-response relationships between volume of prescribed exercise and these psychological outcomes. MATERIALS AND METHODS: Randomized, controlled trials that proposed an exercise intervention to patients with breast cancer undergoing chemotherapy and/or radiotherapy were systematically identified and coded. Psychological outcomes effect sizes were calculated and analyzed for trends using linear and quadratic regressions. RESULTS: Pooled effects of the 17 included studies revealed improvement for all outcomes, significant for fatigue, depression, and QoL with pooled estimates ranging from 0.2 to 0.5 favoring intervention. Significant inverse associations of the volume of prescribed exercise with fatigue and QoL were observed. CONCLUSIONS: Exercise intervention improved fatigue, depression, and QoL in patients with breast cancer receiving adjuvant therapy. Prescription of relatively low doses of exercise (<12 MET h/week) consisting in ~90-120 min of weekly moderate physical exercise seems more efficacious in improving fatigue and QoL than higher doses. PMID- 23041587 TI - Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. AB - BACKGROUND: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION: Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib. PMID- 23041588 TI - Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study. AB - BACKGROUND: The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines irinotecan and bevacizumab). PATIENTS AND METHODS: KRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m2) every 2 weeks. RESULTS: Sixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation. CONCLUSION: Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers. ClinicalTrials.gov Identifier NCT00655499. PMID- 23041589 TI - Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. AB - BACKGROUND: Because follicular lymphoma (FL) patients have heterogeneous outcomes, the FL international prognostic index (FLIPI) was developed to risk stratify patients and to predict survival. However, limited data exist regarding the role of FLIPI in the era of routine first-line rituximab (R) and R chemotherapy regimens and in the setting of community oncology practices. PATIENTS AND METHODS: We evaluated the outcome data from the National LymphoCare Study (NLCS), a prospective, observational cohort study, which collects data on patients with FL in the United States (US) community practices. RESULTS: Among 1068 male and 1124 female patients with FLIPI data, most were treated in US community practices (79%); 35% were FLIPI good risk, 30% intermediate risk, and 35% poor risk. FLIPI risk groups were significant predictors of overall survival (OS) and progression-free survival (PFS) for patients who undergo watchful waiting (WW), and those who receive non-R-containing regimens, R-alone, and R chemotherapy combinations. CONCLUSIONS: In the setting of contemporary practice with routine R use, stratifying patients into good, intermediate, and poor FLIPI risk groups predicts distinct outcomes in terms of OS and PFS. FLIPI remains an important prognostic index in the R era and should be used in clinical practices to support discussions about prognosis. PMID- 23041590 TI - A meta-analysis of alcohol consumption and the risk of brain tumours. AB - BACKGROUND: Alcohol is capable of traversing the blood-brain barrier and is thus a possible risk factor for brain cancer. Several epidemiological studies have been published on the issue, a number of those during recent years, with inconsistent findings. MATERIALS AND METHODS: We performed a systematic literature search in the Medline and EMBASE databases. We found a total of 19 studies providing risk estimates for total alcohol or specific alcoholic beverages. Pooled estimates of the relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models. RESULTS: The pooled RR of brain cancer for alcohol drinkers versus non-drinkers was 0.97 (95% CI 0.82 1.15; based on 12 studies). Moderate (<2 drinks/day) and heavy alcohol drinkers had RRs of 1.01 (95% CI 0.81-1.25) and 1.35 (95% CI 0.85-2.15), respectively. With reference to specific alcoholic beverages, the RRs were 1.01 (95% CI 0.70 1.48) for wine, 0.96 (95% CI 0.82-1.12) for beer, and 1.20 (95% CI 1.01-1.42) for spirit consumption. The RRs for drinkers versus non-drinkers were 0.93 (95% CI 0.81-1.07) for glioma and 0.71 (95% CI 0.45-1.12) for meningioma. CONCLUSIONS: Alcohol drinking does not appear to be associated with adult brain cancer, though a potential effect of high doses deserves further study. PMID- 23041591 TI - Adjuvant therapy with cetuximab for locally advanced squamous cell carcinoma of the oropharynx: results from a randomized, phase II prospective trial. AB - BACKGROUND: Cetuximab combined with radiotherapy (RT) is a treatment option for head and neck cancer. The objectives of this randomized, phase II trial were to evaluate the efficacy and safety of cetuximab maintenance therapy following definitive RT with concomitant cetuximab in patients with oropharyngeal cancer. PATIENTS AND METHODS: Ninety-one patients with stage III-IV M0 oropharyngeal tumors were randomly assigned to the treatment with accelerated concomitant boost RT (69.9 Gy) + cetuximab or the same treatment with the addition of 12 consecutive weeks of cetuximab maintenance therapy. The primary end point was locoregional control (LRC) at 1 year. RESULTS: LRC at 1 year was superior among patients in the experimental arm, treated with cetuximab maintenance (59% versus 47%). However, LRC was similar between both arms after 2 years of follow-up, as a result of increased locoregional recurrences after the first year in the maintenance group. Patients treated with adjuvant cetuximab do recover very soon from toxic effect after combined treatment. CONCLUSIONS: Twelve weeks of cetuximab maintenance therapy after concomitant cetuximab + RT in locally advanced oropharyngeal carcinoma is feasible and improves clinical outcomes measured at 1 year. This improvement is not maintained after the second year suggesting that epidermal growth factor receptor blockade is not sufficient to completely eliminate the minimal residual disease. PMID- 23041592 TI - Screening elderly cancer patients for disabilities: evaluation of study of osteoporotic fractures (SOF) index and comprehensive geriatric assessment (CGA). AB - BACKGROUND: Comprehensive geriatric assessment (CGA) is a multidimensional tool aimed at detecting multiple age-related problems; the study of osteoporotic fractures (SOF) index is a 3-item instrument designed to measure frailty and pre frailty status. The aim of this prospective cohort study was to evaluate the accuracy of the SOF index and CGA in predicting the disability status in elderly cancer patients. PATIENTS AND METHODS: Patients aged >= 70 years with a confirmed diagnosis of a solid or hematologic tumor underwent both CGA and SOF assessment. The sensitivity and specificity of SOF in determining the presence of frailty were analyzed using the CGA as the reference standard. The diagnostic accuracy of SOF < 80% was considered not acceptable. RESULTS: The study involved 400 patients aged >= 70 years (median age 77.2, range 70-97).The SOF and CGA classified, respectively, 33.2% and 31.8% of patients as fit, 67.8% and 68.2% as unfit. The SOF showed a sensibility and a specificity of 89.0 [95% confidence interval (CI) 84.7-92.5] and 81.1 (73.2-87.5) with an accuracy of 86.5 (82.8-89.7). The negative predictive value (NPV) was 103/133, i.e. 77.4% (95% CI 69.4-84.2). CONCLUSIONS: As the SOF proved to reach the end-point of our study, we support its use as a means of screening elderly cancer patients in everyday clinical practice. PMID- 23041593 TI - 17beta-estradiol induces vasorelaxation by stimulating endothelial hydrogen sulfide release. AB - Estrogen exerts vascular protective effects, but the underlying mechanisms remain to be understood fully. In recent years, hydrogen sulfide (H(2)S) has increasingly been recognized as an important signaling molecule in the cardiovascular system. Vascular H(2)S is produced from L-cysteine, catalyzed by cystathionine gamma-lyase (CSE). In our study, apolipoprotein E (ApoE)-deficient mice were ovariectomized and implanted with placebo (OVX mice) or 17beta estradiol (E(2)) pellets (OVX + E(2) mice). Compared with OVX mice, OVX + E(2) mice showed increased plasma H(2)S levels (P = 0.012) and decreased aortic lesion area (P = 0.028). These effects were largely reversed when supplementing with the irreversible CSE inhibitor DL-propargylglycine (PPG) in the OVX + E(2) + PPG mice. Meanwhile, the nitric oxide and prostacyclin-resistant responses to cumulative application of acetylcholine (ACh) were studied among all the three groups of femoral arteries. Compared with the arteries in the OVX group, the vasodilator sensitivity of arteries to ACh was increased in the OVX + E(2) group and attenuated in the OVX + E(2) + PPG group. E(2) and estrogen receptor (ER) alpha agonist 4',4",4'"-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol rapidly increased H(2)S release in human endothelial cells, but not partially selective ERbeta agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile. These effects were inhibited by ER antagonist ICI 182780 or by protein kinase G (PKG) inhibitor KT5823. Furthermore, endothelial PKG activity was increased by E(2) (P = 0.003) and E(2)-induced vasodilation was inhibited by KT5823 (P = 0.009). In conclusion, the endothelial CSE/H(2)S pathway is activated by E(2) through PKG, which leads to vasodilation. These actions may be relevant to estrogen's anti-atherogenic effect. PMID- 23041594 TI - Detection of RD-114 virus by a reverse transcriptase assay based on product enhancement. AB - RD-114 virus is a feline endogenous retrovirus that exists in the genome of all cats. It can be assumed that feline and canine live vaccines manufactured by culturing cells of feline origin are contaminated with the virus. The current study is attempted to develop a product enhanced reverse transcriptase (PERT) assay to detect replication-competent RD-114 virus. Since culture supernatants of Crandell-Rees feline kidney (CRFK) cells do not have detectable reverse transcriptase activity in case of do not passage on other cell lines, these results raise the possibility that RD-114 virus grow efficiently in other retrovirus producing cell lines. For the PERT assay, RD-114 virus isolated from CRFK cells may need to be passaged more than four times on 293T cells to be expressed at appreciable levels. The PERT assay described here provides an accurate method for determining the presence of RD-114 in culture supernatants and will help monitor live vaccines produced in endogenous virus producing cell lines. PMID- 23041595 TI - Increased FDG uptake in association with reduced extremity fat in HIV patients. AB - BACKGROUND: HIV lipodystrophy - characterized by peripheral lipoatrophy, with or without central fat accumulation - confers increased metabolic risk. However, the functional activity of HIV lipodystrophic tissue in relation to metabolic risk has yet to be fully explored in vivo through the use of non-invasive imaging techniques. This study assesses the relationship between FDG uptake in various fat depots and metabolic/immune parameters among subjects with HIV lipodystrophy. METHODS: Lipodystrophic men on antiretroviral therapy underwent whole-body (18)F fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography scans and detailed metabolic/immune phenotyping. RESULTS: FDG uptake in the subcutaneous adipose tissue (SAT) of the extremities (mean standardized uptake value [SUV] of the arm and leg SAT) was found to correlate with the degree of peripheral lipoatrophy (r=0.7; P=0.01). Extremity SAT FDG uptake was positively associated with homeostasis model assessment of insulin resistance (HOMA-IR; r=0.6; P=0.02) and fasting hyperinsulinaemia (r=0.7; P=0.01), while fat percentage of extremities was not. Furthermore, extremity SAT FDG uptake was significantly associated with CD4(+) T-cell count (r=0.6; P=0.05). In multivariate modelling for HOMA-IR, extremity SAT FDG uptake remained significant after controlling for body mass index and tumour necrosis factor-alpha (R(2) for model =0.71, P=0.02; SUV in the extremity SAT beta-estimate 12.3, P=0.009). CONCLUSIONS: In HIV lipodystrophic patients, extremity SAT FDG uptake is increased in association with reduced extremity fat and may contribute to insulin resistance. Non-invasive assessments of in situ inflammation using FDG-PET may usefully complement histological and gene expression analyses of metabolic dysregulation in peripheral fat among HIV-positive patients. PMID- 23041596 TI - The B-lymphocyte stimulator connection in Sjogren's syndrome. PMID- 23041597 TI - Synovial fluid eosinophilia: a case series with a long follow-up and literature review. AB - OBJECTIVES: To establish the frequency and describe the characteristics of a cohort of patients with SF eosinophilia (SFE) and a long clinical follow-up. A systematic review of the literature on this topic was performed. METHODS: From November 2005 to May 2010, 982 consecutive arthrocentesis procedures performed at a tertiary care hospital were reviewed. Clinical and analytical data of patients with SFE at the time of diagnosis and during follow-up until 31 January 2012, were recorded. According to the percentage of eosinophils in SF, SFE was classified as minor (<10%) or major (>10%). Also, a literature search of all publications on eosinophilic synovitis found in MEDLINE, EMBASE and Web of Science without publication date restrictions was performed. RESULTS: Eosinophils in SF were found in 10 of 982 (1.02%) patients: minor SFE was recorded in three patients, all of them with haemorrhagic fluid and without peripheral eosinophilia. Major SFE was found in seven patients, and only two of them had peripheral eosinophilia. In six patients, an underlying cause of the arthritis was found. Only one patient was classified as having idiopathic SFE. Most SFE promptly resolved with NSAIDs without relapses or new deformities. The literature search identified 56 patients with SFE; 49 of them (88%) had major SFE and 7 (12%) had minor SFE. CONCLUSIONS: Eosinophils are infrequently found in SF, and in most cases peripheral eosinophilia was not detected. Most patients with SFE had a benign course with prompt resolution and few relapses. PMID- 23041598 TI - A case of systemic lupus erythematosus with bamboo joint-like corditis as an antecedent symptom. PMID- 23041599 TI - There are many potential medical therapies for atraumatic osteonecrosis. AB - Atraumatic osteonecrosis is a common complication of SLE and is seen in other connective tissue diseases, in patients treated with high doses of CSs, in HIV infected patients and in alcoholic patients. Standard care is confined to analgesia, core decompression if the condition is early and affects the femoral head and joint replacement. However, consideration of the underlying biological mechanisms leads to the recognition of many potential therapies that might either prevent progression or, even, reverse the process if it is not yet too far advanced. These potential therapies merit detailed consideration. Critical points are that (i) histopathological evidence shows that the initial cellular event is apoptosis of osteocytes; and (ii) another requisite, as homeostasis requires that death and rebirth of osteocytes be balanced, is an accompanying inadequate proliferative capacity of osteoblasts. Thus, a logical approach to treatment includes measures that (i) reduce apoptosis of osteocytes and (ii) enhance proliferation of osteoblasts/pre-osteoblasts. Measures to reduce the ongoing apoptosis of osteocytes require reinforcing the effects of members of the Bcl-2 family (Bcl-2 itself and Mcl-1), the Wnt/catenin pathways (using an available sclerostin antibody) and HSPs (by application of local heat using US, deep wave diathermy or infrared), as well as administration of bisphosphonates and nitrates. Measures to enhance proliferation of osteoblasts/pre-osteoblasts include the use of stem cells, extracorporeal shock wave therapy, aspirin, the proteosome inhibitor bortezomib, melatonin and application of local heat. Use of VEGF would encourage proliferation of blood vessels and osteogenesis. Certain drugs that inhibit osteoblast proliferation should be avoided, including NSAIDs, serotonin reuptake inhibitors and thiazolidinediones. PMID- 23041600 TI - Endothelial vulnerability and endothelial damage are associated with risk of graft-versus-host disease and response to steroid treatment. AB - There is accumulating evidence indicating that endothelial factors are involved in the pathogenesis of GVHD. We have recently shown that steroid-refractory, but not sensitive, GVHD is characterized by higher pretransplantation serum levels of angiopoetin-2 (ANG2), a hormone mediating endothelial vulnerability. To evaluate whether endothelial vulnerability is a risk factor for GVHD per se or becomes important only when noticeable GVHD is established, we measured ANG2 along with additional serum markers of endothelial stress, including soluble thrombomodulin (sTM), IL-8 (CXCL8), and hepatocyte growth factor (HGF), in patients with no, low grade, or severe GVHD. Patients with refractory GVHD exhibited elevated serum levels of ANG2, sTM, HGF, and IL-8 posttransplantation compared with patients with sensitive GVHD and patients without GVHD. Pretransplantation ANG2 was the only growth factor correlated with the risk of refractoriness and mortality, and then only within the subset of patients who developed grade III-IV GVHD. In contrast, ANG2 was not predictive of GVHD or nonrelapse mortality (NRM) in patients with no GVHD or low-grade GVHD. These findings provide evidence that endothelial function plays an important role in the pathogenesis of steroid refractoriness in ongoing GVHD; however, endothelial vulnerability does not predict incidence of GVHD. PMID- 23041601 TI - Impact of the direction of HLA mismatch on transplantation outcomes in single unrelated cord blood transplantation. AB - The impact of the direction of HLA mismatch (MM) on outcome in unrelated cord blood (UCB) transplantation has not yet been clarified. We conducted a retrospective study using national registry data on 2977 patients who underwent transplantation using a single UCB for leukemia or myelodysplastic syndrome. HLA matching was assessed by serologic data for HLA-A, -B, and -DR loci. The median age of the recipients at transplantation was 41 years (range, 0-82 years), and 2300 recipients (77%) were age >=16 years. The 2-year overall survival rate was 0.46. The presence of MM only in the graft-versus-host direction or only in the host-versus-graft direction was not associated with overall mortality (hazard ratio [HR], 0.88; P = .317 and HR, 0.95; P = .670, respectively) compared with 1 bidirectional MM. This finding was consistent in both the child and adult cohorts. The presence of MM only in the graft-versus-host direction was associated with a lower incidence of nonrelapse mortality (HR, 0.65; P = .040), significant only in the child cohort. No MM category was associated with relapse. Our findings suggest that the direction of HLA MM does not have a significant impact on overall survival after UCB transplantation. PMID- 23041602 TI - Cancer vaccines and T cell therapy. PMID- 23041603 TI - Enhancing immune reconstitution: from bench to bedside. PMID- 23041604 TI - Double umbilical cord blood transplantation: a study of early engraftment kinetics in leukocyte subsets using HLA-specific monoclonal antibodies. AB - Single cord blood unit (CBU) predominance is usually established within the first month after double umbilical cord blood transplantation (UCBT). However, the kinetics of engraftment of the different leukocyte subsets and the mechanism of graft predominance is largely unknown. To investigate whether a differential engraftment might reveal a specific subset that could play a key role in the mechanism of graft predominance, we studied early engraftment kinetics of different leukocyte subpopulations by flow cytometry using human monoclonal antigen-specific human leukocyte antigen antibodies, directed against mismatched human leukocyte antigen-A or -B antigens between recipient and CBUs. Twenty-two patients, who had received a double UCBT preceded by a reduced-intensity conditioning regimen, were evaluated at days +11, +18, +25, and +32 posttransplantation. Single CBU predominance in the various leukocyte subsets was established within 18 days posttransplantation. CD4+ T cells of the dominant CBU showed early peripheral blood expansion. Moreover, chimerism in CD4+ and CD8+ T cell and natural killer cell subsets at day +11 was predictive of ultimate graft predominance. These findings show that engraftment kinetics of the various leukocyte subsets vary considerably after double UCBT and may suggest an important role for CD4+ T cells in a presumed alloreactive graft-versus-graft rejection. PMID- 23041605 TI - Transplantation conditioning regimens and outcomes after allogeneic hematopoietic cell transplantation in children and adolescents with acute lymphoblastic leukemia. AB - Relapse is common after hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL). Although 1200 cGy total body irradiation (TBI) and cyclophosphamide (Cy) is the standard conditioning regimen, attempts to reduce relapse have led to the addition of a second chemotherapeutic agent and/or higher dose of TBI. We examined HSCT outcomes in patients age <18 years with ALL, in second or subsequent remission or in relapse at transplantation. Most transplantations were performed with the patient in remission. Patients received grafts from an HLA-matched sibling or unrelated donor. Four treatment groups were created: (1) Cy + TBI <= 1200 cGy (n = 304), (2) Cy + etoposide + TBI <= 1200 cGy (n = 108), (3) Cy + TBI >= 1300 cGy (n = 327), and (4) Cy + etoposide + TBI >= 1300 cGy (n = 26). Neither TBI > 1200 cGy nor the addition of etoposide resulted in fewer relapses. The 5-year probability of relapse was 30% for group 1, 28% for group 2, 35% for group 3, and 31% for group 4. However, transplantation-related mortality was higher (35% versus 25%, P = .02) and overall survival lower (36% versus 48%, P = .03) in group 4 compared with group 3. Our findings indicate that compared with the standard regimen, neither TBI > 1200 cGy nor the addition of etoposide improves survival after HSCT for ALL. PMID- 23041607 TI - Caveats of using acetaminophen hepatotoxicity models for natural product testing. AB - In evaluating the potential of natural products and other chemicals to protect against acetaminophen-induced hepatotoxicity, it is critical to use clinically relevant experimental models and evaluate the initial metabolic activation and protein adduct formation. If these basic principles are not considered, the clinical relevance of the hepatoprotection by a natural product is questionable and conclusions regarding potential mechanisms of protection may be unreliable. Therefore, we feel it is necessary to express our concerns regarding a recent publication by Zhao et al. (2012). PMID- 23041606 TI - Metabolic impacts of high dietary exposure to persistent organic pollutants in mice. AB - Persistent organic pollutants (POPs) have been linked to metabolic diseases. Yet, the effects of high exposure to dietary POPs remain unclear. We therefore investigated whether elevated exposure to POPs provided by whale meat supplementation could contribute to insulin resistance. C57BL/6J mice were fed control (C) or very high-fat diet (VHF) containing low or high levels of POPs (VHF(+POPs)) for eight weeks. To elevate the dietary concentrations of POPs, casein was replaced by whale meat containing high levels of pollutants. Feeding VHF(+POPs) induced high POP accumulation in the adipose tissue of mice. However, compared with VHF-fed mice, animals fed VHF(+POPs) had improved insulin sensitivity and glucose tolerance, and reduced body weight. Levels of ectopic fat in skeletal muscles and liver were reduced in mice fed VHF(+POPs). These mice also gained less adipose tissue and had a tendency to reduced energy intake. In pair-feeding experiments, improved insulin action and reduced body weight gain were still observed in VHF(+POPs) compared to VHF pair-fed mice. We concluded that mice fed VHF contaminated with POPs derived from whale meat remain sensitive to insulin and glucose tolerant despite significant body burden of POPs. This indicates complex interactions between organic pollutants and nutrition in the development of metabolic disorders. PMID- 23041608 TI - Activation of the aryl hydrocarbon receptor reduces the number of precursor and effector T cells, but preserves thymic CD4+CD25+Foxp3+ regulatory T cells. AB - Aryl hydrocarbon receptor (AhR) activation suppresses immune responses, including allergic sensitization, by increasing the percentage of regulatory (Treg) cells. Furthermore, AhR activation is known to affect thymic precursor T cells. However, the effect of AhR activation on intrathymic CD4+CD25+Foxp3+ Treg cells is unknown. Therefore, we investigated the effect of AhR activation on the percentage and number of CD4+CD25+Foxp3+ Treg cells during allergic sensitization in relevant immunological organs. C3H/HeOuJ mice were treated on day 0 with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and subsequently sensitized to peanut. On day 8, mice were sacrificed and thymus, spleen and mesenteric lymph nodes (MLN) were isolated. TCDD treatment decreased the number of CD4-CD8-, CD4+CD8+, CD4+CD8- and CD4-CD8+ precursor T cells, but not the number of thymic CD4+CD25+Foxp3+ Treg cells. TCDD treatment increased the number of splenic CD4+CD25+Foxp3+ Treg cells and decreased Th1, Th2 and cytotoxic T cells in the spleen. This appeared to be independent of allergic sensitization. In MLN, TCDD treatment suppressed the increase of the number of CD4+CD25+Foxp3+ Treg cells, Th1, Th2 and cytotoxic T cells induced by peanut sensitization. Together, TCDD treatment preserves thymic CD4+CD25+Foxp3+ Treg cells and decreases peripheral T helper and cytotoxic T cells. This effect of TCDD may contribute to the increased influence of CD4+CD25+Foxp3+ Treg cells on immune mediated responses and to the understanding of how AhR activation modulates immune mediated diseases, including food allergy. PMID- 23041609 TI - Liver X receptor alpha bidirectionally transactivates human CYP1A1 and CYP1A2 through two cis-elements common to both genes. AB - CYP1A1 and CYP1A2 are involved in both detoxification and metabolic activation of xenobiotics. Human CYP1A1 (hCYP1A1) and hCYP1A2 exist in a head-to-head orientation in chromosome 15 with the overlapping 5'-flanking region. We have recently reported that nuclear receptor constitutive androstane receptor (CAR), in addition to aryl hydrocarbon receptor, bidirectionally transactivates these genes through common motifs. In this study, we have investigated a role of liver X receptor alpha (LXRalpha), another liver-enriched nuclear receptor, in the expression hCYP1A1 and hCYP1A2. In reporter assays with dual-reporter constructs containing their promoter region between two different reporter genes, LXRalpha simultaneously transactivated hCYP1A1 and hCYP1A2 through two regions, independent of aryl hydrocarbon receptor. In electrophoretic mobility shift assays, LXRalpha/retinoid X receptor alpha heterodimer bound to two ER8-type motifs found at around -520 and -460 of hCYP1A1. The former corresponds to the CAR-binding motif previously identified. Reporter assays using mutated constructs confirmed the critical roles of these motifs in the LXRalpha-mediated simultaneous transcription of hCYP1A1 and hCYP1A2. hCYP1A1 and hCYP1A2 mRNA levels were increased in human hepatoma HuH-7 cells and human primary hepatocytes, respectively, after treatment with the LXRalpha ligand GW3965. Our results suggest that LXRalpha transactivates the expression of hCYP1A1 and hCYP1A2 through common two cis-elements. PMID- 23041610 TI - More than a lack of control: external explanations can evoke compassion for outgroups by increasing perceptions of suffering (independent of perceived control). AB - People's explanations for social events powerfully affect their socioemotional responses. We examine why explanations affect emotions, with a specific focus on how external explanations for negative aspects of an outgroup can create compassion for the outgroup. The dominant model of these processes suggests that external explanations can reduce perceived control and that compassion is evoked when negative aspects of an outgroup are perceived as beyond their control. We agree that perceived control is important, but we propose a model in which explanations also affect perceived suffering of an outgroup, and that perceived suffering is an additional mechanism connecting external explanations to compassion. Studies are presented that support our integrative dual-mediation model and that pinpoint factors-depth of cognitive processing, expansive sense of identity-that modulate the extent to which the external explanation/perceived suffering mechanism evokes compassion. PMID- 23041611 TI - The use of visual and verbal means of communication across psychological distance. AB - The current study investigated the effect of distance on medium preferences in interpersonal communication. Five experiments showed that people's preference for using pictures (vs. words) is increasingly higher when communicating with temporally, socially, or geographically proximal (vs. distal) others. In contrast, preference for words is increasingly higher when communicating with those who were distal. A sixth experiment showed that communication's medium influences distance preferences, such that people's preference for communicating a message to a distant (vs. proximal) target is greater for verbal compared with pictorial communications. A seventh experiment showed that recipients are more likely to heed a sender's suggestions when the medium and distance are congruent. These findings reflect the suitability of pictures for communication with proximal others and words with distal others. Implications of these findings for construal-level theory, perspective taking, embodied cognition, the development of language, and social skills with children are discussed. PMID- 23041612 TI - The onco-embryonic antigen ROR1 is expressed by a variety of human cancers. AB - ROR1 is an orphan-receptor tyrosine-kinase-like surface antigen that is expressed by many tissues during embryogenesis, some B-cell malignancies, and various cancer cell lines but not by virtually all normal adult tissues. Here, we report that large proportions of many different human cancers also express ROR1, particularly those cancers that have high-grade histology. Primary cancers that expressed ROR1 more commonly expressed high levels of phosphorylated AKT (p-AKT) and phosphorylated cAMP response element binding-factor (p-CREB) than similar cancers that lacked expression of ROR1. Induced expression of ROR1 could enhance basal p-AKT and p-CREB levels and could promote the growth of a cancer cell line, MEC1. Conversely, silencing ROR1 resulted in lower levels of p-AKT and p-CREB, which was associated with impaired tumor cell growth. In summary, this study found that many different human cancers express ROR1 and that ROR1 may play a functional role in promoting tumor cell growth, suggesting that this orphan receptor tyrosine-kinase-like protein may be a potential target for therapy directed against a variety of human cancers. PMID- 23041615 TI - Pathophysiology of the anorexia of aging. AB - PURPOSE OF REVIEW: Anorexia represents a major problem for older persons leading to weight loss, sarcopenia, functional decline, and mortality. There is increasing information on the pathophysiological mechanisms that lead to anorexia. RECENT FINDINGS: Increasing evidence has shown the importance of gastrointestinal hormones (ghrelin, cholecystokinin, and glucagon-like peptide) and adipokines in producing the anorexia of aging. Numerous neurotransmitters have been shown to be involved in this aging anorexia, but evidence in humans is lacking. SUMMARY: The early recognition of anorexia of aging is important to allow intervention and prevent functional deterioration in older persons. Screening tests for anorexia have been developed. New approaches to managing anorexia are being tested. PMID- 23041614 TI - B cell memory following infection and challenge of channel catfish with Ichthyophthirius multifiliis. AB - B cell responses in channel catfish to infection with the parasitic ciliate Ichthyophthirius multifiliis were followed for 3 years. High titers of serum IgM antibodies recognizing I. multifiliis immobilization antigens were present 5weeks after immunizing infection, but by 1 year titers were at low or undetectable levels. Two to three years after infection the numbers of antibody secreting cells recognizing immobilization antigens in skin and head kidney of immune fish had decreased to the level found in uninfected controls. Challenge of immune fish showed they remained immune and that the numbers of antibody secreting cells recognizing immobilization antigens increased in skin but not head kidney. This suggests that antigen-specific memory B cells persisted for 3 years after infection and upon challenge differentiated into antibody secreting cells that localized in skin. Our results suggest that humoral immunity in channel catfish is maintained through IgM(+) memory B cells. PMID- 23041613 TI - E-selectin mediates stem cell adhesion and formation of blood vessels in a murine model of infantile hemangioma. AB - Hemangioma stem cells (HemSCs) are multipotent cells isolated from infantile hemangioma (IH), which form hemangioma-like lesions when injected subcutaneously into immune-deficient mice. In this murine model, HemSCs are the primary target of corticosteroid, a mainstay therapy for problematic IH. The relationship between HemSCs and endothelial cells that reside in IH is not clearly understood. Adhesive interactions might be critical for the preferential accumulation of HemSCs and/or endothelial cells in the tumor. Therefore, we studied the interactions between HemSCs and endothelial cells (HemECs) isolated from IH surgical specimens. We found that HemECs isolated from proliferating phase IH, but not involuting phase, constitutively express E-selectin, a cell adhesion molecule not present in quiescent endothelial cells. E-selectin was further increased when HemECs were exposed to vascular endothelial growth factor-A or tumor necrosis factor-alpha. In vitro, HemSC migration and adhesion was enhanced by recombinant E-selectin but not P-selectin; both processes were neutralized by E-selectin-blocking antibodies. E-selectin-positive HemECs also stimulated migration and adhesion of HemSCs. In vivo, neutralizing antibodies to E-selectin strongly inhibited formation of blood vessels when HemSCs and HemECs were co implanted in Matrigel. These data suggest that endothelial E-selectin could be a major ligand for HemSCs and thereby promote cellular interactions and vasculogenesis in IH. We propose that constitutively expressed E-selectin on endothelial cells in the proliferating phase is one mediator of the stem cell tropism in IH. PMID- 23041616 TI - D-serine: physiology and pathology. AB - PURPOSE OF REVIEW: Here, we discuss the recent data on the role of different N methyl D-aspartate receptor (NMDAR) coagonists, D-serine and glycine, in regulating NMDAR activity and neurotoxicity. RECENT FINDINGS: D-Serine originates from both neurons and astrocytes, from where it is released by different mechanisms. Recent data indicate that like glial D-serine, neuronal D-serine is required for NMDAR-dependent, long-term potentiation at the hippocampal CA1-CA3 synapses and proper synapse formation in the cerebral cortex. D-serine is the physiological coagonist of synaptic NMDAR, whereas glycine action is restricted to extrasynaptic sites. SUMMARY: D-Serine is now recognized as the major NMDAR coagonist at the synapse. The data establish D-serine as a key transmitter or neuromodulator that mediates synaptic NMDAR activation and neurotoxicity. In this context, drugs that inhibit D-serine synthesis or release will provide new neuroprotective strategy. PMID- 23041617 TI - Tissue culture of human alveolar periosteal sheets using a stem-cell culture medium (MesenPRO-RSTM): In vitro expansion of CD146-positive cells and concomitant upregulation of osteogenic potential in vivo. AB - We have previously demonstrated that multilayered periosteal sheets prepared from the explant culture of alveolar periosteum serve as a promising osteogenic grafting material in periodontal tissue regeneration. For the preparation of more potent periosteal sheets, we examined the applicability of stem-cell culture media. Compared to the control medium (Medium 199+10% FBS), periosteal sheets expanded with MesenPRO-RSTM medium exhibited these features: Cells grew three dimensionally and deposited collagen in the extracellular spaces to form thicker multilayers of cells. Chondrocytic markers were not significantly upregulated. Contractile force was generated in proportion with the increased thickness of the periosteal sheets and the formation of cytoplasmic alpha-smooth muscle actin fibers. However, myofibroblastic markers were not significantly upregulated. The surface marker CD146 was substantially upregulated, while both CD73 and CD105 were downregulated. Alkaline phosphatase, a representative osteoblastic marker, was not upregulated by osteogenic induction. However, these expanded periosteal sheets exhibited substantially stronger osteogenic differentiation when implanted in nude mice. Therefore, despite our reservations, MesenPRO medium effectively expanded the cells contained in periosteal sheets to promote the formation of thicker multilayers of cells in vitro, and these enhanced periosteal sheets expressed increased osteogenic potential at implantation sites in vivo. In conjunction with data indicating that CD146-positive cells were notably expanded and the recently proposed concept that CD146 is a marker for osteogenic progenitor cells found in the bone marrow stroma, our findings suggest that MesenPRO medium improves the preparation of highly osteogenic periosteal sheets suitable for clinical application largely through the induction of CD146-positive cells. PMID- 23041618 TI - A randomized trial of a small changes approach for weight loss in veterans: design, rationale, and baseline characteristics of the ASPIRE-VA trial. AB - BACKGROUND: Overweight/obesity rates among veterans are higher than the national average. While weight management treatment has been implemented in the Veterans Health Administration (VHA), program data shows low enrollment, participation, and weight loss. This paper presents the design, rationale and baseline characteristics of a multisite, multi-modality, randomized clinical trial assessing an innovative Small Changes (SC) approach on weight loss compared to the current weight management program in the VHA. METHOD: Overweight/obese veterans were recruited from two VHA medical centers. Participants were randomized to either: 1) sc group, 2) SC phone, or 3) usual care. Participants in the SC arms met with health coaches weekly in months 1-3, bi-weekly in months 4 9, and monthly in months 10-12. Usual care participants met weekly for 12 weeks with limited options for follow-up care. The primary outcome is weight at 12 months. Secondary outcomes include physiological, behavioral, psychosocial outcomes along with participation and adherence. RESULTS: Participants include 481 veterans who are middle-aged (M=55.45, SD=10.00), obese (BMI=36.45, SD=6.24), relatively sedentary (M=4721 steps per day; SD=3115), disabled (52%), men (85%) with a large minority of non-white race/ethnicity (43%) and high prevalence of physical co-morbidities (83%) (Charlson Co-morbidity Index M=1.27, SD=1.75) and mental health disorders (57%) at baseline. CONCLUSION: The present study seeks to determine if an SC approach, delivered either via phone or in-person, will result in greater weight loss and program participation and adherence at 12 months compared to usual care. PMID- 23041620 TI - Structural neurobiological correlates of Mayer-Salovery-Caruso Emotional Intelligence Test performance in early course schizophrenia. AB - OBJECTIVE: The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) is a key measure of social cognition in schizophrenia that has good psychometric properties and is recommended by the MATRICS committee. As a way to further investigate the validity of the MSCEIT, this study sought to examine the neurobiological correlates of MSCEIT performance in patients with early course schizophrenia. METHODS: A total of 51 patients diagnosed with early course, stabilized schizophrenia or schizoaffective disorder completed structural magnetic resonance imaging (MRI) scans and the MSCEIT. Investigation of the associations between MSCEIT performance and gray matter morphology was examined by conducting voxel-based morphometry (VBM) analyses across hypothesized social cognitive regions of interest using automated anatomical labeling in Statistical Parametric Mapping Software, version 5 (SPM5). All VBM analyses utilized general linear models examining gray matter density partitioned images, adjusting for demographic and illness-related confounds. VBM results were then followed up with confirmatory volumetric analyses. RESULTS: Patients with poorer overall and Facilitating, Understanding, and Managing Emotions subscale performances on the MSCEIT showed significantly reduced gray matter density in the left parahippocampal gyrus. Additionally, attenuated performance on the Facilitating and Managing Emotions subscales was significantly associated with reduced right posterior cingulate gray matter density. All associations observed between MSCEIT performance and gray matter density were supported with confirmatory gray matter volumetric analyses, with the exception of the association between the right posterior cingulate and the facilitation of emotions. CONCLUSION: These findings provide additional evidence for the MSCEIT as a valid social-cognitive measure by elucidating its correlates with neurobiological structures commonly implicated in emotion processing. These findings provide additional biological evidence supporting the use of the MSCEIT in cognitive enhancing clinical trials in schizophrenia. PMID- 23041619 TI - Gonadotropin-releasing hormone plasticity: a comparative perspective. AB - Gonadotropin-releasing hormone 1 (GnRH1) is a key regulator of the reproductive neuroendocrine system in vertebrates. Recent developments have suggested that GnRH1 neurons exhibit far greater plasticity at the cellular and molecular levels than previously thought. Furthermore, there is growing evidence that sub populations of GnRH1 neurons in the preoptic area are highly responsive to specific environmental and hormonal conditions. In this paper we discuss findings that reveal large variation in GnRH1 mRNA and protein expression that are regulated by social cues, photoperiod, and hormonal feedback. We draw upon studies using histochemistry and immediate early genes (e.g., c-FOS/ZENK) to illustrate that specific groups of GnRH1 neurons are topographically organized. Based on data from diverse vertebrate species, we suggest that GnRH1 expression within individuals is temporally dynamic and this plasticity may be evolutionarily conserved. We suggest that the plasticity observed in other neuropeptide systems (i.e. kisspeptin) may have evolved in a similar manner. PMID- 23041621 TI - Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells. AB - Recent evidence suggests that Notch signaling may play a role in regulation of cancer stem cell (CSC) self-renewal and differentiation hence presenting a promising target for development of novel therapies for aggressive cancers such as triple negative breast cancer (TNBC). We generated Notch1 monoclonal antibodies (mAbs) that specifically bind to the negative regulatory region of human Notch1. Notch1 inhibition in TNBC Sum149 and patient derived xenograft (PDX) 144580 models led to significant TGI particularly in combination with docetaxel. More interestingly, Notch1 mAbs caused a reduction in mammosphere formation and CD44+/CD24-/lo cell population. It also resulted in decreased tumor incidence upon re-implantation and delay in tumor recurrence. Our data demonstrated a potent antitumor efficacy of Notch1 mAbs, with a remarkable activity against CSCs. These findings suggest that anti-Notch1 mAbs may provide novel therapies to improve the efficacy of conventional therapies by directly targeting the CSC niche. They may also delay tumor recurrence and hence have a major impact on cancer patient survival. PMID- 23041622 TI - AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. AB - Mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia type 28 and spastic ataxia-neuropathy syndrome in humans; however, the pathogenic mechanism is still unclear. AFG3L2 encodes a subunit of the mitochondrial m-AAA protease, previously implicated in quality control of misfolded inner mitochondrial membrane proteins and in regulatory functions via processing of specific substrates. Here, we used a conditional Afg3l2 mouse model that allows restricted deletion of the gene in Purkinje cells (PCs) to shed light on the pathogenic cascade in the neurons mainly affected in the human diseases. We demonstrate a cell-autonomous requirement of AFG3L2 for survival of PCs. Examination of PCs prior to neurodegeneration revealed fragmentation and altered distribution of mitochondria in the dendritic tree, indicating that abnormal mitochondrial dynamics is an early event in the pathogenic process. Moreover, PCs displayed features pointing to defects in mitochondrially encoded respiratory chain subunits at early stages. To unravel the underlying mechanism, we examined a constitutive knockout of Afg3l2, which revealed a decreased rate of mitochondrial protein synthesis associated with impaired mitochondrial ribosome assembly. We therefore propose that defective mitochondrial protein synthesis, leading to early-onset fragmentation of the mitochondrial network, is a central causative factor in AFG3L2-related neurodegeneration. PMID- 23041623 TI - Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma. AB - Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP. PMID- 23041625 TI - The bitter taste of infection. AB - The human innate immune response to pathogens is complex, and it has been difficult to establish the contribution of epithelial signaling in the prevention of upper respiratory tract infection. The prevalence of chronic sinusitis in the absence of systemic immune defects indicates that there may be local defects in innate immunity associated with such mucosal infections. In this issue of the JCI, Cohen and colleagues investigate the role of the bitter taste receptors in airway epithelial cells, and find that these are critical to sensing the presence of invading pathogens. PMID- 23041624 TI - T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. AB - Innate and adaptive defense mechanisms protect the respiratory system from attack by microbes. Here, we present evidence that the bitter taste receptor T2R38 regulates the mucosal innate defense of the human upper airway. Utilizing immunofluorescent and live cell imaging techniques in polarized primary human sinonasal cells, we demonstrate that T2R38 is expressed in human upper respiratory epithelium and is activated in response to acyl-homoserine lactone quorum-sensing molecules secreted by Pseudomonas aeruginosa and other gram negative bacteria. Receptor activation regulates calcium-dependent NO production, resulting in stimulation of mucociliary clearance and direct antibacterial effects. Moreover, common polymorphisms of the TAS2R38 gene were linked to significant differences in the ability of upper respiratory cells to clear and kill bacteria. Lastly, TAS2R38 genotype correlated with human sinonasal gram negative bacterial infection. These data suggest that T2R38 is an upper airway sentinel in innate defense and that genetic variation contributes to individual differences in susceptibility to respiratory infection. PMID- 23041626 TI - Progranulin deficiency promotes neuroinflammation and neuron loss following toxin induced injury. AB - Progranulin (PGRN) is a widely expressed secreted protein that is linked to inflammation. In humans, PGRN haploinsufficiency is a major inherited cause of frontotemporal dementia (FTD), but how PGRN deficiency causes neurodegeneration is unknown. Here we show that loss of PGRN results in increased neuron loss in response to injury in the CNS. When exposed acutely to 1-methyl-4-(2' methylphenyl)-1,2,3,6-tetrahydrophine (MPTP), mice lacking PGRN (Grn-/-) showed more neuron loss and increased microgliosis compared with wild-type mice. The exacerbated neuron loss was due not to selective vulnerability of Grn-/- neurons to MPTP, but rather to an increased microglial inflammatory response. Consistent with this, conditional mutants lacking PGRN in microglia exhibited MPTP-induced phenotypes similar to Grn-/- mice. Selective depletion of PGRN from microglia in mixed cortical cultures resulted in increased death of wild-type neurons in the absence of injury. Furthermore, Grn-/- microglia treated with LPS/IFN-gamma exhibited an amplified inflammatory response, and conditioned media from these microglia promoted death of cultured neurons. Our results indicate that PGRN deficiency leads to dysregulated microglial activation and thereby contributes to increased neuron loss with injury. These findings suggest that PGRN deficiency may cause increased neuron loss in other forms of CNS injury accompanied by neuroinflammation. PMID- 23041627 TI - Adipocyte-derived endotrophin promotes malignant tumor progression. AB - Adipocytes represent a major cell type in the mammary tumor microenvironment and are important for tumor growth. Collagen VI (COL6) is highly expressed in adipose tissue, upregulated in the obese state, and enriched in breast cancer lesions and is a stimulator of mammary tumor growth. Here, we have described a cleavage product of the COL6alpha3 chain, endotrophin (ETP), which serves as the major mediator of the COL6-mediated tumor effects. ETP augmented fibrosis, angiogenesis, and inflammation through recruitment of macrophages and endothelial cells. Moreover, ETP expression was associated with aggressive mammary tumor growth and high metastatic growth. These effects were partially mediated through enhanced TGF-beta signaling, which contributes to tissue fibrosis and epithelial mesenchymal transition (EMT) of tumor cells. Our results highlight the crucial role of ETP as an obesity-associated factor that promotes tumor growth in the context of adipocyte interactions with tumor and stromal cells. PMID- 23041629 TI - PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor trafficking. AB - L-DOPA-induced dyskinesia (LID), a detrimental consequence of dopamine replacement therapy for Parkinson's disease, is associated with an alteration in dopamine D1 receptor (D1R) and glutamate receptor interactions. We hypothesized that the synaptic scaffolding protein PSD-95 plays a pivotal role in this process, as it interacts with D1R, regulates its trafficking and function, and is overexpressed in LID. Here, we demonstrate in rat and macaque models that disrupting the interaction between D1R and PSD-95 in the striatum reduces LID development and severity. Single quantum dot imaging revealed that this benefit was achieved primarily by destabilizing D1R localization, via increased lateral diffusion followed by increased internalization and diminished surface expression. These findings indicate that altering D1R trafficking via synapse associated scaffolding proteins may be useful in the treatment of dyskinesia in Parkinson's patients. PMID- 23041628 TI - Cross-presenting CD103+ dendritic cells are protected from influenza virus infection. AB - CD8+ cytotoxic T cells are critical for viral clearance from the lungs upon influenza virus infection. The contribution of antigen cross-presentation by DCs to the induction of anti-viral cytotoxic T cells remains controversial. Here, we used a recombinant influenza virus expressing a nonstructural 1-GFP (NS1-GFP) reporter gene to visualize the route of antigen presentation by lung DCs upon viral infection in mice. We found that lung CD103+ DCs were the only subset of cells that carried intact GFP protein to the draining LNs. Strikingly, lung migratory CD103+ DCs were not productively infected by influenza virus and thus were able to induce virus-specific CD8+ T cells through the cross-presentation of antigens from virally infected cells. We also observed that CD103+ DC resistance to infection correlates with an increased anti-viral state in these cells that is dependent on the expression of type I IFN receptor. These results show that efficient cross-priming by migratory lung DCs is coupled to the acquisition of an anti-viral status, which is dependent on the type I IFN signaling pathway. PMID- 23041630 TI - MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. AB - Macrophages in atherosclerotic plaques drive inflammatory responses, degrade lipoproteins, and phagocytose dead cells. MicroRNAs (miRs) control the differentiation and activity of macrophages by regulating the signaling of key transcription factors. However, the functional role of macrophage-related miRs in the immune response during atherogenesis is unknown. Here, we report that miR-155 is specifically expressed in atherosclerotic plaques and proinflammatory macrophages, where it was induced by treatment with mildly oxidized LDL (moxLDL) and IFN-gamma. Leukocyte-specific Mir155 deficiency reduced plaque size and number of lesional macrophages after partial carotid ligation in atherosclerotic (Apoe-/-) mice. In macrophages stimulated with moxLDL/IFN-gamma in vitro, and in lesional macrophages, loss of Mir155 reduced the expression of the chemokine CCL2, which promotes the recruitment of monocytes to atherosclerotic plaques. Additionally, we found that miR-155 directly repressed expression of BCL6, a transcription factor that attenuates proinflammatory NF-kappaB signaling. Silencing of Bcl6 in mice harboring Mir155-/- macrophages enhanced plaque formation and CCL2 expression. Taken together, these data demonstrated that miR 155 plays a key role in atherogenic programming of macrophages to sustain and enhance vascular inflammation. PMID- 23041632 TI - Melghirimyces thermohalophilus sp. nov., a thermoactinomycete isolated from an Algerian salt lake. AB - A novel filamentous bacterium, designated Nari11A(T), was isolated from soil collected from a salt lake named Chott Melghir, located in north-eastern Algeria. The strain is an aerobic, halophilic, thermotolerant, Gram-stain-positive bacterium, growing at NaCl concentrations between 5 and 20 % (w/v) and at 43-60 degrees C and pH 5.0-10.0. The major fatty acids were iso-C15 : 0, anteiso-C15 : 0 and iso-C17 : 0. The DNA G+C content was 53.4 mol%. ll-Diaminopimelic acid was the diamino acid of the peptidoglycan. The major menaquinone was MK-7, but MK-6 and MK-8 were also present in trace amounts. The polar lipid profile consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine and three unidentified phospholipids. Results of molecular and phenotypic analyses led to the description of the strain as a novel member to the genus Melghirimyces, family Thermoactinomycetaceae. Strain Nari11A(T) shows 96.7 % 16S rRNA gene sequence similarity to the type strain of Melghirimyces algeriensis. On the basis of phenotypic, physiological and phylogenetic data, strain Nari11A(T) ( = DSM 45514(T) = CCUG 60050(T)) represents the type strain of a novel species, for which the name Melghirimyces thermohalophilus sp. nov. is proposed. PMID- 23041633 TI - Pleomorphobacterium xiamenense gen. nov., sp. nov., a moderate thermophile isolated from a terrestrial hot spring. AB - An aerobic, motile, moderately thermophilic rod, designated strain CLW(T), was isolated from a terrestrial hot spring in an exposition garden in Xiamen City, Fujian Province, the People's Republic of China. Strain CLW(T) formed beige, dry colonies on solid 2216E medium and flocks in liquid medium. Cells were Gram-stain negative, short rods (1.0-3.0 um long and 0.4-0.6 um wide) with six or more polar flagella. The temperature and pH for growth of strain CLW(T) were 28-65 degrees C (optimum, 50-58 degrees C) and pH 5.5-9.5 (optimum, pH 6.0-8.0). Growth occurred in the presence of 0.3-6.0 % NaCl (optimum 2.5-4.5 %). Phylogenetic analysis based on 16S rRNA gene sequences showed that the closest relative of the isolate was Amaricoccus kaplicensis Ben 101(T) (94.3 % sequence similarity). The DNA G+C content of strain CLW(T) was 72.2 mol%. The respiratory quinone was ubiquinone 10. The predominant polar lipids consisted of phosphatidylglycerol and phosphatidylethanolamine. The major fatty acids (>10 %) were summed feature 8 (consisting of C18 : 1omega7c and/or C18 : 1omega6c), C18 : 1omega7c 11-methyl and C18 : 0. Based on phylogenetic, physiological and biochemical data and DNA G+C content, strain CLW(T) is considered to represent a novel species of a new genus in the family Rhodobacteraceae, for which the name Pleomorphobacterium xiamenense gen. nov., sp. nov. is proposed. The type strain of the type species is CLW(T) ( = LMG 26245(T) = CGMCC 1.10808(T) = MCCC 1A06272(T)). PMID- 23041634 TI - Sungkyunkwania multivorans gen. nov., sp. nov., a member of the family Flavobacteriaceae isolated from seawater from a seaweed farm. AB - A Gram-staining-negative, non-flagellated, non-gliding and rod-shaped bacterial strain, designated PDB-16(T), was isolated from seawater from a seaweed farm on the South Sea in Korea, and its taxonomic position was investigated using a polyphasic approach. Strain PDB-16(T) grew optimally at 30 degrees C, at pH 7.0 7.5 and in the presence of 2% (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain PDB-16(T) formed an independent lineage within the evolutionary radiation encompassed by the family Flavobacteriaceae. Strain PDB-16(T) contained MK-6 as the predominant menaquinone and iso-C15:0, iso-C15:1 G and iso-C17:0 3-OH as the major fatty acids. The major polar lipids detected in strain PDB-16(T) were phosphatidylethanolamine and two unidentified lipids. The DNA G+C content of strain PDB-16(T) was 42.1 mol%. Strain PDB-16(T) exhibited very low 16S rRNA gene sequence similarities of less than 89.7% to the type strains of any bacterial species with validly published names and less than 90.1% to uncultured bacteria clones. The 16S rRNA gene sequence similarity values and the differences in phenotypic properties between strain PDB-16(T) and some phylogenetically related genera were sufficient to support the proposal that strain PDB-16(T) should be distinguished from previously known genera of the family Flavobacteriaceae. On the basis of the data presented, strain PDB-16(T) is considered to represent a new genus and novel species, for which the name Sungkyunkwania multivorans gen. nov., sp. nov. is proposed. The type strain of Sungkyunkwania multivorans is PDB-16(T) (=KCTC 32138(T)=CCUG 62952(T)). PMID- 23041631 TI - A novel murine infection model for Shiga toxin-producing Escherichia coli. AB - Enterohemorrhagic E. coli (EHEC) is an important subset of Shiga toxin-producing (Stx-producing) E. coli (STEC), pathogens that have been implicated in outbreaks of food-borne illness and can cause intestinal and systemic disease, including severe renal damage. Upon attachment to intestinal epithelium, EHEC generates "attaching and effacing" (AE) lesions characterized by intimate attachment and actin rearrangement upon host cell binding. Stx produced in the gut transverses the intestinal epithelium, causing vascular damage that leads to systemic disease. Models of EHEC infection in conventional mice do not manifest key features of disease, such as AE lesions, intestinal damage, and systemic illness. In order to develop an infection model that better reflects the pathogenesis of this subset of STEC, we constructed an Stx-producing strain of Citrobacter rodentium, a murine AE pathogen that otherwise lacks Stx. Mice infected with Stx producing C. rodentium developed AE lesions on the intestinal epithelium and Stx dependent intestinal inflammatory damage. Further, the mice experienced lethal infection characterized by histopathological and functional kidney damage. The development of a murine model that encompasses AE lesion formation and Stx mediated tissue damage will provide a new platform upon which to identify EHEC alterations of host epithelium that contribute to systemic disease. PMID- 23041635 TI - Brevundimonas abyssalis sp. nov., a dimorphic prosthecate bacterium isolated from deep-subsea floor sediment. AB - A novel Gram-negative, aerobic, psychrotolerant, alkali-tolerant, heterotrophic and dimorphic prosthecate bacterium, designated strain TAR-001(T), was isolated from deep-sea floor sediment in Japan. Cells of this strain had a dimorphic life cycle and developed an adhesive stalk at a site not coincident with the centre of the cell pole, and the other type of cell, a swarm cell, had a polar flagellum. Colonies were glossy, viscous and yellowish-white in colour. The temperature, pH and salt concentration range for growth were 2-41 degrees C, pH 6.5-10.0 and 1 4% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences confirmed that strain TAR-001(T) belongs to the family Caulobacteraceae of the class Alphaproteobacteria, and lies between the genus Brevundimonas and the genus Caulobacter. Levels of similarity between the 16S rRNA gene sequence of strain TAR-001(T) and those of the type strains of Brevundimonas species were 93.3 95.7%; highest sequence similarity was with the type strain of Brevundimonas diminuta. Levels of sequence similarity between those of the type strains of Caulobacter species were 94.9-96.0%; highest sequence similarity was with the type strain of Caulobacter mirabilis. The G+C content of strain TAR-001(T) was 67.6 mol%. Q-10 was the major respiratory isoprenoid quinone. The major fatty acids were C18:1omega7c and C16:0, and the presence of 1,2-di-O-acyl-3-O-[D glucopyranosyl-(1->4)-alpha-D-glucopyranuronosyl]glycerol suggests strain TAR 001(T) is more closely to the genus Brevundimonas than to the genus Caulobacter. The mean DNA-DNA hybridization levels between strain TAR-001(T) and the type strains of two species of the genus Brevundimonas were higher than that of the genus Caulobacter. On the basis of polyphasic biological features and the 16S rRNA gene sequence comparison presented here, strain TAR-001(T) is considered to represent a novel species of the genus Brevundimonas, for which the name Brevundimonas abyssalis sp. nov. is proposed; the type strain is TAR-001(T) (=JCM 18150(T)=CECT 8073(T)). PMID- 23041636 TI - Roseimicrobium gellanilyticum gen. nov., sp. nov., a new member of the class Verrucomicrobiae. AB - The taxonomic properties of strain DC2a-G7(T), a Gram-negative, ovoid to rod shaped, gellan gum-lysing bacterium, were examined. The 16S rRNA gene sequence similarity showed that DC2a-G7(T) is a member of the phylum Verrucomicrobia and the closest type strain of a species with a validly published name is Verrucomicrobium spinosum DSM 4136(T), with a sequence similarity of 91.2%. In addition to this similarity value lower than 95%, the absence of prostheca, the orangey-red colony colour and the compositions of the major menaquinones and polar lipids also supported the differentiation of this bacterium from the genus Verrucomicrobium. Here, we propose the name Roseimicrobium gellanilyticum gen. nov., sp. nov. for the isolate. The type strain of Roseimicrobium gellanilyticum is DC2a-G7(T) (=NBRC 108606(T)=DSM 25532(T)). PMID- 23041637 TI - Cultivation and characterization of the gut symbionts of honey bees and bumble bees: description of Snodgrassella alvi gen. nov., sp. nov., a member of the family Neisseriaceae of the Betaproteobacteria, and Gilliamella apicola gen. nov., sp. nov., a member of Orbaceae fam. nov., Orbales ord. nov., a sister taxon to the order 'Enterobacteriales' of the Gammaproteobacteria. AB - Gut-associated bacteria were isolated in axenic culture from the honey bee Apis mellifera and the bumble bees Bombus bimaculatus and B. vagans and are here placed in the novel genera and species Snodgrassella alvi gen. nov., sp. nov. and Gilliamella apicola gen. nov., sp. nov. Two strains from A. mellifera were characterized and are proposed as the type strains of Snodgrassella alvi (type strain wkB2(T) =NCIMB 14803(T) =ATCC BAA-2449(T) =NRRL B-59751(T)) and Gilliamella apicola (type strain wkB1(T) =NCIMB 14804(T) =ATCC BAA-2448(T)), representing, respectively, phylotypes referred to as 'Betaproteobacteria' and 'Gammaproteobacteria-1'/'Gamma-1' in earlier publications. These strains grew optimally under microaerophilic conditions, and did not grow readily under a normal atmosphere. The predominant fatty acids in both strains were palmitic acid (C16:0) and cis-vaccenic acid (C18:1omega7c and/or C18:1omega6c), and both strains had ubiquinone-8 as their major respiratory quinone. The DNA G+C contents were 41.3 and 33.6 mol% for wkB2(T) and wkB1(T), respectively. The Snodgrassella alvi strains from honey bees and bumble bees formed a novel clade within the family Neisseriaceae of the Betaproteobacteria, showing about 94% 16S rRNA gene sequence identity to their closest relatives, species of Stenoxybacter, Alysiella and Kingella. The Gilliamella apicola strains showed the highest 16S rRNA gene sequence identity to Orbus hercynius CN3(T) (93.9%) and several sequences from uncultured insect-associated bacteria. Phylogenetic reconstruction using conserved, single-copy amino acid sequences showed Gilliamella apicola as sister to the order 'Enterobacteriales' of the Gammaproteobacteria. Given its large sequence divergence from and basal position to the well-established order 'Enterobacteriales', we propose to place the clade encompassing Gilliamella apicola and O. hercynius in a new family and order, Orbaceae fam. nov. and Orbales ord. nov. PMID- 23041638 TI - Yamadazyma terventina sp. nov., a yeast species of the Yamadazyma clade from Italian olive oils. AB - During an investigation of olive oil microbiota, three yeast strains were found to be divergent from currently classified yeast species according to the sequences of the D1/D2 domain of the gene encoding the rRNA large subunit (LSU) and the internal transcribed spacer region including the gene for 5.8S rRNA. Phylogenetic analysis revealed that these strains, designated CBS 12509, CBS 12510(T) and CBS 12511, represent a novel anascosporogenous species described herein as Yamadazyma terventina sp. nov; the type strain is DAPES 1924(T) (= CBS 12510(T) = NCAIM Y.02028(T)). This novel species was placed in the Yamadazyma clade, with Yamadazyma scolyti, Candida conglobata and Candida aaseri as closest relatives. Y. terventina differs from the above-mentioned species in the ability to strongly assimilate dl-lactate and weakly assimilate ethanol. PMID- 23041639 TI - Cloacibacillus porcorum sp. nov., a mucin-degrading bacterium from the swine intestinal tract and emended description of the genus Cloacibacillus. AB - A novel anaerobic, mesophilic, amino-acid-fermenting bacterium, designated strain CL-84(T), was isolated from the swine intestinal tract on mucin-based media. Cells were curved rods (0.8-1.2 * 3.5-5.0 um), stained Gram-negative and were non motile with no evidence of spores. Strain CL-84(T) produced acetate, propionate, formate and butyrate as the end products of metabolism when grown on serine. Optimum growth occurred at 39 degrees C and pH 6.5. The major cellular fatty acids were iso-C15:0, iso-C15:0 3-OH, iso-C17:0 and C16:0, distinguishing strain CL-84(T) from closely related species. The DNA G+C content of strain CL-84(T) was 55.1 mol%. 16S rRNA gene sequence analysis showed that strain CL-84(T) shared 90 95% similarity with characterized genera within the phylum Synergistetes, family Synergistaceae. Phylogenetic analysis showed that strain CL-84(T) was related to, but distinct from, Cloacibacillus evryensis. Based on these findings, we propose that strain CL-84(T) represents a novel species of the genus Cloacibacillus. We further propose the name Cloacibacillus porcorum sp. nov. be designated for this species. The type strain is CL-84(T) (=DSM 25858(T)=CCUG 62631(T)). An emended description of the genus Cloacibacillus is provided. PMID- 23041640 TI - Arcanobacterium phocisimile sp. nov., isolated from harbour seals. AB - A polyphasic taxonomic study was performed on two previously unidentified Arcanobacterium-like Gram-positive strains isolated from harbour seals. Comparative 16S rRNA gene sequencing showed that both bacteria belonged to the genus Arcanobacterium and were most closely related to Arcanobacterium haemolyticum CIP 103370(T) (98.4% 16S rRNA gene sequence similarity), A. canis P6775(T) (97.4%), A. phocae DSM 10002(T) (97.4%), A. pluranimalium M430/94/2(T) (95.7%) and A. hippocoleae CCUG 44697(T) (95.5%). The presence of the major menaquinone MK-9(H4) supported the affiliation of the isolates with the genus Arcanobacterium. The polar lipid profile consisted of major amounts of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside, an unidentified phospholipid and two unidentified glycolipids. The major fatty acids were C16:0, C18:0, C18:1omega9c and summed feature 5 (comprising C18:2omega6,9c and/or anteiso-C18:0). Physiological and biochemical tests clearly distinguished the isolates from other members of the genus Arcanobacterium. Based on the common origin and various physiological properties comparable to those of A. phocae, it is proposed that the isolates are classified as members of a novel species with the name Arcanobacterium phocisimile sp. nov. The type strain is 2698(T) (=LMG 27073(T) =CCM 8430(T)). PMID- 23041641 TI - Mangrovimonas yunxiaonensis gen. nov., sp. nov., isolated from mangrove sediment. AB - A Gram-negative, short-rod-shaped, orange-pigmented bacterium, strain LYYY01(T), was isolated from a mangrove sediment sample collected from Yunxiao mangrove National Nature Reserve, Fujian Province, China. 16S rRNA gene sequence comparisons showed that strain LYYY01(T) is a member of the family Flavobacteriaceae, forming a distinct lineage with species of the genera Meridianimaribacter, Sediminibacter, Gelidibacter and Subsaximicrobium. The 16S rRNA gene sequence similarity between strain LYYY01(T) and the type strains of related species ranged from 93.9 to 90.9%. Growth was observed at temperatures from 10 to 38 degrees C, at salinities from 1 to 7% and at pH from 6 to 10. The DNA G+C content of the strain was 38.6 mol% and the major respiratory quinone was menaquinone-6 (MK-6). The major fatty acids were iso-C15:1 (27.6%), iso-C15:0 (24.0%), iso-C17:0 3-OH (12.0%) and iso-C16:0 3-OH (6.2%). According to its morphology, physiology, fatty acid composition and 16S rRNA gene sequence data, strain LYYY01(T) is considered to represent a novel species of a new genus in the family Flavobacteriaceae, for which the name Mangrovimonas yunxiaonensis gen. nov., sp. nov. is proposed. The type strain of Mangrovimonas yunxiaonensis is LYYY01(T) (=CGMCC 1.12280(T)=LMG 27142(T)). PMID- 23041642 TI - Algibacter aquimarinus sp. nov., isolated from a marine environment, and reclassification of Pontirhabdus pectinivorans as Algibacter pectinivorans comb. nov. AB - An orange-coloured, rod-shaped, Gram-reaction-negative and aerobic bacterial strain, designated KYW589(T), was isolated from seawater collected from Gwangyang Bay, Republic of Korea. The isolate required sea salts for growth. Gliding motility was observed. Flexirubin-type pigments were absent. Major cellular fatty acids (>10% of the total) were iso-C15:0, iso-C17:0 3-OH, iso-C15:1 G, C16:0, iso C15:0 3-OH and C18:0. The main polar lipids were phosphatidylethanolamine, two unidentified aminolipids and two unidentified lipids. The predominant isoprenoid quinone was MK-6. The DNA G+C content was 38.6 +/- 0.7 mol% (mean +/- sd of three determinations). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain KYW589(T) belongs to the family Flavobacteriaceae, and was related to the genus Algibacter. Based on data from a study using a polyphasic taxonomic approach, it is proposed that strain KYW589(T) represents a novel species belonging to the genus Algibacter, for which the name Algibacter aquimarinus sp. nov. is proposed. The type strain is KYW589(T) (=KCTC 23928(T) =JCM 18287(T)). Reclassification of Pontirhabdus pectinivorans Yi et al. 2011 to the genus Algibacter, as Algibacter pectinivorans comb. nov. (type strain JC2675(T) =KACC 14153(T) =JCM 17107(T)), is also proposed. PMID- 23041643 TI - Tamlicoccus marinus gen. nov., sp. nov., isolated from seawater. AB - A novel actinobacterial strain was isolated from a seawater sample collected on Mara Island, Jeju, Republic of Korea. Cells of this organism were aerobic, Gram positive, non-spore-forming, non-motile cocci that occurred singly or in pairs. Colonies were circular, smooth, convex and white-cream in colour. Phylogenetic analyses based on 16S rRNA gene sequences showed that the organism belonged to the family Dermacoccaceae and formed a monophyletic clade between the type strains of Demetria terragena (96.8% similarity) and Branchiibius hedensis (95.2% similarity). The cell-wall peptidoglycan contained L-lysine, alanine, aspartic acid, glutamic acid, glycine and serine, indicating that the isolate possessed peptidoglycan type A4alpha. The whole-cell sugars were galactose, glucose, mannose, xylose, arabinose, ribose and rhamnose. The major menaquinone was MK 8(H4). The polar lipids contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, an unknown phospholipid and five unknown lipids. The cellular fatty acid profile was represented by large amounts of iso-methyl branched and monounsaturated iso- and anteiso-methyl branched acids, along with the presence of a diagnostic 10-methyl acid. The G+C content of the DNA was 71 mol%. On the basis of data from polyphasic analyses presented here, strain MSW 24(T) is considered to represent a novel species of a new genus in the family Dermacoccaceae, for which the name Tamlicoccus marinus gen. nov., sp. nov. is proposed. The type strain of Tamlicoccus marinus is MSW-24(T) (=KCTC 19485(T)=DSM 21415(T)). PMID- 23041644 TI - Mesorhizobium qingshengii sp. nov., isolated from effective nodules of Astragalus sinicus. AB - In a study on the diversity of rhizobia isolated from root nodules of Astragalus sinicus, five strains showed identical 16S rRNA gene sequences. They were related most closely to the type strains of Mesorhizobium loti, Mesorhizobium shangrilense, Mesorhizobium ciceri and Mesorhizobium australicum, with sequence similarities of 99.6-99.8%. A polyphasic approach, including 16S-23S intergenic spacer (IGS) RFLP, comparative sequence analysis of 16S rRNA, atpD, glnII and recA genes, DNA-DNA hybridization and phenotypic tests, clustered the five isolates into a coherent group distinct from all recognized Mesorhizobium species. Except for strain CCBAU 33446, from which no symbiotic gene was detected, the four remaining strains shared identical nifH and nodC gene sequences and nodulated with Astragalus sinicus. In addition, these five strains showed similar but different fingerprints in IGS-RFLP and BOX-repeat-based PCR, indicating that they were not clones of the same strain. They were also distinguished from recognized Mesorhizobium species by several phenotypic features and fatty acid profiles. Based upon all the results, we suggest that the five strains represent a novel species for which the name Mesorhizobium qingshengii sp. nov. is proposed. The type strain is CCBAU 33460(T) (=CGMCC 1.12097(T)=LMG 26793(T)=HAMBI 3277(T)). The DNA G+C content of the type strain is 59.52 mol% (Tm). PMID- 23041645 TI - Caldicoprobacter guelmensis sp. nov., a thermophilic, anaerobic, xylanolytic bacterium isolated from a hot spring. AB - A hyperthermophilic anaerobic bacterium, designated D2C22(T), was isolated from the hydrothermal hot spring of Guelma in north-east Algeria. The isolate was a Gram-stain-positive, non-sporulating, non-motile rod, appearing singly or in pairs (0.3-0.4 * 8.0-9.0 um). Strain D2C22(T) grew anaerobically at 45-85 degrees C (optimum 65 degrees C), at pH 5-9 (optimum pH 6.8) and with 0-20 g NaCl l(-1). Strain D2C22(T) used glucose, galactose, lactose, fructose, ribose, xylose, arabinose, maltose, cellobiose, mannose, melibiose, sucrose, xylan and pyruvate (only in the presence of yeast extract or biotrypticase) as electron donors. The end products from glucose fermentation were acetate, lactate, CO2 and H2. Nitrate, nitrite, thiosulfate, elemental sulfur, sulfate and sulfite were not used as electron acceptors. The predominant cellular fatty acids were iso-C15:0 and iso-C17:0. The DNA G+C content was 41.6 mol%. Phylogenetic analysis of the 16S rRNA gene sequence indicated that strain D2C22(T) was most closely related to Caldicoprobacter oshimai JW/HY-331(T), Caldicoprobacter algeriensis TH7C1(T) and Acetomicrobium faecale DSM 20678(T) (95.5, 95.5 and 95.3% 16S rRNA gene sequence similarity, respectively). Based on phenotypic, phylogenetic and chemotaxonomic characteristics, strain D2C22(T) is proposed to be a representative of a novel species of the genus Caldicoprobacter within the order Clostridiales, for which the name Caldicoprobacter guelmensis sp. nov. is proposed. The type strain is D2C22(T) (=DSM 24605(T)=JCM 17646(T)). PMID- 23041646 TI - ABCC2 is involved in the hepatocyte perinuclear barrier for small organic compounds. AB - Small organic molecules are believed to freely diffuse across nuclear pores but this may not be so if this route is blocked during protein and nucleic acid transfer. Here we have investigated the existence of transport mechanisms across the nuclear envelope (NE) of hepatocytes. Using nuclei isolated from rat liver cells, evidence for the existence of ATP-dependent transporters of organic compounds was found. In rat hepatocyte NE, with negligible contamination by other membranes, the presence of mature and glycosylated ABCC2, but not other ABC export pumps, was detected. ABCC2 was localized in the same membranes as the conjugating enzyme UGT1A1. Human ABCC2 ORF was tagged with V5 and transfected to human hepatoma cells. ABCC2-V5 protein was detected at perinuclear ER vesicles and at the NE. Both compartments expressing ABCC2-V5 were able to exclude calcein. ABCC2 abundance at the NE of rat hepatocytes was modified by treatments able to increase or reduce the expression of canalicular ABCC2. The sensitivity to mitoxantrone was higher for hepatocytes obtained from TR- rats whose NE lacked ABCC2. Incubation with mitoxantrone after depletion of ATP resulted in a marked accumulation of mitoxantrone in the nucleus of wild-type, but not TR-, hepatocytes. In sum, ABCC2 is present at the NE and perinuclear ER where, in combination with the activity of conjugating enzymes, this pump may be involved in the perinuclear barrier for small organic molecules, playing a role in protecting DNA from genotoxic compounds and in the control of intranuclear concentrations of ligands for nuclear receptors. PMID- 23041647 TI - Metformin reduces airway inflammation and remodeling via activation of AMP activated protein kinase. AB - Recent reports have suggested that metformin has anti-inflammatory and anti tissue remodeling properties. We investigated the potential effect of metformin on airway inflammation and remodeling in asthma. The effect of metformin treatment on airway inflammation and pivotal characteristics of airway remodeling were examined in a murine model of chronic asthma generated by repetitive challenges with ovalbumin and fungal-associated allergenic protease. To investigate the underlying mechanism of metformin, oxidative stress levels and AMP-activated protein kinase (AMPK) activation were assessed. To further elucidate the role of AMPK, we examined the effect of 5-aminoimidazole-4 carboxamide-1-beta-4-ribofuranoside (AICAR) as a specific activator of AMPK and employed AMPKalpha1-deficient mice as an asthma model. The role of metformin and AMPK in tissue fibrosis was evaluated using a bleomycin-induced acute lung injury model and in vitro experiments with cultured fibroblasts. Metformin suppressed eosinophilic inflammation and significantly reduced peribronchial fibrosis, smooth muscle layer thickness, and mucin secretion. Enhanced AMPK activation and decreased oxidative stress in lungs was found in metformin-treated asthmatic mice. Similar results were observed in the AICAR-treated group. In addition, the enhanced airway inflammation and fibrosis in heterozygous AMPKalpha1-deficient mice were induced by both allergen and bleomycin challenges. Fibronectin and collagen expression was diminished by metformin through AMPKalpha1 activation in cultured fibroblasts. Therefore metformin reduced both airway inflammation and remodeling at least partially through the induction of AMPK activation and decreased oxidative stress. These data provide insight into the beneficial role of metformin as a novel therapeutic drug for chronic asthma. PMID- 23041648 TI - Monkey liver cytochrome P450 2C19 is involved in R- and S-warfarin 7 hydroxylation. AB - Cynomolgus monkeys are widely used as primate models in preclinical studies. However, some differences are occasionally seen between monkeys and humans in the activities of cytochrome P450 enzymes. R- and S-warfarin are model substrates for stereoselective oxidation in humans. In this current research, the activities of monkey liver microsomes and 14 recombinantly expressed monkey cytochrome P450 enzymes were analyzed with respect to R- and S-warfarin 6- and 7-hydroxylation. Monkey liver microsomes efficiently mediated both R- and S-warfarin 7 hydroxylation, in contrast to human liver microsomes, which preferentially catalyzed S-warfarin 7-hydroxylation. R-Warfarin 7-hydroxylation activities in monkey liver microsomes were not inhibited by alpha-naphthoflavone or ketoconazole, and were roughly correlated with P450 2C19 levels and flurbiprofen 4-hydroxylation activities in microsomes from 20 monkey livers. In contrast, S warfarin 7-hydroxylation activities were not correlated with the four marker drug oxidation activities used. Among the 14 recombinantly expressed monkey P450 enzymes tested, P450 2C19 had the highest activities for R- and S-warfarin 7 hydroxylations. Monkey P450 3A4 and 3A5 slowly mediated R- and S-warfarin 6 hydroxylations. Kinetic analysis revealed that monkey P450 2C19 had high V(max) and low K(m) values for R-warfarin 7-hydroxylation, comparable to those for monkey liver microsomes. Monkey P450 2C19 also mediated S-warfarin 7 hydroxylation with V(max) and V(max)/K(m) values comparable to those for recombinant human P450 2C9. R-warfarin could dock favorably into monkey P450 2C19 modeled. These results collectively suggest high activities for monkey liver P450 2C19 toward R- and S-warfarin 6- and 7-hydroxylation in contrast to the saturation kinetics of human P450 2C9-mediated S-warfarin 7-hydroxylation. PMID- 23041650 TI - Prevention and amelioration of rodent endotoxin-induced lung injury with administration of a novel therapeutic tripeptide feG. AB - BACKGROUND: The synthetic tripeptide feG is a novel pharmacological agent that decreases neutrophil recruitment, infiltration, and activation in various animal models of inflammatory disease. In human and rat cell culture models, feG requires pre-stimulation in order to decrease in vitro neutrophil chemotaxis. We aimed to investigate the effect of feG on neutrophil chemotaxis in a lipopolysaccharide-induced acute lung injury model without pre-stimulation. METHODS: The efficacy of feG as both a preventative treatment, when administered before lung injury (prophylactic), or as a therapeutic treatment, administered following lung injury (therapeutic), was investigated. RESULTS: Prophylactic or therapeutic feG administration significantly reduced leukocyte infiltration, ameliorated the severity of inflammatory damage, and restored lung function. feG was demonstrated to significantly decrease bronchoalveolar lavage cell infiltration, lung myeloperoxidase activity, lung oedema, histological tissue injury scores, and improve arterial blood oxygenation and respiratory mechanics. CONCLUSIONS: feG reduced leukocyte infiltration, ameliorated the severity of inflammatory damage, and restored lung function when administered prophylactically or therapeutically in a rodent model of lipopolysaccharide induced acute lung injury, without the need for pre-stimulation, suggesting a direct rather than indirect mechanism of action in the lung. PMID- 23041649 TI - Modulation of signaling pathways in prostate cancer by green tea polyphenols. AB - Prostate cancer (PCa) is the most common malignancy found in American men and the risk factors for PCa include age, family history, ethnicity, hormonal status, diet and lifestyle. For the successful development of cancer preventive/therapeutic approaches, consumption of dietary agents capable of inhibiting or delaying the growth and proliferation of cancer cells without significantly affecting normal cells could be an effective strategy. Polyphenols derived from green tea, termed as green tea polyphenols (GTP) have received great attention in recent years for their beneficial effects, in particular, their significant involvement in cancer chemoprevention and chemotherapy. Several studies have reported beneficial effects of GTP using in vitro and in vivo approaches and in human clinical trials. Among green tea catechins, epigallocatechin-3-gallate (EGCG) is best studied for its cancer preventive properties. In this review article, we present available scientific literature about the effects of GTP and EGCG on signaling pathways in PCa. PMID- 23041651 TI - NMR techniques in drug delivery: application to zein protein complexes. AB - Zein is a protein containing a large amount of nonpolar amino acids, which has shown the ability to form aggregates and entrap solutes, such as drugs and amino acids. NMR techniques were used to detect binding interactions and measure affinity between zein and three different drugs: tetracycline, amoxicillin and indomethacin. The release study of zein microparticle formulations containing any of these drugs was confronted with the affinity results, showing a remarkable correlation. The feasible methodology employed, focused in the functionality of the protein-drug interaction, can be very promising for the rational design of appropriate drug vehicles for drug delivery. PMID- 23041652 TI - Construction of integrative plasmids suitable for genetic modification of industrial strains of Saccharomyces cerevisiae. AB - The development of efficient tools for genetic modification of industrial yeast strains is one of the challenges that face the use of recombinant cells in industrial processes. In this study, we examine how the construction of two complementary integrative vectors can fulfill the major requirements of industrial recombinant yeast strains: the use of lactose assimilation genes as a food-grade yeast selection marker, and a system of integration that does not leave hazardous genes in the host genome and involves minimal interference in the yeast physiology. The pFB plasmid set was constructed to co-integrate both LAC4 based and LAC12-based cassettes into the ribosomal DNA (rDNA) locus to allow yeast cells to be selected in lactose medium. This phenotype can also be used to trace the recombinant cells in the environment by simply being plated on X-gal medium. The excisable trait of the LAC12 marker allows the introduction of many different heterologous genes, and makes it possible to introduce a complete heterologous metabolic pathway. The cloned heterologous genes can be highly expressed under the strong and constitutive TPI1 gene promoter, which can be exchanged for easy digestion of enzymes if necessary. This platform was introduced into Saccharomyces cerevisiae JP1 industrial strain where a recombinant with high stability of markers was produced without any change in the yeast physiology. Thus, it proved to be an efficient tool for the genetic modification of industrial strains. PMID- 23041653 TI - Life satisfaction and preterm birth among urban black women: findings from the Baltimore preterm birth study. AB - PURPOSE: Preterm birth (PTB) is a major problem in the United States, and black women have greater risk of PTB than white women. The etiology of PTB and the racial disparity in preterm outcomes are poorly understood. Diminished life satisfaction is associated with adult health, but there are no studies of life satisfaction and PTB. In the research reported in this article, the relationship between life satisfaction and PTB among black women was studied. METHODS: Women were enrolled in this prospective study at the time of the first visit to 5 prenatal clinics in Baltimore. Life satisfaction was assessed at the time of the first prenatal visit. Data on PTB were obtained from medical records. RESULTS: The final sample consisted of 922 women. Among women who were somewhat or not at all satisfied with their lives, 16% had preterm births, whereas among women who were very satisfied with their lives, 10.7% had preterm births (unadjusted odds ratio = 1.6; 95% CI 1.1-2.4). The adjusted odds ratio was 1.6 (95% CI 1.00-2.5). CONCLUSIONS: Women who reported being somewhat or not at all satisfied with their lives had a greater risk of PTB than women who reported being very satisfied with their lives. PMID- 23041654 TI - Correcting for exposure misclassification using survival analysis with a time varying exposure. AB - PURPOSE: Survival analysis is increasingly being used in perinatal epidemiology to assess time-varying risk factors for various pregnancy outcomes. Here we show how quantitative correction for exposure misclassification can be applied to a Cox regression model with a time-varying dichotomous exposure. METHODS: We evaluated influenza vaccination during pregnancy in relation to preterm birth among 2267 non-malformed infants whose mothers were interviewed as part of the Slone Birth Defects Study during 2006 through 2011. The hazard of preterm birth was modeled using a time-varying exposure Cox regression model with gestational age as the time-scale. The effect of exposure misclassification was then modeled using a probabilistic bias analysis that incorporated vaccination date assignment. The parameters for the bias analysis were derived from both internal and external validation data. RESULTS: Correction for misclassification of prenatal influenza vaccination resulted in an adjusted hazard ratio (AHR) slightly higher and less precise than the conventional analysis: Bias-corrected AHR 1.04 (95% simulation interval, 0.70-1.52); conventional AHR, 1.00 (95% confidence interval, 0.71-1.41). CONCLUSIONS: Probabilistic bias analysis allows epidemiologists to assess quantitatively the possible confounder-adjusted effect of misclassification of a time-varying exposure, in contrast with a speculative approach to understanding information bias. PMID- 23041655 TI - Factors associated with intimate partner violence by a former partner by immigration status and length of residence in Canada. AB - PURPOSE: We examined intimate partner violence (IPV) by a former partner among Canadian-born and immigrant women by length of residence in Canada. METHODS: Data from a 2009 national, population-based, telephone survey were used to determine the prevalence of and factors associated with any type of IPV (emotional, financial, physical, and/or sexual) by a former partner with whom there had been contact in the previous 5 years among immigrant women 0 to 19 years in Canada, 20 or more years or longer in Canada, and Canadian-born women (n = 1681). RESULTS: Of immigrant women in Canada for 0 to 19 years, 41.6% had experienced IPV by a former partner; for immigrant women in Canada for 20 or more years or longer, 60.6%, and Canadian-born women, 61.5% (P = .0423). In a logistic regression model adjusted for age and other sociodemographic characteristics, immigrant women in Canada for 0 to 19 years were less likely than Canadian-born women to experience any IPV (odds ratio, 0.266; 95% confidence interval, 0.130-0.544). There was no difference in the occurrence of any IPV between immigrant women in Canada 20 or more years or longer and Canadian-born women. CONCLUSIONS: High rates of any IPV by a former partner were found for both Canadian-born and immigrant women. Within immigrant communities, specific prevention campaigns should address the high risk of experiencing IPV at later stages of resettlement. PMID- 23041656 TI - Through thick and thin: the conundrum of chromatin fibre folding in vivo. PMID- 23041657 TI - Immunohistochemical analysis of sphingosine phosphate lyase expression during murine development. AB - Sphingosine-1-phosphate lyase (SPL) catalyzes the degradation of sphingosine-1 phosphate (S1P), a bioactive lipid that controls cell proliferation, migration and survival. Mice lacking SPL expression exhibit developmental abnormalities, runting and death during the perinatal period, suggesting that SPL plays a role in mammalian development and adaptation to extrauterine life. We investigated the pattern of SPL expression in the mouse embryo and placenta from day 8 to day 18. Our findings reveal that SPL is expressed in the developing brain and neural tube, Rathke's pouch, first brachial arch, third brachial arch, optic stalk, midgut loops, and lung buds. Diffuse signal was high at E12, whereas a recognizable adult SPL pattern was evident by E15 and more intensely at E18, with strong expression in skin, nasal epithelium, intestinal epithelium, cartilage, thymus and pituitary gland. These findings suggest SPL may be involved in development of the mammalian central nervous system (CNS), anterior pituitary, trigeminal nerve, palate and facial bones, thymus and other organs. Our findings are consistent with the SPL expression pattern of the adult mouse and with congenital abnormalities observed in SPL mutant mice. PMID- 23041658 TI - Service provision for autism in mainland China: a service providers' perspective. AB - Qualitative semi-structured interviews were conducted with service providers regarding the current healthcare provision and education services for children with Autism Spectrum Conditions (ASC) and their families in mainland China. 10 service providers described the current policy and identified unmet needs within current practice. Providers perceived that children with ASC were an important but under-served group in mainland China. Two levels of service provision related to ASC were identified: (1) healthcare services mainly provided by government authorities; (2) education services mainly provided by the parents of children with ASC. Little cooperation was reported between the two types of providers. The structure of service provision for ASC is under-developed. There is an important need to establish coherent healthcare and education policies to support children with ASC and their families. PMID- 23041659 TI - I can read it in your eyes: what eye movements tell us about visuo-attentional processes in developmental dyslexia. AB - Most studies today agree about the link between visual-attention and oculomotor control during reading: attention seems to affect saccadic programming, that is, the position where the eyes land in a word. Moreover, recent studies show that visuo-attentional processes are strictly linked to normal and impaired reading. In particular, a large body of research has found evidence of defective visuo attentional processes in dyslexics. What do eye movements tell us about visuo attentional deficits in developmental dyslexia? The purpose of this paper is to explore the link between oculomotor control and dyslexia, taking into account its heterogeneous manifestation and comorbidity. Clinical perspectives in the use of the eye-movements approach to better explore and understand reading impairments are discussed. PMID- 23041660 TI - Comparison of computer based instruction to behavior skills training for teaching staff implementation of discrete-trial instruction with an adult with autism. AB - In the current study, behavior skills training (BST) is compared to a computer based training package for teaching discrete trial instruction to staff, teaching an adult with autism. The computer based training package consisted of instructions, video modeling and feedback. BST consisted of instructions, modeling, rehearsal and feedback. Following training, participants were evaluated in terms of their accuracy on completing critical skills for running a discrete trial program. Six participants completed training; three received behavior skills training and three received the computer based training. Participants in the BST group performed better overall after training and during six week probes than those in the computer based training group. There were differences across both groups between research assistant and natural environment competency levels. PMID- 23041661 TI - Salt bridge switching from Arg290/Glu167 to Arg290/ATP promotes the closed-to open transition of the P2X2 receptor. AB - P2X receptors are trimeric adenosine-5'-triphosphate (ATP)-gated cation channels involved in fast signal transduction in many cell types. In this study, we used homology modeling of the rat P2X2 receptor with the zebrafish P2X4 X-ray template to determine that the side chains of the Glu167 and Arg290 residues are in close spatial vicinity within the ATP-binding pocket when the rat P2X2 channel is closed. Through charge reversal mutation analysis and mutant cycle analysis, we obtained evidence that Glu167 and Arg290 form an electrostatic interaction. In addition, disulfide trapping indicated the close proximity of Glu167 and Arg290 when the channel is in the closed state, but not in the ATP-bound open state. Consistent with a gating-induced movement that disrupts the Glu167/Arg290 salt bridge, a comparison of the closed and open rat P2X2 receptor models revealed a significant rearrangement of the protein backbone and the side chains of the Glu167 and Arg290 residues during the closed-to-open transition. The associated release of the Glu167/Arg290 salt bridge during channel opening allows a strong ionic interaction between Arg290 and a gamma-phosphate oxygen of ATP. We conclude from these results that the state-dependent salt bridge switching from Arg290/Glu167 to Arg290/ATP fulfills a dual role: to destabilize the closed state of the receptor and to promote the ionic coordination of ATP in the ATP-binding pocket. PMID- 23041663 TI - HLA class II high-resolution genotyping in Greek children with celiac disease and impact on disease susceptibility. AB - BACKGROUND: Celiac disease (CD) has been associated with HLA class II heterodimers. This study aimed at determining the HLA genotypic and allelic distribution in Greek children with CD as compared with the general population. METHODS: A total of 118 children with CD and 120 healthy individuals serving as controls were included in the study. RESULTS: Higher frequencies for HLA DQB1*02:01 (40.25 vs. 9.58%, P < 0.001) and DQB1*02:02 (20.34 vs. 5.42%, P < 0.001) were observed in patients with CD, whereas HLA-DQB1*03:01 (16.53 vs. 30.42%, P < 0.001), DQB1*05:01 (0.85 vs. 10%, P < 0.001), and DQB1*05:02 (5.51 vs. 17.92%, P < 0.001) were significantly lower, as compared with the controls. DQA1*02:01 (patients with CD vs. controls: 20.76 vs. 6.67%, P < 0.001) and DQA1*05:01 (40.25 vs. 9.58%, P < 0.001) were significantly more frequent in patients. The frequencies of HLA-DQA1* 01:01, *01:02, *01:04, and *05:05 were significantly lower in patients (P < 0.001). The haplotype mainly associated with CD was DRB1*03-DQB1*02:01-DQA1*05:01; patients with CD vs. controls: 39.83 vs. 9.58%, P < 0.001. In total, 84.75% of patients carried DQ2 (vs. 21.67% in controls, P < 0.001), whereas 11.02% were DQ8 positive/DQ2 negative. CONCLUSION: This study confirms the existing data and provides additional evidence supporting a strong genetic predisposition for CD associated with the class II alleles DQB1*02 and DQA1*05 encoding the serological specificity DQ2. PMID- 23041662 TI - Arginine and citrulline protect intestinal cell monolayer tight junctions from hypoxia-induced injury in piglets. AB - BACKGROUND: Arginine (Arg) is deficient in the serum of the preterm neonate and is lower in those developing intestinal ischemia. We investigated whether Arg or its precursor, citrulline (Cit), protects intestinal tight junctions (TJs) from hypoxia (HX) and determined whether inducible nitric oxide (NO) plays a role. METHODS: Neonatal piglet jejunal IPEC-J2 cell monolayers were treated with Arg or Cit, reversible and irreversible NO synthetase (NOS) inhibitors, and were exposed to HX. TJs were assessed by serial measurements of transepithelial electrical resistance (TEER), flux of inulin-fluorescein isothiocyanate, and immunofluorescent staining of TJ proteins. RESULTS: We found that Arg and Cit were protective against HX-related damage. At the final time point (14 h), the mean TEER ratio (TEER as compared with baseline) for Arg + HX and Cit + HX was significantly higher than that for HX alone. Both Arg and Cit were associated with decreased inulin flux across hypoxic monolayers and qualitatively preserved TJ proteins. Irreversible inhibition of NOS blocked this protective effect. Lipid peroxidation assay showed that our model did not produce oxidant injury. CONCLUSION: Arg and Cit, via a mechanism dependent on NO donation, protected intestinal epithelial integrity. PMID- 23041664 TI - Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model. AB - BACKGROUND: Oxidative stress (oxidant-antioxidant imbalance) plays an important role in the pathophysiology of neonatal sepsis. This study evaluated whether an antisense peptide endothelin receptor antagonist, ETR-P1/fl, could attenuate oxidative stress in a neonatal sepsis model. METHODS: A total of 18 3-d-old piglets were anesthetized and mechanically ventilated. Six piglets received cecal ligation and perforation (CLP group) for induction of sepsis. Six piglets also received continuous infusion (0.05 mg/kg/h) of ETR-P1/fl 30 min after CLP (ETR P1/fl group). Six piglets received a sham operation. Serum total hydroperoxide (TH), biological antioxidant potentials (BAPs), oxidative stress index (OSI, calculated as TH/BAP), interleukin (IL)-6, serum glutamic oxaloacetic transaminase (GOT), and creatinine were measured before CLP and at 1, 3, and 6 h after CLP. RESULTS: CLP evoked a state of shock resulting in elevated TH, OSI, and IL-6 levels. ETR-P1/fl administration after CLP resulted in lower serum TH at 1 and 3 h after CLP, OSI at 1 and 3 h after CLP, IL-6 at 1 and 3 h after CLP, and GOT at 3 and 6 h after CLP as compared with the CLP group. CONCLUSION: ETR-P1/fl treatment significantly attenuated the elevation of serum oxidative stress markers (TH and OSI), IL-6, and GOT in a progressive neonatal sepsis CLP model. PMID- 23041665 TI - Preparation, characterization and in vitro anticoagulant activity of highly sulfated chitosan. AB - This work is the first to report sulfation of chitosans with different molecular weight (Mw, 51.5-112.4 kDa) via their trimethylsilylated derivatives as the precursors. Different from original chitosan, silylated chitosan was easily sulfated with sulfur trioxide-pyridine complex under homogeneous conditions in DMSO, and highly sulfated products with degree of sulfation (DS) in the range of 1.65-2.46 and Mw in the range of 18.1-54.5 kDa were obtained at 20-40 degrees C. Degradation of chitosan was inevitable in the reaction process. However, the extent of degradation reduced with increasing of degree of trimethylsilylation (DT). The results of UV-vis and fluorescence emission spectra indicated that the chitosan degradation involved elimination reaction. Clotting assays showed that highly sulfated chitosans significantly prolonged activated partial thromboplastin time (APTT) and thrombin time (TT), but not prothrombin time (PT). A high DS (>2.1) value was essential for the anticoagulant activity. PMID- 23041666 TI - Characterization and biological activity of Solidago canadensis complex. AB - Polyphenolic-polysaccharide-protein complex has been isolated from flowers of Solidago canadensis L. by hot alkaline extraction procedure. Compositional analyses of S canadensis complex revealed the presence of carbohydrates (43 wt%), protein (27 wt%), phenolics (12 wt%), uronic acids (10 wt%) and inorganic material (8 wt%). The carbohydrate part was rich in neutral sugars (81 wt%) while uronids were determined in lower amount (19 wt%). Monosaccharide analysis of carbohydrate part revealed the presence of five main sugar components, i.e. rhamnose (~23 wt%), arabinose (~20 wt%), uronic acids (~19 wt%), galactose (~17 wt%) and glucose (~14 wt%), and indicated thus the presence of rhamnogalacturonan and arabinogalactan in S. canadensis complex. HPLC analysis of complex showed one single peak of molecule mass at 11.2 kDa. Antitussive activity tests, performed in three doses of Solidago complex, showed the reduction of the number of cough efforts in the dose-dependent manner. Higher doses (50 and 75 mg/kg b.w.) were shown to be by 15 and 20% more effective than that of lower one (25mg/kg b.w.). However, the antitussive effect of the highest dose (75 mg/kg b.w.) was by 10% lower in comparison with that of codeine, the strongest antitussive agent. Besides, the highest dose of the complex (75 mg/kg b.w.) significantly decreased values of specific airways resistance and their effect remained longer as that of salbutamol, a representative of classic antiasthmatic drugs. PMID- 23041667 TI - Controlled release of 5-aminosalicylicacid from chitosan based pH and temperature sensitive hydrogels. AB - A series of temperature and pH responsive hydrogels based on chitosan and poly(N isopropyl acrylamide) (PNIPA) was prepared by redox polymerization. Effect of the composition on swelling behavior of the hydrogels and the release of 5 aminosaylcilic acid (5-ASA) at different temperatures and pHs have been investigated. Ammonium persulphate and TEMED were used as a redox pair at room temperature. As a cross linker, methacrylated chitosan was synthesized through the reaction of chitosan with glycidyl methacrylate (GMA). Introduction of the cross-linker provided the hydrogels with pH and temperature sensitivities. The phase transition temperatures of the hydrogels were determined by derivative differential scanning calorimeter (DDSC). Their phase transition temperatures were increased by chitosan content. Swelling behaviors and the release of 5-ASA varied significantly with pH, temperature and the gel composition. The release of 5-ASA from the hydrogels was followed by UV-Vis and fluorescence spectroscopy. PMID- 23041668 TI - Immune-enhancing activity comparison of sulfated ophiopogonpolysaccharide and sulfated jujube polysaccharide. AB - The immune-enhancing activities of four sulfated polysaccharides, sOPS(t), sOPS(80), sJPS(t) and sJPS(50) picked out in our previous researches, were compared taking four corresponding unmodified polysaccharides as control. In vitro experiment, the effects of eight polysaccharides on chicken peripheral lymphocyte proliferation were determined by MTT assay. The result displayed that four sulfated polysaccharides could significantly stimulate lymphocyte proliferation, their actions were significantly or numerically stronger than those of corresponding unmodified polysaccharides, sOPS(80) presented better efficacy. In vivo experiment, 300 14-day-old chickens were averagely divided into ten groups. The chickens except blank control (BC) group were vaccinated with Newcastle disease vaccine, repeated vaccination at 28 days old. At the same time of the first vaccination, the chickens in eight polysaccharides groups were injected respectively with 0.5 ml (1mg) of eight polysaccharides, in vaccination control (VC) and BC group, with 0.5 mL of physiological saline, once a day for three successive days. On days 7, 14, 21 and 28 after the first vaccination, the peripheral lymphocyte proliferation and serum ND antibody titer were determined. The result showed that four sulfated polysaccharides could significantly promote lymphocyte proliferation and enhance serum antibody titer. Their actions were significantly or numerically stronger than those of corresponding unmodified polysaccharides, sOPS(80) possessed the best efficacy. These results indicated that sulfation modification could enhance the immune-enhancing activity of OPS and JPS, sOPS(80) possessed the best efficacy and would be expected as a component drug of new-type immunopotentiator. PMID- 23041669 TI - Stability of delayed neural networks with time-varying impulses. AB - This paper addresses the stability problem of a class of delayed neural networks with time-varying impulses. One important feature of the time-varying impulses is that both the stabilizing and destabilizing impulses are considered simultaneously. Based on the comparison principle, the stability of delayed neural networks with time-varying impulses is investigated. Finally, the simulation results demonstrate the effectiveness of the results. PMID- 23041670 TI - Convergence analysis of deterministic discrete time system of a unified self stabilizing algorithm for PCA and MCA. AB - Unified algorithms for principal and minor components analysis can be used to extract principal components and if altered simply by the sign, it can also serve as a minor component extractor. Obviously, the convergence of these algorithms is an essential issue in practical applications. This paper studies the convergence of a unified PCA and MCA algorithm via a corresponding deterministic discrete time (DDT) system and some sufficient conditions to guarantee convergence are obtained. Simulations are carried out to further illustrate the theoretical results achieved. PMID- 23041671 TI - Canid progesterone receptors lack activation function 3 domain-dependent activity. AB - Progesterone regulates multiple behavioral, physiological, and pathological aspects of female reproductive biology through its two progesterone receptors (PRs), PR-B and the truncated PR-A. PR-B is necessary for mammary gland development in mice and, compared with PR-A, is overall a stronger transactivator of target genes due to an additional activation function 3 (AF3) domain. In dogs, known for their high sensitivity to progesterone-induced mammary cancer, the PR-B function was studied. Canine PR (cPR)-B appeared to contain multiple mutations within AF3 core sequence motifs and lacks N-terminal ligand-independent posttranslational modifications. Consequently, cPR-B has a weak transactivation potential on progesterone-responsive mouse mammary tumor virus-luc and progesterone response element 2-luc reporters transiently transfected in hamster, human, or canine cells and also on known target genes FKBP5 and SGK in doxycycline-inducible, stable transfected cPR-B in canine mammary cells. The cPR B function was restored to the level of human PR-B by the replacement of canine AF3 domain with the human one. The lack of AF3 domain-dependent transcriptional activity was unique for canids (gray wolf, red fox, and raccoon dog) and not present in closely related caniform species (brown bear, gray seal, and domestic ferret). Despite the limited transactivation potential, canids develop normal mammary glands and frequently mammary tumors. Therefore, these results question the role of PR-B in breast cancer development and may explain unique features of canid reproduction. PMID- 23041673 TI - The cortisol and androgen pathways cross talk in high temperature-induced masculinization: the 11beta-hydroxysteroid dehydrogenase as a key enzyme. AB - In many ectotherm species the gonadal fate is modulated by temperature early in life [temperature-dependent sex determination (TSD)] but the transducer mechanism between temperature and gonadal differentiation is still elusive. We have recently shown that cortisol, the glucocorticoid stress-related hormone in vertebrates, is involved in the TSD process of pejerrey, Odontesthes bonariensis. Particularly, all larvae exposed to a male-producing temperature (MPT, 29 C) after hatching showed increased whole-body cortisol and 11-ketotestosterone (11 KT; the main bioactive androgen in fish) levels and developed as males. Moreover, cortisol administration at an intermediate, mixed sex-producing temperature (MixPT, 24 C) caused increases in 11-KT and in the frequency of males, suggesting a relation between this glucocorticoid and androgens during the masculinization process. In order to clarify the link between stress and masculinization, the expression of hydroxysteroid dehydrogenase (hsd)11b2, glucocorticoid receptors gr1 and gr2, and androgen receptors ar1 and ar2 was analyzed by quantitative real time PCR and in situ hybridization in larvae reared at MPT, MixPT, and female producing temperature (FPT, 17 C) during the sex determination period. We also analyzed the effects of cortisol treatment in larvae reared at MixPT and in adult testicular explants incubated in vitro. MPT and cortisol treatment produced significant increases in hsd11b2 mRNA expression. Also, gonadal explants incubated in the presence of cortisol showed increases of 11-KT levels in the medium. Taken together these results suggest that cortisol promotes 11-KT production during high temperature-induced masculinization by modulation of hsd11b2 expression and thus drives the morphogenesis of the testes. PMID- 23041672 TI - Nuclear export signal of androgen receptor (NESAR) regulation of androgen receptor level in human prostate cell lines via ubiquitination and proteasome dependent degradation. AB - Androgen receptor (AR) plays a key role in prostate development and carcinogenesis. Increased expression and/or stability of AR is associated with sensitization of prostate cancer cells to low levels of androgens, leading to castration resistance. Hence, understanding the mechanisms regulating AR protein stability is clinically relevant and may lead to new approaches to prevent and/or treat prostate cancer. Using fluorescence microscopy, Western blot, and pulse chase assay, we showed that nuclear export signal (NES)(AR), a nuclear export signal in the ligand binding domain (LBD) of AR, can significantly enhance the degradation of fusion protein constructs in PC3 prostate cancer cells. The half life of GFP-NES(AR) was less than 3 h, which was 10 times shorter than that of green fluorescent protein (GFP) control. Further analysis showed that NES(AR) can signal for polyubiquitination and that degradation of NES(AR)-containing fusion proteins can be blocked by proteasome inhibitor MG132. Ubiquitination of GFP-AR or GFP-LBD was suppressed in the presence of dihydrotestosterone, which is known to suppress NES(AR) while inducing nuclear localization signal 2 in AR or LBD, suggesting that the export activity of NES(AR) is required for NES(AR)-mediated polyubiquitination. Treatment with MG132 also induced aggresome formation of NES(AR)-containing fusion proteins in perinuclear regions of the transfected PC3 cells, indicating a role for NES(AR) in inducing unfolded protein responses. The above observations suggest that NES(AR) plays a key role in AR ubiquitination and proteasome-dependent degradation in prostate cancer cells. PMID- 23041674 TI - Epigenetics in inflammatory bowel disease. AB - PURPOSE OF REVIEW: To briefly summarize some of the principles of epigenetics and assess their potential relevance for the disease pathogenesis of inflammatory bowel diseases (IBDs). To review the results of recent IBD-related epigenetic studies, discuss main challenges as well as highlight the opportunities for future research in this field. RECENT FINDINGS: Evidence is accumulating for a major role of epigenetic mechanisms in the disease pathogenesis of several immune mediated diseases. Recent findings indicate that epigenetics may mediate some of the effects of environment, genetic predisposition and intestinal microbiota on IBD pathogenesis. SUMMARY: Epigenetics is a rapidly expanding and hugely promising area of research. At best, it may provide a unifying molecular mechanism to explain complex immune-mediated diseases such as IBD. Future research studies must be carefully designed, performed and analysed taking into account the basic principles of epigenetics in order to ensure the true potential of this field is realized in the understanding of IBD. PMID- 23041675 TI - Gastroparesis. AB - PURPOSE OF REVIEW: Gastroparesis is a common disorder that produces symptoms of gastric retention in the absence of physical obstruction. Extensive research into the clinical features, pathophysiology, diagnostic evaluation, and therapy of gastroparesis in the past several years has offered insight into the condition. This review provides updated information on gastroparesis focusing on new findings from the past few years. RECENT FINDINGS: Large database studies have characterized clinical profiles in idiopathic and diabetic gastroparesis and are defining roles of gastric and extragastric factors in symptom genesis. Dietary deficiencies in gastroparesis have been clarified. Histologic study of full thickness gastric tissue in severe gastroparesis shows heterogeneous enteric neuronal, smooth muscle, interstitial cell, and inflammatory abnormalities. Advances in gastric emptying testing include wireless motility capsules and nonradioactive breath tests. The importance of glycemic control in diabetic gastroparesis is a focus of current investigation. Novel therapies include new prokinetics (ghrelin agonists), increased focus on antiemetic agents including antidepressants, and next generation gastric stimulators. Studies are being initiated to delineate the natural history of gastroparesis. SUMMARY: Much has been learned recently on the causes, clinical presentations, and management of gastroparesis. Current ongoing investigation provides promise for further gains in the years ahead. PMID- 23041676 TI - Maternal farm exposure/ingestion of unpasteurized cow's milk and allergic disease. AB - PURPOSE OF REVIEW: The prevalence of allergic diseases has reached a high prevalence in affluent countries. Yet, there are areas and living conditions associated with very low rates which are attributable to environmental exposures. One example is the low prevalence of childhood asthma and allergies amongst children raised on farms, particularly those exposed to farm animals and unprocessed cow's milk very early in life which are being reviewed in this article. RECENT FINDINGS: Several studies have shown that maternal exposure to various farm animals in pregnancy is related to a reduced risk of atopic dermatitis in the child and immune responses which have generally been regarded as protecting from the development of asthma and allergies. In addition, maternal and infant consumption of unprocessed cow's milk has repeatedly been associated with protection from childhood asthma and allergies. The precise nature of the protective factors remains to be elucidated. Maternal exposures to farm animals result in increased microbial exposures, the diversity of which has been associated with protection from childhood asthma. The beneficial milk constituents may, however, not be contained in the microbial contamination of milk samples but rather in the whey fraction of unprocessed cow's milk. SUMMARY: Better understanding of these protective exposures might in the future enable the development of new prevention strategies. PMID- 23041677 TI - The colonic microbiota in health and disease. AB - PURPOSE OF REVIEW: Diverse research interests have converged on the gut microbiota because of its contribution to immune development, mucosal homeostasis and to the pathogenesis of a diversity of intestinal and extraintestinal disorders. Recent landmark findings are addressed here. RECENT FINDINGS: The impact of lifestyle, including dietary changes and antibiotics, on the microbiota has been mechanistically linked with disease risk. Microbial, immune and metabolic signalling are mutually interactive, with each of these being regulated by diet. Although changes in the microbiota have been found in several disorders and may have important therapeutic implications, some components of the commensal microbiota may behave like pathogens (pathobionts) depending on the context and host susceptibility. SUMMARY: Advances in understanding host-microbe interactions in the gut continue apace, they are relevant to a diversity of infectious, inflammatory, neoplastic and metabolic disorders and are poised for clinical translation. PMID- 23041678 TI - Fecal microbiota transplantation: past, present and future. AB - PURPOSE OF REVIEW: Fecal microbiota transplantation (FMT) re-establishes a balanced intestinal flora with resultant cure of recurrent Clostridium difficile infection (RCDI). FMT has also been used to treat other gastrointestinal (GI) diseases including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and chronic constipation and a variety of non-GI disorders. The purpose of this review is to discuss the intestinal microbiota and FMT treatment of GI and non-GI diseases. RECENT FINDINGS: It is known that an imbalanced intestinal microbiota predisposes to CDI, IBD and IBS. The complex role of intestinal microbiota to maintain health, however, is a newer concept that is being increasingly studied. The microbiome plays an important role in cellular immunity and energy metabolism and has been implicated in the pathogenesis of non-GI autoimmune diseases, chronic fatigue syndrome, obesity and even some neuropsychiatric disorders. SUMMARY: FMT is a highly effective cure for RCDI, but increased knowledge of the intestinal microbiota in health maintenance, as well as controlled trials of FMT in a wide range of disorders are needed before FMT can be accepted and applied clinically. PMID- 23041679 TI - High prevalence of HIV, syphilis and HCV, and low methadone maintenance treatment in a migrant population in Beijing. AB - OBJECTIVES: To provide evidence for policy makers for human immunodeficiency virus (HIV) prevention and control, we investigated HIV, syphilis, and hepatitis C virus (HCV) infection and the availability of methadone maintenance treatment (MMT) among migrant drug users in Beijing. METHODS: A total of 222 participants from 3 main communities where drug abusers reside were interviewed, completed a questionnaire, and were screened for HIV using enzyme-linked immunosorbent assay, confirmed by Western blot. Descriptive statistics, chi tests, and binary logistic regression models were used to analyze differences in HIV and sexually transmitted diseases among different subpopulations. RESULTS: The prevalence of HIV and syphilis in the migrant population was much higher than in permanent residents (43.0% vs 2.1% and 13.3% vs 4.3%, respectively). The HIV-infected cases in the migrant population were 33-fold higher than in permanent residents. Compared with permanent residents, the availability of MMT was much lower in the migrant population (21.9% vs 70.2%), and they were less knowledgeable about MMT (37.0% vs 84.0%). Even for those who were knowledgeable about MMT, methadone treatment was still lower (46.8% vs 82.3%). Compared with the MMT group, higher infection rates of HIV and HCV were found in the no-MMT group (36.7% vs 10.6% and 64.8% vs 50.0%, respectively). Education and employment status contributed to the different distributions between permanent residents and the migrant population and the MMT and no-MMT groups. CONCLUSIONS: The prevalence of HIV, syphilis, and HCV infection was higher, and the use of MMT was lower in the migrant population. The migrant population is a noticeable challenge for HIV prevention and control in Beijing. PMID- 23041681 TI - Eisenmenger syndrome: an unsolved malady. PMID- 23041680 TI - Use of conventional, complementary, and alternative treatments for pain among individuals seeking primary care treatment with buprenorphine-naloxone. AB - Previous studies have not examined patterns of pain treatment use among patients seeking office-based buprenorphine-naloxone treatment (BNT) for opioid dependence. OBJECTIVES: To examine, among individuals with pain seeking BNT for opioid dependence, the use of pain treatment modalities, perceived efficacy of prior pain treatment, and interest in pursuing pain treatment while in BNT. METHODS: A total of 244 patients seeking office-based BNT for opioid dependence completed measures of demographics, pain status (ie, "chronic pain (CP)" [pain lasting at least 3 months] vs "some pain (SP)" [pain in the past week not meeting the duration criteria for chronic pain]), pain treatment use, perceived efficacy of prior pain treatment, and interest in receiving pain treatment while in BNT. RESULTS: In comparison with the SP group (N = 87), the CP group (N = 88) was more likely to report past-week medical use of opioid medication (adjusted odds ratio [AOR] = 3.2; 95% CI, 1.2-8.4), lifetime medical use of nonopioid prescribed medication (AOR = 2.2; 95% CI, 1.1-4.7), and lifetime use of prayer (AOR = 2.8; 95% CI, 1.2-6.5) and was less likely to report lifetime use of yoga (AOR = 0.2; 95% CI, 0.1-0.7) to treat pain. Although the 2 pain groups did not differ on levels of perceived efficacy of prior lifetime pain treatments, in comparison with the SP group, the CP group was more likely to report interest in receiving pain treatment while in BNT (P < 0.001). CONCLUSIONS: Individuals with pain seeking BNT for opioid dependence report a wide range of conventional, complementary, and alternative pain-related treatments and are interested (especially those with CP) in receiving pain management services along with BNT. PMID- 23041682 TI - Can thoracic paravertebral block replace thoracic epidural block in pediatric cardiac surgery? A randomized blinded study. AB - To compare the outcomes of thoracic epidural block with thoracic paravertebral block for thoracotomy in pediatric patients. A prospective double-blind study. 60 pediatric patients aged 1-24 months, ASA II, III scheduled for thoracotomy were randomly allocated into two groups. After induction of general anesthesia, thoracic epidural catheter was inserted in group E (epidural) patients and thoracic paravertebral catheter was inserted in group P (paravertebral) patients. Post operative pain score was recorded hourly for 24 hours. Plasma cortisol level was recorded at three time points. Tidal breathing analysis was done preoperatively and 6 hours postoperatively. Analgesia, serum cortisol level, and pulmonary function parameters were comparable in the two groups. However, failure rate (incorrect placement of catheter) was significantly higher in epidural group than in paravertebral group (7% versus 0%, respectively). The complications were also significantly higher in epidural group (vomiting 14.8%, urine retention 11.1% and hypotension 14.8%) than paravertebral group (0%, 0%, and 3.6%, respectively). We conclude that both thoracic paravertebral block and thoracic epidural block results in comparable pain score and pulmonary function after thoracotomy in pediatric patients; the paravertebral block is associated with significantly less failure rate and side effects. PMID- 23041683 TI - Duration of deep hypothermia during aortic surgery and the risk of perioperative blood transfusion. AB - Deep hypothermia, which is used during thoracic aortic surgery for neuroprotection, is associated with coagulation abnormalities in animal and in vitro models. However, there is a paucity of data regarding the impact of deep hypothermia duration on perioperative bleeding. The objective of the current study was to examine the relationship between the duration of deep hypothermia and perioperative bleeding. A retrospective review of 507 consecutive thoracic aortic surgery patients who had surgery with deep hypothermic circulatory arrest was performed. The degree of bleeding and coagulopathy was estimated using perioperative transfusion. Log linear modeling with Poisson regression was used to analyze the relationship between deep hypothermia duration and perioperative bleeding, while controlling for other preselected variables. There was a significant association between deep hypothermia duration and RBC transfusion (P = 0.001). There was no significant association between deep hypothermia duration and FFP and platelet transfusion (P = 0.18 and P = 0.06). The association between deep hypothermia duration and the amount of bleeding (RBC transfusion) was dependent on total CPB time. In general, for shorter CPB times (approximately 120 to 180 minutes) there was an upward sloping line or positive relationship between deep hypothermia duration and bleeding. However, for cases with longer CPB times (300 to 360 minutes), there was no such relationship. The relationship between deep hypothermia duration and perioperative bleeding is dependent on CPB time. For surgeries with short CPB times (120 to 180 minutes), prolonged deep hypothermia is associated with increased post-operative bleeding, as estimated by RBC transfusion. For cases with longer CPB times (300 to 360 minutes), there appears to be no relationship. PMID- 23041684 TI - A survey on the use of intra-aortic balloon pump in cardiac surgery. AB - Intra-aortic balloon pump (IABP) is an established tool in the management of cardiac dysfunction in cardiac surgery. The best timing for IABP weaning is unknown and varies greatly among cardiac centers. The authors investigated the differences in IABP management among 66 cardiac surgery centers performing 40,675 cardiac surgery procedures in the 12-month study period. The centers were contacted through email, telephone, or in person interview. IABP management was very heterogeneous in this survey: In 43% centers it was routinely removed on the first postoperative day, and in 34% on the second postoperative day. In 50% centers, it was routinely removed after extubation of the patients whereas in 15% centers it was removed while the patients were sedated and mechanically ventilated. In 66% centers, patients were routinely receiving pharmacological inotropic support at the time of removal of IABP. The practice of decreasing IABP support was also heterogeneous: 57% centers weaned by reducing the ratio of beat assistance whereas 34% centers weaned by reducing balloon volume. We conclude that the management of IABP is heterogeneous and there is a need for large prospective studies on the management of IABP in cardiac surgery. PMID- 23041685 TI - Acute kidney injury following cardiac surgery. AB - Acute kidney injury (AKI), a recognized complication of cardiac surgery with cardiopulmonary bypass (CPB) is associated with increased morbidity and mortality (15-30%) with approximately 1% of all the affected patients requiring dialysis. Early detection of AKI would enable intervention before occurrence of irreversible injury and might minimize the morbidity and mortality. Recently developed biomarkers of AKI facilitate its earlier discovery and help assessment of its severity and prognosis. In this article, we review the causes of well known yet inexplicable association between CPB and AKI, the advances in pathophysiologic basis, the diagnostics and the management options. PMID- 23041686 TI - Understanding traumatic blunt cardiac injury. AB - Cardiac injuries are classified as blunt and penetrating injuries. In both the injuries, the major issue is missing the diagnosis and high mortality. Blunt cardiac injuries (BCI) are much more common than penetrating injuries. Aiming at a better understanding of BCI, we searched the literature from January 1847 to January 2012 by using MEDLINE and EMBASE search engines. Using the key word "Blunt Cardiac Injury," we found 1814 articles; out of which 716 articles were relevant. Herein, we review the causes, diagnosis, and management of BCI. In conclusion, traumatic cardiac injury is a major challenge in critical trauma care, but the guidelines are lacking. A high index of suspicion, application of current diagnostic protocols, and prompt and appropriate management is mandatory. PMID- 23041687 TI - Safe management of cesarean section in a patient of Eisenmenger syndrome. AB - We report our experience of a 29-year-old female with a complete atrio ventricular septal defect leading to a single ventricle physiology and Eisenmenger syndrome. The patient successfully underwent spinal anesthesia for cesarean section in the 31 st week of pregnancy. A multidisciplinary approach involving cardiologist, cardiac surgeon, obstetrician, and anesthesiologist was utilized to achieve a safe pregnancy and cesarean for the delivery of the baby. A close clinical assessment is required, especially during the third trimester when the risk of acute right ventricular dysfunction increases. The use of extracorporeal membrane oxygenation (ECMO) (as a bridge to recovery or bridge to salvage) was planned to support oxygenation and circulation in case of acute biventricular dysfunction. The delivery/cesarean section was performed in a cardiac surgery operating room, and to reduce the time-frame for ECMO institution the femoral vessels were exposed surgically before the cesarean section. PMID- 23041688 TI - Anesthetic management of congenital broncho-esophageal fistula in an adult. AB - Broncho-esophageal fistula (BEF) are quite rare in adults, more so the congenital variety. The common causes of BEF in adults include infections, trauma, and malignancies. We report a rare case of congenital BEF manifesting in adulthood with repeated pulmonary infections. We emphasize mainly on the preoperative preparation and perioperative management of this patient. It is essential to have a high index of suspicion to diagnose congenital BEF in adults. Anesthesiologists play an important role in successful management of these cases. PMID- 23041689 TI - Management of a patient with hyperkalemic periodic paralysis requiring coronary artery bypass grafts. AB - Hyperkalemic periodic paralysis (HPP) is an autosomal-dominant inherited muscle disease characterized by episodes of flaccid weakness and intermittent myotonia. There are no previous reports in the literature about anesthesia for cardiac surgery with cardiopulmonary bypass in this disorder. We describe perioperative anesthetic management for on-pump coronary artery bypass grafting in a 75-year old man with a history of hyperkalemic periodic paralysis. This case report outlines our management strategy and the issues encountered during the perioperative period. PMID- 23041690 TI - Anesthetic management of a child with nephrotic syndrome undergoing open heart surgery: report of a rare case. AB - The congenital nephrotic syndrome (NS) in infancy and childhood is an important entity but combination with acyanotic congenital heart disease is uncommon. Anesthesia in such cases is challenging because of associated problems like hypo protienemia, anti-thrombin III deficiency, edema, hyperlipidemia, coagulopathy, cardiomyopathy, immunodeficiency, increased lung water etc. We describe anesthetic management of a patient with childhood NS and sinus venosus atrial septal defect (ASD) undergoing open heart surgery. We also suggest guidelines for safe conduct of anesthesia and CPB in such patients. PMID- 23041691 TI - Incidental discovery of an unusual right atrial membrane in an adult patient. AB - We describe presence of an unusual right atrial membrane in a 30-year old female with end stage renal disease, hypertension and peripheral vascular disease. The patient was scheduled for midline sternotomy and pericardiotomy and removal of a migrated vascular stent in the right pulmonary artery. An intraoperative transesophageal echocardiogram (TEE) revealed an unusual membranous structure with fenestrations that stretched across the right atrium with attachments superiorly at the free wall and inferiorly at the inter-atrial septum. There was no evidence of flow obstruction across the tricuspid valve. Some of the considerations for the likely diagnosis of this structure were a prominent Eustachian valve, persistent Chiari network, aneurysmal inter-atrial septum, an inter-atrial septal cyst or Cor triatriatum dexter (CTD). PMID- 23041692 TI - Transesophageal echocardiography for diagnosis of inadvertant closure of inferior vena cava opening during minimally invasive atrial septal defect closure. AB - Transesophageal echocardiography (TEE) is widely used in cardiac surgery. TEE provides important diagnostic and functional information before and after cardiopulmonary bypass thereby having a very important impact on perioperative clinical outcomes. We describe a case in which intraoperative TEE was instrumental in the timely diagnosis of inadvertant closure of the inferior vena cava (IVC) opening during minimally invasive surgical closure of atrial septal defect. PMID- 23041693 TI - Transradial approach to interventional cardiology: lessons for the anesthesiologist. PMID- 23041694 TI - Coronary artery bypass grafting and dengue fever. PMID- 23041695 TI - Re: disappearing ring in chest cavity. PMID- 23041696 TI - Pericardial effusion causing ventricular arrhythmias: atypical presentation. PMID- 23041697 TI - Iatrogenic superior vena cava syndrome during off pump CABG. PMID- 23041698 TI - Non-linear Coulomb blockade microscopy of a correlated one-dimensional quantum dot. AB - We evaluate the chemical potential of a one-dimensional quantum dot coupled to an atomic force microscope tip. The dot is described within the Luttinger liquid framework, and the conductance peak positions as a function of the tip location are calculated in the linear and non-linear transport regimes for an arbitrary number of particles. The differences between the chemical potential oscillations induced by the Friedel and Wigner terms are carefully analysed in the whole range of interaction strengths. It is shown that Friedel oscillations, unlike the Wigner ones, are sensitive probes for detecting excited spin states and collective spin density waves involved in the transport. PMID- 23041699 TI - Genotoxic and mutagenic properties of Bauhinia platypetala extract, a traditional Brazilian medicinal plant. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bauhinia platypetala Burch. is a traditionally used Brazilian medicinal plant, although no evidence in the literature substantiates the safety of its use. AIM OF THE STUDY: The aim of this study was to investigate the safety of the ethanolic extract and the ethereal fraction of B. platypetala leaves. MATERIALS AND METHODS: The identification of chemical compounds from the B. platypetala ethanolic extract and its ethereal fraction was performed by GC/MS and ESI-MS/MS. The plant's toxicological, cytotoxic, mutagenic and genotoxic properties were determined in Saccharomyces cerevisiae strains and V79 cell culture by survival assays and comet assay. RESULTS: The major compound identified in the B. platypetala ethanolic extract is palmitic acid, kaempferitirin and quercitrin, while the B. platypetala ethereal fraction was found to be rich in phytol, gamma-sitosterol and vitamin E. Moreover, the results indicated that the B. platypetala ethanolic extract has an anti-oxidative effect against H(2)O(2) in yeast. In addition, the B. platypetala ethanolic extract did not induce mutagenic effects on the S. cerevisiae N123 strain, but the ethereal fraction of B. platypetala at higher concentrations (250-500 MUg/mL) induced cytotoxicity and mutagenicity. A slight cytotoxic effect was observed in mammalian V79 cells; however, both the B. platypetala ethanolic extract and its ethereal fraction were able to induce DNA strand breaks in V79 cells, as detected by the alkaline comet assay. CONCLUSION: The B. platypetala ethanolic extract has antioxidant action and showed absence of mutagenic effects in yeast S. cerevisiae. On the other hand B. platypetala ethereal fraction is mutagenic and does not show antioxidant activity in yeast. In mammalian cells B. platypetala ethanolic extract and it's ethereal fraction induce cyotoxic and genotoxic action. PMID- 23041700 TI - In vitro antiplasmodial activity of selected Luo and Kuria medicinal plants. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Drug resistance in malaria is a recurring subject that threatens public health globally. There is an urgent need to seek new antimalarial agents. This study seeking new antimalarials from medicinal plants is guided by ethnobotany. MATERIALS AND METHODS: Medicinal plants of the Luo and Kuria ethnic groups of Kenya with high usage reports were screened in vitro for their antiplasmodial activity using the SYBR Green I fluorescence assay (MSF assay). RESULTS: The IC50's for drugs and total plant extracts ranged from 0.01217 to 10.679 mg/ml. Extracts were more active on chloroquine sensitive than resistant Plasmodium falciparum strains. Tylosema fassoglense, Ageratum conyzoides and Ocimum kilimandscharicum exhibited promising results. Plectranthus barbatus did not show activity. CONCLUSION: Ethnobotanical knowledge was sufficiently reliable for identifying plant extracts with antiplasmodial activity. PMID- 23041701 TI - American ginseng inhibits vascular smooth muscle cell proliferation via suppressing Jak/Stat pathway. AB - ETHNOPHARMCOLOGICAL RELEVANCE: Ginseng, a folk medicine which has been used for thousands of years in Asia, has been promoted for the treatment or prevention of health problems including cardiovascular disease. However, the molecular mechanism of ginseng-induced cardiovascular protection is unclear. Thus, we investigated signaling mechanism by which American ginseng inhibits vascular smooth muscle cell (VSMC) proliferation, a key feature of diverse vascular disease. MATERIALS AND METHODS: A standardized crude extract of American ginseng was supplied by the National Research Council of Canada, Institute for National Measurement Standards. Rat aortic smooth muscle cells (RASMCs) were exposed to fetal bovine serum (FBS), platelet derived growth factor (PDGF), insulin, or angiotensin II (Ang II) to induce proliferation that was examined by measuring DNA synthesis and cell numbers. Western blot was applied to determine the activations of Jak, Stat, Akt, and ERK. RESULTS: American ginseng inhibited RASMC proliferation induced by FBS, PDGF, insulin or Ang II. American ginseng slightly increased both basal and FBS-, PDGF- or Ang II-induced activities of Akt and ERK in RASMCs; however, it dramatically inhibited the activation of Jak2 and Stat3. CONCLUSION: These results demonstrate that American ginseng inhibits VSMC proliferation through suppressing the Jak/Stat pathway. PMID- 23041702 TI - Establishment of a new conditionally immortalized cell line from human brain microvascular endothelial cells: a promising tool for human blood-brain barrier studies. AB - The blood-brain barrier (BBB) is formed by brain microvascular endothelial cells (BMEC) working together with astrocytes and pericytes, in which tight junctions and various transporters strictly regulate the penetration of diverse compounds into the brain. Clarification of the molecular machinery that provides such regulation using in vitro BBB models has provided important insights into the roles of the BBB in central nervous system (CNS) disorders and CNS drug development. In this study, we succeeded in establishing a new cell line, hereinafter referred to as human BMEC/conditionally immortalized, clone beta (HBMEC/cibeta), as part of our ongoing efforts to develop an in vitro human BBB model. Our results showed that HBMEC/cibeta proliferated well. Furthermore, we found that HBMEC/cibeta exhibited the barrier property of restricting small molecule intercellular penetration and possessed effective efflux transporter functions, both of which are essential to a functioning BBB. Because higher temperatures are known to terminate immortalization signals, we specifically examined the effects of higher temperatures on the HBMEC/cibeta differentiation status. The results showed that higher temperatures stimulated HBMEC/cibeta differentiation, marked by morphological alteration and increases in several mRNA levels. To summarize, our data indicates that the newly established HBMEC/cibeta offers a promising tool for use in the development of a practical in vitro human BBB model that could make significant contributions toward understanding the molecular biology of CNS disorders, as well as to CNS drug development. It is also believed that the development of a specific culture method for HBMEC/cibeta will add significant value to the HBMEC/cibeta-based BBB model. PMID- 23041703 TI - Reliability and validity of the SE-HEPA: examining physical activity--and healthy eating-specific self-efficacy among a sample of preadolescents. AB - OBJECTIVE: The purpose of this study was to examine the psychometric properties of the self-efficacy for healthy eating and physical activity measure (SE-HEPA) for preadolescents. METHOD: The reliability of the measure was examined to determine if the internal consistency of the measure was adequate (i.e., alphas > .70). Next, in an effort to determine if a two-factor model was a better fit than a one-factor model, as hypothesized, an exploratory factor analysis in a confirmatory factor analysis framework was used to determine model fit. Additionally, the criterion-related validity of the measure was evaluated by conducting correlational analyses to determine if SE-HEPA scores were associated with preadolescent body mass index. RESULTS: Consistent with the hypotheses, Cronbach's alphas indicated good reliability for the measure (i.e., alphas > .70) and factor analyses indicated the two-factor model provided a better fit than the one-factor model. Additionally, correlations revealed a significant relationship between the two factors (i.e., healthy eating, physical activity) and preadolescent body mass index. CONCLUSIONS: The SE-HEPA will allow researchers and clinicians to better understand self-efficacy for behaviors important to weight loss among preadolescents. This could, in turn, inform future efforts aimed at increasing behaviors that promote healthy weight status among this population within the context of family-based weight loss programs. PMID- 23041704 TI - On measuring community participation in research. AB - Active participation of community partners in research aspects of community academic partnered projects is often assumed to have a positive impact on the outcomes of such projects. The value of community engagement in research, however, cannot be empirically determined without good measures of the level of community participation in research activities. Based on our recent evaluation of community-academic partnered projects centered around behavioral health issues, this article uses semistructured interview and survey data to outline two complementary approaches to measuring the level of community participation in research-a "three-model" approach that differentiates between the levels of community participation and a Community Engagement in Research Index (CERI) that offers a multidimensional view of community engagement in the research process. The primary goal of this article is to present and compare these approaches, discuss their strengths and limitations, summarize the lessons learned, and offer directions for future research. We find that whereas the three-model approach is a simple measure of the perception of community participation in research activities, CERI allows for a more nuanced understanding by capturing multiple aspects of such participation. Although additional research is needed to validate these measures, our study makes a significant contribution by illustrating the complexity of measuring community participation in research and the lack of reliability in simple scores offered by the three-model approach. PMID- 23041705 TI - At the intersection of HIV/AIDS and cancer: a qualitative needs assessment of community-based HIV/AIDS service organizations. AB - Due to advances in treatment, persons living with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) are living longer, but with aging, immune deficits, and lifestyle factors, they are at increased risk for cancer. This challenges community-based AIDS service organizations (ASOs) to address the growing cancer needs of persons living with HIV/AIDS (PLWHA). Community-based participatory research was applied to engage ASOs in exploring their capacities and needs for integrating cancer-focused programming into their services. Focus groups were conducted with a community advisory board (CAB) representing 10 community-based organizations serving PLWHA. Three 90-minute, serial focus groups were conducted with a mean number of seven participants. Topics explored CAB members' organizational capacities and needs in cancer prevention, detection, treatment, and survivorship. Transcript analyses identified six themes: (a) agencies have limited experience with cancer-focused programs, which were not framed as cancer specific; (b) agencies need resources and collaborative partnerships to effectively incorporate cancer services; (c) staff and clients must be educated about the relevance of cancer to HIV/AIDS; (d) agencies want to know about linkages between HIV/AIDS and cancer; (e) cancer care providers should be culturally competent; and (f) agencies see opportunities to improve their services through research participation but are wary. Agency capacities were strong in relationships with clients and cultural competency, a holistic view of PLWHA health, expertise in prevention activities, and eagerness to be on the cutting edge of knowledge. Cancer education and prevention were of greatest interest and considered most feasible, suggesting that future projects develop accordingly. These findings suggest a high level of receptivity to expanding or initiating cancer-focused activities but with a clear need for education and awareness building. Qualitative findings will inform a large quantitative survey to validate identified themes, which will be applied in developing interventions to assist ASOs in adopting or expanding cancer-focused activities. PMID- 23041706 TI - Implementation evaluation of steering teens safe: engaging parents to deliver a new parent-based teen driving intervention to their teens. AB - Parents play a fundamental role in teaching their children safe driving skills to reduce risk of motor vehicle crashes, the leading cause of death for teens. Steering Teens Safe is a new parent-based intervention that equips parents with communication skills to talk about, demonstrate, and practice safe driving behaviors and skills with their teens. This implementation evaluation focuses on a sample of 83 parents who delivered Steering Teens Safe to their teens. One-, 2- and 3-month follow-up assessments were conducted with intervention parents to evaluate the self-reported quantity and quality of talking about, demonstrating, and practicing safe driving goals with teens; perceived success and benefit of the program; and barriers to implementation. Over 3 months of follow-up, parents discussed driving goals with their teens for a median of 101.5 minutes. The most frequently addressed topics were general safety principles, including distracted driving, driving in bad weather, wearing a seat belt, and being a safe passenger. Parents spent a median of 30 minutes practicing safe driving skills such as changing lanes. Sixty-seven percent of parents talked to their children about rural road safety, but just 36% demonstrated and half practiced these skills with their teens. Barriers to implementation include time and opportunity barriers and resistant attitudes of their teens. However, barriers neither affected frequency of engagement nor parents' perceived benefit and comfort in delivering the program. Parents with time/opportunity barriers also had higher practice and demonstration times than parents without these barriers. Findings indicate high acceptability among parent implementers and promise for real-world delivery. Future studies are needed to assess intervention impact. PMID- 23041707 TI - Chronic obstructive pulmonary disease and health-related quality of life in the 2009 Texas Behavioral Risk Factor survey. AB - INTRODUCTION: Individuals with chronic obstructive pulmonary disease (COPD) experience irreversible airflow obstruction, dyspnea, coughing, and fatigue. One of the goals of treating individuals with COPD is to improve their quality of life. The aim of this research was to evaluate the 2009 Texas Behavioral Risk Factor Surveillance System (BRFSS) as a method for surveillance of COPD by identifying factors associated with impaired health-related quality of life (HRQoL) among respondents with COPD as well as comment on differences between the COPD and non-COPD population in a state representative sample. METHOD: Data from 348 COPD respondents were obtained from the 2009 Texas BRFSS. The Andersen behavior model was used to categorize variables as predisposing characteristics, health behaviors, and health service utilization. Self-rated health (SRH) was the HRQoL indicator used in this analysis. Chi-square tests were used to examine differences between COPD and non-COPD respondents. The relation between SRH and risk factors were modeled using domain analysis and logistic regressions. All analyses incorporated the sample weights to be representative of the state population. RESULTS: Adults with COPD reported significantly worse SRH than adults who did not have COPD (p < .001). Among respondents with COPD, the predisposing characteristics associated with impaired HRQoL were obesity, education, and asthma; the health practices and service utilization factors associated with HRQoL included smoking, physical inactivity, having a health plan, and the inability to see a doctor because of costs. CONCLUSIONS: The Texas COPD population experienced increased risk of impaired SRH compared with the non COPD population. The findings from our population-level survey study are similar to results observed at the clinical level. PMID- 23041708 TI - Effects of Find Thirty every day(R): cross-sectional findings from a Western Australian population-wide mass media campaign, 2008-2010. AB - BACKGROUND: Internationally, over the last four decades large-scale mass media campaigns have been delivered to promote physical activity and its associated health benefits. In 2002-2005, the first Western Australian statewide adult physical activity campaign Find Thirty. It's Not a Big Exercise was launched. In 2007, a new iteration of the campaign was proposed with new objectives, executions, and tag line Find Thirty every day((r)). PURPOSE: This article reports on the population-level effects of the Find Thirty every day ((r)) campaign from 2008 to 2010, with a focus on changes in awareness, intention, and physical activity. METHODS: Evaluation of the campaign involved pre- and posttest serial cross-sectional surveys. Baseline data were collected in May 2008, and subsequent surveys in 2009 and 2010. Samples sizes were as follows: baseline (n = 972), first follow-up (n = 938), and second follow-up (n = 937). Data were derived from self-reported responses to a random-sample computer-assisted telephone interview. RESULTS: Total awareness increased from 30.4% at baseline to 48.5% at second follow-up. Total awareness was higher in women and low socioeconomic status adults. Intention was 21.0%, double that reported at baseline. There were positive significant changes from baseline to first follow up across all four categories: walking, moderate, vigorous, and total physical activity. There also were positive significant changes for self-reported walking from baseline to second follow-up. CONCLUSION: Find Thirty every day ((r)) resulted in an increase in awareness, intention, walking, vigorous intensity, and total level of physical activity in priority target groups. Campaign effects should be further examined by subgroups to identify the most receptive population segments. PMID- 23041709 TI - Promoting energy-balance behaviors among ethnically diverse adolescents: overview and baseline findings of The Central Texas CATCH Middle School Project. AB - The Central Texas Coordinated Approach To Child Health (CATCH) Middle School Project is a 3.5-year school-based project aimed at promoting physical activity (PA), healthy eating, and obesity prevention among public middle school students in Texas. This article describes the CATCH intervention model and presents baseline findings from spring 2009. CATCH comprises six core components: CATCH Team, CATCH PE, CATCH Classroom, CATCH Eat Smart Cafeteria, CATCH Family, and CATCH Social Marketing. A group randomized serial cross-sectional design is being employed to test the effect of three program support conditions (n = 10 schools each) on energy-balance behaviors: Basic (training and curriculum only), Basic Plus (training and curriculum plus CATCH facilitator support), and Basic Plus Social Marketing (all inputs plus social marketing component). The study sample is composed of a cross-sectional sample of eighth-grade students (primary outcome evaluation sample) and sixth- and seventh-grade students (PE process evaluation sample) who are selected and measured each year. At baseline, 37.9% of eight grade students (n = 2,841; 13.9 years) were overweight/obese and 19.2% were obese. Eighth-grade students reported, on average, consuming sugar-sweetened beverages more than two times on the previous day and fruits and vegetables roughly three times on the previous day; only two of five school districts surpassed the recommended 50% cut-point for class time spent in moderate-and vigorous PA as measured in classes of sixth- and seventh-grade students. Additional behavioral findings are reported. Body mass index and behaviors were comparable across conditions. Baseline findings underscore the need to promote student energy-balance behaviors. PMID- 23041710 TI - A mechanistic overview of health associated effects of low levels of organochlorine and organophosphorous pesticides. AB - Organochlorine and organophosphate pesticides are compounds that can be detected in human populations as a result of occupational or residential exposure. Despite their occurrence in considerably low levels in humans, their biological effects are hazardous since they interact with a plethora of enzymes, proteins, receptors and transcription factors. In this review we summarize the cell and molecular effects of organochlorine and organophosphate pesticides with respect to their toxicity, with particular emphasis on glucose and lipid metabolism, their interaction with some members of the nuclear receptor family of ligand-activated transcription factors, including the steroid and peroxisome proliferator activated receptors that changes the expression of genes involved in lipid metabolism and xenobiotic detoxification. More importantly, evidence regarding the metabolic degradation of pesticides and their accumulation in tissues is presented. Potential non-cholinergic mechanisms after long-term low-dose organophosphate exposure resulting in neurodevelopmental outcomes and neurodegeneration are also addressed. We conclude that the mechanism of pesticide mediated toxicity is a combination of various enzyme-inhibitory, metabolic and transcriptional events acting at the cellular and molecular level. PMID- 23041712 TI - Green synthesis of shape-defined anatase TiO2 nanocrystals wholly exposed with {001} and {100} facets. AB - Anatase TiO(2) nanocuboids wholly exposed with high-energy {001} and {100} facets were successfully synthesized by a novel, environmentally benign synthetic strategy using acid-delaminated vermiculite (DVMT) and tetramethylammonium hydroxide as synergistic morphology-controlling reagents, where the DVMT layers act as effective hard template selectively stabilizing the {001} facets of TiO(2). PMID- 23041711 TI - Gossypol-induced suicidal erythrocyte death. AB - Side effects of gossypol, a polyphenolic component of Gossypium, with male contraceptive, anticancer, antimicrobial and antiviral activities include anemia due to accelerated demise of erythrocytes. Erythrocytes may be cleared from circulating blood following apoptosis-like suicidal death or eryptosis. Hallmarks of eryptosis are cell shrinkage and cell membrane scrambling with subsequent phosphatidylserine-exposure at the cell surface. Stimulators of eryptosis include increase of cytosolic Ca(2+)-activity ([Ca(2+)](i)). The present study explored, whether gossypol stimulates eryptosis of human erythrocytes. Utilizing flow cytometry, [Ca(2+)](i) was estimated from Fluo-3 fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from annexin-V-binding, and hemolysis from hemoglobin release. A 48 h exposure to gossypol (0.75 MUM) significantly increased [Ca(2+)](i), decreased forward scatter and increased annexin-V-binding. Gossypol exposure was followed by a slight but significant increase of hemolysis. Removal of extracellular Ca(2+) significantly blunted the effect of gossypol (1 MUM) on annexin-V-binding. The present observations reveal a novel effect of gossypol on human erythrocytes, which contributes to or even accounts for the triggering of anemia by this substance. PMID- 23041713 TI - Simultaneous CBF and BOLD mapping of high frequency acupuncture induced brain activity. AB - This study mapped brain activity elicited by high frequency electroacupuncture by simultaneously using blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) contrasts. Forty subjects participated in the study, in which twenty ones were imaged during electrical acupoint stimulation (EAS) to the left LI4 acupoint at a maximal intensity without pain, and the others were with a minimal EAS at a just detectible intensity. Both BOLD and CBF data were acquired simultaneously during alternating blocks of rest and stimulation. The results showed that the minimal-EAS mostly induced the activities in somatosensory region, including those in inferior parietal lobule, SII, insula, and thalamus. On the other hand, EAS activated more including also posterior middle cingulate cortex (pMCC), and deactivated superior temporal gyrus. Moreover, deactivation was found in posterior cingulated cortex (PCC), precuneus from BOLD and in culmen of cerebellum, caudate from CBF. The comparison between EAS and minimal-EAS revealed deactivation in the default mode network in both BOLD and CBF signals, activation in thalamus, insula, and caudal anterior cingulate cortex (ACC) in the CBF signal alone, and deactivation in putamen, rostral ACC and parahippocampal gyrus in the BOLD signal alone. This study provides, for the first time, simultaneous CBF and BOLD responses to high frequency EAS at the LI4 acupoint, revealing concordant and complementary insights into the neural effects of EAS, including modulation of subcortical structures and limbic system. PMID- 23041715 TI - Phylogenetic analysis of Babesia species in China based on Cytochrome b (COB) gene. AB - In this study, a mitochondrial marker consisting of an approximately 550-bp region of the Cytochrome b genes (COB) was amplified by polymerase chain reaction (PCR) and sequenced from individual Babesia species. Sequence variation between Babesia species from China was 1.6-30.8%. The constructed phylogenetic tree based on the three unlinked gene sequences (partial COB gene, 18S rDNA and ITS) that evolve at different rates by the method of Neighbor-joining revealed the phylogenetic relationship of Babesia species in China compared with other published corresponding sequences from Babesia species. These data indicate that the 18S rDNA more reliably distinguish the deeper branches among some Babesia species than the partial COB gene and ITS, however, the partial COB gene sequence is better for recognizing close lineages among some Babesia species than the 18S rDNA and ITS sequences. So the combined phylogenetic analysis based on the multiple unlinked loci with different evolving rates can facilitate to establish the more reliable phylogenetic relationship of the Babesia genus. The data could be applicable for the survey of parasite dynamics, epidemiological studies as well as prevention and control of the disease. PMID- 23041717 TI - A survey of SNOMED CT implementations. AB - The Systematised Nomenclature of Medicine Clinical Terms (SNOMED CT) has been designated as the recommended clinical reference terminology for use in clinical information systems around the world and is reported to be used in over 50 countries. However, there are still few implementation details. This study examined the implementation of SNOMED CT in terms of design, use and maintenance issues involved in 13 healthcare organisations across eight countries through a series of interviews with 14 individuals. While a great deal of effort has been spent on developing and refining SNOMED CT, there is still much work ahead to bring SNOMED CT into routine clinical use. PMID- 23041716 TI - Rule-based support system for multiple UMLS semantic type assignments. AB - BACKGROUND: When new concepts are inserted into the UMLS, they are assigned one or several semantic types from the UMLS Semantic Network by the UMLS editors. However, not every combination of semantic types is permissible. It was observed that many concepts with rare combinations of semantic types have erroneous semantic type assignments or prohibited combinations of semantic types. The correction of such errors is resource-intensive. OBJECTIVE: We design a computational system to inform UMLS editors as to whether a specific combination of two, three, four, or five semantic types is permissible or prohibited or questionable. METHODS: We identify a set of inclusion and exclusion instructions in the UMLS Semantic Network documentation and derive corresponding rule categories as well as rule-categories from the UMLS concept content. We then design an algorithm adviseEditor based on these rule-categories. The algorithm specifies rules for an editor how to proceed when considering a tuple (pair, triple, quadruple, quintuple) of semantic types to be assigned to a concept. RESULTS: Eight rule-categories were identified. A Web-based system was developed to implement the adviseEditor algorithm, which returns for an input combination of semantic types whether it is permitted, prohibited or (in a few cases) requires more research. The numbers of semantic type pairs assigned to each rule category are reported. Interesting examples for each rule-category are illustrated. Cases of semantic type assignments that contradict rules are listed, including recently introduced ones. CONCLUSION: The adviseEditor system implements explicit and implicit knowledge available in the UMLS in a system that informs UMLS editors about the permissibility of a desired combination of semantic types. Using adviseEditor might help accelerate the work of the UMLS editors and prevent erroneous semantic type assignments. PMID- 23041719 TI - Haematological features in Barth syndrome. AB - PURPOSE OF REVIEW: This review highlights recent advances concerning pathogenesis, clinical presentation, diagnosis and treatment of Barth syndrome with particular regard to haematological abnormalities (e.g., neutropenia). RECENT FINDINGS: Directed motility and killing activity of neutrophils is normal in patients with Barth syndrome, but neutrophils and eospinophils show phosphatidylserine exposure without exhibiting other markers of apoptosis. Apparently, neutropenia does not result from apoptosis of myeloid precursors or end-stage neutrophils but from reactive oxygen species triggered exposure of phosphatidylserine, leading to increased clearance of neutrophils by tissue macrophages. Lymphoblasts of patients with Barth syndrome show increased variability of mitochondrial size and increased mitochondrial mass due to increased clustering of fragmented mitochondria inside nuclear invaginations. Lymphoblast mitochondria show reduced cristae density, reduced cristae alignment and heterogenous cristae distribution. Areas of adhesion of opposing inner membranes result in obliteration of the inter-cristae space. Short or extended adhesion zones result in sheets of collapsed cristae, which are packaged as multiple concentric layers. In single patients, neutropenia may favourably respond to biweekly injections of granulocyte colony stimulating factor. SUMMARY: Neutropenia in Barth syndrome is most likely due to reactive oxygen species induced exposure of phosphatidylserine, leading to increased clearance of neutrophils by tissue macrophages. In single patients, application of granulocyte colony stimulating factor may resolve neutropenia in Barth syndrome. PMID- 23041718 TI - Fighting against the dark side of neutrophil extracellular traps in disease: manoeuvres for host protection. AB - PURPOSE OF REVIEW: This review presents a concise summary of the role of neutrophil extracellular traps (NET) in several pathological situations associated with adverse effects of NET. Different strategies are indicated to dampen the unfavourable consequences of NET formation and function. RECENT FINDINGS: A major extracellular antimicrobial mechanism of neutrophils is induced by formation of NET, in which the microorganisms are trapped within the released chromatin from neutrophils and killed by highly concentrated, NET-entangled antimicrobial proteins. In recent years, exaggerated NET formation and the subsequent complications for the host organism have been reported in several pathological conditions. It has been shown that interfering with NET structure and/or components either via DNase to disrupt the DNA backbone of NET or via antihistone approaches to target the major proteins in NET can diminish the pathological symptoms in such diseases. SUMMARY: On the basis of the type of the disease and its severity as well as the outcome of NET generation, different therapeutic strategies may be considered to dampen the inauspicious consequences of exaggerated NET formation and function. Applying combinations of compounds that aim to decrease the adverse activity of DNA and NET-associated proteins/enzymes may increase the efficiency of treatment. PMID- 23041720 TI - Grasping the pain: motor resonance with dangerous affordances. AB - Two experiments, one on school-aged children and one on adults, explored the mechanisms underlying responses to an image prime (hand vs. control object) followed by graspable objects that were, in certain cases, dangerous. Participants were presented with different primes (a male, a female and a robotic grasping-hand; a male and a female static-hand; a control stimulus) and objects representing two risk levels (neutral and dangerous). The task required that a natural/artifact categorization task be performed by pressing different keys. In both adults and children graspable objects activated a facilitating motor response, while dangerous objects evoked aversive affordances, generating an interference-effect. Both children and adults were sensitive to the distinction between biological and non-biological hands, however detailed resonant mechanisms related to the hand-prime gender emerged only in adults. Implications for how the concept of "dangerous object" develops and the relationship between resonant mechanisms and perception of danger are discussed. PMID- 23041721 TI - Xenograft models of chronic lymphocytic leukemia: problems, pitfalls and future directions. AB - Xenotransplantation of human tumor cells into immunodeficient mice has been a powerful preclinical tool in several hematological malignancies, with the notable exception of chronic lymphocytic leukemia (CLL). For several decades, this possibility was hampered by the inefficient and/or short-term engrafment of CLL cells into available animals. The development of new generations of immunocompromised mice has allowed to partially overcome these constraints. Novel humanized animal models have been created that allow to recapitulate the pathogenesis of the disease and the complex in vivo relationships between leukemic cells and the microenvironment. In this review we discuss the development of xenograft models of CLL, how they may help elucidating the mechanisms that account for the natural history of the disease and facilitating the design of novel therapeutic approaches. PMID- 23041723 TI - Body-wing swapping in butterfly {Fe(III)2Ln(III)2} coordination clusters with triethylene glycol as ligand. AB - The first use of triethylene glycol (H(2)teg) in Fe/Ln chemistry affords two series of tetranuclear {Fe(III)(2)Ln(III)(2)} coordination clusters possessing defect-dicubane cores. A change in the synthetic procedure results in a different arrangement of the relative positions of the 3d and 4f elements offering a means to steer the structural and electronic features within a 3d-4f system. PMID- 23041722 TI - Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. AB - Detection of minimal residual disease (MRD) in chronic lymphocytic leukaemia (CLL) is becoming increasingly important as treatments improve. An internationally harmonised four-colour (CLR) flow cytometry MRD assay is widely used but has limitations. The aim of this study was to improve MRD analysis by identifying situations where a less time-consuming CD19/CD5/kappa/lambda analysis would be sufficient for detecting residual CLL, and develop a six-CLR antibody panel that is more efficient for cases requiring full MRD analysis. In 784 samples from CLL patients after treatment, it was possible to determine CD19/CD5/kappa/lambda thresholds that identified cases with detectable MRD with 100% positive predictive value (PPV). However, CD19/CD5/kappa/lambda analysis was unsuitable for predicting iwCLL/NCI response status or identifying cases with no detectable MRD. For the latter cases requiring a full MRD assessment, a six-CLR assay was designed comprising CD19/CD5/CD20 with (1) CD3/CD38/CD79b and (2) CD81/CD22/CD43. There was good correlation between four-CLR and six-CLR panels in dilution studies and clinical samples, with 100% concordance for detection of residual disease at the 0.01% (10(-4)) level (n=59) and good linearity even at the 0.001-0.01% (10(-5)-10(-4)) level. A six-CLR panel therefore provides equivalent results to the four-CLR panel but it requires fewer reagents, fewer cells and a much simpler analysis approach. PMID- 23041724 TI - The local environment of Co2+ ions intercalated in vanadium oxide/hexadecylamine nanotubes. AB - Vanadium oxide nanotubes constitute promising materials for applications in nanoelectronics as cathode materials, in sensor technology and in catalysis. In this work we present a study on hybrid vanadium oxide/hexadecylamine multiwall nanotubes doped with Co ions using state of the art x-ray diffraction and absorption techniques, to address the issue of the dopant location within the nanotubes' structure. The x-ray absorption near-edge structure analysis shows that the Co ions in the nanotubes are in the 2 + oxidation state, while extended x-ray absorption fine structure spectroscopy reveals the local environment of the Co(2+) ions. Results indicate that Co atoms are exchanged at the interface between the vanadium oxide's layers and the hexadecylamines, reducing the amount of amine chains and therefore the interlayer distance, but preserving the tubular shape. The findings in this work are important for describing Co(2+) interaction with vanadium oxide nanotubes at the molecular level and will help to improve the understanding of their physicochemical behavior, which is desired in view of their promising applications. PMID- 23041725 TI - Sexually dimorphic transcriptomic responses in the teleostean hypothalamus: a case study with the organochlorine pesticide dieldrin. AB - Organochlorine pesticides (OCPs) such as dieldrin are a persistent class of aquatic pollutants that cause adverse neurological and reproductive effects in vertebrates. In this study, female and male largemouth bass (Micropterus salmoides) (LMB) were exposed to 3mg dieldrin/kg feed in a 2 month feeding exposure (August-October) to (1) determine if the hypothalamic transcript responses to dieldrin were conserved between the sexes; (2) characterize cell signaling cascades underlying dieldrin neurotoxicity; and (3) determine whether or not co-feeding with 17beta-estradiol (E(2)), a hormone with neuroprotective roles, mitigates responses in males to dieldrin. Despite also being a weak estrogen, dieldrin treatments did not elicit changes in reproductive endpoints (e.g. gonadosomatic index, vitellogenin, or plasma E(2)). Sub-network (SNEA) and gene set enrichment analysis (GSEA) revealed that neuro-hormone networks, neurotransmitter and nuclear receptor signaling, and the activin signaling network were altered by dieldrin exposure. Most striking was that the majority of cell pathways identified by the gene set enrichment were significantly increased in females while the majority of cell pathways were significantly decreased in males fed dieldrin. These data suggest that (1) there are sexually dimorphic responses in the teleost hypothalamus; (2) neurotransmitter systems are a target of dieldrin at the transcriptomics level; and (3) males co-fed dieldrin and E(2) had the fewest numbers of genes and cell pathways altered in the hypothalamus, suggesting that E(2) may mitigate the effects of dieldrin in the central nervous system. PMID- 23041726 TI - Improving cardiovascular health in women & children around the world. PMID- 23041727 TI - Promoting drug safety in elderly--needs a proactive approach. PMID- 23041728 TI - A new approach to hypobaric hypoxia induced cognitive impairment. PMID- 23041729 TI - Socio-economic inequity in health care utilization & expenditures in richer states in India. PMID- 23041730 TI - Post placental insertion of intrauterine contraceptive device. PMID- 23041733 TI - Adverse drug reactions & their risk factors among Indian ambulatory elderly patients. AB - BACKGROUND & OBJECTIVES: Several studies have reported adverse drug events ranging from 5 to 35 per cent in all age group from outpatient setting. However, adverse drug reactions (ADRs) particularly among a large sample of ambulatory elderly patients in India has not been reported. This study has attempted to identify ADRs and assessed their causality, preventability and severity, and also their risk factors in Indian ambulatory elderly patients. METHODS: A 2 year long term prospective study included 4005 ambulatory elderly patients (60 yr or above; either sex) at a public teaching hospital. Suspected ADRs were assessed for causality, preventability and severity using Naranjo's probability scale, modified Schumock and Thornton's criteria, and modified Hartwig's criteria, respectively. RESULTS: Of the total 4005 prescriptions, 406 were identified with ADRs, giving the occurrence of 10 per cent ADRs in elderly. The total number of ADRs was 422 in 406 prescriptions. Type A ADRs accounted for 46 per cent of the total ADRs. Majority of the ADRs (88.6%) were classified as 'probable'. The definitely preventable reactions were 22 per cent. The percentage of moderate reaction was 16 per cent. Only 1.6 per cent ADRs was severe in nature. The most common type of ADR was peripheral oedema. The most commonly offending class of drug was cardiovascular drugs (57.6%). Using logistic regression analysis, the risk factors which contributed to ADRs were age above 80 yr (OR=1.7), prescription of multiple drugs (OR=1.8), longer duration of treatment (OR=2.28) and multiple diagnoses (OR=1.8). INTERPRETATION & CONCLUSIONS: In this study, 10 per cent ambulatory elderly patients were found to have ADRs. This indicates that the elderly patients should be closely monitored for ADRs, to avoid clinically significant harmful consequences. The awareness of risk factors of ADRs would help physicians to identify elderly patients with greater risk of ADRs and, therefore, might benefit from ADRs monitoring and reporting programme. PMID- 23041732 TI - Current status of multimodal & combination therapy for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Surgery offers the only hope for cure. However, the potentially curable method is only possible for a small proportion of those afflicted, for the rest, palliative treatment is indicated. Despite all the treatment options when used as monotherapy, patients with HCC have a poor long term prognosis. In this setting, multimodal and combination therapy has emerged as an alternative treatment modality for HCC. Studies have looked at various forms of combination therapy, including neoadjuvant/adjuvant/downstaging therapy for surgery and the combined modality of non-operative therapies. The novel molecular targeted therapies are also being used as combination regimens for surgery or other non-operative therapies. Some forms of combination therapies, including downstaging therapy for surgery, salvage transplantation, and molecular targeted therapy have been shown to provide survival benefits for well selected patients, and need to be encouraged in the future. And others such as pre-operative bridging therapy for liver transplantation, adjuvant therapy for hepatic resection and combination of local and regional therapies have also shown some benefits in preliminary results, which need confirmation in further studies. In conclusion, multimodal and combination therapy is an encouraging treatment modality for HCC. Future research should continue to unravel the role of combination therapy with properly selected patients and appropriate end points. PMID- 23041731 TI - Dengue in India. AB - Dengue virus belongs to family Flaviviridae, having four serotypes that spread by the bite of infected Aedes mosquitoes. It causes a wide spectrum of illness from mild asymptomatic illness to severe fatal dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). Approximately 2.5 billion people live in dengue-risk regions with about 100 million new cases each year worldwide. The cumulative dengue diseases burden has attained an unprecedented proportion in recent times with sharp increase in the size of human population at risk. Dengue disease presents highly complex pathophysiological, economic and ecologic problems. In India, the first epidemic of clinical dengue-like illness was recorded in Madras (now Chennai) in 1780 and the first virologically proved epidemic of dengue fever (DF) occurred in Calcutta (now Kolkata) and Eastern Coast of India in 1963-1964. During the last 50 years a large number of physicians have treated and described dengue disease in India, but the scientific studies addressing various problems of dengue disease have been carried out at limited number of centres. Achievements of Indian scientists are considerable; however, a lot remain to be achieved for creating an impact. This paper briefly reviews the extent of work done by various groups of scientists in this country. PMID- 23041734 TI - Multi-domain cognitive screening test for neuropsychological assessment for cognitive decline in acclimatized lowlanders staying at high altitude. AB - BACKGROUND & OBJECTIVES: Ascent to high altitude has been reported to cause hippocampal atrophy and cognitive impairment in mountaineers. We assessed the cognitive performance and probable occurrence of mild cognitive impairment (MCI) in acclimatized lowlanders (ALL) staying at altitudes above 4,300 m for duration above 12 months and validated a multi-domain cognitive screening test (MDCST) for future demographic studies on MCI. METHODS: Following evaluation of sensitivity and correlation of the newly developed MDCST battery with Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scores on a group of 28 individuals, the MDCST battery was validated on a population of 843 ALL staying at high altitude MSL >4,300 m and 862 subjects staying at MSL <230 m. EEG recordings were performed on 840 ALL staying at altitudes above 4,300 m and 743 control subjects staying at MSL <230 m. RESULTS: Percentage prevalence of MCI was 4.18 per cent in the ALL population as assessed by MMSE while that of the LL population was <0.42 per cent. The percentage prevalence of MCI based on calculations from the MDCST scores was 12.4 per cent in the ALL population as compared to 1.19 per cent in the LL population. Decrease in alpha wave amplitude at the T3 and T4 sources in MCI subjects was observed in LL group while there was an increase in amplitude for alpha wave in these regions in the ALL groups. Domain specific MDCST showed decline in immediate recall, procedural memory and mind body co-ordination which was negligible in the LL population. INTERPRETATION & CONCLUSIONS: MDCST exhibited excellent psychometric properties in terms of sensitivity, and test-retest reliability qualifying it to be used as a more effective cognitive measure for assessment of MCI in demographic studies in comparison to traditional measures. Our findings also showed increased prevalence of MCI in ALL population staying for longer durations at high altitude which is neurophysiologically distinct from MCI leading to Alzheimer's disease. PMID- 23041736 TI - Post-placental intrauterine device insertion--a five year experience at a tertiary care centre in north India. AB - BACKGROUND & OBJECTIVES: In view of high rate of unintended pregnancy in our country, particularly in post-partum women, there is a need for reliable, effective, long-term contraception such as intrauterine device (IUD) in post partum women. The present study was planned to evaluate the safety and efficacy of immediate post-partum IUD insertion in women delivering vaginally or by caesarian section in a tertiary care centre facility in north India during a period of five years. METHODS: The women recruited had CuT 200B insertion immediately after delivery of placenta in vaginal or caesarean delivery. Women having post-partum haemorrhage (PPH), anaemia, pre-labour rupture of membranes >18 h, obstructed labour and distorted uterine cavity by fibroid or by congenital malformation were excluded from the study. The women were followed up at 6 wk and 6 months after delivery. RESULTS: A total of 1317 women were included in the study. Of these, 1037 (78.7%) came for first follow up. The cumulative expulsion rate at the end of 6 months was 10.68 per cent. There was no case of misplaced IUD. INTERPRETATION & CONCLUSIONS: Although the expulsion rate for immediate post partum insertion was higher than for interval insertion, the benefits of providing highly effective contraception immediately after delivery outweigh this disadvantage, particularly in country where women have limited access to medical care. PMID- 23041735 TI - Health care inequities in north India: role of public sector in universalizing health care. AB - BACKGROUND & OBJECTIVES: Income inequality is associated with poor health. Inequities exist in service utilization and financing for health care. Health care costs push high number of households into poverty in India. We undertook this study to ascertain inequities in health status, service utilization and out of-pocket (OOP) health expenditures in two States in north India namely, Haryana and Punjab, and Union Territory of Chandigarh. METHODS: Data from National Sample Survey 60 th Round on Morbidity and Health Care were analyzed by mean consumption expenditure quintiles. Indicators were devised to document inequities in the dimensions of horizontal and vertical inequity; and redistribution of public subsidy. Concentration index (CI), and equity ratio in conjunction with concentration curve were computed to measure inequity. RESULTS: Reporting of morbidity and hospitalization rate had a pro-rich distribution in all three States indicating poor utilization of health services by low income households. Nearly 57 and 60 per cent households from poorest income quintile in Haryana and Punjab, respectively faced catastrophic OOP hospitalization expenditure at 10 per cent threshold. Lower prevalence of catastrophic expenditure was recorded in higher income groups. Public sector also incurred high costs for hospitalization in selected three States. Medicines constituted 19 to 47 per cent of hospitalization expenditure and 59 to 86 per cent OPD expenditure borne OOP by households in public sector. Public sector hospitalizations had a pro-poor distribution in Haryana, Punjab and Chandigarh. INTERPRETATION & CONCLUSIONS: Our analysis indicates that public sector health service utilization needs to be improved. OOP health care expenditures at public sector institutions should to be curtailed to improve utilization of poorer segments of population. Greater availability of medicines in public sector and regulation of their prices provide a unique opportunity to reduce public sector OOP expenditure. PMID- 23041737 TI - Aetiologic spectrum of mental retardation & developmental delay in India. AB - BACKGROUND & OBJECTIVES: The aetiology of mental retardation is varied and difficult to establish. Reports from India on the spectrum of underlying causative conditions are lacking. This retrospective study was conducted to establish the various aetiologies of mental retardation (MR) and developmental delay (DD) in patients attending a medical genetics centre in north India and to assess the contribution of genetic disorders. METHODS: This retrospective study was conducted at a tertiary care centre in north India. All patients attending the centre with MR or DD from January 2007 to December 2009 were included. The aetiology of MR/DD was ascertained after clinical assessment and targeted laboratory evaluation. The spectrum of causative conditions and contribution of genetic disorders was established. RESULTS: A total of 338 patients were included in the study, of whom definite diagnosis was established in 253 (74.8%). The various aetiological categories were: chromosomal disorders in 112 (33.1%), non chromosomal syndromes in 32 (9.5%), neurometabolic disorders in 34 (10.1%), central nervous system structural defects in 25 (7.4%), cerebral palsy in 43 (12.7%) and environmental insults in 7 (2%). Eighty five patients (25.2%) had idiopathic mental retardation. A total of 196 (58%) patients had a genetic disorder as the cause of MR/DD. INTERPRETATION & CONCLUSIONS: The aetiology of MR/DD is varied and difficult to establish in a significant proportion of patients. Chromosomal and various monogenic disorders contribute to a large number of MR/DD cases and hence a genetic work up is essential for all such patients. PMID- 23041738 TI - The impact of 30 ml/kg hydroxyethyl starch 130/0.4 vs hydroxyethyl starch 130/0.42 on coagulation in patients undergoing abdominal surgery. AB - BACKGROUND & OBJECTIVES: Hydroxyethyl starches (HES) 130/0.4 (Voluven;) and 130/0.42 (Venofundin;) impair coagulation less than older HES solutions with higher molecular weight and molar substitution. Thus, these may be used in high doses up to 50 ml/kg/day. The aim of this study was to investigate and compare the effects of HES 130/0.4 versus HES 130/0.42 on coagulation after the intraoperative infusion of 30 ml/kg in patients undergoing major abdominal surgery. METHODS: Fifty two patients scheduled for elective major abdominal surgery were randomized to receive 30 ml/kg of HES 130/0.4 or HES 130/0.42 intraoperatively. Coagulation variables were assessed before and after infusion of the colloid solution using thrombelastography. RESULTS: Data from 49 patients, 25 patients in the HES 130/0.4 and 24 in the HES 130/0.42 group, were analyzed. Measurements of reaction time, kinetic time, alpha-angle, maximum amplitude and coagulation index before and after colloid infusion did not differ between the groups. Within each group, after colloid infusion, reaction time did not change significantly, while alpha-angle, maximum amplitude and coagulation index values were significantly decreased (P <0.01, P<0.001 and P<0.001, respectively in HES 130/0.4 group and P<0.01, P<0.001 and P<0.01, respectively in HES 130/0.42 group). Kinetic time was significantly increased (P<0.001) in both the groups. In both groups, all thrombelastographic measurements after colloid infusion were found within normal limits. INTERPRETATION & CONCLUSIONS: HES 130/0.4 and HES 130/0.42 showed similar, not clinically significant effects on coagulation, as assessed by thrombelastography, when a dose of 30 ml/kg was administered in patients undergoing major abdominal surgery. PMID- 23041739 TI - Spectrum of malabsorption syndrome among adults & factors differentiating celiac disease & tropical malabsorption. AB - BACKGROUND & OBJECTIVES: Aetiology of malabsorption syndrome (MAS) differs in tropical and temperate countries over time; clinical and laboratory parameters may differentiate between various causes. This study was undertaken to investigate the spectrum of MAS among Indian adults and to find out the features that may help to differentiate between TM and celiac disease. METHODS: Causes of MAS, and factors differentiating tropical malabsorption (TM) from celiac disease (CD) were determined in 275 patients. RESULTS: Using standard criteria, causes in 275 patients [age 37.5+13.2 yr, 170, (61.5%) male] were, TM 101 (37%), CD 53 (19%), small intestinal bacterial overgrowth 28 (10%), AIDS 15 (5.4%), giardiasis 13 (5%), hypogammaglobulinemia 12 (4%), intestinal tuberculosis 7 (2.5%), strongyloidiasis 6 (2%), immunoproliferative small intestinal disease 5 (2%), Crohn's disease 6 (2%), amyloidosis 4 (1.5%), intestinal lymphangiectasia 3 (1%) and unknown 22 (8%). On univariate analysis, patients with CD were younger than TM (30.6+12 vs. 39.3+12.6 yr, P<0.001), had lower body weight (41.3+11.8 vs. 49.9+11.2 kg, P<0.001), longer diarrhoea duration (median 36 inter-quartile range 17.8-120 vs. 24-months, 8-48, P<0.01), lower stool frequency (6/day, 5-8 vs. 8, 5 10, P<0.05), lower haemoglobin (9.4+3.2 vs. 10.4+2.7 g/dl, P<0.05), higher platelet count (2,58,000, range 1,35,500-3,23,500 vs. 1,60,000, 1,26,000 2,58,000/mm 3 , P<0.05), and more often had hepatomegaly (9/53, 17% vs. 4/101, 4%, P<0.01), and subtotal or partial villous atrophy (36/50, 72% vs. 28/87, 32%, P<0.001). Younger age (<35 yr), longer diarrhoea duration, higher platelet count and villous atrophy were significant on multivariate analysis. INTERPRETATION & CONCLUSIONS: TM and CD are common causes of MAS among Indian adults. Younger age (<35 yr), longer diarrhoea duration, higher platelet count and villous atrophy were found to be associated with CD. PMID- 23041740 TI - Effects of cow ghee (clarified butter oil) & soybean oil on carcinogen metabolizing enzymes in rats. AB - BACKGROUND & OBJECTIVES: Our previous study showed that cow ghee relative to soybean oil had a protective effect against carcinogen induced mammary cancer in rats. The objective of this study was to elucidate its biochemical mechanism. METHODS: Two groups of 21 day old rats (20 each) were fed for 44 wk diet containing cow ghee or soybean oil (10%). Five animals from each group were sacrificed at 0 day and at 5, 21 and 44 wk for analysis of phase I and phase II pathways enzymes of carcinogen metabolism. RESULTS: Dietary cow ghee relative to soybean oil decreased the activities of cytochrome P450 (CYP) enzymes, CYP1A1, CYP1A2, CYP1B1 and CYP2B1, responsible for activation of carcinogen in liver. Carcinogen detoxification activities of uridinediphospho-glucuronosyl transferase (UDPGT) and quinone reductase (QR) in liver, and gamma-glutamyltranspeptidase (GGTP) and QR in mammary tissue were significantly higher in cow ghee fed rats than in soybean oil fed rats. The hepatic GGTP activity decreased on soybean oil diet; while in cow ghee group it remained unaffected. INTERPRETATION & CONCLUSIONS: Our findings show that dietary cow ghee compared to soybean oil downregulates the enzyme activities responsible for carcinogen activation in liver and upregulates carcinogen detoxification activities in liver and mammary tissues. PMID- 23041741 TI - Effects of 17-alpha ethynyl estradiol on proliferation, differentiation & mineralization of osteoprecursor cells. AB - BACKGROUND & OBJECTIVES: The steroidal estrogen 17alpha-ethynyl estradiol (EE) is an orally bio-active estrogen used in almost all modern formulations of estrogen progestin combination preparations of oral contraceptives. Contrasting effects of treatment with combined oral contraceptives on bone mineral density of pre-, peri , and post-menopausal women have been reported, and it has been suggested that the estrogen dose and the type of progestogen may be the main contributing factors for these contrasting results. The objective of this study was to evaluate the effects of EE on osteoprecursor cells. METHODS: The effects of single component of oral contraceptive, EE, were tested to see the relationship between EE and osteoblast proliferation, differentiation and mineralization. Tests used included a cell viability test, alkaline phosphatase (ALP) test, alizarin red-S staining, and a Western blot analysis. The effect on cell viability was determined by MTT assay. Differentiation and mineralization were examined using an ALP test and alizarin red-S staining. Protein expressions related to bone formation, such as estrogen receptor-alpha (ER-alpha), estrogen receptor-beta (ER-beta), bone morphogenetic protein-2 (BMP-2), osteocalcin (OCN), and osteopontin (OPN) were evaluated by using a Western blot analysis. RESULTS: Cultures growing in the absence of EE presented the lowest value for the MTT value. However, there were no significant changes in viability/proliferation when EE was added in the medium. Cultures growing in the absence of EE presented the highest value for the ALP activity, and the additional presence of EE resulted in dose-dependent decrease concerning ALP activity. INTERPRETATION & CONCLUSIONS: Our finding showed that EE in tested dosage within MC3T3-E1 cells seem to affect the proliferation and differentiation; however, significant differences are achieved in ALP activity in early differentiation phase and further studies are needed to elucidate the mechanisms of EE on bone. PMID- 23041742 TI - Immunomodulatory effects of cardiotrophin-1 on in vitro cytokine production of monocytes & CD4 + T-lymphocytes. AB - BACKGROUND & OBJECTIVES: In congestive heart failure (CHF), increased concentrations of several cytokines including cardiotrophin-1 (CT-1) and immunactivation are found. This study was performed to evaluate whether CT-1 can induce in vitro cytokines in monocytes and CD4 + T-lymphocytes of healthy volunteers. METHODS: The study was performed in vitro to see whether CT-1 can modulate monocyte or CD4 + T-lymphocyte interleukin (IL)-1beta, -2, -4, -5, -10, interferon gamma (IFNgamma), and tumour necrosis factor alpha (TNFalpha) expression by flow cytometry following stimulation with CT-1 alone or together with lipopolysaccharide (LPS) or phorbol myristate acetate (PMA)/ionomycine (iono). RESULTS: CT-1 increased the number of TNFalpha and IL-1beta positive monocytes. LPS induced IL-10, TNFalpha, and IL-1beta in monocytes but only IL-2 in CD4+ T-lymphocytes, whereas PMA/iono induced all cytokines besides IL-5 in monocytes and IL-1beta in CD4+ T-lymphocytes. In LPS activated monocytes, CT-1 induced a concentration-dependent reduction in the number of TNFalpha positive monocytes. After LPS activation, CT-1 decreased the number of CD4+ lymphocytes positive for IL-2, IL-4, and IL-5. In addition, following PMA/iono stimulation, CT-1 initiated a concentration-dependent decrease of CD4 + T-lymphocytes positive for TNFalpha, IL-4, IL-5, and IL-10. INTERPRETATION & CONCLUSIONS: The present data show that in vitro CT-1 can activate monocytes and modulate cytokine production of activated CD4 + T-lymphocytes. We speculate that CT-1 may at least be partly responsible for immunactivation in CHF. PMID- 23041743 TI - Contribution of hepatitis E virus in acute sporadic hepatitis in north western India. AB - BACKGROUND & OBJECTIVES: Hepatitis E virus (HEV) causes acute viral hepatitis. Majority of the documented studies on hepatitis E have been focused on the incidence of this disease in northern and south central India. Limited data are available on HEV infection among acute sporadic hepatitis cases in north western India. The present study was undertaken to investigate the contribution of hepatitis E virus infection in sporadic hepatitis cases in Rajasthan and neighbouring States. METHODS: Seven hundred and thirty six patients suspected to have viral hepatitis were screened for the hepatotropic viral markers, hepatitis A, B, C and E by using commercial enzyme immunoassay kits with a high sensitivity and specificity. The acute nature of HEV infection was also confirmed by the detection of HEV RNA by nested RT-PCR. RESULTS: Hepatitis E was found to be the major cause of acute sporadic viral hepatitis (49.7%) in this region of India. Mixed infections of HEV-HAV (1.2%), HEV-HBV (6.1%), and HEV-HCV (1.7%) were also detected. No viral marker was detected in 32 per cent cases. INTERPRETATION & CONCLUSION: HEV was found as the major aetiological agent of acute sporadic viral hepatitis in Rajasthan (north western India). It is important to screen primarily for all the common enterically and parenterally transmitted hepatotropic viral markers in acute sporadic viral hepatitis. There is a need to do additional serological and molecular tests to identify the aetiological agent in the cases of acute hepatitis. PMID- 23041744 TI - Molecular & phenotypic characterization of Staphylococcus epidermidis in implant related infections. AB - BACKGROUND & OBJECTIVES: The discrimination between the Staphylococcus epidermidis colonizing the deep seated indwelling devices and those which are mere commensals has always been a challenge for the clinical microbiologist. This study was aimed to characterize the S. epidermidis isolates obtained from device related infection for their phenotypic and molecular markers of virulence and to see whether these markers can be used to differentiate the pathogenic S. epidermidis from the commensals. METHODS: Fifty five S. epidermidis isolates from various device related infections such as endophthalmitis following intra-ocular lens (IOL) implantation, intravascular (IV) catheter related sepsis and orthopaedic implant infections, were studied for slime production, biotyping, antibiotic sensitivity; and mec A and ica positivity by the recommended procedures. RESULTS: Twenty three (41.8%) isolates were multi-drug resistant, 26 (65.2%) were slime producers, 30 (54.5%) were adherent, 23 (41.8%) possessed the intercellular adhesin (ica) gene, and 28 (50.9%) harboured the mec A gene. Biotypes I and III were the commonest, most members of which were multi- drug resistant. Twenty two (73.3%) of the 30 adherent bacteria were slime producers as opposed to only 4 (16%) of the 25 non-adherent bacteria (P<0.001). A vast majority i.e. 21 (91.3%) of the 23 ica positive organisms were adherent to artificial surfaces in contrast to only 9 (28.1%) of the 32 non-ica positive organisms (P<0.001). Twenty (86.9%) of the 23 ica positive bacteria were slime producers, as opposed to only 6 (18.7%) of the 32 ica negative bacteria (P<0.001). Of the 23 multi-drug resistant isolates, 19 (82.6%) carried the mec A gene. INTERPRETATION & CONCLUSIONS: The present findings showed that ica AB and mec A were the two important virulence markers of S. epidermidis in implant infections and slime was responsible for the sessile mode of attachment on the devices. PMID- 23041745 TI - Detection of dengue virus 4 from central India. AB - BACKGROUND & OBJECTIVES: Dengue is an important arboviral disease. All four dengue virus serotypes are reported to be circulating in India. It is also known that different serotypes, genotypes and clades of genotype determine outbreak severity. Dengue affected children are known to have serious disease outcome. We carried out this study to give reliable diagnosis of dengue infection in children and to detect circulating serotype in central India. METHODS: Samples collected from paediatric patients suspected to have dengue fever were subjected to IgM and IgG ELISA to determine dengue virus infection. Samples collected within 0-5 days of onset of illness and positive by IgM ELISA were tested by nested reverse transcription polymerase chain reaction (nRT-PCR). The PCR products were sequenced and analyzed. RESULTS: Of the 89 samples tested, 18 and 7 were positive for dengue IgM and IgG, respectively. Dengue activity was observed in both Jabalpur city and adjoining rural settings. One sample found positive by nRT-PCR was further sequenced to confirm dengue virus 4 as aetiological agent. INTERPRETATION & CONCLUSIONS: Our findings demonstrated dengue virus infection in children and adolescent in central India. Because of continuous changing epidemiology, it is important to monitor dengue virus activity at both serological and molecular level in this part of the country for better patient care and management. PMID- 23041746 TI - Serotype distribution & sensitivity pattern of nasopharyngeal colonizing Streptococcus pneumoniae among rural children of eastern India. PMID- 23041747 TI - A call to integrate musculoskeletal disorders into the national programme for non communicable diseases (NCD). PMID- 23041748 TI - Dupuytren's contracture. PMID- 23041749 TI - Chemo-attractant N-acetyl proline-glycine-proline induces CD11b/CD18-dependent neutrophil adhesion. AB - BACKGROUND: Chronic inflammation in lung diseases contributes to lung tissue destruction leading to the formation of chemotactic collagen fragments such as N acetylated proline-glycine-proline (N-ac-PGP). In the current study, we investigate whether N-ac-PGP influences beta(2)-integrin activation and function in neutrophilic firm adhesion to endothelium. METHODS: Human polymorphonuclear leukocytes (PMNs) were isolated from fresh human blood. Subsequently, a transmigration assay was performed to evaluate the active migration of PMNs towards N-ac-PGP. Furthermore, the effect of the tripeptide on beta(2)-integrin activation was assessed by performing the adhesion assay using fibrinogen as a ligand. To determine whether this effect was due to conformational change of beta(2)-integrins, antibodies against CD11b and CD18 were used in the adhesion assay and the expression pattern of CD11b was determined. RESULTS: Human neutrophils transmigrated through an endothelial cell layer in response to basolateral N-ac-PGP. N-ac-PGP induced also a neutrophil adherence to fibrinogen. Using functional blocking antibodies against CD11b and CD18, it was demonstrated that CD11b/CD18 (Mac-1) was responsible for the N-ac-PGP-induced firm adhesion of neutrophils to fibrinogen. Pertussis toxin decreased the Mac-1 activation indicating the involvement of G-proteins. N-ac-PGP most likely activated Mac-1 by initiating a conformational change, since the expression pattern of Mac-1 on the cell surface did not change significantly. CONCLUSIONS: Chemo-attractant N-acetyl proline-glycine-proline induces CD11b/CD18-dependent neutrophil adhesion. GENERAL SIGNIFICANCE: This is the first study to describe that the chemo-attractant N-ac PGP also activates Mac-1 on the surface of neutrophils, which can additionally contribute to neutrophilic transmigration into the lung tissue during lung inflammation. PMID- 23041750 TI - Broad-complex functions in postembryonic development of the cockroach Blattella germanica shed new light on the evolution of insect metamorphosis. AB - BACKGROUND: Insect metamorphosis proceeds in two modes: hemimetaboly, gradual change along the life cycle; and holometaboly, abrupt change from larvae to adult mediated by a pupal stage. Both are regulated by 20-hydroxyecdysone (20E), which promotes molts, and juvenile hormone (JH), which represses adult morphogenesis. Expression of Broad-complex (BR-C) is induced by 20E and modulated by JH. In holometabolous species, like Drosophila melanogaster, BR-C expression is inhibited by JH in young larvae and enhanced in mature larvae, when JH declines and BR-C expression specifies the pupal stage. METHODS: Using Blattella germanica as a basal hemimetabolous model, we determined the patterns of expression of BR-C mRNAs using quantitative RT-PCR, and we studied the functions of BR-C factors using RNA interference approaches. RESULTS: We found that BR-C expression is enhanced by JH and correlates with JH hemolymph concentration. BR-C factors appear to be involved in cell division and wing pad growth, as well as wing vein patterning. CONCLUSIONS: In B. germanica, expression of BR-C is enhanced by JH, and BR-C factors appear to promote wing growth to reach the right size, form and patterning, which contrast with the endocrine regulation and complex functions observed in holometabolous species. GENERAL SIGNIFICANCE: Our results shed new light to the evolution from hemimetaboly to holometaboly regarding BR-C, whose regulation and functions were affected by two innovations: 1) a shift in JH action on BR-C expression during young stages, from stimulatory to inhibitory, and 2) an expansion of functions, from regulating wing development, to determining pupal morphogenesis. PMID- 23041752 TI - Association of left ventricular motion and central augmentation index in healthy young men. AB - BACKGROUND: Central blood pressure is a determinant of cardiovascular outcome; however, it can be described by parameters other than systolic and diastolic pressure with central augmentation index (AIx) often utilized. Although generally considered as determined by peripheral pressure wave reflection, not all data are consistent with this interpretation of AIx. We hypothesized that the motion of the heart during systole may influence central pressure waveform morphology, including the AIx. METHOD: We studied the carotid pressure waveform, aortic stiffness and endothelial function in 20 healthy young men (full data available in 19). Arterial stiffness was measured by carotid femoral pulse wave velocity (cfPWV), endothelial function by peripheral arterial plethysmography (PAPl) and central blood pressure waveform by carotid applanation tonometry. Basal cardiac motion was assessed with pulsed wave tissue Doppler imaging of the septal mitral annulus. RESULTS: Carotid AIx decreased after the administration of glyceryl trinitrate by 11.3 +/- (sem) 4.6% (P = 0.02); however, time to the inflection point (Ti) did not change. During systolic contraction at both baseline and after glyceryl trinitrate, time to peak annular systolic velocity was directly related to, and always preceded, carotid Ti (R(2) = 0.81; P < 0.01). Carotid Ti and AIx were not related to cfPWV or endothelial function. CONCLUSION: In fit young men, rather than only being a consequence of arterial properties Ti, and therefore central AIx, may be substantially determined by left ventricular systolic function. These findings question the interpretation of central AIx as a measure of pressure wave reflection and aortic stiffness and potentially impact its interpretation in diagnosis and treatment of cardiovascular risk. PMID- 23041751 TI - Relation between adiposity and hypertension persists after onset of clinically manifest arterial disease. AB - OBJECTIVES: To quantify the relation between adiposity and blood pressure (BP) level in patients with symptomatic vascular disease and, thereby, assess whether the obesity paradox can be explained by a causal mechanism involving BP. METHODS: BP and markers of adiposity (i.e. weight, body mass index, waist circumference, waist-to-hip ratio, subcutaneous adipose tissue, and visceral adipose tissue) were recorded in 4556 men and women with symptomatic vascular disease enrolled in the Secondary Manifestations of Arterial Disease Study. Additionally, 185 patients underwent repeated measurements after 3.7 years follow-up. RESULTS: Each 5 kg/m(2) body mass index was associated with +3.8 mmHg (95% confidence interval (CI) 3.0-4.6) SBP difference and +2.3 mmHg (95% CI 1.9-2.8 mmHg) DBP difference in both men and women. Measures of centralized adiposity compared with BMI were equally related with BP. In contrast, subcutaneous adipose tissue was only weakly related with DBP and not related with SBP and pulse pressure. Various methods of adjustment for BP-lowering medication use led to consistent results. Furthermore, 5 kg/m(2) body mass index change during follow-up was associated with +8.1/5.1 mmHg BP change. CONCLUSION: The relation between general and abdominal adiposity and hypertension persists after onset of symptomatic arterial disease both in men and women. This shows that the obesity paradox cannot be explained by a causal mechanism involving BP and, therefore, supports weight control for reducing BP in secondary prevention of cardiovascular events. PMID- 23041754 TI - Gender ratio imbalance effects on HIV risk behaviors in African American women. AB - Although literature suggests that African American women are no more likely to engage in risky sex than their White counterparts, they are more likely to have sex partners with higher HIV risk. Thus, it is not solely an individual's behavior that determines their risk, but also the behavior of their partner and their position within a sexual network. For this reason, it is important to consider the dynamics of heterosexual relationships in the African American community. An important area of concern regarding African American heterosexual relationships is that of partner availability. A shortage of available African American men for potential partnerships exists and is reportedly due to poorer health and higher mortality rates. Some have argued that gender-ratio imbalance may be responsible for increased HIV vulnerability for African American women. This article reviews the literature on gender ratio imbalance and HIV risk in the African American community, and presents implications and suggestions for future research and intervention. PMID- 23041755 TI - Structural properties of PbVO3 perovskites under hydrostatic pressure conditions up to 10.6 GPa. AB - High-pressure synchrotron x-ray powder diffraction experiments were performed on PbVO(3) tetragonal perovskite in a diamond anvil cell under hydrostatic pressures of up to 10.6 GPa at room temperature. The compression behavior of the PbVO(3) tetragonal phase is highly anisotropic, with the c-axis being the soft direction. A reversible tetragonal to cubic perovskite structural phase transition was observed between 2.7 and 6.4 GPa in compression and below 2.2 GPa in decompression. This transition was accompanied by a large volume collapse of 10.6% at 2.7 GPa, which was mainly due to electronic structural changes of the V(4+) ion. The polar pyramidal coordination of the V(4+) ion in the tetragonal phase changed to an isotropic octahedral coordination in the cubic phase. Fitting the observed P-V data using the Birch-Murnaghan equation of state with a fixed [Formula: see text] of 4 yielded a bulk modulus K(0) = 61(2) GPa and a volume V(0) = 67.4(1) A(3) for the tetragonal phase, and the values of K(0) = 155(3) GPa and V(0) = 58.67(4) A(3) for the cubic phase. The first-principles calculated results were in good agreement with our experiments. PMID- 23041753 TI - Elucidating role of salivary proteins in denture stomatitis using a proteomic approach. AB - Denture stomatitis (DS) is the most common oral pathology among denture wearers, affecting over one-third of this group. DS is usually associated with C. albicans. However, unlike other oral candidiasis, most DS patients have intact host immunity. The presence of a denture alone is usually sufficient for DS. Saliva and its protein contents can theoretically predispose some denture wearers to DS and others resistant toward DS. Here we proposed for the first time to define salivary proteomic profiles of denture wearers with and without DS. SELDI TOF/MS analysis suggests that there is a proteomic differentiation among control, localized and generalized DS. Based on initial SELDI-TOF/MS profiling, we further used reversed phase liquid chromatography, MALDI-TOF/MS, and LC-MS/MS to characterize the salivary proteins associated with DS. Nineteen proteins based on SELDI-TOF/MS profiling were found including cystatin-SN, statherin, kininogen-1, desmocollin-2, carbonic anhydrase-6, peptidyl-prolyl cis-trans isomerase A like peptides, cystatin C, and several immunoglobulin fragments. The proteomic content gives evidence of the interaction between host tissue, saliva, and candida. Further examination in larger populations of these proteins may help to gain a better understanding of DS pathological processes and improve DS treatments. PMID- 23041756 TI - Temperature-dependent I-V characteristics for the nanocomposite semiconducting films composed of a thiol end-capped dinuclear macrocyclic complex and Au-NPs bridging 1 MUm gap gold electrodes. AB - A rigid trans pyridine-4-thiol coordinated dinuclear zinc(II) macrocyclic complex trans-[Zn2L(py-4-SH)2](ClO4)2 (1) is introduced for the first time to fabricate self-assembled nanocomposite films with gold nanoparticles (Au-NPs) covering 1 MUm gap gold electrodes. Utilizing the same self-assembled fabrication technique but different concentrations of dithiol 1 and Au-NPs in chloroform, a series of molecular-scale electronic devices 2-5 have been obtained exhibiting typical temperature-dependent (8-300 K) semiconducting I-V characteristics on the order of MUA, nA and pA in the temperature range of 8-300 K. The transformation from an insulating dinuclear zinc(II) macrocyclic complex to a semiconducting nanocomposite thin film is thereby achieved by means of the Au-S bonded contacts between dithiol end-capped molecules and Au-NPs as well as the unique charge separation and electron transportation abilities of Au-NPs. From the classical Arrhenius plots, it is concluded that the temperature-independent tunneling current between Au-NPs in the 1 * 1 MUm2 region dominates the conductance below 100 K. However, the tunneling current is overwhelmed by the temperature-dependent thermal excitation current with the increase of temperature and the hopping conductance finally governs the electron transportation among the molecules. PMID- 23041757 TI - C1 catecholamine neurons form local circuit synaptic connections within the rostroventrolateral medulla of rat. AB - C1 catecholamine neurons reside within the rostroventrolateral medulla (RVLM), an area that plays an integral role in blood pressure regulation through reticulospinal projections to sympathetic preganglionic neurons in the thoracic spinal cord. In a previous investigation we mapped the efferent projections of C1 neurons, documenting supraspinal projections to cell groups in the preautonomic network that contribute to the control of cardiovascular function. Light microscopic study also revealed putative local circuit connections within RVLM. In this investigation we tested the hypothesis that RVLM C1 neurons elaborate a local circuit synaptic network that permits communication between C1 neurons giving rise to supraspinal and reticulospinal projections. A replication defective lentivirus vector that expresses enhanced green fluorescent protein (EGFP) under the control of a synthetic dopamine beta hydroxylase (DbetaH) promoter was used to label C1 neurons and their processes. Confocal fluorescence microscopy demonstrated thin varicose axons immunopositive for EGFP and tyrosine hydroxylase that formed close appositions to C1 somata and dendrites throughout the rostrocaudal extent of the C1 area. Dual-labeled electron microscopic analysis revealed axosomatic, axodendritic and axospinous synaptic contacts with C1 and non-C1 neurons with a distribution recapitulating that observed in the light microscopic analysis. Labeled boutons were large, contained light axoplasm, lucent spherical vesicles, and formed asymmetric synaptic contacts. Collectively these data demonstrate that C1 neurons form a synaptic network within the C1 area that may function to coordinate activity among projection-specific subpopulations of neurons. The data also suggest that the boundaries of RVLM should be defined on the basis of function criteria rather than the C1 phenotype of neurons. PMID- 23041759 TI - Physical training exerts neuroprotective effects in the regulation of neurochemical factors in an animal model of Parkinson's disease. AB - The effect of physical training on the neurochemical and oxidative stress markers were evaluated in the striatum of rats with Parkinson's disease (PD). Untrained+sham-operated (USO), untrained+PD (UPD), trained+sham-operated (TSO), and trained+PD (TPD) were submitted to training on the treadmill. The PD was induced and 7 days after the lesion, the animals underwent a rotational test and euthanasia by decapitation. The striatum was homogenized for Western Blot with anti-tyrosine hydroxylase (TH), anti-brain-derived neurotrophic factor (BDNF), anti-alpha-synuclein, anti-sarcoplasmic reticulum Ca(2+)-ATPase (SERCA II), anti superoxide dismutase (SOD), anti-catalase (CAT), anti-glutathione peroxidase (GPX), and specific buffer for oxidative damage (TBARS and carbonyl content). The UPD and TPD groups showed a clear rotational asymmetry, apart from a significant reduction in the level of TH, BDNF, alpha-synuclein, SOD, CAT, and GPX as well as an increase in the TBARS and carbonyl content, as observed in the UPD group. The TH level was not significantly altered but the TPD group increased the levels of BNDF, SERCA II, SOD, and CAT and decreased the oxidative damage in lipids and protein. The effects of exercise on PD indicate the possibility that exercise, to a certain extent, modulates neurochemical status in the striatum of rats, possibly by improving the oxidative stress parameters. PMID- 23041758 TI - Valproic acid induces the glutamate transporter excitatory amino acid transporter 3 in human oligodendroglioma cells. AB - Glutamate transport in early, undifferentiated oligodendrocytic precursors has not been characterized thus far. Here we show that human oligodendroglioma Hs683 cells are not endowed with EAAT-dependent anionic amino acid transport. However, in these cells, but not in U373 human glioblastoma cells, valproic acid (VPA), an inhibitor of histone deacetylases, markedly induces SLC1A1 mRNA, which encodes for the glutamate transporter EAAT3. The effect is detectable after 8h and persists up to 120h of treatment. EAAT3 protein increase becomes detectable after 24h of treatment and reaches its maximum after 72-96h, when it is eightfold more abundant than control. The initial influx of d-aspartate increases in parallel, exhibiting the typical features of an EAAT3-mediated process. SLC1A1 mRNA induction is associated with the increased expression of PDGFRA mRNA (+150%), a marker of early oligodendrocyte precursor cells, while the expression of GFAP, CNP and TUBB3 remains unchanged. Short term experiments have indicated that the VPA effect is shared by trichostatin A, another inhibitor of histone deacetylases. On the contrary, EAAT3 induction is neither prevented by inhibitors of mitogen-activated protein kinases nor triggered by a prolonged incubation with lithium, thus excluding a role for the GSK3beta/beta-catenin pathway. Thus, the VPA-dependent induction of the glutamate transporter EAAT3 in human oligodendroglioma cells likely occurs through an epigenetic mechanism and may represent an early indicator of commitment to oligodendrocytic differentiation. PMID- 23041760 TI - Aggressive experience increases dendritic spine density within the nucleus accumbens core in female Syrian hamsters. AB - Activity within the mesolimbic dopamine system is associated with the performance of naturally motivated behaviors, one of which is aggression. In male rats, aggressive behavior induces neurochemical changes within the nucleus accumbens, a key structure within the mesolimbic dopamine system. Corresponding studies have not been done in females. Female Syrian hamsters live as isolates and when not sexually responsive are aggressive toward either male or female intruders, making them an excellent model for studying aggression in females. We took advantage of this naturally expressed behavior to examine the effects of repeated aggressive experience on the morphology of medium spiny neurons in the nucleus accumbens and caudate nucleus, utilizing a DiOlistic labeling approach. We found that repeated aggressive experience significantly increased spine density within the nucleus accumbens core, with no significant changes in any other brain region examined. At the same time, significant changes in spine morphology were observed in all brain regions following repeated aggressive experience. These data are significant in that they demonstrate that repeated exposure to behaviors that form part of an animal's life history will alter neuronal structure in a way that may shift neurobiological responses to impact future social interactions. PMID- 23041761 TI - Neurovascular saturation thresholds under high intensity auditory stimulation during wake. AB - Coupling between neural activity and hemodynamic responses is important in understanding brain function, interpreting brain-imaging signals, and assessing pathological conditions. Tissue state is a major factor in neurovascular coupling and may alter the relationship between neural and hemodynamic activity. However, most neurovascular-coupling studies are performed under anesthetized or sedated states which may have severe consequences on coupling mechanisms. Our previous studies showed that following prolonged periods of sleep deprivation, evoked hemodynamic responses were muted despite consistent electrical responses, suggesting that sustained neural activity may decrease vascular compliance and limit blood perfusion. To investigate potential perfusion limitations during natural waking conditions, we simultaneously measured evoked response potentials (ERPs) and evoked hemodynamic responses using optical-imaging techniques to increase intensity auditory stimulation. The relationship between evoked hemodynamic responses and integrated ERPs followed a sigmoid relationship where the hemodynamic response approached saturation at lower stimulus intensities than the ERP. If limits in blood perfusion are caused by stretching of the vessel wall, then these results suggest there may be decreased vascular compliance due to sustained neural activity during wake, which could limit vascular responsiveness and local blood perfusion. Conditions that stress cerebral vasculature, such as sleep deprivation and some pathologies (e.g., epilepsy), may further decrease vascular compliance, limit metabolic delivery, and cause tissue trauma. While ERPs and evoked hemodynamic responses provide an indication of the correlated neural activity and metabolic demand, the relationship between these two responses is complex and the different measurement techniques are not directly correlated. Future studies are required to verify these findings and further explore neurovascular coupling during wake by assessing local field potentials, vascular expansion, hemodynamic response localization. PMID- 23041762 TI - Differential involvement of dorsal raphe subnuclei in the regulation of anxiety- and panic-related defensive behaviors. AB - A wealth of evidence indicates that the dorsal raphe nucleus (DR) is not a homogenous structure, but an aggregate of distinctive populations of neurons that may differ anatomically, neurochemically and functionally. Other findings suggest that serotonergic neurons within the mid-caudal and caudal part of the DR are involved in anxiety processing while those within the lateral wings (lwDR) and ventrolateral periaqueductal gray (vlPAG) are responsive to panic-evoking stimuli/situations. However, no study to date has directly compared the activity of 5-HT and non-5HT neurons within different subnuclei of the DR following the expression of anxiety- and panic-related defensive responses. In the present investigation, the number of doubly immunostained cells for Fos protein and tryptophan hydroxylase, a marker of serotonergic neurons, was assessed within the rat DR, median raphe nucleus (MRN) and PAG following inhibitory avoidance and escape performance in the elevated T-maze, behaviors associated with anxiety and panic, respectively. Inhibitory avoidance, but not escape, significantly increased the number of Fos-expressing serotonergic neurons within the mid-caudal part of the dorsal subnucleus, caudal and interfascicular subnuclei of the DR and in the MRN. Escape, on the other hand, caused a marked increase in the activity of non-5HT cells within the lwDR, vlPAG, dorsolateral and dorsomedial columns of the PAG. These results strongly corroborate the view that different subsets of neurons in the DR are activated by anxiety- and panic-relevant stimuli/situations, with important implications for the understanding of the pathophysiology of generalized anxiety and panic disorders. PMID- 23041763 TI - Characterization of immature and mature 5-hydroxytryptamine 3A receptor expressing cells within the adult SVZ-RMS-OB system. AB - Neural stem cells in the subventricular zone (SVZ) generate progenitors which in turn give rise to neuroblasts. These neuroblasts then migrate along the rostral migratory stream (RMS) in chains and reach the olfactory bulb (OB), where they mature into local interneurons. Interneurons in the OB are heterogeneous, which are mainly located in granular cell layer (GCL), external plexiform layer (EPL) and glomerular layer (GL). In this study, we show that green fluorescent protein expressing (GFP+) cells in the SVZ and RMS of the 5HT3aR-BAC(EGFP) transgenic mouse exclusively express transcription factor Sp8 which is expressed in lateral ganglionic embryonic eminence (LGE) and postnatal SVZ. These GFP+ neuroblasts of the 5HT3aR-BAC(EGFP) transgenic mouse migrate along the RMS to the OB where they differentiate into calretinin+ (CR+), parvabumin+ (PV+), vasoactive intestinal peptide+ (VIP+), somatostatin+ (Som+) and tyrosine hydroxylase+ (TH+), but not calbindin+ (CB+) interneurons. These GFP+ interneurons continuously express Sp8 in the OB. Furthermore, these results suggest that GFP-expressing cells are derived from LGE, and this transgenic mouse line will be a useful tool for studying the development and function of interneurons in both neocortex and OB. PMID- 23041764 TI - Strain-induced delamination of edge-grafted graphite. AB - Edge-selectively grafted graphite (EGG) with poly(ether-ketone) was prepared by the Friedel-Crafts acylation in a mild polyphosphoric acid (PPA)-phosphorous pentoxide (P(2)O(5)) mixture. The homogeneous reaction dope was coagulated in air moisture at different temperatures. The morphology of expanded EGG was changed from balls, balls/rods and rods with respect to coagulation temperatures of 80, 60, 40 and 25 degrees C, respectively. PMID- 23041766 TI - Effects of propofol on the activation of hippocampal CaMKIIalpha in depressed rats receiving electroconvulsive therapy. AB - OBJECTIVES: The aim of this study was to investigate the effects of propofol on the activation of hippocampal calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) in electroconvulsive therapy (ECT) in a rat model of depression. METHODS: Sprague-Dawley rats were stressed repeatedly for 28 days to establish a depressed model. Forty depressed rats were then randomly assigned (n = 10 per group) to the depression group, propofol group (received propofol once a day for 1 week), ECT group (treated with ECT once a day for 1 week), or propofol + ECT group (treated with ECT pretreated and propofol once a day for 1 week). Their depressive state was assessed using the sucrose preference test and open-field test, whereas their learning and memory were evaluated using the Morris water maze task. The expression levels of CaMKIIalpha and phosphorylated CaMKIIalpha (pCaMKIIalpha) were detected by immunohistochemistry. RESULTS: Compared with the depression group, the ECT and propofol + ECT groups had higher sucrose preference percentages and scored higher on the open-field test. The ECT group exhibited longer escape latency, shorter space exploration time, down-regulated expressions of CaMKIIalpha and pCaMKIIalpha in the hippocampus, and lower pCaMKIIalpha/CaMKIIalpha values. The propofol + ECT group showed up-regulated expressions of CaMKIIalpha and pCaMKIIalpha in the hippocampus. Compared with the ECT group, the propofol + ECT group exhibited shorter escape latency, longer space exploration time, up-regulated expressions of CaMKIIalpha and pCaMKIIalpha, and higher pCaMKIIalpha/CaMKIIalpha values. CONCLUSIONS: Propofol may potentially alleviate ECT-induced learning/memory impairment in depressed rats by enhancing CaMKIIalpha activation in the hippocampus. PMID- 23041765 TI - Ciprofloxacin has antifibrotic effects in scleroderma fibroblasts via downregulation of Dnmt1 and upregulation of Fli1. AB - Systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs. The present study was undertaken to examine the effects of ciprofloxacin, a fluoroquinolone antibiotic implicated in matrix remodeling, on dermal and lung fibroblasts obtained from SSc patients. Dermal and lung fibroblasts from SSc patients and healthy subjects were treated with ciprofloxacin. Western blotting was used to analyze protein levels and RT-PCR was used to measure mRNA expression. The pharmacologic inhibitor UO126 was used to block Erk1/2 signaling. SSc dermal fibroblasts demonstrated a significant decrease in collagen type I mRNA and protein levels after antibiotic treatment, while healthy dermal fibroblasts were less sensitive to ciprofloxacin, downregulating collagen only at the protein levels. Connective tissue growth factor (CCN2) gene expression was significantly reduced and matrix metalloproteinase 1 (MMP1) levels were enhanced after ciprofloxacin treatment to a similar extent in healthy and SSc fibroblasts. Ciprofloxacin induced Erk1/2 phosphorylation, and Erk1/2 blockade completely prevented MMP1 upregulation. However, Smad1 and Smad3 activation in response to TGFbeta was not affected. The expression of friend leukemia integration factor 1 (Fli1), a transcriptional repressor of collagen, was increased after treatment with ciprofloxacin only in SSc fibroblasts, and this was accompanied by a decrease in the levels of DNA methyltransferase 1 (Dnmt1). Similar effects were observed in SSc-interstitial lung disease (ILD) lung fibroblasts. In summary, our study demonstrates that ciprofloxacin has antifibrotic actions in SSc dermal and lung fibroblasts via the downregulation of Dnmt1, the upregulation of Fli1 and induction of MMP1 gene expression via an Erk1/2-dependent mechanism. Thus, our data suggest that ciprofloxacin may be an attractive therapy for SSc skin and lung fibrosis. PMID- 23041767 TI - Electroconvulsive therapy in China (II): research on the technical parameters and mechanism of action. AB - OBJECTIVE: This article summarizes the publications in the Chinese scientific literature related to the technical parameters and mechanism of action associated with electroconvulsive therapy (ECT). METHODS: The researchers conducted a comprehensive search of the Chinese language literature identified from searches of the China National Knowledge Infrastructure and the Medline databases (1979 2012). RESULTS: More than 900 journal papers on ECT have been published in the Chinese language between 1979 and 2012. Most studies found that electrode placement, anesthesia, and muscle relaxants are important clinical factors associated with both clinical efficacy and adverse effects. Chinese researchers have reported new leads regarding the possible mechanism of ECT. CONCLUSION: The Chinese medical literature provides an important database that will help advance ECT research in both China and the international community. PMID- 23041768 TI - Canadian survey of perianesthetic care for patients receiving electroconvulsive therapy. AB - OBJECTIVES: We report on the anesthesia subsection of a comprehensive nationwide survey (Canadian Electroconvulsive Therapy Survey/Enquete canadienne sur les electrochocs) on the practice of electroconvulsive therapy (ECT) in Canada. METHODS: This comprehensive survey was sent to the 175 Canadian institutions identified as providers of ECT in 2007. Among other topics, 9 anesthesia-related questions were administered regarding anesthesiology consultation; high-risk patients; credentials of the anesthesia provider; monitoring, airway, and resuscitation equipment; anesthetic induction, muscle relaxant, vasoactive, and other perianesthetic drugs and practices; and postanesthetic discharge. RESULTS: Sixty-one percent (107/175) of the institutions returned completed survey questionnaires. More than 70% of the sites reported pre-ECT anesthesiology consultation for all (61%) or most (11%) patients. In more than 90%, a Canadian Royal College-certified anesthesiologist, or equivalent, provided anesthetic care. Routine use of oximetry, electrocardiography, and blood pressure monitoring were reported by all but 2 sites; use of bite block was reported by all but 4 sites; and preoxygenation was reported by all but 7 sites. Dantrolene and capnography were not reported as readily available by 35% and 40%, respectively, with comparatively less frequent availability at non-operating room and lower volume sites. CONCLUSIONS: These results suggest safe practices of anesthesia for ECT in Canada. Further attention needs to be paid to ready availability of dantrolene and capnography, particularly at non-operating room ECT sites. Improvements in anesthetic care of patients undergoing ECT may be realized through continued knowledge translation efforts and by expanding access to currently unavailable anesthetic induction agents and, in some settings, limited clinical anesthesiology resources. PMID- 23041769 TI - Synthesis and structural characterization of novel cyclam-based zirconium complexes and their use in the controlled ROP of rac-lactide: access to cyclam functionalized polylactide materials. AB - Novel Bn(2)Cyclam-based zirconium complexes of the type (Bn(2)Cyclam)Zr(X)(X') (3, X = X' = OPh; 4, X = X' = SPh; 5, X = Cl, X' = O(i)Pr) were synthesized in good yields via metathesis routes involving the reaction of the dichloro precursor (Bn(2)Cyclam)Zr(Cl)(2) and the appropriate lithium salts. The molecular structures of compounds 3, 4 and 5, as determined by X-ray crystallographic studies, all confirmed the effective chelation of the Bn(2)Cyclam ligand in a kappa(4)-N(2)N(2)' fashion, with the hexa-coordinated Zr center adopting a trigonal prismatic geometry. Complexes 3-5 as well as the diisopropoxide derivative (Bn(2)Cyclam)Zr(O(i)Pr)(2) (2) were all found to initiate the ring opening polymerization (ROP) of rac-lactide in a controlled manner, as deduced from SEC data and linear correlations between molecular weight numbers (M(n)) and monomer conversion as the ROP proceeds. While initiator 2 polymerizes rac-lactide to afford, as expected, an O(i)Pr-ester-end PLA, the ROP of rac-lactide by species 3 or 4 affords an unusual cyclam-end group PLA, as deduced from MALDI-TOF data. The bonding and the electronic structures of the dialkoxides 2 and 3 were assessed by DFT and their possible influence on the polymerization mechanism is discussed. PMID- 23041770 TI - Parallel assembly of particles and wires on substrates by dictating instability evolution in liquid metal films. AB - Liquid metal wires supported on substrates destabilize into droplets. The destabilization exhibits many characteristics of the Rayleigh-Plateau model of fluid jet breakup in vacuum. In either case, breakup is driven by unstable, varicose surface oscillations with wavelengths greater than the critical one (lambda(c)). Here, by controlling the nanosecond liquid lifetime as well as stability of a rivulet as a function of its length by lithography, we demonstrate the ability to dictate the parallel assembly of wires and particles with precise placement. PMID- 23041773 TI - Dosing of antibiotics in obesity. AB - PURPOSE OF REVIEW: Obesity is becoming a major burden on healthcare systems worldwide. The management of infections is problematic due to both an increased risk of morbidity and mortality, as well as a lack of information about dosing of antibiotics in the obese population. Recommendations in this patient group are severely lacking, so clinicians need to consider pharmacokinetic/pharmacodynamic parameters and the relative risks of overdosing and underdosing. RECENT FINDINGS: Since 2011, articles on a number of antibiotics have been published, including cefazolin/cephazolin, cefepime, cefoxitin, clindamycin, cotrimoxazole, daptomycin, ertapenem, levofloxacin, linezolid, meropenem, moxifloxacin, piperacillin/tazobactam and vancomycin. SUMMARY: Obesity causes a number of changes, including an increase in volume of distribution and changes in hepatic metabolism and renal excretion. Several antibiotics have sufficient data to be able to make recommendations, whereas other antibiotics may need to make use of doses at the upper end of the recommended range, or utilize other dose modifications based on pharmacokinetic/pharmacodynamic parameters, in an attempt to reach adequate levels and achieve similar efficacy. PMID- 23041772 TI - 'Old' antibiotics for emerging multidrug-resistant bacteria. AB - PURPOSE OF REVIEW: Increased emergence of bacterial resistance and the decline in newly developed antibiotics have necessitated the reintroduction of previously abandoned antimicrobial agents active against multidrug-resistant bacteria. Having never been subjected to contemporary drug development procedures, these 'old' antibiotics require redevelopment in order to optimize therapy. This review focuses on colistin as an exemplar of a successful redevelopment process and briefly discusses two other old antibiotics, fusidic acid and fosfomycin. RECENT FINDINGS: Redevelopment of colistin led to an improved understanding of its chemistry, pharmacokinetics and pharmacodynamics, enabling important steps towards optimizing its clinical use in different patient populations. A scientifically based dosing algorithm was developed for critically ill patients, including those with renal impairment. As nephrotoxicity is a dose-limiting adverse event of colistin, rational combination therapy with other antibiotics needs to be investigated. SUMMARY: The example of colistin demonstrated that state-of-the-art analytical, microbiological and pharmacokinetic/pharmacodynamic methods can facilitate optimized use of 'old' antibiotics in the clinic. Similar methods are now being applied to fosfomycin and fusidic acid in order to optimize therapy. To improve and preserve the usefulness of these antibiotics rational approaches for redevelopment need to be followed. PMID- 23041774 TI - Are new anthelmintics needed to eliminate human helminthiases? AB - PURPOSE OF REVIEW: Anthelmintic mass drug administration (MDA) has limited pathology and transmission of filariases, schistosomiasis and gastrointestinal nematodiases in many areas of the world. This record has led to the adoption of ambitious goals for eliminating these infections on a global scale within the next decade or two by expansion of MDA with available drugs. This review considers the attributes of anthelmintics that favor or limit attainment of the scaled-up plans for elimination, and highlights situations for which new or reformulated drugs may be needed. RECENT FINDINGS: Many challenges face elimination campaigns. Anthelmintic needs include, first, a macrofilaricidal regimen that speeds up elimination, is safe to use in regions of Onchocerca volvulus and Loa loa coendemicity, and provides a rapid method to resolve infections introduced into previously controlled areas; second, a replacement of praziquantel for schistosomiasis should a resistance arise; third, formulations of praziquantel to enhance compliance, and pediatric formulations for preschool children; fourth, a regimen that provides high efficacy against Trichuris trichiura (new anthelmintic, prolonged dosing strategy or anthelmintic combinations); fifth, pediatric formulations of albendazole and mebendazole compatible with elimination operations; and sixth, an alternative to benzimidazoles in the anticipation of the development of drug resistance. SUMMARY: Expansion of MDA programs to attain elimination of human helminthiases is a noble and worthwhile endeavor. Increased drug pressure should be expected to select resistance alleles. Alternative anthelmintics and regimens should be developed for deployment to ensure that the ambitious goals for elimination are not endangered due to an inadequate pharmacopeia. PMID- 23041775 TI - Is it possible to achieve a target of zero central line associated bloodstream infections? AB - PURPOSE OF REVIEW: Central venous catheter (CVC)-associated bloodstream infections (CLABSIs) result in poorer patient outcomes and increased healthcare costs. Reduced reimbursement for CLABSI events is now provided for hospitalized patients in the United States. Although a zero target is proposed, the feasibility has not been evaluated. The objective of this review is to identify factors contributing to CLABSI and determine whether current evidence supports attainment of a zero infection rate. RECENT FINDINGS: Limitations of current surveillance methods and reporting of aggregate data impact on achieving target CLABSI rates. Standard prevention practices, including physician and patient preparation (e.g. hand hygiene), are frequently incorporated into bundles of care. CVC dwell time has been identified as means of risk stratification. Additional strategies (e.g. chlorhexidine-impregnated dressings, antimicrobial coated devices) may be better used in patients with expected long dwell times. Non-ICU populations are increasingly targeted with prevention strategies, but expected rates of infection have not been proposed. SUMMARY: A zero CLABSI rate should be the target only for ICU populations having CVCs with a dwell time of 1 9 days following aseptic insertion. Additional measures should be reserved for patients with expected longer dwell time. Refinement and validation of surveillance methodology is required before target CLABSI rates can be proposed for non-ICU populations. PMID- 23041776 TI - A translocation t(2;8)(q12;p11) fuses FGFR1 to a novel partner gene, RANBP2/NUP358, in a myeloproliferative/myelodysplastic neoplasm. PMID- 23041777 TI - Evaluation of dopamine transporters and D2 receptors in hemiparkinsonian rat brains in vivo using consecutive PET scans of [18F]FPCIT and [18F]fallypride. AB - The aim of this study was to investigate dopaminergic function in unilaterally lesioned 6-OHDA rats by dual PET radioligands: [(18)F]FPCIT (a dopamine transporter imaging radioligand) and [(18)F]fallypride (a dopamine D2 receptors imaging radioligand). As a result, the brain uptake of [(18)F]FPCIT was significantly reduced and that of [(18)F]fallypride was increased in the ipsilateral striatum (lesion side) of the 6-OHDA rats. These findings implicated that dopamine transporter is down-regulated and dopamine D2 receptor is up regulated in this hemiparkinsonian rat model. PMID- 23041778 TI - An investigation of HPGe gamma efficiency calibration software (ANGLE V.3) for applications in nuclear decommissioning. AB - High resolution gamma spectrometry offers a rapid method to characterise waste materials on a decommissioning nuclear site. To meet regulatory requirements, measurements must be traceable to national standards, meaning that the spectrometers must be calibrated for a wide range of materials. Semi-empirical modelling software (such as ANGLETM) offers a convenient method to carry out such calibrations. This paper describes an assessment of the modelling software for use by a small laboratory based on a nuclear site. The results confirmed the need for accurate information on the detection construction if the calibration were to be accurate to within 10%. PMID- 23041779 TI - Estimating retrospective indoor radon concentrations with a new device. AB - From the (222)Rn mixed with air, the short-lived daughters (218)Po, (214)Pb, (214)Bi, and (214)Po attach to dust particles and are deposited on surfaces where finally (210)Pb and (210)Po are formed. The alpha particles from (210)Po can be measured on surfaces such as window glass or mirrors. The design and construction are presented of a new device using a silicon detector to measure this (210)Po. Some preliminary results are reported and estimates of retrospective radon concentrations are made from them. PMID- 23041780 TI - Multielemental analyses of isomorphous Indian garnet gemstones by XRD and external pixe techniques. AB - Garnet gemstones were collected from parts of Eastern Ghats geological formations of Andhra Pradesh, India and their gemological studies were carried out. Their study of chemistry is not possible as they represent mixtures of isomorphism nature, and none of the individual specimens indicate independent chemistry. Hence, non-destructive instrumental methodology of external PIXE technique was employed to understand their chemistry and identity. A 3 MeV proton beam was employed to excite the samples. In the present study geochemical characteristics of garnet gemstones were studied by proton induced X-ray emission. Almandine variety of garnet is found to be abundant in the present study by means of their chemical contents. The crystal structure and the lattice parameters were estimated using X-Ray Diffraction studies. The trace and minor elements are estimated using PIXE technique and major compositional elements are confirmed by XRD studies. The technique is found very useful in characterizing the garnet gemstones. The present work, thus establishes usefulness and versatility of the PIXE technique with external beam for research in Geo-scientific methodology. PMID- 23041781 TI - Design and optimization of a beam shaping assembly for BNCT based on D-T neutron generator and dose evaluation using a simulated head phantom. AB - A feasibility study was conducted to design a beam shaping assembly for BNCT based on D-T neutron generator. The optimization of this configuration has been realized in different steps. This proposed system consists of metallic uranium as neutron multiplier, TiF(3) and Al(2)O(3) as moderators, Pb as reflector, Ni as shield and Li-Poly as collimator to guide neutrons toward the patient position. The in-air parameters recommended by IAEA were assessed for this proposed configuration without using any filters which enables us to have a high epithermal neutron flux at the beam port. Also a simulated Snyder head phantom was used to evaluate dose profiles due to the irradiation of designed beam. The dose evaluation results and depth-dose curves show that the neutron beam designed in this work is effective for deep-seated brain tumor treatments even with D-T neutron generator with a neutron yield of 2.4*10(12) n/s. The Monte Carlo Code MCNP-4C is used in order to perform these calculations. PMID- 23041782 TI - A chondroitinase-ABC and TGF-beta1 treatment regimen for enhancing the mechanical properties of tissue-engineered fibrocartilage. AB - The development of functionally equivalent fibrocartilage remains elusive despite efforts to engineer tissues such as knee meniscus, intervertebral disc and temporomandibular joint disc. Attempts to engineer these structures often fail to create tissues with mechanical properties on a par with native tissue, resulting in constructs unsuitable for clinical applications. The objective of this study was to engineer a spectrum of biomimetic fibrocartilages representative of the distinct functional properties found in native tissues. Using the self-assembly process, different co-cultures of meniscus cells and articular chondrocytes were seeded into agarose wells and treated with the catabolic agent chondroitinase-ABC (C-ABC) and the anabolic agent transforming growth factor-beta1 (TGF-beta1) via a two-factor (cell ratio and bioactive treatment), full factorial study design. Application of both C-ABC and TGF-beta1 resulted in a beneficial or positive increase in the collagen content of treated constructs compared to controls. Significant increases in both the collagen density and fiber diameter were also seen with this treatment, increasing these values by 32 and 15%, respectively, over control values. Mechanical testing found the combined bioactive treatment to synergistically increase the Young's modulus and ultimate tensile strength of the engineered fibrocartilages compared to controls, with values reaching the lower spectrum of those found in native tissues. Together, these data demonstrate that C-ABC and TGF-beta1 interact to develop a denser collagen matrix better able to withstand tensile loading. This study highlights a way to optimize the tensile properties of engineered fibrocartilage using a biochemical and a biophysical agent together to create distinct fibrocartilages with functional properties mimicking those of native tissue. PMID- 23041783 TI - In situ forming hydrogels composed of oxidized high molecular weight hyaluronic acid and gelatin for nucleus pulposus regeneration. AB - Encapsulation of nucleus pulposus (NP) cells within in situ forming hydrogels is a novel biological treatment for early stage intervertebral disc degeneration. The procedure aims to prolong the life of the degenerating discs and to regenerate damaged tissue. In this study we developed an injectable oxidized hyaluronic acid-gelatin-adipic acid dihydrazide (oxi-HAG-ADH) hydrogel. High molecular weight (1900 kDa) hyaluronic acid was crosslinked with various concentrations of gelatin to synthesize the hydrogels and their viscoelastic properties were analyzed. Interactions between the hydrogels, NP cells, and the extracellular matrix (ECM) were also evaluated, as were the effects of the hydrogels on NP cell gene expression. The hydrogels possess several clinical advantages, including sterilizability, low viscosity for injection, and ease of use. The viscoelastic properties of the hydrogels were similar to native tissue, as reflected in the complex shear modulus (~11-14 kPa for hydrogels, 11.3 kPa for native NP). Cultured NP cells not only attached to the hydrogels but also survived, proliferated, and maintained their round morphology. Importantly, we found that hydrogels increased NP cell expression of several crucial ECM-related genes, such as COL2A1, AGN, SOX-9, and HIF-1A. PMID- 23041784 TI - Structure formation and hydrogen bonding in all-aliphatic segmented copolymers with uniform hard segments. AB - Fully aliphatic segmented poly(ether ester amide) copolymers with uniform hard segments prepared by melt polycondensation of alpha,omega-hydroxyl end functionalized polytetrahydrofuran and short glycine or beta-alanine bisester bisoxalamide units hold promise for biomedical applications. For polymers with the hard block contents varying from 10% to 27%, differential scanning calorimetry and atomic force microscopy reveal a highly phase-separated morphology, with ribbon-like nanocrystals dispersed in the soft segment matrix. To relate the polymer properties to the structure of the hard segment, the monomers were prepared and studied by optical and X-ray diffraction measurements. It was shown that the glycine and beta-alanine carbonyl ester groups are tilted away from the oxalamide plane, which can affect the degradation rate via hydrolysis of the ester bond. PMID- 23041787 TI - Correlation between structural properties and resistivity critical behavior in SrRuO3 thin films. AB - SrRuO(3) is a strong itinerant ferromagnet showing many features of 'bad metals' together with Fermi liquid behavior at very low temperature. The intriguing magnetic and transport properties of SrRuO(3) are tightly related to structure, as commonly observed in transition metal oxides. Here we report on the correlation of structural parameters (lattice constant and surface roughness) with the critical behavior of resistivity at the Curie point in SrRuO(3) thin films deposited on (001) SrTiO(3) by PLD. By varying the deposition conditions we were able to obtain a wide variety of structural properties in our samples, thus allowing us to perform a systematic study. Our analysis demonstrates the direct correlation between the critical temperature T(P) and the lattice out-of-plane parameter. Furthermore, the value of the critical exponent lambda is proved to be a good physical parameter to quantify the microscopic order of SrRuO(3) samples. PMID- 23041785 TI - Preparation of iron oxide nanoparticles stabilized with biomolecules: experimental and mechanistic issues. AB - Nanoparticles (NPs) with magnetic properties based on magnetite (Fe(3)O(4), MAG) modified with oleic acid (OA), chitosan (CS) and bovine serum albumin (BSA) have been prepared. A versatile method of synthesis was employed, involving two steps: (i) co-precipitation of MAG; and (ii) nanoprecipitation of macromolecules on as formed MAG NPs. Experimental variables have been explored to determine the set of conditions that ensure suitable properties of NPs in terms of their size, functionality and magnetic properties. It was found that the presence of OA in Fe(+2)/Fe(+3) solutions yields MAG NPs with lower aggregation levels, while increasing initial amounts of OA may change the capability of NPs to disperse in aqueous or organic media by modifying the stabilization mechanism. Incorporation of CS was verified through Fourier transform IR spectroscopy. This biopolymer stabilizes NPs by electrostatic repulsions leading to stable ferrofluids and minimal fraction of recoverable solid NPs. BSA was successfully added to NP formulations, increasing their functionality and probably their biocompatibility. In this case too stable ferrofluids were obtained, where BSA acts as a polyelectrolyte. From the proposed methodology it is possible to achieve a wide range of NPs magnetically active intended for several applications. The required properties may be obtained by varying experimental conditions. PMID- 23041788 TI - Designing cell walls for improved bioenergy production. PMID- 23041789 TI - Throat pain as a presenting symptom of giant cell arteritis. PMID- 23041790 TI - Corneal endothelial decompansation and ocular hypotony in a case with temporal arteritis. PMID- 23041791 TI - Reconstruction of periodicity of repetitive linear enamel hypoplasia from perikymata counts on imbricational enamel among dry-adapted chimpanzees (Pan troglodytes verus) from Fongoli, Senegal. AB - Periodicity of repetitive linear enamel hypoplasia (rLEH) in apes from high latitudes with single wet and dry seasons annually has not been described. We reconstruct periodicity and duration of rLEH in canine teeth from three recently deceased chimpanzees from Fongoli, Senegal with a marked seven-month dry season. High-resolution dental molds were taken in the field for magnified imaging with digital microscopy. Photomontages allowed counting of perikymata between episodes of rLEH for reconstruction of periodicity and duration of physiological stress. Where rLEH spans the imbricational enamel, the number of events is consistent with years required to form canine imbricational enamel; i.e., periodicity of rLEH seems circannual. We predicted perikymata counts between rLEH events ranging from 52 to 61 based on reported "long counts" of 7-6 days. Counts ranged from 29.5 to 44, individual mean of 36.7. This discrepancy could be explained by recurrent stress with a periodicity of 7.2-8.4 months, or by long counts of 10 days per stria. Neither is supported in the literature. Since we find evidence of rLEH with circannual periodicity, we postulate the existence of non-emergent imbricational striae. Based on evidence that stress at Fongoli recurs annually, we reconstruct stress duration of 2-3 months, longer than reported for chimpanzees living in other habitats, which we attribute to heat stress and food shortage near shrinking waterholes. We conclude that canine teeth from a small mortality cohort of chimpanzees at Fongoli preserve a faithful record of dry season stress in an extreme environment. PMID- 23041792 TI - Cohorts and emerging health disparities: biomorphic trajectories in China, 1989 to 2006. AB - Despite the recent and rapid worldwide rise in body mass index (BMI), little empirical research outside the developed world has systematically considered the role of cohorts in inaugurating emergent biomorphic disparities. This study integrates aspects of the life course perspective (attention to age- and cohort level influences) with fundamental cause theory to investigate how BMI differences have unfurled in the Chinese population. We analyze growth-curve models of adults in the China Health and Nutrition Survey. The results indicate that more recent cohorts have higher levels of BMI and, among women, experience a steeper rate of age-related BMI growth. Moreover, biomorphic change has unfolded in complex ways related to social conditions across successive cohorts. The most pronounced changes are observed among women, who demonstrate an emerging disparity in BMI levels on the basis of education and urban versus rural residence. PMID- 23041793 TI - Personality of mental health caregivers. AB - PURPOSE OF REVIEW: Caring for a family member with a chronic mental illness can be a major challenge with putting caregivers at risk of burden and depression. This review investigated the recent evidence on the role of personality traits and features for caregiver burden and depression in caregivers of care recipients with mental illness. RECENT FINDINGS: Most of the evidence was found for caregivers looking after care recipients with dementia. Neuroticism was the personality trait showing the strongest association with caregiver burden and depression. SUMMARY: Certain personality traits and features can increase the risk of caregiver burden and depression in caregivers looking after family members with a mental illness. More research is needed especially focusing on caregivers looking after care recipients with mental illnesses other than dementia as well as on interventions aiming to support vulnerable caregivers. PMID- 23041794 TI - Personality dimensions and disorders in pathological gambling. AB - PURPOSE OF REVIEW: This review presents the most current research in personality dimensions and disorders with respect to pathological gambling. RECENT FINDINGS: Personality dimensions, such as impulsivity and impulsivity-related variables, are important aspects that may shape our understanding of the pathogenesis and treatment of pathological gambling. Furthermore, a large percentage of pathological gamblers have a co-occurring personality disorder which may impact the clinical presentation of pathological gambling. SUMMARY: Evidence suggests that pathological gamblers exhibit impulsivity or impulsivity-related traits, as well as a range of personality disorders. Subtyping pathological gamblers based on personality domains has been proposed; however, more research is needed to provide support for these models. Overall, recent research represents an advancement in our understanding of how personality impacts pathological gambling, but further research is warranted to better understand how personality impacts the clinical presentation and treatment outcomes of pathological gambling. PMID- 23041795 TI - Differential expression of PTEN in hepatic tissue and hepatic stellate cells during rat liver fibrosis and its reversal. AB - To evaluate the change in phosphatase and tensin homology deleted on chromosome ten (PTEN) expression in liver fibrogenesis, particularly the reversal of fibrogenic liver tissues, and to investigate the relation with the proliferation and apoptosis of hepatic stellate cells (HSCs) in vivo, a rat model of hepatic fibrosis was established by hypodermic injection of carbon tetrachloride (CCl4) mixed with olive oil at the concentration of 40% for 5 weeks (2 ml/kg, twice a week). Reversal of fibrosis was achieved with normal feedings for 4 weeks after CCl4 injection for 5 weeks. The expression of PTEN was measured by immunofluorescence, western blot analysis and real-time PCR. Co-expression of alpha-smooth muscle actin (alpha-SMA) with PTEN and alpha-SMA with terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling (TUNEL) were assessed by confocal laser scanning microscopy. The results displayed that the expression of PTEN was reduced with fibrosis in both rat liver tissues and activated HSCs. By contrast, PTEN expression was increased with the reversal of liver fibrosis. Compared to the fibrogenic state, there were increased numbers of apoptotic activated HSCs during reversal of fibrosis. These data suggest that the dynamic expression of PTEN in rat liver tissues is negatively correlated with liver fibrosis and activated HSCs and is positively correlated with reversal of fibrosis and apoptotic activated HSCs. Modulation of PTEN expression may be an effective and novel method for the treatment of liver fibrosis. PMID- 23041796 TI - Uncertainty estimations for quantitative in vivo MRI T1 mapping. AB - Mapping the longitudinal relaxation time (T(1)) of brain tissue is of great interest for both clinical research and MRI sequence development. For an unambiguous interpretation of in vivo variations in T(1) images, it is important to understand the degree of variability that is associated with the quantitative T(1) parameter. This paper presents a general framework for estimating the uncertainty in quantitative T(1) mapping by combining a slice-shifted multi-slice inversion recovery EPI technique with the statistical wild-bootstrap approach. Both simulations and experimental analyses were performed to validate this novel approach and to evaluate the estimated T(1) uncertainty in several brain regions across four healthy volunteers. By estimating the T(1) uncertainty, it is shown that the variation in T(1) within anatomic regions for similar tissue types is larger than the uncertainty in the measurement. This indicates that heterogeneity of the inspected tissue and/or partial volume effects can be the main determinants for the observed variability in the estimated T(1) values. The proposed approach to estimate T(1) and its uncertainty without the need for repeated measurements may also prove to be useful for calculating effect sizes that are deemed significant when comparing group differences. PMID- 23041797 TI - Implanted, inductively-coupled, radiofrequency coils fabricated on flexible polymeric material: application to in vivo rat brain MRI at 7 T. AB - Combined with high-field MRI scanners, small implanted coils allow for high resolution imaging with locally improved SNR, as compared to external coils. Small flexible implantable coils dedicated to in vivo MRI of the rat brain at 7 T were developed. Based on the Multi-turn Transmission Line Resonator design, they were fabricated with a Teflon substrate using copper micromolding process and a specific metal-polymer adhesion treatment. The implanted coils were made biocompatible by PolyDimethylSiloxane (PDMS) encapsulation. The use of low loss tangent material achieves low dielectric losses within the substrate and the use of the PDMS layer reduces the parasitic coupling with the surrounding media. An implanted coil was implemented in a 7 T MRI system using inductive coupling and a dedicated external pick-up coil for signal transmission. In vivo images of the rat brain acquired with in plane resolution of (150 MUm)(2) thanks to the implanted coil revealed high SNR near the coil, allowing for the visualization of fine cerebral structures. PMID- 23041798 TI - Single bead detection with an NMR microcapillary probe. AB - We have developed a nuclear magnetic resonance (NMR) microcapillary probe for the detection of single magnetic microbeads. The geometry of the probe has been optimized so that the signal from the background water has a similar magnitude compared to the signal from the dephased water nearby a single magnetic bead within the probe detector coil. In addition, the RF field of the coil must be uniform within the effective range of the magnetic bead. Three different RF probes were tested in a 7 T (300 MHz) pulsed NMR spectrometer with sample volumes ranging from 5 nL down to 1 nL. The 1 nL probe had a single-shot signal-to-noise ratio (SNR) for pure water of 27 and a volume resolution that exhibits a 600-fold improvement over a conventional (5 mm tube) NMR probe with a sample volume of 18 MUL. This allowed for the detection of a 1 MUm magnetite/polystyrene bead (m=2*10(-14)Am(2)) with an estimated experimental SNR of 30. Simulations of the NMR spectra for the different coil geometries and positions of the bead within the coil were developed that include the B(0) shift near a single bead, the inhomogeneity of the coils, the local coil sensitivity, the skin effect of the coil conductor, and quantitated estimates of the proximity effect between coil windings. PMID- 23041799 TI - The first observation of Carbon-13 spin noise spectra. AB - We demonstrate the first (13)C NMR spin noise spectra obtained without any pulse excitation by direct detection of the randomly fluctuating noise from samples in a cryogenically cooled probe. Noise power spectra were obtained from (13)C enriched methanol and glycerol samples at 176 MHz without and with (1)H decoupling, which increases the sensitivity without introducing radio frequency interference with the weak spin noise. The multiplet amplitude ratios in (1)H coupled spectra indicate that, although pure spin noise prevails in these spectra, the influence of absorbed circuit noise is still significant at the high concentrations used. In accordance with the theory heteronuclear Overhauser enhancements are absent from the (1)H-decoupled (13)C spin noise spectra. PMID- 23041800 TI - High-pressure hydrogenation of graphene: towards graphane. AB - The conversion of graphene to graphane is of high importance from a technological and scientific point of view. We present here a scalable method for the hydrogenation of graphene based on thermal exfoliation of graphite oxide in a hydrogen atmosphere under high pressure (60-150 bar) and temperature (200-500 degrees C). This method does not require a plasma source and is able to produce gram quantities of the material. The properties of the resultant hydrogenated graphene were studied by scanning and transmission electron microscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, infrared spectroscopy and combustible elemental analysis techniques. Sheet and specific resistance of the graphene and hydrogenated graphene were measured. This scalable synthesis method has great potential to serve as a pathway towards the mass production of graphane. PMID- 23041802 TI - Contribution of a winged phlebotomy device design to blood splatter. AB - BACKGROUND: Despite a proliferation of phlebotomy devices with engineered sharps injury protection (ESIP), the impact of various winged device designs on blood splatter occurring during venipuncture procedures has not been explored. OBJECTIVES: To evaluate the potential for blood splatter of 6 designs of winged phlebotomy devices. DESIGN: A laboratory-based device evaluation without human subjects, using a simulated patient venous system. METHODS: We evaluated 18 winged phlebotomy devices of 6 device designs by Terumo, BD Vacutainer (2 designs), Greiner, Smith Medical, and Kendall (designated A-F, respectively). Scientific filters were positioned around the devices and weighed before and after venipuncture was performed. Visible blood on filters, exam gloves, and devices and measurable blood splatter were the primary units of analysis. RESULTS: The percentages of devices and gloves with visible blood on them and filters with measurable blood splatter ranged from 0% to 20%. There was a statistically significant association between device design and visible blood on devices ([Formula: see text]) and between device design and filters with measurable blood splatter ([Formula: see text]), but not between device design and visible blood on gloves. A wide range of associations were demonstrated between device design and visible blood on gloves or devices and incidence of blood splatter. CONCLUSIONS: The results of this evaluation suggest that winged phlebotomy devices with ESIP may produce blood splatter during venipuncture. Reinforcing the importance of eye protection and developing a methodology to assess ocular exposure to blood splatter are major implications for healthcare personnel who use these devices. Future studies should focus on evaluating different designs of intravascular devices (intravenous catheters, other phlebotomy devices) for blood splatter. PMID- 23041803 TI - Equal efficacy of glucoprotamin and an aldehyde product for environmental disinfection in a hematologic transplant unit: a prospective crossover trial. AB - BACKGROUND: The inanimate hospital environment has emerged as an important reservoir of nosocomial pathogens. In particular, multidrug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus, Acinetobacter species, and Clostridium difficile, play a major role in the transmission of hospital-acquired infections. In Europe, aldehydes, chlorine, and quaternary ammonium compounds have been commonly used for environmental disinfection. Glucoprotamin, a newer active compound for disinfectants, has been clinically tested for disinfection of instruments but not for environmental disinfection. OBJECTIVE: This study evaluated the antimicrobial effectiveness of a glucoprotamin-containing product (Incidin) compared with that of an aldehyde-containing product (Deconex), the current standard at our institution. METHODS: This prospective crossover study was conducted in our access-restricted hematologic transplant unit. A total of 3,086 samples from the environment were processed and examined for overall bacterial burden as well as selectively for S. aureus, C. difficile, and gram negative bacteria. RESULTS: There was no significant difference in residual bacteria after disinfection between the 2 products in terms of overall burden and selected pathogens. Enterococci were the predominant pathogens recovered from surfaces, but no vancomycin-resistant enterococci were recovered. Similarly, C. difficile could not be found in the patients' environment, even in rooms, despite the use of selective media. CONCLUSION: The aldehyde-containing product (Deconex) and the glucoprotamin-containing product (Incidin) demonstrated similar efficacy against environmental contamination in a hematologic transplant unit with the application of selective media for C. difficile, S. aureus, and gram-negative bacteria in addition to standard medium. PMID- 23041804 TI - Novel hospital curtains with antimicrobial properties: a randomized, controlled trial. AB - DESIGN: Privacy curtains that separate patient care areas in hospitals may play an important role in the transmission of healthcare-associated pathogens. The aim of this randomized, controlled trial was to assess the effectiveness in a clinical setting of curtains incorporating a complex element compound (CEC) with antimicrobial properties. SETTING: Twenty-one rooms in a surgical intensive care unit (ICU) and 9 rooms in a medical ICU were randomly selected to receive either a new standard curtain or a new identical-looking CEC curtain. Fifteen rooms received CEC curtains and 15 received standard curtains. METHODS: Cultures were performed of samples that were collected from curtains twice a week for 4 weeks (23 days). Contamination was determined according to standard microbiologic methods. Time to contamination was assessed with the Wilcoxon rank-sum test and survival analysis. Incidence rates of contamination were compared using Poisson regression. RESULTS: The median time to first contamination was 7 times longer for CEC curtains than for standard curtains (14 vs 2 days; [Formula: see text]). CEC curtains were significantly less contaminated than standard curtains according to earlier culture results but not significantly different for later culture results. Fourteen CEC curtains and 13 standard curtains were contaminated at least once ([Formula: see text]). The adjusted rate of contamination was 29% lower among CEC versus standard curtains, but this was not statistically significant (rate ratio, 0.71; 95% CI, 0.48-1.07). CONCLUSIONS: CEC privacy curtains increase the time to first contamination as compared with standard curtains. Use of privacy curtains with antimicrobial properties could increase the time between washings and may potentially play a role in decreasing pathogen transmission. PMID- 23041805 TI - Differences in the risk factors for surgical site infection between total hip arthroplasty and total knee arthroplasty in the Korean Nosocomial Infections Surveillance System (KONIS). AB - OBJECTIVE: To compare the characteristics and risk factors for surgical site infections (SSIs) after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in a nationwide survey, using shared case detection and recording systems. DESIGN: Retrospective cohort study. SETTING: Twenty-six hospitals participating in the Korean Nosocomial Infections Surveillance System (KONIS). PATIENTS: From 2006 to 2009, all patients undergoing THA and TKA in KONIS were enrolled. RESULTS: SSI occurred in 161 (2.35%) of 6,848 cases (3,422 THAs and 3,426 TKAs). Pooled mean SSI rates were 1.69% and 2.82% for THA and TKA, respectively. Of the cases we examined, 42 (26%) were superficial-incisional SSIs and 119 (74%) were "severe" SSIs; of the latter, 24 (15%) were deep-incisional SSIs and 95 (59%) were organ/space SSIs. In multivariate analysis, a duration of preoperative hospital stay of greater than 3 days was a risk factor for total SSI after both THA and TKA. Diabetes mellitus, revision surgery, prolonged duration of surgery (above the 75th percentile), and the need for surgery due to trauma were independent risk factors for total and severe SSI after THA, while male sex and an operating room without artificial ventilation were independent risk factors for total and severe SSI after TKA. A large volume of surgeries (more than 10 procedures per month) protected against total and severe SSI, but only in patients who underwent TKA. CONCLUSIONS: Risk factors for SSI after arthroplasty differ according to the site of the arthroplasty. Therefore, clinicians should take into account the site of arthroplasty in the analysis of SSI and the development of strategies for reducing SSI. PMID- 23041806 TI - Effect of hospital-wide chlorhexidine patient bathing on healthcare-associated infections. AB - BACKGROUND: Chlorhexidine gluconate (CHG) bathing has been used primarily in critical care to prevent central line-associated bloodstream infections and infections due to multidrug-resistant organisms. The objective was to determine the effect of hospital-wide CHG patient bathing on healthcare-associated infections (HAIs). DESIGN: Quasi-experimental, staged, dose-escalation study for 19 months followed by a 4-month washout period, in 3 cohorts. SETTING: Academic medical center. PATIENTS: All patients except neonates and infants. INTERVENTION AND MEASUREMENTS: CHG bathing in the form of bed basin baths or showers administered 3 days per week or daily. CHG bathing compliance was monitored, and the rate of HAIs was measured. RESULTS: Over 188,859 patient-days, 68,302 CHG baths were administered. Adherence to CHG bathing in the adult critical care units (90%) was better than that observed in other units (57.7%, [Formula: see text]). A significant decrease in infections due to Clostridium difficile was observed in all cohorts of patients during the intervention period, followed by a significant rise during the washout period. For all cohorts, the relative risk of C. difficile infection compared to baseline was 0.71 (95% confidence interval [CI], 0.57-0.89; [Formula: see text]) for 3-days-per-week CHG bathing and 0.41 (95% CI, 0.29-0.59; [Formula: see text]) for daily CHG bathing. During the washout period, the relative risk of infection was 1.85 (95% CI, 1.38-2.53; [Formula: see text]), compared to that with daily CHG bathing. A consistent effect of CHG bathing on other HAIs was not observed. No adverse events related to CHG bathing were reported. CONCLUSIONS: CHG bathing was well tolerated and was associated with a significant decrease in C. difficile infections in hospitalized patients. PMID- 23041807 TI - Empirical antimicrobial prescriptions in patients with Clostridium difficile infection at hospital admission and impact on clinical outcome. AB - OBJECTIVE: To determine, among patients with Clostridium difficile infection (CDI) at hospital admission, the impact of concurrent use of systemic, non-CDI related antimicrobials on clinical outcomes and the risk factors associated with unnecessary antimicrobial prescribing. DESIGN: Retrospective cohort study. SETTING: University-affiliated community hospital. METHODS: We reviewed computerized medical records for all patients with CDI at hospital admission during a 24-month period (January 1, 2008, through December 31, 2009). Colectomy, discharge to hospice, and in-hospital mortality were considered to be adverse outcomes. Antimicrobial use was considered unnecessary in the absence of physical signs and laboratory or radiological findings suggestive of an infection other than CDI or in the absence of antimicrobial activity against the organism(s) recovered from clinical cultures. RESULTS: Among the 94 patients with CDI at hospital admission, 62% received at least one non-CDI-related antimicrobial during their hospitalization for CDI. Severe complicated CDI (odds ratio [OR], 7.1 [95% confidence interval {CI}, 1.8-28.5]; [Formula: see text]), duration of non-CDI-related antimicrobial exposure (OR, 1.2 [95% CI, 1.03-1.36]; [Formula: see text]), and age (OR, 1.1 [95% CI, 1.0-1.1]; [Formula: see text]) were independent risk factors for adverse clinical outcomes. One-third of the patients received unnecessary antimicrobial therapy. Sepsis at hospital admission (OR, 5.3 [95% CI, 1.8-15.8]; [Formula: see text]) and clinical suspicion of urinary tract infection (OR, 9.7 [95% CI, 2.9-32.3]; [Formula: see text]) were independently associated with unnecessary antimicrobial prescriptions. CONCLUSIONS: Empirical use of non-CDI-related antimicrobials was common. Prolonged exposure to non-CDI related antimicrobials was associated with adverse clinical outcomes, including increased in-hospital mortality. Minimizing non-CDI-related antimicrobial exposure in patients with CDI seems warranted. PMID- 23041808 TI - Burden of Clostridium difficile infection in long-term care facilities in Monroe County, New York. AB - BACKGROUND: Long-term care facility (LTCF) residents are at increased risk of Clostridium difficile infection (CDI). However, little is known about the incidence, recurrence, and severity of CDI in LTCFs or the extent to which acute care exposure contributes to CDI in LTCFs. We describe the epidemiology of CDI in a cohort of LTCF residents in Monroe County, New York, where recent estimates suggest a CDI incidence in hospitals of 9.2 cases per 10,000 patient-days. DESIGN: Population-based surveillance study. SETTING: Monroe County, New York. Patients. LTCF residents with onset of CDI while in the LTCF or less than 4 calendar-days after hospital admission from the LTCF from January 1 through December 31, 2010. METHODS: We conducted surveillance for CDI in residents of 33 LTCFs. A CDI case was defined as a stool specimen positive for C. difficile obtained from a patient without a C. difficile-positive specimen in the previous 8 weeks; recurrence was defined as a stool specimen positive for C. difficile obtained between 2 and 8 weeks after the last C. difficile-positive stool specimen. RESULTS: There were 425 LTCF-onset cases and 184 recurrences, which yielded an incidence of 2.3 cases per 10,000 resident-days (interquartile range [IQR], 1.2-3.3) and a recurrence rate of 1.0 case per 10,000 resident-days (IQR, 0.3-1.4). The cases occurred in 394 LTCF residents, and 52% of these residents developed CDI within 4 weeks after hospital discharge. Hospitalization for CDI occurred in 70 cases (16%). Of those cases that involved hospitalization for CDI, 70% were severe CDI, and 23% ended in death within 30 days after hospital admission. CONCLUSION: CDI incidence in Monroe County LTCFs is one-fourth the incidence among hospitalized patients. Approximately 50% of LTCF-onset cases occurred more than 4 weeks after hospital discharge, which emphasizes that prevention of CDI transmission should go beyond acute care settings. PMID- 23041809 TI - A clinical history of methicillin-resistant Staphylococcus aureus is a poor predictor of preoperative colonization status and postoperative infections. AB - OBJECTIVE: In the absence of established methicillin-resistant Staphylococcus aureus (MRSA) screening programs, many centers use a history of a positive culture or a nasal screen as a surrogate for preoperative MRSA colonization status. We aimed to evaluate the test characteristics of these surrogates. DESIGN: Retrospective cohort study. PARTICIPANTS: Veterans Affairs Boston Healthcare System surgical patients with a preoperative nasal MRSA polymerase chain reaction (PCR) screen. METHODS: We assessed the performance of a history of a MRSA-positive culture or a positive nasal MRSA PCR screen during the year prior to surgery for predicting the preoperative nasal PCR screen result. The associations between MRSA history and postoperative outcomes, including MRSA cultures and infections, were also evaluated. RESULTS: Among 4,238 patients, a positive MRSA culture history had a sensitivity of 19.7% (95% confidence interval [CI], 15.4%-24.8%) and positive predictive value of 57.3% for the preoperative nasal MRSA status. The specificity of MRSA culture history was 99% (95% CI, 98.5% 99.2%). Prior-year nasal MRSA screen results had similar test characteristics. A history of a MRSA-positive culture was associated with an increased risk of postoperative MRSA-positive cultures (risk ratio [RR], 3.54 [95% CI, 1.70-7.37], [Formula: see text]) but not of infections (RR, 1.71 [95% CI, 0.58-5.01]), after adjustment for preoperative nasal MRSA status, vancomycin surgical prophylaxis, surgical scrub, and age. CONCLUSIONS: A history of a MRSA-positive culture and a positive nasal PCR screen are poor surrogate markers of preoperative colonization status, missing at least 70% of MRSA-colonized patients. Prior-year history is also not independently associated with MRSA-related postoperative infections. Strong consideration should be given to preoperative MRSA screening in patients at high risk for surgical complications. PMID- 23041810 TI - The epidemiology of methicillin-resistant Staphylococcus aureus on a burn trauma unit. AB - OBJECTIVE: We assessed the frequency and relatedness of methicillin-resistant Staphylococcus aureus (MRSA) isolates to determine whether healthcare workers, the environment, or admitted patients could be a reservoir for MRSA on a burn trauma unit (BTU). We also assessed risk factors for MRSA colonization among BTU patients. DESIGN: Prospective cohort study and surveillance for MRSA carriage. SETTING: BTU of a Midwestern academic medical center. PATIENTS AND PARTICIPANTS: Patients admitted to a BTU from February 2009 through January 2010 and healthcare workers on this unit during the same time period. METHODS: Samples for MRSA culture were collected on admission from the nares and wounds of all BTU patients. We also had collected culture samples from the throat, axilla, antecubital fossa, groin, and perianal area of 12 patients per month. Samples collected from healthcare workers' nares and from environmental sites were cultured quarterly. MRSA isolates were typed by pulsed-field gel electrophoresis. RESULTS: Of 144 patients, 24 (17%) carried MRSA in their nares on admission. Male sex (odds ratio [OR], 5.51; 95% confidence interval [95% CI], 1.25-24.30), admission for necrotizing fasciitis (OR, 7.66; 95% CI, 1.64-35.81), and MRSA colonization of a site other than the nares (OR, 23.40; 95% CI, 6.93-79.01) were independent predictors of MRSA nasal carriage. Cultures of samples collected from 4 healthcare workers and 4 environmental cultures had positive results. Two patients were colonized with strains that were indistinguishable from strains collected from a healthcare worker or the environment. CONCLUSIONS: Patients were a major reservoir for MRSA. Infection control efforts should focus on preventing transmission of MRSA from patients who are MRSA carriers to other patients on the unit. PMID- 23041811 TI - Tuberculosis among healthcare workers, United States, 1995-2007. AB - OBJECTIVE: We examined surveillance data to describe the epidemiology of tuberculosis (TB) among healthcare workers (HCWs) in the United States during the period 1995-2007. DESIGN: Cross-sectional descriptive analysis of existing surveillance data. SETTING AND PARTICIPANTS: TB cases reported to the Centers for Disease Control and Prevention from the 50 states and the District of Columbia from 1995 through 2007. RESULTS: Of the 200,744 reported TB cases in persons 18 years of age or older, 6,049 (3%) occurred in individuals who were classified as HCWs. HCWs with TB were more likely than other adults with TB to be women (unadjusted odds ratio [95% confidence interval], 4.1 [3.8-4.3]), be foreign born (1.3 [1.3-1.4]), have extrapulmonary TB (1.6 [1.5-1.7]), and complete TB treatment (2.5 [2.3-2.8]). CONCLUSIONS: Healthcare institutions may benefit from intensifying TB screening of HCWs upon hire, especially persons from countries with a high incidence of TB, and encouraging treatment for latent TB infection among HCWs to prevent progression to TB disease. PMID- 23041812 TI - Outbreak of Mycobacterium mucogenicum bloodstream infections among patients with sickle cell disease in an outpatient setting. AB - OBJECTIVE: To study an outbreak of Mycobacterium mucogenicum bloodstream infections in an outpatient setting. DESIGN: Outbreak investigation and retrospective chart review. SETTING: University outpatient clinic. Patients. Patients whose blood cultures tested positive for M. mucogenicum in May or June 2008. METHODS: An outbreak investigation and a review of infection control practices were conducted. During the process, environmental culture samples were obtained. Isolates from patients and the environment were genotyped with the DiversiLab typing system to identify the source. Chart reviews were conducted to study the management and outcomes of the patients. RESULTS: Four patients with sickle cell disease and implanted ports followed in the same hematology outpatient clinic developed blood cultures positive for M. mucogenicum. A nurse in the clinic had prepared intravenous port flushes on the sink counter, using a saline bag that was hanging over the sink throughout the shift. None of the environmental cultures grew M. mucogenicum except for the tap water from 2 rooms, 1 of which had a faucet aerator. The 4 patient isolates and the tap water isolate from the room with the aerator were found to have greater than 98.5% similarity. The subcutaneous ports were removed, and patients cleared their infections after a course of antibiotic therapy. CONCLUSION: The source of the M. mucogenicum bacteremia outbreak was identified by genotyping analysis as the clinic tap water supply. The preparation of intravenous medications near the sink was likely an important factor in transmission, along with the presence of a faucet aerator. PMID- 23041813 TI - Bed bugs in healthcare settings. AB - Infestations caused by bed bugs have resurfaced during the past decade across all continents. Even though bed bugs primarily cause skin manifestations in humans, a major stigma is placed upon people or institutions found to carry them. It is important for healthcare facilities to be prepared for this pest by implementing policies, carefully selecting materials used for hospital furniture, and educating providers on early identification and control. PMID- 23041814 TI - Association between preoperative statin therapy and postoperative infectious complications in patients undergoing cardiac surgery: a systematic review and meta-analysis. AB - Infectious complications of cardiac surgery are often severe and life threatening. Statins having both immunomodulatory and anti-inflammatory effects were intuitively thought to influence the development of postsurgical infections. We sought to systematically examine whether any association exists between statin use and risk of infectious complications in patients undergoing cardiac surgery. We searched Ovid MEDLINE, Ovid EMBASE, Thomson Scientific Web of Science, and Elsevier Scopus from inception through February 2011 for comparative studies examining the association between statin use and risk of postoperative infections in patients undergoing cardiac surgery. We contacted a study's author for missing information. We conducted a random-effects meta-analysis of individual studies' odds ratios (adjusted for potential confounders). We identified 6 cohort studies for inclusion, 3 of which were conducted in Canada and 3 of which were conducted in the United States. Four were single-center studies, and 2 were population based. Exposure ascertainment was based on a review of admission medication list or prescription databases. Infectious outcomes were heterogeneous and included surgical site infections within 30 days, serious infections (sepsis), or any other postoperative infection. Statin use in the preoperative period was associated with a trend toward reduction in the incidence of postoperative infections in patients who underwent cardiac surgery (odds ratio, 0.81 [95% confidence interval, 0.64-1.01]; [Formula: see text]; [Formula: see text]). Heterogeneity was explained by country effect. Studies performed in Canada showed weaker associations than studies performed in the United States. This difference could not be attributed to study quality alone. We did not find good evidence to support an association between statin use and postoperative infectious complications. However, the trend toward statistical significance for this association indicates that further investigation is warranted. PMID- 23041815 TI - Changing times, changing landscapes: comparing the Society for Healthcare Epidemiology of America's infected provider guidelines with the Centers for Disease Control and Prevention's Guidelines for managing providers INFECTED with hepatitis B virus. PMID- 23041816 TI - Needlestick injuries among employees at a nationwide retail pharmacy chain, 2000 2011. AB - We reviewed a nationwide retail pharmacy chain's centralized needlestick injury reports. From 2000 to 2011, 33 needlestick injuries were reported by 31 different pharmacy locations and were likely preventable. The annual incidence of needlestick injuries ranged from 0 to 3.62 per 100,000 vaccinations and ranged from 0 to 5.65 per 1,000 immunizing pharmacists. PMID- 23041817 TI - Efficacy of improved hydrogen peroxide against important healthcare-associated pathogens. AB - This study was designed to test in vitro efficacy of 2 improved hydrogen peroxide (HP) products against 3 standard HP products and 1 quaternary ammonium compound. Improved HP is significantly superior to standard HP at the same concentration and can be used for disinfection of environmental surfaces or noncritical patient care items. PMID- 23041818 TI - Hospital-onset Clostridium difficile infection rates in persons with cancer or hematopoietic stem cell transplant: a C3IC network report. AB - A multicenter survey of 11 cancer centers was performed to determine the rate of hospital-onset Clostridium difficile infection (HO-CDI) and surveillance practices. Pooled rates of HO-CDI in patients with cancer were twice the rates reported for all US patients (15.8 vs 7.4 per 10,000 patient-days). Rates were elevated regardless of diagnostic test used. PMID- 23041819 TI - What is nosocomial? Large variation in hospital choice of numerators and denominators affects rates of hospital-onset methicillin-resistant Staphylococcus aureus. AB - We calculated hospital-onset methicillin-resistant Staphylococcus aureus (HO MRSA) rates for Orange County, California, hospitals using survey and state data. Numerators were variably defined as HO-MRSA occurring more than 48 hours (37%), more than 2 days (30%), and more than 3 days (33%) postadmission. Survey-reported denominators differed from state-reported patient-days. Numerator and denominator choices substantially impacted HO-MRSA rates. PMID- 23041820 TI - Sites of colonization with extended-spectrum beta-lactamases (ESBL)-producing enterobacteriaceae: the rationale for screening. PMID- 23041821 TI - Antibiotic resistance in non-major metropolitan skilled nursing facilities: prevalence and interfacility variation. PMID- 23041822 TI - What is the optimal period for measuring hand hygiene compliance: are longer periods better than 20-minute periods? PMID- 23041823 TI - Assessing sensitivity and specificity in new diagnostic tests: the importance and challenges of study populations. PMID- 23041824 TI - How long is long enough? Determining the optimal surgical site infection surveillance period. PMID- 23041825 TI - Beyond bundles and coated catheters: effective interventions to decrease central line-associated bloodstream infections (CLABSI). PMID- 23041826 TI - Antimicrobial stewardship on the frontier: a pilot study of training using an electronic learning network. PMID- 23041828 TI - Mesothelioma with signet-ring cell features: report of 23 cases. AB - Signet-ring cell mesothelioma is uncommon and only two case reports have been published on this mesothelioma variant, both of which were initially misdiagnosed as signet-ring cell carcinoma. Herein are reported 23 signet-ring cell mesotheliomas that were investigated by immunohistochemistry, 12 of which were also studied by electron microscopy. Twenty-one of the cases originated in the pleura and two in the peritoneum. For comparison purposes and in order to determine the value of these techniques in the differential diagnosis of these tumors, seven cases of signet-ring cell lung adenocarcinoma were also studied. All signet-ring cell mesotheliomas were positive for calretinin, keratin 5/6, keratin 7, and mesothelin, 93% for podoplanin, and 91% for WT1; whereas, none reacted for MOC-31, CEA, TAG-72, CD15, TTF-1, napsin A, or CDX2. Among signet ring cell lung adenocarcinomas, 100% were positive for keratin 7, CEA, and napsin A, 86% each for TTF-1 and TAG-72, 71% for CD15, and 14% for mesothelin, while all were negative for calretinin, keratin 5/6, WT1, podoplanin, and CDX2. After analyzing the results, it is concluded that the panels of markers used in the differential diagnosis of this mesothelioma variant should include those markers that are usually expressed in mesotheliomas (eg, calretinin, keratin 5/6, WT1, and podoplanin), broad-spectrum carcinoma markers that are frequently expressed in adenocarcinomas regardless of their site of origin (eg, MOC-31 and CEA), and organ-associated markers (eg, TTF-1 and napsin A for lung), which allow the site of origin of a metastatic adenocarcinoma to be established. Electron microscopy can be very useful as it permits the identification of characteristic ultrastructural mesothelioma and adenocarcinoma markers, and it also allows a better understanding of the morphologic features seen on routine light microscopy. Pathologists should be aware of this mesothelioma subtype as it can potentially be confused with other tumors that exhibit signet-ring features. PMID- 23041829 TI - Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma. AB - The V600E mutation of BRAF has emerged as both an effective biomarker and therapeutic target for select benign and malignant cutaneous and non-cutaneous human tumors and is typically determined using DNA-based techniques that include allele-specific PCR and direct DNA sequencing. Recently however, the development of new antibodies directed against the V600E protein has opened the door for an easier and more efficient strategy for identifying this mutation. Our present aim was to determine the efficacy of one such antibody, anti-B-Raf (V600E), a mouse monoclonal antibody in which the immunogen is a synthetic peptide derived from the internal region of BRAFV600E. A total of 35 cases of primary cutaneous melanoma were evaluated using a combination of DNA-based techniques that included allele-specific PCR and/or direct DNA sequencing and immunohistochemistry. Cases of papillary thyroid carcinomas (n=5) and colorectal carcinomas (n=5), known to harbor the BRAFV600E mutation, served as positive controls for the study. DNA analyses revealed that 6 of 35 (17%) cases of the primary cutaneous malignant melanoma possessed the BRAFV600E mutation. For immunohistochemical analyses, cytoplasmic positivity with anti-B-Raf was noted in 7 of 35 (20%) cases of primary melanoma and in all 10 positive controls. Statistical analyses of the data demonstrated that the sensitivity of the immunohistochemistry was 100% and specificity was 97%. Findings from the current study support the potential use of immunohistochemistry as an ancillary screening tool to assess the BRAFV600E mutation status in primary cutaneous melanoma. PMID- 23041830 TI - CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3(+) regulatory T cells with respect to lethal prostate cancer. AB - Prostate cancer represents a major contributor to cancer mortality, but the majority of men with prostate cancer will die of other causes. Thus, a challenge is identifying potentially lethal disease at diagnosis. Conflicting results have been reported when investigating the relationship between infiltration of lymphocytes and survival in prostate cancer. One of the mechanisms suggested is the recruitment of regulatory T cells (T(regs)), a subpopulation of T cells that have a role in promoting tumor growth. T(regs) counteract tumor rejection through suppressive functions on the anti-immune response but their prognostic significance is still unknown. We report here the results of a conducted case control study nested in a cohort of men treated with transurethral resection of the prostate and diagnosed incidentally with prostate cancer. Cases are men who died of prostate cancer (n=261) and controls are men who survived >10 years after their diagnosis (n=474). Infiltration of both T(helper) and T(cytotoxic) cells was frequently observed and the majority of the T(regs) were CD4(+). T(helper) or T(cytotoxic) cells were not associated with lethal prostate cancer. However, we found a nearly twofold increased risk of lethal prostate cancer when comparing the highest with the lowest quartile of CD4(+) T(regs) cells (95% confidence interval: 1.3-2.9). Our conclusion is that men with greater numbers of CD4(+) T(regs) in their prostate tumor environment have an increased risk of dying of prostate cancer. Identification of CD4(+) T(regs) in tumor tissue may predict clinically relevant disease at time of diagnosis independently of other clinical factors. PMID- 23041831 TI - Mitotic figure counts are significantly overestimated in resection specimens of invasive breast carcinomas. AB - Several authors have demonstrated an increased number of mitotic figures in breast cancer resection specimen when compared with biopsy material. This has been ascribed to a sampling artifact where biopsies are (i) either too small to allow formal mitotic figure counting or (ii) not necessarily taken form the proliferating tumor periphery. Herein, we propose a different explanation for this phenomenon. Biopsy and resection material of 52 invasive ductal carcinomas was studied. We counted mitotic figures in 10 representative high power fields and quantified MIB-1 immunohistochemistry by visual estimation, counting and image analysis. We found that mitotic figures were elevated by more than three fold on average in resection specimen over biopsy material from the same tumors (20+/-6 vs 6+/-2 mitoses per 10 high power fields, P=0.008), and that this resulted in a relative diminution of post-metaphase figures (anaphase/telophase), which made up 7% of all mitotic figures in biopsies but only 3% in resection specimen (P<0.005). At the same time, the percentages of MIB-1 immunostained tumor cells among total tumor cells were comparable in biopsy and resection material, irrespective of the mode of MIB-1 quantification. Finally, we found no association between the size of the biopsy material and the relative increase of mitotic figures in resection specimen. We propose that the increase in mitotic figures in resection specimen and the significant shift towards metaphase figures is not due to a sampling artifact, but reflects ongoing cell cycle activity in the resected tumor tissue due to fixation delay. The dwindling energy supply will eventually arrest tumor cells in metaphase, where they are readily identified by the diagnostic pathologist. Taken together, we suggest that the rapidly fixed biopsy material better represents true tumor biology and should be privileged as predictive marker of putative response to cytotoxic chemotherapy. PMID- 23041832 TI - Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants. AB - Recent work has demonstrated that nearly all diffuse gliomas display nuclear immunoreactivity for the bHLH transcription factor OLIG2, and the R132H mutant isocitrate dehydrogenase 1 (IDH1) protein is expressed in the majority of diffuse gliomas other than primary glioblastoma. However, these antibodies have not been widely applied to rarer glioblastoma variants, which can be diagnostically challenging when the astrocytic features are subtle. We therefore surveyed the expression patterns of OLIG2 and IDH1 in 167 non-conventional glioblastomas, including 45 small cell glioblastomas, 45 gliosarcomas, 34 glioblastomas with primitive neuroectodermal tumor-like foci (PNET-like foci), 23 with an oligodendroglial component, 11 granular cell glioblastomas, and 9 giant cell glioblastomas. OLIG2 was strongly expressed in all glioblastomas with oligodendroglial component, 98% of small cell glioblastomas, and all granular cell glioblastomas, the latter being particularly helpful in ruling out macrophage-rich lesions. In 74% of glioblastomas with PNET-like foci, OLIG2 expression was retained in the PNET-like foci, providing a useful distinction from central nervous system PNETs. The glial component of gliosarcomas was OLIG2 positive in 93% of cases, but only 14% retained focal expression in the sarcomatous component; as such this marker would not reliably distinguish these from pure sarcoma in most cases. OLIG2 was expressed in 67% of giant cell glioblastomas. IDH1 was expressed in 55% of glioblastomas with oligodendroglial component, 15% of glioblastomas with PNET-like foci, 7% of gliosarcomas, and none of the small cell, granular cell, or giant cell glioblastomas. This provides further support for the notion that most glioblastomas with oligodendroglial component are secondary, while small cell glioblastomas, granular cell glioblastomas, and giant cell glioblastomas are primary variants. Therefore, in one of the most challenging differential diagnoses, IDH1 positivity could provide strong support for glioblastoma with oligodendroglial component, while essentially excluding small cell glioblastoma. PMID- 23041834 TI - The medico-legal significance of pharmacokinetic interactions with ethanol. AB - In the UK, the maximal permitted ethanol concentration for driving is 80 mg ethanol/100 mL blood, 35 MUg ethanol/100 mL breath or 107 mg ethanol/100 mL urine. Drivers exceeding the prescribed limit face severe penalties, which they are often anxious to avoid, either by acquittal or by putting forward 'special reasons' why they should not be disqualified from driving. One frequently explored defence is that the accused was taking prescribed medication. Defence solicitors often ask the question whether the prescribed medication could have caused significantly altered blood ethanol concentrations. This paper reviews the impact of various medications and how they can influence the blood ethanol concentration. Although many drugs can interact with ethanol at a pharmacodynamic level, causing increased impairment, relatively few drugs interact with ethanol pharmacokinetically leading to significantly altered blood ethanol concentrations. PMID- 23041833 TI - STAT6-dependent and -independent mechanisms in Th2 polarization. AB - Th2 cells play a key role in directing immune responses against helminths. Additionally, Th2 cells are crucial for many types of allergic reactions. Whereas the molecular mechanisms underlying the differentiation of other types of Th cells are well understood, Th2 differentiation is still a controversial topic. IL 4 and its downstream transcription factor signal transducer and activator of transcription (STAT)6 are well-known key mediators in Th2 differentiation. The fact that Th2 cells themselves are the most potent source of IL-4 suggests that additional mechanisms promoting the initiation of Th2 differentiation exist. This article gives an overview on STAT6-dependent and -independent mechanisms involved in the process of Th2 polarization, including Notch, mTORC2, IL-2/STAT5, and Wnt. Furthermore, we emphasize the role of STAT6 not only as a transcriptional activator promoting Th2 development, but also in fine-tuning alternative signaling pathways which are involved in the initiation of Th2 polarization. PMID- 23041835 TI - Medical and legal professionals' attitudes towards confidentiality and disclosure of clinical information in forensic settings: a survey using case vignettes. AB - OBJECTIVE: When potentially dangerous patients reveal criminal fantasies to their therapists, the latter must decide whether this information has to be transmitted to a third person in order to protect potential victims. We were interested in how medical and legal professionals handle such situations in the context of prison medicine and forensic evaluations. We aimed to explore the motives behind their actions and to compare these professional groups. METHOD: A mail survey was conducted among medical and legal professionals using five fictitious case vignettes. For each vignette, participants were asked to answer questions exploring what the professional should do in the situation and to explain their justification for the chosen response. RESULTS: A total of 147 questionnaires were analysed. Agreement between participants varied from one scenario to another. Overall, legal professionals tended to disclose information to a third party more easily than medical professionals, the latter tending to privilege confidentiality and patient autonomy over security. Perception of potential danger in a given situation was not consistently associated with actions. CONCLUSION: Professionals' opinions and attitudes regarding the confidentiality of potentially dangerous patients differ widely and appear to be subjectively determined. Shared discussions about clinical situations could enhance knowledge and competencies and reduce differences between professional groups. PMID- 23041836 TI - Pattern of coroner's autopsies at Health Sciences Authority, Singapore: a retrospective study (2009-2010). AB - Within a two-year period between 2009 and 2010, the Forensic Medicine Division of the Health Sciences Authority conducted a total of 3560 autopsies on cases reported to the coroner. This retrospective study reviews the type and distribution of these cases, and serves as a pilot study for future analysis of the various subgroups. Nearly half of these deaths (48.93%) are a result of natural disease processes, of which a cardiac cause by far predominates (64.64%), followed by diseases of the respiratory (16.92%) and central nervous (5.28%) systems. Of the deaths by unnatural means (51.07%), a substantial number of these deaths are consequent to fall from height, i.e. off a building (35.86%), with a smaller proportion of death arising from traffic and industrial accidents (17.60%), asphyxia (14.25%) and short distance falls (11.00%). Fall from height is the leading mode of suicide in this densely populated urban city where 85% of the population reside in high-rise apartments. PMID- 23041837 TI - Softened magnetic excitations in the s = 3/2 distorted triangular antiferromagnet alpha-CaCr2O4. AB - The spin dynamics and magnetic excitations of the slightly distorted triangular s = 3/2 system alpha-CaCr (2)O (4) are investigated by means of Raman spectroscopy and electron spin resonance (ESR) to elucidate its peculiar magnetic properties. Two-magnon excitations in circular RL symmetry show a multi-maximum structure with a dominant spectral weight at low energies. The temperature dependence of the ESR linewidth is described by a critical broadening DeltaH(pp)(T) is proportional to (T-T(N ))(-p) with the exponent p = 0.38(5) - 0.48(3) for temperatures above T(N) = 42.6 K. The exponent is much smaller than that of other s = 3/2 triangular lattices. This is ascribed to soft roton-like modes, indicative of the instability of a helical 120 degrees phase. As an origin we discuss a complex spin topology formed by four inequivalent nearest neighbor and sizable next-nearest neighbor interactions. PMID- 23041839 TI - C57BL/6 mice need MHC class II Aq to develop collagen-induced arthritis dependent on autoreactive T cells. AB - INTRODUCTION: Collagen-induced arthritis (CIA) has traditionally been performed in MHC class II A(q)-expressing mice, whereas most genetically modified mice are on the C57BL/6 background (expressing the b haplotype of the major histocompatibility complex (MHC) class II region). However, C57BL/6 mice develop arthritis after immunisation with chicken-derived collagen type II (CII), but arthritis susceptibility has been variable, and the immune specificity has not been clarified. OBJECTIVE: To establish a CIA model on the C57BL/6 background with a more predictable and defined immune response to CII. RESULTS: Both chicken and rat CII were arthritogenic in C57BL/6 mice provided they were introduced with high doses of Mycobacterium tuberculosis adjuvant. However, contaminating pepsin was strongly immunogenic and was essential for arthritis development. H-2(b) restricted T cell epitopes on chicken or rat CII could not be identified, but expression of A(q) on the C57BL/6 background induced T cell response to the CII260-270 epitope, and also prolonged the arthritis to be more chronic. CONCLUSIONS: The putative (auto)antigen and its arthritogenic determinants in C57BL/6 mice remains undisclosed, questioning the value of the model for addressing T cell-driven pathological pathways in arthritis. To circumvent this impediment, we recommend MHC class II congenic C57BL/6N.Q mice, expressing A(q), with which T cell determinants have been thoroughly characterised. PMID- 23041840 TI - Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis. AB - BACKGROUND: Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/beta-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. OBJECTIVE: To study variants in the genes encoding these proteins in relation to progression of joint destruction. METHODS: 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. RESULTS: In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). CONCLUSIONS: Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time. PMID- 23041841 TI - A novel disease-modifying osteoarthritis drug candidate targeting Runx1. AB - OBJECTIVES: To identify a new disease-modifying osteoarthritis drug (DMOAD) candidate that can effectively repair cartilage by promoting chondrogenic differentiation and halt osteoarthritis (OA) progression by suppressing aberrant hypertrophy. METHODS: We screened 2500 natural and synthetic small compounds for chondrogenic agents via four steps using the Col2GFP-ATDC5 system and identified a small thienoindazole derivative compound, TD-198946, as a novel DMOAD candidate. We tested its efficacy as a DMOAD via intra-articular injections directly into the joint space in a surgically-induced mouse model of OA both at the onset (prevention model) and 4 weeks after (repair model) OA induction. The downstream molecules were screened by microarray analysis. We further investigated the mechanism of the drug action and its molecular target using in vitro and in vivo assays. RESULTS: TD-198946 strongly induced chondrogenic differentiation without promoting hypertrophy in cell and metatarsal organ cultures. When administered directly into the joint space, TD-198946 successfully prevented and repaired degeneration of the articular cartilage. TD-198946 exerted its effect through the regulation of Runx1 expression, which was downregulated in both mouse and human OA cartilage compared with normal tissue. CONCLUSIONS: Our data suggest that TD-198946 is a novel class of DMOAD candidate, and that targeting Runx1 will provide a promising new approach in the development of disease-modifying drugs against OA. PMID- 23041843 TI - Water binding energies of [Pb(amino acid-H)H2O]+ complexes determined by blackbody infrared radiative dissociation. AB - The water binding energies (E(0)) of eight deprotonated Pb(2+)-amino acid (Aa) complexes of the form [Pb(Aa-H)H(2)O](+) (Aa = Gly, Ala, Val, Leu, Ile, Phe, Glu, and Lys) were determined using blackbody infrared radiative dissociation (BIRD). A Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer was used to trap ions generated by electrospray ionization (ESI) in a "zero"-pressure (~10(-10) torr) cell where dissociation can only occur by absorption of thermally generated photons. Since the [Pb(Aa-H)H(2)O](+) complexes have relatively few vibrational degrees of freedom (36-78) and are within the slow-exchange kinetic limit, the master equation was solved to extract meaningful threshold dissociation energies and thermal unimolecular dissociation rate constants (k(uni)). The master equation analysis uses variable reaction coordinate transition state theory (VRC-TST) to minimize the Rice-Ramsperger-Kassel-Marcus (RRKM) dissociation rate constants. The determined water binding energies range from 76.6 to 113.6 kJ mol(-1), and agree well with 0 K dissociation energies calculated using the B3LYP/6-31+G(d,p) and MP2(full)/6-311++G(2d,2p)//B3LYP/6 31+G(d,p) methods. The relative strengths of the binding energies reflect the known structural isomers (A-, B-, C-, and D-type) of these [Pb(Aa-H)H(2)O](+) complexes. PMID- 23041842 TI - Exacerbation of experimental autoimmune encephalomyelitis in the absence of breast regression protein 39/chitinase 3-like 1. AB - We previously reported that YKL-40, the human analog of mouse breast regression protein 39 ([BRP-39] chitinase 3like 1), is elevated in the cerebrospinal fluid of patients with a variety of neuroinflammatory conditions, such as multiple sclerosis and traumatic brain injury. Expression of YKL-40 in the CNS was predominantly associated with reactive astrocytes in the vicinity of inflammatory lesions. Because previous studies have shown that reactive astrocytes play a critical role in limiting immune infiltration in the mouse model of experimental autoimmune encephalomyelitis, we explored the role of BRP-39 in regulatingneuroinflammation in experimental autoimmune encephalomyelitis. Using BRP-39--deficient (BRP-39(-/-)) mice, we demonstrate the importance of BRP-39 in modulating the severity of clinical experimentalautoimmune encephalomyelitis and CNS neuroinflammation. At disease onset, absence of BRP-39 had little effect on clinical disease orlymphocytic infiltrate, but by 14 days after immunization, differences in clinical scores were evident. By 28 days after immunization, BRP 39(-/-) mice showed more severe and persistent clinical disease than BRP-39(+/+) controls. Histopathological evaluation showed that BRP-39(-/-) mice had more marked lymphocytic and macrophage infiltrates and gliosis versus BRP-39(+/+) mice. These findings support the role of BRP-39 expression in limiting immune cell infiltration into the CNS and offer a new target to modulate neuroinflammation. PMID- 23041844 TI - Two-dimensional diffractive coherent combining of 15 fiber amplifiers into a 600 W beam. AB - We demonstrate coherent beam combining using a two-dimensionally patterned diffractive optic combining element. Fifteen Yb-doped fiber amplifier beams arranged in a 3*5 array were combined into a single 600 W, M2=1.1 output beam with 68% combining efficiency. Combining losses under thermally stable conditions at 485 W were found to be dominated by spatial mode-mismatch between the free space input beams, in quantitative agreement with calculations using the measured amplitude and phase profiles of the input beams. PMID- 23041845 TI - Multiplexing and switching of virtual electrodes in optoelectronic tweezers based on lithium niobate. AB - We introduce a method for trapping and arranging microparticles in arbitrary two dimensional patterns with high flexibility. For this purpose, optoelectronic tweezers based on lithium niobate as photoconductor are used to create virtual electrodes through modulated illumination. The evolving field gradients arrange microparticles due to dielectrophoretic (DEP) forces and enable an all-optical approach for DEP. In order to increase flexibility further, we investigate multiplexed electrode structures for in situ reconfiguration of particle arrangements. Using the all-optical erasure of previously written virtual electrodes, we demonstrate electrode switching and sequential particle trapping in a microchannel for microfluidic applications. PMID- 23041846 TI - Efficient 2.87 MUm fiber laser passively switched using a semiconductor saturable absorber mirror. AB - A passively switched Ho(3+), Pr(3+) codoped fluoride fiber laser using a semiconductor saturable absorber mirror (SESAM) is demonstrated. Q-switching and partial mode-locking were observed with the output power produced at a slope efficiency of 24% with respect to the absorbed pump power. The partially mode locked 2.87 MUm pulses operated at a repetition rate of 27.1 MHz with an average power of 132 mW, pulse energy of 4.9 nJ, and pulse width of 24 ps. PMID- 23041847 TI - Maximal polarization order of random optical beams: reversible and irreversible polarization variations. AB - We discuss the degrees of polarization (DoP) of electromagnetic beams in time and frequency domains. The mean spectral DoP corresponds to the maximal temporal DoP when unitary transformations are applied in frequency domain. We demonstrate that random unitary transformations in frequency domain cannot increase the mean spectral DoP, implying that this quantity is a useful measure of the polarization order of light beams. This leads to a classification of time-domain polarization changes into reversible and irreversible processes. PMID- 23041848 TI - Efficient concept for generation of diffraction-limited green light by sum frequency generation of spectrally combined tapered diode lasers. AB - In order to increase the power of visible diode laser systems in an efficient manner, we propose spectral beam combining with subsequent sum-frequency generation. We show that this approach, in comparison with second harmonic generation of single emitters, can enhance the available power significantly. By combining two distributed Bragg reflector tapered diode lasers we achieve a 2.5 3.2 fold increase in power and a maximum of 3.9 W of diffraction-limited green light. At this power level, green diode laser systems have a high application potential, e.g., within the biomedical field. Our concept can be expanded combining multiple diode lasers to increase the power even further. PMID- 23041849 TI - Tunable and selective resonant absorption in vertical nanowires. AB - We demonstrate that vertical subwavelength diameter nanowires exhibit tunable and selective resonant absorption using numerical simulations and optical waveguide theory. Incident light on vertical nanowires only excites hybrid TM-dominant HE(1m) leaky modes due to symmetry matching requirements. The transverse resonances associated with these hybrid modes result in strong absorption enhancements that may be adjusted by changing the nanowire diameter. In particular, the fundamental HE(11) transverse resonance may be tuned across a wide range of wavelengths and is separated from that of the HE(12) mode by a large spectral gap, which is advantageous for wavelength selectivity. Leaky longitudinal resonances result in weaker absorption peaks at larger wavelengths. We further study the effect of incident light angle on the absorption spectra. PMID- 23041850 TI - Reflection suppression and absorption enhancement of optical field at thin metal gratings with narrow slits. AB - Optically thin metal gratings of high filling factor can support surface plasmon polariton modes at their horizontal metal boundaries and vertical cavity modes inside their slits. These modes are coupled through the metal stripes and the slits. This letter shows that the resonant interactions between the modes critically influence the optical field distribution near the grating and substantially enhance several phenomena such as low reflection, low transmission, and high absorption of the electromagnetic radiation. A high degree of energy confinement is obtained, especially when the energy is stored almost exclusively on the far side of the grating, away from the incident radiation. It is numerically shown that this phenomenon originates from the interaction of field modes with the collective motion of free electrons, as considered in the Drude model. PMID- 23041851 TI - On-chip optical isolation via unidirectional Bloch oscillations in a waveguide array. AB - We propose to use the unidirectionality of the optical Bloch oscillation phenomenon achievable in a magneto-optic asymmetric waveguide array to achieve optical isolation. At the 1.55 MUm telecommunication wavelength, our isolator design exhibits an isolation ratio of 36 dB between forward- and backward propagating waves. The proposed design consists of a waveguide array made in a silicon-on-insulator substrate with a magnetic garnet cover layer. A key role is played by the transverse-magnetic mode nonreciprocal phase shift effect. PMID- 23041852 TI - How to optically count graphene layers. AB - The total thickness of a graphene sample depends upon the number of individually stacked graphene layers. The corresponding surface plasmon resonance (SPR) reflectance alters the SPR angle, depending on the number of graphene layers. Thus, the correlation between the SPR angle shift and the number of graphene layers allows for a nonintrusive, real-time, and reliable counting of graphene layers. A single-layer graphene (SLG) is synthesized by means of chemical vapor deposition, followed by physical transfer to a thin gold film (48 nm) repeatedly, so that multilayer graphene samples with one, three, and five layers can be prepared. Both the measured SPR angles and the entire reflectance curve profiles successfully distinguish the number of graphene layers. PMID- 23041853 TI - Sensing with optical vortices in photonic-crystal fibers. AB - We demonstrate optical polarization vortex generation in a photonic-crystal fiber (PCF) by means of a CO(2) laser-induced long period grating. Vortices are a special subclass of fiber modes that result in polarization-insensitive resonances even when grating perturbations are asymmetric, as is the case with structural perturbations in single-material PCFs. The physics of vortex generation, combined with the use of structural perturbations alone, in single material fibers, opens up a new schematic for realizing harsh-environment sensors. We show that the temperature and polarization stability of our vortex devices is maintained for prolonged periods of time (tested up to 34 h) at temperatures exceeding 1000 degrees C. We envisage that this demonstration opens up a new way of realizing high-temperature sensors in a cost-effective manner. PMID- 23041854 TI - Laser dynamics in sawtooth-like self-mixing signals. AB - In this Letter, we experimentally show that transient phenomenons in self-mixing signals from a moving target contain information about the target reflectivity and distance. These transient phenomenons are well explained with a dynamical model of the laser diode, which is used to trace an abacus giving the target reflectivity and distance from a measured high-bandwidth, self-mixing signal. PMID- 23041855 TI - Lateral laser speckle contrast analysis combined with line beam scanning illumination to improve the sampling depth of blood flow imaging. AB - We present a lateral laser speckle contrast analysis method combined with line beam scanning illumination to improve the sampling depth of blood flow imaging. Both the phantom and animal experimental results suggest that localized illumination and lateral speckle contrast analysis can significantly enhance the deep blood flow signal to improve the sampling depth of laser speckle contrast imaging compared with the traditional full-field illumination laser speckle contrast analysis method. PMID- 23041856 TI - Development of a multilayer mirror for high-intensity monochromatic x-ray using lab-based x-ray source. AB - A parabolic, multilayer x-ray mirror, which can be used with a general lab-based x-ray source, was designed and fabricated. A glass substrate for the mirror was fabricated. Its surface was determined by following the rotation of a parabolic curve and was polished precisely. On the substrate surface, six W/Al bilayers were deposited to form the multilayer mirror. The effects of the mirror on x-ray images were investigated based on the calculated modulation transfer function (MTF) and image intensity values. Higher MTF and intensity values of an x-ray image were obtained using the mirror. PMID- 23041857 TI - Plasmonic nanosensor based on Fano resonance in waveguide-coupled resonators. AB - We propose a plasmonic nanosensor based on Fano resonance in the strong confinement metal-dielectric-metal waveguide side-coupled with a pair of nanoresonators. Due to the coherent interference of the splitting discrete and quasi-continuum modes, the reflection spectrum possesses a sharp asymmetric Fano resonance dip, which is dependent on the cavity-cavity phase and the refractive index change of the dielectric. The physical features contribute to a highly efficient plasmonic sensor for refractive index sensing. The nanosensor yields a sensitivity of ~900 nm/RIU and a figure of merit of ~500, remarkable values compared with those of plasmonic sensors supported by perfect absorbers. PMID- 23041858 TI - Observation of sum-frequency-generation-induced cascaded four-wave mixing using two crossing femtosecond laser pulses in a 0.1 mm beta-barium-borate crystal. AB - We demonstrate the simultaneous generation of multicolor femtosecond laser pulses spanning the wavelength range from UV to near IR in a 0.1 mm Type I beta-barium borate crystal from 800 nm fundamental and weak IR super-continuum white light (SCWL) pulses. The multicolor broadband laser pulses observed are attributed to two concomitant cascaded four-wave mixing (CFWM) processes as corroborated by calculation: (1) directly from the two incident laser pulses; (2) by the sum frequency generation (SFG) induced CFWM process (SFGFWM). The latter signal arises from the interaction between the frequency-doubled fundamental pulse (400 nm) and the SFG pulse generated in between the fundamental and IR-SCWL pulses. The versatility and simplicity of this spatially dispersed multicolor self compressed laser pulse generation offer compact and attractive methods to conduct femtosecond stimulated Raman spectroscopy and time-resolved multicolor spectroscopy. PMID- 23041859 TI - Tunable hybrid Brillouin-erbium comb fiber laser in a composite cavity with a single-mode tellurite fiber. AB - We demonstrate a hybrid Brillouin-erbium fiber laser in a composite cavity with a single-mode tellurite fiber. Only a 200 m long tellurite fiber is used in the cavity due to the high effective nonlinearity. The double pass of the tellurite fiber in the linear part is advantageous for improving the Brillouin gain and increasing the comb lines. With a tunable filter, more than 70 comb lines spaced by 7.888 GHz are obtained at 1565 nm. The line number is kept around 60 in the tunable range of 30 nm from 1535 to 1565 nm. Compared with silica fibers, the tellurite fiber can generate a larger number of Brillouin lines in a wider tunable range. PMID- 23041860 TI - Planar achromatic multiple beam splitter by adiabatic light transfer. AB - We introduce a novel achromatic and robust scheme for n-fold multiple beam splitting based on adiabatic light transfer in a planar geometry of coupled waveguides (WGs). The concept is experimentally verified for a one-to-three beam splitter by using a reconfigurable light-induced WG structure at two operating wavelengths. The demonstrated planar-type achromatic beam splitter opens new opportunities for the realization of ultra-high bandwidth on-chip photonic devices. PMID- 23041861 TI - Spectrally dense comb-like filters fashioned with thick guided-mode resonant gratings. AB - We present the spectral properties of multiline guided-mode resonance filters designed with extremely thick dielectric films. We treat a dielectric membrane in air with a subwavelength grating inscribed into one surface. As the film is very thick on the scale of the wavelength, it supports a large number of resonant modes. In general, the resonant modes yield a dense reflectance spectrum with irregular appearance. We show that by placing an antireflection layer on the backside of the slab, the interference between the directly transmitted zero order and the diffracted order generating the waveguide modes is eliminated. Thus, a well-shaped, unperturbed comb-like spectrum is realized. A titanium dioxide membrane that is 500 MUm thick generates a spectrum with more than 1000 channels separated by ~0.8 nm near the 1.55 MUm wavelength. PMID- 23041862 TI - Single-frequency gain-switched Ho-doped fiber laser. AB - We demonstrate a single-frequency gain-switched Ho-doped fiber laser based on heavily doped silicate glass fiber fabricated in-house. A Q-switched Tm-doped fiber laser at 1.95 MUm was used to gain-switch the Ho-doped fiber laser via in band pumping. Output power of the single-frequency gain-switched pulses has been amplified in a cladding-pumped Tm-Ho-codoped fiber amplifier with 1.2 m active fiber pumped at 803 nm. Two different nonlinear effects, i.e., modulation instability and stimulated Brillouin scattering, could be seen in the 10 MUm-core fiber amplifier when the peak power exceeds 3 kW. The single-frequency gain switched fiber laser was operated at 2.05 MUm, a popular laser wavelength for Doppler lidar application. This is the first demonstration of this kind of fiber laser. PMID- 23041863 TI - Single-exposure complementary aperture phase microscopy with polarization encoding. AB - We introduce a single-exposure widefield system of producing phase gradient images by dividing the illumination and detection apertures into two oblique complementary components and encoding them using polarization. A Wollaston prism splits the images formed by the two respective aperture halves to allow both components to be simultaneously imaged by a single camera. By producing images characteristically similar to differential interference contrast while using a darkfield illumination scheme, sensitivity to weak phase gradients is improved. PMID- 23041864 TI - Observation of Bloch-like revivals in semi-infinite Glauber-Fock photonic lattices. AB - We report the first experimental implementation of Glauber-Fock oscillator lattices. Bloch-like revivals are observed in these optical structures in spite of the fact that the photonic array is effectively semi-infinite and the waveguide coupling is not uniform. This behavior is entirely analogous to the dynamics exhibited by a driven quantum harmonic oscillator. Our observations are in excellent agreement to the analytical results obtained in this fully integrable lattice system. PMID- 23041865 TI - Few-cycle high-contrast vortex pulses. AB - Few-cycle high-contrast vortex beams with pulse durations around 8 fs were generated from a Ti:sapphire laser oscillator with a single diffractive refractive component. Angular and temporal pulse properties were characterized with an advanced time-wavefront sensor. The temporal transfer indicates a fairly complete self-compensation. PMID- 23041866 TI - From classical four-wave mixing to parametric fluorescence in silicon microring resonators. AB - Four-wave mixing (FWM) can be either stimulated or occur spontaneously. The first process is intrinsically much stronger and well understood through classical nonlinear optics. The latter, also known as parametric fluorescence, can be explained only in the framework of a quantum theory of light. We experimentally demonstrated that, in a microring resonator, there is a simple relation between the efficiencies of these two processes that is independent of the nonlinearity and ring size. In particular, we have shown the average power generated by parametric fluorescence can be immediately estimated from a classical FWM experiment. These results suggest that classical nonlinear characterization of a photonic integrated structure can provide accurate information on its nonlinear quantum properties. PMID- 23041867 TI - Polarization and topological charge conversion of exact optical vortex beams at normal incidence on planar dielectric interfaces. AB - We report on the exact resolution of the problem of reflection and refraction of exact circularly polarized Bessel vortex beams impinging at normal incidence on a planar dielectric interface between two isotropic and lossless media. On the one hand, we demonstrate the generation of a new vortex state both in the reflected and refracted fields. On the other hand, we show the possibility to completely convert, at reflection, the incident vortex beam into a vortex beam with orthogonal polarization and topological charge changed by +/-2. The spin-orbit interaction of light occurring at the planar interface is identified as the mechanism responsible for these effects. PMID- 23041868 TI - Wavefront sensing using diffractive elements. AB - In this Letter, we introduce a wavefront slope sensor based on a diffractive element. The diffractive element wavefront sensor (DEWS) produces four double overlapping copies of the incoming wavefront acting like a combination of shearing and pyramidal sensors. The DEWS allows a simple and fast slope estimate. The wavefront sampling can be as high as the number of pixel assigned to cover a wavefront copy, and it can be modified with only binning the CCD pixels. The theory for designing the sensor, its application to extract local slope information, and a simple noise analysis are presented. An application example for atmosphere aberrated wavefronts is demonstrated. PMID- 23041869 TI - Omnidirectional luminescence enhancement of fluorescent SiC via pseudoperiodic antireflective subwavelength structures. AB - In the present work, an approach of fabricating pseudoperiodic antireflective subwavelength structures (ARS) on fluorescent SiC by using self-assembled etch mask is demonstrated. By applying the pseudoperiodic (ARS), the average surface reflectance at 6 degrees incidence over the spectral range of 390-785 nm is dramatically suppressed from 20.5% to 1.62%, and the hydrophobic surface with a large contact angle of 98 degrees is also achieved. The angle-resolved photoluminescence study presents a considerable omnidirectional luminescence enhancement with an integral intensity enhancement of 66.3% and a fairly preserved spatial emission pattern. PMID- 23041870 TI - In-fiber linear polarizer based on UV-inscribed 45 degrees tilted grating in polarization maintaining fiber. AB - We report an in-fiber linear polarizer structured by UV-inscribing a 45 degrees tilted fiber grating (TFG) into polarization maintaining (PM) fiber along its principal axis. The polarization extinction ratio (PER) achieved by a 48 mm long 45 degrees TFG has reached 46 dB at 1550 nm and the overall PER is >40 dB over a 50 nm wavelength range. Such 45 degrees TFG based polarizers have many advantages over conventional products, including low loss, low cost, simple fabrication process, and no physical modification to the fiber, thus offering high stability and capable of handling high power. PMID- 23041871 TI - Surface plasmonic lattice solitons. AB - We reveal the existence of the surface plasmonic lattice solitons (surface PLSs) at the boundary of a semi-infinite metallic-dielectric periodic nanostructure. We find that the truncation of the periodic structure imposes a threshold power for the existence of surface PLSs, and significantly enhances the modal localization. The propagation and excitation of surface PLSs as well as their potential application in the all-optical subwavelength switching are also demonstrated. PMID- 23041873 TI - Tunable all-fiber dissipative-soliton laser with a multimode interference filter. AB - We report on a tunable all-fiber dissipative-soliton laser with a multimode interference filter that consists of a multimode fiber spliced between two single mode fibers. By carefully selecting the fiber parameters, a filter with a central wavelength at 1032 nm and a bandwidth of 7.6 nm is constructed and used for spectral filtering in an all-normal-dispersion mode-locked ytterbium-doped fiber laser based on nonlinear polarization evolution. The laser delivers 31 mW of average output power with positively chirped 7 ps pulses. The repetition rate of the pulses is 15.3 MHz, and pulse energy is 2.1 nJ. Tunable dissipative-soliton over 12 nm is achieved by applying tension to the single-mode-multimode-single mode filter. PMID- 23041872 TI - Fabrication of three-dimensional helical microchannels with arbitrary length and uniform diameter inside fused silica. AB - We demonstrate an improved femtosecond laser irradiation followed by chemical etching process to create complex three-dimensional (3D) microchannels with arbitrary length and uniform diameter inside fused silica. A segmented chemical etching method of introducing extra access ports and a secondary power compensation is presented, which enables the fabrication of uniform 3D helical microchannels with length of 1.140 cm and aspect-ratio of 522. Based on this method, a micromixer which consists of a long helical microchannel and a y-tape microchannel was created inside the fused silica. We measured the mixing properties of the micromixer by injecting the phenolphthalein and NaOH solution through the two inlets of the y-tape microchannel. A rapid and efficient mixing was achieved in the 3D micromixer at a low Reynolds number. PMID- 23041874 TI - Colorless all-optical sum and subtraction of phases for phase-shift keying signals based on a periodically poled lithium niobate waveguide. AB - A colorless all-optical scheme performing the subtraction and addition of phases between phase-shift keying (PSK) signals exploiting cascaded sum and difference frequency generation in a periodically poled lithium niobate waveguide is introduced and experimentally demonstrated. The subtraction of phases of two 40 Gb/s differential quadrature PSK signals has been experimentally tested and performances have been analyzed in terms of bit error rate measurements. PMID- 23041875 TI - Ultraflat optical frequency comb generated based on cascaded polarization modulators. AB - A novel approach to generating an ultraflat and stable optical frequency comb with tunable frequency spacing is proposed and experimentally demonstrated. The proposed generator consists of a polarization modulator (PolM) and a polarizer. The joint operation of a PolM and a polarizer is equivalent to intensity modulation, but with a third controllable parameter in addition to the two controllable parameters in conventional intensity modulation. By tuning the three parameters, an ultraflat optical frequency comb with five comb lines is generated. By cascading the PolM with a second PolM, an ultra-flat optical frequency comb with 25 lines is generated. An experiment using two cascaded PolMs is performed. A 25- line frequency comb with the comb flatness within 1 dB is generated. PMID- 23041877 TI - Control of cascading in multiple-order Raman lasers. AB - In this work we explore a method for controlling Raman cascade within an intracavity Raman laser, with a view to maximizing output power at desired visible wavelengths. Sum-frequency generation is used to suppress unwanted Stokes orders, and prevent their build up. Using this method to control the Raman cascade, we demonstrate increases in output power of 40% at 532 nm, 42% at 559 nm, and 67% at 586 nm. PMID- 23041876 TI - Second-harmonic generation circular dichroism studies of osteogenesis imperfecta. AB - We report the use of second-harmonic generation (SHG) microscopy in conjunction with circular dichroism (CD) to differentiate normal skin from that in the connective tissue disorder osteogenesis imperfecta (OI). Osteogenesis imperfecta results from mutations in the collagen triple helix, where the individual chains are defective, leading to abnormal folding, and ultimately, abnormal fibril/fiber organization. Second-harmonic-generation circular dichroism successfully differentiated normal human and OI skin tissues, whereas other SHG polarization schemes did not provide discrimination, suggesting this approach has high sensitivity for studying the difference in chirality in the mutated collagen. We further suggest that the method has clinical diagnostic value, as it could be performed with minimal invasion. PMID- 23041878 TI - Phase-recovery improvement using analytic wavelet transform analysis of a noisy interferogram cepstrum. AB - We evaluate the extension of the exact nonlinear reconstruction technique developed for digital holography to the phase-recovery problems presented by other optical interferometric methods, which use carrier modulation. It is shown that the introduction of an analytic wavelet analysis in the ridge of the cepstrum transformation corresponding to the analyzed interferogram can be closely related to the well-known wavelet analysis of the interferometric intensity. Subsequently, the phase-recovery process is improved. The advantages and limitations of this framework are analyzed and discussed using numerical simulations in singular scalar light fields and in temporal speckle pattern interferometry. PMID- 23041879 TI - Direct retrieval of Kerr and plasma effects from alignment-induced spatiotemporal modulation. AB - We developed a direct measurement method for comprehensive analyses of Kerr and plasma effects that cooperated or competed with molecular alignment-induced spatiotemporal modulation for intense aligning and weak probing pulses around zero time delay. The mixed influences were revealed by time-resolving the combined spatial focusing or defocusing dynamics under different molecular alignment directions and degrees. The nonlinear refractive index and plasma density were extracted straightforwardly, facilitating accurate explorations on multiphoton ionization and nonlinear optical Kerr effects of aligned molecular gases. PMID- 23041880 TI - Passively continuous-wave mode-locked Er(3+)-doped ZBLAN fiber laser at 2.8 MUm. AB - An Er(3+)-doped ZrF(4)-BaF(2)-LaF(3)-AlF(3)-NaF (ZBLAN) fiber laser was passively mode-locked by inserting a Fe(2+):ZnSe crystal into the free space part of the cavity. Continuous-wave mode-locked pulses at 2.8 MUm with a pulse duration of 19 ps estimated from the spectral bandwidth and an average power of 51 mW were generated when a collimated beam traversed the Fe(2+):ZnSe crystal, while Q switched mode-locked pulses were obtained when the Fe(2+):ZnSe crystal was illuminated by the focused beam. PMID- 23041881 TI - Direct calculation algorithm for two-dimensional reflector design. AB - We have developed a fast algorithm to design two-dimensional reflector surfaces that ties together the supporting paraboloids, linear programming, and numerical integration methods. The algorithm builds upon the properties of conics and is shown to be several orders of magnitude faster than the supporting paraboloids and linear programming methods. The scalability and ease of implementation of the algorithm are discussed. PMID- 23041882 TI - Long-path second-harmonic interferometer with nanosecond time resolution: reliable diagnostic tool for electron density measurement in pulsed plasma devices. AB - We describe the performance of a second-harmonic interferometer (SHI) to measure, on an optical path exceeding 12 m, the electron plasma density of two plasmoids formed in separate theta-pinch chambers and then merged in a central compression chamber after undergoing acceleration and compression. The excellent mechanical stability and a time resolution better than 50 ns suggest the application of SHI, especially in pulsed plasma devices with limited optical accesses. PMID- 23041883 TI - Three-photon electromagnetically induced transparency using Rydberg states. AB - We demonstrate electromagnetically induced transparency in a four-level cascade system where the upper level is a Rydberg state. The observed spectral features are sub-Doppler and can be enhanced due to the compensation of Doppler shifts with AC Stark shifts. A theoretical description of the system is developed that agrees well with the experimental results, and an expression for the optimum parameters is derived. PMID- 23041884 TI - Generation of 43 W of quasi-continuous 780 nm laser light via high-efficiency, single-pass frequency doubling in periodically poled lithium niobate crystals. AB - We demonstrate high-efficiency frequency doubling of the combined output of two 1560 nm 30 W fiber amplifiers via single pass through periodically poled lithium niobate (PPLN) crystals. The temporal profile of the 780 nm output is controlled by adjusting the relative phase between the seeds of the amplifiers. We obtain a peak power of 34 W of 780 nm light by passing the combined output through one PPLN crystal, and a peak power of 43 W by passing through two cascading PPLN crystals. This source provides high optical power, excellent beam quality and spectral purity, and agile frequency and amplitude control in a simple and compact setup, which is ideal for applications such as atom optics using Rb atoms. PMID- 23041885 TI - Role of a localized modulation of chi(2) in Cerenkov second-harmonic generation in nonlinear bulk medium. AB - We study the second-harmonic generation in quadratic nonlinear media with localized spatial modulation of chi((2)) response. We demonstrate that the emission of Cerenkov second-harmonic takes place only when the fundamental beam illuminates the region of chi((2)) variation. This proves that the sharp modulation of the chi((2)) nonlinearity constitutes a sufficient condition for the emission of Cerenkov second harmonic in bulk materials. Our calculations are in excellent agreement with simple analytical approach utilizing the concept of reciprocal vectors representing the Fourier spectrum of the modulation of chi((2)). PMID- 23041887 TI - Supercontinuum generation in the mid-infrared from a dispersion-engineered As2S3 glass rib waveguide. AB - We report the generation of a mid-infrared supercontinuum created by ~7.5 ps duration pulses at 3260 nm passing through a dispersion engineered As(2)S(3) rib waveguide. The threshold for a 6.6 cm long waveguide was around 800 W and at 1700 W the spectrum extended from ~2.9-4.2 MUm and was limited on the long wavelength side by absorption in the cladding of this particular waveguide. PMID- 23041886 TI - Polarization-extinction-based detection of DNA hybridization in situ using a nanoparticle wire-grid polarizer. AB - Metallic wires can discriminate light polarization due to strong absorption of electric fields oscillating in parallel to wires. Here, we explore polarization based biosensing of DNA hybridization in situ by employing metal target conjugated nanoparticles to form a wire-grid polarizer (WGP) as complementary DNA strands hybridize. Experimental results using gold nanoparticles of 15 nm diameter to form a WGP of 400 nm period suggest that polarization extinction can detect DNA hybridization with a limit of detection in the range of 1 nM concentration. The sensitivity may be improved by more than an order of magnitude if larger nanoparticles are employed to define WGPs at a period between 400 and 500 nm. PMID- 23041888 TI - Ultrasensitive label-free coupled optofluidic ring laser sensor. AB - A coupled optofluidic ring laser sensor is fabricated, and its ultrasensitive bulk refractive index and surface mass sensing properties are demonstrated. The sensor consists of a cylindrical ring laser and a thin-walled optofluidic capillary ring resonator. Coupling of the whispering gallery mode in the two resonators generates a largely magnified sensitivity due to the Vernier effect. A sensitivity of 2510 nm/RIU and magnification factor of 355 are achieved experimentally in aqueous solution, which corresponds to a noise equivalent detection limit of 1.6*10(-5) RIU for bulk RI detection. The new sensor configuration provides a convenient way to achieve ultrasensitive biological and chemical sensing. PMID- 23041889 TI - Active quench and reset integrated circuit with novel hold-off time control logic for Geiger-mode avalanche photodiodes. AB - This Letter presents an active quench-and-reset circuit for Geiger-mode avalanche photodiodes (GM-APDs). The integrated circuit was fabricated using a conventional 0.35 MUm complementary metal oxide semiconductor process. Experimental results show that the circuit is capable of linearly setting the hold-off time from several nanoseconds to microseconds with a resolution of 6.5 ns. This allows the selection of the optimal afterpulse-free hold-off time for the GM-APD via external digital inputs or additional signal processing circuitry. Moreover, this circuit resets the APD automatically following the end of the hold-off period, thus simplifying the control for the end user. Results also show that a minimum dead time of 28.4 ns is achieved, demonstrating a saturated photon-counting rate of 35.2 Mcounts/s. PMID- 23041890 TI - Ultrafast field-resolved semiconductor spectroscopy utilizing quantum interference control of currents. AB - We implement a versatile concept to time-resolve optical nonlinearities of semiconductors in amplitude and phase. A probe pulse transmitted through the optically pumped sample is superimposed with first subharmonic spectral components derived from the same laser source. This effective omega/2omega pulse pair induces a coherently controlled current in a time-integrating semiconductor detector. Current interferograms obtained by scanning the omega/2omega time delay then reveal the electric field of the 2omega part as well as its pump-induced modifications. As a paradigm we analyze the excitonic optical nonlinearity of a CdTe thin film at frequencies around 385 THz. We then move on to resolve the pump induced amplitude- and phase-distortions of a probe pulse related to two-photon absorption and cross-phase modulation in ZnSe. PMID- 23041891 TI - Optical coherence tractography using intrinsic contrast. AB - Organs such as the heart and brain possess intricate fiber structures that are best characterized with three-dimensional imaging. For instance, diffusion-based, magnetic resonance tractography (MRT) enables studies of connectivity and remodeling during development and disease macroscopically on the millimeter scale. Here we present complementary, high-resolution microscopic optical coherence imaging and analysis methods that, when used in conjunction with clearing techniques, can characterize fiber architecture in intact organs at tissue depths exceeding 1 mm. We anticipate that these techniques can be used to study fiber architecture in situ at microscopic scales not currently accessible to diffusion magentic resonance (MR), and thus, to validate and complement macroscopic structural imaging techniques. Moreover, as these techniques use intrinsic signals and do not require tissue slicing and staining, they can be used for high-throughput, nondestructive evaluation of fiber architecture across large tissue volumes. PMID- 23041892 TI - Coherent beam combination of two nanosecond fiber amplifiers by an all-optical feedback loop. AB - A passive coherent beam combination of two nanosecond amplifiers is realized by using an all-optical feedback loop. The width of the combined pulses is 9.7 ns, and the pulse repetition frequency is 2.023 MHz. With the least mismatch between pulse period and time of the cavity round trip in our loop, the visibility of far field coherent patterns is more than 71%. The dynamics of passive phase locking is studied, and the established time of phase locking of two pulsed amplifiers is at least 10 cavity round trips in the all-optical feedback loop. PMID- 23041893 TI - Highly efficient dual-wavelength laser operation of cryo-cooled resonantly (in band) pumped Ho3+:YVO4 laser. AB - We have demonstrated a CW, multiwatt, dual-wavelength cryogenically cooled, resonantly (in-band) pumped Ho(3+):YVO(4) laser with nearly quantum-defect limited performance. The Ho(3+)(2%):YVO(4) gain element, which was maintained at ~80 K and pumped by a Tm-fiber laser at 1966 nm, emitted at wavelengths of either 2053 or 2068 nm, or both at the same time, depending on the outcoupling loss and the pump power. We have achieved laser operation with a maximum slope efficiency of ~92%. This is, to the best of our knowledge, the highest slope efficiency ever demonstrated for any Ho(3+)-doped laser. PMID- 23041894 TI - Tailoring a 67 attosecond pulse through advantageous phase-mismatch. AB - A single isolated attosecond pulse of 67 as was composed from an extreme UV supercontinuum covering 55-130 eV generated by the double optical gating technique. Phase mismatch was used to exclude the single-atom cutoff of the spectrum that possesses unfavorable attochirp, allowing the positive attochirp of the remaining spectrum to be compensated by the negative dispersion of a zirconium foil. Two algorithms, PROOF and FROG-CRAB, were employed to retrieve the pulse from the experimental spectrogram, yielding nearly identical results. PMID- 23041895 TI - Er:YAG laser pulse for small-dose splashback-free microjet transdermal drug delivery. AB - The microjet injector system accelerates drugs and delivers them without a needle, which is shown to overcome the weaknesses of existing jet injectors. A significant increase in the delivered dose of drugs is reported with multiple pulses of laser beam at lower laser energy than was previously used in a Nd:YAG system. The new injection scheme uses the beam wavelength best absorbable by water at a longer pulse mode for elongated microjet penetration into a skin target. A 2.9 MUm Er:YAG laser at 250 MUs pulse duration is used for fluorescent staining of guinea pig skin and for injection controllability study. Hydrodynamic theory confirms the nozzle exit jet velocity obtained by the present microjet system. PMID- 23041896 TI - Emerging fixed-shape solutions from a pulsating chaotic soliton. AB - The impact of some higher-order effects (HOEs), namely, intrapulse Raman scattering, self-steepening, and third-order dispersion, on a chaotic pulsating soliton, solution of the quintic complex Ginzburg-Landau equation, is numerically investigated. We show that a proper combination of the three HOEs can control the pulse chaotic behavior and provide a fixed-shape solution. The region of existence of fixed-shape pulses is also presented for some range of the parameter values. PMID- 23041897 TI - Writing of Bragg gratings through the polymer jacket of low-loss As2S3 fibers using femtosecond pulses at 800 nm. AB - Fiber Bragg gratings (FBG) were written through the polymer jacket of low-loss single mode As(2)S(3) chalcogenide fibers by using femtosecond laser pulses at 800 nm and a phase-mask. Peak reflectivity in excess of 99% was obtained at 3440 nm after 5 min of exposure. The resulting FBG maintained a peak reflectivity of 90% after 64 min of thermal annealing at 100 degrees C. This demonstration paves the way to the development of all-fiber mid-infrared laser sources. PMID- 23041898 TI - Optical waveguide mode control by nanoslit-enhanced terahertz field. AB - In this Letter we propose a scheme providing control over an optical waveguide mode by a terahertz (THz) wave. The scheme is based on an optimization of the overlap between the optical waveguide mode and the THz field, with the THz field strength enhanced by the presence of a metallic nanoslit surrounding the waveguide. We find an optimum balance between the optical mode attenuation and Kerr-induced change in the propagation constant. The criterion for a pi/2 cumulative phase shift, for instance for application in a Mach-Zehnder interferometer configuration, requires 10 kV/cm THz field, which in turn is estimated to result in a nonlinear change of the refractive index in the waveguide of 0.001. Our simulations prove that it is quite reasonable to observe the effect experimentally. PMID- 23041899 TI - Spectrogram approach to S2 fiber mode analysis to distinguish between dispersion and distributed scattering. AB - We report on the significant effect that intermodal dispersion can have on spatially and spectrally resolved interferometric (S(2)) fiber mode analysis. This dispersion can significantly broaden the measured intermodal group delay and could be misinterpreted as distributed scattering. In our new approach, the spectral interference data is analyzed over multiple wavelength windows staggered across the measurement bandwidth and assembled together to form a spectrogram that reveals the wavelength dependence of the intermodal group delay. Measurements on standard telecom single-mode and large-mode-area fibers are presented. This spectrogram analysis is a more accurate map of mode conversion along the fiber and is essential for evaluating fibers and fiber devices. PMID- 23041900 TI - Mode-locked, continuous-wave, singly resonant optical parametric oscillator. AB - We report an actively mode-locked continuous-wave (cw) optical parametric oscillator in singly resonant oscillator (SRO) configuration, generating stable 230 ps pulses at 80 MHz repetition rate. The idler-resonant cw SRO, configured in standing-wave cavity, is based on MgO:sPPLT as the nonlinear gain material and pumped at 532 nm. Mode-locking is achieved by direct deployment of an intracavity phase modulator close to one of the SRO cavity end mirrors. The effects of modulation depth and modulation frequency on mode-locked pulse duration and repetition rate are investigated for both idler and signal pulses. Mode-locking is further confirmed by enhancement of single-pass second-harmonic generation of SRO output in the crystal of beta-BaB(2)O(4). PMID- 23041901 TI - Dispersed single-phase-step Michelson interferometer for Doppler imaging using sunlight. AB - A Michelson interferometer is dispersed with a fiber array-fed spectrograph, providing 59 Doppler sensing channels using sunlight in the 510-570 nm wavelength region. The interferometer operates at a single-phase-step mode, which is particularly advantageous in multiplexing and data processing compared to the phase-stepping mode of other interferometer spectrometer instruments. Spectral templates are prepared using a standard solar spectrum and simulated interferometer modulations, such that the correlation function with a measured 1D spectrum determines the Doppler shift. Doppler imaging of a rotating cylinder is demonstrated. The average Doppler sensitivity is ~12 m/s, with some channels reaching ~5 m/s. PMID- 23041902 TI - Plasmonic wavelength splitter based on a large-area dielectric grating and white light illumination. AB - An optical process by which transmission wavelengths can be divided selectively by changing a resonance condition of surface plasmons (SPs) is demonstrated. When white light is incident to an SP resonance substrate with a dielectric grating, SP waves are excited at resonance and transmitted into the air via diffraction by a large-area grating pattern fabricated by nanoimprint lithography. While only a limited range of certain wavelengths is allowed to transmit, the peak transmission wavelength can be tuned continuously in the visible band. We also show that multiple wavelengths are transmitted into different directions simultaneously by using a wedge-shaped white light. PMID- 23041903 TI - Tunable superstructure fiber Bragg grating with chirp-distribution modulation based on the effect of external stress. AB - We report an external stress modulation method for producing a superstructure fiber Bragg grating (FBG) with approximate cascaded resonant cavities composed of different index chirp distributions. The 15 mm uncoated apodized uniform-period FBG is pressed by the vertical stress from the upper 11 pieces of the pattern plate controlled by a piezoelectric ceramic actuator. The piece length is 1 mm, and the interval of the adjacent pieces is 0.4 mm. The reflectivity of the modulated FBG gradually shows six obvious multichannel 75%-85% reflection peaks with the increase of the vertical stress of each pattern-plate piece from 0 to 30 N. The channel spacing is steady at about 10 GHz for a C-band wavelength division multiplexing system. PMID- 23041904 TI - Nanoradar based on nonlinear dimer nanoantenna. AB - We introduce the concept of a nanoradar based on the operation of a nonlinear plasmonic nanoantenna. The nanoradar action originates from modulational instability occurring in a dimer nanoantenna consisting of two subwavelength nonlinear nanoparticles. Modulation instability causes a dynamical energy exchange between the nanoantenna eigenmodes resulting in periodic scanning of the nanoantenna scattering pattern. Such nanoradar demonstrates a wide scanning sector, low operation threshold, and ultrafast time response being potentially useful for many applications in nanophotonics circuitry. PMID- 23041905 TI - Flexible receiver for multiband orthogonal frequency division multiplexing signals at the millimeter waveband based on optical downconversion. AB - A novel (to our knowledge) and flexible photonics-based downconversion scheme is proposed for wireless receivers in base stations. It allows simultaneous detection of multiple signals at carriers up to tens of gigahertz, enabling communications at millimeter waves. Experiments demonstrate the effective downconversion of Wi-Fi signals at 2.4 and 39.8 GHz with the error vector magniture <-43 dB. PMID- 23041907 TI - Emerging therapeutic agents to lower lipoprotein (a) levels. AB - PURPOSE OF REVIEW: Recent epidemiological and genetic studies have suggested that lipoprotein (a) [Lp(a)] is a causal mediator of cardiovascular disease (CVD). There is now interest in evaluating Lp(a) as a therapeutic target. This review will summarize emerging therapeutic agents to lower Lp(a). RECENT FINDINGS: Apheresis is the most efficacious method to lower Lp(a). Currently, there are no approved drugs to specifically lower Lp(a). However, recent data has demonstrated that Lp(a) can be significantly lowered, along with reductions in other apolipoprotein B-100 (apoB) containing lipoproteins, with antisense oligonucleotides to apoB, monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, cholesterol ester transfer protein inhibitors, and thyromimetics. The farnesoid X receptor/fibroblast growth factor axis and interleukin-6 also influence Lp(a) levels and may be targets of therapy. Finally, specific apolipoprotein (a) [apo(a)] inhibitors apo(a) have been developed and reduce apo(a) mRNA and protein levels up to 86% without significantly affecting other lipoproteins. SUMMARY: Lp(a) remains the last major lipoprotein disorder without any specific therapy. With the strong and accumulating data on its role as a causal risk factor for CVD, a rationale exists to develop novel agents to reduce Lp(a) and test the hypothesis that this will lead to reduced CVD events. PMID- 23041906 TI - Prolonged androgen deprivation leads to downregulation of androgen receptor and prostate-specific membrane antigen in prostate cancer cells. AB - Emergence of androgen-independent cancer cells during androgen deprivation therapy presents a significant challenge to successful treatment outcomes in prostate cancer. Elucidating the role of androgen deprivation in the transition from an androgen-dependent to an androgen-independent state may enable the development of more effective therapeutic strategies against prostate cancer. Herein, we describe an in vitro model for assessing the effects of continuous androgen-deprivation on prostate cancer cells (LNCaP) with respect to the expression of two prostate-specific markers: the androgen receptor (AR) and prostate-specific membrane antigen (PSMA). Compared with androgen-containing normal growth medium, androgen-deprived medium apparently induced the concomitant downregulation of AR and PSMA over time. Decreased protein levels were confirmed by fluorescence imaging, western blotting and enzymatic activity studies. In contrast to the current understanding of AR and PSMA in prostate cancer progression, our data demonstrated that androgen-deprivation induced a decrease in AR and PSMA levels in androgen-sensitive LNCaP cells, which may be associated with the development of more aggressive disease-state following androgen deprivation therapy. PMID- 23041908 TI - Prevention of HIV among older adults: a literature review and recommendations for future research. AB - OBJECTIVE: This study reviews the existing literature on the prevention of HIV among older adults, including universal and indicated prevention programs and prevention strategies. METHOD: A literature search was conducted between September and October of 2011 to identify studies for this review. Several different electronic databases and a combination of keywords were used to conduct the search. In addition, the reference section of each article was reviewed for additional articles. RESULTS: A total of 18 articles were identified and reviewed. Three of the articles examined universal prevention, five of the articles examined indicated prevention, and the remainder of the articles provided strategies and recommendations for the prevention of HIV among older adults. DISCUSSION: The existing studies document evidence for preventing future cases of HIV/AIDS among older adults. Additional studies and universal and selected interventions are needed in an effort to reduce the number of older adults being diagnosed with HIV. PMID- 23041909 TI - All inorganic iron pyrite nano-heterojunction solar cells. AB - The large absorption coefficient of iron pyrite (FeS(2)) nanocrystals coupled with their low-cost and vast-abundance shows great promise as a potential photovoltaic absorber. Here, we demonstrate that bulk heterojunction (BHJ) nanostructures consisting of 80 nm FeS(2) nanocubes (NCs) and 4 nm CdS quantum dot (QD) matrix, lead to a well-defined percolation network, which significantly improved open-circuit voltage (V(oc)) to 0.79 V and power conversion efficiency of 1.1% under AM 1.5 solar illumination. The localized surface plasmon resonances (LSPRs) arising from p-type colloidal FeS(2) NCs exhibit plasmonic photoelectron conversion. Our approach can be applied to a wide range of colloidal nanocrystals exhibiting the LSPRs effect and is compatible with solution processing, thereby offering a general tactic to enhancing the efficiency of all inorganic BHJ solar cells and LSPRs-based NIR photodetectors. PMID- 23041910 TI - An agglomeration induced glassy magnetic state in a carbon nanotube/NiO nanocomposite system. AB - A series of nanocomposite materials were synthesized using multi-walled carbon nanotubes (MWCNTs) and NiO nanoparticles by varying the concentration of NiO in the MWCNT host matrix. Such an increment in the NiO particle density actually tunes the degree of isolation among the magnetic nanoparticles. Careful investigation by transmission electron microscopy shows that particle agglomeration increases substantially with NiO particle density. Field dependence of magnetization measurements depict a gradual enhancement of coercivity with increasing NiO concentration, signifying the enhancement of magnetic anisotropy in this nanocomposite system. Furthermore, field cooled and zero field cooled memory effect as well as magnetization relaxation measurements show that a glassy magnetic state gradually develops when the concentration increases. Analysis based on the result of high resolution transmission electron microscopy along with the magnetization data reveals that interparticle magnetic exchange interaction in the presence of interfacial disorders plays the major role in the emergence of the glassy magnetic state in this nanocomposite system. PMID- 23041911 TI - Defining GP practice areas based on true service utilisation. AB - Where patients who are registered with a general practice actually live (the service utilisation area) often differ from what GPs consider their practice boundaries or catchment area to be, as well as from administrative boundaries. A key aim of primary care commissioners is to allocate resources efficiently and to locate services in such a way that access is convenient for patients. To achieve this robust understanding of practice service utilisation areas and the overlap between practices and administrative areas are essential. We used kernel analysis of the postcodes of over 400,000 registered patients to define GP service utilisation areas. We estimated service utilisation for each of 64 practices for a period of five years (2002-2006) exploring the areas in which 99%, 98%, and 95% of registered patients were expected to live. These service utilisation areas were not coterminous with other practices or with administrative boundaries. We present a simple analytical method to define GP catchment areas that captures the true service utilisation area and identifies the extent of overlap. This is a practical tool that can assist health care commissioning. PMID- 23041912 TI - Changes in dental caries and oral hygiene among 7-8 year-old schoolchildren in different regions of Lithuania 1983-2009. AB - The objectives of this study were to evaluate and compare the changes of the dental caries prevalence and severity of 7 to 8 year old schoolchildren in six Lithuanian regions over the past 26 years (1983-2009) and to propose recommendations based on the results of the study. The study is based on the analysis of data, containing 576 cases of children examined in 1983 and comparison with data containing 531 cases added in 2009. The studies were conducted in the same six regions of Lithuania among the children from 7 to 8 years of age. For the study of children the WHO oral assessment methodology was used (WHO Basic methods 1997). Severity of dental caries was described by df-t and DMF-T index. The average of individual df-t and DMF-T indices was calculated for all subjects and sorted by gender. Oral hygiene status was evaluated by applying the simplified Green-Vermilion index-OHI-S (1964) The prevalence of primary dental caries among the children 7 to 8 years of age was 92.4% in 1983 and 88.7% (p=0.43) in 2009. The prevalence of permanent dental caries decreased from 49.6% in 1983 to 29.7% (p<0.001) in 2009. Mean df-t score decreased from 4.9+/-3.4 in 1983 to 4.1+/-2.7 in 2009 and DMF-T index decreased from 1.1+/-1.7 in 1983 to 0.5+/-1.0 in 2009 (p<0.001). The OHI-S index was not significantly different during 1983-2009. In the period of last 26 years a tendency towards the decrease in the prevalence and severity of dental caries was observed. That could be related to the frequent using of the toothpastes with fluoride, as well as implementation of the caries prevention program with sealants among the children of that age. The poor oral hygiene and comparatively high caries prevalence in schoolchildren show that it is still necessary to improve preventive measures in Lithuania. PMID- 23041913 TI - An open letter from the American board of phlebology. PMID- 23041914 TI - Label-free DNA hybridization detection by various spectroscopy methods using triphenylmethane dyes as a probe. AB - A new assay is developed for direct detection of DNA hybridization using triphenylmethane dye as a probe. It is based on various spectroscopic methods including resonance light scattering (RLS), circular dichroism (CD), ultraviolet spectra and fluorescence spectra, as well as atomic force microscopy (AFM), six triphenylmethane dyes interact with double strand DNA (dsDNA) and single strand DNA (ssDNA) were investigated, respectively. The interaction results in amplified resonance light scattering signals and enables the detection of hybridization without the need for labeling DNA. Mechanism investigations have shown that groove binding occurs between dsDNA and these triphenylmethane dyes, which depends on G-C sequences of dsDNA and the molecular volumes of triphenylmethane dyes. Our present approaches display the advantages of simple and fast, accurate and reliable, and the artificial samples were determined with satisfactory results. PMID- 23041915 TI - A non-destructive method for quantification the irradiation doses of irradiated sucrose using Vis/NIR spectroscopy. AB - This article proposes a new method for fast discrimination of irradiation doses of sucrose based on visible-near infrared (Vis/NIR) spectroscopy technology. 250 sucrose samples were categorized into five groups to be irradiated at 0, 1.5, 3.0, 4.5, 6.0 kGy respectively and prepared for the discrimination analysis. The 50 samples of each group were randomly divided into a calibration set containing 40 samples, and a validation set containing the remaining 10 samples. Principal component clustering analysis (PCCA) was applied for the extraction of principal components (PCs) and for clustering analysis. The first five PCs were regarded as the inputs to develop the back propagation neural network (BPNN) model. The performance of the model was validated by the 50 unknown samples and the BPNN achieved an excellent precision and recognition ration of 100%. The results indicated that Vis/NIR spectroscopy could be utilized as a rapid and non destructive method for the classification of different irradiation doses of irradiated sucrose. PMID- 23041916 TI - FT-IR and Raman spectroscopic analysis of some Hofmann type complexes. AB - Some new Hofmann type complexes with chemical formula of M(4 pypp)(2)Ni(CN)(4) (where 4 py pp=4-(1-pyrrolidinyl)piperidine and MNi or Co) were prepared and their FT-IR and Raman spectra were reported in the region of 4000-200 cm(-1) and 4000-100 cm(-1), respectively. The ligand molecule, polymeric sheet and metal ligand bands of the compounds were assigned in detail. Vibrational spectra together with assignments of 4 pypp (C(9)H(18)N(2)) were experimentally and theoretically studied in the region of 400-100 cm(-1). Normal mode frequencies and corresponding vibrational assignments of Ni(CN)(4)(2-) were theoretically examined by standard quantum chemical technique. Reliable vibrational assignments were made on the basis of potential energy distribution (PED) analysis. The results suggest that these compounds are similar in structure to the Hofmann type complexes and the 4 phpy ligand molecule bonds to the metal (M) atom of |M Ni(CN)(4)|(infinity) polymeric layers. PMID- 23041917 TI - Determining the mode of interaction of calf thymus DNA with the drug sumatriptan using voltammetric and spectroscopic techniques. AB - The interaction of native calf thymus DNA with sumatriptan(1-[3-(2 dimethylaminoethyl)-1H-indol-5-yl]-N-methyl-methanesulfonamide) at physiological pH was studied by spectrophotometry, circular dichroism, voltammetry and viscosimetric techniques. Sumatriptan molecule intercalated between base pairs of DNA, showed by a sharp increase in specific viscosity of DNA. In cyclic voltammetry, decrease of the peak current and positive shift indicated that this drug is able to intercalate between the DNA base pairs. In addition, the drug induced changes in the CD spectrum of CT-DNA, as well as hypochromism changes in its UV-vis spectrum. PMID- 23041918 TI - Studies on growth, structural, dielectric, laser damage threshold, linear and nonlinear optical properties of methylene blue admixtured l-arginine phosphate single crystal. AB - L-Arginine phosphate (LAP) and methylene blue dye admixtured L-arginine phosphate single crystals were grown by slow cooling technique and their cell parameters, crystalline perfection, dopant inclusion were confirmed by single crystal, powder X-ray diffraction and high resolution X-ray diffraction analyses respectively. The modes of vibrations of different functional groups present in pure and dye admixtured LAP crystals have been identified by FTIR spectral analysis. The UV Vis-NIR spectral study was performed on the grown crystals and found that the crystals are transparent in the entire visible-NIR region. The dielectric measurement was carried out on the grown crystals as a function of frequency at room temperature. The microhardness hardness study on (100) plane of grown crystals reveals the mechanical behavior of the crystals. The laser damage threshold value significantly enhanced for dye admixtured crystal in comparison with pure LAP crystal. The relative SHG efficiency of methylane blue admixtured LAP crystal was found to be 1.3 times higher than that of pure LAP crystal. PMID- 23041919 TI - Influence of annealing temperature on Raman and photoluminescence spectra of electron beam evaporated TiO2 thin films. AB - Titanium dioxide (TiO(2)) thin films were deposited on fused quartz substrates by electron beam evaporation method at room temperature. The films were annealed at different temperatures in ambient air. The surface morphology/roughness at different annealing temperatures were analyzed by atomic force microscopy (AFM). The crystallinity of the film has improved with the increase of annealing temperature. The effect of annealing temperature on optical, photoluminescence and Raman spectra of TiO(2) films were investigated. The refractive index of TiO(2) films were studied by envelope method and reflectance spectra and it is observed that the refractive index of the films was high. The photoluminescence intensity corresponding to green emission was enhanced with increase of annealing temperature. The peaks in Raman spectra depicts that the TiO(2) film is of anatase phase after annealing at 300 degrees C and higher. The films show high refractive index, good optical quality and photoluminescence characteristics suggest that possible usage in opto-electronic and optical coating applications. PMID- 23041920 TI - Interaction of alkali, alkaline earth and transition metal ions with a ketocyanine dye: a comparative electronic spectroscopic study. AB - Interaction of a dye which is structurally similar to a ketocyanine dye with metal ions (alkali, alkaline earth and transition metal) has been studied by monitoring the electronic absorption, steady state and time resolved fluorescence parameters of the dye. The dye (S(0) state) forms a 1:1 complex with cations as indicated by the appearance of a new band at a longer wavelength. Equilibrium constant and other thermodynamic parameters for complexation have been determined. The interaction between the dye and the cation is mostly electrostatic in nature. Spectroscopic results have been supplemented by DFT calculation. For very low concentration of cations, where complexation is insignificant, the absorption band of the dye undergoes a slight blue shift. Enhancement of fluorescence intensity has been observed in the same concentration range. Both phenomena have been explained in terms of formation of a weak association complex where one/more cation replace equivalent solvent molecules in the cybotatic region around the dye. The binding constant of the weak association complex involving cation and the dye (S(1) state) has been determined and has been found to depend on the charge-to-size ratio of the cations. Measurement of fluorescence lifetime of the dye indicates that the association complex is slowly decaying relative to solvated dye. At higher concentration of metal ions, however, fluorescence of the dye is quenched by the metal ions. A red shift of fluorescence maximum has also been observed in this concentration range. PMID- 23041921 TI - Synthesis, spectroscopic characterization and biological evaluation studies of Schiff's base derived from naphthofuran-2-carbohydrazide with 8-formyl-7-hydroxy 4-methyl coumarin and its metal complexes. AB - Metal complexes of the type ML(2), where M=Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II) and L=Schiff's base derived from the condensation of naphthofuran 2-carbohydrazide with 8-formyl-7-hydroxy-4-methyl coumarin have been synthesized. The chelation of the complexes have been elucidated in the light of analytical, IR, UV-vis, (1)H NMR, mass, ESR spectral data, thermal and magnetic studies. The measured molar conductance values indicate that, the complexes are non electrolytic in nature. The redox behavior of one of the synthesized metal complexes was investigated by cyclic voltammetry. The Schiff's base and its metal complexes have been screened for their in vitro antibacterial and antifungal activities by MIC method. The DNA cleavage activities of all the complexes were studied by agarose gel electrophoresis method. In addition, the free ligand along with its complexes has been studied for their antioxidant activity. PMID- 23041922 TI - Analytical potential energy functions and spectroscopic properties for the ground and low-lying excited states of KRb. AB - The potential energy curves (PECs) of the ground state X(1)Sigma(+) and two low lying excited states 1(3)Sigma(+) and 1(3)P of KRb molecule have been calculated using the multireference configuration interaction method and the effective core potential basis set. The PECs are fitted into analytical potential energy functions (APEFs) using the Morse long-range potential. The spectroscopic parameters for the states are determined using the analytical derivatives of APEFs. The vibrational energy levels have been calculated by solving the radial Schrodinger equation of nuclear motion based on the APEFs, and compared with the theoretical and experimental works available at present. PMID- 23041923 TI - Hydrothermal synthetic mercaptopropionic acid stabled CdTe quantum dots as fluorescent probes for detection of Ag+. AB - Mercaptopropionic acid (MPA) capped CdTe quantum dots (QDs) with particle size 3 nm have been successfully synthesized in aqueous medium by hydrothermal synthesis method. And the effects of different metal ions on MPA capped CdTe QDs fluorescence were studied using fluorescence spectrometry. The results demonstrated that at the same concentration level, Ag(+) could strongly quench CdTe QDs fluorescence, and the other metal ions had little effect on CdTe QDs fluorescence except Cu(2+). On the basis of this fact, a rapid, simple, highly sensitive and selective method based on fluorescence quenching principle for Ag(+) detection in aqueous solution was proposed. Under optimal conditions, the quenched fluorescence intensity (F(0)-F) increased linearly with the concentration of Ag(+) ranging from 4 * 10(-7) to 32 * 10(-7)mol L(-1). The limit of detection for Ag(+) was 4.106 * 10(-8)mol L(-1). The obtained plot of F(0)/F versus [Ag(+)] was an upward curvature, concave towards the y-axis, rather than a straight line. The modified form of the Stern-Volmer equation was third order in Ag(+) concentration. According to the modified Stern-Volmer equation, it can be inferred that dynamic quenching and static quenching simultaneously occurred when Ag(+) interacted with MPA capped CdTe QDs. At the same time other factors might also influence the quenching process. Based on this study, hydrothermal synthesized MPA capped CdTe QDs with particle size 3 nm may be used as a novel fluorescence probe to quantificationally and selectively detect Ag(+). PMID- 23041924 TI - Room temperature synthesis and optical studies on Ag and Au mixed nanocomposite polyvinylpyrrolidone polymer films. AB - Optical properties of silver, gold and bimetallic (Au:Ag) nanocomposite polymer films which are prepared by chemical method have been reported. The experimental data was correlated with the theoretical calculations using Mie theory. We adopt small change in the theoretical calculations of bimetallic/mixed particle nanocomposite and the theory agrees well with the experimental data. Polyvinylpyrrolidone (PVP) was used as reducing and capping agent. Fourier transform infrared spectroscopy (FTIR) study reveals the presence of different functional groups, the possible mechanism that leads to the formation of nanoparticles by using PVP alone as reducing agent. Optical absorption spectra of Ag and Au nanocomposite polymers show a surface plasmon resonance (SPR) band around 430 and 532 nm, respectively. Thermal annealing effect on the prepared samples at 60 degrees C for different time durations result in shift of SPR band maximum and varies the full width at half maximum (FWHM). Absorption spectra of Au:Ag bimetallic films show bands at 412 and 547 nm confirms the presence of Ag and Au nanoparticles in the composite. PMID- 23041925 TI - Novel spectrophotometric method for determination of some macrolide antibiotics in pharmaceutical formulations using 1,2-naphthoquinone-4-sulphonate. AB - New, simple and rapid spectrophotometric method has been developed and validated for the assay of two macrolide drugs, azithromycin (AZT) and erythromycin (ERY) in pure and pharmaceutical formulations. The proposed method was based on the reaction of AZT and ERY with sodium 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline medium at 25 degrees C to form an orange-colored product of maximum absorption peak at 452 nm. All variables were studied to optimize the reaction conditions and the reaction mechanism was postulated. Beer's law was obeyed in the concentration range 1.5-33.0 and 0.92-8.0 MUg mL(-1) with limit of detection values of 0.026 and 0.063 MUg mL(-1) for AZT and ERY, respectively. The calculated molar absorptivity values are 4.3 * 10(4) and 12.3 * 10(4) L mol(-1) cm(-1) for AZT and ERY, respectively. The proposed methods were successfully applied to the determination of AZT and ERY in formulations and the results tallied well with the label claim. The results were statistically compared with those of an official method by applying the Student's t-test and F-test. No interference was observed from the concomitant substances normally added to preparations. PMID- 23041926 TI - Vibrational spectra and factor group analysis of M0.50TiOPO4 oxyphosphates (M=Mg, Zn, Ni, Co, Fe and Cu). AB - Raman spectra of a series of orthophosphates M(0.50)TiO(PO(4)) (M=Mg, Zn, Ni, Co, Fe, and Cu) have been recorded in crystalline state. Factor group analysis has been performed for space group P2(1)/c and assignments of the internal modes of the [PO(4)] tetrahedra and [TiO(6)] octahedra have been made. PMID- 23041928 TI - Visualizing transient low-populated structures of RNA. AB - The visualization of RNA conformational changes has provided fundamental insights into how regulatory RNAs carry out their biological functions. The RNA structural transitions that have been characterized so far involve long-lived species that can be captured by structure characterization techniques. Here we report the nuclear magnetic resonance visualization of RNA transitions towards 'invisible' excited states (ESs), which exist in too little abundance (2-13%) and for too short a duration (45-250 MUs) to allow structural characterization by conventional techniques. Transitions towards ESs result in localized rearrangements in base-pairing that alter building block elements of RNA architecture, including helix-junction-helix motifs and apical loops. The ES can inhibit function by sequestering residues involved in recognition and signalling or promote ATP-independent strand exchange. Thus, RNAs do not adopt a single conformation, but rather exist in rapid equilibrium with alternative ESs, which can be stabilized by cellular cues to affect functional outcomes. PMID- 23041929 TI - Intrinsically determined cell death of developing cortical interneurons. AB - Cortical inhibitory circuits are formed by gamma-aminobutyric acid (GABA) secreting interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis, is that cortical interneurons are overproduced, and then after their migration into cortex the excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we characterize the developmental cell death of mouse cortical interneurons in vivo, in vitro and after transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax (Bcl-2-associated X)-dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by neurons of the central nervous system. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Taken together, our findings indicate that interneuron cell death is determined intrinsically, either cell-autonomously or through a population autonomous competition for survival signals derived from other interneurons. PMID- 23041930 TI - Self-renewal of embryonic-stem-cell-derived progenitors by organ-matched mesenchyme. AB - One goal of regenerative medicine, to use stem cells to replace cells lost by injury or disease, depends on producing an excess of the relevant cell for study or transplantation. To this end, the stepwise differentiation of stem cells into specialized derivatives has been successful for some cell types, but a major problem remains the inefficient conversion of cells from one stage of differentiation to the next. If specialized cells are to be produced in large numbers it will be necessary to expand progenitor cells, without differentiation, at some steps of the process. Using the pancreatic lineage as a model for embryonic-stem-cell differentiation, we demonstrate that this is a solvable problem. Co-culture with organ-matched mesenchyme permits proliferation and self renewal of progenitors, without differentiation, and enables an expansion of more than a million-fold for human endodermal cells with full retention of their developmental potential. This effect is specific both to the mesenchymal cell and to the progenitor being amplified. Progenitors that have been serially expanded on mesenchyme give rise to glucose-sensing, insulin-secreting cells when transplanted in vivo. Theoretically, the identification of stage-specific renewal signals can be incorporated into any scheme for the efficient production of large numbers of differentiated cells from stem cells and may therefore have wide application in regenerative biology. PMID- 23041931 TI - Genetic programs constructed from layered logic gates in single cells. AB - Genetic programs function to integrate environmental sensors, implement signal processing algorithms and control expression dynamics. These programs consist of integrated genetic circuits that individually implement operations ranging from digital logic to dynamic circuits, and they have been used in various cellular engineering applications, including the implementation of process control in metabolic networks and the coordination of spatial differentiation in artificial tissues. A key limitation is that the circuits are based on biochemical interactions occurring in the confined volume of the cell, so the size of programs has been limited to a few circuits. Here we apply part mining and directed evolution to build a set of transcriptional AND gates in Escherichia coli. Each AND gate integrates two promoter inputs and controls one promoter output. This allows the gates to be layered by having the output promoter of an upstream circuit serve as the input promoter for a downstream circuit. Each gate consists of a transcription factor that requires a second chaperone protein to activate the output promoter. Multiple activator-chaperone pairs are identified from type III secretion pathways in different strains of bacteria. Directed evolution is applied to increase the dynamic range and orthogonality of the circuits. These gates are connected in different permutations to form programs, the largest of which is a 4-input AND gate that consists of 3 circuits that integrate 4 inducible systems, thus requiring 11 regulatory proteins. Measuring the performance of individual gates is sufficient to capture the behaviour of the complete program. Errors in the output due to delays (faults), a common problem for layered circuits, are not observed. This work demonstrates the successful layering of orthogonal logic gates, a design strategy that could enable the construction of large, integrated circuits in single cells. PMID- 23041932 TI - The spatial architecture of protein function and adaptation. AB - Statistical analysis of protein evolution suggests a design for natural proteins in which sparse networks of coevolving amino acids (termed sectors) comprise the essence of three-dimensional structure and function. However, proteins are also subject to pressures deriving from the dynamics of the evolutionary process itself--the ability to tolerate mutation and to be adaptive to changing selection pressures. To understand the relationship of the sector architecture to these properties, we developed a high-throughput quantitative method for a comprehensive single-mutation study in which every position is substituted individually to every other amino acid. Using a PDZ domain (PSD95(pdz3)) model system, we show that sector positions are functionally sensitive to mutation, whereas non-sector positions are more tolerant to substitution. In addition, we find that adaptation to a new binding specificity initiates exclusively through variation within sector residues. A combination of just two sector mutations located near and away from the ligand-binding site suffices to switch the binding specificity of PSD95(pdz3) quantitatively towards a class-switching ligand. The localization of functional constraint and adaptive variation within the sector has important implications for understanding and engineering proteins. PMID- 23041933 TI - Effect of the quantity and quality of cortical bone on the failure force of a miniscrew implant. AB - This study examined the influence of the quantity and quality of cortical bone on the failure force of miniscrew implants. Twenty-six titanium alloy miniscrew implants (AbsoAnchor) 1.4mm in diameter and 5 or 7 mm long were placed in cross sectioned maxillae (n = 6) and mandibles (n = 20) of human cadavers. Computed tomography imaging was used to estimate the cortical bone thickness and bone mineral density [total bone mineral density (TBMD, values obtained from cortical bone plus trabecular bone); cortical bone mineral density (CBMD, values obtained from only cortical bone)]. Maximum force at failure was measured in a shear test. Nanoindentation tests were performed to measure the hardness and elastic modulus of cortical bone around the miniscrew implants. The mean failure force of miniscrew implants placed in mandibles was significantly greater than that for implants in maxillae, and the bone hardness of mandibles was significantly greater than that of maxillae. The length of miniscrew implants did not influence the mean failure force in monocortical placement in the mandible. Cortical bone thickness, TBMD, CBMD, and bone hardness were significantly related to the mean failure force. CBMD was related to the mechanical properties of cortical bone. In conclusion, the quantity and quality of cortical bone greatly influenced the failure force of miniscrew implants. PMID- 23041934 TI - Cluster randomized clinical trials in orthodontics: design, analysis and reporting issues. AB - Cluster randomized trials (CRTs) use as the unit of randomization clusters, which are usually defined as a collection of individuals sharing some common characteristics. Common examples of clusters include entire dental practices, hospitals, schools, school classes, villages, and towns. Additionally, several measurements (repeated measurements) taken on the same individual at different time points are also considered to be clusters. In dentistry, CRTs are applicable as patients may be treated as clusters containing several individual teeth. CRTs require certain methodological procedures during sample calculation, randomization, data analysis, and reporting, which are often ignored in dental research publications. In general, due to similarity of the observations within clusters, each individual within a cluster provides less information compared with an individual in a non-clustered trial. Therefore, clustered designs require larger sample sizes compared with non-clustered randomized designs, and special statistical analyses that account for the fact that observations within clusters are correlated. It is the purpose of this article to highlight with relevant examples the important methodological characteristics of cluster randomized designs as they may be applied in orthodontics and to explain the problems that may arise if clustered observations are erroneously treated and analysed as independent (non-clustered). PMID- 23041935 TI - Facial shape and asymmetry in 5-year-old children with repaired unilateral cleft lip and/or palate: an exploratory study using laser scanning. AB - To investigate the feasibility of facial laser scanning in pre-school children and to demonstrate landmark-independent three-dimensional (3D) analyses for assessment of facial deformity in 5-year-old children with repaired non-syndromic unilateral cleft lip and/or cleft palate (UCL/P). Faces of twelve 5-year-old children with UCL/P (recruited from university hospitals in Cardiff and Swansea, UK) and 35 age-matched healthy children (recruited from a primary school in Cardiff) were laser scanned. Cleft deformity was assessed by comparing individual faces against the age and gender-matched average face of healthy children. Facial asymmetry was quantified by comparing original faces with their mirror images. All facial scans had good quality. In a group of six children with isolated cleft palate coincidence with the average norm ranged from 18.8 to 26.4 per cent. There was no statistically significant difference in facial asymmetry when compared with healthy children (P > 0.05). In a group of six children with UCL with or without cleft palate coincidence with the average norm ranged from 14.8 to 29.8 per cent. Forehead, midface and mandibular deficiencies were a consistent finding, ranging from 4 to 10mm. The amount of 3D facial asymmetry was higher in this group (P < 0.05). Facial laser scanning can be a suitable method for 3D assessment of facial morphology in pre-school children, provided children are well prepared. Landmark-independent methods of 3D analyses can contribute to understanding and quantification of facial soft tissue cleft deformity and be useful in clinical practice. PMID- 23041936 TI - Craniofacial morphology of the frontonasal segment in patients with one or two macrodontic maxillary central incisors. AB - The purpose was to describe the craniofacial morphology of the frontonasal segment in patients with one or two macrodontic central incisors. Latero-lateral head radiographs from 21 patients were analyzed. Cephalometric analyses were performed with focus on the morphology of the frontonasal segment of the cranium, including nasal bone, maxilla, thickness of the frontal bone, sella turcica, and the anterior cranial fossa. The macrodontic incisors are located in this frontonasal segment. Increased values compared with normal were observed in the following: the length of the nasal bone (P = 0.038), the thickness of the frontal bone (P = 0.003), the length of the sella turcica (P = 0.006), the cranial base angle (P = 0.036), the length of the anterior cranial fossa (P = 0.002), and the height (P = 0.042) and length (P = 0.011) of the maxilla. The prognathia of the maxilla was significantly decreased (P = 0.003). The depth of the sella turcica and the inclination of the maxilla were normal. This study is a new example of how the morphology of the dentition and the underlying jaw (the frontonasal segment) are interrelated. It is also an example of how the maxillary incisors and jaws are interrelated with the anterior cranial base, including the sella turcica morphology. PMID- 23041939 TI - Recent advances in nutrient sensing and signaling. PMID- 23041938 TI - Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease. AB - OBJECTIVES: To identify non-major histocompatibility complex susceptible genes that might contribute to Behcet's disease (BD). METHODS: We performed a genome wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population (363 BD patients and 272 controls). To evaluate the functional implication of the target single nucleotide polymorphisms (SNP), gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated. RESULTS: We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36.1 (rs1608157, p=6.01*10(-8) in a minor allele dominant model; rs11769828, allele based p=1.60*10(-6)). A fine mapping study identified an association with four additional SNP: rs1522596 (OR=1.45, p=7.70*10(-6)) in GIMAP4; rs10266069 (OR=1.32, p=2.67*10(-4)) and rs10256482 (OR=1.27, p=5.27*10(-4)) in GIMAP2; and rs2286900 (OR=1.61, p=3.53*10(-5)) in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis. CONCLUSIONS: These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD. PMID- 23041940 TI - A cotton BURP domain protein interacts with alpha-expansin and their co expression promotes plant growth and fruit production. AB - Plant growth requires cell wall extension. The cotton AtRD22-Like 1 gene GhRDL1, predominately expressed in elongating fiber cells, encodes a BURP domain containing protein. Here, we show that GhRDL1 is localized in cell wall and interacts with GhEXPA1, an alpha-expansin functioning in wall loosening. Transgenic cotton overexpressing GhRDL1 showed an increase in fiber length and seed mass, and an enlargement of endopleura cells of ovules. Expression of either GhRDL1 or GhEXPA1 alone in Arabidopsis led to a substantial increase in seed size; interestingly, their co-expression resulted in the increased number of siliques, the nearly doubled seed mass, and the enhanced biomass production. Cotton plants overexpressing GhRDL1 and GhEXPA1 proteins produced strikingly more fruits (bolls), leading to up to 40% higher fiber yield per plant without adverse effects on fiber quality and vegetative growth. We demonstrate that engineering cell wall protein partners has a great potential in promoting plant growth and crop yield. PMID- 23041941 TI - Nucleus-encoded light-harvesting chlorophyll a/b proteins are imported normally into chlorophyll b-free chloroplasts of Arabidopsis. AB - Chloroplast-located proteins which are encoded by the nuclear genome have to be imported from the cytosol into the organelle in a posttranslational manner. Among these nuclear-encoded chloroplast proteins are the light-harvesting chlorophyll a/b-binding proteins (LHCPs). After translation in the cytosol, precursor proteins of LHCPs are imported via the TOC/TIC translocase, processed to their mature size to insert into thylakoid membranes where they recruit chlorophylls a and b to form pigment-protein complexes. The translocation of proteins is a highly regulated process which employs several regulators. To analyze whether CAO (chlorophyll a oxigenase) which converts chlorophyll a to chlorophyll b at the inner chloroplast membrane, is one of these regulators, we performed import reactions utilizing a homozygous loss-of-function mutant (cao-1). We imported in vitro translated and (35)S-labeled precursor proteins of light-harvesting proteins of photosystem II LHCB1, LHCB4, and LHCB5 into chloroplasts isolated from cao-1 and show that import of precursor proteins and their processing to mature forms are not impaired in the mutant. Therefore, regulation of the import machinery cannot be responsible for the decreased steady-state levels of light harvesting complex (LHC) proteins. Regulation does not take place at the transcriptional level either, because Lhcb mRNAs are not down-regulated. Additionally, reduced steady-state levels of LHCPs also do not occur due to posttranslational turnover of non-functional LHCPs in chloroplasts. Taken together, our data show that plants in the absence of CAO and therefore devoid of chlorophyll b are not influenced in their import behavior of LHC proteins. PMID- 23041942 TI - Angiopoietin 1 enhances the proliferation and differentiation of skeletal myoblasts. AB - Angiopoietin 1 (Ang1) plays an important role in various endothelial functions, such as vascular integrity and angiogenesis; however, less is known about its function outside of the endothelium. In this study, we examined whether Ang1 has direct effects on skeletal muscle cells. We found that Ang1 exhibited myogenic potential, as it promoted the proliferation, migration, and differentiation of mouse primary skeletal myoblasts. The positive effect of Ang1 on myoblast proliferation could have been mediated by the alpha7 and beta1 integrins. We also found that Ang1 potentiated cellular Ca(2+) movements in differentiated myotubes in response to stimuli, possibly through the increased expression of two Ca(2+) related proteins, namely, Orai1 and calmodulin. Ang1 also increased Orai1 and calmodulin expression in mouse hearts in vivo. These results provide an insight into the molecular mechanisms by which Ang1 directly affects the myogenesis of striated muscle. PMID- 23041943 TI - Multiple myeloma. PMID- 23041945 TI - APPA letter in response to "FMCSA's Medical Review Board: five years of progress in commercial driver medical examinations". PMID- 23041947 TI - How should a commercial driver medical examiner approach determining fitness for duty in a commercial motor vehicle operator with a body mass index >=33 kg/m2? PMID- 23041951 TI - Distant protonated pyridine groups in water-soluble iron porphyrin electrocatalysts promote selective oxygen reduction to water. AB - Fe(III)-meso-tetra(pyridyl)porphyrins are electrocatalysts for the reduction of dioxygen in aqueous acidic solution. The 2-pyridyl derivatives, both the triflate and chloride salts, are more selective for the desired 4e(-) reduction than the isomeric 4-pyridyl complexes. The inward-pointing pyridinium groups influence proton delivery despite their distance from the iron centre. PMID- 23041952 TI - Rapid determination of entropy and free energy of mixtures from molecular dynamics simulations with the two-phase thermodynamic model. AB - The two-phase thermodynamic (2PT) model is generalized to determine the thermodynamic properties of mixtures. In this method, the vibrational density of states (DoS), obtained from the Fourier transform of the velocity autocorrelation function, and quantum statistics are combined to determine the entropy and free energy from the trajectory of a molecular dynamics simulation. In particular, the calculated DoS is decomposed into a solid-like and a gas-like component through the fluidicity parameter, allowing for treatments for the anharmonic effects in fluids. The 2PT method has been shown to provide reliable thermodynamic properties of pure substances over the whole phase diagram with only about a 20 ps MD trajectory. Here we show how the 2PT method can be used for mixtures with the same degree of accuracy and efficiency. We have examined the 2PT determined excess Gibbs free energies of Lennard-Jones (LJ) mixtures over a wide range of conditions (1 <= T* <= 3, 0.5 <= P* <= 2.5, 1 <= sigma(BB)/sigma(AA) <= 2, and 1 <= epsilon(BB)/epsilon(AA) <= 2), including the change of the off-diagonal LJ interactions. The 2PT determined values are in good agreement with those from Widom insertion or thermodynamic integration (TI). Our results suggest that the 2PT method can be a powerful method for understanding thermodynamic properties in more complicated multicomponent systems. PMID- 23041950 TI - Dietary resveratrol does not delay engraftment, sensitize to vincristine or inhibit growth of high-risk acute lymphoblastic leukemia cells in NOD/SCID mice. AB - Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is a high-risk leukemia found in 60-85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse. To evaluate the efficacy of dietary resveratrol in vivo, 5-week-old NOD.CB17-Prkdcscid/J mice were fed a control diet or a diet containing 0.2% w/w resveratrol. After 3 weeks of dietary treatment, mice were engrafted with the human t(4;11) ALL line SEM by tail vein injection. Engraftment was monitored by evaluating the presence of human CD19+ cells in peripheral blood using flow cytometry. Relative to control diet, dietary resveratrol did not delay the engraftment of the leukemia cells. To determine if dietary resveratrol could increase efficacy of a chemotherapeutic agent, vincristine was injected intraperitoneally into leukemic mice fed the control or supplemented diet. Survival curves and monitoring the percentage of human leukemia cells in peripheral blood showed that resveratrol did not inhibit leukemia cell growth or influence the activity of vincristine. Mass spectrometric analysis of mouse serum revealed that the majority of resveratrol was present as glucuronidated and sulfated metabolites. These data do not support the concept that dietary resveratrol has potential as a preventative agent against the growth of high-risk t(4;11) ALL. PMID- 23041953 TI - Synthesis of hollow polymeric nanoparticles for protein delivery via inverse miniemulsion periphery RAFT polymerization. AB - Hollow polymeric nanoparticles with a hydrophilic liquid core have been synthesized in a one-pot approach via a novel inverse miniemulsion periphery RAFT polymerization process. Successful encapsulation and release of a model protein is reported as a potential application. PMID- 23041954 TI - Critical point of a para-ferrimagnetic phase transition of the ANNNI model in a field. AB - The finite field para-ferrimagnetic phase transition in the axial next-nearest neighbor Ising (ANNNI) model is studied by using the linear perturbation real space renormalization group transformation. The method is examined in systems of ferromagnetic and antiferromagnetic Ising chains coupled by ferromagnetic interactions in the longitudinal field. As one would expect, the external field in the first case destroys the continuous phase transition and in the second shifts the critical point toward a lower temperature according to the square law. For the ferromagnetic chains coupled by the competing interchain nearest-neighbor J(1) < 0 and next-nearest-neighbor J(2) < 0 interactions, the external field changes the character of the phase transition from continuous to discontinuous. However, it has been found that for the ratio J(2)/J(1) around 0.5 there is a critical value of the field for which an isolated critical point exists. The temperature dependences of the specific heat for several values of J(2)/J(1) and the external field are presented. PMID- 23041956 TI - Prime time for molecular marker diagnostics in neuro-oncology. PMID- 23041955 TI - Paraneoplastic neurological syndromes. AB - PURPOSE OF REVIEW: This review describes relevant advances in paraneoplastic neurological syndromes (PNS) with emphasis on particular syndromes and the impact of antibodies against surface antigens in their management. RECENT FINDINGS: PNS may present with symptoms that do not raise the suspicion of a paraneoplastic origin. The best example is anti-N-methyl-D-aspartate receptor encephalitis that in adult women frequently associates with ovarian teratoma. An electroencephalogram pattern described as 'extreme delta brush' was recently identified in 30% of patients with this disorder. Isolated myelopathy may have a paraneoplastic origin associated with amphiphysin or CV2 (CRMP5) antibodies. Jaw dystonia and laryngospasm can be the predominant symptom of the brainstem encephalitis associated with Ri antibodies. gamma-Aminobutyric acid (GABA)(B) receptor antibodies are the most common antibodies found in patients with limbic encephalitis and small cell lung cancer, and contactin-associated protein 2 antibodies in patients with Morvan's syndrome and thymoma. Lastly, a recent study identified delta/notch-like epidermal growth factor-related receptor (DNER) as the target antigen of Tr antibodies, a marker of cerebellar ataxia and Hodgkin's lymphoma. SUMMARY: The number of antibodies relevant to PNS is now expanded to those against surface antigens. These antibodies do not confirm the paraneoplastic origin of the syndrome but predict a better response to immunotherapy. PMID- 23041957 TI - How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other? AB - PURPOSE OF REVIEW: This review examines the recent research developments aimed at defining the role of RNA-binding proteins (TDP-43 and FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RECENT FINDINGS: TAR DNA-binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) are RNA binding proteins that form aggregates in ALS and FTLD, and when mutated can drive the pathogenesis of these disorders. However, fundamental questions remain as to the relationship between TDP-43 and FUS aggregation and disease, their normal and pathologic function, and where they converge on the same cellular pathways. Autopsy series point to distinct molecular actions as TDP-43 and FUS neuronal inclusions do not overlap, with FUS inclusions being present in only a small subgroup of patients. By contrast, modeling experiments in lower organisms support a genetic interaction between TDP-43 and FUS, although it is likely indirect. Regardless, the recent finding that additional RNA-binding proteins may also cause ALS, and the observation that TDP-43 aggregation remains a core feature in all of the recently identified genetic forms of ALS (C9ORF72, VCP, UBQLN2, and PFN1), underscores the central role of TDP-43 and RNA metabolism in ALS and FTLD. SUMMARY: Recent discoveries point to an unprecedented convergence of molecular pathways in ALS and FTLD involving RNA metabolism. Defining the exact points of convergence will likely be key to advancing therapeutics development in the coming years. PMID- 23041959 TI - Facilitating implementation of the translational research pipeline in neurological rehabilitation. AB - PURPOSE OF REVIEW: Knowledge translation is a growing area of specialisation. This review summarises the field perspectives and highlights recent work that has particular relevance to neurological rehabilitation. RECENT FINDINGS: Research in knowledge translation can usefully be organised into three overlapping perspectives, namely a linear transfer of codified knowledge, a social interaction perspective, or a multilevel implementation perspective that incorporates contextual factors. Although systematic reviews remain foundational in supporting knowledge translation, they often lack structured updating and can be problematic to implement in complex cases. Knowledge brokers play an important role in evidence use; these may be managers or administrators of rehabilitation services. Organisational support that sustains and structures knowledge brokering roles has been found lacking. Numerous contextual factors influence knowledge translation, including leadership, fidelity monitoring, and divergent stakeholder perspectives. Integrative frameworks have been developed that consolidate the multiple contingencies. SUMMARY: Knowledge translation is a complex process with an incomplete knowledge base; its uniprofessional focus is particularly limiting for neurological rehabilitation. Developing accessible systematic reviews remains central, as well as supporting knowledge brokers, being aware of stakeholder absorptive capacity in developing translational strategies and using integrative frameworks to guide knowledge translation for complex interventions. PMID- 23041958 TI - Origins of Alzheimer's disease: reconciling cerebrospinal fluid biomarker and neuropathology data regarding the temporal sequence of amyloid-beta and tau involvement. AB - PURPOSE OF REVIEW: This review aims to address the temporal sequencing of involvement of amyloid-beta (Abeta) and tau in the pathogenesis of Alzheimer's disease and reconcile apparently conflicting neuropathologic and biomarker data. RECENT FINDINGS: Although neuropathologic studies show that limbic system tau disease occurs ubiquitously in middle-aged individuals before the appearance of amyloid plaques, biomarker studies in living individuals suggest that Abeta disease is the initiating event in Alzheimer's disease and precedes cerebrospinal fluid tau changes. Evidence from neuropathologic, biomarker, genetic and cellular/mouse studies shows that tau accumulation in limbic regions occurs slowly with age and does not induce widespread neurodegeneration, but that Abeta interacts with tau in some way to accelerate neurofibrillary disease and induce neurodegeneration. SUMMARY: Abeta aggregation is the key initial trigger of Alzheimer's disease pathologic changes and interacts with tau to exacerbate age related tauopathy and induce neurodegeneration. PMID- 23041960 TI - Effects of exercise intensity on flow mediated dilation in healthy humans. AB - Previous studies have demonstrated conflicting results on the effects of acute exercise on FMD. The aim of the study was to examine brachial artery FMD before and after 3 bouts of acute exercise performed at different intensities. 10 healthy males (mean+/-SD age: 22+/-1 years) completed 30 min of cycling at 50, 70 and 85% maximal heart rate (HRmax). Brachial artery FMD and the shear rate area under-the-curve (cuff deflation to peak dilation; SRAUC) were assessed pre- and immediately post-exercise using high-resolution echo-Doppler. A generalized estimating equation (GEE) analysis was used to estimate the effect magnitudes of exercise intensity and time (pre/post) on FMD, whilst controlling for the influence of baseline diameter and SRAUC. Both baseline diameter and SRAUC were elevated by exercise. With covariate-control of these variables, the decrease in brachial artery FMD was negligible after exercise at 50% HRmax (6.3+/-2.6 vs. 5.9+/-2.5%; 95%CI for difference: - 0.59-1.34%) with larger decreases in FMD after exercise at 70% (6.1+/-1.8 vs. 4.7+/-1.9%; 95%CI for difference: 0.08 2.58%) and at 85% HRmax (6.6+/-1.6 vs. 3.6+/-2.2%; 95%CI: 0.41-5.42%). In conclusion, even after accounting for exercise-mediated changes in shear and baseline diameter, our data indicate that a negative relationship exists between exercise intensity and FMD. PMID- 23041961 TI - Low-intensity resistance training after high-intensity resistance training can prevent the increase of central arterial stiffness. AB - Although high-intensity resistance training increases arterial stiffness, low intensity resistance training reduces arterial stiffness. The present study investigates the effect of low-intensity resistance training before and after high-intensity resistance training on arterial stiffness. 30 young healthy subjects were randomly assigned to a group that performed low-intensity resistance training before high-intensity resistance training (BLRT, n=10), a group that performed low-intensity resistance training after high-intensity resistance training (ALRT, n=10) and a sedentary control group (n=10). The BLRT and ALRT groups performed resistance training at 80% and 50% of one repetition maximum twice each week for 10 wk. Arterial stiffness was measured using carotid femoral and femoral-ankle pulse wave velocity (PWV). One-repetition maximum strength in the both ALRT and BLRT significantly increased after the intervention (P<0.05 to P<0.01). Both carotid-femoral PWV and femoral-ankle PWV after combined training in the ALRT group did not change from before training. In contrast, carotid-femoral PWV after combined training in the BLRT group increased from before training (P <0.05). Femoral-ankle PWV after combined training in the both BLRT and ALRT groups did not change from before training. These results suggest that although arterial stiffness is increased by low-intensity resistance training before high-intensity resistance training, performing low-intensity resistance training thereafter can prevent the increase of arterial stiffness. PMID- 23041962 TI - Is the new AquaTrainer(r) snorkel valid for VO2 assessment in swimming? AB - The Cosmed AquaTrainer(r) snorkel, in connection with the K4b2 analyzer, is the most recent instrument used for real time gas analysis during swimming. This study aimed to test if a new AquaTrainer(r) snorkel with 2 (SV2) or 4 (SV4) valves is comparable to a standard face mask (Mask) being valid for real time gas analysis under controlled laboratory and swimming pool conditions. 9 swimmers performed 2 swimming and 3 cycling tests at 3 different workloads on separate days. Tests were performed in random order, at constant exercise load with direct turbine temperature measurements, breathing with Mask, SV4 and SV2 while cycling, and with SV2 and SV4 while swimming. A high agreement was obtained using Passing Bablok regression analysis in oxygen consumption, carbon dioxide production, tidal volumes, pulmonary ventilation, expiratory fraction of oxygen and carbon dioxide, and heart rate comparing different conditions in swimming and cycling. Proportional and fixed differences were always rejected (95% CI always contained the value 1 for the slope and the 0 for the intercept). In conclusion, the new SV2 AquaTrainer(r) snorkel, can be considered a valid device for gas analysis, being comparable to the Mask and the SV4 in cycling, and to the SV4 in swimming. PMID- 23041963 TI - Exercise intensity and lymphocyte subset apoptosis. AB - This investigation assessed the lymphocyte subset response to increasing intensity. Participants completed an exertion test (VO(2max)), and later performed a 10-min run at 76% VO(2max), 5-min at 87%, and run to exhaustion at 100% intensity. Blood was sampled at rest, following each intensity, and 1-h post. Cell concentration, apoptosis (annexin V) and migration (CX3CR1) were evaluated in CD4+, CD8+, and CD19+ subsets. Relative data were analyzed using 1 way ANOVA with significance at P<=0.05. Absolute changes from rest (Delta baseline) were calculated for exercise conditions. CX3CR1 displayed relative changes 1-h post, (CD8+ Pre=58%, Post=68%, 1 h-Post=37%, P=0.04) (CD19+ Pre=1.9%, Post=3.2%, 1 h-Post=5.2%, P=0.02). No relative changes were noted for subsets and annexin V. Absolute changes revealed that CD4+/annexin V+ and CD8+/annexin V+ significantly increased at 76%,(P<0.01). Significant absolute increases were observed in CD4+/CX3CR1 at 87% VO2max, and at 87% and 100% VO2max in CD8+/CX3CR1 (P<0.01). Subsets respond differently with intensity with respect to cell count, and markers of apoptosis and cell migration. CD4+ and CD8+ appear to be prone to apoptosis with moderate exercise, but significant increases in migration at higher intensities suggests movement of these cells from the vasculature in postexercise measurements. PMID- 23041964 TI - Resistance exercise enhances cognitive function in mouse. AB - Physical exercise has been shown to increase adult neurogenesis in the hippocampus and to enhance synaptic plasticity. It has been demonstrated that these neuroprotective effects can be observed following aerobic exercise. However, it remains unknown whether plasticity molecules, such as brain-derived neurotrophic factor (BDNF) and cyclic AMP response element-binding protein (CREB), are expressed in the hippocampus following resistance exercise. We applied voluntary progressive-resistance wheel exercise (RE) for 14 days, and measured BDNF and CREB in the hippocampus. The Morris water maze was also performed to estimate learning and memory. Furthermore, we measured RE effects on mammalian target of rapamycin (mTOR) and 70-kDa ribosomal protein S6 kinase (p70S6K) mediating muscle protein synthesis in the soleus. As a result, we found that RE enhanced cognition and elevated BDNF and CREB expressions in the hippocampus. Also, RE activated the mTOR-p70S6K signaling pathway in the soleus. We found that phosphorylated mTOR and p70S6K were significantly positively correlated with BDNF expression. Our results indicated that resistance exercise drove the protein synthesis signaling pathway in the soleus and enhanced hippocampal synaptic plasticity-related molecules. These results suggest the beneficial effects of resistance exercise on cognitive function. PMID- 23041965 TI - Selective effects of weight and inertia on maximum lifting. AB - A novel loading method (loading ranged from 20% to 80% of 1RM) was applied to explore the selective effects of externally added simulated weight (exerted by stretched rubber bands pulling downward), weight+inertia (external weights added), and inertia (covariation of the weights and the rubber bands pulling upward) on maximum bench press throws. 14 skilled participants revealed a load associated decrease in peak velocity that was the least associated with an increase in weight (42%) and the most associated with weight+inertia (66%). However, the peak lifting force increased markedly with an increase in both weight (151%) and weight+inertia (160%), but not with inertia (13%). As a consequence, the peak power output increased most with weight (59%), weight+inertia revealed a maximum at intermediate loads (23%), while inertia was associated with a gradual decrease in the peak power output (42%). The obtained findings could be of importance for our understanding of mechanical properties of human muscular system when acting against different types of external resistance. Regarding the possible application in standard athletic training and rehabilitation procedures, the results speak in favor of applying extended elastic bands which provide higher movement velocity and muscle power output than the usually applied weights. PMID- 23041966 TI - Exercise intensity and gender difference of 3 different salsa dancing conditions. AB - The aims of this study were to estimate the difference in exercise intensity (METs), energy cost (EE) and gender difference between a typical salsa lesson (TSL), rueda de casino lesson (RCL), and salsa dancing at a night club (SDN). Subjects performed 1 pre-testing session and 3 testing conditions. During the pre testing session height, weight and VO2max were assessed. During the testing conditions all subjects performed 3 different kinds of salsa dance. Heart rate was assessed during each dance condition. The exercise intensity of the 3 salsa dancing conditions was moderate ranging from 3.9 to 5.5 METs. A significant difference between genders for HRpeak (P=0.01), max%HRR (P=0.006) and mean EE (P=0.02) were observed. Significant gender*condition interactions for HRpeak (P=0.03), mean %HRR (P=0.02), mean METs (P=0.02) and mean EE (P=0.02) were found. In addition, a significant main effect for each condition was found in all variables (P<0.01). Our results showed that the exercise intensities of all 3 salsa dancing conditions were moderate. Findings showed some significant differences in exercise intensity between males and females and within conditions. Salsa dancing could be useful in achieving a significant training effect in people who have a low level of fitness. PMID- 23041967 TI - Atrial fibrillation in athletes. AB - Many studies have shown a relationship between long-term endurance sport practice and atrial fibrillation. Inflammation, anatomic remodelling, alterations in the autonomic system and neurohormonal activation are all possible explanations for the increased prevalence of this arrhythmia in athletes. Atrial fibrillation may determine disabling symptoms like palpitations and impaired physical performance, compromising eligibility for competitive activities, but exclusion from sport is not necessary for all athletes. Limited data are available on drug therapy and recently ablation resulted to be a particularly attractive option for young athletes with paroxysmal atrial fibrillation. The purpose of this review is to discuss mechanisms, clinical features, management of atrial fibrillation in competitive athletes, including criteria for eligibility and disqualification in sport practice. PMID- 23041968 TI - Is the deleterious effect of cryotherapy on proprioception mitigated by exercise? AB - This study aimed to examine the acute effects of cryotherapy on knee position sense and to determine the time period necessary to normalize joint position sense when exercising after cryotherapy. 12 subjects visited the laboratory twice, once for cryotherapy followed by 30 min of exercise on a cycloergometer and once for cryotherapy followed by 30 min of rest. Sessions were randomly determined and separated by 48 h. Cryotherapy was applied in the form of ice bag, filled with 1 kg of crushed ice, for 20 min. Knee position sense was measured at baseline, after cryotherapy and every 5 min after cryotherapy removal until a total of 30 min. The main effect of cryotherapy was significant showing an increase in absolute (F7,154=43.76, p<0.001) and relative (F7,154=7.97, p<0.001) errors after cryotherapy. The intervention after cryotherapy (rest vs. exercise) revealed a significant main effect only for absolute error (F7,154=4.05, p<0.001), i.e., when subjects exercised after cryotherapy, the proprioceptive acuity reached the baseline values faster (10 min vs. 15 min). Our results indicated that the deleterious effect of cryotherapy on proprioception is mitigated by low intensity exercise, being the time necessary to normalize knee position sense reduced from 15 to 10 min. PMID- 23041969 TI - Effect of cationic side-chains on intracellular delivery and cytotoxicity of pH sensitive polymer-doxorubicin nanocarriers. AB - Fine-tuning the design of polymer-doxorubicin conjugates permits optimization of an efficient nanocarrier to greatly increase intracellular uptake and cytotoxicity. Here, we report synthesis of a family of self-assembled polymer doxorubicin nanoparticles and an evaluation of the effects of various types of side-chains on intracellular uptake and cytotoxicity of the nanocarriers for lymphoma cells. Monomers with three different cationic side-chains (CA) and pK(a)'s, i.e., a guanidinium group (Ag), an imidazole group (Im), and a tertiary amine group (Dm), were comparatively investigated. The cationic monomer, poly(ethylene glycol) (PEG), and doxorubicin (Dox) were reacted with 1,4 (butanediol) diacrylate (BUDA) to prepare a poly(beta-amino ester) (PBAE) polymer via Michael addition. All three polymer-Dox conjugates spontaneously formed nanoparticles (NP) through hydrophobic interactions between doxorubicin in aqueous solution, resulting in NP-Im/Dox, NP-Ag/Dox, and NP-Dm/Dox, with hydrodynamic sizes below 80 nm. Doxorubicin was linked to all 3 types of NPs with a hydrazone bond to assure selective release of doxorubicin only at acidic pH, as it occurs in the tumor microenvironment. Both NP-Im/Dox and NP-Ag/Dox exhibited much higher intracellular uptake by Ramos cells (Burkitt's lymphoma) than NP Dm/Dox, suggesting that the type of side chain in the NPs determines the extent of intracellular uptake. As a result, NP-Im/Dox and NP-Ag/Dox showed cytotoxicity that was comparable to free Dox in vitro. Our findings suggest that the nature of surface cationic group on nanocarriers may profoundly influence their intracellular trafficking and resulting therapeutic efficacy. Thus, it is a crucial factor to be considered in the design of novel carriers for intracellular drug delivery. PMID- 23041971 TI - Aire mediates thymic expression and tolerance of pancreatic antigens via an unconventional transcriptional mechanism. AB - The autoimmune regulator (Aire), mediates central tolerance of peripheral self. Its activity in thymic epithelial cells (TECs) directs the ectopic expression of thousands of tissue-restricted antigens (TRAs), causing the deletion of autoreactive thymocytes. The molecular mechanisms orchestrating the breadth of transcriptional regulation by Aire remain unknown. One prominent model capable of explaining both the uniquely high number of Aire-dependent targets and their specificity posits that tissue-specific transcription factors induced by Aire directly activate their canonical targets, exponentially adding to the total number of Aire-dependent TRAs. To test this "Hierarchical Transcription" model, we analysed mice deficient in the pancreatic master transcription factor pancreatic and duodenal homeobox 1 (Pdx1), specifically in TECs (Pdx1(DeltaFoxn1) ), for the expression and tolerance of pancreatic TRAs. Surprisingly, we found that lack of Pdx1 in TECs did not reduce the transcription of insulin or somatostatin, or alter glucagon expression. Moreover, in a model of thymic deletion driven by a neo-TRA under the control of the insulin promoter, Pdx1 in TECs was not required to affect thymocyte deletion or the generation of regulatory T (Treg) cells. These findings suggest that the capacity of Aire to regulate expression of a huge array of TRAs relies solely on an unconventional transcriptional mechanism, without intermediary transcription factors. PMID- 23041972 TI - Hypoiodous acid initiated rearrangement of tertiary propargylic alcohols to alpha iodoenones. AB - In the presence of an oxidant, sodium iodide is converted into hypoiodous acid which effects the rearrangement of tertiary propargylic alcohols to alpha iodoenones in good yields. PMID- 23041973 TI - Domain wall manipulation in magnetic nanotubes induced by electric current pulses. AB - We propose that the injection of electric currents can be used to independently manipulate the position and chirality of vortex-like domain walls in metallic ferromagnetic nanotubes. We support this proposal upon theoretical and numerical assessment of the magnetization dynamics driven by such currents. We show that proper interplay between the tube geometry, magnitude of the electric current and the duration of a current pulse, can be used to manipulate the position, velocity and chirality of a vortex domain wall. Our calculations suggest that domain wall velocities greater than 1 km s(-1) can be achieved for tube diameters of the order of 30 nm and increasing with it. We also find that the transition from steady to precessional domain wall motion occurs for very high electric current densities, of the order of 10(13) A m(-2). Furthermore, the great stability displayed by such chiral magnetic configurations, and the reduced Ohmic loses provided by the current pulses, lead to highly reproducible and efficient domain wall reversal mechanisms. PMID- 23041975 TI - Structure and stability of cyclic peptide based nanotubes: a molecular dynamics study of the influence of amino acid composition. AB - The stability of self-assembling cyclic peptides (CPs) is attained by the intermolecular backbone-backbone hydrogen bonding (H-bonding) interactions. In addition to these H-bonding interactions, the self-assembled CPs are further stabilized by various intermolecular side chain-side chain interactions. This study investigates the role of amino acids on the structure and stability of self assembled CPs using classical molecular dynamics (MD) simulations and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The amino acids considered for the construction of model structures of cyclic peptide nanotubes (CPNTs) are Ala, Leu, Phe, Gln, Glu, and Trp. The calculated structural parameters from classical MD simulations reveal that the backbone flexibility of CPNTs composed of non-Ala residues results from an intrinsic property of the amino acids. The presence of an Ala residue at the alternate position increases the solvation of side chains of Gln residue. The occurrence of Glu residue does not favour the formation of intermolecular side chain-side chain H-bonding interactions in aqueous medium. It is evident from the calculated free energy of binding that CPNTs composed of non-polar residues are highly stable in aqueous medium. At the same time, CPNTs with polar side chains are less stable in aqueous medium. Results obtained from this study demonstrate the role played by amino acid side chains on the structure and stability of CPNTs and provide valuable suggestions for the design of CPNTs with moderate stability in various solvent environments. PMID- 23041974 TI - Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. AB - Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-kappaB activation. Importantly, increasing the level of SIRT6 or targeting the anti-apoptotic activity of survivin at the initiation stage markedly impairs cancer development. Moreover, in human dysplastic liver nodules, but not in malignant tumours, a specific expression pattern with increased c-Jun-survivin and attenuated c-Fos-SIRT6 levels was identified. These results reveal a regulatory network connecting stress response and histone modification in liver tumour initiation, which could be targeted to prevent liver tumorigenesis. PMID- 23041976 TI - Poor health but not absent: prevalence, predictors, and outcomes of presenteeism. AB - OBJECTIVE: The objective of this study was to examine the prevalence of presenteeism, to develop and test a model of the relationship between workplace factors and presenteeism, and to assess the perceived influence of manager, coworkers, and self on presenteeism. METHODS: We used survey data collected for 6309 employees from seven different organizations. RESULTS: Nearly 60% of the sample reported presenteeism during a 3-month period. The model was supported, with presenteeism linking workplace factors and health outcomes to productivity, as predicted. The majority of participants (67%) indicated that the primary pressure to attend work while sick came from themselves. A substantial minority (20%) also indicated the manager as a source of pressure. CONCLUSIONS: Psychosocial workplace factors are predictive of presenteeism, and efforts to control them, including the use of more effective management, may impact presenteeism rates and the resulting levels of productivity. PMID- 23041977 TI - A small business worksite wellness model for improving health behaviors. AB - OBJECTIVES: To evaluate the effectiveness of a wellness program delivered by WellSteps, LLC, aimed at improving employee health behaviors in small companies that lack the resources to independently develop and manage a wellness program. METHODS: Analyses are based on 618 employees from five diverse companies that completed an initial personal health assessment. RESULTS: Exercise and dietary behaviors significantly improved across the five companies. Significant improvements in health perception and life satisfaction also resulted and were associated with improvements in health behaviors. Three of the five companies, each with fewer than 50 employees, were most effective in influencing positive health behaviors, health perceptions, and life satisfaction. CONCLUSIONS: The worksite wellness program effectively improved health behaviors, health perceptions, and life satisfaction. PMID- 23041978 TI - Effects of 12-O-tetradecanoylphorbol-13-acetate in combination with gemcitabine on Panc-1 pancreatic cancer cells cultured in vitro or Panc-1 tumors grown in immunodeficient mice. AB - In the present study, the effects of 12-O-tetra-decanoylphorbol-13-acetate (TPA) alone or in combination with gemcitabine on the growth of Panc-1 pancreatic cancer cells cultured in vitro or grown in NCr immunodeficient nude mice were investigated. Combinations of TPA and gemcitabine synergi-stically inhibited the growth and induced apoptosis in Panc-1 cells. The combination of TPA (0.16 nM) and gemcitabine (0.5 uM) induced a marked increase in phosphorylated c-Jun NH2 terminal kinase (JNK) in the Panc-1 cells. In animal experiments, NCr nude mice with established Panc-1 tumors received daily intraperitoneal (i.p.) injections of TPA (50 ng/g body weight/day) or gemcitabine (0.5 ug/g body weight/day) alone or in combination for 26 days. Treatment with daily i.p. injections of low doses of TPA or gemcitabine alone had a modest inhibitory effect on the growth of the tumors. However, the combination of low doses of TPA and gemcitabine more potently inhibited the growth of Panc-1 tumors than either agent used individually. Treatment with TPA or gemcitabine alone or in combination did not affect the body weight of the animals. Clinical trials with TPA alone or in combination with gemcitabine on patients with pancreatic cancer are warranted in order to confirm our results. PMID- 23041979 TI - Caveolae regulate Smad signaling as verified by novel imaging and system biology approaches. AB - The contribution of caveolae in Bone Morphogenetic Protein 2 (BMP2) activated Smad signaling was quantified using a system biology approach. BMP2 plays crucial roles during processes such as hematopoiesis, embryogenesis, and skeletal development. BMP2 signaling is tightly regulated on the plasma membrane by its receptors. The localization of BMP receptors in caveolae and endocytosis through clathrin-coated pits are thought to regulate the signaling; however the conclusions in the current literature are inconsistent. Therefore published literature was used to establish a mathematical model that was validated using confocal AFM (atomic force microscopy), confocal microscopy, and sucrose density centrifugation followed by Western blots, and reporter gene assays. The model and experiments confirmed that both caveolae and CCPs regulate the Smad-dependent signaling pathway, however caveolae are centers at the plasma membrane where receptor-ligand interaction is crucial, Smad phosphorylation occurs, and a high degree of Smad signaling is regulated. This demonstrates a role for caveolae that needs to be considered and further studied. PMID- 23041980 TI - Venous and arterial thromboembolic complications associated with HIV infection and highly active antiretroviral therapy. AB - With the advent of highly active antiretroviral therapy (HAART), dramatic improvements have been made in the quality and length of life in people living with HIV/AIDS (PLWA). Complications that are seen with increasing frequency in this group include venous thromboembolism events (VTE) and cardiovascular disease. Recent epidemiologic studies suggest PLWA have a 2-fold to 10-fold greater risk of VTE compared with age-matched controls. Several mechanisms associated with HIV infection, coupled with traditional risk factors, including age, opportunistic infections, and lifestyle choices, may contribute to a heightened risk of VTE and cardiovascular disease. It has been challenging to discern which of these complications are related to HAART. Herein, we review the risk of VTE in the pre-HAART and current HAART era. We call attention to particular instances where components of HAART have been associated with acute myocardial infarction, noncirrhotic portal hypertension and portal vein thrombosis. We also highlight potential drug-drug interactions between HAART and anticoagulant therapy. Additional studies are needed to better understand the mechanisms and risks associated with long-term use of HAART and to what extent HAART contributes to or mitigates the risk of VTE and cardiovascular disease. PMID- 23041982 TI - D-dimer assays in diagnosis and management of thrombotic and bleeding disorders. AB - D-dimer is a global indicator of coagulation activation and fibrinolysis and, therefore, an indirect marker of thrombotic activity. The utility of D-dimer measurement has been evaluated in several clinical situations including the exclusion of venous thromboembolism (VTE), prediction of future risk of VTE, and the diagnosis and monitoring of disseminated intravascular coagulation (DIC). Assay standardization remains problematic and clinicians need to be aware of variability in D-dimer assay performance and the characteristics of their institution's test when making clinical decisions. This article will review the available evidence for the utilization of D-dimer antigen measurement in the management of thrombotic and bleeding disorders. PMID- 23041983 TI - Cocaine-levamisole thrombotic vasculopathy. AB - The syndrome of cocaine-levamisole thrombotic vasculopathy is a tetrad of cutaneous manifestations, arthralgia, leukopenia, and positive antineutrophil cytoplasmic antigen (ANCA). Cocaine is cut with levamisole to potentiate its euphoric effects. However, along with this are the adverse reactions of levamisole such as fatal agranulocytosis, flu-like symptoms, and cutaneous thrombotic vasculopathy. High index of suspicion is needed for its diagnosis. This article will review on its toxicities, especially its prothrombotic effects. PMID- 23041984 TI - Median nerve ultrasound as a screening tool in carpal tunnel syndrome: correlation of cross-sectional area measures with electrodiagnostic abnormality. AB - INTRODUCTION: Sonographically measured median nerve cross-sectional area (CSA) at the wrist is increased in patients with carpal tunnel syndrome (CTS). Ultrasound of the median nerve may be useful in screening for electrodiagnostic (EDx) abnormalities. METHODS: EDx studies were performed on all participants. Sonographic evaluation of median nerve CSA at the wrist and in the forearm was performed by a physician blinded to the EDx results. Multivariate and receiver operating characteristic (ROC) analysis were used to assess the data. RESULTS: Fifty control wrists and 192 symptomatic wrists were analyzed. Sensitivity of ultrasound in excluding EDx abnormality was 99% for CSA of 9 mm(2) and 97% for a wrist-forearm ratio (WFR) of 1.4. There was no clinically significant correlation between ultrasound parameters and EDx severity. CONCLUSIONS: Median nerve ultrasound is a highly sensitive screening tool for EDx abnormality, but it cannot determine severity. This may lead to changes in the current standards for evaluating CTS. PMID- 23041985 TI - Adiabatic RF pulse design for Bloch-Siegert B1+ mapping. AB - The Bloch-Siegert (B-S) B1+ mapping method has been shown to be fast and accurate, yet it suffers from high Specific Absorption Rate (SAR) and moderately long echo time. An adiabatic RF pulse design is introduced here for optimizing the off-resonant B-S RF pulse to achieve more B-S B1+ measurement sensitivity for a given pulse width. The extra sensitivity can be used for higher angle-to-noise ratio B1+ maps or traded off for faster scans. Using numerical simulations and phantom experiments, it is shown that a numerically optimized 2-ms adiabatic B-S pulse is 2.5 times more efficient than a conventional 6-ms Fermi-shaped B-S pulse. The adiabatic B-S pulse performance is validated in a phantom, and in vivo brain B1+ mapping at 3T and 7T are shown. PMID- 23041981 TI - Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. AB - The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in African and Asian populations are concordant with those in individuals of European ancestry; however, frequency distribution of allelic variants can vary considerably between major populations. Future randomized controlled trials in multiethnic settings using population-specific dosing algorithms will allow us to further ascertain the generalizability and cost effectiveness of pharmacogenetics-guided warfarin therapy. Additional genome-wide association studies may help us to improve and refine dosing algorithms and potentially identify novel biological pathways. PMID- 23041986 TI - Quantitative neuromuscular ultrasound in the intensive care unit. AB - INTRODUCTION: Intensive care unit acquired weakness (ICU-AW) results from a complex mixture of nerve and muscle pathology, and early identification is challenging. This pilot study was designed to examine the ultrasonographic changes that occur in muscles during ICU hospitalization. METHODS: Patients admitted to the ICU for acute respiratory failure were enrolled prospectively and underwent serial muscle ultrasound for thickness and gray-scale assessment of the tibialis anterior, rectus femoris, abductor digiti minimi, biceps, and diaphragm muscles over 14 days. RESULTS: Sixteen participants were enrolled. The tibialis anterior (P = 0.001) and rectus femoris (P = 0.041) had significant decreases in gray-scale standard deviation when analyzed over 14 days. No muscles showed significant changes in thickness. CONCLUSIONS: Ultrasound is an informative technique for assessing muscles of patients in the ICU, and lower extremity muscles demonstrated increased homogeneity during ICU stays. This technique should be examined further for diagnosing and tracking those with ICU-AW. PMID- 23041987 TI - Intraoral foreign bodies detected 40 years after a car accident using cone beam computed tomography. AB - Foreign bodies are common findings in the maxillofacial region, most commonly the result of accidents and physical aggression. Among the objects frequently found in the orofacial tissues are fragments of metal, plastic, wood, and glass. Visualization and exact identification of the location of these objects can be challenging but is of major importance prior to surgical removal. The present case report describes the use of cone beam computed tomography to locate, visualize, and surgically remove glass particles in the oral cavity. PMID- 23041988 TI - Lateral lower lip piercing--prevalence of associated oral complications: a split mouth cross-sectional study. AB - OBJECTIVE: To investigate via a split-mouth cross-sectional study the prevalence of gingival recessions associated with lateral lower lip piercing in a population obtained from a nondental setting. METHOD AND MATERIALS: A split-mouth study was performed in a sample of 47 patients with one lateral lower lip piercing. Teeth in direct contact with the intraoral closure of the stud were defined as test teeth; contralateral teeth were selected as controls. Clinical examination included full-mouth plaque and bleeding indices, probing depth, recession, clinical attachment level, periodontal biotype, evaluation of hard tissues, occlusal trauma, stud characteristics, and mucosal inspection and palpation. RESULTS: Midbuccal recession was noted in four test teeth compared with one control tooth (8.5% and 2.1%, respectively; P = .250). The canine and first premolars were the most affected. Tooth chipping occurred in one test tooth and no control teeth. Plaque levels were significantly higher in test than control teeth (P < .001). CONCLUSION: Lateral lower lip piercing is associated with significantly higher plaque accumulation on adjacent teeth. A small percentage of lateral lower lip piercings may cause tooth chipping or buccal recession in adjacent teeth. PMID- 23041989 TI - Reinforced composite restoration following trauma to a mandibular tooth: technique and follow-up treatment. AB - The loss of an entire tooth in the anterior region is accompanied by impairment of esthetics, function, phonetics, and self-esteem. It is common knowledge that treatment with implants during childhood or early adolescence is not an option. Splinting of adjacent teeth during growth and development may interfere with the independent process of teeth realignment and repositioning during that phase of life. Other creative solutions must be offered, such as free-standing composite buildup restorations on compromised broken teeth or single wing/cantilevered restorations adhered to one neighboring tooth during the growth period. The positive effects of reinforced composite materials were researched and presented in the literature. Their use is clearly indicated for interim and economical restorations. Long-term follow-up on a mandibular incisor that experienced trauma, losing its clinical crown and vitality when the patient was 12 years of age, is discussed with all the various aspects of material selection, future considerations, and long-term follow-up to adulthood, when a conventional crown was prepared and delivered. PMID- 23041991 TI - Primary lymphoma of the mandible masquerading as bisphosphonate-related osteonecrosis of jaws. AB - A 66-year-old osteoporotic woman suffered from long-term mental paresthesia (numbness), facial swelling, and a nonhealing extraction site. Fulfilling the three clinical diagnostic criteria for bisphosphonate-related osteonecrosis of the jaw (BRONJ; exposed bone for at least 8 weeks, current bisphosphonate [risedronate] treatment, and no history of head and neck radiation therapy), she was diagnosed and treated accordingly. Nevertheless, a later histopathologic examination revealed malignant lymphoproliferative infiltration of large and intermediate cells. Based on immunostaining and positron-emission tomography, she was diagnosed as having primary diffuse large B-cell lymphoma. This case demonstrates the limitation of the current diagnostic method of BRONJ. Thus, the clinician should be particularly cautious and aware of the differential diagnosis, including malignancy, especially when lesions are accompanied by (mental nerve) neuropathy and long-standing swelling/expansion, and even when plain radiography is not a contributing factor. PMID- 23041990 TI - Comparative evaluation of decalcified freeze-dried bone allograft use alone and in combination with polylactic acid, polyglycolic acid membrane in the treatment of noncontained human periodontal infrabony defects. AB - OBJECTIVE: To compare the regenerative potential of bone graft used alone and in combination with barrier membrane in noncontained human periodontal infrabony defects. METHOD AND MATERIALS: Twelve patients (7 men and 5 women, 30 to 65 years of age) with moderate to severe chronic periodontitis were included in the study. A total of 16 one- or two-walled intraosseous defects were selected and randomly divided for decalcified freeze-dried bone allograft, alone (control group) or in combination with polylactic acid, polyglycolic acid barrier membrane (test group). Pocket probing depth (PPD), clinical attachment level (CAL), radiologic bone fill (RBF), and alveolar height reduction (AHR) were recorded immediately before surgery and after 3 and 6 months postoperatively. The ANOVA and Newman Keuls post hoc tests were used for statistical analysis. A two-tailed probability value of P < .05 was considered to be statistically significant. RESULTS: For bone graft alone, PPD reduction was 2.00 +/- 0.19 mm, CAL gain was 1.38 +/- 0.18 mm, and RBF was 0.63 +/- 0.26 mm: for the test group, PPD reduction was 2.75 +/- 0.37 mm, CAL gain was 1.50 +/- 0.27 mm, and RBF was 1.13 +/- 0.23 mm. AHR for the control and test groups was 0.38 and 0.37 mm, respectively. CONCLUSION: These results confirmed nonsignificant clinical and radiologic differences in regenerative outcome with bone graft alone and with guided tissue regeneration in the treatment of noncontained human periodontal infrabony defects. PMID- 23041993 TI - Prevention--the (sometimes-forgotten) key to success. PMID- 23041992 TI - Reduction of salivary arginine catabolic activity through periodontal therapy. AB - OBJECTIVE: Salivary enzymes may be used to diagnose periodontal conditions. Salivary arginase activity (SAA) is related to susceptibility to bacterial infection. Therefore, the aim of this controlled interventional study was to determine the SAA before and after non-surgical periodontal therapy. METHOD AND MATERIALS: Eighty-nine subjects were selected: 31 periodontally healthy patients (controls), 27 gingivitis patients, and 31 chronic periodontitis patients. Plaque and Gingival Indices, probing depth, and clinical attachment level were monitored. The presence of Campylobacter rectus, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Prevotella intermedia was evaluated by polymerase chain reaction. Salivary total protein level and SAA were also established by spectrophotometry. Clinical and arginase data were analyzed using the Wilcoxon, Mann-Withney, and Kruskal-Wallis tests (P < .05). For microbial data, the chi-square test was used. The Pearson correlation test was also used between each parameter evaluated. RESULTS: After therapy, due to a significant reduction in SAA, the values observed for the gingivitis and periodontitis groups were similar to those found in the healthy group. Interestingly, after therapy, SAA followed the same positive pattern showed by the overall improvement of clinical parameters (gingivitis and periodontitis groups mean values, pre- > posttherapy) and by the reduction of target pathogens (gingivitis group T forsythia, pre- > posttherapy; periodontitis group P. gingivalis, T. denticola, P. intermedia, and T. forsythia, pre- > posttherapy). CONCLUSION: Based on the reduction of SAA after therapy, in accordance with the expected reduction in clinical and microbiologic parameters, it was concluded that SAA has the potential to serve as a reliable method to access to the therapeutic response of chronic periodontitis subjects treated with nonsurgical periodontal therapy. PMID- 23041994 TI - Application of a custom-made inlay structure to a sectional maxillary complete denture for a patient with microstomia: a clinical report. AB - Prosthodontic treatment for edentulous patients with microstomia is a challenge because of the constricted opening of the oral cavity. This clinical report presents the prosthetic management of an edentulous maxilla in a patient with burn-induced microstomia. A sectional maxillary complete denture was fabricated. With the use of a custom-made inlay structure at the overlapping metal base along the palatal midline, the sectional prosthesis was successfully and easily inserted and provided adequate function in the patient's mouth. PMID- 23041995 TI - Randomized trial of aloe vera gel vs triamcinolone acetonide ointment in the treatment of oral lichen planus. AB - OBJECTIVE: To determine the effectiveness of aloe vera gel in the treatment of oral lichen planus when compared with triamcinolone acetonide. METHOD AND MATERIALS: A randomized, double-blind, clinical trial was designed. The study sample constituted 40 patients (23 males and 17 females) who were randomly divided into two equal groups. Group A patients received aloe vera gel, while group B patients received triamcinolone acetonide. RESULTS: Forty patients were included in the study. Most of the sample presented with erosive (n = 18) and atrophic (n = 14) variants of oral lichen planus. When clinical signs and symptoms were observed after 8 weeks of therapy, it was determined that aloe vera gel was more effective than triamcinolone acetonide in the treatment of oral lichen planus. CONCLUSION: Aloe vera gel can be considered a safe alternative treatment for oral lichen planus. PMID- 23041996 TI - Circumferential fit assessment of CAD/CAM single crowns--a pilot investigation on a new virtual analytical protocol. AB - OBJECTIVE: Techniques currently applied to determine the marginal accuracy of dental crown restorations yield inadequate information. This investigation aimed to test a new virtual approach for determining the precision of fit of single crown copings. METHOD AND MATERIALS: Zirconia single crown copings were manufactured on 10 gypsum, single-tooth master casts with two different established computer-aided design/computer-assisted manufacture (CAD/CAM) systems (groups A and B). After cementation, the circumferential fit was assessed with an industrial noncontact scanner and virtual 3D analysis, following a triple-scan protocol. Marginal fit was determined by virtual sectioning; each abutment-coping complex was digitally sliced in 360 vertical sections (1 degree per section). Standardized measurement distances for analyzing the marginal fit (z, xy, xyz) were selected, and a crosshair alignment was utilized to determine whether crowns were horizontally and/or vertically too large or small. The Mann-Whitney test was applied to test for differences between groups. RESULTS: Significant differences in the xy direction (P = .008) were measured between groups. Group A showed a greater number of horizontally overextended margins and a higher frequency of xy distances greater than 150 MUm, in addition to a tendency for excessive z distances (P = .095). CONCLUSION: The mean marginal gap values were clinically acceptable in the present investigation; however, a full circumferential analysis revealed significant differences in marginal coping quality. PMID- 23041997 TI - The efficacy of foam cleaners in removing debris from two endodontic instruments. AB - OBJECTIVE: To compare the efficacy of ProFile File cleaner and a nanostructured foam in removing debris from two rotary nickel-titanium instruments during and after instrumentation. METHOD AND MATERIALS: Twenty mandibular premolars were decoronated and instrumented up to either no. 40.04 RaCe (no. 40.04) or K3 (no. 40.04) instruments (n = 10). Each group of files was randomly divided into two groups: ProFile File cleaner and Nano Foam cleaner. The instruments were examined under a scanning electron microscope (SEM) before and after placement into the canals. Subsequently, instruments were introduced into each cleaner and examined again under SEM. The amount of debris removal from the instruments was determined by ImageJ software. Data were subjected to Kruskal-Wallis and Mann-Whitney tests at a .05 level of significance. RESULTS: The amount of debris removal was significantly different between the groups (P = .002). The amount of debris removed was significantly higher in K3 with Nano Foam cleaner than ProFile File cleaner (P = .009). CONCLUSION: Nanostructured foam can remove debris from endodontic files, especially from those with complex cross-section. This method is recommended to help optimize debris removal with the further possibility of instrument sterilization and reduced risk of cross-contamination. PMID- 23041998 TI - Insertion torque of immediate wide-diameter implants: a finite element analysis. AB - OBJECTIVE: To use finite element analysis to investigate the influence of insertion torque on the stress distribution around an immediately placed oral implant. METHOD AND MATERIALS: Finite element software was used to model a mandibular molar extraction socket. The properties of surrounding cancellous bone and thickness of cortical bone were modified to give four 3D finite element models (I, II, III, and IV). A wide-diameter tapered oral implant was modeled and inserted into the socket. Final insertion torques of 32, 50, and 70 Ncm were applied, and the stress profile in each model was evaluated. The maximum von Mises stresses along the buccal cortical bone adjacent to the implant neck were statistically analyzed to compare the three torque values and four bone models. RESULTS: At the level of the cortical bone, the greatest von Mises stress levels were generated in model IV and diminished as the bone quality increased. Significant increase in stress values at the crestal bone level was observed in all models after using 70 Ncm compared with 32 Ncm. The maximum von Mises stresses at the cancellous bone were higher in model I and reduced with lower level of bone quality (model IV). CONCLUSION: The use of 70 Ncm or more insertion torque during placement of an immediately placed wide-diameter implant substantially increases stresses on the crestal bone. The development of a modified surgical protocol involving moderate insertion torque value (32 to 50 Ncm) may contribute to minimizing the risk of early implant failure in extraction sockets. PMID- 23041999 TI - New insights into biological targets and therapeutic management of infectious diseases. PMID- 23042000 TI - 67 kDa laminin receptor: structure, function and role in cancer and infection. AB - The 67 kDa high affinity laminin receptor (67LR) is a non integrin cell surface receptor for the extracellular matrix whose expression is increased in neoplastic cells and directly correlates with an enhanced invasive and metastatic potential. 67LR derives from homo- or hetero-dimerization of a 37 kDa cytosolic precursor (37LRP), by fatty acid acylation. Interestingly, 37LRP is a multifunctional protein involved in the translational machinery and has also been found in the nucleus, where it is tightly associated with nuclear structures. Acting as a receptor for laminin is not the only function of this protein; indeed, 67LR also acts as a receptor for viruses, such as Sindbis virus and Dengue virus, and is involved in the internalization of the prion protein. Here, we review the current understanding of the structure and function of this molecule, highlighting its role in cancer and infection diseases. PMID- 23042001 TI - The urokinase-receptor in infectious diseases. AB - Cell migration through the extracellular matrix (ECM) or endothelial cells is a basic process in several physiological and pathological events, including the immune host response to pathogens, both in the case of innate and adaptive immunity. The urokinase-type plasminogen activator (uPA) receptor (uPAR) is a GPI anchored cell-surface receptor largely expressed on most of leukocytes, including monocytes/macrophages, granulocytes, immature dendritic cells. uPAR has been detected also in soluble and cleaved forms, which are increased in several pathologies. uPAR focuses the proteolytic activity of its ligand, the serine protease uPA, on the cell membrane, thus promoting localized plasminogen activation and allowing the cell to degrade surrounding ECM and to move across physical barriers. However, the discovery that uPAR can bind with high affinity a component of the ECM, vitronectin (VN), and associates to cell surface molecules to activate signalling pathways inside the cells, largely expanded the role that uPAR can play in cell proliferation/survival and adhesion/migration, which are crucial events for an efficient immune response to infectious agents. This review is focused on the expression and possible functions of the various forms of uPAR in infectious diseases. PMID- 23042002 TI - Hp(2-20) peptide of Helicobacter pylori and the innate immune receptors: specific role(s) of the formyl peptide receptors. AB - Helicobacter pylori (H. pylori) is a microaerophilic, Gram-negative bacterium that affects more than half of the world's population. H. pylori has co-evolved with humans to be transmitted from person to person and to persistently colonize the stomach. A well-choreographed equilibrium between bacterial effectors and host responses permits microbial persistence and health of the host but confers risk of serious diseases. During its long coexistence with humans, H. pylori has evolved complex strategies to limit the degree and extent of gastric mucosal damage and inflammation as well as immune effector activity. In this complex strategy an important role is played by the interaction of H. pylori with a specific class of innate immune receptors, named N-formyl peptide receptor family (FPRs). In the last years several virulence factors have been studied in an effort to correlate bacterial phenotype with specific gastric manifestations and to clarify the pathogenetic mechanisms. Several peptides produced by H. pylori appear to be involved in inflammation associated with the infection. A particular interest has been focused on the Hp(2-20) peptide derived from the bacteria. Thus, aim of the article is to comment on some advances in the elucidation of specific interactions between the Hp(2-20) peptide and FPRs. PMID- 23042003 TI - Low-dose valgancyclovir as cytomegalovirus reactivation prophylaxis in allogeneic haematopoietic stem cell transplantation. AB - The efficacy and safety of low dose oral valgancyclovir (VGCV) as cytomegalovirus (CMV) reactivation prophylaxis was retrospectively evaluated in 32 consecutive patients which underwent allogeneic HLA-matched related and unrelated hematopoietic stem cell transplantation (HSCT). Thirty HSCT recipients showed pretransplant CMV seropositivity. Fifteen received a myeloablative conditioning regimen, while seventeen patients received a reduced-intensity conditioning regimen. Twenty-one patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporin A (CsA) and methotrexate (MTX), and the others CsA with MTX and anti-thymocyte globulin. CMV infection was monitored weekly using polymerase chain reaction (PCR). VGCV was administered orally at a dose of 450 mg daily for six months. Six patients developed a positive CMV-PCR on average 56 days after HSCT successfully treated with VGCV at 1800 mg/day, except one who developed fatal gastrointestinal CMV disease. At the time of CMV reactivation, four patients had been affected by grade II-IV acute GVHD and two by an extensive chronic GVHD. No significant specific VGCV-related toxicity was encountered. Seven patients presented hematological toxicity which did not require drug discontinuation. Our data suggest that low dose VGCV is safe and effective as CMV reactivation prophylaxis in allogeneic HSCT recipients. These results require further validation in prospective randomized studies. PMID- 23042004 TI - Non lymphomatous clonal B-Cell populations in enlarged lymph nodes in acquired immunodeficiency syndrome. AB - Clonal B-cell populations in non-lymphomatous processes have been sporadically reported in enlarged reactive lymph nodes and mucosa-associated lymphoid cell populations. These generally small clones are considered non-malignant proliferations of B-lymphocytes determined by an abnormal response to bacterial or viral antigen stimulation. In cases reported in literature, clonality was detected by light chain assessment and or by polymerase chain reaction (PCR) analysis of immunoglobulin heavy chain (IgH) gene in histologically and clinically proven non lymphomatous processes. In this study the clinical, cytological, phenotypical and pathological features of three HIV patients in which non-lymphomatous clonal B-cell populations detected in enlarged lymph nodes are reported. All the patients complained for later cervical lymph nodes enlargement, positive at the FDG-positron emission tomography scan. Fine needle cytology, coupled with flow cytometry showed atypical lymphoid cell proliferations and kappa (2 cases) or lambda (1 case) light chain restriction. Reactive, non lymphomatous nature of these processes were then proven by histological control in two cases and by clinical follow-up in the last one; corresponding clinical and pathological aspects are discussed. Clonal B-cell populations in non-lymphomatous processes can sporadically occur in enlarged reactive lymph nodes in immunodeficiency as well as in autoimmune processes. Awareness of the phenomenon and attention should be paid in the evaluation of corresponding pathological features and in the clinical management of corresponding patients. PMID- 23042005 TI - Successful management of pulmonary mucormycosis with liposomal amphotericin B and surgery treatment: a case report. AB - Mucormycosis is an increasingly recognized invasive fungal infection (IFI) in patients with acute myeloid leukemia (AML) and after allogeneic (allo) stem cell transplantation (HSCT); it is mainly due to the severe and prolonged neutropenia related to high-dose chemotherapy. In such patients, the lung is the most frequently involved site in mucormycosis. Since rapidly progressive dissemination may occur after pulmonary mucormycosis in hematologic malignancies, early diagnosis and prompt initiation of an effective antifungal therapy is mandatory for a successful outcome. We report the case of a young AML patient who developed, early after the onset of neutropenia in the first induction phase of chemotherapy, a rapidly progressive pulmonary IFI, successfully treated with liposomal Amphotericin-B (LAmB) and then with a limited open toracothomy biopsy, clearly establishing diagnosis of mucormycosis and removing lung infiltrate. Secondary prophylaxis with LamB, applied during both consolidation therapy and myeloablative sibling allogeneic HSCT, was effective to prevent IFI recurrence despite the development of grade I acute graft-versus-host disease (GVHD) and limited chronic GVHD requiring immunosuppressive treatment. Our case report further provide evidence that the combined surgical and LAmB therapy is an effective and safe choice for the management of pulmonary mucormycosis in hematological immunocompromised patients. PMID- 23042006 TI - Stereoconvergent route to chiral cyclohexenone building blocks: formal synthesis of (-)-dysidiolide. AB - A stereoconvergent access to chiral carbocyclic building blocks is reported. 6 (3'-Hydroxy-4'-methylpent-4'-enyl)-3-methoxy cyclohex-2-enone () that consists of four stereoisomers, i.e., racemic ca. 1 : 1 diastereomers, is converted to enantiomerically pure carbocycles through a combination of regioselective catalytic asymmetric reduction and alkylative remote stereoinduction. The present stereoconvergent strategy has allowed the formal synthesis of bioactive (-) dysidiolide. PMID- 23042007 TI - Outcome of acute lymphoblastic leukemia in India: the challenges ahead. PMID- 23042008 TI - A preterm infant with intrauterine skin necrosis. PMID- 23042009 TI - Mayer-Rokitansky-Kuster-Hauser syndrome accompanied by renal cell carcinoma: a case report. AB - Mayer-Rokitansky-Kuster-Hauser anomaly originates from agenesis of the Mullerian duct including agenesis of the uterus and the vagina because of abnormal development of the uterine ducts. This syndrome may be accompanied by the upper urinary tract anomalies such as unilateral renal agenesis, ectopia of 1 or both kidneys, renal hypoplasia, horseshoe kidney, and hydronephrosis. We report a 16 year-old girl, with unilateral renal agenesis, herniating ovary, and renal cell carcinoma in her solitary kidney, associated with Mayer-Rokitansky-Kuster-Hauser syndrome-the first case in the literature to our knowledge. PMID- 23042010 TI - Use of gemcitabine with multi-stage surgical resection as successful second-line treatment of metastatic pancreatoblastoma. AB - Pancreatoblastoma is a rare pediatric pancreatic malignancy. It confers a worse prognosis if there is metastatic or unresectable disease. We report a case of a 12-year-old boy who presented with pancreatoblastoma of the head of the pancreas with multiple intrahepatic metastases. We successfully treated him using aggressive chemotherapy, multi-stage surgery, and gemcitabine chemotherapy, which has not been described as treatment for pancreatoblastoma. Rare childhood malignancies such as pancreatoblastoma require a coordinated, multidisciplinary approach and frequent reassessment of therapeutic interventions. Complete surgical resection is important for cure and may require complex, aggressive, multiple-stage surgical procedures with concurrent or novel chemotherapy. PMID- 23042011 TI - Peripheral T-cell lymphoma in children and adolescents: a single-institution experience. AB - BACKGROUND: Peripheral T-cell lymphoma (PTCL) is rare in pediatric patients and is associated with worse outcome compared with other pediatric non-Hodgkin lymphomas. We report our institutional experience over a 10-year period. METHODS: Patients were identified through the institutional oncology database. Data were abstracted through a detailed retrospective review of patient charts. Those with isolated cutaneous T-cell lymphoma were excluded from this analysis. RESULTS: Thirteen patients were diagnosed with PTCL during the 10-year period. All presented with advanced disease. According to the WHO PTCL classification, 7 patients had PTCL not otherwise specified, 3 had hepatosplenic T-cell lymphoma and 3 had T-cell posttransplant lymphoproliferative disease. Six of the patients had previously received or were receiving immunosuppressive therapy at the time of their diagnosis. Patients were treated with various chemotherapeutic regimens, including B-cell non-Hodgkin lymphomas and T-cell acute lymphoblastic leukemia like therapy. Patients who had refractory or recurrent disease were changed to alternative therapy. Eight patients underwent stem cell transplantation, 7 allogeneic and 1 autologous. Of the 13 patients, 7 died. Three patients died from disease progression, 3 died from treatment-related mortality, and 1 patient died from cardiac rejection. Six patients (46%) are alive and disease free at a median of 21 months (2 to 79 mo). CONCLUSIONS: Children with PTCL have an unfavorable outcome. A standard approach to management of pediatric PTCL needs to be established to improve outcome. Because of the rarity of this condition, this will require collaborative studies. PMID- 23042012 TI - Endobronchial ALK+ anaplastic large-cell lymphoma resembling asthma in a 13-year old girl. AB - Anaplastic large-cell lymphoma is a rare disease in children, and endobronchial localization is extremely rare in any age group. We report the case of a 13-year old girl with endobronchial anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting as asthma, and discuss the diagnostic, therapeutic, and clinical implications. PMID- 23042013 TI - Cytomegalovirus Retinitis in an ALL child on exclusive chemotherapy treated successfully with intravitreal ganciclovir alone. AB - A child suffering from acute lymphoblastic leukemia on treatment with exclusive chemotherapy presented with vision-threatening cytomegalovirus (CMV) retinitis in 1 eye. Prompt diagnosis and treatment with 3 weekly doses of 2 mg/0.1 mL intravitreal ganciclovir resulted in successful healing of CMV retinitis with restoration of visual acuity. In children with acute lymphoblastic leukemia on exclusive chemotherapy without hematopoietic stem cell transplantation, CMV retinitis has been reported in only 1 case in literature. This child was treated successfully with intravenous ganciclovir. This report highlights the use of successful intravitreal ganciclovir in pediatric age group to avoid side effects of systemic ganciclovir. PMID- 23042014 TI - The role of community pharmacists in the management of hematopoietic stem cell transplant recipients: knowledge and training. AB - INTRODUCTION: The patients receiving hematopoietic stem cell transplantation (HSCT) require routine management: the role of the pharmacist has not been extensively considered. This study had 2 aims: to explore the knowledge of community pharmacists relating to pediatric HSCT and to evaluate their expectations in terms of training needs. MATERIALS AND METHODS: We interviewed 40 community pharmacists in May and June 2010 in Paris (France) with a 3 parts questionnaire: information concerning the community pharmacy, analysis of 2 pediatric prescriptions and knowledge about HSCT and professional training. RESULTS: Twenty-nine (72.5%) of the 40 community pharmacies agreed to participate in the study. When asked what pharmacological advice they would give for an episode of fever, 13% of the pharmacists asked said that they would deliver acetaminophen without asking any further questions. Concerning hypertrichosis in patients treated with corticosteroids and ciclosporin, none mentioned the role of ciclosporin. The erroneous indications for HSCT given included road accidents (1 pharmacist; 3.4%) and hemophilia (3 pharmacists; 10.3%). Almost 80% of the pharmacists questioned considered their HSCT knowledge insufficient for their professional practice. An E-learning session adapted to their needs was of interest to almost three quarters of the pharmacists questioned. PMID- 23042015 TI - Metronomic scheduling of anticancer agents for a refractory orbital pseudotumor in a child. PMID- 23042016 TI - Sustained response to weekly vinblastine in 2 children with pilomyxoid astrocytoma associated with diencephalic syndrome. AB - Diencephalic syndrome (DS) related to hypothalamic/chiasmatic region tumor has mainly been reported with low-grade glioma. We described 2 young children with DS related to pilomyxoid astrocytoma. Despite the recognized more agressive clinical behavior of this histologic subtype, we report successful resolution of DS and sustained tumor response with prolonged use of single-agent vinblastine. PMID- 23042017 TI - Impact of multiple prenatal risk factors on newborn iron status at delivery. AB - BACKGROUND: Maternal anemia and several complications of pregnancy can affect fetal iron acquisition. AIM: Because it is unknown whether the effects of demographic and maternal risk factors (RF) are summative, we examined cord iron status in newborns with multiple RF for acquiring iron deficiency. METHODS: Cord blood indices from healthy control newborns with and without RF for newborn or infant iron deficiency were studied. RESULTS: Newborns with greater RF had poorer erythrocyte and storage iron status. Poorest status was seen if mothers with comorbid obesity and diabetes delivered large-for-gestation newborns. Findings highlight the importance of identifying RF. PMID- 23042018 TI - Novel MLL2 mutation in Kabuki syndrome with hypogammaglobulinemia and severe chronic thrombopenia. AB - BACKGROUND: Kabuki syndrome is a rare condition characterized by distinct dysmorphic features and a broad spectrum of organ anomalies. Differentiating it from other syndromes can be difficult, particularly in patients with incomplete phenotypic manifestation. Recently, MLL2 gene mutations were identified as the underlying genetic cause of Kabuki syndrome in the majority of cases. OBSERVATIONS: We report the case of an adolescent with an uncommon combination of manifestations, including hypogammaglobulinemia and severe chronic thrombopenia associated with a novel MLL2 mutation. CONCLUSIONS: This report adds to the growing knowledge on the mutational and phenotypic spectrum of Kabuki syndrome. PMID- 23042019 TI - Non-TBI hematopoietic stem cell transplantation in pediatric AML patients: a single-center experience. AB - BACKGROUND: Hematopoietic stem cell transplantation (HSCT) has been established as a promising treatment in acute myeloid leukaemia (AML). Several studies have been performed to minimize the toxicity of HSCT in children without impairing the efficacy. We report our long-term results of HSCT in pediatric AML patients using non-total body irradiation conditioning regimen. PROCEDURE: From May 1991 to June 2010, 133 pediatric patients with AML (age<15 y) who were referred to our institute underwent autologous (auto-) or allogeneic (allo-) HSCT. The conditioning regimen consisted of oral busulfan plus etoposide in auto-HSCT patients and oral busulfan plus cyclophosphamide in allo-HSCT patients. RESULTS: Overall survival (OS), leukemia-free survival (LFS), probability of relapse, and transplantation-related mortality at 3 years were 67.6%, 62.2.5%, 27.3%, and 10.1%, respectively. There was no significant difference between allo-HSCT and auto-HSCT groups. In multivariable analysis using Cox proportional hazards regression model, male sex was associated with significantly improved OS (P<0.001) and LFS (P=0.022). An age <=3 years was associated with higher relapse (P=0.034) and worse OS (P=0.001) and LFS (P=0.014). CONCLUSIONS: The role of allo HSCT in pediatric AML patients in first complete remission is uncertain. Further randomized studies are recommended to clarify the optimal postremission therapy in these patients. PMID- 23042020 TI - Cyclophosphamide and topotecan as first-line salvage therapy in patients with relapsed ewing sarcoma at a single institution. AB - The combination of cyclophosphamide and topotecan (cyclo/topo) has shown objective responses in relapsed Ewing sarcoma, but the response duration is not well documented. We reviewed characteristics and outcome of 14 patients with Ewing sarcoma, treated uniformly at a single institution and offered cyclo/topo at first relapse. Six patients (43%) had relapse at distant sites. All patients received first-line salvage therapy with cyclophosphamide 250 mg/m and topotecan 0.75 mg/m, daily for 5 days repeated every 21 days. The median number of cycles was 4 (range 1 to 10). All toxicities were manageable, the most common being transient cytopenias. There were also 4 episodes of febrile neutropenia, and 3 episodes of gross hematuria. Response was assessable in 13 patients and showed progressive disease in 6 (46%), stable disease in 4 (31%), and partial response in 3 (23%). Nine patients had local control, consisting of radical surgery in 2, radiation in 3, and a combination in 4 patients. Response, when it occurred, was maintained for a median of 8 months (range, 4 to 28 mo). Four patients (29%) are alive at 3, 7, 9, and 110 months after relapse; 1 is receiving cyclo/topo, 1 is on third-line therapy, and 2 are in second and fourth remission. The low toxicity of this combination, and the lack of sustained responses, warrant its investigation in combination with targeted or novel therapeutic agents in relapsed disease. PMID- 23042021 TI - Efficacy of temozolomide in a central nervous system relapse of neuroblastoma with O 6 -methylguanine methyltransferase (MGMT) promoter methylation. AB - We describe a case of a 5-year-old girl with central nervous system relapse of neuroblastoma after high-dose chemotherapy and autologous stem cell transplantation. Although the brain metastasis was surgically removed, she had a second relapse in the same region with leptomeningeal dissemination despite receiving irinotecan. Administration of temozolomide in addition to irinotecan led to her third complete response and the patient has been in complete response for >24 months. The tumor had no expression of the O -methylguanine methyltransferase (MGMT) gene due to promoter methylation. Temozolomide is an attractive candidate treatment in neuroblastoma with methylated MGMT, especially in central nervous system relapsed cases. PMID- 23042022 TI - Interferon-alpha for unresectable progressive and symptomatic plexiform neurofibromas. AB - Neurofibromas are the most common manifestations of neurofibromatosis type-1. They occasionally cause pain or progressive loss of function due to nerve compression. Optimal treatment approach is still challenging and the current treatment results are not satisfactory. Four cases of plexiform neurofibromas with various clinical presentations and an addendum to a previously published report on a patient who had relief from pain and/or regression of tumor volume after treatment with interferon-alpha 2a are presented. PMID- 23042024 TI - From blood smear to lipid disorder: a case report. AB - Neutral lipid storage disease (Chanarin-Dorfman syndrome) is a rare autosomal recessive disorder of lipid metabolism, characterized by systemic accumulation of neutral lipids in multiple tissues. We report a case of a 14-year-old girl with generalized ichthyosis, liver cirrhosis, and a hearing impairment. A peripheral blood smear demonstrated marked cytoplasmatic vacuoles in most polymorphonuclear cells (Jordan's anomaly). Bone marrow examination revealed vacuoles in myeloid precursors. Genetic analysis showed that the patient was homozygous for the p.Arg312Ter mutation in the CGI-58 gene, a key enzyme in lipid metabolism. The peripheral blood smear is diagnostic, and should be performed in any patient with ichthyosis. PMID- 23042023 TI - Isolated primary testicular B lymphoblastic lymphoma: an unusual presentation. AB - Acute lymphoblastic leukemia (ALL) is the most common cancer in children and adolescents. Clinical presentation often reflects bone marrow involvement and consequences of bone marrow failure. Microscopic involvement of the testis is rare, occurring in about 2% of cases. We present a case of a 3-year-old child who displayed unilateral macroorchidism as the only clinical symptom of ALL. Although the patient presented with localized disease, he was treated with systemic chemotherapy without recurrence. In this report, we review the current literature on ALL testicular involvement, diagnosis, and treatment. PMID- 23042026 TI - Do protocol transplant biopsies improve kidney transplant outcomes? AB - PURPOSE OF REVIEW: The research undertaken on 'protocol' renal transplant biopsies has provided a rich, if not the richest, approach to better understanding of the immune and nonimmune impacts upon the transplant. The purpose of this review is to detail how the direct benefit to the patient also lies in these renamed 'surveillance' biopsies. RECENT FINDINGS: Undertaken at fixed time points after transplantation, biopsy provides individual diagnoses with which the clinician can vary immunosuppression both in intensity and in the type of agent used to modify pathological processes early in their course. Initial nonfunction from acute tubular necrosis, subclinical cellular and humoral rejection, calcineurin inhibitor nephrotoxicity, BK virus nephropathy and recurrent glomerulonephritis are all important diagnoses for which early intervention provides better therapeutic outcomes than delaying until they are clinically evident. SUMMARY: This review provides the recent evidence that has convinced many transplant units to embark upon surveillance programmes for their patients in order to individualize their immunosuppression and thus gain better outcomes. PMID- 23042025 TI - Tolerogenic dendritic cells impede priming of naive CD8+ T cells and deplete memory CD8+ T cells. AB - Type 1 diabetes is a T-cell-mediated autoimmune disease in which autoreactive CD8(+) T cells destroy the insulin-producing pancreatic beta cells. Vitamin D3 and dexamethasone-modulated dendritic cells (Combi-DCs) loaded with islet antigens inducing islet-specific regulatory CD4(+) T cells may offer a tissue specific intervention therapy. The effect of Combi-DCs on CD8(+) T cells, however, remains unknown. To investigate the interaction of CD8(+) T cells with Combi-DCs presenting epitopes on HLA class I, naive, and memory CD8(+) T cells were co-cultured with DCs and proliferation and function of peptide-specific T cells were analyzed. Antigen-loaded Combi-DCs were unable to prime naive CD8(+) T cells to proliferate, although a proportion of T cells converted to a memory phenotype. Moreover, expansion of CD8(+) T cells that had been primed by mature monocyte-derived DCs (moDCs) was curtailed by Combi-DCs in co-cultures. Combi-DCs expanded memory T cells once, but CD8(+) T-cell numbers collapsed by subsequent re-stimulation with Combi-DCs. Our data point that (re)activation of CD8(+) T cells by antigen-pulsed Combi-DCs does not promote, but rather deteriorates, CD8(+) T-cell immunity. Yet, Combi-DCs pulsed with CD8(+) T-cell epitopes also act as targets of cytotoxicity, which is undesirable for survival of Combi-DCs infused into patients in therapeutic immune intervention strategies. PMID- 23042027 TI - Risk prediction in chronic kidney disease: pitfalls and caveats. AB - PURPOSE OF REVIEW: This review aims to describe the challenges and highlight recent advances in the field of risk prediction for patients with chronic kidney disease (CKD). We first focus on methods of model development and metrics of model performance in general, and then highlight important risk prediction tools for patients with CKD, for prediction of kidney failure and all-cause mortality. RECENT FINDINGS: Investigators have used data from patients with CKD stages 1-5 and developed models for predicting the progression to kidney failure and all cause mortality. Models for kidney failure have included estimated glomerular filtration rate, albuminuria, demographic and laboratory variables, and have achieved excellent discrimination. In contrast, model performance for prediction of all-cause mortality has been relatively modest. No validated models exist for predicting the risk of cardiovascular events in patients with CKD. SUMMARY: Models for predicting kidney failure in patients with CKD are highly accurate and clinically usable. The kidney failure risk equation includes routinely collected laboratory data and can predict the progression of CKD to kidney failure with accuracy. Additional validation of the risk equation and development of new models for all-cause mortality and cardiovascular events in patients with CKD are needed. PMID- 23042028 TI - Steroid-free chronic immunosuppression in renal transplantation. AB - PURPOSE OF REVIEW: Over the past two decades, steroid-free immunosuppression has become more widespread, but improvements in long-term kidney transplant survival have been modest, mandating scrutiny of our chronic regimens. RECENT FINDINGS: Current studies and commentary cautiously conclude that steroid-free regimens in low-risk patients seem acceptable for up to 5 years, although most studies are shorter. Patients who will develop chronic rejection cannot be identified prospectively and usually return to steroids. One center continues to report long term steroid-free results that are comparable to or better than national Scientific Registry of Renal Transplant Recipients (SRTR) outcomes, even with 'older' drugs cyclosporine and azathioprine, reaffirming the need for well designed prospective studies. Some authorities question whether minimal side effects with current regimens justify steroid elimination. In low-risk populations, 'steroid-type' studies probably would suggest no short-term benefit of tacrolimus over cyclosporine, or mycophenolate over azathioprine. SUMMARY: The data justifying steroid-free immunosuppression continue to be suboptimal. A larger question is whether to treat an entire population at medical risk or just the higher-risk subgroup that declares itself in the short term. 'Subgroup therapy' might well produce the same quandaries if applied to other accepted transplant immunosuppression. PMID- 23042029 TI - Sodium glucose cotransporter 2 and the diabetic kidney. AB - PURPOSE OF REVIEW: Reabsorption of glucose in the proximal tubule occurs predominantly via the sodium glucose cotransporter 2 (SGLT2). There has been intense interest in this transporter as a number of SGLT2 inhibitors have entered clinical development. SGLT2 inhibitors act to lower plasma glucose by promoting glycosuria and this review aims to outline the effect on the diabetic kidney of this hypoglycaemic agent. RECENT FINDINGS: This review provides an overview of recent findings in this area: the transcriptional control of SGLT2 expression in human proximal tubular cells implicates a number of cytokines in the alteration of SGLT2 expression; experimental data show that SGLT2 inhibition may correct early detrimental effects of diabetes by reducing proximal tubular sodium and glucose transport, suggesting a possible renoprotective effect independent of the glucose lowering effects of these agents; and the nonglycaemic effects of SGLT2 inhibitors may have an impact on renal outcomes. SUMMARY: The available clinical evidence shows consistent reduction in glycaemic parameters and some evidence suggests additional effects including weight loss and mild blood pressure reduction. There are some side effects that warrant further investigation and establishing whether SGLT2 inhibition provides a renal benefit relies on future long-term studies with specific renal end-points. PMID- 23042030 TI - An active-site-accessible porous metal-organic framework composed of triangular building units: preparation, catalytic activity and magnetic property. AB - An active-site-accessible porous metal-organic framework from self-assembling of trinuclear Cu(II) building units exhibits high CO oxidation activity and significant antiferromagnetic behavior. PMID- 23042032 TI - The invalidity of the photo-induced electron transfer mechanism for fluorescein derivatives. AB - The ground and excited state geometries, the excitation and emission energies for a series of fluorescein derivatives in aqueous solutions have been investigated using time-dependent density functional theory (TD-DFT) with B3LYP and a long range corrected CAM-B3LYP functional. The RI-CC2 method was employed to confirm the CAM-B3LYP results. As far as we know, the excited state geometries for a series of fluorescein derivatives were optimized for the first time, and the conformational changes upon photoexcitation were discussed. Importantly, the previous proposed photo induced electron transfer (PeT) mechanism for dictating the fluorescence quantum yield (Phi(fl)) of fluorescein derivatives was not fully supported by our calculations. Internal conversion may still be the most likely mechanism for dictating the Phi(fl) of fluorescein derivatives, which indicates a need for further experimental and theoretical studies on the excited state dynamics of fluorescein derivatives. PMID- 23042033 TI - Cerebrospinal fluid miRNA profile in HIV-encephalitis. AB - MicroRNAs are short non-coding RNAs that modulate gene expression by translational repression. Because of their high stability in intracellular as well as extracellular environments, miRNAs have recently emerged as important biomarkers in several human diseases. However, they have not been tested in the cerebrospinal fluid (CSF) of HIV-1 positive individuals. Here, we present results of a study aimed at determining the feasibility of detecting miRNAs in the CSF of HIV-infected individuals with and without encephalitis (HIVE). We also evaluated similarities and differences between CSF and brain tissue miRNAs in the same clinical setting. We utilized a high throughput approach of miRNA detection arrays and identified differentially expressed miRNAs in the frontal cortex of three cases each of HIV+, HIVE, and HIV- controls, and CSF of 10 HIV-positive and 10 HIV-negative individuals. For the CSF samples, the group of HIV+ individuals contained nine cases of HIV-associated neurological disorders (HAND) and, among those, four had HIVE. All the HIV-negative samples had non-viral acute disseminate encephalomyelitis. A total of 66 miRNAs were found differentially regulated in HIV+ compared to HIV- groups. The greatest difference in miRNA expression was observed when four cases of HIVE were compared to five non-HIVE cases, previously normalized with the HIV-negative group. After statistical analyses, 11 miRNAs were fund significantly up-regulated in HIVE. Although more clinical samples should be examined, this work represents the first report of CSF miRNAs in HIV-infection and offers the basis for future investigation. PMID- 23042034 TI - Spastic cocontraction in hemiparesis: effects of botulinum toxin. AB - INTRODUCTION: In this study of spastic hemiparesis we evaluated cocontraction during sustained agonist/antagonist efforts, before and after botulinum toxin (BoNT) injection in 1 agonist. METHODS: Nineteen hemiparetic subjects performed maximal isometric elbow flexion/extension efforts with the elbow at 100 degrees (extensors stretched). Using flexor and extensor surface electromyography we calculated agonist recruitment/cocontraction indices from 500-ms peak voluntary agonist recruitment, before and 1 month after onabotulinumtoxinA injection (160 U) into biceps brachii. RESULTS: Before injection, agonist recruitment and cocontraction indices were higher in extensors than flexors [0.74 +/- 0.15 vs. 0.59 +/- 0.10 (P < 0.01) and 0.43 +/- 0.25 vs. 0.25 +/- 0.13 (P < 0.05), respectively]. Biceps injection decreased extensor cocontraction index (-35%, P < 0.05) while increasing flexor agonist recruitment and cocontraction indices. CONCLUSIONS: In spastic hemiparesis, stretch may facilitate agonist recruitment and spastic cocontraction. In the non-injected antagonist, cocontraction may be reduced by enhanced reciprocal inhibition from a more relaxed, and therefore stretched, agonist, or through decreased recurrent inhibition from the injected muscle. PMID- 23042035 TI - A RubisCO-like protein links SAM metabolism with isoprenoid biosynthesis. AB - Functional assignment of uncharacterized proteins is a challenge in the era of large-scale genome sequencing. Here, we combine in extracto NMR, proteomics and transcriptomics with a newly developed (knock-out) metabolomics platform to determine a potential physiological role for a ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO)-like protein from Rhodospirillum rubrum. Our studies unraveled an unexpected link in bacterial central carbon metabolism between S-adenosylmethionine-dependent polyamine metabolism and isoprenoid biosynthesis and also provide an alternative approach to assign enzyme function at the organismic level. PMID- 23042037 TI - Dually cationic and anionic pH/temperature-sensitive injectable hydrogels and potential application as a protein carrier. AB - Novel copolymers containing both anionic and cationic pH-sensitive moieties were reported. These amphoteric copolymers exhibited special closed-loop reversible sol-gel-sol phase transitions in response to both pH and temperature. PMID- 23042036 TI - An enzyme-trap approach allows isolation of intermediates in cobalamin biosynthesis. AB - The biosynthesis of many vitamins and coenzymes has often proven difficult to elucidate owing to a combination of low abundance and kinetic lability of the pathway intermediates. Through a serial reconstruction of the cobalamin (vitamin B(12)) pathway in Escherichia coli and by His tagging the terminal enzyme in the reaction sequence, we have observed that many unstable intermediates can be isolated as tightly bound enzyme-product complexes. Together, these approaches have been used to extract intermediates between precorrin-4 and hydrogenobyrinic acid in their free acid form and permitted the delineation of the overall reaction catalyzed by CobL, including the formal elucidation of precorrin-7 as a metabolite. Furthermore, a substrate-carrier protein, CobE, that can also be used to stabilize some of the transient metabolic intermediates and enhance their onward transformation, has been identified. The tight association of pathway intermediates with enzymes provides evidence for a form of metabolite channeling. PMID- 23042039 TI - Falls and spinal muscular atrophy: exploring cause and prevention. AB - INTRODUCTION: Falls can cause injury and may compromise function in spinal muscular atrophy (SMA) patients. Weakness and gait variability are associated with falls in other neurological disorders, and fatigue is well documented in SMA. The relationship of weakness, fatigue, and gait variability to falls has never been investigated. METHODS: Seven ambulatory patients with SMA completed a falls history questionnaire, 6MWT, gait analysis, and strength testing. Pearson correlation coefficients were used to examine associations between these variables. RESULTS: All 7 subjects reported falls in the previous year. Stride length variability was significantly associated with falls, unlike strength, fatigue, or other gait variables. CONCLUSIONS: Stride-length variability was the key variable associated with falls. Preventive strategies to avoid falls should be incorporated into patient management plans. Gait analysis provides actionable information not revealed by standard assessments and should be included in clinical trials designed to address the prevention of falls in the SMA population. PMID- 23042038 TI - PARP6, a mono(ADP-ribosyl) transferase and a negative regulator of cell proliferation, is involved in colorectal cancer development. AB - Poly(ADP-ribose) polymerase (PARP) is an enzyme that mediates post-translational modification of proteins. Seventeen known members of the PARP superfamily can be grouped into three classes based on catalytic activity: (i) classical poly(ADP ribose) polymerases, (ii) mono(ADP-ribosyl) transferases and (iii) catalytically inactive members. PARP6 belongs to the mono(ADP-ribosyl) transferase class, and here we have found that PARP6 is a negative regulator of cell proliferation. Forced expression of PARP6 in HeLa cells induced growth suppression, but a PARP6 mutant with a C-terminal deletion lacking the catalytic domain had no effect. The PARP6-expressing cells accumulated in the S-phase, and the magnitude of S-phase accumulation was observed to be greater in cells expressing a PARP6 mutant with an N-terminal deletion, lacking a putative regulatory domain. Immunohistochemical analysis revealed that PARP6 positivity was found at higher frequencies in colorectal cancer tissues with well-differentiated histology compared to those with poorly differentiated histology. Furthermore, PARP6 positivity negatively correlated with the Ki-67 proliferation index. Kaplan-Meier analysis showed that PARP6-positive colorectal cancer had a good prognosis. Based on these results, we propose that PARP6 acts as a tumor suppressor through its role in cell cycle control. PMID- 23042040 TI - DNA sequence and ancillary ligand modulate the biexponential emission decay of intercalated [Ru(L)2dppz]2+ enantiomers. AB - The bi-exponential emission decay of [Ru(L)(2)dppz](2+) (L = N,N'-diimine ligand) bound to DNA has been studied as a function of polynucleotide sequence, enantiomer, and nature of L (phenanthroline vs. bipyridine). The lifetimes (tau(i)) and pre-exponential factors (alpha(i)) depend on all three parameters. With [poly(dA-dT)](2), the variation of alpha(i) with [Nu]/[Ru] has little dependence on L for Lambda-[Ru(L)(2)dppz](2+) but a substantial dependence for Delta-[Ru(L)(2)dppz](2+). With [poly(dG-dC)](2), by contrast, the Lambda enantiomer alpha(i) values depend strongly on the nature of L, whereas those of the Delta-enantiomer are relatively unaffected. DNA-bound linked dimers show similar photophysical behaviour. The lifetimes are identified with two geometries of minor-groove intercalated [Ru(L)(2) dppz](2+), resulting in differential water access to the phenazine nitrogen atoms. Interplay of cooperative and anti cooperative binding resulting from complex-complex and complex-DNA interactions is responsible for the observed variations of alpha(i) with binding ratio. [Ru(phen)(2)dppz](2+) emission is quenched by guanosine in DMF, which may further rationalise the shorter lifetimes observed with guanine-rich DNA. PMID- 23042041 TI - [HTA report - bone graft or endogenous bone?]. PMID- 23042042 TI - [Sports bar - surgeons warn against hasty OP]. PMID- 23042044 TI - [Cervical spine - sports performance despite artificial disc]. PMID- 23042043 TI - [Doping - hormonal preparations are always being refined]. PMID- 23042045 TI - [Absolute and relative strength-endurance of the knee flexor and extensor muscles: a reliability study using the IsoMed 2000-dynamometer]. AB - BACKGROUND: Isokinetic devices are highly rated in strength-related performance diagnosis. A few years ago, the broad variety of existing products was extended by the IsoMed 2000-dynamometer. In order for an isokinetic device to be clinically useful, the reliability of specific applications must be established. Although there have already been single studies on this topic for the IsoMed 2000 concerning maximum strength measurements, there has been no study regarding the assessment of strength-endurance so far. The aim of the present study was to establish the reliability for various methods of quantification of strength endurance using the IsoMed 2000. METHODS: A sample of 33 healthy young subjects (age: 23.8 +/- 2.6 years) participated in one familiarisation and two testing sessions, 3-4 days apart. Testing consisted of a series 30 full effort concentric extension-flexion cycles of the right knee muscles at an angular velocity of 180 degrees /s. Based on the parameters Peak, Torque and Work for each repetition, indices of absolute (KADabs) and relative (KADrel) strength-endurance were derived. KADabs was calculated as the mean value of all testing repetitions, KADrel was determined in two ways: on the one hand, as the percentage decrease between the first and the last 5 repetitions (KADrelA) and on the other, as the negative slope derived from the linear regression equitation of all repetitions (KADrelB). Detection of systematic errors was performed using paired sample t tests, relative and absolute reliability were examined using intraclass correlation coefficient (ICC 2.1) and standard error of measurement (SEM%), respectively. RESULTS/CONCLUSION: In general, for extension measurements concerning KADabs and - in an weakened form - KADrel high ICC -values of 0.76 0.89 combined with clinically acceptable values of SEM% of 1.2-5.9 % could be found. For flexion measurements this only applies to KADabs, whereas results for KADrel turned out to be clearly weaker with ICC- and SEM% values of 0.42-0.62 and 9.6-17.7 % and leave considerable doubts on the clinical usefulness. However, if there should be after all a need to measure KADrel for flexion, it is - in view of the stronger reliability results - recommended (i) to concentrate on the calculation of KADrelB, (ii) to use the parameter Work and - in view of considerable familiariszation and learning effects of ~10 % - (iii) to include a familiarisation period that extends exceeds the familiarisation session conducted in the present study. PMID- 23042046 TI - Steroidal saponins and pregnane glycosides from Smilax microphylla. AB - Six steroidal saponins and two pregnane glycosides were isolated from the BuOH subfraction of 70% EtOH extract of Smilax microphylla C.H.Wright, among them two were new compounds (1 and 7). Pregnane glycosides were firstly isolated from the genus Smilax (Smilacaceae). Structures of the new compounds were determined on the basis of HR-ESI-MS, 1D and 2D NMR spectroscopic analysis. PMID- 23042047 TI - Synthesis of novel diosgenyl saponin analogues and apoptosis-inducing activity on A549 human lung adenocarcinoma. AB - We synthesized a diosgenyl saponin bearing a unique disaccharide from the natural product beta-hederin, together with twelve glycosylated derivatives and determined their cytotoxicity against five different human cancer cell lines. Most of them showed weak cytotoxicity, with the exception of compound , diosgenyl alpha-L-rhamnopyranosyl-(1->2)-[alpha-L-arabinopyranosyl-(1->4)]-alpha-L arabinopyranoside, which exhibited strong cytotoxicity against A549 cells. The cytotoxicity of was associated with apoptotic cell death, which was characterized by morphological changes, chromatin condensation, DNA fragmentation, and phosphatidylserine externalization. Compound 20 induced apoptosis of A549 cells through a caspase-8-mediated extrinsic pathway and a caspase-9-mediated intrinsic pathway. In addition, phosphorylation of JNK increased but the phosphorylation of ERK decreased after treatment with 20. These results provide a basic mechanism for the anticancer activity of 20. PMID- 23042048 TI - Validation of the nucleotide excision repair comet assay on cryopreserved PBMCs to measure inter-individual variation in DNA repair capacity. AB - Inter-individual susceptibility to mutagens/carcinogens can be assessed by either genotyping DNA repair genes in different pathways or phenotyping DNA repair capacity (DRC) at the molecular or cellular level. Due to the large number of known DNA repair genes, and the interactions between repair pathways, phenotyping is becoming the preferred approach to measure DRC, and reliable assays are therefore increasingly needed. The use of a cellular phenotype comet assay for the nucleotide excision repair (NER) pathway using benzo[a]pyrene diol epoxide (BPDE) has been described in previous papers, but no thorough evaluation of its applicability in large genotype-phenotype studies has been presented. Our aim was to evaluate the possibility of using cryopreserved instead of fresh peripheral blood mononuclear cells (PBMCs) to evaluate intra- and inter-assay variation, and inter-individual variation, for the aphidicolin (APC)-block NER comet assay. Moreover, we measured the variation for the designated internal standard (K562 erythroleukaemia cell line) and we evaluated the feasibility to use lymphoblastoid cell lines (LCLs) as surrogate of PBMCs. Our results showed a low intra-assay [coefficient of variation (CV) 19.9%] and inter-assay (CV 32.3%) variation, with a good inter-individual variation (122 subjects, mean +/- standard deviation 7.38 +/- 4.99; range 0.66-26.14; CV 67.63%). A significant correlation between results derived from cryopreserved and fresh PBMCs from the same individuals was found (10 subjects, r = 0.62, P = 0.05). Results from LCLs and cryopreserved PBMCs from the same subjects showed an inverse significant correlation (10 subjects, r = -0.712, P = 0.02). K562 cells as internal standard showed low intra-assay variation. In the present study the APC-block NER comet assay on cryopreserved PBMCs seemed to be a reliable method to measure DRC variation in epidemiological studies; LCLs were not a good surrogate in this assay. PMID- 23042049 TI - Automatic analysis of the micronucleus test in primary human lymphocytes using image analysis. AB - The in vitro micronucleus test (MNT) is a well-established test for early screening of new chemical entities in industrial toxicology. For assessing the clastogenic or aneugenic potential of a test compound, micronucleus induction in cells has been shown repeatedly to be a sensitive and a specific parameter. Various automated systems to replace the tedious and time-consuming visual slide analysis procedure as well as flow cytometric approaches have been discussed. The ROBIAS (Robotic Image Analysis System) for both automatic cytotoxicity assessment and micronucleus detection in human lymphocytes was developed at Novartis where the assay has been used to validate positive results obtained in the MNT in TK6 cells, which serves as the primary screening system for genotoxicity profiling in early drug development. In addition, the in vitro MNT has become an accepted alternative to support clinical studies and will be used for regulatory purposes as well. The comparison of visual with automatic analysis results showed a high degree of concordance for 25 independent experiments conducted for the profiling of 12 compounds. For concentration series of cyclophosphamide and carbendazim, a very good correlation between automatic and visual analysis by two examiners could be established, both for the relative division index used as cytotoxicity parameter, as well as for micronuclei scoring in mono- and binucleated cells. Generally, false-positive micronucleus decisions could be controlled by fast and simple relocation of the automatically detected patterns. The possibility to analyse 24 slides within 65h by automatic analysis over the weekend and the high reproducibility of the results make automatic image processing a powerful tool for the micronucleus analysis in primary human lymphocytes. The automated slide analysis for the MNT in human lymphocytes complements the portfolio of image analysis applications on ROBIAS which is supporting various assays at Novartis. PMID- 23042050 TI - Risk factors for invasive candidiasis in infants >1500 g birth weight. AB - BACKGROUND: We describe the incidence, risk factors and outcomes of invasive candidiasis in infants >1500 g birth weight. METHODS: We conducted a retrospective cohort study of infants >1500 g birth weight discharged from 305 neonatal intensive care units in the Pediatrix Medical Group from 2001 to 2010. Using multivariable logistic regression, we identified risk factors for invasive candidiasis. RESULTS: Invasive candidiasis occurred in 330 of the 530,162 (0.06%) infants. These were documented from positive cultures from >=1 of these sources: blood (n = 323), cerebrospinal fluid (n = 6) or urine from catheterization (n = 19). Risk factors included day of life >7 (odds ratio [OR]: 25.2; 95% confidence interval: 14.6-43.3), vaginal birth (OR: 1.6 [1.2-2.3]), exposure to broad spectrum antibiotics (OR: 1.6 [1.1-2.4]), central venous line (OR: 1.8 [1.3-2.6]) and platelet count <50,000/mm (OR: 3.7 [2.1-6.7]). All risk factors had poor sensitivities, low positive likelihood ratios and low positive predictive values. The combination of broad-spectrum antibiotics and low platelet count had the highest positive likelihood ratio (46.2), but the sensitivity of this combination was only 4%. Infants with invasive candidiasis had increased mortality (OR: 2.2 [1.3-3.6]). CONCLUSIONS: Invasive candidiasis is uncommon in infants >1500 g birth weight. Infants at greatest risk are those exposed to broad-spectrum antibiotics and with platelet counts of <50,000/mm(3). PMID- 23042057 TI - The history and future of neuro-otology. AB - PURPOSE OF REVIEW: The field of neuro-otology has advanced substantially over the past 150 years. The function of the vestibular system was presumed to be audiologic prior to the groundbreaking work of Prosper Meniere in the late 1800s. Since that time, scientific discovery has advanced our knowledge of the physiology and the pathophysiology of the vestibular system. This article describes where we have been, where we are now, and where we need to go from here. RECENT FINDINGS: Some of the important recent advances include: (1) improved imaging of the brain and inner ear, (2) development of new eye movement recording and analysis techniques, (3) development of new tests of otolith function, (4) particle repositioning maneuvers for all types of benign paroxysmal positional vertigo, and (5) improved bedside diagnosis and treatment of vestibular neuritis. SUMMARY: The cause and treatment for some common neuro otologic disorders is now well delineated. The diagnosis and management of less common disorders has improved as well. Future work is still required to advance the science of vestibular physiology and pathophysiology and ultimately to discover new ways to improve the health of patients with these disorders. PMID- 23042051 TI - Characteristics of young infants in whom human parechovirus, enterovirus or neither were detected in cerebrospinal fluid during sepsis evaluations. AB - BACKGROUND: Human parechovirus (HPeV) causes central nervous system (CNS) infection in infants. To further understand HPeV CNS infection, we describe its clinical, laboratory and epidemiologic characteristics from a Midwestern US tertiary care center. Because HPeV CNS infections have appeared clinically and seasonally similar to enterovirus (EV) infections, we retrospectively compared characteristics of young infants undergoing sepsis evaluations in whom HPeV, EV or neither were detected in cerebrospinal fluid (CSF). METHODS: HPeV real-time reverse-transcription polymerase chain reaction (RT-PCR) assay was performed on frozen nucleic acid extracts of CSF specimens submitted for EV RT-PCR assay from children seen at our hospital in 2009. HPeV genotyping was performed by sequencing of the viral protein 1 region. Clinical data were abstracted from medical records retrospectively for EV-positive, HPeV-positive and age-matched controls in whom neither virus was detected from CSF testing. RESULTS: HPeV was detected in 66 of the 388 (17%) CSF specimens whereas EV was detected in 54 of the 388 (14%) from June through October 2009. Genotyping identified HPeV3 in 51 of the 66 (77%) positive CSF specimens. Males predominated (61%) with the most common presenting symptoms (91%) being fever and irritability. All HPeV-positive patients were <5 months of age. Eight required admission to the pediatric intensive care unit. In multivariate analysis, lower peripheral white blood cell counts with lower absolute lymphocyte count values, higher maximum temperatures, longer fever duration, absence of pleocytosis and longer hospitalization were independently associated with HPeV patients compared with patients with EV or patients negative for both HPeV and EV. CONCLUSIONS: Our data indicate that HPeV3, an emerging CNS pathogen of infants in the United States, should be considered in sepsis-like presentation even without CSF pleocytosis. Addition of HPeV RT-PCR to EV RT-PCR assay for CSF specimens of patients <6 months of age could reduce hospital stay and costs while improving clinical management. PMID- 23042058 TI - Symptoms and signs of neuro-otologic disorders. AB - PURPOSE OF REVIEW: Symptoms and signs of neuro-otologic disorders are critical components in the diagnostic assessment of patients with vestibular symptoms such as vertigo, dizziness, unsteadiness, and oscillopsia. Most diagnoses can be accomplished at the bedside. An understanding of key diagnostic principles is essential for all practicing neurologists, who are often faced with determining whether such patients warrant urgent diagnostic testing or hospital admission. This article introduces readers to core concepts and recent advances in the understanding of directed history taking and physical examination in patients with vestibular symptoms or suspected neuro-otologic disorders. RECENT FINDINGS: International consensus definitions for vestibular symptoms have recently been published. During the past 5 years, a growing body of scientific evidence has demonstrated that the traditional approach to bedside diagnosis of patients with vertigo and dizziness is inadequate. Former teaching that history taking should first rely on categorizing symptoms by type (eg, vertigo, presyncope, disequilibrium, nonspecific dizziness) has been replaced by an emphasis on categorizing timing and triggers for vestibular symptoms, which focuses the clinician's attention on four key syndromic patterns: (1) acute, spontaneous, prolonged vestibular symptoms; (2) episodic, positional vestibular symptoms; (3) episodic, spontaneous vestibular symptoms; and (4) chronic unsteadiness (with or without oscillopsia). Each of these categories delineates a relatively narrow differential diagnosis within which a focused examination distinguishes between benign common causes and dangerous uncommon ones. SUMMARY: A focused approach to bedside assessment of patients with vestibular symptoms is essential for accurate and efficient diagnosis. All neurologists should be aware of major recent advances. PMID- 23042059 TI - Acute constant dizziness. AB - PURPOSE OF REVIEW: This article describes an approach to the diagnosis and management of acute constant dizziness, one of the most unnerving presentations in medicine. Patients with acute constant dizziness can be completely debilitated by the symptoms. Most cases are caused by a self-limited disorder, typically vestibular neuritis. However, a significant proportion of cases harbor a stroke that could be life threatening. Discriminating a self-limited disorder from a life-threatening disorder can be challenging and often hinges on findings, which may be subtle, from the ocular motor examination. RECENT FINDINGS: Early research indicates that bedside ocular motor findings play a critical role in differentiating vestibular neuritis from stroke. SUMMARY: This article describes an approach to the patient with acute constant dizziness. PMID- 23042060 TI - Positional dizziness. AB - PURPOSE: This article reviews the most common conditions that are caused by changes in head or body positions. Practical clinical methods to help distinguish vestibular from nonvestibular and central from peripheral vestibular positional dizziness are discussed. This article also reviews the treatment methods of selected canal variants of benign paroxysmal positional vertigo (BPPV). RECENT FINDINGS: Two recent evidence-based guidelines have established canalith repositioning maneuvers (Epley and Semont maneuvers) as safe and highly effective in the treatment of posterior canal BPPV. Recent studies suggest the Gufoni and the Lempert roll (barbecue) maneuvers are effective in treating lateral canal forms of BPPV. SUMMARY: Most cases of positional vertigo are of peripheral vestibular origin and can be effectively treated by simple positioning maneuvers. This article reviews the variants of BPPV encountered in clinical practice, including mechanistic cause, differential diagnosis, prognosis, and treatment. Generous use of figures is intended to aid in understanding the most effective treatment maneuver techniques for the more common forms of BPPV. Clinicians who can recognize the types of nystagmus associated with the various canal types of BPPV can usually recognize CNS causes as distinct. PMID- 23042061 TI - Recurrent spontaneous attacks of dizziness. AB - PURPOSE OF REVIEW: This article describes the common causes of recurrent vertigo and dizziness that can be diagnosed largely on the basis of history. RECENT FINDINGS: Ninety percent of spontaneous recurrent vertigo and dizziness can be explained by six disorders: (1) Meniere disease is characterized by vertigo attacks, lasting 20 minutes to several hours, with concomitant hearing loss, tinnitus, and aural fullness. Aural symptoms become permanent during the course of the disease. (2) Attacks of vestibular migraine may last anywhere from minutes to days. Most patients have a previous history of migraine headaches, and many experience migraine symptoms during the attack. (3) Vertebrobasilar TIAs affect older adults with vascular risk factors. Most attacks last less than 1 hour and are accompanied by other symptoms from the posterior circulation territory. (4) Vestibular paroxysmia is caused by vascular compression of the eighth cranial nerve. It manifests itself with brief attacks of vertigo that recur many times per day, sometimes with concomitant cochlear symptoms. (5) Orthostatic hypotension causes brief episodes of dizziness lasting seconds to a few minutes after standing up and is relieved by sitting or lying down. In older adults, it may be accompanied by supine hypertension. (6) Panic attacks usually last minutes, occur in specific situations, and are accompanied by choking, palpitations, tremor, heat, and anxiety. Less common causes of spontaneous recurrent vertigo and dizziness include perilymph fistula, superior canal dehiscence, autoimmune inner ear disease, otosclerosis, cardiac arrhythmia, and medication side effects. SUMMARY: Neurologists need to venture into otolaryngology, internal medicine, and psychiatry to master the differential diagnosis of recurrent dizziness. PMID- 23042062 TI - Migraine and motion sensitivity. AB - PURPOSE OF REVIEW: This article describes vestibular migraine and motion sensitivity. Migraine headache is often accompanied by dizziness or unsteadiness. A diagnosis of vestibular migraine requires that a patient meet International Headache Society criteria for migraine headache, have episodic or fluctuating symptoms highly suggestive of a balance disorder, have no recognized alternative neuro-otologic diagnosis, and experience migrainous symptoms during episodes of vertigo or imbalance. This article discusses these diagnostic criteria; the epidemiology of vestibular migraine; laboratory abnormalities in vestibular migraine; the pathophysiology of vestibular migraine; the treatment of vestibular migraine; comorbidities and overlap with other neuro-otologic disorders, including basilar artery migraine, Meniere disease, and anxiety disorders; and the genetics of vestibular migraine. This review also discusses motion sickness and motion sensitivity, including their relationship with migraine, pathophysiology, and treatment. RECENT FINDINGS: Recent findings regarding vestibular migraine include new nomenclature for the disorder, validation of diagnostic criteria, new ideas regarding pathophysiology, and reviews of small treatment trials. SUMMARY: Vestibular migraine is becoming the preferred designation for a neuro-otologic disorder with a migrainous etiology that causes dizziness and disequilibrium. Criteria have been established for diagnosing this disorder. Although pathophysiology is as yet uncertain and randomized trials are lacking, treatment recommendations can be made. Motion sickness represents a condition often associated with migraine that can reduce quality of life. PMID- 23042063 TI - Chronic subjective dizziness. AB - PURPOSE OF REVIEW: In 1986, the German neurologists Thomas Brandt and Marianne Dieterich described a syndrome of phobic postural vertigo (PPV) based on clinical observations of patients with nonvertiginous dizziness that could not be explained by then-known neuro-otologic disorders. Subsequent research by an American team led by Jeffrey Staab and Michael Ruckenstein confirmed the core physical symptoms of PPV, clarified its relationship to behavioral factors, and streamlined its definition, calling the syndrome chronic subjective dizziness (CSD). This article reviews the 26-year history of PPV and CSD and places it within the context of current neurologic practice. RECENT FINDINGS: Recent investigations in Europe, the United States, Israel, and Japan have validated the primary symptoms of CSD; identified its provoking factors and precipitants; elucidated its long-term clinical course, differential diagnosis, and common comorbidities; developed successful treatment strategies with serotonergic antidepressants, vestibular habituation, and possibly cognitive-behavioral therapy; and raised new hypotheses about pathophysiologic processes that initiate and maintain the disorder. In tertiary neuro-otology centers where it is recognized, CSD is the second most common diagnosis among patients presenting with vestibular symptoms. SUMMARY: A quarter century of research has established CSD as a common clinical entity in neurologic and otorhinolaryngologic practice. Its identification and treatment offer relief to many patients previously thought to have enigmatic and unmanageable cases of persistent dizziness. Internationally sanctioned diagnostic criteria for CSD are under development for the first edition of the International Classification of Vestibular Disorders, scheduled for publication in early 2013. PMID- 23042064 TI - Less common neuro-otologic disorders. AB - PURPOSE OF REVIEW: A systematic approach to the history and examination allows the physician to diagnose the most common vestibular disorders of the brain or inner ear. However, some less common disorders require a specific familiarity so that they are not misdiagnosed as one of the more common disorders,treated inappropriately, or misattributed to a psychogenic etiology. This article describes four of the less common disorders that can present with a primary problem of dizziness and imbalance: (1) mal de debarquement syndrome, (2) bilateral vestibulopathy, (3) cerebellar ataxia, and (4) vestibular schwannomas (ie, acoustic neuromas). RECENT FINDINGS: Associated clinical features of mal de debarquement syndrome have recently been investigated to clarify the spectrum of the syndrome. The combination of cerebellar ataxia, neuropathy, and vestibular areflexia (bilateral vestibulopathy) has been summated into a new syndrome. Further refinement of ocular motor features of cerebellar ataxia can narrow genetic testing requirements. Vestibular schwannomas remain an uncommon etiology for isolated dizziness; recent imaging studies have helped quantify the low yield of screening MRI protocols for the evaluation of undefined dizziness. SUMMARY: A working knowledge of these less common disorders will help the physician make the diagnosis efficiently by gathering key elements of the history and fine-tuning diagnostic testing. PMID- 23042065 TI - Grounded for an ethical dilemma: disequilibrium in a commercial airline pilot. AB - This article presents the case of a 41-year-old airline pilot with benign paroxysmal positional vertigo who requests that his diagnosis not be disclosed to his commercial airline employer or his aviation medical examiner because it may result in the suspension of medical certification. The legal and ethical requirements for physicians reporting impaired pilots are discussed as well as practical recommendations for handling such situations. The argument is made that a physician's obligation to honor patient confidentiality should not take precedence over his or her duty to protect the safety and well-being of the airplane passengers and the general public. If the patient chooses not to self report, a physician has an ethical obligation to report the patient's medical condition to the Federal Aviation Administration. PMID- 23042066 TI - Anxiety in a dizzy patient: the importance of communication in improving outcome. AB - Most patients with dizziness have a benign self-limited condition, often of labyrinthine origin; however, some develop a more intractable form of dizziness that can be challenging to evaluate. In many of these patients, brain imaging, vestibular testing, and clinical examination are normal, but the patient is significantly impaired. Many such patients have coexisting anxiety, which can make it difficult to determine whether the anxiety is a reaction to the dizziness or its primary cause. A careful history, including an assessment of the impact of symptoms on quality-of-life, social, and work-related issues is critical, and effective patient communication is essential. The following case exemplifies how a high-functioning person can become severely limited because of the complex intertwining of several types of dizziness with anxiety. PMID- 23042067 TI - Coding for vestibular tests. PMID- 23042068 TI - Guidelines in practice: therapies for benign paroxysmal positional vertigo. AB - Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo. This article describes the presentation and physical examination of a patient with BPPV. The case is then used to explore various features of the diagnosis, examination, and management of BPPV, with a focus on the 2008 AAN practice parameter on therapies for BPPV. PMID- 23042075 TI - Identification of potent VHZ phosphatase inhibitors with structure-based virtual screening. AB - VH1-like phosphatase Z (VHZ) has proved to be a promising target for the development of therapeutics for the treatment of human cancers. Here, we report the first example for a successful application of structure-based virtual screening to identify the novel small-molecule inhibitors of VHZ. These inhibitors revealed high potencies with the associated IC(50) values ranging from 3 to 20 uM and were also screened for having desirable physicochemical properties as a drug candidate. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize inhibitory and anticancer activities. Structural features relevant to the stabilization of the newly identified inhibitors in the active site of VHZ are discussed in detail. PMID- 23042076 TI - Automated large-scale culture and medium-throughput chemical screen for modulators of proliferation and viability of human induced pluripotent stem cell derived neuroepithelial-like stem cells. AB - The aim of this study was to demonstrate proof-of-concept feasibility for the use of human neural stem cells (NSCs) for high-throughput screening (HTS) applications. For this study, an adherent human induced pluripotent stem (iPS) cell-derived long-term, self-renewing, neuroepithelial-like stem (lt-NES) cell line was selected as a representative NSC. Here, we describe the automated large scale serum-free culture ("scale-up") of human lt-NES cells on the CompacT SelecT cell culture robotic platform, followed by their subsequent automated "scale-out" into a microwell plate format. We also report a medium-throughput screen of 1000 compounds to identify modulators of neural stem cell proliferation and/or survival. The screen was performed on two independent occasions using a cell viability assay with end-point reading resulting in the identification of 24 potential hit compounds, 5 of which were found to increase the proliferation and/or survival of human lt-NES on both occasions. Follow-up studies confirmed a dose-dependent effect of one of the hit compounds, which was a Cdk-2 modulator. This approach could be further developed as part of a strategy to screen compounds to either improve the procedures for the in vitro expansion of neural stem cells or to potentially modulate endogenous neural stem cell behavior in the diseased nervous system. PMID- 23042077 TI - Creation of a six-fingered artificial transcription factor that represses the hepatitis B virus HBx gene integrated into a human hepatocellular carcinoma cell line. AB - Chronic hepatitis B virus (HBV) infection is an independent risk factor for the development of hepatocellular carcinoma (HCC). The HBV HBx gene is frequently identified as an integrant in the chromosomal DNA of patients with HCC. HBx encodes the X protein (HBx), a putative viral oncoprotein that affects transcriptional regulation of several cellular genes. Therefore, HBx may be an ideal target to impede the progression of HBV infection-related HCC. In this study, integrated HBx was transcriptionally downregulated using an artificial transcription factor (ATF). Two three-fingered Cys2-His2 zinc finger (ZF) motifs that specifically recognized two 9-bp DNA sequences regulating HBx expression were identified from a phage-display library. The ZF domains were linked into a six-fingered protein that specified an 18-bp DNA target in the Enhancer I region upstream of HBx. This DNA-binding domain was fused with a Kruppel-associated box (KRAB) transcriptional repression domain to produce an ATF designed to downregulate HBx integrated into the Hep3B HCC cell line. The ATF significantly repressed HBx in a luciferase reporter assay. Stably expressing the ATF in Hep3B cells resulted in significant growth arrest, whereas stably expressing the ATF in an HCC cell line lacking integrated HBx (HepG2) had virtually no effect. The targeted downregulation of integrated HBx is a promising novel approach to inhibiting the progression of HBV infection-related HCC. PMID- 23042078 TI - qCMA: a desktop application for quantitative collective cell migration analysis. AB - Collective migration is an important cellular trait, which is intensely studied by both basic and translational researchers. Investigation of the underlying mechanisms necessitates high-throughput assays and computational algorithms capable of generating reproducible quantitative measurements of cell migration. We present a desktop tool that can be used easily by any researcher, to quantify both fluorescent and phase-contrast images produced in the course of commonly used gap closure ("scratch," "wound healing") collective migration assays. The software has a simple graphical interface that allows the user to tune the relevant parameters and process large numbers of images (or movies). The output contains segmented images and the numerical values inferred from them, allowing easy quantitative analysis of the results. PMID- 23042079 TI - Dynamic interactions between cyclodextrin, an organic pollutant, and granular activated carbon in column studies. AB - In this study, the dynamic interactions between cyclodextrin (CD), an organic chemical and granular activated carbon (GAC) were investigated using column studies. Breakthrough curves of a chlorinated solvent, trichloroethylene (TCE) were obtained over a range of concentrations of 2-hydroxypropyl-beta-cyclodextrin (HPCD) (0, 20, and 50 g L(-1)) and flow velocities (1.0, 4.0, and 10.2 mL min( 1)). Important transport parameters (i.e. residence time, dispersion coefficient, retardation factor) were estimated using truncated temporal moment analysis. Our result shows that increasing CD concentration resulted in earlier TCE breakthrough, demonstrated by decreasing residence times which are 306.23, 151.26, and 102.24 pore volumes for 0, 20, and 50 g L(-1) CD respectively. Comparison of the original breakthrough curves (BTCs) under different CD concentrations to the solubility-enhancement-rescaled BTCs showed (1) the presence of CD decreases the relative degree of TCE sorption to GAC and (2) all 3 curves exhibited similar rescaled times at which they reach 50% of the input concentration. The lowest flow rate, (1.0 mL min(-1)), resulted in a more symmetrical BTC, indicating more ideal conditions were achieved under the longer exposure time provided by this flow rate. As the flow rate increases the first appearance of TCE in the eluent occurs relatively earlier and exhibits comparatively greater delay in achieving full breakthrough, suggesting non equilibrium processes are more significant at higher flow rates. PMID- 23042080 TI - Syntaxin 11 is required for NK and CD8+ T-cell cytotoxicity and neutrophil degranulation. AB - Syntaxin 11 (STX11) controls vesicular trafficking and is a key player in exocytosis. Since Stx11 mutations are causally associated with a familial hemophagocytic lymphohistio-cytosis, we wanted to clarify whether STX11 is functionally important for key immune cell populations. This was studied in primary cells obtained from newly generated Stx11(-/-) mice. Our data revealed that STX11 is not only widely expressed in different immune cells, but also induced upon LPS or IFN-gamma treatment. However, Stx11 deficiency does not affect macrophage phagocytic function and cytokine secretion, mast cell activation, or antigen presentation by DCs. Instead, STX11 selectively controls lymphocyte cytotoxicity in NK and activated CD8(+) T cells and degranulation in neutrophils. Stx11(-/-) NK cells and CTLs show impaired degranulation, despite a comparable activation, maturation and expression of the complex-forming partners MUNC18-2 and VTI1B. In addition, Stx11(-/-) CTLs and NK cells produce abnormal levels of IFN-gamma. Since functional reconstitution rescues the defective phenotype of Stx11(-/-) CTLs, we suggest a direct, specific and key role of STX11 in controlling lymphocyte cytotoxicity, cytokine production and secretion. Finally, we show that these mice are a very useful tool for dissecting the role of STX11 in vesicular trafficking and secretion. PMID- 23042081 TI - Spontaneous persistent activity in entorhinal cortex modulates cortico hippocampal interaction in vivo. AB - Persistent activity is thought to mediate working memory during behavior. Can it also occur during sleep? We found that the membrane potential of medial entorhinal cortex layer III (MECIII) neurons, a gateway between neocortex and hippocampus, showed spontaneous, stochastic persistent activity in vivo in mice during Up-Down state oscillations (UDS). This persistent activity was locked to the neocortical Up states with a short delay, but persisted over several cortical UDS cycles. Lateral entorhinal neurons did not show substantial persistence, and current injections similar to those used in vitro failed to elicit persistence in vivo, implicating network mechanisms. Hippocampal CA1 neurons' spiking activity was reduced during neocortical Up states, but was increased during MECIII persistent states. These results provide, to the best of our knowledge, the first direct evidence for persistent activity in MECIII neurons in vivo and reveal its contribution to cortico-hippocampal interaction that could be involved in working memory and learning of long behavioral sequences during behavior, and memory consolidation during sleep. PMID- 23042083 TI - Hydrophilicity control of visible-light hydrogen evolution and dynamics of the charge-separated state in dye/TiO2/Pt hybrid systems. AB - Visible-light-driven H(2) evolution based on Dye/TiO(2)/Pt hybrid photocatalysts was investigated for a series of (E)-3-(5'-{4-[bis(4-R(1)-phenyl)amino]phenyl} 4,4'-(R(2))(2)-2,2'-bithiophen-5-yl)-2-cyanoacrylic acid dyes. Efficiencies of hydrogen evolution from aqueous suspensions in the presence of ethylenediaminetetraacetic acid as electron donor under illumination at lambda>420 nm were found to considerably depend on the hydrophilic character of R(1), varying in the order MOD (R(1)=CH(3)OCH(2), R(2)=H)~MO4D (R(1)=R(2)=CH(3)OCH(2))>HD (R(1)=R(2)=H)>PD (R(1)=C(3)H(7), R(2)=H). In the case of MOD/TiO(2)/Pt, the apparent quantum yield for photocatalyzed H(2) generation at 436 nm was 0.27+/-0.03. Transient absorption measurements for MOD- or PD grafted transparent films of TiO(2) nanoparticles dipped into water at pH 3 commonly revealed ultrafast formation (<100 fs) of the dye radical cation (Dye(.+) ) followed by multicomponent decays, which involve minor fast decays (<5 ps) almost independent of R(1) and major slower decays with significant differences between the two samples: 1) the early decay of the major components for MOD is about 2.5 times slower than that for PD and 2) a redshift of the spectrum occurred for MOD with a time constant of 17 ps, but not for PD. The substituent effects on H(2) generation as well as on transient behavior have been discussed in terms substituent-dependent charge recombination (CR) of Dye(.+) with electrons in bulk, inner-trap, and/or interstitial-trap states, arising from different solvent reorganization. PMID- 23042084 TI - An algorithm for the safety of costal diaphragm electromyography derived from ultrasound. AB - INTRODUCTION: Costal diaphragm electromyography (EMG) remains unpopular due to the risk of pneumothorax. In this study we assessed the safety of the "trans intercostal" method of diaphragm EMG using B-mode ultrasound. METHODS: Twenty healthy subjects participated in this investigation. The diaphragm and the lung were visualized in the most distal intercostal space (dICS) with ultrasound. The risk of pneumothorax was assessed at the mid-clavicular, anterior, and mid axillary levels, during normal and deep breathing, in supine and upright postures. RESULTS: The dICS at the anterior axillary level was the safest landmark for diaphragm EMG during normal breathing, with the subject supine. The mid-clavicular level is the least optimal location for EMG. The upright position and deep breaths increase the risk of pneumothorax. CONCLUSIONS: The safety of the trans-intercostal method of diaphragm EMG depends on the anatomic level chosen to insert the needle, patient position, and breathing pattern. Hence, we have developed a safety algorithm for electromyographers. PMID- 23042085 TI - Calcite surface structure and reactivity: molecular dynamics simulations and macroscopic surface modelling of the calcite-water interface. AB - Calcite-water interactions are important not only in carbon sequestration and the global carbon cycle, but also in contaminant behaviour in calcite-bearing host rock and in many industrial applications. Here we quantify the effect of variations in surface structure on calcite surface reactivity. Firstly, we employ classical Molecular Dynamics simulations of calcite surfaces containing an etch pit and a growth terrace, to show that the local environment in water around structurally different surface sites is distinct. In addition to observing the expected formation of more calcium-water interactions and hydrogen-bonds at lower coordinated sites, we also observed subtle differences in hydrogen bonding around acute versus obtuse edges and corners. We subsequently used this information to refine the protonation constants for the calcite surface sites, according to the Charge Distribution MUltiSite Ion Complexation (CD-MUSIC) approach. The subtle differences in hydrogen bonding translate into markedly different charging behaviour versus pH, in particular for acute versus obtuse corner sites. The results show quantitatively that calcite surface reactivity is directly related to surface topography. The information obtained in this study is not only crucial for the improvement of existing macroscopic surface models of the reactivity of calcite towards contaminants, but also improves our atomic-level understanding of mineral-water interactions. PMID- 23042086 TI - Splitting of dihydrogen by five-membered zirconacycloallenoids: a novel pathway to conjugated diene zirconocene complexes. AB - The five-membered zirconacycloallenoids 2 react rapidly with dihydrogen under mild conditions to yield the corresponding (s-cis-conjugated diene)zirconocenes 3. The reaction involves splitting of the H(2) molecule between the metal center and a ligand carbon atom. PMID- 23042082 TI - OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons. AB - The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types has been hampered by the lack of cell-specific tools. We identified a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells. By combining transgenic mice and optogenetic tools, we found that OLM cells are important for gating the information flow in CA1, facilitating the transmission of intrahippocampal information (from CA3) while reducing the influence of extrahippocampal inputs (from the entorhinal cortex). Furthermore, we found that OLM cells were interconnected by gap junctions, received direct cholinergic inputs from subcortical afferents and accounted for the effect of nicotine on synaptic plasticity of the Schaffer collateral pathway. Our results suggest that acetylcholine acting through OLM cells can control the mnemonic processes executed by the hippocampus. PMID- 23042087 TI - Diaphragm pacing and noninvasive respiratory management of amyotrophic lateral sclerosis/motor neuron disease. AB - INTRODUCTION: Although it is known that continuous noninvasive ventilation (CNIV) can prolong life in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), in this study we explore similar claims for diaphragm pacing (DP). METHODS: NIV and DP users' vital capacities (VCs) over time and duration of NIV and CNIV dependence were analyzed for 354 non-DP and 8 DP ALS/MND patients. RESULTS: Patients had a higher rate of monthly VC decline before NIV use (5.1 +/- 7.6%) than during NIV use (2.5 +/- 3.6%) (P < 0.01, 95% CI 0.84-4.5); the decline for 4 DP users was 3.7-20%. Fifty-five ALS/MND patients used part-time NIV for 19.9 +/- 27.6 months until tracheostomy/death, whereas 113 others used it for 10.9 +/- 10.5 months until CNIV dependence for another 12.8 +/- 16.2 months. After placement, 7 DP users were CNIV dependent in 8.0 +/- 7.0 months, whereas 6 underwent tracheostomy/died in 18.2 +/- 13.7 months. CONCLUSIONS: CNIV prolonged the survival of 113 of the 354 non-DP and 6 DP ALS/MND patients by 12.8 and 10.2 months, respectively. DP provided no benefit on VC or mechanical ventilation-free survival. PMID- 23042088 TI - Regeneration of articular cartilage by adipose tissue derived mesenchymal stem cells: perspectives from stem cell biology and molecular medicine. AB - Adipose-derived stem cells (ASCs) have been discovered for more than a decade. Due to the large numbers of cells that can be harvested with relatively little donor morbidity, they are considered to be an attractive alternative to bone marrow derived mesenchymal stem cells. Consequently, isolation and differentiation of ASCs draw great attention in the research of tissue engineering and regenerative medicine. Cartilage defects cause big therapeutic problems because of their low self-repair capacity. Application of ASCs in cartilage regeneration gives hope to treat cartilage defects with autologous stem cells. In recent years, a lot of studies have been performed to test the possibility of using ASCs to re-construct damaged cartilage tissue. In this article, we have reviewed the most up-to-date articles utilizing ASCs for cartilage regeneration in basic and translational research. Our topic covers differentiation of adipose tissue derived mesenchymal stem cells into chondrocytes, increased cartilage formation by co-culture of ASCs with chondrocytes and enhancing chondrogenic differentiation of ASCs by gene manipulation. PMID- 23042089 TI - Metal-organic framework MIL-53(Al) as a solid-phase microextraction adsorbent for the determination of 16 polycyclic aromatic hydrocarbons in water samples by gas chromatography-tandem mass spectrometry. AB - In this paper, the potential applications of metal-organic framework (MOF) materials as fiber coatings for the solid-phase microextraction (SPME) of polycyclic aromatic hydrocarbons (PAHs) in water samples were explored. Fibers coated with MIL-53(Al, Cr, Fe) materials were fabricated by an adhesive method for SPME. The quantitation was performed by gas chromatography-tandem mass spectrometry (GC-MS/MS) using the multiple reaction monitoring mode. Among the three MIL-53(M) coatings, MIL-53(Al) showed the highest extraction efficiency towards PAHs under the current fabrication procedure. Under optimized conditions, the MIL-53(Al)-coated fiber showed good precision (relative standard deviation <12.5%), low detection limits (0.10 ng L(-1) to 0.73 ng L(-1), S/N = 3), and good linearity (R(2) > 0.98) for aqueous solutions containing 16 PAH . The fiber also offered high thermal and chemical stability. The method developed based on MIL 53(Al) SPME-GC-MS/MS was successfully applied in the analysis of real water samples. Based on the simulation results, the PAHs were adsorbed on MIL-53(Al) primarily through the hydrophobic and pi-pi interactions between PAHs and the organic linker of the material. The results presented in this paper indicate that water-stable MOF materials have great potential for the SPME of aromatic compounds in water samples. PMID- 23042090 TI - Regioselective chlorine-addition reaction toward C54Cl8 and role of chlorine atoms in Stone-Wales rearrangement. AB - By means of density functional theory, detailed studies of regioselective chlorine-addition reactions of two C(54)Cl(8) isomers disclose a highly competitive advantage of (#540)C(54)Cl(8) in the chlorofullerene formation process. The regioselectivity of the addition pattern in (#540)C(54)Cl(8) is found to be dependent on both local and general factors. Special structural relationships reveal that the pristine cage of (#540)C(54)Cl(8) can transform to that of (#864)C(56)Cl(10) and (#913)C(56)Cl(12) through both C(2) addition and Stone-Wales rearrangement. It is found that Stone-Wales rearrangement, which is believed to be a high energy barrier reaction, can be facilitated remarkably well if chlorine atoms participate in the rearrangement process. Furthermore, investigation into the electronic properties of C(54) exohedral fullerenes reveal the different impacts of halogen and hydrogen atoms. PMID- 23042091 TI - Rhodium(II) catalyzed diastereoselective reactions of diazoacetamides with isatins: an efficient approach to 3-hydroxy-3,3'-bioxindoles. AB - The 3,3'-bioxindole derivatives were constructed in a single step via an efficient Rh(2)(OAc)(4) catalyzed reaction of diazoacetamides with isatins. This novel method provides an alternative pathway towards 3-hydroxy-3,3'-bioxindoles in good yield (up to 78%) with high diastereoselectivity (up to 95 : 5). PMID- 23042092 TI - Beyond here there be dragons. PMID- 23042093 TI - Morbid obesity in pregnancy: a review. AB - PURPOSE OF REVIEW: This article aims to draw together recent thinking on pregnancy and obesity, with a particular emphasis on prevention strategies and emerging clinical complications. RECENT FINDINGS: New studies including a large meta-analysis have highlighted that weight reduction strategies are not associated with adverse maternal or perinatal outcomes, and there are suggestions that an approach of dietary modification alone may be associated with reduction in gestational weight gain. These findings are critically discussed with reference to future planned trials. New literature regarding hitherto under reported complications of obesity in pregnancy such as ischaemic heart disease, schizophrenia and sleep disorders is highlighted. SUMMARY: There will be a need to focus on obesity prevention in the pregnant population as resources will not be adequate to the increasing incidence of the problem. PMID- 23042095 TI - Prognostic significance of TIMP3 hypermethylation in post-treatment salivary rinse from head and neck squamous cell carcinoma patients. AB - Hypermethylation in the promoter regions of genes is associated with suppression of gene expression and has been considered a potential molecular marker for several tumor types, including head and neck squamous cell carcinomas (HNSCC). Moreover, hypermethylation can be detected in body fluids such as saliva and can be useful for the diagnosis and prognosis of patients suffering from cancer. To evaluate the hypermethylation profile as a tool for early detection of tumor recurrences, this study determines the methylation status of 24 genes in salivary rinses collected from HNSCC patients at diagnosis, just after the last curative treatment and in the patients' follow-up visit at 6 months after treatment. In the analysis of salivary rinse samples taken at diagnosis of HNSCC patients, five genes (CCNA1, DAPK, DCC, MGMT and TIMP3) showed high specificity and sensitivity. Hypermethylation in any of these five genes was correlated with the presence of tumors in the oral cavity. Patients with TIMP3 methylation in samples collected 6 months after the last curative treatment had lower local recurrence-free survival (P = 0.008). Multivariate analysis confirmed that this hypermethylation pattern remained as an independent prognostic factor for local recurrence (P = 0.025). This study presents, for the first time, the detection of TIMP3 promoter hypermethylation in post-treatment salivary rinse as an independent prognostic maker for local recurrence-free survival in patients with HNSCC, justifying the use of DNA hypermethylation detection in saliva as a tool for identifying and monitoring HNSCC patients' subgroups with high risk of developing local recurrence. PMID- 23042094 TI - Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2. AB - In America and Western Europe, prostate cancer is the second leading cause of death in men. Emerging evidence suggests that chronic inflammation is a major risk factor for the development and metastatic progression of prostate cancer. We previously reported that the chemopreventive polyphenol curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. In this study, we analyze the effects of curcumin on prostate carcinoma growth, apoptosis and metastasis. We show that curcumin inhibits translocation of NFkappaB to the nucleus through the inhibition of the IkappaB-kinase (IKKbeta, leading to stabilization of the inhibitor of NFkappaB, IkappaBalpha, in PC-3 prostate carcinoma cells. Inhibition of NFkappaB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NFkappaB. The combination of curcumin with the synthetic IKKbeta inhibitor, SC-541, shows no additive or synergistic effects indicating that the two compounds share the target. Treatment of the cells with curcumin and siRNA-based knockdown of CXCL1 and -2 induce apoptosis, inhibit proliferation and downregulate several important metastasis-promoting factors like COX2, SPARC and EFEMP. In an orthotopic mouse model of hematogenous metastasis, treatment with curcumin inhibits statistically significantly formation of lung metastases. In conclusion, chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive proinflammatory and prometastatic feedback loop between NFkappaB and CXCL1/-2. Curcumin disrupts this feedback loop by the inhibition of NFkappaB signaling leading to reduced metastasis formation in vivo. PMID- 23042096 TI - DNA damage in exfoliated cells and histopathological alterations in the urinary tract of mice exposed to cigarette smoke and treated with chemopreventive agents. AB - Cigarette smoke (CS) is convincingly carcinogenic in mice when exposure starts at birth. We investigated the induction and modulation of alterations in the kidney and urinary bladder of CS-exposed mice. A total of 484 strain H Swiss mice were either sham-exposed or exposed since birth to mainstream CS (MCS) for 4 months. Dietary agents, including myo-inositol, suberoylanilide hydroxamic acid, bexarotene, pioglitazone and a combination of bexarotene and pioglitazone, were administered after weaning. Comet analyses showed that, after 2 and 4 months, MCS causes DNA damage in exfoliated urothelial cells, which can be prevented by myo inositol and the peroxisome proliferator-activated receptor-gamma ligand pioglitazone. After 7 months, the 17.6% of MCS-exposed male mice exhibited lesions of the urinary tract versus the 6.1% of sham-exposed mice, which emphasizes the role of sex hormones in urinary tract carcinogenesis. Myo-inositol and the RXR-specific retinoid bexarotene did not affect these alterations. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (Vorinostat) increased the incidence of kidney epithelium hyperplasia. Pioglitazone significantly enhanced the incidence of kidney lesions as compared with mice exposed to MCS only, indicating possible adverse effects of this antidiabetic drug, which were lost upon combination with bexarotene according to a combined chemoprevention strategy. RXR is a heterodymeric partner for peroxisome proliferator-activated receptor-gamma, thereby modulating the expression of multiple target genes. In conclusion, there is contrast between the ability of pioglitazone to inhibit DNA damage in exfoliated cells and the alterations induced in the urinary tract of MCS-exposed mice, suggesting the occurrence of non-genotoxic mechanisms for this drug. PMID- 23042098 TI - MAPK signaling in cisplatin-induced death: predominant role of ERK1 over ERK2 in human hepatocellular carcinoma cells. AB - Hepatocellular carcinoma treatment by arterial infusion of cis diamminedichloroplatinum-II (cisplatin) exhibits certain therapeutic efficacy. However, optimizations are required and the mechanisms underlying cisplatin proapoptotic effect remain unclear. The mitogen-activated protein kinase (MAPK) pathway plays a key role in cell response to cisplatin and the functional specificity of the isoform MAPK/ERK kinase 1 and 2 (MEK1/2) and ERK1/2 could influence this response. The individual contribution of each kinase on cisplatin induced death was thus analyzed after a transient or stable specific inhibition by RNA interference in the human hepatocellular carcinoma cells Huh-7 or in knockout mice. We demonstrated here that ERK1 played a predominant role over ERK2 in cisplatin-induced death, whereas MEK1 and MEK2 acted in a redundant manner. Indeed, at clinically relevant concentrations of cisplatin, ERK1 silencing alone was sufficient to protect cells from cisplatin-induced death both in vitro, in Huh-7 cells and ERK1(-/-) hepatocytes, and in vivo, in ERK1-deficient mice. Moreover, we showed that ERK1 activity correlated with the induction level of the proapoptotic BH3-only protein Noxa, a critical mediator of cisplatin toxicity. On the contrary, ERK2 inhibition upregulated ERK1 activity, favored Noxa induction and sensitized hepatocarcinoma cells to cisplatin. Our results point to a crucial role of ERK1 in cisplatin-induced proapoptotic signal and lead us to propose that ERK2-specific targeting could improve the efficacy of cisplatin therapy by increasing ERK1 prodeath functions. PMID- 23042097 TI - Hypoxia-inducible factor-2alpha is essential in activating the COX2/mPGES-1/PGE2 signaling axis in colon cancer. AB - Cyclooxygenase 2 (COX2) is overexpressed in 80% of colon adenocarcinomas. However, the mechanism leading to aberrant COX2 expression in tumors is unclear. Intestinal epithelium-specific disruption of the von Hippel-Lindau tumor suppressor protein (VHL) in adenomatous polyposis coli (Apc)(min/+) mice (Vhl(DeltaIE)/Apc(min/+)) resulted in constitutive activation of hypoxia inducible factor (HIF), robustly enhanced colon carcinogenesis and potentiated COX2 expression in normal colon epithelium and tumors. In this study, we hypothesize that HIF regulates COX2 expression in colon tumors, and this regulation is critical for HIF-mediated colon carcinogenesis. COX2 was demonstrated to be a direct target gene of HIF-2alpha, and genetic disruption of HIF-2alpha abolished the induction of COX2 in tumors. Furthermore, inhibition of COX2 by nimesulide reduced HIF-2alpha-induced colon tumor formation. Interestingly, the levels of prostaglandin E(2) (PGE(2)), the downstream effector of COX2, remained elevated in normal and tumor tissues of the nimesulide-treated Vhl(DeltaIE)/Apc(min/+) mice. Further examination revealed that the terminal PGE(2) synthesis enzyme microsomal prostaglandin E synthase 1 (mPGES-1) was overexpressed in the colon of Vhl(DeltaIE)/Apc(min/+) mice. mPGES-1 was demonstrated to be a direct target gene of HIF-2alpha, and genetic disruption of HIF-2alpha abolished the induction of mPGES-1 in colon tumors. Together, our findings demonstrate that HIF-2alpha is a major regulator of COX2/mPGES-1/PGE(2) pathway in colon tumors. PMID- 23042099 TI - Phytanic acid and the risk of non-Hodgkin lymphoma. AB - Greater consumption of red meat, processed meat and dairy products has been associated with an increased risk of non-Hodgkin lymphoma (NHL) in several previous reports. Phytanic acid, a saturated fatty acid obtained primarily through the consumption of ruminant meat and dairy products, may offer a potential underlying mechanism for these associations. In a population-based case control study of 336 cases and 460 controls conducted in Nebraska during 1999 2002, we examined whether phytanic acid-containing foods or total phytanic acid intake, estimated from a food frequency questionnaire and the published phytanic acid values of 151 food items, were associated with increased NHL risk. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals for overall NHL and the common NHL histologic subtypes. In multivariable models, higher intakes of density-adjusted beef [OR(T3 vs. T1) = 1.5 (1.1-2.2); P(trend) = 0.02], total dairy products [OR = 1.5 (1.1-2.2); P(trend) = 0.02) and milk [OR = 1.6 (1.1-2.3); P(trend) = 0.01] were associated with an increased risk of NHL. Intake of total phytanic acid was positively associated with NHL risk [OR = 1.5 (1.0-2.1); P(trend) = 0.04]. In analyses stratified by NHL subtype, greater consumption of beef was associated with an increased risk of diffuse large B-cell lymphoma, and greater consumption of milk was associated with an increased risk of follicular lymphoma (FL). Total phytanic acid intake was associated with an increased risk of FL and small lymphocytic lymphoma/chronic lymphocytic leukemia. Our results provide support that total phytanic acid and phytanic acid-containing foods may increase NHL risk. PMID- 23042100 TI - Enabling Wittig reaction on site-specific protein modification. AB - An efficient aqueous Wittig reaction was enabled on protein bioconjugation for the first time. By investigating the reaction on small molecules, peptides, and proteins, a site-specific reaction targeting "aldehyde tag" was presented. A variety of functional groups could be introduced into the protein of interest. PMID- 23042101 TI - Intravitreal cellular infiltrate imaged as punctate spots by spectral-domain optical coherence tomography in eyes with posterior segment inflammatory disease. AB - PURPOSE: To investigate the posterior segment in cases of clinically evident intraocular inflammation for punctate reflections consistent with that expected to arise from inflammatory cells. METHODS: Patients with ocular inflammatory diseases imaged with spectral-domain optical coherence tomography (SD-OCT) were retrospectively reviewed. RESULTS: There were 7 patients with mean age of 66.7 years, and the diagnosis was toxoplasmosis in 5 eyes, multiple evanescent white dot syndrome in 1 eye, and posttraumatic outer retinitis in 1 eye. At baseline, the SD-OCT showed vitreous cells as numerous punctate spots in the vitreous in all seven eyes. The SD-OCT also showed similar-sized hyperreflective dots in the retina in all seven eyes. During follow-up, reduced vitreous cellular infiltration was correlated with a decrease in the number of the punctate spots visible by SD-OCT. CONCLUSION: Eyes with intraocular inflammation had SD-OCT images of the vitreous containing punctate spots of a size consistent with that expected from inflammatory cells. Similarly sized punctate spots were seen within the retina in regions of retinitis. Additional characterization of the optical section should permit stereological estimations of actual cell counts per unit volume. PMID- 23042102 TI - Anatomical and functional results of macular hole retinal detachment surgery in patients with high myopia and posterior staphyloma treated with perfluoropropane gas or silicone oil. AB - PURPOSE: To evaluate the use of perfluoropropane gas (C3F8) versus silicone oil (SO) for retinal detachment secondary to macular hole in patients with high myopia and posterior staphyloma. METHODS: In a retrospective study, 30 eyes of 30 patients underwent pars plana vitrectomy, and C3F8 (17 patients) or SO (13 patients) tamponade; internal limiting membrane peeling was performed successfully at the first surgery in 23 patients. High-density silicone oil tamponade was used for reoperations. RESULTS: The mean values of patients' characteristics were as follows: age, 57.7 years; axial length, 29.02 mm; spherical equivalent refraction, -15.40 diopters; initial best-corrected visual acuity, 2.35 logarithm of the minimum angle of resolution; final best-corrected visual acuity, 1.59 logarithm of the minimum angle of resolution. In C3F8 group, best-corrected visual acuity significantly improved (P < 0.001), passing from 2.34 to 1.36 logarithm of the minimum angle of resolution. Vision improvement from blindness to low vision was significantly greater (P = 0.009) in C3F8 group (16 of 17; 94%) than in SO group (6 of 13; 46%). A significant higher initial success (P = 0.025) was found in the C3F8 group (16 of 17; 94%) than in the SO group (7 of 13; 54%). Proliferative vitreoretinopathy was the cause of initial failure; all these subjects achieved anatomical success after being reoperated with high-density silicone oil tamponade. CONCLUSION: C3F8 and internal limiting membrane peeling could represent the most effective strategy in highly myopic patients with macular hole retinal detachment. Other tamponade agents must be investigated. PMID- 23042103 TI - [Neuroendocrine tumours of the GI tract--data from the German NET Registry]. AB - BACKGROUND: Neuroendocrine tumours (NET) are rare and heterogeneous neoplasia. To obtain valid data on epidemiology, diagnostics, therapy, prognosis and risk factors is the aim of the German NET registry. PATIENTS AND METHODS: Data from 2009 histologically proven NET were collected from 35 NET centres between 1999 and 2010. Data collection has been performed prospectively since 2004. Results: Median follow-up was 34.5 months and median age at diagnosis 56.4 years. Primary tumour localisations were pancreas (34.2%), midgut (5.8%), stomach (6.5%), bowel (6.9%), duodenum (4.8%) and neuroendocrine CUP (12.6%). Synchronous metastases were seen in 46% and second malignancies in 12%. From 860 patients, 402 (46.7%) had functional tumours with the following hormone excess syndromes: carcinoid syndrome (19.1%; n = 164), persistent hyperinsulinaemic hypoglycaemia (17.7%; n = 152), Zollinger- Ellison syndrome (7.1%; n = 61), glucagonoma (0.7%; n = 15), Verner-Morrison syndrome (0.4%; n = 8) and somatostatinoma syndrome(0.1%; n = 2). Surgical therapy was performed in 78%, therapy with somatostatin receptor analogues(SSA) in 28%, peptide radioreceptor therapy (PRRT) in 19%, chemotherapy in 18% and interferon therapy in 6.5%. Only surgery was done in 47%, whereas 53% received a second therapy. General mortality rate during follow-up was 14.9%. The tumour-specific survival rates for 2, 5 and 10 years were 94, 85 and 70%. The 5 year survival is dependent on the surgical or non-surgical therapy (82 versus 61%, p < 0.001) and also on the primary tumour site (90/30% for midgut, 85/65% for pancreas, p < 0.001). Grading (G1, G2, G3) based on proliferation index Ki-67 recommended by the ENETS guidelines and WHO classification is highly correlated to the 5-year survival rate (88, 82, 33%, p < 0.001). CONCLUSION: The German NET registry provides valid multicentric data on NET in Germany. Surgical therapy is the most frequent and important therapy with good clinical outcome. In non resectable, metastatic tumours, systemic therapies are common. Continuation and evaluation of the new WHO and TNM classifications for NET and their therapies will be a future focus of the registry. PMID- 23042104 TI - Ciprofloxacin is a potential topoisomerase II inhibitor for the treatment of NSCLC. AB - Lung cancer is one of the most common tumors and its treatment is still inefficient. In our previous work we proved that ciprofloxacin has a different influence on five cancer cell lines. Here, we aimed to compare the biological effect of ciprofloxacin on cell lines representing different responses after treatment, thus A549 was chosen as a sensitive model, C6 and B16 as highly resistant. Three different cell lines were analyzed (A549, B16 and C6). The characterization of continuous cell growth was analyzed with the Real-Time Cell Analyzer (RTCA)-DP system. Cytoskeletal changes were demonstrated using immunofluorescence. The cell cycle was analyzed using flow cytometry. Ciprofloxacin was cytostatic only against the A549 cell line. In the case of other tested cell lines a cytostatic effect was not observed. Cytoskeletal analysis confirms the results obtained with RTCA-DP. A549 cells were inhibited in the G2/M phase suggesting a mechanism related to topoisomerase II inhibition. The biological effects of ciprofloxacin support the hypothesis that this drug can serve as an adjuvant treatment for lung cancer, due to its properties enabling topoisomerase II inhibition. PMID- 23042105 TI - Exercise hemorheology: classical data, recent findings and unresolved issues. AB - The present review focuses on the past and recent knowledge in the field of exercise hemorheology and presents some unresolved issues for opening discussion. Acute exercise is associated with a rise in hematocrit which results in an increase in blood viscosity. Whereas increased blood viscosity was previously viewed as having negative consequences for cardiovascular function and aerobic performance, recent findings suggest dynamic changes in blood viscosity might be useful for vascular function during exercise by increasing nitric oxide production. Other determinants of blood viscosity are altered by exercise (e.g., decreased red blood cell deformability, increased red blood cell aggregation and plasma viscosity) and may, independent of the associated effect on blood viscosity, directly modulate aerobic capacity. However, the data published on the effects of exercise on the hemorheology are not consistent, with some studies showing decreased, unchanged, or increased red blood cell deformability/aggregation when compared with rest. These discrepancies seem to be related to the exercise protocol investigated, the population tested or the methodogy utilized for hemorheological measurements. Finally, this review focuses on the effects of exercise training (i.e. chronic physical activity) on the hemorheological profile of healthy individuals and patients with cardiovascular and metabolic disorders. PMID- 23042106 TI - Multi-armed cationic cyclodextrin:poly(ethylene glycol) polyrotaxanes as efficient gene silencing vectors. AB - A family of branched polyrotaxanes (bPRTx(+)), threaded with multiple cationic alpha-cyclodextrins (alpha-CDs) onto a multi-armed poly(ethylene glycol) (PEG) core, were synthesized and studied as gene silencing vectors. These bPRTx(+) formed stable, positively charged complexes with diameters of 150-250 nm at N/P ratios as low as 2.5. The bPRTx(+) materials were shown to have gene-silencing efficiencies comparable to those of Lipofectamine 2000 (L2k) and bPEI, while displaying similar toxicity profiles. The unique structure of these polyrotaxanes allows them to effectively condense and complex siRNA into nanoparticles at much lower N/P ratios than L2k or bPEI. These findings suggest that bPRTx(+) may be useful materials for gene therapy applications. PMID- 23042107 TI - Effect of simvastatin on passive strain-induced skeletal muscle injury in rats. AB - INTRODUCTION: HMG-CoA reductase inhibitors are the most frequently prescribed drugs for treatment of lipid imbalance, but they have side effects, such as myopathy. Our aim was to assess the effect of simvastatin on the inflammatory process induced by skeletal muscle injury. METHODS: Rats were divided into experimental groups [control group, simvastatin (20 mg/kg) group, group treated with simvastatin (20 mg/kg) and subjected to injury, and group subjected to injury only]. Histological analysis and analyses of creatine kinase activity and C-reactive protein were performed. RESULTS: Animals treated with simvastatin exhibited significantly greater morphological and structural skeletal muscle damage in comparison to the control group and injured animals without treatment. CONCLUSIONS: Although simvastatin has a small anti-inflammatory effect in the early stage after a muscle strain injury, the overall picture is negative, as simvastatin increases the extent of damage to muscle morphology. Further studies are needed. PMID- 23042109 TI - The general public's concern about developing dementia and related factors in Japan. PMID- 23042110 TI - Family functioning, social support, and quality of life for Chinese empty nest older people with depression. PMID- 23042108 TI - Gene by neuroticism interaction and cognitive function among older adults. AB - OBJECTIVES: Both apolipoprotein E (ApoE) epsilon-4 allele(s) and elevated trait neuroticism, the tendency to experience distress, are associated with cognitive function among older adults. We predicted that neuroticism moderates the association between ApoE and cognitive function and also explored whether other personality dimensions (openness to experience, agreeableness, extraversion, and conscientiousness) affect the association between ApoE status and cognitive function. METHOD: Five-hundred and ninety-seven older adults (mean age of 78 years) enrolled in the Ginkgo Evaluation of Memory study completed the NEO five factor inventory of personality. Cognitive function was assessed via the cognitive portion of the Alzheimer's Disease Assessment Scale, and a blood sample for ApoE genotyping was drawn. RESULTS: As hypothesized, regression analysis indicated that neuroticism moderated the relationship between the presence of ApoE epsilon-4 and cognitive function. Individuals with high neuroticism scores had significantly lower scores on the cognitive portion of the Alzheimer's Disease Assessment Scale compared with individuals with low neuroticism scores, but this was true only among carriers of ApoE epsilon-4 (interaction effect beta = 0.124, p = 0.028). There was scant evidence that other personality dimensions moderate the association between ApoE epsilon-4 and cognitive function. CONCLUSIONS: Cognitive function may be affected by ApoE and neuroticism acting in tandem. Research on the underlying physiological mechanisms by which neuroticism amplifies the effect of ApoE epsilon-4 is warranted. The study of genotype by phenotype interactions provides an important and useful direction for the study of cognitive function among older adults and for the development of novel prevention programs. PMID- 23042111 TI - The effect of a Functioning Improvement Tool home visit program on instrumental activities of daily living and depressive status in older people. PMID- 23042112 TI - Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. AB - Although structural brain alterations in schizophrenia have been demonstrated extensively, their quantitative distribution has not been studied over the last 14 years despite advances in neuroimaging. Moreover, a volumetric meta-analysis has not been conducted in antipsychotic-naive patients. Therefore, meta-analysis on cross-sectional volumetric brain alterations in both medicated and antipsychotic-naive patients was conducted. Three hundred seventeen studies published from September 1, 1998 to January 1, 2012 comprising over 9000 patients were selected for meta-analysis, including 33 studies in antipsychotic-naive patients. In addition to effect sizes, potential modifying factors such as duration of illness, sex composition, current antipsychotic dose, and intelligence quotient matching status of participants were extracted where available. In the sample of medicated schizophrenia patients (n = 8327), intracranial and total brain volume was significantly decreased by 2.0% (effect size d = -0.17) and 2.6% (d = -0.30), respectively. Largest effect sizes were observed for gray matter structures, with effect sizes ranging from -0.22 to 0.58. In the sample of antipsychotic-naive patients (n = 771), volume reductions in caudate nucleus (d = -0.38) and thalamus (d = -0.68) were more pronounced than in medicated patients. White matter volume was decreased to a similar extent in both groups, while gray matter loss was less extensive in antipsychotic-naive patients. Gray matter reduction was associated with longer duration of illness and higher dose of antipsychotic medication at time of scanning. Therefore, brain loss in schizophrenia is related to a combination of (early) neurodevelopmental processes-reflected in intracranial volume reduction-as well as illness progression. PMID- 23042113 TI - Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. AB - A genetic bottleneck explains the marked changes in mitochondrial DNA (mtDNA) heteroplasmy that are observed during the transmission of pathogenic mutations, but the precise timing of these changes remains controversial, and it is not clear whether selection has a role. These issues are important for the genetic counseling of prospective mothers and for the development of treatments aimed at disease prevention. By studying mice transmitting a heteroplasmic single-base pair deletion in the mitochondrial tRNA(Met) gene, we show that the extent of mammalian mtDNA heteroplasmy is principally determined prenatally within the developing female germline. Although we saw no evidence of mtDNA selection prenatally, skewed heteroplasmy levels were observed in the offspring of the next generation, consistent with purifying selection. High percentages of mtDNA genomes with the tRNA(Met) mutation were linked to a compensatory increase in overall mitochondrial RNA levels, ameliorating the biochemical phenotype and explaining why fecundity is not compromised. PMID- 23042114 TI - Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. AB - Atopic dermatitis is a common inflammatory skin disease caused by interaction of genetic and environmental factors. On the basis of data from a genome-wide association study (GWAS) and a validation study comprising a total of 3,328 subjects with atopic dermatitis and 14,992 controls in the Japanese population, we report here 8 new susceptibility loci: IL1RL1-IL18R1-IL18RAP (P(combined) = 8.36 * 10(-18)), the major histocompatibility complex (MHC) region (P = 8.38 * 10(-20)), OR10A3-NLRP10 (P = 1.54 * 10(-22)), GLB1 (P = 2.77 * 10(-16)), CCDC80 (P = 1.56 * 10(-19)), CARD11 (P = 7.83 * 10(-9)), ZNF365 (P = 5.85 * 10(-20)) and CYP24A1-PFDN4 (P = 1.65 * 10(-8)). We also replicated the associations of the FLG, C11orf30, TMEM232-SLC25A46, TNFRSF6B-ZGPAT, OVOL1, ACTL9 and KIF3A-IL13 loci that were previously reported in GWAS of European and Chinese individuals and a meta-analysis of GWAS for atopic dermatitis. These findings advance the understanding of the genetic basis of atopic dermatitis. PMID- 23042115 TI - De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. AB - To evaluate evidence for de novo etiologies in schizophrenia, we sequenced at high coverage the exomes of families recruited from two populations with distinct demographic structures and history. We sequenced a total of 795 exomes from 231 parent-proband trios enriched for sporadic schizophrenia cases, as well as 34 unaffected trios. We observed in cases an excess of de novo nonsynonymous single nucleotide variants as well as a higher prevalence of gene-disruptive de novo mutations relative to controls. We found four genes (LAMA2, DPYD, TRRAP and VPS39) affected by recurrent de novo events within or across the two populations, which is unlikely to have occurred by chance. We show that de novo mutations affect genes with diverse functions and developmental profiles, but we also find a substantial contribution of mutations in genes with higher expression in early fetal life. Our results help define the genomic and neural architecture of schizophrenia. PMID- 23042116 TI - LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. AB - LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives. PMID- 23042117 TI - CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. AB - The c-Src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (encoded by PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of CSK with systemic lupus erythematosus (SLE) and refined its location to the intronic polymorphism rs34933034 (odds ratio (OR) = 1.32; P = 1.04 * 10(-9)). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of Lyn. In carriers of the risk allele, there is increased B-cell receptor (BCR)-mediated activation of mature B cells, as well as higher concentrations of plasma immunoglobulin M (IgM), relative to individuals with the non-risk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. This suggests that the Lyp-Csk complex increases susceptibility to lupus at multiple maturation and activation points in B cells. PMID- 23042118 TI - Enhancing sensitivity of liquid chromatographic/ion-trap mass spectrometric determination of jasmonic acid by derivatization with N,N' dicyclohexylcarbodiimide. AB - A simple and sensitive method for the detection of jasmonic acid (JA) by liquid chromatography-ion trap mass spectrometry (LC-IT-MS/MS) after derivatization is described. The highlight of this method was that it involved a rearrangement reaction which was often considered as a side reaction in the formation of amides and esters using N,N'-dicyclohexylcarbodiimide (DCC) as a condensation reagent. While in this study, DCC was used as a derivatization reagent directly. Internal standard dehydrojasmonic acid (DHJA) was used to ensure the accuracy. Derivatives provided good signals corresponding to the protonated molecular ions [M + H](+) and product ions. Sensitivity had been improved 100-fold with the LOD being 0.1 ng mL(-1) in comparison with the LC-IT-MS analysis without derivatization. This proposed method was reliable with good recoveries found in rice floret and wintersweet, allowing quantification in real samples to be more accurate and efficient, thus offering a good way to further study the physiological and biological activities of jasmonic acid in plants. PMID- 23042119 TI - In vivo cleavage of transgene donors promotes nuclease-mediated targeted integration. AB - Targeted DNA integration is commonly used to eliminate position effects on transgene expression. Integration can be targeted to specific sites in the genome via both homology-based and homology-independent processes. Both pathways start the integration process with a site-specific break in the chromosome, typically from a zinc-finger nuclease (ZFN). We previously described an efficient homology independent targeted integration technique that captures short (<100 bp) pieces of DNA at chromosomal breaks created by ZFNs. We show here that inclusion of a nuclease target site on the donor plasmid followed by in vivo nuclease cleavage of both the donor and the chromosome results in efficient integration of large, transgene-sized DNA molecules into the chromosomal double-strand break. Successful targeted integration via in vivo donor linearization is demonstrated at five distinct loci in two mammalian cell types, highlighting the generality of the approach. Finally, we show that CHO cells, a cell type recalcitrant to homology-based integration, are proficient at capture of in vivo-linearized transgene donors. Moreover, we demonstrate knockout of the hamster FUT8 gene via the simultaneous ZFN- or TALE nuclease-mediated integration of an antibody cassette. Our results enable efficient targeted transgene addition to cells and organisms that fare poorly with traditional homology-driven approaches. PMID- 23042120 TI - Chain-like nanostructures from anisotropic self-assembly of semiconducting metal oxide nanoparticles with a block copolymer. AB - A facile method is reported for the preparation of chain-like nanostructures by anisotropic self-assembly of TiO(2) and SnO(2) nanoparticles with the aid of a block copolymer in an aqueous medium. Well-defined crystallographic orientations between neighbouring nanoparticles are observed in TiO(2) nanochains, which is important for tailoring the grain boundaries and thus enhancing charge transport. PMID- 23042122 TI - Gold(I)-catalyzed regiodivergent rearrangements: 1,2- and 1,2'-alkyl migration in skipped alkynyl ketones. AB - A series of 2-alkynyl carbonyl compounds that contain a cyclopentene ring or a heterocycle can be transformed into various fused dihydrobenzofurans and tetrahydrofuro[2,3-c]pyridines by means of a 1,2-alkyl migration process. Both of these reactions proceed with excellent regioselectivity and stereospecificity when using a cationic gold(I) catalyst. Treatment of 4-styrylcyclopent-1 enecarboxylates under different conditions affords a range of highly functionalized dihydrobenzofurans and dihydroisobenzofurans. A divergence in product selectivity, which depends on the anion of the silver salts used, was observed. Interestingly, ring-fused tetrahydroquinolines undergo only 1,2'-alkyl migration reaction by means of a C-C cleavage/cyclization sequence to provide tetrahydroazepine derivatives. Mechanistic studies suggest that the gold complexes catalyze 1,2-alkyl migration reactions through a concerted reaction pathway and 1,2'-alkyl migration reactions through a stepwise reaction pathway. PMID- 23042121 TI - Influence in times of crisis: how social and financial resources affect men's and women's evaluations of glass-cliff positions. AB - In two scenario-based studies, we found that women and men evaluate glass-cliff positions (i.e., precarious leadership positions at organizations in crisis) differently depending on the social and financial resources available. Female and male participants evaluated a hypothetical leadership position in which they would have both social and financial resources, financial resources but no social resources, or social resources but no financial resources. Women evaluated the position without social resources most negatively, whereas men evaluated the position without financial resources most negatively. In study 2, we found that women and men considered different issues when evaluating these leadership positions. Women's evaluations and expected levels of influence as leaders depended on the degree to which they expected to be accepted by subordinates. In contrast, men's evaluations and expected levels of acceptance by subordinates depended on the degree to which they expected to be influential in the position. Our findings have implications for the understanding of the glass-cliff phenomenon and gendered leadership stereotypes. PMID- 23042123 TI - Adjuvant bisphosphonates: a new standard of care? AB - PURPOSE OF REVIEW: Clinical studies show that bisphosphonates can ameliorate bone loss from adjuvant breast cancer therapies, with suggestions of anticancer benefit. Recent long-term studies have provided additional support for a clinical benefit from bisphosphonates in the adjuvant breast cancer setting and suggest that adjuvant bisphosphonates might be an appropriate standard of care. This review evaluates the recent clinical evidence for the effectiveness of adjuvant bisphosphonate therapy in breast cancer. RECENT FINDINGS: Oral bisphosphonates did not affect breast cancer recurrence in premenopausal women and had inconsistent results in postmenopausal women. The intravenous bisphosphonate zoledronic acid demonstrated clear disease-free and overall survival benefits in patient subgroups expected to have low estrogen levels: premenopausal patients undergoing ovarian suppression and postmenopausal women who were 5 years past menopause or 60-65 years or older. SUMMARY: Current clinical evidence is insufficient to support using oral bisphosphonates as a standard adjuvant therapy in breast cancer; however, additional studies are warranted. In contrast, zoledronic acid may be considered a new standard of care in adjuvant breast cancer, at least for some postmenopausal women and premenopausal women undergoing ovarian suppression. PMID- 23042124 TI - Management of microcarcinomas (papillary and medullary) of the thyroid. AB - PURPOSE OF REVIEW: Microcarcinomas of the thyroid gland are defined by the size criteria as tumors measuring less than 1 cm in greatest dimension. The clinical significance of papillary thyroid microcarcinoma (PTMC) and medullary thyroid microcarcinoma (MTMC) is debatable. Variation in practice patterns exist in the United States with regard to diagnosis, treatment, and long-term management. We review the most recent guidelines on the management of these controversial malignancies. RECENT FINDINGS: PTMC has recently been shown to be the most common thyroid malignancy in patients older than 45 years in the United States. The management of patients with PTMC is not well defined, although recent studies have indicated that total or near-total thyroidectomy decreases overall recurrence rate. BRAF mutation testing plays an increasingly important role in perioperative management and has potential for targeted molecular therapies.Prophylactic thyroidectomy is indicated early in life for RET mutation carriers at risk for medullary thyroid cancer. New evidence suggests that timing may be personalized based on specific exon mutations and serum calcitonin levels. The biological significance and surgical management of MTMC have been debated, but the most recent studies indicate a relatively high incidence of lymph node metastases, distant metastases, and persistently elevated postoperative calcitonin; and argue for the aggressive management of even the smallest MTMCs. SUMMARY: Total or near-total thyroidectomy is the treatment of choice in patients with PTMC in order to eradicate multifocal disease and decrease overall recurrence rate. If there are palpable, biopsy-proven, or grossly apparent metastases at the time of operation, central lymphadenectomy should be performed. Prophylactic thyroidectomy in hereditary cases of MTMC may be guided by knowledge of specific exon mutations and calcitonin levels. The extent of operation for both hereditary and sporadic MTMC is nonstandardized, and further studies are needed to clarify this issue. PMID- 23042125 TI - Benefits and limitations of adding hyperbranched polymers to dental resins. AB - Volumetric shrinkage reduction is a constant challenge in the improvement of dental resins. The inclusion of hyperbranched polymers (HBPs) with modified functionalities (hydroxyl, propionate, and methacrylate) instead of conventional dimethacrylate monomers has the potential to reduce shrinkage, but can also affect other properties. The null hypothesis was that the addition of HBPs (from 5 to 40 mass%) to a 50/50 mass% Bis-GMA/TEGDMA mixture reduces shrinkage without affecting degree of conversion, elastic modulus, glass transition temperature, Wallace hardness (before/after ethanol storage), and viscosity. This hypothesis was rejected, since HBP incorporation significantly affected most properties either negatively or positively. When HBP amounts in the resin were increased, the following general trends were observed: Volumetric shrinkage decreased significantly (p < 0.0001), down to about one-third of the control value at 40% HBP; Wallace hardness (both before and after ethanol) and viscosity increased progressively, while elastic modulus showed a parabolic profile, with a maximum at 10% HBP; and finally, degree of conversion and glass transition temperature were relatively stable, regardless of the HBP content. These results indicate that HBPs with modified end groups might be interesting substitutes for Bis GMA/TEGDMA. PMID- 23042126 TI - Inflammation, pain, and pressure--purinergic signaling in oral tissues. AB - Signaling by extracellular purines such as ATP and adenosine has implications for dental research on multiple levels, with the association of purinergic signaling with inflammation, mechanical strain, and pain making the system particularly relevant for the specific challenges in the oral cavity. Oral tissues express a variety of G-protein-coupled P2Y receptors for ATP and P1 receptors for adenosine in addition to ionotropic P2X receptors for ATP. When these receptors are combined with the plethora of extracellular enzymes capable of manipulating extracellular agonist levels, a complex system for regulating oral health emerges, and recent findings have begun to identify a key role for purinergic signaling in oral pathophysiology. For example, the manipulation of extracellular ATP levels by P. gingivalis reduces inflammasome activation and apoptosis linked to P2X(7) receptor activation. Release of ATP by periodontal ligaments may link mechanical strain to bone remodeling. Activation of P2X receptors is implicated in dental pain, and receptor antagonists represent important targets for new analgesics. Altered levels of adenosine receptors in periodontal disease also suggest a role for nucleosides in dental signaling. The intricacies of the purinergic signaling system make it well-suited for the unique concerns of dental research, and future findings will doubtless confirm this importance. PMID- 23042127 TI - Iron-inducible nuclear translocation of a Myb3 transcription factor in the protozoan parasite Trichomonas vaginalis. AB - In Trichomonas vaginalis, a novel nuclear localization signal spanning the folded R2R3 DNA-binding domain of a Myb2 protein was previously identified. To study whether a similar signal is used for nuclear translocation by other Myb proteins, nuclear translocation of Myb3 was examined in this report. When overexpressed, hemagglutinin-tagged Myb3 was localized to nuclei of transfected cells, with a cellular distribution similar to that of endogenous Myb3. Fusion to a bacterial tetracycline repressor, R2R3, of Myb3 that spans amino acids (aa) 48 to 156 was insufficient for nuclear translocation of the fusion protein, unless its C terminus was extended to aa 167. The conserved isoleucine in helix 2 of R2R3, which is important for Myb2's structural integrity in maintaining DNA-binding activity and nuclear translocation, was also vital for the former activity of Myb3, but less crucial for the latter. Sequential nuclear influx and efflux of Myb3, which require further extension of the nuclear localization signal to aa 180, were immediately induced after iron repletion. Sequence elements that regulate nuclear translocation with cytoplasmic retention, nuclear influx, and nuclear efflux were identified within the C-terminal tail. These results suggest that the R2R3 DNA-binding domain also serves as a common module for the nuclear translocation of both Myb2 and Myb3, but there are intrinsic differences between the two nuclear localization signals. PMID- 23042128 TI - Rapid triacylglycerol turnover in Chlamydomonas reinhardtii requires a lipase with broad substrate specificity. AB - When deprived of nitrogen (N), the photosynthetic microalga Chlamydomonas reinhardtii accumulates large quantities of triacylglycerols (TAGs), making it a promising source of biofuel. Prominent transcriptional changes associated with the conditions leading to TAG accumulation have been found, suggesting that the key enzymes for TAG metabolism might be among those that fluctuate in their expression during TAG synthesis and breakdown. Using a Saccharomyces cerevisiae lipase null mutant strain for functional complementation, we identified the CrLIP1 gene from Chlamydomonas based on its ability to suppress the lipase deficiency-related phenotypes of the yeast mutant. In Chlamydomonas, an inverse correlation was found between the CrLIP1 transcript level and TAG abundance when Chlamydomonas cultures were reversibly deprived of N. The CrLIP1 protein expressed and purified from Escherichia coli exhibited lipolytic activity against diacylglycerol (DAG) and polar lipids. The lipase domain of CrLIP1 is most similar to two human DAG lipases, DAGLalpha and DAGLbeta. The involvement of CrLIP1 in Chlamydomonas TAG hydrolysis was corroborated by reducing the abundance of the CrLIP1 transcript with an artificial micro-RNA, which resulted in an apparent delay in TAG lipolysis when N was resupplied. Together, these data suggest that CrLIP1 facilitates TAG turnover in Chlamydomonas primarily by degrading the DAG presumably generated from TAG hydrolysis. PMID- 23042129 TI - Pleiotropic roles of the Msi1-like protein Msl1 in Cryptococcus neoformans. AB - Msi1-like (MSIL) proteins contain WD40 motifs and have a pleiotropic cellular function as negative regulators of the Ras/cyclic AMP (cAMP) pathway and components of chromatin assembly factor 1 (CAF-1), yet they have not been studied in fungal pathogens. Here we identified and characterized an MSIL protein, Msl1, in Cryptococcus neoformans, which causes life-threatening meningoencephalitis in humans. Notably, Msl1 plays pleiotropic roles in C. neoformans in both cAMP dependent and -independent manners largely independent of Ras. Msl1 negatively controls antioxidant melanin production and sexual differentiation, and this was repressed by the inhibition of the cAMP-signaling pathway. In contrast, Msl1 controls thermotolerance, diverse stress responses, and antifungal drug resistance in a Ras/cAMP-independent manner. Cac2, which is the second CAF-1 component, appears to play both redundant and distinct functions compared to the functions of Msl1. Msl1 is required for the full virulence of C. neoformans. Transcriptome analysis identified a group of Msl1-regulated genes, which include stress-related genes such as HSP12 and HSP78. In conclusion, this study demonstrates pleiotropic roles of Msl1 in the human fungal pathogen C. neoformans, providing insight into a potential novel antifungal therapeutic target. PMID- 23042130 TI - Deletion of the fungal gene soft disrupts mutualistic symbiosis between the grass endophyte Epichloe festucae and the host plant. AB - Hyphal anastomosis, or vegetative hyphal fusion, establishes the interconnection of individual hyphal strands into an integrated network of a fungal mycelium. In contrast to recent advances in the understanding of the molecular basis for hyphal anastomosis, knowledge of the physiological role of hyphal anastomosis in the natural habitats of filamentous fungi is still very limited. To investigate the role of hyphal anastomosis in fungal endophyte-plant interactions, we generated mutant strains lacking the Epichloe festucae soft (so) gene, an ortholog of the hyphal anastomosis gene so in the endophytic fungus E. festucae. The E. festucae Deltaso mutant strains grew similarly to the wild-type strain in culture but with reduced aerial hyphae and completely lacked hyphal anastomosis. The most striking phenotype of the E. festucae Deltaso mutant strain was that it failed to establish a mutualistic symbiosis with the tall fescue plant host (Lolium arundinaceum); instead, it killed the host plant within 2 months after the initial infection. Microscopic examination revealed that the death of the tall fescue plant host was associated with the distortion and disorganization of plant cells. This study suggests that hyphal anastomosis may have an important role in the establishment/maintenance of fungal endophyte-host plant mutualistic symbiosis. PMID- 23042131 TI - Roles of Hsl1p and Hsl7p in Swe1p degradation: beyond septin tethering. AB - The morphogenesis checkpoint in Saccharomyces cerevisiae couples bud formation to the cell division cycle by delaying nuclear division until cells have successfully constructed a bud. The cell cycle delay is due to the mitosis inhibitory kinase Swe1p, which phosphorylates the cyclin-dependent kinase Cdc28p. In unperturbed cells, Swe1p is degraded via a mechanism thought to involve its tethering to a cortical scaffold of septin proteins at the mother-bud neck. In cells that experience stresses that delay bud formation, Swe1p is stabilized, accumulates, and promotes a G(2) delay. The tethering of Swe1p to the neck requires two regulators, called Hsl1p and Hsl7p. Hsl1p interacts with septins, and Hsl7p interacts with Swe1p; tethering occurs when Hsl1p interacts with Hsl7p. Here we created a version of Swe1p that is artificially tethered to the neck by fusion to a septin so that Swe1p no longer requires Hsl1p or Hsl7p for its localization to the neck. We show that the interaction between Hsl1p and Hsl7p, required for normal Swe1p degradation, is no longer needed for septin-Swe1p degradation, supporting the idea that the Hsl1p-Hsl7p interaction serves mainly to tether Swe1p to the neck. However, both Hsl1p and Hsl7p are still required for Swe1p degradation, implying that these proteins play additional roles beyond localizing Swe1p to the neck. PMID- 23042133 TI - A study of the influence of isotopic substitution on the melting point and temperature of maximum density of water by means of path integral simulations of rigid models. AB - The melting point of ice I(h), as well as the temperature of maximum density (TMD) in the liquid phase, has been computed using the path integral Monte Carlo method. Two new models are introduced, TIP4PQ_D2O and TIP4PQ_T2O, which are specifically designed to study D(2)O and T(2)O respectively. We have also used these models to study the "competing quantum effects" proposal of Habershon, Markland and Manolopoulos; the TIP4PQ/2005, TIP4PQ/2005 (D(2)O) and TIP4PQ/2005 (T(2)O) models are able to study the isotopic substitution of hydrogen for deuterium or tritium whilst constraining the geometry, while the TIP4PQ_D2O and TIP4PQ_T2O models, where the O-H bond lengths are progressively shortened, permit the study of the influence of geometry (and thus dipole moment) on the isotopic effects. For TIP4PQ_D2O-TIP4PQ/2005 we found a melting point shift of 4.9 K (experimentally the value is 3.68 K) and a TMD shift of 6 K (experimentally 7.2 K). For TIP4PQ_T2O-TIP4PQ/2005 we found a melting point shift of 5.2 K (experimentally the value is 4.49 K) and a TMD shift of 7 K (experimentally 9.4 K). PMID- 23042132 TI - Distribution of the SELMA translocon in secondary plastids of red algal origin and predicted uncoupling of ubiquitin-dependent translocation from degradation. AB - Protein import into complex plastids of red algal origin is a multistep process including translocons of different evolutionary origins. The symbiont-derived ERAD-like machinery (SELMA), shown to be of red algal origin, is proposed to be the transport system for preprotein import across the periplastidal membrane of heterokontophytes, haptophytes, cryptophytes, and apicomplexans. In contrast to the canonical endoplasmic reticulum-associated degradation (ERAD) system, SELMA translocation is suggested to be uncoupled from proteasomal degradation. We investigated the distribution of known and newly identified SELMA components in organisms with complex plastids of red algal origin by intensive data mining, thereby defining a set of core components present in all examined organisms. These include putative pore-forming components, a ubiquitylation machinery, as well as a Cdc48 complex. Furthermore, the set of known 20S proteasomal components in the periplastidal compartment (PPC) of diatoms was expanded. These newly identified putative SELMA components, as well as proteasomal subunits, were in vivo localized as PPC proteins in the diatom Phaeodactylum tricornutum. The presented data allow us to speculate about the specific features of SELMA translocation in contrast to the canonical ERAD system, especially the uncoupling of translocation from degradation. PMID- 23042134 TI - Converting molecular information of redox coenzymes via self-assembly. AB - beta-Nicotinamide adenine dinucleotide (NAD(+)) and its reduced form NADH specifically interact with a cyanine dye in aqueous media, giving distinct spectral and nanostructural characteristics to which molecular information of constituent coenzymes are converted via self-assembly. PMID- 23042135 TI - Bronsted acid promoted benzylic C-H bond functionalization of azaarenes: nucleophilic addition to aldehydes. AB - A practical Bronsted acid promoted benzylic C-H functionalization of 2 methylazaarenes and nucleophilic addition to aldehydes was developed in good to excellent yields. A six-membered hydrogen-bonding transition state is proposed to be crucial for the reaction. Ready availability of the two starting materials, the use of acetic acid as the catalyst and the facile reaction conditions will guarantee this synthetic method attractive to the synthesis of bioactive pyridine and quinoline derivatives. PMID- 23042136 TI - Stimulus duration and pain in nerve conduction studies. AB - INTRODUCTION: It is generally believed that a shorter stimulus duration is less painful in nerve conduction studies (NCS). We investigated whether a shorter duration stimulus is actually less painful when the same physiological effect, such as supramaximal stimulation, is achieved in motor NCS. METHODS: The tibial nerve was stimulated at the ankle in 14 control subjects and the median nerve at the wrist in 20 subjects. Two stimulations of different durations were given blindly, and each subject was asked to report which was more painful. RESULTS: A 0.2-ms-duration stimulus was significantly less painful than those with longer or shorter durations for the tibial nerve. For the median nerve, the 0.05- and 0.2 ms durations were equally less painful than a 1-ms-duration stimulus. CONCLUSIONS: As a common duration for motor NCS, 0.2 ms seems appropriate, because the tibial nerve stimulation was more painful than the median nerve stimulation. PMID- 23042137 TI - Is it better than it seems or just good enough? The tafamidis saga. PMID- 23042138 TI - Middle-term surgical outcomes of microscopic posterior decompression for far-out syndrome. AB - OBJECTIVE: Far-out syndrome (FOS) is a rare incident caused by L5 nerve root entrapment in the far-out area, the L5-S1 extraforaminal area between the transverse process and the sacral ala. The purpose of this study is to disclose the middle-term surgical outcomes of microscopic posterior decompression in the far-out area (MPDFA). MATERIAL AND METHODS: From June 2008 to November 2010, eight patients with FOS (six men and two women, mean age 65.4 years) were treated with MPDFA. Their chief complaint was leg pain in the L5 nerve root distribution area. Nerve root impingements in the far-out area were confirmed by magnetic resonance imaging, computed tomography and selective radiculography. Indications for MPDFA were given when pain was uncontrollable with conservative treatments for more than 1 month. MPDFA was performed according to the following procedure: a 4-to-5-cm skin incision was made just above the far-out area. The far-out area was exposed using Wiltse's intermuscular approach. The nerve root was decompressed with partial resection of the transverse process and the sacral ala, and removal of the iliolumbar ligament. Surgical outcomes were evaluated at periodical examinations with the Japanese Orthopedic Score (JOA) and a Visual Analogue Scale (VAS) of the leg pain. The mean follow-up period was 24.3 months (ranging from 12 to 40 months). RESULTS: All patients had reduced radicular leg pain after their operations. The mean postoperative hospital stay was 11.4 days, and the patients returned to their normal activities of daily living immediately after discharge. Both JOA and the VAS scores improved after surgery. The scores temporarily worsened in two patients with degenerative scoliosis; the worsening was attributed not to recurrence of the radiculopathy but to pain arising from knee arthropathy. The scores were maintained in the other patients at least until the final examinations during the follow-up. CONCLUSION: MPDFA is a less-invasive surgery for treating FOS and can provide a good middle-term surgical outcome. PMID- 23042139 TI - Reversible cortical blindness and internuclear ophthalmoplegia after neurosurgical operation: case report and review of the literature. AB - BACKGROUND: The reversible posterior leukoencephalopathy (RPL) syndrome with typical vasogenic edema in the occipital lobe and associated cortical blindness is a rare finding; however, the brainstem variant is even more infrequent. Etiologies discussed include blood pressure dysregulations, renal failure, or immunosuppression. PATIENT: A 63-year-old man with the characteristic radiographic findings of RPL syndrome presented with reversible cortical blindness and internuclear ophthalmoplegia (INO) after resection of an infratentorial hemangiopericytoma. The patient postoperatively presented with diplopia and mental status alterations followed by visual loss; these symptoms completely recovered within a few days. Fluid-attenuated inversion recovery-, and T2-weighted magnetic resonance imaging (MRI) revealed bilateral hyperintense lesions not only in the white matter of the parieto-occipital region but also in the rostral paramedian mesencephalon and pons. CONCLUSIONS: We hypothesize that the patient had an RPL, coincidentally in classic-, and brainstem localization, caused by perioperative fluctuations of blood pressure. PMID- 23042140 TI - Bilateral orbital and optic nerve endoscopic endonasal decompression for nonspecific inflammatory orbital disease: case report. AB - BACKGROUND: Endoscopic endonasal optic nerve decompression (EEOND) is indicated in traumatic and endocrine orbitopathies as well as in idiopathic intracranial hypertension. CASE: We present a patient with bilateral nonspecific inflammatory orbitopathy (NSIO) and optic nerve compression presenting with acute severe visual loss. Bilateral orbital and optic nerve decompression was performed as an emergency procedure with a favorable ophthalmological result. CONCLUSION: EEOND is an effective and safe technique in acute orbitopathies and should be taken in consideration in atypical clinical settings causing severe acute visual loss. PMID- 23042141 TI - Glossopharyngeal neuralgia treated with an endoscopic assisted midline suboccipital subtonsillar approach: technical note. AB - BACKGROUND: Glossopharyngeal nerve neuralgia (GPN) is an exceptionally rare skull based disorder. It is treated similar to other neurovascular conflicts. The approach, however, is debatable, as the caudal cranial nerves and especially the exit zones at the brainstem are barely visible via the retrosigmoid approach. CLINICAL PRESENTATION: We demonstrate a case of a typical GPN with microsurgical neurovascular decompression according to standard procedures. Continuous electrophysiological monitoring, including motor-evoked potentials of the glossopharyngeal nerve in addition to somatosensory evoked potential (SSEP) monitoring, was set up. In prone position a midline suboccipital osteoplastic craniotomy was performed. Intradurally, an endoscopic-assisted subtonsillar exposure of the lateral recess and the nerve root exit zone of the glossopharyngeal nerve has been chosen. A large compressing branch of the posterior inferior cerebellar artery (PICA) was identified as the cause of the neurovascular conflict and transposed. CONCLUSIONS: A midline subtonsillar approach with endoscopic assistance to the lateral brainstem is a straightforward time- and morbidity-sparing procedure. PMID- 23042142 TI - Is there a place for the endoscope in skull base surgery in children less than 5 years? AB - BACKGROUND: The impact of transnasal endoscopic approaches to the central skull is still increasing. Its use in small children (i.e., under the age of 5 years) is of questionable value. PATIENTS AND METHODS: The present study is a description of a series of five children under the age of 5 years with lesions of the central skull base. RESULTS: Three out of five required a combined external and transnasal endoscopic approach. The transnasal access to the central skull base allowed reducing tissue damage and potentially may reduce growth deceleration. DISCUSSION: Based on our experience on this small series we suggest that a transnasal endoscopic approach to the anterior and central skull base can be applied even in small children. To successfully operate on such delicate pathologies, a well-working interdisciplinary cooperation is mandatory. PMID- 23042143 TI - Clinical outcome of subthalamic stimulation in Parkinson's disease is improved by intraoperative multiple trajectories microelectrode recording. AB - BACKGROUND AND STUDY AIMS: The use of multiple trajectories microelectrode recording (MER) during implantation of deep brain stimulation (DBS) electrodes into the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) is discussed controversially because of possible risks and unclear benefits. The aim of the study is to investigate whether MER combined with intraoperative evaluation of stimulation effects improve clinical outcome in PD patients undergoing STN DBS surgery. MATERIAL AND METHODS: Prior to final DBS electrode implantation, we performed multiple trajectories MER and intraoperative test stimulations after magnetic resonance imaging (MRI)-guided planning in 32 PD patients. In further 10 patients no MER (only intraoperative test stimulation) was used. RESULTS: We found a significantly better clinical outcome (Unified Parkinson's Disease Rating Scale [UPDRS] III) in patients undergoing MER compared with non-MER patients. In MER patients, DBS electrode placement was performed using the central trajectory in 73%. Another than the central trajectory was taken in 27% of the patients. No difference in clinical outcome between DBS electrodes implanted on the central or a decentral trajectory was observed. CONCLUSIONS: DBS surgery based on intraoperative multiple trajectories MER and test stimulation improves clinical outcome if compared with intraoperative test stimulation alone. The data suggest that DBS surgery solely based on MRI and intraoperative test stimulation without MER may lead to nonoptimal placement of DBS electrodes and consequently poorer clinical outcome. PMID- 23042144 TI - Tumor necrosis factor-alpha enhances the transcription of Smad ubiquitination regulatory factor 1 in an activating protein-1- and Runx2-dependent manner. AB - Smad ubiquitination regulatory factor 1 (Smurf1) is an E3 ubiquitin ligase that negatively regulates osteoblast differentiation. Although tumor necrosis factor alpha (TNF-alpha) has been shown to increase Smurf1 expression, the details of the regulatory mechanisms remain unclear. Here, we investigated the molecular mechanism by which TNF-alpha stimulates Smurf1 expression in C2C12 and primary cultured mouse calvarial cells. TNF-alpha treatment rapidly induced the activation of NF-kappaB and MAPKs. Smurf1 induction by TNF-alpha was blocked by the inhibition of JNK or ERK, while the inhibition of NF-kappaB and p38 MAPK had no effect on Smurf1 induction. TNF-alpha treatment or c-Jun overexpression enhanced the activity of a luciferase reporter that contained a 2.7 kb mouse Smurf1 promoter sequence. Site-directed mutagenesis of the Smurf1 reporter and chromatin immunoprecipitation analysis demonstrated that the activating protein-1 (AP-1) binding motif at -922 bp on the mouse Smurf1 promoter mediated TNF alpha/JNK/AP-1-stimulated Smurf1 transcription. Interestingly, Smurf1 expression was not observed in Runx2-null mouse calvarial cells. When Runx2 was ectopically expressed in these cells, the basal and TNF-alpha-induced expression of Smurf1 was restored. Overexpression of Runx2 transactivated the Smurf1 promoter in a dose-dependent manner. Reporter and chromatin immunoprecipitation assays demonstrated that the Runx2-binding motif at -202 bp functioned in Runx2-mediated Smurf1 expression. ERK activation by TNF-alpha treatment or constitutively active MEK1 overexpression increased Smurf1 expression in a Runx2-dependent manner. These results suggest that the JNK/AP-1 and ERK/Runx2 signaling pathways mediate TNF-alpha-dependent Smurf1 transcription. PMID- 23042145 TI - Established breast cancer stem cell markers do not correlate with in vivo tumorigenicity of tumor-initiating cells. AB - The tumor-initiating capacity of primary human breast cancer cells is maintained in vitro by culturing these cells as spheres/aggregates. Inoculation of small cell numbers derived from these non-adherent cultures leads to rapid xenograft tumor formation in mice. Accordingly, injection of more differentiated monolayer cells derived from spheres results in significantly decelerated tumor growth. For our study, two breast cancer cell lines were generated from primary tumors and cultured as mammospheres or as their adherent counterparts. We examined the in vivo tumorigenicity of these cells by injecting serial dilutions into immunodeficient mice. Inoculation of 106 cells per mouse led to rapid tumor formation, irrespective of cell line or culture conditions. However, after injection of only 103 cells, solely sphere cells were highly tumorigenic. In vitro, we investigated differentiation markers, established breast CSC markers and conducted mRNA profiling. Cytokeratin 5 and 18 were increased in both monolayer cell types, indicating a more differentiated phenotype. All cell lines were CD24(-)/CD44(+) and did not express CD133, CD326 or E-cadherin. ALDH1 activity was not detectable in any cell line. A verapamil-sensitive Hoechst side population was present in sphere cells, but there was no correlation with tumorigenicity in vivo. mRNA profiling did not reveal upregulation of relevant transcription factors. In vitro cell cycle kinetics and in vivo tumor doubling times displayed no difference between sphere and monolayer cultures. Our data indicate that intrinsic genetic and functional markers investigated are not indicative of the in vivo tumori-genicity of putative breast tumor-initiating cells. PMID- 23042147 TI - Mesoporous silica nanoparticles: A multifunctional nano therapeutic system. AB - Efficient and safe drug delivery has always been a challenge in medicine. The use of nanotechnology, such as the development of nano drug delivery systems (DDS), has received great attention with high enthusiasm owing to the potential that nanocarriers can theoretically act as "magic bullets" and selectively target affected organs and cells while sparing normal tissues. The family of nano DDS includes conventional nano drug delivery materials such as lipids and polymers that have been scaled to the nanometer size range. With the rapid development of synthesis and characterization techniques for engineered nanomaterials, new DDS platforms have emerged, including inorganic based nanocarriers, such as mesoporous silica nanoparticles (MSNP). MSNP are able to act as a multifunctional delivery platform that is capable of delivering therapeutic elements to a variety of disease models (especially cancer) at cellular and in vivo levels. Furthermore, MSNP have shown to be exceptional delivery platforms capable of protectively packaging hydrophobic and hydrophilic drug molecules as well as other therapeutic elements for controlled on-demand delivery. In addition, MSNP have demonstrated the capability to image the delivery site for theranostic purposes. These functionalities have led to the development of MSNP as novel multifunctional nanocarriers, and therefore provide them with unique advantages compared to other nanocarriers. PMID- 23042146 TI - Prediction, refinement, and persistency of transmembrane helix dimers in lipid bilayers using implicit and explicit solvent/lipid representations: microsecond molecular dynamics simulations of ErbB1/B2 and EphA1. AB - All-atom simulations are carried out on ErbB1/B2 and EphA1 transmembrane helix dimers in lipid bilayers starting from their solution/DMPC bicelle NMR structures. Over the course of microsecond trajectories, the structures remain in close proximity to the initial configuration and satisfy the majority of experimental tertiary contact restraints. These results further validate CHARMM protein/lipid force fields and simulation protocols on Anton. Separately, dimer conformations are generated using replica exchange in conjunction with an implicit solvent and lipid representation. The implicit model requires further improvement, and this study investigates whether lengthy all-atom molecular dynamics simulations can alleviate the shortcomings of the initial conditions. The simulations correct many of the deficiencies. For example, excessive helix twisting is eliminated over a period of hundreds of nanoseconds. The helix tilt, crossing angles, and dimer contacts approximate those of the NMR-derived structure, although the detailed contact surface remains off-set for one of two helices in both systems. Hence, even microsecond simulations are not long enough for extensive helix rotations. The alternate structures can be rationalized with reference to interaction motifs and may represent still sought after receptor states that are important in ErbB1/B2 and EphA1 signaling. PMID- 23042148 TI - Antiphospholipid antibody syndrome. AB - PURPOSE OF REVIEW: Antiphospholipid syndrome is a rare cause of ocular vaso occlusive disease, but is associated with significant systemic morbidity and mortality. Thus, early diagnosis and treatment is essential. RECENT FINDINGS: Although the pathophysiology of antiphospholipid syndrome continues to be poorly understood, there has been continued progress with regard to the relationship between antiphospholipid antibody and its target, beta-2-glycoprotein I. Due to numerous limitations with standard serologic evaluation, new approaches to the evaluation of patient serum are being considered. New guidelines for the treatment and management of antiphospholipid antibody syndrome have been established by the 13th International Committee on Antiphospholipid Antibodies. SUMMARY: A better understanding of the pathophysiology behind antiphospholipid antibody syndrome has led to novel approaches in the diagnosis and treatment of this disease. PMID- 23042149 TI - Efferent manifestations of multiple sclerosis. AB - PURPOSE OF REVIEW: To review the various efferent visual system disorders associated with multiple sclerosis (MS). RECENT FINDINGS: Studies have supported the use of internuclear ophthalmoplegia, a model to study effects of fatigue and heat in MS patients. SUMMARY: There are a host of efferent ocular manifestations that can present throughout the course of MS. These may manifest as blurred vision, potentially misleading both the patient and clinician to suspect an afferent visual deficit. Other efferent symptoms include diplopia, oscillopsia, and vertigo. The efferent system can be divided into broad categories: supranuclear, internuclear, nuclear, and gaze-holding systems. This review will briefly touch on the anatomy as well as the signs and symptoms associated with MS related dysfunction involving these systems. PMID- 23042152 TI - Peroxidase-like activity of chitosan stabilized silver nanoparticles for visual and colorimetric detection of glucose. AB - Chitosan stabilized silver nanoparticles (Ch-Ag NPs) were successfully synthesized by a one-step method and were found to possess intrinsic peroxidase like activity, could catalytically oxidize substrates, such as TMB, and OPD, by H(2)O(2) to produce a typical colour reaction such as from colorless to blue for TMB and from colorless to red for OPD. Our results demonstrate that the Ch-Ag NPs exhibit higher thermal and pH durance than HRP, thus could be suitable in a wider range of harsh conditions. Results of electron paramagnetic resonance (ESR) suggest that the catalyse-mimic activity of the Ch-Ag nanostructures effectively catalyzed the decomposition of H(2)O(2) into OH radicals. Based on this finding, a simple, sensitive and selective visual and colorimetric method with TMB as substrate has been designed for glucose detection when combined with glucose oxidase (GOx). This colorimetric method can be used for detection of glucose in biological samples with a detection limit as low as 100 nM and a dynamic range from 5.0 * 10(-6) to 2.0 * 10(-4) M. PMID- 23042151 TI - Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferons. AB - Toll-like receptors (TLRs) sense pathogen-associated molecules and respond by inducing cytokines and type I interferon. Here we show that genetic ablation of the E3 ubiquitin ligase Pellino3 augmented the expression of type I interferon but not of proinflammatory cytokines in response to TLR3 activation. Pellino3 deficient mice had greater resistance against the pathogenic and lethal effects of encephalomyocarditis virus (EMCV). TLR3 signaling induced Pellino3, which in turn interacted with and ubiquitinated TRAF6. This modification suppressed the ability of TRAF6 to interact with and activate IRF7, resulting in downregulation of type I interferon expression. Our findings highlight a new physiological role for Pellino3 and define a new autoregulatory network for controlling type I interferon expression. PMID- 23042150 TI - Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin specific protease USP25. AB - Interleukin 17 (IL-17) is important in infection and autoimmunity; how it signals remains poorly understood. In this study, we identified the ubiquitin-specific protease USP25 as a negative regulator of IL-17-mediated signaling and inflammation. Overexpression of USP25 inhibited IL-17-triggered signaling, whereas USP25 deficiency resulted in more phosphorylation of the inhibitor IkappaBalpha and kinase Jnk and higher expression of chemokines and cytokines, as well as a prolonged half-life for chemokine CXCL1-encoding mRNA after treatment with IL-17. Consistent with that, Usp25(-/-) mice showed greater sensitivity to IL-17-dependent inflammation and autoimmunity in vivo. Mechanistically, stimulation with IL-17 induced the association of USP25 with the adaptors TRAF5 and TRAF6, and USP25 induced removal of Lys63-linked ubiquitination in TRAF5 and TRAF6 mediated by the adaptor Act1. Thus, our results demonstrate that USP25 is a deubiquitinating enzyme (DUB) that negatively regulates IL-17-triggered signaling. PMID- 23042153 TI - Electron-transfer properties of a nonheme manganese(IV)-oxo complex acting as a stronger one-electron oxidant than the iron(IV)-oxo analogue. AB - Electron-transfer properties of a nonheme Mn(IV)-oxo complex, [(Bn TPEN)Mn(IV)(O)](2+), reveals that Mn(IV)-oxo complex acts as a stronger one electron oxidant than the Fe(IV)-oxo analogue. As a result, an electron transfer process in N-dealkylation has been detected by a transient radical cation intermediate, para-Me-DMA(+), in the oxidation of para-Me-DMA by [(Bn TPEN)Mn(IV)(O)](2+). PMID- 23042154 TI - Optimal time-point for neural stem cell transplantation to delay denervated skeletal muscle atrophy. AB - INTRODUCTION: Transplantation of neural stem cells (NSCs) is a promising treatment to delay denervated skeletal muscle atrophy; however, the optimal time point between peripheral nerve injury and NSC transplantation needs to be determined. METHODS: Improvement in rat gastrocnemius muscle function was evaluated after NSCs were transplanted into sectioned distal tibial nerves. We also assessed survival and differentiation. ANOVA was used to compare the mean value of the number of neuron-like cells, cross-sectional area amelioration, the amount of activated fibers, and latency and amplitude of the gastrocnemius compound muscle action potential. RESULTS: The group in which the NSCs were transplanted 1 week after tibial nerve transection had the largest number of neuron-like cells, maximum cross-sectional area amelioration, and maximum amount of activated gastrocnemius fibers compared with all other groups (P < 0.01). CONCLUSIONS: The optimal time-point for NSC transplantation for delaying denervated skeletal muscle atrophy is 1 week after severing the nerve. PMID- 23042158 TI - Clinical implementation of chromosomal microarray technology in prenatal diagnosis. (Review). AB - Chromosomal microarray technology represents the technical convergence of molecular genetics and cytogenetics, and is rapidly revolutionizing modern cytogenetics. Expected genomic aberrations are accurately identified and provide readily interpretable results that are suitable for clinical risk stratification and therapeutic strategies. The application of array technology in prenatal genetic diagnosis provides distinct advantages over conventional cytogenetic analysis in detecting both the majority of microscopic and submicroscopic chromosomal abnormalities. In the last few years, the validity of array technology has become obvious to medical and laboratory communities involved in prenatal diagnostic testing. However, whether or not microarray analysis is sufficient for the detection of cytogenetic abnormalities in prenatal diagnosis and if traditional cytogenetics continue to be important in this new era has yet to be confirmed. In the present study, we systematically reviewed the current status of microarray technology in the identification of pathogenic genomic imbalances and discussed practical considerations for its routine implementation in prenatal diagnosis. PMID- 23042159 TI - Stepwise reduction of the culture redox potential allows the analysis of microaerobic metabolism and photosynthetic membrane synthesis in Rhodospirillum rubrum. AB - Bacterial growth under oxygen-limited (microaerobic) conditions is often accompanied by phenomena of great interest for fundamental research and industrial application. The microaerobic lifestyle of anoxygenic photosynthetic bacteria like Rhodospirillum rubrum harbors such a phenomenon, as it allows the formation of photosynthetic membranes and related interesting products without light. However, due to the technical difficulties in process control of microaerobic cultivations and the limited sensitivity of available oxygen sensors, the analysis of microaerobic growth and physiology is still underrepresented in current research. The main focus of the present study was to establish an experimental set-up for the systematic study of physiological processes, associated with the growth of R. rubrum under microaerobic conditions in the dark. For this purpose, we introduce a robust and reliable microaerobic process control strategy, which applies the culture redox potential (CRP) for assessing different degrees of oxygen limitation in bioreactor cultivations. To describe the microaerobic growth behavior of R. rubrum cultures for each of these defined CRP reduction steps, basic growth parameters were experimentally determined. Flux variability analysis provided an insight into the metabolic activity of the TCA cycle and implied its connection to the respiratory capacity of the cells. In this context, our results suggest that microaerobic growth of R. rubrum can be described as an oxygen-activated cooperative mechanism. The present study thus contributes to the investigation of metabolic and regulatory events responsible for the redox-sensitive formation of photosynthetic membranes in facultative photosynthetic bacteria. Furthermore, the introduced microaerobic cultivation setup should be generally applicable for any microbial system of interest which can be cultivated in common stirred-tank bioreactors. PMID- 23042160 TI - Creating, characterizing, and controlling chemistry with SERS hot spots. AB - In this perspective we discuss the roles of hot spots in surface-enhanced Raman spectroscopy (SERS). After giving background and defining the hot spot, we evaluate a variety of SERS substrates which often contain hot spots. We compare and discuss the differentiating properties of each substrate. We then provide a thorough analysis of the hot spot contribution to the observed SERS signal both in ensemble-averaged and single-molecule conditions. We also enumerate rules for determining the SERS enhancement factor (EF) to clarify the use of this common metric. Finally, we present a forward-looking overview of applications and uses of hot spots for controlling chemistry on the nanoscale. Although not exhaustive, this perspective is a review of some of the most interesting and promising methodologies for creating, controlling, and using hot spots for electromagnetic amplification. PMID- 23042161 TI - Reply: To PMID 22581550. PMID- 23042162 TI - Genetic diversity of clinical and environmental Vibrio parahaemolyticus strains from the Pacific Northwest. AB - Since 1997, cases of Vibrio parahaemolyticus-related gastroenteritis from the consumption of raw oysters harvested in Washington State have been higher than historical levels. These cases have shown little or no correlation with concentrations of potentially pathogenic V. parahaemolyticus (positive for the thermostable direct hemolysin gene, tdh) in oysters, although significant concentrations of tdh(+) V. parahaemolyticus strains were isolated from shellfish growing areas in the Pacific Northwest (PNW). We compared clinical and environmental strains isolated from the PNW to those from other geographic regions within the United States and Asia for the presence of virulence associated genes, including the thermostable direct hemolysin (tdh), the thermostable-related hemolysin (trh), urease (ureR), the pandemic group specific markers orf8 and toxRS, and genes encoding both type 3 secretion systems (T3SS1 and T3SS2). The majority of clinical strains from the PNW were positive for tdh, trh, and ureR genes, while a significant proportion of environmental isolates were tdh(+) but trh negative. Hierarchical clustering grouped the majority of these clinical isolates into a cluster distinct from that including the pandemic strain RIMD2210633, clinical isolates from other geographical regions, and tdh(+), trh-negative environmental isolates from the PNW. We detected T3SS2 related genes (T3SS2beta) in environmental strains that were tdh and trh negative. The presence of significant concentrations of tdh(+), trh-negative environmental strains in the PNW that have not been responsible for illness and T3SS2beta in tdh- and trh-negative strains emphasizes the diversity in this species and the need to identify additional virulence markers for this bacterium to improve risk assessment tools for the detection of this pathogen. PMID- 23042163 TI - Staphylococcus aureus CC398 clade associated with human-to-human transmission. AB - Staphylococcus aureus clonal complex 398 (CC398) isolates colonize livestock and can spread to human contacts. Genetic analysis of isolates epidemiologically associated with human-to-human, but not livestock, transmission in multiple countries and continents identified a common clade that was negative for tet(M) and positive for bacteriophage 3. Another group of human-to-human-transmitted isolates belonged to the common livestock-associated clade but had acquired a unique 7 bacteriophage. PMID- 23042164 TI - Rare branched fatty acids characterize the lipid composition of the intra-aerobic methane oxidizer "Candidatus Methylomirabilis oxyfera". AB - The recently described bacterium "Candidatus Methylomirabilis oxyfera" couples the oxidation of the important greenhouse gas methane to the reduction of nitrite. The ecological significance of "Ca. Methylomirabilis oxyfera" is still underexplored, as our ability to identify the presence of this bacterium is thus far limited to DNA-based techniques. Here, we investigated the lipid composition of "Ca. Methylomirabilis oxyfera" to identify new, gene-independent biomarkers for the environmental detection of this bacterium. Multiple "Ca. Methylomirabilis oxyfera" enrichment cultures were investigated. In all cultures, the lipid profile was dominated up to 46% by the fatty acid (FA) 10-methylhexadecanoic acid (10MeC(16:0)). Furthermore, a unique FA was identified that has not been reported elsewhere: the monounsaturated 10-methylhexadecenoic acid with a double bond at the Delta7 position (10MeC(16:1Delta7)), which comprised up to 10% of the total FA profile. We propose that the typical branched fatty acids 10MeC(16:0) and 10MeC(16:1Delta7) are key and characteristic components of the lipid profile of "Ca. Methylomirabilis oxyfera." The successful detection of these fatty acids in a peatland from which one of the enrichment cultures originated supports the potential of these unique lipids as biomarkers for the process of nitrite dependent methane oxidation in the environment. PMID- 23042165 TI - Effect of the Bacillus atrophaeus subsp. globigii Spo0F H101R mutation on strain fitness. AB - Sporulation is a critical developmental process in Bacillus spp. that, once initiated, removes the possibility of further growth until germination. Therefore, the threshold conditions triggering sporulation are likely to be subject to evolutionary constraint. Our previous studies revealed two spontaneous hypersporulating mutants of Bacillus atrophaeus subsp. globigii, both containing point mutations in the spo0F gene. One of these strains (Detrick-2; contains the spo0F101 allele with a C:T [His101Arg] substitution) had been deliberately selected in the early 1940s as an anthrax surrogate. To determine whether the experimental conditions used during the selection of the "military" strains could have supported the emergence of hypersporulating variants, the relative fitness of strain Detrick-2 was measured in several experimental settings modeled on experimental conditions employed during its development in the 1940s as a simulant. The congenic strain Detrick-1 contained a wild-type spo0F gene and sporulated like the wild-type strain. The relative fitness of Detrick-1 and Detrick-2 was evaluated in competition experiments using quantitative single nucleotide polymorphism (SNP)-specific real-time PCR assays directed at the C:T substitution. The ancestral strain Detrick-1 had a fitness advantage under all conditions tested except when competing cultures were subjected to frequent heat shocks. The hypersporulating strain gained the maximum fitness advantage when cultures were grown at low oxygen tension and when heat shock was applied soon after the formation of the first heat-resistant spores. This is interpreted as gain of fitness by the hypersporulating strain in fast-changing fluctuating environments as a result of the increased rate of switching to the sporulating phenotype. PMID- 23042166 TI - Anaerobic oxidization of methane in a minerotrophic peatland: enrichment of nitrite-dependent methane-oxidizing bacteria. AB - The importance of anaerobic oxidation of methane (AOM) as a methane sink in freshwater systems is largely unexplored, particularly in peat ecosystems. Nitrite-dependent anaerobic methane oxidation (n-damo) was recently discovered and reported to be catalyzed by the bacterium "Candidatus Methylomirabilis oxyfera," which is affiliated with the NC10 phylum. So far, several "Ca. Methylomirabilis oxyfera" enrichment cultures have been obtained using a limited number of freshwater sediments or wastewater treatment sludge as the inoculum. In this study, using stable isotope measurements and porewater profiles, we investigated the potential of n-damo in a minerotrophic peatland in the south of the Netherlands that is infiltrated by nitrate-rich ground water. Methane and nitrate profiles suggested that all methane produced was oxidized before reaching the oxic layer, and NC10 bacteria could be active in the transition zone where countergradients of methane and nitrate occur. Quantitative PCR showed high NC10 bacterial cell numbers at this methane-nitrate transition zone. This soil section was used to enrich the prevalent NC10 bacteria in a continuous culture supplied with methane and nitrite at an in situ pH of 6.2. An enrichment of nitrite reducing methanotrophic NC10 bacteria was successfully obtained. Phylogenetic analysis of retrieved 16S rRNA and pmoA genes showed that the enriched bacteria were very similar to the ones found in situ and constituted a new branch of NC10 bacteria with an identity of less than 96 and 90% to the 16S rRNA and pmoA genes of "Ca. Methylomirabilis oxyfera," respectively. The results of this study expand our knowledge of the diversity and distribution of NC10 bacteria in the environment and highlight their potential contribution to nitrogen and methane cycles. PMID- 23042167 TI - Fatty acid cosubstrates provide beta-oxidation precursors for rhamnolipid biosynthesis in Pseudomonas aeruginosa, as evidenced by isotope tracing and gene expression assays. AB - Rhamnolipids have multiple potential applications as "green" surfactants for industry, remediation, and medicine. As a result, they have been intensively investigated to add to our understanding of their biosynthesis and improve yields. Several studies have noted that the addition of a fatty acid cosubstrate increases rhamnolipid yields, but a metabolic explanation has not been offered, partly because biosynthesis studies to date have used sugar or sugar derivatives as the carbon source. The objective of this study was to investigate the role of fatty acid cosubstrates in improving rhamnolipid biosynthesis. A combination of stable isotope tracing and gene expression assays was used to identify lipid precursors and potential lipid metabolic pathways used in rhamnolipid synthesis when fatty acid cosubstrates are present. To this end, we compared the rhamnolipids produced and their yields using either glucose alone or glucose and octadecanoic acid-d(35) as cosubstrates. Using a combination of sugar and fatty acids, the rhamnolipid yield was significantly higher (i.e., doubled) than when glucose was used alone. Two patterns of deuterium incorporation (either 1 or 15 deuterium atoms) in a single Rha-C(10) lipid chain were observed for octadecanoic acid-d(35) treatment, indicating that in the presence of a fatty acid cosubstrate, both de novo fatty acid synthesis and beta-oxidation are used to provide lipid precursors for rhamnolipids. Gene expression assays showed a 200- to 600-fold increase in the expression of rhlA and rhlB rhamnolipid biosynthesis genes and a more modest increase of 3- to 4-fold of the fadA beta-oxidation pathway gene when octadecanoic acid was present. Taken together, these results suggest that the simultaneous use of de novo fatty acid synthesis and beta oxidation pathways allows for higher production of lipid precursors, resulting in increased rhamnolipid yields. PMID- 23042168 TI - Evidence against barium in the mushroom Trogia venenata as a cause of sudden unexpected deaths in Yunnan, China. AB - This study examined barium concentrations in the mushroom Trogia venenata, the leading culprit for sudden unexpected deaths in Yunnan, southwest China. We found that barium concentrations in T. venenata from Yunnan were low and comparable to other foods, inconsistent with barium concentrations in this mushroom as a significant contributor to these deaths. PMID- 23042169 TI - Influence of temperature on the physiology and virulence of the insect pathogen Serratia sp. Strain SCBI. AB - The physiology of a newly recognized Serratia species, termed South African Caenorhabditis briggsae Isolate (SCBI), which is both a nematode mutualist and an insect pathogen, was investigated and compared to that of Serratia marcescens Db11, a broad-host-range pathogen. The two Serratia strains had comparable levels of virulence for Manduca sexta and similar cytotoxic activity patterns, but motility and lipase and hemolytic activities differed significantly between them. PMID- 23042171 TI - Microscope-based imaging platform for large-scale analysis of oral biofilms. AB - A microscopic method for noninvasively monitoring oral biofilms at the macroscale was developed to describe the spatial distribution of biofilms of different bacterial composition on bovine enamel surfaces (BES). For this purpose, oral biofilm was grown in situ on BES that were fixed at approximal sites of individual upper jaw acrylic devices worn by a volunteer for 3 or 5 days. Eubacteria, Streptococcus spp., and Fusobacterium nucleatum were stained using specific fluorescence in situ hybridization (FISH) probes. The resulting fluorescence signals were subsequently tested by confocal laser scanning microscopy (CLSM) and monitored by an automated wide-field microscope-based imaging platform (Scan?R). Automated image processing and data analysis were conducted by microscope-associated software and followed by statistical evaluation of the results. The full segmentation of biofilm images revealed a random distribution of bacteria across the entire area of the enamel surfaces examined. Significant differences in the composition of the microflora were recorded across individual as well as between different enamel surfaces varying from sparsely colonized (47.26%) after 3 days to almost full surface coverage (84.45%) after 5 days. The enamel plates that were positioned at the back or in the middle of the oral cavity were found to be more suitable for the examination of biofilms up to 3 days old. In conclusion, automated microscopy combined with the use of FISH can enable the efficient visualization and meaningful quantification of bacterial composition over the entire sample surface. Due to the possibility of automation, Scan?R overcomes the technical limitations of conventional CLSM. PMID- 23042170 TI - Some like it hot: evolution and ecology of novel endosymbionts in bat flies of cave-roosting bats (hippoboscoidea, nycterophiliinae). AB - We investigated previously unknown associations between bacterial endosymbionts and bat flies of the subfamily Nycterophiliinae (Diptera, Streblidae). Molecular analyses revealed a novel clade of Gammaproteobacteria in Nycterophilia bat flies. This clade was not closely related to Arsenophonus-like microbes found in its sister genus Phalconomus and other bat flies. High population infection rates in Nycterophilia across a wide geographic area, the presence of the symbionts in pupae, the general codivergence between hosts and symbionts, and high AT composition bias in symbiont genes together suggest that this host-symbiont association is obligate in nature and ancient in origin. Some Nycterophilia samples (14.8%) also contained Wolbachia supergroup F (Alphaproteobacteria), suggesting a facultative symbiosis. Likelihood-based ancestral character mapping revealed that, initially, obligate symbionts exhibited association with host specific Nycterophilia bat flies that use a broad temperature range of cave environments for pupal development. As this mutualism evolved, the temperature range of bat flies narrowed to an exclusive use of hot caves, which was followed by a secondary broadening of the bat flies' host associations. These results suggest that the symbiosis has influenced the environmental tolerance of parasite life history stages. Furthermore, the contingent change to an expanded host range of Nycterophilia bat flies upon narrowing the ecological niche of their developmental stages suggests that altered environmental tolerance across life history stages may be a crucial factor in shaping parasite-host relationships. PMID- 23042172 TI - Characterization of two virulent phages of Lactobacillus plantarum. AB - We characterized two Lactobacillus plantarum virulent siphophages, ATCC 8014-B1 (B1) and ATCC 8014-B2 (B2), previously isolated from corn silage and anaerobic sewage sludge, respectively. Phage B2 infected two of the eight L. plantarum strains tested, while phage B1 infected three. Phage adsorption was highly variable depending on the strain used. Phage defense systems were found in at least two L. plantarum strains, LMG9211 and WCSF1. The linear double-stranded DNA genome of the pac-type phage B1 had 38,002 bp, a G+C content of 47.6%, and 60 open reading frames (ORFs). Surprisingly, the phage B1 genome has 97% identity with that of Pediococcus damnosus phage clP1 and 77% identity with that of L. plantarum phage JL-1; these phages were isolated from sewage and cucumber fermentation, respectively. The double-stranded DNA (dsDNA) genome of the cos type phage B2 had 80,618 bp, a G+C content of 36.9%, and 127 ORFs with similarities to those of Bacillus and Lactobacillus strains as well as phages. Some phage B2 genes were similar to ORFs from L. plantarum phage LP65 of the Myoviridae family. Additionally, 6 tRNAs were found in the phage B2 genome. Protein analysis revealed 13 (phage B1) and 9 (phage B2) structural proteins. To our knowledge, this is the first report describing such high identity between phage genomes infecting different genera of lactic acid bacteria. PMID- 23042173 TI - Cellulolytic bacteria in the foregut of the dromedary camel (Camelus dromedarius). AB - Foregut digesta from five feral dromedary camels were inoculated into three different enrichment media: cotton thread, filter paper, and neutral detergent fiber. A total of 283 16S rRNA gene sequences were assigned to 33 operational taxonomic units by using 99% species-level identity. LIBSHUFF revealed significant differences in the community composition across all three libraries. PMID- 23042174 TI - Functional analysis of the Lactobacillus casei BL23 sortases. AB - Sortases are a class of enzymes that anchor surface proteins to the cell wall of Gram-positive bacteria. Lactobacillus casei BL23 harbors four sortase genes, two belonging to class A (srtA1 and srtA2) and two belonging to class C (srtC1 and srtC2). Class C sortases were clustered with genes encoding their putative substrates that were homologous to the SpaEFG and SpaCBA proteins that encode mucus adhesive pili in Lactobacillus rhamnosus GG. Twenty-three genes encoding putative sortase substrates were identified in the L. casei BL23 genome with unknown (35%), enzymatic (30%), or adhesion-related (35%) functions. Strains disrupted in srtA1, srtA2, srtC1, and srtC2 and an srtA1 srtA2 double mutant were constructed. The transcription of all four sortase encoding genes was detected, but only the mutation of srtA1 resulted in a decrease in bacterial surface hydrophobicity. The beta-N-acetyl-glucosaminidase and cell wall proteinase activities of whole cells diminished in the srtA1 mutant and, to a greater extent, in the srtA1 srtA2 double mutant. Cell wall anchoring of the staphylococcal NucA reporter protein fused to a cell wall sorting sequence was also affected in the srtA mutants, and the percentages of adhesion to Caco-2 and HT-29 intestinal epithelial cells were reduced for the srtA1 srtA2 strain. Mutations in srtC1 or srtC2 result in an undetectable phenotype. Together, these results suggest that SrtA1 is the housekeeping sortase in L. casei BL23 and SrtA2 would carry out redundant or complementary functions that become evident when SrtA1 activity is absent. PMID- 23042175 TI - Engineering filamentous fungi for conversion of D-galacturonic acid to L galactonic acid. AB - D-Galacturonic acid, the main monomer of pectin, is an attractive substrate for bioconversions, since pectin-rich biomass is abundantly available and pectin is easily hydrolyzed. l-Galactonic acid is an intermediate in the eukaryotic pathway for d-galacturonic acid catabolism, but extracellular accumulation of l galactonic acid has not been reported. By deleting the gene encoding l-galactonic acid dehydratase (lgd1 or gaaB) in two filamentous fungi, strains were obtained that converted d-galacturonic acid to l-galactonic acid. Both Trichoderma reesei Deltalgd1 and Aspergillus niger DeltagaaB strains produced l-galactonate at yields of 0.6 to 0.9 g per g of substrate consumed. Although T. reesei Deltalgd1 could produce l-galactonate at pH 5.5, a lower pH was necessary for A. niger DeltagaaB. Provision of a cosubstrate improved the production rate and titer in both strains. Intracellular accumulation of l-galactonate (40 to 70 mg g biomass( 1)) suggested that export may be limiting. Deletion of the l-galactonate dehydratase from A. niger was found to delay induction of d-galacturonate reductase and overexpression of the reductase improved initial production rates. Deletion of the l-galactonate dehydratase from A. niger also delayed or prevented induction of the putative d-galacturonate transporter An14g04280. In addition, A. niger DeltagaaB produced l-galactonate from polygalacturonate as efficiently as from the monomer. PMID- 23042176 TI - Population genetic structure of 4,12:a:- Salmonella enterica strains from harbor porpoises. AB - According to pulsed-field gel electrophoresis (PFGE) typing, 4,12:a:- Salmonella enterica isolates from harbor porpoises are highly diverse. However, porpoise isolates belong to only two multilocus sequence types within the eBurst group 18 (eBG18) genetic cluster, which also includes S. enterica serovars Bispebjerg and Abortusequi. Isolates of other, serologically similar serovars belong to unrelated eBGs. These assignments to eBGs were supported by eBG-specific sequences of the flagellar gene fliC. PMID- 23042177 TI - Biosynthesis and functions of a melanoid pigment produced by species of the sporothrix complex in the presence of L-tyrosine. AB - Sporothrix schenckii is the etiological agent of sporotrichosis, the main subcutaneous mycosis in Latin America. Melanin is an important virulence factor of S. schenckii, which produces dihydroxynaphthalene melanin (DHN-melanin) in conidia and yeast cells. Additionally, l-dihydroxyphenylalanine (l-DOPA) can be used to enhance melanin production on these structures as well as on hyphae. Some fungi are able to synthesize another type of melanoid pigment, called pyomelanin, as a result of tyrosine catabolism. Since there is no information about tyrosine catabolism in Sporothrix spp., we cultured 73 strains, including representatives of newly described Sporothrix species of medical interest, such as S. brasiliensis, S. schenckii, and S. globosa, in minimal medium with tyrosine. All strains but one were able to produce a melanoid pigment with a negative charge in this culture medium after 9 days of incubation. An S. schenckii DHN-melanin mutant strain also produced pigment in the presence of tyrosine. Further analysis showed that pigment production occurs in both the filamentous and yeast phases, and pigment accumulates in supernatants during stationary-phase growth. Notably, sulcotrione inhibits pigment production. Melanin ghosts of wild-type and DHN mutant strains obtained when the fungus was cultured with tyrosine were similar to melanin ghosts yielded in the absence of the precursor, indicating that this melanin does not polymerize on the fungal cell wall. However, pyomelanin producing fungal cells were more resistant to nitrogen-derived oxidants and to UV light. In conclusion, at least three species of the Sporothrix complex are able to produce pyomelanin in the presence of tyrosine, and this pigment might be involved in virulence. PMID- 23042178 TI - Lipase and protease double-deletion mutant of Pseudomonas fluorescens suitable for extracellular protein production. AB - Pseudomonas fluorescens, a widespread Gram-negative bacterium, is an ideal protein manufacturing factory (PMF) because of its safety, robust growth, and high protein production. P. fluorescens possesses a type I secretion system (T1SS), which mediates secretion of a thermostable lipase (TliA) and a protease (PrtA) through its ATP-binding cassette (ABC) transporter. Recombinant proteins in P. fluorescens are attached to the C-terminal signal region of TliA for transport as fusion proteins to the extracellular medium. However, intrinsic TliA from the P. fluorescens genome interferes with detection of the recombinant protein and the secreted recombinant protein is hydrolyzed, due to intrinsic PrtA, resulting in decreased efficiency of the PMF. In this research, the lipase and protease genes of P. fluorescens SIK W1 were deleted using the targeted gene knockout method. Deletion mutant P. fluorescens DeltatliA DeltaprtA secreted fusion proteins without TliA or protein degradation. Using wild-type P. fluorescens as an expression host, degradation of the recombinant protein varied depending on the type of culture media and aeration; however, degradation did not occur with the P. fluorescens DeltatliA DeltaprtA double mutant irrespective of growth conditions. By homologous expression of tliA and the ABC transporter in a plasmid, TliA secreted from P. fluorescens DeltaprtA and P. fluorescens DeltatliA DeltaprtA cells was found to be intact, whereas that secreted from the wild-type P. fluorescens and P. fluorescens DeltatliA cells was found to be hydrolyzed. Our results demonstrate that the P. fluorescens DeltatliA DeltaprtA deletion mutant is a promising T1SS-mediated PMF that enhances production and detection of recombinant proteins in extracellular media. PMID- 23042180 TI - Silage collected from dairy farms harbors an abundance of listeriaphages with considerable host range and genome size diversity. AB - Since the food-borne pathogen Listeria monocytogenes is common in dairy farm environments, it is likely that phages infecting this bacterium ("listeriaphages") are abundant on dairy farms. To better understand the ecology and diversity of listeriaphages on dairy farms and to develop a diverse phage collection for further studies, silage samples collected on two dairy farms were screened for L. monocytogenes and listeriaphages. While only 4.5% of silage samples tested positive for L. monocytogenes, 47.8% of samples were positive for listeriaphages, containing up to >1.5 * 10(4) PFU/g. Host range characterization of the 114 phage isolates obtained, with a reference set of 13 L. monocytogenes strains representing the nine major serotypes and four lineages, revealed considerable host range diversity; phage isolates were classified into nine lysis groups. While one serotype 3c strain was not lysed by any phage isolates, serotype 4 strains were highly susceptible to phages and were lysed by 63.2 to 88.6% of phages tested. Overall, 12.3% of phage isolates showed a narrow host range (lysing 1 to 5 strains), while 28.9% of phages represented broad host range (lysing >=11 strains). Genome sizes of the phage isolates were estimated to range from approximately 26 to 140 kb. The extensive host range and genomic diversity of phages observed here suggest an important role of phages in the ecology of L. monocytogenes on dairy farms. In addition, the phage collection developed here has the potential to facilitate further development of phage-based biocontrol strategies (e.g., in silage) and other phage-based tools. PMID- 23042179 TI - Genetic diversity among Clostridium botulinum strains harboring bont/A2 and bont/A3 genes. AB - Clostridium botulinum type A strains are known to be genetically diverse and widespread throughout the world. Genetic diversity studies have focused mainly on strains harboring one type A botulinum toxin gene, bont/A1, although all reported bont/A gene variants have been associated with botulism cases. Our study provides insight into the genetic diversity of C. botulinum type A strains, which contain bont/A2 (n = 42) and bont/A3 (n = 4) genes, isolated from diverse samples and geographic origins. Genetic diversity was assessed by using bont nucleotide sequencing, content analysis of the bont gene clusters, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). Sequences of bont genes obtained in this study showed 99.9 to 100% identity with other bont/A2 or bont/A3 gene sequences available in public databases. The neurotoxin gene clusters of the subtype A2 and A3 strains analyzed in this study were similar in gene content. C. botulinum strains harboring bont/A2 and bont/A3 genes were divided into six and two MLST profiles, respectively. Four groups of strains shared a similarity of at least 95% by PFGE; the largest group included 21 out of 46 strains. The strains analyzed in this study showed relatively limited genetic diversity using either MLST or PFGE. PMID- 23042181 TI - 3' Untranslated region-dependent degradation of the aceA mRNA, encoding the glyoxylate cycle enzyme isocitrate lyase, by RNase E/G in Corynebacterium glutamicum. AB - We previously reported that the Corynebacterium glutamicum RNase E/G encoded by the rneG gene (NCgl2281) is required for the 5' maturation of 5S rRNA. In the search for the intracellular target RNAs of RNase E/G other than the 5S rRNA precursor, we detected that the amount of isocitrate lyase, an enzyme of the glyoxylate cycle, increased in rneG knockout mutant cells grown on sodium acetate as the sole carbon source. Rifampin chase experiments showed that the half-life of the aceA mRNA was about 4 times longer in the rneG knockout mutant than in the wild type. Quantitative real-time PCR analysis also confirmed that the level of aceA mRNA was approximately 3-fold higher in the rneG knockout mutant strain than in the wild type. Such differences were not observed in other mRNAs encoding enzymes involved in acetate metabolism. Analysis by 3' rapid amplification of cDNA ends suggested that RNase E/G cleaves the aceA mRNA at a single-stranded AU rich region in the 3' untranslated region (3'-UTR). The lacZ fusion assay showed that the 3'-UTR rendered lacZ mRNA RNase E/G dependent. These findings indicate that RNase E/G is a novel regulator of the glyoxylate cycle in C. glutamicum. PMID- 23042182 TI - Purification and characterization of an NAD+-dependent XylB-like aryl alcohol dehydrogenase identified in Acinetobacter baylyi ADP1. AB - The gene xylB(ADP1) from Acinetobacter baylyi ADP1 (gene annotation number ACIAD1578), coding for a putative aryl alcohol dehydrogenase, was heterologously expressed in Escherichia coli BL21(DE3). The respective aryl alcohol dehydrogenase was purified by fast protein liquid chromatography to apparent electrophoretic homogeneity. The predicted molecular weight of 39,500 per subunit was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. According to the native M(w) as determined by gel filtration, the enzyme forms dimers and therefore seems to be XylB related. The enzyme showed the highest activity at 40 degrees C. For both the reduction and the oxidation reactions, the pH for optimum activity was 6.5. The enzyme was NADH dependent and able to reduce medium- to long-chain n-alkylaldehydes, methyl-branched aldehydes, and aromatic aldehydes, with benzaldehyde yielding the highest activity. The oxidation reaction with the corresponding alcohols showed only 2.2% of the reduction activity, with coniferyl alcohol yielding the highest activity. Maximum activities for the reduction and the oxidation reaction were 104.5 and 2.3 U mg( 1) of protein, respectively. The enzyme activity was affected by low concentrations of Ag(+) and Hg(2+) and high concentrations of Cu(2+), Zn(2+), and Fe(2+). The gene xylB(ADP1) seems to be expressed constitutively and an involvement in coniferyl alcohol degradation is suggested. However, the enzyme is most probably not involved in the degradation of benzyl alcohol, anisalcohol, salicyl alcohol, vanillyl alcohol, cinnamyl alcohol, or aliphatic and isoprenoid alcohols. PMID- 23042183 TI - Glucosylation and other biotransformations of T-2 toxin by yeasts of the trichomonascus clade. AB - Trichothecenes are sesquiterpenoid toxins produced by Fusarium species. Since these mycotoxins are very stable, there is interest in microbial transformations that can remove toxins from contaminated grain or cereal products. Twenty-three yeast species assigned to the Trichomonascus clade (Saccharomycotina, Ascomycota), including four Trichomonascus species and 19 anamorphic species presently classified in Blastobotrys, were tested for their ability to convert the trichothecene T-2 toxin to less-toxic products. These species gave three types of biotransformations: acetylation to 3-acetyl T-2 toxin, glycosylation to T-2 toxin 3-glucoside, and removal of the isovaleryl group to form neosolaniol. Some species gave more than one type of biotransformation. Three Blastobotrys species converted T-2 toxin into T-2 toxin 3-glucoside, a compound that has been identified as a masked mycotoxin in Fusarium-infected grain. This is the first report of a microbial whole-cell method for producing trichothecene glycosides, and the potential large-scale availability of T-2 toxin 3-glucoside will facilitate toxicity testing and development of methods for detection of this compound in agricultural and other products. PMID- 23042186 TI - Terpyridine-porphyrin hetero-Pacman compounds. AB - The two different coordination spheres afforded by Pacman architectures offer cooperativity derived from two different metal centers. A modular strategy is developed to produce a hetero-Pacman scaffold featuring a porphyrin and terpyridine for metal-ion binding. A double Suzuki reaction was employed to first attach a terpyridine moiety to a xanthene backbone and then attach a porphyrin. The new hetero-Pacman scaffold has been characterized and all building blocks have been isolated and structurally characterized. The principle objective to incorporate different metal centers was confirmed by isolating a trinuclear complex comprising two porphyrinic units and a bis(terpyridine)-iron unit. The compounds described herein expand the Pacman scaffold concept by allowing for the incorporation of a terpyridine-metal complex proximate to a porphyrin-cofactor active site for small-molecule activation. PMID- 23042184 TI - Evaluation of a genome-scale in silico metabolic model for Geobacter metallireducens by using proteomic data from a field biostimulation experiment. AB - Accurately predicting the interactions between microbial metabolism and the physical subsurface environment is necessary to enhance subsurface energy development, soil and groundwater cleanup, and carbon management. This study was an initial attempt to confirm the metabolic functional roles within an in silico model using environmental proteomic data collected during field experiments. Shotgun global proteomics data collected during a subsurface biostimulation experiment were used to validate a genome-scale metabolic model of Geobacter metallireducens-specifically, the ability of the metabolic model to predict metal reduction, biomass yield, and growth rate under dynamic field conditions. The constraint-based in silico model of G. metallireducens relates an annotated genome sequence to the physiological functions with 697 reactions controlled by 747 enzyme-coding genes. Proteomic analysis showed that 180 of the 637 G. metallireducens proteins detected during the 2008 experiment were associated with specific metabolic reactions in the in silico model. When the field-calibrated Fe(III) terminal electron acceptor process reaction in a reactive transport model for the field experiments was replaced with the genome-scale model, the model predicted that the largest metabolic fluxes through the in silico model reactions generally correspond to the highest abundances of proteins that catalyze those reactions. Central metabolism predicted by the model agrees well with protein abundance profiles inferred from proteomic analysis. Model discrepancies with the proteomic data, such as the relatively low abundances of proteins associated with amino acid transport and metabolism, revealed pathways or flux constraints in the in silico model that could be updated to more accurately predict metabolic processes that occur in the subsurface environment. PMID- 23042187 TI - Prostaglandins as negative regulators against lipopolysaccharide, lipoteichoic acid, and peptidoglycan-induced inducible nitric oxide synthase/nitric oxide production through reactive oxygen species-dependent heme oxygenase 1 expression in macrophages. AB - Although prostaglandins (PGs) were reported to exert proinflammatory and anti inflammatory effects in macrophages, their action mechanisms remain unclear. The effects of PGs including PGJ2 (J2), Delta-PGJ2 (Delta), 15-deoxy-Delta PGJ2 (15d), PGE2 (E2), and PGF2alpha (F2alpha) on lipopolysaccharide (LPS)-, lipoteichoic acid (LTA)-, and peptidoglycan (PGN)-induced inducible nitric oxide (NO) synthase (iNOS)/NO production by RAW264.7 macrophages were investigated. First, we found that induction of cyclooxygenase 2 (COX-2) protein occurred at a time earlier than that of heme oxygenase 1 (HO-1) protein, and the addition of the COX-2 inhibitor NS398 reduced HO-1 protein expression in LPS-, LTA-, and PGN treated RAW264.7 macrophages. Incubation of RAW264.7 macrophages with the indicated PGs showed that J2, Delta, and 15d significantly induced HO-1 protein expression; however, E2 and F2alpha did not. Heme oxygenase 1 protein induced by J2, Delta, and 15d was inhibited by the transcriptional inhibitor, actinomycin (Act) D; the translational inhibitor, cycloheximide; and the antioxidant, N acetyl cysteine (NAC). Increases in intracellular peroxide levels by J2, Delta, and 15d were detected via a 2',7'TM-dichlorofluorescein diacetate (DCFH-DA) analysis, and they were prevented by the addition of NAC. In addition, J2, Delta, and 15d produced significant inhibition of LPS-, LTA-, and PGN-induced iNOS protein and NO production by RAW264.7 cells, in accordance with increased HO-1 protein expression. Reductions of LPS-, LTA-, and PGN-induced phosphorylated c Jun N-terminal kinase, c-Jun protein, and activator protein 1 luciferase activity by J2, Delta, and 15d were identified, and the addition of the HO-1 inhibitor, tin protoporphyrin, reversed the inhibitory effects of Delta and 15d on LPS- and LTA-induced iNOS/NO, phosphorylated c-Jun N-terminal kinase, and c-Jun protein expressions by macrophages. Knockdown of HO-1 protein expression by HO-1 small interfering RNA blocked Delta and 15d inhibition of LPS- and LTA-induced events. Moreover, the compound, cyclopentenone (CP), which mimics the CP moiety of 15d, and its analog cyclohexenone were used, and cyclohexenone showed more potent induction of the HO-1 protein with effective inhibition of LPS-, LTA-, and PGN induced iNOS/NO production than CP in macrophages. Reactive oxygen species dependent HO-1 protein expression by PGs, which inhibited LPS-, LTA-, and PGN induced iNOS/NO production, was identified in macrophages. PMID- 23042188 TI - Microcirculatory effects of selective receptor blockade during hemorrhagic shock treatment with vasopressin: experimental study in the hamster dorsal chamber. AB - Hemorrhagic shock is a major cause of death in modern societies. Some patients, when treated, fail to sustain normal cardiovascular parameters, requiring fluid therapy and vasoactive drugs. Among drugs with cardiovascular profile other than catecholamine, vasopressin (VP) is emerging as an option. To better understand its effects during hemorrhagic shock, we compared the effects of VP and noradrenaline (NA), associated to fluid therapy. In this work, hamsters were subjected to shock by withdrawal of 40% of their blood volume and were then divided into five groups. One group was treated with saline solution, and the remaining ones with VP (three groups) and NA (one group) combined to fluid resuscitation. To assess receptor role, two more VP groups were pretreated with specific receptor blockers (anti-V1 or anti-V2, respectively) before its infusion. Microcirculatory parameters such as vessel diameter, red blood cell velocity, and functional capillary density were evaluated. In addition, blood gas analysis and lactate levels were also determined. Measurements were performed at baseline, after shock, and after treatment. At the end, leukocyte-endothelium interaction was evaluated, and animals were followed up to determine survival time. Neither saline solution nor NA recovered microcirculatory parameters, but VP treatment returned to near baseline values, except when V2 receptors were blocked. Functional capillary density was higher in the VP group after treatment, without statistical difference from baseline values. When V2 receptors were blocked, recovery was not achieved after treatment. The VP group also had a smaller number of adhering leukocytes and improved 72-h survival time compared with the NA one. This study suggests that, in hemorrhagic shock, treatment with low-dose VP, in combination with fluid therapy, improves tissue perfusion. This outcome is mediated mostly by V2 receptors, eliciting vasodilatation and consequently blood flow redistribution through the microcirculation. PMID- 23042185 TI - Prevalence, environmental loading, and molecular characterization of Cryptosporidium and Giardia isolates from domestic and wild animals along the Central California Coast. AB - The risk of disease transmission from waterborne protozoa is often dependent on the origin (e.g., domestic animals versus wildlife), overall parasite load in contaminated waterways, and parasite genotype, with infections being linked to runoff or direct deposition of domestic animal and wildlife feces. Fecal samples collected from domestic animals and wildlife along the central California coast were screened to (i) compare the prevalence and associated risk factors for fecal shedding of Cryptosporidium and Giardia species parasites, (ii) evaluate the relative importance of animal host groups that contribute to pathogen loading in coastal ecosystems, and (iii) characterize zoonotic and host-specific genotypes. Overall, 6% of fecal samples tested during 2007 to 2010 were positive for Cryptosporidium oocysts and 15% were positive for Giardia cysts. Animal host group and age class were significantly associated with detection of Cryptosporidium and Giardia parasites in animal feces. Fecal loading analysis revealed that infected beef cattle potentially contribute the greatest parasite load relative to other host groups, followed by wild canids. Beef cattle, however, shed host-specific, minimally zoonotic Cryptosporidium and Giardia duodenalis genotypes, whereas wild canids shed potentially zoonotic genotypes, including G. duodenalis assemblages A and B. Given that the parasite genotypes detected in cattle were not zoonotic, the public health risk posed by protozoan parasite shedding in cattle feces may be lower than that posed by other animals, such as wild canids, that routinely shed zoonotic genotypes. PMID- 23042191 TI - Splenic Doppler resistive index for early detection of occult hemorrhagic shock after polytrauma in adult patients. AB - The objective of this study was to evaluate whether direct assessment of splenic circulation by splenic Doppler resistive index (Doppler RI) is a clinically useful noninvasive method for an early detection of occult hemorrhagic shock after polytrauma in adult patients. Splenic Doppler RI was measured in 49 hemodynamically stable adult patients admitted to the emergency department because of polytrauma. Renal Doppler RI was also determined in 20 patients. Spleen size, Injury Severity Score, systolic blood pressure, heart rate, blood lactate, standard base excess, pH, hemoglobin, and inferior vena cava diameter values were recorded at admission and at 24 h. Patients were grouped according to whether signs of hemorrhagic shock did (n = 22) or did not (n = 27) occur within the first 24 h from admission. Patients who developed hemorrhagic shock had significantly higher splenic and renal Doppler RI, higher Injury Severity Score, and lower standard base excess at admission. By multivariate logistic regression, splenic Doppler RI resulted to be a predictor of hemorrhagic shock development within the first 24 h from admission. Splenic Doppler RI may represent a clinically useful noninvasive method for early detection of occult hemorrhagic shock and persistent occult hypoperfusion after polytrauma in adult patients. PMID- 23042190 TI - Radiation combined with thermal injury induces immature myeloid cells. AB - The continued development of nuclear weapons and the potential for thermonuclear injury necessitates the further understanding of the immune consequences after radiation combined with injury (RCI). We hypothesized that sublethal ionization radiation exposure combined with a full-thickness thermal injury would result in the production of immature myeloid cells. Mice underwent either a full-thickness contact burn of 20% total body surface area or sham procedure followed by a single whole-body dose of 5-Gy radiation. Serum, spleen, and peripheral lymph nodes were harvested at 3 and 14 days after injury. Flow cytometry was performed to identify and characterize adaptive and innate cell compartments. Elevated proinflammatory and anti-inflammatory serum cytokines and profound leukopenia were observed after RCI. A population of cells with dual expression of the cell surface markers Gr-1 and CD11b were identified in all experimental groups, but were significantly elevated after burn alone and RCI at 14 days after injury. In contrast to the T-cell-suppressive nature of myeloid-derived suppressor cells found after trauma and sepsis, myeloid cells after RCI augmented T-cell proliferation and were associated with a weak but significant increase in interferon gamma and a decrease in interleukin 10. This is consistent with previous work in burn injury indicating that a myeloid-derived suppressor cell like population increases innate immunity. Radiation combined injury results in the increase in distinct populations of Gr-1CD11b cells within the secondary lymphoid organs, and we propose these immature inflammatory myeloid cells provide innate immunity to the severely injured and immunocompromised host. PMID- 23042192 TI - The acute coagulopathy of trauma: mechanisms and tools for risk stratification. AB - Trauma remains the leading cause of death, with bleeding as the primary cause of preventable mortality. When death occurs, it happens quickly, typically within the first 6 h after injury. The principal drivers of the acute coagulopathy of trauma have been characterized, but another group of patients with early evidence of coagulopathy both physiologically and mechanistically distinct from this systemic acquired coagulopathy has been identified. This distinct phenotype is present in 25% to 30% of patients with major trauma without being exposed to the traditional triggers and is associated with higher morbidity and a 4-fold increase in mortality. Despite improvements in the resuscitation of exsanguinating patients, one of the remaining keys is to expeditiously and reproducibly identify the patients most likely to require transfusion including massive transfusion with damage control resuscitation principles. Several predictive scoring systems/algorithms for transfusion including massive transfusion in both civilian and military trauma populations have been introduced. The models developed usually suggest combinations of physiologic, hemodynamic, laboratory, injury severity, and demographic triggers identified on the initial evaluation. Many use a combination of dichotomous variables that are readily accessible after the patient's arrival to the trauma bay, but others rely on time-consuming mathematical calculations and may thus have limited real-time application. Weighted and more sophisticated systems including higher numbers of variables perform superiorly. A common limitation to all models is their retrospective nature, and prospective validations are needed. Point-of-care viscoelastic testing may be an alternative to early recognize trauma-induced coagulopathy with the risk of ongoing hemorrhage and transfusion. PMID- 23042189 TI - Inducible nitric oxide synthase contributes to immune dysfunction following trauma. AB - Trauma results in a persistent depression in adaptive immunity, which contributes to patient morbidity and mortality. This state of immune paralysis following trauma is characterized by a change in cell-mediated immunity, specifically a depression in T-cell function and a shift toward TH2 T-cell phenotype. Upregulation of inducible nitric oxide synthase (iNOS) is well recognized after injury and contributes to the inflammatory response and organ damage early after trauma. However, it is unknown whether iNOS plays a role in adaptive immune dysfunction after trauma. This study utilized a murine model of severe peripheral tissue injury to show that iNOS is rapidly upregulated in macrophages and a (Gr-1-CD11b) myeloid-derived suppressor cell subpopulation in the spleen. Through the use of iNOS knockout mice, a specific iNOS inhibitor, and a nitric oxide (NO) scavenger, this study demonstrates that iNOS-derived NO is required for the depression in T-lymphocyte proliferation, interferon gamma, and interleukin 2 production within the spleen at 48 h after trauma. These findings support the hypothesis that iNOS regulates immune suppression following trauma and suggest that targeting the sustained production of NO by iNOS may attenuate posttraumatic immune depression. PMID- 23042194 TI - Administration of a peroxynitrite decomposition catalyst into the bronchial artery attenuates pulmonary dysfunction after smoke inhalation and burn injury in sheep. AB - Reactive nitrogen species such as peroxynitrite play a significant role in burn and smoke inhalation injury. The bronchial circulation increases more than 10 fold in response to this combination injury. We hypothesized that direct delivery of low-dose WW-85, a peroxynitrite decomposition catalyst, into the bronchial artery would attenuate burn- and smoke inhalation-induced acute lung injury. In adult female sheep (n = 17), the bronchial artery was cannulated in preparation surgery. After a 5- to 7-day recovery period, sheep were subjected to a burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, <40 degrees C). The animals were divided into three groups following the injury: (i) WW-85 group: 1 h after injury, WW-85 (0.002 mg/kg per hour) was continuously infused into the bronchial artery, n = 5; (ii) control group: 1 h after injury, an equivalent amount of saline was injected into the bronchial artery, n = 6; (iii) sham group: no injury, no treatment, same operation and anesthesia, n = 6. All animals were mechanically ventilated and fluid resuscitated equally. In the control group, the injury induced a severe deterioration of pulmonary oxygenation and shunting and an increase in pulmonary microvascular permeability toward sham. The injury was further associated with an increase in reactive nitrogen species in lung tissues of the control group. All these alterations were significantly attenuated in the WW-85 group. We demonstrated that a low dosage of WW-85 directly administered into the bronchial artery attenuated pulmonary dysfunction to the same extent as higher systemically administered doses in previous experiments. Our data strongly suggest that local airway production of peroxynitrite contributes to pulmonary dysfunction following smoke inhalation and burn injury. PMID- 23042195 TI - Factors influencing compliance with early resuscitation bundle in the management of severe sepsis and septic shock. AB - The Surviving Sepsis Campaign guidelines recommend implementing a 6-h resuscitation bundle, which has been associated with reduced mortality of patients presenting with severe sepsis or septic shock. However, this resuscitation bundle has not yet become a widely implemented treatment protocol. It is still unclear what factors are associated with the rate of compliance with the resuscitation bundle. In this study, we evaluated the potential factors associated with implementation and compliance of a 6-h resuscitation bundle in patients presenting with severe sepsis or septic shock in the emergency department. We conducted a retrospective observational study involving adult patients presenting with severe sepsis or septic shock in the emergency department of a tertiary care hospital during the period between August 2008 and July 2010. The resuscitation bundle consisted of seven interventions according to the Surviving Sepsis Campaign guidelines. The primary outcome measure was the rate of high compliance with the 6-h resuscitation bundle, defined as implementation of more than five of seven interventions. Multivariable logistic regression analysis was used to adjust for the confounding factors. A total of 317 patients were enrolled into the study. One hundred seventy-two patients (54.3%) were assigned to the high compliance group, and 145 patients (45.7%) to the low compliance group. Significant factors associated with high compliance of the 6-h resuscitation bundle were hyperthermia (adjusted odds ratio [OR], 1.37; 95% confidence interval [95% CI], 1.10-1.70), care from experienced nurses who had 3 or more years of clinical experience (adjusted OR, 1.69; 95% CI, 1.10 2.58), and care from senior residents or board-certified emergency physicians (adjusted OR, 3.68; 95% CI, 1.68-6.89). Factors related with lower compliance were cryptic shock (adjusted OR, 0.26; 95% CI, 0.13-0.52) and higher serum lactate levels (adjusted OR, 0.90; 95% CI, 0.82-0.98). Furthermore, we found several potential factors that influence compliance with the sepsis resuscitation bundle. To improve the compliance with the resuscitation bundle, interventions focusing on those factors will be needed. PMID- 23042193 TI - The endogenous bacteria alter gut epithelial apoptosis and decrease mortality following Pseudomonas aeruginosa pneumonia. AB - The endogenous bacteria have been hypothesized to play a significant role in the pathophysiology of critical illness, although their role in sepsis is poorly understood. The purpose of this study was to determine how commensal bacteria alter the host response to sepsis. Conventional and germ-free (GF) C57Bl/6 mice were subjected to Pseudomonas aeruginosa pneumonia. All GF mice died within 2 days, whereas 44% of conventional mice survived for 7 days (P = 0.001). Diluting the dose of bacteria 10-fold in GF mice led to similar survival in GF and conventional mice. When animals with similar mortality were assayed for intestinal integrity, GF mice had lower levels of intestinal epithelial apoptosis but similar levels of proliferation and intestinal permeability. Germ-free mice had significantly lower levels of tumor necrosis factor and interleukin 1beta in bronchoalveolar lavage fluid compared with conventional mice without changes in systemic cytokine production. Under conventional conditions, sepsis unmasks lymphocyte control of intestinal epithelial apoptosis, because sepsis induces a greater increase in gut apoptosis in Rag-1 mice than in wild-type mice. However, in a separate set of experiments, gut apoptosis was similar between septic GF Rag 1 mice and septic GF wild-type mice. These data demonstrate that the endogenous bacteria play a protective role in mediating mortality from pneumonia-induced sepsis, potentially mediated through altered intestinal apoptosis and the local proinflammatory response. In addition, sepsis-induced lymphocyte-dependent increases in gut epithelial apoptosis appear to be mediated by the endogenous bacteria. PMID- 23042196 TI - Glycocalyx degradation causes microvascular perfusion failure in the ex vivo perfused mouse lung: hydroxyethyl starch 130/0.4 pretreatment attenuates this response. AB - The endothelial glycocalyx (GLX) is pivotal to vascular barrier function. We investigated the consequences of GLX degradation on pulmonary microvascular perfusion and, prompted by evidence that hydroxyethyl starch (HES) improves microcirculation, studied the effects of two HES preparations during GLX diminution. C57 BL/6 black mice lungs were explanted and perfused with 1-mL/min buffer solution containing autologous erythrocytes (red blood cells) at a hematocrit of 5%. Microvessel perfusion was quantified by video fluorescence microscopy at 0 and 90 min. To register interstitial edema, alveolar septal width was quantified. Pulmonary artery pressure (PAP), airway pressure, and left atrial pressure were recorded continuously. Lungs were randomly assigned to four groups (each n = 5): (i) control: no treatment, (ii) HEP1: heparinase I (1 mU/mL) was injected for GLX degradation, (iii) HES 130, and (iv) HES 200: one third of perfusion fluid was exchanged for 6% HES 130/0.4 or 10% HES 200/0.5 before GLX degradation. Analysis of variance on ranks and pairwise multiple comparisons were used for statistics, P < 0.05. Compared with control, GLX degradation effected perfusion failure in microvessels, increased PAP, and facilitated interstitial edema formation after a 90-min period of perfusion. In contrast to HES 200/0.5, pretreatment with HES 130/0.4 attenuated all of these consequences. Sequelae of GLX degradation in lung include perfusion failure in microvessels, interstitial edema formation, and increase in PAP. We assume that these effects are a consequence of vascular barrier dysfunction. Beneficial effects of HES 130/0.4 are presumably a result of its lower red blood cell bridging capacity compared with HES 200/0.5. PMID- 23042198 TI - Simvastatin protects against T cell immune dysfunction in abdominal sepsis. AB - Sepsis-triggered immune paralysis including T-cell dysfunction increases susceptibility to infections. Statins exert beneficial effects in patients with sepsis, although the mechanisms remain elusive. Herein, we hypothesized that simvastatin may attenuate T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were pretreated with simvastatin (10 mg/kg) before cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation, and regulatory T cells (CD4CD25Foxp3) were quantified by use of flow cytometry. Formation of interferon gamma (IFN-gamma) and interleukin 4 (IL-4) in the spleen and plasma levels of high-mobility box group 1 (HMBG1) and IL-6 were determined using enzyme linked immunosorbent assay. Cecal ligation and puncture caused a clear-cut increase in apoptosis and decrease in proliferation in splenic CD4 T cells. It was found that simvastatin markedly reduced apoptosis and improved proliferation in CD4 T cells in septic mice. Moreover, CLP-induced formation of regulatory T cells in the spleen was abolished in simvastatin-treated animals. Cecal ligation and puncture greatly decreased the levels of IFN-gamma and IL-4 in the spleen. Simvastatin completely reversed this sepsis-mediated inhibition of IFN-gamma and IL-4 formation in the spleen. We observed that CLP increased plasma levels of HMBG1 by 25-fold and IL-6 by 99,595-fold. Notably, treatment with simvastatin abolished this CLP-evoked increase in HMBG1 and IL-6 levels in the plasma, suggesting that simvastatin is a potent inhibitor of systemic inflammation in sepsis. Lastly, it was found that simvastatin reduced CLP-induced bacteremia. In conclusion, these novel findings suggest that simvastatin is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, these protective effects of simvastatin on T-cell functions help to explain the protective effect of statins in patients with sepsis. PMID- 23042197 TI - STAT3-mediated IL-17 production by postseptic T cells exacerbates viral immunopathology of the lung. AB - Survivors of severe sepsis exhibit increased morbidity and mortality in response to secondary infections. Although bacterial secondary infections have been widely studied, there remains a paucity of data concerning viral infections after sepsis. In an experimental mouse model of severe sepsis (cecal ligation and puncture [CLP]) followed by respiratory syncytial virus (RSV) infection, exacerbated immunopathology was observed in the lungs of CLP mice compared with RSV-infected sham surgery mice. This virus-associated immunopathology was evidenced by increased mucus production in the lungs of RSV-infected CLP mice and correlated with increased IL-17 production in the lungs. Respiratory syncytial virus-infected CLP mice exhibited increased levels of TH2 cytokines and reduced interferon gamma in the lungs and lymph nodes compared with RSV-infected sham mice. In addition, CD4 T cells from CLP mice produced increased IL-17 in vitro irrespective of the presence of exogenous cytokines or blocking antibodies. This increased IL-17 production correlated with increased STAT3 transcription factor binding to the IL-17 promoter in CD4 T cells from CLP mice. Furthermore, in vivo neutralization of IL-17 before RSV infection led to a significant reduction in virus-induced mucus production and TH2 cytokines. Taken together, these data provide evidence that postseptic CD4 T cells are primed toward IL-17 production via increased STAT3-mediated gene transcription, which may contribute to the immunopathology of a secondary viral infection. PMID- 23042199 TI - Fluorofenidone attenuates bleomycin-induced pulmonary inflammation and fibrosis in mice via restoring caveolin 1 expression and inhibiting mitogen-activated protein kinase signaling pathway. AB - Idiopathic pulmonary fibrosis is a progressive, life-threatening, interstitial lung disease with no effective therapy. In this study, we evaluated the effects of fluorofenidone (FD), a novel pyridone agent, on a murine model of bleomycin induced pulmonary inflammation and fibrosis. Institute for Cancer Research mice were intravenously injected with BLM or saline for 14 consecutive days. Fluorofenidone, pirfenidone (500 mg . kg . d, respectively), or vehicle was administered throughout the course of the experiment. Animals were killed on day 28, and various parameters reflecting pulmonary vascular permeability, influx of inflammatory cells, and levels of transforming growth factor beta in the bronchoalveolar lavage fluid were assessed. Collagen I, alpha-smooth muscle actin, and fibronectin were measured by real-time reverse transcriptase polymerase chain reaction or Western blot. Furthermore, caveolin 1 and activation of P38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase were detected by Western blot. Fluorofenidone treatment significantly attenuated the increased pulmonary damage index score, the levels of proteins, transforming growth factor beta, and the influx of cells in bronchoalveolar lavage fluid. Fluorofenidone also markedly reduced the expression of fibronectin, alpha-smooth muscle actin, and collagen I in mouse lung tissues. Inversely, FD restored caveolin 1 protein and mRNA expression, which was significantly downregulated in BLM-induced lung fibrosis. Fluorofenidone also inhibited phosphorylation of extracellular signal-regulated kinase, P38, and c-Jun N-terminal kinase. These findings collectively suggest that FD is an effective agent with antifibrotic and anti-inflammatory properties, and the mechanisms of its antifibrotic effect include regulating caveolin 1 expression and blocking mitogen-activated protein kinase signaling pathways. PMID- 23042200 TI - Effects of small-volume hypertonic saline on acid-base and electrolytes balance in rats with peritonitis-induced sepsis. AB - Our previous study has demonstrated that hypertonic saline (HS) given at 3 h after cecal ligation and puncture (CLP) surgery alleviates circulatory failure, multiple organ dysfunction syndrome, and mortality rate in rats. However, only few data exist on the application of HS in acid-base and electrolyte imbalance of sepsis. In addition, early one-dose HS administration seems to have only modest improvement on mortality rate. Thus, we evaluated the effects of HS on acid-base equilibrium and electrolyte balance in CLP-induced sepsis model and further compared with the effects of two- and one-dose HS administration. Male Wistar rats received CLP or sham operation followed by the administration of saline or HS (7.5% NaCl, 4 mL/kg, intravenously at 3 and 9 h after laparotomy or CLP). The changes in hemodynamics, biochemical variables, blood gas, electrolytes, organ histology, and plasma levels of nitric oxide (NO) and interleukin 1beta (IL 1beta) were examined during the 18-h observation. Hypertonic saline given either at 3 h (one-dose administration) or at 3 and 9 h (two-dose administration) after CLP attenuated circulatory failure, multiple organ dysfunction syndrome, metabolic acidosis, hyperkalemia, neutrophil infiltration, and 18-h mortality. Moreover, both one- and two-dose HS administrations significantly diminished plasma NO and IL-1beta levels in CLP rats. However, only the two-dose HS administration significantly improved hyponatremia and hypocalcemia in septic rats. Beneficial effects of HS in septic rats may be attributed to not only reducing plasma levels of NO and IL-1beta, but also improving metabolic acidosis and electrolyte imbalance. In addition, two-dose HS administration could reverse electrolyte imbalance caused by CLP. PMID- 23042201 TI - A combined trauma model of chest and abdominal trauma with hemorrhagic shock- description of a new porcine model. AB - Despite the high incidence and prognostic relevance of hemorrhagic shock and abdominal and blunt chest trauma in multiply injured patients, there are no animal models combining these injuries. Therefore, we established a new porcine multiple trauma model consisting of blunt chest trauma, penetrating abdominal trauma (two incisions in the right upper liver lobe using a four-edged scalpel and subsequent liver packing), and pressure-controlled hemorrhagic shock with a mean arterial pressure of 30 +/- 5 mmHg (a maximum of 45% of the total blood volume). The combined traumatic insult led to severe signs of hemorrhagic shock and impaired pulmonary function. In conclusion, a consistent, reproducible, and clinically relevant porcine model of multisystem injury with controlled (pressure controlled blood withdrawal) and uncontrolled components of hemorrhage (liver laceration) with the potential for rebleeding was established. PMID- 23042202 TI - Renal resistive index better predicts the occurrence of acute kidney injury than cystatin C. AB - The objective of this study was to determine the predictive value of the renal resistive index (RI) and cystatin C values in serum (SCys) and urine (UCys) in the development of acute kidney injury (AKI) in critically ill patients with severe sepsis or polytrauma. This was a prospective, double-center, descriptive study. There were 58 patients with severe sepsis (n= 28) or polytrauma (n = 30). Renal resistive index, SCys, and UCys were measured within 12 h following admission (day 1 [D1]) to the intensive care unit. Renal function was assessed using the AKI network classification: On day 3 (D3), 40 patients were at stage 0 or 1, and 18 were at stage 2 or 3. Patients with AKI stage 2 or 3 had significantly higher RI (0.80 vs. 0.66, P < 0.0001), SCys (1.23 vs. 0.68 mg/L, P = 0.0002), and UCys (3.32 vs. 0.09 mg/L, P = 0.0008). They also had higher Simplified Acute Physiology Score II, arterial lactate level, and intensive care unit mortality. In multivariate analysis, an RI of greater than 0.707 on D1 was the only parameter predictive of the development of AKI stage 2 or 3 on D3 (P = 0.0004). In the subgroup of patients with AKI stage 2 or 3 on D1, RI remained the only parameter associated with persistent AKI on D3 (P = 0.016). In multivariate analysis comparing the predictive value of RI, SCys, and UCys, RI was the only parameter predictive of AKI stage 2 or 3 on D3. Renal resistive index seems to be a promising tool to assess the risk of AKI. PMID- 23042203 TI - Gene polymorphisms in the heme degradation pathway and outcome of severe human sepsis. AB - Heme and its breakdown products CO, Fe, and bilirubin are being recognized as signaling molecules or even therapeutic agents, but also exert adverse effects when released at high concentrations. Manipulating the pathway confers protection in rodent sepsis models via both control of free heme and formation of its first and higher-order products. Thus, regulatory elements present in human heme oxygenase 1 (HMOX1) and biliverdin reductases (BLVRA/B) genes might impact outcome. We tested whether a highly polymorphic (GT)n microsatellite and single nucleotide polymorphisms in HMOX1 and BLVRA/B genes are associated with outcome of sepsis. Two cohorts (n = 430 and 398 patients) with severe sepsis were screened for single-nucleotide polymorphisms and/or the microsatellite by fragment length analysis and genotyping techniques. Heme oxygenase 1 plasma levels were determined in additional patients with severe sepsis (n = 92) by enzyme-linked immunosorbent assay. Based on mean Sepsis-related Organ Failure Assessment scores, patients homozygous for rs2071746 A allele or medium length (GT)n microsatellites of HMOX1 showed higher 28-day mortality (P = 0.047 and P = 0.033) in one cohort compared with other genotypes, whereas 90-day mortality rates showed no association. The T allele was less frequently observed in both cohorts than would be expected according to Hardy-Weinberg equilibrium. Heme oxygenase 1 plasma levels were elevated in septic patients, independent of the genotype. Single-nucleotide polymorphisms within BLVRA/B showed no association with outcome. Short (GT)n repeats that are in linkage disequilibrium with the T allele of rs2071746 in HMOX1 are associated with favorable outcome, whereas no association with gene variants of BLVRA/B, involved in the generation of higher order metabolites, was noticed. PMID- 23042205 TI - Lung ischemia reperfusion injury: a bench-to-bedside review. AB - Lung ischemia reperfusion injury (LIRI) is a pathologic process occurring when oxygen supply to the lung has been compromised followed by a period of reperfusion. The disruption of oxygen supply can occur either via limited blood flow or decreased ventilation termed anoxic ischemia and ventilated ischemia, respectively. When reperfusion occurs, blood flow and oxygen are reintroduced to the ischemic lung parenchyma, facilitating a toxic environment through the creation of reactive oxygen species, activation of the immune and coagulation systems, endothelial dysfunction, and apoptotic cell death. This review will focus on the mechanisms of LIRI, the current supportive treatments used, and the many therapies currently under research for prevention and treatment of LIRI. PMID- 23042206 TI - Influenza vaccination in solid-organ transplant recipients. AB - PURPOSE OF REVIEW: We reviewed the most recent literature on solid-organ transplant (SOT) recipients regarding the clinical significance of influenza and the immunogenicity and safety of influenza vaccine in this population. RECENT FINDINGS: In SOT recipients, influenza is associated with significant graft dysfunction and even mortality. Early initiation of antiviral therapy is associated with a reduced risk for influenza-associated complications, mainly pneumonia. The main preventive strategy against influenza in SOT recipients remains the administration of yearly influenza vaccine. Although most studies have shown that influenza vaccination is safe after transplantation, impaired responses are expected in more immunosuppressed patients. A lower immunogenicity of influenza vaccine has been described in patients receiving mycophenolate and mammalian target of rapamycin inhibitors. The optimal timing of vaccination after transplant remains to be determined, although vaccination during the early posttransplant period appears to be safe. Novel vaccination strategies, such as intradermal vaccination or use of adjuvanted vaccines, have been evaluated in SOT recipients, with inconclusive results to date. SUMMARY: The administration of influenza vaccination is strongly recommended in SOT recipients and their relatives. Further research is needed for improving the immunogenicity of influenza vaccine in this population. PMID- 23042204 TI - Structural insight for the roles of fas death domain binding to FADD and oligomerization degree of the Fas-FADD complex in the death-inducing signaling complex formation: a computational study. AB - Fas binding to Fas-associated death domain (FADD) activates FADD-caspase-8 binding to form death-inducing signaling complex (DISC) that triggers apoptosis. The Fas-Fas association exists primarily as dimer in the Fas-FADD complex, and the Fas-FADD tetramer complexes have the tendency to form higher order oligomer. The importance of the oligomerized Fas-FADD complex in DISC formation has been confirmed. This study sought to provide structural insight for the roles of Fas death domain (Fas DD) binding to FADD and the oligomerization of Fas DD-FADD complex in activating FADD-procaspase-8 binding. Results show Fas DD binding to FADD stabilized the FADD conformation, including the increased stability of the critical residues in FADD death effector domain (FADD DED) for FADD-procaspase-8 binding. Fas DD binding to FADD resulted in the decreased degree of both correlated and anticorrelated motion of the residues in FADD and caused the reversed correlated motion between FADD DED and FADD death domain (FADD DD). The exposure of procaspase-8 binding residues in FADD that allows FADD to interact with procaspase-8 was observed with Fas DD binding to FADD. We also observed different degrees of conformational and motion changes of FADD in the Fas DD-FADD complex with different degrees of oligomerization. The increased conformational stability and the decreased degree of correlated motion of the residues in FADD in Fas DD-FADD tetramer complex were observed compared to those in Fas DD-FADD dimer complex. This study provides structural evidence for the roles of Fas DD binding to FADD and the oligomerization degree of Fas DD-FADD complex in DISC formation to signal apoptosis. PMID- 23042207 TI - Update in HIV infection in organ transplantation. AB - PURPOSE OF REVIEW: With reductions in AIDS-related mortality, patients with HIV infection are dying and experiencing significant morbidity from end-stage organ disease. However, patients infected with HIV have traditionally been excluded from organ transplantation. Recent advances have had a significant impact on the potential transplant candidacy of these patients. This review will highlight the major issues associated with transplantation in individuals who are infected with HIV. RECENT FINDINGS: Recently published studies showing promising preliminary outcomes among transplant recipients with HIV infection, suggest that it is not any more justifiable to deny transplantation based solely on HIV-infection status. These studies consistently describe stable HIV disease following liver and kidney transplantation. Furthermore, combined pancreas-kidney, heart, and lung transplantation has been successfully reported, although in a much smaller number of patients. Despite these scientific and policy advances, many healthcare providers and patients remain unaware of ongoing progress in this field. SUMMARY: The experience with organ transplantation in HIV-infected patients is evolving and successful outcomes have been observed when specific criteria are used to select candidates. PMID- 23042208 TI - Synthesis of chiral bis-oxazines: a preliminary assessment of helical conformational framework. AB - A series of novel naphthalene attached bis-oxazines were synthesized and characterized. The bis-oxazines were studied by VT-NMR analysis to assess the possibility of conformational twist. The bis-oxazine prepared from (l) methylvalinate show a helical conformational twist in the single crystal X-ray analysis. Three isomers of bis-oxazines were prepared from chiral alpha methylbenzyl amines, the meso isomer showed small optical rotation probably indicating the helical conformational twist in the molecule. PMID- 23042210 TI - Effect of kidney dysfunction on cortical thinning in patients with probable Alzheimer's disease dementia. AB - There are some studies identifying the association between kidney dysfunction and cognitive impairment through various mechanisms including small vessel disease. However, results concerning the relationship between kidney dysfunction and cortical atrophy have been inconsistent. Thus, we aimed to evaluate the relationship among kidney dysfunction, small vessel disease, and cortical thinning in probable Alzheimer's disease (AD) dementia patients. Patients consisted of 162 subjects with probable AD dementia who underwent high-resolution T1-weighted volumetric magnetic resonance imaging (MRI) scans using the same scanner. The estimated glomerular filtration rate (GFR) was calculated and divided into the quartiles of patients for comparison. Volume of white matter hyperintensities (WMH) was automatically measured. Two neurologists counted the number of lacunes. Cortical thickness was measured using a surface-based method. GFR was not associated with WMH and the number of lacunes. However, the lowest quartile group of GFR (GFR 1) had cortical thinning in each lobe, compared to the highest quartile group of GFR (GFR 4). The topography of cortical thinning in the GFR 1 group was distributed predominantly in temporoparietal regions, compared to GFR 4. After further adjustment of small vessel disease MRI markers, the association between GFR and the cortical thinning remained. Our findings suggested that kidney dysfunction, represented by GFR, was related to temporoparietal thinning independent of small vessel disease in probable AD dementia patients. PMID- 23042209 TI - Compact zwitterion-coated iron oxide nanoparticles for in vitro and in vivo imaging. AB - We have recently developed compact and water-soluble zwitterionic dopamine sulfonate (ZDS) ligand coated superparamagnetic iron oxide nanoparticles (SPIONs) for use in various biomedical applications. The defining characteristics of ZDS coated SPIONs are small hydrodynamic diameters, low non-specific interactions with fetal bovine serum, the opportunity for specific labeling, and stability with respect to time, pH, and salinity. We report here on the magnetic characterization of ZDS-coated SPIONs and their in vitro and in vivo performance relative to non-specific interactions with HeLa cells and in mice, respectively. ZDS-coated SPIONs retained the superparamagnetism and saturation magnetization (M(s)) of as-synthesized hydrophobic SPIONs, with M(s) = 74 emu g(-1) [Fe]. Moreover, ZDS-coated SPIONs showed only small non-specific uptake into HeLa cancer cells in vitro and low non-specific binding to serum proteins in vivo in mice. PMID- 23042211 TI - Alzheimer's disease: brain desmosterol levels. AB - Desmosterol is a C27 sterol intermediate in cholesterol synthesis generated during the metabolic pathway that transforms lanosterol into cholesterol. It has become of particular interest in the pathogenesis of Alzheimer's disease (AD) because of the report that the activity of the gene coding for the enzyme DHCR24, which metabolizes desmosterol to cholesterol, is selectively reduced in the affected areas of the brain. Any change in the pattern of C27 sterol intermediates in cholesterol synthesis merits investigation with respect to the pathogenesis of AD, since neurosteroids such as progesterone can modulate the tissue levels. We therefore analyzed the C27 sterol composition using a metabolomics approach that preserves the proportion of the different sterol intermediates. In AD, the proportion of desmosterol was found to be less than that of age-matched controls. The findings do not directly support the focus on Seladin-1, although they could reflect different stages of a slowly progressive disease. PMID- 23042212 TI - Relationship of cognitive function with B vitamin status, homocysteine, and tissue factor pathway inhibitor in cognitively impaired elderly: a cross sectional survey. AB - Elevated homocysteine (Hcy) levels have been associated with an increased risk of cognitive impairment and Alzheimer's disease (AD). Tissue factor pathway inhibitor (TFPI) has recently emerged as a candidate marker of endothelial damage in AD. We investigated the relationship between plasma levels of folate, vitamin B12, Hcy, and TFPI, as well as cognitive function in 321 [100 each with mild cognitive impairment (MCI) and AD, 121 normal subjects] Korean elderly (mean age 74.8 +/- 7.2 years). Plasma folate and vitamin B12 concentrations were analyzed by radioimmunoassay, Hcy by the HPLC-fluorescence method, and TFPI by enzyme linked immunosorbent assay. Plasma Hcy levels were higher in patients with AD and MCI than those in normal subjects (p < 0.001). The AD group had higher proportions of hyperhomocysteinemic (>15 MUM) and folate deficient (<3.0 ng/mL) (p = 0.026) subjects. A multiple regression analysis after adjusting for covariates revealed positive relationships between plasma folate and the MMSE-KC and Boston Naming Test, and between plasma vitamin B12 and the Word List Memory Test in the AD group, but negative associations between plasma Hcy and the Word List Memory and Constructional Recall Tests and between plasma TFPI and the Boston Naming, Word List Recall, and Constructional Recall Tests. In contrast, only plasma folate level was positively associated with the MMSE-KC and Boston Naming Test in the MCI group. No associations were observed in the normal group. These results suggest that plasma folate, vitamin B12, Hcy, and TFPI are associated with cognitive function in cognitively impaired (AD and MCI) elderly and that the association was stronger in patients with AD. PMID- 23042213 TI - Modulation of alpha7 nicotinic acetylcholine receptor and fibrillar amyloid-beta interactions in Alzheimer's disease brain. AB - The nicotinic receptors (nAChRs), which play a critical role in cognitive function, are impaired early in the course of Alzheimer's disease (AD). We have previously demonstrated that amyloid-beta (Abeta) assemblies bind to alpha7 nAChRs and form complexes in AD brain, suggesting that this cooperative process may contribute to disruption of synaptic function in AD. In the current study, we further characterized the interaction between different nAChR subtypes and fibrillar Abeta by binding assays in postmortem brain from AD and control cases using a wide range of drugs with different molecular targets, including selective nAChR subtype agonists, and the amyloid ligand Pittsburgh compound B (PIB) that binds with high (nanomolar) affinity to fibrillar Abeta. The alpha7 nAChR agonists varenicline and JN403, but not the alpha4beta2 nAChR agonist cytisine, increased the 3H-PIB binding in autopsy tissue homogenates from AD and control frontal cortex. This effect was blocked in the presence of the alpha7 nAChR antagonists methyllycaconitine, alpha-bungarotoxin, and mecamylamine, but not by the alpha4beta2 nAChR antagonist dihydro-beta-erythroidine. Increases in (3)H-PIB binding evoked by varenicline and JN403 were also prevented by pre-incubation with another amyloid ligand, BF-227. The acetylcholinesterase inhibitor and allosteric nAChR modulator galantamine as well as the N-methyl-d-aspartate receptor blocker memantine did not significantly alter (3)H-PIB binding levels in AD brain. The present findings further support a specific interaction between fibrillar Abeta and alpha7 nAChRs in the brain, suggesting that treatment with alpha7 nAChR stimulatory drugs can modulate Abeta/alpha7 nAChR pathogenic signaling mechanisms in AD brain. PMID- 23042214 TI - Evidence for early cognitive impairment related to frontal cortex in the 5XFAD mouse model of Alzheimer's disease. AB - The frontal cortex is a brain structure that plays an important role in cognition and is known to be affected in Alzheimer's disease (AD) in humans. Over the past years, transgenic mouse models have been generated to recapitulate the main features of this disease, including cognitive impairments. This study investigates frontal cortex dependent learning abilities in one of the most early onset transgenic murine model of AD, the 5XFAD mice. We compared frontal performance of 2-, 4-, and 6-month-old 5XFAD mice with their wild-type littermates using a newly developed automated device, the olfactory H-maze, in which mice have to discover three different rules consecutively according to the delayed reaction paradigm. We report early cognitive deficits related to frontal cortex appearing in 4-month-old 5XFAD mice before hippocampal-dependent learning and memory impairment, in relation with neuropathologic processes such as strong gliosis and emerging amyloid plaques. The present results demonstrate that the olfactory H-maze is a very sensitive and simple experimental paradigm that allows assessment of frontal functions in transgenic mice and should be useful to test pre-clinical therapeutic approaches to alter the course of AD. PMID- 23042215 TI - Genetic determinants of "cognitive impairment, no dementia". AB - Dementia is a heritable condition with devastating effects on both patients and their caregivers. Studies have identified genetic variants associated with increased susceptibility to late-onset Alzheimer disease (AD)-related dementia; however, no studies have assessed whether genetic variation is associated with the early stages of cognitive decline. Given that cerebrovascular disease is an established mechanism in which chronic ischemia increases susceptibility to dementia, we assessed whether genetic variation associated with either cardio metabolic or AD-related traits is associated with an early stage of cognitive decline called "cognitive impairment, no dementia" (CIND). We studied 484 CIND patients and 459 cognitively healthy controls selected from the Canadian Study of Health and Aging. We tested for association between ~200,000 genetic variants selected from genes associated with cardio-metabolic traits and CIND status using the Cardio-MetaboChip. We also assessed whether AD-related variants and APOE alleles were associated with CIND status, either individually or as part of a composite genetic risk score. We identified a potential association between the ZNF608/GRAMD3 locus, specifically the rs1439568 polymorphism and CIND status (major allele odds ratio [OR] = 1.51; p = 8.4 * 10(-6)). AD-related variants were not associated with CIND status, however APOE E4 allele frequency was significantly higher in CIND patients versus healthy controls (OR = 1.35; p = 0.044). We identified a potential association between the ZNF608/GRAMD3 locus and CIND status, although AD-related variants were not associated with CIND. Additional replication of this association signal is invited. PMID- 23042216 TI - Low serum vitamin D concentrations in Alzheimer's disease: a systematic review and meta-analysis. AB - Vitamin D has been investigated in association with cognitive function in older adults. It is unclear whether hypovitaminosis D could be associated with Alzheimer's disease (AD). Our objective was to systematically review and quantitatively synthesize the association of low serum 25-hydroxyvitamin D (25OHD) concentrations with AD in adults. A Medline and PsycINFO(r) search was conducted on May 2012, with no limit of date, using the MeSH terms "Vitamin D" OR "Hydroxycholecalciferols" combined with the MeSH terms "Alzheimer disease" OR "Dementia" OR "Cognition" OR "Cognition disorders" OR "Memory" OR "Memory Disorders" OR "Executive Function" OR "Attention" OR "Neuropsychological Tests". Of the 284 selected studies, 10 observational studies (including 9 case-controls and 1 cohort study) met the selection criteria. All were of good quality. The number of AD cases ranged from 20 to 211 (40%-100% female). Finally, 7 case control studies were eligible for fixed and random-effects meta-analyses of bias corrected effect size of the difference in serum 25OHD concentrations between AD cases and controls using an inverse-variance method. The pooled effect size in random-effects meta-analysis was 1.40 (95% CI: 0.26;2.54), a 'large' effect size that indicates that serum 25OHD concentrations were 1.4 standard deviation units lower in AD cases compared to cognitively healthy controls (p = 0.016). In conclusion, AD cases had lower serum vitamin D concentrations than matched controls. This reinforces the conceptualization of vitamin D as a 'neurosteroid hormone' and as a potential biomarker of AD. PMID- 23042217 TI - A blood gene expression marker of early Alzheimer's disease. AB - A marker of Alzheimer's disease (AD) that can accurately diagnose disease at the earliest stage would significantly support efforts to develop treatments for early intervention. We have sought to determine the sensitivity and specificity of peripheral blood gene expression as a diagnostic marker of AD using data generated on HT-12v3 BeadChips. We first developed an AD diagnostic classifier in a training cohort of 78 AD and 78 control blood samples and then tested its performance in a validation group of 26 AD and 26 control and 118 mild cognitive impairment (MCI) subjects who were likely to have an AD-endpoint. A 48 gene classifier achieved an accuracy of 75% in the AD and control validation group. Comparisons were made with a classifier developed using structural MRI measures, where both measures were available in the same individuals. In AD and control subjects, the gene expression classifier achieved an accuracy of 70% compared to 85% using MRI. Bootstrapping validation produced expression and MRI classifiers with mean accuracies of 76% and 82%, respectively, demonstrating better concordance between these two classifiers than achieved in a single validation population. We conclude there is potential for blood expression to be a marker for AD. The classifier also predicts a large number of people with MCI, who are likely to develop AD, are more AD-like than normal with 76% of subjects classified as AD rather than control. Many of these people do not have overt brain atrophy, which is known to emerge around the time of AD diagnosis, suggesting the expression classifier may detect AD earlier in the prodromal phase. However, we accept these results could also represent a marker of diseases sharing common etiology. PMID- 23042218 TI - Cognitive enhancers (nootropics). Part 2: drugs interacting with enzymes. AB - Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re uptake transporters, antioxidants, metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-beta and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years. PMID- 23042220 TI - Platinum nanoparticles intermediate layer in solid-state selective electrodes. AB - A platinum nanoparticles (PtNPs) layer is used for the first time as an ion-to electron transducer in a solid-state ion-selective electrode (SC-ISE). The electrode was prepared by adding the PtNPs as an intermediate layer between the ionophore-doped solvent polymeric membrane and the electrical conductor. The PtNPs layer was characterized by high resolution transmission electron microscopy, selected area electron diffraction and X-ray photoelectron spectroscopy. The stability of the electrical potential of the new solid-contact electrode was examined by performing current-reversal chronopotentiometry while the influence of the interfacial water film was assessed by the potentiometric aqueous-layer test. The performance of the new electrode was evaluated by determining K(+). The new electrode presented a Nernstian slope, a very good reproducibility of the standard potential values and a small potential drift. PMID- 23042219 TI - Ultrahigh frequency lensless ultrasonic transducers for acoustic tweezers application. AB - Similar to optical tweezers, a tightly focused ultrasound microbeam is needed to manipulate microparticles in acoustic tweezers. The development of highly sensitive ultrahigh frequency ultrasonic transducers is crucial for trapping particles or cells with a size of a few microns. As an extra lens would cause excessive attenuation at ultrahigh frequencies, two types of 200-MHz lensless transducer design were developed as an ultrasound microbeam device for acoustic tweezers application. Lithium niobate single crystal press-focused (PF) transducer and zinc oxide self-focused transducer were designed, fabricated and characterized. Tightly focused acoustic beams produced by these transducers were shown to be capable of manipulating single microspheres as small as 5 um two dimensionally within a range of hundreds of micrometers in distilled water. The size of the trapped microspheres is the smallest ever reported in the literature of acoustic PF devices. These results suggest that these lensless ultrahigh frequency ultrasonic transducers are capable of manipulating particles at the cellular level and that acoustic tweezers may be a useful tool to manipulate a single cell or molecule for a wide range of biomedical applications. PMID- 23042221 TI - Does general anesthesia increase the diagnostic yield of endoscopic ultrasound guided fine needle aspiration of pancreatic masses? AB - BACKGROUND: : Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of the pancreas has become the preferred method for tissue diagnosis for pancreatic solid masses. The yield of EUS-FNA in this setting is influenced by multiple factors. We hypothesized that general anesthesia (GA) may improve EUS-FNA yield by improving patient cooperation and stillness during the procedure. Our objective was to assess the association between the sedation method employed and the diagnostic yield of EUS-FNA. METHODS: : A retrospective cohort study was conducted involving consecutive patients who received EUS-FNA for diagnosis of a solid pancreatic mass at the Cleveland Clinic (Cleveland, OH) gastrointestinal endoscopy units from 2007 to 2009. We compared the diagnostic yield of EUS-FNA between patients receiving GA provided by an anesthesiologist (GA group) and patients receiving conscious sedation (CS) provided by a qualified registered nurse (CS group). RESULTS: : Of 371 patients, a cytological diagnosis was obtained in 73/88 patients (83%) in the GA group and 206/283 patients (73%) in the CS group. Anesthesiologist-delivered GA was associated with an increased odds of having a successful diagnosis as compared with CS (adjusted odds ratio [95% CI]: 2.56 [1.27-5.17], P = 0.01). However, the incidence of complication during or after the procedure was not different between the groups (P > 0.99). CONCLUSIONS: : Anesthesiologist-delivered GA was associated with a significantly higher diagnostic yield of EUS-FNA. GA should be considered a preferred sedation method for EUS-FNA of a solid pancreatic mass. PMID- 23042223 TI - Intraoperative cardiac arrests in adults undergoing noncardiac surgery: incidence, risk factors, and survival outcome. AB - BACKGROUND: Intraoperative cardiac arrest (ICA) is a rare but potentially catastrophic event. There is a paucity of recent epidemiological data on the incidence and risk factors for ICA. The objective of this study was to assess the incidence, risk factors, and survival outcome of ICAs in adults undergoing noncardiac surgery. METHODS: The authors analyzed prospectively collected data for all noncardiac cases in the American College of Surgeons National Surgical Quality Improvement Program database from the years 2005 to 2007 (n = 362,767). RESULTS: The incidence of ICA was 7.22 per 10,000 surgeries. After adjustment for American Society of Anesthesiologists physical status and other covariates, the odds of ICA increased progressively with the amount of transfusion (adjusted odds ratios = 2.51, 7.59, 11.40, and 29.68 for those receiving 1-3, 4-6, 7-9, and >= 10 units of erythrocytes, respectively). Other significant risk factors for ICA were emergency surgery (adjusted odds ratio = 2.04, 95% CI = 1.45-2.86) and being functionally dependent presurgery (adjusted odds ratio = 2.33, 95% CI = 1.69 3.22). Of the 262 patients with ICA, 116 (44.3%) died within 24 h, and 164 (62.6%) died within 30 days. CONCLUSIONS: Intraoperative blood loss as indicated by the amount of transfusion was the most important predictor of ICA. The urgency of surgery and the preoperative composite indicators of health such as American Society of Anesthesiologists status and functional status were other important risk factors. The high case fatality suggests that primary prevention might be the key to reducing mortality from ICA. PMID- 23042224 TI - Back pain and the mineralocorticoid receptor: is there a connection? PMID- 23042226 TI - Sometimes you have to revisit the past to understand the present. PMID- 23042225 TI - Comparison between respiratory variations in pulse oximetry plethysmographic waveform amplitude and arterial pulse pressure during major abdominal surgery. AB - BACKGROUND: To assess preload dependence, the variation of the plethysmographic waveform of pulse oximetry (DeltaPOP) has been proposed as a surrogate of the pulse pressure variation (DeltaPP). The aim of the study was to assess the ability of the pulse oximeter-derived plethysmographic analysis to accurately trend DeltaPP in patients undergoing major abdominal surgery by using standard monitors. METHODS: A continuous recording of arterial and plethysmographic waveform was performed in 43 patients undergoing abdominal surgery. DeltaPP and DeltaPOP were calculated on validated respiratory cycles. RESULTS: For analysis, 92,467 respiratory cycles were kept (73.5% of cycles recorded in 40 patients). The mean of intrapatient coefficients of correlation was low (r = 0.22). The Bland and Altman analysis showed a systematic bias of 5.21; the DeltaPOP being greater than the DeltaPP, this bias increased with the mean value of the two indices and the limits of agreement were wide (upper 21.7% and lower -11.3%). Considering a DeltaPP threshold at 12% to classify respiratory cycles as responders and nonresponders, the corresponding best cutoff value of DeltaPOP was 13.6 +/- 4.3%. Using these threshold values, the observed classification agreement was moderate (kappa = 0.50 +/- 0.09). CONCLUSIONS: The wide limits of agreement between DeltaPP and DeltaPOP and the weak correlation between both values cast doubt regarding the ability of DeltaPOP to substitute DeltaPP to follow trend in preload dependence and classify respiratory cycles as responders or nonresponders using standard monitor during anesthesia for major abdominal surgery. PMID- 23042228 TI - Noninvasive hemodynamic monitoring: no high heels on the farm; no clogs to the opera. PMID- 23042229 TI - Noradrenergic trespass in anesthetic and sedative states. PMID- 23042230 TI - Aging and health in France: an unexpected expansion of disability in mid adulthood over recent years. AB - OBJECTIVES: The study presents new disability-free life expectancies (DFLE) estimates for France and discusses recent trends in the framework of the three 'health and aging' theories of compression, dynamic equilibrium and expansion of disability. The objectives are to update information for France and to compare two methods to analyse recent trends. METHODS: DFLE at ages 50, 65 and in the 50 65 age group are computed for several disability dimensions, using data from five French surveys over the 2000s. Owing to scarce time series, we used two methods to assess trends and consolidate our conclusions: (i) decomposition of the DFLE changes using the available time series; (ii) linear regression using all the available estimates, classified by disability dimensions. RESULTS: Trends in DFLE65 prolonged the dynamic equilibrium of the previous decades: increasing life expectancy with functional limitations but not with activity restrictions. Meanwhile, partial DFLE50-65 has decreased for various disability dimensions, including some activity restrictions, especially for women. CONCLUSION: France has recently experienced an unexpected expansion of disability in mid-adulthood while it is still on a trend of dynamic equilibrium at older ages. The study highlights the importance of monitoring trends in DFLE for various disability dimensions and broadens the scope of interest to the mid-adulthood. PMID- 23042227 TI - Hypnotic hypersensitivity to volatile anesthetics and dexmedetomidine in dopamine beta-hydroxylase knockout mice. AB - BACKGROUND: Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. METHODS: Using dopamine beta-hydroxylase knockout (Dbh) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. RESULTS: We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators co-packaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. CONCLUSIONS: Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend on inhibition of adrenergic neurotransmission. PMID- 23042233 TI - Recommendations for myasthenia gravis clinical trials. PMID- 23042232 TI - Cell surface complement regulators moderate experimental myasthenia gravis pathology. AB - INTRODUCTION: Intrinsic mouse complement regulators influence the severity of passively induced experimental acquired myasthenia gravis (EAMG). To assess the potential influence of CD59b in the absence of CD59a background, we used the mCD59ab(-/-) mouse model to re-evaluate mCD59 in protecting the neuromuscular junction (NMJ). METHODS: EAMG was induced with monoclonal antibody to the acetylcholine receptor (AChR) in Daf1(-/-) , CD59ab(-/-) , Daf1(-/-) CD59ab(-/-) , and wild-type C57Bl/6 mice. Animals were monitored throughout the experiment. Diaphragms were analyzed for NMJ injury. RESULTS: Daf1(-/-) CD59ab(-/-) mice required euthanasia 24 hours after disease induction because of severe weakness. Histological assessment demonstrated reduced AChR density, simplification of synaptic folds, and disrupted mitochondria. CD59ab-deficient mice demonstrated mild weakness and reduction in weight after 24 hours. In contrast, Daf1(-/-) had more severe weakness at 60 hours. The NMJ of EAMG-induced Daf1(-/-) and CD59ab(-/ ) mice demonstrated similar AChR density. CONCLUSION: NMJs of CD59 and DAF mice are protected from complement-mediated injury of passive EAMG. PMID- 23042234 TI - CD8+ T cells from vitiligo perilesional margins induce autologous melanocyte apoptosis. AB - Cell-mediated autoimmunity has been suggested to be involved in the melanocyte apoptosis that occurs in vitiligo. We investigated the cytotoxicity to autologous melanocytes of CD8+ T cells from the perilesional margins and peripheral blood samples of vitiligo patients. CD8+ T cells isolated from skin biopsied from the edges of depigmented skin patches of vitiligo patients or from peripheral blood samples of the same donors were proliferated in culture medium. The primary cultures of CD8+ T cells and autologous melanocytes were mixed at ratios of 1:1, 1:2 or 1:5 and incubated for 3 days. The apoptosis of the melanocytes was analyzed by flow cytometry. Secreted cytokines in selected samples were measured by cytokine arrays. The results show that the CD8+ T cells were successfully isolated from the vitiligo perilesional margins. This cell population showed a significantly higher percentage of CD69 expression (56.13+/-3.55 versus 29.93+/ 2.35%, p<0.01) and CD137 expression (41.74+/-1.06 versus 25.97+/-1.63%, p<0.01) compared with CD8+ T cells in peripheral blood from the same donors. The co culturing of CD8+ T cells from lesional skin with autologous melanocytes induced apoptosis in the melanocytes (16.63+/-1.21, 16.71+/-0.63 and 18.32+/-1.60% for CD8+ T cells and autologous melanocytes at ratios of 1:1, 1:2 and 1:5, respectively). IL-6 levels were much higher in the co-culture (3.01-fold higher than in a melanocyte monoculture and 17.32-fold higher than in a CD8+ T-cell monoculture). The CD8+ T cells were also demonstrated to secrete more IL-13. Taken together, our data demonstrate that the infiltration of active CD8+ T cells takes place in the vitiligo perilesional margins. Those CD8+ T cells present significantly higher activation levels and higher cytotoxicity to autologous melanocytes than their counterparts from peripheral blood samples. These data suggest that CD8+ T cells are likely to be involved in the pathogenesis of vitiligo. PMID- 23042235 TI - Evolution of polymer photovoltaic performances from subtle chemical structure variations. AB - Conjugated polymers are promising replacements for their inorganic counterparts in photovoltaics due to their low cost, ease of processing, and straightforward thin film formation. New materials have been able to improve the power conversion efficiency of photovoltaic cells up to 8%. However, rules for rational material design are still lacking, and subtle chemical structure variations usually result in large performance discrepancies. The present paper reports a detailed study on the crystalline structure, morphology, and in situ optoelectronic properties of blend films of polythiophene derivatives and [6,6]-phenyl C61-butyric acid methyl ester by changing the alkyl side chain length and position of polythiophene. The correlation among the molecular structure, mesoscopic morphology, mesoscopic optoelectronic property and macroscopic device performance (highest efficiency above 4%) was directly established. Both solubility and intermolecular interactions should be considered in rational molecular design. Knowledge obtained from this study can aid the selection of appropriate processing conditions that improve blend film morphology, charge transport property, and overall solar cell efficiency. PMID- 23042236 TI - Angiogenesis induced by CNS inflammation promotes neuronal remodeling through vessel-derived prostacyclin. AB - Angiogenesis is a prominent feature of central nervous system (CNS) disease and has roles in both the continued promotion of inflammation and the subsequent repair processes. Here we report that prostacyclin (or prostaglandin I(2) (PGI(2))) derived from new vessels promotes axonal remodeling of injured neuronal networks after CNS inflammation. In a localized model of experimental autoimmune encephalomyelitis (EAE), new vessels formed around the inflammatory lesion, followed by sprouting of adjacent corticospinal tract (CST) fibers. These sprouting fibers formed a compensatory motor circuit, leading to recovery of motor function. Capillary endothelial cell-derived prostacyclin bound to its receptor, the type I prostaglandin receptor (IP receptor), on CST neurons, promoting sprouting of CST fibers and contributing to the repair process. Inhibition of prostacyclin receptor signaling impaired motor recovery, whereas the IP receptor agonist iloprost promoted axonal remodeling and motor recovery after the induction of EAE. These findings reveal an important function of angiogenesis in neuronal rewiring and suggest that prostacyclin is a promising molecule for enhancing functional recovery from CNS disease. PMID- 23042237 TI - Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. AB - Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology. Accurate detection of COPD subtypes by image biomarkers is urgently needed to enable individualized treatment, thus improving patient outcome. We adapted the parametric response map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype. We analyzed whole-lung computed tomography (CT) scans acquired at inspiration and expiration of 194 individuals with COPD from the COPDGene study. PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity. PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype while providing detailed spatial information of disease distribution and location. PRM's ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients, complementing standard clinical techniques. PMID- 23042238 TI - Hemin-functionalized reduced graphene oxide nanosheets reveal peroxynitrite reduction and isomerization activity. AB - Facile and efficient reduction of graphene oxide (GO) and novel applications of the reduced graphene oxide (RGO) based materials are of current interest. Herein, we report a novel and facile method for the reduction of GO by using a biocompatible reducing agent dithiothreitol (DTT). Stabilization of DTT by the formation of a six-membered ring with internal disulfide linkage upon oxidation is responsible for the reduction of GO. The reduced graphene oxide is characterized by several spectroscopic and microscopic techniques. Dispersion of RGO in DMF remained stable for several weeks suggesting that the RGO obtained by DTT-mediated reduction is hydrophobic in nature. This method can be considered for large scale production of good quality RGO. Treatment of RGO with hemin afforded a functional hemin-reduced graphene oxide (H-RGO) hybrid material that exhibited remarkable protective effects against the potentially harmful peroxynitrite (PN). A detailed inhibition study on PN-mediated oxidation and nitration reactions indicate that the interaction between hemin and RGO results in a synergistic effect, which leads to an efficient reduction of PN to nitrate. The RGO also catalyzes the isomerization of PN to nitrate as the RGO layers facilitate the rapid recombination of (.)NO(2) with Fe(IV)=O species. In the presence of reducing agents such as ascorbic acid, the Fe(IV)=O species can be reduced to Fe(III), thus helping to maintain the PN reductase cycle. PMID- 23042239 TI - Passages 2013. PMID- 23042240 TI - Liquid phase esterification of acetic acid over WO3 promoted beta-SiC in a solvent free system. AB - A series of tungstate promoted beta-SiC catalysts was synthesized by a wetness impregnation method. The as synthesized catalysts were unambiguously characterized by XRD, Raman, FTIR, XPS, UV-Vis DRS, TEM, BET surface areas and FE SEM, and simultaneously the total amount of the acidity of the catalysts was estimated by NH(3)-TPD. The catalytic activities of the synthesized materials were tested in the liquid phase esterification of acetic acid with n-butanol in a solvent free medium. The reaction parameters were optimized to a temperature of 120 degrees C, molar ratio of butanol and acetic acid of 1:2 and a reaction time of 6 h after performing a number of experiments. Under the optimum conditions, the catalytic esterification revealed a significant effect of 88% conversion with 100% selectivity to butyl acetate in 20 wt% WO(3)/beta-SiC. This is the first report on the effective utilization of beta-SiC as a catalyst support for liquid phase esterification of acetic acid. PMID- 23042241 TI - Synthesis and hybridization properties of oligonucleotides modified with 5-(1 aryl-1,2,3-triazol-4-yl)-2'-deoxyuridines. AB - Oligonucleotides modified with consecutive incorporations of 5-(1-aryl-1,2,3 triazol-4-yl)-2'-deoxyuridine monomers display strong thermal affinity and binding specificity toward RNA targets, due to formation of chromophore arrays in the major groove. PMID- 23042245 TI - Selection is more intelligent than design: improving the affinity of a bivalent ligand through directed evolution. AB - Multivalent molecular interactions can be exploited to dramatically enhance the performance of an affinity reagent. The enhancement in affinity and specificity achieved with a multivalent construct depends critically on the effectiveness of the scaffold that joins the ligands, as this determines their positions and orientations with respect to the target molecule. Currently, no generalizable design rules exist for construction of an optimal multivalent ligand for targets with known structures, and the design challenge remains an insurmountable obstacle for the large number of proteins whose structures are not known. As an alternative to such design-based strategies, we report here a directed evolution based method for generating optimal bivalent aptamers. To demonstrate this approach, we fused two thrombin aptamers with a randomized DNA sequence and used a microfluidic in vitro selection strategy to isolate scaffolds with exceptionally high affinities. Within five rounds of selection, we generated a bivalent aptamer that binds thrombin with an apparent dissociation constant (K(d)) <10 pM, representing a ~200-fold improvement in binding affinity over the monomeric aptamers and a ~15-fold improvement over the best designed bivalent construct. The process described here can be used to produce high-affinity multivalent aptamers and could potentially be adapted to other classes of biomolecules. PMID- 23042244 TI - Mechanism of allele-selective inhibition of huntingtin expression by duplex RNAs that target CAG repeats: function through the RNAi pathway. AB - Huntington's disease is an incurable neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat within one allele of the huntingtin (HTT) gene. Agents that block expression of mutant HTT and preserve expression of wild type HTT target the cause of the disease and are an alternative for therapy. We have previously demonstrated that mismatch-containing duplex RNAs complementary to the expanded trinucleotide repeat are potent and allele-selective inhibitors of mutant HTT expression, but the mechanism of allele selectivity was not explored. We now report that anti-CAG duplex RNA preferentially recruits argonaute 2 (AGO2) to mutant rather than wild-type HTT mRNA. Efficient inhibition of mutant HTT protein expression requires less AGO2 than needed for inhibiting wild-type expression. In contrast, inhibiting the expression of mutant HTT protein is highly sensitive to reduced expression of GW182 (TNRC6A) and its two paralogs, a protein family associated with miRNA action. Allele-selective inhibition may involve cooperative binding of multiple protein-RNA complexes to the expanded repeat. These data suggest that allele-selective inhibition proceeds through an RNA interference pathway similar to that used by miRNAs and that discrimination between mutant and wild-type alleles of HTT mRNA is highly sensitive to the pool of AGO2 and GW182 family proteins inside cells. PMID- 23042246 TI - LCR 5' hypersensitive site specificity for globin gene activation within the active chromatin hub. AB - The DNaseI hypersensitive sites (HSs) of the human beta-globin locus control region (LCR) may function as part of an LCR holocomplex within a larger active chromatin hub (ACH). Differential activation of the globin genes during development may be controlled in part by preferential interaction of each gene with specific individual HSs during globin gene switching, a change in conformation of the LCR holocomplex, or both. To distinguish between these possibilities, human beta-globin locus yeast artificial chromosome (beta-YAC) lines were produced in which the epsilon-globin gene was replaced with a second marked beta-globin gene (beta(m)), coupled to an intact LCR, a 5'HS3 complete deletion (5'DeltaHS3) or a 5'HS3 core deletion (5'DeltaHS3c). The 5'DeltaHS3c mice expressed beta(m)-globin throughout development; gamma-globin was co expressed in the embryonic yolk sac, but not in the fetal liver; and wild-type beta-globin was co-expressed in adult mice. Although the 5'HS3 core was not required for beta(m)-globin expression, previous work showed that the 5'HS3 core is necessary for epsilon-globin expression during embryonic erythropoiesis. A similar phenotype was observed in 5'HS complete deletion mice, except beta(m) globin expression was higher during primitive erythropoiesis and gamma-globin expression continued into fetal definitive erythropoiesis. These data support a site specificity model of LCR HS-globin gene interaction. PMID- 23042247 TI - Binding of hairpin pyrrole and imidazole polyamides to DNA: relationship between torsion angle and association rate constants. AB - N-methylpyrrole (Py)-N-methylimidazole (Im) polyamides are small organic molecules that bind to DNA with sequence specificity and can be used as synthetic DNA-binding ligands. In this study, five hairpin eight-ring Py-Im polyamides 1-5 with different number of Im rings were synthesized, and their binding behaviour was investigated with surface plasmon resonance assay. It was found that association rate (k(a)) of the Py-Im polyamides with their target DNA decreased with the number of Im in the Py-Im polyamides. The structures of four-ring Py-Im polyamides derived from density functional theory revealed that the dihedral angle of the Py amide carbonyl is 14~18 degrees , whereas that of the Im is significantly smaller. As the minor groove of DNA has a helical structure, planar Py-Im polyamides need to change their conformation to fit it upon binding to the minor groove. The data explain that an increase in planarity of Py-Im polyamide induced by the incorporation of Im reduces the association rate of Py-Im polyamides. This fundamental knowledge of the binding of Py-Im polyamides to DNA will facilitate the design of hairpin Py-Im polyamides as synthetic DNA-binding modules. PMID- 23042248 TI - Sequence verification of synthetic DNA by assembly of sequencing reads. AB - Gene synthesis attempts to assemble user-defined DNA sequences with base-level precision. Verifying the sequences of construction intermediates and the final product of a gene synthesis project is a critical part of the workflow, yet one that has received the least attention. Sequence validation is equally important for other kinds of curated clone collections. Ensuring that the physical sequence of a clone matches its published sequence is a common quality control step performed at least once over the course of a research project. GenoREAD is a web based application that breaks the sequence verification process into two steps: the assembly of sequencing reads and the alignment of the resulting contig with a reference sequence. GenoREAD can determine if a clone matches its reference sequence. Its sophisticated reporting features help identify and troubleshoot problems that arise during the sequence verification process. GenoREAD has been experimentally validated on thousands of gene-sized constructs from an ORFeome project, and on longer sequences including whole plasmids and synthetic chromosomes. Comparing GenoREAD results with those from manual analysis of the sequencing data demonstrates that GenoREAD tends to be conservative in its diagnostic. GenoREAD is available at www.genoread.org. PMID- 23042249 TI - Reverse engineering and analysis of large genome-scale gene networks. AB - Reverse engineering the whole-genome networks of complex multicellular organisms continues to remain a challenge. While simpler models easily scale to large number of genes and gene expression datasets, more accurate models are compute intensive limiting their scale of applicability. To enable fast and accurate reconstruction of large networks, we developed Tool for Inferring Network of Genes (TINGe), a parallel mutual information (MI)-based program. The novel features of our approach include: (i) B-spline-based formulation for linear-time computation of MI, (ii) a novel algorithm for direct permutation testing and (iii) development of parallel algorithms to reduce run-time and facilitate construction of large networks. We assess the quality of our method by comparison with ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks) and GeneNet and demonstrate its unique capability by reverse engineering the whole genome network of Arabidopsis thaliana from 3137 Affymetrix ATH1 GeneChips in just 9 min on a 1024-core cluster. We further report on the development of a new software Gene Network Analyzer (GeNA) for extracting context-specific subnetworks from a given set of seed genes. Using TINGe and GeNA, we performed analysis of 241 Arabidopsis AraCyc 8.0 pathways, and the results are made available through the web. PMID- 23042250 TI - An hnRNP-like RNA-binding protein affects alternative splicing by in vivo interaction with transcripts in Arabidopsis thaliana. AB - Alternative splicing (AS) of pre-mRNAs is an important regulatory mechanism shaping the transcriptome. In plants, only few RNA-binding proteins are known to affect AS. Here, we show that the glycine-rich RNA-binding protein AtGRP7 influences AS in Arabidopsis thaliana. Using a high-resolution RT-PCR-based AS panel, we found significant changes in the ratios of AS isoforms for 59 of 288 analyzed AS events upon ectopic AtGRP7 expression. In particular, AtGRP7 affected the choice of alternative 5' splice sites preferentially. About half of the events are also influenced by the paralog AtGRP8, indicating that AtGRP7 and AtGRP8 share a network of downstream targets. For 10 events, the AS patterns were altered in opposite directions in plants with elevated AtGRP7 level or lacking AtGRP7. Importantly, RNA immunoprecipitation from plant extracts showed that several transcripts are bound by AtGRP7 in vivo and indeed represent direct targets. Furthermore, the effect of AtGRP7 on these AS events was abrogated by mutation of a single arginine that is required for its RNA-binding activity. This indicates that AtGRP7 impacts AS of these transcripts via direct interaction. As several of the AS events are also controlled by other splicing regulators, our data begin to provide insights into an AS network in Arabidopsis. PMID- 23042251 TI - Genetics: advances in genetic testing for deafness. AB - PURPOSE OF REVIEW: To provide an update on recently discovered human deafness genes and to describe advances in comprehensive genetic testing platforms for deafness, both of which have been enabled by new massively parallel sequencing technologies. RECENT FINDINGS: Over the review period, three syndromic and six nonsyndromic deafness genes have been discovered, bringing the total number of nonsyndromic deafness genes to 64. Four studies have shown the utility of massively parallel sequencing for comprehensive genetic testing for deafness. Three of these platforms have been released on a clinical or commercial basis. SUMMARY: Deafness is the most common sensory deficit in humans. Genetic diagnosis has traditionally been difficult due to extreme genetic heterogeneity and a lack of phenotypic variability. For these reasons, comprehensive genetic screening platforms have been developed with the use of massively parallel sequencing. These technologies are also accelerating the pace of gene discovery for deafness. Because genetic diagnosis is the basis for molecular therapies, these advances lay the foundation for the clinical care of deaf and hard-of-hearing persons in the future. PMID- 23042252 TI - Epidemiology, trends, assessment and management of sport-related concussion in United States high schools. AB - PURPOSE OF REVIEW: Sport-related concussion affects athletes at every level of participation. The short and long-term effects of concussions that occur during childhood and adolescence are not fully understood. The purpose of this review is to describe the current burden of disease, current practice patterns and current recommendations for the assessment and management of sport-related concussions sustained by United States high school athletes. RECENT FINDINGS: Millions of high school students participate in organized sports in the United States. Current estimates suggest that, across all sports, approximately 2.5 concussions occur for every 10 000 athletic exposures, in which an athletic exposure is defined as one athlete participating in one game or practice. At schools that employ at least one athletic trainer, most high school athletes who sustain sport related concussions will be cared for by athletic trainers and primary care physicians. Approximately 40% will undergo computerized neurocognitive assessment. SUMMARY: The number of high school athletes being diagnosed with sport-related concussions is rising. American football has the highest number of concussions in high school with girls' soccer having the second highest total number. Fortunately, coaches are becoming increasingly aware of these injuries and return-to-play guidelines are being implemented. PMID- 23042253 TI - Field-based measures of head impacts in high school football athletes. AB - PURPOSE OF REVIEW: Recent technological advances have allowed the in-vivo measurement of impacts sustained to the head during helmeted sports. These measurements are of interest to researchers and clinicians for their potential to understand both the underlying mechanics of concussive injuries and the potential for real-time injury diagnostics. Following an overview of impact biomechanics, this review will evaluate the following: in-vivo technology being used in American football players; impact frequencies and magnitudes; and the biomechanical threshold for concussion. RECENT FINDINGS: The average high school athlete sustains over 650 impacts in a season, and the level at which concussion occurs is approximately 100 g and 5500 rad/s/s. SUMMARY: High school athletes sustain a significant number of head impacts each year. The impacts are similar in both volume and magnitude when compared with collegiate athletes. The magnitude of impact that results in concussion is also the same at both levels of play, although the collegiate athlete may have a higher injury tolerance. PMID- 23042254 TI - Clinical diagnosis and management of food protein-induced enterocolitis syndrome. AB - PURPOSE OF REVIEW: To provide an overview of clinical manifestations, diagnosis and pathophysiology of food protein-induced enterocolitis syndrome (FPIES), an under-recognized and often misdiagnosed nonimmunoglobulin E-mediated food hypersensitivity. This review will highlight updates on natural history and clinical management. RECENT FINDINGS: The main developments in FPIES involve epidemiology, common presentation and variants thereof, and natural history. Improved understanding and recognition of FPIES have influenced changes in clinical management. SUMMARY: A large prospective population-based study reported cow's milk-FPIES cumulative incidence to be 0.34% by 1 year of age; immunoglobulin E-mediated cow's milk allergy was 0.5%. A case report has suggested that FPIES pathophysiology involves Th2 activation, and a shift away from Th2 signalling may be associated with resolution. Appreciation of the frequent incidence of multiple food-FPIES has influenced anticipatory guidance. Two case reports have described FPIES to food proteins in maternal breast milk. The threshold dose for FPIES reactivity may decrease with successive episodes. Reports from different populations indicate that children may outgrow FPIES sooner than previously thought. PMID- 23042255 TI - Sequence recombination improves target specificity in a redesigned collagen peptide abc-type heterotrimer. AB - Stability of the collagen triple helix is largely governed by its imino acid content, namely the occurrence of proline and 4R-hydroxyproline at the X and Y positions, respectively, of the periodic (Gly-X-Y)(n) sequence. Although other amino acids at these positions reduce stability of the triple helix, this can be partially compensated by introducing intermolecular side-chain salt bridges. This approach was previously used to design an abc-type heterotrimer composed of one basic, one acidic, and one neutral imino acid rich chain (Gauba and Hartgerink, J Am Chem Soc 2007;129:15034-15041). In this study, an abc-type heterotrimer was designed to be the most stable species using a sequence recombination strategy that preserved both the amino acid composition and the network of interchain salt bridges of the original design. The target heterotrimer had the highest T(m) of 50 degrees C, 7 degrees C greater than the next most stable species. Stability of the heterotrimer decreased with increasing ionic strength, consistent with the role of intermolecular salt bridges in promoting stability. Quantitative meta analysis of these results and published stability measurements on closely related peptides was used to discriminate the contributions of backbone propensity and side-chain electrostatics to collagen stability. PMID- 23042256 TI - A Chinese herbal decoction can increase the intracellular Ca2+ concentration and CatSper1 expression in mouse sperm tails. AB - The aim of this study was to investigate the impact of a Chinese herbal decoction on the intracellular calcium (Ca2+) concentration of sperm and the expression of the cation channel 1 of sperm (CatSper1), which is a calcium-channel protein specific to sperm tail, in a murine model of asthenospermia induced with cyclophosphamide. After 34 days of intragastric administration of Chinese herb decoction to the murine model used, routine analyses of the mouse sperm were conducted, the intracellular Ca2+ concentration of the sperm tails was measured using flow cytometry, and the expression of CatSper1 protein was detected using reverse transcription-polymerase chain reaction (RT-PCR). Sperm concentration, percentage of grade A and B sperm (i.e., sperm activity) and percentage of grade A, B and C sperm (i.e., overall sperm motility) of the model group mice (MG) were markedly lower compared to the control murine group (CG) (one-way ANOVA, P<0.05). Subsequent to treatment, sperm concentration, percentage of sperm activity and overall sperm motility of the large dose of herbal medicine group murine (LG) were markedly increased compared to MG mice (P<0.05). Intracellular Ca2+ concentration in MG mice was markedly lower compared to CG mice (P<0.05). However, following therapy, a significant increase was observed in the intracellular Ca2+ concentration in LG mice as compared to MG mice (P<0.05). In addition, the expression of CatSper1 in LG mice was significantly higher compared to MG mice (P<0.05), while no statistically significant difference was observed for the CG mice. Intraperitoneal injection of cyclophosphamide reduced sperm concentration, percentage of sperm activity and overall sperm motility, intracellular Ca2+ concentration and CatSper1 expression. Large doses of this Chinese herbal decoction increased sperm intracellular Ca2+ concentration, sperm concentration, and percentages of sperm activity and overall sperm motility by upregulating CatSper1 expression. The findings of this study have demonstrated a therapeutic effect of this decoction on asthenospermia. PMID- 23042257 TI - Enhanced cell viability via strain stimulus and fluid flow in magnetically actuated scaffolds. AB - A novel magnetically actuated scaffold was used to explore the effects of strain stimulus on the proliferation and spatial distribution of smooth muscle cells and improve cell viability in the scaffold interior by pumping nutrients throughout the structure. Magnetically actuable scaffolds were fabricated in a tube shape by winding electrospun sheets of a biodegradable polymer modified with magnetic Fe(2)O(3) nanoparticles. Prior to rolling, the sheets were seeded with smooth muscle cells and wound into tubes with diameter 5.2 mm and wall thickness 0.2 mm. The tubular scaffolds were actuated by a magnetic field to induce a cyclic crimping deformation, which applies strain stimulus to the cells and pumps nutrient fluid through the porous tube walls. Comparison with non-actuated controls shows that magnetic actuation increases the total cell count throughout the scaffold after 14 days of incubation. Furthermore, whereas cell density as a function of position through the tube wall thickness showed a minimum in the mid interior in the controls after 14 days due to cell starvation, the actuated scaffolds displayed a maximum cell density. Comparison of cell distributions with the expected spatial variations in strain amplitude and nutrient flux implies that both strain stimulus and nutrient pumping are significant factors in cell proliferation. PMID- 23042258 TI - Prenatal exposure to selective serotonin reuptake inhibitors and infant outcome. AB - BACKGROUND: The selective serotonin reuptake inhibitors are prescribed increasingly also during pregnancy. Although a number of studies have assessed their safety, data concerning congenital malformations and adverse perinatal outcome are conflicting. METHODS: Literature search in PubMed until March 31, 2012, including original research articles, meta-analyses, and reviews. RESULTS: Fluoxetine and paroxetine use in early pregnancy has been associated with a small increased risk for specific cardiovascular malformations in some studies, fluoxetine with ventricular septal defects and paroxetine with right ventricular outflow tract defects. The observed absolute risk for these specific malformations is small. Data on preterm birth, low birth weight, and being small for gestational age have been conflicting; and mother's underlying depression is obviously an important confounder. Respiratory distress and neonatal adaptation problems are common in prenatally exposed infants, and an increased risk for persistent pulmonary hypertension of the newborn has been observed in several studies. Although several studies have not confirmed an increased risk for adverse neurodevelopment, a recent study observed an increased risk for autism spectrum disorders in prenatally exposed offspring. CONCLUSIONS: Causality cannot be confirmed in observational study settings. However, parallel results in individual studies regarding the cardiac malformations and pulmonary hypertension of the newborn, together with an existing biologically plausible mechanism behind these events may support causality. Considering the important role of serotonin in central nervous system development, more studies are needed to assess the possible adverse effects on long-term neurodevelopment. PMID- 23042259 TI - Pharmacogenetic determinant of the drug interaction between tacrolimus and omeprazole. AB - A 17-year-old adolescent with acute nephrotoxicity had CYP3A4-5, CYP2C19, and ABCB1 genotyping performed to understand a suspected drug interaction between tacrolimus and omeprazole. The determinant role of individual pharmacogenetic profile in the occurrence of tacrolimus nephrotoxicity is presented and discussed. PMID- 23042260 TI - Hesperetin impairs glucose uptake and inhibits proliferation of breast cancer cells. AB - The flavanone hesperetin is known to decrease basal glucose uptake, although the inhibitory mechanism is largely unknown. Here, we used MDA-MB-231 breast cancer cells to investigate the molecular pathways affected by hesperetin. The results indicate that the suppression of glucose uptake is caused by the down-regulation of glucose transporter 1 (GLUT1). Hesperetin was also found to inhibit insulin induced glucose uptake through impaired cell membrane translocation of glucose transporter 4 (GLUT4). In addition, the phosphorylation of the insulin receptor beta subunit (IR-beta) and Akt was suppressed. Hesperetin also decreased cellular proliferation, which is likely due to the inhibition of glucose uptake. Cancer cells are highly dependent on glucose and hesperetin may, therefore, have potential application as an anticancer agent. PMID- 23042262 TI - Structural, functional, and lectin histochemical characteristics of rat ovaries and endometrium in experimental hyper- and hypothyroidism. AB - Twenty lectins with different carbohydrate affinities, including five new lectins purified from fungi,were used for histochemical examination of carbohydrate determinants in rat ovaries and endometrium under experimental hyper- and hypothyroidism. In the ovaries of control rats, lectin binding was detected predominantly in the zona pellucida and corona radiata of growing follicles, luteocytes, and leucocytes. Within the endometrium,lectins reacted strongly with the luminal surface, epitheliocytes and secretions of the uterine glands,pre decidual cells, leucocytes, and collagen fibers. As revealed on general morphology and estrous cycle studies,hyperthyroidism induced ovarian luteinization, and increased the content of pre-decidual cells and of collagen fibers in the endometrium, with no reliable effect on the estrous cycle. Hypothyroidism was accompanied by retardation of the estrous cycle, enhanced folliculogenesis and leucocyte infiltration of ovarian and endometrial stroma. Both hyper- and hypothyroidism significantly affected the tissue carbohydrates of the ovaries and endometrium:specific and differential redistribution of DMan, LFuc, NeuNAc, DGlcNAc, DGalNAc, and DGal determinants was detected under both pathological conditions. Hyperthyroidism induced more severe alterations of glycoconjugates than hypothyroidism; the endometrium was more susceptible to thyroxin-modulated impairments than the ovaries. These results give new insights into the pathogenetic mechanisms of the effects of thyroid disorders on the female reproductive organs and demonstrate the suitability of lectin histochemistry methods for monitoring the efficacy of hormonal imbalance correction therapy, as well as the applicability of new lectin preparations for the selective labeling of ovarian and endometrial constituents. PMID- 23042261 TI - Immunohistochemical detection of FSH receptors in pituitary adenomas and adrenal tumors. AB - OBJECTIVES: Follicle stimulating hormone (FSH) receptors (FSHR) are physiologically expressed in the ovary and testis. It is well known that FSHR are also expressed in gonadal cancers, but the data on their incidence in extra gonadal tumors are scarce. Recently, the expression of FSHR in the vascular endothelium within different human cancers was found, but nothing is known on FSHR appearance in non-gonadal endocrine tumors. The present paper reports on the immunohistochemical detection of FSHR in human pituitary adenomas and adrenal tumors. MATERIALS AND METHODS: The study included samples of 28 pituitary adenomas and 36 adrenal tumors. Moreover, 2 samples of non-tumoral adrenal glands were also studied. FSH receptor immunostaining was performed on paraffin sections using the rabbit anti-human FSH-R polyclonal antibody raised against 1-190 amino acid sequence from the human FSH-R (sc-13935). The pituitary adenomas were immunostained to reveal the pituitary hormones and the proliferation marker Ki 67. RESULTS: In the pituitary adenomas, positive immunostaining with anti-FSHR antibody occurred in the adenoma cells cytoplasm and endothelia of the intra- and peritumoral blood vessels. The cytoplasmic immunostaining was found in the majority of investigated tumors but the intensity of staining was weak to moderate. There is some tendency towards the higher cytoplasmic FSHR score in tumors with higher Ki-67 index (atypical adenomas). In contrast to the cytoplasm, the FSHR immunostaining in blood vessels is strong and concerns all the investigated samples. Strong FSHR immunostaining is present in the endothelium of intra- and/or peritumoral blood vessels in the majority of pheochromocytomas, approximatively one half of the adrenocortical adenomas and both cases of the adrenal cancers. The immunostaining is detectable also in the tumoral cell cytoplasm in all but one examined pheochromocytomas. All the investigated adrenocortical adenomas presented strong immunostaining of cell membranes. No immunostained cell membranes were found. in adrenal cancers. The positive immunostaining was found in glandular cells, but not in blood vessels, of non tumoral adrenal cortex and medulla. CONCLUSIONS: Immunostaining of FSHR often occurs in the endothelium of intra- and/or peritumoral blood vessels of pituitary adenomas and benign and malignant adrenal tumors. The immunostaining may be also present in tumoral cells. A role of FSHR expression in these tumors (stimulation of angiogenesis? stimulation of cell growth?) needs further studies to be clarified. PMID- 23042263 TI - Structure of the nucleoli in domestic cattle spermatocytes. AB - The work was aimed at determining the number and morphology of nucleoli in the prophase of the first meiotic division in domestic cattle males. The use of AgNO3 staining, commonly applied in cytogenetics for the identification of nucleolar organiser regions, made it possible to identify nucleoli in first-order spermatocytes. One nucleolus was identified in each analysed cell. Considerable morphological differentiation of the nucleoli during the prophase of the first meiotic division, particularly in leptotene, unobserved in other farm animal species, was noticed. Dark-hued grain-like structures were found within the disintegrating nucleoli, corresponding approximately or exactly to the number of the nucleolar organiser regions in the domestic cattle karyotype. Dark areas were identified in the selected prometaphase chromosomes. Their number corresponded with the number of active NORs defined in the domestic cattle karyotype. PMID- 23042264 TI - Expression of metallothionein I/II and Ki-67 antigen in various histological types of basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most frequent skin cancer, with many different histological subtypes. Recent studies have investigated the expression of proliferative markers, but little is known about the expression of metallothioneins (MT) in different histological subtypes of this cancer and their impact on proliferation intensity in BCC. In this study, we examined MT-I/II expression by immunohistochemistry in 58 different histological subtypes of BCC (38 nodular, six adenoid, eight infiltrative, and six metatypic cases) and correlated its expression with tumor size and Ki-67 proliferation rate. Statistical analysis revealed no significant differences in the expression of studied markers in regard to the histological subtype. A positive correlation between MT and Ki-67 expression was observed for all the studied cases (r = 0.26; p = 0.049), but was even stronger in the metatypic subtype of BCC (r = 0.85; p = 0.033). MT and Ki-67 expression did not correlate with tumor size. In conclusion, it seems that metallothioneins may have an impact on the proliferation rate of BCC,but further studies are required to determine whether MT may be a risk factor of recurrences. PMID- 23042266 TI - Secretomic analysis of large cell lung cancer cell lines using two-dimensional gel electrophoresis coupled to mass spectrometry. AB - The secretome of cancer cells is a valuable source of biomarkers that can ultimately reach the serum or other body fluids. Cancer biomarkers can facilitate early diagnosis and monitoring of the disease, contribute to our understanding of tumor biology, and support the development of more efficient therapies. Recently, high-throughput proteomic analysis of the conditioned media of cancer cell lines has shown potential to identify novel biomarkers in cancer. We used two dimensional gel electrophoresis coupled to liquid chromatography tandem mass spectrometry to identify the secretome of the large cell lung cancer cell lines QU-DB and Mehr-80, which they were established from a Canadian and a Persian patient, respectively. A total of 130 distinct protein species were identified. Of these, 124 were previously found in serum or other body fluids, the membrane compartment or conditioned media of other cancer cell lines. Some of the proteins that we identified, e.g. IL-6, triosephosphate isomerase, PGP9.5, alpha-enolase, Dickkopf-1, and peroxiredoxin-1 are known putative serum markers for lung cancer, whereas others might be candidate markers for further validation in lung cancer body fluids such as IL-25, stathmin, vimentin, peptidyl-prolyl cis-trans isomerase A, transgelin-2, and chloride intracellular channel protein 4. PMID- 23042265 TI - Inverse relationship between TCTP/RhoA and p53 /cyclin A/actin expression in ovarian cancer cells. AB - The translationally controlled tumor protein (TCTP) plays a role in cell growth, cell cycle and cancer progression. TCTP controls negatively the stability of the p53 tumor suppressor protein and interacts with the cellular cytoskeleton. The deregulation of the actin and cytokeratin cytoskeleton is responsible for the increased migratory activity of tumor cells and is linked with poor patient outcome. Recent studies indicate that cyclin A,a key regulator of cell cycle, controls actin organization and negatively regulates cell motility via regulation of RhoA expression. We studied the organization of actin and cytokeratin cytoskeleton and the expression of TCTP, p53,cyclin A, RhoA and actin in HIO180 non-transformed ovarian epithelial cells, and OVCAR3 and SKOV3 (expressing low level of inducible p53) ovarian epithelial cancer cells with different metastatic potential. Immunostaining and ultrastructural analyses illustrated a dramatic difference in the organization of the cytokeratin and actin filaments in non transformed versus cancer cell lines. We also determined that there is an inverse relationship between the level of TCTP/RhoA and actin/p53/cyclin A expression in ovarian cancer cell lines. This previously unidentified negative relationship between TCTP/RhoA and actin/p53/cyclin A may suggest that this interaction is linked with the high aggressiveness of ovarian cancers. PMID- 23042267 TI - Cytological picture of the oral mucosa in patients with gastric and colon cancer. AB - The incidence of malignant gastrointestinal cancers in Poland has been constantly growing, which has led to an intensification of the search for new markers of the early clinical stage of this disease. The oral cavity,as the first part of the gastrointestinal tract, has a very important role. The oral cavity presents symptoms of both typically stomatological and systemic diseases. Oral cancers, benign or malignant, may originate and grow in any of the tissues of the mouth, and within this small area they may be of varied clinical, histological and biological features. These can be lesions typically observed in the oral cavity, but also characteristic of cases where the symptoms occur both in the mouth and in other body parts. The aim of this study was to present a cytological picture of the oral mucosa in patients with gastric and colon cancer and to compare the cytological picture with that obtained from a group of patients with no cancer, using the Papanicolaou classification and the Bethesda system. The study was conducted in 126 patients treated surgically in the II General and Gastroenterological Surgery Clinic between 2006 and 2008. All patients were divided into two groups based on the type of lesions. In both of the studied groups, more than half of the patients did not present any abnormalities in the mucosa of the mouth, lips and cheeks in the physical examination. None of the patients had erosion, ulceration or lesions typical of leukoplakia or lichen planus. No malignant cells were detected in either of the studied groups, and there were no well-defined lesions found in the oral cavity that would distinguish the patients with gastrointestinal cancer. PMID- 23042268 TI - Cell death in HeLa cells upon imperatorin and cisplatin treatment. AB - There is growing evidence that commonly applied chemotherapy regimens can be improved by introducing new, specific, active and low side-effect drugs, or by combining substances to obtain the required clinical effect. The aim of the present study was to investigate the effects of imperatorin and cisplatin, applied separately or in combination, on apoptosis, necrosis and autophagy induction in the human cervical carcinoma cell line(HeLa). Imperatorin appeared to be a potent autophagy inducer, rather than a necrotic or apoptotic one. In contrast, cisplatin induced mainly apoptosis and necrosis after 6 h and 24 h, while longer incubation resulted only in necrosis induction. When HeLa cells were incubated with both drugs, autophagy appeared most frequently,although to a smaller extent than that observed after imperatorin administered alone. At the molecular level, autophagy was correlated with the presence of the cleaved form of microtubule-associated protein 1 light chain LC3 - LC3II. It was also accompanied by the inhibition of heat shock proteins Hsp27 and Hsp72 expression.Our results indicate that imperatorin alone, or in combination with cisplatin, is mainly an autopahgy inducer in HeLa cells. PMID- 23042269 TI - Expression of p130cas, E-cadherin and beta-catenin and their correlation with clinicopathological parameters in non-small cell lung cancer: p130cas over expression predicts poor prognosis. AB - p130cas (p130 Crk-associated substrate) is a scaffolding protein and plays an important role in regulating focal adhesion and driving cell migration. Also, the destruction of E-cadherin/beta-catenin adhesive complex is one of the changes that characterizes the invasive phenotype of tumors. The aim of this study is to evaluate the role of p130cas, E-cadherin, and beta-catenin expression in patients with non-small cell lung cancer (NSCLC). We examined the expression of p130cas, E cadherin, and beta-catenin in 105 lung cancer tissues and paired adjacent normal lung tissues using immunohistochemistry. The overexpression of p130cas was observed in 61.9% (65/105) of lung cancer samples. The overexpression of p130cas was correlated with abnormal expression of E-cadherin and beta-catenin (P=0.002 and P=0.006, respectively). Chi-square test showed that the overexpression of p130cas correlated positively with lymph node metastasis and high TNM stage. The Log-Rank test revealed that the mean survival time of patients with p130cas overexpression (36.31 +/- 5.66 months) was markedly shorter than those with p130cas normal expression (60.57 +/- 6.95 months). Multivariable analysis indicated p130cas overexpression (P<0.001) as an independent significant prognostic factor for NSCLC patients' survival. These results indicate that p130cas may impact a variety of clinicopathological features of NSCLC and may y influence the prognosis of lung cancer patients. PMID- 23042270 TI - Overexpression of glycosylated proteins in cervical cancer recognized by the Machaerocereus eruca agglutinin. AB - In cervical cancer, glycosylation has been suggested as being involved in both its carcinogenesis and invasive capacity. In this work, we analyzed mucin type O glycosylation in biopsies of invasive cervical cancer in FIGO stage II B through histochemistry using lectins specific for O-glycosidically linked glycans. Our results reveal that the lectin Machaerocereus eruca (MeA, specific for Gal in a Fucalpha1,2 (GalNAcalpha1,3) Galbeta1,4) showed increased recognition of tumoral cells and tumoral stroma tissue compared to other lectins with similar specificity; healthy cervical tissue was negative for MeA. Trypsin treatment of recognized tissues abolished MeA's recognition;moreover, interaction of MeA was inhibited with oligosaccharides from mucin. As demonstrated by Western blot of 2 D electrophoresis, MeA recognized ten glycoproteins in the range from 122 to 42 kDa in cervical cancer lysates. The LC-ESI-MS/MS analysis of the MeAs' recognized peptides revealed that the latter matched mainly with the amino acid sequences of lamin A/C, vimentin, elongation factor 2, keratin 1, and beta actin. Our results suggest that MeA recognizes a complex of over-expressed O-glycosidically-linked proteins that play a relevant role in cervical cancer's invasive capacity. O glycosylation participates in the disassembly of intercellular junctions favoring cancer progression. PMID- 23042271 TI - Protein C activation peptide inhibits the expression of ICAM-1, VCAM-1, and interleukin-8 induced by TNF-alpha in human dermal microvascular endothelial cells. AB - Activated protein C (APC) is generated from the cleavage of protein C by thrombin coupled to thrombomodulin and, subsequently, is released as protein C activation peptide (papC). The aim of this study was to evaluate the effect of papC on human dermal microvascular endothelial cells (HMEC-1), activated with 5 ng//mL TNF alpha. Flow cytometry showed that papC inhibited the expression of VCAM-1 and ICAM-1, after activation with TNF-a. Similarly, RT-PCR analysis revealed that 2 and 4 pM papC inhibited the expression of VCAM-1 and IL-8 mRNA in TNF-alpha treated HMEC-1. In addition, the expression of endothelial nitric oxide synthase(eNOS) increased in HMEC-1 treated with papC, compared to those without treatment. Furthermore, Jurkat cell adhesion to HMEC-1 induced by TNF-a was significantly inhibited after the addition of papC, compared to HMEC-1 without papC (p = 0.03). Finally, a control peptide analog to papC showed no effect on the expression of ICAM and VCAM on the surface of HMEC-1. In conclusion, our results suggest that papC exerts anti-inflammatory effects on endothelial cells. PMID- 23042272 TI - Antitumor effect of murine dendritic and tumor cells transduced with IL-2 gene. AB - Interleukin (IL-) 2 acts on a number of types of immune cells promoting their effector functions. To replace systemic administration of recombinant form of this cytokine, various genetically modified cells have been used indifferent preclinical models for tumor growth inhibition. In this study, dendritic or tumor cells transduced with retroviral vector carrying IL-2 gene (JAWS II/IL-2, X63/IL 2, MC38/IL-2 cells) alone or combined with tumor antigen-stimulated dendritic cells (JAWS II/TAg) were exploited to treat colon carcinoma MC38-bearing mice. After the peritumoral injection of vaccine cells, the tumor growth delay and the increase in the number of tumor infiltrating CD4+ and CD8+ T lymphocytes were noted. A considerable increase in CD4+ cell influx into tumor tissue was observed when JAWS II/IL-2 cells or JAWS II/TAg with syngeneic MC38/IL-2 cells were applied. The increase in intensity of CD8+ cell infiltration was associated with immune reaction triggered by the same combination of applied cells or JAWS II/TAg with allogeneic X63/IL-2 cells. The effect observed in vivo was accompanied by MC38/0 cell specific cytotoxic activity of spleen cells in vitro. Thus, the application of vaccines, including IL-2-secreting cells of various origins, was able to induce different antitumor responses polarized by exogenous IL-2 and the encountered tumor antigen. PMID- 23042273 TI - Absolute counts of peripheral blood leukocyte subpopulations in intraabdominal sepsis and pneumonia-derived sepsis: a pilot study. AB - The leading pathophysiological changes during sepsis include systemic abnormalities in the immune response. Due to the general character of these disturbances, sepsis is usually studied as a homogenous clinical condition. We aimed to compare the immune response in intraabdominal sepsis (IAS) and pneumonia derived sepsis (PDS). The following cell populations were examined: white blood cell count (WBC), monocytes, lymphocytes:CD3+, CD4+ and CD8+ T cells, B cells, and NK cells. In both studied groups (i.e. IAS and PDS), the WBC was elevated. However, it was significantly higher in the IAS group than in the PDS group. The difference was due to a lower granulocyte count, as well as a lower monocyte count in PDS. We found no significant correlation between the total lymphocyte number and CD3+CD8+ T cells in either form of sepsis. Similarly, we observed no correlation between the total lymphocyte number and the NK cells subset in IAS. However, the numbers of CD3+CD8+ and NK cells correlated similarly in both types of sepsis. Both studied types of sepsis induced profound lymphocytopenia, with marked loss of CD8+ T cells and the NK cells. However, the similarrelation between them, which was independent of the infection type, suggests that the NK and CD3+CD8+ cellshave shared mechanisms of regulation. The primary site of infection has an impact on the global immune reaction. These alternations include especially myeloid cells: granulocytes and monocytes which disappear from peripheral blood during PDS, but increase in IAS. PMID- 23042274 TI - DGAT2 revealed by the immunogold technique in Arabidopsis thaliana lipid bodies associated with microtubules. AB - The immunogold technique with anti-diacylglycerol acyltransferase 2 (DGAT2) antibody revealed in A. thaliana embryo and root meristematic cells gold particles manifesting the presence of DGAT2 in ER as well as in lipid bodies. This being so, lipid synthesis could take place both in ER and in the lipid bodies. The presence of microtubules around the lipid bodies was evidenced under transmission EM. Detection of tubulin around the lipid bodies using the immunogold technique with anti-a-tubulin is in agreement with the above observations. Connection of lipid bodies with microtubules was also detected by us in other plants where they probably participated in lipid synthesis. A similar phenomenon may take place in A. thaliana. PMID- 23042275 TI - Effect of heavy metal cations on the activity of cathepsin D (in vitro study). AB - We studied the effect of heavy metal cations: Fe2+, Cu2+, Zn2+, Cd2+, Hg2+, Pb2+ on the activity of cathepsin D in human aorta homogenate and blood serum. The concentration of cations was 1 mmol/l. Hemoglobin was the cathepsin D substrate. The activity of cathepsin D was determined at pH 3.5. Only Hg2+ cations inhibit the activity of cathepsin D. Cations Hg2+ damage lysosomes and release cathepsin D from these organelles. PMID- 23042276 TI - Use of X-ray microprobe to diagnose bone tissue demineralization after caffeine administration. AB - Caffeine is a methylxanthine which permeates the placenta. In studies on animals, it has been shown to produce teratogenic and embryotoxic effects in large doses. The objective of this study was to assess the influence of caffeine on the development of bone tissue, with particular reference to elemental bone composition using an X-ray microprobe. The research was conducted on rats. The fertilized females were randomly divided into an experimental and a control group. The experimental group was given caffeine orally in 30 mg/day doses from the 8th to the 21st day of pregnancy, while the control group was given water. The fetuses were used to assess the growth and mineralization of the skeleton. On the basis of double dyeing, a qualitative analysis of the bone morphology and mineralization was conducted. For calcium and potassium analysis, an X-ray microprobe was used. In 67 fetuses from the experimental group, changes in skeleton staining with the alcian-alizarin method were noticed. The frequency of the development of variants in the experimental group was statistically higher. In the experimental group,a significant decrease in the calcium level, as well as an increase in the potassium level, was observed. The X-ray microprobe's undoubted advantage is that is offers a quick qualitative and quantitative analysis of the elemental composition of the examined samples. Employing this new technique may furnish us with new capabilities when investigating the essence of the pathology process. PMID- 23042277 TI - The adipocyte component of bone marrow in heterotopic bone induced by demineralized incisor grafts. AB - The relative proportion of adipocytes to hematopoietic elements in the marrow of heterotopically induced bone evaluated 4-42 weeks post implantation of demineralized murine incisors was estimated by histological analysis of hematoxylin-eosin stained tissue sections. Using computerized image analysis of microphotographs,the proportion of nuclear cells vs. adipocytes was ascertained. The percentage of adipocytes in marrow increases over time. Such an effect, the replacement of myelopoietic marrow by adipogenic (yellow) marrow and the resorption of induced bone, is observed in human osteoporosis. A decline in the non-adipogenic cell compartments of bone marrow accompanying induced bone begins in the fourth week of induction, gradually progresses until the 26th week, and does not change after that. The luminosity, a parameter used in image analysis and proportional to the number of nuclear cells, was 124 +/- 3 in hematopoietic femoral bone marrow, and that of bone marrow of the induced bone was of a similar value (117 +/- 8) in the fourth week. An evident decline in luminosity of bone marrow filling the foci of heterotopic bone was observed in samples taken at nine weeks (82 +/- 20). This process progressed until the 26th week, reaching a luminosity of 70 +/- 21. At the 42nd week, the luminosity remained at the same level (71 +/- 27). This indicates that the replacement of hematopoietic bone marrow of heterotopically induced bone by unilocular adipocytes begins relatively early (the fourth week) and is persistent. PMID- 23042278 TI - The effect of chronic alcohol intoxication and smoking on the activity of oral peroxidase. AB - Peroxidase is the most important antioxidant enzyme in saliva. Through peroxidation of thiocyanate in the presence of H2O2, peroxidase catalyses the formation of bacteriocidic compounds such as hypothiocyanate.The purpose of this study was to evaluate the effect of chronic alcohol intoxication and smoking on the activity of oral peroxidase (OPO). A total of 37 volunteers participated in the study. This cohort consisted of 17 male alcohol-dependent smoking patients after chronic alcohol intoxication (AS group, alcohol + smoking) (mean age: 42 years; range: 26-55) (100-700 g/day of alcohol; 10-20 cigarettes/day) and 20 control male social drinkers(CNS group, control non-smokers) with no history of alcohol abuse or smoking (mean age: 42 years; range:30-53). Salivary peroxidase activity was measured by the colorimetric method. The differences between groups were evaluated using the Mann-Whitney U test. There was significantly higher activity of OPO (p = 0.00001)and significantly lower salivary flow (SF) (p = 0.007) in alcohol-dependent smokers after chronic alcohol intoxication compared to the control group. OPO activity significantly correlated with the number of days of alcohol intoxication, but not with smoking. Gingival index (GI) was significantly higher in smoking alcohol-dependent persons than in the control group, and correlated with OPO activity. The sensitivity of the OPO test was 70% in smoking alcoholics, while specificity was 95%. The increased activity of OPO suggests chronic oxidative stress is more likely due to ethanol action than to smoking. Smoking alcohol-dependent persons have a worse periodontal status than controls. OPO activity as a marker of chronic alcohol abuse may help in the diagnosis of alcoholism. PMID- 23042279 TI - HIF-1 expression in retinal ganglion cells and optic nerve axons in glaucoma. AB - Glaucoma is a result of increased intraocular pressure leading to damage to retinal ganglion cells and optic nerve axons. The aim of this study was to evaluate HIF-1 expression in optic nerve axons and retinal ganglion cells in 42 eyes enucleated because of complete glaucoma compared to eyes removed because of injury.The immunohistochemical reaction was done and specimens were examined under a light microscope. 57% of cases presented HIF-1 expression in the optic nerve axons, and 52.3% in the retinal ganglion cells. 20 out of 42(47.6%) cases were HIF-1 positive both in the optic nerve axons and in the retinal ganglion cells, and the staining was evident mostly in the nuclear and perinuclear area. Our present results indicate that HIF-1 expression in hypoxic conditions in glaucoma might be a very crucial stage in damage to retinal ganglion cells and optic nerve axons, and might be a successful target for the implementation of neuroprotective drugs. PMID- 23042281 TI - Total antioxidant status (TAS) in childhood cancer survivors. AB - Total antioxidant status (TAS), and the influence of treatment and correlation between TAS and parameters involved in metabolic syndrome (MS) in pediatric cancer survivors were evaluated. One hundred children and adolescents were studied. Twenty-five survivors received radiotherapy, 12 were obese or overweight.Additionally, we analyzed TAS in eight children with acute lymphoblastic leukemia (ALL) at diagnosis and during treatment after remission induction. The control group consisted of 22 healthy children. Serum concentrations of TAS, glucose, cholesterol, HDL-cholesterol, triglycerides, fibrinogen and insulin were measured. In cancer survivors, independently of diagnosis and kind of treatment (radiotherapy anthracyclines administration),the mean serum TAS did not differ significantly from the control group. No correlations were observed with age at the time of diagnosis or interval after the end of treatment. TAS values did not correlate with traits of the metabolic syndrome. In a group of eight patients with ALL at diagnosis and after induction of remission,TAS values were lower than in the control and cancer survivor groups. Antioxidant status was not found to be deteriorated in children after anticancer treatment, irrespective of diagnosis or kind of treatment, which might indicate sufficient antioxidant prevention. However, the possibility of the development of MS and cardiovascular disease in adulthood indicates the need for future studies. PMID- 23042280 TI - Complement inhibitory proteins expression in placentas of thrombophilic women. AB - Factors controlling complement activation appear to exert a protective effect on pregnancy. This is particularly important in women with thrombophilia. The aim of this study was to determine the transcript and protein levels of complement decay accelerating factor (DAF) and membrane cofactor protein (MCP) in the placentas of women with acquired and inherited thrombophilia. Also, we assessed immunohistochemistry staining of inhibitors of the complement cascade, DAF and MCP proteins, in the placentas of thrombophilic women.Placentas were collected from eight women with inherited thrombophilia and ten with acquired thrombophilia.The levels of DAF and MCP transcripts were evaluated by qPCR, the protein level was evaluated by Western blot. We observed a higher transcript (p < 0.05) and protein (p < 0.001) levels of DAF and MCP in the placentas of thrombophilic women than in the control group. DAF and MCP were localized on villous syncytiotrophoblast membranes, but the assessment of staining in all groups did not differ. The observed higher expression level of proteins that control activation of complement control proteins is only seemingly contradictory to the changes observed for example in the antiphospholipid syndrome. However, given the hitherto known biochemical changes associated with thrombophilia, a mechanism in which increased expression of DAF and MCP in the placentas is an effect of proinflammatory cytokines, which accompanies thrombophilia, is probable. PMID- 23042282 TI - The usefulness of soluble transferrin receptor (sTfR) in differentiating anemia occurring in young children. AB - We evaluated the usefulness of soluble transferrin receptor (sTfR) and of the sTfR/log ferritin index(sTfR/logF) in the differentiation of anemia in young children. 96 children, aged 6-36 months, were examined.From these, four groups were distinguished: 1 - (IDA): 33 children with anemia due to iron deficiency; 2 (IA): 19 children with infectious anemia without iron deficiency; 3 - (IA + ID): 16 children with infectious anemia and iron deficiency; and 4 - a comparator group (CG): 28 healthy children without iron deficiency. The soluble transferrin receptor, hematological indices and iron balance were evaluated and the sTfR/logF was calculated for each examined child. It was proved that the mean values of sTfR and sTfR/logF were substantially higher in children with anemia due to iron deficiency, and in those with infectious anemia and iron deficiency,vs. those with infectious anemia or in healthy children. This suggests that both sTfR and the sTfR/logF are good indicators of iron deficiency and could be useful in the differential diagnostics of anemia, especially in young children. PMID- 23042283 TI - Is littoral cell angioma of the spleen as rare as previously believed in the pediatric population? AB - Littoral cell angioma (LCA) is a rare primary splenic vascular tumor, originating from the littoral cells lining the red pulp sinuses of the spleen. There are only a handful of case reports of LCA in children to be found in the literature. We performed a retrospective analysis of the medical charts of pediatric patients with splenic lesions who were treated between 2005 and 2010 in the Pediatric Surgery Department of the Medical University of Bialystok. Surprisingly, LCA accounted for 37.5% of the splenic lesions found in our series. The majority of LCA tumors are benign, but given their malignant potential, splenectomy and long term follow-up should be the gold standard for their management. We strongly support the use of further cross-sectional studies to properly elucidate the prevalence of littoral cell angioma of the spleen in the pediatric population. PMID- 23042284 TI - Trichophyton mentagrophytes-associated Majocchi's granuloma treated with cryotherapy. AB - We here report the case of a woman with dermatophytosis of the thighs due to Trichophyton mentagrophytes where an unusual clinical picture posed considerable diagnostic and therapeutic problems. She presented numerous skin lesions located on the dorsolateral face of the left thigh and the medial surface of the right calf. The initial lesions consisted of small itchy pustules that evolved to exfoliation after scratching. Results of histopathologic examination ofa skin biopsy were consistent with dermatophytosis, although the negativity of PAS staining did not allow confirmation of this diagnosis. Direct microscopic examination with 10% KOH was negative; however, skin cultures on BioMerieux media revealed Tr. Mentagrophytes. Following the diagnosis of Trichophyton infection, the patient was treated with a combination of isoconazole nitrate and difluocortolone valerate. After therapy, both direct microscopic mycologic examination and culture on BioMerieux medium were negative; however, the lesions persisted, assuming a completely different aspect. Cryotherapy with liquid nitrogen was started. This led to a spectacular improvement: the surface of the skin became almost normal, merely showing slight discoloration. An unusual clinical presentation and non-responsiveness to treatment should prompt revision of the primary diagnosis. A negative result of direct microscopy should not exclude the diagnosis of dermatophytosis. Cryotherapy should be considered in cases that do not respond to conventional antifungal medication. PMID- 23042285 TI - Estrogen receptor alpha localization in the testes of men with normal spermatogenesis. AB - It is known that estrogens act on the male reproductive tract by binding to estrogen receptors (ER) alpha and beta. However, studies on ER localization in the human testis are discordant. The aim of this study was to investigate the localization of ERalpha in the testes of adult men with normal spermatogenesis. Semen analysis of ten adult men revealed azoospermia. FSH, LH and testosterone serum concentrations were within normal values, and the volume of the testes was normal, hence obstructive azoospermia was suspected. The tissues from testicular surgical biopsies were fixed in Bouin's fluid and embedded in paraffin. Assessments of the seminiferous epithelium (scoring 10 to -1), the number of Leydig cells (scoring 1 to 5), the areal fraction of intertubular space (IS), measurements of seminiferous tubule diameter, and the thickness of the tubular wall, were performed on microscopic sections. Immunohistochemical staining was applied with monoclonal antibodies against ERalpha. The mean spermatogenesis score was 10 points; IS - 30.6 +/- 8.1%; seminiferous tubule diameter - 193.9 +/- 19.4 MUm; thickness of tubular wall - 7.44 +/- 1.1 MUm; number of Leydig cells - 1.6 +/- 1.1 points. Immunohistochemical staining showed the localization of ERalpha to be in the Sertoli and Leydig cell cytoplasm, while ERalpha was absent in germ cells. The results of testicular tissue analysis confirmed its normal structure and normal, full spermatogenesis. The presence of ERalpha in Sertoli and Leydig cells in normal human testis demonstrated in this study suggests that estrogens may affect testicular function. PMID- 23042287 TI - A versatile and green mechanochemical route for aldehyde-oxime conversions. AB - A robust, facile and solvent-free mechanochemical path for aldehyde-oxime transformations using hydroxylamine and NaOH is explored; the method is suitable for aromatic and aliphatic aldehydes decorated with a range of substituents. PMID- 23042286 TI - Early gene regulation of osteogenesis in embryonic stem cells. AB - The early gene regulatory networks (GRNs) that mediate stem cell differentiation are complex, and the underlying regulatory associations can be difficult to map accurately. In this study, the expression profiles of the genes Dlx5, Msx2 and Runx2 in mouse embryonic stem cells were monitored over a 48 hour period after exposure to the growth factors BMP2 and TGFbeta1. Candidate GRNs of early osteogenesis were constructed based on published experimental findings and simulation results of Boolean and ordinary differential equation models were compared with our experimental data in order to test the validity of these models. Three gene regulatory networks were found to be consistent with the data, one of these networks exhibited sustained oscillation, a behaviour which is consistent with the general view of embryonic stem cell plasticity. The work cycle presented in this paper illustrates how mathematical modelling can be used to elucidate from gene expression profiles GRNs that are consistent with experimental data. PMID- 23042288 TI - Applications of light scattering in dye-sensitized solar cells. AB - Light scattering is a method that has been employed in dye-sensitized solar cells for optical absorption enhancement. In conventional dye-sensitized solar cells, large TiO(2) particles with sizes comparable to the wavelength of visible light are used as scatterers by either being mixed into the nanocrystalline film to generate light scattering or forming a scattering layer on the top of the nanocrystalline film to reflect the incident light, with the aim to extend the traveling distance of incident light within the photoelectrode film. Recently, hierarchical nanostructures, for example nanocrystallite aggregates (among others), have been applied to dye-sensitized solar cells. When used to form a photoelectrode film, these hierarchical nanostructures have demonstrated a dual function: providing large specific surface area; and generating light scattering. Some other merits, such as the capability to enhance electron transport, have been also observed on the hierarchically structured photoelectrode films. Hierarchical nanostructures possessing an architecture that may provide sufficient internal surface area for dye adsorption and meanwhile may generate highly effective light scattering, make them able to create photoelectrode films with optical absorption significantly more efficient than the dispersed nanoparticles used in conventional dye-sensitized solar cells. This allows reduction of the thickness of the photoelectrode film and thus lowering of the charge recombination in dye-sensitized solar cells, making it possible to increase further the efficiency of existing dye-sensitized solar cells. PMID- 23042289 TI - Capturing cases of distal symmetric polyneuropathy in a community. AB - INTRODUCTION: Little is known about what constitutes appropriate diagnostic testing in patients with distal symmetric polyneuropathy (DSP). METHODS: Utilizing an ICD-9 screening method and medical record abstraction, we determined the number of new cases of DSP within community neurology practices in Nueces County, Texas. We then compared 2 case capture methods (ICD-9 vs. all-case review screening). RESULTS: The ICD-9 case capture method identified 52 cases over a 3 month period. Comparing case capture methods, the ICD-9 method identified 16 of 17 cases identified by the all-case review method (94%). The ICD-9 method required screening of 84% fewer charts compared with the all-case review. CONCLUSIONS: Many new cases of DSP occur each month within Nueces County. The ICD 9 screening technique combined with medical abstraction is an efficient method to identify new DSP cases in this community. These findings are critical for future epidemiological investigations into patients with DSP. PMID- 23042290 TI - Microfluidic integration of Western blotting is enabled by electrotransfer assisted sodium dodecyl sulfate dilution. AB - We integrate sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) with subsequent antibody probing in a single, monolithic microdevice to realize microfluidic Western blotting. A hurdle to successful on-chip Western blotting lies in restoring antibody recognition of previously sized (denatured, reduced) proteins. To surmount this hurdle, we locally dilute free SDS from SDS-protein complexes using differential electromigration of the species during electrotransfer between SDS-PAGE and blotting regions of a microchamber. Local dilution of SDS minimizes re-association of SDS with proteins offering means to restore antibody binding affinity to proteins after SDS-PAGE. To achieve automated, programmable operation in a single instrument, we utilize a 1 * 2 mm(2) glass microchamber photopatterned with spatially distinct, contiguous polyacrylamide regions for SDS-PAGE, electrotransfer, and antibody blotting. Optimization of both the SDS-PAGE and electrotransfer conditions yields transfer distances of <1 mm (40 s). The Western blot is completed in 180 s, with fully automated assay operation using programmable voltage control. After SDS-PAGE and electrotransfer, we observe ~80% capture of protein band mass on the blotting region for a model protein, C-reactive protein. This novel microfluidic Western blot approach introduces fine transport control for in-transit protein handling to form the basis for an automated, rapid alternative to conventional slab-gel Western blotting. PMID- 23042291 TI - Ruthenium-catalyzed allylation-cyclization reactions of cyclic 1,3-dicarbonyl compounds with 1-vinyl propargyl alcohols. AB - Ruthenium-catalyzed allylation-cyclization reactions of cyclic 1,3-dicarbonyl compounds with 1-vinyl propargyl alcohols that lead to diverse carbo- or heterocyclic products in a one-pot cascade process are reported. These mechanistically distinct reactions are catalyzed by a single ruthenium(0) complex that contains a redox-coupled dienone ligand. The reaction pathway strongly depends on the substrate substitution pattern, which determines the mode of activation of the 1-vinyl propargyl alcohol. The environmentally benign process, which generates water as the only waste product, is of wide scope and allows the atom-economic synthesis of highly functionalized furans, pyrans, and spirocarbocycles. PMID- 23042292 TI - Elfn1 regulates target-specific release probability at CA1-interneuron synapses. AB - Although synaptic transmission may be unidirectional, the establishment of synaptic connections with specific properties can involve bidirectional signaling. Pyramidal neurons in the hippocampus form functionally distinct synapses onto two types of interneurons. Excitatory synapses onto oriens lacunosum moleculare (O-LM) interneurons are facilitating and have a low release probability, whereas synapses onto parvalbumin interneurons are depressing and have a high release probability. Here, we show that the extracellular leucine rich repeat fibronectin containing 1 (Elfn1) protein is selectively expressed by O-LM interneurons and regulates presynaptic release probability to direct the formation of highly facilitating pyramidal-O-LM synapses. Thus, postsynaptic expression of Elfn1 in O-LM interneurons regulates presynaptic release probability, which confers target-specific synaptic properties to pyramidal cell axons. PMID- 23042293 TI - Intramitochondrial transport of phosphatidic acid in yeast by a lipid transfer protein. AB - Mitochondria are dynamic organelles whose function depends on intramitochondrial phospholipid synthesis and the supply of membrane lipids from the endoplasmic reticulum. How phospholipids are transported to and in-between mitochondrial membranes remained unclear. We identified Ups1, a yeast member of a conserved family of intermembrane space proteins, as a lipid transfer protein that can shuttle phosphatidic acid between mitochondrial membranes. Lipid transfer required the dynamic assembly of Ups1 with Mdm35 and allowed conversion of phosphatidic acid to cardiolipin in the inner membrane. High cardiolipin concentrations prevented membrane dissociation of Ups1, leading to its proteolysis and inhibiting transport of phosphatidic acid and cardiolipin synthesis. Thus, intramitochondrial lipid trafficking may involve a regulatory feedback mechanism that limits the accumulation of cardiolipin in mitochondria. PMID- 23042296 TI - Efficient hybrid solar cells based on meso-superstructured organometal halide perovskites. AB - The energy costs associated with separating tightly bound excitons (photoinduced electron-hole pairs) and extracting free charges from highly disordered low mobility networks represent fundamental losses for many low-cost photovoltaic technologies. We report a low-cost, solution-processable solar cell, based on a highly crystalline perovskite absorber with intense visible to near-infrared absorptivity, that has a power conversion efficiency of 10.9% in a single junction device under simulated full sunlight. This "meso-superstructured solar cell" exhibits exceptionally few fundamental energy losses; it can generate open circuit photovoltages of more than 1.1 volts, despite the relatively narrow absorber band gap of 1.55 electron volts. The functionality arises from the use of mesoporous alumina as an inert scaffold that structures the absorber and forces electrons to reside in and be transported through the perovskite. PMID- 23042294 TI - IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. AB - The endoplasmic reticulum (ER) is the primary organelle for folding and maturation of secretory and transmembrane proteins. Inability to meet protein folding demand leads to "ER stress," and activates IRE1alpha, an ER transmembrane kinase-endoribonuclease (RNase). IRE1alpha promotes adaptation through splicing Xbp1 mRNA or apoptosis through incompletely understood mechanisms. Here, we found that sustained IRE1alpha RNase activation caused rapid decay of select microRNAs (miRs -17, -34a, -96, and -125b) that normally repress translation of Caspase-2 mRNA, and thus sharply elevates protein levels of this initiator protease of the mitochondrial apoptotic pathway. In cell-free systems, recombinant IRE1alpha endonucleolytically cleaved microRNA precursors at sites distinct from DICER. Thus, IRE1alpha regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response. PMID- 23042295 TI - Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice. AB - Reconstitution of female germ cell development in vitro is a key challenge in reproductive biology and medicine. We show here that female (XX) embryonic stem cells and induced pluripotent stem cells in mice are induced into primordial germ cell-like cells (PGCLCs), which, when aggregated with female gonadal somatic cells as reconstituted ovaries, undergo X-reactivation, imprint erasure, and cyst formation, and exhibit meiotic potential. Upon transplantation under mouse ovarian bursa, PGCLCs in the reconstituted ovaries mature into germinal vesicle stage oocytes, which then contribute to fertile offspring after in vitro maturation and fertilization. Our culture system serves as a robust foundation for the investigation of key properties of female germ cells, including the acquisition of totipotency, and for the reconstitution of whole female germ cell development in vitro. PMID- 23042297 TI - Loss of Gsx1 and Gsx2 function rescues distinct phenotypes in Dlx1/2 mutants. AB - Mice lacking the Dlx1 and Dlx2 homeobox genes (Dlx1/2 mutants) have severe deficits in subpallial differentiation, including overexpression of the Gsx1 and Gsx2 homeobox genes. To investigate whether Gsx overexpression contributes to the Dlx1/2 mutant phenotypes, we made compound loss-of-function mutants. Eliminating Gsx2 function from the Dlx1/2 mutants rescued the increased expression of Ascl1 and Hes5 (Notch signaling mediators) and Olig2 (oligodendrogenesis mediator). In addition, Dlx1/2;Gsx2 mutants, like Dlx1/2;Ascl1 mutants, exacerbated the Gsx2 and Dlx1/2 patterning and differentiation phenotypes, particularly in the lateral ganglionic eminence (LGE) caudal ganglionic eminence (CGE), and septum, including loss of GAD1 expression. On the other hand, eliminating Gsx1 function from the Dlx1/2 mutants (Dlx1/2;Gsx1 mutants) did not severely exacerbate their phenotype; on the contrary, it resulted in a partial rescue of medial ganglionic eminence (MGE) properties, including interneuron migration to the cortex. Thus, despite their redundant properties, Gsx1 and -2 have distinct interactions with Dlx1 and 2. Gsx2 interaction is strongest in the LGE, CGE, and septum, whereas the Gsx1 interaction is strongest in the MGE. From these studies, and earlier studies, we present a model of the transcriptional network that regulates early steps of subcortical development. PMID- 23042298 TI - Effect of mother's dominance rank on offspring temperament in infant rhesus monkeys (Macaca mulatta). AB - In humans, temperament plays an important role in socialization and personality. Some temperaments, such as behavioral inhibition are associated with an increased risk for psychopathology. Nonhuman primates can serve as a model for neurobiological and developmental contributions to emotional development and several recent studies have begun to investigate temperament in nonhuman primates. In rhesus monkeys, dominance rank is inherited from the mother and is associated with social and emotional tendencies that resemble differences in temperament. The current study assessed differences in temperament in infant rhesus monkeys as a function of maternal dominance rank. Temperament was assessed in 26 infants (13 males) from birth until 6 months of age with a battery that included Brazelton test, human intruder test, human intruder-startle, cortisol stress reactivity, and home cage observations of interactions with peers and the mother. Throughout testing, infants lived with their mothers and a small group of other monkeys in indoor/outdoor runs. Dominance rank of the mothers within each run was rated as either low/middle (N = 18, 9 male) or high/alpha (N = 8, 4 female). Infants of high-ranking mothers displayed more intruder-directed aggression and reduced startle potentiation in the human intruder tests. Dominant offspring also had reduced levels cortisol and startle across development and spent more time away from mothers in the interaction tests. These results suggest that dominance of the mother may be reflected in behavioral reactivity of infants early in life. These findings set up future studies, which may focus on contributing factors to both dominance and temperament such as genetics, rearing, and socialization. Such factors are likely to interact across development in meaningful ways. These results also suggest future human-based studies of a similar relationship may be warranted, although social dominance is clearly more complex in human than macaque societies. PMID- 23042299 TI - Critical analysis of the successes and failures of homology models of G protein coupled receptors. AB - We present a critical assessment of the performance of our homology model refinement method for G protein-coupled receptors (GPCRs), called LITICon that led to top ranking structures in a recent structure prediction assessment GPCRDOCK2010. GPCRs form the largest class of drug targets for which only a few crystal structures are currently available. Therefore, accurate homology models are essential for drug design in these receptors. We submitted five models each for human chemokine CXCR4 (bound to small molecule IT1t and peptide CVX15) and dopamine D3DR (bound to small molecule eticlopride) before the crystal structures were published. Our models in both CXCR4/IT1t and D3/eticlopride assessments were ranked first and second, respectively, by ligand RMSD to the crystal structures. For both receptors, we developed two types of protein models: homology models based on known GPCR crystal structures, and ab initio models based on the prediction method MembStruk. The homology-based models compared better to the crystal structures than the ab initio models. However, a robust refinement procedure for obtaining high accuracy structures is needed. We demonstrate that optimization of the helical tilt, rotation, and translation is vital for GPCR homology model refinement. As a proof of concept, our in-house refinement program LITiCon captured the distinct orientation of TM2 in CXCR4, which differs from that of adrenoreceptors. These findings would be critical for refining GPCR homology models in future. PMID- 23042300 TI - GBP-1 acts as a tumor suppressor in colorectal cancer cells. AB - The human guanylate-binding protein 1 (GBP-1) is among the proteins the most highly induced by interferon-gamma (IFN-gamma) in every cell type investigated as yet. In vivo, GBP-1 expression is associated with the presence of inflammation and has been observed in autoimmune diseases, inflammatory bowel diseases (IBD) and cancer. In colorectal carcinoma (CRC), the expression of GBP-1 in the desmoplastic stroma has been previously reported to correlate with the presence of an IFN-gamma-dominated T helper type 1 (Th1) micromilieu and with an increased cancer-related 5-year survival. In the present study, the analysis of GBP-1 expression in a series of 185 CRCs by immunohistochemistry confirmed that GBP-1 is expressed in stroma cells of CRCs and revealed a significantly less frequent expression in tumor cells, which was contradictory with the broad inducibility of GBP-1. Furthermore, three of six CRC cell lines treated with IFN-gamma were unable to express GBP-1 indicating that colorectal tumor cells tend to downregulate GBP-1. On the contrary, non-transformed colon epithelial cells strongly expressed GBP-1 in vitro in presence of IFN-gamma and in vivo in inflammatory bowel diseases. Reconstitution of GBP-1 expression in a negative CRC cell line inhibited cell proliferation, migration and invasion. Using RNA interference, we showed that GBP-1 mediates the antitumorigenic effects of IFN gamma in CRC cells. In addition, GBP-1 was able to inhibit tumor growth in vivo. Altogether, these results suggested that GBP-1 acts directly as a tumor suppressor in CRC and the loss of GBP-1 expression might indicate tumor evasion from the IFN-gamma-dominated Th1 immune response. PMID- 23042301 TI - Functional genetic variations in the IL-23 receptor gene are associated with risk of breast, lung and nasopharyngeal cancer in Chinese populations. AB - Interleukin-23 receptor (IL-23R) is a key element in the T-helper 17 cell mediated inflammatory process, which plays an important role in the pathogenesis of cancer. In this study, we examined whether genetic polymorphisms in IL-23R are associated with cancer risk in 4936 cancer patients and 5664 control subjects from eastern and southern Chinese populations. We found that the C allele of the rs10889677A>C polymorphism in the 3'-untranslated region of IL-23R was inversely associated with risk of multiple types of cancer, including breast cancer, lung cancer and nasopharyngeal carcinoma. Healthy controls who harbored the rs10889677C allele had significantly decreased cancer risk (odds ratio = 0.74, 95% confidence interval = 0.71-0.78) compared with those who harbored the rs10889677A allele. Biochemical analysis demonstrated that the rs10889677A allele disrupted the binding site for the microRNA miR-let-7f, thereby increasing the transcription of the IL-23R in vitro and in vivo. Furthermore, cancer-free individuals carrying the rs10889677CC homozygous genotype had a lower proportion of regulatory T cells (Tregs) and a higher T-cell proliferation rate upon stimulation with concanavalin A than individuals carrying the rs10889677AA homozygous genotype. Our findings indicate that the IL-23R rs10889677A>C polymorphism may influence T-cell proliferation, resulting in changes in the levels of Tregs in vivo and modifying cancer susceptibility. PMID- 23042302 TI - The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer. AB - Novel drugs and drug combinations are needed for the chemoprevention and treatment of cancer. We show that the histone deacetylase inhibitor vorinostat [suberoylanilide hydroxamic acid (SAHA)] and the methyl ester or ethyl amide derivatives of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien 28-oic acid (CDDO-Me and CDDO-Ea, respectively) cooperated to inhibit the de novo synthesis of nitric oxide in RAW 264.7 macrophage-like cells and in primary mouse peritoneal macrophages. Additionally, SAHA enhanced the ability of synthetic triterpenoids to delay formation of estrogen receptor-negative mammary tumors in MMTV-polyoma middle T (PyMT) mice. CDDO-Me (50 mg/kg diet) and SAHA (250 mg/kg diet) each significantly delayed the initial development of tumors by 4 (P < 0.001) and 2 (P < 0.05) weeks, respectively, compared with the control group in the time required to reach 50% tumor incidence. CDDO-Ea (400 mg/kg diet), as a single agent, did not delay tumor development. The combination of either triterpenoid with SAHA was significantly more potent than the individual drugs for delaying tumor development, with a 7 week (P < 0.001) delay before 50% tumor incidence was reached. SAHA, alone and in combination with CDDO-Me, also significantly (P < 0.05) inhibited the infiltration of tumor-associated macrophages into the mammary glands of PyMT mice and levels of the chemokine macrophage colony-stimulating factor in primary PyMT tumor cells. In addition, SAHA and the synthetic triterpenoids cooperated to suppress secreted levels of the pro-angiogenic factor matrix metalloproteinase-9. Similar results were observed in mouse models of pancreatic and lung cancer. At concentrations that were anti-inflammatory, SAHA had no effect on histone acetylation. These studies suggest that both SAHA and triterpenoids effectively delay tumorigenesis, thereby demonstrating a promising, novel drug combination for chemoprevention. PMID- 23042303 TI - Prediagnostic circulating adipokine concentrations and risk of renal cell carcinoma in male smokers. AB - Despite a well-established link between obesity and renal cell carcinoma (RCC), the mechanism through which obesity acts to increase cancer risk is unclear. Adiponectin, leptin and resistin are adipocyte-secreted peptide hormones that may influence RCC development through their demonstrated effects on inflammation, insulin resistance and cell growth and proliferation. We conducted a nested case control study to evaluate whether prediagnostic serum adiponectin, leptin and resistin levels are associated with RCC risk. This case-control study (273 cases and 273 controls) was nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish male smokers. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using conditional logistic regression models, with analyte levels modeled continuously and categorically (defined using quartiles among controls). High adiponectin levels were significantly associated with reduced RCC risk (Quartile 4 versus Quartile 1: OR = 0.52, 95% CI = 0.30-0.88; P trend = 0.01). This association remained upon additional adjustment for body mass index at blood collection and exclusion of cases diagnosed within the first 2 years of follow-up. In addition, model adjustment for adiponectin resulted in a substantial attenuation of the association between BMI and RCC (OR per 5 kg/m(2) changed from 1.19 to 1.05). No clear associations with RCC were observed for leptin or resistin. Our results suggest that elevated levels of circulating adiponectin are associated with decreased subsequent risk of RCC. These findings provide the strongest evidence to date, suggesting that the association between obesity and RCC is mediated at least in part through the effects of low adiponectin. PMID- 23042305 TI - More poles and more configurations: seeking the Holy Grail for cardiac resynchronization therapy. PMID- 23042304 TI - Effect of CpG methylation at different sequence context on acrolein- and BPDE-DNA binding and mutagenesis. AB - Acrolein (Acr), an alpha,beta-unsaturated aldehyde, is abundant in tobacco smoke and cooking and exhaust fumes. Acr induces mutagenic alpha- and gamma- hydroxy 1,N(2)-cyclic propano-deoxyguanosine adducts in normal human bronchial epithelial cells. Our earlier work has found that Acr-induced DNA damage preferentially occurs at lung cancer p53 mutational hotspots that contain CpG sites and that methylation at CpG sites enhances Acr-DNA binding at these sites. Based on these results, we hypothesized that this enhancement of Acr-DNA binding leads to p53 mutational hotspots in lung cancer. In this study, using a shuttle vector supF system, we tested this hypothesis by determining the effect of CpG methylation on Acr-DNA binding and the mutations in human lung fibroblasts. We found that CpG methylation enhances Acr-induced mutations significantly. Although CpG methylation enhances Acr-DNA binging at all CpG sites, it enhances mutations at selective--TCGA--sites. Similarly, we found that CpG methylation enhances benzo(a)pyrene diol epoxide binding at all -CpG- sites. However, the methylated CpG sequences in which benzo(a)pyrene diol epoxide-induced mutations are enhanced are different from the CpG sequences in which Acr-induced mutations are enhanced. CpG methylation greatly increases Acr-induced G to T and G to A mutation frequency to levels similar to these types of mutations found in the CpG sites in the p53 gene in tobacco smoke-related lung cancer. These results indicate that both CpG sequence context and the chemical nature of the carcinogens are crucial factors for determining the effect of CpG methylation on mutagenesis. PMID- 23042306 TI - Safety of endoscopic procedures after acute myocardial infarction: a systematic review. AB - BACKGROUND: The management of patients who develop gastrointestinal (GI) bleeding after acute myocardial infarction (MI) is difficult due to concerns about possible cardiovascular complications. Gastroenterologists are often reluctant to perform endoscopic procedures despite urgent indications. We performed a systematic review of the literature to determine the safety of endoscopic procedures after MI. METHODS: We searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials for controlled clinical trials or case series examining the diagnostic efficacy and complications of esophagogastroduodenoscopy (EGD), colonoscopy and flexible sigmoidoscopy after MI. Title and abstract screening was followed by full-text review with subsequent data extraction of included studies. RESULTS: A total of seven studies met inclusion criteria. Four studies evaluated safety and efficacy of EGD after MI. The reported complication rate ranged between 1-8%, with a large predominance of minor complications. We found one study addressing safety of flexible sigmoidoscopy that reported minor complications in two patients. We also identified one study addressing the safety of colonoscopy after MI, which showed a complication rate of 9%. Most of these complications were minor. A decision analysis was also included in this review. CONCLUSIONS: Our review demonstrated that endoscopic procedures are safe and beneficial in stable patients with GI bleeding after recent MI and should be performed without a requisite delay. Unstable patients should undergo endoscopic procedures only in the intensive care setting, after stabilization and with close monitoring. PMID- 23042307 TI - 5-fluorouracil induced cardiotoxicity: review of the literature. AB - 5-fluorouracil (5-FU) is a key chemotherapeutic agent in the treatment of many gastrointestinal tract adenocarcinomas. Despite its proven therapeutic efficacy, 5-FU also possesses several undesired cardiac toxicities, including coronary vasospasm, coronary thrombosis, cardiomyopathy, and sudden cardiac death. This review addresses the incidence, mechanisms of action, clinical presentation, risk stratification, and management of 5-FU associated cardiotoxicity; it also highlights the importance of careful pre-administration cardiac risk stratification and close monitoring during and after drug administration. PMID- 23042308 TI - Optimal visualization of heart vessels before percutaneous mitral annuloplasty. AB - BACKGROUND: Multi-slice computed tomography (MSCT) can be useful before percutaneous mitral annuloplasty (PMA) procedures to visualize the relations between the mitral valve (MV), left circumflex artery (LCx) and coronary sinus (CS). METHODS AND RESULTS: We performed a 64-slice MSCT in 196 patients (109 male; age 56.6 +/- 11.4) with suspected coronary artery disease. A retrospective scan with ECG-gating was performed in each. In each case 3D VR and 2D MPR reconstructions were created. We used a subjective assessment of the quality of visualization to find the optimal phases of visualization for LCx, CS and both vessels together (relations). The quality of visualization were graded by 2 experts on 6-points scale. LCx was usually optimally visualized in the diastolic phases (70-80-90%) - 126/196 (64.3%). CS was usually optimally visualized in the systolic phases (30-40-50%) - 177/196 (90.3%). The optimal phase for parallel visualization of LCx/CS (to observe anatomical relations) was 70-80% - 140/196 (71.4%). Good quality visualization was obtained for both vessels: LCx: 3.6 +/- 1.4/CS: 4.1 +/- 1.1. CONCLUSIONS: Reconstructions of parallel visualization of LCx/CS for PMA procedures to observe the relations between those vessels should be considered during diastole. In addition, independent reconstructions should also be performed optimized for the LCx and the CS. PMID- 23042309 TI - Lack of significant association between Helicobacter pylori infection and homocysteine levels in patients with cardiac syndrome X. AB - BACKGROUND: Helicobacter pylori (H.pylori) has been implicated in the pathogenesis of several diseases such as cardiac syndrome X (CSX), which includes chest pain, positive exercise stress test and normal angiography. Also, elevation of homocysteine (Hcy) level is associated with CSX, as it can severely disturb vascular endothelial function. We aimed to elucidate whether the infection of H.pylori affect the level of Hcy in CSX. METHODS: Eighty-eight patients with CSX (32 men, 56 women; mean age: 53.8 +/- 11.9) and 97 healthy controls (36 men, 61 women; mean age: 45.7 +/- 7.3) were enrolled. Plasma samples were tested for the presence of IgG antibody to H.pylori using enzyme linked immunosorbent assay method. Hcy levels were measured enzymatically. RESULTS: Plasma Hcy concentration in CSX patients is higher than control group (13.1 +/- 2.6 vs. 11.8 +/- 2.5 mmol/L; p = 0.002). There was no significant difference between Hcy in H.pylori(+) and H.pylori(-) individuals in CSX group (13.1 +/- 2.7 vs. 12.2 +/- 0.6 mmol/L; p = 0.554) and between two groups in controls, respectively (12.1 +/- 2.2 vs. 11.4 +/- 2.9 mmol/L; p = 0.148). CONCLUSIONS: Although there is Hcy level increase in H.pylori(+) CSX patients and controls comparing to H.pylori(-) subjects, but other factors may affect on Hcy level, too. (Cardiol J 2012; 19, 5: 466-469). PMID- 23042310 TI - Acute and mid-term outcomes of transvenous implant of a new left ventricular quadripolar lead versus bipolar leads for cardiac resynchronization therapy: results from a single-center prospective database. AB - BACKGROUND: The purpose of this study was to evaluate the feasibility of the use of a quadripolar left ventricular (LV) lead for cardiac resynchronization therapy and to compare its acute and mid-term outcomes with those obtained with bipolar leads. Cardiac resynchronization exhibits a high incidence of problems involving the LV lead when conventional leads are used, and these problems may be minimized by using multipolar leads. METHODS: We gathered clinical, implant, and follow-up data at 3 and 9 months from 21 consecutive patients in whom a quadripolar (Group Q) or bipolar (Group B) lead was used for a biventricular defibrillator implant. RESULTS: The leads were successfully implanted in all of the patients. In Group B, more than one lead was used in 20% (p = 0.048) of cases. There were no clinical differences or differences in the implant parameters between the two groups except for the radiation dose, which was greater in group B (p = 0.035). The incidence of problems related to the LV lead during follow-up was higher in group B, but the difference was not significant (42.9% vs. 23.8%, p = 0.326). The use of more than one LV lead was the only variable that was significantly associated with lead-related problems during follow-up (p = 0.03; OR = 10.8; 95% CI 1.07-108.61). CONCLUSIONS: The quadripolar lead was associated with excellent implantation success rates and mid-term performance. The multi-programmability capabilities of quadripolar leads facilitated the achievement of implant goals and helped to reduce problems during the implant and follow-up. PMID- 23042311 TI - N-terminal pro-brain natriuretic peptide and electrocardiographic variables associated with increased risk of complete atrioventricular block and mortality in patients with acute inferior myocardial infarction. AB - BACKGROUND: Although brain natriuretic peptide (BNP) levels are shown to be an important prognostic factor in patients with acute myocardial infarction (MI), the relationship between arrhythmias and BNP levels is not known. This study assessed whether baseline clinical factors, N-terminal-proBNP (NT-proBNP) levels and electrocardiographic patterns of acute inferior MI are associated with greater risk of developing complete atrioventricular block (CAVB) and mortality. METHODS AND RESULTS: Seventy-nine consecutive patients (52 male, 27 female with an avarage age of 64.2 +/- 10.9 years) with CAVB and 119 control patients (93 male, 16 female with an average age of 57.7 +/- 11.4 years) without CAVB were enrolled. Regression analysis revealed that NT-proBNP levels > 104 pg/mL increased the development of CAVB by 16.7 folds, > 1 mm ST elevation in RV4 by 2.7 folds, ratio of elevation in lead III:II > 1.5 by 10.1 folds but the thrombolytic therapy decreased the development of CAVB by 2.8 folds. NT-proBNP > 92 pg/mL increased the mortality by 8.9 folds, a ratio of ST-segment elevation in lead III:II > 1 by 3.1 folds, ST segment elevation > 1 mm in RV4 by 3.5 folds, ejection fraction < 35% by 24.2 folds, age > 65 years by 8.3 folds and CAVB by 6.8 folds, on contrary thrombolytic treatment decreased the mortality by 3.3 folds. CONCLUSIONS: Simple electrocardiographic measurements and NT-proBNP levels at admission can be used as a screening test for development of complications such as CAVB, right ventricular involvement and mortality during acute inferior wall MI. PMID- 23042312 TI - Tissue Doppler echocardiography can be a useful technique to evaluate atrial conduction time. AB - BACKGROUND: The main purpose of this study is to determine the correlation of inter- and intraatrial conduction times between the electrophysiological and tissue Doppler echocardiographic measurements, and to evaluate the appropriateness of tissue Doppler echocardiography for this measurement. METHODS: One-hundred and one patients were included in the study who underwent electrophysiological study for clinical arrhythmias. Inter- and intraatrial conduction times were measured from intracardiac electrograms. Atrial conduction times were also measured by tissue Doppler echocardiography by evaluating atrial electromechanical delay between lateral mitral annulus, septal mitral annulus, and right ventricular tricuspid annulus. The correlation between electrophysiological and echocardiographic atrial conduction times were analyzed. RESULTS: We found a weak correlation between the measurements of interatrial conduction times with the electrophysiological and tissue Doppler techniques (r = 0.308; p = 0.002). The correlation for intraleft atrial conduction times was moderate (r = 0.652; p < 0.001). There was no correlation between the measurements of intra-right atrial conduction times. CONCLUSIONS: We concluded that tissue Doppler echocardiography can be used for the measurement of interatrial and intra-left atrial conduction times. Tissue Doppler echocardiography can be a suitable technique to evaluate atrial substrate. PMID- 23042313 TI - Do statins influence platelet reactivity on acetylsalicylic acid therapy in patients with type 2 diabetes? AB - BACKGROUND: Type 2 diabetes (T2DM) patients are at increased risk of cardiovascular events despite long-term acetylsalicylic acid (ASA) therapy. This study was performed to establish the prevalence of high platelet reactivity (HPR) on ASA in T2DM and to identify its predictors. METHODS: The study included 185 T2DM on chronic ASA therapy and to assess platelet reactivity during long-term ASA therapy, we applied the point-of-care method VerifyNow((r)) aspirin test (Accumetrics, San Diego, CA, USA). RESULTS: Compared with the low platelet reactivity (LPR) group, patients with HPR had higher triglyceride levels (145 vs. 118 mg/dL, p = 0.041), were less frequently treated with statins (57.1% vs. 75.3%; p = 0.038) and tumor necrosis factor-alpha (TNF-alpha) concentrations were higher (2.15 vs. 1.74 pg/mL; p = 0.052). In a multivariate analysis only statin therapy (OR 0.375; 95% CI 0.15-0.91; P = 0.030) and lower concentrations of TNF alpha (for each 1.0 pg/ml: or 1.3; 95% ci 1.00-1.72; p = 0.046) were predictive of LPR. CONCLUSIONS: Our study provides indirect evidence that the beneficial effect of statins on platelet activity may be related to their non-lipid mediated, pleiotropic mechanisms of action. This might have been partly related to decreased platelet reactivity in patients receiving statin therapy. In our study in patients with T2DM, platelet reactivity on ASA therapy measured with VerifyNow((r)) was associated with TNF-alpha concentrations and statin therapy. These results may imply a role for subclinical systemic inflammation and a beneficial effect of statins in the development of HPR in T2DM. PMID- 23042314 TI - The use of short-term analysis of heart rate variability to assess autonomic function in obese children and its relationship with metabolic syndrome. AB - BACKGROUND: The cardiovascular autonomic nervous system in obese children is one of the main initiators of coronary heart disease and hypertension and may have a close relationship with insulin resistance. Heart rate variability is one non invasive method to assess the cardiovascular autonomic system. In this method, low frequency parameters reflect sympathovagal activity, high frequency parameters reflect vagal activity and the ratio of these parameters reflects sympathovagal balance. METHODS: In this study, a short-term analysis of heart rate variability was conducted in 66 obese children and 40 healthy controls. RESULTS: While high frequency parameter values are lower in the obese group compared to the controls (16.02 +/- 12.9 nu vs. 21.45 +/- 13.6 nu, p = 0.046), the low frequency/high frequency ratio is found significantly higher (3.79 +/- 2.34 vs. 2.25 +/- 0.93, p < 0.001). A significant difference was not detected for the low frequency values (p = 0.787). Insulin resistance was found in 33 (50%) patients, dyslipidemia was found in 39 (59%) and hypertension was found in 18 (27%). Metabolic syndrome was detected in 39% patients in the obese group. CONCLUSIONS: We found that vagal activity was decreased in the obese group and the autonomic nervous system balance was impaired in favor of sympathetic activity in the short-term heart rate analysis. PMID- 23042315 TI - The effect of metabolic syndrome on heart rate turbulence in non-diabetic patients. AB - BACKGROUND: Metabolic syndrome (MetS), which includes a cluster of risk factors, is being increasingly recognized as a new risk factor for cardiovascular disease. Heart rate turbulence (HRT) is a Holter-based non-invasive method for detecting cardiac autonomic imbalance and is an independent, powerful predictor of cardiac arrhythmias and sudden cardiac death in different patient groups. This study evaluated the effect of MetS on HRT in non-diabetic patients. METHODS: This study included 80 non-diabetic MetS subjects and 50 healthy subjects. All 130 subjects underwent a 24-h ambulatory Holter electrocardiogram recording. Two indices of HRT were analyzed: turbulence onset (TO) and turbulence slope (TS). HRT values were classified into 3 categories for risk stratification: 1) Category 0, TO and TS were normal; 2) Category 1, either TO or TS was abnormal; 3) Category 2, both TO and TS were abnormal. RESULTS: When we compared MetS rates in the HRT risk stratification groups, there were significant differences for all groups as compared with the controls (Category 0 = MetS 28.8%, n = 15, Control 71.2%, n = 37, p < 0.001; Category 1 = MetS 80.8%, n = 42, Control 19.2%, n = 10, p < 0.001; Category 2 = MetS 88.5%, n = 23, Control 11.5%, n = 3, p < 0.001). In addition, TO and TS abnormalities were correlated with the number of MetS components (r = 0.608, p < 0.001; r = -0.388, p < 0.001, respectively). CONCLUSIONS: To our knowledge, this is the first study to establish a relationship between HRT and MetS. These findings suggest that MetS adversely affects HRT scores. In addition, the number of MetS components is related to impaired HRT scores. PMID- 23042316 TI - Pacemaker lead extraction and recapture of venous access: technical problems arising from extensive venous obstruction. AB - We report the case of the extraction of 18 year-old leads in a patient with a DDD pacemaker, and chronic obstruction of the left subclavian and innominate veins coexisting with extensive stenoses in the upper caval vein. After removal of pacing leads, angiographic guidewires were introduced via the Byrd dilatators and new pacing leads introduced with the use of long sheaths originally dedicated for transvenous left ventricular leads implantation. With this case, we discuss the problems arising during reimplantation of pacing leads in patients with chronic venous occlusion. PMID- 23042317 TI - Asymptomatic multiple intracardiac tuberculomas in a child. AB - Tuberculosis is widely prevalent among children in India, especially in those with coexisting severe malnutrition and immunodeficiency. Uncommon sites for tuberculosis are frequently seen. However, intracardiac tuberculomas are extremely rare in children. To the best of our knowledge, this is the first case report of multiple asymptomatic intracardiac tuberculomas in a child. Most intracardiac tuberculomas cause symptoms, especially in adults. In asymptomatic children non surgical management of intracardiac tuberculomas appears to be a safe treatment option as complete resolution occurs with antituberculous therapy. PMID- 23042318 TI - Tako-tsubo cardiomyopathy as a recurrent disease with doubtful prognosis of recovery and heterogenic symptoms. AB - Tako-tsubo cardiomyopathy, known since 1990, is described as hypo/akinesis of apical heart segments with the hyperkinesis of the basis of the heart which mimics the shape of a traditional Japanese octopus trap. PMID- 23042319 TI - Symptoms in the presence of a giant windsock eustachian valve remnant. AB - We present the case of a 43 year-old female with an isolated episode of atypical chest pain and an ill-defined cardiac murmur who was coincidentally found to possess a large serpiginious residual embryonic structure in right atrium. Multiple modality imaging was required to confirm this to be a rare giant eustachian valve remnant. The eustachian valve in the fetus directs oxygenated blood towards the foramen ovale. While absent or very small in adult life it rarely persists to any significant degree and must be distinguished from other right atrial shelf anomalies. The true potential of these structures to cause pathological interference with cardiac function or symptoms is unknown due to their rarity. PMID- 23042320 TI - Pheochromocytoma-induced reverse tako-tsubo with rapid recovery of left ventricular function. AB - Pheochromocytoma is a rare, catecholamine-secreting tumor of neuroendocrine cells. It has been documented to present atypically as myocardial ischemia, arrhythmias, or congestive heart failure. We present the case of a patient who had transient cardiomyopathy with hypokinesia of the basal portions of the left ventricle and hyperkinesia of the apex triggered by a pheochromocytoma crisis similar to that of tako-tsubo cardiomyopathy, but with an inverse left ventricular contractile pattern ('inverted tako-tsubo'). PMID- 23042321 TI - The role of intravascular ultrasound guidance in the treatment of intramural hematoma probably caused by spontaneous coronary artery dissection in a young woman with acute anterior myocardial infarction. AB - Spontaneous coronary artery dissection (SCAD) is known to be a rare but fatal cause of acute coronary syndromes. It is more frequent in young women, particularly in the peripartum period. Intravascular ultrasound (IVUS) has an important role in the diagnosis and management of SCAD. Intramural hematoma that occurs between adventitial and media layer of the vessel wall may occlude the true lumen. IVUS can identify intimal tears, the extension of intramural hematoma and show the adequate compression of intramural hematoma after percutaneous coronary intervention. We present a case of intramural hematoma caused by SCAD in a young woman presenting with acute anterior myocardial infarction, and the role of IVUS in the diagnosis and management of SCAD. PMID- 23042322 TI - Cardiac 'resynchronization' by a left lateral accessory pathway. AB - We present the case of a 21 year-old woman with unremarkable medical history except for tachycardia episodes. The ECG showed a delta wave pre-excitation by a left lateral pathway. One radiofrequency pulse temporarily terminated the accessory pathway conduction, revealing a nodal conduction with complete left bundle branch block. PMID- 23042323 TI - Unruptured left ventricular pseudoaneurysm following inferior wall myocardial infarction. AB - Left ventricular (LV) pseudoaneurysm is a rare but potentially lethal complication of acute myocardial infarction (MI). We report a very rare case of a 60 year-old woman with a ruptured myocardial wall, and a non-ruptured LV pseudoaneurysm. The patient presented with acutely worsening shortness of breath and exertional dyspnea of one month's duration, and palpitation. She had an inferior wall MI nine months previously. Coronary angiography showed severe stenosis at right coronary artery. Echocardiography, LV angiography, and computed tomography angiography revealed a large pseudoaneurysm postero-inferior to the LV. Surgical resection of the pseudoaneurysm was performed and repair of the ruptured LV wall done, with good results. PMID- 23042324 TI - Patent ductus arteriosus associated with pulmonary hypertension and desaturation. AB - We present the cases of three children with patent ductus arteriosus (PDA), pulmonary arterial hypertension (PAH), and desaturation. One of them had desaturation associated with atrial septal defect (ASD). His ASD, PAH, and desaturation improved after successful device closure of the PDA. The other two had desaturation associated with Down syndrome. One had desaturation only at room air oxygen (21% oxygen) but well saturated with 100% oxygen, subsequently underwent successful device closure of the PDA. The other had experienced desaturation at a younger age but spontaneously recovered when he was older, following attempted device closure of the PDA, with late embolization of the device. PMID- 23042325 TI - Huge interatrial septal aneurysm with fenestrated atrial septal defect. PMID- 23042326 TI - Alternating bundle branch block during atrial bigeminy. PMID- 23042327 TI - Impedance cardiography: recent advancements. AB - The aim of this paper is the presentation of recent advancements in impedance cardiography regarding methodical approach, applied equipment and clinical or research implementations. The review is limited to the papers which were published over last 17 months (dated 2011 and 2012) in well recognised scientific journals. PMID- 23042328 TI - A cucurbit[8]uril sponge. AB - This paper describes a convenient approach to quantitative removal of the synthetic host cucurbit[8]uril (Q8) from aqueous mixtures using a sepharose resin coated in memantine groups to selectively sequester Q8 in the presence of competing hosts and guests. The "Q8 sponge" can separate Q8 from Q6 and reverse the Q8-mediated dimerization of peptides. PMID- 23042329 TI - Repeat after me. PMID- 23042331 TI - US presidential candidates diverge on how to help biopharma. PMID- 23042330 TI - Early-stage therapies target surgery-induced erectile dysfunction. PMID- 23042333 TI - Companies wager high on CD38-targeting drugs for blood cancer. PMID- 23042334 TI - Proposal for San Francisco to negotiate drug prices makes waves. PMID- 23042337 TI - Hantavirus treatments advance amidst outbreak in US park. PMID- 23042338 TI - Straight talk with...Mary Woolley. Interview by Roxanne Khamsi. PMID- 23042340 TI - The new drug circuit. PMID- 23042341 TI - Bioengingeering bacteria for a cure--it's not that easy. PMID- 23042343 TI - Lethal H5N1 influenza viruses are not resistant to interferon action in human, simian, porcine or chicken cells. PMID- 23042344 TI - Heat from calcium cycling melts fat. PMID- 23042345 TI - A complex substitute: antibody therapy for hemophilia. PMID- 23042346 TI - Attacking the flank: targeting new pathways in SBMA. PMID- 23042347 TI - LIF-ting Hippo averts metastasis. PMID- 23042348 TI - Parsing the potential of a new male contraceptive. PMID- 23042349 TI - The ongoing battle against influenza: The challenge of flu transmission. PMID- 23042350 TI - The ongoing battle against influenza: Drug-resistant influenza viruses: why fitness matters. PMID- 23042355 TI - Paradigm shifts in science: insights from the arts. PMID- 23042356 TI - One path to understanding energy transduction in biological systems. PMID- 23042357 TI - Following nature's challenges. PMID- 23042358 TI - How lucky can one be? A perspective from a young scientist at the right place at the right time. PMID- 23042359 TI - The long reach of liver transplantation. PMID- 23042360 TI - "It can't be done". PMID- 23042361 TI - Developmental biology using purified genes. PMID- 23042362 TI - On the road from classical to modern molecular biology. PMID- 23042366 TI - Osteosarcoma cells induce endothelial cell proliferation during neo-angiogenesis. AB - Understanding the mechanisms inducing endothelial cell (EC) proliferation following tumor microenvironment stimuli may be important for the development of antiangiogenic therapies. Here, we show that cyclin-dependent kinase 2 and 5 (Cdk2, Cdk5) are important mediators of neoangiogenesis in in vitro and in vivo systems. Furthermore, we demonstrate that a specific Yin Yang 1 (YY1) protein dependent signal from osteosarcoma (SaOS) cells determines proliferation of human aortic endothelial cells (HAECs). Following tumor cell stimuli, HAECs overexpress Cdk2 and Cdk5, display increased Cdk2 activity, undergo enhanced proliferation, and form capillary-like structures. Moreover, Roscovitine, an inhibitor of Cdks, blunted overexpression of Cdk2 and Cdk5 and Cdk2 activity induced by the YY1 dependent signal secreted by SaOS cells. Furthermore, Roscovitine decreased HAEC proliferation and angiogenesis (the latter by 70% in in vitro and 50% in in vivo systems; P < 0.01 vs. control). Finally, the finding that Roscovitine triggers apoptosis in SaOS cells as well as in HAECs by activating caspase-3/7 indicates multiple mechanisms for the potential antitumoral effect of Roscovitine. Present work suggests that Cdk2 and Cdk5 might be pharmacologically accessible targets for both antiangiogenic and antitumor therapy. PMID- 23042367 TI - Enhanced N-terminal degradation of troponin I blunts cardiac function responsiveness to isoproterenol in 4-week tail-suspended rats. AB - The N-terminal extension of cardiac troponin I (cTnI) is important in regulating cardiac function. Although the normal rat myocardium shows some cTnI N-terminal degradation (cTnI-ND), exposure to 4 weeks of tail-suspension markedly increased cTnI-ND. We hypothesized that the increased cTnI-ND in tail-suspended rats may affect cardiac function, particularly during beta-adrenergic (beta-A) stimulation. The increase in cardiac output with isoproterenol (ISO) treatment was smaller in tail-suspended rats compared with controls. Left ventricular end diastolic pressure was elevated and increases in maximal rates of left ventricular pressure development and relaxation were lower during ISO treatment in tail-suspended rats. Response to ISO, forskolin, DB-cAMP and IBMX was also lower in cardiomyocytes from tail-suspended rats. The increase in shortening and re-lengthening the rates of cardiomyocytes at a maximal dose of ISO, forskolin, DB-cAMP and IBMX treatment was limited in tail-suspended rats. There was no difference in Ca2+ sensitivity of the isometric force between tail-suspended and control rats, although Ca2+ sensitivity was decreased less in tail-suspended rats versus control rats during PKA phosphorylation. There was no difference in PKA protein expression and activation during ISO stimulation between the two groups. Due to the increase in cTnI-ND, ISO-induced phosphorylation of cTnI was reduced in tail-suspended rats. The total phospholamban expression and phosphorylation by ISO was unaltered in tail-suspended rat hearts. These data suggest that enhanced cTnI-ND following 4-week tail-suspension is a major component of the beta-A receptor signaling pathway, depressing cardiac function under ISO stimulation. PMID- 23042368 TI - Andropause (androgen deficiency of the aging male): diagnosis and management. AB - Androgen deficiency of the aging male is a pathological syndrome and should not be viewed simply as a stage in physiological aging. It is often overlooked despite evidence for a deleterious impact on many physiological processes and on quality of life. Its identification should be part of the routine practice of physicians in charge of this population, in particular general practitioners and specialists treating associated comorbidities (e.g. metabolic syndrome, diabetes, cardiovascular disorders) or sexual dysfunction. The consultant urologist has a key role to play in prostate surveillance before and during treatment. Treatment is often simple with few side-effects. However, long-term benefits and side effects need to be investigated in prospective studies. PMID- 23042369 TI - Individualizing hormone-therapy according to cardiovascular risk. AB - There is growing consensus that the benefit to risk profile for hormone therapy is high for healthy, low-risk women initiating therapy within 10 years of menopause or under age 60. However, special considerations are needed for women who are outside those boundaries or for those that have risk factors for cardiovascular disease. PMID- 23042370 TI - Prevention of dementia with sex hormones: a focus on testosterone and cognition in women. AB - Many perimenopausal women and their medical service providers have turned away from estrogens to treat their complaints. This mini-review investigated whether women could be prescribed androgens to promote cognitive function and to prevent dementia. Using PubMed and Google Scholar we identified several treatment studies but the majority had included insufficient controls. Tentatively some studies suggested that adding a testosterone to estrogen treatment promoted complex information processing over that of estrogens alone, but methodology of studies limited firm conclusions. While a larger study showed no effects in naturally menopausal women over that of placebo, some studies including only oophorectomized women showed positive effects of testosterone but these had only been carried out up to two months. Safety profiles of long-term androgen treatment, mode and type of treatment require more research. Observational data suggest that in older women who were not selected for optimal health, endogenous testosterone has a negative association with verbal memory, usually one of the first functions to decline in dementia. PMID- 23042371 TI - Adjustments of heart failure medication after implantation of a cardiac resynchronization therapy defibrillator. AB - AIM: "Optimal" medical therapy is mandatory before implantation of a cardiac resynchronization therapy (CRT) device, but "optimal" is not further specified. We determined the number of patients on a specific drug, the percentages of recommended target doses of the drugs the patients were on and their evolution over time. METHODS: Drug therapy (ACE-inhibitors (ACE-I), AT-receptor antagonists (ARBs), betablockers) of 140 patients with a follow-up of at least one year was studied. Response to CRT was defined as reduction in NYHA class >=1. RESULTS: Age was 66+/-9 years, follow-up 43+/-25 months during which 28 patients (20%) had died. At baseline, 81 % of patients were on a betablocker compared to 95% after 3 years (P-value 0.02). Percentages of target doses were 55+/-34% and increased to 68+/-41% after 3 years (P-value <0.02). Percentages were increased in responders (58+/-40% to 72+/-32%, P-value 0.01 after 3 years), but not in non-responders (57+/-31% to 56+/-38%). At baseline, 97% of patients were on ACE-Is/ARBs and 100% after 3 years. Mean percentages of target doses were 78+/-43% at implant and between 73+/-40% and 79+/-49% during follow-up. Percentages were stable both in responders (83% at implant, 78% after 3 years) and in non-responders (80%/87%, both P-value n.s.). CONCLUSION: Even though quantity and quality of drug therapy at baseline was on an acceptable (betablockers) or high (ACE-Is/ARBs) level, physicians must be very observant on therapy during long-term follow-up, especially on target doses of betablockers in non-responders. PMID- 23042372 TI - Circulating resistin is elevated in patients with non-alcoholic fatty liver disease and is associated with steatosis, portal inflammation, insulin resistance and nonalcoholic steatohepatitis scores. AB - AIM: We aimed to investigate the association between serum levels of resistin and the biochemical and histological features of patients with nonalcoholic fatty liver disease (NAFLD) to determine the usefulness of this relationship in the clinical practice. METHODS: A total of 97 patients with NAFLD and 66 age- and sex matched healthy controls were recruited. Detailed epidemiological, anthropometric and laboratory data were recorded. Serum levels of resistin were measured with ELISA. RESULTS: Serum levels of resistin were significantly higher in patients with NAFLD (32.10+/-10.0 ng/mL and 26.57+/-13.60 ng/mL, respectively) compared with healthy controls (P=0.003). Serum resistin levels were associated with AST, ALT, HOMA-IR, histological steatosis, portal inflammation and nonalcoholic steatohepatitis (NASH) scores. The serum levels of resistin were significantly higher in patients with definite NASH compared to patients with simple steatosis (29+/-13 and 20+/-10 ng/mL, respectively, P=0.03). There was no association between the serum resistin levels and the liver fibrosis stages. CONCLUSION: Our data suggest that resistin levels are elevated in patients with NAFLD and could discriminate simple steatosis from definite NASH. PMID- 23042373 TI - [The role of hypomagnesiuria in urolithiasis and renal colic: results from a prospective study of a metabolic evaluation protocola]. AB - AIM: The stone disease of the urinary tract (urolithiasis) is a growing disease. The identification of metabolic disorders, treatable with prophylactic therapy, appears to be clinically important. The aim of this study was the analysis of metabolic disorders that promote and support the urolithiasis in a cohort of patients with renal colic at an Emergency Department. METHODS: In this prospective case series, we enrolled consecutive patients with renal colic treated at an Emergency Department within a Regional Teaching Hospital. We implemented a structured metabolic evaluation, which included blood chemistry studies, stone analysis and a 24-hour urine collection. We then evaluated the frequency of metabolic abnormalities alone or in combination. RESULTS: We enrolled 39 patients whit renal colic and a diagnosis of urolithiasis: 21 (54%) were males and the median age was 43.6 years (range 20-70). The most frequently observed type of stone was that of calcium oxalate (74%). Hypomagnesiuria was the most common metabolic abnormality found at the 24-hour urine collection (22/39, 56%), followed by hypocalciuria (31%), hypernatruria (20%), hyperuricuria (18%) and hyperoxaluria (15%). Among the associations of metabolic abnormalities, the hypocalciuria /hypomagnesuria was that observed with higher frequency (23%). CONCLUSION: We report an incidence of hypomagnesiuria (60%) in patients with renal colic higher than has ever been described in the literature. This result could be of importance in the knowledge of the pathogenesis of the urolithiasis and could have interesting implications in clinical practice. PMID- 23042374 TI - Vitamin D receptor FokI genotype may modify the susceptibility to schizophrenia and bipolar mood disorder by regulation of dopamine D1 receptor gene expression. AB - AIM: This study is designed to test association of FOKI polymorphism in Vitamin D receptor (VDR) gene and its potential effect on expression of dopamine D1 receptor in schizophrenia and bipolar mood disorder as well as in healthy individuals. METHODS: In this case-control study 196 patient with schizophrenia, 119 patients with bipolar mood disorder and 192 healthy individuals as the control group were recruited. All psychiatric disorders were diagnosed according to DSM IV criteria. Healthy control group denied any family history of such disorders. FOKI was genotyped by means of PCR-RFLP method. The mRNA was extracted from the peripheral blood mononuclear cells (PBMC) and the cDNA was synthesized. RESULTS: Frequency of ff genotype was more common in patients with bipolar disorders compared to the healthy control group (Odds ratio=1.84, 95% CI; 0.81 to 4.17) with increased relative risk (Relative risk=1.31, CI 95%; 0.86 to 1.99). There were significant differences between relative expressions of dopamine D1 receptor gene in various genotypes. Our results indicated that the ff genotype was associated with lower expression of dopamine D1 receptor gene. CONCLUSION: VDR as a nuclear receptor may contribute to bipolar disorders via modification of the expression of the neurotransmitters receptor such as dopamine. PMID- 23042375 TI - [Pancreatic hyperenzymemia: new advances in the field of clinical-diagnostic approach, with particular attention about Gullo's syndrome]. AB - An increase in serum levels of pancreatic enzymes is a well-known manifestation of pancreatic disease, especially of inflammatory or neoplastic nature, even if several extrapancreatic diseases can equally cause that increase. In addition to this pathological type of hyperenzymemia, different "non-pathological" forms have also been identified, including macroamylasemia, salivary, and mixed salivary and pancreatic hyperamylasemia, in all of which only amylase elevations are seen. Nevertheless, in 1996 a new syndrome characterized by an abnormal, chronic, benign increase in levels of serum amylase, pancreatic isoamylase, lipase and trypsin, asymptomatic and usually discovered incidentally, was described for the first time by Lucio Gullo et al. Hyperamylasemia/hyperlipasemia's observation is nowadays on the increase because general practitioners tend to include more frequently amylase and lipase in routine blood tests and, moreover, because the constant evaluation of this biochemical alteration in the Emergency Unit: for this reason, this syndrome was clearly identified only recently. Therefore, it's characterized by serum elevation of all pancreatic enzymes in the absence of underlying diseases; it occurs in either sporadic or familial form and it persists over time with considerable fluctuation in serum enzyme concentrations, including frequent normalizations. Proper diagnosis of this form of hyperenzymemia is important because it reassures the subjects having this anomaly that the syndrome is benign, and because it can prevent multiple and expensive diagnostic tests or useless hospitalizations or therapies. PMID- 23042376 TI - Patent foramen ovale and stroke: rethinking the need for systematic transesophageal echocardiography. PMID- 23042377 TI - Diabetes increases mechanical sensitivity and causes morphological abnormalities in the sural nerve that are prevented by treadmill training. AB - INTRODUCTION: In this investigation we evaluated the effects of treadmill training on mechanical sensitivity and sural nerve morphology in diabetic rats. METHODS: Rats were divided into 3 groups: control (C); diabetic (D); and trained diabetic (TD). Training was performed for 8 weeks. Mechanical sensitivity was evaluated using von Frey filaments. Sural nerve analysis included fiber area, diameter, density of myelinated fibers, area occupied by connective tissue, myelin sheath thickness, and g-ratio. RESULTS: Animals in the D group had a reduced mechanical sensitivity threshold. Morphometric study showed that the D group had a smaller myelinated fiber area and diameter, higher density of fibers and area occupied by connective tissue, thinner myelin sheath, and higher g ratio. The D group had a higher percentage of small myelinated fibers and a lower percentage of large-diameter myelinated fibers than the C and TD groups. CONCLUSION: Training prevents functional and morphological abnormalities in the sural nerve caused by diabetes. PMID- 23042378 TI - Overexpression of peroxisome proliferator-activated receptor alpha in pancreatic beta-cells improves glucose tolerance in diet-induced obese mice. AB - Lipotoxicity is implicated in pancreatic beta-cell dysfunction in obesity-induced type 2 diabetes. In vitro, activation of peroxisome proliferator-activated receptor alpha (PPARalpha) has been shown to protect pancreatic beta-cells from the lipotoxic effects of palmitate, thereby preserving insulin secretion. Utilizing an adeno-associated virus (dsAAV8), overexpression of PPARalpha was induced specifically in pancreatic beta-cells of adult, C57Bl/6 mice fed a high fat diet for 20 weeks and carbohydrate metabolism and beta-cell mass assessed. We show that overexpression of PPARalpha in pancreatic beta-cells in vivo preserves beta-cell function in obesity, and this improves glucose tolerance by preserving insulin secretion in comparison to control mice with diet-induced obesity. No changes in beta-cell mass were observed in PPARalpha-overexpressing mice compared with diet-induced obese control animals. This model of beta-cell-specific PPARalpha overexpression provides a useful in vivo model for elucidating the mechanisms underlying beta-cell lipotoxicity in obesity-induced type 2 diabetes. PMID- 23042379 TI - AVE 0991, a non-peptide Mas-receptor agonist, facilitates penile erection. AB - The renin-angiotensin system plays a crucial role in erectile function. It has been shown that elevated levels of angiotensin II contribute to the development of erectile dysfunction both in humans and in aminals. On the contrary, the heptapeptide angiotensin-(1-7) appears to mediate penile erection by activation of the Mas receptor. Recently, we have shown that the erectile function of Mas gene-deleted mice was substantially reduced, which was associated with a marked increase in fibrous tissue in the corpus cavernosum. We have hypothesized that the synthetic non-peptide Mas agonist, AVE 0991, would potentiate penile erectile function. We showed that intracavernosal injection of AVE 0991 potentiated the erectile response of anaesthetized Wistar rats, measured as the ratio between corpus cavernosum pressure and mean arterial pressure, upon electrical stimulation of the major pelvic ganglion. The facilitatory effect of AVE 0991 on erectile function was dose dependent and completely blunted by the nitric oxide synthesis inhibitor, l-NAME. Importantly, concomitant intracavernosal infusion of the specific Mas receptor blocker, A-779, abolished the effect of AVE 0991. We demonstrated that AVE 0991 potentiates the penile erectile response through Mas in an NO-dependent manner. Importantly, these results suggest that Mas agonists, such as AVE 0991, might have significant therapeutic benefits for the treatment of erectile dysfunction. PMID- 23042380 TI - Palladium-catalyzed mono- and double-carbonylation of indoles with amines controllably leading to amides and alpha-ketoamides. AB - A novel and efficient double-carbonylation of indoles with primary or secondary amines to yield indole-3-alpha-ketoamides has been developed and bioactive molecules could be one-pot synthesized using the current methodology, which could also be selectively switched to mono-carbonylation to afford indole-3-amides only by a slight modification of reaction conditions. PMID- 23042381 TI - Rapid anodic formation of high aspect ratio WO3 layers with self-ordered nanochannel geometry and use in photocatalysis. AB - Channel hopping: the formation of WO(3) layers with an aligned nanochannel morphology by using self-organizing anodization of a tungsten metal substrate is demonstrated. The nanochannel layers with diameters of approximately 9 nm can be grown to about 10 MUm thickness. Layers optimized for length and structure are promising for visible-light photocatalytic applications, such as water-splitting photoanodes. PMID- 23042382 TI - [Prenatal diagnosis of fetal urinary abnormalities and microdeletion on chromosome 1q21.1]. AB - OBJECTIVE: To investigate genetic etiology of fetal urinary abnormalities with array-based comparative genomic hycridization(array-CGH). METHODS: Thirty-two fetuses with variable urinary abnormalities but normal karyotyping by conventional cytogenetic technique were selected. DNA from the fetuses and their parents samples were prepared and hybridization with Affymetrix cytogenetic 2.7M arrays by follwing the manufacture's standard protocol. The data were analyzed by special CHAS software packages. RESULTS: By using array-CGH detection, genomic imbalanced copy number variations (CNVs) were identified in night fetuses(28%), four out of night CNVs were inherited from parental samples; two were indicated to be benign variants(6%) in the database; and the other three CNVs (9%) were all de novo adjacent microdeletions and microduplication mapping on to common chromosome 1q21.1 region, within which was genitourinaty system function associated gene PDZK1. CONCLUSION: The incidence of genomic unbalanced variations in fetuses with congenital urinary malformations is approximately 28%, including about 9% pathogenic variations. Copy number variations (CNVs) of chromosome 1q21.1 region are associated with congenital urinary malformations which may be due to haploinsufficiency or overexpression of PDZK1 gene. PMID- 23042383 TI - [Prenatal diagnosis of two fetuses with de novo small supernumerary markers by single nucleotide polymorphism array based comparative genomic hybridization]. AB - OBJECTIVE: To explore the origins of small de novo mosaic supernumerary marker chromosomes (mars) in two fetuses, and to assess the feasibility of single nucleotide polymorphism array-based comparative genomic hybridization (SNP-array CGH) for prenatal molecular cytogenetic diagnosis. METHODS: Two fetuses with de novo were identified. SNP-array marker chromosomes was applied to define the location and range of marker chromosomes. The karyotype of fetus I was determined to be 47,XX,+ mar[23]/46,XX[16], and that of fetus II was 47,XX,+ mar. Multiplex ligation-dependent probe amplification (MLPA) was applied to verify the genomic imbalance found in fetus II. The karyotypes of parents were normal in both families. RESULTS: SNP-array CGH has indicated a 8.3 Mb duplication at 9p21.1 p21.3 in fetus I, and a 10.8 Mb duplication at 15q11.2-q13.3 in fetus II. MLPA has also confirmed a 15q terminal duplication in fetus II. CONCLUSION: Above cases have illustrated that SNP-array CGH is a rapid, powerful and sensitive technique which may be used for identify the origins of marker chromosomes in prenatal diagnosis. PMID- 23042384 TI - [Analysis of an hereditary protein C deficiency pedigree with compound heterozygous gene mutations]. AB - OBJECTIVE: To analyze genetic mutations and explore its molecular pathogenesis for an hereditary protein C (PC) deficiency pedigree. METHODS: The pedigree has included 15 individuals from 4 generations. Plasma levels of PC activity (PC:A), PC antigen (PC:Ag) and other coagulant parameters were determined for members of the family. The 9 exons and intron-exon boundaries of protein C gene (PROC) of the proband were amplified with PCR and analyzed with direct sequencing. Detected mutations were confirmed with reverse sequencing. Corresponding PCR fragments from the family members were also directly sequenced. RESULTS: Plasma PC:A and PC:Ag for the proband was 26% and 18.60%, respectively, both being lower than normal references. Seven members from the pedigree also had lower PC:A, six had lower PC:Ag. A compound heterozygous missense mutation, including a T to G transition at position 6128 of exon 7, which results in Phe139Val, and a G to C transition at position 8478 in exon 9, which results in Asp255His, were identified in the proband. The paternal grandma, father and two aunts were heterozygous for g.6128 T to G, whilst the mother, the second uncle, sister and son were heterozygous for g.8478 G to C. There were lower PC:A in family members with g.8478 G to C. CONCLUSION: The proband had inherited two independent mutations of the PROC gene including g.6128 T to G in exon 7 and g.8478 G to C in exon 9 from her father and mother, respectively. The resulting compound heterozygous mutation has caused a serious hereditary protein C deficiency. PMID- 23042385 TI - [Study on three common mitochondrial DNA mutations in Leber's hereditary optic neuropathy]. AB - OBJECTIVE: To screen for genetic mutations in 35 patients with Leber's hereditary optic neuropathy (LHON). METHODS: Polymerase chain reaction and DNA sequencing were used to screen for the presence of mitochondrial DNA mutations. RESULTS: The total detection rate of top 3 common LHON mutations were 20.0%, which included 6 cases of ND4 11778 G to A, 1 case of ND1 3460 G to A. No ND6 14484 T to C mutation was detected. A ND4 G11719A synonymous mutation was found in all patients. In addition, 21 other mutations were discovered among 23 patients, among which 13 had a single mutation, 8 had a second mutations, and 2 had a third mutation. Among the 21 mutations, ND4 11778 G to A had a frequency of 28.6%(6/21). ND1 3552 T to A, ND6 14470 T to C, ND4 11794 T to C, ND1 3497 C to T and 3644 T to C respectively had a frequency of 19.0% (4/21), 19.0%(4/21), 14.3%(3/21), 9.5%(2/21) and 9.5%(2/21). Among the 3 patients who harbored a ND4 11794 T to C mutation, 2 were heteroplasmic and one was homoplasmic in nature. CONCLUSION: The ND4 11778 G to A mutation is common in the Top "3" primary mutations of patients with LHON. Candidate LHON mutation ND1 3552 T to A or ND1 3644 T to C resulted in LHON pathogenesis as single or synergistic effect. The visual impairment at onset of the disease with candidate mutation were better than the eyes with the ND4 11778 G to A mutation. PMID- 23042386 TI - [Phenotype and genotype analysis of two Chinese pedigrees with type 3 von Willebrand diseases]. AB - OBJECTIVE: To analyze the phenotype and genotype of two Chinese pedigrees with von Willebrand diseases, and to investigate the molecular pathogenesis. METHODS: Bleeding time (BT), activated partial thromboplastin time (APTT), ristocetin induced platelet aggregation (RIPA), von Willebrand factor-ristocetin cofactor (vWF:Rco), von Willebrand factor antigen (vWF:Ag), von Willebrand factor activity (vWF:A), von Willebrand factor collagen binding assay (vWF:CB) and multimer analysis were used for phenotype diagnosis. DNA was extracted. All of the 52 exons and exon-intron bounda ries of the VWF gene were amplified with polymerase chain reaction(PCR) and analyzed by direct sequencing. RESULTS: APTT and BT were prolonged. Plasma RIPA, vWF:Rco, vWF:Ag, vWF:A and vWF:CB was significantly decreased. No VWF multimer can be found by plasma VWF multimer analysis. Homozygous insertional mutation g.82888_82889insCATG in exon 17 was found in proband A. Compound heterozygous mutations g.94865 G to A (Trp856stop) in exon 20 and g.110698_110699delinsG in exon 28 were found in proband B. CONCLUSION: Homozygous insertional mutation g.82888_82889insCATG and compound heterozygous mutations g.94865G to A(Trp856X) and g.110698_110699delinsG probably have respectively induced type 3 von Willebrand diseases in the two probands. PMID- 23042387 TI - [Identification of a mosaic mutation of NF1 gene in a sporadic case of neurofibromatosis type 1]. AB - OBJECTIVE: To detect NF1 gene mutation in a patient with neurofibromatosis type 1. METHODS: Five fragments encompassing the entire coding sequence of the NF1 gene were amplified with reverse transcription PCR. PCR products were directly sequenced. Suspected mutations were verified by sequencing of DNA amplified by PCR using genomic DNA as template. Corresponding exon of family members was also sequenced. Furthermore, the PCR products were inserted into a pGEM-T cloning vector to quantify cells carrying the mutation in different samples derived from the three embryonic layers. RESULTS: The proband's clinical manifestation was consistent with neurofibromatosis type 1. Sequence analysis has identified a novel heterozygous mutation c.7911 C to T (p.Q2510X) in exon 51 of the NF1 gene in the proband. The same mutation was also detected in peripheral blood cells, uroepithelial cells and oral mucosal cells of the proband, though the signals of uroepithelial cells were significantly weaker. By T cloning-sequencing, recombinants carrying the NF1 gene mutation respectively accounted for 42%, 36% and 12% of all peripheral blood cells, oral mucosal cells and uroepithelial cells . CONCLUSION: It is likely that a mutation of NF1 gene has occurred in early embryogenesis of the proband, which in turn has led to generalized mosaicism of neurofibromatosis type 1. PMID- 23042388 TI - [The role of Smad ubiquitination regulatory factor 1 in hepatocellular carcinoma]. AB - OBJECTIVE: To determine the expression level of Smad ubiquitination regulatory factor 1 (SMURF1) gene in hepatocellular carcinoma, and to explore its role in liver cancer. METHODS: With non-neoplastic adjacent normal tissues as controls, real-time PCR and Western blotting were used for measuring the expression of SMURF1 mRNA and protein in 89 samples of hepatocellular carcinoma. Correlations between SMURF1 expression and clinical features were explored. Following transfection of SMURF1--specific small interference RNA(siRNA), the apoptosis and proliferation of hepatic cancer cells Hep G2 were detected using flow cytometry and MTT assays . RESULTS: The expression of SMURF1 mRNA and protein were significantly higher in hepatocellular cancer tissues compared with the paired normal tissues (P< 0.05). The expression of SMURF1 however did not correlate with any clinical features (P> 0.05). Transfection of SMURF1-specific siRNA can promote the apoptosis whilst inhibit the proliferation of Hep G2 cells. CONCLUSION: The expression of SMURF1 is enhanced in hepatocellular carcinoma, which may have played a role in the disease through affecting apoptosis and proliferation of hepatic cancer cells. PMID- 23042389 TI - [Mechanism of GLI3 gene transcription regulation in idiopathic congenital talipes equinovarus]. AB - OBJECTIVE: To investigate the mechanism of transcription regulation of GLI3 gene in idiopathic congenital talipes equinovarus. METHODS: pGL3-Gli3 luciferase report vectors were constructed, and the activity of Gli3 promoter was explored. A P-Match software was used to analyze the sequence upstream of the transcription start site of rat Gli3 gene, which was subsequently verified with chromatin immunoprecipitation assay (CHIP) and electrophoretic mobility shift assay (EMSA). Expression of the Gli3 gene was analyzed in L6 cells transfected with Hoxd13 small interference RNA(siRNA) and Hoxd13 expression vectors. RESULTS: The 5' region of rat Gli3 gene contains two potential binding sites for the Hoxd13 protein. CHIP and EMSA assays both confirmed that Hoxd13 can directly bind with site 2. As shown in L6 cells, expression of Gli3 may be enhanced with silencing of Hoxd13, whilst exogenous expression of Hoxd13 can down-regulate transcription of Gli3. CONCLUSION: Hoxd13 can directly regulate the expression of Gli3 gene through a Hoxd13 binding site in the limb of rat embryo. PMID- 23042390 TI - [Establishment of a large-scale bi-directional sequencing and genotyping platform for MICA gene exons 2 to 4]. AB - OBJECTIVE: To establish a stable and large-scale bi-directional sequencing platform for genotyping MICA gene exons 2 to 4, and to analyze single nucleotide polymorphisms(SNP) of the region. METHODS: Primers for particular alleles of MICA gene exons 2 to 5 were designed. Optimal conditions for PCR amplification and sequencing reaction were explored. A commercialized one-way sequencing kit for MICA allele was used as a parallel control. Four samples carrying a MICA *010 allele were subjected to cloning and haplotype sequencing. RESULTS: Results of MICA allele typing of 100 samples for a parallel control group were confirmed by the establish method. Twenty-two SNP in MICA gene exons 2 to 4 were detected in Chinese population. Two novel allelic sequences were accepted by GenBank and IMGT/HLA database and officially named as MICA*065 and MICA*066 by the WHO Nomenclature Committee. A novel SNP in MICA gene intron 3 was discovered, with allelic sequence submitted to GenBank and IMGT/HLA database. CONCLUSION: The bi directional sequencing genotyping platform may be applied for large-scale study of MICA allelic polymorphisms, tissue typing, organ transplantation and disease research. PMID- 23042391 TI - [Construction and application of a multiplex PCR system for genotyping of human red blood cell antigens]. AB - OBJECTIVE: A reliable method for genotyping blood group antigens Dib, k, Jsb1910 and Jsb2019 was developed. Through screening for rare blood types, the National Rare Blood Bank of China may be enriched. METHODS: The controls for allele detection of blood groups Dib, k, Jsb1910 and Jsb2019 were prepared via polymerase chain reaction (PCR)-mediated gene site-directed mutagenesis (SDM) technique. Sequence-specific primers were designed according to known single nucleotide polymorphism (SNP) sites of alleles of blood groups antigens Dib, k, Jsb1910 and Jsb2019, a multiplex PCR system was developed by optimizing PCR reaction system. And 4190 random healthy donors samples were screened for the blood group antigens. RESULTS: Using SDM technique, controls for alleles in blood group Dib, k, Jsb1910 and Jsb2019 were successfully generated. And a multiplex PCR system for genotyping above blood groups was developed. After verification, the system has performed with good stability and reproducibility. Two Di (b-) samples have been discovered from 4190 samples, no k- and Js(b-) sample was found. CONCLUSION: Multiplex PCR features rapid detection, high throughput and low cost, and can be used for screening for donors of rare blood types. Information of donors may be registered in a database, which in turn can help those with rare blood types or require long-term blood transfusion to obtain matched blood, thereby reduce the adverse reactions of blood transfusion. PMID- 23042392 TI - [Classification and molecular diagnostic procedure for Chacort-Marie-Tooth disease]. AB - Charcot-Marie-Tooth disease (CMT) is the most common form of hereditary neuropathy with significant clinical and genetic heterogeneity. So far 28 genes have been cloned. The main clinical manifestations of CMT include progressive distal muscle wasting and weakness, impaired distal sensation, and diminishing or loss of tendon reflex. Patients may be classified into demyelinating type (CMT1) and axonal type (CMT2) according to electrophysiological and pathological characteristics. Establishment of a standard diagnostic procedure based on clinical, electrophysiological and pathological findings will enable accurate diagnosis in most CMT patients and provide guidance for gene consulting and prognosis. PMID- 23042393 TI - [Strategies for exome sequence data analysis for discovering genes underlying autosomal recessive disorders]. AB - Introduced in 2009, whole-exome sequencing (WES) is a technology in which target capture methods are used to enrich sequences of coding regions of genes from fragmented total genomic DNA, which is followed by high-throughput sequencing of the captured fragments. As reported, WES has been successfully applied for discovering genes underlying several Mendelian diseases, especially autosomal recessive types. In this review, authors have summarized the main computational strategies which have been applied to identify novel autosomal recessive diseases genes using whole-exome data. PMID- 23042394 TI - [Combined spectral karyotyping and microarray-based comparative genomic hybridization for the diagnosis of a case with ring chromosome 15]. AB - OBJECTIVE: To assess the value of spectral karyotyping (SKY) combined with microarray-based comparative genomic hybridization (array-CGH) for the diagnosis of complex ring chromosome aberration. METHODS: For an 8-year-old boy featuring growth retardation, G-banding analysis has indicated a 46,XY,r(15)? karyotype, which was delineated by SKY in combination with array-CGH. RESULTS: The ring chromosome has originated from chromosome 15 according to SKY analysis. Position of the breakpoint (15q26.3) and a 594 kb deletion were revealed by array-CGH. CONCLUSION: Molecular cytogenetic technologies are efficient tools for clarifying complex chromosomal abnormality, which has provided a powerful tool for conventional cytogenetic analysis. PMID- 23042395 TI - [Study on a novel mutation of B glycosyltransferase gene related with an ABx variant]. AB - OBJECTIVE: To explore the molecular basis of an individual featuring an ABx variant of ABO blood group system. METHODS: Serological assays were used to characterize the erythrocyte phenotypes and salivary ABH secretors. All of the seven exons and flanking introns of ABO glycosyltransferase gene were amplified with polymerase chain reaction (PCR). And the products were sequenced bidirectionally following enzyme digestion. Exons 6 and 7 were also subcloned and analyzed for haplotypes of the ABO gene. RESULTS: Erythrocytes of the proband have expressed a strong A antigen and a weak B antigen, which was identified as a rare ABx variant in addition with other serological features. Nine heterozygous sites in exon 6 (297A/G) and exon 7 (467C/T, 526C/G, 657C/T, 703G/A, 796C/A, 803G/C, 808T/A, 930G/A) of the coding region of the ABO gene were identified. Based on haplotype analysis, one allele was determined as common A102, whilst another was consistent with B101 except for an 808T>A mutation which has resulted in replacement of phenylalanine with isoleucine at position 270 of glycosyltransferase B. CONCLUSION: The 808T>A mutation of the glycosyltransferase B gene may decrease the enzymatic activity and result in the Bx variant. PMID- 23042396 TI - [Association study between age-related macular degeneration and R1210C mutation of CFH gene in Chinese population]. AB - OBJECTIVE: A R1210C mutation of complement factor H (CFH) gene has been associated with age-related macular degeneration (AMD) in Caucasian population. This study was to verify above association in Han Chinese population. METHODS: The mutation was detected by direct sequencing in 258 patients with wet AMD and 426 matched controls. RESULTS: The R1210C mutation has not been identified in either sample. CONCLUSION: The R1210C mutation in CFH gene is not associated with AMD in Han Chinese population. PMID- 23042397 TI - [SRY gene analysis for a case with sex reversal syndrome]. AB - OBJECTIVE: To investigate the molecular mechanism of sex reversal in a 46,XY female patient. METHODS: Clinical data was collected. Peripheral blood lymphocytes were cultured for G-banding chromosomal analysis and DNA extraction. Sex-determining region of Y-chromosome (SRY) gene was analyzed with polymerase chain reaction (PCR) and DNA sequencing . RESULTS: Although the patient has a female appearance, he has a karyotype of 46,XY. The SRY gene can be detected in all samples. The 6th base of SRY gene coding region was deleted, resulting in a frameshifting mutation and premature termination of protein translation. CONCLUSION: The sex reversal of the patient is probably due to abnormal embryonic development caused by the SRY gene mutation. PMID- 23042398 TI - [Correlation of BCL-6, MYC and p53 gene abnormalities with immunological subtypes and prognosis of diffuse large B-cell lymphoma]. AB - OBJECTIVE: To investigate BCL-6, MYC and p53 genes abnormalities in diffuse large B-cell lymphoma (DLBCL) and correlate the result with immunosubtypes and prognosis. METHODS: Interphase fluorescence in situ hybridization (I-FISH) was performed to detect the BCL-6, MYC and p53 genes. Immunohistochemistry (Envision method) was used to measure the expressions of CD3, CD10, CD20, BCL-6, MUM -1, BCL-2 and Ki-67 genes in DLBCL. The patients were classified into germinal center B cell-like (GCB) and non-GCB subtypes according to Hans' algorithm. RESULTS: BCL 6 rearrangement was detected in 10 of 46 DLBCL cases. The presence of gene rearrangement had no correlation with BCL-6 protein expression (P= 0.245). Overall survival (OS, P= 0.138) and progression-free survival (PFS, P= 0.095) were not influenced by BCL-6 rearrangement. All MYC rearrangements were detected in GCB type DLBCL. Deletion of p53 gene was detected in 14 cases and was significantly associated with shorter OS (P= 0.046) and PFS (P= 0.043). CONCLUSION: I-FISH is a rapid, accurate and sensitive method for detecting BCL-6, MYC and p53 abnormalities. No correlation was found between BCL-6 gene rearrangement and BCL-6 protein expression. MYC translocation was more common in GCB type DLBCL compared with non-GCB type ones. Patients with p53 deletion had a poorer prognosis. The p53 gene may provide a useful indicator for the prognosis of DLBCL. PMID- 23042399 TI - [Correlation between JAK2-V617F mutations and variation of peripheral blood cells among BCR/ABL-negative MPD patients]. AB - OBJECTIVE: To assess the correlation between JAK2-V617F mutation and complete blood counts among patients with BCR/ABL-negative myeloproliferative diseases (MPD). METHODS: One hundred and ninety one patients were recruited. Retrospectively, their laboratory data were analyzed for the counts of red blood cells (RBC), white blood cells (WBC) and platelets (PLT). And the incidence of JAK2-V617F mutation was determined. RESULTS: There was significant difference in the incidence of JAK2-V617F mutation between patients with different cell counts (P< 0.01). The incidence of JAK2-V617F mutation has increased with the counts of RBC and PLT, which was the highest (92.86%) among those featuring simultaneous increase in all three series. CONCLUSION: The incidence of JAK2-V617F mutation seems to be strongly associated with variation of peripheral blood cell counts among patients with BCR/ABL-negative MPD. Variation of peripheral blood cells, particularly RBC, may be correlated with the rate of JAK2-V617F mutation. PMID- 23042400 TI - [Establishment and application of median serum markers for second trimester screening in Qingdao region]. AB - OBJECTIVE: To establish the median of serum markers for second trimester screening in Qingdao region and to assess the influence of median correction on the performance of screening. METHODS: Maternal serum alpha-fetoproteins (AFP), human chorionic gonadotrophin, free beta subunit (beta -HCG) and unconjugated oestriol (uE3) were assayed for prenatal screening of 18 188 singleton pregnancies at 15-20(+ 6) weeks gestation from January 2009 to July 2010. The median of serum markers was calculated based on above results and applied for risk estimation in screening for fetal aneuploidy from August 2010 to March 2011. The screening performance, specified in terms of detection rates (DRs), false positive rates (FPRs) and odds of being affected given a positive result (OAPR) were compared between the two groups. The risks of 45 affected pregnancies detected during the study were estimated with both Caucasian and corrected medians. RESULTS: The average level of AFP in local pregnancies was similar to that of the Caucasian population, whilst beta -HCG and uE3 were respectively 11% and 33% higher than those of Caucasians. The multiple of median (MoM) value was between 0.94 and 1.02 for the dataset based on the corrected median. At a cut-off of l in 270, FPR has decreased from 5.2% to 4.9%, and DR of Down syndrome has increased from 60% to 69.2%, and OAPR has increased from 1:79 to 1:59 when evaluating risk based on the corrected median. For the 45 affected pregnancies, three Down syndrome pregnancies could be missed because their risk estimates were lower than the cut-off level based on Caucasian median. CONCLUSION: It is useful to establish and apply population and laboratory-specific medians in order to improve the performance of prenatal screening and diagnosis. PMID- 23042401 TI - [Association between various rs501120 genotypes and progress of unstable coronary atherosclerotic plaque in diabetes mellitus complicated with acute coronary syndrome]. AB - OBJECTIVE: To assess the association between single nucleotide polymorphism rs501120 and progress of unstable coronary atherosclerotic plaque in diabetes mellitus complicated with acute coronary syndrome (ACS). METHODS: Nine hundred and two patients with diabetes complicated with acute coronary syndrome were enrolled. The genotype of rs501120 was determined with TaqMan-MGB probes. Two hundred and five cases of TT genotype, 205 age-and sex-frequency-matched cases of TC genotype and 205 age- and sex-frequency-matched cases of CC genotype were chosen and followed up for 3 years. Clinical data and re-occurrences of ACS were recorded. RESULTS: Patients with TT genotype had a significantly higher incidence of recurrence of ACS than those with CC genotype (TT vs. CC: OR 1.7, 95%CI 1.1 2.7, P= 0.02). And the significance has remained even after adjusting for conventional risk factors by logistic regression (OR 1.6, 95% CI1.05-3.6, P= 0.03). Patients with TT genotype had a significantly higher incidence of myocardial infarction than those with CC genotype(TT vs. CC: OR 1.9, 95% CI 1.2 3.2, P= 0.007). CONCLUSION: Our results has suggested an association between the rs501120 polymorphism and progress of unstable coronary atherosclerotic plaque. PMID- 23042402 TI - [Association between SUMO4 polymorphisms and coronary artery disease with and without type 2 diabetes mellitus]. AB - OBJECTIVE: To assess the role of small ubiquitin-like modifier 4 (SUMO4) gene polymorphisms (rs237025, rs237024 and rs600739) in the susceptibility to coronary artery disease (CAD) with and without type 2 diabetes mellitus (T2DM) in Chinese Han ethnic population in Beijing. METHODS: In this case-control study, 558 subjects with angiography-proven CAD were divided into two groups according to the WHO 1999 criteria: 369 with normal glucose tolerance (CAD group) and 189 with T2DM (T2DM+ CAD group). Meanwhile 500 healthy subjects free of T2DM and CAD were selected as normal controls (control group). Allelic and genotypic distributions of the three single nucleotide polymorphisms (SNPs) were determined with polymerase chain reaction-high resolution melting curve (PCR-HRM) and gene sequencing. Clinical and biochemical data were compared among carriers of different genotypes through a stratified analysis. RESULTS: No significant difference was found in the distribution of genotypes and alleles of each SNP between different groups (P> 0.05). Nevertheless, stratified analysis indicated a significant difference in plasma triglycerides (rs237025) and body mass index (rs600739) among individuals of different genotypes from the T2DM+ CAD group (P= 0.020 and P= 0.049, respectively). Multiple comparison also indicated that GG genotype of rs237025 had a higher level of plasma triglycerides than AA genotype (P< 0.01). CONCLUSION: No association between SUMO4 gene polymorphisms and CAD with and without T2DM was detected. Such polymorphisms may not be a risk factor for Chinese Han ethnic patients in Beijing. PMID- 23042403 TI - [Correlation of recurrent pregnancy loss with sperm parameters and sperm DNA fragmentation]. AB - OBJECTIVE: To evaluate and compare standard sperm parameters and sperm DNA fragmentation in seminal ejaculates from men whose partners had a history of recurrent pregnancy loss (RPL) and a control group of men who had recently established their fertility. METHODS: Semen samples from 85 patients with a history of RPL and 20 men with proven fertility were analyzed according to World Health Organization guidelines. Sperm DNA fragmentation was detected by sperm chromatin dispersion test (SCD). RESULTS: A significant difference (P< 0.05) was observed in sperm motility but not other parameters between the two groups. The mean number of sperm cells with fragmented DNA, represented as DNA fragmentation index, was significantly increased in the RPL group [(34.99+/- 14.62)%] compared with controls [(10.82+/- 4.80)%]. CONCLUSION: This study has indicated that sperm from men with a history of RPL have a higher incidence of DNA damage and poor motility compared with fertile males. PMID- 23042404 TI - [Hereditary multiple exostoses: a pedigree with ten cases]. PMID- 23042405 TI - [A pedigree of split hand/split foot malformation]. PMID- 23042406 TI - In vitro selection of sialic acid specific RNA aptamer and its application to the rapid sensing of sialic acid modified sugars. AB - Sialic acids (SAs) are located on the terminal positions of glycan on a cell surface, which play important role in the spread and metastasis of cancer cells and infection of pathogen. For their detection and diagnosis, the finding of SA specific ligand is an essential prerequisite. Here, RNA aptamer for N acetylneuraminic acid (Neu5Ac), a representative of SAs, with the high affinity of 1.35 nM and the selectivity was screened by in vitro selection method. The strong binding of the screened aptamer was enough to protect the hydrolysis of Neu5Ac by neuraminidase with the stoichiometry of 1:1 molar ratio. For the rapid detection of SAs, the RNA aptamer was further engineered to the aptazyme sensor by conjugating with a ribozyme following the characterization of selected aptamer by RNase footprinting assay. Without additional desialylation, modification, or/and purification processes, the aptazyme indicated high catalytic activities in the presence of Neu5Ac over 20 uM in several minutes. Also, we observed that the aptazyme sensor shows high sensitivities to Neu5Ac-conjugated sugars as well as Neu5Ac monomer, but not in non-Neu5Ac modified sugars. The aptamer for Neu5Ac can support valuable tools in a wide range of bioanalytical applications as well as biosensors. PMID- 23042408 TI - Conjugate hydrotrifluoromethylation of alpha,beta-unsaturated acyl oxazolidinones: synthesis of chiral fluorinated amino acids. AB - A novel conjugate hydrofluoroalkylation of alpha,beta-unsaturated acyl oxazolidinones is described. Using this method, enantiomerically pure beta trifluoromethylated amino acids were prepared. Trifluorovaline and trifluoroisoleucine were incorporated into peptides and found to show extremely low alpha-helix propensities. PMID- 23042407 TI - Neuropeptide Y-immunoreactive neurons in the cerebral cortex of humans and other haplorrhine primates. AB - We examined the distribution of neurons immunoreactive for neuropeptide Y (NPY) in the posterior part of the superior temporal cortex (Brodmann's area 22 or area Tpt) of humans and nonhuman haplorrhine primates. NPY has been implicated in learning and memory and the density of NPY-expressing cortical neurons and axons is reduced in depression, bipolar disorder, schizophrenia, and Alzheimer's disease. Due to the role that NPY plays in both cognition and neurodegenerative diseases, we tested the hypothesis that the density of cortical and interstitial neurons expressing NPY was increased in humans relative to other primate species. The study sample included great apes (chimpanzee and gorilla), Old World monkeys (pigtailed macaque, moor macaque, and baboon) and New World monkeys (squirrel monkey and capuchin). Stereologic methods were used to estimate the density of NPY-immunoreactive (-ir) neurons in layers I-VI of area Tpt and the subjacent white matter. Adjacent Nissl-stained sections were used to calculate local densities of all neurons. The ratio of NPY-ir neurons to total neurons within area Tpt and the total density of NPY-ir neurons within the white matter were compared among species. Overall, NPY-ir neurons represented only an average of 0.006% of the total neuron population. While there were significant differences among species, phylogenetic trends in NPY-ir neuron distributions were not observed and humans did not differ from other primates. However, variation among species warrants further investigation into the distribution of this neuromodulator system. PMID- 23042410 TI - Mechanosynthesis of nanocrystalline fayalite, Fe2SiO4. AB - Nanostructured fayalite (alpha-Fe(2)SiO(4)) with a large volume fraction of interfaces is synthesized for the first time via single-step mechanosynthesis, starting from a 2alpha-Fe(2)O(3) + 2Fe + 3SiO(2) mixture. The nonequilibrium state of the as-prepared silicate is characterized by the presence of deformed polyhedra in the interface/surface regions of nanoparticles. PMID- 23042409 TI - Ephrin-B2 reverse signaling is required for topography but not pattern formation of lateral superior olivary inputs to the inferior colliculus. AB - Graded and modular expressions of Eph-ephrins are known to provide positional information for the formation of topographic maps and patterning in the developing nervous system. Previously we have shown that ephrin-B2 is expressed in a continuous gradient across the tonotopic axis of the central nucleus of the inferior colliculus (CNIC), whereas patterns are discontinuous and modular in the lateral cortex of the IC (LCIC). The present study explores the involvement of ephrin-B2 signaling in the development of projections to the CNIC and LCIC arising from the lateral superior olivary nuclei (LSO) prior to hearing onset. Anterograde and retrograde fluorescent tracing methods in neonatal fixed tissue preparations were used to compare topographic mapping and the establishment of LSO layers/modules in wild-type and ephrin-B2(lacZ/+) mice (severely compromised reverse signaling). At birth, pioneer LSO axons occupy the ipsilateral IC in both groups but are delayed contralaterally in ephrin-B2(lacZ/+) mutants. By the onset of hearing, both wild-type and mutant projections form discernible layers bilaterally in the CNIC and modular arrangements within the ipsilateral LCIC. In contrast, ephrin-B2(lacZ/+) mice lack a reliable topography in LSO-IC projections, suggesting that fully functional ephrin-B2 reverse signaling is required for normal projection mapping. Taken together, these ephrin-B2 findings paired with known coexpression of EphA4 suggest the importance of these signaling proteins in establishing functional auditory circuits prior to experience. PMID- 23042411 TI - Targeting and delivery of platinum-based anticancer drugs. AB - Platinum-based anticancer drugs occupy a crucial role in the treatment of various malignant tumours. However, the efficacy and applicability of platinum drugs are heavily restricted by severe systemic toxicities and drug resistance. Different drug targeting and delivery (DTD) strategies have been developed to prevent the shortcomings of platinum-based chemotherapy. These approaches can be roughly categorized into two groups; namely, active and passive tactics. Active DTD is realized through specific molecular interactions between the drugs and cell or tissue elements, while passive DTD is achieved by exploiting the enhanced permeability and retention effect in tumour tissues. The principal methods for active DTD include conjugation of platinum drugs with selective targeting moieties or encapsulation of platinum drugs in host molecules. Bioactive substances such as hormones, carbohydrates, bisphosphonates, peptides and proteins are commonly used in active DTD. Passive DTD generally involves the fabrication of functionalized polymers or nanoparticles and the subsequent conjugation of platinum drugs with such entities. Polymeric micelles, liposomes, nanotubes and nanoparticles are frequently used in passive DTD. In some cases, both active and passive mechanisms are involved in one DTD system. This review concentrates on various targeting and delivery techniques for improving the efficacy and reducing the side effects of platinum-based anticancer drugs. The content covers most of the related literatures published since 2006. These innovative tactics represent current state-of-the-art developments in platinum based anticancer drugs. PMID- 23042412 TI - A dominant negative Cx43 mutant differentially affects tumorigenic and invasive properties in human metastatic melanoma cells. AB - Previous reports have implicated connexin 43 (Cx43) as a tumor suppressor in early stages of tumorigenesis and in some cases as an enhancer of cell migration in later stages. To address the role of Cx43 in melanoma tumor progression, we utilized two melanoma cell lines derived from the same patient in pre-metastasis (WM793B) and following isolation from a lung metastasis in nude mice (1205Lu). Our results demonstrate a strikingly increased expression of Cx43 in both the pre metastatic and metastatic melanoma cell lines that were actively migrating compared to non-migrating cells. To further investigate the role of Cx43 in these melanoma cells, we overexpressed wild type (wt) Cx43 as well as a mutant dominant negative Cx43 mutant that causes closed channels (T154A). The metastatic 1205Lu cells expressing Cx43-T154A showed a twofold decrease in colony formation on soft agar while the nonmetastatic WM793B cells showed no significant change. In invasion assays through a collagen matrix, the same Cx43-T154A 1205Lu cells demonstrated a three- to fourfold increase in the invasion index compared to either wt Cx43 or vector control cells. The increase in invasiveness was eliminated by migration towards media with charcoal-stripped serum, suggesting that migration may be directed towards a lipophilic compound(s). Our findings demonstrate that a dominant negative Cx43 mutant deficient in channel formation exhibits a dual pattern of regulation in metastatic melanoma cells with a decrease in anchorage-independent growth and an increase in invasive potential. PMID- 23042414 TI - Quantum critical state in a magnetic quasicrystal. AB - Quasicrystals are metallic alloys that possess long-range, aperiodic structures with diffraction symmetries forbidden to conventional crystals. Since the discovery of quasicrystals by Schechtman et al. in 1984, there has been considerable progress in resolving their geometric structure. For example, it is well known that the golden ratio of mathematics and art occurs over and over again in their crystal structure. However, the characteristic properties of the electronic states--whether they are extended as in periodic crystals or localized as in amorphous materials--are still unresolved. Here we report the first observation of quantum (T = 0) critical phenomena of the Au-Al-Yb quasicrystal- the magnetic susceptibility and the electronic specific heat coefficient arising from strongly correlated 4f electrons of the Yb atoms diverge as T->0. Furthermore, we observe that this quantum critical phenomenon is robust against hydrostatic pressure. By contrast, there is no such divergence in a crystalline approximant, a phase whose composition is close to that of the quasicrystal and whose unit cell has atomic decorations (that is, icosahedral clusters of atoms) that look like the quasicrystal. These results clearly indicate that the quantum criticality is associated with the unique electronic state of the quasicrystal, that is, a spatially confined critical state. Finally we discuss the possibility that there is a general law underlying the conventional crystals and the quasicrystals. PMID- 23042413 TI - Engineering the surface structure of MoS2 to preferentially expose active edge sites for electrocatalysis. AB - Controlling surface structure at the atomic scale is paramount to developing effective catalysts. For example, the edge sites of MoS(2) are highly catalytically active and are thus preferred at the catalyst surface over MoS(2) basal planes, which are inert. However, thermodynamics favours the presence of the basal plane, limiting the number of active sites at the surface. Herein, we engineer the surface structure of MoS(2) to preferentially expose edge sites to effect improved catalysis by successfully synthesizing contiguous large-area thin films of a highly ordered double-gyroid MoS(2) bicontinuous network with nanoscaled pores. The high surface curvature of this catalyst mesostructure exposes a large fraction of edge sites, which, along with its high surface area, leads to excellent activity for electrocatalytic hydrogen evolution. This work elucidates how morphological control of materials at the nanoscale can significantly impact the surface structure at the atomic scale, enabling new opportunities for enhancing surface properties for catalysis and other important technological applications. PMID- 23042415 TI - Nanostructured high-energy cathode materials for advanced lithium batteries. AB - Nickel-rich layered lithium transition-metal oxides, LiNi(1-x)M(x)O(2) (M = transition metal), have been under intense investigation as high-energy cathode materials for rechargeable lithium batteries because of their high specific capacity and relatively low cost. However, the commercial deployment of nickel rich oxides has been severely hindered by their intrinsic poor thermal stability at the fully charged state and insufficient cycle life, especially at elevated temperatures. Here, we report a nickel-rich lithium transition-metal oxide with a very high capacity (215 mA h g(-1)), where the nickel concentration decreases linearly whereas the manganese concentration increases linearly from the centre to the outer layer of each particle. Using this nano-functional full-gradient approach, we are able to harness the high energy density of the nickel-rich core and the high thermal stability and long life of the manganese-rich outer layers. Moreover, the micrometre-size secondary particles of this cathode material are composed of aligned needle-like nanosize primary particles, resulting in a high rate capability. The experimental results suggest that this nano-functional full gradient cathode material is promising for applications that require high energy, long calendar life and excellent abuse tolerance such as electric vehicles. PMID- 23042416 TI - Photon management in two-dimensional disordered media. AB - Elaborating reliable and versatile strategies for efficient light coupling between free space and thin films is of crucial importance for new technologies in energy efficiency. Nanostructured materials have opened unprecedented opportunities for light management, notably in thin-film solar cells. Efficient coherent light trapping has been accomplished through the careful design of plasmonic nanoparticles and gratings, resonant dielectric particles and photonic crystals. Alternative approaches have used randomly textured surfaces as strong light diffusers to benefit from their broadband and wide-angle properties. Here, we propose a new strategy for photon management in thin films that combines both advantages of an efficient trapping due to coherent optical effects and broadband/wide-angle properties due to disorder. Our approach consists of the excitation of electromagnetic modes formed by multiple light scattering and wave interference in two-dimensional random media. We show, by numerical calculations, that the spectral and angular responses of thin films containing disordered photonic patterns are intimately related to the in-plane light transport process and can be tuned through structural correlations. Our findings, which are applicable to all waves, are particularly suited for improving the absorption efficiency of thin-film solar cells and can provide a new approach for high extraction-efficiency light-emitting diodes. PMID- 23042417 TI - A magnetic switch for the control of cell death signalling in in vitro and in vivo systems. AB - The regulation of cellular activities in a controlled manner is one of the most challenging issues in fields ranging from cell biology to biomedicine. Nanoparticles have the potential of becoming useful tools for controlling cell signalling pathways in a space and time selective fashion. Here, we have developed magnetic nanoparticles that turn on apoptosis cell signalling by using a magnetic field in a remote and non-invasive manner. The magnetic switch consists of zinc-doped iron oxide magnetic nanoparticles (Zn(0.4)Fe(2.6)O(4)), conjugated with a targeting antibody for death receptor 4 (DR4) of DLD-1 colon cancer cells. The magnetic switch, in its On mode when a magnetic field is applied to aggregate magnetic nanoparticle-bound DR4s, promotes apoptosis signalling pathways. We have also demonstrated that the magnetic switch is operable at the micrometre scale and that it can be applied in an in vivo system where apoptotic morphological changes of zebrafish are successfully induced. PMID- 23042418 TI - Regulatory mechanism of the light-activable allosteric switch LOV-TAP for the control of DNA binding: a computer simulation study. AB - The spatio-temporal control of gene expression is fundamental to elucidate cell proliferation and deregulation phenomena in living systems. Novel approaches based on light-sensitive multiprotein complexes have recently been devised, showing promising perspectives for the noninvasive and reversible modulation of the DNA-transcriptional activity in vivo. This has lately been demonstrated in a striking way through the generation of the artificial protein construct light oxygen-voltage (LOV)-tryptophan-activated protein (TAP), in which the LOV-2 Jalpha photoswitch of phototropin1 from Avena sativa (AsLOV2-Jalpha) has been ligated to the tryptophan-repressor (TrpR) protein from Escherichia coli. Although tremendous progress has been achieved on the generation of such protein constructs, a detailed understanding of their functioning as opto-genetical tools is still in its infancy. Here, we elucidate the early stages of the light-induced regulatory mechanism of LOV-TAP at the molecular level, using the noninvasive molecular dynamics simulation technique. More specifically, we find that Cys450 FMN-adduct formation in the AsLOV2-Jalpha-binding pocket after photoexcitation induces the cleavage of the peripheral Jalpha-helix from the LOV core, causing a change of its polarity and electrostatic attraction of the photoswitch onto the DNA surface. This goes along with the flexibilization through unfolding of a hairpin-like helix-loop-helix region interlinking the AsLOV2-Jalpha- and TrpR domains, ultimately enabling the condensation of LOV-TAP onto the DNA surface. By contrast, in the dark state the AsLOV2-Jalpha photoswitch remains inactive and exerts a repulsive electrostatic force on the DNA surface. This leads to a distortion of the hairpin region, which finally relieves its tension by causing the disruption of LOV-TAP from the DNA. PMID- 23042419 TI - Microfluidic system with integrated microinjector for automated Drosophila embryo injection. AB - Drosophila is one of the most important model organisms in biology. Knowledge derived from the recently sequenced 12 genomes of various Drosophila species can today be combined with the results of more than 100 years of research to systematically investigate Drosophila biology at the molecular level. In order to enable automated, high-throughput manipulation of Drosophila embryos, we have developed a microfluidic system based on a Pyrex-silicon-Pyrex sandwich structure with integrated, surface-micromachined silicon nitride injector for automated injection of reagents. Our system automatically retrieves embryos from an external reservoir, separates potentially clustered embryos through a sheath flow mechanisms, passively aligns an embryo with the integrated injector through geometric constraints, and pushes the embryo onto the injector through flow drag forces. Automated detection of an embryo at injection position through an external camera triggers injection of reagents and subsequent ejection of the embryo to an external reservoir. Our technology can support automated screens based on Drosophila embryos as well as creation of transgenic Drosophila lines. Apart from Drosophila embryos, the layout of our system can be easily modified to accommodate injection of oocytes, embryos, larvae, or adults of other species and fills an important technological gap with regard to automated manipulation of multicellular organisms. PMID- 23042420 TI - Advances in the management of myelofibrosis. AB - BACKGROUND: Myelofibrosis (MF) is a rare and serious hematologic malignancy classified as a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). The disease is more common in males and in older individuals. Of the MPNs, MF presents with the most severe morbidity and greatest mortality. Although the cause of MF is unknown, it is thought to occur from acquired mutations that target the hematopoietic stem cell. METHODS: We reviewed the current literature pertaining to the pathophysiology, clinical presentation, diagnosis, risk stratification, and treatment of MF. The strengths and limitations of present treatment options as well as the emerging clinical experience with Janus kinase 2 (JAK2) inhibitors are explored. RESULTS: Diagnosis is often one of exclusion and is facilitated using the World Health Organization or International Working Group for Myelofibrosis Research and Treatment criteria, depending on whether primary or secondary MF is suspected. Treatment is complicated by a lack of disease familiarity of general practitioners and the advanced age of presenting patients. Although allogeneic stem cell transplant offers a potential cure, most treatments for this condition are limited to symptomatic management, with little to no effect on survival. Appropriate patient assessment and risk stratification are essential for predicting outcomes and allowing treating physicians to tailor therapy accordingly. CONCLUSIONS: Significant advances have been made in understanding the pathophysiology of MF, leading to novel therapeutic approaches. The discovery of the JAK2 mutation and the development of JAK2 inhibitors provide clinicians with a new effective treatment option. Ruxolitinib is the first JAK1/2 inhibitor approved by the Food and Drug Administration (FDA) for the treatment of patients with intermediate- or high-risk MF. In clinical studies, ruxolitinib produced a significantly greater reduction in spleen size and improved quality of life compared with placebo or best available therapy. Several future therapies, including combination therapies with ruxolitinib, are currently under investigation. PMID- 23042421 TI - Use of hand diagrams in screening for ulnar neuropathy: comparison with electrodiagnostic studies. AB - INTRODUCTION: The objective of this study was to determine whether a hand diagram could be used to predict ulnar mononeuropathy. METHODS: This was a prospective study of 117 consecutive patients referred for hand symptoms. Each subject filled out a hand diagram of symptoms and had median and ulnar sensory and motor nerve conduction studies, including ulnar conduction across the elbow. RESULTS: The best model for predicting an ulnar mononeuropathy included hand diagram scores of definite or possible. The model had a sensitivity of 50% and specificity of 93% with an ROC area of 0.90. CONCLUSIONS: The ulnar hand diagram scoring system can be useful as a screening tool in the electrodiagnostic laboratory or for epidemiologic studies. PMID- 23042422 TI - Accommodation of missing data in supportive and palliative care clinical trials. AB - PURPOSE OF REVIEW: Clinical trials to evaluate the supportive and palliative care treatments have some different missing data concerns than the other clinical trials. This study reviews the literature on missing data as it may apply to these trials. RECENT FINDINGS: Prevention of missing data through study design and conduct is a recent area of focus. Missing data can be minimized by simplifying trial participation for patients, their caregivers, and trialists. Run-in periods with active drug or collecting data from observer (proxy) respondents may complicate a trial but may be used to address some specific concerns. Many analyses can accommodate data missing because of nonresponse by multiple imputation, using carefully chosen imputation models. Analysis of trials evaluating end-of-life care should distinguish between missing data and truncation because of death. SUMMARY: Likely patterns for missing data should be discussed when planning a clinical trial, as modifications to trial design can minimize missing data while still addressing study aims. Many statistical analysis methods are available to accommodate missing data, but robustness of study conclusions to assumptions about mechanisms underlying the missingness should be evaluated by sensitivity analyses. PMID- 23042423 TI - Reconstructing analgesic trials: reasons for following the lead of oncologists. AB - PURPOSE OF REVIEW: Changes in drug trial designs in oncology, which involve targeted therapies and well genotyped cancers have important implications to the present trial designs used for analgesic development. RECENT FINDINGS: Pain phenotypes influence analgesic responses. Analgesics can now be targeted to pain phenotypes. IMMPACT strategies should be modified using pharmacokinetic pharmacodynamics and phase II-III trial designs commonly used in oncology. SUMMARY: Modifying analgesic trial designs will facilitate the development of targeted analgesics and improve the 'signal-to-noise' ratio over present analgesic trial strategies, which are largely based on pain severity and changes in pain intensity over time. PMID- 23042424 TI - The role of dietary counseling and nutrition support in head and neck cancer patients. AB - PURPOSE OF REVIEW: Head and neck cancer patients frequently present with malnutrition. Treatment options put the patient at further nutritional risk. Inadequate nutritional status is associated with poor prognosis. Dietary counseling and nutrition support can positively impact prognosis; however, the evidence is sparse and of poor quality. The aim of this review is to summarize the current evidence concerning the role of dietary counseling and nutrition support in head and neck cancer patients undergoing curative treatment. RECENT FINDINGS: There remains a lack of evidence both in quantity and quality. Current findings support a role for dietary counseling and nutrition support from diagnosis through rehabilitation. Prognostic indicators for nutrition support include tumor location, tumor stage, and multimodal treatment. Results of an innovative nutrition-based care delivery model were positive. SUMMARY: Dietary counseling is appropriate for all head and neck cancer patients to enable adequate oral intake from diagnosis through rehabilitation; however, some patients require nutrition support. Prognostic indicators and predictive models have been developed to identify patients who require early nutrition support. Next steps include development of evidence-based nutrition care paths that are tested at multiple sites using well designed longitudinal studies and randomized clinical trials. PMID- 23042425 TI - Consanguineous unions and the burden of disability: a population-based study in communities of Northeastern Brazil. AB - OBJECTIVES: The aim of this study was to identify communities at high risk of transmitting recessive genetic disorders by measuring levels of endogamy and offspring's rate of disabilities. METHODS: In a house-to-house population based survey in the state of Paraiba, 20,462 couples were interviewed regarding kinship relation, number of siblings and offspring affected by mental or physical disabilities. RESULTS: The rate of consanguineous unions in the communities ranged from 6.0% to 41.14%, showing an average value of 20.19% +/- 9.13%. The overall average inbreeding coefficient (F) was 0.00602 +/- 0.00253, ranging from 0.00134 to 0.01182. Communities situated on the backlands had an increased average value of F compared to those closer to the seashore (P = 0.024). The average rate of disabled offspring varied from 2.96% +/- 0.68% for unrelated unions to 10.44% +/- 16.86% for related couples at the level of double first cousins or uncle-niece. The Spearman correlation coefficient between the overall rate of disabled offspring from all couples together and F was 0.510 (P < 0.01). CONCLUSION: Inbreeding increases the risk of disability which is unevenly distributed, varying considerably even in neighboring communities with similar Human Development Index and population density. Higher inbreeding communities are mostly located on the more economically underdeveloped backlands than on the coastal region. The identification of communities at high risk for genetic disorders could serve as basis for the establishment of Community Genetics programs. PMID- 23042426 TI - Synthesis, structure, and reactivity of a dimeric zinc(I) compound stabilized by a sterically demanding diiminophosphinate ligand. AB - The new sterically demanding aminoiminophosphorane Ph(2)P(=NDip)(NHDip) (Dip = C(6)H(3)-2,6-iPr(2); LH, 1) has been prepared as a precursor to the potassium complex [LK] (2) and a series of heteroleptic zinc(II) complexes, namely [(LZnBr)(2)] (3), [LZnMe] (4), [LZnEt] (5), and [(LZnI)(2)] (6). The products have been obtained either through a salt metathesis route by using complex 2 and ZnBr(2) to give compound 3, through a direct reaction of ligand precursor 1 and ZnR(2) (R = Me or Et) yielding complexes 4 or 5, respectively, or through iodination of complexes 4 or 5 by using I(2) to afford compound 6. Reduction of the heteroleptic zinc(II) halide complexes 3 or 6 by using a dimeric magnesium(I) compound as a selective, stoichiometric, and soluble reducing agent afforded the new zinc(I) dimer [(LZn)(2)] (7) in good yield. Compounds 1-7 were crystallographically and spectroscopically characterized and the coordination behavior of the diiminophosphinate ligand has been investigated and compared with related CN-based ligands. An initial reactivity study has been carried out on [(LZn)(2)] (7) by using small-scale reactions and the oxidative addition of small alkyl halides across the Zn-Zn bond has been found to generate equimolar amounts of the alkyl complexes 4 or 5 and the halide complexes 3 or 6, respectively. PMID- 23042427 TI - Preparation and helical folding of aromatic polyamides. AB - Long aromatic polyamide chains are prepared from the corresponding monomers. The resultant polymer adopts a hollow helical conformation that is stabilized by intramolecular H-bonding interaction between side chains. PMID- 23042428 TI - The species concept as a cognitive tool for biological anthropology. AB - Taxonomy is caught between the search for the "perfect" theory and an elusive biological variability. The lack of major advances in issues related to how "species" and other taxonomic categories are defined suggests that perhaps we should avoid excessively rigid formalism in this regard. The risk is a separation between elegant but useless theories and confusing applications of the taxonomic tools. Communication is one of the main functions of taxonomy, and stability one of the main parameters that taxonomy users should be sensitive to. An excess of stability may generate anachronistic consequences while continuous revisions may make the tool of taxonomy scarcely practical. The current tendency pushes toward more and more fragmentation of biologically valid taxa. While taxonomy specialists enjoy such challenges, many taxonomy users feel a bit nervous and discouraged when trying to use a tool that is constantly changing. Debates over taxonomy would seem particularly unrewarding for fields with limited samples and scarce biological diversity, such as palaeoanthropology. In this context, where the information available is rarely sufficient to supply consistent taxonomical evidence, there are frequently excessive efforts to create debate on species separations. The risk is that we maintain the debate on a purely theoretical level, or else we distrust a reliable use of taxonomy. A compromise (and recommended) choice between these two extremes would be to rely on shared and reasonable interpretations of homogeneous evolutionary units, without diving into fine-grained issues that will remain, however, unresolved. Taxonomy should be a tool, not the goal, of the evolutionary biologist. Our mind needs discrete and recognizable objects to structure our perception of reality. There is no reason to expect that nature works the same way. PMID- 23042429 TI - Patients with autoimmune thyroiditis. Prevalence of benign lymphadenopathy. AB - The prevalence of cervical lymphadenopathy in autoimmune thyroiditis (AIT) patients is actually unknown. The aim of the study was the detailed retrospective evaluation of 6 index-patients with lymphadenopathy in Robbins level VI and a prospective study with high resolution ultrasound of lymphadenopathy in AIT patients compared with controls in all compartments of the neck, accessible to sonographic evaluation. PATIENTS, METHODS: The retrospective study comprises six patients with AIT, evaluated for enlarged Robbins level VI-LN. We report the findings of fine-needle aspiration Cytology, clonal analysis, histology, and serological testing. The prospective study evaluated the prevalence of lymphadenopathy in 49 consecutive patients with AIT (group 1) and 49 consecutive patients with normal thyroids or nontoxic goiter (group 2). RESULTS: In the retrospective study, cytology of paratracheal LN revealed reactive lymphoid hyperplasia in 5/6 of the cases and a centroblastic lymphoma in one patient. The presence of monoclonal lymphatic cells was excluded in 5/6 patients and proven in 1/6 patients. Actual viral-infections were ruled out. In the prospective study AIT-patients showed significantly more enlarged LN in Robbins level II-IV and VI compared to controls. We found no correlation between lymphadenopathy, age, thyroid volume and nodularity, or autoantibody levels. During follow-up in 34 group 1-patients, lymphadenopathy remained stable in 28 patients, and decreased in 6 patients. CONCLUSION: Lymphadenopathy in Robbins level II-IV and VI is common in AIT-patients and most probably related to the autoimmune process. PMID- 23042430 TI - Accurate retention time determination of co-eluting proteins in analytical chromatography by means of spectral data. AB - Chromatography is the method of choice for the separation of proteins, at both analytical and preparative scale. Orthogonal purification strategies for industrial use can easily be implemented by combining different modes of adsorption. Nevertheless, with flexibility comes the freedom of choice and optimal conditions for consecutive steps need to be identified in a robust and reproducible fashion. One way to address this issue is the use of mathematical models that allow for an in silico process optimization. Although this has been shown to work, model parameter estimation for complex feedstocks becomes the bottleneck in process development. An integral part of parameter assessment is the accurate measurement of retention times in a series of isocratic or gradient elution experiments. As high-resolution analytics that can differentiate between proteins are often not readily available, pure protein is mandatory for parameter determination. In this work, we present an approach that has the potential to solve this problem. Based on the uniqueness of UV absorption spectra of proteins, we were able to accurately measure retention times in systems of up to four co eluting compounds. The presented approach is calibration-free, meaning that prior knowledge of pure component absorption spectra is not required. Actually, pure protein spectra can be determined from co-eluting proteins as part of the methodology. The approach was tested for size-exclusion chromatograms of 38 mixtures of co-eluting proteins. Retention times were determined with an average error of 0.6 s (1.6% of average peak width), approximated and measured pure component spectra showed an average coefficient of correlation of 0.992. PMID- 23042431 TI - Education and counseling of renal transplant recipients. AB - A large number of factors can influence the clinical outcome of kidney transplant recipients, but the active role of the patient to prevent the possible complications related to transplant and its treatment is often neglected. Poor adherence to prescriptions is frequent in transplant recipients and represents a major contributor to the development of graft failure, cardiovascular disease, infection and/or malignancy. Smoking can render the patient more susceptible to cancer, cardiovascular disease and infection, and can also impair renal allograft function. The risk of malignancy is increased in transplant recipients. Therefore screening for cancer is of paramount importance. Measures that can enable prevention or early detection of cancer include self-exams and screening, physical activity, avoidance of smoking and sun exposure, and a diet rich in fruits and vegetables but limited in fats, red meats, salt and alcohol. Regular exercise can help to prevent cardiovascular disease, diabetes, obesity, osteoporosis and even some forms of cancer. Thus regular exercise is recommended. Yet, too many transplant patients remain sedentary. Weight gain is common in renal allograft recipients and may be associated with hypertension, hyperlipidemia and/or glucose intolerance or overt diabetes. To prevent these complications, patients should follow diet regimens based on low fat and normal/low caloric intake. Small amounts of alcohol may be permitted in view of its potential cardioprotective effect, but a large consumption of alcohol can be responsible for devastating side effects. Last but not least, abidance by hygienic measures may help in preventing cardiovascular and infectious complications. PMID- 23042432 TI - Genetic studies in chronic kidney disease: interpretation and clinical applicability. AB - The tools of modern molecular biology are evolving rapidly, resulting in vastly more efficient approaches to illuminating human genetic variations and their effects on common multifactorial disorders such as chronic kidney disease (CKD). Indeed, candidate gene association studies and genome-wide association studies (GWASs) have generated novel genetic variants in previously unrecognized biological pathways, highlighting disease mechanisms with a potential role in CKD etiology, morbidity and mortality. Nephrologists now need to find ways to make use of these advancements and meet the increasingly stringent requirements for valid study design, data handling and interpretation of genetic studies. Adding to our prior article in this journal, which introduced the basics of genotype phenotype association studies in CKD, this second article focuses on how to ascertain robust and reproducible findings by applying adequate methodological and statistical approaches to genotype-phenotype studies in CKD populations. Moreover, this review will briefly discuss genotype-based risk prediction, pharmacotherapy, drug target identification and individualized treatment solutions, specifically highlighting potentially important findings in CKD patients. This increased knowledge will hopefully facilitate the exciting transition from conventional clinical medicine to gene-based medicine. However, before this can be accomplished, unsolved issues regarding the complex human genetic architecture as well technical and clinically oriented obstacles will have to be overcome. Additionally, new policies and standardized risk evaluations for genetic testing in the clinical setting will have to be established to guarantee that CKD patients are provided with high-quality genotype-guided counseling that will help to improve their poor outcomes. PMID- 23042433 TI - Serum BAFF is elevated in patients with IgA nephropathy and associated with clinical and histopathological features. AB - BACKGROUND: B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) has been found to have the function of activating B cells and participating in the class switching of B cells; however, its clinical application needs further study. In the present study, the serum BAFF levels of patients with IgA nephropathy (IgAN) with different histopathological phenotypes were measured. METHODS: Levels of serum BAFF in 153 patients with IgAN, 55 healthy controls and 20 disease controls were recorded using commercially available ELISA kits. Their correlations with clinical and histopathological features of patients with IgAN were further evaluated. RESULTS: Levels of serum BAFF in patients with IgAN were significantly higher than in controls. Serum BAFF levels were significantly higher in patients with mesangial hypercellularity and segmental glomerulosclerosis than in those without. Serum BAFF levels were associated with the severity of tubular atrophy/interstitial fibrosis. Serum BAFF levels were significantly positively correlated with estimated glomerular filtration rate and serum creatinine. Patients with elevated serum BAFF levels showed significantly greater severity in clinical and histopathological stages. CONCLUSION: Levels of serum BAFF were elevated in patients with IgAN and were associated with clinical and pathological features of the disease. Serum BAFF levels could be a noninvasive biomarker for monitoring disease severity of IgAN. PMID- 23042434 TI - Epidemiology and mortality in dialysis patients with and without polycystic kidney disease: a national study in Taiwan. AB - BACKGROUND: Polycystic kidney disease (PCKD) is one of the most common inherited disorders in end-stage renal disease patients. It is generally thought that the survival of PCKD patients undergoing dialysis surpasses that of general dialysis patients, but the cause of this improved survival is not clear. METHODS: Using Taiwan's national health insurance claims data, we performed a longitudinal cohort study to investigate the survival and impact of comorbidities on mortality in dialysis patients with and without PCKD. We excluded patients without diabetes mellitus (DM) in a further analysis. A Cox proportional hazards model was used to identify the risk factors for all-cause mortality. The Kaplan-Meier method was used to describe overall patient survival. RESULTS: Five hundred and one (2.25%) of 22,298 nondiabetic incident dialysis patients had PCKD. We found no significant difference in survival rates between those with and without PCKD. Being male, being over 65 years old and having congestive heart failure or cerebrovascular accident were each found to be independent predictors of mortality in the PCKD dialysis patients. CONCLUSIONS: Taiwan has a lower incidence rate of PCKD than Western countries. In Taiwan, there is little difference in the long-term survival between dialysis patients with and without PCKD. PMID- 23042435 TI - Relationships between glomerular filtration rate and kidney volume in low-birth weight neonates. AB - BACKGROUND: Low birth weight (LBW), defined as birth weight below 2,500 g, is an important risk factor for the development of hypertension and renal disease in adult life. LBW is associated with a reduced nephron number, which results in hyperfiltration. The objective of this study was to compare the glomerular filtration rates (GFRs) of LBW and normal-birth-weight (NBW) term infants relative to their kidney volumes. METHODS: Term infants (born after 37 weeks of gestation) who had been admitted to Townsville Hospital's neonatal unit were recruited for this study. Serum cystatin C was used to calculate gfr. a kidney ultrasound was used to measure renal volume. all assessments were performed during the first week of life. RESULTS: Data from 39 infants (17 male, 22 female; 13 LBW, 26 NBW) were analyzed. There were no significant differences in the median cystatin C (1.36 mg/L, inter quartile range [IQR] = 1.12 - 1.41, vs. 1.17 mg/L, IQR = 1.10 - 1.39; p = 0.39) and gestational age. There was no significant difference in the median GFR (53.0 ml/min per 1.73 m2, IQR = 50.8-66.9, vs. 63.2 ml/min per m2, IQR = 51.8-69.5; p = 0.39) between LBW and NBW infants, but LBW infants had smaller total renal volume compared with NBW infants (18.0 +/- 4.7 mL vs. 24.4 +/- 6.2 mL; p = 0.002). CONCLUSION: Within 6 days, LBW infants achieved a similar GFR to NBW infants, despite 25% smaller kidney volumes. Thus, the single-nephron glomerular filtration rate must be increased in LBW infants. Prior to this study, it was unclear when hyperfiltration begins, but our results demonstrate that hyperfiltration begins in early life. PMID- 23042436 TI - Acute kidney injury in patients undergoing cardiac surgery. AB - The incidence of postoperative acute kidney injury (AKI) in patients undergoing cardiac surgery ranges from 7.7% to 28.1% in different studies, probably in relation to the criteria adopted to define AKI. AKI markedly increases mortality risk. However, despite the development of less invasive techniques, cardiac surgery remains the first option in many conditions such as severe coronary artery disease, valve diseases and complex interventions. The risk of postsurgery AKI can be reduced by adopting less invasive approaches, such as off-pump coronary artery bypass grafting or transcatheter aortic valve implantation, but these options cannot be employed in all cases. Thus, since traditional cardiac surgery remains the only option in many cases, it is important to adopt strategies helping the clinician to prevent AKI or diagnose it early. Old age, preprocedural chronic kidney disease, obesity, some comorbidities, wide pulse pressure and some pharmacological regimens represent risk factors for postsurgery AKI and mortality. Important intraoperative factor are use and duration of cardiopulmonary bypass. Postoperative efforts should be aimed toward maximizing cardiac output, avoiding drugs vasoconstricting the renal artery, providing adequate crystalloid infusion and alkalinizing urine. Fluid management should not be based on the measurements for cardiac filling pressures, which are mostly unreliable in these patients. Novel biomarkers such as cystatin C, kidney injury molecule-1 and human neutrophil gelatinase-associated lipocalin have been found to change earlier than creatinine, particularly when measured in combination, so their use in clinical practice can facilitate early diagnosis and treatment of AKI. The occurrence of oliguria despite adequate cardiovascular therapy can be managed with furosemide, possibly using continuous infusion, or renal replacement therapy. PMID- 23042437 TI - Ultrasound in clinical setting of secondary hyperparathyroidism. AB - Secondary hyperparathyroidism (sHPT) is one of the most common and serious complications of chronic kidney disease (CKD) and maintenance hemodialysis (MHD). In sHPT, the biology of parathyroid cells changes significantly toward diffuse and nodular hyperplasia. Diagnosis and treatment of sHPT are based on intact parathyroid hormone (i-PTH) serum levels and on the parameters of mineral metabolism. The morphological diagnosis of sHPT relies on 2 complementary imaging techniques: high-resolution ultrasonography with color Doppler imaging (US/CD) and 99mTc-methoxyisobutylisonitrile (MIBI) scintigraphy. The main objective of this review is to stimulate nephrologists to use US/CD of the parathyroid glands during the progression of CKD in order to aid clinical, pharmacological and surgical strategies. The primary role of US/CD in sHPT should be to integrate the clinical diagnosis by defining the number and volume of hyperplastic glands, although the international guidelines do not state when and why to perform US/CD. This review also evaluates the role of US/CD in clinical follow-up and assessment of therapeutic response of sHPT, and it highlights how US/CD can evaluate the effect of therapy with phosphate binders, vitamin D or its analogues and calcimimetics, which are changing the natural history of sHPT and the frequency of parathyroidectomy. Evaluation of the morphological and vascular changes of hyperplastic parathyroids is useful to guide percutaneous ethanol injection therapy and to support clinical, pharmacological and surgical strategies. Epidemiological studies are needed to establish how US/CD could change the management of sHPT and why it should be repeated in patients with high levels of serum i-PTH. PMID- 23042438 TI - Proteomics and nephrology. AB - Proteome analysis has emerged as a new field of protein science offering the possibility of achieving unbiased identification, quantification and functional assessment of all proteins and peptides present in biological samples. Proteomics technologies are being used with increased frequency in the renal community. In this article we aim to highlight investigations in basic renal research and in clinical nephrology making use of recent developments in proteomic methods. Several examples are presented of how proteomics may be helpful to nephrology and affect possible future directions in kidney research. PMID- 23042439 TI - GP support for self-care: the views of people experiencing long-term back pain. AB - BACKGROUND: Promotion of self-care for persistent back pain and other long-term conditions has become a central component in health care policy in the UK, and general practitioners face increasing demands to support patients' self-care efforts. Gaining insight into patients' views may facilitate support. OBJECTIVE: To describe patients' experience of self-care for long-term back pain and their views on provision of support for self-care. METHODS: Adults experiencing persistent back pain were purposively sampled from a community-based survey. In depth qualitative interviews were audiotaped, transcribed and analysed using the constant comparative method to inductively derive a thematic account of the data. RESULTS: Most of the 23 interviewees felt a responsibility to self-care. Individual capacity for self-care, however, was variable and could be inhibited by factors such as caring roles or lack of diagnosis and information. GP support for self-care was largely considered to be desirable, although the feasibility of greater provision of support was questioned. Some interviewees expressed a strong preference for alternative models of care and support. CONCLUSION: Self-care for back pain is contextualized by the individual's capacity to self-care and preferences for support. Doubt over the ability of GPs to provide support for self-care may mean that those who have specific needs are reticent to seek help. The role of self-care in the management of back pain should be discussed openly at the consultation level, and GPs may be well placed to signpost patients and provide guidance on the safety of specific self-care activities. PMID- 23042440 TI - A comparative study on fabrication techniques for on-chip microelectrodes. AB - This paper presents an experimental study on different microelectrode fabrication techniques, with particular focus on the robustness of the surface insulation towards typical working conditions required in lab-on-a-chip applications. Pt microelectrodes with diameters of 50 MUm, 100 MUm and 200 MUm are patterned on a Si substrate with SiO(2) film. Sputtered SiO(2), low-pressure chemical vapor deposition (LPCVD) low-temperature oxide (LTO), Parylene C, SU-8, and dry-film were deposited and patterned on top of the chips as the passivation layer. This paper provides the detailed fabrication processes, the adhesion enhancement strategies, and the major advantages and disadvantages of each fabrication technique. Firstly, the quality and adhesion strength of the passivations were investigated by means of hydrolysis tests, in which sputtered SiO(2) and dry-film resist showed serious delamination issues and LTO showed minor defects. Secondly, the reliability of the microelectrodes was tested by impedance measurements after overnight ethanol incubation and self-assembled monolayer (SAM) formation. Thirty chips, representing a total of 300 electrodes, were measured, and statistical analyses of the results were conducted for each passivation technique. All of the electrodes passivated with these five techniques showed consistent impedance values after ethanol incubation. On the other hand, only LTO, Parylene C, and SU 8 ensured uniform electrical behavior after SAM formation. Having used both hydrolysis and impedance tests to verify the superior quality of the Parylene based passivation, electrochemical experiments were performed to study the long term stability of the passivation layer. Finally, the electrodes were incubated with electroactive alkanethiols functionalized with ferrocene. Square-wave voltammetry measurements demonstrated reproducible results on electrochemical label detection, which confirms the suitability of the Parylene passivation for charge-transfer-based measurements. PMID- 23042442 TI - High resolution crystal structure of Sco5413, a widespread actinomycete MarR family transcriptional regulator of unknown function. AB - The crystal structure of Sco5413 from Streptomyces coelicolor A3(2) has been determined at 1.25 A resolution, the highest resolution reported for a MarR family transcriptional regulator. Putative orthologs are encoded by the majority of sequenced actinomycete genomes, and may play roles in regulating growth and antibiotic production, but they have yet to be assigned a precise function. Sco5413 forms a homodimer and, through comparisons with other MarR family protein structures, we postulate that it adopts a conformation compatible with DNA binding, and that a channel at the dimer interface, lined by well-conserved residues, is the binding site of an unidentified effector ligand. PMID- 23042441 TI - ON cone bipolar cell axonal synapses in the OFF inner plexiform layer of the rabbit retina. AB - Analysis of the rabbit retinal connectome RC1 reveals that the division between the ON and the OFF inner plexiform layer (IPL) is not structurally absolute. ON cone bipolar cells make noncanonical axonal synapses onto specific targets and receive amacrine cell synapses in the nominal OFF layer, creating novel motifs, including inhibitory crossover networks. Automated transmission electron microscopic imaging, molecular tagging, tracing, and rendering of ~400 bipolar cells reveals axonal ribbons in 36% of ON cone bipolar cells, throughout the OFF IPL. The targets include gamma-aminobutyrate (GABA)-positive amacrine cells (gammaACs), glycine-positive amacrine cells (GACs), and ganglion cells. Most ON cone bipolar cell axonal contacts target GACs driven by OFF cone bipolar cells, forming new architectures for generating ON-OFF amacrine cells. Many of these ON OFF GACs target ON cone bipolar cell axons, ON gammaACs, and/or ON-OFF ganglion cells, representing widespread mechanisms for OFF to ON crossover inhibition. Other targets include OFF gammaACs presynaptic to OFF bipolar cells, forming gammaAC-mediated crossover motifs. ON cone bipolar cell axonal ribbons drive bistratified ON-OFF ganglion cells in the OFF layer and provide ON drive to polarity-appropriate targets such as bistratified diving ganglion cells (bsdGCs). The targeting precision of ON cone bipolar cell axonal synapses shows that this drive incidence is necessarily a joint distribution of cone bipolar cell axonal frequency and target cell trajectories through a given volume of the OFF layer. Such joint distribution sampling is likely common when targets are sparser than sources and when sources are coupled, as are ON cone bipolar cells. PMID- 23042443 TI - Neurophysiological examination of dorsal sural nerve. AB - INTRODUCTION: Nerve conduction study of the dorsal sural nerve (DSN) has been reported to be a sensitive method for early detection of peripheral neuropathies. However, normal reference values are scarce and vary greatly among the different studies. METHODS: A comprehensive neurophysiological study, including nerve conduction velocity (NCV) and sensory nerve action potential (SNAP) recording, was performed in 294 healthy subjects (21-86 years) with no evidence of neuropathy. RESULTS: The amplitude of the DSN SNAP ranged from 2.50 to 15.90 MUV, and NCV ranged from 28.9 to 52.8 m/s. A significant age-related decrease in DSN SNAP amplitude and NCV was observed. The mean ratio of sural NCV to DSN NCV was 1.33 +/- 0.19, and the mean ratio of sural nerve SNAP amplitude to DSN SNAP amplitude was 3.17 +/- 1.33. CONCLUSION: These normative data of the DSN might be used as reference values for the study of this very distal peripheral nerve. PMID- 23042444 TI - Tissue engineering in urethral reconstruction--an update. AB - The field of tissue engineering is rapidly progressing. Much work has gone into developing a tissue engineered urethral graft. Current grafts, when long, can create initial donor site morbidity. In this article, we evaluate the progress made in finding a tissue engineered substitute for the human urethra. Researchers have investigated cell-free and cell-seeded grafts. We discuss different approaches to developing these grafts and review their reported successes in human studies. With further work, tissue engineered grafts may facilitate the management of lengthy urethral strictures requiring oral mucosa substitution urethroplasty. PMID- 23042445 TI - Enzalutamide (formerly MDV3100) as a new therapeutic option for men with metastatic castration-resistant prostate cancer. AB - Enzalutamide marks the latest addition to the drugs currently approved by the US Food and Drug Administration for metastatic, castration-resistant prostate cancer (mCRPC). AFFIRMwas a phase III international randomized trial that evaluated the clinical utility of enzalutamide versus placebo in men with mCRPC who have failed prior docetaxel-containing chemotherapy. Enzalutamide showed a remarkable 37% decreased risk of death with a median overall survival of 18.4 months versus 13.6 months for those who received placebo. These findings confirm the validity of further targeting the androgen receptor as a valid therapeutic approach in prostate cancer despite emergence of castration resistance. PMID- 23042447 TI - A modified single-armed technique for microsurgical vasoepididymostomy. AB - This study is to evaluate the effectiveness of a modified single-armed suture technique for microsurgical vasoepididymostomy (VE) in patients with epididymal obstructive azoospermia. From September 2011 to December 2011, microsurgical two suture longitudinal intussusception VEs were performed using our modified single armed suture technique in 17 men with epididymal obstructive azoospermia at our hospital. Two of these patients underwent repeated VEs after previous failed VEs, and one patient underwent unilateral VE because of an occlusion of the left abdominal vas deferens. The presence of sperm in the semen sample at 3 months postoperation was used as the preliminary endpoint of this study. Each patient provided at least one semen sample at the 3-month time point, and the patency was assessed by the reappearance of sperm (>10(4) ml(-1)) in the semen. The mean operative time for the modified technique was 219 min. Patency was noted in 10 men (58.8%), including one patient who underwent repeated VE. The patient who underwent unilateral anastomosis manifested no sperm postoperatively in his semen. Sperm granulomas were not detected in this cohort. The results of this study demonstrate that our modified technique for microsurgical longitudinal intussusception VE is effective. We believe that it is a practical alternative that may reduce operation time and obviate the suture crossing. PMID- 23042446 TI - Genetic polymorphisms in HIF1A are associated with prostate cancer risk in a Chinese population. AB - The hypoxia-inducible factor-1alpha (HIF-1alpha) plays an important role in regulating angiogenesis, which is essential for tumor growth and metastasis. Genetic variations of HIF1A (coding HIF-1alpha) have been shown to influence an individual's susceptibility to many human tumors; however, evidence on associations between HIF1A single-nucleotide polymorphisms (SNPs) and prostate cancer (PCa) risk is conflicting. We genotyped three potentially functional polymorphisms in HIF1A (rs11549465, rs11549467 and rs2057482) using the TaqMan method and assessed their associations with PCa risk in a case-control study of 662 PCa patients and 716 controls in a Chinese Han population. Compared with rs11549467 GG genotype, the variant genotypes GA+AA had a significantly increased PCa risk (adjusted odds ratio (OR)=1.70; 95% confidence interval (CI)=1.06-2.72), particularly among older patients (OR=2.01; 95%CI=1.05-3.86), smokers (OR=2.06; 95%CI=1.07-3.99), never drinkers (OR=2.16; 95%CI=1.20-3.86) and patients without a family history of cancer (OR=1.71; 95%CI=1.02-2.89). Furthermore, patients with rs11549467 variant genotypes were associated with a higher Gleason score (OR=2.14; 95%CI=1.22-3.75). No altered PCa risk was associated with the rs11549465 and rs2057482 polymorphism. However, the combined variant genotypes of rs2057482 and rs11549467 were associated with increased PCa risk (OR=2.10; 95%CI=1.23-3.57 among subjects carrying three or more risk alleles). These results suggest that HIF1A polymorphisms may impact PCa susceptibility and progression in the Chinese Han population. PMID- 23042448 TI - Testosterone is negatively associated with the severity of coronary atherosclerosis in men. AB - This study aimed to determine whether plasma testosterone is associated with the severity of coronary atherosclerosis in a group of 803 men who underwent elective coronary angiography. Testosterone levels were measured in 803 male patients who were categorized into three groups according to testosterone level tertiles. All patients underwent elective coronary angiography, and the severity of coronary artery disease (CAD) was determined by the Gensini score. Moreover, patients were classified into two groups according to Gensini scores (score <=26 and score >26) using the median values as cutoff points. The plasma testosterone levels were measured by an ELISA kit. The level of testosterone was negatively associated with the Gensini score (r=-0.188; P=0.000). A multiple linear regression analysis revealed that testosterone was an independent risk factor for the Gensini score (beta=-0.110; P=0.002) after adjusting for confounding covariates. In a multivariate logistic regression model, the severity of CAD was shown to be significantly lower in the third tertile (highest) of testosterone compared to the first tertile (lowest) of testosterone (odds ratio (OR)=0.465; 95% confidence interval (CI): 0.327-0.662; P=0.000). In this study, patients with lower testosterone levels had higher Gensini scores in a group of 803 men who underwent elective coronary angiography. Additional studies are needed to clarify the direction of causality and possible underlying mechanisms. PMID- 23042449 TI - The ultrasonic harmonic scalpel for circumcision: experimental evaluation using dogs. AB - Male circumcision is one of the most commonly performed operations worldwide, and many novel techniques have been developed for better postoperative outcomes. The purpose of this study was to explore the feasibility of applying the ultracision harmonic scalpel (UHS) for circumcision by using dogs. Sixteen adult male dogs were divided into two groups: the UHS group and the control group. The dogs were circumcised with either the UHS or a conventional scalpel. The UHS circumcision procedure and the effects were imaged 1 week after surgery. The two groups were compared with respect to the operative time and volume of blood loss. Postoperative complications, including oedema, infection, bleeding of the incision and wound dehiscence, were recorded for both groups. The mean operative time for the UHS group was only 5.1 min compared with the 35.5 min of the conventional group. The mean blood loss was less than 2 ml for the UHS group and 15 ml for the conventional group. There was only one case of mild oedema in the UHS group, but the postoperative complications in the conventional group included two cases of mild oedema, one infection of the incision and one case of bleeding of the incision. In conclusion, circumcision using UHS is a novel technique to treat patients with phimosis and excessive foreskin, and this method has a short operative time, less blood loss and fewer complications than the conventional scalpel method. This small animal study provides a basis for embarking on a larger-scale clinical trial of the UHS. PMID- 23042451 TI - Enantioselective construction of sterically hindered tertiary alpha-aryl ketones: a catalytic asymmetric synthesis of isoflavanones. AB - A method for the catalytic asymmetric alpha-arylation of ketones bearing very sterically hindered aryl rings has been developed. This reaction occurs under mild conditions, in short reaction times and has been applied to the first catalytic asymmetric synthesis of isoflavanones. PMID- 23042450 TI - Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters. AB - Vitamin D levels have been linked to various health outcomes including reproductive disorders. The purpose of this study was to explore the association between serum vitamin D level (25-hydroxy-vitamin D, or 25OHD) and semen and hormonal parameters. This is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. The main measures were hormonal (total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone) and semen parameters, adjusted (n=147) for age, body mass index (BMI), season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined a priori. The mean age of the study population was 29.0+/-8.5 years and mean BMI was 24.3+/-3.2 kg m(-2). The mean 25OHD was 34.1+/-15.06 ng ml(-1). BMI showed a negative association with 25OHD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with '25OHD>=50 ng ml(-1)' when compared to men with '20 ng ml(-1)<=25OHD<50 ng ml(-1)'. Total sperm count and total progressive motile sperm count were lower in men with '25OHD<20 ng ml(-1)' when compared to men with '20 ng ml(-1)<=25OHD<50 ng ml(-1)'. The adjusted means of various hormonal parameters did not show statistical difference in the different categories of 25OHD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters. PMID- 23042452 TI - Iterative plug-and-play methodology for constructing and modifying synthetic gene networks. AB - We present a methodology for the design, construction and modification of synthetic gene networks. This method emphasizes post-assembly modification of constructs based on network behavior, thus facilitating iterative design strategies and rapid tuning and repurposing of gene networks. The ease of post construction modification afforded by this approach and the ever-increasing repository of components within the framework will help accelerate the development of functional genetic circuits for synthetic biology. PMID- 23042454 TI - Synthesis and self-organization of zinc beta-(dialkoxyphosphoryl)porphyrins in the solid state and in solution. AB - The first synthesis and self-organization of zinc beta-phosphorylporphyrins in the solid state and in solution are reported. beta-Dialkoxyphosphoryl-5,10,15,20 tetraphenylporphyrins and their Zn(II) complexes have been synthesized in good yields by using Pd- and Cu-mediated carbon-phosphorous bond-forming reactions. The Cu-mediated reaction allowed to prepare the mono-beta (dialkoxyphosphoryl)porphyrins 1 Zn-3 Zn starting from the beta-bromo-substituted zinc porphyrinate ZnTPPBr (TPP = tetraphenylporphyrin) and dialkyl phosphites HP(O)(OR)(2) (R = Et, iPr, nBu). The derivatives 1 Zn-3 Zn were obtained in good yields by using one to three equivalents of CuI. When the reaction was carried out in the presence of catalytic amounts of palladium complexes in toluene, the desired zinc derivative 1 Zn was obtained in up to 72% yield. The use of a Pd catalyzed C-P bond-forming reaction was further extended to the synthesis of beta poly(dialkoxyphosphoryl)porphyrins. An unprecedented one-pot sequence involving consecutive reduction and phosphorylation of H(2)TPPBr(4) led to the formation of a mixture of the 2,12- and 2,13-bis(dialkoxy)phosphorylporphyrins 5 H(2) and 6 H(2) in 81% total yield. According to the X-ray diffraction studies, 1 Zn and 3 Zn are partially overlapped cofacial dimers formed through the coordination of two Zn centers by two phosphoryl groups belonging to the adjacent molecules. The equilibrium between the monomeric and the dimeric species exists in solutions of 1 Zn and 3 Zn in weakly polar solvents according to spectroscopic data (UV/Vis absorption and NMR spectroscopy). The ratio of each form is dependent on the concentration, temperature, and traces of water or methanol. These features demonstrated that zinc beta-phosphorylporphyrins can be regarded as new model compounds for the weakly coupled chlorophyll pair in the photosynthesis process. PMID- 23042453 TI - DNA template strand sequencing of single-cells maps genomic rearrangements at high resolution. AB - DNA rearrangements such as sister chromatid exchanges (SCEs) are sensitive indicators of genomic stress and instability, but they are typically masked by single-cell sequencing techniques. We developed Strand-seq to independently sequence parental DNA template strands from single cells, making it possible to map SCEs at orders-of-magnitude greater resolution than was previously possible. On average, murine embryonic stem (mES) cells exhibit eight SCEs, which are detected at a resolution of up to 23 bp. Strikingly, Strand-seq of 62 single mES cells predicts that the mm 9 mouse reference genome assembly contains at least 17 incorrectly oriented segments totaling nearly 1% of the genome. These misoriented contigs and fragments have persisted through several iterations of the mouse reference genome and have been difficult to detect using conventional sequencing techniques. The ability to map SCE events at high resolution and fine-tune reference genomes by Strand-seq dramatically expands the scope of single-cell sequencing. PMID- 23042456 TI - Parenting stress and emotional wellbeing in mothers and fathers of preschool children. AB - AIMS: The aims of the study were to compare parenting stress and emotional wellbeing in mothers and fathers of preschool children, to look for predictors of different aspects of parenting stress in mothers and fathers, and to discriminate parenting stress from psychological distress and anxiety. METHODS: We studied 256 mothers and 204 fathers of children aged 1-7 years. The Swedish Parenthood Stress Questionnaire (SPSQ) assesses stress related to parenting. Emotional wellbeing was defined by the General Health Questionnaire-28 (GHQ-28) and the State Anxiety Inventory (STAI-X1) that measures psychological distress and anxiety, respectively. RESULTS: Fathers reported significantly more social isolation than mothers (P < 0.001). On all other parameters mothers, had higher scores, representing more stress and less wellbeing than fathers. Anxiety and psychological stress were strong predictors of parental stress in both mothers and fathers. Furthermore, maternal parental stress was predicted by birth of subsequent children and younger child age. Higher educational attainment predicted increased role restriction in fathers and more health problems in mothers. A principal component analysis (PCA) of the SPSQ, GHQ-28, and STAI-X1 showed that all endpoints of the analysis are positively correlated. CONCLUSIONS: Fathers reported significantly more social isolation, but less role restriction, incompetence and state anxiety than mothers. The SPSQ together with GHQ-28 and STAI-X1 allow a targeted screening aimed at contrasting parents who experience reduced emotional wellbeing with those who struggle with stress directly related to their parenting role. PMID- 23042457 TI - Job insecurity and sickness absence: correlations between attrition and absence in 36 occupational groups. AB - AIMS: To investigate how job insecurity, as indicated by attrition rates out of employment, affects sickness absence among remaining workers. METHODS: A longitudinal analysis investigated how the percentage of workers absent due to sickness was affected by attrition out of employment in Norwegian Labour Force Surveys from 1997 to 2005, between 31 quarterly observations at the level of 36 occupational groups. RESULTS: Rising attrition is associated with more sickness absence. CONCLUSIONS: Previous research has argued that job insecurity can lead to more absence because of a stressor effect as well as to less absence because of a disciplinary effect. This research indicates that the stressor effect is stronger than the disciplinary effect. PMID- 23042455 TI - Retinoic acid regulates gap junction intercellular communication in human endometrial stromal cells through modulation of the phosphorylation status of connexin 43. AB - Previous studies revealed that gap junction intercellular communication (GJIC) among uterine stromal cells plays critical roles in modulating decidualization, neovasularization, and embryo implantation. Connexin (Cx) proteins are the major component of gap junctions and Cx43 is the most widely expressed connexin in endometrium. Phosphorylation of Cx43 was found to impair gap junction communication in this tissue. Using primary human endometrial stromal cells (ESCs) and a stable high telomerase-expressing ESC transfectant (T-HESC), we found that retinoic acid (RA) altered the phosphorylation status of Cx43 protein such that there was a decrease in the phosphorylated (P1 and P2) species accompanied by an increase in the non-phosphorylated (P0) form. This process is dependent on protein phosphatase 2A (PP2A) activity since selective PP2A inhibitors prevented the ability of RA to dephosphorylate Cx43. Although RA had no effect on total PP2A expression or activity, it significantly increased the intracellular association of Cx43 and PP2A. Inhibition of transcription and protein synthesis by actinomycin D and cycloheximide, respectively, had no effect on the RA-induced changes in the Cx43 phosphorylation pattern. Furthermore, BMS493, a potent antagonist of the classical RA-mediated transcriptional pathway, did not inhibit RA-induced Cx43 dephosphorylation. Our data indicate that RA stimulates physical association of PP2A with Cx43, resulting in the dephosphorylation of Cx43 and, as a consequence, up-regulation of GJIC in ESCs. This process is independent of new mRNA and protein synthesis and suggests a novel mechanism by which aberrant retinoid metabolism can explain certain reproductive disorders manifested by dysfunctional endometrial cell GJIC. PMID- 23042458 TI - The association between high recreational physical activity and physical activity as a part of daily living in adolescents and availability of local indoor sports facilities and sports clubs. AB - AIM: The aim of this study was to examine how vigorous physical activity (recreational physical activity) (VPA) and moderate to vigorous physical activity as a part of daily life (MVPA) is associated with structural characteristics (availability of sports facilities and sports clubs with child members) in Greenlandic adolescents. MATERIAL AND METHODS: Data from the 2006 Health Behaviour in School-aged Children survey including 2,430 children aged 11-17 years was used. Logistic regression models were developed with dichotomous measures on VPA and MVPA as outcomes, number of indoor sports facilities and of sports clubs with child members as independent variables, and adjusted for age, gender, family affluence (FAS), and type of habitation (capital, town or village). RESULTS: High VPA increased with access to indoor facilities, while high MVPA was less likely (odds ratio (OR) 0.54 (0.42-0.70)) if indoor sports facilities were present, both unadjusted and adjusted. Access to a local sports club increased OR for high VPA both unadjusted and adjusted to about 2.3 for five or more clubs, while access to sports clubs was not associated with unadjusted MVPA, negatively associated if adjusted for age, gender and FAS but positively associated if also adjusted for indoor sports facilities. CONCLUSIONS: Access to indoor sports facilities itself had a positive association with high VPA, but was persistently negatively associated with high MVPA. Presence of sports clubs with child members was positively associated with high VPA while the association with high MVPA was more complex. The findings have implications for public health planning. PMID- 23042459 TI - Low-grade inflammation and depressive symptoms as predictors of abdominal obesity. AB - AIM: Abundant evidence suggests that depression is a risk factor for cardiovascular disease and metabolic syndrome. Systemic low-grade inflammation and evolving abdominal obesity are hypothesised to be underlying mechanisms explaining the relationship. To test this hypothesis we examined the association of depressive symptoms and inflammation in developing abdominal obesity. METHODS: The subjects were 726 non-diabetic men, 42-60 of age at baseline, participating in the Kuopio Ischemic Heart Disease Risk Factor Study. The follow-up data was collected 11 years after the baseline. Low-grade inflammation was defined as serum C-reactive protein >=2 mg/l and depressive symptoms were assessed by the Human Population Laboratory Depression Scale. Incident abdominal obesity was defined as waist girth >102 cm. RESULTS: Men with low-grade inflammation and depressive symptoms were more likely (OR 4.28, 95% CI 1.93-12.01) to develop abdominal obesity during the 11-year follow-up than in men not having either of these conditions, adjusting for age, smoking, alcohol consumption, prevalent cardiovascular disease, physical activity and socioeconomic status. These men were also more likely (OR 3.94, 95% CI 1.38-11.26) to develop metabolic syndrome. CONCLUSIONS: The presence of systemic low-grade inflammation together with depressive symptoms seems to detect men at a particularly high risk of developing abdominal obesity over a long period of time. PMID- 23042460 TI - Are there educational differences in the association between self-rated health and mortality in Norway? The HUNT Study. AB - AIMS: The aim of this study was to test whether the association between self rated health and mortality differs between educational groups in Norway, and to examine whether health problems and health-related behaviour can explain any of these differences within a previously unexplored contextual setting. METHODS: The study used data from the Nord-Trondelag Health Study 84-86 (HUNT) with a 20-year follow up. The analyses were performed for respondents between 25-101 years at baseline (n = 56,788). The association between self-rated health and mortality was tested using Cox regression. RESULTS: The results indicate that although self rated health is associated with mortality there is no difference in the association between self-rated health and mortality between educational groups. Introducing health-related variables did not have an impact on the result. CONCLUSIONS: Given the small educational differences in the association between self-rated health and mortality, this supports the reliability of self-reported health as a measurement for objective health. PMID- 23042461 TI - Transcatheter aortic valve replacement. AB - Symptomatic severe aortic stenosis is a serious life-threatening condition that requires surgical intervention. Until recently, the only available treatment options were through an open-heart surgery technique. A transcatheter aortic valve replacement is a minimally invasive aortic valve replacement procedure that is available for symptomatic patients with severe aortic stenosis and who are considered high-risk surgical candidates. It is an effective procedure for individuals with multiple comorbidities and high risk for mortality. This article reviews aortic stenosis and associated morbidity and mortality, treatment options, complications, education, and implications. PMID- 23042464 TI - A student paper: music in critical care setting for clients on mechanical ventilators: a student perspective. AB - This article written by baccalaureate nursing students briefly discusses the use of music therapy in clients on mechanical ventilation in intensive care units. The article explores the possible benefits of music therapy and its use in other aspects of health care. PMID- 23042465 TI - Achieving tight glycemic control with new technology: the role of the advanced practice nurse. AB - Cardiac surgery remains one of the most commonly performed surgeries in the world. Intensive insulin therapy has shown to reduce infection in patients undergoing open-heart surgery and is considered standard of care. New technologies are available to achieve and maintain recommended blood glucose goals. These include computer-driven intensive insulin protocols (vs paper-based algorithms) and continuous blood glucose monitors. Managing tight glucose control in cardiac surgery patients has been shown to decrease costs in terms of measurable outcomes including infection, mortality, and length of stay. The advanced practice nurse is uniquely qualified to implement new technologies and can be instrumental in increasing compliance with clinical practice guidelines while decreasing hospital costs. PMID- 23042467 TI - A personal reflection: the difficult decision to leave critical care nursing. AB - At some point in their careers, all critical care nurses will decide that it is time for them to leave critical care nursing. Whether this decision happens because of role change, retirement, or burnout, the decision can be a difficult one. This article explains my decision to leave the pediatric critical care unit and explores some of the reasons nurses leave critical care. PMID- 23042468 TI - Supporting each other. PMID- 23042469 TI - Aneurysm prevention: keep the cat out of the bag. PMID- 23042470 TI - Voltage-activated Ca(2+) channels in rat renal afferent and efferent myocytes: no evidence for the T-type Ca(2+) current. AB - AIMS: Based on indirect methods, it has been suggested that both L- and T-type Ca(2+) channels mediate signalling in the renal afferent arteriole and that T type Ca(2+) channels are involved in signalling in the efferent arteriole. However, Ca(2+) currents have never been studied in these two vessels. Our study was initiated to directly determine the type of Ca(2+) channels in these vessels for the first time, using patch clamp. METHODS AND RESULTS: Native myocytes were obtained from individually isolated rat renal afferent and efferent arterioles and from rat tail arteries (TA). TA myocytes, which possess both L- and T-type Ca(2+) currents, served as a positive control. Inward Ca(2+) and Ba(2+) currents (I(Ca) and I(Ba)) were measured in 1.5 mmol/L Ca(2+) and 10 mmol/L Ba(2+), respectively, using the whole-cell configuration. By exploiting known differences in activation and inactivation characteristics and differing sensitivities to nifedipine and kurtoxin, the presence of both L- and T-type Ca(2+) channels in TA myocytes was readily demonstrated. Afferent arteriolar myocytes exhibited relatively large I(Ca) densities (-2.0 +/- 0.2 pA/pF) in physiological Ca(2+) and the I(Ba) was 3.6-fold greater. These currents were blocked by nifedipine, but not by kurtoxin, and did not exhibit the activation and inactivation characteristics of T-type Ca(2+) channels. Efferent arteriolar myocytes did not exhibit a discernible voltage-activated I(Ca) in physiological Ca(2+). CONCLUSION: Our findings support the physiological role of L-type Ca(2+) channels in the afferent, but not efferent, arteriole, but do not support the premise that functional T-type Ca(2+) channels are present in either vessel. PMID- 23042471 TI - Function of Ahnak protein in aortic smooth muscle cell migration through Rac activation. AB - AIMS: Ahnak protein acts as a scaffold protein networking phospholipase C-gamma and protein kinase C-alpha, which subsequently stimulate an extracellular signal regulated kinase (Erk) pathway. In mouse aortic smooth muscle cells (ASMCs), the activation of the signalling cascade ultimately promotes the cell migration through an unknown mechanism. We aimed to dissect the Ahnak-mediated cell signalling network involved in the migration of ASMCs. METHODS AND RESULTS: Migration of ASMCs from wild-type mice was significantly increased by platelet derived growth factor (PDGF) stimulation in transwell chamber and wound-healing assays, whereas migration of ASMCs from Ahnak knockout mice was reduced. Consistently, stimulation of wild-type ASMCs with PDGF resulted in Rac activation mediated lamellipodial protrusion in migrating cells. In contrast, Ahnak knockout ASMCs displayed lower activation of Rac in response to PDGF and slow lamellipodial protrusion rate and cell migration. Ahnak signalling complex was analysed by immunoprecipitation with antibody to p21-activated protein kinase (PAK). Ahnak protein was shown to function as the signalling scaffold interacting with the multiple protein complex of Erk, PAK, and p21-activated kinase interacting exchange factor beta. The proposed role of Ahnak in cell migration was examined using a restenosis model in which the carotid arteries of mice were subjected to post-ligation injury. We show neointimal formation and SMC migration after ligation injury in Ahnak knockout mice were significantly retarded compared with wild-type mice. CONCLUSION: Ahnak protein plays an important scaffolding function connecting Erk and Rac activation in PDGF-dependent migration of ASMC. PMID- 23042472 TI - Cost-effectiveness of self-management methods for the treatment of chronic pain in an aging adult population: a systematic review of the literature. AB - OBJECTIVE: To determine the cost-effectiveness of self-management techniques for older populations (65 and over) with chronic pain and in the absence of such evidence to investigate this question in an aging adult population (average age 60 and over). METHODS: Systematic review of randomized controlled trials (RCTs) with cost-effectiveness data and at least 6 months' follow-up, up to December 2010. RESULTS: No RCT studies reported cost-effectiveness of self-management exclusively in the over 65 age group. Ten RCTs reported participants with an average age of 60 years or over and met all other inclusion criteria. All of these studies measured cost-effectiveness as cost per improvement in primary outcome, 7 of them using the Western Ontario and McMaster Universities Osteoarthritis Index score, of which 6 reported the pain dimension. Six studies reported cost per quality-adjusted life year (QALY)-gained information, with a further 1 reporting EQ-5D. In 7 studies, relative to usual care, self-management was effective, and in the remaining 3 studies, there was no significant difference. Among those reporting cost per QALY-gained results, self-management did not lead to statistically significant QALY gains relative to usual care (with only one exception). Eight studies suggested that the cost of developing and delivering self-management interventions may be partly offset by savings from reduced subsequent health care resource use. CONCLUSIONS: Self-management is effective among an aging adult population (mean age over 60) with chronic pain and may be cost-effective when outcomes are measured using the Western Ontario and McMaster Universities Osteoarthritis Index pain score. Cost-effectiveness is less certain when measured using the QALY metric. Uncertainty over conclusions regarding cost-effectiveness exists partly due to lack of information regarding societal willingness to pay for pain improvement. There is a need for large multicentred high-quality RCTs to confirm the findings of this review exclusively among older aged populations, such as those who have already reached the statutory retirement age. PMID- 23042473 TI - The meaning of global outcome measures in pain clinical trials: more than just change in pain intensity. AB - OBJECTIVES: To understand the factors that contribute to patient and physician global outcome ratings and the extent to which receiving different doses of opioids or placebo might influence the importance of these factors better. METHODS: A secondary analysis was performed using data from a prospective, multicenter, double-blind placebo-controlled, and active-controlled parallel group dose-ranging study comparing the efficacy of oxymorphone extended release (ER) 20 mg (ER20, N=121); oxymorphone ER 40 mg (ER40, N=121); oxycodone controlled release 20 mg (Oxy20, N=125); and placebo (N=124) in a sample of patients with osteoarthritis. We performed 2 regression analyses to identify the predictors of pretreatment to posttreatment improvement in patient and physician global ratings of arthritis status. RESULTS: Improvement in global ratings of arthritis status was strongly associated with a decrease in pain intensity. Pretreatment to posttreatment improvement in physical and psychological functioning made independent contributions to the prediction of both criterion variables. DISCUSSION: The findings underscore the importance of change in pain intensity as a key correlate of ratings of global improvement. However, pain intensity is not the only important factor. In the current sample, improvement in both physical and psychological functioning made independent contributions to improvements in ratings of osteoarthritis status, supporting global ratings as assessing multicomponent domains. Overall, the findings suggest that when a patient or physician reports that the patient is "doing better," the patient is likely reporting less pain intensity and engaging in more physical activity and feeling better emotionally. PMID- 23042474 TI - Research to encourage exercise for fibromyalgia (REEF): use of motivational interviewing, outcomes from a randomized-controlled trial. AB - OBJECTIVES: Regular exercise is associated with important benefits in patients with fibromyalgia (FM). Unfortunately, long-term maintenance of exercise after a structured program is rare. The present study tested the efficacy of Motivational Interviewing (MI) to promote exercise and improve symptoms in patients with FM. METHODS: A total of 216 patients with FM were randomized to 6 MI sessions (n=107) or an equal number of FM self-management lessons (education control/EC, n=109). Co-primary endpoints were an increase of 30 minutes in moderate-vigorous physical activity and improvement in the Fibromyalgia Impact Questionnaire (FIQ)-Physical Impairment score, assessed at pretreatment, posttreatment, and 3-month and 6 month follow-up. Secondary outcomes included clinically meaningful improvements in FIQ score, pain severity ratings, and a 6-minute walk test. RESULTS: There were no significant treatment group differences in either co-primary endpoint at 6-month follow-up. However, more MI participants than controls exhibited meaningful improvements in FIQ score at 6-month follow-up (62.9% vs. 49.5%, P=0.06). Compared with EC participants, MI participants also displayed a larger increment in their 6-minute walk test (43.9 vs. 24.8 m, P=0.03). In addition, MI was superior to EC in increasing the number of hours of physical activity immediately postintervention and in reducing pain severity both immediately after the intervention and at 3-month follow-up. CONCLUSIONS: Despite a lack of benefits on long-term outcome, MI seems to have short-term benefits with respect to self-report physical activity and clinical outcomes. This is the first study in FM that explicitly addresses exercise maintenance as a primary aim. PMID- 23042476 TI - The characteristics and quality of randomized controlled trials in neuropathic pain: a descriptive study based on a systematic review. AB - BACKGROUND: Evidence from randomized controlled trials is regarded as the gold standard in clinical research and yet the quality of the conduct and reporting of trials is variable, even post-Consolidated Standards of Reporting Trials. This study arose from a systematic review and cost-effectiveness analysis of treatment for neuropathic pain. The aim was to provide a description of the included trials and investigate trends in study characteristics and measures of quality over time. METHODS: The review provided data regarding study characteristics (patients, place, time, drugs, outcomes), methodological factors (sample size calculations, randomization, reporting baseline patient data, withdrawals, intention-to-treat (ITT), and statistical analysis (completeness and correctness of reporting of results, methods of analysis). RESULTS: A total of 131 trials from 1969 to 2007 were included. Of these, 63% were parallel-group designs, the remainder were cross-over; 73% were placebo-controlled. Several trial features increased or improved over time: trial size, quality (using Jadad score), presentation of baseline data by group, reporting of power calculations, use of visual analogue score or numerical rating scale scales to assess pain, completeness of reporting of statistical results, use of modeling to allow for baseline pain scores. The proportion of withdrawals was constant over time with a mean of 14.3%. The proportion of studies stating the analysis as ITT, increased over time, but inspection of papers indicated that the proportion confirmed as ITT was unchanged. CONCLUSIONS: There have been a number of improvements regarding the quality and reporting of randomized controlled trials in neuropathic pain, but some failings remain that at best make some results difficult to interpret and at worst lead to bias. PMID- 23042475 TI - Phonophoresis of dexamethasone sodium phosphate may manage pain and symptoms of patients with carpal tunnel syndrome. AB - OBJECTIVES: This study was designed to compare the efficacy of iontophoresis and phonophoresis of dexamethasone sodium phosphate (Dex-P) treatment for mild to moderate carpal tunnel syndrome (CTS). METHODS: Fifty-two hands in 34 consecutive patients with mild to moderate CTS confirmed by electromyography were allocated randomly into 2 groups. One group received iontophoresis of 0.4% Dex-P and the other group received phonophoresis of 0.4% Dex-P. Phonophoresis (using ultrasound 1 MHz, 5-cm probe, 1.0 W/cm, pulse 1:4, 5 min/session) and iontophoresis (using galvanic current, negative electrode, 2 mA/min, total dose 40 mA for 20 min) was applied over the wrist chin for 10 daily treatment sessions (5 sessions/wk). Measurements were performed before and after treatment and at follow-up 4 weeks later, and included pain assessment by visual analogue scale, electroneurographic measurement (motor and sensory latency, motor and sensory action potential amplitude), and pinch and grip strength. RESULTS: Improvement was significantly more pronounced in the phonophoresis group than in the iontophoresis group for motor latency [mean difference 0.8 m/s; 95% confidence interval (CI), 0.5-1.1], motor action potential amplitude (4.1 mV; 95% CI, 3.0-5.2), finger pinch strength (31.6 N; 95% CI, 15.9-47.3), hand grip strength (27.1 N; 95% CI, 13.5-40.5), and pain relief (2.1 points on a 10-point scale; 95% CI, 1.3-2.9). Effects were sustained in the follow-up period. DISCUSSION: Phonophoresis of Dex-P treatment was more effective than iontophoresis of Dex-P for treatment of CTS. Further study is needed to investigate the combination therapy effects of these treatments with other conservative treatments in CTS patients. PMID- 23042477 TI - Four-dimensional structural and Doppler optical coherence tomography imaging on graphics processing units. AB - The authors present the application of graphics processing unit (GPU) programming for real-time three-dimensional (3-D) Fourier domain optical coherence tomography (FdOCT) imaging with implementation of flow visualization algorithms. One of the limitations of FdOCT is data processing time, which is generally longer than data acquisition time. Utilizing additional algorithms, such as Doppler analysis, further increases computation time. The general purpose computing on GPU (GPGPU) has been used successfully for structural OCT imaging, but real-time 3-D imaging of flows has so far not been presented. We have developed software for structural and Doppler OCT processing capable of visualization of two-dimensional (2-D) data (2000 A-scans, 2048 pixels per spectrum) with an image refresh rate higher than 120 Hz. The 3-D imaging of 100*100 A-scans data is performed at a rate of about 9 volumes per second. We describe the software architecture, organization of threads, and optimization. Screen shots recorded during real-time imaging of a flow phantom and the human eye are presented. PMID- 23042478 TI - Development of thermodynamic optimum searching (TOS) to improve the prediction accuracy of flux balance analysis. AB - Flux balance analysis (FBA) has been widely used in calculating steady-state flux distributions that provide important information for metabolic engineering. Several thermodynamics-based methods, for example, quantitative assignment of reaction directionality and energy balance analysis have been developed to improve the prediction accuracy of FBA. However, these methods can only generate a thermodynamically feasible range, rather than the most thermodynamically favorable solution. We therefore developed a novel optimization method termed as thermodynamic optimum searching (TOS) to calculate the thermodynamically optimal solution, based on the second law of thermodynamics, the minimum magnitude of the Gibbs free energy change and the maximum entropy production principle (MEPP). Then, TOS was applied to five physiological conditions of Escherichia coli to evaluate its effectiveness. The resulting prediction accuracy was found significantly improved (10.7-48.5%) by comparing with the (13)C-fluxome data, indicating that TOS can be considered an advanced calculation and prediction tool in metabolic engineering. PMID- 23042479 TI - Nogo-B promotes the epithelial-mesenchymal transition in HeLa cervical cancer cells via Fibulin-5. AB - Cervical cancer is a common malignancy in women worldwide, and the occurrence of invasion and metastasis is the major cause for most cancer-related deaths. Epithelial-mesenchymal transition (EMT) has been implicated in the metastasis of primary tumors and provides molecular mechanisms for cervical cancer metastasis. We previously reported that Nogo-B mediates cell motility by binding Fibulin-5. Herein, we show that the increased expression of Nogo-B is correlated with the degree of cervical cancer metastasis. In HeLa cervical cancer cells, overexpression of Nogo-B induces the EMT and promotes cell migration and invasion, while inhibiting cell adhesion. Furthermore, we found that Nogo-B accumulates and co-localizes with Fibulin-5 in pseudopods, and the downstream effects of overexpression of Nogo-B on cell motility could be partially abolished by RNA interference against Fibulin-5. These results suggest that Nogo-B functions as an inducer of cervical cancer metastasis and that this effect is mediated, at least in part, through Fibulin-5. PMID- 23042480 TI - Heparan sulfate biosynthesis enzymes in embryonic stem cell biology. AB - Embryonic stem (ES) cells are derived from the inner cell mass of the blastocyst and can give rise to all cell types in the body. The fate of ES cells depends on the signals they receive from their surrounding environment, which either promote self-renewal or initiate differentiation. Heparan sulfate proteoglycans are macromolecules found on the cell surface and in the extracellular matrix. Acting as low-affinity receptors on the cell surface, heparan sulfate (HS) side chains modulate the functions of numerous growth factors and morphogens, having wide impact on the extracellular information received by cells. ES cells lacking HS fail to differentiate but can be induced to do so by adding heparin. ES cells defective in various components of the HS biosynthesis machinery, thus expressing differently flawed HS, exhibit lineage-specific effects. Here we discuss recent studies on the biological functions of HS in ES cell developmental processes. Since ES cells have significant potential applications in tissue/cell engineering for cell replacement therapies, understanding the functional mechanisms of HS in manipulating ES cell growth in vitro is of utmost importance, if the stem cell regenerative medicine from scientific fiction ever will be made real. PMID- 23042482 TI - Dynamic expression pattern of neuro-oncological ventral antigen 1 (Nova1) in the rat brain after focal cerebral ischemia/reperfusion insults. AB - The present study aimed to evaluate the expression of neuro-oncological ventral antigen 1 (Nova1) in cerebral ischemia/reperfusion (I/R) insults by immunohistochemistry. The focal cerebral I/R model was induced by right middle cerebral artery occlusion (MCAO) for 120 min followed by 1 day, 7 days, and 14 days of reperfusion in Sprague-Dawley (SD) rats. The results showed that Nova1 was expressed in nearly the whole brain, although with higher density in hippocampus, hypothalamus, cingulate cortex, and medial habenular nucleus. The immunoreactivity of Nova1 neurons was increased dramatically, especially on both sides of the hippocampal CA(1) region, after 1 day of reperfusion. A strong response occurred at the ipsilateral CA(1) region between 1 day and 7 days of reperfusion. Likewise, strong compensatory responses of Nova1 expression were observed on the contralateral side of the striate cortex, dentate gyrus, and hypothalamus. Interestingly, more Nova1 neurons were observed to translocate to the dendrites and growth cones of the axons in the hypothalamus on the ischemic side after 7 days of reperfusion. In conclusion, our data suggest that Nova1 might mediate neuronal responsiveness, and its expression might positively correlate with neural repair after I/R insults in the rat brain. PMID- 23042483 TI - Prognostic impact of human papillomavirus status, survivin, and epidermal growth factor receptor expression on survival in patients treated with radiochemotherapy for very advanced nonresectable oropharyngeal cancer. AB - BACKGROUND: The influence of human papillomavirus (HPV) status on survival for patients with very advanced inoperable oropharyngeal SCC treated with radiochemotherapy (RCT) was studied. METHODS: Patients received either 69.2 Gy with concomitant boost (ccb) or 70 Gy conventionally fractionated (cf), weekly paclitaxel 40 mg/m(2), and carboplatin area under the concentration-time curve (AUC) 1. Tumor was analyzed for the presence of high-risk HPV-DNA using polymerase chain reaction (PCR) and direct DNA sequencing. p16-expression, survivin, and epidermal growth factor receptor (EGFR) expression were evaluated by immunohistochemistry and influence on survival was calculated. RESULTS: Of 52 patients, 25.0% were HPV positive and 75.0% HPV negative. The 2-year progression free survival (PFS) was 70.1% for p16-positive patients and 37.1% for p16 negative patients (p = .005). The 3-year overall survival (OS) rate was 43.9% for all patients and did not significantly differ between the groups. Neither survivin nor EGFR expression influenced PFS or OS significantly. CONCLUSIONS: HPV status influences PFS in patients with advanced, nonresectable tumor stages but not OS. Additional risk factors seem to have a stronger influence on survival than HPV status. PMID- 23042481 TI - Heparan sulfate biosynthesis: regulation and variability. AB - Nearly all vertebrate cells have been shown to express heparan sulfate proteoglycans (HSPGs) at the cell surface. The HSPGs bind to many secreted signaling proteins, including numerous growth factors, cytokines, and morphogens, to affect their tissue distribution and signaling. The heparan sulfate (HS) chains may have variable length and may differ with regard to both degree and pattern of sulfation. As the sulfation pattern of HS chains in most cases will determine if an interaction with a potential ligand will take place, as well as the affinity of the interaction, a key to understanding the function of HSPGs is to clarify how HS biosynthesis is regulated in different biological contexts. This review provides an introduction to the current understanding of HS biosynthesis and its regulation, and identifies research areas where more knowledge is needed to better understand how the HS biosynthetic machinery works. PMID- 23042484 TI - Programmable microfluidic synthesis of spectrally encoded microspheres. AB - Spectrally encoded fluorescent beads are an attractive platform for assay miniaturization and multiplexing in the biological sciences. Here, we synthesize hydrophilic PEG-acrylate polymer beads encoded with lanthanide nanophosphors using a fully automated microfluidic synthesis device. These beads are encoded by including varying amounts of two lanthanide nanophosphors relative to a third reference nanophosphor to generate 24 distinct ratios. These codes differ by less than 3% from their target values and can be distinguished from each other with an error rate of <0.1%. The encoded bead synthesis strategy we have used is readily extensible to larger numbers of codes, potentially up to millions, providing a new platform technology for assay multiplexing. PMID- 23042485 TI - Surgical and postpartum hereditary brachial plexus attacks and prophylactic immunotherapy. AB - INTRODUCTION: Surgery and childbirth can trigger attacks of hereditary brachial plexus neuropathy (HBPN), and inflammation was suggested as a component of the pathogenesis. METHODS: HBPN patients who underwent surgery or parturition from January 1, 1996 to December 31, 2009 were studied. RESULTS: Twenty-five HBPN patients underwent 48 surgeries or parturitions. Seventeen patients (68%) had attacks, including 13 periprocedural and 7 postpartum by varied anesthesia types. Three patients who had 8 earlier combined attacks (after thyroidectomy, laminectomy, and Caesarean section) were given prophylactic immunosuppressive therapy (corticosteroids +/- immunoglobulin). None suffered postoperative attacks, which is uncharacteristic of their prior experience. Five had perioperative attacks as their first HBPN manifestation. Median follow-up was 11 months (3-48 months). Attacks occurred in the operated limb (n = 6) or distant (n = 7) to surgical sites. All attacks interfered with daily living, with frequent incomplete recovery. Five patients had a SEPT9 mutation. CONCLUSIONS: Corticosteroids may prevent parturition and surgical HBPN attacks in some patients. Diverse surgeries, anesthesia, and childbirth frequently trigger HBPN attacks. PMID- 23042486 TI - Probing the redox non-innocence of dinuclear, three-coordinate Co(II) nindigo complexes: not simply beta-diketiminate variants. AB - Reduction of the dinuclear Co(II) nindigo complex dmp(2)Nin[Co(N{SiMe(3)}(2))](2), with 1 or 2 equiv. of K(0) (or KC(8)), affords the reduced complexes [dmp(2)Nin{Co(N{SiMe(3)}(2))}(2)](-) and [dmp(2)Nin{Co(N{SiMe(3)}(2))}(2)](2-), respectively. Inspection of these reduced species reveals ligand-centered reduction, with each cobalt ion retaining a formal 2+ oxidation state. PMID- 23042487 TI - NIS-catalyzed reactions: amidation of acetophenones and oxidative amination of propiophenones. AB - Single-step amination: the N-iodosuccinimide (NIS)-catalyzed amidation of acetophenone derivatives by using tert-butylhydroperoxide (TBHP) as an oxidant is presented. A variety of acetyl derivatives of heterocyclic compounds were easily converted to their corresponding ketoamides under these conditions. A new, NIS catalyzed amination of propiophenone and its derivatives in the presence of TBHP to furnish the corresponding 2-aminoketone derivatives is the first reported single-step amination of propiophenone derivatives. PMID- 23042488 TI - Simple and scalable preparation of highly active Lewis acidic Sn-beta. PMID- 23042489 TI - Synthesis of selenomethylene-locked nucleic acid (SeLNA)-modified oligonucleotides by polymerases. AB - Enzymatic recognition of SeLNA nucleotides was investigated. KOD XL DNA polymerase was found to be an efficient enzyme in primer extension reactions. Polymerase chain reaction (PCR) amplification of SeLNA-modified DNA templates was also efficiently achieved by Phusion and KOD XL DNA polymerases. PMID- 23042490 TI - In situ atomic-scale imaging of electrochemical lithiation in silicon. AB - In lithium-ion batteries, the electrochemical reaction between the electrodes and lithium is a critical process that controls the capacity, cyclability and reliability of the battery. Despite intensive study, the atomistic mechanism of the electrochemical reactions occurring in these solid-state electrodes remains unclear. Here, we show that in situ transmission electron microscopy can be used to study the dynamic lithiation process of single-crystal silicon with atomic resolution. We observe a sharp interface (~1 nm thick) between the crystalline silicon and an amorphous Li(x)Si alloy. The lithiation kinetics are controlled by the migration of the interface, which occurs through a ledge mechanism involving the lateral movement of ledges on the close-packed {111} atomic planes. Such ledge flow processes produce the amorphous Li(x)Si alloy through layer-by-layer peeling of the {111} atomic facets, resulting in the orientation-dependent mobility of the interfaces. PMID- 23042491 TI - Selective molecular sieving through porous graphene. AB - Membranes act as selective barriers and play an important role in processes such as cellular compartmentalization and industrial-scale chemical and gas purification. The ideal membrane should be as thin as possible to maximize flux, mechanically robust to prevent fracture, and have well-defined pore sizes to increase selectivity. Graphene is an excellent starting point for developing size selective membranes because of its atomic thickness, high mechanical strength, relative inertness and impermeability to all standard gases. However, pores that can exclude larger molecules but allow smaller molecules to pass through would have to be introduced into the material. Here, we show that ultraviolet-induced oxidative etching can create pores in micrometre-sized graphene membranes, and the resulting membranes can be used as molecular sieves. A pressurized blister test and mechanical resonance are used to measure the transport of a range of gases (H(2), CO(2), Ar, N(2), CH(4) and SF(6)) through the pores. The experimentally measured leak rate, separation factors and Raman spectrum agree well with models based on effusion through a small number of angstrom-sized pores. PMID- 23042492 TI - Spin injection: Graphene wins the match. PMID- 23042493 TI - Duodenal leishmaniasis after allogeneic hematopoietic SCT. PMID- 23042494 TI - Prediction of transplant-related complications by C-reactive protein levels before hematopoietic SCT. AB - Various biomarkers have been investigated with regard to their ability to predict the outcome of allogeneic hematopoietic SCT (HSCT). In this study, we retrospectively reviewed 90 recipients who received HSCT between 2007 and 2011 in our institution, and evaluated the predictive value of the baseline serum C reactive protein (CRP) levels just before the initiation of conditioning for transplant-related complications after allogeneic HSCT. A receiver-operating characteristic curve revealed that the baseline serum CRP levels had an excellent predictive value for non-relapse mortality (NRM), with an area under the curve of 0.83. The sensitivity and specificity for NRM were 80% and 87%, respectively, with a cutoff of 0.6 mg/dL. With this cutoff value, multivariate analyses revealed that a higher baseline CRP level was an independent risk factor for NRM (HR 6.21, P<0.01), grade III-IV acute GVHD (HR 3.91, P=0.03) and poor overall survival (HR 3.27, P=0.0018). On the other hand, the baseline CRP level did not predict infectious events. These findings suggested that CRP levels before conditioning may be a useful predictive biomarker for poor survival. PMID- 23042496 TI - Improving laboratory test requests can reduce costs in ICUs. PMID- 23042495 TI - Expression of alpha4beta7 integrin on memory CD8(+) T cells at the presentation of acute intestinal GVHD. AB - Acute intestinal GVHD remains a major source of morbidity after allogeneic hematopoietic cell transplantation (HCT). alpha4beta7 integrin is a cell surface molecule that mediates lymphocyte trafficking to intestinal tissue. In this analysis, peripheral blood was collected at the time of presentation of symptoms of acute GVHD and before any treatment. In all, 45 samples were collected and divided into three groups on the basis of subsequent evaluation: intestinal GVHD (n=15), skin GVHD (n=20) and no GVHD (n=10). Two patients developed intestinal GVHD after DLI. The no-GVHD group comprised 10 patients who presented with suspicious symptoms, but evaluation yielded other etiologies. Analysis by flow cytometry showed that intestinal GVHD patients had a significantly higher percentage of alpha4beta7 integrin-expressing memory CD8(+) T cells (median 7.69%; lower and upper quartiles, 1.06% and 11.64%, respectively) compared with patients with skin GVHD (1.26%; 0.57% and 2.49%) and no GVHD (0.96%; 0.44% and 1.85%), P=0.03. No differences were found in alpha4beta7 expression in any CD4(+) T-cell subsets or naive CD8(+) T cells. This study adds to the evidence that alpha4beta7 integrin is involved in lymphocyte trafficking in acute intestinal GVHD. PMID- 23042497 TI - Recombinant tagging system using ribosomal frameshifting to monitor protein expression. AB - For rapid and accurate quantitation of recombinant proteins during expression and after purification, we introduce a new tagging strategy that expresses both target proteins and limitedly tagged target proteins together in a single cell at a constant ratio by utilizing cis-elements of programmed -1 ribosomal frameshifting (-1RFS) as an embedded device. -1RFS is an alternative reading mechanism that effectively controls protein expression by many viruses. When a target gene is fused to the enhanced green fluorescent protein (EGFP) gene with a -1RFS element implanted between them, the unfused target and the target-GFP fusion proteins are expressed at a fixed ratio. The expression ratio between these two protein products is adjustable simply by changing -1RFS signals. This limited-tagging system would be valuable for the real-time monitoring of protein expression when optimizing expression condition for a new protein, and in monitoring large-scale bioprocesses without a large metabolic burden on host cells. Furthermore, this strategy allows for the direct measurement of the quantity of a protein on a chip surface and easy application to proteomewide study of gene products. PMID- 23042498 TI - A rubric for extracting idea density from oral language samples. AB - While past research has demonstrated that low idea density (ID) scores from natural language samples correlate with late life risk for cognitive decline and Alzheimer's disease pathology, there are no published rubrics for collecting and analyzing language samples for idea density to verify or extend these findings into new settings. This unit outlines the history of ID research and findings, discusses issues with past rubrics, and then presents an operationalized method for the systematic measurement of ID in language samples, with an extensive manual available as a supplement to this unit (Analysis of Idea Density, AID). Finally, reliability statistics for this rubric in the context of dementia research on aging populations and verification that AID can replicate the significant association between ID and late-life cognition are presented. PMID- 23042499 TI - Confocal laser scanning microscopic photoconversion: a new method to stabilize fluorescently labeled cellular elements for electron microscopic analysis. AB - Photoconversion, the method by which a fluorescent dye is transformed into a stable, osmiophilic product that can be visualized by electron microscopy, is the most widely used method to enable the ultrastructural analysis of fluorescently labeled cellular structures. Nevertheless, the conventional method of photoconversion using widefield fluorescence microscopy requires long reaction times and results in low-resolution cell targeting. Accordingly, we have developed a photoconversion method that ameliorates these limitations by adapting confocal laser scanning microscopy to the procedure. We have found that this method greatly reduces photoconversion times, as compared to conventional wide field microscopy. Moreover, region-of-interest scanning capabilities of a confocal microscope facilitate the targeting of the photoconversion process to individual cellular or subcellular elements within a fluorescent field. This reduces the area of the cell exposed to light energy, thereby reducing the ultrastructural damage common to this process when widefield microscopes are employed. PMID- 23042500 TI - Use of channelrhodopsin for activation of CNS neurons. AB - Optogenetics-the use of optically activated proteins to control cell function allows for control of neurons with an unprecedented degree of spatial, temporal, and neurochemical precision. Three protocols are presented in this unit describing the use of channelrhodopsin-2 (ChR2), a light-activated cation channel. These protocols emphasize practical issues of working with ChR2, including guidelines for selecting a gene delivery method, light source, and method of tissue implantation, as well as steps for fabricating fiber optic patch cables and chronic implantable optical fibers. The first protocol describes the use of ChR2 in electrophysiological recordings from brain slices. The second and third involve the use of ChR2 in vivo, with light delivered through chronic fiber implants or guide cannula. PMID- 23042501 TI - Culture of mouse olfactory sensory neurons. AB - Olfactory sensory neurons, located in the nasal epithelium, detect and transmit odorant information to the central nervous system. This requires that these neurons form specific neuronal connections within the olfactory bulb and express receptors and signaling molecules specific for these functions. This protocol describes a primary olfactory sensory neuron culture technique that allows in vitro investigation of olfactory sensory neuron differentiation, axon outgrowth, odorant receptor expression, and function. Olfactory epithelium is obtained from the nasal cavity and is enzymatically treated to reduce stroma tissue. Dissociated olfactory sensory neurons are cultured directly on a layer of cortical astrocytes to support their survival. Using this method, cultured olfactory sensory neurons maintain their bipolar morphology and express odorant signal transduction molecules, which are specific for olfactory sensory neurons. PMID- 23042502 TI - Analysis of skilled forelimb movement in rats: the single pellet reaching test and staircase test. AB - Brain damage, stroke, and neurodegenerative diseases such as Parkinson's or Huntington's disease can cause severe motor deficits in skilled forelimb use in both humans and rats. These deficits are typically analyzed in a reach-to-eat paradigm. Skilled reaching in rats has been found to be a good model of human skilled reaching. Therefore, rats serve as an excellent tool to monitor the development of deficits after neurological insults or changes after medical intervention. The following protocols comprise two different tests of rat skilled reaching. The single pellet reaching test is a paradigm that involves detailed rating and analysis of qualitative aspects of the reaching movement itself. The staircase test is an objective, high-throughput reaching task that allows reaching success (number of pellets eaten) to be investigated in multiple rats at the same time. Both tests have been used extensively to investigate motor deficits and effects of treatment. PMID- 23042503 TI - Pentylenetetrazol (PTZ) kindling model of epilepsy. AB - This unit describes a protocol to perform chemical kindling in mice. Kindling is a chronic animal model of epilepsy that has been extensively studied to understand the process of epileptogenesis and discover novel anti-epileptic compounds. Kindling is a phenomenon where a sub-convulsive stimulus (either chemical or electrical), if applied repetitively and intermittently, will ultimately lead to the generation of full-blown convulsions. Kindling can be induced either by (1) electrical stimulation of different brain regions (electrical kindling) or (2) using various chemical agents (chemical kindling). This unit discusses in detail the methodology to execute pentylenetetrazol (PTZ; a GABA(A) receptor antagonist)-induced chemical kindling in mice. PTZ is administered chronically at a sub-convulsive dose for a number of days. Seizure score is calculated after each PTZ injection. The effect of test/reference compounds can be tested by administering them either prior to the initiation of kindling (pre-kindling phase) or after animals are fully kindled (post-kindling phase). PMID- 23042504 TI - Development and evaluation of the DECIDE to move! Physical activity educational video. AB - PURPOSE: To develop a video that provides accessible and usable information about the importance of physical activity to type 2 diabetes self-management and ways of incorporating physical activity into everyday life. CONCLUSION: A 15-minute physical activity educational video narrated by US Surgeon General Dr Regina Benjamin was developed and evaluated. The video addresses the following topics: the effects of exercise on diabetes, preparations for beginning physical activity, types of physical activity, safety considerations (eg, awareness of symptoms of hypoglycemia during activity), and goal setting. Two patient screening groups were held for evaluation and revision of the video. Patient satisfaction ratings ranged 4.6 to 4.9 out of a possible 5.0 on dimensions of overall satisfaction, how informative they found the video to be, how well the video held their interest and attention, how easy the video was to understand, and how easy the video was to see and hear. Patients reported the educational video effective in empowering them to take strides toward increasing and maintaining physical activity in their lives. The tool is currently used in a clinical research trial, Project DECIDE, as one component of a diabetes and cardiovascular disease self-management program. PMID- 23042505 TI - Galectin-3 expression in thyroid fine needle cytology (t-FNAC) uncertain cases: validation of molecular markers and technology innovation. AB - Thyroid cancer is not very common, accounting for 1-2% of all cancers, with a population incidence of about 0.004%. Currently, the ability to discriminate between follicular adenoma and carcinoma represents the major challenge in preclinical diagnosis of thyroid proliferative lesions. Better discrimination between the two would help avoid unnecessary thyroidectomy and save valuable resources. Over the years, galectin-3 (Gal-3) has been proposed as a diagnostic marker with varied success. In this paper, we used Environmental Scanning Electron Microscopy Immunogold Labelling (ESEM-IGL) to investigate the expression of Gal-3 on Thin-Prep fine needle aspiration cytology (FNAC). We optimized the ESEM-IGL method on thyroid cell lines (RO-82 and FTC-133) comparing our membrane Gal-3 labeling data with Western blot. We evaluated 183 thyroid FNAC from Italian patients with a uncertain pre-surgical diagnosis. ESEM-IGL method marker sensitivity is 71.2%, while specificity is 53.3% and diagnostic efficacy is 61.2%. Our results confirmed that Gal-3 expression is associated with situations of hypertrophy and/or cellular hyperproliferation, pathophysiological situations common both to adenomas and to thyroid carcinomas. The innovation of thyroid FNAC Thin-Prep ESEM-IGL shows the levels of Gal-3 immunolabeling clearly, even through the individual cells of a thyroid nodule. However, Gal-3 alone, as a molecular marker of thyroid cancer, can still have a limited application in pre-surgery diagnosis. PMID- 23042506 TI - Expression and clinical significance of HMGB1 in human liver cancer: Knockdown inhibits tumor growth and metastasis in vitro and in vivo. AB - The high-mobility group box 1 (HMGB1) signaling pathway plays a crucial role in tumorigenesis and progression of many malignant cancers. The present study aimed to investigate the expression and clinical significance of HMGB1 in human primary liver cancer, and further explore the molecular mechanisms of HMGB1 in tumor growth and metastasis. Forty cases of human liver cancer and normal liver tissues were collected. The expression of HMGB1 was assessed using RT-PCR and western blot assays in biopsy samples. The HMGB1 pathway in vitro was blocked using transfection of the recombinant small hairpin RNA adenovirus vector rAd5-HMGB1 into the human liver cancer cell line SMMC-7721. The expression of HMGB1, phosphorylated AKT (p-AKT), Ki-67 and matrix metallopeptidase-2 (MMP-2) was detected by Real-PCR and western blot assays. Cell proliferative activities and metastatic capability were determined by MTT and Transwell assays. Cell cycle distribution and apoptosis were detected by flow cytometry. A subcutaneous xenograft tumor model was established, validating the effects of rAd5-HMGB1 on tumor growth in vivo. As a consequence, HMGB1 was found to be highly expressed in liver cancer compared with normal tissues, and was positively associated with pathological grade and distant metastases of liver cancer. Knockdown of HMGB1 downregulated the expression of p-AKT, Ki-67 and MMP-2, inhibited the proliferative activities and metastatic potential of SMMC-7721 cells, induced cell cycle arrest and apoptosis, and slowed the growth of xenograft tumors. Altogether, the expression of HMGB1 is closely correlated with pathological grade and distant metastases of liver cancer, and knockdown of HMGB1 inhibits liver cancer growth and metastasis, suggesting that HMGB1 may be involved in liver cancer development and progression through AKT-mediated regulation of Ki-67 and MMP-2 expression, and represent a potential therapeutic target for this aggressive malignancy. PMID- 23042507 TI - Anionic 1,2,3-triazole-4,5-diylidene: a 1,2-dihapto ligand for the construction of bimetallic complexes. AB - A super pyrazolate: deprotonation of the flanking hydrogen of metal complexes of mesoionic carbenes (MICs) offers a simple and general route for the preparation of bimetallic complexes of a 1,2-dihapto anionic dicarbene ligand that is isoelectronic with widely used pyrazolate ligands, while conferring greater electron donation and stronger M-L bonds. PMID- 23042508 TI - Hydrodynamic resettability for a microfluidic particulate-based arraying system. AB - Precision hydrodynamic controls of microparticles (e.g., microbeads and cells) are critical to diverse lab-on-a-chip applications. Microfluidic particulate based arraying techniques are widely used; however, achieving full microarray resettability without sacrificing trapping performance has remained a significant challenge. Here we present a single-layer hydrodynamic methodology for releasing high numbers of microparticles after a microfluidic arraying process. Experiments with suspended streptavidin-coated polystyrene microbeads (15 MUm in diameter) revealed resetting efficiencies of 100%, with trapping and loading efficiencies of 99% and 99.8%, respectively. Experiments with suspended endothelial cells (13 17 MUm in diameter) revealed trapping efficiencies of 65% and 93% corresponding to arraying of one cell or at least one cell per trap, respectively, with loading efficiencies of 78%. Full cell-based resettability was also observed, with the caveat that reagents that promote cellular detachment from the substrate were required. The presented resettable microarray could be readily integrated into bead-based or cell-based microfluidic platforms to enable: (i) the retrieval of high numbers of microparticles (e.g., for subsequent analyses and/or use in additional experiments), and (ii) microarray reusability. PMID- 23042509 TI - Nanoaggregates of a pentacenequinone derivative as reactors for the preparation of palladium nanoparticles. AB - Fluorescent nanoaggregates of pentacenequinone derivative serve as reactors for the preparation of palladium nanoparticles in aqueous medium. Further, the combination of catalytic quantities of palladium nanoparticles with NaBH(4) smoothly reduces 4-nitrophenol to 4-aminophenol in aqueous medium. PMID- 23042510 TI - Reply to the letter to the editor by Johnson and Wasserman. PMID- 23042511 TI - Nitric oxide prevents atorvastatin-induced skeletal muscle dysfunction and alterations in mice. AB - INTRODUCTION: Myopathy is the most common side effect of statins. Because nitric oxide (NO) has a key role in regulating skeletal muscle function, we studied whether the NO-donating atorvastatin NCX 6560 could show a better profile on skeletal muscle function and structure compared with atorvastatin. METHODS: C57BL/6 mice received atorvastatin 40 mg/kg/day or an equivalent dose of NCX 6560 for 2 months. Muscle function assessed by treadmill test, serum creatine kinase (CK) activity, citrate synthase (CS) activity, and muscle histology were evaluated. RESULTS: Atorvastatin significantly (P < 0.001) reduced muscle endurance, increased serum CK by 6-fold, and induced muscle fiber atrophy. Conversely, NCX 6560 preserved muscle function, prevented CK increase and did not modify muscle structure. Interestingly, atorvastatin reduced CS activity, a marker for mitochondrial function, in gastrocnemius, diaphragm, and heart, whereas NCX 6560 prevented such decrease. CONCLUSIONS: These findings suggest that NO may prevent statin-induced myopathy. PMID- 23042512 TI - Light-emitting electrochemical "swimmers". AB - Swimmer in the dark: propulsion of a conducting object is intrinsically coupled with light emission using bipolar electrochemistry. Asymmetric redox activity on the surface of the swimmer (black bead) causes production of gas bubbles to propel the swimmer in a glass tube with simultaneous electrochemiluminescence (ECL) emission to monitor the progress of the swimmer. PMID- 23042514 TI - Rapid determination of sugar content in biomass hydrolysates using nuclear magnetic resonance spectroscopy. AB - Large populations of potential cellulosic biomass feedstocks are currently being screened for fuel and chemical applications. The monomeric sugar content, released through hydrolysis, is of particular importance and is currently measured with time-consuming HPLC methods. A method for sugar detection is presented here that employs (1)H NMR spectra regressed against primary HPLC sugar concentration data to build partial least squares (PLS) models. The PLS2 model is able to predict concentrations of both major sugar components, like glucose and xylose, and minor sugars, such as arabinose and mannose, in biomass hydrolysates. The model was built with 65 samples from a variety of different biomass species and covers a wide range of sugar concentrations. Model predictions were validated with a set of 15 samples which were all within error of both HPLC and NMR integration measurements. The data collection time for these NMR measurements is less than 20 min, offering a significant improvement to the 1 h acquisition time that is required for HPLC. PMID- 23042513 TI - The microbiome in wound repair and tissue fibrosis. AB - Bacterial colonization occurs in all wounds, chronic or acute, and the break in epithelium integrity that defines a wound impairs the forces that shape and constrain the microbiome at that site. This review highlights the interactions between bacterial communities in the wound and the ultimate resolution of the wound or development of fibrotic lesions. Chronic wounds support complex microbial communities comprising a wide variety of bacterial phyla, genera, and species, including some fastidious anaerobic bacteria not identified using culture-based methods. Thus, the complexity of bacterial communities in wounds has historically been underestimated. There are a number of intriguing possibilities to explain these results that may also provide novel insights into changes and adaptation of bacterial metabolic networks in inflamed and wounded mucosa, including the critical role of biofilm formation. It is well accepted that the heightened state of activation of host cells in a wound that is driven by the microbiota can certainly lead to detrimental effects on wound regeneration, but the microbiota of the wound may also have beneficial effects on wound healing. Studies in experimental systems have clearly demonstrated a beneficial effect for members of the gut microbiota on regulation of systemic inflammation, which could also impact wound healing at sites outside the gastrointestinal tract. The utilization of culture-independent microbiology to characterize the microbiome of wounds and surrounding mucosa has raised many intriguing questions regarding previously held notions about the cause and effect relationships between bacterial colonization and wound repair and mechanisms involved in this symbiotic relationship. PMID- 23042517 TI - Applying optimal model selection in principal stratification for causal inference. AB - Noncompliance to treatment allocation is a key source of complication for causal inference. Efficacy estimation is likely to be compounded by the presence of noncompliance in both treatment arms of clinical trials where the intention-to treat estimate provides a biased estimator for the true causal estimate even under homogeneous treatment effects assumption. Principal stratification method has been developed to address such posttreatment complications. The present work extends a principal stratification method that adjusts for noncompliance in two treatment arms trials by developing model selection for covariates predicting compliance to treatment in each arm. We apply the method to analyse data from the Esprit study, which was conducted to ascertain whether unopposed oestrogen (hormone replacement therapy) reduced the risk of further cardiac events in postmenopausal women who survive a first myocardial infarction. We adjust for noncompliance in both treatment arms under a Bayesian framework to produce causal risk ratio estimates for each principal stratum. For mild values of a sensitivity parameter and using separate predictors of compliance in each arm, principal stratification results suggested that compliance with hormone replacement therapy only would reduce the risk for death and myocardial reinfarction by about 47% and 25%, respectively, whereas compliance with either treatment would reduce the risk for death by 13% and reinfarction by 60% among the most compliant. However, the results were sensitive to the user-defined sensitivity parameter. PMID- 23042516 TI - Long-term treatment of severe recalcitrant atopic dermatitis with omalizumab, an anti-immuno-globulin E. PMID- 23042518 TI - Barrier protective effects of rosmarinic acid on HMGB1-induced inflammatory responses in vitro and in vivo. AB - High mobility group box 1 (HMGB1) protein is a crucial cytokine that mediates response to infection, injury, and inflammation. Rosmarinic acid (RA) is an important component of the leaves of Perilla frutescens and has neuroprotective, anti-microbial, anti-oxidant, and anti-cancer effects but little is known of its effects on HMGB1-mediated inflammatory response. Here, we investigated this issue by monitoring the effects of RA on the lipopolysaccharide (LPS) or cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated modulation of inflammatory responses. RA potently inhibited the release of HMGB1 and down regulated HMGB1-dependent inflammatory responses in human endothelial cells. RA also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. Furthermore, RA reduced CLP-induced HMGB1 release and sepsis-related mortality. Given these results, RA should be viewed as a candidate therapeutic agent for the treatment of various inflammatory diseases via inhibition of the HMGB1 signaling pathway. PMID- 23042519 TI - Ex vivo 1H and 31P magnetic resonance spectroscopy as a means for tumor characterization in ovarian cancer patients. AB - We aimed to determine whether cells obtained from malignant ovarian tumors had different ex vivo 1H- and 31P (phosphorus-31)-magnetic resonance (MR) spectra compared to cells obtained from benign ovarian cysts. In addition, we aimed to assess the metabolic effects of chemotherapy on malignant cells obtained from peritoneal effusions of ovarian cancer patients. We included 20 ovarian cancer patients undergoing explorative laparotomy for tumor resection, 15 patients undergoing oophorectomy for benign ovarian cysts and 8 patients with advanced ovarian cancer with cancerous peritoneal effusion undergoing palliative percutaneous drainage. Ovarian and metastatic tissues were obtained from all patients undergoing laparotomy and analyzed using 1H magnetic resonance spectroscopy (MRS). Cancerous cells from peritoneal effusions were incubated with 3 different anti-mitotic drugs (paclitaxel, cisplatin and carboplatin) at LC50 and the consequent metabolic changes were monitored using 31P-MRS. 1H-MRS revealed significantly higher intracellular lactate levels in cells obtained from ovarian tumors, most prominently in the moderately to poorly differentiated histological types, while total choline (Chol) compounds were higher in the moderately to poorly differentiated subgroup only. Ovarian cancer cells obtained from peritoneal effusions showed a significantly decreased glycerophosphocholine (GPC), glycerophosphoethanolamine (GPE) and uridine diphospho-sugar (UDPS) levels following ex vivo exposure to all 3 anti-mitotic drugs. Ex vivo 1H-MRS identified significant metabolic differences between cells obtained from ovarian tumors compared to those originating in benign ovarian cysts, including increased lactate and total choline compound levels. The 31P-MRS technique allowed characterization and monitoring of metabolic changes occurring in ovarian cancer cells in response to chemotherapy. PMID- 23042520 TI - Ligand-centered redox activity in cobalt(II) and nickel(II) bis(phenolate) dipyrrin complexes. AB - One for all: a trianionic ligand containing the biologically relevant moieties phenolate and porphyrin was designed and synthesized. One-electron oxidation of the nickel and cobalt complexes of these ligands affords an unprecedented and highly stable hybrid porphyrinyl-phenoxyl radical bound to the metal center. Two electron oxidation of these complexes leads to the M(2+) -(close-shell two electron oxidized ligand) species. PMID- 23042521 TI - Deterministic splitting of fluid volumes in electrowetting microfluidics. AB - Conventional droplet generation approaches in digital microfluidics show ~10% variation in droplet volumes and are restricted to creating only small volumes. In this work, we demonstrate a new approach for splitting sample volumes precisely by gradually ramping down voltage, in place of abruptly switching off electrodes. This allows us to eliminate hydrodynamic instabilities responsible for variations in droplet volume. A simple visual method was developed for measuring sample volumes created on-chip. Our results show that generating and measuring arbitrary sample volumes accurately, with < 1% variation, is possible in electrowetting devices. The approach can be easily extended to existing digital microfluidic systems, and can potentially improve performance of applications requiring precise sample metering, such as immunoassays or DNA amplification. PMID- 23042522 TI - A multifunctional nanosensor based on silica nanoparticles and biological applications in living cells. AB - A multifunctional nanosensor based on silica nanoparticles has been designed by importing metal binding sites and hydrogen bonds directly attached to the chromophore. It works well in the recognition of Hg(2+), H(2)PO(4)(-), S(2-)via different combination mechanisms, and intracellular imaging. PMID- 23042523 TI - Letter to the editor: impact of prophylactice percutaneous endoscopic gasatrostomy on malnutrition and QOL in patients with head and neck cancer: a randomized study. PMID- 23042525 TI - Super-resolution microscopy: a comparative treatment. AB - One of the fundamental limitations of optical microscopy is that of diffraction, or in essence, how small a beam of light can be focused by using an optical lens system. This constraint, or barrier if you will, was theoretically described by Ernst Abbe in 1873 and is roughly equal to half the wavelength of light used to probe the system. Many structures, particularly those within cells, are much smaller than this limit and thus are difficult to visualize. Over the last two decades, a new field of super-resolution imaging has been created and been developed into a broad range of techniques that allow routine imaging beyond the far-field diffraction limit of light. In this unit we outline the basic principles of the various super-resolution imaging modalities, paying particular attention to the technical considerations for biological imaging. Furthermore, we discuss their various applications in the imaging of both fixed and live biological samples. PMID- 23042524 TI - Live-animal imaging of renal function by multiphoton microscopy. AB - Intravital microscopy, microscopy of living animals, is a powerful research technique that combines the resolution and sensitivity found in microscopic studies of cultured cells with the relevance and systemic influences of cells in the context of the intact animal. The power of intravital microscopy has recently been extended with the development of multiphoton fluorescence microscopy systems capable of collecting optical sections from deep within the kidney at subcellular resolution, supporting high-resolution characterizations of the structure and function of glomeruli, tubules, and vasculature in the living kidney. Fluorescent probes are administered to an anesthetized, surgically prepared animal, followed by image acquisition for up to 3 hr. Images are transferred via a high-speed network to specialized computer systems for digital image analysis. This general approach can be used with different combinations of fluorescent probes to evaluate processes such as glomerular permeability, proximal tubule endocytosis, microvascular flow, vascular permeability, mitochondrial function, and cellular apoptosis/necrosis. PMID- 23042526 TI - Quantitative fluorescent speckle microscopy (QFSM) to measure actin dynamics. AB - Quantitative fluorescent speckle microscopy (QFSM) is a live-cell imaging method to analyze the dynamics of macromolecular assemblies with high spatial and temporal resolution. Its greatest successes were in the analysis of actin filament and adhesion dynamics in the context of cell migration and microtubule dynamics in interphase and the meiotic/mitotic spindle. Here, focus is on the former application to illustrate the procedures of FSM imaging and the computational image processing that extracts quantitative information from these experiments. QFSM is advantageous over other methods because it measures the movement and turnover kinetics of the actin filament (F-actin) network in living cells across the entire field of view. Experiments begin with the microinjection of fluorophore-labeled actin into cells, which generate a low ratio of fluorescently labeled to endogenously unlabeled actin monomers. Spinning disk confocal or wide-field imaging then visualizes fluorophore clusters (two to eight actin monomers) within the assembled F-actin network as speckles. QFSM software identifies and computationally tracks and utilizes the location, appearance, and disappearance of speckles to derive network flows and maps of the rate of filament assembly and disassembly. PMID- 23042528 TI - Characterization of modified RNA by top-down mass spectrometry. AB - Characteristic mass differences between fragment ions from backbone cleavage of RNA by electron detachment (d, w) and fragment ions from collisionally activated dissociation (c, y) provide extensive sequence information. Structure analysis by this approach should be especially useful for the detailed characterization of synthetic or post-transcriptionally modified RNA. PMID- 23042527 TI - Analysis of protein and lipid dynamics using confocal fluorescence recovery after photobleaching (FRAP). AB - Fluorescence recovery after photobleaching (FRAP) is a powerful, versatile, and widely accessible tool to monitor molecular dynamics in living cells that can be performed using modern confocal microscopes. Although the basic principles of FRAP are simple, quantitative FRAP analysis requires careful experimental design, data collection, and analysis. In this unit, we discuss the theoretical basis for confocal FRAP, followed by step-by-step protocols for FRAP data acquisition using a laser-scanning confocal microscope for (1) measuring the diffusion of a membrane protein, (2) measuring the diffusion of a soluble protein, and (3) analysis of intracellular trafficking. Finally, data analysis procedures are discussed, and an equation for determining the diffusion coefficient of a molecular species undergoing pure diffusion is presented. PMID- 23042529 TI - New technology for cervical cancer screening. AB - BACKGROUND: Cervical cancer is the second most common cancer among women worldwide. With the introduction of organized cervical cytological screening programs, the incidence of cervical cancer has been dramatically reduced. OBJECTIVES: This study aimed to determine the new technology that can potentially afford unique advantages for cervical cancer screening. METHODS: Cervical specimens collected in PreservCyt were processed for ThinPrep cytological test, the new technology test and human papillomavirus detection. RESULTS: The concordance between the new technology and ThinPrep cytological test was 96.34%, with 931 cases positive and 148 cases negative with both tests (kappa = 0.857). The sensitivity and the specificity of the new technology were 99.04% (931/940) and 82.22% (148/180), respectively. Youden index was 0.81. The positive predictive value and the negative predictive value were 96.68% (931/963) and 94.27% (148/157), respectively. In the 124 positive cases of the new technology, human papillomavirus DNA test was positive in 109 cases (87.9%) and negative in 15 cases (12.1%). Compared to the histopathological diagnosis, the sensitivity and the negative predictive value of the new technology were 98.57% (69/70) and 95.45% (21/22), respectively. CONCLUSIONS: The screening design will enable evaluation of several competing screening technologies in reducing the incidence of and mortality from cervical cancer. In particular, if the new technology is used as the screening test, it can be a quick screening test and does not depend on the subjective judgment of the doctors. As such, it could potentially afford unique advantages for screening. PMID- 23042530 TI - MicroRNAs, transforming growth factor beta-1, and tissue fibrosis. AB - MicroRNAs are short noncoding RNA regulators that repress synthesis of their targets post-transcriptionally. On average, each microRNA is estimated to regulate several hundred protein-coding genes, and about 60% of proteins are thought to be regulated by microRNAs in total. A subset of these genes, including the key profibrotic cytokine transforming growth factor beta-1 (TGF-beta1), exhibits particularly strong levels of post-transcriptional control of protein synthesis, involving microRNAs and other mechanisms. Changes in microRNA expression pattern are linked to profound effects on cell phenotype, and microRNAs have an emerging role in diverse physiological and pathological processes. In this review, we provide an overview of microRNA biology with a focus on their emerging role in diseases typified by organ fibrosis. PMID- 23042531 TI - Development of a platform process for adenovirus purification that removes human SET and nucleolin and provides high purity vector for gene delivery. AB - The manufacturing of virus occurs at a modest scale in comparison to many therapeutic proteins mainly because a gene therapy dose is typically only ug of vector. Although modest in scale the generation of high purity virus is challenging due to low viral expression levels and the difficulties in adequately characterizing such a large and complex molecule. A 100 L bioreactor might produce only 100 mg of virus that must be separated from host and process impurities that are typically greater by several orders of magnitude. Furthermore, in the later purification stages the main milieu component is often virus at low concentration (ug/mL) which may non-specifically adsorb to purification surfaces resulting in a lowered virus recovery. This study describes our approach to develop a scalable, manufacturable robust process for an Adenovirus (Ad) gene therapy vector. A number of analytical tools were developed to guide the purification design. During process development, two human proteins, SET and nucleolin, were identified in viral preparations. To our knowledge, this is the first time that SET and nucleolin have been described in Ad. In this report we detail a process for their removal and the robust removal of all process, product and host cell impurities. PMID- 23042532 TI - Relationship between cervical cord 1H-magnetic resonance spectroscopy and clinoco electromyographic profile in amyotrophic lateral sclerosis. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons, leading to limb paralysis and respiratory failure. METHODS: C1-C3 cord (1) H-magnetic resonance spectroscopy ((1) H-MRS) was performed in 19 patients with ALS and 20 controls. N acetylaspartate (NAA), choline-containing compounds, creatine plus phosphocreatine (Cr), and myo-Inositol (m-Ins) were measured. ALS functional rating scale-revised (ALSFRS) and forced vital capacity (FVC) were assessed. The rates of decline were calculated at 6 months before and after (1) H-MRS. RESULTS: NAA/Cr and NAA/m-Ins were decreased significantly, and m-Ins/Cr was increased significantly in ALS patients compared with controls. NAA/Cr and NAA/m-Ins were correlated with ALSFRS and FVC and inversely linked to the decline rates. NAA/Cr, NAA/m-Ins, and m-Ins/Cr were altered markedly in 9 patients with denervation and neurogenic changes in both C2 paraspinal and upper limb muscles. CONCLUSIONS: These metabolite ratios were associated with disease progression and ongoing denervation in neck and hand muscles. C1-C3 cord (1) H-MRS might reflect anterior horn cell damage causing neck/arm weakness and respiratory dysfunction in ALS patients. PMID- 23042533 TI - Enhancement of placenta growth factor expression by oncostatin M in human rheumatoid arthritis synovial fibroblasts. AB - Oncostatin M (OSM) belongs to IL-6 subfamily and is mostly produced by T lymphocytes. High levels of OSM are detected in the pannus of rheumatoid arthritis (RA) patients and it may arouse the inflammation responses in joints and eventually leads to bone erosion. Placenta growth factor (PLGF) is an angiogenic factor and highly homologous with vascular endothelial growth factor (VEGF). It has been recently reported that PLGF is highly expressed in synovial tissue and enhances the production of proinflammatory cytokines including TNF alpha and IL-6. Here, we demonstrated that OSM increased mRNA and protein levels of PLGF in a time- and concentration-dependent manner in RA synovial fibroblasts. Inhibitors of JAK3 and PI3K antagonized OSM-induced production of PLGF. OSM enhanced the phosphorylation of Tyr705-STAT3, Ser727-STAT3, Ser473-Akt, and increased the nuclear translocation of phosphorylated STAT3 time-dependently. Transfection of dominant negative Akt or application of PI3K inhibitorLY294002 significantly inhibited p-Tyr705-STAT3, p-Ser727-STAT3, and PLGF expression, indicating that Akt is involved in JAK3/STAT3/PLGF signaling cascade. To further examine whether STAT3 binds to the promoter region of PLGF, Chip assay was used and it was found that OSM could bind with PLGF promoter, which was inhibited by JAK3 and PI3K inhibitors. Accumulation of PLGF in the pannus may contribute to the inflammation, angiogenesis and joints destruction in RA patients. These findings demonstrated the important role of OSM in the pathology network of RA and provided novel therapeutic drug targets for RA treatment. PMID- 23042534 TI - A novel T cell-based vaccine capable of stimulating long-term functional CTL memory against B16 melanoma via CD40L signaling. AB - The ultimate goal of antitumor vaccines is to develop memory CD8(+) cytotoxic T lymphocytes (CTLs), which are critical mediators of antitumor immunity. We previously demonstrated that the ovalbumin (OVA)-specific CD4(+) T cell-based (OVA-T(EXO)) vaccine generated using OVA-pulsed dendritic cell (DC(OVA))-released exosomes (EXO(OVA)) stimulate CTL responses via IL-2 and costimulatory CD80 signaling. To assess the potential involvement of other costimulatory pathways and to define the key constituent of costimulation for memory CTL development, we first immunized wild-type (WT) C57BL/6 and gene-knockout mice with WT CD4(+) OVA T(EXO) cells or OVA-T(EXO) cells with various molecular deficiencies. We then assessed OVA-specific primary and recall CTL responses using PE-H-2K(b)/OVA(257 264) tetramer and FITC-anti-CD8 antibody staining by flow cytometry. We also examined antitumor immunity against the OVA-expressing B16 melanoma cell line BL6 10(OVA). We demonstrated that CD4(+) OVA-T(EXO) cells stimulated more efficient CTL responses compared to DC(OVA). By assessing primary and recall CTL responses in mice immunized with OVA-T(EXO) or with OVA-T(EXO) lacking the costimulatory molecules CD40L, 4-1BBL or OX40L, we demonstrated that these costimulatory signals are dispensable for CTL priming by OVA-T(EXO). Interestingly, CD40L, but not 4-1BBL or OX40L, plays a crucial role in the development of functional memory CTLs against BL6-10(OVA) tumors. Overall, this work suggests that a novel CD4(+) T cell-based vaccine that is capable of stimulating long-term functional CTL memory via CD40L signaling may represent a novel, efficient approach to antitumor vaccination. PMID- 23042538 TI - Lessons from before and after nanotech. PMID- 23042536 TI - MicroRNA-466l inhibits antiviral innate immune response by targeting interferon alpha. AB - Effective recognition of viral infections and subsequent triggering of antiviral innate immune responses are essential for the host antiviral defense, which is tightly regulated by multiple regulators, including microRNAs (miRNAs). A previous study showed that miR-466l upregulates IL-10 expression in macrophages by antagonizing RNA-binding protein tristetraprolin-mediated IL-10 mRNA degradation. However, the ability of miR-466l to regulate antiviral immune responses remains unknown. Here, we found that interferon-alpha (IFN-alpha) expression was repressed in Sendai virus (SeV)- and vesicular stomatitis virus (VSV)-infected macrophages and in dendritic cells transfected with miR-466l expression. Moreover, multiple IFN-alpha species can be directly targeted by miR 466l through their 3' untranslated region (3'UTR). This study has demonstrated that miR-466l could directly target IFN-alpha expression to inhibit host antiviral innate immune response. PMID- 23042535 TI - Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and beta cell regeneration in a T1D model. AB - Previously, we established a model in which physiologically adequate function of the autologous beta cells was recovered in non-obese diabetic (NOD) mice after the onset of hyperglycemia by rendering them hemopoietic chimera. These mice were termed antea-diabetic. In the current study, we addressed the role of T regulatory (Treg) cells in the mechanisms mediating the restoration of euglycemia in the antea-diabetic NOD model. The data generated in this study demonstrated that the numbers of Treg cells were decreased in unmanipulated NOD mice, with the most profound deficiency detected in the pancreatic lymph nodes (PLNs). The impaired retention of the Treg cells in the PLNs correlated with the locally compromised profile of the chemokines involved in their trafficking, with the most prominent decrease observed in SDF-1. The amelioration of autoimmunity and restoration of euglycemia observed in the antea-diabetic mice was associated with restoration of the Treg cell population in the PLNs. These data indicate that the function of the SDF-1/CXCR4 axis and the retention of Treg cells in the PLNs have a potential role in diabetogenesis and in the amelioration of autoimmunity and beta cell regeneration in the antea-diabetic model. We have demonstrated in the antea-diabetic mouse model that lifelong recovery of the beta cells has a strong correlation with normalization of the Treg cell population in the PLNs. This finding offers new opportunities for testing the immunomodulatory regimens that promote accumulation of Treg cells in the PLNs as a therapeutic approach for type 1 diabetes (T1D). PMID- 23042540 TI - Single molecules: A protein in the spotlight. PMID- 23042541 TI - Quantum information: Blockade at a different level. PMID- 23042542 TI - Scanning probe microscopy: A discerning look at the bonds in a molecule. PMID- 23042543 TI - Molecular electronics: Probing intramolecular circuit laws. PMID- 23042544 TI - Quantum dots: Strain is a problem no more. PMID- 23042545 TI - Thermoelectrics: The panoscopic approach. PMID- 23042546 TI - Microfluidic technologies for accelerating the clinical translation of nanoparticles. AB - Using nanoparticles for therapy and imaging holds tremendous promise for the treatment of major diseases such as cancer. However, their translation into the clinic has been slow because it remains difficult to produce nanoparticles that are consistent 'batch-to-batch', and in sufficient quantities for clinical research. Moreover, platforms for rapid screening of nanoparticles are still lacking. Recent microfluidic technologies can tackle some of these issues, and offer a way to accelerate the clinical translation of nanoparticles. In this Progress Article, we highlight the advances in microfluidic systems that can synthesize libraries of nanoparticles in a well-controlled, reproducible and high throughput manner. We also discuss the use of microfluidics for rapidly evaluating nanoparticles in vitro under microenvironments that mimic the in vivo conditions. Furthermore, we highlight some systems that can manipulate small organisms, which could be used for evaluating the in vivo toxicity of nanoparticles or for drug screening. We conclude with a critical assessment of the near- and long-term impact of microfluidics in the field of nanomedicine. PMID- 23042547 TI - HBV promotes the proliferation of hepatic stellate cells via the PDGF-B/PDGFR beta signaling pathway in vitro. AB - The activation of hepatic stellate cells (HSCs) is closely associated with liver fibrosis in chronic hepatitis B virus (HBV) infection. However, the molecular mechanisms leading to HSC activation remain unclear. It has been reported that the platelet-derived growth factor-B (PDGF-B)/PDGF receptor-beta (PDGFR-beta) signaling pathway is involved in this process. Thus, we investigated whether HBV and its protein contribute to HSC proliferation by the PDGF-B/PDGFR-beta signaling pathway. HBV particles were purified from the supernatant of HepG2.2.15 cells by ultracentrifugation and the cell lines carrying HBV preS, e, c or x genes were obtained. After incubation with HBV particles or co-cultured with the cell lines expressed in the viral protein, the proliferation of LX-2 cells, an HSC cell line, were detected by flow cyto-metry and real-time PCR and the expression of molecules related to the PDGF-B/PDGFR-beta signaling pathway were further measured. Our results indicated that HBV particles, c and x proteins promoted LX-2 proliferation and increased the mRNA levels of PDGF-B, PDGFR-beta, collagen-I and alpha-smooth muscle actin (alpha-SMA), as well as the phosphorylation of PDGFR-beta; however, the expression protein levels of PDGF-B and PDGFR-beta remained unchanged. In conclusion, HBV particles and HBV c and x proteins promote HSC proliferation and fibrogenesis in vitro and the PDGF-B/PDGFR beta signaling pathway is important in this process. PMID- 23042548 TI - SAHA down-regulates the expression of indoleamine 2,3-dioxygenase via inhibition of the JAK/STAT1 signaling pathway in gallbladder carcinoma cells. AB - The aim of the present study was to investigate the role of the JAK/STAT1 signaling pathway in suberoylanilide hydroxamic acid (SAHA)-mediated down regulation of indoleamine 2,3-dioxygenase (IDO) in gallbladder carcinoma cells. We treated SGC-996 gallbladder carcinoma cells with IFN-gamma and SAHA. Western blotting was used to detect the expression of IDO, signal transducer and activator of transcription 1 (STAT1) phosphorylation and interferon regulatory factor genes-1 (IRF-1). Confocal microscopy analysis was used to detect STAT1 translocation. Transient transfection and reporter gene assay was used for detecting the activation of gamma-activated sites (GAS) and interferon-stimulated response elements (ISRE). The results revealed that IDO was expressed in SGC-996 cells in a dose- and time-dependent manner when stimulated with IFN-gamma and SAHA down-regulated the expression of IDO induced by IFN-gamma in a dose dependent manner. SAHA blocked the expression of IRF-1 induced by IFN-gamma and SAHA inhibited IFN-gamma-induced STAT1 phosphorylation and nuclear translocation. In addition, SAHA down-regulated IFN-gamma-induced activation of GAS and ISRE. In conclusion, SAHA down-regulated IDO expression via inhibition of the activation of members of the JAK/STAT1 signaling pathway. Therefore, regulation of the JAK/STAT1 signaling pathway may provide a new gallbladder carcinoma immunotherapeutic strategy to break tumor immune tolerance. PMID- 23042549 TI - Micropatterning of neural stem cells and Purkinje neurons using a polydimethylsiloxane (PDMS) stencil. AB - A new fabrication method of a polydimethylsiloxane (PDMS) stencil embedded microwell plate is proposed and applied to a localized culture of Purkinje neurons (PNs) and neural stem cells (NSCs). A microwell plate combines a PDMS stencil and well plate. The PDMS stencil was fabricated by spin casting from an SU-8 master mold. Gas blowing using nitrogen was adopted to perforate the stencil membrane. An acrylic well plate compartment mold was fabricated using computer numerical control (CNC) machining. By PDMS casting using a stencil placed on an acrylic mold, microwell plates were fabricated without punching or the use of a plasma bonding process. By using the stencil as a physical mask for the cell culture, PNs and NSCs were successfully cultured into micropatterns. The microwell plate could be applied to the localizing and culturing of a cell. The micropatterned NSCs were differentiated into neurons, astrocytes, and oligodendrocytes. The results showed that cells could be cultured and differentiated into micropatterns in a precisely controlled manner in any shape and in specific sizes for bioscience study and bioengineering applications. PMID- 23042550 TI - Crystal morphologies and polymorphs in tolbutamide microcrystalline powder. AB - The growing interest of pharmaceutical companies toward the crystal morphology prediction of active pharmaceutical ingredients is a consequence of the dramatic effect of the crystal habit on the tableting behavior of drugs. In order to help the optimization of the industrial process, molecular mechanics calculations together with X-ray diffraction analysis and optical microscopy (OM) were used to shed light over the structural properties of N-(butylcarbamoyl)-4 methylbenzenesulfonamide-commercially known as tolbutamide-a drug used in the management of type II diabetes, especially in elderly diabetics because of its rapid metabolism. As there are several known polymorphs of this molecule, we first defined, by means of a quantitative phase analysis, performed by X-ray powder diffraction, which and how much each of the five crystallographic structures present in the Cambridge Crystallographic Database represent the commercial crystalline powder. The structures of the resulting candidates were first analyzed by means of molecular mechanics, and the crystal morphologies of the compounds were therefore predicted and compared with the ones observed by means of OM. Analogies and differences among the different morphologies, together with the potential role of crystallization solvents, were commented in the attempt to bridge the gap between the molecular structure-that is, the atomic point of view-and the crystal habit. PMID- 23042551 TI - Nucleomorph genome sequence of the cryptophyte alga Chroomonas mesostigmatica CCMP1168 reveals lineage-specific gene loss and genome complexity. AB - Cryptophytes are a diverse lineage of marine and freshwater, photosynthetic and secondarily nonphotosynthetic algae that acquired their plastids (chloroplasts) by "secondary" (i.e., eukaryote-eukaryote) endosymbiosis. Consequently, they are among the most genetically complex cells known and have four genomes: a mitochondrial, plastid, "master" nuclear, and residual nuclear genome of secondary endosymbiotic origin, the so-called "nucleomorph" genome. Sequenced nucleomorph genomes are ~1,000-kilobase pairs (Kbp) or less in size and are comprised of three linear, compositionally biased chromosomes. Although most functionally annotated nucleomorph genes encode proteins involved in core eukaryotic processes, up to 40% of the genes in these genomes remain unidentifiable. To gain insight into the function and evolutionary fate of nucleomorph genomes, we used 454 and Illumina technologies to completely sequence the nucleomorph genome of the cryptophyte Chroomonas mesostigmatica CCMP1168. At 702.9 Kbp in size, the C. mesostigmatica nucleomorph genome is the largest and the most complex nucleomorph genome sequenced to date. Our comparative analyses reveal the existence of a highly conserved core set of genes required for maintenance of the cryptophyte nucleomorph and plastid, as well as examples of lineage-specific gene loss resulting in differential loss of typical eukaryotic functions, e.g., proteasome-mediated protein degradation, in the four cryptophyte lineages examined. PMID- 23042552 TI - Characterization of genomic regulatory domains conserved across the genus Drosophila. AB - In both vertebrates and insects, the conservation of local gene order among distantly related species (microsynteny) is higher than expected in the presence of highly conserved noncoding elements (HCNEs). Dense clusters of HCNEs, or HCNE peaks, have been proposed to mediate the regulation of sometimes distantly located genes, which are central for the developmental program of the organism. Thus, the regions encompassing HCNE peaks and their targets in different species would form genomic regulatory domains (GRDs), which should presumably enjoy an enhanced stability over evolutionary time. By leveraging genome rearrangement information from nine Drosophila species and using gene functional and phenotypic information, we performed a comprehensive characterization of the organization of microsynteny blocks harboring HCNE peaks and provide a functional portrait of the putative HCNE targets that reside therein. We found that Drosophila HCNE peaks tend to colocalize more often than expected and to be evenly distributed across chromosomal elements. Putative HCNE peak targets are characterized by a tight association with particular promoter motifs, higher incidence of severe mutant phenotypes, and evidence of a more precise regulation of gene expression during important developmental transitions. As for their physical organization, ~65% of these putative targets are separated by a median of two genes from their nearest HCNE peaks. These observations represent the first functional portrait of this euchromatic fraction of the Drosophila genome with distinctive evolutionary dynamics, which will facilitate future experimental studies on the interactions between HCNE peaks and their targets in a genetically tractable system such as Drosophila melanogaster. PMID- 23042553 TI - Evolution of extensively fragmented mitochondrial genomes in the lice of humans. AB - Bilateral animals are featured by an extremely compact mitochondrial (mt) genome with 37 genes on a single circular chromosome. The human body louse, Pediculus humanus, however, has its mt genes on 20 minichromosomes. We sequenced the mt genomes of two other human lice: the head louse, P. capitis, and the pubic louse, Pthirus pubis. Comparison among the three human lice revealed the presence of fragmented mt genomes in their most recent common ancestor, which lived ~7 Ma. The head louse has exactly the same set of mt minichromosomes as the body louse, indicating that the number of minichromosomes, and the gene content and gene arrangement in each minichromosome have remained unchanged since the body louse evolved from the head louse ~107,000 years ago. The pubic louse has the same pattern of one protein-coding or rRNA gene per minichromosome (except one minichromosome with two protein-coding genes, atp6 and atp8) as the head louse and the body louse. This pattern is apparently ancestral to all human lice and has been stable for at least 7 Myr. Most tRNA genes of the pubic louse, however, are on different minichromosomes when compared with their counterparts in the head louse and the body louse. It is evident that rearrangement of four tRNA genes (for leucine, arginine and glycine) was due to gene-identity switch by point mutation at the third anticodon position or by homologous recombination, whereas rearrangement of other tRNA genes was by gene translocation between minichromosomes, likely caused by minichromosome split via gene degeneration and deletion. PMID- 23042554 TI - Rib lesions in skeletons from early neolithic sites in Central Germany: on the trail of tuberculosis at the onset of agriculture. AB - As an infectious disease, tuberculosis (TB) is one of the major causes of death worldwide. Paleopathological and paleomicrobiological studies indicate a long standing association of the causative agent Mycobacterium tuberculosis and its human host. Since the occurrence and the epidemic spread of this pathogen seem to be closely linked to social and biological factors, it is of particular interest to understand better the role of TB during periods of social and nutritional change such as the Neolithic. In this study, 118 individuals from three sites in Saxony-Anhalt (Germany) dating to the Linear Pottery Culture (5400-4800 BC) were examined macroscopically to identify TB related bone lesions. In two individuals, Pott's disease was detected. In addition, periosteal reactions of varying degrees and frequency were observed mainly along the neck of the ribs in 6.5% (2/31) of subadults and 35.1% (20/57) of adults, with one site standing out markedly. Rib lesions, however, are not specific indicators of TB as they can also be caused by other diseases; so additional investigations were undertaken using histology and micro-CT scans to say more about the disease process. Supplementary molecular analyses indicate the presence of pathogens belonging to the Mycobacterium tuberculosis complex in individuals of all sites. Furthermore, we discuss the occurrence and spread of TB during the Neolithic with regard to nutritional aspects and possible risks of infection. The data presented provide important insights into the health status of Early Neolithic populations in Central Germany. PMID- 23042555 TI - Enhanced electroluminescence efficiency in a spiro-acridine derivative through thermally activated delayed fluorescence. AB - Make your OLED fluorescent: an aromatic molecule based on a spiro-acridine derivative was designed, and its photoluminescence and electroluminescence were characterized. By combining the donor and acceptor moieties a small energy gap between the lowest singlet and triplet states was achieved. This design leads to an organic light-emitting diode (OLED) that rivals phosphorescent devices regarding exciton generation efficiency. PMID- 23042556 TI - Reconstitution of cellulose and lignin after [C2mim][OAc] pretreatment and its relation to enzymatic hydrolysis. AB - Although the effects of cellulose crystallinity and lignin content as two major structural features on enzymatic hydrolysis have been extensively studied, debates regarding their effects still exist. In this study, reconstitution of cellulose and lignin after 1-ethyl-3-methylimidazolium acetate ([C(2)mim][OAc]) pretreatment was proposed as a new method to study their effects on enzymatic digestibility. Different mechanisms of lignin content for reduction of cellulose hydrolysis were found between the proposed method and the traditional method (mixing of cellulose and lignin). The results indicated that a slight change of the crystallinity of the reconstituted materials may play a minor role in the change of enzyme efficiency. In addition, the present study suggested that the lignin content does not significantly affect the digestibility of cellulose, whereas the conversion of cellulose fibers from the cellulose I to the cellulose II crystal phase plays an important role when an ionic liquid pretreatment of biomass was conducted. PMID- 23042557 TI - Growth charts of Turkish children with Down syndrome. AB - We present growth curves of 1,726 Turkish children with Down syndrome (DS) between 0 and 18 years of age and investigate the factors that affect growth including congenital heart disease (CHD) and hypothyroidism. Longitudinal measurements of height, weight, and head circumference (HC) were assessed and accompanying major malformations were recorded. Growth curves were monitored using Cole's LMS method. The mean birth length was reduced by -0.5 standard deviation (SD) for Turkish standards in both boys and girls. Pubertal growth spurt of the girls with DS started 1 year earlier, their puberty duration was short and pubertal annual growth rate was inadequate, and as a result the final height was -3.06 SD for Turkish standards. Although the age at onset of pubertal growth spurt and puberty duration of the boys were similar to normal population, their pubertal annual growth rate was inadequate; thus the final height was -2.56 SD for Turkish standards. The final weight values were similar to normal population. The mean HC values of DS children were corresponded to -0.9 SD for Turkish standards at birth; however after 6 months values were below -2 SD. The final HC values were -1.02 SD for boys and -2.21 SD for girls for Turkish standards. We observed that weight was decreased in DS children with severe CHD during first 4 years of life. However, there is no statistically significant difference in values of height and head circumference between patients with or without severe CHD group. In addition, hypothyroidism had no effect on growth in DS patients. PMID- 23042559 TI - Tamoxifen inhibits migration of estrogen receptor-negative hepatocellular carcinoma cells by blocking the swelling-activated chloride current. AB - Tamoxifen is a triphenylethylene non-steroidal antiestrogen anticancer agent. It also shows inhibitory effects on metastasis of estrogen receptor (EsR) independent tumors, but the underlying mechanism is unclear. It was demonstrated in this study that, in EsR-negative and highly metastatic human hepatocellular carcinoma MHCC97H cells, tamoxifen-inhibited cell migration, volume-activated Cl( ) currents (I(Cl,vol)) and regulatory volume decrease (RVD) in a concentration dependent manner with a similar IC(50). Analysis of the relationships between migration, I(Cl,vol) and RVD showed that cell migration was positively correlated with I(Cl,vol) and RVD. Knockdown of the expression of ClC-3 Cl(-) channel proteins by ClC-3 shRNA or siRNA inhibited I(Cl,vol), and cell migration, and these inhibitory effects could not be increased further by addition of tamoxifen in the medium. The results suggest that knockdown of ClC-3 expression may deplete the effects of tamoxifen; tamoxifen may inhibit cell migration by modulating I(Cl,vol) and cell volume. Moreover, tamoxifen decreased the activity of protein kinase C (PKC) and the effects were reversed by the PKC activator PMA. Activation of PKC by PMA could competitively downregulate the inhibitory effects of tamoxifen on I(Cl,vol). PMA promoted cell migration, and knockdown of ClC-3 expression by ClC-3 siRNA abolished the PMA effect on cell migration. The results suggest that tamoxifen may inhibit I(Cl,vol) by suppressing PKC activation; I(Cl,vol) may be an EsR-independent target for tamoxifen in the anti-metastatic action on cancers, especially on EsR-negative cancers. The finding may have an implication in the clinical use of tamoxifen in the treatments of both EsR positive and EsR-negative cancers. PMID- 23042560 TI - Sprouting a new take on stem cell aging. PMID- 23042565 TI - Bacterial physiology: uncovering the circadian clockwork. PMID- 23042566 TI - Cellular microbiology: bacterial tRNAs fatten up. PMID- 23042564 TI - Merging mythology and morphology: the multifaceted lifestyle of Proteus mirabilis. AB - Proteus mirabilis, named for the Greek god who changed shape to avoid capture, has fascinated microbiologists for more than a century with its unique swarming differentiation, Dienes line formation and potent urease activity. Transcriptome profiling during both host infection and swarming motility, coupled with the availability of the complete genome sequence for P. mirabilis, has revealed the occurrence of interbacterial competition and killing through a type VI secretion system, and the reciprocal regulation of adhesion and motility, as well as the intimate connections between metabolism, swarming and virulence. This Review addresses some of the unique and recently described aspects of P. mirabilis biology and pathogenesis, and emphasizes the potential role of this bacterium in single-species and polymicrobial urinary tract infections. PMID- 23042567 TI - Safety and feasibility of every-other-week maintenance cetuximab after first-line chemotherapy in patients with recurrent or metastatic head and neck squamous cell cancer. AB - BACKGROUND: In patients with recurrent and/or metastatic head and neck squamous cell cancer (HNSCC), there are no data about an every-other-week cetuximab maintenance schedule after chemotherapy plus cetuximab as first-line treatment. METHODS: We reviewed the safety and feasibility of every-other-week maintenance cetuximab administered at 3 different European centers. RESULTS: Thirty-one patients with recurrent or metastatic HNSCC were treated from 2006 to 2010. Mean cetuximab dose intensity in the maintenance phase was 93%. The major toxicities reported during every-other-week maintenance cetuximab were skin rash (grade 3, 16%; grade 2, 23%), fatigue (grade 3, 3%; grade 2, 16%), diarrhea (grade 3, 7%; grade 2, 13%), hypomagnesemia (grade 4, 3%; grade 3, 3%; grade 2, 19%), and mucositis (grade 3, 3%; grade 2, 23%). CONCLUSIONS: Every-other-week maintenance cetuximab schedule was well tolerated and did not worsen toxicity that occurred during chemotherapy. In daily practice, this simplified schedule could improve compliance and possibly improve quality of life in patients with recurrent or metastatic HNSCC that showed no progression during first-line chemotherapy. PMID- 23042568 TI - The importance of understanding the human-animal interface : from early hominins to global citizens. AB - The complex relationships between the human and animal species have never ceased to evolve since the emergence of the human species and have resulted in a human animal interface that has promoted the cross-species transmission, emergence and eventual evolution of a plethora of infectious pathogens. Remarkably, most of the characteristics of the human-animal interface-as we know it today-have been established long before the end of our species pre-historical development took place, to be relentlessly shaped throughout the history of our species. More recently, changes affecting the modern human population worldwide as well as their dramatic impact on the global environment have taken domestication, agriculture, urbanization, industrialization, and colonization to unprecedented levels. This has created a unique global multi-faceted human-animal interface, associated with a major epidemiological transition that is accompanied by an unexpected rise of new and emerging infectious diseases. Importantly, these developments are largely paralleled by medical, technological, and scientific progress, continuously spurred by our never-ending combat against pathogens. The human-animal interface has most likely contributed significantly to the evolutionary shaping and historical development of our species. Investment in a better understanding of this human-animal interface will offer humankind a future head-start in the never-ending battle against infectious diseases. PMID- 23042569 TI - Arginine inactivates human herpesvirus 2 and inhibits genital herpesvirus infection. AB - Arginine, among the amino acids, has demonstrated unique properties, including suppression of protein-protein interactions and virus inactivation. We investigated the effects of arginine on the infectivity of human herpesvirus 2 (HHV-2) and the potential application of arginine as a chemotherapeutic agent against genital herpes. Arginine directly inactivated HHV-2 and characterization of the inactivation demonstrated that 1 M arginine at pH 4.3 inactivated the virus more efficiently compared to 0.1 M citrate or 1 M sodium chloride, indicating that neither acidic pH nor ionic strength alone is sufficient for virus inactivation. The effect of arginine was rapid and concentration-dependent. Although virus inactivation was efficient at an acidic pH, arginine inactivated the virus even at a neutral pH, provided that a higher arginine concentration and prolonged incubation time were used. In addition, arginine suppressed the multiplication of HHV-2 under the conditions at which its effect on cell viability was insignificant. Pilot mouse model studies revealed a marked suppression of death by arginine when the mice were infected with HHV-2 through the vaginal route, followed by an intermittent application of acidic arginine by vaginal instillation. PMID- 23042570 TI - Comb-shaped glycopolymer/peptide bioconjugates by combination of RAFT polymerization and thiol-ene "click" chemistry. AB - Comb-shaped glycopolymer/peptide bioconjugates are constructed by grafting reduced glutathione (GSH) onto acrylate-functional block glycocopolymers via thiol-ene click chemistry. In aqueous solution, the glycopolymer/GSH bioconjugate self-assembles to sugar-installed spherical micelles. The size of micelles decreases with increasing pH, demonstrating pH-responsive character. The isoelectric point (IEP) of the PMAGlc/GSH bioconjugate is estimated to be 3.43. The micelles show a specific interaction with the protein Concanavalin A. At endosomal pH, the PMAGlc/GSH bioconjugate can gradually degrade. These pH responsive glycopolymer/peptide micelles with biological recognition and degradation can be used as multifunctional nanocarriers for targeted drug delivery. PMID- 23042571 TI - A microfluidic microelectrode array for simultaneous electrophysiology, chemical stimulation, and imaging of brain slices. AB - In order to understand information processing in neural circuits, it is necessary to detect both electrical and chemical signaling with high spatial and temporal resolution. Although the primary currency of neural information processing is electrical, many of the downstream effects of the electrical signals on the circuits that generate them are dependent on activity-dependent increases in intracellular calcium concentration. It is therefore of great utility to be able to record electrical signals in neural circuits at multiple sites, while at the same time detecting optical signals from reporters of intracellular calcium levels. We describe here a microfluidic multi-electrode array (MMEA) capable of high-resolution extracellular recording from brain slices that is optically compatible with calcium imaging at single cell resolution. We show the application of the MMEA device to record waves of spontaneous activity in developing cortical slices and to perform multi-site extracellular recordings during simultaneous calcium imaging of activity. The MMEA has the unique capability to simultaneously allow focal electrical and chemical stimuli at different locations of the surface of a brain slice. PMID- 23042572 TI - Mechanistic study of the oxidative degradation of the triazole antifungal agent CS-758 in an amorphous form. AB - In this study, the degradates generated from a pharmaceutical solid were characterized, and a mechanistic pathway underlying their formation was proposed. The chemical stability of a novel triazole antifungal drug, CS-758, deteriorated significantly when the crystal was disordered, and characteristic degradates were generated. A total of eight degradates in solution and nine degradates in a solid state were isolated by preparative liquid chromatography. Degradates were characterized using high-performance liquid chromatography-photodiode array, mass spectrometry, and nuclear magnetic resonance. Radical-mediated oxidation is proposed as the main degradation pathway in the solid state. The initiation step of this pathway is hydrogen atom abstraction from a methine carbon that is adjacent to a dien moiety and the formation of a delocalized vinylic radical intermediate. Molecular oxygen is then added to the radical position to form hydroperoxides. There are three potential oxidation routes based on the proposed autoxidation pathway that lead to the generation of the dioxane ring-opening hydroxyl form, the 9,10-epoxide form, or the 11,12-epoxide form, depending on the substituted position of the added molecular oxygen. The epimer compound generated via the vinylic radical intermediate and sulfoxides was characterized. This degradation mechanism provides the scientific foundation for an oxidative stressing system currently under investigation. PMID- 23042573 TI - Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome. AB - Since the discovery in 1993 that Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol biosynthesis, human disorders associated with additional enzymes involved in the conversion of lanosterol to cholesterol have been identified. This review will focus primarily on the clinical aspects of these disorders, highlighting newly described syndromes, such as SC4MOL deficiency and CK syndrome. We will also provide clinical descriptions of additional cases for extremely rare disorders, such as desmosterolosis. We will compare and contrast the findings with those found in SLOS and briefly discuss possible mechanisms of disease pathogenesis. PMID- 23042574 TI - Environmental control of the calicheamicin polyketide synthase leads to detection of a programmed octaketide and a proposal for enediyne biosynthesis. AB - A light in the dark: the fermentation products of the polyketide synthase CalE8 (without its cognate thioesterase) were identified and gave some insight into the elusive early steps of calicheamicin biosynthesis. Fermentation in either the light or dark resulted in different proportions of a new octaketide and led to an updated mechanistic proposal. PMID- 23042575 TI - Carbohydrate derived-pseudo-lignin can retard cellulose biological conversion. AB - Dilute acid as well as water only (hydrothermal) pretreatments often lead to a significant hemicellulose loss to soluble furans and insoluble degradation products, collectively termed as chars and/or pseudo-lignin. In order to understand the factors contributing to reducing sugar yields from pretreated biomass and the possible influence of hemicellulose derived pseudo-lignin on cellulose conversion at the moderate to low enzyme loadings necessary for favorable economics, dilute acid pretreatment of Avicel cellulose alone and mixed with beechwood xylan or xylose was performed at various severities. Following pretreatment, the solids were enzymatically hydrolyzed and characterized for chemical composition and physical properties by NMR, FT-IR, and SEM imaging. It was found that hemicelluloses (xylan) derived-pseudo-lignin was formed at even moderate severities and that these insoluble degradation products can significantly retard cellulose hydrolysis. Furthermore, although low severity (CSF ~ 1.94) dilute acid pretreatment of a xylan-Avicel mixture hydrolyzed most of the xylan (98%) and produced negligible amounts of pseudo-lignin, enzymatic conversion of cellulose dropped significantly (>25%) compared to cellulose pretreated alone at the same conditions. The drop in cellulose conversion was higher than realized for cellulase inhibition by xylooligomers reported previously. Plausible mechanisms are discussed to explain the observed reductions in cellulose conversions. PMID- 23042576 TI - The association of anthropometric indices in adolescence with the occurrence of the metabolic syndrome in early adulthood: Tehran Lipid and Glucose Study (TLGS). AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Little is known about the predictive ability of anthropometric indices in adolescence for prediction of early adulthood metabolic syndrome (MetS). There are controversies about the predictive power of body mass index (BMI) vs. waist circumference (WC) for prediction of MetS in late adolescence; some of the studies did not support the need to measure WC in mid-adolescence, in addition to BMI; on the other hand, some other studies proposed either similar predictability or superiority of WC to identify MetS in late adolescence. WHAT THIS STUDY ADDS: This is the first study to evaluate the adolescent anthropometric indices in relation to early adulthood MetS incidence one decade later in the Middle East region. There is an important sex difference regarding the incidence of MetS in Tehranian adolescents. It is interesting to know that all anthropometric indices in the pubertal age group (11-14 years) had better predictive ability compared to late-pubertal (15-18 years) adolescents. In addition, adolescent abdominal obesity surrogates, including WC and waist-to height ratio, predicted adulthood MetS better than BMI in boys. It seems that WC had an independent role beyond BMI in identification of adulthood MetS in Tehranian boys (11-18 years old). BACKGROUND: Little is known about the predictive ability of anthropometric indices in adolescence for prediction of early adulthood metabolic syndrome (MetS). OBJECTIVE: Our purpose was to explore incidence of MetS and the optimal anthropometric indicator to predict early adulthood MetS in Tehranian adolescents. METHODS: Using data from the population based, prospective, Tehran Lipid and Glucose Study, the utility of four anthropometric indices of adolescents in predicting early adulthood MetS (2009 Joint Scientific Statement definition) was examined among 1100 participants, aged 11-18 years, who were free of MetS at baseline, during a mean of 10.2 years of follow-up. RESULTS: The cumulative incidence of MetS was 25.5% (95% confidence interval [CI]: 21.8-29.2%) for young men and 1.8% (95% CI: 0.6-3%) for young women. In boys, waist circumference (WC) had the highest odds ratio (OR) for the MetS risk, followed by waist-to-height ratio (WHtR). Adjusting body mass index (BMI) in addition to WC did not change the results in the 11-14-year age group (OR for WC: 2.28 [1.64-3.16] without BMI adjustment vs. 1.98 [1.05-3.73] with BMI adjustment), suggesting that WC may predict MetS risk beyond BMI. None of the anthropometric indices were found to have significant associations with subsequent MetS risk in girls. CONCLUSIONS: Measures of abdominal obesity including WHtR and WC predicted early adulthood MetS better than BMI in Tehranian male adolescents (11-18 years old). PMID- 23042577 TI - Microfluidic probes for use in life sciences and medicine. AB - Microfluidic probes (MFPs) combine the concepts of microfluidics and of scanning probes and constitute a contact-free and channel-free microfluidic system. Whereas classically the sample is introduced into the microfluidic device, with a MFP, the microfluidic stream is applied to the sample. MFPs use hydrodynamic flow confinement instead of walls to constrain a microfluidic stream between the MFP tip and a substrate. Because MFPs are free to move, they can be used to process large areas and samples in a selective manner. The development of MFP technology is recent and has numerous potential applications in several fields, most notably in the life sciences. In this review, we discuss the concept of MFPs and highlight their application in surface biopatterning, controlling the cellular microenvironments, local processing of tissue slices, and generating concentration gradients of biochemicals. We hope that this manuscript will serve as an interdisciplinary guide for both engineers as they further develop novel MFPs and applications and for life scientists who may identify novel uses of the MFP for their research. PMID- 23042578 TI - Electrophysiological subtypes and prognosis of Guillain-Barre syndrome in northeastern China. AB - INTRODUCTION: The purpose of this study was to assess the electrophysiological subtypes and prognosis of Guillain-Barre syndrome (GBS) in northeastern China. METHODS: Ninety-nine patients with GBS were recruited between 2006 and 2010 and retrospectively reviewed. RESULTS: Sixty-seven percent of patients had acute inflammatory demyelinating polyneuropathy (AIDP). Patients with acute motor axonal neuropathy (AMAN) had more severe symptoms at onset of GBS, and intravenous immunoglobulin (IVIg) was less effective in these patients. The prognosis may have been associated with the severity of the illness and did not differ between AMAN and AIDP patients. Abnormal motor nerve conduction studies (NCS) of the lower limbs and sensory NCS of the upper limbs with normal sural sensory nerve studies were the main electrophysiological features of AIDP. CONCLUSIONS: AIDP is the main subtype of GBS, and it has specific electrophysiological characteristics in northeastern China. The prognosis of patients with AMAN was similar to that of patients with AIDP. Moreover, IVIg was more effective in patients with AIDP. PMID- 23042580 TI - The CTD code of RNA polymerase II: a structural view. AB - RNA polymerase II (RNA pol II) is not only the fundamental enzyme for gene expression but also the central coordinator of co-transcriptional processing. RNA pol II associates with a large number of enzymes and protein/RNA-binding factors through its C-terminal domain (CTD) that consists of tandem repeats of the heptapeptide consensus Y(1)S(2)P(3) T(4)S(5)P(6)S(7). The CTD is posttranslationally modified, yielding specific patterns (often called the CTD code) that are recognized by appropriate factors in coordination with the transcription cycle. Serine phosphorylations are currently the best characterized elements of the CTD code; however, the roles of the proline isomerization and other modifications of the CTD remain poorly understood. The dynamic remodeling of the CTD modifications by kinases, phosphatases, isomerases, and other enzymes introduce changes in the CTD structure and dynamics. These changes serve as structural switches that spatially and temporally regulate the binding of processing factors. Recent structural studies of the CTD bound to various proteins have revealed the basic rules that govern the recognition of these switches and shed light on the roles of these protein factors in the assemblies of the processing machineries. PMID- 23042579 TI - The diet-body offset in human nitrogen isotopic values: a controlled dietary study. AB - The "trophic level enrichment" between diet and body results in an overall increase in nitrogen isotopic values as the food chain is ascended. Quantifying the diet-body Delta(15) N spacing has proved difficult, particularly for humans. The value is usually assumed to be +3-50/00 in the archaeological literature. We report here the first (to our knowledge) data from humans on isotopically known diets, comparing dietary intake and a body tissue sample, that of red blood cells. Samples were taken from 11 subjects on controlled diets for a 30-day period, where the controlled diets were designed to match each individual's habitual diet, thus reducing problems with short-term changes in diet causing isotopic changes in the body pool. The Delta(15) N(diet-RBC) was measured as +3.50/00. Using measured offsets from other studies, we estimate the human Delta(15) N(diet-keratin) as +5.0-5.30/00, which is in good agreement with values derived from the two other studies using individual diet records. We also estimate a value for Delta(15) N(diet-collagen) of ~60/00, again in combination with measured offsets from other studies. This value is larger than usually assumed in palaeodietary studies, which suggests that the proportion of animal protein in prehistoric human diet may have often been overestimated in isotopic studies of palaeodiet. PMID- 23042581 TI - Crystal structure of human multiple copies in T-cell lymphoma-1 oncoprotein. AB - Overexpression of multiple copies in T-cell lymphoma-1 (MCT-1) oncogene accompanies malignant phenotypic changes in human lymphoma cells. Specific disruption of MCT-1 results in reduced tumorigenesis, suggesting a potential for MCT-1-targeted therapeutic strategy. MCT-1 is known as a cap-binding protein and has a putative RNA-binding motif, the PUA-domain, at its C-terminus. We determined the crystal structure of apo MCT-1 at 1.7 A resolution using the surface entropy reduction method. Notwithstanding limited sequence identity to its homologs, the C-terminus of MCT-1 adopted a typical PUA-domain fold that includes secondary structural elements essential for RNA recognition. The surface of the N-terminal domain contained positively charged patches that are predicted to contribute to RNA-binding. PMID- 23042582 TI - A pivotal role of bone remodeling in granulocyte colony stimulating factor induced hematopoietic stem/progenitor cells mobilization. AB - The majority of hematopoietic stem/progenitor cells (HSPCs) reside in bone marrow (BM) surrounded by a specialized environment, which governs HSPC function. Here we investigated the potential role of bone remodeling cells (osteoblasts and osteoclasts) in homeostasis and stress-induced HSPC mobilization. Peripheral blood (PB) and BM in steady/mobilized state were collected from healthy donors undergoing allogeneic transplantation and from mice treated with granulocyte colony stimulating factor (G-CSF), parathyroid hormone (PTH), or receptor activator of nuclear factor kappa-B ligand (RANKL). The number and the functional markers of osteoblasts and osteoclasts were checked by a series of experiments. Our data showed that the number of CD45(-) Ter119(-) osteopontin (OPN)(+) osteoblasts was significantly reduced from 4,085 +/- 135 cells/femur on Day 0 to 1,032 +/- 55 cells/femur on Day 5 in mice (P = 0.02) and from 21.38 +/- 0.66 on Day 0 to 14.78 +/- 0.65 on Day 5 in healthy donors (P < 0.01). Decrease of osteoblast number leads to reduced level of HSPC mobilization regulators stromal cell-derived factor-1 (SDF-1), stem cell factor (SCF), and OPN. The osteoclast number at bone surface (OC.N/B.s) was significantly increased from 1.53 +/- 0.12 on Day 0 to 4.42 +/- 0.46 on Day 5 (P < 0.01) in G-CSF-treated mice and from 0.88 +/- 0.20 on Day 0 to 3.24 +/- 0.31 on Day 5 (P < 0.01) in human. Serum TRACP-5b level showed a biphasic trend during G-CSF treatment. The ratio of osteoblasts number per bone surface (OB.N/B.s) to OC.N/B.s was changed after adding PTH plus RANKL during G-CSF treatment. In conclusion, short term G-CSF treatment leads to reduction of osteoblasts and stimulation of osteoclasts, and interrupting bone remodeling balance may contribute to HSPC mobilization. PMID- 23042583 TI - Attenuation of KBrO3-induced renal and hepatic toxicity by cloudy apple juice in rat. AB - The aim of the study was to evaluate a protective effect of apple juice on KBrO3 induced oxidative stress in rats. Male Wistar rats were administered apple juice per os, 10 ml/kg b.w. for 28 days. On 27 day of the experiment, some rats were given i.p. a single 125 mg/kg b.w. dose of KBrO3 . Markers of oxidative damage and clinical chemistry parameters were determined. Treatment with apple juice prior to KBrO3 challenge prevented an increase in hepatic and renal microsomal lipid peroxidation by 25 and 44%, respectively, increased the activity of antioxidant enzymes in the liver by 29 - 59% and decreased the plasma content of carbonyl groups by 19%. Aminotransferases activity in plasma was reduced by 19% and 36%, concentrations of plasma bilirubin, cholesterol and creatinine were suppressed by 21%, 16% and 26%, respectively, in rats supplemented with juice before KBrO3 injection. No protective effect of apple juice on nuclear DNA was observed. Supplementation with cloudy apple juice to some extent attenuated oxidative damage induced by KBrO3 in the liver and kidney of rats as evidenced by alterations of certain oxidative stress markers and clinical chemistry parameters. PMID- 23042584 TI - Consistency in the safety labeling of bioequivalent medications. AB - PURPOSE: Bioequivalent medications are required by the Food and Drug Administration to have identical warnings on their labels. This requirement has both clinical and legal importance, yet has never been validated. We sought to determine the real-world consistency of electronic labeling for bioequivalent drugs from different manufacturers. METHODS: Using natural language processing, we indexed the adverse drug reactions (ADRs) found in the Adverse Reactions and Post-Marketing sections of 9105 structured product labels. We calculated the standard deviation in ADR labeling for each bioequivalent drug and the percent deviation of each generic label from its corresponding brand. We also analyzed the performance of individual generic manufacturers. For the 25 drugs with the greatest discrepancy in labeled ADRs, we performed manual review to identify causes of inconsistency. RESULTS: 68% of multi-manufacturer drugs had discrepancies in ADR labeling. For a given drug, the mean deviation in number of labeled ADRs was 4.4, and the median was 0.8 (IQR 0 to 3.2). The mean range in number of labeled ADRs was 12 +/- 0.9, and the median was 2 (IQR 0 to 9). Overall, 77.9% of generic manufacturers produced labels differing from brand. Causes of inconsistency included missing tables, outdated post-marketing reports, and formatting issues. CONCLUSIONS: Despite FDA mandate, bioequivalent drugs often differ in their safety labeling. Physicians should be aware of such differences and regulators should consider new strategies for harmonizing bioequivalent labels. PMID- 23042585 TI - Cognitive and behavioral aspects of Smith-Lemli-Opitz syndrome. AB - The brain's high concentrations of cholesterol make it especially vulnerable to the cholesterol biosynthetic defect that characterizes Smith-Lemli-Opitz syndrome (SLOS). An attempt to characterize the cognitive and behavioral phenotype of SLOS has identified increased rates of intellectual disability, language and motor developmental delay, repeated self-injury behaviors, sensory hyperreactivity, hyperactivity, affect dysregulation, and sleep disturbances. Some research has suggested that carriers of the gene mutation that results in SLOS display increased risk of suicidal behavior. Cholesterol dysregulation impairs neuroplasticity, which may be a mechanism underlying some of the mentioned abnormalities. Discrete positive effects have been reported with the use of cholesterol supplementation in the treatment of SLOS. Research has been limited by the small number of subjects available, and a limited understanding of lipid metabolism in the brain. Hopefully future research will help clarify the role that cholesterol plays in cognitive and behavioral abnormalities like the ones associated with SLOS. This would accelerate the development of treatments for SLOS, and perhaps also further understanding of non-syndromic psychiatric disorders such as autism and attention deficit hyperactivity disorder. PMID- 23042586 TI - Fatigue and daytime sleepiness scale in myotonic dystrophy type 1. AB - INTRODUCTION: Fatigue and excessive daytime sleepiness are frequent complaints in myotonic dystrophy type 1 (DM1) that often overlap. We aimed to construct a combined fatigue and daytime sleepiness rating scale for DM1 using the Rasch measurement model. METHODS: Questionnaires, including the Epworth sleepiness scale, fatigue severity scale, and daytime sleepiness scale, were completed by 354 patients. Data were subjected to Rasch analyses and tested for required measurement issues such as appropriate response categories, absence of item bias, local independence, and unidimensionality. RESULTS: The initial 22 items did not meet Rasch model expectations. After rescoring and removing misfitting items, the final 12-item scale showed good model fit and unidimensionality. High internal consistency (person separation index = 0.80) and validity were demonstrated. CONCLUSIONS: The Rasch-built Fatigue and Daytime Sleepiness Scale, developed specifically for DM1 patients, provides interval measures on a single continuum. Its use is suggested for future clinical trials and therapeutic follow-up. PMID- 23042587 TI - Synthesis, structure, topology and magnetic properties of cobalt(II) coordination polymers with 2-nitrobiphenyl-4,4'-dicarboxylic acid and bis(pyridyl) ligands. AB - Four coordination polymers, [Co2(Hnbpdc)2(nbpdc)(bipy)2]n (1), [Co3(nbpdc)3(bipy)3(H2O)2]n.2nH2O (2), [Co4(nbpdc)4(bipy)(H2O)4]n (3), and [Co2(nbpdc)2(bpee)(3/2)]n.0.25nH2O (4) [H2nbpdc = 2-nitrobiphenyl-4,4' dicarboxylic acid, bipy = 4,4'-bipyridine and bpee = 1,2-di(4-pyridyl)ethane] have been synthesized by hydrothermal methods and studied by means of X-ray crystallography, topological analyses and magnetic analyses. Compounds 1-3 were synthesized from the same reactants under controlled conditions (pH and ligand ratio). Compounds 1, 2 and 4 contain bis(carboxylate)-bridged dinuclear motifs as secondary building units (SBUs). In 1 and 2 the SBUs are connected into 44 layers by bis(chelating) nbpdc and pairwise bipy linkers. In 1, the layers are pillared into a 3D framework with the pcu topology by Hnbpdc, which is coordinated to one layer and hydrogen-bonded to another layer. In 2, the layers and the linear [Co(bipy)]n chains intercalated between the layers are connected by nbpdc to produce a 3D framework exhibiting a rarely observed 4,6-connected topology. In 4 the SBUs are connected by nbpdc [bis(chelating) and bis(bridging)] and bpee (single and pairwise) to yield a 3D framework, which defines a new 6-connected net with point symbol (4(10).5(2).6(3)). Notably, this new net and the known hex 6-P6(2)22 net represent the first examples of topologically different nets having the same coordination sequences, point and vertex symbols. Compound 3 contains carboxylate- and aqua-bridged tetranuclear motifs as SBUs, which are connected by covalent linkers (nbpdc and bipy) and sextuple O-H...O hydrogen bonds to generate a 3D framework, which defines a new 10-connected net with point symbol (4(24).5(12).6(8).7) (considering only covalent linkers) and a new 12-connected net with point symbol (3(12).4(36).5(17).6) (including also the hydrogen bonds as linkers). Magnetic studies on 1 and 2 demonstrated that the bis(syn-skew carboxylate) bridges between octahedral Co(II) ions induce ferromagnetic coupling; 4 is peculiar in that octahedral and tetrahedral Co(II) ions are linked by mixed syn-syn and syn-skew carboxylate bridges, which give rise to antiferromagnetic coupling. PMID- 23042588 TI - Genomic dysregulation in gastric tumors. AB - Gastric cancer is among the most common human malignancies and the second leading cause of cancer-related death. The different epidemiologic and histopathology of subtypes of gastric cancer are associated with different genomic patterns. Data suggests that gene expression patterns of proximal, distal gastric cancers intestinal type, and diffuse/signet cell are well separated. This review summarizes the genetic and epigenetic changes thought to drive gastric cancer and the emerging paradigm of gastric cancer as three unique disease subtypes. PMID- 23042589 TI - A signal transduction score flow algorithm for cyclic cellular pathway analysis, which combines transcriptome and ChIP-seq data. AB - Determination of cell signalling behaviour is crucial for understanding the physiological response to a specific stimulus or drug treatment. Current approaches for large-scale data analysis do not effectively incorporate critical topological information provided by the signalling network. We herein describe a novel model- and data-driven hybrid approach, or signal transduction score flow algorithm, which allows quantitative visualization of cyclic cell signalling pathways that lead to ultimate cell responses such as survival, migration or death. This score flow algorithm translates signalling pathways as a directed graph and maps experimental data, including negative and positive feedbacks, onto gene nodes as scores, which then computationally traverse the signalling pathway until a pre-defined biological target response is attained. Initially, experimental data-driven enrichment scores of the genes were computed in a pathway, then a heuristic approach was applied using the gene score partition as a solution for protein node stoichiometry during dynamic scoring of the pathway of interest. Incorporation of a score partition during the signal flow and cyclic feedback loops in the signalling pathway significantly improves the usefulness of this model, as compared to other approaches. Evaluation of the score flow algorithm using both transcriptome and ChIP-seq data-generated signalling pathways showed good correlation with expected cellular behaviour on both KEGG and manually generated pathways. Implementation of the algorithm as a Cytoscape plug-in allows interactive visualization and analysis of KEGG pathways as well as user-generated and curated Cytoscape pathways. Moreover, the algorithm accurately predicts gene-level and global impacts of single or multiple in silico gene knockouts. PMID- 23042591 TI - Fiber type-specific differences in glucose uptake by single fibers from skeletal muscles of 9- and 25-month-old rats. AB - The primary purpose of this study was to assess the feasibility of applying a novel approach to measure myosin heavy chain (MHC) isoform expression, glucose uptake, fiber volume, and protein abundance in single muscle fibers of adult (9 months) and old (25 months) rats. Epitrochlearis muscle fibers were successfully isolated and analyzed for MHC isoform expression, glucose uptake, fiber volume, and protein (COXIV, APPL1, IkappaB-beta) abundance. Insulin-stimulated glucose uptake by single fibers did not differ between age groups, but there was a significant difference between fiber types (IIA > IIX > IIB/X ~ IIB). There were also significant main effects of fiber type on APPL1 (IIX > IIB) and COXIV (IIA > IIX > IIB/X ~ IIB) abundance, and IIB fibers were significantly larger than IIA fibers. This study established the feasibility of a new approach for assessing age-related differences in muscle at the single-fiber level and demonstrated the magnitude and rank order for fiber-type differences in insulin-stimulated glucose uptake of 9-month-old and 25-month-old rats. PMID- 23042590 TI - Mesenchymal stem cells contribute to endogenous FVIII:c production. AB - Besides the liver, it has been difficult to identify which organ(s) and/or cellular component(s) contribute significantly to the production of human FVIII:c (FVIII). Thus far, only endothelial cells have been shown to constitute a robust extrahepatic source of FVIII, possibly explaining both the diverse presence of FVIII mRNA in the body, and the observed increase in FVIII levels during liver failure. Here, we investigate whether human mesenchymal stem cells (MSC), ubiquitously present in different organs, could also contribute to FVIII production. MSC isolated from human lung, liver, brain, and bone marrow expressed FVIII message as determined by quantitative-RT-PCR. Using an antibody specific for FVIII, confocal microscopy, and umbilical cord-derived endothelial cells (HUVEC) as a negative control, we demonstrated that, in MSC, FVIII protein was not stored in granules; rather, it localized to the perinuclear region. Furthermore, functional FVIII was detected in MSC supernatants and cell lysates by aPTT and chromogenic assays. These results demonstrate that MSC can contribute at low levels to the functional FVIII pool, and advance the understanding of the physiology of FVIII production and secretion. PMID- 23042592 TI - Effect of coriander on thioacetamide-induced hepatotoxicity in rats. AB - Thioacetamide (TAA) is a potent hepatotoxin that causes centrilobulal necrosis and nephrotoxic damage following acute administration. Prolonged exposure to TAA can result in bile duct proliferation and liver cirrhosis histologically similar to that caused due to viral hepatitis infection. Coriander in food increases the antioxidant content, acting as a natural antioxidant and inhibiting undesirable oxidation processes. The present study investigated the antioxidant activity of Coriandrum sativum on TAA-induced hepatotoxicity in the male rats. Phenolic content and antioxidant activity were evaluated in the coriander leaves and seeds. Forty-eight adult male rats were divided into four groups. Group I (control), group II (TAA injected rats), group III (TAA injected rats fed coriander leaves) and group IV (TAA injected rats fed coriander seeds). The results revealed that serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were significantly increased in the groups II, III and IV as compared to the normal control. Oxidative stress in the group II was manifested by a significant rise in nitric oxide (NO), thiobarbituric acid reactive substance (TBARS) levels and myloperoxidase (MPO) activities in the liver tissues as compared with the control group. Rats fed with coriander leaves and seeds showed a decrease in the serum ALT, AST and ALP activities and in the liver NO and TBARS levels as compared to the group II. Histopathological study revealed that coriander feeding attenuated TAA-induced hepatotoxicity in the rats. In conclusion, coriander leaves attenuate hepatotoxicity induced by TAA more than that of seeds due to the higher content of phenolic compounds and antioxidants in the leaves of coriander. Liver of rats intoxicated with TAA exhibited advanced CIRRHOSIS: in the form of macronodular and micronodular structure surrounded by fibrous tissue. Treatment with coriander leaves and seeds helps in improving the adverse effect of TAA-induced hepatotoxicity; also the histological study confirms this finding. PMID- 23042593 TI - Effect of pesticide exposure on platelet indices in farm workers. AB - We aimed to assess the effect of exposure to pesticide on platelet indices including mean platelet volume (MPV) and platelet distribution width (PDW) in farm workers. The study group consisted of 40 farm workers (4 females, 36 males; mean age 42.6 +/- 9.8 years). An age-, gender- and body mass index-matched control group was composed of 38 healthy volunteers (8 females, 30 males; mean age 46.1+/-8.9 years). Platelet indices were assessed in farm workers exposed to pesticides. MPV values were significantly lower in farm workers than in those of controls (6.3 +/- 1.1 vs. 7.6 +/- 0.7 fL, respectively; p < 0.001). Platelet count was significantly lower in farm workers than those of controls (155.7 +/- 35.7 vs. 271.3 +/- 96.2 * 10(9)/L, respectively; p < 0.001). PDW was significantly lower in farm workers than in those of controls (8.9% +/- 2.0% vs. 15.8% +/- 0.8%, respectively; p < 0.001). We have found that MPV and other platelet indices were significantly lower in farm workers exposed to pesticides than those of controls. Our findings suggest that MPV may be a sensitive indicator of a pesticide-exposure effect. PMID- 23042594 TI - Serum bile acid as a screening tool in workers occupationally exposed to mixtures of organic solvents. AB - The aim of the present study was to find out the potential impact of occupational exposure to mixtures of organic solvents on liver function tests. Serum bile acid (BA) was evaluated as a marker of early hepatic derangement and compared to routine liver function tests. The study included two comparable groups: 57 male workers exposed to organic solvents from a paints factory and 59 administrative male controls. Occupational and medical data and serum analysis for liver function parameters (BAs, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total and direct bilirubin) were obtained. Bile acids showed significantly elevated mean levels in the exposed workers compared to the controls (50.2 +/- 47.9 and 5.4 +/- 2.7 umol/L, respectively, p < 0.01). Bile acids were elevated in almost all exposed workers (87.7%) but in none of the controls. Bile acids had significant positive correlation with duration of exposure to organic solvents and lifetime hydrocarbon exposure score (HES) (p < 0.01 and p < 0.05, respectively). All other liver function tests exhibited normal mean levels and did not show statistically significant differences between both groups. The performance of BA versus combined liver enzymes is evaluated using receiver operating characteristic (ROC) curve and likelihood ratios. The area under the curve was significantly high (0.687 > 0.5, p = 0.012) and had optimal decision level (8 umol/L). Serum BA can be recommended as a screening test for exposure to organic solvents. It can be suggested for follow-up every 1-2 years or accordingly. PMID- 23042595 TI - Second-hand tobacco smoke and children. AB - Cigarette smoke contains harmful chemicals with hazardous adverse effects on almost every organ in the body of smokers as well as of nonsmokers exposed to environmental tobacco smoke (ETS). There has been increasing interest in the effects of passive smoking on the health of children. In order to detect the magnitude of passive smoking in children, parental questionnaires, measuring nicotine and cotinine body levels, and evaluating expired carbon monoxide (CO) concentrations, have been used. Passive smoking causes respiratory illness, asthma, poor growth, neurological disorders, and coronary heart diseases. Herein, we focused on the deleterious influences of passive smoking on immunity and liver. Besides, its effects on the concentrations of various biomarker levels related to the oxidant/antioxidant status were considered. Understanding these effects may help clinicians to counsel parents on smoking cessation and smoke exposure elimination. It may also help to develop interventions to improve the health of children. This review potentially demonstrated some nutraceuticals with a promising role in the prevention of smoking-related diseases. PMID- 23042596 TI - The impact of maternal prenatal smoking on the development of childhood overweight in school-aged children. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Maternal smoking during pregnancy likely increase the risk of childhood overweight. Childhood overweight is influenced by socioeconomic characteristics of mothers. Characteristics of child at birth determine the likelihood of overweight. WHAT THIS STUDY ADDS: Children of mothers who smoked 1 year before birth (including pregnancy) were likely to be overweight during school ages than those of mothers who never smoked. Confirmation that socioeconomic characteristics of mothers influence the likelihood of childhood overweight during school age. Smoking cessation should be targeted at mothers 1 year before birth to improve their health status and that of offspring. OBJECTIVES: To examine associations between maternal smoking and overweight among school-aged children and also identify mothers and offspring characteristics that affect children's weight. METHODS: We used data from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development (SECCY). Childhood overweight was defined as having Body Mass Index (BMI) of 85th percentile or above. Smoking patterns among mothers were assessed by questioning smoking behaviour 1 year before birth of the target child: never or ever smoking. Standardized procedures were used to measure height and weight. Descriptive statistics and generalized estimating equations (GEE) were used for the analysis. RESULTS: Descriptive results showed that children of mothers who smoked anytime within 1 year before birth were more likely to be overweight and have higher BMI percentile averages. GEE results showed that children of mothers who were ever smokers 1 year before birth were more likely to be overweight (OR = 1.39, 95% CI: 1.01, 1.94) and have higher BMI percentile averages (beta = 4.46, P = 0.036) from grades 1 through 6 than those of mothers who were never smokers. Additionally, the level of mother's education and birth weight were significantly associated with childhood overweight. CONCLUSIONS: Confirmed relationships between maternal smoking and overweight among school-aged children have important implications for public health policy because this evidence can be used to enhance smoking cessation 1 year before birth to improve the health status of mothers and offspring. PMID- 23042597 TI - Molecular dynamics simulation of PNPLA3 I148M polymorphism reveals reduced substrate access to the catalytic cavity. AB - A missense mutation I148M in PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is significantly correlated with nonalcoholic fatty liver disease (NAFLD). To glean insights into mutation's effect on enzymatic activity, we performed molecular dynamics simulation and flexible docking studies. Our data show that the size of the substrate-access entry site is significantly reduced in mutants, which limits the access of palmitic acid to the catalytic dyad. Besides, the binding free energy calculations suggest low affinity for substrate to mutant enzyme. The substrate-bound system simulations reveal that the spatial arrangement of palmitic acid is distinct in wild-type from that in mutant. The substrate recognition specificity is lost due to the loop where the I148M mutation was located. Our results provide strong evidence for the mechanism by which I148M affects the enzyme activity and suggest that mediating the dynamics may offer a potential avenue for NAFLD. PMID- 23042598 TI - Leonurus cardiaca L. (motherwort): a review of its phytochemistry and pharmacology. AB - Leonurus cardiaca is a perennial plant indigenous to central Europe and Scandinavia, but it is also found in the area spanning temperate Russia to central Asia. It has been introduced to North America and has become established locally in the wild. Motherwort (Leonuri cardiacae herba) consists of aerial parts of Leonurus cardiaca gathered during the flowering period, dried at 35 degrees C and, according to European Pharmacopoeia 7th edition, should contain a minimum of 0.2% flavonoids, expressed as hyperoside. Compounds belonging to the group of monoterpenes, diterpenes, triterpenes, nitrogen- containing compounds, phenylpropanoids, flavonoids and phenolic acids, as well as volatile oils, sterols and tannins, have been identified in motherwort. Traditionally, extracts of the herb have been used internally, mainly for nervous heart conditions and digestive disorders. However, they have also been used for bronchial asthma, climacteric symptoms and amenorrhoea, as well as externally in wounds and skin inflammations. Mild negative chronotropic, hypotonic and sedative effects can be attributed to the herb and preparations thereof. Pharmacological studies have confirmed its antibacterial, antioxidant, anti-inflammatory and analgesic activity, as well as its effects on the heart and the circulatory system. Sedative and hypotensive activity has been demonstrated in clinical trials. PMID- 23042599 TI - The total synthesis of corallopyronin A and myxopyronin B. AB - Leading the way: the synthesis of natural products with new biological targets is one of the driving forces for the development of new antibiotics. The synthesis of the two secondary metabolites corallopyronin and myxopyronin have been achieved, which are prominent leads for the inhibition of bacterial RNA polymerase. PMID- 23042600 TI - Modernization and the onset of overweight and obesity in Bougainville and Solomon Islands children: cross-sectional and longitudinal comparisons between 1966 and 1986. AB - This set of cross-sectional and longitudinal data from children and young adults in certain Bougainville and Solomon Islands populations undergoing rapid modernization during the period 1966-1986 reveals very different responses to essentially the same stimuli-the introduction and widespread availability of western dietary items and reductions in habitual activity. Our analyses of over 2,000 children and young adults first measured in 1966-1972, with follow-up surveys in 1968-1970 and 1985-1986, show changes in overweight/obesity in these communities have their onset around puberty, and are not related to differences in childhood growth stunting. The prevalence of overweight and obesity increased substantially during the period of this study among young adults, particularly women, and in groups with more Polynesian affinities, where the frequency of overweight (BMI >= 25) tripled over this 20-year interval. However, the BMI of the more Papuan groups on Bougainville remained remarkably stable, even though they were close to the epicenter of modernization during this period, the Bougainville Copper Mine. PMID- 23042601 TI - Cajal bodies: where form meets function. AB - The cell nucleus contains dozens of subcompartments that separate biochemical processes into confined spaces. Cajal bodies (CBs) were discovered more than 100 years ago, but only extensive research in the past decades revealed the surprising complexity of molecular and cellular functions taking place in these structures. Many protein and RNA species are modified and assembled within CBs, which have emerged as a meeting place and factory for ribonucleoprotein (RNP) particles involved in splicing, ribosome biogenesis and telomere maintenance. Recently, a distinct structure near histone gene clusters--the Histone locus body (HLB)--was discovered. Involved in histone mRNA 3'-end formation, HLBs can share several components with CBs. Whether the appearance of distinct HLBs is simply a matter of altered affinity between these structures or of an alternate mode of CB assembly is unknown. However, both structures share basic assembly properties, in which transcription plays a decisive role in initiation. After this seeding event, additional components associate in random order. This appears to be a widespread mechanism for body assembly. CB assembly encompasses an additional layer of complexity, whereby a set of pre-existing substructures can be integrated into mature CBs. We propose this as a multi-seeding model of CB assembly. PMID- 23042602 TI - Smith-Lemli-Opitz syndrome and other disorders of cholesterol biosynthesis: An introduction. AB - This issue of Seminars of Medical Genetics features a series of articles on Smith Lemli-Opitz syndrome and other disorders of endogenous cholesterol synthesis. Clinically, many of these disorders have been known for decades, but only in the last 20 years have the molecular genetic and enzymatic defects underlying these disorders been delineated. As a group, disorders of cholesterol synthesis are relatively common and contribute significantly to the burden of human disease. Leading experts in their fields present clinical, behavioral, molecular, and therapeutic aspects of these disorders. PMID- 23042603 TI - Do advanced cancer patients in Denmark receive the help they need? A nationally representative survey of the need related to 12 frequent symptoms/problems. AB - OBJECTIVES: The aim of the study was to investigate the adequacy of help delivered by the healthcare system for 12 symptoms/problems in a national, randomly selected sample of advanced cancer patients in Denmark. METHODS: Advanced cancer patients (n = 1630) from 54 hospital departments across Denmark received the 3-Levels-of-Needs Questionnaire (3LNQ). The 3LNQ measures 'problem burden', the degree to which a symptom or problem is perceived as a problem, and 'felt need', whether the patient receives adequate help. Prevalences were calculated for 'problems' (at least 'a little' of a problem), 'moderate/severe problems' (at least 'quite a bit' of a problem) and 'felt need' (inadequate help or no help despite wanting it). RESULTS: In total, 977 (60%) patients participated. The most frequent 'problems' were fatigue (73%; 'moderate/severe' 36%) and limitations doing physical activities (65%; 'moderate/severe' 36%). For the 12 symptoms/problems assessed the prevalence of 'felt need' was 11-35%. Of the patients who had received help, 34-74% viewed the help as inadequate. Of those who had not received help, 48-78% wished for help. CONCLUSION: Advanced cancer patients are not receiving the help they need. Large proportions of patients were burdened by symptoms/problems. Of those who had received help, many viewed it as inadequate. Better symptom/problem identification and management is warranted for advanced cancer patients. PMID- 23042604 TI - Crystal structure of adenovirus E3-19K bound to HLA-A2 reveals mechanism for immunomodulation. AB - E3-19K binds to and retains MHC class I molecules in the endoplasmic reticulum, suppressing anti-adenovirus activities of T cells. We determined the structure of the adenovirus serotype 2 (Ad2, species C) E3-19K-HLA-A2 complex to 1.95-A resolution. Ad2 E3-19K binds to the N terminus of the HLA-A2 groove, contacting the alpha1, alpha2 and alpha3 domains and beta(2)m. Ad2 E3-19K has a unique structure comprising a large N-terminal domain, formed by two partially overlapping beta-sheets arranged in a V shape, and a C-terminal alpha-helix and tail. The structure reveals determinants in E3-19K and HLA-A2 that are important for complex formation; conservation of some of these determinants in E3-19K proteins of different species and MHC I molecules of different loci suggests a universal binding mode for all E3-19K proteins. Our structure is important for understanding the immunomodulatory function of E3-19K. PMID- 23042605 TI - DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin dependent responses to replication blocks. AB - Ubiquitin-mediated processes orchestrate critical DNA-damage signaling and repair pathways. We identify human DVC1 (C1orf124; Spartan) as a cell cycle-regulated anaphase-promoting complex (APC) substrate that accumulates at stalled replication forks. DVC1 recruitment to sites of replication stress requires its ubiquitin-binding UBZ domain and PCNA-binding PIP box motif but is independent of RAD18-mediated PCNA monoubiquitylation. Via a conserved SHP box, DVC1 recruits the ubiquitin-selective chaperone p97 to blocked replication forks, which may facilitate p97-dependent removal of translesion synthesis (TLS) DNA polymerase eta (Pol eta) from monoubiquitylated PCNA. DVC1 knockdown enhances UV light induced mutagenesis, and depletion of human DVC1 or the Caenorhabditis elegans ortholog DVC-1 causes hypersensitivity to replication stress-inducing agents. Our findings establish DVC1 as a DNA damage-targeting p97 adaptor that protects cells from deleterious consequences of replication blocks and suggest an important role of p97 in ubiquitin-dependent regulation of TLS. PMID- 23042606 TI - LpxI structures reveal how a lipid A precursor is synthesized. AB - Enzymes in lipid metabolism acquire and deliver hydrophobic substrates and products from within lipid bilayers. The structure at 2.55 A of one isozyme of a constitutive enzyme in lipid A biosynthesis, LpxI from Caulobacter crescentus, has a novel fold. Two domains close around a completely sequestered substrate, UDP-2,3-diacylglucosamine, and open to release products either to the neighboring enzyme in a putative multienzyme complex or to the bilayer. Mutation analysis identifies Asp225 as key to Mg(2+)-catalyzed diphosphate hydrolysis. These structures provide snapshots of the enzymatic synthesis of a critical lipid A precursor. PMID- 23042608 TI - Electromyography tests in patients with implanted cardiac devices are safe regardless of magnet placement. AB - INTRODUCTION: METHODS: We compared the problems or complications associated with electrodiagnostic testing in 77 patients with implanted cardiac devices. Thirty tests were performed after magnet placement, and 47 were performed without magnet application. RESULTS: All electrodiagnostic tests were performed safely in all patients without any serious effect on the implanted cardiac devices with or without magnet placement. A significantly higher number of patient symptoms and procedure changes were reported in the magnet group (P < 0.013). No statistical difference was found in the testing difficulty or ECG changes. CONCLUSION: The magnet group patients had an approximately 11-fold greater risk of symptoms than those in the control group. Our data do not support a recommendation that magnet placement is necessary for routine electrodiagnostic testing in patients with implanted cardiac devices, as long as our general and specific guidelines are followed. PMID- 23042609 TI - Heterodinuclear ruthenium(II)-cobalt(III) complexes as models for a new approach to selective cancer treatment. AB - Heterodinuclear ruthenium(II)-cobalt(III) complexes have been prepared as part of investigations into a new approach to selective cancer treatment. A cobalt(III) centre bearing amine ligands, which serve as models for cytotoxic nitrogen mustard ligands, is connected by a bridging ligand to a ruthenium(II)-polypyridyl moiety. Upon excitation of the ruthenium centre by visible light, electron transfer to the cobalt(III) centre results in reduction to cobalt(II) and consequent release of its ligands. We have synthesised several such structures and demonstrated their ability to release ligands upon excitation of the ruthenium centre by visible light. PMID- 23042607 TI - DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage. AB - Ubiquitin-binding domains (UBDs) are crucial for recruiting many proteins to sites of DNA damage. Here we characterize C1orf124 (Spartan; referred to as DVC1), which has an UBZ4-type UBD found predominantly in DNA repair proteins. DVC1 associates with DNA replication factories and localizes to sites of DNA damage in human cells, in a manner that requires the ability of the DVC1 UBZ domain to bind to ubiquitin polymers in vitro and a conserved PCNA-interacting motif. DVC1 interacts with the p97 protein 'segregase'. We show that DVC1 recruits p97 to sites of DNA damage, where we propose that p97 facilitates the extraction of the translesion synthesis (TLS) polymerase (Pol) eta during DNA repair to prevent excessive TLS and limit the incidence of mutations induced by DNA damage. We introduce DVC1 as a regulator of cellular responses to DNA damage that prevents mutations when DNA damage occurs. PMID- 23042610 TI - Dysphonia and dermatomyositis: an unusual manifestation. AB - We report a case of a 39-year-old female with a recent diagnosis of dermatomyositis and dysphonia. Dermatomyositis is a connective tissue disease with multisystem involvement: cardiac, pulmonary, musculoskeletal, gastrointestinal, and dermatologic are the most common. While dermatomyositis affects thousands of individuals in the United States, laryngeal involvement has only been described in a single case report to date. PMID- 23042611 TI - Visfatin induces stromal cell-derived factor-1 expression by beta1 integrin signaling in colorectal cancer cells. AB - Obesity has been shown to be associated with the risk of colorectal cancer (CRC). Adipokines produced by the adipose tissue are linked to some malignancies, including CRC. Visfatin is an adipokine shown to be a biomarker of CRC malignant potential. In addition, the stromal cell-derived factor-1 (SDF-1) has been reported to play a role in CRC progression. Although the relationship between visfatin and CRC has been established, the underlying mechanism has not been clarified. We investigated the molecular mechanism governing the interaction between visfatin stimulation and SDF-1 expression in human CRC cell lines. We found that visfatin stimulation led to an increase in the expression and secretion of SDF-1 in CRC DLD-1 and SW48 cells. Experiments involving specific inhibitors and small interfering RNA demonstrated that the activation of ERK and p38 mitogen-activated protein kinase (MAPK) pathways are critical for visfatin induced SDF-1 expression. Analysis of transcription factor binding using ELISA and luciferase reporter assays revealed that visfatin increased NF-kappaB- and AP 1-DNA-binding activities in DLD-1 cells. Inhibition of NF-kappaB and AP-1 activation blocked the visfatin-induced expression and activity of the SDF-1 promoter. The effect of visfatin on DLD-1 signaling and SDF-1 expression was mediated by beta1 integrin. In summary, these findings provide novel insights pertaining to the pathophysiological role of visfatin in CRC. PMID- 23042612 TI - A pilot randomized controlled trial of a brief early intervention for reducing posttraumatic stress disorder, anxiety and depressive symptoms in newly diagnosed head and neck cancer patients. AB - OBJECTIVE: Head and neck cancer (HNC) patients have a high incidence of cancer related posttraumatic stress disorder (PTSD) and other anxiety and depressive disorders. We report the results from the first pilot randomized controlled trial in which the efficacy of an early cognitive-behavioral therapy (CBT) program was compared with a non-directive supportive counseling (SC) intervention in reducing PTSD, general anxiety and depressive symptoms, and improving perceived quality of life in newly diagnosed, distressed HNC patients undergoing radiotherapy. PATIENTS AND METHODS: Thirty-five HNC patients (mean age=54.8 years; 80% males) with elevated levels of PTSD, depression or anxiety were randomized to seven individual sessions of a multi-modal CBT or non-directive SC, concurrent with patients' radiotherapy. The SC intervention provided non-directive counseling support. PTSD, anxiety and depressive symptoms (primary outcomes), and cancer related appraisals and quality of life (secondary outcomes) were assessed pre intervention (baseline), 1 month, 6 months and 12 months post-intervention by diagnostic clinical interviews and validated self-report questionnaires. RESULTS: The CBT and SC interventions were found to be equal in their effects in reducing PTSD and anxiety symptoms both in the short and longer term. However, up to 67% of patients in the CBT program no longer met clinical or sub-clinical PTSD, anxiety and/or depression by 12 months post-treatment compared with 25% of patients who received SC. CONCLUSION: Findings indicate that the early provision of psychotherapy has utility in reducing PTSD, anxiety and depressive symptoms, and preventing chronic psychopathology in distressed HNC patients. PMID- 23042614 TI - Personalized medicine benefits patients in early trials: matching targeted therapies with gene mutations is associated with better outcomes, even in phase 1 studies. PMID- 23042615 TI - Long-term cancer survivors take more sick leave. PMID- 23042613 TI - Structural features of cholesteryl ester transfer protein: a molecular dynamics simulation study. AB - Cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl esters (CEs) from atheroprotective high-density lipoproteins (HDLs) to atherogenic low-density lipoproteins (LDLs) or very-low-density lipoproteins (VLDLs). Inhibition of CETP raises HDL cholesterol (good cholesterol) levels and reduces LDL cholesterol (bad cholesterol) levels, making it a promising drug target for the prevention and treatment of coronary heart disease. Although the crystal structure of CETP has been determined, the molecular mechanism mediating CEs transfer is still unknown, even the structural features of CETP in a physiological environment remain elusive. We performed molecular dynamics simulations to explore the structural features of CETP in an aqueous solution. Results show that the distal portion flexibility of N-terminal beta-barrel domain is considerably greater in solution than in crystal; conversely, the flexibility of helix X is slightly less. During the simulations the distal end of C-terminal beta-barrel domain expanded while the hydrophilic surface increasing more than the hydrophobic surface. In addition, a new surface pore was generated in this domain. This surface pore and all cavities in CETP are stable. These results suggest that the formation of a continuous tunnel within CETP by connecting cavities is permitted in solution. PMID- 23042616 TI - New research shows why advanced cancers recur after targeted treatments. PMID- 23042617 TI - Receipt of recommended radiation therapy among rural and urban cancer patients. AB - BACKGROUND: Rural populations have limited geographic access to radiation therapy. The current study examines whether rural patients with cancer are less likely than urban patients with cancer to receive recommended radiation therapy, and identifies factors influencing rural versus urban differences in radiation therapy receipt. METHODS: The current study included 14,692 rural and 107,834 urban patients with 5 cancer types and stages for which radiation therapy was recommended. The authors used 2000 to 2004 Surveillance, Epidemiology, and End Results (SEER) Limited-Use Data from 8 state-based (California, Connecticut, Hawaii, Iowa, Kentucky, Louisiana, New Mexico, and Utah) and 3 county-based (Atlanta, rural Georgia, and Seattle/Puget Sound) cancer registries. Adjusted radiation therapy receipt rates were calculated by rural versus urban residence overall, for different sociodemographic and cancer characteristics, and for different states based on logistic regression analyses using general estimating equation methods to account for patient clustering by county. RESULTS: Adjusted rates of radiation therapy receipt were lower for rural (62.1%) than urban (69.1%) patients with breast cancer (P <= .001). Among patients with breast cancer, radiation therapy receipt differed more by sociodemographic characteristics (eg, rural patients aged < 50 years had a 67.1% receipt rate, whereas those aged >= 80 years had a radiation therapy receipt rate of 29.1%) than rural versus urban residence. Adjusted rates of radiation therapy receipt were similar for rural and urban patients with other cancer types overall (66.1% vs 68.2%; difference not significant), although there were differences between urban and rural patients with regard to radiation therapy receipt for patients with stage IIIA nonsmall cell lung cancer (66.2% vs 60.7%; P <= .01). CONCLUSIONS: Sociodemographics, cancer types and stages, and state of residence appear to have a greater influence over receipt of radiation therapy than rural versus urban residence location, suggesting that factors such as social support, receipt of other cancer treatments, and regional practice patterns are important determinants of radiation therapy receipt. PMID- 23042618 TI - Marine prey processed with stone tools by Burmese long-tailed macaques (Macaca fascicularis aurea) in intertidal habitats. AB - Long-tailed macaques (Macaca fascicularis) feed opportunistically in many habitats. The Burmese subspecies (M. f. aurea) inhabits coastal areas in southwestern Thailand and Myanmar, and some of their populations have adapted lithic customs for processing encased foods in intertidal habitats. We investigated the diet of such macaques in Laemson National Park, Thailand, and identified the variety of foods they processed with stones. We conducted 36 shore surveys to study tool sites following feeding activity, during which we counted the minimum number of individual (MNI) food items found at each site. We identified 47 food species (43 animals and four plants), from 37 genera. We counted 1,991 food items during surveys. Nearly all were mollusks (n = 1,924), with the small remainder primarily consisting of crustaceans and nuts. The two most common foods, rock oysters (Saccostrea cucullata; n = 1,062) and nerite snails (Nerita spp.; n = 538), composed 80.2% of our sample. Four prey species comprised 83.2% of the sample (MNI = 1,656), S. cucullata (n = 1,062), Nerita chamaeleon (n = 419), Thais bitubercularis (n = 95), and Monodonta labio (n = 80). Macaques selected a wide variety of foods. However, they heavily concentrated on those that were abundant, easy to access, and sufficiently sized. The Burmese long-tailed macaque stone-processed diet, which focuses on intertidal marine prey, differs from Sapajus and Pan, who use stones primarily for encased nuts and fruits. In terms of diversity of foods exploited, coastal stone-based predation by macaques resembles the diet of coastal-foraging humans (Homo sapiens sapiens). PMID- 23042619 TI - Accelerated carbon-carbon bond-forming reactions in preparative electrospray. PMID- 23042620 TI - In vitro antibacterial activity and synergistic antibiotic effects of phlorotannins isolated from Eisenia bicyclis against methicillin-resistant Staphylococcus aureus. AB - Six phlorotannins, isolated from Eisenia bicyclis, were evaluated for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentrations (MIC) of the compounds were in the range 32 to 64 ug/mL. Phlorofucofuroeckol-A (PFF) exhibited the highest anti-MRSA activity, with an MIC of 32 ug/mL. An investigation of the interaction between these compounds and the beta-lactam antibiotics ampicillin, penicillin, and oxacillin revealed synergistic action against MRSA in combination with compound PFF. To our knowledge, this is the first report on the anti-MRSA activity of phlorotannins from E. bicyclis. The results obtained in this study suggest that the compounds derived from E. bicyclis can be a good source of natural antibacterial agents against MRSA. PMID- 23042625 TI - Meeting report: High-throughput process development--HTPD 2012: June 4-7, 2012, Avignon, France. AB - High throughput process development (HTPD), the application of miniaturized and automated experiments for the development of protein production and purification processes, has been established over the last decade and has found its way into most process development group in the pharmaceutical industry. The first installment of the HTPD meeting in 2010 had been a huge success in bringing together people from academia and industry dedicated to this topic. With its second occasion, the scope of the meeting was broadened while the quality of the contributions and the balance between academic and industrial topics was kept at the excellently high quality underlining this meetings importance and singular position for the field of HTPD. PMID- 23042628 TI - Mutational spectrum of Smith-Lemli-Opitz syndrome. AB - Smith-Lemli-Opitz syndrome (SLOS; OMIM #270400) is an autosomal recessive malformation syndrome characterized by a large spectrum of morphogenic and congenital anomalies. SLOS is caused by mutations in the DHCR7 gene, which encodes 7-dehydrocholesterol reductase, the enzyme that catalyzes the final step in cholesterol biosynthesis. We report on 154 currently known mutations in DHCR7 identified in patients affected with SLOS and discuss their coding consequences. These 154 mutations include 130 missense, 8 nonsense, 8 deletions, 2 insertions, 1 indel, and 5 splice site mutations. Using information available from published case reports and from patients identified in our clinical diagnostic laboratory, we analyzed correlations between genotype, clinical presentation and 7 dehydrocholesterol level. PMID- 23042630 TI - Near-infrared spectroscopy during exercise and recovery in children with juvenile dermatomyositis. AB - INTRODUCTION: We hypothesized that microvascular disturbances in muscle tissue play a role in the reduced exercise capacity in juvenile dermatomyositis (JDM). METHODS: Children with JDM, children with juvenile idiopathic arthritis (clinical controls), and healthy children performed a maximal incremental cycloergometric test from which normalized concentration changes in oxygenated hemoglobin (Delta[O2 Hb]) and total hemoglobin (Delta[tHb]) as well as the half-recovery times of both signals were determined from the vastus medialis and vastus lateralis muscles using near-infrared spectroscopy. RESULTS: Children with JDM had lower Delta[tHb] values in the vastus medialis at work rates of 25%, 50%, 75%, and 100% of maximal compared with healthy children; the increase in Delta[tHb] with increasing intensity seen in healthy children was absent in children with JDM. Other outcome measures did not differ by group. CONCLUSIONS: The results suggest that children with JDM may experience difficulties in increasing muscle blood volume with more strenuous exercise. PMID- 23042629 TI - Physical activity behaviours of highly active preschoolers. AB - BACKGROUND: Understanding the physical activity behaviour of young children who are highly active may provide important guidance for promoting physical activity in preschools. OBJECTIVES: The objective of this study was to describe the movement characteristics of high-active (HA) children during attendance at preschools. METHODS: Children in 20 preschools (n = 231) wore accelerometers and were classified into tertiles of moderate-to-vigorous physical activity. Children's movement characteristics were observed using the Observational System for Recording Physical Activity in Children-Preschool Version. Mixed-model analyses compared movement types between HA children and lower-active (LA) children during the total school day. RESULTS: HA (n = 77) children were observed to be more active than LA children (n = 154) indoors (P < 0.001), but no differences were observed outdoors. HA children were more frequently observed running, crawling, climbing, jumping, skipping, swinging and throwing across the total school day than LA children. Outdoors, HA children participated in more swinging and throwing and less jumping or skipping than LA children. Indoors, HA children spent more time pulling, pushing and running, and less time walking than LA children. CONCLUSIONS: HA children have unique activity patterns. Further interventions to increase physical activity of all preschoolers should increase the time spent outside and include varied activity types throughout the entire school day. PMID- 23042631 TI - Geometric morphometric shape analysis in an ovine model confirms that the upper esophageal sphincter is not round. AB - OBJECTIVES/HYPOTHESIS: Dysfunction of the upper esophageal sphincter (UES) is a common cause of oral-pharyngeal dysphagia (OPD). Dilation is a primary treatment, although current techniques are subject to a high rate of failure and recurrence. Devices available for UES dilation are cylindrical and were designed to distend the round lumen of the esophagus. Our objective was to determine the cross sectional dimension of the UES in an ovine model of OPD and compare it with that of the cervical esophagus. STUDY DESIGN: Prospective cadaveric animal study. METHODS: Three-dimensional casts of the upper aerodigestive tract of 10 fresh cadaveric ewes were constructed using a platinum-cured liquid silicone polymer. Cross-sections at the level of the UES and cervical esophagus were digitized and mathematically compared using geometric morphometric shape analysis. RESULTS: Consensus shape among all 10 animals revealed that the narrowest region of the maximally distended UES has a cross-sectional shape that resembles a kidney, whereas the cervical esophagus approximates a circle. The shape of the UES and cervical esophagus were significantly different (P < .0001), and surface area calculations demonstrated that an inscribed circle significantly underestimated the area implied by the kidney-shaped UES model. CONCLUSIONS: Current dilators used to treat UES dysfunction are cylindrical and based on the assumption that the UES is round. This is the first report to empirically analyze the cross sectional area of the UES utilizing an established ovine model. The data suggest that the cross-sectional area of the UES is shaped like a kidney, and currently available cylindrical dilators are suboptimal for UES distention. PMID- 23042632 TI - An investigation of donor and culture parameters which influence epithelial outgrowths from cultured human cadaveric limbal explants. AB - Limbal stem cell deficiency is a blinding disease which affects the cornea at the front of the eye. The definitive cure involves replacing the corneal epithelial (limbal) stem cells, for example by transplanting cultured limbal epithelial cells. One method of performing cultures is to grow a sheet of epithelial cells from a limbal explant on human amniotic membrane. The growth of limbal tissue can be variable. The aim of this study is to investigate how different donor and culture factors influence the ex vivo growth of cadaveric limbal explants. Limbal explant cultures were established from 10 different cadaveric organ cultured corneo-scleral discs. The growth rate and the time taken for growth to be established were determined. Statistical analysis was performed to assess correlation between these factors and donor variables including donor age, sex, time from donor death to enucleation, time from enucleation to organ culture storage and duration in organ culture. Growth curves consistently showed a lag phase followed by a steeper linear growth phase. Donor age, time between death and enucleation, and time between enucleation and organ culture were not correlated to the lag time or the growth rate. Time in organ culture had a significant correlation with the duration of lag time (P = 0.003), but no relationship with the linear growth rate. This study shows that an important factor correlating with growth variation is the duration of corneo-scleral tissue in organ culture. Interestingly, donor age was not correlated with limbal explant growth. PMID- 23042633 TI - Three enhancements to the inference of statistical protein-DNA potentials. AB - The energetics of protein-DNA interactions are often modeled using so-called statistical potentials, that is, energy models derived from the atomic structures of protein-DNA complexes. Many statistical protein-DNA potentials based on differing theoretical assumptions have been investigated, but little attention has been paid to the types of data and the parameter estimation process used in deriving the statistical potentials. We describe three enhancements to statistical potential inference that significantly improve the accuracy of predicted protein-DNA interactions: (i) incorporation of binding energy data of protein-DNA complexes, in conjunction with their X-ray crystal structures, (ii) use of spatially-aware parameter fitting, and (iii) use of ensemble-based parameter fitting. We apply these enhancements to three widely-used statistical potentials and use the resulting enhanced potentials in a structure-based prediction of the DNA binding sites of proteins. These enhancements are directly applicable to all statistical potentials used in protein-DNA modeling, and we show that they can improve the accuracy of predicted DNA binding sites by up to 21%. PMID- 23042635 TI - PD-1 targeting in cancer immunotherapy. PMID- 23042636 TI - Quantifying lateral femoral condyle ellipticalness in chimpanzees, gorillas, and humans. AB - Articular surfaces of limb bones provide information for understanding animal locomotion because their size and shape are a reflection of habitual postures and movements. Here we present a novel method for quantifying the ellipticalness (i.e., departure from perfectly circular) of the lateral femoral condyle (LFC), applying this technique to hominid femora. Three-dimensional surface models were created for 49 Homo sapiens, 34 Pan troglodytes and 25 Gorilla gorilla femora. Software was developed that fit separate cylinders to each of the femoral condyles. These cylinders were constrained to have a single axis, but could have different radii. The cylinder fit to the LFC was allowed to assume an elliptical cross-section, while the cylinder fit to the medial condyle was constrained to remain circular. The shape of the elliptical cylinder (ratio of the major and minor axes of the ellipse) was recorded, and the orientation of the elliptical cylinder quantified as angles between the major axis of the ellipse and the anatomical and mechanical axes of the femur. Species were compared using analysis of variance and post hoc multiple comparisons tests. Confirming qualitative descriptions, human LFCs are more elliptical than those of chimpanzees and gorillas. Human femora exhibit a narrow range for the angle between the major axis of the elliptical cylinder and femoral axes. Conversely, the chimpanzee sample is bimodal for these angles, exhibiting two ellipse orientations, while Gorilla shows no preferred angle. Our results suggest that like modern human femora, chimpanzee femoral condyles have preferentially used regions. PMID- 23042634 TI - Sekikaic acid and lobaric acid target a dynamic interface of the coactivator CBP/p300. AB - Capturing a coactivator, naturally: the natural products sekikaic acid and lobaric acid, isolated after a high-throughput screen of a structurally diverse extract collection, effectively target the dynamic binding interfaces of the GACKIX domain of the coactivator CBP/p300. These molecules are the most effective inhibitors of the GACKIX domain yet described and are uniquely selective for this domain. PMID- 23042637 TI - Lashing out after stewing over public insults: the effects of public provocation, provocation intensity, and rumination on triggered displaced aggression. AB - Four studies present the first evidence showing that public (vs. private) provocation augments triggered displaced aggression by increasing the perceived intensity of the provocation. This effect is shown to be independent of face saving motivation. Following a public or private provocation, Study 1 participants were induced to ruminate or were distracted for 20 min. They then had an opportunity to aggress against another person who either acted in a neutral or mildly annoying fashion (viz. triggering event). As expected, the magnitude of the greater displaced aggression of those who ruminated before the triggering event compared with those distracted was greater under public than private provocation. Study 2 replicated the findings of Study 1 and confirmed that public provocations are experienced as more intense. Studies 3 and 4 both manipulated provocation intensity directly to show that it mediated the moderating effect of public/private provocation found in Study 1. The greater intensity of a public provocation increases reactivity to a subsequent trigger, which in turn, augments triggered displaced aggression. PMID- 23042638 TI - Inhibitory effects of ginsenoside Rb1 on neuroinflammation following systemic lipopolysaccharide treatment in mice. AB - Ginsenoside Rb1 (GRb1) is a major ingredient of ginseng and has a wide range of neuroprotection effects. Neuroinflammation is a feature of neurodegenerative conditions and is characterized by microglia activation and the expression of major inflammatory mediators. The present study investigated the modulatory effect of GRb1 on microglia activation, the expression of pro-inflammatory cytokines and cyclooxygenase (COX)-2 in the brain induced by systemic lipopolysaccharide (LPS) treatment in C57BL/6 mice. Systemic LPS treatment induces immediate microglia activation in the brain. Based on this information, GRb1 was administered orally, at doses of 10 and 20 mg/kg, 1 h prior to the LPS (3 mg/kg, intraperitoneally) injection. At a dose of 20 mg/kg GRb1 attenuated Iba1 protein expression and morphological activation of microglia by LPS. GRb1 significantly reduced the upregulation of tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6 mRNA in the brain tissue at 4 h after LPS injection. In addition, the expression of COX-2 mRNA and protein in the brain tissue were also attenuated at the 20 mg/kg dose of GRb1. These results indicate that GRb1 plays a modulatory role in microglia activation and neuroinflammation. This study shows that GRb1 attenuates microglia activation in the brain using an in vivo animal model. PMID- 23042639 TI - Regional radiographic damage and functional limitations in patients with ankylosing spondylitis: differences in early and late disease. AB - OBJECTIVE: Both radiographic damage and functional limitations increase with the duration of ankylosing spondylitis (AS). We examined whether radiographic damage contributed more to functional limitations in late AS than in early AS, and if the strength of association varied with the anatomic region of damage. METHODS: In this cross-sectional study of 801 patients with AS, we examined associations of the lumbar modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), the cervical mSASSS, lumbar posterior fusion, cervical posterior fusion, and hip arthritis with the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Health Assessment Questionnaire modified for the spondyloarthritides (HAQ-S). RESULTS: Higher lumbar and cervical mSASSS scores were associated with more functional limitations, but there was an interaction between mSASSS scores and the duration of AS, such that the strength of their association with functional limitations decreased with increasing duration of AS. Cervical posterior fusion was associated with worse functioning independent of mSASSS scores. Hip arthritis was significantly associated with functional limitations independent of spinal damage measures. Among patients with AS duration >=40 years, the number of comorbid conditions accounted for most of the variation in functioning. Results were similar for both the BASFI and the HAQ-S. CONCLUSION: Although both radiographic damage and functional limitations increase over time in AS, the relative contribution of radiographic damage to functional limitations is lower among patients with longstanding AS than with early AS, suggesting patients may accommodate to limited flexibility. Damage in different skeletal regions impacts functioning over the duration of AS. Functional limitations due to comorbidity supervene in late AS. PMID- 23042640 TI - Fluorine-18 radiolabeling and radiopharmacological characterization of a benzodioxolylpyrimidine-based radiotracer targeting the receptor tyrosine kinase EphB4. AB - Members of the Eph receptor tyrosine kinase family play essential roles in the pathogenesis of cancer and are therefore promising candidates for molecular imaging by positron emission tomography (PET), for example. In this regard, radiochemical access to novel PET radiotracers derived from potent inhibitors that target the EphB4 kinase domain and which bear a benzodioxolylpyrimidine structural motif was developed. A synthetic route was established for a new fluorine-18-containing radiotracer and for the desired precursor based on a high affinity benzodioxolylpyrimidine receptor tyrosine kinase inhibitor lead structure. The radiotracer [(18)F]15 was obtained in 16 % radiochemical yield with a specific activity of ~7 GBq MUmol(-1) and >95 % radiochemical purity. Due to the implication of EphB4, particularly in the progression, angiogenesis, and metastasis of melanoma, EphB4-overexpressing human melanoma cells were generated and used as a novel in vitro model for radiopharmacological evaluation of the radiotracer. We demonstrate that the corresponding non-radioactive reference compound regained its functionality as an inhibitor for both EphB4 receptor tyrosine kinase and Src kinase. EphB4 was significantly inhibited at compound concentrations >1 MUM. Cellular uptake studies with [(18)F]15 revealed substantial uptake in both EphB4-overexpressing and control cells. Moreover, NMRI nu/nu mice bearing both EphB4-overexpressing tumors and control tumors were used for radiopharmacological characterization by biodistribution studies ex vivo and by dynamic small-animal PET experiments in vivo. Despite the high metabolic stability of the novel radiotracer observed in vivo, no substantial binding or accumulation in EphB4-overexpressing and control tumors was observed. Nevertheless, we point out that the approach presented herein gives convenient access to novel (18)F-labeled benzodioxolylpyrimidines and is a promising strategy for the further development of novel radiotracers for imaging Eph receptor tyrosine kinases in cancer. PMID- 23042641 TI - Protein phosphatase 2A Calpha regulates osteoblast differentiation and the expressions of bone sialoprotein and osteocalcin via osterix transcription factor. AB - Serine/threonine protein phosphatase 2A (PP2A) participates in regulating many important physiological processes such as cell cycle, growth, apoptosis, and signal transduction. Osterix is a zinc-finger-containing transcription factor that is essential for osteoblast differentiation and regulation of many bone related genes. We have recently reported that decrease in alpha-isoform of PP2A catalytic subunit (PP2A Calpha) accelerates osteoblast differentiation through the expression of bone-related genes. In this study, we further examined the role of PP2A Calpha in osteoblast differentiation by establishing the stable cell lines that overexpress PP2A Calpha. Overexpression of PP2A Calpha reduced alkaline phosphatase (ALP) activity. Osteoblast differentiation and mineralization were also decreased in PP2A Calpha-overexpressing cells, with reduction of bone-related genes including osterix, bone sialoprotein (Bsp), and osteocalcin (OCN). Luciferase assay showed that the transcriptional activity of the Osterix promoter region was decreased in PP2A Calpha-overexpressing cells. Introduction of ectopic Osterix rescued the expression of Bsp and OCN in PP2A Calpha-overexpressing cells. These results indicate that PP2A Calpha and its activity play a negative role in osteoblast differentiation and Osterix is a key factor responsible for regulating the expressions of Bsp and OCN during PP2A Calpha-mediated osteoblast differentiation. PMID- 23042643 TI - Kinetic modeling and occupancy measures of the norepinephrine transporters in baboons using single photon emission computed tomography with (123)I-INER. AB - This study aims to investigate the pharmacokinetics of a recently developed radiotracer for imaging of the norepinephrine transporter (NET) in baboon brain, (123)I-INER, using single photon emission computed tomography (SPECT). In addition, it also aims to determine NET occupancy by atomoxetine and reboxetine, two selective norepinephrine reuptake inhibitors, using (123)I-INER in baboons. Baseline and preblocking studies with a high dose of atomoxetine (0.85 mg/kg) were conducted in three baboons using SPECT with (123)I-INER administered as a bolus. Kinetic modeling analysis was investigated for different models, namely invasive and reference tissue models. Bolus plus constant infusion experiments with displacement at equilibrium using six different doses of atomoxetine (0.03 0.85 mg/kg) and four different doses of reboxetine (0.5-3.0 mg/kg) were carried out in several baboons to obtain occupancy measurements as a function of dose for the two NET selective drugs. Results showed that reference tissue models can be used to estimate binding potential values and occupancy measures of (123)I-INER in different brain regions. In addition, the apparent volume of distribution was estimated by dividing concentration in tissue by the concentration in blood at 3 hours postinjection. After administration of atomoxetine or reboxetine, a dose dependent occupancy was observed in brain regions known to contain high densities of NET. In conclusion, pharmacokinetic properties of (123) I-INER were successfully described, and obtained results may be used to simplify future data acquisition and image processing. Dose-dependent NET occupancy for two selective norepinephrine reuptake inhibitors was successfully measured in vivo in baboon brain using SPECT and (123) I-INER. PMID- 23042644 TI - A novel RAB33B mutation in Smith-McCort dysplasia. AB - Smith-McCort dysplasia (SMC) is a rare autosomal recessive spondylo-epi metaphyseal dysplasia with skeletal features identical to those of Dyggve Melchior-Clausen syndrome (DMC) but with normal intelligence and no microcephaly. Although both syndromes were shown to result from mutations in the DYM gene, which encodes the Golgi protein DYMECLIN, a few SMC patients remained negative in DYM mutation screening. Recently, autozygosity mapping and exome sequencing in a large SMC family have allowed the identification of a missense mutation in RAB33B, another Golgi protein involved in retrograde transport of Golgi vesicles. Here, we report a novel RAB33B mutation in a second SMC case that leads to a marked reduction of the protein as shown by Western blot and immunofluorescence. These data confirm the genetic heterogeneity of SMC dysplasia and highlight the role of Golgi transport in the pathogenesis of SMC and DMC syndromes. PMID- 23042642 TI - Treatment of Smith-Lemli-Opitz syndrome and other sterol disorders. AB - Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic condition with a broad phenotype that results from deficiency of the final enzyme of the cholesterol synthesis pathway. This defect causes low or low-normal plasma cholesterol levels and increased 7- and 8-dehydrocholesterol (DHC) levels. Many therapies for SLOS and other disorders of sterol metabolism have been proposed, and a few of them have been undertaken in selected patients, but robust prospective clinical trials with validated outcome measures are lacking. We review the current literature and expert opinion on treatments for SLOS and other selected sterol disorders, including dietary cholesterol therapy, statin treatment, bile acid supplementation, medical therapies, and surgical interventions, as well as directions for future therapies and treatment research. PMID- 23042645 TI - Cognitive decline and older adults' perception of stigma controllability. AB - Emerging research suggests that older adults who experience age-related declines in regulatory abilities may have more difficulty inhibiting their expression of negative bias to stigmatized individuals as compared with young adults. However, it remains largely unexplored why this might be. For instance, older adults may hold stigmatized individuals more accountable for their conditions as compared with young adults, which could subsequently increase their expression of negative bias. The current study investigated this question by testing 90 older adults and 44 young adults. Researchers found that older adults with relatively impaired executive function placed a greater emphasis on controllability when evaluating stigmatized individuals and rated the stigmatized conditions overall as being more changeable. PMID- 23042646 TI - Survey methods and aging research in an Arab sociocultural context--a case study from Beirut, Lebanon. AB - OBJECTIVES: In Arab countries, the proportion of older adults is rapidly increasing, highlighting the need to conduct research on factors that influence aging. We describe the context-specific challenges faced and the solutions negotiated during the conduct of a survey study on family relations and aging in Greater Beirut, Lebanon. METHOD: Drawing on the experience of a recently completed survey study, we reflect on the context-specific challenges faced and the solutions negotiated during the phases of questionnaire construction, interviewer training, sampling, and participant recruitment as a means to contribute to the growing area of cross-cultural survey research. RESULTS: The social context of family relations influenced the nature of questions that can be included to obtain valid information. The unavailability of demographic data and the presence of cultural norms that promote deference to older adults also presented methodological challenges to the sampling and recruitment of older adults. DISCUSSION: We provided illustrative examples on the importance of learning about a country's social and cultural contexts, and the necessity of exercising flexibility in decision making to ensure the collection of valid data and the successful completion of the study. Lessons learned inform elements of the research process in an Arab country, as well as bring to light unusual, yet generalizable, circumstances that will inform experiences in other cultural settings. PMID- 23042647 TI - When do we believe experts? The power of the unorthodox view. AB - This paper examines the extent to which orthodoxy (degree of typicality) and congruence (degree of similarity with own opinion) mediate the influence of expert advice on decision makers' judgments. Overall, 227 members of the public and 60 police officers completed an online questionnaire involving an investigation into a child sex offence. Participants were asked to first (i) formulate their own "profile" of a likely offender then (ii) estimate the guilt of two presented suspect descriptions (orthodox vs. unorthodox), and, following the presentation of an "expert's" profile that matched either the orthodox or the unorthodox suspect, (iii) re-evaluate their guilt judgments of the two suspects based on this new advice. Finally, (iv) the perceived similarity (congruence) between the participants' own and the expert profile was assessed. Results revealed two key findings. First, expert profiles that matched a suspect's description elevated perceptions of guilt in that suspect, whilst also, simultaneously, very significantly decreasing the perception of guilt of the alternative suspect. This suggests a powerful rejection and downward revision of the other suspect. Second, perceived similarity of the profile (to one's own profile) was only a significant factor in increasing guilt judgments when assigning guilt to the unorthodox (as opposed to orthodox) suspect. Comparisons of lay judgments with those of police officers revealed few significant differences in effects. The finding that advice is most influential when unorthodox and incongruent suggests that decision makers are more likely to reevaluate judgments when expert advice contributes novel information that contradicts their beliefs. The practical implications of these findings are discussed for profilers, police, and decision research in general. PMID- 23042650 TI - Role of inflammatory dendritic cells in innate and adaptive immunity. AB - The major role of cells of the dendritic family in immunity and tolerance has been amply documented. Since their discovery in 1973, these cells have gained increasing interest from immunologists, as they are able to detect infectious agents, migrate to secondary lymphoid tissue, and prime naive T lymphocytes, thereby driving immune responses. Surprisingly, they can also have the opposite function, that is, preventing immune responses, as they are involved in central and peripheral tolerance. Most dendritic cells (DCs) derive from a common precursor and do not arise from monocytes and are considered "conventional" DCs. However, a new population of DCs, namely "inflammatory" DCs, has recently been identified, which is not present in the steady state but differentiates from monocytes during infection/inflammation. In this review, we summarize the role of these "inflammatory" DCs in innate and adaptive immunity. PMID- 23042652 TI - Acquitting an APC: DCs found "not guilty" after trial by ablation. AB - There is a large body of evidence demonstrating that DCs are the most efficient and specialized APCs for T-cell priming, both in the context of host defense against pathogens and during the development of T-cell-mediated autoimmune responses; however, this concept is currently being challenged by a series of conflicting observations using genetically engineered mice in which DCs are either constitutively or inducibly ablated. In this issue of the European Journal of Immunology, Isaksson et al. [Eur. J. Immunol. 2012, 42: 2555-2563] report the use of mice in which CD11c(hi) cells can be ablated by injecting diphtheria toxin in vivo. The authors then induced EAE and found that, surprisingly, the mice were fully susceptible to the disease; thus, challenging the dogma that DCs are a mandatory APC population for the priming of autoimmune T(H) cells or T-cell mediated immune responses. Here, we will analyze the authors' findings in the context of observations made by others and critically discuss whether DCs can really be dismissed as crucial APCs. PMID- 23042651 TI - Basophil modulation by cytokine instruction. AB - Basophils have recently been recognized as critical effector cells in allergic reactions and protective immunity against helminths. Precise characterization of basophil biology could help to develop specific therapies that interfere with differentiation, tissue recruitment, or induction of effector functions and thereby ameliorate allergic disorders. The development, homeostasis, and effector functions of basophils are tightly regulated by extrinsic signals and in particular by cytokines. IL-3, GM-CSF, and thymic stromal lymphopoietin activate the STAT5 pathway that promotes proliferation, activation, and cytokine secretion but also induces a negative feedback loop via Pim-1 and SOCS proteins. Basophils further express receptors for IL-18 and IL-33, which are associated with the signaling adaptor MyD88 and activate the NF-kappaB and MAP kinase pathways. This review focuses on positive and negative regulation of basophils by these cytokines. PMID- 23042655 TI - Enantioselective synthesis of highly functionalized phosphonate-substituted pyrans or dihydropyrans through asymmetric [4+2] cycloaddition of beta,gamma unsaturated alpha-ketophosphonates with allenic esters. AB - Tell me which you want: catalytic asymmetric [4+2] cycloadditions of beta,gamma unsaturated alpha-ketophosphonates with allenic esters catalyzed by organocatalysts derived from different cinchona alkaloids have been developed, affording phosphonate-substituted functionalized pyran and dihydropyran derivatives in excellent yields with high enantioselectivities under mild conditions. The choice of product is controlled by the hydrogen bonding characteristics of the chosen catalyst. PMID- 23042656 TI - Recent advances in the research of heterocyclic compounds as antitubercular agents. AB - Tuberculosis (TB) is a major health problem, with approximately one-third of the world's population infected with Mycobacterium tuberculosis, eight million people in the active disease state, and two million dying annually. Furthermore, the prevalence of TB/HIV co-infection, and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have further aggravated the spread of this disease and thus mortality by it. There is an urgent need for novel antitubercular agents with improved properties, such as lower toxicity, shortened duration of therapy, rapid bactericidal action, and enhanced activity against MDR strains. Fortunately, a number of new potential antitubercular candidate drugs with heterocyclic rings, which are most likely to be effective against resistant strains, have entered clinical trials in recent years. This review highlights recent advances in the research of novel heterocyclic compounds, with particular focus on their antimycobacterial activity, mechanisms of action, toxicity, and structure-activity relationships (SARs). PMID- 23042658 TI - Location constrained approximate message passing for compressed sensing MRI. AB - Iterative thresholding methods have been extensively studied as faster alternatives to convex optimization methods for solving large-sized problems in compressed sensing. A novel iterative thresholding method called LCAMP (Location Constrained Approximate Message Passing) is presented for reducing computational complexity and improving reconstruction accuracy when a nonzero location (or sparse support) constraint can be obtained from view shared images. LCAMP modifies the existing approximate message passing algorithm by replacing the thresholding stage with a location constraint, which avoids adjusting regularization parameters or thresholding levels. This work is first compared with other conventional reconstruction methods using random one-dimention signals and then applied to dynamic contrast-enhanced breast magnetic resonance imaging to demonstrate the excellent reconstruction accuracy (less than 2% absolute difference) and low computation time (5-10 s using Matlab) with highly undersampled three-dimentional data (244 * 128 * 48; overall reduction factor = 10). PMID- 23042659 TI - A risk score based on Get With the Guidelines-Stroke program data works in patients with acute ischemic stroke in China. AB - BACKGROUND AND PURPOSE: There are few validated models for prediction of in hospital mortality after acute ischemic stroke. In 2010, Smith et al developed and internally validated models for predicting in-hospital mortality based on Get With the Guidelines-Stroke program data. We demonstrate the applicability of this Get With the Guidelines risk model in Chinese patients. METHODS: The prognostic model was used to predict survival in 7015 patients with acute ischemic stroke from China National Stroke Registry data set. Model discrimination was quantified by calculating C statistic. To clarify the role of National Institutes of Health Stroke Scale (NIHSS), we also calculated the C statistics for NIHSS alone and for the model without NIHSS. RESULTS: The C statistic was 0.867 (95% CI, 0.839-0.895) through the Get With the Guidelines risk model, suggesting good discrimination in the China National Stroke Registry. The model without NIHSS produced significantly lower C statistic (0.735; 95% CI, 0.701-0.770; P<0.001), indicating the important role of NIHSS in the prediction of survival. Furthermore, a model with NIHSS alone also provided significant discrimination (C statistic, 0.847; 95% CI, 0.816-0.879). A plot of observed versus predicted mortality showed excellent model calibration in the external validation sample from the China National Stroke Registry. CONCLUSIONS: The Get With the Guidelines risk model could correctly predict in-hospital mortality in Chinese patients with ischemic stroke. In addition, the NIHSS provides substantial incremental information on a patient's short-term mortality risk and is the strongest predictor of mortality. PMID- 23042660 TI - Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations. AB - BACKGROUND AND PURPOSE: The contribution of genetics to stroke risk, and whether this differs for different stroke subtypes, remainsuncertain. Genomewide complex trait analysis allows heritability to be assessed from genomewide association study (GWAS) data. Previous candidate gene studies have identified many associations with stoke but whether these are important requires replication in large independent data sets. GWAS data sets provide a powerful resource to perform replication studies. METHODS: We applied genomewide complex trait analysis to a GWAS data set of 3752 ischemic strokes and 5972 controls and determined heritability for all ischemic stroke and the most common subtypes: large-vessel disease, small-vessel disease, and cardioembolic stroke. By systematic review we identified previous candidate gene and GWAS associations with stroke and previous GWAS associations with related cardiovascular phenotypes (myocardial infarction, atrial fibrillation, and carotid intima-media thickness). Fifty associations were identified. RESULTS: For all ischemic stroke, heritability was 37.9%. Heritability varied markedly by stroke subtype being 40.3% for large-vessel disease and 32.6% for cardioembolic but lower for small vessel disease (16.1%). No previously reported candidate gene was significant after rigorous correction for multiple testing. In contrast, 3 loci from related cardiovascular GWAS studies were significant: PHACTR1 in large-vessel disease (P=2.63e(-6)), PITX2 in cardioembolic stroke (P=4.78e(-8)), and ZFHX3 in cardioembolic stroke (P=5.50e(-7)). CONCLUSIONS: There is substantial heritability for ischemic stroke, but this varies for different stroke subtypes. Previous candidate gene associations contribute little to this heritability, but GWAS studies in related cardiovascular phenotypes are identifying robust associations. The heritability data, and data from GWAS, suggest detecting additional associations will depend on careful stroke subtyping. PMID- 23042661 TI - Plasma CXCL12 levels as a predictor of future stroke. AB - BACKGROUND AND PURPOSE: The chemokine ligand CXCL12 is constitutively expressed in the bone marrow and other tissues including the brain endothelium and is responsible for regulating the trafficking of bone marrow progenitor cells. CXCL12 has been shown to play a significant role in animal models of ischemic stroke but its role in human stroke is unclear. The aim of this study was to test the hypothesis that elevated circulating baseline CXCL12 levels are associated with subsequent stroke. METHODS: We prospectively collected demographic and angiographic data from consecutive patients referred for elective coronary angiography. Before coronary angiography a peripheral blood sample was collected for subsequent measurement of CXCL12. One-year stroke risk was calculated using the Framingham Risk Profile. Clinical follow-up was performed at 6 months and 1 year. RESULTS: Of 206 subjects enrolled, 10 (4.9%) sustained an ischemic stroke over the 1 year follow-up. There were no significant differences in baseline clinical characteristics or angiographic findings. However, median CXCL12 levels were significantly higher in those who sustained an ischemic stroke compared with those who did not (10 856 pg/mL versus 2241 pg/mL, P=0.007). The time to stroke distribution between subjects with baseline CXCL12 levels>=10 421 pg/mL and those with baseline CXCL12 levels<10 421 pg/mL was significantly different (log rank P<0.001). The weighted Cox proportional hazard model demonstrated that baseline CXCL12 levels>=10 421 pg/mL were significantly associated with ischemic stroke at follow-up (hazard ratio, 15.29; 95% CI, 3.05-76.71). CONCLUSIONS: Plasma CXCL12 levels may represent a novel biomarker of future ischemic stroke. PMID- 23042662 TI - Application of feedback-controlled bolus plus infusion (FC-B/I) method for quantitative PET imaging of dopamine transporters with [(18)F]beta-CFT-FE in conscious monkey brain. AB - The competitive inhibition of dopamine transporters (DAT) with cocaine, a specific DAT inhibitor, was evaluated with a feedback-controlled bolus plus infusion (FC-B/I) method using animal positron emission tomography (PET) in the living brain of conscious monkey. 2beta-Carbomethoxy-3beta-(4-fluorophenyl)-8-(2 [(18)F]fluoroethyl) nortropane ([(18)F]beta-CFT-FE; Harada et al. [2004] Synapse 54:37-45) was used for this study because it provided specific, fast, and reversible kinetic properties to DAT in the striatum. In FC-B/I method, the real time image reconstruction was started just after intravenous bolus injection of [(18)F]beta-CFT-FE to generate a time-activity curve in the striatum, and the infusion rate was adjusted to achieve an equilibrium state of the striatal radioactivity concentrations by means of a feedback-control algorithm. The first equilibrium state in the brain was reached within 20 min after the infusion start. Intravenous administration of cocaine at the doses of 0.02, 0.1, and 0.5 mg/kg shifted the equilibrium radioactivity level to the second equilibrium state in a dose-dependent manner, while no significant alterations was observed in the cerebellum. The present results demonstrated that the combined use of FC-B/I method and PET probe with fast kinetics like [(18)F]beta-CFT-FE could be useful to assess the occupancy of drugs in the living brain with PET. PMID- 23042663 TI - Diurnal cortisol rhythms and child growth: exploring the life history consequences of HPA activation among the Tsimane'. AB - OBJECTIVE: Although psychosocial stress has also been implicated as a contributor to growth failure by imposing energetic constraints during development, the direct physiological pathways by which these life history trade-offs are imposed are not well understood. This study explores associations between diurnal cortisol rhythms and differential patterns of linear child growth among the Tsimane, a horticulturalist and foraging society in the Bolivian Amazon. METHODS: Waking and bedtime salivary cortisol samples (n = 243) were collected from 53 Tsimane' children ages 1.6-6 over 3 days as part of a larger study of developmental trajectories in hypothalamic-pituitary-adrenal axis dynamics. Anthropometric measurements and survey data were collected in conjunction with the Tsimane' Amazonian panel study (TAPS). RESULTS: Among children under the age of 6, diurnal rhythms in stunted versus nonstunted children vary dramatically: stunted children display elevated cortisol at both the AM (P = 0.03) and PM (P = 0.02) collection points. Multilevel regression analysis demonstrates an inverse relationship between cortisol and height-for-age z-score status (P = 0.00), which is mediated, in part, by infection (P = 0.00), and is strongest among male children (n.s.). Moreover, the poorest statural growth is exhibited among children with high cortisol living in more acculturated Tsimane' communities, a proxy for a more adverse developmental milieu. CONCLUSIONS: This study reports a small, but significant, life history cost of elevated diurnal cortisol rhythms on linear growth among Tsimane' children, and provides critical insight into the developmental origins of health differentials among an indigenous Amazonian population experiencing rapid lifestyle changes. PMID- 23042665 TI - Mechanical and suboptimal pharmacologic prophylaxis and delayed mobilization but not morbid obesity are associated with venous thromboembolism after total knee arthroplasty: a case-control study. AB - BACKGROUND: The FDA-approved dose of low-molecular-weight heparin (LMWH) may not provide adequate thromboprophylaxis in morbidly obese patients after total knee arthroplasty (TKA). Suboptimal dosing, delayed initiation, and overreliance on mechanical methods may also limit the effectiveness of thromboprophylaxis. OBJECTIVE: We explored the associations between the type of thromboprophylaxis, obesity, time of mobilization, and undergoing bilateral TKA on development of symptomatic venous thromboembolism (VTE) after TKA. DESIGN/SETTING/PATIENTS: This was a case-control study of patients undergoing TKA in 15 teaching hospitals between October 2008 and March 2010. Cases were screened using the Agency for Healthcare Research and Quality's Patient Safety Indicator 12 and had objectively documented acute VTE within 9 days of surgery; controls were randomly selected from the same hospital. Multivariable logistic regression was used to analyze risk factors for postoperative VTE, adjusted for age and gender. RESULTS: Among 130 cases with and 463 controls without acute VTE, body mass index (BMI) ranged from 17 to 61 (median = 34). Thromboprophylaxis was LMWH in 284 (48%), warfarin in 189 (32%), both in 55 (10%), and mechanical prophylaxis alone in 120 (20%). Overall, 77% ambulated on day 1 or 2 after surgery. Factors significantly associated with VTE were bilateral simultaneous TKA (odds ratio [OR] = 4.2; 95% confidence interval [CI]: 1.9-9.1), receipt of FDA-approved pharmacological prophylaxis (OR = 0.5; 95% CI: 0.3-0.8), and ambulation by postoperative day 2 (OR = 0.3; 95% CI: 0.1-0.9). Obesity was neither a significant confounder nor a modifier of these effects. CONCLUSIONS: Severe obesity was not a significant independent predictor for VTE and did not modify the beneficial effect of FDA approved pharmacological thromboprophylaxis. Bilateral TKA and failure to ambulate by the second day after surgery were significant risk factors. PMID- 23042666 TI - Preceding the procedure: medical devices and shared decision making. PMID- 23042668 TI - Lead optimization of thiazolo[5,4-c]piperidines: 3-cyclobutoxy linker as a key spacer for H(3)R inverse agonists. AB - The simpler, the better: H(3) histamine receptor (H(3)R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H(3)R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies. PMID- 23042669 TI - Distributed spirals: a new class of three-dimensional k-space trajectories. AB - This work presents a new class of three-dimensional spiral based-trajectories for sampling magnetic resonance data. The distributed spirals trajectory efficiently traverses a cylinder or sphere or intermediate shape in k-space. The trajectory is shown to be nearly as efficient as a conventional stack of spirals trajectory in terms of scan time and signal-to-noise ratio, while reducing coherent aliasing in all three spatial directions and reducing Gibbs ringing due to the nature of collecting data from a sphere in k-space. The trajectory uses a single two dimensional spiral waveform with the addition of a single orthogonal waveform which is scaled with each repetition, making it relatively easy to implement. Blurring from off-resonance only occurs in two dimensions due to the temporal nature of the sampling. PMID- 23042670 TI - Dyspnea assessment and pulmonary hypertension in patients with systemic sclerosis: utility of the University of California, San Diego, Shortness of Breath Questionnaire. AB - OBJECTIVE: The University of California in San Diego Shortness of Breath Questionnaire (UCSD SOBQ) has been used to assess dyspnea-related activity limitation in patients with airway and parenchymal lung disease. We sought to assess the construct validity and responsiveness of the UCSD SOBQ in systemic sclerosis (SSc; scleroderma) patients with incident pulmonary hypertension (PH) and those at high risk of developing PH. METHODS: We used data from 179 patients enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry with pre-PH (defined by criteria on pulmonary function tests and/or echocardiogram) or definite PH with mean pulmonary artery pressure >=25 mm Hg by right-sided heart catheterization within 6 months of enrollment. For this analysis, we included those subjects with complete data for self-reported measures at baseline and at 12 months. RESULTS: At baseline, the UCSD SOBQ had strong correlations in the expected direction with the disability index (DI) of the Health Assessment Questionnaire (HAQ) (r = 0.71, P < 0.0001), dyspnea assessment by visual analog scale (r = 0.71, P < 0.0001), and the Short Form 36 (SF-36) health survey physical component summary (PCS) score (r = -0.77, P < 0.0001), as well as a moderate correlation with the 6-minute walk test distance (r = -0.33, P < 0.0001), Borg dyspnea score (r = 0.47, P < 0.0001), and diffusing capacity of carbon monoxide (r = -0.33, P < 0.0001). Change in the UCSD SOBQ at 12 months correlated in the expected direction with change in the HAQ DI (r = 0.54, P < 0.0001) and change in the SF-36 PCS (r = -0.44, P < 0.0001). Multivariate analysis adjusting for age, sex, and race identified male sex as a significant predictor of death (odds ratio [OR] 7.00, 95% confidence interval [95% CI] 1.55-31.76), while the UCSD SOBQ showed a strong trend toward significance (OR 1.82, 95% CI 0.97-3.41). CONCLUSIONS: The UCSD SOBQ demonstrates good construct validity and responsiveness to change in SSc patients with pulmonary vascular disease. PMID- 23042671 TI - A highly sensitive immunoassay for interleukin-6 in dried blood spots. AB - OBJECTIVE: Interleukin-6 (IL-6) is a pro-inflammatory cytokine that is associated with the production of C-reactive protein, the acute phase response, and chronic low-grade inflammation. In this report, we describe and validate a highly sensitive enzyme-linked immunosorbent assay (ELISA) for quantifying IL-6 at low concentrations in samples of capillary whole blood collected from a simple finger stick and dried on filter paper (dried blood spots, DBS). METHODS: A commercially available ELISA for IL-6 was modified to develop a protocol for the quantification of IL-6 in DBS samples. Procedures for sample elution and incubation were optimized for precision, reliability, accuracy, and lower limit of detection using small volumes of DBS. A set of 46 matched serum/DBS samples were used to evaluate agreement between serum and DBS results. RESULTS: The protocol demonstrated acceptable levels of precision, reliability, accuracy, and agreement with serum-based results. The lower limit of detection was sufficiently low to measure levels of IL-6 associated with both chronic, low-grade inflammation, and acute increases in inflammatory activity. CONCLUSIONS: This protocol adds to the growing panel of analytes validated for quantification in DBS samples and should facilitate future research on the causes and consequences of inflammation in diverse non-clinical settings. PMID- 23042672 TI - Interaction effects between genes involved in the AKT signaling pathway and phytoestrogens in gastric carcinogenesis: a nested case-control study from the Korean Multi-Center Cancer Cohort. AB - SCOPE: To investigate whether genes involved in AKT/nuclear factor kappa B signaling and/or gene-environment interactions between the genes and phytoestrogens may be susceptible factors for gastric cancer. METHODS AND RESULTS: The representative single nucleotide polymorphisms (SNPs) identified during the primary analysis (screening a total of 622 SNPs within +/- 5 kbp of the 51 target gene locations) were further investigated in 317 matched case control sets. The summary odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer were calculated. Interaction effects between the SNPs and phytoestrogen biomarkers (genistein, daidzein, equol, and enterolactone) were computed. CDK1 rs4145643, FAS rs6586161, and FAS rs1468063 in the AKT signaling pathway presented significant genetic effects on gastric cancer (OR = 0.81 (95% CI: 0.66-0.99) for CDK1 rs4145643; OR = 1.27 (95% CI: 1.03-1.58) for FAS rs6586161; OR = 1.29 (95% CI: 1.03-1.56) for FAS rs1468063; Cochran Q statistics > 0.10). Risk alleles of FAS rs6586161, FAS rs1468063, MAP3K1 rs16886448, and MAP3K1 rs252902 showed significant interaction effects with enterolactone (p(interaction) < 0.05). CONCLUSION: CDK1 and FAS genes involved in AKT signaling and influenced by anti-carcinogenic property of phytoestrogens can play a role as susceptible genetic factors in gastric carcinogenesis. FAS and MAP3K1 genes significantly interact with enterolactone, thereby modifying the individual's risk for gastric cancer. PMID- 23042673 TI - Copper-catalyzed silacarboxylation of internal alkynes by employing carbon dioxide and silylboranes. PMID- 23042674 TI - LNCipedia: a database for annotated human lncRNA transcript sequences and structures. AB - Here, we present LNCipedia (http://www.lncipedia.org), a novel database for human long non-coding RNA (lncRNA) transcripts and genes. LncRNAs constitute a large and diverse class of non-coding RNA genes. Although several lncRNAs have been functionally annotated, the majority remains to be characterized. Different high throughput methods to identify new lncRNAs (including RNA sequencing and annotation of chromatin-state maps) have been applied in various studies resulting in multiple unrelated lncRNA data sets. LNCipedia offers 21 488 annotated human lncRNA transcripts obtained from different sources. In addition to basic transcript information and gene structure, several statistics are determined for each entry in the database, such as secondary structure information, protein coding potential and microRNA binding sites. Our analyses suggest that, much like microRNAs, many lncRNAs have a significant secondary structure, in-line with their presumed association with proteins or protein complexes. Available literature on specific lncRNAs is linked, and users or authors can submit articles through a web interface. Protein coding potential is assessed by two different prediction algorithms: Coding Potential Calculator and HMMER. In addition, a novel strategy has been integrated for detecting potentially coding lncRNAs by automatically re-analysing the large body of publicly available mass spectrometry data in the PRIDE database. LNCipedia is publicly available and allows users to query and download lncRNA sequences and structures based on different search criteria. The database may serve as a resource to initiate small- and large-scale lncRNA studies. As an example, the LNCipedia content was used to develop a custom microarray for expression profiling of all available lncRNAs. PMID- 23042675 TI - Pol beta associated complex and base excision repair factors in mouse fibroblasts. AB - During mammalian base excision repair (BER) of lesion-containing DNA, it is proposed that toxic strand-break intermediates generated throughout the pathway are sequestered and passed from one step to the next until repair is complete. This stepwise process is termed substrate channeling. A working model evaluated here is that a complex of BER factors may facilitate the BER process. FLAG-tagged DNA polymerase (pol) beta was expressed in mouse fibroblasts carrying a deletion in the endogenous pol beta gene, and the cell extract was subjected to an 'affinity-capture' procedure using anti-FLAG antibody. The pol beta affinity capture fraction (ACF) was found to contain several BER factors including polymerase-1, X-ray cross-complementing factor1-DNA ligase III and enzymes involved in processing 3'-blocked ends of BER intermediates, e.g. polynucleotide kinase and tyrosyl-DNA phosphodiesterase 1. In contrast, DNA glycosylases, apurinic/aprymidinic endonuclease 1 and flap endonuclease 1 and several other factors involved in BER were not present. Some of the BER factors in the pol beta ACF were in a multi-protein complex as observed by sucrose gradient centrifugation. The pol beta ACF was capable of substrate channeling for steps in vitro BER and was proficient in in vitro repair of substrates mimicking a 3' blocked topoisomerase I covalent intermediate or an oxidative stress-induced 3' blocked intermediate. PMID- 23042676 TI - HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor. AB - The binding of integrase (IN) to lens epithelium-derived growth factor (LEDGF)/p75 in large part determines the efficiency and specificity of HIV-1 integration. However, a significant residual preference for integration into active genes persists in Psip1 (the gene that encodes for LEDGF/p75) knockout (KO) cells. One other cellular protein, HRP2, harbors both the PWWP and IN binding domains that are important for LEDGF/p75 co-factor function. To assess the role of HRP2 in HIV-1 integration, cells generated from Hdgfrp2 (the gene that encodes for HRP2) and Psip1/Hdgfrp2 KO mice were infected alongside matched control cells. HRP2 depleted cells supported normal infection, while disruption of Hdgfrp2 in Psip1 KO cells yielded additional defects in the efficiency and specificity of integration. These deficits were largely restored by ectopic expression of either LEDGF/p75 or HRP2. The double-KO cells nevertheless supported residual integration into genes, indicating that IN and/or other host factors contribute to integration specificity in the absence of LEDGF/p75 and HRP2. Psip1 KO significantly increased the potency of an allosteric inhibitor that binds the LEDGF/p75 binding site on IN, a result that was not significantly altered by Hdgfrp2 disruption. These findings help to rule out the host factor-IN interactions as the primary antiviral targets of LEDGF/p75-binding site IN inhibitors. PMID- 23042677 TI - The extent of sequence complementarity correlates with the potency of cellular miRNA-mediated restriction of HIV-1. AB - MicroRNAs (miRNAs) are 22-nt non-coding RNAs involved in the regulation of cellular gene expression and potential cellular defense against viral infection. Using in silico analyses, we predicted target sites for 22 human miRNAs in the HIV genome. Transfection experiments using synthetic miRNAs showed that five of these miRNAs capably decreased HIV replication. Using one of these five miRNAs, human miR-326 as an example, we demonstrated that the degree of complementarity between the predicted viral sequence and cellular miR-326 correlates, in a Dicer dependent manner, with the potency of miRNA-mediated restriction of viral replication. Antagomirs to miR-326 that knocked down this cell endogenous miRNA increased HIV-1 replication in cells, suggesting that miR-326 is physiologically functional in moderating HIV-1 replication in human cells. PMID- 23042678 TI - A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase- extensive moonlighting in mitochondrial tRNA biogenesis. AB - Transfer RNAs (tRNAs) reach their mature functional form through several steps of processing and modification. Some nucleotide modifications affect the proper folding of tRNAs, and they are crucial in case of the non-canonically structured animal mitochondrial tRNAs, as exemplified by the apparently ubiquitous methylation of purines at position 9. Here, we show that a subcomplex of human mitochondrial RNase P, the endonuclease removing tRNA 5' extensions, is the methyltransferase responsible for m(1)G9 and m(1)A9 formation. The ability of the mitochondrial tRNA:m(1)R9 methyltransferase to modify both purines is uncommon among nucleic acid modification enzymes. In contrast to all the related methyltransferases, the human mitochondrial enzyme, moreover, requires a short chain dehydrogenase as a partner protein. Human mitochondrial RNase P, thus, constitutes a multifunctional complex, whose subunits moonlight in cascade: a fatty and amino acid degradation enzyme in tRNA methylation and the methyltransferase, in turn, in tRNA 5' end processing. PMID- 23042679 TI - A minimal i-motif stabilized by minor groove G:T:G:T tetrads. AB - The repetitive DNA sequences found at telomeres and centromeres play a crucial role in the structure and function of eukaryotic chromosomes. This role may be related to the tendency observed in many repetitive DNAs to adopt non-canonical structures. Although there is an increasing recognition of the importance of DNA quadruplexes in chromosome biology, the co-existence of different quadruplex forming elements in the same DNA structure is still a matter of debate. Here we report the structural study of the oligonucleotide d(TCGTTTCGT) and its cyclic analog d. Both sequences form dimeric quadruplex structures consisting of a minimal i-motif capped, at both ends, by a slipped minor groove aligned G:T:G:T tetrad. These mini i-motifs, which do not exhibit the characteristic CD spectra of other i-motif structures, can be observed at neutral pH, although they are more stable under acidic conditions. This finding is particularly relevant since these oligonucleotide sequences do not contain contiguous cytosines. Importantly, these structures resemble the loop moiety adopted by an 11-nucleotide fragment of the conserved centromeric protein B (CENP B) box motif, which is the binding site for the CENP-B. PMID- 23042680 TI - Phosphorylation of PNKP by ATM prevents its proteasomal degradation and enhances resistance to oxidative stress. AB - We examined the mechanism regulating the cellular levels of PNKP, the major kinase/phosphatase involved in the repair of oxidative DNA damage, and find that it is controlled by ATM phosphorylation and ubiquitylation-dependent proteasomal degradation. We discovered that ATM-dependent phosphorylation of PNKP at serines 114 and 126 in response to oxidative DNA damage inhibits ubiquitylation-dependent proteasomal degradation of PNKP, and consequently increases PNKP stability that is required for DNA repair. We have also purified a novel Cul4A-DDB1 ubiquitin ligase complex responsible for PNKP ubiquitylation and identify serine-threonine kinase receptor associated protein (STRAP) as the adaptor protein that provides specificity of the complex to PNKP. Strap(-/-) mouse embryonic fibroblasts subsequently contain elevated cellular levels of PNKP, and show elevated resistance to oxidative DNA damage. These data demonstrate an important role for ATM and the Cul4A-DDB1-STRAP ubiquitin ligase in the regulation of the cellular levels of PNKP, and consequently in the repair of oxidative DNA damage. PMID- 23042681 TI - Sequence-specific cleavage of the RNA strand in DNA-RNA hybrids by the fusion of ribonuclease H with a zinc finger. AB - Ribonucleases (RNases) are valuable tools applied in the analysis of RNA sequence, structure and function. Their substrate specificity is limited to recognition of single bases or distinct secondary structures in the substrate. Currently, there are no RNases available for purely sequence-dependent fragmentation of RNA. Here, we report the development of a new enzyme that cleaves the RNA strand in DNA-RNA hybrids 5 nt from a nonanucleotide recognition sequence. The enzyme was constructed by fusing two functionally independent domains, a RNase HI, that hydrolyzes RNA in DNA-RNA hybrids in processive and sequence-independent manner, and a zinc finger that recognizes a sequence in DNA RNA hybrids. The optimization of the fusion enzyme's specificity was guided by a structural model of the protein-substrate complex and involved a number of steps, including site-directed mutagenesis of the RNase moiety and optimization of the interdomain linker length. Methods for engineering zinc finger domains with new sequence specificities are readily available, making it feasible to acquire a library of RNases that recognize and cleave a variety of sequences, much like the commercially available assortment of restriction enzymes. Potentially, zinc finger-RNase HI fusions may, in addition to in vitro applications, be used in vivo for targeted RNA degradation. PMID- 23042682 TI - Hundreds of conserved non-coding genomic regions are independently lost in mammals. AB - Conserved non-protein-coding DNA elements (CNEs) often encode cis-regulatory elements and are rarely lost during evolution. However, CNE losses that do occur can be associated with phenotypic changes, exemplified by pelvic spine loss in sticklebacks. Using a computational strategy to detect complete loss of CNEs in mammalian genomes while strictly controlling for artifacts, we find >600 CNEs that are independently lost in at least two mammalian lineages, including a spinal cord enhancer near GDF11. We observed several genomic regions where multiple independent CNE loss events happened; the most extreme is the DIAPH2 locus. We show that CNE losses often involve deletions and that CNE loss frequencies are non-uniform. Similar to less pleiotropic enhancers, we find that independently lost CNEs are shorter, slightly less constrained and evolutionarily younger than CNEs without detected losses. This suggests that independently lost CNEs are less pleiotropic and that pleiotropic constraints contribute to non uniform CNE loss frequencies. We also detected 35 CNEs that are independently lost in the human lineage and in other mammals. Our study uncovers an interesting aspect of the evolution of functional DNA in mammalian genomes. Experiments are necessary to test if these independently lost CNEs are associated with parallel phenotype changes in mammals. PMID- 23042683 TI - Engineering the DNA cytosine-5 methyltransferase reaction for sequence-specific labeling of DNA. AB - DNA methyltransferases catalyse the transfer of a methyl group from the ubiquitous cofactor S-adenosyl-L-methionine (AdoMet) onto specific target sites on DNA and play important roles in organisms from bacteria to humans. AdoMet analogs with extended propargylic side chains have been chemically produced for methyltransferase-directed transfer of activated groups (mTAG) onto DNA, although the efficiency of reactions with synthetic analogs remained low. We performed steric engineering of the cofactor pocket in a model DNA cytosine-5 methyltransferase (C5-MTase), M.HhaI, by systematic replacement of three non essential positions, located in two conserved sequence motifs and in a variable region, with smaller residues. We found that double and triple replacements lead to a substantial improvement of the transalkylation activity, which manifests itself in a mild increase of cofactor binding affinity and a larger increase of the rate of alkyl transfer. These effects are accompanied with reduction of both the stability of the product DNA-M.HhaI-AdoHcy complex and the rate of methylation, permitting competitive mTAG labeling in the presence of AdoMet. Analogous replacements of two conserved residues in M.HpaII and M2.Eco31I also resulted in improved transalkylation activity attesting a general applicability of the homology-guided engineering to the C5-MTase family and expanding the repertoire of sequence-specific tools for covalent in vitro and ex vivo labeling of DNA. PMID- 23042685 TI - A chemodosimetric probe based on a conjugated oxidized bis-indolyl system for selective naked-eye sensing of cyanide ions in water. AB - A new bis-indolyl-based colorimetric probe has been synthesized. This allows a Michael-type adduct formation for the detection of cyanide ions. The probe shows a remarkable color change from red to colorless upon addition of the cyanide ions in pure water. The cyanide ion reacts with the probe and removes the conjugation of the bis-indolyl moiety of the probe with that of the 4-substituted aromatic ring. This renders the probe colorless. The mechanism of the reaction of the probe with the cyanide ion was established by using (1)H and (13)C NMR spectroscopy, mass spectrometry, and kinetic studies. PMID- 23042686 TI - 3D isotropic high-resolution diffusion-weighted MRI of the whole brain with a motion-corrected steady-state free precession sequence. AB - The main obstacle to high-resolution (<1.5 mm isotropic) 3D diffusion-weighted MRI is the differential motion-induced phase error from shot-to-shot. In this work, the phase error is addressed with a hybrid 3D navigator approach that corrects motion-induced phase in two ways. In the first, rigid-body motion is corrected for every shot. In the second, repeatable nonrigid-body pulsation is corrected for each portion of the cardiac cycle. These phase error corrections were implemented with a 3D diffusion-weighted steady- state free precession pulse sequence and were shown to mitigate signal dropouts caused by shot-to-shot phase inconsistencies compared to a standard gridding reconstruction in healthy volunteers. The proposed approach resulted in diffusion contrast more similar to the contrast observed in the reference echo-planer imaging scans than reconstruction of the same data without correction. Fractional anisotropy and Color fractional anisotropy maps generated with phase-corrected data were also shown to be more similar to echo-planer imaging reference scans than those generated without phase correction. PMID- 23042687 TI - Treatment of complex regional pain syndrome in adults: a systematic review of randomized controlled trials published from June 2000 to February 2012. AB - Complex regional pain syndrome (CRPS) is a disabling pain condition with sensory, motor and autonomic manifestations. Uncertainty remains about how CRPS can be effectively managed. We conducted a systematic review of randomized controlled trials (RCTs) for treatment and prophylactic interventions for CRPS published during the period 2000-2012, building on previous work by another group reviewing the period 1966-2000. Bibliographic database searches identified 173 papers which were filtered by three reviewers. This process generated 29 trials suitable for further analysis, each of which was reviewed and scored by two independent reviewers for methodological quality using a 15-item checklist. A number of novel and potentially effective treatments were investigated. Analysing the results from both review periods in combination, there was a steep rise in the number of published RCTs per review decade. There is evidence for the efficacy of 10 treatments (3* strong--bisphosphonates, repetitive transcranial magnetic stimulation and graded motor imagery, 1* moderate and 6* limited evidence), and against the efficacy of 15 treatments (1* strong, 1* moderate and *13 limited). The heterogeneity of trialled interventions and the pilot nature of many trials militate against drawing clear conclusions about the clinical usefulness of most interventions. This and the observed phenomenon of excellent responses in CRPS subgroups would support the case for a network- and multi-centre approach in the conduct of future clinical trials. Most published trials in CRPS are small with a short follow-up period, although several novel interventions investigated from 2000 to 2012 appear promising. PMID- 23042688 TI - The recommendations for glucosamine do not tell the whole story: comment on the article by Hochberg et al. PMID- 23042689 TI - Social relations and resident health in assisted living: an application of the convoy model. AB - PURPOSE: This article, based on analysis of data from a mixed methods study, builds on a growing body of assisted living (AL) research focusing on the link between residents' social relationships and health. A key aim of this analysis, which uses the social convoy model as a conceptual and methodological framework, was to examine the relative importance of coresident relationships and other network ties to residents' subjective well-being. DESIGN AND METHODS: We analyzed data from structured face-to-face interviews and social network mapping conducted with 192 AL residents in 9 AL facilities in Georgia. RESULTS: Having a higher proportion of family ties in one's network was the single most important predictor of well-being, whereas possessing some ties to coresidents and nonfamily members outside AL also had a positive effect. Findings showed that relationships among coresidents generally were important although not emotionally close. Having more close ties was associated with lower well-being, suggesting that not all close ties are beneficial. The majority (84%) of residents' closet ties were with family members. IMPLICATIONS: Findings illuminate the crucial role families play in residents' overall health and well-being and demonstrate the importance of helping residents develop and maintain a range of network ties, including "weak" ties with coresidents and nonfamily outside AL. PMID- 23042690 TI - Integration of fall prevention into state policy in Connecticut. AB - PURPOSE OF STUDY: To describe the ongoing efforts of the Connecticut Collaboration for Fall Prevention (CCFP) to move evidence regarding fall prevention into clinical practice and state policy. METHODS: A university-based team developed methods of networking with existing statewide organizations to influence clinical practice and state policy. RESULTS: We describe steps taken that led to funding and legislation of fall prevention efforts in the state of Connecticut. We summarize CCFP's direct outreach by tabulating the educational sessions delivered and the numbers and types of clinical care providers that were trained. Community organizations that had sustained clinical practices incorporating evidence-based fall prevention were subsequently funded through mini-grants to develop innovative interventional activities. These mini-grants targeted specific subpopulations of older persons at high risk for falls. IMPLICATIONS: Building collaborative relationships with existing stakeholders and care providers throughout the state, CCFP continues to facilitate the integration of evidence-based fall prevention into clinical practice and state-funded policy using strategies that may be useful to others. PMID- 23042691 TI - The high cost of the international aging prisoner crisis: well-being as the common denominator for action. AB - The aging prisoner crisis continues to gain international attention as the high human, social, and economic costs of warehousing older adults with complex physical, mental health, and social care needs in prison continues to rise. According to the United Nations, older adults and the serious and terminally ill are considered special needs populations subject to special international health and social practice and policy considerations. We argue that older adults in prison have unique individual and social developmental needs that result from life course exposure to cumulative risk factors compounded by prison conditions that accelerate their aging. We position these factors in a social context model of human development and well-being and present a review of international human rights guidelines that pertain to promoting health and well-being to those aging in custody. The study concludes with promising practices and recommendations of their potential to reduce the high direct and indirect economic costs associated with mass confinement of older adults, many of whom need specialized long-term care that global correctional systems are inadequately equipped to provide. PMID- 23042692 TI - Decorating PtCo bimetallic alloy nanoparticles on graphene as sensors for glucose detection by catalyzing luminol chemiluminescence. AB - A new type of PtCo(x) @graphene nanocomposite is prepared by a simple chemical solution method, which can dramatically enhance the chemiluminescence (CL) intensity of luminol-H(2)O(2) system, making it possible for the detection of glucose through measuring the H(2)O(2) produced from its catalytic oxidation. PMID- 23042693 TI - Inclusion compound based approach to forming arrays of artificial dipolar molecular rotors: a search for optimal rotor structures. AB - Hexagonal tris(o-phenylenedioxy)cyclotriphosphazene (TPP) is used as ahost for organizing dipolar molecular rotor guests into regular trigonal arrays. Inclusion of molecular rotors with transversely dipolar rotators into TPP channels is followed by solid-state nuclear magnetic resonance, diifferential scanning calorimetry, X-ray diffraction, and dielectric spectroscopy. The more polar of the two rotors does not form an inclusion. The second rotor forms two different inclusions differing in crystallite size and the rotational barriers. PMID- 23042694 TI - A bioorthogonal chemoenzymatic strategy for defined protein dendrimer assembly. PMID- 23042695 TI - A green copper-based metallo-supramolecular polymer: synthesis, structure, and electrochromic properties. PMID- 23042696 TI - Minimum maximum temperature gradient coil design. AB - Ohmic heating is a serious problem in gradient coil operation. A method is presented for redesigning cylindrical gradient coils to operate at minimum peak temperature, while maintaining field homogeneity and coil performance. To generate these minimaxT coil windings, an existing analytic method for simulating the spatial temperature distribution of single layer gradient coils is combined with a minimax optimization routine based on sequential quadratic programming. Simulations are provided for symmetric and asymmetric gradient coils that show considerable improvements in reducing maximum temperature over existing methods. The winding patterns of the minimaxT coils were found to be heavily dependent on the assumed thermal material properties and generally display an interesting "fish-eye" spreading of windings in the dense regions of the coil. Small prototype coils were constructed and tested for experimental validation and these demonstrate that with a reasonable estimate of material properties, thermal performance can be improved considerably with negligible change to the field error or standard figures of merit. PMID- 23042697 TI - Patterns of musculoskeletal pain in the population: a latent class analysis using a nationally representative interviewer-based survey of 4817 Danes. AB - BACKGROUND: Pain from the musculoskeletal system often occurs in more than one site. This appears to affect prognosis negatively. Knowledge about specific pain patterns is lacking. OBJECTIVES: To define specific patterns of musculoskeletal co-complaints occurring alongside a primary musculoskeletal complaint. METHODS: Using data from an interview-based health survey of a nationally representative sample of the adult Danish population in 1991 (n = 4817), we describe the co occurrence of musculoskeletal complaints. Using latent class analysis, we identify clusters of musculoskeletal complaints. RESULTS: Forty percent reported a complaint during a 2-week period; the most common being the low back, neck, shoulder, and knee, and 40% reported more than one complaint. Two latent classes were found for each of the nine primary pain sites except for the low back where three were found. For all primary pain areas, the largest class had site-specific pain only, whereas the smallest class had diffuse pain covering large parts of the body. For participants with a primary musculoskeletal complaint in the spine, the highest probabilities for co-complaints were at other sites in the spine. For primary complaints in the extremities, co-complaints occurred most commonly at adjacent areas. One noticeable exception was a primary complaint of knee pain where co-complaints were found in more remote areas as the neck and low back. CONCLUSIONS: Unique clusters of musculoskeletal co-complaints can be determined based on primary pain site. These patterns are different for persons with a primary complaint in the spine compared with persons with a primary complaint in the extremities. PMID- 23042698 TI - Leflunomide in psoriatic arthritis: results from a large European prospective observational study. AB - OBJECTIVE: To determine the "real-world" clinical effectiveness and safety of leflunomide in patients with psoriatic arthritis (PsA). METHODS: This prospective, multinational 24-week observational study involved adult patients with active PsA who initiated treatment with leflunomide. Patients were evaluated at baseline, 12 weeks, and 24 weeks. The primary outcome was response as assessed by the Psoriatic Arthritis Response Criteria (PsARC) in patients with pre- and posttreatment data. A modified PsARC response analysis included patients with joint counts, but no severity scores. Other effectiveness evaluations included global assessments, fatigue, pain, skin disease, dactylitis, and nail lesions. All patients were evaluated for safety. RESULTS: A total of 514 patients were enrolled in this study (mean age 50.7 years, mean disease duration 6.1 years). In the primary effectiveness analysis, 380 (86.4%) of 440 patients (95% confidence interval 82.8%-89.4%) achieved a PsARC response at 24 weeks. Significant improvements were observed in tender and swollen joint scores and counts, patient and physician global assessments, fatigue, pain, skin disease, dactylitis, and nail lesions. The discontinuation rate was 12.3%. Ninety-eight adverse drug reactions occurred in 62 (12.1%) patients; 3 drug reactions were serious (2 increased liver enzymes, 1 hypertensive crisis). CONCLUSION: Leflunomide is an effective and well-tolerated option for PsA in daily clinical practice, with beneficial effects on peripheral arthritis and on other PsA manifestations, including pain, fatigue, dactylitis, and skin disease. PMID- 23042699 TI - Circular dichroism from chiral nanomaterial fabricated by on-edge lithography. AB - A novel-shaped plasmonic chiral nanomaterial exhibiting circular dichroism in the near-infrared spectral range is presented. Applying on-edge lithography, a large area with these nanostructures is efficiently covered. This fabrication method offers tunability of the operation bandwidth by tailoring the chiral shape. PMID- 23042700 TI - Peptide-surface adsorption free energy comparing solution conditions ranging from low to medium salt concentrations. AB - Multi-technique methods involving surface plasmon resonance spectroscopy and atomic force microscopy provide experimental data for the characterization of peptide adsorption on self-assembled monolayers. A comparative study is carried out in phosphate-buffered saline (PBS) and potassium phosphate-buffered (PPB) water to determine the influence of the salt concentration on the adsorption behavior (see figure; DeltaG(0)(ads) : free energy of peptide adsorption, F(des) : force required for peptide desorption). PMID- 23042701 TI - Amorphous silica nanoparticles promote monocyte adhesion to human endothelial cells: size-dependent effect. AB - There is evidence that nanoparticles can induce endothelial dysfunction. Here, the effect of monodisperse amorphous silica nanoparticles (SiO(2)-NPs) of different diameters on endothelial cells function is examined. Human endothelial cell line (EA.hy926) or primary human pulmonary artery endothelial cells (hPAEC) are seeded in inserts introduced or not above triple cell co-cultures (pneumocytes, macrophages, and mast cells). Endothelial cells are incubated with SiO(2)-NPs at non-cytotoxic concentrations for 12 h. A significant increase (up to 2-fold) in human monocytes adhesion to endothelial cells is observed for 18 and 54 nm particles. Exposure to SiO(2)-NPs induces protein expression of adhesion molecules (ICAM-1 and VCAM-1) as well as significant up-regulation in mRNA expression of ICAM-1 in both endothelial cell types. Experiments performed with fluorescent-labelled monodisperse amorphous SiO(2)-NPs of similar size evidence nanoparticle uptake into the cytoplasm of endothelial cells. It is concluded that exposure of human endothelial cells to amorphous silica nanoparticles enhances their adhesive properties. This process is modified by the size of the nanoparticle and the presence of other co-cultured cells. PMID- 23042702 TI - Enantioselective addition of dialkylzincs to aldehydes catalyzed by (-)-MITH. AB - An effective catalytic system that imparts high enantioselectivity has been disclosed for the synthesis of optically active alcohols, which may undergo further chemical transformations. The enantioselective alkylation of aldehydes with dialkylzincs to afford the corresponding optically active alcohols with excellent enantioselectvities has been achieved in the presence of 0.1-0.5 mol % of the camphor-derived chiral ligand (-)-2-exo-morpholinoisobornane-10-thiol (MITH) (1) at room temperature or at 0 degrees C. PMID- 23042703 TI - Nociceptive responses to thermal and mechanical stimulations in awake pigs. AB - BACKGROUND: Porcine skin exhibits a high degree of homology to human skin, and the pig has recently been used as a cutaneous pain model. However, before the full potential of this novel in vivo cutaneous pain model can be achieved, several methodological aspects related to the management of awake animal studies in a large species require further examination. This manuscript describes the initial development of a porcine model of cutaneous nociception and focuses on interactions between the sensory modality, body size and the anatomical location of the stimulation site. METHODS: Pigs of different body sizes (30 and 60 kg) were exposed to thermal (CO2 laser) and mechanical (pressure application measurement device) stimulations to the flank and the hind legs in a balanced order. The median response latency and the type of behavioural response were recorded. RESULTS: Small pigs exhibited significantly lower pain thresholds (shorter latency to response) than large pigs to thermal and mechanical stimulations. Stimulations at the two anatomical locations elicited very distinct sets of behavioural responses, with different levels of sensitivity between the flank and the hind legs. Furthermore, small animals exhibited lower levels of individual variability between single stimulations. CONCLUSIONS: Our data indicate that this experimental approach may be valuable for use in studies that focus on porcine cutaneous nociception. PMID- 23042704 TI - Clinical control of asthma associates with measures of airway inflammation. AB - BACKGROUND: Control of asthma is the goal of asthma management worldwide. The Global Initiative for Asthma defined control by a composite measure of clinical findings and future risk but without using markers of airway inflammation, the hallmark of asthma. We investigated whether clinical asthma control reflects eosinophilic inflammation in a broad population. METHODS: Control of asthma was assessed over a period of 4 weeks in 111 patients with asthma: 22 totally controlled, 47 well controlled and 42 uncontrolled. Lung function, quality of life, airway hyperresponsiveness to AMP, sputum and blood eosinophils, exhaled nitric oxide (NO) and bronchial biopsies were obtained. RESULTS: The 69 subjects with controlled asthma (totally and well controlled combined) had lower median blood eosinophil numbers, slope of AMP hyperresponsiveness, and alveolar NO levels than the 42 subjects with uncontrolled asthma: 0.18 (range 0.01-0.54) versus 0.22 (0.06-1.16) * 10(9)/litre (p<0.05), 3.8 (-0.4-17 750) versus 39.7 (0.4-28 000) mg/ml (p<0.05) and 5.3 (1.5-14.9) versus 6.7 (2.6-51.7) ppb (p<0.05) respectively. Biopsies from subjects with controlled asthma contained fewer eosinophilic granules and more intact epithelium than uncontrolled subjects: 113 (6-1787) versus 219 (19-5313) (p<0.05) and 11.8% (0-65.3) versus 5.6% (0-47.6) (p<0.05) respectively. Controlled asthmatics had better Asthma Quality of Life Questionnaire scores than uncontrolled patients: 6.7 (5.0-7.0) versus 5.9 (3.7 7.0) (p<0.001). CONCLUSIONS: The level of asthma control, based on a composite measure of clinical findings, is associated with inflammatory markers, particularly eosinophilic inflammation, with little difference between totally controlled and well controlled asthma. PMID- 23042705 TI - Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. AB - BACKGROUND: The active-treatment comparative safety information for all inhaled medications in patients with chronic obstructive pulmonary disease (COPD) is limited. We aimed to compare the risk of overall and cardiovascular death for inhaled medications in patients with COPD. METHODS: Through systematic database searching, we identified randomised controlled trials of tiotropium Soft Mist Inhaler, tiotropium HandiHaler, long-acting beta2 agonists (LABAs), inhaled corticosteroids (ICS), and LABA-ICS combination with at least a 6-month treatment duration. Direct comparison and mixed treatment comparison (MTC) meta-analyses were conducted to estimate the pooled ORs of death for each comparison. RESULTS: 42 trials with 52 516 subjects were included. The MTC meta-analysis with the fixed effect model indicated tiotropium Soft Mist Inhaler was associated with an universally increased risk of overall death compared with placebo (OR 1.51; 95% CI 1.06 to 2.19), tiotropium HandiHaler (OR 1.65; 95% CI 1.13 to 2.43), LABA (OR 1.63; 95% CI 1.10 to 2.44) and LABA-ICS (OR 1.90; 95% CI 1.28 to 2.86). The risk was more evident for cardiovascular death, in patients with severe COPD, and at a higher daily dose. LABA-ICS was associated with the lowest risk of death among all treatments. No excess risk was noted for tiotropium HandiHaler or LABA. The results were similar for MTC and direct comparison meta-analyses, with less precision in the random effects model. CONCLUSION: Our study provided a comparative safety spectrum for each category of inhaled medications. Tiotropium Soft Mist Inhaler had a higher risk of mortality and should be used with caution. PMID- 23042706 TI - Fever and pancytopenia in a patient with Crohn's disease. PMID- 23042707 TI - Single shot trajectory design for region-specific imaging using linear and nonlinear magnetic encoding fields. AB - It has recently been demonstrated that nonlinear encoding fields result in a spatially varying resolution. This work develops an automated procedure to design single-shot trajectories that create a local resolution improvement in a region of interest. The technique is based on the design of optimized local k-space trajectories and can be applied to arbitrary hardware configurations that employ any number of linear and nonlinear encoding fields. The trajectories designed in this work are tested with the currently available hardware setup consisting of three standard linear gradients and two quadrupolar encoding fields generated from a custom-built gradient insert. A field camera is used to measure the actual encoding trajectories up to third-order terms, enabling accurate reconstructions of these demanding single-shot trajectories, although the eddy current and concomitant field terms of the gradient insert have not been completely characterized. The local resolution improvement is demonstrated in phantom and in vivo experiments. PMID- 23042708 TI - Peritoneal transport: getting more complicated. PMID- 23042709 TI - One hundred consecutive kidney transplantations with simultaneous ipsilateral nephrectomy in patients with autosomal dominant polycystic kidney disease. AB - PURPOSE: Surgical management of autosomal dominant polycystic kidney disease (ADPKD) in patients awaiting renal transplantation is a challenging task. METHODS: From 1998 to 2009, a total of 100 consecutive renal transplantations with simultaneous unilateral nephrectomy were performed in 59 men and 41 women with ADPKD and end-stage renal failure. About 38% received kidney allografts from living donors. The ipsilateral polycystic kidney was removed at the time of renal transplantation. Immunosuppressive therapy was not modified. Cold ischaemia time was 155 (38-204 min) versus 910 min (95-2760 min) for living versus deceased donor transplantation. Mean weight of removed kidneys was 2002 g (414-8850 g). Mean follow-up was 3.0 years (0.8-10.0 years). RESULTS: Overall patient and graft survival were 97 and 96% at 1 year and 93 and 80% at 5 years, respectively. Serum creatinine at current follow-up was 1.49 (0.8-2.8) mg/dL. Surgical complications, which might be associated with simultaneous nephrectomy requiring re-operation, occurred in 12% (lymphocele 4%, hernia 4%, post-operative haematoma or bleeding 4%). None of the patients died peri-operatively. CONCLUSION: Renal transplantation with simultaneous unilateral nephrectomy in ADPKD is a reasonable procedure for patients suffering from massively enlarged native kidneys. PMID- 23042710 TI - Resolution limit in plasmonic lithography for practical applications beyond 2x-nm half pitch. AB - A theoretical model is introduced to evaluate the ultimate resolution of plasmonic lithography using a ridge aperture. The calculated and experimental results of the line array pattern depth are compared for various half pitches. The theoretical analysis predicts that the resolution of plasmonic lithography strongly depends on the ridge gap, achieving values under 1x nm with a ridge gap smaller than 10 nm. A micrometer-scale circular contact probe is fabricated for high speed patterning with high positioning accuracy, which can be extended to a high-density probe array. Using the circular contact probe, high-density line array patterns are recorded with a half pitch up to 22 nm and good agreement is obtained between the theoretical model and experiment. To record the high density line array patterns, the line edge roughness (LER) is reduced to ~17 nm from 29 nm using a well-controlled developing process with a smaller molecular weight KOH based developer at a temperature below 10 degrees C. PMID- 23042711 TI - (110)-oriented ZIF-8 thin films on ITO with controllable thickness. AB - (110)-oriented zeolitic imidazolate framework (ZIF)-8 thin films with controllable thickness are successfully deposited on indium tin oxide (ITO) electrodes at room temperature. The method applied uses 3 aminopropyltriethoxysilane (APTES) in the form of self-assembled monolayers (SAMs), followed by a subsequent adoption of the layer-by-layer (LBL) method. The crystallographic preferential orientation (CPO) index shows that the ZIF-8 thin films are (110)-oriented. A possible mechanism for the growth of the (110) oriented ZIF-8 thin films on 3-aminopropyltriethoxysilane modified ITO is proposed. The observed cross-sectional scanning electron microscopy (SEM) images and photoluminescent (PL) spectra of the ZIF-8 thin films indicate that the thickness of the ZIF-8 layers is proportional to the number of growth cycles. The extension of such a SAM method for the fabrication of ZIF-8 thin films as described herein should be applicable in other ZIF materials, and the as-prepared ZIF-8 thin films on ITO may be explored for photoelectrochemical applications. PMID- 23042712 TI - Large-area 2D gold nanorod arrays assembled on block copolymer templates. AB - Various large-area 2D gold nanorod arrays are achieved on plasma-etched block copolymer templates. With the help of capillary forces, aqueous gold nanorods assembled on the templates show good position selectivity and high coverage of the grooves. Furthermore, these nanorod arrays can transform into gold nanowires by a post-etching process. PMID- 23042713 TI - Facile synthesis of well-dispersed silver nanoparticles on hierarchical flower like Ni3Si2O5(OH)4 with a high catalytic activity towards 4-nitrophenol reduction. AB - Layered nickel silicate nanoflowers (NSFs) with a hierarchical nanostructure have been successfully fabricated by a template-free solvothermal method. The as prepared nanoflowers were composed of many interconnected edge-curving lamellae with a thickness of about 15 nm and had a high specific surface area (279 m(2) g(-1)) and large pore volume (0.67 cm(3) g(-1)). The highly dispersed small silver nanoparticles (AgNPs) were immobilized on the surface of NSFs through the in situ reduction of Ag(+) by Sn(2+). The AgNP/NSF nanocomposites showed a high performance in the catalytic reduction of 4-nitrophenol. In particular, there was no visible decrease in the catalytic activity of the reused catalysts even after being recycled four times. The as-prepared AgNP/NSF nanocomposites might be an excellent catalyst owing to their availability, formability, chemical and thermal stability, and high specific surface area. PMID- 23042714 TI - Relay catalysis enables hydrogen gas to participate in asymmetric organocatalytic hydrogenation. PMID- 23042715 TI - Ruthenium complexation in an aluminium metal-organic framework and its application in alcohol oxidation catalysis. AB - A ruthenium trichloride complex has been loaded into an aluminium metal-organic framework (MOF), MOF-253, by post-synthetic modification to give MOF-253-Ru. MOF 253 contains open bipyridine sites that are available to bind with the ruthenium complex. MOF-253-Ru was characterised by elemental analysis, N(2) sorption and X ray powder diffraction. This is the first time that a Ru complex has been coordinated to a MOF through post-synthetic modification and used as a heterogeneous catalyst. MOF-253-Ru catalysed the oxidation of primary and secondary alcohols, including allylic alcohols, with PhI(OAc)(2) as the oxidant under very mild reaction conditions (ambient temperature to 40 degrees C). High conversions (up to >99%) were achieved in short reaction times (1-3 h) by using low catalyst loadings (0.5 mol% Ru). In addition, high selectivities (>90%) for aldehydes were obtained at room temperature. MOF-253-Ru can be recycled up to six times with only a moderate decrease in substrate conversion. PMID- 23042717 TI - Switchable nanodumbbell probes for analyte detection. AB - Nanodumbbell gold nanoparticle (AuNP) dimers connected by DNA show significant change in interparticle distance in the presence of a specific analyte, ATP. The nanodumbbell begins in an extended state, but after the addition of the analyte, the DNA connecting the AuNPs forms a stable hairpin, which causes a large decrease in the interparticle distance. PMID- 23042716 TI - Pseudoprogression after high-dose busulfan-thiotepa with autologous stem cell transplantation and radiation therapy in children with brain tumors: Impact on survival. AB - Children with a brain tumor treated with high-dose busulfan-thiotepa with autologous stem cell transplantation (ASCT) and radiation therapy (RT) often experience radiographic changes during follow-up. The purpose of the study was to identify the incidence, time course, risk factors, and clinical outcome of this complication. From May 1988 through May 2007, 110 patients (median age, 3.6 years; range, 1 month to 15.3 years) with a brain tumor had received 1 course of high-dose busulfan-thiotepa with stem cell rescue, followed or preceded by RT as part of their treatment. All MRI follow-up examinations were systematically reviewed. Twenty-three patients (21%) developed neuroradiological abnormalities at a median time of 9.2 months (range, 5.6-17.3 months) after ASCT. All contrast enhancing lesions appeared in patients who had received RT after ASCT and were localized inside the 50-55Gy isodoses. They disappeared in 14 of 23 patients after a median time of 8 months (range, 3-17 months), leaving microcalcifications in some cases. The presence of MRI abnormalities was an independent prognostic factor for overall survival in the multivariate analysis (hazard ratio, 0.12; 95% confidence interval [CI], 0.04-0.33), with a 5-year overall survival rate of 84% among patients with MRI abnormalities (95% CI, 62-94), compared with 27% (95% CI, 19-37) among those without lesions. MRI-detectable pseudoprogression is a common early finding in children treated with high-dose busulfan-thiotepa followed by radiation therapy and is correlated with a better outcome. PMID- 23042718 TI - Mechanism of the toxicity induced by natural humic acid on human vascular endothelial cells. AB - Humic acid (HA), a group of high-molecular weight organic compounds characterized by an ability to bind heavy metals, is normally found in natural water. Although the impairment of vascular endothelial cells in the presence of humic substances has been reported to be involved in some diseases, the mechanisms responsible for this involvement remain unclear. In this study, we examined the cytotoxicity of HA obtained from peatland in Central Kalimantan, Indonesia, to human vascular endothelial cells, as well as the mechanisms behind these effects. It was found that 50 mg/L HA showed cytotoxicity, which we considered to be mediated by apoptosis through the mitochondrial pathway because of an increase in the expression of caspases 6 and 9 in response to HA administration. In addition, this cytotoxicity was enhanced when cells in this experimental system were exposed to oxidative stress, while it was decreased by the addition of vitamin C. Thus, we conclude that the apoptosis induced by HA depends upon oxidative stress. Furthermore, an iron chelator, DFO, showed a tendency to decrease HA-induced cytotoxicity, suggesting that iron may potentially mediate HA-induced oxidative stress. In conclusion, long-term consumption of HA-rich water obtained from our study area may cause damage to endothelial cells and subsequent chronic health problems. PMID- 23042719 TI - Aerobic oxidation of a tertiary aliphatic amine under visible-light photocatalysis: facile synthesis of methylene-bridged bis-1,3-dicarbonyl compounds. AB - Lights, camera, action! An efficient protocol for the formation of methylene bridged bis-1,3-dicarbonyl compounds has been developed through an aerobic photocatalytic oxidative coupling reaction between 1,3-dicarbonyl compounds and a tertiary aliphatic amine. PMID- 23042720 TI - Equimolar CO2 capture by N-substituted amino acid salts and subsequent conversion. AB - Steric bulk controls CO(2) absorption: N-substituted amino acid salts in poly(ethylene glycol) reversibly absorb CO(2) in nearly 1:1 stoichiometry. Carbamic acid is thought to be the absorbed form of CO(2); this was supported by NMR and in situ IR spectroscopy, and DFT calculations. The captured CO(2) could be converted directly into oxazolidinones and thus CO(2) desorption could be sidestepped. PMID- 23042722 TI - Comment on "Human antitumor CD8+ T cells producing Th1 polycytokines show superior antigen sensitivity and tumor recognition". PMID- 23042723 TI - IFN-alpha in the treatment of melanoma. AB - Among the IFNs, IFN-alpha2 has been the most broadly evaluated clinically. At the molecular level, IFN-alpha has multiple effects in a variety of malignancies that range from antiangiogenic to potent immunoregulatory, differentiation-inducing, antiproliferative, and proapoptotic effects. A multitude of IFN-alpha2 regimens that may be classified as low dose, intermediate dose, and high dose have been evaluated as adjuvant therapy in melanoma. A durable impact on both relapse-free and overall survival was seen only with the regimen utilizing high-dose IFN alpha2b tested in the Eastern Cooperative Oncology Group and intergroup trials E1684, E1690, and E1694 as adjuvant therapy for high-risk surgically resected melanoma (stage IIB or III). Adjuvant pegylated IFN-alpha2b has also been evaluated at maximally tolerable doses compared with the observation group in the European Organization for Research and Treatment of Cancer trial 18991 and has shown relapse-free survival benefits in patients with microscopic nodal disease. PMID- 23042724 TI - A galvanic replacement route to prepare strongly fluorescent and highly stable gold nanodots for cellular imaging. AB - Fluorescent gold nanodots (GNDs) are an important kind of nanoprobes. Herein, the application of galvanic replacement for the preparation of fluorescent GNDs is reported. Using presynthesized and size-controlled Ag nanodots (Ag NDs) as templates, the as-prepared GNDs have strong fluorescence (quantum yields ~10%) with high stability and surface bioactivity. The resultant GNDs show excellent photoluminescence properties with high photo-, time-, metal-, and pH-stability, which are attributed to the protective surface layer of glutathione (GSH) and the presence of Au(I)-S complexes on the surface of the gold core. GSH, a naturally occurring and readily available tripeptide with carboxyl and amino functional groups, allows good dispersion of the as-prepared GNDs in aqueous solution and favorable biocompatibility. These advantages, combined with their small size, mean that the as-prepared GNDs have potential application in biological labeling, especially as a DNA probe for the specific detection of nucleic acids. In this study, the CAL-27 cells are used as a model to evaluate the fluorescence imaging of GNDs. PMID- 23042725 TI - Revised international consensus guidelines for the management of patients with mucinous cysts. PMID- 23042726 TI - Meeting report: 17th International Symposium on Bioluminescence and Chemiluminescence - ISBC 2012, Guelph, Canada. PMID- 23042727 TI - Artificial water channels. PMID- 23042728 TI - Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid organogenesis mouse limbs. AB - In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of VPA, does not inhibit HDAC activity and is a weak teratogen in vivo. The detailed mechanism of action of VPA as a teratogen is not known. The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or VPD in a limb bud culture system. VPA caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its HDAC inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA. In contrast, VPD had little effect on limb morphology and no significant effect on HDAC activity or the expression of marker genes. Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of HDAC inhibition because VPD did not affect their expressions. PMID- 23042729 TI - Establishment of a molecular embryonic stem cell developmental toxicity assay. AB - The mouse embryonic stem cell test (EST) is a 10-day screen for teratogenic potential developed to reduce animal use for embryotoxicity testing of chemicals (Spielmann, 2005; Spielmann et al., 1997). In this study, we used the cytotoxicity IC(50) values and transcriptional expression changes as primary endpoints in a shorter 4-day version of the EST, the molecular embryonic stem cell assay. Mouse D3 embryonic stem cells were used for cytotoxicity assessment (monolayers) or grown as embryoid bodies in low attachment plates for transcriptional profiling. Sixty-five compounds with known in vivo teratogenicity (33 teratogens and 32 nonteratogens) were evaluated to develop a model for classifying compounds with teratogenic potential. The expression of 12 developmentally regulated gene targets (nanog, fgf5, gsc, cd34, axin2, apln, chst7, lhx1, fgf8, sox17, foxa2, and cxcr4) was measured following exposure of embryoid bodies to a single compound concentration (0.1 * the cytotoxicity IC(20)) for 4 days. In the decision-tree model, compounds with IC(50) values < 22 uM were categorized as teratogens, whereas compounds in the two groups with IC(50) values between 22-200 uM and > 200 uM were categorized as teratogens if >= 8 and 12 genes, respectively, were deregulated by at least 10%. Forty-seven of 65 compounds of the training set were correctly identified (72% total concordance). In a test set of 12 additional compounds (5 teratogens, 7 nonteratogens), 10 were correctly classified by this approach (83% concordance). The false positive rate in the training and test sets was 24 and 0%, respectively, indicating that this assay has potential to identify teratogens. PMID- 23042732 TI - Two sequential processes of change detection in hierarchically ordered areas of the human auditory cortex. AB - Auditory deviance detection occurs around 150 ms after the onset of a deviant sound. Recent studies in animals and humans have described change-related processes occurring during the first 50 ms after sound onset. However, it still remains an open question whether these early and late processes of deviance detection are organized hierarchically in the human auditory cortex. We applied a beamforming source reconstruction approach in order to estimate brain sources associated with 2 temporally distinct markers of deviance detection. Results showed that rare frequency changes elicit an enhancement of the Nbm component of the middle latency response (MLR) peaking at 43 ms, in addition to the magnetic mismatch negativity (MMNm) peaking at 115 ms. Sources of MMNm, located in the right superior temporal gyrus, were lateral and posterior to the deviance-related MLR activity being generated in the right primary auditory cortex. Source reconstruction analyses revealed that detection of changes in the acoustic environment is a process accomplished in 2 different time ranges, by spatially separated auditory regions. Paralleling animal studies, our findings suggest that primary and secondary areas are involved in successive stages of deviance detection and support the existence of a hierarchical network devoted to auditory change detection. PMID- 23042730 TI - Tumor necrosis factor-alpha potentiates the cytotoxicity of amiodarone in Hepa1c1c7 cells: roles of caspase activation and oxidative stress. AB - Amiodarone (AMD), a class III antiarrhythmic drug, causes idiosyncratic hepatotoxicity in human patients. We demonstrated previously that tumor necrosis factor-alpha (TNF-alpha) plays an important role in a rat model of AMD-induced hepatotoxicity under inflammatory stress. In this study, we developed a model in vitro to study the roles of caspase activation and oxidative stress in TNF potentiation of AMD cytotoxicity. AMD caused cell death in Hepa1c1c7 cells, and TNF cotreatment potentiated its toxicity. Activation of caspases 9 and 3/7 was observed in AMD/TNF-cotreated cells, and caspase inhibitors provided minor protection from cytotoxicity. Intracellular reactive oxygen species (ROS) generation and lipid peroxidation were observed after treatment with AMD and were further elevated by TNF cotreatment. Adding water-soluble antioxidants (trolox, N acetylcysteine, glutathione, or ascorbate) produced only minor attenuation of AMD/TNF-induced cytotoxicity and did not influence the effect of AMD alone. On the other hand, alpha-tocopherol (TOCO), which reduced lipid peroxidation and ROS generation, prevented AMD toxicity and caused pronounced reduction in cytotoxicity from AMD/TNF cotreatment. alpha-TOCO plus a pancaspase inhibitor completely abolished AMD/TNF-induced cytotoxicity. In summary, activation of caspases and oxidative stress were observed after AMD/TNF cotreatment, and caspase inhibitors and a lipid-soluble free-radical scavenger attenuated AMD/TNF induced cytotoxicity. PMID- 23042731 TI - Meta-analytic connectivity modeling reveals differential functional connectivity of the medial and lateral orbitofrontal cortex. AB - The orbitofrontal cortex (OFC) is implicated in a broad range of behaviors and neuropsychiatric disorders. Anatomical tracing studies in nonhuman primates reveal differences in connectivity across subregions of the OFC, but data on the connectivity of the human OFC remain limited. We applied meta-analytic connectivity modeling in order to examine which brain regions are most frequently coactivated with the medial and lateral portions of the OFC in published functional neuroimaging studies. The analysis revealed a clear divergence in the pattern of connectivity for the medial OFC (mOFC) and lateral OFC (lOFC) regions. The lOFC showed coactivations with a network of prefrontal regions and areas involved in cognitive functions including language and memory. In contrast, the mOFC showed connectivity with default mode, autonomic, and limbic regions. Convergent patterns of coactivations were observed in the amygdala, hippocampus, striatum, and thalamus. A small number of regions showed connectivity specific to the anterior or posterior sectors of the OFC. Task domains involving memory, semantic processing, face processing, and reward were additionally analyzed in order to identify the different patterns of OFC functional connectivity associated with specific cognitive and affective processes. These data provide a framework for understanding the human OFC's position within widespread functional networks. PMID- 23042734 TI - Electrophysiological correlates of adult age differences in attentional control of auditory processing. AB - In addition to sensory decline, age-related losses in auditory perception also reflect impairments in attentional modulation of perceptual saliency. Using an attention and intensity-modulated dichotic listening paradigm, we investigated electrophysiological correlates of processing conflicts between attentional focus and perceptual saliency in 25 younger and 26 older adults. Participants were instructed to attend to the right or left ear, and perceptual saliency was manipulated by varying the intensities of both ears. Attentional control demand was higher in conditions when attentional focus and perceptual saliency favored opposing ears than in conditions without such conflicts. Relative to younger adults, older adults modulated their attention less flexibly and were more influenced by perceptual saliency. Our results show, for the first time, that in younger adults a late negativity in the event-related potential (ERP) at fronto central and parietal electrodes was sensitive to perceptual-attentional conflicts during auditory processing (N450 modulation effect). Crucially, the magnitude of the N450 modulation effect correlated positively with task performance. In line with lower attentional flexibility, the ERP waveforms of older adults showed absence of the late negativity and the modulation effect. This suggests that aging compromises the activation of the fronto-parietal attentional network when processing the competing and conflicting auditory information. PMID- 23042733 TI - Membrane resonance enables stable and robust gamma oscillations. AB - Neuronal mechanisms underlying beta/gamma oscillations (20-80 Hz) are not completely understood. Here, we show that in vivo beta/gamma oscillations in the cat visual cortex sometimes exhibit remarkably stable frequency even when inputs fluctuate dramatically. Enhanced frequency stability is associated with stronger oscillations measured in individual units and larger power in the local field potential. Simulations of neuronal circuitry demonstrate that membrane properties of inhibitory interneurons strongly determine the characteristics of emergent oscillations. Exploration of networks containing either integrator or resonator inhibitory interneurons revealed that: (i) Resonance, as opposed to integration, promotes robust oscillations with large power and stable frequency via a mechanism called RING (Resonance INduced Gamma); resonance favors synchronization by reducing phase delays between interneurons and imposes bounds on oscillation cycle duration; (ii) Stability of frequency and robustness of the oscillation also depend on the relative timing of excitatory and inhibitory volleys within the oscillation cycle; (iii) RING can reproduce characteristics of both Pyramidal INterneuron Gamma (PING) and INterneuron Gamma (ING), transcending such classifications; (iv) In RING, robust gamma oscillations are promoted by slow but are impaired by fast inputs. Results suggest that interneuronal membrane resonance can be an important ingredient for generation of robust gamma oscillations having stable frequency. PMID- 23042735 TI - Higher transport and metabolism of glucose in astrocytes compared with neurons: a multiphoton study of hippocampal and cerebellar tissue slices. AB - Glucose is the most important energy substrate for the brain, and its cellular distribution is a subject of great current interest. We have employed fluorescent glucose probes, the 2-deoxy-D-glucose derivates 6- and 2-([N-(7-nitrobenz-2-oxa 1,3-diazol-4-yl) amino]-2-deoxy-D-glucose) (2-NBDG), to measure transport and metabolism of glucose in acute slices of mouse hippocampus and cerebellum. In the hippocampus, 6-NBDG, which is not metabolized and hence indicates glucose transport, was taken up faster in astrocyte-rich layers (Stratum radiatum [S.r.], Stratum oriens [S.o.]) than in pyramidal cells. Metabolizable 2-NBDG showed larger signals in S.r. and S.o. than in Stratum pyramidale, suggesting faster glucose utilization rate in the astrocyte versus the neuronal compartment. Similarly, we found higher uptake and temperature-sensitive metabolism of 2-NBDG in Bergmann glia when compared with adjacent Purkinje neurons of cerebellar slices. A comparison between 6-NBDG transport and glucose transport in cultured cells using a fluorescence resonance energy transfer nanosensor showed that relative to glucose, 6-NBDG is transported better by neurons than by astrocytes. These results indicate that the preferential transport and metabolism of glucose by glial cells versus neurons proposed for the hippocampus and cerebellum by ourselves (in vitro) and for the barrel cortex by Chuquet et al. (in vivo) is more pronounced than anticipated. PMID- 23042736 TI - Selective involvement by the medial orbitofrontal cortex in biasing risky, but not impulsive, choice. AB - Separate regions of the orbitofrontal cortex (OFC) have been implicated in mediating different aspects of cost-benefit decision-making in humans and animals. Anatomical and functional imaging studies indicate that the medial (mOFC) and lateral OFC may subserve dissociable functions related to reward and decision-making processes, yet the majority of studies in rodents have focused on the lateral OFC. The present study investigated the contribution of the rat mOFC to risk and delay-based decision-making, assessed with probabilistic and delay discounting tasks. In well-trained rats, reversible inactivation of the mOFC increase a risky choice on the probabilistic discounting task, irrespective of whether the odds of obtaining a larger/risky reward decreased (100-12.5%) or increased (12.5-100%) over the course of a session. The increase in risky choice was associated with enhanced win-stay behavior, wherein rats showed an increased tendency to choose the risky option after being rewarded for the risky choice on a preceding trial. In contrast, mOFC inactivation did not alter delay discounting. These findings suggest that the mOFC plays a selective role in decisions involving reward uncertainty, mitigating the impact that larger, probabilistic rewards exert on subsequent choice behavior. This function may promote the exploration of novel options when reward contingencies change. PMID- 23042737 TI - Gli3 controls corpus callosum formation by positioning midline guideposts during telencephalic patterning. AB - The corpus callosum (CC) represents the major forebrain commissure connecting the 2 cerebral hemispheres. Midline crossing of callosal axons is controlled by several glial and neuronal guideposts specifically located along the callosal path, but it remains unknown how these cells acquire their position. Here, we show that the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn) displays agenesis of the CC and mislocation of the glial and neuronal guidepost cells. Using transplantation experiments, we demonstrate that agenesis of the CC is primarily caused by midline defects. These defects originate during telencephalic patterning and involve an up-regulation of Slit2 expression and altered Fgf and Wnt/beta-catenin signaling. Mutations in sprouty1/2 which mimic the changes in these signaling pathways cause a disorganization of midline guideposts and CC agenesis. Moreover, a partial recovery of midline abnormalities in Pdn/Pdn;Slit2( /-) embryos mutants confirms the functional importance of correct Slit2 expression levels for callosal development. Hence, Gli3 controlled restriction of Fgf and Wnt/beta-catenin signaling and of Slit2 expression is crucial for positioning midline guideposts and callosal development. PMID- 23042738 TI - Temporal coupling with cortex distinguishes spontaneous neuronal activities in identified basal ganglia-recipient and cerebellar-recipient zones of the motor thalamus. AB - Neurons of the motor thalamus mediate basal ganglia and cerebellar influences on cortical activity. To elucidate the net result of gamma-aminobutyric acid releasing or glutamatergic bombardment of the motor thalamus by basal ganglia or cerebellar afferents, respectively, we recorded the spontaneous activities of thalamocortical neurons in distinct identified "input zones" in anesthetized rats during defined cortical activity states. Unexpectedly, the mean rates and brain state dependencies of the firing of neurons in basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) were matched during slow-wave activity (SWA) and cortical activation. However, neurons were distinguished during SWA by their firing regularities, low-threshold spike bursts and, more strikingly, by the temporal coupling of their activities to ongoing cortical oscillations. The firing of neurons across the BZ was stronger and more precisely phase-locked to cortical slow (~ 1 Hz) oscillations, although both neuron groups preferentially fired at the same phase. In contrast, neurons in BZ and CZ fired at different phases of cortical spindles (7-12 Hz), but with similar strengths of coupled firing. Thus, firing rates do not reflect the predicted inhibitory-excitatory imbalance across the motor thalamus, and input zone-specific temporal coding through oscillatory synchronization with the cortex could partly mediate the different roles of basal ganglia and cerebellum in behavior. PMID- 23042740 TI - Elevation in type I interferons inhibits HCN1 and slows cortical neuronal oscillations. AB - Central nervous system (CNS) inflammation involves the generation of inducible cytokines such as interferons (IFNs) and alterations in brain activity, yet the interplay of both is not well understood. Here, we show that in vivo elevation of IFNs by viral brain infection reduced hyperpolarization-activated currents (Ih) in cortical pyramidal neurons. In rodent brain slices directly exposed to type I IFNs, the hyperpolarization-activated cyclic nucleotide (HCN)-gated channel subunit HCN1 was specifically affected. The effect required an intact type I receptor (IFNAR) signaling cascade. Consistent with Ih inhibition, IFNs hyperpolarized the resting membrane potential, shifted the resonance frequency, and increased the membrane impedance. In vivo application of IFN-beta to the rat and to the mouse cerebral cortex reduced the power of higher frequencies in the cortical electroencephalographic activity only in the presence of HCN1. In summary, these findings identify HCN1 channels as a novel neural target for type I IFNs providing the possibility to tune neural responses during the complex event of a CNS inflammation. PMID- 23042741 TI - Postnatal development of 2 microcircuits involving fast-spiking interneurons in the mouse prefrontal cortex. AB - Disturbed development of the parvalbumin-positive fast-spiking (FS) interneurons in the prefrontal cortex (PFC) is closely associated with many neuropsychiatric disorders such as schizophrenia and autism. FS interneurons form at least 2 microcircuits in the PFC: one with pyramidal neurons (FS-PN) through chemical synapses; the other with other FS interneurons (FS-FS) via chemical and electrical synapses. It is currently unknown when and how these circuits are established in the PFC during early development. Here, we used G42 mice, in which FS interneurons are specifically labeled with enhanced green fluorescent protein, to make dual whole-cell recordings from postnatal day 3 (P3) to P30 to study the development of FS interneuronal networks in the PFC. We found that FS interneurons were poorly developed in terms of the membrane and network properties during the first postnatal week, both of which exhibited an abrupt maturation during the second postnatal week. The development of FS interneuronal microcircuits lasted throughout early adulthood. Thus, our data suggest that FS interneurons might not be involved in generating cortical oscillatory activity and gamma oscillations during the first postnatal week. Our data also indicate an independent development of electrical and chemical synapses among FS interneuronal networks during the early period. PMID- 23042742 TI - Strength of retinotopic representation of visual memories is modulated by strategy. AB - Human visual cortex shows retinotopic organization during both perception and attention, but whether this remains true for visual short-term memory (VSTM) is uncertain. In 2 functional magnetic resonance imaging experiments, we separated retinotopic activation during perception, attention, and VSTM maintenance. The 2 experiments differed in whether spatial encoding of the VSTM stimuli and prospective attention to the locations of the remembered items was encouraged or discouraged. Using multivoxel pattern analysis to extract a measure of spatial coding in early visual cortex, we saw sensory and attentional retinotopic coding in both experiments. However, significant spatial coding during memory maintenance was only seen where a spatial strategy was encouraged. Furthermore, individual differences in attentional spatial coding predicted performance in both experiments, while individual differences in maintenance spatial coding predicted performance in neither. We conclude that retinotopic coding in the early visual cortex during VSTM maintenance is not obligatory, that attentional processes during stimulus perception modulate memory performance, and that different attentional strategies are used depending on the task in hand. PMID- 23042739 TI - NFIX regulates neural progenitor cell differentiation during hippocampal morphogenesis. AB - Neural progenitor cells have the ability to give rise to neurons and glia in the embryonic, postnatal and adult brain. During development, the program regulating whether these cells divide and self-renew or exit the cell cycle and differentiate is tightly controlled, and imbalances to the normal trajectory of this process can lead to severe functional consequences. However, our understanding of the molecular regulation of these fundamental events remains limited. Moreover, processes underpinning development of the postnatal neurogenic niches within the cortex remain poorly defined. Here, we demonstrate that Nuclear factor one X (NFIX) is expressed by neural progenitor cells within the embryonic hippocampus, and that progenitor cell differentiation is delayed within Nfix(-/-) mice. Moreover, we reveal that the morphology of the dentate gyrus in postnatal Nfix(-/-) mice is abnormal, with fewer subgranular zone neural progenitor cells being generated in the absence of this transcription factor. Mechanistically, we demonstrate that the progenitor cell maintenance factor Sry-related HMG box 9 (SOX9) is upregulated in the hippocampus of Nfix(-/-) mice and demonstrate that NFIX can repress Sox9 promoter-driven transcription. Collectively, our findings demonstrate that NFIX plays a central role in hippocampal morphogenesis, regulating the formation of neuronal and glial populations within this structure. PMID- 23042743 TI - Disrupted cortical conductivity in schizophrenia: TMS-EEG study. AB - Schizophrenia is conceptualized as a failure of cognitive integration, and altered oscillatory properties of neurocircuits are associated with its symptoms. We hypothesized that abnormal characteristics of neural networks may alter functional connectivity and distort propagation of activation in schizophrenic brains. Thus, electroencephalography (EEG) responses to transcranial magnetic stimulation (TMS) of motor cortex were compared between schizophrenia and healthy subjects. There was no difference in the initial response. However, TMS-induced waves of recurrent excitation spreading across the cortex were observed in schizophrenia, while in healthy subjects the activation faded away soon after stimulation. This widespread activation in schizophrenia was associated with increased oscillatory activities in the proximal central leads and in fronto temporo-parietal leads bilaterally. A positive correlation was found between increased TMS-induced cortical activation in gamma frequency and positive symptoms of schizophrenia, while negative symptoms were correlated with activation in theta and delta bands. We suggest that excessive activation in response to stimulation in schizophrenia brains may lead to abnormal propagation of the signal that could potentially result in aberrant activity in areas remote from the activation origin. This mechanism may account for the positive symptoms of schizophrenia and could worsen signal to noise deficits, jeopardizing adequate information processing with ensuing cognitive deficits. PMID- 23042744 TI - Simultaneous analysis of 11 main active components in Cirsium setosum based on HPLC-ESI-MS/MS and combined with statistical methods. AB - A novel method based on high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry was developed for simultaneous determination of the 11 major active components including ten flavonoids and one phenolic acid in Cirsium setosum. Separation was performed on a reversed-phase C(18) column with gradient elution of methanol and 0.10/00 acetic acid (v/v). The identification and quantification of the analytes were achieved on a hybrid quadrupole linear ion trap mass spectrometer. Multiple-reaction monitoring scanning was employed for quantification with switching electrospray ion source polarity between positive and negative modes in a single run. Full validation of the assay was carried out including linearity, precision, accuracy, stability, limits of detection and quantification. The results demonstrated that the method developed was reliable, rapid, and specific. The 25 batches of C. setosum samples from different sources were first determined using the developed method and the total contents of 11 analytes ranged from 1717.460 to 23028.258 MUg/g. Among them, the content of linarin was highest, and its mean value was 7340.967 MUg/g. Principal component analysis and hierarchical clustering analysis were performed to differentiate and classify the samples, which is helpful for comprehensive evaluation of the quality of C. setosum. PMID- 23042745 TI - Association of CD1a-positive dendritic cells with papillary thyroid carcinoma in thyroid fine-needle aspirations: a cytologic and immunocytochemical evaluation. AB - BACKGROUND: In contrast to other primary thyroid neoplasms and benign thyroid tissue, it has been demonstrated histologically that dendritic cells (DCs) are associated with papillary thyroid carcinoma (PTC). However, the presence and potential diagnostic value of DCs in thyroid fine-needle aspirations (FNAs) have not been previously described. METHODS: The authors quantitatively assessed for the presence of DCs that were positive for cluster of differentiation 1a (CD1a) (a 43-49 kD protein expressed on DCs and cortical thymocytes) in cytologic samples of histologically confirmed PTC (n=31) and in a control group of benign thyroid nodules (BTNs) (n=29) using immunocytochemical staining with antibodies against CD1a. A subset of the corresponding PTCs (n=11) and BTNs (n=10) from surgical resection specimens also were assessed immunohistochemically for both CD1a and Langerin (a type II transmembrane cell surface receptor produced by Langerhans cells). RESULTS: CD1a-positive DCs were identified in 97% PTCs (n=30 of 31 PTCs) in thyroid FNA specimens. DCs were largely present in 2 distinct patterns: either as isolated DCs in the background (n=29 of 31) and/or associated with tumor cells (n=30 of 31). Tumor-associated DCs (mean+/-standard deviation: 6.44+/-6.13 DCs per tumor cluster) exhibited multiple dendritic cytoplasmic processes extending over and between malignant cells within groups. The 3 PTC cases with the least DCs corresponded to the follicular variant at excision. In contrast, only 31% of BTNs (n=9 of 29 BTNs; P=.0048) contained CD1a-positive DCs. When DCs were present in BTN, they were isolated primarily in the background (27%; n=8 of 29), although 17% of BTNs (n=5 of 29) contained rare DCs among thyrocytes, revealing both patterns in 4 cases. Both thyrocyte-associated DCs and background DCs were more numerous in PTC FNAs than in BTN FNAs, but only the thyrocyte-associated group of DCs was statistically significant (P<.0001 and P=.1173, respectively). Similar findings were reported in histologic samples in which all PTCs examined (n=11 of 11) contained both CD1a-positive and Langerin positive DCs; only 20% of BTNs (n=2 of 10) contained rare DCs. CONCLUSIONS: CD1a positive DCs were present in FNA specimens of PTC, typically in close association with tumor cells, whereas they were rare in BTNs. The increased presence of CD1a positive DCs in PTC may be a useful diagnostic adjuvant. PMID- 23042747 TI - Maintenance of certification: historical context. PMID- 23042746 TI - An fMRI investigation of working memory and its relationship with cardiorespiratory fitness in pediatric posterior fossa tumor survivors who received cranial radiation therapy. AB - BACKGROUND: The present study investigated the relationship between cardiorespiratory fitness and executive functioning in pediatric brain tumor survivors who received cranial radiation. This population is known to show executive dysfunction and lower rates of aerobic exercise compared to peers. PROCEDURE: Nine adolescent survivors of pediatric posterior fossa tumor completed an n-back working memory task during a functional MRI scan, as well as cardiorespiratory fitness testing on a cycle ergometer. RESULTS: Neuroimaging findings indicated typical activation patterns associated with working memory, mainly in the frontal-parietal network. Higher cardiorespiratory fitness was related to better performance on a behavioral measure of working memory and more efficient neural functioning. CONCLUSIONS: This study provides preliminary evidence that cardiorespiratory fitness may be related to executive functioning, particularly working memory, in pediatric brain tumor survivors. Descriptions of the brain regions recruited for working memory by pediatric brain tumor survivors may be used to inform future interventions or indicators of treatment efficacy. PMID- 23042748 TI - Improvements in recanalization with modern stroke therapy: a review of prospective ischemic stroke trials during the last two decades. AB - INTRODUCTION: A number of recent trials evaluating intra-arterial therapies for acute ischemic stroke have been completed. We present a review of prospective acute ischemic stroke trials reported in a peer-reviewed forum during the last 20 years to provide insight into the general direction of this rapidly evolving field. METHODS: Prospective trials evaluating acute stroke intra-arterial therapies since 1999 were included, with the National Institute of Neurological Disorders and Stroke rtPA trial published in 1995 as a baseline comparator. Patient presenting factors and outcome data were analyzed based on year of publication and best-fit lines and linear regression analyses were generated. RESULTS: Thirteen prospective trials were included. Regression analyses demonstrated no appreciable change in the median NIH Stroke Scale score of subjects at the time of enrollment since 1995 (p=0.44) and no appreciable improvements in good outcome based on a modified Rankin score of 0-2 at 90 days (p=0.66) or mortality at 90 days (p=0.55). A significant increase in time from onset of symptoms to treatment among enrolled patients was noted from 1995 to 2012 (p=0.03). In addition, a significant improvement in recanalization/reperfusion was noted over the last two decades (p=0.02). CONCLUSIONS: This review of prospective acute ischemic stroke trials since 1999 indicates a substantial improvement in revascularization in the setting of a significant increase in time to therapy onset, but no appreciable change in good functional outcome. PMID- 23042749 TI - Highly efficient stereoselective catalytic C(sp3)-H insertions with donor rhodium carbenoids generated from cyclopropenes. PMID- 23042752 TI - Cytopathologic features of mammary analogue secretory carcinoma. AB - BACKGROUND: Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland neoplasm that is defined by ETV6-NTRK3 gene fusion. To the best of the authors' knowledge, only rare case reports of the cytopathologic features of MASC have been published to date. METHODS: A wide variety of archival salivary gland tumors were tested for ETV6 translocation by break-apart fluorescent in situ hybridization. Positive cases with preoperative fine-needle aspiration (FNA) specimens or intraoperative touch preparations were retrieved from the archives of The Johns Hopkins Hospital. All smears were reviewed and the cytologic characteristics were described. RESULTS: Five cases of MASC with cytopathologic material (4 FNA specimens and 1 touch preparation) were identified. The cases occurred in 3 men and 2 women ranging in age from 21 years to 78 years (mean, 52 years). On the cytologic smears, the MASCs were variably cellular and exhibited 2 different architectural patterns: 1) intact tissue fragments with isomorphic cells arranged in a sheet-like or papillary configuration; and 2) dispersed and dissociated cells with a mostly "histiocyte-like" appearance with large cells containing abundant vacuolated cytoplasm. No matrix tissue or stromal spindled cells were present. The cells did not display acinic differentiation in the form of cytoplasmic zymogen granules. In each case, the preoperative FNA correctly identified a neoplasm, and the most frequent diagnostic considerations were acinic cell carcinoma, mucoepidermoid carcinoma, and pleomorphic adenoma. CONCLUSIONS: MASC is a newly described salivary gland tumor that should be considered in the differential diagnosis of low-grade salivary gland neoplasms. Its cytologic features overlap considerably with those of other tumors, especially acinic cell carcinoma and mucoepidermoid carcinoma. PMID- 23042753 TI - Establishing physician to patient ratios and predicting workforce needs for Canadian pediatric hematology-oncology programs. AB - BACKGROUND: A Human Resources (HR) Committee of C17, the national network of Canadian academic pediatric hematology/oncology programs, obtained comprehensive data enabling analysis and planning for the physician workforce. This study establishes physician to patient ratios and predicts workforce needs for Canadian pediatric hematology/oncology programs. PROCEDURES: Over a 10-year period, six surveys were sent to the 17 pediatric tertiary care centers treating children with cancer and blood disorders. Data were obtained on physician demographics, full time equivalent (FTE) positions, and time spent in clinical, research, education, and administrative activities. Survey results were debated at the C17 national meetings to obtain consensus on workload ratios. RESULTS: Since 1999, the pediatric hematologist/oncologist workforce has increased from 71 FTE (43 oncology, 20 hematology, 8 BMT) to 109.5 FTE positions (69.7 oncology, 29.4 hematology, and 10.4 BMT). The median age of pediatric hematologists/oncologists increased from 46 years to 52 years and the male to female ratio changed from 1.8:1 to 0.9:1. The 2011 job profile showed the median time spent on activities was 60% clinical, 15% education, 15% research, and 10% administration. After assessing workload, models of care, and optimal physician FTE per program, the C17 HR Committee recommended a ratio of one oncologist per 15 newly diagnosed patients with malignancy and a ratio of one BMT physician per 15 transplants. For every 2.5 oncologists, a 1.0 hematologist is the minimum required. CONCLUSION: Physician staffing ratios for pediatric hematology/oncology programs have been established and should be adopted across Canadian academic institutions as a standard. PMID- 23042754 TI - Mild and homogeneous cobalt-catalyzed hydrogenation of C=C, C=O, and C=N bonds. PMID- 23042755 TI - A role for the parietal cortex in sensorimotor adaptation of saccades. AB - Sensorimotor adaptation ensures movement accuracy despite continuously changing environment and body. Adaptation of saccadic eye movements is a classical model of sensorimotor adaptation. Beside the well-established role of the brainstem cerebellum in the adaptation of reactive saccades (RSs), the cerebral cortex has been suggested to be involved in the adaptation of voluntary saccades (VSs). Here, we provide direct evidence for a causal involvement of the parietal cortex in saccadic adaptation. First, the posterior intraparietal sulcus (pIPS) was identified in each subject using functional magnetic resonance imaging (fMRI). Then, a saccadic adaptation paradigm was used to progressively reduce the amplitude of RSs and VSs, while single-pulse transcranial magnetic stimulation (spTMS) was applied over the right pIPS. The perturbations of pIPS resulted in impairment for the adaptation of VSs, selectively when spTMS was applied 60 ms after saccade onset. In contrast, the adaptation of RSs was facilitated by spTMS applied 90 ms after saccade initiation. The differential effect of spTMS relative to saccade types suggests a direct interference with pIPS activity for the VS adaptation and a remote interference with brainstem-cerebellum activity for the RS adaptation. These results support the hypothesis that the adaptation of VSs and RSs involves different neuronal substrates. PMID- 23042756 TI - Human elastin-based recombinant biopolymers improve mesenchymal stem cell differentiation. AB - Elastin-based polypeptides are a class of smart biopolymers representing an important model in the design of biomaterials. The combination of biomimetic materials with cells that have great plasticity provides a promising strategy for the realization of highly engineered cell-based constructs for regenerative medicine and tissue repair applications. Two recombinant biopolymers inspired by human elastin are assessed as coating agents to prepare biomimetic surfaces for cell culture. These substrates are assayed for hBM MSC culture. The coated surfaces are also characterized with AFM to evaluate the topographical features of the deposited biopolymers. The results suggest that the elastin-derived biomimetic surfaces play a stimulatory role on osteogenic differentiation of MSCs. PMID- 23042758 TI - So many questions, so little time. PMID- 23042757 TI - Differences in cytokine production in human macrophages and in virulence in mice are attributable to the acidic polymerase protein of highly pathogenic influenza A virus subtype H5N1. AB - BACKGROUND: The pathogenesis of influenza A virus subtype H5N1 (hereafter, "H5N1") infection in humans is not completely understood, although hypercytokinemia is thought to play a role. We previously reported that most H5N1 viruses induce high cytokine responses in human macrophages, whereas some H5N1 viruses induce only a low level of cytokine production similar to that induced by seasonal viruses. METHODS: To identify the viral molecular determinants for cytokine induction of H5N1 viruses in human macrophages, we generated a series of reassortant viruses between the high cytokine inducer A/Vietnam/UT3028II/03 clone 2 (VN3028IIcl2) and the low inducer A/Indonesia/UT3006/05 (IDN3006) and evaluated cytokine expression in human macrophages. RESULTS: Viruses possessing the acidic polymerase (PA) gene of VN3028IIcl2 exhibited high levels of hypercytokinemia related cytokine expression in human macrophages, compared with IDN3006, but showed no substantial differences in viral growth in these cells. Further, the PA gene of VN3028IIcl2 conferred enhanced virulence in mice. CONCLUSIONS: These results demonstrate that the PA gene of VN3028IIcl2 affects cytokine production in human macrophages and virulence in mice. These findings provide new insights into the cytokine-mediated pathogenesis of H5N1 infection in humans. PMID- 23042759 TI - Editorial comment regarding H5N1 influenza article in this issue. PMID- 23042760 TI - Detection of urinary metabolites of AM-2201 and UR-144, two novel synthetic cannabinoids. AB - Synthetic cannabinoids are the psychotropic compounds frequently identified as active components of smoking mixtures easily available via the Internet in several countries. These herbal blends have become extremely popular as a legal alternative to cannabis-based products and are difficult to detect by regular drug tests. Here we report on an in vitro and in vivo metabolism of AM-2201, 1 [(5-fluoropentyl)-1H-indol-3-yl]-(naphthalen-1-yl)methanone, and UR-144 (KM-X1), (1-pentylindol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone isolated using preparative liquid chromatography from the smoking mixtures sold in Russia. After incubation with human liver microsomes (HLM) as well as with cytochrome isoenzymes 3A4 and 2B6, the metabolic pathways were identified by means of liquid chromatography - triple quadrupole and high resolution mass spectrometry with electrospray ionization in positive mode. It was found that the in vitro reactions include mono- and dihydroxylation, loss of N-alkyl side chain and formation of dihydrodiol metabolites in case of AM-2201. The HLM were found to be superior over the other two isoenzymes for generation of cannabinoid metabolites. Finally, forensic urine samples were analyzed to validate the in vitro data and it has been shown that for both cannabimimetics the recommended screening targets are the monohydroxylated metabolites. PMID- 23042761 TI - Aspergillus galactomannan antigen assay and invasive aspergillosis in pediatric cancer patients and hematopoietic stem cell transplant recipients. AB - BACKGROUND: Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised children. We investigated the usefulness of an Aspergillus galactomannan (GM) antigen assay as a diagnostic tool for IA in pediatric cancer patients and hematopoietic cell transplantation (HCT) recipients. PROCEDURE: The GM antigen assay results were analyzed in 749 blood samples from 99 patients. A GM index (GMI) greater than or equal to 0.5 on at least two separate occasions was considered positive. A review of the clinical data was performed for subjects with proven or probable IA. RESULTS: Twenty-one of 23 patients with proven or probable IA had positive GM antigen test results (91.3% sensitivity, 95% CI 71.9-98.9; 81.7% specificity, 95% CI 69.6-90.5; P < 0.0001). The false-positive rate was 18.3%. Being younger than 3 years of age, having a solid tumor, and receiving HCT within 4 weeks of the test were statistically significant factors for causing false-positive results (P < 0.05). Among the 23 patients with IA (six proven, 17 probable), 16 (69.6%) had hematological malignancies, five (22.7%) had solid tumors, and two (8.7%) had primary immunodeficiency. Nineteen patients (82.6%) received HCT. The most common clinical site of IA was the lungs (91.3%), and consolidation was the most frequent finding in chest CT scans (36.8%). The mortality at 12 weeks was 43.5%. CONCLUSIONS: Having a positive GM assay at least twice is useful in diagnosing IA in pediatric patients with cancer and HCT recipients. PMID- 23042762 TI - Glycopolymers and glyco-nanoparticles in biomolecular recognition processes and vaccine development. AB - With advances in polymerization techniques as well as selective chemical modification of carbohydrates, glycopolymers and glyco-nanoparticles are emerging as an important class of materials with tailored properties or novel nanotechnology-based platforms for a number of applications. The field of the so called glyco-nanotechnology is starting to show some promises for future clinical applications. Glyco-nanoparticles, due to their versatile nature, could offer a platform for the design of carbohydrate-based vaccines and possibly allow the development of new single-dose vaccines in disease areas of unmet need. This paper surveys the emerging roles of carbohydrate-based polymeric and nanomaterials for biomolecular recognition processes and vaccine development. PMID- 23042764 TI - International Committee on Systematics of Prokaryotes. Subcommittee on the taxonomy of Bifidobacterium, Lactobacillus and related organisms. Minutes of the meetings, 31 August 2011, Egmond aan Zee, The Netherlands. PMID- 23042766 TI - AMT (3-(2-aminopropyl)indole) and 5-IT (5-(2-aminopropyl)indole): an analytical challenge and implications for forensic analysis. AB - 5-(2-Aminopropyl)indole (5-IT) and 3-(2-aminopropyl)indole (alpha methyltryptamine, AMT) are isomeric substances and their differentiation can be a challenge under routine analytical conditions, especially when reference material is unavailable. 5-IT represents a very recent addition to the battery of new psychoactive substances that are commercially available from online retailers. This report illustrates how subtle differences observed under mass spectral and UV conditions can help to facilitate the differentiation between the two isomers. Analyses included (1) H and (13) C NMR, GC-EI/CI ion trap MS, applications of several U/HPLC-DAD and HPLC-MS methods. Investigations currently underway also highlight the confirmation that AMT was detected in a number of fatal intoxications. These findings also demonstrate that there is a potential risk of misidentification when dealing with both substances. PMID- 23042765 TI - Glucocorticoids and insulin resistance in children with acute lymphoblastic leukemia. AB - BACKGROUND: Children treated for acute lymphoblastic leukemia (ALL) are more likely to become overweight. Prolonged exposure to high-dose glucocorticoids may cause insulin resistance and facilitate development of this phenotype. PROCEDURE: Body mass indices (BMI) and insulin resistance (homeostatic model assessment [HOMA]-IR) were prospectively measured among on- (n = 31) and off-therapy participants (n = 29). On-therapy participants were assessed prior to and while on glucocorticoids (5 days of prednisone 40 mg m(-2) or dexamethasone 6 mg m(-2)) given as part of routine maintenance chemotherapy, with a subset (n = 10) receiving an intravenous glucose tolerance test (IVGTT) while on glucocorticoids. RESULTS: Baseline HOMA-IR values among on- and off-therapy participants were similar, but among on-therapy participants, HOMA-IR increased significantly with glucocorticoid exposure (median 3.39 vs. 1.26; P < 0.01) with 45.2% of participants having values >4.39 (upper 2.5th percentile among normal weight adolescents). Although baseline HOMA-IR was significantly correlated with current BMI (r = 0.48, P < 0.01), change in HOMA-IR following steroid exposure was not correlated with any demographic or treatment characteristic including current BMI. Among those with IVGTT data, HOMA estimates in general correlated with values derived from a minimal model analysis (r ~ 0.7). CONCLUSIONS: High-dose glucocorticoids given as part of routine chemotherapy were associated with a significantly increased insulin resistant state. Given the amount and duration of glucocorticoids children with ALL experience, these physiologic changes could be an important contributor to the development of therapy-related obesity. PMID- 23042767 TI - Biomarker genes highlight intraspecific and interspecific variations in the responses of Pinus taeda L. and Pinus radiata D. Don to Sirex noctilio F. acid gland secretions. AB - Sirex noctilio F., a Eurasian horntail woodwasp recently introduced into North America, oviposits in pines and other conifers and in the process spreads a phytopathogenic fungus that serves as a food source for its larvae. During oviposition the woodwasp also deposits mucus produced in its acid (venom) gland that alters pine defense responses and facilitates infection by the fungus. A 26,496-feature loblolly pine cDNA microarray was used to survey gene expression of pine tissue responding to S. noctilio venom. Six genes were selected for further assessment by quantitative real-time polymerase chain reaction (qRT-PCR), including one that encoded an apparent PR-4 protein and another that encoded a thaumatin-like protein. Expression of both was strongly induced in response to venom, while expression of an apparent actin gene (ACT1) was stable in response to the venom. The pattern of gene response was similar in Pinus taeda L. and Pinus radiata D. Don, but the magnitude of response in P. radiata was significantly stronger for each of the induced genes. The magnitude of the biomarker gene response to venom also varied according to genotype within these two species. The qRT-PCR assay was used to demonstrate that the primary bioactive component in S. noctilio venom is a polypeptide. PMID- 23042768 TI - Interacting effects of elevated CO2 and weather variability on photosynthesis of mature boreal Norway spruce agree with biochemical model predictions. AB - According to well-known biochemical and biophysical mechanisms, the stimulation of C(3) photosynthesis by elevated atmospheric CO(2) concentration ([CO(2)]) is strongly modified by changes in temperature and radiation. In order to investigate whether a static parameterization of the commonly used Farquhar et al. model of photosynthesis (i.e., without CO(2)-induced seasonal or thermal acclimation of photosynthetic capacity) can accurately predict these interactions in mature boreal Norway spruce (Picea abies (L.) Karst.) during the frost-free part of the growing season, shoot gas exchange was continuously measured on trees during their second/third year of exposure to ambient or doubled [CO(2)] inside whole-tree chambers. The relative CO(2)-induced enhancement of net photosynthesis (A(n)) at a given temperature remained stable over the study period, but increased strongly with temperature and radiation, in agreement with predictions by the model. Light-saturated A(n) (+67% at 20 degrees C), dark respiration (+36%) and intercellular to ambient [CO(2)] ratio (c(i)/c(a); +27%) were significantly increased by CO(2) treatment. Stomatal conductance (g(s)) was not significantly affected. Our results demonstrate that the Farquhar et al. model of photosynthesis has the capability to predict interactions between [CO(2)] and seasonal weather variability on A(n) in Norway spruce during the non-frost growing season without accounting for CO(2)-induced seasonal and/or thermal photosynthetic acclimation. However, stomatal model assumptions of reduced g(s) and constant c(i)/c(a) under rising atmospheric [CO(2)] did not hold. PMID- 23042769 TI - Ground-level ozone differentially affects nitrogen acquisition and allocation in mature European beech (Fagus sylvatica) and Norway spruce (Picea abies) trees. AB - Impacts of elevated ground-level ozone (O(3)) on nitrogen (N) uptake and allocation were studied on mature European beech (Fagus sylvatica L.) and Norway spruce (Picea abies [L.] Karst.) in a forest stand, hypothesizing that: (i) chronically elevated O(3) limits nutrient uptake, and (ii) beech responds more sensitively to elevated O(3) than spruce, as previously found for juvenile trees. Tree canopies were exposed to twice-ambient O(3) concentrations (2 * O(3)) by a free-air fumigation system, with trees under ambient O(3) serving as control. After 5 years of O(3) fumigation, (15)NH(4)(15)NO(3) was applied to soil, and concentrations of newly acquired N (N(labelled)) and total N (N(total)) in plant compartments and soil measured. Under 2 * O(3), N(labelled) and N(total) were increased in the bulk soil and tended to be lower in fine and coarse roots of both species across the soil horizons, supporting hypothesis (i). N(labelled) was reduced in beech foliage by up to 60%, and by up to 50% in buds under 2 * O(3). Similarly, N(labelled) in stem bark and phloem was reduced. No such reduction was observed in spruce, reflecting a stronger effect on N acquisition in beech in accordance with hypothesis (ii). In spruce, 2 * O(3) tended to favour allocation of new N to foliage. N(labelled) in beech foliage correlated with cumulative seasonal transpiration, indicating impaired N acquisition was probably caused by reduced stomatal conductance and, hence, water transport under elevated O(3). Stimulated fine root growth under 2 * O(3) with a possible increase of below ground N sink strength may also have accounted for lowered N allocation to above ground organs. Reduced N uptake and altered allocation may enhance the use of stored N for growth, possibly affecting long-term stand nutrition. PMID- 23042770 TI - Functionalized polystyrene nanoparticles trigger human dendritic cell maturation resulting in enhanced CD4+ T cell activation. AB - Nanoparticles (NP) represent a promising tool for biomedical applications. Here, sulfonate- and phosphonate-functionalized polystyrene NP are analyzed for their interaction with human monocyte-derived dendritic cells (DC). Immature dendritic cells (iDC) display a higher time- and dose-dependent uptake of functionalized polystyrene NP compared to mature dendritic cells (mDC). Notably, NP induce an enhanced maturation of iDC but not of mDC (upregulation of stimulatory molecules and cytokines). NP-triggered maturation results in a significantly enhanced T cell stimulatory capacity (increased CD4(+) T cell proliferation and IFN-gamma production), indicating a shift to a pronounced Th1 response. Immunomodulatory properties of NP may be a useful strategy for strengthening the efficacy of NP based approaches in immunotherapy. PMID- 23042771 TI - A randomized controlled trial on the efficacy of thoracic CT screening for lung cancer in non-smokers and smokers of <30 pack-years aged 50-64 years (JECS study): research design. AB - In order to assess the efficacy of lung cancer screening using low-dose thoracic computed tomography, compared with chest roentgenography, in people aged 50-64 years with a smoking history of <30 pack-years, a randomized controlled trial is being conducted in Japan. The screening methods are randomly assigned individually. The duration of this trial is 10 years. In the intervention arm, low-dose thoracic computed tomography is performed for each participant in the first and the sixth years. In the control arm, chest roentgenography is performed for each participant in the first year. The participants in both arms are also encouraged to receive routine lung cancer screening using chest roentgenography annually. The interpretation of radiological findings and the follow-up of undiagnosed nodules are to be carried out according to the guidelines published in Japan. The required sample size is calculated to be 17 500 subjects for each arm. PMID- 23042772 TI - Safety and effectiveness of gemcitabine in 260 patients with biliary tract cancer in a Japanese clinical practice based on post-marketing surveillance in Japan. AB - OBJECTIVE: Gemcitabine was approved for the treatment of biliary tract cancer in 2006 in Japan. While biliary tract cancer is usually associated with patients 70 years of age or older and/or those who tend to have underlying liver dysfunction, data on this population were limited in the Japanese Phase II study of gemcitabine. Thus, further evaluation of safety and effectiveness in this population was planned. This special post-marketing surveillance was conducted as an observational study on the use of gemcitabine in a clinical practice setting. METHODS: Gemcitabine-naive patients with biliary tract cancer were enrolled from 2006 to 2008 and observed over 12 months; one or more doses of gemcitabine were administered during the period. Data such as patient background, treatment details, adverse events occurring during the observational period, laboratory values of liver enzyme and survival status were collected 3 and 12 months after the start of therapy. RESULTS: Of the 285 patients registered for the study, 260 were included in the analysis. The mean age was 66.9 years. There were 120 patients (46.2%) classified as elderly (70 years or older). Haematotoxicities were the most common adverse drug reactions. In the elderly and the non-elderly, adverse drug reactions (serious) occurred in 48.3% (20.8%) and 50.7% (12.9%), respectively. The overall estimated 1-year survival rate was 52.5% (95% confidence interval, 45.9-58.7%). CONCLUSIONS: In line with previous clinical and post-marketing studies conducted in Japan, the results of this study suggest that gemcitabine could be used safely and effectively for biliary tract cancer patients including the elderly. PMID- 23042775 TI - Commentary on Sibinski et al. Management strategies for shoulder reconstruction in obstetric brachial plexus injury with special reference to loss of internal rotation after surgery. PMID- 23042776 TI - Commentary on Abdel-Ghani et al. Tendon transfer for treatment of internal rotation contracture of the shoulder in brachial plexus birth palsy. PMID- 23042773 TI - Autophagy and selective deployment of Atg proteins in antiviral defense. AB - Autophagy is an evolutionarily ancient process eukaryotic cells utilize to remove and recycle intracellular material in order to maintain cellular homeostasis. In metazoans, the autophagy machinery not only functions in this capacity but also has evolved to perform a diverse repertoire of intracellular transport and regulatory functions. In response to virus infections, the autophagy machinery degrades viruses, shuttles viral pathogen-associated molecular patterns to endosomes containing Toll-like receptors, facilitates viral-antigen processing for major histocompatibility complex presentation and transports antiviral proteins to viral replication sites. This is accomplished through canonical autophagy or through processes involving distinct subsets of the autophagy related genes (Atgs). Herein, we discuss how the variable components of the autophagy machinery contribute to antiviral defense and highlight three emerging themes: first, autophagy delivers viral cytosolic components to several distinct endolysosomal compartments; second, Atg proteins act alone, as subgroups or collectively; and third, the specificity of autophagy and the autophagy machinery is achieved by recognition of triggers and selective targeting by adaptors. PMID- 23042777 TI - Commentary on Murata et al. Long-term follow-up of periarterial sympathectomy for chronic digital ischaemia. PMID- 23042778 TI - Re: Manente G, Melchionda D, Staniscia T, D'Archivio C, Mazzone V, Macarini L. Changes in the carpal tunnel while wearing the Manu(r) soft hand brace: a sonographic study. J Hand Surg Eur. 2012, 1753193412446112, first published on 28 May 2012. PMID- 23042779 TI - Statue of Baron Guillaume de Dupuytren. PMID- 23042780 TI - Burke F. The formation of the Hand Club: a 60th anniversary. J Hand Surg Eur. 2012, 37: 585-9. PMID- 23042781 TI - Cochrane corner: antibiotic prophylaxis for mammalian bites (intervention review). AB - BACKGROUND: Bites by mammals are a common problem and they account for up to 1% of all visits to hospital emergency rooms. Dog and cat bites are the most common, and people are usually bitten by their own pets or by an animal known to them. School-age children make up almost a half of those bitten. Prevention of tetanus, rabies and wound infection are the priorities for staff in emergency rooms. The use of antibiotics may be useful to reduce the risk of developing a wound infection. OBJECTIVES: To determine if the use of prophylactic antibiotics in mammalian bites is effective in preventing bite-wound infection. SEARCH METHODS: Relevant randomized controlled trials (RCTs) were identified by electronic searches of MEDLINE, EMBASE, LILACS and the Cochrane Controlled Trials Register databases in November 2000. SELECTION CRITERIA: We included randomized controlled trials that studied patients with bites from all mammals. Comparisons were made between antibiotics and placebo or no intervention. The outcome of interest was the number of infections at the site of the bite. DATA COLLECTION AND ANALYSIS: Two reviewers extracted the data independently. All analyses were performed according to the intention-to-treat method. PMID- 23042782 TI - Mass-producible nano-featured polystyrene surfaces for regulating the differentiation of human adipose-derived stem cells. AB - In this study, we report an efficient and cost-effective method of fabricating polystyrene (PS) nano-featured substrates containing nanopore (NPo) and nanopillar (NPi) arrays based on hot embossing using nickel nano-stamps. We investigate the behavior of adipose-derived stem cells (ASCs), including adhesion, morphology, proliferation and differentiation, on the replicated PS surfaces. Compared to a flat substrate, NPo- and NPi-featured substrates do not alter the morphology of stem cells. However, both NPo- and NPi-featured substrates induce different integrin expression and lower formation of focal adhesion complexes. In addition, ASCs on the NPo-featured substrate exhibit greater adipogenic differentiation, while the NPi-featured substrate induces higher osteogenic differentiation. PMID- 23042783 TI - Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the Fels Longitudinal Study. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Excessive early childhood adiposity is a prevalent and increasing concern in many parts of the world. Parental obesity is one of the several factors previously associated with infant and early childhood weight, length and adiposity. Parental obesity represents a surrogate marker of the complex interplay among genetic, epigenetic and shared environmental factors, and is potentially modifiable. The relative contributions of maternal and paternal body mass index (BMI) to infant and early childhood growth, as well as the timing of such effects, have not been firmly established. WHAT THIS STUDY ADDS: Utilizing serial infant measurements and growth curve modelling, this is the largest study to fully characterize and formally compare associations between maternal and paternal BMI and offspring growth across the entire infancy and early childhood period. Maternal obesity is a stronger determinant of offspring BMI than paternal obesity at birth and from 2 to 3 years of age, suggesting that prevention efforts focused particularly on maternal lifestyle and BMI may be important in reducing excess infant BMI. The observation that maternal BMI effects are not constant, but rather present at birth, wane and re-emerge during late infancy, suggests that there is a window of opportunity in early infancy when targeted interventions on children of obese mothers may be most effective. BACKGROUND/OBJECTIVE: Parental obesity influences infant body size. To fully characterize their relative effects on infant adiposity, associations between maternal and paternal body mass index (BMI) category (normal: <=25 kg m(-2) , overweight: 25 - <30 kg m(-2) , obese: >=30 kg m(-2) ) and infant BMI were compared in Fels Longitudinal Study participants. METHODS: A median of 9 serial weight and length measures from birth to 3.5 years were obtained from 912 European American children born in 1928-2008. Using multivariable mixed effects regression, contributions of maternal vs. paternal BMI status to infant BMI growth curves were evaluated. Cubic spline models also included parental covariates, infant sex, age and birth variables, and interactions with child's age. RESULTS: Infant BMI curves were significantly different across the three maternal BMI categories (Poverall < 0.0001), and offspring of obese mothers had greater mean BMI at birth and between 1.5 and 3.5 years than those of over- and normal weight mothers (P <= 0.02). Average differences between offspring of obese and normal weight mothers were similar at birth (0.8 kg m(-2) , P = 0.0009) and between 2 and 3.5 years (0.7-0.8 kg m(-2) , P < 0.0001). Infants of obese fathers also had BMI growth curves distinct from those of normal weight fathers (P = 0.02). Infant BMI was more strongly associated with maternal than paternal obesity overall (P < 0.0001); significant differences were observed at birth (1.11 kg m(-2) , P = 0.006) and from 2 to 3 years (0.62 kg m(-2) , P3 years = 0.02). CONCLUSION: At birth and in later infancy, maternal BMI has a stronger influence on BMI growth than paternal BMI, suggesting weight control in reproductive age women may be of particular benefit for preventing excess infant BMI. PMID- 23042784 TI - Genome-wide DNA hydroxymethylation changes are associated with neurodevelopmental genes in the developing human cerebellum. AB - 5-Hydroxymethylcytosine (5-hmC) is a newly discovered modified form of cytosine that has been suspected to be an important epigenetic modification in neurodevelopment. While DNA methylation dynamics have already been implicated during neurodevelopment, little is known about hydroxymethylation in this process. Here, we report DNA hydroxymethylation dynamics during cerebellum development in the human brain. Overall, we find a positive correlation between 5 hmC levels and cerebellum development. Genome-wide profiling reveals that 5-hmC is highly enriched on specific gene regions including exons and especially the untranslated regions (UTRs), but it is depleted on introns and intergenic regions. Furthermore, we have identified fetus-specific and adult-specific differentially hydroxymethylated regions (DhMRs), most of which overlap with genes and CpG island shores. Surprisingly, during development, DhMRs are highly enriched in genes encoding mRNAs that can be regulated by fragile X mental retardation protein (FMRP), some of which are disrupted in autism, as well as in many known autism genes. Our results suggest that 5-hmC-mediated epigenetic regulation may broadly impact the development of the human brain, and its dysregulation could contribute to the molecular pathogenesis of neurodevelopmental disorders. Accession number: Sequencing data have been deposited to GEO with accession number GSE40539. PMID- 23042785 TI - Control of epigenetic states by WT1 via regulation of de novo DNA methyltransferase 3A. AB - Although tumour suppressor gene hypermethylation is a universal feature of cancer cells, little is known about the necessary molecular triggers. Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. Specifically, we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression. Consistent with this regulatory role, immunohistochemical analysis shows co-expression of WT1 and DNMT3A proteins in nuclei of blastemal cells in human fetal kidney and Wilms' tumours. Using genome-wide promoter methylation arrays, we show that human embryonal kidney cells over-expressing WT1 acquire DNA methylation changes at specific gene promoters where DNMT3A recruitment is increased, with hypermethylation being associated with silencing of gene expression. Elevated DNMT3A is also demonstrated at hypermethylated genes in Wilms' tumour cells, including a region of long-range epigenetic silencing. Finally, we show that depletion of WT1 in Wilms' tumour cells can lead to reactivation of gene expression from methylated promoters, such as TGFB2, a key modulator of epithelial-mesenchymal transitions. Collectively, our work defines a new regulatory modality for WT1 involving elicitation of epigenetic alterations which is most likely crucial to its functions in development and disease. PMID- 23042786 TI - The FTD/ALS-associated RNA-binding protein TDP-43 regulates the robustness of neuronal specification through microRNA-9a in Drosophila. AB - TDP-43 is an evolutionarily conserved RNA-binding protein currently under intense investigation for its involvement in the molecular pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 is normally localized in the nucleus, but translocated to the cytoplasm in diseased neurons. The endogenous functions of TDP-43 in the nervous system remain poorly understood. Here, we show that the loss of Drosophila TDP-43 (dTDP-43) results in an increased production of sensory bristles and sensory organ precursor (SOP) cells on the notum of some but not all flies. The location of ectopic SOPs varies among mutant flies. The penetrance of this novel phenotype is dependent on the gender and sensitive to environmental influences. A similar SOP phenotype was also observed on the wing and in the embryos. Overexpression of dTDP-43 causes both loss and ectopic production of SOPs. Ectopic expression of ALS-associated mutant human TDP-43 (hTDP-43(M337V) and hTDP-43(Q331K)) produces a less severe SOP phenotype than hTDP-43(WT), indicating a partial loss of function of mutant hTDP-43. In dTDP-43 mutants, miR-9a expression is significantly reduced. Genetic interaction studies further support the notion that dTDP-43 acts through miR-9a to control the precision of SOP specification. These findings reveal a novel role for endogenous TDP-43 in neuronal specification and suggest that the FTD/ALS associated RNA-binding protein TDP-43 functions to ensure the robustness of genetic control programs. PMID- 23042787 TI - Tracking fatty acid kinetics in distinct lipoprotein fractions in vivo: a novel high-throughput approach for studying dyslipidemia in rodent models. AB - Isotopic tracers have been used to examine lipid trafficking for many years, and data from those studies have typically yielded novel insight regarding the pathophysiology of dyslipidemia. Previous experimental designs were suitable for studies in humans because relatively large volumes of plasma could be regularly sampled. We have expanded on the earlier logic by applying high-throughput analytical methods that require reduced sample volumes. Specifically, we have examined the possibility of coupling gel-based separations of lipoproteins (e.g., lipoprint) with LC-MS/MS analyses of complex lipid mixtures as a way to routinely measure the labeling profiles of distinct lipids in discrete lipoprotein subfractions. We demonstrate the ability to measure the incorporation of [U (13)C]oleate into triglycerides (TG), PLs (PL), and cholesterol esters (CE) in VLDL, LDL, and HDL particles in mice. Although rodent models of dyslipidemia are inherently different from humans because of alterations in enzyme activities and underlying metabolism, rodent models can be used to screen novel compounds for efficacy in altering a given biochemical pathway and therein enable studies of target engagement in vivo. We expect that it is possible to translate our approach for application in other systems, including studies in humans. PMID- 23042788 TI - Low band gap donor-acceptor conjugated polymer nanoparticles and their NIR mediated thermal ablation of cancer cells. AB - Low band gap D-A conjugated PNs consisting of 2-ethylhexyl cyclopentadithiophene co-polymerized with 2,1,3-benzothiadiazole (for nano-PCPDTBT) or 2,1,3 benzoselenadiazole (for nano-PCPDTBSe) have been developed. The PNs are stable in aqueous media and showed no significant toxicity up to 1 mg . mL(-1) . Upon exposure to 808 nm light, the PNs generated temperatures above 50 degrees C. Photothermal ablation studies of the PNs with RKO and HCT116 colorectal cancer cells were performed. At concentrations above 100 ug . mL(-1) for nano-PCPDTBSe, cell viability was less than 20%, while at concentrations above 62 ug . mL(-1) for nano-PCPDTBT, cell viability was less than 10%. The results of this work demonstrate that low band gap D-A conjugated polymers 1) can be formed into nanoparticles that are stable in aqueous media; 2) are non-toxic until stimulated by IR light and 3) have a high photothermal efficiency. PMID- 23042789 TI - Nuclear transferred embryonic stem cells for analysis of B1 B-lymphocyte development. AB - The transfer of nuclei of fully differentiated cells into enucleated oocytes is a well-recognized method for the generation of embryonic stem (ES) cells. Here, we demonstrate that nuclear transferred ES (NT-ES) cells can be established with high efficiency using innate-like B lymphocytes as donor cells. We established two mouse lines carrying rearranged immunoglobulin heavy and light chains using NT-ES cells containing nuclei from peritoneal cavity B1 cells. Analysis of B1 clone lines revealed that the B1-cell generation critically depends on the interaction between antigen (possibly self-antigen) and surface immunoglobulin, while the B1-cell maintenance requires the peritoneal environment. The B1-cell expansion takes place in spleen, and is held in check by competitor B2 cells. The results indicate that the NT-ES method could replace the transgenic or knock-in mouse approaches currently used to study the biology of cells that undergo somatic rearrangements of their antigen receptor genes. PMID- 23042790 TI - Physical activity in children and adolescents with autism assessed by triaxial accelerometry. AB - OBJECTIVE: This study aimed to examine physical activity (PA) patterns in children with autism spectrum disorder (ASD) as well as to address PA determinant factors by employing triaxial accelerometry. METHODS: In a school-based cross sectional study of 80 children and adolescents with ASD (mean = 9.6, standard deviation = 1.8), we investigated demographics, children's behavioural and clinical profile, and their PA data as objectively measured using an Actigraph GT3X on the right hip for seven consecutive days. All activity measures were expressed as counts per minute (c.p.m.). RESULTS: There was a substantial reduction in activity across the adolescent years in ASD. Girls were significantly less active than boys with ASD. Participants were remarkably less active in school compared to after-school, and there was a PA decline during weekdays compared to weekends, which was not significant. Household structure, sedentary pursuits, comorbidities and obesity were identified as other determinants of PA in children with ASD. CONCLUSIONS: Given the limited objective assessment of PA in children with ASD, our findings stressed the need for improving PA programmes, particularly for girls and older children with ASD. This study also provided important information for counselling clinicians, families and school policy-makers about health issues in ASD. PMID- 23042791 TI - Antiretroviral therapy protects against frailty in HIV-1 infection. AB - HIV-1-infected patients are surviving longer and by 2015 half will be older than 50 years of age. Frailty is a syndrome associated with advanced age but occurs in HIV-1-infected patients at younger ages. One hundred outpatient HIV-1-infected persons were prospectively tested for clinical markers of frailty: shrinking weight, slowness in walking, decrease in grip strength, low activity, and exhaustion. Age, length of infection with HIV, CD4 count, HIV-1 RNA, and comorbidities were compared. CD4 counts <200 cells/mm(3) were associated with 9 fold increased odds of frailty relative to patients with a CD4 count >350 cells/mm(3) (odds ratio [OR] 9.0, 95% confidence interval [CI] 2.1-44). Seven frail patients were measured 6 months later: 2 died refusing therapy, 4 were no longer frail, and 1 patient remained frail. We conclude that frailty is common in HIV outpatients and is associated with low CD4 counts. However, our data suggest that frailty is transient, especially in younger patients who may revert to their prefrail state unlike uninfected elderly individuals in whom a stepwise decline in function occurs. PMID- 23042792 TI - More than 20 years of research into the quality of life of people with HIV and AIDS--a descriptive review of study characteristics and methodological approaches of published empirical studies. AB - BACKGROUND: The quality of life of people living with HIV and AIDS (PLWHA) is becoming increasingly important--a fact that is also reflected in extensive research efforts. Owing to the almost complete lack of systematic integration of research findings, it is hardly possible to provide an overview of the current status of research, or to derive valid statements about research results. METHODS: A literature search regarding the quality of life of PLWHA was performed in two international research databases. After checking their relevance, 852 publications appearing in scientific journals and explicitly measuring the quality of life of PLWHA were categorized on the basis of various study characteristics. RESULTS: The number of publications per year in our study pool has been rising steadily since 1989. Well over 40 established instruments were used to determine the quality of life, most frequently the MOS-HIV, followed by the SF-36. The great majority of the studies are correlation studies. CD4 cells, gender, and age are the most common variables for which correlations with quality of life are reported. CONCLUSIONS: Our descriptive review stresses both the increasing significance and the challenges of research into quality of life of PLWHA such as the great variety of instruments used. The limits of this review are discussed and we conclude with the formulation of research desiderata concerning comparative review studies on instruments and systematic reviews of frequent research questions. PMID- 23042793 TI - Cohort profile: The Stockholm Public Health Cohort. AB - The Stockholm Public Health Cohort was set up within the Stockholm County Council public health surveys to inform on determinants and consequences of significant contributors to the current burden of disease. Participants are 89 268 randomly selected individuals from the adult population of Stockholm County. Baseline surveys took place in 2002, 2006 and 2010 via self-administered questionnaires. So far, participants recruited in 2002 were re-surveyed twice, in 2007 and 2010, and those enrolled in 2006 were re-surveyed once, in 2010. Self-reported data are regularly supplemented by information from national and regional health data and administrative registers, for study participants and their relatives (including their offspring). Available data are extensive and include a wide array of health, lifestyle, perinatal, demographic, socio-economic and familial factors. The cohort is an international resource for epidemiological research, and the data available to the research community for specific studies obtained approval from the Stockholm Public Health Cohort Steering Committee and the Stockholm Regional Ethical Review Board. PMID- 23042794 TI - Unbiased label-free quantitative proteomic profiling and enriched proteomic pathways in seminal plasma of adult men before and after varicocelectomy. AB - STUDY QUESTION: Does the seminal plasma proteomic profile and functional enrichment of gene ontology terms change after microsurgical varicocelectomy? Are there any potential targets for diagnosis or therapeutic intervention in varicocele? SUMMARY ANSWER: A shift in state from a responsive-to-stress condition before varicocele correction to a responsive-to-environment condition after varicocelectomy was observed in enriched proteomic pathways. WHAT IS KNOWN ALREADY: Varicocele may lead to many adverse effects, including failure of testicular growth and development, and is associated with decreased semen quality and increased semen oxidative stress. Varicocelectomy is the treatment of choice, and is associated with improved semen quality, but little is known regarding the underlying molecular mechanisms and post-genomic pathways following intervention. STUDY DESIGN, SIZE, DURATION: A prospective study was carried out including 18 adult men with varicocele. These patients provided one semen sample before they were submitted for bilateral varicocele repair through microsurgical varicocelectomy, and one other semen sample 90 days after the surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS: An aliquot of each semen sample was used for unbiased proteomics analysis by a label-free quantitative approach (2D nanoUPLC-ESI-MS(E)). Samples were pooled according to group (normalized to protein content) and run in quadruplicate. These quadruplicate runs provided degrees of freedom in order to compare groups using a non-parametric Mann-Whitney test for quantified proteins. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 316 proteins were quantified or identified, of which 91 were exclusively identified or quantified in one of the groups (53 in the pre- and 38 in the post varicocelectomy group), and 68 were quantified in both groups and submitted to statistical analysis, of which 5 were overrepresented in the pre-varicocelectomy group (P < 0.05). In enriched functional analysis, binding and response to stimulus functions were enriched in a common cluster (present in both groups), nitric oxide metabolism and tetratricopeptide repeat domain-binding functions were enriched in the pre-varicocelectomy group, and response to reactive oxygen species, gluconeogenesis, nicotinamide adenine dinucleotide-binding and protein stabilization were enriched in the post-varicocelectomy. LIMITATIONS, REASONS FOR CAUTION: Because a shotgun proteomics analysis was chosen in order to generate a list of putative biomarkers, a targeted follow-up study should be performed to confirm these biomarkers. WIDER IMPLICATIONS OF THE FINDINGS: The proteins found in both groups possess functions usually found in human semen. The enriched function analysis demonstrated a shift back to homeostasis after varicocelectomy, suggesting that varicocele correction promotes return of semen to a physiological state. STUDY FUNDING/COMPETING INTEREST(S): The funding for this project was received from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) as a scholarship for Ms Camargo. There was no conflict of interest. PMID- 23042795 TI - Aberrant DNA methylation of imprinted loci in human spontaneous abortions after assisted reproduction techniques and natural conception. AB - STUDY QUESTION: Do assisted reproduction techniques (ARTs) affect DNA methylation of imprinted genes and does aberrant methylation of imprinted genes account for the incidence of human spontaneous abortion (SA)? SUMMARY ANSWER: Our results show that imprinting errors of imprinted genes may contribute to human SA, and the occurrence of aberrant methylation of imprinted genes in ART pregnancies was comparable with that in natural pregnancies. WHAT IS KNOWN ALREADY: Animal data and human studies demonstrated that in vitro culture of embryos can cause methylation defects in individual genes, which might affect subsequent embryonic development and contribute to SA. However, our previous studies showed an abnormal methylation pattern of PEG1 in human aborted chrionic villus samples (CVS) but an increased occurrence of aberrant methylation in CVS from ART-derived pregnancies was not observed. STUDY DESIGN, SIZE AND DURATION: CVS were collected from women who underwent abortion procedures in the Department of Gynecology and Obstetrics in Nanfang Hospital from May 2008 to July 2011. Muscle samples (MS) were obtained from aborted fetuses and stillbirths. The samples were divided into four experimental groups: (A) SA/stillbirth after ART (n = 75), (B) multi-fetal reduction after ART (n = 73), (C) SA/stillbirth of natural pregnancies (n = 90) and (D) induced abortion (IA) of natural pregnancies (n = 82). PARTICIPANTS/MATERIALS, SETTING AND METHODS: The mean +/- SD age of patients was 31.0 +/- 4.1 (range: 18-45 years). The DNA methylation patterns of one paternally methylated (H19) and two maternally methylated (LIT1 and SNRPN) genes were analyzed in CVS and MS using pyrosequencing and bisulfite sequencing PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Clear hypo-methylation (<10%) or hyper methylation (>90%) were not detected in LIT1 and SNRPN but two regions of hyper methylation (91.7 and 91.4%) were observed in H19. The mean percentage of methylation in the SA samples (groups A and C) was higher than that in the IA samples (groups B and D; P<0.05). Box plot analyses showed that in the 165 SA samples, methylation values for 40/495 (8.1%) differentially methylated regions of the three genes represented outliers. The incidence of outlier was highest for LIT1 (13.3%, 22/165). In contrast, no outliers were found in the 155 IA samples. The receiver operating characteristic curve analyses showed a positive correlation between percentage methylation of all three genes and incidence of SA (P<0.05). In addition, the conception modes (natural versus ART) and the fertilization methods used in ART (IVF and ICSI) did not affect the methylation patterns of the imprinted genes. No increase in the rate of abnormal methylation was found in the ART samples. LIMITATIONS AND REASONS FOR CAUTION: The studied loci represent only a small fraction of developmentally important genes. Further studies are needed to evaluate changes in the expression and the methylation status of other genes that may lead to SA. WIDER IMPLICATIONS OF THE FINDINGS: The findings provide new insights into the etiology of human SA. The possibility that the abnormal methylation seen is a consequence of the defect that led to the SA cannot be excluded. STUDY FUNDING/COMPETING INTEREST(S): None of the authors has any competing interest. This study was supported by National Natural Science Foundation of China (81170574), The National Key Basic Research Development Plan of China (973 Program) (2007CB948104), Comprehensive strategic sciences cooperation projects of Guangdong Province and Chinese Academy (04020416) and Guangzhou Science and Technology Program key projects (11C22120737). PMID- 23042796 TI - Comparison of the obstetric and perinatal outcomes of children conceived from in vitro or in vivo matured oocytes in in vitro maturation treatments with births from conventional ICSI cycles. AB - STUDY QUESTION: Are the obstetric and perinatal outcomes of deliveries following in vitro maturation (IVM) cycles different from births generated from controlled ovarian stimulation (COS) cycles? SUMMARY ANSWER: The obstetric and perinatal outcomes of births from IVM cycles are comparable with those of ICSI treatments, including the incidence of major and minor abnormalities. WHAT IS KNOWN ALREADY: Only few and numerically small reports on the health of IVM children are currently available. STUDY DESIGN, SIZE AND DURATION: Retrospective cohort study involving 196 babies born from IVM cycles carried out with different priming regimens. Of these children, 79 developed from oocytes matured in vitro after 30 h of culture, while 104 originated from oocytes found mature and inseminated on the day of recovery. Thirteen babies were obtained from embryos developed from both types of oocytes. Data of these births were compared with those of 194 children born from COS ICSI cycles performed during the same period (March 2004 to December 2011). PARTICIPANTS/MATERIALS, SETTING AND METHODS: IVM cycles were done in the absence of gonadotrophin administration or with FSH and/or HCG priming. All oocytes were inseminated by microinjection. ICSI and ICSI cycles were chosen as a control group to exclude possible influences of the insemination technique. Couples in which maternal age was >39 years or affected by azoospermia were excluded to rule out major parental effects. MAIN RESULTS AND THE ROLE OF CHANCE: In single births, gestational age at delivery was comparable, but birthweight was significantly higher (P = 0.009) in children from IVM cycles (3091 +/- 669 versus 3269 +/- 619 g). In a separate analysis of the IVM group, comparing singleton births derived with certainty from oocytes matured in vitro (n = 71) or in vivo (n = 74), no statistically significant differences were observed in terms of birthweight (3311 +/- 637 versus 3194 +/- 574 g, respectively) and gestational age (38.9 +/- 2.4 versus 38.4 +/- 2.1 weeks, respectively). In twin births, gestational age was lower in IVM cycles, while weight at birth was comparable (ICSI, 2432 +/- 540 g; IVM, 2311 +/- 577 g). In single births, major and minor abnormalities were 2 (1.4%) and 6 (4.1%) in the ICSI group and 0 (0.0%) and 8 (5.2%) in the IVM category, respectively. In twin children, major and minor abnormalities were 1 (2.2%) and 2 (4.3%) in ICSI babies and 0 (0.0%) and 2 (4.6%) in IVM cycles, respectively. LIMITATIONS AND REASONS FOR CAUTION: The study is the largest conducted so far. Nevertheless, it is limited by its retrospective nature and the fact that most births of IVM treatments derived from oocytes found mature at recovery in cycles primed with HCG. A more comprehensive appraisal of the health status of IVM children will demand larger prospective studies. WIDER IMPLICATIONS OF THE FINDINGS: The study is consistent with previous reports suggesting a possible role of standard ovarian stimulation in determining a reduced birthweight in children born from COS cycles. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought to support this work. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 23042797 TI - Evaluation of a diabetes care program using the effective coverage framework. AB - OBJECTIVE: To measure the effective coverage of a program to control type 2 diabetes. DESIGN: Observational study combining multiple DATA SOURCES: SETTING: Hidalgo state, Mexico. PARTICIPANTS: Adults without social security health benefits and patients with a diagnosis of diabetes participating in the program. MAIN OUTCOME MEASURES: Detection of diabetes; glucose, cholesterol, triglyceride and blood pressure control; education; diabetic retinopathy, diabetic foot and nephropathy prevention. RESULTS: Only 7.1% of individuals with diabetes participated in the control program. Fasting glucose and HbA1c values were available for 95.6 and 35.6 of patients, respectively. There were measurements of total cholesterol (52.1%), triglyceride (50.6%) and blood pressure (99.6%). Educative activities were realized for 64.8% of patients. The most important gaps were related with detection of illness, low-density lipoprotein cholesterol control, glucose control with HbA1c and nephropathy prevention. Effective coverage of these medical actions was 6.22, 5.07, 5.01 and 0.34%, respectively. CONCLUSIONS: The greatest challenge to overcome is the detection of individuals with illness because a large number of individuals with type 2 diabetes do not use health services and the health system does not systematically search them out. Medical actions that require resources that must be paid for by patients tend to be used less and to be of lower quality. The use of effective coverage to measure the performance of diabetes care program provides practical information to improve health services. PMID- 23042798 TI - Infertility and the risk of adverse pregnancy outcomes: a systematic review and meta-analysis. AB - STUDY QUESTION: Do women who conceive without treatment after a long time to pregnancy (TTP) have an increased risk of preterm birth compared with women in the general obstetric population? SUMMARY ANSWER: Based on this meta-analyses of 14 studies, women with a long TTP are at an increased risk of preterm birth: pooled crude odds ratio (OR): 1.38 (95% CI: 1.25-1.54). WHAT IS KNOWN ALREADY: Several studies have shown that women who conceive without treatment after >12 months of trying have an elevated risk of poor pregnancy outcomes. To date, no systematic review or meta-analysis of this evidence has been published. STUDY DESIGN, SIZE, DURATION: This systematic review identified literature from Embase, Medline and Popline published between January 1974 and October 2011, on the association between infertility in a non-treated population and the risk of preterm birth, low birthweight (LBW), small-for-gestational age and birthweight deficits. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two authors independently conducted the searches, selected the studies and abstracted the data. A total of 89 full-text articles were assessed for eligibility and 17 met the inclusion criteria. The pooled analysis of the primary outcome led to a total sample size of 1 269 758 births: 19 983 in the exposed/infertile group and 1 249 775 in the unexposed/fertile group. There were a total 68 885 preterm births in the overall sample: 1644 (8.2%) and 67 241 (5.4%) among the infertile and reference groups, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: A moderate increase in the risk of preterm birth persisted irrespective of the type of pooling. The common OR of the pooled crude preterm birth data compared with the pooled regression adjusted analysis was modestly attenuated: from 1.38 (95% CI: 1.25, 1.54) to 1.31 (95% CI: 1.21, 1.42), with I2 decreasing from 53.2 to 3.9% in the crude to adjusted results, respectively. An association of a similar magnitude was seen between infertility and LBW, due in part to overlapping of outcomes. LIMITATIONS, REASONS FOR CAUTION: Consistency of the estimates across various types of pooling, including the more restricted sensitivity analyses of higher quality studies, is reassuring. While it is possible that systematic error may have been present through misclassification of exposure and confounding, these findings suggest that it would need to be of the same magnitude across diverse studies, which seems unlikely. WIDER IMPLICATIONS OF THE FINDINGS: A long TTP is only a symptom, research is needed to assess whether specific groups of infertile couples are at increased risk of adverse outcome, or whether the increased risk is due to characteristics common to most infertile couples. As long as the contribution of infertility is not clarified, the risks due to assisted reproductive technologies cannot be properly assessed. STUDY FUNDING/COMPETING INTEREST(S): C.M. was supported by a Canadian Institutes of Health Research doctoral research award at the time of this study. No competing interests are declared. PMID- 23042799 TI - Elemental composition of human semen is associated with motility and genomic sperm defects among older men. AB - BACKGROUND: Older men tend to have poorer semen quality and are generally at higher risks for infertility and abnormal reproductive outcomes. METHODS: We employed proton-induced X-ray emission (PIXE, 3 MeV proton beam) to investigate the concentrations of zinc, copper, calcium, sulfur, chlorine, potassium, titanium, iron and nickel in washed sperm and seminal plasma from non-smoking groups of 10 older men (65-80 years old) and 10 younger men (22-28 years old) who were concurrently assayed for sperm function and genomicly defective sperm. RESULTS: The older group showed elevated zinc, copper and calcium in sperm and elevated sulfur in seminal plasma compared with the younger men. The older group also showed reduced motility as well as increased sperm DNA fragmentation, achondroplasia mutations, DNA strand breaks and chromosomal aberrations. Sperm calcium and copper were positively associated with sperm DNA fragmentation (P < 0.03). Seminal sulfur was positively associated with sperm DNA fragmentation and chromosomal aberrations (P < 0.04), and negatively associated with sperm motility (P < 0.05). Sperm calcium was negatively associated with sperm motility, independent of male age (P = 0.01). CONCLUSIONS: We identified major differences in elemental concentrations between sperm and seminal plasma and that higher sperm copper, sulfur and calcium are quantitatively associated with poorer semen quality and increased frequencies of genomic sperm defects. PMID- 23042801 TI - Genotoxic stresses and protein modifications. PMID- 23042800 TI - Combined endovascular treatment of aorto-oesophageal fistula with mediastinitis. AB - False aortic aneurysm is an uncommon complication after oesophageal perforation and results in a high rate of mortality. A 63-year-old patient presented with acute chest pain. Biochemical tests (cardiac enzymes) and electrocardiogram were normal. A thoracic and abdominal CT scan was performed, and showed a foreign body in the posterior mediastinum, with mediastinal cellulitis and a false aortic aneurysm. Surgical endovascular management was performed, with stenting of the thoracic aorta and oesophageal exploration. PMID- 23042802 TI - Shotgun and targeted proteomics reveal that pre-surgery serum levels of LRG1, SAA, and C4BP may refine prognosis of resected squamous cell lung cancer. PMID- 23042803 TI - Diagnosis and management of the epilepsies in children: a summary of the partial update of the 2012 NICE epilepsy guideline. AB - The epilepsies of childhood are a heterogeneous group of disorders with different causes, treatments and outcomes. The choice of anti-epileptic drug is largely determined by its effectiveness in a specific epilepsy syndrome, or seizure type(s) if a syndrome cannot be readily identified, and the drug's safety profile. There are minimal randomised controlled trial data to help inform this decision. In January 2012, the National Institute for Health and Clinical Excellence (NICE) published its partially revised and updated clinical guideline on the pharmacological treatment of the epilepsies in children and adults. This partial update provides additional data and also specific recommendations that improve the evidence base for the use of specific anti-epileptic drugs in treating the epilepsies of childhood. PMID- 23042804 TI - The spectrum of sleep-disordered breathing symptoms and respiratory events in infants with cleft lip and/or palate. AB - OBJECTIVE: To determine the prevalence of sleep-disordered breathing (SDB) symptoms and respiratory events during sleep in infants with cleft lip and/or palate (CL/P). DESIGN: Prospective observational study. SETTING: Cleft palate clinic, tertiary care paediatric hospital, before palate surgery. PATIENTS: Consecutive newborn infants with CL/P. MAIN OUTCOME MEASURES: Demographics, clinical history, sleep symptoms, facial measurement and polysomnography (PSG; sleep study) data. RESULTS: Fifty infants completed PSG at 2.7+/-2.3 months; 56% were male, and 30% had a clinical diagnosis of Pierre Robin sequence (PRS) or a syndrome. The majority of infants (75%) were reported to snore frequently or constantly, while 74% were reported to have heavy or loud breathing during sleep. The frequency of parent-reported difficulty with breathing during sleep was 10% for infants with isolated CL/P, 33% for those with syndrome, and 43% for PRS (chi(2) 16.1, p<0.05). All infants had an Obstructive-Mixed Apnoea-Hypopnoea Index (OMAHI) >1 event/h, and 75% had an OMAHI >3 events/h. Infants with PRS had higher OMAHI (34.3+/-5.1) than infants with isolated CL/P (7.6+/-1.2) or infants with syndromes (15.6+/-5.7, F stat, p<0.001). Multivariate analysis showed that PRS was associated with higher OMAHI (B 0.53+/-0.22, p=0.022), but the majority of the variance for SDB was unexplained (constant B 1.31+/-0.55, p=0.024). CONCLUSIONS: The results highlight that infants across the spectrum of CL/P have a high risk of SDB symptoms and obstructive respiratory events before palate surgery. Clinicians should enquire about symptoms of SDB and consider investigation with polysomnography in all infants with CL/P. PMID- 23042805 TI - Estrogen receptor-alpha, RBCK1, and protein kinase C beta 1 cooperate to regulate estrogen receptor-alpha gene expression. AB - Estrogen receptor alpha (ERalpha) is initially overexpressed in two-thirds of all breast cancers and is involved in its development and proliferation. We previously reported that the RanBP-type and C3HC4-type zinc finger containing 1 (RBCK1) interacts with the ERalpha promoter and that RBCK1 expression positively correlates with ERalpha levels, expression of ERalpha downstream target genes, and proliferation of breast cancer cells. Based on this, and that RBCK1 positively correlates with ERalpha expression in breast cancer samples, we propose RBCK1 as a potential therapeutic target in breast cancer acting as a modulator of ERalpha expression. To further explore this, the molecular mechanism by which RBCK1 regulates ERalpha expression has to be defined. Here, we show that ERalpha, RBCK1, and the RBCK1-interacting protein protein kinase C beta 1 (PKCbeta(I)) co-occupy a previously identified ERalpha binding region in the proximal ERalpha promoter. We describe a number of mechanistic details of this complex including that RBCK1 recruitment to the ERalpha promoter B is facilitated by ERalpha, which in turn facilitates PKCbeta(I) recruitment and PKCbeta(I) dependent histone modifications. Furthermore, ERalpha regulation of its own mRNA expression is facilitated by RBCK1 recruitment, suggesting an ERalpha coactivator function of RBCK1. The interaction between RBCK1 and ERalpha was dependent on the E3 ubiquitin ligase domain of RBCK1 and the activating function-1 domain of ERalpha. The ligand-binding function of ERalpha does not influence the interaction with RBCK1. In summary, our data provide insight into the molecular mechanism by which ERalpha expression is modulated in breast cancer cells. PMID- 23042807 TI - Sequential multiple methods as a contemporary method in learning disability nursing practice research. AB - This paper explores and advocates the use of sequential multiple methods as a contemporary strategy for undertaking research. Sequential multiple methods involve the use of results obtained through one data collection method to determine the direction and implementation of subsequent stages of a research project (Morse, 1991; Morgan, 1998). This paper will also explore the significance of how triangulating research at the epistemological, theoretical and methodological levels could enhance research. Finally the paper evaluates the significance of sequential multiple method in learning disability nursing research practice. PMID- 23042808 TI - Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. AB - Community-based studies suggest that cannabis products that are high in Delta9 tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600 mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases >= 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (chi2=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6 +/- 18.9%) compared with the CBD group (-0.4% +/- 9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health. PMID- 23042809 TI - Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus. AB - BACKGROUND: Human congenital non-syndromic hydrocephalus is a vastly heterogeneous condition. A subgroup of cases are not secondary to a specific cause (eg, a neural tube defect), and within this subgroup, autosomal recessive inheritance has been described. One homozygous mutation in the DAPLE (Dvl associating protein with a high frequency of leucine residues) protein-encoding gene CCDC88C (coiled-coil domain containing 88C) has recently been reported in a single family. The role of this gene has not been validated in another family, and no other autosomal recessive gene has been reported. METHODS: We used homozygosity mapping and whole exome sequencing in two families with primary, non syndromic congenital hydrocephalus from two different ethnic backgrounds. RESULTS: In each family, we identified a novel homozygous mutation of CCDC88C. One mutation produced a premature stop codon at position 312 of the protein, while the second mutation induced a frameshift in the last exon, producing a stop codon that truncated the extreme C-terminus of DAPLE, including the 2026-2028 Gly Cys-Val motif known to bind the post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) (PDZ) domain of Dishevelled. CONCLUSIONS: Our data validate CCDC88C as causing autosomal recessive, primary non-syndromic congenital hydrocephalus, suggesting this gene may be an important cause of congenital hydrocephalus, and underscore the important role of the C-terminal PDZ domain-binding motif in the DAPLE protein. PMID- 23042810 TI - Epigenetic state and expression of imprinted genes in umbilical cord correlates with growth parameters in human pregnancy. AB - BACKGROUND: Genomic imprinting is a process causing genes to be expressed according to parental origin. Imprinting acts to coordinate fetal and prenatal growth, as well as control postnatal adaptations. Studies on human imprinting are confounded by tissue availability, sampling variability and limitations posed by tissue-specific expression and cellular heterogeneity within tissues. The human umbilical cord is an easily available, embryonic-derived fetal tissue with the potential to overcome many of these limitations. METHODS: In a sensitive, gene specific quantitative expression analysis, we show for the first time robust imprinted gene expression combined with methylation analysis in cords isolated from Asian Chinese full-term births. RESULTS: Linear regression analyses revealed an inverse correlation between expression of pleckstrin homology-like domain, family A, member 2 (PHLDA2) with birth weight (BW). Furthermore, we observed significant down-regulation of the paternally expressed gene 10 (PEG10) in low BW babies compared to optimum BW babies. This change in PEG10 gene expression was accompanied by concomitant methylation alterations at the PEG10 promoter. CONCLUSIONS: These data are the first to demonstrate relative expression of an imprinted gene associated with epigenetic changes in non-syndromic fetal growth restriction in babies. They show that perturbed expression in compromised fetal growth may be associated with in utero modulation of the epigenetic state at the imprinting control regions and implicate specific imprinted genes as new biomarkers of fetal growth. PMID- 23042811 TI - Co-occurrence of recurrent duplications of the DiGeorge syndrome region on both chromosome 22 homologues due to inherited and de novo events. AB - BACKGROUND: Genomic rearrangements usually involve one of the two chromosome homologues. Homozygous microdeletion/duplication is very rare. The chromosome 22q11.2 region is prone to recurrent rearrangements due to the presence of low copy repeats. A common 3 Mb microdeletion causes the well-characterised DiGeorge syndrome (DGS). The reciprocal duplication is associated with an extremely variable phenotype, ranging from apparently normal to learning disabilities and multiple congenital anomalies. METHODS AND RESULTS: We describe duplications of the DGS region on both homologues in five patients from three families, detected by array CGH and confirmed by both fluorescence in situ hybridisation and single nucleotide polymorphism arrays. The proband in the first family is homozygous for the common duplication; one maternally inherited and the other a de novo duplication that was generated by nonallelic homologous recombination during spermatogenesis. The 22q11.2 duplications in the four individuals from the other two families are recurrent duplications on both homologues, one inherited from the mother and the other from the father. The phenotype in the patients with a 22q11.2 tetrasomy is similar to the features seen in duplication patients, including cognitive deficits and variable congenital defects. CONCLUSIONS: Our studies that reveal phenotypic variability in patients with four copies of the 22q11.2 genomic segment, demonstrate that both inherited and de novo events can result in the generation of homozygous duplications, and further document how multiple seemingly rare events can occur in a single individual. PMID- 23042812 TI - Unique genes identified in the epidemic extremely drug-resistant KPC-producing Klebsiella pneumoniae sequence type 258. AB - OBJECTIVES: A KPC-producing Klebsiella pneumoniae clone, sequence type (ST) 258, has emerged and spread worldwide. This study aimed to identify putative genes that may contribute to the extraordinary dissemination of the KPC-producing ST258 clone. METHODS: A suppressive subtractive hybridization (SSH) library was constructed using two KPC-producing strains: an epidemic ST258 and a non-epidemic ST376. The fragments obtained were sequenced, analysed and their presence among 27 additional ST258 isolates and 21 isolates of non-epidemic STs was determined. The functions of the putative proteins were extracted from NCBI databases. Localization to plasmid/chromosome was determined by PCR after transformation and by Southern hybridization. In silico homologues for the subtractive fragments were searched among sequences available in the NCBI database. RESULTS: SSH yielded 42 fragments (50 proteins) specific to the ST258 isolate tested, 30 of them located on various plasmids. The ST258 strains examined could be divided into two groups, one in which all 50 genes were ubiquitous and another group that lost 11 fragments, all located on one of the plasmids. This group of 50 genes was absent among other STs tested. Nineteen genes were unique to ST258 strains and 17 to CC258 (where CC stands for clonal complex). Most of the deduced proteins belonged to two major functional groups: 15 to the cell motility and secretion group, and 14 to the DNA repair and modification group. CONCLUSIONS: This study identifies unique genes in ST258 bacteria that may contribute to its epidemiological success as compared with other KPC-producing STs. Conservation of plasmid-encoded genes among ST258 isolates, despite plasmid variation, supports their importance in the success of this clone. PMID- 23042813 TI - Enhancement by novel anti-methicillin-resistant Staphylococcus aureus compound HT61 of the activity of neomycin, gentamicin, mupirocin and chlorhexidine: in vitro and in vivo studies. AB - OBJECTIVES: Previously, we described a small quinoline-derived compound that exhibited selective bactericidal activity against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). It depolarizes the bacterial cell membrane. In this study, we investigated if HT61 was able to enhance the potency of other antibiotics, namely neomycin, gentamicin and mupirocin, and an antiseptic, namely chlorhexidine, against clinical isolates of MSSA and MRSA in vitro and in vivo. METHODS: The MICs were determined by the broth microdilution method. The effect of combinations was examined using the chequerboard method and time-kill curves. A murine skin infection model was used to evaluate the enhancement by HT61 of other antimicrobials. RESULTS: Using the fractional inhibitory concentration index, no interaction was seen in both MSSA and MRSA for the pair HT61 and gentamicin or the pair HT61 and neomycin. Synergism was seen for 65% of both MSSA and MRSA when HT61 was combined with chlorhexidine. There was also no interaction between HT61 and mupirocin. Time kill analysis demonstrated significant synergistic activities when a low level of HT61 was combined with neomycin, gentamicin or chlorhexidine. The effect was more dramatic against non-multiplying bacteria against which the antimicrobials used were inactive on their own. Significant synergistic effects were also seen on mouse infected skin. CONCLUSIONS: We demonstrate that HT61, developed as a topical agent, acts as an enhancer that accelerates the activities of other antimicrobial agents against both MSSA and MRSA. PMID- 23042814 TI - ACE I/D and eNOS E298D gene polymorphisms in Saudi subjects with hypertension. AB - BACKGROUND: Hypertension has a multifactorial background based on genetic and environmental interactive factors. OBJECTIVES: We aimed to test for the association of the angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS) gene polymorphisms with hypertension. SUBJECTS AND METHODS: Participants included 120 Saudi patients with hypertension and 250 normal healthy controls. For all participants, DNA was processed for characterization of ACE I/D and eNOS E298D gene polymorphisms. RESULTS: Hypertensive cases showed a significantly higher frequency of the ACE mutant D allele carriage (98.3% vs. 92.4%, p = 0.028, OR = 4.8). Cases with hypertension associated with diabetes and obesity showed 100% mutant D allele carriage. Regarding the eNOS E298D polymorphism, the frequency of the mutant D allele carriage was only observed to be higher among cases with hypertension associated with diabetes and obesity, in comparison with controls, yet not reaching statistical significance (41.2% vs. 34%, p > 0.05). CONCLUSIONS: There is increased frequency of ACE and eNOS mutant allele carriage among Saudi patients affected with hypertension, particularly if accompanied by obesity and diabetes. PMID- 23042815 TI - Loss of Id3 increases VCAM-1 expression, macrophage accumulation, and atherogenesis in Ldlr-/- mice. AB - OBJECTIVE: Inhibitor of differention-3 (Id3) promotes B cells homing to the aorta and atheroprotection in Apoe(-/-) mice. We sought to determine the impact of loss of Id3 in the Ldlr((-/-)) mouse model of diet-induced atherosclerosis and identify novel Id3 targets in the vessel wall. METHODS AND RESULTS: Ex vivo optical imaging confirmed that Id3((-/-)) Ldlr((-/-)) mice have significantly fewer aortic B cells than Id3((+/+)) Ldlr(-/-) mice. After 8 and 16 weeks of Western diet, Id3((-/-)) Ldlr((-/-)) mice developed significantly more atherosclerosis than Id3((+/+)) Ldlr((-/-)) mice, with Id3(+/-) Ldlr(-/-) mice demonstrating an intermediate phenotype. There were no differences in serum lipid levels between genotypes. Immunostaining demonstrated that aortas from Id3((-/-)) Ldlr((-/-)) mice had greater intimal macrophage density and C-C chemokine ligand 20 and vascular cell adhesion molecule 1 (VCAM-1) expression compared with Id3((+/+)) Ldlr(-/-) mice. Real-time polymerase chain reaction demonstrated increased VCAM-1 mRNA levels in the aortas of Id3(-/-) Ldlr(-/-) mice. Primary vascular smooth muscle cells from Id3((-/-)) mice expressed greater amounts of VCAM-1 protein compared with control. Gain and loss of function studies in primary vascular smooth muscle cells identified a role for Id3 in repressing VCAM 1 promoter activation. Chromatin immunoprecipitation demonstrated interaction of E12 with the VCAM-1 promoter, which is inhibited by Id3. CONCLUSIONS: Id3 is an atheroprotective transcription regulator with targets in both B cells and vessel wall cells leading to reduced macrophage accumulation and reduced atherosclerosis formation. PMID- 23042816 TI - Cholesterol accumulation regulates expression of macrophage proteins implicated in proteolysis and complement activation. AB - OBJECTIVE: Cholesterol accumulation by macrophages plays a key role in atherogenesis. To begin to develop a global picture of this process, we used proteomics and transcriptomics to analyze foam cells generated with acetyl-low density lipoprotein, a classic ligand for scavenger receptors. METHODS AND RESULTS: Tandem mass spectrometry and stringent statistical analysis revealed that foam cells differentially expressed 15 of 542 proteins (2.8%) detected in macrophage-conditioned medium. Apolipoprotein E was one of the most upregulated proteins, confirming that proteins involved in lipid metabolism are important targets for regulation by sterol accumulation. However, levels of proteins linked to complement activation and lysosomal proteolysis also changed markedly. Transcriptional analysis demonstrated that 698 of 19,700 genes (3.5%) were regulated in foam cells, including many genes important in sterol metabolism. We also found that cholesterol accumulation regulated genes implicated in complement activation but failed to affect genes linked to proteolysis and macrophage polarization. Changes in protein levels in macrophage-conditioned medium were largely independent of changes in mRNA levels. CONCLUSIONS: Loading sterol into macrophages regulates levels of complement proteins and lysosomal proteases-key players in the immune system and plaque rupture. Posttranscriptional mechanisms are likely important for controlling levels of most of the proteins detected in macrophage medium. PMID- 23042817 TI - Kruppel-like factor-11, a transcription factor involved in diabetes mellitus, suppresses endothelial cell activation via the nuclear factor-kappaB signaling pathway. AB - OBJECTIVE: Endothelial cell (EC) inflammatory status is critical to many vascular diseases. Emerging data demonstrate that mutations of Kruppel-like factor-11 (KLF11), a gene coding maturity-onset diabetes mellitus of the young type 7 (MODY7), contribute to the development of neonatal diabetes mellitus. However, the function of KLF11 in the cardiovascular system still remains to be uncovered. In this study, we aimed to investigate the role of KLF11 in vascular endothelial inflammation. METHODS AND RESULTS: KLF11 is highly expressed in vascular ECs and induced by proinflammatory stimuli. Adenovirus-mediated KLF11 overexpression inhibits expression of tumor necrosis factors-alpha-induced adhesion molecules. Moreover, small interfering RNA-mediated KLF11 knockdown augments the proinflammatory status in ECs. KLF11 inhibits promoter activity of adhesion molecules induced by tumor necrosis factor-alpha and nuclear factor-kappaB p65 overexpression. Mechanistically, KLF11 potently inhibits nuclear factor-kappaB signaling pathway via physical interaction with p65. Furthermore, KLF11 knockdown results in increased binding of p65 to vascular cell adhesion molecule-1 and E selectin promoters. At the whole organism level, KLF11(-/-) mice exhibit a significant increase in leukocyte recruitment to ECs after lipopolysaccharide administration. CONCLUSIONS: Taken together, our data demonstrate for the first time that KLF11 is a suppressor of EC inflammatory activation, suggesting that KLF11 constitutes a novel potential molecular target for inhibition of vascular inflammatory diseases. PMID- 23042819 TI - Microvascular dysfunction is associated with a higher incidence of type 2 diabetes mellitus: a systematic review and meta-analysis. AB - OBJECTIVE: Recent data support the hypothesis that microvascular dysfunction may be a potential mechanism in the development of insulin resistance. We examined the association of microvascular dysfunction with incident type 2 diabetes mellitus (T2DM) and impaired glucose metabolism by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic. METHODS AND RESULTS: We searched Medline and Embase for articles published up to October 2011. Prospective cohort studies that focused on microvascular measurements in participants free of T2DM at baseline were included. Pooled relative risks were calculated using random effects models. Thirteen studies met the inclusion criteria for this meta-analysis. These studies focused on T2DM or impaired fasting glucose, not on impaired glucose tolerance. The pooled relative risks for incident T2DM (3846 cases) was 1.25 (95% confidence interval, 1.15; 1.36) per 1 SD greater microvascular dysfunction when all estimates of microvascular dysfunction were combined. In analyses of single estimates of microvascular dysfunction, the pooled relative risks for incident T2DM was 1.49 (1.36; 1.64) per 1 SD higher plasma soluble E-selectin levels; 1.21(1.11; 1.31) per 1 SD higher plasma soluble intercellular adhesion molecule-1 levels; 1.48 (1.03; 2.12) per 1 SD lower response to acetylcholine-mediated peripheral vascular reactivity; 1.18 (1.08; 1.29) per 1 SD lower retinal arteriole-to-venule ratio; and 1.43 (1.33; 1.54) per 1 logarithmically transformed unit higher albumin-to-creatinine ratio. In addition, the pooled relative risks for incident impaired fasting glucose (409 cases) was 1.15 (1.01-1.31) per 1 SD greater retinal venular diameters. CONCLUSIONS: These data indicate that various estimates of microvascular dysfunction were associated with incident T2DM and, possibly, impaired fasting glucose, suggesting a role for the microcirculation in the pathogenesis of T2DM. PMID- 23042818 TI - Novel mechanism of aortic aneurysm development in mice associated with smoking and leukocytes. AB - OBJECTIVE: The purpose of this study was to evaluate potential mechanisms promoting abdominal aortic aneurysm development with tobacco smoke (TS) exposure. METHODS AND RESULTS: Experiments used the elastase perfusion model of abdominal aortic aneurysms with smoke-free controls. The effect of TS exposure was evaluated in C57/Bl6 mice, after broad-spectrum matrix metalloproteinase inhibition with doxycycline and in mice deficient in matrix metalloproteinase-9, matrix metalloproteinase-12, Cathepsin-S, and Neutrophil Elastase. Preparations of washed marrow, spleen, and peripheral blood leukocytes were transferred to smoke-free mice from 6-week TS-exposed mice or smoke-free mice. All mice were euthanized 14 days after elastase perfusion, and the percentage of change in aortic diameter (%Delta aortic diameter) was calculated. Electron microscopy of aortic tissue from animals exposed to TS without elastase exposure did not demonstrate any ultrastructural changes. Neither doxycycline nor any specific elastase deficiency was effective at preventing an increase in %Delta aortic diameter in TS-exposed animals. Smoke exposure for 6 weeks increased the %Delta aortic diameter after a smoke-free interval of up to 6 weeks before elastase perfusion. Leukocyte preparations from TS-exposed mice localized to abdominal aortic aneurysms and increased the %Delta aortic diameter in smoke-free mice. CONCLUSIONS: The effect of TS on the development of abdominal aortic aneurysms is not dependent on the activity of elastolytic enzymes and persists for long periods despite cessation of TS. Alterations in leukocyte response to aortic injury appear to mediate this effect. PMID- 23042821 TI - Nephritogenic-antinephritogenic antibody network in lupus glomerulonephritis. AB - Lupus glomerulonephritis (LGN) is one of the most threatening manifestations of systemic lupus erythematosus (SLE) and a major predictor of poor prognosis. The mechanisms leading to kidney inflammation are not completely clear; however, autoantibodies seem to play a pivotal role. Apoptosis dysregulation in SLE is likely to trigger generation of autoantibodies, the released nucleosomes being the driving autoantigen for further epitope amplification and selection of DNA or nucleosome-specific B cells. Growing evidence supports a multistep path to LGN involving initial autoantibody binding to chromatin fragments in the mesangial matrix, where they can induce mesangial inflammation leading to a shut-down of the renal DNase gene, generation and deposition of secondary necrotic chromatin on the glomerular basement membrane favouring antibody binding, complement activation and development of membrano-proliferative glomerular lesions. Anti-DNA IgG antibodies display the major pathogenetic potential in LGN initiation; however, other isotypes (IgA or IgE) as well as autoantibodies targeting other molecules (e.g. anti-C1q, anti-C reactive protein) can perpetuate renal injury. Conversely, protective autoantibodies are also likely in SLE which can contain renal damage targeting either DNA (i.e. IgM anti-DNA) or other molecules (e.g. pentraxin 3). Thus, lupus nephritogenic-antinephritogenic antibodies orchestrate the balance between harm and defence of renal tissue. PMID- 23042822 TI - Incidence and prevalence of adult systemic lupus erythematosus in a large US managed-care population. AB - OBJECTIVE: The objective of this paper is to determine the incidence and prevalence of adult systemic lupus erythematosus (SLE) in a large US managed-care population. METHODS: Subject inclusion in the incidence cohort required a medical claim with an SLE diagnosis and a service date from 2003 to 2008 that satisfied the following criteria: 1) >=18 years on service date; 2) continuously enrolled for 24 months before and 12 months after service date; 3) in the 12 months after service date, >= one inpatient claim or >= two office or ER visits with an SLE diagnosis; 4) no SLE diagnosis 24 months prior to service date; and 5) no SLE medications 12 months prior to service date. Prevalence cohort subjects were identified using a similar algorithm and were not required to satisfy criteria 4) and 5). RESULTS: A total of 1,557 subjects were included in the incidence cohort, and 15,396 were included in the prevalence cohort. The overall age- and gender adjusted SLE incidence rate (2003-2008) was 7.22 cases per 100,000 person-years. The annual prevalence of SLE (per 100,000 individuals) varied from 81.07 in 2003 to 102.94 in 2008. CONCLUSION: The SLE incidence in this large managed-care plan with geographic diversity was slightly higher than previous estimates, and the prevalence was within the range of previous estimates. PMID- 23042823 TI - Protein structure networks. AB - The application of the field of network science to the scientific disciplines of structural biology and biochemistry, have yielded important new insights into the nature and determinants of protein structures, function, dynamics and the folding process. Advancements in further understanding protein relationships through network science have also reshaped the way we view the connectivity of proteins in the protein universe. The canonical hierarchical classification can now be visualized for example, as a protein fold continuum. This review will survey several key advances in the expanding area of research being conducted to study protein structures and folding using network approaches. PMID- 23042820 TI - Fatty acids regulate endothelial lipase and inflammatory markers in macrophages and in mouse aorta: a role for PPARgamma. AB - OBJECTIVE: Macrophage endothelial lipase (EL) is associated with increased atherosclerosis and inflammation. Because of their anti-inflammatory properties we hypothesized that n-3 fatty acids, in contrast to saturated fatty acids, would lower macrophages and arterial EL and inflammatory markers. METHODS AND RESULTS: Murine J774 and peritoneal macrophages were incubated with eicosapentaenoic acid or palmitic acid in the presence or absence of lipopolysaccaride (LPS). LPS increased EL mRNA and protein. Palmitic acid alone or with LPS dose-dependently increased EL mRNA and protein. In contrast, eicosapentaenoic acid dose dependently abrogated effects of LPS or palmitic acid on increasing EL expression. EL expression closely linked to peroxisome proliferator activated receptor (PPAR)gamma expression. Eicosapentaenoic acid blocked rosiglitazone (a PPARgamma agonist)-mediated EL activation and GW9662 (a PPARgamma antagonist) blocked palmitic acid-mediated EL stimulation. Eicosapentaenoic acid alone or with LPS blunted LPS-mediated stimulation of macrophage proinflammatory interleukin-6, interleukin-12p40, and toll-like receptor-4 mRNA and increased anti-inflammatory interleukin-10 and mannose receptor mRNA. In vivo studies in low density lipoprotein receptor knockout mice showed that high saturated fat rich diets, but not n-3 diets, increased arterial EL, PPARgamma, and proinflammatory cytokine mRNA. CONCLUSIONS: n-3 fatty acids, in contrast to saturated fatty acids, decrease EL in parallel with modulating pro- and anti inflammatory markers, and these effects on EL link to PPARgamma. PMID- 23042824 TI - Leaf surface characterization of the Tabu-No-Ki tree Machilus thunbergii using electron microscopy and white light scanning interferometry. AB - Leaf surface features were investigated in the Tabu-No-Ki tree Machilus thunbergii by electron microscopy and white light scanning interferometry. Mature leaves of the tree were air-dried at room temperature and sputter-coated with platinum. The most prominent epicuticular wax structures of M. thunbergii leaves included granules, angular rodlets and transversely ridged rodlets. Wax granules were often observed on the adaxial leaf surface. Meanwhile, the abaxial leaf surface was characterized by transversely ridged rodlets in which the ridges were perpendicular to their longitudinal axis. Having several facets, the angular rodlets were straight and grew among clusters of transversely ridged rodlets. The adaxial leaf surface of M. thunbergii appeared to be smooth and less undulating than the abaxial leaf surface. Clusters of epicuticular waxes were predominant on the abaxial leaf surface. The average heights of the adaxial and abaxial leaf surfaces were 1.79 +/- 0.58 and 3.65 +/- 0.93 MUm, respectively. The average roughness and root-mean-square roughness values were lower those on the adaxial surface than on the abaxial surface. These results suggest that the transversely ridged rodlets significantly contribute to the increased surface roughness on the abaxial leaf surface. PMID- 23042825 TI - Multislice simulation of transmission electron microscopy imaging of helium bubbles in Fe. AB - Formation of nanoscale helium (He) bubbles in reduced activation ferritic/martensitic steels may lead to degradation of mechanical properties of materials. Transmission electron microscopy (TEM) has commonly been used to image the Fresnel contrast of He bubbles, using an underfocus of 0.5-1 um. This paper presents our study of multislice simulation of the size correlation between imaged Fresnel rings and the actual He bubbles. It was found that for bubbles equal to or >3 nm in diameter, the imaged bubble size, represented by its inner diameter of the first dark Fresnel ring (D(in)) in underfocused imaging conditions, increases with increasing electron-beam incoherency, but decreases with increasing underfocus. The electron-beam accelerating voltage, bubble size, bubble position and TEM sample thickness were found to have no significant influence on the deviation of D(in) from the actual bubble size (D(0)). However, for bubbles equal to or <2 nm, D(in)/D(0) increases dramatically with increasing underfocus when it is above a threshold limit (e.g. Deltaf = -1 um for a 2-nm bubble). The results of this study also suggested that He bubbles can be differentiated from argon (Ar) bubbles by contrast differences. PMID- 23042826 TI - A bias-corrected net reclassification improvement for clinical subgroups. AB - BACKGROUND: Comparing prediction models using reclassification within subgroups at intermediate risk is often of clinical interest. OBJECTIVE: To demonstrate a method for obtaining an unbiased estimate for the Net Reclassification Improvement (NRI) evaluated only on a subset, the clinical NRI. STUDY DESIGN: and Setting. We derived the expected value of the clinical NRI under the null hypothesis using the same principles as the overall NRI. We then conducted a simulation study based on a logistic model with a known predictor and a potential predictor, varying the effects of the known and potential predictors to test the performance of our bias-corrected clinical NRI measure. Finally, data from the Women's Health Study, a prospective cohort of 24 171 female health professionals, were used as an example of the proposed method. RESULTS: Our bias-corrected estimate is shown to have a mean of zero in the null case under a range of simulated parameters and, unlike the naive estimate, to be unbiased. We also provide 2 methods for obtaining a variance estimate, both with reasonable type 1 errors. CONCLUSION: Our proposed method is an improvement over currently used methods of calculating the clinical NRI and is recommended to reduce overly optimistic results. PMID- 23042831 TI - Equity in cancer care: pathways, protocols, and guidelines. AB - The quality of patient care varies based on numerous factors, such as health care setting, geographic location, access to medications, insurance coverage, and treatment protocols. Recently, the issue of whether use of clinical pathways can reduce costs and inappropriate variability in care has been the subject of much debate. As clinical treatment guidelines and pathways are increasingly deployed in oncology practice, they have a growing impact on the quality of treatment and how it is delivered. To fulfill the current need to discuss the use of pathways and clinical treatment guidelines in oncology and to address how patient care is impacted by their use, the National Comprehensive Cancer Network convened the NCCN Oncology Policy Summit: Equity in Cancer Care-Pathways, Protocols, and Guidelines. The summit was a forum to discuss the use and implementation of pathways, including how much flexibility pathways should allow in care, pathways' impact on public and private health insurance benefit design, what data is used to select pathway regimens and protocols, and ultimately what impact pathways may have on variation in care. The use and implementation of clinical treatment guidelines in practice was also explored from a variety of perspectives. PMID- 23042832 TI - Nystagmus: an uncommon neurological manifestation of thiamine deficiency as a serious complication of sleeve gastrectomy. AB - Wernicke encephalopathy--a debilitating acute or subacute neurological disorder is caused by a deficiency in thiamine (vitamin B(1)). It is characterized by a classical clinical triad of symptoms: ocular impairment, cerebellar dysfunction, and confusion. Although bariatric surgery can certainly improve the overall health of an obese individual, it can also make him or her more susceptible to serious nutrition deficiencies. Following surgery, inadequate caloric intake, rapid and excessive weight loss, food intolerance, lack of adherence to nutrition supplementation, and/or the onset of prolonged vomiting can lead to severe nutrition deficiencies. It is generally believed that the more malabsorptive the surgery proves, the more likely is it that such a deficiency will occur. The case presented here shows that after sleeve gastrectomy (SG), a patient may also develop dangerous nutrition deficits that can negatively affect his or her life. In this particular case, a patient presented with a severe vitamin B(1) deficiency following SG for morbid obesity. Although patients may exhibit pathophysiologies similar to Wernicke encephalopathy after this surgery, only 2 cases of severe vitamin B(1) deficiency following sleeve gastrectomy have been reported. The grave consequences of thiamine deficiency observed in this patient underscore the importance of supplementation after SG. PMID- 23042833 TI - Anthropometric measures of visceral and subcutaneous fat are important in the determination of metabolic dysregulation in boys and girls at risk for nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasing at alarming rates in obese children. The study aim was to describe body composition/somatotype and its interrelationships to biomarkers of liver disease, insulin resistance, and lipid and cytokine expression in youth with NAFLD. METHODS: Somatotype and body composition of children (7-18 years) diagnosed with NAFLD (n= 18) were compared with obese (n = 11) and lean children (n = 17). Anthropometric variables assessed included weight, height, body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHTR), and multiple skinfold thicknesses. Fat mass (FM) and somatotype analysis were measured using validated methodologies. Fasting liver biochemistries (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyltransferase [GGT]), insulin, glucose, leptin, C-reactive protein (CRP), tumor necrosis factor-alpha, interleukin (IL) factors 6/10, apolipoproteins B-100/B-48 and C-III, triglycerides, and high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol were measured. Insulin resistance was assessed by the homeostasis model of insulin resistance (HOMA-IR). RESULTS: BMI z score, WC, FM, and somatotype did not differ between NAFLD and obese groups; however, lean children were lighter/leaner across all anthropometric measures (P < .001). Children with NAFLD had a higher sum-of-trunk to sum-of-extremity ratio (1.6 +/- 0.4) than did obese (1.3 +/- 0.2) and lean (1.1 +/- 0.5) children (P < .001). Markers of central visceral (WC/WHTR) and subcutaneous fat (subscapular, abdominal, suprailiac skinfolds) were associated with elevated plasma concentrations of insulin, HOMA-IR, ALT, GGT, and AST and lower HDL cholesterol and IL-10 (P < .001). CONCLUSION: Comprehensive assessment of body composition, including measurement of surrogate markers of subcutaneous and visceral fat, provides information regarding metabolic dysregulation and liver disease risk in obese children with NAFLD. PMID- 23042836 TI - Characterization and comparison of methacrylic acid with 2-acrylamido-2-methyl-1 propanesulfonic acid in the preparation of monolithic column for capillary electrochromatography. AB - Butyl methacrylate (BMA)-ethylene dimethacrylate (EDMA)-methacrylic acid (MAA) and BMA-EDMA-2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) monolithic columns were prepared by varying the percentage of ionic monomers for capillary electrochromatography. Monolithic columns with a higher content of ionic monomers provided better column efficiency, and the performance of BMA-EDMA-MAA monoliths was better than BMA-EDMA-AMPS. To characterize and optimize BMA-EDMA-MAA monoliths, the effects of the content of cross-linker and the total monomer in the polymerization mixture on column performance were also studied. Plate heights of 8.2 um for the unretained solute (thiourea) and 12.6 um for the retained solute (naphthalene) were achieved with a monolithic column using 2.5% MAA (Column I). PMID- 23042837 TI - Effect of metoclopramide on the excretion rate of paracetamol using HPLC-DAD. AB - A simple, precise, accurate and robust high-performance liquid chromatography assay was developed and validated for the simultaneous analysis of metoclopramide and paracetamol in human urine. The drugs were isolated from urine samples by solid-phase extraction using C8 cartridges, then analyzed on a C18 reversed-phase column using a mixture of aqueous phase (water containing 0.2% TEA adjusted to pH 3 using ortho-phosphoric acid) and methanol in a ratio of 80:20 (v/v). The method was found to be linear for both drugs in a concentration range of 0.5 to 160 ug/mL using a concentration of 10 ug/mL of internal standard (theophylline) in urine samples (r > 0.999). The accuracy of the method was higher than 91.73% (percentage of the grand mean of recoveries) and the precision was lower than 3.4% (overall percentage of relative standard deviation) for both metoclopramide and paracetamol. The method was applied to the determination of the drugs in urine samples obtained from male volunteers, following the administration of two formulations, one containing paracetamol alone (Paracetamol((r))) and the other containing a mixture of paracetamol and metoclopramide (Migracicid((r))). Determination of the drugs was conducted and the effect of increasing the rate of absorption, consequently increasing the mean urinary excretion of paracetamol due to the presence of metoclopramide in the pharmaceutical formulation, was recorded. PMID- 23042834 TI - Muscle plasticity and ankle control after repetitive use of a functional electrical stimulation device for foot drop in cerebral palsy. AB - BACKGROUND/OBJECTIVES: The primary goal was to determine whether repetitive functional electrical stimulation (FES) for unilateral foot drop increases tibialis anterior (TA) muscle size compared with an untreated baseline and the contralateral side in cerebral palsy (CP). Secondary goals were to determine whether positive changes in muscle size and gait, if found, accumulated during the 3 intervals during which participants used the device. FES devices differ from traditional orthoses that often restrict muscle activation and may exacerbate weakness, promote continued dependence on orthoses, or precipitate functional decline. METHODS: Participants were 14 independent ambulators with inadequate dorsiflexion in swing, with a mean age of 13.1 years, evaluated before and after the 3-month baseline, 1-month device accommodation, 3-month primary intervention, and 3-month follow-up phases. The FES device (WalkAide) stimulated the common fibular nerve to dorsiflex the ankle and evert the foot while monitoring use. TA muscle ultrasound, gait velocity, and ankle kinematic data for barefoot and device conditions are reported. RESULTS: Ultrasound measures of TA anatomic cross-sectional area and muscle thickness increased in the intervention compared with baseline and with the contralateral side and were maintained at follow-up. Maximum ankle dorsiflexion decreased at baseline but improved or was maintained during the intervention phase with and without the device, respectively. Muscle size gains were preserved at follow-up, but barefoot ankle motion returned to baseline values. CONCLUSIONS: This FES device produced evidence of use-dependent muscle plasticity in CP. Permanent improvements in voluntary ankle control after repetitive stimulation were not demonstrated. PMID- 23042838 TI - An ultrasonic assisted extraction procedure to free fatty acids from the liver samples of mice. AB - A procedure was evaluated for the extraction of 16 free fatty acids (FFAs) from liver. Ultrasonic energy was used for the extraction and the variables affecting the extraction efficiency were investigated. The best conditions for extraction were: 2 mL isopropanol-n-hexane (3:2, v/v), 20 min and 80 w. Recoveries ranging from 87.00 to 120.00% were obtained under the optimum conditions, and the linearity as correlation coefficient was higher than 0.9914. Analytical results for the 16 FFAs in the same liver sample, analyzed by ultrasound-assisted and conventional extraction, showed acceptable agreement, thus suggesting the possibility of using ultrasound-assisted extraction instead of the conventional procedure. Moreover, the ultrasound-assisted extraction was successfully applied to the determination of FFAs in the liver of mice with hyperlipidemia and normal mice. PMID- 23042839 TI - Detection of clenbuterol at trace levels in doping analysis using different gas chromatographic-mass spectrometric techniques. AB - This study demonstrates the development of a gas chromatography-triple quadrupole tandem mass spectrometry (GC-MS-MS) assay to detect clenbuterol in human urine and the comparison of this method with GC-MS techniques and gas chromatography high resolution mass spectrometry (GC-HRMS) techniques. Urine samples were hydrolyzed with beta-glucuronidase, extracted with methyl tert-butyl ether and dried under nitrogen. The derivative reagent was N-methyl-N-(trimethylsilyl) trifluoroacetamide with NH4I and was analyzed by GC-MS, GC-MS-MS and GC-HRMS. A validation study was conducted by GC-MS-MS. The analyses of clenbuterol using different mass spectrometric techniques were compared. The limit of detection (LOD) for clenbuterol in human urine was 2 ng/mL by GC-MS (selected ion monitoring mode: SIM mode), 0.06 ng/mL by GC-HRMS and 0.03 ng/mL by GC-MS-MS, respectively, while the LOD by GC-HRMS was 0.06. With GC-MS-MS, the intra-assay and inter-assay precisions were less than 15%, the recoveries were 86 to 112% and the linear range was 0.06 to 8.0 ng/mL. The GC-MS under SIM mode can be used as a screening tool to detect clenbuterol at trace levels in human urine. The GC-MS-MS and GC-HRMS methods can confirm clenbuterol when its concentration is below 2 ng/mL. The results demonstrate that the GC-MS-MS method is quite sensitive, specific and reliable for the detection of clenbuterol in doping analysis. PMID- 23042840 TI - Determination of hexanal in rice using an automated dynamic headspace sampler coupled to a gas chromatograph-mass spectrometer. AB - The aim of this study was to establish a method for the determination of hexanal as a lipid oxidation marker in rice. For the sample preparation, ground rice exhibited better sensitivity and reproducibility for the analysis of hexanal than whole rice. A total flow of purge gas of 300 mL at 20 mL/min of purge was sufficient to obtain the necessary sensitivity for the analysis of hexanal in rice. The total time for sample preparation and analysis for individual samples was approximately 15 min. A low incubation temperature of 30 degrees C was chosen, not only to reduce the effect of water, but also to avoid excess lipid oxidation and loss of hexanal during the analysis. The limits of detection and quantification were 3.7 and 5.1 ng/g, respectively. Good linearity was obtained in the range from 5.1-500.0 ng/g. The recoveries of hexanal in rice were greater than 97.0 and 107.0% at the spiked levels of 5 and 50 ng/g, respectively, with relative standard deviations of 3.3 and 6.1%, respectively. PMID- 23042841 TI - Clinical relevance of torsion to the ophthalmologist. PMID- 23042842 TI - Effect of postoperative aspirin on outcomes in microvascular free tissue transfer surgery. AB - OBJECTIVE: Examine if outcomes and complication rates for free flaps vary when postoperative aspirin is used as pharmacologic thromboprophylaxis compared with no anticoagulation. STUDY DESIGN: Case series with chart review. Setting Oregon Health and Science University, an academic medical center. SUBJECTS AND METHODS: A case series with chart review was performed using a prospectively maintained microvascular reconstructive database to identify cases of free tissue transfer between February 2006 and April 2010. Outcome variables included complications, flap failure, reexploration, and salvage. Chi-square analysis was performed to identify differences based on type of postoperative antithrombotic therapy. RESULTS: A total of 390 consecutive free tissue transfer procedures were performed; 184 received no postoperative thromboprophylaxis, 142 received aspirin, 48 received low molecular weight heparin or a combination of agents, and 16 received a heparin drip. The overall complication rate was 38%, with significantly more complications in the aspirin group compared with no prophylaxis (P = .002). There was no significant difference in bleeding complications (P = .192) or flap failure (P = .839) between aspirin and no anticoagulation. There were more postoperative revisions in the aspirin group (P = .039). CONCLUSION: Postoperative thromboprophylaxis with aspirin after microvascular free tissue transfer does not provide an improvement in free flap survival and may be associated with a higher complication rate. Prospective, randomized studies are required to elucidate the role of postoperative pharmacotherapy for prophylaxis against microvascular thrombosis. PMID- 23042844 TI - Primary laryngotracheal melanoma. PMID- 23042843 TI - Systematic review of effects of adenotonsillectomy on cardiovascular parameters in children with obstructive sleep apnea. AB - OBJECTIVE: To systematically review current studies on the effects of adenotonsillectomy (T&A) for obstructive sleep apnea (OSA) on cardiovascular parameters in children. DATA SOURCES: PubMed database. REVIEW METHODS: A comprehensive PubMed MeSH search was done between 1970 and 2012. RESULTS: Fourteen articles were included. The total number of children was 418. The mean sample size was 30 (range, 1-62), and the mean age of the sample population was 6 years (range, 2-10 years). Criteria used for the diagnosis of OSA ranged from full-night polysomnography (PSG) to clinical parameters. Three studies had results from preoperative and postoperative PSG. Cardiovascular parameters studied included blood pressure, heart rate, cardiac morphology, and cardiac function. All studies reported an improvement in cardiovascular parameters and OSA symptoms after surgery. Three studies reported improvement in blood pressure, 6 reported improvement in mean pulmonary artery pressures, 7 reported improvement in echocardiographic findings, and 1 reported a decrease in pulse rate and pulse rate variability after T&A for OSA. CONCLUSION: There is evidence that cardiovascular morbidities associated with OSA are potentially reversible. T&A may have a significant role in reversing the cardiovascular sequelae of OSA. However, there is a paucity of well-designed and powered studies to address this issue. PMID- 23042845 TI - A 24-year-old Ethiopian farmer with burning feet. AB - Podoconiosis is a non-infectious tropical disease caused by exposure of bare feet to irritant alkalic clay soils. This causes an asymmetrical swelling of the feet and lower limbs due to lymphoedema. This swelling is called "elephantiasis" and may lead to severe disability of the patient. It is found in areas of tropical Africa, Central and South America and north-west India, where such soils coexist with high altitude, high seasonal rainfall and low income. Social stigmatization of people with the disease is widespread and economic losses are enormous. Podoconiosis is unique in being an entirely preventable non-communicable tropical disease. However, so far it has received little attention from health care policy makers. PMID- 23042850 TI - Circulation of QX-like infectious bronchitis virus in the Middle East. PMID- 23042849 TI - Highlights of the 2012 Research Workshop: Using nutrigenomics and metabolomics in clinical nutrition research. AB - The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Research Workshop, "Using Nutrigenomics and Metabolomics in Clinical Nutrition Research," was held on January 21, 2012, in Orlando, Florida. The conference brought together experts in human nutrition who use nutrigenomic and metabolomic methods to better understand metabolic individuality and nutrition effects on health. We are beginning to understand how genetic variation and epigenetic events alter requirements for and responses to foods in our diet (the field of nutrigenetics/nutrigenomics and epigenetics). At the same time, methods for profiling almost all of the products of metabolism in plasma, urine, and tissues (metabolomics) are being refined. The relationships between diet and nutrigenomic metabolomic profiles, as well as between these profiles and health, are being elucidated, and this will dramatically alter clinical practice in nutrition. PMID- 23042846 TI - The history of dengue outbreaks in the Americas. AB - Dengue is a viral disease usually transmitted by Aedes aegypti mosquitoes. Dengue outbreaks in the Americas reported in medical literature and to the Pan American Health Organization are described. The outbreak history from 1600 to 2010 was categorized into four phases: Introduction of dengue in the Americas (1600-1946); Continental plan for the eradication of the Ae. aegypti (1947-1970) marked by a successful eradication of the mosquito in 18 continental countries by 1962; Ae. aegypti reinfestation (1971-1999) caused by the failure of the mosquito eradication program; Increased dispersion of Ae. aegypti and dengue virus circulation (2000-2010) characterized by a marked increase in the number of outbreaks. During 2010 > 1.7 million dengue cases were reported, with 50,235 severe cases and 1,185 deaths. A dramatic increase in the number of outbreaks has been reported in recent years. Urgent global action is needed to avoid further disease spread. PMID- 23042853 TI - The burden of mood disorders. PMID- 23042858 TI - Condensed-matter physics. Supersolidity shot down by its own discoverer. PMID- 23042851 TI - Effects of body weight reduction on blood adipokines and subcutaneous adipose tissue adipokine mRNA expression profiles in obese ponies. AB - Fifteen obese ponies were used in a body weight (BW) reduction programme (BWRP, daily energy intake: 7.0-8.4 MJ/100 kg BW). A frequently sampled intravenous glucose tolerance test was used to assess insulin sensitivity. Subcutaneous adipose tissue biopsies of the tail head were obtained for mRNA gene expression profiles of adiponectin, retinol-binding protein 4 (RBP4), interleukin 6 (IL-6) and macrophage activation marker (CD68) before and after BWRP. Blood samples were analysed for serum leptin, serum RBP4 and plasma adiponectin. Significant BW losses occurred with 7 MJ DE/100 kg BW. Serum leptin and RBP4 were initially similar between insulin-resistant (IR) and insulin-sensitive (IS) ponies, and both significantly decreased during BWRP. Compared with IS ponies, IR ponies initially had significantly lower plasma adiponectin levels. At the beginning of BWRP, mRNA expression of RBP4, adiponectin, IL-6 and CD68 was similar between IR and IS ponies. Plasma adiponectin was strongly related to IR, whereas serum leptin and RBP4 were closely linked to adiposity, independent of insulin sensitivity. Adipose tissue mRNA expression profiles did not clearly reflect these differences. However, the role of subcutaneous adipose tissue in IR remains open. PMID- 23042859 TI - Japan. Utility sacrificed for speed, supercomputer critics say. PMID- 23042860 TI - Climate change. Researchers struggle to assess responses to ocean acidification. PMID- 23042861 TI - Chemistry. 'Awesome' synthesis could boost protein-based drugs. PMID- 23042862 TI - Biomedicine. Pharma firms push for sharing of cancer trial data. PMID- 23042863 TI - Mysteries of the brain. PMID- 23042864 TI - Mysteries of the brain. How are memories retrieved? PMID- 23042865 TI - Mysteries of the brain. Why is mental illness so hard to treat? PMID- 23042866 TI - Mysteries of the brain. Why are our brains so big? PMID- 23042867 TI - Mysteries of the brain. Why are you and your brain unique? PMID- 23042868 TI - Mysteries of the brain. Can we make our brains more plastic? PMID- 23042869 TI - Mysteries of the brain. Brain teasers. PMID- 23042870 TI - NextGen speaks. PMID- 23042871 TI - Energy. Deploying off-grid technology to eradicate energy poverty. PMID- 23042872 TI - Epidemiology. Malaria in the post-genome era. PMID- 23042873 TI - Ecology. How insect herbivores drive the evolution of plants. PMID- 23042874 TI - Developmental biology. Intestinal wound healing requires a Wnt balancing act. PMID- 23042875 TI - Cancer. Bacteria deliver a genotoxic hit. PMID- 23042876 TI - Geophysics. Earthquakes in the lab. PMID- 23042877 TI - Materials science. Melting colloidal crystals from the inside out. PMID- 23042878 TI - Biochemistry. A DNA twist diffuses and hops. PMID- 23042879 TI - Eppendorf winner. When attention wanders. PMID- 23042880 TI - Eppendorf finalist. Striatal interneurons: causes of or cures for movement disorders? PMID- 23042881 TI - Eppendorf finalist. The cellular feeling of pressure. PMID- 23042882 TI - Theory and simulation in neuroscience. AB - Modeling work in neuroscience can be classified using two different criteria. The first one is the complexity of the model, ranging from simplified conceptual models that are amenable to mathematical analysis to detailed models that require simulations in order to understand their properties. The second criterion is that of direction of workflow, which can be from microscopic to macroscopic scales (bottom-up) or from behavioral target functions to properties of components (top down). We review the interaction of theory and simulation using examples of top down and bottom-up studies and point to some current developments in the fields of computational and theoretical neuroscience. PMID- 23042883 TI - Depression. Defeating the dementors. Introduction. PMID- 23042884 TI - Synaptic dysfunction in depression: potential therapeutic targets. AB - Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N-methyl-D-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response. PMID- 23042885 TI - Depression and hippocampal neurogenesis: a road to remission? AB - Adult-generated hippocampal neurons are required for mood control and antidepressant efficacy, raising hopes that someday we can harness the power of new neurons to treat mood disorders such as depression. However, conflicting findings from preclinical research--involving stress, depression, and neurogenesis--highlight the complexity of considering neurogenesis as a road to remission from depression. To reconcile differences in the literature, we introduce the "neurogenic interactome," a platform from which to consider the diverse and dynamic factors regulating neurogenesis. We propose consideration of the varying perspectives--system, region, and local regulation of neurogenesis- offered by the interactome and exchange of ideas between the fields of learning and memory and mood disorder research to clarify the role of neurogenesis in the etiology and treatment of depression. PMID- 23042886 TI - Are we getting closer to valid translational models for major depression? AB - Advances in characterizing the neuropathology and functional dysconnectivity of depression and promising trials with emerging circuit-targeted and fast-onset therapeutics are providing unprecedented opportunities to gain deeper insight into the neurobiology of this devastating and pervasive disorder. Because of practical and ethical limitations to dissecting these mechanisms in humans, continued progress will critically depend on our ability to emulate aspects of depressive symptomatology and treatment response in nonhuman organisms. Although various experimental models are currently available, they often draw skepticism from both clinicians and basic research scientists. We review recent progress and highlight some of the best leads to diversify and improve discovery end points for preclinical depression research. PMID- 23042887 TI - The science of resilience: implications for the prevention and treatment of depression. AB - Human responses to stress and trauma vary widely. Some people develop trauma related psychological disorders, such as posttraumatic stress disorder (PTSD) and depression; others develop mild to moderate psychological symptoms that resolve rapidly; still others report no new psychological symptoms in response to traumatic stress. Individual variability in how animals and humans respond to stress and trauma depends on numerous genetic, developmental, cognitive, psychological, and neurobiological risk and protective factors. PMID- 23042888 TI - The shortest-known-period star orbiting our Galaxy's supermassive black hole. AB - Stars with short orbital periods at the center of our Galaxy offer a powerful probe of a supermassive black hole. Over the past 17 years, the W. M. Keck Observatory has been used to image the galactic center at the highest angular resolution possible today. By adding to this data set and advancing methodologies, we have detected S0-102, a star orbiting our Galaxy's supermassive black hole with a period of just 11.5 years. S0-102 doubles the number of known stars with full phase coverage and periods of less than 20 years. It thereby provides the opportunity, with future measurements, to resolve degeneracies in the parameters describing the central gravitational potential and to test Einstein's theory of general relativity in an unexplored regime. PMID- 23042889 TI - Imaging the homogeneous nucleation during the melting of superheated colloidal crystals. AB - The nucleation process is crucial to many phase transitions, but its kinetics are difficult to predict and measure. We superheated and melted the interior of thermal-sensitive colloidal crystals and investigated by means of video microscopy the homogeneous melting at single-particle resolution. The observed nucleation precursor was local particle-exchange loops surrounded by particles with large displacement amplitudes rather than any defects. The critical size, incubation time, and shape and size evolutions of the nucleus were measured. They deviate from the classical nucleation theory under strong superheating, mainly because of the coalescence of nuclei. The superheat limit agrees with the measured Born and Lindemann instabilities. PMID- 23042890 TI - A local proton source enhances CO2 electroreduction to CO by a molecular Fe catalyst. AB - Electrochemical conversion of carbon dioxide (CO(2)) to carbon monoxide (CO) is a potentially useful step in the desirable transformation of the greenhouse gas to fuels and commodity chemicals. We have found that modification of iron tetraphenylporphyrin through the introduction of phenolic groups in all ortho and ortho' positions of the phenyl groups considerably speeds up catalysis of this reaction by the electrogenerated iron(0) complex. The catalyst, which uses one of the most earth-abundant metals, manifests a CO faradaic yield above 90% through 50 million turnovers over 4 hours of electrolysis at low overpotential (0.465 volt), with no observed degradation. The basis for the enhanced activity appears to be the high local concentration of protons associated with the phenolic hydroxyl substituents. PMID- 23042891 TI - Complex dental structure and wear biomechanics in hadrosaurid dinosaurs. AB - Mammalian grinding dentitions are composed of four major tissues that wear differentially, creating coarse surfaces for pulverizing tough plants and liberating nutrients. Although such dentition evolved repeatedly in mammals (such as horses, bison, and elephants), a similar innovation occurred much earlier (~85 million years ago) within the duck-billed dinosaur group Hadrosauridae, fueling their 35-million-year occupation of Laurasian megaherbivorous niches. How this complexity was achieved is unknown, as reptilian teeth are generally two-tissue structures presumably lacking biomechanical attributes for grinding. Here we show that hadrosaurids broke from the primitive reptilian archetype and evolved a six tissue dental composition that is among the most sophisticated known. Three dimensional wear models incorporating fossilized wear properties reveal how these tissues interacted for grinding and ecological specialization. PMID- 23042892 TI - Rapid acceleration leads to rapid weakening in earthquake-like laboratory experiments. AB - After nucleation, a large earthquake propagates as an expanding rupture front along a fault. This front activates countless fault patches that slip by consuming energy stored in Earth's crust. We simulated the slip of a fault patch by rapidly loading an experimental fault with energy stored in a spinning flywheel. The spontaneous evolution of strength, acceleration, and velocity indicates that our experiments are proxies of fault-patch behavior during earthquakes of moment magnitude (M(w)) = 4 to 8. We show that seismically determined earthquake parameters (e.g., displacement, velocity, magnitude, or fracture energy) can be used to estimate the intensity of the energy release during an earthquake. Our experiments further indicate that high acceleration imposed by the earthquake's rupture front quickens dynamic weakening by intense wear of the fault zone. PMID- 23042893 TI - The efficacy of student-centered instruction in supporting science learning. AB - Transforming science learning through student-centered instruction that engages students in a variety of scientific practices is central to national science teaching reform efforts. Our study employed a large-scale, randomized-cluster experimental design to compare the effects of student-centered and teacher centered approaches on elementary school students' understanding of space-science concepts. Data included measures of student characteristics and learning and teacher characteristics and fidelity to the instructional approach. Results reveal that learning outcomes were higher for students enrolled in classrooms engaging in scientific practices through a student-centered approach; two moderators were identified. A statistical search for potential causal mechanisms for the observed outcomes uncovered two potential mediators: students' understanding of models and evidence and the self-efficacy of teachers. PMID- 23042894 TI - Insect herbivores drive real-time ecological and evolutionary change in plant populations. AB - Insect herbivores are hypothesized to be major factors affecting the ecology and evolution of plants. We tested this prediction by suppressing insects in replicated field populations of a native plant, Oenothera biennis, which reduced seed predation, altered interspecific competitive dynamics, and resulted in rapid evolutionary divergence. Comparative genotyping and phenotyping of nearly 12,000 O. biennis individuals revealed that in plots protected from insects, resistance to herbivores declined through time owing to changes in flowering time and lower defensive ellagitannins in fruits, whereas plant competitive ability increased. This independent real-time evolution of plant resistance and competitive ability in the field resulted from the relaxation of direct selective effects of insects on plant defense and through indirect effects due to reduced herbivory on plant competitors. PMID- 23042895 TI - Natural enemies drive geographic variation in plant defenses. AB - Plants defend themselves against attack by natural enemies, and these defenses vary widely across populations. However, whether communities of natural enemies are a sufficiently potent force to maintain polymorphisms in defensive traits is largely unknown. Here, we exploit the genetic resources of Arabidopsis thaliana, coupled with 39 years of field data on aphid abundance, to (i) demonstrate that geographic patterns in a polymorphic defense locus (GS-ELONG) are strongly correlated with changes in the relative abundance of two specialist aphids; and (ii) demonstrate differential selection by the two aphids on GS-ELONG, using a multigeneration selection experiment. We thereby show a causal link between variation in abundance of the two specialist aphids and the geographic pattern at GS-ELONG, which highlights the potency of natural enemies as selective forces. PMID- 23042898 TI - Network resets in medial prefrontal cortex mark the onset of behavioral uncertainty. AB - Regions within the prefrontal cortex are thought to process beliefs about the world, but little is known about the circuit dynamics underlying the formation and modification of these beliefs. Using a task that permits dissociation between the activity encoding an animal's internal state and that encoding aspects of behavior, we found that transient increases in the volatility of activity in the rat medial prefrontal cortex accompany periods when an animal's belief is modified after an environmental change. Activity across the majority of sampled neurons underwent marked, abrupt, and coordinated changes when prior belief was abandoned in favor of exploration of alternative strategies. These dynamics reflect network switches to a state of instability, which diminishes over the period of exploration as new stable representations are formed. PMID- 23042897 TI - In monkeys making value-based decisions, LIP neurons encode cue salience and not action value. AB - In monkeys deciding between alternative saccadic eye movements, lateral intraparietal (LIP) neurons representing each saccade fire at a rate proportional to the value of the reward expected upon its completion. This observation has been interpreted as indicating that LIP neurons encode saccadic value and that they mediate value-based decisions between saccades. Here, we show that LIP neurons representing a given saccade fire strongly not only if it will yield a large reward but also if it will incur a large penalty. This finding indicates that LIP neurons are sensitive to the motivational salience of cues. It is compatible neither with the idea that LIP neurons represent action value nor with the idea that value-based decisions take place in LIP neurons. PMID- 23042899 TI - Successful use of extracorporeal membrane oxygenation in a patient with combined pulmonary and systemic embolisation. AB - We present a highly unusual case of massive pulmonary embolism with secondary paradoxical systemic embolisation that was successfully resuscitated with veno arterial extracorporeal membrane oxygenation (ECMO). This enabled subsequent successful bridging to pulmonary embolectomy. PMID- 23042896 TI - BDNF is a negative modulator of morphine action. AB - Brain-derived neurotrophic factor (BDNF) is a key positive regulator of neural plasticity, promoting, for example, the actions of stimulant drugs of abuse such as cocaine. We discovered a surprising opposite role for BDNF in countering responses to chronic morphine exposure. The suppression of BDNF in the ventral tegmental area (VTA) enhanced the ability of morphine to increase dopamine (DA) neuron excitability and promote reward. In contrast, optical stimulation of VTA DA terminals in nucleus accumbens (NAc) completely reversed the suppressive effect of BDNF on morphine reward. Furthermore, we identified numerous genes in the NAc, a major target region of VTA DA neurons, whose regulation by BDNF in the context of chronic morphine exposure mediated this counteractive function. These findings provide insight into the molecular basis of morphine-induced neuroadaptations in the brain's reward circuitry. PMID- 23042900 TI - The heparin recall of 2008. AB - Heparin is one of the oldest drugs still in widespread clinical use. Its discovery in 1916 predates the establishment of the Food and Drug Administration. Since 1935, over 15,000 research papers have been published on the effects of heparin. Because the exact chemical formula of heparin is unknown, synthetic manufacturing has proven difficult. In 2008, a worldwide recall of heparin occurred. Scientists determined that a contaminant known as oversulfated chondroitin sulfate was responsible for the numerous deaths and adverse events. This contaminant was first traced to a chemical plant in Changzou, China. This article will review the discovery of heparin and the adulteration process that jeopardized the world's heparin supply. PMID- 23042901 TI - Sexually transmitted infection testing and self-reported diagnoses among a community sample of men who have sex with men, in Scotland. AB - INTRODUCTION: To examine sexually transmitted infection (STI) testing and self reported diagnoses among men who have sex with men (MSM), in Scotland. METHODS: Cross-sectional survey of seven Glasgow gay bars in July 2010 (n=822, 62% response rate); 693 are included in the analyses. RESULTS: 81.8% reported ever having had an STI test; 37.4% had tested in the previous 6 months; 13.2% reported having an STI in the previous 12 months. The adjusted odds of having ever tested were significantly higher for men who had 6+ sexual partners in the previous 12 months (adjusted OR=2.66), a maximum sexual health knowledge score (2.23), and had talked to an outreach worker/participated in counselling (1.96), and lower for men reporting any high-risk unprotected anal intercourse (UAI) in the previous 12 months (0.51). Adjusted odds of recent testing were higher for men who had 6+ sexual partners (2.10), talked to an outreach worker/participated in counselling (1.66), maximum sexual health knowledge (1.59), and higher condom use knowledge (1.04), and lower for men aged >= 25 years (0.46). Adjusted odds of having had an STI in the previous 12 months were higher for men who had 6+ sexual partners (3.96) and any high-risk UAI in the previous 12 months (2.24) and lower for men aged >= 25 years (0.57). CONCLUSIONS: STI testing rates were relatively high, yet still below the minimum recommended for MSM at high risk. Consideration should be given to initiating recall systems for men who test positive for STIs, and to developing behavioural interventions which seek to address STI transmission. PMID- 23042902 TI - Social networks uncovered: 10 tips every plastic surgeon should know. AB - Understanding online social networks is of critical importance to the plastic surgeon. With knowledge, it becomes apparent that the numerous networks available are similar in their structure, usage, and function. The key is communication between Internet media such that one maximizes exposure to patients. This article focuses on 2 social networking platforms that we feel provide the most utility to plastic surgeons. Ten tips are provided for incorporation of Facebook and Twitter into your practice. PMID- 23042903 TI - Type 2 diabetes impairs tendon repair after injury in a rat model. AB - Type 2 diabetes adversely affects the properties of native connective tissue. The underlying mechanisms, however, by which diabetes alters connective tissue metabolism, especially tendon, are poorly defined. The aim of this study was to determine the effect of type 2 diabetes on the mechanical, histological, and molecular properties of the intact and healing Achilles tendon. The right Achilles tendon was transected in 11 male diabetic Goto-Kakizaki (GK) and 10 age- and sex-matched Wistar control rats, while the left Achilles tendon was left intact. At 2 wk postinjury the intact and injured tendons were assessed by biomechanical testing and histology. The gene expression of collagen I and III, biglycan, versican, MMP-13, and MMP-3 was measured by quantitative RT-PCR, and their protein distribution was studied by immunohistochemistry. Intact tendons exhibited only small differences between the groups. In injured tendons, however, a significantly smaller transverse area and lower stiffness was found in diabetic GK compared with Wistar control rats. This correlated with impaired structural organization of collagen fibers and a reduced expression of collagen I and III in the injured tendons of the diabetic GK compared with Wistar control. Moreover, MMP-3 gene expression was downregulated in the injured diabetic GK tendons compared with injured Wistar controls. Our results indicate that in a rat model of diabetes tendon healing is impaired mainly due to altered expression of collagen and MMPs reflecting decreased degradation of matrix proteins and impaired tissue remodeling. Further our data suggest that therapeutic modulation of collagens or MMPs might be targets for new regenerative approaches in operated, injured, or maybe also degenerative tendon diseases in diabetes. PMID- 23042904 TI - Heat shock protein 70 (Hsp70) inhibits oxidative phosphorylation and compensates ATP balance through enhanced glycolytic activity. AB - To address possible effects of heat shock protein 70 (Hsp70) on energy metabolism, we established a cell line expressing different levels of Hsp70 and evaluated changes in glucose and lactate metabolites, as well as ATP levels accordingly. In addition, activities of enzymes involved in glycolysis [phosphofructokinase (PFK) and lactate dehydrogenase (LDH)], Krebs cycle [citric synthase (CS)], and oxidative phosphorylation {NADH dehydrogenase [complex I (CI)] and ubiquinol:cytochrome-c reductase [complex III (CIII)]} were analyzed. The results show that both glucose consumption and lactate excretion were elevated significantly in cells expressing increased levels of Hsp70. Simultaneously, the activities of glycolytic enzymes PFK and LDH were increased markedly in cells overexpressing Hsp70. Activities of enzymes CI and CIII, both involved in oxidative phosphorylation, decreased upon increased expression of Hsp70. These findings were supported by nonsignificant reductions of CS activities in cells that overexpressed Hsp70, whereas intracellular ATP levels remained constant over a wide range of Hsp70 expression. In conclusion, overexpression of Hsp70 in HeLa cells results in downregulation of oxidative phosphorylation, in particular, multiprotein CIII, the main source of reactive oxygen species. In exchange, upregulation of the glycolytic pathway compensates for the homeostasis of cellular ATP supply. PMID- 23042905 TI - Heat and alpha1-adrenergic responsiveness in human skeletal muscle feed arteries: the role of nitric oxide. AB - Increased local temperature exerts a sympatholytic effect on human skeletal muscle feed arteries. We hypothesized that this attenuated alpha(1)-adrenergic receptor responsiveness may be due to a temperature-induced increase in nitric oxide (NO) bioavailability, thereby reducing the impact of the alpha(1) adrenergic receptor agonist phenylephrine (PE). Thirteen human skeletal muscle feed arteries were harvested, and wire myography was used to generate PE concentration-response curves at 37 degrees C and 39 degrees C, with and without the NO synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA). A subset of arteries (n = 4) were exposed to 37 degrees C or 39 degrees C, and the protein content of endothelial NOS (eNOS) and alpha(1)-adrenergic receptors was determined by Western blot analysis. Additionally, cultured bovine endothelial cells were exposed to static or shear stress conditions at 37 degrees C and 39 degrees C and assayed for eNOS activation (phosphorylation at Ser(1177)), eNOS expression, and NO metabolites [nitrate + nitrite (NOx)]. Maximal PE-induced vasocontraction (PE(max)) was lower at 39 degrees C than at 37 degrees C [39 +/- 10 vs. 84 +/- 30% maximal response to 100 mM KCl (KCl(max))]. NO blockade restored vasocontraction at 39 degrees C to that achieved at 37 degrees C (80 +/- 26% KCl(max)). Western blot analysis of the feed arteries revealed that heating increased eNOS protein, but not alpha(1) adrenergic receptors. Heating of bovine endothelial cells resulted in greater shear stress-induced eNOS activation and NOx production. Together, these data reveal for the first time that, in human skeletal muscle feed arteries, NO blockade can restore the heat-attenuated alpha(1)-adrenergic receptor-mediated vasocontraction and implicate endothelium-derived NO bioavailability as a major contributor to heat-induced sympatholysis. Consequently, these findings highlight the important role of vasodilators in modulating the vascular response to vasoconstrictors. PMID- 23042907 TI - Age-related differences in Achilles tendon properties and triceps surae muscle architecture in vivo. AB - This study examined the concurrent age-related differences in muscle and tendon structure and properties. Achilles tendon morphology and mechanical properties and triceps surae muscle architecture were measured from 100 subjects [33 young (24 +/- 2 yr) and 67 old (75 +/- 3 yr)]. Motion analysis-assisted ultrasonography was used to determine tendon stiffness, Young's modulus, and hysteresis during isometric ramp contractions. Ultrasonography was used to measure muscle architectural features and size and tendon cross-sectional area. Older participants had 17% lower (P < 0.01) Achilles tendon stiffness and 32% lower (P < 0.001) Young's modulus than young participants. Tendon cross-sectional area was also 16% larger (P < 0.001) in older participants. Triceps surae muscle size was smaller (P < 0.05) and gastrocnemius medialis muscle fascicle length shorter (P < 0.05) in old compared with young. Maximal plantarflexion force was associated with tendon stiffness and Young's modulus (r = 0.580, P < 0.001 and r = 0.561, P < 0.001, respectively). Comparison between old and young subjects with similar strengths did not reveal a difference in tendon stiffness. The results suggest that regardless of age, Achilles tendon mechanical properties adapt to match the level of muscle performance. Old people may compensate for lower tendon material properties by increasing tendon cross-sectional area. Lower tendon stiffness in older subjects might be beneficial for movement economy in low-intensity locomotion and thus optimized for their daily activities. PMID- 23042906 TI - Effects of aging and exercise training on skeletal muscle blood flow and resistance artery morphology. AB - With old age, blood flow to the high-oxidative red skeletal muscle is reduced and blood flow to the low-oxidative white muscle is elevated during exercise. Changes in the number of feed arteries perforating the muscle are thought to contribute to this altered hyperemic response during exercise. We tested the hypothesis that exercise training would ameliorate age-related differences in blood flow during exercise and feed artery structure in skeletal muscle. Young (6-7 mo old, n = 36) and old (24 mo old, n = 25) male Fischer 344 rats were divided into young sedentary (Sed), old Sed, young exercise-trained (ET), and old ET groups, where training consisted of 10-12 wk of treadmill exercise. In Sed and ET rats, blood flow to the red and white portions of the gastrocnemius muscle (Gast(Red) and Gast(White)) and the number and luminal cross-sectional area (CSA) of all feed arteries perforating the muscle were measured at rest and during exercise. In the old ET group, blood flow was greater to Gast(Red) (264 +/- 13 and 195 +/- 9 ml . min(-1) . 100 g(-1) in old ET and old Sed, respectively) and lower to Gast(White) (78 +/- 5 and 120 +/- 6 ml . min(-1) . 100 g(-1) in old ET and old Sed, respectively) than in the old Sed group. There was no difference in the number of feed arteries between the old ET and old Sed group, although the CSA of feed arteries from old ET rats was larger. In young ET rats, there was an increase in the number of feed arteries perforating the muscle. Exercise training mitigated old age-associated differences in blood flow during exercise within gastrocnemius muscle. However, training-induced adaptations in resistance artery morphology differed between young (increase in feed artery number) and old (increase in artery CSA) animals. The altered blood flow pattern induced by exercise training with old age would improve the local matching of O(2) delivery to consumption within the skeletal muscle. PMID- 23042909 TI - Pulsed high oxygen induces a hypoxic-like response in human umbilical endothelial cells and in humans. AB - It has been proposed that relative changes of oxygen availability, rather than steady-state hypoxic or hyperoxic conditions, play an important role in hypoxia inducible factor (HIF) transcriptional effects. According to this hypothesis describing the "normobaric oxygen paradox", normoxia following a hyperoxic event is sensed by tissues as an oxygen shortage, upregulating HIF-1 activity. With the aim of confirming, at cellular and at functional level, that normoxia following a hyperoxic event is "interpreted" as a hypoxic event, we report a combination of experiments addressing the effects of an intermittent increase of oxygen concentration on HIF-1 levels and the activity level of specific oxygen-modulated proteins in cultured human umbilical vein endothelial cells and the effects of hemoglobin levels after intermittent breathing of normobaric high (100%) and low (15%) oxygen in vivo in humans. Our experiments confirm that, during recovery after hyperoxia, an increase of HIF expression occurs in human umbilical vein endothelial cells, associated with an increase of matrix metalloproteinases activity. These data suggest that endothelial cells "interpret" the return to normoxia after hyperoxia as a hypoxic stimulus. At functional level, our data show that breathing both 15 and 100% oxygen 30 min every other day for a period of 10 days induces an increase of hemoglobin levels in humans. This effect was enhanced after the cessation of the oxygen breathing. These results indicate that a sudden decrease in tissue oxygen tension after hyperoxia may act as a trigger for erythropoietin synthesis, thus corroborating the hypothesis that "relative" hypoxia is a potent stimulator of HIF-mediated gene expressions. PMID- 23042908 TI - Exercise training improves cardiac function and attenuates arrhythmia in CPVT mice. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal ventricular arrhythmia evoked by physical or emotional stress. Recessively inherited CPVT is caused by either missense or null-allele mutations in the cardiac calsequestrin (CASQ2) gene. It was suggested that defects in CASQ2 cause protein deficiency and impair Ca(2+) uptake to the sarcoplasmic reticulum and Ca(2+)-dependent inhibition of ryanodine channels, leading to diastolic Ca(2+) leak, after-depolarizations, and arrhythmia. To examine the effect of exercise training on left ventricular remodeling and arrhythmia, CASQ2 knockout (KO) mice and wild-type controls underwent echocardiography and heart rhythm telemetry before and after 6 wk of training by treadmill exercise. qRT-PCR and Western blotting were used to measure gene and protein expression. Left ventricular fractional shortening was impaired in KO (33 +/- 5 vs. 51 +/- 7% in controls, P < 0.05) and improved after training (43 +/- 12 and 51 +/- 9% in KO and control mice, respectively, P = nonsignificant). The exercise tolerance was low in KO mice (16 +/- 1 vs. 29 +/- 2 min in controls, P < 0.01), but improved in trained animals (26 +/- 2 vs. 30 +/- 3 min, P = nonsignificant). The hearts of KO mice had a higher basal expression of the brain natriuretic peptide gene. After training, the expression of natriuretic peptide genes markedly decreased, with no difference between KO and controls. Exercise training was not associated with a change in ventricular tachycardia prevalence, but appeared to reduce arrhythmia load, as manifested by a decrease in ventricular beats during stress. We conclude that, in KO mice, which recapitulate the phenotype of human CPVT2, exercise training is well tolerated and could offer a strategy for heart conditioning against stress-induced arrhythmia. PMID- 23042910 TI - Transfusion of hemoglobin-based oxygen carriers in the carboxy state is beneficial during transient focal cerebral ischemia. AB - Exchange transfusion of large volumes of hemoglobin (Hb)-based oxygen carriers can protect the brain from middle cerebral artery occlusion (MCAO). Hb in the carboxy state (COHb) may provide protection at relatively low volumes by enhancing vasodilation. We determined whether transfusion of rats with 10 ml/kg PEGylated COHb [polyethylene glycol (PEG)-COHb] at 20 min of 2-h MCAO was more effective in reducing infarct volume compared with non-carbon monoxide (CO) PEG Hb. After PEG-COHb transfusion, whole blood and plasma COHb was <3%, indicating rapid release of CO. PEG-COHb transfusion significantly reduced infarct volume (15 +/- 5% of hemisphere; mean +/- SE) compared with that in the control group (35 +/- 6%), but non-CO PEG-Hb did not (24 +/- 5%). Chemically dissimilar COHb polymers were also effective. Induction of MCAO initially produced 34 +/- 2% dilation of pial arterioles in the border region that subsided to 10 +/- 1% at 2 h. Transfusion of PEG-COHb at 20 min of MCAO maintained pial arterioles in a dilated state (40 +/- 5%) at 2 h, whereas transfusion of non-CO PEG-Hb had an intermediate effect (22 +/- 3%). When transfusion of PEG-COHb was delayed by 90 min, laser-Doppler flow in the border region increased from 57 +/- 9 to 82 +/- 13% of preischemic baseline. These data demonstrate that PEG-COHb is more effective than non-CO PEG-Hb at reducing infarct volume, sustaining cerebral vasodilation, and improving collateral perfusion in a model of transient focal cerebral ischemia when given at a relatively low dose (plasma Hb concentration < 1 g/dl). Use of acellular Hb as a CO donor that is rapidly converted to an oxygen carrier in vivo may permit potent protection at low transfusion volumes. PMID- 23042911 TI - Endurance exercise training normalizes repolarization and calcium-handling abnormalities, preventing ventricular fibrillation in a model of sudden cardiac death. AB - The risk of sudden cardiac death is increased following myocardial infarction. Exercise training reduces arrhythmia susceptibility, but the mechanism is unknown. We used a canine model of sudden cardiac death (healed infarction, with ventricular tachyarrhythmias induced by an exercise plus ischemia test, VF+); we previously reported that endurance exercise training was antiarrhythmic in this model (Billman GE. Am J Physiol Heart Circ Physiol 297: H1171-H1193, 2009). A total of 41 VF+ animals were studied, after random assignment to 10 wk of endurance exercise training (EET; n = 21) or a matched sedentary period (n = 20). Following (>1 wk) the final attempted arrhythmia induction, isolated myocytes were used to test the hypotheses that the endurance exercise-induced antiarrhythmic effects resulted from normalization of cellular electrophysiology and/or normalization of calcium handling. EET prevented VF and shortened in vivo repolarization (P < 0.05). EET normalized action potential duration and variability compared with the sedentary group. EET resulted in a further decrement in transient outward current compared with the sedentary VF+ group (P < 0.05). Sedentary VF+ dogs had a significant reduction in repolarizing K(+) current, which was restored by exercise training (P < 0.05). Compared with controls, myocytes from the sedentary VF+ group displayed calcium alternans, increased calcium spark frequency, and increased phosphorylation of S2814 on ryanodine receptor 2. These abnormalities in intracellular calcium handling were attenuated by exercise training (P < 0.05). Exercise training prevented ischemically induced VF, in association with a combination of beneficial effects on cellular electrophysiology and calcium handling. PMID- 23042912 TI - Exercise alters mRNA expression of telomere-repeat binding factor 1 in skeletal muscle via p38 MAPK. AB - Telomeres protect chromosome ends and shorten with age in most tissues. Integral to the maintenance of telomeres is the protein complex shelterin. The gene expression regulation of shelterin proteins to physiological stressors is not understood in vivo. We have recently reported increased telomere-repeat binding factor 1 (TRF1) protein expression and longer telomere length in skeletal muscle of sedentary compared with chronically active mice. These provocative observations led us to examine the effects of acute physiological stress on shelterin expression in vivo in mice and to further define potential mechanisms associated with gene regulation of shelterin. Three groups of female C57Bl/6 mice were studied: one control group and two groups that underwent a 30-min treadmill running bout and were killed either immediately following or 1-h after the exercise. Following the exercise bout, mRNA expression of Trf1 was significantly reduced in the plantaris muscle, and this reduction was paralleled by significant increases in p38 MAPK phosphorylation. To determine if p38 mediated the decreases in Trf1 mRNA expression, C2C12 myotubes were treated with the calcium ionophore, A23187. In response to the A23187, Trf1 gene expression was significantly reduced, coupled with significant increases in p38 phosphorylation, similar to in vivo data. C2C12 myotubes pretreated with a p38 inhibitor (SB-202190) prevented the A23187-induced decrease in Trf1 mRNA expression, indicating a link between Trf1 gene expression and p38 MAPK activation. While it is too early to definitively report the effect of exercise on telomere biology in rodents or humans, these data provide important mechanistic insights into the paradoxical telomere shortening that occurs in skeletal muscle in response to chronic exercise in mice. PMID- 23042914 TI - Teaching quality essentials: the effectiveness of a team-based quality improvement curriculum in a tertiary health care institution. AB - A unique quality improvement (QI) curriculum was implemented within the Division of General Internal Medicine to improve QI knowledge through multidisciplinary, team-based education, which also met the QI requirement for the American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) and the Mayo Quality Fellows program. Participants completed up to 4 QI learning modules, including pretest and posttest assessments. A participant who successfully completed all 4 modules received certification as a Silver Quality Fellow and credit toward the quality requirement for ABIM MOC. Of 62 individuals invited to participate, 33 (53%) completed all 4 modules and corresponding pretests and posttests. Participants substantially improved knowledge in all 4 quality modules. Study group participants' pretest scores averaged 71.0%, and their posttest scores averaged 92.7%. Posttest scores of reference group participants compared favorably, averaging 89.2%. Initial assessments showed substantial knowledge improvements and successful implementation of staff-developed QI projects. PMID- 23042915 TI - Using qualitative measures to improve quality in radiation oncology. AB - This article introduces the use of qualitative research techniques in the field of radiation oncology with respect to quality improvement initiatives. The qualitative techniques used in this research include field observations and in depth, one-on-one interviews with radiation therapy technologists. The observations were conducted in a fast-paced academic institution. This high pressure, high-throughput environment provided an interesting location for observation of behaviors, workflows, and areas of improvement. Qualitative research is a useful platform for formulating questions and addressing the environment on a larger scale. The information resulting from this research led to immediate changes that improved the efficiency and effectiveness of care provided to patients and identified future initiatives to improve patient safety and the timeliness of care provided. Overall, qualitative research proved to be an exceptional resource for identifying and evaluating a clinical department and demonstrated the usefulness of this method of research for future work. PMID- 23042913 TI - Increased ceramide content and NFkappaB signaling may contribute to the attenuation of anabolic signaling after resistance exercise in aged males. AB - One of the most fundamental adaptive physiological events is the response of skeletal muscle to high-intensity resistance exercise, resulting in increased protein synthesis and ultimately larger muscle mass. However, muscle growth in response to contraction is attenuated in older humans. Impaired contractile induced muscle growth may contribute to sarcopenia: the age-associated loss of muscle mass and function that is manifested by loss of strength, contractile capacity, and endurance. We hypothesized that the storage of ceramide would be increased in older individuals and this would be associated with increases in NFkappaB signaling and a decreased anabolic response to exercise. To test this hypothesis we measured ceramides at rest and anabolic and NFkappaB signaling after an acute bout of high-intensity resistance exercise in young and older males. Using lipidomics analysis we show there was a 156% increase in the accumulation of C16:0-ceramide (P < 0.05) and a 30% increase in C20:0-ceramide (P < 0.05) in skeletal muscle with aging, although there was no observable difference in total ceramide. C16:0-ceramide content was negatively correlated (P = 0.008) with lower leg lean mass. Aging was associated with a ~60% increase in the phosphorylation of the proinflammatory transcription factor NFkappaB in the total and nuclear cell fractions (P < 0.05). Furthermore, there was an attenuated activation of anabolic signaling molecules such as Akt (P < 0.05), FOXO1 (P < 0.05), and S6K1 (P < 0.05) after an acute bout of high-intensity resistance exercise in older males. We conclude that ceramide may have a significant role in the attenuation of contractile-induced skeletal muscle adaptations and atrophy that is observed with aging. PMID- 23042916 TI - Commentary: decentralizing quality improvement. PMID- 23042917 TI - MR imaging of cerebral extraventricular neurocytoma: a report of 9 cases. AB - Extraventricular neurocytoma is a rare entity, most frequently occurring in brain parenchyma outside the ventricular system. The purpose of this study was to characterize the MR imaging findings in a series of 9 patients with EVN verified by results of pathologic examination. All 9 EVNs were solitary and intracranially located. Eight lesions were well demarcated, and 3 showed intratumoral hemorrhage. The solid parts of 7 tumors were primarily isointense on T1-weighted images and heterogeneously enhanced on T1WI with contrast. Although cerebral EVNs can present a wide spectrum of appearances on MR, the imaging patterns appear to vary according to anatomic location and cellularity. Lesions in frontal or parietal lobes often present as well-demarcated large masses with cystic degeneration, hemorrhage, mild-to-moderate edema, and inhomogeneous enhancement. Moreover, the general isointensity of the solid parts of EVN on T1WI may be of some specificity. PMID- 23042918 TI - Assessment of follow-up sonography and clinical improvement among infants with congenital muscular torticollis. AB - BACKGROUND AND PURPOSE: Infants grow rapidly, which causes the SCM to thicken physiologically. Therefore some cases of physiologically-thickened SCM can be confused with a poor response to physical therapy. There have been only a few quantitative ultrasonographic studies on the clinical outcome of rehabilitation for CMT. Our aim was to evaluate whether a new sonographic assessment method that uses the muscular thickness ratio of the SCM can help quantify the outcome of rehabilitation therapy for patients with CMT. MATERIALS AND METHODS: We evaluated 48 patients (male/female, 17:31; mean age, 3.9 months) who were diagnosed with CMT and who underwent initial and follow-up sonography. The ratio of the thickness of the involved SCM to the thickness of the intact SCM (SCM thickness ratio) was calculated. A scoring system based on the range of motion of the neck was used to assess clinical improvement. The correlations between clinical improvement and the thickness of the involved muscle, the difference in involved muscle thickness, the SCM thickness ratio, and the difference in the SCM thickness ratio were evaluated with Spearman rank correlations. RESULTS: Follow up Cheng scores were higher than initial scores; this difference indicates clinical resolution (follow-up, 4.90; initial, 3.38). The SCM thickness ratio at follow-up was lower than that at the initial evaluation (follow-up, 1.29-1.34; initial, 1.65-1.77). Intra- and interobserver agreements were excellent. Most variables were moderately correlated with clinical improvement (correlation coefficients, 0.36-0.509). R1 showed the highest correlation with clinical improvement (0.481 and 0.509), followed by the initial maximal thickness of the SCM (0.434 and 0.488). DeltaP (P1-P2) and DeltaR showed similar correlation coefficients with clinical improvement. CONCLUSIONS: Measurement of the SCM thickness ratio appears to overcome the problem of a false-positive diagnosis of clinical aggravation of CMT resulting from physiologic growth. R1 and DeltaR are accurate objective measurements, which can be used in the management of CMT. PMID- 23042919 TI - Carotid artery plaque characterization using CT multienergy imaging. AB - BACKGROUND AND PURPOSE: Carotid artery plaque types can be categorized with CT according to their HU values. The purpose of this work was to analyze carotid artery plaque characteristics by using multienergy imaging. METHODS AND MATERIALS: Thirty-two consecutive patients (23 men; median age, 70 years) were retrospectively analyzed. Carotid arteries were studied with a multienergy CT scanner. All patients received a 15-mL timing bolus of contrast medium to synchronize the data acquisition followed by an injection of 60 mL of contrast medium at a 5-mL/s flow rate. Plaque analysis in 64 carotid arteries was performed, and datasets were reconstructed by using a dedicated workstation. For each plaque, the HU value was quantified with a 2-mm-square region of interest at monoenergy values of 66, 70, 77, and 86 keV. The Wilcoxon test was used to test the differences in HU values in the plaques at different kiloelectron volts. RESULTS: Four carotid arteries were excluded due to the absence of plaque, and another 7, because of the presence of calcified plaques. In the remaining 53 carotid arteries, Wilcoxon analysis showed a statistically significant difference in HU values among the monoenergy values of 66, 70, 77, and 86 keV (P=.0001). In particular, we found that with the increase in monochromatic kiloelectron volt values, there is a statistically significant reduction in the HU value of the plaque. CONCLUSIONS: Results of this study suggest that the HU values of plaque may significantly change according to the selected kiloelectron volt; therefore, the HU-based plaque type (fatty, mixed, calcified) should be classified according to the energy level applied. PMID- 23042920 TI - Abnormal interhemispheric connectivity in neonates with D-transposition of the great arteries undergoing cardiopulmonary bypass surgery. AB - BACKGROUND AND PURPOSE: Neonates with severe CHD require CPB within the first days of life. White matter injury can occur before surgery, and this may impair the long-term neurodevelopmental and psychosocial outcome. The purpose of this study was to assess the microstructural development of the CC in infants with CHD before and after CPB for transposition of the great arteries. MATERIALS AND METHODS: Fifteen patients with CHD and 11 age-matched HC were recruited. We separately quantified the parallel (E1) and perpendicular (E23) diffusions, the ADC, and FA of the genu of the CC and splenium of the CC before and after surgery. RESULTS: In presurgical measures of the genu of the CC, higher E23 (P = .018), higher ADC (P = .026), and lower FA (P = .033) values were measured compared with those in HC. In the postsurgery scans, the genu of the CC had higher E23 (P = .013), higher ADC (P = .012), and lower FA (P = .033) values compared with those in HC. There was no significant difference in any DTI indices between the pre- and postsurgical groups. CONCLUSIONS: We report abnormal microstructural development in the genu of the CC of infants with d-TGA before and after CPB. High E23, high ADC, and low FA values in the genu of the CC may be explained by abnormal axonal pruning, thinner myelin sheaths, smaller axonal diameters, or more oligodendrocytes. It appears that the genu of the CC is more vulnerable than the splenium of the CC in patients with CHD and may serve as a biomarker to identify infants at highest risk for adverse neurodevelopmental outcome. PMID- 23042921 TI - Parotid gland atrophy in patients with chronic trigeminal nerve denervation. AB - BACKGROUND AND PURPOSE: Trigeminal nerve injury or dysfunction is associated with denervation atrophy of muscles innervated by the mandibular branch of the trigeminal nerve. The purpose of our study was to evaluate the association between chronic CN V denervation and parotid gland atrophy. MATERIALS AND METHODS: Twenty-six patients with chronic masticator muscle atrophy were retrospectively identified and evaluated for the presence of ipsilateral parotid gland atrophy. Twenty-six age-matched control subjects with no clinical or imaging evidence of chronic masticator space atrophy were also identified. Segmentation of the parotid gland was performed to calculate a parotid asymmetry index. The Fisher exact test and t test were respectively used to determine the correlation between parotid gland atrophy and ipsilateral masticator muscle atrophy and to evaluate any difference in the size of the involved parotid gland when compared with that in the control subjects. RESULTS: Ipsilateral parotid gland atrophy was seen in 9/26 (42.8%) patients with fatty replacement of the masticator group of muscles, suggesting a correlation between parotid gland atrophy and CN V denervation (P<.001). The parotid asymmetry index was significantly different in patients with CN V denervation (0.59+/-0.25) compared with control subjects (0.92+/-0.03) (P<.001). CONCLUSIONS: Ipsilateral parotid gland atrophy can accompany chronic CN V denervation change, and its clinical significance remains to be determined. PMID- 23042922 TI - Multicenter, intraindividual comparison of single-dose gadobenate dimeglumine and double-dose gadopentetate dimeglumine for MR angiography of the supra-aortic arteries (the Supra-Aortic VALUE study). AB - BACKGROUND AND PURPOSE: Gadobenate dimeglumine has markedly higher R1 relaxivity compared to gadopentetate dimeglumine meaning that lower doses can be used to achieve similar contrast enhancement. Our aim was to prospectively compare single dose gadobenate dimeglumine with double-dose gadopentetate dimeglumine for contrast-enhanced MRA of the supra-aortic vasculature. MATERIALS AND METHODS: Forty-six patients (37 men, 9 women; mean age, 63.5+/-10.1 years) with known or suspected steno-occlusive disease of the supra-aortic vessels underwent 2 identical CE-MRA examinations at 1.5T. Contrast agents were administered in randomized order, with the 2-fold greater volume of gadopentetate dimeglumine injected at a 2 times faster rate. Image assessment was performed by 3 independent blinded readers for vessel anatomic delineation, detection/exclusion of pathology, and global preference. Diagnostic performance (sensitivity, specificity, accuracy, PPV, and NPV) for detection of >=60% stenosis was determined for 39/46 patients who underwent preinterventional DSA. Data were analyzed by using the Wilcoxon signed-rank, McNemar, and Wald tests in terms of the noninferiority of single-dose gadobenate dimeglumine compared with double dose gadopentetate dimeglumine. Quantitative enhancement (signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR)) was also compared. RESULTS: All images were technically adequate. No differences (P=1.0) were noted by any reader for any qualitative parameter. All readers considered single-dose gadobenate dimeglumine and double-dose gadopentetate dimeglumine equivalent in at least 42/46 patients (91.3% three-reader agreement) for all parameters. Nonsignificant superiority for gadobenate dimeglumine was reported for all diagnostic performance indicators (sensitivity: 82.7%-88.5% versus 75.0%-80.8%; specificity: 96.4%-98.6% versus 94.6%-98.6%; accuracy: 94.6%-96.1% versus 92.4%-94.9%; PPV: 81.5%-91.5% versus 73.7%-90.7%; NPV: 96.8%-97.8% versus 95.4%-96.4%). No differences (P>.05) in quantitative enhancement were noted. CONCLUSIONS: The image quality and diagnostic performance achieved with 0.1-mmol/kg gadobenate dimeglumine is at least equivalent to that achieved with 0.2-mmol/kg gadopentetate dimeglumine. PMID- 23042923 TI - Automated segmentation of hippocampal subfields in drug-naive patients with Alzheimer disease. AB - BACKGROUND AND PURPOSE: Although a few automated hippocampal subfield segmentation methods have been developed, there is no study on the effects of the diagnosis of Alzheimer disease on the hippocampal subfield volume with in vivo MR imaging. The aim of this study was to investigate hippocampal subfield volume differences between drug-naive subjects with AD and healthy elderly controls by using an automated hippocampal subfield segmentation technique. MATERIALS AND METHODS: Thirty-one drug-naive subjects with AD and 33 group-matched healthy control subjects underwent 3T MR imaging, and hippocampal subfield volume was measured and compared between the groups. RESULTS: Subjects with AD had significantly smaller volumes of the presubiculum, subiculum, CA2-3, and CA4 DG compared with healthy subjects (uncorrected, P<.001). In addition, we found significant positive correlations between the presubiculum and the subicular volumes and the MMSE-K and the CERAD-K verbal delayed recall scores in the AD group. CONCLUSIONS: We are unaware of previous imaging studies of automated hippocampal subfield segmentation in AD. These structural changes in the hippocampal presubiculum, subiculum, and CA2-3 might be at the core of underlying neurobiologic mechanisms of hippocampal dysfunction and their relevance to verbal delayed recall impairments in AD. PMID- 23042924 TI - Prediction of aphasia outcome using diffusion tensor tractography for arcuate fasciculus in stroke. AB - BACKGROUND AND PURPOSE: The AF is an important neural tract in language function. We investigated aphasia outcome according to DTT findings for AF in the early stage of stroke. MATERIALS AND METHODS: Twenty-five consecutive patients with aphasia and stroke and 12 control subjects were recruited. The AQ of K-WAB was used for the assessment of aphasia in the early stage of stroke (10-30 days) and at approximately 6 months after onset. We classified the patients into 3 groups according to the severity of left AF injury: type A, the AF was not reconstructed; type B, the AF was disrupted; and type C, the AF was preserved around the lesion. RESULTS: When comparing AQ among AF types at early evaluation, the type C score (32.84+/-18.05) was significantly higher than type A (3.60+/ 2.73) (P<.05). However, no significant difference was observed between types A and B (18.02+/-17.19) or between types B and C (P>.05). At late evaluation, the AQ values of types B (52.43+/-25.75) and C (68.08+/-15.76) were higher than that of type A (10.98+/-3.90) (P<.05). However, there was no significant difference between types B and C. CONCLUSIONS: The aphasia outcome of the patients whose left AF could be reconstructed was better than that in patients whose left AF could not be reconstructed, irrespective of its integrity. We believe that evaluation of the left AF by using DTT in the early stage of stroke could be helpful in predicting aphasia outcome in patients with stroke. PMID- 23042925 TI - Some things are better left unsaid. PMID- 23042926 TI - Neuroradiology critical findings lists: survey of neuroradiology training programs. AB - BACKGROUND AND PURPOSE: The Joint Commission has identified timely reporting of critical results as one of the National Patient Safety Goals. We surveyed directors of neuroradiology fellowships to assess and compare critical findings lists across programs. MATERIALS AND METHODS: A 3-question survey was e-mailed to directors of neuroradiology fellowships with the following questions: 1) Do you currently have a "critical findings" list that you abide by in your neuroradiology division? 2) How is that list distributed to your residents and fellows for implementation, if at all? and 3) Was this list vetted by neurology, neurosurgery, and otolaryngology departments? Programs with CF lists were asked for a copy of the list. Summary and comparative statistics were calculated. RESULTS: Fifty-one of 89 (57.3%) programs responded. Twenty-one of 51 (41.2%) programs had CF lists. Lists were distributed during orientation, sent via Web sites and e-mails, and posted in work areas. Eleven of 21 lists were developed internally, and 5 of 21, with the input from other departments. The origin of 5 of 21 lists was unknown. Forty CF entities were seen in 20 submitted lists (mean, 9.1; range, 2-23). The most frequent entities were the following: cerebral hemorrhage (18 of 20 lists), acute stroke (15 of 20), spinal cord compression (15 of 20), brain herniation (12 of 20), and spinal fracture/instability (12 of 20). Programs with no CF lists called clinicians on the basis of "common sense" and "clinical judgment." CONCLUSIONS: Less than a half (41.2%) of directors of neuroradiology fellowships that responded have implemented CF lists. CF lists have variable length and content and are predominantly developed by radiology departments without external input. PMID- 23042928 TI - Screening cervical spine CT in the emergency department, Phase 2: A prospective assessment of use. AB - BACKGROUND AND PURPOSE: The National Emergency X-Radiography Utilization Study Low-Risk Criteria were established to identify patients with a low probability of cervical spine injury in whom imaging of the cervical spine was unnecessary. The purpose of this study was to ascertain the number of unnecessary cervical spine CT studies on the basis of proper application of established clinical guidelines and, secondarily, to determine indications for ordering studies in the absence of guideline criteria. MATERIALS AND METHODS: All patients presenting to a level I trauma center for whom a screening cervical spine CT was ordered in the setting of blunt trauma were eligible for enrollment. For each study, the requesting clinician completed a survey regarding study indications. CT examinations were evaluated by a board-certified radiologist blinded to survey data to determine the presence or absence of cervical spine injury. RESULTS: Of 507 CT examinations, 5 (1%) were positive and 497 (98.0%) were negative for acute cervical spine injury. Five studies (1%) were indeterminate for acute injury but demonstrated no abnormality on subsequent imaging and clinical follow-up. Of the 502 studies without cervical spine injury, 81 (16.1%) were imaged despite meeting all 5 NEXUS criteria for nonimaging. Of these, the most common study indication was dangerous mechanism of injury (48.1%) followed by subjective neck pain (40.7%). CONCLUSIONS: Strict application of NEXUS criteria could potentially reduce the number of screening cervical spine CT scans in the setting of blunt trauma; this change would avoid a considerable amount of unnecessary radiation and cost. PMID- 23042927 TI - Assessment of disease severity in late infantile neuronal ceroid lipofuscinosis using multiparametric MR imaging. AB - BACKGROUND AND PURPOSE: LINCL is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene that encodes for tripeptidyl peptidase 1, a lysosomal enzyme necessary for the degradation of products of cellular metabolism. With the goal of developing quantitative noninvasive imaging biomarkers sensitive to disease progression, we evaluated a 5-component MR imaging metric and tested its correlation with a clinically derived disease severity score. MATERIALS AND METHODS: MR imaging parameters were measured across the brain, including quantitative measures of the ADC, FA, nuclear spin-spin relaxation times (T2), volume percentage of CSF (%CSF), and NAA/Cr ratios. Thirty MR imaging datasets were prospectively acquired from 23 subjects with LINCL (2.5 8.4 years of age; 8 male/15 female). Whole-brain histograms were created, and the mode and mean values of the histograms were used to characterize disease severity. RESULTS: Correlation of single MR imaging parameters against the clinical disease-severity scale yielded linear regressions with R2 ranging from 0.25 to 0.70. Combinations of the 5 biomarkers were evaluated by using PCA. The best combination included ADC, %CSF, and NAA/Cr (R2=0.76, P<.001). CONCLUSIONS: The multiparametric disease-severity score obtained from the combination of ADC, %CSF, and NAA/Cr whole-brain MR imaging techniques provided a robust measure of disease severity, which may be useful in clinical therapeutic trials of LINCL in which an objective assessment of therapeutic response is desired. PMID- 23042929 TI - Endovascular treatment of posterior communicating artery aneurysms with oculomotor nerve palsy: clinical outcomes and predictors of nerve recovery. AB - BACKGROUND AND PURPOSE: ONP is a well-known presentation of PcomA aneurysms. Reports on recovery of ONP with endovascular coiling have been limited to small case series. We assessed the safety and efficacy of endovascular therapy in a series of PcomA aneurysms with ONP. MATERIALS AND METHODS: We reviewed 37 patients with ONP who underwent endovascular treatment in our institution between 2005 and 2011. Published studies were also reviewed to determine the overall rate of ONP recovery with endovascular therapy. RESULTS: Nineteen patients (51.4%) presented with complete ONP, and 18 (48.6%), with partial ONP. Conventional coiling was performed in 31 (83.8%) patients; stent-assisted coiling, in 4 (10.8%); and balloon remodeling, in 2 (5.4%). There was 1 (2.7%) procedural complication (a transient thromboembolic event). Twenty-seven (73%) patients were treated within 3 days from symptom onset. At the last available clinical follow up, ONP resolution was complete in 14 (37.8%) patients and partial in 19 (51.4%). Only 4 (10.8%) patients showed no signs of nerve recovery. In multivariate analysis, partial ONP and longer follow-up durations were predictors of complete nerve recovery. Treatment timing, type of endovascular embolization, subarachnoid hemorrhage, and initial degree of aneurysm occlusion were not predictors of nerve recovery. Of 169 patients reported in the literature (including ours), ONP resolved completely in 73 (43.2%) patients and partially in 73 (43.2%). CONCLUSIONS: Endovascular therapy is a safe and highly efficient alternative to surgical clipping for PcomA aneurysms with ONP. PMID- 23042930 TI - Multicontrast MR imaging at 7T in multiple sclerosis: highest lesion detection in cortical gray matter with 3D-FLAIR. AB - BACKGROUND AND PURPOSE: 7T MR imaging has led to improved detection and classification of cortical MS lesions, mainly based on T2*-weighted gradient-echo sequences. Depiction of cortical GM by using the recommended MS imaging protocol has not yet been investigated at 7T. We aimed to investigate prospectively which recommended sequence for clinical use has the highest value at 7T, in terms of GM and WM lesion detection. MATERIALS AND METHODS: Thirty-seven patients with MS (mean age, 43.8 years; 25 women) and 7 healthy controls (mean age, 40.4 years; 5 women) underwent multicontrast 7T MR imaging including the recommended clinical 2D-T2WI, 3D-T1WI, 3D-FLAIR, and GM-specific 3D-DIR. Lesions were scored and categorized anatomically by 3 raters, in consensus. The value of sequences was evaluated lesion-wise and patient-wise (Wilcoxon signed-rank test). RESULTS: At 7T, 3D-FLAIR detected the highest number of total cortical GM lesions (217), 89% more than 3D-DIR and 87% and 224% more than 2D-T2WI and 3D-T1WI. Patient-wise analysis showed that this difference between 3D-FLAIR and 3D-DIR was statistically significant (P<.04), and most pronounced for the number of mixed lesions (P<.03). 3D-FLAIR also detected the highest number of total WM lesions (2605), but the difference with 3D-DIR and 3D-T1WI was not significant. CONCLUSIONS: When using recommended clinical sequences at 7T, the best way to detect cortical GM lesions is with 3D-FLAIR and not by GM-specific 3D-DIR or by conventional 2D-T2WI and 3D-T1WI sequences. PMID- 23042931 TI - Ocular volumetry using fast high-resolution MRI during visual fixation. AB - BACKGROUND AND PURPOSE: Volumetry may be useful for evaluating treatment response and prognosis of intraocular lesions. Phantom, volunteer, and patient studies were performed to determine whether ocular MR volumetry is reproducible. MATERIALS AND METHODS: Half-Fourier single-shot RARE and FSPGR sequences at 1.5T with a 76-mm-diameter surface coil were optimized to obtain still ocular images. Volumetry accuracies of each sequence were compared with simulated subretinal phantom volumes. Ocular volumetry was performed in 15 volunteers twice in 1 week by using contiguous axial images of the globes while the subjects stared at a target, and images were acquired in 2 seconds before the subjects were instructed to blink, with this process repeated as necessary. Imaging, intraobserver, and interobserver reproducibility for volumes of the whole eyeball and anterior chamber were assessed. Ocular volumetry was also performed in 6 patients with intraocular tumors before and after treatment. RESULTS: The phantom study demonstrated that measurement error rates with RARE were significantly lower than with FSPGR (P<.01). The volunteer study demonstrated excellent imaging and intraobserver reproducibility of RARE volumetry for whole eyeballs and anterior chambers (P<.01). Although no interobserver differences were observed in anterior chamber volume measurement (P=.33), there was a significant difference between the 2 observers in eyeball volume measurement (P<.01). Follow-up volumetric data were useful for treatment decisions in all patients. CONCLUSIONS: Ocular volumetry from contiguous ultrafast RARE images obtained during visual fixation is feasible in volunteer and patient studies and is superior to FSPGR images. PMID- 23042932 TI - Impact of the HIV epidemic on the incidence rates of anal cancer in the United States. AB - BACKGROUND: The risk of anal cancer is substantially increased in HIV-infected individuals. Thus, the HIV epidemic may have influenced the increasing anal cancer trends in the United States. We estimated the impact of the HIV epidemic on trends in anal cancer incidence in the United States during 1980-2005. METHODS: Data on anal cancer cases with and without AIDS were obtained from the HIV/AIDS Cancer Match Study. The number of HIV-infected anal cancer cases without AIDS was estimated from the number of anal cancers occurring before diagnosis of AIDS. The proportion of anal cancer cases with HIV infection in the general population was calculated. We estimated temporal trends in the incidence rates of anal cancer in the general population overall and after exclusion of HIV-infected cancer cases by calculating annual percent changes and 95% confidence intervals (CIs) using a Joinpoint log-linear model. All incidence rates were standardized to the 2000 US population by age, sex, and race. RESULTS: During 1980-2005, of the 20 533 estimated anal cancer cases, 1665 (8.1%) were HIV-infected. During 2001-2005, the proportion of anal cancer cases with HIV infection was the highest 1.2% (95% CI = 0.93 to 1.4%) among females and 28.4% (95% CI = 26.6 to 29.4%) among males. During 1980-2005, HIV infection did not have an impact on the trends in anal cancer among females (incidence rates increased by 3.3% [95% CI = 3.0 to 3.7%] annually overall, and by 3.3% [95% CI = 2.9 to 3.6%] annually without HIV infected anal cancer cases) but had a strong impact on the trends in anal cancer among males (incidence rates increased by 3.4% [95% CI = 2.9 to 3.9%] annually overall, and by 1.7% [95% CI = 1.2 to 2.3%] annually without HIV infection). CONCLUSION: During 1980-2005, the increasing anal cancer incidence rates in the United States were strongly influenced by the HIV epidemic in males but were independent of HIV infection in females. PMID- 23042934 TI - Re: Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study. PMID- 23042935 TI - JNIS: factoring the impact. PMID- 23042933 TI - Selective inhibition of HER2-positive breast cancer cells by the HIV protease inhibitor nelfinavir. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly aggressive and has higher risk of recurrence than HER2-negative cancer. With few treatment options available, new drug targets specific for HER2 positive breast cancer are needed. METHODS: We conducted a pharmacological profiling of seven genotypically distinct breast cancer cell lines using a subset of inhibitors of breast cancer cells from a screen of the Johns Hopkins Drug Library. To identify molecular targets of nelfinavir, identified in the screen as a selective inhibitor of HER2-positive cells, we conducted a genome-wide screen of a haploinsufficiency yeast mutant collection. We evaluated antitumor activity of nelfinavir with xenografts in athymic nude mouse models (n = 4-6 per group) of human breast cancer and repeated mixed-effects regression analysis. All statistical tests were two-sided. RESULTS: Pharmacological profiling showed that nelfinavir, an anti-HIV drug, selectively inhibited the growth of HER2-positive breast cancer cells in vitro. A genome-wide screening of haploinsufficiency yeast mutants revealed that nelfinavir inhibited heat shock protein 90 (HSP90) function. Further characterization using proteolytic footprinting experiments indicated that nelfinavir inhibited HSP90 in breast cancer cells through a novel mechanism. In vivo, nelfinavir selectively inhibited the growth of HER2-positive breast cancer cells (tumor volume index of HCC1954 cells on day 29, vehicle vs nelfinavir, mean = 14.42 vs 5.16, difference = 9.25, 95% confidence interval [CI] = 5.93 to 12.56, P < .001; tumor volume index of BT474 cells on day 26, vehicle vs nelfinavir, mean = 2.21 vs 0.90, difference = 1.31, 95% CI = 0.83 to 1.78, P < .001). Moreover, nelfinavir inhibited the growth of trastuzumab- and/or lapatinib resistant, HER2-positive breast cancer cells in vitro at clinically achievable concentrations. CONCLUSION: Nelfinavir was found to be a new class of HSP90 inhibitor and can be brought to HER2-breast cancer treatment trials with the same dosage regimen as that used among HIV patients. PMID- 23042936 TI - Role of SPECT/CT, versus traditional practices, in individualizing treatment of thyroid carcinoma. PMID- 23042938 TI - A pathognomonic symptom of bipolar disorder. PMID- 23042939 TI - Does accumulating exposure to illicit drugs bring forward the age at onset in schizophrenia? AB - OBJECTIVE: Whilst cannabis has been associated with an earlier age at onset in schizophrenia, the impact of amphetamine and/or cocaine plus cannabis consumption on age at onset remains unclear. The present study was designed to test the hypothesis that consumption of amphetamine and/or cocaine in addition to cannabis would lead to an earlier age at onset of schizophrenia than that seen for cannabis consumption alone. A secondary objective was to determine what kind of effect additional substance use exerted (e.g. additive, multiplicative). METHOD: Patients with a diagnosis of schizophrenia were recruited from consecutive admissions to the inpatient and outpatient services of a large psychiatric hospital in Perth, Australia and 167 participants were assessed using the Diagnostic Interview for Psychosis, which included detailed inquiry into illicit drug use in the 12 months prior to the onset of psychiatric symptoms. Participants were categorized into four groups: no illicit substance use (n = 65), cannabis use (n = 68), cannabis plus amphetamine use (n = 25), and cocaine plus cannabis/cocaine plus cannabis plus amphetamine use (n = 9). Analysis of variance was performed to detect trends, and linear regression used to analyze the consumption of each additional substance as a predictor of age at onset. RESULTS: We observed a linear trend for mean age at onset: 23.34 (SD = 6.91) years for no illicit substance use, 22.51 (SD = 5.27) years for cannabis use, 20.84 (SD = 3.48) years for cannabis plus amphetamine use, and 19.56 (SD = 3.54) years for cocaine plus cannabis/cocaine plus cannabis plus amphetamine use; the variation in the means between groups was statistically significant: F(1,163) = 5.66, p = 0.008, Cohen's d = 0.38. For the consumption of each additional substance, age at onset was earlier by 1.2 years: R (2) = 0.034, F(1,165) = 5.72, p = 0.018. CONCLUSIONS: Whilst preliminary, these findings suggest that additional consumption of each substance predicted an earlier age at onset by approximately 1 additional year. PMID- 23042940 TI - Fingolimod exacerbated affective psychosis? PMID- 23042941 TI - Aquaporin-9 and urea transporter-A gene deletions affect urea transmembrane passage in murine hepatocytes. AB - In mammals, the majority of nitrogen from protein degradation is disposed of as urea. Several studies have partly characterized expression of urea transporters (UTs) in hepatocytes, where urea is produced. Nevertheless, the contribution of these proteins to hepatocyte urea permeability (P(urea)) and their role in liver physiology remains unknown. The purpose of this study was to biophysically examine hepatocyte urea transport. We hypothesized that the water, glycerol, and urea channel aquaporin-9 (AQP9) is involved in hepatocyte urea release. Stopped flow light-scattering measurements determined that the urea channel inhibitors phloretin and dimethylurea reduced urea permeability of hepatocyte basolateral membranes by 70 and 40%, respectively. In basolateral membranes isolated from AQP9(-/-) and UT-A1/3(-/-) single-knockout and AQP9(-/-):UT-A1/3(-/-) double knockout mice, P(urea) was decreased by 30, 40, and 76%, respectively, compared with AQP9(+/-):UT-A1/3(+/-) mice. However, expression analysis by RT-PCR did not identify known UT-A transcripts in liver. High-protein diet followed by 24-h fasting affected the concentrations of urea and ammonium ions in AQP9(-/-) mouse liver and plasma without generating an apparent tissue-to-plasma urea gradient. We conclude that AQP9 and unidentified UT-A urea channels constitute primary but redundant urea facilitators in murine hepatocytes. PMID- 23042943 TI - Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma. AB - The nuclear receptor farnesoid X receptor (FXR) acts as a liver protector by regulating normal liver homeostasis. Spontaneously developed liver tumors have been found in FXR-null mice. However, the role of FXR in the tumorigenesis of human hepatocellular carcinoma (HCC) is still poorly understood. In this study, we measured the expression of FXR and its primary target gene, small heterodimer partner, and analyzed the clinical significance of FXR expression in HCC patients. A lentiviral vector that selectively overexpresses FXR was used to investigate the function of FXR in HCC cell proliferation both in vitro and in vivo. Our data showed that in human HCC, FXR expression was significantly reduced and was positively correlated with multiple malignant clinicopathological characteristics. Lentivirus-mediated exogenous FXR expression resulted in a marked increase of small heterodimer partner expression, significant repression of liver cancer cell proliferation, and tumor growth in nude mice. These results suggest that FXR may be of clinical and pharmacological importance as a promising biomarker of HCC. PMID- 23042942 TI - Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea. AB - Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0-2 h for SB and 8-24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability (P < 0.001), a borderline increase in colonic permeability (P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8 negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients. PMID- 23042944 TI - The function of suffering as portrayed in the Scarlet Letter and reflected in clinical work. AB - Suffering is commonly seen as an unconscious effort to alleviate painful feelings of guilt. However, suffering also aims at averting loss of ego functions and hence loss of mental stability. This second function of suffering is discussed in the light of Freud's observations of characters wrecked by success and Weiss's ideas about mutual love as a threat to mental stability. Hawthorne's portrayal of Arthur Dimmesdale in The Scarlet Letter (1850), biographical material about the author, material from his diaries, and material from a psychotherapy case and an analysis illustrate the function of suffering to preserve mental stability in the face of heightened success and happiness. Hawthorne, it is argued, intuitively grasped this function of suffering in his novel. PMID- 23042945 TI - The side population phenomenon enriches for designated adrenocortical progenitor cells in mice. AB - Somatic adrenal stem cells are believed to reside in the periphery of the adrenal cortex throughout life for organ maintenance. Herein, we used the side population (SP) phenomenon to enrich for these progenitors, which made up to 0.01-0.64% of the total cell count. Microarray analysis revealed an expression profile of SP cells, which clearly differed from that of non-SP cells. However, a promising adrenal specific stem cell marker could not be identified. In vitro, SP cells could be maintained in long-term culture, whereas non-SP cells did not proliferate. After 4 weeks of culturing, immunohistochemistry revealed the expression of steroidogenic enzymes such as 3beta-HSD, StAR, and P450SCC, suggesting spontaneous differentiation. Interestingly, the quantity of SP cells was significantly diminished in Pbx1 haploinsufficient mice, suggesting a stem cell deficit. By contrast, the subcapsular zone of ACTH-deficient Tpit(-/-) mice was significantly wider compared with wild-type adrenals (Tpit(-/-) 259+/-10.7 vs Tpit(+/-) 100+/-12.3%; P<0.01). Accordingly, the number of SP cells in these mice was significantly higher (Tpit(-/-) 0.45+/-0.16 vs Tpit(+/-) 0.13+/-0.04%; P<0.004). ACTH treatment of these animals reverted the subcapsular zone width and the SP fraction back to normal (130+/-10.2%; P=0.33 and 0.09%), providing indirect evidence for a stem cell 'arrest' in Tpit(-/-) mice and the role of ACTH in adrenocortical stem cell modulation and differentiation. PMID- 23042946 TI - 11beta-Hydroxysteroid dehydrogenase type 2 in zebrafish brain: a functional role in hypothalamus-pituitary-interrenal axis regulation. AB - The type 2, 11beta-hydroxysteroid dehydrogenase (Hsd11b2) converts active glucocorticoids to their inactive derivatives (e.g. cortisol to cortisone). In most vertebrates, Hsd11b2 is essential for conferring aldosterone-specific actions in mineralocorticoid target tissues and for protecting glucocorticoid sensitive tissues during stress. However, teleosts do not synthesize aldosterone, and the function of Hsd11b2 is poorly defined. The distribution of Hsd11b2 in nonmammalian brain is also largely unexplored. We tested the hypothesis that modulation of brain Hsd11b2 activity is involved in stressor-mediated cortisol regulation in zebrafish (Danio rerio). In adult zebrafish, the stress effect on Hsd11b2 expression in the brain was tested using acute air exposure followed by recovery over a 24-h period. hsd11b2 transcripts were found in nearly all peripheral tissues examined, and a spatial map of its mRNA abundance in unstressed zebrafish brain revealed extensive distribution. Stressor exposure increased the conversion of (3)H-cortisol to (3)H-cortisone indicating enhanced Hsd11b2 activity in zebrafish brain. Promoter analysis of zebrafish hsd11b2 gene revealed putative sites for cortisol-mediated transcriptional regulation of this gene. Furthermore, inhibition of Hsd11b2 activity by 18beta-glycyrrhetinic acid resulted in elevated whole-body cortisol levels and preoptic area mRNA abundance of corticotropin-releasing factor and mineralocorticoid receptor. Taken together, our results underscore an important role for brain Hsd11b2 involvement in the negative feedback regulation of cortisol poststress in zebrafish. PMID- 23042947 TI - Exogenous ubiquitin modulates chronic beta-adrenergic receptor-stimulated myocardial remodeling: role in Akt activity and matrix metalloproteinase expression. AB - beta-Adrenergic receptor (beta-AR) stimulation increases extracellular ubiquitin (UB) levels, and extracellular UB inhibits beta-AR-stimulated apoptosis in adult cardiac myocytes. This study investigates the role of exogenous UB in chronic beta-AR-stimulated myocardial remodeling. l-Isoproterenol (ISO; 400 MUg.kg(-1).h( 1)) was infused in mice in the presence or absence of UB (1 MUg.g(-1).h(-1)). Left ventricular (LV) structural and functional remodeling was studied 7 days after infusion. UB infusion enhanced serum UB levels. In most parts, UB alone had no effect on morphometric or functional parameters. Heart weight-to-body weight ratios were increased to a similar extent in the ISO and UB + ISO groups. Echocardiographic analyses showed increased percent fractional shortening, ejection fraction, and LV circumferential stress and fiber-shortening velocity in the ISO group. These parameters were significantly lower in UB + ISO vs. ISO. Isovolumic contraction and relaxation times and ejection time were significantly lower in ISO vs. UB + ISO. The increase in the number of TUNEL-positive myocytes and fibrosis was significantly higher in ISO vs. UB + ISO. Activation of Akt was higher, whereas activation of GSK-3beta and JNKs was lower in UB + ISO vs ISO. Expression of MMP-2, MMP-9, and TIMP-2 was higher in UB + ISO vs ISO. In isolated cardiac fibroblasts, UB enhanced expression of MMP-2 and TIMP-2 in the presence of ISO. Neutralizing UB antibodies negated the effects of UB on MMP-2 expression, whereas recombinant UB enhanced MMP-2 expression. UB activated Akt, and inhibition of Akt inhibited UB + ISO-mediated increases in MMP-2 expression. Thus, exogenous UB plays an important role in beta-AR-stimulated myocardial remodeling with effects on LV function, fibrosis, and myocyte apoptosis. PMID- 23042949 TI - Inhibition of IkappaB phosphorylation prevents load-induced cardiac dysfunction in mice. AB - Pressure overload is known to be a cause of cardiac hypertrophy that often transits to heart failure. Although nuclear factor (NF)-kappaB is a key factor in the progression of cardiac hypertrophy, its pathophysiology is yet to be elucidated. Thus, we aimed to show that inhibition of NF-kappaB activation improves pressure overload-induced cardiac dysfunction. To assess the effect of inhibition on NF-kappaB activation in pressure overload cardiac hypertrophy, we used IMD-1041 in a murine thoracic aortic constriction (TAC) model. IMD-1041 inhibits the phosphorylation of IkappaB via inhibition of IkappaB kinase-beta. IMD-1041 (100 mg.kg(-1).day(-1)) or vehicle was administered orally into mice once a day, and mice were euthanized on day 42 after TAC. TAC resulted in left ventricular wall thickening, cardiac dysfunction, and increases of heart and lung weight, whereas IMD-1041 significantly suppressed the development of cardiac hypertropy 6 wk after TAC. Histologically, developed cardiac fibrosis and cardiomyocyte hypertrophy occurred in the vehicle-treated group, whereas IMD-1041 significantly attenuated these changes. IMD-1041 suppressed the expression of p65 positive cells and nuclear translocation of p65 induced by TAC compared with vehicle. Matrix metalloproteinase-2 activity increased in the vehicle + TAC treated group; however, it was suppressed in the IMD-1041 + TAC-treated group. IMD-1041 treatment from day 28 to day 42 after TAC significantly attenuated the decrease in the percentage of fractional shortening and cardiac fibrosis without an antihypertrophic effect. In conclusion, IMD-1041 may be useful for preventing pressure overload-induced cardiac dysfunction and the transition of cardiac hypertrophy to contraction failure via suppression of NF-kappaB activation. PMID- 23042948 TI - Interpreting genetic effects through models of cardiac electromechanics. AB - Multiscale models of cardiac electromechanics are being increasingly focused on understanding how genetic variation and environment underpin multiple disease states. In this paper we review the current state of the art in both the development of specific models and the physiological insights they have produced. This growing research body includes the development of models for capturing the effects of changes in function in both single and multiple proteins in both specific expression systems and in vivo contexts. Finally, the potential for using this approach for ultimately predicting phenotypes from genetic sequence information is discussed. PMID- 23042950 TI - Macrophages modulate cardiac function in lipotoxic cardiomyopathy. AB - Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the alpha-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes. PMID- 23042951 TI - Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling. AB - Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility. RV free wall preparations were dissected from five failing and five nonfailing human hearts, cannulated and coronary perfused. RV endocardium was optically mapped from an ~6.3 * 6.3 cm(2) field of view. Action potential duration (APD), dispersion of APD, and conduction velocity (CV) were quantified for basic cycle lengths (BCL) ranging from 2,000 ms to the functional refractory period. We found that RV APD was significantly prolonged within the failing group compared with the nonfailing group (560 +/- 44 vs. 448 +/- 39 ms, at BCL = 2,000 ms, P < 0.05). Dispersion of APD was increased in three failing hearts (161 +/- 5 vs. 86 +/- 19 ms, at BCL = 2,000 ms). APD alternans were induced by rapid pacing in these same three failing hearts. CV was significantly reduced in the failing group compared with the nonfailing group (81 +/- 11 vs. 98 +/- 8 cm/s, at BCL = 2,000 ms). Arrhythmias could be induced in two failing hearts exhibiting an abnormally steep CV restitution and increased dispersion of repolarization due to APD alternans. Dispersion of repolarization is enhanced across the RV endocardium in the failing human heart. This dispersion, together with APD alternans and abnormal CV restitution, could be responsible for the arrhythmia susceptibility in human HF. PMID- 23042952 TI - Differential cell-protective function of two resveratrol (trans-3,5,4' trihydroxystilbene) glucosides against oxidative stress. AB - Resveratrol (trans-3,5,4'-trihydroxystilbene; RSV), a natural polyphenol, exerts a beneficial effect on health and diseases. RSV targets and activates the NAD(+) dependent protein deacetylase SIRT1; in turn, SIRT1 induces an intracellular antioxidative mechanism by inducing mitochondrial superoxide dismutase (SOD2). Most RSV found in plants is glycosylated, and the effect of these glycosylated forms on SIRT1 has not been studied. In this study, we compared the effects of RSV and two glycosyl RSVs, resveratrol-3-O-beta-d-glucoside (3G-RSV; polydatin/piceid) and resveratrol-4'-O-beta-d-glucoside (4'G-RSV), at the cellular level. In oxygen radical absorbance capacity and 2,2-diphenyl-1 picrylhydrazyl radical scavenging assays, the antioxidant activity of 3G-RSV was comparable to that of RSV, whereas the radical-scavenging efficiency of 4'G-RSV was less than 50% of that of RSV. However, 4'G-RSV, but not 3G-RSV, induced SIRT1 dependent histone H3 deacetylation and SOD2 expression in mouse C2C12 skeletal myoblasts; as with RSV, SIRT1 knockdown blunted these effects. RSV and 4'G-RSV, but not 3G-RSV, mitigated oxidative stress-induced cell death in C2C12 cells and primary neonatal rat cardiomyocytes. RSV and 4'G-RSV inhibited C2C12 cell proliferation, but 3G-RSV did not. RSV was found in both the intracellular and extracellular fractions of C2C12 cells that had been incubated with 4'G-RSV, indicating that 4'G-RSV was extracellularly deglycosylated to RSV, which was then taken up by the cells. C2C12 cells did not deglycosylate 3G-RSV. Our results point to 4'G-RSV as a useful RSV prodrug with high water solubility. These data also show that the in vitro antioxidative activity of these molecules did not correlate with their ability to protect cells from oxidative stress-induced apoptosis. PMID- 23042956 TI - The analyst's narcissism. PMID- 23042953 TI - Hydrophobic amino acids in the hinge region of the 5A apolipoprotein mimetic peptide are essential for promoting cholesterol efflux by the ABCA1 transporter. AB - The bihelical apolipoprotein mimetic peptide 5A effluxes cholesterol from cells and reduces inflammation and atherosclerosis in animal models. We investigated how hydrophobic residues in the hinge region between the two helices are important in the structure and function of this peptide. By simulated annealing analysis and molecular dynamics modeling, two hydrophobic amino acids, F-18 and W 21, in the hinge region were predicted to be relatively surface-exposed and to interact with the aqueous solvent. Using a series of 5A peptide analogs in which F-18 or W-21 was changed to either F, W, A, or E, only peptides with hydrophobic amino acids in these two positions were able to readily bind and solubilize phospholipid vesicles. Compared with active peptides containing F or W, peptides containing E in either of these two positions were more than 10-fold less effective in effluxing cholesterol by the ABCA1 transporter. Intravenous injection of 5A in C57BL/6 mice increased plasma-free cholesterol (5A: 89.9 +/- 13.6 mg/dl; control: 38.7 +/- 4.3 mg/dl (mean +/- S.D.); P < 0.05) and triglycerides (5A: 887.0 +/- 172.0 mg/dl; control: 108.9 +/- 9.9 mg/dl; P < 0.05), whereas the EE peptide containing E in both positions had no effect. Finally, 5A increased cholesterol efflux approximately 2.5-fold in vivo from radiolabeled macrophages, whereas the EE peptide was inactive. These results provide a rationale for future design of therapeutic apolipoprotein mimetic peptides and provide new insights into the interaction of hydrophobic residues on apolipoproteins with phospholipids in the lipid microdomain created by the ABCA1 transporter during the cholesterol efflux process. PMID- 23042957 TI - The central masturbation fantasy in heterosexual males across the life cycle: masturbation fantasies across the normality-pathology spectrum. AB - Moses Laufer described the central masturbation fantasy as an essentially adolescent phenomenon that leads to the final sexual organization. In this paper the central masturbation fantasy, formulated during the preoedipal and oedipal years, consolidated in adolescence, and in a process of continuous evolution across the life cycle, is considered an essential concept for understanding sexuality in heterosexual males. Sex and aggression, as posited in Freud's dual theory of the drives, are core components of all masturbation fantasies, across the diagnostic spectrum, from the most normal/neurotic to the most criminally bizarre. Clinical examples illustrate both points. The tendency among clinicians, particularly clinical associates, to avoid analyzing all aspects of masturbation is discussed. PMID- 23042954 TI - Efficacy of the GluK1/AMPA receptor antagonist LY293558 against seizures and neuropathology in a soman-exposure model without pretreatment and its pharmacokinetics after intramuscular administration. AB - Control of brain seizures after exposure to nerve agents is imperative for the prevention of brain damage and death. Animal models of nerve agent exposure make use of pretreatments, or medication administered within 1 minute after exposure, in order to prevent rapid death from peripheral toxic effects and respiratory failure, which then allows the testing of anticonvulsant compounds. However, in a real-case scenario of an unexpected attack with nerve agents, pretreatment would not be possible, and medical assistance may not be available immediately. To determine if control of seizures and survival are still possible without pretreatment or immediate pharmacologic intervention, we studied the anticonvulsant efficacy of the GluK1 (GluR5)/alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) in rats that did not receive any treatment until 20 minutes after exposure to the nerve agent soman. We injected LY293558 intramuscularly, as this would be the most likely route of administration to humans. LY293558 (15 mg/kg), injected along with atropine and the oxime HI-6 at 20 minutes after soman exposure, stopped seizures and increased survival rate from 64% to 100%. LY293558 also prevented neuronal loss in the amygdala and hippocampus, and reduced neurodegeneration in a number of brain regions studied 7 days after soman exposure. Analysis of the LY293558 pharmacokinetics after intramuscular administration showed that this compound readily crosses the blood-brain barrier. There was good correspondence between the time course of seizure suppression by LY293558 and the brain levels of the compound. PMID- 23042958 TI - Emerging views on gender and sexuality: celebrating twenty years of new perspectives on lesbian, gay, bisexual, and trans people. PMID- 23042959 TI - A prospective study of psychoanalytic practice and professional development: early career interviews. AB - In 2003 the Columbia Center for Psychoanalytic Training and Research began a prospective study of graduates designed to both describe and understand their professional trajectory. The study has two components: a quantitative component based on an anonymous comprehensive questionnaire given analysts yearly starting with their graduation, and a qualitative component comprising analyst interviews beginning at the end of the first postgraduate year and repeated every two years. Analysis of the first six years of the qualitative study shows that analysts will talk openly about their practice and careers and that when they do, practical issues are a dominant concern. Analysts both immersed and not immersed in four times-weekly analytic cases experiment with adapting skills developed in training to treat cases in analysis seen less frequently. Analysts without four-times weekly case immersion are engaged in analytic careers, participate as faculty at the institute, and report a high degree of career satisfaction. The major findings of this study compel changes in psychoanalytic training programs. The field would do well to address actual clinical practice experience in institute curricula and training programs, thus making analytic training more relevant. PMID- 23042960 TI - A candidate's experience doing research during training. AB - A psychoanalytic candidate explores his experience of participating in a research project at his institute during his training. The candidate has been a member of Sabrina Cherry's prospective study of psychoanalytic practice and professional development conducted at the Columbia University Center for Psychoanalytic Training and Research. While much as been written about candidacy from numerous perspectives, there is little in the literature about how being engaged in research affects a candidate's overall training experience. In particular, attention is paid to understanding the benefits, synergies, conflicts, and tensions in combining research with such aspects of analytic training as the training analysis, control cases, supervision, classes, and institute life. A parallel is drawn between the listening and interpretive skills learned in order to practice analysis and the method of textual analysis employed in the research project. The author believes that his research training and the impact of the specific research topic have enriched and deepened his analytic training, while at the same time revealing certain anxieties in integrating research with the development of his analytic skills and identity. PMID- 23042961 TI - A national survey of candidates: II: motivations, obstacles, and ideas on increasing interest in psychoanalytic training. AB - A national survey of candidates was conducted to identify motivations for pursuing psychoanalytic training, obstacles that prevent progression or completion, and candidates' ideas on how best to increase interest among potential trainees. In 2009-2010, 40 percent of candidates on the affiliate member e-mail list completed an anonymous web-based survey. Candidates strongly endorsed contact with a personal psychotherapist, psychoanalyst, or supervisor as the most important influence in discovering psychoanalysis and deciding to pursue training. They identified the total cost of analytic training as the greatest obstacle. This was followed by the cost of personal analysis, loss of income for low-fee cases, time away from family, and difficulty finding cases. To enhance training, local institutes should work to improve institute atmosphere and provide assistance with finding cases; national organizations should increase outreach activities and publicize psychoanalysis. Psychoanalytic institutes could recruit future candidates by working to increase personal contact with psychoanalysts, reducing the cost of training, improving institute atmosphere, assisting with case-finding, enhancing outreach activities, and widely publicizing psychoanalysis. Narrative comments from candidates and the implications of these findings regarding engagement of future trainees are discussed. PMID- 23042962 TI - Journal Watch review of stability and change of personality across the life course: the impact of age and major life events on mean-level and rank-order stability of the Big Five. PMID- 23042964 TI - Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity. AB - BACKGROUND: Lyme disease is transmitted by the bite of the Ixodes scapularis tick, which can also transmit Anaplasma phagocytophilum, the cause of human granulocytic anaplasmosis (HGA). Conflicting data exist on the frequency of coinfection and on whether Lyme-HGA coinfected patients have more symptoms than patients with Lyme disease alone. METHODS: Blood culture and serology were used to detect HGA infection in patients with early Lyme disease who presented with erythema migrans. The rate of coinfection was determined using different definitions. The clinical and laboratory features of Lyme-HGA coinfection were compared with that of the individual infections. RESULTS: Among 311 patients with erythema migrans, the frequency of coinfection with HGA varied from 2.3% to 10.0%, depending on the definition used (P < .001). Only 1 of 4 groups with presumed coinfection had significantly more symptoms than patients with Lyme disease alone P < .05. High fever and cytopenia were less common in Lyme-HGA coinfection than in patients with HGA alone. CONCLUSION: The results of this study indicate that how HGA is defined in patients with early Lyme disease has an impact on the apparent rate of coinfection and the severity of illness. The findings also suggest that HGA may be less severe than is usually believed, suggesting the existence of referral bias in testing patients preferentially who present with high fever or cytopenia. PMID- 23042965 TI - Editorial commentary: climbing the evidentiary hierarchy for environmental infection control. PMID- 23042967 TI - Does Candida species overgrowth protect against Clostridium difficile infection? PMID- 23042966 TI - Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study. AB - BACKGROUND: The epidemiology and morbidity of Epstein-Barr virus (EBV) infection in pediatric renal transplant recipients have been characterized insufficiently. METHODS: In a prospective, multicenter study among 106 pediatric kidney allograft recipients aged 11.4 +/- 5.9 years, we investigated the epidemiology of EBV infection and the relationship between EBV load, EBV serology, and EBV-related morbidity (posttransplant lymphoproliferative disease [PTLD] or symptomatic EBV infection, defined as flu-like symptoms or infectious mononucleosis). RESULTS: EBV primary infection occurred in 27 of 43 (63%) seronegative patients and reactivation/reinfection in 28 of 63 (44%) seropositive patients. There was no association between the degree or duration of EBV load and EBV-related morbidity: The vast majority (17 of 18 [94%]) of patients with a high, persistent EBV load remained PTLD-free throughout a follow-up of 5.0 +/- 1.3 years, while 2 of 3 (66%) patients with EBV-related PTLD exhibited only a low EBV load beforehand. Eight of 18 (44%) patients with a high, persistent EBV load remained asymptomatic during a follow-up of 5.3 +/- 2.9 years. Multivariate analysis identified the EBV high-risk (D(+)/R(-)) serostatus (odds ratio [OR], 7.07; P < .05), the presence of human leukocyte antigen (HLA)-DR7 (OR, 5.65; P < .05), and the intensity of the immunosuppressive therapy (OR, 1.53; P < .01) as independent risk factors for the development of a symptomatic EBV infection. CONCLUSIONS: Presence of EBV high risk seroconstellation, HLA-DR7, and intensity of immunosuppressive therapy are significant risk factors for a symptomatic EBV infection, whereas there is no close association between the degree or duration of EBV load and EBV-related morbidity. Clinical Trials Registration. NCT00963248. PMID- 23042968 TI - Rabies vaccinations: are abbreviated intradermal schedules the future? AB - Rabies is a deadly disease, and current preexposure vaccination schedules are lengthy and expensive. We identified nine studies investigating abbreviated schedules. Although initial responses were lower, accelerated adequate immune responses were elicited after booster vaccinations. Lower-dose (and therefore cheaper) vaccination schedules may constitute a valid alternative to current vaccination schedules. PMID- 23042969 TI - Neonatal hemolytic uremic syndrome after mother-to-child transmission of a low pathogenic stx2b harboring shiga toxin-producing Escherichia coli. AB - This case describes evidence for a Shiga toxin-producing Escherichia coli (STEC) O146:H28 infection leading to hemolytic uremic syndrome in a neonate. STEC O146:H28 was linked hitherto with asymptomatic carriage in humans. Based on strain characteristics and genotyping data, the mother is a healthy carrier who transmitted the STEC during delivery. STEC strains belonging to the low pathogenic STEC group must also be considered in the workup of neonatal hemolytic uremic syndrome. PMID- 23042970 TI - Sustainable tuberculosis drug development. AB - Six new antituberculosis compounds in 4 classes are presently in clinical trials. Although these show substantial promise for drug-resistant (DR) tuberculosis, the presently planned studies of these compounds will not inform their optimal use, as each will be tested singly vs placebo with existing drugs, rather than in new regimens. Each successive regulatory approval will increase the size, cost, and complexity of trials for those that follow, causing delays during which suboptimal use will occur and resistance will emerge. This paper proposes the development of a novel regimen with the potential for use in both drug-sensitive (DS) and DR tuberculosis. Adaptive licensing for DR tuberculosis based on 2-month sputum culture would shorten time to initial approval by several years. A global outcomes registry would confirm safety and effectiveness in both DS and DR tuberculosis, making possible the second transformation of tuberculosis treatment. We should do our utmost to see it succeed. PMID- 23042972 TI - An evaluation of environmental decontamination with hydrogen peroxide vapor for reducing the risk of patient acquisition of multidrug-resistant organisms. AB - BACKGROUND: Admission to a room previously occupied by a patient with certain multidrug-resistant organisms (MDROs) increases the risk of acquisition. Traditional cleaning strategies do not remove all environmental MDROs. We evaluated the environmental and clinical impact of hydrogen peroxide vapor (HPV) room disinfection. METHODS: We performed a 30-month prospective cohort intervention study on 6 high-risk units in a 994-bed tertiary care hospital. Following a 12-month preintervention phase, HPV was implemented on 3 units to decontaminate the rooms of patients known to be infected or colonized with epidemiologically important MDROs, following their discharge. Monthly environmental samples for MDROs were collected on all study units for 3 preintervention and 6 intervention months. The risk of MDRO acquisition in patients admitted to rooms decontaminated using HPV was compared with rooms disinfected using standard methods. RESULTS: The prior room occupant was known to be infected or colonized with an MDRO in 22% of 6350 admissions. Patients admitted to rooms decontaminated using HPV were 64% less likely to acquire any MDRO (incidence rate ratio [IRR], 0.36; 95% confidence interval [CI], .19-.70; P < .001) and 80% less likely to acquire VRE (IRR, 0.20; 95% CI, .08-.52; P < .001) after adjusting for other factors. The risk of acquiring Clostridium difficile, methicillin-resistant Staphylococcus aureus, and multidrug-resistant gram negative rods individually was reduced, but not significantly. The proportion of rooms environmentally contaminated with MDROs was reduced significantly on the HPV units (relative risk, 0.65, P = .03), but not on non-HPV units. CONCLUSIONS: HPV decontamination reduced environmental contamination and the risk of acquiring MDROs compared with standard cleaning protocols. PMID- 23042973 TI - Response of Treponema pallidum particle agglutination test titers to treatment of syphilis. PMID- 23042971 TI - Invasive mold infections following combat-related injuries. AB - BACKGROUND: Major advances in combat casualty care have led to increased survival of patients with complex extremity trauma. Invasive fungal wound infections (IFIs) are an uncommon, but increasingly recognized, complication following trauma that require greater understanding of risk factors and clinical findings to reduce morbidity. METHODS: The patient population includes US military personnel injured during combat from June 2009 through December 2010. Case definition required wound necrosis on successive debridements with IFI evidence by histopathology and/or microbiology (Candida spp excluded). Case finding and data collected through the Trauma Infectious Disease Outcomes Study utilized trauma registry, hospital records or operative reports, and pathologist review of histopathology specimens. RESULTS: A total of 37 cases were identified: proven (angioinvasion, n=20), probable (nonvascular tissue invasion, n=4), and possible (positive fungal culture without histopathological evidence, n=13). In the last quarter surveyed, rates reached 3.5% of trauma admissions. Common findings include blast injury (100%) during foot patrol (92%) occurring in southern Afghanistan (94%) with lower extremity amputation (80%) and large volume blood transfusion (97.2%). Mold isolates were recovered in 83% of cases (order Mucorales, n=16; Aspergillus spp, n=16; Fusarium spp, n=9), commonly with multiple mold species among infected wounds (28%). Clinical outcomes included 3 related deaths (8.1%), frequent debridements (median, 11 cases), and amputation revisions (58%). CONCLUSIONS: IFIs are an emerging trauma-related infection leading to significant morbidity. Early identification, using common characteristics of patient injury profile and tissue-based diagnosis, should be accompanied by aggressive surgical and antifungal therapy (liposomal amphotericin B and a broad-spectrum triazole pending mycology results) among patients with suspicious wounds. PMID- 23042975 TI - Understanding risk and enhancing safety in immunotherapy trials. PMID- 23042974 TI - Epstein-Barr and other herpesvirus infections in patients with early onset type 1 diabetes treated with daclizumab and mycophenolate mofetil. AB - BACKGROUND: We assessed the morbidity of herpesviruses in patients with type 1 diabetes mellitus (T1D) enrolled in immunosuppressive treatment studies. METHODS: Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV) infections were monitored in 126 participants of a randomized, double-blind, placebo-controlled study of daclizumab (DZB) and mycophenolate mofetil (MMF) including DZB(+)MMF(+), DZB(-)MMF(+), DZB(+)MMF(-), and DZB(-)MMF(-). During the 2-year follow-up, herpesviral infections were monitored clinically, by serology and blood DNA polymerase chain reaction. RESULTS: Among 57 baseline EBV-seronegative participants, 9 developed EBV primary infections, including 2 with infectious mononucleosis syndrome. There were no appreciable differences in the course of the primary EBV infections across treatment groups. Among 69 baseline EBV-seropositive participants, 22 had virologic reactivations, including 1 symptomatic DZB(-)MMF(+) subject. Compared with 7 DZB(-)MMF(-) EBV reactivators, the 9 DZB(+)MMF(+) reactivators tended to have more prolonged viremia (11.4 vs 4.4 months; P = .06) and higher cumulative viral burden (14.2 vs 12.5 log EBV copies/mL; P = .06). Four of 85 baseline CMV seronegative subjects developed asymptomatic primary CMV infections. There were no CMV reactivations. Of 30 baseline HSV-seropositive subjects, 8 developed >=1 episode of herpes labialis; 1 subject had a primary HSV infection; and 1 subject without baseline serology information had a new diagnosis of genital HSV. There were no significant differences in the incidence of HSV recurrences across treatment groups. Of 100 baseline VZV-seropositive subjects, 1 DZB(-)MMF(-) subject developed herpes zoster and 1 DZB(-)MMF(+) subject had Bell's palsy possibly related to VZV. CONCLUSIONS: The use of DZB alone or in combination with MMF was not associated with increased morbidity due to herpesviruses. CLINICAL TRIALS REGISTRATION: NCT00100178. PMID- 23042976 TI - Close monitoring of hepatitis B surface antigen levels helps classify flares during peginterferon therapy and predicts treatment response. AB - BACKGROUND: Alanine aminotransferase (ALT) flares occur frequently during peginterferon (PEG-IFN) therapy. We related occurrence of flares to presence of precore (PC) and/or basal core promoter (BCP) mutants and studied kinetics of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) levels during flares. METHODS: Fifty of 214 (23%) patients treated with PEG-IFN +/- lamivudine for 52 weeks experienced flares. Flares were host-induced (ALT elevation followed by HBV DNA decline, n = 19), virus-induced (HBV DNA increase with subsequent ALT elevation, n = 17) or indeterminate (n = 14). Presence of wild-type (WT) or non-WT (detectable PC/BCP mutants) was studied by lineprobe assay. RESULTS: Fifty-eight percent of host-induced flares occurred in WT HBV patients, whereas 94% of virus-induced flares occurred in patients with PC and/or BCP mutants (P = .003). HBsAg loss was only achieved in patients with a host induced flare, and WT patients with a host-induced flare cleared HBsAg in 64% of cases. Serum HBsAg levels declined after a host-induced flare, whereas virus induced flares were accompanied by stable or increasing levels of HBsAg. Patients with a host-induced flare achieved a mean HBsAg reduction of 3.24 log IU/mL, compared with 0.25 log IU/mL in virus-induced flares (P < .001). Patients who achieved a decline in HBsAg of >0.5 log IU/mL within 4 weeks after the flare cleared HBsAg in 64% (7 of 11) of cases. CONCLUSIONS: Host-induced flares are associated with WT virus and may result in decline and clearance of HBV DNA, HBeAg, and HBsAg. Monitoring of HBsAg levels during and after flares may help predict a favorable treatment outcome. PMID- 23042977 TI - Editorial commentary: environmental risk factors for Pneumocystis pneumonia hospitalization in HIV/AIDS patients. PMID- 23042979 TI - Beliefs about chlamydia testing amongst young people living in relatively deprived areas. AB - BACKGROUND: This study uses the theory of planned behaviour (TPB) as a framework to investigate salient beliefs about chlamydia testing, amongst young people living in relatively deprived areas. These beliefs may form targets for intervention to increase testing in this high-risk population. METHODS: Participants recruited from colleges in deprived areas of a UK city, completed open-ended questions designed to elicit salient beliefs. Responses were content analysed and categorized as describing behavioural, normative or control beliefs. RESULTS: Beliefs were elicited from 128 respondents (51% male; median age = 17). The commonest behavioural belief, which could have a positive or negative impact on screening intentions, was that testing provides information about health status. Partners were referred to most commonly amongst the normative beliefs. Practical aspects and concerns about social implications of testing were common control beliefs. References to several negative emotions emerged throughout. CONCLUSIONS: This study indicates that raising awareness of chlamydia as a serious sexual health problem may not be the best way to increase the uptake of testing in a high-risk population. Promoting chlamydia testing as potentially providing reassurance may be an alternative. It may also be important to reduce perceptions of social disapproval as well as negative emotion regarding chlamydia testing. PMID- 23042978 TI - Environmental risk factors for Pneumocystis pneumonia hospitalizations in HIV patients. AB - BACKGROUND: Pneumocystis pneumonia (PcP) is the second leading cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients in the United States. Although the host risk factors for the development of PcP are well established, the environmental (climatological, air pollution) risk factors are poorly understood. The major goal of this study was to determine the environmental risk factors for admissions of HIV-positive patients with PcP to a single medical center. METHODS: Between 1997 and 2008, 457 HIV-positive patients with microscopically confirmed PcP were admitted to the San Francisco General Hospital. A case-crossover design was applied to identify environmental risk factors for PcP hospitalizations. Climatological and air pollution data were collected from the Environmental Protection Agency and Weather Warehouse databases. Conditional logistic regression was used to evaluate the association of each environmental factor and PcP hospital admission. RESULTS: Hospital admissions were significantly more common in the summer than in the other seasons. Increases in temperature and sulfur dioxide levels were independently associated with hospital admissions for PcP, but the effects of sulfur dioxide were modified by increasing carbon monoxide levels. CONCLUSIONS: This study identifies both climatological and air pollution constituents as independent risk factors for hospitalization of HIV-positive patients with PcP in San Francisco. Thus, the environmental effects on PcP are more likely complex than previously thought. Further studies are needed to understand how these factors exert their effects and to determine if these factors are associated with PcP in other geographic locations. PMID- 23042980 TI - Eplerenone in patients with systolic heart failure and mild symptoms: analysis of repeat hospitalizations. AB - BACKGROUND: Eplerenone is known to reduce time to first hospitalization for heart failure or cardiovascular death in patients with heart failure and mild symptoms. In chronic diseases such as heart failure, characterized by repeat hospitalizations, analyzing all heart failure hospitalizations, not just the first, should give a more complete picture of treatment benefits. METHODS AND RESULTS: The Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF) trial compared eplerenone with placebo in 2737 patients with mild heart failure, followed for a median 2.08 years (interquartile range, 1.08-3.10 years). Data were collected on all hospitalizations, with a focus on those due to heart failure. Heart failure hospitalization rates in the eplerenone and placebo groups were 10.70 and 16.99 per 100 patient-years, respectively. Allowing for skewness in the frequency of hospitalizations by using the negative binomial generalized linear model, the rate ratio (eplerenone versus placebo) was 0.53 (95% confidence interval, 0.42-0.66; P<0.0001). A plot of cumulative hospitalization rates over time revealed that most of the reduced risk on eplerenone occurred in the first year of follow-up. Several baseline variables strongly predicted the risk of hospitalization. More complex statistical methods, adjusting for mortality (as informative censoring), made a negligible difference in these findings. CONCLUSIONS: Eplerenone markedly reduces the risk of heart failure hospitalizations in patients with heart failure and mild symptoms to a greater extent than is captured by only studying the time to first hospitalization. Future clinical trials in heart failure would gain from incorporating repeat hospitalizations into their primary evaluation of treatment effects. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00232180. PMID- 23042981 TI - Oral pain before and after smokeless tobacco cessation in U.K.-resident Bangladeshi women: cross-sectional analyses. AB - INTRODUCTION: Paan quid with tobacco (PQT) use is common in South Asian populations. Oral pain following a PQT cessation attempt is commonly reported. Factors determining this await full exploration. METHODS: This prospective study of PQT chewers used a prepiloted interview and clinical examination. Oral pain, socioeconomic position, oral status, health service use, tobacco use and dependency, and psychological distress measures were collected from U.K.-resident Bangladeshi women before and after their quit attempts. Analysis included descriptive and analytic modeling of oral pain determinants, using multiple logistic regressions and a significance value p <= .05. RESULTS: A total of 150 females (mean age 51.2 [SD = 13.7, range = 24-84] years) completed the study. Baseline oral pain prevalence was 39% and 73% at follow-up. Completed education level predicted baseline oral pain (OR = 3.43, 95% CI [1.66, 7.11], p = .001). Follow-up oral pain was predicted by completed education level (OR = 3.74, 95% CI [1.43, 9.79], p = .007), anxiety (OR = 3.52, 95% CI [1.23, 10.07], p = .019), choosing behavioral support alone in the cessation attempt (OR = 3.12, 95% CI [1.26, 8.70], p = .015), failure to stop tobacco chewing during the cessation attempt (OR = 4.16, 95% CI [1.44, 12.04], p = .009), and tooth wear (attrition) (OR = 5.71, 95% CI [1.84, 17.79], p = .003). Lower dependency level (OR = 0.79, 95% CI [0.64, 0.97], p = .023) was protective. CONCLUSION: Dental care access, nicotine replacement therapy, and anxiety management should be incorporated into cessation service delivery protocols to manage oral pain onset and facilitate successful cessation. PMID- 23042982 TI - The combined effects of single-nucleotide polymorphisms, tobacco products, and ethanol on normal resting blood mononuclear cells. AB - INTRODUCTION: Tobacco and ethanol consumption are crucial factors in the development of various diseases including cancer. In this investigation, we evaluated the combined effects of a number of single nucleotide polymorphisms (SNPs), with ethanol and tobacco products on healthy individuals. METHODS: Pure nicotine, cigarette smoke extract, and Swedish snuff (snus) extract were used. The effects were examined by means of in vitro cell cycle progression and cell death of peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. RESULTS: After 3 days, in vitro, resting PBMCs entered the S and G2 stage in the presence of 100 uM nicotine. The PBMCs only proceeded to S stage, in the presence of 0.2% ethanol. The nicotine- and ethanol-induced normal cell cycle progression correlated to a number of SNPs in the IL12RB2, Rad 52, XRCC2, P53, CCND3, and ABCA1 genes. Certain SNPs in Caspases 8, IL12RB2, Rad 52, MMP2, and MDM2 genes appeared to significantly influence the effects of EtOH-, snus-, and snus + EtOH induced cell death. Importantly, the highest degree of cell death was observed in the presence of smoke + EtOH. The amount of cell death under this treatment condition also correlated to specific SNPs, located in the MDM2, ABCA1, or GASC1 genes. CONCLUSIONS: Cigarette smoke in combination with ethanol strongly induced massive cell death. Long-term exposure to smoke and ethanol could provoke chronic inflammation, and this could be the initiation of disease including the development of cancer at various sites. PMID- 23042984 TI - In vitro particle size distributions in electronic and conventional cigarette aerosols suggest comparable deposition patterns. AB - INTRODUCTION: Electronic cigarette users ("vapers") inhale aerosols of water, nicotine, and propylene glycol (PG) or vegetable glycerin (VG). Aerosol particle sizes should affect deposition patterns in vapers and bystanders. METHODS: Aerosols were generated by a smoking machine and an electronic cigarette filled with 16mg/ml nicotine in aqueous PG or VG solution. A scanning mobility particle sizer (SMPS) counted particles of 10-1,000 nm diameters. A single puff experiment counted particles immediately and after aging 10 and 40 s. A steady-state experiment counted particles emitted from a collection chamber, untreated and after desiccation or organic vapor removal. The International Commission on Radiological Protection (ICRP) human respiratory tract model was used to estimate deposition. Results were compared to similar data from reference cigarettes. RESULTS: Puffs generated peak particle counts at (VG) 180 nm and (PG) 120 nm. Steady-state peaks occurred around 400 nm. Organic vapor removal eliminated small particles and reduced the size and number of large particles. Desiccation reduced the total volume of particles by 70% (VG, small PG) to 88% (large PG). The ICRP model predicted 7%-18% alveolar delivery; 9%-19% venous delivery, mostly in the head; and 73%-80% losses by exhalation. Reference cigarettes generated more particles initially, but were otherwise similar; however, in vivo smoke particle deposition is higher than the model predicts. CONCLUSIONS: Nicotine delivery may depend on vaping technique, particle evolution, and cloud effects. Predicted 10% arterial and 15% venous delivery may describe bystander exposure better than vapers exposure. PMID- 23042983 TI - Abnormal social behavior in nicotinic acetylcholine receptor beta4 subunit-null mice. AB - INTRODUCTION: Tobacco addiction has a strong social component. Therefore, nicotinic acetylcholine receptors (nAChR) may influence social behavior. Because the beta4 nicotinic receptor subunit is important for possibly related behaviors, such as anxiety-like behavior and the effects of nicotine, we studied the social behavior of mice null for the beta4 nAChR subunit. METHODS: To measure social behavior, we used the intruder test for social memory in wild-type and littermate beta4 null mice. In addition, we used a nonsocial olfactory memory test as a control. RESULTS: In the intruder test, beta4 null mice showed social amnesia: Wild-type mice spent less time actively interacting with a younger intruder on Day 2 than on Day 1, but beta4 null mice interacted for a similar time on both days. In the nonsocial olfactory memory test, control littermates and beta4 null mice learnt the associations to a similar extent, showing that the amnesic phenotype in the intruder test is specific for social settings. CONCLUSIONS: We conclude that nAChRs that contain the beta4 subunit are important for social behaviors. As those receptors are necessary to observe several effects of nicotine including withdrawal, it is tempting to speculate that the social component of tobacco use is related to the same neuronal circuits responsible for continuing tobacco use in smokers. PMID- 23042985 TI - Knowledge and views about maternal tobacco smoking and barriers for cessation in Aboriginal and Torres Strait Islanders: A systematic review and meta-ethnography. AB - INTRODUCTION: Maternal smoking rates in Australian Aboriginal women are triple that of the general population, with little evidence for successful interventions. We reviewed the literature to understand smoking and cessation in Aboriginal and Torres Strait Islander women and provide recommendations for targeted interventions. METHODS: Six databases were searched using terms related to smoking, pregnancy, and Aboriginal Australians. Two reviewers independently assessed papers for inclusion and quality. Meta-ethnography synthesized first- and second-order constructs from included studies and constructed a line of argument. RESULTS: Seven relevant studies were analyzed. The synthesis illustrates 11 third-order constructs operating on the levels of self, family, and social networks, the wider Aboriginal community, and broader external influences. Highlighted are social norms and stressors within the Aboriginal community perpetuating tobacco use; insufficient knowledge of smoking harms; inadequate saliency of antismoking messages; and lack of awareness and use of pharmacotherapy. Indigenous Health Workers have a challenging role, not yet fulfilling its potential. Pregnancy is an opportunity to encourage positive change where a sense of a "protector role" is expressed. CONCLUSIONS: This review gives strength to evidence from individual studies across diverse Indigenous cultures. Pregnant Aboriginal and Torres Strait Islander smokers require comprehensive approaches, which consider the environmental context, increase knowledge of smoking harms and cessation methods, and provide culturally targeted support. Long term, broad strategies should de-normalize smoking in Aboriginal and Torres Strait Islander communities. Further research needs to examine causes of resistance to antitobacco messages, clarify contributing roles of stress and depression, and attitudes to pharmacotherapy. PMID- 23042986 TI - Tobacco packaging and mass media campaigns: research needs for Articles 11 and 12 of the WHO Framework Convention on Tobacco Control. AB - INTRODUCTION: Communicating the health risks of smoking remains a primary objective of tobacco-control policy. Articles 11 and 12 of the World Health Organization's Framework Convention on Tobacco Control establish standards for two important forms of communication: packaging regulations (Article 11), and mass media campaigns (Article 12). METHODS: A narrative review approach was used to identify existing evidence in the areas of package labeling regulations (including health warnings, constituent and emission messages, and prohibitions on misleading information) and communication activities (including mass media campaigns and news media coverage). When available, recent reviews of the literature were used, updated with more recent high-quality studies from published literature. RESULTS: Implementation of Articles 11 and 12 share several important research priorities: (a) identify existing consumer information needs and gaps, (b) research on the message source to identify effective types of content for health warnings and media campaigns, (c) research on how messages are processed and the extent to which the content and form of messages need to be tailored to different cultural and geographic groups, as well as subgroups within countries, and (d) research to identify the most cost-effective mix and best practices for sustaining health communications over time. CONCLUSION: A unifying theme of effective health communication through tobacco packaging and mass media campaigns is the need to provide salient, timely, and engaging reminders of the consequences of tobacco use in ways that motivate and support tobacco users trying to quit and make tobacco use less appealing for those at risk of taking it up. PMID- 23042987 TI - AhpC is required for optimal production of enterobactin by Escherichia coli. AB - Escherichia coli alkyl hydroperoxide reductase subunit C (AhpC) is a peroxiredoxin that detoxifies peroxides. Here we show an additional role for AhpC in cellular iron metabolism of E. coli. Deletion of ahpC resulted in reduced growth and reduced accumulation of iron by cells grown in low-iron media. Liquid chromatography-mass spectroscopy (LC-MS) analysis of culture supernatants showed that the ahpC mutant secreted much less enterobactin, the siderophore that chelates and transports ferric iron under iron-limiting conditions, than wild type E. coli did. The ahpC mutant produced less 2,3-dihydroxybenzoate, the intermediate in the enterobactin biosynthesis pathway, and providing 2,3 dihydroxybenzoate restored wild-type growth of the ahpC mutant. These data indicated that the defect was in an early step in enterobactin biosynthesis. Providing additional copies of entC, which functions in the first dedicated step of enterobactin biosynthesis, but not of other enterobactin biosynthesis genes, suppressed the mutant phenotype. Additionally, providing either shikimate or a mixture of para-aminobenzoate, tryptophan, tyrosine, and phenylalanine, which, like enterobactin, are synthesized from the precursor chorismate, also suppressed the mutant phenotype. These data suggested that AhpC affected the activity of EntC or the availability of the chorismate substrate. PMID- 23042989 TI - Transcriptional organization and regulatory elements of a Pseudomonas sp. strain ADP operon encoding a LysR-type regulator and a putative solute transport system. AB - The atzS-atzT-atzU-atzV-atzW gene cluster of the Pseudomonas sp. strain ADP atrazine-degradative plasmid pADP-1, which carries genes for an outer membrane protein and the components of a putative ABC-type solute transporter, is located downstream from atzR, which encodes the LysR-type transcriptional regulator of the cyanuric acid-degradative operon atzDEF. Here we describe the transcriptional organization of these genes. Our results show that all six genes are cotranscribed from the PatzR promoter to form the atzRSTUVW operon. A second, stronger promoter, PatzT, is found within atzS and directs transcription of the four distal genes. PatzT is sigma(N) dependent, activated by NtrC in response to nitrogen limitation with the aid of IHF, and repressed by AtzR. A combination of in vivo mutational analysis and primer extension allowed us to locate the PatzT promoter and map the transcriptional start site. Similarly, we used deletion and point mutation analyses, along with in vivo expression studies and in vitro binding assays, to locate the NtrC, IHF, and AtzR binding sites and address their functionality. Our results suggest a regulatory model in which NtrC activates PatzT transcription via DNA looping, while AtzR acts as an antiactivator that diminishes expression by interfering with the activation process. PMID- 23042988 TI - Staphylococcus aureus NorD, a putative efflux pump coregulated with the Opp1 oligopeptide permease, contributes selectively to fitness in vivo. AB - Staphylococcus aureus readily infects humans, causing infections from mild superficial skin infections to lethal bacteremia and endocarditis. Transporters produced by S. aureus allow the pathogen to adapt to a variety of settings, including survival at sites of infection and in the presence of antibiotics. The native functions of many transporters are unknown, but their potential dual contribution to fitness and antimicrobial resistance highlights their importance in staphylococcal infections. Here, we show that S. aureus NorD, a newly recognized efflux pump of the major facilitator superfamily, contributes to fitness in a murine subcutaneous abscess model. In community-associated methicillin-resistant S. aureus (CA-MRSA) strain MW2, norD was selectively upregulated 36-fold at the infection site relative to growth in vitro, and the norD mutant demonstrated significant fitness impairment in abscesses, with fitness 20- to 40-fold lower than that of the parent MW2 strain. Plasmid-encoded NorD could complement the fitness defect of the MW2 norD mutant. Chromosomal norD expression is polycistronic with the upstream oligopeptide permease genes (opp1ABCDF), which encode an ABC oligopeptide transporter. Both norD and opp1 were upregulated in abscesses and iron-restricted culture medium and negatively regulated by Fur, but only NorD contributed to fitness in the murine abscess model. PMID- 23042991 TI - Calcium causes multimerization of the large adhesin LapF and modulates biofilm formation by Pseudomonas putida. AB - LapF is a large secreted protein involved in microcolony formation and biofilm maturation in Pseudomonas putida. Its C-terminal domain shows the characteristics of proteins secreted through a type I secretion system and includes a predicted calcium binding motif. We provide experimental evidence of specific binding of Ca(2+) to the purified C-terminal domain of LapF (CLapF). Calcium promotes the formation of large aggregates, which disappear in the presence of the calcium chelator EGTA. Immunolocalization of LapF also shows the tendency of this protein to accumulate in vivo in certain extracellular regions. These findings, along with results showing that calcium influences biofilm formation, lead us to propose a model in which P. putida cells interact with each other via LapF in a calcium-dependent manner during the development of biofilms. PMID- 23042990 TI - Polymorphisms in inc proteins and differential expression of inc genes among Chlamydia trachomatis strains correlate with invasiveness and tropism of lymphogranuloma venereum isolates. AB - Chlamydia trachomatis is a human bacterial pathogen that multiplies only within an intracellular membrane-bound vacuole, the inclusion. C. trachomatis includes ocular and urogenital strains, usually causing infections restricted to epithelial cells of the conjunctiva and genital mucosa, respectively, and lymphogranuloma venereum (LGV) strains, which can infect macrophages and spread into lymph nodes. However, C. trachomatis genomes display >98% identity at the DNA level. In this work, we studied whether C. trachomatis Inc proteins, which have a bilobed hydrophobic domain that may mediate their insertion in the inclusion membrane, could be a factor determining these different types of infection and tropisms. Analyses of polymorphisms and phylogeny of 48 Inc proteins from 51 strains encompassing the three disease groups showed significant amino acid differences that were mainly due to variations between Inc proteins from LGV and ocular or urogenital isolates. Studies of the evolutionary dynamics of inc genes suggested that 10 of them are likely under positive selection and indicated that most nonsilent mutations are LGV specific. Additionally, real-time quantitative PCR analyses in prototype and clinical strains covering the three disease groups identified three inc genes with LGV-specific expression. We determined the transcriptional start sites of these genes and found LGV-specific nucleotides within their promoters. Thus, subtle variations in the amino acids of a subset of Inc proteins and in the expression of inc genes may contribute to the unique tropism and invasiveness of C. trachomatis LGV strains. PMID- 23042992 TI - Editorial and policy changes for 2013. PMID- 23042993 TI - Multiple envelope stress response pathways are activated in an Escherichia coli strain with mutations in two members of the DedA membrane protein family. AB - We have reported that simultaneous deletion of two Escherichia coli genes, yqjA and yghB, encoding related and conserved inner membrane proteins belonging to the DedA protein family results in a number of intriguing phenotypes, including temperature sensitivity at 42 degrees C, altered membrane lipid composition, and cell division defects. We sought to characterize these and other phenotypes in an effort to establish a function for this protein family in E. coli. Here, using reporter assays, we show that the major envelope stress response pathways Cpx, Psp, Bae, and Rcs are activated in strain BC202 (W3110; DeltayqjA DeltayghB) at the permissive growth temperature of 30 degrees C. We previously demonstrated that 10 mM Mg(2+), 400 mM NaCl, and overexpression of tatABC are capable of restoring normal growth to BC202 at elevated growth temperatures. Deletion of the cpxR gene from BC202 results in the loss of the ability of these supplements to restore growth at 42 degrees C. Additionally, we report that the membrane potential of BC202 is significantly reduced and that cell division and growth can be restored either by expression of the multidrug transporter MdfA from a multicopy plasmid or by growth at pH 6.0. Together, these results suggest that the DedA family proteins YqjA and YghB are required for general envelope maintenance and homeostasis of the proton motive force under a variety of growth conditions. PMID- 23042994 TI - Reexamining transcriptional regulation of the Bacillus subtilis htpX gene and the ykrK gene, encoding a novel type of transcriptional regulator, and redefining the YkrK operator. AB - HtpX is an integral cytoplasmic membrane metalloprotease well conserved in numerous bacteria. A recent study showed that expression of the Bacillus subtilis htpX gene is under dual negative control by Rok and a novel type of transcriptional regulator, YkrK. Here we report that expression of the B. subtilis htpX gene is strongly heat inducible. Contrary to the previous prediction, ykrK expression has been found to be not subject to autoregulation. We have identified the htpX promoter and the authentic ykrK promoter, which is also distinct from the previously predicted one. We have redefined a conserved inverted repeat sequence to be the YkrK operator, which is somewhat different from the previously proposed one. We provide evidence that YkrK is not a substrate of HtpX and that heat induction of htpX is not YkrK mediated. We have also found that the absence of FtsH or HtpX alone did not impair B. subtilis cell viability on LB agar plates at high temperature, whereas the absence of both FtsH and HtpX caused a severe growth defect under heat stress. This finding supports the notion that FtsH and HtpX may have partially overlapping functions in heat resistance. Finally, we show that htpX expression is subject to transient negative control by sigB under heat stress in a Rok- and YkrK-independent manner. Triple negative control of htpX expression at high temperature by rok, sigB, and ykrK may help cells to prevent uncontrolled and detrimental oversynthesis of the HtpX protease. PMID- 23042995 TI - Biophysical and bioinformatic analyses implicate the Treponema pallidum Tp34 lipoprotein (Tp0971) in transition metal homeostasis. AB - Metal ion homeostasis is a critical function of many integral and peripheral membrane proteins. The genome of the etiologic agent of syphilis, Treponema pallidum, is compact and devoid of many metabolic enzyme genes. Nevertheless, it harbors genes coding for homologs of several enzymes that typically require either iron or zinc. The product of the tp0971 gene of T. pallidum, designated Tp34, is a periplasmic lipoprotein that is thought to be tethered to the inner membrane of this organism. Previous work on a water-soluble (nonacylated) recombinant version of Tp34 established that this protein binds to Zn(2+), which, like other transition metal ions, stabilizes the dimeric form of the protein. In this study, we employed analytical ultracentrifugation to establish that four transition metal ions (Ni(2+), Co(2+), Cu(2+), and Zn(2+)) readily induce the dimerization of Tp34; Cu(2+) (50% effective concentration [EC(50)] = 1.7 MUM) and Zn(2+) (EC(50) = 6.2 MUM) were the most efficacious of these ions. Mutations of the crystallographically identified metal-binding residues hindered the ability of Tp34 to dimerize. X-ray crystallography performed on crystals of Tp34 that had been incubated with metal ions indicated that the binding site could accommodate the metals examined. The findings presented herein, coupled with bioinformatic analyses of related proteins, point to Tp34's likely role in metal ion homeostasis in T. pallidum. PMID- 23042996 TI - New substrates on the block: clinically relevant resistances for EmrE and homologues. AB - Transporters of the small multidrug resistance (SMR) family are small homo- or heterodimers that confer resistance to multiple toxic compounds by exchanging substrate with protons. Despite the wealth of biochemical information on EmrE, the most studied SMR member, a high-resolution three-dimensional structure is missing. To provide proteins that are more amenable to biophysical and structural studies, we identified and partially characterized SMR transporters from bacteria living under extreme conditions of temperature and radiation. Interestingly, these homologues as well as EmrE confer resistance to streptomycin and tobramycin, two aminoglycoside antibiotics widely used in clinics. These are hydrophilic and clinically important substrates of SMRs, and study of their mode of action should contribute to understanding the mechanism of transport and to combating the phenomenon of multidrug resistance. Furthermore, our study of one of the homologues, a putative heterodimer, supports the suggestion that in the SMR family, heterodimers can also function as homodimers. PMID- 23042997 TI - Conjugal transfer of a virulence plasmid in the opportunistic intracellular actinomycete Rhodococcus equi. AB - Rhodococcus equi is a facultative intracellular, Gram-positive, soilborne actinomycete which can cause severe pyogranulomatous pneumonia with abscessation in young horses (foals) and in immunocompromised people, such as persons with AIDS. All strains of R. equi isolated from foals and approximately a third isolated from humans contain a large, ~81-kb plasmid which is essential for the intramacrophage growth of the organism and for virulence in foals and murine in vivo model systems. We found that the entire virulence plasmid could be transferred from plasmid-containing strains of R. equi (donor) to plasmid-free R. equi strains (recipient) at a high frequency and that plasmid transmission reestablished the capacity for intracellular growth in macrophages. Plasmid transfer required living cells and cell-to-cell contact and was unaffected by the presence of DNase, factors pointing to conjugation as the major means of genetic transfer. Deletion of a putative relaxase-encoding gene, traA, located in the proposed conjugative region of the plasmid, abolished plasmid transfer. Reversion of the traA mutation restored plasmid transmissibility. Finally, plasmid transmission to other Rhodococcus species and some additional related organisms was demonstrated. This is the first study showing a virulence plasmid transfer in R. equi, and it establishes a mechanism by which the virulence plasmid can move among bacteria in the soil. PMID- 23042998 TI - Roles of the structural symbiosis polysaccharide (syp) genes in host colonization, biofilm formation, and polysaccharide biosynthesis in Vibrio fischeri. AB - The symbiosis polysaccharide locus, syp, is required for Vibrio fischeri to form a symbiotic association with the squid Euprymna scolopes. It is also required for biofilm formation induced by the unlinked regulator RscS. The syp locus includes 18 genes that can be classified into four groups based on putative function: 4 genes encode putative regulators, 6 encode glycosyltransferases, 2 encode export proteins, and the remaining 6 encode proteins with other functions, including polysaccharide modification. To understand the roles of each of the 14 structural syp genes in colonization and biofilm formation, we generated nonpolar in-frame deletions of each gene. All of the deletion mutants exhibited defects in their ability to colonize juvenile squid, although the impact of the loss of SypB or SypI was modest. Consistent with their requirement for colonization, most of the structural genes were also required for RscS-induced biofilm formation. In particular, the production of wrinkled colonies, pellicles, and the matrix on the colony surface was eliminated or severely decreased in all mutants except for the sypB and sypI mutants; in contrast, only a subset of genes appeared to play a role in attachment to glass. Finally, immunoblotting data suggested that the structural Syp proteins are involved in polysaccharide production and/or export. These results provide important insights into the requirements for the syp genes under different environmental conditions and thus lay the groundwork for a more complete understanding of the matrix produced by V. fischeri to enhance cell-cell interactions and promote symbiotic colonization. PMID- 23043000 TI - Genome sequence of the bacterium Streptomyces davawensis JCM 4913 and heterologous production of the unique antibiotic roseoflavin. AB - Streptomyces davawensis JCM 4913 synthesizes the antibiotic roseoflavin, a structural riboflavin (vitamin B(2)) analog. Here, we report the 9,466,619-bp linear chromosome of S. davawensis JCM 4913 and a 89,331-bp linear plasmid. The sequence has an average G+C content of 70.58% and contains six rRNA operons (16S 23S-5S) and 69 tRNA genes. The 8,616 predicted protein-coding sequences include 32 clusters coding for secondary metabolites, several of which are unique to S. davawensis. The chromosome contains long terminal inverted repeats of 33,255 bp each and atypical telomeres. Sequence analysis with regard to riboflavin biosynthesis revealed three different patterns of gene organization in Streptomyces species. Heterologous expression of a set of genes present on a subgenomic fragment of S. davawensis resulted in the production of roseoflavin by the host Streptomyces coelicolor M1152. Phylogenetic analysis revealed that S. davawensis is a close relative of Streptomyces cinnabarinus, and much to our surprise, we found that the latter bacterium is a roseoflavin producer as well. PMID- 23042999 TI - Genome of Enterobacteriophage Lula/phi80 and insights into its ability to spread in the laboratory environment. AB - The novel temperate bacteriophage Lula, contaminating laboratory Escherichia coli strains, turned out to be the well-known lambdoid phage phi80. Our previous studies revealed that two characteristics of Lula/phi80 facilitate its spread in the laboratory environment: cryptic lysogen productivity and stealthy infectivity. To understand the genetics/genomics behind these traits, we sequenced and annotated the Lula/phi80 genome, encountering an E. coli-toxic gene revealed as a gap in the sequencing contig and analyzing a few genes in more detail. Lula/phi80's genome layout copies that of lambda, yet homology with other lambdoid phages is mostly limited to the capsid genes. Lula/phi80's DNA is resistant to cutting with several restriction enzymes, suggesting DNA modification, but deletion of the phage's damL gene, coding for DNA adenine methylase, did not make DNA cuttable. The damL mutation of Lula/phi80 also did not change the phage titer in lysogen cultures, whereas the host dam mutation did increase it almost 100-fold. Since the high phage titer in cultures of Lula/phi80 lysogens is apparently in response to endogenous DNA damage, we deleted the only Lula/phi80 SOS-controlled gene, dinL. We found that dinL mutant lysogens release fewer phage in response to endogenous DNA damage but are unchanged in their response to external DNA damage. The toxic gene of Lula/phi80, gamL, encodes an inhibitor of the host ATP-dependent exonucleases, RecBCD and SbcCD. Its own antidote, agt, apparently encoding a modifier protein, was found nearby. Interestingly, Lula/phi80 lysogens are recD and sbcCD phenocopies, so GamL and Agt are part of lysogenic conversion. PMID- 23043003 TI - Schmallenberg virus antibodies detected in cattle in Wales. PMID- 23043001 TI - Aquaporin AqpZ is involved in cell volume regulation and sensitivity to osmotic stress in Synechocystis sp. strain PCC 6803. AB - The moderately halotolerant cyanobacterium Synechocystis sp. strain PCC 6803 contains a plasma membrane aquaporin, AqpZ. We previously reported that AqpZ plays a role in glucose metabolism under photomixotrophic growth conditions, suggesting involvement of AqpZ in cytosolic osmolarity homeostasis. To further elucidate the physiological role of AqpZ, we have studied its gene expression profile and its function in Synechocystis. The expression level of aqpZ was regulated by the circadian clock. AqpZ activity was insensitive to mercury in Xenopus oocytes and in Synechocystis, indicating that the AqpZ can be categorized as a mercury-insensitive aquaporin. Stopped-flow light-scattering spectrophotometry showed that addition of sorbitol and NaCl led to a slower decrease in cell volume of the Synechocystis DeltaaqpZ strain than the wild type. The DeltaaqpZ cells were more tolerant to hyperosmotic shock by sorbitol than the wild type. Consistent with this, recovery of oxygen evolution after a hyperosmotic shock by sorbitol was faster in the DeltaaqpZ strain than in the wild type. In contrast, NaCl stress had only a small effect on oxygen evolution. The amount of AqpZ protein remained unchanged by the addition of sorbitol but decreased after addition of NaCl. This decrease is likely to be a mechanism to alleviate the effects of high salinity on the cells. Our results indicate that Synechocystis AqpZ functions as a water transport system that responds to daily oscillations of intracellular osmolarity. PMID- 23043004 TI - US survey shows drop in job offers and salaries for new graduates. PMID- 23043002 TI - The zinc-responsive regulon of Neisseria meningitidis comprises 17 genes under control of a Zur element. AB - Zinc is a bivalent cation essential for bacterial growth and metabolism. The human pathogen Neisseria meningitidis expresses a homologue of the Zinc uptake regulator Zur, which has been postulated to repress the putative zinc uptake protein ZnuD. In this study, we elucidated the transcriptome of meningococci in response to zinc by microarrays and quantitative real-time PCR (qRT-PCR). We identified 15 genes that were repressed and two genes that were activated upon zinc addition. All transcription units (genes and operons) harbored a putative Zur binding motif in their promoter regions. A meningococcal Zur binding consensus motif (Zur box) was deduced in silico, which harbors a conserved central palindrome consisting of hexameric inverted repeats separated by three nucleotides (TGTTATDNHATAACA). In vitro binding of recombinant meningococcal Zur to this Zur box was shown for the first time using electrophoretic mobility shift assays. Zur binding to DNA depended specifically on the presence of zinc and was sensitive to mutations in the palindromic sequence. The Zur regulon among genes of unknown function comprised genes involved in zinc uptake, tRNA modification, and ribosomal assembly. In summary, this is the first study of the transcriptional response to zinc in meningococci. PMID- 23043006 TI - Survey indicates the scale of the unowned pet problem. PMID- 23043007 TI - Top marks for wildlife studies. PMID- 23043010 TI - Progress towards a healthy future discussed at BVA Congress. PMID- 23043009 TI - Sharing expertise on zoo animal health and welfare. PMID- 23043011 TI - Delegates quiz CVOs on bovine TB and other issues. PMID- 23043013 TI - Cats, foxes and scabies: the epidemiological puzzle of sarcoptic mange. PMID- 23043014 TI - Risk of toxoplasmosis from cats and undercooked meat. PMID- 23043015 TI - Bovine TB and badger culling. PMID- 23043022 TI - It takes 2 to thrombopoies in the vascular niche. AB - In this issue of Blood, Pitchford et al demonstrate that intravenous administration of VEGF-A promotes megakaryocyte (Mk) maturation and localization to bone marrow sinusoidal endothelial cells (BMECs), stimulating thrombopoiesis. PMID- 23043023 TI - Carfilzomib in multiple myeloma: gold, silver, or bronze? AB - In this issue of Blood, Siegel and colleagues report that the next-generation proteasome inhibitor carfilzomib, when administered as a single agent, can produce meaningful disease control in heavily pretreated patients with relapsed/refractory multiple myeloma.(1) PMID- 23043024 TI - HU for acute treatment of sickle VOC? AB - In this issue of Blood, Almeida et al report immediate benefits of hydroxyurea (HU) acute administration in diminishing vaso-occlusive processes in sickle cell disease (SCD) mice.(1) PMID- 23043025 TI - Fragmenting the platelet to reduce metastasis. AB - In this issue of Blood, Zhang et al describe an antiplatelet reagent attacking metastasis, the most deadly aspect of cancer.(1) Their experiments outline an early-stage preclinical approach providing proof-of-principle for antiplatelet strategies that may ultimately lead to an improved prognosis for the cancer patient.(1) PMID- 23043026 TI - alpha-1 antitrysin DAMPens GVHD. AB - In this issue of Blood, Brennan et al report that a noninfectious damage associated molecular pattern (DAMP), heparan sulfate (HS),(1) aggravates graft versus-host disease (GVHD) and that this enhanced severity can be dampened by administration of serine protease inhibitor alpha-1 antitrysin (AAT).(2) PMID- 23043027 TI - HLA factors in transplantation for nonmalignant hematologic disorders. AB - In this issue of Blood, a study by Horan and colleagues shows that differences in the HLA alleles of patients and unrelated donors in hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases result in increased risk for adverse treatment outcome.(1) This is the largest dataset examined so far for the evaluation of HLA mismatches in HSCT for nonmalignant diseases. It includes predominantly pediatric patients diagnosed with 39 diseases. Many patients received nonmyeloablative conditioning; a significant proportion of the infused grafts were depleted of T-lymphocytes; 6 diseases account for 77% of the cases. PMID- 23043028 TI - Making up for lost time: STEMI care in 2012. PMID- 23043029 TI - Differences in optical coherence tomographic findings and clinical outcomes between excimer laser and cutting balloon angioplasty for focal in-stent restenosis lesions. AB - AIM: In-stent restenosis (ISR), especially focal ISR, after percutaneous coronary intervention (PCI) remains one of the major clinical problems in the drug-eluting stent (DES) era. Several reports have revealed that excimer laser coronary angioplasty (ELCA) is useful for ISR; however, detailed findings after ELCA are unknown. Therefore, we investigated the condition of the neointima after ELCA for ISR with optical coherence tomography (OCT) and compared the OCT findings and clinical outcome between ELCA and cutting-balloon angioplasty (CBA). METHODS: Twenty-one consecutive patients with focal ISR who underwent ELCA or CBA were enrolled. All patients underwent 12- to 15-month follow-up coronary angiography. OCT was performed immediately after successful PCI to evaluate the neointimal condition in the ISR lesion. We compared the following OCT parameters between ELCA and CBA groups: maximal thickness of remaining in-stent neointima (MTN), number of tears, minimum lumen dimension (MLD), and minimum lumen area (MLA). We also evaluated clinical outcomes, including target vessel revascularization, acute myocardial infarction, death, and stent thrombosis. RESULTS: MLA in the ELCA group (n = 10) was significantly larger than in the CBA group, and number of tears in the ELCA group was significantly lower than in the CBA group. A trend was shown toward lower TLR with ELCA versus CBA (10.0% vs 45.5%). CONCLUSIONS: OCT immediately after ELCA for ISR lesions revealed larger lumen area and smaller number of tears compared with CBA, which may support favorable effects of ELCA for focal ISR. PMID- 23043030 TI - Gender differences in long-term clinical outcomes after percutaneous coronary intervention of chronic total occlusions. AB - INTRODUCTION: Little is known about gender differences among patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). METHODS: A total of 1791 patients with 1852 CTOs underwent PCI at 3 centers in the United States, Italy, and South Korea between 1998 and 2007. We compared baseline characteristics, procedural success rates (residual stenosis <50%), and 5-year clinical event rates in male and female patients. RESULTS: A total of 1534 men (86%) and 248 women (14%) were treated. After multivariate adjustment, procedural success rates were similar in men and women. The median follow-up duration was 2.9 years (interquartile range, 1.5-4.6 years). Successful CTO PCI was associated with reduced mortality (5.7% vs 9.2%; P<.01) and a reduced need for coronary artery bypass graft (CABG) surgery (3.1% vs 14.1%; P<.01) in male patients. In female patients, there was a trend toward a lower need for CABG after successful CTO PCI (4.0% vs 6.9%; P=.09). Rates of major adverse cardiac events (MACE; death, myocardial infarction, and CABG) were lower after successful PCI in both men and women (men, 13.1% vs 24.4% and P<.01; women, 12.3% vs 15.5% and P=.04). There was a significant interaction between gender and procedural success in terms of MACE (P<.01), indicating men had a greater reduction in MACE rate after successful CTO PCI compared with women. CONCLUSION: Our study suggested a greater benefit of a successful CTO intervention in men compared with women. A minority of patients (14%) were women. CTO PCI in women is safe and feasible and should probably be considered more often. A randomized controlled trial is needed to accurately investigate the impact of CTO PCI in both men and women. PMID- 23043031 TI - Intravascular ultrasound comparison of small coronary lesions between novel guidewire-based sirolimus-eluting stents and conventional sirolimus-eluting stents. AB - BACKGROUND: The Sparrow stent system (Biosensors International) consists of a self-expanding, ultra-thin nitinol stent mounted within a 0.014" guidewire designed for small or tortuous coronary lesions. We compared the intravascular ultrasound (IVUS) findings between the novel self-expanding sirolimus-eluting stent (Sparrow-SES) and a conventional balloon-expandable sirolimus-eluting stent (Cypher-SES) in patients with small coronary disease. METHODS: We examined 14 lesions treated with the Sparrow-SES from CARE II, compared with 22 small vessel lesions treated with Cypher-SES. IVUS examination was performed post-procedure and 8 months later. Volumetric data were standardized by length as volume index (VI; mm3/mm). RESULTS: While baseline stent VI trended smaller in Sparrow-SES, follow-up stent VI became similar between the 2 groups due to a significant increase of stent VI in self-expanding Sparrow-SES during the follow-up period. At 8 months, Sparrow-SES showed greater neointima than Cypher-SES (0.8 +/- 0.6 mm3/mm vs 0.2 +/- 0.2 mm3/mm; P<.001). However, the decrease in lumen VI was only 0.3 +/- 0.7 mm3/mm in Sparrow-SES, as compared to 0.1 +/- 0.3 mm3/mm in Cypher SES (P=.259), since the late loss due to neointimal hyperplasia was partly counterbalanced by the chronic stent expansion in Sparrow-SES. CONCLUSION: While 8-month follow-up of Sparrow-SES revealed greater amounts of neointimal hyperplasia compared with conventional Cypher-SES, chronic stent expansion preserved the lumen by increasing stent volume. This novel, guidewire-based, self expanding stent system designed to be delivered through complex anatomies may be useful to treat patients with small-caliber coronary lesions by offering sufficient lumen preservation at follow-up. PMID- 23043032 TI - Comparison of twelve-month outcomes after percutanous coronary intervention with everolimus-eluting versus zotarolimus-eluting or sirolimus-eluting stents from the PROENCY (PROmus ENdeavor CYpher) registry. AB - OBJECTIVES: We compared safety and efficacy outcomes of 3 limus-based drug eluting stents in the 'all-comers' PROENCY (PROmus/ENdeavor/CYpher) registry. BACKGROUND: Limited data are available on head-to-head comparisons of the everolimus-eluting stent (EES) with the zotarolimus-eluting stent (ZES) or the sirolimus- eluting stent (SES) in the treatment of patients with coronary artery disease. METHODS: PROENCY was a prospective, open-label, multicenter, observational study including consecutive patients undergoing planned treatment with EES, ZES, or SES. Seventeen centers were designated to place an EES or SES, 14 other centers were designated to place EES or ZES. The primary endpoint was the composite of cardiac death, myocardial infarction, and target vessel revascularization (TVR) at 12 months. Unadjusted and propensity-adjusted outcomes were compared between groups. RESULTS: A total of 1921 patients were enrolled in the study from February to December 2008, of which 1704 patients received only study stents and were analyzed. At 12 months, the unadjusted major adverse event rate was significantly lower in the EES group versus the ZES group (3.1% vs 8.7%; P=.001) and the SES group (5.2% vs 9.6%; P=.01). This was mainly driven by lower TVR rates [2.6% with EES vs 8.2% with ZES [P<.001] and 4.1% with EES vs 7.0% with SES [P=.05]. Stent thrombosis rates were low and comparable. Adjusted analyses confirmed the unadjusted results. CONCLUSION: There were no differences in safety outcomes of EES, ZES, and SES at 12 months in PROENCY. However, differences in efficacy were observed between the 3 "limus"-based stents in a real-world patient population. PMID- 23043033 TI - Predictive value of renal resistive index in percutaneous renal interventions for atherosclerotic renal artery stenosis. AB - BACKGROUND: The clinical benefit of percutaneous interventional therapies for atherosclerotic renal artery stenosis (ARAS) is still obscure. Randomized trials conducted on general patient populations provided unsatisfactory results in justifying the interventional treatment. In this study, the predictive value of renal resistive index (RRI) was retrospectively analyzed in identifying the patients who may benefit from renal angioplasty and stenting. METHODS: The records of patients who underwent percutaneous intervention for ARAS were analyzed between 2006 and 2010; we compared the clinical outcomes with preprocedural RRI values. Seventy-three patients were included in the analysis. RRI is calculated as follows: RRI = 1 - (Vmin/Vmax). Patients with RRI <= 0.75 were grouped as low RRI (group I) and compared with high RRI patients (RRI >0.75, group II).The comparison was in follow-up systolic and diastolic blood pressures, blood creatinine levels, estimated glomerular filtration rate (eGFR) and need for anti-hypertensive therapy. Data were collected by a customized online database created using Research Electronic Data Capture (REDCap) application. RESULTS: The mean follow-up was 12.4 (9-14) months and 11.1 (5-14) months for groups I and II, respectively (P=NS). After follow-up, group I patients significantly improved compared to baseline in their blood creatinine levels (2.0 +/- 1.2 mg/dL vs 1.5 +/- 0.60 mg/dL; P<.05), eGFR (45.2 +/- 26.2 mL/min vs 51.6 +/- 23.8 mL/min; P<.05), systolic blood pressure (143.6 +/- 31.0 mm Hg vs 129.6 +/- 18.4 mm Hg; P<.05), diastolic blood pressure (73.6 +/- 13.4 mm Hg vs 69.5 +/- 9.5 mm Hg; P<.05), and need for anti-hypertensive drugs (2.2 +/- 0.9 vs 2.0 +/- 0.9; P<.05). However, in group II, follow-up blood creatinine levels (1.8 +/- 0.7 mg/dL vs 2.1 +/- 1.0 mg/dL; P<.05) increased and eGFR (39.99 +/- 22.53 mL/min vs 36.3 +/- 23.2 mL/min; P<.05) decreased, indicating continuing clinical deterioration despite the intervention. CONCLUSION: RRI <= 0.75 may predict better clinical outcomes after renal angioplasty and stenting. Preprocedural RRI can be considered a useful parameter in defining patients who may benefit from interventional procedures. PMID- 23043034 TI - Gore Helex septal occluder for percutaneous closure of patent foramen ovale associated with atrial septal aneurysm: short- and mid-term clinical and echocardiographic outcomes. AB - OBJECTIVES: To evaluate the short- and mid-term clinical and echocardiographic outcome of HELEX Septal Occluder (HSO) implantation in patients with patent foramen ovale (PFO) and atrial septal aneurysm (ASA). BACKGROUND: Percutaneous closure of PFO and ASA with HSO device has not been systematically studied. METHODS: We studied 90 patients with PFO and ASA with documented paradoxical embolic events. The procedural and clinical results of 30 consecutive patients treated with HSO were compared with those obtained in 30 consecutive patients treated with the Amplatzer PFO (APO) and with those of a further 30 consecutive patients treated with the Amplatzer Cribriform (AMF). Primary endpoint was the persistence of moderate to severe residual right-to-left shunting (rRLS) at 6 month follow-up. The incidence of death or recurrent embolic events (REE) at 1 year follow-up were also investigated. RESULTS: The procedure was successfully completed in all patients. There was one HSO device embolization. Immediate moderate RLS was significantly higher in the HSO group compared to APO and AMF groups (20% vs 3% vs 0%, respectively; P=.008). The incidence of moderate rRLS decreased but was still significant at 6-month follow-up (17% in the HSO group vs 3% in the APO group; P=.02). At 1-year follow-up, moderate rRLS persisted only in the HSO group (7%). No deaths or REE were observed during hospitalization or at 1 year follow-up. CONCLUSION: HSO device seems to be a second-line device as compared to Amplatzer occluders for the treatment of PFO and ASA. PMID- 23043035 TI - Drug-eluting stenting of saphenous vein graft versus native coronary artery supplying the same myocardial perfusion territory: a pilot retrospective 3-year follow-up. AB - BACKGROUND: In post-coronary artery bypass graft (CABG) patients undergoing drug eluting stent implantation of either the saphenous vein graft (SVG) versus the native coronary artery supplying the same myocardial perfusion territory, which option confers better clinical outcomes when both lesions are technically feasible? METHODS: From 2005 to 2008 at a single medical center, a total of 178 post-CABG patients (with 241 lesions) underwent PCI due to progressive SVG disease. Of them, 23 patients (with 29 lesions) had amenable disease for PCI in both the SVG and native coronary artery matching the same myocardial perfusion territory; chronic total occlusions were excluded. All patients included in the study were treated with drug-eluting stents. Sixteen patients (19 lesions) underwent PCI of the SVG, and 9 patients (10 lesions) underwent PCI in the native vessels. RESULTS: Primary endpoints were in-hospital and 3-year rates of death, myocardial infarction (MI), target lesion revascularization (TLR), and target vessel revascularization (TVR). There were 2 in-hospital MIs in the SVG-treated group and 0 for the native vessel-treated group. The 3-year clinical follow-up showed 3 MIs, 2 TLRs, 4 TVRs, and 6 deaths in the SVG-treated group; only 1 MI occurred in the native-vessel treated group (P=.02). More PCIs of the SVG were performed than in the native coronary artery (19 vs 10 lesions). CONCLUSIONS: This small study suggests improved clinical outcomes with PCI of the native vessel, but a tendency of operators to choose PCI of the SVG instead. Large, prospective, multicenter, randomized clinical trials with long-term follow-up can validate the advantage of selecting PCI of the native vessel over the SVG when both options are available. PMID- 23043036 TI - Effect of intensive atorvastatin therapy on coronary atherosclerosis progression, composition, arterial remodeling, and microvascular function. AB - BACKGROUND: There is a discrepancy between the marked reduction in adverse events with statins and their modest effect on atheroma regression. We hypothesized that, in a Western population, high-dose atorvastatin will result in alterations in coronary atheroma composition, phenotype, and microvascular function. METHODS: Serial coronary radiofrequency intravascular ultrasound (VH-IVUS), coronary flow reserve (CFR), and hyperemic microvascular resistance (HMR) were performed at baseline and after 6 months of treatment with 80 mg atorvastatin in 20 patients with moderate coronary artery disease (CAD). For each VH-IVUS frame (n = 2249), changes in total plaque atheroma, composition, and phenotype (pathological intimal thickening, fibrotic plaque, fibroatheroma), and serial remodeling were assessed. RESULTS: Total serum cholesterol decreased from 186.0 mg/dL (interquartile range [IQR], 168.0 to 212.5 mg/dL) to 139.0 mg/dL (IQR, 124.3 to 151.3 mg/dL). Percent atheroma volume did not change significantly (-0.5% [IQR, 2.8% to 3.7%]; P=.90) and serial remodeling analysis demonstrated 40% constrictive, 24% incomplete, and 36% expansive patterns. There was a trend toward lower percent fibrous tissue (-3.47 +/- 1.78%; P=.07) and percent fibro fatty tissue (-2.52 +/- 1.24%; P=.06) and increase in percent necrotic core (+2.74 +/- 1.65%; P=.11) and percent dense calcium (+1.99 +/- 0.81; P=.02), which translated into significantly less pathological intimal thickening (4% vs 12%; P<.0001) and more fibroatheromas (67% vs 57%; P<.0001) at follow-up compared to baseline. There were modest non-significant improvements in CFR (+0.26 [IQR, 0.37 to 0.76]; P=.23) and HMR (-0.22 [IQR, -0.56 to 0.28]; P=.12). CONCLUSIONS: In this pilot study of Western patients with moderate CAD, high-dose atorvastatin resulted in alterations in coronary atheroma composition with corresponding changes in plaque phenotype and modest improvement in coronary microvascular function. PMID- 23043038 TI - Ventricular embolization of Edwards SAPIEN prosthesis following transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) is an alternative therapy in patients with severe aortic stenosis (AS) and high surgical risk. Despite continuous improvements in operators' expertise and device technology, complications associated with TAVI are common. We present a case in which an Edwards SAPIEN prosthetic valve dislocated to the left ventricular outflow tract with hemodynamic collapse 4 hours following implantation and embolized into the left ventricle (LV) during resuscitation. PMID- 23043039 TI - Early stenosis in a Gore-Tex graft connected to the left main: an emergency transradial angioplasty for a complication in a Cabrol procedure. AB - This is a case report of a successful transradial percutaneous intervention in a stenosis in a Cabrol graft. Very few reports have been published about percutaneous interventional solutions to complications in this kind of graft, and none have used the transradial approach. The Cabrol technique is used to re implant coronary arteries after aortic root replacement using a Dacron or Gore Tex graft interposed between the aortic root graft and the native coronary artery. Due to the dearth of reports on interventional solutions to complications in Cabrol-Grafts, most interventional cardiologists have little to no experience in approaching postsurgical aortic composite graft-coronary (ostial, body, or distal) lesions percutaneously, when the anatomy has been altered by a Cabrol graft. This article will elaborate on the anatomical considerations essential for performing this type of angioplasty procedures in this type of grafting and it will present the transradial approach as feasible and an excellent option for this type of procedure. We report on a case of an emergency angioplasty to rescue a patient who had persisted with hemodynamic instability after 48 hours of a Cabrol procedure which had been performed to repair an aortic type A dissection, caused during an aortic valve replacement. PMID- 23043037 TI - Age-stratified baseline and outcome characteristics of patients undergoing transcatheter aortic valve implantation: results from the German multicenter registry. AB - OBJECTIVES: To analyze age dependencies in patients currently undergoing transcatheter aortic valve implantation (TAVI) based on the German TAVI registry. BACKGROUND: TAVI is a promising, less invasive treatment option for surgical high risk patients with symptomatic aortic valve stenosis, with the majority being octogenarians treated so far. Younger patients with significant co-morbidities are now increasingly considered for this procedure, but little is known about this population. METHODS: The German TAVI registry is an ongoing non-randomized national multicenter study. Consecutive patients who underwent TAVI between January 2009 and June 2010 were included in this analysis. We compared baseline characteristics, procedural characteristics, and short-term clinical outcome up to 30-day follow-up. RESULTS: A total of 1386 patients were divided into 4 roughly equally-sized groups: group A, n = 347, mean age 73.4 +/- 4.5 years; group B, n = 350, mean age 80.6 +/- 1.1 years; group C, n = 382, mean age 84.5 +/ 1.1 years; and group D, n = 312, mean age 88.9 +/- 2.2 years. Patient characteristics varied significantly, with more co-morbidities in younger patients. Technical success rates were similar in all groups (96.6%-97.7%; P=NS). 30-day major adverse event rates were similar with an all-cause mortality rate of 7.2% (A), 7.1% (B), 9.7% (C) and 8.7% (D; P=NS). Postprocedural improvement of both New York Heart Association and self-reported health status was significant in all groups, with significantly better improvements in the categories 'mobility' and 'ability for self-care' in younger patients. CONCLUSION: TAVI appears to be similarly safe and effective across different age groups with currently applied enrollment criteria, but younger patients present with significantly more co-morbidities. All patient populations experience functional improvements, but this is particularly pronounced for younger patients. PMID- 23043040 TI - Left ventricular assist for high-risk percutaneous coronary intervention. AB - As percutaneous coronary intervention (PCI) is being applied to higher-risk patients, ie, those with unprotected left main, multi-vessel disease, last remaining vessel, compromised left ventricular function, and ongoing ischemia, interventional cardiologists have used different percutaneous assist devices in an attempt to reduce procedure risk. The definition of high risk has varied among trials. There is no definitive evidence for superiority of the more invasive devices over the intra-aortic balloon pump (IABP); furthermore, a prophylactic strategy of IABP insertion has not proven superior to a provisional strategy. The purpose of this report is to review the physiologic mechanism of action of the devices and discuss indications, limitations, and clinical outcomes during high risk PCI. PMID- 23043041 TI - Right coronary artery to coronary sinus fistula. AB - Coronary arteriovenous fistulas are very uncommon. We present a case of a very large right coronary artery to coronary sinus fistula, ultimately leading to congestive heart failure and necessitating surgical intervention. PMID- 23043042 TI - Letter to the editor: The influence of right atrial pressure on fractional flow reserve. PMID- 23043043 TI - Letter to the editor: Feasibility of frequency-domain optical coherence tomography for coronary stent imaging: a matter of definitions. PMID- 23043044 TI - Acute myocardial infarction as a complication of cardiac sarcoma: a rare presentation. AB - We present a case of left atrial sarcoma presenting as acute myocardial infarction. Echocardiographic finding of left atrial mass, absence of angiographic evidence of coronary atherosclerotic disease, and incidental finding of prior splenic infarct strongly point to coronary emboli. The relatively low incidence of cardiac sarcoma and the uncommon presentation of cardiac sarcoma as myocardial infarction make this case unique. PMID- 23043046 TI - Neointimal tissue healing patterns after paclitaxel-eluting balloon treatment of in-stent restenosis: optical coherence tomography and intravascular ultrasound insights. AB - An 80-year-old patient presented with severe in-stent restenosis of an everolimus eluting stent implanted in the left anterior descending coronary artery 3 years previously. We obtained good angiographic result after paclitaxel-eluting balloon dilation. However, on optical coherence tomography (OCT), multiple, angiographically silent, in-stent, and edge-related dissections were readily recognized. Intravascular ultrasound (IVUS) revealed residual neointima with minor disruptions. At 9-month follow-up, an excellent angiographic result was demonstrated with complete resolution of the stent-related dissections on OCT. IVUS and OCT confirmed complete neointimal healing with a larger lumen. This case illustrates the value of OCT and IVUS to provide unique insights on the pathophysiological mechanisms and healing patterns of paclitaxel-eluting balloon treatment of in-stent restenosis. PMID- 23043045 TI - Percutaneous treatment of delayed post-atherectomy superficial femoral artery pseudoaneurysm. AB - SilverHawk atherectomy is commonly used in lower extremity percutaneous interventions. Minor perforations during SilverHawk atherectomy procedures are reported at a range of 0.8%. There are few reported cases in the literature about very late pseuodoaneursym formation after SilverHawk atherectomy. Herein we report a very unusual, late, concealed, acute rupture of superficial femoral artery with a large, painful pseuodoaneursym formation, 1 week after Silver- Hawk atherectomy and its treatment with Viabahn stent graft (W.L. Gore & Associates). PMID- 23043047 TI - Accidental closure of the left upper pulmonary vein with an Amplatzer atrial septal defect occluder. AB - We report the clinical outcome of a 46-year-old man referred for percutaneous closure of an atrial septal defect under transthoracic echocardiographic and fluoroscopic guidance, whose upper left pulmonary vein was erroneously obliterated using an Amplatzer atrial septal defect occluder. Various medical conditions have been associated with pulmonary vein stenosis including dyspnea on exertion or at rest, cough, and hemoptysis. However, there were no short- or long term symptoms in this patient. PMID- 23043048 TI - Guideliner catheter facilitated percutaneous coronary artery intervention of an anteriorly displaced and heavily calcified right coronary artery. AB - Failure to deliver stents is one of the most common causes of procedural failure in contemporary percutaneous coronary intervention practice. The right coronary artery with an anomalous origin is an uncommon and challenging vessel for percutaneous intervention especially if this occurs in combination with heavy calcification. Choosing the appropriate guiding catheter is one important factor in determining procedural success. The technical difficulty of these anomalous vessels is reflected by the long procedure, fluoroscopy times, and high contrast volumes. Despite using the optimal guiding catheter, we may have difficulty advancing the stent in the distal part of the vessel due to the development of significant friction between the stent and the calcified vessel wall. We report a case of successful use of the Guideliner catheter (Vascular Solutions) for distal stent delivery in a patient with a right coronary artery with anomalous origin (anteriorly displaced) and heavy calcification. PMID- 23043049 TI - Late stent thrombosis of a second-generation drug- eluting stent. AB - A 62-year-old male patient presented with acute non-ST elevation myocardial infarction. He underwent successful percutaneous coronary intervention with implantation of an everolimus-eluting stent in the left anterior descending coronary artery. Six months later, he discontinued clopidogrel. Two weeks later, he presented with unstable angina. Despite the unremarkable electrocardiography, cardiac biomarkers, and coronary angiography, optical coherence tomography revealed a thrombus extending throughout the stent, with uncovered and malapposed stent struts in its proximal part. Thrombectomy was performed. The patient was discharged on dual antiplatelet therapy. Eight months later, the follow-up coronary angiography reassured a patent stent with adequate flow and no evidence of thrombi. PMID- 23043050 TI - Successful angioplasty of anomalous coronary arteries with total occlusions. AB - We present 2 cases of successful angioplasty of anomalous coronary arteries with total occlusions. One of our patients had a chronic total occlusion of the right coronary artery and the other had acute total occlusion of the left anterior descending artery with special focus on optimal guide catheter selection. PMID- 23043052 TI - Pumping iron: conserved iron deficiency responses in the plant lineage. PMID- 23043054 TI - The use of regional anesthetic techniques in pain management in patients undergoing primary knee replacement. AB - During last 30 years orthopedic surgery dramatically improved. The most significant progress had place in joint surgery. Today in many orthopedic centers total hip and knee arthroplasties are made and may be counted in hundreds per year. Surgeons can choose among many different implant operation systems. Nevertheless this type of operations is connected with pain in immediate postoperative course. The aim of the paper was presentation of contemporary methods of pain management after big knee surgery, especially after total knee arthroplasty (TKA). Among presented methods of pain management the anesthetic techniques were discussed: epidural anesthesia (EA) and peripheral nerves blocks (PNB). They seem to be most interesting and evolutionary because of possibility of early ambulation and more effective postoperative rehabilitation. It directly corresponds to therapeutic effect of surgical procedure and patient's satisfaction. In the paper there are presented advantages and possible complications of regional techniques, particular block techniques and technical problems with possible modifications of pain management. This review is based on latest medical literature, especially on metaanalyses published during last few years comparing different modes of postoperative pain management. PMID- 23043053 TI - A review of current management of metacarpal base fractures. AB - Metacarpal (MCP) base fractures are less commonly encountered than diaphyseal or metacarpal neck fractures. These are difficult injuries to diagnose and are challenging to treat. Neglect of these injuries, either by missed diagnosis or by inadequate treatment, causes significant disability due a poorly functioning carpo-metacarpal joint. There have been several developments in the management of these injuries, from arthroscopically assisted fixation to bio-absorbable implants. There have been advances in technology used for internal fixation implants and also materials used for arthroplasty in cases of eventual joint degeneration. Here we aim to present significant advances in management of metacarpal base fractures. PMID- 23043051 TI - Systems and trans-system level analysis identifies conserved iron deficiency responses in the plant lineage. AB - We surveyed the iron nutrition-responsive transcriptome of Chlamydomonas reinhardtii using RNA-Seq methodology. Presumed primary targets were identified in comparisons between visually asymptomatic iron-deficient versus iron-replete cells. This includes the known components of high-affinity iron uptake as well as candidates for distributive iron transport in C. reinhardtii. Comparison of growth-inhibited iron-limited versus iron-replete cells revealed changes in the expression of genes in chloroplastic oxidative stress response pathways, among hundreds of other genes. The output from the transcriptome was validated at multiple levels: by quantitative RT-PCR for assessing the data analysis pipeline, by quantitative proteomics for assessing the impact of changes in RNA abundance on the proteome, and by cross-species comparison for identifying conserved or universal response pathways. In addition, we assessed the functional importance of three target genes, Vitamin C 2 (VTC2), monodehydroascorbate reductase 1 (MDAR1), and conserved in the green lineage and diatoms 27 (CGLD27), by biochemistry or reverse genetics. VTC2 and MDAR1, which are key enzymes in de novo ascorbate synthesis and ascorbate recycling, respectively, are likely responsible for the 10-fold increase in ascorbate content of iron-limited cells. CGLD27/At5g67370 is a highly conserved, presumed chloroplast-localized pioneer protein and is important for growth of Arabidopsis thaliana in low iron. PMID- 23043056 TI - Assessment of validity, reliability, responsiveness and bias of three commonly used patient-reported outcome measures in carpal tunnel syndrome. AB - BACKGROUND: In recent years there has been an increase in the use of self administered questionnaires to accurately assess intervention outcomes in hand surgery in order to determine the quality of healthcare. This prospective study aims to evaluate and assess the validity, reliability, responsiveness, and bias of a number of outcome measure for Carpal Tunnel Syndrome (CTS) including the disease-specific Boston questionnaires (BQ), and the region-specific Disability of Arm, Shoulder, and Hand (DASH) questionnaires and Manchester Modified Disabilities of the Arm, Shoulder and Hand (M(2)DASH) questionnaires, and comparing the results to Nerve Conduction Studies (NCS). MATERIALS AND METHODS: Forty-eight patients with clinical signs of CTS confirmed by NCS completed the BQ, DASH and M(2)DASH questionnaire at different time intervals peri-operatively. The scores were analysed to assess validity, reliability, responsiveness, and bias of the questionnaires. Validity analysis for the three questionnaires showed strong positive correlations and there was no age, gender, hand dominance, or side affected bias in the questionnaires. RESULTS: No significant correlation was obtained between the questionnaires and NCS. Significant results for responsiveness were noted in BQ symptom severity scale only. CONCLUSION: 1. This study ha show n that the BQ, DASH and M(2)DASH questionnaires are valid and reliable outcome measures for CTS. 2. In terms of responsiveness, the DASH and M(2)DASH questionnaires are not as responsive as the BQ scores over the initial post-operative recovery period. 3. We would therefore recommend that the Boston Questionnaire be used to assess early post-operative patient related outcome measures for Carpal Tunnel Syndrome. PMID- 23043055 TI - Clinical experience with the use of low molecular weight heparin in orthopaedic treatment of paediatric patients. AB - BACKGROUND: The objective of the paper is to describe our clinical experience with the use of low molecular weight heparin in children treated due to various orthopaedic conditions. MATERIAL AND METHODS: We have studied the treatment outcomes of 35 patients aged 11 to 18 years who were hospitalized in the Department of Paediatric Orthopaedics and Department of Traumatology and Emergency Medicine of the Medical University of Lublin and were treated with a low molecular weight heparin (LMWH). Short-term prophylaxis was applied in 33 patients during immobilization after such orthopaedic procedures as surgical correction of spine deformity and corrective osteotomy of the femoral and tibial bone. Two children received LMWH therapy after reduction and fixation of femoral bone fractures and long-term immobilization following ankle joint distortion with early-stage venous thromboembolism (VTE). RESULTS: None of the patients who received prophylactic treatment showed the clinical manifestations of thrombosis. The VTE symptoms subsided in children treated with the LMWH. Nadroparin was administered for both short-term prophylaxis and treatment, and was administered in doses proportionate to body weight and without prior determination of anti factor Xa activity (anti-Xa assay). No side effects were observed. CONCLUSIONS: The use of the LMWH turned out to be effective and safe in thromboprophylaxis in paediatric patients. PMID- 23043057 TI - Total hip arthroplasty with shortening subtrochanteric Z osteotomy in the treatment of developmental dysplasia with high hip dislocation. AB - BACKGROUND: The work presents the results of total hip arthroplasty in the treatment of arthrosis secondary to for developmental dysplasia with high hip dislocation or corollary to previous surgery of dysplastic high riding hips. In all patients the cup was placed in its anatomical position. In order to avoid excessive lengthening of the operated limb and the associated complications, the femoral shaft was shortened by subtrochanteric Z osteotomy. The osteotomy site was stabilised with a cementless CDH stem. MATERIAL AND METHOD: The technique was used in 10 women at an average age of 53. 4 years between 2006 and 2011. Five patients were operated on due to the degenerative changes secondary to developmental dysplasia with high dislocation of hip joint. The remaining patients had undergone surgery before. Angular osteotomy of the proximal femur was performed in four patients and total hip arthroplasty with high placement of the acetabular component in one. The average preoperative Harris Hip Score was 43.7. Preoperative shortening of the limb ranged from 4 to 10 cm, with an average of 6. 1 cm. RESULTS: The patients were followed up for a mean of 28. 3 months. No postoperative nerve damage has been observed. The operated limb was lengthened in all patients (range: 2.5 to 5 cm, mean: 3.4 cm). Radiographic union at the osteotomy site was obtained after an average of 4.5 months. All patients reported complete or near-complete pain relief and improved function of the operated limb. By the last follow-up visit, the Harris Hip Score had increased to 86 points on average. CONCLUSIONS: Subtrochanteric osteotomy of the femur reduces the risk of postoperative complications associated with excessive limb lengthening and facilitates access to the acetabulum. Total hip arthroplasty with shortening subtrochanteric Z-type osteotomy is a safe method in the treatment of degenerative changes secondary to developmental dysplasia with high hip dislocation. PMID- 23043058 TI - Evaluation of nutritional status of children and adolescents with idiopathic scoliosis: a pilot study. AB - BACKGROUND: Body composition changes during childhood and adolescence. It is markedly different in children with idiopathic scoliosis (IS). This study was carried out to assess the nutritional status of patients with IS based on standard anthropometric indices and bioimpedance measurements (BIA). MATERIAL AND METHODS: 59 patients with IS (45 girls/ 14 boys) at a mean age of 13.37 +/- 2.67 years were qualified into the study. Scoliotic curves were assessed radiographically by measuring Cobb's angle and apical vertebral rotation (AVR, standing A-P view). Height, weight, waist and hip circumferences were measured and the body mass index (BMI), BMI Z-score, waist/height ratio (WHtR) and waist/hip ratio (WHR) were calculated for each participant. A bioelectrical impedance analyzer was used to assess body composition in every child. RESULTS: 64.4% of the children in the study had normal weight, while 23.7% of them were underweight and 11.9% overweight or obese. More patients in the juvenile IS group were underweight and fewer were overweight compared with the adolescent IS (AIS) group. Normal nutritional status was found significantly more frequently in girls. Body composition correlated significantly with scoliotic curve severity in the study group. Higher correlation coefficients were seen in overweight and obese patients, but significance was reached only for predicted muscle mass. WHtR correlated significantly with curve severity in the entire group, in AIS patients and in girls. Scoliotic curve severity also correlated significantly with the degree, as measured by the BMI Z-score, of both overweight (positively) and underweight (negatively). CONCLUSIONS: 1. Overweight and obesity appear to have a similar prevalence in scoliotic adolescents and in the general pediatric population. 2. Scoliotic curve severity appears to be related to body composition parameters, especially in overweight and obese patients. 3. Adipose tissue distribution measured by WHtR seems to be significantly related to the clinical grade of IS. 4. Further investigations concerning the nutritional status of children and adolescents with IS are recommended. PMID- 23043059 TI - Foot and Knee Behaviour During Gait in Response to the Use of Additional Means of Treatment in Cerebral Palsied Children AB - BACKGROUND: Physiological human gait is characterized by tree-dimensional pelvis movements, which make that gait is smooth and does not require excessive energy expenditure. In children with cerebral palsy determinants of the pelvis may be affected, mainly due to pathological afferent synergisms. Therefore many specialists is looking for ways to improve this situation. The aim of this study was to verify whether the use of botulinium toxin or inhibitive casts affects the kinematic parameters of the pelvis during the gait of children with hemiparetic form of cerebral palsy. MATERIAL AND METHODS: The study involved 34 hemiparetic children with cerebral palsy aged 7-14 years who reached the capacity of walking. All were improving by neurodevelop-mental treatment according to NDT-Bobath method. Two groups were created. In the first group inhibiting casting was used in 16 children. In the second group botulinium toxin was injected in 18 children. Gait analysis was performed before and after using those type of treatment. Ultrasonic CMS-HS system (Zebris) was used for three dimensional gait analysis. RESULTS: Despite of the characteristic for hemiplegic gait pattern asymmetry, various ab-normalities of pelvis kinematic parameters were observed. Gait symmetry was improved aafter the treatment. Using inhibiting casts also improved kinematic parameters of the pelvis, especially in those children who are found deficit of decreasing and rotation of the pelvis. CONCLUSIONS: 1) The use of Btx A or inhibitive casts results in improving temporal- spatial parameters of gait of cerebral palsied children with hemiparesis. 2) The improvement of kinematic pelvis parameters are obtained through the use of inhibitive casts, while the use of Btx-A does not have a significant impact on them. PMID- 23043060 TI - Siting stability in skeletally mature patients with scoliosis and myelomeningocele. AB - BACKGROUND: The purpose of the study was to assess the influence of sitting stability in skeletally mature patients on their quality of life and general physical function. We also aimed to assess the relationship between sitting balance and the severity of scoliosis or other disorders of individuals with myelomeningocoele. MATERIAL AND METHODS: The prospective study enrolled 19 patients with a mean age of 21.4 years (min. 13 years). Patients treated operatively for spinal deformity were excluded from the study. Different aspects of the quality of life were assessed with several questionnaires serving to measure overall quality of life, general physical function, self-perception and self-motivation as well as dysfunction related to spine deformity. Walking ability was assessed according to the Hoffer classification and the level of motor neuron injury was evaluated with the International Myelodysplasia Study Protocol. RESULTS: Statistical analysis showed that sitting stability assessed by examiners or parents positively correlated with overall quality of life, general physical function, pelvic obliquity measured by Osebold method, and the level of motor spine dysfunction. It was not related to self-perception and self motivation of patients. There was no statistical correlation between sitting balance and the Cobb angle, walking ability, presence of pressure sores and age. CONCLUSIONS: The value of the Cobb angle is not a good indicator of sitting balance in patients with scoliosis and myelomeningocoele. Stabile sitting is related to better overall quality of life and physical function. PMID- 23043061 TI - Surgical management of congenital radial head dislocation: a case report. AB - Congenital radial head dislocation is a rare condition which is, however, the most common of all congenital pathologies of the elbow joint. This paper is a case report on a patient presenting with moderate pain and discomfort in one of his elbow joints, both of which were found to be affected by this condition. He was treated by surgery which consisted of resection of the proximal radius and partial anterior capsulectomy of the elbow joint. This treatment led to a significant improvement in pain and elbow function compared to the preoperative status. PMID- 23043062 TI - [Fish consumption and cardiovascular disease prevention]. PMID- 23043063 TI - [Reflection on the Breivik verdict]. PMID- 23043064 TI - [Dietary habits and their association with blood pressure among elderly Icelandic people]. AB - OBJECTIVE: Prevalence of hypertension, which is the most common risk factor for cardiovascular disease in elderly people, increases with age. The aim of the study was to investigate the association between diet and blood pressure in elderly Icelanders, with focus on cod liver oil, and to compare their diet to dietary guidelines. MATERIAL AND METHODS: Diet was assessed using three-day weighed food records and blood pressure was measured after a 12-hour-fast in 236, 65-91 years old, Icelanders living in the capital area of Iceland. 99 men (42%) and 137 women (58%) participated in the study. RESULTS: According to Nordic nutrition recommendations, intake of nutrients was above lower intake levels among the majority of participants. However, 19% were under this level for vitamin-D, 13% for iodine, 17% of men for vitamin-B6, and 26% and 12% of men and women, respectively, for iron. Systolic blood pressure was inversely associated with cod liver oil intake, even when adjusted for age, body mass index, gender, and antihypertensive medications (P=0.01). Intake of long-chain omega-3 fatty acids correlated with blood pressure in a similar way. Other dietary factors were not associated with blood pressure. CONCLUSION: The results indicate that intake of cod liver oil is associated with lower blood pressure among elderly people and may therefore have beneficial effects on health. A notable proportion of participants was at risk of vitamin D, vitamin B6, iodine, and iron deficiency. PMID- 23043065 TI - [Bone mineral density of young women with history of anorexia nervosa]. AB - OBJECTIVE: A decrease in bone mineral density (BMD) is frequently seen in patients with anorexia nervosa (AN). This study was designed to assess BMD of young Icelandic women with current or previous history of AN and identify predictors which might be targets for preventive measures. MATERIAL AND METHODS: The study was retrospective. Participants were women aged 18-40 years, with diagnosis of AN (F50.0, F50.1) attending the anorexia unit at Landspitali - The National University Hospital of Iceland - in 2001-2009, who had undergone measurement of BMD by dual-energy X-ray absorptiometry. A control group consisted of 58 healthy 30 years old women participating in a study of bone health in 2001 2003. RESULTS: At time of BMD measurement the median body mass index (BMI: kg/m2) in the AN group (n=40) was 17.4 (12.3-25.2) compared to 23.6 (18.1-43.7) in the control group (p<0,001). Lumbar spine and hip BMD were 15.3-17.5% lower in AN patients than in control subjects (p<0.001). In both groups there was a strong correlation between BMD and body weight (r=0.354-0.604, p<0.05) and lean mass (r=0.425-0.588, p<0.05). Among patients with AN a correlation was also seen between BMD and lowest weight during the illness (r=0.482-0.499, p<0.01). Among the 26 AN patients who had repeated BMD measurement, a significant decrease in BMD at femoral neck (-6.6%, p=0.030) was observed in those who lost weight between the measurements (n=9). Those who had BMI <=17.5 between BMD measurements lost 5.5-7.1% of the BMD at the hip (p<0.05). CONCLUSION: Young women with AN have 15% lower bone mass than healthy young women. The relationship between BMD and body weight seems to be a continuum across disease states. Increased body weight may be the most important factor for recovery of bone mass in AN patients. PMID- 23043066 TI - [Ceruloplasmin (Cp) and iron in connection with Parkinson's disease (PD) and Alzheimer's disease (AD)]. AB - Ceruloplasmin, a multi-copper oxidase with four active copper atoms, oxidizes Fe2+ to Fe3+ and concomittantly fully reduces oxygen to water. The oxygenation of iron is a requisite for transferrin transport of iron and keeping noxious Fe2+ low. In the central nervous system (CNS) Cp is mostly localized in end feet of astrocytes surrounding capillaries and attached by a glycosylphosphatidylinositol anchor. In aceruloplasminaemia, a rare recessive hereditary disease, complete loss of Cp is accompanied by disorders of iron metabolism and lesions in CNS and outside. In PD Cp concentration and oxidative activity in serum are significantly lowered with iron deposits and lesions in substantia nigra and basal ganglia. Changes in Cp-genes might be causative in these disorders. By inducing neuromelanin synthesis Cp may protect neurons in substantia nigra. In AD Cp activity in serum, but not concentration, is significantly lowered. Changes in Cp genes have not been verified in AD. Total amounts of iron are not increased in AD brains although iron deposits and cortical lesions are numerous. Total copper is significantly lowered in AD brains. This may result in defective synthesis of Cp and other copper enzymes. - In conclusion, the defective Cp activity, associated with iron disorders, is seemingly of importance in PD and also in AD with other copper enzyme defects possibly involved. PMID- 23043067 TI - Efavirenz, tenofovir and emtricitabine combined with first-line tuberculosis treatment in tuberculosis-HIV-coinfected Tanzanian patients: a pharmacokinetic and safety study. AB - BACKGROUND: To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed dose combination tablet, and vice versa, in Tanzanian TB-HIV-coinfected patients. METHODS: This was a Phase II open-label multiple dose pharmacokinetic and safety study. This study was conducted in TB-HIV-coinfected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed dose combination tablet was started at week 4 after initiation of TB treatment. A 24-h pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at 2 and 5 h post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART). RESULTS: A total of 25 patients (56% male) completed the study; 21 had evaluable pharmacokinetic profiles. The area under the concentration-time curve 0-24 h post-dose of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were coadministered with TB drugs; geometric mean ratios (90% CI) were 1.08 (0.90, 1.30), 1.13 (0.93, 1.38) and 1.05 (0.85, 1.29), respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no serious adverse events or drug discontinuations were reported. CONCLUSIONS: Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV. PMID- 23043068 TI - The laboratory and the new oral anticoagulants. AB - BACKGROUND: The new oral anticoagulants (NOAs) dabigatran, rivaroxaban, and apixaban have proved effective and safe when used in clinical trials, without a need to adjust the dose in response to laboratory testing. This demonstrated efficacy does not necessarily mean that the laboratory, considered the mainstay for the management of the old anticoagulants, will no longer play a role in treatment with NOAs. CONTENT: Laboratories are involved in the management of anticoagulants in 2 ways. The first, monitoring, implies laboratory testing to assess the drug's effect and to adjust the dosage to maintain anticoagulation within the therapeutic interval. This consideration applies to the old drugs. The second way, measurement, implies laboratory evaluations of drug effect to determine whether patients are under- or over-anticoagulated, information that can be useful for decision-making in special circumstances. The latter applies to NOAs. SUMMARY: Measurements of the effect of NOAs are indicated in several situations: (a) patients with adverse events (i.e., thrombotic/hemorrhagic), particularly those who present with overdosage owing to excessive drug intake or decreased clearance; (b) patients undergoing surgical procedures for ensuring that no residual drug remains in the circulation; (c) patients requiring anticoagulation reversal because of life-threatening hemorrhage; (d) patients with renal insufficiency, who are likely to accumulate the drug in the circulation; (e) patients with liver failure, because NOAs are metabolized by the liver; (f) patients taking other drugs that might increase/decrease the effects of NOAs via drug-drug interactions. The choice of tests is based on such characteristics as availability, linearity of the dose-response curve, standardization, and responsiveness to increasing drug dosage. Practitioners need to be aware that NOAs can interfere with the measurement of common hemostasis parameters. PMID- 23043069 TI - Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis. AB - Myeloproliferative neoplasms (MPNs) are the most common cause of Budd-Chiari syndrome (BCS) and nonmalignant, noncirrhotic portal vein thrombosis (PVT). In this meta-analysis, we determined the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders. MEDLINE and EMBASE databases were searched. Prevalence of MPNs, JAK2V617F, and MPN subtypes were calculated using a random-effects model. A total of 1062 BCS and 855 PVT patients were included. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% (95% CI, 32.9%-49.5%) and 41.1% (95% CI, 32.3%-50.6%), respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% (95% CI, 25.1%-38.8%) and 27.7% (95% CI, 20.8%-35.8%), respectively. JAK2V617F and MPNs were more frequent in BCS compared with PVT (P = .03 and P = .09, respectively). Polycythemia vera was more prevalent in BCS than in PVT (P = .001). JAK2V617F screening in splanchnic vein thrombosis (SVT) patients without typical hematologic MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively. These results demonstrate a high prevalence of MPNs and JAK2V617F in SVT patients and show differences in underlying etiology between these disorders. Furthermore, these results validate routine inclusion of JAK2V617F in the diagnostic workup of SVT patients. PMID- 23043070 TI - Epidermis instructs skin homing receptor expression in human T cells. AB - The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. Although the mechanisms controlling memory T-cell migration to peripheral tissues are poorly understood, the current paradigm includes the localized secretion of "imprinting" signals from tissue-resident dendritic cells in the draining lymph nodes. Here we show that CCR8 expression by newly activated naive T cells is regulated by skin specific factor(s) derived primarily from epidermal keratinocytes, thereby providing a mechanism for the preferential expression of CCR8 by skin-resident memory T cells. Importantly, no such effects were observed after coculture with primary cells from skin-unrelated epithelia, including mesothelium and small intestine. The keratinocyte-derived CCR8-inducing factor(s) were soluble, and independent of vitamins A and D. Furthermore, the induction of CCR8 under these conditions correlated with an increase in cutaneous lymphocyte-associated antigen expression. Our findings challenge current tissue homing paradigms, especially those involving CCR10, and emphasize the importance of steady-state epidermis rather than tissue-resident dendritic cells in controlling the localization of memory T cells within human skin. PMID- 23043071 TI - Differential effects of gammac cytokines on postselection differentiation of CD8 thymocytes. AB - The primary consequence of positive selection is to render thymocytes responsive to cytokines and chemokines expressed in the thymic medulla. In the present study, our main objective was to discover which cytokines could support the differentiation of positively selected thymocytes. To this end, we have developed an in vitro model suitable for high-throughput analyses of positive selection and CD8 T-cell differentiation. The model involves coculture of TCR(hi)CD5(int)CD69( ) double-positive (DP) thymocytes with peptide-pulsed OP9 cells and gammac cytokines. We report that IL-4, IL-7, and IL-21 have nonredundant effects on positively selected DP thymocytes. IL-7 signaling phosphorylates STAT5 and ERK; induces Foxo1, Klf2, and S1pr1; and supports the differentiation of classic CD8 T cells. IL-4 activates STAT6 and ERK and supports the differentiation of CD8(int)PD-L1(hi)CD44(hi)EOMES(+) innate CD8 T cells. IL-21 is produced by thymic epithelial cells and the IL-21 receptor-alpha is strongly induced on DP thymocytes undergoing positive selection. IL-21 signaling phosphorylates STAT3 and STAT5, but not ERK, and does not support CD8 T-cell differentiation. However, IL-21 has a unique ability to up-regulate BCL-6, expand DP thymocytes undergoing positive selection, and increase the production of mature T cells. Our data suggest that injection of recombinant IL-21 might enhance thymic output in subjects with age- or disease-related thymic atrophy. PMID- 23043072 TI - The split personality of regulatory T cells in HIV infection. AB - Natural regulatory T cells (Tregs) participate in responses to various chronic infections including HIV. HIV infection is associated with a progressive CD4 lymphopenia and defective HIV-specific CD8 responses known to play a key role in the control of viral replication. Persistent immune activation is a hallmark of HIV infection and is involved in disease progression independent of viral load. The consequences of Treg expansion, observed in HIV infection, could be either beneficial, by suppressing generalized T-cell activation, or detrimental, by weakening HIV-specific responses and thus contributing to viral persistence. The resulting balance between Tregs contrasting outcomes might have critical implications in pathogenesis. Topics covered in this review include HIV-induced alterations of Tregs, Treg cell dynamics in blood and tissues, Treg-suppressive function, and the relationship between Tregs and immune activation. This review also provides a focus on the role of CD39(+) Tregs and other regulatory cell subsets. All these issues will be explored in different situations including acute and chronic infection, antiretroviral treatment-mediated viral control, and spontaneous viral control. Results must be interpreted with regard to both the Treg definition used in context and to the setting of the disease in an attempt to draw clearer conclusions from the apparently conflicting results. PMID- 23043073 TI - Hyperfunctional coagulation factor IX improves the efficacy of gene therapy in hemophilic mice. AB - Gene therapy may provide a cure for hemophilia and overcome the limitations of protein replacement therapy. Increasing the potency of gene transfer vectors may allow improvement of their therapeutic index, as lower doses can be administered to achieve therapeutic benefit, reducing toxicity of in vivo administration. Here we generated codon-usage optimized and hyperfunctional factor IX (FIX) transgenes carrying an R338L amino acid substitution (FIX Padua), previously associated with clotting hyperactivity and thrombophilia. We delivered these transgenes to hemophilia B mice by hepatocyte-targeted integration-competent and -defective lentiviral vectors. The hyperfunctional FIX transgenes increased FIX activity reconstituted in the plasma without detectable adverse effects, allowing correction of the disease phenotype at lower vector doses and resulting in improved hemostasis in vivo. The combined effect of codon optimization with the hyperactivating FIX-R338L mutation resulted in a robust 15-fold gain in potency and therefore provides a promising strategy to improve the efficacy, feasibility, and safety of hemophilia gene therapy. PMID- 23043074 TI - Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective therapeutics. Periostin has been reported to be elevated in IPF patients relative to controls, but its sources and mechanisms of action remain unclear. We confirm excess periostin in lungs of IPF patients and show that IPF fibroblasts produce periostin. Blood was obtained from 54 IPF patients (all but 1 with 48 wk of follow-up). We show that periostin levels predict clinical progression at 48 wk (hazard ratio = 1.47, 95% confidence interval = 1.03-2.10, P < 0.05). Monocytes and fibrocytes are sources of periostin in circulation in IPF patients. Previous studies suggest that periostin may regulate the inflammatory phase of bleomycin-induced lung injury, but periostin effects during the fibroproliferative phase of the disease are unknown. Wild-type and periostin deficient (periostin(-/-)) mice were anesthetized and challenged with bleomycin. Wild-type mice were injected with bleomycin and then treated with OC-20 Ab (which blocks periostin and integrin interactions) or control Ab during the fibroproliferative phase of disease, and fibrosis and survival were assessed. Periostin expression was upregulated quickly after treatment with bleomycin and remained elevated. Periostin(-/-) mice were protected from bleomycin-induced fibrosis. Instillation of OC-20 during the fibroproliferative phase improved survival and limited collagen deposition. Chimeric mouse studies suggest that hematopoietic and structural sources of periostin contribute to lung fibrogenesis. Periostin was upregulated by transforming growth factor-beta in lung mesenchymal cells, and periostin promoted extracellular matrix deposition, mesenchymal cell proliferation, and wound closure. Thus periostin plays a vital role in late stages of pulmonary fibrosis and is a potential biomarker for disease progression and a target for therapeutic intervention. PMID- 23043075 TI - Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia: role of histone acetylation. AB - High-altitude long-term hypoxia (LTH) is known to induce pulmonary arterial smooth muscle cell (PASMC) proliferation in the fetus, leading to pulmonary arterial remodeling and pulmonary hypertension of the newborn. The mechanisms underlying these conditions remain enigmatic however. We hypothesized that epigenetic alterations in fetal PASMC induced by high-altitude LTH may play an important role in modulating their proliferation during pulmonary arterial remodeling. To test this hypothesis, we have analyzed epigenetic alterations in the pulmonary vasculature of fetal lambs exposed to high-altitude LTH [pregnant ewes were kept at 3,801 m altitude from ~40 to 145 days gestation] or to sea level atmosphere. Intrapulmonary arteries were isolated, and fetal PASMC were cultured from both control and LTH fetuses. Compared with controls, in LTH fetus pulmonary arteries measurements of histone acetylation and global DNA methylation demonstrated reduced levels of global histone 4 acetylation and DNA methylation, accompanied by the loss of the cyclin-dependent kinase inhibitor p21. Treatment of LTH fetal PASMCs with histone deacetylase (HDAC) inhibitor trichostatin A decreased their proliferation rate, in part because of altered expression of p21 at both RNA and protein level. In PASMC of LTH fetuses, HDAC inhibition also decreased PDGF-induced cell migration and ERK1/2 activation and modulated global DNA methylation. On the basis of these observations, we propose that epigenetic alterations (reduced histone acetylation and DNA methylation) caused by chronic hypoxia leads to fetal PASMC proliferation and vessel remodeling associated with vascular proliferative disease and that this process is regulated by p21. PMID- 23043077 TI - Chronic effects of pulmonary artery stenosis on hemodynamic and structural development of the lungs. AB - Pulmonary artery (PA) stenosis is a difficult obstructive defect to manage since clinicians cannot know a priori which obstructions to treat and when. Prognosis of PA stenosis and its chronic effects on lung development are poorly understood. This study aimed to characterize the hemodynamic and structural effects of PA stenosis during development. Fourteen male Sprague-Dawley rats underwent left PA (LPA) banding at age 21 days, and 13 underwent sham operation. Hemodynamic and structural impacts were studied longitudinally at 20, 36, 52, 100, and 160 days. Chronic LPA banding resulted in a significant reduction in LPA flow (P < 0.0001) and size of both proximal LPA (P < 0.0001) and distal LPA (P < 0.01), as well as a significant increase in flow and size of the right PA (P < 0.05) throughout development. Flows and sizes adapted such that normal levels of wall shear were restored after banding. At 160 days, LPA banding resulted in a significant decrease in left lung volume and an increase in right lung volume but no significant differences in total lung volume. There was an elevation of proximal LPA pressure as well as right ventricular hypertrophy in the banded animals. The banded lung exhibited arterial disorganization, loss of vessels, and enlargement of its bronchial arteries, whereas the contralateral lung showed signs of vascular pathology. There are consequences on development of both lungs in the presence of an LPA stenosis at young age. These results suggest that early intervention may be necessary to optimize left lung growth and minimize right lung vascular pathology. PMID- 23043076 TI - Mast cell engraftment of the peripheral lung enhances airway hyperresponsiveness in a mouse asthma model. AB - Allergic asthma is a chronic inflammatory disease, characterized by airway hyperresponsiveness (AHR), inflammation, and tissue remodeling, in which mast cells play a central role. In the present study, we analyzed how mast cell numbers and localization influence the AHR in a chronic murine model of asthma. C57BL/6 (wild-type) and mast cell-deficient B6.Cg-Kit(W-sh) mice without (Wsh) and with (Wsh+MC) mast cell engraftment were sensitized to and subsequently challenged with ovalbumin for a 91-day period. In wild-type mice, pulmonary mast cells were localized in the submucosa of the central airways, whereas the more abundant mast cells in Wsh+MC mice were found mainly in the alveolar parenchyma. In Wsh+MC, ovalbumin challenge induced a relocation of mast cells from the perivascular space and central airways to the parenchyma. Allergen challenge caused a similar AHR in wild-type and Wsh mice in the resistance of the airways and the pulmonary tissue. In Wsh+MC mice the AHR was more pronounced. The elevated functional responses were partly related to the numbers and localization of connective tissue-type mast cells in the peripheral pulmonary compartments. A mast cell-dependent increase in IgE and IL-33 together with impairment of the IL 23/IL-17 axis was evoked in Wsh and Wsh+MC mice by allergen challenge. This study shows that within the same chronic murine asthma model the development of AHR can be both dependent and independent of mast cells. Moreover, the spatial distribution and number of pulmonary mast cells determine severity and localization of the AHR. PMID- 23043078 TI - Evolutionary and ecological responses to anthropogenic climate change: update on anthropogenic climate change. PMID- 23043079 TI - DAC is involved in the accumulation of the cytochrome b6/f complex in Arabidopsis. AB - The biogenesis and assembly of photosynthetic multisubunit protein complexes is assisted by a series of nucleus-encoded auxiliary protein factors. In this study, we characterize the dac mutant of Arabidopsis (Arabidopsis thaliana), which shows a severe defect in the accumulation of the cytochrome b(6)/f complex, and provide evidence suggesting that the efficiency of cytochrome b(6)/f complex assembly is affected in the mutant. DAC is a thylakoid membrane protein with two predicted transmembrane domains that is conserved from cyanobacteria to vascular plants. Yeast (Saccharomyces cerevisiae) two-hybrid and coimmunoprecipitation analyses revealed a specific interaction between DAC and PetD, a subunit of the cytochrome b(6)/f complex. However, DAC was found not to be an intrinsic component of the cytochrome b(6)/f complex. In vivo chloroplast protein labeling experiments showed that the labeling rates of the PetD and cytochrome f proteins were greatly reduced, whereas that of the cytochrome b(6) protein remained normal in the dac mutant. DAC appears to be a novel factor involved in the assembly/stabilization of the cytochrome b(6)/f complex, possibly through interaction with the PetD protein. PMID- 23043080 TI - Differential control of ethylene responses by GREEN-RIPE and GREEN-RIPE LIKE1 provides evidence for distinct ethylene signaling modules in tomato. AB - The factors that mediate specific responses to the plant hormone ethylene are not fully defined. In particular, it is not known how signaling at the receptor complex can control distinct subsets of ethylene responses. Mutations at the Green-ripe (Gr) and reversion to ethylene sensitivity1 (rte1) loci, which encode homologous proteins of unknown function, influence ethylene responses in tomato (Solanum lycopersicum) and Arabidopsis (Arabidopsis thaliana), respectively. In Arabidopsis, AtRTE1 is required for function of the ETR1 ethylene receptor and acts predominantly through this receptor via direct protein-protein interaction. While most eudicot families including the Brassicaceae possess a single gene that is closely related to AtRTE1, we report that members of the Solanaceae family contain two phylogenetically distinct genes defined by GR and GREEN-RIPE LIKE1 (GRL1), creating the possibility of subfunctionalization. We also show that SlGR and SlGRL1 are differentially expressed in tomato tissues and encode proteins predominantly localized to the Golgi. A combination of overexpression in tomato and complementation of the rte1-3 mutant allele indicates that SlGR and SlGRL1 influence distinct but overlapping ethylene responses. Overexpression of SlGRL1 in the Gr mutant background provides evidence for the existence of different ethylene signaling modules in tomato that are influenced by GR, GRL1, or both. In addition, overexpression of AtRTE1 in tomato leads to reduced ethylene responsiveness in a subset of tissues but does not mimic the Gr mutant phenotype. Together, these data reveal species-specific heterogeneity in the control of ethylene responses mediated by members of the GR/RTE1 family. PMID- 23043081 TI - Truncated photosystem chlorophyll antenna size in the green microalga Chlamydomonas reinhardtii upon deletion of the TLA3-CpSRP43 gene. AB - The truncated light-harvesting antenna size3 (tla3) DNA insertional transformant of Chlamydomonas reinhardtii is a chlorophyll-deficient mutant with a lighter green phenotype, a lower chlorophyll (Chl) per cell content, and higher Chl a/b ratio than corresponding wild-type strains. Functional analyses revealed a higher intensity for the saturation of photosynthesis and greater light-saturated photosynthetic activity in the tla3 mutant than in the wild type and a Chl antenna size of the photosystems that was only about 40% of that in the wild type. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western-blot analyses showed that the tla3 strain was deficient in the Chl a/b light harvesting complex. Molecular and genetic analyses revealed a single plasmid insertion in chromosome 4 of the tla3 nuclear genome, causing deletion of predicted gene g5047 and plasmid insertion within the fourth intron of downstream predicted gene g5046. Complementation studies defined that gene g5047 alone was necessary and sufficient to rescue the tla3 mutation. Gene g5047 encodes a C. reinhardtii homolog of the chloroplast-localized SRP43 signal recognition particle, whose occurrence and function in green microalgae has not hitherto been investigated. Biochemical analysis showed that the nucleus-encoded and chloroplast-localized CrCpSRP43 protein specifically operates in the assembly of the peripheral components of the Chl a/b light-harvesting antenna. This work demonstrates that cpsrp43 deletion in green microalgae can be employed to generate tla mutants with a substantially diminished Chl antenna size. The latter exhibit improved solar energy conversion efficiency and photosynthetic productivity under mass culture and bright sunlight conditions. PMID- 23043082 TI - Consequences of climate warming and altered precipitation patterns for plant insect and multitrophic interactions. PMID- 23043083 TI - Randomized controlled trial of chlorhexidine dressing and highly adhesive dressing for preventing catheter-related infections in critically ill adults. AB - RATIONALE: Most vascular catheter-related infections (CRIs) occur extraluminally in patients in the intensive care unit (ICU). Chlorhexidine-impregnated and strongly adherent dressings may decrease catheter colonization and CRI rates. OBJECTIVES: To determine if chlorhexidine-impregnated and strongly adherent dressings decrease catheter colonization and CRI rates. METHODS: In a 2:1:1 assessor-masked randomized trial in patients with vascular catheters inserted for an expected duration of 48 hours or more in 12 French ICUs, we compared chlorhexidine dressings, highly adhesive dressings, and standard dressings from May 2010 to July 2011. Coprimary endpoints were major CRI with or without catheter-related bloodstream infection (CR-BSI) with chlorhexidine versus nonchlorhexidine dressings and catheter colonization rate with highly adhesive nonchlorhexidine versus standard nonchlorhexidine dressings. Catheter colonization, CR-BSIs, and skin reactions were secondary endpoints. MEASUREMENTS AND MAIN RESULTS: A total of 1,879 patients (4,163 catheters and 34,339 catheter days) were evaluated. With chlorhexidine dressings, the major-CRI rate was 67% lower (0.7 per 1,000 vs. 2.1 per 1,000 catheter-days; hazard ratio [HR], 0.328; 95% confidence interval [CI], 0.174-0.619; P = 0.0006) and the CR-BSI rate 60% lower (0.5 per 1,000 vs. 1.3 per 1,000 catheter-days; HR, 0.402; 95% CI, 0.186 0.868; P = 0.02) than with nonchlorhexidine dressings; decreases were noted in catheter colonization and skin colonization rates at catheter removal. The contact dermatitis rate was 1.1% with and 0.29% without chlorhexidine. Highly adhesive dressings decreased the detachment rate to 64.3% versus 71.9% (P < 0.0001) and the number of dressings per catheter to two (one to four) versus three (one to five) (P < 0.0001) but increased skin colonization (P < 0.0001) and catheter colonization (HR, 1.650; 95% CI, 1.21-2.26; P = 0.0016) without influencing CRI or CR-BSI rates. CONCLUSIONS: A large randomized trial demonstrated that chlorhexidine-gel-impregnated dressings decreased the CRI rate in patients in the ICU with intravascular catheters. Highly adhesive dressings decreased dressing detachment but increased skin and catheter colonization. Clinical trial registered with www.clinicaltrials.gov (NCT 01189682). PMID- 23043084 TI - Two microRNA panels to discriminate three subtypes of lung carcinoma in bronchial brushing specimens. AB - RATIONALE: Effective treatment for lung cancer requires accuracy in subclassification of carcinoma subtypes. OBJECTIVES: To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC). METHODS: Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap frozen surgical lung specimens. Quantitative reverse-transcriptase polymerase chain reaction was performed on 153 macrodissected formalin-fixed, paraffin embedded (FFPE) surgical lung specimens to evaluate seven microRNA candidates discovered from microarrays. Two microRNA panels were constructed on the basis of a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and of SQ from AC in 207 bronchial brushing specimens. MEASUREMENTS AND MAIN RESULTS: Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375; area under the curve [AUC], 0.991 and 0.982 for training and validation data set, respectively) and in differentiating SQ from AC (miR-205 and miR-34a; AUC, 0.977 and 0.982 for training and validation data set, respectively) in FFPE surgical lung specimens. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC, 0.947) and SQ from AC (AUC, 0.962) in bronchial brushing specimens. CONCLUSIONS: We found two microRNA panels that accurately discriminated between the three subtypes of lung carcinoma in bronchial brushing specimens. The identified microRNA panels may have considerable clinical value in differential diagnosis and optimizing treatment strategies based on lung cancer subtypes. PMID- 23043085 TI - The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky Pudlak syndrome. AB - RATIONALE: Hermansky-Pudlak syndrome (HPS) is a family of recessive disorders of intracellular trafficking defects that are associated with highly penetrant pulmonary fibrosis. Naturally occurring HPS mice reliably model important features of the human disease, including constitutive alveolar macrophage activation and susceptibility to profibrotic stimuli. OBJECTIVES: To decipher which cell lineage(s) in the alveolar compartment is the predominant driver of fibrotic susceptibility in HPS. METHODS: We used five different HPS and Chediak Higashi mouse models to evaluate genotype-specific fibrotic susceptibility. To determine whether intrinsic defects in HPS alveolar macrophages cause fibrotic susceptibility, we generated bone marrow chimeras in HPS and wild-type mice. To directly test the contribution of the pulmonary epithelium, we developed a transgenic model with epithelial-specific correction of the HPS2 defect in an HPS mouse model. MEASUREMENTS AND MAIN RESULTS: Bone marrow transplantation experiments demonstrated that both constitutive alveolar macrophage activation and increased susceptibility to bleomycin-induced fibrosis were conferred by the genotype of the lung epithelium, rather than that of the bone marrow-derived, cellular compartment. Furthermore, transgenic epithelial-specific correction of the HPS defect significantly attenuated bleomycin-induced alveolar epithelial apoptosis, fibrotic susceptibility, and macrophage activation. Type II cell apoptosis was genotype specific, caspase dependent, and correlated with the degree of fibrotic susceptibility. CONCLUSIONS: We conclude that pulmonary fibrosis in naturally occurring HPS mice is driven by intracellular trafficking defects that lower the threshold for pulmonary epithelial apoptosis. Our findings demonstrate a pivotal role for the alveolar epithelium in the maintenance of alveolar homeostasis and regulation of alveolar macrophage activation. PMID- 23043087 TI - Expression and regulation of interferon-related development regulator-1 in cystic fibrosis neutrophils. AB - A genome-wide association study identified interferon-related development regulator-1 (IFRD1), a protein expressed by neutrophils, as a key modifier gene in cystic fibrosis (CF) lung disease. Here, we investigated the expression and regulation of IFRD1 in CF neutrophils. IFRD1 expression was quantified in peripheral blood and airway neutrophils from patients with CF, patients with non CF lung disease, and healthy control subjects. The regulation of IFRD1 expression was analyzed using isolated neutrophils and ex vivo stimulation assays with CF airway fluids. IFRD1 single-nucleotide polymorphisms (SNPs) were analyzed in a CF cohort (n = 572) and correlated with longitudinal lung function and IFRD1 expression. Patients with CF expressed higher protein levels of IFRD1 in peripheral blood neutrophils compared with healthy or non-CF disease control subjects. Within patients with CF, IFRD1 protein expression levels in neutrophils were lower in airway fluids compared with peripheral blood. High IFRD1 expression was positively associated with the production of reactive oxygen species (ROS) in CF neutrophils. In vitro regulation studies showed that CF airway fluid and the CF-characteristic chemokines CXCL8 and CXCL2 down-regulated IFRD1 expression in neutrophils, an effect that was mediated through CXCR2. Genetic analyses showed that three IFRD1 SNPs were associated with longitudinal declines in lung function, and modulated IFRD1 expression. These studies demonstrate that IFRD1 expression is systemically up-regulated in human CF neutrophils, is linked to the production of ROS, and is modulated by chemokines in CF airway fluids, depending on the IFRD1 genotype. Understanding the regulation of IFRD1 may pave the way for novel therapeutic approaches to target neutrophilic inflammation in CF. PMID- 23043086 TI - Erythrocytes induce proinflammatory endothelial activation in hypoxia. AB - Although exposure to ambient hypoxia is known to cause proinflammatory vascular responses, the mechanisms initiating these responses are not understood. We tested the hypothesis that in systemic hypoxia, erythrocyte-derived H(2)O(2) induces proinflammatory gene transcription in vascular endothelium. We exposed mice or isolated, perfused murine lungs to 4 hours of hypoxia (8% O(2)). Leukocyte counts increased in the bronchoalveolar lavage. The expression of leukocyte adhesion receptors, reactive oxygen species, and protein tyrosine phosphorylation increased in freshly recovered lung endothelial cells (FLECs). These effects were inhibited by extracellular catalase and by the removal of erythrocytes, indicating that the responses were attributable to erythrocyte derived H(2)O(2). Concomitant nuclear translocation of the p65 subunit of NF kappaB and hypoxia-inducible factor-1alpha stabilization in FLECs occurred only in the presence of erythrocytes. Hemoglobin binding to the erythrocyte membrane protein, band 3, induced the release of H(2)O(2) from erythrocytes and the p65 translocation in FLECs. These data indicate for the first time, to our knowledge, that erythrocytes are responsible for endothelial transcriptional responses in hypoxia. PMID- 23043088 TI - Profibrotic role of miR-154 in pulmonary fibrosis. AB - In this study, we explored the regulation and the role of up-regulated microRNAs in idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease of unknown origin. We analyzed the expression of microRNAs in IPF lungs and identified 43 significantly up-regulated microRNAs. Twenty-four of the 43 increased microRNAs were localized to the chromosome 14q32 microRNA cluster. We validated the increased expression of miR-154, miR-134, miR-299-5p, miR-410, miR 382, miR-409-3p, miR-487b, miR-31, and miR-127 by quantitative RT-PCR and determined that they were similarly expressed in embryonic lungs. We did not find evidence for differential methylation in this region, but analysis of transcription factor binding sites identified multiple SMAD3-binding elements in the 14q32 microRNA cluster. TGF-beta1 stimulation of normal human lung fibroblasts (NHLF) caused up-regulation of microRNAs on chr14q32 that were also increased in IPF lungs. Chromatin immunoprecipitation confirmed binding of SMAD3 to the putative promoter of miR-154. Mir-154 was increased in IPF fibroblasts, and transfection of NHLF with miR-154 caused significant increases in cell proliferation and migration. The increase in proliferation induced by TGF-beta was not observed when NHLF or IPF fibroblasts were transfected with a mir-154 inhibitor. Transfection with miR-154 caused activation of the WNT pathway in NHLF. ICG-001 and XAV939, inhibitors of the WNT/beta-catenin pathway, reduced the proliferative effect of miR-154. The potential role of miR-154, one of multiple chr14q32 microRNA cluster members up-regulated in IPF and a regulator of fibroblast migration and proliferation, should be further explored in IPF. PMID- 23043091 TI - Why the NFL is investing in health research. PMID- 23043089 TI - Attenuation of inhibitory prostaglandin E2 signaling in human lung fibroblasts is mediated by phosphodiesterase 4. AB - The etiology of chronic obstructive pulmonary disease (COPD) is complex and involves an aberrant inflammatory response. Prostaglandin (PG)E2 is elevated in COPD, is a key modulator of lung fibroblast functions, and may influence COPD progression. Most studies evaluating the effects of PGE2 on lung fibroblasts have used acute exposures. The current study evaluated whether longer-term exposure would induce attenuation of PGE2 signaling as part of an autoregulatory pathway. Human fetal lung fibroblasts were pretreated with PGE2 for 24 hours, and migration and cAMP accumulation in response to acute stimulation with PGE2 were assessed. Fibroblasts from adults with and without COPD were pretreated, and migration was assessed. PGE2 pretreatment attenuated subsequent PGE2-mediated inhibition of chemotaxis and cAMP stimulation. This attenuation was predominantly due to an increase in phosphodiesterase (PDE)4-mediated degradation of cAMP rather than to decreased activation of PGE2 receptors (receptor desensitization). Albuterol- and iloprost-mediated signaling were also attenuated after PGE2 pretreatment, suggesting that activation of PDE4 was able to broadly modulate multiple cAMP-coupled pathways. Lung fibroblasts from adult control subjects pretreated with PGE2 also developed attenuation of PGE2-mediated inhibition of chemotaxis. In contrast, fibroblasts obtained from patients with COPD maintained inhibitory PGE2 signaling after PGE2 pretreatment. These data identify a PDE4 mediated attenuation of PGE2 inhibitory signaling in normal fibroblasts that appears to be altered in COPD fibroblasts. These alterations may contribute to COPD pathogenesis and could provide novel therapeutic targets. PMID- 23043092 TI - Sagittal T2 weighted magnetic resonance image of the lumbar spine. PMID- 23043090 TI - Classroom based cognitive behavioural therapy in reducing symptoms of depression in high risk adolescents: pragmatic cluster randomised controlled trial. AB - OBJECTIVE: To compare the effectiveness of classroom based cognitive behavioural therapy with attention control and usual school provision for adolescents at high risk of depression. DESIGN: Three arm parallel cluster randomised controlled trial. SETTING: Eight UK secondary schools. PARTICIPANTS: Adolescents (n=5030) aged 12-16 years in school year groups 8-11. Year groups were randomly assigned on a 1:1:1 ratio to cognitive behavioural therapy, attention control, or usual school provision. Allocation was balanced by school, year, number of students and classes, frequency of lessons, and timetabling. Participants were not blinded to treatment allocation. INTERVENTIONS: Cognitive behavioural therapy, attention control, and usual school provision provided in classes to all eligible participants. MAIN OUTCOME MEASURES: Outcomes were collected by self completed questionnaire administered by researchers. The primary outcome was symptoms of depression assessed at 12 months by the short mood and feelings questionnaire among those identified at baseline as being at high risk of depression. Secondary outcomes included negative thinking, self worth, and anxiety. Analyses were undertaken on an intention to treat basis and accounted for the clustered nature of the design. RESULTS: 1064 (21.2%) adolescents were identified at high risk of depression: 392 in the classroom based cognitive behavioural therapy arm, 374 in the attention control arm, and 298 in the usual school provision arm. At 12 months adjusted mean scores on the short mood and feelings questionnaire did not differ for cognitive behavioural therapy versus attention control (-0.63, 95% confidence interval -1.85 to 0.58, P=0.41) or for cognitive behavioural therapy versus usual school provision (0.97, -0.20 to 2.15, P=0.12). CONCLUSION: In adolescents with depressive symptoms, outcomes were similar for attention control, usual school provision, and cognitive behavioural therapy. Classroom based cognitive behavioural therapy programmes may result in increased self awareness and reporting of depressive symptoms but should not be undertaken without further evaluation and research. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19083628. PMID- 23043093 TI - Guidelines should reflect all knowledge, not just clinical trials. PMID- 23043094 TI - Global operation tackles internet trade in fake drugs. PMID- 23043095 TI - More English people are recovering from drug addiction, but recession poses risks. PMID- 23043096 TI - Campaigners start legal action to stop closure of Leeds children's heart surgery unit. PMID- 23043097 TI - Retention in endoplasmic reticulum 1 (RER1) modulates amyloid-beta (Abeta) production by altering trafficking of gamma-secretase and amyloid precursor protein (APP). AB - BACKGROUND: Abeta production is influenced by intracellular trafficking of secretases and amyloid precursor protein (APP). RESULTS: Retention in endoplasmic reticulum 1 (RER1) regulates the trafficking of gamma-secretase and APP, thereby influences Abeta production. CONCLUSION: RER1, an ER retention/retrieval factor for gamma-secretase and APP, modulates Abeta production. SIGNIFICANCE: RER1 and its influence on gamma-secretase and APP may be implicated for a safe strategy to target Abeta production. The presence of neuritic plaques containing aggregated amyloid-beta (Abeta) peptides in the brain parenchyma is a pathological hallmark of Alzheimer disease (AD). Abeta is generated by sequential cleavage of the amyloid beta precursor protein (APP) by beta- and gamma-secretase, respectively. As APP processing to Abeta requires transport through the secretory pathway, trafficking of the substrate and access to the secretases are key factors that can influence Abeta production (Thinakaran, G., and Koo, E. H. (2008) Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615-29619). Here, we report that retention in endoplasmic reticulum 1 (RER1) associates with gamma-secretase in early secretory compartments and regulates the intracellular trafficking of gamma-secretase. RER1 overexpression decreases both gamma-secretase localization on the cell surface and Abeta secretion and conversely RER1 knockdown increases the level of cell surface gamma-secretase and increases Abeta secretion. Furthermore, we find that increased RER1 levels decrease mature APP and increase immature APP, resulting in less surface accumulation of APP. These data show that RER1 influences the trafficking and localization of both gamma-secretase and APP, thereby regulating the production and secretion of Abeta peptides. PMID- 23043098 TI - MicroRNAs and HIV-1: complex interactions. AB - RNAi plays important roles in many biological processes, including cellular defense against viral infection. Components of the RNAi machinery are widely conserved in plants and animals. In mammals, microRNAs (miRNAs) represent an abundant class of cell encoded small noncoding RNAs that participate in RNAi mediated gene silencing. Here, findings that HIV-1 replication in cells can be regulated by miRNAs and that HIV-1 infection of cells can alter cellular miRNA expression are reviewed. Lessons learned from and questions outstanding about the complex interactions between HIV-1 and cellular miRNAs are discussed. PMID- 23043099 TI - Absence of glial alpha-dystrobrevin causes abnormalities of the blood-brain barrier and progressive brain edema. AB - The blood-brain barrier (BBB) plays a key role in maintaining brain functionality. Although mammalian BBB is formed by endothelial cells, its function requires interactions between endotheliocytes and glia. To understand the molecular mechanisms involved in these interactions is currently a major challenge. We show here that alpha-dystrobrevin (alpha-DB), a protein contributing to dystrophin-associated protein scaffolds in astrocytic endfeet, is essential for the formation and functioning of BBB. The absence of alpha-DB in null brains resulted in abnormal brain capillary permeability, progressively escalating brain edema, and damage of the neurovascular unit. Analyses in situ and in two-dimensional and three-dimensional in vitro models of BBB containing alpha-DB-null astrocytes demonstrated these abnormalities to be associated with loss of aquaporin-4 water and Kir4.1 potassium channels from glial endfeet, formation of intracellular vacuoles in alpha-DB-null astrocytes, and defects of the astrocyte-endothelial interactions. These caused deregulation of tight junction proteins in the endothelia. Importantly, alpha-DB but not dystrophins showed continuous expression throughout development in BBB models. Thus, alpha-DB emerges as a central organizer of dystrophin-associated protein in glial endfeet and a rare example of a glial protein with a role in maintaining BBB function. Its abnormalities might therefore lead to BBB dysfunction. PMID- 23043100 TI - The restriction factors of human immunodeficiency virus. AB - Cellular proteins called "restriction factors" can serve as powerful blockades to HIV replication, but the virus possesses elaborate strategies to circumvent these barriers. First, we discuss general hallmarks of a restriction factor. Second, we review how the viral Vif protein protects the viral genome from lethal levels of cDNA deamination by promoting APOBEC3 protein degradation; how the viral Vpu, Env, and Nef proteins facilitate internalization and degradation of the virus tethering protein BST-2/tetherin; and how the viral Vpx protein prevents the premature termination of reverse transcription by degrading the dNTPase SAMHD1. These HIV restriction and counter-restriction mechanisms suggest strategies for new therapeutic interventions. PMID- 23043101 TI - LETM proteins play a role in the accumulation of mitochondrially encoded proteins in Arabidopsis thaliana and AtLETM2 displays parent of origin effects. AB - The Arabidopsis thaliana genome contains two genes with homology to the mitochondrial protein LETM1 (leucine zipper-EF-hand-containing transmembrane protein). Inactivation of both genes, Atletm1 and Atletm2, together is lethal. Plants that are hemizygous for AtLETM2 and homozygous for Atletm1 (letm1(-/-) LETM2(+/-)) displayed a mild retarded growth phenotype during early seedling growth. It was shown that accumulation of mitochondrial proteins was reduced in hemizygous (letm1(-/-) LETM2(+/-)) plants. Examination of respiratory chain proteins by Western blotting, blue native PAGE, and enzymatic activity assays revealed that the steady state level of ATP synthase was reduced in abundance, whereas the steady state levels of other respiratory chain proteins remained unchanged. The absence of a functional maternal AtLETM2 allele in an Atletm1 mutant background resulted in early seed abortion. Reciprocal crosses revealed that maternally, but not paternally, derived AtLETM2 was absolutely required for seed development. This requirement for a functional maternal allele of AtLETM2 was confirmed using direct sequencing of reciprocal crosses of Col-0 and Ler accessions. Furthermore, AtLETM2 promoter beta-glucuronidase constructs displayed exclusive maternal expression patterns. PMID- 23043102 TI - Role of molecular determinants of store-operated Ca(2+) entry (Orai1, phospholipase A2 group 6, and STIM1) in focal adhesion formation and cell migration. AB - BACKGROUND: Store-operated Ca(2+) entry is important for cell migration. RESULTS: This study presents characterization of localization and roles of Orai1, STIM1, and PLA2g6 in adhesion dynamics during cell migration. CONCLUSION: Orai1 and PLA2g6 are involved in adhesion formation at the front, whereas STIM1 participates in both adhesion formation and disassembly. SIGNIFICANCE: Results uncovered new parameters of Orai1, STIM1, and PLA2g6 involvement in cell migration. Store-operated Ca(2+) entry and its major determinants are known to be important for cell migration, but the mechanism of their involvement in this complex process is unknown. This study presents a detailed characterization of distinct roles of Orai1, STIM1, and PLA2g6 in focal adhesion (FA) formation and migration. Using HEK293 cells, we discovered that although molecular knockdown of Orai1, STIM1, or PLA2g6 resulted in a similar reduction in migration velocity, there were profound differences in their effects on number, localization, and lifetime of FAs. Knockdown of STIM1 caused an increase in lifetime and number of FAs, their redistribution toward lamellae region, and an increase in cell tail length. In contrast, the number of FAs in Orai1- or PLA2g6-deficient cells was significantly reduced, and FAs accumulated closer to the leading edge. Assembly rate and Vinculin phosphorylation of FAs was similarly reduced in Orai1, PLA2g6, or STIM1-deficient cells. Although Orai1 and PLA2g6 accumulated and co-localized at the leading edge, STIM1 distribution was more complex. We found STIM1 protrusions in lamellipodia, which co-localized with FAs, whereas major accumulation could be seen in central and retracting parts of the cell. Interestingly, knockdown of Orai1 and PLA2g6 produced similar and non-additive effect on migration, whereas knockdown of STIM1 simultaneously with either Orai1 or PLA2g6 produced additional inhibition. Together these data suggest that although Orai1, PLA2g6, and STIM1 play major roles in formation of new FAs at the leading edge, STIM1 may also be involved in Orai1- and PLA2g6-independent disassembly of FAs in the back of cells. PMID- 23043103 TI - Introduction to thematic minireview series: Understanding human immunodeficiency virus-host interactions at the biochemical level. PMID- 23043104 TI - HIV entry and envelope glycoprotein-mediated fusion. AB - HIV entry involves binding of the trimeric viral envelope glycoprotein (Env) gp120/gp41 to cell surface receptors, which triggers conformational changes in Env that drive the membrane fusion reaction. The conformational landscape that the lipids and Env navigate en route to fusion has been examined by biophysical measurements on the microscale, whereas electron tomography, x-rays, and NMR have provided insights into the process on the nanoscale and atomic scale. However, the coupling between the lipid and protein pathways that give rise to fusion has not been resolved. Here, we discuss the known and unknown about the overall HIV Env-mediated fusion process. PMID- 23043105 TI - 4-Demethylwyosine synthase from Pyrococcus abyssi is a radical-S-adenosyl-L methionine enzyme with an additional [4Fe-4S](+2) cluster that interacts with the pyruvate co-substrate. AB - Wybutosine and its derivatives are found in position 37 of tRNA encoding Phe in eukaryotes and archaea. They are believed to play a key role in the decoding function of the ribosome. The second step in the biosynthesis of wybutosine is catalyzed by TYW1 protein, which is a member of the well established class of metalloenzymes called "Radical-SAM." These enzymes use a [4Fe-4S] cluster, chelated by three cysteines in a CX(3)CX(2)C motif, and S-adenosyl-L-methionine (SAM) to generate a 5'-deoxyadenosyl radical that initiates various chemically challenging reactions. Sequence analysis of TYW1 proteins revealed, in the N terminal half of the enzyme beside the Radical-SAM cysteine triad, an additional highly conserved cysteine motif. In this study we show by combining analytical and spectroscopic methods including UV-visible absorption, Mossbauer, EPR, and HYSCORE spectroscopies that these additional cysteines are involved in the coordination of a second [4Fe-4S] cluster displaying a free coordination site that interacts with pyruvate, the second substrate of the reaction. The presence of two distinct iron-sulfur clusters on TYW1 is reminiscent of MiaB, another tRNA modifying metalloenzyme whose active form was shown to bind two iron-sulfur clusters. A possible role for the second [4Fe-4S] cluster in the enzyme activity is discussed. PMID- 23043106 TI - Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. AB - BACKGROUND: Laminar flow protects from atherosclerosis in endothelium. RESULTS: Laminar flow induces Nrf2 activation dependent on ERK5 activation, leading to up regulation of downstream genes of Nrf2. CONCLUSION: ERK5 requires Nrf2 activation to exert cytoprotective effect on HUVEC. ERK5 inhibitor BIX02189 regulates Nrf2 activation in vivo. SIGNIFICANCE: Identifying ERK5 as a molecular target for regulating flow-mediating Nrf2-dependent gene expression may have significant therapeutic potential for treating atherosclerosis. Atherosclerosis is often observed in areas where disturbed flow is formed, whereas atheroprotective region is found in areas where steady laminar flow is developed. It has been reported that some genes activated by blood flow play important roles in vascular function and pathogenesis of atherosclerosis. Extracellular signal-regulated kinase 5 (ERK5) has been reported to regulate endothelial integrity and protect from vascular dysfunction and disease under laminar flow. Kruppel-like factor 2 (KLF2) and NF-E2-related factor 2 (Nrf2) are major transcriptional factors that contribute to anti-atherogenic responses under laminar flow. Implication of ERK5 in laminar flow-mediated regulation of KLF2-dependent gene has been established, whereas the role of ERK5 in laminar flow-mediated activation of Nrf2 pathway has not been addressed yet. In this study, we found that the blockage of ERK5 either by genetic depletion with siRNA or by biochemical inactivation with a specific chemical compound inhibited laminar flow-induced up-regulation of Nrf2-dependent gene expressions, whereas activation of ERK5 increased transcriptional activity and nuclear translocation of Nrf2, which suggests that ERK5 mediates laminar flow induced up-regulation of Nrf2-dependent gene expression. Further functional studies showed that ERK5 provides protection against oxidative stress-induced cytotoxicity dependent on Nrf2. Molecular interaction between ERK5 and Nrf2 was further induced by laminar flow. Finally, flow-dependent nuclear localization of Nrf2 was inhibited by BIX02189, a specific inhibitor of MEK5, in aorta of mice in vivo. Collectively, these data demonstrate that laminar flow-induced activation of ERK5-Nrf2 signal pathway plays a critical role for anti-inflammatory and anti apoptotic mechanism in endothelial cells. PMID- 23043107 TI - ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. AB - Autophagy is a lysosome-dependent degradation system conserved among eukaryotes. The mammalian Atg1 homologues, Unc-51 like kinase (ULK) 1 and 2, are multifunctional proteins with roles in autophagy, neurite outgrowth, and vesicle transport. The mammalian ULK complex involved in autophagy consists of ULK1, ULK2, ATG13, FIP200, and ATG101. We have used pulldown and peptide array overlay assays to study interactions between the ULK complex and six different ATG8 family proteins. Strikingly, in addition to ULK1 and ULK2, ATG13 and FIP200 interacted with human ATG8 proteins, all with strong preference for the GABARAP subfamily. Similarly, yeast and Drosophila Atg1 interacted with their respective Atg8 proteins, demonstrating the evolutionary conservation of the interaction. Use of peptide arrays allowed precise mapping of the functional LIR motifs, and two-dimensional scans of the ULK1 and ATG13 LIR motifs revealed which substitutions that were tolerated. This information, combined with an analysis of known LIR motifs, provides us with a clearer picture of sequence requirements for LIR motifs. In addition to the known requirements of the aromatic and hydrophobic residues of the core motif, we found the interactions to depend strongly on acidic residues surrounding the central core LIR motifs. A preference for either a hydrophobic residue or an acidic residue following the aromatic residue in the LIR motif is also evident. Importantly, the LIR motif is required for starvation induced association of ULK1 with autophagosomes. Our data suggest that ATG8 proteins act as scaffolds for assembly of the ULK complex at the phagophore. PMID- 23043108 TI - Human immunodeficiency virus reverse transcriptase: 25 years of research, drug discovery, and promise. AB - Synthesis of integration-competent, double-stranded DNA from the (+)-RNA strand genome of retroviruses and long terminal repeat-containing retrotransposons reflects a multistep process catalyzed by the virus-encoded reverse transcriptase (RT). In conjunction with RNA- and DNA-templated DNA synthesis, a hydrolytic activity of the same enzyme (RNase H) is required to remove genomic RNA of the RNA/DNA replication intermediate. Together, these combined synthetic and degradative functions ensure correct selection, extension, and removal of the RNA primers of (-)- and (+)-strand DNA synthesis (tRNA and the polypurine tract, respectively). For HIV-1 RT, a quarter century of research has not only illuminated the biochemical properties, structure, and conformational dynamics of this highly versatile enzyme but has also witnessed drug discovery advances from the first Food and Drug Administration-approved anti-RT drug to recent use of RT inhibitors as potential colorectal microbicides. Salient features of HIV-1 RT and extension of these findings into programs of drug discovery are reviewed here. PMID- 23043109 TI - Retroviral integrase proteins and HIV-1 DNA integration. AB - Retroviral integrases catalyze two reactions, 3'-processing of viral DNA ends, followed by integration of the processed ends into chromosomal DNA. X-ray crystal structures of integrase-DNA complexes from prototype foamy virus, a member of the Spumavirus genus of Retroviridae, have revealed the structural basis of integration and how clinically relevant integrase strand transfer inhibitors work. Underscoring the translational potential of targeting virus-host interactions, small molecules that bind at the host factor lens epithelium derived growth factor/p75-binding site on HIV-1 integrase promote dimerization and inhibit integrase-viral DNA assembly and catalysis. Here, we review recent advances in our knowledge of HIV-1 DNA integration, as well as future research directions. PMID- 23043110 TI - Phosphoinositides differentially regulate protrudin localization through the FYVE domain. AB - Protrudin is a FYVE (Fab 1, YOTB, Vac 1, and EEA1) domain-containing protein involved in transport of neuronal cargoes and implicated in the onset of hereditary spastic paraplegia. Our image-based screening of the lipid binding domain library revealed novel plasma membrane localization of the FYVE domain of protrudin unlike canonical FYVE domains that are localized to early endosomes. The membrane binding study by surface plasmon resonance analysis showed that this FYVE domain preferentially binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)), phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P(2)), and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) unlike canonical FYVE domains that specifically bind phosphatidylinositol 3-phosphate (PtdIns(3)P). Furthermore, we found that these phosphoinositides (PtdInsP) differentially regulate shuttling of protrudin between endosomes and plasma membrane via its FYVE domain. Protrudin mutants with reduced PtdInsP-binding affinity failed to promote neurite outgrowth in primary cultured hippocampal neurons. These results suggest that novel PtdInsP selectivity of the protrudin FYVE domain is critical for its cellular localization and its role in neurite outgrowth. PMID- 23043111 TI - The choreography of HIV-1 proteolytic processing and virion assembly. AB - HIV-1 has been the target of intensive research at the molecular and biochemical levels for >25 years. Collectively, this work has led to a detailed understanding of viral replication and the development of 24 approved drugs that have five different targets on various viral proteins and one cellular target (CCR5). Although most drugs target viral enzymatic activities, our detailed knowledge of so much of the viral life cycle is leading us into other types of inhibitors that can block or disrupt protein-protein interactions. Viruses have compact genomes and employ a strategy of using a small number of proteins that can form repeating structures to enclose space (i.e. condensing the viral genome inside of a protein shell), thus minimizing the need for a large protein coding capacity. This creates a relatively small number of critical protein-protein interactions that are essential for viral replication. For HIV-1, the Gag protein has the role of a polyprotein precursor that contains all of the structural proteins of the virion: matrix, capsid, spacer peptide 1, nucleocapsid, spacer peptide 2, and p6 (which contains protein-binding domains that interact with host proteins during budding). Similarly, the Gag-Pro-Pol precursor encodes most of the Gag protein but now includes the viral enzymes: protease, reverse transcriptase (with its associated RNase H activity), and integrase. Gag and Gag-Pro-Pol are the substrates of the viral protease, which is responsible for cleaving these precursors into their mature and fully active forms (see Fig. 1A). PMID- 23043112 TI - Nuclear transport receptor binding avidity triggers a self-healing collapse transition in FG-nucleoporin molecular brushes. AB - Conformational changes at supramolecular interfaces are fundamentally coupled to binding activity, yet it remains a challenge to probe this relationship directly. Within the nuclear pore complex, this underlies how transport receptors known as karyopherins proceed through a tethered layer of intrinsically disordered nucleoporin domains containing Phe-Gly (FG)-rich repeats (FG domains) that otherwise hinder passive transport. Here, we use nonspecific proteins (i.e., BSA) as innate molecular probes to explore FG domain conformational changes by surface plasmon resonance. This mathematically diminishes the surface plasmon resonance refractive index constraint, thereby providing the means to acquire and correlate height changes in a surface-tethered FG domain layer to Kap binding affinities in situ with respect to their relative spatial arrangements. Stepwise measurements show that FG domain collapse is caused by karyopherin beta1 (Kapbeta1) binding at low concentrations, but this gradually transitions into a reextension at higher Kapbeta1 concentrations. This ability to self-heal is intimately coupled to Kapbeta1-FG binding avidity that promotes the maximal incorporation of Kapbeta1 into the FG domain layer. Further increasing Kapbeta1 to physiological concentrations leads to a "pileup" of Kapbeta1 molecules that bind weakly to unoccupied FG repeats at the top of the layer. Therefore, binding avidity does not hinder fast transport per se. Revealing the biophysical basis underlying the form-function relationship of Kapbeta1-FG domain behavior results in a convergent picture in which transport and mechanistic aspects of nuclear pore complex functionality are reconciled. PMID- 23043113 TI - Efficient -2 frameshifting by mammalian ribosomes to synthesize an additional arterivirus protein. AB - Programmed -1 ribosomal frameshifting (-1 PRF) is a gene-expression mechanism used to express many viral and some cellular genes. In contrast, efficient natural utilization of -2 PRF has not been demonstrated previously in eukaryotic systems. Like all nidoviruses, members of the Arteriviridae (a family of positive stranded RNA viruses) express their replicase polyproteins pp1a and pp1ab from two long ORFs (1a and 1b), where synthesis of pp1ab depends on -1 PRF. These polyproteins are posttranslationally cleaved into at least 13 functional nonstructural proteins. Here we report that porcine reproductive and respiratory syndrome virus (PRRSV), and apparently most other arteriviruses, use an additional PRF mechanism to access a conserved alternative ORF that overlaps the nsp2-encoding region of ORF1a in the +1 frame. We show here that this ORF is translated via -2 PRF at a conserved G_GUU_UUU sequence (underscores separate ORF1a codons) at an estimated efficiency of around 20%, yielding a transframe fusion (nsp2TF) with the N-terminal two thirds of nsp2. Expression of nsp2TF in PRRSV-infected cells was verified using specific Abs, and the site and direction of frameshifting were determined via mass spectrometric analysis of nsp2TF. Further, mutagenesis showed that the frameshift site and an unusual frameshift stimulatory element (a conserved CCCANCUCC motif 11 nucleotides downstream) are required to direct efficient -2 PRF. Mutations preventing nsp2TF expression impair PRRSV replication and produce a small-plaque phenotype. Our findings demonstrate that -2 PRF is a functional gene-expression mechanism in eukaryotes and add another layer to the complexity of arterivirus genome expression. PMID- 23043114 TI - Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response. AB - The hippocampus is a highly plastic brain region particularly susceptible to the effects of environmental stress; it also shows dynamic changes in epigenetic marks in response to stress and learning. We have previously shown that, in the rat, acute (30 min) restraint stress induces a substantial, regionally specific, increase in hippocampal levels of the repressive histone H3 lysine 9 trimethylation (H3K9me3). Because of the large magnitude of this effect and the fact that stress can induce the expression of endogenous retroviruses and transposable elements in many systems, we hypothesized that the H3K9me3 response was targeted to these elements as a means of containing potential genomic instability. We used ChIP coupled with next generation sequencing (ChIP-Seq) to determine the genomic localization of the H3K9me3 response. Although there was a general increase in this response across the genome, our results validated this hypothesis by demonstrating that stress increases H3K9me3 enrichment at transposable element loci and, using RT-PCR, we demonstrate that this effect represses expression of intracisternal-A particle endogenous retrovirus elements and B2 short interspersed elements, but it does not appear to have a repressive effect on long interspersed element RNA. In addition, we present data showing that the histone H3K9-specific methyltransferases Suv39h2 is up-regulated by acute stress in the hippocampus, and that this may explain the hippocampal specificity we observe. These results are a unique demonstration of the regulatory effect of environmental stress, via an epigenetic mark, on the vast genomic terra incognita represented by transposable elements. PMID- 23043115 TI - Plasticity of the asialoglycoprotein receptor deciphered by ensemble FRET imaging and single-molecule counting PALM imaging. AB - The stoichiometry and composition of membrane protein receptors are critical to their function. However, the inability to assess receptor subunit stoichiometry in situ has hampered efforts to relate receptor structures to functional states. Here, we address this problem for the asialoglycoprotein receptor using ensemble FRET imaging, analytical modeling, and single-molecule counting with photoactivated localization microscopy (PALM). We show that the two subunits of asialoglycoprotein receptor [rat hepatic lectin 1 (RHL1) and RHL2] can assemble into both homo- and hetero-oligomeric complexes, displaying three forms with distinct ligand specificities that coexist on the plasma membrane: higher-order homo-oligomers of RHL1, higher-order hetero-oligomers of RHL1 and RHL2 with two to-one stoichiometry, and the homo-dimer RHL2 with little tendency to further homo-oligomerize. Levels of these complexes can be modulated in the plasma membrane by exogenous ligands. Thus, even a simple two-subunit receptor can exhibit remarkable plasticity in structure, and consequently function, underscoring the importance of deciphering oligomerization in single cells at the single-molecule level. PMID- 23043116 TI - Phylogenetic modeling of lateral gene transfer reconstructs the pattern and relative timing of speciations. AB - The timing of the evolution of microbial life has largely remained elusive due to the scarcity of prokaryotic fossil record and the confounding effects of the exchange of genes among possibly distant species. The history of gene transfer events, however, is not a series of individual oddities; it records which lineages were concurrent and thus provides information on the timing of species diversification. Here, we use a probabilistic model of genome evolution that accounts for differences between gene phylogenies and the species tree as series of duplication, transfer, and loss events to reconstruct chronologically ordered species phylogenies. Using simulations we show that we can robustly recover accurate chronologically ordered species phylogenies in the presence of gene tree reconstruction errors and realistic rates of duplication, transfer, and loss. Using genomic data we demonstrate that we can infer rooted species phylogenies using homologous gene families from complete genomes of 10 bacterial and archaeal groups. Focusing on cyanobacteria, distinguished among prokaryotes by a relative abundance of fossils, we infer the maximum likelihood chronologically ordered species phylogeny based on 36 genomes with 8,332 homologous gene families. We find the order of speciation events to be in full agreement with the fossil record and the inferred phylogeny of cyanobacteria to be consistent with the phylogeny recovered from established phylogenomics methods. Our results demonstrate that lateral gene transfers, detected by probabilistic models of genome evolution, can be used as a source of information on the timing of evolution, providing a valuable complement to the limited prokaryotic fossil record. PMID- 23043117 TI - Fragment-guided design of subnanomolar beta-lactamase inhibitors active in vivo. AB - Fragment-based design was used to guide derivatization of a lead series of beta lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K(i) of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with beta-lactamase expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome beta-lactamase-based resistance, a key clinical challenge. PMID- 23043118 TI - Extensive genetic variation in somatic human tissues. AB - Genetic variation between individuals has been extensively investigated, but differences between tissues within individuals are far less understood. It is commonly assumed that all healthy cells that arise from the same zygote possess the same genomic content, with a few known exceptions in the immune system and germ line. However, a growing body of evidence shows that genomic variation exists between differentiated tissues. We investigated the scope of somatic genomic variation between tissues within humans. Analysis of copy number variation by high-resolution array-comparative genomic hybridization in diverse tissues from six unrelated subjects reveals a significant number of intraindividual genomic changes between tissues. Many (79%) of these events affect genes. Our results have important consequences for understanding normal genetic and phenotypic variation within individuals, and they have significant implications for both the etiology of genetic diseases such as cancer and for immortalized cell lines that might be used in research and therapeutics. PMID- 23043119 TI - Feature attention evokes task-specific pattern selectivity in V4 neurons. AB - A hallmark of visual cortical neurons is their selectivity for stimulus pattern features, such as color, orientation, or shape. In most cases this feature selectivity is hard-wired, with selectivity manifest from the beginning of the response. Here we show that when a task requires that a monkey distinguish between patterns, V4 develops a selectivity for the sought-after pattern, which it does not manifest in a task that does not require the monkey to distinguish between patterns. When a monkey looks for a target object among an array of distractors, V4 neurons become selective for the target ~50 ms after the visual latency independent of the impending saccade direction. However, when the monkey has to only make a saccade to the spatial location of the same objects without discriminating their pattern, V4 neurons do not distinguish the search target from the distractors. This selectivity for stimulus pattern develops roughly 40 ms after the same neurons' selectivity for basic pattern features like orientation or color. We suggest that this late-developing selectivity is related to the phenomenon of feature attention and may contribute to the mechanisms by which the brain finds the target in visual search. PMID- 23043120 TI - Measurement of ethyl glucuronide, ethyl sulphate and their ratio in the urine and serum of healthy volunteers after two doses of alcohol. AB - AIMS: Ethyl glucuronide (EtG) and ethyl sulphate (EtS) are minor metabolites of ethanol, and their presence in urine provides a strong indication of recent alcohol administration. In this study, we performed a drinking experiment to investigate the kinetics of EtG and EtS formation and elimination after the administration of two doses of alcohol. METHODS: Nineteen volunteers provided urine and serum (only 18) after administration of 4 and 8 units of alcohol (1 unit corresponds to 10 ml or ~8 g of pure ethanol). The analysis was performed using a validated ultra-performance liquid chromatography-mass spectrometry (UPLC((r))-MS/MS) method. RESULTS: After 4 units, the median EtG maximum concentration (C(max)) was 0.4 ug/ml and the interquartile range (0.3 ug/ml) in serum and 3.5 mg/h (1.2 mg/h) in urine and were reached (T(max)) after 2.0 h (0.8 h) and 3.0 h (1.0 h), respectively. EtS C(max) was 0.2 ug/ml (0.1 ug/ml) in serum and 1.3 mg/h (0.6 mg/h) in urine, and the corresponding T(max) were 1.0 h (1.0 h) and 2.0 h (0.5 h). After 8 units, EtG C(max) was 1.3 ug/ml (0.4 ug/ml) in serum and 10 mg/h (3.4 mg/h) in urine and was reached after 4.0 h (1.8 h) and 4.0 h (2.0 h), respectively. EtS C(max) was 0.6 ug/ml (0.1 ug/ml) in serum and 3.5 mg/h (1.1 mg/h) in urine, the corresponding T(max) were 3.0 h (1.0 h) and 3.0 h (1.0 h). The EtG/EtS ratio increased as a function of the time after alcohol administration in both serum and urine samples but to a lesser extent after 8 units than 4. CONCLUSION: These results correlate with values obtained in previous studies. T(max) of EtG and EtS increased between 4 and 8 units. The EtG:EtS ratio increased in the serum and urine samples of all volunteers as a function of time at least up to 4 h after alcohol administration. PMID- 23043121 TI - Free birth control cuts rates of unwanted pregnancies and abortions in US. PMID- 23043122 TI - Obama and Romney disagree over future of healthcare funding. PMID- 23043123 TI - Presentation of clinical laboratory results: an experimental comparison of four visualization techniques. AB - OBJECTIVE: To evaluate how clinical chemistry test results were assessed by volunteers when presented with four different visualization techniques. MATERIALS AND METHODS: A total of 20 medical students reviewed quantitative test results from 4 patients using 4 different visualization techniques in a balanced, crossover experiment. The laboratory data represented relevant patient categories, including simple, emergency, chronic and complex patients. Participants answered questions about trend, overall levels and covariation of test results. Answers and assessment times were recorded and participants were interviewed on their preference of visualization technique. RESULTS: Assessment of results and the time used varied between visualization techniques. With sparklines and relative multigraphs participants made faster assessments. With relative multigraphs participants identified more covarying test results. With absolute multigraphs participants found more trends. With sparklines participants more often assessed laboratory results to be within reference ranges. Different visualization techniques were preferred for the four different patient categories. No participant preferred absolute multigraphs for any patient. DISCUSSION: Assessments of clinical chemistry test results were influenced by how they were presented. Importantly though, this association depended on the complexity of the result sets, and none of the visualization techniques appeared to be ideal in all settings. CONCLUSIONS: Sparklines and relative multigraphs seem to be favorable techniques for presenting complex long-term clinical chemistry test results, while tables seem to suffice for simpler result sets. PMID- 23043124 TI - Using rule-based natural language processing to improve disease normalization in biomedical text. AB - BACKGROUND AND OBJECTIVE: In order for computers to extract useful information from unstructured text, a concept normalization system is needed to link relevant concepts in a text to sources that contain further information about the concept. Popular concept normalization tools in the biomedical field are dictionary-based. In this study we investigate the usefulness of natural language processing (NLP) as an adjunct to dictionary-based concept normalization. METHODS: We compared the performance of two biomedical concept normalization systems, MetaMap and Peregrine, on the Arizona Disease Corpus, with and without the use of a rule based NLP module. Performance was assessed for exact and inexact boundary matching of the system annotations with those of the gold standard and for concept identifier matching. RESULTS: Without the NLP module, MetaMap and Peregrine attained F-scores of 61.0% and 63.9%, respectively, for exact boundary matching, and 55.1% and 56.9% for concept identifier matching. With the aid of the NLP module, the F-scores of MetaMap and Peregrine improved to 73.3% and 78.0% for boundary matching, and to 66.2% and 69.8% for concept identifier matching. For inexact boundary matching, performances further increased to 85.5% and 85.4%, and to 73.6% and 73.3% for concept identifier matching. CONCLUSIONS: We have shown the added value of NLP for the recognition and normalization of diseases with MetaMap and Peregrine. The NLP module is general and can be applied in combination with any concept normalization system. Whether its use for concept types other than disease is equally advantageous remains to be investigated. PMID- 23043125 TI - A cross-sectional study of the association of age, race and ethnicity, and body mass index with sex steroid hormone marker profiles among men in the National Health and Nutrition Examination Survey (NHANES III). AB - OBJECTIVES: Since sex hormone markers are metabolically linked, examining sex steroid hormones singly may account for inconsistent findings by age, race/ethnicity and body mass index (BMI) across studies. First, these markers were statistically combined into profiles to account for the metabolic relationship between markers. Then, the relationships between sex steroid hormone profiles and age, race/ethnicity and BMI were explored in multinomial logistic regression models. DESIGN: Cross-sectional survey. SETTING: The US Third National Health and Nutrition Examination Survey (NHANES III). PARTICIPANTS: 1538 Men, >17 years. PRIMARY OUTCOME MEASURE: Sex hormone profiles. RESULTS: Cluster analysis was used to identify four statistically determined profiles with Blom-transformed T, E, sex hormone binding globulin (SHBG), and 3-alpha diol G. We used these four profiles with multinomial logistic regression models to examine differences by race/ethnicity, age and BMI. Mexican American men >50 years were associated with the profile that had lowest T, E and 3-alpha diol G levels compared to other profiles (p<0.05). Non-Hispanic Black, overweight (25-29.9 kg/m(2)) and obese (>30 kg/m(2)) men were most likely to be associated with the cluster with the lowest SHBG (p<0.05). CONCLUSION: The associations of sex steroid hormone profiles by race/ethnicity are novel, while the findings by age and BMI groups are largely consistent with observations from single hormone studies. Future studies should validate these hormone profile groups and investigate these profiles in relation to chronic diseases and certain cancers. PMID- 23043126 TI - Coronary and mortality risk of novel oral antithrombotic agents: a meta-analysis of large randomised trials. AB - OBJECTIVE: Oral direct thrombin and anti-Xa inhibitors have been shown to be efficacious in the prevention and treatment of venous thromboembolism, and prevention of embolic events in atrial fibrillation. Recent studies showed that dabigatran may be associated with increased rates of myocardial infarction (MI). Coronary risk for the other agents was unclear. The aim of the study is to determine the coronary risk among four novel antithrombotic agents. DESIGN: Mixed treatment comparison meta-analysis. DATA SOURCES AND STUDY SELECTION: Randomised controlled trials (RCTs) on ximelagatran, dabigatran, rivaroxaban and apixaban were obtained from PubMed search (February 2012) and major scientific meeting in 2011. The random-effects model was used to evaluate the effect of these agents on MI or acute coronary syndrome (MI/ACS), major bleeding complication and all-cause mortality. RESULTS: From 28 RCTs (n=138 948), the risk for MI/ACS was higher for dabigatran (OR 1.30; 95% CI 1.04 to 1.63; p=0.021) but lower for rivaroxaban (OR 0.78; 95% CI 0.69 to 0.89; p<0.001). Ximelagatran showed a higher risk for MI/ACS, which was not statistically significant, while apixaban demonstrated a non-significant lower likelihood. Among the RCTs for MI/ACS among the four agents, only those pertaining to ximelagatran showed heterogeneity. Major bleeding complication rates varied considerably among different agents. Importantly, these agents were associated with a lower all-cause mortality, without heterogeneity among the studies. CONCLUSIONS: The risk for coronary events was significantly higher for dabigatran but not significantly higher for ximelagatran. Conversely, this risk was lower among anti-Xa inhibitors. All-cause mortality was lower among those receiving novel antithrombotic agents. This information may be useful in selecting agents for specific subsets of patients requiring anticoagulation. PMID- 23043128 TI - Statin-induced lung injury: diagnostic clue and outcome. AB - BACKGROUND: Statin-induced lung injury (SILI) is an uncommon but serious complication of statins. The clinical features and outcome of patients with SILI vary widely. Clinical data relevant to diagnosis and outcome of patients with SILI were investigated in this study. METHOD: Four cases of SILI diagnosed at our institute and 12 cases reported in the English literature from 1995 to 2010 were studied. The patients were further divided into favourable and unfavourable outcome groups and compared. RESULTS: Compared with the 12 previously reported cases, fever (p=0.008) and consolidation (p=0.027) were more common and duration of statin treatment was significantly shorter (p=0.030) in our patients. Foamy alveolar macrophages in bronchoalveolar lavage fluid (BALF) were found in our four patients. Patients with cough (p=0.024), fever (p=0.026) and alveolar infiltrates (p=0.036), especially ground-glass opacity (GGO) (p=0.001) shown on thoracic high-resolution CT (HRCT), had a favourable outcome. Conversely, those with fibrosis shown on HRCT (p=0.008) had an unfavourable outcome. Stepwise logistic regression analysis demonstrated that cough (p=0.011), fever (p=0.005), and alveolar infiltrates (p=0.017), GGO (p<0.001) and fibrosis (p=0.002) shown on thoracic HRCT were independent factors affecting the outcome of SILI. CONCLUSIONS: For patients with SILI, pulmonary phospholipidosis, as shown by foamy alveolar macrophages in BALF, may be valuable in diagnosis, and clinical symptoms and thoracic HRCT findings are of value in predicting the outcome. PMID- 23043127 TI - Prospective study of particulate air pollution exposures, subclinical atherosclerosis, and clinical cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). AB - The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45-84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD. PMID- 23043129 TI - Health-related quality of life among patients with symptomatic carotid disease. AB - OBJECTIVES: To evaluate health-related quality of life (HRQoL) in patients with symptomatic carotid disease (amaurosis fugax, transient ischaemic attack, stroke); to compare it with that of the general population; to explore whether HRQoL depends on the severity of the disease and to investigate the possible association between some demographic and clinical characteristics of patients and HRQoL. METHODS: This cross-sectional study involved 175 patients with symptomatic carotid atherosclerotic disease who were referred for endarterectomy between January 2011 and December 2011. HRQoL was measured using Medical Outcome Survey Short Form 36 (SF-36). RESULTS: In comparison to both referent populations, patients with carotid disease had significantly lower mean SF-36 scores for role physical (41.6 vs. 61.5 and 67.8), social functioning (65.4 vs. 73.8 and 80.0), role-emotional (48.2 vs. 68.6 and 80.5) and mental health (51.5 vs. 61.9 and 66.0). The SF-36 scores were significantly lower in female patients with carotid disease than in men (for role-physical 32.3 vs. 46.5; for bodily pain 57.0 vs. 73.0; for general health 55.6 vs. 61.5; for vitality 55.4 vs. 60.1; for social functioning 57.1 vs. 69.8 and for role-emotional 37.2 vs. 54.1). Significantly lower SF-36 scores were also found in patient with comorbidity (for physical functioning 68.1 vs. 77.7; for role-physical 35.1 vs. 52.3; for bodily pain 62.6 vs. 75.4; for general health 56.8 vs. 63.8; for social functioning 61.9 vs. 71.0, for role-emotional 41.6 vs. 59.1and for mental health 52.5 vs 49.8). In a multivariable analysis, education, occupation, body mass index, metabolic syndrome and severity of the disease had a weak influence on patients' HRQoL, while age, marital status, smoking, alcohol consumption, physical activity and the degree of carotid stenosis had no effect on patients' HRQoL. The SF-36 scores did not substantially change after adjustment for confounding variables. CONCLUSIONS: Patients with symptomatic carotid disease had poorer HRQoL, especially its mental components, than the general population. The severity of the disease was significantly associated only with the SF-36 role-physical subscale. HRQoL in patients with symptomatic carotid disease was poorer in women than in men, and was not affected by age and other demographic and clinical characteristics of patients. PMID- 23043130 TI - Complex gynaecological and urological problems in adolescents: challenges and transition. AB - The diagnosis and early management of genitourinary disorders in children is challenging for the child, parents and carers. There have been enormous developments in paediatric care medically and surgically and as a result many patients with complex anomalies reach adult life and have a normal desire for a good quality of life. Adolescence changes the challenges faced as anatomical growth may alter the surgical outcomes both functionally and cosmetically. Emotional and psychological development also creates important challenges that all those involved have to face. These patients need expert care and advice throughout adolescence and into adult life. This should be delivered by a multidisciplinary team that includes urology, gynaecology, nephrology, endocrinology and psychology. This creates a safe clinical and supportive environment for patients and their families. PMID- 23043131 TI - Neglected headache: ignorance, arrogance or insouciance? PMID- 23043132 TI - Illicit drugs and cluster headache: an inevitable discussion. PMID- 23043134 TI - Bioinformatic analysis of alpha/beta-hydrolase fold enzymes reveals subfamily specific positions responsible for discrimination of amidase and lipase activities. AB - Superfamily of alpha-beta hydrolases is one of the largest groups of structurally related enzymes with diverse catalytic functions. Bioinformatic analysis was used to study how lipase and amidase catalytic activities are implemented into the same structural framework. Subfamily-specific positions--conserved within lipases and peptidases but different between them--that were supposed to be responsible for functional discrimination have been identified. Mutations at subfamily specific positions were used to introduce amidase activity into Candida antarctica lipase B (CALB). Molecular modeling was implemented to evaluate influence of selected residues on binding and catalytic conversion of amide substrate by corresponding library of mutants. In silico screening was applied to select reactive enzyme-substrate complexes that satisfy knowledge-based criteria of amidase catalytic activity. Selected CALB variants with substitutions at subfamily-specific positions Gly39, Thr103, Trp104, and Leu278 were produced and showed significant improvement of experimentally measured amidase activity. Based on these results, we suggest that value of subfamily-specific positions should be further explored in order to develop a systematic tool to study structure function relationship in enzymes and to use this information for rational enzyme engineering. PMID- 23043133 TI - Is the relation between ozone and mortality confounded by chemical components of particulate matter? Analysis of 7 components in 57 US communities. AB - Epidemiologic studies have linked tropospheric ozone pollution and human mortality. Although research has shown that this relation is not confounded by particulate matter when measured by mass, little scientific evidence exists on whether confounding exists by chemical components of the particle mixture. Using mortality and particulate matter with aerodynamic diameter <=2.5 um (PM(2.5)) component data from 57 US communities (2000-2005), the authors investigate whether the ozone-mortality relation is confounded by 7 components of PM(2.5): sulfate, nitrate, silicon, elemental carbon, organic carbon matter, sodium ion, and ammonium. Together, these components constitute most PM(2.5) mass in the United States. Estimates of the effect of ozone on mortality were almost identical before and after controlling for the 7 components of PM(2.5) considered (mortality increase/10-ppb ozone increase, before and after controlling: ammonium, 0.34% vs. 0.35%; elemental carbon, 0.36% vs. 0.37%; nitrate, 0.27% vs. 0.26%; organic carbon matter, 0.34% vs. 0.31%; silicon, 0.36% vs. 0.37%; sodium ion, 0.21% vs. 0.18%; and sulfate, 0.35% vs. 0.38%). Additionally, correlations were weak between ozone and each particulate component across all communities. Previous research found that the ozone-mortality relation is not confounded by particulate matter measured by mass; this national study indicates that the relation is also robust to control for specific components of PM(2.5). PMID- 23043135 TI - Moderate dose inhaled corticosteroid-induced symptomatic adrenal suppression: case report and review of the literature. AB - Inhaled corticosteroids (ICS) are drugs of choice for persistent asthma. Less than 500 ug/d of fluticasone are believed to be safe. We found 92 cases of adrenal suppression in PubMed; among these cases there were 13 children who took 500 ug/d or less of fluticasone. Adrenal insufficiency was diagnosed in a 7-year old boy on 460 ug ICS for 16 months, with a diagnosis of chronic persistent asthma. A random cortisol was nondetectable as was an early morning cortisol. ICS have greatly improved the day-to-day lives of children with chronic persistent asthma. Parents of children younger than 12 years, who use at least 400 ug of inhaled fluticasone (or bioequivalent), must be given oral and written instructions about warning symptoms of hypocortisolism. Major stress such as surgery, gastrointestinal, bronchopulmonary, or other systemic infections, and heat stress may mandate a written plan of action for use by hospital physicians. PMID- 23043136 TI - Regulation of a viral proteinase by a peptide and DNA in one-dimensional space: I. binding to DNA AND to hexon of the precursor to protein VI, pVI, of human adenovirus. AB - The precursor to adenovirus protein VI, pVI, is a multifunctional protein with different roles early and late in virus infection. Here, we focus on two roles late in infection, binding of pVI to DNA and to the major capsid protein hexon. pVI bound to DNA as a monomer independent of DNA sequence with an apparent equilibrium dissociation constant, K(d)((app)), of 46 nm. Bound to double stranded DNA, one molecule of pVI occluded 8 bp. Upon the binding of pVI to DNA, three sodium ions were displaced from the DNA. A DeltaG(0)(0) of -4.54 kcal/mol for the nonelectrostatic free energy of binding indicated that a substantial component of the binding free energy resulted from nonspecific interactions between pVI and DNA. The proteolytically processed, mature form of pVI, protein VI, also bound to DNA; its K(d)((app)) was much higher, 307 nm. The binding assays were performed in 1 mm MgCl(2) because in the absence of magnesium, the binding to pVI or protein VI to DNA was too tight to determine a K(d)((app)). Three molecules of pVI bound to one molecule of the hexon trimer with an equilibrium dissociation constant K(d)((app)) of 1.1 nm. PMID- 23043137 TI - Regulation of a viral proteinase by a peptide and DNA in one-dimensional space: II. adenovirus proteinase is activated in an unusual one-dimensional biochemical reaction. AB - Late in an adenovirus infection, the viral proteinase (AVP) becomes activated to process virion precursor proteins used in virus assembly. AVP is activated by two cofactors, the viral DNA and pVIc, an 11-amino acid peptide originating from the C terminus of the precursor protein pVI. There is a conundrum in the activation of AVP in that AVP and pVI are sequence-independent DNA-binding proteins with nm equilibrium dissociation constants such that in the virus particle, they are predicted to be essentially irreversibly bound to the viral DNA. Here, we resolve that conundrum by showing that activation of AVP takes place on the one dimensional contour of DNA. In vitro, pVI, a substrate, slides on DNA via one dimensional diffusion, D(1) = 1.45 * 10(6) bp(2)/s, until it binds to AVP also on the same DNA molecule. AVP, partially activated by being bound to DNA, excises pVIc, which binds to the AVP molecule that cut it out. pVIc then forms a disulfide bond with AVP forming the fully active AVP-pVIc complex bound to DNA. In vivo, in heat-disrupted immature virus, AVP was also activated by pVI in DNA dependent reactions. This activation mechanism illustrates a new paradigm for virion maturation and a new way, by sliding on DNA, for bimolecular complexes to form among proteins not involved in DNA metabolism. PMID- 23043138 TI - Regulation of a viral proteinase by a peptide and DNA in one-dimensional space: IV. viral proteinase slides along DNA to locate and process its substrates. AB - Precursor proteins used in the assembly of adenovirus virions must be processed by the virally encoded adenovirus proteinase (AVP) before the virus particle becomes infectious. An activated adenovirus proteinase, the AVP-pVIc complex, was shown to slide along viral DNA with an extremely fast one-dimensional diffusion constant, 21.0 +/- 1.9 * 10(6) bp(2)/s. In principle, one-dimensional diffusion can provide a means for DNA-bound proteinases to locate and process DNA-bound substrates. Here, we show that this is correct. In vitro, AVP-pVIc complexes processed a purified virion precursor protein in a DNA-dependent reaction; in a quasi in vivo environment, heat-disrupted ts-1 virions, AVP-pVIc complexes processed five different precursor proteins in DNA-dependent reactions. Sliding of AVP-pVIc complexes along DNA illustrates a new biochemical mechanism by which a proteinase can locate its substrates, represents a new paradigm for virion maturation, and reveals a new way of exploiting the surface of DNA. PMID- 23043139 TI - Regulation of a viral proteinase by a peptide and DNA in one-dimensional space: III. atomic resolution structure of the nascent form of the adenovirus proteinase. AB - The adenovirus proteinase (AVP), the first member of a new class of cysteine proteinases, is essential for the production of infectious virus, and here we report its structure at 0.98 A resolution. AVP, initially synthesized as an inactive enzyme, requires two cofactors for maximal activity: pVIc, an 11-amino acid peptide, and the viral DNA. Comparison of the structure of AVP with that of an active form, the AVP-pVIc complex, reveals why AVP is inactive. Both forms have an alpha + beta fold; the major structural differences between them lie in the beta-sheet domain. In AVP-pVIc, the general base His-54 Ndelta1 is 3.9 A away from the Cys-122 Sgamma, thereby rendering it nucleophilic. In AVP, however, His 54 Ndelta1 is 7.0 A away from Cys-122 Sgamma, too far away to be able to abstract the proton from Cys-122. In AVP-pVIc, Tyr-84 forms a cation-pi interaction with His-54 that should raise the pK(a) of His-54 and freeze the imidazole ring in the place optimal for forming an ion pair with Cys-122. In AVP, however, Tyr-84 is more than 11 A away from its position in AVP-pVIc. Based on the structural differences between AVP and AVP-pVIc, we present a model that postulates that activation of AVP by pVIc occurs via a 62-amino acid-long activation pathway in which the binding of pVIc initiates contiguous conformational changes, analogous to falling dominos. There is a common pathway that branches into a pathway that leads to the repositioning of His-54 and another pathway that leads to the repositioning of Tyr-84. PMID- 23043141 TI - Flavinylation and assembly of succinate dehydrogenase are dependent on the C terminal tail of the flavoprotein subunit. AB - BACKGROUND: Succinate dehydrogenase (SDH) requires a covalent addition of FAD for catalytic function. RESULTS: Mutational analyses of Sdh1 implicate C-terminal region Arg residues involvement in covalent flavinylation and SDH assembly. CONCLUSION: SDH assembly is dependent on FAD binding to Sdh1 but not covalent binding. SIGNIFICANCE: These results document the basis for the SDH deficiency and pathology seen with mutations in human Sdh1. The enzymatic function of succinate dehydrogenase (SDH) is dependent on covalent attachment of FAD on the ~70-kDa flavoprotein subunit Sdh1. We show presently that flavinylation of the Sdh1 subunit of succinate dehydrogenase is dependent on a set of two spatially close C-terminal arginine residues that are distant from the FAD binding site. Mutation of Arg(582) in yeast Sdh1 precludes flavinylation as well as assembly of the tetrameric enzyme complex. Mutation of Arg(638) compromises SDH function only when present in combination with a Cys(630) substitution. Mutations of either Arg(582) or Arg(638)/Cys(630) do not markedly destabilize the Sdh1 polypeptide; however, the steady-state level of Sdh5 is markedly attenuated in the Sdh1 mutant cells. With each mutant Sdh1, second-site Sdh1 suppressor mutations were recovered in Sdh1 permitting flavinylation, stabilization of Sdh5 and SDH tetramer assembly. SDH assembly appears to require FAD binding but not necessarily covalent FAD attachment. The Arg residues may be important not only for Sdh5 association but also in the recruitment and/or guidance of FAD and or succinate to the substrate site for the flavinylation reaction. The impaired assembly of SDH with the C-terminal Sdh1 mutants suggests that FAD binding is important to stabilize the Sdh1 conformation enabling association with Sdh2 and the membrane anchor subunits. PMID- 23043142 TI - Left hemispheric predominance of nigrostriatal dysfunction in Parkinson's disease. AB - The aim of this study was to investigate the distribution and the degree of asymmetric putaminal dopamine transporter availability in right-handed patients with Parkinson's disease and its association with the severity of lateralized motor signs. Asymmetry of motor symptoms was defined by the difference between right- and left-sided scores for lateralized items assessed by the Unified Parkinson's Disease Rating Scale Motor Score in a series of 68 patients with Parkinson's disease (disease duration 2.1 +/- 1.5 years; Unified Parkinson's Disease Rating Scale Motor Score 22.7 +/- 9). Putaminal dopamine transporter availability was measured with the radioligand [(123)I]beta-carboxymethyoxy-3 beta-(4-iodophenyl) tropane ([(123)I]beta-CIT) and single photon emission computed tomography. We found that in the right-handed Parkinson's disease cohort, the number of patients who had lower dopamine transporter uptake in the left posterior putamen was significantly greater compared with those with lower uptake in the right posterior putamen (Parkinson's disease-left group, n = 49; Parkinson's disease-right group, n = 19; P < 0.001). In addition, one-way analysis of variance revealed significant reductions of mean total putaminal [(123)I]beta-CIT binding of the Parkinson's disease-right patients compared with Parkinson's disease-left patients (P < 0.05).The preponderance of reduced left putaminal dopamine transporter availability strengthens clinical observations of a greater proportion of right-handed patients with Parkinson's disease with predominantly right-sided motor signs and argues against a randomly distributed asymmetric vulnerability of substantia nigra dopaminergic neurons. The coexistence of a subgroup of right-handed patients with Parkinson's disease with more severe and predominant ipsilateral putaminal dopamine transporter decline suggests that asymmetry of dopaminergic denervation and motor dysfunction in Parkinson's disease cannot be fully explained by hemispheric dominance alone, but that other factors must be involved. PMID- 23043140 TI - Neck rotation and neck mimic docking in the noncatalytic Kar3-associated protein Vik1. AB - BACKGROUND: Kar3Vik1 is a heterodimeric kinesin with one catalytic subunit (Kar3) and one noncatalytic subunit (Vik1). RESULTS: Vik1 experiences conformational changes in regions analogous to the force-producing elements in catalytic kinesins. CONCLUSION: A molecular mechanism by which Kar3 could trigger Vik1's release from microtubules was revealed. SIGNIFICANCE: These findings will serve as the prototype for understanding the motile mechanism of kinesin-14 motors in general. It is widely accepted that movement of kinesin motor proteins is accomplished by coupling ATP binding, hydrolysis, and product release to conformational changes in the microtubule-binding and force-generating elements of their motor domain. Therefore, understanding how the Saccharomyces cerevisiae proteins Cik1 and Vik1 are able to function as direct participants in movement of Kar3Cik1 and Kar3Vik1 kinesin complexes presents an interesting challenge given that their motor homology domain (MHD) cannot bind ATP. Our crystal structures of the Vik1 ortholog from Candida glabrata may provide insight into this mechanism by showing that its neck and neck mimic-like element can adopt several different conformations reminiscent of those observed in catalytic kinesins. We found that when the neck is alpha-helical and interacting with the MHD core, the C terminus of CgVik1 docks onto the central beta-sheet similarly to the ATP-bound form of Ncd. Alternatively, when neck-core interactions are broken, the C terminus is disordered. Mutations designed to impair neck rotation, or some of the neck-MHD interactions, decreased microtubule gliding velocity and steady state ATPase rate of CgKar3Vik1 complexes significantly. These results strongly suggest that neck rotation and neck mimic docking in Vik1 and Cik1 may be a structural mechanism for communication with Kar3. PMID- 23043145 TI - Magnetic flimmers: 'light in the electromagnetic darkness'. AB - Transcranial magnetic stimulation has become an important field for both research in neuroscience and for therapy since Barker in 1985 showed that it was possible to stimulate the human motor cortex with an electromagnet. Today for instance, transcranial magnetic stimulation can be used to measure nerve conduction velocities and to create virtual lesions in the brain. The latter option creates the possibility to inactivate parts of the brain temporarily without permanent damage. In 2008, the American Food and Drugs Administration approved repetitive transcranial magnetic stimulation as a therapy for major depression under strict conditions. Repetitive transcranial magnetic stimulation has not yet been cleared for treatment of other diseases, including schizophrenia, anxiety disorders, obesity and Parkinson's disease, but results seem promising. Transcranial magnetic stimulation, however, was not invented at the end of the 20th century. The discovery of electromagnetism, the enthusiasm for electricity and electrotherapy, and the interest in Beard's concept of neurasthenia already resulted in the first electromagnetic treatments in the late 19th and early 20th century. In this article, we provide a history of electromagnetic stimulation circa 1900. From the data, we conclude that Mesmer's late 18th century ideas of 'animal magnetism' and the 19th century absence of physiological proof had a negative influence on the acceptance of this therapy during the first decades of the 20th century. Electromagnetism disappeared from neurological textbooks in the early 20th century to recur at the end of that century. PMID- 23043143 TI - Spatio-temporal mapping cortical neuroplasticity in carpal tunnel syndrome. AB - Neuroimaging data demonstrate that carpal tunnel syndrome, a peripheral neuropathy, is accompanied by maladaptive central neuroplasticity. To further investigate this phenomenon, we collected magnetoencephalography data from 12 patients with carpal tunnel syndrome and 12 healthy control subjects undergoing somatosensory stimulation of the median nerve-innervated Digits 2 and 3, as well as Digit 5, which is innervated by the ulnar nerve. Nerve conduction velocity and psychophysical data were acquired to determine whether standard clinical measures correlated with brain response. In subjects with carpal tunnel syndrome, but not healthy controls, sensory nerve conduction velocity for Digits 2 and 3 was slower than Digit 5. However, somatosensory M20 latencies for Digits 2 and 3 were significantly longer than those of Digit 5. The extent of the M20 delay for median nerve-innervated Digit 2 was positively correlated with decreasing nerve conduction velocity and increasing pain severity. Thus, slower peripheral nerve conduction in carpal tunnel syndrome corresponds to greater delays in the first somatosensory cortical response. Furthermore, spectral analysis demonstrated weaker post-stimulus beta event-related desynchronization and earlier and shorter event-related synchronization in subjects with carpal tunnel syndrome. The extent of the decreased event-related desynchronization for median nerve-innervated digits was positively correlated with paraesthesia severity. We propose that ongoing paraesthesias in median nerve-innervated digits render their corresponding sensorimotor cortical areas 'busy', thus reducing their capacity to process external stimulation. Finally, subjects with carpal tunnel syndrome demonstrated a smaller cortical source separation for Digits 2 and 3 compared with healthy controls. This supports our hypothesis that ongoing paraesthesias promote blurring of median nerve-innervated digit representations through Hebbian plasticity mechanisms. In summary, this study reveals significant correlation between the clinical severity of carpal tunnel syndrome and the latency of the early M20, as well as the strength of long latency beta oscillations. These temporal magnetoencephalography measures are novel markers of neuroplasticity in carpal tunnel syndrome and could be used to study central changes that may occur following clinical intervention. PMID- 23043144 TI - Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions. AB - The molecular diagnosis of mitochondrial disorders still remains elusive in a large proportion of patients, but advances in next generation sequencing are significantly improving our chances to detect mutations even in sporadic patients. Syndromes associated with mitochondrial DNA multiple deletions are caused by different molecular defects resulting in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia to multi-systemic disorders of variable severity. The mutations underlying these conditions remain undisclosed in half of the affected subjects. We applied next-generation sequencing of known mitochondrial targets (MitoExome) to probands presenting with adult-onset mitochondrial myopathy and harbouring mitochondrial DNA multiple deletions in skeletal muscle. We identified autosomal recessive mutations in the DGUOK gene (encoding mitochondrial deoxyguanosine kinase), which has previously been associated with an infantile hepatocerebral form of mitochondrial DNA depletion. Mutations in DGUOK occurred in five independent subjects, representing 5.6% of our cohort of patients with mitochondrial DNA multiple deletions, and impaired both muscle DGUOK activity and protein stability. Clinical presentations were variable, including mitochondrial myopathy with or without progressive external ophthalmoplegia, recurrent rhabdomyolysis in a young female who had received a liver transplant at 9 months of age and adult-onset lower motor neuron syndrome with mild cognitive impairment. These findings reinforce the concept that mutations in genes involved in deoxyribonucleotide metabolism can cause diverse clinical phenotypes and suggest that DGUOK should be screened in patients harbouring mitochondrial DNA deletions in skeletal muscle. PMID- 23043146 TI - Effects of diazepam and flumazenil on forebrain ischaemia in a rat model of benzodiazepine tolerance. AB - BACKGROUND: Post-ischaemic benzodiazepine administration is neuroprotective, but chronic administration of benzodiazepines can induce tolerance, such that the neuroprotective effect may be reduced. This study investigated whether benzodiazepine tolerance can worsen ischaemic injury and whether neuroprotection by post-ischaemic benzodiazepine administration is affected by benzodiazepine tolerance. We also investigated whether antagonism of benzodiazepine receptors by flumazenil was able to restore neuroprotection during benzodiazepine tolerance. METHODS: Experiments were performed in both benzodiazepine-tolerant and naive rats. Benzodiazepine tolerance was indeed by 4 weeks administration of flurazepam. Bilateral carotid artery occlusion (BCAO) was performed to cause cerebral ischaemia. Four experiments were performed: (1) BCAO with no further interventions; (2) BCAO followed by administration of diazepam; (3) administration of flumazenil before BAO; and (4) administration of flumazenil before and diazepam after BCAO. Neurological and histological assessment was performed 5 days after BCAO. RESULTS: Benzodiazepine tolerance did not affect neuronal injury in the CA1 and CA3 regions and dentate gyrus of the hippocampus after severe ischaemic insult, but did worsen neuronal damage when mild ischaemia was applied (P<0.05). Neuroprotective efficacy of post-ischaemic diazepam was not observed under conditions of benzodiazepine tolerance. Flumazenil treatment before BCAO reduced ischaemic neuronal damage exacerbated by benzodiazepine tolerance (P<0.05), and restored neuroprotection by post-ischaemic diazepam (P<0.05), the effect of which was reduced by benzodiazepine tolerance (P<0.05). However, pre-ischaemic flumazenil treatment in naive animals reduced neuroprotection provided by post-ischaemic diazepam (P<0.01-0.05). CONCLUSIONS: Benzodiazepine tolerance can worsen ischaemic neuronal injury and abolish the neuroprotection provided by post-ischaemic diazepam. Pre-treatment with flumazenil treatment reversed benzodiazepine tolerance and restored neuroprotection by post-ischaemic diazepam. These findings may suggest that management of patient's risk of developing cerebral ischaemia may need to take into account current use. PMID- 23043147 TI - Exercise adherence interventions for adults with chronic musculoskeletal pain. PMID- 23043148 TI - Work reintegration for veterans with mental disorders: a systematic literature review to inform research. AB - BACKGROUND: Some veterans, and especially those with mental disorders, have difficulty reintegrating into the civilian workforce. PURPOSE: The objectives of this study were to describe the scope of the existing literature on mental disorders and unemployment and to identify factors potentially associated with reintegration of workers with mental disorders into the workforce. DATA SOURCES: The following databases were searched from their respective inception dates: MEDLINE, EMBASE, Cumulative Index Nursing Allied Health (CINAHL), and PsycINFO. STUDY SELECTION: In-scope studies had quantitative measures of employment and study populations with well-described mental disorders (eg, anxiety, depression, posttraumatic stress disorder, substance-use disorders). DATA EXTRACTION: A systematic and comprehensive search of the relevant published literature up to July 2009 was conducted that identified a total of 5,195 articles. From that list, 81 in-scope studies were identified. An update to July 2012 identified 1,267 new articles, resulting in an additional 16 in-scope articles. DATA SYNTHESIS: Three major categories emerged from the in-scope articles: return to work, supported employment, and reintegration. The literature on return to work and supported employment is well summarized by existing reviews. The reintegration literature included 32 in-scope articles; only 10 of these were conducted in populations of veterans. LIMITATIONS: Studies of reintegration to work were not similar enough to synthesize, and it was inappropriate to pool results for this category of literature. CONCLUSIONS: Comprehensive literature review found limited knowledge about how to integrate people with mental disorders into a new workplace after a prolonged absence (>1 year). Even more limited knowledge was found for veterans. The results informed the next steps for our research team to enhance successful reintegration of veterans with mental disorders into the civilian workplace. PMID- 23043149 TI - Physical therapist management of patients with ventricular assist devices: key considerations for the acute care physical therapist. AB - This article provides an overview of the utilization of ventricular assist devices (VADs), reviews the common features of VADs and management of VAD recipients, discusses clinical considerations in the rehabilitation process, and describes the role of the acute care physical therapist in the care of VAD recipients. With more than 5 million people in the United States with heart failure, and with a limited ability to manage the progressive and debilitating nature of heart failure, VADs are becoming more commonplace. In order to prescribe a comprehensive and effective plan of care, the physical therapist needs to understand the type and function of the VADs and the goals of the VAD program. The goals for the physical therapist are: (1) to deliver comprehensive rehabilitation services to patients on VAD support, (2) to develop an understanding of the role of functional mobility in recovery, and (3) to understand how preoperative physical function may contribute to the VAD selection process. The acute care physical therapist has an increasing role in providing a complex range of rehabilitation services, as well as serving as a well-educated resource to physical therapists across the health care spectrum, as more VAD recipients are living in the community. PMID- 23043151 TI - Pulmonary cement embolism. PMID- 23043150 TI - Measuring oncogenic signaling pathways in cancer with PET: an emerging paradigm from studies in castration-resistant prostate cancer. AB - As parallel advances in cancer biology and drug development continue to elevate the role of targeted therapies in oncology, the need for imaging biomarkers that systematically measure the biology associated with therapeutic intervention has become more urgent. Although the molecular imaging community has a commitment to develop technologies to this end, few investigational radiotracers directly measure the biology of common oncogenic signaling pathways often addressed by targeted therapies. Visible progress has been achieved with a handful of radiotracers rationally designed to intercalate the pathobiology of prostate cancer, a molecularly heterogeneous disease nevertheless broadly defined by a fairly small repertoire of recurrent oncogenic lesions. SIGNIFICANCE: That variable treatment responses or emergent resistance phenotypes are often documented in humans argues strongly for diagnostic technologies that can be realistically applied posttherapy to capture the dynamic patterns of disease response. The purpose of this review is to describe a collection of radiotracers developed to measure the pathobiology of prostate cancer for improved treatment monitoring, placing particular emphasis on the biologic rationale for their preparation. A chronologic description of radiotracer development programs is outlined, primarily to stress how an ongoing dialectic between earlier and more contemporary imaging technologies has accelerated discovery. PMID- 23043152 TI - Diagnostic value of renal Doppler ultrasonography for detecting nutcracker syndrome in children with recurrent gross hematuria. PMID- 23043153 TI - Enhanced angiotensin II-induced cardiac and aortic remodeling in ACE2 knockout mice. AB - Angiotensin-converting enzyme 2 (ACE2) is present in the heart and thought to exert protective functions. We conducted studies in ACE2 deficient mice to determine whether enzyme loss would exacerbate the cardiac and vascular pathological responses to chronic subcutaneous (sc) angiotensin II (Ang II) infusion. Eight-week-old male ACE2 knockout (KO) and wild type (WT) mice were infused with Ang II (1000 ng/kg per min, 4 weeks) using mini-osmotic pumps. Blood pressure (radiotelemetry), cardiac function (echocardiography, echo), cardiac/aortic structure (histology, collagen, and oxidative stress), and vascular inflammation were examined. Before Ang II infusion, ACE2 KO mice showed unaltered cardiac function and blood pressure. After 4 weeks of Ang II infusion, the mean arterial pressure (MAP) increased from 96 +/- 2 to 136 +/- 17 mm Hg (~40%) in WT and from 104 +/- 5 to 141 +/- 13 mm Hg (~ 35%) in ACE2 KO. While there were no differences in MAP between groups, the ACE2 KO responded differently to the hypertensive stimulus. Echo analysis revealed severe myocardial dysfunction in Ang II-infused ACE2 KO (Ang ACE2 KO). Ejection fraction was lower (39% versus 50%) as was fractional shortening (27% versus 38%) in ACE2 KO versus WT, respectively. Cardiac dysfunction was associated with hypertrophic cardiomyopathy shown by increased left-ventricular wall thickness, average cardiomyocyte cross-sectional area, and heart weight/body weight ratio. Collagen staining in the myocardium and aorta revealed increased collagen in Ang ACE2 KO, suggestive of remodeling. Results also showed enhanced oxidative stress in the myocardium and aorta of Ang ACE2 KO. There was a 3-fold elevation in macrophage inflammatory protein 1alpha (MIP 1alpha) in the aorta of ACE2 KO. Studies in the ACE2 KO model reveal the importance of ACE2 in the maladaptive cardiac and aortic responses to Ang II stimulation, seen as enhanced remodeling using physiological, structural, and biochemical markers. Results document a cardio- and vascular protective role of ACE2 under pathological conditions. PMID- 23043154 TI - Efficiency of using community organisations as catalysts for recruitment to continence promotion trials. AB - BACKGROUND: A major challenge for determining the effectiveness of community based continence promotion campaigns is recruitment of a representative sample of incontinent participants who have not previously sought care. PURPOSE: To evaluate the efficiency of engaging community organisations as catalysts for recruitment of community-dwelling older women with incontinence to the 'Continence across Continents' randomised controlled trial. METHODS: Seniors' and women's community-based organisations throughout the United Kingdom were solicited by telephone or email to assist recruitment for an open-label cluster randomised controlled trial testing three experimental continence promotion interventions and a control intervention for incontinent older women. Women aged 60 years and older who experienced at least weekly urinary incontinence and who had never sought treatment were eligible to participate. The response rate of the organisations and enrolment rate of eligible participants attending the continence promotion workshops were recorded. Differences in recruitment efficiency by intervention group were ascertained using analysis of variance statistics. RESULTS: We contacted 408 community organisations over a 1-year period. Seventy organisations (17%) agreed to host a workshop, 249 (61%) did not provide a response, and 89 (22%) refused. Workshops were administered in a group format to 61 organisations (15%); 667 women attended, 583 (87%) submitted the screening questionnaire, and 437 (66%) met eligibility criteria for inclusion. A total of 192 women consented to participate in the trial, yielding a 44% recruitment efficiency among workshop attendees known to be eligible, with no significant difference in enrolment rates between groups. However, the mean participant recruitment rate per number of attendees at each workshop was only 29%, varying substantially between groups from 19% to 37%, with the lowest rate observed for the control group. The mean annual recruitment rate expressed as the number of enrolled participants per community organisation contacted was 0.5. LIMITATIONS: Reasons for women's non-response were not collected. The findings may be country specific. CONCLUSIONS: The recruitment rate for a continence promotion trial among older women known to be eligible and attending workshops hosted by local community organisations was high (44%). Strategies are needed to bolster community organisations' involvement in health promotion trials in general and for continence issues in particular. PMID- 23043155 TI - Sister chromatid cohesion. AB - During S phase, not only does DNA have to be replicated, but also newly synthesized DNA molecules have to be connected with each other. This sister chromatid cohesion is essential for the biorientation of chromosomes on the mitotic or meiotic spindle, and is thus an essential prerequisite for chromosome segregation. Cohesion is mediated by cohesin complexes that are thought to embrace sister chromatids as large rings. Cohesin binds to DNA dynamically before DNA replication and is converted into a stably DNA-bound form during replication. This conversion requires acetylation of cohesin, which in vertebrates leads to recruitment of sororin. Sororin antagonizes Wapl, a protein that is able to release cohesin from DNA, presumably by opening the cohesin ring. Inhibition of Wapl by sororin therefore "locks" cohesin rings on DNA and allows them to maintain cohesion for long periods of time in mammalian oocytes, possibly for months or even years. PMID- 23043156 TI - Optogenetic strategies to dissect the neural circuits that underlie reward and addiction. AB - Optogenetic strategies for perturbation of neural circuit function have begun to revolutionize systems neuroscience. Whereas optogenetics has proven to be a powerful approach for studying neural systems, the tools to conduct these experiments are still continuously evolving. Here we briefly summarize available hardware and reagents that can be used for studying behaviors related to reward and addiction. In addition, we discuss recent studies in which these strategies have been applied to study neural circuit function in brain slices as well as awake and behaving animals. Collectively, this work serves as a brief introduction to optogenetic techniques and highlights how these tools can be applied to elucidate the neural circuits that underlie reward processing and addiction. PMID- 23043157 TI - HIV transmission. AB - HIV-1 is transmitted by sexual contact across mucosal surfaces, by maternal infant exposure, and by percutaneous inoculation. For reasons that are still incompletely understood, CCR5-tropic viruses (R5 viruses) are preferentially transmitted by all routes. Transmission is followed by an orderly appearance of viral and host markers of infection in the blood plasma. In the acute phase of infection, HIV-1 replicates exponentially and diversifies randomly, allowing for an unambiguous molecular identification of transmitted/founder virus genomes and a precise characterization of the population bottleneck to virus transmission. Sexual transmission of HIV-1 most often results in productive clinical infection arising from a single virus, highlighting the extreme bottleneck and inherent inefficiency in virus transmission. It remains to be determined if HIV-1 transmission is largely a stochastic process whereby any reasonably fit R5 virus can be transmitted or if there are features of transmitted/founder viruses that facilitate their transmission in a biologically meaningful way. Human tissue explant models of HIV-1 infection and animal models of SIV/SHIV/HIV-1 transmission, coupled with new challenge virus strains that more closely reflect transmitted/founder viruses, have the potential to elucidate fundamental mechanisms in HIV-1 transmission relevant to vaccine design and other prevention strategies. PMID- 23043158 TI - Therapeutic effects of PPARalpha agonists on diabetic retinopathy in type 1 diabetes models. AB - Retinal vascular leakage, inflammation, and neovascularization (NV) are features of diabetic retinopathy (DR). Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, has shown robust protective effects against DR in type 2 diabetic patients, but its effects on DR in type 1 diabetes have not been reported. This study evaluated the efficacy of fenofibrate on DR in type 1 diabetes models and determined if the effect is PPARalpha dependent. Oral administration of fenofibrate significantly ameliorated retinal vascular leakage and leukostasis in streptozotocin-induced diabetic rats and in Akita mice. Favorable effects on DR were also achieved by intravitreal injection of fenofibrate or another specific PPARalpha agonist. Fenofibrate also ameliorated retinal NV in the oxygen-induced retinopathy (OIR) model and inhibited tube formation and migration in cultured endothelial cells. Fenofibrate also attenuated overexpression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and vascular endothelial growth factor (VEGF) and blocked activation of hypoxia-inducible factor-1 and nuclear factor-kappaB in the retinas of OIR and diabetic models. Fenofibrate's beneficial effects were blocked by a specific PPARalpha antagonist. Furthermore, Pparalpha knockout abolished the fenofibrate-induced downregulation of VEGF and reduction of retinal vascular leakage in DR models. These results demonstrate therapeutic effects of fenofibrate on DR in type 1 diabetes and support the existence of the drug target in ocular tissues and via a PPARalpha-dependent mechanism. PMID- 23043159 TI - In situ electrophysiological examination of pancreatic alpha cells in the streptozotocin-induced diabetes model, revealing the cellular basis of glucagon hypersecretion. AB - Early-stage type 1 diabetes (T1D) exhibits hyperglucagonemia by undefined cellular mechanisms. Here we characterized alpha-cell voltage-gated ion channels in a streptozotocin (STZ)-induced diabetes model that lead to increased glucagon secretion mimicking T1D. GYY mice expressing enhanced yellow fluorescence protein in alpha cells were used to identify alpha cells within pancreas slices. Mice treated with low-dose STZ exhibited hyperglucagonemia, hyperglycemia, and glucose intolerance, with 71% reduction of beta-cell mass. Although alpha-cell mass of STZ-treated mice remained unchanged, total pancreatic glucagon content was elevated, coinciding with increase in size of glucagon granules. Pancreas tissue slices enabled in situ examination of alpha-cell electrophysiology. alpha cells of STZ-treated mice exhibited the following: 1) increased exocytosis (serial depolarization-induced capacitance), 2) enhanced voltage-gated Na(+) current density, 3) reduced voltage-gated K(+) current density, and 4) increased action potential (AP) amplitude and firing frequency. Hyperglucagonemia in STZ-induced diabetes is thus likely due to increased glucagon content arising from enlarged glucagon granules and increased AP firing frequency and amplitude coinciding with enhanced Na(+) and reduced K(+) currents. These alterations may prime alpha cells in STZ-treated mice for more glucagon release per cell in response to low glucose stimulation. Thus, our study provides the first insight that STZ treatment sensitizes release mechanisms of alpha cells. PMID- 23043160 TI - Proresolution therapy for the treatment of delayed healing of diabetic wounds. AB - Obesity and type 2 diabetes are emerging global epidemics associated with chronic, low-grade inflammation. A characteristic feature of type 2 diabetes is delayed wound healing, which increases the risk of recurrent infections, tissue necrosis, and limb amputation. In health, inflammation is actively resolved by endogenous mediators, such as the resolvins. D-series resolvins are generated from docosahexaenoic acid (DHA) and promote macrophage-mediated clearance of microbes and apoptotic cells. However, it is not clear how type 2 diabetes affects the resolution of inflammation. Here, we report that resolution of acute peritonitis is delayed in obese diabetic (db/db) mice. Altered resolution was associated with decreased apoptotic cell and Fc receptor-mediated macrophage clearance. Treatment with resolvin D1 (RvD1) enhanced resolution of peritonitis, decreased accumulation of apoptotic thymocytes in diabetic mice, and stimulated diabetic macrophage phagocytosis. Conversion of DHA to monohydroxydocosanoids, markers of resolvin biosynthesis, was attenuated in diabetic wounds, and local application of RvD1 accelerated wound closure and decreased accumulation of apoptotic cells and macrophages in the wounds. These findings support the notion that diabetes impairs resolution of wound healing and demonstrate that stimulating resolution with proresolving lipid mediators could be a novel approach to treating chronic, nonhealing wounds in patients with diabetes. PMID- 23043161 TI - Constitutive STAT3 phosphorylation contributes to skeletal muscle insulin resistance in type 2 diabetes. AB - Signal transducer and activator of transcription 3 (STAT3) is involved in cytokine- and nutrient-induced insulin resistance. The role of STAT3 in the development of skeletal muscle insulin resistance and type 2 diabetes (T2D) pathogenesis is incompletely defined. We tested the hypothesis that STAT3 signaling contributes to skeletal muscle insulin resistance in T2D. Protein abundance and phosphorylation of STAT3 signaling molecules were determined in skeletal muscle biopsy specimens from BMI- and age-matched overweight individuals with normal glucose tolerant (NGT) and T2D patients. The direct role of STAT3 in the development of lipid-induced skeletal muscle insulin resistance was determined using small interfering (si)RNA. Phosphorylated STAT3, phosphorylated Janus kinase 2 (JAK2), and suppressor of cytokine signaling 3 (SOCS3) protein abundance was increased in skeletal muscle from T2D patients. STAT3 phosphorylation positively correlated with free fatty acid level and measures of insulin sensitivity in NGT but not T2D patients. Palmitate exposure led to a constitutive phosphorylation of STAT3, increased protein abundance of SOCS3, and development of insulin resistance in L6 myotubes. These effects were prevented by siRNA-mediated STAT3 silencing. In summary, STAT3 is constitutively phosphorylated in skeletal muscle from T2D patients. STAT3 gene silencing prevents lipid-induced insulin resistance in cultured myotubes. Collectively, our results implicate excessive STAT3 signaling in the development of skeletal muscle insulin resistance in T2D. PMID- 23043163 TI - Use of thiazolidinediones and the risk of colorectal cancer in patients with diabetes: a nationwide, population-based, case-control study. AB - OBJECTIVE: Preclinical data suggest that peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have antineoplastic effects in colorectal cancer. We aimed to assess the association between the use of synthetic PPARgamma agonists, represented by thiazolidinediones (TZDs), and the risk of developing colorectal cancer. RESEARCH DESIGN AND METHODS: We conducted a nationwide, population-based, case-control study using the Taiwan National Health Insurance Research Database. Case subjects were defined as patients who were diagnosed with diabetes at least 365 days prior to a new diagnosis of colorectal cancer between 2000 and 2008. We randomly selected diabetic control subjects for each case subject, which were matched by sex, age, and the duration of diabetes. Among the 24,496 eligible case subjects and control subjects, we used conditional logistic regression to assess the risk of colorectal cancer in association with the use of TZDs. An additional analysis was conducted to assess the effects of concomitant use of TZDs and low-dose aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk of colorectal cancer. RESULTS: A decreased risk of colorectal cancer was observed in patients who had used TZDs compared with those who had never used TZDs (adjusted odds ratio 0.86 [95% CI 0.79-0.94]). Furthermore, the benefit of a decreased colorectal cancer risk was also found with concomitant use of TZDs and low-dose aspirin or NSAIDs. CONCLUSIONS: The use of TZDs may be associated with a decreased risk of colorectal cancer in patients with diabetes. Further studies are warranted to confirm our findings. PMID- 23043162 TI - Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. AB - Metabolomic discovery of biomarkers of type 2 diabetes (T2D) risk may reveal etiological pathways and help to identify individuals at risk for disease. We prospectively investigated the association between serum metabolites measured by targeted metabolomics and risk of T2D in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam (27,548 adults) among all incident cases of T2D (n = 800, mean follow-up 7 years) and a randomly drawn subcohort (n = 2,282). Flow injection analysis tandem mass spectrometry was used to quantify 163 metabolites, including acylcarnitines, amino acids, hexose, and phospholipids, in baseline serum samples. Serum hexose; phenylalanine; and diacyl phosphatidylcholines C32:1, C36:1, C38:3, and C40:5 were independently associated with increased risk of T2D and serum glycine; sphingomyelin C16:1; acyl-alkyl phosphatidylcholines C34:3, C40:6, C42:5, C44:4, and C44:5; and lysophosphatidylcholine C18:2 with decreased risk. Variance of the metabolites was largely explained by two metabolite factors with opposing risk associations (factor 1 relative risk in extreme quintiles 0.31 [95% CI 0.21-0.44], factor 2 3.82 [2.64-5.52]). The metabolites significantly improved T2D prediction compared with established risk factors. They were further linked to insulin sensitivity and secretion in the Tubingen Family study and were partly replicated in the independent KORA (Cooperative Health Research in the Region of Augsburg) cohort. The data indicate that metabolic alterations, including sugar metabolites, amino acids, and choline-containing phospholipids, are associated early on with a higher risk of T2D. PMID- 23043164 TI - Comparative pharmacokinetics and insulin action for three rapid-acting insulin analogs injected subcutaneously with and without hyaluronidase. AB - OBJECTIVE: To compare the pharmacokinetics and glucodynamics of three rapid acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant human hyaluronidase (rHuPH20). RESEARCH DESIGN AND METHODS: This double-blind six-way crossover euglycemic glucose clamp study was conducted in 14 healthy volunteers. Each analog was injected subcutaneously (0.15 units/kg) with or without rHuPH20. RESULTS: The commercial formulations had comparable insulin time-exposure and time-action profiles as follows: 50% exposure at 123-131 min and 50% total glucose infused at 183-186 min. With rHuPH20, the analogs had faster yet still comparable profiles: 50% exposure at 71 79 min and 50% glucose infused at 127-140 min. The accelerated absorption with rHuPH20 led to twice the exposure in the first hour and half the exposure beyond 2 h, which resulted in 13- to 25-min faster onset and 40- to 49-min shorter mean duration of insulin action. CONCLUSIONS: Coinjection of rHuPH20 with rapid-acting analogs accelerated insulin exposure, producing an ultra-rapid time-action profile with a faster onset and shorter duration of insulin action. PMID- 23043165 TI - Ultrasonic tissue characterization of carotid plaque improves the prediction of cardiovascular events in diabetic patients: a pilot study. AB - OBJECTIVE: The aim of this study is to evaluate whether noninvasive ultrasonic tissue characterization of carotid plaque using integrated backscatter (IBS) analysis can be a predictor of future cardiovascular events (CVE) in asymptomatic type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We prospectively evaluated the association between Calibrated-IBS value, an ultrasonic marker for tissue characteristics of carotid plaque, and CVE in 85 asymptomatic type 2 diabetic patients with carotid plaque. RESULTS: The median follow-up period was 7.9 years, and there were 20 new CVE. The risk of CVE was significantly higher in the subjects with low Calibrated-IBS values (<-17.1 dB; n = 42) as compared with those with high values (>=-17.1 dB; n = 43) (P = 0.004, log-rank test). Cox proportional hazards regression analysis revealed that both Calibrated-IBS value (hazard ratio [HR] 0.802 [95% CI 0.710-0.906]; P < 0.0001) and plaque thickness (1.938 [1.170-3.213]; P = 0.010) were independently associated with CVE, even after adjustment for the 10-year risk for a general cardiovascular disease estimated by Framingham risk scoring (FRS). Time-dependent receiver operating characteristic curve analysis for CVE at 10 years after the baseline examinations revealed that area under the curve for Calibrated-IBS was 0.76 (0.60-0.90) and substantially higher than those for plaque thickness (0.60 [0.45-0.79]) and FRS (0.60 [0.40-0.78]). These analyses also revealed that the addition of both plaque thickness and Calibrated-IBS value to conventional risk factors significantly improved the event prediction. CONCLUSIONS: Calibrated-IBS value could improve the risk prediction of CVE in asymptomatic type 2 diabetic patients with carotid plaque. PMID- 23043166 TI - Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). AB - OBJECTIVE: To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS: In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7-10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9-4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis. RESULTS: In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI -0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar. CONCLUSIONS: Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec. PMID- 23043167 TI - Early childhood infections and the risk of islet autoimmunity: the Diabetes Autoimmunity Study in the Young (DAISY). AB - OBJECTIVE: Type 1 diabetes is a common chronic childhood disease, and the incidence is increasing globally. Childhood infections are considered a potential environmental trigger of type 1 diabetes. Alternatively, improved hygiene and reduced childhood infections could explain the increase in type 1 diabetes in developed countries. The association of reported illnesses during infancy and later development of islet autoimmunity (IA) were examined in the Diabetes Autoimmunity Study in the Young. RESEARCH DESIGN AND METHODS: Complete illness interviews through 9 months of age were collected for 1,729 children-1,174 without a family history of type 1 diabetes and 555 with a first-degree relative with type 1 diabetes. Persistent IA was defined as positive antibodies to insulin, glutamic acid decarboxylase, or tyrosine phosphatase on at least two consecutive study visits. RESULTS: There were 109 children with persistent IA among the 1,729 children with illness records. A greater number of gastrointestinal illnesses were associated with an increased risk of IA, but only among children who were exposed to gluten-containing grains (wheat or barley) either <4 months of age (hazard ratio 1.37 [95% CI 1.22-1.55]; P < 0.0001) or >=7 months of age (1.12 [1.05-1.19]; P = 0.0005) compared with 4-6 months of age (P for interaction = 0.02). There were no associations of upper respiratory symptoms, respiratory illnesses, or fevers with IA. CONCLUSIONS: Specific pathogens such as enteroviruses or rotavirus may increase the risk of IA in the presence of existing inflammation induced by diet. PMID- 23043168 TI - Complete genome of transmissible gastroenteritis virus AYU strain isolated in Shanghai, China. AB - Transmissible gastroenteritis virus strain AYU was isolated in Shanghai. The complete genome has a length of 28,582 bp and contains seven open reading frames. Sequence analysis suggested that Shanghai strain AYU and U.S. strain Purdue P115 are derived from a common ancestor, as they have 99.6% similarity at the nucleotide level. PMID- 23043169 TI - Nine complete genome sequences of cutaneous human papillomavirus genotypes isolated from healthy skin of individuals living in rural He Nan province, China. AB - Nine novel human papillomavirus (HPV) types were isolated from healthy skin of individuals in rural Anyang, China. All of these isolates belong to the genus Gammapapillomavirus. These data will provide us with useful information for a better understanding of PV evolution and the relationship of PV with the host. PMID- 23043170 TI - Complete genome sequence of a J subgroup avian leukosis virus isolated from local commercial broilers. AB - Subgroup J avian leukosis virus (ALV-J) isolate GDKP1202 was isolated from a 50 day-old local yellow commercial broiler in the Guangdong province of China in 2012. Here we report the complete genomic sequence of the GDKP1202 isolate, which caused high mortality, serious growth suppression, thymic atrophy, and liver enlargement in commercial broilers. A novel potential binding site (5'-GGCACCTCC 3') for c-myb was identified in the GDKP1202 genome. These findings will provide additional insights into the molecular characteristics in the genomes and pathogenicity of ALV-J. PMID- 23043171 TI - Complete genome sequence of an H9N2 avian influenza virus isolated from egret in Lake Dongting wetland. AB - We isolated a recombinant H9N2 avian influenza virus (AIV) from fresh egret feces in the Ardeidae protection region of the Dongting Lake wetland area in China, and it was designated A/Egret/Hunan/1/2012(H9N2). This is the first report of isolating H9N2 AIV from wild birds in the Dongting Lake wetland. Its eight gene segments are generated by reassortment of gene segments of different AIV subtypes. These results are helpful for understanding the epidemiology and evolution of AIV in wild birds during migration. PMID- 23043172 TI - Complete genome sequence of Le Blanc virus, a third Caenorhabditis nematode infecting virus. AB - Orsay virus and Santeuil virus, the first known viruses capable of naturally infecting the nematodes Caenorhabditis elegans and Caenorhabditis briggsae, respectively, were recently identified by high-throughput sequencing of wild Caenorhabditis strains. By similar analysis of another wild C. briggsae isolate, we have now discovered and sequenced the complete genome of a third novel virus, Le Blanc virus, that is distantly related to Orsay and Santeuil viruses. All three viruses are positive-sense RNA viruses with bipartite genomes that are most closely related to nodaviruses. Identification of a third virus capable of infecting Caenorhabditis nematodes enables comparative analysis of this clade of viruses and strengthens this model for investigating virus-host interactions. PMID- 23043173 TI - Genome of a Bombyx mori nucleopolyhedrovirus strain isolated from India. AB - Bombyx mori nucleopolyhedrovirus (BmNPV), a member of the Baculoviridae, is a major pathogen of silkworm and has also been recently developed as an expression vector for heterologous gene expression in the silkworm larvae and pupae. To better understand the diversity of this important baculovirus, we sequenced the complete genome of the BmNPV strain isolated from India, where its host is available throughout the year due to its tropical climate. The genome of the Indian strain consists of 127,879 nucleotides, with a G+C content of 40.36%. There are 138 open reading frames (ORFs) encoding the predicted proteins of more than 50 amino acids. Genomic comparison of the Indian strain with 3 other reported BmNPV strains showed that the baculovirus repeat ORFs (bro) and homologous repeat regions (hr's) are highly variable. These results suggest that the BmNPV strain heterogeneity is mainly caused by single-nucleotide polymorphisms (SNPs) and changes in the hr's and bro genes. PMID- 23043175 TI - Complete genome sequence of an H3N2 avian influenza virus isolated from a live poultry market in eastern China. AB - Previous studies indicate that the H3 influenza virus has the ability to establish infection upon interspecies transmission and poses a threat to mammals. Therefore, it is important to enhance the surveillance of H3 avian influenza viruses (AIVs). In this study, A/duck/Shanghai/C84/2009(H3N2) (C84) was isolated from a live poultry market in Shanghai, China. Using PCR and sequencing analyses, we obtained the whole-genome sequence of this virus. The H3N2 virus proved to be a novel multiple-gene reassortant AIV whose genes were derived from H3N2, H4N6, H6N2, and H9N2. Knowledge regarding the complete genome sequence of the C84 virus will be useful for epidemiological surveillance. PMID- 23043174 TI - Complete genome sequence analysis of a natural reassortant infectious bursal disease virus in China. AB - A novel isolate of infectious bursal disease virus (IBDV) was designated GX-NN-L. The GX-NN-L IBDV was a very virulent infectious bursal disease virus (vvIBDV) isolated from broiler flocks in Guangxi province, China, in 2011. The GX-NN-L IBDV caused high mortality, immunosuppression, low weight gain, and bursal atrophy in commercial broilers. Here, we report the complete genome sequence of the GX-NN-L IBDV, a reassortment strain with segments A and B derived from very virulent strains and attenuated IBDV, respectively. These findings from this study provide additional insights into the genetic exchange between attenuated and very virulent strains of IBDV and continuous monitoring of the spread of the virus in chicken. PMID- 23043176 TI - Complete genome sequence of a novel human parechovirus. AB - Human parechoviruses (HPeVs) belonging to the family Picornaviridae are widely spread pathogens among young children. We report the complete genome sequence of a novel HPeV isolated from the stool sample of a hospitalized child with diarrhea in China. The genome consists of 7,305 nucleotides, excluding the 3' poly(A) tail, and has an open reading frame that maps between nucleotide positions 675 and 7217 and encodes a 2,180-amino-acid polyprotein. The genome sequence of the virus was sufficiently distinct from the 8 known HPeV types. Phylogenetic analysis based on the complete genome indicated that the HPeV strain represents a new genotype. PMID- 23043177 TI - Complete genome sequence of the porcine kobuvirus variant CH/HNXX-4/2012. AB - Porcine kobuvirus, an emerging virus, may be the underlying etiological cause of a large-scale outbreak of diarrhea in suckling piglets in China that started in 2010. We report the complete genome sequence of the porcine kobuvirus variant CH/HNXX-4/2012 with a 30-amino-acid deletion in its 2B-coding region that was isolated in this outbreak. This will help the phenotypic variation and evolutionary characteristics of porcine kobuvirus to be understood. PMID- 23043178 TI - Genome of Thysanoplusia orichalcea multiple nucleopolyhedrovirus lacks the superoxide dismutase gene. AB - Thysanoplusia orichalcea multiple nucleopolyhedrovirus (ThorMNPV) has high virulence to Trichoplusia ni and Pseudoplusia includens larvae, with a potential for biological control of insect pests. The genome of ThorMNPV was sequenced and found to be 132,978 bp, with a G+C content of 37.9%. There are 145 predicted open reading frames (ORFs), encoding proteins of 50 or more amino acid residues with minimal overlap. Of the 145 ORFs, 141 appeared to be homologous to those of Autographa californica MNPV (AcMNPV). In comparison to AcMNPV, 9 ORFs of AcMNPV were absent in ThorMNPV, including the superoxide dismutase (sod) gene. PMID- 23043179 TI - Complete genomic sequence of a novel reassortant H11N3 influenza virus isolated from domestic ducks in Jiangsu, China. AB - For the first time we report the complete genomic sequence of an H11N3 influenza virus from domestic ducks in China. Phylogenetic analysis showed that the H11N3 virus was a novel reassortant with its genes from different subtypes of domestic duck-origin avian influenza viruses, which further underlined that domestic ducks play a key role in the genetic reassortment and evolution of influenza viruses in China. PMID- 23043180 TI - Complete genome sequences of a novel reassortant H4N2 avian influenza virus isolated from a live poultry market in eastern China. AB - A/duck/Shanghai/28-1/2009(H4N2) (DK28) was isolated from a live poultry market in Shanghai, China. Using PCR and sequencing analysis, we obtained the complete genome sequences of the DK28 virus. The sequence analysis demonstrated that this H4N2 virus was a novel multiple-gene reassortant avian influenza virus (AIV) whose genes originated from H1N1, H1N3, H3N3, H4N2, and H4N6. Knowledge regarding the complete genome sequences of the DK28 virus will be useful for epidemiological surveillance. PMID- 23043181 TI - Complete genome sequences of highly divergent torque teno virus type I from swine herds. AB - Here, we report three complete genome sequences of porcine torque teno virus type I (TTV1) which were obtained from swine tissues and sera from southern China through routine and nested PCR amplification and characterized together with other genome sequences already deposited in GenBank. The results showed that the TTV1 sequences were highly divergent and could be divided into 1a and 1b subtypes. PMID- 23043182 TI - Protein N-terminal acetyltransferases act as N-terminal propionyltransferases in vitro and in vivo. AB - N-terminal acetylation (Nt-acetylation) is a highly abundant protein modification in eukaryotes catalyzed by N-terminal acetyltransferases (NATs), which transfer an acetyl group from acetyl coenzyme A to the alpha amino group of a nascent polypeptide. Nt-acetylation has emerged as an important protein modifier, steering protein degradation, protein complex formation and protein localization. Very recently, it was reported that some human proteins could carry a propionyl group at their N-terminus. Here, we investigated the generality of N-terminal propionylation by analyzing its proteome-wide occurrence in yeast and we identified 10 unique in vivo Nt-propionylated N-termini. Furthermore, by performing differential N-terminome analysis of a control yeast strain (yNatA), a yeast NatA deletion strain (yNatADelta) or a yeast NatA deletion strain expressing human NatA (hNatA), we were able to demonstrate that in vivo Nt propionylation of several proteins, displaying a NatA type substrate specificity profile, depended on the presence of either yeast or human NatA. Furthermore, in vitro Nt-propionylation assays using synthetic peptides, propionyl coenzyme A, and either purified human NATs or immunoprecipitated human NatA, clearly demonstrated that NATs are Nt-propionyltransferases (NPTs) per se. We here demonstrate for the first time that Nt-propionylation can occur in yeast and thus is an evolutionarily conserved process, and that the NATs are multifunctional enzymes acting as NPTs in vivo and in vitro, in addition to their main role as NATs, and their potential function as lysine acetyltransferases (KATs) and noncatalytic regulators. PMID- 23043183 TI - Metabolism and disposition of vilanterol, a long-acting beta(2)-adrenoceptor agonist for inhalation use in humans. AB - The metabolism and disposition of vilanterol, a novel long-acting beta(2) adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 MUg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 MUg of [(14)C]vilanterol (74 kBq). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 MUg by the inhalation route. At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules--mainly related to the low chemical doses and complications associated with the inhalation route of administration. PMID- 23043184 TI - Interactions between CYP2E1 and CYP2B4: effects on affinity for NADPH-cytochrome P450 reductase and substrate metabolism. AB - Studies in microsomal and reconstituted systems have shown that the presence of one cytochrome P450 isoform can significantly influence the catalytic activity of another isoform. In this study, we assessed whether CYP2E1 could influence the catalytic activity of CYP2B4 under steady-state turnover conditions. The results show that CYP2E1 inhibits CYP2B4-mediated metabolism of benzphetamine (BNZ) with a K(i) of 0.04 uM. However, CYP2B4 is not an inhibitor of CYP2E1-mediated p nitrophenol hydroxylation. When these inhibition studies were performed with the artificial oxidant tert-butyl hydroperoxide, CYP2E1 did not significantly inhibit CYP2B4 activity. Determinations of the apparent K(M) and k(cat) of CYP2B4 for CPR in the presence of increasing concentrations of CYP2E1 revealed a mixed inhibition of CYP2B4 by CYP2E1. At low concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR increased up to 23-fold with virtually no change in the k(cat) for the reaction, however, at higher concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR decreased to levels similar to those observed in the absence of CYP2E1 and the k(cat) also decreased by 11-fold. Additionally, CYP2E1 increased the apparent K(M) of CYP2B4 for BNZ by 8-fold and the apparent K(M) did not decrease to its original value when saturating concentrations of CPR were used. While the individual apparent K(M) values of CYP2B4 and CYP2E1 for CPR are similar, the apparent K(M) of CYP2E1 for CPR in the presence of CYP2B4 decreased significantly, thus suggesting that CYP2B4 enhances the affinity of CYP2E1 for CPR and this may allow CYP2E1 to out-compete CYP2B4 for CPR. PMID- 23043186 TI - The argument for property rights in body parts: scarcity of resources. AB - This article attempts to answer two basic questions. First, can body parts be the subject of property rights? This requires us to start with a definition of property rights, and this is set out in the first section. In the second section, it will be argued that rights in relation to body parts can come within this definition of property rights. However, as explained in the third section, the fact that body parts can be the subject of property rights does not mean that they should. To answer the question of whether body parts should be the subject of property rights we need to consider policy arguments. This article will develop an argument in favour of the recognition of property rights in body parts which focuses on the notion of scarcity of resources. PMID- 23043187 TI - Improving inhaler technique - who needs teaching? PMID- 23043185 TI - Role of nuclear receptors in lipid dysfunction and obesity-related diseases. AB - This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 12 meeting in San Diego, CA. The presentations discussed the roles of a number of nuclear receptors in regulating glucose and lipid homeostasis, the pathophysiology of obesity-related disease states, and the promise associated with targeting their activities to treat these diseases. While many of these receptors (in particular, constitutive androstane receptor and pregnane X receptor) and their target enzymes have been thought of as regulators of drug and xenobiotic metabolism, this symposium highlighted the advances made in our understanding of the endogenous functions of these receptors. Similarly, as we gain a better understanding of the mechanisms underlying bile acid signaling pathways in the regulation of body weight and glucose homeostasis, we see the importance of using complementary approaches to elucidate this fascinating network of pathways. The observation that some receptors, like the farnesoid X receptor, can function in a tissue-specific manner via well defined mechanisms has important clinical implications, particularly in the treatment of liver diseases. Finally, the novel findings that agents that selectively activate estrogen receptor beta can effectively inhibit weight gain in a high-fat diet model of obesity identifies a new role for this member of the steroid superfamily. Taken together, the significant findings reported during this symposium illustrate the promise associated with targeting a number of nuclear receptors for the development of new therapies to treat obesity and other metabolic disorders. PMID- 23043189 TI - Effects of 25-hydroxyvitamin D3 therapy on bone turnover markers and PTH levels in postmenopausal osteoporotic women treated with alendronate. AB - OBJECTIVE: Our objective was to know the extent to which a fall in bone turnover markers is influenced by serum 25-hydroxyvitamin D (25OHD) levels in patients on alendronate (ALN) treatment. DESIGN, PARTICIPANTS, AND SETTING: A total of 140 postmenopausal osteoporotic women were randomized to receive either ALN or ALN plus 25OHD(3) (ALN+VitD) over a 3-month period. Serum 25OHD, PTH, C-terminal telopeptide of type I collagen (CTX), and amino-terminal propeptide of type I collagen (P1NP) were measured at baseline and at the end of the 3 months. RESULTS: 25OHD rose four times above baseline levels in the ALN+VitD group, whereas no changes were seen in the ALN group. Administering ALN resulted in a significant decline in both serum CTX (53 +/- 24%) and P1NP (46 +/- 19%). After ALN+VitD, the fall in CTX amounted to 61 +/- 20% (P = 0.06 compared with ALN) and P1NP to 50 +/- 23% (P = 0.35). When patients were divided into those below and above 20 ng/ml of baseline serum 25OHD, in those below, CTX decreased by 48 +/- 26% in the ALN group and by 61 +/- 17% in the ALN+VitD group (P = 0.015). For P1NP, the corresponding figures were 43 +/- 20 and 50 +/- 23% (P = 0.2). In patients above 20 ng/ml, no differences were seen regarding CTX (58 +/- 21% decrease in the ALN group and 60 +/- 23% in the ALN+VitD group; P = 0.7) or P1NP (49 +/- 18 and 50 +/- 20%; P = 0.9). CONCLUSIONS: Administration of 25OHD(3) is not an indispensable requirement for bisphosphonates to develop their bone antiresorptive effect. In fact, in patients with vitamin D sufficiency, no benefit is observed when the vitamin is added. However, in patients with vitamin D deficiency, an approximately 25% greater fall in the bone resorption marker CTX is seen with its administration. PMID- 23043188 TI - Comparison of detection of normal puberty in boys by a hormonal sleep test and a gonadotropin-releasing hormone agonist test. AB - CONTEXT: The magnitude of sleep-related gonadotropin rise required to activate pubertal gonadal function is not established. OBJECTIVE: Our objective was to determine the normal relationship between sleep-related pubertal hormone levels and pituitary-testicular responsiveness to a GnRH agonist (GnRHag) test across the pubertal transition. DESIGN/SETTING AND PARTICIPANTS: We conducted a prospective study in a General Clinical Research Center with healthy 9- to 15-yr old volunteer boys. INTERVENTIONS: INTERVENTIONS included overnight blood sampling followed by leuprolide acetate injection (10 MUg/kg). PRIMARY OUTCOME VARIABLES: LH, FSH, and testosterone levels were evaluated. RESULTS: LH levels during sleep and post-GnRHag rose steadily during the late prepubertal years. Sleep peak LH correlated highly with the LH response to GnRHag across groups (r = 0.913). A sleep peak LH level of at least 3.7 U/liter predicted pubertal testicular activation with 100% accuracy. LH of at least 14.8 and at least 19.0 U/liter 4 h after GnRHag, respectively, predicted puberty with 100% sensitivity/94% specificity and 100% specificity/94% sensitivity. Overweight pubertal boys had transiently prolonged responses to GnRHag. FSH rose during both waking and sleeping hours during the prepubertal years, and all pubertal boys had an FSH level of at least 0.9 U/liter awake and at least 1.2 U/liter asleep. Sleep LH was more closely related than FSH to testicular size. CONCLUSIONS: These data suggest that a critical LH level during sleep (>=3.7 U/liter) heralds the onset of pubertal virilization and that this level is predictable by LH of at least 14.8-19 U/liter 4 h after GnRHag. These data also suggest that LH stimulation of testicular androgen production plays a role in stimulating testicular tubule growth once a critical level of FSH is achieved. PMID- 23043190 TI - PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance. AB - CONTEXT: Acrodysostosis is a rare skeletal dysplasia that is associated with multiple resistance to G protein-coupled receptor (GPCR) signaling hormones in a subset of patients. Acrodysostosis is genetically heterogeneous because it results from heterozygous mutations in PRKAR1A or PDE4D, two key actors in the GPCR-cAMP-protein kinase A pathway. OBJECTIVE: Our objective was to identify the phenotypic features that distinguish the two genotypes causing acrodysostosis. PATIENTS AND METHODS: Sixteen unrelated patients with acrodysostosis underwent a candidate-gene approach and were investigated for phenotypic features. RESULTS: All patients had heterozygous de novo mutations. Fourteen patients carried a PRKAR1A mutation (PRKAR1A patients), five each a novel PRKAR1A mutation (p.Q285R, p.G289E, p.A328V, p.R335L, or p.Q372X), nine the reported PRKAR1A p.R368X mutation; two patients harbored a mutation in PDE4D (PDE4D patients) (one novel mutation, p.A227S; one reported, p.E590A). All PRKAR1A, but none of the PDE4D mutated patients were resistant to PTH and TSH. Two PRKAR1A patients each with a novel mutation presented a specific pattern of brachydactyly. One PDE4D patient presented with acroskyphodysplasia. Additional phenotypic differences included mental retardation in PDE4D patients. In addition, we report the presence of pigmented skin lesions in PRKAR1A and PDE4D patients, a feature not yet described in the acrodysostosis entity. CONCLUSIONS: All PRKAR1A and PDE4D patients present similar bone dysplasia characterizing acrodysostosis. Phenotypic differences, including the presence of resistance to GPCR-cAMP signaling hormones in PRKAR1A but not PDE4D patients, indicate phenotype-genotype correlations and highlight the specific contributions of PRKAR1A and PDE4D in cAMP signaling in different tissues. PMID- 23043191 TI - A 2011 survey of clinical practice patterns in the management of Graves' disease. AB - CONTEXT: More than two decades have passed since members from the American Thyroid Association (ATA), European Thyroid Association, and Japan Thyroid Association were surveyed on management practices for patients with hyperthyroidism due to Graves' disease (GD). OBJECTIVE: We sought to document current practices in the management of GD and compare these results both to those documented in earlier surveys and to practice recommendations made in the 2011 ATA/American Association of Clinical Endocrinologists (AACE) hyperthyroidism practice guidelines. Lastly, we sought to examine differences in GD management among international members of U.S.-based endocrine societies. METHODS: Members of The Endocrine Society (TES), ATA, and AACE were invited to participate in a web-based survey dealing with testing, treatment preference, and modulating factors in patients with GD. RESULTS: A total of 730 respondents participated in the survey, 696 of whom completed all sections. Respondents included 641 TES members, 330 AACE members, and 157 ATA members. The preferred mode of therapy in uncomplicated GD was antithyroid drugs (ATDs) by 53.9% of respondents, radioactive iodine (RAI) therapy by 45.0%, and thyroid surgery in 0.7%. Compared with 1991, fewer U.S. (59.7 vs. 69%) and European (13.3% vs. 25%) respondents would use RAI therapy. Methimazole and carbimazole were the preferred ATDs, with only 2.7% of respondents selecting propylthiouracil. Patients with Graves' ophthalmopathy were treated with ATDs (62.9%) or surgery (18.5%) and less frequently with RAI plus corticosteroids (16.9%) or RAI alone (1.9%). CONCLUSIONS: Striking changes have occurred in the management of GD over the past two decades, with a shift away from RAI and toward ATDs in patients with uncomplicated GD. Apparent international differences persist but should be interpreted with caution. Current practices diverge in some areas from recently published guidelines; these differences should be assessed serially to determine the impact of the guidelines on future clinical practice. PMID- 23043192 TI - Long-term follow-up of patients with hypoparathyroidism. AB - CONTEXT: Despite tremendous interest in hypoparathyroidism, large cohort studies describing typical treatment patterns, laboratory parameters, and rates of complications are lacking. OBJECTIVE: Our objective was to characterize the course of disease in a large cohort of hypoparathyroid patients. DESIGN AND SETTING: We conducted a chart review of patients with permanent hypoparathyroidism identified via a clinical patient data registry. Patients were seen at a Boston tertiary-care hospital system between 1988 and 2009. PATIENTS: We identified 120 patients. Diagnosis was confirmed by documented hypocalcemia with a simultaneous low or inappropriately normal PTH level for at least 1 yr. Mean age at the end of the observation period was 52 +/- 19 (range 2-87) yr, and the cohort was 73% female. MAIN OUTCOME MEASURE: We evaluated serum and urine laboratory results and renal and brain imaging. RESULTS: We calculated time weighted average serum calcium measurements for all patients. The time-weighted average for calcium was between 7.5 and 9.5 mg/dl for the majority (88%) of patients. Using linear interpolation, we estimated the proportion of time within the target calcium range for each patient with a median of 86% (interquartile range 67-98%). Of those with a 24-h urine collection for calcium (n = 53), 38% had at least one measurement over 300 mg/d. Of those with renal imaging (n = 54), 31% had renal calcifications, and 52% of those with head imaging (n = 31) had basal ganglia calcifications. Rates of chronic kidney disease stage 3 or higher were 2- to 17-fold greater than age-appropriate norms. CONCLUSIONS: Hypoparathyroidism and its treatment carry a large burden of disease. Renal abnormalities are particularly common. PMID- 23043193 TI - Examining the effects of hyperglycemia on pancreatic endocrine function in humans: evidence for in vivo glucotoxicity. AB - CONTEXT: Investigating the impact of hyperglycemia on pancreatic endocrine function promotes our understanding of the pathophysiology of hyperglycemia related disease. OBJECTIVE: The objective of the study was to test the hypothesis that experimental hyperglycemia impairs insulin and glucagon secretion. DESIGN: A randomized, crossover in healthy controls, compared with type 2 diabetic patients. SETTING: The study was conducted at a university hospital. PARTICIPANTS: Normal glucose-tolerant subjects (n = 10) and patients with type 2 diabetes (n = 10), individually matched by age, sex, and body mass index. INTERVENTIONS: Normal glucose-tolerant subjects underwent 24 h of experimental hyperglycemia (+5.4 mm above basal). Subjects with type 2 diabetes did not undergo an intervention. MAIN OUTCOME MEASURES: Insulin secretion, glucagon secretion, insulin sensitivity, disposition index, and endogenous glucose production (via [6,6-(2)H(2)]glucose infusion) were measured during hyperglycemic clamps combined with infusion of glucagon-like peptide (GLP)-1(7-36) (0.5 pmol/kg . min) and injection of arginine (5 g). RESULTS: Insulin secretion was correlated with glucagon suppression in subjects with normal glucose tolerance only. Individuals with type 2 diabetes had lower insulin sensitivity (-33 +/- 11%) and insulin secretory responses to glucose, GLP-1, and arginine (-40 +/- 11, -58 +/- 7, and -36 +/- 13%, respectively) and higher plasma glucagon and endogenous glucose production compared with normal glucose-tolerant subjects (all P < 0.05). After 24 h of experimental hyperglycemia, insulin sensitivity (-29 +/- 10%), disposition index (-24 +/- 16%), and GLP-1- (-19 +/- 7%) and arginine-stimulated (-15 +/- 10%) insulin secretion were decreased in normal glucose-tolerant subjects (all P < 0.05). However, plasma glucagon responses were not affected. Furthermore, experimental hyperglycemia abolished the correlation between insulin secretion and glucagon suppression. CONCLUSIONS: Experimental hyperglycemia impaired pancreatic beta-cell function but did not acutely impair alpha-cell glucagon secretion in normal glucose-tolerant subjects. PMID- 23043194 TI - Approach to the patient with extremely low HDL-cholesterol. AB - Patients with extremely low high-density lipoprotein-cholesterol (HDL-C) pose distinct challenges to clinical diagnosis and management. Confirmation of HDL-C levels below 20 mg/dl in the absence of severe hypertriglyceridemia should be followed by evaluation for secondary causes, such as androgen use, malignancy, and primary monogenic disorders, namely, apolipoprotein A-I mutations, Tangier disease, and lecithin-cholesterol acyltransferase deficiency. Global cardiovascular risk assessment is a critical component of comprehensive evaluation, although the association between extremely low HDL-C levels and atherosclerosis remains unclear. Therapeutic interventions address reversible causes of low HDL-C, multiorgan abnormalities that may accompany primary disorders and cardiovascular risk modification when appropriate. Uncommon encounters with patients exhibiting extremely low HDL-C provide an opportunity to directly observe the role of HDL metabolism in atherosclerosis and beyond the vascular system. PMID- 23043195 TI - Primary aldosteronism: clinical lateralization and costs. PMID- 23043196 TI - Quality of life in adolescent patients with differentiated thyroid cancer: moving beyond survival. PMID- 23043197 TI - Antenatal glucocorticoid treatment: are we doing harm to term babies? PMID- 23043202 TI - Hormone Health Network's patient guide to detecting and treating hypothyroidism before, during, and after pregnancy. PMID- 23043204 TI - COPD may limit your heart function. Restricted air flow forces your heart to work harder, but treatments can ease the burden. PMID- 23043203 TI - Effects of a free school breakfast programme on children's attendance, academic achievement and short-term hunger: results from a stepped-wedge, cluster randomised controlled trial. AB - BACKGROUND: Free school breakfast programmes (SBPs) exist in a number of high income countries, but their effects on educational outcomes have rarely been evaluated in randomised controlled trials. METHODS: A 1-year stepped-wedge, cluster randomised controlled trial was undertaken in 14 New Zealand schools in low socioeconomic resource areas. Participants were 424 children, mean age 9+/-2 years, 53% female. The intervention was a free daily SBP. The primary outcome was children's school attendance. Secondary outcomes were academic achievement, self reported grades, sense of belonging at school, behaviour, short-term hunger, breakfast habits and food security. RESULTS: There was no statistically significant effect of the breakfast programme on children's school attendance. The odds of children achieving an attendance rate <95% was 0.76 (95% CI 0.56 to 1.02) during the intervention phase and 0.93 (95% CI 0.67 to 1.31) during the control phase, giving an OR of 0.81 (95% CI 0.59 to 1.11), p=0.19. There was a significant decrease in children's self-reported short-term hunger during the intervention phase compared with the control phase, demonstrated by an increase of 8.6 units on the Freddy satiety scale (95% CI 3.4 to 13.7, p=0.001). There were no effects of the intervention on any other outcome. CONCLUSIONS: A free SBP did not have a significant effect on children's school attendance or academic achievement but had significant positive effects on children's short-term satiety ratings. More frequent programme attendance may be required to influence school attendance and academic achievement. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR)-ACTRN12609000854235. PMID- 23043205 TI - Study supports early mitral valve repair even if asymptomatic. Research indicates that damage to the heart can begin well before symptoms appear. PMID- 23043206 TI - Positive emotions may protect against heart disease. Research shows that people with feelings of happiness and contentment are less likely to develop heart disease. PMID- 23043207 TI - Consider your needs when choosing a cardiologist. Get recommendations, do a little research and make sure it's a good fit. PMID- 23043208 TI - Share your herbal supplement use with your doctor. Research shows that some popular supplements may be dangerous for people with cardiovascular diseases. PMID- 23043209 TI - I have a friend who was diagnosed with aortic valve stenosis, caused by calcium forming on the valve. I've heard that the condition can also be caused by rheumatic fever, which I had as a child almost 50 years ago. What exactly is aortic valve stenosis, and am I still at risk after all these years (I take medication for cholesterol and arthritis, but am otherwise pretty healthy)? PMID- 23043210 TI - I have had flare-ups of gout, but lately I've read where gout can increase your chances of having a heart attack. What does gout have to do with heart health, and what can I do about it? PMID- 23043211 TI - "Skin failure" as a cause of pressure ulcers: accurate terminology, misnomer, or cop out? PMID- 23043212 TI - Opportunities for mixed-method designs in nursing research. PMID- 23043213 TI - [Four-branch bypass surgery employing a domino patch method using an arterial graft as a free graft]. PMID- 23043214 TI - [Imaging diagnosis Q & A. Saccular aneurysm of the aortic arch]. PMID- 23043215 TI - Microbial reduction of arsenic-doped schwertmannite by Geobacter sulfurreducens. AB - The fate of As(V) during microbial reduction by Geobacter sulfurreducens of Fe(III) in synthetic arsenic-bearing schwertmannites has been investigated. During incubation at pH7, the rate of biological Fe(III) reduction increased with increasing initial arsenic concentration. From schwertmannites with a relatively low arsenic content (<0.3 wt %), only magnetite was formed as a result of dissimilatory iron reduction. However, bioreduction of schwertmannites with higher initial arsenic concentrations (>0.79 wt %) resulted in the formation of goethite. At no stage during the bioreduction process did the concentration of arsenic in solution exceed 120 MUgL(1), even for a schwertmannite with an initial arsenic content of 4.13 wt %. This suggests that the majority of the arsenic is retained in the biominerals or by sorption at the surfaces of newly formed nanoparticles. Subtle differences in the As K-edge XANES spectra obtained from biotransformation products are clearly related to the initial arsenic content of the schwertmannite starting materials. For products obtained from schwertmannites with higher initial As concentrations, one dominant population of As(V) species bonded to only two Fe atoms was evident. By contrast, schwertmannites with relatively low arsenic concentrations gave biotransformation products in which two distinctly different populations of As(V) persisted. The first is the dominant population described above, the second is a minority population characterized by As(V) bonded to four Fe atoms. Both XAS and XMCD evidence suggest that the latter form of arsenic is that taken into the tetrahedral sites of the magnetite. We conclude that the majority population of As(V) is sorbed to the surface of the biotransformation products, whereas the minority population comprises As(V) incorporated into the tetrahedral sites of the biomagnetite. This suggests that microbial reduction of highly bioavailable As(V)-bearing Fe(III) mineral does not necessarily result in the mobilization of the arsenic. PMID- 23043217 TI - ICSI improves fertilization in isolated teratozoospermic men: a study with strictly controlled external factors and WHO-5 standard. AB - A clear clinical management pathway (conventional in vitro fertilization, IVF or intracytoplasmic sperm injection, ICSI) for treating patients with teratozoospermia is lacking. Here we conducted a retrospective study of fertility indices in 2,178 IVF/ICSI cycles in order to reevaluate clinical management of couples with isolated teratozoospermia (< 4% morphologically normal sperms and normal sperm concentration and motility with the standard of WHO-5).We strictly controlled external factors that could affect oocyte quality or endometrial receptivity to minimize the impact of confounders. Fertilization, total fertilization failure, embryo quality, blastocyst formation rate, and pregnancy rate were studied. Retrospectively, in conventional IVF cycles a significantly lower fertilization rate and higher total fertilization failure rate were observed in couples with isolated teratozoospermia as compared to couples with a normal semen profile. Furthermore, when ICSI was used to treat these teratozoospermic couples, improvement in fertilization was noted. However, the embryo quality, blastocyst formation rate, and pregnancy of couples with isolated teratozoospermia were not enhanced by ICSI. Multiple variable analysis showed that many factors including percentage of morphologically normal sperm are statistically correlated with fertilization rate and total fertilization failure in conventional IVF cycles. In addition the insemination method was correlated with fertilization rate in cases with isolated teratozoospermia. Further studies are warranted to compare outcomes of conventional IVF and ICSI in cases of isolated teratozoospermia, where less than 5 oocytes are retrieved. PMID- 23043216 TI - Real-time fluorescent image analysis of DNA spot hybridization kinetics to assess microarray spot heterogeneity. AB - Current microarray assay technology predominately uses fluorescence as a detectable signal end point. This study assessed real-time in situ surface hybridization capture kinetics for single printed DNA microspots on solid array surfaces using fluorescence. The influence of the DNA target and probe cyanine dye position on oligo-DNA duplex formation behavior was compared in solution versus surface-hybridized single DNA printed spots using fluorescence resonance energy transfer (FRET) analysis. Fluorophore Cy3/Cy5 fluorescence intensities were analyzed both through the printed hybridized DNA spot thickness and radially across single-spot surfaces. Confocal single-spot imaging shows that real-time in situ hybridization kinetics with constant target concentrations changes as a function of the printed probe density. Target-specific imaging in single spots exhibits a heterogeneous printed probe radial density that influences hybridization spatially and temporally via radial hemispherical diffusion of dye labeled target from the outside edge of the spot to the interior. FRET of the surface-captured target occurs irrespective of the probe/target fluorophore position, resulting from excess printed probe density and spot thickness. Both heterogeneous probe density distributions in printed spots and the fluorophore position on short DNA oligomers influence duplex formation kinetics, hybridization efficiencies, and overall fluorescence intensity end points in surface-capture formats. This analysis is important to understanding, controlling, and quantifying the array assay signal essential to reliable application of the surface-capture format. PMID- 23043218 TI - Probing the active site chemistry of beta-glucosidases along the hydrolysis reaction pathway. AB - beta-Glucosidases (EC 3.2.1.21) can be found in all domains of living organisms, where they play essential roles in the removal of terminal glucosyl residues from nonreducing ends of saccharides and glycosides. Two active site amino acid residues, a nucleophile and a proton donor, play key roles in the hydrolytic mechanism. Besides these two highly conserved catalytic residues, there are other conserved amino acids in the active site of beta-glucosidases that make direct hydrogen bonds to the glycosyl moiety at the -1 subsite. In this study, the catalytic mechanism of a GH1 beta-glucosidase (BGlu1) is systematically studied. On the basis of the quantum mechanical studies, the side chain of Tyr315 in an interaction with both O5 of the glucose ring and the nucleophilic glutamate contributes significantly to the energy profile. Glu440 and the conserved Asn175 are the other residues in the polar interaction with -1 glucose with considerable influence on the free energy of the reaction. Gln29, His130, and Trp441, which also form hydrogen bonds to the glycosyl moiety, are found to have relatively a minor effect on the reaction. Different arrangements of active site residues in the high-level [quantum mechanics (QM)] and low-level [molecular mechanics (MM)] regions during the hybrid QM/MM calculations indicate that Tyr315 lowers the energy barrier in the deglycosylation step (by 11.95 kcal/mol) while Glu440 mainly reduces the energy barrier of the glycosylation step. Exclusion of either of these two residues from the QM region results in deviation of the geometric parameters of the enzyme-substrate complex from those expected for the preactivated distorted structure of the substrate. PMID- 23043219 TI - Treatment of relapsed myelodysplastic syndrome following double umbilical cord blood transplantation with interferon alpha and 5-azacytidine. PMID- 23043220 TI - Neonatal outcomes in pregnancies after bariatric surgery: a retrospective multi centric cohort study in three French referral centers. AB - OBJECTIVE: To analyze short-term neonatal outcomes in pregnancies after bariatric surgery according to procedure, to the body mass index (BMI) at the beginning of the pregnancy and to the interval from surgery to conception, using a retrospective multi-centric cohort study in three French tertiary perinatal care and bariatric centers. METHODS: 94 neonates in 79 women were included. Frequencies of adverse neonatal events by procedure, laparoscopic adjustable gastric banding (LAGB, n = 63) or Roux-en-Y gastric bypass (RYGB, n = 31), BMI class (72 women with BMI >= 30 kg/m(2)) and interval between surgery and conception (43 deliveries of patients who conceived during the first postoperative year) were compared with chi(2) tests. For parametric continuous data, t-tests or analysis of variance were used; non-parametric distributions were compared with the Wilcoxon or Kruskal-Wallis tests. RESULTS: Significantly lower mean birth weight (2993 g vs. 3253 g; p = 0.02) was observed after RYGB and the mean Z-score for birth weight was significantly closer to 0 in neonates of the LAGB group than in those of the RYGB group. However, no significant differences were noticed regarding small-for-gestational age (32.3% vs. 17.1%; p = 0.06), umbilical arterial blood pH < 7.0 (9.7% vs. 0%; p = 0.11), low Apgar scores, perinatal mortality, and NICU admission. Neonatal outcomes according to the interval from surgery to conception or to the BMI at the beginning of the pregnancy were not significantly different. CONCLUSIONS: The short-term neonatal outcomes are basically comparable in pregnancies after RYGB than after LAGB. PMID- 23043221 TI - Temperature-dependent, behavioural, and transcriptional variability of a tritrophic interaction consisting of bean, herbivorous mite, and predator. AB - Different organisms compensate for, and adapt to, environmental changes in different ways. In this way, environmental changes affect animal-plant interactions. In this study, we assessed the effect of temperature on a tritrophic system of the lima bean, the herbivorous spider mite Tetranychus urticae and the predatory mite Phytoseiulus persimilis. In this system, the plant defends itself against T. urticae by emitting volatiles that attract P. persimilis. Over 20-40 degrees C, the emission of volatiles by infested plants and the subsequent attraction of P. persimilis peaked at 30 degrees C, but the number of eggs laid by T. urticae adults and the number of eggs consumed by P. persimilis peaked at 35 degrees C. This indicates that the spider mites and predatory mites performed best at a higher temperature than that at which most volatile attractants were produced. Our data from transcriptome pyrosequencing of the mites found that P. persimilis up-regulated gene families for heat shock proteins (HSPs) and ubiquitin-associated proteins, whereas T. urticae did not. RNA interference-mediated gene suppression in P. persimilis revealed differences in temperature responses. Predation on T. urticae eggs by P. persimilis that had been fed PpHsp70-1 dsRNA was low at 35 degrees C but not at 25 degrees C when PpHsp70-1 expression was very high. Overall, our molecular and behavioural approaches revealed that the mode and tolerance of lima bean, T. urticae and P. persimilis are distinctly affected by temperature variability, thereby making their tritrophic interactions temperature dependent. PMID- 23043223 TI - African culturally and linguistically diverse communities' blood donation intentions in Australia: integrating knowledge into the theory of planned behavior. AB - BACKGROUND: The Theory of Planned Behavior (TPB) has been extensively used to examine donation intentions in the general community. This research seeks to examine whether TPB applies to one culturally and linguistically diverse (CALD) community in Australia and also incorporates blood donation knowledge as an antecedent in the model, given that the TPB assumes people make informed decisions regarding blood donation. STUDY DESIGN AND METHODS: A cross-section of 425 members of African CALD communities was surveyed face to face using bilingual workers, ensuring inclusion across literacy levels within the CALD community. Constructs used within the survey were drawn from the TPB blood donation literature (i.e., attitudes, social norms, and self-efficacy). A new measure of blood donation knowledge was included. RESULTS: Structural equation modeling found that the Basic TPB model did not hold for African CALD communities in Australia. The Basic TPB model was modified and within this Adapted TPB model attitudes were found not to impact intentions directly, but had a mediating effect through self-efficacy. An Extended TPB model including overall knowledge was then tested and improved the model fit statistics, explaining 59.8% variation in intentions. Overall knowledge was found to indirectly impact intentions, through self-efficacy, social norms, and attitudes. CONCLUSION: The TPB applies differently when examining African CALD communities' blood donation intentions in Australia. Knowledge is an important mediating component of the Extended TPB model rather than directly affecting intentions. Addressing CALD communities' psychographic characteristics may assist blood services in developing targeted strategies to increase donations within these communities. PMID- 23043222 TI - Identification and characterization of carprofen as a multitarget fatty acid amide hydrolase/cyclooxygenase inhibitor. AB - Pain and inflammation are major therapeutic areas for drug discovery. Current drugs for these pathologies have limited efficacy, however, and often cause a number of unwanted side effects. In the present study, we identify the nonsteroidal anti-inflammatory drug carprofen as a multitarget-directed ligand that simultaneously inhibits cyclooxygenase-1 (COX-1), COX-2, and fatty acid amide hydrolase (FAAH). Additionally, we synthesized and tested several derivatives of carprofen, sharing this multitarget activity. This may result in improved analgesic efficacy and reduced side effects (Naidu et al. J. Pharmacol. Exp. Ther.2009, 329, 48-56; Fowler, C. J.; et al. J. Enzyme Inhib. Med. Chem.2012, in press; Sasso et al. Pharmacol. Res.2012, 65, 553). The new compounds are among the most potent multitarget FAAH/COX inhibitors reported so far in the literature and thus may represent promising starting points for the discovery of new analgesic and anti-inflammatory drugs. PMID- 23043224 TI - Safety and feasibility of outpatient percutaneous native kidney biopsy in the developing world: experience in a large tertiary care centre in Eastern India. AB - AIM: Optimal time of observation following percutaneous biopsy has not been clearly established. Outpatient biopsy protocol was established in our centre for low risk patients and we assessed its efficacy and safety. METHODS: Patients fulfilling the low risk profile underwent a real time ultrasound-guided percutaneous native kidney biopsy. They were observed for 6 h and any complication was recorded. Ultrasound and hematocrit was done only in those patients with complications. Patients were contacted on telephone after 24 h and in case of any emergency. RESULTS: A total of 403 native kidney biopsies were performed from June 2011 to June 2012 of which 115 (28.5%) were on an outpatient basis. This was a 41.4% increase in the number of biopsies compared to the same period in the previous year. Fifteen patients (13.04%) had macroscopic haematuria within 2, 4 and 6 h in eight (53.33%), six (40%) and one (6.67%) patient, respectively. One of them had haematuria on follow-up phone call resolving without intervention. Only two (1.74%) patients developed significant bleeding with a drop in haematocrit needing overnight observation, with one requiring blood transfusion (with perinephric haematoma not requiring intervention). Complication rates were also similar in the 288 patients who had at least an overnight inpatient observation post-biopsy. There was no biopsy related mortality. CONCLUSIONS: Percutaneous native kidney biopsies can be safely performed on an outpatient basis in selected low risk patients. This approach increases the number of procedures, decreases the waiting periods and can have potential cost savings making it an attractive option in the developing world. PMID- 23043225 TI - Assessment of glutathione levels in model solution and grape ferments supplemented with glutathione-enriched inactive dry yeast preparations using a novel UPLC-MS/MS method. AB - A novel, robust and fast ultra-high performance liquid chromatography-MS method has been developed for the simultaneous quantification of reduced glutathione (GSH) and oxidised glutathione (GSSG) in grape juice, wine and model wine solution. Sample preparation is minimal and does not require derivatisation. The method has very good performance in terms of sensitivity and selectivity. The limit of detection was 0.002 and 0.001 mg L(-1) for GSH and GSSG, respectively. The amount of GSH and GSSG released by commercial glutathione-enriched inactivated dry yeast preparations (GSH-IDYs) into a model solution was assessed. Significant differences in the amount of GSH and/or GSSG released into a model wine by different GSH-IDYs were observed, with ethanol influencing this release under certain conditions. The GSH and GSSG levels in grape juice fermentations supplemented with GSH-IDY were also assessed in relation to different addition times during fermentation. GSH-IDY addition can lead to elevated wine GSH levels, provided the supplementation is done early during alcoholic fermentation. PMID- 23043227 TI - Increased coagulation in childhood obesity. AB - OBJECTIVE: This study aims to explore the relation between childhood obesity and procoagulant and anticoagulant systems. METHOD: Fifty-one obese children and 32 normal-weighted children with similar age and gender distribution and between ages of 5 and 16 years were recruited to the study. Antropometric measures of all subjects, existence of any accompanying disease, and medication histories had been recorded. Full blood count, procoagulant, and anticoagulant coagulation tests were run for all subjects. RESULTS: When hematologic variables of obese children were compared with those of healthy controls, it was found that average erythrocyte hemoglobin concentration, erythrocyte distribution width, and platelet count of obese children are significantly higher than healthy control group. It was also found that fibrinogen, thrombin time, factor (F) VIII, FIX, FX, and von Willebrand factor levels of obese children are higher than healthy control group. By contrast, antithrombin levels of obese children are found to be lower. CONCLUSION: In our study, we found that there is a procoagulant increase in the coagulation system activity of obese children compared to non-obese healthy children, whereas there is a significant decrease in anticoagulant system. These changes occurred in obese patients, especially higher levels of plasma procoagulant factors such as fibrinogen, FVIII, FIX, and von Willebrand factor, lead us to think that there is an activity in these patients at endothelial level. Further studies are needed on endothelial activity of obese children. PMID- 23043226 TI - Effects of MU-opioid receptor modulation on the hippocampal network activity of sharp wave and ripples. AB - BACKGROUND AND PURPOSE: Hippocampus-dependent memory involves the activity of sharp wave ripples (SWRs), which are thought to participate in the process of memory consolidation. The hippocampus contains high levels of endogenous opioids and of MU-opioid receptors (MORs). Here, we have assessed the role of MOR agonists in the modulation of SWRs. EXPERIMENTAL APPROACH: Using recordings of extracellular potentials from the CA1 field of rat hippocampal slices, we examined the pharmacological actions of morphine, DAMGO and fentanyl on SWRs and on network excitability and paired-pulse inhibition. KEY RESULTS: All three MOR agonists (1 nM-10 MUM) significantly increased the amplitude of sharp waves and the occurrence of SWR sequences, but reduced the initiation of episodes of SWRs. Fentanyl was most potent in producing these effects and morphine the least. Interestingly, although SWRs were reduced by relatively high concentrations (>=100 nM) of all agonists, they were significantly enhanced by very low concentrations of morphine (5-10 nM). Morphine and DAMGO at moderate-to-high concentrations increased network excitability and reduced inhibition. Furthermore, DAMGO suppressed inhibition more readily than it increased excitation, whereas morphine suppressed inhibition only at high concentrations. These drug effects were reversed by the MOR antagonists naloxone and CTOP. CONCLUSIONS AND IMPLICATIONS: We found that the SWRs were significantly modulated by three MOR agonists and that the SWRs were very sensitive to subtle changes in the excitation/inhibition balance induced by MOR agonists. Such modulation might underlie the effects of these agonists on hippocampus-dependent memory. PMID- 23043228 TI - Structure-function analysis indicates that sumoylation modulates DNA-binding activity of STAT1. AB - BACKGROUND: STAT1 is an essential transcription factor for interferon-gamma mediated gene responses. A distinct sumoylation consensus site (psiKxE) 702IKTE705 is localized in the C-terminal region of STAT1, where Lys703 is a target for PIAS-induced SUMO modification. Several studies indicate that sumoylation has an inhibitory role on STAT1-mediated gene expression but the molecular mechanisms are not fully understood. RESULTS: Here, we have performed a structural and functional analysis of sumoylation in STAT1. We show that deconjugation of SUMO by SENP1 enhances the transcriptional activity of STAT1, confirming a negative regulatory effect of sumoylation on STAT1 activity. Inspection of molecular model indicated that consensus site is well exposed to SUMO-conjugation in STAT1 homodimer and that the conjugated SUMO moiety is directed towards DNA, thus able to form a sterical hindrance affecting promoter binding of dimeric STAT1. In addition, oligoprecipitation experiments indicated that sumoylation deficient STAT1 E705Q mutant has higher DNA-binding activity on STAT1 responsive gene promoters than wild-type STAT1. Furthermore, sumoylation deficient STAT1 E705Q mutant displayed enhanced histone H4 acetylation on interferon-gamma-responsive promoter compared to wild-type STAT1. CONCLUSIONS: Our results suggest that sumoylation participates in regulation of STAT1 responses by modulating DNA-binding properties of STAT1. PMID- 23043231 TI - Iranian cancer patients' perception of spirituality: a qualitative content analysis study. AB - BACKGROUND: Spirituality is a subjective and multi-dimensional concept. The ambiguity in its meaning can create barriers in its application in both education and medicine. The present study aimed to explore the Iranian cancer patients' perception of spirituality. METHODS: A qualitative study, using the content analysis approach, was conducted. Semi-structured interviews were held with 11 cancer patients and six members of their families in one of Tehran's hospitals and a charity institute. The data generated were transcribed verbatim and content analysis approach was used for data reduction, naming data, obtaining analytical code and determining categories and themes. RESULTS: Three themes (and seven sub themes) emerged from the data analysis: 1) God as the spiritual truth (relationship with God and trust in God), 2) Moralities as a spiritual sign (considering personal and social moral codes) and 3) Spiritual resources as the source of hope (religious, personal and social resources). CONCLUSIONS: Overall, in the view of cancer patients, spirituality can be defined in a religious context. However, some of them believe in morality beside religiosity, so health care staff must pay due attention to these aspects, to provide them with the opportunity to use spiritual resources. PMID- 23043229 TI - Pro-inflammatory cytokines and bone fractures in CKD patients. An exploratory single centre study. AB - BACKGROUND: Pro-inflammatory cytokines play a key role in bone remodeling. Inflammation is highly prevalent in CKD-5D patients, but the relationship between pro-inflammatory cytokines and fractures in CKD-5D patients is unclear. We studied the relationship between inflammatory cytokines and incident bone fractures in a cohort of CKD-5D patients. METHODS: In 100 CKD-5D patients (66 on HD, 34 on CAPD; males:63, females:37; mean age: 61 +/- 15; median dialysis vintage: 43 months) belonging to a single renal Unit, we measured at enrolment bone metabolic parameters (intact PTH, bone and total alkaline phosphatase, calcium, phosphate) and inflammatory cytokines (TNF-alpha, IL-6, CRP). Patients were followed-up until the first non traumatic fracture. RESULTS: During follow up (median: 74 months; range 0.5 -84.0) 18 patients experienced fractures. On categorical analysis these patients compared to those without fractures had significantly higher intact PTH (median: 319 pg/ml IQ range: 95-741 vs 135 pg/ml IQ: 53-346; p = 0.04) and TNF-alpha levels (median: 12 pg/ml IQ: 6.4-13.4 vs 7.8 pg/ml IQ: 4.6-11; p = 0.02). Both TNF-alpha (HR for 5 pg/ml increase in TNF alpha: 1.62 95% CI: 1.05-2.50; p = 0.03) and intact PTH (HR for 100 pg/ml increase in PTH: 1.15 95% CI: 1.04-1.27; p = 0.005) predicted bone fractures on univariate Cox's regression analysis. In restricted (bivariate) models adjusting for previous fractures, age, sex and other risk factors both PTH and TNF-alpha maintained an independent association with incident fractures. CONCLUSIONS: In our bivariate analyses TNF-alpha was significantly associated with incident fractures. Analyses in larger cohorts and with adequate number of events are needed to firmly establish the TNF alpha -fracture link emerged in the present study. PMID- 23043232 TI - Catalytic functionalization of methyl group on silicon: iridium-catalyzed C(sp3) H borylation of methylchlorosilanes. AB - A methyl group of methylchlorosilanes undergoes C-H borylation in an iridium catalyzed reaction with bis(pinacolato)diboron in cyclohexane at 80 degrees C, giving (borylmethyl)chlorosilanes selectively. PMID- 23043233 TI - Humalog (lispro) for type 2 diabetes. AB - INTRODUCTION: Type 2 diabetes is a chronic and progressive disease, and ultimately, most patients will require insulin therapy for the optimization of their glycemic control. AREAS COVERED: We review the recent literature investigating the efficacy and safety of the insulin analogue lispro in type 2 diabetes. Relevant publications were identified by means of a PubMed literature search in the period January 1990 to May 2012. We included randomized controlled trials (RCTs), which included at least one arm evaluating insulin lispro in type 2 diabetes. EXPERT OPINION: Insulin is the most effective therapy for reducing hyperglycemia: when the desired decrease of HbA1c is >= 1.5%, it is unlikely than any other antidiabetes drug may work as better as insulin. The pharmacodynamic and pharmacokinetic profiles of lispro analogues offer discrete advantage over human insulin. The preliminary results of comparative RCTs versus insulin glargine or insulin detemir indicate that insulin lispro protamine suspension (ILPS) has a similar effect on glucose control and the risk of hypoglycemia while using lower doses when injected once a day. Lispro/ILPS premixed formulations can be injected immediately before a meal because they are absorbed more rapidly than premixed human insulin, thus allowing more flexibility with insulin therapy. PMID- 23043234 TI - Epidemiology of candidemia in patients with hematologic malignancies and solid tumours in Brazil. AB - Candidemia in cancer patients may differ according to the type of cancer. To characterise the epidemiology and outcome of candidemia in cancer patients from Brazilian hospitals, we compared the characteristics of patients with hematologic malignancies (HM) and solid tumours (ST). A retrospective study was performed, based on data collected from laboratory-based surveillance studies in 18 tertiary care hospitals between March/2003 and December/2007. The characteristics of patients with HM (n = 117) were compared with patients with ST (n = 248). Predictors of 30-day mortality were identified by uni- and multivariate analyses. Candidemia in HM was more likely to occur in the setting of chemotherapy, corticosteroids, neutropenia, mucositis and tunnelled central venous catheter (CVC), whereas surgery, intensive care unit admission and invasive procedures (mechanical ventilation, parenteral nutrition and CVC) were more frequent in ST. The 30-day mortality rate was higher in the ST group (65% vs. 46%, P = 0.001). Factors significantly associated with 30-day mortality were older age and intensive care unit admission. Important differences in the epidemiology and outcome of candidemia in HM and ST were observed. The characterisation of the epidemiology is important to drive preventive measures and to select appropriate therapies. PMID- 23043237 TI - Loss of nuclear flavanols during drought periods in Taxus baccata. AB - Normally, needles of Taxus baccata during the growth period prominently stain blue for nuclear flavanols with the histochemical DMACA procedure. However, under excess heat and drought conditions, nuclear flavanols of current-year needles decline to zero. Nevertheless, greenish-yellow-coloured flavonols (quercetin derivatives) were still observed in nuclei. All of these yellow nuclei were in a silenced state and without mitosis. This link between drought and loss of nuclear flavanols was found in 3 years, 2003, 2007 and 2010. In 2007, exceptional drought occurred in early spring, interrupted by short rains. This, in turn, led to flushing of new sprouts, a characteristic feature in which nuclei were overloaded with flavanols. By the end of three drought periods, all nuclei developed blue coloured nuclear flavanols. The flavanols seem to be associated with the histone proteins of chromatin. The oxidative degradation of catechin in Tris buffer (pH 8.0) containing MgCl2 was studied in the presence of the H4-core fragment TYTEHAKRKTVTAMD, modified according to the epigenetic histone code. The results show that catechin degradation can be significantly inhibited by the non-modified peptides and the methylated peptides (methylation at both lysine residues). The acetylated and formylated peptides do not show this behaviour. These observations indicate that flavanol association at chromosomes appears to be regulated by the epigenetic histone code. PMID- 23043238 TI - Comment on "Review of methane mitigation technologies with application to rapid release of methane from the Arctic". PMID- 23043239 TI - Identification of nitrogen defects in diamond with photoluminescence excited in the 160-240 nm region. AB - Photoluminescence (PL) spectra of natural diamond powders of type IaAB at 300 and 13 K were excited with synchrotron radiation in the wavelength range of 150-260 nm. The spectral features observed in the excitation spectra at 13 K show four vibrational progressions related to nitrogen defects in diamond: A, B, B', and N3. Progression A has a spacing of 1258 +/- 40 cm(-1), associated with the N2 (or A) center; progression B has a spacing of 1181 +/- 40 cm(-1) and progression B' has a spacing of 744 +/- 40 cm(-1) related to the N4 (or B) center; and progression N3 has a spacing of 1417 +/- 40 cm(-1) associated with the N3 center. The PL of these defects comprise continuous emission with two broad lines with maxima of ~420 and 469 nm at 300 K. Upon excitation with light at wavelengths of <200 nm, the distinct zero-phonon lines of N3 and N4 centers in diamond at a temperature of 13 K become prominent at 416.0 and 491.2 nm, respectively. The vibrational progressions in the photoluminescence excitation (PLE) spectra of N2, N3, and N4 centers in diamond of type IaAB at 13 K are identified for the first time. We suggest the use of PL spectra excited in the region of 160-240 nm to analyze and identify the type of diamond. PMID- 23043241 TI - Mechanism-based small molecule cross-linkers of HECT E3 ubiquitin ligase substrate pairs. AB - Here we report the discovery that bifunctional thiol- and amine-reactive electrophiles serve as mechanism-based covalent cross-linkers for HECT E3 ubiquitin ligase-substrate pairs. We demonstrate that these chemical cross linkers covalently cross-link the catalytic Cys residue of the yeast HECT E3 ubiquitin ligase Rsp5 with the Lys of the ubiquitination site in the model substrate Sic60-GFP. This work represents the first example of a mechanism-based covalent cross-link of HECT E3-substrate pairs that converts transiently interacting HECT E3-substrate pairs into stable, covalently cross-linked protein complexes, thereby facilitating their subsequent isolation, identification, and study. PMID- 23043240 TI - Synthesis and in vivo pharmacokinetic evaluation of degradable shell cross-linked polymer nanoparticles with poly(carboxybetaine) versus poly(ethylene glycol) surface-grafted coatings. AB - Nanoparticles with tunable pharmacokinetics are desirable for various biomedical applications. Poly(ethylene glycol) (PEG) is well-known to create "stealth" effects to stabilize and extend the blood circulation of nanoparticles. In this work, poly(carboxybetaine) (PCB), a new nonfouling polymer material, was incorporated as surface-grafted coatings, conjugated onto degradable shell cross linked knedel-like nanoparticles (dSCKs) composed of poly(acrylic acid)-based shells and poly(lactic acid) cores, to compare the in vivo pharmacokinetics to their PEG-functionalized analogues. A series of five dSCKs was prepared from amphiphilic block copolymers, having different numbers and lengths of either PEG or PCB grafts, by supramolecular assembly in water followed by shell cross linking, and then studied by a lactate assay to confirm their core hydrolytic degradabilities. Each dSCK was also conjugated with 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid macrocyclic chelators and tyramine moieties to provide for (64)Cu and/or radiohalogen labeling. The high specific activity of (64)Cu radiolabeling ensured nanogram administration of dSCKs for in vivo evaluation of their pharmacokinetics. Biodistribution studies demonstrated comparable in vivo pharmacokinetic profiles of PCB-grafted dSCKs to their PEG-conjugated counterparts. These results indicated that PCB functionalized dSCKs have great potential as a theranostic platform for translational research. PMID- 23043242 TI - Influence of chlorine or fluorine substitution on the estrogenic properties of 1 alkyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrroles. AB - In continuation of our previous work, several 1-alkyl-2,3,5-tris(4 hydroxyphenyl)aryl-1H-pyrroles with chlorine or fluorine substituents in the aryl residues were synthesized and tested for estrogen receptor (ER) binding at isolated ERalpha/ERbeta receptors (HAP assay) and in transactivation assays using ERalpha-positive MCF-7/2a as well as U2-OS/ERalpha and U2-OS/ERbeta cells. In the competition experiment at ERalpha the compounds displayed very high relative binding affinities of up to 37% (determined for 8m) but with restricted subtype selectivity (e.g., ERalpha/ERbeta (8m) = 9). The highest estrogenic potency in ERalpha-positive MCF-7/2a cells was determined for 2,3,5-tris(2-fluoro-4 hydroxyphenyl)-1-propyl-1H-pyrrole 8m (EC(50) = 23 nM), while in U2-OS/ERalpha cells 2-(2-fluoro-4-hydroxyphenyl)-3,5-bis(4-hydroxyphenyl)-1-propyl-1H-pyrrole 8b (EC(50) = 0.12 nM) was the most potent agonist, only 30-fold less active than estradiol (E2, EC(50) = 0.004 nM). In U2-OS/ERbeta cells for all pyrroles no transactivation could be observed, which indicates that they are selective ERalpha agonists in cellular systems. PMID- 23043243 TI - Single InAs/GaSb nanowire low-power CMOS inverter. AB - III-V semiconductors have so far predominately been employed for n-type transistors in high-frequency applications. This development is based on the advantageous transport properties and the large variety of heterostructure combinations in the family of III-V semiconductors. In contrast, reports on p type devices with high hole mobility suitable for complementary metal-oxide semiconductor (CMOS) circuits for low-power operation are scarce. In addition, the difficulty to integrate both n- and p-type devices on the same substrate without the use of complex buffer layers has hampered the development of III-V based digital logic. Here, inverters fabricated from single n-InAs/p-GaSb heterostructure nanowires are demonstrated in a simple processing scheme. Using undoped segments and aggressively scaled high-kappa dielectric, enhancement mode operation suitable for digital logic is obtained for both types of transistors. State-of-the-art on- and off-state characteristics are obtained and the individual long-channel n- and p-type transistors exhibit minimum subthreshold swings of SS = 98 mV/dec and SS = 400 mV/dec, respectively, at V(ds) = 0.5 V. Inverter characteristics display a full signal swing and maximum gain of 10.5 with a small device-to-device variability. Complete inversion is measured at low frequencies although large parasitic capacitances deform the waveform at higher frequencies. PMID- 23043244 TI - The association between orthodontic treatment with removal of premolars and the angulation of developing mandibular third molars over time. AB - OBJECTIVE: To assess changes in mandibular third molar angulation during orthodontic treatment in subjects having either first or second premolars or neither removed. MATERIALS AND METHODS: In a retrospective study approved by the institutional review board, right and left mandibular third molar angulations were compared to the vertical axis of adjacent second molars before and at the end of orthodontic treatment. The sample included 25 subjects with first premolars removed, 25 subjects with second premolars removed, and 24 subjects with no premolars removed. A decrease in angulation over time of at least 5 degrees , so that the third molar became more vertical, was considered clinically favorable. Data were assessed by a linear mixed effect model and a proportional odds model with significance set at P < .05. RESULTS: Prior to treatment, the average mandibular third molar angulation did not differ significantly among the three study groups (P = .97). The average change during treatment was not significantly affected by group (P = .59), but a higher proportion of mandibular third molars were more vertical by at least 5 degrees in the second premolar extraction group compared to the other two groups at the completion of treatment. CONCLUSION: Although creating space for third molars to erupt and function has intuitive appeal, clinicians should not assume that third molars will move upright to a vertical position even if premolar removal is performed as part of an orthodontic treatment plan. PMID- 23043245 TI - Factors related to alveolar bone thickness during upper incisor retraction. AB - OBJECTIVE: To investigate the factors related to changes in alveolar bone thickness during upper incisor retraction. MATERIALS AND METHODS: The subjects consisted of 23 ongoing orthodontic patients (mean age 20.4 +/- 2.7 years) whose upper incisors were bound for retraction. Changes in alveolar bone thickness in the retracted area were assessed using preretraction (T0) and postretraction (T1) cone-beam computed tomography images. Labial bone thickness (LBT), palatal bone thickness (PBT), and total bone thickness (TBT) were assessed at the crestal, midroot, and apical levels of the retracted incisors. Paired t-tests were used to compare T0 and T1 bone thickness measurements. Spearman's rank correlation analysis was performed to determine the relationship of changes in alveolar bone thickness with the rate of tooth movement, change in inclination, initial alveolar bone thickness, and the extent of intrusion. RESULTS: As the upper incisors were retracted, the LBT at the crestal level and TBT at the apical level significantly increased (P < .005). Changes in alveolar bone thickness were significantly associated with the rate of tooth movement, change in inclination, and extent of intrusion (P < .05) but not initial alveolar bone thickness (P > .05). CONCLUSION: Rate of tooth movement, change in inclination, and extent of intrusion are significant factors that may influence alveolar bone thickness during upper incisor retraction. These factors must be carefully monitored to avoid the undesirable thickening of alveolar bone. PMID- 23043246 TI - 6,6-Dicyanopentafulvenes: electronic structure and regioselectivity in [2 + 2] cycloaddition-retroelectrocyclization reactions. AB - We present an investigation of the electronic properties and reactivity behavior of electron-accepting 6,6-dicyanopentafulvenes (DCFs). The electron paramagnetic resonance (EPR) spectra of the radical anion of a tetrakis(silylalkynyl) DCF, generated by Na metal reduction, show delocalization of both the charge and unpaired electron to the nitrogens of the cyano moieties and also, notably, to the silicon atoms of the four alkynyl moieties. By contrast, in the radical anion of the previously reported tetraphenyl DCF, coupling to the four phenyl rings is strongly attenuated. The data provide physical evidence for the different conjugation between the DCF core and the substituents in both systems. We also report the preparation of new fulvene-based push-pull chromophores via formal [2 + 2] cycloaddition-retroelectrocyclization reaction of DCFs with electron-rich alkynes. Alkynylated and phenylated DCFs show opposite regioselectivity of the cycloaddition, which can be explained by the differences in electronic communication between substituents and the DCF core as revealed in the EPR spectra of the radical anions. PMID- 23043247 TI - Rapid onsite evaluation improves the adequacy of fine-needle aspiration for thyroid lesions: a systematic review and meta-analysis. AB - BACKGROUND: Fine-needle aspiration (FNA) with ultrasonography guidance is one of the optimal techniques for the diagnostic evaluation of thyroid nodules. A significant subset of thyroid FNAs continues to be inadequate for interpretation, which potentially leads to increased costs from repeat aspirations. Numerous studies have been published regarding the influence of rapid onsite evaluation (ROSE) by cytopathologists on thyroid FNAs, some indicating that FNA is more likely to be adequate for interpretation with ROSE, while others refute this idea. To our knowledge, no meta-analysis of the literature on this subject has been undertaken. METHODS: We searched MEDLINE and EMBASE using the following search string: (needle biopsy) AND (assessment or onsite OR onsite or immediate or rapid)/title or abstract. There were no restrictions on study design, language, anatomic site, or time period. Only studies comparing two arms (with/without ROSE) at a single site were eligible for inclusion. Potentially relevant studies were subjected to a citation search (forward search) and reference search (backward search) using SCOPUS. Statistical calculations were performed using Stata Release 12. Meta-analysis was completed using a random effect model as implemented in the metan routine in Stata. RESULTS: An initial search obtained 2179 studies from MEDLINE and EMBASE, and screening yielded 71 potentially relevant studies. A focused review of this subset resulted in seven full studies and one abstract that met our inclusion criteria. Our citation search using SCOPUS yielded no new studies. Overall, the average adequacy rate was 83% without ROSE compared to 92% with ROSE. Visual inspection of the data suggested that the improvement in adequacy due to ROSE may be related to the adequacy rate without ROSE. Metaregression analysis showed that the change in the adequacy rate was strongly correlated (t=-12.7, p<0.001) with the non-ROSE adequacy rate. In addition, the non-ROSE adequacy rate explained all, but 10% of the residual between study variability in the change in the adequacy rates due to ROSE. CONCLUSIONS: ROSE is generally associated with an improvement in adequacy, but the impact of ROSE depends heavily on the initial adequacy rate. Sites with lower initial adequacy rates can benefit the most from the implementation of ROSE. PMID- 23043248 TI - Estrogen and cancer. AB - Estrogen exhibits a broad spectrum of physiological functions ranging from regulation of the menstrual cycle and reproduction to modulation of bone density, brain function, and cholesterol mobilization. Despite the beneficial actions of endogenous estrogen, sustained exposure to exogenous estrogen is a well established risk factor for various cancers. We summarize our current understanding of the molecular mechanisms of estrogen signaling in normal and cancer cells and discuss the major challenges to existing antiestrogen therapies. PMID- 23043249 TI - Platelets in lung biology. AB - Platelets and the lungs have an intimate relationship. Platelets are anucleate mammalian blood cells that continuously circulate through pulmonary vessels and that have major effector activities in hemostasis and inflammation. The lungs are reservoirs for megakaryocytes, the requisite precursor cell in thrombopoiesis, which is the intricate process by which platelets are generated. Platelets contribute to basal barrier integrity of the alveolar capillaries, which selectively restricts the transfer of water, proteins, and red blood cells out of the vessels. Platelets also contribute to pulmonary vascular repair. Although platelets bolster hemostatic and inflammatory defense of the healthy lung, experimental evidence and clinical evidence indicate that these blood cells are effectors of injury in a variety of pulmonary disorders and syndromes. Newly discovered biological capacities of platelets are being explored in the context of lung defense, disease, and remodeling. PMID- 23043251 TI - Translating research into practice: an epilogue. PMID- 23043250 TI - Metabolic and neuropsychiatric effects of calorie restriction and sirtuins. AB - Most living organisms, including humans, age. Over time the ability to do physical and intellectual work deteriorates, and susceptibility to infectious, metabolic, and neurodegenerative diseases increases, which leads to general fitness decline and ultimately to death. Work in model organisms has demonstrated that genetic and environmental manipulations can prevent numerous age-associated diseases, improve health at advanced age, and increase life span. Calorie restriction (CR) (consumption of a diet with fewer calories but containing all the essential nutrients) is the most robust manipulation, genetic or environmental, to extend longevity and improve health parameters in laboratory animals. However, outside of the protected laboratory environment, the effects of CR are much less certain. Understanding the molecular mechanisms of CR may lead to the development of novel therapies to combat diseases of aging and to improve the quality of life. Sirtuins, a family of NAD(+)-dependent enzymes, mediate a number of metabolic and behavioral responses to CR and are intriguing targets for pharmaceutical interventions. We review the molecular understanding of CR; the role of sirtuins in CR; and the effects of sirtuins on physiology, mood, and behavior. PMID- 23043252 TI - Nimotuzumab treatment of malignant gliomas. AB - INTRODUCTION: In spite of new alkylating medication and recently accumulated knowledge about genomics, the prognosis of malignant gliomas remains poor. The introduction of single substances interfering with tumour proliferation dynamics has been disappointing and the lessons learned indicate that a complicated network of proliferation needs time consuming, in-depth analysis in order to more specifically treat now distinguishable subgroups of a disease, which too long was thought of as a uniform entity. AREAS COVERED: The clinical trials using the EGFR antibody nimotuzumab in the treatment of malignant gliomas are reviewed. Pending conformation in future studies the antibody might be part of the treatment of MGMT-negative, EGFR-amplified, not completely resected gliomas of adulthood and juvenile DIPG (pontine gliomas). Upcoming genomic results of the different tumour entities may suggest certain combination partners of the antibody. Recent studies of nimotuzumab indicate the reason for the lack of toxicity, which is the most attractive argument for its clinical use besides modest efficacy. EXPERT OPINION: We await the final results on the use of the antibody together with vinorelbine and radiation therapy for the therapy of DIPG. Adult patients with MGMT-negative, EGFR amplified, not totally resected GBM may also profit from this combination therapy. TK-inhibitors combined with the antibody and irradiation may be an option for a therapeutic trial in paediatric patients. PMID- 23043253 TI - Altered BCR and CD40 signalling are associated with clinical outcome in small lymphocytic lymphoma/chronic lymphocytic leukaemia and marginal zone lymphoma patients. PMID- 23043254 TI - Expression of inhibin/activin subunits in the equine uteri during the early pregnancy. AB - The establishment of equine pregnancy is a unique and long process during which a series of physical and possibly biochemical interactions are required between the conceptus and uterus. In this study, we investigated the expression pattern of inhibin/activin subunits in the uterus during early pregnancy. The uteri from four adult mares on cyclic day 13 or pregnancy day 25 were obtained. Immunohistochemical experiments suggested that inhibin/activin subunits were immunolocalized in the luminal and glandular epithelium on pregnancy day 25. In addition, the inhibin alpha and inhibin/activin betaB subunits were not detected, and inhibin/activin betaA subunit was detected, in the luminal and glandular epithelium on cyclic day 13. Real-time polymerase chain reaction and Western blotting results for the inhibin/activin subunits suggested a significant increase in the expression of inhibin/activin subunit betaB and a significant decrease in the expression of inhibin/activin subunit betaA on pregnancy day 25 compared with those on cyclic day 13. Enzyme-linked immunosorbent assays suggested a significant decrease in the concentration of activin A in endometrium extracts from cyclic day 13 to pregnancy day 25. These results suggest that inhibins or activins synthesized in the uterus, as endocrine factors and necessary nutriments, have different expression patterns and may play different, important roles during early embryonic development of the equine. PMID- 23043256 TI - Does long-distance pollen dispersal preclude inbreeding in tropical trees? Fragmentation genetics of Dysoxylum malabaricum in an agro-forest landscape. AB - Tropical trees often display long-distance pollen dispersal, even in highly fragmented landscapes. Understanding how patterns of spatial isolation influence pollen dispersal and interact with background patterns of fine-scale spatial genetic structure (FSGS) is critical for evaluating the genetic consequences of habitat fragmentation. In the endangered tropical timber tree Dysoxylum malabaricum (Meliaceae), we apply eleven microsatellite markers with paternity and parentage analysis to directly estimate historic gene flow and contemporary pollen dispersal across a large area (216 km(2)) in a highly fragmented agro forest landscape. A comparison of genetic diversity and genetic structure in adult and juvenile life stages indicates an increase in differentiation and FSGS over time. Paternity analysis and parentage analysis demonstrate high genetic connectivity across the landscape by pollen dispersal. A comparison between mother trees in forest patches with low and high densities of adult trees shows that the frequency of short-distance mating increases, as does average kinship among mates in low-density stands. This indicates that there are potentially negative genetic consequences of low population density associated with forest fragmentation. Single isolated trees, in contrast, frequently receive heterogeneous pollen from distances exceeding 5 km. We discuss the processes leading to the observed patterns of pollen dispersal and the implications of this for conservation management of D. malabaricum and tropical trees more generally. PMID- 23043255 TI - The effect of frequent whole blood donation on ferritin, hepcidin, and subclinical atherosclerosis. AB - BACKGROUND: Iron catalyzes the formation of free radicals, which could lead to damaged vascular walls and subsequent atherosclerosis. Blood donation decreases iron stores and can thus decrease cardiovascular risk. Even within blood donors, differences in stored iron are observed. This study investigates whether increasing lifetime number of donations decreases the extent of subclinical atherosclerosis within blood donors. STUDY DESIGN AND METHODS: Subclinical atherosclerosis was evaluated in 269 blood donors by measuring intima-media thickness (IMT), pulse-wave velocity (PWV), and ankle-brachial index (ABI). Lifetime number of whole blood donations was categorized into sex-specific donation tertiles. RESULTS: Ferritin and hepcidin were lower in high-frequency donors compared to low-frequency donors. Donors in the third sex-specific donation tertile had on average a 0.3% (95% confidence interval [CI], -3.6 to +3.0%) lower IMT, a 2.1% (95% CI, -3.9 to +8.0%) higher PWV, and a 1.5% (95% CI, 1.4 to +4.5%) higher ABI compared to donors in the first sex-specific donation tertile. CONCLUSION: With such small differences and no consistent trend across donation groups, it cannot be concluded that blood donation has a beneficial effect on the extent of subclinical atherosclerosis. PMID- 23043257 TI - Comparative germination ecology of two altitudinal vicariant Saxifraga species endemic to the north of Spain. AB - Seeds of high-mountain species are thought to germinate rapidly, synchronously and at high percentages after a cold period, with limited dependence on the external environment; yet, empirical evidence only partially supports this behaviour. We performed a comparative study of the germination response of two closely related taxa along an altitude gradient in northern Spain. Seeds from several maternal families of six populations of Saxifraga trifurcata (lowland species) and S. canaliculata (highland species) were subjected to temperature and stratification treatments. Germination percentages and germination rates were analysed using generalised linear mixed modelling and accelerated failure-time modelling. We found that germination percentages and germination rates were high and dependent on incubation temperature in both species. Within species, seeds from higher altitudes had higher germination percentages under all conditions. Cold-wet stratification negatively affected germination success, particularly in the lowland species. Overall, the highland species was less responsive to the experimental treatments and showed more synchronous germination patterns. We conclude that seeds from these two Saxifraga species germinate as efficiently as species from other habitats, but have a narrower germination response, probably due to the stronger selective pressures in their harsh environments. Finally, a cold, wet stratification period is not a prerequisite for the germination of high mountain S. canaliculata, and its strong negative effect on the germination of its lowland relative S. trifurcata may contribute to the altitudinal segregation of these two species. PMID- 23043258 TI - Institutional delivery service utilization in Munisa Woreda, South East Ethiopia: a community based cross-sectional study. AB - BACKGROUND: Reducing maternal morbidity and mortality is a global priority which is particularly relevant to developing countries like Ethiopia. One of the key strategies for reducing maternal morbidity and mortality is increasing institutional delivery service utilization of mothers under the care of skilled birth attendants. The aim of this study was to determine the level of institutional delivery service utilization and associated factors. METHODS: A community-based cross-sectional survey was conducted from April 1-20, 2011, among mothers who gave birth 12 months before the study began in Munesa Woreda, Arsi Zone, Oromia Region, Southeast Ethiopia. A stratified cluster sampling was used to select a sample of 855 participants. RESULTS: Out of all deliveries, only 12.3% took place at health facilities. Women who were urban residents (AOR = 2.27, 95%CI: 1.17, 4.40), women of age at interview less than 20 years (AOR = 6.06, 95%CI: 1.54, 23.78), women with first pregnancy (AOR = 2.41, 95%CI: 1.17, 4.97) and, women who had ANC visit during the last pregnancy (AOR = 4.18, 95%CI: 2.54, 6.89) were more likely to deliver at health institutions. Secondary and above level of mother's and husband's education had also a significant effect on health institution delivery with AOR = 4.31 (95%CI: 1.62, 11.46) and AOR = 2.77 (95%CI: 1.07, 7.19) respectively. CONCLUSION: Institutional delivery service utilization was found to be low in the study area. Secondary and above level of mother's and husband's education, urban residence and ANC visit were amongst the main factors that had an influence on health institution delivery. Increasing the awareness of mothers and their partners about the benefits of institutional delivery services are recommended. PMID- 23043260 TI - Frnakenstein: multiple target inverse RNA folding. AB - BACKGROUND: RNA secondary structure prediction, or folding, is a classic problem in bioinformatics: given a sequence of nucleotides, the aim is to predict the base pairs formed in its three dimensional conformation. The inverse problem of designing a sequence folding into a particular target structure has only more recently received notable interest. With a growing appreciation and understanding of the functional and structural properties of RNA motifs, and a growing interest in utilising biomolecules in nano-scale designs, the interest in the inverse RNA folding problem is bound to increase. However, whereas the RNA folding problem from an algorithmic viewpoint has an elegant and efficient solution, the inverse RNA folding problem appears to be hard. RESULTS: In this paper we present a genetic algorithm approach to solve the inverse folding problem. The main aims of the development was to address the hitherto mostly ignored extension of solving the inverse folding problem, the multi-target inverse folding problem, while simultaneously designing a method with superior performance when measured on the quality of designed sequences. The genetic algorithm has been implemented as a Python program called Frnakenstein. It was benchmarked against four existing methods and several data sets totalling 769 real and predicted single structure targets, and on 292 two structure targets. It performed as well as or better at finding sequences which folded in silico into the target structure than all existing methods, without the heavy bias towards CG base pairs that was observed for all other top performing methods. On the two structure targets it also performed well, generating a perfect design for about 80% of the targets. CONCLUSIONS: Our method illustrates that successful designs for the inverse RNA folding problem does not necessarily have to rely on heavy biases in base pair and unpaired base distributions. The design problem seems to become more difficult on larger structures when the target structures are real structures, while no deterioration was observed for predicted structures. Design for two structure targets is considerably more difficult, but far from impossible, demonstrating the feasibility of automated design of artificial riboswitches. The Python implementation is available at http://www.stats.ox.ac.uk/research/genome/software/frnakenstein. PMID- 23043261 TI - Use of benzodiazepines or benzodiazepine related drugs and the risk of cancer: a population-based case-control study. AB - AIM: Studies of the carcinogenic potential of benzodiazepines and related drugs (BZRD) have been equivocal. A recent study reported a 35% excess cancer risk among users of hypnotics, including benzodiazepines. METHOD: Using Danish nationwide registers, we conducted a matched case-control study of the association between BZRD and cancer risk. During 1 January 2002 and 31 December 2009, we identified 152 510 cases with a first time cancer who were matched (1:8) by age and gender to 1,220,317 cancer-free controls. A new-user design was applied by excluding all subjects who had used anxiolytics, hypnotics or sedatives during the first 2 years of available prescription data (1995-6). Odds ratios (ORs) with 95% confidence intervals (CI) were estimated using conditional logistic regression, adjusting for potential confounders. In the primary analysis, long term use of BZRD was defined by a cumulative amount of >=500 defined daily doses of BZRD within a period of 1 to 5 years prior to the index date. RESULTS: The adjusted OR for cancer associated with BZRD use was 1.09 (95% CI 1.04, 1.14). ORs were close to unity for most cancer sites, except stomach 1.40 (95% CI 1.05, 1.88), oesophagus 1.43 (95% CI 1.01, 2.02), liver 1.81 (95% CI 1.18, 2.80), lung 1.38 (95% CI 1.23, 1.54), pancreas 1.35 (95% CI 1.02, 1.79) and kidney 1.39 (95% CI 1.01, 1.91). For tobacco-related cancers, the OR was 1.15 (95% CI 1.09, 1.22) and for the remaining cancer sites 1.01 (95% CI 0.94, 1.08). Sub-group analyses revealed only small differences between different levels of exposure or different patient subgroups. CONCLUSION: BZRD use was not associated with an overall increase in cancer risk, except for what is likely explained by minor lifestyle confounding, e.g. smoking. PMID- 23043263 TI - Uptake of perfluorinated alkyl acids by hydroponically grown lettuce (Lactuca sativa). AB - An uptake study was carried out to assess the potential human exposure to perfluorinated alkyl acids (PFAAs) through the ingestion of vegetables. Lettuce (Lactuca sativa) was grown in PFAA-spiked nutrient solutions at four different concentrations, ranging from 10 ng/L to 10 MUg/L. Eleven perfluorinated carboxylic acids (PFCAs) and three perfluorinated sulfonic acids (PFSAs) were analyzed by HPLC-MS/MS. At the end of the experiment, the major part of the total mass of each of the PFAAs (except the short-chain, C4-C7, PFCAs) taken up by plants appeared to be retained in the nonedible part, viz. the roots. Root concentration factors (RCF), foliage/root concentration factors (FRCF), and transpiration stream concentration factors (TSCF) were calculated. For the long chained PFAAs, RCF values were highest, whereas FRCF were lowest. This indicates that uptake by roots is likely governed by sorption of PFAAs to lipid-rich root solids. Translocation from roots to shoots is restricted and highly depending on the hydrophobicity of the compounds. Although the TSCF show that longer-chain PFCAs (e.g., perfluorododecanoic acid) get better transferred from the nutrient solution to the foliage than shorter-chain PFCAs (e.g., perfluoroheptanoic acid), the major fraction of longer-chain PFCAs is found in roots due to additional adsorption from the spiked solution. Due to the strong electron-withdrawing effect of the fluorine atoms the role of the negative charge of the dissociated PFAAs is likely insignificant. PMID- 23043262 TI - Combining QOF data with the care bundle approach may provide a more meaningful measure of quality in general practice. AB - BACKGROUND: A significant minority of patients do not receive all the evidence based care recommended for their conditions. Health care quality may be improved by reducing this observed variation. Composite measures offer a different patient centred perspective on quality and are utilized in acute hospitals via the 'care bundle' concept as indicators of the reliability of specific (evidence-based) care delivery tasks and improved outcomes. A care bundle consists of a number of time-specific interventions that should be delivered to every patient every time. We aimed to apply the care bundle concept to selected QOF data to measure the quality of evidence-based care provision. METHODS: Care bundles and components were selected from QOF indicators according to defined criteria. Five clinical conditions were suitable for care bundles: Secondary Prevention of Coronary Heart Disease (CHD), Stroke & Transient Ischaemic Attack (TIA), Chronic Kidney Disease (CKD), Chronic Obstructive Pulmonary Disease (COPD) and Diabetes Mellitus (DM). Each bundle has 3-8 components. A retrospective audit was undertaken in a convenience sample of nine general medical practices in the West of Scotland. Collected data included delivery (or not) of individual bundle components to all patients included on specific disease registers. Practice level and overall compliance with bundles and components were calculated in SPSS and expressed as a percentage. RESULTS: Nine practices (64.3%) with a combined patient population of 56,948 were able to provide data in the format requested. Overall compliance with developed QOF-based care bundles (composite measures) was as follows: CHD 64.0%, range 35.0-71.9%; Stroke/TIA 74.1%, range 51.6-82.8%; CKD 69.0%, range 64.0 81.4%; and COPD 82.0%, range 47.9-95.8%; and DM 58.4%, range 50.3-65.2%. CONCLUSIONS: In this small study compliance with individual QOF-based care bundle components was high, but overall ('all or nothing') compliance was substantially lower. Care bundles may provide a more informed measure of care quality than existing methods. However, the acceptability, feasibility and potential impact on clinical outcomes are unknown. PMID- 23043264 TI - Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible MU opioid receptor antagonist effects. AB - We have previously shown that cinnamoyl derivatives of 14beta-amino-17 cyclopropylmethyl-7,8-dihydronormorphinone and 7alpha-aminomethyl-6,14 endoethanonororipavine have pronounced pseudoirreversible MU opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism. The fumaroylamino analogues (2a, 5a) of the pseudoirreversible antagonist cinnamoylamino morphinones and oripavines (2b, 5b) were themselves irreversible antagonists in vivo. However the fumaroylamino derivatives had significantly higher MOR efficacy than the cinnamoylamino derivatives in mouse antinociceptive tests. Comparison of 2a and 5a with the prototypic fumaroylamino opioid beta-FNA (1a) shows that they have similar MOR irreversible antagonist actions but differ in the nature of their opioid receptor agonist effects; 2a is a predominant MOR agonist and 5a shows no opioid receptor selectivity, whereas the agonist effect of beta-FNA is clearly kappa opioid receptor (KOR) mediated. PMID- 23043265 TI - Aggregation-prone near-native intermediate formation during unfolding of a structurally similar nonlenticular betagamma-crystallin domain. AB - The folding and unfolding of structurally similar proteins belonging to a family have long been a focus of investigation of the structure-(un)folding relationship. Such studies are yet to reach a consensus about whether structurally similar domains follow common or different unfolding pathways. Members of the betagamma-crystallin superfamily, which consists of structurally similar proteins with limited sequence similarity from diverse life forms spanning microbes to mammals, form an appropriate model system for exploring this relationship further. We selected a new member, Crybg3_D3, the third betagamma crystallin domain of non-lens vertebrate protein Crybg3 from mouse brain. The crystal structure determined at 1.86 A demonstrates that the betagamma-crystallin domain of Crybg3 resembles more closely the lens betagamma-crystallins than the microbial crystallins do. However, interestingly, this structural cousin follows a quite distinct (un)folding pathway via formation of an intermediate state. The intermediate species is in a nativelike conformation with variation in flexibility and tends to form insoluble aggregates. The individual domains of lens betagamma-crystallins (and microbial homologues) do not follow such an unfolding pattern. Thus, even the closest members of a subfamily within a superfamily do not necessarily follow similar unfolding paths, suggesting the divergence acquired by these domains, which could be observed only by unfolding. Additionally, this study provides insights into the modifications that this domain has undergone during its recruitment into the non-lens tissues in vertebrates. PMID- 23043266 TI - Expression of RXFP1 in skin of scleroderma patients and control subjects. AB - OBJECTIVES: Relaxin (RLX) is involved in extracellular matrix and collagen remodelling. The therapeutic role of the circulating isoform RLX-2 as an anti fibrotic factor in systemic sclerosis (SSc) has been investigated. Several RLX family peptide receptors (RXFPs) are recognized in humans: RLX-2 is a ligand for RXFP1/LGR7 and RXFP2/LGR8. The aim of this study was to define the pattern of expression of LGR7 in different types of human skin cells and to compare normal skin with lesional and unaffected skin from patients with limited SSc (lSSc). METHOD: We analysed RXFP1 immunolocalization on skin biopsies and cultured fibroblasts from lSSc patients and control subjects. Western blot analysis was carried out on fibroblast lysates. RESULTS: RXFP1 showed cytoplasmic localization on skin cells from control subjects and non-lesional skin from lSSc patients: keratinocytes, gland epithelial cells, endothelium, smooth muscle cells, and fibroblasts. Immunogold electron microscopy confirmed a diffuse epithelial cytoplasmic localization of RXFP1. A substantially lower RXFP1 expression was observed in scleroderma skin, with a lack of staining in most cells. Occasional weak reactivity was observed in cultured scleroderma fibroblasts, while control fibroblasts showed a diffuse cytoplasmic immunoreactivity of RXFP1, confirmed by Western blot analysis. CONCLUSIONS: The decreased cellular expression of RLX-2 receptor RXFP1 in scleroderma skin might represent a pro-fibrotic factor and contribute to the substantial inefficacy of RLX treatment in SSc, as reported in the literature. The pathophysiology of the decrease in RXFP1 may be linked to high RLX-2 serum levels previously detected in SSc, but it has yet to be elucidated. PMID- 23043267 TI - The big impact of a small detail: cobalt nanocrystal polymorphism as a result of precursor addition rate during stock solution preparation. AB - The control of nanocrystal structures at will is still a challenge, despite the recent progress of colloidal synthetic procedures. It is common knowledge that even small modifications of the reaction parameters during synthesis can alter the characteristics of the resulting nano-objects. In this work we report an unexpected factor which determines the structure of cobalt nanoparticles. Nanocrystals of distinctly different sizes and shapes have resulted from stock solutions containing exactly the same concentrations of [Co{N(SiMe(3))(2)}(2)(thf)], hexadecylamine, and lauric acid. The reduction reaction itself has been performed under identical conditions. In an effort to explain these differences and to analyze the reaction components and any molecular intermediates, we have discovered that the rate at which the cobalt precursor is added to the ligand solution during the stock solution preparation at room temperature becomes determinant by triggering off a nonanticipated side reaction which consumes part of the lauric acid, the main stabilizing ligand, transforming it to a silyl ester. Thus, an innocent mixing, apparently not related to the main reaction which produces the nanoparticles, becomes the parameter which in fine defines nanocrystal characteristics. This side reaction affects in a similar way the morphology of iron nanoparticles prepared from an analogous iron precursor and the same long chain stabilizing ligands. Side reactions are potentially operational in a great number of systems yielding nanocrystals, despite the fact that they are very rarely mentioned in the literature. PMID- 23043268 TI - Congenital pseudarthrosis of the tibia treated with a combination of Ilizarov's technique and intramedullary rodding. AB - BACKGROUND AND PURPOSE: Ilizarov's technique and intramedullary rodding have often been used individually in congenital pseudarthrosis of the tibia. In this series, we attempted to combine the advantages of both methods while minimizing the complications. METHODS: We reviewed 15 cases of congenital pseudoarthrosis of the tibia (CPT) who were treated with a combination of Ilizarov's apparatus and antegrade intramedullary nailing between 2003 and 2008. The mean age at surgery was 7.5 (3-12) years and the mean limb length discrepancy was 2.5 (1.5-5) cm. At a mean follow-up time of 4.5 (1.6-7.2) years after the index surgery, the patients were evaluated clinically and radiographically for ankle function (AOFAS score) and for malalignment, signs of union, limb length discrepancy, and complications. RESULTS: 14 patients achieved union, in 6 patients primary union and in 8 patients after secondary procedures. The AOFAS score improved from a preoperative mean of 40 (20-57) to 64 (47-75). The main complication was refracture in 1 patient, and non-union in 1 patient. INTERPRETATION: The combination of the Ilizarov technique and conventional antegrade intramedullary nailing was successful in achieving union with few complications, though this should be shown in long-term studies lasting until skeletal maturity. PMID- 23043269 TI - Low revision rate after total hip arthroplasty in patients with pediatric hip diseases. AB - BACKGROUND: The results of primary total hip arthroplasties (THAs) after pediatric hip diseases such as developmental dysplasia of the hip (DDH), slipped capital femoral epiphysis (SCFE), or Perthes' disease have been reported to be inferior to the results after primary osteoarthritis of the hip (OA). MATERIALS AND METHODS: We compared the survival of primary THAs performed during the period 1995-2009 due to previous DDH, SCFE, Perthes' disease, or primary OA, using merged individual-based data from the Danish, Norwegian, and Swedish arthroplasty registers, called the Nordic Arthroplasty Register Association (NARA). Cox multiple regression, with adjustment for age, sex, and type of fixation of the prosthesis was used to calculate the survival of the prostheses and the relative revision risks. RESULTS: 370,630 primary THAs were reported to these national registers for 1995-2009. Of these, 14,403 THAs (3.9%) were operated due to pediatric hip diseases (3.1% for Denmark, 8.8% for Norway, and 1.9% for Sweden) and 288,435 THAs (77.8%) were operated due to OA. Unadjusted 10-year Kaplan-Meier survival of THAs after pediatric hip diseases (94.7% survival) was inferior to that after OA (96.6% survival). Consequently, an increased risk of revision for hips with a previous pediatric hip disease was seen (risk ratio (RR) 1.4, 95% CI: 1.3-1.5). However, after adjustment for differences in sex and age of the patients, and in fixation of the prostheses, no difference in survival was found (93.6% after pediatric hip diseases and 93.8% after OA) (RR 1.0, CI: 1.0-1.1). Nevertheless, during the first 6 postoperative months more revisions were reported for THAs secondary to pediatric hip diseases (RR 1.2, CI: 1.0-1.5), mainly due to there being more revisions for dislocations (RR 1.8, CI: 1.4-2.3). Comparison between the different diagnosis groups showed that the overall risk of revision after DDH was higher than after OA (RR 1.1, CI: 1.0-1.2), whereas the combined group Perthes' disease/SCFE did not have a significantly different risk of revision to that of OA (RR 0.9, CI: 0.7-1.0), but had a lower risk than after DDH (RR 0.8, CI: 0.7-1.0). INTERPRETATION: After adjustment for differences in age, sex, and type of fixation of the prosthesis, no difference in risk of revision was found for primary THAs performed due to pediatric hip diseases and those performed due to primary OA. PMID- 23043270 TI - Good short-term outcome of primary total hip arthroplasty with cementless bioactive glass ceramic bottom-coated implants: 109 hips followed for 3-9 years. AB - BACKGROUND AND PURPOSE: Cementless total hip arthroplasty is currently favored by many orthopedic surgeons. The design of the porous surface is critically important for long-term fixation. We examined the clinical and radiographic outcome of the cementless titanium hip implant with a bottom coating of apatite wollastonite containing bioactive glass ceramic. METHODS: We retrospectively reviewed 109 hips (92 patients) that had undergone primary cementless total hip arthroplasty with bioactive glass ceramic bottom-coated implants. The mean follow up period was 7 (3-9) years. Hip joint function was evaluated with the Merle d'Aubigne and Postel hip score, and radiographic changes were determined from anteroposterior radiographs. RESULTS: The mean hip score improved from 9.7 preoperatively to 17 at the final follow-up. The overall survival rate was 100% at 9 years, when radiographic loosening or revision for any reason was used as the endpoint. 3 stems in 2 patients subsided more than 3 mm vertically within 1 year after implantation. Radiographs of the interface of the stem and femur were all classified as bone ingrowth fixation. CONCLUSIONS: The short-term results of this study show good outcome for cementless implants with a bottom coating of apatite-wollastonite containing bioactive glass ceramic. PMID- 23043271 TI - Elevated plasma levels of TIMP-1 in patients with rotator cuff tear. AB - BACKGROUND AND PURPOSE: Extracellular matrix remodeling is altered in rotator cuff tears, partly due to altered expression of matrix metalloproteinases (MMPs) and their inhibitors. It is unclear whether this altered expression can be traced as changes in plasma protein levels. We measured the plasma levels of MMPs and their tissue inhibitors (TIMPs) in patients with rotator cuff tears and related changes in the pattern of MMP and TIMP levels to the extent of the rotator cuff tear. METHODS: Blood samples were collected from 17 patients, median age 61 (39 77) years, with sonographically verified rotator cuff tears (partial- or full thickness). These were compared with 16 age- and sex-matched control individuals with sonographically intact rotator cuffs. Plasma levels of MMPs and TIMPs were measured simultaneously using Luminex technology and ELISA. RESULTS: The plasma levels of TIMP-1 were elevated in patients with rotator cuff tears, especially in those with full-thickness tears. The levels of TIMP-1, TIMP-3, and MMP-9 were higher in patients with full-thickness tears than in those with partial-thickness tears, but only the TIMP-1 levels were significantly different from those in the controls. INTERPRETATION: The observed elevation of TIMP-1 in plasma might reflect local pathological processes in or around the rotator cuff, or a genetic predisposition in these patients. That the levels of TIMP-1 and of certain MMPs were found to differ significantly between partial and full-thickness tears may reflect the extent of the lesion or different etiology and pathomechanisms. PMID- 23043272 TI - Minimally invasive surgery did not improve outcome compared to conventional surgery following unicompartmental knee arthroplasty using local infiltration analgesia: a randomized controlled trial with 40 patients. AB - BACKGROUND AND PURPOSE: There has recently been interest in the advantages of minimally invasive surgery (MIS) over conventional surgery, and on local infiltration analgesia (LIA) during knee arthroplasty. In this randomized controlled trial, we investigated whether MIS would result in earlier home readiness and reduced postoperative pain compared to conventional unicompartmental knee arthroplasty (UKA) where both groups received LIA. PATIENTS AND METHODS: 40 patients scheduled for UKA were randomized to a MIS group or a conventional surgery (CON) group. Both groups received LIA with a mixture of ropivacaine, ketorolac, and epinephrine given intra- and postoperatively. The primary endpoint was home-readiness (time to fulfillment of discharge criteria). The patients were followed for 6 months. RESULTS: We found no statistically significant difference in home-readiness between the MIS group (median (range) 24 (21-71) hours) and the CON group (24 (21-46) hours). No statistically significant differences between the groups were found in the secondary endpoints pain intensity, morphine consumption, knee function, hospital stay, patient satisfaction, Oxford knee score, and EQ-5D. The side effects were also similar in the two groups, except for a higher incidence of nausea on the second postoperative day in the MIS group. INTERPRETATION: Minimally invasive surgery did not improve outcome after unicompartmental knee arthroplasty compared to conventional surgery, when both groups received local infiltration analgesia. The surgical approach (MIS or conventional surgery) should be selected according to the surgeon's preferences and local hospital policies. ClinicalTrials.gov. (Identifier NCT00991445). PMID- 23043273 TI - Deviation between navigated and final 3-dimensional implant position in mini invasive unicompartmental knee arthroplasty: a pilot study in 13 patients. AB - BACKGROUND AND PURPOSE: Unicompartmental knee arthroplasty (UKA) is an established method of treating isolated gonartrosis. Modern techniques such as computer-assisted surgery (CAS) and minimally invasive surgery (MIS) are attractive complementary methods to UKA. However, the positioning of the components remains a concern. Thus, we performed a prospective study to assess whether there was deviation between the navigated implant position and the final implant position. PATIENTS AND METHODS: We performed UKA with MIS and CAS in 13 patients. By comparing intraoperative navigation data with postoperative computed tomography (CT) measurements, we calculated the deviation between the computer assisted implant position and the final 3-D implant position of the femoral and tibial components. RESULTS: The computer-assisted placement of the femoral and tibial component showed adequate position and consistent results regarding flexion-extension and varus-valgus. However, regarding rotation there was a large variation and 6 of 10 patients were outside the target range for both the femoral component and the tibial component. INTERPRETATION: Difficulties in assessing anatomical landmarks with the CAS in combination with MIS might be a reason for the poor rotational alignment of the components. PMID- 23043275 TI - Maternal exposure to high temperatures disrupts OCT4 mRNA expression of rabbit pre-implantation embryos and endometrial tissue. AB - We examined the effect of prolonged high heat stress on reproductive performance and its relationship with gene expression in pre-implantation embryos and endometrial tissue. In experiment 1, primiparous rabbit does were divided into two environments: control does (maintained between 14 and 22 degrees C) and heat treated does housed in a climatic chamber (maintained between 25 and 35 degrees C). Females were reproducing, and the litter size and live born kits were assessed at 2nd and 3rd partum. In heat-treated does, lower litter size (9.7 +/- 0.48 and 11.4 +/- 0.50) and fewer live born kits (7.2 +/- 0.55 and 10.2 +/- 0.57) were observed, although similar ovulation rates and numbers of pre-implantation embryos were noted. In experiment 2, after 3rd partum multiparous non-lactating does from each experimental group were used to obtain pre-implantation embryos and endometrial tissue. mRNA transcripts from OCT-4, VEGF, erbB3, Ifn-gamma, HSP70 and HSP90 were analysed by real-time qPCR. Higher values of OCT-4 expression were observed in embryos and endometrial tissue in females reproduced under heat conditions. Moreover, elevated temperatures have been shown to up regulate VEGF in embryos and down-regulate Ifn-gamma in endometrial tissue. The findings suggest a deleterious temperature effect on litter size and live born kits as a consequence of variation in gene expression pattern of the pre implantational embryo and the endometrium associated with proliferation and differentiation and probably with implantation and uterine and foetal development during gestation. PMID- 23043274 TI - Impact of enhanced detection on the increase in thyroid cancer incidence in the United States: review of incidence trends by socioeconomic status within the surveillance, epidemiology, and end results registry, 1980-2008. AB - BACKGROUND: In the past 3 decades, the incidence of thyroid cancer in the United States has been increasing. There has been debate on whether the increase is real or an artifact of improved diagnostic scrutiny. Our hypothesis is that both improved detection and a real increase have contributed to the increase. METHODS: Because socioeconomic status (SES) may be a surrogate for access to diagnostic technology, we compared thyroid cancer incidence trends between high- and low-SES counties within the Surveillance, Epidemiology, and End Results 9 (SEER 9) registries. The incidence trends were assessed using joinpoint regression analysis. RESULTS: In high-SES counties, thyroid cancer incidence increased moderately (annual percentage change 1 [APC1]=2.5, p<0.05) before the late 1990s and more pronounced (APC2=6.3, p<0.05) after the late 1990s. In low-SES counties, incidence increased steadily with an APC of 3.5 (p<0.05) during the entire study period (1980-2008). For tumors <=4.0 cm, incidence was higher in high-SES counties, and APC was higher for high- than low-SES counties after the late 1990s. For tumors >4.0 cm, high- and low-SES counties had similar increasing incidence trends. Similarly, for tumors <=2.0 cm, the incidence trends differed between counties that are in or adjacent to metropolitan areas and counties that are in rural areas, whereas for tumors >2.0 cm, all counties regardless of area of residence had similar increasing trends. CONCLUSIONS: Enhanced detection likely contributed to the increased thyroid cancer incidence in the past decades, but cannot fully explain the increase, suggesting that a true increase exists. Efforts should be made to identify the cause of this true increase. PMID- 23043277 TI - Expression profiling of genes involved in the formation of aroma in two peach genotypes. AB - The expression profile of flavour-related genes during ripening was investigated in two peach genotypes, Bolero and OroA, which have been selected for their contrasting aroma/ripening behaviour. A new peach microarray containing 4776 oligonucleotide probes corresponding to a set of ESTs specifically enriched in secondary metabolism (MUPEACH2.0) was designed to investigate transcriptome changes during three fruit ripening stages, revealing 1807 transcripts differentially expressed within and between the two genotypes. Differences in the expression of genes involved in the biosynthesis of aroma compounds were detected during the ripening process within and between the two genotypes. In particular, a subset of 12 transcripts involved in metabolism of esters, norisoprenoids, phenylpropanoids and lactones, varied in expression during ripening and between Bolero and OroA. PMID- 23043276 TI - A population genetic signature of human releases in an invasive ladybeetle. AB - Biological invasions have been accelerated by a variety of human activities. Propagule pressure, the number of introduced individuals and independent introductions, is probably to be influenced by these human activities and may be an important factor for successful range expansion in new environments. We tested whether the current distribution of the predatory ladybeetle Coccinella septempunctata in the introduced range (USA) is the result of multiple historical human introductions or natural range expansion from the first established populations in the USA. To test this hypothesis, we compared historical records of propagule size, propagule number, specific introduction locations and the date of each introduction, with estimates of genetic variation in mitochondrial DNA (cytochrome oxidase I). Our results indicated that genetic diversity in the introduced range was positively correlated with historical records of propagule size and number and negatively correlated with distance to nearest introduction point, suggesting that multiple human releases were successful. Higher genetic diversity in populations found near introduction points suggest that initial founder effects were limited, but lower genetic diversity found farther from introduction points is probably the result of serial founder effects during secondary range expansion. These results suggest that the current distribution of C. septempunctata in the introduced range is the result of a combination of human releases and short-range expansion from multiple established populations in the introduced range. PMID- 23043279 TI - HINT1 mutations define a novel disease entity - autosomal recessive axonal neuropathy with neuromyotonia. PMID- 23043278 TI - Cognitive effects of two nutraceuticals Ginseng and Bacopa benchmarked against modafinil: a review and comparison of effect sizes. AB - Over recent years there has been increasing research into both pharmaceutical and nutraceutical cognition enhancers. Here we aimed to calculate the effect sizes of positive cognitive effect of the pharmaceutical modafinil in order to benchmark the effect of two widely used nutraceuticals Ginseng and Bacopa (which have consistent acute and chronic cognitive effects, respectively). A search strategy was implemented to capture clinical studies into the neurocognitive effects of modafinil, Ginseng and Bacopa. Studies undertaken on healthy human subjects using a double-blind, placebo-controlled design were included. For each study where appropriate data were included, effect sizes (Cohen's d) were calculated for measures showing significant positive and negative effects of treatment over placebo. The highest effect sizes for cognitive outcomes were 0.77 for modafinil (visuospatial memory accuracy), 0.86 for Ginseng (simple reaction time) and 0.95 for Bacopa (delayed word recall). These data confirm that neurocognitive enhancement from well characterized nutraceuticals can produce cognition enhancing effects of similar magnitude to those from pharmaceutical interventions. Future research should compare these effects directly in clinical trials. PMID- 23043282 TI - Providing educationally relevant occupational and physical therapy services. PMID- 23043283 TI - Phase I study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukaemia: maintaining immune functions during therapy-induced immunosuppression. PMID- 23043285 TI - Retraction. Biotherapeutic approaches to pancreatic cancer. PMID- 23043286 TI - Loss of aquaporin 3 protein expression constitutes an independent prognostic factor for progression-free survival: an immunohistochemical study on stage pT1 urothelial bladder cancer. AB - BACKGROUND: Treatment of patients with stage pT1 urothelial bladder cancer (UBC) continues to be a challenge due to its unpredictable clinical course. Reliable molecular markers that help to determine appropriate individual treatment are still lacking. Loss of aquaporin (AQP) 3 protein expression has previously been shown in muscle-invasive UBC. The aim of the present study was to investigate the prognostic value of AQP3 protein expression with regard to the prognosis of stage pT1 UBC. METHOD: AQP 3 protein expression was investigated by immunohistochemistry in specimens of 87 stage T1 UBC patients, who were diagnosed by transurethral resection of the bladder (TURB) and subsequent second resection at a high-volume urological centre between 2002 and 2009. Patients underwent adjuvant instillation therapy with Bacillus Calmette-Guerin (BCG). Loss of AQP3 protein expression was defined as complete absence of the protein within the whole tumour. Expression status was correlated retrospectively with clinicopathological and follow-up data (median: 31 months). Multivariate Cox regression analysis was used to assess the value of AQP3 tumour expression with regard to recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS). RFS, PFS and CSS were calculated by Kaplan-Meier analysis and Log rank test. RESULTS: 59% of patients were shown to exhibit AQP3-positive tumours, whereas 41% of tumours did not express the marker. Loss of AQP3 protein expression was associated with a statistically significantly worse PFS (20% vs. 72%, p=0.020). This finding was confirmed by multivariate Cox regression analysis (HR 7.58, CI 1.29 - 44.68; p=0.025). CONCLUSIONS: Loss of AQP3 protein expression in pT1 UBC appears to play a key role in disease progression and is associated with worse PFS. Considering its potential prognostic value, assessment of AQP3 protein expression could be used to help stratify the behavior of patients with pT1 UBC. PMID- 23043287 TI - The natural profilin from Russian thistle (Salsola kali) contains a low IgE binding ability isoform--molecular and immunological characterization. AB - Chenopodiaceae pollens such as those from Salsola kali and Chenopodium album are important causes of allergy in Mediterranean areas because of the progress of desertification in European countries. Among the various allergenic protein families, profilins constitute a group of pan-allergens that are involved in polysensitization and pollen-food allergy syndrome. Two-dimensional electrophoresis analysis of S. kali profilin highlighted a polymorphic pattern, with several isoforms that have different molecular features (isoelectric point and molecular mass) and immunological features. Two isoforms have been cloned and sequenced. Sal k 4.02 and Sal k 4.03 displayed non-conservative amino acid changes in critical positions of the IgE epitopes. Both isoforms were produced in Escherichia coli and structurally and spectroscopically characterized. Changes in the electrophoretic mobility and in their IgG and IgE immunological behavior were observed in comparison with Che a 2, their counterpart from C. album. The IgE binding ability of Sal k 4.03 is similar to that of Che a 2, whereas Sal k 4.02 showed a 35% reduction in IgE binding in 86% of patients, suggesting a hypoallergenic character. Three-dimensional modeling allowed us to propose which amino acid residues are involved in those immunological changes based on epitope mapping studies previously performed in other profilins. These profilin isoforms constitute suitable candidates for specific immunotherapy with recombinant allergens. PMID- 23043288 TI - The role of health extension workers in improving utilization of maternal health services in rural areas in Ethiopia: a cross sectional study. AB - BACKGROUND: Community health workers are widely used to provide care for a broad range of health issues. Since 2003 the government of Ethiopia has been deploying specially trained new cadres of community based health workers named health extension workers (HEWs). This initiative has been called the health extension program. Very few studies have investigated the role of these community health workers in improving utilization of maternal health services. METHODS: A cross sectional survey of 725 randomly selected women with under-five children from three districts in Northern Ethiopia. We investigated women's utilization of family planning, antenatal care, birth assistance, postnatal care, HIV testing and use of iodized salt and compared our results to findings of a previous national survey from 2005. In addition, we investigated the association between several variables and utilization of maternal health services using logistic regression analysis. RESULTS: HEWs have contributed substantially to the improvement in women's utilization of family planning, antenatal care and HIV testing. However, their contribution to the improvement in health facility delivery, postnatal check up and use of iodized salt seems insignificant. Women who were literate (OR, 1.85), listened to the radio (OR, 1.45), had income generating activities (OR, 1.43) and had been working towards graduation or graduated as model family (OR, 2.13) were more likely to demonstrate good utilization of maternal health services. A model family is by definition a family which has fulfilled all the packages of the HEP. CONCLUSIONS: The HEWs seem to have substantial contribution in several aspects of utilization of maternal health services but their insignificant contribution in improving health facility delivery and skilled birth attendance remains an important problem. More effort is needed to improve the effectiveness of HEWs in these regards. For example, strengthening HEWs' support for pregnant women for birth planning and preparedness and referral from HEWs to midwives at health centers should be strengthened. In addition, women's participation in income generating activities, access to radio and education could be targets for future interventions. PMID- 23043289 TI - Enhanced shear-induced platelet aggregation due to low-temperature storage. AB - BACKGROUND: Refrigeration of platelets (PLTs) offers an attractive alternative to the currently practiced storage at room temperature since it may mitigate problems associated with bacterial contamination and extend storage lifetime. Refrigeration causes a number of biophysical and biochemical changes in PLTs and decreases PLT circulation time in vivo. However, the effect of refrigeration on PLT hemostatic functions under physiologic and pathophysiologic shear conditions has not been adequately characterized. STUDY DESIGN AND METHODS: Washed PLTs prepared from either fresh PLT-rich plasma (PRP) or PRP stored at 4 degrees C for 2 days was mixed with exogenous von Willebrand factor (VWF) and fibrinogen and sheared in a cone-and-plate viscometer. PLT aggregation, activation, and VWF binding after shear and glycoprotein (GP) Ibalpha receptor expression and ristocetin-induced PLT agglutination were measured. RESULTS: PLTs stored at 4 degrees C for 2 days aggregated significantly more than fresh PLTs particularly at high shear rates (10,000/sec), and this increase was independent of PLT concentration or suspension viscosity. Further, refrigerated PLTs showed a greater increase in GP Ibalpha-dependent PLT activation under shear and also bound more VWF than fresh PLTs. However, the GP Ibalpha expression levels as measured by three different antibodies were significantly lower in refrigerated PLTs than in fresh PLTs, and refrigeration resulted in a modest decrease in ristocetin-induced PLT agglutination. CONCLUSION: The combined results demonstrate that refrigeration increases PLT aggregation under high shear, but not static, conditions and also increases shear-induced VWF binding and PLT activation. Clinically, enhanced shear-induced PLT aggregation due to low temperature storage may be a beneficial strategy to prevent severe bleeding in trauma. PMID- 23043290 TI - Distinct patterns of notochord mineralization in zebrafish coincide with the localization of Osteocalcin isoform 1 during early vertebral centra formation. AB - BACKGROUND: In chondrichthyans, basal osteichthyans and tetrapods, vertebral bodies have cartilaginous anlagen that subsequently mineralize (chondrichthyans) or ossify (osteichthyans). Chondrocytes that form the vertebral centra derive from somites. In teleost fish, vertebral centrum formation starts in the absence of cartilage, through direct mineralization of the notochord sheath. In a second step, the notochord is surrounded by somite-derived intramembranous bone. In several small teleost species, including zebrafish (Danio rerio), even haemal and neural arches form directly as intramembranous bone and only modified caudalmost arches remain cartilaginous. This study compares initial patterns of mineralization in different regions of the vertebral column in zebrafish. We ask if the absence or presence of cartilaginous arches influences the pattern of notochord sheath mineralization. RESULTS: To reveal which cells are involved in mineralization of the notochord sheath we identify proliferating cells, we trace mineralization on the histological level and we analyze cell ultrastructure by TEM. Moreover, we localize proteins and genes that are typically expressed by skeletogenic cells such as Collagen type II, Alkaline phosphatase (ALP) and Osteocalcin (Oc). Mineralization of abdominal and caudal vertebrae starts with a complete ring within the notochord sheath and prior to the formation of the bony arches. In contrast, notochord mineralization of caudal fin centra starts with a broad ventral mineral deposition, associated with the bases of the modified cartilaginous arches. Similar, arch-related, patterns of mineralization occur in teleosts that maintain cartilaginous arches throughout the spine.Throughout the entire vertebral column, we were able to co-localize ALP-positive signal with chordacentrum mineralization sites, as well as Collagen II and Oc protein accumulation in the mineralizing notochord sheath. In the caudal fin region, ALP and Oc signals were clearly produced both by the notochord epithelium and cells outside the notochord, the cartilaginous arches. Based on immunostaining, real time PCR and oc2:gfp transgenic fish, we identify Oc in the mineralizing notochord sheath as osteocalcin isoform 1 (Oc1). CONCLUSIONS: If notochord mineralization occurs prior to arch formation, mineralization of the notochord sheath is ring-shaped. If notochord mineralization occurs after cartilaginous arch formation, mineralization of the notochord sheath starts at the insertion point of the arches, with a basiventral origin. The presence of ALP and Oc1, not only in cells outside the notochord, but also in the notochord epithelium, suggests an active role of the notochord in the mineralization process. The same may apply to Col II-positive chondrocytes of the caudalmost haemal arches that show ALP activity and Oc1 accumulation, since these chondrocytes do not mineralize their own cartilage matrix. Even without cartilaginous preformed vertebral centra, the cartilaginous arches may have an inductive role in vertebral centrum formation, possibly contributing to the distinct mineralization patterns of zebrafish vertebral column and caudal fin vertebral fusion. PMID- 23043291 TI - Phthalazine derivatives containing imidazole rings behave as Fe-SOD inhibitors and show remarkable anti-T. cruzi activity in immunodeficient-mouse mode of infection. AB - A series of new phthalazine derivatives 1-4 containing imidazole rings were prepared. The monoalkylamino substituted derivatives 2 and 4 were more active in vitro against T. cruzi and less toxic against Vero cells than both their disubstituted analogues and the reference drug benznidazole. Compounds 2 and 4 highly inhibited the antioxidant parasite enzyme Fe-SOD, and molecular modeling suggested that they interact with the H-bonding system of the iron atom moiety. In vivo tests on the acute phase of Chagas disease gave parasitemia inhibition values twice those of benznidazole, and a remarkable decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice. Glucose metabolism studies showed that compounds 1-4 did not affect the succinate pathway but originated important changes in the excretion of pyruvate metabolites. The morphological alterations found in epimastigotes treated with 1-4 confirmed extensive cytoplasm damage and a high mortality rate of parasites. PMID- 23043292 TI - FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions. AB - FTDP-17 mutations in the tau gene lead to early onset frontotemporal dementias characterized by the pathological aggregation of the microtubule-associated protein tau. Tau aggregation is closely correlated with the progression and severity of localized atrophy of certain regions in the brain. These mutations are primarily located in or near the microtubule-binding repeat regions of tau and can have vastly different effects on the protein. Some mutations have been linked to effects such as increased levels of aggregation, hyperphosphorylation, defects in mRNA splicing, and weakened interaction with microtubules. Given the differential effects of the mutations, it may not be surprising that the pathology associated with FTDP-17 can vary widely as well. Despite this variety, several of the mutations are commonly used interchangeably as aggregation inducers for in vitro and in vivo models of tauopathies. We generated recombinant forms of 12 FTDP-17 mutations chosen for their predicted effects on the charge, hydrophobicity, and secondary structure of the protein. We then examined the effects that the mutations had on the properties of in vitro aggregation of the protein and its ability to stabilize microtubule assembly. The group of mutations induced very different effects on the total amount of aggregation, the kinetics of aggregation, and filament morphology. Several of the mutations inhibited the microtubule stabilization ability of tau, while others had very little effect compared to wild-type tau. These results indicate that the mechanisms of disease progression may differ among FTDP-17 mutations and that the effects of the varying mutations may not be equal in all model systems. PMID- 23043293 TI - Legg-Calve-Perthes disease and the risk of injuries requiring hospitalization: a register study involving 2579 patients. AB - BACKGROUND AND PURPOSE: Previous studies have suggested that Legg-Calve-Perthes disease (LCPD) is associated with repetitive trauma, coagulation problems and anatomical abnormalities of the blood supply to the femoral head. The hypothesis that repetitive trauma can affect the blood supply of the femoral head, leading to LCPD, is supported by an animal model. For evidence of an increased risk of repetitive trauma, we investigated whether patients with LCPD have a higher risk for severe injuries requiring hospitalization. PATIENTS AND METHODS: We identified 2579 patients with LCPD in Sweden during the period 1964-2005. 13,748 individuals without LCPD were randomly selected from the Swedish general population, matched by year of birth, sex and region (control group). Cox proportional hazard regression estimated the risks. RESULTS: Compared to the control group, patients with LCPD had a modestly raised hazard ratio (HR) of 1.2 (95% CI 1.1-1.3) for injury requiring hospitalization. The risks were slightly higher for soft tissue injuries (HR = 1.3, 95% CI:1.1-1.4) than for fractures (HR = 1.1, 95% CI: 1.0-1.3) and more pronounced among females. Compared to the control group, the higher risk for injury only applied to the lower extremities (HR = 1.2, 95% CI: 1.0-1.4) in patients with LCPD. INTERPRETATION: Patients with LCPD are vulnerable to injuries which could be interpreted as a marker of hyperactive behavior. It could also implicate that anatomical changes in the bone formation or blood supply of the femoral head - increasing its sensibility for trauma - contribute to the etiology of LCPD. PMID- 23043294 TI - Formation of crystalline Zn-Al layered double hydroxide precipitates on gamma alumina: the role of mineral dissolution. AB - To better understand the sequestration of toxic metals such as nickel (Ni), zinc (Zn), and cobalt (Co) as layered double hydroxide (LDH) phases in soils, we systematically examined the presence of Al and the role of mineral dissolution during Zn sorption/precipitation on gamma-Al(2)O(3) (gamma-alumina) at pH 7.5 using extended X-ray absorption fine structure spectroscopy (EXAFS), high resolution transmission electron microscopy (HR-TEM), synchrotron-radiation powder X-ray diffraction (SR-XRD), and (27)Al solid-state NMR. The EXAFS analysis indicates the formation of Zn-Al LDH precipitates at Zn concentration >=0.4 mM, and both HR-TEM and SR-XRD reveal that these precipitates are crystalline. These precipitates yield a small shoulder at delta(Al-27) = +12.5 ppm in the (27)Al solid-state NMR spectra, consistent with the mixed octahedral Al/Zn chemical environment in typical Zn-Al LDHs. The NMR analysis provides direct evidence for the existence of Al in the precipitates and the migration from the dissolution of gamma-alumina substrate. To further address this issue, we compared the Zn sorption mechanism on a series of Al (hydr)oxides with similar chemical composition but differing dissolubility using EXAFS and TEM. These results suggest that, under the same experimental conditions, Zn-Al LDH precipitates formed on gamma-alumina and corundum but not on less soluble minerals such as bayerite, boehmite, and gibbsite, which point outs that substrate mineral surface dissolution plays an important role in the formation of Zn-Al LDH precipitates. PMID- 23043295 TI - Effects of garlic and ginger oils on hematological and biochemical variables of sea bass Dicentrarchus labrax. AB - This study was conducted to investigate the effects of garlic and ginger oils on hematological and biochemical health characteristics of sea bass Dicentrarchus labrax. Fish were exposed to garlic oil (0.01 or 0.02 mL/L), ginger oil (0.01 or 0.02 mL/L), or a combination of the two oils (each oil at a concentration of 0.005 or 0.01 mL/L) for 96 h via bath immersion. Results showed that the red blood cell count, hematocrit (%), hemoglobin (Hb) concentration (g/dL), mean corpuscular volume (MUm(3)), mean corpuscular Hb (pg), and mean corpuscular Hb concentration (%) were not significantly affected by herb oil exposure. However, some changes in biochemical variables were observed. Sea bass exposed to the 0.005-mL/L garlic oil-ginger oil mixture exhibited a significant increase in serum glucose. Serum total protein and albumin levels decreased in sea bass that were exposed to a garlic oil-ginger oil mixture (0.005 or 0.01 mL/L) or to garlic oil at 0.02 mL/L. Serum globulin levels decreased and triglyceride levels increased in sea bass exposed to 0.02-mL/L garlic oil or to the 0.01-mL/L mixture. The serum lipase level decreased and the cholesterol level increased in fish that were exposed to 0.02-mL/L garlic oil. In summary, ginger oil at 0.01 0.02 mL/L can be used without negative effects, while the garlic oil or garlic oil-ginger oil mixture should be applied at a concentration below 0.005 mL/L for bath immersion of sea bass. This is the first study to examine how garlic oil and ginger oil exposure via bath immersion affects the hematological and biochemical status of sea bass. PMID- 23043296 TI - Mesoscopic CH3NH3PbI3/TiO2 heterojunction solar cells. AB - We report for the first time on a hole conductor-free mesoscopic methylammonium lead iodide (CH(3)NH(3)PbI(3)) perovskite/TiO(2) heterojunction solar cell, produced by deposition of perovskite nanoparticles from a solution of CH(3)NH(3)I and PbI(2) in gamma-butyrolactone on a 400 nm thick film of TiO(2) (anatase) nanosheets exposing (001) facets. A gold film was evaporated on top of the CH(3)NH(3)PbI(3) as a back contact. Importantly, the CH(3)NH(3)PbI(3) nanoparticles assume here simultaneously the roles of both light harvester and hole conductor, rendering superfluous the use of an additional hole transporting material. The simple mesoscopic CH(3)NH(3)PbI(3)/TiO(2) heterojunction solar cell shows impressive photovoltaic performance, with short-circuit photocurrent J(sc)= 16.1 mA/cm(2), open-circuit photovoltage V(oc) = 0.631 V, and a fill factor FF = 0.57, corresponding to a light to electric power conversion efficiency (PCE) of 5.5% under standard AM 1.5 solar light of 1000 W/m(2) intensity. At a lower light intensity of 100W/m(2), a PCE of 7.3% was measured. The advent of such simple solution-processed mesoscopic heterojunction solar cells paves the way to realize low-cost, high-efficiency solar cells. PMID- 23043297 TI - No inbreeding depression but increased sexual investment in highly inbred ant colonies. AB - Inbreeding can lead to the expression of deleterious recessive alleles and to a subsequent fitness reduction. In Hymenoptera, deleterious alleles are purged in haploid males moderating inbreeding costs. However, in these haplodiploid species, inbreeding can result in the production of sterile diploid males. We investigated the effects of inbreeding on the individual and colony level in field colonies of the highly inbred ant Hypoponera opacior. In this species, outbreeding winged sexuals and nest-mating wingless sexuals mate during two separate reproductive periods. We show that regular sib-matings lead to high levels of homozygosity and the occasional production of diploid males, which sporadically sire triploid offspring. On the individual level, inbreeding was associated with an increased body size in workers. On the colony level, we found no evidence for inbreeding depression as productivity was unaffected by the level of homozygosity. Instead, inbred colonies altered their allocation strategies by investing more resources into sexuals than into workers. This shift towards sexual production was due to an increased investment in both males and queens, which was particularly pronounced in the dispersive generation. The absence of inbreeding depression combined with increased reproductive investment, especially in outbreeding sexuals, suggests that these ants have evolved active strategies to regulate the extent and effects of frequent inbreeding. PMID- 23043298 TI - Mutations in ATP1A3 cause alternating hemiplegia of childhood. PMID- 23043299 TI - Two guard cell-preferential MAPKs, MPK9 and MPK12, regulate YEL signalling in Arabidopsis guard cells. AB - We report that two mitogen-activated protein kinases (MAPKs), MPK9 and MPK12, positively regulate abscisic acid (ABA)-induced stomatal closure in Arabidopsis thaliana. Yeast elicitor (YEL) induced stomatal closure accompanied by intracellular reactive oxygen species (ROS) accumulation and cytosolic free calcium concentration ([Ca(2+) ]cyt ) oscillation. In this study, we examined whether these two MAP kinases are involved in YEL-induced stomatal closure using MAPKK inhibitors, PD98059 and U0126, and MAPK mutants, mpk9, mpk12 and mpk9 mpk12. Both PD98059 and U0126 inhibited YEL-induced stomatal closure. YEL induced stomatal closure in the mpk9 and mpk12 mutants but not in the mpk9 mpk12 mutant, suggesting that a MAPK cascade involving MPK9 and MPK12 functions in guard cell YEL signalling. However, YEL induced extracellular ROS production, intracellular ROS accumulation and cytosolic alkalisation in the mpk9, mpk12 and mpk9 mpk12 mutants. YEL induced [Ca(2+) ]cyt oscillations in both wild type and mpk9 mpk12 mutant. These results suggest that MPK9 and MPK12 function redundantly downstream of extracellular ROS production, intracellular ROS accumulation, cytosolic alkalisation and [Ca(2+) ]cyt oscillation in YEL-induced stomatal closure in Arabidopsis guard cells and are shared with ABA signalling. PMID- 23043300 TI - Gela histological scoring system for post-treatment biopsies of patients with gastric MALT lymphoma is feasible and reliable in routine practice. AB - The International Extranodal Lymphoma Study Group (IELSG) promoted this study to determine the inter-observer agreement in the application of the Groupe d' Etude des Lymphomes de l' Adulte (GELA) histological scoring system for evaluating residual disease in post-treatment gastric biopsies of patients with gastric Mucosa-Associated Lymphoid Tissue (MALT) lymphoma (GML). Twenty-one patients with Helicobacter pylori -associated GML and treated with anti-H. pylori therapies were considered. A total of 154 biopsy sets from follow-up endoscopic procedures after H. pylori eradication were examined independently by seven pathologists from four European countries, following histological criteria suggested by the GELA scoring system. The overall concordance rate was 83% with a kappa value of 0.64, indicating a significant agreement among the seven observers. Most non concordant responses clustered across the border of complete remission (CR) and probable minimal residual disease (pMRD), a distinction that does not imply critical clinical impact. Accordingly, when the analysis considered CR/pMRD as a single entity, the responses showed an overall concordance rate of 89% with kappa value of 0.83, thus indicating a high degree of inter-observer agreement. This study provides additional validation of the GELA histological grading system. This scheme can therefore be recommended in routine practice and deserves to be used in prospective clinical trials. PMID- 23043301 TI - The salmonid myostatin gene family: a novel model for investigating mechanisms that influence duplicate gene fate. AB - BACKGROUND: Most fishes possess two paralogs for myostatin, a muscle growth inhibitor, while salmonids are presumed to have four: mstn1a, mstn1b, mstn2a and mstn2b, a pseudogene. The mechanisms responsible for preserving these duplicates as well as the depth of mstn2b nonfunctionalization within the family remain unknown. We therefore characterized several genomic clones in order to better define species and gene phylogenies. RESULTS: Gene organization and sequence conservation was particularly evident among paralog groupings and within salmonid subfamilies. All mstn2b sequences included in-frame stop codons, confirming its nonfunctionalization across taxa, although the indels and polymorphisms responsible often differed. For example, the specific indels within the Onchorhynchus tshawytscha and O. nerka genes were remarkably similar and differed equally from other mstn2b orthologs. A phylogenetic analysis weakly established a mstn2b clade including only these species, which coupled with a shared 51 base pair deletion might suggest a history involving hybridization or a shared phylogenetic history. Furthermore, mstn2 introns all lacked conserved splice site motifs, suggesting that the tissue-specific processing of mstn2a transcripts, but not those of mstn2b, is due to alternative cis regulation and is likely a common feature in salmonids. It also suggests that limited transcript processing may have contributed to mstn2b nonfunctionalization. CONCLUSIONS: Previous studies revealed divergence within gene promoters while the current studies provide evidence for relaxed or positive selection in some coding sequence lineages. These results together suggest that the salmonid myostatin gene family is a novel resource for investigating mechanisms that regulate duplicate gene fate as paralog specific differences in gene expression, transcript processing and protein structure are all suggestive of active divergence. PMID- 23043303 TI - Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates. AB - INTRODUCTION: Present article reviews solid dispersion (SD) technologies and other patented inventions in the area of pharmaceutical SDs, which provide stable amorphous SDs. AREAS COVERED: The review briefly compiles different techniques for preparing SDs, their applications, characterization of SDs, types of SDs and also elaborates the carriers used to prepare SDs. The advantages of recently introduced SD technologies such as RightSize(TM), closed-cycle spray drying (CSD), Lidose(r) are summarized. Stability-related issues like phase separation, re-crystallization and methods to curb these problems are also discussed. A patented carrier-screening tool for predicting physical stability of SDs on the basis of drug-carrier interaction is explained. Applications of SD technique in controlled drug delivery systems and cosmetics are explored. Review also summarizes the carriers such as Soluplus(r), Neusilin(r), Solumer(TM) used to prepare stable amorphous SD. EXPERT OPINION: Binary and ternary SDs are found to be more stable and provide better enhancement of solubility or dissolution of poorly water-soluble drugs. The use of surfactants in the carrier system of SD is a recent trend. Surfactants and polymers provide stability against re crystallization of SDs, surfactants also improve solubility and dissolution of drug. PMID- 23043302 TI - Neuropeptides and diabetic retinopathy. AB - Diabetic retinopathy, a common complication of diabetes, develops in 75% of patients with type 1 and 50% of patients with type 2 diabetes, progressing to legal blindness in about 5%. In the recent years, considerable efforts have been put into finding treatments for this condition. It has been discovered that peptidergic mechanisms (neuropeptides and their analogues, activating a diverse array of signal transduction pathways through their multiple receptors) are potentially important for consideration in drug development strategies. A considerable amount of knowledge has been accumulated over the last three decades on human retinal neuropeptides and those elements in the pathomechanisms of diabetic retinopathy which might be related to peptidergic signal transduction. Here, human retinal neuropeptides and their receptors are reviewed, along with the theories relevant to the pathogenesis of diabetic retinopathy both in humans and in experimental models. By collating this information, the curative potential of certain neupeptides and their analogues/antagonists can also be discussed, along with the existing clinical treatments of diabetic retinopathy. The most promising peptidergic pathways for which treatment strategies may be developed at present are stimulation of the somatostatin-related pathway and the pituitary adenylyl cyclase-activating polypeptide-related pathway or inhibition of angiotensinergic mechanisms. These approaches may result in the inhibition of vascular endothelial growth factor production and neuronal apoptosis; therefore, both the optical quality of the image and the processing capability of the neural circuit in the retina may be saved. PMID- 23043304 TI - Prevalence and incidence rates of pressure ulcers in an Emergency Department. AB - Older patients represent an increasing population in emergency department (ED) with underlying diseases and longer ED length of stay, which are potential risk factors of pressure ulcers (PUs). The aim of the study was to determine the prevalence and incidence rates of PUs in an Emergency Department and to analyse variables related to PUs occurrence. The study was carried out in the Emergency Department of Bordeaux (France), and included 602 patients from 1 to 15 June 2010. All the potential body sites of pressure were examined at admission and discharge for all the patients by trained nurses. Comorbidity score, list of treatment, length of stay (hours), PUs (including stage I) and C-reactive protein (CRP) level were systematically recorded. A total of 47 (7.8%) patients had prevalent PUs at admission and 74 (12.3%) at discharge. The cumulative incidence was 4.9% and the incidence density was 5.4 per 1000 patients per hour. In multivariate analysis, higher comorbidities (OR 1.3; P = 0.014) and CRP levels (OR 1.005; P = 0.017) were both independent risk factors for developing PU. In conclusion, these data show that even a very short stay to the ED is sufficient to induce PUs especially stage I. PMID- 23043305 TI - Detecting consciousness: a unique role for neuroimaging. AB - How can we ever know, unequivocally, that another person is conscious and aware? Putting aside deeper philosophical considerations about the nature of consciousness itself, historically, the only reliable method for detecting awareness in others has been through a predicted behavioral response to an external prompt or command. The answer may take the form of spoken words or a nonverbal signal such as a hand movement or the blink of an eye, but it is this answer, and only this answer, that allows us to infer awareness. In recent years, rapid technological developments in the field of neuroimaging have provided new methods for revealing thoughts, actions, and intentions based solely on the pattern of activity that is observed in the brain. In specialized centers, these methods are now being employed routinely to detect consciousness in behaviorally nonresponsive patients when all existing clinical techniques have failed to provide that information. In this review, I compare those circumstances in which neuroimaging data can be used to infer consciousness in the absence of a behavioral response with those circumstances in which it cannot. This distinction is fundamental for understanding and interpreting patterns of brain activity following acute brain injury and has profound implications for clinical care, diagnosis, prognosis, and medical-legal decision-making (relating to the prolongation, or otherwise, of life after severe brain injury). It also sheds light on more basic scientific questions about the nature of consciousness and the neural representation of our own thoughts and intentions. PMID- 23043306 TI - Systematic in vivo screening of a series of 1-propyl-4-arylpiperidines against dopaminergic and serotonergic properties in rat brain: a scaffold-jumping approach. AB - A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3 benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3 benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients. PMID- 23043307 TI - Multistate models for comparing trends in hospitalizations among young adult survivors of colorectal cancer and matched controls. AB - BACKGROUND: Over the past years, the incidence of colorectal cancer has been increasing among young adults. A large percentage of these patients live at least 5 years after diagnosis, but it is unknown whether their rate of hospitalizations after this 5-year mark is comparable to the general population. METHODS: This is a population-based cohort consisting of 917 young adult survivors diagnosed with colorectal cancer in Ontario from 1992-1999 and 4585 matched cancer-free controls. A multistate model is presented to reflect and compare trends in the hospitalization process among survivors and their matched controls. RESULTS: Analyses under a multistate model indicate that the risk of a subsequent hospital admission increases as the number of prior hospitalizations increases. Among patients who are yet to experience a hospitalization, the rate of admission is 3.47 times higher for YAS than controls (95% CI (2.79, 4.31)). However, among patients that have experienced one and two hospitalizations, the relative rate of a subsequent admission decreases to 3.03 (95% CI (2.01, 4.56)) and 1.90 (95% CI (1.19, 3.03)), respectively. CONCLUSIONS: Young adult survivors of colorectal cancer have an increased risk of experiencing hospitalizations compared to cancer free controls. However this relative risk decreases as the number of prior hospitalizations increases. The multistate approach is able to use information on the timing of hospitalizations and answer questions that standard Poisson and Negative Binomial models are unable to address. PMID- 23043308 TI - Conditional survival of cancer patients: an Australian perspective. AB - BACKGROUND: Estimated conditional survival for cancer patients diagnosed at different ages and disease stage provides important information for cancer patients and clinicians in planning follow-up, surveillance and ongoing management. METHODS: Using population-based cancer registry data for New South Wales Australia, we estimated conditional 5-year relative survival for 11 major cancers diagnosed 1972-2006 by time since diagnosis and age and stage at diagnosis. RESULTS: 193,182 cases were included, with the most common cancers being prostate (39,851), female breast (36,585) and colorectal (35,455). Five year relative survival tended to increase with increasing years already survived and improvement was greatest for cancers with poor prognosis at diagnosis (lung or pancreas) and for those with advanced stage or older age at diagnosis. After surviving 10 years, conditional 5-year survival was over 95% for 6 localised, 6 regional, 3 distant and 3 unknown stage cancers. For the remaining patient groups, conditional 5-year survival ranged from 74% (for distant stage bladder cancer) to 94% (for 4 cancers at different stages), indicating that they continue to have excess mortality 10-15 years after diagnosis. CONCLUSION: These data provide important information for cancer patients, based on age and stage at diagnosis, as they continue on their cancer journey. This information may also be used by clinicians as a tool to make more evidence-based decisions regarding follow-up, surveillance, or ongoing management according to patients' changing survival expectations over time. PMID- 23043309 TI - Measurement of the absolute immature platelet number reflects marrow production and is not impacted by platelet transfusion. AB - BACKGROUND: The ability to distinguish increased platelet (PLT) destruction from PLT hypoproduction is important in the care of patients with marrow failure syndromes and patients receiving high-dose chemotherapy. The measurement of immature circulating PLTs based on RNA content using an automated counter is now feasible. This study evaluated the impact of recent PLT transfusion on measurement of immature PLT variables. STUDY DESIGN AND METHODS: The immature PLT fraction (IPF) and absolute immature PLT number (AIPN) were measured using a hematology analyzer before and after PLT transfusion in nine transfusion dependent patients with marrow failure secondary to aplastic anemia, myelodysplasia, or transplantation conditioning. IPF and AIPN were also measured serially over 5 days of storage in three plateletpheresis components collected from normal donors. RESULTS: PLT transfusion did not significantly change the mean AIPN in transfused patients. In contrast, IPF decreased significantly from 6.6 +/- 4.6% on Day -1 to 2.3 +/- 1.4% on Day 0 before returning to 4.3 +/- 2.3% on Day +1. In the PLT component, AIPN and IPF% increased significantly over 5 days of storage, most likely due to an artifact of the staining and detection process for stored PLTs, no longer detected in vivo once the PLTs were transfused. CONCLUSION: PLT transfusion decreases the IPF due to the resultant increase in circulating PLT count. However, PLT transfusion does not change the circulating AIPN, validating this assay as a reflection of ongoing PLT production by the marrow in various clinical settings, regardless of proximity to PLT transfusion. PMID- 23043310 TI - Primary gastric lymphoma: utility of 18F-fluorodeoxyglucose positron emission tomography-computed tomography for detecting relapse after treatment. AB - The purpose of this study was to evaluate the role of 18F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (PET-CT) in detecting relapse in patients with primary gastric lymphoma (PGL) post-treatment. Data of 39 previously treated patients with PGL (age: 50.3 +/- 13.8 years; male: 24) who underwent 71 (18)F-FDG PET-CT studies for suspected relapse (n = 53) or routine follow-up (n = 18) were retrospectively evaluated. PET-CT images were evaluated both qualitatively and quantitatively (standardized uptake value [SUVmax]). A combination of clinical/imaging follow-up, endoscopy and/or histopathology was taken as the reference standard. The per patient based sensitivity of PET-CT was 96%, specificity 91% and accuracy 93%. The lymph node was the commonest site of relapse on PET-CT. Mean lesion SUVmax was 5.9 +/- 3.1 (2.3-13.6). Accuracy was similar in suspected relapse and routine follow-up groups (90.5% vs. 100%; p = 0.409). Based on the data, (18)F-FDG PET-CT appears to be highly accurate for the detection of relapse in patients with PGL post treatment. PMID- 23043311 TI - Role of individual positive charges in the membrane orientation and activity of transporters of the small multidrug resistance family. AB - The effect of individual positively charged residues on the orientation in the membrane was analyzed in three dual-topology transporters of the small multidrug resistance (SMR) family: AAVE4701aave of Acidovorax avenae, EMREecol of Escherichia coli, and RRUA0272rrub of Rhodospirillum rubrum. It is shown that (i) individual positive charges have different impacts on the orientation, (ii) positive charges that are conserved in the three different proteins do not have the same impact on the orientation, (iii) positive charges in odd- and even numbered loops have different impacts, (iv) for some, but not all, the impact depends on the presence of other positive charges, and (v) proteins from which all positive charges are removed in some cases are dual-topology proteins and in other cases have a single orientation. A small number of positive charges placed in the loops of the latter proteins results in the violation of the so-called positive-inside rule that has been reported previously [Kolbusz, M. A., et al. (2010) J. Mol. Biol. 402, 127-138]. We conclude that each positive charge shifts the distribution between the two orientations toward the state that has the positive charge in the cytoplasm but that intrinsic factors other than positive charges determine the orientation as well. The ability of the mutants of AAVE4701aave and EMREecol to confer resistance against ethidium bromide revealed an essential role in catalysis for a conserved pair of positive charges in the second loop. No significant relation between activity and the relative orientation of the monomeric subunits in the dimer could be demonstrated. PMID- 23043312 TI - Imidazole initiates exsheathing of L3 Teladorsagia circumcincta. AB - The infective larvae of Teladorsagia circumcincta have a protective sheath that is lost soon after they reach the rumen of the sheep (the definitive host). Incubation in vitro with 50 mM imidazole caused more than 75% of L3 T. circumcincta to begin exsheathing within 2 hr. The initiation of exsheathing was less likely at pH 6.2 than at pH 7.8. The apparent pKa of this process was 7.08, similar to that for the conversion of imidazolium(+) to imidazole. Both the extent and the initial rate of exsheathing initiation increased with imidazole concentration (the apparent K(1/2) was about 50 mM). The initial rate of exsheathing initiation was stimulated by lactose and maltose, but not by some other carbohydrates, and by propylamine and imidazole acetic acid, but not by histidine. PMID- 23043313 TI - Chemical markers of shiikuwasha juice adulterated with calamondin juice. AB - Detection of shiikuwasha (Citrus depressa Hayata) juice adulterated with calamondin (Citrus madurensis Lour.) juice was investigated by the analyses of (1) phloretin dihydrochalcone glucoside, 3',5'-di-C-beta-glucopyranosylphloretin (PD) detected by thin-layer chromatography and high-performance liquid chromatography (HPLC), (2) polymethoxylated flavones (PMFs), included nobiletin, tangeretin, and sinensetin, detected by HPLC, and (3) gamma-terpinene peak percentage obtained by headspace solid-phase microextraction gas chromatography with cryofocusing. PD was detected in calamondin juice (25.5 mg/100 mL) but not in shiikuwasha juice. Shiikuwasha juice contained higher levels of nobiletin (48.8 mg/100 mL) than calamondin juice (2.4 mg/100 mL). Shiikuwasha juice was characterized by containing a higher percentage of gamma-terpinene (12.3%) than calamondin juice (0.7%). A discrimination function obtained by a linear discriminant analysis with PMFs and a peak ratio of [nobiletin/tangeretin] and gamma-terpinene detected the adulteration with accuracies of 91.7%. These three chemical markers were useful to detect shiikuwasha juice that is suspected of being adulterated with calamondin juice. PMID- 23043314 TI - Changing climate and sea level alter Hg mobility at Lake Tulane, Florida, U.S. AB - Between 45,000 cal years BP and the beginning of the Holocene, the accumulation rate for Hg in sediments of Lake Tulane, Florida ranged from ~2 to 10 MUg m(-2) yr(-1), compared with 53 MUg Hg m(-2) yr(-1) in the 1985-1990 period of anthropogenic input. The locality experienced regional draw-down of the water table during the Wisconsinan glaciation, which lowered global sea level by nearly 130 m. Natural atmospheric deposition of Hg to the surrounding area resulted in long-term (ca. 100,000 years) sequestration of this atmospheric flux of Hg, primarily by adsorption in the oxic Al- and Fe-hydroxide-rich sandy subsoil. Global sea level rise during deglaciation led to a rising regional water table, flooding the oxidized soils surrounding Tulane. Iron and adsorbed Hg were mobilized by reductive dissolution and transported by groundwater flow to Lake Tulane and ultimately to the accumulating sediment. The accumulation rate of Hg (and Fe) increased rapidly about 16,000 cal years BP, peaked at nearly 60 MUg Hg m(-2) yr(-1) ca. 13,000-14,000 cal years BP, declined sharply during the Younger Dryas, and then increased sharply to a second 60 MUg Hg m(-2) yr(-1) peak about 5000 cal years BP. Thereafter, it declined nearly to background by 900 cal years BP. In similar geologic situations, rapid modern sea level rise will initiate this process globally, and may mobilize large accumulations of Hg and lesser amounts of As, and other redox sensitive metals to groundwater and surface water. PMID- 23043315 TI - Is trichloroacetic acid an insufficient sample quencher of redox reactions? AB - The global protein thiol pool has been reported to play a major role in the defense against oxidative stress as a redox buffer similar to glutathione. The present study uses a novel method to visualize cellular changes of the global protein thiol pool in response to induced oxidative stress. Unexpectedly, the results showed an uneven distribution of protein thiols in resting cells with no apparent change in their level or distribution in response to diamide as has been reported previously. Further analysis revealed that thiol pool oxidation is artificially high due to insufficient activity of the widely used sample quencher trichloroacetic acid (TCA). This suggests that previously published articles based on TCA as a quencher should be interpreted with caution as TCA could have caused similar artifacts. Overall, the results presented here question the major role for the global thiol pool in the defense against oxidative stress. Instead our hypothesis is that the fraction of proteins involved in response to oxidative stress is much smaller than previously anticipated in support of a fine-tuned cell signaling by redox regulation. PMID- 23043316 TI - Ir(I)-catalyzed C-H bond alkylation of C2-position of indole with alkenes: selective synthesis of linear or branched 2-alkylindoles. AB - A cationic iridium-catalyzed C2-alkylation of N-substituted indole derivatives with various alkenes has been developed, which selectively gives linear or branched 2-alkylindoles in high to excellent selectivity. This protocol relies on the use of the carbonyl group on the nitrogen atom of indole as a directing group: a linear product was predominant when an acetyl group was used as a directing group, and a branched product was predominant with a benzoyl group. PMID- 23043317 TI - RHD and RHCE variant and zygosity genotyping via multiplex ligation-dependent probe amplification. AB - BACKGROUND: The presence of a D variant may hamper correct serologic D typing, which may result in D immunization. D variants can be determined via RHD genotyping. However, a convenient single assay to identify D variants is still lacking. We developed and evaluated a multiplex ligation-dependent probe amplification (MLPA) assay to determine clinically relevant RHD and RHCE variant alleles and RHD zygosity. STUDY DESIGN AND METHODS: We analyzed 236 cases (73 normal and 163 selected samples) with the RH-MLPA assay, which is able to determine 79 RHD and 17 RHCE variant alleles and RHD zygosity. To confirm the results, mutations were verified by RHD and/or RHCE exon-specific sequencing and RHD zygosity was verified by quantitative real-time polymerase chain reaction (PCR) for 18 cases. RESULTS: In 99% of the cases, the RH-MLPA assay correctly determined whether a person carried only wild-type RHD and RHCE alleles (n = 69) or (a) variant RHD allele(s) and/or (a) variant RHCE allele(s) (n = 164). In only three cases, including two new RHD variant alleles, the variant allele was not identified, due to lack of detecting probes. These were RHD*DCS2, a new partial RHD allele, RHD*525T (Phe175Leu), and a new D- null allele, RHD*443G (Thr148Arg). All RHD (n = 175) and RHCE variant alleles (n = 79) indicated by the RH-MLPA assay were confirmed by sequencing. RHD zygosity was confirmed by quantitative PCR. Two hematopoietic chimeras were recognized. CONCLUSION: The RH-MLPA genotyping assay is a fast, easy, and reliable method to determine almost all clinically relevant RHD and RHCE variant alleles, RHD zygosity, and RHD+/RHD- chimeras in blood donors, blood recipients, and pregnant women. PMID- 23043318 TI - I123-FP-CIT single-photon emission tomography in patients with long-standing mixed tremor. AB - BACKGROUND AND PURPOSE: Essential tremor is an abnormal movement characterized by postural and/or kinetic tremor. In some essential tremor patients, rest tremor (RT) is observed but it is not clear if this RT is a feature of essential tremor or a symptom of Parkinson's disease (PD). I123-FP-CIT single-photon emission tomography is used to distinguish essential tremor and PD. OBJECTIVES: To analyse I123-FP-CIT single-photon emission tomography in a larger series of patients with mixed tremor (i.e. action tremor associated with RT) without PD criteria. METHODS: We studied 33 consecutives patients (18 men and 15 women) with mixed tremor, clinically and by neuroimaging in all cases. RESULTS: I123-FP-CIT single photon emission tomography was abnormal in 25 of our patients (75.7%) with mixed tremor, and we noted a reduced uptake mostly in the putamen. In our patients with abnormal imaging, RT was unilateral in 52%. In 15 of these 25 patients, putaminal reduced uptake was bilateral and symmetrical. In the other 10 patients, putaminal reduced uptake was asymmetrical or unilateral. In these 10 cases, six had a unilateral RT corresponding to (crossed) predominant reduced uptake in three cases. In our patients with normal imaging, RT was unilateral in 87.5%. CONCLUSIONS: This study shows that mixed tremor is a heterogeneous entity. The majority of patients with mixed tremor showed nigrostriatal dysfunction on I123 FP-CIT single-photon emission tomography, suggesting that mixed tremor may be a parkinsonian syndrome rather than a clinical variant of essential tremor. PMID- 23043319 TI - Dasatinib combined with weekly administration of vincristine as effective therapy in sudden or resistant Ph+ lymphoid blast crisis of chronic myeloid leukaemia. PMID- 23043320 TI - Ecophysiological function of leaf 'windows' in Lithops species - 'Living Stones' that grow underground. AB - Leaf temperatures were lower when light entry at the leaf tip window was prevented through covering the window with reflective tape, relative to leaf temperatures of plants with leaf tip windows covered with transparent tape. This was true when leaf temperatures were measured with an infrared thermometer, but not with a fine-wire thermocouple. Leaf tip windows of Lithops growing in high rainfall regions of southern Africa were larger than the windows of plants (numerous individuals of 17 species) growing in areas with less rainfall and, thus, more annual insolation. The results of this study indicate that leaf tip windows of desert plants with an underground growth habit can allow entry of supra-optimal levels of radiant energy, thus most likely inhibiting photosynthetic activity. Consequently, the size of the leaf tip windows correlates inversely with habitat solar irradiance, minimising the probability of photoinhibition, while maximising the absorption of irradiance in cloudy, high rainfall regions. PMID- 23043321 TI - Molecular mapping of QTLs for plant type and earliness traits in pigeonpea (Cajanus cajan L. Millsp.). AB - BACKGROUND: Pigeonpea is an important grain legume of the semi-arid tropics and sub-tropical regions where it plays a crucial role in the food and nutritional security of the people. The average productivity of pigeonpea has remained very low and stagnant for over five decades due to lack of genomic information and intensive breeding efforts. Previous SSR-based linkage maps of pigeonpea used inter-specific crosses due to low inter-varietal polymorphism. Here our aim was to construct a high density intra-specific linkage map using genic-SNP markers for mapping of major quantitative trait loci (QTLs) for key agronomic traits, including plant height, number of primary and secondary branches, number of pods, days to flowering and days to maturity in pigeonpea. RESULTS: A population of 186 F2:3 lines derived from an intra-specific cross between inbred lines 'Pusa Dwarf' and 'HDM04-1' was used to construct a dense molecular linkage map of 296 genic SNP and SSR markers covering a total adjusted map length of 1520.22 cM for the 11 chromosomes of the pigeonpea genome. This is the first dense intra-specific linkage map of pigeonpea with the highest genome length coverage. Phenotypic data from the F2:3 families were used to identify thirteen QTLs for the six agronomic traits. The proportion of phenotypic variance explained by the individual QTLs ranged from 3.18% to 51.4%. Ten of these QTLs were clustered in just two genomic regions, indicating pleiotropic effects or close genetic linkage. In addition to the main effects, significant epistatic interaction effects were detected between the QTLs for number of pods per plant. CONCLUSIONS: A large amount of information on transcript sequences, SSR markers and draft genome sequence is now available for pigeonpea. However, there is need to develop high density linkage maps and identify genes/QTLs for important agronomic traits for practical breeding applications. This is the first report on identification of QTLs for plant type and maturity traits in pigeonpea. The QTLs identified in this study provide a strong foundation for further validation and fine mapping for utilization in the pigeonpea improvement. PMID- 23043322 TI - Structural basis for selective GABA binding in bacterial pathogens. AB - GABA acts as an intercellular signal in eukaryotes and as an interspecies signal in host-microbe interactions. Structural characteristics of selective eukaryotic GABA receptors and bacterial GABA sensors are unknown. Here, we identified the selective GABA-binding protein, called Atu4243, in the plant pathogen Agrobacterium tumefaciens. A constructed atu4243 mutant was affected in GABA transport and in expression of the GABA-regulated functions, including aggressiveness on two plant hosts and degradation of the quorum-sensing signal. The GABA-bound Atu4243 structure at 1.28 A reveals that GABA adopts a conformation never observed so far and interacts with two key residues, Arg(203) and Asp(226) of which the role in GABA binding and GABA signalling in Agrobacterium has been validated using appropriate mutants. The conformational GABA-analogue trans-4-aminocrotonic acid (TACA) antagonizes GABA activity, suggesting structural similarities between the binding sites of the bacterial sensor Atu4243 and mammalian GABA(C) receptors. Exploration of genomic databases reveals Atu4243 orthologues in several pathogenic and symbiotic proteobacteria, such as Rhizobium, Azospirillum, Burkholderia and Pseudomonas. Thus, this study establishes a structural basis for selective GABA sensors and offers opportunities for deciphering the role of the GABA-mediated communication in several host-pathogen interactions. PMID- 23043323 TI - Quantitative traits and mode of speciation in Martinique anoles. AB - We investigate extensive quantitative trait variation (dewlap hue, colour pattern, dorsum hue, body proportions and scalation) in the Martinique anole across eight transects representing nascent parapatric ecological speciation, nascent allopatric speciation and allopatric divergence without sufficient genetic structure to suggest speciation. Quantitative trait divergence can be extremely large between adjacent sets of populations, but with one exception that this is associated with difference in habitat rather than past allopatry. Nascent ecological speciation shows the greatest level of quantitative trait divergence across all character sets including those implicated in natural, as well as sexual selection. The sole example of nascent allopatric speciation is associated with fairly strong quantitative trait divergence among most character sets, but not the set most implicated in natural (rather than sexual) selection. The role of sexual selection in ecological speciation is discussed, both in terms of female choice with assortative mating and male-male competition with condition dependant sexual signals. PMID- 23043324 TI - The developmental genetics of Hirschsprung's disease. AB - Hirschsprung's disease (HSCR), also known as aganglionic megacolon, derives from a congenital malformation of the enteric nervous system (ENS). It displays an incidence of 1 in 5000 live births with a 4:1 male to female sex ratio. Clinical signs include severe constipation and distended bowel due to a non-motile colon. If left untreated, aganglionic megacolon is lethal. This severe congenital condition is caused by the absence of colonic neural ganglia and thus lack of intrinsic innervation of the colon due in turn to improper colonization of the developing intestines by ENS progenitor cells. These progenitor cells are derived from a transient stem cell population called neural crest cells (NCC). The genetics of HSCR is complex and can involve mutations in multiple genes. However, it is estimated that mutations in known genes account for less than half of the cases of HSCR observed clinically. The male sex bias is currently unexplained. The objective of this review is to provide an overview of the pathophysiology and genetics of HSCR, within the context of our current knowledge of NCC development, sex chromosome genetics and laboratory models. PMID- 23043325 TI - Predictors of mortality among children on Antiretroviral Therapy at a referral hospital, Northwest Ethiopia: a retrospective follow up study. AB - BACKGROUND: An estimated 2.5 million children were living with HIV/AIDS at the end of 2009, 2.3 million (92%) in sub-Saharan Africa. Without treatment, a third of children with HIV will die of AIDS before their first birthday, half dying before two years of age. Hence, this study aimed to assess magnitude and predictors of mortality among children on Antiretroviral Therapy (ART) at a referral hospital in North-West Ethiopia. METHODS: Institution based retrospective follow up study was carried out among HIV-positive children from January 1st, 2006 - March 31st, 2011. Information on relevant variables was collected from patients' charts and registries. Life table was used to estimate the cumulative survival of children. Log rank tests were employed to compare survival between the different categories of the explanatory variables. Multivariate Cox proportional hazards model was fitted to identify predictors of mortality. RESULTS: A total of 549 records were included in the analysis. The mean age at initiation of treatment was 6.35 +/- 3.78 SD years. The median follow up period was 22 months. At the end of the follow up, 41(7.5%) were dead and 384(69.9%) were alive. Mortality was 4.0 deaths per 100 child-years of follow-up period. The cumulative probabilities of survival at 3, 6, 12, 24, and 60 months of ART were 0.96, 0.94, 0.93, 0.92 and 0.83 respectively. Majority (90.2%) of the deaths occurred within the first year of treatment. Absence of cotrimoxazole preventive therapy (adjusted hazard ratio [AHR] = 4.74, 95% CI: 2.17, 10.34), anaemia (haemoglobin level < 10 gm/dl) (AHR=2.44, 95% CI: 1.26, 4.73), absolute CD4 cell count below the threshold for severe immunodeficiency (AHR=2.24, 95% CI: 1.07, 4.69) and delayed or regressing developmental milestones at baseline (AHR=6.31, 95% CI: 2.52, 15.83) were predictors of mortality. CONCLUSIONS: There was a high rate of early mortality. Hence, starting ART very early reduces disease progression and early mortality; close follow up of all children of HIV positive mothers is recommended to make the diagnosis and start treatment at an earlier time before they develop severe immunodeficiency. PMID- 23043326 TI - New perspectives in the therapy of castration resistant prostate cancer. AB - Prostate Cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in men in the Western World. Docetaxel-based chemotherapy has been the mainstay of treatment until a few years ago for metastatic castration resistant prostatic cancer (mCRPC). Recently, a broad range of therapeutic options has become available for mCRPC in a variety of settings, including chemotherapeutic agents (cabazitaxel), androgen synthesis inhibitors (abiraterone acetate), androgen receptor (AR) inhibitors (enzalutamide) and immunotherapy (sipuleucel-T). Multiple novel targeted agents are at an advanced stage of experimentation, including androgen synthesis inhibitors (TAK700), AR inhibitors (ARN509), radiopharmaceuticals (radium-223) and immunotherapeutic agents (poxvirus-based vaccine, ipilimumab). This review describes in detail the latest results obtained with a the most promising agents in prostate cancer, with a focus on CRPC biology and mechanism of resistance to anti-neoplastic treatment. PMID- 23043327 TI - Statins: safety and pharmacological interactions. PMID- 23043328 TI - Future of the European Union regulatory network in the context of the uptake of new medicines. PMID- 23043329 TI - Discovery of selective and potent inhibitors of gram-positive bacterial thymidylate kinase (TMK). AB - Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 MUg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog. PMID- 23043330 TI - Investigation of the drug binding properties and cytotoxicity of DNA-capped nanoparticles designed as delivery vehicles for the anticancer agents doxorubicin and actinomycin D. AB - Oligonucleotide-functionalized gold nanoparticles (AuNP) were designed and synthesized to be delivery vehicles for the clinically used anticancer drugs doxorubicin (DOX) and actinomycin D (ActD). Each vehicle contains a tailorable number of DNA duplexes, each possessing three high-affinity sequences for the intercalation of either DOX or ActD, thus allowing for control of drug loading. Drug binding was evaluated by measuring changes to DNA melting temperature, T(m), hydrodynamic diameter, D(h), and surface plasmon resonance wavelength, lambda(spr), with drug loading. These studies indicate that DOX intercalates at its high-affinity sequence bound at the AuNP, and that ActD exhibits relatively weaker binding to its preferred sequence. Agarose gel electrophoresis further confirmed drug binding and revealed that particle mobilities inversely correlate with D(h). The equilibrium binding constant, K, and dissociation rate constant, beta, were determined by dialysis. Results indicate that the high negative electrostatic potential within the DNA shell of the particle significantly decreases beta and enhances K for DOX but has little effect on K and beta for ActD. The cytotoxicity of the vehicles was studied, with IC(50) = 5.6 +/- 1.1 MUM and 46.4 +/- 9.3 nM for DOX-DNA-AuNP and IC(50) = 0.12 +/- 0.07 MUM and 0.76 +/- 0.46 nM for ActD-DNA-AuNP, in terms of drug and particle concentrations, respectively. PMID- 23043331 TI - Oxidative addition of carbon-carbon bonds with a redox-active bis(imino)pyridine iron complex. AB - Addition of biphenylene to the bis(imino)pyridine iron dinitrogen complexes, ((iPr)PDI)Fe(N(2))(2) and [((Me)PDI)Fe(N(2))](2)(MU(2)-N(2)) ((R)PDI = 2,6-(2,6 R(2)-C(6)H(3)-N?CMe)(2)C(5)H(3)N; R = Me, (i)Pr), resulted in oxidative addition of a C-C bond at ambient temperature to yield the corresponding iron biphenyl compounds, ((R)PDI)Fe(biphenyl). The molecular structures of the resulting bis(imino)pyridine iron metallacycles were established by X-ray diffraction and revealed idealized square pyramidal geometries. The electronic structures of the compounds were studied by Mossbauer spectroscopy, NMR spectroscopy, magnetochemistry, and X-ray absorption and X-ray emission spectroscopies. The experimental data, in combination with broken-symmetry density functional theory calculations, established spin crossover (low to intermediate spin) ferric compounds antiferromagnetically coupled to bis(imino)pyridine radical anions. Thus, the overall oxidation reaction involves cooperative electron loss from both the iron center and the redox-active bis(imino)pyridine ligand. PMID- 23043332 TI - A qualitative study into the use of formal services for dementia by carers from culturally and linguistically diverse (CALD) communities. AB - BACKGROUND: People with dementia and their family carers need to be able to access formal services in the community to help maintain their wellbeing and independence. While knowing about and navigating one's way through service systems is difficult for most people, it is particularly difficult for people from culturally and linguistically diverse (CALD) communities. This study addresses a lack of literature on the use of formal services for dementia by people from CALD backgrounds by examining the experiences and perceptions of dementia caregiving within four CALD communities - Italian, Chinese, Spanish and Arabic-speaking - in south western Sydney, Australia. METHODS: The study used a qualitative design and the methods included focus groups with family carers and one-to-one interviews with bilingual/bicultural community workers, bilingual general practitioners and geriatricians. A total of 121 family carers participated in 15 focus groups and interviews were held with 60 health professionals. All fieldwork was audiotaped, transcribed and subjected to thematic analysis. RESULTS: People from CALD communities are often unfamiliar with the concept of formal services and there may be strong cultural norms about maintaining care within the family, rather than relying on external services. CALD communities often have limited knowledge of services. There is a preference for services that will allow families to keep their relative at home, for safety as well as cultural reasons, and they are particularly reluctant to use residential care. While there is a preference for ethno-specific or multicultural services, mainstream services also need to ensure they are more flexible in providing culturally appropriate care. Positive outcomes occur when ethno specific services work in partnership with mainstream programs. Dementia service providers need to develop a trusting relationship with their local CALD communities and promote their services in a way that is understandable and culturally acceptable to members of these communities. CONCLUSIONS: While members of CALD communities may have difficulties accessing formal services, they will use them if they are culturally and linguistically appropriate and can meet their needs. There are a number of ways to improve service provision to CALD communities and the responsibility for this needs to be shared by a range of stakeholders. PMID- 23043333 TI - Perfluoroalkyl and polyfluoroalkyl substances (PFASs) in mineral water and tap water. AB - The aims of the present study were to determine PFAS (perfluoroalkyl and polyfluoroalkyl substances) concentrations in various sources of water intended for human consumption, use these data to calculate the possible uptake via water as well as to estimate the water related health risk to consumers. A total of 177 water samples (119 mineral waters, 26 tap water samples, 18 spring water samples and 14 raw (untreated) water samples) were analyzed using liquid chromatography tandem mass spectrometry for the presence of 10 or 19 PFASs, respectively. PFAS concentrations above the limit of detection of 1 ng/L were found in 52% of all samples. Short-chain PFASs with less than 8 carbon atoms were responsible for 58% of the total PFAS contamination. The highest concentration (sum of PFASs) of 42.7 ng/L was detected in tap water. The calculated maximum uptake of both components for which a tolerable daily intake (TDI) level exists were 0.17 ng/kg bodyweight/day for PFOS (perfluorooctane sulfonic acid) and 0.21 ng/kg bodyweight/day for PFOA (perfluorooctane carboxylic acid). In regard to the model calculations made here (TDI for adults and for infants), the uptake of PFOS and PFOA via consumption of water can be considered negligible. Supplemental materials are available for this article. Go to the publisher's online edition of Journal of Environmental Science and Health, Part A to view the supplemental file. PMID- 23043334 TI - Polyhalogenated aromatic hydrocarbons in surface sediments from Three Gorges Reservoir. AB - This study was conducted to investigate the current contamination status of polyhalogenated aromatic hydrocarbons (PHAHs) in sediments from the mainstream and 22 primary tributaries of the Yangtze River in the Three Gorges Reservoir region. To accomplish this, the concentrations of 22 polybrominated biphenyl (PBB) congeners, 27 polybrominated diphenyl ether (PBDE) congeners, and 27 polychlorinated biphenyl (PCB) congeners in sediment samples were measured by GC MS/MS. The result showed that the observed values of PBBs and PBDEs were 22.41 and 35.24 pg g(-1) dw, respectively. PBB1, 31 and 103 were the predominant PBB congeners, while PBDE28, 47, 77 and 99 were the predominant PBDE congeners. PBB209 and BDE209 were detected in >39% of the samples, with geometric means 2.43 and 11.92 pg g(-1) dw, respectively. PCBs were found to be the predominant compounds in sediment samples among the three PHAH subfamilies, with a geometric mean of 1,231.11 pg g(-1) dw, and PCB8, 18, 28, 52 and 66 were the primary PCB congeners. The measured levels of PHAHs were compared with results recently reported in the literature and their respective sediment quality guidelines recommended by the USEPA. The levels of PHAHs in the present study were generally lower than their respective threshold-effect levels, or were comparable to those reported in relatively uncontaminated freshwater samples from other regions. Taken together, these results suggest that, in the reservoir, toxic biological effects on aquatic biota in response to PHAHs contamination of sediments can be expected to be negligible. PMID- 23043335 TI - Analysis of aryl hydrocarbon receptor ligands in kraft mill effluents by a combination of yeast bioassays and CG-MS chemical determinations. AB - Aryl Hydrocarbon Receptor (AhR) ligands also known as dioxin-like compounds, constitute a substantial part of the total toxicity from many pollution sources, including pulp mill effluents. The aim of this article was to evaluate dioxin like activity in different kraft mill effluents by a combination of yeast bioassays and gas chromatography-mass spectrometry (GC-MS) chemical analysis. The study includes kraft mill effluents from three sources of raw material: Pinus radiata, Eucalyptus globulus and a combination of both (50% each). The Recombinant Yeast Assay (RYA) showed an effective concentration of AhR ligands more than 30-fold higher in Eucalyptus globulus than in Pinus radiata effluents. Our results suggest that specific ligands, rather than the total amount of extractive material, determined the observed activity. Analysis of extract composition by GC-MS indicated that moderately hydrophobic aromatic compounds were likely responsible for the observed dioxin-like activity. In particular, benzaldehyde derivatives appeared as candidates for eliciting the observed dioxin like activity in pulp mill effluents, giving their structural properties and their high concentration in AhR ligand-rich samples. PMID- 23043336 TI - 1-Hydroxypyrene as a biomarker for assessing the effects of exposure to polycyclic aromatic hydrocarbons on semen quality and sperm DNA integrity. AB - A cross-sectional study was conducted to assess whether urinary 1-hydroxypyrene (1-OHP) could serve as a biomarker to assess the effect of PAHs on cellular and molecular changes of sperm. Urine and semen samples were collected from a total of 65 healthy coke oven workers. Sperm quality parameters (concentration, motility, vitality, and morphology) and semen integrity (DNA fragmentation, 8 oxodGuo, bulky DNA adducts) were analyzed. Sixteen (16) targeted PAHs at the personal breathing zone area were monitored and quantified. Results showed that urinary 1-OHP positively correlated with measured levels of 16 targeted PAHs. Urinary 1-OHP did not significantly correlate with semen quality; however, PAHs with heavy molecular weight, e.g., benzo(g,h,i)perylene and benzo(k)fluoranthene, negatively correlated with morphology and motility of sperms (p = 0.02 and 0.002, p = 0.04 and 0.04, respectively). Urinary 1-OHP positively correlated with the level of 8-oxodGuo and bulky DNA adducts, but not DNA fragmentation. Urinary 1 OHP was a suitable biomarker for an estimate of biologically effective doses of PAH exposure. However, urinary 1-OHP may not be sufficient as a biomarker to assess both cellular and molecular changes of sperm induced by PAHs. PMID- 23043337 TI - A pharmaceutical product as corrosion inhibitor for carbon steel in acidic environments. AB - A pharmaceutical product, Trimethoprim (TMP), IUPAC name: 5-(3,4,5 trimethoxybenzyl)pyrimidine-2,4-diamine was investigated, as inhibitor to prevent carbon steel corrosion in acidic environments. The study was performed using weight loss and electrochemical measurements, in temperatures ranging between 25 55 degrees C. The surface morphology before and after corrosion of carbon steel in 1.0 M HCl solution in the presence and absence of TMP was evaluated using scanning electron microscopy (SEM). The inhibition efficiency (IE) increased with the increasing of the inhibitor concentration, reaching a maximum value of 92% at 25 degrees C and 0.9 mM TMP, and decreased with increasing temperature. The inhibition of carbon steel corrosion by TMP can be attributed to the adsorption ability of inhibitor molecules onto the reactive sites of the metal surface. The adsorption is spontaneous and it is best described by the Langmuir isotherm. The apparent activation energy (E(a)) for the corrosion process in the absence and presence of TMP was evaluated from Arrhenius equation, to elucidate its inhibitive properties. PMID- 23043338 TI - Removal of the organic content from a bleached kraft pulp mill effluent by a treatment with silica-alginate-fungi biocomposites. AB - This study attempts a treatment strategy of a bleached kraft pulp mill effluent with Rhizopus oryzae or Pleurotus sajor caju encapsulated on silica-alginate (biocomposite of silica-alginate-fungi, with the purpose of reducing its potential impact in the environment. Active (alive) or inactive (death by sterilization) Rhizopus oryzae or Pleurotus sajor caju was encapsulated in alginate beads. Five beads containing active and inactive fungus were placed in a mold and filled with silica hydrogel (biocomposites). The biocomposites were added to batch reactors containing the bleached kraft pulp mill effluent. The treatment of bleached kraft pulp mill effluent by active and inactive biocomposites was performed throughout 29 days at 28 degrees C. The efficiency of treatment was evaluated by measuring the removal of organic compounds, chemical oxygen demand and the relative absorbance ratio over time. Both fungi species showed potential for removal of organic compounds, colour and chemical oxygen demand. Maximum values of reduction in terms of colour (56%), chemical oxygen demand (65%) and organic compounds (72-79%) were attained after 29 days of treatment of bleached kraft pulp mill effluent by active Rhizopus oryzae biocomposites. The immobilization of fungi, the need for low fungal biomass, and the possibility of reutlization of the biocomposites clearly demonstrate the industrial and environmental interest in bleached kraft pulp mill effluent treatment by silica-alginate-fungi biocomposites. PMID- 23043339 TI - Airborne particulate collected from central Taiwan induces DNA strand breaks, Poly(ADP-ribose) polymerase-1 activation, and estrogen-disrupting activity in human breast carcinoma cell lines. AB - The objectives of this investigation were to examine whether airborne particles induce DNA damaging and estrogen-disrupting effects and to explore the relationships between them. In this study, airborne particulate was collected at an urban, a suburban, and a rural site in central Taiwan. The organic solvent extracts of airborne particulate were examined in human MCF-7 and T47D-KBluc breast cancer cells. We observed significant increases in reactive oxygen species (ROS) generation in MCF-7 cells after treatment with the particulate extracts whereas aryl hydrocarbon receptor (AhR) antagonist blocked the particulate induced ROS generation in cells. Further, induction of CYP1A1 protein expression was confirmed by immunoblots in cells treated with airborne particles, suggesting the roles of AhR status in mediating the particulate-induced toxicity. In addition, we observed that at non-cytotoxic concentration (~0.01 m(3) air equivalent), airborne particles induced decreases in intracellular NAD(P)H and NAD(+) in MCF-7 cells. These decreases were completely blocked by three types of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Moreover, we demonstrated increases in the number of DNA strand breaks in MCF-7 cells exposed to airborne particles as measured by the single-cell gel electrophoresis (Comet) assay. Overall, this evidence confirms that airborne particles induce decreases in intracellular NAD(P)H and NAD(+) through PARP-1 activation mediated by formation of DNA strand breaks. Furthermore, we confirmed that with series dilution airborne particles (~10(-7)-10(-2) m(3) air equivalent) possess both estrogenic and anti-estrogenic activities as determined by the ERalpha-mediated reporter gene assay in human T47D-KBluc breast cancer cells. In conclusions, we confirmed that the DNA-damaging activity and estrogenicity of airborne particles varied considerably with concentration (air equivalent). Our findings add further support to the theme that ROS formation is a significant determinant factor in mediating the induction of oxidative DNA damage and repair in human breast cancer cells exposed to airborne particles and that oxidative stress and the subsequent induction of DNA damage may, in part, contribute to airborne particle-induced carcinogenesis. PMID- 23043340 TI - Application of geoaccumulation index and enrichment factors on the assessment of heavy metal pollution in the sediments. AB - An investigative study was carried out in Langat River to determine the heavy metal pollution in the sediment with 22 sampling stations selected for the collection of sediment samples. The sediment samples were digested and analyzed for extractable metal ((48)Cd, (29)Cu, (30)Zn, (33)As, (82)Pb) using the Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Parameters, such as pH, Eh, electrical conductivity (EC), salinity, cation exchange capacity (CEC) and loss on ignition (LOI) were also determined. The assessment of heavy metal pollution was derived using the enrichment factors (EF) and geoaccumulation index (I(geo)). This study revealed that the sediment is predominantly by As > Cd > Pb > Zn > Cu. As recorded the highest EF value at 187.45 followed by Cd (100.59), Pb (20.32), Zn (12.42) and Cu (3.46). This is similar to the I(geo), which indicates that the highest level goes to As (2.2), exhibits moderately polluted. Meanwhile, Cd recorded 1.8 and Pb (0.23), which illustrates that both of these elements vary from unpolluted to moderately polluted. The Cu and Zn levels are below 0, which demonstrates background concentrations. The findings are expected to update the current status of the heavy metal pollution as well as creating awareness concerning the security of the river water as a drinking water source. PMID- 23043341 TI - Digital analysis technique for uncertainty reduction in colorimetric arsenic detection method. AB - This article proposes an alternative to increase the reliability and reproducibility of a colorimetric method to measure arsenic (As) concentrations. The method of analysis developed incorporates a digital analysis technique to eliminate the operator dependence of results, and As concentrations are quantitatively determined from digital levels computed from photographs of the colorimetric reaction that emerges during the test. This technique allows the sensitivity of the detection to be increased at low concentration ranges, which is of fundamental importance for the detection of As given the current acceptable limit for drinking water. The results obtained show a very good correlation between As concentrations determined by means of analytical laboratory techniques and the method proposed in this research. PMID- 23043342 TI - Ecotoxicological evaluation of waste water from nitrocellulose production. AB - The present study evaluated the toxic potential and physicochemical characteristics of waste water generated in nitrocellulose production, including effluents from delignification, bleaching, nitration and mixture (composed of these three effluents), from a plant in the Paraiba Valley, Sao Paulo, Brazil. The test organisms used for toxicity assays were Daphnia similis, Danio rerio, Escherichia coli, Pseudomonas putida and Pseudokircheneriella subcaptata. The results showed that the effluents analyzed present acute and chronic toxicity for the organisms tested. Nitration effluent was the least toxic, while delignification and bleaching effluents were the most toxic. The naturally occurring pollutants in wood fiber and cotton, like lignin, probably contributed to effluents toxicity, in addition to higher concentrations of total dissolved solids, which are in non-compliance with Brazilian legislation, conductivity, chemical oxygen demand and color. The discharge of nitrocellulose effluent into an aquatic environment should only occur after appropriate treatment, due to their toxic characteristics. PMID- 23043343 TI - Viscum album versus host (Sorbus aucuparia) as bioindicators of urban areas with various levels of pollution. AB - In this investigation we focus on the concentration of elements in Viscum album and its host (Sorbus aucuparia) as bioindicators of urban pollution. These broadly widespread species, very common in polluted areas may provide important information to monitor environmental quality throughout the year, especially for V. album. Cd, Co, Cr, Cu, Fe, Li, Mg, Mn, Ni, Pb and Zn concentrations were measured in the leaves and soil of the tree S. aucuparia as well as in V. album, a semi-parasite living on this tree species. The tree and the semi-parasite were studied in the urban environment of Olawa (SW Poland). This area was selected because of the influence of a zinc smelter on the level of metal pollution of soil and plants and to compare the ability of S. aucuparia and V. album to accumulate metals. V. album appeared to be a better bioaccumulator of Cd, Ni, Pb and Zn and a weaker accumulator of Co than S. aucuparia in less polluted sites of Olawa. S. aucuparia was a better bioaccumulator of Cd, Ni, Pb and Zn and a weaker accumulator of Co than V. album in more polluted sites. Cluster analysis of Cd, Co, Cr, Cu, Fe, Li, Mg, Mn, Ni, Pb and Zn concentrations in plants distinguished sites with lower and higher pollution levels which suggests a possibility of using these species for bioindication. However, the ratio of metals in V. album to S. aucuparia was different depending on the pollution level. PMID- 23043344 TI - Multi-level stressor analysis from the DNA/biochemical level to community levels in an urban stream and integrative health response (IHR) assessments. AB - The objectives of this study were to identify multi-level stressors at the DNA/biochemical level to the community level in fish in an urban stream and to develop an integrative health response (IHR) model for ecological health diagnosis. A pristine control site (S (c) ) and an impacted site (S (i) ) were selected from among seven pre-screened sites studied over seven years. Various chemical analyses indicated that nutrient enrichment (Nitrogen, Phosphorus) and organic pollution were significantly greater (t > 8.783, p < 0.01) at the S (i) site compared to the S (c) site. Single-cell gel electrophoresis (comet assays) of DNA-level impairment indicated significantly (t = 5.678, p < 0.01) greater tail intensity, expressed as % tail-DNA, at the S (i) site and genotoxic responses were detected in the downstream reach. Ethoxyresorufin-O-deethylase (EROD) assays, as a physiological bioindicator, were 2.8-fold higher (p < 0.05, NK-test after ANOVA) at the S (i) site. Tissue analysis using a necropsy-based health assessment index (NHAI) showed distinct internal organ disorders in three tissues, i.e., liver, kidney, and gill, at the S (i) site. Population-level analysis using the sentinel species Zacco platypus showed that the regression coefficient (b) was 3.012 for the S (i) site and 2.915 for the S (c) site, indicating population skewness in the downstream reach. Community-level health was impaired at the S (i) site based on an index of biological integrity (IBI), and physical habitat modifications were identified by a qualitative habitat evaluation index (QHEI). Overall, the model values for the integrative health response (IHR), developed using the star plot approach, were 3.22 (80.5%) at the S (c) site and 0.74 (18.5%) at the S (i) site, indicating that, overall, ecological health impairments were evident in the urban reach. Our study was based on multi-level approaches using biological organization and the results suggest that there is a pivotal point of linkage between mechanistic understanding and real ecological consequences of environmental stressors. PMID- 23043345 TI - Removal of phosphate from water using six Al-, Fe-, and Al-Fe-modified bentonite adsorbents. AB - This study was part of a larger effort that involves evaluating alternatives to upgrading secondary treatment systems in the United Arab Emirates for the removal of nutrients. In this study, six modified bentonite (BNT) phosphate adsorbents were prepared using solutions that contained hydroxy-polycations of aluminum (Al BNT), iron (Fe-BNT), and mixtures of aluminum and iron (Al-Fe-BNT). The adsorption kinetics and capacities of the six adsorbents were evaluated, and the adsorbents were used to remove phosphorus from synthetic phosphate solutions and from treated wastewater. The experimental adsorption kinetics results were well represented by the pseudo-second-order kinetic model, with R(2) values ranging from 0.99 to 1.00. Similarly, the experimental equilibrium adsorption results were well represented by the Freundlich and Langmuir isotherms, with R(2) values ranging from 0.98 to 1.00. The adsorption capacities of the adsorbents were dependent on the BNT preparation conditions; the types, quantities and combination of metals used; BNT particle size; and adsorption pH. The Langmuir maximum adsorption capacities of the six adsorbents ranged from 8.9-14.5 mg P/g BNT. The results suggested that the BNT preparations containing Fe alone or in combination with Al achieved higher adsorption capacities than the preparations containing only Al. However, the Al-BNT preparations exhibited higher adsorption rates than the Fe-BNT preparation. Three of the six adsorbents were used to remove phosphate from secondarily treated wastewater samples, and the removal results were comparable to those obtained using synthetic phosphate solutions. The BNT adsorbents also exhibited adequate settling characteristics and significant regeneration potential. PMID- 23043346 TI - CCL5/RANTES in ANCA-associated small vessel vasculitis. PMID- 23043347 TI - Alkanethiol-passivated ge nanowires as high-performance anode materials for lithium-ion batteries: the role of chemical surface functionalization. AB - We demonstrate that dodecanethiol monolayer passivation can significantly enhance the anode performance of germanium (Ge) nanowires in lithium-ion batteries. The dodecanethiol-passivated Ge nanowires exhibit an excellent electrochemical performance with a reversible specific capacity of 1130 mAh/g at 0.1 C rate after 100 cycles. The functionalized Ge nanowires show high-rate capability having charge and discharge capacities of ~555 mAh/g at high rates of 11 C. The functionalized Ge nanowires also performed well at 55 degrees C, showing their thermal stability at high working temperatures. Moreover, full cells using a LiFePO(4) cathode were assembled and the electrodes still have stable capacity retention. An aluminum pouch type lithium cell was also assembled to provide larger current (~30 mA) for uses on light-emitting-diodes (LEDs) and audio devices. Investigation of the role of organic monolayer coating showed that the wires formed a robust nanowire/PVDF network through strong C-F bonding so as to maintain structure integrity during the lithiation/delithiation process. Organic monolayer-coated Ge nanowires represent promising Ge-C anodes with controllable low carbon content (ca. 2-3 wt %) for high capacity, high-rate lithium-ion batteries and are readily compatible with the commercial slurry-coating process for cell fabrication. PMID- 23043348 TI - Computer-aided molecular modeling study on antibody recognition of small molecules: an immunoassay for triazine herbicides. AB - Most immunoassays for determination of small molecules are still designed on the basis of the "trial and error" method, due to the lack of understanding of antibody recognition. In the present study, we developed a heterologous indirect competitive enzyme-linked immunosorbent assay for determination of triazine herbicides, with limits of detection for 11 triazines ranging from 0.05 to 29.4 MUg/L. Mechanisms of the antigen-antibody interaction were studied by computer aided molecular modeling (CAMM)-based quantitative structure-activity relationship analyses. Co-effects of the analytes' substructural hydrophobic, electrostatic, and steric fields on antibody recognition were further revealed. Hydrophobicity of the antigens was demonstrated to have the most important impact. Even less exposed substituents provided hydrophobic force to the antigen antibody interaction. Dislocated orientation of analyte functional groups could lead to steric hindrance and hydrophobic misleading of antibody recognition. This may happen even when the antigens contained the same substituent as the hapten. Frontier orbital energies also affect the reaction significantly. This study highlights of the power of CAMM-based analyses, providing insights into antibody recognition of small molecules. PMID- 23043349 TI - Diversity and phylogenetic relationships of hemosporidian parasites in birds of Socorro Island, Mexico, and their role in the re-introduction of the Socorro dove (Zenaida graysoni). AB - The Socorro dove Zenaida graysoni , endemic to Socorro Island, was last reported in the wild in 1972. Fortunately, the species has been propagated in zoos in Europe and the United States, and plans are under way to re-introduce it to its native habitat. This will be the first known attempt to return a bird species extinct in the wild to its ancestral island. In order to assess the disease threats the Socorro dove may face, the avifauna of Socorro Island, with a specific focus on Socorro ground doves Columbina passerina socorroensis and mourning doves Zenaida macroura , as well as Socorro doves in captivity, were screened for blood parasites of the genera Plasmodium , Haemoproteus, Leucocytozoon, and Trypanosoma spp. We found Haemoproteus spp. in 17 (74%) of 23 Socorro ground doves, 23 (92%) of 25 mourning doves, and 3 (14%) of 21 northern mockingbirds; none of the other bird species showed infections. Here, we report the phylogenetic analysis of 19 distinct lineages of Haemoproteus spp. detected in birds of Socorro Island and compare their evolutionary relationships to parasites detected in the avifauna of the Galapagos Islands, continental Latin America, and Europe. Microscopic examination revealed 1 mourning dove infected with Plasmodium ( Haemamoeba ), thus underscoring the importance of using both PCR and microscopy when analyzing avian blood samples for hemosporidian parasites. The study confirms that the Socorro dove will most likely be exposed to Haemoproteus spp. that currently infect mourning doves and Socorro ground doves of Socorro Island. A monitoring program for both birds and vectors should be implemented to establish the prevalence of Plasmodium sp. and as a necessary conservation measure for critically endangered birds on the island. PMID- 23043350 TI - Virtual special issue (VSI) on whole-plant water transport. PMID- 23043351 TI - Virtual special issue on [corrected] mesophyll conductance: constraint on carbon acquisition by C3 plants. PMID- 23043352 TI - Synthesis of enaminones by rhodium-catalyzed denitrogenative rearrangement of 1 (N-sulfonyl-1,2,3-triazol-4-yl)alkanols. AB - Enaminones are synthesized by the rhodium(II)-catalyzed denitrogenative rearrangement reaction of 1-(N-sulfonyl-1,2,3-triazol-4-yl)alkanols, which are readily prepared from propargylic alcohols and N-sulfonyl azides. Intramolecular 1,2-hydride (or -alkyl) migration occurs with an intermediary alpha-imino rhodium(II) carbenoid species generated through denitrogenation of the 1,2,3 triazol-4-yl moiety. The resulting enaminones is converted into various heterocycles with replacement of the N-sulfonyl group. PMID- 23043353 TI - X-ray absorption spectroscopy study of novel inorganic-organic hybrid ferromagnetic Cu-pyz-[M(CN)8]3- assemblies. AB - We present a unique interpretation of X-ray absorption spectroscopy (XAS) spectra at Cu:K, W:L(3), and Mo:K edges of structurally related magnetic Cu(II) [M(V)(CN)(8)](3-) compounds. The approach results in description of the structure of novel three-dimensional (3-D) Cu(II)(3)(pyz)[M(V)(CN)(8)](2).xH(2)O, M = W (1), Mo, (2) polymers. Assemblies 1 and 2 represent hybrid inorganic-organic compounds built of {Cu(II)[W(V)(CN)(8)](-)}(n) double-layers linked by cyanido bridged {Cu(II)-(MU-pyz)(2+)}(n) chains. These Cu(II)-M(V) systems reveal long range magnetic ordering with T(c) of 43 and 37 K for 1 and 2, respectively. The presence of the 3-D coordination networks and 8 cyanido-bridges at M(V) centers leads to the highest Curie temperatures and widest hysteresis loops among Cu(II) [M(V)(CN)(8)](3-) systems. PMID- 23043354 TI - Exome sequencing: an efficient diagnostic tool for complex neurodegenerative disorders. AB - BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. We studied three families diagnosed with ARCA. METHODS: To determine the gene lesions responsible for their disorders, we performed high-density single-nucleotide polymorphism genotyping and exome sequencing. RESULTS: We identified a new mutation in the SACS gene and a known mutation in SPG11. Notably, we also identified a homozygous variant in APOB, a gene previously associated with ataxia. CONCLUSIONS: These findings demonstrate that exome sequencing is an efficient and direct diagnostic tool for identifying the causes of complex and genetically heterogeneous neurodegenerative diseases, early-stage disease or cases with limited clinical data. PMID- 23043355 TI - New life in old frames: HIV, development and the 'AIDS plus MDGs' approach. AB - There have been recent indications that the primacy of AIDS among global health issues may be under threat. In this article we examine one response to have emerged from the AIDS policy community as a result of this perceived threat: the 'AIDS plus Millennium Development Goals (MDGs)' approach, which argues that the AIDS response (the focus of MDG6) is essential to achieving the other MDG targets by 2015, stressing the two-way relationship between AIDS and other development issues. By framing AIDS in this way, the AIDS plus MDGs approach draws on an established narrative of a 'virtuous circle' between health and development, but at the same time makes some important concessions to critics of the AIDS response. This article - the first critical academic analysis of the AIDS plus MDGs approach - uses this case to illuminate aspects of the utilisation of framing in global health, shedding light both on the extent to which new framings draw upon established 'common sense' narratives as well as the ways in which framers must adapt to the changing material and ideational context in which they operate. PMID- 23043356 TI - Strategies and utility of imputed SNP genotypes for genomic analysis in dairy cattle. AB - BACKGROUND: We investigated strategies and factors affecting accuracy of imputing genotypes from lower-density SNP panels (Illumina 3K, 7K, Affymetrix 15K and 25K, and evenly spaced subsets) up to one medium (Illumina 50K) and one high-density (Illumina 800K) SNP panel. We also evaluated the utility of imputed genotypes on the accuracy of genomic selection using Australian Holstein-Friesian cattle data from 2727 and 845 animals genotyped with 50K and 800K SNP chip, respectively. Animals were divided into reference and test sets (genotyped with higher and lower density SNP panels, respectively) for evaluating the accuracies of imputation. For the accuracy of genomic selection, a comparison of direct genetic values (DGV) was made by dividing the data into training and validation sets under a range of imputation scenarios. RESULTS: Of the three methods compared for imputation, IMPUTE2 outperformed Beagle and fastPhase for almost all scenarios. Higher SNP densities in the test animals, larger reference sets and higher relatedness between test and reference animals increased the accuracy of imputation. 50K specific genotypes were imputed with moderate allelic error rates from 15K (2.85%) and 25K (2.75%) genotypes. Using IMPUTE2, SNP genotypes up to 800K were imputed with low allelic error rate (0.79% genome-wide) from 50K genotypes, and with moderate error rate from 3K (4.78%) and 7K (2.00%) genotypes. The error rate of imputing up to 800K from 3K or 7K was further reduced when an additional middle tier of 50K genotypes was incorporated in a 3-tiered framework. Accuracies of DGV for five production traits using imputed 50K genotypes were close to those obtained with the actual 50K genotypes and higher compared to using 3K or 7K genotypes. The loss in accuracy of DGV was small when most of the training animals also had imputed (50K) genotypes. Additional gains in DGV accuracies were small when SNP densities increased from 50K to imputed 800K. CONCLUSION: Population-based genotype imputation can be used to predict and combine genotypes from different low, medium and high-density SNP chips with a high level of accuracy. Imputing genotypes from low-density SNP panels to at least 50K SNP density increases the accuracy of genomic selection. PMID- 23043357 TI - The joint contribution of insomnia and obstructive sleep apnoea on sickness absence. AB - Several studies have indicated a high degree of overlap between insomnia and obstructive sleep apnoea, but little is known regarding how the overlap may affect adverse outcomes associated with each of the disorders. The aim of the current study was to examine the separate and combined effects of symptoms of insomnia and obstructive sleep apnoea on long-term sick leave. We used an historical cohort design with 4 years follow-up. Information on sick leave was obtained from Norwegian official registry data, and merged with health information from the Hordaland Health Study in western Norway, 1997-99. A total of 6892 participants aged 40-45 years were assessed for self-reported symptoms of insomnia and obstructive sleep apnoea (snoring and breathing cessations), as well as confounding factors. The level of overlap between insomnia and obstructive sleep apnoea was low (7-12%). Both insomnia and obstructive sleep apnoea alone were significant risk factors for subsequent sick leave after adjusting for confounding factors (odds ratios ranging from 1.4 to 2.3). Having comorbid insomnia and obstructive sleep apnoea increased the risk significantly. There was an additive interaction effect between the two conditions in the unadjusted analyses, but this was reduced to a non-significant level when adjusting for confounders. This study is the first to report the separate and combined effects of insomnia and obstructive sleep apnoea on any adverse outcome. Having both insomnia and obstructive sleep apnoea increased the risk of later sick leave, but there was no evidence of an independent synergy effect of the two conditions. PMID- 23043359 TI - BCL7A protein expression in normal and malignant lymphoid tissues. PMID- 23043358 TI - People living with HIV/AIDS (PLWHA) and HIV/AIDS associated oral lesions; a study in Malaysia. AB - BACKGROUND: The continuous increase in number of people living with HIV/AIDS (PLWHA) represents a serious health and economic burden. HIV positive individuals with oral lesions have significantly lower oral health-related quality of life than HIV positive individuals without oral lesions. The objective of this study was to assess the knowledge, attitude and practices (KAP) within a cohort of HIV/AIDS positive patients towards HIV/AIDS associated oral lesions. METHODS: Two hundred seventy patients attending a national referral hospital of infectious disease in Malaysia were recruited for the study. The study involved the administration of a validated interview-based questionnaire designed to elicit knowledge, attitude and practices of these patients towards HIV associated oral lesions. The last part of the questionnaire assessed the training provided to the patients in relation to the oral lesions associated with the disease and the effectiveness of this training. Data analysis was carried out using SPSS version 18. RESULTS: Thirty seven percent of patients were reported as knowledgeable, while sixty four percent reported to have positive attitude towards the care of oral hygiene. Sixty six percent of the patients reported that they would seek professional care when experiencing oral lesion. Training was reported effective for 93% patients. CONCLUSIONS: Patients were non-knowledgeable in relation to oral manifestations of the disease and one third of the participating patients showed negative attitudes towards oral health care and reported various measures to manage oral lesions rather than seeking professional care. Developing effective educational methodologies can empower patients with knowledge that may translate to positive attitudes and practices. PMID- 23043361 TI - Insulin-regulated expression of adiponectin receptors in muscle and fat cells. AB - Adp (adiponectin), an adipocyte-secreted hormone, exerts its effect via its specific receptors, AdipoR1 and AdipoR2 (adiponectin receptors 1 and 2), on insulin-sensitive cells in muscle, liver and adipose tissues, and plays an important role in lipid and glucose metabolisms. The study has investigated the effect of insulin on AdipoRs expression in muscle and fat cells. Differentiated fat [3T3-L1 (mouse adipocytes)], L6 (skeletal muscle) and vascular smooth muscle (PAC1) cells were serum starved and exposed to 100 nM insulin for 1-24 h. AdipoR1 and AdipoR2 mRNAs expression was monitored by real-time PCR. The results demonstrate that insulin down-regulates both AdipoR1 and AdipoR2 mRNAs levels in a biphasic manner in L6 and PAC1 cells. Insulin had little or no effect in the regulation of AdipoR1 expression in 3T3-L1 cells, but significantly up-regulated AdipoR2 mRNA level in a biphasic manner. The fact that insulin differentially regulates the expression of AdipoR1 and AdipoR2 in muscle and fat cells suggests this is also dependent on the availability of the endogenous ligand, such as Adp for AdipoR1 and AdipoR2 in fat cells. The effects of globular Adp were also tested on insulin-regulated expression of AdipoRs in L6 cells, and found to up regulate and counter insulin-mediated suppression of AdipoRs expression in L6 cells. PMID- 23043360 TI - The ribosome binding site of a mini-ORF protects a T3SS mRNA from degradation by RNase E. AB - Enterohaemorrhagic Escherichia coli harbours a pathogenicity island encoding a type 3 secretion system used to translocate effector proteins into the cytosol of intestinal epithelial cells and subvert their function. The structural proteins of the translocon are encoded in a major espADB mRNA processed from a precursor. The translocon mRNA should be highly susceptible to RNase E cleavage because of its AU-rich leader region and monophosphorylated 5'-terminus, yet it manages to avoid rapid degradation. Here, we report that the espADB leader region contains a strong Shine-Dalgarno element (SD2) and a translatable mini-ORF of six codons. Disruption of SD2 so as to weaken ribosome binding significantly reduces the concentration and stability of esp mRNA, whereas codon substitutions that impair translation of the mini-ORF have no such effect. These findings suggest that occupancy of SD2 by ribosomes, but not mini-ORF translation, helps to protect espADB mRNA from degradation, likely by hindering RNase E access to the AU-rich leader region. PMID- 23043362 TI - Noradrenergic reuptake inhibition in the treatment of pain. AB - INTRODUCTION: Noradrenergic reuptake inhibitors can be effective analgesics, finding application in a wide variety of clinical pain settings. Due to a shift toward noradrenergic-mediated pain pathways following nerve injury, they are particularly well suited to the treatment of neuropathic pain. This phenotypic shift makes neuropathic pain difficult to control with opioids alone; some noradrenergic reuptake inhibitors have demonstrated synergy with opioids. Agents currently in early clinical trials are discussed and include both novel delivery of old drugs and the development of new drugs. AREAS COVERED: This review was limited to noradrenergic reuptake inhibitors and analgesia. Literature search included the terms adrenergic, noradrenergic, reuptake, inhibitors, analgesia, NET, norepinephrine transporter, and pain using Medline, Google scholar, Web of Knowledge, www.clinicaltrials.gov, and Pharmaprojects (Informa UK Ltd. 2012). EXPERT OPINION: Topical drug delivery and the use of combinations of agents both topically and systemically are under active investigation. The intrathecal delivery of noradrenergic reuptake inhibitors, allowing delivery directly to the central nervous system thus limiting systemic exposure, represents an exciting avenue of investigation. Gaps in current knowledge have complicated the development of prophylactic therapies for susceptible individuals or preemptive intervention. Disease-modifying agents and selective inhibitors would facilitate these treatment strategies. PMID- 23043364 TI - Sex-specific interaction between arbuscular mycorrhizal and dark septate fungi in the dioecious plant Antennaria dioica (Asteraceae). AB - Male and female plants of dioecious species often differ in their resource demands and this has been linked to secondary sexual dimorphism, including sex specific interactions with other organisms such as herbivores and pollinators. However, little is known about the interaction between dioecious plants and fungal root endophytes. Plants may be simultaneously colonised by arbuscular mycorrhizal (AM) and dark septate (DS) fungi. While it is well established that AM mutualism involves reciprocal transfer of photosynthates and mineral nutrients between roots of host plants and these fungi, the role of DS fungi remains controversial. Here, we report the temporal and spatial variation in AM and DS fungi in female, male and non-reproductive Antennaria dioica plants in three natural populations in Finland during flowering and after seed production. Females had higher colonisation by AM fungi, but lower colonisation by DS fungi than male and non-reproductive plants. The higher AM colonisation was observed during flowering, and this difference varied among populations. Our results suggest that females and males of A. dioica interact with AM and DS fungi differently and that this relationship is dependent on soil fertility. PMID- 23043363 TI - Individual RNA base recognition in immobilized oligonucleotides using a protein nanopore. AB - Protein nanopores are under investigation as key components of rapid, low-cost platforms to sequence DNA molecules. Previously, it has been shown that the alpha hemolysin (alphaHL) nanopore contains three recognition sites, capable of discriminating between individual DNA bases when oligonucleotides are immobilized within the nanopore. However, the direct sequencing of RNA is also of critical importance. Here, we achieve sharply defined current distributions that enable clear discrimination of the four nucleobases, guanine, cytosine, adenine, and uracil, in RNA. Further, the modified bases, inosine, N(6)-methyladenosine, and N(5)-methylcytosine, can be distinguished. PMID- 23043365 TI - Neural crest and somitic mesoderm as paradigms to investigate cell fate decisions during development. AB - The dorsal domains of the neural tube and somites are transient embryonic epithelia; they constitute the source of neural crest progenitors that generate the peripheral nervous system, pigment cells and ectomesenchyme, and of the dermomyotome that develops into myocytes, dermis and vascular cells, respectively. Based on the variety of derivatives produced by each type of epithelium, a classical yet still highly relevant question is whether these embryonic epithelia are composed of homogeneous multipotent progenitors or, alternatively, of subsets of fate-restricted cells. Growing evidence substantiates the notion that both the dorsal tube and the dermomyotome are heterogeneous epithelia composed of multipotent as well as fate-restricted precursors that emerge as such in a spatio-temporally regulated manner. Elucidation of the state of commitment of the precedent progenitors is of utmost significance for deciphering the mechanisms that regulate fate segregation during embryogenesis. In addition, it will contribute to understanding the nature of well documented neural crest-somite interactions shown to modulate the timing of neural crest cell emigration, their segmental migration, and myogenesis. PMID- 23043366 TI - Synthesis and evaluation of diastereoisomers of 1,4,7-triazacyclononane-1,4,7 tris-(glutaric acid) (NOTGA) for multimeric radiopharmaceuticals of gallium. AB - In the conventional synthesis of 1,4,7-tris-(glutaric acid)-1,4,7 triazacyclononane (NOTGA), four isomeric species are usually generated by the alkylation of 1,4,7-triazacyclononane with alpha-bromoglutaric acid diester. To estimate their biological efficacies as well as their stability and radiochemistry, the RRR/SSS and RRS/SSR NOTGA-(t)Bu prochelators were isolated and the corresponding cyclic RGDfK (RGD) conjugates with triethylene glycol linkages were prepared. The RRR/SSS and RRS/SSR diastereomers were obtained in 69% and 17% yields, respectively. In the complexation reaction with (67)GaCl(3), both diastereomers provided >98% radiochemical yields at pH 5 within 10 min when the reaction was conducted at room temperature. However, the RRR/SSS diastereomer exhibited more pH-sensitive radiochemical yields between pH 3.5 to 4.5. Despite their diasteromeric nature, both (67)Ga-labeled RGD-NOTGA remained stable during the apo-transferrin challenge, exhibiting similar affinity for integrin alpha(v)beta(3) and biodistribution with predominant renal excretion. Similar tumor uptake was also observed in mice bearing U87MG tumor xenograft, which resulted in impressively high contrast SPECT/CT images. These findings indicate that the RGD-NOTGA conjugates of both diastereomers presented here possess equivalent biological efficacies and their combined usage would be feasible. It is worth noting that specific properties of a given biomolecule, cell expression levels of the corresponding target molecule, and presence or absence of a pharmacokinetic modifier would affect the structural differences between diastereomers on the ligand-receptor interactions and pharmacokinetics. Thus, the preparation of corresponding conjugates and evaluation of their chemical and biological performances still remains important for applying NOTGA to other biomolecules of interest using the diastereomerically pure NOTGA-(t)Bu prochelator. PMID- 23043367 TI - Influence of film composition on the morphology, mechanical properties, and surfactant recovery of phase-separated phospholipid-perfluorinated fatty acid mixed monolayers. AB - Monolayer surfactant films composed of a mixture of phospholipids and perfluorinated (or partially fluorinated) surfactants are of potential utility for applications in pulmonary lung surfactant-based therapies. As a simple, minimal model of such a lung surfactant system, binary mixed monolayer films composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and perfluorooctadecanoic acid (C18F) prepared on a simplified lung fluid mimic subphase (pH 7.4, 150 mM NaCl) have been characterized in terms of mixing thermodynamics and compressibility (measured through pi-A compression isotherms), film morphology (via atomic force, fluorescence, and Brewster angle microscopy), as well as spreading rate and hysteresis response to repeated expansion contraction cycles for a variety of compositions of mixed films. Under all mixing conditions, films and their components were found to be completely immiscible and phase-separated, though there were significant changes in the aforementioned film properties as a function of composition. Of particular note was the existence of a maximum in the extent of immiscibility (characterized by DeltaG(ex)(pi) values) and enhanced surfactant recovery during hysteresis experiments at chi(C18F) >= 0.30. The latter was attributed to the relatively rapid respreading rate of the perfluorinated amphiphile in comparison with DPPC alone at the air-water interface, which enhances the performance of this mixture as a potential pulmonary lung surfactant. Further, monolayer film structure could be tracked dynamically as a function of compression at the air-water interface via Brewster angle microscopy, with the C18F component being preferentially squeezed out of the film with compression, but returning rapidly upon re-expansion. In general, addition of C18F to DPPC monolayers resulted in improvements to mechanical, structural, and respreading properties of the film, indicating the potential value of these compounds as additives to pulmonary lung surfactant formulations. PMID- 23043368 TI - Safety, tolerability and pharmacokinetics of a human anti-interleukin-13 monoclonal antibody (CNTO 5825) in an ascending single-dose first-in-human study. AB - AIMS: To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 5825 following single-dose intravenous (i.v.) and subcutaneous (s.c.) administration in healthy and healthy atopic subjects. METHODS: Sixty-four subjects received a single dose of placebo or CNTO 5825 (0.1, 0.3, 1.0, 3.0, or 10 mg kg(-1) i.v. in a dose-escalating manner, or 3.0 mg kg(-1) s.c. in healthy subjects; and 10 mg kg(-1) i.v. in healthy atopic subjects). Subjects were observed for 96 h postadministration and followed for 16 weeks. Safety and tolerability were monitored, and serum samples were collected to measure CNTO 5825 concentrations, antibodies to CNTO 5825 and PD biomarkers. RESULTS: Most adverse events were mild to moderate in severity and considered to be unrelated to CNTO 5825, with no dose-dependent trends seen. The two serious adverse events were considered to be unrelated to CNTO 5825. After i.v. administration, CNTO 5825 exhibited linear PK, with a terminal half-life of ~22 32 days. After a single 3 mg kg(-1) s.c. dose in healthy subjects, CNTO 5825 was absorbed into the systemic circulation with a median time to maximum serum concentration (tmax) of 5.45 days and absolute bioavailability of ~75%. The PK profile of CNTO 5825 at 10 mg kg(-1) was similar in both healthy and healthy atopic subjects. No antibodies to CNTO 5825 were detected through week 16. In the CNTO 5825-treated healthy atopic subjects, there was a significant reduction in serum IgE and C-C motif chemokine ligand 17 (P = 0.028 and 0.068 vs. placebo, respectively). CONCLUSIONS: CNTO 5825 was well tolerated, had an acceptable safety profile, exhibited linear PK characteristics, and no detected antibodies to CNTO 5825. PMID- 23043369 TI - Polyethylenimine-capped Ag nanoparticle film as a platform for detecting charged dye molecules by surface-enhanced Raman scattering and metal-enhanced fluorescence. AB - Many drugs are charged molecules and are weak bases or acids having counterions. Their binding to biological surfaces is generally difficult to assess by vibrational spectroscopy. In this work, we demonstrated the potential of surface enhanced Raman scattering (SERS) conducted using a polyethylenimine (PEI)-capped Ag nanoparticle film for the quantification of an electrostatic adsorption process of charged drug molecules, by using charged dye molecules such as sulforhodamine B (SRB) and rhodamine-123 (R123) as model drugs. It was possible to detect small-sized anions such as SCN(-) at 1 * 10(-9) M by SERS because of the cationic property of PEI. We were subsequently able to detect a prototype anionic dye molecule, SRB, by SERS at a subnanomolar concentration. On the other hand, it was difficult to detect cationic dyes such as R123 because of the electrostatically repulsive interaction with PEI. Nonetheless, we found that even R123 could be detected at subnanomolar concentrations by SERS by depositing an anionic polyelectrolyte such as poly(sodium 4-styrenesulfonate) (PSS) and poly(acrylic acid) (PAA) onto the PEI-capped Ag nanoparticles. Another noteworthy point is that a subnanomolar detection limit can also be achieved by carefully monitoring the fluorescence background in the measured SERS spectra. This was possible because charged dyes were not in contact with Ag but formed ion pairs with either PEI or PSS (PAA), allowing metal-enhanced fluorescence (MEF). The PEI capped Ag nanoparticle film can thus serve as a useful indicator to detect charged drug molecules by SERS and MEF. PMID- 23043371 TI - The importance of nanocrystal precursor conversion kinetics: mechanism of the reaction between cadmium carboxylate and cadmium bis(diphenyldithiophosphinate). AB - We describe the synthesis of cadmium bis(diphenyldithiophosphinate) (Cd(S(2)PPh(2))(2)) from secondary phosphine sulfides and its conversion to cadmium sulfide nanocrystals. Heating Cd(S(2)PPh(2))(2) and cadmium tetradecanoate (>=4 equiv) to 240 degrees C results in complete conversion of Cd(S(2)PPh(2))(2) to cadmium sulfide nanocrystals with tetradecanoate surface termination. The nanocrystals have a narrow size distribution (d = 3.8-4.1 nm, sigma < 10%) that is evident from the line width of the lowest energy absorption feature (lambda = 412-422 nm, fwhm = 0.17 eV) and display bright photoluminescence (PLQY(band edge+trap) = 36%). Interestingly, the final diameter is insensitive to the reaction conditions, including the total concentration of precursors and initial cadmium to sulfur ratio. Monitoring the reaction with (31)P NMR, UV-visible, and infrared absorption spectroscopies shows that the production of cadmium diphenylphosphinate (Cd(O(2)PPh(2))(2)) and tetradecanoic anhydride co-products is coupled with the formation of cadmium sulfide. From these measurements we propose a balanced chemical equation for the conversion reaction and use it to optimize a synthesis that affords CdS nanocrystals in quantitative yield. In light of these results we discuss the importance of well defined precursor reactivity to reproducible conversion kinetics and the synthesis of nanocrystals with unambiguous chemical composition. PMID- 23043370 TI - (S)-N-(2,5-Dimethylphenyl)-1-(quinoline-8-ylsulfonyl)pyrrolidine-2-carboxamide as a small molecule inhibitor probe for the study of respiratory syncytial virus infection. AB - A high-throughput, cell-based screen was used to identify chemotypes as inhibitors for human respiratory syncytial virus (hRSV). Optimization of a sulfonylpyrrolidine scaffold resulted in compound 5o that inhibited a virus induced cytopathic effect in the entry stage of infection (EC50 = 2.3 +/- 0.8 MUM) with marginal cytotoxicity (CC50 = 30.9 +/- 1.1 MUM) and reduced viral titer by 100-fold. Compared to ribavirin, sulfonylpyrrolidine 5o demonstrated an improved in vitro potency and selectivity index. PMID- 23043372 TI - The galactosamine residue in mycobacterial arabinogalactan is alpha-linked. AB - Previous studies have demonstrated that cell wall arabinogalactan from mycobacteria possesses a single galactosamine (GalN) residue. This moiety, which is one of the rare natural occurrences of galactosamine lacking an acetyl group on the nitrogen, has been identified as a pendant substituent attached to a highly branched arabinofuranose residue in the arabinan core. However, the stereochemistry by which the GalN residue is linked to the polysaccharide remains unknown. We report here the synthesis of two tetrasaccharides, 1 and 2, consisting of GalN attached through either an alpha- or beta-linkage to a trisaccharide fragment of mycobacterial arabinan. These molecules represent the first synthetic GalN-containing oligosaccharides, and the preparation of both targets was achieved from a single donor species by modulation of the reaction solvent. Comparison of the NMR spectra of 1 and 2 with those obtained from a sample derived from the natural glycan revealed that the GalN residue in the polysaccharide is attached via an alpha-linkage. PMID- 23043374 TI - Rheumatoid factor-positive synovitis in a patient with C3 deficiency. PMID- 23043373 TI - Novel polyoxins generated by heterologously expressing polyoxin biosynthetic gene cluster in the sanN inactivated mutant of Streptomyces ansochromogenes. AB - BACKGROUND: Polyoxins are potent inhibitors of chitin synthetases in fungi and insects. The gene cluster responsible for biosynthesis of polyoxins has been cloned and sequenced from Streptomyces cacaoi and tens of polyoxin analogs have been identified already. RESULTS: The polyoxin biosynthetic gene cluster from Streptomyces cacaoi was heterologously expressed in the sanN inactivated mutant of Streptomyces ansochromogenes as a nikkomycin producer. Besides hybrid antibiotics (polynik A and polyoxin N) and some known polyoxins, two novel polyoxin analogs were accumulated. One of them is polyoxin P that has 5 aminohexuronic acid with N-glycosidically bound thymine as the nucleoside moiety and dehydroxyl-carbamoylpolyoxic acid as the peptidyl moiety. The other analog is polyoxin O that contains 5-aminohexuronic acid bound thymine as the nucleoside moiety, but recruits polyoximic acid as the sole peptidyl moiety. Bioassay against phytopathogenic fungi showed that polyoxin P displayed comparatively strong inhibitory activity, whereas the inhibitory activity of polyoxin O was weak under the same testing conditions. CONCLUSION: Two novel polyoxin analogs (polyoxin P and O) were generated by the heterologous expression of polyoxin biosynthetic gene cluster in the sanN inactivated mutant of Streptomyces ansochromogenes. Polyoxin P showed potent antifungal activity,while the activity of polyoxin O was weak. The strategy presented here may be available for other antibiotics producers. PMID- 23043375 TI - Immunomodulatory potential of partially hydrolyzed beta-lactoglobulin and large synthetic peptides. AB - The immunomodulatory potential of fragments derived from the cow's milk allergen bovine beta-lactoglobulin (BLG) was assessed in a mouse model of oral tolerance (OT) [Adel-Patient, K.; Wavrin, S.; Bernard, H.; Meziti, N.; Ah-Leung, S.; Wal, J. M. Oral tolerance and Treg cells are induced in BALB/c mice after gavage with bovine beta-lactoglobulin. Allergy 2011, 66 (10), 1312-1321]. Native BLG (nBLG) and chemically denatured BLG (lacking S-S bridges, dBLG), products resulting from their hydrolysis using cyanogen bromide (CNBr) and some synthetic peptides, were produced and precisely characterized. CNBr hydrolysates correspond to pools of peptides of various sizes that are still associated by S-S bridges when derived from nBLG. nBLG, dBLG, and CNBr hydrolysate of nBLG efficiently prevented further sensitization. CNBr hydrolysate of dBLG was less efficient, suggesting that the association by S-S bridges of peptides increased their immunomodulatory potential. Conversely, synthetic peptides were inefficient even if covering 50% of the BLG sequence, demonstrating that the immunomodulatory potential requires the presence of all derived fragments of BLG and further supporting the use of partially hydrolyzed milk proteins to favor OT induction in infants with a risk of atopy. PMID- 23043376 TI - Do hemodialysis adequacy data reflect reality? AB - Hemodialysis (HD) adequacy requires monitoring in line with standards and at appropriate intervals. However, the use of inappropriate or incorrectly applied techniques in the determination of HD adequacy can lead to highly unfortunate results. This study was intended to identify the path to a solution by determining how far HD adequacy in HD centers in our region reflects reality. Three hundred and thirty HD patients from eight centers were included. On the first visit, predialysis and postdialysis blood collection with the centers' own methods being used were observed and errors were recorded. Kt/V1 was calculated from pre- and postdialysis blood specimens taken by the units themselves. On the second visit, one session later, pre- and postdialysis blood samples were collected in line with guidelines by ourselves, the authors, and Kt/V2 was calculated from these samples. The eight units' total Kt/V2 value was significantly lower compared with Kt/V1 (<0.0001). The level of patients in all centers with Kt/V1 <1.2 was 13.5%, and that of patients with Kt/V2 <1.2 was 22.1%. No center, apart from one unit, managed to complete the collection of blood specimens as recommended by the guidelines. With one exception, blood collection for HD adequacy was not performed using proper technique in any center. This simple but easily overlooked situation, HD being regarded as adequate though in fact it is not, may lead to patients not being treated effectively and accurately and to a rise in mortality and morbidity in the long term. PMID- 23043377 TI - Local structure and global patterning of Cu2+ binding in fibrillar amyloid-beta [Abeta(1-40)] protein. AB - The amyloid-beta (Abeta) protein forms fibrils and higher-order plaque aggegrates in Alzheimer's disease (AD) brain. The copper ion, Cu(2+), is found at high concentrations in plaques, but its role in AD etiology is unclear. We use high resolution pulsed electron paramagnetic resonance spectroscopy to characterize the coordination structure of Cu(2+) in the fibrillar form of full-length Abeta(1 40). The results reveal a bis-cis-histidine (His) equatorial Cu(2+) coordination geometry and participation of all three N-terminal His residues in Cu(2+) binding. A model is proposed in which Cu(2+)-His6/His13 and Cu(2+)-His6/His14 sites alternate along the fibril axis on opposite sides of the beta-sheet fibril structure. The local intra-beta-strand coordination structure is not conducive to Cu(2+)/Cu(+) redox-linked coordination changes, and the global arrangement of Cu sites precludes facile multielectron and bridged-metal site reactivity. This indicates that the fibrillar form of Abeta suppresses Cu redox cycling and reactive oxygen species production. The configuration suggests application of Cu(2+)-Abeta fibrils as an amyloid architecture for switchable electron charge/spin coupling and redox reactivity. PMID- 23043379 TI - Cross-border health care utilization among the Hispanic population in the United States: implications for closing the health care access gap. AB - OBJECTIVES: To examine predictors of health care service utilization in Mexico or any other country in Latin America among the U.S. Hispanic population. METHODS: This study used data from the 2007 Pew Hispanic Healthcare Survey, a nationally representative survey of 4013 Hispanic adults. Using the Behavioral Model of Health Service Use (BMHSU) model, we examined three levels of predictive factors: (1) predisposing characteristics (e.g., language proficiency), (2) enabling resources (e.g., health insurance status), and (3) need (e.g., self-perceived health status). Multivariate logistic regression analyses were conducted to predict odds of seeking health care services in Mexico or any other country in Latin America. RESULTS: As hypothesized, lack of continuous health insurance coverage, perceived lack of quality health care, and low English proficiency increased the likelihood of seeking health care in Mexico or any other Latin American country among US Hispanic adults. Self-reported health status and usual source of care, however, were not significant predictors. CONCLUSIONS: Hispanic immigrants face critical access gaps to health care in the United States. Implications for closing the access gap for this population are discussed within the context of health care system reform and immigration reform in the United States. PMID- 23043378 TI - Molecular characteristics of erythromycin-resistant Streptococcus pneumoniae from pediatric patients younger than five years in Beijing, 2010. AB - BACKGROUND: Streptococcus pneumoniae is the main pathogen that causes respiratory infections in children younger than five years. The increasing incidence of macrolide- and tetracycline-resistant pneumococci among children has been a serious problem in China for many years. The molecular characteristics of erythromycin-resistant pneumococcal isolates that were collected from pediatric patients younger than five years in Beijing in 2010 were analyzed in this study. RESULTS: A total of 140 pneumococcal isolates were collected. The resistance rates of all isolates to erythromycin and tetracycline were 96.4% and 79.3%, respectively. Of the 135 erythromycin-resistant pneumococci, 91.1% were non susceptible to tetracycline. In addition, 30.4% of the erythromycin-resistant isolates expressed both the ermB and mef genes, whereas 69.6% expressed the ermB gene but not the mef gene. Up to 98.5% of the resistant isolates exhibited the cMLSB phenotype, and Tn6002 was the most common transposon present in approximately 56.3% of the resistant isolates, followed by Tn2010, with a proportion of 28.9%. The dominant sequence types (STs) in all erythromycin resistant S. pneumoniae were ST271 (11.9%), ST81 (8.9%), ST876 (8.9%), and ST320 (6.7%), whereas the prevailing serotypes were 19F (19.3%), 23F (9.6%), 14 (9.6%), 15 (8.9%), and 6A (7.4%). The 7-valent pneumococcal conjugate vaccine (PCV7) and 13-valent pneumococcal conjugate vaccine (PCV13) coverage of the erythromycin resistant pneumococci among the children younger than five years were 45.2% and 62.2%, respectively. ST320 and serotype 19A pneumococci were common in children aged 0 to 2 years. CC271 was the most frequent clonal complex (CC), which accounts for 24.4% of all erythromycin-resistant isolates. CONCLUSIONS: The non invasive S. pneumoniae in children younger than five years in Beijing presented high and significant resistance rates to erythromycin and tetracycline. The expressions of ermB and tetM genes were the main factors that influence pneumococcal resistance to erythromycin and tetracycline, respectively. Majority of the erythromycin-resistant non-invasive isolates exhibited the cMLSB phenotype and carried the ermB, tetM, xis, and int genes, suggesting the spread of the transposons of the Tn916 family. PCV13 provided higher serotype coverage in the childhood pneumococcal diseases caused by the erythromycin-resistant isolates better than PCV7. Further long-term surveys are required to monitor the molecular characteristics of the erythromycin-resistant S. pneumoniae in children. PMID- 23043380 TI - Anion-induced self-assembly of luminescent and magnetic homoleptic cyclic tetranuclear Ln4(salen)4 and Ln4(salen)2 complexes (Ln = Nd, Yb, Er, or Gd). AB - Unique homoleptic cyclic tetranuclear Ln(4)(Salen)(4) complexes [Ln(4)(L)(2)(HL)(2)(MU(3)-OH)(2)Cl(2)].2Cl (Ln = Nd, 1; Ln = Yb, 2; Ln = Er, 3; Ln = Gd, 4) or Ln(4)(Salen)(2) complexes [Ln(4)(L)(2)(MU(3)-OH)(2)(OAc)(6)] (Ln = Nd, 5; Ln = Yb, 6; Ln = Er, 7; Ln = Gd, 8) have been self-assembled from the reaction of the hexadentate Salen-type Schiff-base ligand H(2)L with LnCl(3).6H(2)O or Ln(OAc)(6).6H(2)O (Ln = Nd, Yb, Er, or Gd), respectively (H(2)L: N,N'-bis(salicylidene)cyclohexane-1,2-diamine). The result of their photophysical properties shows that the strong and characteristic NIR luminescence for complexes 1-2 and 5-6 with emissive lifetimes in microsecond ranges are observed, and the sensitization arises from the excited state (both (1)LC and (3)LC) of the hexadentate Salen-type Schiff-base ligand with the flexible linker. Temperature dependence (1.8-300 K) magnetic susceptibility studies of the eight complexes suggest the presence of an antiferromagnetic interaction between the Ln(3+) ions. PMID- 23043381 TI - Testing the activitystat hypothesis: a randomised controlled trial protocol. AB - BACKGROUND: The activitystat hypothesis proposes that when physical activity or energy expenditure is increased or decreased in one domain, there will be a compensatory change in another domain to maintain an overall, stable level of physical activity or energy expenditure. To date, there has been no experimental study primarily designed to test the activitystat hypothesis in adults. The aim of this trial is to determine the effect of two different imposed exercise loads on total daily energy expenditure and physical activity levels. METHODS: This study will be a randomised, multi-arm, parallel controlled trial. Insufficiently active adults (as determined by the Active Australia survey) aged 18-60 years old will be recruited for this study (n=146). Participants must also satisfy the Sports Medicine Australia Pre-Exercise Screening System and must weigh less than 150 kg. Participants will be randomly assigned to one of three groups using a computer-generated allocation sequence. Participants in the Moderate exercise group will receive an additional 150 minutes of moderate to vigorous physical activity per week for six weeks, and those in the Extensive exercise group will receive an additional 300 minutes of moderate to vigorous physical activity per week for six weeks. Exercise targets will be accumulated through both group and individual exercise sessions monitored by heart rate telemetry. Control participants will not be given any instructions regarding lifestyle. The primary outcome measures are activity energy expenditure (doubly labeled water) and physical activity (accelerometry). Secondary measures will include resting metabolic rate via indirect calorimetry, use of time, maximal oxygen consumption and several anthropometric and physiological measures. Outcome measures will be conducted at baseline (zero weeks), mid- and end-intervention (three and six weeks) with three (12 weeks) and six month (24 week) follow-up. All assessors will be blinded to group allocation. DISCUSSION: This protocol has been specifically designed to test the activitystat hypothesis while taking into account the key conceptual and methodological considerations of testing a biologically regulated homeostatic feedback loop. Results of this study will be an important addition to the growing literature and debate concerning the possible existence of an activitystat. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000248066. PMID- 23043382 TI - Therapeutic potential of RNA interference: a new molecular approach to antiviral treatment for hepatitis C. AB - Hepatitis C virus (HCV) infection remains a major cause of chronic liver disease with an estimated 170 million carriers worldwide. Current treatments have significant side effects and have met with only partial success. Therefore, alternative antiviral drugs that efficiently block virus production are needed. During recent decades, RNA interference (RNAi) technology has not only become a powerful tool for functional genomics but also represents a new therapeutic approach for treating human diseases including viral infections. RNAi is a sequence-specific and post-transcriptional gene silencing process mediated by double-stranded RNA (dsRNA). As the HCV genome is a single-stranded RNA that functions as both a messenger RNA (mRNA) and replication template, it is an attractive target for the study of RNAi-based viral therapies. In this review, we will give a brief overview about the history and current status of RNAi and focus on its potential application as a therapeutic option for treatment for HCV infection. PMID- 23043383 TI - Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa-2a/ribavirin. AB - It is unclear whether the current threshold for 'high' hepatitis C virus (HCV) RNA level (800,000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono-infected and 176 HIV-HCV co-infected patients treated with peginterferon alfa-2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono-infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400,000 IU/mL was used and 16% (59%vs 43%) when 800,000 IU/mL was used. In HIV-HCV genotype 1 co-infected patients, the difference was 51% (71%vs 20%) when 400,000 IU/mL was used and 43% (61%vs 18%) when 800,000 IU/mL was used. A lower threshold (200,000 IU/mL) was identified for genotype 1 mono-infected patients with 'normal' alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400,000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1-infected individuals with elevated ALT. PMID- 23043384 TI - Modulation of replication efficacy of the hepatitis C virus replicon Con1 by site directed mutagenesis of an NS4B aminoterminal basic leucine zipper. AB - The hepatitis C virus (HCV) nonstructural protein 4B (NS4B) is assumed to function as a membrane anchor and protein hub for the viral replication complex. The aim of the current work was to modulate HCV replication efficacy in the subgenomic Con1 replicon by mutations of specific sites within the aminoterminal located basic leucine zipper (bZIP), a candidate motif for protein-protein interactions involving NS4B. Mutational sites and amino acid substitutes were determined by in-silico sequence analyses of the NS4B-bZIP motif in 357 isolates of HCV genotype 1b from the euHCVdB and LosAlamos database and consecutive analysis of conserved physico-chemical properties at bZIP specific positions. Mutants with predicted minor, medium or major reduction of replication efficacy were tested in the pFKI389neo/NS3-3'/ET plasmid replicon model. Four sites (L25, T29, V39 and W43) of crucial importance for bZIP-mediated protein interaction with predicted apolarity of respective amino acid positions were selected for mutational studies. Substitutes with physico-chemical properties matching the predicted requirements either well (T29A), moderately (L25W, V39W), or insufficiently (T29E, W43E) were associated with slightly improved, moderate and marked decreased replication efficacy, respectively. Spontaneous (T29G) and adaptive (A28G, E40G) mutations occurred in the T29E mutation isolate only and were associated with marked reduction of replication efficacy. The bZIP motif region of NS4B is crucial for RNA replication in the subgenomic Con1 replicon system. RNA replication efficacy can be modulated by site-directed mutagenesis at specific bZIP functional sites. New adaptive amino acid mutations were identified within the HCV NS4B protein. PMID- 23043385 TI - Interferon therapy of acute hepatitis C in dialysis patients: meta-analysis. AB - The efficacy and safety of antiviral therapy in patients with acute hepatitis C on long-term dialysis remains unclear, although a number of small clinical studies have been published addressing this issue. We evaluated the efficacy and safety of interferon therapy in chronic dialysis patients with acute hepatitis C by performing a systematic review of the literature with a meta-analysis of clinical studies. The primary outcome was sustained virological response (SVR, as a measure of efficacy); the secondary outcome was dropout rate (as a measure of tolerability). We used the random effects model of DerSimonian and Laird, with heterogeneity and sensitivity analyses. We identified eight clinical studies (173 unique patients), three (37.5%) being controlled clinical trials (CCTs). Among CCTs, the viral response was much more common in study (patients on antiviral therapy) than control (patients who did not receive therapy) groups; the pooled odds ratio of SVR being 27.06, 95% Confidence Intervals (95% CI), 9.26; 79.1 (P = 0.00001). No difference in the dropout rate between study and control patients was shown, odds ratio = 0.920 (95% CI, 0.367; 1.92), NS. Pooling all study results (n = 8 studies) demonstrated that the summary estimate for SVR and dropout rate was 58% (95% CI, 38; 77) and 9% (95% CI, 4; 14), respectively. The most frequent side-effects requiring interruption of the treatment were flu-like symptoms (n = 4, 18%), followed by haematological changes and loss to follow-up. A strong relationship between increasing age and reported dropout rate was recognized (P = 0.001). The studies were heterogeneous with regard to SVR but not to dropout rate. Our meta-analysis of CCTs showed that the viral response after antiviral therapy was more common than the spontaneous viral clearance in dialysis patients with acute hepatitis C. Pooled analysis demonstrated that IFN based therapy of acute hepatitis C in dialysis populations gives SVR in around one half of patients. These results support IFN-based therapy for acute hepatitis C in patients on maintenance dialysis. PMID- 23043386 TI - Health-related quality of life in subjects with HCV/HIV coinfection: results from ACTG 5178 study. AB - Although health-related quality of life (HRQOL) is diminished in HCV/HIV, the relationship between virologic response and maintenance therapy with HRQOL in this population is unknown. ACTG 5178 was a phase 2, randomized trial, with three steps - Step 1: all subjects received pegylated interferon (PEG-IFN)/ribavirin (P/R) for 12 weeks. Step 2: subjects who failed to achieve early viral response (EVR) were randomized to PEG-IFN or observational control for an additional 72 weeks. Step 3: subjects with EVR from step 1 continued on P/R for a total of 72 weeks with 24 weeks follow-up off-therapy. HRQOL, symptom distress and depression levels were measured at multiple time points. In step 1 (n = 329), there was a significant decline in HRQOL in all dimensions. In step 3 (n = 169), the overall HRQOL and three of its eight dimensions (general health, role function and pain score) were increased, and achievement of sustained virologic response was associated with increased general health and cognitive function. In step 2 (n = 85), there was no significant change in HRQOL and no significant difference between groups (PEG-IFN vs observational control). There was a significant decline in HRQOL during the initial 12 weeks of therapy. Thereafter, the HRQOL profile differed for subjects with EVR vs without EVR. Maintenance therapy with PEG-IFN had no impact on the HRQOL. PMID- 23043387 TI - Five-year on-treatment efficacy of lamivudine-, tenofovir- and tenofovir + emtricitabine-based HAART in HBV-HIV-coinfected patients. AB - Data on the efficacy of lamivudine (LAM)-, tenofovir (TDF)- and emtricitabine (FTC)-based antiretroviral therapy (HAART) in HBV-HIV coinfection are limited. We completed a retrospective analysis of HBV-HIV-coinfected patients treated at the Medical University of Vienna. One-hundred and ten coinfected patients were included, with 57% being initially HBV e-Antigen (HBeAg) positive. Baseline HBV load was significantly higher in HBeAg+ than in HBeAg- patients (5962 +/- 3663 vs 20 +/- 19 * 10(6) IU/mL; P < 0.0001). Over a median observation period of 83 month (range: 26-183), 87% received HAART and 91% showed a suppression of HBV replication. After 5 years of continuous treatment, HBeAg seroconversion was achieved in 21% of LAM-, 50% of TDF- (P = 0.042 vs LAM) and in 57% of TDF + FTC (P = 0.008 vs LAM)-treated patients, respectively. HBsAg loss after 5 years was found in 8% (LAM), 25% (TDF; P = 0.085 vs LAM) and 29% (TDF + FTC; P = 0.037 vs LAM) of HBeAg+ patients. In HBeAg- patients, HBsAg loss was achieved in 11% (LAM), 27% (TDF; P = 0.263 vs LAM) and 36% (TDF + FTC; P = 0.05 vs LAM), respectively. Pretreatment CD4+ counts did not influence rates of HBeAg seroconversion and of HBsAg loss. Patients with HBsAg loss had lower baseline HBV DNA levels and higher AST/ALT levels than patients without HBsAg loss. Transient HAART-related hepatotoxicity was found in 32% (Grade I: 21%; II:7%; III:2%; IV:0%). Most HBV-HIV-coinfected patients achieve complete suppression of HBV replication despite high baseline viremia. TDF-based HAART leads to high rates of HBeAg seroconversion and HBsAg loss after 5 years of continuous exposure. One third of HBV-HIV-coinfected patients may experience transient HAART-related hepatotoxicity. PMID- 23043388 TI - Increased peripheral RORalpha and RORgammat mRNA expression is associated with acute-on-chronic hepatitis B liver failure. AB - T helper cells17 (Th17) have accurate but inconclusive roles in the pathogenesis of acute-on-chronic hepatitis B liver failure (ACHBLF). Retinoic acid-related orphan receptor gamma t(RORgammat) and RORalpha are two lineage-specific nuclear receptors directly mediating Th17 differentiation. This study was aimed to evaluate the gene expression of RORalpha and RORgammat and their potential role in ACHBLF. Forty patients with liver failure, 30 with chronic hepatitis B (CHB) and 20 healthy controls were studied. The mRNA levels of RORalpha and RORgammat in peripheral mononuclear cells were determined by quantitative real-time polymerase chain reaction. The frequency of peripheral Th17 cells was determined using flow cytometry. The serum levels of interleukin-6(IL-6), transforming growth factor -beta (TGF-beta), interleukin-17(IL-17), interleukin-23(IL-23) and interferon-gamma (IFN-gamma) were measured by enzyme-linked immunosorbent assay. The frequency of peripheral Th17 cells in patients with liver failure was significantly increased compared to patients with CHB and controls. The peripheral mRNA levels of RORalpha and RORgammat in hepatitis B-associated acute on-chronic liver failure were significantly higher than in patients with CHB and controls as were the serum levels of IL-6 and TGF-beta. The serum level of IFN gamma in patients with acute-on-chronic liver failure from HBV was significantly higher than patients with CHB but lower than controls. In patients with acute-on chronic liver failure associated with HBV, RORgammat, IL-6 and IL-23 were positively correlated with the frequency of Th17 cells, while RORalpha, TGF-beta and IFN-gamma had no correlation with the latter. The mRNA level of RORgammat was positively correlated with model of end-stage liver disease (MELD) score, but there was no correlation of RORalpha and MELD score. RORgammat plays an important role in the pathogenesis of acute-on-chronic HBV-associated liver failure and might be considered to be a candidate factor consistent with the severity of disease. PMID- 23043389 TI - Genotypes B and C hepatocellular carcinoma-associated hepatitis B virus pre-S mutants: their detection among F1b and A2 - but not F4 - isolates from Argentina. AB - Prevalence rates of hepatocellular carcinoma (HCC)-associated hepatitis B virus (HBV) pre-S mutants among most genotypes are still lacking. In this study, viral (sub)genotypes of 70 Argentine nucleotide sequences (33 newly obtained) were determined by phylogenetic analysis, and the presence of such mutants was assessed in the American continent for the first time. Nucleotide substitutions of the pre-S2 start codon were observed in 10% of the HBV/A2 sequences. Ten per cent of the HBV/A2 and 12.5% of the HBV/F1b - but none of HBV/F4 - exhibited a deletion in the pre-S1/pre-S2 region. The contribution of these variants to liver cirrhosis (LC) and/or HCC development among HBV/F and HBV/A isolates deserves further prospective clinical studies. PMID- 23043390 TI - Tetomilast: new promise for phosphodiesterase-4 inhibitors? AB - INTRODUCTION: Tetomilast is a novel thiazole phosphodiesterase-4 (PDE-4) inhibitor, which may prove useful in both the treatment of inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD). Here, the authors review the pharmacology of the drug, and offer critical review of the available data for use of tetomilast in the treatment of IBD. AREAS COVERED: Peer-reviewed publications, including Phase I and II clinical trials, all other formats included. EXPERT OPINION: Tetomilast may be beneficial in IBD. Small differences in molecules and in recombinant proteins can translate into substantial differences in clinical effects and toxicity in IBD. This is a reasonable approach when exploring new options like tetomilast. PMID- 23043392 TI - Helquat-induced chiroselective aggregation of Au NPs. AB - Au nanoparticles (NPs) are functionalized with chiral (R) or (S) binaphthol phenylboronic acid ligands, (1a) or (1b). The (R)- or (S)-binaphthol phenylboronic acid ligands form donor-acceptor complexes with the chiral dicationic helicene, helquat (P)-HQ(2+) or (M)-HQ(2+), (2a) or (2b). The association constants between (1a)/(2a) and (1a)/(2b) correspond to (7.0 +/- 0.5) * 10(5) M(-1) and (2.5 +/- 0.3) * 10(5) M(-1), respectively, whereas the association constants between (1b)/(2b) and (1b)/(2a) correspond to (4.0 +/- 0.5) * 10(5) M(-1) and (1.8 +/- 0.3) * 10(5) M(-1), respectively. Chiroselective aggregation of chiral binaphthol phenylboronic acid-capped Au NPs triggered by the chiral helquats, is demonstrated. PMID- 23043391 TI - Human labour is associated with a decline in myometrial chemokine receptor expression: the role of prostaglandins, oxytocin and cytokines. AB - PROBLEM: Human labour is an inflammatory process with a heavy infiltration of immune cells into the myometrium and cervix induced by local chemokine production. Myometrial cells also express chemokine receptors, but there is little information about their behaviour or function during pregnancy and labour. METHOD OF STUDY: We studied the behaviour of the receptors (CCR2, CXCR1 and CXCR2) for the CCL2 and CXCL8 in human myometrium, because both have been shown to be important in labour. RESULTS: We found that there was a significant decline in the mRNA expression of all three receptors in the upper segment and a similar trend in the lower segment with the onset of term labour (TL). Chemokine receptor mRNA expression was increased by stretch, reduced by oxytocin and PGF(2alpha) acting via phospholipase C (PLC). CXCR2 declined with exposure to CXCL8, consistent with the negative relationship observed in labouring myometrial tissue. The mRNA changes were confirmed by western analysis and flow cytometry. CONCLUSION: These data show that myometrial chemokine receptor expression is reduced with the onset of term labour probably in response to the increased activity of chemokines, oxytocin and PGF(2alpha) . PMID- 23043393 TI - Mitochondrial beta-oxidation regulates organellar integrity and is necessary for conidial germination and invasive growth in Magnaporthe oryzae. AB - Fatty acids stored as triglycerides, an important source of cellular energy, are catabolized through beta-oxidation pathways predicted to occur both in peroxisomes and mitochondria in filamentous fungi. Here, we characterize the function of Enoyl-CoA hydratase Ech1, a mitochondrial beta-oxidation enzyme, in the model phytopathogen Magnaporthe oryzae. Ech1 was found to be essential for conidial germination and viability of older hyphae. Unlike wild-type Magnaporthe, the ech1Delta failed to utilize C14 fatty acid and was partially impeded in growth on C16 and C18 fatty acids. Surprisingly, loss of beta-oxidation led to significantly altered mitochondrial morphology and integrity with ech1Delta showing predominantly vesicular/punctate mitochondria in contrast to the fused tubular network in wild-type Magnaporthe. The ech1Delta appressoria were aberrant and displayed reduced melanization. Importantly, we show that the significantly reduced ability of ech1Delta to penetrate the host and establish therein is a direct consequence of enhanced sensitivity of the mutant to oxidative stress, as the defects could be remarkably reversed through exogenous antioxidants. Overall, our comparative analyses reveal that peroxisomal lipid catabolism is essential for appressorial function of host penetration, whereas mitochondrial beta oxidation primarily contributes to conidial viability and maintenance of redox homeostasis during host colonization by Magnaporthe. PMID- 23043395 TI - Anxiety: the importunate companion. Psychoanalytic theory of castration and separation anxieties and implications for clinical technique. AB - In this article I consider the implications of our differing psychoanalytic theories of anxiety on clinical technique. Drawing on differentiations between the focus on separation or castration anxiety and the relative neglect of the latter in contemporary writing, I look in detail at two clinical examples of psychoanalysis in borderline young adults to exemplify the issue.(1). PMID- 23043394 TI - Sorafenib treatment improves hepatopulmonary syndrome in rats with biliary cirrhosis. AB - HPS (hepatopulmonary syndrome) is characterized by oxygen desaturation in patients with chronic liver disease. The initiation of HPS comes from abnormal pulmonary vasodilatation and/or angiogenesis. In the present study, we evaluated anti-angiogenesis therapy using sorafenib in experimental HPS animals. HPS was induced by CBDL (common bile duct ligation) in rats. A 2-week 10 mg.(kg of body weight)-1.day-1 treatment regimen of sorafenib or distilled water (control) was initiated 2 weeks after the surgical procedure. Haemodynamics, liver biochemistry, plasma VEGF (vascular endothelial growth factor) measurements and blood gas analysis of the CBDL rats were performed. The livers of the CBDL rats were dissected for histopathology examination, and the lungs were examined by immunohistochemical staining, real-time PCR and Western blot analysis. In another two parallel groups, intrapulmonary shunts were determined. The AaPO2 (alveolar arterial O2 gradient) and plasma VEGF levels were reduced after sorafenib treatment [AaPO2, 7.2+/-3.4 mmHg in sorafenib-treated rats compared with 15.3+/ 4.2 mmHg in controls (P=0.004); VEGF, 45.3+/-2.7 pg/ml in sorafenib-treated rats compared with 54.4+/-7.7 pg/ml in controls (P=0.021)]. Sorafenib attenuated pulmonary VEGF mRNA and VEGF, VEGFR-2 (VEGF receptor 2), phospho-VEGFR-2 and Akt protein expression. In addition, sorafenib significantly attenuated intrapulmonary angiogenesis and decreased the degree of intrapulmonary shunting by 33.7% (11.2+/-5.7% in sorafenib-treated rats compared with 16.9+/-5.9% in controls; P=0.003). Our findings suggest that sorafenib attenuates intrapulmonary shunting and decreases the AaPO2 in CBDL rats, implicating the improvement of HPS in this experimental animal model. The beneficial effect may be attributed to the reduction in intrapulmonary angiogenesis through inhibition of the VEGF/VEGFR 2/Akt pathway. PMID- 23043396 TI - Is psychoanalysis a matter of subjectivation? AB - We are not born subject but become one, in a two-and-fro process between what is played out on the intrapsychic stage and the field of intersubjectivation. The author proposes to examine two of the main movements of psychic life brought into play in this process. In the domain of the 'subjectivating link', becoming a subject depends on the relationship with another, authentically taken into account as a desiring subject and not simply as an object for oneself. In the course of history, this intersubjectivation is only internalized as a lasting preconscious predisposition if sufficient trust is established in the possibility of mutual recognition. When this perspective recedes, the subject tends to fall back on narcissistic positions, in search of an end to lack. Such a narcissistic tendency drives the subject to constitute himself by subjugating his objects, striving to rob them of their otherness. A plurality of subject positions will be recognized in every analytic encounter. Psychoanalytic work can allow for a lasting change insofar as it modifies the equilibrium between diverse psychic trends. The multiplicity of the issues at stake in subjectivation allows us to integrate theoretical pluralism while encouraging us to reflect on the diversification of our practices. PMID- 23043397 TI - Reflections on coma: man deprived of his consciousness. AB - In this paper the authors reflect on the phenomena produced by the surprising communication between the unconscious of a therapist and that of a comatose patient. In a particularly disturbing context, when the patient's sternum is open and exposed, the therapist communicates empathically with the comatose person, identifying the patient's inexpressible experience and generating signs of a response from him in the form of the blinking of his eyelids. The absence of any reaction to pain, a pathognomonic sign of the comatose condition, could be related to the splitting-off of the trauma, as if the situation were frozen, through a denial of the sensory and neurological perception of pain - a kind of self-anaesthesia as a defence against the catastrophic anxieties raised by the threat of the return of the primary trauma. Starting from this encounter a relationship is formed whose guiding thread emerges in the shared illusion of a regression that makes it possible. It involves a process of returning to the past and a re-actualization of the past that includes the question of its change through representation. PMID- 23043398 TI - On procreating today. AB - This work reflects on the suffering and difficulties that men and women often experience during the process of procreation, beginning with the decision to suspend the use of contraception. The shared project that a child represents involves difficulties that are also a consequence of the culture in which we live: subject to early tests, ultrasound scans and so on, a planned pregnancy is dominated, throughout its development, by the secondary process of monitoring. A delay in conception, at times deriving from intolerance towards a body that does not immediately fulfil one's own desires, sets in motion the diagnostic inquiry. During this time, while the long-awaited moment of conception is further delayed, the desire for a son/daughter changes in quality and intensity. In a substantial number of cases, infertility remains unexplained, a situation in turn characterized by the fear that not knowing implies. Although the excessively simplistic and limited notion of psychogenic infertility has faded, a residue of unexpressed horror, difficult to frame even in analysis, persists in the couple. The end of the diagnostic inquiry means that assisted conception must be eventually faced. Fortunately, nowadays in psychoanalytic culture the fundamentalist tendencies that, in the past, led to forecasts of catastrophe, have subsided. Yet this remains a highly problematic area with many questions and few answers. PMID- 23043399 TI - Fresh old news from Ferenczi about the function of dreams: the dream as a Kur, as a treatment and as a Gyogyaszat. AB - This article discusses a text on the function of dreams and their relation to trauma. Ferenczi intended to present this material as a talk at the 12th International Congress of Psychoanalysis, which was to take place in Interlaken, Switzerland the same year that he wrote it (1931). The entire conference, however, was postponed, and parts of this communication's content appeared in other texts in which Ferenczi rethinks the concept of trauma and its clinical significance. In the present article the author makes use of the Freud/Ferenczi correspondence to contextualize Freud's Hungarian follower's originality regarding his theorizations about different aspects of the function of dreams. In the 1931 speech, as well as in this article, Ferenczi used a patient's dream work as a clinical example of a process in which traumatic experiences and unmastered sensory impressions can be repeated to achieve a better working-through for the dreamer. The process Ferenczi describes resembles an effort of self-treatment, of self-Kur. PMID- 23043400 TI - Bion's discovery of alpha function: thinking under fire on the battlefield and in the consulting room. AB - This paper has traced Bion's discovery of alpha function and its subsequent elaboration. His traumatic experiences as a young tank commander in World War I (overlaid on, and intertwined with, childhood conflicts) gave him firsthand exposure to very painful emotions that tested his capacity to manage. Later, in the 1950s, after his analysis with Melanie Klein and marriage to Francesca Bion, he undertook the analysis of psychotic patients and learned how they disassembled their ability to know reality as a defense against unbearable emotional truths in their lives. This led Bion to identify an aspect of dreaming that was necessary in order for reality experience to be given personal meaning so that one may learn from experience. Simultaneous with working out this new theory of dreaming, Bion also revisited his World War I experiences that had remained undigested and all these elements coalesced into a selected fact - his discovery of alpha function. In subsequent writings, Bion explored the constituent factors of alpha function, including the container/contained relationship, the PS<->D balance, reverie, tolerated doubt and other factors which I have termed the 'Constellation for Thinking'. PMID- 23043402 TI - The use of the past and the present in the clinical setting. PMID- 23043401 TI - Hannah Arendt, evil and the eradication of thought. AB - Evil deeds may be committed intentionally or out of madness, but it is those who follow orders that present us with the most complex moral, philosophical and psychological questions. In writing about the banality of evil, Hannah Arendt argues that "in granting pardon, it is the person and not the crime that is forgiven; in rootless evil there is no person left whom one could ever forgive." Arendt postulates that "being a person" necessarily entails the acts of memory and thought. This paper explores Arendt's ideas on memory and thought and how these processes can become subverted in the service of a higher order. Clinical material illustrates Whitmer's idea of dissociation as an "impairment of subjectivity" as distinct from Freud's view of dissociation as a form of repression. This shift in theoretical perspective sheds new light on our understanding of the totalitarian state of mind, i.e. of the mind of a "nobody", and the conditions within which evil is committed. PMID- 23043403 TI - On construction in Freud's work. PMID- 23043404 TI - The screen memory and the act of remembering. AB - Screen memories, seen by Freud, Greenacre and other analysts of a past generation as a key source of data for the reconstruction of psychic and historical reality, have been relatively neglected in contemporary analysis. A fresh look shows that these durable, constant memories have a dual relation to childhood experience: they memorialize both a specific organization of trauma, wish and defense, and a private childhood act of remembering. Close attention to the screen memory itself and the context in which it appears indicates that both aspects of screen memory have meaning for the individual and are represented in fantasy. Both currents of meaning can be seen in a literary screen memory and in the clinical situation, where both play out in transference and countertransference. PMID- 23043405 TI - Constructions in psychoanalysis: on the 'assured conviction of the truth of a construction'. PMID- 23043406 TI - On: Maurizio Balsamo, the analyst at work--Sabina. PMID- 23043407 TI - On: minding our metaphysics. PMID- 23043409 TI - Introduction: three psychoanalytic perspectives on Pedro Almodovar's The Skin I Live In (2011). PMID- 23043410 TI - A perfectly modern Frankenstein: Almodovar's The Skin I Live In (2011, Sony Pictures Classics). PMID- 23043411 TI - Psychic skin and narcissistic rage: reflections on Almodovar's The Skin I Live In. PMID- 23043412 TI - Identity and inability to mourn in The Skin I Live In. PMID- 23043413 TI - Successful isolation and expansion of CMV-reactive T cells from G-CSF mobilized donors that retain a strong cytotoxic effector function. AB - Cytomegalovirus (CMV) infections post-haematopoietic stem cell transplantation (HSCT) can be effectively controlled through the adoptive transfer of donor derived CMV-specific T cells (CMV-T). Current strategies involve a second leukapheresis collection from the original donor to manufacture CMV-T, which is often not possible in the unrelated donor setting. To overcome these limitations we have investigated the use of a small aliquot of the original granulocyte colony stimulating factor (G-CSF) mobilized HSCT graft to manufacture CMV-T. We explored the T cell response to CMVpp65 peptide stimulation in G-CSF mobilized peripheral blood mononuclear cells (PBMC) and subsequently examined isolation of CMV-T based on the activation markers CD154 and CD25. CD25(+) enriched CMV-T from G-CSF mobilized PBMC contained a higher proportion of FoxP3 expression than non-mobilized PBMC and showed superior suppression of T cell proliferation. Expanded CMV-T enriched through CD154 were CD4(+) and CD8(+) , demonstrated a high specificity for CMV, secreted cytotoxic effector molecules and lysed CMVpp65 peptide-loaded phytohaemagglutinin-stimulated blasts. These data provide the first known evidence that CMV-T can be effectively manufactured from G-CSF mobilized PBMC and that they share the same characteristics as CMV-T isolated in an identical manner from conventional non-mobilized PBMC. This provides a novel strategy for adoptive immunotherapy that abrogates the need for successive donation. PMID- 23043414 TI - Notes on the concepts of 'serodiscordance' and 'risk' in couples with mixed HIV status. AB - Serodiscordant primary relationships, in which one partner is HIV-positive and the other is HIV-negative, are increasingly recognised as a key context for the transmission of HIV globally. Yet insights into the dynamics of serodiscordance remain relatively limited. I argue that to understand what makes serodiscordant couples engage in sexual practices that increase the chance of transmission, we need to examine what HIV 'risk' actually means in different cultures and contexts. A 'socially situated' approach to HIV risk moves beyond its scientific conceptualisation as an objective 'fact', revealing a diversity of perceptions and competing risks. It also reveals that couples do not necessarily perceive their mixed HIV status in terms of 'difference', a common assumption that predetermines serodiscordance and thereby obscures its many and complex enactments. I draw on examples from the social research literature to illustrate how serodiscordance is shaped in different ways by local practices, priorities, and meanings. I argue that it is within these lived contexts that perceptions and negotiations of 'risk' arise and, thus, where couples' sexual practices need to be situated and understood. Such insights are timely as HIV research and prevention grapple with emerging scientific data that challenge traditional understandings about HIV transmission risk. PMID- 23043415 TI - (99m)Tc-MAG3-aptamer for imaging human tumors associated with high level of matrix metalloprotease-9. AB - The human matrix metalloprotease 9 (hMMP-9) is involved in many physiological processes such as tissue remodeling. Its overexpression in tumors promotes the release of cancer cells thus contributing to tumor metastasis. It is a relevant marker of malignant tumors. We selected an RNA aptamer containing 2'-fluoro, pyrimidine ribonucleosides, that exhibits a strong affinity for hMMP-9 (K(d) = 20 nM) and that discriminates other human MMPs: no binding was detected to either hMMP-2 or -7. Investigating the binding properties of different MMP-9 aptamer variants by surface plasmon resonance allowed the determination of recognition elements. As a result, a truncated aptamer, 36 nucleotides long, was made fully resistant to nuclease following the substitution of every purine ribonucleoside residue by 2'-O-methyl analogues and was conjugated to S acetylmercaptoacetyltriglycine for imaging purposes. The resulting modified aptamer retained the binding properties of the originally selected sequence. Following (99m)Tc labeling, this aptamer was used for ex vivo imaging slices of human brain tumors. We were able to specifically detect the presence of hMMP-9 in such tissues. PMID- 23043416 TI - Redox-responsive reverse vesicles self-assembled by pseudo[2]rotaxanes for tunable dye release. AB - Reverse vesicles exhibiting functions similar to those of normal vesicles have been constructed through the self-assembly of TTF/CBPQT(4+)-based pseudo[2]rotaxanes in a nonpolar solvent. The ends of the threads of the pseudo[2]rotaxanes are attached with a Frechet-type G-3 dendron and a hydrogen bonded arylamide foldamer. These vesicles exhibit a response to redox. By exploiting the dynamic feature-spontaneously slow disassociation of the pseudorotaxanes-the sustained release of dyes embedded in the reverse vesicles has been demonstrated, which can be further tuned by changing the solvent polarity. PMID- 23043417 TI - Patient safety and falls: a qualitative study of home care nurses in Norway. AB - This study explored patient safety and falls, based on the experiences of home care nurses. Four focus group interviews were conducted with 20 home care nurses. The data were analyzed by content analysis. This study identified the following four themes: (i) patient safety was not viewed as primary prevention; (ii) the lack of investigation into causes of falls; (iii) the frailty of older people who can no longer live at home independently and safely; and (iv) patient autonomy versus patient safety. In this study, we showed that home care nurses felt that healthcare personnel were more concerned with the treatment of falls, rather than fall prevention. In addition, home care nurses rarely focused on falls before they occurred. The patient's autonomy was placed before patient safety. This study illustrates that home care nurses might be more aware of fall prevention in clinical practice. Additional research is recommended to shed more light on this topic. PMID- 23043418 TI - Ethnicity and age disparities in Ewing sarcoma outcome. AB - This institutional retrospective review studied Ewing sarcomas from 1987-2011. Among 135 patients, 127 (19 Hispanic and 108 white/non-Hispanic) were analyzed (excluding small sample sized groups) finding 15% Hispanic, 85% non-Hispanic, 27% <18 years, 21% >40 years and 1-272 months follow-up (median 41). Age was significantly associated with overall survival (OS) (p = 0.01), whereby <18 years had a higher probability of 5-year survival (OS 61%) than >40 years (OS 37.6%). Ethnicity was marginally statistically significant (OS, p = 0.065); whereby median survival was clinically significant (white non-Hispanic 63 months and Hispanic 23 months). Hispanic ethnicity and older age are independent poor prognostic factors. PMID- 23043419 TI - The genus Shewanella: from the briny depths below to human pathogen. AB - The genus Shewanella is currently composed of more than 50 species that inhabit a range of marine environs and ecosystems. Several members of this genus, including S. oneidensis, have been identified that could potentially play key roles in environmental processes such as bioremediation of toxic elements and heavy metals and serving as microbial fuel cells. In contrast to this beneficial role, shewanellae are increasingly being implicated as human pathogens in persons exposed through occupational or recreational activities to marine niches containing shewanellae. Documented illnesses linked to Shewanella include skin and soft tissue infections, bacteremia, and otitis media. At present, it is unclear exactly how many Shewanella species are truly bona fide human pathogens. Recent advances in the taxonomy and phylogenetic relatedness of members of this genus, however, support the concept that most human infections are caused by a single species, S. algae. Some phylogenetic data further suggest that some current members of the genus are not true Shewanella species sensu stricto. The current review summarizes our present knowledge of the distribution, epidemiology, disease spectrum, and identification of microbial species focusing on a clinical perspective. PMID- 23043420 TI - Discovery and pharmacological profile of new 1H-indazole-3-carboxamide and 2H pyrrolo[3,4-c]quinoline derivatives as selective serotonin 4 receptor ligands. AB - Since the discovery of the serotonin 4 receptor (5-HT(4)R), a large number of receptor ligands have been studied. The safety concerns and the lack of market success of these ligands have mainly been attributed to their lack of selectivity. In this study we describe the discovery of N-[(4-piperidinyl)methyl] 1H-indazole-3-carboxamide and 4-[(4-piperidinyl)methoxy]-2H-pyrrolo[3,4 c]quinoline derivatives as new 5-HT(4)R ligands endowed with high selectivity over the serotonin 2A receptor and human ether-a-go-go-related gene potassium ion channel. Within these series, two molecules (11 ab and 12 g) were identified as potent and selective 5-HT(4)R antagonists with good in vitro pharmacokinetic properties. These compounds were evaluated for their antinociceptive action in two analgesia animal models. 12 g showed a significant antinociceptive effect in both models and is proposed as an interesting lead compound as a 5-HT(4)R antagonist with analgesic action. PMID- 23043421 TI - Creating antibacterial surfaces with the peptide chrysophsin-1. AB - Immobilization of antimicrobial peptides (AMPs) holds potential for creating surfaces with bactericidal properties. In order to successfully incorporate AMPs into desired materials, increased fundamental understanding of the relationship between AMP immobilization and the efficacy of bound peptides as antibacterial agents is required. In this study, we characterize the relationship between surface binding of the AMP and subsequent ability of the peptide to kill bacteria. Surface immobilization of the AMP chrysophsin-1 (CHY1) via a flexible linker is studied in real-time, using a quartz crystal microbalance with dissipation monitoring (QCM-D). Depending on whether the AMP is physically adsorbed to the surface or attached covalently via a zero-length or flexible cross-linker, changes could be observed in AMP orientation, surface density, flexibility, and activity against bacteria. Covalent surface binding of CHY1 led to the formation of solvated monolayers of vertically positioned peptide molecules, while the physical adsorption of CHY1 led to the deposition of rigid monolayers of horizontally positioned peptide molecules on the sensor surface. Covalently bound peptides were not removed by extensive washing and did not leach from the surface. Zero-length immobilization of the peptide decreased its ability to kill E. coli to 34% +/- 7% of added bacteria, while binding via a flexible linker resulted in 82% +/- 11% of bacteria being killed by the AMP. PMID- 23043422 TI - Hepatic sinusoidal obstruction syndrome reduces the effect of oxaliplatin in colorectal liver metastases. PMID- 23043423 TI - Changes in the mechanical properties of chemically treated bovine pericardium after a short uniaxial cyclic test. AB - The mechanical behavior of calf pericardium, a biomaterial utilized in the manufacture of cardiac bioprostheses, in response to a short tensile cyclic test has been evaluated. The trial involved 120 samples cut longitudinally or transversely, subjected to 10 cycles until a stress of between 1 and 3 MPa was reached. Tests of hardness and tear propagation were performed, and the results were compared with a control series. The energy loss was also computed, and it was approximately 10-fold greater in the first cycle than the loss in the subsequent nine cycles. Despite this singularity, they correlated very precisely. The effect of the direction in which the tissue is cut on energy loss was not significant nor the difference between hardness prior to and after testing. The results of the tear propagation tests gave no statistical differences prior to and after testing. From the obtained results, it seems that the test carried out does not affect significantly the mechanical properties of calf pericardium. PMID- 23043424 TI - Synthesis of substituted thiophenes by palladium-catalyzed heterocyclodehydration of 1-mercapto-3-yn-2-ols in conventional and nonconventional solvents. AB - A variety of readily available 1-mercapto-3-yn-2-ols 5 were conveniently converted into the corresponding thiophenes 6 in good to high yields in MeOH as the solvent at 50-100 degrees C in the presence of catalytic amounts (1-2%) of PdI(2) in conjunction with KI (KI:PdI(2) molar ratio = 10). The catalyst could be made recyclable employing an ionic liquid, such as BmimBF(4), as the solvent under suitable conditions. PMID- 23043425 TI - The factor structure of the Turkish version of the Revised Illness Perception Questionnaire (IPQ-R) in patients with diabetes and cardiovascular disease. AB - BACKGROUND: The Revised Illness Perception Questionnaire (IPQ-R) has been used extensively in the study of illness perceptions across different populations. Only few confirmatory factor analytic (CFA) studies of the questionnaire are available. This study examines the construct and discriminant validity of the Turkish IPQ-R in patients with diabetes and cardiovascular disease focusing on the hypothesized seven dimensions of personal controllability, treatment controllability, timeline acute/chronic, timeline cyclical, coherence, consequences and emotional representations. METHODS: 302 patients (60.6% women) with a medically confirmed diagnosis of diabetes or cardiovascular disease and a mean age of 53.9 years were recruited from out-patient clinics in Turkey and surveyed by means of standardized interviews. Direct maximum likelihood confirmatory factor analysis was conducted. RESULTS: Several areas of ill-fit were identified in the original measurement model of the IPQ-R. Four items (items 17, 19, 20, and 31) were deleted because of poor factor loadings. Also, two error covariances (between items 33 and 34 and between items 7 and 8) were added and item 6 respecified to obtain a good model fit. The modified 34-item model showed good reliability and discriminant validity. CONCLUSION: In accordance with studies on other language adaptations of the questionnaire, we identified certain items of the IPQ-R as potential sources of poor model fit. Their inclusion should be reconsidered in future applications of the questionnaire and researchers should examine whether our reduced set of items is stable across different populations. Our modified 34-item model showed a good reliability and discriminant validity and hence could be a valuable instrument in the assessment of illness perceptions in the Turkish health care setting, provided that the model is confirmed in subsequent research. PMID- 23043426 TI - Rhodium-catalyzed ring opening of benzocyclobutenols with site-selectivity complementary to thermal ring opening. AB - A rhodium catalyst induced ring opening of benzocyclobutenols with selective cleavage of the C(sp(2))-C(sp(3)) bond adjacent to the hydroxyl group. The site selectivity markedly contrasted with that of their thermal ring-opening reaction. The rhodium-catalyzed ring opening led to the development of a new alkyne insertion reaction constructing a dihydronaphthalene framework. PMID- 23043427 TI - Tuning the built-in electric field in ferroelectric Pb(Zr(0.2)Ti(0.8))O3 films for long-term stability of single-digit nanometer inverted domains. AB - The emergence of new technologies, such as whole genome sequencing systems, which generate a large amount of data, is requiring ultrahigh storage capacities. Due to their compactness and low power consumption, probe-based memory devices using Pb(Zr(0.2)Ti(0.8))O(3) (PZT) ferroelectric films are the ideal candidate for such applications where portability is desired. To achieve ultrahigh (>1 Tbit/in(2)) storage densities, sub-10 nm inverted domains are required. However, such domains remain unstable and can invert back to their original polarization due to the effects of an antiparallel built-in electric field in the PZT film, domain-wall, and depolarization energies. Here, we show that the built-in electric-field can be tuned and suppressed by repetitive hydrogen and oxygen plasma treatments. Such treatments trigger reversible Pb reduction/oxidation activity, which alters the electrochemistry of the Pb overlayer and compensates for charges induced by the Pb vacancies. This tuning mechanism is used to demonstrate the writing of stable and equal size sub-4 nm domains in both up- and down-polarized PZT films, corresponding to eight inverted unit-cells. The bit sizes recorded here are the smallest ever achieved, which correspond to potential 60 Tbit/in(2) data storage densities. PMID- 23043428 TI - Perceived racial/ethnic discrimination, problem behaviors, and mental health among minority urban youth. AB - OBJECTIVES: We examined perceived frequency and intensity of racial/ethnic discrimination and associations with high-risk behaviors/conditions among adolescents. DESIGN: With surveys from 2490 racial/ethnic minority adolescents primarily with low socioeconomic status, we used regression analysis to examine associations between racial/ethnic discrimination and behavioral health outcomes (alcohol use, marijuana use, physical aggression, delinquency, victimization, depression, suicidal ideation, and sexual behaviors). RESULTS: Most adolescents (73%) experienced racial/ethnic discrimination and 42% of experiences were 'somewhat-' or 'very disturbing.' Adolescents reporting frequent and disturbing racial/ethnic discrimination were at increased risk of all measured behaviors, except alcohol and marijuana use. Adolescents who experienced any racial/ethnic discrimination were at increased risk for victimization and depression. Regardless of intensity, adolescents who experienced racial/ethnic discrimination at least occasionally were more likely to report greater physical aggression, delinquency, suicidal ideation, younger age at first oral sex, unprotected sex during last intercourse, and more lifetime sexual partners. CONCLUSION: Most adolescents had experienced racial/ethnic discrimination due to their race/ethnicity. Even occasional experiences of racial/ethnic discrimination likely contribute to maladaptive behavioral and mental health outcomes among adolescents. Prevention and coping strategies are important targets for intervention. PMID- 23043430 TI - Pyrimidine-fused heterocycle derivatives as a novel class of inhibitors for alpha glucosidase. AB - The needs for diverse inhibitors of alpha-glucosidase (alpha-Gls) encouraged us to synthesize five different poly-hydroxy functionalized pyrimidine-fused heterocyclic (PHPFH) molecules, having either aliphatic or aromatic side chains (C1-C5) and their inhibitory activities were examined spectroscopically against yeast and mouse intestinal alpha-Gls. The results revealed that aromatic substitution of the synthetic compounds has significant impact on their inhibitory properties. Moreover C3 with the substituted moiety as 4-(4 aminophenylsulfonyl) phenyl (4-APSP) revealed strong inhibitory activity with non competitive and competitive inhibition modes against yeast and mouse alpha-Gls, respectively. Furthermore, in the presence of increasing concentration of C3, both Trp and 1-anilinonaphthalene-8-sulfonic acid (ANS) fluorescence intensities of yeast alpha-Gls were gradually decreased, suggesting that C3 binding induced significant structural alteration which was accompanied with the reduction of hydrophobic surfaces. Also, the interaction between yeast alpha-Gls and C3 was proved to be spontaneous and driven mainly by hydrophobic forces. Overall, this study suggests that aromatic substitution on pyrimidine-fused heterocyclic (PFH) scaffold may represent a novel class of promising inhibitors of alpha-Gls. PMID- 23043429 TI - Scheffersomyces stipitis: a comparative systems biology study with the Crabtree positive yeast Saccharomyces cerevisiae. AB - BACKGROUND: Scheffersomyces stipitis is a Crabtree negative yeast, commonly known for its capacity to ferment pentose sugars. Differently from Crabtree positive yeasts such as Saccharomyces cerevisiae, the onset of fermentation in S. stipitis is not dependent on the sugar concentration, but is regulated by a decrease in oxygen levels. Even though S. stipitis has been extensively studied due to its potential application in pentoses fermentation, a limited amount of information is available about its metabolism during aerobic growth on glucose. Here, we provide a systems biology based comparison between the two yeasts, uncovering the metabolism of S. stipitis during aerobic growth on glucose under batch and chemostat cultivations. RESULTS: Starting from the analysis of physiological data, we confirmed through 13C-based flux analysis the fully respiratory metabolism of S. stipitis when growing both under glucose limited or glucose excess conditions. The patterns observed showed similarity to the fully respiratory metabolism observed for S. cerevisiae under chemostat cultivations however, intracellular metabolome analysis uncovered the presence of several differences in metabolite patterns. To describe gene expression levels under the two conditions, we performed RNA sequencing and the results were used to quantify transcript abundances of genes from the central carbon metabolism and compared with those obtained with S. cerevisiae. Interestingly, genes involved in central pathways showed different patterns of expression, suggesting different regulatory networks between the two yeasts. Efforts were focused on identifying shared and unique families of transcription factors between the two yeasts through in silico transcription factors analysis, suggesting a different regulation of glycolytic and glucoenogenic pathways. CONCLUSIONS: The work presented addresses the impact of high-throughput methods in describing and comparing the physiology of Crabtree positive and Crabtree negative yeasts. Based on physiological data and flux analysis we identified the presence of one metabolic condition for S. stipitis under aerobic batch and chemostat cultivations, which shows similarities to the oxidative metabolism observed for S. cerevisiae under chemostat cultivations. Through metabolome analysis and genome-wide transcriptomic analysis several differences were identified. Interestingly, in silico analysis of transciption factors was useful to address a different regulation of mRNAs of genes involved in the central carbon metabolism. To our knowledge, this is the first time that the metabolism of S. stiptis is investigated in details and is compared to S. cerevisiae. Our study provides useful results and allows for the possibility to incorporate these data into recently developed genome-scaled metabolic, thus contributing to improve future industrial applications of S. stipitis as cell factory. PMID- 23043431 TI - Effect of maternal excessive iodine intake on neurodevelopment and cognitive function in rat offspring. AB - BACKGROUND: Iodine deficiency and iodine excess are both associated with adverse health consequences. Iodine deficiency during pregnancy leads to insufficient maternal thyroid hormone, subsequently causing irreversible adverse effects on the neurological and cognitive functions of the offspring. The results of our previous epidemiological study suggested that mild iodine excess might increase the prevalence of subclinical hypothyroidism. In the present study, female Wistar rats maintained on low-iodine grain were randomly assigned to three groups based on iodated water concentration: low iodine (LI, 1.2 MUg/d), normal iodine (NI, 5 6 MUg/d), and 3-fold high iodine (3HI, 15-16 MUg/d). The present study investigated whether higher-than-normal iodine intake (3HI) by rats from before pregnancy until breastfeeding affects the postnatal (PN) neurodevelopment (PN7 and PN45) of their offspring during particularly sensitive periods in brain development. RESULTS: After 12 weeks of treatment (before pregnancy), iodine concentrations in urine and thyroid tissue and circulating thyroxine of adult females correlated with iodine intake. Brain-derived neurotrophic factor (BDNF) expression in the hippocampi of pups on PN7 and PN45 was decreased in 3HI group compared to the NI controls (P < 0.05, all) On PN7 and PN45, the BDNF levels of the 3HI pups were 83.5% and 88.8%, respectively, that of the NI pups. In addition, the 3HI group had a higher neuroendocrine-specific protein A (NSP-A) level than the NI controls on PN7 (P < 0.05). NSP-A levels of the 3HI pups were 117.0% that of the NI pups. No significant difference was observed in the expressions of c-Fos or c-Jun in the hippocampal CA1 region of the 3HI group compared to the controls (P > 0.05). Results from the Morris water maze test revealed that pups of the 3HI group had mild learning and spatial memory deficits. CONCLUSIONS: The neurodevelopmental and cognitive deficits of the 3HI pups were mild and temporary, likely related to the changes in hippocampal protein expressions of BDNF and NSP-A. PMID- 23043433 TI - Type I: families, planning and errors. PMID- 23043432 TI - A binuclear Mn(III) complex of a scorpiand-like ligand displaying a single unsupported Mn(III)-O-Mn(III) bridge. AB - The crystal structure of a binuclear Mn(III) complex of a scorpiand-like ligand (L) displays an unsupported single oxo bridging ligand with a Mn(III)-O-Mn(III) angle of 174.7 degrees . Magnetic susceptibility measurements indicate strong antiferromagnetic coupling between the two metal centers. DFT calculations have been carried out to understand the magnetic behavior and to analyze the nature of the observed Jahn-Teller distortion. Paramagnetic (1)H NMR has been applied to rationalize the formation and magnetic features of the complexes formed in solution. PMID- 23043435 TI - Temporary and permanent trapping of the metastable twisted conformer of an overcrowded chromic alkene via encapsulation. AB - An overcrowded alkene with an anti-folded conformation was converted to its twisted conformer, accompanied by a dramatic color change from yellow to deep purple, by inclusion in a self-assembled T(d)-symmetric coordination cage. The shape of the caged cavity was suitable and desirable for trapping of the twisted conformer. The twisted conformation was temporarily memorized in the alkene even after guest ejection. Permanent trapping of the twisted conformation was achieved by bromination of the twisted conformer formed in situ in the cage. PMID- 23043434 TI - Does uric acid qualify as an independent risk factor for cardiovascular mortality? AB - UA (uric acid) is the final product of purine metabolism in humans and is implicated in many disease conditions. Sustained hyperuricaemia has putative adverse roles in cardiovascular diseases. Despite strong evidence emerging from large epidemiological studies supporting the hypothesis that UA independently influences cardiovascular disease outcomes and mortality, a causal role is yet to be established. Serum UA is also considered as a useful biomarker for mortality in high-risk patients with acute coronary syndromes, heart failure and hypertension and in patients with Type 2 diabetes mellitus. Post-hoc analyses of clinical trial data suggest beneficial effects of reducing serum UA. However, these findings are inconclusive and are only hypothesis-generating. In the present issue of Clinical Science, Ndrepepa and co-workers have investigated the prognostic role of UA in high-risk Type 2 diabetic patients with established coronary artery disease in predicting 1-year survival and cardiovascular mortality. These results support the independent role of serum UA in predicting survival in Type 2 diabetic patients. However, long-term follow-up studies are required with serial UA measurement to establish the time-dependent association of UA with mortality outcomes. PMID- 23043436 TI - Toll-like receptor 9 gene polymorphisms in polymyalgia rheumatica and giant cell arteritis. PMID- 23043437 TI - Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance. AB - With the manufacture of imatinib, researchers introduced tyrosine kinase inhibitors (TKIs) into the clinical setting in 2000 to treat cancers; approximately fifteen other TKIs soon followed. Imatinib remains the most successful agent, whereas all the others have had modest effects on the cancers that they target. The current challenge is to identify the agents that need to be combined with TKIs to maximize their efficacy. One of the most promising approaches is to combine immune therapy with TKI treatment. In this review, the therapeutic potential of TKIs for treatment is discussed. PMID- 23043440 TI - The adaptive value of morphological, behavioural and life-history traits in reproductive female wolves. AB - Reproduction in social organisms is shaped by numerous morphological, behavioural and life-history traits such as body size, cooperative breeding and age of reproduction, respectively. Little is known, however, about the relative influence of these different types of traits on reproduction, particularly in the context of environmental conditions that determine their adaptive value. Here, we use 14 years of data from a long-term study of wolves (Canis lupus) in Yellowstone National Park, USA, to evaluate the relative effects of different traits and ecological factors on the reproductive performance (litter size and survival) of breeding females. At the individual level, litter size and survival improved with body mass and declined with age (c. 4-5 years). Grey-coloured females had more surviving pups than black females, which likely contributed to the maintenance of coat colour polymorphism in this system. The effect of pack size on reproductive performance was nonlinear as litter size peaked at eight wolves and then declined, and litter survival increased rapidly up to three wolves, beyond which it increased more gradually. At the population level, litter size and survival decreased with increasing wolf population size and canine distemper outbreaks. The relative influence of these different-level factors on wolf reproductive success followed individual > group > population. Body mass was the primary determinant of litter size, followed by pack size and population size. Body mass was also the main driver of litter survival, followed by pack size and disease. Reproductive gains because of larger body size and cooperative breeding may mitigate reproductive losses because of negative density dependence and disease. These findings highlight the adaptive value of large body size and sociality in promoting individual fitness in stochastic and competitive environments. PMID- 23043439 TI - Escherichia coli DNA polymerase III is responsible for the high level of spontaneous mutations in mutT strains. AB - Reactive oxygen species induce oxidative damage in DNA precursors, i.e. dNTPs, leading to point mutations upon incorporation. Escherichia coli mutT strains, deficient in the activity hydrolysing 8-oxo-7,8-dihydro-2'-deoxyguanosine 5' triphosphate (8-oxo-dGTP), display more than a 100-fold higher spontaneous mutation frequency over the wild-type strain. 8-oxo-dGTP induces A to C transversions when misincorporated opposite template A. Here, we report that DNA pol III incorporates 8-oxo-dGTP ~ 20 times more efficiently opposite template A compared with template C. Single, double or triple deletions of pol I, pol II, pol IV or pol V had modest effects on the mutT mutator phenotype. Only the deletion of all four polymerases led to a 70% reduction of the mutator phenotype. While pol III may account for nearly all 8-oxo-dGTP incorporation opposite template A, it only extends ~ 30% of them, the remaining 70% being extended by the combined action of pol I, pol II, pol IV or pol V. The unique property of pol III, a C-family DNA polymerase present only in eubacteria, to preferentially incorporate 8-oxo-dGTP opposite template A during replication might explain the high spontaneous mutation frequency in E. coli mutT compared with the mammalian counterparts lacking the 8-oxo-dGTP hydrolysing activities. PMID- 23043441 TI - Grafting efficiency of synthetic polymers onto biomaterials: a comparative study of grafting-from versus grafting-to. AB - In the present study, the two grafting techniques grafting-from - by activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) - and grafting-to - by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) - were systematically compared, employing cellulose as a substrate. In order to obtain a meaningful comparison, it is crucial that the graft lengths of the polymers that are grafted from and to the substrates are essentially identical. Herein, this was achieved by utilizing the free polymer formed in parallel to the grafting-from reaction as the polymer for the grafting-to reaction. Four graft lengths were investigated, and the molar masses of the four free polymers (21 <= M(n) <= 100 kDa; 1.07 <= D(M) <= 1.26), i.e. the polymers subsequently employed in the grafting-to reaction, were shown to be in the same range as the molar masses of the polymers grafted from the surface (23 <= M(n) <= 87 kDa; 1.08 <= D(M) <= 1.31). The molecular weights of the chains grafted from the surface were established after cleavage from the cellulose substrates via size exclusion chromatography (SEC). High-resolution Fourier transform infrared microscopy (FT-IRM) was employed as an efficient tool to study the spatial distribution of the polymer content on the grafted substrates. In addition, the functionalized substrates were analyzed by X-ray photoelectron spectroscopy (XPS), contact angle (CA) measurements, and field-emission scanning electron microscopy (FE-SEM). For cellulose substrates modified via the grafting-from approach, the content of polymer on the surfaces increased with increasing graft length, confirming the possibility to tailor not only the length of the polymer grafts but also the polymeric content on the surface. In comparison, for the grafting-to reaction, the grafted content could not be controlled by varying the length of the preformed polymer: the polymer content was essentially the same for the four graft lengths. Consequently, the obtained results, when employing cellulose as a substrate and under these conditions, suggest that the grafting from approach is superior to the grafting-to technique with respect to controlling the distribution of the polymeric content on the surface. PMID- 23043442 TI - Rational design of conformationally constrained cyclopentapeptide antagonists for C-x-C chemokine receptor 4 (CXCR4). AB - In the absence of an experimentally determined binding mode for the cyclopentapeptide CXCR4 antagonists, we have rationally designed conformationally constrained analogues to further probe the small peptide binding pocket of CXCR4. Two different rigidification strategies were employed, both resulting in highly potent ligands (9 and 13). The information provided by this cyclopentapeptide ligand series will be very valuable in the development of novel peptidomimetic CXCR4 antagonists. PMID- 23043438 TI - Creating order from chaos: cellular regulation by kinase anchoring. AB - Second messenger responses rely on where and when the enzymes that propagate these signals become active. Spatial and temporal organization of certain signaling enzymes is controlled in part by A-kinase anchoring proteins (AKAPs). This family of regulatory proteins was originally classified on the basis of their ability to compartmentalize the cyclic adenosine monophosphate (cAMP) dependent protein kinase (also known as protein kinase A, or PKA). However, it is now recognized that AKAPs position G protein-coupled receptors, adenylyl cyclases, G proteins, and their effector proteins in relation to protein kinases and signal termination enzymes such as phosphodiesterases and protein phosphatases. This arrangement offers a simple and efficient means to limit the scope, duration, and directional flow of information to sites deep within the cell. This review focuses on the pros and cons of reagents that define the biological role of kinase anchoring inside cells and discusses recent advances in our understanding of anchored second messenger signaling in the cardiovascular and immune systems. PMID- 23043443 TI - Analyzing the spatio-temporal relationship between dengue vector larval density and land-use using factor analysis and spatial ring mapping. AB - BACKGROUND: Dengue, a mosquito-borne febrile viral disease, is found in tropical and sub-tropical regions and is now extending its range to temperate regions. The spread of the dengue viruses mainly depends on vector population (Aedes aegypti and Aedes albopictus), which is influenced by changing climatic conditions and various land-use/land-cover types. Spatial display of the relationship between dengue vector density and land-cover types is required to describe a near-future viral outbreak scenario. This study is aimed at exploring how land-cover types are linked to the behavior of dengue-transmitting mosquitoes. METHODS: Surveys were conducted in 92 villages of Phitsanulok Province Thailand. The sampling was conducted on three separate occasions in the months of March, May and July. Dengue indices, i.e. container index (C.I.), house index (H.I.) and Breteau index (B.I.) were used to map habitats conducible to dengue vector growth. Spatial epidemiological analysis using Bivariate Pearson's correlation was conducted to evaluate the level of interdependence between larval density and land-use types. Factor analysis using principal component analysis (PCA) with varimax rotation was performed to ascertain the variance among land-use types. Furthermore, spatial ring method was used as to visualize spatially referenced, multivariate and temporal data in single information graphic. RESULTS: Results of dengue indices showed that the settlements around gasoline stations/workshops, in the vicinity of marsh/swamp and rice paddy appeared to be favorable habitat for dengue vector propagation at highly significant and positive correlation (p = 0.001) in the month of May. Settlements around the institutional areas were highly significant and positively correlated (p = 0.01) with H.I. in the month of March. Moreover, dengue indices in the month of March showed a significant and positive correlation (p <= 0.05) with deciduous forest. The H.I. of people living around horticulture land were significantly and positively correlated (p = 0.05) during the month of May, and perennial vegetation showed a highly significant and positive correlation (p = 0.001) in the month of March with C.I. and significant and positive correlation (p <= 0.05) with B.I., respectively. CONCLUSIONS: The study concluded that gasoline stations/workshops, rice paddy, marsh/swamp and deciduous forests played highly significant role in dengue vector growth. Thus, the spatio-temporal relationships of dengue vector larval density and land-use types may help to predict favorable dengue habitat, and thereby enables public healthcare managers to take precautionary measures to prevent impending dengue outbreak. PMID- 23043444 TI - Association between myasthenia gravis and systemic lupus erythematosus: three case reports and review of the literature: comments on the article by I Castrejon et al. PMID- 23043446 TI - Insights into the dual activation mechanism involving bifunctional cinchona alkaloid thiourea organocatalysts: an NMR and DFT study. AB - In-depth understanding of the activation mechanism in asymmetric organocatalysis is of great importance for rational development of highly efficient catalytic systems. In this Article, the mechanism for the direct vinylogous Michael reaction of alpha,beta-unsaturated gamma-butyrolactam (Nu) and chalcone (EI) catalyzed by the bifunctional cinchona alkaloid thiourea organocatalyst (Cat) was studied with a combination of experimental (NMR) and theoretical (DFT) approaches, through which a new dual activation pathway was found. The key feature of this new dual activation mechanism (Pathway C) is that one N-H(A) of the thiourea moiety and the N-H of the protonated amine in Cat simultaneously activate Nu, while the other N-H(B) of the thiourea moiety activates EI. Both the NMR measurement and the DFT calculation identified that the interaction of Cat with Nu is stronger than that with EI in the catalyst-substrate complexes. Kinetic studies via variable-temperature NMR measurements indicated that, with the experimental activation energy E(a) of 10.2 kcal/mol, the reaction is all first-order in Nu, EI, and Cat. The DFT calculation further revealed that the C-C bond formation is both the rate-determining and the stereoselectivity-controlling steps. In agreement with the experimental data, the energy barrier for the rate determining step along Pathway C was calculated as 8.8 kcal/mol. The validity of Pathway C was further evidenced by the calculated enantioselectivity (100% ee) and diastereoselectivity (60:1 dr), which are in excellent match with the experimental data (98% ee and >30:1 dr, respectively). Mechanistic study on the Michael addition of nitromethane to chalcone catalyzed by the Catalyst I further identified the generality of this new dual activation mechanism in cinchona alkaloid thiourea organocatalysis. PMID- 23043447 TI - High incidence of Fanconi anaemia in patients with a morphological picture consistent with refractory cytopenia of childhood. PMID- 23043448 TI - Gold nanocluster-conjugated amphiphilic block copolymer for tumor-targeted drug delivery. AB - Two kinds of core-shell structured multifunctional nanocarriers of gold nanoclusters (Au NCs) as core and folate (FA)-conjugated amphiphilic hyperbranched block copolymer as shell based on poly(L-lactide) (PLA) inner arm and FA-conjugated sulfated polysaccharide (GPPS-FA) outer arm (Au NCs-PLA-GPPS FA) were synthesized for targeted anticancer drug delivery. The structure and properties of Au NCs-PLA-GPPS-FA copolymers were characterized and determined by 1H NMR spectrum, FT-IR spectra, dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopic (TEM) analyses. The anticancer drug, camptothecin (CPT) was used as a hydrophobic model anticancer drug. In vitro, two kinds of the nanocarriers presented a relatively rapid release in the first stage (up to 1 h) followed by a sustained release period (up to 15 h), and then reached a plateau at pH 5.3, 7.4, and 9.6. The release results indicated that CPT release from two kinds of the nanocarriers at pH 9.6 was much greater than that at both pH 5.3 and 7.4. The cytotoxicity studies showed that the CPT-loaded nanocarriers provided high anticancer activity against Hela cells. Furthermore, nanocarriers gained specificity to target some cancer cells because of the enhanced cell uptake mediated by FA moiety. The fluorescent images studies showed that the nanocarriers could track at the cellular level for advance therapy. The results indicated that the Au NCs-PLA-GPPS-FA copolymers not only had great potential as tumor-targeted drug delivery carrier, but also had an assistant role in the treatment of cancer. PMID- 23043449 TI - Breast surgeons' perceptions and attitudes towards contralateral prophylactic mastectomy. AB - BACKGROUND: The rates of contralateral prophylactic mastectomy (CPM) are increasing worldwide. This study investigated Australian and New Zealand's breast surgeons' perceptions, knowledge and attitudes towards CPM, and explored if demographic characteristics of surgeons were associated with an increased tendency to recommend or perform CPM. METHODS: A cross sectional research design was employed, with breast surgeons completing a self-report questionnaire. The questionnaire collected information including surgeons' perceptions on CPM in their clinical practice, their attitudes and knowledge of CPM and surgeons' demographic information. RESULTS: Eighty-one of 220 (37%) breast surgeons contacted via BreastSurgANZ participated in this study. Forty-four per cent of surgeons perceived that the rates of CPMs they performed had increased over the last year. CPM rates were found to be unrelated to surgeons' age (P = 0.773) or gender (P = 0.941). The main reasons a surgeon recommended a CPM to patients included known BRCA+ mutation, family history of breast cancer and patient factors including fear and anxiety and a desire to avoid further breast cancer treatment. CONCLUSIONS: Breast surgeons perceived that rates of CPM were increasing in their own clinical practice. CPM rates were unrelated to surgeon demographics including age and gender. While surgeons are aware of the objective risk factors that make performing a CPM advisable, they also report taking into account subjective factors, including patient fear and anxiety and a desire for breast symmetry when recommending a CPM. PMID- 23043450 TI - Results of the European clinical trial of Arrow CorAide left ventricular assist system. AB - The aim of this study was to evaluate the safety and performance of the Arrow CorAide left ventricular assist system (LVAS) (Arrow International, Reading, PA, USA), a continuous-flow left ventricular assist device, as bridge to transplantation or recovery as well as destination therapy in patients with New York Heart Association (NYHA) class IV heart failure. Twenty-one patients were implanted with the CorAide LVAS between February 2005 and February 2006 in a prospective, multicenter, nonrandomized trial. Seventeen patients (81%) survived to >180 days or to transplantation. The cumulative time on device was 16.58 patient years (range 23-796 days, median 192 days). No intraoperative technical issues were observed at the time of implantation. Of the 21 implants, nine patients died on device, two were converted to other devices, and 10 were transplanted. Three patient deaths were attributed to pump polymer coating delamination. Postmortem device inspection determined delamination of the polymer coating on the pump's internal surface to be the cause of the late hemolysis and sudden fatal pump stops. No embolic or driveline infection event was recorded. The automatic flow control algorithm functioned reliably throughout the trial. Primary performance trial endpoint was achieved with 81% survival to 180 days or transplantation. Delamination of the polymer coating on the internal surface of the pump with resultant hemolysis and pump stops was the sole major device event in this trial. Elimination of the polymer coating and replacement with an amorphous carbon coating has resolved this in preclinical testing, prior to initiation of further clinical testing of this device. PMID- 23043451 TI - Arginine L-alpha-ketoglutarate, methylsulfonylmethane, hydrolyzed type I collagen and bromelain in rotator cuff tear repair: a prospective randomized study. AB - OBJECTIVE: Arthroscopic rotator cuff repair generally provides satisfactory result, in terms of decreasing shoulder pain, resulting in improvement in range of motion. Unfortunately, imaging studies have shown that after surgical repair re-rupture rate is potentially high. Literature data indicate that each of the components present in a commercial supplement sold in Italy as Tenosan * (arginine L-alpha-ketoglutarate, methylsulfonylmethane, hydrolyzed type I collagen and bromelain) have a potential role in tendon healing and mitigating the pain due to tendonitis. We evaluated the clinical and MRI results of rotator cuff repair with and without the employment of this oral supplement in patients with a large, postero-superior rotator cuff tear (RCT). RESEARCH DESIGN AND METHODS: We enrolled 90 consecutive patients who had a large, postero-superior RCT. All the lesions were managed with an arthroscopic repair. Patients were randomized and treated either with (Group I) or without (Group II) the supplement. The primary outcomes were the difference between the pre- and post operative Constant score and repair integrity assessed by MRI according to Sugaya's classification. The secondary outcome was the pre- and post-operative Simple Shoulder Test. RESULTS: No statistically significant differences were identified between the two groups for each considered variable, except for shoulder pain (follow-up: 6 months) and repair integrity (final follow-up). Intensity of shoulder pain was lower in the Group I patients (p < 0.001). Analogously, in Group I, the percentage of patients with a better repair integrity result was significantly higher than Group II. CONCLUSION: The use of the supplement for 3 months after cuff repair decreases shoulder post-operative pain and leads to a slight improvement in repair integrity. This improvement does not seem to correlate with an better objective functional outcome. However, these effects could facilitate and abbreviate the post-operative rehabilitation program and reduce re-rupture rate. The main limitations of this study are the relative short follow-up period and small number of patients studied. PMID- 23043452 TI - Strong enhancement of light-matter interaction in graphene coupled to a photonic crystal nanocavity. AB - We demonstrate a large enhancement in the interaction of light with graphene through coupling with localized modes in a photonic crystal nanocavity. Spectroscopic studies show that a single atomic layer of graphene reduces the cavity reflection by more than a factor of one hundred, while also sharply reducing the cavity quality factor. The strong interaction allows for cavity enhanced Raman spectroscopy on subwavelength regions of a graphene sample. A coupled-mode theory model matches experimental observations and indicates significantly increased light absorption in the graphene layer. The coupled graphene-cavity system also enables precise measurements of graphene's complex refractive index. PMID- 23043453 TI - Treatment of HIV infection with once-daily regimens. AB - INTRODUCTION: Treatment for HIV infection requires a lifetime antiretroviral therapy. In order to improve adherence, once daily (OD) is thus a preferred regimen. AREAS COVERED: Evidence-based information and most recent guidelines recommendation, both from resource-rich and resource-limited settings, on antiretroviral regimens that can be administered OD will be reviewed. Sources of evidences were from the late clinical development studies (Phase III and II) published in Medline or major international conferences. EXPERT OPINION: Nine OD US FDA-approved regimens and one new integrase inhibitor OD regimen have been shown to be efficient and well tolerated. For the fixed-dose single-tablet regimens (STRs), there are two currently approved regimens: Atripla(r) and Complera(r). Another STR elvitegravir/cobicistat/emtricitabine/tenofovir (QUAD, Stribild(r)) is recently approved by the US FDA (August 20, 2012), whereas two additional SRTs, including abacavir/lamivudine/dolutegravir and darunavir/cobicistat/emtricitabine/GS-7340 are undergoing Phase III and II trials, respectively. Three OD regimens are currently recommended by the US DHHS guidelines as the preferred regimens for treatment-naive patients (efavirenz, boosted atazanavir and boosted darunavir). EFV-based regimen is the only OD regimen available for resource-limited countries. Nevertheless, it should be noted that each of these OD regimens has its own advantages and disadvantages and therefore should be selected accordingly. PMID- 23043455 TI - Preparation of hollow Co3O4 microspheres and their ethanol sensing properties. AB - The hollow Co(3)O(4) microspheres were prepared by a gas-liquid diffusion reaction in the presence of ionic liquid [Bmim][BF(4)] in combination with calcination at 300 degrees C. Their structures and morphologies were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, Raman spectrometry, and X-ray photoelectron spectroscopy. The growth mechanism of hollow Co(3)O(4) microspheres was proposed. The ethanol sensing properties were measured using a WS-30A gas sensor measurement system. The influence of working temperatures, ethanol concentrations, and specific surface areas of Co(3)O(4) microspheres on the ethanol sensing properties was investigated. The hollow Co(3)O(4) microspheres showed excellent sensitivity to ethanol vapor at a lower operating temperature. PMID- 23043454 TI - Characterization of the activity and expression of arginine decarboxylase in human and animal Chlamydia pathogens. AB - Chlamydia pneumoniae encodes a functional arginine decarboxylase (ArgDC), AaxB, that activates upon self-cleavage and converts l-arginine to agmatine. In contrast, most Chlamydia trachomatis serovars carry a missense or nonsense mutation in aaxB abrogating activity. The G115R missense mutation was not predicted to impact AaxB functionality, making it unclear whether AaxB variations in other Chlamydia species also result in enzyme inactivation. To address the impact of gene polymorphism on functionality, we investigated the activity and production of the Chlamydia AaxB variants. Because ArgDC plays a critical role in the Escherichia coli acid stress response, we studied the ability of these Chlamydia variants to complement an E. coli ArgDC mutant in an acid shock assay. Active AaxB was detected in four additional species: Chlamydia caviae, Chlamydia pecorum, Chlamydia psittaci, and Chlamydia muridarum. Of the C. trachomatis serovars, only E appears to encode active enzyme. To determine when functional enzyme is present during the chlamydial developmental cycle, we utilized an anti AaxB antibody to detect both uncleaved and cleaved enzyme throughout infection. Uncleaved enzyme production peaked around 20 h postinfection, with optimal cleavage around 44 h. While the role ArgDC plays in Chlamydia survival or virulence is unclear, our data suggest a niche-specific function. PMID- 23043456 TI - Distribution of the branched chain aminotransferase proteins in the human brain and their role in glutamate regulation. AB - The branched chain aminotransferase enzymes (BCAT) serve as nitrogen donors for the production of 30% of de novo glutamate synthesis in rat brain. Despite the importance of this major metabolite and excitatory neurotransmitter, the distribution of BCAT proteins in the human brain (hBCAT) remains unreported. We have studied this and report, for the first time, that the mitochondrial isoform, hBCATm is largely confined to vascular endothelial cells, whereas the cytosolic hBCATc is restricted to neurons. The majority of hBCATc-labelled neurons were either GABA-ergic or glutamatergic showing both cell body and axonal staining indicating a role for hBCATc in both glutamate production and glutamate release during excitation. Strong staining in hormone secreting cells suggests a further role for the transaminases in hormone regulation potentially similar to that proposed for insulin secretion. Expression of hBCATm in the endothelial cells of the vasculature demonstrates for the first time that glutamate could be metabolized by aminotranferases in these cells. This has important implications given that the dysregulation of glutamate metabolism, leading to glutamate excitotoxicity, is an important contributor to the pathogenesis of several neurodegenerative conditions, where the role of hBCATm in metabolizing excess glutamate may factor more prominently. PMID- 23043458 TI - Interconversion between discrete and a chain of nanocages: self-assembly via a solvent-driven, dimension-augmentation strategy. AB - Using a ligand bearing a bulky hydrophobic group, a "shish kabob" of nanocages, has been assembled through either a one-fell-swoop or a step-by-step procedure by varying the dielectric constant of the assembly mixture. A hydrophobic solvent breaks down the chain to discrete nanocages, while a hydrophilic solvent reverses the procedure. Although the shish kabob of nanocages has exactly the same chemical composition and even the same Archimedean-solid structure as those of its discrete analogue, its gas-adsorption capacity is remarkably improved because assembly of a chain exposes the internal surface of an individual cage. This dimension-augmentation strategy may have general implications in the preparation of porous materials. PMID- 23043459 TI - A public health approach to eating disorders prevention: it's time for public health professionals to take a seat at the table. AB - BACKGROUND: The societal burden of eating disorders is clear, and though there is a compelling need for a public health approach to eating disorders prevention, public health professionals have yet to take up the challenge. DISCUSSION: The article lays out an argument for what steps need to be taken to bring a public health approach to eating disorders prevention. First, stock is taken of what the field has achieved so far, using tools from the prevention science literature, and, second, a research plan of action is offered that plays to the unique strengths of public health, drawing on a triggers-to-action framework from public health law. Minimal participation was found from public health professionals in eating disorders prevention research, and the vast majority of prevention research to date was found to be concentrated within the disciplines of psychology and psychiatry. Extreme disciplinary concentration of the research has led to a preponderance of individually targeted prevention strategies with little research focused on environmental targets, particularly at the macro level. New environmental initiatives are now emerging, such as a government-sponsored mass media anti-dieting campaign, and legal bans on extremely thin models in advertising, but for the most part, they have yet to be evaluated. A triggers-to action framework, which focuses on evidentiary base, practical considerations, and political will, developed in public health law provides a basis for a strategic research plan for a public health approach to eating disorders prevention. SUMMARY: There is enormous potential for growth in the scope and diversity of eating disorder prevention research strategies, particularly those targeting the macro environment. A public health approach will require a strategic plan for research that leverages the macro environment for prevention. The full engagement of public health professionals will bring to the field the much broader range of preventive strategies and perspectives needed to tackle the problem of eating disorders. PMID- 23043460 TI - Neutral lipids associated with haemozoin mediate efficient and rapid beta haematin formation at physiological pH, temperature and ionic composition. AB - BACKGROUND: The malaria parasite disposes of host-derived ferrihaem (iron(III)protoporphyrin IX, Fe(III)PPIX) by conversion to crystalline haemozoin in close association with neutral lipids. Lipids mediate synthetic haemozoin (beta-haematin) formation very efficiently. However, the effect on reaction rates of concentrations of lipid, Fe(III)PPIX and physiologically relevant ions and biomolecules are unknown. METHODS: Lipid emulsions containing Fe(III)PPIX were prepared in aqueous medium (pH 4.8, 37 degrees C) to mediate beta-haematin formation. The reaction was quenched at various times and free Fe(III)PPIX measured colorimetrically as a pyridine complex and the kinetics and yields analysed. Products were also characterized by FTIR, TEM and electron diffraction. Autofluorescence was also used to monitor beta-haematin formation by confocal microscopy. RESULTS: At fixed Fe(III)PPIX concentration, beta-haematin yields remained constant with decreasing lipid concentration until a cut-off ratio was reached whereupon efficiency decreased dramatically. For the haemozoin-associated neutral lipid blend (NLB) and monopalmitoylglycerol (MPG), this occurred below a lipid/Fe(III)PPIX (L/H) ratio of 0.54. Rate constants were found to increase with L/H ratio above the cut-off. At 16 MUM MPG, Fe(III)PPIX concentration could be raised until the L/H ratio reached the same ratio before a sudden decline in yield was observed. MPG-mediated beta-haematin formation was relatively insensitive to biologically relevant cations (Na(+), K(+), Mg(2+), Ca(2+)), or anions (H(2)PO(4)(-), HCO(3)(-), ATP, 2,3-diphosphoglycerate, glutathione). Confocal microscopy demonstrated beta-haematin formation occurs in association with the lipid particles. CONCLUSIONS: Kinetics of beta-haematin formation have shown that haemozoin-associated neutral lipids alone are capable of mediating beta-haematin formation at adequate rates under physiologically realistic conditions of ion concentrations to account for haemozoin formation. PMID- 23043461 TI - Efficacy and safety of intraoperative dexmedetomidine for acute postoperative pain in children: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Aim of the current meta-analysis was to assess the effects of intraoperative dexmedetomidine on postoperative pain, analgesic consumption, and adverse events in comparison with placebo or opioids in children undergoing surgery. METHODS: This meta-analysis was performed according to the recommendations of the PRISMA statement and the Cochrane collaboration. For dichotomous and continuous outcomes of efficacy and adverse events, the Revman((r)) (The Nordic Cochrane Centre, Copenhagen, Denmark) statistical software was used to calculate relative risk (RR), mean difference (MD), and 95% confidence intervals (CI). RESULTS: We included 11 randomized controlled trials - 434 children received dexmedetomidine, 440 received control. In comparison with placebo, children receiving dexmedetomidine showed a reduced RR for postoperative opioids (0.4; 95% CI: 0.26-0.62; P < 0.00001) and postoperative pain (0.51; 95% CI: 0.32-0.81; P = 0.004). Similar results were obtained for the comparison with intraoperative opioids: reduced RR for postoperative pain (0.49; 95% CI: 0.25 0.94; P = 0.03) and the need for postoperative opioids (0.77; 95% CI: 0.60-1.09; P = 0.05). CONCLUSIONS: This meta-analysis revealed a lower risk for postoperative pain and the need for postoperative opioids following intraoperative dexmedetomidine in comparison with placebo or opioids in children undergoing surgery; however, the influence of dexmedetomidine on postoperative opioid consumption is less clear. Although there were only a limited number of adverse events, further studies focusing on procedure specific dexmedetomidine dosing and adverse events are urgently needed. PMID- 23043462 TI - Songaricalarins A-E, cytotoxic oplopane sesquiterpenes from Ligularia songarica. AB - Five new highly oxygenated oplopane sesquiterpenes, songaricalarins A-E (1-5), and two known analogues (6 and 7) were isolated from the roots and rhizomes of Ligularia songarica. Their structures and configurations were elucidated by spectroscopic methods, including 2D-NMR techniques, and the structure of 1 was confirmed by single-crystal X-ray diffraction. All compounds were evaluated for in vitro cytotoxic activity against cultured A-549, MCF-7, KB, and KBVIN cells, and 4 exhibited cytotoxicity with EC50 values of 4.9, 0.8, 3.4, and 3.2 MUg/mL, respectively. PMID- 23043463 TI - microRNAs targeting DEAD-box helicases are involved in salinity stress response in rice (Oryza sativa L.). AB - BACKGROUND: Rice (Oryza sativa L.), one of the most important food crop in the world, is considered to be a salt-sensitive crop. Excess levels of salt adversely affect all the major metabolic activities, including cell wall damage, cytoplasmic lysis and genomic stability. In order to cope with salt stress, plants have evolved high degrees of developmental plasticity, including adaptation via cascades of molecular networks and changes in gene expression profiles. Posttranscriptional regulation, through the activity of microRNAs, also plays an important role in the plant response to salinity conditions. MicroRNAs are small endogenous RNAs that modulate gene expression and are involved in the most essential physiological processes, including plant development and adaptation to environmental changes. RESULTS: In the present study, we investigated the expression profiles of osa-MIR414, osa-MIR408 and osa-MIR164e along with their targeted genes, under salinity stress conditions in wild type and transgenic rice plants ectopically expressing the PDH45 (Pea DNA Helicase) gene. The present miRNAs were predicted to target the OsABP (ATP-Binding Protein), OsDSHCT (DOB1/SK12/helY-like DEAD-box Helicase) and OsDBH (DEAD-Box Helicase) genes, included in the DEAD-box helicase family. An in silico characterization of the proteins was performed and the miRNAs predicted targets were validated by RLM-5'RACE. The qRT-PCR analysis showed that the OsABP, OsDBH and OsDSHCT genes were up-regulated in response to 100 and 200 mM NaCl treatments. The present study also highlighted an increased accumulation of the gene transcripts in wild type plants, with the exception of the OsABP mRNA which showed the highest level (15.1-fold change compared to control) in the transgenic plants treated with 200 mM NaCl. Salinity treatments also affected the expression of osa-MIR414, osa-MIR164e and osa-MIR408, found to be significantly down regulated, although the changes in miRNA expression were limited. CONCLUSIONS: Osa-MIR414, osa-MIR164e and osa-MIR408 were experimentally validated for the first time in plants as targeting the OsABP, OsDBH and OsDSHCT genes. Our data showed that that the genes were up-regulated and the miRNAs were down-regulated in relation to salt stress. The negative correlation between the miRNAs and their targets was proven. PMID- 23043464 TI - Theoretical study on water-mediated excited-state multiple proton transfer in 7 azaindole: significance of hydrogen bond rearrangement. AB - Excited-state multiple proton transfer (ESMPT) in the cluster of 7-azaindole with three water molecules [7-azaindole(H(2)O)(3)] is theoretically investigated by the TDDFT, CASPT2, and CC2 methods. Examination of the potential energy surface in the first excited state indicates that ESMPT in 7-azaindole(H(2)O)(3) proceeds initially with the rearrangement of hydrogen bond structure of water molecules from a bridged-planar isomer to a cyclic-nonplanar isomer, followed by triple proton transfer in the latter. This reaction is found to be energetically more favorable than quadruple proton transfer in the bridged-planar isomer without hydrogen bond reorganization. It is also shown that all proton-transfer processes follow a concerted mechanism rather than a stepwise mechanism. The computational results show good consistency with the unexpected experimental observations as to the electronic spectra and excited-state lifetime. In particular, the barrier of the hydrogen bond rearrangement is found to be less than 1 kcal/mol, consistent with the missing vibronic bands for 7-azaindole(H(2)O)(3) with an excess energy of more than 200 cm(-1) in the S(1) state. PMID- 23043466 TI - Active intermediates of polyhydroxyalkanoate synthase from Aeromonas caviae in polymerization reaction. AB - Polyhydroxyalkanoate (PHA) synthase from Aeromonas caviae FA440 (PhaC(Ac), BAA21815) is one of the most valuable PHA synthase, because of its function to synthesize a practical bioplastic, poly[(R)-3-hydroxybutyrate-co-(R)-3 hydroxyhexanoate] [P(3HB-co-3HHx)]. However, biochemical activity and active intermediates of PhaC(Ac) have not been clarified until now. In the present study, a gene of PhaC(Ac) was cloned and overexpressed by a cell-free protein expression system. Both the polymerization activity and oligomerization behavior of the purified PhaC(Ac) were characterized in order to clarify the active intermediates of PhaC(Ac) based on the hydrodynamic diameters and specific activities of PhaC(Ac). The influences of a substrate, (R)-3-hydroxybutyryl-CoA (3HB-CoA), on the oligomerization of PhaC(Ac) (7.5 MUM) were also investigated, and then the Hill coefficient (n = 2.6 +/- 0.4) and the microscopic dissociation constant (K(m) = 77 +/- 5 MUM) were determined. Based on the results, the active intermediate of PhaC(Ac) was concluded to be the dimeric PhaC(Ac) containing 3HB CoA as an activator for its dimerization. This information is critical for revealing the relationships between its dimerization and function in PHA synthesis. PMID- 23043465 TI - Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus. AB - Staphylococcus aureus is a pathogen that infects multiple anatomical sites leading to a diverse array of diseases. Although vertebrates can restrict the growth of invading pathogens by sequestering iron within haem, S. aureus surmounts this challenge by employing high-affinity haem uptake systems. However, the presence of excess haem is highly toxic, necessitating tight regulation of haem levels. To overcome haem stress, S. aureus expresses the detoxification system HrtAB. In this work, a transposon screen was performed in the background of a haem-susceptible, HrtAB-deficient S. aureus strain to identify the substrate transported by this putative pump and the source of haem toxicity. While a recent report indicates that HrtAB exports haem itself, the haem-resistant mutants uncovered by the transposon selection enabled us to elucidate the cellular factors contributing to haem toxicity. All mutants identified in this screen inactivated the menaquinone (MK) biosynthesis pathway. Deletion of the final steps of this pathway revealed that quinone molecules localizing to the cell membrane potentiate haem-associated superoxide production and subsequent oxidative damage. These data suggest a model in which membrane-associated haem and quinone molecules form a redox cycle that continuously generates semiquinones and reduced haem, both of which react with atmospheric oxygen to produce superoxide. PMID- 23043467 TI - Preoperative biliary drainage for distal biliary obstruction and post-operative infectious complications. AB - BACKGROUND: Preoperative biliary drainage (PBD) for distal bile duct obstruction may increase post-operative complications. This study examined the effect of PBD on positive bile culture (PBC) rates and complications after biliary bypass or pancreaticoduodenectomy. Bilirubin levels in the non-PBD cohort were also analysed to determine the impact on outcome. METHODS: A retrospective case-note analysis from 2005 to the present day was undertaken. Statistical analysis was undertaken using Students's t-test, chi-squared test, receiver operator characteristics, correlation coefficient and relative risk ratios. RESULTS: A total of 422 patients were identified undergoing pancreaticoduodenectomy or biliary bypass for either benign or malignant distal biliary obstruction. One hundred ninety-six patients had complete data regarding PBD and bile cultures. PBD resulted in a significantly higher relative risk of both infectious complications and positive bile cultures. Overall complication rate was greater in patients undergoing PBD. The major complication rate was equivalent between the two groups. Bilirubin levels in the non-PBD cohort did not correlate or predict length of stay, high-dependency stay, and mortality or complication rate. CONCLUSION: There seems to be little value in PBD for patients with distal biliary obstruction other than to defer definitive surgery to a non-emergency setting. For most hepato-pancreato-biliary units, avoidance of PBD will prove logistically difficult. PMID- 23043468 TI - Setting CME standards in Europe: guiding principles for medical education. AB - OBJECTIVE: The requirement for formal Continuing Medical Education (CME) is growing in Europe with a concomitant focus on quality and independence of medical educational programmes, together with a need for measurable effects on patient outcomes. However, during this rapid evolution, it has become clear that there are misunderstandings and confusion amongst CME providers in relation to standard and regulations. To address this challenging situation, the Good CME Practice Group undertook an initiative to establish a set of standard core principles with a view to adoption by European CME providers and other key organisations involved in provision of CME programmes. METHODS: The Good CME Practice Group developed four core principles relating to (a) appropriate education, (b) effective education, (c) fair balance and (d) transparency. In order to seek advice and input from peer groups and others involved in CME including accrediting bodies and medical societies, 93 representatives from these bodies were asked to complete a questionnaire and provide comments on the core principles. Participants for the consultation process were generated by a systematic search for European organisations with sections committed to medical education across all therapy areas and all key accrediting bodies. Following the consultation phases, the core principles were reviewed in light of responses and feedback and amended as appropriate. RESULTS: The response rate amongst invited participants was 42% and similar across all groups with the exception of European medical societies. However, despite this limitation, there were significant levels of endorsement of the principles by all stakeholders with 90-95% recommending adoption of principles relating to appropriate education, fair balance and transparency. The principle relating to the measure of effective education was also highly endorsed with 89% of respondents recommending uptake. In response, however, to some questions relating to feasibility of implementation, the principle was revised accordingly. Overall, the stakeholders have recommended uptake of all core principles. CONCLUSIONS: The overall goal of the Good CME Practice Group is to guide how European CME providers contribute to improving public health outcomes by championing best practice in CME, maintaining and improving standards, mentoring and educating and working in collaboration with critical stakeholders. The significant endorsement of the four core principles has confirmed that this is a timely and well-received initiative that is aligned with the objectives of key organisations involved in provision of CME-accredited programmes. The Good CME Practice Group will continue to have dialogues with CME accreditation authorities, regulatory bodies and other key stakeholders in order to facilitate collaboration in improving standards across Europe. PMID- 23043469 TI - HbA2 levels in normal adults are influenced by two distinct genetic mechanisms. AB - Using a genome-wide association study, we found that common inter-individual differences in haemoglobin A(2) (HbA(2) , alpha(2) delta(2) ) levels are largely governed by genetic factors (42% of variability). The influence of age (1%) and sex (4%) was small. HbA(2) levels were influenced by two loci: the HBS1L-MYB locus on chromosome 6q, which has been shown to have pleiotropic effects on other haematological traits; and a second locus surrounding HBB, the gene encoding beta globin. Our results suggest that HbA(2) levels in adults are influenced by two different biological processes: one via kinetics of erythropoiesis, and the other, via competition between HBB and HBD activity. PMID- 23043470 TI - In situ observation of electrostatic and thermal manipulation of suspended graphene membranes. AB - Graphene is nature's thinnest elastic membrane, and its morphology has important impacts on its electrical, mechanical, and electromechanical properties. Here we report manipulation of the morphology of suspended graphene via electrostatic and thermal control. By measuring the out-of-plane deflection as a function of applied gate voltage and number of layers, we show that graphene adopts a parabolic profile at large gate voltages with inhomogeneous distribution of charge density and strain. Unclamped graphene sheets slide into the trench under tension; for doubly clamped devices, the results are well-accounted for by membrane deflection with effective Young's modulus E = 1.1 TPa. Upon cooling to 100 K, we observe buckling-induced ripples in the central portion and large upward buckling of the free edges, which arises from graphene's large negative thermal expansion coefficient. PMID- 23043471 TI - Carbohydrate-based synthetic vaccines: does the synthesis of longer chains of carbohydrates make this a step ever closer? PMID- 23043472 TI - The development of swine models in drug discovery and development. PMID- 23043473 TI - Novel strategies to control lipid metabolism: can the antisense drug mipomersen fulfill the unmet need? PMID- 23043475 TI - Ask the experts: the challenges and benefits of flow chemistry to optimize drug development. AB - Against a backdrop of a struggling economic and regulatory climate, pharmaceutical companies have recently been forced to develop new ways to provide more efficient technology to meet the demands of a competitive drug industry. This issue, coupled with an increase in patent legislation and a rising generics market, makes these themes common issues in the growth of drug development. As a consequence, the importance of process chemistry and scale-up has never been more under the spotlight. Future Medicinal Chemistry wishes to share the thoughts and opinions of a variety of experts from this field, discussing issues concerning the use of flow chemistry to optimize drug development, the potential regulatory and environmental challenges faced with this, and whether the academic and industrial sectors could benefit from a more harmonized system relevant to process chemistry. PMID- 23043476 TI - Exploring bioactive peptides from natural sources for oxytocin and vasopressin drug discovery. PMID- 23043477 TI - The central role of chemistry in 'quality by design' approaches to drug development. AB - The quality of medicines reaching the consumer is strictly controlled and maintained by the regulatory agencies of the world. Pharmaceutical companies have to meet and maintain these regulatory quality standards. For this purpose, an increasing number of processes are incorporating quality by design (QbD) principles. Implementation of QbD involves chemistry in several ways, such as in the development of new synthetic and analytical methods, avoiding formation of genotoxic impurities and designing drug-like compounds to improve the quality of biological profile of medicines. A combined effort from regulatory authorities, pharmaceutical industries and academic research groups could also facilitate QbD implementation. PMID- 23043479 TI - The potentiality of vanadium in medicinal applications. AB - In the early treatment of diabetes with vanadium, inorganic vanadium compounds have been the focus of attention; organic vanadium compounds are nowadays increasingly attracting attention. A key compound is bis(maltolato)oxidovanadium, which became introduced into clinical tests Phase IIa. Organic ligands help modulate the bioavailability, transport and targeting mechanism of a vanadium compound. Commonly, however, the active onsite species is vanadyl (VO(2+)) or vanadate (H(2)VO(4) (-)), generated by biospeciation. The mode of operation can be ascribed to interaction of vanadate with phosphatases and kinases, and to modulation of the level of reactive oxygen species interfering with phosphatases and/or DNA. This operating mode has also been inferred for most cancerostatic vanadium compounds, although some, for example vanadocenes, may directly intercalate with DNA. Novel medicinal potentiality of vanadium compounds is geared towards endemic diseases in tropical countries, in particular leishmaniasis, Chagas' disease and amoebiasis, and viral infections such as Dengue fever, SARS and HIV. PMID- 23043478 TI - Advances in zebrafish chemical screening technologies. AB - Due to several inherent advantages, zebrafish are being utilized in increasingly sophisticated screens to assess the physiological effects of chemical compounds directly in living vertebrate organisms. Diverse screening platforms showcase these advantages. Morphological assays encompassing basic qualitative observations to automated imaging, manipulation, and data-processing systems provide whole organism to subcellular levels of detail. Behavioral screens extend chemical screening to the level of complex systems. In addition, zebrafish-based disease models provide a means of identifying new potential therapeutic strategies. Automated systems for handling/sorting, high-resolution imaging and quantitative data collection have significantly increased throughput in recent years. These advances will make it easier to capture multiple streams of information from a given sample and facilitate integration of zebrafish at the earliest stages of the drug-discovery process, providing potential solutions to current drug-development bottlenecks. Here we outline advances that have been made within the growing field of zebrafish chemical screening. PMID- 23043480 TI - Development and strategies of VEGFR-2/KDR inhibitors. AB - VEGF is an important signaling protein involved in both vasculogenesis and angiogenesis. As an essential receptor protein tyrosine kinase propagating cellular signal transduction processes, VEGFR-2 is a central target for drug discovery against tumor-associated angiogenesis. Since the autophosphorylation of VEGFR-2 represents a key step in this signal pathway that contributes to angiogenesis, the discovery of small molecule inhibitors that block this reaction has attracted great interest for novel drugs research and development. Advances in the understanding of catalytic cleft and the conformational changes of DFG motif have resulted in the development of small molecule inhibitors known as type I and type II. High-resolution crystal structures of various inhibitors in complex with the receptor offer an insight into the relationship among binding modes, inhibition mechanisms, activity, selectivity and resistance. To control selectivity, improve activity and introduce intellectual property novelty, the strategies for the further development are discussed through structural and conformational analysis in this review. PMID- 23043481 TI - Recent development of small antimicrobial peptidomimetics. AB - Antimicrobial peptides (AMPs) hold promise to circumvent the emergence of drug resistance occurring in the treatment of bacteria using many conventional antibiotics. Antimicrobial peptidomimetics, which mimic bactericidal mechanisms of AMPs, may overcome the disadvantages of AMPs and become the new generation of antibiotic therapeutics. In this review, some recent examples in the development of antimicrobial peptidomimetics are highlighted. The potential of antimicrobial agents has been demonstrated for therapeutic uses. Meanwhile, perspectives on their further development and applications are also presented. PMID- 23043483 TI - Universal metal-semiconductor hybrid nanostructured SERS substrate for biosensing. AB - We demonstrate here a novel high surface area GaN nanowall network substrate with plasmonic Ag nanodroplets, that can be employed as a highly sensitive, reproducible, and charge independent SERS substrate. The uniformity of the size and distribution of the Ag droplets and the absence of linker ligands result in large near-field intensity, while the GaN nanowall network morphology provides multiple reflections for signal enhancement. FDTD calculations simulate the observed hot-spot distribution and reiterate the higher performance of this hybrid substrate over conventional ones. Our studies on oppositely charged proteins provide a proof of concept for employing this as a versatile charge independent label free SERS substrate for trace biomolecule detection. PMID- 23043484 TI - Endoscopic vision-based tracking of multiple surgical instruments during robot assisted surgery. AB - Robot-assisted minimally invasive surgery is effective for operations in limited space. Enhancing safety based on automatic tracking of surgical instrument position to prevent inadvertent harmful events such as tissue perforation or instrument collisions could be a meaningful augmentation to current robotic surgical systems. A vision-based instrument tracking scheme as a core algorithm to implement such functions was developed in this study. An automatic tracking scheme is proposed as a chain of computer vision techniques, including classification of metallic properties using k-means clustering and instrument movement tracking using similarity measures, Euclidean distance calculations, and a Kalman filter algorithm. The implemented system showed satisfactory performance in tests using actual robot-assisted surgery videos. Trajectory comparisons of automatically detected data and ground truth data obtained by manually locating the center of mass of each instrument were used to quantitatively validate the system. Instruments and collisions could be well tracked through the proposed methods. The developed collision warning system could provide valuable information to clinicians for safer procedures. PMID- 23043485 TI - Real-time monitoring of cell apoptosis and drug screening using fluorescent light up probe with aggregation-induced emission characteristics. AB - Real-time monitoring of cell apoptosis could provide valuable insights into early detection of therapy efficiency and evaluation of disease progression. In this work, we designed and synthesized a new live-cell-permeable, fluorescent light-up probe for real-time cell apoptosis imaging. The probe is comprised of a hydrophilic caspase-specific Asp-Glu-Val-Asp (DEVD) peptide and a hydrophobic tetraphenylethene (TPE) unit, a typical fluorogen with aggregation-induced emission characteristics. In aqueous solution, the probe is almost nonfluorescent but displays significant fluorescence enhancement in response to caspase-3/-7, which are activated in the apoptotic process and able to cleave the DEVD moieties. This fluorescence "turn-on" response is ascribed to aggregation of cleaved hydrophobic TPE residues, which restricts the intramolecular rotations of TPE phenyl rings and populates the radiative decay channels. The light-up nature of the probe allows real-time monitoring of caspase-3/-7 activities both in solutions and in living cells with a high signal-to-noise ratio. The probe provides a new opportunity to screen enzyme inhibitors and evaluate the apoptosis associated drug efficacy. PMID- 23043486 TI - TRPC6 inhibited NMDA receptor activities and protected neurons from ischemic excitotoxicity. AB - Excitotoxicity induced by NMDA receptor-mediated intracellular Ca(2+) ([Ca(2+) ](i)) overload is a major cause of delayed neuronal death in cerebral ischemia. Transient receptor potential canonical (TRPC) 6 protects neurons from ischemic brain damage. However, the mechanisms by which TRPC6 protects neurons are largely unknown. Here, we reported that TRPC6 suppressed the [Ca(2+)](i) elevation induced by NMDA and protected neurons from excitotoxicity. Over-expressing or down-regulating TRPC6 suppressed or aggravated Ca(2+) overload under excitotoxicity, respectively. TRPC6 protected cultured neurons from damage caused by NMDA toxicity or oxygen glucose deprivation (OGD). Moreover, the infarct volume in TRPC6 transgenic (Tg) mice was smaller than that in wild-type (WT) littermates. The TRPC6 Tg mice had better behavior performance and lower mortality than their WT littermates. Thus, TRPC6 inhibited NMDA receptor triggered neurotoxicity and protected neurons from ischemic brain damage. Increase in TRPC6 activity could be a potential strategy for stroke prevention and therapy. PMID- 23043487 TI - Comparative study of activation methods on tuning gas sorption properties of a metal-organic framework with nanosized ligands. AB - Presented here is a new porous metal-organic framework based on a nanosized tris((4-carboxyl)phenylduryl)amine ligand, which features a 2-fold interpenetrating hms network and shows distinct gas adsorption behaviors dependent on different activation methods. PMID- 23043488 TI - Genotypic characteristics of a Mycobacterium sp. isolated from yellowtail Seriola quinqueradiata and striped jack Pseudocaranx dentex in Japan. AB - In Japan, a Mycobacterium marinum-like mycobacterium was isolated from the yellowtail, Seriola quinqueradiata. The species was identified as M. marinum by a commercial mycobacterial DNA-DNA hybridization kit. Nevertheless, PCR restriction analysis of the DNA of its RNA polymerase beta-subunit gene definitively showed that this Mycobacterium sp. was M. ulcerans. PCR analysis revealed the genotypic characteristics of M. ulcerans in the Mycobacterium sp., only the mup053 gene sequence being absent, as has been found previously in other piscine mycobacteria such as M. marinum strains DL240490 and DL045 and M. pseudoshottsii. With one exception, this Mycobacterium sp. and M. pseudoshottsii had identical 16S rRNA gene sequences, which is also probably true of M. marinum strains DL240490 and DL045. Similarly, according to comparisons of the 16S rRNA gene, ITS region, and hsp65 gene sequences, this Mycobacterium sp. is more closely related to M. pseudoshottsii than to M. ulcerans or M. marinum. A PCR product of approximately 2000 bp was amplified from region of difference 9 in the Mycobacterium sp. The nucleotide sequence revealed insertion of IS2404, the sequence of which is 1366 bp long. The novel single nucleotide polymorphisms identified in this region distinguished this Mycobacterium sp. from M. marinum strain DL240490 and M. pseudoshottsii. The present findings raise the possibility that these species have a common ancestor. Further studies are required to improve our understanding of the relationship between their geographical origin and genetic diversity. PMID- 23043489 TI - Surfactant deactivation in a pediatric model induces hypovolemia and fluid shift to the extravascular lung compartment. AB - BACKGROUND: Surfactant deficiency is the pivotal abnormality in Neonatal and Acute Respiratory Distress Syndrome. Surfactant deactivation can produce hypoxemia, loss of lung compliance, and pulmonary edema, but its circulatory consequences are less understood. OBJECTIVE: To describe the sequential hemodynamic changes and pulmonary edema formation after surfactant deactivation in piglets. METHODS: Surfactant deactivation was induced by tracheal instillation of polysorbate 20 in 15 anesthetized and mechanically ventilated Large White piglets. The hemodynamic consequences of surfactant deactivation were assessed at 30, 120, and 240 min by transpulmonary thermodilution and traditional methods. RESULTS: Surfactant deactivation caused hypoxemia, reduced lung compliance, and progressively increased lung water content (P < 0.01). Early hypovolemia was observed, with reductions of the global end-diastolic volume and stroke volume (P < 0.05). Reduced cardiac output was observed at the end of the study (P < 0.05). Standard monitoring was unable to detect these early preload alterations. Surprisingly, the bronchoalveolar protein content was greatly increased at the end of the study compared with baseline levels (P < 0.01). This finding was inconsistent with the notion that the pulmonary edema induced by surfactant deactivation was exclusively caused by high surface tension. CONCLUSIONS: Hypovolemia develops early after surfactant deactivation, in part due to the resulting fluid shift from the intravascular compartment to the lungs. PMID- 23043490 TI - Development and evaluation of a modification of the Fried frailty criteria using population-independent cutpoints. AB - OBJECTIVES: To develop and evaluate a modification of the Fried frailty assessment using population-independent cutpoints and to determine frailty prevalence of community-dwelling elderly people in a German population. DESIGN: Cross-sectional analysis of 8-year follow-up data of a large German cohort study. SETTING: Saarland, Germany. PARTICIPANTS: Three thousand one hundred twelve community-dwelling adults aged 59 and older. MEASUREMENTS: Frailty was operationalized using modified Fried frailty criteria. Criteria were categorized according to quintiles (lowest-quintile approach) or using population-independent cutpoints derived from the literature (population-independent approach). Agreement and construct validity of frailty classification according to both approaches were evaluated according to weighted kappa (kappa) and Spearman rank correlation (r(Sp) ). Associations between frailty and covariates were assessed using multiple logistic regression models. RESULTS: Although more participants were identified as frail according to the population-independent index (8.9%) than the lowest-quintile index (6.5%), agreement and correlation of frailty classification using both approaches was high (kappa = 0.75 and r(Sp) = 0.84). Sex differences in frailty prevalence were more pronounced when the population independent approach was used (women 11.4%; men 6.1%). Similarly strong significant associations with sociodemographic, lifestyle, and medical factors such as older age, female sex, smoking, and obesity were seen for both approaches. CONCLUSION: The modified Fried index using literature-derived cutpoints independent from the frailty criteria distributions in the underlying study population showed good correlation with the lowest-quintile approach and enables prevalence estimates that are directly comparable between different populations. PMID- 23043491 TI - Delayed diagnosis of systemic lupus erythematosus due to misinterpretation of dengue serology: comments on the article by Santosa et al. PMID- 23043492 TI - Glioblastoma: molecular analysis and clinical implications. AB - Glioblastoma, the most common malignant primary brain tumor, carries an invariably poor prognosis. Targeting underlying biological foundations of the disease will be crucial to developing more effective treatment strategies. Although increasing evidence clearly indicates that glioblastoma is a molecularly heterogeneous disorder, recent large-scale expression profiling has provided a framework for categorizing the tumor into 3 to 4 distinct subclasses, each with its own characteristic genomic alterations. As such, there remains the enticing possibility that glioblastoma subclasses themselves might represent predictive biomarkers, particularly in the context of specific targeted agents. This review focuses on how best to ascertain the functional relevance of molecular subclass in glioblastoma through both preclinical and clinical investigations. The availability of appropriate mouse modeling systems along with expanded molecular profiling capabilities in the clinical setting should aid such efforts. However, significant systematic challenges remain, particularly in the setting of clinical trials. PMID- 23043493 TI - Antibody-drug conjugates in cancer therapy. AB - An antibody-drug conjugate (ADC) provides the possibility of selectively ablating cancer cells by combining the specificity of a monoclonal antibody (mAb) for a target antigen with the delivery of a highly potent cytotoxic agent. ADC target antigens are typically highly expressed on the surface of cancer cells compared to normal cells. The tumor target, the cytotoxic agent, and the manner in which the agent is attached to the antibody are key determinants of clinical activity and tolerability. Recently, several clinical trials have demonstrated that ADCs achieve higher clinical response rates than unconjugated mAbs targeting the same cell surface antigen. Brentuximab vedotin represents one such ADC that has recently been approved for the treatment of relapsed Hodgkin and systemic anaplastic large cell lymphomas--both characterized by high expression of the target antigen, CD30, on the surface of malignant cells. This review summarizes key characteristics of current, clinically active ADCs and highlights recent clinical data illustrating the benefit of antibody-targeted delivery of cytotoxic agents to cancer cells. PMID- 23043494 TI - Role of hyperconjugation in the 1,2-shift reactivity of bicyclo[2.1.0]pentane and cyclopropane radical cations: a computational study. AB - Hyperconjugation and its relationship with the 1,2-shift rearrangement reactivity in bicyclo[2.1.0]pentane and cyclopropane radical cations have been studied with density functional theory (PBE0/6-311G**). Hyperconjugation has been evaluated by calculating the (1)H hyperfine coupling constants, atomic spin densities, and dihedral angles of beta hydrogens with respect to the axes of the nearest p orbitals bearing the main part of the localized spin density. The calculated hyperfine couplings are in good agreement with the experimental values, and the calculated couplings and angles satisfy the Heller-McConnell relationship, which validates our approach to measure hyperconjugation. Significantly, it is the endo beta-hydrogen on the single methylene bridge of the housanes 1a, 1b, and 1d that has the largest hyperconjugative interaction, and this is also the migrating hydrogen in the 1,2-shift reaction leading to the rearrangement of these housanes to cyclopentene radical cations. As a result of this stereoelectronic preference, the migrating entity from the methylene bridge is the endo rather than the exo bond, irrespective of the nature of the substituent. Accordingly, for the 1a-1d housanes, the key role of hyperconjugation lowers the endo C-H or C-Me bond strength selectively, and thereby assists the preferred sigmatropic migration of the endo substituent to the bridgehead carbon. By comparison, the extent of hyperconjugation is found to be much reduced in the cyclopropane radical cations 2a-2d, and the latter species do not undergo the corresponding 1,2-shift rearrangement reaction. This absence of reactivity in 2a-2d is therefore attributed to the weaker hyperconjugative interaction as well as to the less favorable energetics for the overall reaction. PMID- 23043495 TI - Surveillance of the efficacy of artemether-lumefantrine and artesunate amodiaquine for the treatment of uncomplicated Plasmodium falciparum among children under five in Togo, 2005-2009. AB - BACKGROUND: Malaria remains a major public health problem in Togo. The national malaria control programme in Togo changed the anti-malarial treatment policy from monotherapy to artemisinin combination therapy in 2004. This study reports the results of therapeutic efficacy studies conducted on artemether-lumefantrine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Togo, between 2005 and 2009. METHODS: Children between 6 and 59 months of age, who were symptomatically infected with P. falciparum, were treated with either artemether-lumefantrine or artesunate-amodiaquine. The primary end-point was the 28-day cure rate, PCR-corrected for reinfection and recrudescence. Studies were conducted according to the standardized WHO protocol for the assessment of the efficacy of anti-malarial treatment. Differences between categorical data were compared using the chi-square test or the Fisher's exact test where cell counts were <= 5. Differences in continuous data were compared using a t-test. RESULTS: A total of 16 studies were conducted in five sentinel sites, with 459, 505 and 332 children included in 2005, 2007 and 2009, respectively. The PCR-corrected 28-day cure rates using the per-protocol analysis were between 96%-100% for artemether-lumefantrine and 94%-100% for artesunate amodiaquine. CONCLUSIONS: Both formulations of artemisinin-based combination therapy were effective over time and no severe adverse events related to the treatment were reported during the studies. PMID- 23043496 TI - Quantitative RT-PCR based platform for rapid quantification of the transcripts of highly homologous multigene families and their members during grain development. AB - BACKGROUND: Cereal storage proteins represent one of the most important sources of protein for food and feed and they are coded by multigene families. The expression of the storage protein genes exhibits a temporal fluctuation but also a response to environmental stimuli. Analysis of temporal gene expression combined with genetic variation in large multigene families with high homology among the alleles is very challenging. RESULTS: We designed a rapid qRT-PCR system with the aim of characterising the variation in the expression of hordein genes families. All the known D-, C-, B-, and gamma-hordein sequences coding full length open reading frames were collected from commonly available databases. Phylogenetic analysis was performed and the members of the different hordein families were classified into subfamilies. Primer sets were designed to discriminate the gene expression level of whole families, subfamilies or individual members. The specificity of the primer sets was validated before successfully applying them to a cDNA population derived from developing grains of field grown Hordeum vulgare cv. Barke. The results quantify the number of moles of transcript contributed to a particular gene family and its subgroups. More over the results indicate the genotypic specific gene expression. CONCLUSIONS: Quantitative RT-PCR with SYBR Green labelling can be a useful technique to follow gene expression levels of large gene families with highly homologues members. We showed variation in the temporal expression of genes coding for barley storage proteins. The results imply that our rapid qRT-PCR system was sensitive enough to identify the presence of alleles and their expression profiles. It can be used to check the temporal fluctuations in hordein expressions or to find differences in their response to environmental stimuli. The method could be extended for cultivar recognition as some of the sequences from the database originated from cv. Golden Promise were not expressed in the studied barley cultivar Barke although showed primer specificity with their cloned DNA sequences. PMID- 23043497 TI - Physicochemical and antioxidant properties of Bangladeshi honeys stored for more than one year. AB - BACKGROUND: There is no available information on physicochemical and antioxidant properties on Bangladeshi honey. We investigated five different monofloral and three different multifloral honey samples collected from different parts of Bangladesh. METHODS: The levels of phenolics, flavonoids, ascorbic acid, ascorbic acid equivalent antioxidant content (AEAC), proline, protein and antioxidants were determined in the honey samples using ferric reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. RESULTS: The highest level of phenolic was 688.5 +/- 5.9 mg Gallic acid/kg, and the highest level of flavonoid was 155 +/- 6.9 mg Catechin/kg. The highest color intensity was 2034.00 +/- 17.5 mAU, and the highest protein content was 8.6 +/- 0.0mg/g. High levels of proline (2932.8 +/- 3.7 mg/kg), ascorbic acid (154.3 +/- 0.3 mg/kg), AEAC (34.1 +/- 1.4mg/100 g) and FRAP (772.4 +/- 2.5 MUmol Fe (II)/100 g) were detected in some of the samples, especially the multifloral honey samples, indicating good antioxidant properties. A strong positive correlation was found between phenolics, flavonoids, DPPH, FRAP and color intensity, indicating that in addition to total phenolic and flavonoid concentrations, color intensity and amino acid are good indicators of the antioxidant potential of honey. Except for a single sample (BDH-6), the honey samples stored for 1.5 years at room temperature still had 5-hydroxymethylfurfural (HMF) values within the recommended range (mean = 10.93 mg/kg), indicating that the rate of HMF production in Bangladeshi honey samples is low. CONCLUSION: It is postulated that the low rate of HMF formation could be attributed to the acidic and low moisture content in the samples. In general, multifloral honeys have higher antioxidant properties based on their high levels of phenolics, flavonoids, AEAC, DPPH and FRAP when compared to monofloral honeys. We also found that monofloral honey samples from Guizotia abyssinica and Nigella sativa had high antioxidant properties. PMID- 23043498 TI - Herbarone, a rearranged heptaketide derivative from the sea hare associated fungus Torula herbarum. AB - Herbarone (1), a novel heptaketide with a tetrahydro-5,9-methanobenzo[8]annulen 10(5H)-one skeleton, together with the new ent-astropaquinones B (2) and C (3) and four known pyranonaphthoquinones (4-7), was isolated from the sea hare associated fungus Torula herbarum. The structures of the new compounds were elucidated by detailed spectroscopic analysis, and the absolute configurations were determined by solution TDDFT/ECD calculations. Absolute configurations of the known compounds were studied by ECD measurements and calculations. The isolation of heptaketide 1 suggests that an intramolecular aldol reaction takes place to form the tricyclic scaffold. PMID- 23043499 TI - Patterns of response in patients with pretreated metastatic melanoma who received ipilimumab 3 mg/kg in a European expanded access program: five illustrative case reports. AB - Ipilimumab 3 mg/kg was the first agent to improve survival of pretreated advanced melanoma patients. Nonconventional response patterns to ipilimumab have been reported widely, but most of these data were from studies with ipilimumab 10 mg/kg. Here, case reports from five patients treated within an expanded access program (EAP) with ipilimumab at its licensed dose of 3 mg/kg illustrate the efficacy of ipilimumab in an expanded access setting and the range of different tumor response patterns encountered. The durable clinical benefit seen in these patients despite the observed atypical response patterns highlights the necessity for comprehensive clinical decision making. PMID- 23043500 TI - Robust tests of equivalence for k independent groups. AB - A common question of interest to researchers in psychology is the equivalence of two or more groups. Failure to reject the null hypothesis of traditional hypothesis tests such as the ANOVA F-test (i.e., H0 : MU(1) = ... = MU(k)) does not imply the equivalence of the population means. Researchers interested in determining the equivalence of k independent groups should apply a one-way test of equivalence (e.g., Wellek, 2003). The goals of this study were to investigate the robustness of the one-way Wellek test of equivalence to violations of homogeneity of variance assumption, and compare the Type I error rates and power of the Wellek test with a heteroscedastic version which was based on the logic of the one-way Welch (1951) F-test. The results indicate that the proposed Wellek Welch test was insensitive to violations of the homogeneity of variance assumption, whereas the original Wellek test was not appropriate when the population variances were not equal. PMID- 23043501 TI - Combination therapy of radiofrequency ablation and bevacizumab monitored with power Doppler ultrasound in a murine model of hepatocellular carcinoma. AB - PURPOSE: The purpose of this study was to monitor tumour blood flow with power Doppler ultrasound following antiangiogenic therapy with bevacizumab in order to optimally time the application of radiofrequency (RF) ablation to increase ablation diameter. MATERIALS AND METHODS: Athymic nude mice bearing human hepatocellular carcinoma xenografts were treated with bevacizumab and imaged daily with power Doppler ultrasound to quantify tumour blood flow. Mice were treated with RF ablation alone or in combination with bevacizumab at the optimal time, as determined by ultrasound. Ablation diameter was measured with histology and tumour microvascular density was calculated with immunohistochemistry. A computational thermal model of RF ablation was used to estimate ablation volume. RESULTS: A maximum reduction of 27.8 +/- 8.6% in tumour blood flow occurred on day 2 following antiangiogenic therapy, while control tumours increased 29.3 +/- 17.1% (p < 0.05). Tumour microvascular density was similarly reduced by 45.1 +/- 5.9% on day 2 following antiangiogenic therapy. Histology demonstrated a 13.6 +/- 5.6% increase in ablation diameter (40 +/- 21% increase in volume) consistent with a computational model. CONCLUSION: Quantitative power Doppler ultrasound is a useful biomarker to monitor tumour blood flow following antiangiogenic treatment and to guide the application of RF ablation as a drug plus device combination therapy. PMID- 23043502 TI - Phenothiazine-sensitized organic solar cells: effect of dye anchor group positioning on the cell performance. AB - Effect of positioning of the cyanoacrylic acid anchoring group on ring periphery of phenothiazine dye on the performance of dye-sensitized solar cells (DSSCs) is reported. Two types of dyes, one having substitution on the C-3 aromatic ring (Type 1) and another through the N-terminal (Type 2), have been synthesized for this purpose. Absorption and fluorescence studies have been performed to visualize the effect of substitution pattern on the spectral coverage and electrochemical studies to monitor the tuning of redox levels. B3LYP/6-31G* studies are performed to visualize the frontier orbital location and their significance in charge injection when surface modified on semiconducting TiO2. New DSSCs have been built on nanocrystalline TiO2 according to traditional two electrode Gratzel solar cell setup with a reference cell based on N719 dye for comparison. The lifetime of the adsorbed phenothiazine dye is found to be quenched significantly upon immobilizing on TiO2 suggesting charge injection from excited dye to semiconducting TiO2. The performances of the cells are found to be prominent for solar cells made out of Type 1 dyes compared to Type 2 dyes. This trend has been rationalized on the basis of spectral, electrochemical, computational, and electrochemical impedance spectroscopy results. PMID- 23043503 TI - New high-nuclearity carbonyl and carbonyl-substituted rhodium clusters and their relationships with polyicosahedral carbonyl-substituted palladium- and gold thiolates. AB - A reinvestigation of the synthesis of [H(5-n)Rh(13)(CO)(24)](n-) (n = 2, 3) led to isolation of a series of Rh(19), Rh(26), and Rh(33) high-nuclearity carbonyl and carbonyl-substituted rhodium clusters. The [Rh(19)(CO)(31)](5-) (1) is electronically equivalent with [Pt(19)(CO)(22)](4-), but poor crystal diffraction data of all salts obtained to date have prevented its geometrical analysis. The structures of Rh(26)(CO)(29)(CH(3)CN)(11) (2) as 2.2CH(3)CN and [Rh(33)(CO)(47)](5-) (3) as [NEt(4)](5)[3].Me(2)CO were determined from complete X-ray diffraction determinations. The latter two species adopt polyicosahedral metal frameworks, and notably, [Rh(33)(CO)(47)](5-) represents the molecular group 9 metal carbonyl cluster of highest nuclearity so far reported. PMID- 23043504 TI - Influence of constraint-induced movement therapy upon evoked potentials in rats with cerebral infarction. AB - Constraint-induced movement therapy (CIMT) is an effective treatment promoting motor recovery of upper extremity function in stroke patients. The objective of the present study was to determine the effect of CIMT on the evoked potentials in rats with focal cerebral cortical ischemia induced by endothelin-1 (ET-1). Thirty rats were randomly assigned to the sham, infarct or CIMT groups. ET-1 was injected stereotaxically into the forelimb area of the cerebral cortex in the dominant hemisphere. Custom-made constraint jackets were applied to limit movement of the unaffected forelimb in the CIMT group. Motor and sensory function of the forelimb was evaluated by a pellet retrieval task and forearm asymmetry test. Electrophysiologic changes were evaluated by motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SEPs). The location and extent of cerebral ischemia were confirmed and compared histologically. The CIMT group showed better recovery in the pellet retrieval task. Forelimb use was more symmetrical in the CIMT group. The waveform of the SEP was reversed and delayed in the infarct group, but it was preserved in the CIMT group with amplitude decrease only. The estimated volume of infarction was smaller in the CIMT group, although statistically not significant. The results demonstrate that CIMT can promote recovery of motor function in focal cerebral cortical infarcts, and that recovery may be related to reorganization of the cerebral neuronal network in the somatosensory pathway. PMID- 23043505 TI - Therapeutic potential of Moringa oleifera extracts against acetaminophen-induced hepatotoxicity in rats. AB - CONTEXT: Moringa oleifera Lam. (Moringaceae) is a rich source of essential minerals and antioxidants; it has been used in human and animal nutrition. The leaves and flowers are being used by the population with great dietary importance. OBJECTIVE: The present study was to investigate the therapeutic effects of the hydroethanolic extract of Moringa oleifera (MO) leaves and flowers against hepatotoxicity induced by acetaminophen (APAP) in rats. MATERIALS AND METHODS: In the hepatoprotective study, either flowers or leaves of hydroethanolic extract (200 or 400 mg/kg bw through IP injection) were administered an hour after APAP administration. N-Acetylcysteine (NAC) was used as the positive control for this study. Liver and kidney function tests including lipid peroxidation levels were analyzed and histopathological changes of liver and kidney were also observed. RESULTS: Acetaminophen-induced hepatotoxicity increased the activities of liver marker enzymes. Histologically, the liver was observed to have inflammation and bridging necrosis. Liver marker enzymes were significantly reduced when treated with flower and leaf extracts of MO in animals with APAP induced toxicity. In addition, there were no significant changes observed in clinical markers of kidney function. Histological observation on liver tissue from the rats treated with MO flower and leaf extract showed reduction in the severity of the liver damage. DISCUSSION AND CONCLUSION: These results indicated the possible therapeutic action of flower and leaf extract from MO in protecting liver damage in rats given an over dosage of APAP. PMID- 23043506 TI - Protein engineering of Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase into parkeol synthase. AB - A Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase mutant, ERG7(T384Y/Q450H/V454I), produced parkeol but not lanosterol as the sole end product. Parkeol undergoes downstream metabolism to generate compounds 9 and 10. In vitro incubation of parkeol produced a product profile similar to that of the in vivo experiment. In summary, parkeol undergoes a metabolic pathway similar to that of cycloartenol in yeast but distinct from that of lanosterol in yeast, suggesting that two different metabolic pathways of postoxidosqualene cyclization may exist in S. cerevisiae. PMID- 23043507 TI - Diversity in bacterial lysis systems: bacteriophages show the way. AB - Bacteriophages have developed multiple host cell lysis strategies to promote release of descendant virions from infected bacteria. This review is focused on the lysis mechanisms employed by tailed double-stranded DNA bacteriophages, where new developments have recently emerged. These phages seem to use a least common denominator to induce lysis, the so-called holin-endolysin dyad. Endolysins are cell wall-degrading enzymes whereas holins form 'holes' in the cytoplasmic membrane at a precise scheduled time. The latter function was long viewed as essential to provide a pathway for endolysin escape to the cell wall. However, recent studies have shown that phages can also exploit the host cell secretion machinery to deliver endolysins to their target and subvert the bacterial autolytic arsenal to effectively accomplish lysis. In these systems the membrane depolarizing holin function still seems to be essential to activate secreted endolysins. New lysis players have also been uncovered that promote degradation of particular bacterial cell envelopes, such as that of mycobacteria. PMID- 23043508 TI - Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications. PMID- 23043509 TI - A lysosome-targetable and two-photon fluorescent probe for monitoring endogenous and exogenous nitric oxide in living cells. AB - A lysosome-specific and two-photon fluorescent probe, Lyso-NINO, demonstrates high selectivity and sensitivity toward NO, lower cytotoxicity, and perfect lysosomal localization. With the aid of Lyso-NINO, the first capture of NO within lysosomes of macrophage cells has been achieved using both two-photon fluorescence microscopy and flow cytometry. PMID- 23043510 TI - S-nitrosylated protein disulfide isomerase contributes to mutant SOD1 aggregates in amyotrophic lateral sclerosis. AB - A major hallmark of mutant superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis is SOD1-immunopositive inclusions found within motor neurons. The mechanism by which SOD1 becomes aggregated, however, remains unclear. In this study, we aimed to investigate the role of nitrosative stress and S-nitrosylation of protein disulfide isomerase (PDI) in the formation of SOD1 aggregates. Our data show that with disease progression inducible nitric oxide synthase (iNOS) was up-regulated, which generated high levels of nitric oxide (NO) and subsequently induced S-nitrosylation of PDI in the spinal cord of mutant SOD1 transgenic mice. This was further confirmed by in vitro observation that treating SH-SY5Y cells with NO donor S-nitrosocysteine triggered a dose-dependent formation of S-nitrosylated PDI. When mutant SOD1 was over-expressed in SH-SY5Y cells, the iNOS expression was up-regulated, and NO generation was consequently increased. Furthermore, both S-nitrosylation of PDI and the formation of mutant SOD1 aggregates were detected in the cells expressing mutant SOD1(G93A). Blocking NO generation with the NOS inhibitor N-nitro-L-arginine attenuated the S nitrosylation of PDI and inhibited the formation of mutant SOD1 aggregates. We conclude that NO-mediated S-nitrosylation of PDI is a contributing factor to the accumulation of mutant SOD1 aggregates in amyotrophic lateral sclerosis. PMID- 23043513 TI - Local structure of Si-Al-Ca-Na-O glasses from coupled neutron and X-ray total scattering data. AB - Amorphous materials became significantly important and more widely studied during the last few decades, due the their increasingly widespread applications in materials science and technology. Their local structure seems to have a very strong bond with those properties: in this paper, the local structure of Si-Al-Ca Na-O glasses is studied by means of total scattering. EPSR simulations, coupling neutron, and X-ray data have been used to study glass samples (as a function of composition), with a composition close to the one used in their technological applications (ceramic glazes), providing a consistent structural model. The disordered structure of these materials has been evaluated in terms of network forming/modifier elements. The network-forming elements (silicon and aluminum) show coordination numbers and bond angles that are consistent with a tetrahedral arrangement. In contrast, network-modifying elements (Ca and Na, whose content is different in all samples) depolymerize the network, increasing the number of nonbridging oxygens. This structural information is required to rationalize many important technological properties of these materials, such as the glass transition temperatures and thermal expansion, that control their efficiency as glazes. PMID- 23043512 TI - Emergence delirium in children: a comparison of sevoflurane and desflurane anesthesia using the Paediatric Anesthesia Emergence Delirium scale. AB - OBJECTIVES/AIM: This randomized control trial was designed to evaluate the incidence of emergence delirium (ED) in preschool children receiving sevoflurane or desflurane anesthesia combined with an effective caudal block. BACKGROUND: While ED has been described in children receiving sevoflurane or desflurane anesthesia, a direct comparison between the two agents using a validated ED assessment tool has not been reported previously. METHODS/MATERIALS: Two hundred and sixty preschool children scheduled for elective sub-umbilical surgery were randomized to receive sevoflurane or desflurane anesthesia combined with a caudal block. ED was defined as a Paediatric Anesthesia Emergence Delirium scale (PAED) >= 10 points. A delirium-specific score (ED I) was calculated from the first three items of the PAED score (eye contact, purposeful actions, awareness of the surroundings) and a nonspecific score (ED II) from the last two items on the PAED score (restlessness and inconsolability) to test the hypothesis that some items of the PAED scale may better reflect clinical ED than others. RESULTS: Thirty-one (25%) children in each group demonstrated ED after awakening with ED being of shorter duration in the desflurane group than the sevoflurane group. An ED I score of nine points had a sensitivity of 0.93 and a specificity of 0.94 for ED. An ED II score of five points had a sensitivity of 0.34 and specificity of 0.95 for ED. CONCLUSION: Sevoflurane and desflurane anesthesia were associated with similar incidences of ED in children undergoing sub-umbilical surgery and receiving effective regional anesthesia. High scores on the first three items of the PAED scale were highly correlated with ED. The items restlessness and inconsolability had lower sensitivity for the diagnosis of ED. PMID- 23043514 TI - Meconium-stained amniotic fluid and the need for paediatrician attendance. AB - AIM: To determine perinatal parameters among term newborn infants born by vaginal delivery with meconium-stained amniotic fluid (MSAF) that needed paediatrician assistance. METHODS: Paediatricians who were in attendance in the delivery room due to MSAF among term infants completed 775 reports regarding the infants' delivery conditions, and the assistance provided. We defined 'paediatrician attendance needed' for a subgroup of infants for whom we retrospectively determined that paediatrician attendance in the delivery room was required. RESULTS: 'Paediatrician attendance needed' was determined in 31 (4%) cases. Among cases with documented normal foetal monitor, only 10 (1.8%) were defined as 'paediatrician attendance needed', a percentage significantly lower than among infants born following non-reassuring foetal monitor: 21 (9.7%) (p < 0.001). 'Paediatrician attendance needed' was predicted by non-reassuring foetal monitor [OR 6.02 (CI 2.72-13.31), p < 0.001], maternal fever [OR 6.34 (1.92-20.92), p = 0.002] and younger maternal age (for every year) [OR 0.889 (CI 0.82-0.96), p = 0.003]. CONCLUSIONS: Term newborn infants born by vaginal delivery with MSAF with documented normal tracing foetal monitor are at low risk of the need for paediatrician assistance. Paediatrician attendance in the delivery room in labour involving MSAF should be recommended when non-reassuring foetal monitor tracing is observed and should also be considered when maternal fever is recorded, and/or thick meconium is observed. PMID- 23043515 TI - Optical properties of gallium oxide clusters from first-principles calculations. AB - The optical properties of the (Ga(2)O(3))(n) clusters, with n = 1-10, have been studied within the framework of time dependent density functional theory. The gallium oxide cluster geometries showed evolution from planar configuration (C(2v)) for Ga(2)O(3) to layered globular configuration (C(s)) for (Ga(2)O(3))(10) via corundum configuration (D(3d)) for (Ga(2)O(3))(4). For n <= 5, with the increase in coordination of Ga and O atoms, the polarizability decreases with the size of the cluster. For n >= 6, with the stabilization of average coordination number for gallium and oxygen atoms, the decrease in polarizability is very small. Further, the optical absorption spectra and the corresponding optical gap have been calculated. The overall shape of the calculated spectra strongly depend on cluster geometries. With the increase in size, the discrete spectra of small clusters evolves into quasicontinuous spectra. For n = 10, the spectra show a smooth absorption edge that is a characteristic of the bulk. It is observed that the optical gap oscillate with an increase in the cluster size. The calculated optical gap of these clusters are lower than the band gap of alpha- and beta-Ga(2)O(3) phases. The underestimation of the calculated values of the cluster optical gap is due to the use of local density approximation. PMID- 23043516 TI - Office based dermatological surgery and Mohs surgery: a prospective audit of surgical procedures and complications in a procedural dermatology practice. AB - BACKGROUND/OBJECTIVES: Dermatologists commonly perform surgical procedures, including Mohs micrographic surgery, in an outpatient, office-based setting. Although this may be widely perceived to be safe and effective, formal data on the practice are limited. The aim of this study was to examine the range of surgical procedures and associated complications in an Australian specialist dermatology and Mohs surgery practice. METHODS: All surgical procedures over a 55 week period were prospectively logged, with data collection on sex, age, type of procedure, body site, diagnosis and complications. All procedures were performed under conditions that were usual for the practice, with a combination of sterile and clean surgical techniques, depending on the procedure. RESULTS: In all, 2370 surgical procedures were performed during the study period, including 934 Mohs surgery cases. Most procedures (68%) were performed on head and neck sites. A total of 56 complications were recorded in 51 patients. Bacterial wound infections occurred in 13 cases (0.5%). Bleeding complications occurred in five cases (0.2%). There were no complications requiring hospital admission or i.v. antibiotics. CONCLUSIONS: This study supports the view that dermatological surgery, including significant procedures such as Mohs micrographic surgery, flaps and grafts, can be performed on an ambulatory basis in an office-based procedure room setting, with low complication rates. PMID- 23043517 TI - Selection of student-selected component [SSCs] modules across the medical undergraduate curriculum: relationship with motivational factors. AB - Student-selected components (SSCs) encourage the following within the undergraduate medical curriculum: greater exploration of core curriculum topics; exploration of non-core subjects/experiences; research and self-directed learning; and personal and professional development opportunities. This study examined the motivational factors which influence SSC choice to assess (a) SSC selection patterns across each year of the curriculum (direct and graduate entry) and (b) motivation underlying SSC selection across the curriculum. During SSC registration at University College Cork, all medical undergraduates (years 1-3, graduate-entry medicine) were required to select an SSC and provide a written justification for their selection. Five primary motivational factors were identified: correction of perceived deficits; genuine interest in subject and wish to study in more depth; career strategy; exam strategy; and taking a chance. A complex pattern of relationships emerged in relation to matching of motivational factors with SSC categories, e.g. selection of research skills SSCs was strongly associated with the 'career strategy' motivation. Significant differences were observed across curriculum years, as well as between direct entry versus graduate-entry undergraduates, with respect to SSC selections and underlying motivation. This study provides insight into changing patterns of SSC selection in medicine, as well as accompanying motivational factors, across the undergraduate years. PMID- 23043519 TI - Auditory and otological manifestations in adults with HIV/AIDS. AB - OBJECTIVES: This study describes the prevalence and nature of auditory and otological manifestations in adults with HIV/AIDS through clinical examinations and self-reported symptoms across stages of disease progression. DESIGN: Descriptive cross-sectional group design. STUDY SAMPLE: Two hundred HIV positive adult patients (56.5% male; 43.5% female; mean age: 37.99 +/- 6.66 years) attending the Infectious Disease Clinic of a tertiary referral hospital in Pretoria, South Africa were included. Patients were interviewed, medical files were reviewed, and clinical examinations, including otoscopy, tympanometry, pure tone audiometry, and distortion product otoacoustic emissions, were conducted. A matched HIV negative control group was used to compare hearing loss prevalence. RESULTS: Tinnitus (26%), vertigo (25%) hearing loss (27.5%), otalgia (19%), and ear canal pruritis (38%) were prevalent self-reported symptoms. Abnormalities in otoscopy, tympanometry, and otoacoustic emissions were evident in 55%, 41%, and 44% of patients respectively. Pure-tone average (PTA) hearing loss > 25 dBHL was evident in 14% of patients and 39% for hearing loss > 15 dBHL (PTA). Significant differences across average thresholds in the HIV positive and HIV negative control group was present. An increase in self reported vertigo, self reported hearing loss, OAE abnormalities, and hearing loss (PTA > 15 dBHL and PTA > 25 dBHL) was seen with disease progression but was not statistically significant. A significant increase (p <.05) in sensorineural hearing loss was however evident with disease progression. CONCLUSIONS: Auditory and otological symptoms are more common in patients with HIV with a general increase of symptoms, especially sensorineural hearing loss, towards advanced stages of disease progression. PMID- 23043518 TI - Hand hygiene to reduce community transmission of influenza and acute respiratory tract infection: a systematic review. AB - Hand hygiene may be associated with modest protection against some acute respiratory tract infections, but its specific role in influenza transmission in different settings is unclear. We aimed to review evidence that improving hand hygiene reduces primary and secondary transmission of (i) influenza and (ii) acute respiratory tract infections in community settings. We searched Medline, Embase, Global Health and Cochrane databases up to 13 February 2012 for reports in any language of original research investigating the effect of hand hygiene on influenza or acute respiratory tract infection where aetiology was unspecified in community settings including institutions such as schools, and domestic residences. Data were presented and quality rated across outcomes according to the Grading of Recommendations Assessment, Development and Evaluation system. Sixteen articles met inclusion criteria. There was moderate to low-quality evidence of a reduction in both influenza and respiratory tract infection with hand hygiene interventions in schools, greatest in a lower-middle-income setting. There was high-quality evidence of a small reduction in respiratory infection in childcare settings. There was high-quality evidence for a large reduction in respiratory infection with a hand hygiene intervention in squatter settlements in a low-income setting. There was moderate- to high-quality evidence of no effect on secondary transmission of influenza in households that had already experienced an index case. While hand hygiene interventions have potential to reduce transmission of influenza and acute respiratory tract infections, their effectiveness varies depending on setting, context and compliance. PMID- 23043520 TI - Caregiver recall and understanding of paediatric diagnostic information and assessment feedback. AB - OBJECTIVE: Providing appropriate feedback to caregivers is an important part of the paediatric audiological assessment. This preliminary study explored caregiver recall and understanding of audiological diagnostic information subsequent to an initial paediatric diagnostic assessment. DESIGN: A qualitative study was conducted at an audiology clinic at a hospital in South Africa. Data collection included observation and video-recording of assessment and feedback sessions as well as post-session semi-structured interviews with the audiologists and caregivers. Recorded sessions were analysed using sociolinguistic methods and a transcription-less approach. Interviews were analysed via content analysis. STUDY SAMPLE: Participants included four audiologists and five caregivers whose children had been referred for an initial audiological assessment. RESULTS: Feedback sessions included explanations of the hearing mechanism, tests, audiogram, diagnosis and recommendations. Most caregivers were able to recall the final diagnosis and recommendations, but demonstrated poor recall and understanding of explanations of the audiogram and hearing mechanism. CONCLUSIONS: Results highlight the importance of tailoring information towards specific caregiver needs during feedback sessions and acknowledging the goals and agenda of the caregiver. There is a need for a greater focus on information counselling in curricula and training programmes, and several suggestions are made in this regard. PMID- 23043522 TI - Long-term storage limits PCR-based analyses of malaria parasites in archival dried blood spots. AB - BACKGROUND: Blood samples collected in epidemiological and clinical investigations and then stored, often at room temperature, as blood spots dried on a filter paper have become one of the most popular source of material for further molecular analyses of malaria parasites. The dried blood spots are often archived so that they can be used for further retrospective investigations of parasite prevalence, or as new genetic markers come to the fore. However, the suitability of the template obtained from dried blood spots that have been stored for long periods for DNA amplification is not known. METHODS: DNA from 267 archived blood spots collected over a period of 12 years from persons with microscopically confirmed Plasmodium falciparum infection was purified by one of two methods, Chelex and Qiagen columns. These templates were subjected to highly sensitive nested PCR amplification targeting three parasite loci that differ in length and/or copy number. RESULTS: When a 1.6 kb fragment of the parasites' small subunit ribosomal RNA was targeted (primary amplification), the efficiency of P. falciparum detection decreased in samples archived for more than six years, reaching very low levels for those stored for more than 10 years. Positive amplification was generally obtained more often with Qiagen-extracted templates. P. falciparum could be detected in 32 of the 40 negative Qiagen-extracted templates when a microsatellite of about 180 bp was targeted. The remaining eight samples gave a positive amplification when a small region of 238 bp of the higher copy number (20 to 200) mitochondrial genome was targeted. CONCLUSIONS: The average length of DNA fragments that can be recovered from dried blood spots decreases with storage time. Recovery of the DNA is somewhat improved, especially in older samples, by the use of a commercial DNA purification column, but targets larger than 1.5 kb are unlikely to be present 10 years after the initial blood collection, when the average length of the DNA fragments present is likely to be around a few hundred bp. In conclusion, the utility of archived dried blood spots for molecular analyses decreases with storage time. PMID- 23043523 TI - Metabotyping of the C. elegans sir-2.1 mutant using in vivo labeling and (13)C heteronuclear multidimensional NMR metabolomics. AB - The roles of sir-2.1 in C. elegans lifespan extension have been subjects of recent public and academic debates. We applied an efficient workflow for in vivo(13)C-labeling of C. elegans and (13)C-heteronuclear NMR metabolomics to characterizing the metabolic phenotypes of the sir-2.1 mutant. Our method delivered sensitivity 2 orders of magnitude higher than that of the unlabeled approach, enabling 2D and 3D NMR experiments. Multivariate analysis of the NMR data showed distinct metabolic profiles of the mutant, represented by increases in glycolysis, nitrogen catabolism, and initial lipolysis. The metabolomic analysis defined the sir-2.1 mutant metabotype as the decoupling between enhanced catabolic pathways and ATP generation. We also suggest the relationship between the metabotypes, especially the branched chain amino acids, and the roles of sir 2.1 in the worm lifespan. Our results should contribute to solidifying the roles of sir-2.1, and the described workflow can be applied to studying many other proteins in metabolic perspectives. PMID- 23043521 TI - CCl4-induced hepatotoxicity: protective effect of rutin on p53, CYP2E1 and the antioxidative status in rat. AB - BACKGROUND: Rutin is a polyphenolic natural flavonoid which possesses antioxidant and anticancer activity. In the present study the hepatoprotective effect of rutin was evaluated against carbon tetrachloride (CCl4)-induced liver injuries in rats. METHODS AND MATERIALS: 24 Sprague-Dawley male rats were equally divided into 4 groups for the assessment of hepatoprotective potential of rutin. Rats of group I (control) received only vehicles; 1 ml/kg bw of saline (0.85%) and olive oil (3 ml/kg) and had free access to food and water. Rats of group II, III and IV were treated with CCl4 (30% in olive oil, 3 ml/kg bw) via the intraperitoneal route twice a week for four weeks. The rutin at the doses of 50 and 70 mg/kg were administered intragastrically after 48 h of CCl4 treatment to group III and IV, respectively. Protective effect of rutin on serum enzyme level, lipid profile, activities of antioxidant enzymes and molecular markers were calculated in CCl4 induced hepatotoxicity in rat. RESULTS: Rutin showed significant protection with the depletion of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (gamma-GT) in serum as was raised by the induction of CCl4. Concentration of serum triglycerides, total cholesterol and low density lipoproteins was increased while high-density lipoprotein was decreased with rutin in a dose dependent manner. Activity level of endogenous liver antioxidant enzymes; catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSHpx), glutathione-S transferase (GST) and glutathione reductase (GSR) and glutathione (GSH) contents were increased while lipid peroxidation (TBARS) was decreased dose dependently with rutin. Moreover, increase in DNA fragmentation and oxo8dG damages while decrease in p53 and CYP 2E1 expression induced with CCl4 was restored with the treatment of rutin. CONCLUSION: From these results, it is suggested that rutin possesses hepatoprotective properties. PMID- 23043524 TI - National surveillance for radiological exposures and intentional potassium iodide and iodine product ingestions in the United States associated with the 2011 Japan radiological incident. AB - BACKGROUND: In March of 2011, an earthquake struck Japan causing a tsunami that resulted in a radiological release from the damaged Fukushima Daiichi nuclear power plant. Surveillance for potential radiological and any iodine/iodide product exposures was initiated on the National Poison Data System (NPDS) to target public health messaging needs within the United States (US). Our objectives are to describe self-reported exposures to radiation, potassium iodide (KI) and other iodine/iodide products which occurred during the US federal response and discuss its public health impact. METHODS: All calls to poison centers associated with the Japan incident were identified from March 11, 2011 to April 18, 2011 in NPDS. Exposure, demographic and health outcome information were collected. Calls about reported radiation exposures and KI or other iodine/iodide product ingestions were then categorized with regard to exposure likelihood based on follow-up information obtained from the PC where each call originated. Reported exposures were subsequently classified as probable exposures (high likelihood of exposure), probable non-exposures (low likelihood of exposure), and suspect exposure (unknown likelihood of exposure). RESULTS: We identified 400 calls to PCs associated with the incident, with 340 information requests (no exposure reported) and 60 reported exposures. The majority (n = 194; 57%) of the information requests mentioned one or more substances. Radiation was inquired about most frequently (n = 88; 45%), followed by KI (n = 86; 44%) and other iodine/iodide products (n = 47; 24%). Of the 60 reported exposures, KI was reported most frequently (n = 25; 42%), followed by radiation (n = 22; 37%) and other iodine/iodide products (n = 13; 22%). Among reported KI exposures, most were classified as probable exposures (n = 24; 96%); one was a probable non exposure. Among reported other iodine/iodide product exposures, most were probable exposures (n = 10, 77%) and the rest were suspect exposures (n = 3; 23%). The reported radiation exposures were classified as suspect exposures (n = 16, 73%) or probable non-exposures (n = 6; 27%). No radiation exposures were classified as probable exposures. A small number of the probable exposures to KI and other iodide/iodine products reported adverse signs or symptoms (n = 9; 26%). The majority of probable exposures had no adverse outcomes (n = 28; 82%). These data identified a potential public health information gap regarding KI and other iodine/iodide products which was then addressed through public health messaging activities. CONCLUSION: During the Japan incident response, surveillance activities using NPDS identified KI and other iodine/iodide products as potential public health concerns within the US, which guided CDC's public health messaging and communication activities. Regional PCs can provide timely and additional information during a public health emergency to enhance data collected from surveillance activities, which in turn can be used to inform public health decision-making. PMID- 23043526 TI - Socket grafting with calcium phosphosilicate alloplast putty: a histomorphometric evaluation. AB - BACKGROUND: Socket grafting with a bone graft substitute immediately after extraction is essential to preserve the ridge architecture for implant placement. Several bone graft substitutes have been tested for their ability to effectively regenerate osseous tissue in the sockets. Evidence suggests that socket bone typically regenerates during a period of 6 to 8 months or longer, depending on several factors including the original ridge dimensions, type of graft, and the overall systemic health of the individual. The purpose of this study is to histologically evaluate the bone regeneration potential of a novel synthetic calcium phosphosilicate putty (CPS) graft substitute. METHODS: After extraction of the involved teeth, CPS putty graft was placed, and the sockets were covered with a collagen plug. Cores were taken from 20 patients for histological evaluation prior to implant placement. Ten cores were processed decalcified with hematoxylin and eosin (H&E) stain and the remaining 10 were processed undecalcified. Histomorphometric data obtained from both sets is presented. RESULTS: Histomorphometric analysis revealed an average vital bone content of 49.5 (+/- 20.7). A residual graft content of 4.3% (+/- 7.8) was observed following a healing time of 4.9 (+/- 0.8) months. CONCLUSIONS: Clinical and histomorphometric data suggests that CPS putty is a good choice for socket bone regeneration in implant-related surgeries. PMID- 23043525 TI - Oral lichen planus: a report and review of an autoimmune-mediated condition in gingiva. AB - Oral lichen planus (OLP) is a chronic autoimmune, mucocutaneous disease that affects the oral mucosa as well as the skin, genital mucosa, scalp, and nails. It is one of the most common dermatological diseases presenting in the oral cavity. An immune-mediated pathogenesis is recognized in lichen planus, although the exact etiology is unknown. The disease most commonly affects middle-aged females. It is infrequently found in children, with a prevalence of about 0.03%, and reports of this are scarce in the literature. The erosive and atrophic forms of OLP are less common, yet they are more likely to cause symptoms. OLP is the target of much controversy, especially in relation to its potential for malignancy. Thus, it is important for clinicians to maintain a high index of suspicion for all intraoral lichenoid lesions. Periodic follow-up of all patients with OLP is recommended. In view of the above, the authors highlight a case of gingival erosive lichen planus affecting a 17-year-old adolescent without concomitant cutaneous lesions, with special emphasis on clinical and microscopic characteristics of the condition and management with retinoids and steroid therapy. PMID- 23043527 TI - Buccinator muscle repositioning: a case report. AB - Anatomical abnormalities are frequently associated with problems. One such abnormality is crestal attachment of the frenum or muscle on the alveolar process. Crestal attachment of buccinator muscle is a rare phenomenon. It may cause various problems in routine oral exercises or restoring the edentulous area. Presented here is a case of abnormal buccinator muscle attachment, which was relocated apically by surgical means using an acrylic stent. The healing was uneventful, and significant apical repositioning was observed. The area was then considered for prosthodontic therapy. A fixed bridge was fabricated and the long term results of the fixed bridge therapy were assured, because the patient could maintain oral hygiene well after the muscle repositioning operation. PMID- 23043529 TI - New models of follow-up in prostate cancer: a role for information technology? PMID- 23043528 TI - Anesthetic implications of infants with mandibular hypoplasia treated with mandibular distraction osteogenesis. AB - OBJECTIVES: To document the incidence of difficult intubation following mandibular distraction osteogenesis (MDO) in children with severe mandibular hypoplasia. BACKGROUND: Syndromes associated with significant mandibular hypoplasia, especially Pierre Robin sequence, provide a challenge in airway management both in and out of the operating room. Mandibular advancement using mandibular distraction osteogenesis devices has been used in infants in an attempt to reduce the incidence of acute life-threatening airway obstruction. Whether MDO also reduces the incidence of difficult intubation has not been adequately described. METHODS: A retrospective chart review of 51 infants with upper airway obstruction secondary to mandibular hypoplasia who required MDO between January 2002 and 2012. The primary outcome was the incidence of difficult or failed intubation. Secondary outcomes were the relationship between syndrome type and the incidence of difficult intubation. RESULTS: Fifty-one PRS infants were identified. Twenty-eight patients had isolated PRS, six had syndromic PRS, seven had Treacher Collins syndrome, and 10 had another coexisting syndrome. Prior to mandibular distraction osteogenesis (MDO), the incidence of difficult intubation was 71%, with the highest incidence in patients with Treacher Collins syndrome (100%), sPRS syndrome (100%), and PRS (65%). Following MDO, the incidence of difficult intubation was 8.3%. The difference was statistically significant for all patients (Kruskal-Wallis rank test P = 0.0001) those with isolated PRS (P = 0.0001), syndromic PRS (P = 0.0023), and other syndromes (P = 0.0002), but not for Treacher Collins syndrome (P = 0.21). Three patients had pre existing tracheostomies. CONCLUSIONS: In a select group of infants with severe upper airway obstruction who have failed nonsurgical airway interventions, mandibular distraction osteogenesis reduces the incidence of difficult mask ventilation and difficult intubation. We were not able to compare the improvement in airway management to a comparable group of PRS infants who did not undergo surgical intervention. The improvement in laryngeal view was most marked for infants with isolated PRS but no significant benefit was demonstrated in infants with TCS. PMID- 23043530 TI - Sacchachitin, a novel chitin-polysaccharide conjugate macromolecule present in Ganoderma lucidum: purification, composition, and properties. AB - CONTEXT: The extraction method and the crude wound healing effects of sacchachitin from Ganoderma tsugae Murr. (Ganodermataceae) has been cited. However, its purity is still largely limited. OBJECTIVE: An improvement of the fractionation protocol to purify the sacchachitin from Ganoderma lucidum L. (Ganodermataceae) (SGL) is needed. METHODS: Fruiting bodies were extracted with double distilled water and subsequently the residue treated with 95% ethanol and then 40% ethanol. After being filtered, the pH of the supernatant was adjusted to 4.0 with 1 N HCl and lyophilized. The supernatant was added (3:1 v/v) ethanol, the precipitate was collected, 2% NaOH was added and refluxed. The supernatant was collected with pH adjusted to 4.0, then treated with 10% potassium hydroxide (KOH) with repeating acid precipitation and (3:1) ethanol precipitation twice more to obtain the sacchachitin. RESULTS: SGL had a hexosamine content 16.3% (w/w), firmly linked to a talomannan. Its Fourier Transform Infrared Spectroscopy (FTIR) spectrum revealed specific absorption (in cm(-1)) nu(O-H) 3455.5 b,s, amide nu(C=O) 1678.5, and amide I degrees delta(N-H) 1550.4. The percentage deacetylation degree was 37.6 and 39.4% for SGL and MSC, respectively. As contrast, MSC contained only 6.6% of hexosamine with a low protein/carbohydrate ratio 0.35 comparing to 0.82 for SGL. SGL was only moderately strong antioxidant regarding the anti-DPPH, antihydroxyl free radical, and antisuperoxide anion capabilities, exhibiting an IC(33) values of 10 mg/mL (the highest scavenging capability never exceeding 33%), 0.9 mg/mL, and 4.8 mg/mL, respectively. CONCLUSION: We have successfully isolated the pure sacchachitin from the fruiting bodies of G. lucidum that exhibits potent antioxidative activity and may be useful in fabrication of the artificial skin composite substitute. PMID- 23043531 TI - Asymmetric approach toward chiral cyclohex-2-enones from anisoles via an enantioselective isomerization by a new chiral diamine catalyst. AB - A 3-step asymmetric approach toward the optically active chiral cyclohex-2-enones from anisoles has been developed. The crucial asymmetric induction step is an unprecedented catalytic enantioselective isomerization of beta,gamma-unsaturated cyclohex-3-en-1-ones to the corresponding alpha,beta-unsaturated chiral enones. This new asymmetric transformation was realized by cooperative iminium-base catalysis with an electronically tunable new organic catalyst. The synthetic utility of this methodology is highlighted by the enantioselective total synthesis of (-)-isoacanthodoral. PMID- 23043532 TI - Confocal Raman microscopy probing of temperature-controlled release from individual, optically-trapped phospholipid vesicles. AB - Control of permeability of phospholipid vesicle (liposome) membranes is critical to their applications in analytical sensing, in fundamental studies of chemistry in small volumes, and in encapsulation and release of payloads for site-directed drug delivery. Applications of liposome formulations in drug delivery often take advantage of the enhanced permeability of phospholipid membranes at their gel-to fluid phase transition, where the release of encapsulated molecules can be initiated by an increase in temperature. Despite numerous successful liposome formulations for encapsulation and release methods to study the kinetics, this process has been limited to investigations of bulk vesicle dispersions, which provide little or no information about the vesicle membrane structure and its relationship to the kinetics of trans-membrane transport. In this work, confocal Raman microscopy is adapted to study temperature-dependent release of a model compound, 3-nitrobenzene sulfonate (3-NBS), from individual optically trapped phospholipid vesicles, while simultaneously monitoring structural changes in the vesicle membrane reported by vibrational modes of phospholipid acyl chains and the local environment of the encapsulated compound. The confocal geometry allows efficient excitation and collection of Raman scattering from a single vesicle, while optical trapping allows more than hour-long observations of the same vesicle. With window factor analysis to resolve component spectra, temperature controlled release of 3-NBS through vesicle membranes composed of pure 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was measured and compared to transport through a lysolipid-containing membrane specifically formulated for efficient drug delivery. PMID- 23043533 TI - The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug: comments on the article by Soderlin et al. PMID- 23043535 TI - Treatment outcome and its predictors among Asian problem drinkers. AB - INTRODUCTION AND AIMS: Evidence of treatment effectiveness for alcohol use disorders (AUD) have emerged predominantly from Western studies, using highly controlled trials that may not reflect real-world settings. This paper examines treatment outcome and its predictors among Asian problem drinkers participating in a treatment outcome monitoring program at an addiction treatment centre in Singapore. DESIGN AND METHODS: Data were collected at intake and 3, 6 and 12 months, although the focus of this paper is on reliable change at 3 months among the 70% who were followed up. Five hundred and forty-one AUD-diagnosed outpatients presenting for treatment, over a 2-year period, were assessed on drinking behaviours and administered the Addiction Severity Index-Lite, Personal Wellbeing Index (PWI) and Treatment Perceptions Questionnaire. RESULTS: At 3 months, drinking days, alcohol units and alcohol use severity had more than halved and 69% were either abstinent or had reliably reduced their drinking days. Baseline drinking days and treatment satisfaction predicted 3-month drinking frequency but not severity. Positive alcohol outcomes observed at 3 months were sustained among those followed up until 12 months. Mean PWI score improved significantly and fell within the 'normal' range. Treatment satisfaction also emerged as the only significant predictor of reliable positive change in both drinking days and PWI score. DISCUSSION AND CONCLUSIONS: Significant reductions in drinking frequency and severity are possible for Asian problem drinkers after 12 weeks of outpatient treatment. The identified predictors suggest that more frequent drinkers and patients with past/current psychiatric comorbidities may require a more intensive treatment approach to optimise treatment outcomes. PMID- 23043536 TI - Seroprevalence of 2009 H1N1 virus infection and self-reported infection control practices among healthcare professionals following the first outbreak in Bangkok, Thailand. AB - A serologic study with simultaneous self-administered questionnaire regarding infection control (IC) practices and other risks of influenza A (H1N1) pdm09 (2009 H1N1) infection was performed approximately 1 month after the first outbreak among frontline healthcare professionals (HCPs). Of 256 HCPs, 33 (13%) were infected. Self-reported adherence to IC practices in >90% of exposure events was 82.1%, 73.8%, and 53.5% for use of hand hygiene, masks, and gloves, respectively. Visiting crowded public places during the outbreak was associated with acquiring infection (OR 3.1, P = 0.019). Amongst nurses, exposure to HCPs with influenza-like illness during the outbreak without wearing a mask was the only identified risk factor for infection (OR = 2.3, P = 0.039). PMID- 23043537 TI - Upregulation of IL-6, IL-8 and CXCL-1 production in dermal fibroblasts by normal/malignant epithelial cells in vitro: Immunohistochemical and transcriptomic analyses. AB - BACKGROUND INFORMATION: Considering an analogy between wound healing and tumour progression, we studied chemokine and cytokine transcription and expression in normal fibroblasts by co-culture and in situ. RESULTS: Whole-genome transcriptome profiling revealed strong upregulation for the interleukin (IL)-6, IL-8 and the chemokine CXCL-1 in in vitro co-cultures of normal fibroblasts with either normal or malignant epithelial cells compared to fibroblast cultures. The same ILs/chemokines were distinctly upregulated in clinical samples of squamous cell carcinoma when compared with paired normal mucosae. Analysis of culture supernatants showed that during the course of co-culture of the fibroblasts with the epithelial cells, IL-6, IL-8 and CXCL-1 were secreted to the culture medium. Experiments with addition of any of the proteins to the culture medium supported the notion that these ILs/chemokines strongly contributed to maintenance of a low differentiation phenotype of epithelial cells, evaluated by the detection of keratin-8. Simultaneous addition of all factors increased the extent of the effect. These studies were extended by experiments with epithelial cells, either cultured in medium conditioned by preceding use for malignant keratinocytes without and in the presence of normal or cancer-associated fibroblasts or medium containing antibodies against IL-6, IL-8 and CXCL-1. CONCLUSIONS: Our results indicate an analogy between wound healing and tumour growth, support the importance of epithelial-mesenchymal interaction in this model system and establish a potential bio-inspired anticancer therapy. PMID- 23043538 TI - Perceived malaria in the population of an urban setting: a skipped reality in Dakar, Senegal. AB - BACKGROUND: Urban malaria remains a public health problem. Dakar is located in a low endemic area. However, anti-malarial drugs consumption is reported to be high despite the decline of malaria announced by health authorities. The objective of the present study was to assess the burden of reported malaria attacks (RMAs) in 2008 and to describe care-seeking behaviours in the population of Dakar, Senegal. METHODS: In this cross-sectional study, 2,952 households selected from 50 sites were visited. In each household, a women and a child between two and 10 years old were interviewed about a malaria episode that occurred in 2008. The following information was recorded: age, education level, sex (for children), type of care seeking, method of diagnosis, use of anti-malarial treatment, place of medication purchase, bed net use, malaria-related deaths in the family, and perceptions of the frequency of mosquito bites. After a description of the variables in each subsample, a Pearson's chi-square test was used to compare proportions, and logistic regression was performed to identify the association between RMAs and other covariates. RESULTS: Among women, 31.8% reported a malaria attack in 2008; among children, the rate of malaria attacks reported by mothers or caretakers was 39.0%. With regard to care-seeking, 79.5% of women and 81.5% of children with a RMA had visited health facilities (HFs). Younger women and children under five years old were more likely to visit a HF (P<0.001). Presumptive diagnosis was the primary method that was used to identify malaria in HFs. For those who had visited a HF, the rate of anti-malarial treatment was 77% in women and 60% in children. Finally, 43.6% of women and 42.0% of children declared the use of bed nets. In a multivariate analysis, the malaria-related death of a relative and perceptions of mosquito bites were significantly associated with RMAs in women. In children, age was associated with RMAs. CONCLUSION: The frequent perceptions of the occurrence of malaria in the population were confirmed at the HF by the high presumptive diagnosis of health professionals. Despite the decline of malaria that has been announced by health authorities, the population will continue to complain of malaria and seek care directly at private pharmacies. This situation may sustain the circulation of anti-malarial drugs and increase the risk of an emergence of anti-malarial resistance. PMID- 23043540 TI - Can treating persistent inflammation limit protein energy wasting? PMID- 23043541 TI - Liver specificity of the carcinogenicity of NOCs: a chemical-molecular perspective. AB - This study aimed to determine the most significant molecular features associated with the liver specificity of the carcinogenicity of N-nitroso compounds (NOCs). Accordingly, quantitative structure-activity relationship (QSAR) analysis was performed to extract molecular information from NOCs using a topological substructural molecular descriptor (TOPS-MODE) approach. A linear discriminant analysis (LDA) model of a series of NOCs for rat liver was developed using TOPS MODE descriptors to predict nonliver- and liver-carcinogenic NOCs. Two descriptors exclusively calculated from the molecular structures of the compounds were selected by a genetic algorithm. The descriptors were then weighted with bond distances as well as the Abraham solute descriptor partition between water and aqueous solvent systems to indicate the importance of their roles in liver specificity. The performances of the LDA model were rigorously validated by leave one-out cross-validation and external validation, with the prediction accuracy reaching 88.3% and 80.0%, respectively. The contributions of the different molecular fragments to rat-liver specificity were computed. The results served as important information related to liver specificity and were analyzed from the chemical-molecular perspective. The resulting model can provide an efficient method to discriminate between as well as extrapolate nonliver- and liver carcinogenic NOCs. The contribution of the entire nitrosamine molecule was determined as being responsible for the liver specificity of nitrosamine carcinogenicity. Although the QSAR showed limitations in complex hepatocarcinogenicity, the proposed method may considerably help elucidate the role of nitrosamines in liver specificity from the chemical-molecular perspective. The nature of these enzyme-substrate interactions is characterized. Insight into the chemical-structural and biological factors related to the liver specific biological activity of NOCs is also provided. PMID- 23043539 TI - Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia. AB - Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1 yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children. PMID- 23043542 TI - Do solid-state structures reflect Lewis acidity trends of heavier group 13 trihalides? Experimental and theoretical case study. AB - Lewis acidity trends of aluminum and gallium halides have been considered on the basis of joint X-ray and density functional theory studies. Structures of complexes of heavier group 13 element trihalides MX(3) (M = Al, Ga; X = Cl, Br, I) with monodentate nitrogen-containing donors Py, pip, and NEt(3) as well as the structure of the AlCl(3).PPh(3) adduct have been established for the first time by X-ray diffraction studies. Extensive theoretical studies (B3LYP/TZVP level of theory) of structurally characterized complexes between MX(3) and nitrogen-, phosphorus-, arsenic-, and oxygen-containing donor ligands have allowed us to establish the Lewis acidity trends Al > Ga, Cl ~ Br > I. Analysis of the experimental and theoretical results points out that the solid state masks the Lewis acidity trend of aluminum halides. The difference in the Al-N bond distances between AlCl(3).D and AlBr(3).D complexes in the gas phase is small, while in the condensed phase, shorter Al-N distances for AlBr(3).D complexes are observed with 9-fluorenone, mdta, and NEt(3) donors. The model based on intermolecular (H...X) interactions in solid adducts is proposed to explain this phenomenon. Thus, the donor-acceptor bond distance in the solid complexes cannot always be used as a criterion of Lewis acidity. PMID- 23043543 TI - A vesicular variant of pseudoverrucous papules and nodules in the genital area of an incontinent 4-year-old. AB - Irritant contact dermatitis is a common cause of chronic vulvitis in patients wearing diapers and incontinence garments. In most cases the diagnosis is obvious; however, atypical presentations may mimic more serious dermatoses. We present a 4-year-old girl who presented at birth with cloacal atresia corrected surgically and resulting in chronic incontinence requiring full-time diapers. She presented with crops of herpetiform vesicles and bullae on a base that ranged from normal skin to severe erythema and oedema. A histological examination revealed a well-demarcated lesion showing a thickened epidermis with hyperkeratosis and parakeratosis, acanthosis and an abrupt transition to pallor of the upper half. Focal full thickness epidermis necrosis and small areas of spongiosis, acantholysis and apoptotic keratinocytes were seen. Immunofluorescence was negative. The lesions improved with the treatment of secondary infection and minimal topical therapy with an emollient only. This case represents an unusual vesicular variant of pseudoverrucous papules and nodules, which has been reported only once previously. PMID- 23043545 TI - Meta-regression models to address heterogeneity and inconsistency in network meta analysis of survival outcomes. AB - BACKGROUND: Recently, network meta-analysis of survival data with a multidimensional treatment effect was introduced. With these models the hazard ratio is not assumed to be constant over time, thereby reducing the possibility of violating transitivity in indirect comparisons. However, bias is still present if there are systematic differences in treatment effect modifiers across comparisons. METHODS: In this paper we present multidimensional network meta analysis models for time-to-event data that are extended with covariates to explain heterogeneity and adjust for confounding bias in the synthesis of evidence networks of randomized controlled trials. The impact of a covariate on the treatment effect can be assumed to be treatment specific or constant for all treatments compared. RESULTS: An illustrative example analysis is presented for a network of randomized controlled trials evaluating different interventions for advanced melanoma. Incorporating a covariate related to the study date resulted in different estimates for the hazard ratios over time than an analysis without this covariate, indicating the importance of adjusting for changes in contextual factors over time. CONCLUSION: Adding treatment-by-covariate interactions to multidimensional network meta-analysis models for published survival curves can be worthwhile to explain systematic differences across comparisons, thereby reducing inconsistencies and bias. An additional advantage is that heterogeneity in treatment effects can be explored. PMID- 23043544 TI - Hypoxic preconditioning induces stroke tolerance in mice via a cascading HIF, sphingosine kinase, and CCL2 signaling pathway. AB - The induction of ischemic tolerance by preconditioning provides a platform to elucidate endogenous mechanisms of stroke protection. In these studies, we characterize the relationship between hypoxia-inducible factor (HIF), sphingosine kinase 2 (SphK2), and chemokine (C-C motif) ligand 2 (CCL2) in models of hypoxic or pharmacological preconditioning-induced ischemic tolerance. A genetics-based approach using SphK2- and CCL2-null mice showed both SphK2 and CCL2 to be necessary for the induction of ischemic tolerance following preconditioning with hypoxia, the hypoxia-mimetic cobalt chloride, or the sphingosine-1-phosphate (S1P) agonist FTY720. A pharmacological approach confirmed the necessity of HIF signaling for all three preconditioning stimuli, and showed that the SphK/S1P pathway transduces tolerance via the S1P(1) receptor. In addition, our data suggest significant cross-talk between HIF and SphK2-produced S1P signaling, which together act to up-regulate CCL2 expression. Overall, HIF, SphK, S1P, and CCL2 participate in a signaling cascade to induce the gene expression responsible for the stroke-tolerant phenotype established by hypoxic and FTY720 preconditioning. The identification of these common molecular mediators involved in signaling the genomic response to multiple preconditioning stimuli provides several targets for therapeutic manipulation. PMID- 23043546 TI - Dual-task effects of simulated lane navigation and story recall in older adults with and without memory impairment. AB - While driving is a complex task, it becomes relatively automatic over time although unfamiliar situations require increased cognitive effort. Much research has examined driving risk in cognitively impaired elders and found little effect. This study assessed whether mildly memory impaired elders made disproportionate errors in driving or story recall, under simultaneous simulated driving and story recall. Forty-six healthy (61% women; mean age = 76.4) and 15 memory impaired (66% women, mean age = 79.4) elders participated. Cognitive status was determined by neuropsychological performance. Results showed that during dual-task conditions, participants stayed in lane more, and recalled stories more poorly, than when they did the tasks separately. Follow-up analysis revealed that verbatim recall, in particular, was reduced while driving for healthy participants. While memory impaired participants performed more poorly than healthy controls on both tasks, cognitive status was not associated with greater dual-task costs when driving and story recall were combined. PMID- 23043547 TI - 1'-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations. AB - BACKGROUND: Oral cancers although preventable, possess a low five-year survival rate which has remained unchanged over the past three decades. In an attempt to find a more safe, affordable and effective treatment option, we describe here the use of 1'S-1'-acetoxychavicol acetate (ACA), a component of Malaysian ginger traditionally used for various medicinal purposes. METHODS: Whether ACA can inhibit the growth of oral squamous cell carcinoma (SCC) cells alone or in combination with cisplatin (CDDP), was explored both in vitro using MTT assays and in vivo using Nu/Nu mice. Occurrence of apoptosis was assessed using PARP and DNA fragmentation assays, while the mode of action were elucidated through global expression profiling followed by Western blotting and IHC assays. RESULTS: We found that ACA alone inhibited the growth of oral SCC cells, induced apoptosis and suppressed its migration rate, while minimally affecting HMEC normal cells. ACA further enhanced the cytotoxic effects of CDDP in a synergistic manner as suggested by combination index studies. We also found that ACA inhibited the constitutive activation of NF-kappaB through suppression of IKKalpha/beta activation. Human oral tumor xenografts studies in mice revealed that ACA alone was as effective as CDDP in reducing tumor volume, and further potentiated CDDP effects when used in combination with minimal body weight loss. The effects of ACA also correlated with a down-regulation of NF-kappaB regulated gene (FasL and Bim), including proinflammatory (NF-kappaB and COX-2) and proliferative (cyclin D1) biomarkers in tumor tissue. CONCLUSION: Overall, our results suggest that ACA inhibits the growth of oral SCC and further potentiates the effect of standard CDDP treatment by modulation of proinflammatory microenvironment. The current preclinical data could form the basis for further clinical trials to improve the current standards for oral cancer care using this active component from the Malaysian ginger. PMID- 23043548 TI - Capturing students' learning experiences and academic emotions at an interprofessional training ward. AB - An important goal for interprofessional education (IPE) in clinical settings is to support healthcare students in collaboratively developing their understanding of interprofessional teamwork. The aim of this study was to investigate students' learning experiences and academic emotions as they occur in actual context in relation to collaborative and trialogical activities during a clinical IPE course. The contextual activity sampling system methodology was used to collect data via mobile phones. Thirty-seven healthcare students (medical, nursing, physiotherapy and occupational therapy) reported their experiences, learning activities and academic emotions several times a day via their mobile phones during their 2-week course at an interprofessional training ward (IPTW). The results provided understanding of the students' experiences of their academic emotions and how they created new knowledge collaboratively. These collaborative knowledge creation activities occurred mostly when students from different professions were collaborating as a team (e.g. discussing patient care or participating in a ward round) and were also significantly related to optimal experiences, i.e. "flow" (high challenge in combination with high competence). In conclusion, these results emphasize the importance of collaboration among students during IPTW courses. Our results might help to optimize the design of IPE learning activities in clinical healthcare contexts. PMID- 23043549 TI - Developing interprofessional collaboration: a longitudinal case of secondary prevention for patients with osteoporosis. AB - The aim of this study was to explore the development of interprofessional collaboration aiming to improve secondary prevention of osteoporosis by studying this topic expansively from the perspectives of different stakeholders. The method used was a longitudinal single case study with both qualitative and quantitative data sources. The findings elucidate that the bottom-up structure used triggers a freedom to act for the professionals and a changed leadership. Such an approach seems to make managers aware of the need for a horizontal organizational focus that, in this case, was crucial for developing interprofessional collaboration. Furthermore, the study shows that continuous feedback was central to motivate professionals to collaborate. Constructive feedback was created by interprofessional and patient-centered interaction skills, facilitated by confirming leadership promoting ability to recognize the efficacy of joint collaboration. The interprofessional collaboration resulted in an improved chain of care with increased transparency and collective control with benefits for both patients and providers. Outcomes at the system level showed an appreciable increase in patients investigated for osteoporosis: 88% were followed up in primary care and nearly half had improved their health behavior. The implementation of a bottom-up structure where leaders and professionals are developing interdependency, measuring collective performance and using feedback loops generated, in this case, motivational forces for interprofessional collaboration. It is reasonable to assume that these findings could be transferable to similar healthcare settings. PMID- 23043550 TI - What the Internet can and cannot tell us about emerging toxicologic outbreaks. PMID- 23043552 TI - Patterns of synthetic cannabinoid use in Australia. AB - INTRODUCTION AND AIMS: To assess the demographic profile, use patterns, market characteristics, reasons for first use and self-reported harms associated with use of synthetic cannabinoids in Australia. DESIGN AND METHODS: An online questionnaire was administered to a purposive sample of 316 Australian synthetic cannabinoid users [96% cannabis users, 77% male, median age 27 years, interquartile range (IQR) 23-34] who self-reported demographic and drug use characteristics. RESULTS: The median duration of synthetic cannabinoid use was 6 months (IQR 2-10), 35% reported use weekly or more often and 7% reported daily use. Reasons for first use included curiosity (50%), legality (39%), availability (23%), recreational effects (20%), therapeutic effects (9%), non-detection in standard drug screening assays (8%) and to aid the reduction or cessation of cannabis use (5%). Users reported buying a median of 3 g (IQR 3-6) and paying a median of AU$60 (IQR 37-90). Most (68%) reported at least one side-effect during their last session of use, including decreased motor co-ordination (39%), fast or irregular heartbeat (33%), dissociation (22%), dizziness (20%), paranoia (18%) and psychosis (4%). 4 respondents reported seeking help. A greater number of side effects were reported by males, those aged 18-25 years, water pipe ('bong') users and concurrent alcohol drinkers. DISCUSSION AND CONCLUSIONS: The sample reported first using synthetic cannabinoids due to curiosity, legality, availability, effects, non-detection in drug testing and to reduce their cannabis use. Harms were widely reported yet help-seeking was minimal. Inclusion of questions regarding synthetic cannabinoids in household surveys is warranted. PMID- 23043551 TI - Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2. AB - Epigenetic regulation is involved in numerous physiological and pathogenic processes. Among the key regulators that orchestrate epigenetic signaling are over 50 human protein lysine methyltransferases (PKMTs). Interrogation of the functions of individual PKMTs can be facilitated by target-specific PKMT inhibitors. Given the emerging need for such small molecules, we envisioned an approach to identify target-specific methyltransferase inhibitors by screening privileged small-molecule scaffolds against diverse methyltransferases. In this work, we demonstrated the feasibility of such an approach by identifying the inhibitors of SETD2. N-propyl sinefungin (Pr-SNF) was shown to interact preferentially with SETD2 by matching the distinct transition-state features of SETD2's catalytically active conformer. With Pr-SNF as a structure probe, we further revealed the dual roles of SETD2's post-SET loop in regulating substrate access through a distinct topological reconfiguration. Privileged sinefungin scaffolds are expected to have broad use as structure and chemical probes of methyltransferases. PMID- 23043554 TI - Resonant coupling of Rayleigh waves through a narrow fluid channel causing extraordinary low acoustic transmission. AB - Coupling of Rayleigh waves propagating along two metal surfaces separated by a narrow fluid channel is predicted and experimentally observed. Although the coupling through a fluid (water) is weak, a strong synchronization in propagation of Rayleigh waves even for the metals with sufficiently high elastic contrast (brass and aluminum) is observed. Dispersion equation for two polarizations of the coupled Rayleigh waves is derived and experimentally confirmed. Excitation of coupled Rayleigh waves in a channel of finite length leads to anomalously low transmission of acoustic energy at discrete set of resonant frequencies. This effect may find useful applications in the design of acoustic metamaterial screens and reflectors. PMID- 23043556 TI - Can women 'refuse' condoms? Dilemmas of condom negotiation among men living with HIV in South Africa. AB - This paper describes challenges that men living with HIV experience in negotiating condom use with sexual partners. After testing HIV-positive, the men in this study attended support groups of people living with HIV. Here they were taught to behave 'responsibly' by adopting safer sex measures. However, some men faced strong resistance from women concerning condom use, particularly from women with whom they had been sexually involved prior to testing HIV-positive. This paper explores the reasoning behind the rejection of condoms by women, focusing specifically on the nature of relationships, disclosure of HIV status and gender power dynamics. Analysis of the findings, which are taken from an ethnographic study conducted over 14 months, indicates that efforts to initiate condom use allowed women to challenge men's authority in sexual affairs and assert their own (limited) agency - albeit by demanding unprotected sex. However, women's rejection of condoms occurred in a knowledge vacuum about their own HIV risk because male partners had failed to disclose their HIV status prior to initiating condoms. Interventions need to encourage men to disclose their HIV status before they initiate condom use with their sexual partners. Furthermore men need to encourage their partners to be open about their sexual needs. PMID- 23043555 TI - Periodontal diseases and systemic inflammation. PMID- 23043557 TI - Finding parasites and finding challenges: improved diagnostic access and trends in reported malaria and anti-malarial drug use in Livingstone district, Zambia. AB - BACKGROUND: Understanding the impact of malaria rapid diagnostic test (RDT) use on management of acute febrile disease at a community level, and on the consumption of anti-malarial medicines, is critical to the planning and success of scale-up to universal parasite-based diagnosis by health systems in malaria endemic countries. METHODS: A retrospective study of district-wide community level RDT introduction was conducted in Livingstone District, Zambia, to assess the impact of this programmed on malaria reporting, incidence of mortality and on district anti-malarial consumption. RESULTS: Reported malaria declined from 12,186 cases in the quarter prior to RDT introduction in 2007 to an average of 12.25 confirmed and 294 unconfirmed malaria cases per quarter over the year to September 2009. Reported malaria-like fever also declined, with only 4,381 RDTs being consumed per quarter over the same year. Reported malaria mortality declined to zero in the year to September 2009, and all-cause mortality declined. Consumption of artemisinin-based combination therapy (ACT) dropped dramatically, but remained above reported malaria, declining from 12,550 courses dispensed by the district office in the quarter prior to RDT implementation to an average of 822 per quarter over the last year. Quinine consumption in health centres also declined, with the district office ceasing to supply due to low usage, but requests for sulphadoxine-pyrimethamine (SP) rose to well above previous levels, suggesting substitution of ACT with this drug in RDT-negative cases. CONCLUSIONS: RDT introduction led to a large decline in reported malaria cases and in ACT consumption in Livingstone district. Reported malaria mortality declined to zero, indicating safety of the new diagnostic regime, although adherence and/or use of RDTs was still incomplete. However, a deficiency is apparent in management of non malarial fever, with inappropriate use of a low-cost single dose drug, SP, replacing ACT. While large gains have been achieved, the full potential of RDTs will only be realized when strategies can be put in place to better manage RDT negative cases. PMID- 23043559 TI - Cytotoxic and proapototic activities of imidoselenocarbamate derivatives are dependent on the release of methylselenol. AB - In the search for new molecules with potential antiangiogenic activity, we found that several imidoselenocarbamate derivatives effectively suppressed the expression of vascular endothelial growth factor (VEGF) induced by hypoxia in NCI H157 tumor cells. Mechanistic studies indicated that these compounds inhibited STAT3 phosphorylation triggered by hypoxia, suggesting that inhibition of STAT3 function may play a role in VEGF inhibition. Moreover, these molecules showed interesting proapoptotic and antiproliferative effects. Both the presence of selenium, but not sulfur, and the nature of the radical substituents were important for activity. Interestingly, under hypoxic conditions, several methyl imidoselenocarbamate derivatives released methylselenol, a highly reactive and cytotoxic gas, which was responsible for their biological activities. The kinetics of the release of methylselenol by these molecules was highly dependent on the nature of the substituent radicals and correlated with their early proapoptotic activity. Our results support the notion that pharmacological activities reported for methyl imidoselenocarbamate derivatives are dependent on the release of methylselenol. Given the well-known antitumor activities of this compound, imidoselenocarbamate derivatives represent a promising approach to develop new drugs that release methylselenol in a controlled way. PMID- 23043560 TI - Melamine sensing in milk products by using surface enhanced Raman scattering. AB - Simple and rapid detection of trace amounts of melamine in milk products has been achieved with a portable sensor system based on surface-enhanced Raman scattering (SERS). The sensor system comprised high-performance gold nanofinger SERS sensor chips and a custom-built prototype portable Raman spectrometer. Compared to the FDA procedure and previously reported studies that were limited to laboratory settings, our sampling and analytical methods are simple (with one sampling step), less time-consuming, and cost-effective. We found the limit of detection (LOD) of the melamine is 120 parts per trillion (ppt) in water and 100 parts per billion (ppb) in infant formula, which are well below the FDA's tolerance level of 1 ppm in infant formula. PMID- 23043561 TI - The lower airways - some unusual aspects. PMID- 23043562 TI - Dinuclear complexes containing linear M-F-M [M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II)] bridges: trends in structures, antiferromagnetic superexchange interactions, and spectroscopic properties. AB - The reaction of M(BF(4))(2).xH(2)O, where M is Fe(II), Co(II), Ni(II), Cu(II), Zn(II), and Cd(II), with the new ditopic ligand m-bis[bis(3,5-dimethyl-1 pyrazolyl)methyl]benzene (L(m)*) leads to the formation of monofluoride-bridged dinuclear metallacycles of the formula [M(2)(MU-F)(MU-L(m)*)(2)](BF(4))(3). The analogous manganese(II) species, [Mn(2)(MU-F)(MU-L(m)*)(2)](ClO(4))(3), was isolated starting with Mn(ClO(4))(2).6H(2)O using NaBF(4) as the source of the bridging fluoride. In all of these complexes, the geometry around the metal centers is trigonal bipyramidal, and the fluoride bridges are linear. The (1)H, (13)C, and (19)F NMR spectra of the zinc(II) and cadmium(II) compounds and the (113)Cd NMR of the cadmium(II) compound indicate that the metallacycles retain their structure in acetonitrile and acetone solution. The compounds with M = Mn(II), Fe(II), Co(II), Ni(II), and Cu(II) are antiferromagnetically coupled, although the magnitude of the coupling increases dramatically with the metal as one moves to the right across the periodic table: Mn(II) (-6.7 cm(-1)) < Fe(II) ( 16.3 cm(-1)) < Co(II) (-24.1 cm(-1)) < Ni(II) (-39.0 cm(-1)) ? Cu(II) (-322 cm( 1)). High-field EPR spectra of the copper(II) complexes were interpreted using the coupled-spin Hamiltonian with g(x) = 2.150, g(y) = 2.329, g(z) = 2.010, D = 0.173 cm(-1), and E = 0.089 cm(-1). Interpretation of the EPR spectra of the iron(II) and manganese(II) complexes required the spin Hamiltonian using the noncoupled spin operators of two metal ions. The values g(x) = 2.26, g(y) = 2.29, g(z) = 1.99, J = -16.0 cm(-1), D(1) = -9.89 cm(-1), and D(12) = -0.065 cm(-1) were obtained for the iron(II) complex and g(x) = g(y) = g(z) = 2.00, D(1) = 0.3254 cm(-1), E(1) = -0.0153, J = -6.7 cm(-1), and D(12) = 0.0302 cm(-1) were found for the manganese(II) complex. Density functional theory (DFT) calculations of the exchange integrals and the zero-field splitting on manganese(II) and iron(II) ions were performed using the hybrid B3LYP functional in association with the TZVPP basis set, resulting in reasonable agreement with experiment. PMID- 23043558 TI - Roles of proteolysis in regulation of GPCR function. AB - The enzymatic activity of peptidases must be tightly regulated to prevent uncontrolled hydrolysis of peptide bonds, which could have devastating effects on biological systems. Peptidases are often generated as inactive propeptidases, secreted with endogenous inhibitors, or they are compartmentalized. Propeptidases become active after proteolytic removal of N-terminal activation peptides by other peptidases. Some peptidases only become active towards substrates only at certain pHs, thus confining activity to specific compartments or conditions. This review discusses the different roles proteolysis plays in regulating GPCRs. At the cell-surface, certain GPCRs are regulated by the hydrolytic inactivation of bioactive peptides by membrane-anchored peptidases, which prevent signalling. Conversely, cell-surface peptidases can also generate bioactive peptides, which directly activate GPCRs. Alternatively, cell-surface peptidases activated by GPCRs, can generate bioactive peptides to cause transactivation of receptor tyrosine kinases, thereby promoting signalling. Certain peptidases can signal directly to cells, by cleaving GPCR to initiate intracellular signalling cascades. Intracellular peptidases also regulate GPCRs; lysosomal peptidases destroy GPCRs in lysosomes to permanently terminate signalling and mediate down regulation; endosomal peptidases cleave internalized peptide agonists to regulate GPCR recycling, resensitization and signalling; and soluble intracellular peptidases also participate in GPCR function by regulating the ubiquitination state of GPCRs, thereby altering GPCR signalling and fate. Although the use of peptidase inhibitors has already brought success in the treatment of diseases such as hypertension, the discovery of new regulatory mechanisms involving proteolysis that control GPCRs may provide additional targets to modulate dysregulated GPCR signalling in disease. PMID- 23043563 TI - Positive predictive value of prostate biopsy indicated by prostate-specific antigen-based prostate cancer screening: trends over time in a European randomized trial*. AB - Study Type--Diagnosis (validating cohort) Level of Evidence 1b. What's known on the subject? and What does the study add? The European Randomized study of Screening for Prostate Cancer (ERSPC) showed a reduction in prostate cancer mortality of 21% for PSA-based screening at a median follow-up of 11 years. In the ERSPC, men are screened at 4-year intervals. A prostate biopsy is recommended for men with a PSA level >= 3.0 ng/mL. The study shows that the positive predictive value (PPV) of a prostate biopsy indicated by PSA-based screening remains equal throughout consecutive screening rounds in men without a previous biopsy. In men who have previously had a benign biopsy, the PPV drops considerably, but 20% of the cancers detected still show aggressive characteristics. OBJECTIVE: * To assess the positive predictive value (PPV) of prostate biopsy, indicated by a prostate-specific antigen (PSA) threshold of >= 3.0 ng/mL, over time, in the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC). PATIENTS AND METHODS: * In the Rotterdam section of the ERSPC, a total of 42,376 participants, aged 55-74 years, identified from population registries were randomly assigned to a screening or control arm. * For the ERSPC men undergo PSA screening at 4-year intervals. A total of three screening rounds were evaluated; therefore, only men aged 55-69 years at the first screening were eligible for the present study. RESULTS: * PPVs for men without previous biopsy remained equal throughout the three subsequent screenings (25.5, 22.3 and 24.8% respectively). * Conversely, PPVs for men with a previous negative biopsy dropped significantly (12.0 and 15.2% at the second and third screening, respectively). * Additionally, in men with and without previous biopsy, the percentage of aggressive prostate cancers (clinical stage >T2b, Gleason score >= 7) decreased after the first round of screening from 44.4 to 23.8% in the second (P < 0.001) and 18.6% in the third round (P < 0.001). * Repeat biopsies accounted for 24.6% of all biopsies, but yielded only 8.6% of all aggressive cancers. CONCLUSIONS: * In consecutive screening rounds the PPV of PSA based screening remains equal in previously unbiopsied men. * In men with a previous negative biopsy the PPV drops considerably, but 20% of cancers detected still show aggressive characteristics. * Individualized screening algorithms should incorporate previous biopsy status in the decision to perform a repeat biopsy with the aim of further reducing unnecessary biopsies. PMID- 23043564 TI - Hydrodynamic shear stress to remove Listeria monocytogenes biofilms from stainless steel and polytetrafluoroethylene surfaces. AB - AIMS: To calculate the shear stress needed to remove sessile Listeria monocytogenes cells from stainless steel (SS) and polytetrafluoroethylene (PTFE) surfaces. METHODS AND RESULTS: Listeria monocytogenes biofilms were formed on SS and PTFE surfaces. Shear stress was calculated using a radial flow chamber device and cells quantified by staining with 4',6-diamidino-2-phenylindole. Results showed that shear stress between 24 and 144 N m(-2) removed up to 98% of cells from SS surfaces. PTFE presents a very hydrophobic surface, and a significant lower removal (P < 0.05) of only 63% was achieved; moreover, on PTFE discs, detachment of L. monocytogenes biofilms was more efficient at a lower shear stress (between 8.6 and 34 N m(-2) ). CONCLUSIONS: Water flow is more effective in removing L. monocytogenes biofilms from SS surfaces than from PTFE materials. SIGNIFICANCE AND IMPACT OF THE STUDY: This work clearly demonstrates that water flow does not have the same efficiency in removing cells from different material surfaces and shows the need to optimize cleaning and sampling procedures by considering the conditions in which cells attach to surfaces and the physicochemistry of the surfaces. PMID- 23043565 TI - Analysis of glycan-related genes expression and glycan profiles in mice with liver fibrosis. AB - Protein glycosylation plays an important role in the pathogenesis and progression of various liver diseases. However, little is known about the precise alterations in protein glycosylation or the potential correlation between glycan-related genes expression and glycan profiles in liver fibrosis. The aim of the study was to investigate potential associations between glycan-related genes expression and glycan profiles to evaluate liver fibrosis in a mouse model. Analyses of glycan related genes expression and glycan profiles were performed using oligonucleotide microarrays and lectin microarrays, respectively. Real-time PCR and Western blot were used to confirm any altered glycan-related genes expression levels and protein levels. Moreover, altered glycan patterns on the surface of hepatocytes were verified by lectin histochemistry. These results revealed that the mRNA levels of 10 glycan-related genes were significantly altered in fibrotic liver. Furthermore, we observed an increase in multivalent sialic acid, poly-LacNAc, sialyl-T-antigen, Fucosealpha-1,3/6GlcNAc, and GalNAcalpha1-3Gal in fibrotic liver specimens, whereas GlcNAc oligomers was decreased in fibrotic liver. Our findings indicated that the synthetic pathway of "Tn antigen -> T antigen (core 1) -> sialyl-T antigen" was activated for O-glycan during the process of liver fibrosis. PMID- 23043566 TI - Taiwanese long-term care facility residents' experiences of caring: a qualitative study. AB - BACKGROUND: Until now, caring research has focused on constructs, processes and outcomes of caring traits exhibited mainly by nurses or nursing students in hospitals. Few studies have considered the perspectives of elderly residents of long-term care facilities (LTCFs). AIMS: The aim of this study was to elucidate the nature of caring by describing the experience of elderly residents of Taiwan LTCFs. METHODS: Data collected by semi-structured interviews with 12 elderly residents of LTCFs were analysed by content analysis. RESULTS: The caring perceived by the sample was thematically categorized as calming the body, respectful communication and enriching life. CONCLUSION: The findings of this study confirm the need for managers of LTCFs to address the physical and psychosocial needs of their residents. The findings can be used to develop education programmes and clinical protocols for nurses in the caring field and to develop instruments for measuring perceived caring in LTCFs. PMID- 23043567 TI - Inter- and intra-fraction motion during radiation therapy to the whole breast in the supine position: a systematic review. AB - Inter- and intra-fraction motion during radiation therapy for breast cancer has been a widely researched topic. Recently, however, with the emergence of new technologies and techniques such as intensity modulated radiation therapy (IMRT), field in field, volumetric modulated arc therapy (VMAT), tomotherapy and partial breast irradiation (PBI), the magnitude of this movement has become more important. The aim of this study is to provide a comprehensive summary of the literature relating to the magnitude of motion during radiation therapy for a breast cancer patient. A systematic review of the literature was conducted using Medline, Cinhal, Embase, Scopus and Web of Science. Studies included were limited to women having radical radiation therapy to the whole breast in the supine position. Studies needed to report quantitatively on the magnitude of inter- and intra-fraction motion using electronic portal imaging, port films or kilovoltage imaging techniques. Eighteen articles fitted the selection criteria. The averages of random and systematic error for inter- and intra-fraction movement were reported using central lung distance, central irradiated width, central beam edge to skin distance and cranio-caudal distance measurements, or isocentric matching techniques. Inter-fraction motion was consistently larger than intra-fraction motion but, on average, within a 5 mm tolerance. There were, though, large maximum inter- and intra-fraction variations observed in the measurements of individual patients, which indicate the need for daily inter- and intra- fraction motion management before implementing IMRT, VMAT, tomotherapy or PBI techniques. PMID- 23043569 TI - Adherence to Canadian C-Spine Rule in a regional hospital: a retrospective study of 406 cases. AB - INTRODUCTION: Cervical spine radiography may be over-utilised in an emergency department setting. The Canadian C-Spine Rule has been developed to reduce unnecessary radiography. Our aim was to retrospectively determine the proportion of cervical spine radiographs requested through the emergency department for trauma patients that were clinically indicated, according to the Canadian C-Spine Rule. METHODS: This was a cross-sectional survey conducted at a regional centre in Northern Queensland, Australia. All cervical spine radiographs for trauma, performed at the Mackay Base Hospital from 1 January 2009 to the 31 December 2009, were reviewed. The relevant patient charts were audited for evidence of indications for radiography. RESULTS: Of 406 patients in the study, 155 patients (38%) (95% confidence interval 33.3%, 42.7%) had cervical spine imaging performed that was not indicated according to the Canadian C-Spine Rule. None of these patients had a significant cervical spine injury on radiography. CONCLUSION: Applying the Canadian C-Spine Rule would have safely reduced the incidence of cervical spine radiography by 38%. This would also reduce costs, patient morbidity and radiation exposure. PMID- 23043568 TI - Evaluating the true clinical utility of the red dot system in radiograph interpretation. AB - INTRODUCTION: The 'red dot', or 'asterisk', system is used in many hospitals as a method for radiographers to identify potential abnormalities on plain radiographs prior to reporting by radiologists. While published studies into the accuracy of the 'red dot' system exist, analysis of its reliability in identifying subtle pathology is lacking. This is relevant because the prevalence and apparent success of the 'red dot' system has been cited by some authors as justification for non-radiologist reporting of medical imaging. It is important that all systems within medical imaging add value, and this audit evaluates the accuracy and clinical value of the 'red dot' system, particularly in the critical area of detecting undisplaced fractures. METHODS: All appendicular musculoskeletal trauma radiographs performed in the Department of Emergency Medicine at a major Australian metropolitan hospital over a continuous four-month period were retrospectively assessed to evaluate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the 'red dot' system. The presence or absence of an asterisk was correlated with validated radiologist reports. A sub-analysis of fractures displaced <1mm was also performed. RESULTS: A total of 3638 radiographs were assessed and 938 (25.8%) fractures identified; 338 (9.3%) contained undisplaced fractures. Overall sensitivity and specificity of the 'red dot' in detecting appendicular fractures are 80.4% and 98.0%, respectively. PPV is 93.6% and NPV is 93.5%. However, the accuracy of the 'red dot' in detecting undisplaced fractures is significantly reduced, with a sensitivity of 45.9% and a PPV of 74.8%. CONCLUSIONS: Detection of subtle abnormalities is fundamental to the service provided by radiologists. The 'red dot's' inability to reliably detect undisplaced fractures following trauma limits its value within a tertiary radiology department and suggests that role extension of plain film reporting to non-radiologists has potential to yield less accurate assessments. To maintain the highest quality of medical imaging services and standards of patient care, it is optimal that clinical decisions are based upon radiograph reports issued by medical specialists who have completed appropriate radiology training. Strategies to maintain this are suggested. PMID- 23043570 TI - The pitfalls of ultrasonography in the evaluation of soft tissue masses. AB - INTRODUCTION: Ultrasonography is associated with a high error rate in the evaluation of soft tissue masses. The purposes of this study were to examine the nature of the diagnostic errors and to identify areas in which reporting could be improved. METHODS: Patients who had soft tissue tumours and received ultrasonography during a 10-year period (1999-2009) were identified from a local tumour registry. The sonographic and pathological diagnoses were categorised as either 'benign' or 'non-benign'. The accuracy of ultrasonography was assessed by correlating the sonographic with the pathological diagnostic categories. Recommendations from radiologists, where offered, were assessed for their appropriateness in the context of the pathological diagnosis. RESULTS: One hundred seventy-five patients received ultrasonography, of which 60 had 'non benign' lesions and 115 had 'benign' lesions. Ultrasonography correctly diagnosed 35 and incorrectly diagnosed seven of the 60 'non-benign' cases, and did not suggest a diagnosis in 18 cases. Most of the diagnostic errors related to misdiagnosing soft tissue tumours as haematomas (four out of seven). Recommendations for further management were offered by the radiologists in 144 cases, of which 52 had 'non-benign' pathology. There were eight 'non-benign' cases where no recommendation was offered, and the sonographic diagnosis was either incorrect or unavailable. CONCLUSIONS: Ultrasonography lacks accuracy in the evaluation of soft tissue masses. Ongoing education is required to improve awareness of the limitations with its use. These limitations should be highlighted to the referrers, especially those who do not have specific training in this area. PMID- 23043571 TI - Effect of prone versus supine positioning on left ventricular ejection fraction (LVEF) and heart rate using ECG gated Tl-201 myocardial perfusion scans and gated cardiac blood pool scans. AB - INTRODUCTION: There is limited data on the effect of posture on LVEF. The study aim was to determine any difference in LVEF using gated cardiac blood pool scanning (GCBPS) and Tl-201 gated myocardial perfusion scanning (MPS) in prone or supine positions. METHOD: In 50 patients undergoing evaluation for varying heart conditions, automated LVEF, end diastolic volume (EDV), end systolic volume (ESV) measurements were obtained at rest during gated MPS on Discovery NM 530c (GE Healthcare). In another 50 patients, semi-automated LVEF measurements were obtained using GCBPS on dual-headed gamma cameras. Average heart rate (HR) was recorded. Differences between prone and supine LVEF, HR, EDV and ESV were compared using paired two-tailed t-tests (P < 0.05 considered significant). Pearson's correlation, difference plots, mean, standard deviation and 95% confidence interval of the differences were also derived to analyse LVEF results. RESULTS: Using GCPBS or MPS, no significant difference in LVEF or LV volumes (from gated MPS) was demonstrated between postures. Increased HR was noted in prone positioning. CONCLUSION: Posture did not affect measured LVEF or LV volumes. However HR was higher on prone imaging. PMID- 23043572 TI - High pressure versus standard port system: comparison of implantation and complications. AB - INTRODUCTION: Completely implantable access ports for high pressure contrast media injection have been in use in clinical routine for a relatively short time. The purpose of our study was to compare a high pressure port system with a standard port system with regard to implantation and complications. METHODS: In 94 oncological patients a completely implantable access port was implanted. Patients (n = 49) planned for oncological follow-up computed tomography (CT) received a high pressure port system. Other patients (n = 45) received a standard port system. Intrainterventional pain perception, postinterventional catheter tip migration and complications were analyzed. RESULTS: No major periinterventional complications occurred. Intrainterventional pain perception was not significantly different between the two groups. A significantly lower rate of tip migration was observed in the high pressure port group (P = 0.03) and when the port system was implanted on the right side (P = 0.03). In the standard port group catheter occlusion occurred in three patients (7%) and a catheter loop in one patient (2%) whereas no such complications occurred within the high pressure port group. Venous thrombosis was detected in one patient (2%) with a high pressure port; this did not occur in the standard port group. CONCLUSIONS: Implantation and use of a high pressure port device is safe and reliable: the complications are comparable to those of a standard port device. High pressure port systems should be considered for implantation, especially in patients who will require frequent CTs. PMID- 23043573 TI - Extra-medullary haematopoiesis: a pictorial review of its typical and atypical locations. AB - Extra-medullary haematopoiesis (EMH) occurs in many haematological disorders and is secondary to insufficient bone marrow function or ineffective erythropoiesis. It usually presents as haematopoietic masses in several typical and atypical body locations. This pictorial review briefly discusses the common EMH locations encountered in clinical practice, including the liver, spleen, lymph nodes and paravertebral regions. Unusual presentation as focal hepatic and splenic masses is also discussed. Some atypical EMH locations are then presented together with their pathophysiology and relevant illustrations. These include EMH in the intra spinal canal, pre-sacral region, nasopharynx and paranasal sinuses. Intra-spinal EMH can cause cord compression and present with neurological symptoms. In these cases, urgent treatment may be required. Haematopoietic masses in the other atypical locations can present with obstructive symptoms or may be diagnosed incidentally on imaging. EMH in unusual locations need to be monitored with follow-up imaging to ensure their stability. In some circumstances, tissue biopsy is appropriate to confirm the diagnosis and exclude other sinister pathology (e.g. malignancy). Treatment is only required where symptoms are present. Management options include blood transfusion, radiotherapy, hydroxyurea or surgical resection in selected cases. PMID- 23043574 TI - Pulmonary arteriovenous malformation: a rare anterior mediastinal mass. AB - Pulmonary arteriovenous malformations are rare pulmonary vascular lesions which are associated with Osler Weber Rendu syndrome (hereditary haemorrhagic telangectasia). They act as right-to-left shunts and have cardiovascular and embolic complications. We present a patient with an apparent anterior mediastinal mass secondary to a pulmonary arteriovenous malformations which was successfully treated percutaneously. PMID- 23043575 TI - Outcomes following treatment for patients with cranial nerve involvement from nasopharyngeal cancer. AB - INTRODUCTION: Patients with locally advanced nasopharyngeal carcinoma (NPC) commonly present with cranial nerve (CN) involvement, which can cause significant morbidity. We aimed to characterise the pattern of involvement and outcomes of these patients, as well as determine if these differed according to the mode of diagnosis. METHODS: Patients were included if they had non-distant metastatic NPC, presented with CN involvement and completed radiotherapy treatment between 2002 and 2008. The clinical response was categorised as complete response, partial response, stable or progressive disease. The radiological response was assessed using the Response Evaluation Criteria in Solid Tumors criteria. The loco-regional control and disease-free survival rates were estimated with the Kaplan-Meier method. RESULTS: Forty-seven patients fulfilled the inclusion criteria. CN lesions were diagnosed on clinical examination in 15% of patients, radiologically in 40% and both clinically and radiologically in 45% of patients. A complete or partial response of the CN lesions was seen clinically in 82% and radiologically in 95% of patients. The 3-year local relapse free survival was 64.3%, distant metastasis-free survival was 46.1% and overall survival was 82.8%. There were no differences in outcomes between patients with clinically versus radiologically detected CN lesions. CONCLUSION: Most of these patients are likely to undergo clinical and/or radiological resolution of the nerve lesions following chemoradiotherapy, but the outcome was not determined by the mode of diagnosis (radiological or clinical). PMID- 23043576 TI - Clinical outcomes of brain metastases treated with Gamma Knife radiosurgery with 3.0 T versus 1.5 T MRI-based treatment planning: have we finally optimised detection of occult brain metastases? AB - INTRODUCTION: The goal of this study was to determine if clinically relevant endpoints were changed by improved MRI resolution during radiosurgical treatment planning. METHODS AND MATERIALS: Between 2003 and 2008, 200 consecutive patients with brain metastases treated with Gamma Knife radiosurgery (GKRS) using either 1.5 T or 3.0 T MRI for radiosurgical treatment planning were retrospectively analysed. The number of previously undetected metastases at time of radiosurgery, distant brain failures, time delay to whole brain radiotherapy (WBRT), overall survival and likelihood of neurological death were determined. RESULTS: Additional metastases were detected in 31.3% and 24.5% of patients at time of radiosurgery with 3.0 T and 1.5 T MRI, respectively (P = 0.27). Patients with multiple metastases at diagnostic scan were more likely to have additional metastases detected by 3.0 T MRI (P < 0.1). Median time to distant brain failure was 4.87 months and 5.43 months for the 3.0 T and 1.5 T cohorts, respectively (P = 0.44). Median time to WBRT was 5.8 months and 5.3 months for the 3.0 T and 1.5 T cohorts, respectively (P = 0.87). Median survival was 6.4 months for the 3.0 T cohort, and 6.1 months for the 1.5 T cohort (P = 0.71). Likelihood of neurological death was 25.3% and 16.7% for the 3.0 and 1.5 T populations, respectively (P = 0.26). CONCLUSIONS: The 3.0 T MRI-based treatment planning for GKRS did not appear to affect the likelihood of distant brain failure, the need for WBRT or the likelihood of neurological death in this series. PMID- 23043577 TI - Use of stereotactic body radiation therapy for medically inoperable multiple primary lung cancer. AB - INTRODUCTION: To review outcomes of medically inoperable patients treated with stereotactic body radiation therapy (SBRT) for multiple primary lung cancer (MPLC). METHODS: We retrospectively reviewed the charts of 10 patients (21 lesions) treated with SBRT for synchronous (seven), metachronous (one) or synchronous/metachronous lung cancers. All patients were male, medically inoperable and had a median age of 66 years. Eight patients had bilateral disease and two had unilateral disease. All patients had a histological diagnosis in at least one of the two lesions and four patients (44.4%) had both lesions biopsied. There were 18 T1 lesions and three T2 lesions. SBRT was in three fractions of 20 Gy or five fractions of 11-12 Gy to each lesion. RESULTS: Mean and median follow up were 18.8 and 15.5 months, respectively. At analysis, six patients (60.0%) are alive, and five of these living patients (83.3%) have no evidence of disease recurrence or progression. Four patients (44.4%) developed distant metastatic disease. Twenty lesions (95.2%) achieved in-field local control. No patients experienced acute pulmonary complications and only two patients (22.2%) experienced late grade I lung toxicity as per the Radiation Therapy Oncology Group toxicity criteria. CONCLUSION: SBRT for MPLC in medically inoperable patients is a safe, feasible and effective treatment approach. PMID- 23043578 TI - The addition of temozolomide does not change the pattern of progression of glioblastoma multiforme post-radiotherapy. AB - INTRODUCTION: To determine whether the pattern of progressive disease (PD) for glioblastoma multiforme (GBM) patients has changed with the introduction of the current standard of care protocol - postoperative conformal radiotherapy to a dose of 60 Gray in 30 fractions with concurrent low-dose (75-100 mg/m(2) ) temozolomide, followed by six cycles of adjuvant high-dose (150-200 mg/m(2) ) temozolomide - as compared with radiotherapy alone. METHODS: For GBM patients commencing combined modality treatment between October 2005 and August 2009, the MRI scan confirming progression (if any) was co-registered with the original planning CT scan, and progression site(s) marked. Coverage of the composite progression volume (PDvol) by the original 95% prescription isodose volume was obtained from dose-volume histogram (DVH) data, and assigned as 'central', 'in field', 'marginal' and 'out of field', corresponding to >95%, >80%, 20-80% and <20% coverage. RESULTS: Of 68 consecutive patients identified, 54 (79.4%) had documented PD. Of the 47 (87%) evaluable patients, 43 (91%) had in field progression with 36 (77%) of these being central. Of the remaining four cases, three (6%) had marginal progression, and only one patient (2%) had out of field progression. Median overall and progression-free survival were 11.6 and 6.6 months, respectively. CONCLUSION: The pattern of progression in our GBM patients does not appear to have been altered by the addition of temozolomide. The overwhelming majority of first PD occurred within the original radiotherapy planning target volume, as is the case in patients treated with radiotherapy alone. Major changes to radiotherapy volumes are not indicated, with alternative strategies required to improve outcomes. PMID- 23043579 TI - RE: A phase I trial of radiation dose escalation using accelerated concomitant boost radiotherapy concurrently with weekly carboplatin/paclitaxel in patients with good performance status and Stage IIB-IIIA/B non-small cell lung cancer. PMID- 23043581 TI - Differential contributions of conformation extension and domain unfolding to properties of fibronectin nanotextiles. AB - Fibronectin (FN) textiles are built as nanometer-thick fabrics. When uniaxially loaded, these fabrics exhibit a distinct threshold between elastic and plastic deformation with increasing stretch. Fabric mechanics are modeled using an eight chain network and two-state model, revealing that elastic properties of FN depend on conformational extension of the protein and that plastic deformation depends on domain unfolding. Our results suggest how the molecular architecture of a molecule can be exploited for designer mechanical properties of a bulk material. PMID- 23043582 TI - The usefulness of dermoscopy for the recognition of basal cell carcinoma- seborrhoeic keratosis compound tumours. PMID- 23043584 TI - Illness Mapping: a time and cost effective method to estimate healthcare data needed to establish community-based health insurance. AB - BACKGROUND: Most healthcare spending in developing countries is private out-of pocket. One explanation for low penetration of health insurance is that poorer individuals doubt their ability to enforce insurance contracts. Community-based health insurance schemes (CBHI) are a solution, but launching CBHI requires obtaining accurate local data on morbidity, healthcare utilization and other details to inform package design and pricing. We developed the "Illness Mapping" method (IM) for data collection (faster and cheaper than household surveys). METHODS: IM is a modification of two non-interactive consensus group methods (Delphi and Nominal Group Technique) to operate as interactive methods. We elicited estimates from "Experts" in the target community on morbidity and healthcare utilization. Interaction between facilitator and experts became essential to bridge literacy constraints and to reach consensus.The study was conducted in Gaya District, Bihar (India) during April-June 2010. The intervention included the IM and a household survey (HHS). IM included 18 women's and 17 men's groups. The HHS was conducted in 50 villages with1,000 randomly selected households (6,656 individuals). RESULTS: We found good agreement between the two methods on overall prevalence of illness (IM: 25.9% +/-3.6; HHS: 31.4%) and on prevalence of acute (IM: 76.9%; HHS: 69.2%) and chronic illnesses (IM: 20.1%; HHS: 16.6%). We also found good agreement on incidence of deliveries (IM: 3.9% +/-0.4; HHS: 3.9%), and on hospital deliveries (IM: 61.0%. +/- 5.4; HHS: 51.4%). For hospitalizations, we obtained a lower estimate from the IM (1.1%) than from the HHS (2.6%). The IM required less time and less person-power than a household survey, which translate into reduced costs. CONCLUSIONS: We have shown that our Illness Mapping method can be carried out at lower financial and human cost for sourcing essential local data, at acceptably accurate levels. In view of the good fit of results obtained, we assume that the method could work elsewhere as well. PMID- 23043585 TI - Introduction to a Virtual Special Issue on ecological stoichiometry and global change. PMID- 23043586 TI - Whole genome sequencing (WGS) meets biogeography and shows that genomic selection in forest trees is feasible. PMID- 23043587 TI - Keeping it in the family: segregation of genetic variation in Glomus irregulare. PMID- 23043588 TI - Differential gene expression within the cyanobacterial cell population of a lichen thallus. PMID- 23043589 TI - Synthetic biology. 4th New Phytologist Workshop, Bristol, UK, June 2012. PMID- 23043590 TI - 'Raising the bar': improving the standard and utility of weed and invasive plant research. A workshop held at B-Bar Ranch, Emigrant, Montana, USA, June 2012. PMID- 23043591 TI - Association of the UCP-1 single nucleotide polymorphism A-3826G with the dampness phlegm pattern among Korean stroke patients. AB - BACKGROUND: Patients with stroke have various syndromes and symptoms. Through pattern identification (PI), traditional Korean medicine (TKM) classifies the several syndromes and symptoms of stroke patients into five categories: Fire-heat (FH), Dampness-phlegm (DP), Yin-deficiency (YD), Qi-deficiency (QD) and Blood stasis (BS). DP has been associated with obesity and hyperlipidemia. Uncoupling protein-1 (UCP-1), which plays a major role in thermogenesis and energy expenditure can increase the risk of obesity and can be related metabolic disorders. In this study, we elucidated the association of three polymorphisms located in the UCP-1 promoter and coding region with DP among Korean stroke patients. METHODS: 1,593 patients with cerebral infarction (583/DP, 1,010/non-DP) and 587 normal subjects were enrolled. The genotypes A-3826G, G-1766A and Ala64Thr (G+1068A) for each subject were determined by polymerase chain reaction with TaqMan probes and five percent of subjects were re-genotyped by sequencing method to confirm the accuracy of genotyping. The results were analyzed using a multiple logistic regression model to evaluate the genetic associations: the UCP 1polymorphisms of normal versus those of DP subjects and those of normal versus those of non-DP subjects. RESULTS: A significantly higher percentage of subjects in the DP group possessed the A-3826G G allele than the A allele (OR=1.508, p=0.006). Furthermore, the number of subjects with the GG type of A-1766G was significantly lower in the non-DP group than the normal group in the recessive model (OR=0.606, p=0.042). In addition, an analysis of the relationship among 2 SNPs of UCP-1 and lipid serum concentration showed that the serum level of HDL cholesterol was significantly higher in subjects with the A-3826G G allele in the normal group (p=0.032). Serum triglyceride and HDL cholesterol were also associated with the A-1766G variant in the recessive model (p=0.002, p=0.046). CONCLUSIONS: These results suggest that that the A-3826G and A-1766G UCP-1 polymorphisms, which are related to obesity, might be candidate genetic markers for the DP pattern in the TKM diagnosis system. PMID- 23043592 TI - Powder flow in an automated uniaxial tester and an annular shear cell: a study of pharmaceutical excipients and analytical data comparison. AB - BACKGROUND: An automated version of uniaxial powder flow testing has recently been developed and there is a need for experimental data from pharmaceutical powders. PURPOSE: To compare the novel testing method with an annular shear cell using different pharmaceutical excipients. A particular aim was to gain an improved understanding of potential differences in the obtained flow results. METHODS: Nine excipients were studied with both flow testers at different consolidation levels. Unconfined yield strengths were determined at similar major consolidation stresses. Finally, an anisotropic stress factor was calculated and the fractal character of the powders was assessed by means of image analysis in a rotating drum. RESULTS: Data correlated generally well; however, the unconfined yield strength from uniaxial testing resulted mostly in lower values compared to annular shear cell testing. Differences were specific for the given excipients and mannitol demonstrated the highest discrepancy of measured flow parameters. The differences were first discussed by considering wall friction, anisotropy of forces, brittleness as well as the fractal nature of the powder surface. This heterogeneity of the powder as well as the anisotropy of forces was also found to be important for the relative flow index. CONCLUSIONS: The automated uniaxial method demonstrated faster and more reproducible flow testing as compared to an annular shear cell. Therefore, the new method has a high potential in pharmaceutics for example in the quality-control of powders. PMID- 23043593 TI - Relationship between incidence of fracture and health-related quality-of-life in metastatic breast cancer patients with bone metastases. AB - OBJECTIVE: This retrospective observational study describes treatment patterns and longitudinal health-related quality-of-life (HRQoL) among metastatic breast cancer patients with bone metastasis from nine community oncology clinics. METHODS: For description of treatment patterns, patients were classified as treated if they started zoledronic acid within 60 days of diagnosis of bone metastasis, were considered untreated if they had not, and were considered unclassified if they died or experienced fracture before 60 days had elapsed. Medical record review provided demographic and disease characteristics as well as history of treatment. Patients completed Patient Care Monitor (PCM) assessments of patient reported outcomes during routine care for up to 2 years from the date of bone metastasis diagnosis. RESULTS: The overall rate of fracture in the sample was 17.4%. Of the 321 patients enrolled, 160 were treated as of 60 days after diagnosis of bone metastasis, 147 were untreated, and 14 were unclassified. Of the 147 untreated as of 60 days, 82 did eventually receive zoledronic acid. More than half of all patients treated with zoledronic acid delayed the start of treatment by more than 30 days after diagnosis of bone metastasis. Patients who had a fracture showed decreased mobility and increased pain and anxiety at fracture, with recovery taking ~16 months. LIMITATIONS: Key limitations included: convenience sample with information limited to medical record content, low rate of observed fractures possibly due to limited 2-year follow-up, and exclusion of non-zoledronic acid bisphosphonate use. CONCLUSIONS: Whereas the proportion of patients experiencing a fracture was small, the impact of fracture on HRQoL was significant and was more prominently seen to impact specific dimensions of HRQoL. PMID- 23043594 TI - Cost-effectiveness analysis of pancreatin minimicrospheres in patients with pancreatic exocrine insufficiency due to chronic pancreatitis. AB - OBJECTIVE: Chronic pancreatitis (CP) is the most common cause of pancreatic exocrine insufficiency (PEI). Management of PEI due to CP is achieved through lifelong treatment with pancreatic enzyme replacement therapy (PERT). To the authors' knowledge, no cost-effectiveness analysis on the benefit of PERT in CP patients with PEI has been performed to date. The objective of this analysis was to examine the cost-effectiveness of Creon (pancreatin minimicrospheres [MMS]), one of the main PERTs available in Poland, in treating patients with CP-related PEI. METHODS: The cost-effectiveness of pancreatin MMS in the treatment of patients with CP-related PEI vs no PERT treatment was estimated using a decision analysis based on clinical data from relevant studies. The model horizon was 20 years. Main outcomes included the percentage of patients with controlled PEI, survival, total medical costs, number of quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). All costs were analysed from the Polish payer perspective. RESULTS: The model included clinical data from 176 patients treated in five pancreatin MMS randomized trials. Treatment with pancreatin MMS resulted in a considerably higher proportion of patients with controlled PEI compared to those not treated with any PERT. Over a horizon of 20 years, the total treatment cost and the ICER for pancreatin MMS was ?8223 and ?6312 per QALY, respectively. LIMITATIONS: Important limitations include the lack of long-term and comparative clinical data available. The use of 'no PERT treatment' as a comparator against pancreatin MMS treatment may not accurately reflect current practice in Poland. CONCLUSIONS: Treatment of CP-related PEI with pancreatin MMS is cost-effective from a Polish payer perspective, with an ICER below the accepted 'willingness to pay' threshold of 3-times gross domestic product (GDP) per capita. These results are likely to apply to other European countries. PMID- 23043595 TI - Hybrid solar cells with outstanding short-circuit currents based on a room temperature soft-chemical strategy: the case of P3HT:Ag2S. AB - P3HT:Ag(2)S hybrid solar cells with broad absorption from the UV to NIR band were directly fabricated on ITO glass by using a room temperature, low energy consumption, and low-cost soft-chemical strategy. The resulting Ag(2)S nanosheet arrays facilitate the construction of a perfect percolation structure with organic P3HT to form ordered bulk heterojunctions (BHJ); without interface modification, the assembled P3HT:Ag(2)S device exhibits outstanding short-circuit current densities (J(sc)) around 20 mA cm(-2). At the current stage, the optimized device exhibited a power conversion efficiency of 2.04%. PMID- 23043596 TI - Two distinct regions of HA2 glycopolypeptide of influenza virus hemagglutinin elicit cross-protective immunity against influenza. AB - Currently, a new trend in development of vaccines against influenza with broader spectrum of efficacy is focused on conserved antigens of influenza virus. The HA2 glycopolypeptide (HA2 gp) is one of conserved antigens, potentially suitable as immunogens inducing cross-protection against influenza. We selected two distinct domains of HA2 gp originating from influenza A virus (IAV) of H3 subtype for induction of antiviral immune response: the ectodomain (EHA2) comprising aa 23 185 and the fusion peptide (FP) comprising N-terminal aa 1-38. BALB/c mice were immunized with three doses of EHA2 and FP, respectively, and subsequently challenged with 2 LD50 of IAV of homologous (H3) or heterologous (H7) HA subtype. Both peptides induced significant antibody response and protected mice against the lethal infection. The most efficient protection was achieved with EHA2 against homologous virus. KEYWORDS: influenza A virus; cross-protection; HA2 glycopolypeptide; HA2 ectodomain; fusion peptide; mice; vaccine. PMID- 23043597 TI - Partial genome analysis of murine gammaherpesvirus 4556. AB - Murine gammaherpesvirus 68 (MHV-68) -infected mouse is an animal model of gammaherpesvirus infection in man and domestic animals. Murine gammaherpesvirus 4556 (MHV-4556), isolated from Apodemus flavicollis ticks has been considered a close relative of MHV-68 but different in some features of infection in vitro and in vivo. Previous comparison of MHV-4556 with MHV-68 has revealed their diversity in immune evasion protein MK3. In this study, HindIII and EcoRI restriction profiles of the MHV-4556 genome disclosed absence of the deletion that has been identified previously at the left end of genomes of murine gammaherpesvirus 76 (MHV-76) and murine gammaherpesvirus Sumava (MHV-Sumava). A 22, 565 bp portion of MHV-4556 genome sequence was sequenced, analyzed and compared with that of MHV 68. Nucleotide sequences of 21 genes of MHV-4556 and deduced amino acid sequences revealed their identity to those of MHV-68 except for differences in 15 nucleotides and 8 amino acids in 5 genes and their proteins, respectively. Due to these differences, immune evasion protein M4 and structural proteins encoded by ORF8 (gB), ORF11 (p43), ORF26 and ORF52, respectively, are predicted to have a reduced hydrophilicity and surface exposure compard with their MHV-68 counterparts. These differences obviously contribute to some different pathogenetical features of these viruses and could explain the weaker immunogenicity of MHV-4556 in comparison with MHV-68. KEYWORDS: murine gammaherpesvirus 4556; restriction analysis; partial genome sequence. PMID- 23043598 TI - Molecular characterization and an infectious clone construction of sweet potato leaf curl virus (SPLCV) isolated from Korea. AB - Sweet potato leaf curl disease (SPLCD) was primarily identified in sweet potato fields in Korea in 2003, and the complete genomic sequence of sweet potato leaf curl virus (SPLCV) has been cloned. The genome of the Korean SPLCV isolate (SPLCV KR) comprises 2,828 nucleotides with six open reading frames in DNA-A, similar to a monopartite begomovirus. Additionally, neither the genome B genomic component nor the DNA beta sequence was detected. The results of phylogenetic analysis using the maximum parsimony method showed that SPLCV-KR is more closely related to SPLCV-US (US) than SPLCV-CN (China) and SPLCV-JP (Japan). A tandem repeat dimer of SPLCV-KR was cloned and found to be infectious in sweet potatoes (Ipomoea batatas) via biolistic inoculation. The SPLCV-infected sweet potatoes exhibited mild leaf curl symptoms of SPLCD, and the newly-replicated viral DNA was detected via Southern blot analysis. Results of biotic, molecular, and phylogenetic characterization suggest that SPLCV-KR is a new strain of SPLCV and is importantly placed in the evolutionary progression from curtoviruses to begomoviruses. KEYWORDS: sweet potato leaf curl virus; sweet potato leaf curl disease; phylogenetic analysis; infectious clone; biolistic infection. PMID- 23043599 TI - Identification of cellular proteins interacting with influenza A virus PB1-F2 protein. AB - The influenza A virus (IAV) protein PB1-F2, which is encoded by an alternative ORF of the PB1 polymerase gene, has been implicated as an important virulence factor and apoptosis inducer. However, the molecular mechanism of PB1-F2 function remains elusive. In this study, eight cellular proteins were identified as potential PB1-F2 interacting partners using the yeast two-hybrid system. Two positive candidate proteins, guanine nucleotide binding protein (G protein) beta polypeptide 2 (Gbeta2) and macrophage migration inhibitory factor (MIF), were selected to be further characterized. The interaction of MIF and Gbeta2 with PB1 F2 was confirmed by both GST pull-down and co-immunoprecipitation assays. Confocal laser microscopy showed that the interaction between PB1-F2 and the two cellular proteins occurred in the cytoplasm. The novel interactions between PB1 F2 and host proteins provide further pieces of evidence in the investigation of the pathogenic mechanism of IAV. KEYWORDS: influenza A virus; PB1-F2; yeast two hybrid; protein-protein interaction. PMID- 23043600 TI - Genetic variety of bovine viral diarrhea virus 1 strains isolated from sheep and goats in India. AB - Antigenic and genetic typing of pestiviruses isolated from Indian sheep and goats was carried out. Testing of 1777 sheep and 1026 goat blood samples collected between 2004 and 2008 resulted in isolation of twelve pestiviruses, seven from sheep and five from goats. All of them were antigenically typed as bovine viral diarrhea virus 1 (BVDV-1). Both the partial 5'-UTR and entire non-structural autoprotease (Npro) gene of the pestiviruses were amplified by RT-PCR and sequenced. The phylogenetic analysis confirmed all twelve sheep and goat pestiviruses as BVDV-1 and they were further classified into two subtypes, BVDV 1b (seven) and BVDV-1c (five). This is for the first time that BVDV-1c was detected in sheep and goats. However, no association between the subtype and geographic area of origin was observed. Although closely related, BVDV-1b and BVDV-1c isolates of sheep and goats were placed in a different clade than previously reported Indian BVDV-1b/BVDV-1c isolates. This study confirmed widespread prevalence of BVDV-1 in Indian sheep and goats that has significance in the epidemiology of bovine viral diarrhea. KEYWORDS: bovine viral diarrhea virus; BVDV-1; goat; Npro; genetic typing; sheep; 5'-UTR. PMID- 23043601 TI - The adenine-rich tract in the 5'-end of the hepatitis C virus ORF encodes a peptide regulating the binding of the C protein to RNA. AB - Hepatitis C virus (HCV) core (C) protein is thought to bind to viral RNA before it undergoes oligomerization leading to RNA encapsidation. Details of these events are so far unknown. The 5'-terminal C protein coding sequence that includes an adenine (A)-rich tract is a part of an internal ribosome entry site (IRES). This nucleotide sequence but not the corresponding protein sequence is needed for proper initiation of translation of viral RNA by an IRES-dependent mechanism. In this study, we examined the importance of this sequence for the ability of the C protein to bind to viral RNA. Serially truncated C proteins with deletions from 10 up to 45 N-terminal amino acids were expressed in Escherichia coli, purified and tested for binding to viral RNA by a gel shift assay. The results showed that truncation of the C protein from its N-terminus by more than 10 amino acids abolished almost completely its expression in E. coli. The latter could be restored by adding a tag to the N-terminus of the protein. The tagged proteins truncated by 15 or more amino acids showed an anomalous migration in SDS PAGE. Truncation by more than 20 amino acids resulted in a complete loss of ability of tagged C protein to bind to viral RNA. These results provide clues to the early events in the C protein - RNA interactions leading to C protein oligomerization, RNA encapsidation and virion assembly. KEYWORDS: hepatitis C virus; core protein; RNA binding. PMID- 23043602 TI - A mouse model of swine influenza virus H9N2 infection with acute lung injury. AB - BALB/c mice inoculated intranasally with A/swine/HeBei/012/2008/ (H9N2) virus (SIV), showing acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), were observed for morbidity (lung histopathology, lung coefficient, lung wet/dry weight (W/D) ratio, arterial blood gas characteristics and inflammatory cells in bronchial alveolar lavage fluid (BALF)) and mortality. The results showed that, (1) on days 1-4 post infection (p.i.), mice appeared depressed and showed ruffled fur, reduced food intake, weight loss and hypoxemia with a decreased arterial partial oxygen pressure and an increased partial carbon dioxide pressure. (2) From day 4 p.i., mice began to die and showed pulmonary edema, hemorrhage and inflammatory cells in the alveolar exudate. The lung coefficient and lung W/D ratio significantly increased. (3) On days 3-8 p.i., inflammatory cells, especially alveolar macrophages and polymorphonuclears (PMNs) in BALF significantly increased. (4) The mortality rate reached 62.5%. This study established a successful animal model of ALI induced by infection with H9N2 SIV which may help in further investigations of the pathogenesis of human ALI/ARDS induced by H9N2 SIV infection. KEYWORDS: wine influenza virus; H9N2 subtype; acute lung injury; mouse. PMID- 23043603 TI - Hepatitis C virus and other risk factors in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) increased in Egypt in the past years, becoming the most common cancer among men. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the known primary risk factors for HCC. This study describes the viral profile of HCC in a predominantly rural area in Egypt. We included 148 HCC cases and 148 controls from the Tanta Cancer Center and the Gharbiah Cancer Society in the Nile delta region. Serological (ELISA) and molecular (PCR) analysis for HBV and HCV infection were performed on plasma samples from each subject. Epidemiologic, environmental, and medical histories were collected by interviewing of subjects. Around 90.5% of cases and controls were from rural areas. HCV infection was high in both cases and controls (89.2% and 49.3%, for cases and controls respectively by serology). HCV was the most important HCC risk factor [OR 9.7 (95% CI: 3.3-28.0, P <0.01)], and HBV infection showed marginal tendency of increased risk [OR 5.4 (95% CI: 0.9-31.8, P <0.06)]. Ever worked in farming [OR 2.8 (95% CI: 1.1-7.2, P <0.03)] and history of cirrhosis [OR 3.6 (95% CI: 1.6-8.1, P <0.01)] or blood transfusion [OR 4.2 (95% CI: 0.99-17.8, P <0.05)] were also associated with increased HCC risk. This study in a predominantly rural area in Egypt supports previous reports from other parts of Egypt that HCV infection is the primary HCC risk factor in Egypt. Further understanding of the relationship between infection and other risk factors in the development of HCC could lead to targeted interventions for at-risk individuals. KEYWORDS: hepatocellular carcinoma; hepatitis; rural; risk factors; Egypt. PMID- 23043604 TI - Characterization of the deoxyuridine triphosphatase gene of Ophiusa disjungens nucleopolyhedrovirus. AB - Ophiusa disjungens is one of the main insect pests that attack Myrtaceae species. Nucleopolyhedroviruses (NPVs) of the Baculoviridae family have been used for decades as biological pesticides to control insect pests. A new NPV, named Ophiusa disjungens nucleopolyhedrovirus (OpdiNPV), was recently isolated from OpdiNPV-infected O. disjungens larvae. In this study, a PstI fragment of OpdiNPV genome containing the deoxyuridine triphosphatase (dUTPase) gene was successfully cloned, sequenced and analyzed. Upstream of a 402 bp long ORF of the dUTPase gene, encoding a 133 aa long protein, typical transcription promoter boxes CAGT and TATA were found. The dUTPase was first expressed in his-tagged form in Escherichia coli as a 35.5 kDa protein. Then it was successfully expressed in insect Trichoplusia ni (Tn) cells in the form of an EGFP-fusion protein. It first appeared (at 24 hrs post infection (p.i.)) in the cell nucleus, but later (at 72 hrs p.i.) it was excluded from the nucleus and diffusely scattered all over the cell. These findings may serve as basis for development of engineered OpdiNPVs as biopesticides to control O. disjungens and other Lepidoptera insects. KEYWORDS: Ophiusa disjungens; nucleopolyhedrovirus; dUTPase. PMID- 23043605 TI - Isolation of rickettsia helvetica from ticks in Slovakia. AB - To date, only three rickettsial species have been found in ticks in Slovakia by serological and/or molecular-biological techniques, namely Rickettsia slovaca, Candidatus rickettsia IRS, and Rickettsia raoultii. Recently, we succeeded in isolation of the forth species, Rickettsia helvetica from Ixodes ricinus, the most frequent tick in Slovakia. The isolation, positive for 10% of tested ticks, was performed on XTC cells by the shell-vial technique, Gimenez staining and light microscopy. The infected cell cultures contained rod-shaped particles morphologically identical to rickettsiae. The isolation was confirmed by direct detection of a fragment of the R. helvetica gene for citrate synthase in the positive ticks by PCR and its subsequent cloning, sequencing and comparison with the database. KEYWORDS: Rickettsia helvetica; isolation; Ixodes ricinus; Slovakia. PMID- 23043606 TI - A reduced expression of surfactant protein D in the lungs of fatal influenza H1N1 cases in 2009. PMID- 23043607 TI - Evolutionary changes in avian influenza H5N1 viruses in Thailand. PMID- 23043608 TI - Characterization and complete nucleotide sequence of potato virus M isolated from tomato in China. PMID- 23043609 TI - Characterization of recent Getah virus isolates from South Korea. PMID- 23043611 TI - Determination of cadmium and zinc in vegetables with online FAAS after simultaneous pre-concentration with 1,5-diphenylthiocarbazone immobilised on naphthalene. AB - The concentration of cadmium and zinc in vegetables was determined by using an online flame atomic absorption spectrophotometer after simultaneous pre concentration based on the complexation of Cd and Zn with 1,5 diphenylthiocarbazone immobilised on naphthalene. The effect of pH, sample flow rate and amount of 1,5-diphenylthiocarbazone on adsorption was investigated. After pre-concentration, Cd and Zn were eluted from the sorbent with hydrochloric acid. A pre-concentration factor of 20 and 33 was achieved for Cd and Zn, respectively. The calibration curve was linear in the range of 0.2-1 ug ml(-1) for Cd and Zn. The regression coefficients for the lines were 0.9914 and 0.9989 for Cd and Zn, respectively. The detection limits were calculated as three times the standard deviation of nine replicates of blanks: 0.00123 ug ml(-1) for Cd and 0.00176 ug ml(-1) for Zn. PMID- 23043610 TI - 4-O-methylhonokiol, a PPARgamma agonist, inhibits prostate tumour growth: p21 mediated suppression of NF-kappaB activity. AB - BACKGROUND AND PURPOSE: The effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated. EXPERIMENTAL APPROACH: The anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model. KEY RESULTS: MH increased the expression of PPARgamma in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARgamma. MH also increased transcriptional activity of PPARgamma but decreased NF-kappaB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARgamma antagonist GW9662. MH induced apoptotic cell death and this was related to G(0) -G(1) phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-kappaB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARgamma, and the expression of apoptotic proteins and p21 in tumour tissues. CONCLUSIONS AND IMPLICATION: MH inhibits growth of human prostate cancer cells through activation of PPARgamma, suppression of NF-kappaB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer. PMID- 23043613 TI - Leading infectious diseases problems in Turkey. AB - Turkey has significant geographical and socio-economic differences throughout a vast area of the country. These characteristics affect the epidemiology of infectious diseases, some of which are rarely seen in western Europe. However, effectively implemented control measures have resulted in decreased rates of many community-acquired infections, including tuberculosis and malaria, that were major health problems only a few decades ago. There are high rates of antimicrobial resistance in various nosocomial isolates of Gram-positive and Gram negative bacteria. A recently implemented, nationwide, electronic resistance surveillance system in hospitals is expected to produce reliable data, and possibly will help to develop an effective strategy to decrease antimicrobial resistance in bacteria that currently plague many tertiary-care hospitals in the country. This article summarizes the most frequently encountered community acquired infections, and gives an overview of current antimicrobial resistance in both outpatient and hospital settings in Turkey. PMID- 23043612 TI - Importance of glycolysis and oxidative phosphorylation in advanced melanoma. AB - Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma. To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma. Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2. Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS), we subsequently determined using tissue microarray (TMA) analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes. To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT) 1 and 4. Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma. Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS. Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy. PMID- 23043614 TI - Preventing and treating inflammation: role of dialysis access management. PMID- 23043615 TI - White paint dot-like lesions of the scrotum: Microsporum gypseum infection. AB - A 29-year-old renal transplant patient taking mycophenolate mofetil 1 g b.i.d., cyclosporine 100 mg b.i.d. and prednisone 10 mg q.d. presented with white paint, dot-like incrustations on the skin of his right scrotum. A 10% potassium hydroxide preparation of scrapings from the lesions showed septate hyphae and Microsporum gypseum was cultured. Topical bifonazole 1% cream cleared the lesions within 2 weeks. At the 2-month follow up there was no relapse. PMID- 23043616 TI - Metabolic engineering of sugars and simple sugar derivatives in plants. AB - Carbon captured through photosynthesis is transported, and sometimes stored in plants, as sugar. All organic compounds in plants trace to carbon from sugars, so sugar metabolism is highly regulated and integrated with development. Sugars stored by plants are important to humans as foods and as renewable feedstocks for industrial conversion to biofuels and biomaterials. For some purposes, sugars have advantages over polymers including starches, cellulose or storage lipids. This review considers progress and prospects in plant metabolic engineering for increased yield of endogenous sugars and for direct production of higher-value sugars and simple sugar derivatives. Opportunities are examined for enhancing export of sugars from leaves. Focus then turns to manipulation of sugar metabolism in sugar-storing sink organs such as fruits, sugarcane culms and sugarbeet tubers. Results from manipulation of suspected 'limiting' enzymes indicate a need for clearer understanding of flux control mechanisms, to achieve enhanced levels of endogenous sugars in crops that are highly selected for this trait. Outcomes from in planta conversion to novel sugars and derivatives range from severe interference with plant development to field demonstration of crops accumulating higher-value sugars at high yields. The differences depend on underlying biological factors including the effects of the novel products on endogenous metabolism, and on biotechnological fine-tuning including developmental expression and compartmentation patterns. Ultimately, osmotic activity may limit the accumulation of sugars to yields below those achievable using polymers; but results indicate the potential for increases above current commercial sugar yields, through metabolic engineering underpinned by improved understanding of plant sugar metabolism. PMID- 23043617 TI - Pearl extract enhances the migratory ability of fibroblasts in a wound healing model. AB - CONTEXT: For 2000 years, traditional Chinese medicine has been used as a remedy for general health improvement, including the fight against aging. Pearl powder has recently been used as a health food that has antioxidant, antiaging, antiradioactive, and tonic activities for cells; it is also applied to cure aphthous ulcer, gastric ulcer, and duodenal ulcer on clinical therapy. In addition, the mother of pearl, nacre, could enhance the cell adhesion and tissue regeneration of skin fibroblasts. OBJECTIVE: Fibroblast is regarded as indispensable in the processes of wound healing. Therefore, the effect of pearl extract (PL) on fibroblasts is investigated in this study. MATERIALS AND METHODS: PL is produced by a room temperature super extraction system (Taiwan patent no. I271 220). DMEM medium containing PL (300 MUg/mL) was used to examine the effect of migration-promoting potential on human fibroblast cell line or human primary fibroblast cells in a wound healing model in vitro. RESULTS: Medium containing PL (300 MUg/mL) demonstrated that the migratory cell numbers of fibroblasts were three times more than that without PL, and mRNA expression of collagen type III was higher than in collagen type I in fibroblasts. It revealed a migration promoting potential of human fibroblasts in a wound healing model in vitro. DISCUSSION AND CONCLUSION: The present study found that the migration-promoting effect in PL, which could be a supplement in cell culture. These data suggest PL could be useful for enhancing the wound healing of fibroblasts. PMID- 23043618 TI - Procalcitonin and procalcitonin kinetics for diagnosis and prognosis of intravascular catheter-related bloodstream infections in selected critically ill patients: a prospective observational study. AB - BACKGROUND: Procalcitonin (PCT) has emerged as a valuable marker of sepsis. The potential role of PCT in diagnosis and therapy monitoring of intravascular catheter-related bloodstream infections (CRBSI) in intensive care unit (ICU) is still unclear and was evaluated. METHODS: Forty-six patients were included in the study, provided they were free of infection upon admission and presented the first episode of suspected CRBSI during their ICU stay. Patients who had developed any other infection were excluded. PCT was measured daily during the ICU hospitalization. Primary endpoint was proven CRBSI. Therapy monitoring as according to infection control was also evaluated. RESULTS: Among the 46 patients, 26 were diagnosed with CRBSI. Median PCT on the day of infection suspicion (D0) was 7.70 and 0.10 ng/ml for patients with and without proven CRBSI, respectively (p < 0.001). The area under the curve (AUC) for PCT was 0.990 (95% CI; 0.972 - 1.000), whereas a cut-off value of 0.70 ng/ml provided sensitivity and specificity of 92.3 and 100% respectively. In contrast, the AUC for white blood cells (WBC) was 0.539 (95% CI; 0.369 - 0.709), and for C-reactive protein (CRP), 0.603 (95% CI; 0.438 - 0.768). PCT was the best predictor of proven infection. Moreover, an increase >0.20 ng/ml of PCT between the D0 and any of the 4 preceding days was associated with a positive predictive value exceeding 96%. PCT concentrations from the D2 to D6 after suspected infection tended to decrease in controlled patients, whereas remained stable in non-controlled subjects. A PCT concentration exceeding 1.5 ng/ml during D3 was associated with lack of responsiveness to therapy (p = 0.028). CONCLUSIONS: We suggest that PCT could be a helpful diagnostic and prognostic marker of CRBSI in critically ill patients. Both absolute values and variations should be considered. PMID- 23043619 TI - Cloning, expression and decoding of the cold adaptation of a new widely represented thermolabile subtilisin-like protease. AB - AIMS: Cloning, expression and characterization of a new cold-adapted protease with potential biotechnological application, isolated from Antarctic bacteria. METHOD AND RESULTS: A subtilisin-like gene was isolated from several Antarctic bacterial genus using CODPEHOP-designed primers and a genome walking method. This gene encodes a precursor protein, which undergoes an autocatalytic cleavage resulting in a 34.6 kDa active cold-adapted protease with a maximum activity at 25-35 degrees C and optimum pH of 8.0-9.0. It showed a higher catalytic efficiency at lower temperatures compared to its mesophilic counterpart. Heat induced inactivation resulted in a very low melting point. Local packing analysis using the homology model indicated Ala284 as an important cold-adaptation determinant, which was corroborated by the site-directed mutagenesis. CONCLUSIONS: A new thermolabile subtilisin-like protease has been successfully cloned and analysed, and an important hot spot in the evolution of the cold adaptation and substrate specificity of this enzyme was identified and tested. SIGNIFICANCE AND IMPACT OF THE STUDY: This work reports a new cold-adapted protease with a vast representation amongst Antarctic genus, suggesting therefore its evolutionary success in this cold environment. Likewise, important sites for genetic potentiation have been identified, which are extrapolated to other enzymes of the same kind. PMID- 23043620 TI - Effect of beta,gamma-CHF- and beta,gamma-CHCl-dGTP halogen atom stereochemistry on the transition state of DNA polymerase beta. AB - Recently, we synthesized the first individual beta,gamma-CHX-dGTP diastereomers [(R)- or (S)-CHX, where X is F or Cl] and determined their structures in ternary complexes with DNA polymerase beta (pol beta). We now report stereospecificity by pol beta on the mixed beta,gamma-CHX diastereomer pairs using nuclear magnetic resonance and on the separate diastereomers using transient kinetics. For both the F and Cl diastereomers, the R isomer is favored over the S isomer for G.C correct incorporation, with stereospecificities [(k(pol)/K(d))(R)/(k(pol)/K(d))(S)] of 3.8 and 6.3, respectively, and also for G.T misincorporation, with stereospecificities of 11 and 7.8, respectively. Stereopreference for the (R)-CHF-dGTP diastereomer was abolished for k(pol) but not K(d) with mutant pol beta (R183A). These compounds constitute a new class of stereochemical probes for active site interactions involving halogen atoms. As Arg183 is unique in family X pols, the design of CXY deoxyribonucleotide analogues to enhance interaction is a possible strategy for inhibiting BER selectively in cancer cells. PMID- 23043622 TI - Surface plasmon resonance sensor for dissolved and gaseous carbon dioxide. AB - We describe a novel kind of sensor for carbon dioxide. It is based on surface plasmon resonance (SPR) and a polymer blend that is capable of fully reversibly binding carbon dioxide. The interaction results in a change in the polarity and refractive index that can be detected via SPR. The sensor responds with high specificity. The method is simple and, unlike previous ones, enables continuous sensing over extended periods of time. It can be applied to sense both dissolved and gaseous carbon dioxide. The limits if detection of gaseous CO(2) is as low as 10 ppm. PMID- 23043621 TI - The mirror crack'd: both pigment and structure contribute to the glossy blue appearance of the mirror orchid, Ophrys speculum. AB - The Mediterranean orchid genus Ophrys is remarkable for its pseudocopulatory pollination mechanism; naive male pollinators are attracted to the flowers by olfactory, visual and tactile cues. The most striking visual cue is a highly reflective, blue speculum region at the centre of the labellum, which mimics the corresponding female insect and reaches its strongest development in the mirror orchid, O. speculum. We explored the structure and properties of the much discussed speculum by scanning and transmission electron microscopic examination of its ultrastructure, visible and ultraviolet (UV) angle-resolved spectrophotometry of the intact tissue, and mass spectrometry of extracted pigments. The speculum contrasts with the surrounding labellar epidermis in being flat-celled with a thick, smooth cuticle. The speculum is extremely glossy, reflecting intense white light in a specular direction, but at more oblique angles it predominantly reflects blue and UV light. Pigments in the speculum, dominantly the cyanidin 3-(3''-malonylglucoside), are less diverse than in the surrounding regions of the labellar epidermis and lack quercetin copigments. Several physical and biochemical processes interact to produce the striking and much-discussed optical effects in these flowers, but the blue colour is not produced by structural means and is not iridescent. PMID- 23043623 TI - Reawakening atlas: chemical approaches to repair or replace dysfunctional musculature. AB - Muscle diseases are major health concerns. For example, ischemic heart disease is the third most common cause of death. Cell therapy is an attractive approach for treating muscle diseases, although this is hampered by the need to generate large numbers of functional muscle cells. Small molecules have become established as attractive tools for modulating cell behavior and, in this review, we discuss the recent, rapid research advances made in the development of small molecule methods to facilitate the production of functional cardiac, skeletal, and smooth muscle cells. We also describe how new developments in small molecule strategies for muscle disease aim to induce repair and remodelling of the damaged tissues in situ. Recent progress has been made in developing small molecule cocktails that induce skeletal muscle regeneration, and these are discussed in a broader context, because a similar phenomenon occurs in the early stages of salamander appendage regeneration. Although formidable technical hurdles still remain, these new advances in small molecule-based methodologies should provide hope that cell therapies for patients suffering from muscle disease can be developed in the near future. PMID- 23043624 TI - Co(III) imidos exhibiting spin crossover and C-H bond activation. AB - The reaction of ((Ar)L)Co(py) with (t)BuN(3) afforded the isolable three coordinate Co-imido complex ((Ar)L)Co(N(t)Bu), which is paramagnetic at room temperature. Variable-temperature (VT) (1)H NMR spectroscopy, VT crystallography, and magnetic susceptibility measurements revealed that ((Ar)L)Co(N(t)Bu) undergoes a thermally induced spin crossover from an S = 0 ground state to a quintet (S = 2) state. The reaction of ((Ar)L)Co(py) with mesityl azide yielded an isolable S = 1 terminal imido complex that was converted into the metallacycloindoline ((Ar)L)Co(kappa(2)-NHC(6)H(2)-2,4-Me(2)-6-CH(2)) via benzylic C-H activation. PMID- 23043625 TI - Cognitive abilities of street children: low-SES Bolivian boys with and without experience of living in the street. AB - OBJECTIVES: This study compared results on cognitive tests measuring nonverbal visualization and reasoning, executive functions, and creativity between 36 boys with experience of living in the street and 31 housed yet socioeconomically equivalent boys, in Bolivia. RESULTS: The street children scored significantly higher on the creativity measure, which is discussed in relation to contextual relevance. No significant differences were found on the other cognitive tests. Time elapsed after living in the street and drug use were strongly associated with cognition, while age was not. Both groups scored below average compared to Western norms. The results are discussed in terms of the cultural relevance of the tests and the impact of socioeconomic status, stress, and stimulation on cognition. PMID- 23043626 TI - Thymoquinone in liposomes: a study of loading efficiency and biological activity towards breast cancer. AB - Thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone) is a herbal-derived drug with potential chemopreventive and chemotherapeutic activity. However, thymoquinone suffers from high hydrophobicity causing poor solubility which limits its bioavailability and high lipophilicity causing poor formulation characteristics. Liposomes are versatile drug carriers that can be used to solve problems of drug solubility, instability, and bio-distribution. In this study, we were able to prepare thymoquinone-loaded liposomes (TQ-LP) and thymoquinone loaded in liposomes modified with Triton X-100 (XLP) with diameters of about 100 nm, and entrapment efficiency of more than 90% for TQ-LP and of 49.6% for XLP. The TQ-LP liposomes were effective in suppressing the proliferation of breast cancer cell lines MCF-7 and T47D, and at the same time exerting very low toxicity on normal periodontal ligament fibroblast. Altogether, this report describes the first successful encapsulation of thymoquinone into liposome; which maintains stability, improves bioavailability and maintains its anticancer activity. PMID- 23043627 TI - The effect of customized growth charts on the identification of large for gestational age newborns. AB - OBJECTIVE: To determine the effect of using customized vs. standard population birthweight curves to define large for gestational age (LGA) infants. METHODS: We analyzed data obtained from 2,097 singleton pregnancies using three different methods of classifying newborn birthweight: standard population curves, British or Spanish customized curves. We recorded maternal characteristics, proportion of LGA newborns when using each method, percentage of LGA according to one method but not for the others, and concordance between the different methods. RESULTS: The proportion of LGA newborns according to Spanish customized curves was significantly lower than that calculated using either standard general population birthweight curves or British curves (p < 0.001). A third (33.9%) of the infants classified as LGA according to the general population method were adequate for gestational age (AGA) when the Spanish customized curves were used, and 18.5% of non-LGA were LGA according to customized curves (p < 0.001). Concordance between the different models high, but on excluding AGA the concordance coefficient was low (Cohen's kappa <0.4). CONCLUSIONS: The use of customized curves allows differentiation between constitutional LGA and cases of fetal overgrowth, leading to a decrease in the rate of both false-positives and negatives as well as the overall proportion of LGA babies. PMID- 23043628 TI - Central serous chorioretinopathy in young adults. PMID- 23043629 TI - Therapeutic writing and chronic pain: experiences of therapeutic writing in a cognitive behavioural programme for people with chronic pain. AB - AIMS AND OBJECTIVES: To examine the experiences of therapeutic writing from the perspectives of patients attending a chronic pain management programme. BACKGROUND: Pain is a multifaceted experience. Increased awareness, understanding and gaining new insights are essential aspects of dealing with chronic pain. It is crucial to find powerful ways to cope with chronic pain. Several studies point to writing as a tool for managing such demanding life experiences. Therapeutic writing in a cognitive behavioural approach may be used to facilitate the rehabilitation process. DESIGN: A qualitative study with a descriptive and explorative design including a phenomenological perspective was used. METHODS: A consecutive sample of 34 outpatients with chronic pain was recruited to an eight week group-based pain management programme. A therapeutic writing tool was developed and included as part of the homework tasks. Guidelines were used to initiate and guide the therapeutic writing activity. Written reports were collected after completion. RESULTS: Three thematic findings emerged from the analysis: 'increased understanding of chronic pain as a multifaceted experience', 'new insights into managing the chronic pain situation' and 'different performances lead to different experiences with therapeutic writing'. CONCLUSIONS: Increased awareness, understanding and new insights are essential to dealing with chronic pain. People with chronic pain need tools and skills for optimal adaptation. Our findings suggest therapeutic writing may strengthen cognitive behavioural therapy by facilitating cognitive restructuring processes. RELEVANCE TO CLINICAL PRACTICE: Therapeutic writing may be used as a tool to express individual experiences and to improve adaptation to chronic pain. PMID- 23043630 TI - Protective effects of Sonchus asper (L.) Hill, (Asteraceae) against CCl(4 )induced oxidative stress in the thyroid tissue of rats. AB - BACKGROUND: Sonchus asper (L.) Hill, (Asteraceae) is used in Pakistan as a traditional ("folk") medicine for the treatment of hormonal disorders and oxidative stress. The present study was aimed to evaluate the efficacy of Sonchus asper (L.) Hill, (Asteraceae) methanolic extract (SAME) on hormonal dysfunction in thyroid tissue after carbon tetrachloride (CCl4)-induced oxidative stress. METHODS: To examine the effects of SAME against the oxidative stress of CCl4 in thyroid tissue, 30 male albino rats were used. Protective effects of SAME were observed on thyroid hormonal levels, activities of antioxidant enzymes, lipid peroxidation (TBARS) and DNA damage. RESULTS: Treatment with CCl4 significantly (P<0.01) reduced the levels of T3 and T4 and increased TSH levels. CCl4 exposure in rats reduced the activities of antioxidant enzymes but increased lipid peroxidation and DNA damage. Co-administration of SAME significantly (P<0.01) improved these alterations with respect to hormonal levels, activities of antioxidant enzymes and lipid peroxidation close to those seen in control rats. CONCLUSION: These results suggest that SAME can protect thyroid tissue against oxidative damage, possibly through the antioxidant effects of its bioactive compounds. PMID- 23043632 TI - Effects of hypoxia on the expression of inflammatory markers IL-6 and TNF-a in human normal peritoneal and adhesion fibroblasts. AB - Inflammation is known to be involved in the postoperative adhesion development. Interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha are cytokines that stimulate the acute-phase reaction, which leads to a systemic reaction including inflammation, fever, and activation of the complement and clotting cascades. The goal of this study was to examine the expression of these inflammatory markers, under normal and hypoxic conditions, in normal and adhesion fibroblasts. Primary cultures of fibroblasts were established from normal peritoneum and adhesion tissues from the same patient(s) and cultured under 20% O(2) or hypoxic 2% O(2) conditions for 24 hours. Cells were harvested and total RNA was isolated. Complimentary DNA was generated by reverse transcription and subjected to real time RT-PCR using specific primers for IL-6 and TNF-alpha. Both normal peritoneal and adhesion fibroblasts expressed IL-6 and TNF-alpha. Adhesion fibroblasts exhibited significantly higher levels of IL-6 and TNF-alpha mRNA as compared to normal peritoneal fibroblasts (p < 0.05). Both IL-6 and TNF-alpha mRNA levels were upregulated in response to hypoxia in both normal peritoneal and adhesion fibroblasts. The increase in IL-6 and TNF-alpha mRNA levels of normal fibroblasts reached the levels observed in adhesion fibroblasts. Our results suggest that hypoxia promotes the development of the adhesion phenotype by the induction of inflammatory markers, which may contribute to the development of postoperative adhesions. The inhibition of inflammation may be a potential therapeutic approach in the prevention and/or reduction of postoperative adhesion development. PMID- 23043631 TI - Differential effects of cathinone compounds and MDMA on body temperature in the rat, and pharmacological characterization of mephedrone-induced hypothermia. AB - BACKGROUND AND PURPOSE: Recreational users report that mephedrone has similar psychoactive effects to 3,4-methylenedioxymethamphetamine (MDMA). MDMA induces well-characterized changes in body temperature due to complex monoaminergic effects on central thermoregulation, peripheral blood flow and thermogenesis, but there are little preclinical data on the acute effects of mephedrone or other synthetic cathinones. EXPERIMENTAL APPROACH: The acute effects of cathinone, methcathinone and mephedrone on rectal and tail temperature were examined in individually housed rats, with MDMA included for comparison. Rats were killed 2 h post-injection and brain regions were collected for quantification of 5-HT, dopamine and major metabolites. Further studies examined the impact of selected alpha-adrenoceptor and dopamine receptor antagonists on mephedrone-induced changes in rectal temperature and plasma catecholamines. KEY RESULTS: At normal room temperature, MDMA caused sustained decreases in rectal and tail temperature. Mephedrone caused a transient decrease in rectal temperature, which was enhanced by alpha(1) -adrenoceptor and dopamine D(1) receptor blockade, and a prolonged decrease in tail temperature. Cathinone and methcathinone caused sustained increases in rectal temperature. MDMA decreased 5-HT and/or 5-hydroxyindoleacetic acid (5-HIAA) content in several brain regions and reduced striatal homovanillic acid (HVA) levels, whereas cathinone and methcathinone increased striatal HVA and 5-HIAA. Cathinone elevated striatal and hypothalamic 5-HT. Mephedrone elevated plasma noradrenaline levels, an effect prevented by alpha-adrenoceptor and dopamine receptor antagonists. CONCLUSIONS AND IMPLICATIONS: MDMA and cathinones have different effects on thermoregulation, and their acute effects on brain monoamines also differ. These findings suggest that the adverse effects of cathinones in humans cannot be extrapolated from previous observations on MDMA. PMID- 23043633 TI - Malignant epithelioid angiomyolipoma of the kidney with pulmonary metastases and p53 gene mutation. AB - Angiomyolipoma (AML) is a rare tumor mainly arising in the kidney. Here we report the case of a 55-year-old woman with malignant epithelioid angiomyolipoma with p53 gene mutation. After 7 years from radical nephrectomy of the left kidney, the patient developed multiple lung metastases that showed morphologic features overlapping those of the previously lesion, which was misdiagnosed as renal cell carcinoma. Both renal and pulmonary tumors were reevaluated by immunohistochemical assay, which were showed positive for HMB-45 and p53 protein (95%), but negative for epithelial markers and S-100 protein. A correct diagnosis of malignant epithelioid angiomyolipoma was made on the basis of those results. Meanwhile exon 8 mutation of p53 gene was detected in the renal tumor by microdissection-PCR-SSCP and sequencing technique indicating that p53 gene mutation may play an important role in malignant transformation. The patient was died of respiratory failure after 15 years' follow-up. This is the second report of renal malignant angiomyolipoma with p53 gene mutation. PMID- 23043634 TI - Rapid purification method for fumonisin B1 using centrifugal partition chromatography. AB - Fumonisin B1 (FB1) is a highly toxic mycotoxin produced by fungal strains belonging to the Fusarium genus, which can be found mainly in maize products, and is gaining interest in food safety. To produce large amounts of pure FB1, a novel purifying method was developed by using centrifugal partition chromatography, which is a prominent member of the liquid-liquid chromatographic techniques. Rice cultured with Fusarium verticillioides was extracted with a mixture of methanol/water and found to contain 0.87 mg of FB1 per gram. The crude extracts were purified on a strong anion-exchange column and then separated by using a biphasic solvent system consisting of methyl-tert-butyl-ether-acetonitrile-0.1% formic acid in water. The collected fractions were analysed by flow injection mass spectrometry and high-performance liquid chromatography coupled with Corona charged aerosol detector and identified by congruent retention time on high performance liquid chromatography and mass spectrometric data. This method produced approximately 120 mg of FB1 with a purity of more than 98% from 200 g of the rice culture. The whole purification process is able to produce a large amount of pure FB1 for analytical applications or for toxicological studies. PMID- 23043635 TI - Lyme endocarditis. AB - Lyme borreliosis is a common tick-borne disease with a wide variety of clinical manifestations. Cardiac involvement has been reported during both the acute phase (atrioventricular block, pericarditis) and the chronic stage (dilated cardiomyopathy), but is rare (<5%). Here we describe the first case of Borrelia afzelii Lyme endocarditis, in a 61-year-old man living in an endemic area of France. The diagnosis was confirmed by detection of B. afzelii DNA in the mitral valve by specific real-time PCR. He was treated empirically with amoxicillin for 6 weeks and remains well 12 months later. PMID- 23043636 TI - Abstracts of the Fourth International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin's Lymphoma. November 1-3, 2012. New York, New York, USA. PMID- 23043637 TI - A phase 2 study evaluating the efficacy and safety of a novel, proprietary, nano formulated, lower dose oral diclofenac. AB - BACKGROUND: Safety concerns associated with nonsteroidal anti-inflammatory drugs (NSAIDs) have prompted the development of new formulations that minimize adverse events (AEs) and maintain efficacy. OBJECTIVES: To determine the analgesic efficacy and safety of an investigational, proprietary, nano-formulated, oral diclofenac (nano-formulated diclofenac) compared with placebo in subjects with acute dental pain. METHODS: A Phase 2, multisite, randomized, double-blind, single-dose, parallel-group, active- and placebo-controlled study was carried out in 202 subjects (18-50 years old) who had extraction of >=2 third molars (>=1 had to be a fully or partially impacted mandibular third molar) and experienced moderate to severe pain intensity <=6 hours postsurgery (NCT00985439). Subjects received nano-formulated diclofenac 35 mg or 18 mg, celecoxib 400 mg, or placebo. The primary efficacy variable was the sum of total pain relief (TOTPAR) over 0-12 hours (TOTPAR-12) after Time 0. Secondary end points included TOTPAR over 0-4 hours (TOTPAR-4), TOTPAR over 0-8 hours (TOTPAR-8), and time to onset of analgesia. RESULTS: Mean +/- standard deviation TOTPAR-12 for nano-formulated diclofenac 35 mg and 18 mg, celecoxib, and placebo were 16.81 +/- 12.76, 17.76 +/ 13.76, 14.61 +/- 15.05, and 5.65 +/- 11.53, respectively (P < 0.001, nano formulated diclofenac compared with placebo). Similar improvements were observed for TOTPAR-4, TOTPAR-8, mean time to first perceptible pain relief (P < 0.001), and peak relief (P < 0.05). Celecoxib treatment was not statistically different than placebo for these latter two parameters. Treatment-emergent AEs were similar across all treatment groups. CONCLUSIONS: Lower dose, nano-formulated diclofenac demonstrated good overall efficacy, prompt pain relief, and was well tolerated. These data suggest lower dose nano-formulated NSAIDs could be effective for acute pain and may potentially improve safety and tolerability as a result of using a lower overall dose. PMID- 23043638 TI - Fluid overload and inflammation--a vicious cycle. PMID- 23043640 TI - The necessity of microscopy to characterize the optical properties of size selected, nonspherical aerosol particles. AB - It is currently unknown whether mineral dust causes a net warming or cooling effect on the climate system. This uncertainty stems from the varied and evolving shape and composition of mineral dust, which leads to diverse interactions of dust with solar and terrestrial radiation. To investigate these interactions, we have used a cavity ring-down spectrometer to study the optical properties of size selected calcium carbonate particles, a reactive component of mineral dust. The size selection of nonspherical particles like mineral dust can differ from spherical particles in the polydispersity of the population selected. To calculate the expected extinction cross sections, we use Mie scattering theory for monodisperse spherical particles and for spherical particles with the polydispersity observed in transmission electron microscopy images. Our results for calcium carbonate are compared to the well-studied system of ammonium sulfate. While ammonium sulfate extinction cross sections agree with Mie scattering theory for monodisperse spherical particles, the results for calcium carbonate deviate at large and small particle sizes. We find good agreement for both systems, however, between the calculations performed using the particle images and the cavity ring-down data, indicating that both ammonium sulfate and calcium carbonate can be treated as polydisperse spherical particles. Our results indicate that having an independent measure of polydispersity is essential for understanding the optical properties of nonspherical particles measured with cavity ring-down spectroscopy. Our combined spectroscopy and microscopy techniques demonstrate a novel method by which cavity ring-down spectroscopy can be extended for the study of more complex aerosol particles. PMID- 23043639 TI - Hand disinfection in a neonatal intensive care unit: continuous electronic monitoring over a one-year period. AB - BACKGROUND: Good hand hygiene compliance is essential to prevent nosocomial infections in healthcare settings. Direct observation of hand hygiene compliance is the gold standard but is time consuming. An electronic dispenser with built-in wireless recording equipment allows continuous monitoring of its usage. The purpose of this study was to monitor the use of alcohol-based hand rub dispensers with a built-in electronic counter in a neonatal intensive care unit (NICU) setting and to determine compliance with hand hygiene protocols by direct observation. METHODS: A one-year observational study was conducted at a 27 bed level III NICU at a university hospital. All healthcare workers employed at the NICU participated in the study. The use of bedside dispensers was continuously monitored and compliance with hand hygiene was determined by random direct observations. RESULTS: A total of 258,436 hand disinfection events were recorded; i.e. a median (interquartile range) of 697 (559-840) per day. The median (interquartile range) number of hand disinfection events performed per healthcare worker during the day, evening, and night shifts was 13.5 (10.8 - 16.7), 19.8 (16.3 - 24.1), and 16.6 (14.2 - 19.3), respectively. In 65.8% of the 1,168 observations of patient contacts requiring hand hygiene, healthcare workers fully complied with the protocol. CONCLUSIONS: We conclude that the electronic devices provide useful information on frequency, time, and location of its use, and also reveal trends in hand disinfection events over time. Direct observations offer essential data on compliance with the hand hygiene protocol. In future research, data generated by the electronic devices can be supplementary used to evaluate the effectiveness of hand hygiene promotion campaigns. PMID- 23043641 TI - Coexistence of Langerhans cell histiocytosis, Rosai-Dorfman disease and splenic lymphoma with fatal outcome after rapid development of histiocytic sarcoma of the liver. AB - The coexistence of skin-limited Langerhans cell histiocytosis (LCH) and Rosai Dorfman disease (RDD) is an exceptional finding. The association of lymphomas and histiocytosis is also infrequent. We report the case of a 68-year-old man which presented an exceptional association of cutaneous LCH and RDD and splenic marginal zone lymphoma. He was stable for few years. Suddenly, the patient was admitted into Hematology Department with a remarkable enlargement of spleen and liver without enlargement of lymphadenopathies or skin lesions flare. He died 24 h later despite treatment with systemic chemotherapy combined with prednisone. Pre-mortem biopsy showed infiltration with histiocytic sarcoma. We think that a transdifferentiation phenomenon could explain our case, although we could not show a clonal relationship between the cutaneous and the liver diseases. We also want to pay attention to the fact that a fast transformation to a more aggressive disease can occur long time after the presentation of the first lesion, a problem that stresses the importance of performing a close and permanent follow-up of these patients. PMID- 23043642 TI - Size-selected subnanometer cluster catalysts on semiconductor nanocrystal films for atomic scale insight into photocatalysis. AB - We introduce size-selected subnanometer cluster catalysts deposited on thin films of colloidal semiconductor nanocrystals as a novel platform to obtain atomic scale insight into photocatalytic generation of solar fuels. Using Pt-cluster decorated CdS nanorod films for photocatalytic hydrogen generation as an example, we determine the minimum amount of catalyst necessary to obtain maximum quantum efficiency of hydrogen generation. Further, we provide evidence for tuning photocatalytic activities by precisely controlling the cluster catalyst size. PMID- 23043643 TI - Identification of a suppressor of retinal degeneration in Drosophila photoreceptors. AB - During sensory transduction, Drosophila photoreceptors experience substantial increases in intracellular Ca(2+) levels ([Ca(2+)](i)). Nevertheless in a number of mutants associated with excessive Ca(2+) influx through transient receptor potential (TRP) channels, Drosophila photoreceptors undergo loss of normal cellular structure manifest as a retinal degeneration. However, the molecular mechanisms that underpin this degeneration process remain unclear. The authors previously isolated a mutant, su(40), that is able to suppress the retinal degeneration seen in photoreceptors from loss-of-function alleles of rdgA that are known to have constitutively active TRP channels. Here the authors report the genetic mapping of su(40) as well the isolation of additional alleles of su(40). Studies of su(40) as well as these new alleles should facilitate the understanding of the mechanisms by which excessive Ca(2+) influx results in retinal degeneration. PMID- 23043645 TI - Color-tunable properties of Eu3+- and Dy3+-codoped Y2O3 phosphor particles. AB - Rare-earth phosphors are commonly used in display panels, security printing, and fluorescent lamps, and have potential applications in lasers and bioimaging. In the present study, Eu3+- and Dy3+-codoped uniform-shaped Y2O3 submicron particles were prepared using the urea homogeneous precipitation method. The structure and morphology of the resulting particles were characterized by X-ray diffraction, field emission scanning electron microscope, and field emission transmission electron microscope, whereas their optical properties were monitored by photoluminescence spectroscopy. The room-temperature luminescence color emission of the synthesized particles can be tuned from red to yellow by switching the excitation wavelength from 254 to 350 nm. The luminescence intensities of red and yellow emissions could be altered by varying the dopant concentration. Strong quenching was observed at high Eu3+ and Dy3+ concentrations in the Y2O3 host lattice. PMID- 23043644 TI - Discrimination between CO and O(2) in heme oxygenase: comparison of static structures and dynamic conformation changes following CO photolysis. AB - Heme oxygenase (HO) catalyzes heme degradation, one of its products being carbon monoxide (CO). It is well known that CO has a higher affinity for heme iron than does molecular oxygen (O(2)); therefore, CO is potentially toxic. Because O(2) is required for the HO reaction, HO must discriminate effectively between CO and O(2) and thus escape product inhibition. Previously, we demonstrated large conformational changes in the heme-HO-1 complex upon CO binding that arise from steric hindrance between CO bound to the heme iron and Gly-139. However, we have not yet identified those changes that are specific to CO binding and do not occur upon O(2) binding. Here we determine the crystal structure of the O(2)-bound form at 1.8 A resolution and reveal the structural changes that are specific to CO binding. Moreover, difference Fourier maps comparing the structures before and after CO photolysis at <160 K clearly show structural changes such as movement of the distal F-helix upon CO photolysis. No such changes are observed upon O(2) photolysis, consistent with the structures of the ligand-free, O(2)-bound, and CO bound forms. Protein motions even at cryogenic temperatures imply that the CO bound heme-HO-1 complex is severely constrained (as in ligand binding to the T state of hemoglobin), indicating that CO binding to the heme-HO-1 complex is specifically inhibited by steric hindrance. The difference Fourier maps also suggest new routes for CO migration. PMID- 23043646 TI - Insights into the role of heme in the mechanism of action of antimalarials. AB - By using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in hemozoin and concomitant increase in toxic free heme in cultured Plasmodium falciparum that is directly correlated with parasite survival. Transmission electron microscopy techniques have further shown that heme is redistributed from the parasite digestive vacuole to the cytoplasm and that CQ disrupts hemozoin crystal growth, resulting in mosaic boundaries in the crystals formed in the parasite. Extension of the cell fractionation study to other drugs has shown that artesunate, amodiaquine, lumefantrine, mefloquine, and quinine, all clinically important antimalarials, also inhibit hemozoin formation in the parasite cell, while the antifolate pyrimethamine and its combination with sulfadoxine do not. This study finally provides direct evidence in support of the hemozoin inhibition hypothesis for the mechanism of action of CQ and shows that other quinoline and related antimalarials inhibit cellular hemozoin formation. PMID- 23043648 TI - Comparative study of liposomes, transfersomes and ethosomes as carriers for improving topical delivery of celecoxib. AB - Topical administration of celecoxib proved to be an effective mean of preventing skin cancer development and improving anticancer drugs effectiveness in skin tumors treatment. The aim of this study was the development of an effective topical formulation of celecoxib, able to promote drug skin delivery, providing its in depth penetration through the skin layers. Three kinds of vesicular formulations have been investigated as drug carriers: liposomes containing a surfactant, or transfersomes and ethosomes, containing suitable edge activators. Firstly, the effect of membrane composition variations on the system performance has been evaluated for each vesicle type. Selected formulations were characterized for particle size, polydispersity index and encapsulation efficiency. The best formulations were subjected to ex vivo permeation studies through excised human skin. All vesicular formulations markedly (p < 0.001) improved the drug amount penetrated into the skin with respect to an aqueous suspension, from 2.0 to 6.5, up to 9.0 folds for liposomes, transfersomes and ethosomes, respectively. In particular, ethosomes containing Tween 20 as edge activator not only showed the best vesicle dimensions and homogeneity, and the highest encapsulation efficacy (54.4%), but also enabled the highest increase in drug penetration through the skin, probably due to the simultaneous presence in their composition of ethanol and Tween 20, both acting as permeation enhancers. Therefore, among the various vesicular formulations examined in the study, Tween 20-ethosomes can be considered the most promising one as carrier for topical celecoxib applications aimed to prevent skin cancer development and increase the anticancer drugs effectiveness against skin tumors. PMID- 23043650 TI - Relics going green. PMID- 23043651 TI - Maintaining a consistent big picture: meaningful use of a Web-based POC EHR system. AB - OBJECTIVE: To test the hypothesis that Hands-on Automated Nursing Data System (HANDS) "big picture summary" can be implemented uniformly across diverse settings, and result in positive registered nurse (RN) and plan of care (POC) data outcomes across time. DESIGN: In a longitudinal, multisite, full test study, a representative convenience sample of eight medical-surgical units from four hospitals (one university, two large community, and one small community) in one Midwestern state implemented the HANDS intervention for 24 (four units) or 12 (four units) months. MEASUREMENTS: (a) RN outcomes-percentage completing training, satisfaction with standardized terminologies, perception of HANDS usefulness, POC submission compliance rate. (b) POC data outcomes-validity (rate of optional changes/episode); reliability of terms and ratings; and volume of standardized data generated. RESULTS: One hundred percent of the RNs who worked on the eight study units successfully completed the required standardized training; all units selected participated for the entire 12- or 24-month designated period; compliance rates for POC entry at every patient hand-off were 78-92%; reliability coefficients for use of the standardized terms and ratings were moderately strong; the pattern of optional POC changes per episode declined but remained reasonable across time; and the nurses generated a database of 40,747 episodes of care. LIMITATIONS: Only RNs and medical-surgical units participated. CONCLUSION: It is possible to effectively standardize the capture and visualization of useful "big picture" healthcare information across diverse settings. Findings offer a viable alternative to the current practice of introducing new health information layers that ultimately increase the complexity and inconsistency of information for frontline users. PMID- 23043652 TI - Methods for establishing the accuracy of clinical indicators in predicting nursing diagnoses. AB - PURPOSE: To describe the methodological stages in determining the accuracy of clinical indicators in identifying nursing diagnoses. DATA SOURCES: Literature review of diagnostic tests. DATA SYNTHESIS: The methodological stages described include concept analysis, content analysis by experts, and accuracy analysis of clinical indicators. CONCLUSIONS: The theory underlying the development of diagnostic tests can be used to evaluate the accuracy of clinical indicators in identifying nursing diagnoses. IMPLICATIONS FOR NURSING PRACTICE: Knowledge of the accuracy characteristics of clinical indicators allows the identification and discrimination of the most suitable nursing diagnoses. PMID- 23043653 TI - Psychometric evaluation of the Functional Health Pattern Assessment Screening Tool (FHPAST). AB - PURPOSE: To report findings of psychometric testing of the Functional Health Pattern Screening Tool (FHPAST). METHODS: Psychometric evaluation including internal consistency and principal components analysis. FINDINGS: The findings indicate that the FHPAST is a reliable, three-component, 57-item valid instrument. CONCLUSIONS: Psychometric testing supports the use of the FHPAST in research. The instrument captures each of the 11 functional health patterns as described by Gordon (1994) and has been translated into, and is available in, several languages. PRACTICE IMPLICATIONS: Continued testing and refinement is needed across populations to support the findings from this investigation and to evaluate the outcomes of patient-centered interventions over time. PMID- 23043654 TI - Measuring elderly care through the use of a nursing conceptual model and the international classification for nursing practice((r)). AB - INTRODUCTION: Nursing models and terminologies can contribute to research the nature of nursing care. AIM: The aim of this study was to describe nursing diagnoses in acute- and long-term elderly care. METHODS: A point prevalence survey was conducted on 240 patients. The International Classification for Nursing Practice was used to describe nursing diagnoses, and a conceptual model was used to categorize them in nursing needs. RESULTS: A total of 2,673 diagnoses were detected. Mean was higher in nursing home than in hospital (t test =-3.688; p = .0003). Prevalent diagnoses were significantly different. DISCUSSION: High complexity, with different issues for nurses, was observed both in acute- and in long-term settings. CONCLUSION: The results could help to comprehend the nature of older persons needs and could contribute to the development of an International Classification for Nursing Practice catalogue for elderly care. PMID- 23043655 TI - Cross-cultural adaptation of the Quality of Diagnoses, Interventions and Outcomes (Q-DIO) instrument into Brazilian Portuguese. AB - PURPOSE: To describe the cross-cultural adaptation of the Quality of Diagnoses, Interventions and Outcomes instrument into Brazilian Portuguese. METHOD: This process entailed translation, synthesis, back-translation, expert committee review, and pretesting. FINDINGS: Six items were altered in the Brazilian version, and the scoring system was changed from a five-point to a three-point Likert-type scale. Pretesting was conducted on a sample of 40 randomly selected nursing records. Overall reliability as measured by Cronbach's alpha was 0.96. CONCLUSIONS: Adaptation resulted in a preliminary version of the instrument. IMPLICATIONS FOR NURSING PRACTICE: Assessment of the psychometric properties of the instrument in a larger sample of nursing records is required, and such a study is underway. PMID- 23043656 TI - A clinical validation study of impaired physical mobility of patients submitted to cardiac catheterization. AB - PURPOSE: To conduct a Fehring model-based clinical validation of the defining characteristics of the nursing diagnosis of impaired physical mobility in a sample of 250 patients. METHOD: Cross-sectional study. FINDINGS: Three of the 11 NANDA-International defining characteristics assessed in this study were validated: limited range of motion, limited ability to perform gross motor skills, and difficulty turning. Although discomfort was not validated due to the rarity of occurrence, there was excellent interrater agreement as to its relevance (kappa coefficient). CONCLUSIONS: In this setting, three characteristics were validated. IMPLICATIONS FOR NURSING PRACTICE: Validation studies are important for advancing evidence-based practice. PMID- 23043657 TI - Software application that evaluates the diagnostic accuracy of nursing students. AB - PURPOSE: Apply the educational software Fuzzy Kitten with undergraduate Brazilian nursing students. METHODS: This software, based on fuzzy logic, generates performance scores that evaluate the ability to identify defining characteristics/risk factors present in clinical cases, relate them with nursing diagnoses, and determine the diagnoses freely or using a decision support model. FINDINGS: There were differences in student performance compared to the year of the course. The time to perform the activity did not present a significant relation to the performance. The students' scores in the diagnoses indicated by the model was superior (p= .01). CONCLUSIONS: The software was able to evaluate the diagnostic accuracy of students. IMPLICATIONS: The software enables an objective evaluation of diagnostic accuracy. PMID- 23043658 TI - Nurse competence: a concept analysis. AB - PURPOSE: The purpose of this analysis was to explore the concept of nurse competence. DATA SOURCES: Data sources include EBSCOhost, Gale PowerSearch, ProQuest, PubMed Medline, Google Scholar, and Online Journal of Issues in Nursing. DATA SYNTHESIS: This paper utilizes Rodgers' evolutionary method to analyze the concept of nurse competence. CONCLUSION: Antecedents to nurse competence include personal and external motivations. Attributes include integrating knowledge into practice, experience, critical thinking, proficient skills, caring, communication, environment, motivation, and professionalism. Consequences include confidence, safe practice, and holistic care. Implications for nursing responsibility regarding defining nurse competence and ensuring nurse competence need to be identified. More research is needed to determine the best evaluation methods for the different facets of nurse competence. PMID- 23043659 TI - Using standardized nursing languages in end-of-life care plans. AB - PURPOSE: This case study demonstrates the challenges to achieve dignified life closure and a comfortable death for a middle-aged woman with terminal cancer and her family. DATA SOURCES: Data were obtained from a patient known through the author's clinical experiences, personal family experiences, and published sources. DATA SYNTHESIS: The appropriate nursing diagnosis, patient outcomes, and nursing interventions were identified through the use of NANDA-International, the Nursing Outcomes Classification, and the Nursing Interventions Classification. CONCLUSIONS: This case study illustrates the appropriate nursing diagnosis, interventions, and outcomes pertinent to an individual with emotional distress at the end of life. IMPLICATIONS FOR NURSING PRACTICE: Employing the NANDA-International standardized nursing diagnosis, the Nursing Interventions Classification and the Nursing Outcomes Classification provided the needed constructs for considering and improving a dying patient's care in a primary and home setting. PMID- 23043660 TI - A systematic review and meta-analysis of studies comparing laparoscopic and open distal pancreatectomy. AB - OBJECTIVES: Currently, laparoscopic distal pancreatectomy (LDP) is regarded as a safe and effective surgical approach for lesions in the body and tail of the pancreas. This review compares outcomes of the laparoscopic technique with those of open distal pancreatectomy (ODP) and assesses the efficacy, safety and feasibility of each type of procedure. METHODS: Comparative studies published between January 1996 and April 2012 were included. Studies were selected based on specific inclusion and exclusion criteria. Evaluated endpoints were operative outcomes, postoperative recovery and postoperative complications. RESULTS: Fifteen non-randomized comparative studies that recruited a total of 1456 patients were analysed. Rates of conversion from LDP to open surgery ranged from 0% to 30%. Patients undergoing LDP had less intraoperative blood loss [weighted mean difference (WMD) -263.36.59 ml, 95% confidence interval (CI) -330.48 to 196.23 ml], fewer blood transfusions [odds ratio (OR) 0.28, 95% CI 0.11-0.76], shorter hospital stay (WMD -4.98 days, 95% CI -7.04 to -2.92 days), a higher rate of splenic preservation (OR 2.98, 95% CI 2.18-3.91), earlier oral intake (WMD 2.63 days, 95% CI -4.23 to 1.03 days) and fewer surgical site infections (OR 0.37, 95% CI 0.18-0.75). However, there were no differences between the two approaches with regard to operation time, time to first flatus and the occurrence of pancreatic fistula and other postoperative complications. CONCLUSIONS: Laparoscopic resection results in improved operative and postoperative outcomes compared with open surgery according to the results of the present meta-analyses. It may be a safe and feasible option for patients with lesions in the body and tail of the pancreas. However, randomized controlled trials should be undertaken to confirm the relevance of these early findings. PMID- 23043662 TI - Inverse relationship between cirrhosis and massive tumours in hepatocellular carcinoma. AB - BACKGROUND: A subset of patients with hepatocellular carcinoma (HCC) present with massive tumours. It is unknown why certain patients develop these massive tumours, and whether this presentation is specific to the underlying viral aetiology or patient demographics such as gender, race and age. METHODS: All patients with HCC at Bellevue Hospital Center, New York from 1998 to 2012 were identified and relevant demographic and clinical information was collected. Computed tomography/magnetic resonance imaging (CT/MRI) images were reviewed and the maximal tumour diameter on axial sections was recorded. Cirrhosis was defined histologically or by radiographical criteria. The two cohorts of massive and non massive HCC were compared. RESULTS: A total of 361 patients with HCC were identified, of which 58 were categorized as having a massive HCC using a 13 cm size cut-off. Univariate and multivariate analysis demonstrated a significant association of massive HCC with age <40 years; hepatitis B or Asian ethnicity; and a lack of cirrhosis or platelet count >100. DISCUSSION: Massive HCC represents a tumour subtype that is associated with young, chronic hepatitis B carriers with non-cirrhotic livers. The clinical implications of this finding are that patients with massive HCC are typically excellent resection candidates barring the presence of gross vascular invasion or distant metastases. PMID- 23043661 TI - Invasive biliary mucinous cystic neoplasm: a review. AB - OBJECTIVES: Biliary mucinous cystic neoplasms (BMCNs) are recently redefined rare liver tumours in which insufficient recognition frequently leads to an incorrect initial or delayed diagnosis. A concise review of the subtle, sometimes non specific, clinical, serologic and radiographic features will allow for a heightened awareness and more comprehensive understanding of these entities. METHODS: Literature relating to the presentation, diagnosis, treatment, pathology and outcomes of BMCNs and published prior to March 2012 was reviewed. RESULTS: Biliary mucinous cystic neoplasms most commonly occur in females (>=60%) in the fifth decade of life. Clinical symptoms, serologic markers and imaging modalities are unreliable for diagnosis of BMCNs, which leads to misdiagnosis in 55-100% of patients. Perioperative cyst aspiration is not recommended as invasive BMCNs can only be differentiated from non-invasive BMCNs by microscopic evaluation for the presence of ovarian-type stroma. Intraoperative biopsy and frozen section(s) are essential to differentiate BMCNs from other cystic liver lesions. The treatment of choice is complete excision and can result in excellent survival with initial correct diagnosis. CONCLUSIONS: A low threshold for considering BMCN in the differential diagnosis of cystic liver lesions and increased attentiveness to its subtle diagnostic characteristics are imperative. The complete surgical resection of BMCNs and the use of appropriate nomenclature are necessary to improve outcomes and accurately define prognosis. PMID- 23043663 TI - Importance of conserving middle hepatic vein distal branches for homogeneous regeneration of the left liver after right hepatectomy. AB - BACKGROUND: Liver regeneration enables repeat surgical procedures to achieve a potential cure in liver cancer patients. However, data regarding segmental regeneration and liver anatomy after liver resection are scarce. This study examined left liver regeneration after right hepatectomy and the impact of hepatic venous drainage on the regeneration of the paramedian sector (Couinaud's segment IV). METHODS: Twenty patients in whom right hepatectomy with conservation of the middle hepatic vein (MHV) on healthy liver had been performed were analysed for segmental volumes and vascular anatomy. Volumetric analysis of left liver segments and three-dimensional MHV reconstruction were conducted using pre- and postoperative computed tomography. The volumetric proportions represented by each segment within the left liver were compared and MHV anatomy was analysed to determine its potential role in the regeneration of left liver segments. RESULTS: After right hepatectomy, the proportion represented by segment IV within the left liver decreases by 13%, whereas the proportion represented by segments II and III increases by 15%. This heterogeneous regeneration is particularly observed in patients in whom a venous branch for segment IVb is sacrificed, leading to an altered outflow similar to that observed in MHV deprivation. The risk for venous branch deprivation in IVb is correlated to the depth of the bifurcation of the MHV in liver parenchyma. CONCLUSIONS: It is crucial to conserve the MHV in its distal part if homogeneous left liver regeneration after right hepatectomy that will allow potential repeat liver resection is to be achieved. PMID- 23043665 TI - Left-sided hepatic resection for hepatolithiasis: a longitudinal study of 110 patients. AB - BACKGROUND: Hepatolithiasis affecting the left hepatobiliary system is common in the Asia Pacific region. This aim of this study was to describe an experience with the diagnosis and treatment of patients with isolated left-sided hepatolithiasis. METHODS: One hundred and ten patients with isolated left-sided hepatolithiasis who underwent a left-sided hepatic resection between January 1999 and February 2010 were included for further analysis. The clinical profile, cholangiograms, operative procedures and early and late results were examined. RESULTS: Analysis of magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) findings revealed left hepatic ductal anatomical details in 101 patients. Three types of left hepatic ductal variations were observed (type 1 in 90.1%, type 2 in 5.9% and type 3 in 4.0% patients). Eighty-four (76.4%) patients had the presence of strictures in the left hepatic ductal system and in 26 (23.6%) patients no strictures could be seen. Out of 84 patients with strictures, 78 could be classified (type I in 89.7% and type II in 10.3%). Of the 110 patients, 75 (68.2%) underwent a left lateral sectionectomy, 33 (30%) a left hepatectomy and 2 (1.8%) patients were treated with a left hepatectomy combined with a caudate lobe resection. Of the patients who underwent a left hepatectomy 11.4% developed a bile leak. Eight per cent of patients who underwent a left lateral sectionectomy had infective complications. During a median follow-up period of 63 (range 3-134) months, 2 (2.1%) patients were discovered to have residual stones and five (5.2%) others possessed recurrent stones. CONCLUSIONS: This study highlights the impact of the presence or absence of bile duct stricture on the clinical and histological profile of patients as well as their operative and the post-operative behaviour. It is concluded that hepatic resection is an appropriate treatment modality in localized left-sided hepatolithiasis. PMID- 23043664 TI - Molecular analysis of Helicobacter pylori virulent-associated genes in hepatobiliary patients. AB - OBJECTIVES: The Helicobacter pylori virulence-associated genes in hepatobiliary patients, including vacA, iceA, babA2, cagA and cagE, have not been reported. The aim of this study was to investigate these genes and the association of those and the clinical outcomes in hepatobiliary diseases. METHODS: Eighty H. pylori-PCR positive cases were obtained from hepatobiliary patients, representing both cholangiocarcinoma (CCA) (n= 58) and cholelithiasis (n= 22). The diversity of virulence genes was examined by polymerase chain reaction and DNA sequencing. Phylogenetic analysis of cagA was determined using the maximum parsimony method. RESULTS: The vacAs1a + c/m1, iceA1 and babA2 genes were the most predominant genotypes in both CCA and cholelithiasis patients. The cagA and cagE genes were found significantly more frequently in patients with CCA than those with cholelithiasis (P < 0.05). The cagA positive samples were the Western-type cagA and showed that almost all of the detected sequences in Thai hepatobiliary and Thai gastric cancer patients were classified in the same cluster but separated from the cluster of Japan and other countries. CONCLUSIONS: The cagA and cagE genes may be associated in the pathogenesis of hepatobiliary diseases, especially of CCA. Besides the bacterial variation, other host factors may be involved in the pathogenesis of hepatobiliary cancer. PMID- 23043666 TI - Gastrointestinal stromal tumour of the duodenum: single institution experience. AB - BACKGROUND: Primary gastrointestinal stromal tumours (GISTs) of the duodenum are rare. The aim of this study was to review the surgical management of GISTs in this anatomically complex region. METHODS: Retrospective review from January 1999 to August 2011 of patients with primary GISTs of the duodenum. RESULTS: Forty-one patients underwent resection of duodenal GISTs. All operations were performed with intent to cure with negative margins of resection. The most common location of origin was the second portion of the duodenum. Local excision (n= 19), segmental resection with primary anastomosis (n= 11) and a pancreatoduodenectomy (n= 11) were performed. Two patients underwent an ampullectomy with local excision. Peri-operative mortality and overall morbidity were 0 and 12, respectively. Patients with high-risk GISTs (P= 0.008) and those who underwent a pancreatoduodenectomy (P= 0.021) were at a greater risk for morbidity. The median follow-up was 18 months. Eight patients developed recurrence. High-risk GISTs and neoplasms with ulceration had the greatest risk for recurrence (P= 0.017, P= 0.029 respectively). The actuarial 3- and 5-year survivals were 85% and 74%, respectively. CONCLUSION: The choice and type of resection depends on the proximity to the ampulla of Vater, involvement of adjacent organs and the ability to obtain negative margins. The morbidity depends on the type of procedure for GIST. PMID- 23043667 TI - Intrahepatic cholangiocarcinoma in a low endemic area: rising incidence and improved survival. AB - BACKGROUND: To explore trends in the incidence and survival of patients with intrahepatic cholangiocarcinoma (ICC) an unselected population in Western Europe was studied. METHODS: Between 1989 and 2009, all patients newly diagnosed with ICC were selected from the Netherlands Cancer Registry (n= 809). Trends in incidence, treatment and relative survival were calculated according to gender and age. Follow-up for vital status was complete until 1st January 2010. RESULTS: The incidence rates of ICC increased significantly between 1999 and 2009, especially in the age group 45-59 years [estimated annual percentage change +3.0%, 95% confidence interval (CI) 0.2-5.8]. In the other age groups ICC incidence remained stable. Patients diagnosed with tumour lymph node metastasis (TNM) stage I mainly underwent surgery (68%), and the majority of the patients with stage II, III and IV received best supportive care (73%). One-year relative survival for patients with ICC increased significantly from 24% in 1989-1994 to 28% in 2005-2009 (P= 0.03), and corresponding 3-year relative survival improved from 4% to 8% (P= 0.02). Three-month and 1-year relative survival for patients with ICC receiving surgery was 91% and 71%, respectively. DISCUSSION: Between 1999 and 2009, the incidence of ICC rose, especially in the age group 45-59 years, suggesting aetiological influences. Survival rates have improved during the study period. PMID- 23043668 TI - Staged hepatectomy for bilobar colorectal hepatic metastases. AB - OBJECTIVES: This study describes the management of patients with bilobar colorectal liver metastases (CRLM). METHODS: A retrospective collection of data on all patients with CRLM who were considered for staged resection (n= 85) from January 2003 to January 2011 was performed. Patients who underwent one hepatic resection were considered to have had a failed staged resection (FSR), whereas those who underwent a second or third hepatic resection to produce a cure were considered to have had a successful staged resection (SSR). Survival was calculated from the date of diagnosis of liver metastases. Complete follow-up and dates of death were obtained from the Government of Quebec population database. RESULTS: Median survival was 46 months (range: 30-62 months) in the SSR group and 22 months (range: 19-29 months) in the FSR group. Rates of 5-year survival were 42% and 4% in the SSR and FSR groups, respectively. Fifteen of the 19 patients who remained alive at the last follow-up date belonged to the SSR group. CONCLUSIONS: In patients in whom staged resection for bilobar CRLM is feasible, surgery would appear to offer benefit. PMID- 23043670 TI - Psychometric validation of Emotional Reaction Instrument-English to measure American children's emotional responses to hospitalisation. AB - AIMS AND OBJECTIVES: The aim of this study was to test the initial psychometric properties of the Emotional Reactions Instrument-English with hospitalised American children, ages 7-12 years, in the USA. BACKGROUND: Children's negative emotional responses have been a subject of concern for paediatric clinicians and researchers, especially because negative emotional responses following or during hospitalisation are associated with adverse patient outcomes. Existing self report paediatric instruments have a number of limitations including lack of clinical feasibility and psychometric evidence. DESIGN: A survey and psychometric approach was used to test initial reliability and validity of the Emotional Reactions Instrument-ENGLISH. METHODS: Two hundred hospitalised American children, 7-12 years of age, who were admitted to a Children's Hospital in the USA were recruited for this study. The children were administered the Emotional Reactions Instrument-English, the Facial Affective Scale, and a demographic form. RESULTS: Internal consistency was supported by a Cronbach's alpha of 0.83 for the total scale. Alpha coefficients for subscales ranged from 0.59-0.82. Construct validity was tested with exploratory factor analysis. Through principal component analysis, four factors were identified that explained 64% of the variance. Concurrent validity was supported by most items in the Emotional Reactions Instrument-English being significantly correlated with the Facial Affective Scale (r = 0.18-0.59). The instrument can be administered to hospitalised children in 5 10 minutes. CONCLUSIONS: The results of this exploratory study provide initial support for the psychometric adequacy of the Emotional Reactions Instrument English with hospitalised American children ages 7-12 years. Further testing of the Emotional Reactions Instrument-English is required to validate the subscales and evaluate the instrument's use with children of different ages, race and ethnicity. RELEVANCE TO CLINICAL PRACTICE: This study introduces a new, clinically feasible instrument to measure children's diverse emotional responses to hospitalisation. PMID- 23043671 TI - Evaluating health worker performance in Benin using the simulated client method with real children. AB - BACKGROUND: The simulated client (SC) method for evaluating health worker performance utilizes surveyors who pose as patients to make surreptitious observations during consultations. Compared to conspicuous observation (CO) by surveyors, which is commonly done in developing countries, SC data better reflect usual health worker practices. This information is important because CO can cause performance to be better than usual. Despite this advantage of SCs, the method's full potential has not been realized for evaluating performance for pediatric illnesses because real children have not been utilized as SCs. Previous SC studies used scenarios of ill children that were not actually brought to health workers. During a trial that evaluated a quality improvement intervention in Benin (the Integrated Management of Childhood Illness [IMCI] strategy), we conducted an SC survey with adult caretakers as surveyors and real children to evaluate the feasibility of this approach and used the results to assess the validity of CO. METHODS: We conducted an SC survey and a CO survey (one right after the other) of health workers in the same 55 health facilities. A detailed description of the SC survey process was produced. Results of the two surveys were compared for 27 performance indicators using logistic regression modeling. RESULTS: SC and CO surveyors observed 54 and 185 consultations, respectively. No serious problems occurred during the SC survey. Performance levels measured by CO were moderately higher than those measured by SCs (median CO - SC difference = 16.4 percentage-points). Survey differences were sometimes much greater for IMCI trained health workers (median difference = 29.7 percentage-points) than for workers without IMCI training (median difference = 3.1 percentage-points). CONCLUSION: SC surveys can be done safely with real children if appropriate precautions are taken. CO can introduce moderately large positive biases, and these biases might be greater for health workers exposed to quality improvement interventions. TRIAL NUMBER: http://clinicaltrials.gov Identifier NCT00510679. PMID- 23043672 TI - Light, polarizing, and transmission electron microscopy: three methods for the evaluation of sperm quality. AB - Semen from 33 patients were evaluated by light microscopy (LM) obtaining sperm concentration, percent motility, percentage of sperm with normal morphology (PAP staining), and percentage of dead sperm (Eosin Y stained). The samples were observed by polarizing microscopy (PM), that evaluates sperm morphology and the viability by birefringence of organelles, and it provides a PM index (percentage of birefringent, viable, motile sperm) and a percentage of dead, non-birefringent sperm. Sperm were processed for transmission electron microscopy (TEM) and TEM data were elaborated with a mathematical formula able to provide a fertility index (FI, number of sperm free of structural defects) and percentages of sperm immaturity and necrosis (dead sperm). To test the reliability of these techniques, the values of normal acrosome, nucleus, midpiece, and tail and the presence of cytoplasmic residues obtained with the three methods were compared. With the exception of cytoplasmic residues (P = 0.40), significant differences in the evaluation of each organelle were observed and TEM analysis resulted as the most stringent screening. In addition, relationships among relevant sperm variables were investigated. Motility showed positive correlations with the percentage of normal tail, midpiece, and PM index (P < 0.01), but it exhibited negative correlations with indices of sperm death (non-birefringent sperm: P < 0.05; percentage of eosin Y stained sperm: P < 0.05; necrosis: P < 0.01), which were positively correlated with each other (P < 0.01). Positive correlations were found between indices expressing normal sperm morphology: FI with PM index (P < 0.01) and with the percentage of normal sperm (PAP staining) (P < 0.01), which in turn were correlated with the PM index (P < 0.001). Sperm immaturity showed positive correlations (P < 0.01) with the presence of cytoplasmic residues detected with the three methods. In conclusion, LM, PM, and TEM are reliable techniques in evaluating sperm quality. PM appears to offer several advantages 'midway' between LM and TEM and it should be considered in sperm analysis. PMID- 23043673 TI - A repository based on a dynamically extensible data model supporting multidisciplinary research in neuroscience. AB - BACKGROUND: Robust, extensible and distributed databases integrating clinical, imaging and molecular data represent a substantial challenge for modern neuroscience. It is even more difficult to provide extensible software environments able to effectively target the rapidly changing data requirements and structures of research experiments. There is an increasing request from the neuroscience community for software tools addressing technical challenges about: (i) supporting researchers in the medical field to carry out data analysis using integrated bioinformatics services and tools; (ii) handling multimodal/multiscale data and metadata, enabling the injection of several different data types according to structured schemas; (iii) providing high extensibility, in order to address different requirements deriving from a large variety of applications simply through a user runtime configuration. METHODS: A dynamically extensible data structure supporting collaborative multidisciplinary research projects in neuroscience has been defined and implemented. We have considered extensibility issues from two different points of view. First, the improvement of data flexibility has been taken into account. This has been done through the development of a methodology for the dynamic creation and use of data types and related metadata, based on the definition of "meta" data model. This way, users are not constrainted to a set of predefined data and the model can be easily extensible and applicable to different contexts. Second, users have been enabled to easily customize and extend the experimental procedures in order to track each step of acquisition or analysis. This has been achieved through a process-event data structure, a multipurpose taxonomic schema composed by two generic main objects: events and processes. Then, a repository has been built based on such data model and structure, and deployed on distributed resources thanks to a Grid based approach. Finally, data integration aspects have been addressed by providing the repository application with an efficient dynamic interface designed to enable the user to both easily query the data depending on defined datatypes and view all the data of every patient in an integrated and simple way. RESULTS: The results of our work have been twofold. First, a dynamically extensible data model has been implemented and tested based on a "meta" data-model enabling users to define their own data types independently from the application context. This data model has allowed users to dynamically include additional data types without the need of rebuilding the underlying database. Then a complex process-event data structure has been built, based on this data model, describing patient-centered diagnostic processes and merging information from data and metadata. Second, a repository implementing such a data structure has been deployed on a distributed Data Grid in order to provide scalability both in terms of data input and data storage and to exploit distributed data and computational approaches in order to share resources more efficiently. Moreover, data managing has been made possible through a friendly web interface. The driving principle of not being forced to preconfigured data types has been satisfied. It is up to users to dynamically configure the data model for the given experiment or data acquisition program, thus making it potentially suitable for customized applications. CONCLUSIONS: Based on such repository, data managing has been made possible through a friendly web interface. The driving principle of not being forced to preconfigured data types has been satisfied. It is up to users to dynamically configure the data model for the given experiment or data acquisition program, thus making it potentially suitable for customized applications. PMID- 23043674 TI - Modeling autism: a systems biology approach. AB - Autism is the fastest growing developmental disorder in the world today. The prevalence of autism in the US has risen from 1 in 2500 in 1970 to 1 in 88 children today. People with autism present with repetitive movements and with social and communication impairments. These impairments can range from mild to profound. The estimated total lifetime societal cost of caring for one individual with autism is $3.2 million US dollars. With the rapid growth in this disorder and the great expense of caring for those with autism, it is imperative for both individuals and society that techniques be developed to model and understand autism. There is increasing evidence that those individuals diagnosed with autism present with highly diverse set of abnormalities affecting multiple systems of the body. To this date, little to no work has been done using a whole body systems biology approach to model the characteristics of this disorder. Identification and modelling of these systems might lead to new and improved treatment protocols, better diagnosis and treatment of the affected systems, which might lead to improved quality of life by themselves, and, in addition, might also help the core symptoms of autism due to the potential interconnections between the brain and nervous system with all these other systems being modeled. This paper first reviews research which shows that autism impacts many systems in the body, including the metabolic, mitochondrial, immunological, gastrointestinal and the neurological. These systems interact in complex and highly interdependent ways. Many of these disturbances have effects in most of the systems of the body. In particular, clinical evidence exists for increased oxidative stress, inflammation, and immune and mitochondrial dysfunction which can affect almost every cell in the body. Three promising research areas are discussed, hierarchical, subgroup analysis and modeling over time. This paper reviews some of the systems disturbed in autism and suggests several systems biology research areas. Autism poses a rich test bed for systems biology modeling techniques. PMID- 23043676 TI - Evaluation of maxillary sinus width on cone-beam computed tomography for sinus augmentation and new sinus classification based on sinus width. AB - PURPOSE: The degree of difficulty in performing lateral window sinus augmentation may depend on the morphology of the maxillary sinus. The aim of this was to measure the distances between the medial and lateral sinus wall (sinus width [SW]) at different levels and apply those SW values to formulate a new sinus classification. MATERIALS AND METHODS: Edentulous sites adjacent to maxillary sinuses with inadequate ridge height (RH; <10 mm) were included from cone-beam computed tomography database in the University of Michigan. SW was measured at the heights of 5, 7, 10, 13, and 15 mm from alveolar crest at the edentulous sites. Mean SW was stratified by residual RH into three different groups (group 1: <4 mm, group 2: >=4 and <7, and group 3: >=7 and <10), study sites (first and second premolars and molars), and measurement levels. RESULTS: Three hundred and twenty subjects (mean 50.1 years old) with 422 edentulous sites were included. Mean SW was wider at molar sites, higher measurement levels, and sites with shorter residual RH. Mean SW at the lower (average 2.3 mm from sinus floor) and higher boundary (15 mm from the alveolar crest) of lateral window osteotomy was 9.0 (2.8) and 16.0 (4.4) mm, respectively. Narrow, average, or wide sinuses were classified when the SW was <8, 8-10 and >10 mm at the lower boundary or <14, 14 17 and >17 mm at the upper boundary, respectively. CONCLUSION: SW at levels that were relevant to lateral window sinus augmentation was measured. The proposed sinus classification could facilitate communication between health providers and determine the degree of easiness of sinus augmentation. It might be particularly useful for the selection of grafting materials and surgical approaches. Further studies are required to test its clinical implications. PMID- 23043677 TI - Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. PMID- 23043675 TI - The monoacylglycerol lipase inhibitor JZL184 attenuates LPS-induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action. AB - BACKGROUND AND PURPOSE: JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme that preferentially catabolizes the endocannabinoid 2 arachidonoyl glycerol (2-AG). Here, we have studied the effects of JZL184 on inflammatory cytokines in the brain and plasma following an acute immune challenge and the underlying receptor and molecular mechanisms involved. EXPERIMENTAL APPROACH: JZL184 and/or the CB1 receptor antagonist, AM251 or the CB2 receptor antagonist, AM630 were administered to rats 30 min before lipopolysaccharide (LPS). 2 h later cytokine expression and levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen. KEY RESULTS: JZL184 attenuated LPS-induced increases in IL-1beta, IL-6, TNF-alpha and IL-10 but not the expression of the inhibitor of NFkB (IkappaBalpha) in rat frontal cortex. AM251 attenuated JZL184 induced decreases in frontal cortical IL-1beta expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE2 and PGD2 were unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184. In plasma, LPS induced increases in TNF-alpha and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1beta in the presence, but not absence, of JZL184. CONCLUSION AND IMPLICATIONS: Inhibition of peripheral MAGL in rats by JZL184 suppressed LPS-induced circulating cytokines that in turn may modulate central cytokine expression. The data provide further evidence for the endocannabinoid system as a therapeutic target in treatment of central and peripheral inflammatory disorders. PMID- 23043678 TI - Indoor particle levels in small- and medium-sized commercial buildings in California. AB - This study monitored indoor and outdoor particle concentrations in 37 small and medium commercial buildings (SMCBs) in California with three buildings sampled on two occasions, resulting in 40 sampling days. Sampled buildings included offices, retail establishments, restaurants, dental offices, and hair salons, among others. Continuous measurements were made for both ultrafine and fine particulate matter as well as black carbon inside and outside of the building. Integrated PM(2.5), PM(2.5-10), and PM(10) samples were also collected inside and outside the building. The majority of the buildings had indoor/outdoor (I/O) particle concentration ratios less than 1.0, indicating that contributions from indoor sources are less than removal of outdoor particles. However, some of the buildings had I/O ratios greater than 1, indicating significant indoor particle sources. This was particularly true of restaurants, hair salons, and dental offices. The infiltration factor was estimated from a regression analysis of indoor and outdoor concentrations for each particle size fraction, finding lower values for ultrafine and coarse particles than for submicrometer particles, as expected. The I/O ratio of black carbon was used as a relative measure of the infiltration factor of particles among buildings, with a geometric mean of 0.62. The contribution of indoor sources to indoor particle levels was estimated for each building. PMID- 23043679 TI - Atmospheric solid analysis probe-ion mobility mass spectrometry of polypropylene. AB - Polyolefin, including polypropylene (PP), constitutes an important class of materials. In particular, the recent interest in recycling plastic wastes necessitates their characterization as well as their degradation mechanism being understood. PP materials characterization by mass spectrometry, including polymer and additives parts, is not direct and generally involves a pyrolysis step to produce ionizable species. In this study, we extended the use of atmospheric solid analysis probe (ASAP) in combination with traveling wave ion mobility mass spectrometry (TWIM-MS) for the characterization of PP materials, including polymer as well as additives. Different commercial PP samples, from polymer standard to plastic item, were studied. The use of ASAP allow analysis to be done without any sample preparation, while TWIM-MS permitted a clear separation of polymer ions and additive signals. Several series of polymer pyrolysis residues, similar to those produced by classic pyrolysis, were obtained. Moreover, additive characterization has been done and supported by accurate mass measurements and tandem mass spectrometry experiments. Finally, this strategy put in evidence the role of additives in polymer degradation. PMID- 23043680 TI - Preclinical pharmacological profile of nomegestrol acetate, a synthetic 19-nor progesterone derivative. AB - BACKGROUND: Nomegestrol acetate (NOMAC), a synthetic progestogen derived from 19 nor-progesterone, recently completed clinical trials for use with 17beta estradiol in a new monophasic combined oral contraceptive. In this review, published as well as previously unpublished preclinical studies that detail the effects of NOMAC on estrogenic, progestogenic, and androgenic systems, as well as mineralocorticoid, glucocorticoid, bone, and metabolic indices are described. METHODS: In vitro assays to determine NOMAC structure-activity relationships used tissue derived from rat uteri. Transactivation profiles were performed using Chinese hamster ovary (CHO) cells transfected with cDNAs encoding human steroid receptors. Estrogenic and anti-estrogenic activities were monitored in vivo in rats as well as in vitro in human breast cancer cells. Standard in vivo techniques were used in rats to determine progestational activity; antigonadotropic, androgenic, mineralocorticoid, and glucocorticoid activities; as well as effects on bone and other metabolic indices. Ovulation inhibition was monitored in rats and primates. NOMAC's effects on cardiovascular systems were determined in dogs and primates. RESULTS: NOMAC was without significant agonistic or antagonistic activity for estrogen receptor alpha or beta in vitro, and inhibited ovulation in rats and monkeys (2.5 mg/kg and 1 mg/kg, respectively). NOMAC lacked androgenic, antimineralocorticoid, glucocorticoid, and metabolic activity and exhibited moderate anti-androgenic activity in rats. NOMAC did not affect bone mineral density (BMD) in rats or hemodynamic and electrophysiologic parameters in dogs and primates. CONCLUSIONS: NOMAC is a selective progestogen structurally similar to progesterone that has modest anti-androgenic activity and does not affect lipid or carbohydrate metabolism, BMD, or many cardiovascular parameters in selected animal models. PMID- 23043681 TI - Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. AB - OBJECTIVE: To test whether the combined use of total plasma/serum bilirubin (TSB) levels and clinical risk factors more accurately identifies infants who receive phototherapy than does the use of either method alone. STUDY DESIGN: We recruited healthy infants of >=35 weeks' gestation at 6 centers that practiced universal predischarge TSB screening. Transcutaneous bilirubin (TcB) was measured at 24 hours, with TSB at 24-60 hours and at 3- to 5- and 7- to 14-day follow-up visits. Clinical risk factors were identified systematically. RESULTS: Of 1157 infants, 1060 (92%) completed follow-up, and 982 (85%) had complete datasets for analysis. Infant characteristics included 25% were nonwhite and 55% were Hispanic/Latino; >90% were breastfed. During the first week, jaundice was documented in 84% of subjects. Predischarge TSB identified the 41 (4.2%) and 34 (3.5%) infants who received phototherapy before and after discharge, respectively. Prediction of postdischarge phototherapy was similar for combined clinical risk factors (earlier gestational age [GA], bruising, positive direct antiglobulin test, Asian race, exclusive breastfeeding, blood type incompatibility, jaundice extent) and age-adjusted TSB (area under the curve [AUC] = .86 vs .87), but combined screening was better (AUC = .95). TcB/TSB combined with GA alone was equally predictive (AUC = .95; 95% CI .93-.97). CONCLUSIONS: Jaundice is present in 4 of 5 (84%) healthy newborns. Predischarge TcB/TSB (adjusted for postnatal age) combined with specific clinical factors (especially GA) best predicts subsequent phototherapy use. Universal implementation of this strategy in the US should improve outcomes of healthy newborns discharged early. PMID- 23043682 TI - Newborn radiographic clues for undiagnosed posterior urethral valves. PMID- 23043683 TI - Vitamin D does not improve the metabolic health of patients with chronic kidney disease stage 3-4: a randomized controlled trial. AB - AIM: To assess the impact of vitamin D supplementation (cholecalciferol) on the insulin sensitivity and metabolic health of patients with chronic kidney disease (CKD). METHODS: Twenty-eight adult patients with CKD stages 3-4 were recruited from the outpatient department of the Princess Alexandra Hospital (Brisbane, Australia) to a double-blind randomized trial of cholecalciferol (vitamin D3) 2000 IU/day or placebo for 6 months. Metabolic parameters at baseline were compared with 20 non-CKD adults. The primary outcome was an improvement in insulin resistance (glucose disposal rate, GDR) at 6 months (quantified by hyperinsulinaemic euglycaemic clamp). Carbohydrate and lipid oxidation rates were assessed by indirect calorimetry. RESULTS: At baseline, patients were significantly insulin-resistant compared with lean younger non-CKD individuals (n = 9; GDR 3.42 vs. 5.76 mg/kg per minute, P = 0.001), but comparable with their age-, gender- and weight-matched non-CKD counterparts (n = 11; 3.42 vs. 3.98 mg/kg per minute, P = 0.4). 25-Hydroxyvitamin D did not change in the placebo group, but rose from 95 +/- 37 to 146 +/- 25 nmol/L with treatment (P = 0.0001). Post treatment, there was no difference in GDR between groups (GDR 3.38 vs. 3.52 mg/kg per minute, ancova P = 0.4). There was a relative increase in hyperinsulinaemic oxidative disposal of glucose with treatment (within-group P = 0.03). CONCLUSION: Supplementation with cholecalciferol in CKD 3-4 results in appreciable increases in 25-hydroxyvitamin D concentrations, but does not increase insulin sensitivity. The insulin resistance observed was similar among age-, sex- and body mass index-matched individuals with and without CKD. Whether renal dysfunction per se has any influence on the insulin sensitivity of an individual should be the subject of future work. PMID- 23043684 TI - Laparoscopic excision of endometriomas and ovarian reserve. PMID- 23043685 TI - Differential expression of G-protein-coupled estrogen receptor-30 in human myometrial and uterine leiomyoma smooth muscle. AB - OBJECTIVE: To determine differential expression of G-protein-coupled receptor 30 (GPR30) in uterine leiomyoma and its matched myometrium. DESIGN: GPR30 expression examined in both tissues and cultured cells. SETTING: Research laboratories. PATIENT(S): Women 35 to 50 years old with uterine leiomyomas. INTERVENTION(S): Hysterectomy. MAIN OUTCOME MEASURE(S): GPR30 expression profile. RESULT(S): Using Western blot and real-time quantitative polymerase chain reaction analyses, we found that GPR30 was highly expressed in uterine leiomyomas compared with their matched myometrium. In only three out of nine patients examined was GPR30 protein detectable by Western blot analysis in myometrial tissues, but at statistically significantly lower levels than in their leiomyomas. Confocal microscopy revealed the nuclear localization of GPR30 in leiomyoma tissues and cultured leiomyoma smooth muscle cells (SMCs). Treatment with 0.1 MUM 17beta-estradiol increased mRNA expression of GPR30 in leiomyoma SMCs but decreased expression in myometrial SMCs. Treatment with G-1, a GPR30 agonist, stimulated phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) in both SMC types. PD98059, the MEK inhibitor, completely inhibited G-1-induced phosphorylation of p44/42 in myometrium SMCs, but not in SMCs from leiomyoma. CONCLUSION(S): GPR30 is abundantly expressed in uterine leiomyomas, likely resulting from estrogen stimulation. PMID- 23043687 TI - Reply of the authors. PMID- 23043686 TI - Association, prevalence, and clearance of human papillomavirus and antisperm antibodies in infected semen samples from infertile patients. AB - OBJECTIVE: To evaluate prevalence, association, and clearance of human papillomavirus (HPV) and antisperm antibodies (ASAs) in infected semen samples from infertile patients. DESIGN: Cross-sectional clinical study. SETTING: Andrology and microbiology sections at a university hospital. PATIENT(S): Three groups of subjects: 61 infertile patients with HPV semen infection, 104 noninfected infertile subjects, and 92 control subjects. INTERVENTION(S): Semen analysis, spermMar test, fluorescence in situ hybridization for sperm aneuploidy and for HPV, and immunofluorescence for HPV 16-L1 and immunoglobulins (IgA, IgG, and IgM) determination. MAIN OUTCOME MEASURE(S): Association of sperm procedures, HPV sperm infection, sperm aneuploidies, and sperm ASAs. RESULT(S): Infertile patients with HPV semen infection showed high percentages of ASAs. In these patients HPV sperm infection was associated with lower sperm motility, which was worse in subjects with ASAs. No alterations of sperm chromosomes were observed. To obtain a significant clearance of both HPV sperm infection and ASAs at least 24 months of follow-up were needed. CONCLUSION(S): Human papillomavirus has been recently suggested to have an important role in male infertility. This study demonstrated that HPV sperm infection can be long lasting and frequently associated with ASAs that may further reduce male fertility. Infertile patients with positive spermMar test results should be considered for investigation for HPV, especially if they are candidates for assisted reproduction. PMID- 23043688 TI - Number and sequence of preceding miscarriages and maternal age for the prediction of antiphospholipid syndrome in women with recurrent miscarriage. AB - OBJECTIVE: To investigate the relationship between the number and sequence of preceding miscarriages and antiphospholipid syndrome (APS). DESIGN: Retrospective cohort study. SETTING: Recurrent miscarriage (RM) clinic. PATIENT(S): Women who attended the RM clinic from 1988 to 2006. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Number, type, and sequence of previous pregnancies were compared between women with APS and women with unexplained RM. RESULT(S): A total of 1,719 patients were included; 312 (18%) had APS, and 1,407 (82%) had unexplained RM. The mean maternal age (32.6 years) did not differ between women with and without APS. The median number of miscarriages was three in both groups. A total of 865 women (50%) had a history of at least one live birth, with no difference between the two groups. In both groups, 97% of the women had a history of consecutive miscarriages. CONCLUSION(S): The number of preceding miscarriage, type and sequence of previous pregnancies, and maternal age were not associated with APS in women with RM. There is no increased diagnostic yield for APS after three miscarriages rather than after two miscarriages and no increased diagnostic yield for APS after consecutive miscarriages rather than after nonconsecutive miscarriages. Therefore, APS testing should be considered for all women with two or more miscarriages. PMID- 23043689 TI - Proteomics of the human endometrium and uterine fluid: a pathway to biomarker discovery. AB - Failure of the endometrium to achieve receptivity results in infertility, and it is also a rate-limiting step in in vitro fertilization (IVF) success. The microenvironments provided by the endometrium during the receptive phase and that support implantation are highly complex and constantly changing as implantation progresses. Although a number of gene array studies have defined mRNA changes across the cycle, with infertility, and in IVF cycles, these have not generally been informative due in part to the subsequent regulation of transcription and posttranslational modifications of the proteins. State-of-the-art proteomic technologies now enable analysis of changes in the endometrium and its secretome related to cycle phase and associated with infertility. These techniques include two-dimensional differential in-gel electrophoresis, isobaric tags for relative and absolute quantitation, and multiplex analyses of selected panels of markers. Subsequent definition of cellular location, timing of production of identified proteins, and their regulation by steroid hormones and blastocyst-derived factors provide indications of their functions and their relationship to the establishment of pregnancy. Proteins discovered by proteomic analyses and fully evaluated will provide the differentiative profiles necessary to inform clinical practice and serve as an end point for optimizing stimulation cycles in IVF clinics as well as more clearly defining the molecular mechanisms underlying successful implantation. PMID- 23043690 TI - Reduced versus nonreduced twin pregnancies: obstetric performance in a cohort of interventional conceptions. AB - OBJECTIVE: To describe the obstetric performance of a selected population of twin pregnancies, comparing reduced vs. nonreduced twin pregnancies after the successful completion of the 12th week. DESIGN: Prospective cohort study. SETTING: Outpatient fertility center. PATIENT(S): A cohort of 464 twin pregnancies including both ovulation induction and assisted reproductive technology pregnancies. INTERVENTION(S): Fetal reduction. MAIN OUTCOME MEASURE(S): Pregnancy outcome and prematurity rate. RESULT(S): The study group included a cohort of 464 twin pregnancies in a single outpatient fertility center: 70 cases of twin pregnancies after a reduction procedure (15.1%) and 394 cases of nonreduced twins (84.9%). Of the nonreduced twin pregnancies, 8.6% went through an abortion, as compared with 4.3% in the reduced group. Mean age at delivery was also comparable between the two groups (35.8 weeks in the reduced group, 35.6 weeks in the nonreduced group), as was the rate of severe prematurity (3.3% in the nonreduced group, 2.9% in the reduced group). CONCLUSION(S): Our work supports a lack of causative relationship between fetal reduction and pregnancy endpoint. PMID- 23043691 TI - State-related alterations of gene expression in bipolar disorder: a systematic review. AB - OBJECTIVE: Alterations in gene expression in bipolar disorder have been found in numerous studies. It is unclear whether such alterations are related to specific mood states. As a biphasic disorder, mood state-related alterations in gene expression have the potential to point to markers of disease activity, and trait related alterations might indicate vulnerability pathways. This review therefore evaluated the evidence for whether gene expression in bipolar disorder is state or trait related. METHODS: A systematic review, using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline for reporting systematic reviews, based on comprehensive database searches for studies on gene expression in patients with bipolar disorder in specific mood states, was conducted. We searched Medline, Embase, PsycINFO, and The Cochrane Library, supplemented by manually searching reference lists from retrieved publications. RESULTS: A total of 17 studies were included, comprising 565 patients and 418 control individuals. Six studies evaluated intraindividual alterations in gene expression across mood states. Two of five studies found evidence of intraindividual alterations in gene expression between a depressed state and a euthymic state. No studies evaluated intraindividual differences in gene expression between a manic state and a euthymic state, while only one case study evaluated differences between a manic state and a depressed state, finding altered expression in seven genes. No study investigated intraindividual variations in gene expression between a euthymic state and multiple states of various polarities (depressive, manic, hypomanic). Intraindividual alterations in expression of the same genes were not investigated across studies. Only one gene (the brain-derived neurotrophic factor gene; BDNF) was investigated across multiple studies, showing no alteration between bipolar disorder patients and control individuals. CONCLUSIONS: There is evidence of some genes exhibiting state-related alterations in expression in bipolar disorder; however, this finding is limited by the lack of replication across studies. Further prospective studies are warranted, measuring gene expression in various affective phases, allowing for assessment of intraindividual differences. PMID- 23043692 TI - Endogenous cytokinin and auxin profiles during in vitro organogenesis from vegetative buds of Pinus radiata adult trees. AB - In Pinus radiata D. Don, the transition from the juvenile to the mature phase is characterized by a reduction in the tree's organogenic potential, which is usually reverted in breeding programs by reinvigoration procedures to enable vegetative propagation. In this work, we have determined the best culture conditions for in vitro reinvigoration of radiata pine buds, tested different cytokinin (CK) types [N6-benzyladenine (BA), meta-topolin (mT) and trans-zeatin] and concentrations (25 and 50 uM), and studied the effect of culture conditions on endogenous CK and indole-3-acetic acid (IAA) levels at different stages of the organogenic process. To this end, the levels of 43 CKs and IAA were determined in P. radiata buds before and during the reinvigoration process. When BA or mT was applied to the induction medium, we did not observe any significant increase or decrease in endogenous isoprenoid CK content. We also report for the first time the presence of O-glucosides in non-treated P. radiata explants from the field and remark the importance of O-glucosides as storage forms. PMID- 23043693 TI - [Public health law]. PMID- 23043694 TI - [The COPSOQ: a new French questionnaire for psychosocial risk assessment]. AB - The purpose of this study was to validate the French version of the Copenhagen Psychosocial Questionnaire (COPSOQ). The COPSOQ is used to assess psychosocial risk factors at work. The current French version comprises 46 items grouped in 24 scales and referring to six dimensions. The questionnaire was administered to 3,166 employees of a large French company based in ten cities of the Paris region and the provinces. The psychometric analyses (internal consistency analysis, exploratory and confirmatory factor analysis and concurrent validity analysis) were satisfactory and demonstrated the validity of the French version of the COPSOQ. Large amounts of data are currently being collected with a view to making comparisons between occupations and between different types of companies. PMID- 23043695 TI - [Risk perception of the general public of cell phone towers and cancer: trend and associated factors, 2005-2010]. AB - The purpose of this study was to assess risk perception related to living near a cell phone tower based on data from two national telephone surveys conducted in France in 2005 and 2010. In 2005, 48.5% of French people aged 16-75 years considered that living near a cell phone tower increases the risk of cancer, compared to 68.9% in 2010. In addition, the number of ?don't know' responses decreased. The increase in risk perception was far greater than the increase in perceptions related to other potential environmental factors of cancer (nuclear power plant, air pollution, chemically-treated food). In 2005, the perceived risk of cancer due to exposure to cell phone tower radiation was correlated to gender, level of income, size of town and sensitivity to other environmental causes of cancer. However, these correlations were weaker in 2010. This risk perception may reflect non-specific fears and a lack of trust in the authorities, but is also rooted in a local context. PMID- 23043696 TI - [Smoking in public middle schools in Casablanca]. AB - The transition period between elementary and middle school is a high-risk period for smoking initiation. Hence the importance of primary prevention programs in adolescent populations. The development and implementation of appropriate preventive measures requires information on tobacco use among adolescents. The objective of this study was to estimate the prevalence of smoking among middle school students in Casablanca and to describe associated drug use. A cross sectional study was conducted in 2010 in six colleges (middle schools) in Casablanca. The average age of the students was 16.3 years (SD = 2.1). 55% of the students were female. Overall smoking prevalence was 7.5% (CI 95% = 5.5% - 10.1%) ? 11.4% among boys and 4.6% among girls. 52.5% of the smokers began smoking between the ages of 14 and 18. The reasons for smoking included smoking as a way of escaping from problems (30%), relaxation (16%) and experience (7%). Smoking behavior was associated with drug use in 23.3% of smokers, compared to 0.6% among non-smokers (p < 10?3). These results suggest the need for prevention measures aimed at strengthening tobacco control policies in schools and other gathering places for young people. PMID- 23043697 TI - [The National Health Agency: the challenge of a unified national program rejecting technocratic and centralized approaches]. AB - The creation of Regional Health Agencies precipitated the need for an overhaul of national health policy management. The National Steering Committee created as part of the HPST law is only a step in the right direction. We need to go beyond the coordination of national policy-makers in order to develop and implement an effective health policy. The creation of a National Health Agency (ANS) is generally considered to be the best way to develop a national steering mechanism capable of developing and implementing a global health policy. The purpose of this new body is not to act as a "super health agency" encompassing all existing health agencies. Rather, the ANS should aim to be an instrument of regulation acting on health care organization and funding and the quality and effectiveness of health care practices. In this sense, its role is to bring together state services and National health insurance services. However, there are two different conceptions of the agency's role ? as an autonomous technical entity based on the current model of the CNAMTS or as a body under the authority of the Ministry of Health. In both cases, the ANS may serve to increase the emphasis on technocratic and centralized approaches to health management. An intermediate solution between the ANS and the current status quo would involve increasing the authority of the Secretary-General of the Social Ministries over the central bodies of the Ministry of Health, the National health insurance services and the National Solidarity Fund for Autonomy. As part of this mission, the Secretary General would oversee a specific body with national jurisdiction. While integrating a more coherent national policy as well as maintaining the decision making bodies of the current administrative system, this intermediate solution would help to avoid a radical restructuring of existing national institutions at a time when current challenges in the area of population health require immediate attention. PMID- 23043698 TI - [Developing a national health policy: a realistic ambition]. AB - The current national health policy in France is almost impossible to pin down and define, spread as it is across thirty or so schemes and a hundred or so targets set by a law adopted in 2004. Yet the current legislation defines the national health policy as a standard reference for public policies developed and implemented by the Ministry of Health and associated bodies. In addition, the current policy involves little consultation and is not systematically monitored and evaluated. Developing an interdepartmental health policy combining several intervention strategies and using different regulation tools may seem like an impossible task. It may also seem somewhat imprudent when it claims to define priorities and strategies. In order to overcome these difficulties and inherent contradictions, we need to develop a policy based on three key elements (a strategy, plans and policies, and policy decentralization and devolution). However, it is not enough to merely develop a framework; it is also important to define the steering and oversight plan, the consultation process and a monitoring and evaluation system. The foundations of a policy based on these principles have already been laid. The authorities simply need to continue along the lines of recent policy developments, including the creation of regional agencies (ARS), the creation of a national steering committee, and the various public health plans developed over the last 20 years. PMID- 23043699 TI - [The case for a new French public health law at the service of a fairer and more effective national health policy]. AB - The next public health law in France will need to address a number of issues. A?series of recent reports have highlighted both sharp disparities in health status ? with high rates of premature death and increasing social inequalities in health ? and the need to organize public health. The incoherence of public health policies, the lack of inter-ministerial coordination (a prerequisite for the reduction of health inequalities) and the lack of structure and evaluation in the area of prevention are major weaknesses that the new public health law will need to address. Beyond the inevitable core measures, the new law will also need to promote deep structural reforms, including a unified national policy refocused on key priorities and incorporating non-health sectors, the development of a more effective and coherent prevention policy and, finally, a focus on the issue of inequalities requiring clearly defined integrated measures, not only as a stated principle but as an outcome to be achieved by all health policies. The next public health law will need to be a vehicle for an inevitable and long overdue structuring of public health policy. PMID- 23043700 TI - [Transsexualism : an obsolete nosological category]. AB - Transsexualism is a recent medical invention. In France, the diagnosis and clinical assessment of transsexualism are carried out jointly by lawyers, doctors and psychiatrists. However, recent quantitative and qualitative studies have shown that current uses of the concept of "transsexualism" no longer meet the demands of all trans people. Only a minority of trans people undergo a public protocol of transsexualization for the transition process. This finding is supported by evidence from a quantitative survey conducted by Alain Giami, and is apparent in the life stories of people who avoid using the "transsexual" label and criticize the clinical process for mistreating people. The purpose of this paper is to analyze the mechanisms of the subjective depsychiatrization and depathologization of trans identities and to examine current conceptions of trans "becomings". PMID- 23043702 TI - The investigation of early warning signs of aggression in forensic patients by means of the 'Forensic Early Signs of Aggression Inventory'. AB - AIMS AND OBJECTIVES: The Forensic Early Warning Signs of Aggression Inventory (FESAI) was developed to assist nurses and patients in identifying early warning signs and constructing individual early detection plans (EDP) for the prevention of aggressive incidents. The aims of this research were as follows: First, to study the prevalence of early warning signs of aggression, measured with the FESAI, in a sample of forensic patients, and second, to explore whether there are any types of warning signs typical of diagnostic subgroups or offender subgroups. BACKGROUND: Reconstructing patients' changes in behaviour prior to aggressive incidents may contribute to identify early warning signs specific to the individual patient. The EDP comprises an early intervention strategy suggested by the patient and approved by the nurses. Implementation of EDP may enhance efficient risk assessment and management. DESIGN: An explorative design was used to review existing records and to monitor frequencies of early warning signs. METHODS: Early detection plans of 171 patients from two forensic hospital wards were examined. Frequency distributions were estimated by recording the early warning signs on the FESAI. Rank order correlation analyses were conducted to compare diagnostic subgroups and offender subgroups concerning types and frequencies of warning signs. RESULTS: The FESAI categories with the highest frequency rank were the following: (1) anger, (2) social withdrawal, (3) superficial contact and (4) non-aggressive antisocial behaviour. There were no significant differences between subgroups of patients concerning the ranks of the four categories of early warning signs. CONCLUSION: The results suggest that the FESAI covers very well the wide variety of occurred warning signs reported in the EDPs. No group profiles of warning signs were found to be specific to diagnosis or offence type. RELEVANCE TO CLINICAL PRACTICE: Applying the FESAI to develop individual EDPs appears to be a promising approach to enhance risk assessment and management. PMID- 23043704 TI - Impact of ethnicity and socio-economic status on Staphylococcus aureus bacteremia incidence and mortality: a heavy burden in Indigenous Australians. AB - BACKGROUND: Investigations of the impact of ethnicity and socio-economic status on incidence and outcomes of Staphylococcus aureus bacteraemia are limited. METHODS: We prospectively identified all S. aureus bacteraemia episodes in the Australian New Zealand Cooperative on Outcomes in Staphylococcal Sepsis cohort study between 2007 and 2010. We calculated population level incidence rates using regional postcodes and stratified the analysis by ethnicity, age and socio economic status indexes. RESULTS: There were 7539 episodes of S. aureus bacteraemia with an annual incidence of 11.2 episodes per 100,000 population. The age-adjusted incidence in the Indigenous population was 62.5 per 100,000 population with an age standardized incidence rate ratio of 5.9 compared to the non-Indigenous population and an incidence rate ratio of 29.2 for community associated methicillin-resistant S. aureus (MRSA). Populations in the lowest socio-economic status quintile had an increased S. aureus bacteraemia incidence compared to higher quintiles. However, there was a disparity between Indigenous and non-Indigenous populations across all socio-economic status quintiles. The lower 30-day mortality for Indigenous patients (7%) compared to non-Indigenous patients (17%) was explained by differences in age. CONCLUSIONS: Indigenous Australians suffer from a higher rate of S. aureus bacteraemia than non Indigenous Australians, particularly for community-associated MRSA. Ethnicity and socio-economic status had little impact on subsequent mortality, with other host factors contributing more significantly. PMID- 23043705 TI - Attributes of interdisciplinary research teams: a comprehensive review of the literature. AB - PURPOSE: To solve large complex health-related problems, there has been a progressive movement towards interdisciplinary research teams; however, there has been minimal investigation into the attributes of successful teams. The purpose of this literature review was to examine the attributes that are important for the effective functioning of these teams. METHOD: Literature from medicine, nursing and psychology databases, published between 1990 and 2010, was reviewed. PRINCIPAL FINDINGS: Thematic organization of the findings identified seven attributes important to effective interdisciplinary research teams: team purpose, goals, leadership, communication, cohesion, mutual respect and reflection. These attributes are described in depth. CONCLUSION: Identification of these attributes could form the basis of a new measure to monitor interdisciplinary research team effectiveness, identify weaknesses and promote team development. PMID- 23043706 TI - Advances in molecular targets for the treatment of medulloblastomas. AB - PURPOSE: To present an assortment of molecular targets evident from a variety of signal transduction pathways and downstream effectors, which may have clinical relevance for the treatment of medulloblastomas. SOURCE: Data were archived from MEDLINE, using Boolean-formatted queries on the keywords including: medulloblastoma, pathology, prognosis, classification, tumor regression, inhibition, therapy, clinical trial, therapeutic agent, drug, molecular inhibitor, and signalling pathway. Only the most reputable articles were selected for critical analyses based on the qualitative assessment of the citation index, novelty of the findings and relevance to prospective novel ways of targeted therapies for medulloblastomas. PRINCIPAL FINDINGS: Medulloblastomas are highly aggressive embryonal tumors of the cerebellum, akin to primitive neuroectodermal tumors elsewhere in the brain. Current treatments for medulloblastomas which include a combination of surgery, chemotherapy and radiation, remain challenging especially, for younger patients; however, advances in understanding regulatory pathways in medulloblastomas are crucial to develop more effective therapeutic targets. Evidence showing several molecular and pharmacological targets within key signalling pathways, such as HEDGEHOG, WNT, NOTCH, Receptor Tyrosine Kinase (ERB, IGF-IR, c-MET, PDGF, Estrogen, p75NTR) , their downstream effectors like PI3K/AKT, c-MYC and STAT3, and as well as other targets such as telomerase and cytoskeletal elements, is summarized. All molecular and pharmacological targets have pivotal roles in the pathogenesis of medulloblastomas. Most importantly, these pathways can be effectively pharmacologically targeted to regress the growth of medulloblastomas. Pre-clinical studies were routinely undertaken with a variety of human and murine cell lines and as well as murine models of medulloblastomas. Thus far, two drugs which target the NOTCH and HEDGEHOG signalling have completed Phase I clinical trials, but with evidence of low efficacies; hence, reinforcing the importance of continuing investigations in search of new therapeutic agents and targets. CONCLUSION: Novel therapies, based on better understanding key biological pathways in medulloblastomas, hold promise for improved treatments in due course among patients with medulloblastomas. PMID- 23043707 TI - Cosmetic and cognitive outcomes of positional plagiocephaly treatment. AB - PURPOSE: Positional plagiocephaly is an acquired deformation of an intrinsically normal infant skull by sustained or excessive extrinsic forces. Non-surgical techniques include counter-positioning, supervised prone time and orthotic molding for more refractory cases. Long-term effects of positional plagiocephaly on development remain undefined, and this study evaluated cosmetic and cognitive outcomes of plagiocephaly management. METHOD: Surveys were administered to parents of patients treated for positional plagiocephaly through the Children's Hospital of Eastern Ontario. Categorical responses interrogated cosmetic outcome, school performance, language skills, cognitive development and societal function. Pearson coefficient analysis tested outcomes dependency on gender, age, and plagiocephaly side at the 0.05 level of significance. RESULTS: Eighty respondents (51 male, 29 female) were divided as 58 right- and 22 left-sided pathology. Positional therapy was uniformly applied, and a helmet orthosis was utilized in 36% of cases. Median follow-up age was nine years with normal head appearance in 75% of cases. Only 4% of parents and 9% of patients observed significant residual asymmetry. These results did not vary by gender, age or deformity side. Left sided disease predicted poorer language development and academic performance. Expressive speech abnormality occurred in twice as many patients with left-sided disease (36% versus 16%, p=0.04) along with three-fold greater special education requirements (27% versus 10%, p=0.04). CONCLUSIONS: Non-surgical plagiocephaly management achieved good cosmetic outcome among patients in this study. Children with left-sided disease frequently encountered difficulties with cognitive and scholastic endeavors, although the roles of the underlying disease and the treatment measures in this delay cannot be differentiated. PMID- 23043708 TI - Sputum microRNA profiling: a novel approach for the early detection of non-small cell lung cancer. AB - PURPOSE: MicroRNAs (miRNAs) post-transcriptionally regulate hundreds of gene targets involved in tumorigenesis thereby controlling vital biological processes, including cellular proliferation, differentiation and apoptosis. MiRNA profiling is an emerging tool for the potential early detection of a variety of malignancies. This study was conducyed to assess the feasibility and methodological robustness of quantifying sputum miRNAs, employing quantitative real-time polymerase chain reaction (RT-qPCR) and cluster analysis on an optimized miRNA profile as a novel approach for the early detection of non-small cell lung cancer (NSCLC). METHODS: The relative expressions of 11 miRNAs in sputum (miR-21, miR-145, miR-155, miR-205, miR-210, miR-92, miR-17-5p, miR-143, miR-182, miR-372, and let-7a) in addition to U6 were retrospectively assessed in four NSCLC-positive and four negative controls. Subsequently, a set of five miRNAs (miR-21, miR-143, miR-155, miR-210, miR-372) was selected because of degree of relatedness observed in the cluster analysis and tested in the same sputum sample set. The five optimized miRNAs accurately clustered these eight retrospective patients into NSCLC positive cases and negative controls. The five miRNA panel was then prospectively quantified in the sputum of 30 study patients (24 NSCLC cases and six negative controls) in a double-blind fashion to validate a five miRNA panel using hierarchical cluster analysis. RESULTS: The optimized five miRNA panel detected NSCLC (83.3% sensitivity and 100% specificity) in 30 prospectively accrued study patients. CONCLUSION: Sputum miRNA profiling using cluster analysis is a promising approach for the early detection of non-small cell lung cancer. Further investigation using this approach is warranted. PMID- 23043709 TI - Advanced glycation end-products activate the renin-angiotensin system through the RAGE/PI3-K signaling pathway in podocytes. AB - PURPOSE: The purpose of this study was to investigate the effects of advanced glycation end-products (AGEs) on the components of the renin-angiotensin system (RAS) in podocytes and to understand the mechanism of these effects. METHODS: Immortalized mouse podocytes were exposed to various concentrations of AGEs for different time intervals. The expression levels of angiotensinogen (AGT), angiotensin II type 1 and 2 receptors (AT1R and AT2R) and renin were examined by real-time PCR and western blot; the receptor for AGEs (RAGE) and both Akt and phosphorylated Akt were examined by western blot; levels of angiotensin II (Ang II) were assayed by ELISA, and the activity of angiotensin-converting enzyme (ACE) was evaluated by measuring the production of hippuric acid in vitro. RESULTS: Treatment with AGEs resulted in significant increases in the expression of AGT (62%, P=0.002) and AT1R (59%, P=0.01). Moreover, Ang II levels increased significantly in both cell lysates (70%, P=0.018) and conditioned media (65%, P=0.01). ACE activity was also significantly higher in cell lysates (68% , P= 0.035) and conditioned media (65%, P=0.023). There were no changes in renin or AT2R expression (P > 0.05). AGEs did increase the expression of RAGE by 50% (P=0.012) and the phosphorylation of Akt by 100% (P=0.001). When podocytes were pretreated with anti-RAGE antibody (50 ug/ml) or the phosphoinositide 3-kinase (PI3-K) inhibitor, LY294002 (10 uM), the AGEs-induced increases in AGT and AT1R expression were reduced. Likewise, Ang II levels and ACE activity decreased significantly. CONCLUSION: AGEs activate the RAS in podocytes through the RAGE PI3-K/Akt-dependent pathway and lead to an increase in podocyte apoptosis. PMID- 23043710 TI - Up-regulated expression of Fas antigen in peripheral T cell subsets in patients with myasthenia gravis. AB - PURPOSE: Recent reports have linked various autoimmune diseases to defective Fas mediated apoptosis or Fas expression. Here we aimed to determine whether Fas mediated apoptosis is involved in the pathogenesis of myasthenia gravis (MG). METHODS: The expression of Fas antigen in peripheral T cell subsets from 17 Chinese patients with MG and 13 healthy individuals was determined by flow cytometry, and its associations with clinical classification, thymus pathology, the concomitance with hyperthyroidism (HT) and corticosteroid treatment were investigated. RESULTS: Compared with normal controls, a significantly up regulated expression of Fas antigen was observed in the peripheral CD4+, CD4+CD8- and CD4-CD8- T cell subsets from patients with MG. Fas expression in CD4-CD8+ T cells of MG patients with normal thymus was significantly higher than that of patients with thymoma. Fas expressions in CD4+CD8+ T cells in MG patients with HT was significantly higher than controls and the ones without HT. Enhanced Fas expressions was found in CD4-CD8+ and CD4-CD8- T cells of MG patients with corticosteroid treatment, but no significant difference of Fas expression in peripheral T cells between patients with ocular MG (OMG) and general MG (GMG) was observed. CONCLUSION: Fas antigen may play a role in the pathogenesis of MG. It may be involved in the mechanisms of corticosteroid treatment, and with the occurrence of HT. OMG may represent a systemic disease, similar to that of GMG. PMID- 23043711 TI - Atrial electromechanical delay and diastolic dysfunction in primary Sjogren syndrome. AB - PURPOSE: In this study we aimed to investigate myocardial function and atrial electromechanical properties by conventional and tissue doppler echocardiography in patients with primary Sjogren syndrome. METHODS: Forty patients with Sjogren syndrome (SS) and 25 age- and sex-matched healthy volunteers were enrolled in the study. Using transthoracic echocardiography, myocardial performance index and atrial electromechanical properties were measured. RESULTS: Basal characteristics were similar between two groups. Myocardial performance index values were disturbed in patients with Sjogren syndrome (0.41 vs. 0.32, p < 0.01). There was significant intraatrial (16.4+/-6.4, 5.0+/-4.5, p < 0.01) and interatrial (30.6+/ 10.1, 15.4+/-5.9, p < 0.01) electromechanical delay in this patient group. CONCLUSION: Myocardial function is disturbed and there is significant atrial electromechanical delay in patients with primary SS. This study is the first to show altered myocardial function and atrial electromechanical properties in primary SS. PMID- 23043712 TI - Immune status and the development of Listeria monocytogenes infection in aged and young guinea pigs. AB - PURPOSE: Consuming even low numbers of the foodborne pathogen, Listeria monocytogenes, places the elderly at risk for severe illness. The impact of immunomodulation on the development of listerial infection within a young and aged population after low dose challenge with L. monocytogenes was investigated. METHODS: Animals received daily supplementation of vitamin E for a period of 21 days to promote immunomodulation, and were then orally challenged with 100 CFU of L. monocytogenes. Levels of CD8+, CD4+ and CD3+ T cells were used as markers to determine the influence of daily supplementation with vitamin E on immune response; the spleen and liver were harvested for microbiological analysis. RESULTS: Higher numbers of animals became infected in control groups than in vitamin E-treated group. During the post-challenge period, vitamin E-treated aged animals showed faster CD8+ T cell proliferation than control aged animals. CONCLUSION: Daily supplementation with vitamin E was more beneficial in young compared with aged animals in mitigating listerial infection. Results suggest exposure to even low numbers of L. monocytogenes can result in infection in both healthy young and aged populations. PMID- 23043713 TI - A practical pressure measuring method for the upper urinary tract during ureteroscopy. AB - PURPOSE: The purpose of this study was to develop and test a method for measuring pressure in the upper urinary tract during ureteroscopic operations and to evaluate its efficacy and clinical significance. METHODS: A total of 44 patients, each with a ureteral calculus in the proximal ureteral segment, were enrolled in the study group: 21 patients with an acute and 23 with a chronic obstruction. The ureteroscope was passed forward to the upper segment of the obstructed ureter immediately after the calculus was broken and the intraluminal ureteral pressure was then transmitted along with the irrigant flow (0.9% sodium chloride). RESULTS: The mean ureteral pressures of the acute obstruction subgroup, the chronic obstruction subgroup and the control group were 74.5 mmHg (22-180 mmHg), 32.5 mmHg (9-53 mmHg) and 10.2 mmHg (8-13 mmHg), respectively. A significant correlation was found between ureteral pressure and the following indexes: the duration of the obstruction (r=0.985), the diameter of the ureter above the calculus (r=0.878) and the depth of the hydronephrosis of the renal pelvis (r=0.862). No associations were observed between the pressure and the serum creatinine level (r=0.214) or the urinary leukocyte count (r=0.047). The intraluminal pressure correlated with the glomerular flow rate (GFR) of the affected kidney (r =0.975, P =0.001). CONCLUSIONS: This new method is non invasive, practical and reproducible. Measuring the intraluminal pressure of the ureter can provide a valuable index to quantify the severity of the obstruction of the upper urinary tract, which is helpful for the prediction of the affected renal function prognosis. PMID- 23043714 TI - Genome-wide association studies-derived susceptibility loci in type 2 diabetes: confirmation in a Chinese population. AB - PURPOSE: Several novel genetic variants for type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWAS). A case-controll study was performed to investigate the association of five new European or South Asian GWAS-derived susceptibility loci with T2DM in a Chinese population. METHODS: Five single nucleotide polymorphisms (SNPs) were genotyped: rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, and rs231362 near KCNQ1, by high-resolution melting (HRM) of small amplicons. The association between T2DM and related quantitative traits in a total of 900 Chinese individuals, including 498 type 2 diabetic patients and 402 ethnically matched control subjects, were examined. RESULTS: After adjusting for age and gender, rs1802295 (OR 5.724, P=0.03) and rs231362 (OR=5.683, P=0.016) were found to be associated with T2DM. Triglyceride levels were higher in TT and CT carriers for rs16861329 (1.05 (0.8-1.34) mmol/l) than in CC carriers (0.91 (0.73-1.23) mmol/l) with P=0.008 and that high-density lipoprotein cholesterol (HDL-C) was lower in TT and CT carriers (1.17 (1.02-1.33) mmol/l) than in CC carriers (1.21 (1.05-1.41) mmol/l), with P=0.034. For rs3923113, the HDL-C levels were lower in the GG carriers (1.08 (0.90-1.18) mmol/l) than in the GT+TT carriers (1.21 (1.04 1.38) mmol/l), with P=0.018. Ours is the first report of this association. CONCLUSION: rs231362-KCNQ1 and rs1802295-VPS26A are associated with T2DM in the Chinese population. The remaining three SNPs are associated with other aspects of lipid metabolism. PMID- 23043715 TI - The relation of fragmented QRS with tissue Doppler derived parameters in patients with b-thalassaemia major. AB - PURPOSE: The most important complication encountered in patients with b thalassaemia major is degenerative fibrosis developing as a result of iron accumulation in myocardial tissue. Dysfunction pursues this accumulation. Recently, presence of fragmented QRS (fQRS) in ECG has been regarded as a predictor of myocardial fibrosis. We aimed in our study to investigate the frequency with which fQRS develops in patients with b-thalassaemia major and to disclose the correlation between fQRS frequency and Doppler-derived indices. METHODS: The patients with b-thalassaemia major (n=66; mean age: 23+/-6 years) and healthy controls (n=30; mean age: 23+/-4 years) were included. fQRS pattern was described as presence of RSR' manifested as existence of additional R wave and notching in either R or S waves in ECG recordings. 2D, M-mode, conventional Doppler, tissue Doppler echocardiography parameters were assessed. Mean serum ferritin levels over past 5 years were also calculated. RESULTS: When compared to those in control group, fQRS was more frequent in b-thalassaemia major group, indicating statistical significance (p = 0.001). While E/Em and ferritin level exhibited statistically significant increase in thalassaemia patients with fQRS (p < 0.05), the mean Em and Sm values were found to be significantly low (p < 0.05). CONCLUSIONS: fQRS was frequently observed in the patients with b thalassaemia major, which was of statistical significance. Tissue Doppler-derived diastolic and systolic indices in thalassaemia cases with fQRS showed statistically significant impairment compared to those without fQRS. In conclusion, fQRS may represent a novel noninvasive marker for cardiac involvement in patients with b-thalassaemia major. PMID- 23043716 TI - Single-chain polymers achieved from radical polymerization under single-initiator conditions. AB - Radical polymerization from a single initiator molecule in a microenvironment is a nearly ideal system in which bimolecular termination, solution concentration, and viscosity changes could be neglected. In this study, we provide two facile methods of preparing polymers via atom-transfer radical polymerization (ATRP) under single-initiator conditions: tether initiators on planar substrates at superlow density through mixed self-assembled monolayers (SAMs) and encapsulated single initiators in microfluidic droplets. The molecular weight (MW) of the resultant polymers characterized by atomic force microscope-based single-molecule force spectroscopy (AFM-based SMFS) showed that the single-chain ATRP had an extraordinarily faster chain propagation rate (2 unit/s) on planar substrates and gave polymers with much higher MWs (10(5)-10(6) g/mol) than those obtained from traditional ATRP (10(3)-10(5) g/mol). The former method offered a general platform for single-chain polymer synthesis and investigation, and the latter could be amplified to obtain abundant single-chain polymers with ultrahigh molecular weight (UHMW) for commercial applications. PMID- 23043717 TI - Implementation of joint health indicators in Europe - Joint Action for ECHIM. Arpo Aromaa on behalf of the ECHIM core group. AB - The story of the implementation of the joint EU health indicators (ECHI indicators) began in the 1990s after the Amsterdam Treaty. The first concrete step in establishing a health monitoring capacity for EU was the Commission working group set up in 1997. Several consecutive and parallel projects, notably the health indicator projects ECHI-1 and ECHI-2 between the years 2000 and 2005 led to a preparedness to implement the jointly agreed health indicators (ECHI shortlist) in all European countries. ECHIM (2005 - 2008) and the Joint Action for ECHIM (2009 - ) laid the foundation for the implementation of health indicators, and initiated Europe wide implementation proper. After the European recession of 2008 the circumstances in different countries were not optimal. Also the collaboration with the Commission could have been better. Nevertheless, the implementation process of the ECHI indicators is now well underway in most countries. By June 2012 half of the Member States had incorporated the ECHI indicators into their national health information system, and, if work can continue, by 2014 most countries are likely to have done so. Unfortunately, a gap may occur between the current programme and the next public health programme. The current momentum must not be lost. Therefore, all those responsible need to urge that the Commission (DG SANCO) together with the Member States helps to bridge the gap from June 2012 to January 2014. The new Public Health Programme provides the necessary financial instruments for setting up a permanent EU health information and reporting system. PMID- 23043718 TI - Accuracy of ultrasound-guided superficial trigeminal nerve blocks using methylene blue in cadavers. AB - OBJECTIVE: To describe a technique for and assess accuracy of ultrasound-guided supraorbital, infraorbital, and mental nerve injections in a cadaveric model. Prior studies have shown that peripheral trigeminal nerve injections can be beneficial for a subgroup of patients for whom surgical treatment is not appropriate. Accurate injection is necessary to limit side effects and improve its efficacy. Ultrasound guidance may improve the accuracy of an injection that is typically performed using a blind technique. METHODS: A single operator completed 36 ultrasound-guided injections with methylene blue dye on six embalmed cadavers. Three cadavers were injected using an in-plane approach and three cadavers using an out-of-plane approach. Injections staining the target nerve were considered "accurate," whereas "inaccurate" injections resulted in no nerve staining. RESULTS: The accuracy rate was 100% (18 of 18) for the in-plane approach and 94% (17 of 18) for the out-of-plane approach. Thirty-five injections were considered accurate (97%) with overflow, and one injection was inaccurate. CONCLUSION: This cadaveric investigation suggests that ultrasound guidance can be used to inject the peripheral trigeminal nerve with a high degree of accuracy. Clinicians should consider using ultrasound guidance to inject the trigeminal nerve for diagnostic or therapeutic purposes. PMID- 23043719 TI - Template-free fabrication of silicon micropillar/nanowire composite structure by one-step etching. AB - A template-free fabrication method for silicon nanostructures, such as silicon micropillar (MP)/nanowire (NW) composite structure is presented. Utilizing an improved metal-assisted electroless etching (MAEE) of silicon in KMnO4/AgNO3/HF solution and silicon composite nanostructure of the long MPs erected in the short NWs arrays were generated on the silicon substrate. The morphology evolution of the MP/NW composite nanostructure and the role of self-growing K2SiF6 particles as the templates during the MAEE process were investigated in detail. Meanwhile, a fabrication mechanism based on the etching of silver nanoparticles (catalyzed) and the masking of K2SiF6 particles is proposed, which gives guidance for fabricating different silicon nanostructures, such as NW and MP arrays. This one step method provides a simple and cost-effective way to fabricate silicon nanostructures. PMID- 23043720 TI - Implementation of an antimicrobial stewardship program on the medical-surgical service of a 100-bed community hospital. AB - BACKGROUND: Antimicrobial stewardship has been promoted as a key strategy for coping with the problems of antimicrobial resistance and Clostridium difficile. Despite the current call for stewardship in community hospitals, including smaller community hospitals, practical examples of stewardship programs are scarce in the reported literature. The purpose of the current report is to describe the implementation of an antimicrobial stewardship program on the medical-surgical service of a 100-bed community hospital employing a core strategy of post-prescriptive audit with intervention and feedback. METHODS: For one hour twice weekly, an infectious diseases physician and a clinical pharmacist audited medical records of inpatients receiving systemic antimicrobial therapy and made non-binding, written recommendations that were subsequently scored for implementation. Defined daily doses (DDDs; World Health Organization Center for Drug Statistics Methodology) and acquisition costs per admission and per patient day were calculated monthly for all administered antimicrobial agents. RESULTS: The antimicrobial stewardship team (AST) made one or more recommendations for 313 of 367 audits during a 16-month intervention period (September 2009 - December 2010). Physicians implemented recommendation(s) from each of 234 (75%) audits, including from 85 of 115 for which discontinuation of all antimicrobial therapy was recommended. In comparison to an 8-month baseline period (January 2009 - August 2009), there was a 22% decrease in defined daily doses per 100 admissions (P = .006) and a 16% reduction per 1000 patient-days (P = .013). There was a 32% reduction in antimicrobial acquisition cost per admission (P = .013) and a 25% acquisition cost reduction per patient-day (P = .022). CONCLUSIONS: An effective antimicrobial stewardship program was implemented with limited resources on the medical-surgical service of a 100-bed community hospital. PMID- 23043721 TI - Leucine co-ingestion improves post-prandial muscle protein accretion in elderly men. AB - BACKGROUND & AIMS: It has been speculated that the amount of leucine in a meal largely determines the post-prandial muscle protein synthetic response to food intake. The present study investigates the impact of leucine co-ingestion on subsequent post-prandial muscle protein accretion following the ingestion of a single bolus of dietary protein in elderly males. METHODS: Twenty-four elderly men (74.3+/-1.0 y) were randomly assigned to ingest 20 g intrinsically L-[1 (13)C]phenylalanine-labeled casein protein with (PRO+LEU) or without (PRO) 2.5 g crystalline leucine. Ingestion of specifically produced intrinsically labeled protein allowed us to create a plasma phenylalanine enrichment pattern similar to the absorption pattern of phenylalanine from the ingested protein and assess the subsequent post-prandial incorporation of L-[1-(13)C] phenylalanine into muscle protein. RESULTS: Plasma amino acid concentrations increased rapidly following protein ingestion in both groups, with higher leucine concentrations observed in the PRO+LEU compared with the PRO group (P<0.01). Plasma L-[1-(13)C]phenylalanine enrichments increased rapidly and to a similar extent in both groups following protein ingestion. Muscle protein-bound L-[1-(13)C]phenylalanine enrichments were significantly greater after PRO+LEU when compared with PRO at 2 h (72%; 0.0078+/ 0.0010 vs. 0.0046+/-0.00100 MPE, respectively; P<0.05) and 6 h (25%; 0.0232+/ 0.0015 vs. 0.0185+/-0.0010 MPE, respectively; P<0.05) following protein ingestion. The latter translated into a greater muscle protein synthetic rate following PRO+LEU compared with PRO over the entire 6 h post-prandial period (22%; 0.049+/-0.003 vs. 0.040+/-0.003% h(-1), respectively; P<0.05). CONCLUSION: Leucine co-ingestion with a bolus of pure dietary protein further stimulates post prandial muscle protein synthesis rates in elderly men. PMID- 23043722 TI - Enhanced feeding in very-low-birth-weight infants may cause electrolyte disturbances and septicemia--a randomized, controlled trial. AB - BACKGROUND & AIMS: High supply of protein and energy has been introduced to very low-birth-weight infants to improve growth and cognitive development. The aim of this study was to compare two different feeding strategies on postnatal growth and clinical outcome during neonatal hospitalization. METHODS: Fifty very-low birth-weight infants were randomized to either an enhanced or a standard feeding protocol within 24 h after birth. Chi-square and T-tests were applied. RESULTS: First week protein, fat and energy supply was significantly higher in the intervention group compared to the control group (all P < 0.001). After inclusion of 50 patients we observed a higher occurrence of septicemia in the intervention group, 63% vs. 29% (P = 0.02), and no more patients were included. The infants in the intervention group demonstrated improved postnatal growth, but they also disclosed significant electrolyte deviations during the first week of life with hypophosphatemia, hypokalemia and hypercalcemia. First week phosphate nadir was lower in the infants experiencing septicemia (1.23 (0.50) mmol/L) as compared to the infants without (1.61 (0.61) mmol/L) (P = 0.03). CONCLUSION: Our study implies that enhanced feeding may induce electrolyte imbalances in VLBW infants, and that deleterious side effects similar to those seen in refeeding syndrome may occur. ClinicalTrials.gov, number NCT01103219 and the EudraCT number is 2010 020464-38. PMID- 23043723 TI - Assessment of the effect on blood loss and transfusion requirements when adding a polyethylene glycol sealant to the anastomotic closure of aortic procedures: a case-control analysis of 102 patients undergoing Bentall procedures. AB - BACKGROUND: The use of CoSeal((r)), a polyethylene glycol sealant, in cardiac and vascular surgery for prevention of anastomotic bleeding has been subject to prior investigations. We analysed our perioperative data to determine the clinical benefit of using polyethylene glycol sealant to inhibit suture line bleeding in aortic surgery. METHODS: From January 2004 to June 2006, 124 patients underwent aortic surgical procedures such as full root replacements, reconstruction and/or replacement of ascending aorta and aortic arch procedures. A Bentall procedure was employed in 102 of these patients. In 48 of these, a polyethylene glycol sealant was added to the anastomotic closure of the aortic procedure (sealant group) and the other 54 patients did not have this additive treatment to the suture line (control group). RESULTS: There were no significant between-group differences in the demographic characteristics of the patients undergoing Bentall procedures. Mean EuroSCORES (European System for Cardiac Operative Risk Evaluation) were 13.7 +/- 7.7 (sealant group) and 14.4 +/- 6.2 (control group), p = NS. The polyethylene glycol sealant group had reduced intraoperative and postoperative transfusion requirements (red blood cells: 761 +/- 863 versus 1248 +/- 1206 ml, p = 0.02; fresh frozen plasma: 413 +/- 532 versus 779 +/- 834 ml, p = 0.009); and less postoperative drainage loss (985 +/- 972 versus 1709 +/- 1302 ml, p = 0.002). A trend towards a lower rate of rethoracotomy was observed in the sealant group (1/48 versus 6/54, p = 0.07) and there was significantly less time spent in the intensive care unit or hospital (both p = 0.03). Based on hypothesis generating calculations, the resulting economic benefit conferred by shorter intensive care unit and hospital stays, reduced transfusion requirements and a potentially lower rethoracotomy rate is estimated at ?1,943 per patient in this data analysis. CONCLUSIONS: The use of this polymeric surgical sealant demonstrated improved intraoperative and postoperative management of anastomotic bleeding in Bentall procedures, leading to reduced postoperative drainage loss, less transfusion requirements, and a trend towards a lower rate of rethoracotomy. Hypothesis-generating calculations indicate that the use of this sealant translates to cost savings. Further studies are warranted to investigate the clinical and economic benefits of CoSeal in a prospective manner. PMID- 23043724 TI - Exploratory study of the typology of various grades of mature skin. AB - BACKGROUND: Post-menopausal skin aging has intrinsic as well as extrinsic origins, and this process induces important disparities of appearance and feeling within an age range. OBJECTIVE: The objective of this study was to identify 3 grades of maturity of the facial skin of menopausal women. MATERIAL AND METHOD: One hundred and fifty women aged between 50 and 80 (63 +/- 7 years) were enrolled. The investigations combined clinical scoring, biometrological measurements (corneometry, cutometry, digital photography, and 3D analysis by fringe projection), and questionnaires. Images elaborated from photographs and 3D views were scored by 2 investigators to classify the subjects according to 3 grades of skin maturity. RESULTS: STEPDISC statistical analysis revealed that the most relevant variables to differentiate the maturity grades were elastosis, wrinkles on the cheeks, wrinkles on the upper lip, roughness, spots, and elasticity. CONCLUSION: The age does not reveal the degree of maturity of mature skin. Three grades of skin maturity in menopausal women, based on clinical and physiological patterns, have been differentiated in this study. Cosmetic treatments specifically adapted to the needs of menopausal women can therefore be developed. PMID- 23043725 TI - Clarifying the structure of granadaene: total synthesis of related analogue [2] granadaene and confirmation of its absolute stereochemistry. AB - Streptococcus agalactiae is an important agent in the infection of neonates in the first world. One of the most extended methods for its identification is based on the detection of a characteristic red pigment in the patient samples, named [12]-granadaene (1). In this article, we present a modular and flexible approach to simple analogues of this ornithine rhamno-polyene 1 and the elucidation of the most important features of its structure: the absolute configuration at C-27, the stereochemistry of the anomeric center and the link of the amino acid ornithine to the rest of the structure. PMID- 23043726 TI - Sulfonates-PMMA nanoparticles conjugates: a versatile system for multimodal application. AB - We report herein the viability of a novel nanoparticles (NPs) conjugated system, namely the attachment, based on ionic and hydrophobic interactions, of different sulfonated organic salts to positively charged poly(methylmethacrylate) (PMMA) based core-shell nanoparticles (EA0) having an high density of ammonium groups on their shells. In this context three different applications of the sulfonates@EA0 systems have been described. In detail, their ability as cytotoxic drugs and pro drugs carriers was evaluated in vitro on NCI-H460 cell line and in vivo against human ovarian carcinoma IGROV-1 cells. Besides, 8-hydroxypyrene-1,3,6-trisulfonic acid, trisodium salt (HPTS) was chosen for NPs loading, and its internalization as bioimaging probe was evaluated on Hep G2 cells. Overall, the available data support the interest for these PMMA NPs@sulfonates systems as a promising formulation for theranostic applications. In vivo biological data strongly support the potential value of these core-shell NPs as delivery system for negatively charged drugs or biologically active molecules. Additionally, we have demonstrated the ability of these PMMA core-shell nanoparticles to act as efficient carriers of fluorophores. In principle, thanks to the high PMMA NPs external charge density, sequential and very easy post-loading of different sulfonates is achievable, thus allowing the preparation of nanocarriers either with bi-modal drug delivery behaviour or as theranostic systems. PMID- 23043727 TI - Neural associative memories and sparse coding. AB - The theoretical, practical and technical development of neural associative memories during the last 40 years is described. The importance of sparse coding of associative memory patterns is pointed out. The use of associative memory networks for large scale brain modeling is also mentioned. PMID- 23043728 TI - Role of TNF-alpha in the mechanisms responsible for preterm delivery induced by Stx2 in rats. AB - BACKGROUND AND PURPOSE: Infections with a strain of Escherichia coli producing Shiga toxins could be one of the causes of fetal morbidity and mortality in pregnant women. We have previously reported that Shiga toxin type 2 (Stx2) induces preterm delivery in pregnant rats. In this study, we evaluate the role of TNF-alpha, PGs and NO in the Stx2-induced preterm delivery. EXPERIMENTAL APPROACH: Pregnant rats were treated with Stx2 (0.7 ng g(-1)) and killed at different times after treatment. Placenta and decidua were used to analyse NOS activity by the conversion of L-[(14)C]arginine into L-[(14)C]citrulline, levels of PGE(2) and PGF(2alpha) assessed by radioimmunoassay, and cyclooxygenase (COX) proteins by Western blot. TNF-alpha level was analysed in serum by ELISA and by cytotoxicity in L929 cells. The inhibitor of inducible NOS, aminoguanidine, the COX-2 inhibitor, meloxicam, and the competitive inhibitor of TNF-alpha, etanercept, were used alone or combined to inhibit NO, PGs and TNF-alpha production respectively, to prevent Stx2-induced preterm delivery. KEY RESULTS: Stx2 increased placental PGE(2) and decidual PGF(2alpha) levels as well as COX-2 expression in both tissues. Aminoguanidine and meloxicam delayed the preterm delivery time but did not prevent it. Etanercept blocked the TNF-alpha increase after Stx2 treatment and reduced the preterm delivery by approximately 30%. The combined action of aminoguanidine and etanercept prevented Stx2-induced preterm delivery by roughly 70%. CONCLUSION AND IMPLICATIONS: Our results demonstrate that the increased TNF-alpha and NO induced by Stx2 were the predominant factors responsible for preterm delivery in rats. PMID- 23043729 TI - Potential clinical impact of cardiovascular magnetic resonance assessment of ejection fraction on eligibility for cardioverter defibrillator implantation. AB - BACKGROUND: For the primary prevention of sudden cardiac death, guidelines provide left ventricular ejection fraction (EF) criteria for implantable cardioverter defibrillator (ICD) placement without specifying the technique by which it should be measured. We sought to investigate the potential impact of performing cardiovascular magnetic resonance (CMR) for EF on ICD eligibility. METHODS: The study population consisted of patients being considered for ICD implantation who were referred for EF assessment by CMR. Patients who underwent CMR within 30 days of echocardiography were included. Echocardiographic EF was determined by Simpson's biplane method and CMR EF was measured by Simpson's summation of discs method. RESULTS: Fifty-two patients (age 62+/-15 years, 81% male) had a mean EF of 38 +/- 14% by echocardiography and 35 +/- 14% by CMR. CMR had greater reproducibility than echocardiography for both intra-observer (ICC, 0.98 vs 0.94) and inter-observer comparisons (ICC 0.99 vs 0.93). The limits of agreement comparing CMR and echocardiographic EF were - 16 to +10 percentage points. CMR resulted in 11 of 52 (21%) and 5 of 52 (10%) of patients being reclassified regarding ICD eligibility at the EF thresholds of 35 and 30% respectively. Among patients with an echocardiographic EF of between 25 and 40%, 9 of 22 (41%) were reclassified by CMR at either the 35 or 30% threshold. Echocardiography identified only 1 of the 6 patients with left ventricular thrombus noted incidentally on CMR. CONCLUSIONS: CMR resulted in 21% of patients being reclassified regarding ICD eligibility when strict EF criteria were used. In addition, CMR detected unexpected left ventricular thrombus in almost 10% of patients. Our findings suggest that the use of CMR for EF assessment may have a substantial impact on management in patients being considered for ICD implantation. PMID- 23043731 TI - Domains contributing to disability in activities of daily living. AB - OBJECTIVE: The WHO International Classification of Functioning, Disability, and Health (ICF)-model describes disability in activities of daily living (ADL) as a multifactorial concept. According to this model, ADL disability is influenced by health conditions, body function and structures, environmental and personal factors, and participation. Current research on ADL disability often focuses on one domain and the contribution of multiple domains is not taken into account. The aim was to investigate which domains contribute to ADL disability. DESIGN: Cross-sectional study. SETTING: General community. PARTICIPANTS: A total of 537 middle-aged and older persons. MEASUREMENTS: Health conditions included number of chronic diseases. Body function comprised Mini-Mental State Examination (MMSE), processing speed, memory, grip strength, physical performance score (PPS), physical activity, sensory problems, body mass index (BMI), intra-abdominal fat, and cholesterol/HDL ratio. Body structure included atherosclerosis and bone mineral density. Environmental factors comprised the degree of urbanization. Personal factors included age, sex, education, smoking, self-management abilities, quality of life, anxiety/panic disorders, and depressive symptoms. Associations between candidate predictors and ADL disability, measured on the Katz ADL-scale, were examined by multivariable adjusted logistic regression analysis. Nagelkerke R(2)-statistic was calculated to investigate the contribution of each domain to ADL disability. RESULTS: Number of chronic diseases (domain health condition), MMSE, PPS, physical activity, BMI, intra abdominal fat (domain body function), atherosclerosis (domain body structure) and sex, education, smoking, quality of life, and depressive symptoms (domain personal factors) were significant predictors of ADL disability. Fifty-seven percent of the variance in ADL disability was explained by the model. For each domain, the explained variance materially decreased after its exclusion, except for environmental factors. CONCLUSION: The present study shows that multiple domains (ie, health condition, body function, body structure, and personal factors) contribute to current ADL disability. PMID- 23043730 TI - [Perception of work environment of nurses in hospitals of the Spanish national health system. RN4CAST-Spain project]. AB - OBJECTIVE: To appraise the perception of Registered Nurses working at Spanish National Health System (SNHS) hospitals about work environment, quality of care and burnout. METHOD: Cross-sectional study addressed to 7539 nurses in 59 Spanish public hospitals over 150 beds belonging to the NHS between 2009 and 2010. Data was collected on: socio-demographic and academic background, job satisfaction, perception of work environment (PES-NWI) and burnout (MBI). RESULTS: Among 7539 questionnaires, 5654 were collected (75%). The nurses' average age was 37,5 (SD=9,5) years old, 88% (4929) were female and they had a median of 12 years of experience. The patient/nurse ratio was 11/1. 26% of nurses (1468) showed their intention to leave the hospital. 55% of nurses (3080) showed moderate job satisfaction. The work environment was unfavorable for 48% (2729) of nurses. 22% (1091) showed high burnout levels. CONCLUSIONS: The results show a high nurses' participation, who relate moderate job satisfaction. However, on PES-NWI, nearly half of nurses show an unfavorable work environment. PMID- 23043732 TI - Endogenous ascorbate restrains apoplastic peroxidase activity during sunflower leaf development. AB - Several apoplastic enzymes have been implicated in the control of elongation growth of plant cells. Among them, peroxidases contribute to both loosening and stiffening of the cell wall. They appear to be regulated by various mechanisms, including the action of extracellular inhibitors. To obtain evidence of the role of the enzyme-inhibitor interaction during leaf development, the intercellular washing fluids from Helianthus annuus leaves of different ages were isolated using standard methods of vacuum infiltration and centrifugation. Peroxidase activities, assessed using tetramethylbenzidine as substrate, increased during leaf development, reaching a maximum value after the leaves were fully expanded. An inhibitor, chemically characterised as ascorbate, co-localised with the enzyme in the apoplast. Moreover, there was a strong negative correlation between the action of peroxidase and the micromolar concentration of ascorbate in the apoplastic fluid. The results show that in growing leaves, the in planta ascorbate concentration is able to restrain peroxidase enzyme activity. Then, at the time of growth cessation, the loss of extracellular ascorbate relieves the inhibition on this enzyme that contributes to wall fixation. PMID- 23043733 TI - Unstable gait due to spasticity of the rectus femoris: gait analysis and motor nerve block. AB - We present the case of a 54 year-old man presenting with a right Brown-Sequard plus syndrome (BSPS) after a traumatic cervical spinal cord injury. After being operated on with selective tibial neurotomy and triceps surae lengthening because of a right spastic equinus foot, he developed a gait disorder at high speed. The patient complained about an instability of the right knee. Observational gait analysis exhibited an oscillating, flexion/extension motion of the right knee during stance, which was confirmed by gait analysis. Dynamic electromyographic recordings exhibited a clonus of the right rectus femoris (RF) during stance. The spastic activity of the RF and the abnormal knee motion totally reversed after a motor nerve block of the RF, as well as after botulinum toxin type A injection into the RF. We emphasize that complex, spastic gait disorders can benefit from a comprehensive assessment including gait analysis and nerve blocks. PMID- 23043734 TI - [The public domain of parenthood]. PMID- 23043735 TI - [Trends and current issues in childbirth and parenting education]. AB - Childbirth and parenting education is a key component of health education in perinatal care. It has its origins in the notion of painless childbirth derived from the Lamaze method, based on an educational model, a behavioral model and a biomedical model. In 2005, the French Health Authority (Haute Autorite de Sante) made a number of recommendations for the clinical practice of childbirth and parenting education. By redefining its objectives and changing its name, and drawing on the principles of both the Ottawa Charter and the concept of health promotion, the French Health Authority has promoted the development of new practices in this area. These changes imply new theoretical models (both educational and health-related), which could potentially lead to a new form of empowerment for women, but also for midwives, who play a key role in childbirth and parenting education. PMID- 23043736 TI - [The limits of patient education in short-term hospitalization: the case of cardiovascular patients]. AB - The purpose of this study was to examine the limitations of therapeutic education for patients with cardiovascular risk factors during short hospital stays. The paper presents the results of a qualitative study conducted over the course of a year involving 18 case studies of professional practices and 18 interviews with 5 health professionals and 13 patients. The results show that professionals and patients have conflicting views about the time spent in hospital, as well as conflicting concerns and expectations, thus limiting the effectiveness of educational care. The findings suggest that after acute myocardial infarction or a stroke, patients tend to view themselves as survivors during their experience of short-term hospitalization in a care unit. As a result, short-term hospitalization may not be conducive to the mobilization of patients' cognitive and emotional capacities in a therapeutic education program. PMID- 23043737 TI - [Health professionals' perceptions and screening for hepatitis B and C among migrants: a qualitative study in Cote-d'Or, France]. AB - Hepatitis B and C continue to be major public health problems in France, particularly among migrants. The fact of being born in hepatitis B and C-endemic countries or of being a long-term resident of these countries are common risk factors, especially in the case of hepatitis B. Screening for both types of infection remains low among migrants. The main purpose of this study was to examine perceptions of the risk of viral hepatitis B and C in migrants among health professionals in Cote-d'Or (Burgundy, France) and to understand the factors promoting or hindering screening. The paper presents the results of a qualitative study based on face-to-face interviews with 23 healthcare providers and 8 social workers. The participating health professionals were interviewed about their involvement in the fight against hepatitis B and C and their perceptions of the risk of infection among migrants. The interviews conducted with social workers focused mostly on the conditions of social and health support provided to migrants. The study found that hepatitis B and C screening among migrants was associated with HIV screening. Screening was found to be associated with formalities relating to the legal and administrative status of migrants, the type of accommodation or housing, health professionals' knowledge of the risk factors associated with the epidemiological and social/health context in the countries of origin, and their own involvement in humanitarian aid. Migrants seeking political asylum and living in reception centers were found to be more likely to undergo screening. The findings suggest that awareness of the importance of systematic screening for hepatitis B and C in migrants from hepatitis B and C-endemic areas needs to be promoted among social workers and health professionals, as recommended by the National Prevention and Control Program (2009-2012). PMID- 23043738 TI - [Prevalence and risk factors of overweight among 5- to 11-year-old schoolchildren in Narbonne, France]. AB - In order to address the increasing prevalence of overweight and obesity in children, the French city of Narbonne recently began monitoring childhood obesity with a view to developing and implementing targeted actions to stabilize the prevalence of overweight. The main purpose of this study was to assess the risk factors for overweight in children. The study was conducted during the 2008-2009 academic year and was based on a sample of 1,476 preschool and primary school children from all public and private schools in Narbonne. The prevalence of overweight and obesity were 14.9% and 3.7%, respectively. The study found that watching television for more than 2 hours a day, short sleep duration (less than 10 hours per night), a low socioeconomic status and parental obesity are risk factors for overweight and obesity in children. The findings suggest that priority actions among poor populations and overweight mothers are required in order to stabilize the prevalence of overweight and obesity in children, including providing advice on healthy eating, fighting against sedentary lifestyles and promoting sleep. PMID- 23043739 TI - [Adult vaccination coverage: surveys in four populations - Isere (France), 2002 2003]. AB - In order to assess their vaccination policy, the public health authorities in Isere (France) conducted several surveys to determine the vaccination coverage rate among adults. In France, the current state of knowledge in this area is limited. Four separate surveys were conducted in 2002-2003: (1) a telephone survey of 976 adults, 18% of whom had vaccination certificates; (2) a survey of 44 general practitioners (805 patients); (3) a survey of occupational health centers (82 practitioners and 1,119 employees); and (4) a survey of 1,214 patients vaccinated at the international vaccination center in Grenoble (France). The same data were recorded in all four surveys (last vaccination date, either declared by the patient or proven by a vaccination certificate). Based on certified evidence, vaccination coverage for tetanus, diphtheria, and poliomyelitis ranged from 31.6% to 83.9%, from 24.1% to 44.0%, and from 25.9% to 71.9%, respectively. Compared to general practitioners, vaccination coverage was higher among staff working at the occupational health center and lower in the general population. The four surveys covered only part of the adult population and provided only an estimate of vaccination coverage. The study found that tetanus vaccination coverage was the highest, but was still below expected levels. For the other vaccines, vaccination coverage among adults appears to be inadequate. The findings suggest that all health professionals involved in adult vaccination (occupational health doctors, general practitioners, hospital doctors, etc.) should be invited to participate in working groups on vaccination. PMID- 23043740 TI - [Characteristics of parent-adolescent communication about sexuality and HIV in Bobo-Dioulasso, Burkina Faso]. AB - Adolescent females are a key target audience in the fight against sexually transmitted infections and HIV in sub-Saharan Africa. One issue is that families in Africa play a very limited role in sex education. The objective of this study was to examine parent-child communication from a qualitative perspective by exploring the characteristics and quality of parent-child communication. A cross sectional study was conducted between April and September 2009 in Bobo-Dioulasso (Burkina Faso). The study included 40 parent-child pairs (50% of in-school children and 50% of out-of-school children). Individual interviews and focus groups were conducted. The data were analyzed using Stata version 9.1 (quantitative data) and QSR Nvivo 2.0 (qualitative data). The study found that 74% (14/19) of out-of-school children communicated with their parents, compared to just 45% of in-school children (p = 0.07). Mother-child communication was found to be the most common type of parent-child communication, with 59% (13/22) of families who communicated about sexuality and HIV preferring mother-child communication. Further research is needed to identify the factors determining better communication among out-of-school children. PMID- 23043741 TI - [An evaluation of the implementation of the national treatment protocol for uncomplicated malaria in rural areas of Burkina Faso]. AB - The purpose of this study was to evaluate the implementation of a treatment protocol based on artemisinin-based combination therapy for the treatment of uncomplicated malaria in rural areas. Population and methods. A descriptive and comparative study was conducted in the rural health district of Hounde (Burkina Faso). The study involved health care providers, managers of essential drug depots and health centers, and patients receiving a prescription for an antimalarial drug. The data were entered and analyzed using the Epi Info 3.3.1 software package. The Chi-square test was used to compare proportions at the 0.05 level. A total of 130 prescribers and 30 managers of essential drug depots were interviewed in 28 health centers. In addition, 165 prescriptions including an antimalarial drug were collected. Of the 130 prescribers surveyed, 84.6% knew about the new treatment guidelines for uncomplicated malaria. The study found that 64.8% of the prescriptions were for ACTs, while quinine accounted for 35.2% of the prescriptions. Artesunate-amodiaquine combination therapy accounted for 98.1% of the prescriptions for antimalarial drug combination therapy. 82.4% of the prescriptions were adequate, with significantly more adequate prescriptions in clinics than in maternity hospitals (p = 0.009). Children under 5 years of age were treated better than other age groups (p < 0.001). In 89.7% of drug depots, there was evidence of a shortage of artemisinin-based combination drugs at least once in the two months before the study, most notably in the case of artesunate amodiaquine therapy. The results highlight the importance of continuing training for treatment providers and of strict procedures for managing stocks of artemisinin-based combination drugs. PMID- 23043742 TI - [A survey of sustainable funding mechanisms for essential drugs in Loumbila, Burkina Faso]. AB - Households are the main source of health care financing in Burkina Faso. The current system based on out-of-pocket health payments is a major cause of poverty. The purpose of this study was to contribute to the improvement of local health funding in Loumbila and throughout the country. A descriptive and analytical study was conducted among 271 household heads, 3 health committee members, the prefet (the top state official in the area), and the secretary general of the municipality between 25 June and 5 August 2010. A survey guide and questionnaires were used to collect data. The standard public health survey method was used to collect, process, analyze and discuss the results. The results of the survey indicate that 82.3% of the participating households were willing to contribute to the creation of a local health fund in the village. The study found that the average contribution rate of each household amounted to 9% of their annual income. The best periods for collecting funds are during the harvest season (in the case of farmers) or any favorable period (in the case of other households). The municipal committee will need to be responsible for managing and coordinating the municipal health fund. This requires the participation of the state, health districts, NGOs and other partners. The cost of effective treatment for the top ten priority diseases in the village in 2010 is estimated to be 4,011,300 FCFA. If all the households in the village were to contribute to the municipal health fund, the total amount of contributions would amount to 15,575,515 FCFA. Under this system, all households within the village can have access to essential drugs. The municipal health fund can also support municipal development boards to improve the independence and sustainability of the system. PMID- 23043745 TI - Year in review: health protection in NSW, 2011. PMID- 23043743 TI - Clinical evaluation of analytical variations in serum creatinine measurements: why laboratories should abandon Jaffe techniques. AB - BACKGROUND: Non-equivalence in serum creatinine (SCr) measurements across Dutch laboratories and the consequences hereof on chronic kidney disease (CKD) staging were examined. METHODS: National data from the Dutch annual external quality organization of 2009 were used. 144 participating laboratories examined 11 pairs of commutable, value-assigned SCr specimens in the range 52-262 MUmol/L, using Jaffe or enzymatic techniques. Regression equations were created for each participating laboratory (by regressing values as measured by participating laboratories on the target values of the samples sent by the external quality organization); area under the curves were examined and used to rank laboratories. The 10th and 90th percentile regression equation were selected for each technique separately. To evaluate the impact of the variability in SCr measurements and its eventual clinical consequences in a real patient population, we used a cohort of 82424 patients aged 19-106 years. The SCr measurements of these 82424 patients were introduced in the 10th and 90th percentile regression equations. The newly calculated SCr values were used to calculate an estimated glomerular filtration rate (eGFR) using the 4-variable Isotope Dilution Mass Spectrometry traceable Modification of Diet in Renal Disease formula. Differences in CKD staging were examined, comparing the stratification outcomes for Jaffe and enzymatic SCr techniques. RESULTS: Jaffe techniques overestimated SCr: 21%, 12%, 10% for SCr target values 52, 73 and 94 MUmol/L, respectively. For enzymatic assay these values were 0%, -1%, -2%, respectively. eGFR using the MDRD formula and SCr measured by Jaffe techniques, staged patients in a lower CKD category. Downgrading to a lower CKD stage occurred in 1-42%, 2-37% and 12-78.9% of patients for the 10th and 90th percentile laboratories respectively in CKD categories 45-60, 60-90 and >90 ml/min/1.73 m2. Using enzymatic techniques, downgrading occurred only in 2-4% of patients. CONCLUSIONS: Enzymatic techniques lead to less variability in SCr measurements than Jaffe techniques, and therefore result in more accurate staging of CKD. Therefore the specific enzymatic techniques are preferably used in clinical practice in order to generate more reliable GFR estimates. PMID- 23043746 TI - Sample size calculations for the design of health studies: a review of key concepts for non-statisticians. AB - Sample size calculations before conducting a health study or clinical trial are important to provide evidence that the proposed study is capable of detecting real associations between study factors. This review aims to clarify statistical issues related to the calculation of sample sizes and is illustrated with an example of a recent study design to improve health outcomes related to water and sewage in NSW Aboriginal communities. The effect of power, significance level and effect size on sample size are discussed. Calculations of sample sizes for individual-based studies are modified for more complex trial designs by multiplying individual-based estimates by an inflationary factor. PMID- 23043747 TI - Typhoid and paratyphoid fever in Western Sydney Local Health District, NSW, January-June 2011. AB - We undertook a study of enteric fever, caused by Salmonella enterica enterica subtypes Typhi and Paratyphi A, presenting in residents of the Western Sydney Local Health District for the period January-June 2011. Twelve cases of S. Typhi and eight of S. Paratyphi A were notified. Patients were predominantly young adults (median age 26 years, 70% female) who had been visiting friends and relatives in India, Samoa, Bangladesh or Sri Lanka. No cases were associated with travel for less than 3 weeks; 17 (85%) required hospitalisation. None received pre-travel vaccination; reasons cited for this included pregnancy, expense, being too busy, or considering the disease too mild to warrant vaccination. Three S. Typhi isolates acquired at large social gatherings in Samoa had the same phage [corrected] type and susceptibility profiles; these results were communicated to Samoan public health personnel. There are opportunities to strengthen enteric fever prevention, including pre-travel health advice and S. Typhi vaccination for people visiting endemic areas for 3 or more weeks, especially those in the vulnerable 'visiting friends and relative' category. PMID- 23043748 TI - Trends and risk factors for hepatitis A in NSW, 2000-2009: the trouble with travel. AB - AIM: To analyse trends in hepatitis A notifications and information on exposure to risk factors, in particular international travel, collected through routine surveillance in NSW. METHODS: Hepatitis A notification data for the period 2000 2009 were extracted from the Notifiable Diseases Database and analysed by age group, gender, area of residence and exposure risk factors, including travel, food eaten and contact with other possible infectious cases. RESULTS: The notification rate for hepatitis A in NSW fell from 3.0 cases per 100000 population in 2000 to 1.4 cases per 100000 population in 2009. Notification rates were highest among people aged 20-24 years and residents of metropolitan Sydney. Travel to a country where hepatitis A is endemic was a risk exposure identified in 43% of cases. CONCLUSION: International travel to highly endemic countries continues to be the most common risk factor for hepatitis A infection notified in NSW despite recommendations that travellers be vaccinated prior to travel to these areas. PMID- 23043749 TI - HealthStats in the bulletin: overweight and obesity are common in rich and poor. PMID- 23043750 TI - Bug breakfast in the bulletin: rapid health assessments. PMID- 23043751 TI - Bug breakfast in the bulletin: One Health and Hendra virus: a collaborative approach in action. PMID- 23043752 TI - Communicable diseases report, NSW, May and June 2012. PMID- 23043754 TI - Probability of twin formation on self-catalyzed GaAs nanowires on Si substrate. AB - We attempted to control the incorporation of twin boundaries in self-catalyzed GaAs nanowires (NWs). Self-catalyzed GaAs NWs were grown on a Si substrate under various arsenic pressures using molecular beam epitaxy and the vapor-liquid-solid method. When the arsenic flux is low, wurtzite structures are dominant in the GaAs NWs. On the other hand, zinc blende structures become dominant as the arsenic flux rises. We discussed this phenomenon on the basis of thermodynamics and examined the probability of twin-boundary formation in detail. PMID- 23043753 TI - Fas-deficient mice have impaired alveolar neutrophil recruitment and decreased expression of anti-KC autoantibody:KC complexes in a model of acute lung injury. AB - BACKGROUND: Exposure to mechanical ventilation enhances lung injury in response to various stimuli, such as bacterial endotoxin (LPS). The Fas/FasL system is a receptor ligand system that has dual pro-apoptotic and pro-inflammatory functions and has been implicated in the pathogenesis of lung injury. In this study we test the hypothesis that a functioning Fas/FasL system is required for the development of lung injury in mechanically ventilated mice. METHODS: C57BL/6 (B6) and Fas deficient lpr mice were exposed to either intra-tracheal PBS followed by spontaneous breathing or intra-tracheal LPS followed by four hours mechanical ventilation with tidal volumes of 10 mL/kg, respiratory rate of 150 breaths per minute, inspired oxygen 0.21 and positive end expiratory pressure (PEEP) of 3 cm of water. RESULTS: Compared with the B6 mice, the lpr mice showed attenuation of the neutrophilic response as measured by decreased numbers of BAL neutrophils and lung myeloperoxidase activity. Interestingly, the B6 and lpr mice had similar concentrations of pro-inflammatory cytokines, including CXCL1 (KC), and similar measurements of permeability and apoptosis. However, the B6 mice showed greater deposition of anti-KC:KC immune complexes in the lungs, as compared with the lpr mice. CONCLUSIONS: We conclude that a functioning Fas/FasL system is required for full neutrophilic response to LPS in mechanically ventilated mice. PMID- 23043755 TI - Use of a sealant to prevent prolonged air leaks after lung resection: a prospective randomized study. AB - BACKGROUND: Pulmonary air leaks are common complications of lung resection and result in prolonged hospital stays and increased costs. The purpose of this study was to investigate whether, compared with standard care, the use of a synthetic polyethylene glycol matrix (CoSeal(r)) could reduce air leaks detected by means of a digital chest drain system (DigiVentTM), in patients undergoing lung resection (sutures and/or staples alone). METHODS: Patients who intraoperatively showed moderate or severe air leaks (evaluated by water submersion tests) were intraoperatively randomized to receive just sutures/staples (control group) or sutures/staples plus CoSeal(r) (sealant group). Differences among the groups in terms of air leaks, prolonged air leaks, time to chest tube removal, length of hospital stay and related costs were assessed. RESULTS: In total, 216 lung resection patients completed the study. Nineteen patients (18.1%) in the control group and 12 (10.8%) patients in the sealant group experienced postoperative air leaks, while a prolonged air leak was recorded in 11.4% (n=12) of patients in the control group and 2.7% (n=3) of patients in the sealant group. The difference in the incidence of air leaks and prolonged air leaks between the two groups was statistically significant (p=0.0002 and p=0.0013). The mean length of hospital stay was significantly shorter in the sealant group (4 days) than the control group (8 days) (p=0.0001). We also observed lower costs in the sealant group than the control group. CONCLUSION: The use of CoSeal(r) may decrease the occurrence and severity of postoperative air leaks after lung resection and is associated with shorter hospital stay. TRIAL REGISTRATION: Not registered. The trial was approved by the Institutional Review Board of the IRCCS-CROB Basilicata Regional Cancer Institute, Rionero in Vulture, Italy. PMID- 23043756 TI - Common variable immunodeficiency: an update. AB - Common variable immunodeficiency (CVID) describes a heterogeneous subset of hypogammaglobulinemias of unknown etiology. Typically, patients present with recurrent bacterial infections of the respiratory and gastrointestinal tract. A significant proportion of CVID patients develops additional autoimmune, inflammatory or lymphoproliferative complications. CVID is the most frequent symptomatic primary immunodeficiency encountered in adults. Informative monogenetic defects have been found in single patients and families but in most cases the pathogenesis is still elusive. Numerous immunological studies have demonstrated phenotypic and functional abnormalities of T cells, B cells and antigen-presenting cells. A hallmark is the impaired memory B-cell formation that has been taken advantage of for classifying CVID patients. Clinical multi-center studies have demonstrated a correlation between immunological markers and clinical presentation. Long-term outcome is significantly influenced by delay of diagnosis and treatment and the presence of chronic inflammatory complications. While immunoglobulin replacement therapy plus antibiotics can control infections in most cases, patients with non-infectious inflammatory complications such as granulomatous inflammation, interstitial lung disease, inflammatory bowel disease, lymphoproliferation and developing malignancies still represent a therapeutic challenge. In this review we provide a systematic overview of the immunological, clinical, diagnostic and therapeutic aspects of CVID and highlight recent developments in these fields. PMID- 23043758 TI - Structure and properties of maize starch processed with a combination of alpha amylase and pullulanase. AB - The dissolution and digestion characteristics of maize starch processed with a combination of alpha-amylase and pullulanase (ERS) were investigated. The results were compared with those of high pressure-processed RS (HRS) and regular maize starch. The ERS exhibited a considerably lower dissolution and digestibility than the HRS under conditions that simulated the stomach and small intestine in vitro. Infrared spectroscopy showed two bands at 1047 and 1002 cm(-1) for ERS, which suggested an easily produced RS during the retrogradation process after enzymatic treatment. High-performance size-exclusion chromatography showed a hydrolyzed ERS forming a critical molecular weight fraction (MW 4833 Da; DP 29.8). X-ray diffraction analysis also revealed a significant difference between the types of HRS (B+V type) and ERS (in the transformation from B+V to V type) crystallinities, and the crystal structure change leads to improved anti enzymatic properties of ERS. These results indicate that the enzyme-combined method is a more promising technique than high pressure to prepare RS from maize starch with greater resistance. PMID- 23043757 TI - On optimizing the blocking step of indirect enzyme-linked immunosorbent assay for Epstein-Barr virus serology. AB - BACKGROUND: Because blocking agent occupies most binding surface of a solid phase, its ability to prevent nonspecific binding determines the signal-to-noise ratio (SNR) and reliability of an enzyme-linked immunosorbent assay (ELISA). METHODS: We demonstrate a stepwise approach to seek a compatible blocking buffer for indirect ELISA, via a case-control study (n=176) of Epstein-Barr virus (EBV) associated nasopharyngeal carcinoma (NPC). RESULTS: Regardless of case-control status, we found that synthetic polymer blocking agents, mainly Ficoll and poly(vinyl alcohol) (PVA) were able to provide homogeneous backgrounds among samples, as opposed to commonly used blocking agents, notably nonfat dry milk (NFDM). The SNRs for NPC samples that correspond to blocking using PVA were approximately 3-fold, on average, higher than those blocking using NFDM. Both intra- and inter-assay precisions of PVA-based assays were <14%. CONCLUSION: A blocking agent of choice should have tolerable sample backgrounds from both cases and controls to ensure the reliability of an immunoassay. PMID- 23043759 TI - Antiherpetic activity of an Agaricus brasiliensis polysaccharide, its sulfated derivative and fractions. AB - Agaricus brasiliensis is an edible mushroom, traditionally used for the treatment of several diseases. In this paper, a polysaccharide (PLS) from A. brasiliensis, its carboxymethylated (CPLS) and sulfated (SPLS) derivatives, as well as, fractions (F1-F3) obtained from the PLS were investigated for their effect in the replication of herpes simplex virus and bovine herpes virus in HEp-2 cell cultures. The PLS, SPLS and F3 inhibited both virus strains similarly, in a dose dependent curve. F1, F2 and CPLS did not show significant effect even at higher concentrations. All the compounds showed neither virucidal or viral adsorption inhibition activities nor effect when cells were treated prior to infection. Our study demonstrated that the extracts of A. brasiliensis, can be promising for future antiviral drug design and its biotechnological production is economically feasible. PMID- 23043760 TI - Negative interaction between twospotted spider mites and aphids mediated by feeding damage and honeydew. AB - Among the herbivorous arthropods that feed on strawberry, the most important are the two-spotted spider mite (TSSM), Tetranychus urticae Koch, and several species of aphids. Mites and aphids belong to different guilds that coexist in the field and feed on the undersides of strawberry leaflets. However, the occurrence of large numbers of individuals of both species on the same leaflet is rarely recorded. We hypothesize that negative interactions between TSSM and aphids explain the intraplant distribution of these herbivores. We first examined the spatial coincidence of both herbivores in the field. Under experimental conditions, we then analyzed: (i) the rate of increase of TSSM and the aphid Chaetosiphon fragaefolii (Cockerell), growing individually and together; (ii) the effect of honeydew on TSSM preference; and (iii) the effect of previous strawberry leaflet damage by TSSM on C. fragaefolii preference. The proportion of TSSM that coincided with at least one aphid decreased as the percentage of leaflets with TSSM increased. The spatial coincidence index between aphids and TSSM increased together with the percentage of TSSM-infested leaflets. TSSM showed both a lower rate of increase when they shared the same leaflet with C. fragaefolii and lower fecundity on strawberry discs with honeydew. The rate of increase of C. fragaefolii did not change on co-occupied leaves, but the aphid species moved to the other side of leaflets shared with TSSM. Negative interactions resulting in a tendency for species to avoid each other, such as demonstrated herein, can affect distribution and performance of herbivorous arthropods. PMID- 23043761 TI - Orphan receptor TR3 is essential for the maintenance of stem-like properties in gastric cancer cells. AB - The orphan receptor TR3 is an important regulator of cell proliferation and apoptosis. However, whether TR3 is involved in regulating the stem-like properties of cancer cells remains unknown. The present study shows that TR3 expression is increased in gastric tumorsphere cells and is positively correlated with cancer stem cell (CSC) characteristics. Knocking down TR3 leads to the suppression of its stem-like properties in both gastric cancer cells and tumorsphere cells. This process involves the decreased expression of the stemness related genes Oct-4 and Nanog and the invasion-related gene MMP-9. We further identify Nanog as a new target for the transcription factor TR3. Together, these data demonstrate for the first time that TR3 is essential for the maintenance of stem-like properties in human gastric cancer cells and implicate TR3 as a new therapeutic target for gastric cancer. PMID- 23043762 TI - Immunospecific targeting of CD45 expressing lymphoid cells: towards improved detection agents of the sentinel lymph node. AB - This study was designed to demonstrate the potential of small nanoparticulate lymphotropic contrast agents designed to bind with high affinity to lymphoid cells overexpressing the CD45 antigen. To this end, small gold nanoparticles used as model were conjugated to anti-CD45 antibodies and injected in mice in the dorsal toe of the fore/hind paw. Chemical analysis demonstrated rapid uptake and transport of the nanoparticles in the lymphatic as well as significant retention of the nanoparticles with high binding affinity to lymphoid cells in the popliteal and axillary lymph nodes in comparison to non-targeted nanoparticles. PMID- 23043763 TI - Implementation of a dose-response curve for gamma-radiation in the Portuguese population by use of the chromosomal aberration assay. AB - An in vitro dose-response curve following exposure to gamma-radiation was determined at the IST/ITN, by use of the chromosomal aberration assay. This is the first study of this kind carried out among the Portuguese population. Un irradiated and gamma-irradiated peripheral blood lymphocytes from 16 healthy donors were cultured. A total of 22,395 metaphases were analyzed for frequency and distribution of dicentrics and centric rings, as a function of the radiation dose. The dose-response data for dicentrics and dicentrics plus centric rings were fitted by use of a linear-quadratic model: Y(dic)=(0.0011+/ 0.0006)+(0.0105+/-0.0035)D+(0.0480+/-0.0019)D(2) and Y(dic+rings)=(0.0011+/ 0.0006)+(0.0095+/-0.0036)D+(0.0536+/-0.0020)D(2). Also, calibration curves related to age and gender were determined, but no significant differences were found. Following the establishment of the dose-response curves, a validation experiment was carried out with three individuals. Real and estimated doses, obtained with the dose-response curves, were in agreement. These results give us confidence to apply both dose-response calibration curves in future biological dosimetry requirements. PMID- 23043764 TI - Design, synthesis, and evaluation of 2-substituted ethenesulfonic acid ester derivatives as protein tyrosine phosphatase 1B inhibitors. AB - Thirty-two 2-substituted ethenesulfonic acid ester derivatives were designed, synthesized, and evaluated for their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) and selectivity over T-Cell protein tyrosine phosphatase (TCPTP). Preliminary structure-activity relationship studies demonstrated that the substitution at the aromatic center and the length of linker between the hydrophobic tail and aromatic center markedly affected the inhibitory activity against PTP1B and the selectivity over TCPTP. Specifically, compounds 43 and 36 revealed excellent inhibitory activity to PTP1B with IC(50) = 1.3 MUM and 1.5 MUM, respectively, and marked 10- and 20-fold selectivity over TCPTP. Cytotoxicity data showed low cytotoxicity for COS-7 cell with IC(50) values >100 MUM for most synthesized chemicals. PMID- 23043765 TI - Synthesis and antithrombotic evaluation of novel dabigatran prodrugs containing a cleavable moiety with anti-platelet activity. AB - A novel series of prodrugs consisting of dabigatran and 2-hydroxymethyl-3,5,6 trimethylpyrazine (HTMP) were synthesized. The pharmacological results show that all of them possess the effect of anti-platelet aggregation induced by thrombin in vitro. Moreover, one of those compounds, Y-2 (ED(50) = 2.1 +/- 1.3 mg/kg) shows more potent activity for inhibiting thrombosis in vivo than that of dabigatran etexilate (ED(50) = 4.4 +/- 2.2 mg/kg). PMID- 23043766 TI - Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity. AB - Novel quinoline-2-one based chalcones were synthesized from a Claisen-Schmidt condensation by using the couple KOH/1,4-dioxane as reaction medium. A relatively stable aldol was isolated and identified as the intermediate species in the formation of the target chalcones. Nine of the obtained compounds were in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines. Products 16c, 16d, 16h and 27 exhibited the highest activity, being compound 27 the most active, displaying remarkable activity against 50 human tumor cell lines, thirteen of them with GI(50) values <=1.0 MUM, being the HCT-116 (Colon, GI(50) = 0.131 MUM) and LOX IMVI (Melanoma, GI(50) = 0.134 MUM) the most sensitive strains. Compound 27 was referred to in vivo acute toxicity and hollow fiber assay by the Biological Evaluation Committee of the NCI. The acute toxicity study indicated that compound 27 was well tolerated intraperitoneally (150 mg/kg/dose) by athymic nude mice. This compound may possibly be used as lead compound for developing new anticancer agents. PMID- 23043767 TI - Resistive switching of Au/ZnO/Au resistive memory: an in situ observation of conductive bridge formation. AB - A special chip for direct and real-time observation of resistive changes, including set and reset processes based on Au/ZnO/Au system inside a transmission electron microscope (TEM), was designed. A clear conducting bridge associated with the migration of Au nanoparticles (NPs) inside a defective ZnO film from anode to cathode could be clearly observed by taking a series of TEM images, enabling a dynamic observation of switching behaviors. A discontinuous region (broken region) nearby the cathode after reset process was observed, which limits the flow of current, thus a high resistance state, while it will be reconnected to switch the device from high to low resistance states through the migration of Au NPs after set process. Interestingly, the formed morphology of the conducting bridge, which is different from the typical formation of a conducting bridge, was observed. The difference can be attributed to the different diffusivities of cations transported inside the dielectric layer, thereby significantly influencing the morphology of the conducting path. The current TEM technique is quite unique and informative, which can be used to elucidate the dynamic processes in other devices in the future. PMID- 23043768 TI - Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells. AB - Angiogenesis is a major obstacle for wound healing in patients with diabetic foot wounds. Mesenchymal stem cells (MSCs) have an important function in wound repair, and neurotrophin-3 (NT-3) can promote nerve regeneration and angiogenesis. We investigated the effect of NT-3 on accelerating wound healing in the diabetic foot by improving human bone marrow MSC (hMSC) activation. In vitro, NT-3 significantly promoted VEGF, NGF, and BDNF secretion in hMSCs. NT-3 improved activation of the hMSC conditioned medium, promoted human umbilical vein endothelial cell (HUVEC) proliferation and migration, and significantly improved the closure rate of HUVEC scratches. In addition, we produced nanofiber mesh biological tissue materials through the electrospinning technique using polylactic acid, mixed silk, and collagen. The hMSCs stimulated by NT-3 were implanted into the material. Compared with the control group, the NT-3-stimulated hMSCs in the biological tissue material significantly promoted angiogenesis in the feet of diabetic C57BL/6J mice and accelerated diabetic foot wound healing. These results suggest that NT-3 significantly promotes hMSC secretion of VEGF, NGF, and other vasoactive factors and that it accelerates wound healing by inducing angiogenesis through improved activation of vascular endothelial cells. The hMSCs stimulated by NT-3 can produce materials that accelerate wound healing in the diabetic foot and other ischemic ulcers. PMID- 23043770 TI - Bone marrow edema and osteitis in rheumatoid arthritis: the imaging perspective. AB - Magnetic resonance imaging bone marrow edema is an imaging feature that has been described in many conditions, including osteomyelitis, overuse syndromes, avascular necrosis, trauma, and inflammatory arthritides. In rheumatoid arthritis (RA), bone edema has special significance as it has been shown to be a common and widespread lesion that is often apparent at the hands and wrists but has also been described elsewhere, including the feet. It may occur in early or late disease and has been shown in several large cohort studies to have major negative implications for prognosis. It is the strongest predictor of erosive progression yet to be identified and characteristically occurs in those patients with the most aggressive and potentially disabling disease. In patients with undifferentiated arthritis, bone edema also predicts progression to criteria positive RA, both independently and to a greater extent when combined with anti cyclic citrullinated peptide status or rheumatoid factor positivity. Its histological correlate in the late stages of RA has been shown to be osteitis, in which the bone marrow beneath the joint is invaded by an inflammatory and vascular lymphoplasmacytic infiltrate. This lies adjacent to trabecular bone, where increased numbers of osteoclasts have been observed within resorption lacunae, suggesting a mechanistic link between inflammation and erosive bone damage. This could lead to erosion both of the overlying cortex, leading to classic radiographic rheumatoid erosions, and of local trabecular bone, possibly contributing to periarticular osteopenia and cyst formation. In addition to synovitis, osteitis is now regarded as a major rheumatoid lesion that is responsive to therapeutic intervention. PMID- 23043771 TI - A clinical investigation of motivation to change standards and cognitions about failure in perfectionism. AB - BACKGROUND: Clinical perfectionism is a transdiagnostic process that has been found to maintain eating disorders, anxiety disorders and depression. Cognitive behavioural models explaining the maintenance of clinical perfectionism emphasize the contribution of dichotomous thinking and resetting standards higher following both success and failure in meeting their goals. There has been a paucity of research examining the predictions of the models and motivation to change perfectionism. Motivation to change is important as individuals with clinical perfectionism often report many perceived benefits of their perfectionism; they are, therefore, likely to be ambivalent regarding changing perfectionism. AIMS: The aim was to compare qualitative responses regarding questions about motivation to change standards and cognitions regarding failure to meet a personal standard in two contrasting groups with high and low negative perfectionism. Negative perfectionism refers to concern over not meeting personal standards. METHOD: A clinical group with a range of axis 1 diagnoses who were elevated on negative perfectionism were compared to a group of athletes who were low on negative perfectionism. RESULTS: Results indicated that the clinical group perceived many negative consequences of their perfectionism. They also, however, reported numerous benefits and the majority stated that they would prefer not to change their perfectionism. The clinical group also reported dichotomous thinking and preferring to either keep standards the same or reset standards higher following failure, whilst the athlete group reported they would keep standards the same or set them lower. CONCLUSIONS: The findings support predictions of the cognitive behavioural model of clinical perfectionism. PMID- 23043772 TI - Unpredicted ovulations and conceptions during early pregnancy: an explanatory mechanism of human superfetation. AB - In this bioessay, a literature review on human superfetation was performed in order to find epidemiological variables associated with this phenomenon. Thereafter, an explanatory mechanism of superfetation compatible with the endocrinological, histological and physiological changes undergone by women during early pregnancy is proposed. Superfetation can be defined as the ovulation, fertilisation and implantation of a second or additional embryo(s) during pregnancy. The literature review evidences a small discordance in gestational age between dizygotic twins in humans (range: 2-4 weeks; mean +/- s.e.m.: 3.3 +/- 0.3 weeks). This difference is compatible with a luteal out-of phase (LOOP; i.e. atypical increase in E2 levels in the mid-luteal phase)-like event occurring between 1 and 3 weeks after the ovulation that allowed the first pregnancy to take place. The LOOP-like event may allow passive sperm transport from the vaginal fornix to the Fallopian tube ipsilateral to the ovulatory ovary and trigger a LH peak and ovulation. Furthermore, during very early pregnancy, the decidual reaction is not yet completed and at least one proximal Fallopian ostium may be opened, allowing the passage of the spermatozoa ascending to the fertilisation site and the extra embryo(s) descending to the implantation site(s). PMID- 23043773 TI - The intensive terahertz electroluminescence induced by Bloch oscillations in SiC natural superlattices. AB - : We report on efficient terahertz (THz) emission from high-electric-field biased SiC structures with a natural superlattice at liquid helium temperatures. The emission spectrum demonstrates a single line, the maximum of which shifts linearly with increases in bias field. We attribute this emission to steady-state Bloch oscillations of electrons in the SiC natural superlattice. The properties of the THz emission agree fairly with the parameters of the Bloch oscillator regime, which have been proven by high-field electron transport studies of SiC structures with natural superlattices. PMID- 23043774 TI - Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) after laparoscopic Roux-en-Y gastric bypass for morbid obesity: a case report. AB - INTRODUCTION: Kikuchi-Fujimoto disease, or histiocytic necrotizing lymphadenitis, is a rare, benign, autoimmune condition characterized by lymphadenopathy, fever and neutropenia. It is a self-limited condition of unknown etiology. CASE PRESENTATION: We report the case of a 45-year-old Caucasian man with the first known case of Kikuchi disease associated with dramatic weight loss after bariatric surgery. CONCLUSION: Although the association between Kikuchi disease and bariatric surgery may be entirely coincidental, we speculate whether the immune dysfunction associated with weight loss may have played an etiologic role in this process. PMID- 23043776 TI - The effect of otolith malformation on behavior and cortisol levels in juvenile red drum fish (Sciaenops ocellatus). AB - Captive-raised red drum fish were observed with phenotypic abnormalities, including deformities of the spine, jaw, and cephalic region, that were consistent with vitamin C deficiency during the larval stage. In light of their visible exterior skeletal abnormalities, we suspected that the affected fish would also have abnormal otoliths. Otoliths are dense calcareous structures that function in fish hearing. We hypothesized that abnormal fish would have irregular otoliths that would alter behavior and cortisol levels as compared with those of phenotypically normal fish. The normal and abnormal fish had statistically significant differences in behavior, cortisol levels, and otolith volume and density. MicroCT assessment of abnormal fish revealed operculum abnormalities, malocclusions, and several types of otolith malformations. Therefore, the affected fish had not only an abnormal skeletal appearance but also significantly abnormal behavior and cortisol responses. PMID- 23043777 TI - Ulcerative dermatitis in C57BL/6 mice lacking stearoyl CoA desaturase 1. AB - Ulcerative dermatitis (UD) is a common cause of morbidity and euthanasia in mice with a C57BL/6 (B6) background. The purposes of the current study were to determine whether UD lesions could be reliably produced in B6 mice lacking stearoyl-CoA desaturase 1 (SCD1(-/-) mice), to ascertain whether the UD lesions in SCD1(-/-) mice were similar to those found in other B6 mice, and to characterize the cell invasion phenotype of Staphlococcus xylosus cultured from the lesions. S. xylosus isolates from the environment and human skin were used as controls. SCD1(-/-) (n = 8 per group) and nontransgenic B6 control mice (n = 22 mice pooled from 3 groups that received different concentrations of conjugated linoleic acid) were fed standard rodent chow or a semipurified diet (NIH AIN76A) for 4 wk. Samples from other B6 mice with UD (field cases; n = 7) also were submitted for histology and culture. All of the SCD1(-/-) mice developed UD lesions by 4 wk on NIH AIN76A. None of SCD1(-/-) fed standard rodent chow and none of the wildtype B6 mice fed NIH AIN76A developed UD. Supplementation with conjugated linoleic acid did not affect ulcerogenesis. UD lesions in SCD1(-/-) mice and field cases were grossly and histologically similar. S. xylosus was isolated from SCD1(-/-) mice with UD (71%) and field cases of UD (43%). These isolates were the most cell-invasive, followed by the environmental isolate, and finally the human skin isolate. Our results provide a basis for further pathologic and clinical study of UD. PMID- 23043778 TI - Aortic response to balloon injury in obese Zucker rats. AB - The small diameter of the carotid artery is not compatible with the evaluation of clinically available endovascular devices in the carotid balloon-injury (BI) model. We developed an endovascular BI model in the rat descending aorta, whose size is compatible with available endovascular instruments. We also tested the hypothesis that neointima formation is enhanced in the aorta of obese Zucker rats (OZR) compared with lean Zucker rats (LZR). Left external carotid arteriotomies and BI of the thoracic and abdominal aorta were performed by using a balloon catheter. Aortograms and aortic pathology were examined at 2, 4, and 10 wk after BI. At 10 wk after BI, the abdominal aorta in OZR had narrowed 8.3% +/- 1.1% relative to baseline compared with an expansion of 2.4% +/- 2.2% in LZR. Simultaneously, the thoracic aorta had expanded 9.5% +/- 4.3% in LZR compared with stenosis of 2.8% +/- 1.6% in OZR. Calculation of the intimal:medial thickness ratio revealed significantly increased neointimal formation in the OZR descending aorta compared with that in LNR. In conclusion, this minimally invasive BI model involving the rat descending aorta is compatible with available endovascular instruments. The descending aorta of OZR demonstrates enhanced neointimal formation and constrictive vascular remodeling after BI. PMID- 23043779 TI - Effect of prophylactic supplementation with grape polyphenolics on endotoxin induced serum secretory phospholipase A2 activity in rats. AB - This study investigated whether dietary supplementation of polyphenolics-rich grape extract (GE) could attenuate endotoxin-induced serum secretory phospholipase A(2) (sPLA(2)) activity, a modulator of inflammation. Male Sprague Dawley rats were fed a control diet or the diet supplemented with polyphenolic rich GE (100 or 300 mg/kg daily) for 3 wk prior to intraperitoneal injection of 3 or 15 mg/kg LPS. A fluorometric assay was used to measure serum sPLA(2) activity during a 5-d period before and after LPS injection. Body weight, hematocrit, and serum C-reactive protein level were also measured. Administration of LPS induced a rapid increase in sPLA(2) activity, which peaked 1 to 2 d after LPS injection and resolved to near-baseline values on days 4 to 5. Marked declines in body weight and hematocrit, increases in C-reactive protein levels, and effects on health status also occurred. GE supplementation significantly attenuated the LPS induced increase in sPLA(2) activity and decline in hematocrit, but its effects on the loss of body weight and C-reactive protein levels were not significant. Among the measurements, serum sPLA(2) was the only marker that showed a dose dependent response to both LPS and GE supplementation. The current findings show that oral consumption of polyphenolic-rich GE suppresses endotoxin-induced sPLA(2) activity. PMID- 23043780 TI - Adenocarcinoma of the dorsal glands in 2 European ground squirrels (Spermophilus citellus). AB - Olfactory communication is an important aspect of the biology of ground squirrels; accordingly, some of their integumentary glands are associated with scent-marking behavior. Although reports of neoplasms in ground squirrels are limited, the literature on tumors in this family of rodents is extensive, with hepatocellular carcinomas in woodchucks and fibromas in squirrels being the 2 most common neoplasms. Apocrine gland tumors occur frequently in domestic animals such as cats and dogs but to our knowledge have not previously been reported in squirrels. Here we describe 2 cases of adenocarcinoma of the dorsal glands in privately owned European ground squirrels (Spermophilus citellus). The skin nodules were characterized histologically by proliferation of epithelial cells, which were arranged in a tubuloacinar pattern with neoplastic emboli within the blood vessels. Adenocarcinoma of the dorsal glands was diagnosed in light of the anatomic localization, immunohistochemistry results, and histochemistry findings. PMID- 23043782 TI - Cloning of porcine platelet glycoprotein Ibalpha and comparison with the human homolog. AB - Glycoprotein Ib-IX-V (GPIb-IX-V) is a platelet adhesion receptor complex that initiates platelet aggregation. Glycoprotein Ibalpha (GPIbalpha) is the central component of the GPIb-IX-V complex, anchoring the complex to the cytoskeleton and harboring the binding site for von Willebrand factor (vWF). Previous studies suggest that the coagulation function in pigs differs from that in humans, especially with respect to the interaction between vWF and platelets. However, we have little knowledge about the function of porcine platelets, which is important with regard to studies of cardiovascular disease, clotting, and surgery that use pigs as animal models. To extend this information, we cloned and analyzed the porcine GPIbalpha sequence. Porcine GPIbalpha contains 1891 nucleotides and includes an open reading frame that encodes 627 amino acids. The nucleotide sequence showed 67% identity with human GPIbalpha, whereas the deduced amino acid sequences were 59% identical. The vWF binding domain shares the highest identity among different species, whereas the PEST domain shows variations. Evaluation of platelet function by using ristocetin-induced platelet aggregation revealed remarkably lower levels of aggregation in porcine than human platelets. According to the sequence analysis and platelet aggregation tests, we propose that the function of GPIbalpha, especially regarding the ristocetin-vWF GPIbalpha interaction, differs between pigs and humans. This characterization of porcine GPIbalpha will enhance our knowledge of the porcine coagulation system. PMID- 23043781 TI - Effects of a diet high in salt, fat, and sugar on telemetric blood pressure measurements in conscious, unrestrained adult Yucatan miniature swine (Sus scrofa). AB - Radiotelemetry was used to evaluate diet-related elevation of blood pressure in adult Yucatan miniature swine. Systolic arterial blood pressure (SAP), diastolic atrial blood pressure (DAP), heart rate, and locomotor activity were assessed in 9- or 11-mo-old Yucatan miniature pigs fed a standard diet or a North American type diet high in salt, fat, and sugar (HSFS). Compared with pigs fed standard diet, pigs fed HSFS diet showed markedly elevated SAP (132 +/- 3 compared with 156 +/- 6 mm Hg), whereas DAP was unchanged (92 +/- 2 compared with 99 +/- 5 mm Hg). In addition, all pigs were modestly sensitive to short-term changes in dietary salt, as indicated by a 6% to 7% response in blood pressure parameters. According to these data, the increase in SAP for pigs on the HSFS diet was too large to be explained by the NaCl content of the diet alone. We found no evidence of endothelial dysfunction, and the relaxation responses of isolated coronary arteries actually were enhanced in the HSFS group. In conclusion, in a Yucatan miniature pigs model chronically fed a HSFS diet, DAP did not increase, but SAP and pulse pressure appeared to be affected by high dietary levels of fat or sugar (or both). PMID- 23043783 TI - Edema and tetraparesis in a miniature pig after allogeneic hematopoietic cell transplantation. AB - A 3-mo-old, 12-kg, intact, miniature pig presented with severe neurologic signs on day 8 after hematopoietic cell transplantation. This pig had received an immunosuppressive regimen before transplantation that included an antiCD3 immunotoxin for T-cell depletion, 100 cGy of total-body irradiation, and cyclosporine for 45 d. The pig began exhibiting erythematous lesions on posttransplantation day 7. He also demonstrated increased conscious proprioceptive deficits and recumbency but normal mentation. Neurologic signs worsened over several days; the pig became lethargic but remained afebrile. Conjunctival swelling developed on posttransplantation day 9, which subsequently spread to the animal's head, ears and hocks by day 10. Analgesics were given for pain, and cyclosporine levels were decreased. Despite the measures taken, neurologic signs progressed. Given the worsening subcutaneous edema and neurologic status, Escherichia coli infection was suspected, and treatment with a third-generation cephalosporin was instituted. The clinical signs resolved within 12 h after the start of antibiotics. 'Shiga-like' toxin from E. coli can cause peracute toxemia and induce ataxia, paralysis, and recumbency. Other common and pathognomonic findings include periocular edema and variable edema in other subcutaneous regions. A fecal sample demonstrated an overgrowth of gram-negative, lactose-fermenting colonies. On the basis of the clinical presentation, exclusion of other potential conditions compatible with edema and neurologic diseases, physical exam findings, microbiology and the resolution of signs after therapy, the pig was diagnosed with edema disease. PMID- 23043784 TI - Alternative activation of macrophages in rhesus macaques (Macaca mulatta) with endometriosis. AB - Endometriosis is one of the most frequently encountered gynecologic diseases and a common cause of chronic pelvic pain and infertility. The pathophysiology of this syndrome can best be described as the presence of ectopic endometrium and a pelvic inflammatory process with associated immune dysfunction and alteration in the peritoneal environment. Macrophages play an important role in the progression and propagation of endometriosis. Alternative macrophage activation occurs in rodents and women with endometriosis but had not been examined previously in nonhuman primates. This case-control study aimed to characterize macrophage polarization in the ectopic and eutopic endometrial tissue of nonhuman primates with and without endometriosis. In addition, circulating cytokines in endometriosis cases and normal controls were investigated in an effort to identify serum factors that contribute to or result from macrophage polarization. Endometriosis lesions demonstrated increased infiltration by macrophages polarized toward the M2 phenotype when compared with healthy control endometrium. No serum cytokine trends consistent with alternative macrophage activation were identified. However, serum transforming growth factor alpha was elevated in macaques with endometriosis compared with healthy controls. Findings indicated that the activation state of macrophages in endometriosis tissue in nonhuman primates is weighted toward the M2 phenotype. This important finding enables rhesus macaques to serve as an animal model to investigate the contribution of macrophage polarization to the pathophysiology of endometriosis. PMID- 23043785 TI - Efficacy of antibiotic-impregnated polymethylmethacrylate beads in a rhesus macaque (Macaca mulatta) with osteomyelitis. AB - Here we describe the successful surgical implementation of antibiotic-impregnated polymethylmethacrylate beads in a rhesus macaque (Macaca mulatta) with marked osteomyelitis. The macaque presented to the veterinary clinic with grossly contaminated bite wounds in the left ankle secondary to conspecific trauma. Radiographic findings were highly suggestive of osteomyelitis. Additional differential diagnoses included bony infarct, fracture, and cellulitis. In light of the location of the lesion and extensive tissue trauma, the animal had a poor prognosis. Systemic, broad-spectrum antibiotics were instituted. After 2 wk of care, lesions did not respond to empirical therapies. On consultation, a veterinary orthopedic surgeon at another facility recommended placement of antibiotic-impregnated polymethylmethacrylate beads at the sites of osteomyelitis. The animal underwent minor surgery in which beads were introduced into the wound. The monkey had a positive response to therapy. The animal regained full function and was returned to outdoor social housing. Veterinarians are encouraged to consider using antibiotic-impregnated polymethylmethacrylate beads when treating osteomyelitis in other nonhuman primates and in other traditional laboratory animal species. PMID- 23043786 TI - An outbreak of tularemia in a colony of outdoor-housed rhesus macaques (Macaca mulatta). AB - Since an epizootic and detection of clinical cases of tularemia (Francisella tularensis) in 1996 at the Oregon National Primate Research Center, only 8 cases were identified in the succeeding 13 y. However, within a period of 7 mo, primarily during Winter 2010, 6 rhesus macaques were confirmed positive for Francisella tularensis type B by the Centers for Disease Control and Prevention by culture and fluorescent antibody testing. All cases had similar gross pathologic findings, which included necrotizing splenitis and lymphadenitis. Recent colony management efforts have focused on minimizing nonhuman primate exposure to commonly observed reservoir species and controlling rodent access to corral-style housing. Strategies continue to evolve with regard to managing a large breeding colony of nonhuman primates in the presence of this threat. PMID- 23043787 TI - Cerebrovascular accident (stroke) in captive, group-housed, female chimpanzees. AB - Over a 5-y period, 3 chimpanzees at our institution experienced cerebrovascular accidents (strokes). In light of the increasing population of aged captive chimpanzees and lack of literature documenting the prevalence and effectiveness of various treatments for stroke in chimpanzees, we performed a retrospective review of the medical records and necropsy reports from our institution. A survey was sent to other facilities housing chimpanzees that participate in the Chimpanzee Species Survival Plan to inquire about their experience with diagnosing and treating stroke. This case report describes the presentation, clinical signs, and diagnosis of stroke in 3 recent cases and in historical cases at our institution. Predisposing factors, diagnosis, and treatment options of cerebral vascular accident in the captive chimpanzee population are discussed also. PMID- 23043788 TI - Human adult periodontal ligament-derived cells integrate and differentiate after implantation into the adult mammalian brain. AB - Previous studies suggest that neural crest (NC)-derived stem cells may reside in NC derivatives including the human periodontal ligament (hPDL). The isolation and manipulation of autologous NC-derived cells could be an accessible source of adult neural stem cells for their use in cell replacement and gene transfer to the diseased central nervous system. In this study, we examined the expression of NC markers and neural differentiation potential of hPDL-derived cells both in vitro and in vivo. In vitro we found that hPDL-derived cells expressed stem cell markers (Oct3/4, Nestin, Sox2, and Musashi-1) and a subset of NC cell markers (Slug, p75(NTR), Twist, and Sox9). hPDL-derived cells differentiated into neural like cells based on cellular morphology and neural marker expression (TUJ1, MAP2, MAP1b, GAD65/67, GABA, NeuN, ChAT, GAT1, synaptophysin, GFAP, NG2, and O4). In vivo, hPDL-derived cells survive, migrate, and give rise to DCX(+), NF-M(+), GABA(+), GFAP(+), and NG2(+) cells after grafting the adult mouse brain. Some of the grafted hPDL-derived cells were located in stem cell niches such as the ventricular epithelium and the subventricular zone of the anterolateral ventricle wall as well as in the subgranular zone of the hippocampal dentate gyrus. Thus, the hPDL contains stem cells that originate from the NC and can differentiate into neural cells. The engraftment and differentiation properties of hPDL-derived cells in the adult brain indicate that they are a potential stem cell source to be used in neuroregenerative and/or neurotrophic medicine. PMID- 23043790 TI - Evidence that hyperprolactinaemia is associated with ovarian acyclicity in female zoo African elephants. AB - African elephants of reproductive age in zoos are experiencing high rates of ovarian cycle problems (>40%) and low reproductive success. Previously, our laboratory found that 1/3 of acyclic females exhibit hyperprolactinaemia, a likely cause of ovarian dysfunction. This follow-up study re-examined hyperprolactinaemia in African elephants and found the problem has increased significantly to 71% of acyclic females. Circulating serum progestagens and prolactin were analysed in 31 normal cycling, 13 irregular cycling and 31 acyclic elephants for 12 months. In acyclic females, overall mean prolactin concentrations differed from cycling females (P < 0.05), with concentrations being either higher (n = 22; 54.90 +/- 13.31 ngmL(-1)) or lower (n = 9; 6.47 +/- 1.73 ngmL(-1)) than normal. No temporal patterns of prolactin secretion were evident in elephants that lacked progestagen cycles. In cycling females, prolactin was secreted in a cyclical manner, with higher concentrations observed during nonluteal (34.38 +/- 1.77 and 32.75 +/- 2.61 ngmL(-1)) than luteal (10.51 +/- 0.30 and 9.67 +/- 0.42 ngmL(-1)) phases for normal and irregular females, respectively. Of most concern was that over two-thirds of acyclic females now are hyperprolactinemic, a dramatic increase over that observed 7 years earlier. Furthermore, females of reproductive age constituted 45% of elephants with hyperprolactinaemia. Until the cause of this problem is identified and a treatment is developed, reproductive rates will remain suboptimal and the population nonsustaining. PMID- 23043789 TI - Enhanced reward-facilitating effects of d-amphetamine in rats in the quinpirole model of obsessive-compulsive disorder. AB - The underlying neurobiology of addictive or repetitive behaviours, such as obsessive-compulsive disorder (OCD), involves dopaminergic dysregulation. While addictive behaviour depends strongly on mesolimbocortical dopaminergic responses, repetitive behaviours have been associated with dopaminergic dysregulation in the basal ganglia-thalamo-cortical circuitry. The present study investigates differences in brain stimulation reward in rats with quinpirole-induced compulsive checking behaviour, in order to examine if deficits in reward processing are also relevant for OCD. Rats were tested in the intracranial self stimulation (ICSS) paradigm, which targets reward-related responses. After phenotype induction, animals were implanted with a monopolar stimulation electrode in the left medial forebrain bundle and trained to press a lever to self-administer electric stimulation of varying frequency. The curve-shift method was used to assess the reward-facilitating effects of d-amphetamine and the reward-attenuating effects of haloperidol (a D(2) antagonist). Thresholds for ICSS were estimated before and after drug/saline injection. The reward facilitating effects of d-amphetamine were enhanced in quinpirole-treated rats in comparison to controls. This finding suggests that chronic quinpirole-treatment induces changes within the reward circuitry relevant for compulsive behaviour in the rat. PMID- 23043791 TI - Embryo losses in sheep during short-term nutritional supplementation. AB - To test whether a nutritional supplement fed from 6 days before until 15 days after insemination reduces progesterone concentrations and increases embryo losses, Merino ewes were artificially inseminated (Day 0). Control ewes (n = 116) were not supplemented whereas Lupin6 ewes (n = 112) were supplemented with 500 g lupin grain daily for 6 days before insemination, and Lupin6+15 ewes (n = 122) from 6 days before until 15 days after insemination. There were no major differences between treatment groups in progesterone concentrations over the first 17 days of pregnancy. Embryo losses over Days 10-17 were lower in the Lupin6+15 than in the Control and Lupin6 groups, but the opposite occurred from Day 17-30. The concentrations of insulin and IGF-I were higher in Lupin6+15 ewes on Days 5, 12 and 17, compared with Lupin6 and Control ewes, while leptin concentrations decreased by Day 17 in the Lupin6+15 group. We conclude that feeding ewes for 15 days after mating improved embryo survival, which was associated with an increase in the concentrations of metabolic hormones and lower progesterone concentrations. However, the decrease in leptin concentrations promoted by the interruption of supplementation seems be linked to increased embryo mortality up to Day 30. PMID- 23043792 TI - Glucogenic supply increases oocyte developmental competence in sheep. AB - The present study aimed to determine the influence of a glucogenic supply on oocyte developmental competence. Oestrous cycles were synchronised in 22 Sarda ewes by the insertion (Day 0) of one intravaginal progestagen-impregnated sponge that was removed after 6 days. After removal, the ewes were randomly allocated into two experimental groups (treated and control ewes) and, from Day 7 to Day 11, treated ewes received oral administration of a glucogenic mixture, whereas control animals received water. Follicular development was stimulated by FSH administration from Days 8 to 10. Glucose metabolism was assessed from Days 7 to 11, whilst follicle and corpus luteum growth dynamics and functionality were evaluated between Days 6 and 11. At Day 11 ovaries were collected and processed for in vitro embryo production. Glucogenic treatment increased both the plasma levels of glucose, progesterone, oestradiol and the number of 2-3-mm follicles (P < 0.05). Higher fertilisation and blastocyst rates (P < 0.05) were obtained after IVM of oocytes recovered from treated ewes compared with control ones. In conclusion, glucogenic treatment modifies follicle and corpus luteum functionality and improves oocyte quality, as evaluated by in vitro developmental kinetics and blastocyst output. PMID- 23043793 TI - Caloric restriction, but not caloric loading, affects circulating fetal and maternal C-type natriuretic peptide concentrations in late ovine gestation. AB - The factors regulating the greatly elevated concentrations of maternal plasma C type natriuretic peptide (CNP) forms in ruminant pregnancy are largely unknown, but nutrient status is likely to be important. Previous work has shown that increases in maternal plasma CNP, sourced from the placenta, occur in response to caloric restriction in late gestation. Whether oversupply of nutrients also regulates CNP secretion in pregnancy has not been studied. Hypothesising that CNP in fetal and maternal tissues will be responsive to both deficiency and excess, we studied changes in CNP and a cosecreted fragment, namely N-terminal pro-CNP (NTproCNP), during short-term periods of caloric restriction (CR) and loading (CL). Twin-bearing ewes received CR (fasted Days 121-124), CL (Days 110-124) or control maintenance diets. During CR, fetal plasma CNP forms, insulin-like growth factor (IGF)-1 and liveweight all fell, and maternal plasma NTproCNP increased. During CL, fetal IGF-1 increased, whereas CNP forms and liveweight were unchanged, as were maternal concentrations of CNP forms. The high abundance of CNP peptides in placental tissues was unaffected by these short-term changes in nutrient supply. We conclude that CNP in the fetal-maternal unit is acutely responsive to undernutrition, but is unaffected by oversupply in late gestation. PMID- 23043794 TI - Growth factor expression pattern of homologous feeder layer for culturing buffalo embryonic stem cell-like cells. AB - The present study examined the expression profile of buffalo fetal fibroblasts (BFF) used as a feeder layer for embryonic stem (ES) cell-like cells. The expression of important growth factors was detected in cells at different passages. Mitomycin-C inactivation increased relative expression levels of ACTIVIN-A, TGF-beta1, BMP-4 and GREMLIN but not of fibroblast growth factor-2 (FGF-2). The expression level of ACTIVIN-A, transforming growth factor-beta1 (TGF beta1), bone morphogenetic protein-4 (BMP-4) and FGF-2 was similar in buffalo fetal fibroblast (BFF) cultured in stem cell medium (SCM), SCM+1000IU mL(-1) leukemia inhibitory factor (LIF), SCM+5 ngmL(-1) FGF-2 or SCM+LIF+FGF-2 for 24 h whereas GREMLIN expression was higher in FGF-2-supplemented groups. In spent medium, the concentration of ACTIVIN-A was higher in FGF-2-supplemented groups whereas that of TGF-beta1 was similar in SCM and LIF+FGF-2, which was higher than when either LIF or FGF-2 was used alone. Following culture of ES cell-like cells on a feeder layer for 24 h, the TGF-beta1 concentration was higher with LIF+FGF-2 than with LIF or FGF-2 alone which, in turn, was higher than that in SCM. In the LIF+FGF-2 group, the concentration of TGF-beta1 was lower and that of ACTIVIN-A was higher in spent medium at 24 h than at 48 h of culture. These results suggest that BFF produce signalling molecules that may help in self-renewal of buffalo ES cell-like cells. PMID- 23043795 TI - Impact of mouse pregnancy on thymic T lymphocyte subsets. AB - It has been reported that fetal lymphoid progenitor cells are acquired during gestation and are able to develop in the maternal mouse thymus into functional T cells. Moreover, previous pregnancies increase the number of fetal cells in the mother. In the present study, we investigated whether mouse pregnancy induces changes in T lymphocyte subsets in the maternal thymus. We determined the T lymphocyte subsets in two allogeneic cross-breedings, namely CBA/J*BALB/c (normal) and CBA/J*DBA/2 (abortion prone), and investigated the effects of the age and parity of the female, as well as pregnancy outcome, on thymocyte populations. In addition, hormonal effects were evaluated in a syngeneic combination (CBA/J*CBA/J). We found that during pregnancy both hormonal and allogeneic stimuli induced a reduction in the CD4(+)CD8(+) subset with an increase in the CD4(+)CD8(-) population. Only young females of the normal combination exhibited an increase in the CD4(-)CD8(+) population. All young mice showed an increase in CD4(+)CD25(+)FoxP3(+) T cells. Interestingly, the gammadeltaT thymus pool was increased in all females of the normal allogeneic pregnancy only, suggesting the participation of this pool in the observed beneficial effect of multiparity in this cross-breeding. Our results demonstrate that allogeneic pregnancies induce important variations in maternal thymocyte subpopulations depending on the age of the female and the male component of the cross-breeding. PMID- 23043796 TI - Initial stage growth of GexSi1-x layers and Ge quantum dot formation on GexSi1-x surface by MBE. AB - Critical thicknesses of two-dimensional to three-dimensional growth in GexSi1-x layers were measured as a function of composition for different growth temperatures. In addition to the (2 * 1) superstructure for a Ge film grown on Si(100), the GexSi1-x layers are characterized by the formation of (2 * n) reconstruction. We measured n for all layers of Ge/GexSi1-x/Ge heterosystem using our software with respect to the video recording of reflection high-energy electron diffraction (RHEED) pattern during growth. The n reaches a minimum value of about 8 for clear Ge layer, whereas for GexSi1-x films, n is increased from 8 to 14. The presence of a thin strained film of the GexSi1-x caused not only the changes in critical thicknesses of the transitions, but also affected the properties of the germanium nanocluster array for the top Ge layer. Based on the RHEED data, the hut-like island form, which has not been previously observed by us between the hut and dome islands, has been detected. Data on the growth of Ge/GexSi1-x/Ge heterostructures with the uniform array of islands in the second layer of the Ge film have been received. PMID- 23043797 TI - Recurrent adult-onset hypophyseal Langerhans cell histiocytosis after radiotherapy: a case report. AB - INTRODUCTION: Langerhans cell histiocytosis is a rare disease within the adult population, with very few cases reported as solitary hypophyseal lesions in adults. Of the reported cases, most have been treated successfully with surgery, radiotherapy, and/or chemotherapy. Radiotherapy has been thought to be curative at the relatively low dose of 20Gy. Here we report a case of recurrent hypophyseal Langerhans cell histiocytosis 9 months after radiotherapy with an interval period of symptomatic and radiographic response to therapy. CASE PRESENTATION: A 50-year-old Caucasian woman who had headaches, memory difficulties, and diabetes insipidus was found to have a 2.5cm suprasellar mass. Langerhans cell histiocytosis was diagnosed following stereotactic brain biopsy. Further workup revealed no other lesions. Initial radiation treatment succeeded in shrinking the tumor and relieving clinical symptoms temporarily; however, growth and recurrence of clinical symptoms was noted at 9 months. Re-irradiation was well tolerated and the patient had no acute side effects. CONCLUSION: Isolated hypophyseal involvement by Langerhans cell histiocytosis in adults is a unique presentation of a rare disease. Although radiotherapy doses as low as 20Gy have been reported to offer control, this case demonstrates that higher doses may be warranted to ensure tumor control. With modern imaging and radiotherapy techniques higher doses should offer little increased more durable risk to surrounding critical structures. PMID- 23043798 TI - Local and systemic immunological parameters associated with remission of asthma symptoms in children. AB - The immunological and clinical parameters that are associated with asthma remission are poorly understood. The cytokine and local mediator changes associated with the resolution of asthma symptoms were examined in three groups of subjects 12-18 years of age (n = 15 in each group): (a) continuing asthma group (CA) who had persistent symptoms since early childhood, (b) an age, sex and atopic status-matched group who had persistent symptoms in early childhood but in whom these had resolved (RA), and (c) a non-atopic, non-asthmatic control group. Clinical parameters, sputum cell counts, peripheral blood mononuclear cell (PBMC) cytokine production and activation marker expression were determined. All of the CA had methacholine airway hyperresponsiveness compared with only half of the RA subjects. The CA showed elevated numbers of eosinophils and increased ECP and IL 5 in sputum, which were not observed in the RA. PBMC cytokine studies revealed increased production of the type 1 cytokines IL-12, IFN-gamma and TNF-alpha in the CA group compared with the RA group, under a range of activation conditions, however, the production of IL-4 and IL-5 were unchanged. These findings suggest that decreased type 1 cytokine expression as well as decreased eosinophilic inflammation is associated with the resolution of asthma symptoms. PMID- 23043799 TI - SSEA4-positive pig induced pluripotent stem cells are primed for differentiation into neural cells. AB - Neural cells derived from induced pluripotent stem cells (iPSCs) have the potential for autologous cell therapies in treating patients with severe neurological disorders or injury. However, further study of efficacy and safety are needed in large animal preclinical models that have similar neural anatomy and physiology to humans such as the pig. The pig model for pluripotent stem cell therapy has been made possible for the first time with the development of pig iPSCs (piPSCs) capable of in vitro and in vivo differentiation into tissues of all three germ layers. Still, the question remains if piPSCs are capable of undergoing robust neural differentiation using a system similar to those being used with human iPSCs. In this study, we generated a new line of piPSCs from fibroblast cells that expressed pluripotency markers and were capable of embryoid body differentiation into all three germ layers. piPSCs demonstrated robust neural differentiation forming betaIII-TUB/MAP2+ neurons, GFAP+ astrocytes, and O4+ oligodendrocytes and demonstrated strong upregulation of neural cell genes representative of all three major neural lineages of the central nervous system. In the presence of motor neuron signaling factors, piPSC-derived neurons showed expression of transcription factors associated with motor neuron differentiation (HB9 and ISLET1). Our findings demonstrate that SSEA4 expression is required for piPSCs to differentiate into neurons, astrocytes, and oligodendrocytes and furthermore develop specific neuronal subtypes. This indicates that the pigs can fill the need for a powerful model to study autologous neural iPSC therapies in a system similar to humans. PMID- 23043800 TI - Sedation or inhalant anesthesia before euthanasia with CO2 does not reduce behavioral or physiologic signs of pain and stress in mice. PMID- 23043802 TI - Total IgE as a serodiagnostic marker to aid murine fur mite detection. PMID- 23043805 TI - Litter size predicts adult stereotypic behavior in female laboratory mice. AB - Stereotypic behaviors are repetitive invariant behaviors that are common in many captive species and potentially indicate compromised welfare and suitability as research subjects. Adult laboratory mice commonly perform stereotypic bar gnawing, route-tracing, and back-flipping, although great individual variation in frequency occurs. Early life factors (for example, level of maternal care received) have lasting effects on CNS functioning and abilities to cope with stress and therefore may also affect stereotypic behavior in offspring. Access to maternal resources and care are influenced by the number of pups in a litter; therefore, we examined both litter size and its potential correlate, weight at weaning, as early environmental predictors of adult stereotypic behavior in laboratory mice. Further, we assessed the effects on offspring stereotypic behavior of delaying the separation of mother and pups (weaning) beyond the standard 21 d of age. Analyzing stereotypic behavior in 3 different mouse colonies composed of 2 inbred strains (C57BL/6N and C57BL/6J) and an outbred stock (CD1[ICR]) revealed significant positive correlation between litter size and stereotypic behavior in female, but not male, mice. Weight and age at weaning did not significantly affect levels of stereotypy in either sex. Litter size therefore may be a useful indicator of individual predisposition to stereotypic behavior in female laboratory mice. PMID- 23043804 TI - Variation in airway responsiveness of male C57BL/6 mice from 5 vendors. AB - Mice are now the most commonly used animal model for the study of asthma. The mouse asthma model has many characteristics of the human pathology, including allergic sensitization and airway hyperresponsiveness. Inbred strains are commonly used to avoid variations due to genetic background, but variations due to rearing environment are not as well recognized. After a change in mouse vendors and a switch from C57BL/6J mice to C57BL/6N mice, we noted significant differences in airway responsiveness between the substrains. To further investigate the effect of vendor, we tested C57BL/6N mice from 3 other vendors and found significant differences between several of the substrains. To test whether this difference was due to genetic drift or rearing environment, we purchased new groups of mice from all 5 vendors, bred them in separate vendor specific groups under uniform environmental conditions, and tested male first generation (F1) offspring at 8 to 10 wk of age. These F1 mice showed no significant differences in airway responsiveness, indicating that the rearing environment rather than genetic differences was responsible for the initial variation in pulmonary phenotype. The environmental factors that caused the phenotypic variation are unknown. However, differences between vendor in feed components, bedding type, or microbiome could have contributed. Whatever the basis, investigators using mouse models of asthma should be cautious in comparing data from mice obtained from different vendors. PMID- 23043806 TI - Preliminary evaluation on the effects of feeds on the growth and early reproductive performance of zebrafish (Danio rerio). AB - This study evaluated the effects of several commercially available feeds and different feeding regimes on the growth and early reproductive performance of zebrafish (Danio rerio). Juvenile zebrafish (n = 20; 5.06 +/- 0.69 mg) were stocked into each of 24 tanks (volume, 2 L); 3 tanks were assigned to each of 8 feeding combinations for a period of 60 d. At the end of 60 d, 2 male and 2 female fish from each tank were pooled by dietary treatment (n = 6) and used to evaluate the effects of feeding combinations on early reproductive performance. Zebrafish fed dietary treatments 3 and 7 had significantly greater weight gain than zebrafish fed diet 5. Mean spawning success was significantly greater in zebrafish fed the control diet (Artemia only) than in those fed diet 1. Mean hatch rates were greater in zebrafish fed the control feed and diets 1, 2, 3, 5, and 6 than zebrafish fed diet 4. Additional results suggest that female zebrafish are sexually mature after 90 d post fertilization and that fertilization rates are the limiting factor in early reproduction. PMID- 23043807 TI - Structural and functional concepts in current mouse phenotyping and archiving facilities. AB - Collecting and analyzing available information on the building plans, concepts, and workflow from existing animal facilities is an essential prerequisite for most centers that are planning and designing the construction of a new animal experimental research unit. Here, we have collected and analyzed such information in the context of the European project Infrafrontier, which aims to develop a common European infrastructure for high-throughput systemic phenotyping, archiving, and dissemination of mouse models. A team of experts visited 9 research facilities and 3 commercial breeders in Europe, Canada, the United States, and Singapore. During the visits, detailed data of each facility were collected and subsequently represented in standardized floor plans and descriptive tables. These data showed that because the local needs of scientists and their projects, property issues, and national and regional laws require very specific solutions, a common strategy for the construction of such facilities does not exist. However, several basic concepts were apparent that can be described by standardized floor plans showing the principle functional units and their interconnection. Here, we provide detailed information of how individual facilities addressed their specific needs by using different concepts of connecting the principle units. Our analysis likely will be valuable to research centers that are planning to design new mouse phenotyping and archiving facilities. PMID- 23043808 TI - Prevalence of murine Helicobacter spp. Infection is reduced by restocking research colonies with Helicobacter-free mice. AB - Most academic research colonies of mice are endemically infected with enterohepatic Helicobacter spp. (EHS). We evaluated EHS prevalence in surveillance mice before and after a 10-y period of requiring that imported mice be free of EHS by embryo transfer rederivation or purchase from approved vendors. In 2009, composite fecal samples from CD1 surveillance mice representing colony health in 57 rooms located in 6 facilities were evaluated for EHS infection by using PCR assays. Fecal samples were screened with primers designed to detect all known EHS, and positive samples were further assayed by using primers specific for H. hepaticus, H. bilis, H. rodentium, and H. typhlonicus. Most EHS were detected in surveillance mice within the first month of dirty bedding exposure, with prevalence ranging from 0% to 64% as monoinfections or, more commonly, infections with multiple EHS. Compared with 1999 prevalence data, EHS remained endemic in colonies importing the lowest number of EHS-free mice. EHS were absent or the prevalence was greatly reduced in colonies receiving the highest percentage of EHS-free mice. This study demonstrates that the management decision to require exclusive importation of EHS-free mice reduced EHS prevalence on an institutional scale without intensive labor and expense associated with other techniques or interference with research objectives. PMID- 23043809 TI - Low prevalence of Chagas parasite infection in a nonhuman primate colony in Louisiana. AB - Chagas disease, an important cause of heart disease in Latin America, is caused by the parasite Trypanosoma cruzi, which typically is transmitted to humans by triatomine insects. Although autochthonous transmission of the Chagas parasite to humans is rare in the United States, triatomines are common, and more than 20 species of mammals are infected with the Chagas parasite in the southern United States. Chagas disease has also been detected in colonies of nonhuman primates (NHP) in Georgia and Texas, and heart abnormalities consistent with Chagas disease have occurred at our NHP center in Louisiana. To determine the level of T. cruzi infection, we serologically tested 2157 of the approximately 4200 NHP at the center; 34 of 2157 primates (1.6%) tested positive. Presence of the T. cruzi parasite was confirmed by hemoculture in 4 NHP and PCR of the cultured parasites. These results strongly suggest local transmission of T. cruzi, because most of the infected NHP were born and raised at this site. All 3 species of NHP tested yielded infected animals, with significantly higher infection prevalence in pig tailed macaques, suggesting possible exploration of this species as a model organism. The local T. cruzi strain isolated during this study would enhance such investigations. The NHP at this center are bred for use in scientific research, and the effects of the Chagas parasite on infected primates could confuse the interpretation of other studies. PMID- 23043810 TI - Effect of pain management on immunization efficacy in mice. AB - Immunization with complete Freund adjuvant (CFA) or incomplete Freund adjuvant (IFA) is commonly viewed as painful, yet rodents may not receive analgesics due to concerns that these drugs affect the desired immune responses. Here we tested the hypothesis that pain associated with immunization with CFA or IFA in mice can be relieved without compromising the effectiveness of the immune response. After subcutaneous immunization in the leg with antigen in CFA or IFA, mice were assessed for signs of pain by using behavioral tests, including unrestricted locomotion in an open field, forced running on an automated treadmill, and voluntary wheel running. Effects of the analgesics acetaminophen, meloxicam, and buprenorphine on behavioral and antibody responses were assessed after primary and secondary immunization with the model antigen ovalbumin and after repeated immunization with a limiting dose of recombinant protective antigen from Bacillus anthracis. Open field activity and the distance traveled during forced gait analysis and voluntary wheel running both decreased after immunization. Treatment with each of the analgesics normalized some but not all of these behaviors but did not decrease the mean or maximal antibody titer after primary or repeated immunization with a moderate dose of ovalbumin or after repeated immunization with a limiting dose of protective antigen. In summary, after immunization with CFA or IFA, mice showed behavioral responses suggestive of pain. Acetaminophen, meloxicam, and buprenorphine attenuated these effects without decreasing antibody responses. Therefore, the use of these analgesics for managing rodent pain associated with CFA- or IFA-containing vaccines can be encouraged. PMID- 23043811 TI - Effects of different anesthetics on oscillations in the rat olfactory bulb. AB - Different types of oscillations in the olfactory bulb (OB), including theta (1 to 4 and 5 to 12 Hz), beta (13 to 30 Hz), and gamma oscillations (31 to 64 and 65 to 90 Hz), are important in olfactory information processing and olfactory-related functions and have been investigated extensively in recent decades. The awake and anesthetized states, 2 different brain conditions, are used widely in electrophysiologic studies of OB. Chloral hydrate, pentobarbital, and urethane are commonly used anesthetics in these studies. However, the influence of these anesthetics on the oscillations has not been reported. In the present study, we recorded the local field potential (LFP) in the OB of rats that were freely moving or anesthetized with these agents. Chloral hydrate and pentobarbital had similar effects: they slightly affected the power of theta oscillations; significantly increased the power of beta oscillations; significantly decreased the power of gamma oscillations, and showed similar recovery of gamma oscillations. Urethane had very different effects: it significantly increased oscillations at 1 to 4 Hz but decreased those at 5 to 12 Hz, decreased beta and gamma oscillations, and showed no overt recovery in gamma oscillations. These results provide experimental evidence of different effects of various anesthetics on OB oscillations and suggest that the choice of anesthetic should consider the experimental application. PMID- 23043812 TI - Pharmacologic parameters of MS222 and physiologic changes in frogs (Xenopus laevis) after immersion at anesthetic doses. AB - We evaluated the anesthetic efficacy of MS222 (dose, 1 or 2 g/L; pH 7) administered as an immersion bath (duration, 20 min) for nonbreeding female Xenopus leavis frogs (n = 33; average body weight, 103 +/- 16 g). The acid acetic test, the withdrawal reflex, righting behavior, heart rate, respiratory frequency, and blood oxygen saturation were used to evaluate the level of anesthesia. Acetic acid and withdrawal reflex responses were present at 30 and 60 min following immersion for the 1- and 2-g/L doses, respectively. MS222 had no effect on heart rate or oxygen saturation, but caused pronounced respiratory depression, as expected. Microscopic observations of selected tissues (heart, lung, liver, kidneys, and skin) showed no evidence of lesions at 24 h after immersion. In addition, we calculated the pharmacokinetics of MS222 in plasma and analyzed the drug by HPLC-tandem mass spectrometry. The calculated half-life of MS222 is 3.2 h. We conclude that MS222 administered at 1 or 2 g/mL via immersion bath for 20 min is an effective anesthetic that can be used for surgical procedures of less than 30 or 60 min, respectively, in Xenopus leavis. PMID- 23043814 TI - Effect of repeated freezing and thawing on 18 clinical chemistry analytes in rat serum. AB - In a preclinical research laboratory, using serum samples that have been frozen and thawed repeatedly is sometimes unavoidable when needing to confirm previous results or perform additional analysis. Here we determined the effects of multiple cycles of refrigeration or freezing and thawing of rat serum at 3 temperature conditions for different storage times on clinical chemistry analytes. Serum samples obtained from adult Wistar rats were stored at 2 to 8 degrees C and -10 to -20 degrees C for as long as 72 h and at -70 degrees C for as long as 30 d. At different time points (24, 48, and 72 h for samples stored at 2 to 8 degrees C or -10 to -20 degrees C and 1, 7, and 30 d for samples stored at -70 degrees C), the samples were brought to room temperature, analyzed, and then stored again at the designated temperature. The results obtained after each storage cycle were compared with those obtained from the initial analysis of fresh samples. Of the 18 serum analytes evaluated, 14 were stable without significant changes, even after 3 freeze-thaw cycles at the tested temperature ranges. Results from this study will help researchers working with rat serum to interpret the biochemical data obtained from serum samples that have been frozen and thawed repeatedly. PMID- 23043813 TI - Assessment of routine procedure effect on breathing parameters in mice by using whole-body plethysmography. AB - We used whole-body plethysmography to investigate the effect of restraint, ear marking, tail vein and retroorbital blood sampling, and tail clipping on respiration in Balb/c * TCR-HA +/- F1 hybrid mice (F1h). Baseline values of breathing parameters were determined. During the experiment, mice experienced a procedure and then plethysmographic recordings were obtained immediately and at 4, 24, and 48 h afterward. Baseline breathing parameters showed significant differences between sexes. Restraint affected minute volume differently than did handling in male mice and to a lesser extent in female mice. Ear marking significantly changed minute volume compared with handling but not restraint in male mice and in the opposite manner in female mice. Tail vein blood sampling changed minute volume in a significant manner compared with restraint but not compared with handling in both sexes. Retroorbital blood sampling significantly changed minute volume compared with values for both handling and restraint in male mice but only compared with handling in female mice. Tail clipping modified minute volume significantly compared with handling in male mice and compared with restraint in both sexes. Analysis of data showed that routine procedures affect minute volume in mice depending on invasiveness of maneuver and in a sex-biased manner for as long as 24 h after the procedure. Our experiment shows that procedures performed on laboratory mice can change respiratory parameters and can be investigated by plethysmography. PMID- 23043815 TI - Comparison of noncontact infrared thermometry and 3 commercial subcutaneous temperature transponding microchips with rectal thermometry in rhesus macaques (Macaca mulatta). AB - This study compared a noncontact infrared laser thermometer and 3 different brands of subcutaneous temperature transponding microchips with rectal thermometry in 50 rhesus macaques (Macaca mulatta). The data were analyzed by using intraclass correlation coefficients and limits of agreement. In addition, the technical capabilities and practicality of the thermometers in the clinical setting were reviewed. None of the alternative techniques investigated was equivalent to rectal thermometry in rhesus macaques. Temperatures obtained by using microchips had higher correlation and agreed more closely with rectal temperatures than did those obtained by the noncontact infrared method. However, transponding microchips did not yield consistent results. Due to difficulty in positioning nonsedated macaques in their homecage, subcutaneous microchips were not practical in the clinical setting. Furthermore, pair-housed macaques may be able to break or remove microchips from their cagemates. PMID- 23043817 TI - Osteomyelitis and pyoarthritis resulting from local paracoccidioidomycosis in an immunocompetent patient: a case report. AB - INTRODUCTION: Paracoccidioidomycosis is a type of mycosis that is endemic to Brazil and is triggered by the fungus Paracoccidioides brasiliensis. Isolated bone involvement in this disease is very rare, especially in children. To the best of our knowledge this report documents the first case of an immunocompetent pediatric patient in which paracoccidioidomycosis of the hip articulation was the sole manifestation of the disease (that is, there were no pulmonary or skin lesions). CASE PRESENTATION: An 11-year-old Brazilian Caucasian boy from a rural area was examined in the orthopedic ward of our emergency department. Our patient reported a three-month history of pain in the right hip with intermittent claudication and also complained of recurring episodes of intense pain and an inability to walk, which he had been experiencing for the previous five days. He additionally presented with a fever that had persisted for two days. Our patient's medical history did not include any clinical respiratory manifestations, skin lesions, history of trauma or immunosuppression risk factors. CONCLUSIONS: This is one of the very few reported cases of isolated articular involvement in osteomyelitis in a pediatric immunocompetent patient. Paracoccidioidomycosis should be considered among the differential diagnoses in such cases, especially in cases of patients who reside in rural areas where the condition is considered to be endemic, in order to administer the proper course of treatment in a timely fashion and improve the chances of a favorable prognosis. PMID- 23043816 TI - The challenges of developing an instrument to assess health provider motivation at primary care level in rural Burkina Faso, Ghana and Tanzania. AB - BACKGROUND: The quality of health care depends on the competence and motivation of the health workers that provide it. In the West, several tools exist to measure worker motivation, and some have been applied to the health sector. However, none have been validated for use in sub-Saharan Africa. The complexity of such tools has also led to concerns about their application at primary care level. OBJECTIVE: To develop a common instrument to monitor any changes in maternal and neonatal health (MNH) care provider motivation resulting from the introduction of pilot interventions in rural, primary level facilities in Ghana, Burkina Faso, and Tanzania. DESIGN: Initially, a conceptual framework was developed. Based upon this, a literature review and preliminary qualitative research, an English-language instrument was developed and validated in an iterative process with experts from the three countries involved. The instrument was then piloted in Ghana. Reliability testing and exploratory factor analysis were used to produce a final, parsimonious version. RESULTS AND DISCUSSION: This paper describes the actual process of developing the instrument. Consequently, the concepts and items that did not perform well psychometrically at pre-test are first presented and discussed. The final version of the instrument, which comprises 42 items for self-assessment and eight for peer-assessment, is then shown. This is followed by a presentation and discussion of the findings from first use of the instrument with MNH providers from 12 rural, primary level facilities in each of the three countries. CONCLUSIONS: It is possible to undertake work of this nature at primary health care level, particularly if the instruments are kept as straightforward as possible and well introduced. However, their development requires very lengthy preparatory periods. The effort needed to adapt such instruments for use in different countries within the region of sub Saharan Africa should not be underestimated. PMID- 23043819 TI - Control of Campylobacter jejuni in chicken breast meat by irradiation combined with modified atmosphere packaging including carbon monoxide. AB - Campylobacter is one of the leading causes of human foodborne illnesses originating from meat and poultry products. Cross-contamination of this organism occurs in many poultry processing plants, and can occur in the kitchens and refrigerators of consumers. Therefore, new intervention strategies are needed for meat and poultry products to better protect consumers from this pathogen. Vacuum or modified atmosphere packaging is a common packaging technique used by the meat and poultry industry to extend the shelf life of meat products. In addition, irradiation has been well established as an antibacterial treatment to reduce pathogens on meat and poultry products. Irradiation in combination with high-CO(2) + CO modified atmosphere packaging (MAP) was investigated in this study for the control of Campylobacter jejuni in chicken breast meat. The radiation sensitivity (D(10)-value) of this foodborne pathogen in chicken breast meat was similar in vacuum or high-O(2) MAP (0.31 +/- 0.01 kGy in vacuum packaging and 0.29 +/- 0.03 kGy in MAP). C. jejuni survived in both vacuum and high-CO(2) MAP through 6 weeks of refrigerated storage. Irradiation was effective for eliminating C. jejuni from meat or poultry packaged in vacuum or MAP, and should reduce the chance of cross-contamination in retail stores or home kitchens. However, irradiated off-odor and sour aroma were observed for raw, irradiated chicken breast packaged with either vacuum or MAP. Therefore, additional means to mitigate quality changes appear necessary for these products. PMID- 23043818 TI - Motor modules in robot-aided walking. AB - BACKGROUND: It is hypothesized that locomotion is achieved by means of rhythm generating networks (central pattern generators) and muscle activation generating networks. This modular organization can be partly identified from the analysis of the muscular activity by means of factorization algorithms. The activity of rhythm generating networks is described by activation signals whilst the muscle intervention generating network is represented by motor modules (muscle synergies). In this study, we extend the analysis of modular organization of walking to the case of robot-aided locomotion, at varying speed and body weight support level. METHODS: Non Negative Matrix Factorization was applied on surface electromyographic signals of 8 lower limb muscles of healthy subjects walking in gait robotic trainer at different walking velocities (1 to 3 km/h) and levels of body weight support (0 to 30%). RESULTS: The muscular activity of volunteers could be described by low dimensionality (4 modules), as for overground walking. Moreover, the activation signals during robot-aided walking were bursts of activation timed at specific phases of the gait cycle, underlying an impulsive controller, as also observed in overground walking. This modular organization was consistent across the investigated speeds, body weight support level, and subjects. CONCLUSIONS: These results indicate that walking in a Lokomat robotic trainer is achieved by similar motor modules and activation signals as overground walking and thus supports the use of robotic training for re-establishing natural walking patterns. PMID- 23043820 TI - Efficacy of organic acids, bacteriocins, and the lactoperoxidase system in inhibiting the growth of Cronobacter spp. in rehydrated infant formula. AB - Thirty-three antimicrobial agents, including antimicrobial peptides (nisin, lacticin 3147, isracidin), organic acids, emulsifiers (organic acid esters), glycine, lysozyme, tocopherol, EDTA, milk fat globule membrane, and the lactoperoxidase system (LPOS) were screened for anti-Cronobacter sakazakii activity. The compounds were initially screened individually in parallel in synthetic media. Those showing antimicrobial activity were then tested in reconstituted whole milk and finally in reconstituted powdered infant formula (PIF), using mild temperatures of reconstitution and prolonged storage at room temperature. Propionic acid and monocaprylin (as POEM M-100) in combination showed inhibitory activity at sufficiently low concentrations (0.1 to 0.2%) in milk to be considered as potential antimicrobial additives for the inhibition of C. sakazakii in reconstituted PIF. More interestingly, LPOS, when combined with the broad-spectrum bacteriocins nisin or lacticin 3147, inhibited outgrowth of C. sakazakii at 37 degrees C for 8 h. The combined effects of POEM M-100 and either acetate or propionate and LPOS with lacticin 3147 or nisin were evaluated under the Food and Agriculture Organization of the United Nations-World Health Organization high-risk scenario for PIF, i.e., low temperature of reconstitution and long storage or feeding times at ambient temperature. In the presence of LPOS and lacticin 3147, growth of Cronobacter spp. was inhibited for up to 12 h when the PIF was rehydrated at 40 or 50 degrees C. These results highlight the potential of combinatory approaches to improving the safety of infant milk formula. PMID- 23043821 TI - Selection of in vivo expressed genes of Escherichia coli O157:H7 strain EDL933 in ground meat under elevated temperature conditions. AB - Enterohemorrhagic Escherichia coli O157:H7 strains are important foodborne pathogens that are often transmitted to humans by the ingestion of raw or undercooked meat of bovine origin. To investigate adaptation of this pathogen during persistence and growth in ground meat, we established an in vivo expression technology model to identify genes that are expressed during growth in this food matrix under elevated temperatures (42 degrees C). To improve on the antibiotic-based selection method, we constructed the promoter trap vector pAK-1, containing a promoterless kanamycin resistance gene. A genomic library of E. coli O157:H7 strain EDL933 was constructed in pAK-1 and used for promoter selection in ground meat. The 20 in vivo expressed genes identified were associated with transport processes, metabolism, macromolecule synthesis, and stress response. For most of the identified genes, only hypothetical functions could be assigned. The results of our study provide the first insights into the complex response of E. coli O157:H7 to a ground meat environment under elevated temperatures and establish a suitable vector for promoter studies or selection of in vivo induced promoters in foods such as ground meat. PMID- 23043822 TI - Sensitivity of Shiga toxin-producing Escherichia coli, multidrug-resistant Salmonella, and antibiotic-susceptible Salmonella to lactic acid on inoculated beef trimmings. AB - Studies were performed to determine whether lactic acid treatments used to reduce Escherichia coli O157:H7 on beef trimmings are also effective in controlling non O157 Shiga toxin-producing E. coli (nSTEC), and multidrug-resistant and antibiotic-susceptible Salmonella. Beef trimming pieces (10 by 5 by 1 cm) were inoculated (3 log CFU/cm(2)) separately with four-strain mixtures of rifampin resistant E. coli O157:H7, O26, O45, O103, O111, O121, and O145. Similarly, in a second study, trimmings were separately inoculated with rifampin-resistant E. coli O157:H7, and antibiotic-susceptible or multidrug-resistant (MDR and/or MDR AmpC) Salmonella Newport and Salmonella Typhimurium. Inoculated trimmings were left untreated (control) or were immersed for 30 s in 5% lactic acid solutions (25 or 55 degrees C). No differences (P >= 0.05) were obtained among surviving counts of E. coli O157:H7 and those of the tested nSTEC serogroups on lactic acid treated (25 or 55 degrees C) samples. Counts (3.1 to 3.3 log CFU/cm(2)) of E. coli O157:H7 and nSTEC were reduced (P < 0.05) by 0.5 to 0.9 (25 degrees C lactic acid) and 1.0 to 1.4 (55 degrees C lactic acid) log CFU/cm(2). Surviving counts of Salmonella on treated trimmings were not influenced by serotype or antibiotic resistance phenotype and were similar (P >= 0.05) or lower (P < 0.05) than surviving counts of E. coli O157:H7. Counts (3.0 to 3.3 log CFU/cm(2)) were reduced (P < 0.05) by 0.5 to 0.8 (E. coli O157:H7) and 1.3 to 1.5 (Salmonella) log CFU/cm(2) after treatment of samples with 25 degrees C lactic acid. Corresponding reductions following treatment with lactic acid at 55 degrees C were 1.2 to 1.5 (E. coli O157:H7) and 1.6 to 1.9 (Salmonella) log CFU/cm(2). Overall, the results indicated that lactic acid treatments used against E. coli O157:H7 on beef trimmings should be similarly or more effective against the six nSTEC serogroups and against multidrug-resistant and antibiotic-susceptible Salmonella Newport and Salmonella Typhimurium. PMID- 23043823 TI - Multistate outbreak of Escherichia coli O157:H7 infections associated with in store sampling of an aged raw-milk Gouda cheese, 2010. AB - In 2010, 41 patients ill with Escherichia coli O157:H7 isolates determined to be indistinguishable by pulsed-field gel electrophoresis were identified among residents of five Southwestern U.S. states. A majority of patients reported consuming complimentary samples of aged raw-milk Gouda cheese at national warehouse chain store locations; sampling Gouda cheese was significantly associated with illness (odds ratio, 9.0; 95 % confidence interval, 1.7 to 47). Several Gouda samples yielded the O157:H7 outbreak strain, confirming the food vehicle and source of infections. Implicated retail food-sampling operations were inconsistently regulated among affected states, and sanitation deficiencies were common among sampling venues. Inspection of the cheese manufacturer indicated deficient sanitation practices and insufficient cheese curing times. Policymakers should continue to reexamine the adequacy and enforcement of existing rules intended to ensure the safety of raw-milk cheeses and retail food sampling. Additional research is necessary to clarify the food safety hazards posed to patrons who consume free food samples while shopping. PMID- 23043824 TI - Effect of chemical sanitizers on Salmonella enterica serovar Poona on the surface of cantaloupe and pathogen contamination of internal tissues as a function of cutting procedure. AB - Survival of Salmonella enterica subsp. enterica serovar Poona on surface and stem scar portions of inoculated cantaloupe following sanitizer application, transfer of pathogen from the rind to the flesh during cutting, and growth of Salmonella Poona on cantaloupe cubes over 15 days of refrigerated storage were investigated. Cantaloupes inoculated with a rifampin-resistant strain of Salmonella Poona (10(7) CFU/ml) for 3 min and dried for 12 h were washed with chlorine (200 mg free chlorine per liter, 3 min), lactic acid (2%, 2 min), or ozone (30 mg/liter, 5 min). Fresh-cut cantaloupe cubes were prepared by (i) cutting the cantaloupe and then removing the rind or by (ii) peeling the rind and then cutting the flesh into pieces. The numbers of Salmonella bacteria recovered were higher in the stem scar portion (6.3 +/- 0.3 log CFU/cm(2)) than the surface (4.8 +/- 0.2 log CFU/cm(2)). Surface treatment with tap water or chlorine did not reduce Salmonella numbers, while treatment with lactic acid or ozone reduced Salmonella by 2.5 or 2.3 log CFU/cm(2), respectively. The use of lactic acid to sanitize the cantaloupes resulted in less Salmonella transfer to flesh during cutting; Salmonella numbers decreased to below detectable levels over 9 days of refrigerated (4 degrees C) storage. Cutting cantaloupes after peeling the rind was more effective at reducing transfer of Salmonella to the internal tissue than cutting of cantaloupes prior to rind removal. These data suggest that treatment of cantaloupe rinds with lactic acid or ozone may be effective at reducing Salmonella numbers, while lactic acid application resulted in reduction of Salmonella transfer to cantaloupe flesh. PMID- 23043825 TI - Antibiotic resistance in bacterial pathogens from retail raw meats and food producing animals in Japan. AB - To determine the prevalence and antimicrobial susceptibility profiles of Campylobacter, Salmonella, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and vancomycin-resistant enterococci (VRE) in food-producing animals and retail raw meats in Japan, raw meat samples as well as food-producing animal feces, cutaneous swabs, and nasal swabs collected from 2004 to 2006 were analyzed. Isolation rates of Campylobacter jejuni and Campylobacter coli, Salmonella, and S. aureus were 34.6% (363 of 1,050), 2.7% (28 of 1,050), and 32.8% (238 of 725), respectively. MRSA was isolated from 3% (9 of 300) of meat samples. No VRE were isolated in this study. Antibiotic resistance in C. coli was higher than that in C. jejuni. Three C. jejuni isolates from a patient with diarrhea in a hospital of Shizuoka Prefecture and two chicken samples that exhibited resistance to ciprofloxacin had identical pulsed-field gel electrophoresis patterns, suggesting that ciprofloxacin-resistant C. jejuni could have been distributed in meat. S. aureus isolates showed the highest level of resistance to ampicillin and tetracycline. Resistance to tetracycline in S. aureus isolates from beef was lower than that seen in isolates from chicken and pork (P < 0.01). This study revealed that the prevalence of MRSA and VRE were low in food-producing animals and retail domestic meats in Japan, although Campylobacter isolates resistant to fluoroquinolone and erythromycin were detected. The occurrence of antimicrobial-resistant pathogens should be monitored continuously to improve the management of the risks associated with antimicrobial drug resistance transferred from food-producing animals to humans. PMID- 23043826 TI - Growth of Clostridium perfringens during cooling of refried beans. AB - Outbreaks of Clostridium perfringens have been associated with dishes containing refried beans from food service establishments. However, growth of C. perfringens in refried beans has not been investigated, and predictive models have not been validated in this food matrix. We investigated the growth of C. perfringens during the cooling of refried beans. Refried beans (pinto and black, with and without salt added) were inoculated with 3 log CFU/g C. perfringens spores and incubated isothermally at 12, 23, 30, 35, 40, 45, and 50 degrees C. The levels of C. perfringens were monitored 3, 5, 8, and 10 h after inoculation, and then fitted to the Baranyi primary model and the Rosso secondary model prior to solving the Baranyi differential equation. The final model was validated by dynamic cooling experiments carried out in stockpots, thus mimicking the worst possible food service conditions. All refried beans samples supported the growth of C. perfringens, and all models fit the data with pseudo-R(2) values of 0.95 or greater and mean square errors of 0.3 or lower. The estimated maximum specific growth rates were generally higher in pinto beans, with or without salt added (2.64 and 1.95 h(-1), respectively), when compared with black beans, with or without salt added (1.78 and 1.61 h(-1), respectively). After 10 h of incubation, maximum populations of C. perfringens were significantly higher in samples with no salt added (7.9 log CFU/g for both pinto and black beans) than in samples with salt added (7.3 and 7.2 log CFU/g for pinto and black beans, respectively). The dynamic model predicted the growth of C. perfringens during cooling, with an average root mean squared error of 0.44. The use of large stockpots to cool refried beans led to an observed 1.2-log increase (1.5-log increase predicted by model) in levels of C. perfringens during cooling. The use of shallower pans for cooling is recommended, because they cool faster, therefore limiting the growth of C. perfringens. PMID- 23043827 TI - Clostridium tyrobutyricum strains show wide variation in growth at different NaCl, pH, and temperature conditions. AB - Outgrowth from Clostridium tyrobutyricum spores in milk can lead to butyric acid fermentation in cheeses, causing spoilage and economical loss to the dairy industry. The aim of this study was to investigate the growth of 10 C. tyrobutyricum strains at different NaCl, pH, and temperature conditions. Up to 7.5-fold differences among the maximum growth rates of different strains in the presence of 2.0% NaCl were observed. Five of 10 strains were able to grow in the presence of 3.0% NaCl, while a NaCl concentration of 3.5% was completely inhibitory to all strains. Seven of 10 strains were able to grow at pH 5.0, and up to 4- and 12.5-fold differences were observed among the maximum growth rates of different strains at pH 5.5 and 7.5, respectively. The maximum growth temperatures varied from 40.2 to 43.3 degrees C. The temperature of 10 degrees C inhibited the growth of all strains, while 8 of 10 strains grew at 12 and 15 degrees C. Despite showing no growth, all strains were able to survive at 10 degrees C. In conclusion, wide variation was observed among different C. tyrobutyricum strains in their ability to grow at different stressful conditions. Understanding the physiological diversity among the strains is important when designing food control measures and predictive models for the growth of spoilage organisms in cheese. PMID- 23043828 TI - Yogurt containing bioactive molecules produced by Lactobacillus acidophilus La-5 exerts a protective effect against enterohemorrhagic Escherichia coli in mice. AB - An active fraction extracted from Lactobacillus acidophilus La5 cell-free spent medium (LAla-5AF) was incorporated in a dairy matrix and tested to assess its antivirulent effect against enterohemorrhagic Escherichia coli (EHEC). Mice in experimental groups were fed for 4 days with yogurt supplemented with LAla-5AF. On the fifth day, mice were challenged with a single dose (10(7) CFU per mouse) of E. coli O157:H7. The clinical manifestations of the infection were significantly less severe in mice fed the yogurt supplemented with LAla-5AF. EHEC attachment and colonization was attenuated by LAla-5AF. Tumor necrosis factor alpha production was down-regulated, which might indicate a protective effect in the kidney during EHEC infection. To investigate the mechanisms associated with the in vivo effects observed, LAla-5AF was tested by reverse transcription real-time PCR to confirm its effects on the expression of several virulence genes of EHEC O157. The results showed that these fractions were able to down-regulate several virulence genes of EHEC, including stxB2, qseA, luxS, tir, ler, eaeA, and hlyB. PMID- 23043829 TI - Method for identifying heat-resistant fungi of the genus Neosartorya. AB - Species of the genus Neosartorya are heat-resistant fungi that cause the spoilage of heat-processed acidic foods due to the formation of heat-resistant ascospores, and they produce mycotoxins, such as fumitremorgins and gliotoxin. Their anamorphs are phylogenetically and morphologically very close to Aspergillus fumigatus, which has never been reported as a spoilage agent in heat-processed food products. Therefore it is important to discriminate between the species of Neosartorya and A. fumigatus in the food industry. In the present study, we examined beta-tubulin and calmodulin genes to identify Neosartorya and A. fumigatus at the species level and found a region for specifically detecting these species. We succeeded in developing the PCR method of differentiating and identifying Neosartorya and A. fumigatus using specific primer sets. Moreover, we developed specific primer sets to identify Neosartorya species, N. fischeri, N. glabra, N. hiratsukae, N. pseudofischeri, and N. spinosa-complex, which are important in food spoilage; these fungi vary in heat resistance and productivity of mycotoxins, depending on the species. PCR using these primer sets did not detect other fungi involved in food spoilage and environmental contamination. These identification methods are rapid and simple with extremely high specificity. PMID- 23043830 TI - Biogenic amine content, histamine-forming bacteria, and adulteration of pork in tuna sausage products. AB - Twenty-five tuna sausage products were purchased from retail markets in Taiwan. The rates of occurrence of biogenic amines, histamine-forming bacteria, and adulteration by pork and poultry were determined. The average content of various biogenic amines in all tested samples was less than 2.0 mg/100 g (<0.05 to 1.85 mg/100 g). Thirteen histamine-producing bacterial strains isolated from tested samples produced 12.1 to 1,261 ppm of histamine in Trypticase soy broth supplemented with 1.0% L-histidine. Among them, Raoultella ornithinolytica (one strain), Enterobacter aerogenes (one strain), and Staphylococcus pasteuri (two strains) were identified as prolific histamine formers. PCR assay revealed that the adulteration rates were 80% (20 of 25) and 4% (1 of 25) for pork and poultry, respectively, in tuna sausage. The fish species in the tuna sausage samples were identified as Thunnus albacares for 22 samples (88%), Thunnus alalunga for 1 sample (4%), and Thunnus thynnus for 1 sample (4%), whereas the remaining sample was identified as Makaira nigricans (blue marlin). PMID- 23043831 TI - Dynamics of radioactive cesium (134Cs and 137Cs) during the milling of contaminated Japanese wheat cultivars and during the cooking of udon noodles made from wheat flour. AB - The fate of radioactive cesium ((134)Cs plus (137)Cs) during the milling of contaminated Japanese wheat cultivars harvested in FY2011, and during the cooking of Japanese udon noodles made from the wheat flour, was investigated. Grain samples containing various radioactive cesium concentrations (36.6 to 772 Bq/kg [dry weight]) were milled using a laboratory-scale test mill to produce eight fractions: three break flours (1B, 2B, and 3B), three reduction flours (1M, 2M, and 3M), bran, and shorts. The concentrations of radioactive cesium were found to be highest in the bran fractions of all the samples tested, with 2.3- to 2.5 fold higher values than that of the whole grain. Shorts contained radioactive cesium levels similar to that of the whole grain. In contrast, radioactive cesium concentrations in other fractions were found to be less than half the concentration in whole grain. The average processing factor (PF) value calculated for patent flour (0.401 +/- 0.048), made from the mixture of 1B, 2B, 1M, and 2M for human consumption, or for low-grade flour (0.467 +/- 0.045), made from the mixture of 3B and 3M, was found to be less than 0.5; whereas the average PF value (2.07 +/- 0.232) for feed bran (mixture of bran and shorts), which has been used mainly as livestock feed in Japan, was over 2.0. Boiling udon noodles (made from patent flour) resulted in a substantial reduction (>70 % of initial amount) of radioactive cesium. Moreover, radioactive cesium was reduced further (<10 % of the initial amount) in the subsequent rinsing process, and the PF value of boiled noodles was recorded as 0.194. These results demonstrated that patent flour containing radioactive cesium can be made safe for human consumption by adopting the standard limit for radioactive cesium in wheat grain and that radioactive cesium in udon noodles is substantially reduced by cooking. PMID- 23043832 TI - Investigating the potential benefits of on-site food safety training for Folklorama, a temporary food service event. AB - Folklorama in Winnipeg, Manitoba, Canada, is a 14-day temporary food service event that explores the many different cultural realms of food, food preparation, and entertainment. In 2010, the Russian pavilion at Folklorama was implicated in a foodborne outbreak of Escherichia coli O157 that caused 37 illnesses and 18 hospitalizations. The ethnic nature and diversity of foods prepared within each pavilion presents a unique problem for food inspectors, as each culture prepares food in their own very unique way. The Manitoba Department of Health and Folklorama Board of Directors realized a need to implement a food safety information delivery program that would be more effective than a 2-h food safety course delivered via PowerPoint slides. The food operators and event coordinators of five randomly chosen pavilions selling potentially hazardous food were trained on-site, in their work environment, focusing on critical control points specific to their menu. A control group (five pavilions) did not receive on-site food safety training and were assessed concurrently. Public health inspections for all 10 pavilions were performed by Certified Public Health Inspectors employed with Manitoba Health. Critical infractions were assessed by means of standardized food protection inspection reports. The results suggest no statistically significant difference in food inspection scores between the trained and control groups. However, it was found that inspection report results increased for both the control and trained groups from the first inspection to the second, implying that public health inspections are necessary in correcting unsafe food safety practices. The results further show that in this case, the 2-h food safety course delivered via slides was sufficient to pass public health inspections. Further evaluations of alternative food safety training approaches are warranted. PMID- 23043833 TI - Rapid monitoring of Campylobacter in high-shedding flocks for targeted disease control. AB - Broilers excreting Campylobacter spp. at high levels (>7 log CFU/g of feces) were described in the Dutch Campylobacter Risk Management and Assessment project as an important source of carcass contamination. The researchers concluded that the risk of infection to humans could be economically and efficiently minimized by eliminating these flocks from fresh poultry meat chains. In the present study, we evaluated a simple and rapid gold-labeled immunosorbent assay (GLISA) for the identification of Campylobacter spp. in flocks shedding high levels of the pathogen. Results were obtained within 2 h. Pooled samples from 102 of the 114 Campylobacter-positive flocks produced positive results, resulting in a test sensitivity of 89.5% (95% confidence interval, 82.6 to 94.2%) and a test specificity of 94.5% (86.7 to 98.2%). Given a GLISA detection limit of 7.3 log CFU/g of feces, nearly all Campylobacter-positive flocks were identified as "high shedders." Therefore, reduction of the incidence of Campylobacter infections by elimination of high-shedding flocks from fresh meat production is an unrealistic approach. Under the constraints given, a reduction in the incidence of Campylobacter spp. in Austria will require either improved hygiene or an intensive carcass decontamination strategy in fresh meat production facilities. PMID- 23043834 TI - Antibiotic susceptibility of Salmonella, Campylobacter coli, and Campylobacter jejuni isolated from Northern German fattening pigs. AB - This study was conducted to assess the antimicrobial susceptibility rate of Salmonella and Campylobacter spp. isolated from Northern German fattening pigs. From 540 lymph node samples, 16 Salmonella Typhimurium, 1 Salmonella Brandenburg, 37 Campylobacter coli, and 11 Campylobacter jejuni strains were isolated. Antibiotic susceptibility testing was carried out by the broth dilution method. The 14 tested antibiotics for Salmonella were ampicillin, cefotaxime, ceftazidime, chloramphenicol, ciprofloxacin, colistin, florfenicol, gentamicin, kanamycin, nalidixic acid, streptomycin, sulfamethoxazole, tetracycline, and trimethoprim. The eight tested antibiotics for Campylobacter spp. were ampicillin, ampicillin-sulbactam (2:1), ciprofloxacin, erythromycin, gentamicin, nalidixic acid, sulfamethoxazole-trimethoprim (1:19), and tetracycline. In total, 93.7% (n = 16) of Salmonella Typhimurium, 75.7% (n = 37) of C. coli, and 54.5% (n = 11) of C. jejuni isolates were resistant to at least one of the tested antibiotics. Multiresistance to three antibiotics was observed in 75% of Salmonella Typhimurium, 16.2% of C. coli, and 0% of C. jejuni isolates. Pansusceptibility was detected in 6.3% of Salmonella Typhimurium, 24.3% of C. coli, and 45.5% of C. jejuni isolates. Multiresistance is defined as resistance to three or more antibiotics, and pansusceptibility is defined as not having resistance to any antibiotic. Regarding drugs of last resort--cefotaxime, ciprofloxacin, and nalidixic acid--resistance was not common among Salmonella (6.3%). The resistance rate of Campylobacter spp. to last-resort drugs- erythromycin, ciprofloxacin, and nalidixic acid--varied between species. The observed trend was not statistically significant. No C. coli isolates and few C. jejuni isolates (9.1%) were resistant to erythromycin. In contrast to C. jejuni, the C. coli isolates were more likely to be resistant to ciprofloxacin (9.1 and 18.9%, respectively) and nalidixic acid (0 and 13.5%, respectively). The same phenomenon was detected for tetracycline (27.3 and 62.2%, respectively), sulfamethoxazole (9.1 and 43.2%, respectively), and ampicillin (9.1 and 21.6%, respectively). PMID- 23043835 TI - Prevalence and molecular characteristics of Vibrio spp. isolated from preharvest shrimp of the North Western Province of Sri Lanka. AB - This study investigated the prevalence and molecular characteristics of Vibrio spp. in farmed shrimp (Penaeus monodon) in Sri Lanka. A total of 170 shrimp samples (100 g of whole shrimp each) taken from individual ponds from 54 farms were collected 1 week prior to harvest from the North Western Province of Sri Lanka. Overall, 98.1% of the farms and 95.1% of the ponds were positive for Vibrio spp. in shrimp; at the pond level, V. parahaemolyticus (91.2%) was most common, followed by V. alginolyticus (18.8%), V. cholerae non-O1/non-O139 (4.1%), and V. vulnificus (2.4%). Multiple Vibrio spp. were detected in 20.6% of the ponds. None of the V. parahaemolyticus isolates (n = 419) were positive for the virulence-associated tdh (thermostable direct hemolysin) and trh (TDH-related hemolysin) genes. V. cholerae was confirmed by the presence of ompW, and all isolates (n = 8) were negative for the cholera toxin (ctxA) gene. V. cholerae isolates were serogrouped by PCR and identified as V. cholerae non-O1/non-O139. All four V. vulnificus strains, isolated from different ponds of two geographical regions, showed pathogenic potential; they belonged to vcgC sequence type, type B 16S rRNA genotype and contained a pilF polymorphism associated with human pathogenicity. The results of this study revealed the ubiquitous nature of vibrios in farmed shrimp. To minimize the potential risk of Vibrio infections due to handling or consumption of raw or undercooked seafood products, good manufacturing practices as well as proper handling and processing should be addressed. PMID- 23043836 TI - Prevalence of Salmonella on chicken carcasses from retail markets in Vietnam. AB - This study was conducted to estimate the prevalence of Salmonella on chicken carcasses collected from six regions in Vietnam. A total of 1,000 whole, dressed chicken carcasses were collected from five cities and seven provinces across the six regions in Vietnam. Of these, 900 samples were collected from wet markets and 100 from supermarkets. All samples were analyzed for the presence of Salmonella according to a method recommended by the U. S. Department of Agriculture, Food Safety and Inspection Service. The overall Salmonella prevalence was 45.9%. There was no significant difference (P > 0.05) in Salmonella prevalence by (i) location (Ha Noi city, 51.1%; Hai Phong city, 45.6%; Da Nang and Can Tho cities, 45.5%; Bac Ninh province and Ho Chi Minh city, 44.7%; Dong Nai province, 44.6%; Ha Tinh province, 44.4%; Phu Tho province, 43.8%; Lao Cai province, 43.5%; Kien Giang province, 41.9%; and Lam Dong province, 40.9%), (ii) market type (wet market, 46.2%; supermarket samples, 43.0%), and (iii) storage temperature at retail (ambient storage, 46.4%; chilled storage, 45.1%). Hence, Salmonella presence on poultry meat in Vietnam was not associated with a specific city or province, market type, or storage temperature at retail. Strategies to reduce Salmonella levels on raw poultry in Vietnam should be undertaken to improve the safety of poultry products and reduce the incidence of human salmonellosis from poultry consumption. PMID- 23043837 TI - Modeling antimicrobial activity of lipopeptides from Bacillus amyloliquefaciens ES-2 against Shewanella putrefaciens in shrimp meat using a response surface method. AB - Bacillus amyloliquefaciens ES-2 can produce antimicrobial lipopeptides, including surfactin and fengycin. In this study, the model of antimicrobial activity against Shewanella putrefaciens in shrimp meat by antimicrobial lipopeptides from B. amyloliquefaciens ES-2 was researched by response surface methodology. The results showed that S. putrefaciens had high sensitivity to antimicrobial lipopeptides, which had a MIC of 0.6 mg/ml. A quadratic mathematical model representative of the action of antimicrobial lipopeptides on S. putrefaciens in shrimp meat was developed as a function of concentration, time, and temperature. A reduction of S. putrefaciens cells of over 2 log cycles could be realized when the temperature was below 5.4 degrees C, the time was over 6 h, and the concentration of the lipopeptides was over 0.3 mg/g. PMID- 23043838 TI - A preliminary microbiological assessment of process hygiene of traditional outdoor camel slaughter in Sahrawi refugee camps. AB - The aim of this study was to investigate the hygiene performance of a camel (Camelus dromedarius) slaughtering process as carried out with the traditional method in the Sahrawi refugee camps located in southwestern Algeria. The camel slaughtering process in this region differs significantly from that carried out in commercial abattoirs. Slaughtering is performed outdoors in desert areas, and dehiding of the carcass is approached via the dorsoventral route rather than the classic ventrodorsal route. Samples were taken from 10 camel carcasses from three different areas: the hide, the carcass meat immediately after dehiding, and the meat after final cutting. Enterobacteriaceae counts (EC) were enumerated employing conventional laboratory techniques. Carcass meat samples resulted in EC below the detection limit more frequently if the hide samples from the same carcass had also EC counts below the detection limit. Because of the low number of trials, the calculation of statistical significance of the results was not possible. Further experimental research is needed in order to validate the results presented in this study. The comparison of the microbiological hygiene performance between dorsal dehiding and traditional ventral dehiding of slaughtered animals could serve to validate the hypothesis of the potential positive impact of the dorsal dehiding method in carcass meat hygiene. PMID- 23043839 TI - An Australian national survey of the microbiological quality of frozen boneless beef and beef primal cuts. AB - The fourth national baseline microbiological survey of Australian beef was conducted in 2011, including frozen boneless beef and, for the first time, samples from selected beef primal cuts. Cartons of frozen boneless beef (n = 1,165) sampled at 29 boning (fabrication) plants were found to have a mean total viable count of 2.2 log CFU/g, and the mean count for the 2.1% of samples with detectable Escherichia coli was 1.3 log CFU/g. The mean total viable counts for striploins (longissimus dorsi, n = 572) and outsides (biceps femoris, n = 572) were 1.3 and 1.5 log CFU/cm(2) respectively. E. coli isolates were obtained from 10.7 and 25.2% of striploins and outsides, respectively, with mean counts of -0.5 and -0.3 log CFU/cm(2) on positive samples. E. coli O157:H7, Salmonella, and Campylobacter were not isolated from any primal cut samples, and Salmonella was not isolated from any of the boneless product (E. coli O157:H7 and Campylobacter were not tested for). Listeria spp. were not detected in any of the boneless product, and one Listeria isolate was obtained on 1 (0.2%) of 572 striploin samples. Coagulase-positive staphylococci were isolated from 3.4% of boneless beef samples, 7.7% of beef striploins, and 8.4% of beef outsides, with positive samples having mean log counts of 1.9 CFU/g, 0.2 CFU/cm(2), and 0.2 CFU/cm(2), respectively. PMID- 23043840 TI - Spray method for recovery of heat-injured Salmonella Typhimurium and Listeria monocytogenes. AB - Selective agar is inadequate for supporting recovery of injured cells. During risk assessment of certain foods, both injured and noninjured cells must be enumerated. In this study, a new method (agar spray method) for recovering sublethally heat-injured microorganisms was developed and used for recovery of heat-injured Salmonella Typhimurium and Listeria monocytogenes. Molten selective agar was applied as an overlay to presolidified nonselective tryptic soy agar (TSA) by spray application. Heat-injured cells (55 degrees C for 10 min in 0.1% peptone water or 55 degrees C for 15 min in sterilized skim milk) were inoculated directly onto solidified TSA. After a 2-h incubation period for cell repair, selective agar was applied to the TSA surface with a sprayer, and the plates were incubated. The recovery rate for heat-injured Salmonella Typhimurium and L. monocytogenes with the spray method was compared with the corresponding rates associated with TSA alone, selective media alone, and the conventional overlay method (selective agar poured on top of resuscitated cells grown on TSA and incubated for 2 h). No significant differences (P > 0.05) were found in pathogen recovery obtained with TSA, the overlay method, and the spray method. However, a lower recovery rate (P < 0.05) was obtained for isolation of injured cells on selective media. Overall, these results indicate that the agar spray method is an acceptable alternative to the conventional overlay method and is a simpler and more convenient approach to recovery and detection of injured cells. PMID- 23043841 TI - Pasteurization of fruit juices of different pH values by combined high hydrostatic pressure and carbon dioxide. AB - The inactivation of the selected vegetative bacteria Escherichia coli, Listeria innocua, and Lactobacillus plantarum by high hydrostatic pressure (HHP) in physiological saline (PS) and in four fruit juices with pHs ranging from 3.4 to 6.3, with or without dissolved CO(2), was investigated. The inactivation effect of HHP on the bacteria was greatly enhanced by dissolved CO(2). Effective inactivation (>7 log) was achieved at 250 MPa for E. coli and 350 MPa for L. innocua and L. plantarum in the presence of 0.2 M CO(2) at room temperature for 15 min in PS, with additional inactivation of more than 4 log for all three bacteria species compared with the results with HHP treatment alone. The combined inactivation by HHP and CO(2) in tomato juice of pH 4.2 and carrot juice of pH 6.3 showed minor differences compared with that in PS. By comparison, the combined effect in orange juice of pH 3.8 was considerably promoted, while the HHP inactivation was enhanced only to a limited extent. In another orange juice with a pH of 3.4, all three strains lost their pressure resistance. HHP alone completely inactivated E. coli at relatively mild pressures of 200 MPa and L. innocua and L. plantarum at 300 MPa. Observations of the survival of the bacteria in treated juices also showed that the combined treatment caused more sublethal injury, which increased further inactivation at a relatively mild pH of 4.2 during storage. The results indicated that the combined treatment of HHP with dissolved CO(2) may provide an effective method for the preservation of low- or medium-acid fruit and vegetable juices at relatively low pressures. HHP alone inactivated bacteria effectively in high-acid fruit juice. PMID- 23043842 TI - Antimicrobial activity of salmon extracts derived from traditional First Nations smoke processing. AB - Freshly caught salmon were hot smoked with the traditional smoke processing methods of the Tl'azt'en and Lheidli T'enneh First Nations communities, producing both half-smoked and fully smoked food products. To ascertain the nature of antimicrobial effects related to the smoking process, the residue content of 16 polyaromatic hydrocarbons (PAH) and total PAHs of smoked products were determined and correlated with smoking process duration. When compared with fully smoked samples, partially smoked fish had significantly less total PAHs and were composed solely of low-molecular-weight components, with phenanthrene, acenaphthylene, and napthlalene, respectively, being the most abundant. In contrast, fully smoked products possessed significantly higher levels of low- and high-molecular-weight PAHs, including benzo[a]pyrene. Sequential extractions of water, ethyl acetate, and hexane were performed to identify antimicrobial activity imparted by the traditional smoking process. No activity was observed in water or ethyl acetate extractions, whereas hexane extracts were inhibitory to Staphylococcus aureus, with more inhibition observed in fully smoked samples when compared with partially smoked samples. This study provides evidence that traditional smoke processing methods used by First Nations communities can provide value toward producing food products that have extended shelf lives, and protect against a prevalent common pathogen easily transmitted by humans to processed food through direct contact. PMID- 23043843 TI - Endophytic fungi from plums (Prunus domestica) and their antifungal activity against Monilinia fructicola. AB - Enophytic fungi were isolated from plum (Prunus domestica) leaves, identified with ITS1 and ITS4 primers, and their antagonistic activity was tested against Monilinia fructicola, which causes brown rot, blossom blight, and twig blight of stone fruits, and Colletotrichum gloeosporioides, which causes anthracnose on a variety of fruit crops. The production of antifungal compounds was determined in agar-diffusion and volatile inverted-plate tests. A total of 163 fungi were recovered from 30 plum trees, representing 22 cultivars. Twenty-nine morphotypes were detected, but only 14 species were identified genetically. The most frequently isolated species was Phaeosphaeria nodorum, constituting 86.5% of the total isolates. Four isolates produced inhibitory volatiles to M. fructicola; however, no isolate produced volatiles inhibitory to C. gloeosporioides. The volatiles produced by these fungi were identified as ethyl acetate, 3-methyl-1 butanol, acetic acid, 2-propyn-1-ol, and 2-propenenitrile. The fungal volatiles inhibited growth and reduced width of the hyphae, and caused disintegration of the hyphal content. This is the first study describing fungal endophytes in stone fruits. The P. nodorum strains producing inhibitory volatiles could play a significant role in reduction of M. fructicola expansion in plum tissues. Potential of these strains for biological control of this pathogen on stone fruits warrants further investigation. PMID- 23043844 TI - Total and inorganic arsenic in freshwater fish and prawn in Thailand. AB - Total and inorganic arsenic levels were determined in 120 samples of eight freshwater animal species collected from five distribution centers in the central region of Thailand between January and March 2011. Eight species with the highest annual catch, consisting of seven fish species and one prawn species, were analyzed. Concentrations of inorganic arsenic (on a wet weight basis) ranged from 0.010 MUg/g in giant prawn (Macrobrachium rosenbergii) to 0.230 MUg/g in striped snakehead (Channa striata). Climbing perch (Anabas testudineus) exhibited the highest mean concentrations of total arsenic (0.459 +/- 0.137 MUg/g), inorganic arsenic (0.121 +/- 0.044 MUg/g), and percentage of inorganic arsenic (26.2%). Inorganic arsenic levels found in freshwater animals in this study were much lower than the Thai regulatory standard of 2 MUg/g. PMID- 23043845 TI - Evidence for horizontal and vertical transmission in Campylobacter passage from hen to her progeny. AB - Campylobacter is an important human pathogen, and consumption of undercooked poultry has been linked to significant human illnesses. To reduce human illness, intervention strategies targeting Campylobacter reduction in poultry are in development. For more than a decade, there has been an ongoing national and international controversy about whether Campylobacter can pass from one generation of poultry to the next via the fertile egg. We recognize that there are numerous sources of Campylobacter entry into flocks of commercial poultry (including egg transmission), yet the environment is often cited as the only source. There has been an abundance of published research globally that refutes this contention, and this article lists and discusses many of them, along with other studies that support environment as the sole or primary source. One must remember that egg passage can mean more than vertical, transovarian transmission. Fecal bacteria, including Campylobacter, can contaminate the shell, shell membranes, and albumen of freshly laid fertile eggs. This contamination is drawn through the shell by temperature differential, aided by the presence of moisture (the "sweating" of the egg); then, when the chick emerges from the egg, it can ingest bacteria such as Campylobacter, become colonized, and spread this contamination to flock mates in the grow house. Improvements in cultural laboratory methods continue to advance our knowledge of the ecology of Campylobacter, and in the not-so-distant future, egg passage will not be a subject continuously debated but will be embraced, thus allowing the development and implementation of more effective intervention strategies. PMID- 23043846 TI - The excess burden of rheumatoid arthritis in Ontario, Canada. AB - OBJECTIVES: The purpose of this study was to estimate the excess burden of RA in Ontario, the largest province in Canada. METHODS: The records of all adult Ontarians who participated in the Canadian Community Health Survey (CCHS) cycle 1.1 (2000/2001) and provided consent to data linkage were linked to the Ontario Health Insurance Program (OHIP) physician claims database and the Discharge Abstract Database (DAD) In-Patient (i.e. hospitalisation) and Day-Procedure databases. RA individuals (n=233) were identified using CCHS 1.1 and the physician claims database. A control group matched by age, gender and rural/urban status was created with three controls for one case (n=699). Socio-demographic variables, medical characteristics, health-related quality of life (HRQoL) and one-year physician services, hospitalizations and day procedures costs were determined for the RA and non-RA groups. Regression techniques were used to identify predictors of medical characteristics, utility and cost data. RESULTS: The mean age of the population was 59 years and 76% were female. Compared to the matched control group, individuals with RA were statistically more likely to be obese, less educated, physically inactive and have a lower income. RA individuals also reported a statistically higher number of comorbidities and a lower HRQoL. Although no statistical differences were observed between the RA and non-RA groups for the costs associated with hospitalisations, the physician ($1,015 vs. $624, respectively) and day procedure ($102 vs. $51, respectively) costs were statistically higher among RA individuals. CONCLUSIONS: These results indicate that the human and economic burden of RA in Ontario is considerable. PMID- 23043847 TI - Stem cell-based therapy for spinal cord injury. AB - Stem cells (SCs) represent a new therapeutic approach for spinal cord injury (SCI) by enabling improved sensory and motor functions in animal models. The main goal of SC-based therapy for SCI is the replacement of neurons and glial cells that undergo cell death soon after injury. Stem cells are able to promote remyelination via oligodendroglia cell replacement to produce trophic factors enhancing neurite outgrowth, axonal elongation, and fiber density and to activate resident or transplanted progenitor cells across the lesion cavity. While several SC transplantation strategies have shown promising yet partial efficacy, mechanistic proof is generally lacking and is arguably the largest impediment toward faster progress and clinical application. The main challenge ahead is to spur on cooperation between clinicians, researchers, and patients in order to define and optimize the mechanisms of SC function and to establish the ideal source/s of SCs that produce efficient and also safe therapeutic approaches. PMID- 23043848 TI - Tetanus following replantation of an amputated finger: a case report. AB - INTRODUCTION: Tetanus is an infectious disease caused by tetanus toxin produced by Clostridium tetani and induces severe neurological manifestations. We treated a patient who developed tetanus during hospitalization for replantation of an amputated finger. To the best of our knowledge, this is the first published case report of such an entity. CASE PRESENTATION: A 49-year-old Japanese man had an amputation of his right middle finger at the distal interphalangeal joint region in an accident at work. His middle finger was successfully replanted, but his fingertip was partially necrotized because of crushing and so additional reconstruction with a reverse digital arterial flap was performed 15 days after the injury. Tetanus developed 21 days after replantation of the middle finger, but symptoms remitted via rapid diagnosis and treatment. CONCLUSIONS: In replantation after finger trauma with exposure of nerve and blood vessel bundles, concern over injuring nerves and blood vessels may prevent irrigation and debridement from being performed sufficiently; these treatments may have been insufficiently performed in this patient. It is likely that the replanted middle finger partially adhered, and Clostridium tetani colonized the partially necrotized region. Even when there is only limited soil contamination, administration of tetanus toxoid and anti-tetanus immunoglobulin is necessary when the fingers are injured outdoors and the finger nerves and blood vessels are exposed. The drugs should be administered just after replantation if the finger has been amputated. However, if clinicians pay attention to the possibility of tetanus development, treatment can be rapidly initiated. PMID- 23043849 TI - Mannitol test results in asthmatic adults receiving inhaled corticosteroids. PMID- 23043850 TI - The advanced endoscopy fellowship match: an update and perspectives. PMID- 23043851 TI - Prospective, randomized, single-center trial comparing double-balloon enteroscopy and spiral enteroscopy in patients with suspected small-bowel disorders. AB - BACKGROUND: Double-balloon enteroscopy (DBE) is an established method in diagnostic and therapeutic small-bowel enteroscopy. OBJECTIVE: Spiral enteroscopy (SE) appears to be a promising new technique. A randomized, prospective study was conducted to compare both methods. DESIGN: Randomized, prospective study. SETTING: Single tertiary referral center. PATIENTS: Between September 2009 and March 2011, 26 patients with suspected mid-GI disorders completed the study. INTERVENTIONS: Patients were randomly assigned to DBE or SE. The oral examination was conducted first, with the deepest point reached being marked with India ink. An additional anal examination followed the day after, with the aim of reaching the ink mark. MAIN OUTCOME MEASUREMENTS: The primary endpoint of the study was the rate of complete enteroscopies achieved. RESULTS: The rate of complete enteroscopies with DBE was 12 times the rate achieved with SE (8% in the SE group and 92% in the DBE group; P = .002). With regard to the secondary study criteria, much longer examination times but greater depths of insertion were associated with DBE. There were no statistically significant differences in the diagnostic or therapeutic outcomes between the SE and DBE groups (diagnostic yield, P = .428; therapeutic yield, P = 1.0; Fisher exact test). One perforation occurred during an anal examination as a relevant adverse event in SE. LIMITATIONS: Single center study, small sample size. CONCLUSION: SE does not represent an alternative to DBE with regard to the depth of insertion or the rate of complete enteroscopies achieved. However, SE is advantageous in that it involves significantly shorter examination times. Further technical improvements will be necessary before SE can compete with DBE for complete enteroscopies. PMID- 23043852 TI - Peroral endoscopic myotomy for treatment of achalasia: from bench to bedside (with video). AB - BACKGROUND: Peroral endoscopic myotomy (POEM) is a novel approach to performing esophageal myotomy through a long submucosal tunnel. OBJECTIVE: This study aimed to investigate the feasibility and safety of POEM for treatment of achalasia. DESIGN: Preclinical animal study and prospective clinical study. PATIENTS: Consecutive patients diagnosed with achalasia with high-resolution manometry. INTERVENTIONS: POEM was standardized for preclinical and clinical studies. After submucosal injection, a mucosal incision was made 15 cm above the gastroesophageal junction (GEJ). A long submucosal tunnel was created to extend below the GEJ. The endoscopic myotomy started 10 cm above and extended 2 cm below the GEJ. We first conducted a preclinical animal study to confirm the safety of POEM. POEM was then performed for the treatment of achalasia in humans. MAIN OUTCOME MEASUREMENTS: Relief from dysphagia assessed by the dysphagia score and Eckhardt score. High-resolution manometry and pH monitoring were performed to evaluate the posttreatment effects and esophageal acid exposure. RESULTS: Seven 30-kg porcine models underwent POEM in the survival study. All of the pigs survived except 1, which sustained pneumomediastinum. POEM was performed for the treatment of achalasia in 16 patients. The mean operating time was 117.0 +/- 34.1 minutes. All patients tolerated food on day 2, with a contrast study confirming no leakage. The median follow-up was 176.5 days (range 98-230 days). The postoperative basal lower esophageal sphincter pressure was significantly reduced (mean reduction, 13.9 +/- 14.5 mm Hg; P = .005) and 4-second integrated relaxation pressure of the GEJ (mean reduction, 10.1 +/- 7.4 mm Hg; P = .001). Of these patients, 58.3% had a normalized 4-second integrated relaxation pressure, whereas 20% had excessive esophageal acid exposure after the procedure. There was a significant improvement in quality of life 6 months after POEM measured by the Short Form-36 questionnaire. LIMITATION: Small sample size. CONCLUSIONS: POEM is a feasible, safe, and effective treatment for achalasia. PMID- 23043853 TI - In situ demineralisation of human enamel studied by synchrotron-based X-ray microtomography--a descriptive pilot-study. AB - An in situ study was designed to investigate naturally developed demineralisation in human enamel in a widely non-destructive manner in combination with X-ray microtomography. Samples of human enamel were carried in the oral cavity of participants for 24 h daily for either 21 or 29 days using so-called intraoral mandibular appliances (ICTs). Demineralisation was thereby generated in a natural way without causing caries in the subjects' dentition. By employing synchrotron based X-ray microtomography (XMT) in combination with volume image analysis, a quantification and three-dimensional visualisation of different stages of mineral density loss was possible. Basic features of the demineralised samples were similar to those reported in earlier in vitro studies. However, the analysed samples showed significant differences in the morphology of surface attack and the degree of mineral density loss depending on the carrier, the exposure time and the position within the ICT. In particular, the varying local conditions within a carrier's oral cavity seem to be different than in an in vitro study. Our results show that the combination of ICTs and quantitative image analysis applied to XMT data provides an analytical tool which is highly suited for the fundamental investigation of naturally developed demineralisation processes. PMID- 23043854 TI - [Transfusion in children with sickle cell disease]. AB - Sickle cell disease is a genetic hemoglobinopathy characterised by vasoocclusive events and chronic haemolytic anaemia. Transfusion is a major therapeutic modality in this disease by decreasing the percentage of abnormal haemoglobin Hb S while increasing oxygen carrying capacity. Simple transfusions or exchange transfusions can be indicated occasionally or on a chronic transfusion program. Iron overload, vascular access and alloimmunization to erythrocyte antigens are causes of great concern in these young patients. PMID- 23043855 TI - [National survey of transfusion practices in the neonatal period for the development of recommendations based on the "Haute Autorite de Sante methodology"]. AB - Although transfusion practices have changed these last years, the neonatal period remains one period when the transfusion of blood components (in particular in red blood cells concentrates) is frequent, particularly for low birth weight premature babies. It is thus important to know well the pathophysiological characteristics specific to this age of life in order to reduce the risks of transfusion and to allow an optimal effectiveness of this treatment. Various studies on neonatal transfusion show that transfusion practices during the neonatal period are very heterogeneous from a team to another, and even within the same team. Therefore, we wanted to know the practices in France, by addressing a questionnaire to neonatology centres, in collaboration with the French Society Vigilance and Transfusion Therapy and the French Society of Neonatology (SFN). The results obtained confirm the heterogeneity of practices. To follow up on this study, we constituted a working group, in partnership with the SFN, the SFVTT and the EFS, with an aim of proposing good practice recommendations according to the methodology of the French "High Authority for Health", in order to homogenize at the national level transfusion practices of the new-born baby. PMID- 23043856 TI - [Hospital haemovigilance and adverse events or reactions: who notifies and what?]. AB - The French haemovigilance system designates a physician in charge of haemovigilance in each hospital. She/he collects the adverse reactions and events reported by medical staff or nurses. In 2010, 7360 (2.42/1000 units) adverse reactions and 518 adverse events (excepted donors) were reported. These results mean that the system is particularly effective in hospitals. This study collected the opinion of physicians in charge of haemovigilance about this organization. PMID- 23043857 TI - The operation of pattern separation and pattern completion processes associated with different attributes or domains of memory. AB - Pattern separation and pattern completion processes are central to how the brain processes information in an efficient manner. Research into these processes is escalating and deficient pattern separation is being implicated in a wide array of genetic disorders as well as in neurocognitive aging. Despite the quantity of research, there remains a controversy as to precisely which behavioral paradigms should be used to best tap into pattern separation and pattern completion processes, as well as to what constitute legitimate outcome measures reflecting impairments in pattern separation and pattern completion. This review will discuss a theory based on multiple memory systems that provides a framework upon which behavioral tasks can be designed and their results interpreted. Furthermore, this review will discuss the nature of pattern separation and pattern completion and extend these processes outside the hippocampus and across all domains of information processing. After these discussions, an optimal strategy for designing behavioral paradigms to evaluate pattern separation and pattern completion processes will be provided. PMID- 23043859 TI - Comparison of indirect immunofluorescence and line immunoassay for autoantibody detection. AB - OBJECTIVES: The aim of the present paper is to evaluate the diagnostic performance of indirect immunofluorescence (IIF) and line immunoassay (LIA) for autoantibody (autoAb) detection and provide sufficient information to interpret the results of autoAb tests. METHODS: The study included 1,052 patients for whom IIF and LIA tests had been performed simultaneously for a systemic autoimmune disease work-up. All patients were divided into either the systemic autoimmune group or non-autoimmune group, and the systemic autoimmune group was further divided into systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome, systemic sclerosis (SSc), and dermatomyositis/polymyositis (DM/PM). The diagnostic performance of IIF and LIA was analysed according to the distribution of IIF patterns and autoAbs identified by LIA. RESULTS: The overall sensitivity/specificity of IIF and LIA for systemic autoimmune disease was 63.5%/80.3% and 66.1%/83.2%, respectively. IIF showed higher sensitivity for SLE than LIA, but the sensitivity of LIA was higher for Sjogren's syndrome and DM/PM. The speckled pattern was the most commonly observed pattern in systemic autoimmune diseases with the exception of SSc. In the majority of systemic autoimmune diseases and their various IIF patterns, both anti-Ro-52 and anti-SS-A were the most prevalent autoAbs. In addition, a majority of the systemic autoimmune diseases showed specific dominant positive patterns or a combination of IIF and LIA results that were disease specific. CONCLUSIONS: Utilising both methods together not only increased the sensitivity in most cases but also provided more information from the combination of results, augmenting their interpretation with the advantage of simultaneous identification of autoAbs. PMID- 23043860 TI - The role of endogenous hydrogen sulfide in pathogenesis of chronotropic dysfunction in rats with cirrhosis. AB - Endogenous hydrogen sulfide is produced by cystathionine-gamma-lyase and cystathionine-beta-synthase in a variety of tissues and has recently been implicated in the regulation of cardiac functions. Acceleration of the heart rate in response to catecholamines is impaired in patients with cirrhosis. The present study was aimed to examine the role of endogenous hydrogen sulfide in the pathogenesis of chronotropic dysfunction in rats with cirrhosis. Cirrhosis was induced by surgical ligation of bile duct in rats. There was no significant difference in atrial cystathionine-gamma-lyase and cystathionine-beta-synthase mRNA levels in control and cirrhotic rats as assessed by quantitative RT-PCR. Four weeks after bile duct ligation or sham surgery the atria were isolated and chronotropic responsiveness to adrenergic stimulation was assessed using standard organ bath. Incubation of the atria with propargylglycine (PAG, a cystathionine gamma-lyase inhibitor) and amino-oxyacetic acid (AOAA, a cystathionine-beta synthase inhibitor) was associated with a significant desensitization of chronotropic response to adrenergic stimulation in controls rats. This indicates that endogenous hydrogen sulfide might be involved in modulation of adrenergic signaling in the atrium. Bile duct ligation was associated with impaired chronotropic responsiveness to adrenergic stimulation in comparison with sham operated rats. In contrast to control group, incubation of the atria with PAG and AOAA was able to partially improve the chronotropic responsiveness to adrenergic stimulation in cirrhotic rats. Our data shows that local inhibition of endogenous hydrogen sulfide in atria has opposite effect in cirrhotic versus control rats and may play a role in physiological modulation of adrenergic signaling in the atrium. PMID- 23043861 TI - C2-di-ethyl-ceramide-1-phosphate as an inhibitor of group IVA cytosolic phospholipase A2. AB - Ceramide-1-phosphate (C1P) has been shown to bind with C2 domain in group IVA cytosolic phospholipase A(2) (cPLA(2)alpha, PLA2G4A) and activate the enzyme activity directly. In cells, C1P causes translocation of cPLA(2)alpha to perinuclear regions including the Golgi complex by interacting with C2 domain in the enzyme, and then cPLA(2)alpha releases arachidonic acid from substrate phospholipids in the regions. In this study, we synthesized new di-ethyl (DE) phosphate ester analogs of C1P with N-acyl chains of different lengths, and examined their effects on cPLA(2)alpha. A DE-C1P analog with a C2-N-acyl chain (C2-DE-C1P), but not DE-C1P analogs with longer N-acyl chain, such as C6- and C16 DE-C1P, inhibited release of arachidonic acid via cPLA(2)alpha activation in CHO W11A cells expressing platelet-activating factor (PAF) receptors without changing secretory phospholipase A(2)-induced release. Treatment with C2-DE-C1P did not modify phosphorylation of extracellular signal-regulated kinase 1/2 and cPLA(2)alpha and increase of intracellular Ca(2+) level induced by PAF, but inhibited Ca(2+)- and PAF-induced accumulation of cPLA(2)alpha in the Golgi complex. Phosphatidylcholine vesicles containing C2-DE-C1P reduced cPLA(2)alpha activity in vitro. C2-DE-C1P disturbed the binding of the enzyme to glycerophospholipids in the lipid-protein overlay assay, and the reagent alone did not bind to the enzyme. Interestingly, C2-DE-C1P inhibited neither Ca(2+)- and PAF-induced accumulation of C2 domain of cPLA(2)alpha in the Golgi complex nor binding of cPLA(2)alpha to C16-C1P. These results suggest that C2-DE-C1P appeared to inhibit cPLA(2)alpha, probably by interaction with a site in the catalytic domain of the enzyme, not with the site in C2 domain responsible for native C1P. PMID- 23043862 TI - Infrared thermography of cutaneous melanoma metastases. AB - BACKGROUND: Differentiating melanoma metastasis from benign cutaneous lesions currently requires biopsy or costly imaging, such as positron emission tomography scans. Melanoma metastases have been observed to be subjectively warmer than similarly appearing benign lesions. We hypothesized that infrared (IR) thermography would be sensitive and specific in differentiating palpable melanoma metastases from benign lesions. MATERIALS AND METHODS: Seventy-four patients (36 females and 38 males) had 251 palpable lesions imaged for this pilot study. Diagnosis was determined using pathologic confirmation or clinical diagnosis. Lesions were divided into size strata for analysis: 0-5, >5-15, >15-30, and >30 mm. Images were scored on a scale from -1 (colder than the surrounding tissue) to +3 (significantly hotter than the surrounding tissue). Sensitivity and specificity were calculated for each stratum. Logistical challenges were scored. RESULTS: IR imaging was able to determine the malignancy of small (0-5 mm) lesions with a sensitivity of 39% and specificity of 100%. For lesions >5-15 mm, sensitivity was 58% and specificity 98%. For lesions >15-30 mm, sensitivity was 95% and specificity 100%, and for lesions >30 mm, sensitivity was 78% and specificity 89%. The positive predictive value was 88%-100% across all strata, and the negative predictive value was 95% for >15-30 mm lesions and 80% for >30 mm lesions. CONCLUSIONS: Malignant lesions >15 mm were differentiated from benign lesions with excellent sensitivity and specificity. IR imaging was well tolerated and feasible in a clinic setting. This pilot study shows promise in the use of thermography for the diagnosis of malignant melanoma with further potential as a noninvasive tool to follow tumor responses to systemic therapies. PMID- 23043863 TI - Margin status after lumpectomy: does surgical method matter? PMID- 23043864 TI - Pancreaticobiliary surgery for the treatment of malignancy: spread the word. PMID- 23043866 TI - Does lumbar microdiscectomy affect adjacent segmental disc degeneration? A finite element study. AB - BACKGROUND: Microdiscectomy is a common surgical procedure used to treat lumbar disc herniation. Following microdiscectomy, the space of the excised nucleus pulposus is replaced by fibrocartilaginous granulation tissue. This results in alterations of both the material properties of the intervertebral disc and the biomechanics of the lumbar motion segments, potentially contributing to adjacent segmental disc degeneration. To our knowledge, there is no published study in the English literature investigating this potential effect. MATERIALS AND METHODS: A previously developed three-dimensional finite element model of L3-L5 was used as a normal control. From this normal model, two different grades of disc degeneration models (mild and moderate) and corresponding microdiscectomy models were developed by changing either the geometry or associated material properties of L4-L5 segment. The 800 N pre-compressive loading plus 10 Nm moments simulating flexion, extension, lateral bending, and axial rotation were imposed on L3 superior end plate of each model. The intradiscal pressure, intersegmental rotation, and tresca stress of annulus fibrosus in L3-L4 segment were investigated. RESULTS: The intradiscal pressure, intersegmental rotation, and tresca stress of L3-L4 segment in mild degeneration microdiscectomy model are higher than those in the mild degeneration model under all motion directions. The above parameters in moderate degeneration microdiscectomy model present a similar trend to the mild degeneration microdiscectomy model. However, the intersegmental rotation of L3-L4 in moderate degeneration microdiscectomy model is lower than that in the moderate degeneration model in lateral bending, and the intradiscal pressure of L3-L4 in moderate degeneration microdiscectomy model is lower than that in the moderate degeneration model in axial rotation. CONCLUSIONS: Lumbar microdiscectomy can result in altered biomechanics, which may have an adverse effect on the development of adjacent upper segmental disc degeneration. PMID- 23043865 TI - Altered thyroid function in severely injured patients. AB - BACKGROUND: Hemorrhagic shock profoundly affects the neuroendocrine profile of trauma patients, and we hypothesized that massive resuscitation would negatively impact thyroid function. METHODS: A prospective, observational study investigating thyroid function in hypotensive trauma patients (systolic blood pressure <90 mm Hg * 2) who survived >48 h was conducted at a Level I center over a 6-mo period. Blood samples for thyroid function were collected at time of presentation to the trauma bay and serially for 48 h. Collected data included demographics, injury data, vital signs, transfusion needs, crystalloid use, and vasopressor requirements. Patients receiving >5 units packed red blood cells (PRBC) within 12 h were compared with those receiving <=5 units. RESULTS: Patients who required >5 units of PRBC/12 h had significantly lower total and free T4 levels on initial presentation, and levels remained significantly depressed over the next 48 h when compared with patients who required a less aggressive resuscitative effort. T3 values were markedly suppressed during the initial 48 h post trauma in all patients, but were significantly lower in patients requiring >5 units PRBC. TSH levels remained within the normal range for all time points. Lower trauma admission T4 levels were associated with the need for greater crystalloid resuscitation within the first 24 h. CONCLUSION: Measurements of thyroid function are significantly altered in severely injured patients on initial presentation, and low T4 levels predict the need for large resuscitation. Further research investigating the profile and impact of thyroid function in trauma patients during resuscitation and recovery is warranted. PMID- 23043867 TI - Commentary: Empiric antibiotics pending bronchoalveolar lavage data in patients without pneumonia significantly alters the flora but not the resistance profile if a subsequent pneumonia develops. PMID- 23043868 TI - Is thyroidectomy in patients with Hashimoto thyroiditis more risky? AB - BACKGROUND: Hashimoto thyroiditis (HT) is an organ-specific autoimmune disease characterized by the production of antibodies such as antithyroperoxidase, which leads to the destruction of the thyroid gland and a decrease in normal thyroid function. Thyroidectomy is performed when the patient presents with symptoms or potential neoplastic degeneration occurs; however, surgery can be difficult because of the dense inflammatory process around the thyroid gland. We hypothesized that patients with HT may have a higher rate of complications after thyroid surgery. METHODS: We identified 1791 consecutive patients who underwent thyroidectomy from May 1994 to December 2009. Patients with HT were compared with those without HT with regard to outcomes with analysis of variance and chi-square test (SPSS, Inc). RESULTS: Patients with HT were significantly younger and more likely to be female. There was no significant difference between the two groups in the rate of malignancy. However, patients undergoing thyroidectomy with HT had a significantly higher postoperative complication rate. Specifically, the rates of overall, transient, and permanent complications were all increased in HT patients. CONCLUSION: Patients with HT had a higher rate of complications after thyroidectomy compared with those without HT. Therefore, careful consideration must be taken before pursuing operative treatment in patients with HT including providing adequate informed consent regarding the increased risks of surgery. PMID- 23043869 TI - Project DyAdd: visual attention in adult dyslexia and ADHD. AB - In this study of the project DyAdd, three aspects of visual attention were investigated in adults (18-55years) with dyslexia (n=35) or attention deficit/hyperactivity disorder (ADHD, n=22), and in healthy controls (n=35). Temporal characteristics of visual attention were assessed with Attentional Blink (AB), capacity of visual attention with Multiple Object Tracking (MOT), and spatial aspects of visual attention with Useful Field of View (UFOV) task. Results showed that adults with dyslexia had difficulties performing the AB and UFOV tasks, which were explained by an impaired ability to process dual targets, longer AB recovery time, and deficits in processing rapidly changing visual displays. The ADHD group did not have difficulties in any of the tasks. Further, performance in the visual attention tasks predicted variation in measures of phonological processing and reading when all of the participants were considered together. Thus, difficulties in tasks of visual attention were related to dyslexia and variation of visual attention had a role in the reading ability of the general population. PMID- 23043870 TI - Hemispheric asymmetries in meaning selection: evidence from the disambiguation of homophonic vs. heterophonic homographs. AB - Research investigating hemispheric asymmetries in meaning selection using homophonic homographs (e.g., bank), suggests that the left hemisphere (LH) quickly selects contextually relevant meanings, whereas the right hemisphere (RH) maintains a broader spectrum of meanings including those that are contextually irrelevant (e.g., Faust & Chiarello, 1998). The present study investigated cerebral asymmetries in maintaining the multiple meanings of two types of Hebrew homographs: homophonic homographs and heterophonic homographs (e.g., tear). Participants read homographs preceded by a biasing, or a non-biasing sentential context, and performed a lexical decision task on targets presented laterally, 1000ms after the onset of the sentence-final ambiguous prime. Targets were related to either the dominant or the subordinate meaning of the preceding homograph, or unrelated to it. When targets were presented in the LVF/RH, dominant and subordinate meanings, of both types of homographs, were retained only when they were supported by context. In a non-biasing context, only dominant meanings of homophonic homographs were retained. Alternatively, when targets were presented in the RVF/LH, priming effects for homophonic homographs were only evident when meanings were supported by both context and frequency (i.e., when context favored the dominant meaning). In contrast, heterophonic homographs resulted in activation of dominant meanings, in all contexts, and activation of subordinate meanings, only in subordinate-biasing contexts. The results challenge the view that a broader spectrum of meanings is maintained in the right than in the left hemisphere and suggest that hemispheric differences in the time course of meaning selection (or decay) may be modulated by phonology. PMID- 23043871 TI - Association between Anaplasma phagocytophilum seroprevalence in dogs and distribution of Ixodes ricinus and Ixodes persulcatus ticks in Latvia. AB - Anaplasma phagocytophilum has been detected in ticks in Latvia; however, this is the first study to investigate this pathogen in dogs in Latvia. The aims of this study were: (i) to determine A. phagocytophilum seroprevalence in dogs, (ii) to correlate A. phagocytophilum seroprevalence in dogs with the geographic distribution of the tick species Ixodes ricinus and Ixodes persulcatus, and (iii) to determine if seroprevalence for A. phagocytophilum is higher in dogs with clinical signs suggestive of canine granulocytic anaplasmosis (CGA). Peripheral venous blood samples were collected from 3 dog groups: (i) clinically healthy dogs (HD, n=400), (ii) clinically healthy hunting dogs (HHD, n=41), and (iii) dogs with a clinical suspicion of anaplasmosis (SD, n=29). Sampling was carried out in regions inhabited by I. ricinus (IR), I. persulcatus (IP), and in regions where both tick species were present (M). SNAP 4Dx test (IDEXX) was used to detect antibodies against A. phagocytophilum in the blood of all dogs; nested PCR was performed in selected dogs of the SD group. Seroprevalence for A. phagocytophilum was calculated and correlated with the prevalent tick species in the region. A. phagocytophilum seroprevalence was 11.0% in HD, 12% in HHD, and 17% in SD with no significant differences among groups. In the IR region, seroprevalence was 12.5% (34/272) while seroprevalence in the M region was 17% (13/76), and both were significantly higher than the seroprevalence of 2% in the IP region (2/93; p<0.0005). One CGA case was diagnosed. We conclude that A. phagocytophilum seroprevalence in Latvia is within the range reported from other European countries. CGA should be included in the differential list in Latvian dogs with appropriate clinical signs and laboratory abnormalities, especially in I. ricinus habitat areas. PMID- 23043873 TI - A pilot and feasibility study of computer-based training for visual processing deficits in schizophrenia. PMID- 23043872 TI - North American Prodrome Longitudinal Study (NAPLS 2): overview and recruitment. AB - The North American Prodrome Longitudinal Study (NAPLS) is a consortium of eight programs focusing on the psychosis prodrome. Funded by the National Institute of Mental Health (NIMH), the sites are located at Emory University, Harvard University, University of Calgary, UCLA, UCSD, University of North Carolina Chapel Hill, Yale University, and Zucker Hillside Hospital. Although the programs initially developed independently, they previously collaborated to combine their historical datasets and to produce a series of analyses on predictors of psychosis in one of the largest samples of longitudinally followed prodromal subjects worldwide. This led to the development of a five year prospective study "Predictors and Mechanisms of Conversion to Psychosis", (also known as NAPLS-2) with three major aims: (1) to prospectively test the prediction algorithm developed in NAPLS-1, (2) to investigate the neuroanatomical, neurophysiological, neurocognitive, and neurohormonal factors that may contribute to the development of psychosis, and (3) to develop a repository of DNA, RNA, and plasma from participants meeting diagnostic criteria for a clinical high risk (CHR) state and from demographically similar healthy subjects. Funded by NIMH in 2008, NAPLS-2 will generate the largest CHR for psychosis sample with 720 CHR and 240 healthy comparison subjects, and thus will provide statistical power and scientific scope that cannot be duplicated by any single site study. This paper describes the overall methodology of the NAPLS-2 project and reports on the ascertainment and demographics at the midway point of the study with (360 CHR) and 180 controls. PMID- 23043874 TI - Insight and empathy in schizophrenia. PMID- 23043875 TI - Augmented breaths ('sighs') are suppressed by morphine in a dose-dependent fashion via naloxone-sensitive pathways in adult rats. AB - Morphine treatment can eliminate augmented breaths (ABs; 'sighs') during spontaneous breathing. In the present study, unanesthetized rats were studied to: (1) determine the involvement of naloxone-sensitive receptor pathways, and (2) establish the dose-response relationship of this side effect. At a dosage of 5mg/kg (2-10mg/kg is recommended range for analgesia) morphine eliminated ABs from the breathing rhythm across nearly 100 min post-administration (vs. 6.2 +/- 1.6 ABs in 15 min, control condition, p<0.001). This occurred despite no apparent effect on indices of ventilation. By contrast, when naloxone was co-administered with morphine, the occurrence of ABs was not different compared to control. The suppression of ABs by morphine followed a sigmoidal pattern across the low-mid dosage range (R(2)=0.83), whereas tidal volume and breathing frequency were unaffected. We conclude that the opioid-induced suppression of ABs is mediated by naloxone-sensitive opioid receptor pathways, and that this side effect is potent across the low-mid dosage range, and cannot be simply avoided by restricting dosage. PMID- 23043876 TI - Oxygen uptake kinetics at work onset: role of cardiac output and of phosphocreatine breakdown. AB - The hypothesis that variability in individual's cardiac output response affects the kinetics of pulmonary O2 uptake (VO2) was tested by investigating the time constants of cardiac output (Q) adjustment (tau(Q)), of PCr splitting (tau(PCr)), and of phase II pulmonary O2 uptake (tau(VO2)) in eight volunteers. VO2, Q, and gastrocnemius [PCr] (by (31)P-MRS) were measured at rest and during low intensity two-legged exercise. Steady state VO2 and Q increased (DeltaVO2(s) = 182 +/- 58 mL min-1; DeltaQ = 1.3 +/- 0.4 L min-1), whereas [PCr] decreased significantly (21 +/- 8%). tau(VO2), tau(PCr) and tau(Q) were significantly different from each other (38.3 +/- 4.0, 23.9 +/- 2.5, 11.6 +/- 4.6 s, respectively; p<0.001). tau(PCr) assumed to be equal to the time constant of VO2 at the muscle level (tau(mVO2)), was not related to tau(Q), whereas tau(VO2) and tau(Q) were significantly related (p<0.05) as were tau(VO2) and tau(PCr) (p<0.05). Venous blood O2 stores changes, as determined from arterio-to-mixed-venous O2 content, were essentially equal to those estimated as (tau(VO2)-tau(PCr)).DeltaVO2(s). This suggests that cardiac output responses affect O2 stores utilization and hence tau(VO2) : thus tau(VO2) is not necessarily a good estimate of tau(mVO2). PMID- 23043877 TI - Interferon-beta-induced pulmonary sarcoidosis in a 30-year-old woman treated for multiple sclerosis: a case report. AB - INTRODUCTION: With the increasing use of recombinant alpha and beta interferon therapy for the treatment of various disorders, cases of interferon-associated sarcoidosis have been reported in the literature. The majority of these have been cases of interferon-alpha-induced sarcoidosis. We present the first case, to the best of our knowledge, of interferon-induced pulmonary sarcoidosis in a patient whose multiple sclerosis was treated with interferon-beta. CASE PRESENTATION: We present the case of a 30-year-old Caucasian woman who presented with unusually persistent bilateral areas of lung consolidation on serial radiographs. Pulmonary sarcoidosis was diagnosed on transbronchial lung biopsy five months after the initiation of treatment with interferon-beta for multiple sclerosis. CONCLUSIONS: Sarcoidosis should be considered in the differential diagnosis of a patient who develops clinical or radiological pulmonary disease while undergoing interferon therapy. It is important to note that interferon-induced sarcoidosis, though usually seen in cases with interferon-alpha, can occur with interferon-beta. Neurologists managing patients with multiple sclerosis should be aware of this association between interferon-beta and sarcoidosis and promptly refer patients developing respiratory symptoms for further investigation. PMID- 23043878 TI - Dental trauma among Brazilian schoolchildren: prevalence, treatment and associated factors. AB - AIM: To assess the prevalence of traumatic dental injury (TDI), as well as associated factors, behaviour of affected schoolchildren and normative treatment needs. METHODS: The present cross-sectional study involved 590 children aged 7-14 years at state schools in Campina Grande, Brazil. The O'Brien classification [1994] was used for the diagnosis of TDI and the body mass index (BMI) was used as an indicator of overweight/obesity. Clinical tests were carried out by two duly calibrated examiners (intra-observer and inter-observer agreement: 0.87 and 0.90, respectively). The Chi-square test was used (5% level of significance) to determine whether TDI was associated with age, gender, ethnicity, overweight/obesity, lip seal and overjet. Backward stepwise multivariate regression analysis was performed. Normative treatment needs were determined based on the criteria of the International Association of Dental Traumatology (IADT). When the absence of treatment was detected, each child/adolescent was asked about the reason for non-treatment. RESULTS: The prevalence of TDI was 12.7%. The most common type of trauma was enamel fracture (67.0%), followed by enamel-dentine fracture (25.3%). TDI was 4.9-fold greater (95% CI: 1.6-14.4) among children aged 13 and 14 years, 1.9- fold greater (95% CI: 1.1-3.2) among males and 2.6-fold greater (95% CI: 1.2-5.4) among those with inadequate lip seal. The majority of schoolchildren did not undergo treatment (82.6%) due to a belief that it was unnecessary (53.2%). The normative clinical evaluation revealed that adhesive restoration was the most common form of treatment (84.0%). CONCLUSION: The prevalence of TDI was low. Age, gender and inadequate lip seal were associated with dental trauma. A significant number of schoolchildren did not receive treatment for dental trauma. PMID- 23043879 TI - Oral microflora and dietary intake in infants with congenital heart disease: a case control study. AB - BACKGROUND: Infants with moderate to severe congenital heart disease (CHD) are at a higher risk for growth failure and malnutrition due to increased metabolic demands and inadequate energy intake. This state requires meals that are more frequent and a special enriched diet, which may have negative implications on oral health. AIM: To examine the oral colonisation of some bacteria associated with caries development during infancy; mutans streptococci (MS) and lactobacilli (LCB) in infants with CHD and whether their dietary intake had an impact on the bacterial levels. DESIGN: This was a prospective case-control study. 11 infants with CHD and 22 healthy, age-matched infants were enrolled. Saliva samples and food diaries were collected at 6, 9, and 12 months of age. The total viable counts of MS and LCB in saliva were determined, and energy intake, meal frequency, intake of proteins, fat, carbohydrates and sucrose were calculated. RESULTS: At 12 months of age, the MS count was higher in the CHD group than in the controls (p<0.01), and MS constituted a higher ratio of the total viable count of oral bacteria (p<0.01). Meal frequency was higher in the CHD group at 6 and 9 months of age than in the controls (p<0.05). The intake of sucrose did not differ between the groups, while the total carbohydrate intake was higher in the control group at 6 and 12 months of age (p<0.05). Compared with the control group, which had six courses of antibiotic administration, the CHD infants had 21 courses (p<0.05). CONCLUSIONS: Infants with severe CHD have higher levels of MS at 12 months of age than the healthy controls. A higher meal frequency and use of diuretic medication and antibiotics may have influenced MS colonisation. PMID- 23043880 TI - Development of a new technique (ATP) for training visually impaired children in oral hygiene maintenance. AB - AIM: To develop a special oral health education technique and compare plaque scores before and after health education. STUDY DESIGN: Non-randomised before and after comparison trial without controls. METHODS: The final study population comprised of 96 visually impaired children aged 6-18 years old. Silness and Loe plaque index scores were recorded at baseline. 'Audio tactile performance technique' (ATP Technique) a specially designed health education method was used to educate these children regarding oral hygiene maintenance. Periodic reinforcement of health education was performed at an interval of 9 months. Re examination was carried out after 18 months of health education to assess plaque scores. STATISTICS: Wilcoxon's sign rank test and paired t test was used to assess the difference between the scores before and after health education. RESULTS: There was increase in frequency of tooth brushing after health education. The mean plaque scores pre- and post-health education were 1.41 (+/ 0.58) and 0.63 (+/-0.39) respectively. The difference was statistically significant (p<0.001). CONCLUSION: Visually impaired children could maintain an acceptable level of oral hygiene when taught using special customised methods. PMID- 23043881 TI - Effect of non-functional teeth on accumulation of supra-gingival calculus in children. AB - AIM: To evaluate the occurrence of supra-gingival calculus in children aged 6-9 years with disuse conditions such as: presence of dental pain, open-bite or erupting teeth. METHODS: A cohort of 327 children aged 7.64+/-2.12 (range: 6-9) years (45% girls) were screened for presence of supra-gingival calculus in relation to open bite, erupting teeth and dental pain. Presence of dental calculus was evaluated dichotomically in the buccal, palatinal/lingual and occlusal surfaces. Plaque index (PI) and gingival index (GI) were also evaluated. RESULTS: Supra-gingival calculus was found in 15.9% of the children mainly in the mandibular incisors. Children aged 6-7 years had a higher prevalence of calculus as compared to children aged 7-8 years (23% vs. 13.5%, p=0.057) or 8-9 years (23% vs. 12.4%, p=0.078), respectively. No statistical relation was found between plaque and gingival indices and presence of calculus. The prevalence of calculus among children with openbite was significantly higher than that of children without open-bite (29.4% vs. 10.7%, p=0.0006, OR=3.489). The prevalence of calculus among children with erupting teeth in their oral cavity was higher than that of children without erupting teeth (17.7% vs. 9%, respectively, p=0.119). No statistical correlation was found between presence of dental pain and calculus (15.4% vs. 15.9%; p=0.738). CONCLUSION: Accumulation of calculus in children aged 6-10 years was found mainly in the mandibular incisors, decreased with age and was correlated with open-bite. PMID- 23043883 TI - Association of anthropometric measures and dental caries among a group of adolescent cadets of Udupi district, South India. AB - AIM: To evaluate the relationship between anthropometric measures and dental caries among a group of adolescent cadets of Udupi district, India. METHODS: Demographic information such as age, sex and parental education were collected. Various anthropometric measures such as weight, body mass index (BMI), height, mid-upper arm circumference, waist circumference (WC) and hip circumference were recorded as per standard guidelines. Dental caries was recorded using mouth mirrors and CPI probes. RESULTS: A total of 211 cadets with age range of 12-19 years constituted the final sample. Caries experience was significantly different with respect to age and gender (p=0.049 and 0.05 respectively). Multivariate analysis was performed using Poisson regression with DMFT as dependent variable. Height, weight, BMI and WC showed significant association with dental caries status (OR = 10.61, 1.03, 1.09 and 1.02 respectively). Stratified analysis showed no association with anthropometric measures (height, weight, BMI and WC) and dental caries in 12-14 years. Among 15-19 years age group, there was a significant association between anthropometric measures (height, weight and BMI) and dental caries. CONCLUSIONS: There was a significant association between anthropometric measures and caries status in 15-19 years age group while no association was found in 12-14 years age group. Obesity and dental caries have common risk determinants and require a comprehensive multi-disciplinary approach by health care professionals. PMID- 23043882 TI - In vitro evaluation of apical microleakage of a new MTA-based sealer. AB - AIM: To evaluate the apical microleakage of a new MTAbased sealer; MTA Fillapex (Angelus) and compare it with ProRoot MTA (Dentsply) and AH Plus (Dentsply). METHODS: 51 single-rooted permanent teeth were selected and the roots were prepared using a rotary system. The samples were divided randomly into 3 groups (n=15). Six roots were used as positive and negative controls. The teeth were obturated with respectively; A. AH Plus and gutta percha (DiaDent); B. MTA Fillapex and gutta percha; C. ProRoot MTA. Specimens were placed in 2% methylene blue dye for 72h. Then linear dye penetration was measured. Measurements were analysed statistically. RESULTS: MTA Fillapex group had significantly higher microleakage values (p<0.05). There were no statistically significant differences between MTA and AH Plus groups (p>0.05). CONCLUSION: The sealing ability of AH Plus and MTA were similar whilst MTA Fillapex showed more microleakage than the other two materials. PMID- 23043884 TI - Cross-sectional microhardness of bovine enamel subjected to three paediatric liquid oral medicines: an in vitro study. AB - AIM: This study aimed to investigate the in vitro effects of three paediatric liquid oral medicines on bovine dental enamel subsurfaces under pH cycling conditions. METHODS: Bovine enamel blocks were evaluated for surface hardness at baseline for sample selection. 52 intact bovine enamel blocks (16mm(2)) were randomly divided into four groups (n=13) according to the immersion treatments: G1: antibiotic (Klaricid(r)), G2: antihistamine (Claritin(r)), G3: antihistamine (Dimetapp(r)) and G4: control (de-ionised water). The blocks were submitted to pH cycling treatments twice a day for 12 days. The medicines were evaluated for pH, viscosity, and concentration of calcium, phosphate and fluoride. After the treatment period, cross-sectional microhardness (CSMH) measurements of the enamel blocks were taken and the data, expressed in Knoop hardness number (kg/mm(2)) was used to calculate the DeltaS. STATISTICS: ANOVA followed by the Tukey test were used for statistical analyses (p<0.05). RESULTS: The antibiotic Klaricid(r) showed the highest concentration of fluoride, calcium and phosphate. Considering pH and viscosity, the following pattern was observed according to the treatment group: G4>G1>G2>G3 and G1>G2>G3>G4 respectively. Regarding the demineralisation pattern, the following results were observed: G4>G3>G2>G1. Compared to the control, the antibiotic and both the antihistamines provoked less demineralisation of the enamel blocks (p<0.05). CONCLUSIONS: Antibiotic G1 (Klaricid(r)) presented an in vitro protective effect against acid attacks probably due to its mineral content and viscosity. PMID- 23043885 TI - Therapeutic management of a case of generalised aggressive periodontitis in an 8 year old child: 18-month results. AB - BACKGROUND: Generalised aggressive periodontitis (GAP) is a rare condition associated with rapid periodontal destruction, in multiple teeth. The paper aims to present a case of an 8-year old with GAP and discuss his response to treatment. CASE REPORT: An 8-year old male was referred to the postgraduate clinic of paediatric dentistry of the University of Athens due to increased mobility in his primary dentition. At initial clinical examination, plaque accumulation, gingival inflammation and temporary restorations were noted. Detailed periodontal examination revealed bleeding on probing, pocket depths of up to 9 mm and second degree mobility in primary teeth. Radiographic examination showed advanced bone loss and carious lesions. Microbiological analysis revealed increased percentages of peri-opathogens in pooled subgingival samples. Final diagnosis of GAP was made after ruling out any underlying systemic disorder. TREATMENT: Periodontal therapy involved non-surgical subgingival debridement, systemic administration of antibiotics and retention of periodontally involved teeth. FOLLOW-UP: This was based on a monthly recall program for the first 6 months and a 3-monthly regime thereafter. At 18-months after initial examination, a substantial improvement in clinical parameters was seen, while levels of periodontal pathogens were sustained at low levels. CONCLUSION: Non-surgical root debridement along with systemic administration of antibiotics and retention of the periodontally involved teeth, can be successful in achieving improvement and maintenance of periodontal health in the mixed dentition. PMID- 23043886 TI - Interactive wiimote gaze stabilization exercise training system for patients with vestibular hypofunction. AB - BACKGROUND: Peripheral vestibular hypofunction is a major cause of dizziness. When complicated with postural imbalance, this condition can lead to an increased incidence of falls. In traditional clinical practice, gaze stabilization exercise is commonly used to rehabilitate patients. In this study, we established a computer-aided vestibular rehabilitation system by coupling infrared LEDs to an infrared receiver. This system enabled the subjects' head-turning actions to be quantified, and the training was performed using vestibular exercise combined with computer games and interactive video games that simulate daily life activities. METHODS: Three unilateral and one bilateral vestibular hypofunction patients volunteered to participate in this study. The participants received 30 minutes of computer-aided vestibular rehabilitation training 2 days per week for 6 weeks. Pre-training and post-training assessments were completed, and a follow up assessment was completed 1 month after the end of the training period. RESULTS: After 6 weeks of training, significant improvements in balance and dynamic visual acuity (DVA) were observed in the four participants. Self-reports of dizziness, anxiety and depressed mood all decreased significantly. Significant improvements in self-confidence and physical performance were also observed. The effectiveness of this training was maintained for at least 1 month after the end of the training period. CONCLUSION: Real-time monitoring of training performance can be achieved using this rehabilitation platform. Patients demonstrated a reduction in dizziness symptoms after 6 weeks of training with this short-term interactive game approach. This treatment paradigm also improved the patients' balance function. This system could provide a convenient, safe and affordable treatment option for clinical practitioners. PMID- 23043887 TI - Affective inhibitory control in adults with attention deficit hyperactivity disorder: abnormalities in electrocortical late positivity. AB - Boys afflicted with ADHD (Attention-deficit/hyperactivity disorder) are characterized by deficient response inhibition and reduced electrocortical late positivity when presented with facial expressions of anger. This deficit might contribute to their problems in social interactions. We conducted the present event-related potential study with 15 men suffering from ADHD and 15 healthy controls in order to investigate whether similar dysfunctions are present in adult ADHD. The participants underwent an emotional version of a Go/NoGo task while event-related potentials (ERPs) were recorded. They were instructed to inhibit a motor response to one of four facial emotional expressions: anger, fear, sadness, or happiness. There were no behavioral differences in inhibitory control between the ADHD and the control group. However, the patients showed a reduced right parietal late positivity when instructed to inhibit a response to negative emotions. Obviously, the patients have learned to compensate for their deficit on a behavioral level, while it is still visible on the electrocortical level in this relatively simple task. Interestingly, the reduced positivity correlated with lowered self-reported emotional intelligence in the ADHD group. PMID- 23043888 TI - Riluzole effect on occipital cortex: a structural and spectroscopy pilot study. AB - BACKGROUND: To investigate the mechanism underlying the anxiolytic properties of riluzole, a glutamate-modulating agent, we previously studied the effect of this drug on hippocampal N-acetylaspartate (NAA) and volume in patients with generalized anxiety disorder (GAD). In the same cohort, we now extend our investigation to the occipital cortex, a brain region that was recently implicated in the antidepressant effect of riluzole. METHODS: Fourteen medication free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. The healthy group did not receive riluzole treatment. Both groups underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. Hamilton Anxiety Rating Scale (HAM-A) and Penn State Worry Questionnaire (PSWQ) were used as the primary and secondary outcome measures, respectively. RESULTS: At baseline, we found clusters of increased cortical thickness in the occipital region in GAD compared to healthy subjects. In the right hemisphere, 8 weeks of treatment reduced occipital cortical thickness in the GAD group (t=3.67, p=0.004). In addition, the improvement in HAM A scores was negatively correlated with post-treatment right occipital NAA (r= 0.68, p=0.008), and with changes in NAA levels (r=-0.53, p=0.051). In the left hemisphere, we found positive associations between changes in occipital cortical thickness and improvement in HAM-A (r=0.60, p=0.04) and PSWQ (r=0.62, p=0.03). CONCLUSION: These pilot findings implicate the occipital cortex as a brain region associated with pathology and clinical improvement in GAD. In addition, the region specific effect of riluzole implies a distinct pathophysiology in the occipital cortex - compared to other, previously studied, frontolimbic brain structures. PMID- 23043889 TI - Judging hand laterality from my or your point of view: interactions between motor imagery and visual perspective. AB - Motor imagery tasks (hand laterality judgment) are usually performed with respect to a self-body (egocentric) representation, but manipulations of stimulus features (hand orientation) can induce a shift to other's body (allocentric) reference frame. Visual perspective taking tasks are also performed in self-body perspective but a shift to an allocentric frame can be triggered by manipulations of context features (e.g., another person present in the to-be-judged scene). Combining hand laterality task and visual perspective taking, we demonstrated that both stimulus and context features can modulate motor imagery performance. In Experiment 1, participants judged laterality of a hand embedded in a human or non-human silhouette. Results showed that observing a human silhouette interfered with judgments on "egocentric hand stimuli" (right hand, fingers up). In Experiment 2, participants were explicitly required to judge laterality of a hand embedded in a human silhouette from their own (egocentric group) or from the silhouette's perspective (allocentric group). Consistent with previous results, the egocentric group was significantly faster than the allocentric group in judging fingers-up right hand stimuli. These findings showed that concurrent activation of egocentric and allocentric frames during mental transformation of body parts impairs participants' performance due to a conflict between motor and visual mechanisms. PMID- 23043890 TI - Melatonin supplementation delays the decline of adult hippocampal neurogenesis during normal aging of mice. AB - Melatonin modulates adult hippocampal neurogenesis in adult mice. Also, plasma melatonin levels and new neuron formation decline during aging probably causing cognitive alterations. In this study, we analyzed the impact of exogenous supplementation with melatonin in three key events of hippocampal neurogenesis during normal aging of mice. The analysis was performed in rodents treated with melatonin during 3, 6, 9 or 12 months. We found an increase in cell proliferation in the dentate gyrus of the hippocampus after 3, 6 and 9 months of treatment (>90%). Additionally, exogenous melatonin promoted survival of new cells in the dentate gyrus (>50%). Moreover, melatonin increased the number of doublecortin labeled cells after 6 and 9 months of treatment (>150%). In contrast, melatonin administered during 12 months did not induce changes in hippocampal neurogenesis. Our results indicate that melatonin also modulates the neurogenic process in the hippocampus during normal aging of mice. Together, the data support melatonin as one of the positive endogenous regulators of neurogenesis during aging. PMID- 23043891 TI - Nicotinamide induces male-specific body weight loss in the postnatal period through molecular regulation of the hypothalamus and liver. AB - Molecular mechanisms of body weight control have been discovered recently and much research focuses on the hypothalamic regulation of food intake and the hepatic regulation of glucose utility. We previously reported that postnatal nicotinamide treatment reduced brain dopamine and body weight. To further investigate the differential effects of nicotinamide-mediated body weight loss, nicotinamide (i.p. 100mg/kg) was injected into postnatal and adult mice twice a week for 4 weeks. Interestingly, following nicotinamide treatment, male postnatal mice displayed reduced body weight and spontaneous motor activity. No significant changes were observed in adult and postnatal female mice or adult male mice following nicotinamide treatment. In male postnatal mice, hypothalamic agouti related peptide (AGRP) and proopiomelanocortin (POMC) levels were increased in the arcuate nucleus following nicotinamide treatment. Neuropeptide Y (NPY) levels were unchanged in both male and female mice. Additionally, nicotinamide-injected male postnatal mice had increased glucose 6-phosphatase (G6Pase) and decreased phosphoenolpyruvate carboxykinase (PEPCK) expression in liver. These results indicate that hypothalamic POMC and hepatic PEPCK are important molecules that mediate nicotinamide-induced weight loss in postnatal male mice. PMID- 23043892 TI - Clinical transplantation of individualized recipient serum-adapted cornea reduces the risk of graft rejection after keratoplasty. AB - Corneal diseases cause severe visual impairment that necessitates corneal transplantation and frequently repetitive procedures due to graft rejection. We tested the hypothesis that exposure of donor corneas to recipient serum-derived factors during eye banking triggers a preoperative adaptation that is beneficial for postoperative tolerance. Donor corneas were incubated in a medium containing human serum (HS) obtained in each case from the prospective graft recipient in order to individually expose the donor cornea to the recipient's serum. All recipient serum-adapted corneas (RSACs) fulfilled the clinical criteria required by the national law and were transplanted successfully. The postoperative ophthalmological examination extended up to 8 years. All RSACs were tolerated by their recipients and did not cause postoperative complications and no rejection. Proteomic analysis of corneas cultivated in culture medium containing either fetal calf serum (FCS) that is routinely used for cornea banking or HS revealed different patterns of proteins. HS-cultured corneas showed a greater proteomic similarity with native human corneas than did the FCS-cultured corneas, indicating a differential nutrification of the cultured corneal tissue by HS derived factors. The clinical results show for the first time that postoperative complications such as tissue intolerance and graft rejection might be managed if the corneal tissue is individually adapted to the recipient's serum trophic factors. This new donor tissue treatment procedure offers incontrovertible advantages and could be adapted for low-risk eyes as well as other transplantable tissues. PMID- 23043893 TI - Epidemiology of invasive meningococcal disease in Germany, 2002-2010, and impact of vaccination with meningococcal C conjugate vaccine. AB - OBJECTIVES: To analyse serogroup (Sg)- and finetype-specific invasive meningococcal disease burden (IMD) in Germany, 2002-2010, with emphasis on effects of vaccination with conjugate SgC vaccines targeting one-year old children since 2006, including individual-based catch-up to 17 years of age. METHODS: Serogroup- and age-specific IMD incidence and trends were calculated using statutory surveillance data. The national reference laboratory performed genetic finetyping. Vaccination uptake data were obtained from school entry surveys and prescription monitoring. RESULTS: In persons <25 years, SgB and SgC IMD incidence decreased significantly from 0.63 to 0.32/100,000 and 0.26 to 0.10/100,000, respectively. The decline was significantly steeper for SgC than SgB in 1-5 year-olds, the primary vaccination target group, but not other ages. The slope of the SgC incidence curves was similar before and after vaccination implementation in all age groups; however, the decrease in incidence was steeper in states with higher vaccination uptake. Declining SgC incidence was associated with decreased SgC finetype diversity. An increase in SgY incidence was limited to adults. CONCLUSIONS: Results suggest effects of the German SgC vaccination strategy are limited, although interpretation is complicated by already low and decreasing incidence before vaccination. More effective use of vaccination resources might be achieved by rigorously targeting adolescents in addition to 1 year-olds. PMID- 23043894 TI - Use of autologous stem cell transplantation in adult patients with idiopathic inflammatory myopathies: a case-report and review of the literature. PMID- 23043896 TI - Enhanced oxygen supply improves islet viability in a new bioartificial pancreas. AB - The current epidemic of diabetes with its overwhelming burden on our healthcare system requires better therapeutic strategies. Here we present a promising novel approach for a curative strategy that may be accessible for all insulin-dependent diabetes patients. We designed a subcutaneous implantable bioartificial pancreas (BAP)-the "beta-Air"-that is able to overcome critical challenges in current clinical islet transplantation protocols: adequate oxygen supply to the graft and protection of donor islets against the host immune system. The system consists of islets of Langerhans immobilized in an alginate hydrogel, a gas chamber, a gas permeable membrane, an external membrane, and a mechanical support. The minimally invasive implantable device, refueled with oxygen via subdermally implanted access ports, completely normalized diabetic indicators of glycemic control (blood glucose intravenous glucose tolerance test and HbA1c) in streptozotocin induced diabetic rats for periods up to 6 months. The functionality of the device was dependent on oxygen supply to the device as the grafts failed when oxygen supply was ceased. In addition, we showed that the device is immuno-protective as it allowed for survival of not only isografts but also of allografts. Histological examination of the explanted devices demonstrated morphologically and functionally intact islets; the surrounding tissue was without signs of inflammation and showed visual evidence of vasculature at the site of implantation. Further increase in islets loading density will justify the translation of the system to clinical trials, opening up the potential for a novel approach in diabetes therapy. PMID- 23043895 TI - Dissociating fatty liver and diabetes. AB - Fatty liver disease is epidemiologically associated with type 2 diabetes (T2D), leading to a speculation of a reciprocal cause-effect relationship and a vicious cycle of pathology. Here, we summarize recent literature reporting dissociation of hepatosteatosis from insulin resistance in genetic mouse models and clinical studies. We highlight rhythmic flows of metabolic intermediates between hepatic lipid synthesis and glucose production in normal circadian physiology. Blocking triglyceride (TG) secretion, subcellular lipid sequestration, lipolysis deficiency, enhanced lipogenesis, gluconeogenesis defects, or inhibition of fatty acid oxidation all result in hepatosteatosis without causing hyperglycemia or insulin resistance, suggesting that the cause-effect relationship between hepatosteatosis and diabetes does not exist in all situations. PMID- 23043897 TI - Bartonella henselae infection during tocilizumab therapy. PMID- 23043898 TI - Differences in MMPs and TIMP-1 expression between intervertebral disc and disc herniation. PMID- 23043899 TI - Necrotizing fasciitis: contribution and limitations of diagnostic imaging. AB - Necrotizing fasciitis is a rare, rapidly spreading, deep-seated infection causing thrombosis of the blood vessels located in the fascia. Necrotizing fasciitis is a surgical emergency. The diagnosis typically relies on clinical findings of severe sepsis and intense pain, although subacute forms may be difficult to recognize. Imaging studies can help to differentiate necrotizing fasciitis from infections located more superficially (dermohypodermitis). The presence of gas within the necrotized fasciae is characteristic but may be lacking. The main finding is thickening of the deep fasciae due to fluid accumulation and reactive hyperemia, which can be visualized using computed tomography and, above all, magnetic resonance imaging (high signal on contrast-enhanced T1 images and T2 images, best seen with fat saturation). These findings lack specificity, as they can be seen in non-necrotizing fasciitis and even in non-inflammatory conditions. Signs that support a diagnosis of necrotizing fasciitis include extensive involvement of the deep intermuscular fascias (high sensitivity but low specificity), thickening to more than 3mm, and partial or complete absence on post-gadolinium images of signal enhancement of the thickened fasciae (fairly high sensitivity and specificity). Ultrasonography is not recommended in adults, as the infiltration of the hypodermis blocks ultrasound transmission. Thus, imaging studies in patients with necrotizing fasciitis may be challenging to interpret. Although imaging may help to confirm deep tissue involvement and to evaluate lesion spread, it should never delay emergency surgical treatment in patients with established necrotizing fasciitis. PMID- 23043901 TI - [Reflections on the XXIII Semfyc Congress: quality of care under financial crisis and innovation in self-knowledge management]. PMID- 23043900 TI - Frontotemporal degeneration, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development. AB - Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled "FTD, the Next Therapeutic Frontier," which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases. PMID- 23043902 TI - The classification and nomenclature of 'medically unexplained symptoms': conflict, performativity and critique. AB - Persistent medically unexplained symptoms (MUS)--including the many syndromes that fall under this umbrella--involve a discrepancy between professional knowledge and lay experience and are often associated with latent or explicit dynamics of conflict. Although this conflictual dimension has been amply documented, little critical attention has been paid to how nomenclature and classification feed into the conflictual dynamic and are informed by it in turn. In this paper I engage with this question from a social-theoretical perspective informed by the concept of performativity. The paper offers a critical review of debates around the medical terminology in use, and a discussion of the alternative terminology developed by social scientists. Based on these, I argue that medical and social scientific discourse unwittingly collude in a disavowal of the psychological dimension of 'MUS'. I then discuss the paradoxical character of this disavowal and suggest that it tends to perpetuate polemical modes of engagement around 'MUS'. I conclude with suggestions on how further research might counteract this tendency. PMID- 23043904 TI - How stable is activation in the amygdala and prefrontal cortex in adolescence? A study of emotional face processing across three measurements. AB - Prior developmental functional magnetic resonance imaging (fMRI) studies have demonstrated elevated activation patterns in the amygdala and prefrontal cortex (PFC) in response to viewing emotional faces. As adolescence is a time of substantial variability in mood and emotional responsiveness, the stability of activation patterns could be fluctuating over time. In the current study, 27 healthy adolescents (age: 12-19 years) were scanned three times over a period of six months (mean test-retest interval of three months; final samples N=27, N=22, N=18). At each session, participants performed the same emotional faces task. At first measurement the presentation of emotional faces resulted in heightened activation in bilateral amygdala, bilateral lateral PFC and visual areas including the fusiform face area. Average activation did not differ across test sessions over time, indicating that at the group level activation patterns in this network do not vary significantly over time. However, using the Intraclass Correlation Coefficient (ICC), fMRI reliability demonstrated only fair reliability for PFC (ICC=0.41-0.59) and poor reliability for the amygdala (ICC<0.4). These findings suggest substantial variability of brain activity over time and may have implications for studies investigating the influence of treatment effects on changes in neural levels in adolescents with psychiatric disorders. PMID- 23043903 TI - The various faces of autoimmune endocrinopathies: non-tumoral hypergastrinemia in a patient with lymphocytic colitis and chronic autoimmune gastritis. AB - Serum gastrin levels exceeding 1000pg/ml (normal, <100) usually raise the suspicion for a neuroendocrine tumor (NET) that secretes gastrin. Rarely, such elevated gastrin levels are seen in patients with pernicious anemia which most commonly is associated with autoimmune gastritis (AG). AG can occur concomitantly with other autoimmune disorders including lymphocytic colitis (LC). Gastrin stimulates enterochromaffin-like cells which increase histamine secretion. Histamine excess can cause diarrhea as can bacterial overgrowth or LC. We present a 57-year-old woman with diarrhea, sporadic epigastric pain, and bloating. She also had a history of interstitial cystitis and took pentosan polysulfate and cetirizine. She had no history of ulcers, renal impairment or carcinoid syndrome. Fasting serum gastrin was 1846pg/ml. Esophagoduodenal gastroscopy and biopsies revealed chronic gastritis and a pH of 7 with low stomach acid. Serum gastrin and plasma chromogranin A were suggestive of a gastrinoma or NET. Pernicious anemia was unlikely. Imaging studies did not reveal any tumor. Random colonic biopsy was compatible with LC, possibly explaining her diarrhea, although we also considered excessive histamine from elevated gastrin, bacterial overgrowth, and pentosan polysulfate which can cause diarrhea and be misleading in this setting, pointing to the diagnosis of gastrinoma. At 4year follow-up in 2012, fasting serum gastrin was 1097pg/ml and the patient asymptomatic taking only cetirizine for nasal allergies. This case illustrates that diarrhea may be associated with very high serum gastrin levels in the setting of chronic gastritis, LC, and interstitial cystitis (pentosan use), without clear evidence for a gastrinoma or NET. If no history of ulcers or liver metastases is present in such cases, watchful observation rather than an extensive/invasive and costly search for a NET may be justified. Considering the various forms of polyglandular syndrome, this may represent a variant and we here provide an algorithm for working up such patients, while also reviewing literature on the intertwined relationship between the immune and endocrine systems. PMID- 23043905 TI - Mining SOM expression portraits: feature selection and integrating concepts of molecular function. AB - BACKGROUND: Self organizing maps (SOM) enable the straightforward portraying of high-dimensional data of large sample collections in terms of sample-specific images. The analysis of their texture provides so-called spot-clusters of co expressed genes which require subsequent significance filtering and functional interpretation. We address feature selection in terms of the gene ranking problem and the interpretation of the obtained spot-related lists using concepts of molecular function. RESULTS: Different expression scores based either on simple fold change-measures or on regularized Student's t-statistics are applied to spot related gene lists and compared with special emphasis on the error characteristics of microarray expression data. The spot-clusters are analyzed using different methods of gene set enrichment analysis with the focus on overexpression and/or overrepresentation of predefined sets of genes. Metagene related overrepresentation of selected gene sets was mapped into the SOM images to assign gene function to different regions. Alternatively we estimated set related overexpression profiles over all samples studied using a gene set enrichment score. It was also applied to the spot-clusters to generate lists of enriched gene sets. We used the tissue body index data set, a collection of expression data of human tissues as an illustrative example. We found that tissue related spots typically contain enriched populations of gene sets well corresponding to molecular processes in the respective tissues. In addition, we display special sets of housekeeping and of consistently weak and high expressed genes using SOM data filtering. CONCLUSIONS: The presented methods allow the comprehensive downstream analysis of SOM-transformed expression data in terms of cluster-related gene lists and enriched gene sets for functional interpretation. SOM clustering implies the ability to define either new gene sets using selected SOM spots or to verify and/or to amend existing ones. PMID- 23043907 TI - PET imaging in the differential diagnosis of vascular dementia. AB - Aging leads to a small loss of cortical neurons, but to a significant reduction of synapses, dendrites and myelinated fibers. These age-related changes may cause some cognitive impairment, brain atrophy and frontally accentuated diffuse decrease in metabolism. In pathological disorders leading to dementia, most frequently degenerative Alzheimer's disease, cerebrovascular disease or a combination of both, the changes are more severe, affect predominantly specific regions and result in significant loss of neurons. The differential diagnosis of these disorders is based on symptoms of cognitive and memory impairment and is supported by results of neuropsychological tests and of imaging. Whereas computed tomography and magnetic resonance imaging are able to detect morphologic lesions, these modalities cannot determine functional consequences of the underlying pathologies. Positron emission tomography allows imaging of the localized and/or diffuse metabolic disturbances responsible for cognitive impairment and dementia, and is effective in differentiating vascular from degenerative dementia, as Alzheimer's disease. It can also detect inflammatory changes and their interaction with amyloid depositions for the development of mixed dementias after stroke. Imaging of neurotransmitters and of synaptic function additionally yields insight into disease specific pathophysiology. Despite that the broad clinical application of PET is limited, this technology has a great impact on research in dementia. PMID- 23043908 TI - Characteristics of neurological Wilson's disease without Kayser-Fleischer ring. AB - BACKGROUND: Although Kayser-Fleischer ring has been regarded as a key diagnostic feature of neurologic Wilson's disease, there have been previous reports of neurologic Wilson's disease patients without Kayser-Fleischer ring. We assessed the characteristics of neurologic Wilson's disease patients without Kayser Fleischer ring. METHODS: We enrolled neurologic Wilson's disease patients from 4 university hospitals by review of medical records in this study. Patients with neurologic Wilson's disease were diagnosed based on the neurologic symptoms and international scoring system for the diagnosis of Wilson's disease. All subjects were divided into two groups according to the presence of a Kayser-Fleischer ring. We compared demographic data, laboratory findings and imaging findings of the liver and brain between the two groups. RESULTS: There were 12 (26.7%) patients without Kayser-Fleischer ring out of a total of 45 neurologic Wilson's disease patients. The Wilson's disease patients without Kayser-Fleischer ring demonstrated a higher ceruloplasmin concentration and serum copper level than those with Kayser-Fleischer ring. In addition, liver cirrhosis and typical signal changes in brain magnetic resonance imaging were less common in neurologic Wilson's disease patients without Kayser-Fleischer ring. CONCLUSION: Based on our results, the absence of Kayser-Fleischer ring can be regarded as a form of neurologic Wilson's disease with less copper involvement. In addition, it is important to understand these features and to perform further investigations if patients without Kayser-Fleischer ring are suspected of having neurologic Wilson's disease. PMID- 23043906 TI - Thrombin promotes the expression of thrombospondin-1 and -2 in a rat model of intracerebral hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH) is one of the most severe types of stroke. Thrombin has been reported to participate in brain repair following ICH and play an important role in angiogenesis. Our previous studies have shown that ICH induces angiogenesis in damaged rat brain, accompanied by upregulation of expression of thrombospondin (TSP)-1 and TSP-2. The aim of the present study was to investigate whether the expression of TSP-1 and TSP-2 was regulated by thrombin in rat brain following ICH. A rat model of ICH was induced by injection of autologous blood into the right globus pallidus (GP). Hirudin, a thrombin specific inhibitor, or thrombin was injected into the GP. Immunohistochemistry, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) and western blot assays were applied. Results showed that ICH induced an increase in the expression of TSP-1 mRNA and TSP-2 mRNA after ICH, whereas hirudin significantly inhibited the expression of TSPs mRNA after ICH (P<0.05). In contrast, sole thrombin treatment in normal rats induced strong expression of TSP 1 or TSP-2 in the blood vessels around the damaged brain region when compared with those without thrombin treatment. Western blot analysis data confirmed that the protein levels of TSPs were significantly increased when compared with those in the sham control group (P<0.01). These findings support that thrombin positively regulates the expression of TSP-1 and TSP-2 after ICH, which may be involved in modulating angiogenesis in injured brains following ICH. PMID- 23043909 TI - Virulence factors are released in association with outer membrane vesicles of Pseudomonas syringae pv. tomato T1 during normal growth. AB - Outer membrane vesicles (OMVs) are released from Pseudomonas syringae pv. tomato T1 (Pst T1) during their normal growth. These extracellular compartments are comprised of a complete set of biological macromolecules that includes proteins, lipids, lipopolysaccharides, etc. It is evident from proteomics analyses the OMVs of Pst T1 contain membrane- and virulence-associated proteins. In addition, OMVs of this organism are also associated with phytotoxin, coronatine. Therefore, OMVs of Pst T1 must play a significant role during pathogenicity to host plant. However, further studies are required whether these structures can serve as "vehicles" for the transport of virulence factors into the host membrane. PMID- 23043910 TI - Respiratory variations of inferior vena cava diameter to predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure: need for a cautious use. AB - INTRODUCTION: To investigate whether respiratory variation of inferior vena cava diameter (cIVC) predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure (ACF). METHODS: Forty patients with ACF and spontaneous breathing were included. Response to fluid challenge was defined as a 15% increase of subaortic velocity time index (VTI) measured by transthoracic echocardiography. Inferior vena cava diameters were recorded by a subcostal view using M Mode. The cIVC was calculated as follows: (Dmax - Dmin/Dmax) * 100 and then receiver operating characteristic (ROC) curves were generated for cIVC, baseline VTI, E wave velocity, E/A and E/Ea ratios. RESULTS: Among 40 included patients, 20 (50%) were responders (R). The causes of ACF were sepsis (n = 24), haemorrhage (n = 11), and dehydration (n = 5). The area under the ROC curve for cIVC was 0.77 (95% CI: 0.60-0.88). The best cutoff value was 40% (Se = 70%, Sp = 80%). The AUC of the ROC curves for baseline E wave velocity, VTI, E/A ratio, E/Ea ratio were 0.83 (95% CI: 0.68-0.93), 0.78 (95% CI: 0.61-0.88), 0.76 (95% CI: 0.59-0.89), 0.58 (95% CI: 0.41-0.75), respectively. The differences between AUC the ROC curves for cIVC and baseline E wave velocity, baseline VTI, baseline E/A ratio, and baseline E/Ea ratio were not statistically different (p = 0.46, p = 0.99, p = 1.00, p = 0.26, respectively). CONCLUSION: In spontaneously breathing patients with ACF, high cIVC values (>40%) are usually associated with fluid responsiveness while low values (< 40%) do not exclude fluid responsiveness. PMID- 23043911 TI - Dissemination of IncFII(K)-type plasmids in multiresistant CTX-M-15-producing Enterobacteriaceae isolates from children in hospital paediatric oncology wards. AB - In this study, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae isolates in children with malignancies hospitalised at a paediatric oncology department in the Czech Republic were investigated. From June 2009 to January 2010, a total of 50 ESBL-producing faecal isolates of Enterobacteriaceae were obtained from 28 patients. These isolates were characterised with regard to ESBL enzymes, plasmid-mediated quinolone resistance genes, multilocus sequence typing (MLST) and plasmids conferring resistance to cephalosporins and fluoroquinolones. ESBL-producing isolates included Klebsiella pneumoniae (n=36), Escherichia coli (n=7), Klebsiella oxytoca (n=3), Enterobacter cloacae (n=2) and Citrobacter freundii (n=2). Klebsiella pneumoniae isolates belonged to 7 MLST types, including sequence types ST280, ST321, ST323 and ST416 as well as the novel types ST626, ST627 and ST628. The multiresistant epidemic clone E. coli B2-O25b-ST131 was detected in one patient. The gene bla(CTX-M-15) was found on large conjugative IncFII(K) plasmids along with bla(TEM-1), bla(OXA 1), qnrB1, aac(6')-Ib-cr, strA, sul2, aac(3')-II and tet(A) genes in most isolates. Dissemination of IncFII(K) plasmids among various Enterobacteriaceae isolates was considered an important aspect of nosocomial colonisation in the wards by Enterobacteriaceae species producing ESBLs. This is the first study documenting multiple antibiotic resistance elements, including qnr genes, in IncFII(K) plasmids in various bacterial species isolated in a single hospital department. The results highlight the evolution of IncFII(K) plasmids into new variants containing novel antibiotic resistance elements and their important role in spreading ESBL-producing bacteria among hospitalised patients. PMID- 23043912 TI - Role of phenolics as antioxidants, biomolecule protectors and as anti-diabetic factors--evaluation on bark and empty pods of Acacia auriculiformis. AB - OBJECTIVE: To search for an efficient and inexpensive source of phytoconstituents with antioxidant potential and health promoting traits from bark and empty pods of Acacia auriculiformis (A. auriculiformis). METHODS: Samples of bark and empty pod extracts were analyzed for bioactives (phenolics, flavonoids and proanthocyanidins) and subjected to free radical scavenging activity on DPPH, ABTS+, OH, O(2)*- and NO along with the determination of reducing power, iron chelating activity and peroxidation inhibition. Defensive action of extracts on biomolecules and cell membranes were evaluated by DNA nicking assay and haemolysis inhibition assay respectively. alpha-amylase and alpha-glucosidase inhibitory potentials were also determined. RESULTS: All the bioactives analyzed were higher in bark (B) than empty pods (EP) [TPC: B (574.51+/-16.11); EP (96.80+/-3.45) mg GAE/g. TFC: B (94.71+/-7.65); EP (247.87+/-20.45) mg RE/g. Proanthocyanidins: B (2.81+/-0.31); EP (1.25+/-0.01) mg LE/100 g DM] except flavonoids. Both the extracts showed higher quenching capacity on DPPH and ABTS (DPPH: B (0.21+/-0.01); EP (1.51+/-0.17) g extract/g DPPH. ABTS: B (111 519.14+/ 79 340.91); EP (80 232.55+/-32 894.12) mmol TE/g) with the FRAP of B (84 515.63+/ 3 350.69) and EP (47 940.79+/-1 257.60) mmol Fe (II)/g. Iron chelation was not observed. In addition, they showed lower quenching activity on OH() (B (48.95+/ 1.72); EP (34.94+/-1.62)%) and equivalent quenching on O(2)*- (B (53.47+/-3.92); EP (24.41+/-2.61)%), NO (B (49.04+/-5.04); EP (51.00+/-5.13)%), peroxidation inhibition (B (67.50+/-5.50); EP (55.1+/-2.3)%) and antihaemolytic potential (B (87.60+/-6.84)%) towards authentic antioxidant standards. Interestingly, Empty pod extracts are devoid of antihaemolytic activity. Both the extracts showed dose dependent DNA protection. Besides this, bark and empty pod extracts exhibited dual inhibiting potential against alpha -amylase and alpha-glucosidase enzymes. CONCLUSIONS: On summarization, it insinuated that both bark and empty pods can be used for the preparation of antioxidant/nutraceutical supplements and in anti diabetic formulations. PMID- 23043913 TI - Radical scavenging and antibacterial activity of Arnebia benthamii methanol extract. AB - OBJECTIVE: To evaluate in vitro antioxidant and antibacterial activity of methanolic extract of Arnebia benthamii (A. benthamii) whole plant. METHODS: Plasmid damage was analyzed by agarose gell electrophoresis. Calf thymus DNA was monitored by TBARS formation. DPPH, reducing power and lipid peroxidation was evaluated by using standard procedures. Antibacterial assay was monitored by disc diffusion method. RESULTS: DPPH radical scavenging and hydroxyl radical scavenging potential of the plant revealed that the extract to be active radical scavenger. Reducing (Fe(3+)-Fe(2+)) power and lipid peroxidation inhibition efficiency (TBARS assay) of the extract was also evaluated and the extract showed promising activity in preventing lipid peroxidation and might prevent oxidative damages to biomolecules. The extract offered a significant protection against plasmid and calf thymus DNA damage induced by hydroxyl radicals. The extract was also evaluated on different bacterial strains and the maximum antibacterial activity was exhibited against Escherichia coli (E. coli) when compared with standard drug. CONCLUSIONS: These findings demonstrate that the methanol extract of A. benthamii has excellent anti-oxidant activities and could be considered as a potential source of lead molecules for pharmaceutical industries. PMID- 23043914 TI - Antibacterial activity of various honey types of Algeria against Staphylococcus aureus and Streptococcus pyogenes. AB - OBJECTIVE: To assess the in vitro antibacterial activity of honey from different geographical location on Gram negative organisms. METHODS: Different concentrations (Undiluted honey, 10 %, 30%, 50% and 70% wt/vol) of honey were studied in vitro using Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes), briefly, two-fold dilutions of honey solutions were tested to determine the minimum inhibitory concentration (MIC) against each type of microorganism, followed by more assays within a narrower dilution range to obtain more precise MIC values. MICs were determined by both visual inspection and spectrophotometric assay at 620 nm. These honey samples were compared with standard antibiotics like ampicillin, penicillin G, amoxicillin, gentamycin, tobramycin, erythromycin and chloramphenicol was determined by the disc diffusion method. RESULTS: The diameter of zone of the inhibition (ZDI) of honey has various concentrations tested for the isolates ranged 0-46 mm for S. aureus, 0-44 mm for S. pyogenes. While the MIC (%) ranged 12%-95%, 25%-73% respectively. CONCLUSIONS: Algeria honey, in-vitro, possess antibacterial activity. PMID- 23043915 TI - Antitubercular activity of the semi-polar extractives of Uvaria rufa. AB - OBJECTIVE: To investigate the inhibitory activity of the chloroform extract, petroleum ether and chloroform sub-extracts, lead-acetate treated chloroform extract, fractions and secondary metabolites of Uvaria rufa (U. rufa) against Mycobacterium tuberculosis (M. tuberculosis) H(37)Rv. METHODS: The antituberculosis susceptibility assay was carried out using the colorimetric Microplate Alamar blue assay (MABA). In addition, the cytotoxicity of the most active fraction was evaluated using the VERO cell toxicity assay. RESULTS: The in vitro inhibitory activity against M. tuberculosis H(37)Rv increased as purification progressed to fractionation (MIC up to 23 MUg/mL). The chloroform extract and its sub-extracts showed moderate toxicity while the most active fraction from chloroform sub-extract exhibited no cytotoxicity against VERO cells. Meanwhile, the lead acetate-treated crude chloroform extract and its fractions showed complete inhibitions (100%) with MIC values up to 8 MUg/mL. Phytochemical screening of the most active fraction showed, in general, the presence of terpenoids, steroids and phenolic compounds. Evaluation of the antimycobacterial activity of known secondary metabolites isolated showed no promising inhibitory activity against the test organism. CONCLUSIONS: The present results demonstrate the potential of U. rufa as a phytomedicinal source of compounds that may exhibit promising antituberculosis activity. In addition, elimination of polar pigments revealed enhanced inhibition against M. tuberculosis H(37)Rv. While several compounds known for this plant did not show antimycobacterial activity, the obtained results are considered sufficient reason for further study to isolate the metabolites from U. rufa responsible for the antitubercular activity. PMID- 23043916 TI - Evaluation of anti-nociceptive activity of methanolic extract of Tecomaria capensis Thunb. (Bignoniaceae) leaves in rats. AB - OBJECTIVE: To evaluate the anti-nociceptive activity of Tecomaria capensis (T. capensis) leaves extract (TCLE) using different models in rats by acetic acid induced writhing test, (b) tail-flick test (c) tail-clip test. METHODS: TCLE (100, 300, 1000 and 2000 mg/kg body wt.) was given to rats orally to observe acute toxicity for 14 d. Then test drug TCLE were given at dose of 100, 200 and 500 mg/kg p.o. and standard drug aspirin were given at a dose of 100 mg/kg p.o. RESULTS: No mortality was reported even after 14 d. This indicates that the methanol extract is safe up to a single dose of 2 000 mg/kg body weight. TCLE (100, 200 and 500 mg/kg p.o.) significantly inhibited abdominal constrictions (writhing) induced by acetic acid and increased the latency period in the tail flick and tail clip test. TCLE at the dose of 500 mg/kg showed significant anti nociceptive activity compared to standard aspirin. DISCUSSIONS: The results of this study show that methanol extract of T. capensis possesses anti-nociceptive activity which may be mediated by the central and peripheral mechanisms. PMID- 23043917 TI - Bioassay evaluation on the efficacy of alpha-cypermethrin impregnated into long lasting insecticide treated nets using Anopheles stephensi. AB - OBJECTIVE: To evaluate the bioefficacy of alpha-cypermethrin impregnated into long lasting insecticide treated nets (LLITNs-INTERCEPTOR(r)) against main malaria vector, Anopheles stephensi (An. stephensi). METHODS: The effectiveness of bed net impregnated with alpha-cypermethrin (INTERCEPTOR(r)) with washing was evaluated. The washing procedure and bioassay tests were carried out according to the WHO-recommended methods. Malaria vector, An. stephensi was exposed to impregnated bed net for three minutes and then mortality measured after 24 h recovery period. Knockdown was also measured according to the logarithmic times. RESULTS: Result of cone bioassay method showed that bioefficacy of alpha cypermethrin decreased from 100% in unwashed to 15% in 20 washes. KT(50) was measure as one minute in one wash and increased to 40 min in 20 washes. DISCUSSION: Findings of this study provide guideline for malaria vector control authorities and people using pyrethroid-impregnated bed nets. PMID- 23043918 TI - Spatial outline of malaria transmission in Iran. AB - OBJECTIVE: To conduct for modeling spatial distribution of malaria transmission in Iran. METHODS: Records of all malaria cases from the period 2008-2010 in Iran were retrieved for malaria control department, MOH&ME. Metrological data including annual rainfall, maximum and minimum temperature, relative humidity, altitude, demographic, districts border shapefiles, and NDVI images received from Iranian Climatologic Research Center. Data arranged in ArcGIS. RESULTS: 99.65% of malaria transmission cases were focused in southeast part of Iran. These transmissions had statistically correlation with altitude (650 m), maximum (30 degrees C), minimum (20 degrees C) and average temperature (25.3 degrees C). Statistical correlation and overall relationship between NDVI (118.81), relative humidity (?45%) and rainfall in southeast area was defined and explained in this study. CONCLUSIONS: According to ecological condition and mentioned cut-off points, predictive map was generated using cokriging method. PMID- 23043919 TI - Comparative analysis of urinary schistosomiasis among primary school children and rural farmers in Obollo-Eke, Enugu State, Nigeria: implications for control. AB - OBJECTIVE: To determine the prevalence, sex-age related intensity of urinary schistosomiasis and to compare such parameters among rural school children and rural farmers in selected communities in Obollo-Eke located in Southeast, Nigeria. METHODS: A cross-sectional survey involving 1 337 school children and farmers was conducted in Obollo-Eke community between September 2006 and July 2007. Demographic data of subjects was collected using a questionnaire prepared for this purpose. Urine samples were collected and examined for haematuria and ova of Schistosoma haematobium (S. haematobium) using Medi-test Combi 9 and sedimentation technique respectively. RESULTS: The prevalence of urinary schistosomiasis based on microscopic examination of the urine sediment for the ova of S. haematobium was 17.5% while the prevalence of haematuria was 15.6%. Infection intensity varied from light to heavy. In general, the prevalence was higher among males (20.8%) than females (14.6%; P>0.05) and was slightly higher among primary school children (18.0%; n=762) than farmers (16.9%; n=575; P>0.05). The age-specific prevalence of schistosomiasis among the study subjects ranged from 8.3% to 21.2% in 0-5 years and 11-15 years age groups respectively. CONCLUSIONS: Haematuria and mean egg/10 mL urine (r = 0.95; P<0.01) showed that both procedures are reliable for the diagnosis of the disease and can be used to ascertain the prevalence of the disease in any community. The comparative analysis of urinary bilharziasis among primary school children and rural farmers demonstrated that the infection is moderately high in these two risk population groups at Obollo-Eke. A robust intervention strategy is clearly needed. PMID- 23043920 TI - Malaria helminth co-infections and their contribution for aneamia in febrile patients attending Azzezo health center, Gondar, Northwest Ethiopia: a cross sectional study. AB - OBJECTIVE: To assess the prevalence of malaria helminth co-infections and their contribution for aneamia in febrile patients attending Azzezo health center, Gondar, Northwest Ethiopia. METHODS: A cross section study was conducted among febrile patients attending Azezo health center from February-March 30, 2011. Convenient sampling technique was used to select 384 individuals. Both capillary blood and stool were collected. Giemsa stained thick and thin blood film were prepared for identification of Plasmodium species and stool sample was examined by direct wet mount and formalin-ether concentration technique for detection of intestinal helminthes parasites. Haemoglobin concentration was determined using a portable haemoglobin spectrophotometer, Hemocue Hb 201 analyzer. RESULTS: Out of 384 febrile patients examined for malaria parasites, 44 (11.5%) individuals were positive for malaria parasites, of which Plasmodium vivax accounted for 75.0% (33), Plasmodium falciparum for 20.5% (9) infectious, whereas two person (4.5%) had mixed species infection. Prevalence of malaria was higher in males (28) when compared with prevalence in females (16). More than half (207, 53.9%) of study participants had one or more infection. Prevalence was slightly higher in females (109, 52.7%) than in males (98, 47.3%). About helminths, Ascaris lumbricoides was the predominant isolate (62.1%) followed by hookworms (18.4%). Only 22 participants were co-infected with malaria parasite and helminths and co infection with Ascaris lumbricoides was predominant (45.0%). The prevalence of anemia was 10.9% and co-infection with Plasmodium and helminth parasites was significantly associated with (P< 0.000 1) higher anemia prevalence compared to individuals without any infection. CONCLUSIONS: Prevalence of malaria and soil transmitted helminths is high and the disease is still major health problem in the study area. Hence, simultaneous combat against the two parasitic infections is very crucial to improve health of the affected communities in economically developing countries. PMID- 23043921 TI - Seroprevalence of toxoplasmosis and rubella in pregnant women attending antenatal private clinic at Ouagadougou, Burkina Faso. AB - OBJECTIVE: To evaluate the prevalence of toxoplasmosis and rubella among pregnant women at Ouagadougou in Burkina Faso. METHODS: All patient sera were tested for rubella and toxoplasmosis anti-IgG using commercial ELISA kits (PlateliaTM Rubella IgG and PlateliaTM Toxo IgG). The presence of anti-rubella and anti toxoplasmosis IgM in serum samples was tested using commercial ELISA kits Platelia Rubella IgM and Platelia Toxo IgM. RESULTS: Among all the pregnant women tested for toxoplasmosis and rubella, their prevalence were 20.3% and 77.0%, respectively. Pregnant women in the age group of 18-25 years showed the highest frequency of anti-toxoplasmosis (34.5%) and anti-rubella IgG (84.6%). The prevalence of anti-toxoplasma and anti-rubella IgG decreased between 2006 and 2008 from 32.7% to 12.1% and 84.6% to 65.0%, respectively. There was no significant association between age and the mean titer of anti-toxoplasmosis IgG among pregnant women. CONCLUSIONS: The diagnosis of toxoplasmosis and rubella is necessary in pregnant women in Burkina Faso because of the low immunization coverage rate of rubella and the high level of exposure to these two infections which can be harmful to the newborn if contracted by women before the third trimester of pregnancy. PMID- 23043922 TI - A preliminary analysis of some epidemiological factors involved in porcine cysticercosis in Bafut and Santa subdivisions, North West Region of Cameroon. AB - OBJECTIVE: To examine the magnitude and some risk factors of porcine cysticercosis in Bafut and Santa, two sub-divisions noted for pig farming in the North West Region of Cameroon. METHODS: A total of 499 pigs in 300 households were examined by tongue inspection and serologically by Ag-ELISA. Information was sought on the age and sex of the animals, prevailing husbandry systems, types of feed, the state of each pen and the state of toilets. Futhermore, a questionnaire was administered to the farmers to determine their awareness on taeniasis/cysticercosis and related factors. RESULTS: The prevalence of the disease was significantly higher in Santa (10.2%) than in Bafut (4.2%), although there was a higher level of awareness in both localities (62.3%). Age of pigs, traditional rearing systems (roaming, tethered, earth floor pen, raised floor pen), faecal disposal in the environment and poor sanitation significantly influenced the seroprevalence of porcine cysticercosis in both localities. Most farmers (79.7%) used a combination of concentrate, grass and kitchen waste to feed pigs. Financial loss from porcine cysticercosis was estimated at 346 900 CFA representing 2% of total income. CONCLUSIONS: Control measures advanced here include sensitization campaigns, periodic examination and treatment of infected pigs by veterinarians, improved husbandry systems, proper use of standard latrines regularly inspected by sanitary officers, and sound hygienic and sanitary practices. PMID- 23043923 TI - Efficacy of Yiqiyangxin Chinese medicine compound combined with cognitive therapy in the treatment of generalized anxiety disorders. AB - OBJECTIVE: To observe the clinical efficacy of Yiqiyangxin Chinese medicine compound combined with cognitive therapy on generalized anxiety disorders. METHODS: A total of 202 generalized anxiety disorders patients were randomly allocated to a control condition (Paroxetine combined with cognitive therapy) or a treatment condition (Yiqiyangxin Chinese medicine compound combined with cognitive therapy). Subsequently, scores of Hamilton Anxiety Scale (HAMA), Zung Self-rating Anxiety Scale (SAS) and blood routine, urine routine, liver function, renal function, electrocardiogram were detected before treatment, 3 months, 6 months after treatment and 6 months after medicine withdrawal, respectively. RESULTS: HAMA and SAS scores were significantly reduced in two groups (P<0.001) after treatment, but the differences in HAMA and SAS scores, apparent effect and effectiveness were not significant (P>0.05). HAMA and SAS scores were significantly increased in two groups (P<0.05) after medicine withdrawal, and there were significant differences in HAMA and SAS scores, recurrent disease and adverse reaction (P<0.001). The incidence of recurrent disease and adverse reaction in treatment group was low. Both two groups showed no apparent abnormality in blood routine, urine routine, liver and renal function, and electrocardiogram. CONCLUSIONS: Yiqiyangxin Chinese medicine compound combined with cognitive therapy can significantly reduce the recurrence after medicine withdrawal and is effective on generalized anxiety disorders. Furthermore, the incidence of adverse reactions is low. The treatment program is worthy clinic application in the further. PMID- 23043924 TI - Effect analysis of chemoradiotherapy after operation in patients with stage III A non-small cell lung cancer. AB - OBJECTIVE: To investigate the effect of chemoradiotherapy after surgery on III A stage non-small cell lung cancer (NSCLC). METHODS: A total of 156 NSCLC patients undergoing total pneumonectomy or pulmonary lobectomy were included in this study. The chemotherapy group (n=75) received the protocol of cisplatin (DDP) + gemcitabine (GEM) / docetaxel (DOC) / vinorelbine (NVB); the radiotherapy + chemotherapy group (n=81) received sequential chemoradiotherapy. The response rate, local control rate in 1 to 2 years, overall survival (OS), progression-free survival (PFS) and adverse reactions were evaluated. RESULTS: The overall response rate was obviously higher in radiotherapy + chemotherapy group (79.4%) than in chemotherapy group (56.8%) (P<0.01). The 1 year local control rates for chemotherapy group and radiotherapy + chemotherapy group were (69.1+/-7.9)% and (77.8+/-8.2)% respectively and the difference reached statistical significance (P<0.001). The 2 year local control rates were (42.1+/-6.1)% and (61.5+/-6.9)% respectively (P<0.001). The difference in median follow-up time between the two groups did not reach statistical meaning (P>0.05), while the median PFS of two groups were 10.8 months and 16.9 months respectively (P<0.001). 1-year and 3-year survival rates were obviously higher in radiotherapy + chemotherapy group than in chemotherapy group, and the difference reached statistical significance (P<0.05 or P<0.01). The adverse reactions manifested as hematological toxicity and digestive tract reaction in the two groups. In the radiotherapy + chemotherapy group, incidences of radiation-induced esophagus injury and lung injury were 24.7% and 34.6% respectively, all occurring within 2 to 6 weeks after the start of radiation and both below grade 2. CONCLUSIONS: Chemoradiotherapy after surgery can improve local control rate and reduce or prevent distant metastasis, but there are still many controversies. In clinical work, we should carefully evaluate each patient's age, lung function, basic physical condition scoring and complications to choose a therapeutic schedule that is suitable for the patient. PMID- 23043925 TI - Delay enhancement patterns in apical hypertrophic cardiomyopathy by phase sensitive inversion recovery sequence. AB - OBJECTIVE: Late gadolinium enhancement (LGE) patterns of cardiovascular magnetic resonance (CMR) relying on PSIR (phase-sensitive inversion recovery sequence) techniques had been used to determine the characteristics of LGE in apical hypertrophic cardiomyopathy (ApHCM). METHODS: Forty patients pure ApHCM [age, (60.2+/-10.4) years, 31 men] were enrolled. LGE images were acquired using PSIR, and analyzed using a 17-segment model. Summing the LGE areas in all short axis slices yielded the total volume of late enhancement, which was subsequently presented as a proportion of total LV myocardium (% LGE). RESULTS: Mean maximal apical wall thickness was (17.9+/-2.3) mm, and mean left ventricular (LV) ejection fraction was (67.7+/-8.0)%. LGE was detected in 130 segments of 30 patients (75.0%), occupying (4.9+/-5.5)% of LV myocardium. LGE was mainly detected at the junction between left and right ventricles in 12 (30%) and at the apex in 28 (70%), although LGE-positive areas were widely distributed, and not limited to the apex. Focal LGE at the non-hypertrophic LV segments was found in some ApHCM patients, even without LGE of hypertrophied apical segments. CONCLUSIONS: LGE was frequently observed not only in the thickened apex of the heart but also in other LV segments, irrespective of the presence or absence of hypertrophy. The simple presence of LGE on CMR was not representative of adverse prognosis in this population. PMID- 23043926 TI - Clinical effects of psychological intervention and drug therapy against peptic ulcer. AB - OBJECTIVE: To evaluate the clinical effects of psychological interventions and drug therapy against peptic ulcer. METHODS: 96 patients with peptic ulcer were divided into control group with Tagamet 800 mg per evening p.o. and trial group with psychological intervention on the basis of drug treatment. RESULTS: There were significant differences between the two groups (P<0.05), the trial group showed that the anxiety and depression cases declined obviously and effective rate of ulcer therapy was much higher than control group. CONCLUSIONS: In sum, psychological intervention combined with drug therapy provides an effective method for ulcer treatment. PMID- 23043927 TI - Primary tuberculous appendicitis presented with caecal perforation: a case report. AB - Gastrointestinal tuberculosis accounts for 3% of the extrapulmonary tuberculosis with ileocaecal region being the common site of involvement up to 75%. Primary involvement of appendix is very rare and accounts for only 0.6% to 2.9% of gastrointestinal tuberculosis in the absence tubercular focus elsewhere. The pre operative investigations usually give non-specific results. The diagnosis in most instances made only after histopathology. Here we report a case of primary appendicular tuberculosis in a patient presented with caecal perforation. PMID- 23043928 TI - Linezolid resistant Staphylococcus haemolyticus: first case report from India. AB - Linezolid is being increasingly used in the treatment of infections with gram positive organisms especially methicillin resistant Staphylococcal isolates. Though resistance to this antimicrobial is emerging but it is extremely rare. Here we document first case of linezolid resistant Staphylococcus haemolyticus (S.haemolyticus) from India. This organism was isolated from pus oozing from a postsurgical site in 61 year old male hailing from an adjoining state of Haryana. PMID- 23043929 TI - Quick screening and easy detection method of NDM-gene in clinical isolates: a need of the time. PMID- 23043931 TI - Novel URAT1 mutations caused acute renal failure after exercise in two Chinese families with renal hypouricemia. AB - Renal hypouricemia (RHUC), as an infrequent hereditary disease, is associated with severe complications such as exercise-induced acute renal failure (EIARF). Loss-of-function mutations in urate transporter gene URAT1 (Type 1) and in glucose transporter gene GLUT9 (Type 2) are major causes of this disorder. In this study, URAT1 and GLUT9 were screened in two uncorrelated families from mainland China and a total of five mutations were identified in exons, including two novel heterozygous URAT1 mutations. In four members of the first family, c.151delG (p.A51fsX64) in exon 1 was detected, which resulted in a frameshift and truncated the original 553-residue-protein to 63 amino acid protein. A missense mutation c.C1546A (p.P516T) in exon 9 in GLUT9 was revealed in the second family, which caused a functional protein substitution at codon 516. These two novel mutations were neither identified in the subsequent scanning of 200 ethnically matched healthy control subjects with normal serum UA level nor in a 1000 genome project database. Thus our report identifies two novel loss-of-function mutations (c.151delG in URAT1 and p.P516T in GLUT9) which cause RHUC and renal dysfunction in two independent RHUC pedigrees. PMID- 23043932 TI - CFTR haplotypes in northern Iranian population. AB - BACKGROUND: Cystic fibrosis (CF) is a multiorganic autosomal recessive disorder, caused by mutation in cystic fibrosis transmembrane conductance regulator (CFTR). CF is highly heterogeneous in Iranian population and molecular diagnosis based on direct identification of mutations is not completely efficient. The use of polymorphic intragenic markers not only can facilitate phenotype prediction in prenatal diagnosis by gene tracking, but also can lead to the demonstration of possible associations between haplotypes and specific mutations. METHODS: 60 CF patients and 53 fertile normal subjects originating from North of Iran were analyzed for F508del mutation and c.1210-12T(5_9), c.1408A>G and c.744 33GATT(6_8) polymorphisms. RESULTS: c.1210-12T[7] is the most prevalent allele in normal individuals and CF non-F508del patients with 87.7%and 86.7% frequencies respectively. c.1408A>G survey showed that frequency of allele G and A is nearly equal in both non-F508del CF patients and normal individuals. c.744-33GATT(6_8) study showed that 7 repeat is the most prevalent allele in normal individuals and non-F508del CF patients with 80.2% and 82.1% frequencies respectively. The [c.1408A; c.1210-12T[9]; c.744-33GATT[6]] haplotype was only associated with mutant alleles including F508del. CONCLUSIONS: The allelic distribution and heterozygosity results suggest that c.1408A>G, c.1210-12T(5_9) and c.744 33GATT(6_8) can contribute to carrier detection and prenatal diagnosis of CF in Iranian families with previous history of the disease. PMID- 23043930 TI - 18S rRNA is a reliable normalisation gene for real time PCR based on influenza virus infected cells. AB - BACKGROUND: One requisite of quantitative reverse transcription PCR (qRT-PCR) is to normalise the data with an internal reference gene that is invariant regardless of treatment, such as virus infection. Several studies have found variability in the expression of commonly used housekeeping genes, such as beta actin (ACTB) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), under different experimental settings. However, ACTB and GAPDH remain widely used in the studies of host gene response to virus infections, including influenza viruses. To date no detailed study has been described that compares the suitability of commonly used housekeeping genes in influenza virus infections. The present study evaluated several commonly used housekeeping genes [ACTB, GAPDH, 18S ribosomal RNA (18S rRNA), ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide (ATP5B) and ATP synthase, H+ transporting, mitochondrial Fo complex, subunit C1 (subunit 9) (ATP5G1)] to identify the most stably expressed gene in human, pig, chicken and duck cells infected with a range of influenza A virus subtypes. RESULTS: The relative expression stability of commonly used housekeeping genes were determined in primary human bronchial epithelial cells (HBECs), pig tracheal epithelial cells (PTECs), and chicken and duck primary lung-derived cells infected with five influenza A virus subtypes. Analysis of qRT-PCR data from virus and mock infected cells using NormFinder and BestKeeper software programmes found that 18S rRNA was the most stable gene in HBECs, PTECs and avian lung cells. CONCLUSIONS: Based on the presented data from cell culture models (HBECs, PTECs, chicken and duck lung cells) infected with a range of influenza viruses, we found that 18S rRNA is the most stable reference gene for normalising qRT-PCR data. Expression levels of the other housekeeping genes evaluated in this study (including ACTB and GPADH) were highly affected by influenza virus infection and hence are not reliable as reference genes for RNA normalisation. PMID- 23043933 TI - Genetic variability of glutathione S-transferase enzymes in human populations: functional inter-ethnic differences in detoxification systems. AB - Glutathione S-Transferase enzymes (GSTs) constitute the principal Phase II superfamily which plays a key role in cellular detoxification and in other biological processes. Studies of GSTs have revealed that genetic polymorphisms are present in these enzymes and that some of these are Loss-of-Function (LoF) variants, which affect enzymatic functions and are related to different aspects of human health. The aim of this study was to analyze functional genetic differences in GST enzymes among human populations. Attention was focused on LoF polymorphisms of GSTA1, GSTM1, GSTO1, GSTO2, GSTP1 and GSTT1 genes. These LoF variants were analyzed in 668 individuals belonging to six human groups with different ethnic backgrounds: Amhara and Oromo from Ethiopia; Colorado and Cayapa Amerindians and African Ecuadorians from Ecuador; and one sample from central Italy. The HapMap database was used to compare our data with reference populations and to analyze the haplotype and Linkage Disequilibrium diversity in different ethnic groups. Our results highlighted that ethnicity strongly affects the genetic variability of GST enzymes. In particular, GST haplotypes/variants with functional impact showed significant differences in human populations, according to their ethnic background. These data underline that human populations have different structures in detoxification genes, suggesting that these ethnic differences influence disease risk or response to drugs and therefore have implications for genetic association studies involving GST enzymes. In conclusion, our investigation provides data about the distribution of important LoF variants in GST genes in human populations. This information may be useful for designing and interpreting genetic association studies. PMID- 23043934 TI - Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia. AB - Monogenic hypobetalipoproteinemias include three disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) with recessive transmission and familial hypobetalipoproteinemia (FHBL) with dominant transmission. We investigated three unrelated Tunisian children born from consanguineous marriages, presenting hypobetalipoproteinemia associated with chronic diarrhea and retarded growth. Proband HBL-108 had a moderate hypobetalipoproteinemia, apparently transmitted as dominant trait, suggesting the diagnosis of FHBL. However, she had no mutations in FHBL candidate genes (APOB, PCSK9 and ANGPTL3). The analysis of MTTP gene was also negative, whereas SAR1B gene resequencing showed that the patient was homozygous for a novel mutation (c.184G>A), resulting in an amino acid substitution (p.Glu62Lys), located in a conserved region of Sar1b protein. In the HBL-103 and HBL-148 probands, the severity of hypobetalipoproteinemia and its recessive transmission suggested the diagnosis of ABL. The MTTP gene resequencing showed that probands HBL-103 and HBL-148 were homozygous for a nucleotide substitution in the donor splice site of intron 9 (c.1236+2T>G) and intron 16 (c.2342+1G>A) respectively. Both mutations were predicted in silico to abolish the function of the splice site. In vitro functional assay with splicing mutation reporter MTTP minigenes showed that the intron 9 mutation caused the skipping of exon 9, while the intron 16 mutation caused a partial retention of this intron in the mature mRNA. The predicted translation products of these mRNAs are non-functional truncated proteins. The diagnosis of ABL and CMRD should be considered in children born from consanguineous parents, presenting chronic diarrhea associated with hypobetalipoproteinemia. PMID- 23043935 TI - Beyond barcoding: a mitochondrial genomics approach to molecular phylogenetics and diagnostics of blowflies (Diptera: Calliphoridae). AB - Members of the Calliphoridae (blowflies) are significant for medical and veterinary management, due to the ability of some species to consume living flesh as larvae, and for forensic investigations due to the ability of others to develop in corpses. Due to the difficulty of accurately identifying larval blowflies to species there is a need for DNA-based diagnostics for this family, however the widely used DNA-barcoding marker, cox1, has been shown to fail for several groups within this family. Additionally, many phylogenetic relationships within the Calliphoridae are still unresolved, particularly deeper level relationships. Sequencing whole mt genomes has been demonstrated both as an effective method for identifying the most informative diagnostic markers and for resolving phylogenetic relationships. Twenty-seven complete, or nearly so, mt genomes were sequenced representing 13 species, seven genera and four calliphorid subfamilies and a member of the related family Tachinidae. PCR and sequencing primers developed for sequencing one calliphorid species could be reused to sequence related species within the same superfamily with success rates ranging from 61% to 100%, demonstrating the speed and efficiency with which an mt genome dataset can be assembled. Comparison of molecular divergences for each of the 13 protein-coding genes and 2 ribosomal RNA genes, at a range of taxonomic scales identified novel targets for developing as diagnostic markers which were 117-200% more variable than the markers which have been used previously in calliphorids. Phylogenetic analysis of whole mt genome sequences resulted in much stronger support for family and subfamily-level relationships. The Calliphoridae are polyphyletic, with the Polleninae more closely related to the Tachinidae, and the Sarcophagidae are the sister group of the remaining calliphorids. Within the Calliphoridae, there was strong support for the monophyly of the Chrysomyinae and Luciliinae and for the sister-grouping of Luciliinae with Calliphorinae. Relationships within Chrysomya were not well resolved. Whole mt genome data, supported the previously demonstrated paraphyly of Lucilia cuprina with respect to L. sericata and allowed us to conclude that it is due to hybrid introgression prior to the last common ancestor of modern sericata populations, rather than due to recent hybridisation, nuclear pseudogenes or incomplete lineage sorting. PMID- 23043936 TI - Matrix metalloproteinase (MMP)-2 gene polymorphisms affect circulating MMP-2 levels in patients with migraine with aura. AB - Matrix metalloproteinases (MMP) are involved in the disruption of blood-brain barrier (BBB) during migraine attacks. In the present study, we hypothesized that two functional polymorphisms (C(-1306)T and C(-735)T) in MMP-2 gene and MMP-2 haplotypes are associated with migraine and modify MMP-2 and tissue inhibitor of MMP (TIMP)-2 levels in migraine. Genotypes for MMP-2 polymorphisms were determined by real time-PCR using Taqman allele discrimination assays. Haplotypes were inferred using the PHASE program. Plasma MMP-2 and TIMP-2 concentrations were measured by gelatin zymography and ELISA, respectively, in 148 healthy women without history of migraine and in 204 women with migraine (153 without aura; MWA, and 51 with aura; MA). Patients with MA had higher plasma MMP-2 concentrations and MMP-2/TIMP-2 ratios than patients with MWA and controls (P<0.05). While MMP-2 genotype and haplotype distributions for the polymorphisms were similar among the groups (P>0.05), we found that the CC genotype for C( 735)T polymorphism and the CC haplotype were associated with higher plasma MMP-2 concentrations in MA group (P<0.05). Our findings may help to understand the role of MMP-2 and its genetic variants in the pathophysiology of migraine and to identify a particular group of migraine patients with increased MMP-2 levels that would benefit from the use of MMP inhibitors. PMID- 23043937 TI - A brief critical comment on a recent meta-analysis. PMID- 23043938 TI - How to extend the travel range of a nanobeam with a robust adaptive control scheme: a dynamic surface design approach. AB - In this study, an adaptive robust tracking control scheme for a nanomechanical beam is proposed. The mathematical nanobeam model takes into consideration the presence of parametric uncertainties, and external disturbances, and fringing field effects and intermolecular forces, are also incorporated. The proposed backstepping controller is enhanced with an adaptive dynamic surface technique and an H(infinity) control scheme. The overall effectiveness of the designed controller is checked and illustrated with the presented results. These results show that the desired transient output tracking performance is achieved, and that the closed loop system exhibits good robustness to system uncertainties. Particular attention has been paid, so as to identify any relevance between the variations in the controller's design parameter and the system's output response and performance. PMID- 23043939 TI - The Swedish A(H1N1) vaccination campaign--why did not all Swedes take the vaccination? AB - BACKGROUND: In Sweden, a mass vaccination campaign against the influenza A(H1N1) 2009 resulted in 60% vaccination coverage. However, many countries had difficulty in motivating citizens to be vaccinated. To be prepared for future vaccination campaigns, it is important to understand people's reasons for not taking the vaccination. OBJECTIVE: The aim of this qualitative study was to explore motives, beliefs and reactions of individuals with varying backgrounds who did not get vaccinated. DATA AND METHODS: The total 28 individuals participating in the interviews were permitted to speak freely about their experiences and ideas about the vaccination. Interviews were analysed using a Grounded Theory approach. The strength of participants' decisions not to be vaccinated was also estimated. FINDINGS: Patterns of motives were identified and described in five main categories: (A) distinguishing between unnecessary and necessary vaccination, (B) distrust, (C) the idea of the natural, (D) resisting an exaggerated safety culture, and (E) injection fear. The core category, upholding autonomy and own health, constitutes the base on which the decisions were grounded. CONCLUSION: A prerequisite for taking the vaccine would be that people feel involved in the vaccination enterprise to make a sensible decision regarding whether their health will be best protected by vaccination. PMID- 23043940 TI - The TheraCyteTM device protects against islet allograft rejection in immunized hosts. AB - Clinically, many candidates for islet transplantation are already immunized, which increases their risk of graft rejection. Encapsulation of pancreatic islets using the TheraCyteTM device has been shown to protect against allograft rejection in nonimmunized recipients. However, the capacity of the TheraCyteTM device to prevent rejection in immunized recipients has not yet been studied. In this study, the protective capacity of the TheraCyteTM device was evaluated in an allogeneic rat model. Lewis rats were used as islet donors, and nonimmunized (control) and alloimmunized, diabetic Wistar-Furth (WF) rats were used as recipients. Graft survival was shorter in immunized recipients than in nonimmunized recipients (mean survival, 5.3 +/- 2.7 and 9.3 +/- 1.6 days, respectively, p < 0.01) when nonencapsulated islets were transplanted under the kidney capsule. When islets were transplanted into the TheraCyteTM device, graft function was maintained during the 6-month study period in both immunized and nonimmunized rats. In oral glucose tolerance tests performed at 1 month after transplantation, both groups had similar insulin and blood glucose levels indicating similar metabolic functions. Volume densities and absolute volumes of tissue inside the devices 6 months after transplantation were also comparable between the two groups, indicating that both groups maintained similar amounts of endocrine tissue. A higher number of IFN-gamma-producing CD8+ T-cells were detected in immunized WF rats compared to control WF rats transplanted with encapsulated islets. This suggests that donor-specific alloreactivity in recipient rats was sustained throughout the study period. This study suggests that the TheraCyteTM device protects islet allografts also in immunized recipients. Our results further highlight the potential for using macroencapsulation to avoid immunosuppressive therapy in clinical islet transplantation. PMID- 23043941 TI - Development of foot-and-mouth disease virus (FMDV) serotype O virus-like particles (VLPs) vaccine and evaluation of its potency. AB - Foot-and-mouth disease (FMD) is an economically significant viral disease that rampage dairy and other livestock industries in many countries. The disease is being controlled by the use of an inactivated vaccine. However, a recombinant marker vaccine, which avoids the use of live virus, may be an option for the unambiguous differentiation of infected animals from vaccinated animals. A recombinant baculovirus clone containing P1-2A-3C coding sequences of foot-and mouth disease virus (FMDV) serotype O(1) Manisa was generated. The FMDV structural proteins along with the 3C protease were expressed in Sf9 cells and the generation of virus like particles (VLP) was studied. The recombinant protein was formulated as vaccine using an oil adjuvant, ISA 206 and potency of the vaccine was tested in cattle. The vaccine had a potency value (PD(50)) of 5.01 and most of the vaccinated animals exhibited neutralizing antibody titers after two immunizations. PMID- 23043942 TI - Modulation of TLR9 response in a mouse model of herpes simplex virus encephalitis. AB - We evaluated the effects of agonists and antagonist of toll-like receptor (TLR) 9 in comparison with a TLR3 agonist in a mouse model of herpes simplex virus type 1 (HSV-1) encephalitis (HSE). BALB/c mice received a single intranasal dose of either a TLR3 agonist (polyinosinic:polycytidylic acid; PIC), TLR9 agonists (oligodeoxynucleotides (ODNs) 1585, 1826 or 2395) or a TLR9 antagonist (ODN 2088), 1 day before and, for selected groups, 3 days after infection with HSV-1. Mice that received the pre-treatment with vehicle, PIC, ODNs 1585, 1826, 2395 and 2088 before infection had survival rates of 25%, 65%, 55%, 40%, 55% and 30%, respectively (P<0.05 for PIC and ODNs 1585 and 2395 versus vehicle). Infected mice subsequently treated with vehicle, ODNs 2395 and 2088 had survival rates of 9%, 0% and 30%, respectively (P<0.05, ODN 2088 versus other groups). The pre treatment of mice with ODN 2395 reduced both the viral load (P<0.05 at day 5) and the production of CCL2, IL-6 and CCL5 at days 3, 4 and 5 (P<0.05 for IL-6 at day 3 and P<0.05 for CCL2 and CCL5 at day 4). Treatment of infected mice with ODN 2088 reduced the production of the same cytokines (P=0.07 for CCL2 and P=0.09 for IL-6 at day 5). Pre-treatment of mice with TLR9 agonists before infection reduces brain viral load and cytokine levels resulting in increased HSE survival rates. On the other hand, TLR9 antagonists can be helpful to control the inflammatory response that could be detrimental after infection. PMID- 23043943 TI - Elevated level of 17beta-estradiol is associated with overexpression of FSHR, CYP19A1, and CTNNB1 genes in porcine ovarian follicles after prenatal and neonatal flutamide exposure. AB - Recent studies suggest that disturbed androgen action during gestational and neonatal periods leads to reprogramming of the trajectory of ovarian development, manifested by altered follicular functioning in adulthood. In this study, we tested whether prenatal and neonatal exposure to antiandrogen flutamide affected ovarian 17beta-estradiol (E(2)) synthesis and the associated gene expression in large antral follicles of adult pigs. Flutamide was injected into pregnant gilts between Days 80 and 88 of gestation and into female piglets between Days 2 and 10 postnatally. After animals reached sexual maturity, the ovaries were collected from treated and nontreated (control) pigs. The analysis of E(2) concentration in follicular tissues, as well as FSH and LH levels in plasma of control and flutamide-treated animals were conducted. In addition, the expression of mRNAs and proteins for FSH receptor (FSHR), cytochrome P450 aromatase (CYP19A1) and beta-catenin (CTNNB1) was examined in large antral follicles of adult pigs. The E(2) concentration was greater in response to flutamide administered prenatally (P < 0.05) and neonatally (P < 0.01), whereas there was no changes in plasma gonadotropin concentration. Real-time polymerase chain reaction analysis revealed significant upregulation of FSHR, CYP19A1, and CTNNB1 at the mRNA level after maternal (P < 0.001, P < 0.01, P < 0.05, respectively) and neonatal (P < 0.001, P < 0.001, P < 0.01, respectively) flutamide exposure. The expression of FSHR protein was higher (P < 0.01) only after neonatal exposure to flutamide, whereas CYP19A1 and CTNNB1 proteins were upregulated in response to both prenatal (P < 0.01) and neonatal (P < 0.001) flutamide administration. Furthermore, membranous CTNNB1 immunolocalization indicates that it is not involved in regulation of FSH mediated CYP19A1 activity as a transcription factor, but rather contributes to the intercellular adhesion. Concluding, it appears that the higher E(2) level in response to flutamide treatments is a result of the intensified aromatization and local E(2) action at the ovary level. The observed changes might influence the normal follicle development and pig fertility as a consequence. PMID- 23043944 TI - Evaluation of the 5-day versus a modified 7-day CIDR breeding program in dairy heifers. AB - Dairy heifers were used to compared the effects of two timed AI + controlled internal drug release (CIDR) protocols (5-day vs. a modified 7-day) on: (1) luteal regression to initiate a new ovarian follicular wave; (2) ovarian response to the initial GnRH injection; and (3) pregnancy outcomes. Holstein heifers (N = 543) were assigned randomly to two treatments: (1) 25 mg PGF(2alpha) (im) and a CIDR insert on Day -7 followed by 100 MUg of GnRH (GnRH-1) on Day -5 and 25 mg PGF(2alpha) (im) at CIDR insert removal (7-day [7D]) on Day 0; or (2) 100 MUg GnRH (GnRH-1) and insertion of a CIDR on Day -5 and 25 mg PGF(2alpha) (im) at CIDR removal (5-day [5D]) on Day 0. Insemination with frozen-thawed conventional or gender-biased semen occurred after detected estrus from Days 0 to 2 or by appointment at 72 h after PGF(2alpha) when a second 100-MUg dose of GnRH was given. Blood was collected on Days -7, -5, 0, and 3 to determine concentrations of progesterone and incidence of luteolysis. Ovaries were scanned on Days -5 and 0. Luteolysis in the 7D treatment by 48 h after the initial PGF(2alpha) was greater (P < 0.01) than what occurred spontaneously in the 5D treatment (36.2% vs. 19.7%, respectively). Incidence of ovulation after GnRH-1 on Day -5 was greater (P < 0.05) for 7D than for 5D heifers, but the proportion of heifers with an induced CL on Day 0 did not differ between treatments. Heifers inseminated after detected estrus (166/543, 30.6%) on Days 0, 1, and 2 had greater (P < 0.05) pregnancy per AI (P/AI) at 32 days post AI than after timed AI (38.2% vs. 28.3%) on Day 3. Pregnancy P/AI, however, was greater (P < 0.05) for 7D heifers inseminated at estrus (46.5%) than for 7D heifers receiving the timed AI (26.8%) and differed (P < 0.05) from all 5D heifers regardless of insemination time at estrus (30.5%) or at timed AI at 72 h (29.9%). At the Florida location in which conventional and sexed semen were used during two breeding clusters, P/AI using sexed semen (43.9%, N = 56) did not differ from that of conventional semen (21.2%, N = 50). Remaining replicates of sexed semen produced similar P/AI at the other two locations (sexed = 27.6%, N = 71; and sexed = 31.9%, N = 215). We concluded that the modified 7-day CO-Synch + CIDR program produced more P/AI in heifers inseminated at estrus than a standard 5-day CO-Synch + CIDR program, but when timed AI occurred at 72 h after PGF(2alpha) and CIDR insert removal, P/AI did not differ between programs. PMID- 23043945 TI - Effect of heat stress on body temperature in healthy early postpartum dairy cows. AB - Measurement of body temperature is the most common method for an early diagnosis of sick cows in fresh cow protocols currently used on dairy farms. Thresholds for fever range from 39.4 degrees C to 39.7 degrees C. Several studies attempted to describe normal temperature ranges for healthy dairy cows in the early puerperium. However, the definition of a healthy cow is variable within these studies. It is challenging to determine normal temperature ranges for healthy cows because body temperature is usually included in the definition. Therefore, the objectives of this study were to identify factors that influence body temperature in healthy dairy cows early postpartum and to determine normal temperature ranges for healthy cows that calved in a moderate (temperature humidity index: 59.8 +/- 3.8) and a hot period (temperature humidity index: 74.1 +/- 4.4), respectively, excluding body temperature from the definition of the health status. Furthermore, the prevalence of fever was calculated for both periods separately. A subset of 17 (moderate period) and 15 cows (hot period) were used for analysis. To ensure their uterine health only cows with a serum haptoglobin concentration <= 1.1 g/L were included in the analysis. Therefore, body temperature could be excluded from the definition. A vaginal temperature logger that measured vaginal temperature every 10 min was inserted from Day 2 to 10 after parturition. Additionally rectal temperature was measured twice daily. Day in milk (2 to 10), period (moderate and hot), and time of day had an effect on rectal and vaginal temperature. The prevalence of fever (>= 39.5 degrees C) was 7.4% and 28.1% for rectal temperature in the moderate and hot period, respectively. For vaginal temperature (07.00 to 11.00 h) it was 10% and 33%, respectively, considering the same threshold and period. This study demonstrates that body temperature in the early puerperium is influenced by several factors (day in milk, climate, time of day). Therefore, these factors have to be considered when interpreting body temperature measures to identify sick cows. Furthermore, the prevalence of fever considering different thresholds is higher during hot than moderate periods. However, even in a moderate period healthy cows can exhibit a body temperature that is considered as fever. This fact clearly illustrates that fever alone should not be considered the decision criterion whether a cow is allocated to an antibiotic treatment, although it is the most important one that is objectively measurable. PMID- 23043946 TI - Modifying the double-Ovsynch protocol to include human chorionic gonadotropin to synchronize ovulation in dairy cattle. AB - The objectives were to determine whether rates of conception, ovulation, presynchronization, or follicle and CL characteristics were altered after modifying the Double-Ovsynch (DO) protocol to include hCG compared with the DO protocol. Primiparous and multiparous lactating dairy cows (N = 183), and nulliparous dairy heifers (N = 51) were used. Cows were blocked by parity and heifers were stratified by age and breed before being randomly assigned to one of two treatments. All females received either 100 MUg GnRH or 2000 IU hCG im, at initiation of the Pre-Ovsynch (PO) portion of the DO protocol (PO: GnRH/hCG, 7 days PGF(2alpha) and 3 days GnRH). After 7 days, females started the Breeding Ovsynch portion of the DO protocol (Breeding-Ovsynch: GnRH, 7 days, PGF(2alpha), 48 or 56 h and GnRH 16 hours timed artificial insemination with sex-sorted semen). Transrectal ultrasonography and blood samples were used to assess ovarian structures, ovulation, pregnancy diagnosis, and concentration of progesterone in plasma. Conception rates were similar in females treated with GnRH or hCG in cows (32.2 and 25.0%) and in heifers (30.8 and 36.0%). Ovulation rates in cows at the onset of PO were increased with hCG compared to GnRH (77.2 vs. 62.2%, P < 0.05). Concentrations of progesterone 7 days post-hCG or GnRH were greater in cows treated with hCG compared with GnRH (least significant mean +/- SEM; 4.3 +/- 0.3 and 3.0 +/- 0.3 ng/mL, P < 0.01), but did not differ in heifers (4.5 +/- 0.9 and 2.9 +/- 0.9 ng/mL). More cows ovulated within 7 days post-hCG and a greater proportion of these cows tended to have failed luteal regression by Day 3 post PGF(2alpha) compared with cows that had ovulated to GnRH (29.6 vs. 16.1%, P <= 0.10). The overall percentage of females which were synchronized to PO did not differ between GnRH- or hCG-treated cows (61.5% and 52.2%) and heifers (42.3% and 40.0%). In conclusion, no overall improvement in fertility was achieved by replacing the first injection of GnRH in the DO protocol with hCG. PMID- 23043948 TI - Effects of twinning on the subsequent reproductive performance and productive lifespan of high-producing dairy cows. AB - This study was designed to determine the effects of twinning on the subsequent reproductive performance and productive lifespan of high milk-producing dairy cows. The data analyzed were taken from complete reproductive records for 4861 Holstein Friesian cows comprising a commercial herd, including data for 12 587 calving events from April 1, 2001 to March 31, 2012. The twinning rate was 5.6%, and 9.6% of the cows delivered twins at least once during their life. Conception rates before Days 90, 120, and 300 postpartum were 20.8%, 36.9%, and 74.5%, and 34.2%, 51.8%, and 85.0% for cows delivering twins and singletons, respectively. Cox regression analysis revealed that twinning reduced the chances of conception before Day 90 by a factor of 0.76. Also, the median calving to conception interval was significantly longer for cows calving twins (134 +/- 4.5 days) than for cows delivering singletons (108 +/- 0.8 days; P < 0.001). Moreover, in cows in which conception was successful, the risk of abortion was higher for cows that calved twins than for those calving singletons (13.7% vs. 10.3%, respectively; P = 0.01). Culling rates before Days 90, 120, and 300 postpartum were 15.6%, 16.1%, and 28.6%, and 7.6%, 8.7%, and 15.9% for cows calving twins and singletons, respectively. Cox regression analysis of the factors affecting the culling rate before Day 300 postpartum revealed a 1.41 times greater hazard ratio of culling for cows calving twins than cows calving singletons. Further, mean productive lifespan was almost 300 days shorter for primiparous twinners (N = 48, 602 +/- 493 days) than for nontwinners (N = 2592; 899 +/- 581 days; P < 0.01), and 200 days shorter for secundiparous twinners (N = 126, 914 +/- 429 days) than for nontwinners undergoing at least two lactations (N = 1936, 1101 +/- 522 days; P < 0.01). Kaplan-Meier survival curves for productive lifespan differed between primiparous twinners and non-twinners (P < 0.001), and between secundiparous twinners and nontwinners having at least two lactations (P = 0.017). Differences in culling patterns for twinners and nontwinners were not restricted to the subsequent lactation but continued as long as 800 days after first calving, strongly suggesting long-term negative effects of twinning. As an economic implication of our findings, we suggest that twin embryo reduction at the moment of pregnancy diagnosis could be a profitable strategy to cut twinning rates and abolish their detrimental effects on subsequent reproductive performance and productive lifespan. PMID- 23043947 TI - Assessment LOPU-IVF in Japanese sika deer (Cervus nippon nippon) and application to Vietnamese sika deer (Cervus nippon pseudaxis) a related subspecies threatened with extinction. AB - In mammals, recovery of oocytes by laparoscopic ovum pick-up (LOPU) coupled with in vitro production (IVP) of embryos represents a promising strategy for both amplification and genetic management of sparse animals from captive endangered wild species. As integrated technique developed mainly for domestic livestock, LOPU-IVP requires several studies to set up protocols for follicular stimulation or optimization of IVP before envisaging successful transposition to wild species. In deer, many endangered subspecies would be potentially concerned by applying such an approach using common subspecies for protocols optimization. The aim of the present study was to assess efficiency of follicle stimulation using ovine FSH (oFSH) for recovery of oocytes by LOPU in common sika deer (Cervus nippon nippon) before transposition of an optimized methodology for IVP of embryos from endangered Vietnamese sika deer hinds (Cervus nippon pseudaxis). In common sika deer, two doses of oFSH (0.25 and 0.5 U) and two frequencies of administration (12 and 24 h) were compared by monitoring of subsequent ovarian response, quality of oocytes recovered by LOPU, and in vitro developmental competence. In a first experiment, the dose of oFSH administered did not significantly affect the total number of follicles aspirated per hind per session (8.6 +/- 1.0 vs. 8.2 +/- 1.6 with 0.5 vs. 0.25 U oFSH, respectively; not significant). In a second experiment, frequency of 0.25 U oFSH administration did not affect ovarian response. Efficiency of IVP determined on blastocysts rates after in vitro maturation, fertilization, and development in oviduct epithelial cells coculture was increased when FSH was administered at 12-h intervals. Immune response after several follicular stimulations was detected against exogenous oFSH in plasma from the majority of sika deer hinds but was not associated with decreased ovarian response. When 0.25 U oFSH was administered at 12-h intervals to Vietnamese sika deer (N = 4), good quality cumulus oocyte complexes with complete and compact cumulus investments were recovered allowing a high cleavage rate after in vitro maturation and fertilization. Development to the blastocyst stage occurred in a high proportion (30% of oocytes) after coculture with ovine epithelial cells allowing cryobanking of transferable embryos from Vietnamese sika deer. These results confirm that LOPU-IVF after ovarian stimulation with oFSH may be a successful tool for cryobanking transferable embryos from endangered sika deer subspecies. PMID- 23043950 TI - Regulation of prostacyclin synthase expression and prostacyclin content in the pig endometrium. AB - Prostaglandins (PGs) are critical regulators of a number of reproductive processes, including embryo development and implantation. In the present study, prostacyclin (PGI(2)) synthase (PGIS) mRNA and protein expression, as well as 6 keto PGF(1alpha) (a PGI(2) metabolite) concentration, were investigated in the pig uterus. Endometrial tissue and uterine luminal flushings were obtained on Days 4 to 18 of the estrous cycle and pregnancy. Additionally, conceptuses were collected and examined for PGIS mRNA expression and 6-keto PGF(1alpha) concentration. Regulation of PGI(2) synthesis in the porcine endometrium by steroids, conceptus products, and cytokines was studied in vitro and/or in vivo. Endometrial PGIS protein level increased on Days 12 and 16 in pregnant but not in cyclic gilts. Moreover, higher PGIS protein expression on Day 12 of pregnancy was accompanied by a greater content of 6-keto PGF(1alpha) in the endometrium. The concentration of 6-keto PGF(1alpha) in uterine luminal flushings increased substantially on Days 16 and 18 in pregnant gilts and was higher than in cyclic animals. Greater PGIS mRNA expression and PGI(2) metabolite concentration were detected in Day 12 and 14 conceptuses, respectively. Incubation of endometrial explants with conceptus-conditioned medium resulted in upregulation of PGIS protein expression and increased PGI(2) secretion. Moreover, PGIS mRNA and protein expression were upregulated in the endometrium collected from gravid uterine horn on Day 14 of pregnancy. In summary, PGIS is differentially expressed in the endometrium of cyclic and pregnant gilts resulting in higher PGI(2) synthesis in pregnant animals. Porcine conceptuses are important regulators of endometrial PGIS expression and PGI(2) release during the implantation period. PMID- 23043949 TI - No single way to explain cytoplasmic maturation of oocytes from prepubertal and cyclic gilts. AB - The objective of this study was to evaluate selected aspects of cytoplasmic maturation in oocytes from prepubertal and cyclic crossbred gilts before and after in vitro maturation. For this purpose, cortical granule redistribution, mitochondrial DNA content and mitochondria translocation were analyzed. Moreover, for the first time the fatty acid profiles in follicular fluid (FF) of both gilt categories was evaluated. The nuclear maturation (the percentage of metaphase II oocytes was 83% in prepubertal gilts compared with 87% in cyclic gilts), cortical granule relocation from the cortex to peripheral ooplasm (98.7% vs. 98.8% of oocytes, respectively) and mitochondrial DNA content (227 543 vs. 206 660, respectively) was not affected by sexual maturity of the donor gilt. However, the redistribution of active mitochondria during in vitro maturation was observed only in the oocytes of cyclic gilts. With regard to FF analysis, saturated, unsaturated, and monounsaturated fatty acids were significantly more abundant in the FF of prepubertal females. In particular, stearic (C18:0) and palmitic (C16:0) fatty acids had significantly higher concentrations in the FF of prepubertal gilts. In conclusion, although the oocytes of prepubertal gilts matured in vitro at a rate similar to those of cyclic gilts, they differed with respect to the selected factors attributed to cytoplasmic maturation. We suggest that the higher content of particular fatty acids, which is known to have a negative influence on oocyte maturation, as well as impaired mitochondria redistribution are factors limiting the maturation potential of oocytes from prepubertal gilts. PMID- 23043951 TI - The administration of exogenous prostaglandin may improve ovulation in pacu (Piaractus mesopotamicus). AB - Based on the reports of unsuccessful ovulation in pacu (Piaractus mesopotamicus) by fish farmers and researchers undertaking artificial reproduction programs, we evaluated the use of prostaglandin F (PGF) to improve pacu ovulation. This study was conducted during two spawning seasons (2009/2010 and 2010/2011) with two samplings in the first season and one sampling in the second season. A total of 45 females was sampled in this study. The control group was injected with carp pituitary extract (crude extract, 6 mg/kg), and the treatment group received PGF (2 mL per fish in the 2009/2010 season and 5 mL per fish in the 2010/2011 season) in addition to the crude extract. In both seasons, 100% (N = 4, 2009/2010 first sampling; N = 5, 2009/2010 second sampling; and N = 3, 2010/2011) of the PGF treated fish spawned. In contrast, 53.0% (N = 9) and 83.3% (N = 10) of the control fish spawned in the first and second samplings of the 2009/2010 season, respectively, and only 25.0% (N = 1) spawned in the 2010/2011 season. Fecundity, fertility, and hatching rates did not differ (P > 0.05) between the treated and control fish. Based on oocyte volume frequency analysis, ovaries of the control fish had more (P < 0.05) vitellogenic oocytes with germinal vesicle breakdown that remained unovulated after spawning, whereas more (P < 0.05) of previtellogenic oocytes were present in the ovaries of the PGF-treated fish. In conclusion, administration of exogenous prostaglandin may improve the outcome of hormonally induced spawning in tropical migratory fish. PMID- 23043952 TI - Outcome predictors in patients with idiopathic inflammatory myopathies. PMID- 23043953 TI - Safety and One-Year revascularization outcome of excimer laser ablation therapy in treating in-stent restenosis of femoropopliteal arteries: A retrospective review from a single center. AB - BACKGROUND: Treatment of in-stent restenosis of the femoropopliteal (FP) arteries is challenging with a high rate of restenosis. Excimer laser atherectomy (ELA) has a theoretical advantage of ablating restenotic tissue and reducing or delaying the need for repeat revascularization. We present a retrospective analysis from our center on the outcomes of ELA in the treatment of in-stent restenosis of the FP arteries. METHODS: Demographic, clinical, angiographic and procedural data were collected on all patients that underwent ELA for in-stent restenosis from February 2005 to April 2010 at a single medical center. Major adverse events and one-year target lesion revascularization (TLR) and target vessel revascularization (TVR) were obtained by reviewing of medical records. Descriptive analysis was performed on all variables. Kaplan-Meier survival curves for TLR were plotted. RESULTS: 40 consecutive patients (mean age 67.7+/-9.0years, 57.5% males) were included and followed for 1year. Adjunctive balloon angioplasty was performed in 100% at a mean pressure of 12.4+/-2.9atm. Acute procedural success (<30% angiographic residual narrowing) occurred in 92.5% of patients. Embolic filter protection (EFP) was used in 57.5% of patients. Bailout stenting was 50.0%. Macrodebris was noted in 65.2% of filters. The following adverse events were reported: distal embolization (DE) requiring treatment 2.5% (1 patient with no EFP); planned minor amputation 2.6%, planned major amputation 2.6%, total death 7.7% (all cardiac related). One perforation occurred treated successfully with stenting and balloon inflation. At one year, TLR and TVR occurred in 48.7% and 48.7% respectively. CONCLUSION: ELA has an overall favorable acute result in treating in-stent restenosis of the FP arteries. At one year TLR and TVR remain clinically significant. DE also occurs significantly with ELA and is effectively prevented with EFP. PMID- 23043954 TI - Forensic evaluation of 11 non-standard STR loci in Bangladeshi population. AB - Allele frequencies and forensic efficiency parameters of 11 non-standard autosomal STR loci, D21S1437, D22S683, D8S1110, D10S2325, D12S1090, D17S1294, D3S1744, D14S608, D20S470, D18S536 and D13S765 were evaluated in a sample of 102 unrelated Bangladeshi individuals. No significant deviation from Hardy-Weinberg equilibrium was observed in any of the loci studied. Statistical parameters of forensic importance, the power of discrimination (PD), observed and expected heterozygosity (H), polymorphism information content (PIC), matching probability (MP), power of exclusion (PE) and typical paternity index (TPI) were calculated for the loci. The most informative locus among the 11 STR loci was D10S2325 (PD=0.958), while the least informative was D17S129 (PD=0.876). The combined PD (1-PM) and MP was calculated to be 0.9999999999997 and 2.23*10(-23), respectively. These parameters indicated the usefulness of the loci in forensic personal identification and parentage testing among Bangladeshi population. PMID- 23043955 TI - Allelic polymorphic investigation of 21 autosomal short tandem repeat loci in a Chinese Bai ethnic group. AB - Population genetic data of 21 autosomal short tandem repeats (STRs) were obtained in a sample of 106 unrelated healthy individuals of Bai ethnic minority born in the Dali Bai Autonomous Prefecture in Yunnan Province. We observed 138 alleles with corresponding allelic frequencies ranging from 0.005 to 0.575. The genotypic frequency distributions at those STR loci were consistent with Hardy-Weinberg equilibrium (Bonferroni's correction was used for Hardy-Weinberg equilibrium tests). The combined probability of exclusion, power of discrimination, probability of matching value for all 21 STR loci were 0.9999975729, 0.999999999999999999872 and 1.28*10(-19), respectively. The population data in this study showed significant differences from the previously published population data of Tibetan and Salar groups in some loci. PMID- 23043956 TI - Postmortem serum tenascin-C (TN-C) concentrations in forensic autopsy cases: A pilot study. AB - In forensic investigations, autopsy findings offer major clues for the diagnosis of the cause of death. Thus, various clinical biochemical markers are now being tested to complement conventional investigation in the field of forensic medicine. In this study, we focused on tenascin-C (TN-C), a glycoprotein present in the extracellular matrix and expressed in pathological states. We reviewed autopsy cases for a 4-year period (2006-2009) using autopsy records, and analyzed the blood serum concentrations of TN-C and C-reactive protein (CRP) in these cases (N=101). The TN-C levels were relatively higher in the postmortem serum samples than in the samples from healthy individuals, and in cases of head injury, both TN-C and CRP levels were high in the postmortem serum sample. Moreover, high TN-C levels were observed particularly in cases with a long survival period. These findings indicate that postmortem serum TN-C levels may represent a useful tool for identifying the cause of specific fatal traumas. PMID- 23043957 TI - Role of matrix metalloproteinases in migration and neurotrophic properties of nasal olfactory stem and ensheathing cells. AB - Adult olfactory ectomesenchymal stem cells (OE-MSCs) and olfactory ensheathing cells (OECs), both from the nasal olfactory lamina propria, display robust regenerative properties when transplanted into the nervous system, but the mechanisms supporting such therapeutic effects remain unknown. Matrix metalloproteinases (MMPs) are an important family of proteinases contributing to cell motility and axonal outgrowth across the extracellular matrix (ECM) in physiological and pathological conditions. In this study, we have characterized for the first time in nasal human OE-MSCs the expression profile of some MMPs currently associated with cell migration and invasiveness. We demonstrate different patterns of expression for MMP-1, MMP-2, MMP-9, and MT1-MMP upon cell migration when compared with nonmigrating cells. Our results establish a correspondence between the localization of these proteinases in the migration front with the ability of cells to migrate. Using various modulators of MMP activity, we also show that at least MMP-2, MMP-9, and MT1-MMP contribute to OE MSC migration in an in vitro 3D test. Furthermore, we demonstrate under the same conditions of culture used for in vivo transplantation that OE-MSCs and OECs secrete neurotrophic factors that promote neurite outgrowth of cortical and dorsal root ganglia (DRG) neurons, as well as axo-dendritic differentiation of cortical neurons. These effects were abolished by the depletion of MMP-2 and MMP 9 from the culture conditioned media. Altogether, our results provide the first evidence that MMPs may contribute to the therapeutic features of OE-MSCs and OECs through the control of their motility and/or their neurotrophic properties. Our data provide new insight into the mechanisms of neuroregeneration and will contribute to optimization of cell therapy strategies. PMID- 23043958 TI - Detection of a new insect flavivirus and isolation of Aedes flavivirus in Northern Italy. AB - BACKGROUND: During recent years, numerous novel 'insect flaviviruses' have been discovered in natural mosquito populations. In a previous study we described the presence of flavivirus DNA sequences integrated in Aedes albopictus (Asian tiger mosquito) populations from Northern Italy in 2007. METHODS: During 2008 we collected and tested Aedes females for flavivirus presence and developed phylogenetic analysis, virus isolation, electron microscopy studies and RNAse treatments. RESULTS: We detected a high prevalence of flavivirus in Ae. albopictus (77.5%). The phylogenetic analysis identified the insect flavivirus sequences as Aedes flavivirus (AEFV) recently described in Japan, and that may have been introduced in Italy travelling with the tiger mosquito. Some of these pools grew in C6/36 cells, producing cytopathic effects, and the RNase treatment results showed the presence of the detected sequences in RNA forms. Furthermore, we detected a new insect flavivirus in one pool of Aedes cinereus/geminus mosquitoes. Phylogenetic analysis of this virus shows that it forms a distinct cluster within the clade of insect flavivirus. CONCLUSIONS: This is the first study to report a high prevalence, to describe the seasonal activity and an isolation of the insect flavivirus Aedes flavivirus in Europe. Moreover we describe the detection of a new insect flavivirus detected from Ae. cinereus mosquitoes from Italy. These flavivirus may be common, ubiquitous and diverse in nature and we discuss the implications of the insect flavivirus group in virus evolution and transmission. PMID- 23043959 TI - Positive feedback regulation of heat shock protein 70 (Hsp70) is mediated through Toll-like receptor 4-PI3K/Akt-glycogen synthase kinase-3beta pathway. AB - Alarmins, the endogenous molecules that recruit and activate innate immune cells, are considered as subgroups of damage-associated molecular patterns. Heat shock protein 70 (Hsp70) is one of putative alarmins together with high mobility group box 1, S100s, interleukin-1alpha, and annexins. It has cytokine-like functions as well as molecular chaperone functions. However, the cytokine function of Hsp70 has not been clear. Here, we demonstrated that there exists the positive feedback regulation of Hsp70 induction in innate immune cells. Heat stress (HS) increased intracellular Hsp70 (iHsp70) and it was actively released into extracellular space through the Golgi complex. Human recombinant Hsp70 (rhHsp70) up-regulated iHsp70 expression and induced pro-inflammatory cytokine secretion via Toll-like receptor 4 (TLR4). rhHsp70 rapidly activated Akt, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Moreover, glycogen synthase kinase-3beta (GSK-3beta) was inactivated by rhHsp70-induced Akt activation. Knockdown of TLR4 and overexpression of dominant negative TLR4 (DN-TLR4) suppressed the above effects of rhHsp70. The effects of rhHsp70 were not due to endotoxin contamination. Akt-dependent GSK-3beta inactivation was responsible for iHsp70 induction by rhHsp70. Overexpression of DN-Akt or constitutively active GSK-3beta or pretreatment of LY294002 inhibited rhHsp70-induced iHsp70 up regulation, which was similar to the mechanism of HS-mediated induction of Hsp70. Thus, these data suggest the positive feedback regulatory mechanism of iHsp70 induction. PMID- 23043960 TI - A systematic study of captopril-loaded polyester fiber mats prepared by electrospinning. AB - In this study, drug-loaded nanofibers were prepared by electrospinning captopril (CPL) with aliphatic biodegradable polyesters. Poly(L-lactic acid) (PLLA), poly(lactic-co-glycolic acid) (PLGA), and poly(lactic-co-epsilon-caprolactone) (PLCL) were used as filament-forming matrix polymers, and the concentration of CPL in each fiber type was varied. Scanning electron microscopy indicated that the morphology and diameters of the fibers were influenced by the concentration of polymer in the spinning solution and the drug loading. CPL was found to be distributed in the polymer fibers in an amorphous manner using differential scanning calorimetry and X-ray diffraction. FTIR indicated that hydrogen bonding existed between the drug molecules and the carrier polymers. In vitro dissolution tests showed that drug release from the fibers was highly dependent on the release medium, temperature, and on the polymer used. A range of kinetic models were fitted to the drug-release data obtained, and indicated that release was diffusion controlled in all cases. The different polymer fibers have application in diverse areas of drug delivery, for instance as sub-lingual or sustained release systems. Furthermore, by combining different CPL-loaded fibers, it would be possible to produce a bespoke formulation with tailored drug-release properties. PMID- 23043961 TI - Editorial. PMID- 23043962 TI - Successful repair of aortic valve perforation in pediatric Libman-Sacks endocarditis. PMID- 23043963 TI - Outcomes of interrupted aortic arch repair using the carotid artery turndown procedure. AB - OBJECTIVE: Interrupted aortic arch is a rare congenital anomaly affecting 1.5% of infants with congenital heart disease. Multiple surgical modalities exist to address this defect. We evaluate the long-term outcome of interrupted aortic arch with the left carotid artery turndown technique from a single institution. METHODS: Patients with interrupted aortic arch who underwent the carotid turndown procedure were identified between September 1982 and March 2010. Medical and surgical records were reviewed. Mortality data were obtained from state death records. RESULTS: Forty-seven patients met inclusion criteria. Median follow-up was 6.2 years (5 days to 23.2 years). Twenty-one patients (45%) had genetic syndromes. There were 4 operative deaths (8.5%) and 9 late deaths (19%). One-year and 5-year survivals were 80.2% and 72.6%, respectively. Seventeen patients (36.2%) required reoperation or other interventions on the aortic arch. CONCLUSIONS: Left carotid artery turndown offers a favorable surgical outcome. It compares with end-to-end repair, while providing a tension-free anastomosis and avoiding neonatal circulatory arrest and cardiopulmonary bypass. Disadvantages include a 2-stage repair and a significant reintervention rate, particularly when compared with the aortic arch advancement technique. Nevertheless, the reduced exposure to circulatory arrest and bypass and avoidance of left bronchial obstruction are important considerations that may offset these limitations. PMID- 23043964 TI - Abecedarium: who am I? E'.... PMID- 23043965 TI - Efficacy of moxibustion for pre- or stage I hypertension: study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Hypertension is a risk factor for cardiovascular disease, and the prevalence of hypertension tends to increase with age. Current treatments for hypertension have adverse side effects and poor adherence. The purpose of this study is to evaluate the effects of moxibustion on blood pressure in individuals with pre- or stage I hypertension. METHODS/DESIGN: Forty-five subjects with pre- or stage I hypertension will be randomized into three groups: treatment group A (2 times/week), treatment group B (3 times/week), and the control group (non treated group). The inclusion criteria will be as follows: (1) aged between 19 and 65 years; (2) prehypertension or stage I hypertension (JNC 7, Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure); (3) the participants are volunteers and written consent obtained.The participants in the treatment group A will undergo indirect moxibustion 2 times per week for 4 weeks, and the participants in the treatment group B will undergo indirect moxibustion 3 times per week for 4 weeks. The participants in the control group (non-treated group) will maintain their current lifestyle, including diet and exercise. The use of antihypertensive medication is not permitted. The primary endpoint will be a change in patient blood pressure. The secondary endpoints will be the body mass index, lipid profile, EuroQol and Heart Rate Variability. The data will be analyzed with the Student's t-test and analysis of variance (ANOVA) (p < 0.05). DISCUSSION: The results of this study will help to establish the optimal approach for the care of adults with pre- or stage I hypertension. TRIAL REGISTRATION: Clinical Research Information Service KCT0000469. PMID- 23043966 TI - Ectomesenchymal chondromyxoid tumor: report of a case with description of histologic and immunohistochemical findings. PMID- 23043967 TI - Long-term effect of repeated lidocaine injections into the external oblique for upper camptocormia in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is occasionally complicated by camptocormia. In a previous study, we classified camptocormia into upper and lower types based on the inflection point, and reported that lidocaine injection into the external oblique muscle, but not into the internal oblique or rectus abdomen, improved upper camptocormia in PD. The effect of a single lidocaine injection disappeared over a period of few days. In this study, we used repeated lidocaine injections into the external oblique for 4-5 days and evaluated the effects of such treatment for up to 90 days. METHODS: The study subjects were 12 patients with PD and upper camptocormia who were treated with repeated lidocaine injections into the bilateral external oblique followed by rehabilitation. The effect of treatment was evaluated by measuring the angle of truncal flexion before and after the injection. Patients who showed improvement with repeated injections were evaluated during a 90-day period. RESULTS: Eight out of 12 patients showed significant improvement in posture after a single lidocaine injection. However, the effect subsided several days after treatment. Repeated injections produced long-term improvement in 9 out of 12 patients, which was maintained during the 90 day observation period in eight of these patients. CONCLUSIONS: Our results showed that repeated lidocaine injections into the external oblique improved upper camptocormia, and that the effect was maintained in the majority of patients during the 90-day observation period, indicating that repeated lidocaine injections into the external oblique have therapeutic effect on upper camptocormia in patients with Parkinson's disease. PMID- 23043968 TI - Cortical basis for dichotic pitch perception in developmental dyslexia. AB - The current study examined auditory processing deficits in dyslexia using a dichotic pitch stimulus and functional MRI. Cortical activation by the dichotic pitch task occurred in bilateral Heschl's gyri, right planum temporale, and right superior temporal sulcus. Adolescents with dyslexia, relative to age-matched controls, illustrated greater activity in left Heschl's gyrus for random noise, less activity in right Heschl's gyrus for all auditory conditions, and less activity in right superior temporal sulcus for a dichotic melody. Subsequent analyses showed that these group differences were attributable to dyslexic readers who performed poorly on the psychophysical task. Furthermore, behavioral performance on phonological reading was correlated to activity from dichotic conditions in right Heschl's gyrus and right superior temporal sulcus. It is postulated that these differences between reader groups is primarily due to a noise exclusion deficit shown previously in dyslexia. PMID- 23043969 TI - Comparability of differential proteomics data generated from paired archival fresh-frozen and formalin-fixed samples by GeLC-MS/MS and spectral counting. AB - In this study, a Veterinary Department repository composed by paired formalin fixed paraffin-embedded (FFPE) and fresh-frozen (FrFr) sets of the same tissues, routinely archived in the typical conditions of a clinical setting, was exploited to perform a comparative evaluation of the results generated by GeLC-MS/MS (1-DE followed by in-gel digestion and LC-MS/MS) and spectral counting with the two types of archival samples. Therefore, two parallel differential proteomic studies were performed using 3 canine mammary carcinomas and 3 normal controls in a paired fashion (6 FrFr and 6 FFPE in total). As a result, the FrFr and FFPE differential proteomic datasets exhibited fair consistency in differential expression trends, according to protein molecular function, cellular localization, networks, and pathways. However, FFPE samples were globally slightly less informative, especially concerning the high-MW subproteome. As a further investigation, new insights into the molecular aspects of protein fixation and retrieval were obtained. In conclusion, archival FFPE samples can be reliably used for differential proteomics studies employing a spectral counting GeLC-MS/MS approach, although some typical biases need to be taken into account, and FrFr specimens (when available) should still be considered as the gold standard for clinical proteomics. PMID- 23043970 TI - Baseline quality of life and performance status as prognostic factors in patients with extensive-stage disease small cell lung cancer treated with pemetrexed plus carboplatin vs. etoposide plus carboplatin. AB - BACKGROUND: Small cell lung cancer (SCLC) is associated with poor prognosis due to its early metastatic potential and lack of improved outcomes with newer cytotoxic agents. Identifying factors associated with clinical outcomes can help clinicians determine which patients are more likely to benefit from therapy. Functional Assessment of Cancer Therapy (FACT) subscales and Eastern Cooperative Oncology Group performance status (ECOG PS) were retrospectively analyzed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage disease (ED)-SCLC. METHODS: Using data from a Phase III trial of pemetrexed-carboplatin vs. etoposide-carboplatin, the effect of the prognostic factors on OS and PFS was analyzed via Cox models. The Kaplan Meier method was used to estimate OS and PFS parameters for the prognostic subgroups (defined by baseline FACT scores and ECOG PS). RESULTS: Patients with higher baseline FACT-General (FACT-G) score (>= median) had significantly higher OS (hazard ratio [HR]=0.62, P<.0001) and PFS (HR=0.83, P=.032) compared with patients with lower FACT-G score (= 30% of the time in half of the categories. Mean scores in anatomy (76%) were the highest, and mean scores in vascular (60%) were the lowest (P < 0.001). The mean score per category was significantly higher for practicing neurosurgeons (71.5% +/- 8.9) than residents (60.5% +/- 12.6; P < 0.001). Residents answered questions incorrectly >= 30% of the time in all 18 categories versus 7 categories for attending neurosurgeons. Among residents, the highest mean scores were achieved in anatomy and the lowest were achieved in vascular (P < 0.001); this differential response was also reflected among attending neurosurgeons. CONCLUSIONS: SANS demonstrated areas of knowledge gaps in a broad group of neurosurgeons. There were also significant differences between residents and attending neurosurgeons. Identification of areas of deficiency could prove useful in future educational endeavors. PMID- 23043995 TI - Mini-open pedicle subtraction osteotomy: surgical technique. AB - OBJECTIVE: Minimally invasive spinal surgery (MISS) has many favorable attributes that would be of great benefit to patients with an adult spinal deformity. Decreased blood loss, lower infection rates, and faster mobilization may help to reduce the high rate of complications associated with these interventions. Although correction of coronal deformity has been well demonstrated with MISS, improvements in lordosis and sagittal balance have remained relatively elusive using the MISS approach. With open surgery, the most powerful techniques for improving sagittal balance include some form of a spinal osteotomy. METHODS: In this report, we describe the evolution of a technique for treating thoracolumbar kyphoscoliosis using a mini-open pedicle subtraction osteotomy (PSO) combined with interbody fusion and percutaneous pedicle screws. RESULTS: The patient underwent a T10 to S1 percutaneous posterior instrumented with an L3 PSO and right L4/5 minimally invasive transforaminal interbody fusion. Clinically, the patient had excellent improvement and regained the ability to ambulate independently for distances of up to one half mile. Imaging demonstrated good correction of coronal imbalance (1.8 to 9.5 cm) and sagittal imbalance (sagittal vertical axis of 22.5 to 7 cm). CONCLUSIONS: The correction of sagittal plane deformities remains difficult using MISS approaches. In this report, we describe a new technique using a mini-open PSO technique to achieve significant improvement in thoracolumbar lordosis. PMID- 23043996 TI - Impact of ultra-low-field intraoperative magnetic resonance imaging on extent of resection and frequency of tumor recurrence in 104 surgically treated nonfunctioning pituitary adenomas. AB - OBJECTIVE: To analyze the impact of intraoperative ultra-low-field magnetic resonance imaging (MRI) on the extent of tumor resection in nonfunctioning pituitary adenomas (NFPAs). METHODS: Retrospective analysis was performed of 104 consecutive cases undergoing intraoperative MRI-guided transsphenoidal surgery for NFPA. General patient data; endocrinologic parameters; neurologic examinations; preoperative and postoperative symptoms; preoperative, intraoperative, and postoperative imaging; and proliferation index were evaluated with an overall mean follow-up of 34 months. RESULTS: The use of intraoperative MRI led to an increase of the overall remission rate by 52.2%, from 44.2% to 67.3%. Tumor characteristics such as size and invasiveness had an important impact on postoperative remission rate. In patients with macroadenoma and without previous pituitary surgery, a remission rate of 82.2% was achieved. Overall, the sensitivity of intraoperative MRI in the study was 32.4%. There were no false positive interpretations. A higher proliferation index was found in the 15 patients with postoperative enlargement of residual adenomas or tumor recurrence compared with the other patients of the study group. CONCLUSIONS: This study shows that the outcome of surgical treatment of NFPAs was improved by the use of intraoperative MRI owing to more radical resection. The remission rate seems to depend on tumor characteristics. Recurrent disease might be reduced by the use of intraoperative MRI leading to more complete surgical resection of NFPAs. PMID- 23043997 TI - Management of aneurysms at the origin of duplicated middle cerebral artery: series of four patients with review of the literature. AB - OBJECTIVE: To review the management of aneurysms arising at the origin of a duplicated middle cerebral artery (DMCA), which is an extremely rare entity. METHODS: Four patients with internal carotid artery-DMCA aneurysms are presented, and 24 previously published cases are reviewed. RESULTS: Of the 28 internal carotid artery-DMCA aneurysms, 17 were ruptured, and 11 were unruptured. The aneurysms were equally distributed on the right and left sides and were small in size (<=6 mm) except for two that were of medium size. All aneurysms were treated surgically except for two very small aneurysms, which have been managed conservatively and followed for 9 years. CONCLUSIONS: Although all previously published clinical cases of internal carotid artery-DMCA aneurysms were treated surgically, conservative management with follow-up is a viable option in very small unruptured aneurysms. PMID- 23043998 TI - Endoscopic transventricular selective amygdalohippocampectomy: cadaveric demonstration of a new operative approach. AB - OBJECTIVE: The microsurgical anatomy of the temporal region has been well described. However, there is a paucity of information about the transventricular endoscopic anatomy of the mesial temporal lobe, and little is known about endoscopic approaches to this region. In this report, we describe the technique of endoscopic amygdalohippocampectomy (AH). The endoscopic anatomy of the mesial temporal region both before and after AH is shown. METHODS: We used 4 silicon injected cadaver heads for the study in our minimally invasive neurosurgery laboratory. The lateral ventricle was accessed through an occipital burr hole. RESULTS: Predissection transventricular endoscopic anatomy of this region showed the choroid plexus, hippocampus, amygdala, choroid fissure, and collateral eminence. The hippocampus, parahippocampal gyrus, and amygdala were removed endoscopically, keeping the pia on the inferior surface of the mesial temporal region intact. Postdissection anatomy of the mesial temporal region showed a clear view of the brainstem, posterior cerebral vessels, choroidal vessels, and tentorium. CONCLUSIONS: We studied the transventricular endoscopic anatomy of the mesial temporal region and described a technique for safe endoscopic AH. The advantages and potential risks of endoscopic AH are discussed, along with suggestions for minimizing complications. We believe that knowledge of the endoscopic anatomy of the mesial temporal lobe will be useful for endoscopic AH and the removal of other lesions in this region. PMID- 23043999 TI - Endovascular recanalization of the chronically occluded brachiocephalic and subclavian arteries: technical considerations and an argument for embolic protection. AB - OBJECTIVE: We described our endovascular techniques for the recanalization of chronic occlusions of the brachiocephalic and subclavian arteries. Given their large caliber, origins from the aorta, and proximity to the carotid and vertebral arteries, various complex endovascular techniques are required to achieve revascularization. Navigation of distal embolic protection devices into the carotid and vertebral arteries mandates varied catheter approaches. METHODS: Four women harboring chronic occlusions of the brachiocephalic and subclavian arteries were evaluated for their presenting symptoms, neurologic status, endovascular treatment, complications, and radiographic and clinical follow-up. We reviewed three specific treatment scenarios and analyzed predictive factors associated with treatment failure. RESULTS: Three chronic occlusions of the subclavian artery and 1 chronic occlusion of the brachiocephalic artery were identified in the four patients. All patients previously had experienced a stroke in the affected vascular territory or transient ischemic attacks from steal syndromes. Three target vessels were reopened successfully with angioplasty and stenting. In all cases, distal embolic protection devices were used, and multiple access points, including radial, brachial, and femoral catheterization, were required. Angiographic follow-up (range, 6-18 months) demonstrated stable patency of the stents in the three successfully treated patients. There were no transient or permanent complications. CONCLUSIONS: Endovascular recanalization of the great vessels with the use of distal embolic protection devices requires multiple catheters and complex endovascular techniques but is feasible and safe. A significant percentage of these occlusions can likely be reopened through endovascular techniques. PMID- 23044000 TI - Deep brain stimulation in the treatment of obsessive-compulsive disorder. AB - BACKGROUND: Deep brain stimulation (DBS) has emerged as a treatment for severe cases of therapy-refractory obsessive-compulsive disorder (OCD), and promising results have been reported. The literature might, however, be somewhat unclear, considering the different targets used, and due to repeated inclusion of individual patients in multiple publications. The aim of this report was to review the literature on DBS for OCD. METHODS: The modern literature concerning studies conducted on DBS in the treatment of OCD was reviewed. RESULTS: The results of DBS in OCD have been presented in 25 reports with 130 patients, of which, however, only 90 contained individual patients. Five of these reports included at least 5 individual patients not presented elsewhere. Sixty-eight of these patients underwent implantation in the region of the internal capsule/ventral striatum, including the nucleus accumbens. The target in this region has varied between groups and over time, but the latest results from bilateral procedures in this area have shown a 50% reduction of OCD scores, depression, and anxiety. The subthalamic nucleus has been suggested as an alternative target. Although beneficial effects have been demonstrated, the efficacy of this procedure cannot be decided, because only results after 3 months of active stimulation have been presented so far. CONCLUSIONS: DBS is a promising treatment for therapy-refractory OCD, but the published experience is limited and the method is at present an experimental therapy. PMID- 23044001 TI - Resolution of cystic deterioration of the C1-2 articulation with posterior fusion: treatment implications for asymptomatic patients. AB - BACKGROUND: The authors previously reported anterior decompression of C1-2 synovial cysts and subsequent posterior fusion in a large series. Although the surgical morbidity and mortality were acceptable, prior reports of stand-alone C1 2 fusion with resolution of cyst compression presumptively by correction of joint instability were intriguing and did not involve the morbidity associated with the transoral procedure. METHODS: Three cases of retroodontoid cysts that resolved after posterior instrumentation and fusion are presented. These cysts were not associated with rheumatoid arthritis. An additional nine cases from the literature in which fusion was performed without cyst extirpation are reviewed. RESULTS: Three patients presented with retroodontoid cysts. Two patients underwent posterior occipitocervical fusion with instrumentation alone. One patient underwent transoral decompression followed by occipitocervical fusion with instrumentation. In this one patient, magnetic resonance imaging performed early after the transoral procedure demonstrated substantial residual cyst. In all cases, follow-up magnetic resonance imaging performed 6-19 months later demonstrated near-complete resolution of the cysts. A literature review was done to find all other similar cases. Demographics, clinical presentation, imaging, and surgical outcome of these cases were analyzed. CONCLUSIONS: In asymptomatic patients with a synovial cyst of the atlantoaxial junction, posterior fusion alone may lead to complete resolution of the cyst; however, in neurologically symptomatic patients with similar lesions, cyst decompression coupled with posterior fusion is recommended to ensure the highest chance of cyst resolution and clinical improvement. PMID- 23044002 TI - Minimally invasive thoracic microendoscopic diskectomy: surgical technique and case series. AB - OBJECTIVE: To present operative details and clinical follow-up of a series of patients with thoracic disk herniation treated with the minimally invasive technique of thoracic microendoscopic diskectomy (TMED). METHODS: TMED was performed in 16 consecutive patients (age range, 18-79 years old) with 18 thoracic disk herniations. One patient with a calcified herniation in a direct ventral location was not included in this series. Patients were positioned prone, and a tubular retractor system was placed through a muscle dilating approach. The procedure was performed with endoscopic visualization. Outcomes were assessed using modified McNab criteria. RESULTS: There were no complications, and no case required conversion to an open procedure. The mean operative time was 153 minutes per level, and mean blood loss was 69 mL per level. Mean hospital stay was 21 hours. At a mean follow-up of 24 months (median, 22 months), 13 patients (81%) had excellent or good outcomes, 1 patient (6%) had a fair outcome, and 2 patients (13%) had poor outcomes. The two patients with poor outcomes had neurologic diagnoses (multiple sclerosis and multiple systems atrophy) that were ultimately found to be responsible for their symptoms and deficits. CONCLUSIONS: TMED is a safe and effective minimally invasive posterolateral approach for the treatment of thoracic disk herniations that lacks the morbidity associated with traditional approaches. PMID- 23044003 TI - Endoscopic scoring system for extraparenchymal neurocysticercosis. AB - OBJECTIVE: To propose a scoring system using endoscopy for assessment of the inflammatory alterations caused by neurocysticercosis (NCC) inside the ventricular cavities and the basal subarachnoid space. METHODS: Video recordings of the endoscopic procedures in patients with hydrocephalus secondary to NCC were assessed in a two-phase study. In the first phase (n = 10), the assigned score of each patient was correlated with the cerebrospinal fluid values obtained by lumbar and ventricular puncture. Reproducibility was determined using an intraclass correlation coefficient. In the second phase (n = 30), the prognostic value of the score was tested by comparing it with the patient's Karnofsky performance score (KPS) 3 months after endoscopy. RESULTS: The score included four main components: ependymal findings, number of involved sites, abnormalities in the subarachnoid space, and other alterations. These values were summed to produce a total score, which correlated strongly with both protein and cell counts from ventricular cerebrospinal fluid. The intraclass correlation coefficient of the global score was 0.85. In the second phase, the scores were divided into mild, moderate, and severe categories (6, 15, and 9 patients). The initial KPS was similar between the groups (P = 0.56); however, when measured 3 months later, there were significant differences (P = 0.02). The logistic regression analysis of patients with a score in the severe range (odds ratio = 0.09; 95% confidence interval, 0.06-0.64) showed a reduced chance for achieving a good outcome (KPS >=90) after 3 months. CONCLUSIONS: Our scoring system enables endoscopic classification of the damage caused by NCC in the ventricular and basal subarachnoid space. The score has a biologic basis and a good internal reproducibility. The score seems to be useful for determining the short-term prognosis, and patients with high scores require additional therapeutic measures to improve their outcomes. PMID- 23044005 TI - Does methotrexate increase the risk of varicella or herpes zoster infection in patients with rheumatoid arthritis? A systematic literature review. AB - OBJECTIVES: Methotrexate (MTX) has become the foundation disease-modifying anti rheumatic drug (DMARD) for RA. However, concern exists regarding its possible association with infectious complications including varicella zoster virus (VZV) and herpes zoster (HZ). Furthermore, no consensus exists regarding pre-MTX VZV screening or the use of VZV vaccine. METHODS: We undertook systematic literature review (SLR) investigating the relationship between the use of MTX in patients with RA and VZV and HZ infection. Additionally, the European Centre for Disease Prevention and Control, HPA, the CDC, Rheumatology societies and WHO web sites and publications were consulted. RESULTS: Thirty-five studies fulfilled the inclusion criteria comprising 29 observational studies and 6 case reports. The case reports and 13 observation studies considered the association between MTX and HZ. Three of the observational studies reported a positive association although in 5 cases, patients were concurrently treated with prednisolone. Five studies concluded that there was no association between HZ and MTX. Three studies comparing the infection rates of MTX with other RA therapies found that MTX did not result in higher HZ infection rates. Three studies examining the association between HZ and MTX treatment duration failed to show a link. CONCLUSIONS: No evidence exists to support an association between MTX and VZV infection in RA patients and the data regarding the role of MTX in HZ development is conflicting. The role of pre-MTX VZV screening is controversial and, as it may delay initiation of RA treatment, we suggest against VZV screening in this context. PMID- 23044006 TI - Insulin related compounds and identification. AB - Insulin-related compounds (IRCs), which originate during the expression and purification of human insulin using recombinant Escherichia coli, were purified and identified. We investigated the identity of IRCs and their origin. We also presented methods for inhibiting IRC formation. The strains used in this report were E. coli B5K and E. coli H27R. E. coli B5K had a 6-amino acid-fused peptide at the N-terminus of proinsulin, and E. coli H27R had a 28-amino acid-fused peptide at the N-terminus of proinsulin. We investigated the identity of IRCs and their origin by mainly using High Performance Liquid Chromatography (HPLC). The well-known IRCs, desamido human insulin and desthreonine human insulin, formed in both strains. In addition to these two IRCs, the B5K strain produced three different IRCs, Arg(A(0))-insulin (IRC 1), prepeptide-insulin (IRC 2), and Glu(A(22))-insulin (IRC 3). The amounts of IRC 1, IRC 2, IRC 3 were approximately 0.1-0.3% after final purification step. Among these IRCs, Arg(A(0))-insulin, prepeptide-insulin, and desthreonine insulin originated from incomplete enzyme reaction. Glu(A(22))-insulin was formed when we used a double stop codon during the expression of preproinsulin; that is, it was formed by the misreading of the first stop codon through the amber mutation. The major IRCs of the H27R strain were human insulin fragment (B1-B21) (IRC 4), and A9(Ser->Asn) amino acid single mutation human insulin (IRC 5), Arg(B(31))-insulin (IRC 6). Human insulin fragment (B1-B21) was formed by beta-mercaptoethanol, which was added during refolding. It formed when the disulfide bonds between A-chain and B-chain of human insulin were cut by beta-mercaptoethanol, followed by cleavage of the B chain by trypsin and carboxypeptidase B. A9(Ser->Asn) amino acid single mutation human insulin originated from the mistranslation of A9 serine, such that asparagine was translated instead of serine. Arg(B(31))-insulin originated from incomplete enzyme reaction. The amount of IRC 4 was 10-15% after enzyme reaction. The amounts of IRC 5, IRC 6 were around 0.2% after final purification step. We present methods for inhibiting the formation of IRCs by controlling the amount of enzyme, controlling the rate of enzyme reaction, using a single stop codon, using hydrogen peroxide (H(2)O(2)) to inhibit beta-mercaptoethanol, and modifying the A9 codon. PMID- 23044004 TI - Diet and density dependent competition affect larval performance and oviposition site selection in the mosquito species Aedes albopictus (Diptera: Culicidae). AB - BACKGROUND: Oviposition-site choice is an essential component of the life history of all mosquito species. According to the oviposition-preference offspring performance (P-P) hypothesis, if optimizing offspring performance and fitness ensures high overall reproductive fitness for a given species, the female should accurately assess details of the heterogeneous environment and lay her eggs preferentially in sites with conditions more suitable to offspring. METHODS: We empirically tested the P-P hypothesis using the mosquito species Aedes albopictus by artificially manipulating two habitat conditions: diet (measured as mg of food added to a container) and conspecific density (CD; number of pre-existing larvae of the same species). Immature development (larval mortality, development time to pupation and time to emergence) and fitness (measured as wing length) were monitored from first instar through adult emergence using a factorial experimental design over two ascending gradients of diet (2.0, 3.6, 7.2 and 20 mg food/300 ml water) and CD (0, 20, 40 and 80 larvae/300 ml water). Treatments that exerted the most contrasting values of larval performance were recreated in a second experiment consisting of single-female oviposition site selection assay. RESULTS: Development time decreased as food concentration increased, except from 7.2 mg to 20.0 mg (Two-Way CR ANOVA Post-Hoc test, P > 0.1). Development time decreased also as conspecific density increased from zero to 80 larvae (Two-Way CR ANOVA Post-Hoc test, P < 0.5). Combined, these results support the role of density-dependent competition for resources as a limiting factor for mosquito larval performance. Oviposition assays indicated that female mosquitoes select for larval habitats with conspecifics and that larval density was more important than diet in driving selection for oviposition sites. CONCLUSIONS: This study supports predictions of the P-P hypothesis and provides a mechanistic understanding of the underlying factors driving mosquito oviposition site selection. PMID- 23044007 TI - Hospital-based prevalence of high-risk cervical HPV types infecting the general population and female sex workers in Huzhou, China. AB - OBJECTIVE: To evaluate the prevalence of high-risk HPV types among female sex workers and the general population in Huzhou, China. METHODS: Cervical samples from the general population (n=292) and female sex workers (n=288) in Huzhou, China, were collected between April, 2008, and October, 2009. Demographic, behavioral, and clinical data were obtained by interview. Genotyping of the HPV L1 gene was done via a PGMY09/PGMY11 PCR-based assay, and the cervical samples were subjected to cytology analysis. RESULTS: The prevalence of HPV was higher among female sex workers (66.7%) than among the general population (19.2%). Among female sex workers, HPV-16 (28.8%) was the most prevalent, followed by HPV-58 (24.0%) and HPV-52 (20.8%). The percentage of cervical abnormalities was higher among female sex workers (20.8%) than among the general population (4.8%). Multivariate analysis showed that education level and condom use during coitus were significantly associated with HPV infection (P<0.05). HPV-16, HPV-58 and HPV 52 were the dominant types, and were significantly associated with abnormal cervical cytology (P<0.05). CONCLUSION: Female sex workers in Huzhou, China, were found to have a greater probability of being infected with high-risk HPV, and novel vaccines against HPV-58 and HPV-52 should be developed. Using condoms could reduce the risk of infection. PMID- 23044008 TI - Outcomes and feasibility of laparoscopic sacrocolpopexy among obese versus non obese women. AB - OBJECTIVE: To compare complication rates and short-term outcomes of laparoscopic sacrocolpopexy among obese and non-obese women. METHODS: A retrospective multicenter study of 39 obese women and 111 non-obese women was conducted. Obesity was defined as a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) above 30. Operative parameters (length of operation, associated procedures, complication rate, and length of hospitalization) and short-term (2 months) objective and subjective results were evaluated. RESULTS: The median BMI in the obese group was 30.5 (interquartile range [IQR] 30-32) versus 23 (IQR 21-25) in the non-obese group (P<0.0001). Short term anatomic results (postoperative stage of prolapse) were comparable in the obese and non-obese groups: stage 0-1, 87.1% versus 91.6% (P=0.60); stage 2, 10.2% versus 5.5% (P=0.60); stage 3-4, 2.5% versus 2.5% (P=0.60). Complication rates were also similar in the obese and non-obese groups: bladder injury, 2.5% versus 5.4% (P=0.77); laparoconversion, 5.1% versus 4.5% (P=0.77). Rates of reoperation (excluding women with de novo urinary stress incontinence) were 12.8% in the obese group and 8.1% in the non-obese group (P=0.58). CONCLUSION: Laparoscopic sacrocolpopexy has similar complication rates and short-term outcomes among both obese and non-obese women. PMID- 23044009 TI - Effects of positively charged redox molecules on disulfide-coupled protein folding. AB - In vitro folding of disulfide-containing proteins is generally regulated by redox molecules, such as glutathione. However, the role of the cross-disulfide-linked species formed between the redox molecule and the protein as a folding intermediate in the folding mechanism is poorly understood. In the present study, we investigated the effect of the charge on a redox molecule on disulfide-coupled protein folding. Several types of aliphatic thiol compounds including glutathione were examined for the folding of disulfide-containing-proteins, such as lysozyme and prouroguanylin. The results indicate that the positive charge and its dispersion play a critical role in accelerating disulfide-coupled protein folding. PMID- 23044010 TI - Direct reprogramming of adult somatic cells into other lineages: past evidence and future perspectives. AB - Direct reprogramming of an adult cell into another differentiated lineage-such as fibroblasts into neurons, cardiomyocytes, or blood cells-without passage through an undifferentiated pluripotent stage is a new area of research that has recently emerged alongside stem cell technology and induced pluripotent stem cell reprogramming; indeed, this avenue of investigation has begun to play a central role in basic biological research and regenerative medicine. Even though the field seems new, its origins go back to the 1980s when it was demonstrated that differentiated adult cells can be converted into another cell lineage through the overexpression of transcription factors, establishing mature cell plasticity. Here, we retrace transdifferentiation experiments from the discovery of master control genes to recent in vivo reprogramming of one somatic cell into another from the perspective of possible applications for the development of new therapeutic approaches for human diseases. PMID- 23044012 TI - Does galactocerebrosidase activity predict Krabbe phenotype? AB - This study sought to determine whether galactocerebrosidase activity is predictive of Krabbe onset age, or of survival from onset when controlling for age at onset of signs. We analyzed data on 55 symptomatic patients from the Hunter James Kelly Research Institute's World-Wide Registry. They were tested for galactocerebrosidase activity at Jefferson Medical College (Philadelphia, PA), using survival models in a path model context. Higher galactocerebrosidase activity was predictive of later symptom onset times (P = 0.0011), but did not predict survival after symptom onset (P = 0.9064) when controlling for the logarithm of age at onset. No child with early infantile (aged 0-6 months) phenotype demonstrated galactocerebrosidase activity >0.1 nmol/hour/mg protein. Survival times within a given phenotype did not vary with galactocerebrosidase activity. Although low galactocerebrosidase activity does not predict phenotype, higher activity in the abnormal range (>0.1 nmol/hour/mg protein in this sample) was not identified in the early infantile variant. Galactocerebrosidase activity may be important to consider when predicting phenotype in the newborn screening population. Our findings provide empiric evidence that the upper end (0.15 nmol/hour/mg protein) of the high-risk galactocerebrosidase group in the New York State newborn screening program is conservatively appropriate. PMID- 23044011 TI - Early-onset epileptic encephalopathies: Ohtahara syndrome and early myoclonic encephalopathy. AB - Ohtahara syndrome and early myoclonic encephalopathy are the earliest presenting of the epileptic encephalopathies. They are typically distinguished from each other according to specific clinical and etiologic criteria. Nonetheless, considerable overlap exists between the two syndromes in terms of clinical presentation, prognosis, and electroencephalographic signature. Newer understandings of underlying etiologies of these conditions may support the previously suggested concept that they represent a single spectrum of disease rather than two distinct disorders. We review both syndromes, with particular focus on the underlying genetics and pathophysiology and implications regarding the classification of these conditions. PMID- 23044013 TI - Neonatal adrenoleukodystrophy: a clinical, pathologic, and biochemical study. AB - Neonatal adrenoleukodystrophy constitutes a distinct genetic disorder of autosomal recessive inheritance, and is distinguishable from the cerebro-hepato renal syndrome of Zellweger and X-linked juvenile adrenoleukodystrophy, although all three conditions store very long chain fatty acids. Abnormal clinical features in neonatal adrenoleukodystrophy are generally present at birth, and include muscle hypotonia, severe psychomotor retardation, and failure to thrive. These infants are generally blind and deaf, with seizures developing during their first few weeks. A retinopathic "leopard spot" is common, and should help identify this disorder. The brains of four infants who died of neonatal adrenoleukodystrophy were biochemically analyzed for complex lipids, including cholesterol, cholesterol esters, total phospholipids, total galactolipids, and gangliosides. Additional analyses included the separation and identification of very long chain fatty acids and various forms of brain plasmalogen. Analyses of brains with neonatal adrenoleukodystrophy revealed the chemical identification of at least two stored lipid products. Very long chain fatty acids are present, especially in cholesterol esters, and vinyl ether ethanolamine plasmalogens are markedly elevated. The storage of vinyl ether plasmalogen in brains of infants dying of neonatal adrenoleukodystrophy clearly distinguishes them from those with cerebro-hepato-renal syndrome of Zellweger, which fail to synthesize plasmalogens. PMID- 23044015 TI - Decreased head circumference velocity as related to developmental deficit in infancy. AB - We evaluated the significance of head circumference growth velocity as related to developmental deficits during infancy. Head circumferences, lengths, and developmental diagnoses were retrieved in a standard manner at >= 2 time points from 437 infants with developmental deficits, and 3909 normally developing infants. Infants' ages ranged from 1-24 months, with final diagnoses ascertained at age 24 months. Increased velocity during the first 2 months in typical infants was evident in the study group during the period 2-4 months. A differential head circumference growth velocity was observed, and infants diagnosed with motor delay presented decreased velocity between ages 2-4 months, compared with infants receiving other nonmotor developmental diagnoses. These differences remained after controlling for birth weight and length. No significant sex effect was evident. Infants with developmental deficits demonstrate delayed acceleration of head circumference velocity, compared with typical infants in the first 2 months. Infants with motor delay manifest decreased velocity, compared with infants presenting other developmental deficits. These differences may be related to delayed white matter maturation. PMID- 23044014 TI - Maternal antibody reactivity to lymphocytes of offspring with autism. AB - The study examined whether maternal serum antibodies from mothers of autistic children preferentially bind to lymphocytes of their autistic children compared with unaffected siblings. In a previous study, maternal serum antibodies from mothers mediated cytotoxicity with complement to lymphocytes of their autistic children. Here, maternal serum antibody binding was examined by flow cytometry. We compared levels of mothers' serum binding against peripheral blood monocytes of their autistic children vs unaffected siblings. Because the level of binding to peripheral blood monocytes could be low, binding was examined in specific lymphocyte subpopulations. In 19 samples, the mean level of maternal serum immunoglobulin G binding to CD4 and CD8 T cells, B cells, natural killer cells, and macrophages was not significantly different from the mean level of binding to unaffected siblings. The percentages of different subpopulations were not significantly different between autistic children and unaffected siblings, although a trend (P < 0.1) emerged, i.e., autistic children displayed a higher percentage of natural killer cells and a lower percentage of B cells. These findings cast doubt on a direct effect of maternal antibodies, but do not preclude potential intrauterine pathogenic immune mechanisms in autism. PMID- 23044016 TI - Peripheral magnetic stimulation to decrease spasticity in cerebral palsy. AB - Muscle spasticity in pediatric cerebral palsy limits movement and disrupts motor performance, thus its reduction is important in rehabilitation to optimize functional motor development. Our pilot study used repetitive peripheral magnetic stimulation, because this emerging technology influences spinal and cerebral synaptic transmission, and its antispastic effects were reported in adult neurologic populations. We tested whether five sessions of tibial and common peroneal nerve stimulation exerted acute and long-term effects on spasticity of the ankle plantar flexor muscles in five spastic diparetic children (mean age, 8 years and 3 months; standard deviation, 1 year and 10 months). Muscle resistance to fast stretching was measured with a manual dynamometer as a spasticity indicator. A progressive decrease was observed for the more impaired leg, reaching significance at the third session. This sustained reduction of spasticity may reflect that the peripheral stimulation improved the controls over the spinal circuitry. It thus suggests that a massive stimulation-induced recruitment of sensory afferents may be able to influence central nervous system plasticity in pediatric cerebral palsy. PMID- 23044017 TI - Does antenatal tobacco or alcohol exposure influence a child's cerebral palsy? A population-based study. AB - Antenatal tobacco and alcohol exposure are established risk factors for premature birth and an independent risk factor for cerebral palsy. Both exert adverse effects on fetal development. In children with cerebral palsy, whether antenatal exposure to tobacco or alcohol is associated with a difference in clinical profile remains unknown. The Quebec Cerebral Palsy Registry was used to compare neurologic subtypes, gross motor functional impairment, and comorbidities in children with cerebral palsy who were or were not prenatally exposed to alcohol or tobacco. Information on in utero exposure was available in 249 children with cerebral palsy born from 1999-2002, of whom 77 were exposed to alcohol and 62 to tobacco in utero. No association was evident between exposure to tobacco or alcohol during pregnancy and neurologic subtype, Gross Motor Function Classification System score, mean number of comorbidities experienced, or each of eight comorbidities explored. Adjusting for prematurity or low birth weight exerted no effect on these results. In utero exposure to tobacco or alcohol does not assist in predicting clinical profiles of cerebral palsy. PMID- 23044018 TI - Epilepsy in Muenke syndrome: FGFR3-related craniosynostosis. AB - Epilepsy, a neurologic disorder characterized by the predisposition to recurrent unprovoked seizures, is reported in more than 300 genetic syndromes. Muenke syndrome is an autosomal-dominant craniosynostosis syndrome characterized by unilateral or bilateral coronal craniosynostosis, hearing loss, intellectual disability, and relatively subtle limb findings such as carpal bone fusion and tarsal bone fusion. Muenke syndrome is caused by a single defining point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Epilepsy rarely occurs in individuals with Muenke syndrome, and little detail is reported on types of epilepsy, patient characteristics, and long-term outcomes. We present seven patients with Muenke syndrome and seizures. A review of 789 published cases of Muenke syndrome, with a focus on epilepsy and intracranial anomalies in Muenke syndrome, revealed epilepsy in six patients, with intracranial anomalies in five. The occurrence of epilepsy in Muenke syndrome within our cohort of 58 patients, of whom seven manifested epilepsy, and the intracranial anomalies and epilepsy reported in the literature, suggest that patients with Muenke syndrome may be at risk for epilepsy and intracranial anomalies. Furthermore, the impact of Muenke syndrome on the central nervous system may be greater than previously thought. PMID- 23044019 TI - Cases of pediatric narcolepsy after misdiagnoses. AB - Narcolepsy is characterized by recurrent brief attacks of irresistible sleepiness. Signs can begin during childhood. However, diagnoses are frequently delayed by 10-15 years because of unfamiliarity with pediatric narcolepsy and variable presentations of its associated features (cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis). Therefore, patients may remain untreated during their formative years. Three children with narcolepsy who were initially misdiagnosed are described. Each child's signs were initially related to depression, hypothyroidism, jaw dysfunction, or conversion disorder. However, after a multiple sleep latency test, the diagnosis of narcolepsy was established. All three patients were treated appropriately with stimulant medications, selective serotonin reuptake inhibitors, or sodium oxybate, and demonstrated positive responses. Although no definitive cure exists for narcolepsy, early recognition and appropriate symptomatic treatment with medications can allow affected children to improve quality of life and achieve normality, both academically and socially. PMID- 23044020 TI - Acute unilateral ophthalmoplegia as the presenting sign of acute myeloid leukemia in a 15-month-old girl. AB - Central nervous system manifestations of acute myeloid leukemia are rare at presentation. Acute cranial nerve findings on neurologic examination can be indications for brain imaging. Magnetic resonance imaging can highlight cranial nerves emerging from the brainstem, particularly if they are gadolinium-enhanced or thickened. We describe a 15-month-old girl with acute unilateral ophthalmoplegia as the presenting sign of acute myeloid leukemia. Her presentation emphasizes the importance of appropriate laboratory and radiographic evaluation in a toddler with new-onset strabismus, which may be discounted as a previously unrecognized or benign finding. PMID- 23044021 TI - Ventriculoperitoneal shunt strategy for cerebrospinal fluid rhinorrhea repair: a case report and review of the literature. AB - We present a 10-year-old boy with a greater than 5-year history of cerebrospinal fluid rhinorrhea. He experienced nine episodes of bacterial meningitis and underwent four surgical repairs, including two endoscopic repairs via the lateral nasal cavity, a craniotomy repair via forehead epidural, and endoscopic repair in combination with a ventriculoperitoneal shunt. The first three surgeries failed, but the fourth was successful, with no recurrence during 2.5 years of follow-up. We suggest that ventriculoperitoneal shunts be considered for refractory recurrent cerebrospinal fluid rhinorrhea, particularly in patients after multiple failures of conventional surgical repair, to reduce intracranial hypertension caused by long-term chronic cerebrospinal fluid compensatory production. PMID- 23044022 TI - Immune-mediated mechanisms in the pathogenesis of Hopkins syndrome. AB - Hopkins syndrome occurs after an acute asthma attack. An immune-mediated mechanism has been suggested. Immunoglobulin or methylprednisone pulse therapies comprise the most useful treatment. We describe a 3-year-old girl who developed severe weakness in her left arm, 7 days after an acute asthma attack. A complete blood count with autoimmune biomarkers, immunoglobulin profile, and virology study and magnetic resonance of the brain, spine, and brachial plexus produced normal results. In the cerebrospinal fluid, T lymphocytes comprised the predominant leukocyte population, and oligoclonal bands were positive. An electromyogram revealed a partial axonal lesion (normal motor nerve conduction velocity with low amplitude) of the axillary, musculocutaneus, and interosseous nerves of the left arm, with normal sensory nerve conduction and partial denervation. We began therapy with intravenous immunoglobulin for 5 consecutive days, repeated every 4 weeks for 2 months. Afterward, our patient recovered. This report contributes to understanding the role of immune-mediated mechanisms in the pathogenesis of this disease, and the importance of immunotherapy in its treatment. PMID- 23044023 TI - Vici syndrome associated with sensorineural hearing loss and laryngomalacia. AB - The phenotypically heterogeneous, autosomal recessive Vici syndrome was first described in 1988 in a sister and brother with oculocutaneous albinism, agenesis of the corpus callosum, cataract, cardiomyopathy, cleft lip, and immunodeficiency. Only 14 cases of Vici syndrome have yet been reported, several involving morphologic and functional defects in addition to those described in the initial case. We report on a 3-month-old Turkish girl with Vici syndrome associated with laryngomalacia, further expanding the clinical spectrum. We also review clinical features in all 15 Vici syndrome patients, to distinguish general from less common signs. To the best of our knowledge, this report is the first of a Turkish patient with Vici syndrome. PMID- 23044024 TI - Acquired immunodeficiency syndrome with subacute sclerosing panencephalitis. AB - A 7-year-old boy with acquired immunodeficiency syndrome, receiving antiretroviral drugs for 2 years, presented with a recent onset of myoclonic jerks and cognitive deterioration. On examination, he manifested myoclonic jerks once every 10-15 seconds. His electroencephalogram indicated periodic complexes, and his cerebrospinal fluid tested positive for measles antibodies. PMID- 23044025 TI - Involvement of the globus pallidus in giant axonal neuropathy. AB - Giant axonal neuropathy is a rare autosomal recessive disorder commonly characterized by chronic, progressive dysfunction in the peripheral nervous system. Lesions also can occur in the central nervous system, especially in the brainstem and cerebellum. We present cranial magnetic resonance imaging and magnetic resonance spectroscopy findings in a 5-year-old Turkish girl with giant axonal neuropathy. This study is the second to describe involvement of the globus pallidus on T(2)-weighted imaging in giant axonal neuropathy. Magnetic resonance spectroscopy of cerebellar white matter lesions and globus pallidus revealed metabolic changes, including increased choline/creatine ratios, increased lactate, and reduced N-acetyl aspartate/creatine ratios. Thus, magnetic resonance spectroscopy did not produce findings specific to giant axonal neuropathy, but indicated progressive neuronal loss, demyelination, and gliosis in the cerebellar white matter. PMID- 23044026 TI - Role of interleukin-6 and vascular endothelial growth factor in Henoch-Schonlein purpura with posterior reversible encephalopathy syndrome. PMID- 23044028 TI - A sensemaking perspective on framing the mental picture of air traffic controllers. AB - It has long been recognized that controller strategies are based on a 'mental picture' or representation of traffic situations. Earlier studies indicated that controllers tend to maintain a selective representation of traffic flows based on a few salient traffic features that point out to interesting events (e.g., potential conflicts). A field study is presented in this paper that examines salient features or 'knowledge variables' that constitute the building blocks of controller mental pictures. Verbal reports from participants, a field experiment and observations of real-life scenarios provided insights into the cognitive processes that shape and reframe the mental pictures of controllers. Several cognitive processes (i.e., problem detection, elaboration, reframing and replanning) have been explored within a particular framework of sensemaking stemming from the data/frame theory (Klein et al., 2007). Cognitive maps, representing standard and non-standard air traffic flows, emerged as an explanatory framework for making sense of traffic patterns and for reframing mental pictures. The data/frame theory proved to be a useful theoretical tool for investigating complex cognitive phenomena. The findings of the study have implications for the design of training curricula and decision support systems in air traffic control systems. PMID- 23044027 TI - Chemical regulation of mid- and late-life longevities in Drosophila. AB - We tested the effects of a Class I histone deacetylase inhibitor (HDAcI), sodium butyrate (NaBu), on the longevity of normal- and long-lived strains of Drosophila melanogaster. This HDAcI has mixed effects in the normal-lived Ra strain as it decreases mortality rates and increases longevity when administered in the transition or senescent spans, but decreases longevity when administered over the health span only or over the entire adult lifespan. Mostly deleterious effects are noted when administered by either method to the long-lived La strain. Thus "mid- to late-life" drugs may have different stage-specific effects on different genomes of a model organism. A different HDAcI (suberoylanilide hydroxamic acid, SAHA) administered to the normal-lived strain showed similar late-life extending effects, suggesting that this is not an isolated effect of one drug. These data also show that the use of an HDAcI can significantly alter the mortality rate of the senescent span by decreasing its vulnerability, or short-term risk of death, in a manner similar to that of dietary restriction. These studies may help to shed light on the frailty syndrome affecting some aging organisms. PMID- 23044029 TI - Therapeutic potential of human induced pluripotent stem cells in experimental stroke. AB - Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) is a major type of stroke, but there are currently very limited therapeutic options for its cure. Neural stem cells (NSCs) or neural precursor cells (NPCs) derived from various sources are known to survive and improve neurological functions when they are engrafted in animal models of stroke. Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients are novel cells that promise the autologous cell therapy for stroke. In this study, we successfully differentiated iPSCs derived from human fibroblasts into NPCs and found their robust therapeutic potential in a rodent MCAo stroke model. We observed the significant graft induced behavioral recovery, as well as extensive neural tissue formation. Animal MRI results indicated that the majority of contralaterally transplanted iPSC derived NPCs migrated to the peri-infarct area, showing a pathotropism critical for tissue recovery. The transplanted animals exhibited the significant reduction of stroke-induced inflammatory response, gliosis and apoptosis, and the contribution to the endogenous neurogenesis. Our results demonstrate that iPSC derived NPCs are effective cells for the treatment of stroke. PMID- 23044030 TI - Use of species sensitivity distributions to predict no-effect concentrations of an antifouling biocide, pyridine triphenylborane, for marine organisms. AB - We used species sensitivity distributions (SSDs) and a Bayesian statistical model to carry out a primary risk assessment for pyridine triphenylborane (PTPB) in Hiroshima Bay, Japan. We used SSDs derived from toxicity values, such as EC50 and LC50, obtained from this study and previous work to calculate hazardous concentrations that should protect 95% and 99% of species (HC5 and HC1) and demonstrated that the medians of the HC5 and HC1 were 0.78 and 0.17 MUg/L, respectively. We also used liquid chromatography/mass spectrometry to investigate the occurrence of PTPB in seawater from several coastal sites of Hiroshima Bay and detected PTPB at concentrations of 4.8-21 pg/L. Comparison of environmental concentrations to the HC values suggests that the current ecological risk posed by PTPB in Hiroshima Bay is low. This is the first report of the detection of PTPB in the natural marine environment. PMID- 23044031 TI - Occurrence and distribution of organochlorine residues in surface sediments of the Candarli Gulf (Eastern Aegean). AB - The residual levels of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were determined in surface sediments collected from Candarli Gulf. Total concentrations of OCPs and PCBs in sediments ranged from 10.2 to 57.3 and 2.8 to 205 ng g-1 dwt, respectively. DDTs in sediments were derived from the aged and weathered agricultural soils in 61% of the sampling stations while 39% of the sites originated from the recent DDT inputs. Their concentrations appeared to be relatively low by global standards and only sediments receiving the impact from the Bakircay River and petrochemical industry approached the sediment quality guidelines for PCBs and DDTs. Based on ERL/ERM guidelines, DDT and PCBs posed ecological risk to the bottom-dwelling consumers. PMID- 23044032 TI - Competitive sorption of persistent organic pollutants onto microplastics in the marine environment. AB - Plastics are known to sorb persistent organic pollutants from seawater. However, studies to quantify sorption rates have only considered the affinity of chemicals in isolation, unlike the conditions in the environment where contaminants are present as complex mixtures. Here we examine whether phenanthrene and 4,4'-DDT, in a mixture, compete for sorption sites onto PVC with no added additives (unplasticised PVC or uPVC) and Ultra-High Molecular Weight polyethylene. Interactions were investigated by exposing particles of uPVC and UHMW PE to mixtures of 3H and 14C radiolabelled Phe and DDT. Changes in sorption capacity were modelled by applying a Freundlich binding sorption isotherms. An Extended Langmuir Model and an Interaction Factor Model were also applied to predict equilibrium concentrations of pollutants onto plastic. This study showed that in a bi-solute system, DDT exhibited no significantly different sorption behaviour than in single solute systems. However, DDT did appear to interfere with the sorption of Phe onto plastic, indicating an antagonistic effect. PMID- 23044033 TI - [Primary meningococcal B osteomyelitis and arthritis with multifocal pyomyositis in a child: a case report]. AB - Neisseria meningitidis is associated with severe invasive infections such as meningitis and fulminant septicemia. Septic arthritis due to N. meningitidis is rare and bone infections have been reported exceptionally. We report the case of a 7-year-old boy who presented with septic arthritis of the right hip associated with a septic location on the pelvis and pyomyositis of the adjacent muscle. Culture of the joint fluid was sterile but universal 16S polymerase chain reaction (PCR) of this fluid revealed group B N. meningitidis. Our patient had never presented any symptoms of meningitis or septicemia and blood cultures were all sterile. Despite appropriate antibiotic treatment, the course of the disease was unusually long and his status did not improve until surgical lavage of the hip was performed. Moreover, MRI imaging showed bilateral hypersignals of the adjacent muscles and revealed an abscess formation in the left gluteus maximus muscle. Presumptive diagnosis bacterial myositis was confirmed by an elevation of creatine phosphokinase in the sera up to 21-fold the normal value but the culture of the abscess, performed 10 days after initiation of antibiotics, was sterile. Despite an initially unfavorable course, this patient's status improved after surgical drainage and he fully recovered 1 month later. This observation illustrates an unusual presentation of invasive meningococcal infection. The respective roles of infection and an inflammatory phenomenon during the course of the disease are discussed. Moreover, this case emphasizes the value of PCR for bacteriological diagnosis of bone and joint infections. PMID- 23044034 TI - [Sickle cell disease revealed by venous thrombosis]. PMID- 23044035 TI - Dairy intake and related self-regulation improved in college students using online nutrition education. AB - BACKGROUND: Dairy intake by college students is markedly lower than recommendations. Interventions to improve dairy intake based on Social Cognitive Theory (SCT) have potential to successfully change behavior by improving mediators that influence dietary choices. OBJECTIVE: We aimed to use SCT to improve social support, self-efficacy, outcome expectations, self-regulation, and behavior related to dairy intake in college students. DESIGN: We conducted a randomized nutrition education intervention. PARTICIPANTS/SETTING: Participants included 211 college students (mean age 20.2 +/- 0.1 years; 63% women and 37% men) recruited from a university campus. Participants in the intervention group (n=107) and comparison group (n=104) received an 8-week dairy intake or stress management intervention, respectively, via electronic mail. Data collection included dairy intake from 7-day food records and SCT variables from questionnaires administered during January 2008 and April 2008. MAIN OUTCOME MEASURES: Changes in dairy intake and SCT variables (ie, social support, self efficacy, outcome expectations, and self-regulation). STATISTICAL ANALYSES PERFORMED: Multivariate analysis of covariance, with age and sex as covariates (P<0.05). RESULTS: Ninety-one percent of participants (n=97 intervention, n=94 comparison) provided data; complete data were analyzed for 85% of participants (n=90 intervention, n=89 comparison). Participants in the intervention group reported higher intake of total dairy foods (P=0.012) and improved use of self regulation strategies for consuming three servings per day of total dairy (P=0.000) and low-fat dairy foods (P=0.002) following the intervention. CONCLUSIONS: Nutrition education via electronic mail based on an SCT model improved total dairy intake and self-regulation. Participants reported increased dairy intake and better use of self-regulation strategies. Future interventions should focus on benefits of consuming low-fat vs higher-fat dairy foods. PMID- 23044036 TI - HIV-1 drug resistance genotyping from antiretroviral therapy (ART) naive and first-line treatment failures in Djiboutian patients. AB - In this study we report the prevalence of antiretroviral drug resistant HIV-1 genotypes of virus isolated from Djiboutian patients who failed first-line antiretroviral therapy (ART) and from ART naive patients. PATIENTS AND METHODS: A total of 35 blood samples from 16 patients who showed first-line ART failure (>1000 viral genome copies/ml) and 19 ART-naive patients were collected in Djibouti from October 2009 to December 2009. Both the protease (PR) and reverse transcriptase (RT) genes were amplified and sequenced using National Agency for AIDS Research (ANRS) protocols. The Stanford HIV database algorithm was used for interpretation of resistance data and genotyping. RESULTS: Among the 16 patients with first-line ART failure, nine (56.2%) showed reverse transcriptase inhibitor resistant HIV-1 strains: two (12.5%) were resistant to nucleoside (NRTI), one (6.25%) to non-nucleoside (NNRTI) reverse transcriptase inhibitors, and six (37.5%) to both. Analysis of the DNA sequencing data indicated that the most common mutations conferring drug resistance were M184V (38%) for NRTI and K103N (25%) for NNRTI. Only NRTI primary mutations K101Q, K103N and the PI minor mutation L10V were found in ART naive individuals. No protease inhibitor resistant strains were detected. In our study, we found no detectable resistance in ~ 44% of all patients who experienced therapeutic failure which was explained by low compliance, co-infection with tuberculosis and malnutrition. Genotyping revealed that 65.7% of samples were infected with subtype C, 20% with CRF02_AG, 8.5% with B, 2.9% with CRF02_AG/C and 2.9% with K/C. CONCLUSION: The results of this first study about drug resistance mutations in first-line ART failures show the importance of performing drug resistance mutation test which guides the choice of a second-line regimen. This will improve the management of HIV-infected Djiboutian patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2051206212753973. PMID- 23044037 TI - [Neuro-ophthalmological assessments in the Ophthalmology Department at University Medical Center, Brest: retrospective study of 269 patients (January 2004-October 2009)]. AB - AIMS: To evaluate the neuro-ophthalmological assessments carried out in the ophthalmology department of the university medical center, Brest, identifying the population seen, the examinations performed, the pathologies treated and patient outcomes, so as to suggest solutions to improve quality of care. METHODOLOGY: Retrospective study over a period of more than five years, between January 1st, 2004 and October 31st, 2009. Data were collected from each patient's chart with the help of a standardized spreadsheet including epidemiological, clinical, paraclinical and treatment data. RESULTS: Analysis of the 269 charts reveals that optic neuropathies are the most frequently encountered etiologies. In addition to the standardized assessment currently used on the service, we suggest adding a specific neuro-ophthalmological clinical intake form so as to standardize and perfect the diagnostic approach. CONCLUSION: Optimization of quality of care in neuro-ophthalmology involves a multidisciplinary approach, requiring close collaboration between ophthalmologists, neurologists and radiologists. A careful, regular analysis of our practice patterns with respect to scientific advances should improve consistency and quality of care for our patients. PMID- 23044038 TI - Division polarity in developing stomata. AB - Stomata are generated via asymmetric cell division in both dicots and monocots. Intrinsic or extrinsic polarity cues are perceived and acted upon to generate mother cell polarity and determine asymmetric division planes. Arabidopsis employs both intrinsic and extrinsic cues to orient a variable series of asymmetric stomatal divisions, using novel proteins such as BASL and POLAR to generate polarity. In contrast, maize appears to employ only extrinsic cues to orient the polarities of divisions occurring in an invariant sequence to generate stomatal complexes. Although both plants use receptor-like kinases to generate or orient division polarity in developing stomata, there are few similarities in the proteins and pathway identified to date as regulators of these processes. PMID- 23044039 TI - Visualizing Ca(2+) signatures in plants. AB - Ca(2+) is a key player in an astonishing variety of plant signal transduction pathways where transient, spiking or oscillatory changes in cytosolic Ca(2+) levels help to couple environmental or developmental cues to appropriate cellular responses. Understanding whether and how much Ca(2+) signaling contributes to defining stimulus-response specificity has long been a challenge, but recent work has provided strong evidence that specific information can indeed be encoded in the spatiotemporal characteristics of Ca(2+) signals. Identification of the Ca(2+) binding proteins that transduce Ca(2+) signals by regulating downstream effector proteins has revealed a complex network of Ca(2+) sensor families, of which some members show distinct patterns of expression and subcellular localization. By utilizing genetically encoded fluorescent Ca(2+) probes to monitor Ca(2+) changes at high spatiotemporal resolution, it is now possible to explore whether such spatial heterogeneities in Ca(2+) sensor distribution are coordinated with subcellular microdomains of Ca(2+) signaling. Such visualization of Ca(2+) signaling will also help to address which cellular compartments and transporters contribute to mobilizing and sequestering Ca(2+) and thus define stimulus-specific Ca(2+) signatures. PMID- 23044040 TI - Health-related quality of life in severe cryoglobulinaemic vasculitis and improvement after B-cell depleting therapy. AB - OBJECTIVES: To study the health-related quality of life (HRQOL) in severe cryoglobulinaemic vasculitis (CV) associated with hepatitis C virus infection (HCV) and to describe the effect of rituximab on HRQOL. METHODS: HRQOL was evaluated with the Medical Outcomes Study Short Form 36 (SF-36). Health Survey questionnaire was submitted to 15 patients with severe CV. SF-36 questionnaire was evaluated at baseline and after rituximab. Physical Health Composite Summary (PCS) and Mental Health Composite Summary (MCS) scores were calculated according to standard protocols, and normalised to healthy controls. SF-36 summary scores were compared with those of HCV positive patients without CV, and other vasculitis published in the literature. European Quality of Life-5 dimensions (EQ5D) scores were also derived. RESULTS: Physical and mental domain scores were all reduced if compared with those of the healthy population, with physical domains being greatly affected. HRQOL of CV was comparable with HRQOL reported for the other small vessel vasculitis. The development of CV in HCV positive patients worsened PCS rather than MCS score. Birmingham Vasculitis Activity Score (BVAS) did not correlate with HRQOL, while the presence of peripheral neuropathy was associated with a worse HRQOL. Early rituximab treatment improved both PCS and MCS scores, with long-term effects. CONCLUSIONS: PCS rather than MCS was affected in HCV positive patients when CV is present. Rituximab improved both physical and mental domains, thus supporting its use before antiviral therapy in severe HCV-related CV. The cost/benefits ratio of a sequential therapy may be supported. PMID- 23044041 TI - Real-time visualization of pH-responsive PLGA hollow particles containing a gas generating agent targeted for acidic organelles for overcoming multi-drug resistance. AB - Chemotherapy research highly prioritizes overcoming the multi-drug resistance (MDR) effect in cancer cells. To overcome the drug efflux mediated by P glycoprotein (P-gp) transporters, we developed pH-responsive poly(D,L-lactic-co glycolic acid) hollow particles (PLGA HPs), capable of delivering doxorubicin (DOX) into MDR cells (MCF-7/ADR). The shell wall of PLGA HPs contained DiO (a hydrophobic dye), and their aqueous core carried DOX hydrochloride salt and sodium bicarbonate, a gas-generating agent when present in acidic environments. Both DiO and DOX could serve as fluorescence probes to localize HPs and visualize their intracellular drug release in real-time. Real-time confocal images provided visible evidences of the acid-responsive intracellular release of DOX from PLGA HPs in MDR cells. Via the macropinocytosis pathway, PLGA HPs taken up by cells experienced an increasingly acidic environment as they trafficked through the early endosomes and then matured into more acidic late endosomes/lysosomes. The progressive acidification of the internalized particles in the late endosomes/lysosomes generated CO(2) bubbles, leading to the disruption of HPs, prompt release of DOX, its accumulation in the nuclei, and finally the death of MDR cells. Conversely, taken up via a passive diffusion mechanism, free DOX was found mainly at the perimembrane region and barely reached the cell nuclei; therefore, no apparent cytotoxicity was observed. These results suggest that the developed PLGA HPs were less susceptible to the P-gp-mediated drug efflux in MDR cells and is a highly promising approach in chemotherapy. PMID- 23044042 TI - SIAH-mediated ubiquitination and degradation of acetyl-transferases regulate the p53 response and protein acetylation. AB - Posttranslational modification of proteins by lysine acetylation regulates many biological processes ranging from signal transduction to chromatin compaction. Here we identify the acetyl-transferases CBP/p300, Tip60 and PCAF as new substrates for the ubiquitin E3 ligases SIAH1 and SIAH2. While CBP/p300 can undergo ubiquitin/proteasome-dependent degradation by SIAH1 and SIAH2, the two other acetyl-transferases are exclusively degraded by SIAH2. Accordingly, SIAH deficient cells show enhanced protein acetylation, thus revealing SIAH proteins as indirect regulators of the cellular acetylation status. Functional experiments show that Tip60/PCAF-mediated acetylation of the tumor suppressor p53 is antagonized by the p53 target gene SIAH2 which mediates ubiquitin/proteasome mediated degradation of both acetyl-transferases and consequently diminishes p53 acetylation and transcriptional activity. The p53 kinase HIPK2 mediates hierarchical phosphorylation of SIAH2 at 5 sites, which further boosts its activity as a ubiquitin E3 ligase for several substrates and therefore dampens the late p53 response. PMID- 23044044 TI - Mutations in sFRP1 or sFRP4 are not a common cause of craniotubular hyperostosis. AB - Sclerosing bone dysplasias are a heterogeneous group of rare diseases marked by increased BMD caused by either increased bone formation or by decreased bone resorption. In this study we have focused on craniotubular hyperostoses mainly affecting the long bones and the skull. Currently, there are three causative genes identified namely LRP5, SOST and LRP4. All three genes are involved in the canonical Wnt signalling pathway. These findings support the role of this pathway in regulating bone formation. The secreted Frizzled related proteins (sFRPs) can modulate the Wnt signalling pathway by binding to Wnt ligands or Frizzled receptors. Studies using mice showed that two members of this family, sFRP1 and sFRP4, have an important effect on bone formation. Sfrp1-/- mice have increased BMD values especially after peak BMD was reached. On the contrary, sfrp4 overexpression mice exhibit reduced BMD. Therefore, we selected sFRP1 and sFRP4, two members of the secreted Frizzled related protein (sFRP) family, as candidate genes for mutation analysis in patients with craniotubular hyperostosis. Using Sanger sequencing we screened the exons and intron/exon boundaries of sFRP1 and sFRP4 in 53 patients. In all patients mutations in LRP5, SOST and LRP4 were excluded. We identified two unknown heterozygous variants both in sFRP1. The first variant in sFRP1 is an intronic variant which, according to prediction programs, does not affect the splicing of the gene. The second variant (p.Trp131Arg/-) was identified in a young boy whose healthy mother does not carry the variant. In conclusion, our studies indicate that mutations neither in sFRP1 nor in sFRP4 are a common cause of craniotubular hyperostoses. As a consequence, further research will be necessary to identify the disease causing gene(s) in this group of patients. PMID- 23044043 TI - Modulation of medial prefrontal cortical activity using in vivo recordings and optogenetics. AB - BACKGROUND: The medial prefrontal cortex (mPFC) serves major executive functions. mPFC output to subcortical brain areas such as the amygdala controls emotional processing and plays an important role in fear extinction. Impaired mPFC function correlates with extinction deficits in anxiety disorders such as PTSD and with cognitive decision-making deficits in neuropsychiatric disorders and persistent pain. Controlling mPFC output is a desirable therapeutic goal in neuropsychiatric disorders but functional differences of cell types (pyramidal cells and interneurons) and regions (infralimbic and prelimbic) represent a challenge. This electrophysiological study used optogenetics for the cell- and region-specific modulation of mPFC pyramidal output in the intact anesthetized animal. RESULTS: Extracellular single-unit recordings were made from infralimbic (IL) pyramidal cells, IL interneurons and prelimbic (PL) pyramidal cells 2-3 weeks after intra IL injection of a viral vector encoding channel rhodopsin 2 (ChR2) under the control of the CaMKII promoter (rAAV5/CaMKIIa-ChR2(H134R)-EYFP) or a control vector that lacked the ChR2 sequence (rAAV5/CaMKIIa-EYFP). Optical stimulation with laser-generated blue light pulses delivered through an optical fiber to the IL increased spontaneous and evoked action potential firing of ChR2 expressing IL pyramidal cells but had no effect on IL interneurons that were distinguished from pyramidal cells based on their higher firing rate and shorter spike duration. Optical activation of IL pyramidal cells also inhibited PL pyramidal cells, suggesting that IL output controls PL output. The effects were light intensity dependent and reversible. Confocal microscopy confirmed ChR2-EYFP or control vector expression in mPFC pyramidal cells but not in GABAergic cells. CONCLUSIONS: The novelty of our study is the analysis of optogenetic effects on background and evoked activity of defined cell types in different mPFC regions. The electrophysiological in vivo results directly demonstrate the optogenetic modulation of mPFC activity in a region- and cell type-specific manner, which is significant in conditions of impaired mPFC output. PMID- 23044045 TI - A temporary decrease in mineral density in perinatal mouse long bones. AB - Fetal and postnatal bone development in humans is traditionally viewed as a process characterized by progressively increasing mineral density. Yet, a temporary decrease in mineral density has been described in the long bones of infants in the immediate postnatal period. The mechanism that underlies this phenomenon, as well as its causes and consequences, remain unclear. Using daily MUCT scans of murine femora and tibiae during perinatal development, we show that a temporary decrease in tissue mineral density (TMD) is evident in mice. By monitoring spatial and temporal structural changes during normal growth and in a mouse strain in which osteoclasts are non-functional (Src-null), we show that endosteal bone resorption is the main cause for the perinatal decrease in TMD. Mechanical testing revealed that this temporary decrease is correlated with reduced stiffness of the bones. We also show, by administration of a progestational agent to pregnant mice, that the decrease in TMD is not the result of parturition itself. This study provides a comprehensive view of perinatal long bone development in mice, and describes the process as well as the consequences of density fluctuation during this period. PMID- 23044047 TI - The early mouse 3D osteocyte network in the presence and absence of mechanical loading. AB - Osteocytes are considered to act as mechanosensory cells in bone. They form a functional synctia in which their processes become interconnected to constitute a three-dimensional (3D) network. Previous studies reported that in mice, the two dimensional osteocyte network becomes progressively more regular as they grow, although the key factors governing the arrangement of the osteocyte network during bone growth remain unknown. In this study, we characterized the 3D formation of the osteocyte network during bone growth. Morphological skeletal changes have been reported to occur in response to mechanical loading and unloading. In order to evaluate the effect of mechanical unloading on osteocyte network formation, we subjected newborn mice to sciatic neurectomy in order to immobilize their left hind limb as an unloading model. The osteocyte network was visualized by staining osteocyte cell bodies and processes with fluorescently labeled phalloidin. First, we compared the osteocyte network in the femora of embryonic and 6-week-old mice in order to understand the morphological changes that occur with normal growth and mechanical loading. In embryonic mice, the osteocyte network in the femur cortical bone displayed a random cell body distribution, non-directional orientation of cell processes, and irregularly shaped cells. In 6-week-old mice, the 3D network contained spindle-shaped osteocytes, which were arranged parallel to the longitudinal axis of the femur. In addition, more and longer cell processes radiated from each osteocyte. Second, we compared the cortical osteocyte networks of 6-week-old mice that had or had not undergone sciatic neurectomy in order to evaluate the effect of unloading on osteocyte network formation. The osteocyte network formation in both cortical bone and cancellous bone was affected by mechanical loading. However, there were differences in the extent of network formation between cortical bone and cancellous bone in response to mechanical loading with regard to the orientation, nuclear shape and branch formation. PMID- 23044046 TI - Angiogenesis is required for stress fracture healing in rats. AB - Although angiogenesis and osteogenesis are critically linked, the importance of angiogenesis for stress fracture healing is unknown. In this study, mechanical loading was used to create a non-displaced stress fracture in the adult rat forelimb. Fumagillin, an anti-angiogenic agent, was used as the water soluble analogue TNP-470 (25mg/kg) as well as incorporated into lipid-encapsulated alpha(v)beta(3) integrin targeted nanoparticles (0.25mg/kg). In the first experiment, TNP-470 was administered daily for 5 days following mechanical loading, and changes in gene expression, vascularity, and woven bone formation were quantified. Although no changes in vascularity were detected 3 days after loading, treatment-related downregulation of angiogenic (Pecam1) and osteogenic (Bsp, Osx) genes was observed at this early time point. On day 7, microCT imaging of loaded limbs revealed diminished woven bone formation in treated limbs compared to vehicle treated limbs. In the second experiment, alpha(v)beta(3) integrin targeted fumagillin nanoparticles were administered as before, albeit with a 100-fold lower dose, and changes in vascularity and woven bone formation were determined. There were no treatment-related changes in vessel count or volume 3 days after loading, although fewer angiogenic (CD105 positive) blood vessels were present in treated limbs compared to vehicle treated limbs. This result manifested on day 7 as a reduction in total vascularity, as measured by histology (vessel count) and microCT (vessel volume). Similar to the first experiment, treated limbs had diminished woven bone formation on day 7 compared to vehicle treated limbs. These results indicate that angiogenesis is required for stress fracture healing, and may have implications for inducing rapid repair of stress fractures. PMID- 23044048 TI - Intercontinental differences in overweight of adopted Koreans in the United States and Europe. AB - A greater proportion of the United States (US) population is overweight or obese (with BMI over 25kg/m(2)) relative to all Western European populations, and it might be expected that migrants to either the US or Western Europe would develop patterns of overweight and obesity that reflect this difference. This paper examines the effects of obesogenic environments on Asians by reporting differences in rates of overweight (which is taken to include obesity in this analysis) among 261 adult South Koreans, which had been adopted in early-life into white middle class families living in the US and in Western European Nations. Data collected during an international adoption survey carried out for the Korean government in 2008 were analyzed. The prevalence of overweight of adopted Koreans raised in the US significantly exceeds the level among adopted Koreans in Europe by 11.3%. These intercontinental differences are statistically significant after controlling for sex, current age, age of adoption, and education. This paper supports the view that life-style factors are more detrimental for the weight status of people in the US than in Western Europe. PMID- 23044049 TI - Developing a conceptual model of teenage and young adult experiences of cancer through meta-synthesis. AB - OBJECTIVES: To systematically identify and analyse published research exploring teenage and young adult experience of cancer to inform the development of a patient-reported outcome survey intended to explore if a correlation exists between specialist cancer care and quality of life for young people with cancer. DESIGN: Systematic review and meta-synthesis. DATA SOURCES: Medline, CINAHL Plus and PsycInfo were searched for literature published between 1987 and 2011. REVIEW METHODS: Search terms included those for: population (e.g. teen, young adult); intervention (e.g. cancer); outcome (e.g. experience); and study type (e.g. qualitative). INCLUSION CRITERIA: adolescents and young adults were both represented; diagnosis of cancer; published in English; and used qualitative methods to report an aspect of the cancer experience. Studies were excluded if they were reporting: palliative care experience; secondary data; or proxy views, i.e. parent or health professional perspective. Methodological quality was assessed using Cesario criteria and meta-synthesis involved deconstruction and decontextualising findings to identify common themes. RESULTS: Three hundred and fifteen studies were identified, 17 fulfilled the inclusion criteria. Of these, most (59%), were assessed as being high quality, none were rated poor. Nine common themes were identified: psychosocial function, importance of peers, experience of healthcare, importance of support, impact of symptoms, striving for normality, impact of diagnosis, positive experiences, and financial consequences. CONCLUSIONS: The conceptual model developed from the meta-synthesis depicts the mediators and consequences of cancer care that impact on young people's quality of life after a cancer diagnosis. The model highlights areas that require further exploration. PMID- 23044050 TI - Low job satisfaction does not identify nurses at risk of future sickness absence: results from a Norwegian cohort study. AB - BACKGROUND: Sickness absence is high in healthcare and contributes to nursing staff shortages reducing the efficiency and quality of patient care. Assessing the risk of sickness absence in working nurses opens opportunities for preventive strategies. Job satisfaction has attracted much attention in healthcare research and has been associated with sickness absence among nurses. OBJECTIVES: To investigate if job satisfaction scores are useful to identify working nurses at risk of future sickness absence. DESIGN: Prospective cohort study with a baseline period from November 2008 to March 2009 and 1-year follow-up. SETTINGS: Hospitals, nursing homes, and ambulant care settings in Norway. PARTICIPANTS: 2059 Norwegian nurses, of whom 1582 (77%) could be followed-up. METHODS: Nurses received a questionnaire at baseline and after 1-year follow-up. The questionnaire contained the Job Satisfaction Index (JSI), a 5-item scale measuring overall job satisfaction, and asked for sickness absence in the last 12 months. Baseline JSI scores were included in a logistic regression model with self-rated sickness absence at 1-year follow-up as outcome variable. Predictions of sickness absence were calibrated by the Hosmer-Lemeshow goodness-of-fit test. The ability of JSI scores to discriminate between nurses with and without sickness absence was examined by receiver operating characteristic analysis and expressed as area under the curve (AUC). RESULTS: Low job satisfaction was associated with higher odds of sickness absence (odds ratio [OR]=1.05; 95% confidence interval [CI] 1.01-1.09) and high (>= 31 days) sickness absence (OR=1.10; 95% CI 1.06-1.14). Calibration was acceptable, but job satisfaction neither discriminated between nurses with and without sickness absence (AUC=0.54; 95% CI 0.51-0.58) nor between nurses with and without high (>= 31 days) sickness absence (AUC=0.58; 95% CI 0.54-0.63). CONCLUSIONS: The results of this study indicated that job satisfaction was associated with sickness absence, though job satisfaction scores as measured with the JSI did not identify working nurses at risk of sickness absence. PMID- 23044051 TI - Impact of myocardial infarction on cardiac autonomic function in diabetic rats. AB - AIMS: We evaluated autonomic and hemodynamic parameters and maximal oxygen consumption (VO(2)max) as possible determinants of mortality in streptozotocin (STZ) diabetic rats after myocardial infarction (MI). METHOD: Male Wistar rats were divided into (n=8 of each): control sham (CS), diabetes sham (DS), MI (I), and diabetes+MI (DI). MI was induced 15 days after STZ induction. VO(2)max was measured at 3 (basal), 30, 60, and 91 days after MI. Hemodynamic and autonomic parameters were evaluated 92 days after MI. RESULTS: MI area was similar in infarcted groups (~44%). Mortality rate increased in the DI (70%) compared with I (53%) group. Cardiopulmonary baroreflex, sympathetic (48%) and vagal (33%) tonus, low frequency (LF) band (57%), and LF/high frequency (HF) band ratio (53%) were reduced in DI compared with I animals. Furthermore, cardiac output (CO), peripheral vascular resistance (PVR) impairment, and VO(2)max reductions were observed in the DI compared with the I group. CONCLUSIONS: Our data suggest that the CO and PVR changes as well as VO(2)max reduction were probably associated with additional cardiac autonomic control impairment, and, consequently, increased mortality rate in diabetic rats after a chronic myocardial infarction. PMID- 23044052 TI - Cerebral venous thrombosis after lumbar puncture and intravenous high dose corticosteroids: a case report of a childhood multiple sclerosis. AB - The association between cerebral venous thrombosis (CVT) and multiple sclerosis (MS) has already been reported in several adult patients with clinically definite MS, in a suspected relation to i.v. corticosteroids or previously performed lumbar puncture (LP). We are reporting a case, which is, to our knowledge, the first one concerning a child patient with a MS, who developed multiple CVT after LP and during high-dose i.v. corticosteroid. Our conclusions are that the sequence LP followed by high dose corticosteroids may be a contributory factor for the development of CVT when associated with other risk factors. PMID- 23044053 TI - Congenital disorder of glycosylation type Ic: report of a Japanese case. AB - Congenital disorders of glycosylation (CDG) are inherited metabolic diseases affecting N-linked glycosylation pathways with variable clinical presentations characterized by psychomotor retardation, seizures, ataxia and hypotonia. CDG-Ic is caused by mutation in the ALG6 gene encoding alpha-1,3-glucosyltransferase. We present a 9-year-old girl diagnosed as having CDG-Ic. She developed severe psychomotor retardation, epileptic seizures, muscle hypotonia, strabismus and some dysmorphic features without inverted nipples or fat pads. She showed a fluctuating serum transaminase level with or without some infection, and a characteristically low level of antithrombin III. MR imaging of the brain at age 2years demonstrated the lower limit of normal myelination, mild atrophy of the cerebrum, and mild hypoplasia of the brainstem and cerebellum. The patient exhibited a CDG type I pattern of serum transferrin on isoelectric focusing and mass spectrometric profiling. Sequence analysis of the ALG6 gene showed two heterozygous mutations, c.998C>T (A333V) and c.1061C>T (P354L). The patient was diagnosed as having CDG-Ic with a novel mutation, making her the first Japanese case. It was suggested that the severe psychomotor retardation in the patient was due to the existence of multiple mutant ALG6 alleles. PMID- 23044054 TI - Caffeine neuroprotects against dexamethasone-induced anxiety-like behaviour in the Zebrafish (Danio rerio). AB - The early-life stress has critical impact on brain development which can lead to long-term effects on brain functions during adulthood. It has been reported that caffeine possesses a protective effect in neurodegenerative diseases. Thus, this study investigates the potential of caffeine to protect brain functions from adverse effects due to stress exposure during early-life development in the male zebrafish. In the first part of this study, synthetic glucocorticoid, dexamethasone (DEX) (2-200 mg/L for 24 h) was used to induce stress effects in the zebrafish larvae from 4 to 5 days post-fertilisation (dpf) and the effect of DEX administration on zebrafish larvae on anxiety-like behaviour during adulthood in novel tank test was investigated. Next, the possible protective effect of caffeine pre-treatment (5-50 mg/L for 24 h from 3 to 4dpf) before DEX administration was studied. DEX-treated adult male zebrafish showed higher anxiety levels in behavioural tests, as seen in longer latency to enter the top part of the tank, lower transition numbers between the top and bottom parts with more time spent at the bottom and lesser time spent at the top and lower distance travelled at top part. The effect of DEX on anxiety-like behaviour was dose dependent. Importantly, adult male zebrafish pre-treated with caffeine before DEX treatment did not show any anxiety-like behaviour. These results show that exposure to stress during early-life leads to anxiety-like behaviour in the adult male zebrafish but pre-treatment with caffeine protects from stress-induced anxiety. PMID- 23044055 TI - Identification of Toxoplasma gondii in-vivo induced antigens by cDNA library immunoscreening with chronic toxoplasmosis sera. AB - Toxoplasmosis is an infection caused by the parasite Toxoplasma gondii. Chronically-infected individuals with a compromised immune system are at risk for reactivation of the disease. In-vivo induced antigen technology (IVIAT) is a promising method for the identification of antigens expressed in-vivo. The aim of the present study was to apply IVIAT to identify antigens which are expressed in vivo during T. gondii infection using sera from individuals with chronic toxoplasmosis. Forty serum samples were pooled, pre-adsorped against three different preparations of antigens, from each in-vitro grown T. gondii and Escherichia coli XLBlue MRF', and then used to screen a T. gondii cDNA expression library. Sequencing of DNA inserts from positive clones showed eight open reading frames with high homology to T. gondii genes. Expression analysis using quantitative real-time PCR showed that SAG1-related sequence 3 (SRS3) and two hypothetical genes were up-regulated in-vivo relative to their expression levels in-vitro. These three proteins also showed high sensitivity and specificity when tested with individual serum samples. Five other proteins namely M16 domain peptidase, microneme protein, elongation factor 1-alpha, pre-mRNA-splicing factor and small nuclear ribonucleoprotein F had lower RNA expression in-vivo as compared to in-vitro. SRS3 and the two hypothetical proteins warrant further investigation into their roles in the pathogenesis of toxoplasmosis. PMID- 23044056 TI - Virulence factors in isolates of Enterococcus faecalis from infective endocarditis and from the normal flora. AB - Infective endocarditis (IE) is a severe infection associated with significant morbidity and mortality. Enterococcus faecalis is among the most common causes of this disease, and yet little is known about the pathogenesis of E. faecalis IE. We screened 21 E. faecalis isolates from IE and 21 isolates from normal flora for the putative virulence factors ace, asa1, gelE, and esp with PCR. In addition, we determined the ability of the isolates to form biofilm and to aggregate platelets. With the exception of biofilm formation, which was more pronounced in the normal flora group, there was no difference between the groups, indicating that many isolates have virulence properties and that host factors might determine if E. faecalis causes IE. PMID- 23044057 TI - Supramalleolar osteotomy for realignment of the ankle joint. AB - Ankle replacement systems have not been as reliable as hip replacements in providing long-term relief of pain, increased motion, and return to full activity. Supramalleolar Osteotomy is an extraarticular procedure that realigns the mechanical axis, thereby restoring ankle function. The literature discussing knee arthritis has shown that realignment osteotomies of the tibia improve function and prolong total knee replacement surgery. The success of the procedure is predicated on understanding the patient's clinical and radiographic presentation and proper preoperative assessment and planning. PMID- 23044058 TI - Osteochondral talar lesions and defects. AB - Talar dome lesions (TDL) have increasingly been the focus of interest of many foot and ankle surgeons over the past decade. The most important treatment aspect of TDL is diagnosis, so that appropriate treatment protocols can be enacted in a timely and stepwise manner. Minor or mild TDL may be treated conservatively, while severe acute or chronic TDL can be addressed with various surgical interventions. By being aware of all practical treatment options and their indications, success rates, benefits, risks, and alternative options, specialists will be able to make an informed decision on appropriate care selection after perusing this article. PMID- 23044059 TI - Ankle arthrodiastasis and interpositional ankle exostectomy. AB - Arthrosis of the ankle joint, typically posttraumatic in nature, can affect younger and older populations alike. A multitude of procedures exist for treatment, such as arthrodesis, total joint replacement, arthrodiastasis, and articular repair. Current literature has demonstrated success in articular surface repair and arthrodiastasis as separate procedures. This article reviews the technique of ankle arthrodiastasis and interpositional ankle exostectomy, consisting of background, mechanism of action, indications, patient selection criteria, complications, and advantages in the current literature. PMID- 23044060 TI - Ankle arthrodesis: a literature review. AB - Ankle joint arthrodesis should be considered the gold standard procedure for end stage ankle arthritis in the appropriate patient. Incisional approach and fixation technique should be based on the patient and specific needs. Arthrodesis can be achieved with adequate resection of cartilage, good compression across the fusion site, stable fixation, proper postoperative protocol, and patient compliance. It is important to remember that positioning of the ankle joint is a keystone in ankle arthrodesis. There are complications that can arise from the ankle fusion, including the need for further surgical intervention owing to arthritis in the subtalar and midtarsal joints. PMID- 23044061 TI - Tibiotalocalcaneal arthrodesis. AB - Combined arthrodesis of the ankle and subtalar joint is a challenging but potentially rewarding procedure for certain patients. The author discusses multiple aspects of the procedure from patient counseling to postoperative complications. PMID- 23044062 TI - Total ankle replacement: a historical perspective. AB - In the early 1970s, total ankle replacement was criticized because of poor outcomes with initial implant designs. Modifications were made that lead to the development of several generations of implants. The early shortcomings gave researchers and surgeons the impetus to improve implant designs and surgical technique. Total ankle replacement has become more widely accepted in recent years because of improved design and survivorship rates for the implants, as well as improved patient satisfaction scores. Indications for total ankle replacement have broadened. To continue these successes, it is important for surgeons to select appropriate patients for this procedure. PMID- 23044063 TI - Revision of failed ankle implants. AB - Total ankle joint replacement (TAR) has been offered as an alternative to ankle joint arthrodesis since the 1970s. TAR offers the benefit of perseveration of joint motion, with potential decreased occurrence of adjacent joint degeneration, and a more expedient path to weight bearing. Since their introduction, TAR devices have undergone a variety of modifications, specifically in regards to the number and type of components used. PMID- 23044064 TI - Pinch graft harvesting technique for surgical closure of the diabetic foot. AB - Skin grafting provides an efficient way for diabetic wound closure when standard conservative therapy has failed and primary surgical closure is not an option. Pinch grafting provides an alternate method that can provide durable closure for soft tissue loss in the diabetic foot. An overview of this technique and its indications for diabetic foot wounds is presented. PMID- 23044065 TI - An overview of bone grafting techniques for the diabetic Charcot foot and ankle. AB - Surgical options for diabetic Charcot neuroarthropathy of the foot and ankle must take into consideration the challenging environment for bone healing that accompanies these complex pathologic conditions. Bone grafting has established an important role in reconstructive surgery to promote bone formation, replacement, and repair. This article provides an overview of available bone grafting methods in conjunction with a review of the literature on these techniques as they pertain to diabetic Charcot foot and ankle reconstruction. PMID- 23044066 TI - Foreward: ankle arthritis. PMID- 23044067 TI - Preface: ankle arthritis. PMID- 23044068 TI - Differential sensitivity of honey bees and bumble bees to a dietary insecticide (imidacloprid). AB - Currently, there is concern about declining bee populations and the sustainability of pollination services. One potential threat to bees is the unintended impact of systemic insecticides, which are ingested by bees in the nectar and pollen from flowers of treated crops. To establish whether imidacloprid, a systemic neonicotinoid and insect neurotoxin, harms individual bees when ingested at environmentally realistic levels, we exposed adult worker bumble bees, Bombus terrestris L. (Hymenoptera: Apidae), and honey bees, Apis mellifera L. (Hymenoptera: Apidae), to dietary imidacloprid in feeder syrup at dosages between 0.08 and 125MUg l(-1). Honey bees showed no response to dietary imidacloprid on any variable that we measured (feeding, locomotion and longevity). In contrast, bumble bees progressively developed over time a dose dependent reduction in feeding rate with declines of 10-30% in the environmentally relevant range of up to 10MUg l(-1), but neither their locomotory activity nor longevity varied with diet. To explain their differential sensitivity, we speculate that honey bees are better pre-adapted than bumble bees to feed on nectars containing synthetic alkaloids, such as imidacloprid, by virtue of their ancestral adaptation to tropical nectars in which natural alkaloids are prevalent. We emphasise that our study does not suggest that honey bee colonies are invulnerable to dietary imidacloprid under field conditions, but our findings do raise new concern about the impact of agricultural neonicotinoids on wild bumble bee populations. PMID- 23044069 TI - Evaluation of a xeno-free protocol for long-term cryopreservation of cord blood cells. AB - Cord blood is regarded as a powerful source for adult stem cells. Cord blood transplants have been used successfully to treat children and adults in autologous and allogeneic settings. Nevertheless, in many cases, the clinically relevant cell number (CD34+ cells and total leukocytes) is a limiting factor. To enable standardized cell banking and future in vitro expansion of adult stem/progenitor cells, elimination of serum, which inevitably differs from lot to lot and donor to donor, is highly desirable. Here, we demonstrate the feasibility of a xeno-free, chemically defined cryopreservation procedure for cord blood derived cells over a period of 1 year. Cell recoveries with respect to retrieval of clinically relevant CD34+ cells, colony-forming units, and in vitro cultures of erythroid progenitor cells under standardized conditions were analyzed after 1 week or 1 year of cryopreservation and found to be very high and similar to the samples before freezing. The established xeno-free procedure is an important step toward using the full potential of adult stem cells from cord blood, enabling the elimination of serum-derived factors negatively influencing proliferation, differentiation, and survival of hematopoietic stem cells. PMID- 23044070 TI - Reproducibility of lymphoscintigraphy before and after excisional biopsy of primary breast lesions: a study using superficial peri-areolar injection of the radiotracer. AB - OBJECTIVE: A major controversial issue in the sentinel node biopsy of the breast is the applicability of sentinel node mapping in patients with the history of previous excisional biopsy of the breast lesions. In the current study, we evaluated the reproducibility of lymphoscintigraphy before and after excisional biopsy of the primary breast lesions using superficial peri-areolar injection of the radiotracer. MATERIAL AND METHODS: Eighteen patients scheduled for excisional biopsy of breast lesions were included into the study. The patients received intra-dermal injection of the radiotracer in the peri-areolar area of the index quadrant 1 to 2h before surgery. Imaging was performed the day after surgery. Immediately after completion of the first imaging, the patients received another injection of the radiotracer with the same technique, dose, and location. Other sets of lymphoscintigraphy imaging were taken immediately and 4h post second injection. The two sets of lymphoscintigraphy images were compared. RESULTS: In 2 patients, sentinel node could not be identified in either set of images. In the remaining 16 patients, one sentinel node was detected in both lymphoscintigraphy image sets. The sentinel nodes of the second image sets were all in the same location of the first sets with at least 5 times higher count. CONCLUSIONS: Excisional biopsy of the primary breast lesions does not seem to change the superficial lymphatic drainage pattern from the areola of the breast and sentinel node mapping can be performed after this procedure using superficial periareolar technique. PMID- 23044071 TI - Richter's syndrome: Utility of 18F-FDG PET/CT. AB - Richter's syndrome (RS) refers to transformation of the chronic lymphoid leukemia (CLL) to a diffuse large cell lymphoma. Prognosis of patients with RS is generally considered unfavorable. We present two cases of patients with history of CLL, who had an increased of the lymphadenopathy, with elevated lactate dehydrogenase (LDH) in serum and increased (18)F-FDG uptake of the neck lymph nodes, with subsequent confirmation of RS by histology. PMID- 23044072 TI - Therapeutic effect of BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) in a rodent model of middle cerebral artery occlusion. AB - Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) represents the major type of stroke; however, there are still very limited therapeutic options for the stroke-damaged patients. In this study, we evaluated the neurogenic and therapeutic potentials of human neural stem cells (NSCs) overexpressing brain-derived neurotrophic factor (HB1.F3.BDNF) following transplantation into a rodent model of MCAo. F3.BDNF human NSCs (F3.BDNF) were transplanted into the contralateral side of striatum at 7 days after MCAo, and the transplanted animals were monitored up to 8 weeks using animal MRI and various behavioral tests before they were sacrificed for immunohistochemical analysis. Interestingly, animal MRI results indicate that the majority of contralaterally transplanted neural stem cells were migrated to the peri-infarct area, showing a pathotropism. Transplanted animals exhibited significant behavioral improvements in stepping, rotarod, and modified neurological severity score (mNSS) tests. We also found that the transplanted human cells were colocalized with nestin, DCX, MAP2, DARPP-32, TH, GAD65/67-positive cells, of which results can be correlated with neural regeneration and behavioral recovery in the transplanted animals. More importantly, we were able to detect high levels of human BDNF protein expression, presumably derived from the transplanted F3.BDNF. Taken together, these results provide strong evidence that human neural stem cells (F3.BDNF) are effective in treating stroke animal models. PMID- 23044073 TI - Global epidemiology of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA). AB - During the 1990s, various reports of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections appeared in the literature, caused by novel strains genetically distinct from traditional healthcare-associated MRSA (HA-MRSA). Numerous lineages of CA-MRSA have since emerged on every continent, several of which have spread internationally, most notably USA300. CA-MRSA strains are increasingly implicated in nosocomial infections, and may eventually displace HA-MRSA strains in hospitals. Consequently, distinctions based on clinical epidemiology and susceptibility are becoming less relevant, arguing in favor of genotypic definitions. We review the current molecular epidemiology of CA-MRSA with respect to genetic diversity, global distribution, and factors related to its emergence and spread. PMID- 23044074 TI - Long-term efficacy and improvement of health-related quality of life in patients with Takayasu's arteritis treated with infliximab. AB - OBJECTIVES: To explore the efficacy in the long-term and the impact on Health Related Quality of Life (HRQOL) of infliximab in patients suffering from Takayasu's arteritis (TA). METHODS: Clinical data were retrospectively collected in 15 patients with TA. Evaluation of Medical Outcomes Study Short Form 36 (SF 36) questionnaires was made at baseline and at the last follow-up in 10 patients continuing infliximab at the last follow-up. RESULTS: Follow-up after initiation of infliximab was 71+/-44 months (range 10-162). Remission at the last follow-up was noted in 11/15 (73.3%). Significant reduction in BVAS score was noted at the last follow-up [from 4.0 (1-16) to 3.0 (0-9), p=0.003]. Significant steroid dose reduction was recorded [from 10 mg/day (0-50) to 2.5 mg/day (0-15), p=0.005)]. Steroid suspension occurred in 5/11 responder patients. Inflammatory markers were normalised in about two thirds of the patients. Radiological disease activity was assessed in 13/15 during infliximab therapy, with evidence of improvement in 2/13, stable disease activity in 9/13, and worsening in 2/13. No relevant side effects or severe infections were recorded during the whole follow-up under infliximab. One patient stopped infliximab at the third infusion for acute reaction. HRQOL in patients with TA was impaired, with major involvement of physical domains [(body pain (BP) and global health (GH)]. Infliximab significantly improved HRQOL, in particular BP (40.0+/-32.3 vs. 67.2+/-27.6, p=0.035), GH (31.2+/-21.5 vs. 54.9+/-21.1, p=0.007) and Vitality (VT) (47.0+/ 28.7 vs. 67.0+/-20.3, p=0.01) domains. CONCLUSIONS: Infliximab determined a sustained clinical improvement in the long-term in TA, with significant benefits on HRQOL. PMID- 23044075 TI - Oral mucosal fixed drug eruption: characteristics and differential diagnosis. AB - BACKGROUND: Little is known about the characteristic features of oral mucosal fixed drug eruption (FDE). OBJECTIVE: To present the clinical highlights and the differential diagnosis of oral mucosal FDE in a relatively large group of patients from Turkey. METHODS: This was a methodological, retrospective, cross sectional study of 61 patients with oral mucosal FDE. The causative drug was established mainly by oral provocation test. RESULTS: The age range of 61 patients (38 females, 23 males) was 7 to 62 years. Naproxen and cotrimoxazole were the main inducers. Fourteen patients (23%) had a solitary oral lesion predominantly located on the dorsum of the tongue, or on the hard palate, the former statistically significantly associated with cotrimoxazole. Bullous/erosive (n = 47), aphthous (n = 12), and erythematous (n = 2) morphology were observed. A considerable number of patients were referred with a prior clinical diagnosis of herpes simplex and Behcet's disease; some of them were already receiving long term treatment with acyclovir and colchicine, respectively. LIMITATIONS: The main limitation of the present study resides in its retrospective design. CONCLUSIONS: Isolated oral lesions, aphthous lesions, severe bullous/erosive lesions, and the absence of residual pigmentation are the main features that may cause difficulties in the differential diagnosis. It is important to differentiate dysmenorrhea-related monthly attacks of oral FDE in female patients caused by nonsteroidal anti-inflammatory drugs from menstruation-triggered attacks of herpes simplex infection, and isolated orogenital aphthous FDE from Behcet's disease, especially in countries with a high frequency of the disease in order to prevent irrelevant therapies. PMID- 23044076 TI - Successful treatment of pemphigus with biweekly 1-g infusions of rituximab: a retrospective study of 47 patients. AB - BACKGROUND: Rituximab is increasingly being appreciated as a remarkably effective treatment for pemphigus, mostly concomitantly with other immunosuppressive medications. The majority of studies have used a single cycle of rituximab with the same dosage as approved for the treatment of lymphomas, ie, 375 mg/m(2) weekly * 4 weeks. Rituximab is also approved for the treatment of rheumatoid arthritis, with a different dosing regimen: 1000 mg * 2, days 1 and 15. OBJECTIVE: We aimed to assess the clinical response of patients with pemphigus to a single cycle of rituximab at the dosage used in rheumatoid arthritis. We also evaluated the response to repeated cycles of rituximab. METHODS: A total of 47 patients with pemphigus who were treated with rituximab at a dosage of 1000 mg * 2, days 1 and 15, most with concurrent immunosuppressive medications, were retrospectively studied. RESULTS: Remission rates after the first treatment cycle reached 76%. Repeating the treatment further increased the remission rates to 91%. There was a 22% relapse rate at a median time of 8 months, but 75% of relapsing patients achieved remission again with additional cycles. The side effect profile was similar to previous reports, except for an immediate postinfusion pemphigus exacerbation in 4 patients. LIMITATIONS: This was a retrospective study with a limited follow-up period. CONCLUSION: The rheumatoid arthritis dosage of rituximab was efficacious and well tolerated in patients with pemphigus. Patients who fail to achieve remission after 1 cycle or patients who relapse seem to benefit from repeated rituximab cycles. PMID- 23044078 TI - Antioxidant phenolic glycosides from the roots of Illicium dunnianum. AB - Eight new phenolic glycosides, dunnianosides A-H (1-8), and nine known phenolic glycosides (9-17), were isolated from the roots of Illicium dunnianum. The structures of these new compounds were elucidated by spectroscopic methods including 1D and 2D NMR, HRESIMS, and chemical methods. Compounds 1-5, 7, and 9 exhibited potent antioxidant activities against Fe(2+)-cystine-induced rat liver microsomal lipid peroxidation, with IC(50) values ranging from 3.8 +/- 0.6 to 23.0 +/- 2.2 MUM. PMID- 23044077 TI - Primary mucinous cystadenoma of the spermatic cord within the inguinal canal. AB - We report a hitherto not documented case of primary mucinous cystadenoma arising in the spermatic cord within the right inguinal canal of a78-year-old man. The tumor was painless, hard and mobile. A computed tomography scan on the pelvis revealed an oval shaped, low attenuation mass, measuring 5.0x2.5x2.1 cm, that was present adjacent to the vas deferens. Grossly, the excised mass was multicystic mucinous tumor, filled with thick mucoid materials. Microscopically, the cystic wall was irregularly thickened. The cystic epithelium commonly showed short papillae lined by a single layer of columnar to cuboidal mucinous epithelial cells without significant stratification or cytologic atypia. Goblet cells were also frequently present. Immunohistochemically, the neoplastic cells showed positive reaction to carcinoembryonic antigen, cytokeratin 20, CDX2, epithelial membrane antigen, and CD15. However, they were negative for PAX8 and Wilms' tumor 1 protein. Pathological diagnosis was a papillary mucinous cystadenoma of the spermatic cord. Although mucinous cystadenoma in this area is extremely rare, it is important that these lesions be recognized clinically and pathologically in order to avoid unnecessary radical surgery. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1720965948762004. PMID- 23044079 TI - The pro-inflammatory action of tumour necrosis factor-alpha in non-alcoholic steatohepatitis is independent of the NSMAF gene product. AB - BACKGROUND: The role of tumour necrosis factor-alpha (TNF-alpha) in the development of non-alcoholic steatohepatitis remains unclear. AIMS: We evaluated the role of TNF-alpha and NSMAF gene product factor associated with neutral sphingomyelinase activation, a protein adaptor of the TNF-alpha receptor-1, in a mouse model of non-alcoholic steatohepatitis. METHODS: Mice deficient either for TNF-alpha or factor associated with neutral sphingomyelinase activation, as well as control animals, were fed a methionine and choline-deficient diet for 5 weeks. Liver histology, serum glucose, triglycerides, cholesterol and alanine aminotransferase levels were compared between groups. RESULTS: Weight loss, decrease of serum triglyceride and glucose levels and increase of alanine aminotransferase levels were attenuated in TNF(-/-) mice. Similarly, we found a significantly lower lobular inflammation in TNF(-/-) mice. Liver expression of transforming growth factor-beta, peroxisome proliferator-activated receptor gamma(1, 2) and monocyte chemoattractant protein-1 was attenuated in TNF(-/-) mice. In addition, the phosphatidylcholine/phosphatidylethanolamine liver ratio decrease was less important in TNF(-/-) mice. The increase in hepatic sphingomyelin and ceramide levels was less pronounced in TNF(-/-) animals. CONCLUSION: Whereas TNF-alpha modulates the inflammatory process that underlies methionine and choline-deficient diet-induced non-alcoholic steatohepatitis, its effects are not mediated by factor associated with neutral sphingomyelinase activation. Whether changes in liver lipids, like phosphatidylcholine and ceramide, are causally involved in tumour necrosis factor-mediated liver inflammation remains an open issue. PMID- 23044080 TI - Endosymbiotic heterocystous cyanobacteria synthesize different heterocyst glycolipids than free-living heterocystous cyanobacteria. AB - The heterocysts of limnetic nitrogen-fixing filamentous cyanobacteria contain unique glycolipids in their cell wall that create the distinctive gas impermeability of the heterocyst cell wall as well as serve as biomarker lipids for these microbes. It has been assumed that marine free-living and endosymbiotic cyanobacteria synthesize the same glycolipids although they have not been investigated in any detail. Here we report the glycolipid composition of several marine free-living heterocystous cyanobacteria as well as the heterocystous endosymbiont Richelia intracellularis found in the biogeochemically important diatoms Hemiaulus hauckii and Hemiaulus membranaceus. In the marine cyanobacteria Nostoc muscorum and Calothrix sp., we detected the same glycolipids as found in freshwater representatives of these genera. However, we did not detect these glycolipids in the Hemiaulus-Richelia association. Instead, we identified glycolipids which comprised a C5 sugar, ribose, rather than the C6 sugars normally encountered in glycolipids of free-living cyanobacteria. In addition, the glycolipids had slightly longer chain lengths (C30 and C32 versus C26 and C28) in the aglycone moiety. The different glycolipid composition of the marine endosymbotic heterocystous cyanobacteria compared to their free-living counterparts may be an adaptation to the high intracellular O2 concentrations within their host. These glycolipids may provide unique tracers for the presence of these microbes in marine environments and permit exploration of the evolutionary origins of these symbioses. PMID- 23044081 TI - [Pasteurella multocida: a rare cause of cerebral abscess]. PMID- 23044082 TI - Cutaneous infections, good use of antibiotics and diagnostic accuracy. AB - The medical dashboard (DB) recording our clinical practices indicated on one hand the use of two different diagnosis terms, acute dermohypodermitis (ADH) or cellulitis, and on the other hand, an important antibiotic prescription heterogeneity. Our aim was to define these two diagnosis groups and to document compliance to our antibiotic therapy protocol. METHOD: ADH and cellulitis were selected in our medical DB that records all patient data. Our local antibiotic therapy protocol was designed in April 2009; the prescription of recommended antibiotic agents defined the compliance to recommendations. The patient files indicating non-consensual therapy were analyzed to determine the reasons for inappropriate prescription. RESULTS: Three hundred and four cases of ADH and 82 of cellulitis were diagnosed over 6.5years. ADH was associated with older age (P=0.007), a higher frequency of venous insufficiency (P=0.015), a lower frequency of cancer (P=0.007), and was more often located on lower limbs (P<0.001), compared to cellulitis. The diagnosis of ADH was associated with higher compliance to our antibiotic therapy protocol, compared to cellulitis: 68% versus (vs.) 24%, P<0.001, and after April 2009: 53% vs. 64%, P=0.033. Among the 162 inappropriate antibiotic prescriptions (42%), 75 were deemed justified after analyzing the patient file, but less frequently for ADH compared to cellulitis: 49% vs. 11,5%, P<0.001. CONCLUSION: ADH presents different clinical characteristics compared to cellulitis. The antibiotic therapy protocol for ADH cannot be applied to cellulitis. PMID- 23044083 TI - Management of tuberculosis and HIV co-infection in Cotonou, Benin. AB - OBJECTIVES: The authors had for aim to assess the management of tuberculosis and HIV co-infection in Cotonou, Benin. PATIENTS AND METHODS: We made a cross sectional, retrospective, and descriptive study comparing the clinical presentation and outcome of patients with tuberculosis and HIV co-infection versus patients with tuberculosis alone, all managed at the National Pneumophtisiology Center in Cotonou, Benin, in 2009. RESULTS: The rate of HIV screening in TB patients was 99%. One thousand and eighty-six TB patients were included and 259 were HIV positive. The mean age of co-infected patients was 36 years, versus 34 for TB mono-infected patients. The sex ratio among co-infected was 1.15 versus 2.25 among TB patients. Positive pulmonary sputum was less frequent with co-infection. Two hundred and fifty-seven over 259 patients were treated with cotrimoxazole. One hundred and eighty-five over 234 (79.05%) had CD4 counts<350. Eighty-five (46%) of the 185 patients with CD4<350, were given antiretroviral therapy. Treatment success rate was lower for co-infected (75%) than for patients with TB alone (86%), and death rates were higher in co-infected patients (10% vs. 3%). CONCLUSION: High death rate and high rate of lost to follow-up are arguments for systematic antiretroviral treatment of co-infected patients. Early screening for TB and HIV, and reviewing the current national recommendations, as well as an increased governmental effort to provide medicines to all patients in need of ARV are mandatory. PMID- 23044084 TI - Appropriate use of carbapenems in the Besancon university hospital. AB - INTRODUCTION: The excessive and inappropriate use of carbapenems is responsible for the development of resistance. The scientific community has been requiring caution and using these agents in specific cases only. OBJECTIVES: The authors had for aim to evaluate the appropriate use of carbapenems in a French university hospital. DESIGN: A retrospective survey was made over two months as a clinical audit to assess professional practices. The evaluation criteria for this audit were: the appropriateness of the indication, the possibility of alternative therapeutic strategies, the choice of an antibiotic combination, duration of treatment and dosage. RESULTS: During the audit period, 103 carbapenem prescriptions were included. Ninety-nine cases were analyzed. Among the carbapenem prescriptions, 28.3% (28/99) did not meet the criterion "appropriateness of the indication". Carbapenems were mostly prescribed empirically (60/99 [60%]) and most often for lung infections or nosocomial urinary tract infections. Finally, 66.7% (66/99) of all prescriptions were considered inappropriate for at least one criterion. The rate of inappropriateness ranged around 30% for each criterion. CONCLUSIONS: This study allowed us to assess professional practices for carbapenem prescriptions. The overall rate of inappropriateness was quite important. Carbapenems were not always used appropriately. These findings highlight the need of new regional guidelines and regular updating of local best practices recommendations. Finally, a stricter validation of carbapenem prescriptions will be implemented at the hospital pharmacy level. PMID- 23044085 TI - [Invasive infection due to Kodamaea ohmeri]. PMID- 23044086 TI - [Hepatic artery mycotic aneurysm and Streptococcus gallolyticus endocarditis]. PMID- 23044087 TI - Voriconazole stability in cement spacers. PMID- 23044088 TI - Working memory of somatosensory stimuli: an fMRI study. AB - In a previous study, we have shown that passive recognition of tactile geometrical shapes (i.e. no exploratory movement) engages prefrontal and premotor areas in addition to somatosensory regions (Savini et al., 2010). In the present study we tested the hypothesis that these regions are involved not only in the perception but also during working memory of such somatic information. We performed functional magnetic resonance imaging (fMRI) during the execution of N BACK tasks, with 2D geometrical shapes blindly pressed on the subjects' right hand palm. Three conditions with increasing memory load (0-BACK, 1-BACK, 2-BACK) were used. Results showed that primary somatosensory area (SI), secondary somatosensory area (SII) and bilateral Insula were active in all conditions, confirming their importance in coding somatosensory stimuli. Activation of fronto parietal circuit in supplementary motor area (SMA), right superior parietal lobe (rSPL), bilateral middle frontal gyrus, left inferior frontal gyrus, and right superior frontal sulcus was significantly larger during 1-BACK and 2-BACK than 0 BACK. Left superior parietal lobe and right frontal eye field showed a higher activation during the 2-BACK than 0-BACK. Finally, SMA and rSPL were characterized by a statistically significant higher activation during 2-BACK than 1-BACK, revealing their sensitivity to the memory load. These results suggest that working memory of tactile geometrical shapes (no exploratory movement) involves a complex circuit of modal and supramodal fronto-parietal areas. PMID- 23044090 TI - Influence of test tasks with different cognitive demands on salivary cortisol concentrations in school students. AB - This study aimed to investigate the effects of test tasks with different cognitive demands on salivary cortisol concentrations in school students. The salivary cortisol levels of 93 students (56 males and 37 females, mean age 17.86 yrs.) were measured before and after 2 brief tests and 2 control situations, respectively. One of the tests comprised reproductive, the other transfer and problem-solving tasks. In the control groups, students were instructed to either write whatever they want, or to wait. Statistical analysis (ANOVA) indicated a significant main effect of the experimental treatment on the cortisol response. The cortisol increase was significantly higher following the reproduction tasks as compared to both control conditions. Although not significant the cortisol increase during reproduction tasks was over twice as much in males compared to females. In contrast the increase during transfer and problem solving tasks does not differ significantly from the control conditions under which the cortisol concentration remains nearly the same and decreases respectively. These findings indicate an influence of the task demand on the cortisol concentration. Furthermore, it can be assumed that reproduction tasks in particular have the potential to be a major stressor during school examinations. PMID- 23044089 TI - Catecholamine predictors of complicated grief treatment outcomes. AB - Could sympathetic hyperarousal limit treatment success in complicated grief? The present study investigated persons with complicated grief, a chronic condition with distinct symptoms including persistent intense yearning and longing for the person who died, avoidance of reminders that the person is gone, deep relentless sadness, self-blame, bitterness, or anger in connection with the death, and an inability to gain satisfaction or joy through engaging in meaningful activities or relationships with significant others. Length of bereavement did not correlate with complicated grief scores. Catecholamines (i.e., epinephrine, norepinephrine, dopamine) in plasma were assessed pre- and post-psychotherapeutic treatment. Participants with the highest levels of epinephrine at pre-treatment had the highest levels of complicated grief symptoms at post-treatment, accounting for baseline levels of symptoms. This predictive relationship was not seen for depressive symptoms. The present study supports the hypothesis that catecholamine levels are affected by bereavement, and in turn, can affect the ability of those with complicated grief to benefit from psychotherapy. PMID- 23044091 TI - Effects of sub-lethal exposure of rats to the herbicide glyphosate in drinking water: glutathione transferase enzyme activities, levels of reduced glutathione and lipid peroxidation in liver, kidneys and small intestine. AB - Glyphosate (GLP), the active ingredient of many weed killing formulations, is a broad spectrum herbicide compound. Wistar rats were exposed during 30 or 90 days to the highest level (0.7 mg/L) of GLP allowed in water for human consumption (US EPA, 2011) and a 10-fold higher concentration (7 mg/L). The low levels of exposure to the herbicide did not produce histomorphological changes. The production of TBARS was similar or tended to be lower compared to control animals not exposed to the herbicide. In rats exposed to GLP, increased levels of reduced glutathione (GSH) and enhanced glutathione peroxidase (GPx) activity may act as a protective mechanism against possible detrimental effects of the herbicide. Overall, this work showed certain biochemical modifications, even at 3-20-fold lower doses of GLP than the oral reference dose of 2mg/kg/day (US EPA, 1993). The toxicological significance of these findings remains to be clarified. PMID- 23044092 TI - Effect of polyphenols extracts from Brassica vegetables on erythrocyte membranes (in vitro study). AB - The aim of this work was to estimate the in vitro effects of polyphenol extracts from Brassica vegetables (Brussels sprouts and red cabbage) on erythrocyte membranes with normal and high concentration of cholesterol. To determine the effect of phenolic compounds we prospectively studied cholesterol concentration, lipid peroxidation, membrane fluidity and ATPase activity. Polyphenol extracts from Brassica vegetables resulted in statistically significant reductions in cholesterol concentrations in hypercholesterolemic erythrocytes. For control erythrocytes, no significant reduction of cholesterol levels was observed for both extracts. Decreases in lipid peroxidation intensity were observed after incubation of hypercholesterolemic erythrocytes with the extracts. No changes in membrane fluidity for both extracts were noted for normal and hypercholesterolemic erythrocytes. The activity of ATPase decreased after incubation of normal and hypercholesterolemic erythrocytes with extract from Brassica vegetables. Our results indicate that polyphenols from red cabbage and Brussels sprout may directly influence erythrocyte membrane properties. PMID- 23044093 TI - Arsenic trioxide improves hematopoiesis in refractory severe aplastic anemia. AB - We investigated the efficacy of arsenic trioxide (ATO) in patients with refractory severe aplastic anemia (SAA). A total of 5 consecutive adults were enrolled. The patients received ATO at a dose of 0.15 mg/kg intravenously daily for 5 days every week for 8 weeks. If necessary, a second course was performed after an interval of one week. All patients achieved clinically significant responses to ATO. The overall complete response rate and overall response rate at 17 weeks were 60% (3/5) and 100%(5/5), respectively. So treatment with ATO may be a feasible approach in patients with refractory SAA. PMID- 23044094 TI - Establishment of an in vitro photoallergy test using NCTC2544 cells and IL-18 production. AB - Differentiation between photoallergenic and phototoxic reactions induced by low molecular weight compounds represents a current problem. The use of keratinocytes as a potential tool for the detection of photoallergens as opposed to photoirritants is considered an interesting strategy for developing in vitro methods. We have previously demonstrated the possibility to use the human keratinocyte cell line NCTC2455 and the production of interleukin-18 (IL-18) to screen low molecular weight sensitizers. The purpose of this work was to explore the possibility to use the NCTC2544 assay to identify photoallergens and discriminate from phototoxic chemicals. First, we identified suitable condition of UV-irradiation (3.5 J/cm(2)) by investigating the effect of UVA irradiation on intracellular IL-18 on untreated or chloropromazine (a representative phototoxic compound)-treated NCTC2544 cells. Then, the effect of UVA-irradiation over NCTC2544 cells treated with increasing concentrations of 15 compounds including photoallergens (benzophenone, 4-ter-butyl-4-methoxy-dibenzoylmethane, 2-ethylexyl p-methoxycinnamate, ketoprofen, 6-methylcumarin); photoirritant and photoallergen (4-aminobenzoic acid, chlorpromazine, promethazine); photoirritants (acridine, ibuprofen, 8-methoxypsoralen, retinoic acid); and negative compounds (lactic acid, SDS and p-phenilendiamine) was investigated. Twenty-four hours after exposure, cytotoxicity was evaluated by the MTT assay or LDH leakage, while ELISA was used to measure the production of IL-18. At the maximal concentration assayed with non-cytotoxic effects (CV80 under irradiated condition), all tested photoallergens induced a significant and a dose-dependent increase of intracellular IL-18 following UVA irratiation, whereas photoirritants failed. We suggest that this system may be useful for the in vitro evaluation of the photoallergic potential of chemicals. PMID- 23044095 TI - Plasma phospholipid fatty acid composition in ischemic stroke: importance of docosahexaenoic acid in the risk for intracranial atherosclerotic stenosis. AB - OBJECTIVE: While data on the relationship between fatty acid (FA) composition and the risk for total stroke have accumulated, the association between FA composition and the risk for intracranial atherosclerotic stenosis (ICAS) has never been studied. We compared plasma phospholipid FA composition between non stroke control and ischemic stroke in Korean population, to discern the FA that distinguishes ICAS from total ischemic stroke patients. METHODS: Non-stroke controls (n = 215) and stroke patients (no cerebral atherosclerotic stenosis, NCAS: n = 144 and ICAS: n = 104) were finally included in the analysis. Plasma phospholipid FA compositions were analyzed. RESULTS: Age, coexistence of hypertension/diabetes were significantly different among the groups. Phospholipid FA compositions were significantly different between non-stroke control and ischemic stroke patients, and interestingly, between NCAS and ICAS in stroke patients. Pattern analysis showed that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the omega3-polyunsaturated FAs were important FAs in distinguishing NCAS and ICAS in strokes. Particularly, the risk of ICAS was inversely associated with levels of DHA contents in phospholipids (OR: 0.590, 95% CI: 0.350-0.993, p < 0.05), indicating that the risk may be increased at lower levels of DHA contents. CONCLUSION: DHA and EPA are important FAs for distinguishing NCAS and ICAS in strokes. Additionally, the risk of ICAS was inversely associated with the levels of phospholipid DHA, which indicates that sufficient amounts of DHA in plasma or in diet may reduce the risk of ICAS. PMID- 23044096 TI - Defensive coping and subclinical vascular disease risk - associations with autonomic exhaustion in Africans and Caucasians: the SABPA study. AB - OBJECTIVE: The defensive active coping response is a recognised cardiovascular risk factor in Africans, especially in men. It is uncertain whether autonomic dysfunction might be the underlying cause. We therefore investigated associations between salivary MHPG (3-methoxy-4-hydroxyphenolglycol), as a marker of sympathetic activity, and subclinical vascular disease risk in defensive coping Africans and Caucasians. METHODS: The Coping Strategy Indicator questionnaire identified participants who preferably utilise defensive coping. Ambulatory blood pressure was monitored for 24 h and carotid intima-media thickness (CIMT) was determined from ultrasound images, as an indicator of subclinical vascular disease risk. Salivary MHPG was analysed with high performance liquid chromatography. RESULTS: Defensive active coping Africans (n = 143) showed overall poorer health than Caucasians (n = 148), with higher self-reported stress, alcohol abuse, hypertension, abdominal obesity, and risk of diabetes (p <= 0.05). African women demonstrated lower levels of MHPG compared with Caucasian women, although no differences in men were found. Furthermore, Africans revealed a trend of increased low grade inflammation and glycated haemoglobin which was associated with increased CIMT. There was an inverse association between MHPG and CIMT [beta = -0.22 (-0.40, -0.03)], in African men with a high risk of subclinical vascular disease (n = 30). CONCLUSIONS: Novel findings revealed that defensive active coping Africans are more at risk of subclinical vascular disease, possibly resultant of autonomic exhaustion (decreased MHPG). When defensive coping fails, sympathetic hyperactivity may be followed by autonomic exhaustion and sympatho-adrenal-medullary system desensitisation, resulting in pathology. PMID- 23044097 TI - The calcium chloride-induced rodent model of abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) affects ~5% men aged over 65 years and is an important cause of death in this population. Research into AAA pathogenesis has been fuelled by the need to identify new diagnostic biomarkers and therapeutic targets for this disease. One animal model of AAA involves peri-vascular application of calcium chloride (CaCl(2)) onto the infra-renal aorta of mice and rats to induce extracellular matrix remodelling. Twenty-three studies assessing CaCl(2)-induced AAA and six studies assessing AAA induced by a modified CaCl(2) method were identified. In the current report the preparation and pathological features of this AAA model are discussed. We also compared this animal model to human AAA. CaCl(2)-induced AAA shows the following pathological characteristics typically found in human AAA: calcification, inflammatory cell infiltration, oxidative stress, neovascularisation, elastin degradation and vascular smooth muscle cell apoptosis. A number of mechanisms involved in CaCl(2)-induced AAA have been identified which may be relevant to the pathogenesis of human AAA. Key molecules include c-Jun N-terminal kinase, peroxisome proliferator-activated receptor-gamma, chemokine (C-C motif) receptor 2, group x secretory phospholipase A2 and plasminogen. CaCl(2)-induced AAA does not display aortic thrombus, atherosclerosis and rupture which are classical features of human AAA. Advantages of the CaCl(2)-induced AAA technique include (1) it can be applied to wild type mice making assessment of transgenic rodent models more straight forward and rapid; and (2) CaCl(2)-induced AAAs are usually developed in the infra-renal abdominal aorta, which is the most common location of human AAA. Currently findings obtained from the CaCl(2)-induced AAA model or other animal models of AAA have not been translated into the human situation. It is hoped that this deficiency will be corrected over the next decade with a number of clinical trials currently examining novel treatment options for AAA patients. PMID- 23044098 TI - A comparative study of the anticoagulant activities of eleven fucoidans. AB - Seven fucoidans that differed only with respect to the average molecular weight and four fucoidans that differed with respect to both the molar ratio of fucose to galactose and the average molecular weight were obtained. The anticoagulant activities of these fucoidans were determined in order to understand the effects of the average molecular weight and the content of galactose. Fucoidans Y5-Y11, with the average molecular weight in the range of 50.1-8.4 kDa, showed decreasing activity at three concentrations and dose-dependent activity in the APTT and TT assays. Y1-Y4, which differed with respect to the average molecular weight and the molar ratio of fucose to galactose, exhibited complicated results in the APTT and TT assays. It was shown that not only the average molecular weight but also the molar ratio of fucose to galactose affected the anticoagulant activity of fucoidans. PMID- 23044099 TI - Fabrication and properties of chitin/hydroxyapatite hybrid hydrogels as scaffold nano-materials. AB - Novel hybrid hydrogels were prepared by introducing nano-hydroxyapatite (nHAp) into chitin solution dissolved in NaOH/urea aqueous solution at low temperature, and then by cross-linking with epichlorohydrin (ECH). Their structure and morphology were characterized by FTIR spectra, wide-angle X-ray diffraction (WAXD), thermo-gravimetric analysis (TGA), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Our findings revealed that hydroxyapatite nano-particles were uniformly dispersed in chitin hydrogel networks. The chitin/nHAP hybrid hydrogel (Gel2) exhibited about 10 times higher mechanical properties (compressive strength: 274 kPa) than that of chitin hydrogel. Moreover, COS-7 cell culture experiment proved that cells could adhere and proliferate well on the chitin/nHAp hydrogels, suggesting good biocompatibility. All these results signified that these bio-materials could be potential candidates as scaffolds for tissue engineering. PMID- 23044100 TI - Characterization of conducting cellulose acetate based polymer electrolytes doped with "green" ionic mixture. AB - Polymer electrolytes were developed by solution casting technique utilizing the materials of cellulose acetate (CA), lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and deep eutectic solvent (DES). The DES is synthesized from the mixture of choline chloride and urea of 1:2 ratios. The increasing DES content well plasticizes the CA:LiTFSI:DES matrix and gradually improves the ionic conductivity and chemical integrity. The highest conducting sample was identified for the composition of CA:LiTFSI:DES (28 wt.%:12 wt.%:60 wt.%), which has the greatest ability to retain the room temperature ionic conductivity over the entire 30 days of storage time. The changes in FTIR cage peaks upon varying the DES content in CA:LiTFSI:DES prove the complexation. This complexation results in the collapse of CA matrix crystallinity, observed from the reduced intensity of XRD diffraction peaks. The DES-plasticized sample is found to be more heat-stable compared to pure CA. Nevertheless, the addition of DES diminishes the CA:LiTFSI matrix's heat-resistivity but at the minimum addition the thermal stability is enhanced. PMID- 23044101 TI - Bacterial exopolysaccharide based nanoparticles for sustained drug delivery, cancer chemotherapy and bioimaging. AB - Introduction of a novel biocompatible, stable, biomaterial for drug delivery application remains always challenging. In the present study, we report the synthesis of an extremophilic bacterial sulfated polysaccharide based nanoparticle as a stable biocompatible material for drug delivery, evaluation of anticancer efficacy and bioimaging. Mauran (MR), the sulfated exopolysaccharide extracted from a moderately halophilic bacterium, Halomonas maura was used for the synthesis of nanoparticles along with chitosan (CH). MR/CH nanoparticles were synthesized by simple polyelectrolyte complexation of anionic MR and cationic CH. The MR/CH hybrid nanoparticles formed were ranging between 30 and 200 nm in diameter with an overall positive zeta potential of 27.5+/-5 mV and was found to be stable under storage in solution for at least 8 weeks. In vitro drug release studies showed a sustained and prolonged delivery of 5-fluorouracil (5FU) for 10 12 days from MR/CH nanoparticles under three different pHs of 4.5, 6.9 and 7.4 respectively. Cytotoxicity assay revealed that MR/CH nanoparticles were non cytotoxic towards normal cells and toxic to cancer cells. Also, 5FU loaded MR/CH nanoparticles were found more effective than free 5FU in its sustained and controlled manner of killing breast adenocarcinoma cells. Fluorescein isothiocyanate (FITC) labeled MR/CH nanoparticles were used for cell binding and uptake studies; thereby demonstrating the application of dye tagged MR/CH nanoparticles for safe and nontoxic mode of live cellular imaging. We report the introduction of an extremophilic bacterial polysaccharide, MR, for the first time as a novel biocompatible and stable biomaterial to the world of nanotechnology, pharmaceutics and biomedical technology. PMID- 23044102 TI - Free radical scavenging and immunomodulatory activities of Ganoderma lucidum polysaccharides derivatives. AB - Polysaccharides extracted from the fruit body of Ganoderma lucidum were sulfated and carboxymethylated as reported. Free radical scavenging and immunomodulatory effects of sulfated and carboxymethylated polysaccharides were studied. Generally, sulfated polysaccharides showed better bioactivities than that of carboxymethylated polysaccharides. The two derivatives were injected intraperitoneally with or without 5-fluorouracil over a period of 7 days in BALB/c female mice. The polysaccharide derivatives increased mouse thymus and spleen index, an indication of improved immunity in mice. At the same time, they improved superoxide dismutase and glutathione peroxidase contents in the mice body. PMID- 23044103 TI - Corn starch granules with enhanced load-carrying capacity via citric acid treatment. AB - This research investigated conditions by which maize starch granule porosity and load-carrying capacity (LCC) might be enhanced via treatment with varying citric acid concentrations (0.5-1.5 M), temperatures (40-60 degrees C), and lengths of treatment (1-8 h). At the lowest temperatures (40 and 50 degrees C), citric acid treatment induced minimal physicochemical changes to granules. In contrast, both aqueous and oil LCCs of starches treated at 60 degrees C (0.5 M citric acid, 2 h) were almost doubled (15.69 and 14.48 mL/10 g starch, respectively), recovering 92% of the granular starch after treatment. Such treatment increased starch hydration capacity (0.97-1.91) and reduced gelatinization enthalpy (10.6-7.4 J/g). More severe treatment conditions adversely impacted aqueous LCC (due to excessive granule swelling), but improved oil absorption. The basis for LCC enhancement by citric acid treatment was ascribed to leaching of starch material from granules and partial disruption of the granule crystalline structure, as opposed to starch hydrolysis or chemical substitution. PMID- 23044104 TI - Development and evaluation of 5-fluorouracil loaded chitin nanogels for treatment of skin cancer. AB - This study focuses on development and evaluation of 5-fluorouracil (5-FU) loaded chitin nanogels (FCNGs). It formed good, stable aqueous dispersion with spherical particles in 120-140 nm size range and showed pH responsive swelling and drug release. The FCNGs showed toxicity on melanoma (A375) in a concentration range of 0.4-2.0mg/mL, but less toxicity toward human dermal fibroblast (HDF) cells by MTT assay. Confocal analysis revealed uptake of FCNGs by both cells. From skin permeation experiments, FCNGs showed almost same steady state flux as that of control 5-FU but the retention in the deeper layers of skin was found to be 4-5 times more from FCNGs. Histopathological evaluation revealed loosening of the horny layer of epidermis by interaction of cationically charged chitin, with no observed signs of inflammation and so FCNGs can be a good option for treatment of skin cancers. PMID- 23044105 TI - Trimethyl and carboxymethyl chitosan carriers for bio-active polymer-inorganic nanocomposites. AB - The carrier properties of carboxymethyl chitosan (CMC) and trimethyl chitosan (TMC) in combination with polyoxometalates (POMs) as inorganic drug prototypes are compared with respect to the influence of polymer matrix charge and structure on the emerging composites. A direct crosslinking approach with TMC and K(6)H(2)[CoW(11)TiO(40)].13H(2)O ({CoW(11)TiO(40)}) as a representative anticancer POM affords nanocomposites with a size range of 50-90nm. The obtained POM-chitosan composites are characterized with a wide range of analytical methods, and POM encapsulation into positively charged TMC brings forward different nanocomposite morphologies and properties than CMC as a carrier material. Furthermore, uptake of fluorescein isothiocyanate (FITC) labeled POM CMC and POM-TMC by HeLa cells was monitored, and the influence of chlorpromazine (CP) as inhibitor of the clathrin mediated pathway revealed different cellular uptake behavior of composites and pristine carriers. TMC/{CoW(11)TiO(40)} nanocomposites are taken up by HeLa cells after short incubation times around 30 min at low concentrations. The anticancer activity of pristine {CoW(11)TiO(40)} and its TMC-nanocomposites was investigated in vitro with MTT assays and compared to a reference POM. PMID- 23044106 TI - Atractylodis macrocephalae Koidz. polysaccharides enhance both serum IgG response and gut mucosal immunity. AB - Fifty-six mice were randomly divided into four groups with 14 mice in each. Two groups were subcutaneously injected twice with a foot-and-mouth disease vaccine with 2-week intervals; each of them had been orally administered 0.89% saline or Atractylodis macrocephalae Koidz. polysaccharides (RAMPS) 0.05 g for 4 days before immunization. The rest were not immunized but treated in the same way. One week after the primary and two weeks after the booster immunization, half in each group were sacrificed to measure serum IgG and the parameters for the intestinal mucosal immunity. Results indicated that oral administration of RAMPS increased both serum specific IgG response and intestinal mucosal immunity as shown by elevated total sIgA, mRNA expression of TGF-beta, IL-6, TNF-alpha, IgA(+) cells and intestinal intraepithelial lymphocytes in duodenum. It is suggested that increased serum IgG response may be associated with enhanced local mucosal immunity by oral administration of RAMPS. PMID- 23044107 TI - Removal of anionic dyes from aqueous solutions by an ion-exchanger based on pullulan microspheres. AB - Pullulan-graft-poly(3-acrylamidopropyl trimethylammonium chloride) (P-g-pAPTAC) microspheres were prepared by suspension cross-linking of the pullulan previously grafted with cationic moieties. Adsorption of Azocarmine B by the P-g-pAPTAC microspheres was used as a model to demonstrate the removal of anionic dyes from aqueous solutions. Batch adsorption studies concerning the effect of the contact time, pH, initial dye concentration, temperature, grafting, and the nature of sulfonated anionic dyes on the adsorption kinetics were investigated. Adsorption was shown to be independent of pH. The experimental data best fitted to the pseudo-second order model which provided values of the rate constant k(2) of 1.4*10(-4) g mg(-1) min(-1) for 100 mg L(-1) solution and of 3.7*10(-4) g mg(-1) min(-1) for 500 mg L(-1) solution. From the Langmuir isotherm linear equation, the maximum adsorption capacity determined was 113.63 mg of Azocarmine B per gram of adsorbent; the negative value of the free energy change indicated the spontaneous nature of the adsorption process. PMID- 23044108 TI - Rice starch vs. rice flour: differences in their properties when modified by heat moisture treatment. AB - Starch and flour from the same rice grain source (with 20, 25 and 30% moisture content) were exposed to heat-moisture treatment (HMT) at 100 degrees C for 16 h in order to investigate whether there were differences in their susceptibility to modification by HMT and, if any, to determine the main causes of the differences. HMT had a far greater effect on paste viscosity of flour than of starch. A significant increase in paste viscosity after removal of proteins from HMT flour as well as images of fast green-stained HMT flour gels - indicated that an important role was played by proteins in affecting properties of the modified samples. Greater effects of HMT on thermal parameters of gelatinization and gel hardness values of flours were observed - more so than those for starches. Following this observation, it was ascertained that components in rice flour other than rice starch granules also underwent alterations during HMT. PMID- 23044109 TI - Sulfated chitosan as tear substitute with no antimicrobial activity. AB - Chitosan of high molar mass and with 82% deacetylation was sulfated using two procedures and characterized. In the first method sample chitosan-S1 was produced using chlorosulfonic acid as the sulfating agent and N,N-dimethylformamide as the medium, and in the second method (chitosan-S2) formic acid was also used. The degrees of sulfation were 0.87 (chitosan-S1) and 0.67 (chitosan-S2). FTIR spectra showed bands at 1230, 800 and 580 cm(-1), attributed to sulfation. Moisture content followed the order: chitosan-S-0.87>chitosan-S-0.67>chitosan. Chain depolymerization was verified by GPC. Aqueous solutions showed pseudoplastic behavior and the viscosity at a concentration of 0.3% (w/v) was higher than that of healthy human tears (close to 3 mPas at shear rate 130 s(-1)). Substitutions in the C2NH and in C6OH groups were verified by NMR. Antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa was not observed. Considering that chitosan-S-0.67 had a higher solubility, less chain depolymerization, higher yield and better thermal stability in comparison with chitosan-S-0.87, the derivative with DS 0.67 offered the greatest potential for use in formulations of tear substitutes. PMID- 23044111 TI - Interactions with beta-cyclodextrin as a way for encapsulation and separation of camphene and fenchene. AB - The separation of isomeric monoterpenes, camphene and fenchene by complexation with beta-cyclodextrin is presented. Both of the monoterpenes form complexes with beta-cyclodextrin (as shown by both gas chromatography and (1)H NMR) with similar stability constants nevertheless it is possible to separate them by re crystallization. The crystal structure of beta-cyclodextrin with fenchene was also studied by X-ray diffraction. PMID- 23044110 TI - kappa-Carrageenan hydrogel nanocomposites with release behavior mediated by morphological distinct Au nanofillers. AB - In this work we investigate the effect of spherical and rod-shaped Au nanoparticles (NPs) in the microstructure, thermomechanical and release properties of thermosensitive kappa-carrageenan hydrogels. Thermal and mechanical analyses of the composites revealed that the Au NPs reinforce the structure of the hydrogel and the mechanism of gel reinforcement is discussed. The effect of the NPs on the microstructure and strength of the hydrogel had implications in the mechanism of controlled release as demonstrated by in vitro release studies using a drug model (methylene blue: MB). Noteworthy, the mechanism of MB release followed either a diffusion or polymer relaxation mechanism, depending on the morphology of the Au NPs incorporated in the hydrogel. Consequently, kappa carrageenan hydrogels containing Au NPs exhibited not only optical features modulated by the fillers morphology, but also showed a behavior as drug carriers that can be also adjusted by Au NPs characteristics. PMID- 23044112 TI - Facile and durable antimicrobial finishing of cotton textiles using a silver salt and UV light. AB - In this study, we present facile antimicrobial finishing of cotton textiles. Screen printing was used for surface-finishing of cotton using a printing paste containing silver nitrate. UVC irradiation was applied to convert silver nitrate into a color product, thus also changing the color of the textiles. The color, its strength and stability of samples, depend on absorbed UVC energy and the formula of the printing paste. Scanning electron microscopy with the energy dispersive X-ray spectrometry revealed formation of silver particles on cotton threads; X-ray diffraction analysis and the time-of-flight secondary ion mass spectrometry did not provide clear information on these products. Microbiological studies revealed that the samples inhibited proliferation of Escherichia coli, Bacillus subtilis and Staphylococcus aureus. Washing fastness tests confirmed resistance of the samples to at least 50 washings. Additionally, the inhibition zones increased as the number of washing cycles increased, which is unique for such samples. This work also presents an approach to the design of antimicrobially finished workwear. PMID- 23044113 TI - Structure characterization of an exopolysaccharide produced by Bifidobacterium animalis RH. AB - An exopolysaccharide fraction (EPSb) produced by Bifidobacterium animalis RH isolated from the feces of centenarians was purified to illustrate its structure and conformational characterization. Results from Fourier-transform infrared spectrometry, gel permeation chromatography, high-pH anion-exchange chromatography with pulsed amperometric detection, periodate oxidation and Smith degradation, methylation and gas chromatography-mass spectrometry, and nuclear magnetic response analysis indicated that EPSb (M(w)=21.3 kDa) was composed of rhamnose (Rha), arabinose (Ara), galactose (Gal), glucose (Glc), and mannose (Man) in a molar ratio of 0.4:0.3:1.6:0.8:1.2. This compound had a backbone of (1 >3,4)-linked Man, (1->4)-linked Rha, (1->4)-linked Gal, and (1->4)-linked Glc. It was branched with Gal and terminated with Gal and Glc residues. The molecular structure of EPSb was observed via atomic force microscopy. EPSb showed spherical lumps and a ring-like network. Conformational analysis revealed the non-triple helical conformation of EPSb. PMID- 23044114 TI - Blends of cross-linked high amylose starch/pectin loaded with diclofenac. AB - Polymers blends represent an important approach to obtain materials with modulated properties to reach different and desired properties in designing drug delivery systems in order to fulfill therapeutic needs. The aim of this work was to evaluate the influence of drug loading and polymer ratio on the physicochemical properties of microparticles of cross-linked high amylose starch pectin blends loaded with diclofenac for further application in controlled drug delivery systems. Thermal analysis and X-ray diffractograms evidenced the occurrence of drug-polymer interactions and the former pointed also to an increase in thermal stability due to drug loading. The rheological properties demonstrated that drug loading resulted in formation of weaker gels while the increase of pectin ratio contributes to origin stronger structures. PMID- 23044115 TI - N,O6-partially acetylated chitosan nanoparticles hydrophobically-modified for controlled release of steroids and vitamin E. AB - Diosgenin, two synthetic analogs of brassinosteroids, testosterone and dl-alpha tocopherol were covalently linked to synthetic water-soluble N,O6-partially acetylated chitosan, for their controlled release. Drug linking was confirmed by FTIR spectroscopy and proton NMR. Conjugates were also characterized by differential scanning calorimetry and wide-angle X-ray diffraction. These conjugates formed self-assembled nanoparticles in aqueous solution with particle sizes ranging from 197 to 358 nm and drug contents between 11.8 and 56.4% (w/w). Spherical 30-60 nm nanoparticles were observed by scanning electron microscopy and transmission electron microscopy upon drying. In vitro release studies performed at acid pH indicated a drug release dependence on substitution degree and particle sizes. Almost constant release rates were observed during the first 6-8h. Brassinosteroids-modified nanoparticles showed good agrochemical activity in radish seeds bioassay at 10(-1) to 10(-4) mg mL(-1). Tocopheryl-modified nanoparticles exhibited radical scavenging activity in DPPH test. PMID- 23044116 TI - Synthesis of chitosan-stabilized gold nanoparticles by atmospheric plasma. AB - We report a facile method to prepare gold nanoparticles by atmospheric plasma. Chitosan, was used as a stabilizing agent and gold precursor. In chitosan solution was reduced by atmospheric plasma at room temperature. We find the plasma treatment is effective for reducing the gold precursor and the process only takes minutes. The obtained gold nanoparticles were characterized with UV vis spectroscopy and transmission electron microscopy. The results indicated that the morphology and size distribution of gold nanoparticles prepared varied with treatment time and the ratio of chitosan to precursor metal salts. Additionally, a preliminary study on air component analysis indicated that the moisture in air plays an important role in producing the active ingredient for the production of gold nanoparticles. PMID- 23044117 TI - Direct saccharification and ethanol fermentation of cello-oligosaccharides with recombinant yeast. AB - Ethanol was produced at good rates by direct saccharification and fermentation of cello-oligosaccharides with pYBGA1 yeast, a recombinant laboratory yeast expressing beta-glucosidase. Cellobiose in the concentration of 50 g/L was directly fermented for 60 h with 1*10(8) cells/mL of pYBGA1 yeast at 30 degrees C to give ethanol at an 80% theoretical conversion rate and a concentration of more than 20 g/L of concentration. Conversion to ethanol increased with increasing cellobiose concentration in the feed. When cellobiose was used at the concentration of 100g/L, ethanol conversion and concentration increased to 85% and 45 g/L, respectively, in 96 h incubation. Other cello-oligosaccharides, cellotriose, cellotetraose, and cellopentaose at the concentration of 50 g/L, respectively, were also fermented directly for 72 h with 1*10(8) cells/mL of pYBGA1 yeast to produce ethanol in the conversion rates and concentrations of 71 73% and 18.0-18.5 g/L, respectively. The direct saccharification and fermentation mechanism of cello-oligosaccharides with pYBGA1 yeast, as revealed by HPLC measurements, suggesting that cellotetraose, for example, was saccharificated to cellotriose, cellobiose, and glucose and then fermented to give ethanol. These results suggest that the direct saccharification and fermentation of cello oligosaccharides with pYBGA1 has several advantages as a simple procedure and for time, cost, and energy consumptions. PMID- 23044118 TI - Microwave synthesis of cellulose/CuO nanocomposites in ionic liquid and its thermal transformation to CuO. AB - The purpose of this study is to develop a green strategy to synthesize the cellulose-based nanocomposites and open a new avenue to the high value-added applications of biomass. Herein, we reported a microwave-assisted ionic liquid route to the preparation of cellulose/CuO nanocomposites, which combined three major green chemistry principles: using environmentally friendly method, greener solvents, and sustainable resources. The influences of the reaction parameters including the heating time and the ratio of cellulose solution to ionic liquid on the products were discussed by X-ray powder diffraction, Fourier transform infrared spectrometry, and scanning electron microscopy. The crystallinity of CuO increased and the CuO shape changed from nanosheets to bundles and to particles with increasing heating time. The ratio of cellulose solution to ionic liquid also affected the shapes of CuO in nanocomposites. Moreover, CuO crystals were obtained by thermal treatment of the cellulose/CuO nanocomposites at 800 degrees C for 3 h in air. PMID- 23044119 TI - Novel bio-antifelting agent based on waterborne polyurethane and cellulose nanocrystals. AB - Novel nanocomposites made from cellulose nanocrystals and waterborne polyurethane were employed as wool antifelting agents. The cellulose nanocrystals, prepared by acid hydrolysis of cellulose microcrystalline, are in rod form with lengths of 70 150 nm and diameters of 10-20 nm in aqueous suspension, respectively. After the two aqueous suspensions were mixed homogeneously, cellulose nanocrystal reinforced polyurethane composite (nanocomposite) films were prepared and evaluated by means of transmission electron microscopy, scanning electron microscopy and dynamic mechanical analysis. Then the nanocrystal films were applied onto surfaces of wools by a pad-dry-cure process with nanocomposites containing different cellulose nanocrystal contents. The results indicated that with increasing cellulose nanocrystal content from 0 to 1.0 wt%, the area shrinking rate of the treated wool fabrics was decreased from 5.24% to 0.70%, and the tensile strength of the fabric was increased by 14.95% and decreased about 44% use of waterborne polyurethane. PMID- 23044120 TI - Pectic-oligosaccharides prepared by dynamic high-pressure microfluidization and their in vitro fermentation properties. AB - Pectic-oligosaccharides (POSs) were prepared from apple pectin by dynamic high pressure microfluidization (DHPM). Operating under selected conditions (pectin concentration 1.84%, solution temperature 63 degrees C, DHPM pressure 155MPa and number of cycles 6 passes), 32.92% of the pectin was converted into POS. The resulting POS contains 29.56% galacturonic acid and 58.53% neutral sugars. The prebiotic properties of POS were then evaluated using a fecal batch culture fermentation. The POS increased the number of Bifidobacteria and Lactobacilli, and produced a higher concentration of acetic, lactic, and propionic acid than their parent pectin. Furthermore, POS decreased the number of Bacteroides and Clostridia while their parent pectin increased them. Moreover, the effects of POS on the growth of these bacteria and production of short-chain fatty acids are comparable to those of the most studied prebiotic, fructooligosaccharide. These results indicated that the POS prepared by DHPM has a potential to be an effective prebiotic. PMID- 23044121 TI - Network formation of nanofibrillated cellulose in solution blended poly(methyl methacrylate) composites. AB - Composites of poly(methyl methacrylate) (PMMA) and nanofibrillated cellulose (NFC) were prepared by solution blending and further processed by injection and compression molding. To improve adhesion at the PMMA/NFC interface, the nanofibrils were covalently grafted with PMMA. Formation of a percolating nanofibril network was observed between 1 and 5 wt.% of NFC by dynamic rotational rheometry in molten state. This observation was further supported by the behavior of glass transition temperature which decreased at low NFC concentrations but recovered above the percolation threshold, indicating a decreased mobility of the matrix polymer. This effect was more pronounced with ungrafted NFC, possibly due to a stronger network. The unmodified NFC induced a minor degradation of the molar mass of PMMA. As thin plates, the composites were transparent at low NFC concentrations but became partially aggregated at the highest NFC concentrations. Despite the continuous NFC network, tensile testing showed no improvement of the mechanical properties. PMID- 23044122 TI - Biochemical activities of 6-carboxy beta-chitin derived from squid pens. AB - TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical)-mediated 6-carboxy beta chitin derivatives (T-chitin) with different carboxylate content were successfully synthesized by controlling the addition level of NaClO as the primary oxidant. The structural and biochemical properties of the derivatives were investigated. The carboxylate contents of the derivatives calculated by electrical conductivity titration were 1.33, 1.68, 1.80, and 2.08 mmol/g, respectively. The yield of T-chitin with carboxylate content of 2.08 mmol/g reached 74.55%. T-chitin exhibited stronger bile acid binding capacities than that of beta-chitin. The scavenging ability of T-chitin against hydroxyl radicals improved with increasing concentration, and EC(50) values were below 1.2 mg/mL. All T-chitin exhibited a strong ferrous ion chelating effect. At 8 mg/mL, the chelating effects of T-chitin with carboxylate content of 0.81 mmol/g reached 80.15%. These results showed that T-chitin had good bile acid binding capacity and antioxidant activities and it may be a potential antioxidant in vitro. PMID- 23044123 TI - Optimization of chitosan and beta-cyclodextrin molecularly imprinted polymer synthesis for dye adsorption. AB - In this study, two types of novel molecularly imprinted polymers (MIPs) were prepared, for toxic and carcinogenic dyes adsorption. Substrates of the polymeric matrix of the two MIPs were beta-cyclodextrin and chitosan. The conditions in the polymerization/imprinting stage and in the rebinding/adsorption step were optimized. The effect of a range of parameters (polymer, cross-linker, and initiator concentrations, reaction time and pH) on the selectivity and adsorption capacity of the dye-MIPs were investigated. Their dye rebinding properties were demonstrated by equilibrium batch experiments (fitting with Freundlich model) and their kinetic rates were exported by the pseudo-first order model. Additionally, a thermodynamic evaluation was carried out through the determination of enthalpy, entropy, and free energy. The selectivity of MIPs was elucidated by their different rebinding capabilities in a trichromatic mixture (composed of related structurally dyes). Regeneration/reuse of the dye-loaded polymers was evaluated via sequential adsorption-desorption cycles. PMID- 23044124 TI - Mutational analysis and characterization of dextran synthesizing enzyme from wild and mutant strain of Leuconostoc mesenteroides. AB - Dextransucrase producing Leuconostoc mesenteroides KIBGE IB-22 was subjected to mutagenesis by exposing the strain to UV irradiation. The dextransucrase produced by both the strains (wild and mutant) were characterized and the catalytic properties of both wild and mutant dextransucrase were compared. Among 42 mutants, KIBGE IB-22M20 exhibited 6.75 times increase in dextransucrase activity as compared to the wild one. Wild dextransucrase showed specific activity of 31.3 DSU/mg of protein with V(max) and K(m) of 18.84 DSU/ml/h and 77.09 mM, respectively at 30 degrees C in 0.3 M citrate buffer (pH 4.5) using sucrose as substrate. Whereas, mutant dextransucrase exhibited a specific activity of 173.2 DSU/mg with V(max) and K(m) values of 104.2DSU/ml/h and 101.7 mM, respectively at 35 degrees C in 0.3 M citrate buffer (pH 5.0) keeping the same substrate as for wild. Dextransucrase from both wild and mutant showed an approximate molecular weight of 221 kDa by SDS-PAGE. PMID- 23044125 TI - beta-Cyclodextrin-based oil-absorbent microspheres: preparation and high oil absorbency. AB - This article reports the preparation and evaluation of polymeric microspheres as a new class of oil-absorbent (POAMs). Based on our earlier oil-absorbents, the present microspheres contained beta-cyclodextrin (beta-CD) moieties as both cross linking agent and porogen agent, and showed exciting high oil absorbency, fast oil absorption speed and good reusability. Such microspheres were prepared via suspension polymerization with octadecyl acrylate and butyl acrylate as co monomers, beta-CD derivative as cross-linking agent, 2,2'-azoisobutyronitrile as initiator and polyvinylalcohol as stabilizer. Oil absorbency of the POAMs was, for CCl(4), 83.4; CHCl(3), 75.1; xylene, 48.7; toluene, 42.8; gasoline, 30.0; kerosene 27.1; and diesel, 18.2 g/g (oil/POAMs). Saturation oil absorption reached within 3h in CCl(4). The POAMs exhibited high oil retention percentage (>90%), and can be reused for at least 10 times while keeping oil absorbency almost unchanged. PMID- 23044126 TI - The preparation and characterization of liquefied wood based primary fibers. AB - The preparation of primary fibers were performed from liquefied wood in phenol by melt-spinning with different spinnerettes of length/diameter ratio (L/D) (0, 2, and 4), to investigate the effect of the size of spinnerette on the thermal stability and structural properties of primary fibers. High thermal transition temperatures and small weight loss percentages of resultant primary fibers representing good thermal stability were obtained with L/D of spinnerette increasing. Besides, few defective structure occurred on cross section and surface of primary fibers in comparison with those prepared with spinnerette of L/D=0. We found that these improvements were caused by the formation of hydrogen bond among phenolic hydroxyl groups in the period of flow entering the cylindrical die of spinnerette. Thus, the precursor, with either porous structure for preparing activated carbon fibers or defect-free structure for preparing carbon fibers with high performance, can be probably prepared by controlling the spinnerette system. PMID- 23044127 TI - Extraction and characterization of nanocellulose structures from raw cotton linter. AB - This study aimed to characterize nanocellulose extracted from cotton (Gossypium hirsutum) linters. The nanocellulose was subjected to electronic microscopy, thermal analysis, X-ray diffractometry, light scattering, and contact angle. The properties of the nanocellulose are considerably different from the linter. The acidic hydrolyses applied to extract the nanocrystals increased the crystallinity index and the hydrophilicity and decreased the thermal stability. On average, the nanocrystals were 177 nm long and 12 nm wide, with an aspect ratio of 19 when measured by microscopy. The light scattering results were coherent with the crystal dimensions. Cotton linter is a potential source of nanocellulose crystals, particularly to be used in the production of hydrophilic nanocomposites. Extraction of nanocellulose from raw cotton linter does not require pulping. PMID- 23044128 TI - Chitosan-caffeic acid-genipin films presenting enhanced antioxidant activity and stability in acidic media. AB - The use of chitosan films has been limited due to their high degradability in aqueous acidic media. In order to produce chitosan films with high antioxidant activity and insoluble in acid solutions caffeic acid was grafted to chitosan by a radical mechanism using ammonium cerium (IV) nitrate (60 mM). Genipin was used as cross-linker. This methodology originated films with 80% higher antioxidant activity than the pristine film. Also, these films only lost 11% of their mass upon seven days immersion into an aqueous solution at pH 3.5 under stirring. The films surface wettability (contact angle 105 degrees ), mechanical properties (68 MPa of tensile strength and 4% of elongation at break), and thermal stability for temperatures lower than 300 degrees C were not significantly influenced by the covalent linkage of caffeic acid and genipin to chitosan. Due to their characteristics, mainly higher antioxidant activity and lower solubility, these are promising materials to be used as active films. PMID- 23044129 TI - Development and in vitro evaluation of coated pellets containing chitosan to potential colonic drug delivery. AB - In this work pellets containing chitosan for colonic drug delivery were developed. The influence of the polysaccharide in the pellets was evaluated by swelling, drug dissolution and intestinal permeation studies. Drug-loaded pellets containing chitosan as swellable polymer were coated with an inner layer of Kollicoat((r)) SR 30 D and an outer layer of the enteric polymer Kollicoat((r)) MAE 30 DP in a fluidized-bed apparatus. Metronidazole released from pellets was assessed using Bio-Dis dissolution method. Swelling, drug release and intestinal permeation were dependent on the chitosan and the coating composition. The drug release data fitted well with the Weibull equation, indicating that the drug release was controlled by diffusion, polymer relaxation and erosion occurring simultaneously. The film coating was found to be the main factor controlling the drug release and the chitosan controlling the drug intestinal permeation. Coated pellets containing chitosan show great potential as a system for drug delivery to the colon. PMID- 23044130 TI - Plasticized-starch/poly(ethylene oxide) blends prepared by extrusion. AB - Blends based on plasticized-wheat starch (as matrix or rich phase) and poly(ethylene oxide) (PEO) (as dispersed phase) were prepared by melt processing in a twin-screw extruder. The extrusion of the plasticized-starch is significantly facilitated by blending with PEO. Plasticized-starch and PEO are immiscible in the range of the investigated blend ratios (90/10-50/50). The phase inversion takes place when the PEO content is 50 wt.% in the blend. Both the thermal stability and the tensile properties of plasticized-starch are improved by blending with PEO. Also, a synergistic effect between plasticized-starch and PEO is noticed at 25-40 wt.% PEO content in the blend, the Young's modulus of the materials obtained being the highest and higher than both neat polymer components at those blending ratios. PMID- 23044131 TI - Antioxidant activity and potential hepatoprotective effect of polysaccharides from Cyclina sinensis. AB - In the present study, we investigated the preliminary structure, in vitro antioxidant and in vivo hepatoprotective activities of polysaccharides from Cyclina sinensis (CSPS). The analytic results of Fourier transform-infrared spectroscopy indicated the presence of alpha-type glycosidic linkages in CSPS-1 or CSPS-2, and the average molecular weights for CSPS-1, CSPS-2 and CSPS-3 were 69, 81 and 101 kDa, respectively. For antioxidant activities in vitro, crude CSPS, CSPS-1, CSPS-2 and CSPS-3 showed moderate H(2)O(2) scavenging activity, lipid peroxidation inhibition effect and strong Fe(2+) chelating activity. For hepatoprotective activity in vivo, the administration of CSPS significantly decreased serum levels of alanine aminotransferase and aspartate aminotransferase, inhibited the formation of malondialdehyde and enhanced the activities of liver superoxide dismutase and glutathione peroxidase in carbon tetrachloride-induced liver injury mice. These results suggested that CSPS had potent antioxidant and hepatoprotective activities. PMID- 23044132 TI - Long-alkane-chain modified N-phthaloyl chitosan membranes with controlled permeability. AB - A series of N-phthaloyl acylated chitosan membranes with controlled permeability were synthesized by the regioselective protection of the chitosan amino groups as the corresponding phthalimides followed by reaction with the long-chain dodecanoyl chloride. Fourier transform infrared (FT-IR) and (1)H nuclear magnetic resonance ((1)H NMR) analysis suggested that the degree of substitution (DS) ranged from 2.8 to 3.6. Contact angles, water retention values and mechanical examinations demonstrated that the hydrophobicity and mechanical properties of the membranes were all improved significantly following the modifications, together with their solubility in many organic solvents. Thermal weight change analysis demonstrated that a higher DS provided enhanced thermal properties. The controlled permeability of the membranes was determined by measuring the diffusion of urea, and the amount of urea released decreased significantly with increasing DS. The comprehensive properties of the membranes could be tuned by regulating their DS values as required. PMID- 23044133 TI - Synthesis and urea sustained-release behavior of an eco-friendly superabsorbent based on flax yarn wastes. AB - In order to develop an eco-friendly superabsorbent composite, flax yarn waste (FYW) was used as raw material to synthesize a novel flax yarn waste-g poly(acrylic acid-co-acrylamide) (FYW/PAA) superabsorbent composite. Acrylic acid (AA) and acrylamide (AM) were grafted onto the pretreated flax yarn waste (PFYW) by free-radical graft copolymerization in homogeneous aqueous solution. The properties and synthesis conditions of the FYW/PAA superabsorbent composite were investigated. As a result, the prepared FYW/PAA attained the best water absorbency of 875 g/g in distilled water, 490 g/g in rainwater and 90 g/g in 0.9 wt% NaCl solution. The urea loading percentage of FYW/PAA could be modulated by the concentration of urea. The release of urea from FYW/PAA in water showed a typical three-stages sustained release behavior. Meanwhile, a weight residue of 53.6 wt% was attained after being buried in soil for 90 d. PMID- 23044134 TI - Polycaprolactone and polycaprolactone/chitosan nanofibres functionalised with the pH-sensitive dye Nitrazine Yellow. AB - Nanofibres functionalised with pH-sensitive dyes could greatly contribute to the development of stimuli-responsive materials. However, the application of biocompatible polymers is vital to allow for their use in (bio)medical applications. Therefore, this paper focuses on the development and characterisation of pH-sensitive polycaprolactone (PCL) nanofibrous structures and PCL/chitosan nanofibrous blends with 20% chitosan. Electrospinning with added Nitrazine Yellow molecules proved to be an excellent method resulting in pH responsive non-wovens. Unlike the slow and broad response of PCL nanofibres (time lag of more than 3h), the use of blends with chitosan led to an increased sensitivity and significantly reduced response time (time lag of 5 min). These important effects are attributed to the increased hydrophilic nature of the nanofibres containing chitosan. Computational calculations indicated stronger interactions, mainly based on electrostatic interactions, of the dye with chitosan (DeltaG of -132.3 kJ/mol) compared to the long-range interactions with PCL (DeltaG of -35.6 kJ/mol), thus underpinning our experimental observations. In conclusion, because of the unique characteristics of chitosan, the use of PCL/chitosan blends in pH-sensitive biocompatible nanofibrous sensors is crucial. PMID- 23044135 TI - Amphoteric amylopectin: a novel polymeric flocculant. AB - Novel flocculant based on amphoteric amylopectin for wastewater and industrial effluents treatment has been developed in authors' laboratory. Amphoteric flocculants have anionic and cationic moieties on the same macromolecule and is used to remove both positively and negatively charged contaminant particles in suspensions. Amylopectin based flocculants have been found to be highly efficient flocculant and hence it has been chosen as base polysaccharide. By grafting of polyacrylamide and subsequent hydrolysis, anionic amylopectin has been synthesized. Afterwards, a cationic moiety has been inserted both by chemical/microwave processing. The flocculation efficiency of the amphoteric amylopectin has been tested in kaolin and iron ore suspensions. The results indicate its high efficiency in comparison with anionic, grafted, and base amylopectin. The amphoteric amylopectin prepared via microwave irradiation showed best flocculation efficiency. PMID- 23044136 TI - High production of cellulose degrading endo-1,4-beta-D-glucanase using bagasse as a substrate from Bacillus subtilis KIBGE HAS. AB - Sugarcane bagasse is a cheap carbon source for endo-1,4-beta-D-glucanase production as it is easily available as by-product from sugar industries. Fermentation conditions for endo-1,4-beta-D-glucanase production by Bacillus subtilis KIBGE HAS were optimized by using un-treated sugarcane bagasse for induction of endo-1,4-beta-D-glucanase and it was found that 2.0 g% bagasse in fermentation medium induced maximum endo-1,4-beta-D-glucanase production. It was also found that when sugarcane bagasse was supplemented with different carbon sources, the results showed that lactose, xylose, maltose and sucrose favored endo-1,4-beta-D-glucanase production, whereas cellobiose and fructose inhibit enzyme production. Maximum endo-1,4-beta-D-glucanase production was obtained at 40 degrees C keeping the initial pH of the medium at 7.0 before sterilization. Maximum endo-1,4-beta-D-glucanase production was obtained after 48 h incubation. Among different nitrogen sources, ammonium nitrate enhanced endo-1,4-beta-D glucanase production. The optimal temperature and pH for enzyme activity were 60 degrees C and 7.0, respectively. PMID- 23044137 TI - Glutaraldehyde-chitosan and poly (vinyl alcohol) blends, and fluorescence of their nano-silica composite films. AB - In this study, a commercial chitosan cross-linked with glutaraldehyde (GA chitosan) having the autofluorescent property was effectively blended with a poly (vinyl alcohol) (PVA) matrix, in the formation of a transparent and fluorescent blend film. The fluorescent efficiency of the film was enhanced with red-shifted emission band by increasing the concentrations of the GA-chitosan and decreasing the PVA crystallinity. It was found that the incorporation of silica nanoparticles could further decrease the PVA crystallinity, enhance the fluorescent efficiency, and largely redshift the emission band, as compared with the neat GA-chitosan-PVA blend film. This fluorescent property could be finely tuned by careful doping of the silica nanoparticles and change of the PVA crystallinity. These phenomena could be reasonably explained by high extent of isolation of the fluorophores, increase of the stiffness of the fluorescent conjugated planar structure, and further decrease of the PVA crystallinity. In addition, the introduction of the nano-silica could improve the water and heat resistances of the GA-chitosan-PVA based silica nanocomposites. PMID- 23044138 TI - Structural investigation of water-soluble polysaccharides extracted from the fruit bodies of Coprinus comatus. AB - Water-soluble polysaccharide material, extracted from the stipes of the fruit bodies of Coprinus comatus by hot water, was fractionated by sequential weak anion-exchange and size-exclusion chromatography. The relevant fractions were subjected to structural analysis, including (d/l) monosaccharide/methylation analysis and 1D/2D NMR spectroscopy. Besides the disaccharide alpha,alpha trehalose [alpha-D-Glcp-(1<->1)-alpha-D-Glcp], high-molecular-mass alpha-D glucans (the most abundant component) consisting of [->4)-alpha-D-Glcp-(1->](n) backbones with ~10% branching at C-6 by terminal alpha-D-Glcp-(1->6)- or alpha-D Glcp-(1->6)-alpha-D-Glcp-(1->6)- units, lower-molecular-mass linear beta-D glucans consisting of [->6)-beta-D-Glcp-(1->](m) sequences, and a lower-molecular mass pentasaccharide-repeating alpha-L-fuco-alpha-D-galactan, {->6)-alpha-D-Galp (1->6)-[alpha-L-Fucp-(1->2)-]alpha-D-Galp-(1->6)-alpha-D-Galp-(1->6)-alpha-D-Galp (1->}(p), were found to be present. PMID- 23044139 TI - Fe3O4/cyclodextrin polymer nanocomposites for selective heavy metals removal from industrial wastewater. AB - In this work, carboxymethyl-beta-cyclodextrin (CM-beta-CD) polymer modified Fe(3)O(4) nanoparticles (CDpoly-MNPs) was synthesized for selective removal of Pb(2+), Cd(2+), Ni(2+) ions from water. This magnetic adsorbent was characterized by TEM, FTIR, XPS and VSM. The adsorption of all studied metal ions onto CDpoly MNPs was found to be dependent on pH, ionic strength, and temperature. Batch adsorption equilibrium was reached in 45 min and maximum uptakes for Pb(2+), Cd(2+) and Ni(2+) in non-competitive adsorption mode were 64.5, 27.7 and 13.2 mg g(-1), respectively at 25 degrees C. Adsorption data were fitted well to Langmuir isotherm and pseudo-second-order models for kinetic study. The polymer grafted on MNPs enhanced the adsorption capacity because of the complexing abilities of the multiple hydroxyl and carboxyl groups in polymer backbone with metal ions. In competitive adsorption experiments, CDpoly-MNPs could preferentially adsorb Pb(2+) ions with an affinity order of Pb(2+)>>Cd(2+)>Ni(2+) which can be explained by hard and soft acids and bases (HASB) theory. Furthermore, we explored the recyclability of CDpoly-MNPs. PMID- 23044140 TI - Synthesis and photobiocidal properties of cationic porphyrin-grafted paper. AB - We report on the synthesis of cellulose paper bearing a cationic porphyrin, designed for antimicrobial applications. Tricationic porphyrin has been covalently grafted on paper, without previous chemical modification of the cellulosic support, using 1,3,5-triazine derivative as linker. The obtained porphyrin-grafted paper was characterized by infrared (ATR-FTIR), UV-visible and diffuse reflectance UV-vis (DRUV) spectroscopies to confirm the triazine linkage. Thermogravimetric analysis (TGA) was used to investigate thermal properties of grafted paper. Antimicrobial activity of porphyrin-cellulose material was tested under visible light irradiation against Staphylococcus aureus and Escherichia coli. The two bacterial strains deposited on the resulting photosensitizing filter paper are efficiently killed after illumination. PMID- 23044141 TI - The mechanism of thermal activated radical formation in potato starch studied by electron paramagnetic resonance and Raman spectroscopies. AB - Degradation of starch and the constituent fractions: amylopectin and amylose during thermal treatment in the range 423-503 K was investigated by electron paramagnetic resonance (EPR) and Raman spectroscopy. Degradation process was accompanied by the generation of carbon-centered stable radicals. EPR provided data on the nature and structure of radicals and on their evolution upon thermal treatment, whereas Raman spectroscopy allowed monitoring the changes of bonds in polysaccharides. It was found that amylose was the most susceptible toward high temperatures and the process of radical generation started at lower temperature than in amylopectin and starch, which were more resistant to thermal degradation. PMID- 23044142 TI - Green, microwave-assisted synthesis of silver nanoparticles using bamboo hemicelluloses and glucose in an aqueous medium. AB - A green, straightforward, microwave-assisted method of synthesizing silver nanoparticles in an aqueous medium was developed using bamboo hemicelluloses as stabilizer and glucose as reducer. The effects of irradiation time as well as initial concentrations of hemicelluloses, glucose, and AgNO(3) on the silver nanoparticle formation were studied. The silver nanoparticles were characterized by UV-vis spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The results indicated the formation of spherical, nanometer-sized particles. The reaction parameters significantly affected the formation rate, size and distribution of the silver nanoparticles. The average particle size was 8.3-14.8 nm based on TEM analysis. XRD analysis revealed that the particles calcined at 300 degrees C were face centered cubic. XPS characterization showed that silver Ag(0) coexisted with silver Ag(I). The synthesis process of silver nanoparticles was rapid and eco friendly. PMID- 23044144 TI - Chemical modification of cotton fabrics for improving utilization of reactive dyes. AB - The cotton fabric was chemically modified with the acrylamide through Michael addition reaction and Hoffman degradation reaction. And the optimum chemical modification conditions were determined. The molecular structure of the modified cotton fabric was identified by Fourier transform infrared spectroscopy (FTIR). The structures of both the raw and modified cotton fabrics were investigated by X ray diffraction and scanning electronic microscopy. The raw and modified cotton fabrics were dyed using commercial reactive dyes with vinyl-sulfone groups. The results showed that the total dye utilization of modified cotton fabrics in the salt-free dyeing was higher than that of raw cotton fabrics in the conventional dyeing. And the color fastness properties and tear strength of modified fabrics were both satisfactory. PMID- 23044143 TI - Statistics-based optimization of the extraction process of kelp polysaccharide and its activities. AB - Statistics-based response surface methodology (RSM) was used to optimize the extraction process of kelp polysaccharide and its activities were evaluated. Single factor experiment was first designed for determining the optimal range of each of four factors and these factors were further optimized using RSM with a CCD design. The optimal conditions were as follows: pH 3.4, temperature 83 degrees C, extraction time 3.95 h and ratio of water to kelp 1:23. Under the above conditions, the yield of kelp polysaccharide obtained was 1.26%. Scavenging percentages of free radicals OH, O(2)(-) and DPPH by kelp polysaccharide were up to 90.8% (1.6 mg/mL), 85% (1 mg/mL) and 23.8% (1 mg/mL), respectively. An increase of 86% in the biosynthetic activity of collagen was obtained at a kelp polysaccharide concentration of 0.25%. All these results indicate that kelp polysaccharide may be a good candidate as an effective ingredient of cosmetics for future use. PMID- 23044145 TI - Structural characterisation of a complex heteroglycan from the cyanobacterium Nostoc commune. AB - An alkali-extractable O-methylated ribofuranose-containing heteroglycan, Nc-5-s, was isolated from wild-growing field colonies of the cyanobacterium Nostoc commune collected in Iceland, using ethanol fractionation and anion-exchange chromatography. The average molecular weight was estimated to be 1500 kDa. Structural characterisation of the heteroglycan was performed by high-field NMR spectroscopy (1D proton, 2D-COSY, 2D-NOESY, 2D-TOCSY, (1)H (13)C-HSQC, HMBC, H2BC and HSQC-NOESY) as well as monosaccharide analysis after methanolysis by GC and supported by linkage analysis by GC-MS. According to the data obtained, the structure of Nc-5-s is composed of repeating units of 1, 1a, 1b and 2 and 2a in approximate molar ratio of (10:25:50:5:10). PMID- 23044146 TI - Morphology and thermal properties of PLA-cellulose nanofibers composites. AB - Biodegradable nanocomposites were obtained from polylactic acid (PLA) and cellulose nanofibers with diameters ranging from 11 nm to 44 nm. The influence of treated (with 3-aminopropyltriethoxysilane) and untreated nanofibers on the thermal properties of PLA was investigated in detail using multiple session Differential Scanning Calorimetry (DSC) analysis. The nucleating effect of the cellulose nanofibers was confirmed by all the DSC runs (two melting and two crystallization steps). The morphology of both neat PLA and nanocomposites was explored for the first time using a new powerful AFM technique, Peak Force QNM (Quantitative Mechanical Property Mapping at the Nanoscale), which emphasized the nanolevel characteristics by elastic modulus mapping. QNM analyses showed a better dispersion of the silane treated nanofibers in the matrix as compared to the untreated ones. Moreover, a higher degree of crystallinity was detected in the PLA composites containing untreated nanofibers compared to the composites with treated ones. PMID- 23044147 TI - Storage stability and antioxidant activity of complex of astaxanthin with hydroxypropyl-beta-cyclodextrin. AB - Storage stability of astaxanthin/hydroxypropyl-beta-cyclodextrin (HPCD) inclusion complex was evaluated and which was compared with native astaxanthin. The storage stability of astaxanthin was enhanced after included in HPCD under 4 degrees C and 25 degrees C storage conditions. Antioxidant activity of astaxanthin/HPCD inclusion complex was also assayed using ascorbic acid as a control sample. The reducing power and DPPH radical scavenging activity of native astaxanthin were lower than ascorbic acid, while which of the complex were higher at low concentration for the good water solubility. The hydroxyl radical scavenging activities of astaxanthin and astaxanthin/HPCD complex far outclassed that of ascorbic acid, and the activity of the complex was a little lower than that of the native astaxanthin. PMID- 23044148 TI - Effect of glucosamine and chitooligomer on the toxicity of arsenite against Escherichia coli. AB - Escherichia coli was selected as the sample to study the toxicity of arsenite in the presence of saccharides. The effect of glucosamine, N-acetylglucosamine, glucose, lactose, sucrose, glucosamine and cyclodextrin on the toxicity of arsenite against E. coli was investigated by microcalorimetry. The glucosamine and the tested chitooligomer decreased the toxicity of arsenite on cells of E. coli, and the effect of glucosamine was stronger than that of the chitooligomer. These results suggest that the glucosamine and chitooligomer may be employed as the assistant antidote for arsenite. PMID- 23044149 TI - Rheological and physical properties of spray-dried mucilage obtained from Hylocereus undatus cladodes. AB - This study examines the rheological behavior of reconstituted spray-dried mucilage isolated from the cladodes of pitahaya (Hylocereus undatus), the effects of concentration and its relationship with physical properties were analyzed in reconstituted solutions. Drying process optimization was carried out through the surface response method, utilizing a factorial 2(3) design with three central points, in order to evaluate yield and rheological properties. The reconstituted mucilage exhibited non-Newtonian shear-thinning behavior, which adequately fit the Cross model (R(2)>0.95). This dynamic response suggests a random coil configuration. The steady-shear viscosity and dynamic response are suitably correlated through the Cox-Merz rule, confirming the mucilage's stability of flow. Analysis of the physical properties of the mucilage (Tg, DTP, and particle morphology) explains the shear-thinning behavior. PMID- 23044151 TI - Modification and cross-linking parameters in hyaluronic acid hydrogels- definitions and analytical methods. AB - Definitions and methods for the quantification of degree of modification and cross-linking in cross-linked hyaluronic acid (HA) hydrogels are outlined. A novel method is presented in which the HA hydrogel is degraded by the enzyme chondroitinase AC and the digest product analyzed by size exclusion chromatography combined with electrospray ionization mass spectrometry (SEC-ESI MS). This method allows for the determination of effective cross-linker ratio (CrR) which together with the degree of modification (MoD), determined by, e.g. (1)H NMR spectroscopy, enables the calculation of the degree of substitution (DS) and degree of cross-linking (CrD). The method, could be applicable to the major cross-linked HA hydrogels currently on the market, and is exemplified here by application to two HA hydrogels. The definitions and methods presented are important contributions in attempts to find relationships between MoD, DS and CrD to mechanical properties as well as to biocompatibility of HA hydrogels. PMID- 23044150 TI - Anti-metastatic and anti-angiogenic activities of sulfated polysaccharide of Sepiella maindroni ink. AB - A previous study demonstrated that SIP-SII, a sulfated Sepiella maindroni ink polysaccharide, suppressed the invasion and migration of cancer cells via the inhibition of the proteolytic activity of matrix metalloproteinase-2 (MMP-2). Therefore, this study investigated the anti-metastatic effect of SIP-SII in vivo. SIP-SII (15 and 30 mg/kg d) markedly decreased B16F10 pulmonary metastasis in mice models by 85.9% and 88.0%, respectively. Immunohistochemistry showed that SIP-SII decreased the expression of the intercellular adhesion molecule 1 (ICAM 1) and basic fibroblast growth factor (bFGF) in lung metastasis nodules. In addition, SIP-SII inhibited neovascularization in chick chorioallantoic membrane assay at 0.08-2 mg/mL. In the in vitro experiments, SIP-SII (0.8-500 MUg/mL) significantly decreased the protein and mRNA expression of ICAM-1 and bFGF in SKOV3 and EA.hy926 cells, respectively. These results suggested that SIP-SII might suppress melanoma metastasis via the inhibition of the tumor adhesion mediated by ICAM-1 and the angiogenesis mediated by bFGF, as well as resulting in depression of the invasion and migration of carcinoma cells. PMID- 23044152 TI - Carbon nanotube-incorporated multilayered cellulose acetate nanofibers for tissue engineering applications. AB - We report the fabrication of a novel carbon nanotube-containing nanofibrous polysaccharide scaffolding material via the combination of electrospinning and layer-by-layer (LbL) self-assembly techniques for tissue engineering applications. In this approach, electrospun cellulose acetate (CA) nanofibers were assembled with positively charged chitosan (CS) and negatively charged multiwalled carbon nanotubes (MWCNTs) or sodium alginate (ALG) via a LbL technique. We show that the 3-dimensional fibrous structures of the CA nanofibers do not appreciably change after the multilayered assembly process except that the surface of the fibers became much rougher than that before assembly. The incorporation of MWCNTs in the multilayered CA fibrous scaffolds tends to endow the fibers with improved mechanical property and promote fibroblast attachment, spreading, and proliferation when compared with CS/ALG multilayer-assembled fibrous scaffolds. The approach to engineering the nanofiber surfaces via LbL assembly likely provides many opportunities for new scaffolding materials design in various tissue engineering applications. PMID- 23044153 TI - Controllable antioxidative xylan-chitosan Maillard reaction products used for lipid food storage. AB - Controllable antioxidative xylan-chitosan Maillard reaction products (MRPs) were prepared by co-heating xylan and chitosan at different time periods and used for lipid food storage in lecithin model system and refrigerated pork meat. The results of antioxidant protective effect on lecithin liposome peroxidation induced by 2,2'-azobis(2-methylpropionamidine) dihydrochloride revealed that the MRPs heated for 120 min and 180 min showed much higher inhibitory activity than chitosan or MRP heated for 60 min. In the experiment of fresh pork protection, the MRPs heated for 60 and 120 min retarded the growth of spoilage organisms more effectively. Lipid oxidation potential of the meat, determined by thiobarbituric acid reactive substances, also showed that the samples treated by the MRPs heated for 60 and 120 min had higher acceptance than others. These results demonstrate that the MRPs of xylan and chitosan are promising controllable antioxidative preservatives for lipid food formulations, and the antioxidant behavior depends not only on the antioxidant substances, but also on the interaction of the food systems. PMID- 23044154 TI - Cationic-cellulose nanofibers: preparation and dyeability with anionic reactive dyes for apparel application. AB - Continuous effort in research and development of nanofibers for apparel usage has been focused within their functional properties only. We investigated esthetic properties by producing colored cationic-cellulose nanofibers for the very first time for the potential application of apparel use. The cellulose acetate nanofibers were electrospun followed by deacetylation and cationization to produce functional cationic-cellulose nanofibers and then dyed with anionic reactive dyes. The spectrophotometric measurement of dyed samples was carried out to determine color coordinates and color yield values. The cationic-cellulose nanofibers showed enhanced color yield and dye fixation without addition of an electrolyte in comparison to cellulose nanofibers. The cationization of cellulose nanofibers significantly enhanced the color yield values of around 76% at dye concentrations of 5%. Excellent color fastness results demonstrate that these new colored and breathable materials can potentially be considered as future apparel for casual or fashion. PMID- 23044155 TI - Characterisation of large scale structures in starch granules via small-angle neutron and X-ray scattering. AB - Small angle scattering (SAS) techniques have a distinguished track record in illuminating the semi-crystalline lamellar structure of the starch granule. To date, there have been few attempts to use SAS techniques to characterise larger scale structures reported from imaging techniques such as growth rings, blocklets or pores, nor how these structures would modulate the well-known scattering arising from the semi-crystalline lamellar structure. In this study, SAS data collected over an extended q range were gathered from dry and hydrated starch powders from varied botanical sources. The use of neutrons and X-rays, as well as comparing dry and hydrated granules, allowed different levels of contrast in scattering length density to be probed and therefore selected structural regions to be highlighted. The lowest q range, 0.002-0.04 A(-1), was found to be dominated by scattering from the starch granules themselves, especially in the dry powders; however an inflection point from a low contrast structure was observed at 0.035 A(-1). The associated scattering was interpreted within a unified scattering framework with the inflexion point correlating with a structure with radius of gyration ~90 A - a size comparable to small blocklets or superhelices. In hydrated starches, it is observed that there is an inflection point between lamellar and q(-4) power-law scattering regions at approximately 0.004 A(-1) which may correlate with growth rings and large blocklets. The implications of these findings on existing models of starch lamellar scattering are discussed. PMID- 23044156 TI - Biomedical applications of carboxymethyl chitosans. AB - This review outlines the recent developments on carboxymethyl chitosan-based bio medical applications. Carboxymethyl chitosan, a water soluble derivative of chitosan, with enhanced biological and physicochemical properties compared to chitosan, has emerged as a promising candidate for different biomedical applications. Introducing small chemical groups like carboxymethyl to the chitosan structure can drastically increase the solubility of chitosan at neutral and alkaline pH values without affecting their characteristic properties. Due to improved biocompatibility, high moisture retention ability more viscosity and enhanced antimicrobial property of carboxymethyl chitosan than chitosan makes it promising candidate for hydrogels and wound healing applications. The biodegradability and biocompatibility of carboxymethyl chitosan has significant interest with application as biomaterial for tissue engineering. Apart from this, the easy of carboxymethyl chitosan can be easily processed into nanoparticles so it has shown promise for drug delivery, bioimaging, biosensors and gene therapy applications. The contribution of carboxymethyl chitosan to green chemistry in the recent years has also been given in detail. This review will focus on preparative methods and physicochemical and biological properties of carboxymethyl chitosan with particular emphasis on biomedical and pharmaceutical applications of this derivative of chitosan. PMID- 23044158 TI - Build-up dynamics of heavy metals deposited on impermeable urban surfaces. AB - A method using thin boards (3 cm thick, 0.56 m(2)) comprising different paving materials typically used in urban environments (2 asphalt types and concrete) was employed to specifically investigate air-borne deposition dynamics of TSS, zinc, copper and lead. Boards were exposed at an urban car park near vehicular traffic to determine the rate of contaminant build-up over a 13-day dry period. Concentration profiles from simulated rainfall wash-off were used to determine contaminant yields at different antecedent dry days. Maximum contaminant yields after 13 days of exposure were 2.7 kg ha(-1) for TSS, 35 g ha(-1) zinc, 2.3 g ha( 1) copper and 0.4 g ha(-1) lead. Accumulation of all contaminants increased over the first week and levelled off thereafter, supporting theoretical assumptions that contaminant accumulation on impervious surfaces asymptotically approaches a maximum. Comparison of different surface types showed approximately four times higher zinc concentrations in runoff from asphalt surfaces and two times higher TSS concentrations in runoff from concrete, which is attributed to different physical and chemical compositions of the pavement types. Contaminant build-up and wash-off behaviours were modelled using exponential and saturation functions commonly applied in the US EPA's Stormwater Management Model (SWMM) showing good correlation between measured and modelled concentrations. Maximum build-up, half saturation time, build-up rate constants and wash-off coefficients, necessary for stormwater contaminant modelling, were determined for the four contaminants studied. These parameters are required to model contaminant concentrations in urban runoff assisting in stormwater management decisions. PMID- 23044157 TI - A sulfated polysaccharide, fucans, isolated from brown algae Sargassum vulgare with anticoagulant, antithrombotic, antioxidant and anti-inflammatory effects. AB - Fucan (SV1) sulfated polysaccharides from the brown algae Sargassum vulgare were extracted, fractionated in acetone and examined with respect to chemical composition, anticoagulant, anti-inflammatory, antithrombotic effects and cellular proliferation. These polysaccharides contain low levels of protein, high level of carbohydrate and sulfate. Monosaccharides analysis revealed that SV1 was composed of fucose, galactose, xylose, glucuronic acid and mannose. SV1 polysaccharide prolonged activated partial thromboplastin time (aPTT) and exhibited high antithrombotic action in vivo, with a concentration ten times higher than heparin activity. PSV1, a purified form in gel filtration showed very low biological activities. SV1 stimulated the enzymatic activity of FXa. Its action on DPPH radical scavenging activity was 22%. This polymer has no cytotoxic action (hemolytic) on ABO and Rh blood types in different erythrocyte groups. It displays strong anti-inflammatory action at all concentrations tested in the carrageenan-induced paw edema model, demonstrated by reduced edema and cellular infiltration. PMID- 23044159 TI - A case of childhood T cell acute lymphoblastic leukemia with a complex t(9;9) and homozygous deletion of CDKN2A gene associated with a Philadelphia-positive minor subclone. PMID- 23044160 TI - Health benefits of nut consumption with special reference to body weight control. AB - Nuts are an integral part of the Mediterranean food patterns, and their incorporation into the regular diets of human beings is believed to provide many health benefits. The recent recognition of nuts as "heart-healthy" foods by the U.S. Food and Drug Administration has given a major boost to the positive image of nuts. Nut consumption has been associated with several health benefits, such as antioxidant, hypocholesterolemic, cardioprotective, anticancer, anti inflammatory, and antidiabetic benefits, among other functional properties. However, although nuts possess these many health benefits, their consumption has been hampered by a lack of adequate information regarding those benefits. In addition, because nuts are energy-dense foods with high-fat content, there is a misconception among consumers that increased consumption may lead to unwanted gain in body weight with the risk of developing overweight/obesity. Nonetheless, available epidemiologic studies and short-term controlled feeding trials have supported the theory that the inclusion of nuts in the typical diet does not induce weight gain, despite an expected increase in total caloric intake. To address the misperception about nuts and body weight gain, the present review focuses mainly on the relation between nut consumption and body weight gain, in the context of the many health benefits of nuts. PMID- 23044161 TI - Pre- and perioperative factors affecting infection after living donor liver transplantation. AB - OBJECTIVE: Infectious complications, including sepsis, that often occur after liver transplantation (LT) comprise the most frequent causes of in-hospital death. This study investigated the predictors of post-transplantation infectious complications to establish a strategy with which to improve short-term outcomes after LT. METHODS: We used univariate and multivariate analyses to assess pre- and perioperative risk factors for post-transplantation infectious complications in 100 consecutive patients who underwent living donor LT from February 2008 through February 2010 at our institute. RESULTS: Multivariate analysis showed that low preoperative body cell mass and the absence of preoperative supplementation with branched-chain amino acids were of prognostic significance for post-transplantation sepsis. In addition, Child-Pugh classification C and massive operative blood loss were independent risk factors for post transplantation bacteremia, and preoperative low body cell mass was an independent risk factor for in-hospital death from infection. CONCLUSION: Pretransplantation nutritional intervention and decreases in operative blood loss would help prevent post-transplantation infectious complications from developing during living donor LT. Branched-chain amino acid supplementation before LT affects the occurrence of infectious complications. PMID- 23044162 TI - Nutritional status in relation to adipokines and oxidative stress is associated with disease activity in patients with rheumatoid arthritis. AB - OBJECTIVE: We assessed whether disease activity was associated with dietary habits, nutritional status, adipokines, and oxidative stress in patients with rheumatoid arthritis. METHODS: The subjects were 37 patients with RA. The assessment of the nutritional status included anthropometric and biochemical parameters. A food-frequency questionnaire and a 3-d diet record to assess dietary intake were used. The serum levels of adipokines and oxidative stress markers in sera and saliva were measured. The disease activity was determined using the 28 Disease Activity Score (DAS28). We divided the subjects into high (DAS28 >=3.2) and low (DAS28 <3.2) disease activity groups. RESULTS: The serum leptin and albumin levels were significantly lower, whereas the inflammatory markers were increased, in the high disease activity group. The dietary intake assessment showed a lower intake of fish oil and a lower ratio of monounsaturated fatty acid intake in the high disease activity group. There was a negative correlation between the DAS28 and the dietary intake of the ratio of monounsaturated fatty acid to total fatty acid intake. The serum oxidative stress marker (reactive oxygen metabolites) showed a positive correlation to the DAS28. The salivary reactive oxygen metabolites also correlated with C-reactive protein and serum reactive oxygen metabolites. CONCLUSION: Altered serum adipokine levels with decreased albumin may reflect the deterioration that is associated with rheumatoid arthritis. An increased oxidative stress was observed in sera and saliva. Intakes of omega-3 polyunsaturated fatty acids, fish oil, and monounsaturated fatty acid seem to affect disease activity and may have beneficial effects by decreasing inflammation. PMID- 23044163 TI - Evidence of zinc deficiency in competitive swimmers. AB - OBJECTIVE: The aim of this study was to assess the nutritional zinc (Zn) status of elite swimmers during different training periods. METHODS: A longitudinal paired study was performed at the University of Sao Paulo in eight male swimmers 18 to 25 y old who had been swimming competitively at the state and national levels for at least 5 y. The swimmers were evaluated over a total period of 14 wk: before the basic and specific preparatory period (BSPP-baseline), at the end of the basic and specific preparatory period (post-BSPP), and at the end of the polishing period (PP). Levels of Zn were determined in the plasma, erythrocyte, urine, and saliva by atomic absorption spectrophotometry. Anthropometric measurements and a 3-d food record were also evaluated. RESULTS: The median plasma Zn concentration was below the reference value in all training periods (BSPP-baseline 59 MUg/dL, post-BSPP 55.9 MUg/dL, after PP 58.8 MUg/dL, P > 0.05), as were threshold values for erythrocytes (BSPP-baseline 36.5 MUg of Zn/g of hemoglobin, post-BSPP 42 MUg of Zn/g of hemoglobin, after PP 40.7 MUg of Zn/g of hemoglobin, P > 0.05), urinary Zn (BSPP-baseline 280 MUg/24 h, post-BSPP 337 MUg/24 h, after PP 284 MUg/24 h, P > 0.05), and salivary Zn (BSPP-baseline 66.1 MUg/L, post-BSPP 54.1 MUg/L, after PP 79.7 MUg/L, P > 0.05). Salivary Zn did not correlate with plasma and erythrocyte Zn levels. CONCLUSION: The results suggest that the elite swimmers studied presented a possible Zn deficiency and that salivary Zn was not adequate to evaluate the Zn nutritional status. PMID- 23044164 TI - Intelligence quotient and cognitive functions in severe restricting-type anorexia nervosa before and after weight gain. AB - OBJECTIVE: Restricting-type anorexia nervosa (AN-R), characterized by severe emaciation with long-term food restriction, is often difficult to treat. The present study investigated the overall intelligence quotient (IQ) scores and cognitive functions of patients with AN-R. METHODS: Fourteen female inpatients with AN-R (body mass index 12.84 +/- 0.41 kg/m2) and 10 healthy female participants participated in this study from 2007 through 2010. The Wechsler Adult Intelligence Scale, Third Edition and the Eating Disorder Inventory-II were administered. This research was performed at Kagoshima University Hospital. RESULTS: In the AN-R group, overall IQ scores showed borderline intelligence (e.g., full-scale IQ 75.86 +/- 1.79, P < 0.01); the scores were significantly lower than those in the comparison group. There were negative correlations between lower IQs and higher Eating Disorder Inventory-II scores. After the weight restoration, the IQ scores of subjects with AN-R with regard to the visuospatial scales were significantly higher than before (P < 0.01); however, the auditory cognitive scores were unchanged. CONCLUSION: These lower IQ scores could be connected to the psychological and behavioral traits in patients with AN R. These problems should be considered by medical staff members who seek to treat patients with AN-R successfully. PMID- 23044165 TI - Arginyl-glutamine dipeptide or docosahexaenoic acid attenuate hyperoxia-induced lung injury in neonatal mice. AB - OBJECTIVES: Supplementation studies of glutamine, arginine, and docosahexaenoic acid (DHA) have established the safety of each of these nutrients in neonates. However, the potential for a more stable and soluble dipeptide, arginyl-glutamine (Arg-Gln) or DHA, a long-chain omega-3 fatty acid with anti-inflammatory properties, to exert benefits on hyperoxia-induced lung injury has not to our knowledge been investigated. The aim of this study was to investigate whether Arg Gln dipeptide or DHA could attenuate markers of injury and inflammation in neonatal mouse lungs exposed to hyperoxia. METHODS: Seven-day-old mouse pups were placed with their dams in 75% oxygen for 5 d. After 5 d of hyperoxic exposure (postnatal days 7-12), pups were removed from hyperoxia and allowed to recover in atmospheric conditions for 5 d (postnatal days 12-17). Mouse pups received Arg Gln (5 g . kg-1 . d-1) or DHA (5 g . kg-1 . d-1) or saline orally from postnatal days 12 through 17. Histologic changes, myeloperoxidase, lactate dehydrogenase, inflammatory cytokines, and nuclear factor-kappaB inhibitor levels were checked in each group. RESULTS: The Arg-Gln and DHA prevented the development of key markers of injury, including histologic changes, myeloperoxidase, lactate dehydrogenase, and inflammatory cytokines interleukin-6 and C-X-C motif ligand 1 (CXCL1)/keratinocyte-derived chemokine (KC). The highly beneficial effects of Arg Gln on the reversal of oxygen-induced lung damage was associated with restoration of levels of nuclear factor-kappaB inhibitor. CONCLUSION: The Arg-Gln and DHA, with protective effects on hyperoxic lung injury in neonatal mice, are promising nutritional adjuncts that may prevent lung damage owing to oxygen toxicity in infants. PMID- 23044166 TI - A rational approach to vitamin D supplementation. PMID- 23044167 TI - Novel approach to identifying autoantibodies in rheumatoid synovitis with a biotinylated human autoantigen library and the enzyme-labeled antigen method. AB - Synovial tissue in rheumatoid arthritis (RA) shows dense infiltration of plasmacytes. The purpose of the present study is to identify and localize autoantibodies produced in these immunocytes in RA synovitis. We developed a novel screening system for detecting specific autoantigens. Protein antigens recognized by antibodies in the serum and synovial tissue extract from five RA patients were screened with the AlphaScreen method. For screening, a biotinylated human autoantigen library was constructed by the wheat germ cell-free protein synthesis system. The AlphaScreen analysis of 2183 proteins detected a limited number of antigens reactive with the serum and synovial tissue extract. Eighteen biotinylated proteins, containing top five showing high signals in each synovitis tissue extract, were utilized as probes for the enzyme-labeled antigen method, in order to visualize the site of specific antibody production in synovial lesions. Specific antibodies against two proteins, tripartite motif-containing 21 (TRIM21, also known as SSA/Ro52) and F-box only protein 2 (FBXO2), were visualized in the cytoplasm of plasmacytes in two RA synovitis lesions, respectively. Absorption experiments using unlabeled proteins confirmed the specificity of staining. No positive signals against these two proteins were identified in the additionally evaluated RA and osteoarthritis synovial lesions. The present study indicated 1) the usefulness of screening the human autoantigen library with the AlphaScreen assay for detecting autoantibodies in RA synovitis, and 2) the applicability of biotinylated proteins to the enzyme-labeled antigen method for visualizing the site of autoantibody production within the lesion. PMID- 23044168 TI - [Resistance to thyroid hormone and attention deficit hyperactivity disorder]. PMID- 23044169 TI - [Rhabdomyomatous mesenchymal hamartoma]. AB - Rhabdomyomatous mesenchymal hamartoma is a rare congenital lesion which consists of randomly arranged striated muscle fibers interspersed with mesenchymal elements. We describe the clinical and histopathological features of a rhabdomyomatous mesenchymal hamartoma in a one year-old patient presenting a bilobulated lesion in the mid-cervical line. No associated congenital malformations were observed. PMID- 23044170 TI - A very elevated D-dimer level may potentially be useful. PMID- 23044171 TI - What happens after prothrombin complex concentrate administration? PMID- 23044172 TI - Chinks in the armor: percutaneous injuries from hollow bore safety-engineered sharps devices. AB - BACKGROUND: Despite their overwhelming efficacy, safety-engineered sharp devices (SESDs) cause a residual fraction of injuries. Although the fraction of injuries from SESDs is less than that reported for nonsafety devices, it remains a "preventable fraction" and is a sizable target for further advances. METHODS: A retrospective review of 3,297 percutaneous injuries from hollow bore safety engineered devices occurring between 2001 and 2009 was conducted examining the Exposure Prevention Information Network (EPINet) needlestick surveillance data. RESULTS: Nurses sustain 64.6% of all SESD injuries. 42.9% Of SESD injuries occur after device use and are likely preventable through consistent and effective use of safety-engineered technology. Excluding injuries that occurred during device use or between procedural steps, 71.8% (n/N = 28/39) of physician injuries, 58.2% (n/N = 645/1,109) of injuries to nurses, and 45.8% (n/N = 88/192) of injuries to phlebotomists occurred when an available SESD was not fully activated. CONCLUSION: Passive devices that do not require action on the part of the end user to engage a safety feature currently represent a small portion of the SESD market. Wider dissemination of a broader array of passive SESDs coupled with continual education of end users is essential to an effective sharps injury prevention program. PMID- 23044174 TI - Experience gathered from retrospective series on renal cell carcinoma is useful, but now it is time for a global claim for academically driven prospective studies. PMID- 23044173 TI - Simultaneous determination of ofloxacin and gatifloxacin on cysteic acid modified electrode in the presence of sodium dodecyl benzene sulfonate. AB - A novel cysteic acid modified carbon paste electrode (cysteic acid/CPE) based on electrochemical oxidation of L-cysteine was developed to simultaneously determine ofloxacin and gatifloxacin in the presence of sodium dodecyl benzene sulfonate (SDBS). Fourier transform infrared spectra (FTIR) indicated that L-cysteine was oxidated to cysteic acid. Electrochemical impedance spectroscopy (EIS) and cyclic voltammograms (CV) indicated that cysteic acid was successfully modified on electrode. The large peak separation (116 mV) between ofloxacin and gatifloxacin was obtained on cysteic acid/CPE while only one oxidation peak was found on bare electrode. And the peak currents increased 5 times compared to bare electrode. Moreover, the current could be further enhanced in the presence of an anionic surfactant, sodium dodecyl benzene sulfonate. The differential pulse voltammograms (DPV) exhibited that the oxidation peak currents were linearly proportional to their concentrations in the range of 0.06-10 MUM for ofloxacin and 0.02-200 MUM for gatifloxacin, and the detection limits of ofloxacin and gatifloxacin were 0.02 MUM and 0.01 MUM (S/N=3), respectively. This proposed method was successfully applied to determine ofloxacin and gatifloxacin in pharmaceutical formulations and human serum samples. PMID- 23044176 TI - Further characterisation of the LPS model of Parkinson's disease: a comparison of intra-nigral and intra-striatal lipopolysaccharide administration on motor function, microgliosis and nigrostriatal neurodegeneration in the rat. AB - Chronic neuroinflammation has been established as one of the many processes involved in the pathogenesis of Parkinson's disease (PD). Because of this, researchers have attempted to replicate this pathogenic feature in animal models using the potent inflammagen, lipopolysaccharide (LPS), in order to gain better understanding of immune-mediated events in PD. However, although the effect of intra-cerebral LPS on neuroinflammation and neurodegeneration has been relatively well characterised, its impact on motor function has been less well studied. Therefore, the aim of this study was to further characterise the neuropathological and behavioural impact of intra-nigral and intra-striatal administration of LPS. To do, LPS (10 MUg) or vehicle (sterile saline) were stereotaxically injected into the adult rat substantia nigra or striatum on one side only. The effect of LPS administration on lateralised motor function was assessed using the Corridor, Stepping and Whisker tests for two weeks post injection, after which, amphetamine-induced rotational asymmetry was completed. Post-mortem, the impact of LPS on nigrostriatal degeneration and microgliosis was assessed using quantitative tyrosine hydroxylase and OX-42 immunohistochemistry respectively. We found that intra-nigral administration of LPS led to localised microgliosis in the substantia nigra and this was accompanied by nigrostriatal neurodegeneration and stable spontaneous motor deficits. In contrast, intra striatal administration of LPS led to localised microgliosis in the striatum but this did not lead to any nigrostriatal neurodegeneration and only induced transient motor dysfunction. In conclusion, this study reveals the impact of intra-cerebral LPS administration on PD-related neuropathology and motor function, and it indicates that the intra-nigral model may be a highly relevant model as it is associated with stable motor decline underpinned by nigral microgliosis and nigrostriatal neurodegeneration. PMID- 23044179 TI - Improving importance estimation in pool-based batch active learning for approximate linear regression. AB - Pool-based batch active learning is aimed at choosing training inputs from a 'pool' of test inputs so that the generalization error is minimized. P-ALICE (Pool-based Active Learning using Importance-weighted least-squares learning based on Conditional Expectation of the generalization error) is a state-of-the art method that can cope with model misspecification by weighting training samples according to the importance (i.e., the ratio of test and training input densities). However, importance estimation in the original P-ALICE is based on the assumption that the number of training samples to gather is small, which is not always true in practice. In this paper, we propose an alternative scheme for importance estimation based on the inclusion probability, and show its validity through numerical experiments. PMID- 23044177 TI - Strain influences on inflammatory pathway activation, cell infiltration and complement cascade after traumatic brain injury in the rat. AB - Increasing evidence suggests that genetic background affects outcome of traumatic brain injuries (TBI). Still, there is limited detailed knowledge on what pathways/processes are affected by genetic heterogeneity. The inbred rat strains DA and PVG differ in neuronal survival following TBI. We here carried out global expressional profiling to identify differentially regulated pathways governing the response to an experimental controlled brain contusion injury. One of the most differentially regulated molecular networks concerned immune cell trafficking. Subsequent characterization of the involved cells using flow cytometry demonstrated greater infiltration of neutrophils and monocytes, as well as a higher degree of microglia activation in DA compared to PVG rats. In addition, DA rats displayed a higher number of NK cells and a higher ratio of CD161bright compared to CD161dim NK cells. Local expression of complement pathway molecules such as C1 and C3 was higher in DA and both the key complement component C3 and membrane-attack complex (MAC) could be demonstrated on axons and nerve cells. A stronger activation of the complement system in DA was associated with higher cerebrospinal fluid levels of neurofilament-light, a biomarker for nerve/axonal injury. In summary, we demonstrate substantial differences between DA and PVG rats in activation of inflammatory pathways; in particular, immune cell influx and complement activation associated with neuronal/axonal injury after TBI. These findings suggest genetic influences acting on inflammatory activation to be of importance in TBI and motivate further efforts using experimental forward genetics to identify genes/pathways that affect outcome. PMID- 23044178 TI - Differential expression of protamine 1 and 2 genes in mature spermatozoa of normal and motility impaired semen producing crossbred Frieswal (HF*Sahiwal) bulls. AB - Mature spermatozoa contain thousands of mRNA transcripts. These untranslated mRNA may perhaps serve as a "footprint" of spermatogenesis since many of them might directly or indirectly be involved in fertilization, early embryo cleavage, poor semen quality and fertility. In this study, we tried to isolate high-quality RNA from mature spermatozoa and to monitor the expression profile of protamine 1 (PRM1) and protamine 2 (PRM2) gene in ejaculated spermatozoa of normal (good, % initial progressive motility: 57.61+/-1.41, n=9) and motility impaired (poor, % initial progressive motility: 18.45+/-1.61, n=8) crossbred Frieswal (HF*Sahiwal) bulls semen using real time quantitative PCR. Semen samples were subjected to discontinuous (45:90) Percoll gradient centrifugation, specifically to eliminate damaged spermatozoa and contaminating somatic cells. Total RNA was extracted from sperm pellets and cDNA was synthesized. Furthermore, the absence of contamination of germ cells, epithelial cells and leucocytes in all the RNA extractions was tested by RT-PCR targeting specific molecular markers like KIT, CDH1 and CD4, respectively. The presence of transcripts like PRM1, PRM2, DAZL, and PPIA were demonstrated in ejaculated spermatozoa using appropriate PCR primers without RNA amplification. Expression of PRM1 and PRM2 genes were evaluated by real time quantitative PCR using TaqMan chemistry, where PPIA was used as internal control. The cDNA synthesized from normal buffalo testicular tissue was served as positive control. The good quality semen producing group showed significantly higher level of PRM1 mRNAs expression as compared to the poor quality semen producers (P<0.05) indicating putative role of the gene and semen quality parameters especially initial progressive motility. However, PRM2 transcript levels were not significantly different between the groups (P>0.05). PMID- 23044180 TI - Blood sample tube transporting system versus point of care technology in an emergency department; effect on time from collection to reporting? A randomised trial. AB - BACKGROUND: Time is a crucial factor in an emergency department and the effectiveness of diagnosing depends on, among other things, the accessibility of rapid reported laboratory test results; i.e.: a short turnaround time (TAT). Former studies have shown a reduced time to action when point of care technologies (POCT) are used in emergency departments. This study assesses the hypothesis, that using Point of Care Technology in analysing blood samples versus tube transporting blood samples for laboratory analyses results in shorter time from the blood sample is collected to the result is reported in an emergency department. METHODS: The study was designed as a randomised controlled trial with consecutive allocation into two groups and rated 1:1. Blood samples were collected on all included patients and then randomised into either POCT analyses or tube transporting for central laboratory analyses. RESULTS: Blood samples from a total of 319 patients were included.The mean time from collecting to reporting was 24 minutes for the POCT analysis and 70 minutes for the tube transported analysis. An unpaired Students t-test showed a significant reduction in time from collecting to reporting using POCT (p<.0001). CONCLUSION: We found a significantly reduced time from collecting to reporting using Point of Care Technology (POCT) in an emergency department compared to tube transported blood samples for central laboratory analyses. PMID- 23044181 TI - A "One Health" surveillance and control of brucellosis in developing countries: moving away from improvisation. AB - Although a "One Health" approach has been successfully implemented for emerging infectious zoonotic diseases with pandemic potential, we still lack a conceptual framework to address enzootic diseases like brucellosis. The vast majority of published brucellosis studies in the developing world rely solely on serology. An important shortcoming of brucellosis serology is the impossibility to infer which (smooth) Brucella spp. induced antibodies in the host. In this respect, mixed farming and especially raising small ruminants along with cattle, a common practice in the developing world, is reported to be a risk factor and a central question that has to be answered is whether cattle are infected with B. melitensis or with B. abortus or with both Brucella species. Therefore the isolation, identification and molecular characterization of Brucella spp. in human and the different livestock species needs to be undertaken to define a sound conceptual framework, identify the source of infection and plan appropriate control measures. PMID- 23044183 TI - An optogenetic application of proton pump ArchT to C. elegans cells. AB - Application of novel light-driven ion channel/pumps would benefit optogenetic studies of Caenorhabditis elegans. A recent study showed that ArchT, a novel light-driven outward proton pump, is >3 times more light-sensitive than the Arch proton pump. Here we report the silencing effect of ArchT in C. elegans cells. ArchT expressed by using a body-wall muscle or pan-neuronal-promoters caused a quick and reliable locomotion paralysis when worms were illuminated by green light. Unlike the report on mouse neurons, however, light sensitivity of ArchT is similar to that of Arch in C. elegans. ArchT-mediated acute silencing of serotonergic neurons quickly triggered backward locomotion. This response was abolished in the presence of exogenously added serotonin, suggesting that, in a normal situation, serotonin is secreted in a constitutive fashion to repress backward movement. PMID- 23044184 TI - Targeted expression of a chimeric channelrhodopsin in zebrafish under regulation of Gal4-UAS system. AB - Channelrhodopsin (ChR)-wide receiver (ChRWR), one of the chimeric molecule of ChR1 and ChR2, has several advantages over ChR2 such as improved expression in the plasma membrane and enhanced photocurrent with small desensitization. Here we generated transgenic zebrafish (Danio rerio) expressing ChRWR as a conjugate of EGFP under the regulation of UAS promoter (UAS:ChRWR-EGFP). When crossed with a Gal4 line, SAGFF36B, ChRWR-EGFP was selectively expressed in primary mechanosensory Rohon-Beard (RB) neurons. The direct photoactivation of RB neurons was sufficient to trigger the escape behavior. The UAS:ChRWR-EGFP line could facilitate a variety of investigations of neural networks and behaviors of zebrafish in vivo. PMID- 23044182 TI - Dual roles of dopamine in food and drug seeking: the drive-reward paradox. AB - The question of whether (or to what degree) obesity reflects addiction to high energy foods often narrows to the question of whether the overeating of these foods causes the same long-term neuroadaptations as are identified with the late stages of addiction. Of equal or perhaps greater interest is the question of whether common brain mechanisms mediate the acquisition and development of eating and drug-taking habits. The earliest evidence on this question is rooted in early studies of brain stimulation reward. Lateral hypothalamic electrical stimulation can be reinforcing in some conditions and can motivate feeding in others. That stimulation of the same brain region should be both reinforcing and drive inducing is paradoxical; why should an animal work to induce a drive-like state such as hunger? This is known as the drive-reward paradox. Insights into the substrates of the drive-reward paradox suggest an answer to the controversial question of whether the dopamine system--a system downstream from the stimulated fibers of the lateral hypothalamus--is more critically involved in wanting or in liking of various rewards including food and addictive drugs. That the same brain circuitry is implicated in the motivation for and the reinforcement by both food and addictive drugs extends the argument for a common mechanism underlying compulsive overeating and compulsive drug taking. PMID- 23044185 TI - Effects of age-related dopaminergic neuron loss in the substantia nigra on the circadian rhythms of locomotor activity in mice. AB - Elderly people often develop sleep and autonomic dysfunctions, which are regulated by circadian rhythm. Recently, we reported on the degradation of neural output from the central circadian clock in the suprachiasmatic nucleus (SCN) with aging. However, it is likely that many other factors contribute to the age related decline in the functioning of the circadian system. In this study, we examined the effects of dopaminergic neuronal loss in the substantia nigra (SN) on circadian rhythms of mice to assess whether age-related degeneration of the dopamine system influences circadian rhythm. Young male C57BL/6J mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a compound that selectively destroys dopaminergic neurons in the SN, and their wheel-running activities were recorded. We observed that MPTP-treated mice lost 43% of their dopaminergic neurons in the SN (on average) and demonstrated longer period of wheel-running activity rhythm in constant darkness compared with control mice. However, all the remaining circadian parameters in the MPTP-treated mice remained constant. Our findings suggest that in addition to SCN output dysfunction, age related degeneration in the dopamine system of the brain leads to circadian rhythm irregularities. PMID- 23044186 TI - Cooperativity governs the size and structure of biological interfaces. AB - Interfaces, defined as the surface of interactions between two parts of a system at a discontinuity, are very widely found in nature. While it is known that the specific structure of an interface plays an important role in defining its properties, it is less clear whether or not there exist universal scaling laws that govern the structural evolution of a very broad range of natural interfaces. Here we show that cooperativity of interacting elements, leading to great strength at low material use, is a key concept that governs the structural evolution of many natural interfaces. We demonstrate this concept for the cases of beta-sheet proteins in spider silk, gecko feet, legs of caterpillars, and self assembling of penguins into huddles, which range in scales from the submolecular to the macroscopic level. A general model is proposed that explains the size and structure of biological interfaces from a fundamental point of view. PMID- 23044187 TI - Leiomyoma of the tunica albuginea, a case report of a rare tumour of the testis and review of the literature. AB - BACKGROUND: Leiomyomas are benign tumours that originate from smooth muscles. They are often seen in the uterus, but also in the renal pelvis, bladder, spermatic cord, epididymis, prostate, scrotum or the glans penis. Leiomyomas of the tunica albuginea are extremely rare. CASE PRESENTATION: A 59-year-old white male has noted an asymptomatic tumour on the right side of his scrotal sac for several years. This tumour has increased slowly and caused local scrotal pain. An inguinal incision was performed, in which the hypoplastic testis, the epididymis and the tumour could be easily mobilized. Macroscopically the tumour showed a solid round nonencapsulated whorling cut surface. Histologically the diagnosis of a leiomyoma was made. CONCLUSION: We report here a very interesting and rare case of a leiomyoma of the tunica albuginea. Leiomyomas can be a possible differential diagnosis in this area. VIRTUAL SLIDES: http://www.diagnosticpathology.diagnomx.eu/vs/2585095378537599. PMID- 23044189 TI - Functional stability (at +4 degrees C) of hematopoietic stem and progenitor cells amplified ex vivo from cord blood CD34+ cells. AB - Our previously published ex vivo expansion procedure starting from cord blood CD34+ cells enables a massive expansion of total and CD34+ cells and committed progenitors without negative impact on stem cells exhibiting both short- and long term repopulating capacity. It was upgraded to clinical scale [Macopharma HP01((r)) medium in presence of SCF, FLT3-L (100 ng/ml each), G-SCF (10 ng/ml), and TPO (20 ng/ml)] and is in use for an ongoing clinical trial (adult allogeneic context), yielding encouraging results. In order to test the possibility to use the expanded cells in distant transplantation centers, we studied the functional stability at +4 degrees C (usual temperature of transportation) of hematopoietic progenitors and stem cells 48 h after expansion. If the cells were washed and resuspended in 4% albumin solution (actual procedure for immediate injection), only one half of total nucleated and CD34+ cells and 30% of committed progenitors survived after 24 h. This condition has also an evident negative impact on stem cells in expansion product as demonstrated on the basis of reconstitution of NSG mice bone marrow by human CD45, CD33, CD19+ cells as well as by human committed progenitors (CFU). Surprisingly, if the cells were stored 48 h at +4 degrees C in culture medium, very good survival of total and CD34+ cells (90 to 100%) and colony forming unit cells (CFCs; around 70%) was obtained, as well as the maintenance of stem cells (the same in vivo assay with NSG mice). These data point to the possibility of the maintenance of the full functional capacity of expanded grafts for 2 days, the time allowing for its transportation to any transplantation center worldwide. PMID- 23044188 TI - Chondrogenically tuned expansion enhances the cartilaginous matrix-forming capabilities of primary, adult, leporine chondrocytes. AB - When expanded through passage, chondrocytes lose their ability to produce high quality cartilaginous matrix. This study attempts to improve the properties of constructs formed with expanded chondrocytes through alterations in the expansion protocol and the ratio of primary to expanded chondrocytes used to form cartilage constructs. A chondrogenically tuned expansion protocol provided similar monolayer growth rates as those obtained using serum-containing medium and enhanced cartilaginous properties of resultant constructs. Various ratios of primary to chondrogenically expanded chondrocytes were then self-assembled to form neocartilage. Biochemical analysis showed that constructs formed with only expanded cells had twice the GAG per wet weight and collagen II/collagen I ratio compared to constructs formed with primary chondrocytes. Biomechanically, compressive properties of constructs formed with only passaged cells matched the instantaneous modulus and exceeded the relaxation modulus of constructs formed with only primary cells. These counterintuitive results show that, by applying proper expansion and three-dimensional culture techniques, the cartilage-forming potential of adult chondrocytes expanded through passage can be enhanced over that of primary cells. PMID- 23044190 TI - The concept of RNA-assisted protein folding: representation of amino acid kinetics at the tRNA level. AB - Transfer RNA molecules (tRNA) have the thermodynamic potential to interact with each other to form dimers (hybridization energy, dG=-33.2+/-6.7 kcal/mole, compared to the folding energy of the cloverleaf configuration, dG=-25+/-4.4 kcal/mole, p<0.0001). The dG values have a strong negative correlation with the frequency of co-locations and substitutions of associated amino acids. We suggest that tRNA interactions participate in determining amino acid interactions (co locations) and consequently the 3D structures of peptides. PMID- 23044191 TI - Evolutionary suicide as a consequence of runaway selection for greater aggregation tendency. AB - Aggregation of individuals is a common phenomenon in nature. By aggregating, individuals can reap benefits but may also be subject to associated costs from increased competition. The benefits of aggregation can depend on population density, which in turn can be affected by aggregation when it determines reproductive success of individuals. The Allee effect is often considered to be one of the factors that can explain the evolution of aggregation behavior. We investigated this hypothesis with a mathematical model which integrates population dynamics and evolution. Individuals gain synergistically from aggregation but suffer from scramble competition with aggregation tendency as an evolving trait. We found that aggregation behavior can stabilize the population dynamics and reduce population growth. The results show that the Allee effect alone is not sufficient for aggregative behavior to evolve as an evolutionarily stable strategy. We also found that weak local competition does not promote aggregation due to feedback from the population level: under low competition, the population can achieve high density such that aggregation becomes costly rather than beneficial. Our model instead exhibits an escalation of aggregation tendency, leading to the extinction of the population in a process known as evolutionary suicide. We conclude that for aggregation to evolve as an evolutionarily stable strategy we need to consider other factors such as inter patch dispersal to new patches and avoidance of excessively large groups. PMID- 23044192 TI - Musculoskeletal ultrasound in Mexico 10 years after its inception. PMID- 23044193 TI - Lack of spirometry use in Danish patients initiating medication targeting obstructive lung disease. AB - BACKGROUND: Research indicates that a large proportion of patients using medication targeting obstructive lung disease have no history of spirometry testing. OBJECTIVE: To investigate the use of spirometry when initiating pulmonary medication targeting obstructive lung disease and to explore possible patient characteristics associated with undergoing spirometry. METHODS: Population-based cohort study. Three Danish National registers were linked enabling a retrieval of data on all primary and secondary healthcare services provided in the time period 2007-2010. RESULTS: In 2008 a total of 40,969 patients were registered as first time users of pulmonary medication targeting obstructive lung disease. The mean age of the study cohort was 55.6 yrs (SD 18.7). Spirometry test had been performed in 20,262 (49.5%) of the study cohort in the period from 6 months before to 12 months after their first prescription. Just above one third of the cohort, 14,275 (34.8%), had undergone spirometry in the two-month period close to redemption of their first prescription. Women and patients in the oldest age categories were less likely to have spirometry performed. CONCLUSIONS: Many patients initiate medication targeting obstructive pulmonary disease without having airway obstruction confirmed through spirometry. Only one third of the study cohort had a spirometry performed when initiating medication and half had still not undergone spirometry after a year. There should be an increased focus on confirming airway obstruction when initiating medication. PMID- 23044194 TI - Influence of DMSO on antifungal activity during susceptibility testing in vitro. AB - Dimethylsulfoxide (DMSO) binds within the plasma membrane of cells and increases membrane permeability. DMSO is used in antifungal (AF) susceptibility assays for water insoluble agents. DMSO was observed to cause Candida albicans to express enhanced, diminished, or no change in growth compared to control medium, suggesting DMSO could influence the efficacy of water-insoluble AF agents. The activity of 4 water soluble AF agents against 6 yeast species was tested under conditions similar to the CSLI M27-A3 method. Growth response to 0.5% and 1% DMSO was variable. In 15 of 67 AF assays, DMSO resulted in a different MIC-2 (substantial inhibition of growth) value compared to control. Two of these involved differences of two doubling dilutions. The results imply that, in some cases of water-insoluble AF drug-yeast combinations, the MIC-2 may be skewed from the more clinically relevant MIC, providing one reason for possible discordance between MIC results and clinical outcomes. PMID- 23044195 TI - Increase of myocardial performance by Rhodiola-ethanol extract in diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhodiola rosea (also known as golden root or roseroot) is a perennial plant of the Crassulaceae family that grows in the Arctic and in the mountainous regions of Europe, Asia, and North America. The rhizome and roots of this plant have been long used as traditional medicine in Eastern Europe and Asia for enhancing physical and mental performance. AIM OF THE STUDY: The present study is designed to investigate the cardiac action of Rhodiola-ethanol extract in streptozotocin-induced diabetic rats (STZ-diabetic rats) with heart failure. MATERIALS AND METHODS: Diabetes was induced in Wistar rats by injection of streptozotocin. We measured the changes of body weight, water intake, and food intake in three groups of age-matched rats; the normal control received vehicle, STZ-diabetic rat received Rhodiola-ethanol extract or vehicle. Cardiac output, heart rate, blood pressure, and hemodynamic dP/dt in addition to plasma insulin and glucose level were also determined. The mRNA and protein levels of PPARdelta were measured using real-time PCR and Western blotting, respectively. RESULTS: Food intake, water intake and blood glucose were raised in STZ-diabetic rats showing lower body weight and plasma insulin, as compared with the control. Also, cardiac output, heart rate, blood pressure and hemodynamic dP/dt were markedly reduced in STZ-diabetic rats indicating the heart failure physiologically. After a 21-day treatment with Rhodiola-ethanol extract, cardiac output was raised in STZ-rats while the diabetic parameters were not modified. The PPARdelta expression of both mRNA and protein was markedly elevated in the heart of STZ-rats receiving treatment with Rhodiola-ethanol extract. Also, the increased phosphorylation level of cardiac troponin-I was restored by this treatment with Rhodiola-ethanol extract. Otherwise, increase of cardiac output by Rhodiola-ethanol extract was blocked by antagonist of PPARdelta in STZ-diabetic rats. CONCLUSIONS: Our results suggest that ethanol extract of Rhodiola has an ability to increase the cardiac output in STZ-diabetic rats showing heart failure. Also, increase of PPAR-delta is responsible for this action of Rodiola ethanol extract. PMID- 23044196 TI - A method for the integration of satellite vegetation activities observations and magnetic susceptibility measurements for monitoring heavy metals in soil. AB - We present a procedure for monitoring heavy metals in soil based on the integration of satellite and ground-based techniques, tested in an area affected by high anthropogenic pressure. High resolution multispectral satellite data were elaborated to obtain information on vegetation status. Magnetic susceptibility measurements of soils were collected as proxy variable for monitoring heavy metal presence. Chemical analyses of heavy metals were used for supporting and validating the integrated monitoring procedure. Magnetic and chemical measurements were organized in a GIS environment to be overlapped to satellite based elaborations and to analyze the pattern distribution. Results show the presence of correlation between anomalies in vegetation activity and soil characteristics. The relationship between the distribution of normalized difference vegetation index anomalies and magnetic susceptibility values provides hints for adopting the integrated procedure as preliminary screening to minimize monitoring efforts and costs by supporting the planning activities of field campaigns. PMID- 23044197 TI - Environmentally friendly chemical recycling of poly(bisphenol-A carbonate) through phase transfer-catalysed alkaline hydrolysis under microwave irradiation. AB - The various and widespread uses of polycarbonate (PC) polymers require a meaningful and environmentally friendly disposal method. In this study, depolymerisation of polycarbonate with water in a microwave reactor is suggested as a recycling method. Hydrolysis was investigated in an alkaline (NaOH) solution using a phase-transfer catalyst. All of the experiments were carried out in a sealed microwave reactor, in which the reaction pressure, temperature and microwave power were continuously controlled and recorded. In the hydrolysis products, bisphenol-A monomer was obtained and identified by FTIR measurements. PC degradation higher than 80% can be obtained at 160 degrees C after a microwave irradiation time of either 40 min or 10 min using either a 5 or 10% (w/v) NaOH solution, respectively. GPC, TGA and DSC measurements of the PC residues revealed that surface erosion is the degradation mechanism. First-order reaction kinetics were estimated by implementing a simple kinetic model. Finally, greater than 85% degradation was achieved when waste CDs were treated with the same method. The results confirm the importance of the microwave power technique as a promising recycling method for PC-based waste plastics, resulting in monomer recovery in addition to substantial energy savings. PMID- 23044198 TI - Effect of the adsorbate kinetic diameter on the accuracy of the Dubinin Radushkevich equation for modeling adsorption of organic vapors on activated carbon. AB - This paper investigates the effect of the kinetic diameter (KD) of the reference adsorbate on the accuracy of the Dubinin-Radushkevich (D-R) equation for predicting the adsorption isotherms of organic vapors on microporous activated carbon. Adsorption isotherms for 13 organic compounds on microporous beaded activated carbon were experimentally measured, and predicted using the D-R model and affinity coefficients. The affinity coefficients calculated based on molar volumes, molecular polarizabilities, and molecular parachors were used to predict the isotherms based on four reference compounds (4.3<=KD<=6.8 A). The results show that the affinity coefficients are independent of the calculation method if the reference and test adsorbates are from the same organic group. Choosing a reference adsorbate with a KD similar to that of the test adsorbate results in better prediction of the adsorption isotherm. The relative error between the predicted and the measured adsorption isotherms increases as the absolute difference in the kinetic diameters of the reference and test adsorbates increases. Finally, the proposed hypothesis was used to explain reports of inconsistent findings among published articles. The results from this study are important because they allow a more accurate prediction of adsorption capacities of adsorbents which allow for better design of adsorption systems. PMID- 23044200 TI - [Multivariate analysis of hepatic encephalopathy occurrence in patients with liver failure]. AB - To investigate the risk factors of hepatic encephalopathy in patients with liver failure. Nine-hundred-and-seventy-six hepatitis B virus (HBV) patients with liver failure were retrospectively analyzed. Clinical data (sex, age, family history, liver cirrhosis, diabetes, celiac infection, pulmonary infection, liver kidney syndrome, upper gastrointestinal hemorrhage) and laboratory findings (albumin, globulin, total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase (AST), gamma-glutamyl transferase, alkaline phosphatase, cholesterol, cholinesterase, K+, Na+, creatinine, international normalized ratio (INR), alpha-fetoprotein, HBV DNA, white blood cell, hemoglobin, platelet) were collected and used to screen the risk factors for hepatic encephalopathy by univariate and multiple regress analyses. Multiple logistic regression analysis indicated that upper gastrointestinal hemorrhage [risk (R) = 0.993, relative hazard (RH) = 2.699, 95% confidence interval (CI): 1.567-4.651], pulmonary infection [R = 1.043, RH = 2.839, 95% CI: 1.680-4.797], INR [R = 0.257, RH = 1.293, 95% CI: 1.220-1.370], AST level [R = 0.001, RH = 1.001, 95% CI: 1.000 1.001], and cirrhosis [R = 0.569, RH = 1.815, 95% CI: 1.112-2.965] were closely correlated with hepatic encephalopathy. HBV-infected patients presenting with upper gastrointestinal haemorrhage, pulmonary infection, prolonged INR, elevated AST, or liver cirrhosis should be carefully monitored for indications of hepatic encephalopathy to initiate timely therapeutic interventions. PMID- 23044199 TI - Arsenic extractability and uptake by velvetgrass Holcus lanatus and ryegrass Lolium perenne in variously treated soils polluted by tailing spills. AB - Phytostabilization should be considered as an appropriate phytoremediation technique to restore the area affected by tailing spills in Zloty Stok, where arsenic ores were mined and processed for several centuries. The study aimed to compare the suitability of velvetgrass (Holcus lanatus L.) and ryegrass (Lolium perenne L.) for development of plant cover in that area. Various treatments commonly applied to support phytostabilization were examined. A pot experiment was carried out to assess the effects of soil amendment with phosphate (P), sewage sludge (SS) and iron salts (Fe) on arsenic extractability and its uptake by grass. Four kinds of soil material, containing 356-5350 mg kg(-1) As, were examined. Velvetgrass proved to be more resistant than ryegrass to the toxicity of soil arsenic. Ammonium sulphate extractability of As in soils correlated well with As concentrations in the biomass of both grass species. In three of four tested soils, application of Fe failed to decrease As extractability and to reduce its concentrations in the aboveground parts of grasses. Application of P and SS resulted in increased As solubility in soils, but their effects on plant biomass and As uptake were ambiguous. SS had a strong beneficial influence on the growth of velvetgrass, while such an effect was not observed for ryegrass. PMID- 23044201 TI - [Efficacy of lamivudine on acute-on-chronic liver failure in patients with chronic hepatitis B]. AB - To observe the therapeutic effects of lamivudine treatment in patients with early to mid-stage hepatitis B virus-related acute-on-chronic liver failure (HBV ACLF). Clinical data of 73 hospitalized patients with HBV-ACLF were retrospectively analyzed. Prothrombin time (PT, active coagulation), HBV DNA, and model for end-stage liver disease (MELD) score data from treatment weeks 4, 8, 24, and 48 were collected and analyzed using the statistical t-test. During the treatment duration, the complete virologic response rates were 57.5% (42/73) at 4 weeks, 71.0% (44/62) at 8 weeks, 83.1% (49/59) at 24 weeks, and 86.5% (45/52) at 48 weeks. The partial virologic response rates were 30.1% (22/73) at 4 weeks, 25.8% (16/62) at 8 weeks, 17.0% (10/59) at 24 weeks, and 13.5% (7/52) at 48 weeks. At week 48, the survival rate was 71.2% (52/73) and the probability of survival was higher in the complete virological response rate (VRR) group than in the partial VRR group [45/73 (61.6%) vs. 7/73 (30.1%), respectively; P = 0.000]. In addition, there were significant improvements in the serum normalization rate of HBV DNA, alanine aminotransferase, aspartate aminotransferase, albumin, total bilirubin, PT and MELD score in surviving patients compared to baseline (P less than 0.05) and in the complete VRR group compared to the partial VRR group (P less than 0.05). Antiviral therapy using lamivudine may be an effective therapeutic option for patients with HBV-ACLF. PMID- 23044202 TI - [Comparison of peg-interferon monotherapy to peg-interferon and nucleoside analogue combination therapy for hepatitis B: a meta-analysis of randomized controlled trials]. AB - To evaluate the efficacy and safety of pegylated-interferon (Peg-IFN) treatment as monotherapy or in combination with nucleoside analogues (NAs) for treating chronic hepatis B (CHB) infection.Searches of PubMed, OVID, EMBASE, and the Chinese Medical (WanFang, CNKI, and VIP) databases were conducted to identify all relevant randomized controlled trials published since January 1990. Twelve studies comparing Peg-IFN monotherapy to NA combination therapy (lamivudine (LAM), n =8); adefovir (ADV), n = 4) met the inclusion criteria (treatment duration, range: 48-52 weeks; follow-up, range: 24 weeks to three years). Meta analysis was performed with RevMan 5.0 using the fixed-effects and random-effects models. Patients who had received combination therapy had a higher biochemical response rate at the end of treatment than those who had received monotherapy (51.1% vs. 38.9%, odds ratio (OR) = 1.63, 95% confidence interval (CI): 1.33 2.01, P less than 0.01). Subgroup analysis of Peg-IFN combination therapies with LAM or ADV indicated that neither NA type significantly enhanced the increased efficacy of combination therapy compared to monotherapy. The combination therapy subgroups also had higher virologic response rates at the end of treatment than the monotherapy subgroups (LAM: 65.9% vs. 34.9%, OR = 3.57, 95% CI: 1.83-6.95, P less than 0.01; ADV: 74.6% vs. 46.2%, OR = 3.66, 95% CI: 2.13-6.30, P less than 0.01). Moreover, the combination therapy group had a higher sustained biochemical response rate at the end of follow-up than the monotherapy group (47.6% vs. 42.1%, OR = 1.28, 95% CI: 1.05-1.55, P less than 0.05). The LAM combination therapy subgroup had a significantly higher biochemical response rate than the monotherapy subgroup, but there was no significant difference between the LAM and ADV combination therapy subgroups. At the end of follow-up, the ADV combination therapy subgroup had a significantly lower rate of hepatitis B e antigen (HBeAg) than the monotherapy subgroup, but there was no significant difference between the ADV and LAM combination therapy subgroups for HbeAg reduction. The combination therapy group and monotherapy group showed no statistically significant differences in HBsAg reduction or occurrence of severe adverse events. Peg-IFN/NA combination therapy produces a higher biochemical response rate in CHB patients than PEG-IFN monotherapy. Moreover, Peg-IFN/ADV combination therapy produces a greater reduction in HBeAg than Peg-IFN monotherapy. PMID- 23044203 TI - [Correlative analysis of different HBV genotypes and autoantibodies in hepatitis B patients]. AB - To study the genotypes of hepatitis B virus (HBV) in patients from Chongqing district and determine the prevalence of autoantibodies in these patients. HBV genotyping was carried out by restriction fragment length polymorphism analysis of venous blood serum samples from 252 chronic hepatitis B (CHB) patients and 25 healthy controls. Indirect immunofluorescent assay was used to detect autoantibodies, including antinuclear antibody, anti-mitochondrial antibody, anti smooth muscle (SM) antibody, and anti-liver and kidney microsomal antibody. Immunospot assay was used to detect anti-ribonucleoprotein/anti-SM antibodies, anti-SS-A antibody, anti-SS-B antibody, anti-scl-70 antibody, and anti-Jo-1 antibody. Correlations between the production of autoantibodies and patient age and sex and various genetypes of HBV were analyzed by the Chi-squared test. The most frequent HBV genotype in CHB patients was B (67.3%), followed by genotype C (32.7%). Genotypes A, D, E, F, G and H were not detected in any of the CHB patients. The positive rate of autoantibodies was higher in the CHB patients than in the healthy group (76.98% vs. 12.00%, X2 = 44.60, P less than 0.05). There was no significant differences in the autoantibodies profiles of CHB patients carrying the B or C genotypes ( X2 = 0.0016, P more than 0.05). The main HBV genotypes in CHB patients in the Chongqing district are B and C. Autoantibodies are prevalent among these CHB patients, and are correlated with patient age and course of liver disease but not HBV genotype or patient sex. PMID- 23044204 TI - [Effects of hydroxycamptothecin on TGFb1, a-SMA and collagen I expression in rat hepatic satellite cells]. AB - To investigate the molecular mechanism of hydroxycamptothecin (HCPT)-mediated anti-hepatic fibrosis by evaluting its effects on expression of tumor growth factor-beta 1 (TGFb1), alpha-smooth muscle actin (a-SMA) and collagen I (Col I) in hepatic satellite cells (HSCs). Cultured HSCs were treated with different concentrations of HCPT: low-dose group, 0.25 mg/L; middle-dose group, 0.5 mg/L; high-dose group, 0.75 mg/L; and control group, 0 mg/L. Cell proliferation was assessed by the MTT assay. The mRNA expressions of TGFb1, a-SMA and Col I were determined by reverse transcription-polymerase chain reaction. The protein expressions of TGFb1 and a-SMA were detected by Western blot. The content of Col I in the cultured HSCs' supernatant was measured by enzyme-linked immunosorbent assay. The MTT absorbance values of the low-dose group (0.631+/-0.074), middle dose group (0.469+/- 0.012) and high-dose group (0.204+/- 0.001) were significantly lower than that of the control group (0.793+/-0.098; F = 82.86, P less than 0.01). Compared with the control group, the HCPT-treated groups showed significantly down-regulated gene expressions of TGFb1 (control: 0.716+/-0.064 vs. low: 0.611+/-0.040, middle: 0.510+/-0.014, high: 0.403+/-0.026), a-SMA (control: 0.696+/-0.075 vs. low: 0.579+/-0.037, middle: 0.470+/-0.024, high: 0.299+/-0.017), and Col I (control: 1.019+/-0.056 vs. low: 0.835+/-0.022, middle: 0.696+/-0.055, high: 0.322+/-0.104) (all, P less than 0.01). Meanwhile, HCPT treated HSCs showed significantly reduced protein expressions of TGFb1 (control: 0.872+/-0.053 vs. low: 0.654+/-0.047, middle: 0.545+/-0.042, high: 0.436+/-0.039) and a-SMA (control: 0.858+/-0.050 vs. low: 0.620+/-0.045, middle: 0.525+/-0.042, high: 0.434+/-0.052) (all, P less than 0.01). The Col I levels secreted by HSCs were significantly lower in the HCPT-treated groups (low: 168.367+/-16.453 ng/ml; middle: 141.284+/-11.731 ng/ml; high: 132.910+/-10.048 ng/ml) than in the control group (188.733 +/-18.299 ng/ml) (all, P less than 0.01). The mechanism of HCPT mediated anti-hepatic fibrosis may involve down-regulation of TGFb1 expression to inhibit HSC proliferation and activation, as well as reduction of Col I synthesis and secretion. PMID- 23044206 TI - [Relationship between IL6 -572G/C polymorphism and hepatocellular carcinoma in men]. AB - To study the relationship between the interleukin (IL)6 -572G/C polymorphism and risk of hepatocellular carcinoma (HCC) in men.A hospital-based case-control study was conducted with 500 male HCC patients without tumor history in other organs and 590 healthy male controls without history of tumors or chronic diseases. All HCC cases were diagnosed by histopathology. The controls were recruited from the Department of Orthopedic Trauma and Ophthalmology at the same hospital. The IL-6 promoter -572G/C polymorphism and its genotype variants were detected by real time fluorescence quantitative PCR. The Chi-squared test and unconditional logistic regression analyses were applied to determine the risk of HCC among men carrying the different genotype variants.The frequencies of alleles and distribution of genotypes in the -572G/C loci were not significantly different between the HCC cases and controls (P more than 0.05). The Chi-squared test indicated that the polymorphisms of the loci were not associated with HCC in our male population. However, after adjusting by multivariate logistic regression, the odds ratio (OR) of HCC for the G allele (CG + GG genotypes) carriers was 1.31 (95% confidence interval (CI): 1.00 - 1.71) compared with the CC genotype. Among the male HBV carriers, the CG genotype increased HCC risk significantly (OR = 1.60, 95% CI: 1.14 - 2.24) compared with the CC genotype. A trend test indicated that HCC risk was significantly increased with the numbers of G alleles (P trend less than 0.05). Breslow-Day tests of homogeneity of the ORs indicated an interaction between hepatitis B virus (HBV) infection and polymorphisms of IL-6 (P less than 0.05). The synthetic odds ratio (OReg) of HBV infection and harboring a G allele was 5.95 (95% CI: 3.99-8.87), which represented a super multiplication interaction.Polymorphism of the IL-6 promoter -572 loci may be associated with HCC occurrence in men. Moreover, there is a super multiplication interaction for HCC risk between HBV infection and harboring the IL-6 G allele. PMID- 23044205 TI - [Angiotensin (1-7) inhibits angiotensin II-stimulated expression of connective tissue growth factor mRNA in hepatic stellate cells]. AB - To explore the angiotensin peptide [Ang (1-7)]-mediated inhibition of Ang II in human hepatic stellate cells (HSCs) and determine the involvement of the ACE2-Ang (1-7)-Mas axis. The human HSC line, LX2, was used in all experiments, and divided into control (unstimulated) and Ang II-stimulated (10-6 mol/L) groups. The Ang II stimulated cells were further divided among several pre-treatment (prior to Ang II) groups: ROCK-inhibited (Y27632 blocking agent, 10-6 mol/L); irbesartan inhibited (AT-1 receptor antagonist, 10-6 mol/L); and Mas receptor-inhibited (A779 Mas receptor antagonist, 10-6 mol/L). To explore the potential inhibitory effects of various Ang family members, the Ang II-stimulated and pre-treated LX2 cells were exposed to Ang (1-7) (10-6 mol/L) for 24 h. Western blot, reverse transcription-polymerase chain reaction (RT-PCR), and QuantiGene assay were used to assess changes in protein and mRNA expression levels of RhoA, ROCK, and connective tissue growth factor (CTGF). Compared with the control group, Ang II stimulated cells showed significantly increased levels of RhoA protein (0.337+/ 0.074 vs. 0.870+/-0.093), ROCK2 mRNA (0.747+/-0.061 vs. 0.368+/-0.023), and CTGF mRNA (0.262+/-0.007 vs. 0.578+/-0.028) (all, P less than 0.01). Pre-treatment with irbesartan or Y27632 eliminated these responses. Ang (1-7) inhibited the Ang II-stimulated up-regulation of RhoA, ROCK, and CTGF. Ang (1-7) can inhibit the Ang II-stimulated up-regulation of RhoA, ROCK and CTGF in hepatic stellate cells, indicating that the ACE2-Ang (1-7)-Mas axis, an important branch of the renin-Ang aldosterone system is involved in the occurrence and development of liver fibrosis. PMID- 23044207 TI - [Identification of HBx-related integration sites in HBsAg-positive hepatocellular carcinoma biopsy]. AB - To identify the integration sites in the host genome for the hepatitis B virus (HBV)-encoded X protein (HBx) in hepatocellular carcinoma (HCC) biopsies that are positive for hepatitis B surface antigen (HBsAg). HCC biopsies were obtained from six patients that were HBV carriers, as demonstrated by the presence of HBsAg in their serum and sero-negativity for antibody to HBsAg. DNA was extracted from the tissue, fractionated, and circularized. Primers were designed according to the HBx sequence and used to amplify the circularized DNA templates by inverse polymerase chain reaction (IPCR). The amplified DNA fragments were checked by electrophoresis, cloned into the PMD18-T expression vector, and sequenced. Sequence alignment was performed by the Blast algorithms. Seven electrophoresis bands yielded 22 sequencing results, which represented a total of three HBx integration sites in the host genome: 19q12, 2q32.2, 22q12. The 19q12 integration site encompasses the CCNE1 gene, which encodes a G1/S-specific cyclin-E1. HBx related integration sites exist in HBsAg-positive HCC biopsies. The CCNE1 gene may play a role in the development of HBx-related HCC. PMID- 23044208 TI - Serum levels of perfluorinated compounds and sperm Y:X chromosome ratio in two European populations and in Inuit from Greenland. AB - This study investigated whether perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS), which exhibit reproductive toxicity in experimental animals, affect sperm sex chromosome ratio. The Y:X ratio was determined by fluorescence in situ hybridization. Serum concentrations of PFOA and PFOS were measured in 607 men from Greenland, Poland and Ukraine using liquid chromatography-tandem mass spectrometry. Data was analyzed by linear and nonlinear regression. We observed no associations between PFOA and Y:X ratio (p=0.845 in a linear model, p=0.296 in a nonlinear model). A positive nonlinear association between PFOS and Y:X ratio was observed (p=0.016), with no association in a linear model (p=0.118). Analyzing the populations separately, a negative trend between categorized PFOS exposure and Y:X ratio was observed for the Inuit (B=-0.002, p=0.044). In conclusion, there was a negative trend between Y:X ratio and PFOS in the Inuit, while there was no association between PFOA and the Y:X ratio in adult men. PMID- 23044209 TI - Synthesis of polyethylene glycol- and sulfobetaine-conjugated zwitterionic poly(L lactide) and assay of its antifouling properties. AB - A new antifouling polyester monomethoxy-poly(ethylene glycol)-b-poly(L-lactide)-b poly(sulfobetaine methacrylate) (MPEG-PLA-PSBMA) was obtained by ring-opening polymerization of L-lactide, and subsequent click chemistry to graft the azide end-functionalized poly(sulfobetaine methacrylate) (polySBMA) moieties onto the alkyne end-functionalized MPEG-PLA (MPEG-PLA-alkyne). The chemical structure of the polymer was characterized using (1)H nuclear magnetic resonance and Fourier transform infrared spectroscopy, and its physical properties (including molecular weight, glass transition temperature, and melting point) were determined using gel permeation chromatography and differential scanning calorimetry. To investigate its hydrophilicity and stability, as well as its antifouling properties, the polymer was also prepared as a surface coating on glass substrates. The wettability and stability of this polyester was examined by contact angle measurements. Furthermore, its antifouling properties were investigated via protein adsorption, cell adhesion studies, and bacterial attachment assays. The results suggest that the prepared zwitterionic polyester exhibits durable wettability and stability, as well as significant antifouling properties. The new zwitterionic polyester MPEG-PLA-PSBMA could be developed as a promising antifouling material with extensive biomedical applications. PMID- 23044210 TI - [Usefulness of haemoperfusion in the treatment of the severe septic patient: an update]. AB - Haemoperfusion is an extracorporeal technique that removes endotoxin and/or inflammatory mediators by means of an adsorptive mechanism during the passage of the blood through a porous filter. Most of the studies in the literature use polymyxin B as the adsorptive agent. This treatment is based on the assumption that the removal of endotoxin and inflammatory mediators from the circulation attenuates the inflammatory response in sepsis. This review summarizes the theoretical basis, and the experimental and clinical results published to date with the use of haemoperfusion. Although most of the studies show positive results, some doubts have arisen about the suitability of the methods described (small number of cases, low quality of the experimental design, and excessive mortality in the control groups). There are also some inconsistencies regarding the theoretical basis of its use (lack of positive effects after the removal of endotoxin from the circulation using alternative mechanisms, discrepancies regarding the best moment to initiate the therapy, unexplained beneficial effects in the absence of increased endotoxin levels). It is the opinion of the authors that haemoperfusion represents a promising therapy for the treatment of sepsis, but consider that its usefulness requires confirmation in well designed studies before being included in protocols. PMID- 23044211 TI - Metals in blood and urine, and thyroid function among adults in the United States 2007-2008. AB - The thyroid is integral to regulation of development and metabolism. Certain metals have been shown to affect thyroid function in occupationally exposed persons, but few studies have been conducted in the general population. This study evaluates the association between biomarkers of metal exposure and thyroid hormones in the US population. Analyses included adults participating in the 2007 2008 National Health and Nutrition Examination Survey, with no history of thyroid disease or use of thyroid medications, and with data on metals in blood (lead, cadmium and mercury) and urine (lead, cadmium, mercury, barium, cobalt, cesium, molybdenum, antimony, thallium, tungsten and uranium), and thyroid hormones (TSH, free and total T3 and T4) in serum (N=1587). Multivariate linear regression was used to model the association between thyroid hormone levels, and metals in either urine (creatinine-adjusted) or blood. Metal concentrations were considered as both continuous and categorical variables. Models were adjusted for: age, sex, race, BMI, serum lipids, serum cotinine, pregnancy and menopausal status, and use of selected medications. Few participants (<5%) had free T3, free T4, or TSH levels outside the reference range. However, 9.2% (SE=1.2%) had low T3 and 9.4% (SE=1.1%) had low T4. Metals were detected in nearly all blood and urine samples, with the highest levels seen for urinary molybdenum (median 42.5MUg/L). When including all blood metals, mercury was associated with decreases in T3 and T4, while cadmium was associated with decreased TSH. Urinary cadmium was associated with increases in both T3 and T4 (models including all metals measured in urine). Urinary thallium and barium were associated with decreased T4 (both) and T3 (barium). For TSH, cesium was associated with decreased, and tungsten with increased levels. Given the high prevalence of exposure to metals, associations of the size reported here could indicate an appreciable contribution of metals exposure to the prevalence of thyroid disorders. These findings indicate the importance of further research to further examine these relationships. PMID- 23044212 TI - D-Lys(3)-GHRP-6 antagonizes the effect of unacylated but not of acylated ghrelin on the growth of HECa10 murine endothelial cells. AB - Recent studies demonstrate that ghrelin can be an endogenous regulator of angiogenesis. We studied direct effects of human acylated (hAG) and unacylated (hUAG) ghrelin, as well as of rat acylated ghrelin (rAG) on the growth of HECa10 murine endothelial cells. Ghrelin was applied separately or together with D Lys(3)-GHRP-6, which is commonly used as an antagonist of ghrelin receptor type 1a - GHS-R1a. The growth of HECa10 cells was assessed with Mosmann and in selected study conditions also with BrdU and TUNEL methods. Both hAG and hUAG (10(-5) M to 10(-12) M) inhibited the growth of HECa10 cells in 24h and 72 h cultures. Similarly, rAG decreased the growth of the cells after 24h (10(-7) M and 10(-11) M), and after 72 h (10(-7) M, 10(-8) M and 10(-11) M). Unexpectedly, D-Lys(3)-GHRP-6 itself also inhibited the growth of these cells at 10(-4) to 10( 6) M in 24h, 48 h (dose-response effect) and 72 h cultures. D-Lys(3)-GHRP-6 did not modify the inhibitory effect of rAG. However, D-Lys(3)-GHRP-6 at the concentration of 10(-4) M diminished, abolished or even reversed the inhibitory effect of hUAG in 72 h culture and this was dependent on ghrelin concentrations. These data indicate that both AG and UAG have antiangiogenic properties at least at the level of endothelial growth, through decreased metabolic activity of the cells or stimulation of apoptosis. D-Lys(3)-GHRP-6 (inhibitor of GHS-R1a) seems not to be an appropriate antagonist in this experimental condition. Similar effects of these substances on HECa10 cells suggest that they are not mediated by GHS-R1a. PMID- 23044213 TI - Time for a view on screen time. PMID- 23044214 TI - Proposed alternative phase ratio variation method for the calculation of liquid vapour partition coefficients of volatiles. AB - The phase ratio variation PRV method is a classical way to determine the partition coefficients of volatile compounds between their solution and vapour phases in a variety of circumstances. However, some results obtained by this method can be disappointing. A new PRV equation in which the initial liquid-phase solute concentration is replaced by the liquid-phase solute concentration at equilibrium is proposed. This proposed PRV equation is a second-order polynomial equation. To thoroughly examine the possible modes of calculation, noisy dummy data were generated using both the classical, first-order PRV model (PRV(1)) and the proposed, second-order model (PRV(2)). Thus, pseudo-data obtained from simulations were compared to published experimental data. We observed that the second-order model, PRV(2), produces a lower variability, allowing improved K precision. Moreover, the obtained K(PRV(2)) values are very close to those obtained by classical equilibrium headspace analysis (EHSA). The PRV(2) model we propose responds to the demand for a simple, reliable method and is a useful alternative for the calculation of liquid-vapour partition coefficients. PMID- 23044215 TI - Effects of mobile phase composition and temperature on the supercritical fluid chromatography enantioseparation of chiral fluoro-oxoindole-type compounds with chlorinated polysaccharide stationary phases. AB - The indole ring is present in many pharmaceutically active compounds, as in MaxiPostTM (or BMS-204352), an active pharmaceutical ingredient for post-stroke neuroprotection. Two different fluoro-oxindole-type chiral solutes derived from MaxiPost were prepared. The structural modification was placed on the NH indole function, which is probably taking part in the bioactivity, but also probably in the chromatographic enantiomer separation. Baseline resolution of the enantiomers of MaxiPost and the two derivatives was achieved on two commercial chlorinated polysaccharide stationary phases: cellulose tris-(3-chloro-4 methylphenylcarbamate) and amylose tris-(5-chloro-2-methylphenylcarbamate) (Lux Cellulose-2 and Lux-Amylose-2 from Phenomenex) in supercritical fluid chromatography (SFC). The effects of molecular structure on SFC retention and enantioresolution are studied. The effect of temperature, modifier nature (methanol or ethanol) and proportion were investigated in order to select the best conditions for preparative purposes. A temperature study led to Van't Hoff plots that were strongly dependent on the mobile phase composition. From linear portions of the plots for separation, thermodynamic parameters of the separation could be calculated. Incidentally, particular adsorption-desorption effects were observed. Semi-preparative resolution was then achieved, allowing retrieving about 10mg purified enantiomers for bioactivity testing. PMID- 23044216 TI - Optimization of the peak capacity per unit time. AB - The peak capacity per unit time or chromatographic productivity, P(c)(t), was calculated and optimized for four different sample mixtures (small molecules, peptides from protein digests, and mixtures of small and large intact proteins) analyzed on 4.6 mm I.D. columns packed with three different brands of core-shell particles. The calculations were based on the column permeabilities and on their van Deemter curves measured under isocratic conditions. The 3D plots of the peak capacity are provided as a function of the gradient steepness and the column length at three values of the inlet pressure and two temperatures. The maximum peak capacities obtained per unit time were 103 min(-1) for small molecules, 111 min(-1) for peptides, 63 min(-1) for small proteins, and 22 min(-1) for large proteins. They are all achieved for the shortest column lengths run at the maximum achievable flow rate (5 mL/min) and for an optimum gradient steepness, which had to be calculated. Remarkably, the best separation productivity of these columns cannot be achieved with modern UPLC instruments that deliver flow rates no larger than 5 mL/min. With instruments able to deliver a 15 mL/min flow rate and acquire data at 320 Hz, 4.6 mm * 50 mm columns packed with shell particles operated at 600 bar and a temperature of 60 degrees C, would give peak capacities per unit time of 256 min(-1) for small molecules, 237 min(-1) for peptides, 186 min(-1) for small proteins, and 59 min(-1) for large proteins. PMID- 23044217 TI - Application of dispersive solid-phase extraction and ultra-fast liquid chromatography-tandem quadrupole mass spectrometry in food additive residue analysis of red wine. AB - A novel and effective dispersive solid-phase extraction (dSPE) procedure with rapid magnetic separation using ethylenediamine-functionalized magnetic polymer as an adsorbent was developed. The new procedure had excellent clean-up ability for the selective removal of the matrix in red wine. An accurate, simple, and rapid analytical method using ultra-fast liquid chromatography-tandem quadrupole mass spectrometry (UFLC-MS/MS) for the simultaneous determination of nine food additives (i.e., acesulfame, saccharin, sodium cyclamate, aspartame, benzoic acid, sorbic acid, stevioside, dehydroacetic acid, and neotame) in red wine was also used and validated. Recoveries ranging from 78.5% to 99.2% with relative standard deviations ranging from 0.46% to 6.3% were obtained using the new method. All target compounds showed good linearities in the tested range with correlation coefficients (r) higher than 0.9993. The limits of quantification for the nine food additives were between 0.10 MUg/L and 50.0 MUg/L. The proposed dSPE UFLC-MS/MS method was successfully applied in the food-safety risk monitoring of real red wine in Zhejiang Province, China. PMID- 23044218 TI - A survey of plants and plant products traditionally used in livestock health management in Buuri district, Meru County, Kenya. AB - BACKGROUND: Up till now, nomadic communities in Africa have been the primary focus of ethnoveterinary research. Although mainly arable and/or mixed arable/pastoral farmers, Ameru of central Kenya are known to have a rich history of ethnoveterinary knowledge. Their collective and accumulative ethnoveterinary knowledge (EVK) is likely to be just as rich and worth documenting. The aim of the study was to document and analyse the ethnoveterinary knowledge of the Ameru. METHODS: Non-alienating, dialogic, participatory action research (PAR) and participatory rural appraisal (PRA) approaches involving 21 women and men aged between 50 and 79 years old were utilized. A combination of snowball and purposive sampling methods were used to select 21 key respondents. The methods comprised a set of triangulation approach needed in EVK for non-experimental validation of ethnoknowledge of the Ameru. RESULTS: A total of 48 plant species distributed in 26 families were documented with details of diseases/ill-health conditions, parts of plants used and form of preparation and administration methods applied to different animal groups. Of these families, Fabaceae had the highest number of species (16.67%), followed by Solanaceae (12.5%), Asteraceae and Euphorbiacea (each comprising 8.33%), Lamiaceae (6.25%), Apocynaceae and Boraginaceae (each comprising 4.17%), while the rest of the 19 families, each was represented by a single plant species. About 30 livestock diseases/ill-health conditions were described, each treated by at least one of the 48 plant species. Most prevalent diseases/ill-health conditions included: - anaplasmosis, diarrhea, East Coast fever, pneumonia, helminthiasis, general weakness and skin diseases involving wounds caused by ectoparasites. CONCLUSION: The study showed that there was a rich knowledge and ethnopractices for traditional animal healthcare amongst the Ameru. This study therefore provides some groundwork for elucidating the efficacy of some of these plants, plant products and ethnopractices in managing livestock health as further research may lead to discovery of useful ethnopharmaceutical agents applicable in livestock industry. PMID- 23044220 TI - Can sleep heal memory? PMID- 23044221 TI - [Establishment of a stable urethral stricture model in New Zealand rabbits]. AB - OBJECTIVE: To explore the method of building a stable urethral stricture (US) model in New Zealand white rabbits. METHODS: Through 10X magnification optical microscope, a resection of 1.0cm urethral mucosa was made in 6 male rabbits and other 6 male rabbits were controlled. After 60 days, the rabbits were evaluated with urethrography, urethral pressure profile (UPP) and histology. RESULT: Urethrography demonstrated a stricture with narrow lumen and discontinuous mucosa in the resection group. The urethras of the control animals were all normal. UPP showed that the urethral pressure on operative site in the controlled group was 14.67+/-2.16cmHO, and 27.83+/-3.71 cmHO in the resection group. There was significant statistical difference between the two groups (P<.01). The urothelium was well-distributed, covered without any inflammatory cells in the controlled group, which had 3-4 layers of the epithelial cells. And the urothelium was unequally covered with neutrophils and lymphocytes in the resection group. CONCLUSIONS: We establish the way to build a stable urethral stricture model of New Zealand rabbits by the microsurgical technique, which is a good laboratory model to research all kinds of urethral stricture. Urethrography and histology combined UPP are the reliable methods to identify the urethral stricture. PMID- 23044219 TI - Coherence and frequency in the reticular activating system (RAS). AB - This review considers recent evidence showing that cells in the reticular activating system (RAS) exhibit (1) electrical coupling mainly in GABAergic cells, and (2) gamma band activity in virtually all of the cells. Specifically, cells in the mesopontine pedunculopontine nucleus (PPN), intralaminar parafascicular nucleus (Pf), and pontine dorsal subcoeruleus nucleus dorsalis (SubCD) (1) show electrical coupling, and (2) all fire in the beta/gamma band range when maximally activated, but no higher. The mechanism behind electrical coupling is important because the stimulant modafinil was shown to increase electrical coupling. We also provide recent findings demonstrating that all cells in the PPN and Pf have high threshold, voltage-dependent P/Q-type calcium channels that are essential to gamma band activity. On the other hand, all SubCD, and some PPN, cells manifested sodium-dependent subthreshold oscillations. A novel mechanism for sleep-wake control based on transmitter interactions, electrical coupling, and gamma band activity is described. We speculate that continuous sensory input will modulate coupling and induce gamma band activity in the RAS that could participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. PMID- 23044223 TI - Reduced efficacy of mesenchymal stromal cells in preventing graft-versus-host disease in an in vivo model of haploidentical bone marrow transplant with leukemia. AB - Mesenchymal stromal cell (MSC) immunosuppressive properties have been applied to treat graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplants (HSCTs). We have previously demonstrated that MSC infusions early after haplo-HSCT prevent GVHD in a haploidentical-HSCT mouse model. Now, we investigated the impact that MSCs' immunosuppressive properties have on the graft versus-leukemia (GVL) effect. First, to mimic a chronic myeloid leukemia (CML) relapse after a haploidentical HSCT, lethally irradiated mice were coinfused with haploidentical donor bone marrow cells plus syngenic hematopoietic progenitors transduced with a retroviral vector encoding both the BCR/ABL oncogene and the DeltaNGFR marker gene. As expected, a CML-like myeloproliferative syndrome developed in all the recipient animals. The addition of haploidentical splenocytes to the transplanted graft prevented CML development by a GVL effect, and all transplanted recipients died of GVHD. This GVL mouse model allowed us to investigate the impact of MSCs infused to prevent GVHD on days 0, 7, and 14 after HSCT, on the GVL effect, expecting an increase in leukemic relapse. Strikingly, a high mortality of the recipients was observed, caused by GVHD, and only few leukemic cells were detected in the recipient animals. In contrast, GVHD prevention by MSCs in the absence of BCR/ABL leukemic cells resulted in a significant survival of the recipients. In vitro data pointed to an inability of MSCs to control strong CTLs responses against BCR/ABL. Our results show that, although an evident increase in leukemic relapses induced by MSCs could not be detected, they showed a reduced efficacy in preventing GVHD that precluded us to draw clear conclusions on MSCs' impact over GVL effect. PMID- 23044222 TI - New emerging roles for epithelial cell extrusion. AB - Epithelia use a unique process called 'cell extrusion' to remove cells from a layer, while preserving their barrier function. Specifically, a cell destined to die triggers formation of an actin and myosin-ring in the live neighboring epithelial cells surrounding it, which squeeze the dying cell out. During extrusion, the surrounding cells expand toward one another and meet to fill the gap left by the extruded cell. Recent studies have revealed new roles of extrusion in controlling developmental morphogenesis, maintaining homeostatic cell numbers, and how this process is usurped during bacterial pathogenesis. Here, we review recent advances in new processes that require cell extrusion and the signaling pathways controlling it. PMID- 23044224 TI - Low-molecular weight chitosan/vascular endothelial growth factor short hairpin RNA for the treatment of hepatocellular carcinoma. AB - AIMS: Vascular endothelial growth factor (VEGF) has been shown to be a key driving force for angiogenesis and tumor growth in hepatocellular carcinoma (HCC). As an emerging approach to block this angiogenic stimulator, the RNA interference (RNAi) technique has rapidly developed but is hindered for in vivo applications due to low cellular uptake and poor stability of small RNA. Based on low molecular weight chitosan (LMWC), a gene delivery system of short hairpin RNA (shRNA) directed against VEGF was constructed. The objective of this study was to investigate whether LMWC/shRNA nano-complexes can effectively inhibit VEGF expression in cancer cells and tumor tissues and suppress tumor growth in different HCC models. MAIN METHODS: The transfection experiment and Real-time qPCR assay were used to evaluate the transfection efficiency and gene suppression activity of LMWC/shRNA complexes in Hepa 1-6 murine hepatocarcinoma cells. The therapeutic effect of LMWC/ VEGF shRNA was further tested in ectopic and orthotopic liver cancer models. KEY FINDINGS: LMWC/VEGF shRNA complexes significantly inhibited VEGF expression of HCC cells and liver tumor tissues. LMWC obviously enhanced and prolonged the deposition of shRNA at the tumor site when LMWC/shRNA complexes were intravenously injected into orthotopic allograft liver tumor-bearing mice. The administration of LMWC/VEGF shRNA complexes by intratumoral or intravenous injection demonstrated more effective suppression of tumor angiogenesis and tumor growth in different HCC models compared with naked shRNA. SIGNIFICANCE: This study demonstrated the feasibility of using LMWC as a potential carrier for RNA interference drugs in liver cancer therapy. PMID- 23044225 TI - Nitric oxide has no obligatory role in isoflurane late preconditioning against myocardial stunning. AB - AIMS: Isoflurane has been demonstrated to produce late preconditioning against myocardial stunning. We tested the hypothesis that this effect is dependent upon an increased production of nitric oxide. MAIN METHODS: Studies were performed in 18 conscious dogs, chronically instrumented to measure coronary blood flow and myocardial wall thickening (WT). In Group 1 (control; n=7), a 10-min coronary occlusion was produced followed by reperfusion; WT was monitored until full recovery. In Group 2 (n=6), the same occlusion-reperfusion protocol was performed 24h after inhalation of 1 MAC isoflurane (1.4% in O(2)) for 60 min. In Group 3 (n=5), the late anti-stunning effect of isoflurane was evaluated following non selective inhibition of NOS with N-nitro-l-arginine (l-NA, 30 mg/kg on 3 days beginning 1 day prior to isoflurane). Expression of eNOS and iNOS protein was measured by Western blotting. KEY FINDINGS: Two to 3h of reperfusion was required for recovery of WT following isoflurane (Group 2). In contrast, without isoflurane (Group 1), WT remained markedly reduced (30% below baseline) at this time point and required more than 6h of reperfusion for recovery. Treatment with l-NA (Group 3) did not alter time-course of recovery of WT following isoflurane. Isoflurane caused an increased expression of eNOS, but not of iNOS. SIGNIFICANCE: Isoflurane produced late preconditioning against myocardial stunning. Although this effect was associated with an up-regulation of eNOS, its persistence following l-NA suggested that an increased production of nitric oxide did not play an obligatory role. PMID- 23044226 TI - Further evidence for the anti-inflammatory activity of oleocanthal: inhibition of MIP-1alpha and IL-6 in J774 macrophages and in ATDC5 chondrocytes. AB - AIMS: Given the relevance of degenerative joint diseases in our society, the development of a novel pharmacologic intervention is a critically important public health goal. Recently, oleocanthal, a polyphenolic natural compound from extra virgin olive oil, has emerged as a potential therapeutic weapon for the treatment of inflammatory degenerative diseases. The goal of this study was to further evaluate the anti-inflammatory activity of oleocanthal in murine macrophages J774 and murine chondrocytes ATDC5 with a particular focus on the inhibition of gene expression of pro-inflammatory factors such as MIP-1alpha and IL-6. MAIN METHODS: ATDC5 murine chondrogenic cells and murine macrophages J774 were used. J774 macrophages were tested with different doses of oleocanthal and cell viability was evaluated using the MTT assay. Western blot analysis was carried on in J774 cells using anti NOS2 antibody. Nitrite accumulation was determined in culture supernatant using the Griess reaction. MIP-1alpha and IL-6 mRNA levels were determined using SYBR Green-based quantitative RT-PCR. MIP 1alpha and IL-6 protein levels were evaluated using specific ELISA assay. Several cytokines, involved in the inflammatory response, were also tested by BioPlex assay. KEY FINDINGS: First, oleocanthal inhibits LPS-induced NO production in J774 macrophages, without affecting cell viability. Moreover, it inhibits MIP 1alpha and IL-6 mRNA expression, as well as protein synthesis, in both ATDC5 chondrocytes and J774 macrophages. Oleocanthal also inhibits IL-1beta, TNF-alpha and GM-CSF protein synthesis from LPS-stimulated macrophages. SIGNIFICANCE: Our data confirm a clear potent role of oleocanthal as anti-inflammatory therapeutic agent for future treatment of arthritis or other inflammatory diseases. PMID- 23044227 TI - Protective effects of anthocyanins on the ectonucleotidase activity in the impairment of memory induced by scopolamine in adult rats. AB - AIMS: We investigated whether the treatment with anthocyanins prevents the scopolamine-induced memory deficits and whether ectonucleotidase activities and purine levels are altered in the cerebral cortex (CC) and hippocampus (HC) in this model of mnemonic deficit in rats. MAIN METHODS: The animals were divided into 4 experimental groups: control (vehicle), anthocyanins (Antho), scopolamine (SCO), and scopolamine plus anthocyanins (SCO+Antho). After seven days of treatment, they were tested in the inhibitory avoidance task and open field test and submitted to euthanasia. The CC and the HC were collected for biochemical assays. The effect of treatment with Antho (200 mgkg(-1), i.p.) was investigated in rats trained to a stable level of performance and post-treated with SCO (1 mgkg(-1), i.p. 30 min after training). KEY FINDINGS: The treatment with SCO decreased the step-down latency in inhibitory avoidance task. Antho prevented the scopolamine-induced memory impairment and also the increase of NTPDase activity in the CC and HC. Furthermore, the treatment with anthocyanins prevents the decrease in 5'-nucleotidase activity and the increase in adenosine deaminase activity induced by SCO in HC. In addition, the treatment with Antho prevented the decrease in ATP levels induced by SCO in the CC and HC. SIGNIFICANCE: Our results show that scopolamine may affect purinergic enzymatic cascade or cause alterations in energy metabolism inducing loss of memory. In contrast Antho could reverse these changes, suggesting a neuroprotective effect of Antho on ectonucleotidase activities and neuronal energetic metabolism. PMID- 23044228 TI - Clioquinol-induced increase and decrease in the intracellular Zn2+ level in rat thymocytes. AB - AIMS: Clioquinol is emerging as a potential therapy for some diseases, such as Alzheimer disease and cancer. This agent is a lipophilic chelator of Zn(2+). In this study, the effect of clioquinol on the intracellular Zn(2+) level was examined in order to gain insights into the toxicological profile of clioquinol. MAIN METHODS: The effect of clioquinol was estimated using a flow cytometer and FluoZin-3, a fluorescent indicator for Zn(2+), in rat thymocytes. KEY FINDINGS: Clioquinol, at concentrations ranging from 10 to 300 nM, augmented FluoZin-3 fluorescence in a concentration-dependent manner. However, the effect induced by 1 MUM clioquinol was less than that by 300 nM clioquinol. Removal of extracellular Zn(2+), using the membrane impermeable Zn(2+)-chelator diethylenetriamine-N,N,N',N",N"-pentaacetic acid (DTPA), abolished the clioquinol induced augmentation of FluoZin-3 fluorescence. Clioquinol did not augment Fluo-3 fluorescence, an indicator of intracellular Ca(2+), in the presence of DTPA. The results suggested that clioquinol caused an extracellular Zn(2+)-dependent increase in the intracellular Zn(2+) concentration. However, in the presence of DTPA, clioquinol at micromolar concentrations (1-10 MUM) attenuated FluoZin-3 fluorescence in a concentration-dependent manner. Clioquinol even at 10 MUM did not affect FluoZin-3 fluorescence under cell-free condition. The concentration response relationship for the clioquinol induced change in Zn(2+) level appeared to be bell-shaped. These results indicate that micromolar concentrations of clioquinol, without chelated Zn(2+), decrease intracellular Zn(2+) concentration. SIGNIFICANCE: The effect of clioquinol on the intracellular Zn(2+) level varies, depending on the extracellular Zn(2+) concentration and the clioquinol concentration. Clioquinol may therefore exert various types of Zn(2+)-dependent cytotoxicity. PMID- 23044229 TI - Quality of isolated pig islets is improved using perfluorohexyloctane for pancreas storage in a split lobe model. AB - Pancreas transportation between donor center and islet production facility is frequently associated with prolonged ischemia impairing islet isolation and transplantation outcomes. It is foreseeable that shipment of pig pancreases from distant centralized biosecure breeding facilities to institutes that have a long term experience in porcine islet isolation is essentially required in future clinical islet xenotransplantation. Previously, we demonstrated that perfluorohexyloctan (F6H8) is significantly more efficient to protect rat and human pancreata from ischemically induced damage compared to perfluorodecalin (PFD). To evaluate the effect of F6H8 on long-term stored pig pancreases in a prospective study, we utilized the split lobe model to minimize donor variability. Retrieved pancreases were dissected into the connecting and splenic lobe, intraductally flushed with UW solution and immersed alternately in either preoxygenated F6H8 or PFD for 8-10 h. Prior to pancreas digestion, the intrapancreatic pO2 and the ratio of ATP-to-inorganic phosphate was compared utilizing 31P-NMR spectroscopy. Isolated islets were cultured for 2-3 days at 37 degrees C and subjected to quality assessment. Pancreatic lobes stored in preoxygenated F6H8 had a significantly higher intrapancreatic pO2 compared to pancreata in oxygen-precharged PFD (10.11 +/- 3.87 vs. 1.64 +/- 1.13 mmHg, p < 0.05). This correlated with a higher ATP-to-inorganic phosphate ratio (0.30 +/- 0.04 vs. 0.14 +/- 0.01). No effect was observed concerning yield and purity of freshly isolated islets. Nevertheless, a significantly improved glucose stimulated insulin response, increased viability and postculture survival (57.2 +/- 5.7 vs. 39.3 +/- 6.4%, p < 0.01) was measured in islets isolated from F6H8 preserved pancreata. The present data suggest that F6H8 does not increase islet yield but improves quality of pig islets isolated after prolonged cold ischemia. PMID- 23044230 TI - Real-time PCR using SYBR Green for the detection of Shigella spp. in food and stool samples. AB - Shigella spp are exquisitely fastidious Gram negative organisms that frequently get missed in the detection by traditional culture methods. For this reason, this work has adapted a classical PCR for detection of Shigella in food and stool specimens to real-time PCR using the SYBR Green format. This method follows a melting curve analysis to be more rapid and provide both qualitative and quantitative data about the targeted pathogen. A total of 117 stool samples with diarrhea and 102 food samples were analyzed in Public Health Regional Laboratory of Nabeul by traditional culture methods and real-time PCR. To validate the real time PCR assay, an experiment was conducted with both spiked and naturally contaminated stool samples. All Shigella strains tested were ipaH positive and all non-Shigella strains yielded no amplification products. The melting temperature (T(m) = 81.5 +/- 0.5 degrees C) was consistently specific for the amplicon. Correlation coefficients of standard curves constructed using the quantification cycle (C(q)) versus copy numbers of Shigella showed good linearity (R2 = 0.995; slope = 2.952) and the minimum level of detection was 1.5 * 103 CFU/g feces. All food samples analyzed were negative for Shigella by standard culture methods, whereas ipaH was detected in 8.8% culture negative food products. Moreover, the ipaH specific PCR system increased the detection rate over that by culture alone from 1.7% to 11.1% among patients with diarrhea. The data presented here shows that the SYBR Green I was suitable for use in the real time PCR assay, which provided a specific, sensitive and efficient method for the detection and quantification of Shigella spp in food and stool samples. PMID- 23044231 TI - [Prospective controlled trial of safety of human umbilical cord derived mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis]. AB - OBJECTIVE: To evaluate the safety of human umbilical cord derived-mesenchymal stem cell (UC-MSC) transplantation therapy in patients with decompensated liver cirrhosis. METHODS: UC-MSCs were transplanted intravenously into patients with decompensated liver cirrhosis. Serum levels of glucose (GLU), total cholesterol (TC), blood urea nitrogen (BUN), alpha fetoprotein (AFP), white blood cells (WBC), and prothrombin activity (PA) were detected at different time points after UC-MSCs transplantation. RESULTS: Most UC-MSC transplanted patients experienced an improvement in quality of life, to varying degrees. With the exception of low grade fever in a few patients, side effects and oncogenic events were rare (treatment group: 1/38 vs. control group: 1/16; P more than 0.05). The UC-MSCs transplantation showed no effect on GLU, TC, BUN, AFP, WBC, or PA. CONCLUSION: UC MSCs transplantation in patients with decompensated liver cirrhosis is safe and may improve the patient's quality of life. PMID- 23044232 TI - [Significance of lipopolysaccharide binding protein in serum and ascites of patients with hepatic cirrhosis complicated with spontaneous bacterial peritonitis]. AB - OBJECTIVE: To investigate the levels of lipopolysaccharide binding protein (LBP) in serum and ascites of cirrhotic patients, and determine their diagnostic value for spontaneous bacterial peritonitis (SBP). METHODS: Cirrhotic patients were divided into groups according to diagnosis of SBP, ascites without SBP, no ascites. To explore the significance of LBP in clinically suspect SBP cases, the ascites without SBP group was sub-divided into two groups according to the symptoms of abdominal pain or elevated white blood cell (WBC) count, and abdominal pain combined with elevated WBC count. Two control groups were composed of patients with intraperitoneal pus and a group of healthy, non-cirrhotic individuals. The LBP levels in serum and ascites were determined by enzyme-linked immunosorbent assay (ELISA). The ascites routine, ascites culture and albumin assay were carried out in the Second Affiliated Hospital of Chongqing Medical University. Data between the two groups were compared using the t-test or nonparametric test of independent samples, and the areas under the curve were compared using the Z test. Results The levels of LBP in serum and pus were significantly higher in the intraperitoneal pus group than in the cirrhosis group with ascites (P less than 0.01). RESULTS: The level of serum LBP was significantly higher in the cirrhosis group with SBP than in the cirrhosis group without SBP but with ascites and the cirrhosis group with no ascites (P less than 0.01). There was no significant difference in the level of ascites LBP in the cirrhosis group with SBP and the cirrhosis group without SBP but with ascites (P more than 0.05). In the clinically suspect cases with SBP, the levels of LBP in serum and ascites were significantly higher than those in the cirrhosis group without SBP but with ascites (228.00 mug/ml vs. 80.95 mug/ml and 22.50 mug/ml vs. 11.45 mug/ml, P less than 0.05). Determination of serum LBP had a higher sensitivity than the determination of ascites LBP or ascites WBC. CONCLUSION: Gram-negative bacteria infection in the intra-abdominal cavity causes serum and body fluid levels of LBP to increase significantly. Patients with cirrhosis complicated with SBP have significantly elevated levels of serum LBP. The serum and ascites LBP levels are significantly elevated in SBP patients with suspected clinical diagnosis. Measurements of both the serum LBP and ascites LBP may have diagnostic value for SBP. PMID- 23044233 TI - [Study of potential protective effects of blueberry on hepatic cytochrome P450 2E1 expression in rats with immune hepatic fibrosis]. AB - OBJECTIVE: To study the protective effects of blueberry against rat immune hepatic fibrosis, specifically through the expression of hepatic cytochrome P450 2E1. METHOD: Fifty Wistar rats were randomly divided into five study groups (n = 10 each): Group A: normal control group, Group B: hepatic fibrosis model group, Group C: preventive group administered blueberry juice, Group D: preventive group administered Fu-Fang-Bie-Jia-Ruan-Gan tablet, and Group E: preventive group administered a combination of blueberry juice and Fu-Fang-Bie-Jia-Ruan-Gan tablet. The hepatic fibrosis model was established by intraperitoneal injection of porcine serum once daily for 12 weeks. Simultaneously, rats in preventive groups (Groups C-E) were perfused with blueberry juice or Fu-Fang-Bie-Jia-Ruan Gan tablet or combinations of blueberry juice and Fu-Fang-Bie-Jia-Ruan-Gan tablet, respectively, for 12 weeks. The normal control group was perfused with saline for 12 weeks. All animals were sacrificed at the end of the 12 weeks, and serum levels of alanine aminotransferase (ALT) were measured and activities of superoxide dismutase (SOD), malondialdehyde (MDA), and hydroxyproline (Hyp) in liver homogenates were determined. Pathology of hepatic fibrosis was evaluated by hematoxylin-eosin (HE) and Masson staining. Expression of CYP2E1 was detected by real-time RT-PCR, immunohistochemical techniques, and Western blotting. RESULTS: Serum ALT levels were not significantly different in the control and treatment groups (F=4.056, P more than 0.05): A: 37.87+/-4.53 U/L, B: 49.23+/-9.81 U/L, C: 39.94+/-6.32 U/L, D: 40.50+/-5.70 U/L, and E: 38.24+/-8.43 U/L. Compared with Group B, the pathological stages of hepatic fibrosis were significantly reduced in the prevention groups (C-E) (F=95.097, P less than 0.05). Hyp and MDA in liver homogenates of groups C-E were significantly lower than those of Group B (Hyp: C: 472.68+/-44.14 mug/g, D: 416.12+/-39.38 mug/g, E: 429.51+/-55.14 mug/g vs. B: 603.16+/-68.92 mug/g, F=39.315, P less than 0.05; MDA: C: 0.83+/-0.06 nmol/mg, D: 0.96+/-0.08 nmol/mg, E: 0.85+/-0.06 nmol/mg vs. B: 1.24+/-0.15 nmol/mg, F=46.376, P less than 0.05). In contrast, SOD activities in Group C-E were significantly higher than those in Group B (C: 2.47+/-0.38 U/mg, D: 1.95+/-0.45 U/mg, E: 2.16+/ 0.23 U/mg vs. B: 1.56+/-0.41 U/mg, F=25.557, P less than 0.05). Compared with Group A, the mRNA and protein expressions of CYP2E1 were increased in groups B-E, however the differences did not reach statistical significance (mRNA: F=0.897, protein: F=0.492, both P more than 0.05). The mRNA and protein expressions of CYP2E1 in groups C-E were lower than those of Group B, however the differences did not reach statistical significance (mRNA: F=0.897, protein: F=0.492, P more than 0.05). CONCLUSION: Blueberry exhibits certain protective effects against porcine serum-induced hepatic fibrosis in rats. The expression of hepatic cytochrome P450 2E1 in rats with immune hepatic fibrosis is not significantly different from the normal rats. Blueberry has no effect on the expression of hepatic cytochrome P4502E1. PMID- 23044234 TI - [The mechanisms of inhibitory effect of adenovirus-mediated wild-type PTEN gene on the proliferation in activated hepatic stellate cells in vitro]. AB - OBJECTIVE: Using an adenoviral vector, the wild-type PTEN gene was transduced into activated hepatic stellate cell (HSC) cultured in vitro and cell cycle markers and were detect. Thereby, the potential mechanisms of inhibitory effect of the wild-type PTEN overexpression on the proliferation in activated HSC was investigated. METHODS: The wild type PTEN gene was transduced into activated HSC (HSC-T6 ) cultured in vitro mediated by adenoviral vector. PTEN expression in HSC was measured by Western blot and Real-time fluorescent quantitation PCR. Flow cytometry (FCM) was then used to detect cell cycle phase of activated HSC. And the expressions of cyclinD1 and cyclin dependent kinase 4 (CDK4) in HSC were determined by Western blot. RESULTS: The data showed that exogenous wild type PTEN gene was successfully transduced and expressed in activated HSC cultured in vitro. The over-expression of wild type PTEN resulted in the increased number of HSC at G0/G1 phase ( P less than 0.01), and the number of HSC at S phase and G2/M phase were decreased significantly, P less than 0.01. Furthermore, there were decreased cyclinD1 and CDK4 expression in HSC infected with Ad-PTEN, P less than 0.01. CONCLUSION: The over-expression of wild type PTEN inhibit transition of activated HSC in vitro from G1 to S phase and arrest cell cycle of them at G0/G1 phase via the down-regulated expressions of cyclinD1 and CDK4, and then inhibit HSC proliferation. PMID- 23044235 TI - [Effect of reduced glutathione on proliferation of rat hepatic stellate cells and the Nrf2/HO-1 signaling pathway]. AB - OBJECTIVE: To explore the effects of reduced glutathione (GSH) on the proliferation of hepatic stellate cells and the nuclear factor erythroid 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. METHODS: The rat HSC-T6 cell line was activated by lipopolysaccharide (LPS; 0.1 mug/ml) and incubated with various concentrations of GSH (0, 1, 2, 5 and 10 mmol/L) for 24 h. Cell proliferation was evaluated by the MTT colorimetric assay. Collagen IV and hyaluronic acid (HA) contents were measured by chemiluminescence immunoassay of cell supernatants. Nrf2 and HO-1 protein expression was observed by immunohistochemistry. Nrf2 and HO-1 mRNA expression was assessed by semi quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). HO-1 activity was analyzed by spectrophotometer. RESULTS: GSH treatment inhibited HSC T6 proliferation and decreased the secretion of HA and collagen IV (P less than 0.05); GSH treatment of HSC-T6 cells also led to increased expression of Nrf2 and HO-1, and increased activity of HO-1 (P less than 0.05). CONCLUSION: GSH can inhibit the proliferation of hepatic stellate cells in vitro and reduce secretion of hyaluronic acid and collagen IV. The underlying mechanism in HSC-T6 cells may involve regulation of the Nrf2/HO-1 signaling pathway. PMID- 23044236 TI - [A randomized, double-blind, double-dummy, controlled, multicenter study of entecavir maleate versus entecavir for treatment of HBeAg-negative chronic hepatitis B: results at week 48]. AB - OBJECTIVE: To evaluate the efficacy and safety of entecavir (ETV) maleate versus ETV in Chinese patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). METHODS: This was a randomized, double-blind, double-dummy, controlled, multicenter study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A; n = 26) or 0.5 mg/day ETV maleate (n = 31). Hepatitis B virus (HBV) DNA levels were measured at weeks 12, 24, and 48 by the Roche Cobas Ampliprep/Taqman PCR assay. Adverse events (AE) were recorded. RESULTS: Baseline characteristics were similar between the two groups. At weeks 12, 24, and 48, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 4.24, 4.61 and 4.88 log10 IU/mL vs. B: 4.01, 4.50 and 4.99 log10 IU/mL, respectively; all P more than 0.05). Patients who achieved undetectable levels of serum HBV DNA (less than 20 IU/mL) at week 48 were similar in the two groups (A: 69.23% vs. B: 80.65%; P more than 0.05). Both groups achieved similar normalization of ALT at week 48 (A: 96.00% vs. B: 83.87%; P more than 0.05). The overall AE incidence was similar for the two groups (A: 22.22% vs. B: 9.38%; P more than 0.05). CONCLUSION: Entecavir maleate and entecavir showed similar efficacy and safety in patients with HBeAg-negative CHB. PMID- 23044237 TI - [Assessment of the factors associated with insulin resistance in patients with chronic hepatitis B infection]. AB - OBJECTIVE: To investigate the factors associated with insulin resistance (IR) in patients with chronic hepatitis B virus (HBV) infection. METHODS: Sixty-eight patients with mild chronic hepatitis B (MCHB) caused by HBV were recruited for study. Sixty-seven healthy individuals with no hepatitis virus infections and normal liver function were enrolled as controls. Demographic, anthropometric, clinical, and blood biochemical parameters were compared between the two groups. IR was determined by the homeostasis model assessment (HOMA-IR). The MCHB group was further divided into patients with IR (HOMA-IR: > 2.7) and patients without IR (HOMA-IR: less than 2.7). Demographic, anthropometric, clinical, and blood biochemical parameters were compared between the two sub-groups. Finally, the potential factors associated with IR were evaluated. RESULTS: Compared to the healthy controls, the MCHB patients had significantly higher serum insulin (Z = 5.451, P less than 0.01), alanine aminotransferase (ALT) (Z = -8.211, P less than 0.01) and HOMA-IR (Z = -5.631, P less than 0.01). IR was detected in 44.12% (30/68) of the MCHB patients. The levels of ALT and body mass index (BMI) were significantly different between the MCHB patients with IR and without IR (t = 2.358, and t = -3.566, P less than 0.05). There was a significant correlation between BMI, ALT, and HOMA-IR in the MCHB patients (r = 0.374, r = 0.282, P less than 0.05), but not with the HBV DNA loads (r = 0.015, P = 0.904). Binary logistic regression analysis indicated that BMI [Exp(B): 1.859, P less than 0.01] and ALT [Exp(B): 1.022, P less than 0.05] were independent risk factors of IR in MCHB. CONCLUSION: There is a high prevalence of insulin resistance in patients with mild hepatitis caused by chronic HBV infection. In these patients, IR is correlated with abnormal liver function and BMI, and not HBV load. PMID- 23044238 TI - [Dynamics of serum HBV DNA levels during the terminal phases of acute-on-chronic hepatitis B liver failure with different HBeAg status]. AB - OBJECTIVE: To investigate the dynamics and clinical significance of serum hepatitis B virus (HBV) DNA levels during the terminal phase of acute-on-chronic liver failure (ACLF) with different hepatitis B e antigen (HBeAg) status. METHODS: One-hundred-and-seven patients with terminal ACLF were tested for HBeAg status by electrochemiluminescence immunoassay and serum HBV DNA levels by real time PCR at three chronological time ranges, representing increasing severity of disease phases prior to death (day 0): 29-56 d, 15-28 d, and 0-14 d. RESULTS: In the 37 HBeAg(+) patients, HBV DNA levels at above-mentioned phases were 6.10+/ 1.63, 5.61+/-1.50, and 5.29+/-1.96 log10 copies/mL. In the 70 anti-HBe(+) patients, HBV DNA levels were 4.63+/-1.82, 5.81+/-1.78, and 4.93+/-1.73 log10 copies/mL. Phase to phase comparisons revealed that the HBV DNA level in the HBeAg(+) group was significantly higher than that in the anti-HBe(+) group at 29 56 d (P less than 0.05), and that 15-28 d and 0-14 d were not significantly different (P more than 0.05). Intragroup comparisons of phases revealed no significant differences in the HBeAg(+) group (P more than 0.05), but a significant difference between 15-28 d and 0-14 d (P less than 0.05) for the anti HBe(+) group. CONCLUSION: Serum levels of HBV DNA in patients with HBeAg positivity are higher than those in patients with anti-HBe positivity as the disease phase of ACLF nears fatality. Following the deterioration to liver failure, the HBV DNA load in HBeAg(+) patients remains stable while that in anti HBe(+) patients decreases. PMID- 23044239 TI - [Effect of RNAi-mediated silencing of SREBP2 gene on inflammatory cytokine induced cholesterol accumulation in HepG2 cells]. AB - OBJECTIVE: To investigate the effect of RNA interference (RNAi)-mediated silencing of the SREBP2 on inflammatory cytokine-induced cholesterol accumulation in HepG2 cells. METHODS: Short-hairpin (sh)RNA targeting SREBP2 or negative control (NC) shRNA were transfected into HepG2 cells by a liposomal method. G418 selective culturing was used to obtain the SREBP2 shRNA HepG2 and NC shRNA HepG2 cell lines. The two cell lines were cultured in serum-free medium and left untreated (control) or treated with TNF-a (20 ng/ml), low-density lipoprotein (LDL) loading (100 mug/ml), or a combination LDL plus TNF-a treatment. Lipid accumulation was evaluated by oil red O (ORO) staining. Intracellular cholesterol level was measured by enzymatic assay. The mRNA and protein levels of SREBP2 and its downstream target genes, LDL receptor (LDLr), and HMGCoA reductase, were measured by real-time PCR and Western blotting, respectively. RESULTS: SREBP2 shRNA HepG2 and NC shRNA HepG2 stable cell lines were successfully established. ORO staining and cholesterol quantitative analysis showed that LDL loading significantly increased intracellular cholesterol and that expression of SREBP2 further exacerbated the inflammatory cytokine-induced lipid accumulation, as seen in NC shRNA HepG2 cells. LDL loading of NC shRNA HepG2 decreased the gene and protein expressions of SREBP2, LDLr, and HMGCoA reductase, but the suppressive effect was overridden by inflammatory cytokine. SREBP2 shRNA HepG2 cells showed lower levels of cholesterol accumulation under LDL loading and inflammatory stress conditions. Moreover, the mRNA and protein levels of SREBP2, LDLr, and HMGCoA reductase were much lower than in NC shRNA HepG2 cells under the same conditions. CONCLUSION: Inflammatory cytokine exacerbated cholesterol accumulation in HepG2 via disrupting SREBP2. RNAi-mediated inhibition of SREBP2 expression significantly ameliorated the cholesterol accumulation induced by inflammatory cytokine. PMID- 23044240 TI - [A nude mouse model of hepatocellular carcinoma single cell-derived organ site specific metastasis]. AB - OBJECTIVE: To establish a single cell-derived organ site-specific metastatic model of human hepatocellular carcinoma (HCC) in the nude mouse. METHODS: Using the limited dilution method, HCCLM3-R-LM1 and HCCLM3-R-LnM1 cell lines were used to generate eight (LM1-S2, -S3, -S4, -S5, -S11, -S15, -S21, and -S23) and five (LnM1-S7, -S11, -S13, -S17, and -S20) single cell-derived monoclonal cell lines, respectively. The monoclonal cell lines were seeded into 4-week-old nude mice, and three weeks later the resultant subcutaneous tumor tissues were orthotopically transplanted into the livers of nude mice. At six weeks after implantation, lung and lymph node were extracted for analysis of the metastatic foci fluorescence area and pathology to assess the number of metastatic foci. RESULTS: Among the 13 mice implanted with the established monoclonal cell lines, six grew subcutaneous tumors. When orthotopically transplanted, the six tumors showed remarkably different metastatic potential and organ site-specific tropism. The fluorescence areas of lung metastatic foci were: LM1-S3, 80 923+/-10 162; LM1 S4, 1506 000+/-297 064; LM1-S5, 36 140+/-8 210; and LM1-S11, 508 448+/-134 272 (P less than 0.01); no lymph node metastases were found for these lines. For LnM1 S11, the fluorescence areas of lung and lymph node metastatic foci were 435 062+/ 206 620 and 1 254 000+/-225 171, respectively. CONCLUSION: We successfully established several monoclonal cell lines and nude mouse models of HCC with different metastatic potential and organ tropism. Among them, LM1-S3, LM1-S4, LM1 S5, and LM1-S11 have metastasis organotropism to lung. The LnM1-S11 line exhibits dual metastasis organotropism to lung and lymph node. These monoclonal cell lines and nude mouse models may represent useful tools for study of HCC metastasis organotropism. PMID- 23044241 TI - [Effect of magnesium isoglycyrrhizinate on PLA2 during liver tissue injury following limb ischemia/reperfusion in rats]. AB - OBJECTIVE: To investigate the effects of magnesium isoglycyrrhizinate (MI) on the changes of phospholipase A2 (PLA2) induced during liver tissue injury following limb ischemia/reperfusion (I/R) in rats. METHOD: Twenty-four healthy male Sprague Dawley rats weighing (230+/-30) g were randomly divided into three groups (n = 8 each) as follows: control (Group C: anesthetization without any ischemia); I/R injury (Group I/R: 4 h ischemia induced by rubber band ligation of the left hind limb around the roots of the hind limb, followed by 6 h of reperfusion, with 1 mL normal saline given via tail vein prior to reperfusion); MI-treated group (Group MI: underwent ischemia and reperfusion, with 1 mL MI (30 mg/kg) infused prior to reperfusion). Levels of TNFa and PLA2 in plasma and liver tissue were measured by enzyme-linked immunosorbent assay (ELISA). Levels of plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), myeloperoxidase (MPO), and malondialdehyde (MDA), and activities of MPO and MDA in liver tissue were measured by colorimetry. Ultrastructural changes of liver tissue were observed by electron microscopy. RESULTS: The MI group had significantly lower PLA2 and TNFa in liver homogenates and serum than the I/R group (both P less than 0.05). Serum ALT, AST, LDH, and CK were significantly lower in the MI group than in the I/R group (all P less than 0.05), as were the levels of MPO and MDA in liver homogenates and serum (all P less than 0.05). The I/R group showed significantly more liver tissue damage, which appeared to be attenuated in the MI group. CONCLUSION: MI treatment can inhibit the I/R-induced TNFa, PLA2, and MDA in plasma and liver tissue, as well as decrease the I/R-induced MPO activity in rats. Thus, MI may have protective effects against liver tissue injury following limb ischemia/reperfusion. PMID- 23044242 TI - Are there any seasonal changes of cognitive impairment, depression, sleep disorders and quality of life in hemodialysis patients? AB - OBJECTIVE: Cognitive impairment, depression, sleep disorders and impaired quality of life are very common in hemodialysis (HD) patients. However, whether there are any seasonal changes of cognitive impairment, depression, sleep disorders and quality of life in HD patients is not known. METHODS: The laboratory parameters, depressive symptoms, health-related quality of life, sleep quality (SQ) and cognitive function, were measured twice. RESULTS: A total of 66 HD patients were enrolled. Pre-dialysis systolic blood pressure (BP) and pre-dialysis diastolic BP were higher, whereas predialysis creatinine and sodium were lower in January compared to July. Among domains of Short Form 36 (SF-36), physical functioning, role-physical limitation, general health perception, vitality, role emotional, Physical Component Summary Score (PCS) were higher, whereas Beck Depression Inventory (BDI) score was lower in July compared to January. Stepwise linear regression analysis revealed that only change in albumin and smoking status were related with seasonal change of BDI scores. Additionally only change in Mental Component Summary score of SF-36 were related with change in PCS score of SF-36 scores. CONCLUSIONS: Depressive symptoms and quality of life but not SQ and cognitive function showed seasonal variability in HD patients. PMID- 23044243 TI - Obsessive compulsive disorder in veterans in primary care: prevalence and impairment. AB - OBJECTIVE: Obsessive compulsive disorder (OCD) is a severely impairing psychiatric disorder with an estimated 12-month prevalence of 0.39% to 1.20% in community settings. However, there has been little research on the prevalence of OCD in primary care settings and veteran samples. Thus, the present study investigated prevalence, comorbidity, and physical and mental health impairment of veterans with OCD. METHOD: A total of 854 veterans participated in a cross sectional investigation in primary care clinics in four Veteran Affairs Medical Centers. Participants completed the Mini International Neuropsychiatric Interview, Clinician-Administered PTSD Scale and Short-Form Health Survey. RESULTS: A total of 1.9% of participants met the diagnostic criteria for OCD based on the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition. Participants with OCD were significantly younger and demonstrated greater psychiatric comorbidity than participants without OCD. Participants with OCD also reported significantly more severe physical health impairment (role limitation, pain, general health), mental health impairment (emotional well being, role limitations, energy/fatigue) and impairment in social functioning than participants without OCD. CONCLUSIONS: These findings demonstrate moderately high prevalence and severe impairment associated with OCD in veterans, thus highlighting the need for improved recognition, assessment and specialized treatments for OCD in primary care settings and with veteran patients. PMID- 23044244 TI - Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. AB - OBJECTIVE: Benzodiazepines (BDZs) safety profiles in pregnancy suggest that the risk of major malformations (MMs) cannot be considered simply as a "class effect". The aim of this paper was to review and update the available literature on the risks of MMs in women exposed to BDZs in the first trimester of pregnancy. METHODS: PubMed was searched for English-language articles, from January 2001 to November 2011, introducing as keywords "teratogens", " major malformation", "foetus", "infant", "newborn", "pregnancy", in conjunction with "benzodiazepines" as a keyword or BDZ generic name as text words. RESULTS: Twelve studies were selected for the review. BDZ exposure during the first trimester of pregnancy seems not to be associated with an increasing risk of congenital MMs. Diazepam and chlordiazepoxide should be considered drugs of first choice. CONCLUSIONS: Data published in the last 10 years did not indicate an absolute contraindication in prescribing BDZs during the first gestational trimester. In any case, studies analyzed suffer from a number of methodological limitations such as lack of careful report of BDZ patterns of use in pregnancy, possible influences of recall bias, lack of controlling for confounding factors and lack of data concerning possible MMs in aborted fetuses. PMID- 23044245 TI - Association between uremic toxins and depression in patients with chronic kidney disease undergoing maintenance hemodialysis. AB - OBJECTIVE: Patients with chronic kidney disease (CKD) who are undergoing maintenance hemodialysis have a higher prevalence of depression than the general population. The underlying cause of this association is unknown, but may be related to accumulation of uremic toxins. Little is known about the association of accumulation of uremic toxins and depression in hemodialysis patients. METHOD: We conducted a cross-sectional study of 209 CKD patients from a single institution to evaluate the associations of a soluble small uremic toxin (urea), a soluble large uremic toxin (beta2 microglobulin) and two protein-bound uremic toxins [total p-cresol sulfate (PCS) and indoxyl sulfate (IS)] with the presence of depression. RESULTS: A total of 47 patients (22.4%) had depression. Depressive patients had lower body mass index, lower serum creatinine, lower serum albumin and lower total IS. Univariate and multivariate logistic regression analyses that adjusted for age, gender and other statistically significant variables indicated that depression was significantly and independently associated with lower serum albumin and lower total IS. The levels of urea, beta2 microglobulin and PCS were not significantly associated with depression. CONCLUSION: Our results indicate that depression in patients with CKD was significantly and independently associated with lower serum albumin and lower total IS. However, the pathological mechanisms underlying these associations are unknown. PMID- 23044246 TI - Associations between health risk behaviors and symptoms of schizophrenia and bipolar disorder: a systematic review. AB - OBJECTIVE: To systematically review the literature to determine if health risk behaviors in patients with schizophrenia or bipolar disorder are associated with subsequent symptom burden or level of functioning. METHOD: Using the PRISMA systematic review method we searched PubMed, Cochrane, PsychInfo and EMBASE databases with key words: health risk behaviors, diet, obesity, overweight, BMI, smoking, tobacco use, cigarette use, sedentary lifestyle, sedentary behaviors, physical inactivity, activity level, fitness, sitting AND schizophrenia, bipolar disorder, bipolar illness, schizoaffective disorder, severe and persistent mental illness, and psychotic to identify prospective, controlled studies of greater than 6 months duration. Included studies examined associations between sedentary lifestyle, smoking, obesity, physical inactivity and subsequent symptom severity or functional impairment in patients with schizophrenia or bipolar disorder. RESULTS: Eight of the 2130 articles identified met inclusion criteria and included 508 patients with a health risk behavior and 825 controls. Six studies examined tobacco use, and two studies examined weight gain/obesity. Seven studies found that patients with schizophrenia or bipolar illness and at least one health risk behavior had more severe subsequent psychiatric symptoms and/or decreased level of functioning. CONCLUSION: Tobacco use and weight gain/obesity may be associated with increased severity of symptoms of schizophrenia and bipolar disorder or decreased level of functioning. PMID- 23044247 TI - Male erectile dysfunction: integrating psychopharmacology and psychotherapy. AB - OBJECTIVE: Erectile dysfunction (ED), defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance, is the most common sexual problem in men. ED arises when there is disruption of the complex interplay between vascular, neurologic, hormonal and psychologic factors necessary for normal erectile function. It may have a significant effect on quality of life and portend undetected cardiovascular disease. Risk factors for development of ED include advancing age, tobacco use, a history of pelvic irradiation or surgery and antipsychotic use (Table 1) [1]. Treatment guidelines continue to evolve for optimal management of ED. In this article, we review diagnostic and treatment strategies for ED relevant to psychiatrists. METHOD: We present an integrative approach to the treatment of ED based on a review of the urologic and psychiatric literature. RESULTS: ED is multifactorial in origin and responsive to a variety of therapeutic interventions, including psychopharmacology and psychotherapy in which cognitive underpinnings of poor sexual performance, including diminished self-esteem, lack of confidence and perceived failures in the male role, are examined. CONCLUSIONS: Psychiatrists can readily perform a basic workup for ED as they integrate both a medical and therapeutic model when confronted with such patients. PMID- 23044248 TI - Cancer syndromes and therapy by stop-codon readthrough. AB - Several hereditary cancer syndromes are associated with nonsense mutations that create premature termination codons (PTC). Therapeutic strategies involving readthrough induction partially restore expression of proteins with normal function from nonsense-mutated genes, and small molecules such as aminoglycosides and PTC124 have exhibited promising results for treating patients with cystic fibrosis and Duchenne muscular dystrophy. Transgenic expression of suppressor tRNAs and depleting translation termination factors are, among others, potential strategies for treating PTC-associated diseases. In this review, the potential of using readthrough strategies as a therapy for cancer syndromes is discussed, and we consider the effect of nonsense-mediated decay and other factors on readthrough efficiency. PMID- 23044249 TI - First detection of Ixodes ricinus on beef cattle in Israel. AB - This is the first report of the presence of Ixodes ricinus on beef cattle in Israel. Up to now, in the Middle East this tick was considered to be confined to Turkey and northern Iran. In the present study, tick samples collected from field grazing beef cattle in western Galilee (northern Israel) were first examined morphologically for species-specific taxonomical features and then by molecular characterization. Ticks identified morphologically as I. ricinus were then examined by PCR with four different molecular markers: 12S rRNA, 16S rRNA, COX1 and cytochrome B. The PCR products were sequenced and compared with annotated I. ricinus sequences in GenBankTM and the analyzed sequences from the collected samples shared 98-99% identity with reported I. ricinus sequences. In contrast, sequences from the collected ticks shared identity of 91% or less with annotated sequences from other Ixodes species. Multiple alignments and neighbor-joining analyses performed for each of the four markers reinforced the results obtained from pairwise alignments. These findings demonstrated for the first time the presence in Israel of the tick species I. ricinus - with results confirmed by a combination of morphological examination and molecular analyses. PMID- 23044250 TI - Optimization of the pepsin digestion method for anisakids inspection in the fishing industry. AB - During the last 50 years human anisakiasis has been rising while parasites have increased their prevalence at determined fisheries becoming an emergent major public health problem. Although artificial enzymatic digestion procedure by CODEX (STAN 244-2004: standard for salted Atlantic herring and salted sprat) is the recommended protocol for anisakids inspection, no international agreement has been achieved in veterinary and scientific digestion protocols to regulate this growing source of biological hazard in fish products. The aim of this work was to optimize the current artificial digestion protocol by CODEX with the purpose of offering a faster, more useful and safer procedure for factories workers, than the current one for anisakids detection. To achieve these objectives, the existing pepsin chemicals and the conditions of the digestion method were evaluated and assayed in fresh and frozen samples, both in lean and fatty fish species. Results showed that the new digestion procedure considerably reduces the assay time, and it is more handy and efficient (the quantity of the resulting residue was considerably lower after less time) than the widely used CODEX procedure. In conclusion, the new digestion method herein proposed based on liquid pepsin format is an accurate reproducible and user-friendly off-site tool, that can be useful in the implementation of screening programs for the prevention of human anisakiasis (and associated gastroallergic disorders) due to the consumption of raw or undercooked contaminated seafood products. PMID- 23044251 TI - Theileria orientalis MPSP types in Australian cattle herds associated with outbreaks of clinical disease and their association with clinical pathology findings. AB - Between September 2010 and November 2011, 350 EDTA blood samples were received from 73 Australian cattle herds, as cases suspected to be infected with Theileria orientalis. Beef cattle were predominantly affected, with Angus and Angus crossbred cattle representing 48% of smear positive samples examined. DNA extracts were tested in conventional polymerase chain reaction (PCR) assays for genes encoding the p32, Ikeda, Chitose and Buffeli major piroplasm surface proteins (MPSP). PCR findings were compared with results of clinical pathology examinations of stained blood smears for parasitaemia and packed cell volume (PCV). PCR testing was much more sensitive than clinical pathology examinations in detecting T. orientalis infections, and concurrent testing of neat and diluted extracts gave significantly more PCR positive results than testing of neat extract alone. Significant associations and correlations were shown between PCR results of p32 and Ikeda assays with PCV levels indicative of anaemia, and with the level of parasitaemia estimated by smears. A high proportion of samples had concurrent Ikeda and Chitose infection, and significantly more clinical cases of theileriosis were associated with the Ikeda MPSP type as the sole infection, compared with sole infection with types Chitose or Buffeli. The findings indicate Ikeda type organisms were significantly associated with clinical parameters of theileriosis in cattle herds in eastern Australia, and that this type is most likely to be responsible for outbreaks of theileriosis experienced in affected Australian herds. In New South Wales, 11 of 14 regulatory districts yielded Ikeda positive samples, with five (Mid-Coast, Cumberland, Central North, Hume and Lachlan) containing 234/307 (76%) of the Ikeda positive samples. PMID- 23044252 TI - [A bariatric surgery programme in adolescents. Preliminary results]. PMID- 23044253 TI - [The biliary complications in live donor liver transplant do not affect the long term results]. AB - INTRODUCTION: Living donor liver transplantation (LDLT) is an effective treatment for patients with terminal chronic liver disease, despite the high incidence of biliary complications. The objective is to evaluate the results and long-term impact of biliary complications after THDV. PATIENTS AND METHODS: From 2000 to 2010, 70 right lobe LDLT were performed. Biliary complications (leakage and stenosis) of the 70 LDLT recipients were collected prospectively and analyzed retrospectively. RESULTS: A total of 39 patients (55.7%) had some type of biliary complication. Twenty nine presented a leak, and of these, 14 subsequently developed a stricture. In addition, 10 patients had a stenosis without prior leakage. The median time to onset of stenosis was almost a year. Patients with previous biliary leakage were more likely to develop stenosis (58% vs. 29.5% at 5 years, P=.05). With a median follow up of 80 months, 70.8% of patients were successfully treated by interventional radiology. After excluding early mortality, there were no differences in survival according to biliary complications. A decrease of biliary complications was observed in the last 35 patients compared with the first 35. CONCLUSIONS: LDLT is associated with a high incidence of biliary complications. However, long-term outcome of patients is not affected. After a median follow-up time of nearly seven years, no differences were found in survival according to the presence of biliary complications. PMID- 23044254 TI - Integrated and translational nonclinical in vivo cardiovascular risk assessment: gaps and opportunities. AB - Cardiovascular (CV) safety concerns are a significant source of drug development attrition in the pharmaceutical industry today. Though current nonclinical testing paradigms have largely prevented catastrophic CV events in Phase I studies, many challenges relating to the inability of current nonclinical safety testing strategies to model patient outcomes persist. Contemporary approaches include a spectrum of evaluations of CV structure and function in a variety of laboratory animal species. These approaches might be improved with a more holistic integration of these evaluations in repeat-dose studies, addition of novel endpoints with greater sensitivity and translational application, and use of more relevant animal models. Particular opportunities present with advances in imaging capabilities applicable to rodent and non-rodent species, technical capabilities for measuring CV function in repeat-dose animal studies, detection and quantitation of microRNAs and wider use of alternative animal models. Strategic application of these novel opportunities considering putative CV risk associated with the molecular drug target as well as inherent risks present in the target patient population could tailor or 'personalize' nonclinical safety assessment as a more translational evaluation. This paper is a call to action for the clinical and nonclinical drug safety communities to assess these opportunities to determine their utility in filling potential gaps in our current cardiovascular safety testing paradigms. PMID- 23044256 TI - Comparison of fenestrated endovascular and open repair of abdominal aortic aneurysms not suitable for standard endovascular repair. AB - BACKGROUND: Abdominal aortic aneurysms that are unsuitable for a standard endovascular repair (EVAR) could be considered for fenestrated endovascular repair (f-EVAR). The aim of this study was to conduct a risk-adjusted retrospective concurrent cohort comparison of f-EVAR and open repair for such aneurysms. METHODS: All patients who underwent repair of an abdominal aortic aneurysm that was unsuitable for a standard EVAR due to inadequate neck within one institution between January 2006 and December 2010 were identified. Case notes were retrieved for clinical data, Vascular Physiological and Operative Severity Score for enUmeration of Mortality and Morbidity (V-POSSUM) score, and aneurysm morphology. Computed tomography scans were reviewed to establish aneurysm morphology. RESULTS: A total of 107 patients were identified. The open surgery cohort included 54 patients (35 men) who were a median age of 72 years (interquartile range [IQR], 9.5; range, 60-86 years). The aortic cross-clamp was infrarenal in 20 patients, suprarenal or above in 21, and inter-renal in eight. Postoperatively, 63 major complications were noted in 30 patients, nine of whom required 16 reinterventions. Cumulative hospital stay of the cohort was 1170 days (median, 12; IQR, 13; range, 1-205 days) of which 234 days (median, 28; IQR, 36; range, 1-77 days) were in the intensive therapy unit (ITU). Perioperative mortality was 9.2% (n = 5), exactly as estimated by V-POSSUM. The f-EVAR cohort included 53 patients (47 men) who were a median age of 76 years (IQR, 11.50; range, 55-87 years). Two fenestrations and one scallop was the most frequent configuration (n = 31). Postoperatively, 37 major complications were noted in 18 patients, six requiring reintervention. Hospital stay was 559 days (median, 7; IQR, 4.5; range, 4-64 days), of which 31 days (median, 4; IQR, 10.5; range, 1-15 days) were in the ITU. Two patients died perioperatively (3.7%), resulting in an observed crude absolute risk reduction of 5.5% compared with open repair. The V POSSUM estimated perioperative death in five patients (9.4%) in the f-EVAR cohort. In a hypothetic scenario of the f-EVAR cohort undergoing open repair, V POSSUM estimated seven deaths (13.2%), resulting in an estimated risk-adjusted absolute risk reduction due to f-EVAR of 9.5%. CONCLUSIONS: In this group of patients, f-EVAR reduced mortality and morbidity substantially compared with open repair and also reduced total hospital stay and ITU utilization. PMID- 23044255 TI - Quantitative LC-MS/MS analysis of arachidonoyl amino acids in mouse brain with treatment of FAAH inhibitor. AB - An additional class of endogenous lipid amides, N-arachidonoyl amino acids (Ara AAs), is growing in significance in the field of endocannabinoids. The development, validation, and application of a sensitive and selective method to simultaneously monitor and quantify the level of Ara-AAs along with anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in mouse brain has been established. The linearity of the method over the concentration ranges of 0.2-120 pg/MUl for the standards of N-arachidonoyl amino acids, N-arachidonoyl alanine (NAAla), serine (NASer), gamma-aminobutyric acid (NAGABA), and glycine (NAGly); 0.7-90 pg/MUl for AEA-d(0)/d(8); and 7.5-950 pg/MUl for 2-AG was determined with R(2) values of 0.99. Also the effects of the FAAH inhibitor URB 597 on the endogenous levels of these analytes were investigated. AEA and NASer brain levels exhibit a dose dependent increase after systemic administration of URB 597, whereas NAGly and NAGABA were significantly decreased after treatment. NAAla and 2-AG were not altered after URB 597 treatment. The potential benefit of establishing this assay extends beyond the quantification of the Ara-AAs along with AEA and 2-AG in mouse brain, to reveal a variety of pharmacological effects and physiological roles of these analytes. PMID- 23044257 TI - Randomized controlled trial of remote endarterectomy versus endovascular intervention for TransAtlantic Inter-Society Consensus II D femoropopliteal lesions. AB - OBJECTIVE: This study evaluated outcomes of remote endarterectomy (RE) vs endovascular (ENDO) interventions on TransAtlantic Inter-Societal Consensus (TASC)-II D femoropopliteal lesions and identified factors predictive of restenosis. METHODS: From October 2004 to December 2008, 95 patients with TASC-II D lesions were randomized 1:1 to receive RE of the superficial femoral artery (SFA) with end point stenting (51 patients) or ENDO, consisting of subintimal angioplasty with stenting (44 patients). The groups were balanced for age, sex, atherosclerotic risk factors, and comorbidities. Categoric data were analyzed with chi2 tests, and time to event provided two-sided P values with a level of significance at .05 and 95% confidence intervals (CIs). Survival curves for primary patency were plotted using the Kaplan-Meier method. Univariate analysis for diabetes, hypertension, dyslipidemia, smoking, and critical ischemia was performed according to the Cox proportional hazards model. RESULTS: The mean follow-up was 52.5 months (range, 35-75 months). Five RE patients and four ENDO patients were lost to follow-up (censored). Primary patency was 76.5% (39 of 51) in RE and 56.8% (25 of 44) in ENDO (hazard ratio [HR], 2.6; 95% CI, 0.99-4.2; P=.05) at 24 months and was 62.7% (32 of 46) in RE and 47.7% (21 of 40) in ENDO (HR, 1.89; 95% CI, 0.94-3.78; P=.07) at 36 months. Assisted primary patency was 70.6% (36 of 51) in RE and 52.3% (23 of 44) in ENDO (HR, 2.45; 95% CI, 1.20-5.02; P=.01). Secondary patency overlapped the primary comparison data at 12 and 24 months; at 36 months, there was a slight but significative advantage for RE (HR, 2.26; 95% CI, 1.05-4.86; P=.03). Univariate analysis demonstrated that hypercholesterolemia and critical limb ischemia (CLI) were significantly related to patency failure, whereas diabetes was significant only in ENDO. These factors (hypercholesterolemia and CLI) were independent predictors of patency on Cox multivariate analysis. CONCLUSIONS: RE is a safe, effective, and durable procedure for TASC-II D lesions. Our data demonstrate a significantly higher primary, assisted primary, and secondary patency of RE vs ENDO procedures. Furthermore, overall secondary patency rates remain within the standard limits, although preoperative CLI and dyslipidemia continue to be associated with worse outcomes. Taken together, these data suggest that RE should be considered better than an endovascular procedure in SFA long-segment occlusion treatment. PMID- 23044258 TI - Fractured superior mesenteric artery stents after fenestrated endovascular aneurysm repair. AB - Stent fracture after fenestrated endovascular aneurysm repair is a recognized complication. In this report, we record the occurrence of superior mesenteric artery stent fractures in our series and describe the management of embolized stent fragments during secondary intervention. PMID- 23044259 TI - Exercise capacity is the strongest predictor of mortality in patients with peripheral arterial disease. AB - OBJECTIVE: The objective of this study was to assess the predictive value of clinical and exercise test variables in patients with peripheral arterial disease (PAD). METHODS: A customized symptom-limited ramp treadmill protocol was used to assess 725 PAD patients referred for exercise testing at the Palo Alto Veterans Hospital between 1997 and 2011. Detailed clinical and exercise test data were collected at baseline, and patients were followed up for a mean of 11.3 +/- 6.3 years. RESULTS: During follow-up, there were 364 deaths. Baseline exercise capacity was 7.0 +/- 2.6 metabolic equivalents (METs) among survivors and 5.5 +/- 2.4 METs in those who died (P < .001). Although several physiologic parameters differed between survivors and nonsurvivors, age-adjusted Cox regression revealed that exercise capacity was the strongest independent predictor of death. Each additional MET achieved was associated with age-adjusted 18% and 20% reductions in all-cause and cardiovascular mortality, respectively (P < .001 for both). This variable surpassed all classical risk factors (including smoking and history of congestive heart failure) and all measured exercise test responses (including symptoms and electrocardiograph abnormalities). CONCLUSIONS: Among PAD patients, reduced exercise capacity is the most powerful harbinger of long-term mortality. This factor has predictive power beyond traditional risk factors and confirms the critical importance of fitness in this cohort. PMID- 23044260 TI - Energy from Waste--clean, efficient, renewable: transitions in combustion efficiency and NOx control. AB - Traditionally EfW (Energy from Waste) plants apply a reciprocating grate to combust waste fuel. An integrated steam generator recovers the heat of combustion and converts it to steam for use in a steam turbine/generator set. This is followed by an array of flue gas cleaning technologies to meet regulatory limitations. Modern combustion applies a two-step method using primary air to fuel the combustion process on the grate. This generates a complex mixture of pyrolysis gases, combustion gases and unused combustion air. The post-combustion step in the first pass of the boiler above the grate is intended to "clean up" this mixture by oxidizing unburned gases with secondary air. This paper describes modifications to the combustion process to minimize exhaust gas volumes and the generation of noxious gases and thus improving the overall thermal efficiency of the EfW plant. The resulting process can be coupled with an innovative SNCR (Selective Non-Catalytic Reduction) technology to form a clean and efficient solid waste combustion system. Measurements immediately above the grate show that gas compositions along the grate vary from 10% CO, 5% H(2) and 0% O(2) to essentially unused "pure" air, in good agreement with results from a mathematical model. Introducing these diverse gas compositions to the post combustion process will overwhelm its ability to process all these gas fractions in an optimal manner. Inserting an intermediate step aimed at homogenizing the mixture above the grate has shown to significantly improve the quality of combustion, allowing for optimized process parameters. These measures also resulted in reduced formation of NO(x) (nitrogenous oxides) due to a lower oxygen level at which the combustion process was run (2.6 vol% O(2,)(wet) instead of 6.0 vol% O(2,)(wet)). This reduction establishes optimal conditions for the DyNORTM (Dynamic NO(x) Reduction) NO(x) reduction process. This innovative SNCR technology is adapted to situations typically encountered in solid fuel combustion. DyNORTM measures temperature in small furnace segments and delivers the reducing reagent to the exact location where it is most effective. The DyNORTM distributor reacts precisely and dynamically to rapid changes in combustion conditions, resulting in very low NO(x) emissions from the stack. PMID- 23044261 TI - Measurement of F2- isoprostanes and isofurans using gas chromatography-mass spectrometry. AB - F2-Isoprostanes (IsoPs) are isomers of prostaglandin F2alpha formed from the nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. Since discovery of these molecules by Morrow and Roberts in 1990, F2-IsoPs have been shown to be excellent biomarkers as well as potent mediators of oxidative stress in vivo in humans. Isofurans (IsoFs) are also oxidation products generated from the nonenzymatic oxidation of arachidonic acid. IsoFs are preferentially formed instead of F2-IsoPs in settings of increased oxygen tension. The protocol presented herein is the current methodology that our laboratory uses to quantify F2-IsoPs and IsoFs in biological tissues and fluids using gas chromatography/mass spectrometry (GC/MS). A variety of analytical procedures to measure F2-IsoPs, including other GC/MS methods and liquid chromatography/MS and immunological approaches, are reported in the literature. This method provides a very low limit of quantitation and is suitable for analysis of both F2-IsoPs and IsoFs from a variety of biological sources including urine, plasma, tissues, cerebral spinal fluid, exhaled breath condensate, and amniotic fluid, among others. PMID- 23044262 TI - Antioxidants counteract lipopolysaccharide-triggered alterations of human colonic smooth muscle cells. AB - Gut dysmotility develops in individuals during and after recovering from infective acute gastroenteritis and it is apparently due to a direct effect of circulating lipopolysaccharides (LPS). This is an endotoxin with a prooxidant activity derived from gram-negative bacteria. Due to the lack of human models available so far, the mechanisms underlying LPS-induced gut dysmotility are, however, poorly investigated. In the present work long-term effects of LPS and their reversibility have been assessed by means of different analytical cytology methods on pure primary cultures of human colonic smooth muscle cells. We found that LPS triggered the following alterations: (i) a redox imbalance with profound changes of contractile microfilament network, and (ii) the induction of cell cycle progression with dedifferentiation from a contractile to a synthetic phenotype. These alterations persisted also after LPS removal. Importantly, two unrelated antioxidants, alpha-tocopherol and N-acetylcysteine, were able to reverse the cytopathic effects of LPS and to restore normal muscle cell function. The present data indicate that LPS is capable of triggering a persistent and long term response that could contribute to muscle dysfunction occurring after an infective and related inflammatory burst and suggest a reappraisal of antioxidants in the management of postinfective motor disorders of the gut. PMID- 23044263 TI - Preventive effect of N-acetyl-L-cysteine on oxidative stress and cognitive impairment in hepatic encephalopathy following bile duct ligation. AB - Oxidative stress caused by ammonia toxicity is known to play a key role in the pathogenesis of hepatic encephalopathy (HE). The present study was designed to evaluate the protective effect of N-acetyl-L-cysteine (NAC) supplementation in a bile duct ligation (BDL)-induced model of HE. Three weeks after BDL, rats developed biliary fibrosis which was supported by liver function tests, ammonia levels, and hydroxyproline content. Impaired cognitive and motor functions were observed along with decreased acetylcholinesterase activity in the brain of BDL rats. Cerebral cortex and cerebellum of BDL animals showed an increase in lipid peroxidation and reduction in total and nonprotein thiols along with reduction in antioxidant enzymes. Histopathological examination of cortex and cerebellum of BDL rats showed astrocytic swelling, inflammation, necrosis, and white matter edema. One week after BDL surgery, animals administered with NAC at a daily dose 100 mg/kg for 2 weeks showed significant improvement in the activity of liver marker enzymes and restored structural morphology of liver. NAC was able to ameliorate spatial memory and motor coordination deficits observed in BDL rats. NAC supplementation decreased lipid peroxidation and was also able to restore the activity of antioxidant enzymes as well as structural deficits observed in the cortex and cerebellum of BDL animals. The results clearly demonstrate that the protective effect of NAC in an experimental model of HE is mediated through attenuation of oxidative stress, suggesting a therapeutic role for NAC in individuals withHE. PMID- 23044264 TI - Paradoxical potentiation of methylene blue-mediated antimicrobial photodynamic inactivation by sodium azide: role of ambient oxygen and azide radicals. AB - Sodium azide (NaN(3)) is widely employed to quench singlet oxygen during photodynamic therapy (PDT), especially when PDT is used to kill bacteria in suspension. We observed that addition of NaN(3) (100 MUM or 10 mM) to gram positive Staphylococcus aureus and gram-negative Escherichia coli incubated with methylene blue (MB) and illuminated with red light gave significantly increased bacterial killing (1-3 logs), rather than the expected protection from killing. A different antibacterial photosensitizer, the conjugate between polyethylenimine and chlorin(e6) (PEI-ce6), showed reduced PDT killing (1-2 logs) after addition of 10mM NaN(3). Azide (0.5mM) potentiated bacterial killing by Fenton reagent (hydrogen peroxide and ferrous sulfate) by up to 3 logs, but protected against killing mediated by sodium hypochlorite and hydrogen peroxide (considered to be a chemical source of singlet oxygen). The intermediacy of N(3)() was confirmed by spin-trapping and electron spin resonance studies in both MB-photosensitized reactions and Fenton reagent with addition of NaN(3). We found that N(3)() was formed and bacteria were killed even in the absence of oxygen, suggesting the direct one-electron oxidation of azide anion by photoexcited MB. This observation suggests a possible mechanism to carry out oxygen-independent PDT. PMID- 23044267 TI - Treatment of failed Roux-en-Y hepaticojejunostomy after post-cholecystectomy bile ducts injuries. AB - BACKGROUND: Roux-en-Y hepaticojejunostomy (RYHJ) is the most well-accepted treatment for most post-cholecystectomy bile duct injuries (BDI). RYHJ failure is a complex situation that requires expert planning and the possibility of using a combination of operative, radiologic, and endoscopic techniques. The aim of this study was to report our experience with a multidisciplinary approach to failed RYHJ after post-cholecystectomy BDI. METHODS: Between January 1996 and March 2008, 44 consecutive patients were managed for RYHJ failure in our department. They presented with recurrent cholangitis in 40 patients (91%) and/or jaundice in 9 (20%). First-line treatment consisted of primary revisionary surgery in 26 cases (59%; repeat RYHJ in 22 and hepatectomy in 4) and a percutaneous approach in 18 cases (41%; biliary interventions in 16 and portal vein embolization in 2). RESULTS: Postoperative mortality was nil. Postoperative morbidity was 11% after repeat RYHJ without hepatectomy, 80% (bile leaks) after hepatectomy, and 10% (mild cholangitis and hemobilia) after a percutaneous approach. Delayed revisionary surgery with the intent to wait for bile duct dilation failed in all 5 patients. With a mean follow-up of 49 +/- 40 months, second- or third-line treatment was attempted in 7 patients (16%). One patient (2%) died because of suicide. Overall clinical success defined by the absence of incapacitating biliary symptoms after treatment was achieved in 39 patients (89%). CONCLUSION: An immediate, multidisciplinary approach including repeat biliary surgery and/or a percutaneous approach in a tertiary hepatobiliary center is required to obtain good, long-term results when treating the failure of RYHJ post-cholecystectomy BDI. PMID- 23044266 TI - The effect of preoperative biliary drainage on infectious complications after hepatobiliary resection with cholangiojejunostomy. AB - BACKGROUND: Arguments against biliary drainage before pancreatoduodenectomy have been gaining momentum recently. The benefits of biliary drainage before hepatobiliary resection, ie, combined liver and extrahepatic bile duct resection, however, are still debatable. OBJECTIVE: To review the outcomes of patients who underwent hepatobiliary resection, with special attention to preoperative biliary drainage, to investigate whether biliary drainage increases the risk of postoperative infectious complications. METHODS: This study involved 587 patients who underwent hepatobiliary resection with cholangiojejunostomy, including 475 patients who underwent preoperative biliary drainage and 112 patients who did not. Before each operation, surveillance bile cultures were performed at least once a week. Postoperatively, the bile and drainage fluid were cultured on days 1, 4, and 7. The hospital records of consecutive patients who underwent hepatobiliary resection were reviewed retrospectively. RESULTS: Of the 475 patients with biliary drainage, 356 (74.9%) had a positive bile culture during the preoperative period. The incidence of postoperative infectious complications, including surgical-site infection and bacteremia, was similar between patients with biliary drainage and those without (28.2% vs 28.6%, P = .939). A positive bile culture during the perioperative period was highly associated with infectious complications and was one of the independent predictive factors related to infectious complications in a multivariate analysis. CONCLUSION: Preoperative biliary drainage is unlikely to increase the incidence of infectious complications after hepatobiliary resection. Perioperative surveillance bile culture is useful for the perioperative selection of appropriate antibiotics because of the high likelihood that micro-organisms isolated from infected sites are identical to those isolated from bile. PMID- 23044268 TI - Solvothermal synthesis of well-dispersed ZnSe microspheres. AB - Well-defined crystalline ZnSe microspheres have been fabricated successfully via a simple solvothermal route under mild conditions in the presence of ethylenediamine tetraacetic acid disodium salt (Na(2)EDTA) and octadecylamine (ODA). X-ray powder diffraction (XRD), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectrum (EDS), X-ray photoelectron spectra (XPS), Fourier transform-infrared spectroscopy (FT-IR), and photoluminescence spectra (PL) were used to characterize the phase structures, morphologies, and properties of the products. The result of XRD demonstrated that we obtained ZnSe products crystallized well with a stilleite structure. The influencing elements such as reaction time, sodium hydroxide (NaOH), addition of chelating reagent Na(2)EDTA, and the water/ethanol volume ratio were investigated, and the possible formation mechanism was also proposed. Furthermore, the experimental result indicated that ZnSe microspheres showed blue emission under ultraviolet excitation. PMID- 23044269 TI - Adhesion of quantum dots-induced membrane damage of Escherichia coli. AB - The toxicity of CdTe QDs modified with three different ligands, namely mercaptopropionic acid (MPA), N-acetyl-L-cysteine (NAC), and glutathione (GSH), were investigated via microcalorimetric, spectroscopic, and microscopic methods. The three ligand-modified QDs have nearly identical hydrodynamic size. The results of the calorimetric experiments and optical density measurements indicate that the QDs inhibited the growth of Gram-negative Escherichia coli. The toxicity order of the three QDs is MPA-CdTe QDs>GSH-CdTe QDs>NAC-CdTe QDs. The inhibitory effects of the QDs, cadmium chloride (CdCl(2)), MPA, and the CdCl(2) and MPA mixture on E. coli growth indicate that the toxicity mechanism of QDs may be related to their bacterial adhesion. When dispersed in the cell suspensions, QDs tend to have their high surface energy reduced through adsorption to the bacterial surface, as confirmed by transmission electron microscopy and inductively coupled plasma atomic emission spectroscopy results. Furthermore, the effect of QDs on the membrane fluidity and permeability was investigated. GSH CdTe QDs have a greater effect on the membrane function of E. coli than those of MPA-CdTe and NAC-CdTe QDs. This result may be attributed to the stronger lipophilicity of GSH compared with those of MPA and NAC. PMID- 23044270 TI - Selective deposition of organic molecules onto DPPC templates--a molecular dynamics study. AB - The site-selective deposition of organic molecules onto template structures to create ordered micro/nanoscale arrangements has drawn more and more attention because of the broad possibility, for example, application in organic electronic devices. Here we present a molecular dynamics study toward the selective deposition of organic molecules 3(5)-(9-anthryl) pyrazole (ANP), perylene and sexiphenyl (6P) onto template structures made of the phospholipid L-alpha dipalmitoyl-phosphatidylcholine (DPPC) in alternating liquid expanded (LE) and liquid condensed (LC) states. The simulation results indicate, first of all, that the molecules immerge into both LE and LC phases instead of staying on top of them. Furthermore, the simulations replicate the empirically observed higher diffusion constants of the organic molecules on LE phase compared to LC phase of the underlying DPPC layer. Additionally, we propose a possible mechanism for the diffusion barrier between LE/LC phase needed to explain the experimental findings of the selective deposition. Altogether, this study supports the notions suggested by the experiments on the causes of the selective deposition while giving a deeper insight into the molecular processes involved. PMID- 23044271 TI - Reduction of gold(III) chloride to gold(0) on silicate surfaces. AB - The mechanism of adsorption and reduction of the gold chloride complex on silicate minerals is investigated. Gold chloride, supplied as HAuCl(4) solution, is rapidly adsorbed on the silicate surfaces, the Au(III) is reduced to metallic gold, and gold particles grow on the surface. SEM images show agglomerates of gold unevenly distributed on the surface of the silicates, including in some areas forming agglomerates, especially on quartz and feldspar. Silica gel forms via dissolution of silicates in acidic conditions and also has strong adsorption/reduction potential for gold. A mechanism for the adsorption and reduction is proposed, involving ligand substitution between gold chloride and OH() groups on defect sites in silicate surfaces. Consequently, gold can be reduced by hydrogen or silicon radicals at the defect sites. Adsorption of Au(III) by silicate minerals, followed by reduction, could play an important role in the deposition of gold in natural systems, as well as causing loss of gold from leaching processes during hydrometallurgical gold recovery. PMID- 23044265 TI - Lipid peroxidation triggers neurodegeneration: a redox proteomics view into the Alzheimer disease brain. AB - Lipid peroxidation involves a cascade of reactions in which production of free radicals occurs selectively in the lipid components of cellular membranes. Polyunsaturated fatty acids easily undergo lipid peroxidation chain reactions, which, in turn, lead to the formation of highly reactive electrophilic aldehydes. Among these, the most abundant aldehydes are 4-hydroxy-2-nonenal (HNE) and malondialdehyde, while acrolein is the most reactive. Proteins are susceptible to posttranslational modifications caused by aldehydes binding covalently to specific amino acid residues, in a process called Michael adduction, and these types of protein adducts, if not efficiently removed, may be, and generally are, dangerous for cellular homeostasis. In the present review, we focused the discussion on the selective proteins that are identified, by redox proteomics, as selective targets of HNE modification during the progression and pathogenesis of Alzheimer disease (AD). By comparing results obtained at different stages of the AD, it may be possible to identify key biochemical pathways involved and ideally identify therapeutic targets to prevent, delay, or treat AD. PMID- 23044272 TI - Interactions of bovine serum albumin with cationic imidazolium and quaternary ammonium gemini surfactants: effects of surfactant architecture. AB - The interactions of BSA with a series of cationic imidazolium gemini surfactants ([C(n)-s-C(n)im]Br(2), n=10, 12, 14, s=2, 4, 6), quaternary ammonium surfactants (C(12)C(2)C(12)), and their corresponding monomers ([C(12)mim]Br and DTAB) are investigated by fluorescence using pyrene as a molecular probe, synchronous fluorescence, circular dichroism (CD), and UV-visible absorption spectra. These surfactants are used to elucidate the effects of surfactant hydrophilic head group, spacer length, and hydrophobic chain length on the conformation of BSA. The results of fluorescence spectra and CD show that the imidazolium gemini surfactants with shorter spacers or with longer hydrophobic chains have a larger effect on BSA unfolding, and the imidazolium gemini surfactant interacts with BSA more strongly than its corresponding monomer and the quaternary ammonium gemini surfactant. These conclusions have been confirmed by the binding constants (K(a)) and binding sites (n) for the BSA/surfactant system. Stern-Volmer quenching constants K(SV) of cationic surfactants binding to BSA are obtained, indicating that the probable quenching mechanism is initiated by ground-state complex formation rather than by dynamic collision. Moreover, the synchronous fluorescence spectra show that the surfactants mainly interact with tryptophan residues of BSA. PMID- 23044273 TI - Self-assembly of colloidal spheres and application as solvent responding polymer film. AB - It is the first time to fabricate and apply responsive colloidal crystal (CC) films on biocomposite material - bamboo strand board (BSB). The responsive film can be easily prepared directly through the self-assembly of soft colloidal polymer spheres containing hydrophilic monomers at ambient pressure and temperature without complicate equipment. In this approach, soft colloidal polymer spheres are synthesized by emulsion polymerization using polymerizable emulsifier. Then, the polymer latex is loaded onto the surface of BSB. The colloidal polymer spheres can directly self-assemble into a robust and transparent colloidal crystal (CC) film on BSB. Neither soft matrix nor posttreatment is needed. Compared with the traditional responsive CC, the polymer film on BSB not only had sensitive response behaviors but also had good reversibility and mechanical strength, which would provide a new method for fabrication and application of responsive CC. PMID- 23044274 TI - A facile approach to the synthesis of non-porous and microporous sub-micron spherical zirconia and alumina-zirconia solid solution. AB - Amorphous monodisperse sub-micron spherical zirconia and alumina/zirconia solid solution particles were prepared by hydrolysis of zirconium and aluminum salts in ethanol. The heat-treatment process of the amorphous materials in air atmosphere at 500 degrees C for 2h leaded to the production of non-porous zirconia and alumina/zirconia solid solution in tetragonal phase. The alkaline etching process of the as-prepared alumina/zirconia solid solution resulted in the formation of mono-modal microporous material with specific surface area of 125.0 m(2) g(-1) in comparison with 2. 9m(2) g(-1) for the parent material. Thermal analysis of the solid solution revealed that the incorporation of aluminum ions in the zirconia structure has decreased the phase transformation temperature from amorphous to crystalline structure. Moreover, optical study confirmed the presence of oxygen vacancy defect by substitution of tetravalent cations, Zr(4+) by trivalent cations, Al(3+) in zirconia lattice. PMID- 23044275 TI - Electrophysiological markers of syllable frequency during written word recognition in French. AB - Several empirical lines of investigation support the idea that syllable-sized units may be involved in visual word recognition processes. In this perspective, the present study aimed at investigating further the nature of the process that causes syllabic effects in reading. To do so, the syllable frequency effect was investigated in French using event related potentials while participants performed a lexical decision task (experiment 1). Consistent with previous studies, manipulating the frequency of the first syllable in words and pseudowords yielded two temporally distinct effects. Compared to items with a first syllable of low frequency, items with a syllable of high frequency elicited a weaker P200 component, reflecting early sub-lexical facilitation, and a larger N400 component, supposed to ensue from competition between syllabic neighbours. To examine which factors determine the strength of interference during lexical access, regression analyses were conducted on the late temporal window potentials. The inhibitory syllable frequency effect was best predicted by leader strength, that is, the frequency ratio between the most frequent syllabic neighbour and the others. When this variable was directly manipulated while controlling for syllable frequency and number of higher frequency syllabic neighbours (experiment 2), electrophysiological data confirmed the impact of leader strength. The results are discussed in the context of interactive activation-based models augmented with syllabic representations. PMID- 23044276 TI - When compensation fails: attentional deficits in healthy ageing caused by visual distraction. AB - Age related changes in frontal lobe functions are often related to attentional deficits that lead to increased distractibility by irrelevant stimuli. However, attentional functions have been reported not to decline in general with increasing age but simply be too slow to deal properly with distraction in time. Therefore older people might be able to compensate for distraction quite efficiently with sufficient processing time. Compensation, however, might fail when early perceptual processing is affected by distraction already. In the present study, a change in luminance or in orientation had to be detected in a sequence of two visual frames. Older participants showed reduced performance only when luminance and orientation changes were presented simultaneously at separate locations (perceptual conflict condition). Sensory ERP components were not overall altered with increasing age. Only in conflicting trials, a strong bias towards physically more salient information was observed. Additionally, older adults showed markedly delayed ERP-correlates of fronto-central control mechanisms in the conflict condition. The data indicate that processing deceleration cannot compensate for perceptual conflicts induced by mis-weighting of incoming information. PMID- 23044277 TI - Unmasking the contribution of low-level features to the guidance of attention. AB - The role of low-level stimulus-driven control in the guidance of overt visual attention has been difficult to establish because low- and high-level visual content are spatially correlated within natural visual stimuli. Here we show that impairment of parietal cortical areas, either permanently by a lesion or reversibly by repetitive transcranial magnetic stimulation (rTMS), leads to fixation of locations with higher values of low-level features as compared to control subjects or in a no-rTMS condition. Moreover, this unmasking of stimulus driven control crucially depends on the intrahemispheric balance between top-down and bottom-up cortical areas. This result suggests that although in normal behavior high-level features might exert a strong influence, low-level features do contribute to guide visual selection during the exploration of complex natural stimuli. PMID- 23044278 TI - State-dependent changes of connectivity patterns and functional brain network topology in autism spectrum disorder. AB - Anatomical and functional brain studies have converged to the hypothesis that autism spectrum disorders (ASD) are associated with atypical connectivity. Using a modified resting-state paradigm to drive subjects' attention, we provide evidence of a very marked interaction between ASD brain functional connectivity and cognitive state. We show that functional connectivity changes in opposite ways in ASD and typicals as attention shifts from external world towards one's body generated information. Furthermore, ASD subject alter more markedly than typicals their connectivity across cognitive states. Using differences in brain connectivity across conditions, we ranked brain regions according to their classification power. Anterior insula and dorsal-anterior cingulate cortex were the regions that better characterize ASD differences with typical subjects across conditions, and this effect was modulated by ASD severity. These results pave the path for diagnosis of mental pathologies based on functional brain networks obtained from a library of mental states. PMID- 23044279 TI - Attentional shifts induced by uninformative number symbols modulate neural activity in human occipital cortex. AB - Number processing interacts with space encoding in a wide variety of experimental paradigms. Most intriguingly, the passive viewing of uninformative number symbols can shift visuo-spatial attention to different target locations according to the number magnitude, i.e., small/large numbers facilitate processing of left/right targets, respectively. The brain architecture dedicated to these attention shifts associated with numbers remains unknown. Evoked potential recordings indicate that both early and late stages are involved in this spatio-numerical interaction, but the neuro-functional anatomy needs to be specified. Here we use, for the first time, functional magnetic resonance imaging (fMRI) to investigate attentional orienting following uninformative Arabic digits. We show that BOLD response in occipital visual regions is modulated by the congruency between digit magnitude (small/large) and target side (left/right). Additionally, we report higher BOLD responses following large (8, 9) compared to small (1, 2) digits in two bilateral parietal regions, yielding a significant effect of digit magnitude. We propose and discuss the view that encoding of semantic representations related to number symbols in parietal cortex leads to shifts in visuo-spatial attention and enhances visual processing in the occipital cortex according to number-space congruency rules. PMID- 23044280 TI - [Analysis of organ failure and mortality in sepsis due to secondary peritonitis]. AB - OBJECTIVES: To identify the organs most susceptible to develop multiorgan dysfunction syndrome (MODS) in patients with sepsis due to secondary peritonitis, and to determine the outcome and mortality predicting utility of the SOFA (Sequential Organ Failure Assessment) system. DESIGN: A prospective, observational cohort study was made. SETTING: The resuscitation unit of a third level university hospital. PATIENTS: A prospective, observational cohort study was made of 102 patients with sepsis of abdominal origin and failure of at least one organ related to the infection. The demographic characteristics were documented, along with the abdominal origin of sepsis, mortality after 28 days, and the daily SOFA score. RESULTS: The mortality rate after 28 days was 55%. A total of 53% of the patients presented failure of two or more organs on the first day of admission. The mean daily SOFA score was significantly higher among the patients that died after day 4 of admission. The variables showing a statistically significant correlation to increased mortality were: MODS (P=.000), central nervous system failure (P=.000) and SOFA score on day 4 of admission (P=.012). The area under the ROC curve showed the mortality predicting capacity of the SOFA score on day 4 of admission to be 0.703 (95%CI 0.538-0.853; P=.026). The maximum discriminating capacity was recorded for MODS, with an area under the ROC curve of 0.776 (95%CI 0.678-0.874; P=.000). CONCLUSIONS: Organ failure outcome as predicted by the SOFA score showed high precision - the mean SOFA score on day 4 of admission being a good mortality predictor. MODS was the main cause of death, while central nervous system, renal and respiratory failure were identified as the mortality risk factors. PMID- 23044281 TI - Alpha code. The start of a new non-heart beating donor program. AB - OBJECTIVE: To present the preliminary results of a non-heart beating donor (NHBD) program in a city of under 500,000 inhabitants. DESIGN: A prospective observational study was conducted between 2010 and 2011. SETTING: Virgen de las Nieves Hospital and metropolitan area of Granada (Spain). POPULATION: NHBD and brain dead donors (BDD) in the province of Granada during 2010 and 2011. STUDY VARIABLES: Characteristics of NHBD, out- and in-hospital times, family and legal refusals, preservation methods, and family information procedure. Organs: reasons for organ non-validness, and harvested and transplanted organs. Recipients: hemodialysis sessions and creatinine at discharge. BDD: number of real donors (RD) and of kidney transplants. RESULTS: Among the BDD there were 102 RD and 104 kidney transplants were carried out. In asystole, 22 potential donors, 21 eligible donors, 20 RD and 13 used donors were registered. The mean age among the RD was 50 years (range 33-62)(16 males and 4 females). Twenty-one kidney and two liver transplants from NHBD were performed. There were a number of reasons for organ non-validness. The mean number of post-transplantation hemodialysis sessions was 1.4 (range 0-6). The mean hospital stay was 25 days (range 14-41), and the mean creatinine concentration at discharge was 3.4mg/dl (range 1.5-6.4). There was one family rejection and no legal (court-ruled) rejections. The preservation methods and family information procedure are described. CONCLUSIONS: The preliminary results support the development of NHBD programs in cities with under 500,000 inhabitants. In 2011, NHBD accounted for 20.19% of the kidney transplants and 19.60% of the global organ donations in the province of Granada. PMID- 23044282 TI - An unusual case of organizing pneumonia and infection by P. jirovecii. PMID- 23044283 TI - [Mycotic pseudoaneurysm produced by Salmonella enteritidis in a patient with fever of unknown origin]. PMID- 23044284 TI - Temperament personality profiles in suicidal behaviour: an investigation of associated demographic, clinical and genetic factors. AB - BACKGROUND: Personality traits have been suggested as possible risk factors for suicidal behaviours. Cloninger's model of personality (TCI), given its neurobiological background, might provide an ideal tool for the identification of dimensions associated with suicide attempt. METHODS: A number of 1333 suicide attempters and 589 non-suicide attempters suffering from different DSM-IV Axis I disorders were assessed using either the temperament and character inventory (TCI) or the tridimensional personality questionnaire (TPQ), as well as other self-report questionnaires evaluating dimensions associated with suicidal behaviour, such as impulsivity and anger traits. The severity of suicide attempts and the methods used were also assessed. Subjects were genotyped for polymorphisms within the key genes involved in monoaminergic pathways and the HPA axis. RESULTS: Compared with non-suicide attempters, suicide attempters scored higher for harm avoidance (HA) and novelty seeking (NS), and lower for self directedness (SD). The difference was independent of Axis I disorders. Higher HA and NS scores were associated with a greater severity of suicidal behaviour. A multivariate model showed that HA was the single temperamental dimension independently related to suicide attempt history, beside impulsivity and anger related traits. The genetic factors investigated did not play a significant role in modulating these temperamental dimensions. LIMITATIONS: The TCI was available for only half of the sample. CONCLUSIONS: Early detection of subjects displaying high HA and low SD, associated with high impulsivity and poor anger control, may help to prevent suicidal behaviours. Physicians should therefore be aware of these risk factors so that they can offer the best primary care intervention. PMID- 23044285 TI - Respondent and item level patterns of response of aripiprazole in the acute treatment of pediatric bipolar I disorder. AB - BACKGROUND: Few studies have evaluated the value of a parent- and subject-rated scale in detecting symptom change in response to pharmacologic treatment. METHODS: This was a post-hoc analysis of data from a 4-week, randomized, double blind, placebo-controlled study to evaluate which informants detect response to treatment with aripiprazole in pediatric subjects experiencing a mixed or manic episode associated with bipolar I disorder. Efficacy assessments included clinician-rated scales and the parent- and subject-rated 10-item General Behavior Inventory Mania (GBI-M10) and Depression (GBI-D10) scales. Cohen's d quantified effect sizes for total scale scores and individual line items. RESULTS: Parent GBI-M10 total, clinician-rated Young Mania Rating Scale (YMRS) total, and Clinical Global Impression-Bipolar Disorder (CGI-BP) Mania scores produced similar effect sizes, suggesting that the parent-GBI-M10 is sensitive to treatment-related improvements in manic symptoms. Aripiprazole improved a broad spectrum of parent-rated mania symptoms; six parent-GBI-M10 line item effect sizes were moderate (>0.5) in at least one of the two aripiprazole treatment arms (10 or 30 mg/day). Subject-completed GBI-M10 line item effect sizes were consistently smaller, indicating that the subjects' experience of treatment effects were less pronounced. LIMITATIONS: Study inclusion/exclusion criteria may limit generalizability of these findings. CONCLUSIONS: Parent ratings of mania severity were in agreement with clinician ratings, indicating that parent-rated assessments can be valuable in detecting symptom change over the course of treatment. These data support the use of the parent-GBI-M10 as an outcome measure in research and clinical settings. PMID- 23044286 TI - Excitation functions for 7Be, 22,24Na production in Mg and Al by deuteron irradiations up to 50 MeV. AB - New experimental data for production of (7)Be and (22,24)Na in deuteron irradiation of (nat)Mg and Al up to 50 MeV are presented. The induced activity, measured with HPGe spectroscopy, allows us to determine excitation functions of (nat)Mg(d,x) and (27)Al(d,x) reactions involved in the activation process with reference to (nat)Ti(d,x)(48)V monitor cross sections. A comparison with experimental literature values and results from updated theoretical codes is discussed. Thick target yields were derived from fits to our cross-sections and integrated personnel dose was calculated for different irradiation cycles and exposure scenarios around high power deuteron accelerator facilities. PMID- 23044289 TI - Optimizing prevention of contrast-induced acute kidney injury in type 2 diabetic patients with at least moderate renal impairment. PMID- 23044287 TI - Phenotypic and genotypic characterisation of drug-resistant Plasmodium vivax. AB - In this review we present recent developments in the analysis of Plasmodium vivax clinical trials and ex vivo drug-susceptibility assays, as well approaches currently being used to identify molecular markers of drug resistance. Clinical trials incorporating the measurement of in vivo drug concentrations and parasite clearance times are needed to detect early signs of resistance. Analysis of P. vivax growth dynamics ex vivo have defined the criteria for acceptable assay thresholds for drug susceptibility testing, and their subsequent interpretation. Genotyping and next-generation sequencing studies in P. vivax field isolates are set to transform our understanding of the molecular mechanisms of drug resistance. PMID- 23044288 TI - Do malaria parasites manipulate mosquitoes? AB - Malaria parasites have been suggested to alter the behavior of mosquito vectors to increase the likelihood of transmission. Some empirical evidence supports this hypothesis, yet the role of manipulation is ignored in most epidemiological models, and behavioral differences between infected and uninfected females are not considered in the development or implementation of control measures. We suggest that this disconnect exists because the link between behavioral alteration and actual transmission in the field has yet to be demonstrated or quantified fully. We review and discuss the current evidence for manipulation, explore its potential significance for malaria transmission, and suggest ways to move this hypothesis forward from theory to potential application in malaria control. PMID- 23044290 TI - Preventive effects of anisodamine against contrast-induced nephropathy in type 2 diabetics with renal insufficiency undergoing coronary angiography or angioplasty. AB - BACKGROUND: Anisodamine is widely used in therapy for treating acute glomerulonephritis and diabetic nephropathy because it can improve renal microcirculation. We performed a study to evaluate the preventive effects of anisodamine against contrast-induced nephropathy (CIN) in type 2 diabetics with renal insufficiency undergoing coronary angiography or angioplasty. METHODS: A total of 260 patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) of 60 ml(-1)*min(-1)*1.73 m(-2) or less, who were undergoing coronary angiography or angioplasty, were randomly assigned to receive an infusion of either sodium chloride (control group, n = 128) or anisodamine (treatment group, n = 132). Patients in the treatment group received an infusion of anisodamine at a rate of 0.2 ug*kg(-1)*min(-1) from 12 hours before to 12 hours after coronary angiography or angioplasty, while patients in the control group received an infusion of sodium chloride with the same volume as the treatment group. All patients received intravenous sodium chloride hydration. CIN was defined as a 25% increase in serum creatinine from baseline or an absolute increase of > 0.5 mg/dl within three days after contrast exposure. The primary end point was the incidence of CIN. The secondary end point was a 25% or greater reduction in eGFR. RESULTS: There were no significant differences between the two groups with regard to age, gender, risk factors, laboratory results, medications and interventions. The incidence of CIN was 9.8% (13/132) in the treatment group and 20.3% (26/128) in the control group (P < 0.05). The secondary end point was 6.0% (8/132) in the treatment group and 16.4% (21/128) in the control group (P < 0.05). CONCLUSION: These results indicate the preventive effects of anisodamine against CIN in type 2 diabetics with renal insufficiency who are undergoing coronary angiography or angioplasty. PMID- 23044291 TI - A randomized, prospective, two-center comparison of sirolimus-eluting stent and zotarolimus-eluting stent in acute ST-elevation myocardial infarction: the SEZE trial. AB - BACKGROUND: The zotarolimus-eluting stent has shown larger in-stent late lumen loss compared to sirolimus-eluting stents in previous studies. However, this has not been thoroughly evaluated in ST elevation myocardial infarction. METHODS: This was a prospective, randomized, controlled trial evaluating angiographic outcomes in patients presenting with ST elevation myocardial infarction, treated with zotarolimus-eluting stents or sirolimus-eluting stents. From March 2007 to February 2009, 122 patients were randomized to zotarolimus-eluting stents or sirolimus-eluting stents in a 1:1 fashion. The primary endpoint was 9-month in stent late lumen loss confirmed by coronary angiography, and secondary endpoints were percent diameter stenosis, binary restenosis rate, major adverse cardiac events (a composite of cardiac death, non-fatal myocardial infarction, and target vessel revascularization), and late-acquired incomplete stent apposition. RESULTS: Angiographic in-stent late lumen loss was significantly higher in the zotarolimus-eluting stent group compared to the sirolimus-eluting stent group ((0.49 +/- 0.65) mm vs. (0.10 +/- 0.46) mm, P = 0.001). Percent diameter stenosis at 9-month follow-up was also larger in the zotarolimus-eluting stent group ((30.0 +/- 17.9)% vs. (17.6 +/- 14.0)%, P < 0.001). In-segment analysis showed similar findings. There were no significant differences in binary restenosis rate, major adverse cardiac events, and late-acquired incomplete stent apposition. CONCLUSIONS: Compared to sirolimus-eluting stents, the zotarolimus eluting stent is associated with significantly higher in-stent late lumen loss at 9-month angiographic follow-up in the treatment of ST elevation myocardial infarction. Although there was no significant difference in 1-year clinical outcomes, the clinical implication of increased late lumen loss should be further studied. PMID- 23044292 TI - Comparison of paclitaxal vs. sirolimus eluting stents with bio-degradable polymer for the treatment of coronary bifurcation lesions: subgroup analysis from DKCRUSH I and DKCRUSH-II studies. AB - BACKGROUND: The difference in clinical outcome between paclitaxal-eluting stents (PES) and sirolimus-eluting stents with bio-degradable polymer (SES-BDP) for bifurcation lesions remains unclear. The present study aimed to investigate the one-year clinical outcome after DK crush stenting using PES (Taxus(TM)) vs. SES BDP (Excel(TM)) from our database. METHODS: A total of 275 patients (90 from the DKCRUSH-I and 185 from the DKCRUSH-II study) were studied. The primary endpoint was the occurrence of major adverse cardiac events (MACE) at 12 months; including cardiac death, myocardial infarction (MI), or target vessel revascularization (TVR). The rate of binary restenosis and stent thrombosis served as secondary endpoints. RESULTS: At follow-up, minimal luminal diameter (MLD) in the Taxus group was (2.11 +/- 0.66) mm, with resultant increased target lesion revascularization (TLR) 12.2% and TVR 14.4%, significantly different from the Excel group; (2.47 +/- 0.56) mm, P < 0.001, 3.2%, P = 0.006, 4.9%, P = 0.019, respectively. As a result there was a significant difference in MACE between the Taxus (20.0%) and Excel (10.3%, P = 0.038) groups. Overall stent thrombosis was monitored in 11 patients (4.0%), with five in the Excel group (2.7%) and six in the Taxus group (6.7%). All stent thrombosis in the Excel group was classified as early, and all were defined as late in the Taxus group. CONCLUSION: The Excel stent had lower rate of stent thrombosis, TLR, TVR, and composite MACE at 12 month after an indexed stenting procedure, compared to the Taxus stent. PMID- 23044293 TI - Assessment of early radial injury after transradial coronary intervention by high resolution ultrasound biomicroscopy: innovative technology application. AB - BACKGROUND: Transradial coronary intervention (TRI) introduces injury to the radial artery (RA) which will affect repeat transradial coronary procedure and the quality as a bypass conduit. We sought to compare the early radial injury after TRI between first-TRI and repeat-TRI by ultrasound biomicroscopy (UBM). METHODS: A total of 1116 patients who underwent the transradial coronary procedures were enrolled. The patients depending on whether for the first time to accept transradial coronary procedure were divided into first-TRI group and repeat-TRI group. The RA was examined by UBM before and one day after the procedure. RESULTS: Compared with first-TRI group, the mean RA diameter of repeat TRI one day after the procedure decreased significantly (P < 0.05). In first-TRI group, the mean RA diameter was (2.32 +/- 0.53) and (1.93 +/- 0.57) mm before procedure and one day after the procedure respectively (P < 0.05). In repeat-TRI group, the mean RA diameter was (2.37 +/- 0.51) and (1.79 +/- 0.54) mm before procedure and one day after the procedure, respectively (P < 0.01). Compared with first-TRI group, the mean RA diameter was reduced significantly in repeat-TRI group one day after the procedure (P < 0.05). The early radial injuries and intimal thickening were compared between first-TRI and repeat-TRI. The mean intima-media thickness of RA was (0.24 +/- 0.13) mm and (0.59 +/- 0.28) mm before procedure and one day after the procedure in first-TRI group. The mean intima media thickness of RA was (0.29 +/- 0.16) mm and (0.68 +/- 0.32) mm before procedure and one day after the procedure in repeat-TRI group. Compared with first-TRI group, the mean intimal thickening was increased significantly in repeat-TRI group one day after the procedure (P < 0.05). Intimal dissection, stenosis and occlusion were all significantly greater in repeat-TRI RAs (P < 0.05). Linear regression analysis revealed that diameter, repeated TRI procedure and PCI procedure were the independent predictors of intimal thickening. CONCLUSIONS: RA early injuries were greater in repeat-TRI patients than in first TRI patients. We first use high-resolution UBM imaging to demonstrate the rate of radial injury and revealed that diameter, repeated TRI procedure and PCI procedure were the independent predictors of intimal thickening. PMID- 23044294 TI - Six-month angiographic and one-year clinical outcomes of polymer free paclitaxel eluting stent in patients with ST-segment elevation myocardial infarction: a comparison with permanent polymer sirolimus-eluting stent. AB - BACKGROUND: Since permanent polymer is implicated in adverse events associated with delayed vessel healing after drug eluting stents (DES) implantation, great efforts have been made to develop more biocompatible DES with biodegradable polymer or without polymer. The present study aimed to evaluate the safety and efficacy of polymer free paclitaxel-eluting stents (PF-PES) in comparison with permanent polymer sirolimus-eluting stents (PP-SES) in patients with acute ST segment elevation myocardial infarction (STEMI). METHODS: Patients with STEMI were randomly assigned to receive PP-SES (n = 55), and PF-PES (n = 50). The 6 month angiographic and 1-year clinical outcomes were compared between the two groups. Target lesion failure (TLF) was defined as the composite of cardiac death, recurrent nonfatal myocardial infarction (Re-MI), or target lesion revascularization (TLR). RESULTS: Follow-up angiography at six months was performed in 72.7% of the PP-SES group and 70.0% of the PF-PES group (P = 0.757). The two groups had comparable angiographic outcomes including minimal luminal diameter, diameter stenosis, late loss and binary restenosis. All patients were clinically followed up to one year. The two groups had similar clinical outcomes with relatively low rates of target lesion failure (10.9% PP-SES vs. 12.0% PF PES, P = 0.861) and definite or probable stent thrombosis (1.8% PP-SES vs. 2.0% PF-PES, P = 1.000) at one year. CONCLUSIONS: The present study suggests that the safety and efficacy of PF-PES in the setting of STEMI are comparable to PP-SES. Further randomized trials with larger study populations are needed to get definite conclusions. PMID- 23044295 TI - Sirolimus-eluting stents for treatment of drug-eluting versus bare-metal stents restenosis: 42-month clinical outcomes from a Chinese single center. AB - BACKGROUND: Restenosis of bare-metal stents (BMS) and drug-eluting stents (DES) has been increasingly treated with sirolimus-eluting stents (SES), but the long term outcomes are unknown. METHODS: In our study, 388 consecutive patients (144 DES restenosis and 244 BMS restenosis) with 400 lesions (147 DES restenosis and 253 BMS restenosis) treated with SES were included. The rates of target lesion revascularization (TLR) and major adverse cardiac events (MACE) at 42 months were analyzed. RESULTS: At the mean follow-up of 42 months, the rates of death (3.5% vs. 3.3%, P = 1.000) and myocardial infarction (2.8% vs. 1.2%, P = 0.431) in the DES group and BMS group were comparable. Compared with the BMS group, ischemia driven TLR occurred with a higher frequency in the DES group (18.8% vs. 10.7%, P = 0.024). This translated into an increased rate of MACE in the DES group (22.2% vs. 14.0%, P = 0.034). Stent thrombosis occurred with a similar frequency in both groups (2.8% vs. 1.6%, P = 0.475). Multivariate analysis showed that DES restenosis (OR = 1.907, 95%CI 1.108 - 3.285, P = 0.020) and smoking (OR = 2.069; 95%CI 1.188 - 3.605; P = 0.010) were independent predictors of MACE. CONCLUSIONS: Although SES implantation appears to be safe and effective, it was associated with higher TLR recurrence for DES than BMS restenosis. PMID- 23044296 TI - Factors influencing pre-hospital delay among patients with acute myocardial infarction in Iran. AB - BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of morbidity and disability among Iranian population. Pre-hospital delay is an important cause of increasing early and also late mortality in AMI. Thus the aim of the present study was to identify the factors influencing pre-hospital delay among patients with AMI in Iran. METHODS: Between August 2010 and May 2011, a cross-sectional and single-center survey was conducted on 162 consecutive patients with ST elevation myocardial infarction (STEMI) admitted to Cardiac Care Unit (CCU) of Dr. Heshmat Hospital, Rasht. All patients were interviewed by the third author within 7 days after admission by using a four-part questionnaire including socio demographic, clinical, situational and cognitive factors. Data were analyzed by descriptive and Logistic regression model at P < 0.05 using SPSS 16. RESULTS: Mean age was (60.11 +/- 12.29) years in all patients. Majority of patients (65.4%) were male. The median of pre-hospital delay was 2 hours, with a mean delay of 7.4 hours (+/- 16.25 hours). Regression analysis showed that admission in weekend (P < 0.04, OR = 1.033, 95%CI = 1.187 - 2.006) and misinterpretation of symptoms as cardiac origin (P < 0.002, OR = 1.986, 95%CI = 1.254 - 3.155) and perceiving symptoms to not be so serious (P < 0.003, OR = 3.264, 95%CI = 1.492 - 7.142) were factors influencing pre-hospital delay > 2 hours. CONCLUSIONS: Our findings highlight the importance of cognitive factors on decision-making process and pre-hospital delays. Health care providers can educate the public on AMI to enable them recognize the signs and symptoms of AMI correctly and realize the benefits of early treatment. PMID- 23044297 TI - Risk factors and risk index of cardiac events in pregnant women with heart disease. AB - BACKGROUND: Pregnant women with heart disease are at high risk. Studies of risk factors of these patients are of great significance to improve maternal and fetal outcomes. In this paper, we try to discuss the main risk factors of cardiac events in pregnant women with heart disease and to establish a risk assessment system. METHODS: A retrospective analysis was carried out for pregnancies in 1741 women with heart disease who delivered in Shanghai Obstetrical Cardiology Intensive Care Center between January 1993 and September 2010. A Logistic regression model was used to identify independent risk factors of cardiac events and calculate the risk index in pregnant women with heart disease. RESULTS: The composition of heart disease in pregnant women was arrhythmia (n = 662, 38.00%), congenital heart disease (CHD; n = 529, 30.40%), cardiomyopathy (n = 327, 18.80%), rheumatic heart disease (RHD; n = 151, 8.70%), and cardiopathy induced by pre-eclampsia (n = 53, 3.00%). Main cardiac events were heart failure (n = 110, 6.32%), symptomatic arrhythmia needing medication (n = 43, 2.47%), cardiac arrest (n = 2, 0.11%), syncope (n = 3, 0.17%), and maternal death (n = 10, 0.57%). Six independent risk factors to predict cardiac events in pregnant women with heart disease were cardiac events before pregnancy (heart failure, severe arrhythmia, cardiac shock, etc., P = 0.000), New York Heart Association (NYHA) class > II (P = 0.000), oxygen saturation < 90% (P = 0.018), pulmonary artery hypertention (PAH) > 50 mmHg (P = 0.025), cyanotic heart disease without surgical correction (P = 0.015), and reduced left ventricular systolic function (ejection fraction < 40%, P = 0.003). Every risk factor was calculated as 1 score. The incidence of cardiac events in patients with scores 0, 1, 2, 3, and >= 4 was 2.10%, 31.61%, 61.25%, 68.97%, and 100.00% respectively. CONCLUSIONS: Pregnancy with heart disease could lead to undesirable pregnancy outcomes. The risk of cardiac events in pregnant women with heart disease could be assessed by risk index. PMID- 23044298 TI - Assessment of the morphology and mechanical function of the left atrial appendage by real-time three-dimensional transesophageal echocardiography. AB - BACKGROUND: The left atrial appendage (LAA) is an important source of thrombus formation. We investigated the feasibility of the recently developed real-time three-dimensional transesophageal echocardiography (RT3D-TEE) method in assessment of the morphology and function of the LAA. METHODS: Ninety-six consecutive patients (58 males with a mean age of (43.4 +/- 12.5) years) who were referred for 2-dimensional (2D) transesophageal echocardiography (TEE) underwent additional RT3D-TEE. LAA morphology was visualized in multiple views. Orifice size, depth, volumes and ejection fraction (EF) of the LAA, were measured. RESULTS: All the patients underwent RT3D-TEE examination without complications. Ninety-two patients (95.8%) had adequate images for visualization and quantitative analysis of the LAA. The LAA exhibited great variability with respect to relative dimensions and morphology. LAA orifice area was (3.8 +/- 1.2) cm(2) with a diameter of (2.4 +/- 0.9) cm * (1.4 +/- 0.6) cm. The mean depth of the LAA was (2.9 +/- 0.7) cm. End-diastolic volume (EDV-LAA), end-systolic volume (ESV-LAA) and EF of the LAA were (6.2 +/- 3.7) ml, (4.1 +/- 2.8) ml, and 0.35 +/- 0.16, respectively. EDV-LAA, ESV-LAA and the orifice area of the LAA in patients with atrial fibrillation (AF) were larger than those without AF, whereas the EF was smaller in the AF patients. CONCLUSIONS: Defining LAA morphology and quantitative analysis of the size and function of the LAA with superior quality and resolution of images using RT3D-TEE is feasible. This technique may be an ideal tool for guidance of the LAA occlusion procedure. Determination of LAA volumes and volume-derived EF by RT3D-TEE provides new insights into the analysis of LAA function. PMID- 23044299 TI - Home monitoring system improves the detection of ventricular arrhythmia and inappropriate shock. AB - BACKGROUND: The impact of home monitoring system in the early detection of ventricular arrhythmia and inappropriate shock in daily work is not clear. The aim of this study was to investigate the impact of home monitoring system on the early detection of ventricular arrhythmia and inappropriate shock in daily clinical practice. METHODS: Cases of implantable cardioverter defibrillator (ICD) implantation with or without the home monitoring system from June 2010 to October 2011 at our center were reviewed. Follow-up was scheduled after implantation. Data relating to the home monitoring ICD were retrieved using a remote transmitter system. Data relating to the other devices were obtained during scheduled follow-up or unscheduled visits. RESULTS: Our study involved 69 patients (mean age (68.4 +/- 17.6) years, 64.3% males, 26 in the home monitoring group vs. 43 in the non-home monitoring group). In all, 561 ventricular arrhythmia episodes were detected in 17 patients (39.5%) in the non-home monitoring group: 495 episodes were ventricular tachycardia and 66 episodes were ventricular fibrillation; among these, 476 episodes of ventricular tachycardia and 45 episodes of ventricular fibrillation were appropriately diagnosed (96.1% and 68.2%, respectively). In the home monitoring group, 389 ventricular arrhythmia episodes were transmitted by the home monitoring system in nine patients (34.6%): 348 ventricular tachycardia episodes and 41 ventricular fibrillation episodes. Device detection was appropriate in 348 ventricular tachycardia episodes (100.0%) and 36 ventricular fibrillation episodes (87.8%). The home monitoring group showed a higher appropriate detection rate of ventricular tachycardia (P < 0.01) and ventricular fibrillation (P = 0.02). The proportion of inappropriate shock was comparable in the two groups (6/11 in the non-home monitoring group vs. 1/7 in the home monitoring group; P = 0.08). CONCLUSIONS: The home monitoring ICD was able to provide information relating to inappropriate detection and shock earlier than conventional devices. It proved to be a reliable tool and has a strong potential to provide greater reaction time in the case of inappropriate shock. PMID- 23044300 TI - Efficacy of catheter ablation of atrial fibrillation beyond HATCH score. AB - BACKGROUND: HATCH score is an established predictor of progression from paroxysmal to persistent atrial fibrillation (AF). The purpose of this study was to determine if HATCH score could predict recurrence after catheter ablation of AF. METHODS: The data of 488 consecutive paroxysmal AF patients who underwent an index circumferential pulmonary veins (PV) ablation were retrospectively analyzed. Of these patients, 250 (51.2%) patients had HATCH score = 0, 185 (37.9%) patients had HATCH score = 1, and 53 (10.9%) patients had HATCH score >= 2 (28 patients had HATCH score = 2, 23 patients had HATCH score = 3, and 2 patients had HATCH score = 4). RESULTS: The patients with HATCH score >= 2 had significantly larger left atrium size, the largest left ventricular end systolic diameter, and the lowest ejection fraction. After a mean follow-up of (823 +/- 532) days, the recurrence rates were 36.4%, 37.8% and 28.3% from the HATCH score = 0, HATCH score = 1 to HATCH score >= 2 categories (P = 0.498). Univariate analysis revealed that left atrium size, body mass index, and failure of PV isolation were predictors of AF recurrence. After adjustment for body mass index, left atrial size and PV isolation, the HATCH score was not an independent predictor of recurrence (HR = 0.92, 95% confidence interval = 0.76 - 1.12, P = 0.406) in multivariate analysis. CONCLUSION: HATCH score has no value in prediction of AF recurrence after catheter ablation. PMID- 23044301 TI - The electrocardiographic changes in acute brain injury patients. AB - BACKGROUND: Electrocardiographic (ECG) changes occurring during the course of acute brain injury (ABI) have been described frequently, but their significances remain uncertain. The present study was designed to investigate the relation of ECG abnormalities to outcome in the patients with ABI. METHODS: We performed a retrospective, observational study on the ABI patients admitted to the Department of Neurosurgery of the Beijing Tiantan Hospital between December 2005 and December 2007. All the patients accepted 12-lead electrocardiographic examination within 24 hours after injury, then divided into three groups according to the Glasgow coma score (GCS). In-hospital mortality and one-month outcome assessed by the Glasgow outcome score (GOS) were investigated. RESULTS: Of 335 ABI patients (mean ages 32.4 years), 246 patients (73.4%) had abnormal ECGs. The most common abnormality was ST-T changes (41.5%), followed by sinus tachycardia (23.6%). ECG changes had a significant association with the severity and outcome. Logistic regression analysis showed the presence of ST-T changes (OR 2.587, 95%CI 1.009 to 6.629, P = 0.048) and QT dispersion prolongation (OR 4.656, 95%CI 1.956 to 11.082, P = 0.001) significantly associated with short outcomes. CONCLUSIONS: ABI can lead to myocardial damage and ECG changes had a significant association with the severity. ST-T changes and QT dispersion prolongation were the independent prognosis factors for the negative outcome of ABI patients. PMID- 23044302 TI - Current pattern of Chinese dialysis units: a cohort study in a representative sample of units. AB - BACKGROUND: Understanding the characteristics of Chinese dialysis patients and the current practice trends is the first step to evaluate the association between practice pattern and outcome in these populations. In the present study, we evaluated the status of medical treatment and characteristic features of chronic dialysis patients in China. METHODS: Through a clustering sampling, we selected 9 centers from the largest dialysis facilities in 6 cities around China. All adult undergoing dialysis in the selected units were screened. A total of 2388 (1775 on hemodialysis (HD) and 613 on peritoneal dialysis (PD)) patients were finally enrolled. All data were collected at enrollment on the bases of review of medical records. RESULTS: In this cohort, 1313 (55.0%) were male. The mean age was 54 years old. The median time for dialysis was 26 months (12 - 51 months). Seventy five percent of patients were on HD and 25.0% on PD. Among PD patients, about 21% patients did not receive dialysis adequacy. For HD patients, about 14.0% of them did not achieve dialysis adequacy when the target of kt/V was set as 1.2. Only 44.7% of patients achieved blood pressure target of 140/90 mmHg. About 60% of patients did not reach the hemoglobin target of 110 g/L even though 85.0% of them were treated with erythropoietin. In addition, 48.5% of the patients had uncontrolled mineral metabolism revealed by the high calcium-phosphate product. Compared with HD patients, higher level of serum glucose, triglyceride, and total and low density lipoprotein cholesterol were more common in PD patients. CONCLUSIONS: This observational study suggests that many Chinese dialysis patients did not achieve the therapeutic target, particularly in blood pressure control, anemia correction, and mineral balance. PD patients were more likely to suffer metabolic disturbance. PMID- 23044304 TI - Vasculogenic mimicry is a key prognostic factor for laryngeal squamous cell carcinoma: a new pattern of blood supply. AB - BACKGROUND: Recurrence and local lymph node metastasis affected the prognosis of patients with laryngeal cancer. The aim of this study was to analyze clinical and pathological significance of vasculogenic mimicry (VM) in laryngeal squamous cell carcinoma (LSCC) and evaluate its contribution to prognosis. METHODS: Data of 168 cases of LSCC were reviewed retrospectively to reveal clinical pathology and prognostic significance of VM. CD31 and periodic acid-Schiff double staining was used to identify VM. RESULTS: VM in LSCC contributed to lymph node metastasis (P = 0.003) and clinical progression. VM correlated to histopathology grade (P = 0.001) of LSCC. VM was an adverse prognostic factor for both disease-specific survival (P = 0.039) and metastasis-free survival (P = 0.042) by univariate survival analyses. And it was an independent prognostic factor for only disease specific survival (P = 0.003) by multivariate survival analyses. CONCLUSIONS: VM existed in LSCC. LSCC with VM has more potential to invasion and metastasis. PMID- 23044303 TI - Chemerin and apelin are positively correlated with inflammation in obese type 2 diabetic patients. AB - BACKGROUND: As two novel adipocytokines, chemerin and apelin play a key role in the pathological process of insulin resistance (IR), glucose metabolism and obesity, researchers have found that the levels of chemerin and apelin changed significantly in type 2 diabetic patients with obesity, however, the underlying mechanism involved remains unclear. The aim of this study was to investigate whether chemerin and apelin play an important role in the pathophysiologic proceeding of diabetes. METHODS: This study enrolled 81 newly diagnosed obese type 2 diabetes mellitus (T2DM) patients (T2DM group, n = 81). All the patients were randomly assigned to DM1 group treated with metformin (n = 41) and DM2 group treated with pioglitazone (n = 40). After hypoglycemic agents treatment, patients under better blood glucose control were chosen to be given antioxidant treatment. Another 79 subjects without T2DM were recruited as normal control group (NC group), including 40 subjects (NC1 group) with normal body mass index (BMI) and 39 obese subjects (NC2 group). Levels of chemerin, apelin, BMI, tumor necrosis factor-alpha (TNF-alpha), homeostasis model assessment of IR (HOMA-IR) and 8 isoprotaglandim F2alpha (8-iso-PGF2alpha) were examined at baseline and post treatment. The relationship between chemerin, apelin and BMI, TNF-alpha, HOMA-IR, 8-iso-PGF2alpha was analyzed. RESULTS: The baseline levels of chemerin, apelin, TNF-alpha, HOMA-IR and 8-iso-PGF2alpha in T2DM group were significantly higher than normal control group (P < 0.001). All indices mentioned above were significantly decreased after treatment (P < 0.05). In T2DM patients treated with pioglitazone, indices mentioned above except for HOMA-IR, were decreased significantly compared with patients treated with metformin (P < 0.05). After antioxidant treatment using lipoic acid, levels of chemerin, apelin, TNF-alpha and 8-iso-PGF2alpha were further significantly decreased (P < 0.05). Correlation analysis showed that the levels of chemerin and apelin correlated positively with BMI, TNF-alpha, HOMA-IR and 8-iso-PGF2alpha before and after treatment with hypoglycemic agents (P < 0.01). The levels of chemerin and apelin also had positive correlation with TNF-alpha and 8-iso-PGF2alpha after antioxidant treatment (P < 0.05). CONCLUSIONS: The levels of chemerin and apelin in obese T2DM patients are closely related to IR. The increased levels may be a result of compensatory response to IR, and also may be the causative factor of IR. The levels of chemerin and apelin correlate closely with oxidative stress and inflammation. The two adipokines may be inflammatory factors playing important roles in the initiation and development of obese T2DM. Chemerin and apelin are related to the pathophysiology of IR, oxidative stress and inflammation. PMID- 23044305 TI - Extensive contact tracing and screening to control the spread of vancomycin resistant Enterococcus faecium ST414 in Hong Kong. AB - BACKGROUND: Proactive infection control management is crucial in preventing the introduction of multiple drug resistant organisms in the healthcare setting. In Hong Kong, where vancomycin-resistant enterococci (VRE) endemicity is not yet established, contact tracing and screening, together with other infection control measures are essential in limiting intra- and inter-hospital transmission. The objective of this study was to illustrate the control measures used to eradicate a VRE outbreak in a hospital network in Hong Kong. METHODS: We described an outbreak of VRE in a healthcare region in Hong Kong, involving a University affiliated hospital and a convalescent hospital of 1600 and 550 beds respectively. Computer-assisted analysis was utilized to facilitate contact tracing, followed by VRE screening using chromogenic agar. Multi-locus sequence typing (MLST) was performed to assess the clonality of the VRE strains isolated. A case-control study was conducted to identify the risk factors for nosocomial acquisition of VRE. RESULTS: Between November 26 and December 17, 2011, 11 patients (1 exogenous case and 10 secondary cases) in two hospitals with VRE colonization were detected during our outbreak investigation and screening for 361 contact patients, resulting in a clinical attack rate of 2.8% (10/361). There were 8 males and 3 females with a median age of 78 years (range, 40 - 87 years). MLST confirmed sequence type ST414 in all isolates. Case-control analysis demonstrated that VRE positive cases had a significantly longer cumulative length of stay (P < 0.001), a higher proportion with chronic cerebral and cardiopulmonary conditions (P = 0.001), underlying malignancies (P < 0.001), and presence of urinary catheter (P < 0.001), wound or ulcer (P < 0.001), and a greater proportion of these patients were receiving beta-lactam/beta-lactamase inhibitors (P = 0.009), carbapenem group (P < 0.001), fluoroquinolones (P = 0.003), or vancomycin (P = 0.001) when compared with the controls. CONCLUSION: Extensive contact tracing and screening with a "search-and-confine" strategy was a successful tool for outbreak control in our healthcare region. PMID- 23044306 TI - Molecular epidemiology of Mycobacterium tuberculosis in Gansu province of China. AB - BACKGROUND: Mycobacterial interspersed repetitive units-variable number tandem repeat (MIRU-VNTR) and Beijing family typing based on detecting the deletion of RD105 sequence are two common genotyping methods used to study the molecular epidemiologic characteristics of Mycobacterium (M.) tuberculosis. We collected 218 strains of M. tuberculosis between 2004 and 2006 in the Linxia Hui Autonomous Prefecture of Gansu province in Northwest China. METHODS: MIRU-VNTR analysis and Beijing family typing based on detecting the deletion of RD105 sequence were used to type the 218 strains, and their typing power was evaluated to look for practical and efficient genotyping methods suitable for the region. RESULTS: The MIRU typing yielded 115 distinct genotypes, including 98 unique isolates and 17 different clusters containing 120 isolates (55.05%); the cluster rate was 47.25%. By detecting the deletion of RD105 sequence, 188 of 218 (86.23%) isolates belonged to Beijing family. Combination of Beijing family typing and MIRU typing yielded 118 distinct patterns, including 101 unique isolates and 17 clusters containing 117 isolates (54.13%). The largest cluster contained 58 strains with MIRU genotype of 223325173533 which contained 50 strains belonging to Beijing family and 8 strains belonging to non-Beijing family. CONCLUSIONS: The Beijing family strains occupied a large proportion and the Beijing family MIRU genotype 223325173533 is a dominant strain in Linxia of Gansu. Combining detecting the deletion of RD105 and MIRU typing together provides a simple, fast, and effective method which is low in cost and might be practical and suitable for M. tuberculosis genotyping in China. PMID- 23044307 TI - Impact of compromised pulmonary function on major lung resection for non-small cell lung cancer: retrospective study of 127 cases. AB - BACKGROUND: Radical lung resection is the best chance for cure in patients with anatomically resectable non-small cell lung cancer. A retrospective study was performed in an attempt to investigate general rules of major lung resection for non-small cell lung cancer in patients with compromised pulmonary function. METHODS: Between June 2002 and December 2008, major lung resection was performed in 127 non-small cell lung cancer patients at our institution, who met the criteria of compromised pulmonary function defined as preoperative forced vital capacity < 50% of prediction or preoperative forced expiratory volume in one second < 50% of prediction. Clinical data of the patients were retrospectively reviewed. RESULTS: The patients consisted of 108 males (85.0%) and 19 females (15.0%) with a mean age of 61.7 years. The morbidity rate was 44.1% (56/127) and the mortality rate was 4.7% (6/127). Multivariate analysis identified PaCO2 (P = 0.023, OR = 2.959, 95%CI 1.164 - 7.522), the percent predicted postoperative diffusing capacity of the lung for carbon monoxide (P = 0.001, OR = 0.176, 95%CI 0.064 - 0.480) and comprehensive preoperative preparation (P = 0.048, OR = 0.417, 95%CI 0.176 - 0.993) as the independent predictors of postoperative cardiopulmonary complications that were found in 45 cases. Overall 1-, 3- and 5 year survival rates were 90%, 55% and 37% respectively. For overall survival, multivariate analysis revealed that TNM staging (P = 0.004, OR = 1.585, 95%CI 1.154 - 2.178) was the only independent prognostic factor. CONCLUSIONS: On the premise of integrated preoperative evaluation and comprehensive preoperative preparation, major lung resection provides an optimal therapeutic for selected non-small cell lung cancer patients with compromised pulmonary function. Hypercapnea and the percent predicted postoperative diffusing capacity of the lung for carbon monoxide < 40% could be considered as the independent predictive factors for operative risk in those patients. PMID- 23044308 TI - Hydrogen peroxide preconditioning enhances the therapeutic efficacy of Wharton's Jelly mesenchymal stem cells after myocardial infarction. AB - BACKGROUND: Exposure of cells to sublethal concentrations of hydrogen peroxide (H2O2) can alleviate subsequent oxidative stress-induced apoptosis. We assessed the effects of H2O2 preconditioning on the therapeutic potential of human umbilical cord Wharton's Jelly mesenchymal stem cells (WJ-MSCs) in a murine model of myocardial infarction. METHODS: WJ-MSCs were incubated in the media for 2 hours with or without 200 umol/L H2O2. Mice underwent left anterior descending coronary artery ligation, and received injection of phosphate buffered saline, 1*10(6) WJ-MSCs, or 1*10(6) H2O2 preconditioned WJ-MSCs 3 hours later via tail vein. Echocardiography was performed 0, 7, 14 and 28 days after surgery, and the mice were euthanized on day 28 for histological analysis. In vitro cytokine concentrations in the WJ-MSC cell supernatant were measured by enzyme-linked immunosorbent assay (ELISA). The effect of WJ-MSC cell supernatant on the migration and proliferation of endothelial cells were observed by transwell migration and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide (MTT) assays. RESULTS: Echocardiographic measurements revealed a significant improvement in the left ventricular contractility of the WJ-MSCs-H2O2 group compared to the WJ-MSCs group. Histological analysis revealed increased neovascularization and reduced myocardial fibrosis in the WJ-MSCs-H2O2 group compared to the WJ-MSCs group. Pretreatment of WJ-MSCs with H2O2 increased the secretion of interleukin-6 (IL-6) into the cell culture supernatant by approximately 25-fold. The culture supernatant from WJ-MSCs-H2O2 significantly increased the migration and proliferation of endothelial cells; these effects could be blocked using an anti-IL-6 antibody. CONCLUSIONS: This study demonstrates that H2O2 preconditioning significantly enhanced the therapeutic potential of WJ-MSCs, possibly by stimulating the production of IL-6 by WJ-MSCs, which may cause migration and proliferation of endothelial cells and increase neovascularization. PMID- 23044309 TI - MicroRNA alterations in senescent endothelial progenitor cells induced by remnant like lipoproteins. AB - BACKGROUND: Remnant-like lipoproteins (RLPs) have been demonstrated to accelerate the onset of endothelial progenitor cells (EPCs) senescence. Recent study has determined that microRNAs (miRNAs) were closely associated with cellular proliferation and senescence. This study aimed to examine whether RLPs lead to an alteration of miRNAs in senescent EPCs. METHODS: RLPs were prepared from plasma samples with immunoaffinity method. After 8 days of culture, EPCs were identified by flow cytometry analysis. Cells were incubated with RLPs for 72 hours. The senescent markers p16INK4a and senescence-associated beta-galactosidase (SA-beta gal) were detected by Western blotting analysis and beta-gal staining assay, respectively. A human miRNA microarray containing 723 miRNAs was used to detect the expression profile of miRNAs in control and senescent EPCs. The result from the above microarray was qualified by RT-PCR assay. RESULTS: RLPs dose dependently up-regulated the protein level of p16(INK4a) in EPCs, and RLPs at a concentration of 100 ug/ml induced a significant increase in the percentage of SA beta-gal-positive EPCs. Of 723 miRNAs, four miRNAs expressed differentially and significantly in RLPs-treated EPCs (P < 0.05), then their changes in expression were validated by real-time RT-PCR. Among them miR-148b and miR-155 were upregulated while miR-574-3p was down-regulated significantly when compared with control (P < 0.01). CONCLUSIONS: RLPs result in the onset of EPCs senescence. Senescent EPCs induced by RLPs exhibit a different profile of miRNAs. These three miR-148b and miR-155 and miR-574-3p reach a significant difference when compared with control, indicating that microRNA might take part in RLPs-induced EPCs senescence. PMID- 23044310 TI - Sevoflurane postconditioning alleviates action potential duration shortening and L-type calcium current suppression induced by ischemia/reperfusion injury in rat epicardial myocytes. AB - BACKGROUND: It has been proved that sevoflurane postconditioning (SpostC) could protect the heart against myocardial ischemia/reperfusion injury, however, there has been few research focused on the electrophysiological effects of SpostC. The objective of the study was to investigate the effects of SpostC on action potential duration (APD) and L-type calcium current (I(Ca, L)) in isolated cardiomyocytes. METHODS: Langendorff perfused SD rat hearts were randomly assigned to one of the time control (TC), ischemia/reperfusion (I/R, 25 minutes of ischemia followed by 30 minutes of reperfusion), and SpostC (postconditioned with 3% sevoflurane) groups. At the end of reperfusion, epicardial myocytes were dissociated enzymatically for patch clamp studies. RESULTS: Sevoflurane directly prolonged APD and decreased peak I(Ca, L) densities in epicardial myocytes of the TC group (P < 0.05). I/R injury shortened APD and decreased peak I(Ca, L) densities in epicardial myocytes of the I/R group (P < 0.05). SpostC prolonged APD and increased peak I(Ca, L) densities in epicardial myocytes exposed to I/R injury (P < 0.05). SpostC decreased intracellular reactive oxygen species (ROS) levels, reduced the incidence of ventricular tachycardia and ventricular fibrillation, and decreased reperfusion arrhythmia scores compared with the I/R group (all P < 0.05). CONCLUSIONS: SpostC attenuates APD shortening and I(Ca, L) suppression induced by I/R injury. The regulation of APD and I(Ca, L) by SpostC might be related with intracellular ROS modulation, which contributes to the alleviation of reperfusion ventricular arrhythmia. PMID- 23044311 TI - Comparison of neonatal tolerance to thoracoscopic and open repair of esophageal atresia with tracheoesophageal fistula. AB - BACKGROUND: Advances in minimally invasive surgical techniques and neonatal intensive care for neonates have allowed for repair of the neonatal esophageal atresia with tracheoesophageal fistula (EA/TEF) to be approached endoscopically. However, thoracoscopic surgery in children is still performed in only a few centers throughout the world. The aim of this study was to compare the neonatal tolerance to the thoracoscopic repair (TR) and the open repair (OR) and also to discuss anesthetic management in thoracoscopic procedure. METHODS: We performed a prospective study enrolling newborns diagnosed with EA with distal TEF (type C) receiving the repair surgery between June 2009 and January 2012 in our institution. Data collected included the newborns' gestational age and weight at the time of the operation, operative time, parameters of intraoperative mechanical ventilation, oxygenation, end-tidal carbon dioxide (ETCO2), and analysis of blood gases. Time to extubation and length of stay were also recorded. RESULTS: Intravenous induction with muscle paralysis followed by pressure-control ventilation and tracheal intubation regardless of the position of the fistula can be performed uneventfully in EA/TEF newborns with no additional airway anomalies and large, pericarinal fistulas in our experiences. The thoracoscopic approach appeared to take longer than the open approach. During the procedure of repair, hypercarbia and acidosis developed immediately 1 hour after pneumothorax in both groups. CO2 insufflation did have additional influence on the respiratory function of the newborns in the TR group; values of PaCO2 and ETCO2 were higher in the TR group but the difference did not reach statistical significance. By the end of the procedure, values of PaCO2 and ETCO2 returned to the baseline levels while pH did not, but all parameters made no difference in the two groups. Besides, time to extubation was shorter in the TR group. CONCLUSIONS: Thoracoscopic repair of EA/TEF is comparable to the open repair, and is believed to be safe and tolerable in selected patients. A wider range of neonates may be acceptable for thoracoscopic EA/TEF repair with increasing surgical experience. PMID- 23044312 TI - Risk factors of juvenile onset recurrent respiratory papillomatosis in the lower respiratory tract. AB - BACKGROUND: Juvenile onset recurrent respiratory papillomatosis (JORRP) is a relatively rare disease. It affects the larynx in most cases. Because reports on JORRP to the lower respiratory tract (LRT) are few, we investigated clinical features of patients with a history of JORRP to analyze the risk factors of this disease. METHODS: Data from 208 JORRP patients admitted to Beijing Tongren Hospital from January 2008 to December 2010 were reviewed. Gender, age at onset of symptoms, age at first surgery, duration of symptoms before the first surgical procedure, the number of surgical procedures, mean interval between surgical interventions, and the number of tracheotomies in patients with and without LRT spread of JORRP were analyzed. The data from patients with and without tracheotomy were recorded and compared. Two cases of primary tracheal papillomatosis were reviewed. RESULTS: Papillomas extension down to the LRT was observed in 46 children (22.1%). Patients with LRT papillomatosis had a shorter time from the onset of the symptoms until the first surgery, required significantly more surgical procedures, and had a shorter mean surgical interval. Tracheotomy was performed in 13/162 (8.0%) children with laryngeal papillomatosis vs. 36/46 (78.3%) children with LRT papillomatosis. After tracheotomy, 36/49 (73.5%) children developed LRT papillomatosis and 10/157 (6.4%) children who did not have a tracheotomy developed LRT papillomatosis. Patients with tracheotomy required a significantly higher number of surgical procedures. The younger the patient had a tracheotomy, the longer the duration of cannulation was. CONCLUSIONS: JORRP patients with LRT spread are prone to develop more aggressive disease. Tracheotomy resulted in a significant increase of LRT involvement. PMID- 23044313 TI - Association of vitamin D receptor FokI and ApaI polymorphisms with human cytomegalovirus disease in the first three months following kidney transplantation. AB - BACKGROUND: Untreated human cytomegalovirus (CMV) disease (CMVD) is an identified risk factor for reduced rates of patient (and graft) survival, death or retransplantation in kidney transplant recipients due to increased immunological tolerance after transplant. Vitamin D receptor (VDR) gene polymorphisms have an obvious relationship with autoimmune diseases but the relationship between VDR gene polymorphisms and CMVD are not well understood. This study investigated the relationship between VDR FokI and ApaI gene polymorphisms and CMVD, and their value for predicting risk of CMVD. METHODS: Ninety-eight kidney transplantation recipients were randomly chosen for which peripheral blood samples and case histories for the first three months after kidney transplantation were obtained. Using polymerase chain reaction-restriction fragment length polymorphisms, 30 recipients were found to be homozygous for the FokI gene (FF), 47 heterozygous (Ff), and 21 were homozygous (ff). Likewise, similar analyses determined that 12 recipients were homozygous for the ApaI gene (AA), 36 heterozygous (Aa), and 50 homozygous (aa). Factors affecting the prognosis of the kidney transplantation were compared for all genotypes by statistical analysis before operation. Infection by CMV for all recipients was detected by immunofluorescence assay to diagnose CMVD. RESULTS: No statistical significance was observed for the factors affecting the prognosis of the kidney transplantation between both genotypes; however, statistical differences in CMVD among the FokI genotypes were identified. It was determined that the risk of CMVD was significantly increased for recipients of the ff genotype than for other genotypes. There was no statistical significance observed for CMVD among ApaI genotypes. CONCLUSIONS: The recessive f allelic gene of VDR can be regarded as a risk factor of CMVD while FF recipients have lower incidence of CMVD after kidney transplantation. ApaI genotypes showed no relationship with predisposition to CMVD. PMID- 23044314 TI - Effects of backrest density on lumbar load and comfort during seated work. AB - BACKGROUND: Seated workplaces have greatly increased in China. Many researchers have found that seated work is a risk factor in the development of low-back pain. Backrest can reduce the load on the lower back by transmitting more of the weight from the upper body to the floor via the backrest so as to prevent low-back pain. To design a suitable chair backrest for seated office work, some backrest parameters must be optimized. In this study, the role of backrest density on lumbar load and comfort were investigated. The goal of the study was to help establish criteria with which backrests that alleviate and prevent low back pain during seated office work can be designed and selected. METHODS: Twenty volunteers (10 men and 10 women) were seated in three backrest conditions (10 kg/m(3), 25 kg/m(3), and 40 kg/m(3)). Pressure data, including contact pressure (CP), peak contact pressure (PCP) and contact area were collected during 15 minute trial. Subjective data were collected after each pressure test. RESULTS: Backrest density had a significant effect on backrest pressure variables. CP and PCP increased with increasing backrest density. Contact area decreased with increased density. In terms of user preference, the backrest with low density was most highly rated. CONCLUSIONS: Backrest density plays an important role in lumbar load and comfort during seated work. During designing and selecting backrests, backrest density should be focused on so as to alleviate and prevent low-back pain during seated office work. Backrest density at 10 kg/m(3) got the lowest CP and PCP and largest contact area. Backrest with low density can reduce lumbar pressure and increase support contact area, which could raise comfort feeling. Backrest density at 10 kg/m(3) is better to maintain a balance between providing effective support and alleviating excess lordosis. PMID- 23044315 TI - Clinical efficacy and safety of selective trans-cystic intra-operative cholangiography in primary suture following three-port laparoscopic common bile duct exploration. AB - BACKGROUND: Intra-operative cholangiography has been shown to be a sensitive and specific method of demonstrating bile duct stones. This study investigated the feasibility, safety, and clinical value of selective trans-cystic intra-operative cholangiography in primary suture following three-port laparoscopic common bile duct exploration, and identified the factors that positively predict the presence of common bile duct stones. METHODS: From January 2008 to January 2011, 252 of 1013 patients undergoing laparoscopic cholecystectomy received selective trans cystic intra-operative cholangiography and primary suture following three-port laparoscopic common bile duct exploration. Their clinical data were analyzed retrospectively. RESULTS: All operations were successful and none was converted to open surgery. The intra-operative cholangiography time was (8.3 +/- 2.5) minutes, and the operative duration was (105.4 +/- 23.1) minutes. According to selective intra-operative cholangiography, the positive predictive values of current jaundice, small gallstones (< 0.5 cm) and dilated cystic duct (> 0.3 cm), dilated common bile duct (> 0.8 cm), history of jaundice or gallstone pancreatitis, abnormal liver function test, and preoperative demonstration of suspected common bile duct stones on imaging were 87%, 25%, 42%, 15%, 32%, and 75% for common bile duct stones, respectively. Patients with several factors suggestive of common bile duct stones yielded higher numbers of positive cholangiograms. Unexpected stones were found in 13 patients (5.2%) by intra operative cholangiography. The post-operative hospital stay was (4.7 +/- 2.2) days. Post-operative bile leakage occurred in two cases, and these patients recovered by simple drainage for 3 - 7 days without re-operation. Of the 761 patients who underwent laparoscopic cholecystectomy alone, 5 (0.7%) presented with a retained common bile duct stone requiring intervention. The median follow up was 12 months, and only one patient who once suffered from bile leakage presented with obstructive jaundice due to bile duct stenosis 6 months postoperatively. The other patients recovered without any serious complications. CONCLUSIONS: Selective intra-operative cholangiography yields acceptably high positive results. It is a safe, effective, and minimally invasive approach in patients with suspected choledocholithiasis and primary suture following three port laparoscopic common bile duct exploration. PMID- 23044316 TI - Expansion of China's free antiretroviral treatment program. AB - BACKGROUND: In 2003, China's National Free Antiretroviral Treatment Program (NFATP) was initiated as a pilot, which covered only 100 HIV/AIDS patients. By 2011, the pilot had evolved into a nationwide program and had provided free treatment for over 150 000 patients. The objective of this study was to report and evaluate the progress of China's free antiretroviral treatment program. METHODS: The NFATP Database was systematically reviewed and a total of 150 692 HIV/AIDS patients were included in this study. Program progress indicators including the number of treated HIV/AIDS patients, follow-up visit rate, CD4 test rate, and viral load test rate were summarized and examined over a calendar year to evaluate the progress of NFATP quantitatively and qualitatively. RESULTS: By the end of 2011, a total of 150 692 HIV/AIDS patients had been treated through the NFATP and 122 613 of them were still on treatment. Of all patients, about 72% were enrolled during the past four years. The dominant transmission route was blood related in the early phase of the NFATP, but gradually changed to sexual contact. Besides quantitative improvements, progress indicators also demonstrated significant qualitative improvements that the program had made during the past 9 years. CONCLUSIONS: Great achievement has been made by China's NFATP. China's experience indicates the importance of a comprehensive response to the success of its treatment program. However, to ensure the quality and sustainability of treatment in the long term, more attention and resources should be paid towards program management. PMID- 23044317 TI - Heredity factor in myopia development among a sample in Klang Valley, Malaysia. AB - BACKGROUND: Development of myopia among young children is often contributed to the refractive status of the parents. This study was conducted to determine whether myopia can be inherited across the generation among a sample in the Klang Valley. Three generations involved are: G1 (grandparents), G2 (parents) and G3 (children). METHODS: Sixty-two families were screened and forty families were selected to participate in this study. The inclusion criterion is having at least one myopic member in any of the three generations. Subjects (G2) were first asked to fill up a questionnaire form before their refractive status was determined by clinical examination that provided acuity of 6/6 or better. Refractive status of G1 was determined using information from the questionnaire while for G2 and G3 through clinical examination. RESULTS: Generally, the prevalence of myopia is seen to increase throughout the generations from G1 being the lowest (25.6%) to G3 being the highest (41.1%). Strong genetic influence can be found between G1 and G2 as majority of myopes in G2 is when both parents were myopic. However, although the prevalence of myopia increased from G2 to G3, there was no strong genetical influence. Majority of subjects in G3 were non-myopes when both their parents were myopic. CONCLUSION: Parental history accounts for a limited proportion of variance in myopia development. PMID- 23044318 TI - Epigenetic regulation of Wnt signaling pathway gene SRY-related HMG-box 17 in papillary thyroid carcinoma. AB - BACKGROUND: SRY-related HMG-box 17 (SOX17) encodes a member of the SOX (SRY related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. Recently, it was considered as a tumor suppressor gene to inhibit canonical Wnt/beta-catenin signaling pathway in several malignancies. However, the function of SOX17 in thyroid cancer was unknown. Therefore, we investigated the epigenetic changes and the function of SOX17 in thyroid cancer. METHODS: The methylation status of the promoter region of SOX17 was detected using methylation-specific PCR in 63 papillary thyroid carcinoma (PTC) tissue, 10 normal thyroid tissue, and two thyroid cancer cell lines. Semi-quantitative RT-PCR was used to assess mRNA expression of SOX17 before and after 5-aza-2'-deoxycytidine treatment in thyroid cancer cell lines. Expression of SOX17 and beta-catenin were detected by immunohistochemistry in PTC and adjacent tissue. Luciferase reporter assay, colony formation, transfection, and Western blotting were employed to analyze the effect of SOX17 on thyroid cancer cell proliferation and the function of SOX17 in the Wnt signal pathway. RESULTS: Loss of SOX17 expression was correlated to the promoter region hypermethylation in thyroid cancer cell lines. Re-expression of SOX17 was found in TPC-1 cell line after 5-aza-2'-deoxycytidine treatment. In primary thyroid cancer, 60.3% (38/63) were methylated and 39.7% (25/63) unmethylated. But no methylation was found in noncancerous thyroid tissues. Methylation of SOX17 was associated reversely with beta-catenin expression in the cytoplasm or nucleus significantly in the PTC (P < 0.05). Colony formation was inhibited by re-expression of SOX17 in TPC-1 cells. SOX17 suppressed the Wnt signaling pathway and the HMG domain was essential for this effect. CONCLUSIONS: SOX17 was frequently methylated in human PTC. Loss of SOX17 expression was induced by promoter region hypermethylation. SOX17 inhibited thyroid cancer proliferation. Methylation of SOX17 activated the Wnt signaling pathway in human thyroid cancer. PMID- 23044319 TI - Effect of high-fat diet on liver and placenta fatty infiltration in early onset preeclampsia-like mouse model. AB - BACKGROUND: Preeclampsia, especially early onset of preeclampsia (PE), is a common and serious disorder with high maternal and perinatal morbidity and mortality. Dietary factor is one of the most important factors which may affect the occurrence and development of the disease. The aim of this study is to investigate the effects of dietary factors on pathological changes of liver and placenta in preeclampsia-like mouse model by establishing the model at multiple stages of gestation. METHODS: Wild-type (WT) mice were injected subcutaneously with nitric oxide synthase (NOS) inhibitor L-arginine methyl ester (L-NAME, 50 mg*kg(-1)*d(-1)) to establish PE-like model (L-NAME group) at early-, mid-, and late-pregnant periods respectively; simultaneously, the control mice were injected with normal saline (NS group). All the groups were divided into subgroups, standard chow group (SC), and high-fat diet group (HF). ApoE(-/-) pregnant mice served as a control group. Systolic blood pressure (SBP), urine protein, and histopathologic changes of placenta and liver in all groups were observed and statistically analyzed. RESULTS: In WT and apoE(-/-) L-NAME subgroups, blood pressure and urine protein were significantly higher than those in all the gestational age matched NS groups (P < 0.05). Compared to other groups, remarkable liver fatty infiltration and lipid storage in placenta were found in early- and mid-L-NAME subgroups in apoE(-/-) mice (P < 0.05), especially in the early- and mid-HF+L-NAME subgroups in apoE(-/-) mice (P < 0.05). More lipid storage droplets both in liver and placenta were found in ApoE(-/-) mice than that of WT groups (P < 0.05). Morphology histopathologic examination of placentas showed varying degrees of fibrinoid necrosis and villous interstitial edema in early- and mid-L-NAME both in HF and SC of apoE(-/-) and WT subgroups compared to NS controls (P < 0.05). But there was no significant difference between HF and SC subgroups (P > 0.05), and no difference between apoE(-/-) and WT groups (P > 0.05). CONCLUSIONS: Preeclampsia-like conditions could be induced by L-NAME in mice at different gestational stages. Both WT and apoE(-/-) genotype mice with preeclampsia-like symptoms in early and mid stages of pregnancy presented lipid deposition in the placenta and hepatic fatty infiltration. To alter the environmental condition by feeding high-fat diet was harmful to the mother and the fetus. High-fat diet aggravated the impact of liver fatty infiltration at early and mid gestational stages especially in the apoE(-/-) mouse model. These results further revealed the association between early-onset preeclampsia and the dysoxidation of fatty acids. PMID- 23044320 TI - Effect of an Ilex asprella root decoction on the related genes of lipid metabolism from chronic stress and hyperlipidemic fatty liver in rats. AB - BACKGROUND: The gradually increasing changes in a human hyperlipidemic diet along with chronic stress might play an important role in the increased numbers of fatty liver. This study investigated the effects of Ilex asprella root decoction on related genes of lipid metabolism in chronic stress in hyperlipidemic fatty liver in rats. METHODS: Forty-eight male Wistar rats were randomly divided into four groups: normal control group, model control group, simvastatin group, and Ilex asprella root group. To establish chronic stress and hyperlipidemic fatty liver models in rats, the levels of serum lipids, glucose, liver index, insulin (INS), insulin resistant (IR) index, adiponectin, superoxide dismutase (SOD), glutathione peroxidase (GSH-pX), glutathione (GSH), liver X receptor (LXR), and sterol responsive element binding protein (SREBP)-1c in rats were measured. RESULTS: When compared to the normal control group, the levels of serum lipids, glucose, liver index, INS, IR index, and GSH in the model control group significantly increased (P < 0.01). The protein levels of LXRalpha and SREBP-1c increased (P < 0.05), and the serum adiponectin and the SOD and GSH-pX decreased significantly (P < 0.01). When compared to the model control group, the levels of serum lipids, glucose, liver index, INS, IR index, SOD, and GSH-pX in the simvastatin group and Ilex asprella root group increased in varying degrees (P < 0.01 or 0.05); the serum adiponectin and GSH decreased (P < 0.05), while the protein levels of LXRalpha and SREBP-1c decreased in varying degrees (P < 0.01 or 0.05). When compared to the simvastatin group, the IR index and protein levels of LXRalpha in the Ilex asprella root group decreased (P < 0.05), and the serum adiponectin and SOD increased (P < 0.05). CONCLUSION: The Ilex asprella root decoction has some protective effects on regulating the related genes of lipid metabolism caused by chronic stress and hyperlipidemic fatty liver in rats. PMID- 23044321 TI - Clinical evaluation of valsartan and metoprolol tartrate in treatment of diabetic nephropathy with positive beta1-adrenergic and anti-angiotensin II type 1 receptor antibody. AB - BACKGROUND: Studies have confirmed that angiotensin II receptor blocker (ARB) and angiotensin converting enzyme inhibitors (ACEI) in the treatment of diabetic nephropathy (DN) has special advantages. We observed the effects of valsartan and metoprolol tartrate hydrchloride in treatment of DN patients with positive beta1 adrenergic and anti-angiotensin II type 1 (AT1) receptor antibody. METHODS: The epitopes of the second extracellular loop of beta1 receptor (197 - 222) and AT1 receptor (165 - 191), were synthesized and used respectively to screen serum autoantibodies from patients with DN (n = 371, group A), diabetes mellitus (DM) without renal failure (n = 107, group B) and healthy blood donors (n = 47, control, group C) by enzyme-linked immunosorbent assay (ELISA). Metoprolol tartrate 25 - 50 mg, three times per day, valsartan 160 mg, once a day, aspirin 100 mg, once a day, and nitrendipine 10 - 20 mg, three times per day, were given to DN patients with positive or negative autoantibodies. The cystatin C level and 24-hour urinary protein were measured before and after treatment. RESULTS: In DN patients, the positive rate of the autoantibodies against beta1 receptors and AT1 receptor was 47.7% and 51.5%, respectively, which were significantly higher than those in DM patients and healthy controls (all P < 0.01). Patients with anormalous cystatin C had higher positive rates of the autoantibodies than patients with normal cystatin C. Valsartan and metoprolol tartrate reduced proteinuria significantly (P < 0.01) in DN patients with positive autoantibodies. CONCLUSIONS: The findings suggest that these autoantibodies against beta1 and AT1 receptor may play important roles in the pathogenesis of DN. Valsartan and metoprolol tartrate are effective and safe in the treatment of DN. PMID- 23044322 TI - Application of echocardiography in resynchronization treatment of heart failure patients. AB - OBJECTIVE: To review the updated research progress about the application of echocardiography in resynchronization treatment of chronic heart failure patients. DATA SOURCES: The data used in this review were from PubMed, published in English and using the key terms "heart failure", "echocardiography" and "cardiac resynchronization therapy". STUDY SELECTION: Relevant articles were reviewed and selected to address the stated purpose. RESULTS: Increasing numbers of studies have suggested the importance of echocardiography in resynchronization treatment of chronic heart failure patients. Echocardiography can evaluate atrioventricular, inter- and intra-ventricular mechanical dyssynchrony before cardiac resynchronization therapy (CRT), as a guidance to assess the optimal left ventricular (LV) pacing location, optimize the atrioventricular and interventricular delays and predict response to CRT. CONCLUSIONS: Echocardiography is both non invasive and easily repeatable, and plays a crucial role in appraisal of heart synchronism, instruction of actuator placement, optimization of the device procedure, and prediction of the response to CRT. PMID- 23044323 TI - Arsenic trioxide: an ancient drug revived. AB - OBJECTIVE: To summarize the clinical applications of arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL), as well as non-APL malignancies and to discuss the mechanisms and adverse effects involved in ATO administration. DATA SOURCES: The data in this article were collected from PubMed and CHKD database with relevant English and Chinese articles published from 1957 to 2011, with key words including acute promyelocytic leukemia, arsenic trioxide, treatment, and mechanism. STUDY SELECTION: Articles including any information about ATO in the treatment of APL were selected. RESULTS: APL is a rare subtype of acute myeloid leukemia, with dismal prognosis under treatment with traditional chemotherapy. ATO impressively increases the complete remission rate and prolongs survival of patients with APL, with only mild and transient adverse effects. The advances in the understanding of multiple mechanisms involved in ATO treatment will benefit more cancers in future. CONCLUSION: Deeper understanding of mechanisms involved in ATO treatment may provide rationales for future clinical applications in a number of human malignancies. PMID- 23044324 TI - Peripheral vascular bifurcation: features and techniques. PMID- 23044325 TI - Back to the future: drug eluting balloon in bifurcation intervention. PMID- 23044326 TI - Tips and tricks of left main artery stenting. PMID- 23044327 TI - Clinical application of real time-polymerase chain reaction in determining cytomegalovirus viral DNA load in renal transplant recipients. AB - BACKGROUND: Cytomegalovirus (CMV) remains a significant clinical problem among immunosuppressed renal transplant patients. Quantitative PCR assays have become the most common methods in the determination of CMV infections in transplant patients. This study was to determine the relationship between CMV infection and the acute rejection of the transplanted kidney. METHODS: Plasma samples from 77 renal transplant patients that were pre-transplant negative for CMV infection were tested using real-time quantitative PCR and CMV gene-specific primers. The detected viral loads were retrospectively compared with the acute rejection rate and the chronic or mild rejection rates of the renal transplant. RESULTS: CMV-DNA was detected in 29 of 77 recipients, yielding a positive rate of detection of 37.7% for this procedure. Twelve of the 21 recipients (57.1%) who suffered acute rejection had positive CMV-DNA. Among the 56 recipients suffered from chronic or mild rejection, 17 (30.4%) had positive CMV-DNA plasma. Moreover, of the 29 recipients who had detectable CMV-DNA after transplant, 12 (41.4%) suffered from acute rejection; of the 48 recipients with undetectable CMV-DNA, only nine (18.8%) developed acute rejection. Post-transplant patients with acute rejection had a higher rate (57.1% vs. 30.4%, P = 0.03) of post-transplant CMV infection than those with chronic or mild rejection. CONCLUSION: CMV infection is a risk factor of acute renal transplant rejection and CMV infection should be prevented and treated in renal transplant recipients. PMID- 23044328 TI - Outcome of conservative treatment and subsequent assisted reproductive technology for patients with early-stage endometrial adenocarcinoma and poor fertility potential. AB - Conservative treatment with high doses of progestin is an alternative to standard hysterectomy for young patients with early-stage endometrial adenocarcinoma who desire to preserve their fertility. Here we report a patient with well differentiated early-stage endometrial adenocarcinoma and poor fertility potential who failed to become pregnant in two in vitro fertilization-embryo transfer cycles and suffered a relapse after conservative treatment. This case illustrates that assessment of fertility potential is critical at the time of initial evaluation and conservative treatment planning for patients with endometrial adenocarcinoma. PMID- 23044329 TI - Coronary tortuosity is associated with reversible myocardial perfusion defects in patients without coronary artery disease. PMID- 23044330 TI - Individualized treatment of ruptured intracranial aneurysms by microsurgical clipping and endovascular coiling: results from a consecutive series of 212 patients. PMID- 23044331 TI - Clinical analysis of arrhythmia in 297 Ebstein's anomaly patients. PMID- 23044332 TI - Acute myocardial infarction due to myocardial bridge. PMID- 23044333 TI - Single coronary artery arising from right sinus of valsalva. PMID- 23044334 TI - Cupping therapy-induced elevated D-dimer. PMID- 23044335 TI - Imaging manifestations of renal primary neuroectodermal tumors. PMID- 23044336 TI - Manage orbital apex lesions via posterior lateral orbitotomy. PMID- 23044337 TI - Inhibition of vascular smooth muscle cell proliferation: an indispensable target in treatment. PMID- 23044338 TI - Imaging neural stem cell graft-induced structural repair in stroke. AB - Stem cell therapy ameliorates motor deficits in experimental stroke model. Multimodal molecular imaging enables real-time longitudinal monitoring of infarct location, size, and transplant survival. In the present study, we used magnetic resonance imaging (MRI) and positron emission tomography (PET) to track the infarct evolution,tissue repair, and the fate of grafted cells. We genetically engineered embryonic stem cell-derived neural stem cells (NSCs) with a triple fusion reporter gene to express monomeric red fluorescence protein and herpes simplex virus-truncated thymidine kinase for multimodal molecular imaging and SPIO labeled for MRI. The infarct size as well as fate and function of grafted cells were tracked in real time for 3 months using MRI and PET. We report that grafted NSCs reduced the infarct size in animals with less than 0.1 cm(3) initial infarct in a dose-dependent manner, while larger stroke was not amenable to such beneficial effects. PET imaging revealed increased metabolic activity in grafted animals and visualized functioning grafted cells in vivo. Immunohistopathological analysis demonstrated that, after a 3-month survival period, grafted NSCs dispersed in the stroke-lesioned parenchyma and differentiated into neurons, astrocytes, and oligodendrocytes. Longitudinal multimodal imaging provides insights into time course dose-dependent interactions between NSC grafts and structural changes in infarcted tissue. PMID- 23044339 TI - Human amnion epithelial cells repair established lung injury. AB - With a view to developing a cell therapy for chronic lung disease, human amnion epithelial cells (hAECs) have been shown to prevent acute lung injury. Whether they can repair established lung disease is unknown. We aimed to assess whether hAECs can repair existing lung damage induced in mice by bleomycin and whether the timing of cell administration influences reparative efficacy. In addition, we aimed to characterize the effect of hAECs on fibroblast proliferation and activation, investigating possible mechanisms of reparative action. hAECs were administered intraperitoneally (IP) either 7 or 14 days after bleomycin exposure. Lungs were assessed 7 days after hAEC administration. Bleomycin significantly reduced body weight and induced pulmonary inflammation and fibrosis at 14 and 21 days. Delivery of hAECs 7 days after bleomycin had no effect on lung injury, whereas delivery of hAECs 14 days after bleomycin normalized lung tissue density, collagen content, and alpha-SMA production, in association with a reduction in pulmonary leucocytes and lung expression of TGF-beta, PDGF-alpha, and PDGF-beta. In vitro, hAECs reduced proliferation and activation of primary mouse lung fibroblasts. Our findings suggest that the timing of hAEC administration in the course of lung disease may impact on the ability of hAECs to repair lung injury. PMID- 23044340 TI - All-trans retinoic acid rescues memory deficits and neuropathological changes in mouse model of streptozotocin-induced dementia of Alzheimer's type. AB - Recent studies have revealed that aberrant vitamin A signaling may lead to memory deficits in rodents. Present study investigates the potential of all-trans retinoic acid (ATRA) an agonist at retinoid acid family of receptors, in cognitive dysfunctions associated with experimental dementia. Streptozotocin (STZ) [3 mg/kg, intracerebroventricularly (i.c.v)] was administered on alternate days (day 1 and day 3) to induce dementia in Swiss albino mice. STZ mice were administered ATRA (10 mg/kg; 20 mg/kg, p.o.) for a total of 19 days following second i.c.v injection of STZ [day 4 to day 22]. Morris water maze (MWM) test was performed on days 19, 20, 21, 22 and 23 to assess learning and memory of the animals. Following MWM test, the animals were sacrificed for biochemical and histopathological studies. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice showed marked accentuation of AChE activity, TBARS and MPO levels along with fall in GSH level. Further the stained micrographs of STZ-treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. ATRA treatment significantly attenuated STZ-induced memory deficits, biochemical and histopathological alterations. The findings demonstrate that the memory restorative ability of ATRA may be attributed to its anti-cholinesterase, anti oxidative and anti-inflammatory potential. PMID- 23044341 TI - Association study of DRD2 and MAOA genes with subtyped alcoholism comorbid with bipolar disorder in Han Chinese. AB - BACKGROUND: Several studies have hypothesized that genes involved in the dopamine system, including dopamine type-2 receptor (DRD2)-related TaqIA polymorphism and monoamine oxidase-A upstream variable number tandem repeat (uVNTR), may be associated with alcoholism. But their results were contradictory because of alcoholism's heterogeneity. Therefore, we examined whether the DRD2TaqIA and MAOA uVNTR gene polymorphisms are susceptibility factors for alcoholism comorbid with bipolar disorder (ALC+BP) in Han Chinese in Taiwan. METHODS: We recruited 101 Han Chinese men with comorbid alcoholism and bipolar disorder, and 328 healthy male controls from the community. Genotyping was done using PCR-RFLP. RESULTS: There were no significant differences in the genotypic frequencies of the DRD2TaqIA or the MAOA-uVNTR polymorphisms between the 2 groups. The MAOA-uVNTR 3-repeat had a significant protective effect on the ALC+BP (odds ratio=0.432, p=0.035) but not on the healthy controls. However, the interaction between the MAOA-uVNTR 3-repeat and DRD2 A1/A2 was a risk factor in the ALC+BP (odds ratio=3.451, p=0.018). CONCLUSIONS: We indicated the impact of the association between MAOA-uVNTR 3 repeat and DRD2 A1/A2 with ALC+BP. PMID- 23044342 TI - Effects of puerarin on the inflammatory role of burn-related procedural pain mediated by P2X(7) receptors. AB - BACKGROUND: Burn injury can induce an inflammatory response in the blood and wound of patients. Procedural activities in burn patients are particularly problematic in burn care due to their high intensity and frequency; hence, procedural pain evoked by burn dressing changes is a common severe issue. Previous studies demonstrated that purinergic signalling is one of the major pathways involved in the initiation, progression and down-regulation of the inflammatory response. Adenosine 5'-triphosphate (ATP) contributes to inflammation, and increased extracellular ATP levels amplify inflammation in vivo via the P2X7 receptor. In the present study, the effect of puerarin, an active ingredient extracted from Chinese herbal medicine Ge Gen, on pain relief of burn patients during dressing change and the mechanism related to the regulation of the purinergic signalling pathway were investigated. METHODS: Burn patients were randomly divided into the normal saline group (NS-treated burn patients) and the puerarin-treated group (PUE-treated burn patients), and healthy volunteers were recruited as a control group. The visual Analogue Scale (VAS) scores, heart rate (HR) and respiratory rate (RR) of NS- and PUE-treated burn patients were observed. In addition, interleukin (IL)-1 and IL-4 levels in blood samples, as well as expression of P2X7 receptor messenger RNA (mRNA) and protein in peripheral blood mononuclear cells (PBMCs) were determined. RESULTS: The IL-1 levels in the PUE-treated burn patients at post-dressing changes were significantly decreased in comparison with those in NS-treated burn patients; in contrast, the IL-4 levels in PUE-treated burn patients were increased. The expression levels of P2X7 protein and mRNA in PBMCs of PUE-treated burn patients were significantly decreased in comparison with those in NS-treated burn patients. CONCLUSIONS: The inflammation and associated pain involved in dressing changes of burn patients were relieved by puerarin treatment. The effects were correlated with the decreased expression level of P2X7 receptor mRNA and protein in PBMCs of burn patients. PMID- 23044343 TI - Could routine saphenous vein ultrasound mapping reduce leg wound complications in patients undergoing coronary artery bypass grafting? AB - A best evidence topic was written in cardiothoracic surgery based on a structured protocol. The question addressed was whether ultrasound mapping of the long saphenous vein (LSV) might reduce leg wound complications by reducing unnecessary leg incisions due to poor quality veins. Altogether, 32 abstracts were identified from the search, from which 5 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Surgical site infections can be extremely distressing for patients, and it is estimated that treating a surgical wound can cost up to L1554 each. Ultrasound mapping of the LSV has been reported to be an accurate way of assessing vein quality preoperatively, reducing unnecessary surgical dissection, theatre time and cost to both the patient and the health service. We identified four studies that showed that ultrasound scanning preoperatively could accurately predict the anatomy and quality of the LSV (correlation coefficient 0.87). One paper showed that ultrasound scanning reduced length of incision (P = 0.005), harvest time (P = 0.04) and hospital stay and reduced morbidity (although not statistically significant). However, one study found that it could not accurately predict vein wall changes. Evidence from the papers supports the use of preoperative ultrasound assessment of the saphenous vein. Benefits to the patient include a smaller scar, reduced harvest time and minimizing unnecessary incisions. PMID- 23044344 TI - Successful treatment of an infected new vascular graft. AB - A 71-year old male who underwent total aortic arch replacement using a newly developed uncoated vascular prosthesis (Triplex(r)) developed postoperative mediastinitis due to a methicillin-resistant Staphylococcus infection. The Triplex(r) vascular prosthesis has a unique three-layer structure with a non porous elastomer middle layer material and has several advantages over more traditional prosthesis, namely, good manipulability, good patency, dilatation resistance, and low inflammatory tissue reaction. This is the first reported case of a postoperative prosthesis infection that was successfully treated by omentum wrapping and closed irrigation with triphenylmethane dye. Bacterial cultures of blood samples were negative throughout the course of treatment, and 8 months after the initial operation. Computer tomographs revealed no evidence of infection or anastomotic pseudoaneurysms. In conclusion, the combination of omentum wrapping and the closed irrigation procedure using triphenylmethane dye can be considered to be an effective treatment for Triplex(r) graft infection. PMID- 23044345 TI - The role of nuclear receptors in controlling the fine balance between proliferation and differentiation of neural stem cells. AB - In the central nervous system (CNS) of vertebrates a large variety of cell types are specified from a pool of highly plastic neural stem/progenitor cells (NSCs) via a combined action of extrinsic morphogenetic cues and intrinsic transcriptional regulatory networks. Nuclear receptors and their ligands are key regulators of fate decisions in NSCs during development and adulthood, through their ability to control transcription of downstream genes. In the last few years considerable progress has been made towards the understanding of the actions of nuclear receptors in NSCs as well as elucidating the mechanistic basis for these actions. Here we summarize recent progress in the role of nuclear receptors in the biology of NSCs. These studies highlight the importance of this family of transcriptional regulators in CNS development and function in health and disease. Furthermore, they raise the intriguing possibility of using nuclear receptors as therapeutic targets for nervous system related diseases and traumas. PMID- 23044346 TI - [Endometritis secondary to Staphylococcus aureus producing Panton-Valentine leukocidin]. PMID- 23044347 TI - [Hypothermia at admission increases the risk of pulmonary contusion's infection in intubated trauma patients]. AB - OBJECTIVES: Pulmonary contusion (PC) is common in cases of polytrauma. The aim of this study was to perform a multivariate analysis of risk factors associated with the occurrence of infection in PC and analyze the microbiological epidemiology. PATIENTS AND METHODS: All patients with PC admitted to the intensive care unit (ICU) between January 2002 and December 2006 were included in this retrospective observational study. Patients with penetrating thoracic trauma or those who died in the 48hours following admission to hospital were excluded. Diagnosis of bacterial infection in PC was performed if hyperthermia was associated with a positive quantitative culture (103 colony forming units/mL) on the bronchial sample. Univariate analysis provided statistical difference between variables that were integrated in the multivariate analysis model. Multivariate analysis was then performed to determine the risk factors of bacterial infection in PC. RESULTS: One hundred and seventeen patients were included. The incidence of bacterial infection in PC was 33.3% (39 patients). The most frequently encountered bacteria were Haemophilus sp., Staphylococcus aureus, Enterobacteriaceae, Pseudomonas sp. and Streptococcus sp. According to multivariate analysis, the existence of hypothermia at hospital admission increased the risk of PC infection (OR=2.61; IC 95% [4.2-13.3]). CONCLUSION: In conclusion, PC was infected in 33.3% of cases. The existence of hypothermia was identified as a risk factor. A prospective study is warranted to confirm these results. PMID- 23044348 TI - Pyrosequencing of epizootic rabbit enteropathy inocula and rabbit caecal samples. AB - The aetiological agent of epizootic rabbit enteropathy (ERE) is still unknown although a bacterial infection seems the most likely hypothesis. In this study, amplification of the V5 and V6 regions of 16SrDNA from four virulent and two non virulent caecal samples was performed using a pyrosequencing platform. The virulent samples did not group in the same cluster. The bacterial flora identified was both different and richer than the cultivable bacterial flora. These findings highlight the need for biomolecular techniques to identify the aetiological agent of ERE. PMID- 23044349 TI - Is routine histological examination of mastectomy scars justified? An analysis of 619 scars. AB - BACKGROUND: The increasing incidence of breast cancer is paralleled by an increasing demand for post-mastectomy breast reconstruction. At the time of breast reconstruction routine submission of mastectomy scars has been considered appropriate clinical practice to ensure that no residual cancer exists. However, this practice has been challenged by some and has become the topic of controversy. In a retrospective analysis we wished to assess whether routine submission of mastectomy scars altered treatment. METHODS: Utilizing the Stanford Translational Research Integrated Database Environment (STRIDE) all patients who underwent implant-based breast reconstruction with routine histological analysis of mastectomy scars were identified. The following parameters were retrieved and analyzed: age, cancer histology, cancer stage (according to the American Joint Committee on Cancer staging system), receptor status (estrogen receptor [ER], progesterone receptor [PR], Her2neu), time interval between mastectomy and reconstruction, and scar histology. RESULTS: A total of 442 patients with a mean age of 45.9 years (range, 22-73 years) were included in the study. Mastectomy with subsequent reconstruction was performed for in-situ disease and invasive cancer in 83 and 359 patients, respectively. A total of 619 clinically unremarkable mastectomy scars were sent for histological analysis, with the most common finding being unremarkable scar tissue (i.e. collagen fibers). Of note, no specimen revealed the presence of carcinoma. CONCLUSION: According to published reports routine histological examination of mastectomy scars may detect early local recurrence. However, we were not able to detect this benefit in our patient population. As such, particularly in the current health-care climate the cost effectiveness of this practice deserves further attention. A more selective use of histological analysis of mastectomy scars in patients with tumors that display poor prognostic indicators may be a more reasonable utilization of resources. PMID- 23044350 TI - The impact of the menstrual cycle on intra-operative and postoperative bleeding in abdominoplasty patients. AB - BACKGROUND: Hormonal changes that take place during the menstrual cycle may have an effect on perioperative bleeding. Previous studies have confirmed a relationship between the menstrual cycle and surgical bleeding in rhinoplasty and breast reduction surgery; yet both surgical sites display changes in accordance with sex hormone levels during the menstrual phase. AIM: The aim of this study was to determine the effect of the menstrual cycle on perioperative bleeding when undergoing surgeries of sites not directly related to menstrual hormonal changes. MATERIALS AND METHODS: Forty-one patients undergoing abdominoplasty were grouped as group A - perimenstrual (0-7, 21-28 days), group B - periovulatory (8-20 days) and group C - postmenopausal. Intra-operative blood loss was calculated during surgery while postoperative blood loss was determined by measuring the amount of drainage. All menstrual data were recorded. Age, body mass index and weight of the resected tissue were also considered as factors that can affect the amount of bleeding and therefore were also evaluated in terms of significance. RESULTS: There was no significant difference between groups regarding intra-operative and postoperative blood loss. Body mass index and weight of the resected tissue had a strong influence on the time of drain removal and the amount of intra-operative and postoperative blood loss. CONCLUSION: This study strongly suggests that the menstrual period does not affect perioperative blood loss for operations on areas less sensitive to sex hormone levels such as the abdomen. In light of the results, we can conclude that the patient's menstrual date is not of vital importance regarding perioperative blood loss when planning surgery for areas with less sensitivity to menstrual hormonal changes. PMID- 23044351 TI - Effects of monorhamnolipid and dirhamnolipid on sorption and desorption of triclosan in sediment-water system. AB - The effects of monorhamnolipid (RL-F1) and dirhamnolipid (RL-F2) on the sorption and desorption of triclosan (TCS) in sediment-water system were investigated in this study. Results of the bath equilibrium experiments showed that RL-F2 provided much higher solubilization enhancement for TCS than RL-F1. Sorption of both rhamnolipids by the sediments was highly correlated with the sediment clay content. Moreover, the apparent distribution coefficients of TCS K(d)(*) decreased with the increase of rhamnolipid concentration (0.05-7.5 mM), and RL-F2 presented a larger distribution capacity of TCS into the aqueous phase at relatively higher concentrations (>2.5 mM). Further results also indicated that the release of TCS from sediment could be enhanced by both rhamnolipids. RL-F2 was more efficient than RL-F1 in desorbing TCS from the sediment with low clay content. The TCS desorption percentages R(d)(*) of RL-F2 (5mM) was 1.8-2.4 times that of RL-F1. These findings could provide useful guidelines for the application of rhamnolipid-enhanced remediation technologies for TCS contaminated sediment. PMID- 23044352 TI - Time-integrated sampling of glyphosate in natural waters. AB - Environmental monitoring of pesticide residues in surface water is often done with time-integrated sampling where a specified volume is sampled each hour during, e.g., a week, thus avoiding at momentary high or low extreme concentrations. However, sampling over an extended period of time can result in losses of easily degradable analytes, why the stability of the target analytes over the timespan of the sampling must be checked. Glyphosate is one of the most widely used herbicides. Because of its chemical complexity, glyphosate binds differently to metals and colloids at different pH, and the degradation may also be affected. Recovery of glyphosate from spiked natural waters after 1 and 3 weeks of storage was higher when the samples were acidified to approximately pH 2 rather than at their natural pH. Keeping the samples refrigerated to 4 degrees C in darkness also enhanced recovery, while glyphosate losses were substantial from samples kept at their natural pH at 20 degrees C. Total loss of glyphosate was observed in some samples kept at natural pH, 20 degrees C, and daylight; a loss partly due to binding to metals or colloids that could only partially be reversed by acidification. For 1-week time-integrated sampling a small amount of hydrochloric acid in a piece of heat-sealed hydrophobic micro-porous tubing is added to the sampling bottles before deployment, a procedure that acidifies the samples during collection keeping them below pH 2 until analysis, thus minimising losses of glyphosate. The method also allows determination of the primary degradation product aminomethylphosphonic acid (AMPA). PMID- 23044353 TI - Pharmacological therapies, lifestyle choices and nitric oxide deficiency: a perfect storm. AB - Over the past 10 years, despite a slight increase in life expectancy and a decrease in all causes of deaths, the percentage of the US population with heart disease, cancer, diabetes, hypertension and obesity has increased. So even though Americans are living longer, they are plagued by increasing incidences of morbidities. This trend is also reflective of the global population, where 17.3 million people died from cardiovascular disease in 2008, and an estimated 23.6 million are expected to die from this disease in 2030. Whereas access to medical care and management of certain diseases has improved, it is clear that the incidence and treatment of chronic disease has not kept pace. The discovery of nitric oxide (NO) production in the human body is a relatively new advancement of modern medicine. Unfortunately, NO is still not at the forefront of therapy. In the clinical setting, there are no standard laboratory diagnostics for NO status and no prescription therapies to safely and effectively restore NO homeostasis, despite being recognized as the earliest indicator for a number of different chronic diseases. This review will reveal how many modern therapies and western lifestyles actually lead to a decrease in NO homeostasis in patients, from pediatrics to geriatrics. The findings outlined here highlight why nitric oxide homeostasis should be accounted for and considered in the treatment of patients and in the development of new therapies. Understanding NO homeostasis in each patient and how treatments and procedures affect NO homeostasis should allow for better medical care and improved outcomes. PMID- 23044354 TI - A new simple and high-yield synthesis of 5alpha-dihydrotestosterone (DHT), a potent androgen receptor agonist. AB - We have devised an efficient procedure for the synthesis of 5alpha dihydrotestosterone (DHT) (1) starting from 3beta-hydroxy-5alpha-androstan-17 one, providing the product in unprecedented 82% yield. A reported method of using toxic Jones reagent is replaced by milder oxidizing agent (NMO/TPAP) in the synthesis of a key intermediate 17beta-[(tert-butyldimethylsilyl)oxy]-5alpha androstan-3-one (18). This new procedure is simple, does not require special apparatus/precautions or chromatographic purification in most of the steps. PMID- 23044356 TI - Repair of tympanic membrane perforation using novel adjuvant therapies: a contemporary review of experimental and tissue engineering studies. AB - OBJECTIVE: To perform a contemporary review of experimental studies to describe the effects of various novel adjuvant therapies in enhancing tympanic membrane (TM) perforation healing. METHODS: A PubMed search for articles from January 2000 to June 2012 related to TM perforation, along with the references of those articles, was performed. Inclusion and exclusion criteria were applied to all experimental studies assessing adjuvant therapies to TM healing. RESULTS: Many studies have assessed the efficacy of biomolecules or growth factors, such as epidermal growth factors and basic fibroblast growth factors, in TM regeneration with significant success. More recent strategies in TM tissue engineering have involved utilizing bioengineered scaffold materials, such as silk fibroin, chitosan, calcium alginate, and decellularized extracellular matrices. Most scaffold materials demonstrated biocompatibility and faster TM perforation healing rates. CONCLUSION: Although several studies have demonstrated promising results, many questions still remain, such as the adequacy of animal models and long-term biocompatibility of adjuvant materials. As well, further studies comparing various adjuvant substances and bioscaffolds are required prior to clinical application. PMID- 23044355 TI - Human liver endothelial cells, but not macrovascular or microvascular endothelial cells, engraft in the mouse liver. AB - Liver cell transplantation has had limited clinical success so far, partly due to poor engraftment of hepatocytes. Instead of hepatocytes. other cell types, such as endothelial cells, could be used in ex vivo liver gene therapy. The goal of the present study was to compare the grafting and repopulation capacity of human endothelial cells derived from various tissues. Human endothelial cells were isolated from adult and fetal livers using anti-human CD31 antibody-conjugated magnetic beads. Human macrovascular endothelial cells were obtained from umbilical vein. Human microvascular endothelial cells were isolated from adipose tissue. Cells were characterized using flow cytometry. Liver engraftment and repopulation of endothelial cells was studied after intrasplenic transplantation in monocrotaline-treated immunodeficient mice. Following transplantation, human liver endothelial cells engrafted throughout the mouse liver. With immunoscanning electron microscopy, fenestrae in engrafted human liver endothelial cells were identified, a characteristic feature of liver sinusoidal endothelial cells. In contrast, CD31-negative liver cells, human macrovascular and microvascular endothelial cells were not capable of repopulating mouse liver. Characterization of human liver, macrovascular, and microvascular endothelial cells demonstrated expression of CD31, CD34, and CD146 but not CD45. Our study shows that only human liver endothelial cells, but not macro- and microvascular endothelial cells, have the unique capacity to engraft and repopulate the mouse liver. These results indicate that mature endothelial cells cannot transdifferentiate in vivo and thus do not exhibit phenotypic plasticity. Our results have set a basis for further research to the potential of human liver endothelial cells in liver-directed cell and gene therapy. PMID- 23044357 TI - The role of advanced practice providers in pediatric otolaryngology academic practices. AB - OBJECTIVE: The goal of this study was to examine the roles of Physician Assistants (PAs) and Nurse Practitioners (NPs) in pediatric academic otolaryngology programs to provide a better understanding of their scope of practice, levels of autonomy, clinical duties, teaching opportunities and research participation. DESIGN: An anonymous web-based electronic survey tool was sent to all pediatric otolaryngology fellowship program directors in the United States. RESULTS: Nurse Practitioners and Physician Assistants are utilized in approximately 3 out of every 4 pediatric otolaryngology practices. The top three job activities of both the PA and NP were: (1) seeing patients independently, (2) working alongside doctors in clinic, and (3) answering phone lines/parental calls. A higher percentage of PAs (83%), worked alongside doctors in clinic, as compared to NPs, where only 55% work alongside MDs. Over half of PAs round with the in-patient team and see consults as compared to just over one third of NPs who participate in such activities. Twenty-five percent of practices reported that PAs cover call and assist in the OR. Most PAs/NPs saw between 11 and 15 patients per clinic which provides a clear productivity advantage when looking to screen patients, provide medical care, generate surgical cases, and maximize billings. CONCLUSION: NPs and PAs have complimentary skill sets ideal for the pediatric otolaryngology workplace, although job activities and "best fit" are hospital and practice dependent. Our study suggests that the use of PAs and NPs will continue to grow to meet increased demand for services in the field of pediatric otolaryngology. Employing advanced practice providers enables academic centers to improve access, provide additional financial remuneration, reduce wait times for new patients, and allow attending physicians to meet increased practice demands. PMID- 23044358 TI - Effect of anti-adhesion barrier solution containing ciprofloxacin-hydrocortisone on abraded mucosa with otitis media. AB - OBJECTIVE: No study to date has assessed the anti-adhesive effect of new middle ear (ME) packing agents in. This study compared the anti-inflammatory and anti adhesive effect of antibiotic-steroid containing packing agents in abraded mucosa of the ME inflammation. MATERIALS AND METHODS: Transbullar injection of a saline suspension of Pseudomonas aeruginosa lipopolysaccharide (LPS) induced otitis media. ME mucosa of guinea pigs was abraded using a pick 30 min after LPS inoculation. The animals were divided into four groups of 10 guinea pigs each. In group A, ME cavity was preserved without any packing. In group B, ME cavity was packed with soluble hyaluronic acid-carboxymethyl cellulose (HA-CMC). In group C, the ME cavity was packed with soluble HA-CMC. In group D, the ME cavity was packed with antibiotic-steroid containing soluble HA-CMC. Otoendoscopic examination, auditory brainstem responses (ABRs), and radiographic examination using computerized tomography (CT) were performed at 2 weeks post-surgery. Histopathological evaluation for ME mucosa was performed by light microscopy (LM) and scanning electron microscopy (SEM). RESULTS: Otoendoscopic findings and CT findings revealed that group D showed the best recovery of aeration in the ME compared to other groups. Recovery of ABRs threshold was significantly attenuated in group D. In LM and SEM findings, group D showed normalized mucosal thickening compared to other groups. CONCLUSION: ME packing by antibiotic-steroid containing soluble HA-CMC may be useful in the abraded mucosa of the ME inflammation. PMID- 23044359 TI - The accessibility of a new oral motor pacifier to infants. AB - OBJECTIVE: The aim of the present study was to examine whether infants would accept an oral motor pacifier (OMP). CHILDREN AND METHODS: Sixteen infants were examined for their immediate acceptance of an OMP. The pacifier was regarded as accepted, if the child took it in the mouth and kept it there actively, i.e. sucked it in one way or other. Their parents were informed verbally and in writing literally about how to offer the OMP to the child and how to use it. The OMP was presented to the child and the child permitted to insert it into her/his mouth by her/himself or if the child failed to do so, the OMP was gently put to the child's mouth. The subjects' reactions were structurally evaluated in terms of 11 statements. The parents of the children received a structured questionnaire with a space for optional free comments and personal opinions. RESULTS: The median age (6 females, 10 males) was 18 months (mean 19.2 months, s.d. 10.6 and range 2-38 months). The statement scores showed no significant differentiation based on the age of the subject. The parents' reports indicated that 14 (87.5%) of the 18 subjects accepted the OMP, 13 (81.3%) enjoyed watching the pacifier as it was shown to them, and 11 (68.8%) explored it with their fingers while holding it in their hands. CONCLUSION: The vast majority of the children accepted the new OMP either at the first trial or after a few trials. PMID- 23044360 TI - The midwifery miniCEX--a valuable clinical assessment tool for midwifery education. AB - BACKGROUND: Midwifery students, clinicians and educators in Australia identified the need for improved feedback for midwifery students whilst they are on clinical placement; in particular formative assessment. The miniCEX or mini-clinical evaluation exercise is one approach to assessment that has been proven valid and reliable in medical education. The aim of this research was to develop, implement and evaluate a miniCEX tool for midwifery education. METHODS: Using an action research approach, this project engaged midwifery clinicians and midwifery students to adapt and implement the miniCEX in a postnatal ward environment. Focus groups were held to establish the clinical expectations and develop performance guidelines of students across the domains of midwifery practice, as well as evaluate their use in practice. FINDINGS: Evaluation of the midwifery miniCEX, including its applicability from the perspective of staff and students was positive. The miniCEX was found to be easy to use, time efficient and valuable for learning. DISCUSSION: The miniCEX is an innovative approach to assessment and feedback in midwifery education, and there is currently no identified evidence of its use in midwifery education despite broad use globally in medical education. CONCLUSION: The implementation of the midwifery miniCEX offers broad benefit to both midwifery students and midwifery clinicians and educators globally. PMID- 23044362 TI - Titanium dioxide nanoparticles inhibit proliferation and induce morphological changes and apoptosis in glial cells. AB - Titanium dioxide nanoparticles (TiO(2) NPs) are widely used in the chemical, electrical and electronic industries. TiO(2) NPs can enter directly into the brain through the olfactory bulb and be deposited in the hippocampus region. We determined the effect of TiO(2) NPs on rat and human glial cells, C6 and U373, respectively. We evaluated proliferation by crystal violet staining, internalization of TiO(2) NPs, and cellular morphology by TEM analysis, as well as F-actin distribution by immunostaining and cell death by detecting active caspase-3 and DNA fragmentation. TiO(2) NPs inhibited proliferation and induced morphological changes that were related with a decrease in immuno-location of F actin fibers. TiO(2) NPs were internalized and formation of vesicles was observed. TiO(2) NPs induced apoptosis after 96h of treatment. Hence, TiO(2) NPs had a cytotoxic effect on glial cells, suggesting that exposure to TiO(2) NPs could cause brain injury and be hazardous to health. PMID- 23044361 TI - [1st National Meeting of Multidisciplinary Work in Oncogeriatrics: expert consensus document]. AB - On 2nd of June 2011 the Institut Catala d' Oncologia l'Hospitalet--Hospital Duran i Reynals hosted the first Meeting of Multidisciplinary Work in Oncogeriatrics. The reason for the meeting, which follows on from an initiative of the Medical Societies of Radiotherapy, Oncology, Geriatrics and Gerontology and Palliative Care and Medical Oncology, was to initiate a joint line of work among the different specialties that generally take part in the handling of the elderly patient suffering from oncologic pathologies. This document summarises the different subjects covered during the Meeting. PMID- 23044363 TI - Therapeutic superiority for cartilage repair by CD271-positive marrow stromal cell transplantation. AB - Recent reports indicated that human isolated CD271+ bone marrow mesenchymal stromal cells (BM-MSCs) have a greater expansion and potential for multipotent differentiation including chondrogenesis than classical plastic adherent (PA) BM MSCs in vitro. Therefore, we set up a hypothesis that CD271+ MSCs may have a greater chondrogenic potential than PA-MSCs in vitro and in vivo. We investigated the superiority of CD271+ MSCs on chondrogenesis using in vitro expansion and pellet culture system and in vivo rat model of cartilage defect when compared to PA-MSCs. In the in vitro study, CD271+ MSCs showed higher expansion potential and produced larger pellets with higher expressions of chondrogenic genes when compared to the control groups. During the culture, CD271 expression decreased, which resulted in decreased chondrogenesis. In the in vivo study, immunohistochemical staining demonstrated differentiated human chondrocytes identified as double-stained cells with human-specific collagen type 2 and human leukocyte antigen-ABC in CD271+ and PA groups. The number of double-stained cells was significantly higher in the CD271+ group than PA group. Real-time RT-PCR analysis of tissue RNA isolated from the chondral defect site for human-specific chondrogenic markers demonstrated a significantly higher expression in CD271+ group than PA group. Macroscopic examination of chondral defect sites at week 8 revealed glossy white and well-integrated repaired tissues in the CD271+ and PA groups, but not in the PBS group. The average histological score in the CD271+ group was significantly greater than in the other groups. Apoptosis analysis at the cell transplanted site with TUNEL staining showed that the CD271+ group had significantly fewer apoptotic chondrocytes compared with the PA group. These results indicate that CD271+ MSCs have a greater chondrogenic potential than PA MSCs in both in vitro and in vivo conditions. PMID- 23044364 TI - Community participation, supports, and barriers of school-age children with and without disabilities. AB - OBJECTIVE: To examine patterns of community participation and environmental factors that affect community participation for school-age children with and without disabilities. DESIGN: Cross-sectional, descriptive, and exploratory study. SETTING: Parents from the United States and Canada completed the main outcome measure online in their homes or communities. PARTICIPANTS: Parents (N=576) reported on their children aged 5 to 17 years with disabilities (n=282) and without disabilities (n=294). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Participation and Environment Measure for Children and Youth. RESULTS: Group differences in summary scores and many items were significant (P<.001). Children with disabilities participated less frequently, were less involved, and had less environmental support in the community than children without disabilities. Parents of children with disabilities desired more change in their child's participation than parents of children without disabilities. Effect sizes for summary scores were moderate to very large (n(2)p from .11-.40), with the largest group difference found in environment scores. Overall, the largest group differences in participation were in "unstructured physical activities" and "getting together with other children"-also the 2 areas where parents of children with disabilities most frequently desired change. The largest differences in environmental impact were in physical, social, and cognitive activity demands and availability/adequacy of programs and services. CONCLUSIONS: Results provide insights about where greater efforts are needed to support community participation of school-age children with disabilities. Further study with a more diverse sample in terms of race/ethnicity, family income/education levels, and geographic region is needed to determine the extent to which results may be generalized. PMID- 23044365 TI - Is MRI a useful tool to distinguish between serous and mucinous borderline ovarian tumours? AB - AIM: To analyse the morphological magnetic resonance imaging (MRI) features of borderline ovarian tumours (BOT) and to evaluate whether MRI can be used to distinguish serous from mucinous subtypes. MATERIALS AND METHODS: A retrospective study of 72 patients who underwent BOT resection was undertaken. MRI images were reviewed blindly by two radiologists to assess MRI features: size, tumour type, grouped and irregular thickened septa, number of septa, loculi of different signal intensity, vegetations, solid portion, signal intensity of vegetations, normal ovarian parenchyma, and pelvic ascites. Statistical analysis was performed using Mann-Whitney and Fisher's exact tests. Logistic regression analysis was used to assess the predictive value of the MRI findings for histological subtypes. RESULTS: At histology, there were 33 serous BOT (SBOT) and 39 mucinous BOT (MBOT). Predictive MRI criteria for SBOT were bilaterality, predominantly solid tumour, and the presence of vegetations, especially exophytic or with a high T2 signal (p < 0.01), whereas predictive MRI criteria for MBOT were multilocularity, number of septa, loculi of different signal intensity, and grouped and irregular thickened septa (p < 0.01). Using multivariate analysis, vegetations were independently associated with SBOT [odds ratio (OR) = 29.5] and multilocularity with MBOT (OR = 3.9). CONCLUSION: Vegetations and multilocularity are two independent MRI features that can help to distinguish between SBOT and MBOT. PMID- 23044366 TI - Synthesis of 6-amino-2-vinylpurine derivatives for cross-linking and evaluation of the reactivity. AB - Oligodeoxynucleotides (ODNs) have been widely used for inhibiting the gene expression in antisense or antigene methods, and the interstrand cross-linking (ICL) forming ODNs have been expected to ensure the inhibition by these methods. Previously, we reported a highly efficient and selective ICL reaction toward cytosine using the 2-amino-6-vinylpurine derivative under acidic conditions. In this Letter, we report the synthesis of ODN containing 6-amino-2-vinylpurine derivatives and evaluation of the cross-linking reactivity. PMID- 23044367 TI - Isolation, characterization and cytotoxic activity of benzophenone glucopyranosides from Mahkota Dewa (Phaleria macrocarpa (Scheff.) Boerl). AB - Two benzophenone glucopyranosides have been isolated from the nut shell part of Mahkota Dewa. The structures were identified as 2,4',6-trihydroxy-4-methoxy benzophenone-2-O-beta-d-glucoside (Mahkoside A) and 2,4',6-trihydroxy-4-methoxy 6"-acetyl-benzophenone-2-O-beta-d-glucoside (Mahkoside B). Mahkoside B was recognized as a novel compound. Furthermore, a series of benzophenone glucopyranoside derivatives (compounds 3-18) were synthesized and their bioactivities were characterized. Our results demonstrated that compound 18 has significant cytotoxicity against two esophageal cancer cell lines, stomach cancer cell line and prostate cancer cell line, with IC(50) less than 10 MUM, indicating its potential activity against cancer cells. PMID- 23044368 TI - The trifluoromethyl transformation synthesis, crystal structure and insecticidal activities of novel 2-pyrrolecarboxamide and 2-pyrrolecarboxlate. AB - Two series of 2-phenylpyrroles: 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2 carboxamide (5a-5d) and 3-bromo-5-(4-chlorophenyl)-4-cyanopyrrole-2-carboxylate (6a-6c) were synthesized by a novel trifluoromethyl transformation. The result of insecticidal bioassays indicated that 6a-6c had moderate larvicidal activity against oriental armyworm and 6b also had good acaricidal activity, so 3-bromo-5 (4-chlorophenyl)-4-cyanopyrrole-2-carboxylate derivatives were expected to become lead compounds for new pesticides. PMID- 23044369 TI - Use of structure based design to increase selectivity of pyridyl-cinnoline phosphodiesterase 10A (PDE10A) inhibitors against phosphodiesterase 3 (PDE3). AB - We report our successful effort to increase the PDE3 selectivity of PDE10A inhibitor pyridyl cinnoline 1 using a combination of computational modeling and structural-activity relationship investigations. An analysis of the PDE3 catalytic domain compared to the co-crystal structure of cinnoline analog 1 in PDE10A revealed two areas of structural differences in the active sites and suggested areas on the scaffold that could be modified to exploit those unique structural features. Once SAR established the cinnoline as the optimal scaffold, modifications on the methoxy groups of the cinnoline and the methyl group on the pyridine led to the discovery of compounds 33 and 36. Both compounds achieved significant improvement in selectivity against PDE3 while maintaining their PDE10A inhibitory activity and in vivo metabolic stability comparable to 1. PMID- 23044371 TI - 2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives, a novel class of SENP1 inhibitors: Virtual screening, synthesis and biological evaluation. AB - Prostate cancer is one of the most prevalent types of malignant cancers in men and has a high mortality rate among all male cancers. Previous studies have demonstrated that Sentrin/SUMO-specific protease 1 (SENP1) plays an important role in the occurrence and development of prostate cancer, and has been identified as a novel drug target for development of small molecule drugs against prostate cancer. In this paper, we used virtual screening and docking to identify compound J5 as a novel lead compound inhibiting SENP1, from SPECS library. We further investigated the SAR (structure-activity relationship) of the benzoate substituent of compound J5, and discovered compounds 8d and 8e as better small molecule inhibitors of SENP1. Both compounds are the high potent SENP1 small molecule inhibitors discovered up to date, and further lead optimization may lead to a series of novel anti-SENP1 agents. Further SAR studies are in process and will be reported in due course. PMID- 23044370 TI - Synthesis of pyrazole peptidomimetics and their inhibition against A549 lung cancer cells. AB - A series of novel pyrazole peptidomimetics was synthesized from 3-aryl-1 arylmethyl-1H-pyrazole-5-carboxylic acid and amino acid ester. Structures of the compounds were characterized by means of IR, (1)H NMR and mass spectroscopy. Compounds 5e and 5k suppress effectively the growth of A549 lung cancer cells. Preliminary research on the mechanism of action showed that the inhibition might perform through combination of apoptosis, autophagy and cell cycle arrest. PMID- 23044372 TI - Observations on Middle Stone Age human teeth from Klasies River Main Site, South Africa. AB - The human fossils, artefacts and faunal remains from the Middle Stone Age (MSA) deposits of Klasies River Main Site have featured prominently in discussions of the evolution of modern human morphology and the emergence of human behavioral modernity. Nearly 40 human fossils were uncovered by John Wymer's (1967-1968) excavations, and subsequent work by Hilary Deacon (1984-1995) has produced an additional dozen specimens. Many of the latter have been described, but most of the dental remains have been afforded only cursory mention and provisional identification. These specimens are documented here, and questions of individual association among some of the fossils from Wymer's excavations are also addressed. Three teeth provide the first indisputable evidence for juvenile individuals in the deposit. The proportion of juvenile to adult remains in the MSA levels at Klasies is notably lower than in other penecontemporaneous South African coastal MSA sites such as Die Kelders Cave 1 and Blombos Cave, where the proportion of juveniles is seemingly in closer keeping with coastal, geographically proximate Later Stone Age sites such as Oakhurst Shelter and Matjes River Cave. The sizes of most of the recently identified human teeth from Klasies seem to affirm at least one arguable aspect of morphometric modernity in the MSA at this site in the form of a tendency for tooth size reduction. PMID- 23044374 TI - The use of questions as problem-solving strategies during early childhood. AB - This study examined the strategic use of questions to solve problems across early childhood. Participants (N=54, 4-, 5-, and 6-year-olds) engaged in two tasks: a novel problem-solving question task that required asking questions to an informant to determine which card in an array was located in a box and a cognitive flexibility task that required classifying stimuli by multiple dimensions. The results from the question task indicated that there were age differences in the types of questions asked, with 6-year-olds asking more constraint-seeking questions than 4- and 5-year-olds. The number of constraint seeking questions asked was the only significant predictor of accuracy. Performance on the cognitive flexibility task correlated with both constraint seeking strategy use and accuracy in the question task. In sum, our results provide evidence that the capacity to use questions to generate relevant information develops before the capacity to apply this information successfully and consistently to solve complex problems. We propose that the process of using questions as strategic tools is an ideal context for examining how children come to gain active and intentional control over problem solving. PMID- 23044373 TI - Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis. AB - Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very different functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, independent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psychedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psilocybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenology and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis. PMID- 23044375 TI - Congenital hemiscrotal agenesis: report of a rare entity. AB - Congenital scrotal agenesis is the rarest anomaly of scrotal development disorder and is characterized by the absence of scrotal rugae in the perineum between the penis and anus. We report here a case of hemiscrotal agenesis in a 2-year-old boy. To the best of our knowledge, our patient is the second reported case of hemiscrotal agenesis in the English literature. PMID- 23044377 TI - Childhood vesicoureteral reflux studies: registries and repositories sources and nosology. AB - Despite several recent studies, the advisability of antimicrobial prophylaxis and certain imaging studies for urinary tract infections (UTIs) remains controversial. The role of vesicoureteral reflux (VUR) on the severity and re infection rates for UTIs is also difficult to assess. Registries and repositories of data and biomaterials from clinical studies in children with VUR are valuable. Disease registries are collections of secondary data related to patients with a specific diagnosis, condition or procedure. Registries differ from indices in that they contain more extensive data. A research repository is an entity that receives, stores, processes and/or disseminates specimens (or other materials) as needed. It encompasses the physical location as well as the full range of activities associated with its operation. It may also be referred to as a biorepository. This report provides information about some current registries and repositories that include data and samples from children with VUR. It also describes the heterogeneous nature of the subjects, as some registries and repositories include only data or samples from patients with primary reflux while others also include those from patients with syndromic or secondary reflux. PMID- 23044376 TI - Contemporary review of testicular torsion: new concepts, emerging technologies and potential therapeutics. AB - Testicular torsion is one of the few emergencies in pediatric urology which requires an accurate and timely diagnosis in order to avoid testis loss. It is not an uncommon event affecting a young male population. In fact, testicular torsion is more common than testicular tumors for this same age group, yet testicular torsion has not been given the public attention it deserves as a male health risk. In this review we highlight the new information published over the past four years regarding testicular torsion. We will discuss a variety of topics associated with torsion including: medical legal issues, etiology and genetics, imaging diagnostics, innovative surgical techniques, management controversies, fertility, and new drug therapies. PMID- 23044378 TI - [The place of consent in relationships between physicians and patients: a philosophical point of view]. AB - In the past, doctors did not hesitate to impose their point of view to patients. Today, informing patients and obtain their consent is the norm. But the patient is really in a position to make a decision about his health, when in a vulnerable situation? Which are the limits of informed consent? Does exist a link between the ability that everyone has to self-determination (autonomy), and the specific choices that we have to do when we are sick? We offer a philosophical approach on the relationship between autonomy, freedom and consent in the context of relations between doctors and patients. PMID- 23044380 TI - Pink ribbon program: empowering the body after breast surgery. PMID- 23044381 TI - Harmonizing lung cancer screening guidelines. PMID- 23044382 TI - Promising immunotherapy technique. PMID- 23044383 TI - Molecular mechanisms of the shrimp clotting system. AB - Shrimp, like other invertebrates, relies solely on its innate immune system, to combat invading pathogens. The invertebrate immune system has ancient origins that involve cellular and humoral responses. The clotting system of the humoral immune response is the first line of defense against pathogens and also serves to prevent blood loss during injury and wound healing. Tranglutaminase and clotting protein are molecules involved in the blood clotting system of crayfish and shrimp. Studies have shown that the shrimp clotting system is linked with the activation of antimicrobial peptides, similar to that of the horseshoe crab. Unlike the horseshoe crab and crayfish blood coagulation which are well studied systems, blood clotting in shrimp remains poorly understood. Here we review the shrimp clotting system and its involvement in innate immunity. PMID- 23044384 TI - [Characterization of methicillin- and linezolid-resistant Staphylococcus epidermidis and S. haemolyticus strains in a Spanish hospital]. AB - INTRODUCTION: Linezolid resistance is mainly due to mutations in the 23S rRNA target. The aim of this study was to characterize linezolid and methicillin resistant Staphylococcus epidermidis (SE-LM(R)) and S. haemolyticus (SH-LM(R)) strains detected in a Spanish hospital. METHODS: SE-LM(R) and SH-LM(R) strains obtained in the period June 2009-August 2011 in a second level hospital were recorded along with the epidemiological characteristics of the patients. These strains were typed, and their resistance, phenotype, genotype and the factors determining their virulence were analysed. RESULTS: Linezolid resistance was explained by the presence of G2603T mutation (23S rRNA) and aminoacid changes in L3 and L4 ribosomal proteins. The 25 SE-LM(R) strains belonged to sequence type ST2, presented SCCmec typeIII, and two different PFGE patterns. The two SH-LM(R) strains showed non-typeable SCCmec. SE-LM(R) strains harboured the resistance genes aac(6')-aph(2"), and dfrS1. SH-LM(R) strains contained these genes and the gene erm(C). No lincomycin resistance mechanism was identified in SE-LM(R) strains regardless of showing lincomycin resistance and diminished susceptibility to clindamycin. CONCLUSIONS: Linezolid resistance is of concern in hospitals, and requires continued vigilance. Several linezolid resistance mechanisms (mutation in 23S RNAr and amino acid changes in L3 and L4) were identified in this study. PMID- 23044385 TI - Exploring epiallele stability in a population-epigenetic model. AB - Differences in transgenerational epigenetic stability can result in a diversity of phenotypes among genetically identical individuals. Here we present a model that encapsulates non-genomic phenotypic variation in a population over two distinct environments that each act as a stimulus for epigenetic modification. By allowing different levels of epigenetic resetting, thereby increasing epigenetic diversity, we explore the dynamics of multiple epiallelic states subject to selection in a population-epigenetic model. We find that both epigenetic resetting and the environmental frequency are crucial parameters in this system. Our results illustrate the regions of parameter space that enable up to three equilibria to be simultaneously locally stable. Furthermore, it is clear that both continued environmental induction and epigenetic resetting prevent epigenetic fixation, maintaining phenotypic variation through different epiallelic states. However, unless both environments are reasonably common, levels of epigenetically-maintained variation are low. We argue that it is vital that non-genomic phenotypic diversity is not ignored in evolutionary theory, but instead regarded as distinct epiallelic variants. Ultimately, a critical goal of future experiments should be to determine accurate rates of epigenetic resetting, especially over several generations, in order to establish the long-term significance of epigenetic inheritance. PMID- 23044386 TI - Treatment of unscheduled bleeding in women using extended- or continuous-use combined hormonal contraception: a systematic review. AB - BACKGROUND: Unscheduled uterine bleeding is common among women who choose extended or continuous combined hormonal contraception and may subsequently lead to method discontinuation. This systematic review evaluates the evidence on treatments for unscheduled bleeding for women using continuous or extended combined hormonal contraception. STUDY DESIGN: We searched the PubMed database for peer-reviewed articles that were published in any language from inception of the database through January 2012 and were relevant to therapeutic or prophylactic treatments for unscheduled uterine bleeding during extended or continuous combined hormonal contraception use. We used standard abstract forms and grading systems to summarize and assess the quality of the evidence. RESULTS: Four articles met the inclusion criteria. Evidence from two randomized controlled trials, both of fair quality, suggested that a short hormone-free interval of 3 or 4 days improved a current unscheduled bleeding episode. Evidence from one randomized controlled trial of fair quality suggested that oral doxycycline (100 mg twice daily) did not improve a current unscheduled bleeding episode. One good quality randomized controlled trial suggested that prophylactic treatment with a daily low dose of oral doxycycline (40 mg) caused earlier onset of amenorrhea in new extended combined oral contraceptive users. CONCLUSIONS: Limited evidence suggests that introducing a short hormone-free interval when unscheduled bleeding occurs during continuous or extended hormonal contraceptive use may reduce unscheduled bleeding days; one study suggests that twice-daily oral doxycycline initiated at the time of unscheduled bleeding is an ineffective treatment. Limited data suggest that prophylactic low-dose daily oral doxycycline may induce earlier amenorrhea among new extended combined hormonal contraceptive users. PMID- 23044387 TI - Inhibition of enamel mineral loss by fissure sealant: an in situ study. AB - OBJECTIVES: This study evaluated the effect of fluoride and non-fluoride sealants on hardness decrease (HD) and marginal adaptation (MA) on enamel substrates after cariogenic challenge. METHODS: Occlusal enamel blocks, from human third molars, were randomly divided into six groups (n=12), according to occlusal fissures condition (S - sound; C - caries-like lesion; CF - caries-like lesion+topical fluoride) and sealants (F - FluroShield; H - Helioseal Clear Chroma). Lesion depths were 79.3+/-33.9 and 61.3+/-23.9 for C and CF groups, respectively. Sealants were placed on occlusal surface and stored at 100% humidity (37 degrees C; 24h/d). HD was measured by cross-sectional microhardness analysis at the sealant margin distances: -1 (under sealant), 0 (sealant margin), 1, 2 (outer sealant). Sealant MA was observed by polarized light microscopy and scored according to: 0 - failure (no sealant MA or total sealant loss); 1 - success (sealant MA present). MA and HD were analysed by ANOVA-R and mixed model analysis, respectively. RESULTS: For HD (DeltaS), F values (6900.5+/-3686.6) were significantly lower than H values (8534.6+/-5375.3) regardless of enamel substrates and sealant margin distances. Significant differences were observed among sealant margin distances: -1 (5934.0+/-3282.6)<0 (8701.5+/-6175.7)=1 (8473.2+/-4299.4)=2 (7761.5+/-4035.1), regardless of sealant and substrate. MA was similar for all groups (p>=0.05). CONCLUSION: MA was not affected by sealant type or substrate condition, whereas enamel HD was favourably impacted by fluoride in the sealant. In addition, sealants were more effective as a physical barrier than as its chemical potency in reducing enamel HD. CLINICAL SIGNIFICANCE: Sealing with a fluoride material is a recommended procedure to prevent caries of occlusal permanent molars in high-caries-risk patients, even though those exhibiting white spot lesions, since the enamel hardness decrease when fluoride sealant was used in vitro. PMID- 23044388 TI - Surface characterisation and bonding of Y-TZP following non-thermal plasma treatment. AB - OBJECTIVES: (1) To chemically characterise Y-TZP surface via X-ray photoelectron spectroscopy (XPS) and evaluate the surface energy levels (SE) after non-thermal plasma (NTP). (2) To test the microtensile bond strength (MTBS) of Y-TZP bonded to cured composite disks, after a combination of different surface conditioning methods. METHODS: Twenty-four Y-TZP discs (13.5mm*4mm) were obtained from the manufacturer and composite resin (Z-100) discs with similar dimensions were prepared. All discs were polished to 600 grit and divided into 8 groups (n=3 disks each), four control (non-NTP treated) and four experimental (NTP treated for 10s) groups. All groups received one of the four following treatments prior to cementation with Rely*Unicem cement: sand-blasting (SB), a Clearfil ceramic primer (MDP), sand-blasting+MDP (SBMDP), or baseline (B), no treatment. SE readings and surface roughness parameters were statistically analysed (ANOVA, Tukey's, p<0.05). Mixed model and paired samples t-tests were used to compare groups on MTBS. RESULTS: XPS showed increase in O and decrease in C elements after NTP. The polar component increased for BP (42.20mN/m) and SBP (43.77mN/m). MTBS values for groups BP (21.3MPa), SBP (31MPa), MDPP (30.1MPa) and SBMDPP (32.3MPa) were significantly higher in specimens treated with NTP than their untreated counterparts B (9.1MPa), SB (14.4MPa), MDP (17.8MPa) and SBMDP (24.1MPa). CONCLUSIONS: (1) Increase of O and decrease of C led to higher surface energy levels dictated by the polar component after NTP; (2) NTP application increased MTBS values of Y-TZP surfaces. PMID- 23044389 TI - Concurrent evaluation of composite internal adaptation and bond strength in a class-I cavity. AB - OBJECTIVES: This study investigated class-I cavity floor adaptation by swept source optical coherence tomography (OCT) in combination with microtensile bond strength (MTBS) using different filling methods. METHODS: Two adhesive systems; Tokuyama Bond Force and Tri-S Bond Plus were used in conjunction with a universal composite (Estelite Sigma Quick) placed either incrementally (oblique) or in bulk with or without a flowable composite lining (Palfique Estelite LV). Ten serial B scan images were obtained throughout each cavity by OCT (center wavelength: 1319nm). In order to evaluate adaptation defined as the cavity floor percentage showing no gap, a significant increase in the signal intensity was considered as gap at the bonded interface of the cavity floor. The same specimens were then cut into beams to measure MTBS at the cavity floor. RESULTS: Two-way ANOVA demonstrated that the interaction of adhesive systems and filling techniques was significantly affecting both adaptation and MTBS (p<0.05). There was a significant correlation between MTBS and adaptation at cavity floor (p<0.05). Cavity floor adaptation and MTBS were improved when incremental filling technique was applied, while the outcome of lining technique was variable. CONCLUSIONS: Quantitative assessment by OCT can non-destructively provide information on the performance and effectiveness of dental composites and restoration techniques. There was a moderate correlation between floor adaptation and bond strength in class-I cavities. Incremental application of composite restoration showed the best performance in terms of bond strength and internal adaptation. CLINICAL SIGNIFICANCE: Incremental application of composite restoration was the most advantageous placement technique in terms of bond strength and internal adaptation. The lack of placement pressure with flowable composites may affect their adaptation to all-in-one adhesives; therefore, the outcome of cavity lining by flowable composite was variable. PMID- 23044390 TI - Effect of ranolazine on ventricular repolarization in class III antiarrhythmic drug-treated rabbits. AB - BACKGROUND: Ranolazine exhibits a synergistic effect in combination with class III drugs to suppress atrial fibrillation. OBJECTIVE: To investigate whether a combination therapy affects repolarization and provokes ventricular tachyarrhythmias (VT) in a sensitive model of proarrhythmia. METHODS: Thirty seven rabbits were assigned to 3 groups and fed with amiodarone (50 mg/kg/d; n = 10) or dronedarone (50 mg/kg/d; n = 10) over a period of 6 weeks. A third group was used as control (n = 17). After obtaining baseline data in Langendorff perfused control hearts, sotalol (100 MUM) was administered in this group. Thereafter, ranolazine (10 MUM) was additionally infused on top of amiodarone, dronedarone, or sotalol. RESULTS: Chronic treatment with amiodarone or dronedarone as well as sotalol significantly increased action potential duration at 90% repolarization (APD(90)). Additional treatment with ranolazine further increased APD(90) in amiodarone- and dronedarone-pretreated hearts but not in sotalol-treated hearts. Ranolazine increased postrepolarization refractoriness as compared with amiodarone or dronedarone alone owing to a marked effect on the refractory period. In contrast to amiodarone and dronedarone, acute application of sotalol increased dispersion of repolarization (P < .05). Additional treatment with ranolazine did not further increase spatial or temporal dispersion. After lowering extracellular [K(+)] in bradycardic hearts, no proarrhythmia occurred in amiodarone- or dronedarone-treated hearts whereas 11 of 17 sotalol-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with ranolazine reduced the number of VT episodes in sotalol-treated hearts and did not cause proarrhythmia in combination with amiodarone or dronedarone. CONCLUSIONS: Application of ranolazine on top of class III drugs does not cause proarrhythmia despite a marked effect on ventricular repolarization. The effect of ranolazine on the repolarization reserve is associated with the lack of effect on early afterdepolarizations and dispersion of repolarization. PMID- 23044391 TI - Denitrification and aerobic respiration, hybrid electron transport chains and co evolution. AB - This paper explores the bioenergetics and potential co-evolution of denitrification and aerobic respiration. The advantages and disadvantages of combining these two pathways in a single, hybrid respiratory chain are discussed and the experimental evidence for the co-respiration of nitrate and oxygen is critically reviewed. A scenario for the co-evolution of the two pathways is presented. This article is part of a Special Issue entitled: The evolutionary aspects of bioenergetic systems. PMID- 23044392 TI - Insight into the evolution of the iron oxidation pathways. AB - Iron is a ubiquitous element in the universe. Ferrous iron (Fe(II)) was abundant in the primordial ocean until the oxygenation of the Earth's atmosphere led to its widespread oxidation and precipitation. This change of iron bioavailability likely put selective pressure on the evolution of life. This element is essential to most extant life forms and is an important cofactor in many redox-active proteins involved in a number of vital pathways. In addition, iron plays a central role in many environments as an energy source for some microorganisms. This review is focused on Fe(II) oxidation. The fact that the ability to oxidize Fe(II) is widely distributed in Bacteria and Archaea and in a number of quite different biotopes suggests that the dissimilatory Fe(II) oxidation is an ancient energy metabolism. Based on what is known today about Fe(II) oxidation pathways, we propose that they arose independently more than once in evolution and evolved convergently. The iron paleochemistry, the phylogeny, the physiology of the iron oxidizers, and the nature of the cofactors of the redox proteins involved in these pathways suggest a possible scenario for the timescale in which each type of Fe(II) oxidation pathways evolved. The nitrate dependent anoxic iron oxidizers are likely the most ancient iron oxidizers. We suggest that the phototrophic anoxic iron oxidizers arose in surface waters after the Archaea/Bacteria-split but before the Great Oxidation Event. The neutrophilic oxic iron oxidizers possibly appeared in microaerobic marine environments prior to the Great Oxidation Event while the acidophilic ones emerged likely after the advent of atmospheric O(2). This article is part of a Special Issue entitled: The evolutionary aspects of bioenergetic systems. PMID- 23044394 TI - The placental vascular component in early and late intrauterine fetal death. AB - OBJECTIVE: To compare the placental histopathological findings between pregnancies complicated by early (<34 weeks' gestation) and late (>= 34 weeks' gestation) intrauterine fetal death (IUFD) and pregnancies with live births. MATERIAL & METHODS: Placentas of patients with unexplained IUFD between 22-42 weeks of gestation were analyzed for maternal vascular supply lesions that include those related to maternal underperfusion (villous changes and vascular lesions), fetal vascular supply lesions that include findings consistent with fetal thrombo-occlusive disease (villous changes and vascular lesions) and maternal and fetal inflammatory response lesions. The clinical characteristics and placental findings were compared with those from live birth controls adjusted for gestational age. RESULTS: In the early IUFD group (n=28), compared to controls with early delivery, a higher rate of vascular lesions consistent with fetal thrombo-occlusive disease (28.6% vs. 0, p=0.002), villous changes consistent with fetal thrombo-occlusive disease (21.4 vs. 3.6%, p=0.043), and cord related lesions (46.4% vs. 0, p<0.001), respectively, were observed. A similar high rate of maternal vascular supply lesions was detected in both groups. In the late IUFD group (n=30), compared to controls, a higher rate of cord related lesions, 40% vs. 0, respectively, p<0.001, were found. In contrast, maternal and fetal inflammatory response lesions were more common in controls than in placentas from early and late IUFD. CONCLUSIONS: The involvement of placental fetal vascular supply lesions is more extensive in early IUFD than in late IUFD, when compared with matched controls. PMID- 23044393 TI - Sirtuin-4 modulates sensitivity to induction of the mitochondrial permeability transition pore. AB - The sustained opening of the mitochondrial permeability transition pore (PTP) is a decisive event in the onset of irreversible cell injury. The PTP is modulated by numerous exogenous and endogenous effectors, including mitochondrial membrane potential, ions and metabolites. Mitochondrial sirtuins have recently emerged as pivotal mediators of mitochondrial metabolism. In the present study, we demonstrate that sirt-4 modulates sensitivity to PTP onset induced by calcium and the oxidative cross linking reagent phenylarsine oxide, and PTP dependent cytotoxicity brought about by TNF or doxorubicin. Moreover, the ability of sirt-4 to modulate onset of the PTP is dependent on the expression of glutamate dehydrogenase-1. PMID- 23044395 TI - Stem cell-based therapy for ischemic heart disease. AB - Despite great advances in therapy over the past decades, ischemic heart disease (IHD) remains the leading cause of death worldwide because the decrease in mortality after acute myocardial infarction (AMI) leads to a longer life span in patients with chronic postinfarct heart failure (HF). There are no existing medical treatments that can cure chronic HF and the only currently available therapeutic option for end-stage HF is heart transplantation. However, transplantation is limited by the shortage of donor organs and patients require lifelong immunosuppression. In the past 10 years, stem cell-based cardiac therapy has been proposed as a promising approach for the treatment of IHD. There is a variety of potential stem cell types for cardiac repair and regeneration, including bone marrow cells (BMCs), resident cardiac stem cells (CSCs) and induced pluripotent stem cells (iPSCs). Stem cell-based therapy may comprise cell transplantation or cardiac tissue engineering (CTE), which might be an attractive alternative to solve the problems of low retention and poor survival of transplanted cells. This review focuses on the characteristics of stem cells from various sources and discusses the strategies of stem cell-based therapy for the treatment of IHD. PMID- 23044396 TI - The role of information in cell regulation. AB - The organised state of living cells must derive from information internal to the system; however, there are strong reasons, based on sound evidence, to reject the base sequence information encoded in the genomic DNA as being directly relevant to the regulation of cellular phenotype. Rather, it is argued here that highly specific relational information, encoded on the gene products, mainly proteins, is responsible for phenotype. This regulatory information emerges as the peptide folds into a tertiary structure in much the same way as enzymic activity emerges under the same circumstances. The DNA coding sequence serves as a "data base" in which a second category of relational information is stored to enable accurate reproduction of the cellular peptides. In the context of the cell, therefore, information is physical in character and contributes, through its ability to dissipate free energy, to the maximisation of the entropy of the cell according to the 2nd law of thermodynamics. PMID- 23044397 TI - A biological relativity view of the relationships between genomes and phenotypes. AB - This article explores the relativistic principle that there is no privileged scale of causality in biology to clarify the relationships between genomes and phenotypes. The idea that genetic causes are primary views the genome as a program. Initially, that view was vindicated by the discovery of mutations and knockouts that have large and specific effects on the phenotype. But we now know that these form the minority of cases. Many changes at the genome level are buffered by robust networks of interactions in cells, tissues and organs. The 'differential' view of genetics therefore fails because it is too restrictive. An 'integral' view, using reverse engineering from systems biological models to quantify contributions to function, can solve this problem. The article concludes by showing that far from breaking the supervenience principle, downward causation requires that it should be obeyed. PMID- 23044398 TI - Phylogenetic analyses of endoparasitic Acanthocephala based on mitochondrial genomes suggest secondary loss of sensory organs. AB - The metazoan taxon Syndermata (Monogononta, Bdelloidea, Seisonidea, Acanthocephala) comprises species with vastly different lifestyles. The focus of this study is on the phylogeny within the syndermatan subtaxon Acanthocephala (thorny-headed worms, obligate endoparasites). In order to investigate the controversially discussed phylogenetic relationships of acanthocephalan subtaxa we have sequenced the mitochondrial (mt) genomes of Echinorhynchus truttae (Palaeacanthocephala), Paratenuisentis ambiguus (Eoacanthocephala), Macracanthorhynchus hirudinaceus (Archiacanthocephala), and Philodina citrina (Bdelloidea). In doing so, we present the largest molecular phylogenetic dataset so far for this question comprising all major subgroups of Acanthocephala. Alongside with publicly available mt genome data of four additional syndermatans as well as 18 other lophotrochozoan (spiralian) taxa and one outgroup representative, the derived protein-coding sequences were used for Maximum Likelihood as well as Bayesian phylogenetic analyses. We achieved entirely congruent results, whereupon monophyletic Archiacanthocephala represent the sister taxon of a clade comprising Eoacanthocephala and monophyletic Palaeacanthocephala (Echinorhynchida). This topology suggests the secondary loss of lateral sensory organs (sensory pores) within Palaeacanthocephala and is further in line with the emergence of apical sensory organs in the stem lineage of Archiacanthocephala. PMID- 23044399 TI - Molecular evidence that the deadliest sea snake Enhydrina schistosa (Elapidae: Hydrophiinae) consists of two convergent species. AB - We present a striking case of phenotypic convergence within the speciose and taxonomically unstable Hydrophis group of viviparous sea snakes. Enhydrina schistosa, the 'beaked sea snake', is abundant in coastal and inshore habitats throughout the Asian and Australian regions, where it is responsible for the large majority of recorded deaths and injuries from sea snake bites. Analyses of five independent mitochondrial and nuclear loci for populations spanning Australia, Indonesia and Sri Lanka indicate that this 'species' actually consists of two distinct lineages in Asia and Australia that are not closest relatives. As a result, Australian "E. schistosa" are elevated to species status and provisionally referred to Enhydrinazweifeli. Convergence in the characteristic 'beaked' morphology of these species is probably associated with the wide gape required to accommodate their spiny prey. Our findings have important implications for snake bite management in light of the medical importance of beaked sea snakes and the fact that the only sea snake anti-venom available is raised against Malaysian E. schistosa. PMID- 23044401 TI - Remarkable phylogenetic resolution of the most complex clade of Cyprinidae (Teleostei: Cypriniformes): a proof of concept of homology assessment and partitioning sequence data integrated with mixed model Bayesian analyses. AB - Despite many efforts to resolve evolutionary relationships among major clades of Cyprinidae, some nodes have been especially problematic and remain unresolved. In this study, we employ four nuclear gene fragments (3.3kb) to infer interrelationships of the Cyprinidae. A reconstruction of the phylogenetic relationships within the family using maximum parsimony, maximum likelihood, and Bayesian analyses is presented. Among the taxa within the monophyletic Cyprinidae, Rasborinae is the basal-most lineage; Cyprinine is sister to Leuciscine. The monophyly for the subfamilies Gobioninae, Leuciscinae and Acheilognathinae were resolved with high nodal support. Although our results do not completely resolve relationships within Cyprinidae, this study presents novel and significant findings having major implications for a highly diverse and enigmatic clade of East-Asian cyprinids. Within this monophyletic group five closely-related subgroups are identified. Tinca tinca, one of the most phylogenetically enigmatic genera in the family, is strongly supported as having evolutionary affinities with this East-Asian clade; an established yet remarkable association because of the natural variation in phenotypes and generalized ecological niches occupied by these taxa. Our results clearly argue that the choice of partitioning strategies has significant impacts on the phylogenetic reconstructions, especially when multiple genes are being considered. The most highly partitioned model (partitioned by codon positions within genes) extracts the strongest phylogenetic signals and performs better than any other partitioning schemes supported by the strongest 2Deltaln Bayes factor. Future studies should include higher levels of taxon sampling and partitioned, model based analyses. PMID- 23044400 TI - Capsid protein evolution and comparative phylogeny of novel porcine parvoviruses. AB - In addition to the well known "classical" porcine parvovirus (PPV1; responsible for reproductive failure of susceptible sows) several new porcine parvoviruses have been recognized (PPV2, PPV3 and PPV4) in recent years. The genetic variation, characteristics and evolutionary factors shaping these novel PPVs were studied by comparing the complete capsid (cap) genes of PPVs from domestic pigs and wild boars. Using Bayesian coalescent methods we estimated the rate of nucleotide substitution for PPV2, PPV3 and PPV4 to be of the order of 3.86 * 10( 4)-8.23 * 10(-4) subs site(-1) year(-1), similar to those commonly measured for RNA viruses, although this rate in case of PPV2 is probably influenced by frequent recombination events. Given such rapid evolutionary dynamics, it is likely that novel PPVs will continue to improve their capacity to spread among Suidae hosts worldwide. The mean time to the most recent common ancestor for the sampled genetic diversity of the newly discovered porcine parvoviruses was estimated. The results indicated that novel PPVs originated within approximately the last 70 years. Incongruent phylogenetic relationships of several strains suggested recombination events supported by several recombination-detecting methods and by split-decomposition phylogenetic networks. Analyses of the selective constraints acting on each codon suggest that some regions of PPV cap genes were under positive selection. This study showed that inter- and intraspecies recombination and diversifying selection pressures are prevalent across the cap genes of novel PPVs, and beside host switching and gene flow are important driving forces of their evolution and may be significant factors in the emergence of new viral variants. PMID- 23044402 TI - Cenozoic extinction and recolonization in the New Zealand flora: the case of the fleshy-fruited epacrids (Styphelieae, Styphelioideae, Ericaceae). AB - The origins and evolutionary history of the New Zealand flora has been the subject of much debate. The recent description of Cyathodophyllum novaezelandieae from early Miocene sediments in New Zealand provides possible evidence for the antiquity of the fleshy fruited epacrids (tribe Styphelieae, Ericaceae) in New Zealand. Yet the extant species in this tribe are thought to be very closely related to or conspecific with Australian taxa, suggesting recent trans-Tasman origins. In order to investigate the origins and evolution of the extant New Zealand Styphelieae we produced molecular phylogenetic trees based on sequences of three plastid regions that include representatives of all the genera of the tribe and eight of the ten New Zealand species. We estimated the range of minimum ages of the New Zealand lineages with Bayesian relaxed-clock analyses using different calibration methods and relative dating. We found strong support for each of the eight extant species of New Zealand Styphelieae being a distinct lineage that is nested within an Australian clade. In all except one case the sister is from Tasmania and/or the east coast of mainland Australia; for Acrothamnus colensoi the sister is in New Guinea. Estimated dates indicate that all of the New Zealand lineages diverged from their non-New Zealand sisters within the last 7 Ma. Time discontinuity between the fossil C.novae-zelandiae (20 23 Ma) and the origins of the extant New Zealand lineages (none older than 5 Ma) indicates that the fossil and extant Styphelieae in New Zealand are not related. The relative dating analysis showed that to accept this relationship, it would be necessary to accept that the Styphelieae arose in the early-mid Mesozoic (210-120 Ma), which is starkly at odds with multiple lines of evidence on the age of Ericales and indeed the angiosperms. Therefore, our results do not support the hypothesis that Styphelieae have been continuously present in New Zealand since the early Miocene. Instead they suggest a historical biogeographical scenario in which the lineage to which C. novae-zelandiae belongs went extinct in New Zealand, and the extant New Zealand Styphelieae are derived from Australian lineages that recolonised (presumably by long distance dispersal) no earlier than the late Miocene to Pliocene. PMID- 23044403 TI - Understanding the formation of ancient intertropical disjunct distributions using Asian and Neotropical hinged-teeth snakes (Sibynophis and Scaphiodontophis: Serpentes: Colubridae). AB - Numerous taxa show ancient intertropical disjunct distributions. Many can be explained by well-known processes of historical vicariance, such as the breakup of Gondwanaland. Others, such as Asian-Neotropical divergences are not as well understood. To clarify the phylogenetic position and understand biogeographic and temporal origins of the geographically disjunct and morphologically unique genera of hinged-teeth snakes, Scaphiodontophis (n=1) and Sibynophis (n=9; Colubridae), we inferred a time-calibrated phylogeny with additional 107 taxa representing the superfamily Colubroidea using four genes (c-mos, cyt-b, ND2, RAG-1; 3085 bp). We used this tree to estimate ancestral areas for the group. The results show that Scaphiodontophis is sister to Sibynophis, both originated in the late Eocene/Oligocene in Asia and likely dispersed through Beringia to the New World, but unlike other snake groups left no extant species in temperate North America. Current recognition of Scaphiodontophiinae renders Colubrinae paraphyletic, and we resurrect the previously named subfamily Sibynophiinae to encompass both genera and use the tribes Sibynophiini (Sibynophis) and Scaphiodontophiini (Scaphiodontophis) to highlight the geographically distinct areas occupied by these taxa. These results suggest that intercontinental dispersal with extinction in intermediate areas can explain puzzling patterns of ancient intertropical disjunct distributions. PMID- 23044404 TI - Mineralocorticoid receptor antagonist spironolactone prevents chronic corticosterone induced depression-like behavior. AB - High level of serum corticosteroid is frequently associated with depression, in which a notable HPA (hypothalamus-pituitary-adrenal) axis hyperactivity is often observed. There are two types of corticosteroid receptors expressed in the hippocampus that provide potent negative feedback regulation on the HPA axis but dysfunction during depression, i.e. the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The balance between hippocampal MR and GR during chronic stress plays an important role in the occurrence of depression. The aim of this study is to explore if chronic corticosterone administration would induce depression-like behavior and affect the expression and function of hippocampal MR and GR, in addition to assess whether manipulation of corticosteroid receptors would modulate depressive behaviors. Hence, mice were treated with corticosterone (40 mg/kg) for 21 days followed by assessment in a battery of depression-like behaviors. The results show that chronic corticosterone-treated animals displayed an increased immobility time in a forced-swimming test, decreased preference to sucrose solution and novel object recognition performance, and enhanced hippocampal serotonin but decreased MR expression in both hippocampus and hypothalamus. On the other hand, co-administration of MR antagonist, spironolactone (25mg/kg, i.p. * 7 days) in corticosteroid-treated animals reduced immobility time in a forced-swimming test and improved performance in a novel object recognition test. In conclusion, we demonstrate that chronic corticosterone treatment triggers several depression-like behaviors, and in parallel, down-regulates MR expression in the hippocampus and hypothalamus. Administration of an MR antagonist confers an anti-depressant effect in chronic corticosterone-treated animals. PMID- 23044405 TI - Plasma beads loaded with Candida albicans cytosolic proteins impart protection against the fungal infection in BALB/c mice. AB - The development of a prophylactic vaccine against systemic candidiasis, employing Candida albicans cytosolic proteins (Cp) as antigen and fibrin cross-linked plasma beads as an antigen bearing dual delivery system is described. Groups of mice were administered either with free Cp, or Cp entrapped in plasma beads, Cp entrapped in liposomes or liposome encapsulated Cp further entrapped in plasma beads. Humoral immunity was studied by measuring the anti-Cp antibody titers in the sera of the immunized animals. Induction of cell-mediated immunity was assessed by delayed type hypersensitivity (DTH), NO production, up-regulation of co-stimulatory molecules viz. CD80, CD86 on APCs on one hand and T-cells proliferation as well as induction of IFN-gamma and IL-4 on the other. The efficacy of various vaccine formulations in protecting mice against a lethal challenge with C. albicans, was assessed by determining animal survival rate and fungal burden in the systemic circulation and vital organs. Among various Cp based vaccines investigated, the preparation containing liposomized Cp entrapped in plasma beads imparted superior protection in the immunized mice as compared to other antigens delivery systems. PMID- 23044407 TI - Development of new generation influenza vaccines: recipes for success? AB - As infectious diseases cause approximately 25% of the annual global mortality, vaccines are found to be a time proven and promising response to infectious disease need. However, like for pharmaceutical small molecules, vaccine development is lengthy, risky and resource demanding. Faced with an attrition rate estimated around 80%, key opinion leaders were interviewed with the question: is there a recipe for success? PMID- 23044406 TI - Measles vaccination using a microneedle patch. AB - Measles vaccination programs would benefit from delivery methods that decrease cost, simplify logistics, and increase safety. Conventional subcutaneous injection is limited by the need for skilled healthcare professionals to reconstitute and administer injections, and by the need for safe needle handling and disposal to reduce the risk of disease transmission through needle re-use and needlestick injury. Microneedles are micron-scale, solid needles coated with a dry formulation of vaccine that dissolves in the skin within minutes after patch application. By avoiding the use of hypodermic needles, vaccination using a microneedle patch could be carried out by minimally trained personnel with reduced risk of blood-borne disease transmission. The goal of this study was to evaluate measles vaccination using a microneedle patch to address some of the limitations of subcutaneous injection. Viability of vaccine virus dried onto a microneedle patch was stabilized by incorporation of the sugar, trehalose, and loss of viral titer was less than 1 log10(TCID50) after storage for at least 30 days at room temperature. Microneedle patches were then used to immunize cotton rats with the Edmonston-Zagreb measles vaccine strain. Vaccination using microneedles at doses equaling the standard human dose or one-fifth the human dose generated neutralizing antibody levels equivalent to those of a subcutaneous immunization at the same dose. These results show that measles vaccine can be stabilized on microneedles and that vaccine efficiently reconstitutes in vivo to generate a neutralizing antibody response equivalent to that generated by subcutaneous injection. PMID- 23044409 TI - Electrical noise to a knee joint stabilizes quiet bipedal stance. AB - Studies have shown that a minute, noise-like electrical stimulation (ES) of a lower limb joint stabilizes one-legged standing (OS), possibly due to the noise enhanced joint proprioception. To demonstrate the practical utility of this finding, we assessed whether the bipedal stance (BS), relatively stable and generally employed in daily activities, is also stabilized by the same ES method. Twelve volunteers maintained quiet BS with or without an unperceivable, noise like ES of a knee joint. The results showed that the average amplitude, peak-to peak amplitude, and standard deviation of the foot center of pressure in the anteroposterior direction were significantly attenuated by the ES (P<0.05). These results indicate that the BS also can be stabilized by an unperceivable, noise like ES of a knee joint. PMID- 23044408 TI - Clinical management guidelines for subarachnoid haemorrhage. Diagnosis and treatment. AB - OBJECTIVE: To update the Spanish Society of Neurology's guidelines for subarachnoid haemorrhage diagnosis and treatment. MATERIAL AND METHODS: A review and analysis of the existing literature. Recommendations are given based on the level of evidence for each study reviewed. RESULTS: The most common cause of spontaneous subarachnoid haemorrhage (SAH) is cerebral aneurysm rupture. Its estimated incidence in Spain is 9/100 000 inhabitants/year with a relative frequency of approximately 5% of all strokes. Hypertension and smoking are the main risk factors. Stroke patients require treatment in a specialised centre. Admission to a stroke unit should be considered for SAH patients whose initial clinical condition is good (Grades I or II on the Hunt and Hess scale). We recommend early exclusion of aneurysms from the circulation. The diagnostic study of choice for SAH is brain CT (computed tomography) without contrast. If the test is negative and SAH is still suspected, a lumbar puncture should then be performed. The diagnostic tests recommended in order to determine the source of the haemorrhage are MRI (magnetic resonance imaging) and angiography. Doppler ultrasonography studies are very useful for diagnosing and monitoring vasospasm. Nimodipine is recommended for preventing delayed cerebral ischaemia. Blood pressure treatment and neurovascular intervention may be considered in treating refractory vasospasm. CONCLUSIONS: SAH is a severe and complex disease which must be managed in specialised centres by professionals with ample experience in relevant diagnostic and therapeutic processes. PMID- 23044410 TI - Effects of a gait training session combined with a mass on the non-paretic lower limb on locomotion of hemiparetic patients: a randomized controlled clinical trial. AB - BACKGROUND: Results of recent studies have suggested that restraint of non paretic lower limb movement could improve locomotion in hemiplegic patients. The aim of this study was therefore to determine if a mass applied to the non-paretic lower limb during a single gait training session (GTS) would specifically improve spatio-temporal, kinematic and kinetic gait parameters (GP) of the paretic lower limb. METHODS: Sixty chronic hemiplegic subjects were included in this randomized study. Each participated in one of four GTS conditions: overground or on a treadmill while wearing or not wearing an ankle mass. All subjects were assessed before, immediately after and 20 min after the end of the GTS using 3D gait analysis. RESULTS: The results showed that restraining the non-paretic lower limb during a GTS had no specific effect on GP of the paretic limb, whereas it increased braking force of the non-paretic limb. CONCLUSION: Restraining the non paretic lower limb of hemiparetic patients with a mass applied to the ankle does not seem to be an effective approach to improve paretic lower limb parameters during a single GTS. PMID- 23044411 TI - Normal coordinate analysis and vibrational spectroscopy (FT-IR and FT-Raman) studies of (2S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid using ab initio HF and DFT method. AB - The FT-IR and FT-Raman spectra of (2S)-2-amino-3-(3,4-dihydroxyphenyl)-2 methylpropanoic acid (2ADMA) were recorded in the region 4000-400 cm(-1) and 4000 100 cm(-1), respectively. The geometrical structure, harmonic vibrational frequency, infrared intensity, Raman activities and bonding features of this compound was carried out by ab initio HF and DFT methods with 6-31G (d,p) basis set. The complete vibrational frequency assignments were made by normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology (SQMF). The electric dipole moment (MU) and the first-order hyperpolarizability (beta(0)) values have been the computed quantum mechanically. The calculated HOMO and LUMO energies show that, the charge transfer occurs within the molecule. The charge delocalizations of these molecules have been analyzed using NBO analysis. The solvent effects have been calculated using TD DFT in combination with the polarized continuum model (PCM), and the results are in good agreement with experimental measurements. The other molecular properties like Mulliken population analysis, electrostatic potential (ESP) and thermodynamic properties of the title compound at the different temperatures have been calculated. Finally, the calculation results were applied to simulate infrared and Raman spectra of the title compound which shows good agreement with observed spectra. PMID- 23044412 TI - Predicting a pulse: can monitoring heart rate and end-tidal carbon dioxide minimize compression pauses and impact outcomes in out-of-hospital cardiac arrest? PMID- 23044413 TI - Moderate hypothermia for severe cardiogenic shock (COOL Shock Study I & II). AB - AIM OF THE STUDY: Hypothermia exerts profound protection from neurological damage and death after resuscitation from circulatory arrest. Its application during concomitant cardiogenic shock has been discussed controversially, and still hypothermia is used with reserve when haemodynamic parameters are impaired. On the other hand hypothermia improves force development in isolated human myocardium. Thus, we hypothesized that hypothermia could beneficially affect cardiac function in patients during cardiogenic shock. METHODS: 14 Patients, admitted to Intensive Care Unit for cardiogenic shock under inotropic support, were enrolled and moderate hypothermia (33 degrees C) was induced for either one (n=5, short-term) or twenty-four (n=9, mid-term) hours. RESULTS: 12 patients suffered from ischaemic cardiomyopathy, 2 were female, and 6 were included after cardiac arrest and resuscitation. Body temperature was controlled by an intravascular cooling device. Short-term hypothermia consistently decreased heart rate, and increased stroke volume, cardiac index and cardiac power output. Metabolic and electrocardiographic parameters remained constant during cooling. Improved cardiac function persisted during mid-term hypothermia, but was reversed during re-warming. No severe or persistent adverse effects of hypothermia were observed. CONCLUSION: Moderate Hypothermia is safe and feasable in patients during cardiogenic shock. Moreover, hypothermia improved parameters of cardiac function, suggesting that hypothermia might be considered as a positive inotropic intervention rather than a risk for patients during cardiogenic shock. PMID- 23044414 TI - Reply to letter: Drowning: guidelines extant, evidence-based risk for rescuers. PMID- 23044415 TI - Expression of cyclin D1 and cyclin E significantly associates with human papillomavirus subtypes in Bowenoid papulosis. AB - Human papillomavirus (HPV) incorporates high-risk HPV (hrHPV) and low-risk HPV (lrHPV) subtypes according to its contribution to oncogenesis. Different HPV subtypes could regulate the cell cycle of infected cells at different levels. To date, the expression of cyclin D1 and cyclin E in Bowenoid papulosis (BP) tissues and its association with HPV infection still remains elusive. In the present study, genotyping was performed to identify the HPV subtypes in 44 BP specimens. In addition, immunohistochemistry was performed to detect the expression of cell cycle related proteins cyclin D1 and cyclin E in BP tissues as well as normal tissues. We found that there were 20 patients with hrHPV subtypes, 6 patients with lrHPV subtypes, and 18 patients with combined high and low (hr/lr) HPV subtypes. Cyclin D1 expression in patients with hrHPV subtypes (P=0.0408), in patients with lrHPV subtypes (P=0.0002) and in patients with hr/lr HPV subtypes (P=0.0047) was significantly higher than that in normal controls, respectively. Cyclin D1 expression in patients with hr/lr HPV subtypes (P<0.0001) and in patients with lrHPV subtypes (P=0.0244) was significantly higher than that in patients with hrHPV subtypes, respectively. Cyclin E expression in patients with hrHPV subtypes (P<0.0001), in patients with lrHPV subtypes (P=0.0005), and in patients with hr/lr HPV subtypes (P<0.0001) was significantly higher than that in normal controls, respectively. Cyclin E expression in patients with hrHPV subtypes was significantly higher than that in patients with lrHPV subtypes (P=0.0032). Our data suggest that HPV infection is strongly associated with the pathogenesis of BP, and further support the notion that HPV may be involved in the regulation of the expression of cell cycle related proteins, cyclin D1 and cyclin E, in the pathogenesis of BP. PMID- 23044416 TI - Fibroblast growth factor 2 inhibits up-regulation of bone morphogenic proteins and their receptors during osteoblastic differentiation of human mesenchymal stem cells. AB - Understanding the interactions between growth factors and bone morphogenic proteins (BMPs) signaling remains a crucial issue to optimize the use of human mesenchymal stem cells (HMSCs) and BMPs in therapeutic perspectives and bone tissue engineering. BMPs are potent inducers of osteoblastic differentiation. They exert their actions via BMP receptors (BMPR), including BMPR1A, BMPR1B and BMPR2. Fibroblast growth factor 2 (FGF2) is expressed by cells of the osteoblastic lineage, increases their proliferation and is secreted during the healing process of fractures or in surgery bone sites. We hypothesized that FGF2 might influence HMSC osteoblastic differentiation by modulating expressions of BMPs and their receptors. BMP2, BMP4, BMPR1A and mainly BMPR1B expressions were up-regulated during this differentiation. FGF2 inhibited HMSCs osteoblastic differentiation and the up-regulation of BMPs and BMPR. This effect was prevented by inhibiting the ERK or JNK mitogen-activated protein kinases which are known to be activated by FGF2. These data provide a mechanism explaining the inhibitory effect of FGF2 on osteoblastic differentiation of HMSCs. These crosstalks between growth and osteogenic factors should be considered in the use of recombinant BMPs in therapeutic purpose of fracture repair or skeletal bioengineering. PMID- 23044417 TI - Defective ER associated degradation of a model luminal substrate in yeast carrying a mutation in the 4th ER luminal loop of Sec61p. AB - The major constituent of the eukaryotic ER protein-translocation channel (Sec61p in yeast, Sec61alpha in higher eukaryotes) shows a high degree of evolutionary conservation from yeast to humans. The vast majority of eukaryotic species have a conserved di-tyrosine in the 4th ER luminal loop. Previously, we discovered through a screen of ethylnitrosourea- (ENU-) mutagenized mice that substitution of the latter of these tyrosines with histidine (Y344H) of the murine Sec61alpha protein results in diabetes and hepatic steatosis in mice that is a result of ER stress. To further characterize the mechanism behind ER stress in these mice we made the homologous mutation in yeast Sec61p (Y345H). We found that this mutation increased sensitivity of yeast to ER stressing agents and to reduction of Inositol Requiring Enzyme 1 (IRE1) activity. Furthermore, we found that, while this mutation did not affect translocation, it did delay degradation of the model ER-associated degradation (ERAD) substrate CPY(*). Replacing both ER luminal tyrosines with alanines resulted in a destabilization of the Sec61 protein that was rescued by over expression of Sss1p. This double mutant still lacked a noticeable translocation defect after stabilization by Sss1p, but exhibited a similar defect in CPY(*) degradation. PMID- 23044418 TI - Overexpression of soybean GmCBL1 enhances abiotic stress tolerance and promotes hypocotyl elongation in Arabidopsis. AB - Although extensive studies and remarkable progress have been made with Arabidopsis calcineurin B-like proteins (CBLs), knowledge of their functions in other plant species is still limited. Here we isolated gene GmCBL1 from soybean, a homolog of AtCBL1 in Arabidopsis. GmCBL1 was differentially induced by multiple abiotic stress and plant hormones, and its transcripts were abundant in seedlings and mature roots. We over-expressed GmCBL1 in Arabidopsis and found that it enhanced tolerances to both high salt and drought stresses in the transgenic plants. Overexpression of GmCBL1 also promoted hypocotyl elongation under light conditions. GmCBL1 may regulate stress tolerance through activation of stress related genes, and may control hypocotyl development by altering the expression of gibberellin biosynthesis-related genes. This study identifies a putative soybean CBL gene that functions in both stress tolerance and light-dependent hypocotyl development. PMID- 23044419 TI - Leptospira interrogans shotgun phage display identified LigB as a heparin-binding protein. AB - LigB is an adhesin from pathogenic Leptospira that is able to bind to extracellular matrix and is considered a virulence factor. A shotgun phage display genomic library was constructed and used for panning against Heparan Sulfate Proteoglycan (HSPG). A phage clone encoding part of LigB protein was selected in panning experiments and showed specific binding to heparin. To validate the selected clone, fragments of LigB were produced as recombinant proteins and showed affinity to heparin and to mammalian cells. Heparin was also able to reduce the binding of rLB-Ct to mammalian cells. Our data suggests that the glycosaminoglycan moiety of the HSPG is responsible for its binding and could mediate the attachment of the recombinant protein rLB-Ct. Thus, heparin may act as a receptor for Leptospira to colonize and to invade the host tissue. PMID- 23044420 TI - Surface modification of amorphous nanosilica particles suppresses nanosilica induced cytotoxicity, ROS generation, and DNA damage in various mammalian cells. AB - Recently, nanomaterials have been utilized in various fields. In particular, amorphous nanosilica particles are increasingly being used in a range of applications, including cosmetics, food technology, and medical diagnostics. However, there is concern that the unique characteristics of nanomaterials might induce undesirable effects. The roles played by the physical characteristics of nanomaterials in cellular responses have not yet been elucidated precisely. Here, by using nanosilica particles (nSPs) with a diameter of 70nm whose surface was either unmodified (nSP70) or modified with amine (nSP70-N) or carboxyl groups (nSP70-C), we examined the relationship between the surface properties of nSPs and cellular responses such as cytotoxicity, reactive oxygen species (ROS) generation, and DNA damage. To compare the cytotoxicity of nSP70, nSP70-N, or nSP70-C, we examined in vitro cell viability after nSP treatment. Although the susceptibility of each cell line to the nSPs was different, nSP70-C and nSP70-N showed lower cytotoxicity than nSP70 in all cell lines. Furthermore, the generation of ROS and induction of DNA damage in nSP70-C- and nSP70-N-treated cells were lower than those in nSP70-treated cells. These results suggest that the surface properties of nSP70 play an important role in determining its safety, and surface modification of nSP70 with amine or carboxyl groups may be useful for the development of safer nSPs. We hope that our results will contribute to the development of safer nanomaterials. PMID- 23044421 TI - The nuclear protein Artemis promotes AMPK activation by stabilizing the LKB1-AMPK complex. AB - AMP-activated protein kinase (AMPK) is a hetero-trimeric Ser/Thr kinase composed of a catalytic alpha subunit and regulatory beta and gamma subunits; it functions as an energy sensor that controls cellular energy homeostasis. In response to an increased cellular AMP/ATP ratio, AMPK is activated by phosphorylation at Thr172 in the alpha-subunit by upstream AMPK kinases (AMPKKs), including tumor suppressor liver kinase B1 (LKB1). To elucidate more precise molecular mechanisms of AMPK activation, we performed yeast two-hybrid screening and isolated the complementary DNA (cDNA) encoding the nuclear protein Artemis/DNA cross-link repair 1C (DCLRE1C) as an AMPKalpha2-binding protein. Artemis was found to co immunoprecipitate with AMPKalpha2, and the co-localization of Artemis with AMPKalpha2 in the nucleus was confirmed by immunofluorescence staining in U2OS cells. Moreover, over-expression of Artemis enhanced the phosphorylation of AMPKalpha2 and the AMPK substrate acetyl-CoA carboxylase (ACC). Conversely, RNAi mediated knockdown of Artemis reduced AMPK and ACC phosphorylation. In addition, Artemis markedly increased the physical association between AMPKalpha2 and LKB1. Taken together, these results suggest that Artemis functions as a positive regulator of AMPK signaling by stabilizing the LKB1-AMPK complex. PMID- 23044422 TI - WNK-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone. AB - Blood pressure and renal salt excretion show circadian rhythms. Recently, it has been clarified that clock genes regulate circadian rhythms of renal transporter expression in the kidney. Since we discovered the WNK-OSR1/SPAK-NaCl cotransporter (NCC) signal cascade, which is important for regulating salt balance and blood pressure, we have sought to determine whether NCC protein expression or phosphorylation shows diurnal rhythms in the mouse kidneys. Male C57BL/6J mice were sacrificed every 4h (at 20:00, 0:00, 4:00, 8:00, 12:00, and 16:00), and the expression and phosphorylation of WNK4, OSR1, SPAK, and NCC were determined by immunoblot. (Lights were turned on at 8:00, which was the start of the rest period, and turned off at 20:00, which was the start of the active period, since mice are nocturnal.) Although expression levels of each protein did not show diurnal rhythm, the phosphorylation levels of OSR1, SPAK, and NCC were increased around the start of the active period and decreased around the start of the rest period. Oral administration of eplerenone (10mg/day) attenuated the phosphorylation levels of these proteins and also diminished the diurnal rhythm of NCC phosphorylation. Thus, the activity of the WNK4-OSR1/SPAK-NCC cascade was shown to have a diurnal rhythm in the kidney that may be governed by aldosterone. PMID- 23044423 TI - [Prevalence of inapropriate LDL cholesterol levels in patients with coronary disease and/or type 2 diabetes]. AB - BACKGROUND AND OBJECTIVE: Clinical practice guidelines recommend achieving concentrations of LDL cholesterol less than 100 mg/dl (and in some cases less than 70 mg/dl) in patients with coronary artery disease and/or diabetes mellitus type 2 (DM2). We have examined the compliance with these objectives in patients treated in Spain with these conditions. METHODS: Cross-sectional epidemiological study. Data were obtained during the visit of the study or, in their absence, based on data contained in the medical record by 874 doctors of the 17 autonomous communities in Spain. Demographic information, risk factors, cardiovascular and prescribed treatments were collected. RESULTS: In the final analysis 6.988 (62.7% male) patients were included. 2586 (37%) had coronary disease, 2654 (38%) DM2 and 1748 (25%) both conditions. 65% had metabolic syndrome. Vascular risk factors median number was 4. 57% and 86% showed a concentration of LDL cholesterol >100 and >70 mg/dl respectively. The proportion patients with LDL concentration >100 mg/dl was 4% greater in the DM2 (62.4%) than in coronary patients (57.1%; p0.0001). Concentration of triglycerides >150 mg/dl was higher in patients with DM2 (50.5%) than in coronary patients (43.5%; p0.0001). The proportion of patients with LDL>70 mg/dl was similar in the coronary group and in the DM2 Group (88.4% and 87.0%, respectively). More than half of patients with coronary heart disease (57.5%) or DM2 (55.7%) showed inadequate levels of HDL (<40 mg/dl men; <50 mg/dl women). CONCLUSIONS: More than a half of patients with diabetes mellitus and/or coronary artery disease enrolled in the CODIMET study do not achieve the recommended LDL cholesterol target for high cardiovascular risk patients. PMID- 23044424 TI - Dual-chamber pacemaker implantation in a CoreValve recipient with a persistent left superior vena cava. PMID- 23044426 TI - Combined endurance-resistance training improves submaximal exercise capacity in elderly heart failure patients: a systematic review of randomized controlled trials. PMID- 23044425 TI - Impact of weight loss on mortality in chronic heart failure: findings from the RICA Registry. AB - BACKGROUND: Obesity increases the risk of heart failure (HF), but a significant survival benefit in obese patients has been described once they have been diagnosed with HF. There is little information about the effects of weight loss among patients with HF. We aimed to assess the frequency of weight loss in patients with HF from the RICA Registry and whether weight loss is associated with mortality. METHODS: We investigated weight changes in 731 patients with HF and analysed the effect of weight loss of 5% or more of their baseline bodyweight during follow-up. RESULTS: 419 (57.3%) patients lost weight during follow-up but only 152 (20.8%) lost at least 5% of the baseline bodyweight. We did not find significant differences in demographic, clinical, functional and analytical parameters between patients with and without weight loss or 5% or more of their bodyweight. We observed a significant improvement in the mean NYHA functional class value and a non-significant improvement in the LVEF in all patients. A significant decrease in the natriuretic peptide levels was only observed in the patients who lost weight. Survival rates at 1year follow-up for patients with and without weight loss or 5% or more were 75.7% (95% CI: 67.1-84.3%) and 77.1% (95% CI: 72.8-81.4%), respectively (p=0.92). Re-admission rates for patients with and without weight loss were 52.7% (95% CI: 42.9-62.43%) and 50.0% (95% CI: 45.3 54.7%), respectively (p=0.34). CONCLUSIONS: Significant weight loss occurred in 20.8% of patients with HF. Weight loss was not associated with mortality or readmission. PMID- 23044427 TI - Correlation of syncopal burden with anxiety symptoms score in recurrent vasovagal syncope. PMID- 23044428 TI - Development of a novel two-dimensional directed differentiation system for generation of cardiomyocytes from human pluripotent stem cells. AB - BACKGROUND: Human pluripotent stem cells (hPSCs) hold great promise for treating ischemic heart disease. However, current protocols for differentiating hPSCs either result in low yields or require expensive cytokines. METHODS: Here we developed a novel two dimensional (2D) stepwise differentiation system that generates a high yield of cardiomyocytes (CMs) from hPSCs without using special cytokines. Initially, undifferentiated hPSCs were transferred onto Matrigel coated plates without forming embryoid bodies (EBs) for a few days and were cultured in bFGF-depleted human embryonic stem cells (hESCs) medium. When linear cell aggregation appeared in the margins of the hPSC colonies, the medium was changed to DMEM supplemented with 10% fetal bovine serum (FBS). Thereafter when cell clusters became visible, the medium was changed to DMEM with 20% FBS. RESULTS AND CONCLUSIONS: At about two weeks of culture, contracting clusters began to appear and the number of contracting clusters continuously increased, reaching approximately 70% of all clusters. These clusters were dissociated by two-step enzyme treatment to monolayered CMs, of which ~90% showed CM phenotypes confirmed by an alpha-myosin heavy chain reporter system. Electrophysiologic studies demonstrated that the hPSC-derived CMs showed three major CM action potential types with 61 to 78% having a ventricular-CM phenotype. This differentiation system showed a clear spatiotemporal role of the surrounding endodermal cells for differentiation of mesodermal cell clusters into CMs. In conclusion, this system provides a novel platform to generate CMs from hPSCs at high yield without using cytokines and to study the development of hPSCs into CMs. PMID- 23044430 TI - Mitochondrial function in cardiac hypertrophy. AB - Cardiac hypertrophic program is a chronic, complex process, and occurs in response to long-term increases of hemodynamic load related to a variety of pathophysiological conditions. Mitochondria, known as "the cellular power plants", occupy about one-third of cardiomyocyte volume and supply roughly 90% of the adenosine triphosphate (ATP). Impairment of energy metabolism has been regarded as one of the main pathogenesis of cardiac hypertrophy. Thus, we summarize here the molecular events of mitochondrial adaptations, including the mitochondrial genesis, ATP generation, ROS signaling and Ca(2+) homeostasis in cardiac hypertrophy, expecting that this effort will shed new light on understanding the maladaptive cardiac remodeling. PMID- 23044429 TI - Red blood cell fatty acid levels improve GRACE score prediction of 2-yr mortality in patients with myocardial infarction. AB - BACKGROUND: Blood omega-3 and omega-6 fatty acid levels have been associated with reduced risk for total mortality in patients with stable coronary heart disease (CHD), but their relationships with mortality in the setting of myocardial infarction (MI) are unknown. OBJECTIVE: To determine the association between red blood cell (RBC) fatty acid levels measured at admission and 2-year mortality in MI patients, independent of the GRACE risk score, a traditional mode of risk stratification. DESIGN: Admission RBC fatty acid levels were measured in patients enrolled in a prospective, 24-center MI registry (TRIUMPH). Two-year mortality was modeled with Cox proportional hazards regression to assess the extent to which the inclusion of fatty acid levels would improve, over and above the GRACE score, risk stratification for 2-year mortality. RESULTS: RBC fatty acid data were available from 1144 patients who did not report taking fish oil supplements after discharge. Two RBC fatty acids [eicosapentaenoic acid (EPA) and docosapentaenoic n-6 (DPA)] were univariate predictors of total mortality. The combined fatty acid c-statistic (0.60, p<0.001) improved the c-statistic of the GRACE score alone from 0.747 (p<0.001) to 0.768 (p<0.05 vs. GRACE alone). The net reclassification index improved by 31% (95% CI, 15% to 48%) and the relative incremental discrimination index improved by 19.8% (7.5% to 35.7%). CONCLUSION: RBC EPA and DPA n-6 levels improved the prediction of 2-yr mortality over and above the GRACE score in MI patients. PMID- 23044431 TI - Leonardo da Vinci's studies of the heart. AB - Leonardo da Vinci's detailed drawings are justly celebrated; however, less well known are his accounts of the structures and functions of the organs. In this paper, we focus on his illustrations of the heart, his conjectures about heart and blood vessel function, his experiments on model systems to test those conjectures, and his unprecedented conclusions about the way in which the cardiovascular system operates. In particular, da Vinci seems to have been the first to recognize that the heart is a muscle and that systole is the active phase of the pump. He also seems to have understood the functions of the auricles and pulmonary veins, identified the relationship between the cardiac cycle and the pulse, and explained the hemodynamic mechanism of valve opening and closure. He also described anatomical variations and changes in structure and function that occurred with age. We outline da Vinci's varied career and suggest ways in which his personality, experience, skills and intellectual heritage contributed to these advances in understanding. We also consider his influence on later studies in anatomy and physiology. PMID- 23044432 TI - Left ventricular dyssynchrony is associated with recurrence of ischemic mitral regurgitation after restrictive annuloplasty. AB - BACKGROUND: In our study, we investigated the impact of papillary muscle systolic dyssynchrony (DYS-PAP) obtained by 2D speckle-tracking echocardiography (2D-STE) in the prediction of recurrent ischemic mitral regurgitation (MR) after restrictive annuloplasty. METHODS: The study population consisted of 524 consecutive patients who survived coronary artery bypass grafting (CABG) and restrictive annuloplasty, performed between 2001 and 2010 at 3 different Institutions and who met inclusion criteria. The assessment of DYS-PAP was performed preoperatively and at follow-up (median 45.3 months [IQR 26-67]) by 2D STE in the apical four-chamber view for the anterolateral papillary muscle (ALPM) and apical long-axis view for the posteromedial papillary muscle (PMPM). RESULTS: Recurrence of MR (>= 2+ in patients with no/trivial MR at discharge) was found in 112 patients (21.3%) at follow-up. Compared to patients without recurrence of MR, these patients had higher DYS-PAP values at baseline (60.6 +/- 4.4 ms vs. 47.2 +/ 2.9 ms, p<0.001) which significantly worsened at follow-up (74.4 +/- 5.2 ms, p=0.002 vs. baseline). In contrast, in patients with no MR recurrence, DYS-PAP was significantly reduced (25.3 +/- 4.4 ms, p=0.002 vs. baseline). At logistic regression analysis DYS-PAP (odds ratio [OR]: 4.8, 95% Confidence Interval [CI]: 3.4-8.2, p<0.001), was the strongest predictor of recurrent MR with a cutoff >= 58 ms (95%CI 51-66 ms). The model showed an area under the Receiver Operating Characteristic (ROC) curve of 0.97 (CI 0.94-0.99 [optimism-corrected 0.94; CI 0.89-0.95]) with 98% sensitivity (CI 96-100% [optimism-corrected 95%; CI 91-96%]) and 90% specificity (CI 85-94% [optimism-corrected 87%; CI 82-90%]). CONCLUSIONS: DYS-PAP represents a reliable tool to identify patients with ischemic MR who can benefit from restrictive annuloplasty. PMID- 23044433 TI - Pulmonary vein isolation using a single size cryoballoon chosen according to transesophageal echocardiography information. AB - BACKGROUND: Pulmonary vein isolation (PVI) using cryoballoon (CB) catheter is a new technique for atrial fibrillation (AF) ablation. Previous studies used computer tomography (CT) or magnetic resonance imaging (MRI) scan to determine the pulmonary vein (PV) diameter and anatomy for choosing the CB size. We evaluated pre-ablation transoesophageal-echocardiography (TEE) as an alternative to CT/MRI scan in patients undergoing AF ablation for determining the appropriate size of the CB. METHODS: Fifty-five consecutive patients (men=43, women=12) with a mean age of 63 +/- 12.5 years, and with drug-refractory paroxysmal AF (34 patients) or persistent AF (21 patients) were included in this prospective study. All patients underwent pre-ablation TEE. RESULTS: Hypertension was present in 19 patients (34%). Mean anterior-posterior left atrium diameter was 45.1 +/- 8.9 mm. In total, 217 PV were targeted using a single 23-mm (n=14) or 28-mm (n=40) CB catheter chosen according to TEE-obtained measurements. PVI was achieved in 195 PV (90%). Mean number of CB applications per patient was 9.8 +/- 2.1 (range 8 14). Mean procedure duration and fluoroscopy times were 131 +/- 27 min (90-190 min) and 36 +/- 12 min (22-66 min) respectively. Phrenic nerve palsy occurred in 3 patients (5.4%) and was transient (<1 month) in all of them. CONCLUSION: This study suggests that TEE is an easily available and effective tool to select the size of the CB for PVI according to evaluated PV diameters and anatomy. PMID- 23044434 TI - The heart's content-renewable resources. AB - Heart regeneration is a huge, complex area involving numerous lines of research ranging from the stem cell therapy to xenografts and bioengineering. This review will focus on two avenues of regenerative research, cardiac progenitor cells and adult cardiomyocyte proliferation, both of which offer great promise for the field of heart regeneration. However, the principles behind how this could be achieved by either technique are very different. Cardiac progenitor cells represent a population of somatic stem cells which reside within the adult heart. These cells appear to have the capacity to proliferate and differentiate into the different cell types found within the adult heart and thus have the potential, if the correct stimuli can be found, to effectively regenerate a heart damaged by ischemia/infarction. Inducing adult cardiomyocytes to proliferate offers a different approach to achieving the same goal. In this case, the cardiomyocytes that remain after the damage has occurred would need to be stimulated into effecting a regenerative response. In this review, we will discuss the current understanding of how heart regeneration could be achieved by either of these very different approaches. PMID- 23044435 TI - Imbalance of Th17/Treg cells in mice with chronic cigarette smoke exposure. AB - BACKGROUND: Recent studies have revealed that autoimmune responses mediated by CD4(+) T cells may contribute to the development of chronic obstructive pulmonary disease (COPD). Meanwhile, imbalance of Th17/Treg has been reported to play a key role in the pathogenesis of autoimmune diseases. However, information on Th17/Treg balance in COPD is relatively limited. METHOD: We established a mouse model of COPD induced by chronic cigarette smoke (CS) exposure. Th17 and Treg in lung tissue and peripheral blood were quantified by flow cytometry. The level of the specific transcription factors of both T cell subsets in lung tissue was determined by real-time PCR. The expressions of Th17- and Treg-related cytokines in serum and bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that mice with chronic CS exposure showed significant increase in lung Th17 prevalence, retinoic acid orphan receptor (ROR)-gammat mRNA and Th17-related cytokines (IL-17A, IL-6 and IL-23). Meanwhile, there was obvious decrease in Treg cell prevalence, Forkhead box (Fox) p3 mRNA and Treg-related cytokine IL-10, as compared to mice underwent sub-acute CS exposure and air-exposure. Similar tendency was also found for the Th17/Treg ratio in peripheral blood. CONCLUSIONS: Our study thus reveals that the Th17/Treg imbalance exists in mice with chronic CS exposure, suggesting its potential role in the breakdown of immune self-tolerance in COPD. Further research on regulation of Th17/Treg balance may provide insights into the development of new therapeutic targets for this disease. PMID- 23044437 TI - The morning after pill as an 'easy' option: the implication for STIs. PMID- 23044436 TI - Modelling national HIV/AIDS epidemics: revised approach in the UNAIDS Estimation and Projection Package 2011. AB - OBJECTIVE: United Nations Programme on HIV/AIDS reports regularly on estimated levels and trends in HIV/AIDS epidemics, which are evaluated using an epidemiological model within the Estimation and Projection Package (EPP). The relatively simple four-parameter model of HIV incidence used in EPP through the previous round of estimates has encountered challenges when attempting to fit certain data series on prevalence over time, particularly in settings with long running epidemics where prevalence has increased recently. To address this, the most recent version of the modelling package (EPP 2011) includes a more flexible epidemiological model that allows HIV infection risk to vary over time. This paper describes the technical details of this flexible approach to modelling HIV transmission dynamics within EPP 2011. METHODOLOGY: For the flexible modelling approach, the force of infection parameter, r, is allowed to vary over time through a random walk formulation, and an informative prior distribution is used to improve short-term projections beyond the last year of data. Model parameters are estimated using a Bayesian estimation approach in which models are fit to HIV seroprevalence data from surveillance sites. RESULTS: This flexible model can yield better estimates of HIV prevalence over time in situations where the classic EPP model has difficulties, such as in Uganda, where prevalence is no longer falling. Based on formal out-of-sample projection tests, the flexible modelling approach also improves predictions and CIs for extrapolations beyond the last observed data point. CONCLUSIONS: We recommend use of a flexible modelling approach where data are sufficient (eg, where at least 5 years of observations are available), and particularly where an epidemic is beyond its peak. PMID- 23044438 TI - Unlocking the potential: longitudinal audit finds multifaceted education for general practice increases HIV testing and diagnosis. AB - BACKGROUND: This longitudinal study aimed to evaluate the impact of a multifaceted educational intervention (Sexual Health in Practice, SHIP) on general practice HIV testing rates in a high prevalence London area. INTERVENTION: SHIP offered training in sexual health clinical skills to general practitioners (GPs) and practice nurses (PNs) in Haringey. SHIP training aims to break down stigma in sexual health and provide sexual history and communication tools (e.g. differential diagnosis), and provides resources to practices (including condoms). DESIGN: Numbers of GP HIV tests were collected from laboratories for 24 months prior, 19 months during and 5 months after training. Attendance data and practice list sizes were obtained. RESULTS: 39 of 51 practices had at least one trained individual. These 'trained' practices conducted an average 526 HIV tests p.a. before training began which rose to a projected 1556 p.a. (on the basis of the last 6 months of data). Testing rates of trained and untrained practices increased from 2.29 to 6.66 and 1.54 to 1.90 tests/1000 registered patients/year (p=0.0016 and p=0.5195) respectively. The rate of positive diagnosis was high in the trained group (18.0 and 16.7 positives/1000 tests before and after training began; p=0.7908). This equates to a rise from 9.5 to 22 new diagnoses p.a. CONCLUSIONS: The training intervention has been found to significantly increase general practice HIV testing rates in the absence of financial incentives. Positivity rates are substantially higher than that found in pilots of screening in London, suggesting that the training nurtured and supplemented complex clinical skills. PMID- 23044439 TI - Electronic states in heterostructures formed by ultranarrow layers. AB - Low-energy electronic states in heterostructures formed by ultranarrow layers (single or several monolayers in thickness) are studied theoretically. The host material is described within the effective mass approximation and the effect of ultranarrow layers is taken into account within the framework of the transfer matrix approach. Using the current conservation requirement and the inversion symmetry of an ultranarrow layer, the transfer matrix is evaluated through two phenomenological parameters. The binding energy of localized state, the reflection (transmission) coefficient for the single ultranarrow layer case, and the energy spectrum of the superlattice are determined by these parameters. The spectral dependency of absorption due to photoexcitation of electrons from localized states into minibands of the superlattice is determined by the ultranarrow layer characteristics. Such a dependency can be used for verification of the transfer matrix and should modify the characteristics of optoelectronic devices with ultranarrow layers. Comparison with experimental data shows that the effective mass approach is not valid for the description of ultranarrow layers. PMID- 23044440 TI - Letter to the editor: response to letter from Dr. Kim et al. PMID- 23044441 TI - Chest radiography for tuberculosis screening is back on the agenda. PMID- 23044442 TI - Antioxidants and asthma: will the patient benefit? PMID- 23044443 TI - The knowns and unknowns of the immunopathogenesis of tuberculosis. AB - In this review, we discuss the 'knowns' and 'unknowns' of host defence towards Mycobacterium tuberculosis. With regard to the 'knowns', both protective and immunopathogenic mechanisms are discussed, including recently discovered new pathways of host defence and inflammatory immunopathology. With regard to the 'unknowns', there will be emphasis on unanswered key questions, accompanied by a perspective on needs and priorities for future research. The role of the inflammatory response and its dysregulation in tuberculosis-related immune reconstitution inflammatory syndrome will also be discussed. PMID- 23044444 TI - Implementation and community involvement in DOTS strategy: a systematic review of studies in China. AB - OBJECTIVE: To summarise data on the implementation of the DOTS strategy in China in terms of actual observation and treatment adherence, and to review the effectiveness of quality improvement interventions for tuberculosis (TB) control in China. DESIGN: We included survey studies that reported data on the implementation of DOTS in China and controlled studies that evaluated TB care in specified communities. We excluded studies outside mainland China, pharmacological intervention trials and reviews. RESULTS: We included 12 survey studies that reported on the performance of TB control services in China. The pooled analysis showed that more than half of TB patients were treated by self administration (52%) and that only 20% actually had their treatment observed by health workers. We include 85 intervention studies that evaluated the effect of quality improvement interventions. Treatment observers were family members in 37 studies, and health workers in 20 studies. The pooled odds ratio (OR) for cure was 2.48 (95%CI 1.97-3.11, I(2) = 70.9%, P < 0.001); the pooled OR for treatment completion was 2.87 (95%CI 2.23-3.69, I(2) = 66.3%, P < 0.001). Sensitivity analysis found that the estimated treatment effects in meta-analyses using reported and imputed data were much reduced, but still statistically significant. CONCLUSION: The proportion of TB patients whose treatment was strictly observed was much lower than reported by official statistics in China. The treatment completion rate was not optimal, which may be an important reason for the reported increases in drug resistance. Community health personnel have become the main work force for TB control in China. PMID- 23044445 TI - Heterogeneity of Mycobacterium tuberculosis strains in Makassar, Indonesia. AB - SETTING: Patients with suspected pulmonary tuberculosis (TB) visiting government TB diagnostic and treatment centres in Makassar City, South Sulawesi Province, Indonesia, from February to October 2008 were included in the study. OBJECTIVE: To determine the distribution of Mycobacterium tuberculosis genotypes in Makassar. DESIGN: Cross-sectional study. Spoligotyping, mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) and principal genetic grouping (PGG) were used to genotype the M. tuberculosis clinical isolates. RESULTS: Among 179 isolates derived from pulmonary TB patients, distribution of spoligotypes comprised the East Africa-Indian (30.2%), T (17.9%), H (12.3%) and Beijing (9.5%) lineages. Other lineages found in smaller proportions were the Latin American-Mediterranean, MANU, S and X lineages. Nineteen isolates (10.6%) could not be grouped into any of the reported lineages or shared types. Single nucleotide polymorphism analysis of katG(463) and gyrA(95) grouped these isolates primarily into PGG1 (9/19, 47%). CONCLUSION: Only a few genetically identical clustered isolates were identified within the 9 month study period, and most isolates were genetically diverse. Furthermore, 15 spoligopatterns identified in our study have not been reported previously. To our knowledge, this is the first comprehensive study describing genotypes of M. tuberculosis clinical isolates in Sulawesi. PMID- 23044446 TI - Outcomes of Category III DOTS treatment in immunocompetent patients with tuberculosis pleural effusion. AB - OBJECTIVES: To study the efficacy and safety of Category III DOTS treatment (intermittent thrice-weekly rifampicin [RMP], isoniazid [INH] and pyrazinamide for 2 months, followed by RMP and INH for 4 months) under India's Revised National Tuberculosis Control Programme in patients with uncomplicated small unilateral pleural effusion (<1500 ml). DESIGN: This prospective, multicentre, observational study recruited 351 patients between 2006 and 2010. Patients were regularly followed up clinically as well as with ultrasound examination of the chest. RESULTS: Successful outcome (clinical response with complete resolution on ultrasound examination at 6 months) was seen in 274 patients (78.1%). Efficacy was 88.9% (excluding defaulters), and 94% among those completing follow-up as per protocol. None of the patients received corticosteroids. Other outcomes included treatment extension (n = 26, 7.4%), default (n = 43, 12.2%), treatment failure (n = 3, 0.9%) and death (n = 3, 0.9%). Seventy-nine mild/moderate adverse events and one treatment-related serious adverse event were noted; one patient developed recurrent drug-induced hepatotoxicity. Two patients (0.7%) had relapse/re infection at 24 months follow-up. CONCLUSION: Intermittent thrice-weekly treatment for 6 months with three drugs in the intensive phase is effective and safe for unilateral small pleural effusion in immunocompetent patients. Although Category III no longer exists in the programme, the results are reassuring for intermittent treatment in extra-pulmonary TB under programme conditions. PMID- 23044447 TI - Low prevalence of vitamin D deficiency in Ugandan HIV-infected patients with and without tuberculosis. AB - OBJECTIVE: To examine whether hypovitaminosis D is a risk factor for the development of tuberculosis (TB) associated immune reconstitution inflammatory syndrome (IRIS). METHODS: We measured serum 25-hydroxyvitamin D (25D) concentrations in four groups of patients at Mulago Hospital, Kampala, Uganda: 1) patients co-infected with TB and the human immunodeficiency virus (HIV) receiving anti-tuberculosis treatment (HIV+TB+; n = 92) who did and did not develop TB-IRIS after starting antiretroviral treatment (ART), 2) HIV-infected patients without TB (HIV+TB-; n = 20) starting ART, 3) non-HIV-infected individuals with TB (HIV-TB+; n = 27), and 4) those without TB (HIV-TB-; n = 23). RESULTS: The prevalence of optimal 25D levels (>75 nmol/l) was as follows: 59% in HIV+TB+, 65% in HIV+TB-, 63% in HIV-TB+ and 35% in HIV-TB- patients. 25D concentrations decreased during the first 3 months of ART in HIV+TB+ individuals who developed IRIS (P = 0.005) and those who did not (P = 0.002), and in HIV+TB- individuals (P = 0.015); however, 25D concentration in patients who did or did not develop TB-IRIS did not differ. CONCLUSION: The prevalence of optimal vitamin D status was relatively high in HIV-infected patients with and without TB living near the equator. No difference in 25D concentrations was observed between TB IRIS and non-IRIS. However, 25D concentrations decreased during ART. PMID- 23044448 TI - Tuberculosis diagnosis after bleach processing for early stage tuberculosis laboratory capacity building. AB - The diagnosis of tuberculosis is seriously hampered in the absence of standard biosafety laboratory facilities for specimen concentration and Mycobacterium tuberculosis culture. Within a laboratory twinning arrangement, heat-fixed direct smear and sediment from 74 bleach-processed and 20 non-processed specimens from Cumura Hospital, Guinea-Bissau, were sent to Lisbon for molecular evaluation of rifampicin resistance. Sequence analysis of a 369 base-pair rpoB locus detected 3.2% (3/94) resistant specimens. To our knowledge, this represents the first report on the molecular analysis of M. tuberculosis from bleach-processed sputum, an alternative to current diagnostic practice in low-resource settings. PMID- 23044449 TI - The impact of total antioxidant capacity on pulmonary function in asthma patients. AB - BACKGROUND: Oxidative stress, mediated by an imbalance between oxidants and antioxidants, contributes significantly to the pathogenesis of asthma. OBJECTIVE: To evaluate the impact of serum total antioxidant capacity (TAC) on the pulmonary function of Korean asthma patients. METHOD: A total of 104 adult asthma patients enrolled from the COREA (Cohort for Reality and Evolution of Adult Asthma in Korea) programme participated in the study. Baseline clinical parameters at enrolment, and the results of pulmonary function tests at baseline and 1 and 2 years after enrolment were collected. TAC at baseline was measured using a Trolox-equivalent antioxidant capacity assay. Patients were divided into two groups based on TAC levels, and various clinical parameters were compared. RESULT: Serum TAC levels correlated with forced expiratory volume in 1 second (FEV(1)) at baseline (r = 0.22, P = 0.03). The group with higher baseline TAC levels maintained greater mean FEV(1) both 1 and 2 years after enrolment, even after adjusting for sex, age, height, weight, body mass index and smoking status. CONCLUSION: These results suggest an important link between serum TAC levels and pulmonary function, indicating that higher TAC levels may be a biomarker for favourable prognosis in asthma patients. PMID- 23044450 TI - Can LED fluorescence microscopy replace Ziehl-Neelsen microscopy in tuberculosis detection? PMID- 23044451 TI - In reply to 'Can LED fluorescence microscopy replace Ziehl-Neelsen microscopy in tuberculosis detection?'. PMID- 23044452 TI - Change to patient-centred terminology in tuberculosis: an important step, but what about the treatment strategies? PMID- 23044453 TI - Xpert(r) MTB/RIF diagnosed disseminated smear-negative MDR-TB in a sub-district hospital in India. PMID- 23044454 TI - Prevalence of hypothyroidism among MDR-TB patients in Botswana. PMID- 23044455 TI - In vitro susceptibility of Mycobacterium bovis against moxifloxacin. PMID- 23044456 TI - Y-Maze memory task in zebrafish (Danio rerio): the role of glutamatergic and cholinergic systems on the acquisition and consolidation periods. AB - The interest in the behavioral features of zebrafish has significantly increased over the past two decades. However, most available protocols have used longer training periods and have been based on reinforcement/reward or avoidance. The Y Maze memory task has the advantage of using a simple and rapid training session, but it has not been established in zebrafish. Here, we have characterized this task for zebrafish, with the addition of pharmacological interventions in the acquisition and consolidation memory phases. The results show that zebrafish spend more time in the novel arm than in the other arms of the Y-Maze, both in response to novelty and spatial memory training-test intervals (TTIs). We have also studied the involvement of the glutamatergic and cholinergic systems with pre- and post-training treatments with the NMDA receptor antagonist MK-801 (20 MUM) and the cholinergic blocker scopolamine (200 MUM). After 1h of TTI, pre training MK-801 and scopolamine-treated fish reduced their exploration of the novel arm when compared to the control group, with no changes in their locomotor activity. Post-training of MK-801 treatment also impaired their Y-Maze performance, while post-training of any scopolamine treatment failed to affect novel arm exploration. In conclusion, the Y-Maze memory task can be reliably used for zebrafish, providing a new, rapid, and preference/avoidance independent task for the study of memory in this teleost. In addition, our results highlight the implication of the glutamatergic and cholinergic systems in the memory of zebrafish. PMID- 23044457 TI - Indices of extinction-induced "depression" after operant learning using a runway vs. a cued free-reward delivery schedule. AB - Loss of reward is one of the etiological factors leading to affective disorders, such as major depression. We have proposed several variants of an animal model of depression based on extinction of reinforced behavior of rats. A number of behaviors emitted during extinction trials were found to be attenuated by antidepressant treatment and, thus, qualified as indices of extinction-induced "despair". These include increases in immobility in the Morris water maze and withdrawal from the former source of reward as well as biting behavior in operant chambers. Here, we assess the effects of reward omission on behaviors after learning of (a) a cued free-reward delivery in an operant chamber and (b) food reinforced runway behavior. Sixty adult male Wistar rats were either trained to receive food reinforcement every 90 s (s) after a 5s lasting cue light (FI 90), or to traverse an alley to gain food reward. Daily drug treatment with either the selective serotonin reuptake inhibitor citalopram or the tricyclic antidepressant imipramine (each 10mg/kg) or vehicle was begun either 25 days (operant chamber) or 3 days (runway) prior to extinction. The antidepressants suppressed rearing behavior in both paradigms specifically during the extinction trials, which indicates this measure as a useful marker of depression-related behavior, possibly indicating vertical withdrawal. In the operant chamber, only marginal effects on operant learning responses during extinction were found. In the runway, the operant learned responses run time and distance to the goal, as well as total distance moved, grooming and quiescence were also influenced by the antidepressants, providing a potential set of markers for extinction-induced "depression" in the runway. Both paradigms differ substantially with respect to the anticipation of reward, behaviors that are learned and that accompany extinction. Accordingly, antidepressant treatment influenced different sets of behaviors in these two learning tasks. PMID- 23044458 TI - Application of an independent dose calculation software for estimating the impact of inter-fractional setup shifts in Helical Tomotherapy treatments. AB - The purpose of this study is to validate the capability of in-house independent point dose calculation software to be used as a second check for Helical Tomotherapy treatment plans. The software performed its calculations in homogenous conditions (using the Cheese phantom, which is a cylindrical phantom with radius 15 cm and length 18 cm) using a factor-based algorithm. Fifty patients, who were treated for pelvic (10), prostate (14), lung (10), head & neck (12) and brain (4) cancers, were used. Based on the individual patient kVCT images and the pretreatment MVCT images for each treatment fraction, the corresponding daily patient setup shifts in the IEC-X, IEC-Y, and IEC-Z directions were registered. For each patient, the registered fractional setup shifts were grouped into systematic and random shifts. The average systematic dosimetric variations showed small dose deviation for the different cancer types (1.0%-3.0%) compared to the planned dose. Of the fifty patients, only three had percent differences larger than 5%. The average random dosimetric variations showed relatively small dose deviations (0.2%-1.1%) compared to the planned dose. None of the patients had percent differences larger than 5%. By examining the individual fractions of each patient, it is observed that only in 31 out of 1358 fractions the percent differences exceeded the border of 5%. These results indicate that the overall dosimetric impact from systematic and random variations is small and that the software is a capable platform for independent point dose validation for the Helical Tomotherapy modality. PMID- 23044459 TI - Nonlinear dynamical analysis of laryngeal, esophageal, and tracheoesophageal speech of Cantonese. AB - Esophageal (SE) and tracheoesophageal (TE) speech are the most commonly used alaryngeal voicing types after total laryngectomy-a surgical procedure of removing a pathological larynx. Both SE and TE voices show more aperiodicity than normal laryngeal (NL) voices, and the vocal characteristics of alaryngeal voices are notoriously difficult to extract. The present study investigated the difference in vocal characteristics among NL, SE, and TE voices using perception measures and nonlinear dynamical analysis. Correlation dimension (D(2)) and sample entropy (SampEn) were obtained from 90 voice samples produced by 10 TE, 10 SE, and 10 NL male Cantonese speakers. Correlation between nonlinear dynamical parameters and perceptual ratings of different voices was also examined. Results show that both D(2) and SampEn values were significantly higher for TE and SE voices than NL voice. The overall perceptual judgment of SE and TE voice quality was negatively correlated with D(2) and SampEn. This finding supports the validity of using nonlinear dynamical parameters in assessing voice quality. Results of the present study also indicate that nonlinear dynamical analysis could be a supplemental tool to traditional acoustic analysis, especially for analyzing the voice quality of alaryngeal speech. PMID- 23044460 TI - Connections between voice ergonomic risk factors and voice symptoms, voice handicap, and respiratory tract diseases. AB - OBJECTIVES: The aim of the study was to investigate the connections between voice ergonomic risk factors found in classrooms and voice-related problems in teachers. METHODS: Voice ergonomic assessment was performed in 39 classrooms in 14 elementary schools by means of a Voice Ergonomic Assessment in Work Environment--Handbook and Checklist. The voice ergonomic risk factors assessed included working culture, noise, indoor air quality, working posture, stress, and access to a sound amplifier. Teachers from the above-mentioned classrooms reported their voice symptoms, respiratory tract diseases, and completed a Voice Handicap Index (VHI). RESULTS: The more voice ergonomic risk factors found in the classroom the higher were the teachers' total scores on voice symptoms and VHI. Stress was the factor that correlated most strongly with voice symptoms. Poor indoor air quality increased the occurrence of laryngitis. CONCLUSIONS: Voice ergonomics were poor in the classrooms studied and voice ergonomic risk factors affected the voice. It is important to convey information on voice ergonomics to education administrators and those responsible for school planning and taking care of school buildings. PMID- 23044461 TI - Cross-cultural adaptation and validation of the Voice Handicap Index into Croatian. AB - This article presents preliminary results of cultural adaptation and validation of the Croatian version of Voice Handicap Index (VHI). The translated version was completed by 38 subjects with voice disorders and 30 subjects without voice complaints. Compared with the subjects in the control group, subjects with voice disorders had significantly higher average total VHI score and scores in each of the three VHI domains (functional, physical, and emotional). Cronbach alpha for total VHI was .94, and coefficients obtained for the three VHI subscales were as follows: alpha = .87 for functional, alpha = .88 for physical, and alpha = .85 for emotional subscales. Intraclass correlation coefficient estimation was also high, for both total VHI (0.92) and subscales (0.85 for functional subscale, 0.87 for physical subscale, and 0.81 for emotional subscale). The overall VHI score positively correlated with auditory perceived grade of dysphonia. In the group with voice disorders, age was not correlated to the total VHI or the subscales. Also, there was no significant difference between male and female voice subjects in total VHI or the subscales. Preliminary findings of this research indicate that the Croatian VHI could provide a reliable and clinically valid measure of patient's current perception of voice problem and its reflection on the quality of life. PMID- 23044462 TI - Prediction of coexistent carcinomas risks by subjective EIN diagnosis and comparison with WHO classification in endometrial hyperplasias. AB - Endometrial intraepithelial neoplasia (EIN) classification is proposed as a new diagnostic system to resolve the limitations of the World Health Organization (WHO) classification in routine practice. Our aim was to find out whether EIN classification excels the WHO classification regarding the accurate prediction of coexisting endometrial carcinomas (EC) in biopsy specimens. We retrospectively re classified 139 WHO-classified endometrial hyperplasia (EH) cases by subjective EIN diagnosis and compared the incidence of coexisting carcinomas using two classification systems by re-evaluating biopsy and corresponding hysterectomy specimens. Of 139 WHO-classified hyperplasia cases, 36 and 103 were classified as benign and EIN cases, respectively. Forty of 93 cases with atypical EH had EC at hysterectomy as compared with 2/46 cases without atypical EH, while EC was detected in 42/103 cases with EIN, and in 0 of 36 cases without EIN. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for atypical EH vs. non-atypical EH in biopsy specimen was 95.2%, 45.4%, 43.0% and 95.7%, respectively. For EIN vs. benign, the sensitivity was 100% and the specificity was 37.1%. The incidence of coexisting carcinomas in EIN cases was similar to that in atypical EH cases. However, regarding the exclusion of coexisting carcinomas, EIN criteria of benign lesions excelled the WHO criteria of non-atypical EH/CH. PMID- 23044463 TI - A systematic review of creative thinking/creativity in nursing education. AB - OBJECTIVE: This systematic review aimed to identify the types of nursing course structure that promotes students' creative thinking and creativity. DESIGN: Systematic review. DATA SOURCES: Five electronic databases: The British Nursing Index, CINAHL, PsycINFO, Scopus and Ovid Medline. REVIEW METHODS: The databases were systematically searched to identify studies that discussed the concept of creative thinking in nursing education or reported a strategy that improved students' creative thinking. Qualitative studies or studies that included qualitative data were included. After reading the full content of the included studies, key themes and concepts were extracted and synthesized. RESULTS: Eight studies were identified. Four main themes relating to the course structure in teaching creativity were developed: diversity learning, freedom to learn, learning with confidence and learning through group work. CONCLUSIONS: To promote creative thinking in nursing students, educators themselves need to be creative in designing courses that allow students to learn actively and convert thoughts into actions. Educators should balance course freedom and guidance to allow students to develop constructive and useful ideas. Confidence and group work may play significant roles in helping students to express themselves and think creatively. PMID- 23044464 TI - Erving Goffman and the total institution. PMID- 23044465 TI - Early surgical site infections in adult spinal trauma: a prospective, multicentre study of infection rates and risk factors. AB - INTRODUCTION: Spine surgery is known to have a high risk of surgical site infection (SSI). Multiple studies have looked into the risk factors and incidence of SSI during elective surgery, but only two retrospective studies have specifically evaluated SSI during surgery following spine trauma. MATERIALS AND METHODS: This work was based on a prospective cohort study that included all the patients operated on for spinal trauma at 13 French hospitals over a three-month period. The main endpoint was the occurrence of a SSI during the three-month period. Patients with multiple trauma or open fractures were excluded from the study. RESULTS: Of the 169 patients re-examined after a minimum of three months, six had had an acute SSI (3.55%). The following factors were significantly related to a SSI: age, ASA score, diabetes, procedure duration, delay elapsed between accident and procedure, number of levels fused, bleeding and prolonged presence of urinary catheter. DISCUSSION: Our results were consistent with the published infection rates of 2 to 10%. The risk factors identified have all been described in previous studies on elective spine surgery. LEVEL OF EVIDENCE: Level IV, prospective cohort study. PMID- 23044466 TI - The percutaneous compression plate versus the dynamic hip screw for treatment of intertrochanteric hip fractures: a systematic review and meta-analysis of comparative studies. AB - BACKGROUND: The use of a percutaneous compression plate (PCCP) provides a minimally invasive technique for the fixation of stable intertrochanteric femoral fractures. It has several theoretically potential advantages over the dynamic hip screw (DHS) such as shorten incision and lower incidence of wound infection. HYPOTHESIS: PCCP have several advantages than DHS, such as reduced blood loss, transfusion, mortality, shorter operative time, and lower incidence of complications. This systematic review and meta-analysis was performed to identify the clinical outcomes and safety of patients with stable intertrochanteric hip fractures operated on using PCCP compared with DHS. MATERIALS AND METHODS: A systematic search of all studies published through April 2012 was conducted using the Medline, Embase, Sciencedirect, OVID and the Cochrane Central database. The randomized controlled trials (RCTs) and quasi-randomised control trials (qRCTs) that compared PCCP with DHS in treating adult patients with stable intertrochanteric hip fractures and provided data on safety and clinical effects were identified. Demographic characteristics, adverse events and clinical outcomes were manually extracted from all of the selected studies. RESULTS: Nine studies encompassing 914 patients met the inclusion criteria. Overall, the result of meta-analysis indicated that over DHS, PCCP allowed significantly shorter operative time, reduced blood loss as well as transfusion, diminished incidence of cardiovascular events. However, there were no significant differences in length of hospitalization, rate of walking without help, early mortality and other complications. DISCUSSION: Significant differences favoring PCCP were found with regard to operative time, blood loss, transfusion and lower incidence of cardiovascular events. However, owing to the limitations of this systematic review, future RCTs are still needed to confirm this data and the clinical efficiency of PCCP. LEVEL OF EVIDENCE: Level II: low-powered prospective randomized trial. PMID- 23044467 TI - Removal of infected cemented hinge knee prostheses using extended femoral and tibial osteotomies: six cases. AB - Extended femoral and tibial osteotomies were performed to remove infected cemented hinged knee prostheses in five patients (six knees) with a mean age of 72 years (44-85) and a history of multiple knee surgeries. A tibial osteotomy was used to mobilise the distal quadriceps insertion and to release the tibial extension. The femoral component was extracted by downward traction and its cement mantle was cleared through an anterior osteotomy (n=4) or via the distal approach (n=2). The bone flaps were re-approximated by wire cerclage over articulating acrylic spacers. Mean time to re-implantation of a new knee prosthesis was 11 months (6-24). Revision prostheses with cement fixation restricted to the epiphyseal-metaphyseal region were used. Infection recurred in two cases at 16 and 4 months after the prosthetic re-implantation, and was managed by joint fusion for one and irrigation/lavage for the other, respectively. At last follow-up after a mean of 53 months, the mean Parker score was 4 +/- 2, the mean IKS knee score was 66 +/- 25 (28-93), and the mean IKS function score was 7 +/- 16 (0-40). This technique facilitates the removal of infected cemented components of hinge prostheses and of the cement mantle, most notably in the absence of loosening, without compromising re-implantation of a new knee prosthesis. PMID- 23044468 TI - Sigma-1 receptor chaperone and brain-derived neurotrophic factor: emerging links between cardiovascular disease and depression. AB - Epidemiological studies have demonstrated a close relationship between depression and cardiovascular disease (CVD). Although it is known that the central nervous system (CNS) contributes to this relationship, the detailed mechanisms involved in this process remain unclear. Recent studies suggest that the endoplasmic reticulum (ER) molecular chaperone sigma-1 receptor and brain-derived neurotrophic factor (BDNF) play a role in the pathophysiology of CVD and depression. Several meta-analysis studies have showed that levels of BDNF in the blood of patients with major depressive disorder (MDD) are lower than normal controls, indicating that blood BDNF might be a biomarker for depression. Furthermore, blood levels of BDNF in patients with CVD are also lower than normal controls. A recent study using conditional BDNF knock-out mice in animal models of myocardial infarction highlighted the role of CNS-mediated mechanisms in the cardioprotective effects of BDNF. In addition, a recent study shows that decreased levels of sigma-1 receptor in the mouse brain contribute to the association between heart failure and depression. Moreover, sigma-1 receptor agonists, including the endogenous neurosteroid dehydroepiandosterone (DHEA) and the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, show potent cardioprotective and antidepressive effects in rodents, via sigma-1 receptor stimulation. Interestingly, agonist activation of sigma-1 receptors increased the secretion of mature BDNF from its precursor proBDNF via chaperone activity in the ER. Given the role of ER stress in the pathophysiology of CVD and MDD, the author will discuss the potential link between sigma-1 receptors and BDNF-TrkB pathway in the pathophysiology of these two diseases. Finally, the author will make a case for potent sigma-1 receptor agonists and TrkB agonists as new potential therapeutic drugs for depressive patients with CVD. PMID- 23044469 TI - Comparison of kinematics of ACL-deficient and healthy knees during passive flexion and isometric leg press. AB - BACKGROUND: Studying the kinematics of the ACL deficient (ACLD) knees, during different physiological activities and muscle contraction patterns, can improve our understanding of the joint's altered biomechanics due to ACL deficiency as well as the efficacy and safety of the rehabilitations exercises. METHODS: Twenty five male volunteers, including 11 normal and 14 unilateral ACLD subjects, participated in this study. The kinematics of the injured knees of the ACLD subjects was compared with their intact knees and the healthy group during passive flexion and isometric leg press with the knees flexed from full extension to 45 degrees flexion, with 15 degrees intervals. An accurate registration algorithm was used to obtain the three dimensional kinematical parameters, from magnetic resonance images. RESULTS: The ACL deficiency mainly altered the tibial anterior translation, and to some extent its internal rotation, with the change in other parameters not significant. During leg press, the anterior translation of the ACLD knees was significantly larger than that of the normal knees at 30 degrees flexion, but not at 45 degrees . Comparison of the anterior translations of the ACLD knees during leg press with that of the passive flexion revealed improved consistency (CVs changed from 1.2 and 4.0 to 0.6 and 0.6, at 30 degrees and 45 degrees flexion, respectively), but considerable larger translations (means increased by 6.2 and 4.9mm, at 30 degrees and 45 degrees flexion, respectively). CONCLUSION: The simultaneous contraction of the quadriceps and hamstrings during leg press, although reduces the knee laxity, cannot compensate for the loss of the ACL to restore the normal kinematics of the joint, at least during early flexion. PMID- 23044471 TI - Abstract and concrete phrases processing differentially modulates cortico-spinal excitability. AB - An important challenge of embodied theories is to explain the comprehension of abstract sentences. The aim of the present study was to scrutinize the role of the motor cortex in this process. We developed a new paradigm to study the abstract-concrete dimension by combining concrete (i.e., action-related) and abstract (i.e., non-action-related) verbs with nouns of graspable and non graspable objects. Using these verb-noun combinations we performed a Transcranial Magnetic Stimulation (TMS) on the left primary motor cortex while participants performed a sentence sensibility task. Single-TMS pulses were delivered 250ms after verb or noun presentation in each of four combinations of abstract and concrete verbs and nouns. To evaluate cortico-spinal excitability we registered the electromyographic activity of the right first dorsal interosseous muscle. As to verb-noun integration, analysis of motor evoked potentials (MEPs) after TMS pulse during noun presentation revealed greater peak-to-peak amplitude in phrases containing abstract rather than concrete verbs. Response times were also collected and showed that compatible (Concrete-Concrete and Abstract-Abstract) combinations were processed faster than mixed ones; moreover in combinations containing concrete verbs, participants were faster when the pulse was delivered on the first word (verb) than on the second one (noun). Results support previous findings showing early activation of hand-related areas after concrete verbs processing. The prolonged or delayed activation of the same areas by abstract verbs will be discussed in the framework of recent embodied theories based on multiple types of representation, particularly theories emphasizing the role of different acquisition mechanisms for concrete and abstract words (Borghi and Cimatti, 2009,2012). PMID- 23044470 TI - Distinct development of GABA system in the ventral and dorsal horns in the embryonic mouse spinal cord. AB - In the adult brain, gamma-amino butyric acid (GABA) is an inhibitory neurotransmitter, whereas it acts as an excitatory transmitter in the immature brain, and may be involved in morphogenesis. In the present study, we immunohistochemically examined the developmental changes in GABA signaling in the embryonic mouse cervical spinal cord. Glutamic acid decarboxylase and GABA were markers for GABA neurons. Vesicular GABA transporter was a marker for GABAergic and glycinergic terminals. Potassium chloride cotransporter 2 was a marker for GABAergic inhibition. We found five points: (1) In the ventral part, GABA neurons were divided into three groups. The first differentiated group sent commissural axons after embryonic day 11 (E11), but disappeared or changed their transmitter by E15. The second and third differentiated groups were localized in the ventral horn after E12, and sent axons to the ipsilateral marginal zone. There was a distal-to-proximal gradient in varicosity formation in GABAergic axons and a superficial-to-deep gradient in GABAergic synapse formation in the ventral horn; (2) In the dorsal horn, GABA neurons were localized after E13, and synapses were diffusely formed after E15; (3) GABA may be excitatory for several days before synapses formation; (4) There was a ventral-to-dorsal gradient in the development of GABA signaling. The GABAergic inhibitory network may develop in the ventral horn between E15 and E17, and GABA may transiently play crucial roles in inhibitory regulation of the motor system in the mouse fetus; (5) GABA signaling continued to develop after birth, and GABAergic system diminished in the ventral horn. PMID- 23044472 TI - Neuroprotective effect of resveratrol against prenatal stress induced cognitive impairment and possible involvement of Na(+), K(+)-ATPase activity. AB - Resveratrol, an active ingredient of red wine extracts, has been shown to exhibit neuroprotective effects in several experimental models. Hence in the present study, the protective effects of resveratrol on cognitive deficits induced by prenatal stress were evaluated in offspring, and the possible involvement of Na(+), K(+)-ATPase in learning deficits were explored. Pregnant rats were subjected to restraint stress during early or late gestational period. Another set of rats received resveratrol during the entire gestational period along with early or late gestational stress. The study parameters included various behavioral tests like open field test and Morris water maze test. At the end of the behavioral tests (on 40th postnatal day), the offspring were sacrificed, and their brain homogenate was subjected to Na(+), K(+)-ATPase estimation. Early and late gestational stress affected spatial learning and memory and prenatal resveratrol has reversed these cognitive deficits. The Na(+), K(+)-ATPase activity in the offspring brain homogenate was reduced in the late gestational stress group; however prenatal resveratrol treatment has not affected this activity. These data suggest the neuroprotective efficacy of resveratrol against prenatal stress induced cognitive impairment. Though late gestational stress involves Na(+), K(+)-ATPase activity in rat brain homogenate, this would not be the primary cause in prenatal stress-induced cognitive dysfunction. PMID- 23044473 TI - Bayesian network as an aid for Food Chain Information use for meat inspection. AB - Current ante mortem inspection involves a check of relevant Food Chain Information (FCI) transmitted by the farmer to the slaughterhouse on a regulatory FCI document. Since 2000, a farm sanitary form with FCI data has been used for all consignments of broiler chickens in France. However, the FCI needs to be standardized for the collection and interpretation of data. A study was conducted to develop an expert system, undertaken to elaborate on a simple decision support system capable of predicting whether the flocks will present a high condemnation risk, based on FCI. For this, 'optimal' (i.e. on-farm survey data) and 'worthy' (i.e. farmers' declaration on existing farm sanitary form) data quality conditions were considered to estimate the lower and upper reference bounds of the confidence that the decision-makers could have in such a tool. Chicken broiler flocks (404) were randomly selected in 15 slaughterhouses located in Western France in 2005. Condemnation proportion and farm sanitary form were collected for each selected flock. Information about health history and technical performances were also specifically collected on farm. Condemnation risk category was modelled from the on-farm collected information, using a Bayesian network and assuming this represented the optimal data quality conditions. Corresponding information declared by the farmer on the existing farm sanitary form was secondly used in the network to evaluate the impact of the uncertainty of such information on the condemnation classification obtained with the expert system. The learnt Bayesian network had 16 explanatory variables pertaining to technical characteristics and sanitary features of the flock. Using a threshold of 1% of condemned carcases to define high risk, the network sensitivity and specificity were 55% and 93%, respectively, corresponding to positive and negative predictive values of 70% and 87%. When declared existing information was used in the network, the sensitivity and specificity were 16% and 96%, respectively, corresponding to positive and negative predictive values of 57% and 80%. Results suggested that the predictive network developed may be insufficient for correctly classifying chicken flocks for targeting of management procedures, and in its current form, the expert system may be unlikely to be implemented in the field. However, it could help to improve the standardization of both form design and FCI interpretation at a national level. PMID- 23044474 TI - Quantitative risk assessment of human campylobacteriosis by consumption of salad cross-contaminated with thermophilic Campylobacter spp. from broiler meat in Argentina. AB - Here, we developed a quantitative risk assessment for thermophilic Campylobacter spp. related to the consumption of salad prepared alongside broiler meat. The assessment considered initial contamination levels, cross-contamination and decontamination events during the broiler slaughter process and distribution, and storage and consumption patterns in Argentina and other Latin American countries. The model predicted an infection risk of 3.32*10(-4) per serving. This estimation was variable according to the dose-response model used. Considering the number of chickens slaughtered annually in Argentina, the estimated number of people who could suffer campylobacteriosis related to poultry meat consumption was, on average, 484,304. The risk of human campylobacteriosis was most sensitive to the probability of infection from a Campylobacter (r=0.72), the number of Campylobacter spp. per serving (r=0.40), the frequency of washing the cutting board (r=-0.31), the preparation of raw poultry before salad using the same cutting board (r=0.14), and the frequency of hand washing (r=-0.14). The most sensitive stages of the process identified through the risk assessment can be used as a basis for measures of risk management. Public campaigns on hygiene habits during food preparation at home should focus on the importance of washing the cutting board before preparing raw and ready-to-eat foods and of washing the hands during food preparation. PMID- 23044475 TI - Prevalence of zoonotic intestinal parasites in domestic and stray dogs in a rural area of Iran. AB - Certain zoonotic parasites are enteropathogens in dogs that cause serious human disease such as cystic echinococcosis, human alveolar echinococcosis, visceral larva migrans, and ocular larva migrans. This study investigated the prevalence of intestinal parasites in dogs in the Chenaran County, Razavi Khorasan Province, Iran. Sampling was carried out randomly in 17 villages from November 2009 to January 2010. Seventy-seven fecal samples from 28 domestic and 49 stray dogs were examined using sieving/flotation and modified Ziehl-Neelsen staining. Intestinal parasites were found in 51 of the 77 (66%) dogs most common being Toxascaris leonina (29%, 22/77), Toxocara spp. (25%, 19/77), Eimeria spp. (19%, 15/77), Taenia/Echinococcus spp. (18%, 14/77), Sarcocystis spp. (17%, 13/77), and Dicrocoelium dendriticum (14%, 11/77). Lower infection rates of parasites were observed for Trichuris vulpis (6%, 5/77), Cryptosporidium spp. (5%, 4/77), and Physaloptera spp. (3%, 2/77). Prevalence of infection by Dipylidium caninum, Capillaria spp., Cystoisospora spp., and hookworms was similar (1%, 1/77). This study is the first report of the prevalence of intestinal parasites of domestic and stray dogs in Chenaran County, Northeast Iran. The higher prevalence of zoonotic intestinal parasites such as Toxascaris leonina, Toxocara spp. and Taenia/Echinococcus spp. compared to other parasites indicates the need for control programs to minimize the risk of transmission of zoonotic disease, particularly cystic echinococcosis, alveolar echinococcosis, visceral larva migrans, and ocular larva migrans to people living in these areas. PMID- 23044476 TI - The atomic structure of the threefold surface of the icosahedral Ag-In-Yb quasicrystal. AB - We report a study of the atomic structure of the threefold icosahedral (i-)Ag-In Yb quasicrystal surface using scanning tunneling microscopy (STM) and low energy electron diffraction (LEED). The LEED confirms that the surface exhibits quasicrystalline long-range order with the threefold symmetry expected from the bulk. The STM reveals large atomically flat terraces separated by steps of different heights. A comparison of atomically resolved STM images for the terraces and the step-height distribution with the bulk structure of isostructural i-Cd-Yb shows that the terraces are formed at bulk planes intersecting the centers of the rhombic triacontahedral clusters that make up the bulk structure of the system. However, the stability of particular terraces may be influenced by the density of atoms in the interstices (glue atoms that bind the clusters) in the terraces and also by the chemical environment in the underlying atomic plane. The surface exhibits screw dislocations, which is explained in terms of a continuous atomic density along the threefold axis. PMID- 23044477 TI - The effect of the dorsal intercarpal ligament on lunate extension after distal scaphoid excision. AB - PURPOSE: After a distal scaphoid excision, most wrists develop a mild form of carpal instability-nondissociative with dorsal intercalated segment instability. Substantial dysfunctional malalignment is only occasionally seen. We hypothesized that distal scaphoid excision would lead to carpal instability-nondissociative with dorsal intercalated segment instability in cadavers and that the dorsal intercarpal (DIC) ligament plays a role in preventing such complications. METHODS: We used 10 cadaver upper extremities in this experiment. A customized jig was used to load the wrist with 98 N. Motion of the capitate and lunate was monitored using the Fastrak motion tracking system. Five specimens had a distal scaphoid excision first, followed by excision of the DIC ligament, whereas the other 5 specimens first had excision of the DIC ligament and then had a distal scaphoid excision. Rotation of the lunate and capitate was calculated as a sum of the relative motions between each intervention and was compared with its original location before intervention (control) for statistical analysis. RESULTS: Distal scaphoid excision and subsequent DIC ligament excision both led to significant lunate extension. DIC ligament excision alone resulted in lunate flexion that was not statistically significant. After DIC ligament excision, distal scaphoid excision led to significant lunate extension. Capitate rotation was minimal in both groups, verifying that the overall wrist position did not change with loading. CONCLUSIONS: Distal scaphoid excision leads to significant lunate extension through an imbalance in the force couple between the scaphotrapeziotrapezoidal joint and the triquetrum-hamate joint. The DIC ligament may serve as a secondary stabilizer to the lunocapitate joint and prevent further lunate extension with the wrist in neutral position. CLINICAL RELEVANCE: The development of a clinically symptomatic carpal instability-nondissociative with dorsal intercalated segment instability with lunocapitate subluxation after distal scaphoid excision may be due to an incompetent DIC ligament. PMID- 23044478 TI - A systematic review of the outcomes of distal upper extremity bypass surgery with arterial and venous conduits. AB - PURPOSE: To conduct a systematic review of literature evaluating efficacy of venous and arterial grafts for distal upper extremity bypass surgery. METHODS: A PubMed search using MeSH terms "veins/surgery" OR "arteries/surgery" AND "radial artery/surgery" OR "ulnar artery/surgery" yielded 794 studies. Manual review produced 42 studies based on inclusion criteria of reported distal upper extremity bypass surgery, complete information on graft type used, examined patency of reconstruction, and described method for determining patency. Studies meeting inclusion criteria underwent data extraction focusing on demographics, revascularization site, conduit type, microsurgical technique, subjective/objective outcomes, and postoperative anticoagulation regimens. RESULTS: Sixteen studies met the inclusion criteria. In 145 patients, 152 grafts were performed for upper extremity revascularization, including 120 grafts for revascularization of distal ulnar artery circulation, 31 for distal radial artery circulation, and 1 for both distal ulnar and radial artery occlusions. Overall patency rate was 87% at an average follow-up of 34 months. Of 152 bypass grafts, 19 were arterial conduits. Donor sites included the deep inferior epigastric artery, subscapular artery, thoracodorsal artery, and descending branch of the lateral femoral circumflex artery. At a mean follow-up of 18 months, arterial conduit patency was 100%. The remaining 133 bypass procedures used vein grafts from various donor sites, including the saphenous, cephalic, and basilic veins. At an average follow-up of 37 months, overall vein graft patency rate was 85%. There was a statistically significant difference between patency rates of arterial conduits compared with venous conduits. All studies reported improved ischemic symptoms including reduction of cold sensitivity, pain, and digital ulceration. CONCLUSIONS: This review showed a high patency rate and clinical efficacy of distal upper extremity bypass surgery with a mean follow-up of almost 3 years. There may be a benefit of using arterial versus venous conduits, although further examination is needed given the small number of arterial reconstructions reported. PMID- 23044479 TI - Treatment of unstable distal ulna fractures associated with distal radius fractures in patients 65 years and older. AB - PURPOSE: To prospectively compare the clinical and radiological outcomes of 2 treatment methods for unstable distal ulna fractures associated with distal radius fractures in patients 65 years of age and older. METHODS: From February 2008 to March 2010, the first 29 ulnas were treated surgically (group 1) and the next 32 ulnas were treated nonoperatively (group 2). The mean final follow-up period was 34 months (range, 24-56 mo). All radiuses were fixed internally, in both groups. Clinical outcomes were compared between groups using a visual analog scale for postoperative pain; Disabilities of the Arm, Shoulder, and Hand scores; active range of motion; grip strength; and the modified system of Gartland and Werley. Radiological outcomes, including ulnar variance, were evaluated. Arthrosis was evaluated at the radiocarpal joint or distal radioulnar joint (DRUJ) according to the system of Knirk and Jupiter. RESULTS: There were no significant differences between the groups in any of the clinical outcomes. No significant differences were observed for radiological outcomes including ulnar variance, distal radius, and union rate. There were no patients in either group with symptomatic arthritic changes in the radiocarpal joint or DRUJ at the final follow-up. In group 2, 1 patient had malunion (angulated, 14 degrees ) on the anteroposterior view without evidence of arthrosis in the DRUJ, and functional outcomes were good. CONCLUSIONS: In this population distal ulna fractures can be successfully managed nonoperatively when they occur in combination with distal radius fractures. PMID- 23044480 TI - Factors affecting outcome of triceps motor branch transfer for isolated axillary nerve injury. AB - PURPOSE: Triceps motor branch transfer has been used in upper brachial plexus injury and is potentially effective for isolated axillary nerve injury in lieu of sural nerve grafting. We evaluated the functional outcome of this procedure and determined factors that influenced the outcome. METHODS: A retrospective chart review was performed of 21 patients (mean age, 38 y; range, 16-79 y) who underwent triceps motor branch transfer for the treatment of isolated axillary nerve injury. Deltoid muscle strength was evaluated using the modified British Medical Research Council grading at the last follow-up (mean, 21 mo; range, 12-41 mo). The following variables were analyzed to determine whether they affected the outcome of the nerve transfer: the age and sex of the patient, delay from injury to surgery, body mass index (BMI), severity of trauma, and presence of rotator cuff lesions. The Spearman correlation coefficient and multiple linear regression were performed for statistical analysis. RESULTS: The average Medical Research Council grade of deltoid muscle strength was 3.5 +/- 1.1. Deltoid muscle strength correlated with the age of the patient, delay from injury to surgery, and BMI of the patient. Five patients failed to achieve more than M3 grade. Among them, 4 patients were older than 50 years and 1 was treated 14 months after injury. In the multiple linear regression model, the delay from injury to surgery, age of the patient, and BMI of the patient were the important factors, in that order, that affected the outcome of this procedure. CONCLUSIONS: Isolated axillary nerve injury can be treated successfully with triceps motor branch transfer. However, outstanding outcomes are not universal, with one fourth failing to achieve M3 strength. The outcome of this procedure is affected by the delay from injury to surgery and the age and BMI of the patient. PMID- 23044481 TI - Simultaneous dislocation of the radiocapitellar and distal radioulnar joints without fracture: case report. AB - Simultaneous dislocation of the distal radioulnar joint and the radial head without fracture is an uncommon injury. Prior reports have described closed treatment of this injury. We report a case of paired dislocation without fracture that required open reduction of both articulations in the acute setting. Potential mechanisms responsible for this pattern and recommendations for management of similar patients are described. PMID- 23044482 TI - Protecting and expanding Medicaid. PMID- 23044484 TI - A documentation policy development proposal for clinicians caring for people living with HIV/AIDS. AB - In Canada, nondisclosure prosecutions against people living with HIV/AIDS (PHAs) have increased. Nurses who provide services to PHAs could become involved in such criminal cases because they (a) elicit sensitive information about their clients' sexual practices, and (b) adhere to documentation standards. Currently, HIV documentation policies do not exist for clinicians working with PHAs in Canada or abroad. Sexual assault nursing, which includes documentation guidelines, may offer guidance in the creation of a PHA care policy because sexual assault nursing and PHA care both intersect with the justice system. A PHA care policy may have several benefits: It can increase clinician confidence in patient interactions and documentation by clarifying roles and scope of responsibilities, reduce inconsistencies in practice, diminish conflict among professionals, and reduce the stress involved in clinical practice. The outcome of these improvements could be an increase in PHAs' level of comfort with nurses knowing that policies exist. PMID- 23044483 TI - Political climate and smoke-free laws in rural Kentucky communities. AB - The purpose was to determine factors associated with rural communities' political readiness to enact smoke-free laws. Data from baseline assessment of a longitudinal intervention study to promote smoke-free policy in rural Kentucky communities; key informants (n = 144) and elected officials (n = 83) from 29 counties participated in cross-sectional telephone interviews. Controlling for population size and county-level smoking rate, the following factors predicted elected officials' perception of the likelihood of a local smoke-free law passing in the next 12 months: (1) support from the local board of health; (2) support from local leaders; and (3) smoke-free hospitals. Communities with lower adult smoking prevalence were more ready for smoke-free laws. Rural health advocates can increase political readiness for smoke-free laws by educating and engaging Board of Health members and local leaders, promoting the voluntary adoption of smoke-free policies in rural hospitals, and investing in effective population based approaches to evidence-based tobacco treatment in rural communities. PMID- 23044485 TI - The regulation of dietary supplements in the United States: advocating for a reasonable approach, protecting patient safety, and the role of nursing. AB - Many Americans report using dietary supplements (DS) and there is evidence that the use of such products is increasing. Under the current regulatory system DS are not tested for safety or effectiveness, as with over the counter and prescription drugs, and the Food and Drug Administration (FDA) has limited authority to protect Americans from potential harm. DS in the United States have become a major public health and patient safety issue with injuries, illnesses, and deaths attributed to their use. Efforts in congress to legislate safer regulations have been met with limited success, in part because of the lobbying efforts of the DS industry. Although there is near consensus in the literature and among stakeholder government agencies that a modified FDA role is needed, resolving the issue requires a multifaceted approach. Along with political and legislative action, effort must be made to increase the American public's knowledge of DS. PMID- 23044486 TI - Complexation between triptycene-based macrotricyclic host and pi-extended viologens: formation of supramolecular poly[3]pseudorotaxanes. AB - Triptycene-based macrotricyclic host containing two dibenzo-30-crown-10 moieties could form ladder-like supramolecular poly[3]pseudorotaxanes with pi-extended viologens in both high concentration solution and solid state. PMID- 23044487 TI - GCN5 acetylates and regulates the stability of the oncoprotein E2A-PBX1 in acute lymphoblastic leukemia. AB - The t(1;19) translocation in pediatric pre-B-cell acute lymphoblastic leukemia (ALL) fuses the genes, which encode the transcriptional activator E2A and homeobox pre-B-cell leukemia transcription factor 1 (PBX1), resulting in expression of the chimeric transcription factor E2A-PBX1. E2A-PBX1 can promote cell transformation both in vitro and in vivo; however, the mechanisms by which E2A-PBX1 contributes to malignancy merit further investigation. In the current work we report, for the first time, a physical and functional interaction between the SPT3-TAFII31-GCN5L acetylase (STAGA) complex and E2A-PBX1. STAGA, and its acetyltransferase subunit GCN5, directly interacted with the E2A portion of E2A PBX1. GCN5 acetylated E2A-PBX1 and increased the stability of E2A-PBX1 protein in cells. Moreover, the GCN5 inhibitor alpha-methylene-gamma-butyrolactone 3 (MB-3) decreased E2A-PBX1 acetylation and E2A-PBX1 protein levels in leukemic cells, indicating that GCN5 inhibitors have potential value as therapeutic agents for ALL. In addition, we show that the E3 ubiquitin ligase HDM2 potentiates the degradation of E2A-PBX1. We suggest that dynamic regulation of E2A-PBX1 protein levels in vivo has a fundamental role in ALL. PMID- 23044488 TI - Amino acid residues at the N- and C-termini are essential for the folding of active human butyrylcholinesterase polypeptide. AB - Human serum butyrylcholinesterase (HuBChE) is currently the most suitable bioscavenger for the prophylaxis of highly toxic organophosphate (OP) nerve agents. A dose of 200mg of HuBChE is envisioned as a prophylactic treatment that can protect humans from an exposure of up to 2 * LD50 of soman. The limited availability and administration of multiple doses of this stoichiometric bioscavenger make this pretreatment difficult. Thus, the goal of this study was to produce a smaller enzymatically active HuBChE polypeptide (HBP) that could bind to nerve agents with high affinity thereby reducing the dose of enzyme. Studies have indicated that the three-dimensional structure and the domains of HuBChE (acyl pocket, lip of the active center gorge, and the anionic substrate binding domain) that are critical for the binding of substrate are also essential for the selectivity and binding of inhibitors including OPs. Therefore, we designed three HBPs by deleting some N- and C-terminal residues of HuBChE by maintaining the folds of the active site core that includes the three active site residues (S198, E325, and H438). HBP-4 that lacks 45 residues from C-terminus but known to have BChE activity was used as a control. The cDNAs for the HBPs containing signal sequences were synthesized, cloned into different mammalian expression vectors, and recombinant polypeptides were transiently expressed in different cell lines. No BChE activity was detected in the culture media of cells transfected with any of the newly designed HBPs, and the inactive polypeptides remained inside the cells. Only enzymatically active HBP-4 was secreted into the culture medium. These results suggest that residues at the N- and C-termini are required for the folding and/or maintenance of HBP into an active stable, conformation. PMID- 23044489 TI - Ketamine combinations for the field treatment of soman-induced self-sustaining status epilepticus. Review of current data and perspectives. AB - Organophosphorus nerve agents (NA), potent irreversible cholinesterase inhibitors, could induce severe seizures, status epilepticus (SE), seizure related brain damage (SRBD) and lethality. Despite the lack of data in the case of NA, clinical evidences suggest that SE survivors could suffer from neurological/cognitive deficits and impairments such as spontaneous recurrent seizures (epilepsy) after a latent period of epileptogenesis. It is beyond doubt that an effective and quick management of the initial seizures and prevention of SRBD are critical to prevent these long-term consequences, explaining why most experimental data are focusing on the 5-40min post-exposure time frame. However, in field conditions, treatment may be delayed and with the exception of NMDA receptor antagonists, currently no drug provides protection (against lethality, seizures, SRBD and neurological consequences) when seizures are left unabated for one hour or more. Ketamine (KET) is the only NMDA antagonist licensed as an injectable drug in different countries and remains an anesthetic of choice in some difficult field conditions. In this short review paper, after a presentation of some of the key points of the pathophysiology of NA-induced SE and a quick survey of the potential therapeutic avenues in the context of delayed treatment of NA-induced SE, we will review the recent data we obtained showing that KET, in combination with atropine sulfate (AS), with or without a benzodiazepine, considerably reduces soman-induced neuroinflammation, provides neuroprotection, histologically and functionally, and also positively modify soman-induced changes in brain metabolism. Finally, we will also mention some results from safety studies including those bringing evidence that, at difference with MK-801, KET does not impair thermoregulation and even seems to reduce AS-induced heat stress. All in all, KET, in combination, appears a good candidate for the out-of-hospital treatment of severe NA-induced SE. PMID- 23044492 TI - Vibrons in finite size molecular lattices: a route for high-fidelity quantum state transfer at room temperature. AB - A communication protocol is proposed in which vibron-mediated quantum state transfer takes place in a molecular lattice. We consider two distant molecular groups grafted on each side of the lattice. These groups form two quantum computers where vibrational qubits are implemented and received. The lattice defines the communication channel along which a vibron delocalizes and interacts with a phonon bath. Using quasi-degenerate perturbation theory, vibron-phonon entanglement is taken into account through the effective Hamiltonian concept. A vibron is thus dressed by a virtual phonon cloud whereas a phonon is clothed by virtual vibronic transitions. It is shown that three quasi-degenerate dressed states define the relevant paths followed by a vibron to tunnel between the computers. When the coupling between the computers and the lattice is judiciously chosen, constructive interference takes place between these paths. Phonon-induced decoherence is minimized and a high-fidelity quantum state transfer occurs over a broad temperature range. PMID- 23044493 TI - Computed tomography colonography: emerging evidence to further support clinical effectiveness. AB - PURPOSE OF REVIEW: Computed tomography colonography (CTC) continues to mature and evolve as a noninvasive imaging test of the large intestine. The aim of this review is to provide an update on the recent and emerging data that further supports the clinical effectiveness of CTC. RECENT FINDINGS: The diagnostic performance of CTC for detecting colorectal polyps and masses is well established, but its precise clinical role is yet to be determined. Recent data on test performance, patient acceptance, and study technique may help to clarify the role of CTC and accelerate its clinical implementation. SUMMARY: Recent advances and refinements in CTC should help to clarify and expand its clinical role, both as a screening and diagnostic test. High patient acceptance for CTC could lead to increased adherence rates. Ultimately, the complementary nature of CTC and optical colonoscopy should result in improved patient care. PMID- 23044495 TI - Somatosensory cortical plasticity after toe-to-index transfer. AB - We quantified and compared neuroimaging data and behavioral data (cortical plasticity and hand sensibility, respectively) from a patient who underwent toe to-index transplantation. Magnetoencephalographic (MEG) recordings of somatosensory-evoked fields (SEFs) response to mechanical tactile stimulation of the index and little fingers of both hands were obtained in parallel with a hand sensibility test from the patient at multiple sessions (week 4, 12, and 24 after the operation). Cortical plasticity refers to SEFs' latency, dipole strength, and primary somatosensory representation, and the Euclidean distance between primary somatosensory representations of the index and the little fingers. Hand sensibility refers to a patient's conscious perception of tactile stimulation applied to the transplanted index finger and scored by Semmes-Weinstein monofilaments. SEFs recordings from six healthy participants at one session were used for comparative purposes. At week 4, although the patient had no conscious perception in the left transplanted index to tactile stimulation, SEFs were recorded in response to tactile stimulation. At weeks 12 and 24, the Euclidean distance between primary somatosensory representations of the transplanted index and little fingers increased, together with SEFs dipole strength, whereas SEFs latencies decreased. These occurred in parallel to improvement in hand sensibility. Primary somatosensory representations of the index and little fingers of the patient's intact right hand were similar to those of the healthy participants' right hand, indicating the consistency of MEG recording during the follow-up sessions. In conclusion, a combination of neuroimaging and behavioral data may be essential for better assessment of functional recovery after a toe-to digit operation because the cortical recovery observed by MEG preceded that of hand sensibility observed clinically. PMID- 23044494 TI - Genetic variation in innate immunity and inflammation pathways associated with lung cancer risk. AB - BACKGROUND: Pulmonary inflammation may contribute to lung cancer etiology. The authors conducted a broad evaluation of the association of single nucleotide polymorphisms (SNPs) in innate immunity and inflammation pathways with lung cancer risk and conducted comparisons with a lung cancer genome-wide association study (GWAS). METHODS: In total, 378 patients with lung cancer (cases) and a group of 450 controls from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were included. A proprietary oligonucleotide pool assay was used to genotype 1429 SNPs. Odds ratios and 95% confidence intervals were estimated for each SNP, and P values for trend (P(trend) ) were calculated. For statistically significant SNPs (P(trend) < .05), the results were replicated with genotyped or imputed SNPs in the GWAS, and P values were adjusted for multiple testing. RESULTS: In the PLCO analysis, a significant association was observed between lung cancer and 81 SNPs located in 44 genes (P(trend) < .05). Of these 81 SNPS, there was evidence for confirmation in the GWAS for 10 SNPs. However, after adjusting for multiple comparisons, the only SNP that retained a significant association with lung cancer in the replication phase was reference SNP rs4648127 (nuclear factor of kappa light polypeptide gene enhancer of B-cells 1 [NFKB1]) (multiple testing-adjusted P(trend) = .02). The cytosine-thymine (CT)/TT genotype of NFKB1 was associated with reduced odds of lung cancer in the PLCO study (odds ratio, 0.56; 95% confidence interval, 0.37-0.86) and the in the GWAS (odds ratio, 0.79; 95% confidence interval, 0.69-0.90). CONCLUSIONS: A significant association was observed between a variant in the NFKB1 gene and the risk of lung cancer. The current findings add to evidence implicating inflammation and immunity in lung cancer etiology. PMID- 23044496 TI - Machine learning classifier using abnormal brain network topological metrics in major depressive disorder. AB - Resting state functional brain networks have been widely studied in brain disease research. However, it is currently unclear whether abnormal resting state functional brain network metrics can be used with machine learning for the classification of brain diseases. Resting state functional brain networks were constructed for 28 healthy controls and 38 major depressive disorder patients by thresholding partial correlation matrices of 90 regions. Three nodal metrics were calculated using graph theory-based approaches. Nonparametric permutation tests were then used for group comparisons of topological metrics, which were used as classified features in six different algorithms. We used statistical significance as the threshold for selecting features and measured the accuracies of six classifiers with different number of features. A sensitivity analysis method was used to evaluate the importance of different features. The result indicated that some of the regions exhibited significantly abnormal nodal centralities, including the limbic system, basal ganglia, medial temporal, and prefrontal regions. Support vector machine with radial basis kernel function algorithm and neural network algorithm exhibited the highest average accuracy (79.27 and 78.22%, respectively) with 28 features (P<0.05). Correlation analysis between feature importance and the statistical significance of metrics was investigated, and the results revealed a strong positive correlation between them. Overall, the current study demonstrated that major depressive disorder is associated with abnormal functional brain network topological metrics and statistically significant nodal metrics can be successfully used for feature selection in classification algorithms. PMID- 23044497 TI - Publication subsidies: challenges and dilemmas facing South African researchers. PMID- 23044498 TI - Comparison of the effects of gelatin, Ringer's solution and a modern hydroxyl ethyl starch solution after coronary artery bypass graft surgery. AB - OBJECTIVE: The aim of this study was to compare the effect of 6% hydroxyl ethyl starch solution with 4% gelatin and Ringer's solutions on the haemodynamic stability of patients after coronary artery bypass graft (CABG) surgery and immediately after discontinuation of cardiopulmonary bypass (CPB). METHODS: This was a randomised, double-blind clinical trial of 92 patients who were candidates for on-pump CABG. After discontinuation of CPB, all patients were transferred to the intensive care unit (ICU) and divided randomly into three groups. The first group received Ringer's solution, the second group 4% gelatin, and the third 6% hydroxyl ethyl starch (HES) solution (Voluven). Haemodynamic parameters such as heart rate, mean arterial pressure, systolic blood pressure, diastolic blood pressure, central venous pressure, cardiac output and the presence of arrhythmias were documented. RESULTS: The volume needed for maintaining normal blood pressure and central venous pressure in the range of 10-14 mmHg was less in the HES group than in the other groups. The volume was similar however in the gelatin and Ringer's groups in the first 24 hours after surgery. Urinary output in the first four and 24 hours after surgery were significantly higher in the HES group than in the other two groups. Mean creatinine levels were significantly lower in the HES group. CONCLUSION: HES (6%) had a better volume-expanding effect than gelatin (4%) and Ringer's solutions, and its short-term effects on renal function were also better than gelatin and Ringer's solutions. PMID- 23044499 TI - Association of waist circumference, body mass index and conicity index with cardiovascular risk factors in postmenopausal women. AB - In menopause, changes in body fat distribution lead to increasing risk of cardiovascular disease and metabolic disorders. The aim of this study was to assess the association of adiposity using the conicity index (CI), body mass index (BMI) and waist circumference (WC) with cardiovascular risk factors (hypertension, diabetes and dyslipidaemia). The sample of this cross-sectional study was collected from June to October 2010 and 165 consecutive menopausal women who had attended the Health and Treatment Centre and Endocrine Research Centre of Firoozgar Hospital in Tehran, Iran were assessed. Age, weight, height, WC, waist-hip ratio (WHR), CI and fat mass were measured. Systolic and diastolic blood pressure (SBP and DBP), fasting blood glucose, insulin, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) levels were also determined. All statistical analyses were performed by SPSS version 17 (SPSS Inc, Chicago, IL, USA). Results showed that BMI was positively and significantly associated with SBP (r = 0.21; p = 0.009). WC was positively and significantly correlated with SBP (r = 0.26; p = 0.02) and DBP (r = 0.16; p = 0.05). WHR was also significantly and positively associated with SBP (r = 0.29; p = 0.001). Age and WC were associated with CI quartiles at the 0.05 significance level. The correlation of CI quartiles with SBP and weight were at the 0.01 significance level. We showed a significant association of WC with SBP and DBP, and that BMI could be an important determining factor of SBP. For assessing the association between CI and cardiovascular risk factors, future studies with larger sample sizes are recommended. PMID- 23044500 TI - Accuracy of D-dimer:fibrinogen ratio to diagnose pulmonary thromboembolism in patients admitted to intensive care units. AB - INTRODUCTION: Pulmonary thromboembolism (PTE) may increase D-dimer and decrease fibrinogen levels. However, in settings such as intensive care units (ICU) and in long-term hospitalised patients, several factors may influence D-dimer and fibrinogen concentrations and make them unreliable indicators for the diagnosis of PTE. The aim of this study was to evaluate the accuracy of D-dimer:fibrinogen ratio (DDFR) for the diagnosis of PTE in ICU patients. METHODS: ICU patients who were suspected of having a first PTE and had no history of using anti-coagulants and contraceptives were included in the study. Levels of D-dimer and fibrinogen were measured for each patient prior to any intervention. Angiography or CT angiography was done in order to establish a definite diagnosis for each patient. Suitable analytical tests were performed to compare means. RESULTS: Eighty-one patients were included in the study, of whom 41 had PTE and 40 did not. Mean values of D-dimer and fibrinogen were 3.97 +/- 3.22 ug/ml and 560.6 +/- 197.3 mg/dl, respectively. Significantly higher levels of D-dimer (4.65 +/- 3.46 vs 2.25 +/- 2.55 ug/ml, p = 0.006) and DDFR (0.913 +/- 0.716 vs 483 +/- 0.440 * 10 (3), p = 0.003) were seen in PTE patients than in those without PTE. Receiver operating characteristic (ROC) analysis showed a 70.3% sensitivity and 70.1% specificity with a D-dimer value of 2.43 ug/ml (AUC = 0.714, p = 0.002) as the best cut-off point; and a 70.3% sensitivity and 61.6% specificity with a DDFR value of 0.417 * 10-(3) (AUC = 0.710, p = 0.004) as the best cut-off point. In backward stepwise regression analysis, DDRF (OR = 0.72, p = 0.025), gender (OR = 0.76, p = 0.049) and white blood cell count (OR = 1.11, p = 0.373) were modelled (p = 0.029, R(2) = 0.577). CONCLUSION: For diagnosis of PTE, DDFR can be considered to have almost the same importance as D-dimer level. Moreover, it was possible to rule out PTE with only a D-dimer cut-off value < 0.43 mg/dl, without the use of DDFR. However, these values cannot be used as a replacement for angiography or CT angiography. PMID- 23044501 TI - Role of four-week resistance exercise in preserving the heart against ischaemia reperfusion-induced injury. AB - OBJECTIVE: We studied the cardioprotective effect of resistance training against ischaemia-reperfusion-induced injury. METHODS: Forty male rats were divided into trained and sedentary groups (n = 20 for each). The trained rats were exercised at 12 repetitions/set, four sets/day and five days/week for four weeks. Transient regional ischaemia of the left anterior descending coronary artery (40 min) was followed by 80 min of reperfusion. RESULTS: Baseline developed and diastolic pressures and coronary flow were similar in the two groups. While diastolic pressure increased and developed pressure and coronary flow decreased in both the ischaemic and perfusion periods (as indices of cardiac damage), there were no statistically significant differences between the trained and sedentary groups in these parameters. Resistance training did not significantly change the infarct size and apoptosis rate. CONCLUSION: We did not see a cardioprotective effect of resistance exercise against ischaemia-reperfusion-induced injury in this study. A precise conclusion about this issue needs more investigations. PMID- 23044502 TI - The effect of the first office blood pressure reading on hypertension-related clinical decisions. AB - The effect of the first office blood pressure reading (FBPR) on hypertension related decisions was evaluated using blood pressure (BP) readings taken with the BpTRU BPM-100 device. BP readings were grouped into three pairs: (1) single readings (first and second readings), (2) computed average of three readings (one including and one excluding the first reading), and (3) computed average of five readings (one including and one excluding the first reading). Categorisation of BP readings under JNC-7 classes and distribution into < 140/90 and >= 140/90 mmHg groups were selected as parameters guiding hypertension-related decisions. Readings including FBPR had strong positive correlations to those excluding FBPR (Pearson's correlation coefficient ranged from 0.86-1.00). Also, FBPR-included and FBPR-excluded readings did not differ statistically in JNC-7 categorisation or distribution into < 140/90 or >= 140/90 mmHg groups. Our findings suggest that exclusion of FBPR may have no significant impact on hypertension-related clinical decisions. PMID- 23044504 TI - A systematic overview of prospective cohort studies of cardiovascular disease in sub-Saharan Africa: reply to Bovet et al., and Gao et al. PMID- 23044503 TI - The effects of medicinal plants on renal function and blood pressure in diabetes mellitus. AB - Diabetes mellitus is one of the most common chronic global diseases affecting children and adolescents in both the developed and developing nations. The major types of diabetes mellitus are type 1 and type 2, the former arising from inadequate production of insulin due to pancreatic beta-cell dysfunction, and the latter from reduced sensitivity to insulin in the target tissues and/or inadequate insulin secretion. Sustained hyperglycaemia is a common result of uncontrolled diabetes and, over time, can damage the heart, eyes, kidneys and nerves, mainly through deteriorating blood vessels supplying the organs. Microvascular (retinopathy and nephropathy) and macrovascular (atherosclerotic) disorders are the leading causes of morbidity and mortality in diabetic patients. Therefore, emphasis on diabetes care and management is on optimal blood glucose control to avert these adverse outcomes. Studies have demonstrated that diabetic nephropathy is associated with increased cardiovascular mortality. In general, about one in three patients with diabetes develops end-stage renal disease (ESRD) which proceeds to diabetic nephropathy (DN), the principal cause of significant morbidity and mortality in diabetes. Hypertension, a well-established major risk factor for cardiovascular disease contributes to ESRD in diabetes. Clinical evidence suggests that there is no effective treatment for diabetic nephropathy and prevention of the progression of diabetic nephropathy. However, biomedical evidence indicates that some plant extracts have beneficial effects on certain processes associated with reduced renal function in diabetes mellitus. On the other hand, other plant extracts may be hazardous in diabetes, as reports indicate impairment of renal function. This article outlines therapeutic and pharmacological evidence supporting the potential of some medicinal plants to control or compensate for diabetes-associated complications, with particular emphasis on kidney function and hypertension. PMID- 23044505 TI - High patient compliance with nicacin/laropiprant in large clinical trial: interim safety and tolerability results from HPS-2 THRIVE study released at 2012 ESC congress: drug trends in cardiology. PMID- 23044506 TI - Increasing pneumococcal vaccination for immunosuppressed patients: a cluster quality improvement trial. AB - OBJECTIVE: Pneumococcal vaccination is important for patients taking immunosuppressive medications, but prior studies suggest that most patients do not undergo vaccination. The aim of this study was to evaluate the effects of a point-of-care paper reminder form as a quality improvement (QI) strategy to increase the numbers of immunosuppressed patients being kept up-to-date with pneumococcal vaccination in a rheumatology practice. METHODS: Selected rheumatologists at 5 ambulatory practice sites received a point-of-care paper reminder form to be applied to patients who were not up-to-date with pneumococcal vaccination. Interrupted time-series analyses were used to measure the effect of the intervention on the pneumococcal vaccination rates among patients, comparing the rates in the intervention group with those in a control group of rheumatologists who did not receive the intervention. Adjusted Cox proportional hazards models were examined to identify independent predictors of being up-to date with pneumococcal vaccination. RESULTS: We evaluated a total of 3,717 patients (66.0% with rheumatoid arthritis) who were taking immunosuppressive medications (74.1% women, mean age 53.7 years). Rheumatologists who received the intervention had a significant increase in the rate of patients who were up-to date with pneumococcal vaccination, from 67.6% to 80.0% (P=0.006), in the time period following the intervention, compared to a rate that remained stable, from 52.3% to 52.0% (P=0.90), among patients in the nonintervention control group during this same time period. In regression models, positive predictors of being up-to-date with pneumococcal vaccination at the patient level included the following: having received the intervention (hazard ratio [HR] 3.58, 95% confidence interval [95% CI] 2.46-5.20), having a primary care physician affiliated with Brigham and Women's Hospital (HR 1.68, 95% CI 1.44-1.97), having a diagnosis of diabetes mellitus (HR 1.57, 95% CI 1.02-2.41), and being age 56-65 years at baseline, compared to age<=45 years (HR 1.24, 95% CI 1.01-1.51). CONCLUSION: A QI strategy involving a simple point-of-care paper reminder form significantly increased the rate of being up-to-date with pneumococcal vaccination among patients receiving immunosuppressive medications in our rheumatology practices over a 6-month period. PMID- 23044507 TI - Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity. AB - CONTEXT Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies. OBJECTIVE To determine the involvement of BDNF in human psychopathology. DESIGN Case-control study. SETTING Microarray based comparative genomic hybridization data from 7 molecular diagnostic centers including 38 550 affected subjects and 28 705 unaffected subjects. PATIENTS Subjects referred to diagnostic screening centers for microarray-based comparative genomic hybridization for physical or cognitive impairment. MAIN OUTCOME MEASURES Genomic copy number gains and losses. RESULTS We report 5 individuals with psychopathology and genomic deletion of a critical region including BDNF. The defined critical region was never disrupted in control subjects or diagnostic cases without developmental abnormalities. CONCLUSION Hemizygosity of the BDNF region contributes to variable psychiatric phenotypes including anxiety, behavioral, and mood disorders. PMID- 23044508 TI - Body dysmorphic disorder and nonweight-related body image concerns in individuals with eating disorders. AB - OBJECTIVE: Research on the prevalence of body dysmorphic disorder (BDD) in individuals with eating disorders (EDs) is scarce. Nonweight-related appearance concerns, which can be considered as variants of BDD concerns, have also rarely been examined in EDs. This study therefore investigates BDD prevalence and nonweight-related appearance concerns in EDs. METHOD: One hundred individuals with EDs (49 inpatients with anorexia nervosa, 51 inpatients with bulimia nervosa) completed structured diagnostic interviews and self-report questionnaires. RESULTS: Twelve individuals with EDs (12.0%) suffered from comorbid BDD, with their body dysmorphic concerns being unrelated to weight and shape. BDD lifetime-prevalence was 15.0%. There was a high prevalence of dissatisfaction with nonweight-related body features such as skin, hair, teeth, nose, and height (20.8 to 53.5%). DISCUSSION: Findings indicate that BDD is a frequent comorbid disorder in individuals with EDs. Furthermore, along with weight and body shape, nonweight-related appearance concerns are also common in individuals with EDs. PMID- 23044509 TI - The secreted Alzheimer-related amyloid precursor protein fragment has an essential role in C. elegans. AB - Mutations in the gene encoding the amyloid precursor protein (APP) or the enzymes that process APP are correlated with familial Alzheimer disease. Alzheimer disease is also associated with insulin resistance (type 2 diabetes). In our recently published study, ( 1) we obtained genetic evidence that the extracellular fragment of APL-1, the C. elegans ortholog of human APP, may act as a signaling molecule to modulate insulin and nuclear hormone pathways in C. elegans development. In addition, independent of insulin and nuclear hormone signaling, high levels of the extracellular fragment of APL-1 (sAPL-1) leads to a temperature-sensitive embryonic lethality, which is dependent on activity of a predicted receptor protein tyrosine phosphatase (MOA-1/R155.2). Furthermore, this embryonic lethality is enhanced by knockdown of a predicted prion-like protein (pqn-29). The precise molecular mechanisms underlying these processes remain to be determined. Here, we present hypothetical models as to how sAPL-1 signaling influences metabolic and developmental pathways. Together, with previous findings in mammals that the extracellular domain of mammalian APP (sAPP) binds to a death receptor, ( 2) our findings support the model that sAPP signaling affects critical biological processes. PMID- 23044510 TI - Prions, proteinase K and infectivity. AB - It has been described that the breakdown of beta-sheets in PrP (Sc) by denaturation results in loss of infectivity and PK-sensitivity, suggesting a relationship between the structure and PK-resistance. It is also known that an important fraction of total PrP (Sc) is PK-sensitive and can be isolated by the method we already described. Consequently, we decided to employ the PK-sensitive fraction of PrP (Sc) as a potential and useful tool for structural studies. Thus, two essential questions were addressed in our recent article. First, the difference in the infectivity between the sensitive and resistant fractions and second, whether sensitive and resistant PrP (Sc) shared the same conformation or were only different size multimers with the same basic conformation. Here we discuss our latest data in light of recent infectivity studies and their possible implications on the conformation of the prion. PMID- 23044511 TI - Improved RF performance of travelling wave MR with a high permittivity dielectric lining of the bore. AB - Application of travelling wave MR to human body imaging is restricted by the limited peak power of the available RF amplifiers. Nevertheless, travelling wave MR advantages like a large field of view excitation and distant location of transmit elements would be desirable for whole body MRI. In this work, improvement of the B1+ efficiency of travelling wave MR is demonstrated. High permittivity dielectric lining placed next to the scanner bore wall effectively reduces attenuation of the travelling wave in the longitudinal direction and at the same time directs the radial power flow toward the load. First, this is shown with an analytical model of a metallic cylindrical waveguide with the dielectric lining next to the wall and loaded with a cylindrical phantom. Simulations and experiments also reveal an increase of B1+ efficiency in the center of the bore for travelling wave MR with a dielectric lining. Phantom experiments show up to a 2-fold gain in B1+ with the dielectric lining. This corresponds to a 4-fold increase in power efficiency of travelling wave MR. In vivo experiments demonstrate an 8-fold signal-to-noise ratio gain with the dielectric lining. Overall, it is shown that dielectric lining is a constructive method to improve efficacy of travelling wave MR. PMID- 23044512 TI - Psychosocial impact of lymphedema: a systematic review of literature from 2004 to 2011. AB - OBJECTIVE: This systematic review aimed to evaluate the level of evidence of contemporary peer-reviewed literature published from 2004 to 2011 on the psychosocial impact of lymphedema. METHODS: Eleven electronic databases were searched and 1311 articles retrieved; 23 met inclusion criteria. Twelve articles utilized qualitative methodology and 11 used quantitative methodology. An established quality assessment tool was used to assess the quality of the included studies. RESULTS: The overall quality of the 23 included studies was adequate. A critical limitation of current literature is the lack of conceptual or operational definitions for the concept of psychosocial impact. Quantitative studies showed statistically significant poorer social well-being in persons with lymphedema, including perceptions related to body image, appearance, sexuality, and social barriers. No statistically significant differences were found between persons with and without lymphedema in the domains of emotional well-being (happy or sad) and psychological distress (depression and anxiety). All 12 of the qualitative studies consistently described negative psychological impact (negative self-identity, emotional disturbance, and psychological distress) and negative social impact (marginalization, financial burden, perceived diminished sexuality, social isolation, perceived social abandonment, public insensitivity, and non-supportive work environment). Factors associated with psychosocial impact were also identified. CONCLUSIONS: Lymphedema has a negative psychosocial impact on affected individuals. The current review sheds light on the conceptualization and operationalization of the definitions of psychosocial impact with respect to lymphedema. Development of a lymphedema-specific instrument is needed to better characterize the impact of lymphedema and to examine the factors contributing to these outcomes in cancer and non-cancer-related populations. PMID- 23044513 TI - Functions of neurotrophins and growth factors in neurogenesis and brain repair. AB - The identification and isolation of multipotent neural stem and progenitor cells in the brain, giving rise to neurons, astrocytes, and oligodendrocytes initiated many studies in order to understand basic mechanisms of endogenous neurogenesis and repair mechanisms of the nervous system and to develop novel therapeutic strategies for cellular regeneration therapies in brain disease. A previous review (Trujillo et al., Cytometry A 2009;75:38-53) focused on the importance of extrinsic factors, especially neurotransmitters, for directing migration and neurogenesis in the developing and adult brain. Here, we extend our review discussing the effects of the principal growth and neurotrophic factors as well as their intracellular signal transduction on neurogenesis, fate determination and neuroprotective mechanisms. Many of these mechanisms have been elucidated by in vitro studies for which neural stem cells were isolated, grown as neurospheres, induced to neural differentiation under desired experimental conditions, and analyzed for embryonic, progenitor, and neural marker expression by flow and imaging cytometry techniques. The better understanding of neural stem cells proliferation and differentiation is crucial for any therapeutic intervention aiming at neural stem cell transplantation and recruitment of endogenous repair mechanisms. PMID- 23044514 TI - Polychlorinated biphenyls in prospectively collected serum and Parkinson's disease risk. AB - Evidence suggests possible Parkinson's disease (PD)-relevant neural effects of exposure to polychlorinated biphenyls. Limited epidemiological evidence suggests that polychlorinated biphenyl exposure may increase PD risk, but no studies have involved biomarkers of polychlorinated biphenyl exposure before PD onset. We examined the prospective association between serum polychlorinated biphenyls and PD. We conducted a nested case-control study within the Finnish Mobile Clinic Health Examination Survey with serum samples collected during 1968-1972 and analyzed in 2005-2007 for polychlorinated biphenyls. Incident PD cases were identified through the Social Insurance Institution's registry and were confirmed by medical record review (n = 101). Controls (n = 349) were matched on age, sex, municipality, and vital status. We used logistic regression to estimate adjusted odds ratios. There was no evidence of increasing risk of PD with increasing polychlorinated biphenyl exposure in adjusted analyses. Instead, there was a trend toward lower odds of PD with increasing serum polychlorinated biphenyl concentrations, which was most pronounced for the sum of all measured polychlorinated biphenyl congeners and the sum of dioxin-like congeners. Compared with that of those in the lowest quintile, the odds ratio of PD among those in the highest quintile of total polychlorinated biphenyls was 0.29 (95% confidence interval, 0.12-0.70; P trend = .02) and for dioxin-like congeners was 0.34 (95% confidence interval, 0.13-0.90; P trend = .05). These results do not support an increased risk of PD from polychlorinated biphenyl exposure and instead suggest a possible protective effect of polychlorinated biphenyl exposure. PMID- 23044515 TI - The influence of genetic factors on brain plasticity and recovery after neural injury. AB - PURPOSE OF REVIEW: The fields of clinical genetics and pharmacogenetics are rapidly expanding. Genetic factors have numerous associations with injury and with treatment effects in the setting of neural plasticity and recovery. RECENT FINDINGS: Evidence is reviewed that established genetic variants, as well as some more recently described variants, are related to outcome after neural injury and in some cases are useful for predicting clinical course. In many cases, the interaction of genetics with clinical factors such as experience and therapy may be important. As an extension of this, genetic factors have been associated with differential response to a number of forms of therapy, including pharmacological, brain stimulation, psychotherapy, and meditation. Genetic variation might also have a significant effect on plasticity and recovery through key covariates such as depression or stress. A key point is that genetic associations might be most accurately identified when studied in relation to distinct forms of a disorder rather than in relation to broad clinical syndromes. SUMMARY: Understanding genetic variation gives clinicians a biological signal that could be used to predict who is most likely to recover from neural injury, to choose the optimal treatment for a patient, or to supplement rehabilitation therapy. PMID- 23044517 TI - The magnetic and quantum transport properties of benzene-vanadium-borazine mixed sandwich clusters: a new kind of spin filter. AB - Using density functional theory and the non-equilibrium Green's function technique, we performed theoretical investigations on the magnetic and quantum transport properties of benzene-vanadium-borazine mixed organic/inorganic ligand sandwich clusters. The calculated results show that these finite sandwich clusters coupled to Ni electrodes exhibit novel quantum transport properties such as half-metallicity, negative differential resistance and spin-reversal effect, and can be viewed as a new kind of spin filter. However, for the infinite molecular wire, the ground state was identified as a ferromagnetic semiconductor with high stability. These findings suggest that the mixed organic/inorganic ligand sandwich clusters and molecular wires are promising materials for application in molecular electronics and spintronics. PMID- 23044518 TI - Comparison between sarcoidosis and IgG4-related disease by whole-body 67Ga scintigraphy. AB - PURPOSE: The aim of this study was to compare uptake lesions in sarcoidosis and IgG4-related disease through gallium-67 ((67)Ga) scintigraphy to differentiate between the two diseases. MATERIALS AND METHODS: Whole-body (67)Ga scintigraphy findings of 27 patients with sarcoidosis and 16 with IgG4-related disease were reviewed between 2005 and 2011 at our hospital. RESULTS: In the case of patients with sarcoidosis, significant accumulation of (67)Ga was observed in the lacrimal gland in the case of 26 patients (96%), in mediastinal lymph nodes (LNs) in 23 (85%), in pulmonary hilar LNs in 21 (78%), in the parotid gland in 10 (38%), in supraclavicular LNs in eight (30%), in muscles in seven (26%), in the lung in five (18%), in inguinal LNs in four (15%), in submandibular LNs in two (7%), and in the heart, spleen, kidney and para-aorta in one patient (4%). In patients with IgG4-related disease, abnormal uptake was detected in the pulmonary hilar LNs in 12 patients (75%), in the lacrimal gland in 10 (62%), in the pancreas in 10 (62%), in the parotid gland in six (37%), in the submandibular gland in six (37%), in the para-aorta in three (19%), in the lung in three (19%), in mediastinal LNs in two (12%), and in the kidney in the case of two patients (12%). Asymmetrical accumulation in the submandibular gland was observed in three of six patients (50%) with IgG4-related disease and in none of the two patients (0%) with sarcoidosis. Significant differences were observed in the uptake ratio of the lacrimal gland, the submandibular gland, supraclavicular LNs, mediastinal LNs, pancreas, and muscle between the two groups (P<0.05). CONCLUSION: (67)Ga scintigraphy was useful in differentiating between the two diseases. Uptake in mediastinal LNs, in supraclavicular LNs, and in the muscle was specific to sarcoidosis, whereas uptake in the pancreas and in the submandibular gland indicated IgG4-related disease. PMID- 23044516 TI - Genetics of hearing and deafness. AB - This article is a review of the genes and genetic disorders that affect hearing in humans and a few selected mouse models of deafness. Genetics is playing an increasingly critical role in the practice of medicine. This is not only in part to the importance that genetic knowledge has on traditional genetic diseases but also in part to the fact that genetic knowledge provides an understanding of the fundamental biological process of most diseases. The proteins coded by the genes related to hearing loss (HL) are involved in many functions in the ear, such as cochlear fluid homeostasis, ionic channels, stereocilia morphology and function, synaptic transmission, gene regulation, and others. Mouse models play a crucial role in understanding of the pathogenesis associated with these genes. Different types of familial HL have been recognized for years; however, in the last two decades, there has been tremendous progress in the discovery of gene mutations that cause deafness. Most of the cases of genetic deafness recognized today are monogenic disorders that can be broadly classified by the mode of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance) and by the presence of associated phenotypic features (i.e., syndromic; and nonsyndromic). In terms of nonsyndromic HL, the chromosomal locations are currently known for ~ 125 loci (54 for dominant and 71 for recessive deafness), 64 genes have been identified (24 for dominant and 40 for recessive deafness), and there are many more loci for syndromic deafness and X linked and mitochondrial DNA disorders (http://hereditaryhearingloss.org). Thus, today's clinician must understand the science of medical genetics as this knowledge can lead to more effective disease diagnosis, counseling, treatment, and prevention. PMID- 23044520 TI - Determination of accurate 1H positions of an alanine tripeptide with anti parallel and parallel beta-sheet structures by high resolution 1H solid state NMR and GIPAW chemical shift calculation. AB - The accurate (1)H positions of alanine tripeptide, A(3), with anti-parallel and parallel beta-sheet structures could be determined by highly resolved (1)H DQMAS solid-state NMR spectra and (1)H chemical shift calculation with gauge-including projector augmented wave calculations. PMID- 23044521 TI - Human cochlea: anatomical characteristics and their relevance for cochlear implantation. AB - This is a review of the anatomical characteristics of human cochlea and the importance of variations in this anatomy to the process of cochlear implantation (CI). Studies of the human cochlea are essential to better comprehend the physiology and pathology of man's hearing. The human cochlea is difficult to explore due to its vulnerability and bordering capsule. Inner ear tissue undergoes quick autolytic changes making investigations of autopsy material difficult, even though excellent results have been presented over time. Important issues today are novel inner ear therapies including CI and new approaches for inner ear pharmacological treatments. Inner ear surgery is now a reality, and technical advancements in the design of electrode arrays and surgical approaches allow preservation of remaining structure/function in most cases. Surgeons should aim to conserve cochlear structures for future potential stem cell and gene therapies. Renewal interest of round window approaches necessitates further acquaintance of this complex anatomy and its variations. Rough cochleostomy drilling at the intricate "hook" region can generate intracochlear bone-dust inducing fibrosis and new bone formation, which could negatively influence auditory nerve responses at a later time point. Here, we present macro- and microanatomic investigations of the human cochlea viewing the extensive anatomic variations that influence electrode insertion. In addition, electron microscopic (TEM and SEM) and immunohistochemical results, based on specimens removed at surgeries for life-threatening petroclival meningioma and some well-preserved postmortal tissues, are displayed. These give us new information about structure as well as protein and molecular expression in man. Our aim was not to formulate a complete description of the complex human anatomy but to focus on aspects clinically relevant for electric stimulation, predominantly, the sensory targets, and how surgical atraumaticity best could be reached. PMID- 23044525 TI - A case of unexplained cyanosis. AB - It is now clear that hepatopulmonary syndrome (HPS) may occur and contribute significantly to gas exchange abnormalities in the setting of other cardiopulmonary abnormalities. Since there is no gold-standard diagnostic test for HPS, diagnosis rests on documenting arterial oxygenation abnormalities resulting from intrapulmonary vasodilatation in the setting of liver disease. Retrospective studies suggest that many patients with HPS develop progressive intrapulmonary vasodilatation over time and that mortality is significant. This case highlights the clinical value in investigating for HPS and right-to-left shunts when confronted with a patient presenting with unexplained hypoxia in combination with platypnoea and/or orthodeoxia. PMID- 23044523 TI - Pharmacokinetic modelling of efavirenz, atazanavir, lamivudine and tenofovir in the female genital tract of HIV-infected pre-menopausal women. AB - BACKGROUND AND OBJECTIVES: A previously published study of antiretroviral pharmacokinetics in the female genital tract of HIV-infected women demonstrated differing degrees of female genital tract penetration among antiretrovirals. These blood plasma (BP) and cervicovaginal fluid (CVF) data were co-modelled for four antiretrovirals with varying CVF exposures. METHODS: Six paired BP and CVF samples were collected over 24 h, and antiretroviral concentrations determined using validated liquid chromatography (LC) with UV detection or LC-mass spectrometry analytical methods. For each antiretroviral, a BP model was fit using Bayesian estimation (ADAPT5), followed by addition of a CVF model. The final model was chosen based on graphical and statistical output, and then non linear mixed-effects modelling using S-ADAPT was performed. Population mean parameters and their variability are reported. Model-predicated area under the concentration-time curve during the dosing interval (AUC(tau)) and exposure ratios of CVF AUC(tau):BP AUC(tau) were calculated for each drug. RESULTS: The base model uses first-order absorption with a lag time, a two-compartment model, and a series of transit compartments that transfer the drug from BP to CVF. Protein-unbound drug transfers into CVF for efavirenz and atazanavir; total drug transfers for lamivudine and tenofovir. CVF follows a one-compartment model for efavirenz and atazanavir, and a two-compartment model for lamivudine and tenofovir. As expected, inter-individual variability was high. Model-predicted CVF AUC(tau):BP AUC(tau) ratios are consistent with published results. CONCLUSIONS: This is the first pharmacokinetic modelling of antiretroviral disposition in BP and CVF. These models will be further refined with tissue data, and used in clinical trials simulations to inform future studies of HIV pre exposure prophylaxis in women. PMID- 23044526 TI - Single coronary artery from the right coronary sinus with proximal origin of the left anterior descending coronary artery and left circumflex as distal continuation of the right coronary artery: a rare variant. AB - A single coronary artery is a rare coronary anomaly. A 68-year-old male underwent coronary angiography for recent inferior wall myocardial infarction. It revealed a common coronary trunk arising from the right sinus of Valsalva and bifurcated into the right coronary artery (RCA) and anterior descending coronary arteries. The RCA, after its usual distribution in the right atrioventricular groove, continued as the left circumflex artery in the left atrioventricular groove. There were significant stenoses in the mid and distal RCA, which were treated percutaneously. PMID- 23044527 TI - A young patient with coronary artery anomaly, whose left anterior descending artery originated from the pulmonary artery, underwent cardiac arrest. AB - A rare congenital anomaly of the coronary arteries, in which the left coronary arterial system starts from the arteria pulmonalis, is known as Bland-White Garland (BWG) syndrome. Isolated left anterior descending (LAD) or circumflex (Cx) arteries originating from the pulmonary artery are even more rare. These anomalies may cause myocardial ischaemia, myocardial infarction, arrhythmia and sudden death. Even if the patient is asymptomatic, he/she should undergo corrective surgery. Here we present the case of an 18-year-old male who survived sudden cardiac arrest during exercise. We identified intra-myocardial blood flow from transthoracic echocardiography, and performed coronary and computed tomographic (CT) angiography, which showed that all the coronary arteries were ectatic and curly and there were disseminated collaterals among the coronary arteries. We diagnosed 'anomalous left coronary artery from the pulmonary artery' (ALCAPA) syndrome, as additionally, the LAD originated from the pulmonary artery. We treated the patient with a left internal mammarian artery - left anterior descending artery (LIMA-LAD) graft. PMID- 23044528 TI - An unusual embolic complication of percutaneous coronary artery intervention and simple percutaneous treatment. AB - Emboli are among the most feared complications of interventional cardiology. Although surgery is needed in most cases for the removal of peripheric foreign body emboli, some may be extracted by percutaneous intervention. We present a case of retrieval of a femoral sheath fragment via contralateral femoral access, wiring of the sheath fragment, and retrieval with an 'anchoring balloon' system. PMID- 23044529 TI - Anomalous left coronary artery arising from the pulmonary artery. AB - A 24-year-old female presented to her general practitioner with shortness of breath. She was referred for an echocardiogram, which demonstrated features suggestive of a right coronary artery fistula, and referred to our institute. We performed a contrast-enhanced, prospectively triggered cardiac CT angiogram, which demonstrated the primary and secondary features of anomalous left coronary artery arising from the pulmonary artery (ALCAPA), also known as the Bland-White Garland syndrome, a rare congenital abnormality of the origin of the left main coronary artery. PMID- 23044530 TI - Belatacept in kidney transplantation. AB - PURPOSE OF REVIEW: In June 2011 the US Food and Drug Administration approved belatacept (Nulojix; Bristol-Myers Squibb, Princeton, New Jersey, USA) for the prophylaxis of organ rejection in adult kidney transplant recipients. This review will discuss the use of belatacept for the prevention of acute rejection as part of a maintenance immunosuppression regimen. RECENT FINDINGS: Belatacept is a selective costimulation blocker designed to provide effective immunosuppression while avoiding the toxicities associated with calcineurin inhibitors. Phase 3 trial data have demonstrated that belatacept is noninferior to cyclosporine in 1 year patient and allograft survival. Three-year data demonstrate an ongoing improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. Overall, there seemed to be an improvement in cardiometabolic parameters in patients treated with belatacept compared with cyclosporine. There was a trend toward higher rates of early rejection episodes in patients treated with belatacept. One safety issue that must be considered when using belatacept is the potential for increased risk of posttransplant lymphoproliferative disease, especially in Epstein-Barr virus-seronegative recipients or patients treated with lymphocyte-depleting agents. SUMMARY: Belatacept is the first new agent available in kidney transplant that may achieve the goal of improved long-term renal function. PMID- 23044531 TI - The local metallicity of gadolinium doped compound semiconductors. AB - The local metallicities of Hf(0.97)Gd(0.03)O(2), Ga(0.97)Gd(0.03)N, Eu(0.97)Gd(0.04)O and EuO films were studied through a comparison of the findings from constant initial state spectroscopy using synchrotron light. Resonant enhancements, corresponding to the 4d -> 4f transitions of Eu and Gd, were observed in some of the valence band photoemission features. The resonant photoemission intensity enhancements for the Gd 4f photoemission features are far stronger for the more insulating host systems than for the metallic system Eu(0.96)Gd(0.04)O. The evidence seems to suggest a correlation between the effective screening in the films and the resonant photoemission process. PMID- 23044532 TI - A trial of scheduled deep brain stimulation for Tourette syndrome: moving away from continuous deep brain stimulation paradigms. AB - OBJECTIVE: To collect the information necessary to design the methods and outcome variables for a larger trial of scheduled deep brain stimulation (DBS) for Tourette syndrome. DESIGN: We performed a small National Institutes of Health sponsored clinical trials planning study of the safety and preliminary efficacy of implanted DBS in the bilateral centromedian thalamic region. The study used a cranially contained constant-current device and a scheduled, rather than the classic continuous, DBS paradigm. Baseline vs 6-month outcomes were collected and analyzed. In addition, we compared acute scheduled vs acute continuous vs off DBS. SETTING: A university movement disorders center. PATIENTS: Five patients with implanted DBS. MAIN OUTCOME MEASURE: A 50% improvement in the Yale Global Tic Severity Scale (YGTSS) total score. RESULTS Participating subjects had a mean age of 34.4 (range, 28-39) years and a mean disease duration of 28.8 years. No significant adverse events or hardware-related issues occurred. Baseline vs 6 month data revealed that reductions in the YGTSS total score did not achieve the prestudy criterion of a 50% improvement in the YGTSS total score on scheduled stimulation settings. However, statistically significant improvements were observed in the YGTSS total score (mean [SD] change, -17.8 [9.4]; P=.01), impairment score (-11.3 [5.0]; P=.007), and motor score (-2.8 [2.2]; P=.045); the Modified Rush Tic Rating Scale Score total score (-5.8 [2.9]; P=.01); and the phonic tic severity score (-2.2 [2.6]; P=.04). Continuous, off, and scheduled stimulation conditions were assessed blindly in an acute experiment at 6 months after implantation. The scores in all 3 conditions showed a trend for improvement. Trends for improvement also occurred with continuous and scheduled conditions performing better than the off condition. Tic suppression was commonly seen at ventral (deep) contacts, and programming settings resulting in tic suppression were commonly associated with a subjective feeling of calmness. CONCLUSIONS: This study provides safety and proof of concept that a scheduled DBS approach could improve motor and vocal tics in Tourette syndrome. Refinements in neurostimulator battery life, outcome measure selection, and flexibility in programming settings can be used to enhance outcomes in a future larger study. Scheduled stimulation holds promise as a potential first step for shifting movement and neuropsychiatric disorders toward more responsive neuromodulation approaches. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01329198. PMID- 23044536 TI - Reactivation of autophagy ameliorates LMNA cardiomyopathy. AB - Mutations in the LMNA gene, which encodes lamin A and C (lamin A/C), cause a diverse spectrum of tissue-selective diseases termed laminopathies. The most prevalent form affects striated muscles as dilated cardiomyopathy with variable skeletal muscle involvement, which includes autosomal Emery-Dreifuss muscular dystrophy. Mechanisms underlying the disease pathogenesis are beginning to be understood and they point toward defects in cell signaling. We therefore assessed putative signaling defects in a mouse model carrying a point mutation in Lmna (Lmna (H222P/H222P) ) that faithfully recapitulates human Emery-Dreifuss muscular dystrophy. We found that AKT-mechanistic target of rapamycin (MTOR) signaling was hyperactivated in hearts of Lmna (H222P/H222P) mice and that reducing MTOR activity by pharmacological intervention ameliorated cardiomyopathy. Given the central role of MTOR in regulating autophagy, we assessed fasting-induced autophagic responses and found that they were impaired in hearts of these mice. Moreover, the improved heart function associated with pharmacological blockade of MTOR was correlated with enhanced autophagy. These findings demonstrated that signaling defects that impair autophagy underlie pathogenesis of dilated cardiomyopathy arising from LMNA mutation. PMID- 23044537 TI - Interconversion between different stoichiometric forms of a three-component crystal via liquid-assisted grinding. AB - A second polymorphic form of a 1 : 2 : 3 pamoate : DABCO : water salt has been obtained by liquid-assisted grinding, and it is shown that interconversion between this salt and a salt with 1 : 1 : 2 stoichiometry is facile via liquid assisted grinding with additional amounts of pamoic acid (to generate the 1 : 1 : 2 salt) or DABCO (to generate the 1 : 2 : 3 salt). PMID- 23044538 TI - MesoRD 1.0: Stochastic reaction-diffusion simulations in the microscopic limit. AB - SUMMARY: MesoRD is a tool for simulating stochastic reaction-diffusion systems as modeled by the reaction diffusion master equation. The simulated systems are defined in the Systems Biology Markup Language with additions to define compartment geometries. MesoRD 1.0 supports scale-dependent reaction rate constants and reactions between reactants in neighbouring subvolumes. These new features make it possible to construct physically consistent models of diffusion controlled reactions also at fine spatial discretization. AVAILABILITY: MesoRD is written in C++ and licensed under the GNU general public license (GPL). MesoRD can be downloaded at http://mesord.sourceforge.net. The MesoRD homepage, http://mesord.sourceforge.net, contains detailed documentation and news about recently implemented features. CONTACT: johan.elf@icm.uu.se. PMID- 23044540 TI - A novel missense-mutation-related feature extraction scheme for 'driver' mutation identification. AB - MOTIVATION: It becomes widely accepted that human cancer is a disease involving dynamic changes in the genome and that the missense mutations constitute the bulk of human genetic variations. A multitude of computational algorithms, especially the machine learning-based ones, has consequently been proposed to distinguish missense changes that contribute to the cancer progression ('driver' mutation) from those that do not ('passenger' mutation). However, the existing methods have multifaceted shortcomings, in the sense that they either adopt incomplete feature space or depend on protein structural databases which are usually far from integrated. RESULTS: In this article, we investigated multiple aspects of a missense mutation and identified a novel feature space that well distinguishes cancer-associated driver mutations from passenger ones. An index (DX score) was proposed to evaluate the discriminating capability of each feature, and a subset of these features which ranks top was selected to build the SVM classifier. Cross validation showed that the classifier trained on our selected features significantly outperforms the existing ones both in precision and robustness. We applied our method to several datasets of missense mutations culled from published database and literature and obtained more reasonable results than previous studies. AVAILABILITY: The software is available online at http://www.methodisthealth.com/software and https://sites.google.com/site/drivermutationidentification/. CONTACT: xzhou@tmhs.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23044539 TI - Gene set analysis for self-contained tests: complex null and specific alternative hypotheses. AB - MOTIVATION: The analysis of differentially expressed gene sets became a routine in the analyses of gene expression data. There is a multitude of tests available, ranging from aggregation tests that summarize gene-level statistics for a gene set to true multivariate tests, accounting for intergene correlations. Most of them detect complex departures from the null hypothesis but when the null hypothesis is rejected, the specific alternative leading to the rejection is not easily identifiable. RESULTS: In this article we compare the power and Type I error rates of minimum-spanning tree (MST)-based non-parametric multivariate tests with several multivariate and aggregation tests, which are frequently used for pathway analyses. In our simulation study, we demonstrate that MST-based tests have power that is for many settings comparable with the power of conventional approaches, but outperform them in specific regions of the parameter space corresponding to biologically relevant configurations. Further, we find for simulated and for gene expression data that MST-based tests discriminate well against shift and scale alternatives. As a general result, we suggest a two-step practical analysis strategy that may increase the interpretability of experimental data: first, apply the most powerful multivariate test to find the subset of pathways for which the null hypothesis is rejected and second, apply MST-based tests to these pathways to select those that support specific alternative hypotheses. CONTACT: gvglazko@uams.edu or yrahmatallah@uams.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23044541 TI - Pinstripe: a suite of programs for integrating transcriptomic and proteomic datasets identifies novel proteins and improves differentiation of protein-coding and non-coding genes. AB - MOTIVATION: Comparing transcriptomic data with proteomic data to identify protein coding sequences is a long-standing challenge in molecular biology, one that is exacerbated by the increasing size of high-throughput datasets. To address this challenge, and thereby to improve the quality of genome annotation and understanding of genome biology, we have developed an integrated suite of programs, called Pinstripe. We demonstrate its application, utility and discovery power using transcriptomic and proteomic data from publicly available datasets. RESULTS: To demonstrate the efficacy of Pinstripe for large-scale analysis, we applied Pinstripe's reverse peptide mapping pipeline to a transcript library including de novo assembled transcriptomes from the human Illumina Body Atlas (IBA2) and GENCODE v10 gene annotations, and the EBI Proteomics Identifications Database (PRIDE) peptide database. This analysis identified 736 canonical open reading frames (ORFs) supported by three or more PRIDE peptide fragments that are positioned outside any known coding DNA sequence (CDS). Because of the unfiltered nature of the PRIDE database and high probability of false discovery, we further refined this list using independent evidence for translation, including the presence of a Kozak sequence or functional domains, synonymous/non-synonymous substitution ratios and ORF length. Using this integrative approach, we observed evidence of translation from a previously unknown let7e primary transcript, the archetypical lncRNA H19, and a homolog of RD3. Reciprocally, by exclusion of transcripts with mapped peptides or significant ORFs (>80 codon), we identify 32 187 loci with RNAs longer than 2000 nt that are unlikely to encode proteins. AVAILABILITY AND IMPLEMENTATION: Pinstripe (pinstripe.matticklab.com) is freely available as source code or a Mono binary. Pinstripe is written in C# and runs under the Mono framework on Linux or Mac OS X, and both under Mono and .Net under Windows. CONTACT: m.dinger@garvan.org.au or j.mattick@garvan.org.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23044543 TI - ncPRO-seq: a tool for annotation and profiling of ncRNAs in sRNA-seq data. AB - SUMMARY: Non-coding RNA (ncRNA) PROfiling in small RNA (sRNA)-seq (ncPRO-seq) is a stand-alone, comprehensive and flexible ncRNA analysis pipeline. It can interrogate and perform detailed profiling analysis on sRNAs derived from annotated non-coding regions in miRBase, Rfam and RepeatMasker, as well as specific regions defined by users. The ncPRO-seq pipeline performs both gene based and family-based analyses of sRNAs. It also has a module to identify regions significantly enriched with short reads, which cannot be classified under known ncRNA families, thus enabling the discovery of previously unknown ncRNA- or small interfering RNA (siRNA)-producing regions. The ncPRO-seq pipeline supports input read sequences in fastq, fasta and color space format, as well as alignment results in BAM format, meaning that sRNA raw data from the three current major platforms (Roche-454, Illumina-Solexa and Life technologies-SOLiD) can be analyzed with this pipeline. The ncPRO-seq pipeline can be used to analyze read and alignment data, based on any sequenced genome, including mammals and plants. AVAILABILITY: Source code, annotation files, manual and online version are available at http://ncpro.curie.fr/. CONTACT: bioinfo.ncproseq@curie.fr or cciaudo@ethz.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23044542 TI - VIPR HMM: a hidden Markov model for detecting recombination with microbial detection microarrays. AB - MOTIVATION: Current methods in diagnostic microbiology typically focus on the detection of a single genomic locus or protein in a candidate agent. The presence of the entire microbe is then inferred from this isolated result. Problematically, the presence of recombination in microbial genomes would go undetected unless other genomic loci or protein components were specifically assayed. Microarrays lend themselves well to the detection of multiple loci from a given microbe; furthermore, the inherent nature of microarrays facilitates highly parallel interrogation of multiple microbes. However, none of the existing methods for analyzing diagnostic microarray data has the capacity to specifically identify recombinant microbes. In previous work, we developed a novel algorithm, VIPR, for analyzing diagnostic microarray data. RESULTS: We have expanded upon our previous implementation of VIPR by incorporating a hidden Markov model (HMM) to detect recombinant genomes. We trained our HMM on a set of non-recombinant parental viruses and applied our method to 11 recombinant alphaviruses and 4 recombinant flaviviruses hybridized to a diagnostic microarray in order to evaluate performance of the HMM. VIPR HMM correctly identified 95% of the 62 inter-species recombination breakpoints in the validation set and only two false positive breakpoints were predicted. This study represents the first description and validation of an algorithm capable of detecting recombinant viruses based on diagnostic microarray hybridization patterns. AVAILABILITY: VIPR HMM is freely available for academic use and can be downloaded from http://ibridgenetwork.org/wustl/vipr. CONTACT: davewang@borcim.wustl.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23044544 TI - KGBassembler: a karyotype-based genome assembler for Brassicaceae species. AB - MOTIVATION: The Brassicaceae family includes the most important plant model Arabidopsis thaliana and many cruciferous vegetable crops. A number of close relatives of Arabidopsis and economically important Brassica species are being sequenced with whole-genome shotgun sequencing technologies. However, de novo assembly of full chromosomes is difficult, since many non-model Brassicaceae species are lacking genetic and/or physical maps. As a unique feature for Brassicaceae, the genome of each member is composed of 24 conserved chromosomal blocks, and the arrangement of the 24 blocks can be obtained from karyotype analysis via comparative chromosome painting experiments. Taking this advantage, we developed a bioinformatic tool named KGBassembler to automatically finalize assembly of full chromosomes from contigs and/or scaffolds based on available karyotypes of Brassicaceae species. AVAILABILITY: KGBassembler was implemented in C++ with a graphical user interface. It is freely available to academic users at http://www.cmbb.arizona.edu/KGBassembler/. CONTACT: xwang1@cals.arizona.edu. PMID- 23044545 TI - fRMA ST: frozen robust multiarray analysis for Affymetrix Exon and Gene ST arrays. AB - SUMMARY: Frozen robust multiarray analysis (fRMA) is a single-array preprocessing algorithm that retains the advantages of multiarray algorithms and removes certain batch effects by downweighting probes that have high between-batch residual variance. Here, we extend the fRMA algorithm to two new microarray platforms--Affymetrix Human Exon and Gene 1.0 ST--by modifying the fRMA probe level model and extending the frma package to work with oligo ExonFeatureSet and GeneFeatureSet objects. AVAILABILITY AND IMPLEMENTATION: All packages are implemented in R. Source code and binaries are freely available through the Bioconductor project. Convenient links to all software and data packages can be found at http://mnmccall.com/software CONTACT: mccallm@gmail.com. PMID- 23044546 TI - miR-EdiTar: a database of predicted A-to-I edited miRNA target sites. AB - MOTIVATION: A-to-I RNA editing is an important mechanism that consists of the conversion of specific adenosines into inosines in RNA molecules. Its dysregulation has been associated to several human diseases including cancer. Recent work has demonstrated a role for A-to-I editing in microRNA (miRNA) mediated gene expression regulation. In fact, edited forms of mature miRNAs can target sets of genes that differ from the targets of their unedited forms. The specific deamination of mRNAs can generate novel binding sites in addition to potentially altering existing ones. RESULTS: This work presents miR-EdiTar, a database of predicted A-to-I edited miRNA binding sites. The database contains predicted miRNA binding sites that could be affected by A-to-I editing and sites that could become miRNA binding sites as a result of A-to-I editing. AVAILABILITY: miR-EdiTar is freely available online at http://microrna.osumc.edu/mireditar. CONTACT: alessandro.lagana@osumc.edu or carlo.croce@osumc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23044547 TI - Robust design of microbial strains. AB - MOTIVATION: Metabolic engineering algorithms provide means to optimize a biological process leading to the improvement of a biotechnological interesting molecule. Therefore, it is important to understand how to act in a metabolic pathway in order to have the best results in terms of productions. In this work, we present a computational framework that searches for optimal and robust microbial strains that are able to produce target molecules. Our framework performs three tasks: it evaluates the parameter sensitivity of the microbial model, searches for the optimal genetic or fluxes design and finally calculates the robustness of the microbial strains. We are capable to combine the exploration of species, reactions, pathways and knockout parameter spaces with the Pareto-optimality principle. RESULTS: Our framework provides also theoretical and practical guidelines for design automation. The statistical cross comparison of our new optimization procedures, performed with respect to currently widely used algorithms for bacteria (e.g. Escherichia coli) over different multiple functions, reveals good performances over a variety of biotechnological products. AVAILABILITY: http://www.dmi.unict.it/nicosia/pathDesign.html. CONTACT: nicosia@dmi.unict.it or pl219@cam.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23044548 TI - 'Location, Location, Location': a spatial approach for rare variant analysis and an application to a study on non-syndromic cleft lip with or without cleft palate. AB - MOTIVATION: For the analysis of rare variants in sequence data, numerous approaches have been suggested. Fixed and flexible threshold approaches collapse the rare variant information of a genomic region into a test statistic with reduced dimensionality. Alternatively, the rare variant information can be combined in statistical frameworks that are based on suitable regression models, machine learning, etc. Although the existing approaches provide powerful tests that can incorporate information on allele frequencies and prior biological knowledge, differences in the spatial clustering of rare variants between cases and controls cannot be incorporated. Based on the assumption that deleterious variants and protective variants cluster or occur in different parts of the genomic region of interest, we propose a testing strategy for rare variants that builds on spatial cluster methodology and that guides the identification of the biological relevant segments of the region. Our approach does not require any assumption about the directions of the genetic effects. RESULTS: In simulation studies, we assess the power of the clustering approach and compare it with existing methodology. Our simulation results suggest that the clustering approach for rare variants is well powered, even in situations that are ideal for standard methods. The efficiency of our spatial clustering approach is not affected by the presence of rare variants that have opposite effect size directions. An application to a sequencing study for non-syndromic cleft lip with or without cleft palate (NSCL/P) demonstrates its practical relevance. The proposed testing strategy is applied to a genomic region on chromosome 15q13.3 that was implicated in NSCL/P etiology in a previous genome-wide association study, and its results are compared with standard approaches. AVAILABILITY: Source code and documentation for the implementation in R will be provided online. Currently, the R-implementation only supports genotype data. We currently are working on an extension for VCF files. CONTACT: heide.fier@googlemail.com. PMID- 23044549 TI - MGAviewer: a desktop visualization tool for analysis of metagenomics alignment data. AB - SUMMARY: Numerous metagenomics projects have produced tremendous amounts of sequencing data. Aligning these sequences to reference genomes is an essential analysis in metagenomics studies. Large-scale alignment data call for intuitive and efficient visualization tool. However, current tools such as various genome browsers are highly specialized to handle intraspecies mapping results. They are not suitable for alignment data in metagenomics, which are often interspecies alignments. We have developed a web browser-based desktop application for interactively visualizing alignment data of metagenomic sequences. This viewer is easy to use on all computer systems with modern web browsers and requires no software installation. AVAILABILITY: http://weizhongli-lab.org/mgaviewer PMID- 23044550 TI - SemMedDB: a PubMed-scale repository of biomedical semantic predications. AB - SUMMARY: Effective access to the vast biomedical knowledge present in the scientific literature is challenging. Semantic relations are increasingly used in knowledge management applications supporting biomedical research to help address this challenge. We describe SemMedDB, a repository of semantic predications (subject-predicate-object triples) extracted from the entire set of PubMed citations. We propose the repository as a knowledge resource that can assist in hypothesis generation and literature-based discovery in biomedicine as well as in clinical decision-making support. AVAILABILITY AND IMPLEMENTATION: The SemMedDB repository is available as a MySQL database for non-commercial use at http://skr3.nlm.nih.gov/SemMedDB. An UMLS Metathesaurus license is required. CONTACT: kilicogluh@mail.nih.gov. PMID- 23044551 TI - COPE: an accurate k-mer-based pair-end reads connection tool to facilitate genome assembly. AB - MOTIVATION: The boost of next-generation sequencing technologies provides us with an unprecedented opportunity for elucidating genetic mysteries, yet the short read length hinders us from better assembling the genome from scratch. New protocols now exist that can generate overlapping pair-end reads. By joining the 3' ends of each read pair, one is able to construct longer reads for assembling. However, effectively joining two overlapped pair-end reads remains a challenging task. RESULT: In this article, we present an efficient tool called Connecting Overlapped Pair-End (COPE) reads, to connect overlapping pair-end reads using k mer frequencies. We evaluated our tool on 30* simulated pair-end reads from Arabidopsis thaliana with 1% base error. COPE connected over 99% of reads with 98.8% accuracy, which is, respectively, 10 and 2% higher than the recently published tool FLASH. When COPE is applied to real reads for genome assembly, the resulting contigs are found to have fewer errors and give a 14-fold improvement in the N50 measurement when compared with the contigs produced using unconnected reads. AVAILABILITY AND IMPLEMENTATION: COPE is implemented in C++ and is freely available as open-source code at ftp://ftp.genomics.org.cn/pub/cope. CONTACT: twlam@cs.hku.hk or luoruibang@genomics.org.cn PMID- 23044552 TI - Predicting pseudoknotted structures across two RNA sequences. AB - MOTIVATION: Laboratory RNA structure determination is demanding and costly and thus, computational structure prediction is an important task. Single sequence methods for RNA secondary structure prediction are limited by the accuracy of the underlying folding model, if a structure is supported by a family of evolutionarily related sequences, one can be more confident that the prediction is accurate. RNA pseudoknots are functional elements, which have highly conserved structures. However, few comparative structure prediction methods can handle pseudoknots due to the computational complexity. RESULTS: A comparative pseudoknot prediction method called DotKnot-PW is introduced based on structural comparison of secondary structure elements and H-type pseudoknot candidates. DotKnot-PW outperforms other methods from the literature on a hand-curated test set of RNA structures with experimental support. AVAILABILITY: DotKnot-PW and the RNA structure test set are available at the web site http://dotknot.csse.uwa.edu.au/pw. CONTACT: janaspe@csse.uwa.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23044555 TI - Perspectives on the care and management of infants with trisomy 18 and trisomy 13: striving for balance. AB - PURPOSE OF REVIEW: At the time of diagnosis of the trisomy 18 and trisomy 13, parents and care providers face difficult and challenging decisions regarding management. Because of the increased infant mortality and developmental outcome associated with both conditions, the conventional approach to management has been to withhold technological support. In recent years, an active dialogue on this topic has emerged. The purpose of this review is to summarize the literature on the outcome of infants with trisomy 18 and 13 and to discuss the key themes in this emerging dialogue. RECENT FINDINGS: In recent years, several important studies have appeared that have analyzed the issues relevant to this topic, including parental autonomy, best interest of the child standard, and quality of life. Some authorities state that in areas of ambiguity it is best to defer to parents' views, whereas others indicate concern that the best interest standard has given way to parental autonomy. Information on the actual experience of parents of children with trisomy 18 and 13 has been limited until recently. SUMMARY: The author recommends a balanced approach to counseling families of the newborn with trisomy 18 and 13 at the time of diagnosis. The counseling process should include presentation of accurate survival figures, avoidance of language that assumes outcome, communication of developmental outcome that does not presuppose perception of quality of life, and respect for the family's choice, whether it be comfort care or intervention. PMID- 23044556 TI - Comparison of breast tissue measurements using magnetic resonance imaging, digital mammography and a mathematical algorithm. AB - Women with mostly mammographically dense fibroglandular tissue (breast density, BD) have a four- to six-fold increased risk for breast cancer compared to women with little BD. BD is most frequently estimated from two-dimensional (2D) views of mammograms by a histogram segmentation approach (HSM) and more recently by a mathematical algorithm consisting of mammographic imaging parameters (MATH). Two non-invasive clinical magnetic resonance imaging (MRI) protocols: 3D gradient echo (3DGRE) and short tau inversion recovery (STIR) were modified for 3D volumetric reconstruction of the breast for measuring fatty and fibroglandular tissue volumes by a Gaussian-distribution curve-fitting algorithm. Replicate breast exams (N = 2 to 7 replicates in six women) by 3DGRE and STIR were highly reproducible for all tissue-volume estimates (coefficients of variation <5%). Reliability studies compared measurements from four methods, 3DGRE, STIR, HSM, and MATH (N = 95 women) by linear regression and intra-class correlation (ICC) analyses. Rsqr, regression slopes, and ICC, respectively, were (1) 0.76-0.86, 0.8 1.1, and 0.87-0.92 for %-gland tissue, (2) 0.72-0.82, 0.64-0.96, and 0.77-0.91, for glandular volume, (3) 0.87-0.98, 0.94-1.07, and 0.89-0.99, for fat volume, and (4) 0.89-0.98, 0.94-1.00, and 0.89-0.98, for total breast volume. For all values estimated, the correlation was stronger for comparisons between the two MRI than between each MRI versus mammography, and between each MRI versus MATH data than between each MRI versus HSM data. All ICC values were >0.75 indicating that all four methods were reliable for measuring BD and that the mathematical algorithm and the two complimentary non-invasive MRI protocols could objectively and reliably estimate different types of breast tissues. PMID- 23044557 TI - Tumor necrosis factor-alpha and the cytokine network in psoriasis. AB - New molecular methods of research have greatly expanded the knowledge about the role of cytokines in several diseases, including psoriasis. The work orchestrated by these peptides is essential for the communication between resident inflammatory cells (keratinocytes and endothelial cells) and infiltrating cells (neutrophils, lymphocytes, Langerhans cells). This is a complex network due to redundancy, synergism and, sometimes, the antagonism of cytokines, which prevents full understanding of the pathogenesis of the disease. Currently, it seems premature to try to establish a main actor, but TNFalpha participates in all stages of psoriatic plaque development, as we shall see. PMID- 23044558 TI - Action of topical mometasone on the pigmented halos of micrografting in patients with vitiligo. AB - BACKGROUND: Vitiligo is a prevalent skin pigmentation disorder worldwide. The treatments available still offer limited results to some patients. For patients with clinically stable vitiligo, melanocyte transplantation is an appropriate treatment option, and the technique of autologous punch grafting shows good repigmentation. OBJECTIVE: To evaluate the effect of topical mometasone on the halos of repigmentation after autologous punch grafting in patients with clinically stable vitiligo. METHODS: Between 2009 and 2010, 11 patients with clinically stable vitiligo (7 generalized, 2 focal and 2 segmental) underwent autologous punch grafting in the achromic patches. According to the clinical type of vitiligo, patients were instructed to use the corticosteroid ointment during 6 months, only on a few grafted lesions. In the first month, the mometasone ointment was used twice a day and after that just once. They were reassessed 1, 3 and 6 months after the procedure. Grafted halos were photographed and recorded using the software fotofinder. After 6 months, all the treated and untreated areas of the repigmentation halos were measured and analyzed comparatively. RESULTS: The median area of the repigmentation halos after 6 months of treatment with mometasone was larger (25,96 mm(2)) than the one of the untreated halos (13,86 mm(2)), showing a statistically significant difference (p = 0,026). CONCLUSION: In this study, the use of mometasone ointment increased the area of the repigmentation halos after punch grafting. However, this should be further investigated in larger samples in order to validate this positive action in the treatment of stable vitiligo. PMID- 23044559 TI - Dermoscopic findings in female androgenetic alopecia. AB - BACKGROUND: Androgenetic alopecia is the most common form of hair loss. It is a clinical entity of relevant interest and presents a significant psychosocial impact as it undermines self-esteem and quality of life in female patients due to the importance of the hair for people's facial balance. OBJECTIVE: The purpose of the present study is to evaluate dermoscopic signs in women clinically diagnosed with androgenetic alopecia. METHOD: Observational study with 34 women between 17 and 68 years old who were diagnosed with androgenetic alopecia. All of them underwent photographic sessions with a 10x magnification dermoscope and a digital camera zoom set to 20x magnification and 40x magnification on the scalp frontal midline. RESULTS: All patients showed miniaturization. A peripilar brown halo was found in 22 patients, honeycomb-like scalp pigmentation was found in 14 and yellow dots in only 1 patient. Recent studies show dermoscopy as the new tool for diagnosis assistance and treatment follow up in scalp disorders. Our study used an ordinary dermoscope and we evaluated several findings reported in the literature with significant clarity and easiness. CONCLUSION: The dermoscope, which is used by dermatologists on a daily basis, is an excellent tool to assist in early diagnosis and assessment of therapeutic response in androgenetic alopecia. PMID- 23044561 TI - DRESS: clinicopathological features of 10 cases from an University Hospital in Sao Paulo. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms is a severe form of drug-induced reaction with multiorgan involvement. OBJECTIVES: The aim of this study is to evaluate the epidemiological, clinical and pathological features and prognosis of this drug reaction among patients seen at a dermatology service. METHOD: Retrospective review of medical records of ten patients diagnosed with drug reaction with eosinophilia and systemic symptoms at the Federal University of Sao Paulo, from august 2008 to may 2011. RESULTS: Phenytoin was the leading cause of drug reaction with eosinophilia and systemic symptoms in our cases, followed by allopurinol. Abnormal liver function tests were observed in 7 patients and renal function impairment in 2 patients. In all cases, patients were hospitalized and the culprit drug was withdrawn. The main treatment was systemic corticosteroid. Drug reaction with eosinophilia and systemic symptoms resulted in death in 2 cases. The causes of death were septic shock and hepatic failure. CONCLUSION: Our mortality rate of 20%, supports that drug reaction with eosinophilia and systemic symptoms is a severe form of drug-induced reaction and must be recognized by all dermatologists. PMID- 23044560 TI - Assessment of the quality of life of pediatric patients at a center of excellence in dermatology in southern Brazil. AB - BACKGROUND: Skin diseases cause negative impact on the emotional state, social relationships and daily activities, due to the stigma caused by the appearance of the lesions. OBJECTIVE: This study aimed to assess the quality of life of pediatric patients with skin diseases attending a dermatology service, compare the scores obtained among the dermatoses found in the sample and associate them to the variables, in addition to observing how the skin disease specifically affects quality of life. METHODS: Cross-sectional study, with patients between 5 and 16 years attending the Dermatology Service of the University of Health Sciences of Porto Alegre, Brazil, between July 2010 and February 2011. The data collection instruments were the Children's Dermatology Life Quality Index questionnaire and the AUEQI questionnaire. RESULTS: A total of 161 patients were interviewed, with mean age of 9,66 years. The main dermatoses were atopic dermatitis (29.8%), warts (13%) and molluscum contagiosum (7.5%). Chronic diseases (73.9%) were the most prevalent. The overall mean Children's Dermatology Life Quality Index score was 5.01 for chronic dermatoses and 2.07 for acute illnesses, indicating a compromised quality of life among chronically ill patients. The comparison between the scores obtained with the AUEQI scale and the Children's Dermatology Life Quality Index scores indicates that the overall quality of life is less affected than the specific quality of life related to the dermatosis. CONCLUSIONS: The data presented reinforce how important it is that the patients, their families and caregivers understand the symptoms, triggers and treatment of the skin disease in question. This information facilitates adherence to the treatment and justifies the conduct adopted by the dermatologist. PMID- 23044563 TI - Scientific output of Brazilian dermatologists during the last 25 years in the five highest impact factor journals in dermatology. AB - BACKGROUND: The qualitative and quantitative scientific output of Brazilian dermatologists in journals of high impact factor is little known. OBJECTIVE: To describe the scientific output of dermatologists from Brazilian institutions in journals of high impact factor. METHODS: The five journals with the highest impact factor in dermatology were analyzed. All articles produced from Brazilian institutions between 1986 and 2010 were compiled and the following aspects were analyzed: position of Brazilian researchers in the list of authors, selected theme, experimental design, studied disease, area of interest and year of publication. RESULTS: Seventy-four articles written with the participation of Brazilian dermatologists have been identified. Upon grouping the articles in five year periods, an important increase was observed in the Brazilian production from the year 2006 onwards. The dermatologists were placed as second authors in the majority of cases (53.66%). According to the selected theme to be studied, the majority of the articles had a laboratory focus (45.95%). The majority of the articles reported cross-sectional studies or non-controlled clinical trials (both at 17.57%), and pemphigus foliaceus was the most studied disease (29.73%). CONCLUSION: The increase in the number of publications by Brazilian dermatologists over the last years is encouraging, but it is still small in comparison to the total number of articles published in these five periodicals. PMID- 23044562 TI - Immunohistochemical profile of HIF-1alpha, VEGF-A, VEGFR2 and MMP9 proteins in tegumentary leishmaniasis. AB - BACKGROUND: Leishmaniasis is one of the most important infectious diseases worldwide. Our study can provide more knowledge about angiogenic and hypoxic events in leishmaniasis. We attempted to verify whether the HIF-1 alpha protein expression may be associated to VEGF-A, VEGFR2 and MMP9 in leishmanial lesions. OBJECTIVES: Besides understanding the pathway, we performed the correlation of VEGF-A, VEGFR2 and MMP9 proteins. METHODS: In this study, we gathered 54 paraffin blocks taken from skin lesions in patients from northern Minas Gerais, Brazil, with confirmed diagnosis of tegumentary leishmaniasis. Immunohistochemistry was used to evaluate the expression of the proteins. The expression of HIF-1alpha was categorized into two groups according to the median: HIF-1 alpha lower and HIF-1 alpha higher. RESULTS: We observed increase of VEGFR2 and MMP9 protein expressions in HIF-1 alpha higher group of epithelial cells. Spearman analyses in epithelial cells showed correlation between VEGF-A and MMP9, VEGFR2 and MMP9 protein expression. CONCLUSIONS: HIF-1 alpha higher group showed increase of VEGFR2 and MMP9 proteins. In epithelial cells, VEGF-A was correlated to MMP9 protein. Furthermore, considering leukocyte cells, VEGFR2 was negatively correlated to MMP9 protein levels. This pathway possibly prepares the cells for a higher activity in a hypoxic or an angiogenic microenvironment. Other in vitro and in vivo studies may clarify the activation mechanism and the response from the proteins HIF-1 alpha, VEGFR2 and MMP-9 in tegumentary leishmaniasis. PMID- 23044564 TI - Quality of life in children and teenagers with atopic dermatitis. AB - BACKGROUND: Atopic Dermatitis is a disease which has increased during the past years despite our improved understanding of it. OBJECTIVE: To assess the impact of Atopic Dermatitis in the quality of life of children and teenagers and their family. METHOD: A descriptive cross-sectional method with prospective data collection of 50 children and teenagers diagnosed with Atopic Dermatitis ranging in age from 5-16 years. Fifty parents and/or guardians answered the quality of life questionnaires The Children's Dermatology Life Quality Index and Family Dermatitis Impact Questionnaire. The socio-demographic and clinical variables were evaluated by a clinical record chart designed specifically for the research and socioeconomic standardized questionnaire by the Brazilian Association of Research Enterprises, which evaluates assets acquired and the educational level of the head of the household. RESULTS: Thirty-five out of the 50 patients were female (70%), and 28 (56%) of them were from social class C. The Questionnaire Children's Dermatology Life Quality Index showed that 19 (38%) patients ranged from 7 to 12 points (moderate impact of atopic dermatitis) and 17 patients (34%) ranged from 13 to 30 points (high impact of atopic dermatitis). The Family Dermatitis Impact Questionnaire revealed that 15 (30%) families had scores between 7 and 12 points and 22 families (44%) scored between 13 and 30 points. CONCLUSION: The results show that there is a very high impact on the QoL for atopic dermatitis patients and their families. This makes us suggest the importance of including the quality of life study in clinical evaluations. PMID- 23044565 TI - Atopy patch test (APT) in the diagnosis of food allergy in children with atopic dermatitis. AB - BACKGROUND: Atopic Dermatitis is a chronic inflammatory skin disease. Food allergens are important in the pathogenesis in 1/3 of the cases. Several mechanisms are involved in the pathogenesis of Atopic Dermatitis. Immediate reactions are identified by both measurement of specific IgE and skin prick test. Atopy Patch Test seems to be relevant in the investigation of patients with suspected delayed-type reactions. OBJECTIVES: To evaluate the standardization of this method concerning allergen concentration, occlusion time and interpretation, and determine the specificity and sensitivity of the Atopy Patch Test according to the skin prick test and specific IgE levels in food allergy diagnosis in children with Atopic Dermatitis. METHODS: Seventy-two children, aged 2-12 years were selected and followed at the allergy clinic of the Hospital Sao Zacharias. Skin prick test, specific IgE and food Atopy Patch Test (cow's milk, egg, soy and wheat) were carried out. Three groups were submitted to the Atopy Patch Test: (1) Atopic Dermatitis with or without Rhinitis and Asthma; (2) Rhinitis and or Asthma without AD; (3) Healthy individuals. RESULTS: In group 1, 40% of the patients presented positive reactions. The longer the exposure time (48h and 72h), the higher the sensitivity. In group 2, the test was more specific than sensitive for all the extracts, with increased sensitivity the longer the time of exposure (72h). In group 3, 8.3% presented positive tests. CONCLUSION: APT evidenced a great diagnostic value in late-phase reactions to food, with high specificity. It showed to be a specific and reliable tool in comparison with the healthy group's results. PMID- 23044566 TI - Bacterial skin colonization and infections in patients with atopic dermatitis. AB - Atopic Dermatitis is a chronic inflammatory skin disease that affects a large number of children and adults. The disease results from an interaction between genetic predisposition, host environment, skin barrier defects, and immunological factors. A major aggravating factor associated with Atopic Dermatitis is the presence of microorganisms on the patient's skin surface. Staphylococcus aureus and Streptococcus pyogenes, for instance, can exacerbate chronic skin inflammation. As a result, antimicrobials have often been prescribed to control the acute phase of the disease. However, increased bacterial resistance to antimicrobial agents has made it difficult for dermatologists to prescribe appropriate medication. In the presence of disseminated dermatitis with secondary infection, systemic antibiotics need to be prescribed; however, treatment should be individualized, in an attempt to find the most effective antibiotic with fewer side effects. Also, the medication should be used for as short as possible in order to minimize bacterial resistance. PMID- 23044567 TI - Pruritus: still a challenge. AB - Pruritus is a symptom that may be associated with a wide array of diseases - skin diseases, systemic diseases or even those without a defined cause. According to its severity and evolution, it may compromise the patients' quality of life in a significant way. New therapeutic approaches, in which histamine release is not the main event, are being described for pruritus control. Therefore, taking into account the origin of the mediators of pruritus, we conducted a review of the available resources emphasizing that, although very important, anti-histamines are not the answer for every kind of pruritus. PMID- 23044568 TI - Clinical and histological challenge in the differential diagnosis of diffuse alopecia: female androgenetic alopecia, telogen effluvium and alopecia areata - part I. AB - Diffuse androgenetic alopecia (female pattern hair loss), telogen effluvium, and diffuse alopecia areata may have similar clinical manifestations. Subtle details on physical examination and dermoscopy of the scalp may help to identify those disorders. The authors present a practical discussion on how to approach the patient with diffuse alopecia, considering clinical history, physical examination, and dermoscopic findings. If the diagnosis remains unclear after a careful analysis of the clinical signs, a scalp biopsy may help to distinguish between the three diseases. In this first part of our study, an objective review of female androgenetic alopecia is presented and the most important histological changes are discussed. PMID- 23044569 TI - Autoimmune thyroiditis presenting as interstitial granulomatous dermatitis. AB - A 54-year-old female presented with recurrent, widespread, erythematous, painful plaques, over a 3-month period. Skin biopsy was compatible with interstitial granulomatous dermatitis. Additional investigation revealed hypothyroidism and positive anti-thyroid antibodies. Normalization of thyroid function and high potency topical corticosteroids provided only transitory improvement of the dermatosis. Interstitial granulomatous dermatitis is a histologic inflammatory reaction, with variable cutaneous expression. It has been reported in association with several drugs, lymphoproliferative diseases and autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus and vasculitis, but association with autoimmune thyroiditis is rare. Optimal therapy for this condition is yet to be established, but topical corticosteroids have been a mainstay of treatment. In most cases, this disease is characterized by flares and remissions. PMID- 23044570 TI - Calciphylaxis, a diagnostic and therapeutic challenge: report of a successful case. AB - Calciphylaxis, also known as calcific uremic arteriolopathy, is a severe complication often observed in patients with hyperparathyroidism secondary to chronic renal failure, which occurs mainly in women. It is characterized by ischemic tissue loss secondary to progressive vascular compromise. This is a rare and severe condition and its pathogenesis is unclear. The best treatment is prevention, especially in order to maintain adequate levels of calcium and phosphorus. We describe a case of this disease in a patient with hyperparathyroidism secondary to chronic renal failure who underwent medical treatment, surgical debridement and total skin autografts, with resolution of symptoms after 6 months. PMID- 23044571 TI - Corymbiform nodular amyloidosis. AB - Amyloidosis is part of a group of deposition diseases. Nodular amyloidosis is a rare form of primary cutaneous amyloidosis. It affects men and women, usually over the age of 60 years. Presenting manifestation of the disease are yellowish erythematous or brownish nodules or plaques in single or multiple infiltrates. Systemic evaluation should be performed to rule out involvement of other organs. Follow-up of the patient is important because the condition may progress to systemic amyloidosis. We report a case of nodular amyloidosis in which the lesion had a corymbiform aspect without systemic involvement and no recurrence after two years of follow-up. PMID- 23044572 TI - Melolabial fold interpolated flap for reconstruction of complex nasal defects. AB - Complex surgical nasal defects are often technically difficult. We report the case of a 71-year old male diagnosed with a malignant melanoma (animal type; Breslow 1.5; Clark IV) on the right nasal ala. Radial excision with margins of approximately 1.5 cm was performed, creating a complex full-thickness surgical defect involving the free wall and margin of the right nasal ala, the right soft triangle, nasal lobe and columella, which was reconstructed using a melolabial interpolated flap, with highly satisfactory final esthetic result. Interpolated flaps are viable surgical options for the reconstruction of surgical defects for which local flaps and skin grafts are not suitable. PMID- 23044573 TI - Mucormycosis and chromoblastomycosis occurring in a patient with leprosy type 2 reaction under prolonged corticosteroid and thalidomide therapy. AB - Mucormycosis is an uncommon fungal infection caused by Mucorales. It frequently occurs in patients with neutropenia, diabetes, malignancy and on corticoid therapy. However, it is rare in patients with AIDS. Clinical disease can be manifested in several forms. The case reported illustrates the rare occurrence of chromoblastomycosis and mucormycosis in an immunosuppressed patient with multibacillary leprosy, under prolonged corticosteroid and thalidomide therapy to control leprosy type 2 reaction. Neutrophil dysfunction, thalidomide therapy and work activities are some of the risk factors in this case. Chromoblastomycosis was treated by surgical excision and mucormycosis with amphotericin B. Although the prognosis of mucormycosis is generally poor, in the reported case the patient recovered successfully. This case should alert dermatologists to possible opportunistic infections in immunosuppressed patients. PMID- 23044574 TI - Recurrence of peripheral T-cell lymphoma as granulomas in the lower limbs. AB - The presence of granulomas in the skin of T-cell lymphoma patients is a rare but well-known phenomenon. The authors present the case of a 44-year-old Caucasian male, with a previously treated peripheral T-cell lymphoma, with cutaneous infiltration and extensive dyschromia on his lower limbs. Skin biopsies revealed the presence of sarcoid granulomas associated with the recurrence of the lymphoma, confirmed by immunostaining and molecular analysis. Although a new scheme of chemotherapy was started, he died 18 months later. There are two different patterns of skin granulomas associated with lymphoma: granulomatous infiltrates admixed with neoplastic cells and cutaneous granulomas constituting a nonspecific manifestation of the underlying lymphoma, but presently there is no evidence supporting their relationship with lymphoma prognosis. PMID- 23044575 TI - Graham-Little Piccardi Lassueur syndrome: case report. AB - A 33-year-old woman presented with a 3-year history of progressive alopecia of the scalp. Past treatment with hydroxicloroquine did not show improvement. Physical examination revealed multiple areas of alopecia with atrophic aspect of the scalp, and axillary and pubic hypotrichosis. Dermoscopy showed hyperkeratosis and accentuation of follicular ostia. Anatomopathological examination revealed decrease in the number of hair follicles, upper perifollicular infiltrate and areas with fibrosis. The Piccardi-Lassueur-Graham-Little syndrome is a rare disorder, characterized by the triad of multifocal scarring alopecia of the scalp, keratotic follicular eruption and hypotrichosis of axillary and pubic regions. Management is a challenge and many medications tried have controversial results. We report a case of this rare syndrome which improved with corticoids. PMID- 23044576 TI - Kindler syndrome: report of two cases. AB - Kindler syndrome is a rare autosomal recessive genodermatosis characterized by trauma-induced blisters, progressive poikiloderma and varying degrees of photosensitivity. In 2003, loss-of-function mutations were identified in the gene KIND1 mapped to chromosome 20p12.3. In this paper, we report Kindler syndrome in two children born to consanguineous parents presenting acral blistering, photosensitivity, poikiloderma, cutaneous atrophy and periodontitis. PMID- 23044577 TI - In vivo reflectance confocal microscopy in a typical case of melasma. AB - Melasma is a common disorder of hypermelanosis that affects mainly young and middle-aged women of Fitzpatrick's phototypes III-V. The disease significantly impacts their lives. In vivo reflectance confocal microscopy, a spreading technology for the noninvasive evaluation of the skin up to the papillary dermis, provides real-time en face images with cellular resolution. We present a case of melasma with in vivo reflectance confocal microscopy findings closely correlated to the histopathological features described in the literature. PMID- 23044579 TI - White piedra and pediculosis capitis in the same patient. AB - White piedra is a superficial mycosis caused by the genus Trichosporon. It is characterized by nodules on the hair shaft. Pediculosis capitis is caused by Pediculus humanus var. capitis of the suborder Anoplura. Whereas pediculosis is a common infestation, clinical reports of white piedra are rare. Molecular biology procedures identified T. inkin as the agent of white piedra in this case report. The authors present associations between the two diseases in the same patient in order to highlight their clinical differences. PMID- 23044580 TI - Case for diagnosis. Adult-type xanthogranuloma. AB - Male patient, 28 years old, presented with an asymptomatic yellowish erythematous papule on his right thigh. Excisional biopsy was performed for histopathological examination of the lesion. Multinucleated cells (Touton giant cells) were observed. S100 immunohistochemistry was negative for CD1a and positive for CD4 and CD68. Based on clinical and histopathological findings associated with immunohistochemistry, we concluded that it was a case of adult-type xanthogranuloma. Because it was a solitary lesion without other clinical signs and symptoms, the medical conduct adopted was patient orientation. PMID- 23044581 TI - Case for diagnosis. Riga-Fede disease. AB - Riga-Fede disease is a rare, benign disorder characterized by reactive ulceration of the oral mucosa associated with repetitive dental traumatism. It was first described in children with neurologic disorders and is very rare in adults. This case report describes the occurrence of a large ulcer of the tongue, resembling squamous cell carcinoma, in an adult with hemiparesis. The lesion cleared after neurologic recovery. This case highlights the importance of considering this disorder in the differential diagnosis of oral mucosal ulcerations. PMID- 23044582 TI - Case for diagnosis. Papular-purpuric gloves and socks syndrome. AB - Papular-purpuric gloves and socks syndrome is a rare, highly contagious dermatosis caused by parvovirus B19, which may result in the abrupt cessation of red blood cell production in patients with preexisting hematological diseases. It affects predominantly children and young adults and has an unusual presentation. PMID- 23044583 TI - Dimensioning the fear of dermatologic diseases. AB - The symbolic representation of a disease is related to personal perceptions and cultural background. In the present study, the authors evaluate the population knowledge and fears related to skin and other prevalent or severe diseases. This survey was based on a semi-structured form to investigate demographic aspects, dermatologic consultations, fears and knowledge of 19 dermatoses and 11 prevalent or severe diseases. We interviewed 302 people, of which 54% were women and the mean age was 39 years. Some fears of dermatoses surpass those of severe diseases. Skin cancer and total alopecia disclosed fears similar to that of myocardial infarction. PMID- 23044584 TI - Results of patch-tests from Santa Casa de Belo Horizonte Dermatology Clinic, Belo Horizonte, Brazil, from 2003 to 2010. AB - This Dermatology Clinic tests referred patients who have suspected allergic contact dermatitis. The patch-test results (1406 patients) from July 1(st), 2003 to June 30(th), 2010 will be reported and compared to the data from the Brazilian Contact Dermatitis Study Group (GBEDC). A standardized patch test (30 allergens) was used in all of these patients. Depending on the complaint and suspected allergen another battery was also used (cosmetic battery).The most frequent allergens of Brazilian Standard Patch Test Series and Cosmetic Brazilian Standard Patch Test Series were nickel and tosylamide formaldehyde resin, respectively. Allergic contact dermatitis was the final diagnosis in 58.2%. Studies about allergen frequency may enable the performance of prevention programmes. PMID- 23044585 TI - Impetigo. PMID- 23044586 TI - Napsi. PMID- 23044592 TI - Psychogenic nonepileptic seizures: time to abandon the term pseudoseizures. PMID- 23044593 TI - Slowly progressive ataxia, neuropathy, and oculomotor dysfunction. AB - A 54-year-old white man presented with slowly progressive incoordination and weakness. He had normal motor development until, at 16 years of age, he noted difficulty walking and difficulty reading despite normal visual acuity. By the fourth decade of life, he developed poor coordination and balance, as well as inability to walk. In subsequent years, he developed progressive, painless sensory loss, weakness, and atrophy in his distal arms and legs. His vision problems progressed and he also developed dysarthria without dysphagia. Family history was negative except for an uncle who was described as "clumsy." Results of an oculomotor examination were notable for increased square-wave jerks, persistent bilateral gaze-evoked nystagmus with saccadic pursuit, intact vestibulo-ocular reflex, and saccadic dysmetria. He had a mixed dysarthria with flaccid and ataxic characteristics and severe weakness and atrophy in the distal limb muscles. Sensation was diminished to the midforearms and midthighs in all modalities. Deep tendon reflexes were absent throughout, with no response to plantar stimulation. He had marked appendicular ataxia with mild axial ataxia. Magnetic resonance imaging of the brain revealed severe cerebellar atrophy. Results of an electrodiagnostic study suggested a severe axonal sensorimotor polyneuropathy with active and chronic denervation. The differential diagnosis in a patient with ataxia, neuropathy, and oculomotor features is discussed; a methodical approach to the diagnostic workup is suggested; and the final diagnosis is revealed. PMID- 23044595 TI - Cerebral and cervical venous outflow abnormalities are dynamic. PMID- 23044596 TI - Age, statin use, and the risk for incident Parkinson disease. PMID- 23044598 TI - Potassium caffeate/caffeic acid co-crystal: the rat race between the catecholic and carboxylic moieties in an atypical co-crystal. AB - The vast literature concerning caffeic acid and its derivatives lacks any reference to the solid state structures of its inorganic salts as these crystals are quite difficult grow. Most of the already published works deal with computational studies of these compounds as well as investigations of their behaviour in solution. Having obtained good quality potassium caffeate/caffeic acid co-crystals, we solved their structure and used a robust approach, already applied to caffeic acid alone, to compare the X-ray structure with the one inferred by Molecular Dynamics (MD), focusing our attention on the structure property relationships. The reliability of this method is confirmed by the overall agreement extended up to the anisotropic displacement parameters calculated, on one hand, by means of MD and the ones gathered, on the other hand, by X-ray measurements. Moreover, the lack of experimental evidence of an enthalpically favored polymorph, arising from the MD calculations, were explained on the basis of the Shannon's entropy. PMID- 23044599 TI - An enzyme-responsive nanocontainer as an intelligent signal-amplification platform for a multiple proteases assay. AB - Based on selective pore-opening in the presence of protease, we have developed a novel signal amplification assay for multiple proteases detection and their inhibition using protein-capped mesoporous scaffolding as the substrate. PMID- 23044601 TI - Pharmacogenomic update on multiple sclerosis: a focus on actual and new therapeutic strategies. AB - Multiple sclerosis (MS) is an inflammatory and demyelinating disease of central nervous system comprising several subtypes. Pharmacological treatment involves only few drugs. Among these, interferon beta (IFN-beta) and glatiramer acetate were the most used. Although evidence supports the efficacy of these agents in treating MS symptoms, actual studies allowed to introduce new innovative drugs in clinical practice. Applying pharmacogenetic approach to MS, IFN-beta and several other immune pathways were abundantly investigated. Numerous reports identified some promising therapy markers but only few markers have emerged as clinically useful. This may be partially due to differences in clinical and methodological criteria in the studies. Indeed, responder and non-responder definitions lack standardized clinical definition. The goal of this review is to treat advances in research on the pharmacogenetic markers of MS drugs and to highlight possible correlations between type of responses and genetic profile, with regard to clinical and methodological discrepancies in the studies. PMID- 23044602 TI - Pharmacogenomics of phase II metabolizing enzymes and drug transporters: clinical implications. AB - The clinical impact of pharmacogenomics remains a hot topic of current research efforts. Although pharmacogenomics of phase I metabolizing enzymes seems to have been well studied, knowledge on the clinical impact of genetic variability of phase II metabolizing enzymes and drug transporters is more limited. This paper reviews data on the pharmacogenomics of phase II metabolizing enzymes as well as of ATP binding cassette transporters and of solute carrier transporters focusing on clinical implications for drug efficacy and drug toxicity. The clinical impact of some of these polymorphisms has been well defined i.e. the association between polymorphisms of organic anion transporter polypeptides and statin induced myopathy. However, as the same drug may be substrate for different enzymes and different transporters, it is difficult to elucidate the impact of each polymorphism. Investigating the impact of multiple polymorphisms might be more clinically meaningful, although methodologically challenging. PMID- 23044603 TI - Pharmacogenetics of nonsteroidal anti-inflammatory drugs. AB - With the beginning of the Human Genome Project, an emerging field of science was brought to the forefront of the pharmaceutical community. Pharmacogenetics facilitates optimization of the current patient-centered care model and pharmacotherapy as a whole. Utilizing these ever-expanding branches of science to nonsteroidal anti-inflammatory drugs (NSAIDs) can provide novel opportunities to affect patient care. With a wide range of NSAID choices available as treatment options for relieving pain and/or reducing inflammation or fever, a more systematic way of selecting the ideal agent for the patients based upon their genetic information could spare them from a potentially permanent health-care condition. Furthermore, if a patient possesses or lacks certain alleles, serious adverse events can be anticipated and avoided. The tailoring of drug therapy can be achieved using the published data and cutting-edge genetic testing to attain a higher standard of care for patients. PMID- 23044605 TI - Enhanced risk stratification with noninvasive measurement of coronary flow reserve using positron emission tomography. PMID- 23044606 TI - Quest for genes and mechanisms linking the human chromosome 9p21.3 locus to cardiovascular disease. PMID- 23044607 TI - Understanding the low penetrance of bone morphogenetic protein receptor 2 gene mutations: another needle in the haystack. PMID- 23044608 TI - Catheter-assisted pulmonary embolectomy. PMID- 23044609 TI - A bloody mass: rare cardiac tumor as a cause of symptomatic ventricular arrhythmias. PMID- 23044610 TI - First multiparametric cardiovascular magnetic resonance study using ultrasmall superparamagnetic iron oxide nanoparticles in a patient with acute myocardial infarction: new vistas for the clinical application of ultrasmall superparamagnetic iron oxide. PMID- 23044611 TI - Analysis of aortopulmonary window using cardiac magnetic resonance imaging. PMID- 23044613 TI - Letter by van Gelder and Bracke regarding article, "Left ventricular versus simultaneous biventricular pacing in patients with heart failure and a QRS complex >120 milliseconds". PMID- 23044614 TI - Sodium-23 magnetic resonance imaging during and after transient cerebral ischemia: multinuclear stroke protocols for double-tuned (23)Na/(1)H resonator systems. AB - A double-tuned 23Na/1H resonator system was developed to record multinuclear MR image data during and after transient cerebral ischemia. 1H-diffusion-, (1H perfusion, 1H T2-, 1H arterial blood flow- and 23Na spin density-weighted images were then acquired at three time points in a rodent stroke model: (I) during 90 min artery occlusion, (II) directly after arterial reperfusion and (III) one day after arterial reperfusion. Normal 23Na was detected in hypoperfused stroke tissue which exhibited a low 1H apparent diffusion coefficient (ADC) and no changes in 1H T2 relaxation time during transient ischemia, while 23Na increased and ADC values recovered to normal values directly after arterial reperfusion. For the first time, a similar imaging protocol was set-up on a clinical 3T MRI site in conjunction with a commercial double-tuned 1H/23Na birdcage resonator avoiding a time-consuming exchange of resonators or MRI systems. Multinuclear 23Na/1H MRI data sets were obtained from one stroke patient during both the acute and non-acute stroke phases with an aquisition time of 22 min. The lesion exhibiting low ADC was found to be larger compared to the lesion with high 23Na at 9 h after symptom onset. It is hoped that the presented pilot data demonstrate that fast multinuclear 23Na/1H MRI preclinical and clinical protocols can enable a better understanding of how temporal and regional MRI parameter changes link to pathophysiological variations in ischemic stroke tissue. PMID- 23044615 TI - Cystic benign melanosis of the conjunctiva. AB - PURPOSE: To report the clinical and histologic features of cystic benign melanosis. METHODS: This case series reports on the clinical and histopathologic features of 3 patients with enlarging, cystic, brown, pigmented, conjunctival lesions. RESULTS: Slit-lamp examination showed cystic melanotic lesions of bulbar conjunctiva. Histopathologic examination of the biopsy specimens showed epithelial lined cysts in the substantia propria, goblet cells, and secondary pigmentation of basilar keratinocytes. CONCLUSIONS: Cystic benign melanosis, a unique conjunctival lesion, should be differentiated from cystic nevus and primary acquired melanosis. PMID- 23044616 TI - Manual no-fold push-in DSAEK graft insertion technique. AB - PURPOSE: To describe the manual no-fold push-in technique for Descemet stripping automated endothelial keratoplasty (DSAEK) graft insertion and analyze postoperative endothelial cell loss. METHODS: Twenty consecutive patients underwent DSAEK surgery using the manual no-fold push-in technique. This insertion technique uses a 6-mm limbal wound, a Sheets glide, and a Sinskey hook without the need for an inserter or additional instrumentation. RESULTS: Three patients developed graft dislocation, requiring re-bubbling. No primary graft failures were encountered. With an average postoperative follow-up of 13.22 months (SD, 7.94; range, 2.23-26.87), average automated endothelial cell count was 2329.62 cells per mm (SD, 312.78; range, 1657-2928) and the average cell loss was 23.31% (SD, 11.33; range, 5.56-42.76). CONCLUSIONS: This technique uses standard instrumentation and is simple to perform. This series demonstrates that manual graft insertion techniques can be effectively used in DSAEK surgery and provide patients with excellent postoperative results. PMID- 23044619 TI - Symptomatic calcifying pseudotumor of the thoracic spine that resolved with the indomethacin treatment: a case report. AB - STUDY DESIGN: Case report. OBJECTIVE: To report a rare case of calcifying pseudotumor of the thoracic spine that resolved completely with Indomethacin treatment. SUMMARY OF BACKGROUND DATA: A 48-year-old male patient presented with a complaint of left T9 radiculopathy. Computed tomography scan and magnetic resonance images showed a calcifying pseudotumor of the thoracic spine. The nature of this disease remains unknown. This lesion behaves as a tumor-like lesion that is probably inflammatory in nature with a bone-forming potential. METHODS: The patient was treated conservatively with Indomethacin 25 mg 3 times daily for 8 weeks. The lesion was monitored with computed tomography and magnetic resonance imaging at 8 weeks and at 16 weeks after initiation of treatment. RESULTS: The patient had radicular pain for 8 weeks and sleep disturbance for 6 weeks prior to treatment. After he started taking Indomethacin 25 mg 3 times daily, the radicular pain resolved on the third day of Indomethacin treatment. The size of the mass reduced significantly at eighth week follow-up and resolved completely at 16 weeks of follow-up. CONCLUSION: Calcifying pseudotumor of spine should be treated with a trial of Indomethacin before surgical option is offered, unless the patient has a significant progressive neurological deficit that requires urgent surgical intervention. PMID- 23044618 TI - Blood salvage produces higher total blood product costs in single-level lumbar spine surgery. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To determine the incremental cost effectiveness of cell saver for single-level posterior lumbar decompression and fusion (PLDF). SUMMARY OF BACKGROUND DATA: Intraoperative cell salvage is used during surgery to reduce the need for perioperative allogeneic blood transfusion. Although the use of cell saver may be beneficial in certain circumstances, its utility has not been clearly established for the common procedure of an adult single-level PLDF. METHODS: Randomly selected adult patients treated with a single-level PLDF between July 2010 and June 2011 at a single institution were identified. Patients who had a combined anterior and posterior approach were excluded. The final study sample for analysis consisted of 180 patients. Hospital records were reviewed to determine whether: (1) cell saver was available during surgery, (2) recovered autologous blood was infused, and (3) the patient received intra- or postoperative allogeneic transfusions. Estimated blood loss, levels fused, volume(s) transfused, and all related complications were recorded. Costs included the cost of allogeneic blood transfusion, setting up the cell saver recovery system, and infusing autologous blood from cell saver, whereas effectiveness measures were allogeneic blood transfusions averted and quality adjusted life years. RESULTS: The incremental cost-effectiveness ratio was $55,538 per allogeneic transfusion averted, with a decrease in the transfusion rate from 40.0% to 38.7% associated with the cell saver approach. This translated into an incremental cost-effectiveness ratio of $5,555,380 per quality adjusted life years gained, which is well above the threshold for an intervention to be considered cost-effective ($100,000 per quality adjusted life years gained). CONCLUSION: The use of cell saver during a single-level PLDF does not significantly reduce the need for allogeneic blood transfusion and is not cost effective. The high cost of cell saver in combination with the low complication rate of allogeneic blood transfusion, suggest that cell saver should not be used for single-level PLDF. Further studies are needed to evaluate the necessity for cell saver among other types of spinal surgery. PMID- 23044621 TI - Unknown case: part 1. PMID- 23044620 TI - Changes in bone mineral density in the intertransverse fusion mass after instrumented single-level lumbar fusion: a prospective 1-year follow-up. AB - STUDY DESIGN: Prospective cohort. OBJECTIVE: The purpose of this study was to evaluate changes in bone mineral density (BMD) in the intertransverse fusion mass as representative for the process of bone remodeling after spinal fusion. SUMMARY OF BACKGROUND DATA: Intertransverse bone graft is frequently applied to facilitate bony fusion between 2 spinal levels. The biological process of bone graft remodeling leading to eventual fusion is, however, poorly understood. METHODS: In 20 patients with a single-level instrumented posterolateral lumbar fusion for low-grade spondylolisthesis, radiographs, and clinical outcome scores (visual analogue scale for back and leg pain, Oswestry Disability Index, Short Form-36) were obtained. Locally harvested laminectomy bone was used as intertransverse bone graft. The BMD in selected "regions of interest" at both intertransverse fusion areas was assessed on days 4 and 3, after a period of 6 and 12 months after surgery using dual-energy x-ray absorptiometry scans. Eventual fusion status was assessed on computed tomographic scan at 12 months. RESULTS: All clinical outcome scores significantly improved at the final follow up (P < 0.05). Baseline BMD in both paraspinal fusion areas was expressed as 100%, which significantly decreased from 81% to 75% and 77% to 70% at 3 and 6 months, for regions of interest 1 and 2, respectively (P < 0.001). From 6 to 12 months, there was an increase in BMD from 90% to 80%, for regions of interest 1 and 2 (P = 0.296). On computed tomography scan a complete fusion was noticed in 70% of the patients. CONCLUSION: Repeated dual-energy x-ray absorptiometry was able to elucidate the biological process of bone graft remodeling in the intertransverse fusion mass. An active bone remodeling process was quantified with profound resorption or demineralization of the graft during the first 6 months, followed by subsequent bone apposition and restoration of BMD at the final follow-up. No difference in trend in BMD change between patients with and without fusion could be established; however, no firm conclusions can be drawn from small patient numbers. PMID- 23044622 TI - Unknown case: part 2. PMID- 23044623 TI - Posterior vertebral column resection for the treatment of dystrophic kyphosis associated with type-1 neurofibromatosis: a case report and review of the literature. AB - STUDY DESIGN: Case report. OBJECTIVE: To describe the use of posterior-only vertebral column resection and postoperative traction for spinal deformity associated with type-1 neurofibromatosis (NF1). SUMMARY OF BACKGROUND DATA: Vertebral deformity, namely, thoracic scoliosis, is the predominant orthopedic manifestation of NF1. Patients may present with debilitating pain and rarely, myelopathy. The commonly dystrophic nature of these deformities makes them particularly recalcitrant to surgical correction. Traditionally, circumferential arthrodesis via combined anterior and posterior approaches has been recommended. METHODS: Clinical and radiographical case review. RESULTS: A 14-year-old adolescent boy with NF1, severe cervicothoracic angular kyphosis, thoracic dislocation, and myelopathy presented status postmultiple anterior and posterior spinal fusions. The patient underwent posterior-only vertebral column resection after 6 weeks of halo-gravity traction. The surgery consisted of thoracic laminectomies, total corpectomies of T3 and T4, circumferential fusion, and posterior instrumentation from the occiput to T11. Autologous rib and iliac crest grafts were used as fusion substrate. Postoperatively, a halo vest was worn for 4 months to support the correction of his chin-on-chest deformity. The patient's neurological status returned to normal by 6 weeks postoperatively, and solid fusion was radiologically evident after 1 year. CONCLUSION: We think that posterior-only vertebral column resection represents a safe and efficacious but technically challenging option for the treatment of angular kyphotic spinal deformity and associated neurological deficit in patients with NF1. PMID- 23044624 TI - Effect of hepatocyte growth factor and angiotensin II on rat cardiomyocyte hypertrophy. AB - Angiotensin II (Ang II) plays an important role in cardiomyocyte hypertrophy. The combined effect of hepatocyte growth factor (HGF) and Ang II on cardiomyocytes is unknown. The present study was designed to determine the effect of HGF on cardiomyocyte hypertrophy and to explore the combined effect of HGF and Ang II on cardiomyocyte hypertrophy. Primary cardiomyocytes were isolated from neonatal rat hearts and cultured in vitro. Cells were treated with Ang II (1 uM) alone, HGF (10 ng/mL) alone, and Ang II (1 uM) plus HGF (10 ng/mL) for 24, 48, and 72 h. The amount of [3H]-leucine incorporation was then measured to evaluate protein synthesis. The mRNA levels of beta-myosin heavy chain and atrial natriuretic factor were determined by real-time PCR to evaluate the presence of fetal phenotypes of gene expression. The cell size of cardiomyocytes was also studied. Ang II (1 uM) increased cardiomyocyte hypertrophy. Similar to Ang II, treatment with 1 uM HGF promoted cardiomyocyte hypertrophy. Moreover, the combination of 1 uM Ang II and 10 ng/mL HGF clearly induced a combined pro-hypertrophy effect on cardiomyocytes. The present study demonstrates for the first time a novel, combined effect of HGF and Ang II in promoting cardiomyocyte hypertrophy. PMID- 23044625 TI - The RecX protein interacts with the RecA protein and modulates its activity in Herbaspirillum seropedicae. AB - DNA repair is crucial to the survival of all organisms. The bacterial RecA protein is a central component in the SOS response and in recombinational and SOS DNA repairs. The RecX protein has been characterized as a negative modulator of RecA activity in many bacteria. The recA and recX genes of Herbaspirillum seropedicae constitute a single operon, and evidence suggests that RecX participates in SOS repair. In the present study, we show that the H. seropedicae RecX protein (RecX Hs) can interact with the H. seropedicaeRecA protein (RecA Hs) and that RecA Hs possesses ATP binding, ATP hydrolyzing and DNA strand exchange activities. RecX Hs inhibited 90% of the RecA Hs DNA strand exchange activity even when present in a 50-fold lower molar concentration than RecA Hs. RecA Hs ATP binding was not affected by the addition of RecX, but the ATPase activity was reduced. When RecX Hs was present before the formation of RecA filaments (RecA ssDNA), inhibition of ATPase activity was substantially reduced and excess ssDNA also partially suppressed this inhibition. The results suggest that the RecX Hs protein negatively modulates the RecA Hs activities by protein-protein interactions and also by DNA-protein interactions. PMID- 23044627 TI - Effect of heat and moisture exchangers on the prevention of ventilator-associated pneumonia in critically ill patients. AB - Ventilator-associated pneumonia (VAP) remains one of the major causes of infection in the intensive care unit (ICU) and is associated with the length of hospital stay, duration of mechanical ventilation, and use of broad-spectrum antibiotics. We compared the frequency of VAP 10 months prior to (pre intervention group) and 13 months after (post-intervention group) initiation of the use of a heat and moisture exchanger (HME) filter. This is a study with prospective before-and-after design performed in the ICU in a tertiary university hospital. Three hundred and fourteen patients were admitted to the ICU under mechanical ventilation, 168 of whom were included in group HH (heated humidifier) and 146 in group HME. The frequency of VAP per 1000 ventilator-days was similar for both the HH and HME groups (18.7 vs 17.4, respectively; P = 0.97). Duration of mechanical ventilation (11 vs 12 days, respectively; P = 0.48) and length of ICU stay (11 vs 12 days, respectively; P = 0.39) did not differ between the HH and HME groups. The chance of developing VAP was higher in patients with a longer ICU stay and longer duration of mechanical ventilation. This finding was similar when adjusted for the use of HME. The use of HME in intensive care did not reduce the incidence of VAP, the duration of mechanical ventilation, or the length of stay in the ICU in the study population. PMID- 23044628 TI - Clinicopathological significance of PTPN12 expression in human breast cancer. AB - Protein tyrosine phosphatase non-receptor type 12 (PTPN12) is a recently identified tumor suppressor gene (TSG) that is frequently compromised in human triple-negative breast cancer. In the present study, we investigated the expression of PTPN12 protein by patients with breast cancer in a Chinese population and the relationship between PTPN12 expression levels and patient clinicopathological features and prognosis. Additionally, we explored the underlying down-regulation mechanism from the perspective of an epigenetic alteration. We examined PTPN12 mRNA expression in five breast cancer cell lines using semi-quantitative reverse-transcription PCR, and detected PTPN12 protein expression using immunohistochemistry in 150 primary invasive breast cancer cases and paired adjacent non-tumor tissues. Methylation-specific PCR was performed to analyze the promoter CpG island methylation status of PTPN12. PTPN12 was significantly down-regulated in breast cancer cases (48/150) compared to adjacent noncancerous tissues (17/150; P < 0.05). Furthermore, low expression of PTPN12 showed a significant positive correlation with tumor size (P = 0.047), lymph node metastasis (P = 0.001), distant metastasis (P = 0.009), histological grade (P = 0.012), and survival time (P = 0.019). Additionally, promoter CpG island hypermethylation occurs more frequently in breast cancer cases and breast cancer cell lines with low PTPN12 expression. Our findings suggest that PTPN12 is potentially a methylation-silenced TSG for breast cancer that may play an important role in breast carcinogenesis and could potentially serve as an independent prognostic factor for invasive breast cancer patients. PMID- 23044629 TI - Sex ratios among children of lupus pregnancies. PMID- 23044630 TI - The roles of identity formation and moral identity in college student mental health, health-risk behaviors, and psychological well-being. AB - OBJECTIVES: This study examined the roles of identity formation and moral identity in predicting college student mental health (anxiety and depressive symptoms), health-risk behaviors (hazardous alcohol use and sexual risk taking), and psychological well-being (self-esteem and meaning). METHOD: The sample comprised 9,500 college students (aged 18-25 years, mean = 19.78, standard deviation = 1.61; 73% female; 62% European American), from 31 different universities, who completed an online self-report survey. RESULTS: Structural equation models found that identity maturity (commitment making and identity synthesis) predicted 5 of the health outcomes (except sexual risk taking), and moral identity predicted all of the health outcomes. In most cases identity maturity and moral identity also interacted in predicting mental health and psychological well-being, but not health-risk behaviors. CONCLUSIONS: The maturity and specific contents of identity may both play unique and often interactive roles in predicting college student health. Thus, college student health might be bolstered by helping them establish appropriate identity commitments. PMID- 23044631 TI - Laser patterning of conductive gold micronanostructures from nanodots. AB - Gold nanodots were used as the precursory material to form micronanopatterns under pinpoint scanning by a tightly focused femtosecond laser beam. Different from the widely reported metal ions photoreduction mechanism, here gradient force in an optical trap generated around the laser focus is considered as the major mechanism for particle accumulation (focusing). It has been proven to be an effective method for gold micronanostructure fabrication, and the electronic resistivity of the resulting metals reached as high as 5.5 * 10(-8) Omega m, only twice that of the bulk material (2.4 * 10(-8) Omega m). This merit makes it a novel free interconnection technology for micronanodevice fabrication. PMID- 23044632 TI - Comparing work productivity in obesity and binge eating. AB - OBJECTIVE: To examine productivity impairment in individuals with obesity and/or binge eating. METHOD: Based on current weight and eating behavior, 117,272 employees who had completed a health risk appraisal and psychosocial functioning questionnaire were classified into one of four groups. Gender-stratified analyses compared groups on four measures: absenteeism, presenteeism, total work productivity impairment, and (non-work) activity impairment. RESULTS: Overall group differences were statistically significant for all measures with lowest impairment in non-obese men and women without binge eating (n = 34,090, n = 39,198), higher levels in individuals without binge eating (n = 15,570, n = 16,625), yet higher levels in non-obese men and women with binge eating (n = 1,381, n = 2,674), and highest levels in obese men and women with binge eating (Group 4, n = 2,739, n = 4,176). DISCUSSION: Health initiatives for obese employees should include screening and interventions for employees with binge eating. PMID- 23044633 TI - Incorporation of penicillin-producing fungi into living materials to provide chemically active and antibiotic-releasing surfaces. AB - Living materials: artificial biological niches are loaded with the penicillin producing mold Penicillium chrysogenum. This living material consumes food through a nanoporous top layer and releases the antibiotic on-site. No reloading of the active compound is needed. Gram-positive bacteria were efficiently killed if nearby, whereas Gram-negative bacteria (control experiment, not sensitive to penicillin) were not affected. PMID- 23044635 TI - The safety of escitalopram during pregnancy and breastfeeding: a comprehensive review. AB - OBJECTIVE: Escitalopram (ESC) is considered one of the most effective selective serotonin reuptake inhibitors for the treatment of major depression. However, little is known on its potential risk of inducing major malformations (MMs) and perinatal complications (PCs). Hence, aim of the present study is to provide a comprehensive review of the available literature on the safety profile of ESC during pregnancy and breastfeeding. METHODS: MEDLINE and PubMed databases were searched for English language articles by using the following keywords: escitalopram, selective serotonin reuptake inhibitors, major malformations, perinatal complications, pregnancy, and breastfeeding. RESULTS: Although some cases of MMs have been reported after maternal exposure to ESC during early pregnancy, the rate of these adverse events is substantially in the range of those reported in unexposed women. On the contrary, exposure to ESC seems to be significantly associated with some PCs. No adverse effects have been reported in the few studies evaluating its safety during breastfeeding. CONCLUSIONS: The available data seem to support the notion that ESC might be considered safe during pregnancy, in particular as far as MMs is concerned. However, similar to other selective serotonin reuptake inhibitors, it could be associated with an increased risk of PCs. Given the paucity of the studies published so far, no definitive conclusions can be drawn on its safety profile during breastfeeding. PMID- 23044634 TI - RchyOptimyx: cellular hierarchy optimization for flow cytometry. AB - Analysis of high-dimensional flow cytometry datasets can reveal novel cell populations with poorly understood biology. Following discovery, characterization of these populations in terms of the critical markers involved is an important step, as this can help to both better understand the biology of these populations and aid in designing simpler marker panels to identify them on simpler instruments and with fewer reagents (i.e., in resource poor or highly regulated clinical settings). However, current tools to design panels based on the biological characteristics of the target cell populations work exclusively based on technical parameters (e.g., instrument configurations, spectral overlap, and reagent availability). To address this shortcoming, we developed RchyOptimyx (cellular hieraRCHY OPTIMization), a computational tool that constructs cellular hierarchies by combining automated gating with dynamic programming and graph theory to provide the best gating strategies to identify a target population to a desired level of purity or correlation with a clinical outcome, using the simplest possible marker panels. RchyOptimyx can assess and graphically present the trade-offs between marker choice and population specificity in high dimensional flow or mass cytometry datasets. We present three proof-of-concept use cases for RchyOptimyx that involve 1) designing a panel of surface markers for identification of rare populations that are primarily characterized using their intracellular signature; 2) simplifying the gating strategy for identification of a target cell population; 3) identification of a non-redundant marker set to identify a target cell population. PMID- 23044636 TI - Time encoded multicolor fluorescence detection in a microfluidic flow cytometer. AB - We describe an optical detection technique that delivers high signal-to-noise discrimination to enable a multi-parameter flow cytometer that combines high performance, robustness, compactness and low cost. The enabling technique is termed "spatially modulated detection" and generates a time-dependent signal as a continuously fluorescing (bio-) particle traverses an optical transmission pattern along the fluidic channel. Correlating the detected signal with the expected transmission pattern achieves high discrimination of the particle signal from background noise. Additionally, the particle speed and its fluorescence emission characteristics are deduced from the correlation analysis. Our method uses a large excitation/emission volume along the fluidic channel in order to increase the total flux of fluorescence light that originates from a particle while requiring minimal optical alignment. Despite the large excitation/detection volume, the mask pattern enables a high spatial resolution in the micron range. This allows for detection and characterization of particles with a separation (in flow direction) comparable to the dimension of individual particles. In addition, the concept is intrinsically tolerant of non-encoded background fluorescence originating from fluorescent components in solution, fluorescing components of the chamber and contaminants on its surface. The optical detection technique is illustrated with experimental results of multicolor detection with a single large area detector by filtering fluorescence emission of different particles through a patterned color mask. Thereby the particles' fluorescence emission spectrum is encoded in a time dependent intensity signal and color information can be extracted from the correlation analysis. The multicolor detection technique is demonstrated by differentiation of micro-beads loaded with PE (Phycoerythrin) and PE-Cy5 that are excited at 532 nm. PMID- 23044637 TI - Assessment of left ventricular 2D flow pathlines during early diastole using spatial modulation of magnetization with polarity alternating velocity encoding: a study in normal volunteers and canine animals with myocardial infarction. AB - A high-temporal resolution 2D flow pathline analysis method to study early diastolic filling is presented. Filling patterns in normal volunteers (n = 8) and canine animals [baseline (n = 1) and infarcted (n = 6)] are studied. Data are acquired using spatial modulation of magnetization with polarity alternating velocity encoding, which permits simultaneous quantification of 1D blood velocities (using phase contrast encoding) and myocardial strain (using spatial modulation of magnetization tagging and harmonic phase analysis) at high-temporal resolution of 14 ms within a single breath hold. Virtual emitter particles, released from the mitral valve plane every time frame during rapid filling, are tracked to depict the 2D pathlines on the imaged plane. The pathline regional distribution is compared with myocardial longitudinal strains and to regional pressure gradients. Quantitative analysis of net kinetic energy of pathlines is finally performed. Our results demonstrate a linear correlation (r(2) = 0.85) between pathline spatial distribution and myocardial strain. Peak net kinetic energy of 0.06 +/- 0.01 mJ in normal volunteers, 0.043 mJ in baseline dog, 0.143 +/- 0.03 mJ in infarcted dogs with nominal flow dysfunction, and 0.016 +/- 0.007 mJ in infarcted dogs with severe flow dysfunction is observed. In conclusion, 2D pathline analysis provides a direct regional assessment of early diastolic filling patterns and is sensitive to abnormalities in early diastolic filling. PMID- 23044638 TI - The effect of very small air gaps on small field dosimetry. AB - The purpose of this study was to investigate the effect of very small air gaps (less than 1 mm) on the dosimetry of small photon fields used for stereotactic treatments. Measurements were performed with optically stimulated luminescent dosimeters (OSLDs) for 6 MV photons on a Varian 21iX linear accelerator with a Brainlab uMLC attachment for square field sizes down to 6 mm * 6 mm. Monte Carlo simulations were performed using EGSnrc C++ user code cavity. It was found that the Monte Carlo model used in this study accurately simulated the OSLD measurements on the linear accelerator. For the 6 mm field size, the 0.5 mm air gap upstream to the active area of the OSLD caused a 5.3% dose reduction relative to a Monte Carlo simulation with no air gap. A hypothetical 0.2 mm air gap caused a dose reduction >2%, emphasizing the fact that even the tiniest air gaps can cause a large reduction in measured dose. The negligible effect on an 18 mm field size illustrated that the electronic disequilibrium caused by such small air gaps only affects the dosimetry of the very small fields. When performing small field dosimetry, care must be taken to avoid any air gaps, as can be often present when inserting detectors into solid phantoms. It is recommended that very small field dosimetry is performed in liquid water. When using small photon fields, sub millimetre air gaps can also affect patient dosimetry if they cannot be spatially resolved on a CT scan. However the effect on the patient is debatable as the dose reduction caused by a 1 mm air gap, starting out at 19% in the first 0.1 mm behind the air gap, decreases to <5% after just 2 mm, and electronic equilibrium is fully re-established after just 5 mm. PMID- 23044639 TI - Inappropriate prescribing and related hospital admissions in frail older persons according to the STOPP and START criteria. AB - BACKGROUND: Over the last few years, the Screening Tool of Older Person's Prescriptions (STOPP) and Screening Tool to Alert doctors to Right Treatment (START) criteria have been increasingly used to evaluate the prevalence of inappropriate prescribing. However, very few studies have evaluated the link between these criteria and clinical outcomes. OBJECTIVES: The objectives of this study were to evaluate the prevalence of inappropriate prescribing according to STOPP and START in a population of frail elderly persons admitted acutely to hospital; to evaluate whether these inappropriate prescribing events contributed to hospital admissions; and to identify determinants of hospital admissions potentially related to inappropriate prescribing. METHODS: This was a cross sectional study including all frail older patients admitted to a 975-bed teaching hospital over a 12-month period. A pharmacist and a geriatrician independently detected events of prescribing of potentially inappropriate medication (PIM) and potential prescribing omission (PPO), using the STOPP and START criteria, respectively, in all patients included in the study. They determined whether the inappropriate prescribing event was the main cause or a contributory cause of hospital admission. Demographic, clinical and geriatric clinical syndromes (i.e. cognitive impairment, falls) were evaluated as potential determinants of hospital admissions related to inappropriate prescribing, using multivariate methods (i.e. logistic regression and a classification tree). RESULTS: 302 frail older persons (median age 84 years) were included in the study. PIMs (prevalence 48%) mainly involved overuse and/or misuse of benzodiazepines, aspirin and opiates. PPOs (prevalence 63%) were mainly related to underuse of calcium and vitamin D supplementation, aspirin and statins. Overall, inappropriate prescribing according to STOPP (54 PIMs) and/or START (38 PPOs) led or contributed to hospital admission in 82 persons (27%). The multivariate analyses indicated a relation between PIM-related admissions and a history of previous falls (p < 0.001), while the PPO-related admissions were associated with a history of osteoporotic fracture (p < 0.001) and atrial fibrillation (p = 0.004). CONCLUSIONS: Using the STOPP and START criteria, it was found that inappropriate prescribing events (both PIMs and PPOs) were frequent and were associated with a substantial number of acute hospital admissions in frail older persons. Fall induced osteoporotic fracture was the most important cause of hospital admission related to inappropriate prescribing and should be a priority for pharmacological optimization approaches. PMID- 23044640 TI - Melatonin prolonged release: in the treatment of insomnia in patients aged >=55 years. AB - Melatonin prolonged release (PR) 2 mg is approved for the treatment of primary insomnia characterized by poor sleep quality in patients aged >=55 years in the EU and elsewhere. Patients may receive treatment with melatonin PR for up to 13 weeks. Production of endogenous nocturnal melatonin, which helps regulate circadian rhythm, may be decreased in older adults. Administration of melatonin PR 2 mg 1-2 h before bedtime mimics the natural secretion pattern of melatonin, thereby leading to improvements in the circadian regulation of the sleep-wake cycle. In older adults, melatonin PR 2 mg had no effect on psychomotor functions, memory recall or driving skills during the night or the next morning relative to placebo, and was associated with significantly less impairment on many of these tasks relative to zolpidem 10 mg alone or in combination with melatonin PR 2 mg. In 3-week and 6-month, randomized, double-blind clinical trials in patients with primary insomnia aged >=55 years, melatonin PR 2 mg 1-2 h before bedtime was associated with significant improvements relative to placebo in many sleep and daytime parameters, including sleep quality and latency, morning alertness and health-related quality of life. Melatonin PR 2 mg was very well tolerated in clinical trials in older patients, with a tolerability profile that was similar to that of placebo. Short- or longer-term treatment with melatonin PR 2 mg was not associated with dependence, tolerance, rebound insomnia or withdrawal symptoms. PMID- 23044643 TI - Home HIV testing: good news but not a game changer. PMID- 23044645 TI - Smoking and survival after radical cystectomy for bladder cancer. AB - OBJECTIVE: To present our long-term follow-up data to investigate whether cigarette smoking is associated with the prognosis of bladder cancer after radical cystectomy. Despite the close link between cigarette smoking and the development of bladder cancer, little is known about the influence of cigarette smoking on the bladder cancer prognosis after radical cystectomy. MATERIALS AND METHODS: The cigarette smoking status of 602 patients who had undergone radical cystectomy for bladder cancer was determined using questionnaires completed before surgery. The effect of cigarette smoking on recurrence-free survival, cancer-specific survival, and overall survival was determined. RESULTS: Of the 340 patients with a smoking history, 159 were current smokers. The smokers were younger (P = .001) and more likely to be male (P = .001) than were the nonsmokers. The 5-year recurrence-free survival rate of the smokers and nonsmokers was 62.1% and 56.8% (P = .182), the 5-year cancer-specific survival rate was 67.3%, 63.9% (P = .436), and the 5-year overall survival rate was 63.0% and 58.8% (P = .309), respectively. Multivariate analysis revealed that smoking was not an independent predictor of recurrence-free survival or cancer-specific survival. After adjusting for other prognostic variables, cigarette smoking status (non-, ex-, or current smoker), cumulative exposure, and years from smoking cessation were not associated with cancer-specific survival (P = .378, P = .827, and P = .876, respectively). CONCLUSION: The results of the present study found no association between cigarette smoking and the prognosis of bladder cancer after radical cystectomy. PMID- 23044646 TI - ICEFormat-the image cytometry experiment format. PMID- 23044644 TI - The cochlear implant: historical aspects and future prospects. AB - The cochlear implant (CI) is the first effective treatment for deafness and severe losses in hearing. As such, the CI is now widely regarded as one of the great advances in modern medicine. This article reviews the key events and discoveries that led up to the current CI systems, and we review and present some among the many possibilities for further improvements in device design and performance. The past achievements include: (1) development of reliable devices that can be used over the lifetime of a patient; (2) development of arrays of implanted electrodes that can stimulate more than one site in the cochlea; and (3) progressive and large improvements in sound processing strategies for CIs. In addition, cooperation between research organizations and companies greatly accelerated the widespread availability and use of safe and effective devices. Possibilities for the future include: (1) use of otoprotective drugs; (2) further improvements in electrode designs and placements; (3) further improvements in sound processing strategies; (4) use of stem cells to replace lost sensory hair cells and neural structures in the cochlea; (5) gene therapy; (6) further reductions in the trauma caused by insertions of electrodes and other manipulations during implant surgeries; and (7) optical rather electrical stimulation of the auditory nerve. Each of these possibilities is the subject of active research. Although great progress has been made to date in the development of the CI, including the first substantial restoration of a human sense, much more progress seems likely and certainly would not be a surprise. PMID- 23044647 TI - Anti-mullerian hormone and ovarian reserve in systemic lupus erythematosus. AB - OBJECTIVE: To study the level of anti-mullerian hormone (AMH) and its relationship to age and previous exposure to cyclophosphamide (CYC) in patients with systemic lupus erythematosus (SLE). METHODS: Consecutive female patients ages 18-52 years who had menses at least once during the preceding 12 months and fulfilled >=4 American College of Rheumatology criteria for SLE were recruited. AMH was determined using an enzyme-linked immunosorbent assay (ELISA) kit. Serum AMH levels were compared in patients with and without previous use of immunosuppressive agents. The relationship of the AMH level to the patient's age and CYC exposure was studied by linear regression and receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 216 patients were studied (mean+/-SD age 35.1+/-10.1 years, mean+/-SD SLE duration 7.6+/-5.9 years). The mean+/-SD AMH level was significantly lower in patients previously exposed to CYC therapy than in those who had not been exposed after adjustment for age (1.58+/-2.92 versus 1.73+/-2.11 ng/ml; P=0.04). The median time interval between the AMH assay and the last dose of CYC administered was 6.7 years (interquartile range 3.4-8.5). AMH levels in users versus nonusers of other immunosuppressive agents, including mycophenolate mofetil, azathioprine, and the calcineurin inhibitors, were not statistically different. Linear regression revealed increasing age (beta -0.32, P=0.02) and each 5 gm of CYC exposure (beta 0.28, P=0.047) were independently associated with a lower AMH level. In patients ages 30 years and younger, a cumulative CYC dose cutoff of 5.9 gm yielded a sensitivity of 0.75 and a specificity of 0.80 for the prediction of undetectable AMH level on ROC curve analysis. CONCLUSION: AMH is a sensitive marker for ovarian damage due to previous CYC exposure in women with SLE. PMID- 23044648 TI - Three-dimensional assemblies of graphene prepared by a novel chemical reduction induced self-assembly method. AB - In this study, three-dimensional (3D) graphene assemblies are prepared from graphene oxide (GO) by a facile in situ reduction-assembly method, using a novel, low-cost, and environment-friendly reducing medium which is a combination of oxalic acid (OA) and sodium iodide (NaI). It is demonstrated that the combination of a reducing acid, OA, and NaI is indispensable for effective reduction of GO in the current study and this unique combination (1) allows for tunable control over the volume of the thus-prepared graphene assemblies and (2) enables 3D graphene assemblies to be prepared from the GO suspension with a wide range of concentrations (0.1 to 4.5 mg mL(-1)). To the best of our knowledge, the GO concentration of 0.1 mg mL(-1) is the lowest GO concentration ever reported for preparation of 3D graphene assemblies. The thus-prepared 3D graphene assemblies exhibit low density, highly porous structures, and electrically conducting properties. As a proof of concept, we show that by infiltrating a responsive polymer of polydimethylsiloxane (PDMS) into the as-resulted 3D conducting network of graphene, a conducting composite is obtained, which can be used as a sensing device for differentiating organic solvents with different polarity. PMID- 23044649 TI - Cyclopentadienylruthenium pi complexes of subphthalocyanines: a "drop-pin" approach to modifying the electronic features of aromatic macrocycles. AB - Facing facts: Coordination of Cp*Ru (Cp*=C(5)Me(5)) to the concave and convex pi surfaces of subphthalocyanines constitutes a new approach to the functionalization of subazaporphyrins. While the convex face shows higher reactivity, coordination to the concave side produces a stronger diatropic influence on the Cp* ligand and a greater perturbation of the macrocyclic pi electronic features. PMID- 23044650 TI - Increased emergency department use by adolescents and young adults with eating disorders. AB - OBJECTIVE: This study describes patterns of emergency department (ED) utilization by patients who screen positive for eating disorders. METHOD: ED patients aged 14 20 years (n = 1,920) completed a computerized questionnaire. The analyses compared the rates of ED use between patients who screened positive for an eating disorder and those who did not and examined the reasons for ED use amongst patients with eating disorders. RESULTS: ED patients who screened positive for eating disorders were significantly more likely to have previously visited the ED and, on average, utilized the ED at a rate 1.6 times higher than patients who screen negative for eating disorders. The most common chief complaints among patients who screen positive for eating disorders were abdominal pain and other gastrointestinal-related problems. DISCUSSION: Patients with eating disorders utilize the ED more frequently than those without and commonly present for complaints seemingly unrelated to their eating disorder. PMID- 23044651 TI - Post-traumatic stress disorder symptoms in emotionally distressed individuals referred for a depression prevention intervention: relationship to problem solving skills. AB - OBJECTIVES: This study examined the rates of syndromal and subthreshold post traumatic stress disorder (PTSD) and PTSD symptom scores in participants with symptoms of emotional distress, subsyndromal depression, and a history of traumatic exposure. Participants had been referred to a study of an indicated depression prevention intervention using problem-solving therapy in primary care. We hypothesized that higher severity of PTSD symptom scores would predict poorer problem-solving skills. In addition, some reports have suggested that there are higher rates of PTSD in minority populations relative to Caucasians; thus we hypothesized that race would also predict problem-solving skills in these individuals. METHODS: We examined the rates of traumatic exposure, syndromal, and subthreshold PTSD. In those exposed to trauma, we performed a multiple linear regression to examine the effects of PTSD symptoms, depression symptoms, race, age, and gender on social problem-solving skills. RESULTS: Of the 244 participants, 64 (26.2%) reported a traumatic event; 6/234 (2.6%) had syndromal PTSD, and 14/234 (6.0%) had subthreshold PTSD. By way of regression analysis, higher PTSD symptom scores predicted poorer problem-solving skills. In addition, racial status (Caucasian vs. African American) predicted problem-solving skills; Caucasians exhibited lower levels of problem-solving skills. CONCLUSIONS: Individuals presenting with subsyndromal depressive symptoms may also have a history of traumatic exposure, subthreshold and syndromal PTSD. Thus, screening these individuals for PTSD symptoms is important and may inform clinical management decisions because problem-solving skills are lower in those with more severe PTSD symptoms (even after adjusting for race, age, gender, and depressive symptoms). PMID- 23044652 TI - Pleural infections: a 9-year review of bacteriology, case characteristics and mortality. AB - BACKGROUND: Despite advances in medical therapies, pleural infections remain a common disease. The characteristics of this disease seem to change over time, with alterations in patient characteristics and bacteriology. The purpose of this study was to provide a retrospective descriptive analysis of pleural infections during a 9-year period. METHODS: We performed a single-center retrospective review of all culture-positive pleural infections between January 2000 and December 2008. The primary outcome was assessment of long-term survival and associated independent risk factors affecting survival. Length of survival was determined using the Social Security Death Index. Case characteristics and bacteriology were reviewed for descriptive analysis. RESULTS: During a 9-year period, 187 culture-positive pleural infections were identified. Review of bacteriology revealed gram-positive cocci as the predominate organisms, most commonly Streptococcus and Staphylococcus. Anaerobes were found in 9.1% of the cases. Independent risk factors associated with risk of death based on multivariable survival analysis were age older than 65, cirrhosis and past and present malignancy. The hospital mortality was 10.7%, and the 1-year, 3-year and 5-year estimated survival rates were 73.8%, 63.3% and 60.6%, respectively. CONCLUSIONS: Pleural infections continue to remain a major health problem and carry significant morbidly and mortality. The importance of Staphylococcus aureus in this population has yet to be fully examined, and although potentially underestimated in this study, anaerobic infections remain a common pathogen. PMID- 23044653 TI - Inhaled sevoflurane may promote progression of amnestic mild cognitive impairment: a prospective, randomized parallel-group study. AB - BACKGROUND: Amnestic mild cognitive impairment (aMCI) is thought to be a transitional stage between normal aging and the development of Alzheimer's disease (AD). Recent studies have suggested that the inhalational anesthetic isoflurane can induce caspase activation and apoptosis, increase aggregates of beta-amyloid (Abeta) levels, and enhance Abeta aggregation. The aim of this study was to investigate whether previous exposure to different anesthetics induced progression of aMCI. METHODS: A prospective, randomized parallel-group study was completed with 180 patients with aMCI who were randomly assigned to a sevoflurane, propofol or lidocaine epidural anesthesia group (n = 60 per group) during an L3 to L4 or an L4 to L5 spinal surgery. Sixty additional outpatients with aMCI served as a control group. Before surgery, all subjects underwent a neuropsychological assessment. Cerebrospinal fluid (CSF) was obtained by lumbar puncture, and neuropsychological assessments were completed in the clinic. CSF Abeta42, total tau and phosphorylated tau181 were quantitatively assayed. The neuropsychological assessments were repeated after 2 years. RESULTS: Two years after anesthesia, the number of AD cases that emerged did not differ significantly between the groups. However, the number of cases of progressive MCI was greater in the sevoflurane group than in the control group. Age correlated linearly with aMCI progression, whereas sex did not. Both patients with AD and progressive MCI had decreased CSF Abeta42, increased total tau and increased phosphorylated tau levels compared with those with stable MCI and the controls. CONCLUSIONS: Inhaled sevoflurane accelerated the progression of aMCI to progressive MCI in this selected Chinese population. PMID- 23044654 TI - Is risk factor control and guideline-based medical therapy optimal in patients with nonobstructive coronary artery disease? A Veterans Affairs study. AB - BACKGROUND: Aggressive risk factor modification using evidence-based secondary prevention strategies is recommended in coronary artery disease (CAD). Utilization of such strategies was compared in patients with nonobstructive CAD (NOCAD) and obstructive CAD (OCAD). METHODS: Patients undergoing coronary angiography (excluding normal coronary angiograms), between January 2006 and June 2006, at the Veterans Affairs Medical Center were included. Demographic, clinical and treatment data were compared between the groups at baseline and 1 year. RESULTS: Of the 354 patients who underwent coronary angiography, 222 (63%) had follow-up data available at 12 +/- 2 months. The mean age in the NOCAD (n = 119) and OCAD (n = 103) groups was similar. There was a lower prevalence of hypertension and heart failure (P < 0.05) in the NOCAD group. Compared with the OCAD group, aspirin use was similar but statin use was lower in the NOCAD group (P = 0.008). At 1 year, statin use (P = 0001) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (P = 0.001) were significantly lower, whereas the use of aspirin was numerically lower (P = 0.06) in the NOCAD group. Mean low-density lipoprotein cholesterol levels were at goal (<100 mg/dL) in the NOCAD group at baseline and 1 year, whereas the same slightly worsened in the OCAD group at 1 year. CONCLUSIONS: The use of evidence-based medical therapy is lower in patients with NOCAD compared with those with OCAD. Improved awareness among health care providers and a unified effort to implement secondary prevention strategies may help correct such deficiencies. PMID- 23044656 TI - Matriptase is highly upregulated in chronic lymphocytic leukemia and promotes cancer cell invasion. PMID- 23044655 TI - Optical stimulation and imaging of functional brain circuitry in a segmented laminar flow chamber. AB - Microfluidic technology is emerging as a useful tool for the study of brain slices, offering precise delivery of chemical factors along with robust oxygen and nutrient transport. However, continued reliance upon electrode-based physiological recording poses inherent limitations in terms of physical access, as well as the number of sites that can be sampled simultaneously. In the present study, we combine a microfluidic laminar flow chamber with fast voltage-sensitive dye imaging and laser photostimulation via caged glutamate to map neural network activity across large cortical regions in living brain slices. We find that the closed microfluidic chamber results in greatly improved signal-to-noise performance for optical measurements of neural signaling. These optical tools are also leveraged to characterize laminar flow interfaces within the device, demonstrating a functional boundary width of less than 100 MUm. Finally, we utilize this integrated platform to investigate the mechanism of signal propagation for spontaneous neural activity in the developing mouse hippocampus. Through the use of localized Ca(2+) depletion, we provide evidence for Ca(2+) dependent synaptic transmission. PMID- 23044657 TI - Quantification of mitochondrial toxicity in HIV-infected individuals by quantitative PCR compared to flow cytometry. AB - BACKGROUND: Non-invasive diagnostic assays to evaluate mitochondrial toxicity could have significant clinical utility for HIV-infected individuals on antiretroviral therapy (ART). METHODS: This study compared the ratio of mitochondrial to nuclear DNA determined by quantitative polymerase chain reaction (qPCR) to the ratio of mitochondrial to nuclear-encoded proteins by flow cytometry, in peripheral blood mononuclear cells from 73 HIV-infected individuals with and without risk factors for mitochondrial toxicity. RESULTS: PCR detected similar mitochondrial/nuclear DNA in HIV-infected individuals without a history of ART, and those receiving ART with lipodystrophy, lipoatrophy, or a history of suspected lactic acidosis. However, the ratio was significantly greater in ART untreated compared to those receiving either stavudine or didanosine. In contrast, flow cytometry did not detect any differences in mitochondrial/nuclear protein (Lin et al., Cytometry B 2009;76B:181-190). There was no correlation between the assays (rho = -0.05, P = 0.65). CONCLUSIONS: Assessment of the mitochondrial/nuclear DNA ratio by qPCR performed better than the mitochondrial/nuclear-encoded protein ratio by flow cytometry to detect adverse effects of nucleoside analogs on mitochondria. PMID- 23044658 TI - Changes in bone sclerostin levels in mice after ovariectomy vary independently of changes in serum sclerostin levels. AB - We examined the effects that ovariectomy had on sclerostin mRNA and protein levels in the bones of 8-week-old mice that were either sham-operated (SHAM) or ovariectomized (OVX) and then euthanized 3 or 6 weeks later. In this model, bone loss occurred between 3 and 5 weeks postsurgery. In calvaria, ovariectomy significantly decreased sclerostin mRNA levels at 6 weeks postsurgery (by 52%) but had no significant effect at 3 weeks. In contrast, sclerostin mRNA levels were significantly lower in OVX femurs at 3 weeks postsurgery (by 53%) but equal to that of SHAM at 6 weeks. The effects of ovariectomy on sclerostin were not a global response of osteocytes because they were not mimicked by changes in the mRNA levels for two other relatively osteocyte-specific genes: DMP-1 and FGF-23. Sclerostin protein decreased by 83% and 60%, at 3 and 6 weeks postsurgery in calvaria, respectively, and by 38% in lumbar vertebrae at 6 weeks. We also detected decreases in sclerostin by immunohistochemistry in cortical osteocytes of the humerus at 3 weeks postsurgery. However, there were no significant effects of ovariectomy on sclerostin protein in femurs or on serum sclerostin at 3 and 6 weeks postsurgery. These results demonstrate that ovariectomy has variable effects on sclerostin mRNA and protein in mice, which are dependent on the bones examined and the time after surgery. Given the discrepancy between the effects of ovariectomy on serum sclerostin levels and sclerostin mRNA and protein levels in various bones, these results argue that, at least in mice, serum sclerostin levels may not accurately reflect changes in the local production of sclerostin in bones. Additional studies are needed to evaluate whether this is also the case in humans. PMID- 23044659 TI - Updated analysis of standardized photoprovocation in patients with cutaneous lupus erythematosus. AB - OBJECTIVE: To determine the frequency and reproducibility of standardized photoprovocation in patients with cutaneous lupus erythematosus (CLE) and report our long-term experience. METHODS: Photoprovocation using a standardized protocol was evaluated retrospectively in 566 patients. A diagnosis of CLE was clinically and/or histologically confirmed in 431 patients, and 315 patients with polymorphic light eruption (PLE) were additionally included as controls. Data were statistically analyzed using an SPSS database. RESULTS: A total of 61.7% of the 431 CLE patients exhibited a positive photoprovocation, with a significantly longer latency period for the development of skin lesions after ultraviolet (UV) A and/or UVB irradiation than PLE patients (P < 0.001). The frequency of positive photoprovocation varied among the CLE subtypes, and intermittent CLE was the most photosensitive disease entity (74.8%). Subsequent photoprovocation in 35 patients demonstrated that CLE patients with an initial positive result exhibited a significantly higher frequency of a positive photoprovocation at a later time point (P = 0.013). However, an initial positive photoprovocation did not definitively predict a positive reaction at a later time point. Moreover, patient history of photosensitivity was not a predictor for the photoprovocation outcome. CONCLUSION: Standardized photoprovocation is a useful tool to reproducibly induce skin lesions and objectively evaluate photosensitivity in patients with CLE. These data further suggest that the reaction to UV light may change during the course of this heterogeneous disease and that photosensitivity should not be excluded in patients with a negative history of photosensitivity. PMID- 23044660 TI - The rheumatoid arthritis synovial fluid citrullinome reveals novel citrullinated epitopes in apolipoprotein E, myeloid nuclear differentiation antigen, and beta actin. AB - OBJECTIVE: To generate a catalog of citrullinated proteins that are present in the synovia of patients with rheumatoid arthritis (RA) and to elucidate their relevance for the anti-citrullinated protein antibody response in RA. METHODS: Polypeptides isolated from the synovial fluid of patients with RA were identified by mass spectrometry. Three proteins (apolipoprotein E [Apo E], myeloid nuclear differentiation antigen [MNDA], and beta-actin) were studied in more detail, using immunoprecipitation and Western blotting. The presence of autoantibodies to synthetic peptides derived from these proteins in sera from patients with RA, sera from patients with other diseases, and sera from healthy control subjects was studied by enzyme-linked immunosorbent assay (ELISA). RESULTS: RA synovial fluid samples displayed several distinct patterns of citrullinated proteins. Using mass spectrometry, (fragments of) 192 proteins were identified, including 53 citrullinated proteins, some of which contained multiple citrullinated residues. In addition to previously reported citrullinated proteins in RA synovia (e.g., vimentin and fibrinogen), a series of novel citrullinated proteins, including Apo E, MNDA, beta-actin, and cyclophilin A, was identified. Immunoprecipitation experiments confirmed the citrullination of Apo E and MNDA. ELISAs demonstrated the presence of autoreactive citrullinated epitopes in Apo E, MNDA, and beta-actin. CONCLUSION: Synovial fluid samples from the inflamed joints of patients with RA contain many citrullinated proteins. Citrullinated Apo E, MNDA, and beta-actin are novel antigens identified in RA synovial fluid, and only a limited number of their citrullinated epitopes are targeted by the immune system in RA. PMID- 23044662 TI - The Relationship between Sexual Minority Verbal Harassment And Utilization of Health Services: Results from Countywide Risk Assessment Survey (CRAS) 2004. AB - We examined the prevalence of and associations between sexual orientation-based verbal harassment and reported utilization of health services across levels of sexual orientation in a diverse sample of adult recipients of Los Angeles County funded HIV-related health and social services. Thirty-two percent reported they had experienced verbal harassment, the majority (80.3%) of whom identified as lesbian, gay, orbisexual. Those who reported being verbally harassed received significantly more services overall than those who were not verbally harassed, and service utilization varied by sexual orientation. These findings inform future efforts to identify and assess social discrimination in health and social service settings. PMID- 23044664 TI - Progress toward development of a multichannel vestibular prosthesis for treatment of bilateral vestibular deficiency. AB - This article reviews vestibular pathology and the requirements and progress made in the design and construction of a vestibular prosthesis. Bilateral loss of vestibular sensation is disabling. When vestibular hair cells are injured by ototoxic medications or other insults to the labyrinth, the resulting loss of sensory input disrupts vestibulo-ocular reflexes (VORs) and vestibulo-spinal reflexes that normally stabilize the eyes and body. Affected individuals suffer poor vision during head movement, postural instability, chronic disequilibrium, and cognitive distraction. Although most individuals with residual sensation compensate for their loss over time, others fail to do so and have no adequate treatment options. A vestibular prosthesis analogous to cochlear implants but designed to modulate vestibular nerve activity during head movement should improve quality of life for these chronically dizzy individuals. We describe the impact of bilateral loss of vestibular sensation, animal studies supporting feasibility of prosthetic vestibular stimulation, the current status of multichannel vestibular sensory replacement prosthesis development, and challenges to successfully realizing this approach in clinical practice. In bilaterally vestibular-deficient rodents and rhesus monkeys, the Johns Hopkins multichannel vestibular prosthesis (MVP) partially restores the three-dimensional (3D) VOR for head rotations about any axis. Attempts at prosthetic vestibular stimulation of humans have not yet included the 3D eye movement assays necessary to accurately evaluate VOR alignment, but these initial forays have revealed responses that are otherwise comparable to observations in animals. Current efforts now focus on refining electrode design and surgical technique to enhance stimulus selectivity and preserve cochlear function, optimizing stimulus protocols to improve dynamic range and reduce excitation-inhibition asymmetry, and adapting laboratory MVP prototypes into devices appropriate for use in clinical trials. PMID- 23044665 TI - Identification and characterization of kidney transplants with good glomerular filtration rate at 1 year but subsequent progressive loss of renal function. AB - BACKGROUND: After the first year after kidney transplantation, 3% to 5% of grafts fail each year but detailed studies of how grafts progress to failure are lacking. This study aimed to analyze the functional stability of kidney transplants between 1 and 5 years after transplantation and to identify initially well-functioning grafts with progressive decline in allograft function. METHODS: The study included 788 adult conventional kidney transplants performed at the Mayo Clinic Rochester between January 2000 and December 2005 with a minimum graft survival and follow-up of 2.6 years. The modification of diet in renal disease equation for estimating glomerular filtration rate (eGFR(MDRD)) was used to calculate the slope of renal function over time using all available serum creatinine values between 1 and 5 years after transplantation. RESULTS: Most transplants demonstrated good function (eGFR(MDRD) >=40 mL/min) at 1 year with positive eGFR(MDRD) slope between 1 and 5 years after transplantation. However, a subset of grafts with 1-year eGFR(MDRD) >=40 mL/min exhibited strongly negative eGFR(MDRD) slope between 1 and 5 years suggestive of progressive loss of graft function. Forty-one percent of this subset reached graft failure during follow up, accounting for 69% of allograft failures occurring after 2.5 years after transplantation. This pattern of progressive decline in estimated glomerular filtration rate despite good early function was associated with but not fully attributable to factors suggestive of enhanced antidonor immunity. CONCLUSIONS: Longitudinal analysis of serial estimated glomerular filtration ratemeasurements identifies initially well-functioning kidney transplants at high risk for subsequent graft loss. For this subset, further studies are needed to identify modifiable causes of functional decline. PMID- 23044666 TI - Lack of relationship between microvascular and macrovascular disease in heart transplant recipients. AB - BACKGROUND: A key determinant of long-term survival in heart transplant recipients is the development of coronary vasculopathy. Both coronary macrovascular and microvascular disease are prognostically important. However, the relationship between these in transplant patients and the determinants of microvascular disease are not known. METHODS: We reviewed the simultaneously obtained endomyocardial biopsies and intravascular ultrasound (IVUS) images of coronary arteries in 33 heart transplant recipients. Coronary microvascular disease was classified by light microscopy into four grades based on thickening of endothelial cell layer and stenotic versus nonstenotic medial wall thickening. Macrovascular disease was evaluated from IVUS studies and assigned into one of five grades based on the Stanford classification. Coronary microvascular and macrovascular diseases were compared. RESULTS: Age at transplantation was 26 (18) years; 67% were men, and the average time to posttransplantation study was 4 years. Endomyocardial biopsy revealed more advanced grade C and D microvascular disease in 45% and 36% of the patients, respectively. However, IVUS analysis for macrovascular disease revealed mostly lesser changes with grade 1 in 12%, grade 2 in 61%, and grade 3 in 21%. There was no significant correlation between grades of microvascular and macrovascular disease (P=0.10). Microvascular disease correlated positively with donor age (P=0.06) and treatment with tacrolimus (0=0.02) and statins (P=0.05). CONCLUSIONS: There is a poor relationship between coronary microvascular and macrovascular disease in patients with cardiac transplants, likely indicating divergent pathogenetic mechanisms. Microvascular disease increases with donor age. There is an intriguing positive relationship between microvascular disease and treatment with statins and tacrolimus. PMID- 23044667 TI - Influence of anisotropic conductivity in the skull and white matter on transcranial direct current stimulation via an anatomically realistic finite element head model. AB - To establish safe and efficient transcranial direct current stimulation (tDCS), it is of particular importance to understand the electrical effects of tDCS in the brain. Since the current density (CD) and electric field (EF) in the brain generated by tDCS depend on various factors including complex head geometries and electrical tissue properties, in this work, we investigated the influence of anisotropic conductivity in the skull and white matter (WM) on tDCS via a 3D anatomically realistic finite element head model. We systematically incorporated various anisotropic conductivity ratios into the skull and WM. The effects of anisotropic tissue conductivity on the CD and EF were subsequently assessed through comparisons to the conventional isotropic solutions. Our results show that the anisotropic skull conductivity significantly affects the CD and EF distribution: there is a significant reduction in the ratio of the target versus non-target total CD and EF on the order of 12-14%. In contrast, the WM anisotropy does not significantly influence the CD and EF on the targeted cortical surface, only on the order of 1-3%. However, the WM anisotropy highly alters the spatial distribution of both the CD and EF inside the brain. This study shows that it is critical to incorporate anisotropic conductivities in planning of tDCS for improved efficacy and safety. PMID- 23044668 TI - Client perceptions of therapy component helpfulness in group cognitive-behavioral therapy for anxiety disorders. AB - OBJECTIVE(S): Treatment credibility and client satisfaction have received relatively little research attention, but extant findings indicate that some clients and therapists differ in their perceptions of what is helpful about therapy, with greater divergence related to poorer outcomes. This study examined relationships between treatment credibility, perceptions of therapy helpfulness, and treatment response. METHOD: Participants were 48 individuals (60.4% female; 53.2% Caucasian; mean age 32.79 years) with an anxiety disorder diagnosis. Participants completed a 12-week transdiagnostic treatment protocol; treatment credibility was rated after session 2, and treatment component helpfulness was rated posttreatment. RESULTS: Treatment response was significantly correlated with perceived helpfulness of cognitive restructuring and exposure techniques, but not treatment credibility. Treatment responders recognized the helpfulness of factors considered to be important therapeutic processes. CONCLUSIONS: Findings emphasize the importance of client perceptions of cognitive and behavioral techniques in treatment and suggest the need to monitor client perceptions throughout the treatment process. PMID- 23044670 TI - Colectomy for endoscopically unresectable polyps: how often is it cancer? AB - BACKGROUND: Colonoscopy has an established role in reducing the burden of colorectal cancer through early detection and removal of polyps. For endoscopically unresectable polyps, colectomy is generally indicated to prevent malignant transformation or to remove cancer already present. OBJECTIVE: This study aimed to determine the incidence of malignancy and the factors predictive of malignancy in surgically resected benign polyps. DESIGN/PATIENTS/SETTING: This study was a retrospective chart review of patients undergoing a colectomy for a colonic polyp (no preoperative diagnosis of cancer) in 4 hospitals within the Mayo Clinic Health System. MAIN OUTCOME MEASURES: Patient characteristics, endoscopic location and size, and preoperative and operative polyp pathology were tabulated. Correlations between these features and the finding of invasive carcinoma on surgical pathology were assessed. RESULTS: A total of 750 patients met our inclusion criteria. Patients were predominantly male (55.2%) with an average age of 69.4 +/- 9.8 years. A majority of polyps were located in the right colon (70.9%). Invasive cancer was identified in 133 patients (17.7%). Multivariate analysis revealed polyps in the left colon (adjusted OR 2.13, 95% CI (1.22-3.72)), and those with high-grade dysplasia (adjusted OR 4.60, 95% CI (2.91 7.27)) were more likely to harbor carcinoma. Age, sex, polyp dimension, and villous features were not predictive of malignancy. Of the patients with cancer, 31 (23.3%) had nodal disease. LIMITATIONS: This study is limited by its retrospective nature, the change in terminology and technique over time, and the partially subjective nature of an endoscopically unresectable polyp. CONCLUSIONS: The finding that polyp size and villous features do not strongly predict malignancy differs from previous endoscopic studies. This study confirms that polyps located in the left colon or with high-grade dysplasia are more likely to harbor cancer. The results of this study suggest that endoscopically unresectable polyps are best treated by radical oncologic resection. PMID- 23044671 TI - Rectal cancer patients' quality of life with a temporary stoma: shifting perspectives. AB - BACKGROUND: Patients with rectal cancer who have a temporary ostomy report good quality of life despite identifying a number of stoma-related difficulties. OBJECTIVE: This study aimed to qualitatively explore the experiences of patients with rectal cancer who have a temporary ileostomy to better understand the discordant findings of previous quantitative quality-of-life studies. DESIGN/SETTING: We conducted in-depth qualitative interviews with patients with stage I to III rectal cancer who underwent sphincter-preserving surgery that resulted in a temporary ileostomy. PATIENTS: Twenty-six patients (54% male, median age 54) participated. Sixty-five percent had stage III disease, and 88% received neoadjuvant therapy. MAIN OUTCOME MEASURES: Interviews examined preoperative expectations, overall experience, and stoma impact on quality of life. With the use of grounded theory, 2 investigators independently performed line-by-line content analysis to identify key themes. Analysis continued until data saturation. RESULTS: Two major themes were identified: stoma-related difficulties and perceived response shift. Patients reported difficulty in exercise, sleep, social activities, sexuality, and clothing. Patients' perception of quality of life with a temporary stoma appears to have undergone a response shift through recalibration of their standards for measuring quality of life (internal measurement scale altered by side effects of neoadjuvant/adjuvant treatment, temporary nature of stoma, and accommodation to stoma) and reconceptualization of what "good quality of life" is (stoma difficulties were felt to be less important in comparison with cancer-related mortality). LIMITATIONS: Although qualitative research is, by design, not generalizable, these data support our previous quantitative work. This convergence of findings suggests that our data may be representative. CONCLUSIONS: A temporary ileostomy represents significant difficulties for patients with rectal cancer. However, because of response shift, these difficulties may not be perceived as important to overall quality of life when considered within the context of the cancer experience. Our results can inform preoperative consultations with patients who have rectal cancer to assist in aligning patient expectations of what life with a temporary ileostomy may be like. PMID- 23044673 TI - A comparison of the quality of life of ulcerative colitis patients after IPAA vs ileostomy. AB - BACKGROUND: Total proctocolectomy with IPAA is frequently considered the procedure of choice for surgical patients with ulcerative colitis, presumably owing to an expectation of improved quality of life in comparison with an ileostomy. OBJECTIVE: The goal of our study was to determine whether long-term quality of life among patients with a pelvic pouch is better than those who chose a permanent stoma. DESIGN: This investigation is a cross-sectional observational study using a prospective database. SETTING: This study was conducted at an academic medical center. PATIENTS: Consecutive patients who had undergone IPAA or a permanent ileostomy for ulcerative colitis by a single surgeon, presenting for their annual follow-up visit from July through September 2011, were offered participation in the study. A randomly chosen group of subjects who did not have scheduled appointments during the study period were sent a letter inviting them to participate in the study. MAIN OUTCOME MEASURES: The primary outcome measures used were EQ-5D-3L, the Short Quality of Life in Inflammatory Bowel Disease questionnaire, the Cleveland Global Quality of Life instrument, the Fecal Incontinence Quality of Life scale, and the Stoma Quality of Life scale. RESULTS: Thirty-five patients with a pelvic pouch and 24 ostomates were accrued and comprehensively studied. Global quality-of-life scores were virtually identical for the 2 groups. Patients with a pelvic pouch had better subscores in current quality of health and energy level, Fazio score, sexuality/body image, and work/social function. LIMITATIONS: This study was limited by its small sample size, and some of our patients were enrolled through mailed surveys and, hence, nonresponse bias may be present. The follow-up time since surgery was longer in the pelvic pouch group than in the ileostomy group. CONCLUSION: Informed patients with ulcerative colitis choosing an ileostomy have a health-related global quality of life very similar to patients with a pelvic pouch. Better outcomes in patients with an ileal pouch were most evident in the areas of sexuality/body image and work/social function. PMID- 23044672 TI - Positive histological inflammatory margins are associated with increased risk for intra-abdominal septic complications in patients undergoing ileocolic resection for Crohn's disease. AB - BACKGROUND: Rates of postoperative complications are particularly high among patients with Crohn's disease. OBJECTIVE: The aim of this study was to assess whether positive inflammatory histological margins, among other factors, pose a risk for intra-abdominal septic complications in patients with Crohn's disease undergoing ileocolic resection. DESIGN: A retrospective study of patient records, during 2000-2010, was conducted. SETTINGS: This investigation was performed at a single medical center. PATIENTS: Included were 166 individuals with Crohn's disease (85 males, mean age 35.6). INTERVENTION: Ileocolic resection with primary anastomosis was performed. MAIN OUTCOME MEASURE: The primary outcomes measured were postoperative intra-abdominal septic complications. RESULTS: Twenty-five patients (15%) developed intra-abdominal septic complications, including anastomotic leak, intra-abdominal abscesses and collections, and enterocutaneous fistulas. There were no postoperative deaths. Univariate analysis revealed that a long course of disease before surgery, an emergency surgery, steroid treatment of more than 3 months before surgery, additional sigmoidectomy, and positive surgical margins detected on histopathological examination were associated with intra-abdominal septic complications. In a multivariate analysis, only disease duration longer than 10 years (OR 4.575 (CI 1.592-13.142), p = 0.005), additional sigmoidectomy (OR 5.768 (CI 1.088-30.568), p = 0.04), and positive histological resection margins (OR 2.996 (CI 1.085-8.277), p = 0.03) were found to be independent risk factors. LIMITATIONS: This study was limited by the incomplete data regarding preoperative albumin levels. CONCLUSIONS: Positive histological margins, disease duration of more than 10 years, and added sigmoidectomy are independent risk factors that are associated with postoperative intra-abdominal septic complications in patients undergoing ileocolic resection for Crohn's disease. These risk factors should be considered when the need for a diverting stoma is questionable. A frozen section of the margins may assist in the decision as to a temporary ileostomy construction. PMID- 23044674 TI - Venous thromboembolism after surgery for inflammatory bowel disease: are there modifiable risk factors? Data from ACS NSQIP. AB - BACKGROUND: Although it is commonly reported that IBD patients are at increased risk for venous thromboembolic events, little real-world data exist regarding their postoperative incidence and related outcomes in everyday practice. OBJECTIVE: We aimed to identify the rate of venous thromboembolism and modifiable risk factors within a large cohort of surgical IBD patients. DESIGN: We performed a retrospective review of IBD patients who underwent colorectal procedures. PATIENTS: Patient data were obtained from the American College of Surgeons National Surgical Quality Improvement Program 2004 to 2010 Participant Use Data Files. MAIN OUTCOME MEASURES: The primary outcomes measured were short-term (30 day) postoperative venous thromboembolism (deep vein thrombosis and pulmonary embolism). Clinical variables were analyzed by univariate and multivariate analyses to identify modifiable risk factors for these events. RESULTS: A total of 10,431 operations were for Crohn's disease (52.1%) or ulcerative colitis (47.9%), and 242 (2.3%) venous thromboembolic events occurred (178 deep vein thromboses, 46 pulmonary embolisms, 18 both) for a combined rate of 1.4% in Crohn's disease and 3.3% in ulcerative colitis. Deep vein thrombosis and pulmonary embolism each occurred at a mean of 10.8 days postoperatively (range for each, 0-30 days). A multivariate model found that bleeding disorder, steroid use, anesthesia time, emergency surgery, hematocrit <37%,malnutrition, and functional status were potentially modifiable risk factors that remained associated (p < 0.05) with venous thromboembolism on regression analysis. Patients with thromboembolism had longer length of stay (18.8 vs 8.9 days), more complications (41% vs 18%), and a higher risk of death (4% vs 0.9%). LIMITATIONS: This study was limited by its retrospective design and its limited generalizability to nonparticipating hospitals. CONCLUSIONS: Inflammatory bowel disease patients are at increased risk for postoperative venous thromboembolism. Reducing preoperative anemia, steroid use, malnutrition, and anesthesia time may also reduce venous thromboembolism in this at-risk population. Risk-reducing, preventative strategies are needed in this at-risk population. PMID- 23044675 TI - Mutation in TAGAP is protective of anal sepsis in ileocolic Crohn's disease. AB - BACKGROUND: Anal complications of Crohn's disease range from painless skin tags to debilitating fistulas that are imperfectly treated with tumor necrosis factor antagonists. The recent discovery of more than 190 single-nucleotide polymorphisms associated with Crohn's disease offers the opportunity to genetically define the severity of anal disease in Crohn's disease and possibly predict prognosis and anti-tumor necrosis factor response. OBJECTIVES: This study aimed to identify single nucleotide polymorphisms associated with anal disease generally, septic anal disease specifically and the responsivity to anti-tumor necrosis factor treatment. DESIGN: All patients with ileocolonic Crohn's disease were identified from our IBD registry. One hundred ninety-six Crohn's disease related single-nucleotide polymorphisms were analyzed by the use of a custom microarray chip. Patients' response to anti-tumor necrosis factor treatment was then assessed. RESULTS: One hundred sixteen patients with ileocolonic Crohn's disease were identified and assigned to septic anal disease (abscesses/fistulas, n = 35), benign anal disease (skin tags/fissures/isolated pain, n = 17), and no anal disease (n = 64) cohorts. Single-nucleotide polymorphism rs212388 negatively correlated with the presence of anal disease overall and septic disease specifically. The presence of the non-wild-type allele 'G' was protective of anal sepsis with homo- and heterozygotes having a 75% chance of no anal disease (p = 0.0001). The homozygous wild-type group had the highest risk of septic disease and included 3 of 4 patients requiring diverting ileostomies. Twenty-four patients were treated with anti-tumor necrosis factors. Nine had a beneficial response (assessed at >6 months); however, no single-nucleotide polymorphism correlated with anti-tumor necrosis factor response. Rs212388 is associated with the TAGAP molecule involved in T-cell activation. CONCLUSIONS: Rs212388 most significantly correlated with the presence and severity of anal disease in ileocolonic Crohn's disease. A single copy of the risk allele was protective, whereas wild-type homozygotes had the highest risk of septic disease and stoma creation. In this select group, no single-nucleotide polymorphism was predictive of anti-tumor necrosis factor response. Mutations in TAGAP may predict a more benign form and course of anal disease in Crohn's disease. PMID- 23044676 TI - Body surface area: a new predictor factor for conversion and prolonged operative time in laparoscopic colorectal surgery. AB - BACKGROUND: Body surface area is a measurement of body size used in clinical settings. Its impact on laparoscopic colorectal surgery has not been previously studied. OBJECTIVE: The aim of this study was to assess the impact of body surface area on the conversion rate and laparoscopic operative time. DESIGN: This study was conducted as a retrospective analysis of prospectively collected data. SETTING: This study was conducted at a single tertiary care institution. PATIENTS: Nine hundred sixteen consecutive patients operated on between January 2004 and August 2011 were identified from a prospective database. MAIN OUTCOME MEASURES: Conversion rate and laparoscopic operative time were analyzed related to age, sex, obesity, disease location (colon vs rectum), type of disease (neoplastic vs nonneoplastic), history of previous surgery, and body surface area; body surface area was calculated by the Mosteller formula. Body surface area was analyzed by the use of median and quartile cutoff values (1.6, 1.8, and 2.0). Multivariate models were adjusted for different confounders. Interaction between body surface area and BMI was ruled out. RESULTS: The conversion rate was 10%. Conversion rates for quartiles 1, 2, 3, and 4 were 4.4%, 8.3%, 12.7%, and 14.8%, p = 0.001. Patients with body surface area >= 1.8 had a higher conversion rate than those with body surface area <1.8 (13.9% vs 5.3%, OR: 2.35 (95% CI: 1.45-3.86; p = 0.0001)). Multivariate analysis showed that body surface area >= 1.8 was associated with conversion (OR: 2, 95% CI: 1.1-3.7, p = 0.02) and a longer operative time after adjusting for sex, age, obesity, disease location (rectum vs colon), and type of laparoscopic approach. LIMITATION: This was a single-institution retrospective study. CONCLUSION: Body surface area is a predictor for conversion and longer laparoscopic operative time. It should be considered when informing patients, selecting cases in the early learning curve, and assessing standard of care. PMID- 23044677 TI - Preoperative oral antibiotics reduce surgical site infection following elective colorectal resections. AB - BACKGROUND: Surgical site infection is a major cause of morbidity after colorectal resections. Despite evidence that preoperative oral antibiotics with mechanical bowel preparation reduce surgical site infection rates, the use of oral antibiotics is decreasing. Currently, the administration of oral antibiotics is controversial and considered ineffective without mechanical bowel preparation. OBJECTIVE: The aim of this study is to examine the use of mechanical bowel preparation and oral antibiotics and their relationship to surgical site infection rates in a colorectal Surgical Care Improvement Project cohort. DESIGN: This retrospective study used Veterans Affairs Surgical Quality Improvement Program preoperative risk and surgical site infection outcome data linked to Veterans Affairs Surgical Care Improvement Project and Pharmacy Benefits Management data. Univariate and multivariable models were performed to identify factors associated with surgical site infection within 30 days of surgery. SETTINGS: This study was conducted in 112 Veterans Affairs hospitals. PATIENTS: Included were 9940 patients who underwent elective colorectal resections from 2005 to 2009. MAIN OUTCOME MEASURE: The primary outcome measured was the incidence of surgical site infection. RESULTS: Patients receiving oral antibiotics had significantly lower surgical site infection rates. Those receiving no bowel preparation had similar surgical site infection rates to those who had mechanical bowel preparation only (18.1% vs 20%). Those receiving oral antibiotics alone had an surgical site infection rate of 8.3%, and those receiving oral antibiotics plus mechanical bowel preparation had a rate of 9.2%. In adjusted analysis, the use of oral antibiotics alone was associated with a 67% decrease in surgical site infection occurrence (OR=0.33, 95% CI 0.21-0.50). Oral antibiotics plus mechanical bowel preparation was associated with a 57% decrease in surgical site infection occurrence (OR=0.43, 95% CI 0.34-0.55). Timely administration of parenteral antibiotics (Surgical Care Improvement Project-1) had a modest protective effect, with no effect observed for other Surgical Care Improvement Project measures. Hospitals with higher rates of oral antibiotics use had lower surgical site infection rates (R = 0.274, p < 0.0001). LIMITATIONS: Determination of the use of oral antibiotics and mechanical bowel preparation is based on retrospective prescription data, and timing of actual administration cannot be determined. CONCLUSIONS: Use and type of preoperative bowel preparation varied widely. These results strongly suggest that preoperative oral antibiotics should be administered for elective colorectal resections. The role of oral antibiotics independent of mechanical bowel preparation should be examined in a prospective randomized trial. PMID- 23044678 TI - Is the abdominal repair of rectal prolapse safer than perineal repair in the highest risk patients? An NSQIP analysis. AB - BACKGROUND: Although the perineal approach in the surgical management of rectal prolapse has a higher recurrence, it is the accepted approach for higher-risk patients because of its lower morbidity. OBJECTIVE: The aim of this study was to determine outcomes of abdominal versus perineal approaches to rectal prolapse repair. DESIGN SETTINGS: A retrospective study was performed comparing outcomes of patients undergoing different types of surgical approaches (open abdominal, laparoscopic, perineal) for rectal prolapse. PATIENTS: The American College of Surgeons National Surgical Quality Improvement Participant User Data Files (2008 2009) were queried for patients undergoing adult, elective procedures for rectal prolapse. MAIN OUTCOME MEASURES: Univariate analysis and multivariate logistic regression were performed to look at age, ASA classification, procedure type, and resultant mortality rate. RESULTS: One thousand four hundred sixty-nine patients meeting our criteria were identified. Older patients (age>80) and higher-risk patients (ASA classifications 3 and 4) were significantly associated with the selection of the perineal approach. The overall mortality rate was 0.5%. The mortality rate for all perineal procedures was 0.9% in comparison with 0.13% for all abdominal operations (p = 0.033). The mortality rate for the highest-risk groups (ASA 3 and 4) for perineal procedures was 1.3% in comparison with 0.35% in the abdominal procedure group; the relative risk for mortality was 4 times greater in the perineal procedure group than in the abdominal procedure group. LIMITATIONS: The retrospective design and standardized outcomes measured use administrative-level data and prevent the assessment of procedure-specific outcomes. CONCLUSIONS: Hospital mortality for the surgical repair of rectal prolapse is uncommon. The decision to choose the abdominal approach for the repair of rectal prolapse may not be as prohibitive as previously thought for higher-risk patients. Because of the broad range of functionality within each ASA classification, the operation offered should always be individualized, and patient selection is the most important factor. PMID- 23044679 TI - Does ligation of the intersphincteric fistula tract raise the bar in fistula surgery? AB - BACKGROUND: The ligation of the intersphincteric fistula tract procedure has been reported to have high cure rates, with minimal impairment of continence. OBJECTIVE: The aim of this study was to evaluate the success rates and functional outcome after the ligation of the intersphincteric fistula tract procedure. DESIGN: This study was performed as a retrospective review. SETTINGS: The study was conducted at the Division of Colon and Rectal Surgery, University of Minnesota and at affiliated hospitals in Minneapolis and St. Paul, Minnesota, between March 2007 and September 2011. PATIENTS: Ninety-three patients with transsphincteric cryptoglandular anal fistula were included. INTERVENTIONS: Ligation of the intersphincteric fistula tract procedure was performed. MAIN OUTCOME MEASURES: Failure was defined as persistent or recurrent drainage, air leakage from a patent external opening, or intersphincteric incision or reoperation for recurrent fistula. Success was defined as healing of the external fistula opening and intersphincteric incision. Patients were followed up with a questionnaire to assess the recurrence rate and the Wexner incontinence score. RESULTS: The median follow-up time for was 19 months (range, 4-55). Thirty patients (32%) had a history of previous surgery for their fistula. The success rate of fistula healing was 40% after the first ligation of the intersphincteric fistula tract procedure. When including patients with repeat ligation of the intersphincteric fistula tract and subsequent intersphincteric fistulotomy after ligation of the intersphincteric fistula tract repair, the success rates were 47% and 57%. Patients with successful fistula closure reported a mean Cleveland Clinic Florida Fecal Incontinence score of 1.0 (SD 2.3). No predictor for successful fistula closure was found. LIMITATIONS: Retrospective design, limited accuracy of diagnosing fistula failure, and lack of baseline continence were limitations of this study. CONCLUSION: The present study indicates that the ligation of the intersphincteric fistula tract procedure for transsphincteric fistulas has a significant risk for failure but good functional outcome in patients with no recurrence. PMID- 23044680 TI - Single-incision laparoscopic sigmoid resection: a technical video of a standardized approach. AB - BACKGROUND: Initially described in 2008, single-incision laparoscopic colectomy has evolved into a safe and feasible surgical approach. Noted advantages include elimination of trocar-site incisions and improved cosmesis. Additional benefits including reduced abdominal wall trauma, diminished pain, and shorter length of hospitalization have been proposed. Following utilization in over 150 colectomies, we present a standardized approach and describe our technique for single-incision laparoscopic sigmoid resection through a single-port access device. TECHNIQUE: A 2.5-cm umbilical incision is used for insertion of the single-incision access device. A 30 degrees 5-mm camera with a right-angle light cord adaptor and 2 bowel graspers are inserted through the access device. Exploration and lysis of adhesions are performed before placing the patient in a steep Trendelenburg position with 20 degrees left-sided elevation. Dissection commences in a medial-to-lateral fashion, developing the presacral avascular plane while ensuring nerve preservation. The retroperitoneal plane is established from the sacral promontory to the lateral peritoneal reflection. After identification of the left ureter and isolation of the vascular pedicle, the inferior mesenteric artery is isolated and ligated. The lateral attachments of the left colon and rectosigmoid are then divided, followed by additional pelvic dissection along the presacral avascular plane. The mesentery of the distal resection margin is divided before transection of the corresponding bowel using a stapling device. The bowel is then extracted and resected at the site of the single-incision access device. An intracorporeal primary end-to-end anastomosis is fashioned. CONCLUSION: We present a dynamic article with video illustrating a standardized medial-to-lateral approach for single-incision laparoscopic sigmoid resection. The technique effectively avoids the use of multiple trocar sites, maintains basic oncologic principles of resection, and affords the benefits of minimally invasive surgery. PMID- 23044681 TI - Perioperative systemic lidocaine for postoperative analgesia and recovery after abdominal surgery: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Postoperative pain management remains a significant challenge after abdominal surgery. OBJECTIVE: The aim of this meta-analysis was to evaluate the efficacy of systemic lidocaine for postoperative pain management and recovery after abdominal surgery. DATA SOURCE: Data were derived from Medline (1966-2010), CINAHL, The Cochrane Central Register of Controlled Trials, and Scopus. STUDY SELECTION: Randomized controlled trials of systemic administration of lidocaine for postoperative analgesia and recovery after abdominal surgery in adults, ie, >18 years, were considered. INTERVENTIONS: Combined data were analyzed with use of a random-effects model. MAIN OUTCOMES MEASURES: Data on opioid consumption, postoperative pain intensity, opioid-related side effects, time to first flatus, time to first bowel movement, and length of hospital stay were extracted. RESULTS: Twenty-one trials comparing systemic lidocaine with placebo or blank control for postoperative analgesia and recovery after abdominal surgery were included in this meta-analysis. Weighted mean difference for cumulative analgesic opioid (morphine) consumption 48 hours after surgery was -7.04 mg (95% CI: 10.40, -3.68, I2= 46.1%).Systemic lidocaine also significantly reduced postoperative pain intensity(visual analog scale, 0-100 mm) 6 hours after surgery at rest (weighted mean difference: -8.07 mm (95% CI: -14.69, -1.49); I2 = 90.6%) and during activity (weighted mean difference: -10.56 mm (95% CI: -16.89, -4.23), I2 = 82%). The time to first flatus and bowel movement was significantly shortened with lidocaine intervention by 6.92 hours (95% CI: -9.21, -4.63, I2 = 62.8%) and 11.74 hours (95% CI:-16.97, -6.51, I2 = 0). Moreover, systemic lidocaine also reduced hospital length of stay following the open procedure (weighted mean difference: -0.71 days (95% CI: -1.35, -0.07); I2 = 37.3%). LIMITATIONS: Heterogeneity of study results is the main limitation of this meta analysis. CONCLUSION: Perioperative systemic lidocaine may be a useful adjunct for postoperative pain management by decreasing postoperative pain intensity, reducing opioid consumption, facilitating GI function, and shortening length of hospital stay. PMID- 23044682 TI - Is splenic flexure mobilization necessary in laparoscopic anterior resection? PMID- 23044683 TI - Is splenic flexure mobilization necessary in laparoscopic anterior resection? Another view. PMID- 23044684 TI - Re: Management of deeply infiltrating endometriosis involving the rectum. PMID- 23044685 TI - Right colonic transposition technique. PMID- 23044687 TI - Conventional vs nonconventional strictureplasties for Crohn's disease. PMID- 23044689 TI - T4a and t4b colorectal cancer: what does this mean nowadays? PMID- 23044694 TI - A skin rash to remember. PMID- 23044696 TI - Prepared to fail? PMID- 23044697 TI - Health secretary sparks controversy by his support for a 12 week limit for abortion. PMID- 23044698 TI - Patterned growth of tungsten oxide and tungsten oxynitride nanorods from Au coated W foil. AB - This manuscript first describes a simple synthesis of tungsten oxide (WO(x)) nanorods from templated W foil using a chemical vapour deposition (CVD) technique at 600-750 degrees C, then presents the formation of tungsten oxynitride (WO(x)N(y)) nanorods via nitridation at 650 degrees C for different reaction times. The W foil, blade engraved, acid etched, or spin coated with Au-block copolymer composites then plasma etched, was used as a substrate for the nanorod growth. The Au patterns that were created on the surface of a W foil following the removal of the copolymer, led to a reverse patterned growth of WO(x) nanorods on the Au free areas. Consequently, following the oxide-to-nitride conversion, WO(x)N(y) nanorods were obtained with an identical patterned feature as to that of the parental WO(x). Combined techniques including XRD, SEM, TEM and Raman were used to visualise and analyse the resulting WO(x) and WO(x)N(y) nanorods. The diameter, length, and chemical composition of the nanorods are found to vary with reaction time and temperatures, as well as different substrate pre-treatments. This result represents a simple, innovative and efficient process for reverse patterned growth of new nanomaterials. PMID- 23044699 TI - Age differences in satisfaction with and perceived benefit from mental health services: results from the collaborative psychiatric epidemiology surveys. AB - OBJECTIVE: This study examined variation by age in satisfaction with and perceived benefit from mental health services (MHS). METHODS: Drawn from the nationally representative Collaborative Psychiatric Epidemiology Surveys (2001 2003), the current sample included 1286 adults from age 18 to 87 years who had at least one DSM-IV diagnosis and had used MHS during the past year. Multiple linear regression analyses were used to predict satisfaction with and perceived benefit from past year MHS use. Independent variables were sociodemographic factors and objective and perceived needs. RESULTS: Results from multiple linear regression analyses showed that older age was positively associated with both MHS satisfaction (p < 0.05, beta = 0.105) and perceived amount of benefit (p < 0.05, beta = 0.106), as was better self-rated mental health (p < 0.001, beta = 0.186; p < 0.001, beta = 0.177). A greater number of comorbid psychiatric diagnoses was negatively associated with satisfaction (p < 0.05, beta = -0.089). Marital status was found to be a moderator of the effect of age: for married respondents, age had a significant effect on both outcome variables (p < 0.05, beta = 0.102; p < 0.05, beta = 0.105), but for unmarried respondents, it did not. CONCLUSIONS: Our findings show clear evidence of age differences in satisfaction with and perceived benefit from MHS. The findings provide important implications for future interventions targeted to improve MHS satisfaction. Age-specific strategies should be developed to prevent delay in mental health treatment. PMID- 23044700 TI - Improving DNA capture on microarrays by integrated repeated denaturing. AB - Hybridization of nucleic acids to microarrays is a crucial step for several biological and biomedical applications. However, the poor efficiency and resulting long incubation times are major drawbacks. In addition to diffusion limitation, back hybridization to complementary strands in solution is shown to be an important cause of the low efficiency. In this paper, repeated denaturing in an integrated device has been investigated in order to increase the efficiency of microarray hybridization. The sample solution is circulated from the microarray chamber over a denaturing zone and back in a closed loop. In addition to the improved binding rate due to flow, repeated denaturing significantly increases the total amount of molecules bound. Our results demonstrate that cyclic repeated denaturing improves the efficiency of hybridization by up to an order of magnitude over a broad range of concentrations studied (1 pM to 100 nM). PMID- 23044701 TI - Effects of alfacalcidol on back extensor strength gained through back extensor exercise in postmenopausal women with osteoporosis. AB - OBJECTIVE: The aim of this study was to investigate the additive effect of the active form of vitamin D3 on the gain in back extensor strength through a back extensor exercise. DESIGN: A total of 107 postmenopausal women with osteoporosis were randomly divided into two groups: the D3 group and the control group. Both groups were treated with calcium and alendronate and undertook the back extensor exercise. Alfacalcidol was prescribed only to the D3 group. RESULTS: There was no significant difference in the demographic data between the two groups. Ninety four participants who completed a 4-mo intervention were subjected to per protocol analysis. There was no significant difference in the improvement in back extensor strength between two the groups (P = 0.349). All subjects were further categorized into two subgroups by age. In the older subgroup (>=68 yrs), no significant difference was found in the improvement in back extensor strength (P = 0.316). In the younger subgroup (<68 yrs), the back extensor strength in the D3 group was significantly more improved than in the control group (P = 0.034). CONCLUSIONS: The results of this study suggest that the administration of the active form of vitamin D3 enhances the beneficial effects of the back extensor exercise in patients younger than those in their late 60s. PMID- 23044702 TI - Effect of eccentric strengthening on pain, muscle strength, endurance, and functional fitness factors in male patients with achilles tendinopathy. AB - OBJECTIVE: The aim of this study was to investigate the effect of eccentric strengthening on pain, muscle strength, endurance, and functional fitness factors in Achilles tendinopathy patients. DESIGN: Thirty-two male patients with Achilles tendinopathy were assigned to either the experimental group that performed eccentric strengthening or the control group that performed concentric strengthening (n = 16, both groups) for 8 wks (50 mins per day, three times per week). A visual analog scale, an isokinetic muscle testing equipment, the side step test, and the Sargent jump test were used to assess pain, muscle strength, endurance, and functional fitness factors before and after the intervention. RESULTS: In comparison with the control group, the experimental group showed significant improvement in pain, ankle dorsiflexion endurance, total balance index, and agility after the intervention (P < 0.05). However, there was no significant difference in dexterity between the two groups. CONCLUSIONS: Eccentric strengthening was more effective than concentric strengthening in reducing pain and improving function in patients with Achilles tendinopathy; therefore, regular eccentric strengthening is important for patients in a clinical setting. PMID- 23044703 TI - Cauda equina syndrome after cesarean section. AB - This report describes a case of cauda equina syndrome possibly caused by arachnoiditis due to levobupivacaine after spinal-epidural anesthesia. A 39-yr old woman delivered by cesarean section under a combined spinal-epidural anesthesia. After an uneventful procedure and surgery, she complained of weakness in her lower extremities, which increased in a few hours. Neurologic examination revealed severe weakness in both her lower extremities, perianal anesthesia, and absence of muscle stretch reflexes. She was unable to urinate. Magnetic resonance imaging performed immediately revealed entirely normal results; however, gadolinium-enhanced magnetic resonance imaging 10 days later revealed contrast enhancement in the cauda equina fibers concordant with arachnoiditis. The patient was included in an intense rehabilitation program with a diagnosis of cauda equina syndrome and recovered completely in 8 wks. Practitioners should be aware of neurologic complications of spinal-epidural anesthesia. Early detection and treatment of the complication are important to minimize the risk of adverse outcome. PMID- 23044704 TI - The effectiveness of extracorporeal shock wave therapy vs. local steroid injection for management of carpal tunnel syndrome: a randomized controlled trial. AB - OBJECTIVE: Local corticosteroid (CS) injection has been widely used to treat carpal tunnel syndrome, but its invasiveness can cause several complications. In this study, the authors tested the efficacy of a new treatment method, extracorporeal shock wave therapy (ESWT), compared with CS injection. DESIGN: The authors carried out a randomized controlled trial comparing one session of ESWT (1000 shots at the maximal tolerable intensity) with one session of CS injection in 36 patients with carpal tunnel syndrome. Outcome measures including nerve conduction studies, a visual analog scale, and the Levine Self-assessment Questionnaire were performed at baseline and at 1 and 3 mos after treatment. RESULTS: At baseline, there were no significant differences between the groups with respect to the outcome parameters. Both groups showed a significant reduction in the visual analog scale at 1 and 3 mos after treatment compared with baseline. For the symptom severity score on the Levine Self-assessment Questionnaire, the ESWT group showed a significant reduction at 1 and 3 mos after treatment, whereas the CS injection group showed a significant reduction at 3 mos after treatment. For the nerve conduction parameters, there were mild but no significant improvements in the ESWT group, whereas the sensory nerve conduction velocity, the sensory nerve action potential amplitude, and the distal sensory and motor latencies of the median nerve were significantly improved in the CS injection group. CONCLUSIONS: ESWT can be as useful as CS injection for relieving symptoms of carpal tunnel syndrome. Furthermore, in contrast to CS injection, it has the merit of being noninvasive. PMID- 23044705 TI - Gestational environment programs adult depression-like behavior through methylation of the calcitonin gene-related peptide gene. AB - Early life exposure to specific environmental factors can increase risk for developing psychopathology including major depression in adulthood. However, the molecular pathways and epigenetic mechanisms that mediate the effects of early environments on adult mood remain poorly understood. We examined the effects of different gestational and rearing conditions on adult anxiety- and depression like behavior using a combined reciprocal outcrossing and cross-fostering design in Balb/cJ (cJ) and C57BL/6J (B6) mouse strains. First filial (F1) hybrid offspring, which were gestated by B6 or cJ dams and then reared by either strain, were evaluated for behavior and whole-genome hippocampal gene expression during adulthood. Adult hybrid mice gestated by B6 dams showed increased depression-like behavior in the forced swim and sucrose preference tests, increased hippocampal expression of alpha calcitonin gene-related peptide (alphaCGRP) transcripts, and decreased methylation of the alphaCGRP promoter compared with those gestated by cJ dams. Differential expression of alphaCGRP in adulthood did not result from genomic imprinting, and differences between B6 and cJ mitochondrial DNA were not responsible for behavioral phenotypes observed. Finally, central administration of alphaCGRP to adult hybrid mice increased depression-like behavior, whereas the CGRP1 receptor antagonist CGRP8-37 reduced depression-like behavior in the forced swim test. Our findings suggest that gestational factors influence adult depression-like behavior through methylation of the alphaCGRP gene. PMID- 23044706 TI - Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels. AB - Opioid drugs are highly addictive and their abuse has a strong genetic load. Dopamine-glutamate interactions are hypothesized to be important for regulating neural systems central for addiction vulnerability. Balanced dopamine-glutamate interaction is mediated through several functional associations, including a physical link between discs, large homolog 4 (Drosophila) (DLG4, PSD-95) and dopamine receptor 1 (DRD1) within the postsynaptic density to regulate DRD1 trafficking. To address whether genetic associations with heroin abuse exist in relation to dopamine and glutamate and their potential interactions, we evaluated single-nucleotide polymorphisms of key genes within these systems in three populations of opiate abusers and controls, totaling 489 individuals from Europe and the United States. Despite significant differences in racial makeup of the separate samples, polymorphisms of DRD1 and DLG4 were found to be associated with opiate abuse. In addition, a strong gene-gene interaction between homer 1 homolog (Drosophila) (HOMER1) and DRD1 was predicted to occur in Caucasian subjects. This interaction was further analyzed by evaluating DRD1 genotype in relation to HOMER1b/c protein expression in postmortem tissue from a subset of Caucasian subjects. DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amygdala; the correlation was inversed in opiate abusers as compared with controls. Cumulatively, these results support the hypothesis that there may be significant, genetically influenced interactions between glutamatergic and dopaminergic pathways in opiate abusers. PMID- 23044707 TI - Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts. AB - Copy number variants (CNVs) have a major role in the etiology of autism spectrum disorders (ASD), and several of these have reached statistical significance in case-control analyses. Nevertheless, current ASD cohorts are not large enough to detect very rare CNVs that may be causative or contributory (that is, risk alleles). Here, we use a tiered approach, in which clinically significant CNVs are first identified in large clinical cohorts of neurodevelopmental disorders (including but not specific to ASD), after which these CNVs are then systematically identified within well-characterized ASD cohorts. We focused our initial analysis on 48 recurrent CNVs (segmental duplication-mediated 'hotspots') from 24 loci in 31 516 published clinical cases with neurodevelopmental disorders and 13 696 published controls, which yielded a total of 19 deletion CNVs and 11 duplication CNVs that reached statistical significance. We then investigated the overlap of these 30 CNVs in a combined sample of 3955 well-characterized ASD cases from three published studies. We identified 73 deleterious recurrent CNVs, including 36 deletions from 11 loci and 37 duplications from seven loci, for a frequency of 1 in 54; had we considered the ASD cohorts alone, only 58 CNVs from eight loci (24 deletions from three loci and 34 duplications from five loci) would have reached statistical significance. In conclusion, until there are sufficiently large ASD research cohorts with enough power to detect very rare causative or contributory CNVs, data from larger clinical cohorts can be used to infer the likely clinical significance of CNVs in ASD. PMID- 23044709 TI - Overexpression of H1 calponin in osteoblast lineage cells leads to a decrease in bone mass by disrupting osteoblast function and promoting osteoclast formation. AB - H1 calponin (CNN1) is known as a smooth muscle-specific, actin-binding protein which regulates smooth muscle contractive activity. Although previous studies have shown that CNN1 has effect on bone, the mechanism is not well defined. To investigate the role of CNN1 in maintaining bone homeostasis, we generated transgenic mice overexpressing Cnn1 under the control of the osteoblast-specific 3.6-kb Col1a1 promoter. Col1a1-Cnn1 transgenic mice showed delayed bone formation at embryonic stage and decreased bone mass at adult stage. Morphology analyses showed reduced trabecular number, thickness and defects in bone formation. The proliferation and migration of osteoblasts were decreased in Col1a1-Cnn1 mice due to alterations in cytoskeleton. The early osteoblast differentiation of Col1a1 Cnn1 mice was increased, but the late stage differentiation and mineralization of osteoblasts derived from Col1a1-Cnn1 mice were significantly decreased. In addition to impaired bone formation, the decreased bone mass was also associated with enhanced osteoclastogenesis. Tartrate-resistant acid phosphatase (TRAP) staining revealed increased osteoclast numbers in tibias of 2-month-old Col1a1 Cnn1 mice, and increased numbers of osteoclasts co-cultured with Col1a1-Cnn1 osteoblasts. The ratio of RANKL to OPG was significantly increased in Col1a1-Cnn1 osteoblasts. These findings reveal a novel function of CNN1 in maintaining bone homeostasis by coupling bone formation to bone resorption. PMID- 23044708 TI - Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. AB - OBJECTIVE: Earlier studies of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), with limited patient numbers and followup durations, demonstrated that clinical presentation at diagnosis, but not outcome, differed according to antineutrophil cytoplasmic antibody (ANCA) status. This study was undertaken to describe the main characteristics of a larger patient cohort and their long-term outcomes. METHODS: A retrospective study of EGPA patients in the French Vasculitis Study Group cohort who satisfied the American College of Rheumatology criteria and/or Chapel Hill definitions was conducted. Patient characteristics and outcomes were compared according to ANCA status and year of diagnosis. RESULTS: We identified 383 patients diagnosed between 1957 and June 2009 (128 [33.4%] before 1997 or earlier) and followed up for a mean+/-SD of 66.8+/-62.5 months. At diagnosis, their mean+/-SD age was 50.3+/-15.7 years, and 91.1% had asthma (duration 9.3+/-10.8 years). Main manifestations included peripheral neuropathy (51.4%); ear, nose, and throat (ENT) signs (48.0%); skin lesions (39.7%); lung infiltrates (38.6%); and cardiomyopathy (16.4%). Among the 348 patients tested at diagnosis for ANCA, the 108 ANCA-positive patients (31.0%) had significantly more frequent ENT manifestations, peripheral neuropathy, and/or renal involvement, but less frequent cardiac manifestations, than the ANCA negative patients. Vasculitis relapses occurred in 35.2% of the ANCA-positive versus 22.5% of the ANCA-negative patients (P=0.01), and 5.6% versus 12.5%, respectively, died (P<0.05). The 5-year relapse-free survival rate was 58.1% (95% confidence interval [95% CI] 45.6-68.6) for ANCA-positive and 67.8% (95% CI 59.8 74.5) for ANCA-negative patients (P=0.35). Multivariable analysis identified cardiomyopathy, older age, and diagnosis during or prior to 1996 as independent risk factors for death and lower eosinophil count at diagnosis as predictive of relapse. CONCLUSION: The characteristics and long-term outcomes of EGPA patients differ according to their ANCA status. Although EGPA relapses remain frequent, mortality has declined, at least since 1996. PMID- 23044711 TI - Mechanical, thermal and morphological properties of poly(lactic acid)/epoxidized palm olein blend. AB - Poly(lactic acid) (PLA) is known to be a useful material in substituting the conventional petroleum-based polymer used in packaging, due to its biodegradability and high mechanical strength. Despite the excellent properties of PLA, low flexibility has limited the application of this material. Thus, epoxidized palm olein (EPO) was incorporated into PLA at different loadings (1, 2, 3, 4 and 5 wt%) through the melt blending technique and the product was characterized. The addition of EPO resulted in a decrease in glass transition temperature and an increase of elongation-at-break, which indicates an increase in the PLA chain mobility. PLA/EPO blends also exhibited higher thermal stability than neat PLA. Further, the PLA/1 wt% EPO blend showed enhancement in the tensile, flexural and impact properties. This is due to improved interaction in the blend producing good compatible morphologies, which can be revealed by Scanning Electron Microscopy (SEM) analysis. Therefore, PLA can be efficiently plasticized by EPO and the feasibility of its use as flexible film for food packaging should be considered. PMID- 23044710 TI - Relationship of intermuscular fat volume in the thigh with knee extensor strength and physical performance in women at risk of or with knee osteoarthritis. AB - OBJECTIVE: To determine the extent to which thigh intermuscular fat (IMF) and quadriceps muscle (QM) volumes explained variance in knee extensor strength and physical performance in women with radiographic knee osteoarthritis (ROA) and without. METHODS: Baseline data from 125 women (age >=50 years) in the Osteoarthritis Initiative study, with or at risk of knee ROA were included. Knee extensor strength was measured using a fixed force transducer, normalized to body mass (N/kg). Physical performance was the time required for 5 repeated chair stands (seconds). The IMF and QM volumes, normalized to height (cm(3) /meter), were yielded from analyses of T1-weighted axial magnetic resonance images of the midthigh. Mean IMF and QM volumes, extensor strength, and physical performance were compared between women with and without ROA, controlling for age. Hierarchical multiple regressions determined whether IMF and QM volumes were related to strength and performance after controlling for age, ROA status (yes/no), alignment, and pain. RESULTS: Compared to subjects with ROA, the subjects without ROA were stronger and performed chair stands faster (P < 0.05). After adjusting for age, those subjects without ROA had less mean +/- SD IMF (61.1 +/- 20.3 cm(3) /meter) compared to mean +/- SD ROA (72.0 +/- 25.0 cm(3) /meter; P < 0.05). In the entire sample, 21.1% of variance in knee extensor strength was explained by alignment, pain, and IMF. A model explaining 13.4% of variance in physical performance included OA status and IMF. QM volume was unrelated to strength and physical performance. CONCLUSION: IMF volume explained a small amount of variance in knee extensor strength and physical performance among women with or at risk of knee ROA. PMID- 23044712 TI - Optimization of ultrasound-assisted extraction of crude oil from winter melon (Benincasa hispida) seed using response surface methodology and evaluation of its antioxidant activity, total phenolic content and fatty acid composition. AB - In the present study, ultrasound-assisted extraction of crude oil from winter melon seeds was investigated through response surface methodology (RSM). Process variables were power level (25-75%), temperature (45-55 degrees C) and sonication time (20-40 min). It was found that all process variables have significant (p < 0.05) effects on the response variable. A central composite design (CCD) was used to determine the optimum process conditions. Optimal conditions were identified as 65% power level, 52 degrees C temperature and 36 min sonication time for maximum crude yield (108.62 mg-extract/g-dried matter). The antioxidant activity, total phenolic content and fatty acid composition of extract obtained under optimized conditions were determined and compared with those of oil obtained by the Soxhlet method. It was found that crude extract yield (CEY) of ultrasound-assisted extraction was lower than that of the Soxhlet method, whereas antioxidant activity and total phenolic content of the extract obtained by ultrasound-assisted extraction were clearly higher than those of the Soxhlet extract. Furthermore, both extracts were rich in unsaturated fatty acids. The major fatty acids of the both extracts were linoleic acid and oleic acid. PMID- 23044713 TI - Numerical solutions of the gamma-index in two and three dimensions. AB - The gamma-index is used routinely to establish correspondence between two dose distributions. The definition of the gamma-index can be written with a single equation but solving this equation at millions of points is computationally expensive, especially in three dimensions. Our goal is to extend the vector equation method in Bakai et al (2003 Phys. Med. Biol.48 3543-53) to higher order for better accuracy and, as important, to determine the magnitude of accuracy in a higher order solution. We construct a numerical framework for calculating the gamma-index in two and three dimensions and present an efficient method for calculating the gamma-index with zeroth-, first- and second-order methods using tricubic spline interpolation. For an intensity-modulated radiation therapy example with 1.78 * 106 voxels, the zeroth-order, first-order, first-order iterations and semi-second-order methods calculate the three-dimensional gamma index in 1.5, 4.7, 34.7 and 35.6 s with 36.7%, 1.1%, 0.2% and 0.8% accuracy, respectively. The accuracy of linear interpolation with this example is 1.0%. We present efficient numerical methods for calculating the three-dimensional gamma index with tricubic spline interpolation. The first-order method with iterations is the most accurate and fastest choice of the numerical methods if the dose distributions may have large second-order gradients. Furthermore, the difference between iterations can be used to determine the accuracy of the method. PMID- 23044714 TI - The anatomical and physiological framework for vestibular prostheses. AB - This article reviews the structure function of the vestibular system and its pathology with respect to requirements for the design and construction of a functional vestibular prosthesis. The ultimate goal of a vestibular prosthesis is to restore balance and equilibrium through direct activation of vestibular nerve fibers. An overview of the peripheral and central vestibular systems that highlights their most important functional aspects re: the design of a prosthesis is provided. Namely, the peripheral labyrinth faithfully transduces head motion and gravity in both the time and frequency domains. These signals are described in hopes that they may be prosthetically replicated. The peripheral and central connections of the vestibular nerve are also discussed in detail, as are the vestibular nuclei in the brainstem that receive VIIIth nerve innervation. Lastly, the functional effector pathways of the vestibular system, including the vestibulo-ocular, vestibulo-spinal, vestibulo-colic, vestibulo-autonomic, and vestibular efferent innervation of the labyrinth are reviewed. PMID- 23044715 TI - Implementing high-value, cost-conscious diabetes mellitus care through the use of low-cost medications and less-intensive glycemic control target. PMID- 23044716 TI - Knowing where they're going: destination-specific pregaming behaviors in a multiethnic sample of college students. AB - OBJECTIVES: To examine how legal age status, gender, and self-reported reasons for pregaming are linked to pregaming for two common drinking contexts: a bar and a Greek party. METHOD: Participants who reported pregaming at least once a month (n = 2888 students aged 18-25 years) were recruited from 30 colleges/universities across the United States. RESULTS: Many students pregame for social reasons regardless of pregaming destination. Multivariate analyses indicated that legal age students were more likely than underage students to pregame before going to a bar, whereas the opposite was true with respect to pregaming for a Greek party. Women were more likely than men to pregame before going to a bar or a Greek party, whereas men reported higher levels of consumption while pregaming for these destinations compared with women. CONCLUSIONS: The present findings suggest areas for targeted intervention efforts and promising avenues for research on context-specific pregaming behaviors among college students. PMID- 23044717 TI - Innovative use of self-expanded polytetrafluoroethylene endoprosthesis for percutaneous endovascular interventions. AB - VIABAHN(r) endoprosthesis (Gore & Associates, Flagstaff, AZ), a nitinol self expanding polytetrafluoroethylene (PTFE) lined stent, has demonstrated utility for percutaneous treatment of chronic occlusive disease involving the superficial femoral artery. In a case series communication we aimed to describe the feasibility of a PTFE-lined stent for percutaneous treatment of conditions other than chronic occlusive disease. We report the successful use of PTFE endoprosthesis to percutaneously treat several vascular conditions, including arterio-venous fistula closure, reconstruction of a distal limb of an aorto femoral endoprosthesis aneurysm, femoral artery perforation repair, and an exclusion of large saphenous vein graft aorto-coronary bypass aneurysm. This case series illustrates the feasibility of the "off-label" use of self-expanded PTFE endoprosthesis to percutaneously treat several conditions, which would otherwise require "open" surgical reconstructions. PMID- 23044718 TI - Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer. AB - Encapsulation of hydrophobic agents in polymer micelles can improve the water solubility of cargos, contributing to develop novel drugs. Quercetin (QU) is a hydrophobic agent with potential anticancer activity. In this work, we encapsulated QU into biodegradable monomethoxy poly(ethylene glycol)-poly(epsilon caprolactone) (MPEG-PCL) micelles and tried to provide proof-of-principle for treating ovarian cancer with this nano-formulation of quercetin. These QU loaded MPEG-PCL (QU/MPEG-PCL) micelles with drug loading of 6.9% had a mean particle size of 36 nm, rendering the complete dispersion of quercetin in water. QU inhibited the growth of A2780S ovarian cancer cells on a dose dependent manner in vitro. Intravenous administration of QU/MPEG-PCL micelles significantly suppressed the growth of established xenograft A2780S ovarian tumors through causing cancer cell apoptosis and inhibiting angiogenesis in vivo. Furthermore, the anticancer activity of quercetin on ovarian cancer cells was studied in vitro. Quercetin treatment induced the apoptosis of A2780S cells associated with activating caspase-3 and caspase-9. MCL-1 downregulation, Bcl-2 downregulation, Bax upregulation and mitochondrial transmembrane potential change were observed, suggesting that quercetin may induce apoptosis of A2780S cells through the mitochondrial apoptotic pathway. Otherwise, quercetin treatment decreased phosphorylated p44/42 mitogen-activated protein kinase and phosphorylated Akt, contributing to inhibition of A2780S cell proliferation. Our data suggested that QU/MPEG-PCL micelles were a novel nano-formulation of quercetin with a potential clinical application in ovarian cancer therapy. PMID- 23044719 TI - Growth kinetics of CdSe quantum dots generated in polar polymers. AB - Growth kinetics of CdSe nanocrystals generated inside three selected polymers (polyvinylpyrrolidone--PVP, polyethyleneglycol--PEG and polyvinylalcohol--PVA) are demonstrated to follow a self-catalytic path, with growth rates depending on the nature of the polymer, i.e. on the capability to activate the cadmium species present in the solution of a metal precursor. A two-step process drives the size evolution of nanocrystals and a critical diameter value can be identified at which the growth regime changes. The medium-term stability evaluation of nanocomposites indicates that, after an initial rearrangement, polymers keep stable the embedded CdSe nanocrystals. PMID- 23044720 TI - Heterosynaptic long-term depression mediated by ATP released from astrocytes. AB - Heterosynaptic long-term depression (hLTD) at untetanized synapses accompanying the induction of long-term potentiation (LTP) spatially sharpens the activity induced synaptic potentiation; however, the underlying mechanism remains unclear. We found that hLTD in the hippocampal CA1 region is caused by stimulation-induced ATP release from astrocytes that suppresses transmitter release from untetanized synaptic terminals via activation of P2Y receptors. Selective stimulation of astrocytes expressing channelrhodopsin-2, a light-gated cation channel permeable to Ca(2+) , resulted in LTD of synapses on neighboring neurons. This synaptic modification required Ca(2+) elevation in astrocytes and activation of P2Y receptors, but not N-methyl-D-aspartate receptors. Furthermore, blocking P2Y receptors or buffering astrocyte intracellular Ca(2+) at a low level prevented hLTD without affecting LTP induced by SC stimulation. Thus, astrocyte activation is both necessary and sufficient for mediating hLTD accompanying LTP induction, strongly supporting the notion that astrocytes actively participate in activity dependent synaptic plasticity of neural circuits. PMID- 23044721 TI - Peg-filgrastim and cabazitaxel in prostate cancer patients. AB - To determine the impact of prophylaxis with granulocyte-colony stimulating growth factor (G-CSF) on the risk of febrile neutropenia in a cohort of patients enrolled at the University Federico II of Naples and treated with cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC). We carried out a retrospective review of prospectively collected data of patients enrolled at our institution in a compassionate-use programme with cabazitaxel, aimed at providing early access to the drug before its commercial availability in mCRPC patients. Besides baseline clinical and demographic characteristics, data on treatment efficacy and toxicity, as well as those on the use of G-CSF per patient per cycle were extracted. Progression-free survival and overall survival were calculated using the Kaplan-Meier method. Fisher's exact test was used to explore a relationship between a single event of grade 3 or more neutropenia or febrile neutropenia and previous use of G-CSF. Univariate analysis was carried out to evaluate predictors of grade 3 or more neutropenia and/or febrile neutropenia. Of 34 patients enrolled at our institution from December 2010 to December 2011, 32 had received at least one dose of cabazitaxel and were included in the analysis. Patients received a median of 10 cabazitaxel cycles. Grade 3 or more neutropenia was common, occurring in 64.5% of patients. Three patients (9.3%) developed febrile neutropenia. Twenty-seven patients received prophylaxis with G-CSF during at least one cycle using peg-filgrastim. The risk of grade 3 or more neutropenia and/or febrile neutropenia per patient and per cycle was seven times lower when G CSF was used. Baseline neutrophil count of less than 4570/mm was the strongest predictor of grade 3 or more neutropenia and/or febrile neutropenia. No toxic death was reported. Only one patient discontinued cabazitaxel because of an adverse event. Our analysis suggests that prophylaxis with peg-filgrastim may considerably reduce the incidence of grade 3 or more neutropenia and, possibly, of febrile neutropenia in mCRPC patients treated with cabazitaxel. Further analyses involving a larger population are warranted to confirm our results. PMID- 23044722 TI - Management of toxicities associated with high-dose interleukin-2 and biochemotherapy. AB - High-dose interleukin-2, administered as a single agent or in combination with antineoplastic agents, known as biochemotherapy, holds the promise of durable remissions for patients with metastatic renal cell carcinoma and metastatic melanoma. The toxicities arising from high-dose interleukin-2-based therapies affect every organ system, causing significant acute morbidity. Administration of high-dose interleukin-2-based therapies requires specialized care and knowledge because of the severity and uniqueness of toxicities compared with the toxicities encountered with other forms of anticancer therapy. However, the toxicities of high-dose interleukin-2-based therapies are predictable and manageable by vigilant monitoring and appropriate supportive care protocols. To maximize outcomes, both acute and delayed toxicities require vigilant monitoring and adroit symptom management. This review details the pathophysiology, monitoring parameters, and management strategies for patients receiving high-dose interleukin-2-based therapy, with a focus on new and important management principles. PMID- 23044723 TI - Key multiplicity issues in clinical drug development. AB - Much progress has been made over the past decade with the development of novel methods for addressing increasingly more complex multiplicity problems arising in confirmatory Phase III clinical trials. This includes traditional problems with a single source of multiplicity, for example, analysis of multiple endpoints or dose-placebo contrasts. In addition, more advanced problems with several sources of multiplicity have attracted attention in clinical drug development. These problems include two or more families of objectives such as multiple endpoints evaluated at multiple dose levels or in multiple patient populations. This paper provides a review of concepts that play a central role in defining and solving multiplicity problems (error rate definitions) and introduces main classes of multiple testing procedures widely used in clinical trials (nonparametric, semiparametric, and parametric procedures). The paper also presents recent advances in multiplicity research, including gatekeeping procedures for clinical trials with multiple sets of objectives. The concepts and methods introduced in the paper are illustrated using several case studies on the basis of real clinical trials. Software implementation of commonly used multiple testing and gatekeeping procedures is discussed. PMID- 23044724 TI - Education: DNA replication using microscale natural convection. AB - There is a need for innovative educational experiences that unify and reinforce fundamental principles at the interface between the physical, chemical, and life sciences. These experiences empower and excite students by helping them recognize how interdisciplinary knowledge can be applied to develop new products and technologies that benefit society. Microfluidics offers an incredibly versatile tool to address this need. Here we describe our efforts to create innovative hands-on activities that introduce chemical engineering students to molecular biology by challenging them to harness microscale natural convection phenomena to perform DNA replication via the polymerase chain reaction (PCR). Experimentally, we have constructed convective PCR stations incorporating a simple design for loading and mounting cylindrical microfluidic reactors between independently controlled thermal plates. A portable motion analysis microscope enables flow patterns inside the convective reactors to be directly visualized using fluorescent bead tracers. We have also developed a hands-on computational fluid dynamics (CFD) exercise based on modeling microscale thermal convection to identify optimal geometries for DNA replication. A cognitive assessment reveals that these activities strongly impact student learning in a positive way. PMID- 23044725 TI - In-depth proteome mining of cultured Catharanthus roseus cells identifies candidate proteins involved in the synthesis and transport of secondary metabolites. AB - Madagascar periwinkle (Catharanthus roseus) is the major source of terpenoid indole alkaloids, such as vinblastine or vincristine, used as natural drugs against various cancers. In this study, we have extensively analyzed the proteome of cultured C. roseus cells. Comparison of the proteomes of two independent cell lines with different terpenoid indole alkaloid metabolism by 2D-DIGE revealed 358 proteins that differed quantitatively by at least a twofold average ratio. Of these, 172 were identified by MS; most corresponded to housekeeping proteins. Less abundant proteins were identified by LC separation of tryptic peptides of proteins from one of the lines. We identified 1663 proteins, most of which are housekeeping proteins or involved in primary metabolism. However, 63 enzymes potentially involved in secondary metabolism were also identified, of which 22 are involved in terpenoid indole alkaloid biosynthesis and 16 are predicted transporters putatively involved in secondary metabolite transport. About 30% of the proteins identified have an unclear or unknown function, indicating important gaps in knowledge of plant metabolism. This study is an important step toward elucidating the proteome of C. roseus, which is critical for a better understanding of how this plant synthesizes terpenoid indole alkaloids. PMID- 23044726 TI - Safety of intradermal skin tests for inhalants and foods: a prospective study. AB - BACKGROUND: Intradermal skin testing is a useful allergy diagnostic tool. Although considered safe when properly performed, systemic reactions have been reported. This is the first large, prospective study to record and evaluate all systemic reactions from intradermal skin testing (IDT) to inhalant or food antigens. METHODS: A 24-month prospective study by 40 physician practices, recording all IDT tests, including reactions, symptoms, severity, time after injection, and reaction treatments. RESULTS: Eighty systemic reactions (22 major) occurred among 20,530 patients (878,583 wheals). Nine had epinephrine treatment, 4 were observed in an emergency department, and there were no hospitalizations or fatalities. The overall systemic reaction risk was 0.009%. The risk of having a major reaction was 0.003%, or 1 reaction per 933 patients. CONCLUSION: Intradermal skin tests for inhalants or foods, when performed with appropriate precautions, have a safety profile comparable to skin prick tests. PMID- 23044727 TI - Reducing health risks of physical inactivity by cardiac rehabilitation. PMID- 23044728 TI - Advanced age should not be a contraindication for cardiac resynchronization therapy. PMID- 23044729 TI - Ultrasound joint inflammation in rheumatoid arthritis in clinical remission: how many and which joints should be assessed? AB - OBJECTIVE: To investigate the sensitivity for detecting subclinical synovitis of different reduced joint ultrasound (US) assessment models as compared with a comprehensive US assessment in rheumatoid arthritis (RA) patients in clinical remission. METHODS: Sixty-seven RA patients (50 women, 17 men) in clinical remission as judged by their consultant rheumatologist and treated with methotrexate were prospectively recruited. Patients were evaluated for disease activity according to the Disease Activity Score in 28 joints (DAS28) and the Simplified Disease Activity Index (SDAI) by the same investigator. Each patient underwent a 44-joint B-mode and power Doppler (PD) assessment by a rheumatologist blinded to the clinical and laboratory data. B-mode synovial hypertrophy (SH) and synovial PD signal were scored from 0-3 at each joint. Global indices for SH and PD signal were calculated for the 44-joint and different joint combination models for each patient. RESULTS: SH was detected in 87.8% of patients with a DAS28 <2.6 and in 81.8% of patients with an SDAI <3.3. Synovial PD signal was detected in 46.3% of patients with a DAS28 <2.6 and in 36.4% of patients with an SDAI <3.3. Wrist, second through fifth metacarpophalangeal (MCP), ankle, and second through fifth metatarsophalangeal (MTP) joint and 12-joint US assessments showed the highest correlations with the comprehensive US assessment. The wrist, MCP, ankle, and MTP joint US assessment showed the highest sensitivity for detecting SH and synovial PD signal in patients in remission according to the DAS28 and SDAI as compared to the comprehensive US assessment. CONCLUSION: US assessment of the wrist, MCP, ankle, and MTP joints can be highly sensitive for detecting residual B-mode and Doppler joint inflammation in RA patients. PMID- 23044730 TI - Acute damage threshold for infrared neural stimulation of the cochlea: functional and histological evaluation. AB - This article provides a mini review of the current state of infrared neural stimulation (INS), and new experimental results concerning INS damage thresholds. INS promises to be an attractive alternative for neural interfaces. With this method, one can attain spatially selective neural stimulation that is not possible with electrical stimulation. INS is based on the delivery of short laser pulses that result in a transient temperature increase in the tissue and depolarize the neurons. At a high stimulation rate and/or high pulse energy, the method bears the risk of thermal damage to the tissue from the instantaneous temperature increase or from potential accumulation of thermal energy. With the present study, we determined the injury thresholds in guinea pig cochleae for acute INS using functional measurements (compound action potentials) and histological evaluation. The selected laser parameters for INS were the wavelength (lambda = 1,869 nm), the pulse duration (100 MUs), the pulse repetition rate (250 Hz), and the radiant energy (0-127 MUJ/pulse). For up to 5 hr of continuous irradiation at 250 Hz and at radiant energies up to 25 MUJ/pulse, we did not observe any functional or histological damage in the cochlea. Functional loss was observed for energies above 25 MUJ/pulse and the probability of injury to the target tissue resulting in functional loss increased with increasing radiant energy. Corresponding cochlear histology from control animals and animals exposed to 98 or 127 MUJ/pulse at 250 Hz pulse repetition rate did not show a loss of spiral ganglion cells, hair cells, or other soft tissue structures of the organ of Corti. Light microscopy did not reveal any structural changes in the soft tissue either. Additionally, microcomputed tomography was used to visualize the placement of the optical fiber within the cochlea. PMID- 23044731 TI - Effect of ultrasound on adherent microbubble contrast agents. AB - An investigation into the effect of clinical ultrasound exposure on adherent microbubbles is described. A flow phantom was constructed in which targeted microbubbles were attached using biotin-streptavidin linkages. Microbubbles were insonated by broadband imaging pulses (centred at 2.25 MHz) over a range of pressures (peak negative pressure (PNP) = 60-375 kPa). Individual adherent bubbles were observed optically and classified as either being isolated or with a single neighbouring bubble. It is found that bubble detachment and deflation are two significant effects, even during low amplitude ultrasound exposure. Specifically, while at very low acoustic pressure (PNP < 75 kPa) 95% of the bubbles were not affected, at medium pressure (151 kPa < P < 225 kPa) 53% of the bubbles detached and at higher pressures (301 kPa < P < 375 kPa) 96% of the bubbles detached. In addition, more than 50% of the bubbles underwent deflation at pressures between 301 and 375 kPa. At pressures between 226 and 300 kPa, more adherent bubbles detached when there was a neighbouring bubble, suggesting the role of multiple scattering and secondary Bjerknes force on bubble detachment. The flow shear, primary and secondary Bjerknes forces exerted on each bubble were calculated and compared to the estimated forces acting on the bubble due to oscillations. The oscillation force is shown to be much higher than other forces. The mechanisms of bubble detachment are discussed. PMID- 23044732 TI - Molecular adaptations to concurrent training. AB - This study investigated the chronic effects of concurrent training (CT) on morphological and molecular adaptations. 37 men (age=23.7+/-5.5 year) were divided into 4 groups: interval (IT), strength (ST) and concurrent (CT) training and a control group (C) and underwent 8 weeks of training. Maximum strength (1RM) and muscle cross-sectional area (CSA) were evaluated before and after training. Muscle samples were obtained before the training program and 48 h after the last training session. VO2max improved in 5+/-0.95% and 15+/-1.3% (pre- to post-test) in groups CT and IT, respectively, when compared to C. Time to exhaustion (TE) improved from pre- to post-test when compared to C (CT=6.1+/-0.58%; IT=8.3+/ 0.88%; ST=3.2+/-0.66%). 1RM increased from pre-to post-test only in ST and CT groups (ST=18.5+/-3.16%; CT=17.6+/-3.01%). Similarly, ST and CT groups increased quadriceps CSA from pre-to post-test (6.2+/-1.4%; 7.8+/-1.66%). The p70S6K1 total protein content increased after CT. The ST group showed increased Akt phosphorylation at Ser473 (45.0+/-3.3%) whereas AMPK phosphorylation at Thr172 increased only in IT group, (100+/-17.6%). In summary, our data suggest that despite the differences in molecular adaptations between training regimens, CT did not blunt muscle strength and hypertrophy increments when compared with ST. PMID- 23044736 TI - Kidney biopsy in the critically ill patient, results of a multicentre retrospective case series. AB - BACKGROUND: The impact of a contributive result of kidney biopsy on the management of patients in the intensive care unit (ICU) has not been extensively investigated yet. METHODS: This was a retrospective study conducted between 2000 and 2011 in five French ICUs. The study included 56 patients. They had at least one non-renal organ failure, as defined by a Sequential Organ Failure Assessment (SOFA) score >=3 on ICU admission, and kidney biopsy was performed during ICU stay. Kidney samples were obtained by percutaneous (N.=55) or transjugular biopsy (N.=1). RESULTS: The mean Simplified Acute Physiology Score II and total SOFA scores on ICU admission were 52+/-19 years and 10.3+/-3.6, respectively. ICU mortality was 23%. The median (interquartile range) time between ICU admission and kidney biopsy was 9 days (5-21). Pathologic findings in the 54 analyzable kidney biopsies were acute tubular necrosis (N.=26), glomerulonephritis (N.=14), acute vascular nephritis (N.=11), acute interstitial nephritis (N.=6), and deposit disease (N.=3). Kidney biopsy was contributive to the management of 40 patients. In 23 of these, new treatments were started, in 13 ongoing treatments were stopped, including four life-sustaining therapies, and in 13 it was decided to start chronic renal replacement. Severe bleeding was observed in 7 patients, with fatal outcome in one case. CONCLUSION: Kidney biopsy may have a significant impact on the management of critically ill patients. Further studies should be done to identify the groups of ICU patients likely to benefit from the procedure with minimum risk. PMID- 23044737 TI - Lumbar epidural corticosteroid injection for refractory postoperative acute pain developed after tibiofemoral external fixation. PMID- 23044738 TI - Mallampati class zero in a four-year-old with cleft lip and palate. PMID- 23044739 TI - A systematic technical review of the systems for the continuous positive airway pressure. AB - Continuous positive airway pressure (CPAP) is the application in the airways of continuous positive pressure, close to the positive end expiratory pressure. The two common available systems are by a continuous (high/low) flow system and by a mechanical ventilator. Aim of this study was to compare the mechanical performance of the CPAP systems in intubated and not intubated patients. Medical literature databases (MEDLINE and EMBASE) were searched for articles on "clinical trials" and "randomized controlled trials". The key words "continuous positive airway pressure" and "CPAP", were combined with any of these key words: adult, work of breathing, continuous flow, mechanical valve, water valve, balloon reservoir, mechanical ventilator, pressure triggering, flow triggering, lung model, demand valve, equipment. Thirty-two articles (18 human and 14 bench studies) met the inclusion criteria. The continuous flow systems are able to maintain acceptable airway pressure variations during normal breathing. The most recent mechanical ventilators equipped with flow by systems compared to the first one, presented a similar or better work of breathing compared to the continuous flow systems due to the application of a little amount of pressure support. Although the use of a continuous flow is cheaper compared to mechanical ventilators, it does not allow a continuous respiratory monitoring. PMID- 23044741 TI - Endogeneous endophthalmitis by Klebsiella pneumoniae complicated with corneal perforation in Intensive Care Unit. PMID- 23044742 TI - A new application for thrombelastography in pregnant women at term. PMID- 23044743 TI - Prehospital transient airway management using the I-gel with sustained spontaneous breathing in different emergency situations. PMID- 23044744 TI - Performance of GlideScope Cobalt(r) for tracheal intubation in pediatric patients. PMID- 23044745 TI - It is not enough to aim; you must hit. PMID- 23044746 TI - Comment on "neuromonitoring in traumatic brain injury". PMID- 23044747 TI - Aortic valve morphology is associated with outcomes following balloon valvuloplasty for congenital aortic stenosis. AB - OBJECTIVES: Evaluate the incidence of various morphologic types of congenital AS, and the association between valve morphology and long-term outcomes, including repeat BAV, AVR, and death/transplant. BACKGROUND: Reports on long-term outcomes have low agreement on the influence of morphologic type. METHODS: We queried our institutional database and hospital billing records to identify all patients who underwent balloon aortic valvuloplasty (BAV) from 1992 through 2009. We excluded cases where morphology was not clear based on the description in the pre-BAV echocardiogram report and patients who underwent single ventricle palliation. The primary outcome of the study was the occurrence of any of the following events: repeat valvuloplasty, AVR, heart transplant, or death. RESULTS: There were 147 patients in our study cohort. The most common morphology was functionally bicuspid (n = 92, 63%), followed by functionally unicuspid (n = 20, 14%), dysplastic (n = 16, 11%), true bicuspid (n = 13, 9%), and true unicuspid (n = 6, 4%). The primary endpoint was less likely to occur in patients with functionally bicuspid valves (P < 0.01) and patients with true bicuspid valves (P = 0.03), whereas it was more likely to occur in patients with functionally unicuspid valves (P = 0.02) and patients with true unicuspid valves (P = 0.05). Multivariate Cox regression analysis demonstrated that valve type other than functionally bicuspid was associated with diminished freedom from repeat intervention, death or transplant (HR 3.3, CI 1.2 - 8.6, P = 0.02). CONCLUSIONS: In our cohort, patients with functionally bicuspid aortic valves, the most common type, had improved outcomes as compared with all other morphologic types. PMID- 23044749 TI - Enantioselective construction of multifunctionalized spirocyclohexaneoxindoles through organocatalytic Michael-Aldol cyclization of isatin derived alkenes with linear dialdehydes. AB - Optically active spirocyclohexaneoxindole motifs are very important building blocks for preparations of biologically active complexes, natural products, and pharmaceutical compounds. Herein, we report the syntheses of enantiopure spirocyclohexaneoxindoles through domino Michael-Aldol reactions between isatin derived alkenes and pentane-1,5-dial in the presence of diphenylprolinol silyl ether as an aminocatalyst. As a result, a series of multistereogenic and functionalized spirocyclohexaneoxindoles have been obtained in good yields with moderate diastereoselectivities and excellent enantioselectivities. In addition, electronic circular dichroism (ECD) spectroscopy and time-dependent density functional theory (TD-DFT) were used to investigate the rational structures of spirocyclohexaneoxindoles. PMID- 23044748 TI - Association of body mass index and risk of death from pancreas cancer in Asians: findings from the Asia Cohort Consortium. AB - We aimed to examine the association between BMI and the risk of death from pancreas cancer in a pooled analysis of data from the Asia Cohort Consortium. The data for this pooled analysis included 883 529 men and women from 16 cohort studies in Asian countries. Cox proportional-hazards models were used to estimate the hazard ratios and 95% confidence intervals for pancreas cancer mortality in relation to BMI. Seven predefined BMI categories (<18.5, 18.5-19.9, 20.0-22.4, 22.5-24.9, 25.0-27.4, 27.5-29.9, >= 30) were used in the analysis, with BMI of 22.5-24.9 serving as the reference group. The multivariable analyses were adjusted for known risk factors, including age, smoking, and a history of diabetes. We found no statistically significant overall association between each BMI category and the risk of death from pancreas cancer in all Asians, and obesity was unrelated to the risk of mortality in both East Asians and South Asians. Age, smoking, and a history of diabetes did not modify the association between BMI and the risk of death from pancreas cancer. In planned subgroup analyses among East Asians, an increased risk of death from pancreas cancer among those with a BMI less than 18.5 was observed for individuals with a history of diabetes; hazard ratio=2.01 (95% confidence interval: 1.01-4.00) (P for interaction=0.07). The data do not support an association between BMI and the risk of death from pancreas cancer in these Asian populations. PMID- 23044751 TI - Aspartic protease from Aspergillus (Eurotium) repens strain MK82 is involved in the hydrolysis and decolourisation of dried bonito (Katsuobushi). AB - BACKGROUND: Katsuobushi is a dried, smoked and fermented bonito used in Japanese cuisine. During the fermentation process with several Aspergillus species, the colour of Katsuobushi gradually changes from a dark reddish-brown derived from haem proteins to pale pink. The change in colour gives Katsuobushi a higher ranking and price. This study aimed to elucidate the mechanism of decolourisation of Katsuobushi. RESULTS: A decolourising factor from the culture supernatant of Aspergillus (Eurotium) repens strain MK82 was purified to homogeneity. The purification was monitored by measuring the decolourising activity using equine myoglobin and bovine haemoglobin as substrates. It was found that the decolourising factor had protease activity towards myoglobin and haemoglobin. Complete inhibition of the enzyme by the inhibitor pepstatin A and the internal amino acid sequence classified the protein as an aspartic protease. The enzyme limitedly hydrolysed myoglobin between 1-Met and 2-Gly, 43-Lys and 44-Phe, and 70 Leu and 71-Thr. The purified enzyme decolourised blood of Katsuwonus pelamis (bonito) and a slice of dried bonito. CONCLUSION: It is proposed that aspartic protease plays a role in the decolourisation of Katsuobushi by the hydrolysis of haem proteins that allows the released haem to aggregate in the dried bonito. PMID- 23044752 TI - Scrutinizing negative thermal expansion in MOF-5 by scattering techniques and ab initio calculations. AB - Complementary experimental techniques and ab initio calculations were used to determine the origin and nature of negative thermal expansion (NTE) in the archetype metal-organic framework MOF-5 (Zn(4)O(1,4-benzenedicarboxylate)(3)). The organic linker was probed by inelastic neutron scattering under vacuum and at a gas pressure of 175 bar to distinguish between the pressure and temperature responses of the framework motions, and the local structure of the metal centers was studied by X-ray absorption spectroscopy. Multi-temperature powder- and single-crystal X-ray and neutron diffraction was used to characterize the polymeric nature of the sample and to quantify NTE over the large temperature range 4-400 K. Ab initio calculations complement the experimental data with detailed information on vibrational motions in the framework and their correlations. A uniform and comprehensive picture of NTE in MOF-5 has been drawn, and we provide direct evidence that the main contributor to NTE is translational transverse motion of the aromatic ring, which can be dampened by applying a gas pressure to the sample. The linker motion is highly correlated rather than local in nature. The relative energies of different framework vibrations populated in MOF-5 are suggested by analysis of neutron diffraction data. We note that the lowest-energy motion is a librational motion of the aromatic ring which does not contribute to NTE. The libration is followed by transverse motion of the linker and the carboxylate group. These motions result in unit-cell contraction with increasing temperature. PMID- 23044753 TI - Application of cell-based therapies in facial transplantation. AB - The main purpose of cellular therapy application in face transplantation is the continuous need for the development of new strategies that would eliminate the use of toxic immunosuppressive protocols. Cellular therapy in transplantation can significantly benefit allograft survival and shorten healing time. Cells used for a therapeutic purpose are isolated mostly from bone marrow and adipose tissues. They have the ability to proliferate and differentiate in the transplanted tissue and have immunomodulatory activity. Most of the cellular therapies such as T regulatory, dendritic, and chimeric cells are still in the experimental stage. Molecular characterization of these cells and the mechanism of their participation in allograft acceptance and rejection are not well established and will contribute to the future of modern transplantology. PMID- 23044754 TI - Acute transfer of superficial radial nerve to the medial nerve: case report. AB - Distal nerve transfers have proven to be an important addition to the armamentarium for reconstruction of peripheral nerve injuries. As new nerve transfer procedures are developed, the indications for their uses continue to broaden. We report a case of a 77-year-old male who had a 9-cm-long gap of the median nerve after experiencing an avulsion injury to his right forearm. This was successfully treated by transferring superficial radial nerve to the median nerve at the carpal tunnel level, thus restoring thumb, index, and first web sensation. Our report emphasizes that nerve transfers in the emergency setting may be the treatment of first choice in cases where conventional nerve grafting is known to result in poorer outcomes such as in long nerve gaps or in the elderly patient population. PMID- 23044750 TI - Adaptor protein complex 2-mediated, clathrin-dependent endocytosis, and related gene activities, are a prominent feature during maturation stage amelogenesis. AB - Molecular events defining enamel matrix removal during amelogenesis are poorly understood. Early reports have suggested that adaptor proteins (AP) participate in ameloblast-mediated endocytosis. Enamel formation involves the secretory and maturation stages, with an increase in resorptive function during the latter. Here, using real-time PCR, we show that the expression of clathrin and adaptor protein subunits are upregulated in maturation stage rodent enamel organ cells. AP complex 2 (AP-2) is the most upregulated of the four distinct adaptor protein complexes. Immunolocalization confirms the presence of AP-2 and clathrin in ameloblasts, with strongest reactivity at the apical pole. These data suggest that the resorptive functions of enamel cells involve AP-2 mediated, clathrin dependent endocytosis, thus implying the likelihood of specific membrane-bound receptor(s) of enamel matrix protein debris. The mRNA expression of other endocytosis-related gene products is also upregulated during maturation including: lysosomal-associated membrane protein 1 (Lamp1); cluster of differentiation 63 and 68 (Cd63 and Cd68); ATPase, H(+) transporting, lysosomal V0 subunit D2 (Atp6v0d2); ATPase, H(+) transporting, lysosomal V1 subunit B2 (Atp6v1b2); chloride channel, voltage-sensitive 7 (Clcn7); and cathepsin K (Ctsk). Immunohistologic data confirms the expression of a number of these proteins in maturation stage ameloblasts. The enamel of Cd63-null mice was also examined. Despite increased mRNA and protein expression in the enamel organ during maturation, the enamel of Cd63-null mice appeared normal. This may suggest inherent functional redundancies between Cd63 and related gene products, such as Lamp1 and Cd68. Ameloblast-like LS8 cells treated with the enamel matrix protein complex Emdogain showed upregulation of AP-2 and clathrin subunits, further supporting the existence of a membrane-bound receptor-regulated pathway for the endocytosis of enamel matrix proteins. These data together define an endocytotic pathway likely used by ameloblasts to remove the enamel matrix during enamel maturation. PMID- 23044755 TI - Objective quantification of subjective parameters in scars by use of a portable stereophotographic system. PMID- 23044759 TI - The masque of facial plastic surgery. PMID- 23044757 TI - The estimation of tissue loss during tangential hydrosurgical debridement. AB - The preservation of healthy tissue during surgical debridement is desirable as this may improve clinical outcomes. This study has estimated for the first time the amount of tissue lost during debridement using the VERSAJET system of tangential hydrosurgery. A multicenter, prospective case series was carried out on 47 patients with mixed wound types: 21 (45%) burns, 13 (28%) chronic wounds, and 13 (28%) acute wounds. Overall, 44 (94%) of 47 patients achieved appropriate debridement after a single debridement procedure as verified by an independent photographic assessment. The percentage of necrotic tissue reduced from a median of 50% to 0% (P < 0.001). Median wound area and depth increased by only 0.3 cm (6.8%) and 0.5 mm (25%), respectively. Notably, 43 (91%) of 47 wounds did not progress into a deeper compartment, indicating a high degree of tissue preservation. PMID- 23044760 TI - Syngas generation from n-butane with an integrated MEMS assembly for gas processing in micro-solid oxide fuel cell systems. AB - An integrated system of a microreformer and a carrier allowing for syngas generation from liquefied petroleum gas (LPG) for micro-SOFC application is discussed. The microreformer with an overall size of 12.7 mm * 12.7 mm * 1.9 mm is fabricated with micro-electro-mechanical system (MEMS) technologies. As a catalyst, a special foam-like material made from ceria-zirconia nanoparticles doped with rhodium is used to fill the reformer cavity of 58.5 mm(3). The microreformer is fixed onto a microfabricated structure with built-in fluidic channels and integrated heaters, the so-called functional carrier. It allows for thermal decoupling of the cold inlet gas and the hot fuel processing zone. Two methods for heating the microreformer are compared in this study: a) heating in an external furnace and b) heating with the two built-in heaters on the functional carrier. With both methods, high butane conversion rates of 74%-85% are obtained at around 550 degrees C. In addition, high hydrogen and carbon monoxide yields and selectivities are achieved. The results confirm those from classical lab reformers built without MEMS technology (N. Hotz et al., Chem. Eng. Sci., 2008, 63, 5193; N. Hotz et al., Appl. Catal., B, 2007, 73, 336). The material combinations and processing techniques enable syngas production with the present MEMS based microreformer with high performance for temperatures up to 700 degrees C. The functional carrier is the basis for a new platform, which can integrate the micro-SOFC membranes and the gas processing unit as subsystem of an entire micro-SOFC system. PMID- 23044761 TI - Monocytes from patients with osteoarthritis display increased osteoclastogenesis and bone resorption: the In Vitro Osteoclast Differentiation in Arthritis study. AB - OBJECTIVE: To compare the osteoclastogenic capacity of peripheral blood mononuclear cells (PBMCs) from patients with osteoarthritis (OA) to that of PBMCs from self-reported normal individuals. METHODS: PBMCs from 140 patients with OA and 45 healthy donors were assayed for CD14+ expression and induced to differentiate into osteoclasts over 3 weeks in vitro. We assessed the number of osteoclasts, their resorptive activity, osteoclast apoptosis, and expression of the following cytokine receptors: RANK, interleukin-1 receptor type I (IL-1RI), and IL-1RII. A ridge logistic regression classifier was developed to discriminate OA patients from controls. RESULTS: PBMCs from OA patients gave rise to more osteoclasts that resorbed more bone surface than did PBMCs from controls. The number of CD14+ precursors was comparable in both groups, but there was less apoptosis in osteoclasts obtained from OA patients. Although no correlation was found between osteoclastogenic capacity and clinical or radiographic scores, levels of IL-1RI were significantly lower in cultures from patients with OA than in cultures from controls. Osteoclast apoptosis and expression levels of IL-1RI and IL-1RII were used to build a multivariate predictive model for OA. CONCLUSION: During 3 weeks of culture under identical conditions, monocytes from patients with OA display enhanced capacity to generate osteoclasts compared to cells from controls. Enhanced osteoclastogenesis is accompanied by increased resorptive activity, reduced osteoclast apoptosis, and diminished IL-1RI expression. These findings support the possibility that generalized changes in bone metabolism affecting osteoclasts participate in the pathophysiology of OA. PMID- 23044762 TI - Time-varying coefficient proportional hazards model with missing covariates. AB - Missing covariates often arise in biomedical studies with survival outcomes. Existing approaches for missing covariates generally assume proportional hazards. The proportionality assumption may not hold in practice, as illustrated by data from a mouse leukemia study with covariate effects changing over time. To tackle this restriction, we study the missing data problem under the varying-coefficient proportional hazards model. On the basis of the local partial likelihood approach, we develop inverse selection probability weighted estimators. We consider reweighting and augmentation techniques for possible improvement of efficiency and robustness. The proposed estimators are assessed via simulation studies and illustrated by application to the mouse leukemia data. PMID- 23044763 TI - Understanding resistant germplasm-induced virulence variation through analysis of proteomics and suppression subtractive hybridization in a maize pathogen Curvularia lunata. AB - Curvularia lunata is an important pathogen causing Curvularia leaf spot in maize. Significant pathogenic variation has been found in C. lunata. To better understand the mechanism of this phenomenon, we consecutively put the selective pressures of resistant maize population on C. lunata strain WS18 (low virulence) artificially. As a result, the virulence of this strain was significantly enhanced. Using 2DE, 12 up-regulated and four down-regulated proteins were identified in virulence-increased strain compared to WS18. Our analysis revealed that melanin synthesis-related proteins (Brn1, Brn2, and scytalone dehydratase) and stress tolerance-related proteins (HSP 70) directly involved in the potential virulence growth as crucial markers or factors in C. lunata. To validate 2DE results and screen differential genes at mRNA level, we constructed a subtracted cDNA library (tester: virulence-increased strain; driver: WS18). A total of 188 unigenes were obtained this way, of which 14 were indicators for the evolution of pathogen virulence. Brn1 and hsp genes exhibited similar expression patterns corresponding to proteins detected by 2DE. Overall, our results indicated that differential proteins or genes, being involved with melanin synthesis or tolerance response to stress, could be considered as hallmarks of virulence increase in C. lunata. PMID- 23044764 TI - mTOR kinase, a key player in the regulation of glial functions: relevance for the therapy of multiple sclerosis. AB - The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase with a central role in the regulation of cell growth and proliferation, and several intracellular processes, such as mRNA transcription and translation, autophagy and cytoskeletal organization. The relevance of this pathway in the regulation of the immune system is well characterized. mTOR is essential for the proper activation and proliferation of effector T cells, restricts the development of regulatory T cells, and downregulates innate immune responses. Recently, a direct role of mTOR in the modulation of glial functions has also been recognized. Data from our group and others support the notion that mTOR is involved in microglial proinflammatory activation. The kinase regulates several intracellular processes in astrocytes, among which the rate of mRNA degradation of the inducible form of NO synthase. Therefore, the inhibition of mTOR kinase activity in glial cells results in anti-inflammatory actions, suggesting possible beneficial effects of mTOR inhibitors (like rapamycin) in the treatment of inflammatory-based pathologies of the central nervous system. In contrast, mTOR plays an important role in the regulation of oligodendrocyte development and myelination process as well as several neuronal functions, which may limit this therapeutic approach. Nevertheless, as reviewed here, there is robust evidence that rapamycin ameliorates the clinical course of both the relapsing-remitting and the chronic experimental autoimmune encephalomyelitis (EAE), and significantly reduces the hyperalgesia observed before clinical development of EAE. These findings may have important clinical implications for the therapy of multiple sclerosis. PMID- 23044765 TI - Performance of matrix-based risk models for rapid radiographic progression in a cohort of patients with established rheumatoid arthritis. AB - OBJECTIVE: Matrix-based risk models have been proposed as a tool to predict rapid radiographic progression (RRP) in rheumatoid arthritis (RA), but the experience with such models is limited. We tested the performance of 3 risk models for RRP in an observational cohort. METHODS: Subjects from an observational RA cohort with hand radiographs and necessary predictor variables to be classified by the risk models were identified (n = 478). RRP was defined as a yearly change in the Sharp/van der Heijde score of >=5 units. Patients were placed in the appropriate matrix categories, with a corresponding predicted risk of RRP. The mean predicted probability for cases and noncases, integrated discrimination improvement, Hosmer Lemeshow statistics, and C statistics were calculated. RESULTS: The median age was 59 years (interquartile range [IQR] 50-66 years), the median disease duration was 12 years (IQR 4-23 years), the median swollen joint count was 6 (IQR 2-13), 84% were women, and 86% had erosions at baseline. Twelve percent of patients (32 of 271) treated with synthetic disease-modifying antirheumatic drugs (DMARDs) at baseline and 10% of patients (21 of 207) treated with biologic DMARDs experienced RRP. Most of the predictor variables had a skewed distribution in the population. All models had a suboptimal performance when applied to this cohort, with C statistics of 0.59 (model A), 0.65 (model B), and 0.57 (model C), and Hosmer Lemeshow chi-square P values of 0.06 (model A), 0.005 (model B), and 0.05 (model C). CONCLUSION: Matrix risk models developed in clinical trials of patients with early RA had limited ability to predict RRP in this observational cohort of RA patients. PMID- 23044766 TI - Paranasal sinus cholesterol granuloma: systematic review of diagnostic and management aspects. AB - BACKGROUND: Cholesterol granuloma (CG) is an expansile, cystic lesion most commonly observed in the temporal bone. CG is rarely encountered in the paranasal sinuses. Given its paucity in this region, the diagnostic and management aspects remain to be elucidated. METHODS: Systematic review of the literature yielded 66 cases reported as individual data in 37 articles; an additional 69 cases were reported as aggregate data in 5 case series. RESULTS: The mean age of the 135 patients was 43.8 years, with a male:female ratio of 5.6:1. The most common presenting symptoms were orbital (66%), followed by headaches (19.3%). The most common location for CG was the frontal sinus (60%), followed by maxillary (34.1%) and ethmoid (3.7%) sinuses. Computed tomography (CT) imaging was used in 84 patients (63.3%), with bone erosion being noted in 80% of cases. Magnetic resonance imaging (MRI) was reported in only 9 cases (6.7%); high signal on T1- and T2-weighted images was evident in 77.8% and 66.7%, of cases respectively. Surgical data was available on 65 cases; drainage was achieved by open and endoscopic techniques in 52 (80%) and 13 (20%) cases, respectively. Primary symptom improvement and CG cavity patency was achieved in 92% of cases at a mean follow-up of 34.5 months. CONCLUSION: Paranasal sinus CG is most commonly observed in middle-aged males, arises in the frontal sinus, and typically presents with orbital symptoms. Both open and endoscopic techniques can be used with high success rate. The present study represents the first attempt in the literature to construct a clinical profile of this rare entity. PMID- 23044767 TI - Microbiota of de-novo pediatric IBD: increased Faecalibacterium prausnitzii and reduced bacterial diversity in Crohn's but not in ulcerative colitis. AB - OBJECTIVES: The gastrointestinal microbiota is considered important in inflammatory bowel disease (IBD) pathogenesis. Discoveries from established disease cohorts report reduced bacterial diversity, changes in bacterial composition, and a protective role for Faecalibacterium prausnitzii in Crohn's disease (CD). The majority of studies to date are however potentially confounded by the effect of treatment and a reliance on established rather than de-novo disease. METHODS: Microbial changes at diagnosis were examined by biopsying the colonic mucosa of 37 children: 25 with newly presenting, untreated IBD with active colitis (13 CD and 12 ulcerative colitis (UC)), and 12 pediatric controls with a macroscopically and microscopically normal colon. We utilized a dual methodology approach with pyrosequencing (threshold >10,000 reads) and confirmatory real-time PCR (RT-PCR). RESULTS: Threshold pyrosequencing output was obtained on 34 subjects (11 CD, 11 UC, 12 controls). No significant changes were noted at phylum level among the Bacteroidetes, Firmicutes, or Proteobacteria. A significant reduction in bacterial alpha-diversity was noted in CD vs. controls by three methods (Shannon, Simpson, and phylogenetic diversity) but not in UC vs. controls. An increase in Faecalibacterium was observed in CD compared with controls by pyrosequencing (mean 16.7% vs. 9.1% of reads, P=0.02) and replicated by specific F. prausnitzii RT-PCR (36.0% vs. 19.0% of total bacteria, P=0.02). No disease-specific clustering was evident on principal components analysis. CONCLUSIONS: Our results offer a comprehensive examination of the IBD mucosal microbiota at diagnosis, unaffected by therapeutic confounders or changes over time. Our results challenge the current model of a protective role for F. prausnitzii in CD, suggesting a more dynamic role for this organism than previously described. PMID- 23044768 TI - Andrographis paniculata extract (HMPL-004) for active ulcerative colitis. AB - OBJECTIVES: Andrographis paniculata has in vitro inhibitory activity against TNF alpha, IL-1beta and NF-kappaB. A pilot study of A. paniculata extract (HMPL-004) suggested similar efficacy to mesalamine for ulcerative colitis. METHODS: A randomized, double-blind, placebo-controlled trial evaluated the efficacy of A. paniculata extract (HMPL-004) in 224 adults with mild-to-moderate ulcerative colitis. Patients were randomized to A. paniculata extract (HMPL-004) 1,200 mg or 1,800 mg daily or placebo for 8 weeks. RESULTS: In total, 45 and 60% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical response at week 8, compared with 40% of those who received placebo (P=0.5924 for 1,200 mg vs. placebo and P=0.0183 for 1,800 mg vs. placebo). In all, 34 and 38% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical remission at week 8, compared with 25% of those who received placebo (P=0.2582 for 1,200 mg vs. placebo and P=0.1011 for 1,800 mg vs. placebo). Adverse events developed in 60 and 53% of patients in the A. paniculata 1,200 mg and 1,800 mg daily groups, respectively, and 60% in the placebo group. CONCLUSIONS: Patients with mildly to moderately active ulcerative colitis treated with A. paniculata extract (HMPL-004) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo. PMID- 23044769 TI - A highly sensitive and temporal visualization system for gaseous ethanol with chemiluminescence enhancer. AB - A two-dimensional gaseous ethanol visualization system has been developed and demonstrated using a horseradish peroxidase-luminol-hydrogen peroxide system with high-purity luminol solution and a chemiluminescence (CL) enhancer. This system measures ethanol concentrations as intensities of CL via the luminol reaction. CL was emitted when the gaseous ethanol was injected onto an enzyme-immobilized membrane, which was employed as a screen for two-dimensional gas visualization. The average intensity of CL on the substrate was linearly related to the concentration of standard ethanol gas. These results were compared with the CL intensity of the CCD camera recording image in the visualization system. This system is available for gas components not only for spatial but also for temporal analysis in real time. A high-purity sodium salt HG solution (L-HG) instead of standard luminol solution and an enhancer, eosin Y (EY) solution, were adapted for improvement of CL intensity of the system. The visualization of gaseous ethanol was achieved at a detection limit of 3 ppm at optimized concentrations of L-HG solution and EY. PMID- 23044770 TI - Lyoluminescence, thermoluminescence and mechanoluminescence studies in gamma-ray irradiated Dy3+ activated potassium chloride phosphor for accidental radiation dosimetry. AB - The lyoluminescence (LL), thermoluminescence (TL) and mechanoluminescence (ML) of gamma-ray-irradiated coloured powder of KCl:Dy (0.05-0.5 mol%) phosphors are reported in this paper. To understand the mechanism of LL and ML, the LL and ML spectra are compared with TL studies. The variation of intensity of respective luminescence with different gamma-ray doses and with different concentrations of Dy3+ ion doped in KCl is found to be similar in nature. The intensities differ from each other, but their nature is found to be similar with gamma-ray exposures. The ML glow peak intensity is linear up to high 1 kGy exposure as compared to LL (up to 0.5 kGy) and TL (up to 0.75 kGy) techniques. Therefore, according to our results, the recommendation is that KCl:Dy (0.1 mol%) phosphor prepared by wet chemical technique is useful for high-dose measurements using the ML technique for accidental radiation dosimetry. PMID- 23044771 TI - Thermal luminescence spectra of polyamides and their Maillard reaction with reducing sugars. AB - Thermal luminescence (TL) spectra of polyamides were measured with a Fourier transform chemiluminescence spectrometer to elucidate the emission mechanism. A TL band of epsilon-polylysine with a peak at 542 nm observed at 403 K was assigned to the emission due to the interaction of the -CO-NH- group with oxygen molecules by comparison with nylon-6, polyglycine, and polyalanine. When the sample was kept at 453 K, the intensity of the TL band decreased and the wavelength of the peak shifted to 602 nm, which was assigned to the emission due to the interaction of the NH2 group on the side chain with oxygen molecules by comparison with monomeric lysine. A weak emission with a peak at 668 nm was assigned to the advanced glycosylation end products (AGEs) yielded by the Maillard reaction with a catalytic amount of water. To understand this reaction and to examine the TL emission of AGEs, we measured TL spectra of mixtures of polylysine and reducing sugars such as glucose, maltose, lactose, and dextrin. The minimum temperature for TL emission, wavelength of the peak and the relative intensities of the TL emission were found to depend on the size of the sugars. PMID- 23044772 TI - Determination of nitrate and nitrite in freshwaters using flow-injection with luminol chemiluminescence detection. AB - A simple and sensitive flow-injection (FI) method for the determination of nitrate and nitrite in natural waters, based on luminol chemiluminescence (CL) detection, is reported. Nitrate was reduced online to nitrite via a copperized cadmium (Cu-Cd) column and then reacted with acidic hydrogen peroxide to form peroxynitrous acid. CL emission was observed from the oxidation of luminol in an alkaline medium in the presence of the peroxynitrite anion. The limits of detection (S:N = 3) were 0.02 and 0.01 ug N/L, with sample throughputs of 40 and 90 /h for nitrate and nitrite, respectively. Calibration graphs were linear over the range 0.02-50 and 0.01-50 ug N/L [R2 = 0.9984 (n = 8) and R2 = 0.9965 (n = 7)] for nitrate and nitrite, respectively, with relative standard deviations (RSDs; n = 3) in the range 1.8-4.6%. The key chemical and physical variables (reagent concentrations, buffer pH, flow rates, sample volume, Cu-Cd reductor column length) were optimized and potential interferences investigated. The effect of cations [Ca(II), Mg(II), Co(II), Fe(II) and Cu(II)] was masked online with EDTA. Common anions (PO4(3-) , SO4(2-) and HCO3-) did not interfere at their maximum admissible concentrations in freshwaters. The effect of salinity on the luminol CL reaction with and without nitrate and nitrite (2 and 0.5 ug N/L, respectively) was also investigated. The method was successfully applied to freshwaters and the results obtained were in good agreement with those obtained by an automated segmented flow analyser reference method. PMID- 23044773 TI - Sensitive spectrofluorimetric determination of tizanidine in pharmaceutical preparations, human plasma and urine through derivatization with dansyl chloride. AB - A sensitive spectrofluorimetric method was developed for the determination of tizanidine in human plasma, urine and pharmaceutical preparations. The method is based on reaction of tizanidine with 1-dimethylaminonaphthalene-5-sulphonyl chloride (dansyl chloride) in an alkaline medium to form a highly fluorescent derivative that was measured at 511 nm after excitation at 383 nm. The different experimental parameters affecting the fluorescence intensity of tizanidine was carefully studied and optimized. The fluorescence-concentration plots were rectilinear over the ranges 50-500 and 20-300 ng/mL for plasma and urine, respectively, detection limits of 1.81 and 0.54 ng/mL and quantification limits of 5.43 and 1.62 ng/mL for plasma and urine, respectively. The method presents good performance in terms of linearity, detection and quantification limits, precision, accuracy and specificity. The proposed method was successfully applied for the determination of tizanidine in pharmaceutical preparations. The results obtained were compared with a reference method, using t- and F-tests. PMID- 23044774 TI - Radiotherapy: Diabetes risk after radiation--not out of the woods. PMID- 23044775 TI - Urological cancer: Enzalutamide in metastatic CRPC-old dog, new tricks. PMID- 23044776 TI - Gastrointestinal cancer: A promising horizon for cediranib? PMID- 23044777 TI - Urological cancer: Aspirin and the risk of prostate cancer mortality. PMID- 23044779 TI - Biomedical engineering principles of modern cochlear implants and recent surgical innovations. AB - This review covers the most recent clinical and surgical advances made in the development and application of cochlear implants (CIs). In recent years, dramatic progress has been made in both clinical and basic science aspect of cochlear implantation. Today's modern CI uses multi-channel electrodes with highly miniaturized powerful digital processing chips. This review article describes the function of various components of the modern multi-channel CIs. A selection of the most recent clinical and surgical innovations is presented. This includes the preliminary results with electro-acoustic stimulation or hybrid devices and ongoing basic science research that is focused on the preservation of residual hearing post-implantation. The result of an original device that uses a binaural stimulation mode with a single implanted receiver/stimulator is also presented. The benefit and surgical design of a temporalis pocket technique for the implant's receiver stimulator is discussed. Advances in biomedical engineering and surgical innovations that lead to an increasingly favorable clinical outcome and to an expansion of the indication of CI surgery are presented and discussed. PMID- 23044780 TI - Unity leads to progress. PMID- 23044781 TI - Metal-free catalyzed oxidative trimerization of indoles by using TEMPO in air: a biomimetic approach to 2-(1H-indol-3-yl)-2,3'-biindolin-3-ones. AB - A simple, convenient and efficient metal-free catalyzed oxidative trimeric reaction of indoles toward a variety of 2-(1H-indol-3-yl)-2,3'-biindolin-3-one derivatives in moderate to excellent yields has been developed. This transformation proceeds via a tandem oxidative homocoupling reaction by using TEMPO in air as an environmentally benign oxidant. This methodology provides an alternative approach for the direct generation of all-carbon quaternary centers at the C3 position of indoles. PMID- 23044782 TI - Preventing depression in adolescents. PMID- 23044783 TI - Cancer and heart disease networks face cuts, say charities. PMID- 23044784 TI - Officials raise questions over cost of Scotland's free public services. PMID- 23044785 TI - Synthesis of novel haptens against ciprofloxacin and production of generic monoclonal antibodies for immunoscreening of fluoroquinolones in meat. AB - BACKGROUND: The residues of fluoroquinolone drugs in foods of animal origin are dangerous to the consumers. The objective of this study was to produce a generic monoclonal antibody for determination of fluoroquinolone residues in meat. RESULTS: Two novel haptens of ciprofloxacin containing a free amidogen group on the piperazinyl ring were synthesised that were used to produce the monoclonal antibodies. The antibodies obtained simultaneously recognised 12 fluoroquinolones (ciprofloxacin, enrofloxacin, norfloxacin, sarafloxacin, diflocaxin, danofloxacin, ofloxacin, marbofloxacin, pefloxacin, lomefloxacin, amifloxacin and enofloxacin). After evaluation of different coating antigen-antibody combinations, a heterologous competitive indirect ELISA was used to determine the 12 drugs. The cross-reactivities were in the range of 23-120% and the limits of detection were in the range of 1.0-4.5 ng mL(-1). Eight fluoroquinolone drugs licensed as veterinary drugs in China were fortified into blank chicken for analysis. The recoveries were in the range of 61.5-82.5% with coefficients of variation in the range of 7.5-15.2%. CONCLUSION: This method could be used as a rapid screening tool for routine monitoring the residues of these fluoroquinolone drugs in animal-derived foods. PMID- 23044787 TI - Facile synthesis of novel hierarchical graphene-Bi2O2CO3 composites with enhanced photocatalytic performance under visible light. AB - A facile template-free hydrothermal approach is developed to synthesize hierarchical flower-like graphene-Bi(2)O(2)CO(3) microcomposites. The as-prepared samples were systematically characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, Fourier transform infrared spectroscopy, N(2) adsorption desorption and UV-visible diffuse reflectance spectroscopy. The photocatalytic activity of the as-prepared samples was evaluated towards degradation of Rhodamine B (RhB) under visible light. Compared to hierarchical Bi(2)O(2)CO(3), hierarchical flower-like graphene-Bi(2)O(2)CO(3) microcomposites show enhanced photocatalytic activity. In addition, our results indicate that both the physico chemical properties and associated photocatalytic activity of graphene Bi(2)O(2)CO(3) composites are shown to be dependent on graphene loadings. The highest photocatalytic performance can be achieved for the graphene Bi(2)O(2)CO(3) microcomposites with 1.0 wt% graphene. The underlying mechanism responsible for the formation of graphene-Bi(2)O(2)CO(3) composites and enhanced photoreactivity was discussed. Results from this study illustrate an entirely new approach to fabricate semiconductor composites containing graphene-bismuth with high visible-responsive photocatalytic performance. PMID- 23044786 TI - An observational study of the frequency, severity, and etiology of failures in postoperative care after major elective general surgery. AB - OBJECTIVE: To investigate the nature of process failures in postoperative care, to assess their frequency and preventability, and to explore their relationship to adverse events. BACKGROUND: Adverse events are common and are frequently caused by failures in the process of care. These processes are often evaluated independently using clinical audit. There is little understanding of process failures in terms of their overall frequency, relative risk, and cumulative effect on the surgical patient. METHODS: Patients were observed daily from the first postoperative day until discharge by an independent surgeon. Field notes on the circumstances surrounding any nonroutine or atypical event were recorded. Field notes were assessed by 2 surgeons to identify failures in the process of care. Preventability, the degree of harm caused to the patient, and the underlying etiology of process failures were evaluated by 2 independent surgeons. RESULTS: Fifty patients undergoing major elective general surgery were observed for a total of 659 days of postoperative care. A total of 256 process failures were identified, of which 85% were preventable and 51% directly led to patient harm. Process failures occurred in all aspects of care, the most frequent being medication prescribing and administration, management of lines, tubes, and drains, and pain control interventions. Process failures accounted for 57% of all preventable adverse events. Communication failures and delays were the main etiologies, leading to 54% of process failures. CONCLUSIONS: Process failures are common in postoperative care, are highly preventable, and frequently cause harm to patients. Interventions to prevent process failures will improve the reliability of surgical postoperative care and have the potential to reduce hospital stay. PMID- 23044788 TI - Annual intravenous zoledronic acid for three years increased cancellous bone matrix mineralization beyond normal values in the HORIZON biopsy cohort. AB - The efficacy of 3 years of annual intravenous administration of zoledronic acid (ZOL) in reducing vertebral and nonvertebral fractures in postmenopausal osteoporosis has been shown by the HORIZON pivotal fracture trial. Histomorphometric analysis of transiliac bone biopsies from the HORIZON participants revealed significantly improved trabecular architecture and reduced bone remodeling for the ZOL-treated versus placebo-treated patients. The aim of our study was to evaluate the cancellous and cortical bone mineralization density distribution (BMDD) in these biopsies by quantitative backscattered electron imaging (qBEI). The study cohort comprised 82 patients on active treatment (ZOL, yearly doses of 5 mg) and 70 treated with placebo, and all received adequate Ca and VitD supplementation. Comparison of ZOL-treated versus placebo-treated cancellous (Cn.) and cortical (Ct.) BMDD-derived variables resulted in significantly higher average (Cn.CaMean + 3.2%, Ct.CaMean + 2.7%) and mode calcium concentrations (Cn.CaPeak + 2.1%, Ct.CaPeak + 1.5%), increased percentages of highly mineralized bone areas (Cn.CaHigh + 64%, Ct.CaHigh + 31%), lower heterogeneity of mineralization (Cn.CaWidth -14%, Ct.CaWidth -13%), and decreased percentages of low mineralized bone areas (Cn.CaLow -22%, Ct.CaLow 26%) versus placebo (all p < 0.001). Cn. BMDD from the patients on active treatment also revealed a statistically significant shift to higher Ca concentrations when compared to a historical normal reference BMDD. These differences in BMDD from ZOL patients compared to the other groups were in line with the correlation of BMDD variables with previously determined cancellous mineralizing surface per bone surface (Cn. MS/BS, a primary histomorphometric index for bone turnover), showing that those with lower Cn. MS/BS had a higher degree of bone matrix mineralization. However, the differences in BMDD variables between the study groups remained when adjusted for Cn. MS/BS, suggesting that other factors in addition to reduced bone turnover might contribute to the higher bone matrix mineralization after ZOL treatment. PMID- 23044789 TI - [Disorders of the larynx and chronic inflammatory diseases]. AB - Chronic inflammatory diseases including tuberculosis, rheumatic disorders (rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, Wegeners's granulomatosis, relapsing polychondritis) and reflux disease are considered as systemic diseases, and may affect the larynx. The clinical symptoms are often unspecific, leading to prolonged intervals to diagnosis. Solid and haematological tumours should be considered in differential diagnosis and may require bioptic sampling. Treatment may require interdisciplinary approach. PMID- 23044790 TI - [Acute lung edema following surgery of a parapharyngeal abscess]. PMID- 23044791 TI - Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis. AB - OBJECTIVE: While medications used to treat rheumatoid arthritis (RA) may affect survival in RA, few studies take into account the propensity for medication use, which may reflect selection bias in treatment allocation in survival models. We undertook this study to examine the relationship between methotrexate (MTX) use and mortality in RA, after controlling for individual propensity scores for MTX use. METHODS: We studied 5,626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use, modeled in time-varying Cox regression models. We used the random forest method to generate individual propensity scores for MTX use at study entry and during followup in a time varying manner; these scores were included in the multivariate model. We also investigated whether selective discontinuation of MTX immediately prior to death altered the risk of mortality, and we examined the association of duration of MTX use with survival. RESULTS: During followup, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30 [95% confidence interval 0.09-1.03]). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use. CONCLUSION: MTX use was associated with a 70% reduction in mortality in RA. PMID- 23044792 TI - Patient-specific protein aggregates in myofibrillar myopathies: laser microdissection and differential proteomics for identification of plaque components. AB - Myofibrillar myopathies (MFMs) are histopathologically characterized by desmin positive protein aggregates and myofibrillar degeneration. While about half of all MFM are caused by mutations in genes encoding sarcomeric and extra-sarcomeric proteins (desmin, filamin C, plectin, VCP, FHL1, ZASP, myotilin, alphaB crystallin, and BAG3), the other half of these diseases is due to still unresolved gene defects. The present study aims at the proteomic characterization of pathological protein aggregates in skeletal muscle biopsies from patients with MFM-causing gene mutations. The technical strategy is based on the dissection of plaque versus plaque-free tissue areas from the same individual patient by laser dissection microscopy, filter-aided sample preparation, iTRAQ-labeling, and analysis on the peptide level using offline nano-LC and MALDI-TOF-TOF MS/MS for protein identification and quantification. The outlined workflow overcomes limitations of merely qualitative analyses, which cannot discriminate contaminating nonaggregated proteins. Dependent on the MFM causing mutation, different sets of proteins were revealed as genuine (accumulated) plaque components in independent technical replicates: (i) alphaB-crystallin, desmin, filamin A/C, myotilin, PRAF3, RTN2, SQSTM, XIRP1, and XIRP2 (patient with defined MFM mutation distinct from FHL1) or (ii) desmin, FHL1, filamin A/C, KBTBD10, NRAP, SQSTM, RL40, XIRP1, and XIRP2 (patient with FHL1 mutation). The results from differential proteomics indicate that plaques from different patients exhibit protein compositions with partial overlap, on the one hand, and mutation dependent protein contents on the other. The FHL1 mutation-specific pattern was validated for four patients with respect to desmin, SQSTM, and FHL1 by immunohistochemistry. PMID- 23044794 TI - Rituximab maintenance versus retreatment in follicular lymphoma. AB - Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Although the introduction of the anti-CD20 monoclonal antibody rituximab has represented a major breakthrough, FL remains incurable with standard chemoimmunotherapies. The goals of therapy in symptomatic FL patients include the following: obtaining high response rates, extending the duration of remission, prolongation of survival and improving quality of life, while minimizing adverse events. To extend remission duration and possibly survival outcomes, maintenance therapy with rituximab has been shown to be effective in both frontline and relapsed/refractory settings. However, the optimal timing, schedule and length of maintenance therapy are controversial. Herein, we review the current data for maintenance rituximab in FL, discuss the current controversies for this modality, attempt to define its role relative to the more conservative retreatment approach and provide practical recommendations for its clinical use. PMID- 23044795 TI - Integrated synthesis of poly(o-phenylenediamine)-derived carbon materials for high performance supercapacitors. AB - Poly(o-phenylenediamine) (POPD)-derived functional carbon materials with excellent capacitive performance are successfully synthesized by means of an integrated one-step process, in which FeCl(3) not only oxidizes the polymerization of the organic monomers but also activates the carbonization. Furthermore, extensive research has proved that this strategy to discover novel carbons is useful not only for capacitors but also for other energy storage/conversion devices. PMID- 23044793 TI - Optical imaging techniques for point-of-care diagnostics. AB - Improving access to effective and affordable healthcare has long been a global endeavor. In this quest, the development of cost-effective and easy-to-use medical testing equipment that enables rapid and accurate diagnosis is essential to reduce the time and costs associated with healthcare services. To this end, point-of-care (POC) diagnostics plays a crucial role in healthcare delivery in both developed and developing countries by bringing medical testing to patients, or to sites near patients. As the diagnosis of a wide range of diseases, including various types of cancers and many endemics, relies on optical techniques, numerous compact and cost-effective optical imaging platforms have been developed in recent years for use at the POC. Here, we review the state-of the-art optical imaging techniques that can have a significant impact on global health by facilitating effective and affordable POC diagnostics. PMID- 23044796 TI - Bilingualism enriches the poor: enhanced cognitive control in low-income minority children. AB - This study explores whether the cognitive advantage associated with bilingualism in executive functioning extends to young immigrant children challenged by poverty and, if it does, which specific processes are most affected. In the study reported here, 40 Portuguese-Luxembourgish bilingual children from low-income immigrant families in Luxembourg and 40 matched monolingual children from Portugal completed visuospatial tests of working memory, abstract reasoning, selective attention, and interference suppression. Two broad cognitive factors of executive functioning-representation (abstract reasoning and working memory) and control (selective attention and interference suppression)-emerged from principal component analysis. Whereas there were no group differences in representation, the bilinguals performed significantly better than did the monolinguals in control. These results demonstrate, first, that the bilingual advantage is neither confounded with nor limited by socioeconomic and cultural factors and, second, that separable aspects of executive functioning are differentially affected by bilingualism. The bilingual advantage lies in control but not in visuospatial representational processes. PMID- 23044797 TI - Retrieval-induced forgetting predicts failure to recall negative autobiographical memories. AB - There is a positivity bias in autobiographical memory such that people are more likely to remember positive events from their past than they are to remember negative ones. Inhibition may promote this positivity bias by deterring negative memories from being retrieved. In our first experiment, we measured individual differences in retrieval-induced forgetting, a phenomenon believed to be the consequence of retrieval inhibition, and correlated that measure with individual differences in the recall of positive and negative autobiographical memories. Participants who exhibited lower levels of retrieval-induced forgetting recalled significantly more negative memories despite recalling fewer positive memories. In our second experiment, participants attempted to recall negative memories from childhood and from the previous month. Participants who exhibited lower levels of retrieval-induced forgetting recalled significantly more negative memories in both conditions. These results suggest that inhibition plays a key role in preventing the retrieval of negative autobiographical memories. PMID- 23044798 TI - How much do incidental values affect the judgment of time? PMID- 23044800 TI - Obesity: sugar-sweetened beverages--fueling the epidemic of childhood obesity? PMID- 23044799 TI - The use of image-guided surgery in endoscopic sinus surgery: an evidence-based review with recommendations. AB - BACKGROUND: The frequency of endoscopic sinus surgery (ESS) appears to be increasing, and the use of image-guided surgery (IGS) in these procedures is becoming more widespread. The use of IGS in ESS and anterior skull base surgery is predicated on the notion that its ability to aid in anatomic identification during surgery will lead to fewer complications and improved surgical outcomes. The purpose of this article is to provide an evidence-based examination of the benefits of IGS in ESS. METHODS: A systematic review of the literature was performed and recommendations were created based on the Clinical Practice Guideline Manual, Conference of Guideline Standardization (COGS), and the Appraisal of Guidelines and Research Evaluation (AGREE) instruments. RESULTS: This review identified and evaluated literature regarding the effect of IGS on surgical complications and on postoperative outcomes in ESS. Currently, there is grade C evidence to support the use of IGS in ESS. CONCLUSION: Based on the best available evidence in the literature, the use of IGS has not clearly been shown to decrease surgical complications or improve surgical outcomes. These evidence based recommendations are based on limited literature with suboptimal research methodology. However, the importance, utility, and acceptance of IGS through expert opinion and consensus are supported by the available literature. Therefore, the use of IGS in ESS is an option and should be based on clinical judgment and applied on a case-by-case basis. PMID- 23044801 TI - Diabetes: inhibit VEGF-B to treat T2DM? PMID- 23044802 TI - A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. PMID- 23044803 TI - RNAi screening of the human colorectal cancer genome identifies multifunctional tumor suppressors regulating epithelial cell invasion. PMID- 23044804 TI - In vitro generation of platelets through direct conversion: first report in My Knowledge (iMK). AB - Blood transfusion medicine requires a constant supply of platelets, which is now totally donor dependent. Recent advances in the generation of platelets in vitro through megakaryocytes (MKs) may provide protocols not only via pluripotent stem cells, including induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), but also via induced MKs (iMKs). For the first time, mouse and human fibroblasts are successfully transdifferentiated into iMKs by the introduction of three factors, p45NF-E2, Maf G, and Maf K. PMID- 23044805 TI - Stress-mediated p38 activation promotes somatic cell reprogramming. AB - Environmental stress-mediated adaptation plays essential roles in the evolution of life. Cellular adaptation mechanisms usually involve the regulation of chromatin structure, transcription, mRNA stability and translation, which eventually lead to efficient changes in gene expression. Global epigenetic change is also involved in the reprogramming of somatic cells into induced pluripotent stem (iPS) cells by defined factors. Here we report that environmental stress such as hyperosmosis not only facilitates four factor-mediated reprogramming, but also enhances two or one factor-induced iPS cell generation. Hyperosmosis-induced p38 activation plays a critical role in this process. Constitutive active p38 mimics the positive effect of hyperosmosis, while dominant negative p38 and p38 inhibitor block the effect of hyperosmosis. Further study indicates stress mediated p38 activation may promote reprogramming by reducing the global DNA methylation level and enhancing the expression of pluripotency genes. Our results demonstrate how simple environmental stress like hyperosmosis helps to alter the fate of cells via intracellular signaling and epigenetic modulation. PMID- 23044807 TI - Association of XRCC1, XRCC3, and XPD genetic polymorphism with an increased risk of hepatocellular carcinoma because of the hepatitis B and C virus. AB - OBJECTIVE: The south-east Asian and sub-Saharan African populations are the most susceptible to hepatocellular carcinoma (HCC). We aimed to establish whether XRCC1, XRCC3, and XPD are associated with liver cancer in Pakistan and to examine the interaction of hepatitis B virus (HBV) or hepatitis C virus (HCV) with repaired genes in the occurrence of liver cancer. MATERIALS AND METHODS: We enrolled 74 healthy individuals, 75 had either HBV or HCV, and 50 were HCC patients. The characteristic information of all the study participants were collected through a standard interviewer-administered questionnaire. The PCR-RFLP was used to identify the genotype of the patients. RESULTS: The results of our study indicated that the patients infected with HBV or HCV had a four or three fold greater risk of developing liver cancer. Patients older than 55 years of age had a significantly higher risk of developing cancer compared with younger patients. The homozygous wild types Arg/Arg for 280 and Thr/Thr for 241 were more frequent in the controls than in the cases. The allelic frequency of mutant 280His and 399Gln was more pronounced among HCC cases than the controls or the HBV-infected patients. CONCLUSION: The frequency of the XPD gene in the controls was in Hardy-Weinberg equilibrium, indicating that the gene played a protective role in the Pakistani population. XRCC1 or XRCC3 was associated with liver cancer in the Pakistani population; however, the XPD gene played a vital role in the repair of DNA damage. PMID- 23044808 TI - Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation: experience at a single center and review of the literature. AB - AIMS: The aim of this study was to assess the safety and efficacy of sorafenib, with or without everolimus, in the treatment of recurrent hepatocellular carcinoma (HCC) after an orthotopic liver transplantation (OLT). METHODS: We reviewed the outcome of our consecutive cohort series of patients. Eleven patients (nine men) with recurrent HCC after OLT were treated. Four patients received cyclosporine plus sorafenib at a starting dose of 400 mg twice daily; seven received the combination of sorafenib (same dosage) and everolimus. Sorafenib was reduced or stopped according to the drug label. RESULTS: The median time to recurrence was 12 months (range 2-66). The mean age at the start of treatment was 57 +/- 9 years. Sorafenib was withdrawn because of intolerance or side-effects in four (36%) patients. Dose reduction because of adverse events or intolerance was required in 91% of patients after 26 +/- 11 days from the start of treatment. The average length of treatment was 68 days (range 15-444). One patient died because of a massive gastrointestinal bleeding while receiving sorafenib and everolimus. The most frequent adverse events were fatigue (54%), skin toxicity (45%), and hypophosphatemia (36%). Two patients (18%) showed a radiological partial response, one (9%) had a stable disease, and six (54%) showed a progressive disease. None of the patients achieved a complete response. Treatment response could not be assessed in two (18%) patients. The overall median survival since the start of treatment was 5 months. One-year survival was 18%. CONCLUSION: Sorafenib, with or without mammalian target of rapamycin inhibitors, is poorly tolerated and rarely effective in the treatment of recurrent HCC after OLT. PMID- 23044809 TI - Occult hepatitis B infection in Portuguese patients with chronic hepatitis C liver disease: prevalence and clinical significance. AB - INTRODUCTION: Occult hepatitis B virus (HBV) infection, defined as the presence of HBV DNA in the liver (with detectable or undetectable HBV DNA in the serum), has been reported in patients with chronic hepatitis C. Some data suggest its association with a more severe liver disease and a worse response to interferon therapy in this subgroup of patients. However, the clinical significance of this condition is still under debate. AIM: To determine the prevalence of occult HBV infection and its clinical significance in patients with chronic hepatitis C liver disease. MATERIALS AND METHODS: A prospective analysis of consecutive outpatients with chronic hepatitis C who underwent a liver biopsy recruited between January 2008 and June 2011 was carried out. Data included patient's sex and age, source of hepatitis C virus (HCV) infection, HCV genotype and viral load, presence of serologic markers of previous HBV infection, HBV DNA presence in the liver, histologic findings, and response to interferon and ribavirin treatment. HBV DNA and HCV RNA detection were carried out using a sensitive commercially available PCR kit. HBV DNA was tested in liver samples using a nested PCR procedure. RESULTS: One hundred patients were included, 73% men, mean age 49 +/- 11.9 years. Most patients had a genotype 1, with a high viral load, HCV infection. Of the patients, 33% had HBV serologic markers of past infection. The presence of HBV DNA in liver samples was found in 57% of the patients. No statistically significant difference in the epidemiological, histological, or virological or response to therapy data was found in patients with occult HBV infection. CONCLUSION: Occult HBV infection occurred in a high percentage of patients but was not clinically significant. PMID- 23044810 TI - Conclusiveness of the Cochrane Reviews in Pediatric-Gastroenterology: a systematic analysis. AB - AIM: To assess the conclusiveness of the Cochrane Reviews (CRs) in the field of Pediatric-Gastroenterology. We tested the hypotheses that (a) the majority of CRs are inconclusive, (b) the majority of CRs recognize the need for further studies, (c) the ability to reach a conclusion is dependent on both the number of studies and the number of patients. We also studied whether the conclusiveness of CRs changed over time. METHODS: We selected all CRs in the field of Pediatric Gastroenterology available in the Cochrane library. Each CR was analyzed for the number of randomized clinical trials (RCTs) found, the number of RCTs included for analysis, the number of patients enrolled, the stated need for further studies, and the conclusiveness of the CR. RESULTS: Sixty-eight out of 85 CRs (80%) were conclusive. The percentage of articles included in conclusive studies was significantly higher than that in inconclusive ones (P<0.00001). Thus, the average number of RCTs retained in the analyses was significantly higher in conclusive CRs. The total number of patients in the RCTs retained for analysis was significantly higher in conclusive CRs (P<0.0001). The majority of inconclusive CRs (82.4%) recognized the need for further studies compared with 44.1% in conclusive ones (P=0.002). The percentage of conclusive CRs was not affected by the year of publication. CONCLUSION: In the field of Pediatric Gastroenterology, CRs appear to be a potent clinical tool that allows, in 80% of the cases, to reach a valid (from a clinical standpoint) conclusion, while emphasizing the weaknesses of available, published evidence and delineating future avenues of research. PMID- 23044811 TI - Helicobacter pylori is not the predominant etiology for liver cirrhosis patients with peptic ulcer disease. AB - OBJECTIVES: Patients with liver cirrhosis (LC) often develop peptic ulcers. The differentiation of Helicobacter pylori etiology in LC patients from that of peptic ulcers in non-LC patients is critical. This study aimed to determine whether H. pylori plays a central role in LC patients with peptic ulcers. METHODS: LC was defined by International Classifications of Diseases, Revision 9, and Clinical Modification (ICD-9-CM) codes 571.2, 571.5, and 571.6. To be defined as non-LC, we did not identify patients in an inpatient setting or by one or more ambulatory care claims containing the International Classifications of Diseases, Revision 9, and Clinical Modification codes 571.2, 571.5, and 571.6. The sample included 9465 H. pylori-positive patients and 3418 H. pylori-negative patients. A logistic regression model was used to calculate the odds ratio (OR) and a 95% confidence interval was used to determine whether LC was an independent factor of lower H. pylori infection rates in peptic ulcer patients. RESULTS: This study included 102 decompensated LC patients with peptic ulcers, 39 H. pylori-positive and 63 H. pylori-negative. There were 360 compensated LC patients with peptic ulcers, 193 H. pylori-positive and 167 H. pylori-negative. Among the non-LC patients with peptic ulcers, 9233 were H. pylori-positive and 3188 were H. pylori negative. On the basis of logistic regression analysis, decompensated LC patients (OR=0.23, P<0.001) and compensated LC patients (OR=0.48, P<0.001) had lower H. pylori infection rates. CONCLUSION: H. pylori is not the predominant etiology for LC, especially the decompensated type, either with peptic ulcer disease or with recurrent ulcer disease. PMID- 23044812 TI - A novel organ of corti explant model for the study of cochlear implantation trauma. AB - This study presents a novel in vitro model of electrode insertion trauma-induced hair cell (HC) damage and loss and its application for testing the efficacy of otoprotective drugs. In the cochlear implant (CI) procedure as a treatment for profound deafness, an electrode array is surgically inserted to provide electrical stimulation to the auditory nerve. Mechanical trauma from insertion of a CI electrode into the scala tympani can lead to inflammation and a high level of oxidative stress, which can initiate the apoptosis of auditory HCs and intracochlear fibrosis. HC apoptosis and intracochlear fibrosis are thought to be causes of poor CI functional outcomes. In order to gain insight into the molecular mechanisms that initiate HC apoptosis and scala tympani fibrosis following electrode insertion trauma (EIT), and the otoprotective effects of dexamethasone (DXM) observed in previous studies, an in vitro model of EIT was designed. Here we present and characterize a novel, reproducible in vitro model for the study of cellular and molecular events that occur following an EIT procedure. Cochleae from 3-day-old rats were subjected to a cochleostomy and were then divided into three groups: (1) control, (2) EIT, and (3) EIT + DXM (20 MUg/mL). In Groups 2 and 3, a 0.28-mm diameter monofilament fishing line was introduced through the small cochleostomy located next to the round window area, allowing for an insertion of between 110 degrees and 150 degrees . HC counts, gene expression for pro-inflammatory cytokines (i.e., TNFalpha and IL-1beta), pro inflammatory inducible enzymes (i.e., iNOS and COX-2) and growth factors (i.e., TGFbeta1, TGFbeta3 and CTGF), oxidative stress (i.e., CellROX), and analyses of apoptosis pathways (i.e., caspase-3, apoptosis induced factor and Endonuclease G) were carried out on all explants at different time points. The results of this EIT in vitro model show the initiation of wound healing in which an inflammatory response is followed by a proliferative-fibrosis phase. Moreover, DXM treatment of EIT explants inhibited the inflammatory response and promoted a nonscarring wound healing process. The novel in vitro model described here will improve our understanding of mechanisms underlying CI insertion trauma and protective strategies such as DXM treatment. PMID- 23044813 TI - Functional properties of carotenoids originating from algae. AB - Carotenoids are isoprenoid molecules which are synthesised de novo by photosynthetic plants, fungi and algae and are responsible for the orange, yellow and some red colours of various fruits and vegetables. Carotenoids are lipophilic compounds, some of which act as provitamins A. These compounds can be divided into xanthophylls and carotenes. Many macroalgae and microalgae are rich in carotenoids, where these compounds aid in the absorption of sunlight. Industrially, these carotenoids are used as food pigments (in dairy products, beverages, etc.), as feed additives, in cosmetics and in pharmaceuticals, especially nowadays when there is an increasing demand by consumers for natural products. Production of carotenoids from algae has many advantages compared to other sources; for example, their production is cheap, easy and environmentally friendly; their extraction is easier, with higher yields, and there is no lack of raw materials or limited seasonal variation. Recently, there has been considerable interest in dietary carotenoids with respect to their antioxidant properties and their ability to reduce the incidence of some chronic diseases where free radicals are involved. Possibly, carotenoids protect cells from oxidative stress by quenching singlet oxygen damage with various mechanisms. Therefore, carotenoids derived from algae could be a leading natural resource in the research for potential functional ingredients. PMID- 23044814 TI - Co-crystallisation of competing structural modes in geometrically constrained Jahn-Teller manganese(III) complexes. AB - The combination of Jahn-Teller distortion and chelating ligands produces a fine balance between competing coordination modes in manganese(III) resulting in well ordered co-crystallization of two distinct assemblies from one set of components under a single set of conditions. PMID- 23044815 TI - Methotrexate saves lives: a pearl of observational research. PMID- 23044818 TI - Exon and intron definition in pre-mRNA splicing. AB - One of the fundamental issues in RNA splicing research is represented by understanding how the spliceosome can successfully define exons and introns in a huge variety of pre-mRNA molecules with nucleotide-precision. Since its first description, researchers in this field have identified and characterized many fundamental elements and players capable of affecting the splicing process, both in a negative and positive manner. Indeed, it can be argued that today we know a great deal about the forces that make an exon, an exon and an intron, an intron. As will be discussed in this review, these decisions are a result of a complex combinatorial control resulting from many different factors/influences. Most importantly, these influences act across several levels of complexity starting from the relatively simple interaction between two consensus 5' and 3' splice sites to much more complex factors: such as the interplay between silencer or enhancer sequences, transcriptional processivity, genomic milieu, nucleosome positioning, and histone modifications at the chromatin level. Depending on local contexts, all these factors will act either antagonistically or synergistically to decide the exon/intron fate of any given RNA sequence. At present, however, what we still lack is a precise understanding of how all these processes add up to help the spliceosome reach a decision. Therefore, it is expected that future challenges in splicing research will be the careful characterization of all these influences to improve our ability to predict splicing choices in different organisms or in specific contexts. PMID- 23044816 TI - Ethnic variability in bone geometry as assessed by hip structure analysis: findings from the hip strength across the menopausal transition study. AB - Racial/ethnic origin plays an important role in fracture risk. Racial/ethnic differences in fracture rates cannot be fully explained by bone mineral density (BMD). Studies examining the influence of bone geometry and strength on fracture risk have focused primarily on older adults and have not included people from diverse racial/ethnic backgrounds. Our goal was to explore racial/ethnic differences in hip geometry and strength in a large sample of midlife women. We performed hip structure analysis (HSA) on hip dual-energy X-ray absorptiometry (DXA) scans from 1942 premenopausal and early perimenopausal women. The sample included white (50%), African American (27%), Chinese (11%), and Japanese (12%) women aged 42 to 52 years. HSA was performed using software developed at Johns Hopkins University. African American women had higher conventional (8.4% to 9.7%) and HSA BMD (5.4% to 19.8%) than other groups with the exception being Japanese women, who had the highest HSA BMD (9.7% to 31.4%). HSA indices associated with more favorable geometry and greater strength and resistance to fracture were more prevalent in African American and Japanese women. Femurs of African American women had a smaller outer diameter, a larger cross-sectional area and section modulus, and a lower buckling ratio. Japanese women presented a different pattern with a higher section modulus and lower buckling ratio, similar to African American women, but a wider outer diameter; this was offset by a greater cross sectional area and a more centrally located centroid. Chinese women had similar conventional BMD as white women but a smaller neck region area and HSA BMD at both regions. They also had a smaller cross-sectional area and section modulus, a more medially located centroid, and a higher buckling ratio than white women. The observed biomechanical differences may help explain racial/ethnic variability in fracture rates. Future research should explore the contribution of hip geometry to fracture risk across all race/ethnicities. PMID- 23044817 TI - The effect of recombinant stromal cell-derived factor-1 treatment on hypoxic ischemic brain injury in neonatal mice. AB - BACKGROUND: Stromal cell-derived factor-1 (SDF-1) plays a critical role in adult brain injury repair including neurogenesis and vasculogenesis. However, the effects of recombinant SDF-1(rSDF-1) treatment on hypoxic-ischemic (HI) brain injury in neonatal mice are not clear. MATERIALS AND METHODS: Seven-day-old (P7) C57BL/6J mice were divided into sham group, control group, and rSDF-1 group. Mice brains were collected to determine histopathological damage and the expression level of SDF-1, caspase-3, and Ki67 on P8, P10, P14, and P21. Passive avoidance and elevated plus-maze tests were also assessed on P20 and P21. RESULTS: Compared with control group, rSDF-1 treatment increased the weight ratio of left and right brain hemisphere (p < 0.05), reduced the number of electric foot shocks (p < 0.05) and the percentage of time spent in the open arms (p < 0.05), meanwhile, increased the retention latency (p < 0.05) and the percentage of time spent in the enclosed arms (p < 0.05) on P20 and P21. High expression of Ki67 and low expression of caspase-3 were also observed. DISCUSSION: This study showed that rSDF-1 treatment effectively alleviated brain injury shown by reducing in caspase 3 expression and increasing in Ki67 expression. Moreover, rSDF-1 treatment significantly improved behavioral performances in juvenile mice after HI. PMID- 23044819 TI - Synthesis of 2-arylindole derivatives and evaluation as nitric oxide synthase and NFkappaB inhibitors. AB - Development of small molecule drug-like inhibitors blocking both nitric oxide synthase and NFkappaB could offer a synergistic therapeutic approach in the prevention and treatment of inflammation and cancer. During the course of evaluating the biological potential of a commercial compound library, 2 phenylindole (1) displayed inhibitory activity against nitrite production and NFkappaB with IC(50) values of 38.1 +/- 1.8 and 25.4 +/- 2.1 MUM, respectively. Based on this lead, synthesis and systematic optimization have been undertaken in an effort to find novel and more potent nitric oxide synthase and NFkappaB inhibitors with antiinflammatory and cancer preventive potential. First, chemical derivatizations of 1 and 2-phenylindole-3-carboxaldehyde (4) were performed to generate a panel of N-alkylated indoles and 3-oxime derivatives 2-7. Second, a series of diversified 2-arylindole derivatives (10) were synthesized from an array of substituted 2-iodoanilines (8) and terminal alkynes (9) by applying a one-pot palladium catalyzed Sonogashira-type alkynylation and base-assisted cycloaddition. Subsequent biological evaluations revealed 3-carboxaldehyde oxime and cyano substituted 2-phenylindoles 5 and 7 exhibited the strongest nitrite inhibitory activities (IC(50) = 4.4 +/- 0.5 and 4.8 +/- 0.4 MUM, respectively); as well as NFkappaB inhibition (IC(50) = 6.9 +/- 0.8 and 8.5 +/- 2.0 MUM, respectively). In addition, the 6'-MeO-naphthalen-2'-yl indole derivative 10at displayed excellent inhibitory activity against NFkappaB with an IC(50) value of 0.6 +/- 0.2 MUM. PMID- 23044821 TI - Effects of poly- and monodisperse surfactants on 14C-epoxiconazole diffusion in isolated cuticles of Prunus laurocerasus. AB - BACKGROUND: Surfactants are known to enhance the foliar uptake of agrochemicals. It was the aim of this study to compare the enhancing effect of three polydisperse surfactants (Brij 30, Plurafac LF300 and Wettol LF700) and five monodisperse alcohol ethoxylates (C12 E3, C12 E4, C12 E5, C12 E6 and C12 E8) on (14)C-epoxiconazole diffusion in cuticles isolated from cherry laurel (Prunus laurocerasus L.). RESULTS: Rate constants (k*) of (14) C-epoxiconazole diffusion were measured in the presence and in the absence of the surfactants. Polydisperse surfactants increased the rates of foliar penetration of (14) C-epoxiconazole by factors of between 8 and 16. With monodisperse surfactants, enhancing effects on cuticular penetration were 2-16-fold. Effects were highest with alcohol ethoxylates of intermediate size, whereas they were lower for the smaller, more lipophilic and the larger, more polar monomers. In addition, diffusion of four monodisperse alcohol ethoxylates (C12 E3, C12 E4, C12 E5 and C12 E6 ) across cuticles was measured. Rate constants of alcohol ethoxylates decreased with decreasing lipophility and increasing molecular weight. CONCLUSION: The results indicate that enhancement of foliar penetration across cuticles by surfactants was most efficient when both (14)C-epoxiconazole and surfactants had similar mobilities in the transport-limiting barrier of the cuticles. This observation should be of interest in future strategies to optimise foliar uptake of agrochemicals using surfactants. PMID- 23044820 TI - Binary regression: total gain in positive and negative predictive values. AB - Models that predict disease incidence or disease recurrence are attractive for clinicians as well as for patients. The usefulness of a risk prediction model is linked to the two questions whether the observed outcome is confirmed by the prediction and whether the risk prediction is accurate in predicting the future outcome, respectively. The first phrasing of the question is linked to considering sensitivity and specificity and the latter to the positive and negative predictive values. We present the measures of standardized total gain in positive and negative predictive values dealing with the performance or accuracy of the prediction model for a binary outcome. Both measures provide a useful tool for assessing the performance or accuracy of a set of predictor variables for the prediction of a binary outcome. This concept is a tool for evaluating the optimal prediction model in future research. PMID- 23044822 TI - Influence of D/A ratio on photovoltaic performance of a highly efficient polymer solar cell system. AB - A new copolymer PIDTDTQx based on indacenodithiophene and quinoxaline is synthesized and characterized. The correlation between the D/A ratio, mobility, and photovoltaic properties, as well as morphology of the D/A blend based on a PIDTDTQx:PC(70) BM system is investigated. The power conversion efficiency of the polymer solar cells based on PIDTDTQx/PC(70) BM (1:4, w/w) reaches 7.51%. PMID- 23044823 TI - Lab on a chip: Scandinavia. PMID- 23044824 TI - The inflammation theory of disease. The growing realization that chronic inflammation is crucial in many diseases opens new avenues for treatment. PMID- 23044825 TI - Genetics of germ cell development. AB - The germ line represents a continuous cellular link between generations and between species, but the germ cells themselves develop in a specialized, organism specific context. The model organisms Caenorhabditis elegans, Drosophila melanogaster and the mouse display striking similarities, as well as major differences, in the means by which they control germ cell development. Recent developments in genetic technologies allow a more detailed comparison of the germ cells of these three organisms than has previously been possible, shedding light not only on universal aspects of germline regulation, but also on the control of the pluripotent state in vivo and on the earliest steps of embryogenesis. Here, we highlight themes from the comparison of these three alternative strategies for navigating the fundamental cycle of sexual reproduction. PMID- 23044828 TI - Disease genomics: Associations go metagenome-wide. PMID- 23044826 TI - Genome-wide association studies in mice. AB - Genome-wide association studies (GWASs) have transformed the field of human genetics and have led to the discovery of hundreds of genes that are implicated in human disease. The technological advances that drove this revolution are now poised to transform genetic studies in model organisms, including mice. However, the design of GWASs in mouse strains is fundamentally different from the design of human GWASs, creating new challenges and opportunities. This Review gives an overview of the novel study designs for mouse GWASs, which dramatically improve both the statistical power and resolution compared to classical gene-mapping approaches. PMID- 23044827 TI - Evolution of the cancer genome. AB - The advent of massively parallel sequencing technologies has allowed the characterization of cancer genomes at an unprecedented resolution. Investigation of the mutational landscape of tumours is providing new insights into cancer genome evolution, laying bare the interplay of somatic mutation, adaptation of clones to their environment and natural selection. These studies have demonstrated the extent of the heterogeneity of cancer genomes, have allowed inferences to be made about the forces that act on nascent cancer clones as they evolve and have shown insight into the mutational processes that generate genetic variation. Here we review our emerging understanding of the dynamic evolution of the cancer genome and of the implications for basic cancer biology and the development of antitumour therapy. PMID- 23044829 TI - Dose-dependent effects of differential rearing on amphetamine-induced hyperactivity. AB - Differential rearing decreases psychostimulant-induced hyperactivity. In general, environmental enrichment decreases the locomotor response to low unit doses of psychostimuluants, whereas isolation increases the response. It is not clear whether the changes in locomotor activity are due to an enrichment-induced decrease or an isolation-induced increase. Therefore, the current experiments examined the ability of enrichment rearing, as compared with isolation and standard rearing, to attenuate amphetamine-induced hyperactivity following acute administration, repeated administration, and sensitization of a low (0.3 mg/kg) and moderate (1.0 mg/kg) dose of amphetamine. Rats were reared under enriched, isolated, or standard conditions. Enrichment slowed the acquisition of amphetamine-induced hyperactivity and attenuated the expression of amphetamine induced sensitization, but only at the low unit dose. Enrichment did not protect against the expression of conditioned hyperactivity at either of the doses tested. The behavior of standard condition rats was generally closer to that of isolated condition rats than enriched condition rats, suggesting that the enrichment attenuates the response to amphetamine as opposed to isolation rearing increasing the response to amphetamine. These results suggest that the effects of enrichment are because of enrichment manipulation and not simply a contrast from the effects of isolation. PMID- 23044830 TI - Interactions between Delta(9)-tetrahydrocannabinol and heroin: self administration in rhesus monkeys. AB - The cannabinoid receptor agonist Delta(9)-tetrahydrocannabinol (THC) enhances the antinociceptive effects of u-opioid receptor agonists, raising the possibility of using a combination of THC and opioids for treating pain. This study examined the effects of noncontingent and contingent administration of THC on intravenous heroin self-administration in rhesus monkeys. Self-administration of different unit doses of heroin (0.0001-0.1 mg/kg/infusion) generated a typical inverted U shaped dose-response curve. In one experiment (n=4), noncontingent THC (0.1-1.0 mg/kg) dose dependently shifted the heroin dose-response curve downward in three monkeys and slightly leftward in one monkey. In a second experiment (n=4), monkeys could self-administer THC alone (0.0032-0.032 mg/kg/infusion), heroin alone, or a mixture of THC and heroin. THC alone did not maintain responding above that obtained with saline; however, increasing the THC dose with heroin dose dependently decreased the number of infusions received and the rate of responding, as compared with data that were obtained with heroin alone. These results indicate that THC does not significantly enhance the positive reinforcing effects of heroin, further supporting the view that combining cannabinoid and opioid receptor agonists (e.g. for treating pain) does not increase, and might decrease, the abuse liability of individual drugs. PMID- 23044831 TI - (-)-Epigallocatechin-3-gallate decreases the impairment in learning and memory in spontaneous hypertension rats. AB - Oxidative stress induced by hypertension has been reported to cause alterations in neural cytoarchitecture and cognitive dysfunction. Green tea catechins, especially (-)-epigallocatechin-3-gallate (EGCG), have potent antioxidative properties and protect against various oxidative damages. In this study, we examined the impact of hypertension in rats on locomotor activity, learning, and memory, and EGCG was tested for its potential therapeutic effects in treating hypertension-induced impairment. Blood pressure was measured by the tail-cuff method to confirm high blood pressure in spontaneous hypertension rats (SHRs). Locomotor activity in the open field was increased in SHRs, along with learning and memory impairment in the Morris water maze. Daily EGCG treatment reduced the progressive increase in blood pressure in SHRs, and prevented most of the increased locomotor activity in addition to improving learning and memory. EGCG treatment also decreased the increased level of lipid peroxide production in SHRs and enhanced the antioxidation power in plasma that was observed to be decreased in SHRs. EGCG also decreased the concentration of reactive oxygen species in the hippocampi of SHRs. These indicate a therapeutic effect of EGCG in treating hypertension-induced learning and memory impairment, most probably through its powerful antioxidative properties. PMID- 23044832 TI - Topical therapies in the management of chronic rhinosinusitis: an evidence-based review with recommendations. AB - BACKGROUND: Topical therapies have become an integral component in the management plan for chronic rhinosinusitis (CRS). Several topical therapy strategies have been evaluated, but a formal comprehensive evaluation of the evidence has never been performed. The purpose of this article is to provide an evidence-based approach for the utilization of topical therapies in the management of CRS. METHODS: A systematic review of the literature was performed and the guidelines for development of an evidence-based review with recommendations were followed. Study inclusion criteria were: adult population >18 years old; chronic rhinosinusitis (CRS) based on published diagnostic criteria; and clearly defined primary clinical end-point. We focused on reporting higher-quality studies (level 2b or higher), but reported on lower-level studies if the topic contained insufficient evidence. We excluded drug-eluting spacer and stent therapy from this review. RESULTS: This review identified and evaluated the literature on 5 topical therapy strategies for CRS: saline irrigation, topical steroid, topical antibiotic, topical antifungal, and topical alternatives (surfactant, manuka honey, and xylitol irrigations). CONCLUSION: Based on the available evidence, sinonasal saline irrigation and standard topical nasal steroid therapy are recommended in the topical treatment of CRS. Nonstandard (off-label) topical sinonasal steroid therapies can be an option for managing CRS. The evidence recommends against the use of topical antifungal therapy and topical antibiotic therapy delivered using nebulized and spray techniques in routine cases of CRS. There is insufficient clinical research to provide recommendations for alternative therapies or topical antibiotic therapy delivered using other delivery methods (eg, irrigations). PMID- 23044833 TI - Bioavailability of arsenic, cadmium, iron and zinc in leafy vegetables amended with urban particulate matter suspension. AB - BACKGROUND: Urban particulate matter (PM) can affect green plants either via deposition on the above-ground biomass, where the contaminants can penetrate the leaf surface, or indirectly via soil-root interaction. This experiment assessed the potential risk of PM-derived risk elements contained in vegetables. The bioavailable portions of arsenic (As), cadmium (Cd), iron (Fe), and zinc (Zn) in leafy vegetables amended by PM via soil and/or foliar application were investigated in a model pot experiment, in which lettuce and chard were cultivated. RESULTS: By using the physiologically based extraction test simulating in vitro human digestive processes in the stomach and small intestine, the bioavailable portions of toxic elements from PM-amended plant biomass were extracted. Extractable portions of elements by a simulated gastric solution from biomass decreased for lettuce in the order Zn > Cd > As > Fe; while for chard, the order was As > Zn > Cd > Fe. No significant effects of PM physical fractions or soil were observed. CONCLUSIONS: Although the bioavailable element portions in the PM samples were lower compared to plants, the bioavailable element contents in foliar PM-amended plant leaves exceeded the control and soil PM amendment levels, even after biomass washing. PMID- 23044835 TI - Professional practice leadership roles: the role of organizational power and personal influence in creating a professional practice environment for nurses. AB - Professional practice leadership (PPL) roles are those roles responsible for expert practice, providing professional leadership, facilitating ongoing professional development, and research. Despite the extensive implementation of this role, most of the available literature focuses on the implementation of the role, with few empirical studies examining the factors that contribute to PPL role effectiveness. This article will share the results of a research study regarding the role of organizational power and personal influence in creating a high-quality professional practice environment for nurses. Survey results from nurses and PPLs from 45 hospitals will be presented. Path analysis was used to test the hypothesized model and relationships between the key variables of interest. Results indicate that there is a direct and positive relationship between PPL organizational power and achievement of PPL role functions, as well as an indirect, partially mediated effect of PPL influence tactics on PPL role function. There is also a direct and positive relationship between PPL role functions and nurses' perceptions of their practice environment. The evidence generated from this study highlights the importance of organizational power and personal influence as significantly contributing to the ability of those in PPL roles to achieve desired outcomes. This information can be used by administrators, researchers, and clinicians regarding the factors that can optimize the organizational and systematic strategies for enhancing the practice environment for nursing and other health care professionals. PMID- 23044836 TI - The business case for provider participation in clinical trials research: an application to the National Cancer Institute's community clinical oncology program. AB - BACKGROUND: Provider-based research networks (PBRNs) make clinical trials available in community-based practice settings, where most people receive their care, but provider participation requires both financial and in-kind contributions. PURPOSE: The aim of this study was to explore whether providers believe there is a business case for participating in PBRNs and what factors contribute to the business case. METHODOLOGY/APPROACH: We use a multiple case study methodology approach to examine the National Cancer Institute's community clinical oncology program, a long-standing federally funded PBRN. Interviews with 41 key informants across five sites, selected on the basis of organizational maturity, were conducted using a semistructured interview guide. We analyzed interview transcripts using an iterative, deductive process to identify themes and subthemes in the data. FINDINGS: We found that a business case for provider participation in PBRNs may exist if both direct and indirect financial benefits are identified and included in the analysis and if the time horizon is long enough to allow those benefits to be realized. We identified specific direct and indirect financial benefits that were perceived as important contributors to the business case and the perceived length of time required for a positive return to accrue. PRACTICE IMPLICATIONS: As the lack of a business case may result in provider reluctance to participate in PBRNs, knowledge of the benefits we identified may be crucial to encouraging and sustaining participation, thereby preserving patient access to innovative community-based treatments. The results are also relevant to federally funded PBRNs outside of oncology or to providers considering participation in any clinical trials research. PMID- 23044840 TI - Nitric oxide inhibits autophagy in human chondrocytes: comment on the article by Sasaki et al. Reply. PMID- 23044834 TI - The use of neurotrophin therapy in the inner ear to augment cochlear implantation outcomes. AB - Severe to profound deafness is most often secondary to a loss of or injury to cochlear mechanosensory cells, and there is often an associated loss of the peripheral auditory neural structures, specifically the spiral ganglion neurons and peripheral auditory fibers. Cochlear implantation is currently our best hearing rehabilitation strategy for severe to profound deafness. These implants work by directly electrically stimulating the remnant auditory neural structures within the deafened cochlea. When administered to the deafened cochlea in animal models, neurotrophins, specifically brain derived neurotrophic factor and neurotrophin-3, have been shown to dramatically improve spiral ganglion neuron survival and stimulate peripheral auditory fiber regrowth. In animal models, neurotrophins administered in combination with cochlear implantation has resulted in significant improvements in the electrophysiological and psychophysical measures of outcome. While further research must be done before these therapies can be applied clinically, neurotrophin therapies for the inner ear show great promise in enhancing CI outcomes and the treatment of hearing loss. PMID- 23044841 TI - Pharmacological inhibition of PPARgamma increases osteoblastogenesis and bone mass in male C57BL/6 mice. AB - Infiltration of bone marrow with fat is a prevalent feature in people with age related bone loss and osteoporosis, which correlates inversely with bone formation and positively with high expression levels of peroxisomal proliferator activated receptor gamma (PPARgamma). Inhibition of PPARgamma thus represents a potential therapeutic approach for age-related bone loss. In this study, we examined the effect of PPARgamma inhibition on bone in skeletally mature C57BL/6 male mice. Nine-month-old mice were treated with a PPARgamma antagonist, bisphenol-A-diglycidyl ether (BADGE), alone or in combination with active vitamin D (1,25[OH](2) D(3) ) for 6 weeks. Micro-computed tomography and bone histomorphometry indicated that mice treated with either BADGE or BADGE + 1,25(OH)(2) D(3) had significantly increased bone volume and improved bone quality compared with vehicle-treated mice. This phenotype occurred in the absence of alterations in osteoclast number. Furthermore, the BADGE + 1,25(OH)(2) D(3) -treated mice exhibited higher levels of unmineralized osteoid. All of the treated groups showed a significant increase in circulating levels of bone formation markers without changes in bone resorption markers, while blood glucose, parathyroid hormone, and Ca(+) remained normal. Furthermore, treatment with BADGE induced higher levels of expression of vitamin D receptor within the bone marrow. Overall, treated mice showed higher levels of osteoblastogenesis and bone formation concomitant with decreased marrow adiposity and ex vivo adipogenesis. Taken together, these observations demonstrate that pharmacological inhibition of PPARgamma may represent an effective anabolic therapy for osteoporosis in the near future. PMID- 23044842 TI - [Compulsory without Compulsion?]. PMID- 23044843 TI - [Psychiatric Rehabilitation will be a Future Topic for Psychiatry - Pro & Contra]. PMID- 23044844 TI - [Psychiatric Rehabilitation will be a Future Topic for Psychiatry - Pro & Contra]. PMID- 23044845 TI - [Analysis of patterns of in-patient and out-patient mental health care by use of routine data]. AB - OBJECTIVE: The Centre of Psychiatry Suedwuerttemberg routinely records data on service use of in-patient units, day hospitals and out-patient services on a daily basis as well as data on the respective patients according to the German Basic Documentation (BADO). Other psychiatric services in the catchment area of the districts Ravensburg and Bodenseekreis such as services of sheltered living, residential homes and vocational services collect identical data per day of use. Aim of the study is to compare routinely recorded data of mental health service use and direct cost of service use with sample data. We compared analyses of mental health service use and direct cost of service use with routinely recorded data with analyses using sample data. METHODS: Concerning the year 2008, we joined these different data sets, processing them in order to obtain pseudonymity and fulfil data protection requirements. This joint data set maps the total expenditures for psychiatric care utilisation in this region. RESULTS: Using a data set of this kind, analyses of health economy are possible which are comparable or even superior to those from sample data. CONCLUSION: Routinely recorded data are a cost-saving alternative to sample data. PMID- 23044846 TI - [A pilot study for handling errors in psychotherapy - therapists report from practical experience]. AB - OBJECTIVE: To assess the views of psychotherapists regarding management of treatment errors by reviewing and analyzing interviews with therapists. METHODS: A literature search was used to identify topics for the interview guide. Semi structured interviews with 30 psychotherapists were conducted and analyzed according to qualitative content analysis, a framework approach. RESULTS: Psychotherapists report an open approach to handling treatment errors: the majority claim that they would discuss errors with their patients. Experiences with error disclosure were on the whole rather positive. Errors of colleagues would be discussed in a supervisory way or, in more serious cases, be reported. CONCLUSION: In psychotherapy, a constructive and open handling of errors seems to prevail. Therapists tend to be cautious when judging errors of colleagues. PMID- 23044847 TI - [Heavy use of psychiatric hospitals and the use of outpatient services in Switzerland]. AB - OBJECTIVE: To identify user groups of inpatient psychiatry. METHODS: Retrospective cohort study over two years (n = 1295). Identification of patient subgroups based on the number of inpatient admissions and inpatient days by means of latent class analysis. RESULTS: Two patient groups were identified: 28 % heavy users and 72 % ordinary users. Heavy users were often diagnosed with schizophrenia and they also showed increased use of outpatient services. CONCLUSIONS: Integrated service models should be developed and tested for patients with schizophrenia and HU. PMID- 23044848 TI - [Impact of gender on the utilization of outpatient health service for adult ADHD]. AB - OBJECTIVE: There is only scarce knowledge of gender differences in adult ADHD. Thus, we studied a large population of adults referred to a specialized ambulance for adult ADHD for possible gender differences regarding age, ADHD core and associated psychopathology, severity of symptoms and subjective burden from the disorder. METHODS: We analyzed data from 776 adult patients, who had been referred to a specialized ambulance for ADHD. 275 male and 236 female patients were diagnosed with ADHD. Standardized self-rating and expert-rating instruments of the Homburg ADHD Scales for adults (HASE) were used for diagnosis and assessment. RESULTS: Male and female patients did not differ significantly regarding their prevalence of admittance, age at diagnosis of ADHD, ADHD subtype according to DSM-IV, symptom severity and subjective burden from the disorder. CONCLUSIONS: More female than male patients as could be expected from epidemiological data were referred to the ambulance suggesting that males with ADHD are less disposed for psychiatric support. No major differences regarding clinical aspects of ADHD have to be considered between male and female patients, except a higher prevalence of symptoms of emotional dysregulation, which are more prominent in female patients. PMID- 23044849 TI - [Mantra biopsychosocial - claim and reality in psychosomatic medicine and psychotherapy]. PMID- 23044850 TI - Polyoxometalates as potent and selective inhibitors of alkaline phosphatases with profound anticancer and amoebicidal activities. AB - The biological significance of polyoxometalates is well renowned owing to their anticancer, antiviral and antibiotic properties. Here another therapeutic aspect of polyoxometalates has been explored as alkaline phosphatase inhibitors along with the remarked anticancer and amoebicidal properties. Synthesis and inhibitory studies of a set of seven polyoxotungstates against two major isozymes of alkaline phosphatase i.e. tissue specific and tissue non-specific alkaline phosphatase revealed their promising activity as alkaline phosphatase inhibitors. All compounds exhibited alkaline phosphatase inhibitory potency in nanomolar ranges. For tissue specific alkaline phosphatase, Na(10)[H(2)W(12)O(42)].27H(2)O (A6) was found to be the most potent inhibitor (K(i) value 313 +/- 7 nM), while for tissue non-specific alkaline phosphatase Na(33)[H(7)P(8)W(48)O(184)].92H(2)O (A3) showed the highest inhibition potency (K(i) values 135 +/- 10 nM). Moreover cytotoxicity evaluation of these compounds against lung carcinoma cells and immortalized human corneal epithelial cells demonstrated their anticancer potential with no cytotoxic effects on normal human cell lines. All anticancer drugs result in an impaired immune system and such immunocompromised persons become vulnerable to opportunistic infections specially Acanthamoeba which causes granulomatous amoebic encephalitis (GAE) which almost always results in death. The exclusive property of our tested polyoxotungstates is their strong amoebicidal activity against Acanthamoeba. Hence the study reveals a new window towards cancer therapy with the combined control of elevated levels of alkaline phosphatase and granulomatous amoebic encephalitis in cancer patients. PMID- 23044851 TI - New cylindrical peptide assemblies defined by extended parallel beta-sheets. AB - A new approach to non-covalent peptide-based nanotubular or rod-like structures is presented, whereby the monomeric units are preorganised into a beta-strand geometry that templates the formation of an extended and unusual parallel beta sheet rod-like structure. The conformational constraint is introduced by Huisgen cycloaddition to give a triazole-based macrocycle, with the resulting self assembled structures stabilized by a well-defined series of intermolecular hydrogen bonds. PMID- 23044852 TI - Biological activity of sedaxane---a novel broad-spectrum fungicide for seed treatment. AB - BACKGROUND: Sedaxane is a new broad-spectrum seed treatment fungicide developed by Syngenta Crop Protection for control of seed- and soil-borne diseases in a broad range of crops. Its physicochemical properties and activity spectrum have been optimised for use as a seed treatment providing both local and systemic protection of the seed and roots of target crops. RESULTS: Sedaxane inhibits respiration by binding to the succinate dehydrogenase complex in the fungal mitochondrium. Its activity spectrum covers seed-borne fungi such as Ustilago nuda, Tilletia caries, Monographella nivalis and Pyrenophora graminea, as well as the soil-borne fungi Rhizoctonia solani, R. cerealis and Typhula incarnata. Under greenhouse conditions, sedaxane showed high levels and consistent protection against U. nuda, P. graminea and Rhizoctonia spp. Under field conditions, efficacy against Rhizoctonia spp. resulted in increased yield compared with the untreated check. Efficacy against snow mould has been shown under very high disease pressure conditions. The combination of sedaxane plus fludioxonil against snow mould can provide resistance management for sustainable use. CONCLUSIONS: The broad spectrum and high level of activity in combination with excellent crop tolerance allow the use of sedaxane as a seed treatment in a wide variety of crops. It is a potential tool for precautionary resistance management when combined with other fungicides, especially against pathogens showing a potential for resistance development, such as M. nivalis. PMID- 23044853 TI - YM-175 induces apoptosis of human native monocyte-lineage cells via inhibition of prenylation. AB - Nitrogen-containing bisphosphonates (NCBPs) have been widely used as standard supportive therapy to reduce skeletal-related events (SREs) in myeloma patients through suppression of osteoclast activity. In various prospective randomized trials that were performed following preliminary reports concerning efficacy, NCBPs have shown a significant beneficial effect on myeloma bone disease through both suppression of bone resorption and direct antimyeloma activity. Thus, NCBPs have an influence on many types of human cells. In this study, we examined the effect of an NCBP (YM-175) on an apoptosis of a monocytic cell line and of human native monocytes/macrophages and dendritic cells (DCs). We confirmed that monocytes, monocyte-derived macrophages, DCs, and a monoblastic cell line (THP-1) showed dose-dependent and time-dependent apoptosis related to the activation of caspases after exposure to YM-175 at concentrations below that at which the apoptosis of myeloma cell lines was induced. Such apoptosis of monocytic cells was suppressed by the addition of farnesol or geranylgeraniol. These findings suggest that the inhibition of monocyte-lineage cells or DCs by NCBPs might interfere with phagocytic activity or pathogen-presenting activity. PMID- 23044855 TI - Sleeve gastrectomy and Roux-en-Y gastric bypass exhibit differential effects on food preferences, nutrient absorption and energy expenditure in obese rats. AB - OBJECTIVE: All available treatments directed towards obesity and obesity-related complications are associated with suboptimal effectiveness/invasiveness ratios. Pharmacological, behavioral and lifestyle modification treatments are the least invasive, but also the least effective options, leading to modest weight loss that is difficult to maintain long-term. Gastrointestinal weight loss surgery (GIWLS) is the most effective, leading to >60-70% of excess body weight loss, but also the most invasive treatment available. Sleeve gastrectomy (SGx) and Roux-en Y gastric bypass (RYGB) are the two most commonly performed GIWLS procedures. The fundamental anatomic difference between SGx and RYGB is that in the former procedure, only the anatomy of the stomach is altered, without surgical reconfiguration of the intestine. Therefore, comparing these two operations provides a unique opportunity to study the ways that different parts of the gastrointestinal (GI) tract contribute to the regulation of physiological processes, such as the regulation of body weight, food intake and metabolism. DESIGN: To explore the physiologic mechanisms of the two procedures, we used rodent models of SGx and RYGB to study the effects of these procedures on body weight, food intake and metabolic function. RESULTS: Both SGx and RYGB induced a significant weight loss that was sustained over the entire study period. SGx induced weight loss was slightly lower compared with that observed after RYGB. SGx-induced weight loss primarily resulted from a substantial decrease in food intake and a small increase in locomotor activity. In contrast, rats that underwent RYGB exhibited a substantial increase in non-activity-related (resting) energy expenditure and a modest decrease in nutrient absorption. Additionally, while SGx-treated animals retained their preoperative food preferences, RYGB treated rats experienced a significant alteration in their food preferences. CONCLUSIONS: These results indicate a fundamental difference in the mechanisms of weight loss between SGx and RYGB, suggesting that the manipulation of different parts of the GI tract may lead to different physiologic effects. Understanding the differences in the physiologic mechanisms of action of these effective treatment options could help us develop less invasive new treatments against obesity and obesity-related complications. PMID- 23044857 TI - Readability assessment of the American Rhinologic Society patient education materials. AB - BACKGROUND: The extensive amount of medical literature available on the Internet is frequently accessed by patients. To effectively contribute to healthcare decision-making, these online resources should be worded at a level that is readable by any patient seeking information. The American Medical Association and National Institutes of Health recommend the readability of patient information material should be between a 4th to 6th grade level. In this study, we evaluate the readability of online patient education information available from the American Rhinologic Society (ARS) website using 9 different assessment tools that analyze the materials for reading ease and grade level of the target audience. METHODS: Online patient education material from the ARS was downloaded in February 2012 and assessed for level of readability using the Flesch Reading Ease, Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook (SMOG) Grading, Coleman-Liau Index, Gunning-Fog Index, FORCAST formula, Raygor Readability Estimate, the Fry Graph, and the New Dale-Chall Readability Formula. Each article was pasted as plain text into a Microsoft(r) Word(r) document and each subsection was analyzed using the software package Readability Studio Professional Edition Version 2012.1. RESULTS: All healthcare education materials assessed were written between a 9th grade and graduate reading level and were considered "difficult" to read by the assessment scales. CONCLUSION: Online patient education materials on the ARS website are written above the recommended 6th grade level and may require revision to make them easily understood by a broader audience. PMID- 23044854 TI - Ter-dependent stress response systems: novel pathways related to metal sensing, production of a nucleoside-like metabolite, and DNA-processing. AB - The mode of action of the bacterial ter cluster and TelA genes, implicated in natural resistance to tellurite and other xenobiotic toxic compounds, pore forming colicins and several bacteriophages, has remained enigmatic for almost two decades. Using comparative genomics, sequence-profile searches and structural analysis we present evidence that the ter gene products and their functional partners constitute previously underappreciated, chemical stress response and anti-viral defense systems of bacteria. Based on contextual information from conserved gene neighborhoods and domain architectures, we show that the ter gene products and TelA lie at the center of membrane-linked metal recognition complexes with regulatory ramifications encompassing phosphorylation-dependent signal transduction, RNA-dependent regulation, biosynthesis of nucleoside-like metabolites and DNA processing. Our analysis suggests that the multiple metal binding and non-binding TerD paralogs and TerC are likely to constitute a membrane-associated complex, which might also include TerB and TerY, and feature several, distinct metal-binding sites. Versions of the TerB domain might also bind small molecule ligands and link the TerD paralog-TerC complex to biosynthetic modules comprising phosphoribosyltransferases (PRTases), ATP grasp amidoligases, TIM-barrel carbon-carbon lyases, and HAD phosphoesterases, which are predicted to synthesize novel nucleoside-like molecules. One of the PRTases is also likely to interact with RNA by means of its Pelota/Ribosomal protein L7AE like domain. The von Willebrand factor A domain protein, TerY, is predicted to be part of a distinct phosphorylation switch, coupling a protein kinase and a PP2C phosphatase. We show, based on the evidence from numerous conserved gene neighborhoods and domain architectures, that both the TerB and TelA domains have been linked to diverse lipid-interaction domains, such as two novel PH-like and the Coq4 domains, in different bacteria, and are likely to comprise membrane associated sensory complexes that might additionally contain periplasmic binding protein-II and OmpA domains. We also show that the TerD and TerB domains and the TerY-associated phosphorylation system are functionally linked to many distinct DNA-processing complexes, which feature proteins with SWI2/SNF2 and RecQ-like helicases, multiple AAA+ ATPases, McrC-N-terminal domain proteins, several restriction endonuclease fold DNases, DNA-binding domains and a type-VII/Esx-like system, which is at the center of a predicted DNA transfer apparatus. These DNA processing modules and associated genes are predicted to be involved in restriction or suicidal action in response to phages and possibly repairing xenobiotic-induced DNA damage. In some eukaryotes, certain components of the ter system appear to be recruited to function in conjunction with the ubiquitin system and calcium-signaling pathways. PMID- 23044858 TI - The growth performance of Jade Tiger cultured abalone fed diets supplemented with fish oil and vegetable oils. AB - BACKGROUND: The effects of fish oil (FO) supplementation and the dietary replacement of FO with flaxseed oil (FlaxO) and canola oil (CO) on the growth of cultured abalone was investigated. The study involved three growth experiments: (E1) diets containing 0.5, 1.0, 1.5, 2.0 and 2.5% of FO, respectively; (E2) diets in which FO was serially replaced by 25, 50, 75 and 100% FlaxO, respectively; and (E3) diets in which FO was serially replaced by 25, 50, 75 and 100% CO, respectively. RESULTS: In Experiment 1, abalone fed a diet supplemented with 1.5% FO showed a significantly higher (121.2 +/- 1.1 mg day(-1)) daily growth rate of weight (DGRw ) compared to control (70.1 +/- 1.71 mg day(-1)). In Experiment 2, abalone fed 1.5% FO diet and diets containing 25-75% FlaxO showed no significant differences in DGRw. The diet containing 100% FlaxO showed significantly lower (63.3 +/- 6.7 mg day(-1)) DGRw. In Experiment 3, abalone fed diets containing 25% and 50% CO showed similar DGRw as those fed a 1.5% FO diet. The diet containing 75% and 100% CO showed significantly lower (63.7 +/- 5.0 to 95.4 +/- 5.1 mg day( 1)) DGRw. CONCLUSION: Supplementation with 1.5% of dietary FO can improve growth performance in cultured abalone. It is feasible to replace 75% of dietary FO with FlaxO and 50% of dietary FO with CO, without negative effect on growth performance. PMID- 23044856 TI - Predicting weight outcomes in preadolescence: the role of toddlers' self regulation skills and the temperament dimension of pleasure. AB - OBJECTIVES: To investigate the role of toddlers' self-regulation skills and temperament in predicting weight outcomes in preadolescence. METHODS: Participants for this study included 195 children (114 girls) obtained from three different cohorts participating in a larger ongoing longitudinal study. At 2 years of age, participants participated in several laboratory tasks designed to assess their self-regulation abilities, including emotion regulation, sustained attention and delay of gratification, whereas parents filled out a temperament questionnaire to assess toddlers' pleasure expression. Height and weight measures were collected when children were 4, 5, 7 and 10 years of age. Children also filled out a body image and eating questionnaire at the 10-year visit. RESULTS: Self-regulation skills in toddlers were associated with body mass index (BMI) development and pediatric obesity as well as body image/eating concerns. The temperament dimension of pleasure was also associated with BMI development and pediatric obesity but not body image/eating concerns. CONCLUSIONS: Self regulation difficulties across domains as well as temperament-based pleasure in toddlers represented significant individual risk factors for the development of pediatric obesity 8 years later. Early self-regulation difficulties also contributed to body image and eating concerns that typically accompanied overweight children. The mechanisms by which early self-regulation skills and temperament-based pleasure may contribute to the development of pediatric obesity and associated weight concerns are discussed. PMID- 23044859 TI - Forty years in academic cardiology. PMID- 23044860 TI - On-chip quantum optics with quantum dot microcavities. AB - A novel concept for on-chip quantum optics using an internal electrically pumped microlaser is presented. The microlaser resonantly excites a quantum dot microcavity system operating in the weak coupling regime of cavity quantum electrodynamics. This work presents the first on-chip application of quantum dot microlasers, and also opens up new avenues for the integration of individual microcavity structures into larger photonic networks. PMID- 23044861 TI - Nitric oxide inhibits autophagy in human chondrocytes: comment on the article by Sasaki et al. PMID- 23044862 TI - The Trk A, B, C's of neurotrophins in the cochlea. AB - The spiral ganglion neurons (SGNs) are the afferent neurons of the cochlea, connecting the auditory sensory cells-hair cells-to the brainstem cochlear nuclei. The neurotrophins neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) are expressed in the cochlea and both support SGN survival during development. These neurotrophins remain expressed in the postnatal cochlea and continue to play additional roles for SGNs, contributing to maintenance of hair cell-SGN synapses and regulating expression of ion channels, presynaptic and postsynaptic proteins, and SGN membrane electrical properties in a physiologically important spatial pattern. Remarkably, NT-3 and BDNF have different, even opposing, effects on SGN physiology despite the close similarity of their receptors TrkB and TrkC. Recent studies have also raised the possibility that precursor proneurotrophin forms of the neurotrophins play a role in responses to trauma in the cochlea, signaling through the proneurotrophin receptor p75(NTR) . Here, we review expression and function of neurotrophins and their p75(NTR) and Trk-family receptors in the cochlea. We focus, in particular, on neurotrophin functions other than support of SGN survival, including regulation of SGN neurite growth, synaptic and membrane physiology. These functions, unlike survival, are ones for which BDNF and NT-3 substantially differ in their effects. Signal transduction mechanisms of p75(NTR) and of Trk-family receptors are discussed, indicating how these lead to different responses, and we speculate on how BDNF and NT-3 can cause different phenotypic changes in SGNs. Because these complex signaling interactions remain incompletely understood, use of neurotrophins as therapeutic agents in the cochlea should be approached with caution. PMID- 23044863 TI - Evolution of sound and balance perception: innovations that aggregate single hair cells into the ear and transform a gravistatic sensor into the organ of corti. AB - Here, we review the molecular basis of mechanosensory cell and mechanosensory organ development and evolution with an emphasis on the conservation of transcription factors and emerging data on conserved gene networks. The ear, the organ of vertebrates dedicated to the perception of sound and balance, perceives these stimuli with the use of mechanosensory cells. The developmental gene regulatory network used during mechanosensory cellular development has been conserved from ancient bilaterian cells, and modified for the extraction of specific mechanical stimuli resulting in phenotypic changes. In the vertebrate lineage, mechanosensory cells became specialized as gravistatic sensors after they became aggregated to form the ear. After this aggregation, growth, including duplication and segregation of existing neurosensory epithelia, gave rise to new epithelia and can be appreciated by comparing sensory epithelia from the inner ears of different vertebrates and their innervation by different neuronal populations. Novel directions of differentiation were apparently further expanded by incorporating unique molecular modules in newly developed sensory epithelia. For example, the saccule gave rise to the auditory epithelium and corresponding neuronal population of tetrapods, starting possibly in an aquatic environment. This novel sensory perception was followed by emergence of the central auditory nuclei and a selective cochlear nucleus projection. The data for this process is outlined and contrasted with other ideas dealing with a subset of the data. PMID- 23044864 TI - Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database. AB - Ocular inflammatory reactions have been described in patients on bisphosphonate treatment. We estimated the incidence rate of ocular inflammation at 3 and 12 months in patients treated for osteoporosis using a register-based cohort linked to prescription data (hospitals and private practice) and hospital data. From January 1, 1997 to December 31, 2007, a total of 88,202 patients beginning osteoporosis therapy were identified. Of those patients, 82,404 (93%) began oral bisphosphonates and 5798 (7%) nonbisphosphonates. Within the first year of treatment, 4769 (5.4%) of patients on osteoporosis therapy filled one or more prescriptions for topical eye steroids (TES). TES treatment rates (per 1000 patient-years) in the first year of osteoporosis treatment were 44 (95% confidence interval [CI] 42 to 46) for alendronate, 40 (95% CI 38 to 43) for etidronate, 45 (95% CI 35 to 57) for risedronate, 32 (95% CI 27 to 37) for raloxifene, and 64 (95% CI 49 to 83) for strontium ranelate. After adjustment for age, Charlson index, and the number of comedications, pulmonary disease in men was associated with an increased use of TES (odds ratio [OR] = 1.48; 95% CI 1.17 to 1.86; p = 0.001). In women, malignant disease (OR = 1.27; 95% CI 1.02 to 1.60; p = 0.04) and pulmonary disease (OR = 1.32; 95% CI 1.07 to 1.62; p = 0.01) were significant predictors at 3 months and rheumatic diseases at 12 months (OR = 1.20; 95% CI 1.10 to 1.31; p < 0.001). There was no significant difference between the different drug classes (bisphosphonates versus nonbisphosphonates, alendronate versus nonalendronate-bisphosphonates) for risk of ocular inflammation, with age and the number of comedications being the only significant predictors. Hospital-treated uveitis (48 patients, or 0.05%) showed a similar trend. In conclusion, after initiation of treatment for osteoporosis, the risk of inflammatory eye reactions requiring TES is relatively low and not significantly different between bisphosphonate and nonbisphosphonate users. Patients with a rheumatic or pulmonary disease are at increased risk. PMID- 23044866 TI - Copper-64 labelling of triazacyclononane-triphosphinate chelators. AB - The 1,4,7-triazacyclononane-1,4,7-tris(methylenephosphinic acid) chelators TRAP and NOPO are complexing copper-64 with similar efficiency as 1,4,7 triazacyclononane-triacetic acid (NOTA). The kinetic stability of Cu-64-labelled TRAP-peptides is sufficient for PET imaging at early time points (1-2 h post injection). For labelling of TRAP conjugates, Cu-64 can be recommended as an alternative to Ga-68 to achieve higher resolution of PET images. PMID- 23044867 TI - Survival and development of a stored-product pest, Sitophilus zeamais (Coleoptera: Curculionidae), and its natural enemy, the parasitoid Lariophagus distinguendus (Hymenoptera: Pteromalidae), on transgenic Bt maize. AB - BACKGROUND: The effect of transgenic maize (Zea mays L.) containing a lepidopteran-specific Bt toxin on a stored-product pest, Sitophilus zeamais Motschulsky, and its parasitoid, Lariophagus distinguendus Forster, was examined in the laboratory to test the impact of transgenic maize on stored-product pests and their biological control. RESULTS: Weevils were not harmfully affected by transgenic Bt maize in their development characteristics (development time, body mass), and females emerging from transgenic maize kernels were larger. However, significantly fewer parasitoid females emerged from weevils that developed in transgenic kernels, although parasitoids did not develop more slowly and were not different in size or mass from their conspecifics emerging from hosts in non transgenic maize kernels. CONCLUSION: The emergence of female parasitoids was reduced in transgenic Bt maize, and this effect cannot be explained by the known lepidopteran-specific toxicity of Bt Cry1Ab toxin. PMID- 23044868 TI - Introduction to guest editors. PMID- 23044869 TI - Preface: disorders of sex development. PMID- 23044870 TI - Advice on the management of ambiguous genitalia to a young endocrinologist from experienced clinicians. AB - The birth of a child with ambiguous genitalia is a challenging and distressing event for the family and physician and one with life-long consequences. Most disorders of sexual differentiation (DSD) associated with ambiguous genitalia are the result either of inappropriate virilization of girls or incomplete virilization of boys. It is important to establish a diagnosis as soon as possible, for psychological, social, and medical reasons, particularly for recognizing accompanying life-threatening disorders such as the salt-losing form of congenital adrenal hyperplasia. In most instances, there is sufficient follow up data so that making the diagnosis also establishes the appropriate gender assignment (infants with congenital adrenal hyperplasia, those with androgen resistance syndromes), but some causes of DSD such as steroid 5alpha-reductase 2 deficiency and 17beta-hydroxysteroid dehydrogenase deficiency are associated with frequent change in social sex later in life. In these instances, guidelines for sex assignment are less well established. PMID- 23044871 TI - The molecular genetics of sex determination and sex reversal in mammals. AB - The process of sex determination in mammals normally unfolds in three distinct stages: (1) establishment of chromosomal sex at fertilization (XX or XY); (2) commitment to the appropriate pathway of gonadal differentiation with respect to chromosomal sex, through the action (or absence) of the Y chromosome gene SRY; and (3) correct development of secondary sexual characteristics, including internal and external genitalia, in accordance with gonadal sex. At any of these three steps, the process of sex determination can go awry, leading to disorders of sexual development. In this article, we review the typical mechanism and process of mammalian sex determination, with an emphasis on the well characterized mouse and human models. We also consider aberrant mammalian sex determination, focusing on examples of sex reversal stemming from gene defects. PMID- 23044872 TI - Testicular anti-Mullerian hormone: clinical applications in DSD. AB - Male fetal sexual differentiation of the genitalia is driven by Leydig cell secreted androgens and Sertoli cell-secreted anti-Mullerian hormone (AMH). Disorders of sex development (DSD) may be due to abnormal morphogenesis of genital primordia or to defective testicular hormone secretion or action. In dysgenetic DSD, due to an early fetal-onset primary hypogonadism affecting Leydig and Sertoli cells, the fetal gonads are incapable of producing normal levels of androgens and AMH. In non-dysgenetic DSD, either Leydig cells or Sertoli cells are affected but not both. Persistent Mullerian duct syndrome (PMDS) may result from Sertoli cell-specific dysfunction due to mutations in the AMH gene; these patients have Fallopian tubes and uterus, but male external genitalia. In DSD due to insensitivity to testicular hormones, fetal Leydig and Sertoli cell function is normal. Defective androgen action is associated with female or ambiguous genitalia whereas insensitivity to AMH results in PMDS with normal serum AMH. Clinical and biological features of PMDS due to mutations in the genes coding for AMH or the AMH receptor, as well as genetic aspects and clinical management are discussed. PMID- 23044874 TI - Inactivating mutations of the human luteinizing hormone receptor in both sexes. AB - The human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) plays a fundamental role in male and female reproductive physiology. Over the past 15 years, several homozygous or compound heterozygous loss-of-function mutations in the LHCGR gene have been described in males and females. In genetic males, mutations in LHCGR were associated with distinct degrees of impairment in pre- and postnatal testosterone secretion resulting in a phenotypic spectrum. Patients with the severe form of LH resistance have predominantly female external genitalia and absence of secondary sex differentiation at puberty. Patients with milder forms have predominantly male external genitalia with micropenis and/or hypospadias or only infertility without ambiguity. The undermasculization is associated with low basal, as well as human CG-stimulated, testosterone levels and elevated LH levels after pubertal age, without abnormal step-up in testosterone biosynthesis precursors. The testes have only slightly reduced size but mature Leydig cells are absent or scarce (Leydig cell hypoplasia). Genetic females with inactivating LHCGR mutations have female external genitalia, spontaneous breast and pubic hair development at puberty, and normal or late menarche followed by oligoamenorrhea and infertility. Estradiol and progesterone levels are normal for the early to midfollicular phase, but do not reach ovulatory or luteal phase levels. Serum LH levels are high whereas follicle stimulating hormone levels are normal or only slightly increased. Pelvic ultrasound has demonstrated a small or normal uterus and normal or enlarged ovaries with cysts. The inactivating mutations of the LHCGR have provided important insights into distinct physiological roles of LH in reproduction of both sexes. PMID- 23044875 TI - WNT4, RSPO1, and FOXL2 in sex development. AB - The idea that the female sexual development happens by default was born in the middle of the last century after Jost performed his innovative experiments to study the bases of differentiation of the reproductive tract and found that the female reproductive tract develops even in the absence of any gonad. The term default (passive) attributed to the whole female developmental pathway, therefore, established itself, even if it was not originally so intended. However, recent developments have demonstrated that ovarian development is an active process. Wingless type MMTV integration site family, member 4 (WNT4), one of a few factors with a demonstrated function in the ovarian-determination pathway, has been found to be involved in sexual differentiation by suppressing male sexual differentiation, promoting Mullerian duct differentiation, and maintaining oocyte health. WNT4 expression in the ovary seems to be regulated by R-spondin 1 (RSPO1), a thrombospondin family member protein. The role and interactions of WNT4, RSPO1, and other factors such as forkhead transcription factor 2 in ovarian development and function will be discussed. PMID- 23044873 TI - Steroidogenic factor-1 and human disease. AB - Steroidogenic factor-1 (SF-1) (Ad4BP, NR5A1) is a nuclear receptor that plays a key role in adrenal and reproductive development and function. Deletion of the gene encoding Sf-1 (Nr5a1) in mice results in severe developmental defects of the adrenal gland and gonad. Consequently, initial work on the potential effects of SF-1 disruption in humans focused on individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis, and Mullerian structures. This is a rare phenotype, but has been reported on two occasions, because of alterations that affect key DNA-binding domains of SF-1. Attention then turned to a potential wider role of SF-1 in human adrenal and reproductive disorders. Although changes in SF-1 only very rarely cause isolated adrenal failure, it is emerging that variations in SF-1 are a surprisingly frequent cause of reproductive dysfunction in humans. In 46,XY disorders of sex development, a spectrum of phenotypes has been reported including severe and partial forms of gonadal (testicular) dysgenesis, hypospadias, anorchia with microphallus, and even male factor infertility. In 46,XX females, alterations in SF-1 are associated with primary ovarian insufficiency. Thus, SF-1 seems be a more significant factor in human reproductive health than was first envisioned, with implications for adults as well as children. PMID- 23044876 TI - An update on prenatal diagnosis and treatment of congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia causes genital ambiguity in females affected with the severe form of the disease; yet the abnormality is preventable with prenatal dexamethasone treatment that must be given to the mother before the ninth week of gestation. In the period from 1978 to March 2011 we have made prenatal diagnosis in 719 pregnancies. Our results indicate that the average Prader score of those fetuses treated with dexamethasone was 1.7, which is much lower than the average Prader score of 3.73 in those not treated. While our data demonstrate no significant abnormalities in the long-range medical and cognitive outcomes in patients prenatally treated with dexamethasone, the current protocol involves invasive procedures such as chorionic villus sampling or amniocentesis, and all fetuses are treated unnecessarily for several weeks before the sex and the affection status of the fetus is known. We are collaborating with Dr. Dennis Lo in Hong Kong to develop a noninvasive protocol, whereby at the sixth to seventh week of gestation we can determine the sex and the affection status of the fetus by harvesting fetal DNA from the maternal plasma. The method will eliminate invasive procedures and unnecessary prenatal treatment and bring noninvasive prenatal diagnosis to underdeveloped areas where amniocentesis and chorionic villus sampling are not available. PMID- 23044877 TI - Congenital adrenal hyperplasia due to 21 hydroxylase deficiency: from birth to adulthood. AB - The most frequent form of congenital adrenal hyperplasia (CAH) is steroid 21 hydroxylase deficiency, accounting for more than 90% of cases. Affected patients cannot synthesize cortisol efficiently. Thus the adrenal cortex is stimulated by corticotropin (ACTH) and overproduces cortisol precursors. Some precursors are diverted to sex hormone biosynthesis, causing signs of androgen excess including ambiguous genitalia in newborn females and rapid postnatal growth in both sexes. In the most severe "salt wasting" form of CAH (~75% of severe or "classic" cases), concomitant aldosterone deficiency may lead to salt wasting with consequent failure to thrive, hypovolemia, and shock. Newborn screening minimizes delays in diagnosis, especially in males, and reduces morbidity and mortality from adrenal crises. CAH is a recessive disorder caused by mutations in the CYP21 (CYP21A2) gene, most of which arise from recombination between CYP21 and a nearby pseudogene, CYP21P (CYP21A1P). Phenotype is generally correlated with genotype. Classic CAH patients require chronic glucocorticoid treatment at the lowest dose that adequately suppresses adrenal androgens and maintains normal growth and weight gain, and most require mineralocorticoid (fludrocortisone). Transition of care of older patients to adult physicians should be planned in advance as a structured, ongoing process. PMID- 23044878 TI - MAMLD1 and 46,XY disorders of sex development. AB - MAMLD1 (mastermind-like domain containing 1) is a recently discovered causative gene for 46,XY disorders of sex development (DSD), with hypospadias as the salient clinical phenotype. To date, microdeletions involving MAMLD1 have been identified in six patients, and definitive mutations (nonsense and frameshift mutations that are predicted to undergo nonsense mediated mRNA decay [NMD]) have been found in six patients. In addition, specific MAMLD1 cSNP(s) and haplotype may constitute a susceptibility factor for hypospadias. Furthermore, in vitro studies have revealed that (1) the mouse homolog is expressed in fetal Sertoli and Leydig cells around the critical period for sex development; (2) transient Mamld1 knockdown results in significantly reduced testosterone production primarily because of compromised 17alpha-hydroxylation and Cyp17a1 expression in Murine Leydig tumor cells; (3) MAMLD1 localizes to the nuclear bodies and transactivates the promoter activity of a non-canonical Notch target gene hairy/enhancer of split 3, without demonstrable DNA-binding capacity; and (4) MAMLD1 is regulated by steroidogenic factor 1 (SF1). These findings suggest that the MAMLD1 mutations cause 46,XY DSD primarily because of compromised testosterone production around the critical period for sex development. Further studies will provide useful information for the molecular network involved in fetal testosterone production. PMID- 23044879 TI - Defects in androgen biosynthesis causing 46,XY disorders of sexual development. AB - At least one genetic defect in each reaction of the classical androgen biosynthesis pathway has been described. For some steps, such as the conversion of cholesterol to pregnenolone and the 17,20-lyase reaction, two or three genetic defects cause similar disorders with overlapping phenotypes and biochemical profiles. The elucidation of the molecular basis for these diseases has helped to define the pathways, essential genes, and enzymatic steps required to make androgens, and this knowledge is being exploited to develop better treatments of androgen-dependent diseases. Furthermore the description of nonclassical lipoid CAH and the protean manifestations of P450 oxidoreductase (POR) deficiencies has expanded the spectrum of human disease caused by disordered steroidogenesis. Finally, the recognition of the backdoor pathway to DHT has added a new dimension to our understanding of how steroid flux is maintained in normal and pathologic states. The traditional view of male external genital development has been that fetal testicular testosterone is converted to DHT by 5alpha-reductase Type 2 in genital skin, which then acts in a paracrine fashion to stimulate fusion of the labio-scrotal folds and phallic growth. This view is consistent with the incomplete external genital development in persons with severe deficiencies of 5alpha-reductase type 2. The new observations concerning AKR1C2/4 and the backdoor pathway indicate that DHT produced in the testis via the backdoor pathway also acts as a hormone to induce labio-scrotal fusion. Thus, both the classic and backdoor pathways are needed, and DHT acts in male genital development as both a paracrine factor and as a hormone. These surprising findings are revising our understanding of the mechanisms by which male sexual differentiation occurs, and illustrate the importance of detailed studies of rare patients with 46,XY DSD. PMID- 23044880 TI - DSD due to 5alpha-reductase 2 deficiency - from diagnosis to long term outcome. AB - Most of the patients with 5alpha-RD 2 deficiency are reared in the female social sex due to their severely undervirilized external genitalia but ~60% who have not been submitted to orchiectomy in childhood undergo male social sex change at puberty. In our cohort of 30 cases from 18 families, all subjects were registered in the female social sex except for two children-one who had an affected uncle and the other who was diagnosed before being registered. The majority of the patients were satisfied with the long-term results of their treatment and surprisingly, penile length was not associated with satisfactory or unsatisfactory sexual activity. Steroid 5alpha-RD2 deficiency should be included in the differential diagnosis of all newborns with 46,XY DSD with normal testosterone production before gender assignment or any surgical intervention because these patients should be considered males at birth. PMID- 23044881 TI - Androgen insensitivity syndrome. AB - The androgen insensitivity syndromes (AIS) fall within the generic category of 46,XY DSD (disorder of sex development) and present as phenotypes associated with complete or partial resistance to the action of androgens. Three categories are recognized: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), mild androgen insensitivity syndrome (MAIS). The androgen receptor (AR) is encoded by an 8 exon gene on the X chromosome long arm. More than 800 mutations in the AR gene have been reported in AIS patients (www.androgendb.mcgill.ca/). They are distributed throughout the gene with a preponderance located in the ligand binding domain. The most severe mutations are generally associated with a CAIS phenotype, but the correlation is less defined in PAIS. CAIS presents typically as primary amenorrhoea in an adolescent female and less commonly in infancy with bilateral inguinal/labial swellings due to testes. The differential diagnosis in CAIS is limited, whereas in PAIS, numerous other causes of DSD can also produce the typical phenotype of micropenis, severe hypospadias and bifid scrotum. Management issues in CAIS involve timing of gonadectomy, appropriate hormone replacement therapy and assessment of the need for vaginal dilation or rarely, vaginal surgery. The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Expert psychological counseling is mandatory to manage the disconnect between chromosomal, gonadal and phenotypic sex and to choreograph the evolving process of disclosure from late childhood through to maturity. It is implicit that management in AIS requires a multidisciplinary team and engagement with patient advocacy groups. PMID- 23044882 TI - Psychological aspects of the treatment of patients with disorders of sex development. AB - Research on the psychological development of persons with Disorders of Sex Development (DSD) has focused on understanding the influence of atypical sex hormone exposure during steroid-sensitive periods of prenatal brain development on the process of psychosexual differentiation (i.e., gender identity, gender role, and sexual orientation). In contrast, analysis of clinical management strategies has focused on gender assignment and the desirability and timing of genital surgery. This review focuses on the psychological issues that confront clinicians managing the care of persons born with DSD and their families. Particular attention is paid to processes and factors that potentially mediate or moderate psychosocial and psychosexual outcomes within and across developmental stages. PMID- 23044883 TI - Lilliputian hallucinations in schizophrenia: a case report. PMID- 23044884 TI - Aetiological understanding important for preventing mistreatment of dual diagnosis patients. PMID- 23044885 TI - Psychiatric contributions from South Africa: ex Africa semper aliquid novi. AB - Given that humans originated in Africa, it is likely that many seminal psychological observations and interventions originate in the continent. Relatively little attention has been paid, however, to more recent African contributions to the scientific fields of psychiatry and clinical psychology. This article notes that a number of major contributions to the understanding of brain-mind disorders have emerged from South Africa in particular. It briefly covers seminal contributions in evolutionary theory, psychotherapy, and neuroscience, as well as conceptual and practical contributions to reconciliation. PMID- 23044886 TI - A survey of risk behaviour for contracting HIV among adult psychiatric patients. A South African study - Part 1. AB - OBJECTIVE: Various studies have reported increased prevalence of HIV infection among psychiatric patients. Psychiatric patients are under-evaluated in terms of their HIV risk behaviour. The study sought to establish the prevalence of HIV risk behaviour and determine the association between risk behaviour and demographic and clinical variables. METHOD: Participants were 113 consenting adult in-patients. A structured interview was conducted with each participant. A total risk behaviour score was calculated. From the risk score, three risk behaviour categories were identified: 0 = no risk; 1 to 3 = medium risk; 4 to 9 = high risk. Associations between HIV risk behaviour and demographic and clinical variables were analysed. RESULTS: Of the 113 participants, 68% were men and 32% women. The mean age was 38. Forty-five per cent were sexually active and 48% fell into the "no-risk group", 29% in the "medium-risk" group, and 23% in the "high risk" group. Female patients with a history of treatment for sexually transmitted disease and a diagnosis of personality disorder were associated with being sexually abused. Having multiple sex partners was associated with diagnoses of substance-related disorders and cognitive disorders. Sex with someone known for less than 24 hours was associated with long-term hospitalisation and diagnoses of cognitive and personality disorders. CONCLUSION: The study confirmed that mentally ill patients are vulnerable and may be victimised. The study also suggests that mental illness may impair appreciation of consequences and lead to high-risk behaviour for contracting HIV. Special care should be taken to protect female patients in psychiatric institutions. PMID- 23044887 TI - A survey of HIV-related knowledge among adult psychiatric patients. A South African Study - Part 2. AB - OBJECTIVE: Studies have reported an increased prevalence of HIV infection among psychiatric patients. Inaccurate HIV knowledge is included as a factor in the increased risk of HIV infection in the mentally ill, but few studies have looked specifically at this factor. The aims of the study were to determine the knowledge of HIV and its transmission among adult psychiatric patients at Weskoppies Hospital and to determine the relationship between HIV knowledge and HIV risk behaviour. METHOD: Structured interviews were conducted with 113 consenting adult patients at Weskoppies Hospital. They were divided into three groups according to their length of hospital stay. The structured interview included questions about demographic data, the diagnoses and the AIDS Risk Behaviour Knowledge Test (AIDS-KT). Scores of 13 out of 13 represented accurate knowledge of HIV (level I); scores of 10-12 represented good knowledge (level II); scores of <= 9 represented poor knowledge (level III). RESULTS: A total of 104 patients (92%) demonstrated excellent knowledge of HIV and its transmission (levels I and II). There was no significant linear association between HIV knowledge and risk-behaviour scores (Pearson's correlation coefficient r= -0.11). CONCLUSION: The presence of high-risk behaviours despite good HIV-related knowledge in this group of patients, leads us to think that knowledge alone will not limit HIV risk behaviours. For this reason, educational programmes should not be limited to interventions that simply increase knowledge about HIV infection but should extend to clinical factors, including patients' motivation and readiness to change their behaviour. PMID- 23044888 TI - Social support and the psychological wellbeing of people living with HIV/AIDS in Ghana. AB - OBJECTIVE: The current study sought to investigate the association between age, gender, social support and the psychological wellbeing of people living with HIV and AIDS (PLHA) in Ghana. METHOD: Cross-sectional data containing information on demographics, social support and psychological well-being (stress, depression, and anxiety), were collected from 107 men and women living with HIV/AIDS. To explore age group differences, participants were stratified by age (< 39 vs. 40+ years). Three anonymous self-administered questionnaires were used, namely the demographic data questionnaire, Sources of Social Support Scale, and the Depression Anxiety Stress Scale (DASS- 42). RESULTS: Correlation analysis revealed that social support was negatively associated with depression, stress and anxiety. Compared with males living with HIV, women reported higher levels of stress, depression and anxiety. Female gender and low social support were significant predictors of depression and stress after controlling for selected independent variables. Older participants experienced higher levels of stress than their younger counterparts. CONCLUSION: Public health personnel and AIDS professionals may consider further interventions to promote psychological health in HIV/AIDS-positive individuals. More attention should be paid to the social environment of individuals diagnosed with HIV as the quality of social relationships may be particularly important for successful psychological adaptation to HIV. PMID- 23044889 TI - A preliminary investigation of the AUDIT and DUDIT in comparison to biomarkers for alcohol and drug use among HIV-infected clinic attendees in Cape Town, South Africa. AB - OBJECTIVE: There is growing concern about the effect of substance use on HIV treatment outcomes. The study objectives included: (i) evaluating whether the use of validated questionnaires (AUDIT and DUDIT) provide useful and consistent information of alcohol and drug consumption when compared with the use of biomarkers of alcohol in (urine and hair) and drugs in (urine) and (ii) assessing the feasibility of using self-report measures compared with urine and hair tests. METHOD: Participants were HIV positive patients attending an HIV community health clinic in Kraaifontein, Cape Town. Hair and urine samples were collected and analysed for alcohol, in Fatty Acid Ethyl Esters (FAEE) and in Ethyl Glucuronide and (EtG), and drugs. Biological markers were compared with self-report measures of alcohol and drug consumption in terms of sensitivity, specificity. Forty-three participants completed the self-report measures, while 30 provided hair and urine samples. RESULTS: On the AUDIT, 18 (41.9%) participants screened positive for harmful and hazardous drinking and 13 (30.2%) participants on the DUDIT screened positive for having a drug-related problem. Two of 30 participants (7%) tested positive for alcohol abuse on FAEE analysis. For EtG, 6 of 24 (25%) participants tested positive for alcohol abuse. On hair drug analysis, all 30 participants tested negative for cannabis, amphetamines, opiates, cocaine, PCP and methaqualone. On the urinalysis, 1 of 30 participants tested positive for cannabis and everyone tested negative for all other drugs included in the screening. CONCLUSION: Substance use among patients attending HIV clinics appears to be a problem, especially alcohol. Self-report measures seem to be a more cost effective option for screening of alcohol and drug abuse in resource poor settings. PMID- 23044890 TI - Adolescent alcohol use in rural South African high schools. AB - OBJECTIVE: To examine psychosocial correlates of lifetime alcohol use among adolescents in rural South African high schools. METHOD: Questionnaires were administered to 1600 students from 20 randomly selected high schools in the Mankweng district within Limpopo province. Self-report data on alcohol use, demographic, environmental and psychosocial variables were collected. RESULTS: About 22% of the students had ever used alcohol. Males were 2.4 times more likely to use alcohol than females. For students who attended religious services, the odds of ever having used alcohol were double those of students who did not attend religious services. The fitted logistic regression model shows that gender, age, ever having smoked a cigarette, ever damaged property, walking home alone at night, easy availability of alcohol, thinking alcohol use was wrong, attending religious services and number of friends who used alcohol are the best predictors of alcohol use among high school students in this setting. CONCLUSION: The results underline the importance of addressing personal, family, peer and school conduct factors as part of alcohol education initiatives. Efforts to prevent alcohol use among rural high school students should focus on changing drinking behaviour and on reducing risk factors for problem drinking. PMID- 23044891 TI - Attention deficit hyperactivity symptoms and disorder (ADHD) among African children: a review of epidemiology and co-morbidities. AB - OBJECTIVE: To review literature from Africa on the epidemiology of ADHD as well attention deficit hyperactivity symptoms and associated co-morbid conditions among African children. METHOD: A literature search was done through Pubmed/MEDLINE and Google Scholar using then following terms, "attention deficit", "hyperactivity disorders", "epidemiology", "co-morbid conditions", "Africa". Nine studies met the inclusion criteria with four studies coming from South Africa, two each from Democratic Republic of Congo and Nigeria respectively and one from Ethiopia. RESULTS: The prevalence of ADHD varied with rates of between 5.4% and 8.7%, amongst school children, 1.5% amongst children from the general population between 45.5% to 100.0% amongst special populations of children with possible organic brain pathology. Common associated co-morbid conditions were oppositional defiant disorder, conduct disorder as well as anxiety/depressive symptoms. CONCLUSION: Published data from Africa is limited. For effective healthcare policy further studies are needed to define the magnitude and burden of ADHD and other childhood neurodevelopmental disorders in Africa. PMID- 23044892 TI - Efficacy and safety of a once-daily sublingual immunotherapy without escalation regimen in house dust mite-induced allergic rhinitis. AB - BACKGROUND: The conventional escalation regimen for sublingual immunotherapy (SLIT) in patients with allergic rhinitis has been proven to be safe and successful in reducing allergic symptoms. However, few studies compared the efficacy and safety between a conventional escalation regimen for SLIT and once daily SLIT. The aim of the present study was to compare the efficacy and safety of once-daily SLIT without escalation (SLITsE) to conventional escalation therapy (SLITwE). METHODS: This study was a nonrandomized open label observational study. In total, 153 patients suffering from allergic rhinitis symptoms and sensitized to the perennial house dust mite allergens Dermatophagoides pteronyssinus and Dermatophagoides farinae, were enrolled in this study from July 2008 to December 2009. The patients were divided into 2 groups, SLITwE and SLITsE. Each patient was followed with a diary card on which a symptom score, a rescue medication score, and adverse events were recorded. RESULTS: All of the nasal symptoms, including rhinorrhea, sneezing, nasal obstruction, itching, and olfactory symptoms, defined as a total nasal symptom score, were reduced after 6 months in both groups (p < 0.05). The rescue medication score, defined as the sum of all of the allergy medications used, also decreased in both groups. Adverse events were similar in both groups, and no major adverse events, such as anaphylaxis, were reported. CONCLUSION: Once-daily SLITsE was well tolerated and showed safe and comparable efficacy compared with a conventional SLITwE regimen. PMID- 23044893 TI - Localized insulin-derived amyloidosis: a potential pitfall in the diagnosis of systemic amyloidosis by fat aspirate. PMID- 23044894 TI - Primary immunodeficiency diseases: past, present and future. PMID- 23044895 TI - Measurement invariance of the Beck Depression Inventory-Second Edition (BDI-II) across gender, race, and ethnicity in college students. AB - Measurement invariance of the Beck Depression Inventory-Second Edition (BDI-II) across gender, race, and ethnic groups was evaluated in a large sample of college students, using pooled data from 11 universities from diverse geographical regions in the United States (N = 7,369). Confirmatory factor analysis was used to test the fit of several possible factor structures, and the results from these analyses indicated that the BDI-II was most adequately represented by a hierarchical four-factor structure, composed of three first-order factors and one second-order factor. Results based on analyses of covariance structures indicated there was factorial invariance for this hierarchical four-factor structure across groups, suggesting that the BDI-II provides an assessment of severity of depressive symptoms that is equivalent across gender, race, and ethnicity in college students. PMID- 23044896 TI - Commercial metal-organic frameworks as heterogeneous catalysts. AB - Metal-organic frameworks (MOFs) are porous crystalline materials that have promising applications as heterogeneous catalysts. After describing the composition, textural properties and crystal structure of four commercially available MOFs, we summarize organic transformations for which these commercial MOFs exhibit higher catalytic activity than the corresponding soluble metal salts or metal ion-exchanged zeolites. In the present article, we have focused on reactions requiring Lewis-acid sites or redox centers to illustrate the potential applications and limitations of commercial MOFs. In a final section, we provide our views on future developments whose ultimate target will be the use of a commercial MOF as a heterogeneous catalyst for a real industrial process in fine chemistry, thus, realizing the advantages of these materials with respect to zeolites or other solid catalysts in liquid-phase reactions. PMID- 23044898 TI - The use of errorless learning strategies for patients with Alzheimer's disease: a literature review. AB - The aim of this article was to review the evidence of errorless learning on learning outcomes in patients with early-stage Alzheimer's disease. A computer aided literature search from 1999 to 2011 was carried out using MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and PsycArticles. Keywords included 'errorless learning or practice' and 'Alzheimer's disease'. Four studies that fulfilled the inclusion criteria were selected and reviewed. Two of the studies were clinical controlled trials: one was a single group pretest-post-test trial and the other was a multiple single-participant study. Demographic variables, design, treatment and outcome measures were summarized. Recall trials were used as the primary outcome measure. Results indicate that the use of errorless learning promotes better retention of specific types of information. Errorless learning is effective in memory rehabilitation of older adults with Alzheimer's disease. However, it would require more studies with unified outcome measures to allow for the formulation of standardized clinical protocol and recommendations. PMID- 23044897 TI - In-depth study of the protein molecular structures of different types of dried distillers grains with solubles and their relationship to digestive characteristics. AB - BACKGROUND: Dried distillers grains with solubles (DDGS) have been extensively utilised in ruminant rations in western Canada and USA, and it is important to ensure their consistent quality. Traditional chemical methods do not consider the inherent structural changes of feed ingredients. Synchrotron-based Fourier transform infrared microspectroscopy (SFTIRM) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFT) have been utilised to detect the changes in molecular structure of several feedstuffs (e.g. barley, flaxseed and alfalfa). However, similar structural information is lacking for DDGS. The objectives of this study were to identify differences in protein molecular structures between different grains (wheat, triticale and corn) and DDGS (wheat DDGS, triticale DDGS, corn DDGS and wheat and corn blend DDGS) using SFTIRM and DRIFT and to reveal the relationship between changes in protein molecular structure and the digestive characteristics of the protein in DDGS when fed to dairy cattle. RESULTS: The protein molecular structure studies showed significant decreases (P < 0.01) in the amide I to amide II ratio and the alpha-helix to beta-sheet ratio between grains and their DDGS. Protein digestive characteristics were correlated with protein molecular structures in grains and DDGS, and prediction equations were established to estimate protein digestive characteristics of DDGS using protein molecular structure parameters. For the DVE/OEB-1994 model, one of the best prediction equations was for truly absorbed protein in the small intestine (DVE) = 296.17 - 38.98 * the amide I to amide II ratio (R(2) = 0.72). For the NRC 2001 system, one of the best prediction equations was for metabolisable protein (MP) = 300.96 - 43.32 * the amide I to amide II ratio (R(2) = 0.76). CONCLUSION: Protein molecular structure varies between different DDGS and their original grains, and this variation is associated with the digestive characteristics of the proteins in the DDGS and their original grains. PMID- 23044899 TI - Butterfly vertebra. PMID- 23044900 TI - Full color tunable photonic crystal from crystalline colloidal arrays with an engineered photonic stop-band. AB - An electrically tunable photonic crystal is developed utilizing crystalline colloidal arrays of high refractive index particles. Through modulation of the refractive index of the particle, and the applied electric field, both the bandwidth and position of the photonic bandgap could be tuned. Full color modulation with high optical quality is achieved, which paves a way to develop a novel reflective display. PMID- 23044901 TI - Auditory brainstem implants: how do they work? AB - This review covers the design, structure, and function of auditory brainstem implants. Auditory brainstem implants (ABIs) are auditory prostheses initially designed to treat deafness in patients with neurofibromatosis type 2 (NF2). NF2 typically results in deafness due to disruption of the cochlear nerves. When the tumors are removed the auditory nerve is usually cut or nonfunctional anymore. In these cases, patients cannot benefit from peripheral devices such as cochlear implants (CI). Another cause of VIII nerve loss is bilateral temporal bone fracture. Worldwide, more than 500 persons have received an ABI after removal of the tumors that occur with NF2. More recently, some extensions of indications have been proposed to include subjects who would not benefit enough from a cochlear implant (i.e. cochlear ossification). The ABI is similar in design and function to a CI, except that the electrode is placed on the first auditory relay station in the brainstem, the cochlear nucleus (CN). The ABI electrode array is a small paddle that contains plate electrode contacts. The CN has not a single linear tonotopic organization from base to apex like the cochlea but different tonotopic subunits. The CN comprises multiple neuron types that are characterized by specific properties (morphology, regional distribution and cell-membrane characteristics), synaptic input and responses to acoustic stimuli. As the ABI electrode array is placed along the surface of the CN, each electrode likely activates a variety of neuron types, possibly with different characteristic frequencies. Patients undergoing ABI have variable benefit with regard to sound and speech comprehension. For the majority of patients, this improvement is essentially obtained by an augmentation of lip reading performances. Speech comprehension without lip-reading is not as good as with cochlear implants. PMID- 23044902 TI - Are we attacking the wrong targets in the fight against obesity?: the importance of intervention in women of childbearing age. PMID- 23044903 TI - When commonsense does not make sense. PMID- 23044907 TI - Conservation of hearing and protection of hair cells in cochlear implant patients' with residual hearing. AB - This review covers the molecular mechanisms involved in hair cell and hearing losses which can result from trauma generated during the process of cochlear implantation and the contributions of both the intrinsic and extrinsic cell death signaling pathways in producing these trauma/inflammation induced losses. Application of soft surgical techniques to conserve hearing and protect auditory sensory cells during the process of cochlear implantation surgery and insertion of the electrode array during the process of cochlear implantation are reviewed and discussed. The role of drug therapy and mode of drug delivery for the conservation of a cochlear implant patient's residual hearing is presented and discussed. PMID- 23044908 TI - Differing effects of PTH 1-34, PTH 1-84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: an 18-month open-labeled observational study using HR-pQCT. AB - Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1-84 or fragment PTH 1-34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high-resolution peripheral quantitative computed tomography (HR pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1-34 (20 ug sc daily, n = 18) or PTH 1-84 (100 ug sc daily, n = 20) for 18 months in an open label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1-34 32 +/- 37%, PTH 1-84 39 +/- 32%, both p < 0.001) and tibia (PTH 1-34 13 +/- 27%, PTH 1-84 15 +/- 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1 34, increases in cortical thickness in radius (2.0 +/- 3.8%, p < 0.05) and tibia (3.8 +/- 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1-34 (4.2 +/- 7.1%, p < 0.05) and PTH 1-84 (5.3 +/- 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 +/- 3.5%, p < 0.01), total (2.7 +/- 2.5%, p < 0.001) and cortical density (1.5 +/- 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 +/- 5.1%, p < 0.05) and tibia (2.2 +/- 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1-34 and zoledronic acid at both sites, whereas it decreased with PTH 1-84 in radius (-2.8 +/- 5.8%, p < 0.05) and tibia (-3.9 +/- 4.8%, p < 0.001). Conclusively, divergent treatment-specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1-84 treatment was surprising and warrants confirmation. PMID- 23044910 TI - Modified surgical approach to cervical neurinomas with intraforaminal components: minimal invasive facet joint sparing "open-tunnel" technique. AB - BACKGROUND: The conventional posterior approaches, which may involve multilevel laminectomies and facetectomies, may lead to spinal deformities, instability, or subluxation. Our objective was to develop a minimally invasive approach suitable for exploring neuromas with an intraforaminal component in the cervical spine, with the aim of preserving mechanically relevant bone structures and the facet joints as much as possible. METHODS: The authors used the hemi-semi-laminectomy combined with partial lateral facetectomy "open-tunnel" technique in nine adult patients with neuromas of the cervical spine extending into the foramen. RESULTS: The operating field under the operating microscope was sufficient for tumor removal according to the keyhole concept. The approach did not affect the extent of tumor resection or neurological outcome. Complete removal was achieved in all patients, as confirmed by magnetic resonance imaging (MRI). The affected nerve roots included C3 in three cases, C2 and C4 in two, and C5 and C6 in one case. Average follow-up was 12 months, with a range from 8 to 18 months. Histological results were as follows: six schwannomas and three neurofibromas. Computed tomographic scans demonstrated the extension of the keyhole approaches and the moderately affected bony structures and facet joints. Instability was detected in none of the patients on the flexion or extension lateral radiographs during the follow-up period. CONCLUSION: This modified surgical approach fulfills the requirements of other minimally invasive techniques and lowers the risk of damage to the crucial posterior stabilizers of the spine; furthermore, disintegration of vertebral arches and facet joints is reduced. The approach is suitable for exploring and removing neuromas located in the spinal canal and in the neuroforamen. PMID- 23044911 TI - Endoscopic transoral excision of odontoid process in irreducible atlantoaxial dislocation: our experience of 34 patients. AB - BACKGROUND: The endoscopic excision of the odontoid process in irreducible atlantoaxial dislocation (AAD) can be achieved by transnasal, transoral, and transcervical approaches. Endoscopic transoral technique has been found to be effective and safe. It avoids palatal splitting or prolonged retraction. We are reporting our experience of 34 cases. The relevant literature is reviewed. MATERIAL AND METHODS: This was a prospective study of 34 patients treated during the past 5 years. Detailed history was taken and a thorough physical examination was made to record preoperative status. X-ray cervical spine lateral view (in neutral, flexion, and extension), anteroposterior (AP), and transoral view for the odontoid process were taken. Preoperative computed tomography (CT) and magnetic resonance imaging (MRI) scans and postoperative CT scans were done in all cases. Postoperative status at 1, 6, and 12 months was recorded. RESULTS: Age ranged from 15 to 56 years. There were 22 male and 12 female patients. Symptom duration ranged from 6 to 18 months.Preoperatively, there were 26 and 8 patients in Ranawat grades 3A and 3B, respectively. Five patients had tenth cranial nerve paresis. There were 23, 10, and 1 cases of AAD, AAD with basilar invasion, and tuberculosis, respectively. Palatal splitting was not required in any of the cases. All patients improved after surgery. No deaths occurred. One patient had cerebrospinal fluid (CSF) leak, which stopped after external lumbar drainage. Follow-up ranged from 12 to 65 months. CONCLUSION: Endoscopic transoral odontoidectomy is a safe and effective alternative technique for odontoid excision. It can be performed in patients with small oral openings. Angled scopes improved exposure of clivus and palatal splitting was not required even in basilar invasion. PMID- 23044912 TI - Temporobasal, transsphenoidal meningoencephalocele becoming symptomatic with spontaneous cerebrospinal fluid rhinorrhea: diagnostic work-up and microsurgical strategy. AB - BACKGROUND: We report the rare case of an adult transsphenoidal meningoencephalocele and outline the microneurosurgical strategy. Clinical history, the findings of computerized tomography (CT) scans and magnetic resonance imaging (MRI), the microsurgical procedure, and histopathology are reported. CASE REPORT: A 54-year-old female patient complained about cerebrospinal fluid (CSF) rhinorrhea; a transnasal biopsy of a mass in the maxillar sinus prior to diagnostic work-up was performed elsewhere. Persisting CSF leakage prompted CT and MRI, which showed brain tissue extending from the left middle cranial fossa into the left sphenoid sinus through several bony defects. The diagnosis of a transsphenoidal meningoencephalocele was made, and the lesion was targeted via a subtemporal intradural approach with resection of the herniated brain tissue and closure of the bony as well as of dural defects. The postoperative course was uneventful without recurrence of the CSF fistula. CONCLUSION: The transsphenoidal subtype of basal meningoencephaloceles is exceedingly rare. Nonetheless, it has to be considered as a differential diagnosis if a nasal or intrasphenoidal mass is diagnosed. Otherwise, unjustified biopsy or unsuccessful management of CSF leakage could not be avoided. The intradural subtemporal approach is effective to treat the transsphenoidal type of basal meningoencephaloceles. PMID- 23044914 TI - Hydrogenation of imines catalysed by ruthenium(II) complexes based on lutidine derived CNC pincer ligands. AB - The preparation of new Ru(II) complexes incorporating fac-coordinated lutidine derived CNC ligands is reported. These derivatives are selectively deprotonated by (t)BuOK at one of the methylene arms of the pincer, leading to catalytically active species in the hydrogenation of imines. PMID- 23044915 TI - New drug: caution indicated. PMID- 23044913 TI - Hemoglobin decline, function, and mortality in the elderly: the cardiovascular health study. AB - While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied. We evaluated the determinants and consequences of hemoglobin decline in 3,758 non-anemic participants from the Cardiovascular Health Study, a prospective cohort of community-dwelling elderly >=65 years old at baseline and followed for up to 16 years. Hemoglobin was measured at baseline and 3 years later and anemia defined by World Health Organization (WHO) criteria. We modeled hemoglobin decline in two ways: (1) per each 1 g/dL decrease in hemoglobin and (2) development of anemia by the WHO criteria. Among participants without baseline anemia, hemoglobin decreased by 0.4 g/dL and 9% developed anemia over 3 years. Baseline increasing age, female sex, diabetes, and kidney disease predicted hemoglobin decline over 3 years. Baseline increasing age, being African-American, and kidney disease predicted anemia development over 3 years. Hemoglobin decline was associated with subsequent worse cognitive function in men and anemia development with subsequent worse cognitive function in women. Both anemia development (HR 1.39, 95% CI 1.15, 1.69) and hemoglobin decline (HR 1.11, 95% CI 1.04, 1.18 per 1 g/dL decrease) predicted subsequent mortality in men and women. Hemoglobin decreases identified a large group of elderly individuals at risk for subsequent adverse outcomes who would not be identified using the WHO anemia criteria. These data may allow clinicians to identify at-risk elderly individuals for early intervention to improve the quality and quantity of life. PMID- 23044917 TI - Should we be using fractional flow reserve more routinely to select stable coronary patients for percutaneous coronary intervention? AB - PURPOSE OF REVIEW: To address the clinical benefit of fractional flow reserve (FFR) measurement in stable coronary artery disease (CAD) patients. RECENT FINDINGS: The efficacy of revascularization in patients with stable CAD has been debatable. However, there has been consensus that revascularization for ischemic producing lesions may improve clinical outcomes. FFR is considered nowadays as the gold standard for the invasive assessment of ischemic potential of intermediate coronary artery stenosis. Intermediate stenosis with FFR of greater than 0.80 has been demonstrated to be safely deferred with annual event rate less than 1%. Recently, preliminary data of FAME II trial presented that revascularization for stenosis with FFR of 0.80 or less has clinical benefits over optimal medical treatment with respect to the reduction of unplanned hospitalization and urgent revascularization in stable CAD patients. A large randomized controlled trial demonstrated that FFR-guided percutaneous coronary intervention (PCI) improved clinical outcomes while reducing the medical costs in multivessel CAD. Therefore, current guidelines recommend the consideration of FFR measurements as level of evidence 'A' when the ischemic potential for specific target lesions is questionable. SUMMARY: Much clinical evidence indicates that use of this dedicated invasive functional method may help in selecting appropriate patients and lesions for treatment, avoiding unnecessary procedures, reducing medical costs, and improving each patient's clinical outcomes. Therefore, we should use FFR more routinely to select stable coronary patients for PCI. PMID- 23044916 TI - Morphological study of the sinus node and its artery in yak. AB - The sinus node of yak has been studied by the histological methods and transmission electron microscopy. The sinus node artery of yak was also determined by the injection-corrosion casting technique, the angiography, and histological methods. The results showed that the sinus node of yak contained an extensive framework of collagen and two main type cells: pacemaker cells (P cells) and transitional cells (T cells). The P cells had a perinuclear clear zone, contained less myofibrils, and appeared smaller mitochondria than T cells. The T cells were longer and slender than P cells, and had a variety of shapes. At the periphery of sinus node there were many nerve fibers and ganglions. Gap junction did not reveal reaction with anti-connexin43, but it was detected by electron microscopy in the central part of sinus node of yak. The sinus node artery of yak originated from left coronary artery more frequently (98%) than by right (2%). The artery located at the periphery of sinus node. It had an internal elastic membrane throughout its course, and a large nerve bundle was found running in a longitudinal direction. PMID- 23044918 TI - Triptycene based luminescent metal-organic gels for chemosensing. AB - We report a novel luminescent Al-based metal-organic gel G1 comprising 1,4,5,8 triptycenetetracarboxylic acid, which exhibits highly sensitive detection towards nitro aromatic compounds particularly picric acid. Furthermore, under identical reaction conditions, using a Co(II) salt instead, a novel 3D framework material, trip-MOF-1, was isolated and its sensitivity towards picric acid was also evaluated. PMID- 23044919 TI - Intravenous tranexamic acid and intraoperative visualization during functional endoscopic sinus surgery: a double-blind randomized controlled trial. AB - BACKGROUND: Bleeding during endoscopic sinus surgery (ESS) can hinder surgical progress and may be associated with increased complications. Tranexamic acid is an antifibrinolytic that is known to reduce operative bleeding. The current study was designed to assess the effect of adjunctive intravenous tranexamic acid on intraoperative bleeding and the quality of the surgical field during ESS. METHODS: Double-blind, randomized, controlled trial. Patients undergoing ESS for the primary diagnosis of chronic rhinosinusitis with or without polyposis were included. Sample size calculation based on a clinically relevant difference in the Wormald surgical field score yielded a sample of 28. In addition to standard measures to minimize blood loss, study patients received intravenous tranexamic acid with control patients receiving intravenous normal saline. Outcome measures included the Wormald grading scale to assess the intraoperative surgical field and estimated blood loss based on suction container contents with irrigation fluid subtracted. RESULTS: Twenty-eight patients (median age, 45 years; range, 23 80 years) were included in the study. Diagnoses included chronic rhinosinusitis without polyposis (n = 5), chronic rhinosinusitis with polyposis (n = 23). The use of the tranexamic acid was not associated with a statistically significant decrease in estimated blood loss (201 vs 231 mL; p = 0.60) or Wormald grading scale (5.84 vs 5.80; p = 0.93). There were no adverse events or complications during the study. CONCLUSION: Adjunctive intravenous tranexamic acid does not appear to result in a clinically meaningful reduction in blood loss or improve visualization of the surgical field during ESS. PMID- 23044921 TI - Reverse harvesting sequence of nasoseptal flaps during endoscopic skull base surgery: technical modification to deal with the severe septal spur. PMID- 23044920 TI - Loss of parvalbumin-positive neurons from the globus pallidus in animal models of Parkinson disease. AB - The external segment of the globus pallidus (GPe) in humans and the equivalent structure in rodents, the globus pallidus (GP), influence signal processing in the basal ganglia under normal and pathological conditions. Parvalbumin (PV) immunoreactivity defines 2 main neuronal subpopulations in the GP/GPe: PV immunopositive cells that project mainly to the subthalamic nucleus and the internal segment of the GP and PV-negative cells that mainly project to the striatum. We evaluated the number of neurons in the GP/GPe in animal models of Parkinson disease. In rats, dopaminergic denervation with 6-hydroxydopamine (6 OHDA) provoked a significant decrease in the number of GP neurons (12% +/- 4%, p < 0.05), which specifically affected the PV subpopulation. A similar trend was observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Markers of GABAergic activity (GAD65 and GAD67 mRNA) were not different from those of controls in 6-OHDA-lesioned rats. Taken together, these findings provide evidence for nondopaminergic neuronal cell loss in the basal ganglia of 6-OHDA lesioned rats and suggest that a similar loss may occur in the MPTP monkey. These data suggest that in patients with Parkinson disease, the loss of GABAergic neurons projecting to the subthalamic nucleus may contribute to the hyperactivity of this nucleus despite the absence of gross alterations in GAD mRNA expression. PMID- 23044922 TI - Nordihydroguaiaretic acid inhibition of NFATc1 suppresses osteoclastogenesis and arthritis bone destruction in rats. AB - Nordihydroguaiaretic acid (NDGA) is known to have prominent anticancer activity against several cancers, and is also known to be an inhibitor of 5-lipoxygenase (5-LO). In this study, we investigated the regulatory function of NDGA on inflammatory bone destruction mediated by osteoclasts. NDGA markedly inhibited receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL)-induced formation of osteoclasts in cultures of murine osteoclast precursor cell line RAW D cells and primary bone marrow-derived macrophages culture systems. The inhibitory effect of NDGA on osteoclastogenesis did not arise from the inhibition of 5-LO activity. NDGA did not affect MAPKs, such as p38, JNK, and NF-kappaB, but significantly inhibited the induction of NFATc1, a key transcription factor for osteoclastogenesis. NDGA also suppressed activation of ERK in osteoclast precursors. RANKL-induced calcium oscillation observed in osteoclast precursors was completely diminished by the addition of NDGA. In mature osteoclasts, RANKL induced nuclear translocation of NFATc1 was clearly inhibited by NDGA treatment. Finally, in vivo studies demonstrated that administration of NDGA significantly reduced severe bone destruction and osteoclast recruitment in the ankle joint of rats with adjuvant-induced arthritis. These results indicate the potential utility of NDGA as a therapeutic agent for ameliorating inflammatory bone destruction in rheumatoid arthritis. PMID- 23044923 TI - Lack of MMP10 exacerbates experimental colitis and promotes development of inflammation-associated colonic dysplasia. AB - Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) represent serious health burdens because of both the tissue-damaging disease itself and an elevated risk of colon cancer. The increased expression of many members of the matrix metalloproteinase (MMP) family of enzymes that occurs in colitis has long been associated with the destructive nature of the disease. Recent findings in cancer and other MMP-associated diseases, however, led us to question whether MMPs are indeed detrimental in the setting of colitis. Here, we focus on a single MMP family member, MMP10, and assess its role in a murine model of colonic tissue damage induced by dextran sulfate sodium (DSS) treatment. Using mice genetically deficient for MMP10, we find that absence of this enzyme leads to significantly worse disease scores and failure to resolve inflammation even after extended recovery periods. We show that MMP10 is produced predominantly by infiltrating myeloid cells in both murine and human colitis. Through bone marrow transplant experiments, we confirm that bone marrow-derived MMP10 contributes to colitis severity. Mice lacking MMP10 have a significantly higher propensity for development of dysplastic lesions in the colon after two rounds of DSS exposure. Thus, we conclude that MMP10 is required for resolution of DSS-induced colonic damage, and in its absence, chronic inflammation and ultimately dysplasia occurs. PMID- 23044925 TI - Highly diastereo- and enantioselective organocatalytic one-pot sequential 1,4 addition/dearomative-fluorination transformation. AB - Fluorination: A wide range of nitroolefins and pyrazol-5-ones undergo a sequential 1,4-addition/dearomative-fluorination transformation when treated with a catalytic amount of a tertiary-amine-thiourea compound and the terminal electrophile, N-fluorobenzenesulfonimide, to give fluorinated products in 72-95% yield with up to 99:1 d.r. and 98% ee. Notably, these products contain adjacent tertiary and alpha-fluoro quaternary stereocenters (see scheme). PMID- 23044924 TI - A novel human autoantigen, endothelial cell growth factor, is a target of T and B cell responses in patients with Lyme disease. AB - OBJECTIVE: Autoantigen presentation by HLA-DR molecules is thought to be a central component of many autoimmune diseases, but identifying disease-relevant autoantigens has been a difficult challenge. In this study we aimed to identify autoantigens in patients with antibiotic-refractory Lyme arthritis, in which infection-induced autoimmunity is thought to play an important role. METHODS: Using tandem mass spectrometry, naturally presented HLA-DR self peptides from a patient's synovium were identified, synthesized, and reacted with his peripheral blood mononuclear cells (PBMCs). Immunoreactive peptides and their source proteins were then tested for T and B cell responses using large numbers of patient cells or sera. RESULTS: Of 120 HLA-DR-presented self peptides identified from one patient, one peptide derived from endothelial cell growth factor (ECGF) caused his PBMCs to proliferate. T and B cell responses to ECGF occurred systemically in ~10-30% of patients with early or late manifestations of Lyme disease, primarily in those with refractory arthritis-associated HLA-DR alleles, such as DRB1*0101 and 0401. Compared with patients with antibiotic-responsive arthritis, those with antibiotic-refractory arthritis had significantly higher concentrations of ECGF in synovial fluid (P<0.0001) and more often had ECGF antibody reactivity. Among non-antibiotic-treated historical patients who developed arthritis, 26% had ECGF reactivity, which often developed before the onset of arthritis and was associated with significantly longer courses of arthritis. CONCLUSION: T and B cell responses to ECGF occur in a subset of patients with Lyme disease, particularly in those with antibiotic-refractory arthritis, providing the first direct evidence of autoimmune T and B cell responses in this illness. PMID- 23044927 TI - Early development of the vertebrate inner ear. AB - This is a review of the biological processes and the main signaling pathways required to generate the different otic cell types, with particular emphasis on the actions of insulin-like growth factor I. The sensory organs responsible of hearing and balance have a common embryonic origin in the otic placode. Lineages of neural, sensory, and support cells are generated from common otic neuroepithelial progenitors. The sequential generation of the cell types that will form the adult inner ear requires the coordination of cell proliferation with cell differentiation programs, the strict regulation of cell survival, and the metabolic homeostasis of otic precursors. A network of intracellular signals operates to coordinate the transcriptional response to the extracellular input. Understanding the molecular clues that direct otic development is fundamental for the design of novel treatments for the protection and repair of hearing loss and balance disorders. PMID- 23044926 TI - Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome. AB - The impact of glucocorticoids (GC) on skeletal development has not been established. The objective of this study was to examine changes in volumetric bone mineral density (vBMD) and cortical structure over 1 year in childhood nephrotic syndrome (NS) and to identify associations with concurrent GC exposure and growth. Fifty-six NS participants, aged 5 to 21 years, were enrolled a median of 4.3 (0.5 to 8.1) years after diagnosis. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained at enrollment and 6 and 12 months later. Sex, race, and age-specific Z-scores were generated for trabecular vBMD (TrabBMD Z), cortical vBMD (CortBMD-Z), and cortical area (CortArea-Z) based on >650 reference participants. CortArea-Z was further adjusted for tibia length-for-age Z-score. Quasi-least squares regression was used to identify determinants of changes in pQCT Z-scores. At enrollment, mean TrabBMD-Z (-0.54 +/- 1.32) was significantly lower (p = 0.0001) and CortBMD-Z (0.73 +/- 1.16, p < 0.0001) and CortArea-Z (0.27 +/- 0.91, p = 0.03) significantly greater in NS versus reference participants, as previously described. Forty-eight (86%) participants were treated with GC over the study interval (median dose 0.29 mg/kg/day). On average, TrabBMD-Z and CortBMD-Z did not change significantly over the study interval; however, CortArea-Z decreased (p = 0.003). Greater GC dose (p < 0.001), lesser increases in tibia length (p < 0.001), and lesser increases in CortArea-Z (p = 0.003) were independently associated with greater increases in CortBMD-Z. Greater increases in tibia length were associated with greater declines in CortArea-Z (p < 0.01); this association was absent in reference participants (interaction p < 0.02). In conclusion, GC therapy was associated with increases in CortBMD-Z, potentially related to suppressed bone formation and greater secondary mineralization. Conversely, greater growth and expansion of CortArea-Z (ie, new bone formation) were associated with declines in CortBMD-Z. Greater linear growth was associated with impaired expansion of cortical area in NS. Studies are needed to determine the fracture implications of these findings. PMID- 23044928 TI - Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors. AB - BCR/ABL (Breakpoint Cluster Region protein/Abelson tyrosine-protein kinase 1) kinase domain (KD) mutations represent the most frequently described mechanism of resistance to the treatment with tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML). Mutations may impair TKI activity by directly or indirectly impairing the drug binding to the protein. We report the discovery of three new BCR/ABL mutations, L248R, T315V, and F317R identified in two patients with CML (L248R and T315V) and in one patient with Ph+ acute lymphoblastic leukemia (ALL) (F317R). Mutations were screened against second generation (bosutinib, nilotinib, and dasatinib), as well as third-generation TKIs (ponatinib/AP-24534 and DCC-2036). Furthermore, the activity profile of ponatinib and DCC-2036 against a panel of 24 clinically relevant BCR/ABL mutants is presented and compared to the other TKIs. The IC50 values for each TKI against the mutants and the IC50 increase over wild type BCR/ABL (relative resistance, RR) were calculated to define four resistance levels: sensitive (RR <= 2), moderately resistant (2 < RR <= 4), resistant (4 < RR <= 10), or highly resistant (RR > 10). L248R and T315V showed high resistance to imatinib, bosutinib, dasatinib, and nilotinib, intermediate resistance to ponatinib, but were sensitive to DCC-2036. Interestingly, F317R showed a moderate resistance to imatinib and nilotinib, but is resistant/highly resistant to dasatinib, bosutinib, ponatinib, and DCC-2036. The availability of drugs activity profiles may become a useful tool for clinicians dealing with the treatment of drug resistant CML patients. PMID- 23044929 TI - Two one-dimensional compounds based on pyramidal {TbCu4} units and formate ligand: chair-like [(H2O)2(ClO4)2]2- clusters and slow relaxation of magnetization. AB - With formate as ligand, two 1-D 3d-4f compounds (linear and zigzag) based on pyramidal {TbCu(4)} unit were obtained. Chair-like [(H(2)O)(2)(ClO(4))(2)](2-) clusters and MU(5)-eta(1):eta(4) bridging mode of formate were observed in the linear one which also displays slow relaxation of the magnetization. PMID- 23044930 TI - Improved clinical assessment of a mouse model of retinopathy of prematurity. PMID- 23044931 TI - HIV racial disparities: time to close the gaps. PMID- 23044932 TI - Canalostomy as a surgical approach for cochlear gene therapy in the rat. AB - This article presents a unique approach for the delivery of gene therapy vectors into the cochlea of the laboratory rat. Mice and guinea pigs are established in vivo models for cochlear gene therapy each of which has distinct advantages and disadvantages. The rat has some of the molecular advantages of a mouse model combined with size advantages for surgical approaches. Vector delivery via cochleostomy or injection through the round window causes concomitant sensorineural hearing loss and is therefore not suitable for studies where the change in hearing is being followed. Compared to the mouse, the rat does not demonstrate easily recognizable landmarks that allow for use of the semicircular canal as an approach to the inner ear. We analyzed sagittal and coronal temporal bone sections of Long Evans rats and identified the bony entrance of the facial nerve as a crucial landmark for canalostomy. Auditory brainstem response and distortion product otoacustic emission measurements revealed minimal differences in the hearing threshold after adenovirus vector application when large volumes of vector were infused to the inner ear. Canalostomy and infusion of adenoviral vectors also resulted in temporary balance disturbance in the rat. Immunohistochemical assessment after delivery of a green fluorescent protein expressing vector showed significant GFP expression in the cochlea. PMID- 23044933 TI - Thiophene fluorination to enhance photovoltaic performance in low band gap donor acceptor polymers. AB - We report the first synthesis of a tetrafluorinated 4,7-bis(3,4-difluorothiophen 2-yl)-2,1,3-benzothiadiazole monomer and its polymerisation with dithieno[3,2 b:2',3'-d]germole by Stille coupling to afford a low band gap polymer with a high ionisation potential. Direct comparison to the non-fluorinated analogue demonstrates that fluorination results in an increase in ionisation potential with no change in optical band gap, and enhanced aggregation over the non fluorinated polymer. These desirable properties result in a significant enhancement in OPV device performance in blends with PC(71)BM. PMID- 23044934 TI - Effects of different resistance training volumes on strength and power in team sport athletes. AB - The aim of this study was to compare the effects of 3 different volume of resistance training (RT) on maximum strength and average power in college team sport athletes with no previous RT experience. Thirty-two subjects (20 men and 12 women, age = 23.1 +/- 1.57 years) were randomly divided into 4 groups: low volume (LV; n = 8), 1 set per exercise and 3 sets per muscle group; moderate volume (MV; n = 8), 2 sets per exercise and 6 sets per muscle group; high volume (HV; n = 8), 3 sets per exercise and 9 sets per muscle group; and a non-RT control group (n = 8). The 3 intervention groups were trained for 6 weeks thrice weekly after a nonperiodized RT program differentiated only by the volume. Before (T1) and after training (T2), 1 repetition maximum (1RM) and maximal average power (AP) produced on the bench press (BP), upright row (UR), and squat (SQ) were assessed by progressive resistance tests. One repetition maximum-BP and 1RM-UR increased significantly in the 3 interventions groups (p < 0.05), whereas only the HV group significantly improved 1RM-SQ (p < 0.01). The MV and HV groups increased AP-BP (p < 0.05), whereas only the LV group improved AP-SQ (p < 0.01). Moderate effect sizes (ES; >0.20 < 0.60) were observed for the 1RM-BP and 1RM-UR in the 3 training groups. High-volume group showed the larger ES for 1RM-BP (0.45), 1RM-UR (0.60), and 1RM-SQ (0.47), whereas the LV produced the higher ES for SQ-AP (0.53). During the initial adaptation period, a HV RT program seems to be a better strategy for improving strength, whereas during the season, an LV RT could be a reasonable option for maintaining strength and enhancing lower-body AP in team sport athletes. PMID- 23044935 TI - Olfactory and sinonasal outcomes in endoscopic transsphenoidal skull-base surgery. AB - BACKGROUND: Endoscopic anterior skull-base surgery has been previously suggested to cause a significant deterioration in olfactory function. Given the impact on quality of life, the objective of this study was to determine the effect of a unilateral middle-turbinate-sacrificing approach on olfactory function and sinonasal outcome. METHODS: Prospective cohort study comparing olfactory and sinonasal outcomes pre- and post-transsphenoidal skull-base surgery. Olfaction was the primary outcome and was measured prospectively using the University of Pennsylvania Smell Identification Test (SIT). Sinonasal symptoms were assessed subjectively via sinonasal-specific questions from the 22-item Sino-Nasal Outcome Test (SNOT-22), and objectively via the Lund-Kennedy Endoscopic Scoring system (LKES). RESULTS: Twenty-two patients met study inclusion criteria and completed all data acquisition. The mean preoperative SIT score was 34.8 and the mean postoperative SIT value was 35.1 (p = 0.37). The average change in score (delta) was an increase of 0.3, with changes ranging from -3 to +4. When examined categorically, 91% of patients maintained their preoperative olfactory function classification. There was no significant difference in mean pre- and postoperative symptom scores. A small increase in the LKES was noted, from a mean of 0.6 to 2.5 (p = 0.001) in the early postoperative period. CONCLUSION: Olfactory function, as measured by the SIT test, was preserved with a middle turbinate-sacrificing skull-base approach. Subjective sinonasal symptom scores were unaffected, but a slight worsening of objective endoscopic appearance was noted. PMID- 23044936 TI - Psychological dating violence perpetration and victimization: trajectories from middle to high school. AB - Despite evidence documenting the negative consequences, psychological dating violence occurs frequently in adolescent dating relationships. No information exists on the trajectories that adolescents follow and their association to nonphysical peer violence. The sample comprised 624 randomly selected 6th graders. In yearly surveys from 6th through 12th grade, 550 of the 624 students reported dating at least twice during the 3 months prior to completing the survey. These students responded to questions about frequency of engagement in psychological dating violence perpetration and victimization. We used Proc TRAJ to identify developmental trajectories of behavior over time and generalized estimating equation models to examine the associations of the trajectories and peer aggression. Adolescents followed three distinct developmental trajectories related to psychological dating violence victimization and perpetration: low, increasing, and high. Based on the joint probabilities of victimization and perpetration, we identified four predominant groups: low victimization/low perpetration (LVLP; 36%), increasing victimization/increasing perpetration (40%), high victimization/high perpetration (HVHP; 15%), and increasing victimization/low perpetration (IVLP; 7%). The LVLP had significantly more boys and White students; the HVHP group had an even gender distribution and more African-American students. For all groups, peer aggression decreased from Grade 6 to 12; students in the HVHP group reported the highest peer aggression, and students in the LVLP reported the lowest peer aggression. Findings suggest a strong, reciprocal relationship in the developmental trajectories of adolescents who experience and perpetrate psychological dating violence. Those highly engaged in these behaviors were also more likely to be violent toward peers. PMID- 23044937 TI - New drugs and safety: what happened to new active substances approved in Canada between 1995 and 2010? PMID- 23044938 TI - Neuropeptide Y is a critical modulator of leptin's regulation of cortical bone. AB - Leptin signaling is required for normal bone homeostasis; however, loss of leptin results in differing effects on cortical and cancellous bone, as well as altered responses between the axial and appendicular regions. Local beta-adrenergic actions are responsible for the greater cancellous bone volume in leptin deficient (ob/ob) mice; however, the mechanism responsible for the opposing reduction in cortical bone in ob/ob mice is not known. Here we show that blocking the leptin-deficient increase in neuropeptide Y (NPY) expression reverses the cortical bone loss in ob/ob mice. Mice null for both NPY and leptin (NPY(-/-) ob/ob), display greater cortical bone mass in both long-bones and vertebra, with NPY(-/-) ob/ob mice exhibiting thicker and denser cortical bone, associated with greater endocortical and periosteal mineral apposition rate (MAR), compared to ob/ob animals. Importantly, these cortical changes occurred without significant increases in body weight, with NPY(-/-) ob/ob mice showing significantly reduced adiposity compared to ob/ob controls, most likely due to the reduced respiratory exchange ratio seen in these animals. Interestingly, cancellous bone volume was not different between NPY(-/-) ob/ob and ob/ob, suggesting that NPY is not influencing the adrenergic axis. Taken together, this work demonstrates the critical role of NPY signaling in the regulation of bone and energy homeostasis, and more importantly, suggests that reduced leptin levels or leptin resistance, which occurs in obesity, could potentially inhibit cortical bone formation via increased central NPY signaling. PMID- 23044940 TI - Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. AB - OBJECTIVE: To evaluate the efficacy and complications of intravitreal chemotherapy for viable vitreous seeding from retinoblastoma. METHODS: Intravitreal injection of melphalan (8-50 MUg in 0.05 mL) followed by injection site cryotherapy. RESULTS: Among 12 treated cases, success with control of vitreous seeds was achieved in 10 of 12 cases at immediate follow-up (0-3 months), 8 of 10 cases at short-term follow-up (3-6 months), and 6 of 10 cases at long-term (>6 months) follow-up. Among those 8 cases that received an 8- to 10 MUg dose, control was achieved in 6 of 8 cases at immediate follow-up, 5 of 7 cases at short-term follow-up, and 3 of 7 cases at long-term follow-up. Complications with the 8- to 10-MUg dose were minor and included preretinal hemorrhage and retinal vasculitis with retinal pigment epithelial alterations. Of those 4 that received a 50-MUg dose, immediate, short-term, and long-term control was 100%, but complications of cataract, vitreous hemorrhage, subretinal hemorrhage, severe hypotonia, and phthisis lead to enucleation in 2 cases. There was no case of orbital tumor recurrence or retinoblastoma metastasis (follow-up range, 8-66 months). CONCLUSIONS: Intravitreal melphalan for recurrent vitreous seeds from retinoblastoma appears to provide vitreous seed control in some patients. A high dose (50 MUg) of melphalan is toxic and should be avoided. PMID- 23044941 TI - Safety of pars plana vitrectomy in eyes with plaque-irradiated posterior uveal melanoma. AB - OBJECTIVE: To determine the long-term safety of pars plana vitrectomy (PPV) in eyes with plaque-irradiated posterior uveal melanoma. METHODS: In this retrospective case series, patients with plaque-irradiated posterior uveal melanoma subsequently underwent PPV for vitreous hemorrhage. The main outcome measures are the rates of intraocular melanoma dissemination, extrascleral extension of melanoma, local melanoma recurrence, and systemic melanoma metastasis after PPV. RESULTS: Forty-seven eyes of 47 patients underwent PPV for vitreous hemorrhage after iodine 125-labeled plaque radiotherapy for choroidal melanoma. The mean interval between the onset of vitreous hemorrhage and PPV was 13 (median, 10; range, 0-52) months. The mean time from PPV to last follow-up was 5 (range, 0.5-16) years. There were no cases of intraocular melanoma dissemination or extrascleral extension of melanoma. One patient (2%) developed local choroidal melanoma recurrence (2 years after PPV and 5 years after initial plaque radiotherapy) and was successfully managed with transpupillary thermotherapy. Systemic melanoma metastasis occurred in 4 patients (9%) during a mean interval of 5 years after plaque radiotherapy. During follow-up, 43 patients (91%) were alive without systemic metastasis and 4 patients (9%) were alive with metastasis. CONCLUSION: Management of vitreous hemorrhage by PPV in eyes with previously irradiated uveal melanoma appears to be safe and without increased risk for intraocular, local, orbital, or systemic dissemination of the tumor. PMID- 23044942 TI - Evaluation of normal human foveal development using optical coherence tomography and histologic examination. AB - OBJECTIVE: To assess outer retinal layer maturation during late gestation and early postnatal life using optical coherence tomography and histologic examination. METHODS: Thirty-nine participants 30 weeks' postmenstrual age or older were imaged using a handheld optical coherence tomography system, for a total of 102 imaging sessions. Foveal images from 16 participants (21 imaging sessions) were normal and evaluated for inner retinal excavation and the presence of outer retinal reflective bands. Reflectivity profiles of central, parafoveal, and parafoveal retina were extracted and were compared with age-matched histologic sections. RESULTS: The foveal pit morphologic structure in infants was generally distinguishable from that in adults. Reflectivity profiles showed a single hyperreflective band at the fovea in all the infants younger than 42 weeks' postmenstrual age. Multiple bands were distinguishable in the outer retina at the peri fovea by 32 weeks' postmenstrual age and at the fovea by 3 months' postterm. By 17 months' postnatal, the characteristic appearance of 4 hyperreflective bands was evident across the foveal region. These features are consistent with previous results from histologic examinations. A "temporal divot" was present in some infants, and the foveal pit morphologic structure and the extent of inner retinal excavation were variable. CONCLUSIONS: Handheld optical coherence tomography is a viable technique for evaluating neonatal retinas. In premature infants who do not develop retinopathy of prematurity, the foveal region seems to follow a developmental time course similar to that associated with in utero maturation. CLINICAL RELEVANCE: As pediatric optical coherence tomography becomes more common, a better understanding of normal foveal and macular development is needed. Longitudinal imaging offers the opportunity to track postnatal foveal development among preterm infants in whom poor visual outcomes are anticipated or to follow up treatment outcomes in this population. PMID- 23044944 TI - Identification of a novel mutation in the CDHR1 gene in a family with recessive retinal degeneration. AB - OBJECTIVES: To describe the clinical phenotype and identify the molecular basis of disease in a consanguineous family of Palestinian origin with autosomal recessive retinal degeneration. METHODS: Eight family members were evaluated with visual acuity and perimetry tests, color fundus photographs, full-field electroretinography, and optical coherence tomography. Cone photoreceptors surrounding the fovea were imaged in 2 members, using adaptive optics scanning laser ophthalmoscopy. Exome was captured using probes and sequenced. Readings were mapped to reference hg19. Variant calls and annotations were performed, using published protocols. Confirmation of variants and segregation analysis was performed using dideoxy sequencing. RESULTS: Analysis detected 24 037 single nucleotide variants in one affected family member, of which 3622 were rare and potentially damaging to encoded proteins. Further analysis revealed a novel homozygous nonsense change, c.1381 C>T, p.Gln461X in exon 13 of the CDHR1 gene, which segregated with retinal degeneration in this family. Affected members had night blindness beginning during adolescence with progressive visual acuity and field loss and unmeasurable electroretinographic responses, as well as macular outer retinal loss, although residual cones with increased cone spacing were observed in the youngest individual. CONCLUSIONS: Exome analysis revealed a novel CDHR1 nonsense mutation segregating with progressive retinal degeneration causing severe central vision loss by the fourth decade of life. High-resolution retinal imaging revealed outer retinal changes suggesting that CDHR1 is important for normal photoreceptor structure and survival. CLINICAL RELEVANCE: Exome sequencing is a powerful technique that may identify causative genetic variants in families with autosomal recessive retinal degeneration. PMID- 23044945 TI - Traumatic sinolacrimocutaneous fistula managed with endonasal dacryocystorhinostomy and anterior ethmoidectomy. AB - A 31-year-old man with epiphora and mucous discharge from a traumatic lacrimal fistula underwent a computed tomographic dacryocystogram, revealing a fistula extending from the anterior ethmoid air cells through the lacrimal sac to the overlying skin with coexisting nasolacrimal duct obstruction. Endoscopic dacryocystorhinostomy enabled complete marsupialization of the lacrimal sac and agger nasi air cell, removing the tract between these structures. Simultaneous probing of the common canaliculus and fistula tract under direct visualization allowed the identification of the internal fistula origin in relation to the internal ostium on the lateral sac wall. The fistula was excised with a trephine over a guide wire via an external approach. Use of the endoscopic technique for excision of acquired lacrimal fistulas may be especially helpful in cases with coexisting nasolacrimal duct obstruction where the fistula extends to the sinus cavity or suspected foreign bodies. PMID- 23044946 TI - Management of macular edema associated with retinal vein occlusion. PMID- 23044947 TI - The magician with a meningioma. PMID- 23044948 TI - Cell-based therapy for glaucomatous optic nerve degeneration. PMID- 23044949 TI - Quinupristin/dalfopristin in vancomycin-resistant Staphylococcus aureus endophthalmitis. PMID- 23044950 TI - Spectral-domain optical coherence tomographic characteristics of autosomal recessive isolated foveal hypoplasia. PMID- 23044951 TI - Morning glory disc anomaly with peripheral retinal nonperfusion in 4 consecutive cases. PMID- 23044952 TI - Ocular injury after laser hair reduction treatment to the eyebrow. PMID- 23044953 TI - Iris ring melanoma with extrascleral extension. PMID- 23044954 TI - Retinal glioneuronal hamartoma in neurofibromatosis type 1. PMID- 23044955 TI - Surgical removal of an atypical macular epiretinal membrane in neurofibromatosis type 2: clinicopathologic correlation and visual outcome. PMID- 23044956 TI - Central serous chorioretinopathy in myopic patients. PMID- 23044957 TI - Unilateral retinal pigment epithelium dysgenesis may be a bilateral disease. PMID- 23044958 TI - Levofloxacin-associated panuveitis with chorioretinal lesions.